PMID- 27932094 TI - Non-Heart-Beating Donor Kidney Transplantation Survival Is Similar to Donation After Brain Death: Comparative Study With Controls in a Regional Program. AB - Non-heart-beating donors (NHBD) are an increasing source of organs for kidney transplantation (KT) compared with donation after brain death (DBD), but the results in each regional transplantation program require local analysis. We compared 164 KT from NHBD (83 Maastrich type II A-B [T2] and 81 type III [T3]) with 328 DBD controls. NHBD kidneys were implanted with less cold ischemia, mean time on renal replacement therapy for NHBD recipients before transplantation was less too, and a higher proportion of thymoglobulin was also used. Besides NHBD-T2 more frequently showing the A group and patients being younger (48.9 +/- 11 vs DBD 55.2 +/- 15 years old; P < .001), there was a lower proportion of retransplant recipients and HLA sensitization; HLA-DR compatibility was slightly worse. Proportion of nonfunctioning allograft and necessity of dialysis after transplantation for NHBD were 4.9 and 68.3% versus DBD 4.3 and 26.9% (P < .001); renal function after a year was significantly less in NHBD (serum creatinine 1.79 +/- 0.9 mg/dL vs 1.46 +/- 0.5 in DBD; P < .001). NHBD recipient survival rates were 96% and 96% for the 1st and 3rd years, respectively, versus 96% and 94% for DBD, respectively (not significant [NS]). Graft survival rates censored by death were 91% and 89% (1st and 3rd years, respectively) versus 95% and 94% for DBD, respectively (NS). We did not find significant differences about survival between NHBD-T2 and T3. In the multivariable survival study (Cox, covariables with statistical significance demonstrated previously in our region), NHBD is not a prognosis factor for recipient or graft survival. Regarding current criteria for choosing donors and the graft allocation applied in Andalusia, short-term survival for NHBD transplantation is similar to DBD. Renal function in the short term is slightly worse, which is why it is important to monitor results over a long term, especially those from NHBD-T2. PMID- 27932095 TI - Implementation of a National Priority Allocation System for Hypersensitized Patients in Spain, Based on Virtual Crossmatch: Initial Results. AB - Access to kidney transplantation for patients with high levels of antibodies against HLA is a major challenge. This issue makes it difficult to detect compatible donors for those patients in a certain geographical area. Consequently, hypersensitized patients remain on the waiting list for long periods and their quality of life deteriorates. Our purpose was to increase access to transplantation for highly sensitized patients by developing a national priority allocation system based on virtual crossmatch. Between June 15, 2015, and May 15, 2016, 675 patients on the kidney transplant waiting list with calculated panel-reactive antibodies >=98% and undergoing dialysis for at least 12 months were included in the study; 86.1% of the patients had previously received at least one transplant. Solid-phase immunoassays were used to identify class I and II HLA antibodies in all patients. Participating hospitals assigned to the program one of the kidneys of every identified brain-dead real donor between 18 and 70 years old. Survival data were collected for the recipients transplanted between June 15, 2015, and December 31, 2015. In all, 475 (290 male and 185 female) brain-dead donors were assigned to the program. Virtual crossmatch was negative for 191 (41%) donors, 149 offers were accepted, and 102 (21.8%) kidneys were transplanted. At the end of the study, patient and graft survival were both 93.4%. The implementation of a national prioritization system based on virtual crossmatch increased access to transplantation for highly sensitized patients, with excellent results in terms of patient and graft survival. PMID- 27932096 TI - Study of beta2-Glycoprotein I Polymorphisms in Patients With Chronic Renal Failure as a Predisposing Factor for the Development of Anti-beta2-Glycoprotein I Auto-Antibodies. AB - BACKGROUND: Immunoglobulin (Ig)A anti-beta2-glycoprotein I (aB2GP1) antibodies are associated with thrombotic events, cardiovascular morbidity, and death in dialysis patients. About 30% of patients with chronic renal disease are positive for IgA aB2GP1; however, the origin of these antibodies is unknown. It has been speculated that dialysis membranes, age, or etiology of renal base disease are possible precipitating factors, although these factors do not appear to be the source of antibodies. B2GP1 is a protein of 326 amino acids grouped into five domains. Eight polymorphisms have been described; the most important are Val/Leu247, which appears to predispose aB2GP1 antibody production in patients with anti-phospholipid syndrome, and Trp/Ser316, which appears to have protective antibody production of aB2GP1. METHODS: DNA samples from 92 patients with renal failure on hemodialysis were randomly collected with a 1:1 ratio for the positivity for IgA aB2GP1. Forty-six samples were positive for IgA aB2GP1 (group 1) and 46 negative for IgA aB2GP1 (group 2). All samples were anonymized to study polymorphism Val/Leu247 and polymorphism Trp/Ser316. RESULTS: No significant differences were observed between those who were positive or negative for IgA aB2GP1 in patients with renal failure treated with hemodialysis and the polymorphism located in codons 247 and 316. CONCLUSIONS: The two groups of patients have the same prevalence in polymorphisms 247 and 316, and therefore there appears not to be a genetic predisposition in our population. New trigger factors must be studied. PMID- 27932098 TI - Urinary Clara Cell Protein in Kidney Transplant Patients: A Preliminary Study. AB - OBJECTIVE: The aim of this exploratory study was to analyze the urinary excretion of Clara cell protein (CC16), a new marker of proximal tubular dysfunction (PTD), in kidney transplantation (KT). MATERIALS AND METHODS: Urinary concentrations of CC16, beta2-microglobulin (beta2m), and N-acetyl-glucosaminidase (NAG) were measured in 50 KT patients (72% men; mean age 50.4 +/- 12.4 years; diabetes in 24%; duration of KT 4.3 +/- 3.1 years) and 10 healthy controls (6 men; mean age 33.6 +/- 13.4 years). RESULTS: Urinary levels of beta2m, NAG, and CC16 were significantly higher in KT patients than in controls: beta2m: 0.77 (interquartile range [IQ] 0.22 to 4.62) g/g vs 0.069 (IQ 0.05 to 0.10) g/g; NAG: 3.16 (IQ 2.09 to 5.33) U/g vs 1.73 (IQ 1.25 to 2.07) U/g; CC16: 26.01 (IQ 8.62 to 123.3) g/g vs 2.51 (IQ 0.83 to 7.18) g/g (P < .001). Elevated levels of beta2m, NAG, and CC16 were found in 81%, 28%, and 71% of KT patients, respectively. Urinary levels of beta2m, NAG, and CC16 significantly increase as glomerular filtration rate (GFR) decreases. Interestingly, in patients with GFR >60 mL/min, we still found high levels of beta2m, NAG, and CC16 in 77%, 13%, and 52%, respectively. Diabetic subjects had significant higher levels of the 3 markers compared with nondiabetic subjects, without differences in albumin excretion or GFR. CC16 showed a positive correlation with urinary albumin (r = 0.42, P < .001), NAG (r = 0.352, P < .05), and beta2m (r = 0.75, P < .001). CONCLUSION: PTD is highly prevalent in KT patients. This is the first study that analyzes CC16 in KT patients, showing that the urinary excretion of this protein is significantly increased in this population. Further studies are needed to examine the clinical value of CC16 in KT patients. PMID- 27932097 TI - Desensitization Protocol in Recipients of Deceased Kidney Donor With Donor Specific Antibody-Low Titers. AB - BACKGROUND: Kidney transplantation is the better option for end-stage renal disease (ESRD), but for patients with human leukocyte antigen (HLA) sensitization, the wait times are significantly longer than for patients without antibodies. Many desensitization protocols have been described involving strong immunosuppression, the use of apheresis, and B-cell-modulating therapies. We have designed a desensitization protocol from day 0 for deceased donor kidney transplantation. Our aim was to present our initial experience with five kidney transplant patients. METHODS: All patients had a negative complement-dependent cytotoxicity cross-match. The desensitization protocol included five to seven doses of thymoglobulin (1.25 mg/kg) and three sessions of plasmapheresis (PP) within the first week after transplantation, with intravenous immunoglobulin (500 mg/kg) after each PP session and one dose of rituximab on day 8. The presence of donor-specific antibodies (DSA) was analyzed by use of Luminex technology; levels between 1000 and 3000 mean fluorescence intensity were considered for desensitization. RESULTS: The median age was 44 years and median renal replacement therapy time was 9 years. All recipients presented 1 to 3 DSA specificities. There were no severe side effects related to PP, infusion of intravenous immunoglobulin, or rituximab. The median follow-up period was 19.3 months. Median serum creatinine level at last follow-up was 1.7 mg/dL. A kidney biopsy was performed in all patients. Graft and patient survival was 100%. CONCLUSIONS: Until now, few data are available concerning whether HLA incompatible kidney transplantation after desensitization would benefit patients with ERSD. The desensitization strategy using the combination of PP, low doses of intravenous immunoglobulin, and rituximab at our center resulted in a satisfactory clinical outcome. PMID- 27932099 TI - Antibody-Mediated Rejection in Kidney Transplantation Without Evidence of Anti HLA Antibodies? AB - INTRODUCTION: The definition of antibody-mediated rejection (AMR) is based on serologic (presence and/or development of donor-specific anti-HLA antibodies [DSAs]) and histologic (C4d deposition and endothelial damage) criteria. However, several cases of AMR have been described without C4d deposition, and other cases of histologic AMR without DSAs, which could be driven by other non-HLA alloantibodies such as anti-MICA or anti-angiotensin II type I receptor (AT1R). Here we studied clinical and histologic humoral rejection in kidney transplant recipients without evidence of anti-HLA antibodies. MATERIALS AND METHODS: Fifteen kidney transplant recipients with AMR defined as C4d+ and/or histologic g+ptc without anti-HLA antibodies in screening test were studied. Sera at the moment of biopsy and 2 months earlier were studied for anti-HLA antibodies by Luminex, in neat, diluted 1/160, and sera after treatment with dithiothreitol (DTT) and confirmed by single-antigen test. The anti-AT1R was measured by enzyme linked immunosorbent assay. RESULTS: A lack of anti-HLA and MICA antibodies was confirmed after anti-HLA screening test in all conditions (neat, diluted, and DTT treated) and de novo development of AT1R antibodies was ruled out. Nevertheless, after single-antigen test, 3 patients were identified with a weak reaction against class I antigen and another 4 patients against class II antigen. Due to the lack of locus-C typing in the donors, the DSA assignment cannot be confirmed, whereas anti-HLA class II antigens were DSA. CONCLUSIONS: A low sensitivity in the screening of anti-HLA antibody testing was observed. Our results suggest performing single-antigen test in seronegative patients with clinical humoral rejection after screening to confirm the presence of DSA. PMID- 27932100 TI - More Than 1000 Kidney Transplants Performed in Pamplona, Navarra: Data From the Collaborative Transplant Study. AB - INTRODUCTION: The Kidney Transplant Program started at the Clinica Universidad de Navarra (Pamplona, Spain) in September of 1969. The 1000th kidney transplant was performed in September 2015. Data from kidney transplants have been included in the Collaborative Transplant Study since 1983. MATERIALS AND METHODS: Data on patient and graft survival of the 635 kidney transplants (557 first kidney transplants and 78 second kidney transplants) performed in the Clinica Universidad de Navarra between 1990 and 2014, as well as the estimated average life of the grafts are described and compared with data from the more than 150,000 European kidney transplants included in the Collaborative Transplant Study in the same period. RESULTS: Data of our patient and graft survival are statistically significantly better (P < .05) than those of the over 150,000 European transplants analyzed in the Collaborative Transplant Study in the same period. The estimated half-life of the kidney transplants performed in our Center is 18.5 years for first transplants and 15.7 years for second transplants, compared to 13.9 and 11.2 years, respectively, calculated for the European transplants. CONCLUSIONS: Data obtained from the Collaborative Transplant Study confirm excellent graft survival in our Center with an estimated half-life higher than that of the European transplants included in this study. PMID- 27932101 TI - Graft Survival in Patients Who Received Second Allograft, Comparing Those With or Without Previous Failed Allograft Nephrectomy. AB - INTRODUCTION: Nowadays, the number of patients receiving a second graft is growing, and the management of failed grafts is still controversial. OBJECTIVE: Our objective was to analyze the influence of graft nephrectomy on graft and patient survival. MATERIALS AND METHODS: We retrospectively evaluated the demographic features and graft outcomes of 63 recipients who received second allografts between August 1985 and April 2013. They were divided into two groups: group A, those who underwent nephrectomy of failed graft (n = 21, 33.3%), and group B, those whose failed graft was retained (n = 42, 66.6%). chi2 and Mann Whitney U tests were used to compare demographic characteristics and graft features in both groups. Kaplan-Meier test was used to analyze graft and patient survival. Finally, univariate and multivariate analysis was done using Cox regression. RESULTS: Demographic characteristics of donor and receptors were similar in both groups. Overall panel-reactive antibody (P = .040) showed statistically significant differences between groups (72.0 +/- 25.3 in group A and 54.8 +/- 30.0 in group B). Hemodialysis duration was longer in group A (P = .023, 112.2 +/- 72.8 vs 70.9 +/- 66.9 months). The percentage of patients who had delayed graft function was higher in group A (58.8% vs 27.3%, P = .029). Kaplan Meier test found no differences between groups (P = .344); group A, 107.4 months (95% confidence interval [CI] 74.0 to 140.8) and group B, 82.7 months (95% CI 62.5 to 102.8). We found no differences in terms of patient survival (P = .798) with the Kaplan-Meier test. In group A, patient survival was 164.5 months (CI 137.7 to 191.31) and in group B, 152.0 months (95% CI 125.5 to 178.5). CONCLUSIONS: Failed graft nephrectomy did not show a negative impact on graft and patient survival. PMID- 27932102 TI - Kidney Transplantation Results in Very Highly Sensitized Patients Included in a Virtual Crossmatch Program: Analysis of Kidney Pairs. AB - BACKGROUND: Kidney transplantation in highly-sensitized (HS) patients can improve with organ-exchange strategies based on virtual crossmatch (V-XM). Experience in very-HS patients is limited. METHODS: In June 2012, Andalusia started a V-XM protocol for very-HS patients (calculated panel reactive antibodies >=95%). After organ allocation a cytotoxic-XM performed immediately before transplantation had to be negative for surgery to proceed. We analyzed results up until December 2015. Whenever possible we also compared the course of the recipient (non-HS) of the other kidney from the same donor. RESULTS: Of the 57 grafts, 52 kidney transplantations were performed (the pretransplantation cytotoxic-XM was positive in 5; predictive value 91.3%). Five patients (9.6%) experienced acute rejection (4 antibody-mediated rejections [AMRs]; 7.6%). Donor-specific antibodies developed in 10 patients. No patient died. One-year graft survival was 98%. We compared the course of the non-HS recipient of the other kidney, excluding cases with no pair (n = 5), pairs who were children recipients (n = 3), pancreas-kidney recipients (n = 5), or pairs already included in the V-XM protocol (n = 4). Finally, 35 pairs were studied. More HS-patients developed donor-specific antibodies (P = .016). No significant differences were seen in acute rejection, but AMR was more common (P = .057). No deaths occurred in either group, and there were no differences in graft survival or renal function. CONCLUSIONS: Although a few patients still developed AMR, our V-XM based protocol with a final pretransplantation cytotoxic-XM achieved very satisfactory results. Although the number of patients was limited, the initial survival of these high-risk recipients was comparable to the controls. PMID- 27932103 TI - Prognostic Value of Modified Banff Score in the Evolution of Renal Function. AB - BACKGROUND: Some lesions not included in the Banff classification, such as inflammation in the scarred areas and total inflammation, have been described to have prognostic value in the evaluation of graft biopsies. Our aim was to reassess kidney graft biopsies and study the impact of histopathologic lesions, both those graded in the Banff classification and those related to inflammation, on the graft function and evolution. METHODS: We selected 20 biopsies exhibiting chronic pathology without a specific phenotype, and we reevaluated them with the use of a modified Banff score. RESULTS: We found statistically significant association between the presence of total inflammation (P = .048; P = .038), the presence of inflammation in scared area (P = .037; P = .018), and creatinine at the time of renal biopsy and 1 year after the renal biopsy, respectively. CONCLUSIONS: Our results suggest that the presence of both inflammation in the scarred areas and total inflammation are related to renal function at the time of the biopsy and to renal function 1 year after the biopsy. PMID- 27932104 TI - Short-Term Outcomes of 100 Consecutive Kidney Transplantations in a 3-Year Period: A Single-Center Experience. AB - BACKGROUND: The results of kidney transplantation have improved significantly in the last decade with patient and graft survival rates that range from 92% to 95%. METHODS: We analyzed the clinical results in the last 100 consecutive patients with a follow-up of 6-42 months at our institution. We also made a general evaluation of the patients before surgery as candidates for transplantation and divided them into 3 groups (good, moderate, and poor). RESULTS: We had 8 living donors and 92 cadaveric kidney transplantation cases. Principal cause of donor death was cerebrovascular disease accounting for 64%. Mean age of recipients was 55.1 +/- 12.9 years with a total of 65 males. Currently there are 96 functioning allografts. During this 3-year period, 2 patients suffered graft loss and 2 patients died with a functioning allograft. We studied whether there were statistically significant differences in renal function (Modification of Diet in Renal Disease Study Equation [MDRD]) at 12 months and at last visit with respect to the evaluation of recipient as candidate for renal transplantation. CONCLUSION: Our observations suggest great improvement of early results of renal transplantation in recent years, including complex cases. In this 3-year period we had a patient survival rate of 98% and a graft survival rate of 96% of cases. Further dedicated prospective studies that aim to evaluate or to propose possible recipient-related predictors for kidney transplantation outcomes in different populations are needed. PMID- 27932105 TI - B-Cell-Activating Factor Levels Are Associated With Antibody-Mediated Histological Damage in Kidney Transplantation. AB - INTRODUCTION: Along with death engraftment, in recent years, antibody-mediated damage has been identified as the leading cause of loss of kidney transplants. Despite the recognition of the role of the B-lymphocyte subpopulation in the development of both tolerance and rejection, little is known about the trigger mechanisms and effectors of this humoral response. BACKGROUND: We analyzed the relationship between B lymphocyte subpopulations and levels of B-cell-activating factor (BAFF) with the histological findings in biopsies of renal transplantation. MATERIAL AND METHODS: We selected 35 patients whose kidney transplant biopsy was performed between January and November 2015. The biopsy specimens were classified according to Banff criteria. At the moment of the biopsy BAFF levels and B-lymphocyte subpopulations in blood were measured using enzyme-linked immunosorbent assay (ELISA) and using flow cytometry, respectively. RESULTS: Mean BAFF levels were 493 +/- 245 pg/mL. The median performance of biopsy post-transplantation was 12.9 (11.7-23.9) months. BAFF levels correlated with pretransplantation antibodies (r = 0.523; P = .002) but not with kidney function. In biopsies performed more than 1 year after transplantation BAFF levels correlated with the severity of chronic glomerular (cg) involvement (r = 0.625; P = .003). Histological variables related to antibody-mediated injury selected by principal component analysis (glomerulitis, peritubular capillary, and chronic glomerulopathy) related to BAFF levels (B factor, 116; 95% confidence interval [CI], 12-220; P = .029). Biopsy specimens with transplant glomerulopathy (TG) showed lower levels of circulating naive CD19 + subpopulation, IgD+, and CD27- (32.7 +/- 28.1 vs 87.9 +/- 79.1; P = .017) compared with biopsy specimens without TG. CONCLUSIONS: Elevated levels of BAFF are associated with increased presence and severity of TG and a set of variables related to antibody-mediated histological damage. TG is associated with changes in circulating B-lymphocyte subpopulations that could contribute to its pathogenesis. PMID- 27932106 TI - Assessment of Kidney Graft Function Evolution Measured by Creatinine and Cystatin C. AB - INTRODUCTION: The 2013 Kidney Disease Outcomes Quality Initiative Clinical Practice Guideline suggests measuring cystatin C (sCys) in adults with glomerular filtration rate (GFR) based on creatinine (sCr) between 45 and 59 mL/min/1.73 m2 if confirmation of chronic kidney disease (CKD) is required. There is not enough evidence to recommend the use of sCys or sCr to estimate GFR in kidney transplant recipients. OBJECTIVES: Our aims were to describe the evolution of sCr, sCys, and GFR in a group of kidney transplant patients and to determine their association with some markers of morbidity at 1 year. METHODS: A total of 54 patients were included. Analytical and clinical data were recorded. Renal function was analyzed using the CKD Epidemiology Collaboration (EPI) sCr equation and CKD-EPI sCys equation. RESULTS: sCys-estimated GFR was higher than estimated from sCr by CKD EPI. The values of sCys have more variability than those of sCr. The agreement between the stages of CKD by sCr or sCys-estimated GFR measured by Cohen's kappa coefficient was only fair. One-year CKD-associated variables correlated differently with sCr and sCys-estimated GFR. Hemoglobin, uric acid, calcium, and phosphorus related to sCr-estimated GFR, whereas serum albumin was associated with sCys-estimated GFR. CONCLUSIONS: sCys values have a higher variability than sCr in kidney transplant recipients. sCys- or sCr-based GFRs have a nonsimilar behavior in these patients with weak agreement to stratify CKD stages and a different relationship to CKD-related comorbid conditions. PMID- 27932107 TI - Antibody-Mediated Acute Vascular Rejection of Kidney Allografts: Fifteen-Year Follow-up. AB - BACKGROUND: Although acute vascular rejection (AVR) is associated with a high risk of graft loss, it remains unclear whether AVR with accompanied cellular or humoral rejection (AHR) has dissimilar outcomes. The aim of this study was to examine the association between subtypes of AVR and graft loss. METHODS: We assessed patients who provided biopsy samples for acute allograft rejection from 1998 to 2014. To investigate distinct rejection patterns, we retrospectively assessed rejection episodes with review of graft histology as well as donor specific anti-HLA antibodies when available. RESULTS: A total of 1,004 patients were biopsied and included in the main analyses, of which 259 (32.87%) had acute biopsy-proven rejection. We identified three patterns of graft rejection defined according to the presence of peritubular capillaritis (ptc): a) T-cell-mediated acute vascular rejection if ptc free; b) humoral-mediated acute vascular rejection if ptc >0; and c) T-cell-mediated rejection if vasculitis = 0 and ptc = 0 (148 [57%], 70 [27%], and 41 [16%], respectively). At 5 years, graft survival was lower among patients with ptc-vascular rejection than those with T-cell vascular rejection (72.3% vs 83.2%; P = .010). T-cell-mediated rejection without vasculitis had similar survival compared with rejection absence (89.3% vs 8 9.2%; P = .698). Multivariate analysis adjusted by age and sex showed that risk of graft loss was higher in biopsies with high scores of glomerulitis (g2-g3); vasculitis (v2-v3), capillaritis (ptc2-ptc3), or interstitial inflammation (i2 i3). However, tubulitis and C4d were not statically significant. CONCLUSIONS: We conclude that antibody-mediated AVR involves a poorer prognosis than T-cell mediated AVR. The presence of tubulitis does not seem to determine a poor long term renal graft prognosis. PMID- 27932109 TI - Risk Evaluation and Outcome of Pneumocystis jirovecii Pneumonia in Kidney Transplant Patients. AB - Pneumocystis jirovecii pneumonia (PJP) affects immunocompromised patients. As a result of effective prophylaxis in the 1st months after kidney transplantation, PJP is increasingly diagnosed in the long term after transplantation. The present study evaluates course and outcome of PJP in a single transplant center from 2010 to 2015. Twenty-three patients presented with PJP at a mean of 53.7 +/- 50.2 months after transplantation. Of these, 3 patients underwent ABO-incompatible (ABO-i) living-donor transplantation and 3 patients were treated with the use of belatacept. For risk estimation, 3 control cohorts were defined: a control group of all kidney transplant patients presenting for routine follow up (n = 575), all patients transplanted in an ABO-i setting (n = 45), and all patients treated with belatacept in our clinic (n = 69). Mortality in patients with PJP was 3/23 (13%) and graft loss after PJP was 3/23 (13%) resulting in patient and graft survivals of 87% and 73.9%, respectively. All patients were without PJP prophylaxis at time of diagnosis. Five of the 23 PJP patients received rejection therapy or dose escalation of immunosuppression 6 months before PJP infection, and 1 patient experienced acute rejection within 6 months after PJP treatment. In the course of PJP, 8 patients developed acute respiratory insufficiency. At time of PJP diagnosis, patients presented with severe lymphopenia (mean +/- SD lymphocyte count, 0.64 +/- 0.27/nL; normal range: 1.5-3/nL). Patients after ABO-i transplantation, as well as patients treated with belatacept, showed an increased risk for PJP (7.3% and 4.3%, respectively); however, in belatacept patients, other risk factors, such as age, low estimated glomerular filtration rate (eGFR), and lymphopenia seemed to contribute to this increased risk. PMID- 27932108 TI - Donor-Specific Antibodies After Starting Hemodialysis in Nonrenal Solid Organ Transplant Recipients: Role of TH17. AB - BACKGROUND: Nonrenal transplantation could cause a progressive deterioration in renal function until need dialysis. It is important to know if these patients increased their risk to develop de novo donor-specific anti-HLA antibody (DSA) after starting hemodialysis (HD) and if so, try to find the mechanism. MATERIAL AND METHODS: In this double-phase study, we first analyzed the incidence of development DSA in nonrenal transplant recipients after starting HD by a retrospective study. Secondly, a prospective study was designed to analyze the pharmacokinetics of immunosuppressive drugs and the cytokine profile of these patients. RESULTS: Of 179 pancreas transplant recipients, 16 needed to start HD, and 62.5% of these patients developed de novo DSA after starting HD, with 80% of them class I DSA. In the second phase of the study, the plasma levels of the immunosuppressive drugs as measured by a limited sampling strategy of 3 sample time points (C0, C2, and C4) were stable. The cytokine profile showed that there was an increase in Th1 cytokine (interferon gamma of 0.045 ng/mL) and also in Th17 cytokines (transforming growth factor beta >10 ng/mL). CONCLUSION: Our data suggest that the development of DSA after starting HD in nonrenal transplant recipients could be mediated by Th17 immune response mechanisms. PMID- 27932110 TI - Effect of Cytomegalovirus Infection on Survival of Older Kidney Transplant Patients (D+/R+): Impact of Valganciclovir Prophylaxis Versus Preemptive Therapy. AB - BACKGROUND: Kidney transplant patients with D+/R+ serology can be treated with either prophylaxis or preemptive valganciclovir. The older transplant population suffers severe immunosenescence, especially patients with latent cytomegalovirus (CMV) infection (R+). They are more likely to develop indirect CMV effects. Likewise, many patients have significant cardiovascular comorbidity, which makes them more sensitive to these indirect effects. The aim of this study was to evaluate the incidence of CMV viremia and indirect effects on survival, comparing prophylaxis (V) against preemptive (P) valganciclovir in an older kidney transplant population. METHODS: We analyzed the data of 233 recipients from 2002 (age, >55 years; D+/R+) with >=6 months of follow-up. The patients were divided into 2 groups: 167 (71.7%) in the V group and 66 (28.3%) in the P group. RESULTS: The incidence of CMV infection in the P group was 32% versus 6% in V group. Patients with CMV viremia showed worse survival values than patients without viremia (log rank P = .031). Five-year survivals were 74% vs 88%, respectively. Cox regression showed that the adjusted effect of CMV infection on overall survival was a significant risk (hazard ratio [HR], 2.07; 95% CI, 1.003-4.29). Patients with CMV viremia showed worse cardiovascular survival than patients without viremia, with 5-year survivals of 79% vs 94%. Cox regression showed that the adjusted effect of CMV infection was a significant risk (HR, 2.62). CONCLUSIONS: CMV infection has a detrimental effect on the survival of older patients. Valganciclovir prophylaxis induces a protective effect against CMV infection and could improve survival of older patients with cardiovascular comorbidities. PMID- 27932112 TI - Short-Term Outcome of Untreated Versus Treated Asymptomatic Bacteriuria in Renal Transplant Patients. AB - BACKGROUND: Infection of the urinary tract (UTI) is the most common form of bacterial infection in renal transplant patients, but its management is still controversial. We compared symptomatic and asymptomatic bacteriuria, treated or untreated, during two different months (summer or winter). METHODS: This longitudinal, prospective study involved routine urine cultures collected during September 2014 or March 2015. Demographic, clinical, and microbiological characteristics from the patients with positive urine cultures were described. The main outcomes were the need of hospitalization, the bacterial clearance, and the selection of the resistant pathogen. RESULTS: From the 538 urine cultures collected, only 61 were positive urine cultures. Twenty were untreated asymptomatic bacteriuria (AB), 28 were treated AB, and 13 were treated symptomatic bacteriuria. The more prevalent micro-organisms were E coli (27%), K pneumoniae (11%), and E faecalis (7%). There were no differences in the demographic, clinical, and microbiological characteristics depending on the month when the urine cultures were collected. Only 10 patients required hospitalization during follow-up, and all of them belonged to the treated group. Bacterial clearance after the treatment occurred in 20 patients of the 41 treated (48.9%) and spontaneously in 14 of the 20 patients untreated (70%). Of the treated patients, 47.6% developed a new resistance to another antibiotic. CONCLUSIONS: Only 7.6% of the routine urine cultures on renal transplant were positive. Untreated AB did not require hospitalization, and 70% had spontaneous bacterial clearance. PMID- 27932111 TI - Hepatitis C Virus in Kidney Transplant Recipients: A Problem on the Path to Eradication. AB - BACKGROUND: Hepatitis C virus (HCV) still has significant prevalence in kidney transplant (KT) recipients and is related to poor recipient and graft survival. New direct-acting antivirals (DAA) are leading to a radical change in the problem. METHODS: We studied HCV prevalence at the time of transplantation and in follow-up patients, the way cases are handled, and the results of DAA. RESULTS: A total of 2,001 KT had been performed in our center since 1978. Pre- or post transplantation HCV serology was present in 1,880 cases and was positive in 13.4%. A total of 1,195 transplant recipients were still being monitored by us, with only 60 (5%) HCV+ and 45 (3.6%) RNA+ cases. Of these 45 HCV+/RNA+, 25 had been or were being treated, 7 were about to begin treatment, 1 was awaiting new DAA treatment owing to low glomerular filtration rate (GFR), 3 were being evaluated, 2 had been excluded owing to high comorbidity, 2 refused to be treated, 2 needed to return to hemodialysis, and 1 was lost to follow-up. Except 1 case where Viekira Pak was used because of low GFR, all cases included sofosbuvir as the main drug associated with either ledipasvir (70%) or daclatasvir (25%). Ribavirin was added as coadjuvant in 35% of cases. Twenty-one patients had completed treatment (84%). Two patients had to interrupt DAA therapy (8%), one because of hepatotoxicity and the other as a result of a liver transplantation. In every case, the graft maintained function and negativization of viral replication occurred. CONCLUSIONS: Side effects have been low, anemia related to ribavirin being the main one. Just one case needed to be interrupted at the 7th week of DAA therapy due to hepatotoxicity. It has frequently been necessary to adjust immunosuppression treatment with the use of higher doses of tacrolimus. PMID- 27932113 TI - Hepatitis C Treatment With Direct-Acting Antivirals in Kidney Transplant: Preliminary Results From a Multicenter Study. AB - Hepatitis C (HC) is a very relevant negative prognosis factor for graft and transplant recipient survival. New direct-acting antivirals (DAAs) allow us to solve this problem in an effective way. It is crucial to understand their real impact in our daily practice. We analyzed treatment results with DAA, free of interferon, in kidney transplant recipients (KTRs) from 15 Spanish hospitals (Grupo Espanol de Actualizacion en Trasplante), regarding effectiveness, tolerance, and impact on immunosuppression, renal function-proteinuria, and diabetes. One hundred nineteen KTRs were included (9 combined liver-kidney transplants). The main DAA used was sofobusvir (91%) combined with ledipasvir (55%), simeprevir (14%), or daclatasvir (13%); in 9 cases (7%), a paritaprevir ritonavir-ombitasvir-dasabuvir combination (3D) was used; Ribavirin was used as a coadjuvant in 18%. Side effects were limited (23.5%) and without relevance in general, except in 7 patients for whom we needed to interrupt the treatment due to neurotoxicity (1) caused by drug interaction (3D and tacrolimus) or anemia (3) by Ribavirin or others. Ninety-four patients had completed the treatment when data were analyzed: virological response was seen in 97.8% % of cases. Liver function analysis improved: 84% normal versus 21% before starting the treatment (P < .001). Renal function and proteinuria did not change. Tacrolimus level at the end of DAA-treatment was significantly lower with respect to the beginning (5.8 +/- 2.1 ng/mL vs. 7.4 +/- 1.8 ng/mL, P = .03), despite a slight increase in the dose (2.6 mg/d vs. 2.3 mg/d, P = .17). DAA are highly effective in the treatment of hepatitis C in KTRs with good tolerance in general, making it possible to solve the problem and have a good chance to improve the prognosis in our transplantation patients. The use of these therapies in KTRs requires special control and coordination with digestive professionals, especially if 3D or Ribavirin is used. PMID- 27932114 TI - Presence of T-275A and C-2152T Polymorphisms of the Promoter Region of Uridine Diphosphate-Glucuronosyltransferase 1A9 Increases Mortality From Digestive Tumors: Results After 10 Years of Follow-up in a Renal Transplant Population. AB - BACKGROUND: The aim of this study was to determine the distribution of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) promoter region T-275A and C 2152T single-nucleotide polymorphisms (SNPs) in stable transplant patients and to investigate the impact of these SNPs on the evolution of this population after 10 years of follow-up. METHODS: White renal transplant recipients (n = 873) were studied. The median time of follow-up was 91.8 months (P25-75 46-146). Amplification with specific "primers" to delimit the study area was performed for each polymorphism. Amplification was performed with the use of real-time polymerase chain reaction. RESULTS: T-275A promoter mutation was detected in 13% of patients and C-2152T in 12% of patients. Survival analysis was performed on 873 renal transplants, carried out between 2004 and 2013. We found a higher frequency of death from cancer among polymorphism carriers (P = .001). CONCLUSIONS: It appears that carriers of T-275A and C-2152T SNPs of the UGT1A9 gene promoter region show a greater incidence of death from cancer, with a significantly higher cumulative incidence of death from gastrointestinal tumors. PMID- 27932115 TI - Relationship Between Albuminuria During the First Year and Antibody-Mediated Rejection in Protocol Biopsies in Kidney Transplant Recipients. AB - BACKGROUND: Antibody-mediated rejection is the main cause of deterioration of kidney transplants and frequently is detected only by means of protocol biopsies. The aim of this study was to relate the presence of albuminuria throughout the 1st year to the histologic findings detected by 1-year protocol biopsies in kidney graft recipients. METHODS: Retrospective observational study of 86 protocol biopsies 1 year after transplantation. Albuminuria was measured at 3, 6, 9, and 12 months in urine samples and expressed as albumin/creatinine (mg/g). RESULTS: Analysis of biopsies, reflected according to the Banff criteria, the following categories: fibrosis and tubular atrophy, 35 (40.7%); cellular rejection, 13 (15.1%); antibody-mediated rejection, 8 (9.3%); chronic glomerulopathy, 10 (11.6%); normal, 14 (16.3%); recurrence, 1 (1.2%); and other, 5 (5.8%). The proportions of patients with albuminuria for Banff scale scores (0 vs >=1, respectively) at 6 and 12 months, respectively, after transplantation, were: for marker glomerulitis, 45.5% versus 59.3% (P = .021) and 36.4% versus 70.4% (P < .001); for marker glomerulopathy, 49.1% versus 50.0% (P = .051) and 42.1% versus 58.3% (P = .019); for marker peritubular capillaritis, 45.8% versus 60.9% (P = .047) and 39.0% versus 69.6% (P = .276); and for marker C4d, 49.2% versus 56.3% (P = .894) and 46.2% versus 56.3% (P = .774). CONCLUSIONS: The presence of albuminuria after renal transplantation is common, especially in patients with proteinuria. Persistent albuminuria after transplantation, even at low levels, can be indicative of subclinical antibody-mediated rejection. Additional broader studies to relate the albuminuria to histologic changes observed in protocol biopsies are required. PMID- 27932116 TI - Surgical Complications in En Bloc Renal Transplantation. AB - En bloc pediatric transplantation (EBPT) began with the aim of increasing the donor pool due to the existing high demand for donors. At its inception, it was considered a type of suboptimal transplantation due to its association with a high incidence of vascular, urologic, and immunologic complications. The main objective of this study was to update information on EBPT with the largest case series that exists on a worldwide scale. In a retrospective study, the results obtained from brain-dead donors (BDDs; n = 770) were compared to those of EBPT (n = 100) from January 1990 to December 2012. The median of follow-up was 12.8 years (interquartile range 8.1 to 17.2). The variables collected for analysis were demographic factors (age and sex of recipients, age and weight of donors), renal function, graft survival, recipient survival, surgical complications (thrombosis, lymphocele, urologic complications, and renal artery stenosis and need for revascularization with angioplasty and/or stents). Subsequently in a second analysis, we studied the association between graft survival, thrombosis, angioplasty, stents, and appearance of lymphoceles with the different factors that were considered to be related in accordance with published literature and our own experience. Graft loss due to surgical complications was more frequent in EBPT than in BDD (15% vs 2.2 % in BDD; P < .001), and interstitial fibrosis and tubular atrophy were more frequent in BDD (13% vs 2%; P < .001). EBPT offers a good survival rate after overcoming the possible surgical complications that may arise. PMID- 27932118 TI - Relationship Between Vitamin D Blood Levels and Cancer Development in Renal Transplant Patients: A Case-Control Study. AB - BACKGROUND: Malignancy is one of the most common long-term complications in renal transplant patients, often related to immunosuppressive treatment although other factors could be considered. Vitamin D plays an important role in reducing cancer risk. After kidney transplantation (KT), 25-hydroxyvitamin D (25OH-D, or calcidiol) insufficiency concerns >85%. The main aim of the present study was to determine the relationship between calcidiol blood levels and cancer development in KT recipients. METHODS: This was a retrospective observational case-control study including patients who received transplants in our hospital from 2003 to 2009 with a follow-up period to 2015. A total of 738 patients were included; 94 of them developed malignancy process, 80 of whose tumor data were analyzed in the cancer group, and the rest composed the control group. At the moment of cancer presentation, age, sex, primary kidney disease, time after surgery, immunosuppressant schedule, and 25OH-D blood levels were collected. RESULTS: The mean patient age was 57 years. The percentages of man and women were 59.5% and 41.5%. The predominant etiology of kidney disease was chronic glomerulonephritis in 31.9%. There were no significant differences between sex, primary kidney disease, immunosuppressant schedule, or incidence of neoplasm in each group of patients. There were no significant differences in 25OH-D blood levels. The incidence of cancer was 7.1%-13.7% per year. The mean time between the graft surgery and the event was 5.6 years. CONCLUSIONS: In patients with functioning KT, we found no correlation between blood levels of calcidiol and the incidence of cancer. PMID- 27932117 TI - Risk Factors of Recurrence of Diabetic Nephropathy in Renal Transplants. AB - BACKGROUND: Renal transplantation has been established as the treatment of choice for end-stage renal disease (ESRD) due to diabetic nephropathy. This study aimed to investigate the risk factors for recurrence of diabetic nephropathy (RDN) in renal allografts. METHODS: We studied 1,011 renal transplant patients from 1986 to 2003, of which 95 had ESRD due to diabetic nephropathy. We retrospectively analyzed the clinical characteristics and outcomes of RDN after renal transplantation. RESULTS: Of the 95 recipients with ESRD due to diabetic nephropathy, 41 developed RDN and 11 of those 41 underwent graft biopsy. The mean durations from transplantation to RDN and to renal replacement therapy was 81.58 months (range, 54-120 mo), and 109.66 months (range, 27-188.4 mo), respectively. At 5 years, treatment on statins and renin-angiotensin-aldosterone system (RAAS) blockers were associated with a higher survival free from RND (82.2% vs 63.2% [P = .070] and 100% vs 80% vs 0.6% [P = .013], respectively). Compared with cyclosporine, tacrolimus was associated with a higher risk for RND (odds ratio [OR], 4.27; 95% confidence interval [CI], 1.75-5.13; P = .047). High doses of prednisone (>0.06 mg/kg) were also associated with a higher risk of RDN (OR, 3.03; 95% CI, 1.19-8.30; P = .029). The combination of calcineurin inhibitor and mammalian target of rapamycin inhibitor (mTORi) demonstrated the highest risk of RDN (OR, 14.08; 95% CI, 3.72-53.29; P < .01). CONCLUSIONS: Treatment with tacrolimus and mTORi is the most diabetogenic immunosuppressive regimen. Treatment with tacrolimus entails a greater risk of RDN than with cyclosporine. The administration of statins or RAAS blockers could delay the progression of RDN. PMID- 27932119 TI - Oncological Evaluation by Positron-emission Tomography, Circulating Tumor Cells and Alpha Fetoprotein in Patients With Hepatocellular Carcinoma on the Waiting List for Liver Transplantation. AB - INTRODUCTION: The objectives of this study are the determination of the number of circulating tumor cells (CTCs), by means of the IsoFlux enrichment system (Fluxion Biosciences Inc, San Francisco, California, United States) in patients with hepatocellular carcinoma (HCC) in compliance with the Milan criteria and on the waiting list for hepatic transplantation, as well as the study of its relation with the of alpha-fetoprotein levels (AFP) and positron-emission tomography-computed tomography (PET-CT) findings. PATIENTS AND METHODS: An oncologycal evaluation with PET-CT, CTCs, and AFP was conducted in 24 consecutive patients with HCC eligible for orthotopic liver transplantation according to the Milan criteria. The diagnosis of HCC was made according to clinical, biological, and radiological findings. RESULTS: We detected CTCs in peripheral blood in 21 of 24 patients (87.5%) before liver transplantation, with a mean number CTCs of 156 +/- 370 (range, 2 to 1768) with statistically significant association between number of CTCs detected in peripheral blood and the time within the waiting list (P < .05), but not betwen AFP levels and standard uptake value and time to orthotopic liver transplantation (P > .05). CONCLUSIONS: PET-TC, CTCs, and AFP levels could be an essential key for the correct management of the patients with HCC on the waiting list for liver transplantation. PMID- 27932120 TI - Prognostic Value of Pre-transplantation Serum Alpha-Fetoprotein Levels in Hepatocellular Carcinoma Recurrence. AB - Serum alpha-fetoprotein (AFP) value is still not included in the consensus guidelines to make decisions referring to liver transplantation (LT) for hepatocellular carcinoma (HCC). Many studies demonstrated the influence of high AFP level in poor prognosis after LT for HCC. We studied 301 consecutive recipients transplanted for HCC from January 2002 to December 2011. The median follow-up was 64.3 months (interquartile range, 41.6-90.8). HCC recurrence was 31.6% when AFP was >400 ng/mL and 50% when AFP was >1,000 ng/mL. Specificity to predict HCC recurrence was 95.1% (95% confidence interval [CI], 91.9-97.1) when AFP was >400 ng/mL and 98.9% (95% CI, 96.8-99.6) when AFP was >1,000 ng/mL. The overall survival (P = .008) and disease-free survival (P = .004) differed between patients groups when an AFP cutoff level of 1,000 ng/mL was used. The predictive accuracy of high pre-transplantation serum AFP level for HCC post-transplantation recurrence should be used in decision algorithms for LT. PMID- 27932121 TI - Up-to-7 Criteria for Hepatocellular Carcinoma Liver Transplantation: A Retrospective Analysis of Experiences. AB - INTRODUCTION: The expansion of criteria for hepatocellular carcinoma (HCC) liver transplantation should produce satisfactory outcomes in terms of survival and recurrence. OBJECTIVES: To investigate if the up-to-7 criteria are applicable to liver transplantation for HCC. METHODS: A review of all liver transplantations performed at our unit between January 2002 and December 2010 was conducted (645 patients). The 91 patients of the sample who had HCC were divided into 3 groups: in Milan criteria (MC; n = 74), in up-to-7 criteria (UTSC; n = 12), and outside of up-to-7 criteria (OUTSC; n = 5). A descriptive retrospective study was carried out to analyze the characteristics of liver tumors and recipients and to estimate recurrence and survival rates for this population of patients. RESULTS: The characteristics of transplant recipients of the 3 groups were comparable. Statistically significant differences were observed in the number of tumors (1 +/ 0.65 for MC, 3 +/- 1.05 for UTSC, 6 +/- 4.10 for OUTSC; P < .001), largest tumor size (2.47 +/- 1.12 cm for MC, 3.78 +/- 0.04 cm for UTSC, 4.04 +/- 1.73 cm for OUTSC; P < .001), and recurrence (5.4% for MC; 33.3% for UTSC; 20% for OUTSC; P = .008). Survival rates (MC, UTSC, and OUTSC) at 3 and 5 years were 71.6%, 66.7%, and 60%, and 58.1%, 58.3%, and 40%, respectively, whereas tumor-free survival rates were 70.3%, 58.3%, and 60%, and 58.1%, 50%, and 40%, respectively. CONCLUSIONS: Survival in patients with HCC transplanted under up-to-7 criteria is acceptable. However, the expansion of criteria involves an increase in the number of patients included in the waiting list and a higher probability of relapse. PMID- 27932122 TI - Analysis of the First 1000 Liver Transplants in Virgen del Rocio Hospital. AB - The goal of this work has been to analyze the first 1000 liver transplantations (LTs) performed in the Virgen del Rocio Hospital of Seville and to evaluate the changes in that time. We included 916 patients who had 1000 LTs. We distinguish 2 stages in the follow-up: the first stage, between 1990 and 2002, and the second, from 2003 to 2013 (Model for End-stage Liver Disease [MELD] stage). We analyzed recipient features, LT indications, donation criteria, surgical technique, complications, and survival both for patients and grafts. The median age of recipients was 53.50 +/- 46.49 years old, with a noticeable increase after 2000. There were 3 times as many men as women. The most frequent indications for LT were hepatocellular disease (48.8%), followed by hepatocarcinoma (17.8%), retransplantation (8.1%), and cholestatic diseases (3.6%). Donors of Andalusian centers accounted for 88.2% of LTs, and 8.3% of LTs presented some arterial or venous complication. Biliary complications occurred in 15.6%. Patient survival at 1, 5, and 10 years was 77%, 63.5%, and 51.3%, respectively. In conclusion, some of the factors that negatively influenced survival of the patient were stage of the LT, hepatitis C virus-positive recipient, emergency cases, hepatocarcinoma, high consumption of blood products, and second transplantations. PMID- 27932123 TI - Serum Levels of Interleukin-34 During Acute Rejection in Liver Transplantation. AB - INTRODUCTION: Accumulating evidence indicates that interleukin (IL)-34 participates in T-cell homeostasis and tolerance due to the ability of IL-34 to trigger apoptosis of Th1, Th17, and Tc1 cells, but spare Th2 cells and Treg. In addition, IL-34 exerts anti-inflammatory effects by impairing leukocyte adhesion and transendothelial migration, and reducing the secretion of proinflammatory cytokines. The aim of our study was to investigate the time course of serum levels of IL-34 during hepatic allograft rejection. METHODS: Serum levels of IL 34 were determined in 20 healthy subjects and 45 hepatic transplant recipients. These patients were divided into 2 groups: group I was composed of 15 patients with acute rejection, and group II was composed of 30 patients without acute rejection. Samples were collected on days 1 and 7 after liver transplantation and on the day of liver biopsy. RESULTS: The concentrations of IL-34 were higher in the rejection group vs nonrejection group during the entire postoperative period. The whole transplant group, including those with stable graft function, showed higher IL-34 serum levels than the controls at all times after liver transplantation. CONCLUSIONS: Our preliminary results could be related to the recent finding that IL-34 may play an immune-suppressive role in liver transplantation. In our case, although we must be cautious with serum data, increased IL-34 would help to control alloresponse during rejection and protect from graft lost. PMID- 27932125 TI - Survival Outcomes in Liver Transplantation With Elderly Donors: Analysis of Andalusian Transplant Register. AB - Recently, there has been a large discrepancy between the number of patients on the waiting list for a liver transplant and the availability of deceased donors, with an increase in annual wait list mortality rates. Elderly donor livers are thought to be marginal grafts; however, in recent years, their utilization has constantly increased. The aim of this study is to evaluate the utilization of elderly donors in Andalusia and post-transplant outcomes. This retrospective observational study of 2408 liver transplants, performed in Andalusia between 2000 and 2014, analyzes the outcomes from donors aged 70 plus (n = 423) in terms of survival rates of the graft and the recipient, the type of transplant, donor age, and D-MELD score (product of donor age and preoperative Model for End-stage Liver Disease score). The most frequent indications for transplant were alcoholic cirrhosis (49.2%), hepatitis C cirrhosis (13%), and hepatocellular carcinoma (12.5%). The overall survival at 5 years was 64%, with a significant fall in survival for recipients with a D-MELD greater than 1500 (57%; P = .045). In the 70-year-old-plus donor group, the overall patient survival was 58.4%. The retransplant rate increased proportionately with donor age. In the alcoholic cirrhosis recipient subgroup, the overall survival at 5 years was 67.6% (P < .05) compared with 33.5% in patients with hepatitis C. Use of elderly donors is a safe strategy to reduce the scarcity of donors, provided that a D-MELD score below 1500 is obtained. Retransplant rates increase progressively with donor age. It is necessary to carefully screen recipients of older organs, taking into account that the best results are obtained for alcoholic cirrhosis, negative viral load hepatitis C, and a D-MELD score below 1500. PMID- 27932124 TI - De Novo Donor-Specific Anti-Human Leukocyte Antigen Antibody Detection in Long Term Adult Liver Transplantation. AB - INTRODUCTION: Information about the consequences of de novo donor-specific anti human leukocyte antigen (DSA) antibody development in the long term after adult liver transplantation (LT) is scarce. We conducted a cross-sectional study in LT patients with a follow-up of at least 6 years. METHODS: A total of 28 adult LT patients were included, with a median follow-up of 77 months (range, 63 to 96) and without preformed anti- human leukocyte antigen (HLA) antibodies prior to LT. The anti-HLA identification was performed with LABScreen Single Antigen, whereas the ability to fix the complement was demonstrated with C1q test (One Lambda). In both assays, a value >3.500 mean fluorescence intensity (MFI) was considered positive. The anti-HLA antibody specificities were compared with donor HLA antigens to confirm them as DSA. Hepatic fibrosis was assessed by transient elastography. RESULTS: In 5 patients (17.8%), de novo DSA were detected, all them against DQ locus. In all of these cases (100%) the complement fixation was confirmed by C1q binding. The grade of hepatic fibrosis in de novo DSA patients was significantly higher compared with No-DSA patients (13.2 +/- 9.2 KPa vs 7.3 +/- 3.7 KPa; P = .02). It is noteworthy that in both groups of patients the levels of liver function tests (LFT) at the time of the study were normal or near the normal range with no difference between patients with or without de novo DSA. CONCLUSIONS: Our preliminary results are consistent with those previously demonstrated in pediatric LT, where de novo DSA production and humoral response could contribute to the liver fibrosis observed in the long term after LT in pediatric patients with normal or near-normal LFT. PMID- 27932127 TI - Recurrent Hepatocellular Carcinoma After Liver Transplantation: Analysis of Risk Factors. AB - BACKGROUND: Survival after orthotopic liver transplantation (LT) for hepatocellular carcinoma (HCC) is influenced by tumor recurrence. This study examines the survival of patients who underwent LT for HCC and developed recurrence of tumor after transplantation. METHODS: A retrospective analysis was performed of the 200 patients who underwent LT secondary to HCC from 1990 to 2014. We excluded 19 patients from the study owing to early postoperative deaths in the 1st month. We divided our sample into 2 groups according to the presence of recurrence. We performed a univariate analysis to identify variables that are significantly associated with the risk of recurrence. Afterward we use multivariate analysis regression analysis to find independent significance. RESULTS: Univariate analysis shows significant relationship between high Edmondson-Steiner grades (G3-G4) and the development of tumor recurrence. Tumor size, vascular invasion, and capsular invasion were found to be independent risk factors of tumor recurrence in the multivariate analysis. CONCLUSIONS: Tumor recurrence defines survival of patients who underwent LT for HCC. In this study we discuss which histologic factor are associated with higher risk of tumor recurrence, and therefore a negative the impact on patient's survival. PMID- 27932126 TI - Pretransplant CD28 Biomarker (Levels of Expression and Quantification of Molecules per Cell) in Peripheral CD4+ T Cells Predicts Acute Rejection Episodes in Liver and Kidney Recipients. AB - BACKGROUND: Acute rejection (AR) remains a significant cause of graft loss. Better approaches to predict AR are being investigated. Surface CD28 protein is essential for T-cell proliferation and survival as well as cytokine production. PATIENTS AND METHODS: Pretransplant CD4+CD28+ peripheral T cells were examined in 30 liver recipients (LRs) and 31 kidney recipients (KRs) by flow cytometry. RESULTS: Pretransplant CD4+CD28+ T cells in LRs were significantly lower in rejectors than nonrejectors (P = .002). Furthermore, the total number of CD28 molecules per cell in LRs (P = .02) as well as KRs (P = .047) was significantly lower in rejectors than nonrejectors. The healthy group did not display differences when compared with patients with end-stage liver disease or renal failure; however, stratification analysis displayed higher levels of CD4+CD28+ when compared with rejected LRs (P = .04) but not KRs. CD28 levels <41.94% were able to discriminate LRs at high risk of AR (P = .003). Similarly, a total number of CD28 molecules <=8359 (P = .031) in LRs and <=7669 (P = .046) in KRs correlated with high risk of AR. CONCLUSION: The preliminary results presented herein exhibit a fast and noninvasive method that assists clinicians to prevent AR by monitoring CD4+CD28+ peripheral T cells. PMID- 27932128 TI - Liver Transplantation Results by Donor Age. AB - OBJECTIVE: The objective of this study was to compare liver transplantation outcomes as a function of donor age. MATERIAL AND METHODS: We performed 212 liver transplantations between 2008 and 2014. We described a prospective cohort study and grouped the patients by liver donor age. We compared quantitative and categorical variables using statistical analysis. RESULTS: No statistically significant differences were found among any graft age groups in gender (always more males), time on waiting list, age, height, Child Pugh Turcotte (CHILD) score, Model for End-stage Liver Disease (MELD) score, need for intraoperative blood products, or intensive care unit stay. The most frequent etiology of liver failure was alcohol. A brain-dead donor was the most frequent type in all groups. The whole graft was used except in 4 cases. No statistically significant differences were found among groups in the surgical technique, postreperfusion syndrome, arterial complications, biliary complications, venous complications, acute rejection, and retransplantation. The 3-year patient survival rate was 64% in the <60-year graft age group, 48% in the 60- to 69-year group, 64% in the 70- to 79-year group, and 40% in the >=80-year group (P = .264). The 3-year graft survival rate was 62% in the <60-year graft age group, 47% in the 60- to 69-year group, 65% in the 70- to 79-year group, and 40% in the >=80-year group (P = .295). CONCLUSIONS: Given the need to increase the pool of liver donors, older donors should be considered as a source for liver transplantation, although careful selection is required. PMID- 27932129 TI - Predictors of Poor Prognosis in Recurrent Hepatitis C After Liver Transplantation. AB - BACKGROUND: Hepatitis C is a common indication for liver transplantation (LT). Hepatitis C virus (HCV) recurrence is universal in viremic patients. This recurrence is frequently very aggressive, with graft loss in less than 5 years. Our aim is to detect which factors are related to worse fibrosis at 1 year post LT. PATIENTS AND METHODS: Records of all HCV-positive transplanted patients in Hospital Universitario Nuestra Senora de la Candelaria from 1996 to 2014 were collected. The variables analyzed were donor and recipient age and gender, hypertension, diabetes, viral genotype, viral load at LT, hepatocellular carcinoma in the explant, anticoagulation or antiplatelet treatment, year of transplantation, and mean levels of tacrolimus in the first month. Severe recurrence was defined as fibrosis F3 by biopsy, liver stiffness > 9.5 kPa by transient elastography, or hepatic venous pressure gradient > 5 mm Hg at 1 year post-LT. Univariate and multivariate analyses were performed. RESULTS: From a sample of 112 patients, 88 patients met inclusion criteria. Mean recipient age was 52.8 +/- 8.0 years and 70.5% were men. Mean donor age was 46.4 +/- 16.1 years and 59.1% were men. Severe recurrence occurred in 23.9%. Univariate analyses showed 3 variables were statistically significant: donor age (P = .03), recipient age (P = .008), and presence of hepatocellular carcinoma (P = .01). Only the 2 first variables remained significant in the multivariate model (P = .009 and P = .044 respectively). Hepatocellular carcinoma was probably related to older recipients becoming a confounding factor. CONCLUSIONS: In our study, donor and recipient age both conferred a worse prognosis in terms of fibrosis progression in patients with liver transplant due to HCV. PMID- 27932130 TI - Acute Liver Failure Caused by Primary Non-Hodgkin's Lymphoma of the Liver. AB - INTRODUCTION: Acute liver failure (ALF) is a rare syndrome involving maximum liver dysfunction. This disease is characterized by a less than 26-week history of coagulopathy (INR >=1.5) and hepatic encephalopathy and generally occurs in patients without any previously known disease. METHODS: We report the case of a healthy 25-year-old subject who presented with fulminant liver failure caused by a primary non-Hodgkin's lymphoma of the liver that required emergency liver transplantation. Diagnosis was based on pathologic confirmation of T cell/histiocyte-rich large B-cell lymphoma and submassive hepatocyte necrosis. One year after surgery, the patient remains in complete remission. CONCLUSIONS: Fulminant liver failure is a sudden-onset severe disease that can be caused by a primary non-Hodgkin's lymphoma of the liver, which accounts for <1% of extranodal lymphomas. The diagnosis of this rare disease demands high diagnostic suspicion, and progression can be prevented through liver transplantation. PMID- 27932131 TI - T-tube Systematic Use in the Biliary Anastomosis: Comparison of Two Consecutive Series of Liver Transplantation. AB - OBJECTIVES: The authors sought to check the frequency of biliary complications with the use of a T-tube. In 2012, throughout the year, it was carried out systematically in all liver transplantations regardless of the characteristics of the bile duct. Despite the long experience, biliary complications remain a common cause of postoperative morbidity and mortality. MATERIAL AND METHODS: In this study we compared complications in 23 consecutive transplantation cases using T tube biliary anastomosis during the year 2012 with 23 consecutive transplantation cases without T-tube during the year 2013. We evaluated postoperative complications and long-term outcomes (for 2 years to 3 years). RESULTS: Of the 23 patients with anastomosis with a T-tube, 2 patients (8.69%) had biliary stricture that required prosthesis by endoscopic retrograde cholangiopancreatography, 1 of them (4.34%) was operated by incorrect placement of the T-tube, and in 4 patients (17.39%) bile leakage (endoscopic retrograde cholangiopancreatography prostheses in 3 cases and hepaticojejunostomy in 1). During follow-up at 3 years, only 2 patients had minimal bile duct dilatation without clinical relevance. In the patients who underwent transplantation without a T-tube, 18 (78.26%) had no complications, 3 (13.04%) showed stenosis (prosthesis placement), and 2 (8.69%) had bile leakage (hepaticojejunostomy and prosthesis). During follow-up at 2 years to 3 years, no patient had biliary dilatation or alteration of cholestatic parameters. In the comparative study of both groups we found no statistically significant differences. CONCLUSIONS: We have not seen an improvement in complications with the use of T-tube (69.56% vs. 78.23%) that encourage us to work systematically, although the small number of cases does not allow statistically significant conclusions. PMID- 27932132 TI - Collateral Development in Thrombosis of the Hepatic Artery After Transplantation. AB - OBJECTIVES: The authors sought to identify strictures or hepatic artery obstruction with posterior collateral transformation in our series of liver transplantation, treatment, and evolution. The thrombosis or severe hepatic artery stenosis sometimes presents a compensation mechanism, the collateral transformation of the artery. MATERIAL AND METHODS: From April 2002 to December 2011 we collected 18 cases of collateral transformation. We analyzed data regarding the transplantation, diagnosis, treatment, clinical evolution, liver function, and Doppler-ultrasound. RESULTS: The main indication was alcoholic cirrhosis, followed by hepatocellular carcinoma - hepatitis C virus. The mean cold ischemia time was 292.2 minutes mean hot ischemia was 48.8. The anastomosis was performed on the gastroduodenal-splenic patch donor in 14 cases, the celiac trunk in 2 cases, and on grafts to the aorta in another 2. Doppler ultrasound showed 8 cases without complications, 8 with low flows, and 2 cases with alterations of the right hepatic artery. Computed tomographic (CT) angiography was performed in patients with impaired eco-Doppler and found 4 obstructions, 2 cases with kinking, 1 stenosis, and 3 normal cases. Three patients with low flows were re-operated and another re-transplanted. After diagnosis of collateral transformation, all were treated with antiplatelet agents. Two cases of angioplasty were associated. The collaterals were diagnosed 1 month to 44.8 months after transplantation. Five patients died. In the latest data, 10 patients do not have analytical alteration. The Doppler ultrasound shows 7 cases being normal and 6 with flow but low resistances. CONCLUSIONS: In our series, all patients with collateral transformation, except one who was transplanted, maintain good liver function with permeable vessels. PMID- 27932133 TI - Metabolic Syndrome After Liver Transplantation: Five-Year Prevalence and Risk Factors. AB - Survival after orthotopic liver transplantation (OLT) has increased over the last decades, focusing on the metabolic complications that contribute to patient morbidity and mortality. The aim of our study was to describe the prevalence of metabolic syndrome (MS), its components, and its associated factors in patients who underwent OLT in a hospital in Spain. From November 2001 to January 2014, we performed 415 transplantations in 386 patients. We analyzed 204 patients with a minimum follow-up of 1 year (77.6% were male and the mean age was 54.2+/-9.5 years). The most frequent etiology was alcohol (41%), followed by hepatitis C virus (29.1%). The indication was decompensated cirrhosis in 51.8% and hepatocellular carcinoma in 34%. According to modified National Cholesterol Education Program-Adult Treatment Panel-III (NCEP-ATP III) criteria, 5 years post transplantation MS was diagnosed in 38.2% of patients. Significant independent predictors of post-transplantation MS on logistic regression analysis were as follows: pretransplantation obesity (odds ratio [OR], 3.09; P = .056), 1-year post-transplantation obesity (OR, 3.95; P = .009), pretransplantation diabetes (OR, 4.63; P = .001), 1-year post-transplantation diabetes (OR, 3.01; P = .015), 1-year post-transplantation hypertension (OR, 1.85; P = .176), and hypertriglyceridemia at the first year after transplantation (OR, 2.32; P = .063). In our center the prevalence of MS at 5 years after OLT is slightly lower than published. The most important risk factors were obesity and diabetes (both pretransplantation and the first year post-transplantation). PMID- 27932134 TI - Efficacy and Safety of Therapy With Simeprevir and Sofosbuvir in Liver Transplant Recipients Infected by Hepatitis C Virus Genotype 4: Cohort Spanish Society of Liver Transplantation Cohort. AB - BACKGROUND: Patients with hepatitis C virus (HCV) genotype 4 infection are poorly represented in clinical trials of 2nd-generation direct-acting antivirals (DAAs), and more data are needed to help guide treatment decisions. We still have even fewer data concerning liver transplant patients. Simeprevir (SIM) and sofosbuvir (SOF) combination is useful to treat this genotype. The aim of this study was to know the efficacy and safety of the combination SIM + SOF +/- ribavirin (RBV) in a group of liver transplant patients with HCV genotype 4 infection in Spain in real life. METHODS: This was a multicenter retrospective study, including 28 HCV genotype 4 patients from 11 liver transplant centers who were treated with SIM + SOF +/- RBV. We included in the analysis demographic, clinical, and virologic data and details of serious adverse events (SAEs), including mortality rate 6 months after treatment. RESULTS: All patients were male, mean age 52 +/- 9.43 years, and 50% were IL28B CT and 37.5% TT; 46.42% of them were pretreated and 76.9 were null responders. Fibrosis stage 4 was found in 38.7% of patients; in 67.8% of those cases the diagnosis of fibrosis was made with the use of Fibroscan, in 21.4% by liver biopsy. The average Fibroscan was 13.86 KPa. The average Model for End-Stage Liver Disease (MELD) score of cirrhotic patients was 10.9 and the Child-Pugh score was A in 70%, B in 20%, and C in 10%. We included RBV in 75% of patients, and treatment duration was 12 weeks in all patients. The sustained virologic response at week 12 (SVR12) was 95.23%. There were no discontinuations due to SAEs, but the mortality rate at 6 months after treatment was 7.14%. All deceased patients were cirrhotic, Child C, and with an average MELD score of 20. CONCLUSIONS: The combination SIM + SOF +/- RBV to treat HCV genotype 4 in liver transplant patients is an option with high rates of SVR12 and very safe, similarly to genotype 1. There was no treatment-related mortality, but when it is administered in advanced stages of fibrosis it may not be enough to prevent mortality associated with cirrhotic hepatitis C recurrence after transplantation. PMID- 27932135 TI - Influence of Body Mass Index on Venous Thrombotic Complications of Liver Transplants. AB - OBJECTIVE: To analyze venous thrombotic complications in transplanted patients as a function of their body mass index (BMI). MATERIALS AND METHODS: This single center, observational retrospective study of individuals undergoing liver transplantation between January 2008 and December 2014 analyzed the frequency of pretransplant portal thrombosis, post-transplant venous complications (early and late portal thrombosis), deep vein thrombosis, pulmonary thromboembolism and the survival outcomes as a function of World Health Organization BMI class. RESULTS: Liver transplantation was performed in 208 patients during the study period. No statistically significant differences in study variables were found as a function of BMI in bivariate analyses (P < .05), and Kaplan-Meier survival analysis results were also nonsignificant. CONCLUSION: No differences in the rate of venous thrombotic complications or survival were found as a function of the BMI class of these liver transplant recipients. These findings are in line with previous reports that complication rates are not higher in obese patients and support the proposal that obesity should not be considered a contraindication for liver transplantation based on the risk of venous complications. PMID- 27932136 TI - Prognostic Value of High-Sensitivity Troponin-T to Identify Patients at Risk of Left Ventricular Graft Dysfunction After Heart Transplantation. AB - Primary graft dysfunction after heart transplantation (HTx) has a very high mortality rate, especially if the left ventricle (PGD-LV) is involved. Early diagnosis is important to select the appropriate therapy to improve prognosis. The value of high-sensitivity troponin T (HS-TNT) measurement obtained at patient arrival at the intensive care unit was analyzed in 71 HTx patients. Mild or moderate PGD-LV was defined by hemodynamic compromise with one of the following criteria: left ventricular ejection fraction <40%, hemodynamic compromise with right atrial pressure >15 mm Hg, pulmonary capillary wedge pressure >20 mm Hg, cardiac index <2.0 L/min/m2, hypotension (mean arterial pressure <70 mm Hg), and need for high-dose inotropes (inotrope score >10) or newly placed intra-aortic balloon pump. The mean recipient age was 54 +/- 12 years (73% men), and donor age was 47 +/- 11 years. Ischemic time was 200 +/- 51 minutes, and coronary bypass time was 122 +/- 31 minutes. Nine (13%) HTx patients were diagnosed with PGD-LV post-HTx, 8 with biventricular dysfunction. Four patients died, 2 with PGD-LV (22%) and 2 without PGD (4%). Mean HS-TNT before HTx was 158 +/- 565 ng/L, and post-HT was 1621 +/- 1269 ng/L. The area under the curve (receiver-operator characteristic) of HS-TNT to detect patients at risk of PGD-LV was 0.860 (P < .003). A cutoff value of HS-TNT >2000 ng/L had a sensitivity of 75% and specificity of 87% to identify patients at risk of PGD-LV. Multivariate analysis identified HS-TNT >2000 ng/L (P < .02) and coronary bypass-time (P < .01) as independent predictors of PGD-LV. HS-TNT >2000 ng/L at intensive care admission after HT and prolonged coronary bypass time were the most powerful predictors of PGD-LV. HS-TNT may be helpful for early detection of HTx patients at risk of PGD LV. PMID- 27932137 TI - Quality of Life According to Urgency Status in De Novo Heart Transplant Recipients. AB - INTRODUCTION: Elective heart transplantation (HTX) aims to improve physical ability, increase survival, and improve health-related quality of life (HRQoL) in patients with chronic heart failure. Nevertheless, most patients who undergo urgent HTX are previously healthy, and a transplant could be perceived as a limitation. The aim of this study is to compare HRQoL between elective and urgent heart transplant recipients. METHODS: Cohort study including patients undergoing heart transplantation between January 1998 and March 2012 in a single center. Patients with retransplantation or multiorgan transplantation were excluded. Clinical variables including comorbidities were collected. For assessment of HRQoL, the Kansas City Cardiomyopathy Questionnaire (KCCQ) was completed by the survivors on March 2013. Univariate analysis (Mann-Whitney U test) was performed. RESULTS: Questionnaires were collected from 95 of 106 elective recipients and 28 of 33 urgent recipients. Urgent heart recipients were younger, with more cardiovascular risk factors, and ischemic etiology was the leading cause of transplant. All domain results were higher in elective heart transplant recipients, but after univariate analysis only the punctuation of the self efficacy domain remained superior in the elective HTX group (87.5 vs 79.7, P = .034). CONCLUSION: Both urgent and elective heart transplant patients reported a good HRQoL, and there were no significant differences between their scores. PMID- 27932138 TI - Potential Immunomodulatory Role of Specific Anticytomegalovirus Intravenous Immunoglobulin in Heart Recipients. AB - BACKGROUND: Specific anticytomegalovirus (anti-CMV) intravenous immunoglobulin (IVIG) has the potential to influence the immune response, but its complex mode of action has not been well evaluated. METHODS: An immunologic study of 6 CMV seronegative heart transplant patients receiving anti-CMV prophylaxis with the use of ganciclovir and CMV-IVIG (150 mg/kg within 24 hours after transplantation and 100 mg/kg on days 2, 7, 14, 22, 35, 56, and 77 after transplantation) was performed in a single center. Lymphocyte subsets were evaluated by means of 4 color flow cytometry at the time of inclusion in the waiting list and at 3 months after transplantation. RESULTS: High-risk heart recipients receiving CMV-IVIG showed a clear reduction in the frequency of activated CD4+CD38+DR+ T-helper cells at 3 months after transplantation compared with a group of 27 untreated control subjects who received only anti-CMV prophylaxis with the use of ganciclovir. In this study, an increase of CD19+CD27-IgM+IgD+ naive B cells was also observed in seronegative recipients after prophylaxis with the use of CMV IVIG but not in control subjects. None of the CMV-IVIG-treated recipients developed acute cellular rejection during the 1st 6 months after transplantation. CONCLUSIONS: The immune modulation of activated CD4+ lymphocyte and of naive B cell subsets after CMV-IVIG use should be further evaluated in future prospective studies with higher numbers of patients. PMID- 27932139 TI - De Novo Anti-HLA Antibodies After Heart Transplantation Are Associated With Adverse Events in the Long-term Follow-up of Cardiac Transplant Recipients. AB - BACKGROUND AND OBJECTIVES: Long-term morbidity and mortality after heart transplantation (HTx) remain very high. Several reports have suggested that anti HLA antibodies (anti-HLA-AB) detected after HTx might be associated with poor survival, but the implication of isolated anti-HLA-AB is still under debate. The aim of the study was to analyze the incidence of de novo anti-HLA-AB and whether they are associated with adverse events after HTx. METHODS: This retrospective study analyzed the presence of anti-HLA-AB assessed by fluorimetry (Luminex) and quantified by a single-antigen bead assay in 119 HTx patients. Mortality, graft dysfunction, antibody-mediated rejection (AMR), and cardiac allograft vasculopathy (CAV) were recorded. Cardiovascular mortality of patients with and without anti-HLA-AB was compared according Kaplan-Meier curves. Cox regression analyses were performed to identify predictors for global mortality and for a combined endpoint (cardiovascular mortality, AMR, and CAV). Mean age of recipients and donors was 49 +/- 15 and 38 +/- 14 years, 70% were men, 29% were urgent transplants, and mean ischemic time was 195 +/- 56 minutes. RESULTS: Anti HLA-AB were detected in 23 patients (19%). These patients had higher rates of AMR (39% vs 1%; P < .05) and cardiovascular mortality (17% vs 2%; P < .05). By multivariate analysis, anti-HLA-AB were the only predictor of the combined endpoint (hazard ratio 3.1; confidence interval 1.3 to 7.5; P = .01). Kaplan Meier curves showed the worse cardiovascular survival of patients with anti-HLA AB (72% vs 97%; P = .003). CONCLUSIONS: Presence of anti-HLA-AB identifies a group of HTx patients with worse prognosis. Better understanding of the immunologic relevance of anti-HLA-AB is expected to improve long-term survival after HTx. PMID- 27932140 TI - Influence of Donor and Recipient Ages in Survival of Simultaneous Pancreas-Kidney Transplantation. AB - INTRODUCTION: Simultaneous pancreas-kidney transplantation (SPKT) is a well treatment for patients with insulin-dependent diabetes and end-stage renal disease. Donor age is a barrier to the acceptance of organs. Age matching has been extensively studied in kidney transplantation; however, there are no studies in graft survival after SPKT. We aimed to study the combined influence of the ages of the donors and recipients in graft survival after SPKT. MATERIAL AND METHODS: Donors and recipients are classified as younger (age <40 years) or older (age >=40 years). There were four study groups (young-young, young-old, old young, and old-old). They were evaluated retrospectively for demographic and clinical characteristics of donors and recipients and the long-term survival between 2001 and 2012 of kidney pancreas transplantation patients at our center. RESULTS: A total of 115 transplantations were performed. The four groups had 55 young-young, 40 young-old, 10 old-young, and 10 old-old patients. Serious complications occurred in 32%, 42%, 30%, and 40%, respectively, and deaths were 2%, 5%, 0%, and 20%, respectively, in the groups. Pancreas graft survival at 3 years for each group was 80%, 87, 5%, 90%, and 60%, respectively, and kidney graft survival was 92.7%, 90%, 90%, and 70%, respectively. Panel-reactive antibodies (PRAs) >30% were associated with poor graft survival, and serious postoperative complications associated with poor pancreas-kidney graft survival. CONCLUSIONS: In conclusion, both younger and older recipients show excellent long term graft and patient survival after SPKTs from younger donors. We recommended that older-recipient SPKT be transplanted from younger donors because older recipients who have been transplanted from older donors had decreased survival. PMID- 27932141 TI - Validation of the Pancreatic Donor Risk Index in Simultaneous Pancreas-Kidney Transplantation Performed in Cordoba Hospital From 2000 to 2015. AB - BACKGROUND: The Pancreatic Donor Risk Index (PDRI) was developed in 2010 in the United States to predict graft survival after pancreas transplantation, based on donor characteristics and logistical and technical conditions. The aim of the study was to validate the utility of PDRI as a pancreas allograft survival predictor in simultaneous pancreas-kidney transplantation (SPK) transplants performed in our hospital between 2000 and 2015. METHODS: This retrospective analysis of 126 SPK transplants was performed by the same surgical team from the years 2000 to 2015. Donor variables that are integrated in the PDRI were calculated (age, sex, race, creatinine serum levels, body mass index, height, cold ischemia time, cause of death, type of pancreas transplant). Pancreatic graft survival at 1 and 5 years was calculated by use of the Kaplan-Meier test. Comparison of survival curves between PDRI risk quartiles was calculated by use of the log-rank test. Association between graft survival and variables integrating the PDRI was calculated by use of univariate Cox regression analysis. RESULTS: Log-rank analysis found no statistically significant association between global graft survival and PDRI quartiles. Univariate Cox regression analysis showed a statistically significant association between graft survival and cold ischemia time (P < .05). CONCLUSIONS: PDRI was not a useful tool to predict pancreatic graft outcomes in a Spanish reference population. PMID- 27932142 TI - Pancreas Preservation With Viaspan, Celsior, and Custodiol Solutions: An Initial Experience. AB - BACKGROUND: There is still controversy about which preservation solution in pancreas transplantation could be the best. The aim of this study was to analyze our initial experience with Custodiol solution (CuS) compared with Viaspan solution (VS) and Celsior solution (CS) in pancreas transplantation. METHODS: A retrospective study included 94 consecutive pancreatic transplants, from 2007 until 2015. We compared 3 groups, depending on preservation solution: Viaspan (n = 41), Celsior (n = 40), or Custodiol (n = 13). The primary end point was patient and pancreas survival at 1 year after pancreas transplantation. RESULTS: The recipient and donor characteristics were similar except in cold ischemia time; it was higher with Celsior. No differences were found in postoperative complications and pancreas graft function at 3 months, 6 months, and 1 year (glucose, HbA1c, C peptide, creatinine). The pancreas and patient survival at 1 year was comparable (pancreas survival: VS, 80%; CS, 90%; CuS, 92%; log-rank, 0.875; and patient survival: VS, 92%; CS, 97%; CuS, 100%; log-rank, 0.9). CONCLUSIONS: In our institution, the Custodiol solution in pancreas transplantation presented similar outcomes in terms of postoperative complications, pancreas graft function, and 1 year survival. PMID- 27932143 TI - Report From the First and Second Spanish Killer Immunoglobulin-Like Receptor Genotyping Workshops: External Quality Control for Natural Killer Alloreactive Donor Selection in Haploidentical Stem Cell Transplantation. AB - An important factor affecting the success in the setting of related haploidentical hematopoietic stem cell transplantation (HSCT) is the graft-versus leukemia effect mediated by natural killer (NK) cells when the donor displays NK alloreactivity versus the recipient. NK cell function is regulated by killer immunoglobulin-like receptors (KIR) and it has been described that donor KIR genotype influences transplantation outcome. This has led to a requirement of laboratories to have a quality assurance program for validation and control of their KIR genotyping methods. The goal of the 1st and 2nd Spanish KIR Genotyping Workshops was to provide an external proficiency testing program in KIR genotyping for Spanish immunology and transplant laboratories. These workshops were conducted during the years 2014-2016 and consisted of 17 participating laboratories typing a set of 20 samples. The presence/absence of 16 mandatory KIR loci (2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 2DP1, 3DL1, 3DL2, 3DL3, 3DS1, and 3DP1) was evaluated per sample. Methods for KIR genotyping included polymerase chain reaction with the use of sequence-specific primers and sequence-specific oligoprobes. Consensus typing was reached in all samples, and the performance of laboratories in external proficiency testing was satisfactory in all cases. The polymorphism detected in the small sample studied in both workshops is indicative of an ample variety of KIR gene profiles in the Spanish population. PMID- 27932145 TI - Establishing the Number of Procedures for Optimal Renal Transplantation Training With the Use of a Canine Model. AB - BACKGROUND: The training of surgeons that perform renal transplantations can be diverse. For example, the training profile can vary greatly, involving urologists to general surgeons. The efficacy of training programs directed at transplantation surgeons is influenced by numerous factors, including the specialist profile who is trained, the number of procedures available to trainees in a given teaching hospital, and the duration of training. Here we determine the number of procedures necessary to consolidate and contribute to proficiency in renal transplantation technique. METHODS: We used a canine model, comparing 32 renal transplantations performed by a urologist and by a general surgeon who had completed their respective training in renal transplantation. RESULTS: Our results demonstrated that with 12 surgical procedures, surgeons were able to consolidate their skills in renal transplantation, regardless of their educational background. CONCLUSIONS: This is an initial effort in the establishment of a system for targeted training of transplantation surgeons directed specifically at correcting deficiencies and consolidating skills acquired during training programs. These efforts should contribute to the improvement of patient safety in public and private health systems. PMID- 27932144 TI - Inhibition of JAK3 and PKC via Immunosuppressive Drugs Tofacitinib and Sotrastaurin Inhibits Proliferation of Human B Lymphocytes In Vitro. AB - BACKGROUND: Antibody-mediated response in solid organ transplantation is critical for graft dysfunction and loss. The use of immunosuppressive agents partially inhibits the B-lymphocyte response leading to a risk of acute and chronic antibody-mediated rejection. This study evaluated the impact of JAK3 and PKC inhibitors tofacitinib (Tofa) and sotrastaurin (STN), respectively, on B-cell proliferation, apoptosis, and activation in vitro. METHODS: Human B cells isolated from peripheral blood of healthy volunteers were cocultured with CD40 ligand-transfected fibroblasts as feeder cells in the presence of interleukin (IL) 2, IL-10, and IL-21. The cocultures were treated with immunosuppressants Tofa, STN, and rapamycin (as a control), to analyze the proliferation and apoptosis of B cells by means of Cyquant and flow cytometry, respectively. CD27 and IgG staining were applied to evaluate whether treatments modified the activation of B cells. RESULTS: Tofa and STN were able to inhibit B-cell proliferation to the same extent as rapamycin, without inducing cell apoptosis. After 6 days in coculture with feeder cells, all B cells showed CD27 memory B cell phenotype. None of the immunosuppressive treatments modified the proportion between class-switched and non-class-switched memory B cells observed in nontreated cultures. The high predominance of CD27+CD24+ phenotype was not modified by any immunosuppressive treatment. CONCLUSIONS: Our results show that Tofa and STN can suppress B-cell antibody responses to an extent similar to rapamycin, in vitro; therefore these compounds may be a useful therapy against antibody-mediated rejection in transplantation. PMID- 27932146 TI - Organ Donation After Euthanasia in the Netherlands: A Case Report. AB - In 2014, there was still a shortage of available organs for transplantation, and 1044 patients were waiting for an organ in the Netherlands. Maximizing the pool of organ donors is part of the solution. In 2001, the Dutch Termination of Life on Request and Assisted Suicide Act was adopted, legalizing euthanasia under strict conditions. In 2010, 3136 reports were made of euthanasia and assisted suicide; in 2014, 5306 reports were made. Among them were patients with a desire to donate their organs after their deaths. Although a potential source of donor organs, only a few cases of organ donation after active euthanasia have been described. Since 2012, 16 combinations of these procedures have been performed in the Netherlands. The literature mentions 16 Belgian cases between 2005 and 2013. This limited number can be the result of lack of knowledge about this subject among healthcare professionals or because of practical, ethical, and/or legal considerations. Performing this combination has possible advantages, both in number as well as in transplantation outcomes. By describing a recent case in our center, we will try to outline the state of the art in the Netherlands and disseminate knowledge about the possibilities and limitations of organ donation after active euthanasia. PMID- 27932147 TI - Case Report Demonstrating the Safe and Effective Means of Expanding the Donor Pool With Livers Recovered From Brain-Dead Donors After Ethylene Glycol Toxicity. AB - The growing disparity between organ supply and demand has become the greatest hurdle facing transplant professionals and life-saving transplants. Because the organ shortage has become the rate-limiting step to effective transplants, it is critical for the transplant community to identify viable mechanisms to expand the donor pool and use every available allograft. Although using kidneys from deceased donors whose demise was secondary to ethylene glycol (EG) toxicity requires great deliberation and precise timing as described by Barbas et al [5], using hepatic allografts in this setting involves far less risk. The following is a discussion of a 61-year-old male who was diagnosed with end-stage liver disease secondary to non-alcoholic steatohepatitis and ultimately underwent a life-saving transplant with a liver recovered from a donor with EG-induced brain death and allocated nationally due to trepidation by local and regional centers to use the liver from a donor after EG toxicity. PMID- 27932148 TI - Low-dose Spinal Block With Continuous Epidural Infusion for Renal Transplantation in a Patient With Alport Syndrome: A Case Report. AB - OBJECTIVE: We aim to describe management of a patient receiving renal transplantation for chronic renal failure due to Alport syndrome with low dose of intrathecal bupivacaine and continuous epidural infusion of local anesthetic. CASE REPORT: A 38-years-old man with chronic renal failure secondary to Alport syndrome underwent kidney transplantation. Because of a high risk of respiratory and cardiovascular complications related to the patient's baseline lung disease and abnormalities in heart conduction, we selected combined spinal-epidural anesthesia. The block was ultrasound-guided and performed at the T12-L1 interspace with 4.5 mg of 0.5% intrathecal hyperbaric bupivacaine followed by a continuous epidural infusion of 0.5% levobupivacaine mixed with 25 MUg of Fentanyl at the initial rate of 8 mL/h. Sensory block to T5-T6 was obtained within 10 minutes. The patient then received mild sedation with Propofol and Remifentanil. Methylprednisolone and diuretics were administered before vascular unclamping according to our internal protocol. Surgery lasted 3 hours with no clinical or procedural complication. CONCLUSIONS: Although renal transplantation is usually performed under general anesthesia, in a particularly complex patient with chronic renal failure, chronic obstructive pulmonary disease and a worsened respiratory mechanics, we applied a combined approach with a low dose of intrathecal bupivacaine and continuous epidural infusion of local anesthetic. The technique did not affect hemodynamics while having a positive impact on recovery of function of the transplanted organ with rapid improvement of urine output, serum creatinine, and blood urea nitrogen levels. PMID- 27932149 TI - Portal Vein Inflow From Enlarged Coronary Vein in Liver Transplantation: Surgical Approach and Technical Tips: A Case Report. AB - Portal vein thrombosis is common in patients with end-stage liver disease, with an incidence as high as 26% in liver transplant candidates. It is known to be associated with a high risk of morbidity and mortality posttransplantation, and its management can be challenging. The management options range from a simple thrombendvenectomy to multivisceral transplantation in cases with diffuse portomesenteric thrombosis. We report a case of liver transplantation in which we performed a rare reconstruction of the portal vein. Briefly, the patient had diffuse portomesenteric thrombosis, calcified aneurysmosis, and a large collateral coronary vein, to which we directly anastomosed the donor portal vein in an end-to-side fashion. This report describes a unique surgical approach for similar cases of severe portal vein thrombosis in liver transplant candidates. PMID- 27932150 TI - Real-time Intraoperative Fluorescent Lymphography: A New Technique for Lymphatic Sparing Surgery. AB - BACKGROUND: Many surgical procedures can produce persistent lymphorrhea, lymphoceles, and lymphedema after lymph node and lymph vessel damage. Appropriate visualization of the lymphatic system is challenging. Indocyanine green (ICG) is a well-known nontoxic dye for lymphatic flow evaluation. ICG fluorescence-guided lymphography has emerged as a promising technique for intraoperative lymphatic mapping. OBJECTIVE: Our goal was to develop a high spatial resolution, real-time intraoperative imaging technique to avoid or recognize early deep lymphatic vessel damage. METHODS: We intraoperatively performed ICG fluorescence-guided lymphography during a kidney transplant. ICG was injected in the subcutaneous tissue of the patient's groin in the Scarpa's triangle. A dedicated laparoscopic high-definition camera system was used. RESULTS: Soon after ICG injection, the lymphatic vessels were identified in the abdominal retroperitoneal compartment as fluorescent linear structures running side by side to the iliac vessels. Surgical dissection was therefore performed, avoiding iatrogenic damage to major lymphatic structures. Another ICG injection at the end of the procedure confirmed that the lymphatic vessels were intact without lymph spread. CONCLUSIONS: Intraoperative lymphatic mapping with an ICG fluorescence-sensitive camera system is a safe and feasible procedure. ICG real-time fluorescence lymphography can be used to avoid or recognize early deep lymphatic vessel damage and reduce postoperative complications related to the lymphatic system. PMID- 27932151 TI - Kidney Transplantation With Ultralong-Term (42 Years) Survival of a 100-Year-Old Graft. AB - BACKGROUND: In kidney transplantation, long-term graft survival has improved over the last few decades. Study to understand ultralong-term graft survival with graft functioning is rare, but a few researchers have tried to explain the factors involved in long-term graft survival. In this report, we explore the predictive factors that can be involved in ultralong-term graft survival. MATERIAL AND METHODS: Immunologic evaluations of the patients were performed using crossmatch (XM), serological, and high-resolution HLA typing for 8 loci. A transplant recipient was treated with azathioprine as immunosuppressive monotherapy for 42 years. Donor-specific antibodies (DSAs) were identified using panel reactive antibody single antigen beads (PRA-SAB) followed by EpVix and Matchmaker epitope analysis to define the immunogenic mismatch eplets. RESULTS: The patient and donor were haploidentical for 7 loci and identical at the HLA DPA1* locus. Among 61 identified eplet mismatches, DSAs were not detected against 59 eplets after 42 years of exposure to the patient's immune system with the exceptions of antibodies against the public eplets 9Y and 9YL from allele HLA DPB1*03:01, and the transplanted kidney exhibited preserved structures. CONCLUSION: The transplanted kidney has the preserved structure based on magnetic resonance imaging, the 2 DSAs were not deleterious to the graft until now, and the eplet mismatches were considered acceptable. The patient is in good clinical condition living with a 100-year-old graft, a serum creatinine level of 1.5 mg/dL, and an estimated glomerular filtration rate of 50 mL/1.72 m2. PMID- 27932152 TI - Successful Second Allogeneic Stem Cell Transplantation From a Sibling Donor for Relapse of Myelodysplastic Syndrome in a Recipient of a Renal Transplant From His Mother: Case Report. AB - There have been few reports on allogeneic stem cell transplantation in patients who have previously undergone solid organ transplantation. The clinical course of such patients is not yet well recognized. Therefore, appropriate immunosuppressive prophylaxis for the rejection of a solid organ graft or for graft-versus-host disease has not yet been established. We present the case of a successful allogeneic stem cell transplantation in a patient who relapsed after a first allogeneic stem cell transplantation for myelodysplastic syndrome and who had previously undergone renal transplantation. The prophylaxis in this case for graft-versus-host disease and rejection of the transplanted kidney was mycophenolate mofetil and tacrolimus. No hyperacute rejection of the transplanted kidney was observed. However, the patient's renal function deteriorated after the cessation of the mycophenolate mofetil and the reduction of the tacrolimus. This deterioration seemed to be due to rejection with humoral immunity of donor lymphocytes, and we were able to control it by resuming the mycophenolate mofetil and local graft irradiation. PMID- 27932153 TI - A Heartbreaking Renal Transplantation: Is Norepinephrine the Culprit to Blame? AB - INTRODUCTION: Takotsubo cardiomyopathy (TCM), also known as "broken heart syndrome," "apical ballooning syndrome," and "stress-induced cardiomyopathy," was first described in Japanese patients in 1990 by Sato et al. TCM is an increasingly recognized syndrome characterized by transient and reversible systolic dysfunction of the apical and middle segments of the left ventricle. This syndrome resembles acute myocardial infarction in the absence of evident coronary artery occlusion. Herein, we present a case of a 51-year-old male who underwent his second deceased-donor renal transplantation for end-stage-renal disease due to a work-related accident. Perioperatively, initiation of continuous infusion of noradrenaline was decided to achieve adequate graft perfusion due to persistently low blood pressure. On the second postoperative day, the patient experienced tachycardia and atypical angina-like chest pain. Electrocardiogram (ECG) showed signs of myocardial infarction and elevated troponin levels were observed. Urgent coronary angiography was normal and transthoracic echocardiography (TEE) was indicative for Takotsubo cardiomyopathy. DISCUSSION: Although, the precise pathophysiology of Takotsubo cardiomyopathy is still unknown, it seems that it is associated with excessive sympathetic stimulation, microvascular dysfunction, coronary artery vasospasm, and abnormal myocardial tissue metabolism. The development of patient's symptoms after the initiation of norepinephrine along with their immediate resolution after the discontinuation of the drug might suggest a causal relationship. This is the first time that TCM after renal transplantation is thought to be linked with the administration of exogenous catecholamines. PMID- 27932154 TI - Successful Preemptive Kidney Transplantation With Rituximab Induction in a Patient With Focal Segmental Glomerulosclerosis and Massive Nephrotic Syndrome: A Case Report. AB - Primary focal segmental glomerulosclerosis (FSGS) recurs in 30% of patients receiving their first kidney transplant and often leads to graft loss. In the past, patients with FSGS and overt nephrotic syndrome rarely underwent transplantation. Rituximab (RTX), an anti-CD20-specific monoclonal antibody, was previously reported to be a valuable option in treating relapsing FSGS after kidney transplantation. We report here the first successful kidney transplantation in a young patient with primary FSGS and massive nephrotic syndrome treated with RTX induction. The patient was a 24-year-old woman who had developed nephrotic syndrome at the age of 4 years. FSGS was confirmed by results of a kidney biopsy, with subsequent treatment with cyclosporine and steroids, without remission. She was referred for a preemptive, deceased donor kidney transplant despite proteinuria levels reaching ~10 g/d. She received induction therapy with 2 doses of RTX (375 mg/m2) at days 0 and 7, followed by tacrolimus 5 mg twice daily, mycophenolate mofetil 500 mg twice daily, and steroids after transplantation. Immediate kidney graft function was observed, with no proteinuria since day 13 posttransplant. The pretransplant soluble urokinase-type plasminogen activator receptor serum concentration was 4550 pg/mL; it decreased to 2191 pg/mL at day 13 and was 2073 pg/mL at 6 months' posttransplant. Thirty months after transplantation, the patient's serum creatinine level is 0.8 mg/dL, and no proteinuria has been observed. Successful kidney transplantation in a patient with pretransplant overt nephrotic syndrome secondary to FSGS, using rituximab as an induction therapy, is possible. Further recommendations for transplantation in such patients, however, should be based on results from larger clinical trials. PMID- 27932155 TI - Late Allograft Renal Vein Thrombosis Treated With Anticoagulation Alone: A Case Report. AB - BACKGROUND: Allograft renal vein thrombosis is a rare complication of kidney transplantation. Most cases occur in the first 2 weeks after transplantation, but there are cases described many years after the transplant surgery. Allograft loss is the usual outcome. METHODS: We present a case of a renal transplant recipient with allograft renal vein thrombosis associated with deep venous thrombosis of a lower limb, 9 years after transplantation. He was successfully treated with anticoagulation alone, with recovery of allograft function. RESULTS: The patient was given unfractioned heparin and elastic compression stockings. Five days later, the patient recovered diuresis and hemodialysis treatment was discontinued. Doppler ultrasound was done and revealed partial re permeabilization of allograft renal vein, with maximal velocity of 15 cm/s. After 30 months of follow-up, the patient was maintained on oral anticoagulation with warfarin, and no thromboembolic or hemorrhagic events were documented. The patient's serum creatinine was stable, between 1.6 and 1.8 mg/dL. CONCLUSIONS: Our patient demonstrated that anticoagulation alone and dialytic support might be able to promote total recovery of allograft function after renal vein thrombosis. PMID- 27932156 TI - Dosing Eculizumab for Antibody-Mediated Rejection in Kidney Transplantation: A Case Report. AB - Severe antibody-mediated rejection (AMR) of a blood type-incompatible (ABOi) living donor kidney transplantation (LDKT) can lead to graft failure, and aggressive therapies, such as the anticomplement antibody eculizumab, are often used to rescue the affected graft. Eculizumab therapy can be crippling financially. Current literature suggests a wide variation in the amount and timing of eculizumab given as rescue therapy in the setting of AMR. Herein we describe a limited-eculizumab regimen in the setting of severe AMR that is both clinically and cost effective. Treatment included escalation in plasmapheresis and intravenous immunoglobulin (PP/IVIg) and eculizumab. Eculizumab therapy was discontinued at the first sign of clinical improvement (2-fold decrease in anti ABO titer and stabilization of serum creatinine). The current standard of care is to redose eculizumab after any PP treatment, and, in some series, continue with maintenance eculizumab doses. In these 2 cases, discontinuing eculizumab therapy upon observed clinical improvement saved 6 unnecessary doses at a cost of $90,000. Both patients have more than 1 year of follow-up and functioning allografts. Although this is a small and limited study, we suggest that a dosing regimen of eculizumab similar to that presented here may be effective in rescuing a graft following AMR while simultaneously limiting cost. PMID- 27932157 TI - Belatacept and Eculizumab for Treatment of Calcineurin Inhibitor-induced Thrombotic Microangiopathy After Kidney Transplantation: Case Report. AB - Thrombotic microangiopathy (TMA) after kidney transplantation is an uncommon and challenging cause of graft dysfunction and is associated with early graft loss. An idiosyncratic endothelial reaction to calcineurin inhibitors (CNIs) has been implicated as a frequent cause of TMA. This reaction is marked by uncontrolled activation of complement and subsequent cellular destruction. Usual therapy consists of withdrawal of the inciting drug and plasmapheresis to minimize levels of circulating complement. Recently, eculizumab, a monoclonal antibody to complement component C5, has been used for the treatment of atypical hemolytic uremic syndrome. Belatacept, an inhibitor of T cell costimulatory protein CTLA-4 has been used in immunosuppression strategies aimed at minimization of CNI. Here we report the first case of treatment of CNI-associated TMA/hemolytic uremic syndrome with withdrawal of tacrolimus and initiation of both belatacept and eculizumab. The case describes a favorable clinical course for both graft and patient, and is accompanied by a review of the literature. PMID- 27932158 TI - Everolimus and Advagraf Ab Initio in Combined Liver and Kidney Transplant With Donor-Specific Antibodies: A Case Report. AB - Although donor-specific antibodies are regarded as a contraindication for kidney transplantation, the data available for combined liver and kidney transplantation (cLKTx) are scarce, and there is no established therapeutic approach for this category of transplant recipients. De novo use of everolimus and a reduced dose of calcineurin inhibitor reportedly provides excellent kidney function compared with a standard regimen containing a calcineurin inhibitor. This strategy, however, has been applied in only some recipient categories. Here we report a case of A highly sensitized male patient who underwent a cLKTx and received everolimus with low-dose tacrolimus (once-daily prolonged-release formulation) as ab initio immunosuppressive treatment. The pretransplant panel-reactive antibody estimate was 97%, and multiple anti-HLA antibodies were detected at the time of transplantation. Thus far, patient and allograft survival have reached 2 years, with the recipient remaining on a regimen of immunosuppression with everolimus and low-dose tacrolimus, with no episodes of rejection. PMID- 27932159 TI - Fulminant Clostridium perfringens Sepsis in Kidney Transplant: A Case Report. AB - BACKGROUND: Infections, particularly urinary tract infections, and cardiovascular accidents are the main causes of morbidity and mortality during the 1st year after kidney transplantation (KT). Bacteria and viruses, such as Escherichia coli, Enteroccoci, and Polyoma BK virus are common in the 1st 6 months, so they are controlled routinely. On the other hand, Clostridium perfringens infection is a rare life-threatening condition, associated with a high mortality rate especially in the transplant population, that is not controlled routinely. CASE REPORT: A 50-year-old man with end-stage renal disease secondary to hypertension and focal segmental glomerulosclerosis underwent living-related KT. He recovered well and was discharged 11 days after KT. Two weeks after his discharge, he presented with severe abdominal pain, fever, and vomiting. Radiologic assessment showed pneumoperitoneum. Urgent exploratory laparotomy revealed significant amount of gas and no bowel perforation. However, right retroperitoneal gas collection was noted and drained. Blood culture was positive for C perfringens. Patient died after 48 hours, with signs of multiorgan failure. CONCLUSIONS: Clostridium perfringens sepsis is severe and usually lethal in the transplant population. Prevention is difficult because the origin of the infection is unclear. Keeping high suspicion in patients with sudden and unexplained septic shock and aggressive surgical and medical treatment are fundamental. PMID- 27932160 TI - Successful Short-Term Intravenous Treatment of Disseminated Nocardia farcinica Infection with Severe Hyponatremia After Kidney Transplantation: A Case Report. AB - BACKGROUND: Nocardia is a genus of gram-positive Actinomycetes that are ubiquitous in decaying organic material, soil, and water. Some Nocardia species can infect humans, mainly by airborne transmission. Several reports describe disseminated infections, which are rare and mostly affect strongly immunocompromised patients because intact T-cell-mediated immunity is the major protective mechanism. CASE REPORT: We report a case of disseminated pulmonary, cerebral, and cutaneous infection with Nocardia farcinica in a 66-year-old kidney transplant recipient treated with low-dose triple immunosuppression. The patient was initially admitted because of severe hyponatremia and pneumonia with radiologic signs of pleural effusion. The infectious agent was isolated when cutaneous lesions developed. Oral trimethoprim/sulfamethoxazole treatment led to severe hyponatremia; therefore, long-term treatment with parenteral amikacin and minocycline was initiated. After 7 months of consistent intravenous treatment, the lesions completely resolved and treatment was stopped, against some expert suggestions. The patient had remained free of relapse at the time of writing. CONCLUSIONS: Disseminated Nocardia infection in immunocompromised patients is a rare but life-threatening disease. Owing to its infrequency, the variety of clinical patterns, antimicrobial resistance, and often fatal complications of standardized therapy, the diagnosis and treatment of this infection remain challenging and protracted. PMID- 27932161 TI - Sofosbuvir Monotherapy for Asymptomatic and Noncirrhotic Hepatitis C Infection in a Renal Retransplantation Recipient: A Case Report. AB - Renal transplant recipients infected with hepatitis C virus (HCV) have a high risk of progressing to cirrhosis, end-stage liver diseases, and hepatocellular carcinoma. It is also considered as an independent risk for graft loss and is correlated with proteinuria, transplant glomerulopathy, HCV-associated glomerulonephritis, and chronic rejection. Previous therapy involving interferon alfa and ribavirin led to treatment complications, including toxicity, anemia, sepsis, and drug-drug interactions with calcineurin inhibitors, as well as reduced tolerability and efficacy. New direct-acting antiviral drugs simplify and shorten the treatment along with increasing tolerability and efficacy. Nevertheless, limited data and no specific regimen with direct-acting antiviral drugs have been described in the literature for renal transplant recipients with chronic HCV. We describe here the case of a 52-year-old Chinese man who diagnosed with chronic renal failure in 1997 and underwent renal transplantation the same year. In 2012, he was diagnosed with renal graft failure and again underwent hemodialysis. The patient then underwent his second renal transplantation and was administered an immunosuppressive cyclosporine-based regimen in 2015. During hemodialysis, he acquired asymptomatic genotype 1b HCV infection. Serologic test results reflecting liver cirrhosis were all negative, and ultrasound showed no abnormalities in the liver. The patient later required oral sofosbuvir monotherapy for 12 weeks after the second kidney transplantation. Curing HCV in renal transplant recipients is necessary. Although our treatment did not successfully result in a sustained virologic response, it suggests that genotype 1b HCV may have a poor response to a sofosbuvir monotherapy regimen. Specific and effective regimens for renal transplant recipients with HCV infection need to be confirmed in the future. PMID- 27932162 TI - Rapidly Fatal Hemophagocytic Lymphohistiocytosis Developing Within Six Days Following Deceased-Donor Renal Transplantation: Case Report. AB - Hemophagocytic lymphohistiocytosis (HLH) is an often fatal hyperinflammatory syndrome that may complicate malignancy, infection, rheumatic disease, or immunosuppression. HLH after kidney transplantation is most often triggered by infection, usually Herpes viruses such as cytomegalovirus and Epstein-Barr virus (EBV). It usually occurs early after transplantation. We present a case of HLH triggered by reactivation of EBV that pursued a rapidly fatal course within 6 days of receiving a deceased-donor kidney transplant. This case serves to remind transplant clinicians to consider HLH when cytopenias and hyperinflammation are atypical for the usual post-transplantation course. We discuss pitfalls in diagnosis and suggestions for treatment in this setting. PMID- 27932163 TI - Testicular Seminoma Occurring After Kidney Transplantation in a Patient Previously Treated for Teratoma: De Novo Malignancy or Recurrence in a Different Histologic Form? AB - The most common testicular tumor is seminoma, but it is one of the rarest malignancies in kidney transplant recipients, with only 15 cases published in the English-language literature. Except in 1 case of recurrence, all cases were de novo malignancies after transplantation. We bring a case of a patient treated for testicle teratoma at age 24 years who received a kidney transplant at age 40 years, and 19 months after transplantation was diagnosed with a metastatic seminoma. To the best of our knowledge, there are no data of germ cell tumor late recurrence after kidney transplantation. In addition, this is the 1st case of a giant cell tumor occurring in a form of seminoma in general or transplanted population. PMID- 27932164 TI - Retzius Space Preservation Technique for Robotic-Assisted Laparoscopic Radical Prostatectomy in a Kidney Transplant Patient: First Case in Thailand and Our First Experience. AB - OBJECTIVE: The aim of this work was to report our experience in robotic-assisted laparoscopic radical prostatectomy for the treatment of localized prostate cancer in a kidney transplant recipient. METHODS: A 73-year-old man with chronic renal failure underwent living-donor kidney transplantation (KT) in 1993. His baseline creatinine after KT was ~1.2 mg/dL. He developed lower urinary tract symptoms in 1999. He was diagnosed with benign prostatic hyperplasia and treated accordingly. He was followed regularly with the use of digital rectal examination and measurement of serum prostatic-specific antigen (PSA). In 2014, his serum PSA was 11.53 ng/mL. Prostate biopsy was done and revealed localized prostatic adenocarcinoma with a Gleason score of 7 (3+4). We performed robotic-assisted laparoscopic radical prostatectomy with the use of the Retzius space preservation technique. RESULTS: The patient underwent successful robotic-assisted laparoscopic radical prostatectomy without any complications. The operative time was 210 minutes with estimated blood loss of 250 mL. The patient tolerated the procedure well and was discharged on the 6th day after surgery with a retained Foley catheter. A cystogram was done on the 13th day after surgery and showed no urethrovesical anastomosis leakage. After Foley catheter removal, the patient could urinate normally without urinary incontinence. Pathologic analysis revealed positive surgical margin with no extraprostatic extension and no seminal vesical invasion. One month after the operation, PSA was 0.08 ng/mL and renal function remained stable. CONCLUSIONS: Robotic-assisted laparoscopic radical prostatectomy is technically feasible and safe for the treatment of localized prostate cancer in the renal transplant patient. The Retzius space preservation technique is helpful in minimizing the manipulation of transplanted kidney and urinary bladder during the operation, resulting in favorable postoperative renal function and continence outcome. PMID- 27932165 TI - Lymphangioma-like Kaposi Sarcoma in Transplant-Associated Iatrogenic Immunosuppression: A Case Report. AB - Lymphangioma-like Kaposi sarcoma (LLKS) is a rare histologic presentation of Kaposi sarcoma (KS), with only 28 cases reported in the literature. LLKS has been described in acquired immunodeficiency syndrome and in endemic African-type as well as classic indolent KS. We present the 1st reported case of LLKS in a transplant-associated iatrogenic immunosuppressed patient. PMID- 27932167 TI - Gangliocytoma Presenting With Tacrolimus Neurotoxicity in a Renal Transplant Recipient: Case Report. AB - Tacrolimus is a widely used macrolide immunosuppressant in transplant surgery, with mild and major neurologic side effects. A 21-year-old woman had undergone preemptive transplantation of a kidney from her mother. On the 1st postoperative day, the patient had headache, nausea, vomiting, and agitation. Magnetic resonance imaging (MRI) of the brain showed hyperintensity and a lesion in the right mesial temporal lobe. After we switched from tacrolimus to cyclosporine, the symptoms regressed. Persistence of the lesion, confirmed by repeated MRI, required that the patient be operated on. Pathologic examination showed the gangliocytoma, a rare brain tumor. Our case shows that preexisting brain lesions may cause tacrolimus-induced neurotoxicity in the early postoperative period. PMID- 27932166 TI - Renal Allograft Failure After Ipilimumab Therapy for Metastatic Melanoma: A Case Report and Review of the Literature. AB - Transplant recipients are at an increased risk of malignant melanoma, a result of chronic immunosuppression. Ipilimumab is a newer biological agent targeting T lymphocytes to potentiate an immune response against melanoma, and the use of this agent results in a new adverse effect profile that the clinician must be aware of while a patient is on therapy. We report the case of a male renal transplant recipient who developed graft failure while treated with ipilimumab and minimal immunosuppressive therapy for metastatic ocular melanoma, with biopsy evidence of glomerulonephritis and acute rejection. We highlight the immunological side effects that can manifest from ipilimumab therapy and conclude that it did influence graft function in this patient. Our case illustrates the importance of weighing the risks and benefits to graft function and long-term survival as well as the importance of considering other treatment modalities in this specific group of melanoma patients. PMID- 27932168 TI - Spindle Cell Lipoma in an End-Stage Renal Allograft: Case Report. AB - BACKGROUND: Spindle cell lipoma is an uncommon variant of lipoma and usually occurs as a solitary, subcutaneous, and well circumscribed lesion in the posterior neck, shoulders, and back of older men. Primary renal lipomas are rarely reported. Spindle cell lipoma in the kidney has not been previously described in the literature. CASE REPORT: A 60-year-old Chinese man suffered graft failure 10 years after living related donor kidney transplantation. During cancer surveillance, he was found to have a mass in the renal allograft, which increased in size and was suspicious for renal cell carcinoma on computerized tomographic scan. The patient underwent renal graft explantation. Grossly, the kidney was atrophic, containing a 6.5 cm yellowish solid lesion without hemorrhage and necrosis in the renal sinus fat. Microscopically, the lesion was composed of variably sized adipocytes and cellular areas of bland spindle cells with no cytologic atypia. There were prominent slender blood vessels within the lesion, along with focal myxoid change as well as scattered mast cells and inflammatory cells. Lipoblasts were not identified. The spindle cells were positive for CD34 and negative for Melan-A, HMB45, S100, and SMA. Pax-2 stain was nonspecific. MDM2 amplification by means of fluorescence in situ hybridization (FISH) and overexpression by immunohistochemistry were negative. The Ki-67 proliferation index was <1%. Interphase FISH revealed loss of 13q and 16q in the tumor. CONCLUSIONS: Renal spindle cell lipoma is a rare benign tumor. Angiomyolipoma and well differentiated liposarcoma are the main differential diagnoses. Immunohistochemistry and cytogenetic techniques are helpful in differentiating it from malignant entities. PMID- 27932169 TI - Invasive Aspergillosis of the Stomach and Co-infection With Candida krusei in a Patient With Terminal Liver Failure: A Case Report. AB - Invasive aspergillosis (IA) is diagnosed almost exclusively in immunocompromised patients. It is located mainly in the lungs or paranasal sinuses, but occasionally other organs and the gastrointestinal tract may also be affected either alone or as a part of a disseminated disease. The main risk factors predisposing to IA are neutropenia, immunosuppressive and steroid therapy, as well as severe underlying disease. Despite progress in diagnostics and therapy of IA, it is still characterized by a high mortality rate. In the disseminated aspergillosis of the gastrointestinal tract, mainly the small or large intestine are affected, rarely the upper gastrointestinal tract. To our best knowledge only a very few cases of IA of the gastric wall have been reported so far in the literature. We describe a unique case of this very rare location of IA in the stomach in a patient who underwent orthotopic liver transplantation in the course of active IA and Candida krusei infection of the stomach wall. The patient's condition improved on combination therapy of voriconazole and caspofungin. PMID- 27932170 TI - Living Donor Liver Transplantation in a Patient With Extensive Portomesenteric Venous Thrombosis: Case Report. AB - Extensive portomesenteric venous thrombus preventing restoration of adequate portal venous flow used to be considered a contraindication to liver transplantation. The subject was a 49-year-old male with hepatitis B cirrhosis and extensive thrombosis of portal, splenic, and superior mesenteric veins, and two large collateral vessels; one dilated and tortuous inferior to the pancreaticoduodenal vein and relevant to splanchnic venous return and the other a dilated coronary vein relevant to splenic venous return. During operation, the portal vein was anastomosed to these large collateral vessels using cryopreserved iliac vein. In conclusion, portal reconstruction with large collateral vessels in living-donor liver transplantation could be used selectively for patients with extensive portomesenteric venous thrombosis. PMID- 27932171 TI - Recurrence of Progressive Familial Intrahepatic Cholestasis Type 2 Phenotype After Living-donor Liver Transplantation: A Case Report. AB - BACKGROUND: Progressive familial intrahepatic cholestasis 2 (PFIC2) is the result of mutations in the ABCB11, which encodes for bile salt export pump (BSEP). An absence of BSEP in the canalicular membrane causes cholestasis and leads to the development of end-stage liver disease in the first decade of life. Liver transplantation (LT) has been considered curative for BSEP disease. However, patients with PFIC2 having undergone LT have recently been reported to develop recurrence of cholestasis together with the clinical and histological features of primary BSEP disease. CASE REPORT: We herein present a rare case of a patient with PFIC2 who developed post-transplantation recurrence of progressive intrahepatic cholestasis due to antibodies against BSEP after living-donor LT, which mimicked primary BSEP disease. The patient had mutations in the ABCB11 gene, resulting in the complete absence of BSEP in the native liver, explaining the lack of tolerance. Immunofluorescence staining of normal human liver sections with the patient's serum and using an anti-human immunoglobulin G antibody to detect serum antibodies showed reactivity to the BSEP epitope in the canalicular membrane. We suggest that the patients having undergone LT had been associated with a risk of autoantibody formation against the BSEP protein. The absence of primary tolerance for the BSEP epitopes may explain the formation of the anti BSEP antibodies after LDLT. PMID- 27932172 TI - Liver Transplantation in an Adult Recipient With Situs Inversus Totalis: Case Report and Review of the Literature. AB - BACKGROUND: Over the past few decades, reports have demonstrated the feasibility of liver transplantation in adult patients with situs inversus. However, this disease entity remains rare and experience remains limited in adult recipients with situs inversus undergoing transplantation. METHODS: A 23-year-old woman with situs inversus totalis and end-stage liver disease secondary to congenital biliary atresia was referred to our center and underwent a successful orthotopic liver transplantation. RESULTS: We report our experience and review the literature. We performed a modified piggy-back technique with cavo-cavostomy. Using a triangulated wide orifice, the suprahepatic cava was anastomosed in an end-to-side fashion. The patient underwent an uneventful hospitalization and recovery. CONCLUSION: Situs inversus remains a rare condition. Careful perioperative planning, thorough anatomic knowledge of both donor and recipient liver, and use of a variety of different novel techniques can lead to successful outcomes. PMID- 27932173 TI - A Case Report of Severe Hepatic Artery Vasospasm Induced by Hepatic Arterial Buffer Response After Liver Transplantation. AB - The management of severe hepatic artery vasospasm soon after liver transplantation (LT) is challenging because it can lead to hepatic artery thrombosis and subsequent graft failure. A 61-year-old man with hepatitis C cirrhosis and portal vein thrombosis received a deceased donor LT. On postoperative day 1, Doppler ultrasonography revealed a high-resistance waveform in the hepatic artery. Angiography showed severe vasospasm of the donor hepatic artery on postoperative day 3. Strong hepatic arterial buffer response (HABR) was considered for this etiology due to high portal vein velocity. Therefore, vasodilators, including nitroglycerin and prostaglandin E1, were initiated. The waveform of the hepatic artery vasospasm gradually improved as portal vein velocity decreased by Doppler ultrasonography within 7 days after LT. In conclusion, hepatic arterial buffer response can induce hepatic artery vasospasm immediately after LT. This vasospasm type may be managed conservatively with a positive outcome. PMID- 27932174 TI - Salvage Splenic Artery Embolization for Saving Falling Living Donor Graft due to Portal Overflow: A Case Report. AB - Portal decompression is an approach for reducing portal overflow caused by small for-size syndrome. We report the case of a patient who recovered from rapidly progressing hyperbilirubinemia caused by a small graft by decompressing portal overflow with splenic artery embolization following a living donor liver transplantation (LDLT). The patient was a 54-year-old man with end-stage liver disease secondary to alcoholic liver cirrhosis; the donor was his 54-year-old wife. The graft volume of the left lobe was 444 mL, which was 34.8% of the standard liver volume (SLV) and insufficient for the recipient; thus, the plan was to use the right lobe for the graft. The patient underwent LDLT with a right lobe graft; the volume to SLV ratio was 39.1%, and the graft-to-recipient-weight ratio was 0.72%. Although portal pressure was low during the operation, the patient eventually developed small-for-size syndrome after LDLT. It was conceivable that because the patient had splenomegaly, portal decompression would be effective. Splenic arterial embolization was performed successfully on postoperative day (POD) 7. The patient's total bilirubin level was increased to 40 mg/dL on POD16. Decreased portal flow, which was shown by ultrasound screening to be "to-and-flo," increased again on POD23 to one-third of that on POD1. He was discharged without any infectious complications. Additional splenic artery embolization after LDLT may be a convenient option for reducing portal overflow for patients with splenomegaly if the portal decompression was not performed for some reason at the surgery. PMID- 27932175 TI - First Attempt of Sequential Living Donor Liver and Hematopoietic Stem Cell Transplantation in a Child With Advanced Hepatocellular Carcinoma: Case Report. AB - Effective therapeutic options for advanced hepatocellular carcinoma are limited. Hematopoietic stem cell transplantation may offer a graft-versus-tumor effect. Combined liver and hematopoietic stem cell transplantation from the same donor with preparatory conditioning may promote tolerogenicity to the liver allograft and offers the potential for immunosuppression withdrawal. We report our experience with the use of this approach in a pediatric patient with invasive hepatocellular carcinoma and pulmonary metastases who underwent a living-donor liver transplantation followed by reduced-toxicity myeloablative conditioning and hematopoietic stem cell transplant from the same parental donor. Neutrophil engraftment and full donor chimerism was achieved without liver allograft dysfunction. Despite normal liver function and marrow engraftment, the patient succumbed to multisystem organ failure from disseminated toxoplasmosis. At autopsy, there was no histologic evidence of tumor recurrence. No pulmonary nodules were found. Regardless of the unfortunate overall result, this case demonstrates preliminary feasibility of sequential living-donor liver transplantation and hematopoietic stem cell transplantation for unresectable and metastasized hepatic tumors. Future studies in select pediatric patients require evaluation of the optimal conditioning regimen and prevention strategies for opportunistic infections to determine both graft-versus-tumor effect on hepatic tumors and durability of tolerogenicity and possible immunosuppression withdrawal. PMID- 27932176 TI - Intrahepatic Artery Pseudoaneurysm-induced Hemobilia Caused by a Plastic Biliary Stent After ABO-incompatible Living-donor Liver Transplantation: A Case Report. AB - Bile leakage after duct-to-duct anastomosis in living-donor liver transplantation (LDLT) can mostly be managed by therapeutic endoscopic retrograde cholangiopancreatography. Following this, various complications such as biliary infection, pancreatitis, perforation, and bleeding can occur, and endoscopic sphincterotomy is primarily associated with post- endoscopic retrograde cholangiopancreatography bleeding; other causes have been published in case reports. In the present case, a plastic biliary stent used for treating liver abscesses and leakage at the bile duct anastomosis site after ABO-incompatible LDLT resulted in an intrahepatic artery pseudoaneurysm and hemobilia, which were managed by angiography and coil embolization. Although the complex postoperative course after LDLT can obscure the prompt diagnosis of an intrahepatic artery pseudoaneurysm and hemobilia, biliary stenting should be considered as a possible cause. PMID- 27932177 TI - Cardiac Tamponade due to Suprahepatic Surgical Exploration in Liver Retransplantation: A Case Report. AB - BACKGROUND: Cardiac tamponade is an emergency condition that requires early recognition and prompt pericardial decompression. Little has been reported on cardiac tamponade in liver retransplantation (reLT), but most cases are fatal. We managed a case of reLT complicated by accidental cardiac tamponade. CASE REPORT: A 59-year-old man underwent an emergency reLT because of liver cirrhosis with recurrent hepatitis B. During the dissection, suprahepatic exploration was attempted, but this resulted in severe hemorrhage because of the many tissue adhesions. After 1 hour of allograft reperfusion, the cardiac index and blood pressure dropped markedly despite volume resuscitation, and the central venous pressure increased abruptly. Using transthoracic echocardiography, cardiac tamponade was diagnosed, and an urgent pericardiotomy was performed. Although bizarre changes in the electrocardiogram were observed briefly, the vital signs normalized. After a short period of hypotension and hyperlactatemia in the intensive care unit, the patient was transferred to a ward in satisfactory condition on postoperative day 7. CONCLUSION: This case demonstrates the need for careful monitoring of hemodynamics during suprahepatic exploration with marked tissue adhesions in reLT. PMID- 27932178 TI - Extra-anatomical Meso-portal Venous Jump Graft Repair for Early Portal Vein Thrombosis After Liver Transplant in an Infant With a Hypoplastic Portal Vein: A Case Report. AB - BACKGROUND AND PURPOSE: Small infants with biliary atresia and hypoplastic portal veins (PV) are at risk for portal vein thrombosis (PVT) after liver transplantation (LT), which can lead to graft loss and mortality. Extra anatomical PV reconstruction techniques have been established for adult cases of PVT; however, they have not been widely accepted for infants. METHODS: Here, we report the successful use of an extra-anatomical meso-portal venous jump graft to treat early PVT after LT in a 6-month-old infant with biliary atresia and PV hypoplasia. At the time of LT, despite a reduced-sized left lateral graft, we had to create a temporary abdominal closure with silastic mesh. FINDINGS: On postoperative day 1, PVT was detected by Doppler ultrasound of the liver. Surgical thrombectomy was attempted. We removed the blood clots and reconstructed the PV using an interposition venous graft. As the PV flow was still not sufficient, we performed an extra-anatomical meso-portal venous jump graft procedure from the recipient superior mesenteric vein to the donor PV. This resulted in a significant improvement in PV flow. CONCLUSION: For small infants at high risk for PVT, a detailed pretransplantation surgical plan and treatment options for possible early PVT are mandatory. An extra-anatomical meso-portal venous jump graft is a viable surgical technique for early PVT in infants. PMID- 27932179 TI - Combined Kidney Transplantation and Splenic Fossa Auxiliary Heterotopic Liver Transplantation in a Highly Sensitized Recipient: A Case Report. AB - BACKGROUND: Combined kidney and auxiliary orthotopic liver transplantation from the same donor is used to treat highly sensitized renal transplant recipients. Auxiliary liver can protect the transplanted kidney against hyperacute rejection. METHODS: In the current case, combined kidney and splenic fossa auxiliary heterotopic liver transplantation was performed from the same donor for a highly sensitized recipient without preoperative preconditioning. No postoperative hyperacute rejection occurred. RESULTS: Seven days after surgery, preexisting antibody levels rose and decreased after treatment; meanwhile, the function of transplanted kidney returned to normal. During 24 months of follow-up, the grafts showed good blood perfusion and functioned well. The levels of preexisting antibodies, donor-specific antibodies (DSA) and C1q-fixing human leukocyte antigen (C1q-HLA) antibodies, all decreased. CONCLUSIONS: Combined kidney and splenic fossa auxiliary heterotopic liver transplantation can be used in renal transplantation for highly sensitized recipients. PMID- 27932180 TI - Liver Transplant Recipient With Tumefactive Demyelinating Lesions: A Case Report and Literature Review. AB - Tumefactive demyelinating lesions (TDLs) that may resemble brain neoplasms or abscesses are uncommon but noteworthy. A solid knowledge of how to distinguish TDLs from malignancy or infection is a key step to avoid unnecessary medical or surgical interventions. Almost all the intracranial demyelination diseases after liver transplantation (LT) refer to central pontine myelinolysis or extrapontine myelinolysis; TDLs after LT have never been reported. In 2005, a 45-year-old Chinese male underwent orthotopic LT due to "acute on chronic liver failure" in our hospital. He took triple anti-rejection drugs including tacrolimus, mycophenolate mofetil, and corticosteroids after LT. In 2010, he was admitted for right limb weakness, and the head magnetic resonance imaging and magnetic resonance spectroscopy revealed the lesions were more likely to be TDLs. His symptoms disappeared after he was administered corticosteroid therapy which proved the diagnosis. Five years later, he was admitted again to hospital with dizziness and double version. The magnetic resonance image and magnetic resonance spectroscopy showed that the new solitary lesion in the cerebellum may in fact be the new TDL. He received corticosteroid therapy and was discharged after symptoms improved. Herein, to our knowledge, we reported the first case of TDL after LT. We reported this case to provide helpful information to clinicians about intracranial demyelination diseases after LT which maybe are not always central pontine myelinolysis or extrapontine myelinolysis. PMID- 27932181 TI - Use of Terlipressin in an Elderly Patient With Moderate Aortic Valve Stenosis Accompanied by Episodic Atrial Fibrillation During Liver Transplantation: A Case Report. AB - Anesthesia for patients with moderate aortic stenosis accompanied by atrial fibrillation during high-risk surgery such as liver transplantation remains a challenge in maintaining control of heart rate and maintenance of cardiac output. The action of terlipressin on vasopressin receptors (mainly V1 receptors) leads to splanchnic vasoconstriction and is the key mechanism responsible for increasing systemic vascular resistance and reducing heart rate. We report successful anesthetic management using low-dose terlipressin infusion in an elderly patient who had moderate aortic stenosis with atrial fibrillation during urgent deceased-donor liver transplantation. PMID- 27932182 TI - Recovery After Critical Illness Polyneuropathy in a Patient With Orthotopic Liver Transplantation: A Case Report. AB - After liver transplantation, some patients show neuromuscular abnormalities. A 43 year-old man with liver cirrhosis due to hepatitis C virus underwent living-donor liver transplantation. He developed severe neuromuscular dysfunction after sepsis, and acute respiratory distress syndrome. After the inflammatory reaction gradually improved, we observed bilateral weakness of the extremities and foot drop. Electrophysiological studies indicated primary axonal degeneration of peripheral motor and sensory fibers without inflammation. Critical illness polyneuropathy was diagnosed. During follow-up, complaints gradually recovered with rehabilitation by approximately 1 year later. Based on this case, we suggest that paralysis should be evaluated for critical illness polyneuropathy in patients with unexplained muscle weakness. PMID- 27932183 TI - Rhino-Orbita-Maxillary Mucormycosis After Liver Transplantation: A Case Report. AB - Mucormycosis is a rare lethal complication of organ transplantation that progresses rapidly, and the prognosis is dismal if diagnosed late. We present a surviving liver transplant recipient in whom severe rhino-orbita-maxillary mucormycosis developed 1 month after liver transplantation. Prompt diagnosis with tissue biopsy, local control of the underlying condition with aggressive surgical debridement, and appropriate administration of systemic antifungal therapies are essential to improve prognosis and survival. PMID- 27932184 TI - Intrapancreatic Splenule in a Pancreas Allograft: Case Report. AB - A 16-year-old white man was involved in a motor vehicle collision and suffered head, chest, and abdominal trauma. Despite initial resuscitative efforts, he progressed to brain death and was designated to be an organ donor by his family. He had no earlier medical or surgical history and no high-risk behaviors. Blood work revealed normal creatinine, liver function tests, lipase, and amylase. Viral serologies were negative except for cytomegalovirus IgG and Epstein-Barr virus nucleic acid. Imaging revealed a right kidney contusion, a manubrial fracture, and fractures of right first rib and bilateral scapulae. No other abdominal trauma was identified, specifically to the pancreas, duodenum, or spleen. Our transplant center accepted the pancreas from this donor. During back-table inspection of the pancreas, a 1.5 * 1.5 cm dark purple rubbery mass was identified within the parenchyma of the pancreas in the tail. An incisional biopsy of the lesion was sent for frozen section, which yielded a mixed inflammatory infiltrate consisting of neutrophils and lymphocytes and an overlying fibrous capsule. The diagnosis of lymphoma or another neoplasm could not be definitely ruled out. Owing to uncertainty in diagnosis, the entire lesion was excised along with the distal pancreas with the use of a linear stapler. The staple line was oversewn with running 4-0 polypropylene suture, and the pancreas was transplanted. After surgery, the pancreas allograft functioned well with a small pancreatic leak, which had resolved by the first postoperative outpatient visit. PMID- 27932185 TI - Inferior Vena Cava-Duodenal Drainage in Pancreas Alone Transplantation for Chronic Pancreatitis: A Case Report. AB - Enteric drainage has been the main trend in solitary pancreas transplantation. Compared with bladder drainage, it does not cause metabolic or urologic complications, but there is no way to perform immunologic monitoring, except by graft pancreas biopsy. Additionally, although portal drainage of the graft vein is considered physiological drainage, it has more of a risk for surgical complications. To overcome these disadvantages, we successfully performed inferior vena cava (IVC)-duodenal drainage in pancreas alone transplantation. A 44-year-old man underwent pancreas alone transplantation. He had insulin dependent diabetes because of chronic pancreatitis, thus he had taken a pancreatic enzyme. After right-sided medial visceral rotation, the IVC was dissected for anastomosis with a graft portal vein. The right common iliac artery was anastomosed with a Y-graft in the pancreas graft. The graft duodenum was anastomosed with recipient duodenum using the side-to-side manner. Postoperatively, he underwent protocol biopsies of the graft duodenum through endoscopy two times. There was no evidence of graft thrombosis or rejection. He had a normal glucose level without any diabetic drugs, and he required no pancreatic enzyme for digestion. The IVC-duodenum drainage procedure was a feasible method for preventing thrombosis and providing an opportunity for direct graft monitoring through endoscopy. PMID- 27932186 TI - Late Graft Rejection in Association With T-Large Granular Lymphocyte Expansion of Recipient Origin After Human Leukocyte Antigen-Haploidentical Stem Cell Transplantation: A Case Report. AB - BACKGROUND: Large granular lymphocyte (LGL) expansion occasionally occurs after allogeneic stem cell transplantation (allo-SCT), and is thought to be a good prognostic sign that is associated with a lower relapse rate. However, there have been no reports of late graft failure (LGF) due to graft rejection in association with oligoclonal LGL expansion. We herein report a case of LGF associated with the transient expansion of recipient-derived T-LGL after allo-SCT. CASE REPORT: A 65-year-old man underwent peripheral blood stem cell transplantation (PBSCT) from his human leukocyte antigen (HLA)-haploidentical son for the treatment of acute myeloid leukemia, which had evolved from a myelodysplastic syndrome (MDS). Neutrophil engraftment occurred on day 20. A chimerism analysis on day 29 showed both granulocytes and mononuclear cells in the peripheral blood to be completely of donor origin. However, his neutrophil count gradually decreased and a chimerism analysis on day 61 showed that 84% of the patient's T cells were of recipient origin while the granulocytes were 100% donor-derived. His LGLs rapidly increased to 4.01 * 109/L on day 113 and decreased thereafter. The percentage of donor cells in his granulocytes gradually decreased, and the patient's leukocytes were completely replaced by recipient cells on day 177. CONCLUSIONS: The clinical course suggests that the expansion of recipient-derived T-LGLs after allo-SCT can be a sign of graft rejection. Early intervention may be needed if the LGL expansion is recipient-derived. PMID- 27932187 TI - Successful T-cell Replete Hematopoietic Stem Cell Boost Without Conditioning for Late Graft Failure. AB - Late graft failure is a rare but significant complication after allogeneic stem cell transplantation, which is often complicated by severe infections. We report a case of late graft failure, which was successfully treated with a T-cell replete hematopoietic stem cell boost without conditioning that induced rapid engraftment and relieved the patient of infection. Discontinuation of immunosuppressants and nilotinib administration suppressed the host cells. Achieving full donor chimerism allowed us to administer a peripheral blood stem cell boost without conditioning. PMID- 27932188 TI - Successful Single-Lung Transplant for Severe Lung Graft-Versus-Host Disease Two Years After Sibling Allograft for Acute Lymphoblastic Leukemia: A Case Report. AB - Bone marrow transplantation (BMT) has been performed as a successful life-saving treatment for hematological and neoplastic diseases. Despite the predictable long term survival rates in BMT, pulmonary complications reduce the survival rates significantly mainly because of chronic graft-versus-host disease (GVHD). This report briefly discusses a successful lung transplantation case for severe lung GVHD after allograft for acute lymphoblastic leukemia. This case report supports the scarce evidence in the literature for the importance of lung transplantation as a therapeutic option for patients who develop respiratory failure secondary to BMT. PMID- 27932189 TI - Recurrence Pattern of Pulmonary Langerhans Cell Histiocytosis After Lung Transplantation: A Case Report. AB - Pulmonary Langerhans cell histiocytosis is an uncommon indication for lung transplantation. The recurrence of the primary pathology after transplantation is rare. Extra-pulmonary involvement of Langerhans cell histiocytosis before transplantation and resuming of smoking after transplantation are risk factors for recurrence. Herein, we present a 48-year-old woman with a recurrence pattern 24 months after bilateral sequential lung transplantation. On thoracic computed tomography, progressive parenchyma infiltrates were present without clinical symptoms. Infiltrations regressed and respiratory status of the patient was improved with steroid therapy. No events had occurred at follow-up of 31 months. PMID- 27932190 TI - Erratum. PMID- 27932191 TI - IgA nephropathy clinicopathologic study following the Oxford classification: Progression peculiarities and gender-related differences. AB - BACKGROUND AND AIM: Immunoglobulin A nephropathy (IgAN) is the most frequent glomerular disease worldwide and one of the main causes of chronic kidney disease. We aimed to investigate clinicopathological correlations in IgAN patients by gender. MATERIALS AND METHODS: The study was based on a retrospective analysis of renal biopsy data and clinical manifestations of the disease. Consecutive 73 biopsy-proven IgAN cases of male (62%) and female (38%) patients were investigated. Renal biopsies were reviewed using the new Oxford classification assessing the MEST (mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis/adhesion, tubular atrophy/interstitial fibrosis) score. The most powerful IgAN prognostic risk factors, morphological (segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis) as well as clinical (proteinuria and hypertension) were taken into account in the correlation analysis. The mean rate of renal function decline was expressed as a slope of eGFR during the follow-up (FU) dividing delta GFR with the FU years. RESULTS: The mean age of the patients was 33.7 years (range, 16-76). Follow-up data were available for 64 patients with the mean follow-up of 4.1 years. The mean proteinuria at biopsy was 0.79g/24h. The mean arterial pressure (MAP) was 94.5+/-16.7mmHg and 7% of the patients were hypertensive. The initial mean estimated glomerular filtration rate (eGFR) was 94.9+/-30.7mL/min, at the end of the follow-up it was 86.2+/-27.1mL/min. The mean rate of renal function decline was -3.4+/-11.9mL/min/1.73m2 per year in males (P<0.05) and -0.7+/ 5.3mL/min/1.73m2 per year in females. The Spearman correlation analysis confirmed a higher MEST score in the whole cohort and in males correlated with disease progression. In patients with proteinuria below 1.0g/24h, disease progression was faster in males. CONCLUSIONS: According to the correlation analysis of the main prognostic risk factors, affecting the progression of IgAN, we can conclude that IgA nephropathy in males progresses more rapidly compared to females. PMID- 27932192 TI - Dobutamine-stress echocardiography speckle-tracking imaging in the assessment of hemodynamic significance of coronary artery stenosis in patients with moderate and high probability of coronary artery disease. AB - BACKGROUND AND OBJECTIVE: Myocardial deformation indices are considered as sensitive markers of ischemia and may be useful in the quantification of hemodynamic significance of coronary artery disease (CAD). We sought to determine the diagnostic value of speckle-tracking echocardiography derived myocardial deformation parameters at rest and during stress to determine hemodynamically significance coronary artery stenosis in patients with moderate and high probability of CAD. MATERIALS AND METHODS: In 81 patients (mean age, 64+/-8.6 years) with stable CAD inducible myocardial ischemia was evaluated by dobutamine stress echocardiography (DSE) and adenosine magnetic resonance imaging (AMRI). Based on AMRI patients were divided into two groups: nonpathologic (n=41) and pathologic (n=40). Strain and strain rate (SR) parameters and their changes from the rest (BASE) to low stress (MIN), peak stress (MAX), and recovery (REC) were analyzed using 2D speckle-tracking imaging (STI). RESULTS: In the nonpathologic group, systolic longitudinal and circumferential strain increased significantly from BASE to MIN, as well as systolic SR from BASE to MIN and from MIN to MAX in longitudinal plane. In contrast, in the pathologic group, insignificant longitudinal systolic SR increase and radial and circumferential systolic SR decrease from MIN to MAX was observed. Discriminant function analysis revealed that select STI derived parameters best classify patients into predefined AMRI groups (pathologic and nonpathologic) with the accuracy respectively 90.9% and 83.3%. According to ROC analysis these myocardial deformation parameters had the greatest predictive value of significant coronary artery stenoses: longitudinal strain at high dose (AUC 0.811, sensitivity 89.4%, specificity 64.7%), longitudinal strain rate at high dose (AUC 0.855, sensitivity 88.1%, specificity 71.0% at high doses). The sensitivity and specificity of inducible wall motion abnormalities were 74.0% and 85.0% (AUC 0.798) and was lower compared with the diagnostic value of longitudinal myocardial deformation parameters. CONCLUSIONS: Left ventricular strain and strain rate analyses during DSE can be used in the assessment of hemodynamic significance of coronary artery stenosis in patients with moderate and high risk for CAD. PMID- 27932193 TI - Associations between built environment and physical activity of 7-8-year-old children. Cross-sectional results from the Lithuanian COSI study. AB - BACKGROUND AND AIM: Research shows that regular engagement in physical activity in childhood is associated with multiple physical and psychosocial health benefits. The data on associations between children physical activity level and built environment in Lithuania are limited. The built environment is one of many variables thought to affect children physical activity level. But consequently there is growing interest in how physical environment influences physical activity of school age children. The aim of this paper is to evaluate associations between physical activity of primary school age children and built environment (road safety, travel distance, playgrounds, etc.) in Lithuania. MATERIALS AND METHODS: Data were obtained participating in the WHO European Childhood Obesity Surveillance Initiative (COSI). The study protocol was granted ethical approval from Lithuanian Bioethics Committee (No. 6B-10-02). Parents/guardians provided written informed consent. A cross-sectional study was carried out in 2013. A multilevel sampling method was employed for composing a national representative sample. The representing data were collected by means of standardized questionnaires, which were filled out by 3802 parents of the selected first-formers. RESULTS: The mean age of the first-formers was 7.3 years (SD 0.5). More than half (62.2%) of parents stated that roads to schools were safe; most (78.7%) of adults notified that children had where to play and exercise in their living area. Place of residence of family and recreation areas in living environment were significant predictors of children's daily physical activity and possibility to attend sport or dancing clubs. CONCLUSIONS: Results from the national survey of 7-8-year-old children of Lithuania reveal that urban living area of families, availability of playgrounds and recreational facilities were associated with higher possibilities of children to be sufficiently physically active. PMID- 27932194 TI - Associations between NOD2, IRGM and ORMDL3 polymorphisms and pediatric-onset inflammatory bowel disease in the Lithuanian population. AB - BACKGROUND AND OBJECTIVE: Recent GWAS and meta-analyses have revealed about 200 susceptibility genes/loci for inflammatory bowel diseases (IBD). However, only a small number of studies were performed in early-onset IBD. The aim of this study was to assess the association between NOD2, IL23R, ATG16L1, IRGM, IL10, NKX2-3 and ORMDL3 variants and early-onset IBD. MATERIALS AND METHODS: A total of 76 affected individuals (30 with Crohn's disease [CD] and 46 with ulcerative colitis [UC]) at the age of <=17 years and 158 matched controls recruited in Lithuania were genotyped for the known genetic susceptibility variants in NOD2 (Arg702Trp (rs2066844), Gly908Arg (rs2066845) and Leu1007insC (rs2066847)), IL23R (rs11209026), ATG16L1 (rs2241880), IRGM (rs4958847), IL10 (rs3024505), NKX2-3 (rs11190140) and ORMDL3 (rs2872507) genes. RESULTS: Variants in NOD2 (Leu1007insC) and IRGM genes increased risk for CD (OR=6.56, 95% CI: 2.54-16.91, P=1.21*10-5 and OR=2.32, 95% CI: 1.05-5.14, P=0.033; respectively); whereas a variant in ORMDL3 gene was strongly associated with UC (OR=1.99, 95% CI: 1.23 3.20, P=4.15*10-3). CONCLUSIONS: The results confirmed that polymorphisms in NOD2 (Leu1007insC) and IRGM genes are associated with increased risk of CD; whereas the ORMDL3 variant is associated with susceptibility to UC in the Lithuanian early-onset IBD population. PMID- 27932195 TI - Sex-related differences in attention and memory. AB - BACKGROUND AND OBJECTIVES: The sex differences and similarities in cognitive abilities is a continuing topic of major interest. Besides, the influences of trends over time and possible effects of sex steroid and assessment time on cognition have expanded the necessity to re-evaluate differences between men and women. Therefore, the aim of this study was to compare cognitive performance between men and women in a strongly controlled experiment. MATERIALS AND METHODS: In total, 28 men and 25 women were investigated. Variables of body temperature and heart rate were assessed. A cognitive test battery was used to assess attention (visual search, unpredictable task switching as well as complex visual search and predictable task switching tests) and memory (forced visual memory, forward digit span and free recall test). RESULTS: The differences in heart rate and body temperatures between men and women were not significant. There were no differences in the mean values of attention and memory abilities between men and women. Coefficients of variation of unpredictable task switching response and forward digit span were lower (P<0.05) in men. Coefficients of variation positively correlated (P<0.05) with attention task incorrect response and negatively correlated (P<0.05) with correct answers in the memory task. CONCLUSIONS: Current study showed no sex differences in the mean values of cognition, whereas higher intra-individual variability of short-term memory and attention switching was identified in women, indicating that their performance was lower on these cognitive abilities. PMID- 27932196 TI - A mini volume loading test (mVLT) using 2.5-mLkg-1 boluses of crystalloid for indication of perioperative changes in hydration status. AB - BACKGROUND AND OBJECTIVE: A mini volume loading test (mVLT) evaluating hemodilution during step-wise crystalloid infusion has established that the arterio-capillary plasma dilution difference is inversely correlated to the body hydration level of subjects. This observational study aimed to test whether this can be replicated in a perioperative setting using a 2.5-mLkg-1 boluses. MATERIALS AND METHODS: The mVLT was performed before induction of regional anesthesia and 24h later. Step-wise infusion implied six mini fluid challenges. These consisted of 2.5-mLkg-1 boluses of Ringer's acetate infused during 2-3min and followed by 5-min periods with no fluids. Invasive (arterial) and noninvasive (capillary) measurements of hemoglobin were performed before and after each mini fluid challenge, as well as after a 20-min period without fluid following the last bolus. Hemoglobins were used to calculate the arterio-capillary plasma dilution difference which is used as an indication of changes in body hydration level. The 24-h fluid balance was calculated. RESULTS: Subjects were 69.5 (6.0) years old, their height was 1.62m (1.56-1.65), weight was 87.0kg (75.5-97.5) and body mass index (BMI) was 33.5kg/m2 (31.0-35.1). Preoperative arterio-capillary plasma dilution difference was significantly higher than postoperative (0.085 [0.012-0.141] vs. 0.006 [-0.059 to 0.101], P=0.000). The perioperative 24-h fluid balance was 1976mL (870-2545). CONCLUSIONS: The mVLT using 2.5-mLkg-1 boluses of crystalloid was able to detect the higher postoperative body hydration level in total knee arthroplasty patients. PMID- 27932197 TI - Crucial role of carotid ultrasound for the rapid diagnosis of hyperacute aortic dissection complicated by cerebral infarction: A case report and literature review. AB - Aortic dissection is a life-threatening rare condition that may virtually present by any organ system dysfunction, the nervous system included. Acute cerebral infarction among multiple other neurological and non-neurological presentations is part of this acute aortic syndrome. Rapid and correct diagnosis is of extreme importance keeping in mind the possibility of thrombolytic treatment if a patient with a suspected ischemic stroke arrives to the Emergency Department within a 4.5 h window after symptom onset. Systemic intravenous thrombolysis in the case of an acute brain infarction due to aortic dissection may lead to fatal outcomes. In this neurological emergency it is important to rule out underlying aortic dissection by choosing appropriately quick and accurate diagnostic tool. We aimed to present a prospective follow-up case, where carotid ultrasound examination was the primary key method that led to a correct diagnosis in hyperacute (<24h) Stanford type A aortic dissection presenting as an acute ischemic stroke, and thereafter with a repeated contrast-enhanced computed tomography and transthoracic echocardiography, helped to monitor topography of intravascular processes and hemodynamic properties during the clinical course of a disease, which influenced treatment decisions. Thus, we reviewed the literature mainly focusing on the various neurological aspects associated with aortic dissection. PMID- 27932198 TI - Behaviour of health professionals concerning the recommendations for prophylaxis for infectious endocarditis in our setting: Are the guidelines followed? AB - OBJECTIVES: The prophylaxis regimens for infectious endocarditis recommended by the clinical practice guidelines have recently changed. We do not know whether the current regimens are correctly followed in our setting. Our objective was to describe the approaches of various health professionals concerning these guidelines. MATERIAL AND METHODS: We conducted a survey in Cordoba, using a 16 item online questionnaire on this topic. We randomly selected a sample of 180 practitioners (20 cardiologists, 80 dentists and 80 primary care physicians), of whom 173 responded. RESULTS: Half of the participants were men; 52% had more than 20 years of professional experience. Some 88.3% of the participants considered that prophylaxis of endocarditis is effective (77.8% of the cardiologists, 93.7% of the dentist; p=.086). In general, prophylaxis is performed in conditions of clearly established risk (>90% of those surveyed). However, prophylaxis is also performed in a high proportion of cases with no risk of endocarditis, varying between 30 and 60% according to the procedure (mostly the dentists, between 36 and 67%, followed by the primary care physicians, between 28 and 59%). The antibiotic regimens employed varied significantly. The primary care physicians were furthest from the recommended regimen (only 25.8% used the recommended regimen vs. 54.4% of dentists and 72.2% of cardiologists; p=.002). CONCLUSIONS: Compliance with the recommendations on prophylaxis for endocarditis should be improved in our setting. We observed a tendency, especially among noncardiologists, to "overindicate" the prophylaxis. PMID- 27932199 TI - Underdiagnosed chronic somatic illnesses in patients with severe mental disorder. PMID- 27932200 TI - The seroprevalence of hepatitis B, hepatitis C, and human immunodeficiency virus in patients undergoing septoplasty. AB - INTRODUCTION: Worldwide, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus are major health problems. Healthcare workers are at risk of transmitting blood-borne viruses, and surgeons have a higher risk of exposure to blood and higher rates of percutaneous injury than other healthcare workers. Septoplasty is among the 3 most commonly performed otolaryngological surgeries worldwide. OBJECTIVE: To determine the seroprevalence of Hepatitis B surface antigen, Hepatitis C virus antibody, and Human Immunodeficiency Virus antibody in patients undergoing septoplasty with and without turbinate surgery under general anesthesia, and to determine if preoperative testing should be performed in such patients. METHODS: This retrospective cross-sectional study included 3731 patients that underwent septoplasty with and without turbinate surgery between January 2005 and July 2015. HBsAg, anti-HCV, and anti-HIV seropositivity in the patients was evaluated retrospectively. RESULTS: Mean age of the patients was 36 years (range: 11-81 years). In all, 117 (3.6%) patients were positive for HBsAg, 12 (0.3%) were positive for anti-HCV, and 7 (0.2%) were positive for anti-HIV. CONCLUSIONS: Education of healthcare workers combined with routine preoperative serological testing in patients undergoing septoplasty under general and local anesthesia are needed to increase awareness of hepatitis B and C, and HIV infection among healthcare workers and patients in order to decrease the transmission rate. PMID- 27932201 TI - Percutaneous sacroplasty for sacral fracture by osteoporotic insufficiency. PMID- 27932202 TI - Environmental factors associated with familial or non-familial forms of Paget's disease of bone. AB - OBJECTIVES: The most frequent mutation linked to Paget's disease of bone (PDB), p.Pro392Leu within SQSTM1 gene, leads to phenotypic characteristics of PDB, but this mutation is seemingly insufficient to result in complete pagetic osteoclast phenotype, suggesting that possible environmental factors play a role in PDB pathogenesis. We performed an exploratory study to identify environmental factors potentially associated with familial or non-familial form of PDB in the French Canadian population. METHODS: We investigated environmental factors through a questionnaire in 176 pagetic patients, including 86 patients with a familial form, and 147 healthy controls. All participants lived in the same geographic area, within a 120km radius of Quebec City. Associations between environmental factors and familial and non-familial forms of PDB were searched. RESULTS: In the multivariate model adjusted for intra-familial correlation, PDB was associated with wood fired heating in childhood and/or adolescence (OR=2.10; 95% CI 1.13 3.90, P=0.02). In the multivariate model without considering correlation for family relatedness, familial form of PDB was associated with residency near a mine (OR=11.70; 95% CI 2.92-46.80, P<0.01) and hunting (OR=2.92; 95% CI 1.14 7.47, P=0.03). Wood fired heating during childhood and/or adolescence (P=0.02) was associated with both familial and non-familial forms. CONCLUSIONS: In conclusion, PDB was significantly associated with wood fired heating in childhood and/or adolescence, regardless of the form of PDB, familial or not. PMID- 27932203 TI - Neural connection supporting endogenous 5-hydroxytryptamine influence on autonomic activity in medial prefrontal cortex. AB - 5-hydroxytryptamine (5-HT) transmission in the medial prefrontal cortex (mPFC) enhances or suppresses signal outflow to influence emotion-/cognition-based function performances and, putatively, the autonomic responses. The top-down cortical modulation of autonomic activities may be mediated in part through projections from mPFC to brain stem dorsal vagal complex (DVC). The abundant and heterogeneous densities of 5-HT fibers across laminae in mPFC suggest serotonergic innervation of mPFC-DVC projection neurons whereby endogenous 5-HT acts to regulate autonomic activities. The present study investigated the physical relationship between 5-HT fibers and the autonomic-related mPFC neurons by examining and quantitatively characterizing the 5-HT contacts upon retrogradely labeled mPFC-DVC projection neurons in pre- and infra-limbic cortices (PrL/IL) with light and electron microscopies combined with immunocytochemistry for 5-HT and presynaptic vesicle marker synaptophysin (Syn). 5-HT varicosities were observed, under confocal microscope, to form close appositions to or, at ultrastructural level, to form asymmetric axodendritic synapses and direct contacts upon the target neurons. About 16% of the entire 5 HTergic varicosities in lamina V of PrL/IL coexpressed Syn and about 24% of the peri-somatic 5-HTergic swellings demonstrated Syn-immunoreactivity (ir), suggesting a low frequency of putative synapses estimated at optical level. Ultrastructurally, examination of thirty-seven serially cut thin 5-HT boutons closely apposed to the labeled dendritic profiles demonstrated that only three contacts presented with identifiable asymmetric, synaptic membrane specializations. These data provide the first and direct morphological evidence supporting that endogenous 5-HT may be released mainly via direct contacts bearing no identifiable synaptic specializations as well as synapses, targeting autonomic-related mPFC neurons for autonomic regulation. PMID- 27932204 TI - Total renal denervation reduces sympathoexcitation to different target organs in a model of chronic kidney disease. AB - It is known that increased sympathetic nerve activity in chronic kidney disease (CKD) progressively worsens kidney function and hypertension. We tested the hypothesis that total renal denervation contributes to reduce sympathetic activation to different beds and improves renal function in 5/6 nephrectomy model of CKD in male Wistar rats. After eight weeks of 5/6 nephrectomy surgery there was an increase in mean arterial pressure (CKD 179+/-22mmHg, n=6 vs. control animals 108+/-9; p<0.05, n=6) with no changes in heart rate (HR). Sympathetic nerve activity was increased at different levels to the remaining kidney, splanchnic and lumbar beds compared to control (CTL) group (CKD rSNA: 150+/-50, n=9 vs. CTL 96+/-15, n=9; CKD sSNA: 129+/-51, n=5 vs. CTL 34+/-14, n=6; CKD lSNA: 203+/-35, n=8 vs. CTL 146+/-21, spikes/s, n=7, p<0.05). Three weeks after total renal denervation (DNX) MAP was normalized in the CKD rats (124+/-19mmHg, n=5, p<0.05), with no change in HR. The lSNA was normalized (151+/-40, n=5, vs. CKD 203+/-35 spikes/s, n=8) and sSNA was decreased in 49% (64+/-34, n=5 vs. CKD 129+/ 51 spikes/s, n=5, p<0.05). Renal function, assessed by creatinine plasma levels was improved after renal denervation (CKD 1.50+/-0.64, n=8; vs. CKD+DNX 0.82+/ 0.22mg/mL, n=8, p<0.05). These findings demonstrate that renal nerves contribute to the maintenance of hypertension in CKD by increasing sympathoexcitation to other beds. PMID- 27932205 TI - Cold-induced sympathetic tone modifies the impact of endothelium-dependent vasodilation in the finger pulp. AB - OBJECTIVE: In thermoneutral and cold subjects, the sympathetic nervous system regulates skin blood flow by adjusting frequency of the tonic vasoconstrictor impulses. However, the way these thermoregulatory impulses influence the vascular endothelium is not well known. We studied how the sympathetic nervous system influences endothelium-dependent vasodilation (EDV) caused by shear stress in skin containing arteriovenous anastomoses (AVAs) and arterioles in healthy subjects. METHODS: Thirteen healthy subjects were exposed to thermoneutral (29 degrees C) and cold (22 degrees C) ambient temperatures on separate days. EDV was induced by releasing suprasystolic pressure cuff applied to the forearm or third finger after 4min. Bilateral laser Doppler flux from the finger pulp, dorsal finger and dorsal wrist was measured together with ultrasound Doppler from the right radial artery. Absolute EDV response (EDV peak minus baseline) and normalized relative EDV response (ratio EDV peak/baseline) were calculated (median, 95% confidence interval). The relative EDV response reflect the size of EDV response independent of the baseline level and is thus used to compare the EDV responses in the finger pulp and wrist skin in the two temperature conditions. RESULTS: In finger pulp (dominated by AVAs), the absolute EDV response (flux, au) in thermoneutral (137.8 (67.5, 168.8)) and cold (130.3 (97.2, 154.9)) was the same (p=0.85), whereas the relative EDV response was significantly higher in cold (3.6 (2.5, 5.9)) than in thermoneutral (1.4 (1.1, 1.6), p=0.002). The same patterns were found in the radial artery. In the dorsal wrist (dominated by arterioles) the absolute EDV response (flux, au) was smaller in cold (30.9 (15.91, 38.0)) than in thermoneutral (52.1 (38.4, 57.8), p=0.04), whereas the relative EDV responses in cold (3.5 (2.3, 4.2)), and thermoneutral (2.3 (1.6, 2.7)) were equal (p=0.16). CONCLUSIONS: The relative EDV responses show that the impact of EDV on skin perfusion in cold conditions is significantly greater in the finger pulp than in wrist skin. However, the absolute EDV responses indicate that vascular smooth muscle relaxation during EDV is probably not affected by higher mild cold-induced sympathetic activity either in AVAs or in arterioles. PMID- 27932206 TI - Detailed analysis of BALB/c mice challenged with wild type rotavirus EDIM provide an alternative for infection model of rotavirus. AB - Mouse is one of the infection animal models for rotavirus. Since the optimal age of mouse sensitive to rotavirus infection thus far has not been unified, we elucidated clinical symptoms, immune responses and pathological changes of mice in different ages after challenged by murine rotavirus wild strain EDIM (Epidemic Diarrhea of Infant Mice) to provide data for the estimation. One-week-old, two week-old, and three-week-old BALB/c mice were inoculated with EDIM in the challenge dose of 235 ID50, 470 ID50 and 705 ID50 respectively and were compared to mock-infected controls. Diarrhea illness, mobility, bodyweight were recorded, viral shedding and immune responses including serum IgA, fecal sIgA were detected, and small intestine tissue was evaluated for virus distribution and pathological changes. All the mice in one-week-old and two-week-old groups were completely unavoidable to be infected by EDIM and have been found to be malaise, activity reduced and even diarrhea, while three-week-old mice partly resist the challenge with 40% mice free from diarrhea. Meanwhile, EDIM infection has greater impact to the bodyweight of two-week-old group than those of one-week-old, three week-old (0.9860 vs 1.2340, 1.2375g/day). One peak of virus shedding in three groups was observed in day 1-2 post infection, but the duration shortened with age increase. Feces sIgA in both two-week-old and three-week-old groups began to increase in day 4, 2-3days earlier than that in one-week-old group, and grow to the peak in day 8, which is about 2 fold of that in one-week-old group. Stronger serum IgA response was found in two-week-old group, it increased to the peak in day 15 and the level was 2 fold of three-week-old group and 4 fold of one-week old group. The pathological changes included vacuolar degeneration, edema and congestion of intestinal wall, integrity destruction of enteric epithelium, and the changes relieved with the increase of age. Besides, rotavirus particles were found in small intestine tissues, especially in the surface and crypt of villi. In conclusion, the two-week-old mice were more sensitive to EDIM infection and initiated more effective immune response. In combination with that 14days old mice equals to 2 months infant when the first dose of rotavirus vaccine should be administrated, two-week-old mice is preferred to be used as infection model for the study of pathogenicity and immunogenicity of rotavirus. PMID- 27932208 TI - A novel approach to deprescribing in long-term care settings: The SMART campaign. AB - There have been numerous calls within the medical community urging providers to consider the complex problem of inappropriate polypharmacy and inappropriate medication use among nursing home residents. It is clear that innovative, longitudinal policy-supported interventions are needed to better understand prescribing practices in long-term care settings and to curtail the negative, cascading outcomes associated with inappropriate polypharmacy among elderly patients. The Indiana Safer Medication Administration Regimens and Treatment (SMART) campaign is funded by the Indiana State Department of Health for a pilot period of 2 years (2016-18) with the objectives of: 1. Reducing the average number of medications per resident, 2. Reducing use of antipsychotic, anxiolytic, and hypnotic medications, and 3. Reducing overall medication costs within participating facilities. In this report we comment upon what is new about the Indiana approach, and what we believe is worthy of consideration by other states. PMID- 27932209 TI - Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver. PMID- 27932207 TI - The current state of therapeutic and T cell-based vaccines against human papillomaviruses. AB - Human papillomavirus (HPV) is known to be a necessary factor for many gynecologic malignancies and is also associated with a subset of head and neck malignancies. This knowledge has created the opportunity to control these HPV-associated cancers through vaccination. However, despite the availability of prophylactic HPV vaccines, HPV infections remain extremely common worldwide. In addition, while prophylactic HPV vaccines have been effective in preventing infection, they are ineffective at clearing pre-existing HPV infections. Thus, there is an urgent need for therapeutic and T cell-based vaccines to treat existing HPV infections and HPV-associated lesions and cancers. Unlike prophylactic vaccines, which generate neutralizing antibodies, therapeutic, and T cell-based vaccines enhance cell-mediated immunity against HPV antigens. Our review will cover various therapeutic and T cell-based vaccines in development for the treatment of HPV associated diseases. Furthermore, we review the strategies to enhance the efficacy of therapeutic vaccines and the latest clinical trials on therapeutic and T cell-based HPV vaccines. PMID- 27932210 TI - Valproate induced cerebellar atrophy presenting as movement disorder. PMID- 27932212 TI - Atmospheric deposition of particles at a sensitive alpine lake: Size-segregated daily and annual fluxes from passive sampling techniques. AB - Lake Tahoe, a North American alpine lake long appreciated for its clear water and geographic setting, has experienced a trend of declining water clarity due to increasing nutrient and particle inputs. Contributions from atmospheric deposition of particulate matter (PM) could be important, yet they are inadequately quantified. This study established a yearlong deposition monitoring network in the northern Lake Tahoe Basin. Dry deposition was quantified on surrogate surfaces while wet deposition was based on particles suspended in precipitation at 24-hour resolution. The particle size ranges by these passive techniques were 1-64MUm and 0.5-20MUm in diameter for dry and wet deposition, respectively. Dry deposition of submicrometer (0.5-1MUm) particles was also estimated by extrapolation of a lognormal size distribution. Higher daily number deposition fluxes (NDFdry and NDFwet) were found at a near-shore site, confirming substantial impacts of commercial and tourist activities. The two more isolated sites indicated a uniform regional background. On average, daily NDFdry is about one order of magnitude lower than daily NDFwet. Dry deposition velocities increased rapidly with particle size, as evidenced by collocated measurements of NDFdry and ambient particle number concentrations, though it seems less so for wet deposition due to different scavenging mechanisms. Despite fewer "wet" days than "dry" days during the monitoring period, wet processes dominated seasonal particle deposition, particularly in winter and spring when most precipitation occurred. Adopting sediment (insoluble, inorganic) particle fraction estimates from the literature, this study reports an annual particle flux of 2.9-5.2*1010#m 2yr-1 for sediment particles with 1-20MUm diameter and 6.1-11*1010#m-2yr-1 for those with 0.5-20MUm diameter. Implications of these findings to the current knowledge of atmospheric deposition in the Lake Tahoe Total Maximum Daily Load (TMDL) are discussed. PMID- 27932211 TI - A novel class of somatic mutations in blood detected preferentially in CD8+ cells. AB - Somatic mutations have a central role in cancer but their role in other diseases such as autoimmune disorders is poorly understood. Earlier work has provided indirect evidence of rare somatic mutations in autoreactive T-lymphocytes in multiple sclerosis (MS) patients but such mutations have not been identified thus far. We analysed somatic mutations in blood in 16 patients with relapsing MS and 4 with other neurological autoimmune disease. To facilitate the detection of somatic mutations CD4+, CD8+, CD19+ and CD4-/CD8-/CD19- cell subpopulations were separated. We performed next-generation DNA sequencing targeting 986 immune related genes. Somatic mutations were called by comparing the sequence data of each cell subpopulation to other subpopulations of the same patient and validated by amplicon sequencing. We found non-synonymous somatic mutations in 12 (60%) patients (10 MS, 1 myasthenia gravis, 1 narcolepsy). There were 27 mutations, all different and mostly novel (67%). They were discovered at subpopulation-wise allelic fractions of 0.2%-4.6% (median 0.95%). Multiple mutations were found in 8 patients. The mutations were enriched in CD8+ cells (85% of mutations). In follow up after a median time of 2.3years, 96% of the mutations were still detectable. These results unravel a novel class of persistent somatic mutations, many of which were in genes that may play a role in autoimmunity (ATM, BTK, CD46, CD180, CLIP2, HMMR, IKFZF3, ITGB3, KIR3DL2, MAPK10, CD56/NCAM1, RBM6, RORA, RPA1 and STAT3). Whether some of this class of mutations plays a role in disease is currently unclear, but these results define an interesting hitherto unknown research target for future studies. PMID- 27932213 TI - Relating hydraulic conductivity and hyporheic zone biogeochemical processing to conserve and restore river ecosystem services. AB - River management practices commonly attempt to improve habitat and ecological functioning (e.g. biogeochemical processing or retention of pollutants) by restoring hydrological exchange with the hyporheic zone (i.e. hyporheic flow) in an effort to increase mass transfer of solutes (nutrients, carbon and electron acceptors such as oxygen or nitrate). However, even when hyporheic flow is increased, often no significant changes in biogeochemical processing are detected. Some of these apparent paradox result from the simplistic assumption that there is a direct relationship between hyporheic flow and biogeochemical processing. We propose an alternative conceptual model that hyporheic flow is non linearly related with biogeochemical processing. Based on the different solute mass transfer and area available for colonization among hydraulic conductivities, we hypothesize that biogeochemical processing in the hyporheic zone follows a Gaussian function depending on hyporheic hydraulic conductivity. After presenting the conceptual model and its domain of application, we discuss the potential implications, notably for river restoration and further hyporheic research. PMID- 27932214 TI - A regional assessment of chemicals of concern in surface waters of four Midwestern United States national parks. AB - Anthropogenic chemicals and their potential for adverse biological effects raise concern for aquatic ecosystem health in protected areas. During 2013-15, surface waters of four Midwestern United States national parks were sampled and analyzed for wastewater indicators, pharmaceuticals, personal care products, and pesticides. More chemicals and higher concentrations were detected at the two parks with greater urban influences (Mississippi National River and Recreation Area and Indiana Dunes National Lakeshore) than at the two more remote parks (Apostle Islands National Lakeshore and Isle Royale National Park). Atrazine (10 15ng/L) and N,N-diethyl-meta-toluamide (16-120ng/L) were the only chemicals detected in inland lakes of a remote island national park (Isle Royale National Park). Bisphenol A and organophosphate flame retardants were commonly detected at the other sampled parks. Gabapentin and simazine had the highest observed concentrations (>1000ng/L) in three and two samples, respectively. At the two parks with urban influences, metolachlor and simazine concentrations were similar to those reported for other major urban rivers in the United States. Environmental concentrations of detected chemicals were often orders of magnitude less than standards or reference values with three exceptions: (1) hydrochlorothiazide exceeded a human health-based screening value in seven samples, (2) estrone exceeded a predicted critical environmental concentration for fish pharmacological effects in one sample, and (3) simazine was approaching the 4000ng/L Maximum Contaminant Level in one sample even though this concentration is not expected to reflect peak pesticide use. Although few environmental concentrations were approaching or exceeded standards or reference values, concentrations were often in ranges reported to elicit effects in aquatic biota. Data from this study will assist in establishing a baseline for chemicals of concern in Midwestern national parks and highlight the need to better understand the sources, pathways, and potential adverse effects to aquatic systems in national parks. PMID- 27932215 TI - The land-use legacy effect: Towards a mechanistic understanding of time-lagged water quality responses to land use/cover. AB - Numerous studies have linked land use/land cover (LULC) to aquatic ecosystem responses, however only a few have included the dynamics of changing LULC in their analysis. In this study, we explicitly recognize changing LULC by linking mechanistic groundwater flow and travel time models to a historical time series of LULC, creating a land-use legacy map. We then illustrate the utility of legacy maps to explore relationships between dynamic LULC and lake water chemistry. We tested two main concepts about mechanisms linking LULC and lake water chemistry: groundwater pathways are an important mechanism driving legacy effects; and, LULC over multiple spatial scales is more closely related to lake chemistry than LULC over a single spatial scale. We applied statistical models to twelve water chemistry variables, ranging from nutrients to relatively conservative ions, to better understand the roles of biogeochemical reactivity and solubility on connections between LULC and aquatic ecosystem response. Our study illustrates how different areas can have long groundwater pathways that represent different LULC than what can be seen on the landscape today. These groundwater pathways delay the arrival of nutrients and other water quality constituents, thus creating a legacy of historic land uses that eventually reaches surface water. We find that: 1) several water chemistry variables are best fit by legacy LULC while others have a stronger link to current LULC, and 2) single spatial scales of LULC analysis performed worse for most variables. Our novel combination of temporal and spatial scales was the best overall model fit for most variables, including SRP where this model explained 54% of the variation. We show that it is important to explicitly account for temporal and spatial context when linking LULC to ecosystem response. PMID- 27932216 TI - Arsenic contamination of drinking water in Ireland: A spatial analysis of occurrence and potential risk. AB - The presence of arsenic in groundwater has become a global concern due to the health risks from drinking water with elevated concentrations. The Water Framework Directive (WFD) of the European Union calls for drinking water risk assessment for member states. The present study amalgamates readily available national and sub-national scale datasets on arsenic in groundwater in the Republic of Ireland. However, due to the presence of high levels of left censoring (i.e. arsenic values below an analytical detection limit) and changes in detection limits over time, the application of conventional statistical methods would inhibit the generation of meaningful results. In order to handle these issues several arsenic databases were integrated and the data modelled using statistical methods appropriate for non-detect data. In addition, geostatistical methods were used to assess principal risk components of elevated arsenic related to lithology, aquifer type and groundwater vulnerability. Geographic statistical methods were used to overcome some of the geographical limitations of the Irish Environmental Protection Agency (EPA) sample database. Nearest-neighbour inverse distance weighting (IDW) and local indicator of spatial association (LISA) methods were used to estimate risk in non-sampled areas. Significant differences were also noted between different aquifer lithologies, indicating that Rhyolite, Sandstone and Shale (Greywackes), and Impure Limestone potentially presented a greater risk of elevated arsenic in groundwaters. Significant differences also occurred among aquifer types with poorly productive aquifers, locally important fractured bedrock aquifers and regionally important fissured bedrock aquifers presenting the highest potential risk of elevated arsenic. No significant differences were detected among different groundwater vulnerability groups as defined by the Geological Survey of Ireland. This research will assist management and future policy directions of groundwater resources at EU level and guide future research focused on understanding arsenic mobilisation processes to facilitate in guiding future development, testing and treatment requirements of groundwater resources. PMID- 27932217 TI - Highly efficient and stable Zr-doped nanocrystalline PbO2 electrode for mineralization of perfluorooctanoic acid in a sequential treatment system. AB - Zr-doped nanocrystalline PbO2 (Zr-PbO2) film electrodes were prepared at different bath temperatures. The Zr-PbO2 electrode doped at 75 degrees C (75-Zr PbO2) featured high oxygen evolution overpotential, large effective area and good electrocatalytic performance. The oxygen evolution potential and the effective area of 75-Zr-PbO2 achieved 1.91V (vs. SCE) and 9.1cm2, respectively. The removal efficiency and the defluorination ratio of PFOA reached 97.0% and 88.1% after 90min electrolysis. The primary mineralization products (i.e., F- and intermediates) and their change trends were determined. The 75-Zr-PbO2 electrode was introduced to sequentially treat the PFOA wastewater. In an 116h of 75-Zr PbO2 electrocatalysis sequential process, the PFOA, PFHpA, PFHxA, PFPeA, PFBA, PFPrA, TFA, and TOC concentrations were reduced to below 30, 2.5, 1.3, 1.0, 0.5, 0.2, 0.1, and 9mgL-1, respectively, demonstrating the promising application of the sequential treatment system for the treatment of PFOA wastewater. PMID- 27932218 TI - Bisphenol A (BPA) in the serum of pet dogs following short-term consumption of canned dog food and potential health consequences of exposure to BPA. AB - Bisphenol A (BPA) is a widely present endocrine disruptor chemical found in many household items. Moreover, this chemical can bioaccumulate in various terrestrial and aquatic sources; thereby ensuring continual exposure of animals and humans. For most species, including humans, diet is considered the primary route of exposure. However, there has been little investigation whether commercial-brands of dog foods contain BPA and potential health ramifications of BPA-dietary exposure in dogs. We sought to determine BPA content within dog food, whether short-term consumption of these diets increases serum concentrations of BPA, and potential health consequences, as assessed by potential hematological, serum chemistry, cortisol, DNA methylation, and gut microbiome changes, in dogs associated with short-term dietary exposure to BPA. Fourteen healthy privately owned dogs were used in this study. Blood and fecal samples were collected prior to dogs being placed for two-weeks on one of two diets (with one considered to be BPA-free), and blood and fecal samples were collected again. Serum/plasma samples were analyzed for chemistry and hematology profiles, cortisol concentrations, 5 methylcytosine in lymphocytes, and total BPA concentrations. Fecal samples were used for microbiome assessments. Both diets contained BPA, and after two-weeks of being on either diet, dogs had a significant increase in circulating BPA concentrations (pre-samples=0.7+/-0.15ng/mL, post-samples=2.2+/-0.15ng/mL, p<0.0001). Elevated BPA concentrations positively correlated with increased plasma bicarbonate concentrations and associated with fecal microbiome alterations. Short-term feeding of canned dog food increased circulating BPA concentrations in dogs comparable to amounts detected in humans, and greater BPA concentrations were associated with serum chemistry and microbiome changes. Dogs, who share our internal and external environments with us, are likely excellent indicators of potential human health concerns to BPA and other environmental chemicals. These findings may also have relevance to aquatic and terrestrial wildlife. PMID- 27932219 TI - The effects of long-term management on patterns of carbon storage in a northern highbush blueberry production system. AB - Perennial crops potentially provide a sink for atmospheric carbon. However, there is a poor understanding of how perennial crops differ in their carbon allocation patterns, and few studies have tested how agronomic practices such as fertilization influence long-term patterns of carbon allocation in actual production systems. In this study, we report results of a long-term field experiment that tested the individual and combined effects of organic matter incorporation and nitrogen fertilization on carbon allocation. The mature (nine year-old) blueberry plants in this study had an average standing carbon stock of 1147gCm-2 and average annual Net Primary Production (NPP) of 523gCm-2yr-1, values that are similar to those reported for other woody crops. Forty-four percent of blueberry annual NPP was sequestered in persistent biomass, 19% was exported as harvested fruit, and 37% entered the detrital pathway. Nitrogen applied at rates typical for blueberry production throughout the span of the study had no significant effect on total plant or soil C. However, pre-planting organic matter incorporation and periodic mulching with sawdust significantly increased both soil organic matter and soil C. Pre-planting organic matter incorporation also increased total standing plant C nine years later at maturity. At the field scale, we estimate that fields receiving pre-planting organic matter incorporation would have 4.8% (4.5Mgha-1) more standing C relative to non-amended fields, although the difference is within the range of uncertainty of the estimated values. These results suggest that blueberry production can provide a valuable medium-term carbon store that is comparable in magnitude to that of temperate tree crops, but overall carbon budgets are influenced by management practices over the first decade after planting. PMID- 27932220 TI - Risk management for optimal land use planning integrating ecosystem services values: A case study in Changsha, Middle China. AB - Land-use change has direct impact on ecosystem services and alters ecosystem services values (ESVs). Ecosystem services analysis is beneficial for land management and decisions. However, the application of ESVs for decision-making in land use decisions is scarce. In this paper, a method, integrating ESVs to balance future ecosystem-service benefit and risk, is developed to optimize investment in land for ecological conservation in land use planning. Using ecological conservation in land use planning in Changsha as an example, ESVs is regarded as the expected ecosystem-service benefit. And uncertainty of land use change is regarded as risk. This method can optimize allocation of investment in land to improve ecological benefit. The result shows that investment should be partial to Liuyang City to get higher benefit. The investment should also be shifted from Liuyang City to other regions to reduce risk. In practice, lower limit and upper limit for weight distribution, which affects optimal outcome and selection of investment allocation, should be set in investment. This method can reveal the optimal spatial allocation of investment to maximize the expected ecosystem-service benefit at a given level of risk or minimize risk at a given level of expected ecosystem-service benefit. Our results of optimal analyses highlight tradeoffs between future ecosystem-service benefit and uncertainty of land use change in land use decisions. PMID- 27932221 TI - What are the most important variables for Poaceae airborne pollen forecasting? AB - In this paper, the problem of predicting future concentrations of airborne pollen is solved through a computational intelligence data-driven approach. The proposed method is able to identify the most important variables among those considered by other authors (mainly recent pollen concentrations and weather parameters), without any prior assumptions about the phenological relevance of the variables. Furthermore, an inferential procedure based on non-parametric hypothesis testing is presented to provide statistical evidence of the results, which are coherent to the literature and outperform previous proposals in terms of accuracy. The study is built upon Poaceae airborne pollen concentrations recorded in seven different locations across the Spanish province of Madrid. PMID- 27932222 TI - Using a contextualized sensemaking model for interaction design: A case study of tumor contouring. AB - Sensemaking theories help designers understand the cognitive processes of a user when he/she performs a complicated task. This paper introduces a two-step approach of incorporating sensemaking support within the design of health information systems by: (1) modeling the sensemaking process of physicians while performing a task, and (2) identifying software interaction design requirements that support sensemaking based on this model. The two-step approach is presented based on a case study of the tumor contouring clinical task for radiotherapy planning. In the first step of the approach, a contextualized sensemaking model was developed to describe the sensemaking process based on the goal, the workflow and the context of the task. In the second step, based on a research software prototype, an experiment was conducted where three contouring tasks were performed by eight physicians respectively. Four types of navigation interactions and five types of interaction sequence patterns were identified by analyzing the gathered interaction log data from those twenty-four cases. Further in-depth study on each of the navigation interactions and interaction sequence patterns in relation to the contextualized sensemaking model revealed five main areas for design improvements to increase sensemaking support. Outcomes of the case study indicate that the proposed two-step approach was beneficial for gaining a deeper understanding of the sensemaking process during the task, as well as for identifying design requirements for better sensemaking support. PMID- 27932223 TI - Relationship between Psychophysical Measures of Retinal Ganglion Cell Density and In Vivo Measures of Cone Density in Glaucoma. AB - PURPOSE: Considerable between-individual variation in retinal ganglion cell (RGC) density exists in healthy individuals, making identification of change from normal to glaucoma difficult. In ascertaining local cone-to-RGC density ratios in healthy individuals, we wished to investigate the usefulness of objective cone density estimates as a surrogate of baseline RGC density in glaucoma patients, and thus a more efficient way of identifying early changes. DESIGN: Exploratory cohort study. PARTICIPANTS: Twenty glaucoma patients (60% women) with a median age of 54 years and mean deviation (MD) in the visual field of -5 dB and 20 healthy controls (70% women) with a median age of 57 years and a mean MD of 0 dB were included. METHODS: Glaucoma patients and healthy participants underwent in vivo cone imaging at 4 locations of 8.8 degrees eccentricity with a modified Heidelberg Retina Angiograph HRA2 (scan angle, 3 degrees ). Cones were counted using an automated program. Retinal ganglion cell density was estimated at the same test locations from peripheral grating resolution acuity thresholds. MAIN OUTCOME MEASURES: Retinal cone density, estimated RGC density, and cone-to-RGC ratios in glaucoma patients and healthy controls. RESULTS: Median cone-to-RGC density was 3.51:1 (interquartile range [IQR], 2.59:1-6.81:1) in glaucoma patients compared with 2.35:1 (IQR, 1.83:1-2.82:1) in healthy participants. Retinal ganglion cell density was 33% lower in glaucoma patients than in healthy participants; however, cone density was very similar in glaucoma patients (7248 cells/mm2) and healthy controls (7242 cells/mm2). The area under the receiver operator characteristic curve was 0.79 (95% confidence interval [CI], 0.71-0.86) for both RGC density and cone-to-RGC ratio and 0.49 (95% CI, 0.39-0.58) for cone density. CONCLUSIONS: Local measurements of cone density do not differ significantly from normal in glaucoma patients despite large differences in RGC density. There was no statistically significant association between RGC density and cone density in the normal participants, and the range of cone-to-RGC density ratios was relatively large in healthy controls. These findings suggest that estimates of baseline RGC density from cone density are unlikely to be precise and offer little advantage over determination of RGC alone in the identification of early glaucomatous change. PMID- 27932224 TI - Unmet needs in Parkinson's disease: New horizons in a changing landscape. AB - The success of levodopa and other classes of drugs have meant that most people with Parkinson's disease enjoy a good quality of life for many years. However, despite the availability of several drugs and formulations that can be used as monotherapy and in combination, there are a number of disease features that the current therapies are unable to address. The disease continues to progress despite treatment, patients suffer from a myriad of motor and non-motor symptoms, and a neuroprotective therapy is urgently required. To move forward with medical and surgical management, it is important to consider new insights that recent research offers and in this review we examine how a better understanding of the disease pathology and progression might improve and enrich our daily clinical practice. It is also timely to consider the service provision changes that will increasingly be needed to effectively manage the needs of the aging population. PMID- 27932225 TI - Hospitalizations of children with sickle cell disease in the Brazilian Unified Health System in the state of Minas Gerais. AB - OBJECTIVE: To identify and characterize hospital admissions and readmissions in the Brazilian Unified Public Health System (Sistema Unico de Saude [SUS]) in children with sickle cell disease diagnosed by the Minas Gerais Newborn Screening Program between 1999 and 2012. METHODS: Hospital Admission Authorizations with the D57 (International Classification of Diseases-10) code in the fields of primary or secondary diagnosis were retrieved from the SUS Databank (1999-2012). There were 2991 hospitalizations for 969 children. RESULTS: 73.2% of children had hemoglobin SS/Sbeta0-thalassemia and 48% were girls. The mean age was 4.3+/-3.2 years, the mean number of hospitalizations, 3.1+/-3.3, and the hospital length of stay, 5+/-3.9 days. Hospital readmissions occurred for 16.7% of children; 10% of admissions were associated with readmission within 30 days after discharge; 33% of readmissions occurred within seven days post-discharge. There were 41 deaths, 95% of which were in-hospital. Secondary diagnoses were not recorded in 96% of admissions, making it impossible to know the reason for admission. In 62% of cases, hospitalizations occurred in the child's county of residence. The total number of hospitalizations of children under 14 with sickle cell disease relative to the total of pediatric hospitalizations increased from 0.12% in 1999 to 0.37% in 2012. CONCLUSIONS: A high demand for hospital care in children with sickle cell disease was evident. The number of hospitalizations increased from 1999 to 2012, suggesting that the disease has become more "visible." Knowledge of the characteristics of these admissions can help in the planning of care for these children in the SUS. PMID- 27932226 TI - Value on the Front End: Making the Effective Diagnosis for Optimal Treatment. AB - Much effort is being made to quantitate and improve the outcomes associated with medical treatment. These outcomes are defined as how the patient did after an intervention and may be termed "value on the back end" of the treatment process. The diagnosis guides the content and timing of the treatment, and may be considered the "value on the front end" that optimizes the treatment process. The diagnosis can be defined as "that body of information, collected through the process of evaluating the patient's health problem, that determines the content and timing of the treatment of the health problem." An Institute of Medicine monograph has documented "troubling" deficiencies in the diagnostic process and has suggested guidelines to establish a comprehensive and effective diagnosis, which should include anatomic and patient-derived factors, have multidisciplinary input, have implications for treatment content and timing, and relate to outcomes. The monograph establishes a linear relationship and direct linkage between the diagnosis and treatment. There is much evidence in orthopaedics that these deficiencies exist and often limit the implementation of the most beneficial treatments. Efforts should be made to improve the effectiveness of the diagnostic process to optimize the entire treatment process. The 5 A's framework can be used as a template for the accumulation of information that can guide the treatment process. PMID- 27932227 TI - Impact of ethnicity and obesity on insulin resistance in two ethnic groups at very high risk of type 2 diabetes. PMID- 27932228 TI - The end of almost 10 years of negative RCTs in advanced hepatocellular carcinoma. PMID- 27932230 TI - Department of Error. PMID- 27932229 TI - Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. AB - BACKGROUND: There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. METHODS: In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (>=400 mg/day for >=20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and alpha-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. FINDINGS: Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0.63 (95% CI 0.50-0.79; one-sided p<0.0001); median survival was 10.6 months (95% CI 9.1-12.1) for regorafenib versus 7.8 months (6.3-8.8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand-foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group. INTERPRETATION: Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib. FUNDING: Bayer. PMID- 27932231 TI - Discovery of novel antibacterials. PMID- 27932232 TI - Schizophrenia polygenic risk score and prepubertal developmental impairments. PMID- 27932233 TI - Schizophrenia risk alleles and neurodevelopmental outcomes in childhood: a population-based cohort study. AB - BACKGROUND: Schizophrenia typically onsets after puberty but is often preceded by observable childhood neurodevelopmental impairments. Whether these childhood antecedents index genetic liability is unknown. We used polygenic risk scores derived from a patient discovery sample as indicators of the genetic liability of schizophrenia. Our aim was to identify the early childhood manifestations of this liability in a UK population-based cohort. METHODS: The study sample was the Avon Longitudinal Study of Parents and Children, a prospective population-based cohort study of 14701 children. Data were primarily analysed with regression-based analyses. Polygenic risk score were generated from a published Psychiatric Genomics Consortium genome-wide association study. Outcomes were childhood (age 4 9 years) dimensional measures in four developmental domains with 12 indicators: cognition and learning, social and communication, emotion and mood regulation, and behaviour (n=5100-6952). FINDINGS: At age 7-9 years, schizophrenia polygenic risk scores showed associations with lower performance intelligence quotient (beta -0.056, OR 1.13 [95% CI 1.04-1.23]), poorer social understanding (beta 0.032, OR 1.08 [1.00-1.17]), worse language intelligibility and fluency (beta 0.032, OR 1.10 [1.02-1.20]), more irritability (beta 0.032, OR 1.07 [1.01-1.14]), and more headstrong behaviour (beta 0.031, OR 1.08 [1.02-1.15]). The schizophrenia polygenic risk scores also predicted social and behavioural impairments as early as age 4 years. INTERPRETATION: Childhood cognitive, social, behavioural, and emotional impairments, implicated as antecedents to schizophrenia in high-risk, developmental studies, might represent early manifestations of genetic liability. FUNDING: Medical Research Council. PMID- 27932234 TI - Integrity of Ayurveda. PMID- 27932235 TI - Foreword: International Conference on Environmental Radioactivity ENVIRA2015 - New Challenges with New Analytical Technologies. PMID- 27932236 TI - Reply to the letter: "Sweet taste disorder and vascular complications in patients with abnormal glucose tolerance". PMID- 27932237 TI - Spontaneous coronary artery dissection was missed but not misdiagnosed as takotsubo syndrome. PMID- 27932238 TI - Gender differences in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy: Clinical manifestations, electrophysiological properties, substrate characteristics, and prognosis of radiofrequency catheter ablation. AB - BACKGROUND: Gender differences in the penetrance and clinical expression of genetic mutations have been reported in patients with arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C). Our study aimed at clarifying the impact of gender on ventricular substrates and clinical outcomes after radiofrequency catheter ablation (RFCA). METHODS: Patients with ARVD/C underwent RFCA for drug-refractory ventricular arrhythmias (VAs) were consecutively enrolled. Baseline characteristics, electrocardiograms, ventricular substrates, and VA recurrences after RFCA were extracted for comparison between genders. RESULTS: A total of 70 consecutive unselected patients with definite ARVD/C (36 men [51%], age 45+/-14years) were studied. Male patients had a higher incidence of sustained ventricular tachycardia and ventricular fibrillation or sudden cardiac arrest as initial manifestations. Electroanatomical mapping demonstrated that men with ARVD/C had a larger epicardial RV unipolar low-voltage zone, a larger endocardial and epicardial area with late potentials, and longer local abnormal ventricular activity. Cox regression analysis demonstrated that gender and late potential area predicted the recurrences of VAs. CONCLUSION: Patients with ARVD/C displayed different characteristics of VAs and substrate properties between men and women. Male gender and the presence of larger area of abnormal electrograms independently predicted VA recurrences after RFCA. PMID- 27932239 TI - The therapeutic effect of rosuvastatin and propylthiouracil on ameliorating high cholesterol diet-induced rabbit aortic atherosclerosis and stiffness. AB - BACKGROUND: We tested the hypothesis that arteriosclerosis-augmented aortic pulse wave velocity (PWV) and -impaired vasorelaxation were attenuated by rosuvastatin (Rosu) and propylthiouracil (PTU) therapy. METHODS AND RESULTS: Thirty-two New Zealand rabbits were equally divided into group 1 (sham-control), group 2 [high cholesterol-diet (HCD) for 8weeks], group 3 [HCD-Rosu (20mg/kg/day administration after 4-week HFD for 4weeks)], and group 4 [HCD-PTU (0.1% PTU in drinking water), the treatment course as group 3]. KCl-induced vasoconstriction of carotid artery (CA) was significantly higher in group 2 than in other groups (all p<0.01), but showed no differences among groups 1, 3 and 4, whereas acetylcholine-induced vasorelaxation exhibited an opposite pattern of KCl-induced vasoconstriction among the four groups (p<0.001). Basic nitric-oxide release from endothelial cells of CA was highest in group 1, lowest in group 2, but showed no difference between groups 3 and 4 (all p<0.001). PWV value was highest in group 2, lowest in group 1, and significantly higher in group 4 than in group 3 (all p<0.001). Serum levels of total-cholesterol, LDL and TG showed an identical pattern to PWV (all p<0.001), whereas the levels of free T4, sugar, and body weight did not differ among the four groups (all p>0.4). Aortic inflammatory biomarkers in cellular (CD68+/IL-1beta+/CD14+) and protein (TNF-alpha/NF-kappaB/IL-1beta/MMP-9/MCP 1/ICAM-1/PDGF) levels, and aortic oxidative-stress biomarkers in cellular (8 OHdG) and protein (NOX-1/NOX-2/oxidized protein) levels showed an identical pattern to PWV among the four groups (all p<0.001). CONCLUSION: Rosu-PTU therapy ameliorated aortic stiffness and inflammation/oxidative-stress, and improved endothelial-cell function after HCD challenge in rabbit. PMID- 27932240 TI - Surgery Versus 5% Imiquimod for Nodular and Superficial Basal Cell Carcinoma: 5 Year Results of the SINS Randomized Controlled Trial. AB - We previously reported modest clinical 3-year benefit for topical imiquimod compared with surgery for superficial or nodular basal cell carcinoma at low-risk sites in our noninferiority randomized controlled SINS trial. Here we report 5 year data. Participants were randomized to imiquimod 5% cream once daily (superficial basal cell carcinoma, 6 weeks; nodular basal cell carcinoma, 12 weeks) or excisional surgery (4-mm margin). The primary outcome was clinical absence of initial failure or signs of recurrence at the 3-year dermatology review. Five-year success was defined as 3-year success plus absence of recurrences identified through hospital, histopathology, and general practitioner records. Of 501 participants randomized, 401 contributed to the modified intention-to-treat analyses at year 3 (primary outcome), 383 (96%) of whom had data at year 5. Five-year success rates for imiquimod were 82.5% (170/206) compared with 97.7% (173/177) for surgery (relative risk of imiquimod success = 0.84, 95% confidence interval = 0.77-0.91, P < 0.001). These were comparable to year 3 success rates of 83.6% (178/213) and 98.4% (185/188) for imiquimod and surgery, respectively. Most imiquimod treatment failures occurred in year 1. Although surgery is clearly superior to imiquimod, this study shows sustained benefit for lesions that respond early to topical imiquimod. PMID- 27932241 TI - Nonspecific effects of gap paradigm on swallowing. AB - OBJECTIVE: Analogous to the gap paradigm in experiments for saccadic eye movements with very short reaction times, we hypothesized that the initiation of oropharyngeal swallowing movements guided by visual cues are encouraged under experimental conditions using a similar gap paradigm. METHODS: A red visual cue indicating to hold a bolus in the mouth and a blue one indicating to swallow the bolus were sequentially provided on a computer display to 11 healthy participants. The gap period between these cues varied from 0 to 800ms. Swallowing kinetics and kinematics were recorded using surface electromyography and a laser displacement sensor, respectively. RESULTS: In comparison with the no gap paradigm, the delay from the onset of muscle activities to initiation of movement significantly decreased with a 100- (p<0.01) and 200-ms (p<0.005) gap period. With other gap periods, no significant change was detected in the delay. CONCLUSIONS: Initiation of visually guided swallowing was enhanced by a gap paradigm of 100-200ms. Wrist flexion was boosted in a similar manner. Thus, the gap effect may be a generalized warning effect. SIGNIFICANCE: Our findings might provide insights into the contribution of the basal ganglia to volitional swallowing. PMID- 27932242 TI - Elevated salivary IgA, decreased anxiety, and an altered oral microbiota are associated with active participation on an undergraduate athletic team. AB - BACKGROUND: Previous reports indicate that regular, but not excessive, exercise can moderate the response to anxiety and alter the immune response, therefore we hypothesized that college student athletes who were actively participating on an NCAA Division III athletics team ("in-season") would have lower levels of anxiety and higher salivary IgA levels than similar college athletes who were in their "off-season". NCAA Division III athletes participate in athletics at a level of intensity that is more moderate compared to other NCAA divisions. Alterations in the microbiome have been associated with alterations in psychosocial well-being and with exercise. Therefore, we also proposed that the oral microbiota would be different in "in-season" versus "off-season" athletes. METHOD: In this pilot study, nineteen female students participating on a NCAA Division III athletic team (hockey="in-season"; soccer="off-season") were compared for level of fitness (modified Balke test of VO2 max), salivary IgA levels by immunoassay, anxiety (using a GAD-7 survey), salivary cortisol levels by immunoassay, and numbers of culturable bacteria by growth of CFU/ml on blood agar, mitis salivarius agar and Staphylococcus 110 agar. RESULTS: The proportion of subjects reporting "severe anxiety" on an anxiety scale (GAD-7) were significantly greater in the "off season" group compared to the "in-season" group (p=0.047, Chi-squared test). "In season" athletes had significantly higher salivary IgA/total protein levels than "off-season" athletes (one-sided Student's t-test; p=0.03). Cortisol levels were not significantly different in the two groups. The total culturable bacteria counts were higher among "in-season" athletes (p=0.0455, Wilcoxon Rank Sum test), as measured by CFUs on blood agar plates, an estimate of total culturable bacteria, including pathogenic and non-pathogenic bacteria. In contrast, there was a decrease in the growth of bacteria from the oral cavity of the "in-season" athletes, when the growth of bacteria on mitis salivarius agar (primarily oral streptococcus) was measured (p=0.0006, Wilcoxon Rank Sum test). There was a negative correlation (Spearman Rank correlation coefficient=-0.651, p=0.0018 one sided) between high IgA levels and the growth of bacteria on mitis salivarius agar in the combined group of "in-season" and "off-season" athletes, suggesting a protective response of high IgA levels to the typical oral pathogenic bacteria. Anxiety levels (GAD-7) in the "in-season" group were positively correlated with growth of oral bacteria on blood agar (Spearman Rank correlation coefficient of 0.622 for "in-season", p value=0.033 one-sided) and mitis salivarius agar (Spearman Rank correlation coefficient=0.671 for "in-season, p value=0.021 one sided), and negatively correlated in "off-season" athletes on blood agar (-0.689 for "off-season", p value=0.028 one-sided), supporting the hypothesis that the microbiota are distinct in "in-season" and "off-season" athletes and may be associated with anxiety levels. CONCLUSION: These findings are supportive of the hypothesis that participation in college level athletics has a positive effect on student-athlete health, specifically enhanced protective oral immunity, reduced anxiety, and alterations in oral microbial populations. PMID- 27932243 TI - Inhibition of mTOR/eIF4E by anti-viral drug ribavirin effectively enhances the effects of paclitaxel in oral tongue squamous cell carcinoma. AB - Upregulation of eIF4E is associated with poor clinical outcome in many human cancers and represents a potential therapeutic target. However, the function of eIF4E remains unknown in oral tongue squamous cell carcinoma (OTSCC). In this work, we show that ribavirin, an anti-viral drug, effectively augments sensitivity of OTSCC cells to paclitaxel via inhibiting mTOR/eIF4E signaling pathway. Ribavirin dose-dependently inhibits proliferation and induces apoptosis in SCC-9 and CAL27 cells. Combination of ribavirin and paclitaxel are more effective in inhibiting proliferation and inducing apoptosis in OTSCC cells. Importantly, the in vivo efficacy of ribavirin and its synergism with paclitaxel is confirmed by two independent OTSCC xenograft mouse models. Mechanistically, ribavirin significantly decreases mTOR/eIF4E signaling pathway in OTSCC cells via suppressing phosphorylation of Akt, mTOR, 4EBP1 and eIF4E. Overexpression of the phosphor-mimetic form of eIF4E (eIF4E S209D) but not the nonphosphorylatable form (eIF4E S209A) reverses the effects of ribavirin, confirming that eIF4E inhibition is the mechanism of action of ribavirin in OTSCC cells. In addition, eIF4E depletion significantly enhances the anti-proliferative and pro-apoptotic effects of paclitaxel, demonstrating the critical role of eIF4E in OTSCC cell response to paclitaxel. Our work is the first to demonstrate the efficacy of ribavirin as a single agent and synergism as combination with paclitaxel in OTSCC in vitro and in vivo. Our findings also demonstrate the therapeutic value of inhibiting eIF4E in OTSCC treatment. PMID- 27932244 TI - Transcriptional response to mitochondrial protease IMMP2L knockdown in human primary astrocytes. AB - IMMP2L encodes the inner membrane peptidase subunit 2, a mitochondrial protease involved in cleaving the space-sorting signals of mitochondrial membrane proteins. IMMP2L has been implicated in Tourette syndrome, but how its dysfunction contributes to the neurodevelopmental phenotype remains unclear. Here we show that IMMP2L transcription requires Topoisomerase I in human primary astrocytes, and characterize the downstream effects of IMMP2L knockdown on gene expression. We demonstrate that IMMP2L knockdown leads to dysregulation of genes involved in central nervous system development. We also find that the transcriptional response to IMMP2L knockdown partially overlaps the one induced by mitochondrial complex III inhibition. Overall, these data bring further insight into the molecular consequences of IMMP2L dysfunction in the brain. PMID- 27932245 TI - Knockdown of TREM-1 suppresses IL-1beta-induced chondrocyte injury via inhibiting the NF-kappaB pathway. AB - Triggering receptor expressed on myeloid cells 1 (TREM-1) is a recently discovered molecule that modulates inflammatory responses. This study aimed to investigate the specific function of TREM-1 in chondrocytes and its association with the pathophysiology of osteoarthritis (OA). We observed upregulation of TREM 1 in OA cartilage compared to normal tissues. Knockdown of TREM-1 suppressed interleukin 1 beta (IL-1beta)-induced extracellular matrix (ECM) metabolic imbalance, pro-inflammatory cytokine production, decrease in cell viability and apoptosis. Mechanistic analyses further revealed that IL-1beta-induced activation of the NF-kappaB pathway is suppressed upon TREM-1 knockdown, similar to the effect of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB. TREM-1 expression was consistently increased in a mouse OA model in vivo, and its silencing led to inhibition of matrix metallopeptidase-13 (MMP-13) production, increased collagen type II synthesis and decreased NF-kappaB signaling. Our data collectively suggest that TREM-1 plays a critical in OA development through regulation of NF-kappaB signaling. Pharmacological inhibition of TREM-1 may therefore present an effective novel therapeutic approach for OA. PMID- 27932246 TI - Denaturing action of adjuvant affects specificity of polyclonal antibodies. AB - Influence of the immunization procedure on the specificity of the produced antibodies towards different conformations of the antigen was investigated. It was demonstrated that intravenous immunization of a rabbit with an adjuvant-free solution of recombinant sperm-specific glyceraldehyde-3-phosphate dehydrogenase (dN-GAPDS) resulted in production of antibodies recognizing only native conformation of dN-GAPDS and exhibiting no cross-reaction with somatic isoenzyme of glyceraldehyde-3-phosphate dehydrogenase. A subcutaneous immunization with human dN-GAPDS mixed with Freund's complete adjuvant yielded antibodies recognizing both native and denatured conformation of dN-GAPDS. The oil component of the adjuvant was shown to cause inactivation and partial denaturation of dN GAPDS, leading to exposure of the epitopes that are masked in the native protein, which resulted in production of the antibodies to the denatured antigen. These results may be of importance for biochemical research that often require polyclonal antibodies recognizing different conformations of antigens. PMID- 27932247 TI - Crystal structure of the PDZ domain of mouse Dishevelled 1 and its interaction with CXXC5. AB - Dishevelled (Dvl) plays a crucial role in Wnt signaling by interacting with membrane-bound receptors and downstream molecules through its PDZ domain. CXXC5 is one of the key molecules that interacts with Dvl and negatively regulates the Wnt/beta-catenin pathway in osteoblast differentiation. Recently, the Dvl-CXXC5 interaction has been identified as an excellent target for osteoporosis treatment. Therefore, it is desirable to have detailed structural information for the Dvl-CXXC5 interaction. Although solution structures of the Dvl1 PDZ domain have been reported, a high-resolution crystal structure would provide detailed sidechain information that is essential for drug development. Here, we determined the first crystal structure of the Dvl-1 PDZ domain at a resolution of 1.76 A, and compared it with its previously reported solution structure. The Dvl1 PDZ domain crystal belonged to the space group H32 with unit-cell parameters a = b = 72.837, c = 120.616, alpha = beta = 90.00, gamma = 120.00. The crystal structure of Dvl1 PDZ shared its topology with the previously reported structure determined by nuclear magnetic resonance (NMR); however, the crystal structure was quite different from the solution structure in both the secondary structural region and the ligand-binding pocket. Molecular modeling based on NMR and X-ray crystallographic data yielded detailed information about the Dvl1/CXXC5 interaction, which will be useful for designing inhibitors. PMID- 27932248 TI - Effect of Template Reporting of Brain MRIs for Multiple Sclerosis on Report Thoroughness and Neurologist-Rated Quality: Results of a Prospective Quality Improvement Project. AB - PURPOSE: To assess the impact of structured reporting templates on the objective and subjective quality of radiology reports for brain MRIs in patients with multiple sclerosis (MS). METHODS: A HIPAA-compliant prospective quality improvement initiative was undertaken to develop and implement a 12-item structured reporting template for brain MRI examinations in patients with known or suspected MS based on published guidelines. Reports created 1 year before implementing the template served as the baseline. A random sample of 10 template and 10 non-template reports was sent to five neurologists outside the study institution with MS expertise, who reviewed the reports for comprehensiveness and quality. The number of MS-relevant elements in template and non-template reports were compared with unpaired t tests. Proportions were compared with chi2 and Fisher exact tests. RESULTS: There were 63 reports in the pre-template period and 93 reports in the post-template period. Use of the template increased over time in the post-template period (P = .04). All 12 MS-relevant findings were addressed more often and with less variability in template reports: (11.1 +/- 0.7 findings versus 5.8 +/- 2.2 findings in non-template reports, P < .001). Neurologists were more likely to give the template reports the highest positive rating (56% [107/190] versus 28% [56/199], P < .001) and less likely to give the template reports a lower rating (7% [13/190] versus 15% [29/199], P = .01) compared with the non-template reports. CONCLUSION: Template reporting of brain MRI examinations increases the rate at which MS-relevant findings are included in the report. Standardized reports are preferred by neurologists with MS expertise. PMID- 27932249 TI - Toxicologic effects of 28-day dietary exposure to the flame retardant 1,2-dibromo 4-(1,2-dibromoethyl)-cyclohexane (TBECH) in F344 rats. AB - The brominated flame retardant TBECH is used as an additive to delay ignition and inhibit fires in construction materials and consumer goods. Trends in human exposure are not clear, although humans may be exposed to TBECH via indoor dust and air. In birds and fish there is some evidence of disruption in endocrine and reproductive parameters due to TBECH. In vitro studies indicate that TBECH is an androgen receptor agonist. In this study rats were exposed to 0, 10, 50, 250, 1250 or 5000mg/kg technical TBECH for 28days in diet, corresponding to 0, 0.9, 4.2, 21.3, 98.0 or 328.9mg TBECH/kg bw/d in males and 0, 0.8, 3.9, 19.4, 91.7 or 321.4mg TBECH/kg bw/d in females. Dose-dependent increases in alpha- and beta- TBECH were detected in serum, liver and adipose. Rats in the 5000mg/kg group lost weight rapidly and were euthanized after 15-18days. At study termination rats displayed dose-dependent clinical and histopathological changes consistent with mild hepatic and renal inflammation. In male rats, evidence of gender-specific alpha2u-globulin nephropathy was not considered predictive of renal toxicity in humans. Frank immunosuppression or inappropriate immunostimulation were not apparent, nor was there a primary effect of TBECH on adaptive immunity. Some evidence of hormone disruption was observed, including changes in serum testosterone levels in males and changes in serum T3 and T4 levels in females. Apparent increases in thyroid follicular cell hypertrophy and hyperplasia in male and female rats were not statistically significant. Benchmark dose (BMD) modelling indicated that clinical changes indicative of mild nephrotoxicity and increased blood monocyte numbers indicative of inflammation and tissue damage were the most sensitive outcomes of TBECH exposure that could be modelled. Preliminary evidence of hormone disruption supports the need for rodent studies using more sensitive models of growth, development and reproduction. PMID- 27932250 TI - False-negative MRI breast screening in high-risk women. AB - AIM: To determine the frequency of and reasons for false-negative breast magnetic resonance imaging (MRI) examinations in high-risk women undergoing annual screening. MATERIALS AND METHODS: The family history clinic database was interrogated and women at high risk of breast cancer who had undergone screening MRI and been diagnosed with breast cancer within 2 years of the MRI examination were identified. All available MRI examinations were reviewed and classified by two radiologists. RESULTS: Of 32 women diagnosed with breast cancer, 23 had MRI images available for review. Fourteen were diagnosed at MRI, four at interim mammography, two symptomatically, one incidentally on ultrasound, and two at risk reducing mastectomy. Ten women (43%) had potentially avoidable delays in diagnosis. The preceding MRIs were classified as false-negative screens in five women (one prevalent, four incident), false-negative assessment in seven and minimal signs in three (three women were assigned dual classifications). Common reasons for diagnostic delay included small enhancing masses that were overlooked, areas of non-mass enhancement that showed little or no change between screens, false reassurance from normal conventional imaging at assessment, and overreliance on short-interval repeat MRI. CONCLUSION: Small enhancing foci, masses, and areas of segmental non-mass enhancement are common MRI features of early breast cancer. Lack of change of non-mass enhancement on serial examinations does not exclude malignancy. Double reading of both screening and assessment examinations is recommended. Ready access to MRI biopsy is essential. Short-interval repeat MRI should be limited to reassessing low suspicion areas likely to be benign glandular enhancement. Annual mammography remains important in these women. PMID- 27932251 TI - A meta-analysis of arterial spin labelling perfusion values for the prediction of glioma grade. AB - AIM: To investigate the ability of arterial spin labelling (ASL) perfusion parameters to distinguish high-grade from low-grade gliomas. MATERIALS AND METHODS: The PubMed and EMBASE databases were systematically searched for relevant articles published up to September 2015. Studies that evaluated both high- and low-grade gliomas using ASL were included. The random effect model was used to calculate the standardised mean difference (SMD) of maximum mean absolute tumour blood flow values (aTBFmax, aTBFmean) and maximum mean relative tumour blood flow (rTBFmax, rTBFmean) between high- and low-grade gliomas. RESULTS: Nine studies encompassing 305 patients with high- and low-grade gliomas, met all inclusion and exclusion criteria and were included in the study. Compared with low-grade gliomas, high-grade gliomas had a significant increase in all ASL perfusion values: aTBFmax (SMD=0.70, 95% confidence interval [CI]: 0.22-1.19, p=0.0046); aTBFmean (SMD=0.86, 95% CI: 0.2-1.52, p=0.01); rTBFmax (SMD=1.08, 95% CI: 0.54-1.63, p=0.0001) and rTBFmean (SMD=0.88, 95% CI: 0.35-1.4, p=0.0011). CONCLUSIONS: The current study results indicate that tumour blood flow from ASL differs significantly with respect to the glioma grade. Despite some limitations, there is evidence that ASL may be useful to distinguish high- and low-grade gliomas. Further larger-scale studies are necessary to examine the utility of ASL to distinguish tumour grade. PMID- 27932252 TI - Changes in primary care provision in Turkey: A comparison of 1993 and 2012. AB - Since the early 1990s, the primary care system in Turkey has undergone fundamental changes. In the first decade of the millennium family doctor scheme was introduced to the Turkish primary care sector and the name of the primary care doctors (PCDs) changed from "general practitioner" (GP) to "family doctor" (FD). This study aims to give an insight into those changes and to compare the service profiles of PCDs in 1993 and 2012. Data, based on cross sectional surveys among Turkish doctors working in primary care are derived from the 1993 European GP Task Profile study (n=199) and the 2012 Quality and Costs of Primary Care in Europe (QUALICOPC) study (n=299). The study focuses on the changes in the primary care service provision based on selected aspects such as the first contact of care, preventive care, and the knowledge exchange and collaboration with other health professionals. Compared to GPs in 1993, FDs in 2012 reported that their involvement in treatment of chronic diseases, first contact care, antenatal and child health care have increased. FDs have more contact with other primary healthcare workers but their contact with hospital consultants have decreased. Overall, the services provided by PCDs seem to be expanded. However, the quality of care given by FDs and its effects on health indicators are needed to be explored by further studies. PMID- 27932253 TI - Regulation of cyclin D1 by arsenic and microRNA inhibits adipogenesis. AB - Low-dose chronic exposure to arsenic in drinking water represents a global public health concern with established risks for metabolic and cardiovascular disease, as well as cancer. While the linkage between arsenic and disease is strong, further understanding of the molecular mechanisms of its pathogenicity is required. Previous reports demonstrated the ability of arsenic to interfere with adipogenesis, which may mediate its effects in promoting metabolic disease. We hypothesized that microRNA are important regulators of most if not all mesenchymal stem cell processes that are dysregulated by arsenic exposure to impair lipogenesis. Arsenic increased the expression of miR-29b in white adipose tissue, as well as human mesenchymal stem cells (hMSCs) isolated from adipose tissue. Exposing hMSCs to arsenic increased abundance of miR-29b and cyclin D1 to promote proliferation over differentiation. Paradoxically, inhibition of miR-29b enhanced the inhibitory effect of arsenic on differentiation. This paradox was attributed to a requirement for miR-29 in regulating cyclin D1 expression as stable inhibition of miR-29b eliminated the cyclic pattern of cyclin D1 expression. Temporal regulation of cyclin D1 is critical for adipogenic differentiation, and the data suggest a paradigm where arsenic disruption of miR 29b regulatory pathways impairs adipogenic differentiation and ultimately adipose metabolic homeostasis. PMID- 27932255 TI - Triolein reduces MMP-1 upregulation in dermal fibroblasts generated by ROS production in UVB-irradiated keratinocytes. AB - BACKGROUND: Cytokine production and oxidative stress generated by ultraviolet radiation B (UVB) skin exposure are main factors of skin photoaging. Interleukin 6 (IL-6) produced by irradiated keratinocytes is proposed to have a role in metalloproteinases (MMPs) expression activation in dermal fibroblasts. OBJECTIVES: We examined the effect of triolein treatment of UVB-irradiated keratinocytes on MMP1 (interstitial collagenase) expression response of dermal fibroblasts. We assayed UVB-irradiated keratinocytes soluble signals, mainly IL-6 and reactive oxygen species (ROS). METHODS: IL-6 expression and ROS generation were assayed in UVB-irradiated keratinocytes. MMP1 mRNA expression response was assayed in fibroblasts grown in keratinocytes conditioned medium. We evaluated the effect of treating keratinocytes with triolein on IL-6 expression and ROS generation in keratinocytes, and MMP1 expression in fibroblasts. RESULTS: The irradiation of epidermal cells with sublethal UVB doses increased IL-6 expression and ROS generation. Conditioned culture medium collected from keratinocytes was used to culture dermal fibroblasts. MMP1 mRNA expression increase was observed in fibroblasts cultured in medium collected from UVB-irradiated keratinocytes. Triolein treatment reduced the IL-6 expression and ROS generation in keratinocytes and this effect was reflected in downregulation of MMP1 expression in fibroblasts. CONCLUSIONS: Triolein reduces both the expression of IL-6 and ROS generation in irradiated keratinocytes. It seems to exert an anti-inflammatory and anti-oxidative stress effect on irradiated keratinocytes that in turn reduces MMP1 expression in dermal fibroblasts. Collectively, these results indicate that triolein could act as a photoprotective agent. PMID- 27932254 TI - Investigating possible biological targets of Bj-CRP, the first cysteine-rich secretory protein (CRISP) isolated from Bothrops jararaca snake venom. AB - Cysteine-rich secretory proteins (CRISPs) are commonly described as part of the protein content of snake venoms, nevertheless, so far, little is known about their biological targets and functions. Our study describes the isolation and characterization of Bj-CRP, the first CRISP isolated from Bothrops jararaca snake venom, also aiming at the identification of possible targets for its actions. Bj CRP was purified using three chromatographic steps (Sephacryl S-200, Source 15Q and C18) and showed to be an acidic protein of 24.6kDa with high sequence identity to other snake venom CRISPs. This CRISP was devoid of proteolytic, hemorrhagic or coagulant activities, and it did not affect the currents from 13 voltage-gated potassium channel isoforms. Conversely, Bj-CRP induced inflammatory responses characterized by increase of leukocytes, mainly neutrophils, after 1 and 4h of its injection in the peritoneal cavity of mice, also stimulating the production of IL-6. Bj-CRP also acted on the human complement system, modulating some of the activation pathways and acting directly on important components (C3 and C4), thus inducing the generation of anaphylatoxins (C3a, C4a and C5a). Therefore, our results for Bj-CRP open up prospects for better understanding this class of toxins and its biological actions. PMID- 27932256 TI - A panorama of bacterial inulinases: Production, purification, characterization and industrial applications. AB - Inulinases are important hydrolysing enzymes which specifically act on beta-2, 1 linkages of inulin to produce fructose or fructooligosaccharides. Fungi, yeasts and bacteria are the potent microbial sources of inulinases. The data on bacterial inulinases is scarce as compared to other microbial sources. Inulinases yield from bacteria is very less as compared to fungal and yeast sources of inulinases. Submerged fermentation (SmF) is the method of choice for the production of inulinases from bacterial sources. Moreover, inulin is a potent substrate for the production of inulinases in SmF. Many bacterial inulinases have been reported to display magnificent environment abiding features and variability in their biophysical and biochemical properties. These properties have attracted intention of many researchers towards exploring adverse ecological niches for more distinctive inulinase producing bacterial strains. Inulinases are substantially important in current biotechnological era due to their numerous industrial applications. High fructose syrup and fructooligosaccharides are two major industrial applications of inulinases. Additionally, there are many reports on the production of various metabolites like citric acid, lactic acid, ethanol, biofuels, butanediol etc. using mixed cultures of inulinase producing organisms with other microorganisms. The present review mainly envisages inulinase producing bacterial sources, inulinase production, purification, characterization and their applications. PMID- 27932258 TI - Heteroglycan of an edible mushroom Pleurotus cystidiosus: Structural characterization and study of biological activities. AB - A water soluble heteroglycan (PCPS) was isolated from the aqueous extract of an edible mushroom Pleurotus cystidiosus. Structural characterization of the heteroglycan was carried out using total hydrolysis, methylation analysis, periodate oxidation, Smith degradation, and 1D/2D NMR experiments. Sugar analysis indicated the presence of glucose, galactose, and mannose in a molar ratio of nearly 6:2:1 respectively. The chemical and NMR analysis of the PCPS indicated the presence of a repeating unit with a backbone consisting of one unit of (1->6) beta-d-glucopyranosyl, two (1->3)-beta-d-glucopyranosyl, one (1->3)-alpha-d glucopyranosyl, one (1->6)-alpha-d-glucopyranosyl, and two (1->6)-alpha-d galactopyranosyl moieties respectively, out of which one (1->3)-beta-d glucopyranosyl residue was branched at O-6 with terminal beta-d-glucopyranosyl and another (1->6)-alpha-d-galactopyranosyl residue was branched at O-2 with terminal beta-d-mannopyranosyl moiety. The polysaccharide was found to exhibit cellular activities at different concentrations (10, 25, 50, 100, 200, 400MUg/mL) and maintained the redox balance as well as reduced lipid per oxidation which protect the cell destruction. PMID- 27932257 TI - Antioxidant, antibacterial and anti-aging activities of intracellular zinc polysaccharides from Grifola frondosa SH-05. AB - In present work, the strain of Grifola frondosa SH-05 was used as a vector of zinc biotransformation to produce the IZPS. The bioactivities including antioxidant and antibacterial activities in vitro and anti-aging properties in vivo of IZPS were investigated comparing with the IPS. The results which were in consistent with the results of histopathology assay demonstrated that the IZPS had superior antioxidant and anti-aging activities by scavenging the hydroxyl and DPPH radicals, increasing enzyme activities, decreasing the MDA contents and ameliorating the anile condition of mice. Besides, the IZPS also showed potential antibacterial activities. The IZPS with higher bioactivities was composed of were Rha, Ino and Glu with a molar ratio of 4.7:3.6:1. These conclusions indicated that the IZPS might be a potential source of natural antioxidant, antibacterial agent and anti-aging agent. PMID- 27932259 TI - A comparative study for lipase immobilization onto alginate based composite electrospun nanofibers with effective and enhanced stability. AB - In this study, lipase was successfully immobilized on polyvinyl alcohol/alginate and polyethylene oxide/alginate nanofibers that were prepared by electrospinning. Results showed that nanofibers (especially polyvinyl alcohol/alginate) enhanced the stability properties of lipase. When the free lipase lost its all activity after 40-60min at high temperatures, both lipase immobilized nanofibers kept almost 65-70% activity at the same time. The lipase immobilized poly vinyl alcohol/alginate and polyethylene oxide/alginate nanofibers protected approximately all of their activities until pH 9. Lipase immobilized polyvinyl alcohol/alginate and polyethylene oxide/alginate nanofibers maintained 60% of their activities after 14 and 7 reuses, respectively. The morphology of nanofibers was characterized by Scanning Electron Microscope, Fourier Transform Infrared Spectroscopy and Thermal Gravimetric Analyzer. As a result, this nanofiber production method, electrospinning, is simple, versatile and economical for preparing appropriate carrier to immobilize the enzymes. PMID- 27932260 TI - Equilibrium adsorption of caffeic, chlorogenic and rosmarinic acids on cationic cross-linked starch with quaternary ammonium groups. AB - In the present study, the equilibrium adsorption of caffeic acid (CA) and its derivatives, namely, chlorogenic (CGA) and rosmarinic (RA) acids on cationic cross-linked starch (CCS) with degree of substitution of quaternary ammonium groups of 0.42 have been investigated in relation to the structure and acidity of phenolic acids. The Langmuir, Freundlich and Dubinin-Radushkevich adsorption models have been used to describe the equilibrium adsorption of CA, CGA and RA from their initial solutions and solutions having the equimolar amount of NaOH at different temperatures. In the case of adsorption from the initial solutions of acids the values of adsorption parameters were closely related to the dissociation constants of investigated acids. According to the increasing effectiveness of adsorption, phenolic acids could be arranged in the following order: CA=0.3). At MVA Cox regression analyses, there was no effect of CIS on survival outcomes in pT3-pT4 patients (all P>0.2); on the contrary, the presence of CIS was associated with worse CSM in pT0-pT2 patients only (hazard ratio [HR] = 1.82; CI: 1.01-3.29; P = 0.04). At MVA competing risk analyses predicting urothelial recurrence only, the presence of CIS was associated to an increased risk of urothelial recurrence in pT0-pT2 patients (HR = 2.99; CI: 1.05-8.53; P = 0.04), pT3-pT4 patients (HR = 10.29; CI: 1.40-75.75; P = 0.02), and in the overall population (HR = 4.47; CI: 1.81-11.07; P = 0.001). CONCLUSION: An increased risk of developing urothelial recurrence only was recorded in patients diagnosed with CIS at RC. Physicians should consider this aspect ensuring a more severe follow-up schemes in patients who harbored this pathological feature. PMID- 27932270 TI - Prognostic value of lymph node yield during nephroureterectomy for upper tract urothelial carcinoma. AB - INTRODUCTION: Lymph node dissection (LND) performed during radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) remains controversial and difficult to evaluate. The aim of this study was to investigate whether removal of more lymph nodes during RNU is safe and improves oncologic outcomes. METHODS: We evaluated 422 patients who underwent RNU with concomitant LND for upper tract urothelial carcinoma between 1976 and 2015, assessing for an association between total nodes removed, recurrence-free survival, and cancer specific survival using Cox proportional hazards models. We also investigated the relationship between nodal yield and perioperative metrics and intersurgeon variability using linear regression. RESULTS: In our cohort of 442 patients, 239 developed recurrences and 94 patients died of disease. Median follow-up among survivors was 3.7 years (interquartile range: 1.2, 7.4). The median nodal yield was 9 (interquartile range: 4, 16). Among patients with node-positive disease (pN1), we observed a significant improvement in recurrence-free survival (hazard ratio = 0.84 per 5 nodes removed, P = 0.039) and a nonsignificant improvement in cancer-specific survival with an increase in the nodal yield (hazard ratio = 0.90 per 5 nodes removed, P = 0.2). There was no evidence of an association between node yield and operative time, estimated blood loss, or 30-day complications on multivariable analysis. There was significant heterogeneity among surgeons regarding the extent of LND (P<0.0001). CONCLUSIONS: We found that a more extensive node dissection may improve oncologic outcomes in a subset of high-risk patients without significantly increasing operative time or serious complications. Additionally, we identified considerable intersurgeon heterogeneity regarding the extent of LND furthering the notion of surgeon variability as a nonstandardized factor. PMID- 27932271 TI - Deactivation of Left Ventricular Assist Devices: Differing Perspectives of Cardiology and Hospice/Palliative Medicine Clinicians. AB - BACKGROUND: Beliefs around deactivation of a left ventricular assist device (LVAD) vary substantially among clinicians, institutions, and patients. Therefore, we sought to understand perspectives regarding LVAD deactivation among cardiology and hospice/palliative medicine (HPM) clinicians. METHODS AND RESULTS: We administered a 41-item survey via electronic mail to members of 3 cardiology and 1 HPM professional societies. A convergent parallel mixed-methods design was used. From October through November 2011, 7168 individuals were sent the survey and 440 responded. Three domains emerged: (1) LVAD as a life-sustaining therapy; (2) complexities of the process of LVAD deactivation; and (3) legal and ethical considerations of LVAD deactivation. Most respondents (cardiology 92%; HPM 81%; P = .15) believed that an LVAD is a life-sustaining treatment for patients with advanced heart failure; however, 60% of cardiology vs 2% of HPM clinicians believed a patient should be imminently dying to deactivate an LVAD (P < .001). Additionally, 87% of cardiology vs 100% of HPM clinicians believed the cause of death following LVAD deactivation was from underlying disease (P < .001), with 13% of cardiology clinicians considering it to be a form of euthanasia or physician-assisted suicide. CONCLUSION: Cardiology and HPM clinicians have differing perspectives regarding LVAD deactivation. Bridging the gaps and engaging in dialog between these 2 specialties is a critical first step in creating a more cohesive approach to care for LVAD patients. PMID- 27932272 TI - Two new triterpenoids and a new naphthoquinone derivative isolated from a hard coral-derived fungus Scopulariopsis sp. AB - Scopulariopsis sp. isolated from the Red Sea hard coral Stylophora sp. yielded two new triterpenoids (1-2) and a new naphthoquinone derivative (8) when cultured on white beans. In addition, fourteen known compounds including three triterpene analogues (3-5), two sesquiterpenoids (6-7), two polyketides (9-10) and seven nitrogenous compounds (11-17) were isolated. All structures were determined through extensive analysis of the NMR and MS data as well as by comparison with literature data. All isolated compounds were evaluated for their cytotoxic, antibacterial and antitubercular activities. However, none of them showed significant activity. PMID- 27932273 TI - Response: Electrocardiographic Markers in Patients With Takotsubo Cardiomyopathy. PMID- 27932274 TI - A glutathione-S-transferase (TuGSTd05) associated with acaricide resistance in Tetranychus urticae directly metabolizes the complex II inhibitor cyflumetofen. AB - Cyflumetofen is a recently introduced acaricide with a novel mode of action, acting as an inhibitor of complex II of mitochondrial electron transport chain. It is activated by hydrolysis and the resulting de-esterified metabolite is a much stronger inhibitor. Cyflumetofen represents a great addition for the control of mite species including Tetranychus urticae, a major agricultural pest, which has the ability to develop resistance to most classes of pesticides rapidly. A resistant strain (Tu008R) was recently described and synergism experiments pointed towards the involvement of GSTs. Here, we conducted genome-wide gene expression analysis, comparing Tu008R with its parental susceptible strain, and identified the delta GST TuGSTd05 as the prime resistance-conferring candidate. Docking analysis suggests that both cyflumetofen and its de-esterified metabolite are potential substrates for conjugation by TuGSTd05. Several amino acids were identified that might be involved in the interaction, with Y107 and N103 possibly having an important role. To further investigate interaction as well as the role of Y107 and N103 in vitro, we recombinantly expressed and kinetically characterized the wild type TuGSTd05, TuGSTd05 Y107F and TuGSTd05 N103L mutants. While cyflumetofen was not found to act as a strong inhibitor, the de-esterified metabolite showed strong affinity for TuGSTd05 (IC50 = 4 MUM), which could serve as a mechanism of rapid detoxification. Y107 and N103 might contribute to this interaction. HPLC-MS analysis provided solid indications that TuGSTd05 catalyzes the conjugation of ionized glutathione (GS-) to cyflumetofen and/or its de esterified metabolite and the resulting metabolite and possible site of attack were identified. PMID- 27932275 TI - Complete genome sequence of Serinicoccus sp. JLT9, an actinomycete isolated from the shallow-sea hydrothermal system. AB - Serinicoccus sp. JLT9 was a novel rare actinomycete, isolated from the shallow sea hydrothermal system. Here, we present the complete genome sequence of Serinicoccus sp. JLT9, which consists of 3,610,932bp with a GC content of 72.43%. The genome data provides insight into microbial adaption to the shallow-sea hydrothermal system and facilitates the discovery of natural compounds in the future. PMID- 27932276 TI - The why and how of amino acid analytics in cancer diagnostics and therapy. AB - Pathological alterations in cell functions are frequently accompanied by metabolic reprogramming including modifications in amino acid metabolism. Amino acid detection is thus integral to the diagnosis of many hereditary metabolic diseases. The development of malignant diseases as metabolic disorders comes along with a complex dysregulation of genetic and epigenetic factors affecting metabolic enzymes. Cancer cells might transiently or permanently become auxotrophic for non-essential or semi-essential amino acids such as asparagine or arginine. Also, transformed cells are often more susceptible to local shortage of essential amino acids such as methionine than normal tissues. This offers new points of attacking unique metabolic features in cancer cells. To better understand these processes, highly sensitive methods for amino acid detection and quantification are required. Our review summarizes the main methodologies for amino acid detection with a particular focus on applications in biomedicine and cancer, provides a historical overview of the methodological pre-requisites in amino acid analytics. We compare classical and modern approaches such as the combination of gas chromatography and liquid chromatography with mass spectrometry (GC-MS/LC-MS). The latter is increasingly applied in clinical routine. We therefore illustrate an LC-MS workflow for analyzing arginine and methionine as well as their precursors and analogs in biological material. Pitfalls during protocol development are discussed, but LC-MS emerges as a reliable and sensitive tool for the detection of amino acids in biological matrices. Quantification is challenging, but of particular interest in cancer research as targeting arginine and methionine turnover in cancer cells represent novel treatment strategies. PMID- 27932277 TI - Detection of subclinical ultrasound enthesopathy and nail disease in patients at risk of psoriatic arthritis. AB - OBJECTIVES: To detect subclinical entheses and nail abnormalities using gray scale (GS) and power Doppler ultrasonography (PDUS) between patients with nail psoriasis and those with inverse and scalp psoriasis. METHODS: In this prospective monocentric study, patients with nail, inverse and scalp psoriasis, without psoriatic arthritis or systemic treatment, were included. Clinical evaluation and ultrasonographic assessment of 14 entheses and 12 nails were done by a dermatologist (clinical assessment) and a rheumatologist (ultrasonographic assessment). RESULTS: 518 entheses were analyzed, with no statistical difference between the two groups when considering GS enthesopathy (P=0.66). PDUS signal of the entheses were low (<1%) in both groups. Matrix thickness was significantly higher in patients with nail disease (1.94mm vs. 1.77mm; P=0.007). PDUS of the skin thickness at the level of distal joint and the loss of the trilaminar appearance were also significantly associated with nail psoriasis (P=0.037 and P<0.0001 respectively). CONCLUSION: Detection of subclinical US enthesopathy is not so rare in both groups, unlike PD signal, but with no statistical difference. US are a good tool to evaluate the different components of psoriatic nails (loss of trilaminar appearance, nail thickening and inflammation of the skin thickness) which are significantly associated with nail psoriasis. PMID- 27932278 TI - Patient-perceived flares in rheumatoid arthritis: A sub-analysis of the STRASS treatment tapering strategy trial. AB - OBJECTIVES: Patient's and physician's perspective can differ in rheumatoid arthritis (RA). The aim was to define the concept of patient-reported flares. METHODS: Post-hoc analysis of a randomized controlled trial of a step-down strategy in RA patients treated with anti-TNF, in DAS28-remission for >=6 months, randomized to either "spacing" or "maintaining" anti-TNF. The occurrence of patient-reported flares (PRF) was evaluated every 3 months for 18 months by: "Over the last 3 months, did you experience symptoms suggestive of disease exacerbation?". Visits with and without PRF were compared, using a linear mixed effects model, in terms of symptoms, disability based on the Health Assessment Questionnaire, quality of life based on Short Form 36 Health Survey and DAS28 based relapses (DBR), defined as an increase of DAS28>0.6 and an absolute value of DAS28>2.6. The agreement between PRF and DBR was measured by the kappa coefficient on repeated data. RESULTS: In all, 137 patients were analyzed: mean age 55+/-11 years, females 78%, mean RA duration 9.5+/-8.0 years. Over the 18 months, PRF concerned 27.2% of the 940 available visits. DBR and PRF were observed in 24% and 16% of 940 visits for 137 patients respectively. All the items were associated with PRF with standardized effect size between -0.58 (SF36 PCS) and 0.87 (DAS28). The agreement between PRF and DBR was moderate (kappa=0.44). CONCLUSION: The concept of flare refers to more than just RA disease activity. PMID- 27932279 TI - Severe gout: Strategies and innovations for effective management. AB - Severe gout is characterised by frequent polyarticular flares, numerous tophi, joint damage, and musculoskeletal disability. This is a preventable condition and in many cases, represents a disease that has been insufficiently managed for years. Standard management recommendations may be insufficient for patients with severe gout; these patients frequently require intensive individualised pharmacological management with combinations of urate-lowering therapy and anti inflammatory agents. In this article, we aim to integrate recent therapeutic advances to provide a practical framework for optimal management of severe gout. PMID- 27932280 TI - Hydroxychloroquine and joint involvement in systemic sclerosis: Preliminary beneficial results from a retrospective case-control series of an EUSTAR center. PMID- 27932281 TI - Nutcracker syndrome: A rare cause of left flank pain that can also manifest as unexplained pelvic pain. AB - Nutcracker syndrome (NCS) is symptomatic unilateral renal venous hypertension due to compression of the left renal vein between the superior mesenteric artery and aorta (anterior NCS) or between the aorta and spine (posterior NCS). The left ovarian or spermatic vein empties into the left renal vein and is an additional site of venostasis in about half the cases of NCS. The presenting symptom of NCS in about half the cases is atypical left flank pain suggesting a disorder of the lower ribs or thoracolumbar spinal junction, particularly as the pain worsens with standing and increased lumbar lordosis. NCS may be suggested by any combination of the following manifestations: hematuria, which is often only microscopic; orthostatic proteinuria; varicocele and infertility; dyspareunia and other gynecological symptoms; varicose veins in the pelvis, buttocks, or upper thighs; orthostatic hypotension and fatigue; and abdominal pain. Narrowing of the left renal vein on imaging studies is required but far from sufficient to establish the diagnosis. Several converging clinical findings and a marked pressure gradient between the left renal vein and inferior vena cava must be present also. Urological procedures and vascular surgery are being superseded by endovascular stenting with or without simultaneous treatment of the acquired gonadal vein insufficiency by embolization. PMID- 27932282 TI - Serum cardiac troponin I in canine syncope and seizures. AB - OBJECTIVE: To determine if serum cardiac troponin I (cTnI) concentration distinguishes between cardiogenic syncope and collapsing dogs presenting with either generalized epileptic seizures (both with and without cardiac disease) or vasovagal syncope. ANIMALS: Seventy-nine prospectively recruited dogs, grouped according to aetiology of collapse: generalized epileptic seizures (group E), cardiogenic syncope (group C), dogs with both epileptic seizures and cardiac disease (group B), vasovagal syncope (group V) or unclassified (group U). METHODS: Most patients had ECG (n = 78), echocardiography (n = 78) and BP measurement (n = 74) performed. Dogs with a history of intoxications, trauma, evidence of metabolic disorders or renal insufficiency (based on serum creatinine concentrations >150 MUmol/L and urine specific gravity <1.030) were excluded. Serum cTnI concentrations were measured and compared between groups using non parametric statistical methods. Multivariable regression analysis investigated factors associated with cTnI. Receiver operator characteristic curve analysis examined whether cTnI could identify cardiogenic syncope. RESULTS: Median cTnI concentrations were higher in group C than E (cTnI: 0.165 [0.02-27.41] vs. 0.03 [0.01-1.92] ng/mL; p<0.05). Regression analysis found that serum cTnI concentrations decreased with increasing time from collapse (p=0.015) and increased with increasing creatinine concentration (p=0.028). Serum cTnI diagnosed cardiogenic syncope with a sensitivity of 75% and specificity of 80%. CONCLUSIONS: Serum cTnI concentrations were significantly different between groups C and E. However, due to the overlap in cTnI concentrations between groups cTnI, measurement in an individual is not optimally discriminatory to differentiate cardiogenic syncope from collapse with generalized epileptic seizures (both with and without cardiac disease) or vasovagal syncope. PMID- 27932283 TI - Development and validation of a liquid chromatography tandem mass spectrometry assay for the measurement of faecal metronidazole. AB - BACKGROUND: Metronidazole is an oral antibiotic which is widely used in the treatment of patients with Clostridium difficile associated disease. METHODS: This article describes the validation of a LC-MS/MS assay for the measurement of metronidazole in human faecal samples. RESULTS: Matrix matched and aqueous standards showed no significant difference in performance for the routine calibration of the assay. D4 deuterated metronidazole internal standard eluted with a different retention time to the undeuterated metronidazole on chromatography, hence zidovudine was used as an internal standard. Ion suppression was noted for both metronidazole and zidovudine due to unidentified compounds present in the faecal matrix and this was improved by extracting a smaller quantity of faeces and diluting the extract prior to analysis. Measurement uncertainty was 13% at 28,400ng/ml, 7.2% at 3300ng/ml, 3.9% at 320ng/ml, 13.6% at 109ng/ml and 30.9% at 20ng/ml. The assay was shown to be linear on dilution and the sensitivity of the assay was superior to HPLC assays using UV detection. The limit of detection was 5ng/ml, the limit of quantitation was 66ng/ml and the upper limit of the working range was 30,000ng/ml. Patient samples were stable at -20 degrees C for 12months and extracted faecal samples were stable on storage for 1week at 4 degrees C. There were no specific requirements for patient preparation or time of sample collection relative to taking metronidazole. CONCLUSIONS: Metronidazole can be quantified in faecal samples using LC-MS/MS which opens up opportunities for further research in this area. PMID- 27932284 TI - Genetic diversity of coronaviruses in bats in Lao PDR and Cambodia. AB - South-East Asia is a hot spot for emerging zoonotic diseases, and bats have been recognized as hosts for a large number of zoonotic viruses such as Severe Acute Respiratory Syndrome (SARS), responsible for acute respiratory syndrome outbreaks. Thus, it is important to expand our knowledge of the presence of viruses in bats which could represent a risk to humans. Coronaviruses (CoVs) have been reported in bat species from Thailand, China, Indonesia, Taiwan and the Philippines. However no such work was conducted in Cambodia or Lao PDR. Between 2010 and 2013, 1965 bats were therefore sampled at interfaces with human populations in these two countries. They were tested for the presence of coronavirus by consensus reverse transcription-PCR assay. A total of 93 samples (4.7%) from 17 genera of bats tested positive. Sequence analysis revealed the presence of potentially 37 and 56 coronavirus belonging to alpha-coronavirus (alphaCoV) and beta-CoV (betaCoV), respectively. The betaCoVs group is known to include some coronaviruses highly pathogenic to human, such as SARS-CoV and MERS CoV. All coronavirus sequences generated from frugivorous bats (family Pteropodidae) (n=55) clustered with other bat betaCoVs of lineage D, whereas one coronavirus from Pipistrellus coromandra fell in the lineage C of betaCoVs which also includes the MERS-CoV. alphaCoVs were all detected in various genera of insectivorous bats and clustered with diverse bat alphaCoV sequences previously published. A closely related strain of PEDV, responsible for severe diarrhea in pigs (PEDV-CoV), was detected in 2 Myotis bats. We highlighted the presence and the high diversity of coronaviruses circulating in bats from Cambodia and Lao PDR. Three new bat genera and species were newly identified as host of coronaviruses, namely Macroglossus sp., Megaerops niphanae and Myotis horsfieldii. PMID- 27932285 TI - Candidate new rotavirus species in Schreiber's bats, Serbia. AB - The genus Rotavirus comprises eight species designated A to H and one tentative species, Rotavirus I. In a virus metagenomic analysis of Schreiber's bats sampled in Serbia in 2014 we obtained sequences likely representing novel rotavirus species. Whole genome sequencing and phylogenetic analysis classified the representative strain into a tentative tenth rotavirus species, we provisionally called Rotavirus J. The novel virus shared a maximum of 50% amino acid sequence identity within the VP6 gene to currently known members of the genus. This study extends our understanding of the genetic diversity of rotaviruses in bats. PMID- 27932286 TI - Imbalance of Th17 and Treg in peripheral blood mononuclear cells of active tuberculosis patients. AB - OBJECTIVE: Maintaining a right balance between Th17 and Treg might be critical to the immunopathogenesis of active tuberculosis (TB). This study aimed to assess whether the Th17/Treg balance is altered in active TB patients. METHODS: 250 study subjects (90 active TB patients, 80 latent TB subjects, and 80 healthy controls) were recruited for the study. The expression of Th17 and Treg in peripheral blood mononuclear cells (PBMCs) in the 250 subjects was investigated by flow cytometry. Plasma levels of cytokines IL-17 and IL-10, which are related to Th17 and Treg, respectively, were determined by ELISA. RESULTS: The percentages of Th17 and Treg in PBMCs from active TB patients were significantly higher than those from latent TB or control groups (Th17: 4.31+/-1.35% vs. 1.58+/ 0.71% or 1.15+/-0.49%, p<0.05; Treg: 11.44+/-2.69% vs. 7.54+/-1.56% or 4.10+/ 0.99%, p<0.05). The expression of IL-17 and IL-10 was significantly increased in active TB patients in comparison to that in latent TB or control groups (IL-17: 16.85+/-9.68 vs. 7.23+/-5.19 or 8.21+/-5.51pg/mL, p<0.05; IL-10: 28.70+/-11.27 vs. 20.25+/-8.57 or 13.94+/-9.00pg/mL, p<0.05). CONCLUSIONS: Our study demonstrated an altered balance of Treg/Th17 in active TB patients, with higher percentages of Th17 and Treg in PBMCs. Further research on this imbalance may offer a new direction for TB treatment. PMID- 27932287 TI - Serum levels of neurotrophic factors in active toxoplasmic retinochoroiditis. AB - : Toxoplasmic retinochoroiditis (TR) is the most common identifiable cause of posterior uveitis in Brazil. Response to treatment and clinical presentation may vary significantly. We assessed serum levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin (NT)-3, and NT-4/5 in patients with active TR, before and after TR treatment. METHODS: Twenty patients with active lesion and 15 healthy controls were enrolled in the study. Serum concentration of neurotrophic factors was determined by enzyme-linked immunosorbent assay. RESULTS: BDNF levels were significantly higher in patients before treatment when compared with controls (p=0.0015). There was no significant difference in pro-BDNF, NGF, GDNF, NT-3, and NT-4/5 levels between TR patients and controls. Treatment did not affect the levels of these factors. CONCLUSION: BDNF may be released in the context of the active TR inflammatory response. PMID- 27932288 TI - Pressure ulcer as a reservoir of multiresistant Gram-negative bacilli: risk factors for colonization and development of bacteremia. AB - The purpose of this study was to identify the risk factors that predispose patients who are hospitalized with pressure ulcers (PUs) colonized by Gram negative bacilli (GNB) to develop bacteremia. In addition, we also detected main phenotypes of resistance in infected and uninfected PUs. A prospective cohort study was conducted at the Clinical Hospital of the Federal University of Uberlandia including patients with Stage II or greater PUs, colonized or not with GNB, from August 2009 to July 2010. Infected ulcers were defined based on clinical signs and on positive evaluation of smears of wound material translated by a ratio of polymorphonuclear cells to epithelial cells >=2:1, after Giemsa staining. A total of 60 patients with Stage II PUs were included. Of these 83.3% had PUs colonized and/or infected. The frequency of polymicrobial colonization was 74%. Enterobacteriaceae and GNB non-fermenting bacteria were the most frequent isolates of PUs with 44.0% of multiresistant isolates. Among patients who had infected PUs, six developed bacteremia by the same microorganism with a 100% mortality rate. In addition, PUs in hospitalized patients were major reservoir of multiresistant GNB, also a high-risk population for the development of bacteremia with high mortality rates. PMID- 27932289 TI - Peroxiredoxin 6 in the repair of peroxidized cell membranes and cell signaling. AB - Peroxiredoxin 6 represents a widely distributed group of peroxiredoxins that contain a single conserved cysteine in the protein monomer (1-cys Prdx). The cys when oxidized to the sulfenic form is reduced with glutathione (GSH) catalyzed by the pi isoform of GSH-S-transferase. Three enzymatic activities of the protein have been described:1) peroxidase with H2O2, short chain hydroperoxides, and phospholipid hydroperoxides as substrates; 2) phospholipase A2 (PLA2); and 3) lysophosphatidylcholine acyl transferase (LPCAT). These activities have important physiological roles in antioxidant defense, turnover of cellular phospholipids, and the generation of superoxide anion via initiation of the signaling cascade for activation of NADPH oxidase (type 2). The ability of Prdx6 to reduce peroxidized cell membrane phospholipids (peroxidase activity) and also to replace the oxidized sn-2 fatty acyl group through hydrolysis/reacylation (PLA2 and LPCAT activities) provides a complete system for the repair of peroxidized cell membranes. PMID- 27932290 TI - The diagnosis of idiopathic pulmonary fibrosis: current and future approaches. AB - With the recent development of two effective treatments for patients with idiopathic pulmonary fibrosis, an accurate diagnosis is crucial. The traditional approach to diagnosis emphasises the importance of thorough clinical and laboratory evaluations to exclude secondary causes of disease. High-resolution CT is a critical initial diagnostic test and acts as a tool to identify patients who should undergo surgical lung biopsy to secure a definitive histological diagnosis of usual interstitial pneumonia pattern. This diagnostic approach faces several challenges. Many patients with suspected idiopathic pulmonary fibrosis present with atypical high-resolution CT characteristics but are unfit for surgical lung biopsy, therefore preventing a confident diagnosis. The state of the art suggests an iterative, multidisciplinary process that incorporates available clinical, laboratory, imaging, and histological features. Recent research has explored genomic techniques to molecularly phenotype patients with interstitial lung disease. In the future, clinicians will probably use blood-specific or lung specific molecular markers in combination with other clinical, physiological, and imaging features to enhance diagnostic efforts, refine prognostic recommendations, and influence the initial or subsequent treatment options. There is an urgent and increasing need for well designed, large, prospective studies measuring the effect of different diagnostic approaches. Ultimately, this will help to inform the development of guidelines and tailor clinical practice for the benefit of patients. PMID- 27932291 TI - Influenza not MERS CoV among returning Hajj and Umrah pilgrims with respiratory illness, Kashmir, north India, 2014-15. AB - BACKGROUND: The increasing reports of Middle East Respiratory Syndrome (MERS) caused by MERS coronavirus (MERS-CoV) from many countries emphasize its importance for international travel. Muslim pilgrimages of Hajj and Umrah involve mass gatherings of international travellers. We set out to assess the presence of influenza and MERS-CoV in Hajj/Umrah returnees with acute respiratory infection. . METHODS: Disembarking passengers (n = 8753) from Saudi Arabia (October 2014 to April 2015) were interviewed for the presence of respiratory symptoms; 977 (11%) reported symptoms and 300 (age 26-90, median 60 years; 140 male) consented to participate in the study. After recording clinical and demographic data, twin swabs (nasopharyngeal and throat) were collected from each participant, pooled in viral transport media and tested by real-time RT PCR for MERS-CoV and influenza A and B viruses and their subtypes. RESULTS: The participants had symptoms of 1-15 days (median 5d); cough (90%) and nasal discharge (86%) being the commonest. None of the 300 participants tested positive for MERS-CoV; however, 33 (11%) tested positive for influenza viruses (A/H3N2 = 13, A/H1N1pdm09 = 9 and B/Yamagata = 11). Eighteen patients received oseltamivir. No hospitalizations were needed and all had uneventful recovery. CONCLUSION: Despite a high prevalence of acute respiratory symptoms, MERS coV was not seen in returning pilgrims from Hajj and Umrah. However detection of flu emphasises preventive strategies like vaccination. PMID- 27932292 TI - Graduated Compression Stockings Does Not Decrease Walking Capacity and Muscle Oxygen Saturation during 6-Minute Walk Test in Intermittent Claudication Patients. AB - BACKGROUND: We analyze the effects of graduated compression stoking (GCS) on walking capacity and oxygen saturation in intermittent claudication (IC) patients. METHODS: Eighteen patients with IC performed the 6-minute walking test in 2 conditions in random order: GCS or placebo sock. Onset claudication distance and total walking distance were obtained. The calf muscle oxygen saturation was continuously monitored before, during, and after 6-minute walk test. Comparisons of the walking capacity and StO2 parameters between GCS and placebo conditions were analyzed by Wilcoxon rank-sum test. RESULTS: The onset claudication distance (GCS: 120 +/- 99 meters vs. placebo: 150 +/- 126 meters; P = 0.798) and total walking distance (GCS: 330 +/- 108 meters vs. placebo: 324 +/- 60 meters; P = 0.130) were similar between conditions. There were no differences in StO2 parameters between conditions (P > 0.05). CONCLUSIONS: GCS does not decrease walking performance and calf muscle oxygenation saturation during 6-minute walk test in patients with IC. PMID- 27932293 TI - The Macroautophagy Machinery in Endo- and Exocytosis. AB - Macroautophagy and the autophagy-related gene (Atg) machinery execute during their canonical function cytoplasmic constituent degradation in lysosomes. This canonical function contributes to pathogen restriction and intracellular antigen presentation on major histocompatibility complex (MHC) class II molecules to CD4+ T cells. However, in the recent years, it has become clear that the Atg machinery is also used for other membrane transport functions, including endocytosis and exocytosis. This review describes these non-canonical functions in the context of antigen presentation on MHC class I and II molecules to CD8+ and CD4+ T cells, respectively, and during viral replication. Future studies will need to address how the Atg machinery is modified for these non-canonical functions, gets recruited to the respective sites of membrane modification, and recruits alternative Atg interactors to execute endo- and exocytosis instead of macroautophagy. PMID- 27932294 TI - Large-Scale Structure-Based Prediction and Identification of Novel Protease Substrates Using Computational Protein Design. AB - Characterizing the substrate specificity of protease enzymes is critical for illuminating the molecular basis of their diverse and complex roles in a wide array of biological processes. Rapid and accurate prediction of their extended substrate specificity would also aid in the design of custom proteases capable of selectively and controllably cleaving biotechnologically or therapeutically relevant targets. However, current in silico approaches for protease specificity prediction, rely on, and are therefore limited by, machine learning of sequence patterns in known experimental data. Here, we describe a general approach for predicting peptidase substrates de novo using protein structure modeling and biophysical evaluation of enzyme-substrate complexes. We construct atomic resolution models of thousands of candidate substrate-enzyme complexes for each of five model proteases belonging to the four major protease mechanistic classes serine, cysteine, aspartyl, and metallo-proteases-and develop a discriminatory scoring function using enzyme design modules from Rosetta and AMBER's MMPBSA. We rank putative substrates based on calculated interaction energy with a modeled near-attack conformation of the enzyme active site. We show that the energetic patterns obtained from these simulations can be used to robustly rank and classify known cleaved and uncleaved peptides and that these structural-energetic patterns have greater discriminatory power compared to purely sequence-based statistical inference. Combining sequence and energetic patterns using machine learning algorithms further improves classification performance, and analysis of structural models provides physical insight into the structural basis for the observed specificities. We further tested the predictive capability of the model by designing and experimentally characterizing the cleavage of four novel substrate motifs for the hepatitis C virus NS3/4 protease using an in vivo assay. The presented structure-based approach is generalizable to other protease enzymes with known or modeled structures, and complements existing experimental methods for specificity determination. PMID- 27932297 TI - Dynamic self-organisation of haematopoiesis and (a)symmetric cell division. AB - A model of haematopoiesis that links self-organisation with symmetric and asymmetric cell division is presented in this paper. It is assumed that all cell divisions are completely random events, and that the daughter cells resulting from symmetric and asymmetric stem cell divisions are, in general, phenotypically identical, and still, the haematopoietic system has the flexibility to self renew, produce mature cells by differentiation, and regenerate undifferentiated and differentiated cells when necessary, due to self-organisation. As far as we know, no previous model implements symmetric and asymmetric division as the result of self-organisation. The model presented in this paper is inspired by experiments on the Drosophila germline stem cell, which imply that under normal conditions, the stem cells typically divide asymmetrically, whereas during regeneration, the rate of symmetric division increases. Moreover, the model can reproduce several of the results from experiments on female Safari cats. In particular, the model can explain why significant fluctuation in the phenotypes of haematopoietic cells was observed in some cats, when the haematopoietic system had reached normal population level after regeneration. To our knowledge, no previous model of haematopoiesis in Safari cats has captured this phenomenon. PMID- 27932296 TI - Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells. AB - Recent studies suggest there is a high incidence of elevated low-density lipoprotein (LDL) levels in Chronic Lymphocytic Leukemia (CLL) patients and a survival benefit from cholesterol-lowering statin drugs. The mechanisms of these observations and the kinds of patients they apply to are unclear. Using an in vitro model of the pseudofollicles where CLL cells originate, LDLs were found to increase plasma membrane cholesterol, signaling molecules such as tyrosine phosphorylated STAT3, and activated CLL cell numbers. The signaling effects of LDLs were not seen in normal lymphocytes or glycolytic lymphoma cell-lines but were restored by transduction with the nuclear receptor PPARdelta, which mediates metabolic activity in CLL cells. Breakdown of LDLs in lysosomes was required for the amplification effect, which correlated with down-regulation of HMGCR expression and long lymphocyte doubling times (LDTs) of 53.6+/-10.4months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels in a subgroup of patients. These observations suggest LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Prospective clinical trials are needed to confirm the therapeutic potential of lowering LDL concentrations in CLL, particularly in patients with indolent disease in the "watch-and-wait" phase of management. PMID- 27932295 TI - The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion. AB - Autophagy is a cellular degradation process integral for promoting cellular adaptation during metabolic stress while also functioning as a cellular homeostatic mechanism. Mounting evidence also demonstrates that autophagy is induced upon loss of integrin-mediated cell attachments to the surrounding extracellular matrix (ECM). Analogous to its established cytoprotective role during nutrient starvation, autophagy protects cells from detachment-induced cell death, termed anoikis. Here, we review the significance of autophagy as an anoikis resistance pathway, focusing on the intracellular signals associated with integrins that modulate the autophagy response and dictate the balance between cell death and survival following loss of cell-matrix contact. In addition, we highlight recent studies demonstrating that autophagy functions in the upstream regulation of integrin-mediated cell adhesion via the control of focal adhesion remodeling, and discuss how these emerging interconnections between integrin mediated adhesion pathways and autophagy influence cancer progression and metastasis. PMID- 27932298 TI - Modeling birds on wires. AB - In this paper we introduce a mathematical model to study the group dynamics of birds resting on wires. The model is agent-based and postulates attraction repulsion forces between the interacting birds: the interactions are "topological", in the sense that they involve a given number of neighbors irrespective of their distance. The model is first mathematically analyzed and then simulated to study its main properties: we observe that the model predicts birds to be more widely spaced near the borders of each group. We compare the results from the model with experimental data, derived from the analysis of pictures of pigeons and starlings taken in New Jersey: two different image elaboration protocols allow us to establish a good agreement with the model and to quantify its main parameters. We also discuss the potential handedness of the birds, by analyzing the group organization features and the group dynamics at the arrival of new birds. Finally, we propose a more refined mathematical model that describes landing and departing birds by suitable stochastic processes. PMID- 27932300 TI - Synchronous or Metachronous Occurrence of Lesions of Different Histologic Types in Patients With Esophageal Cancer. PMID- 27932301 TI - GH/IGF-I/insulin system in centenarians. AB - The endocrine system plays a major role in the regulation of several biological activity and in the ageing process. Evolutionary conservation of GH/IGF-I/insulin pathway from worms to mice and similarities in this system between mice and humans raised expectations that downregulated activity of the GH/IGF-I/insulin pathway could be beneficial for the extension of human life span. Centenarians represent the best example of successful ageing having reached the very extremes of the human life span, escaping and delaying the occurrence of several fatal age related diseases, such as cancer and cardiovascular diseases. This review describes the endocrine profile of centenarians concerning the GH/IGF-I/insulin system, focusing on the relevance of this pathway on the modulation of ageing and longevity. PMID- 27932302 TI - Hippocampal asymmetry: differences in the left and right hippocampus proteome in the rat model of temporal lobe epilepsy. AB - : The hippocampus is a complex brain structure and undergoes severe sclerosis and gliosis in temporal lobe epilepsy (TLE) as the most common type of epilepsy. The key features of the TLE may be reported in chronic animal models of epilepsy, such as pilocarpine model. Therefore, the current study was conducted in a rat pilocarpine model of acquired epilepsy. Two-dimensional gel electrophoresis based proteomic technique was used to compare the proteome map of the left and right hippocampus in both control and epileptic rats. Generally, 95 differentially expressed spots out of 1300 spots were identified in the hippocampus proteome using MALDI-TOF-TOF/MS. Within identified proteins, some showed asymmetric expression related to the mechanisms underlying TLE imposed by pilocarpine. Assessment of lateralization at the molecular level demonstrated that expression of proteins involved in dopamine synthesis was significantly more in the right hippocampus than the left one. In the epileptic model, reduction in dopamine pathway proteins was accompanied by an increase in the expression of proteins involved in polyamine synthesis, referring to a new regulating mechanism. Our results revealed changes in the laterality of protein expression due to pilocarpine-induced status epilepticus that could present some new proteins as potential candidates for antiepileptic drug design. BIOLOGICAL SIGNIFICANCE: In the current study, two-dimensional gel electrophoresis (2-DE) based proteomic technique was used to profile changes in the left and right hippocampus proteome after pilocarpine induced status epilepticus. Spots of proteome maps for two hemispheres were excised and identified with MALDI-TOF-TOF/MS. Analysis of proteome map of the left and right hippocampus revealed a lateralization at the molecular level, in which the expression of proteins involved in dopamine synthesis and release were significantly more in right hippocampi than the left ones in the normal rats. Also, the expression of proteins involved in polyamine synthesis significantly increased in epileptic hippocampus (considerably higher in right hippocampi), whilst the proteins which included in dopamine pathways were decreased. Our results revealed changes in the laterality of protein expression due to pilocarpine-induced status epilepticus that could present some new proteins as potential candidates for antiepileptic drug design. PMID- 27932299 TI - Provisional matrix: A role for versican and hyaluronan. AB - Hyaluronan and versican are extracellular matrix (ECM) components that are enriched in the provisional matrices that form during the early stages of development and disease. These two molecules interact to create pericellular "coats" and "open space" that facilitate cell sorting, proliferation, migration, and survival. Such complexes also impact the recruitment of leukocytes during development and in the early stages of disease. Once thought to be inert components of the ECM that help hold cells together, it is now quite clear that they play important roles in controlling cell phenotype, shaping tissue response to injury and maintaining tissue homeostasis. Conversion of hyaluronan-/versican enriched provisional matrix to collagen-rich matrix is a "hallmark" of tissue fibrosis. Targeting the hyaluronan and versican content of provisional matrices in a variety of diseases including, cardiovascular disease and cancer, is becoming an attractive strategy for intervention. PMID- 27932303 TI - One Sample, One Shot - Evaluation of sample preparation protocols for the mass spectrometric proteome analysis of human bile fluid without extensive fractionation. AB - : The proteome analysis of bile fluid represents a promising strategy to identify biomarker candidates for various diseases of the hepatobiliary system. However, to obtain substantive results in biomarker discovery studies large patient cohorts necessarily need to be analyzed. Consequently, this would lead to an unmanageable number of samples to be analyzed if sample preparation protocols with extensive fractionation methods are applied. Hence, the performance of simple workflows allowing for "one sample, one shot" experiments have been evaluated in this study. In detail, sixteen different protocols implying modifications at the stages of desalting, delipidation, deglycosylation and tryptic digestion have been examined. Each method has been individually evaluated regarding various performance criteria and comparative analyses have been conducted to uncover possible complementarities. Here, the best performance in terms of proteome coverage has been assessed for a combination of acetone precipitation with in-gel digestion. Finally, a mapping of all obtained protein identifications with putative biomarkers for hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) revealed several proteins easily detectable in bile fluid. These results can build the basis for future studies with large and well-defined patient cohorts in a more disease-related context. BIOLOGICAL SIGNIFICANCE: Human bile fluid is a proximal body fluid and supposed to be a potential source of disease markers. However, due to its biochemical composition, the proteome analysis of bile fluid still represents a challenging task and is therefore mostly conducted using extensive fractionation procedures. This in turn leads to a high number of mass spectrometric measurements for one biological sample. Considering the fact that in order to overcome the biological variability a high number of biological samples needs to be analyzed in biomarker discovery studies, this leads to the dilemma of an unmanageable number of necessary MS based analyses. Hence, easy sample preparation protocols are demanded representing a compromise between proteome coverage and simplicity. In the presented study, such protocols have been evaluated regarding various technical criteria (e.g. identification rates, missed cleavages, chromatographic separation) uncovering the strengths and weaknesses of various methods. Furthermore, a cumulative bile proteome list has been generated that extends the current bile proteome catalog by 248 proteins. Finally, a mapping with putative biomarkers for hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) derived from tissue-based studies, revealed several of these proteins being easily and reproducibly detectable in human bile. Therefore, the presented technical work represents a solid base for future disease-related studies. PMID- 27932304 TI - Vitamin D and type 2 diabetes. AB - Vitamin D deficiency is associated with a decreased insulin release, insulin resistance and type 2 diabetes in experimental and epidemiological studies. Animal studies show that 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) stimulates the pancreatic beta-cell to secrete insulin. The relationship between vitamin D deficiency and insulin resistance could develop through inflammation, as vitamin D deficiency is associated with increased inflammatory markers. In addition, genetic polymorphisms of vitamin D -related genes may predispose to impaired glycemic control and type 2 diabetes. Epidemiologic studies showed an association between low serum 25-hydroxyvitamin D3 (25(OH)D3) concentration and an increased risk for the metabolic syndrome and type 2 diabetes. This may be partly explained by an increased fat mass. A possible causal relationship between vitamin D deficiency and type 2 diabetes should be proven by randomized clinical trials showing that either type 2 diabetes can be prevented or insulin release and insulin sensitivity can be improved by vitamin D supplements. The results of randomized clinical trials on the effect of vitamin D versus placebo, sometimes combined with calcium, in patients with impaired glucose tolerance ("prediabetes") or type 2 diabetes are inconsistent. Some studies showed a slight decrease of fasting plasma glucose or improvement of insulin resistance, but often only in posthoc analyses. These effects are mainly visible in patients with vitamin D deficiency and impaired glucose tolerance at baseline. Meta-analyses of randomized clinical trials in general did not show significant effects of vitamin D supplementation on glycemic control. Currently, several large scale randomized clinical trials with vitamin D supplementation in doses of 1600-4000IU/d are ongoing with glycemic control or incidence of diabetes mellitus as outcome. Vitamin D deficiency needs to be prevented or cured, but until the results of these trials are published, high-dose vitamin D supplementation cannot be recommended for prevention or amelioration of type 2 diabetes. PMID- 27932305 TI - Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis. AB - Cognitive dysfunction is a major comorbidity of the epilepsies; however, treatments targeting seizure-associated cognitive dysfunction, particularly deficits in learning and memory are not available. Isoketals and neuroketals, collectively known as gamma-ketoaldehydes are formed via the non-enzymatic, free radical catalyzed oxidation of arachidonic acid and docosahexaenoic acid, respectively. They are attractive candidates for oxidative protein damage and resultant cognitive dysfunction due to their formation within the plasma membrane and their high proclivity to form cytotoxic adducts on protein lysine residues. We tested the hypothesis that gamma-ketoaldehydes mechanistically contribute to seizure-associated memory impairment using a specific gamma-ketoaldehyde scavenger, salicylamine in the kainic acid and pilocarpine rat models of temporal lobe epilepsy. We show that gamma-ketoaldehydes are increased following epileptogenic injury in hippocampus and perirhinal cortex, two brain regions imperative for learning and memory. Treatment with an orally bioavailable, brain permeable scavenger, salicylamine attenuated 1) spatial memory deficits 2) reference memory deficits and 3) neuronal loss and astrogliosis in two mechanistically distinct models of epilepsy without affecting the epileptogenic injury or the development of chronic epilepsy. We have previously demonstrated that reactive oxygen species and the lipid peroxidation biomarkers, F2 isoprostanes are produced following status epilepticus. However, which reactive species specifically mediate oxidative damage to cellular macromolecules remains at large. We provide novel data suggesting that memory impairment occurs via gamma-ketoaldehyde production in two models of epilepsy and that treatment with a gamma-ketoaldehyde scavenger can protect vulnerable neurons. This work suggests a novel target and therapy to treat seizure-induced memory deficits in epilepsy. PMID- 27932306 TI - Analysis of the Outcomes in Central Venous Access Port Implantation Performed by Residents via the Internal Jugular Vein and Subclavian Vein. AB - OBJECTIVE: The central venous access port (CVAP) has played an important role in the safe administration of chemotherapy and parenteral nutrition. The aim of the present study was to clarify the optimal access vein for CVAP implantation when performed by residents rather than attending surgeons. METHODS: A consecutive cases of CVAP implantation via the subclavian vein (SV) using a landmark-guided technique or via the internal jugular vein (JV) using an ultrasound-guided technique were divided into 2 groups according to whether the intervention was performed by a resident or an attending surgeon. Early and late complications were compared retrospectively between the 2 groups, and the outcomes of the CVAPs were compared between those implanted via the SV and those implanted via the JV in resident group. RESULTS: A total of 207 cases of CVAP implantation were performed. Overall, 114 implantations were performed by residents, and another 93 implantations were performed by attending surgeons. Early complications were seen more frequently in the resident group (6.1%) than in the attending-surgeon group (1.1%), but the difference was not significant. No differences in operating time or late complications were observed between the 2 groups. In the resident group, CVAP implantations via the JV using the ultrasound-guided technique were associated with a shorter operating time compared with the SV approach. CONCLUSIONS: Residents can perform CVAP implantations safely using both the SV and JV approaches. However, the JV approach using an ultrasound-guided technique can be performed in less time than the SV approach. PMID- 27932307 TI - Modular Training for Robot-Assisted Radical Prostatectomy: Where to Begin? AB - OBJECTIVE: Effective training is paramount for patient safety. Modular training entails advancing through surgical steps of increasing difficulty. This study aimed to construct a modular training pathway for use in robot-assisted radical prostatectomy (RARP). It aims to identify the sequence of procedural steps that are learnt before surgeons are able to perform a full procedure without an intervention from mentor. DESIGN: This is a multi-institutional, prospective, observational, longitudinal study. We used a validated training tool (RARP Score). Data regarding surgeons' stage of training and progress were collected for analysis. A modular training pathway was constructed with consensus on the level of difficulty and evaluation of individual steps. We identified and recorded the sequence of steps performed by fellows during their learning curves. SETTING AND PARTICIPANTS: We included 15 urology fellows from UK, Europe, and Australia. RESULTS: A total of 15 surgeons were assessed by mentors in 425 RARP cases over 8 months (range: 7-79) across 15 international centers. There were substantial differences in the sequence of RARP steps according to the chronology of the procedure, difficulty level, and the order in which surgeons actually learned steps. Steps were not attempted in chronological order. The greater the difficulty, the later the cohort first undertook the step (p = 0.021). The cohort undertook steps of difficulty level I at median case number 1. Steps of difficulty levels II, III, and IV showed more variation in median case number of the first attempt. We recommend that, in the operating theater, steps be learned in order of increasing difficulty. A new modular training route has been designed. This incorporates the steps of RARP with the following order of priority: difficulty level > median case number of first attempt > most frequently undertaken in surgical training. CONCLUSIONS: An evidence-based modular training pathway has been developed that facilitates a safe introduction to RARP for novice surgeons. PMID- 27932308 TI - Reaching to virtual targets: The oblique effect reloaded in 3-D. AB - Perceiving and reproducing direction of visual stimuli in 2-D space produces the visual oblique effect, which manifests as increased precision in the reproduction of cardinal compared to oblique directions. A second cognitive oblique effect emerges when stimulus information is degraded (such as when reproducing stimuli from memory) and manifests as a systematic distortion where reproduced directions close to the cardinal axes deviate toward the oblique, leading to space expansion at cardinal and contraction at oblique axes. We studied the oblique effect in 3-D using a virtual reality system to present a large number of stimuli, covering the surface of an imaginary half sphere, to which subjects had to reach. We used two conditions, one with no delay (no-memory condition) and one where a three-second delay intervened between stimulus presentation and movement initiation (memory condition). A visual oblique effect was observed for the reproduction of cardinal directions compared to oblique, which did not differ with memory condition. A cognitive oblique effect also emerged, which was significantly larger in the memory compared to the no-memory condition, leading to distortion of directional space with expansion near the cardinal axes and compression near the oblique axes on the hemispherical surface. This effect provides evidence that existing models of 2-D directional space categorization could be extended in the natural 3-D space. PMID- 27932309 TI - Binge alcohol alters exercise-driven neuroplasticity. AB - Exercise is increasingly being used as a treatment for alcohol use disorders (AUD), but the interactive effects of alcohol and exercise on the brain remain largely unexplored. Alcohol damages the brain, in part by altering glial functioning. In contrast, exercise promotes glial health and plasticity. In the present study, we investigated whether binge alcohol would attenuate the effects of subsequent exercise on glia. We focused on the medial prefrontal cortex (mPFC), an alcohol-vulnerable region that also undergoes neuroplastic changes in response to exercise. Adult female Long-Evans rats were gavaged with ethanol (25% w/v) every 8h for 4days. Control animals received an isocaloric, non-alcohol diet. After 7days of abstinence, rats remained sedentary or exercised for 4weeks. Immunofluorescence was then used to label microglia, astrocytes, and neurons in serial tissue sections through the mPFC. Confocal microscope images were processed using FARSIGHT, a computational image analysis toolkit capable of automated analysis of cell number and morphology. We found that exercise increased the number of microglia in the mPFC in control animals. Binged animals that exercised, however, had significantly fewer microglia. Furthermore, computational arbor analytics revealed that the binged animals (regardless of exercise) had microglia with thicker, shorter arbors and significantly less branching, suggestive of partial activation. We found no changes in the number or morphology of mPFC astrocytes. We conclude that binge alcohol exerts a prolonged effect on morphology of mPFC microglia and limits the capacity of exercise to increase their numbers. PMID- 27932311 TI - Daclatasvir Prevents Hepatitis C Virus Infectivity by Blocking Transfer of the Viral Genome to Assembly Sites. AB - BACKGROUND & AIMS: Daclatasvir is a direct-acting antiviral agent and potent inhibitor of NS5A, which is involved in replication of the hepatitis C virus (HCV) genome, presumably via membranous web shaping, and assembly of new virions, likely via transfer of the HCV RNA genome to viral particle assembly sites. Daclatasvir inhibits the formation of new membranous web structures and, ultimately, of replication complex vesicles, but also inhibits an early assembly step. We investigated the relationship between daclatasvir-induced clustering of HCV proteins, intracellular localization of viral RNAs, and inhibition of viral particle assembly. METHODS: Cell-culture-derived HCV particles were produced from Huh7.5 hepatocarcinoma cells in presence of daclatasvir for short time periods. Infectivity and production of physical particles were quantified and producer cells were subjected to subcellular fractionation. Intracellular colocalization between core, E2, NS5A, NS4B proteins, and viral RNAs was quantitatively analyzed by confocal microscopy and by structured illumination microscopy. RESULTS: Short exposure of HCV-infected cells to daclatasvir reduced viral assembly and induced clustering of structural proteins with non-structural HCV proteins, including core, E2, NS4B, and NS5A. These clustered structures appeared to be inactive assembly platforms, likely owing to loss of functional connection with replication complexes. Daclatasvir greatly reduced delivery of viral genomes to these core clusters without altering HCV RNA colocalization with NS5A. In contrast, daclatasvir neither induced clustered structures nor inhibited HCV assembly in cells infected with a daclatasvir-resistant mutant (NS5A-Y93H), indicating that daclatasvir targets a mutual, specific function of NS5A inhibiting both processes. CONCLUSIONS: In addition to inhibiting replication complex biogenesis, daclatasvir prevents viral assembly by blocking transfer of the viral genome to assembly sites. This leads to clustering of HCV proteins because viral particles and replication complex vesicles cannot form or egress. This dual mode of action of daclatasvir could explain its efficacy in blocking HCV replication in cultured cells and in treatment of patients with HCV infection. PMID- 27932310 TI - Loss of dopamine D1 receptors and diminished D1/5 receptor-mediated ERK phosphorylation in the periaqueductal gray after spinal cord lesion. AB - Neuropathic pain resulting from spinal cord injury is often accompanied by maladaptive plasticity of the central nervous system, including the opioid receptor-rich periaqueductal gray (PAG). Evidence suggests that sensory signaling via the PAG is robustly modulated by dopamine D1- and D2-like receptors, but the effect of damage to the spinal cord on D1 and D2 receptor protein expression and function in the PAG has not been examined. Here we show that 21days after a T10 or C6 spinothalamic tract lesion, both mice and rats display a remarkable decline in the expression of D1 receptors in the PAG, revealed by western blot analysis. These changes were associated with a significant reduction in hindpaw withdrawal thresholds in lesioned animals compared to sham-operated controls. We investigated the consequences of diminished D1 receptor levels by quantifying D1 like receptor-mediated phosphorylation of ERK1,2 and CREB, events that have been observed in numerous brain structures. In naive animals, western blot analysis revealed that ERK1,2, but not CREB phosphorylation was significantly increased in the PAG by the D1-like agonist SKF 81297. Using immunohistochemistry, we found that SKF 81297 increased ERK1,2 phosphorylation in the PAG of sham animals. However, in lesioned animals, basal pERK1,2 levels were elevated and did not significantly increase after exposure to SKF 81297. Our findings provide support for the hypothesis that molecular adaptations resulting in a decrease in D1 receptor expression and signaling in the PAG are a consequence of SCL. PMID- 27932313 TI - 3rd congress on applied synthetic biology in Europe (Costa da Caparica, Portugal, February 2016). AB - The third meeting organised by the European Federation of Biotechnology (EFB) on advances in Applied Synthetic Biotechnology in Europe (ASBE) was held in Costa da Caparica, Portugal, in February 2016. Abundant novel applications in synthetic biology were described in the six sessions of the meeting, which was divided into technology and tools for synthetic biology (I, II and III), bionanoscience, biosynthetic pathways and enzyme synthetic biology, and metabolic engineering and chemical manufacturing. The meeting presented numerous methods for the development of novel synthetic strains, synthetic biological tools and synthetic biology applications. With the aid of synthetic biology, production costs of chemicals, metabolites and food products are expected to decrease, by generating sustainable biochemical production of such resources. Also, such synthetic biological advances could be applied for medical purposes, as in pharmaceuticals and for biosensors. Recurrent, linked themes throughout the meeting were the shortage of resources, the world's transition into a bioeconomy, and how synthetic biology is helping tackle these issues through cutting-edge technologies. While there are still limitations in synthetic biology research, innovation is propelling the development of technology, the standardisation of synthetic biological tools and the use of suitable host organisms. These developments are laying a foundation to providing a future where cutting-edge research could generate potential solutions to society's pressing issues, thus incentivising a transition into a bioeconomy. PMID- 27932312 TI - Targeted Apoptosis of Parietal Cells Is Insufficient to Induce Metaplasia in Stomach. AB - Parietal cell atrophy is considered to cause metaplasia in the stomach. We developed mice that express the diphtheria toxin receptor specifically in parietal cells to induce their death, and found this to increase proliferation in the normal stem cell zone and neck but not to cause metaplastic reprogramming of chief cells. Furthermore, the metaplasia-inducing agents tamoxifen or DMP-777 still induced metaplasia even after previous destruction of parietal cells by diphtheria toxin. Atrophy of parietal cells alone therefore is not sufficient to induce metaplasia: completion of metaplastic reprogramming of chief cells requires mechanisms beyond parietal cell injury or death. PMID- 27932314 TI - TIS21/BTG2 inhibits doxorubicin-induced stress fiber-vimentin networks via Nox4 ROS-ABI2-DRF-linked signal cascade. AB - Activities of TIS21/BTG2 gene regulating cancer cell senescence were investigated in hepatoma cells by using low dose doxorubicin (Doxo, 100ng/mL). Treatment of Huh7 cells with Doxo increased linear actin nucleation e.g., transverse arcs and ventral stress fibers, as opposed to loss of filopodia. The linear actin nucleation was accompanied with thick vimentin networks at periphery of the cells, when examined by super-resolution STED microscope. However, expression of TIS21 inhibited ABI2-DRF pathway by inhibiting DRF expression and reducing ABI2 protein stability. The change lead to downregulation of stress fiber formations and thick vimentin networks at the periphery of Huh7 cells. In addition, TIS21 inhibited NADPH oxidase 4 (Nox4)-derived reactive oxygen species (ROS) generation that regulates actin nucleator, DRF family gene expression. Taken together, TIS21 attenuated Doxo-induced cancer cell senescence by inhibiting linear actin nucleation via Nox4-ROS-ABI2-DRF signal cascade, implying that expression of TIS21 overcomes resistance of senescent cells to cancer chemotherapy via inhibiting linear actin nucleation. PMID- 27932315 TI - Design and Testing of the Safety Agenda Mobile App for Managing Health Care Managers' Patient Safety Responsibilities. AB - BACKGROUND: Adverse events are a reality in clinical practice. Reducing the prevalence of preventable adverse events by stemming their causes requires health managers' engagement. OBJECTIVE: The objective of our study was to develop an app for mobile phones and tablets that would provide managers with an overview of their responsibilities in matters of patient safety and would help them manage interventions that are expected to be carried out throughout the year. METHODS: The Safety Agenda Mobile App (SAMA) was designed based on standardized regulations and reviews of studies about health managers' roles in patient safety. A total of 7 managers used a beta version of SAMA for 2 months and then they assessed and proposed improvements in its design. Their experience permitted redesigning SAMA, improving functions and navigation. A total of 74 Spanish health managers tried out the revised version of SAMA. After 4 months, their assessment was requested in a voluntary and anonymous manner. RESULTS: SAMA is an iOS app that includes 37 predefined tasks that are the responsibility of health managers. Health managers can adapt these tasks to their schedule, add new ones, and share them with their team. SAMA menus are structured in 4 main areas: information, registry, task list, and settings. Of the 74 users who tested SAMA, 64 (86%) users provided a positive assessment of SAMA characteristics and utility. Over an 11-month period, 238 users downloaded SAMA. This mobile app has obtained the AppSaludable (HealthyApp) Quality Seal. CONCLUSIONS: SAMA includes a set of activities that are expected to be carried out by health managers in matters of patient safety and contributes toward improving the awareness of their responsibilities in matters of safety. PMID- 27932316 TI - Evaluation of Diet-Related Infographics on Pinterest for Use of Behavior Change Theories: A Content Analysis. AB - BACKGROUND: There is increasing interest in Pinterest as a method of disseminating health information. However, it is unclear whether the health information promoted on Pinterest is evidence-based or incorporates behavior change theory. OBJECTIVES: The objective of the study was to determine the presence of health behavior theory (HBT) constructs in pins found on Pinterest and assess the relationship between various pin characteristics and the likelihood of inclusion of HBT. METHODS: A content analysis was conducted on pins collected from Pinterest identified with the search terms "nutrition infographic" and "healthy eating infographic." The coding rubric included HBT constructs, pin characteristics, and visual communication tools. Each HBT construct was coded as present or not present (yes=1, no=0). A total theory score was calculated by summing the values for each of the 9 constructs (range 0-9). Adjusted regression analysis was used to identify factors associated with the inclusion of health behavior change theory in pins (P<.05). RESULTS: The mean total theory score was 2.03 (SD 1.2). Perceived benefits were present most often (170/236, 72%), followed by behavioral capability (123/238, 51.7%) and perceived severity (79/236, 33.5%). The construct that appeared the least was self-regulation/self control (2/237, 0.8%). Pin characteristics associated with the inclusion of HBT included a large amount of text (P=.01), photographs of real people (P=.001), cartoon pictures of food (P=.01), and the presence of references (P=.001). The number of repins (P=.04), likes (P=.01), and comments (P=.01) were positively associated with the inclusion of HBT. CONCLUSIONS: These findings suggest that current Pinterest infographics targeting healthy eating contain few HBT elements. Health professionals and organizations should create and disseminate infographics that contain more elements of HBT to better influence healthy eating behavior. This may be accomplished by creating pins that use both text and images of people and food in order to portray elements of HBT and convey nutritional information. PMID- 27932317 TI - End of life care for infants, children and young people with life limiting conditions: summary of NICE guidance. PMID- 27932318 TI - Angiotensin Receptor Blocker Protects Alzheimer's Disease Brain From Ischemic Insult. PMID- 27932320 TI - "I didn't want to be known": finding healthcare when you are homeless. PMID- 27932322 TI - Carbone PP, Bono V, Frei E III, Brindley CO. Clinical studies with vincristine. Blood. 1963;21(5):640-647. PMID- 27932323 TI - Targeting hedgehog in T-ALL. PMID- 27932324 TI - Deregulation of NF-kappaB, ie, a useful PMBL marker. PMID- 27932325 TI - Twisting IL-1 signaling to kill CML stem cells. PMID- 27932326 TI - Mechanism of O2-sensitive red cell properties. PMID- 27932327 TI - Ticagrelor: agonising over its mechanisms of action. PMID- 27932328 TI - Losing your GRP on platelet activation. PMID- 27932329 TI - RUSH for G6PD! PMID- 27932331 TI - Crivello P, Heinold A, Rebmann V, et al. Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT. Blood. 2016;128(1):120-129. PMID- 27932330 TI - von Willebrand disease type 2B. PMID- 27932332 TI - The Anterolateral Capsule of the Knee Behaves Like a Sheet of Fibrous Tissue. AB - BACKGROUND: The function of the anterolateral capsule of the knee has not been clearly defined. However, the contribution of this region of the capsule to knee stability in comparison with other anterolateral structures can be determined by the relative force that each structure carries during loading of the knee. Purpose/Hypothesis: The purpose of this study was to determine the forces in the anterolateral structures of the intact and anterior cruciate ligament (ACL) deficient knee in response to an anterior tibial load and internal tibial torque. It was hypothesized that the anterolateral capsule would not function like a traditional ligament (ie, transmitting forces only along its longitudinal axis). STUDY DESIGN: Controlled laboratory study. METHODS: Loads (134-N anterior tibial load and 7-N.m internal tibial torque) were applied continuously during flexion to 7 fresh-frozen cadaveric knees in the intact and ACL-deficient state using a robotic testing system. The lateral collateral ligament (LCL) and the anterolateral capsule were separated from the surrounding tissue and from each other. This was done by performing 3 vertical incisions: lateral to the LCL, medial to the LCL, and lateral to the Gerdy tubercle. Attachments of the LCL and anterolateral capsule were detached from the underlying tissue (ie, meniscus), leaving the insertions and origins intact. The force distribution in the anterolateral capsule, ACL, and LCL was then determined at 30 degrees , 60 degrees , and 90 degrees of knee flexion using the principle of superposition. RESULTS: In the intact knee, the force in the ACL in response to an anterior tibial load was greater than that in the other structures ( P < .001). However, in response to an internal tibial torque, no significant differences were found between the ACL, LCL, and forces transmitted between each region of the anterolateral capsule after capsule separation. The anterolateral capsule experienced smaller forces (~50% less) compared with the other structures ( P = .048). For the ACL-deficient knee in response to an anterior tibial load, the force transmitted between each region of the anterolateral capsule was 434% greater than was the force in the anterolateral capsule ( P < .001) and 54% greater than the force in the LCL ( P = .036) at 30 degrees of flexion. In response to an internal tibial torque at 30 degrees , 60 degrees , or 90 degrees of knee flexion, no significant differences were found between the force transmitted between each region of the anterolateral capsule and the LCL. The force in the anterolateral capsule was significantly smaller than that in the other structures at all knee flexion angles for both loading conditions ( P = .004 for anterior tibial load and P = .04 for internal tibial torque). CONCLUSION: The anterolateral capsule carries negligible forces in the longitudinal direction, and the forces transmitted between regions of the capsule were similar to the forces carried by the other structures at the knee, suggesting that it does not function as a traditional ligament. Thus, the anterolateral capsule should be considered a sheet of tissue. CLINICAL RELEVANCE: Surgical repair techniques for the anterolateral capsule should restore the ability of the tissue to transmit forces between adjacent regions of the capsule rather than along its longitudinal axis. PMID- 27932333 TI - UK is ranked 15th for heart care in European index. PMID- 27932334 TI - Hospital doctors warn of massive job losses if Obamacare is repealed. PMID- 27932335 TI - Multicentre randomised placebo-controlled trial of oral anticoagulation with apixaban in systemic sclerosis-related pulmonary arterial hypertension: the SPHInX study protocol. AB - INTRODUCTION: Systemic sclerosis (SSc) is a severe and costly multiorgan autoimmune connective tissue disease characterised by vasculopathy and fibrosis. One of the major causes of SSc-related death is pulmonary arterial hypertension (PAH), which develops in 12-15% of patients with SSc and accounts for 30-40% of deaths. In situ thrombosis in the small calibre peripheral pulmonary vessels resulting from endothelial dysfunction and an imbalance of anticoagulant and prothrombotic mediators has been implicated in the complex pathophysiology of SSc related PAH (SSc-PAH), with international clinical guidelines recommending the use of anticoagulants for some types of PAH, such as idiopathic PAH. However, anticoagulation has not become part of standard clinical care for patients with SSc-PAH as only observational evidence exists to support its use. Therefore, we present the rationale and methodology of a phase III randomised controlled trial (RCT) to evaluate the efficacy, safety and cost-effectiveness of anticoagulation in SSc-PAH. METHODS AND ANALYSIS: This Australian multicentre RCT will compare 2.5 mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3 years as adjunct therapy to stable oral PAH therapy. The composite primary outcome measure will be the time to death or clinical worsening of PAH. Secondary outcomes will include functional capacity, health-related quality of life measures and adverse events. A cost effectiveness analysis of anticoagulation versus placebo will also be undertaken. ETHICS AND DISSEMINATION: Ethical approval for this RCT has been granted by the Human Research Ethics Committees of all participating centres. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. The findings of this RCT are to be published in open access journals. TRIAL REGISTRATION NUMBER: ACTRN12614000418673, Pre-results. PMID- 27932336 TI - Heat stress, hydration and uric acid: a cross-sectional study in workers of three occupations in a hotspot of Mesoamerican nephropathy in Nicaragua. AB - OBJECTIVES: To study Mesoamerican nephropathy (MeN) and its risk factors in three hot occupations. DESIGN: Cross-sectional. SETTING: Chinandega and Leon municipalities, a MeN hotspot on the Nicaraguan Pacific coast, January-February 2013. PARTICIPANTS: 194 male workers aged 17-39 years: 86 sugarcane cutters, 56 construction workers, 52 small-scale farmers. OUTCOME MEASURES: (1) Differences between the three occupational groups in prevalences/levels of socioeconomic, occupational, lifestyle and health risk factors for chronic kidney disease (CKD) and in biomarkers of kidney function and hydration; (2) differences in prevalences/levels of CKD risk factors between workers with reduced estimated glomerular filtration rate (eGFRCKD-EPI <80 mL/min/1.73 m2) and workers with normal kidney function (eGFRCKD-EPI >=80 mL/min/1.73 m2). RESULTS: Sugarcane cutters were more exposed to heat and consumed more fluid on workdays and had less obesity, lower blood sugar, lower blood pressure and a better lipid profile. Reduced eGFR occurred in 16%, 9% and 2% of sugarcane cutters, construction workers and farmers, respectively (trend cane > construction > farming, p=0.003). Significant trends (cane > construction > farming) were also observed for high serum urea nitrogen (blood urea nitrogen (BUN) >20 mg/dL), high serum creatinine (SCr >1.2 mg/dL), low urinary pH (<=5.5) and high BUN/SCr ratio (>20) but not for high urinary specific gravity (>=1.030). Sugarcane cutters also more often had proteinuria and blood and leucocytes in the urine. Workers with eGFR <80 mL/min/1.73 m2 reported a higher intake of water and lower intake of sugary beverages. Serum uric acid levels related strongly and inversely to eGFR levels (adj beta -10.4 mL/min/1.73 m2, 95% CI -12.2 to -8.5, p<0.001). No associations were observed for other metabolic risk factors, pesticides, non-steroidal anti inflammatory drugs or alcohol. Among cane cutters, consumption of electrolyte hydration solution appeared preventive (adj beta 8.1 mL/min/1.73 m2, p=0.09). CONCLUSIONS: Heat stress, dehydration and kidney dysfunction were most common among sugarcane cutters. Kidney dysfunction also occurred to a lesser extent among construction workers, but hardly at all among small-scale farmers. High serum uric acid was associated with reduced kidney function. PMID- 27932337 TI - Development of a critical appraisal tool to assess the quality of cross-sectional studies (AXIS). AB - OBJECTIVES: The aim of this study was to develop a critical appraisal (CA) tool that addressed study design and reporting quality as well as the risk of bias in cross-sectional studies (CSSs). In addition, the aim was to produce a help document to guide the non-expert user through the tool. DESIGN: An initial scoping review of the published literature and key epidemiological texts was undertaken prior to the formation of a Delphi panel to establish key components for a CA tool for CSSs. A consensus of 80% was required from the Delphi panel for any component to be included in the final tool. RESULTS: An initial list of 39 components was identified through examination of existing resources. An international Delphi panel of 18 medical and veterinary experts was established. After 3 rounds of the Delphi process, the Appraisal tool for Cross-Sectional Studies (AXIS tool) was developed by consensus and consisted of 20 components. A detailed explanatory document was also developed with the tool, giving expanded explanation of each question and providing simple interpretations and examples of the epidemiological concepts being examined in each question to aid non-expert users. CONCLUSIONS: CA of the literature is a vital step in evidence synthesis and therefore evidence-based decision-making in a number of different disciplines. The AXIS tool is therefore unique and was developed in a way that it can be used across disciplines to aid the inclusion of CSSs in systematic reviews, guidelines and clinical decision-making. PMID- 27932338 TI - Meaning of living with severe chronic obstructive lung disease: a qualitative study. AB - OBJECTIVES: To explore what it means for patients to live with chronic obstructive pulmonary disease (COPD) as an incurable and constantly progressing disease. DESIGN: Qualitative longitudinal study using narrative and semistructured interviews. This paper presents findings of the initial interviews. Analysis using grounded theory. SETTING: Lung care clinics and community care in Lower Saxony, Germany. PARTICIPANTS: 17 patients with advanced stage COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) III/IV). FINDINGS: Analysis shows that these patients have difficulties accepting their life situation and feel at the mercy of the disease, which could be identified as a core-experienced phenomenon. Over a long period of time, patients have only a vague feeling of being ill, caused by uncertain knowledge, slow progress and doubtful attribution of clinical symptoms of the disease (causal conditions). As an action strategy, patients try to maintain daily routines for as long as possible after diagnosis. Both effective standard and rescue medication, which helps to reduce breathlessness and other symptoms, and the feeling of being faced with one's own responsibility (intervening conditions) support this strategy, whereby patients' own responsibility is too painful to acknowledge. As a consequence, patients try to deny the threat to life for a long period of time. Frequently, they need to experience facing their own limits, often in the form of an acute crisis, to realise their health situation. The experience of the illness is contextualised by a continuous increase in limited mobility and social isolation. CONCLUSION: In order to help patients to improve disease awareness, to accept their life situation and to improve their reduced quality of life, patients may benefit from the early integration of palliative care (PC), considering its multiprofessional patient-centred and team-centred approach. Psychological support and volunteer work, which are relevant aspects of PC, should be appropriate to address psychosocial needs. More research is needed to evaluate how patients could benefit from early PC. PMID- 27932339 TI - Predictors of treatment failure on second-line antiretroviral therapy among adults in northwest Ethiopia: a multicentre retrospective follow-up study. AB - BACKGROUND: The number of patients using second-line antiretroviral therapy (ART) has increased over time. In Ethiopia, 1.5% of HIV infected patients on ART are using a second-line regimen and little is known about its effect in this setting. OBJECTIVE: To estimate the rate and predictors of treatment failure on second line ART among adults living with HIV in northwest Ethiopia. SETTING: An institution-based retrospective follow-up study was conducted at three tertiary hospitals in northwest Ethiopia from March to May 2015. PARTICIPANTS: 356 adult patients participated and 198 (55.6%) were males. Individuals who were on second line ART for at least 6 months of treatment were included and the data were collected by reviewing their records. PRIMARY OUTCOME MEASURE: The primary outcome was treatment failure defined as immunological failure, clinical failure, death, or lost to follow-up. To assess our outcome, we used the definitions of the WHO 2010 guideline. RESULT: The mean+/-SD age of participants at switch was 36+/-8.9 years. The incidence rate of failure was 61.7/1000 person years. The probability of failure at the end of 12 and 24 months were 5.6% and 13.6%, respectively. Out of 67 total failures, 42 (62.7%) occurred in the first 2 years. The significant predictors of failure were found to be: WHO clinical stage IV at switch (adjusted HR (AHR) 2.1, 95% CI 1.1 to 4.1); CD4 count <100 cells/mm3 at switch (AHR 2.0, 95% CI 1.2 to 3.5); and weight change (AHR 0.92, 95% CI 0.88 to 0.95). CONCLUSIONS: The rate of treatment failure was highest during the first 2 years of treatment. WHO clinical stage, CD4 count at switch, and change in weight were found to be predictors of treatment failure. PMID- 27932340 TI - Is Walk Score associated with hospital admissions from chronic diseases? Evidence from a cross-sectional study in a high socioeconomic status Australian city state. AB - OBJECTIVES: To explore patterns of non-communicable diseases (NCDs) in the Australian Capital Territory (ACT).To ascertain the effect of the neighbourhood built environmental features and especially walkability on health outcomes, specifically for hospital admissions from NCDs. DESIGN: A cross-sectional analysis of public hospital episode data (2007-2013). SETTING: Hospitalisations from the ACT, Australia at very small geographic areas. PARTICIPANTS: Secondary data on 75 290 unique hospital episodes representing 39 851 patients who were admitted to ACT hospitals from 2007 to 2013. No restrictions on age, sex or ethnicity. MAIN EXPOSURE MEASURES: Geographic Information System derived or compatible measures of general practitioner access, neighbourhood socioeconomic status, alcohol access, exposure to traffic and Walk Score walkability. MAIN OUTCOME MEASURES: Hospitalisations of circulatory diseases, specific endocrine, nutritional and metabolic diseases, respiratory diseases and specific cancers. RESULTS: Geographic clusters with significant high and low risks of NCDs were found that displayed an overall geographic pattern of high risk in the outlying suburbs of the territory. Significant relationships between neighbourhood walkability as measured by Walk Score and the likelihood of hospitalisation with a primary diagnosis of myocardial infarction (heart attack) were found. A possible relationship was also found with the likelihood of being hospitalised with 4 major lifestyle-related cancers. CONCLUSIONS: Our research augments the growing literature underscoring the relationships between the built environment and health outcomes. In addition, it supports the importance of walkable neighbourhoods, as measured by Walk Score, for improved health. PMID- 27932341 TI - Older patient considering treatment for advanced renal disease: protocol for a scoping review of the information available for shared decision-making. AB - INTRODUCTION: Older adults constitute the largest group of patients on dialysis in most parts of the world. Management of advanced renal disease in the older adult is complex; treatment outcomes and prognosis can be markedly different from younger patients. Clinical teams caring for such patients are often called on to provide information regarding prognosis and outcomes with treatment-particularly, the comparison between having dialysis treatment versus not having dialysis. These discussions can be difficult for clinicians because they have to contend with incomplete or nascent data regarding prognosis and outcomes in this age group. We aim to summarise the currently available information regarding the prognosis and outcomes of advanced renal disease in the older adult by means of a scoping review of the literature. This article discusses our protocol. METHODS: This scoping review will be undertaken in accordance with the Joanna Briggs Institute's methodology for scoping reviews. A directed search will look for relevant articles in English (within electronic databases and the grey literature), written between 2000 and 2016, which have studied older patients with advanced renal disease (estimated glomerular filtration rate <30 mL/min/1.73 m2). After screening by two independent reviewers, selected articles will be analysed using a data charting tool. Reporting will include descriptions, analysis of themes using qualitative software and display of information using charts. ETHICS AND DISSEMINATION: This scoping review will analyse previously collected data, and so does not require ethical approval. Results will be disseminated through academic journals, conferences and seminars. We anticipate that our summary of the currently available knowledge regarding the older adult with advanced renal disease will be a repository of information for clinicians in the field. We expect to identify areas of study that are suited to systematic reviews. Our findings can also be expected to influence guidelines and clinical practice recommendations in the future. PMID- 27932342 TI - Time-saving screening for diabetes in patients with coronary artery disease: a report from EUROASPIRE IV. AB - BACKGROUND: WHO advocates 2-hour oral glucose tolerance test (OGTT) for detecting diabetes mellitus (DM). OGTT is the most sensitive method to detect DM in patients with coronary artery disease (CAD). Considered time consuming, the use of OGTT is unsatisfactory. A 1-hour plasma glucose (1hPG) test has not been evaluated as an alternative in patients with CAD. OBJECTIVES: To create an algorithm based on glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and 1hPG limiting the need of a 2-hour plasma glucose (2hPG) in patients with CAD. METHODS: 951 patients with CAD without DM underwent OGTT. A 2hPG>=11.1 mmol/L was the reference for undiagnosed DM. The yield of HbA1c, FPG and 1hPG was compared with that of 2hPG. RESULTS: Mean FPG was 6.2+/-0.9 mmol/L, and mean HbA1c 5.8+/ 0.4%. Based on 2hPG>=11.1 mmol/L 122 patients (13%) had DM. There was no value for the combination of HbA1c and FPG to rule out or in DM (HbA1c>=6.5%; FPG>=7.0 mmol/L). In receiver operating characteristic analysis a 1hPG>=12 mmol/L balanced sensitivity and specificity for detecting DM (both=82%; positive and negative predictive values 40% and 97%). A combination of FPG<6.5 mmol/L and 1hPG<11 mmol/L excluded 99% of DM. A combination of FPG>8.0 mmol/L and 1hPG>15 mmol/L identified 100% of patients with DM. CONCLUSIONS: Based on its satisfactory accuracy to detect DM an algorithm is proposed for screening for DM in patients with CAD decreasing the need for a 2-hour OGTT by 71%. PMID- 27932343 TI - Influence of the day care, home and neighbourhood environment on young children's physical activity and health: protocol for the PLAYCE observational study. AB - INTRODUCTION: The early years are a critical period in a child's health and development, yet most preschool children fail to meet physical activity guidelines. Outside of the home and neighbourhood, children spend a large proportion of time within early childhood education and care (ECEC) services such as long day care. Research is required to determine how the design of day care outdoor (and indoor) spaces provides opportunities or constraints for physical activity. A significant evidence gap surrounds what objectively measured attributes of the home and neighbourhood environment influence preschoolers' physical activity. The PLAY Spaces & Environments for Children's Physical Activity (PLAYCE) study will empirically investigate the relative and cumulative influence of the day care, home and neighbourhood environment on preschoolers' physical activity. METHODS AND ANALYSIS: The PLAYCE study is a cross-sectional observational study (April 2015 to April 2018) of 2400 children aged 2-5 years attending long day care in metropolitan Perth, Western Australia. Accelerometers will measure physical activity with indoor physical activity measured using radio frequency identification. Global positioning systems will be used to determine outdoor location of physical activity around the home and neighbourhood for a subsample (n=310). The day care environment will be objectively measured using a validated audit tool. Other potential individual, social and physical environmental influences on preschoolers' physical activity will be collected by geographic information systems measures, parent and day care educator surveys. ETHICS AND DISSEMINATION: Ethical approval has been granted by The University of Western Australia Human Ethics Research Committee, approval number RA/4/1/7417. Findings will be published in international peer-reviewed journals and presented at international conferences. Key findings will be disseminated to stakeholders, collaborators, policymakers and practitioners working in the ECEC sector. Day care centre directors and parents will be given a summary report of the key findings. PMID- 27932344 TI - Using Robust Normative Data to Investigate the Neuropsychology of Cognitive Aging. AB - Objective: The extent to which increasing age is associated with impairment in cognitive function, termed cognitive aging, may have been overestimated in prior studies. The inclusion of individuals with severe or uncontrolled systemic medical illness or prodromal neurodegenerative disease in normal aging samples is likely to bias estimates toward lower cognitive performance and inflate estimates of variability. Method: Unbiased estimates of cognitive aging in 658 adults aged 60-84, who underwent rigorous screening to ensure their general and cognitive health, were computed. The first study screened the psychometric properties of a battery of neuropsychological tests in order to identify those with optimal properties to evaluate cognitive aging. The second study used the selected tests to compare baseline performance within 5-year age bands from 60 to 84. Results: The first study identified a battery of 12 tests that provided reliable measures of memory, psychomotor speed, attention, and executive function and were appropriate for investigating age-related cognitive changes. The second study observed moderate to large age-related impairment for performance on tests of complex psychomotor function, category fluency, verbal learning, and verbal and visual memory. No, or only small, age effects were observed for working memory, phonemic fluency, learning of visual information, and reaction time. Conclusions: These data suggested that while increasing age is associated with impairment in cognitive function, this impairment is less severe and is evident only on more complex neuropsychological tests than estimated previously in samples selected using less rigorous criteria to ensure cognitive health. PMID- 27932345 TI - Comprehensive Cognitive Assessments are not Necessary for the Identification and Treatment of Learning Disabilities. AB - There is considerable controversy about the necessity of cognitive assessment as part of an evaluation for learning and attention problems. The controversy should be adjudicated through an evaluation of empirical research. We review five sources of evidence commonly provided as support for cognitive assessment as part of the learning disability (LD) identification process, highlighting significant gaps in empirical research and where existing evidence is insufficient to establish the reliability and validity of cognitive assessments used in this way. We conclude that current evidence does not justify routine cognitive assessment for LD identification. As an alternative, we offer an instructional conceptualization of LD: a hybrid model that directly informs intervention and is based on documenting low academic achievement, inadequate response to intensive interventions, and a consideration of exclusionary factors. PMID- 27932346 TI - Identifying arthralgia suspicious for progression to rheumatoid arthritis. PMID- 27932348 TI - Toggling the EGFR Signaling Pathway. PMID- 27932347 TI - Immunoscintigraphic detection of tumour necrosis factor by radiolabelled certolizumab pegol in patients with erosive hand osteoarthritis: a proof-of concept study. PMID- 27932349 TI - NADPH Oxidase-2 and Atherothrombosis: Insight From Chronic Granulomatous Disease. AB - The phagocytic cell enzyme NADPH oxidase-2 (Nox2) is critical for killing micro organisms via production of reactive oxygen species and thus is a key element of the innate immune system. Nox2 is also detectable in endothelial cells and platelets where it has vasoconstrictive and aggregating properties, respectively. Patients with X-linked chronic granulomatous disease with hereditary Nox2 deficiency not only have impaired bacterial killing but, in association with loss of Nox2 function, also have enhanced carotid artery dilation, impaired platelet related thrombosis, and reduced carotid atherosclerotic burden. Experimental studies corroborated these reports in chronic granulomatous disease by demonstrating (1) Nox2 is upregulated in atherosclerotic plaque, and this upregulation significantly correlates with oxidative stress and (2) pharmacological inhibition of Nox2 is associated with a delayed atherosclerotic progression in animal models. Furthermore, the role of Nox2 in platelet associated thrombosis was substantiated by experiments showing impaired platelet activation in animals treated with a Nox2 inhibitor or impaired platelet aggregation along with reduced platelet-related thrombosis in the mouse knockout model of Nox2. Interestingly, in chronic granulomatous disease patients and in the mouse knockout model of Nox2, no defects of primary hemostasis were detected. This review analyses experimental and clinical data suggesting Nox2 is a potential target for counteracting the atherothrombotic process. PMID- 27932350 TI - Role of Noncanonical Wnt Signaling Pathway in Human Aortic Valve Calcification. AB - OBJECTIVE: The mechanisms underlying the pathogenesis of aortic valve calcification remain unclear. With accumulating evidence demonstrating that valve calcification recapitulates bone development, the crucial roles of noncanonical Wnt ligands WNT5a, WNT5b, and WNT11 in osteogenesis make them critical targets in the study of aortic valve calcification. APPROACH AND RESULTS: Using immunohistochemistry, real-time qPCR, Western blotting, and tissue culture, we examined the tissue distribution of WNT5a, WNT5b, and WNT11 in noncalcified and calcified aortic valves and their effects on human aortic valve interstitial cells (HAVICs). Only focal strong immunostaining for WNT5a was seen in and around areas of calcification. Abundant immunostaining for WNT5b and WNT11 was seen in inflammatory cells, fibrosis, and activated myofibroblasts in areas of calcified foci. There was significant correlation between WNT5b and WNT11 overall staining and presence of calcification, lipid score, fibrosis, and microvessels (P<0.05). Real-time qPCR and Western blotting revealed abundant expression of both Wnts in stenotic aortic valves, particularly in bicuspid valves. Incubation of HAVICs from noncalcified valves with the 3 noncanonical Wnts significantly increased cell apoptosis and calcification (P<0.05). Treatment of HAVICs with the mitogen activated protein kinase-38beta and GSK3beta inhibitors significantly reduced their mineralization (P<0.01). Raman spectroscopy identified the inorganic phosphate deposits as hydroxyapatite and showed a significant increase in hydroxyapatite deposition in HAVICs in response to WNT5a and WNT11 (P<0.05). Similar crystallinity was seen in the deposits found in HAVICs treated with Wnts and in calcified human aortic valves. CONCLUSIONS: These findings suggest a potential role for noncanonical Wnt signaling in the pathogenesis of aortic valve calcification. PMID- 27932351 TI - Telomerase Reverse Transcriptase Deficiency Prevents Neointima Formation Through Chromatin Silencing of E2F1 Target Genes. AB - OBJECTIVE: Aberrant proliferation of smooth muscle cells (SMC) in response to injury induces pathological vascular remodeling during atherosclerosis and neointima formation. Telomerase is rate limiting for tissue renewal and cell replication; however, the physiological role of telomerase in vascular diseases remains to be determined. The goal of the present study was to determine whether telomerase reverse transcriptase (TERT) affects proliferative vascular remodeling and to define the molecular mechanism by which TERT supports SMC proliferation. APPROACH AND RESULTS: We first demonstrate high levels of TERT expression in replicating SMC of atherosclerotic and neointimal lesions. Using a model of guidewire-induced arterial injury, we demonstrate decreased neointima formation in TERT-deficient mice. Studies in SMC isolated from TERT-deficient and TERT overexpressing mice with normal telomere length established that TERT is necessary and sufficient for cell proliferation. TERT deficiency did not induce a senescent phenotype but resulted in G1 arrest albeit hyperphosphorylation of the retinoblastoma protein. This proliferative arrest was associated with stable silencing of the E2F1-dependent S-phase gene expression program and not reversed by ectopic overexpression of E2F1. Finally, chromatin immunoprecipitation and accessibility assays revealed that TERT is recruited to E2F1 target sites and promotes chromatin accessibility for E2F1 by facilitating the acquisition of permissive histone modifications. CONCLUSIONS: These data indicate a previously unrecognized role for TERT in neointima formation through epigenetic regulation of proliferative gene expression in SMC. PMID- 27932352 TI - Local Vascular Gene Therapy With Apolipoprotein A-I to Promote Regression of Atherosclerosis. AB - OBJECTIVE: Gene therapy, delivered directly to the blood vessel wall, could potentially prevent atherosclerotic lesion growth and promote atherosclerosis regression. Previously, we reported that a helper-dependent adenoviral (HDAd) vector expressing apolipoprotein A-I (apoA-I) in carotid endothelium of fat-fed rabbits reduced early (4 weeks) atherosclerotic lesion growth. Here, we tested whether the same HDAd-delivered to the existing carotid atherosclerotic lesions could promote regression. APPROACH AND RESULTS: Rabbits (n=26) were fed a high fat diet for 7 months, then treated with bilateral carotid gene transfer. One carotid was infused with an HDAd expressing apoA-I (HDAdApoAI) and the other with a control nonexpressing HDAd (HDAdNull). The side with HDAdApoAI was randomized. Rabbits were then switched to regular chow, lowering their plasma cholesterols by over 70%. ApoA-I mRNA and protein were detected in HDAdApoAI-transduced arteries. After 7 weeks of gene therapy, compared with HDAdNull-treated arteries in the same rabbits, HDAdApoAI-treated arteries had significantly less vascular cell adhesion molecule-1 expression (28%; P=0.04) along with modest but statistically insignificant trends toward decreased intimal lesion volume, lipid and macrophage content, and intercellular adhesion molecule-1 expression (9%-21%; P=0.1-0.4). Post hoc subgroup analysis of rabbits with small-to-moderate-sized lesions (n=20) showed that HDAdApoAI caused large reductions in lesion volume, lipid content, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 expression (30%-50%; P<=0.04 for all). Macrophage content was reduced by 30% (P=0.06). There was a significant interaction (P=0.02) between lesion size and treatment efficacy. CONCLUSIONS: Even when administered on a background of aggressive lowering of plasma cholesterol, local HDAdApoAI vascular gene therapy may promote rapid regression of small-to-moderate-sized atherosclerotic lesions. PMID- 27932353 TI - Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting: The CuVIC Trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction After Coronary Stenting), a Multicenter Randomized Controlled Trial. AB - OBJECTIVES: We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting. APPROACH AND RESULTS: We conducted a multicenter, prospective, randomized, open-label, blinded end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6- to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83+/-23 mg/dL in S versus 67+/-23 mg/dL in E+S; P<0.0001), with significant decreases in oxidized low-density lipoprotein and oxysterol levels. Among patients without target vessel failure, 46 out of 89 patients (52%) in the S arm and 34 out of 96 patients (35%) in the E+S arm were found to have coronary endothelial dysfunction (P=0.0256), and the incidence of target vessel dysfunction at follow-up was significantly decreased in the E+S arm (69/112 (62%) in S versus 47/109 (43%) in E+S; P=0.0059). A post hoc analysis of post-treatment low-density lipoprotein cholesterol-matched subgroups revealed that the incidence of both target vessel dysfunction and coronary endothelial dysfunction significantly decreased in the E+S arm, with significant reductions in oxysterol levels. CONCLUSIONS: The CuVIC trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction after Coronary Stenting) has shown that ezetimibe with statins, compared with statin monotherapy, improves functional prognoses, ameliorating endothelial dysfunction in stented coronary arteries, and was associated with larger decreases in oxysterol levels. PMID- 27932355 TI - Familial Hypercholesterolemia Phenotype in Chinese Patients Undergoing Coronary Angiography. AB - OBJECTIVE: Familial hypercholesterolemia (FH) is characterized by an elevated low density lipoprotein cholesterol and increased risk of premature coronary artery disease. However, the general picture and mutational spectrum of FH in China are far from recognized, representing a missed opportunity for the investigation. APPROACH AND RESULTS: A total of 8050 patients undergoing coronary angiography were enrolled. The diagnosis of clinical FH was made using Dutch Lipid Clinic Network criteria, and the information of relatives was obtained by inquiring for the probands or from their own medical records of certain clinics/hospitals. Molecular analysis of FH was performed using target exome sequencing in LDLR (low density lipoprotein cholesterol receptor gene), APOB (apolipoprotein B gene), and PCSK9 (proprotein convertase subtilisin/kexin type 9 gene). As a result, 3.5% of the patients with definite/probable FH phenotype (definite 1.0% and probable 2.5%) were identified. Women FH had fewer premature coronary artery disease (women <60, or men <55 years of age) when compared with men FH (70.6% versus 82.7%; P<0.001), whereas angiographic extension of coronary artery disease was significantly increased with FH diagnosis in both men and women (P<0.001). Patterns of medication use in definite/probable FH were as follows: nontreated, 20.6%; low intensity, 6.0%; moderate intensity, 68.3%; and high intensity, 5.0%. However, none of them had achieved the low-density lipoprotein cholesterol <100 mg/dL. Additionally, mutational analysis was performed in 245 definite/probable FH cases, and risk variants were identified in 115 patients, giving a detection rate of 46.9%. CONCLUSIONS: We showed firsthand a common identification but poor treatment of patients with FH phenotype in Chinese coronary angiography patients. Genetic data in our FH cases might contribute to update the frequency and spectrum of Chinese FH scenarios. PMID- 27932356 TI - Is the higher mortality among men with hip fracture explained by sex-related differences in quality of in-hospital care? A population-based cohort study. AB - Background: mortality after hip fracture is two-fold higher in men compared with women. It is unknown whether sex-related differences in the quality of in hospital care contribute to the higher mortality among men. Objective: to examine sex-related differences in quality of in-hospital care, 30-day mortality, length of hospital stay and readmission among patients with hip fracture. Design: population-based cohort study. Measures: using prospectively collected data from the Danish Multidisciplinary Hip Fracture Registry, we identified 25,354 patients >=65 years (29% were men). Outcome measures included quality of in-hospital care as reflected by seven process performance measures, 30-day mortality, length of stay (LOS) and readmission within 30 days after discharge. Data were analysed using multivariable regression techniques. Results: in general, there were no substantial sex-related differences in quality of in-hospital care. The relative risk for receiving the individual process performance measure ranged from 0.91 (95% confidence interval (CI) 0.85-0.97) to 0.97 (95% CI 0.94-0.99) for men compared with women. The 30-day mortality was 15.9% for men and 9.3% for women corresponding to an adjusted odds ratio (OR) of 2.30 (95% CI 2.09-2.54). The overall readmission risk within 30 days after discharge was 21.6% for men and 16.4% for women (adjusted OR of 1.38 (95% CI 1.29-1.47)). No difference in LOS was observed between men and women. Conclusions: sex differences in the quality of in-hospital care appeared not to explain the higher mortality and risk of readmission among men hospitalised with hip fracture. PMID- 27932354 TI - Longitudinal Impact of Smoking and Smoking Cessation on Inflammatory Markers of Cardiovascular Disease Risk. AB - OBJECTIVE: To evaluate longitudinal changes in 6 inflammatory markers that predict cardiovascular disease events among smokers making a quit attempt and to characterize their cross-sectional associations between smoking and smoking heaviness. APPROACH AND RESULTS: In a longitudinal cohort study of contemporary smokers (n=1652), we evaluated (1) independent associations of smoking heaviness markers (exhaled carbon monoxide, cigarettes/d, pack-years) with inflammatory markers (C-reactive protein, D-dimer, fibrinogen, urinary F2 isoprostane:creatinine [F2:Cr] ratio, white blood cell [WBC] count, myeloperoxidase) and (2) the effects of smoking cessation and continued smoking on these inflammatory markers after 1 year, among the 888 smokers who made an aided quit attempt as part of a randomized comparative effectiveness trial or standard care. There were strong, independent associations between smoking heaviness markers and the F2:Cr ratio, WBC, and myeloperoxidase (all Padj<0.001), but not high-sensitivity C-reactive protein, D-dimer, or fibrinogen. Participants were mean (SD) 49.6 years old (11.6), 54% women, 34% non-white, and smoked 16.8 cigarettes/d (8.5) for 27.3 pack-years (18.6). After 1 year, the 344 successful abstainers gained more weight (4.0 [6.0] versus 0.4 [5.7] pounds; P<0.001) and had larger increases in insulin resistance scores (P=0.02) than continuing smokers. Despite these increases, abstainers had significant decreases in F2:Cr ratio (P<0.001) and WBC counts (P<0.001). Changes in other markers were not related to quitting. CONCLUSIONS: Smoking heaviness is associated with increased F2:Cr ratio, myeloperoxidase, and WBC counts. Cessation improves the F2:Cr ratio and WBC counts independent of weight change, suggesting reduced inflammation related to less oxidant stress. PMID- 27932357 TI - Using quality assessment tools to critically appraise ageing research: a guide for clinicians. AB - Evidence based medicine tells us that we should not accept published research at face value. Even research from established teams published in the highest impact journals can have methodological flaws, biases and limited generalisability. The critical appraisal of research studies can seem daunting, but tools are available to make the process easier for the non-specialist. Understanding the language and process of quality assessment is essential when considering or conducting research, and is also valuable for all clinicians who use published research to inform their clinical practice.We present a review written specifically for the practising geriatrician. This considers how quality is defined in relation to the methodological conduct and reporting of research. Having established why quality assessment is important, we present and critique tools which are available to standardise quality assessment. We consider five study designs: RCTs, non randomised studies, observational studies, systematic reviews and diagnostic test accuracy studies. Quality assessment for each of these study designs is illustrated with an example of published cognitive research. The practical applications of the tools are highlighted, with guidance on their strengths and limitations. We signpost educational resources and offer specific advice for use of these tools.We hope that all geriatricians become comfortable with critical appraisal of published research and that use of the tools described in this review - along with awareness of their strengths and limitations - become a part of teaching, journal clubs and practice. PMID- 27932358 TI - Association between lower limb osteoarthritis and incidence of depressive symptoms: data from the osteoarthritis initiative. AB - Background: osteoarthritis (OA) is associated with a number of medical morbidities. Although the prevalence of depression and depressive symptoms is presumed to be high in people with OA, no prospective comparative study has analyzed its incidence. Objective: to determine whether OA was associated with an increased odds of developing depressive symptoms. Design: longitudinal cohort study (follow-up: 4.2 years). Setting: data were gathered from the North American Osteoarthritis Initiative (OAI) dataset. Subjects: people at higher risk developing OA. Methods: OA diagnosis was defined as the presence of OA at hand, knee, hip, back/neck or other sites at baseline. Depressive symptoms were defined using the 20-item Center for Epidemiologic Studies-Depression (cut-off 16 points) after 4 years. Results: a total of 3,491 people without depressive symptoms at baseline were analyzed (1,506 with OA/1,985 without). Using an adjusted logistic regression analysis for 12 potential confounders, people with OA had a similar odds of depressive symptoms at follow-up compared to those without OA (odds ratio (OR): 1.26; 95% confidence of interval (CI): 0.95-1.67). However, multi-site OA (i.e. OA >=2 sites; OR: 1.48, 95% CI: 1.07-2.05) and the specific presence of hip (OR: 1.72; 95% CI: 1.08-2.73) or knee OA (OR: 1.43; 95% CI: 1.03-1.98) were associated with a greater odds of developing depressive symptoms compared to people without OA. Conclusions: this is the first study of longitudinal data to demonstrate people with multi-site, hip or knee OA have a greater odds of developing depressive symptoms compared to people without OA. This suggests that OA may be associated with future mental health burden. PMID- 27932359 TI - Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) case presentation and comparison with other polyarthritides affecting older people. AB - Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome mainly affects elderly men and responds well to steroids. Since this syndrome can resemble other diseases, its diagnosis is a significant challenge. Through the following paper, we hope to improve the diagnosis of RS3PE by presenting a table comparing RS3PE to two other common polyarthritic conditions affecting the elderly. PMID- 27932361 TI - Multi-compartment compliance aids-a clinical reminder. PMID- 27932360 TI - The effects of a high-intensity functional exercise group on clinical outcomes in hospitalised older adults: an assessor-blinded, randomised-controlled trial. AB - Objective: to investigate a high-intensity functional exercise (HIFE) group in hospitalised older adults. Design: assessor-blinded, randomised-controlled trial. Setting: sub-acute wards at a metropolitan rehabilitation hospital. Participants: older adults >=65 years (n = 468) able to stand with minimum assistance or less from a chair and follow instructions. Intervention: 'group' participants were offered a standing HIFE group three times a week and individual physiotherapy sessions twice a week. Control participants were offered daily individual physiotherapy sessions. Main outcome measures: the primary outcome measure was the Elderly Mobility Scale (EMS). Secondary measures included the Berg Balance Scale, gait speed, Timed Up and Go Test, falls, length of stay and discharge destination. Results: participants' mean age was 84.3 (7.1) years and 61% were female. There was no difference between groups for the improvement in EMS from admission to discharge (effect size -0.07, 95% confidence interval: -0.26 to 0.11, P = 0.446) and no difference in discharge destination, P = 0.904. Therapists saved 31-205 min/week treating group participants compared with control participants. Conclusion: the results suggest that a HIFE group programme combined with individual physiotherapy may improve mobility to a similar extent to individual physiotherapy alone in hospitalised older adults. Providing physiotherapy in a group setting resulted in increased therapist efficiency. A high-intensity exercise group with individual physiotherapy may be an effective and efficient method to provide care to older inpatients. PMID- 27932362 TI - Predicting functional decline in older emergency patients-the Safe Elderly Emergency Discharge (SEED) project. AB - Objective: to profile the trajectory of, and risk factors for, functional decline in older patients in the 30 days following Emergency Department (ED) discharge. Methods: prospective cohort study of community-dwelling patients aged >=65 years, discharged home from a metropolitan Melbourne ED, 31 July 2012 to 30 November 2013. The primary outcome was functional decline, comprising either increased dependency in personal activities of daily living (ADL) or in skills required for living independently instrumental ADL (IADL), deterioration in cognitive function, nursing home admission or death. Univariate analyses were used to select risk factors and logistic regression models constructed to predict functional decline. Results: at 30 days, 34.4% experienced functional decline; with 16.7% becoming more dependent in personal ADL, 17.5% more dependant in IADL and 18.4% suffering deterioration in cognitive function. Factors independently associated with decline were functional impairment prior to the visit in personal ADL (Odds Ratio [OR] 3.21, 95% confidence interval [CI] 2.26-4.53) or in IADL (OR 6.69, 95% CI 4.31-10.38). The relative odds were less for patients with moderately impaired cognition relative to those with normal cognition (OR 0.38, 95% CI 0.19-0.75). There was a 68% decline in the relative odds of functional decline for those with any impairment in IADL who used an aid for mobility (OR 0.32, 95% CI 0.14-0.7). Conclusion: older people with pre-existing ADL impairment were at high risk of functional decline in the 30 days following ED presentation. This effect was largely mitigated for those who used a mobility aid. Early intervention with functional assessments and appropriate implementation of support services and mobility aids could reduce functional decline after discharge. PMID- 27932363 TI - Monocyte count as a predictor of cardiovascular mortality in older Korean people. AB - Background: white blood cells (WBCs) have been known to mediate the inflammatory process, which may be a pivotal mechanism for atherosclerosis and cardiovascular mortality. Objective: we investigated which WBC subtypes increased cardiovascular mortality and explored its connection to coronary artery diseases in a prospective study among older Koreans. Study design and subjects: this study was conducted from 2005 to 2011 as a part of the Korean Longitudinal Study on Health and Aging and included 439 men and 561 women over 65-year old. Outcomes: the primary endpoints were all-cause and cardiovascular mortality. Results: in the cox proportional hazard models, subjects in the higher tertiles of monocyte count were at a higher risk for cardiovascular mortality even in the fully adjusted model (2nd tertile hazard ratio = 2.51; 3rd tertile = 2.81). However, the total WBC, neutrophil and lymphocyte counts did not affect cardiovascular mortality. Logistic regression models revealed that subjects in the 3rd tertile of monocyte count had an increased risk for any coronary artery plaque, vulnerable plaque and calcified plaque (odds ratio = 1.80, 2.68, 1.59, respectively) but not for significant stenosis. Other WBC subtypes were not related to coronary artery diseases. Conclusion: the results showed that a high monocyte count is a risk factor for cardiovascular mortality as well as coronary artery plaque formation. PMID- 27932364 TI - Mortality in the Hertfordshire Ageing Study: association with level and loss of hand grip strength in later life. AB - Background: weak hand grip strength in later life is a risk factor for disability, morbidity and mortality and is central to definitions of sarcopenia and frailty. It is unclear whether rate of change in grip strength adds to level of grip strength as a risk factor for poor ageing outcomes. Methods: study participants were 292 community-dwelling men and women whose grip strength was measured during the 1994/5 (average age 67) and 2003/5 (average age 76) phases of the Hertfordshire Ageing Study, UK. Individual rate of change in grip strength was estimated using a residual change method. Mortality was followed-up to 2011 (42 men and 21 women died). Results: average grip strengths in 2003/5 were 38.4 kg (standard deviation [SD] = 8.1) and 23.7 kg (SD = 6.6) for men and women respectively. Average annualised rates of change in grip strength (2003/5 minus 1994/5) were modest owing to a healthy-participant effect (men: -0.12 kg/y, SD = 0.71; women: 0.08 kg/y, SD = 0.54) but varied widely. Mortality risk varied according to level and rate of change in grip strength (P = 0.03); death rates per 100 person years of follow-up were 6.7 (95% CI: 4.6, 9.6) among participants who lost grip over time and had low grip in 2003/5, in contrast with 0.8 (95% CI: 0.1, 5.8) among participants whose grip changed little over time and remained high in 2003/5. Conclusions: levels of grip strength in later life should be considered in conjunction with estimates of change in grip strength identified by repeat measurement over time. Normative data for longitudinal change in grip strength are required. PMID- 27932365 TI - Danish register-based study on the association between specific antipsychotic drugs and fractures in elderly individuals. AB - Background: antipsychotic drugs (APs) have been associated with falls and fractures in elderly individuals but limited knowledge on specific drugs exist. Objective: to investigate the association between individual APs and fractures in elderly persons. Design and setting: nationwide register-based cohort study. Subjects: all Danish individuals aged >=65 who had not been in treatment with any AP in the year before inclusion. Methods: incidence rate ratios (IRRs) of fractures of hip, pelvis or upper extremities during treatment with commonly used APs were assessed in multivariable Poisson models. Exposure was divided into time periods from initiation of treatment: 0-30 days, 31-365 days or >365 days. Results: one year prior to inclusion, 1,540,915 individuals >=65 years had not received APs and of these 93,298 initiated treatment with APs. Mean follow-up was 9.6 years. During follow-up, 246,057 (16%) experienced a fracture. Associations were for all APs highest in the initial treatment period (0-30 days) with IRRs for risperidone 1.97 (95% CI: 1.70-2.28), olanzapine 2.31 (95% CI: 1.96-2.73), quetiapine 2.09 (95% CI: 1.73-2.52), zuclopenthixol 2.19 (95% CI: 1.82-2.63), chlorprothixen 1.62 (95% CI: 1.18-2.24), flupenthixol 1.43 (95% CI: 1.06-1.93), levomepromazine 1.19 (95% CI 0.86-1.66), haloperidol 2.98 (95% CI 2.57-3.45), compared with the background population. Conclusions: use of APs is associated with fractures in elderly persons especially in the initial treatment period. If AP use in an elderly person is deemed necessary, individual falls prophylaxis should be considered. PMID- 27932366 TI - Sauna bathing is inversely associated with dementia and Alzheimer's disease in middle-aged Finnish men. AB - Background: there are no previous studies linking repeated heat exposure of sauna and the risk of memory diseases. We aimed to investigate whether frequency of sauna bathing is associated with risk of dementia and Alzheimer's disease. Setting: prospective population-based study. Methods: the frequency of sauna bathing was assessed at baseline in the Kuopio Ischaemic Heart Disease population based prospective cohort study of 2,315 apparently healthy men aged 42-60 years at baseline, with baseline examinations conducted between 1984 and 1989. Hazard ratios (HRs) with 95% confidence intervals (CIs) for dementia and Alzheimer's disease were ascertained using Cox-regression modelling with adjustment for potential confounders. Results: during a median follow-up of 20.7 (interquartile range 18.1-22.6) years, a total of 204 and 123 diagnosed cases of dementia and Alzheimer's disease were respectively recorded. In analysis adjusted for age, alcohol consumption, body mass index, systolic blood pressure, smoking status, Type 2 diabetes, previous myocardial infarction, resting heart rate and serum low density lipoprotein cholesterol, compared with men with only 1 sauna bathing session per week, the HR for dementia was 0.78 (95% CI: 0.57-1.06) for 2-3 sauna bathing sessions per week and 0.34 (95% CI: 0.16-0.71) for 4-7 sauna bathing sessions per week. The corresponding HRs for Alzheimer's disease were 0.80 (95% CI: 0.53-1.20) and 0.35 (95% CI: 0.14-0.90). Conclusion: in this male population, moderate to high frequency of sauna bathing was associated with lowered risks of dementia and Alzheimer's disease. Further studies are warranted to establish the potential mechanisms linking sauna bathing and memory diseases. PMID- 27932367 TI - Changing the way "we" view and talk about frailty.... AB - This commentary discusses the perception of frailty by different key stakeholders most notably older people. It considers the need to integrate predominantly medically driven understandings of frailty within a wider conceptual framework. This is imperative if the potential of frailty as a construct, around which the optimisation of health and well-being of older people can take place, is to be realised. PMID- 27932368 TI - Longitudinal associations between body composition, sarcopenic obesity and outcomes of frailty, disability, institutionalisation and mortality in community dwelling older men: The Concord Health and Ageing in Men Project. AB - Background: to explore the longitudinal associations between body composition measures, sarcopenic obesity and outcomes of frailty, activities of daily living (ADL) and instrumental ADL (IADL) disability, institutionalisation and mortality. Methods: men aged >= 70 years (2005-07) from the Concord Health and Ageing in Men Project were assessed at baseline (n = 1,705), 2 (n = 1,366) and 5 years (n = 954). The main outcome measures were frailty (adapted Fried criteria), ADL, including personal care and mobility and IADL disability (ability to perform tasks for independent living), institutionalisation and mortality. The Foundation for the National Institutes of Health cut-points were used for low muscle mass: appendicular lean mass (ALM):Body Mass Index (BMI) ratio (ALMBMI) <0.789 and obesity was defined as >30% fat. Generalised estimating equations were used to examine the longitudinal associations between the independent variables (obesity alone, low muscle mass and sarcopenic obesity) and frailty, ADL and IADL disability. Results: in unadjusted, age adjusted and fully adjusted analysis, men with low muscle mass showed increased risk of frailty and IADL disability. In fully adjusted analysis, men with sarcopenic obesity had an increased risk of frailty (odds ratio (OR): 2.00 (95% confidence of interval (CI): 1.42, 2.82)) ADL disability (OR: 1.58 (95% CI: 1.12, 2.24)) and IADL disability (OR: 1.36 (95% CI: 1.05, 1.76)). Obesity alone was protective for institutionalisation (OR: 0.51 (95% CI: 0.31, 0.84)) but was not associated with any other outcomes. Conclusions: low muscle mass and sarcopenic obesity were associated with poor functional outcomes, independent of confounders. This would suggest that future trials on frailty and disability prevention should be designed to intervene on both muscle mass and fat mass. PMID- 27932369 TI - Patient safety in community dementia services: what can we learn from the experiences of caregivers and healthcare professionals? AB - Objectives: this study aims to explore how patient safety in community dementia services is understood by caregivers, and healthcare professionals. Methods: cross-sectional analysis of guided one-to-one interviews with 10 caregivers, and 10 healthcare professionals. Results: caregivers and healthcare professionals identified a range of issues including medication errors, mis-communication between professionals, unclear service pathways and the effects of stress on caregivers' behaviour. Caregivers and professionals differed in their attitudes to balancing safety with patient autonomy and who is responsible for managing safety. Conclusions: this article helps to define the nature of safety issues in the context of community care for people with dementia. In contrast to hospital medicine, where the ideal treatment world is safe with all risks managed or minimised, in dementia some risks are actively taken in the interests of promoting autonomy. Caregivers' views differ from those of health professionals but both parties see potential for collaborative working to manage risk in this context, balancing the promotion of autonomy with the minimisation of potential harm. PMID- 27932370 TI - Doege-Potter syndrome: hypoglycaemic coma in a 90-year old due to a solitary fibrous tumour. AB - Solitary fibrous tumour of the pleura (SFTP) is a rare primary tumour of the pleura associated with 4% of cases with a paraneoplastic hypoglycaemia, termed Doege-Potter syndrome (DPS). We report a case of DPS presenting with severe coma in a 90-year-old woman. The cause was a malignant SFTP treated with surgical resection, from which the patient made a full recovery with prevention of recurrent hypoglycaemia. Surgical resection of the SFTP presenting with symptomatic hypoglycaemia should be considered even in elderly patients. PMID- 27932371 TI - Shingles vaccine coverage for 70 year olds is falling. PMID- 27932372 TI - Denton Cooley. PMID- 27932375 TI - MP and former GP challenges Uruguay's compulsory breast screening programme. PMID- 27932374 TI - Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. AB - STOP second generation (2G)-tyrosine kinase inhibitor (TKI) is a multicenter observational study designed to evaluate 2G-TKI discontinuation in chronic myeloid leukemia (CML). Patients receiving first-line or subsequent dasatinib or nilotinib who stopped therapy after at least 3 years of TKI treatment and in molecular response 4.5 (MR4.5) with undetectable BCR-ABL1 transcripts for the 2 preceding years at least were eligible for inclusion. This interim analysis reports outcomes of 60 patients with a minimum follow-up of 12 months (median 47, range: 12-65). Twenty-six patients (43.3%) experienced a molecular relapse defined as the loss of a major molecular response (MMR). Relapses occurred after a median time of 4 months (range: 1-38). Cumulative incidences of molecular relapse by 12 and 48 months were 35% (95% confidence interval [CI], 24.79% to 49.41%) and 44.76% (95% CI, 33.35% to 59.91%), respectively. Treatment-free remission (TFR) rates at 12 and 48 months were 63.33% (95% CI, 51.14% to 75.53%) and 53.57% (95% CI, 40.49% to 66.65%), respectively. In univariate analysis, prior suboptimal response or TKI resistance was the only baseline factor associated with significantly worse outcome. A landmark analysis demonstrated that loss of MR4.5 3 months after stopping TKI was predictive of failure to maintain MMR later on. During the treatment-free phase, no progression toward advanced phase CML occurred, and all relapsing patients regained MMR and MR4.5 after restarting therapy. In conclusion, discontinuation of first-line or subsequent 2G-TKI yields promising TFR rates without safety concerns. Further research is encouraged to better define conditions that will offer patients the highest chance to remain free from 2G-TKI therapy. PMID- 27932376 TI - What triggers puberty? PMID- 27932373 TI - Sickle cell trait is not associated with an increased risk of heart failure or abnormalities of cardiac structure and function. PMID- 27932377 TI - Pfizer is fined L84m for "exploiting opportunity" to hike price of phenytoin. PMID- 27932381 TI - Improving the Efficiency of Care for Pediatric Patients Hospitalized With Asthma. AB - BACKGROUND: Asthma exacerbations are a leading cause of hospitalization among children. Despite the existence of national pediatric asthma guidelines, significant variation in care persists. At Duke Children's Hospital, we determined that our average length of stay (ALOS) and cost for pediatric asthma admissions exceeded that of our peers. Our aim was to reduce the ALOS of pediatric patients hospitalized with asthma from 2.9 days to 2.6 days within 12 months by implementing an asthma pathway within our new electronic health record. METHODS: We convened a multidisciplinary committee charged with reducing variability in practice, ALOS, and cost of inpatient pediatric asthma care, while adhering to evidence-based guidelines. Interventions were tested through multiple "plan-do-study-act" cycles. Control charts of the ALOS were constructed and annotated with interventions, including testing of an asthma score, implementation of order sets, use of a respiratory therapy-driven albuterol treatment protocol, and provision of targeted education. Order set usage was audited as a process measure. Readmission rates were monitored as a balancing measure. RESULTS: The ALOS of pediatric patients hospitalized with asthma decreased significantly from 2.9 days to 2.3 days. Comparing baseline with intervention variable direct cost data revealed a savings of $1543 per case. Improvements occurred in the context of high compliance with the asthma pathway order sets. Readmission rates remained stable throughout the study period. CONCLUSIONS: Implementation of an asthma care pathway based on the electronic health record improved the efficiency and variable direct costs of hospital care, reduced variability in practice, and ensured adherence to high-quality national guidelines. PMID- 27932380 TI - Absence of vitamin D receptor (VDR)-mediated PPARgamma suppression causes alopecia in VDR-null mice. AB - Vitamin D receptor (VDR) mutations in humans and mice cause alopecia. VDR-null (VDR-/-) mice exhibit lack of postmorphogenic hair cycles as a result of impaired keratinocyte stem cell (KSC) function. To identify the molecular basis for abnormal KSC function, RNA sequencing of wild-type (WT) and VDR-/- KSCs was performed. These studies demonstrated that >80% of differentially expressed genes are up-regulated in VDR-/- KSCs; thus, the VDR is a transcriptional suppressor in WT KSCs. Peroxisome proliferator-activated receptor gamma (PPARgamma), PPARgamma coactivator 1beta (PGC1beta), and lipoprotein lipase (LPL) were among the up regulated genes identified. Chromatin immunoprecipitation analyses demonstrated that these genes are direct VDR targets in WT keratinocytes. Notably, VDR occupancy of the PPARgamma regulatory region precludes PPARgamma occupancy of this site, based on the observation that PPARgamma interacts with these sequences in VDR-/- but not WT keratinocytes. This contrasts with the VDR and PPARgamma co occupancy observed on PGC1beta and LPL gene regulatory regions identified. Studies in mice with keratinocyte-specific PPARgamma haploinsufficiency were performed to identify the functional consequences of enhanced PPARgamma expression. PPARgamma haploinsufficiency normalized PPARgamma mRNA levels in VDR /- keratinocytes and restored anagen responsiveness in vivo in VDR-/- mice, resulting in hair regrowth. Thus, absence of VDR-mediated PPARgamma suppression underlies alopecia in VDR-/- mice.-Saini, V., Zhao, H., Petit, E. T., Gori, F., Demay, M. B. Absence of vitamin D receptor (VDR)-mediated PPARgamma suppression causes alopecia in VDR-null mice. PMID- 27932382 TI - Structures and developmental alterations of N-glycans of zebrafish embryos. AB - Zebrafish is a model organism suitable for studying vertebrate development. We analyzed the N-glycan structures of zebrafish embryos and their alterations during zebrafish embryogenesis to obtain basic data for studying the roles of N glycosylation. Multiple modes of high-performance liquid chromatography and multistage mass spectrometry were used for structural analysis of N-glycans. The N-glycans from deyolked embryos at 36 hours postfertilization, a mid-pharyngula stage, contained relatively higher amounts of complex- and hybrid-type glycans with LacNAc (Galbeta1-4GlcNAc) and/or sialyl LacNAc without additional beta1,4 Gal, which are commonly found in mammalian tissues, as well as abundant oligomannose-type glycans. Some of the complex- and hybrid-type glycans possessed various extended LacNAc structures, such as Galbeta1-4LacNAc, LacNAc-repeat or unique (+/- dHex)-GalNAcalpha1-GlcNAcbeta1-LacNAc. In contrast, the yolk of the embryo contains predominant oligomannose-type glycans and complex-type glycans with Galbeta1-4(Siaalpha2-3)Galbeta1-4(Fucalpha1-3)GlcNAc antennae. N-Glycan profiles obtained from deyolked embryos at different stages showed stage dependent variation of complex- and hybrid-type glycans. At gastrula and early segmentation stages, complex- and hybrid-type glycans were minor components, and their antenna structures were mainly sialyl LacdiNAc (Siaalpha2-6GalNAcbeta1 4GlcNAc). From the mid-segmentation to pharyngula stages, those with LacNAc and/or alpha2,6-sialyl LacNAc antenna structures increased remarkably, and those with alpha2,3-sialyl LacNAc antenna, core alpha1,6-Fuc and bisecting GlcNAc modifications increased gradually. These results suggest the presence of mechanisms for regulating the antenna structures of complex/hybrid N-glycan biosynthesis in the phylotypic stage of vertebrate development. PMID- 27932383 TI - Comparison of the glycosphingolipids of human-induced pluripotent stem cells and human embryonic stem cells. AB - High expectations are held for human-induced pluripotent stem cells (hiPSC) since they are established from autologous tissues thus overcoming the risk of allogeneic immune rejection when used in regenerative medicine. However, little is known regarding the cell-surface carbohydrate antigen profile of hiPSC compared with human embryonic stem cells (hESC). Here, glycosphingolipids were isolated from an adipocyte-derived hiPSC line, and hiPSC and hESC glycosphingolipids were compared by concurrent characterization by binding assays with carbohydrate-recognizing ligands and mass spectrometry. A high similarity between the nonacid glycosphingolipids of hiPSC and hESC was found. The nonacid glycosphingolipids P1 pentaosylceramide, x2 pentaosylceramide and H type 1 heptaosylceramide, not previously described in human pluripotent stem cells (hPSC), were characterized in both hiPSC and hESC. The composition of acid glycosphingolipids differed, with increased levels of GM3 ganglioside, and reduced levels of GD1a/GD1b in hiPSC when compared with hESC. In addition, the hESC glycosphingolipids sulf-globopentaosylceramide and sialyl globotetraosylceramide were lacking in hiPSC. Neural stem cells differentiating from hiPSC had a reduced expression of sialyl-lactotetra, whereas expression of the GD1a ganglioside was significantly increased. Thus, while sialyl-lactotetra is a marker of undifferentiated hPSC, GD1a is a novel marker of neural differentiation. PMID- 27932384 TI - Wise words. PMID- 27932385 TI - France shows what has gone wrong in the UK and US. PMID- 27932386 TI - Aberrant Expression of FBXO2 Disrupts Glucose Homeostasis Through Ubiquitin Mediated Degradation of Insulin Receptor in Obese Mice. AB - Insulin resistance is a critical factor in the development of metabolic disorders, including type 2 diabetes (T2DM). However, its molecular mechanisms remain incompletely understood. In this study, we found that F-box only protein 2 (FBXO2), a substrate recognition component of the Skp1-Cul1-F-box protein (SCF) E3 ubiquitin ligase complex, was upregulated in livers of obese mice. Furthermore, using a protein purification approach combined with high-performance liquid chromatography/tandem mass spectrometry, we carried out a system-wide screening of FBXO2 substrates, in which the insulin receptor (IR) was identified as a substrate for FBXO2. SCFFBXO2 acts as an E3 ligase targeting the IR for ubiquitin-dependent degradation to regulate insulin signaling integrity. As a result, adenovirus-mediated overexpression of FBXO2 in healthy mice led to hyperglycemia, glucose intolerance, and insulin resistance, whereas ablation of FBXO2 alleviated diabetic phenotypes in obese mice. Therefore, our results identify SCFFBXO2 as an E3 ligase for the IR in the liver, which might provide a novel therapeutic target for treating T2DM and related metabolic disorders. PMID- 27932387 TI - The Long Noncoding RNA Transcriptome of Dictyostelium discoideum Development. AB - Dictyostelium discoideum live in the soil as single cells, engulfing bacteria and growing vegetatively. Upon starvation, tens of thousands of amoebae enter a developmental program that includes aggregation, multicellular differentiation, and sporulation. Major shifts across the protein-coding transcriptome accompany these developmental changes. However, no study has presented a global survey of long noncoding RNAs (ncRNAs) in D. discoideum To characterize the antisense and long intergenic noncoding RNA (lncRNA) transcriptome, we analyzed previously published developmental time course samples using an RNA-sequencing (RNA-seq) library preparation method that selectively depletes ribosomal RNAs (rRNAs). We detected the accumulation of transcripts for 9833 protein-coding messenger RNAs (mRNAs), 621 lncRNAs, and 162 putative antisense RNAs (asRNAs). The noncoding RNAs were interspersed throughout the genome, and were distinct in expression level, length, and nucleotide composition. The noncoding transcriptome displayed a temporal profile similar to the coding transcriptome, with stages of gradual change interspersed with larger leaps. The transcription profiles of some noncoding RNAs were strongly correlated with known differentially expressed coding RNAs, hinting at a functional role for these molecules during development. Examining the mitochondrial transcriptome, we modeled two novel antisense transcripts. We applied yet another ribosomal depletion method to a subset of the samples to better retain transfer RNA (tRNA) transcripts. We observed polymorphisms in tRNA anticodons that suggested a post-transcriptional means by which D. discoideum compensates for codons missing in the genomic complement of tRNAs. We concluded that the prevalence and characteristics of long ncRNAs indicate that these molecules are relevant to the progression of molecular and cellular phenotypes during development. PMID- 27932388 TI - From Embryo to Adult: piRNA-Mediated Silencing throughout Germline Development in Drosophila. AB - In metazoan germ cells, transposable element activity is repressed by small noncoding PIWI-associated RNAs (piRNAs). Numerous studies in Drosophila have elucidated the mechanism of this repression in the adult germline. However, when and how transposable element repression is established during germline development has not been addressed. Here, we show that homology-dependent trans silencing is active in female primordial germ cells from late embryogenesis through pupal stages, and that genes related to the adult piRNA pathway are required for silencing during development. In larval gonads, we detect rhino dependent piRNAs indicating de novo biogenesis of functional piRNAs during development. Those piRNAs exhibit the molecular signature of the "ping-pong" amplification step. Moreover, we show that Heterochromatin Protein 1a is required for the production of piRNAs coming from telomeric transposable elements. Furthermore, as in adult ovaries, incomplete, bimodal, and stochastic repression resembling variegation can occur at all developmental stages. Clonal analysis indicates that the repression status established in embryonic germ cells is maintained until the adult stage, suggesting the implication of a cellular memory mechanism. Taken together, data presented here show that piRNAs and their associated proteins are epigenetic components of a continuous repression system throughout germ cell development. PMID- 27932389 TI - Fifteen-minute consultation: investigation and management of an infant with stridor. AB - Stridor is an abnormal sound caused by turbulent airflow through the airway. In an infant under 3 months of age presenting with stridor, there are many different underlying aetiologies. Some key assessment points help to differentiate those patients who can be reassured and monitored versus those requiring referral to an ear, nose and throat (ENT) surgeon for further assessment or management. We present a structured approach to guide the clinician through initial assessment, examination and management, including referral to ENT surgery. PMID- 27932390 TI - Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. AB - BACKGROUND: Individuals infected with Mycobacterium tuberculosis (Mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection [LTBI]). Tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain. METHODS: A task force supported by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence. The evidence was then used as the basis for recommendations about the diagnosis of tuberculosis disease and LTBI in adults and children. The recommendations were formulated, written, and graded using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided. Six of the recommendations are strong, whereas the remaining 17 are conditional. CONCLUSIONS: These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances. PMID- 27932392 TI - Digital gene expression profiling analysis of DNA repair pathways in colon cancer stem population of HT29 cells. AB - Cancer stem cells (CSCs) contribute to the relapse and development of new neoplasm lesions. While most available clinical approaches, such as chemical and radiation therapies, will kill the majority of cancer cells, they do not kill them all. Some resisting cells, like CSCs, are able to survive due to their excellent self-maintaining capabilities, even in challenging environments. In the present study, we investigated the mRNA level of DNA repair genes of colon CSCs from the HT29 cell line in response to single-strand damage and double-strand breaks, as well as the evident upregulation of key genes in base excision repair, mismatch repair, non-homologous end-joining, and homologous recombination pathways in these cells. Digital gene expression analysis identified upregulated genes in CD44+ HT29 cells that may play important roles in DNA repair. Our results reveal that colon CSCs bear efficient DNA repair abilities, which might explain the survival of colon CSCs after repeated chemical and radiation therapy. PMID- 27932391 TI - Healthy Dietary Patterns and Risk of Mortality and ESRD in CKD: A Meta-Analysis of Cohort Studies. AB - BACKGROUND AND OBJECTIVES: Patients with CKD are advised to follow dietary recommendations that restrict individual nutrients. Emerging evidence indicates overall eating patterns may better predict clinical outcomes, however, current data on dietary patterns in kidney disease are limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This systematic review aimed to evaluate the association between dietary patterns and mortality or ESRD among adults with CKD. Medline, Embase, and reference lists were systematically searched up to November 24, 2015 by two independent review authors. Eligible studies were longitudinal cohort studies reporting the association of dietary patterns with mortality, cardiovascular events, or ESRD. RESULTS: A total of seven studies involving 15,285 participants were included. Healthy dietary patterns were generally higher in fruit and vegetables, fish, legumes, cereals, whole grains, and fiber, and lower in red meat, salt, and refined sugars. In six studies, healthy dietary patterns were consistently associated with lower mortality (3983 events; adjusted relative risk, 0.73; 95% confidence interval, 0.63 to 0.83; risk difference of 46 fewer (29-63 fewer) events per 1000 people over 5 years). There was no statistically significant association between healthy dietary patterns and risk of ESRD (1027 events; adjusted relative risk, 1.04; 95% confidence interval, 0.68 to 1.40). CONCLUSIONS: Healthy dietary patterns are associated with lower mortality in people with kidney disease. Interventions to support adherence to increased fruit and vegetable, fish, legume, whole grain, and fiber intake, and reduced red meat, sodium, and refined sugar intake could be effective tools to lower mortality in people with kidney disease. PMID- 27932393 TI - Biological characteristics of embryonic epicardial cells in vitro correlate with embryonic day. AB - The epicardial cell (EpiC) culture system plays an important role in investigating the specific mechanisms and signaling molecules that are involved in the development of EpiCs. From this early formation until adulthood, EpiCs undergo dynamic changes in the expression of embryonic genes that correlate with changes in the embryonic EpiC properties. The differences of embryonic EpiC properties may affect the related results of experiments in which EpiC culture system is used; however, these differences have not been explored. Therefore, in this study we examined the differences in the biological characteristics of EpiCs on different embryonic days in vitro EpiCs were isolated from embryonic ventricle explants on embryonic day (E) 11.5, E13.5, and E15.5. The differences in the migration, proliferation and differentiation were studied in EpiCs of different embryonic day by scratch assay, cell cycle analysis and platelet derived growth factor-bb (PDGF-BB) treatment. The results showed that EpiCs were successfully cultured from E11.5, E13.5, and E15.5 embryonic ventricle explants. The time windows of E11.5, E13.5, and E15.5 EpiC isolation out of the explants were different. The migration abilities of E11.5, E13.5, and E15.5 EpiCs decreased during embryonic development. Smooth muscle cell differentiation potential of early stage EpiCs was better than that of the later stage EpiCs. Although the proliferation ability of E11.5 EpiCs was significantly weaker than those of E13.5 and E15.5 EpiCs, the proliferation abilities of E13.5 and E15.5 EpiCs did not differ. These results suggest that the biological characteristics of EpiCs correlate with the timing of embryonic development, and different embryonic stage of ventricle should be properly chosen for culturing EpiCs depending on the purposes of the specific experiments. PMID- 27932395 TI - Ubiquitination and the Regulation of Membrane Proteins. AB - Newly synthesized transmembrane proteins undergo a series of steps to ensure that only the required amount of correctly folded protein is localized to the membrane. The regulation of protein quality and its abundance at the membrane are often controlled by ubiquitination, a multistep enzymatic process that results in the attachment of ubiquitin, or chains of ubiquitin to the target protein. Protein ubiquitination acts as a signal for sorting, trafficking, and the removal of membrane proteins via endocytosis, a process through which multiple ubiquitin ligases are known to specifically regulate the functions of a number of ion channels, transporters, and signaling receptors. Endocytic removal of these proteins through ubiquitin-dependent endocytosis provides a way to rapidly downregulate the physiological outcomes, and defects in such controls are directly linked to human pathologies. Recent evidence suggests that ubiquitination is also involved in the shedding of membranes and associated proteins as extracellular vesicles, thereby not only controlling the cell surface levels of some membrane proteins, but also their potential transport to neighboring cells. In this review, we summarize the mechanisms and functions of ubiquitination of membrane proteins and provide specific examples of ubiquitin dependent regulation of membrane proteins. PMID- 27932396 TI - Narrative Aversion: Challenges for the Illness Narrative Advocate. AB - Engaging in self-narrative is often touted as a powerful antidote to the bad effects of illness. However, there are various examples of what may broadly be termed "aversion" to illness narrative. I group these into three kinds: aversion to certain types of illness narrative; aversion to illness narrative as a whole; and aversion to illness narrative as an essentially therapeutic endeavor. These aversions can throw into doubt the advantages claimed for the illness narrator, including the key benefits of repair to the damage illness does to identity and life-trajectory. Underlying these alleged benefits are two key presuppositions: that it is the whole of one's life that is narratively unified, and that one's identity is inextricably bound up with narrative. By letting go of these assumptions, illness narrative advocates can respond to the challenges of narrative aversions. PMID- 27932397 TI - Sound Trust and the Ethics of Telecare. AB - The adoption of web-based telecare services has raised multifarious ethical concerns, but a traditional principle-based approach provides limited insight into how these concerns might be addressed and what, if anything, makes them problematic. We take an alternative approach, diagnosing some of the main concerns as arising from a core phenomenon of shifting trust relations that come about when the physician plays a less central role in the delivery of care, and new actors and entities are introduced. Correspondingly, we propose an applied ethics of trust based on the idea that patients should be provided with good reasons to trust telecare services, which we call sound trust. On the basis of this approach, we propose several concrete strategies for safeguarding sound trust in telecare. PMID- 27932398 TI - Knowledge and Belief in Placebo Effect. AB - The beliefs involved in the placebo effect are often assumed to be self fulfilling, that is, the truth of these beliefs would merely require the patient to hold them. Such a view is commonly shared in epistemology. Many epistemologists focused, in fact, on the self-fulfilling nature of these beliefs, which have been investigated because they raise some important counterexamples to Nozick's "tracking theory of knowledge." We challenge the self-fulfilling nature of placebo-based beliefs in multi-agent contexts, analyzing their deep epistemological nature and the role of higher-order beliefs involved in the placebo effect. PMID- 27932400 TI - Grading the quality of evidence in complex interventions: a guide for evidence based practitioners. AB - Evidence-based practitioners who want to apply evidence from complex interventions to the care of their patients are often challenged by the difficulty of grading the quality of this evidence. Using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and an illustrative example, we propose a framework for evaluating the quality of evidence that depends on obtaining feedback from the evidence user (eg, guideline panel) to inform: (1) proper framing of the question, (2) judgements about directness and consistency of evidence and (3) the need for additional contextual and qualitative evidence. Using this framework, different evidence users and based on their needs would consider the same evidence as high, moderate, low or very low. PMID- 27932399 TI - Novel Hybrid Phenotype Revealed in Small Cell Lung Cancer by a Transcription Factor Network Model That Can Explain Tumor Heterogeneity. AB - Small cell lung cancer (SCLC) is a devastating disease due to its propensity for early invasion and refractory relapse after initial treatment response. Although these aggressive traits have been associated with phenotypic heterogeneity, our understanding of this association remains incomplete. To fill this knowledge gap, we inferred a set of 33 transcription factors (TF) associated with gene signatures of the known neuroendocrine/epithelial (NE) and non neuroendocrine/mesenchymal-like (ML) SCLC phenotypes. The topology of this SCLC TF network was derived from prior knowledge and was simulated using Boolean modeling. These simulations predicted that the network settles into attractors, or TF expression patterns, that correlate with NE or ML phenotypes, suggesting that TF network dynamics underlie the emergence of heterogeneous SCLC phenotypes. However, several cell lines and patient tumor specimens failed to correlate with either the NE or ML attractors. By flow cytometry, single cells within these cell lines simultaneously expressed surface markers of both NE and ML differentiation, confirming the existence of a "hybrid" phenotype. Upon exposure to standard-of care cytotoxic drugs or epigenetic modifiers, NE and ML cell populations converged toward the hybrid state, suggesting possible escape from treatment. Our findings indicate that SCLC phenotypic heterogeneity can be specified dynamically by attractor states of a master regulatory TF network. Thus, SCLC heterogeneity may be best understood as states within an epigenetic landscape. Understanding phenotypic transitions within this landscape may provide insights to clinical applications. Cancer Res; 77(5); 1063-74. (c)2016 AACR. PMID- 27932401 TI - Medium- to long-term outcomes of anatomical reconstruction of the radioulnar ligament to the ulnar fovea. AB - : We examined the medium- to long-term outcome of the original reconstruction technique of the radioulnar ligament using a half-slip of the extensor carpi ulnaris tendon for chronic foveal avulsion of the triangular fibrocartilage complex. We treated 37 wrists in 36 patients with a minimum follow-up of 5 years. Of 36 patients, 12 had more than 10 years follow-up. At final follow-up, 30 patients (31 wrists) reported no pain, five patients (five wrists) reported mild occasional pain and one patient reported severe persistent pain. Two patients had lost 30 degrees of supination. Complete stability of the distal radio-ulnar joint was achieved in 31 wrists, moderate instability was noted in five and severe distal radio-ulnar joint instability remained in one. The size of the bone tunnel was assessed radiologically: in two it had enlarged; in 23 it was unchanged; and in 12 it appeared to have closed over the tendon graft. The overall clinical outcomes were 28 excellent, four good, four fair and one poor. The 12 wrists with more than 10 years follow-up had seven excellent, three good and two fair clinical results. This reattachment technique appears to work and last over the medium- to long-term. LEVEL OF EVIDENCE: IV. PMID- 27932402 TI - Australian medical college fights accusations of misconduct in presidential election. PMID- 27932403 TI - Using the De Jong Gierveld Loneliness Scale With Early Adolescents: Factor Structure, Reliability, Stability, and External Validity. AB - The present investigation is the first examination of the factor structures, reliability, external validity, longitudinal invariance, and stability of the De Jong Gierveld Loneliness Scale (DJGLS), as used with early adolescents. It is based on a two-wave, large, representative sample of Polish primary school pupils. The results demonstrate that the model most reflective of the factor structure of the DJGLS is the bifactor model, which assumes the occurrence of one, highly reliable, general factor (overall sense of loneliness) and two, relatively irrelevant, subfactors. Essential unidimensionality (the general factor accounting for three fourth of the common variance) suggest that the interpretation of the subfactors over and above the general factor is inappropriate. The longitudinal confirmatory factor analysis indicated that the bifactor structure of the DJGLS is invariant over time. Correlations with self rated loneliness, sociometric acceptance/rejection, social self-efficacy, identification with class group, family structure, and gender provide support for the validity of the DJGLS. This implies that it could be used as a measure of loneliness in adolescence, which does not involve references to the school context, making it possible to conduct studies that go beyond school period and compare the intensity of the feeling of loneliness in that group with other age groups. PMID- 27932404 TI - Margaret McCartney: Vocation, vocation, vocation. PMID- 27932405 TI - Dentoskeletal effects of oral appliance wear in obstructive sleep apnoea and snoring patients. AB - Objectives: To evaluate the dentoskeletal changes associated with long-term and continuous mandibular advancement device (MAD) use in sleep-related breathing disorder patients. Methods: Cephalometric measurements and three-dimensional model analysis were performed at baseline and after 3.5 +/- 1.1 years in 20 snoring and obstructive sleep apnoea patients treated with the Silensor(r) appliance. Intra-group differences were compared using paired t-test or Wilcoxon signed-rank test. A regression analysis was performed for variables that showed a statistically significant difference between time points to evaluate the influence of treatment time and patient's initial characteristics on their variations. The statistical significance was set at P < 0.05. Results: At cephalometric assessment, the maxilla revealed a significant decrease in horizontal position (SNA: -0.4 +/- 0.72 degree, P = 0.021) and a significant retroclination of the upper incisor (-1.59 +/- 1.07 degree, P < 0.001), while the mandible displayed a significant downward rotation (0.88 +/- 1.28 degree, P = 0.006) and a proclination of the lower incisor (2.27 +/- 1.38 degree, P < 0.001). Model analysis showed a decrease in upper total space discrepancy (-0.66 +/- 0.72 mm, P < 0.002), overjet (OJ; -0.34 +/- 0.47 mm, P < 0.011), and overbite (-0.4 +/ 0.52 mm, P < 0.004). In the regression analysis, treatment time influenced the lower incisor inclination (Beta = -0.713, P = 0.018) and OJ (Beta = -0.218, P = 0.018); patients' initial characteristics had an effect on OJ (Beta = -0.195, P = 0.011). Limitations: A larger sample size could increase the generalizability of the findings. Conclusion: MAD wear after a mean of 3.5 years determines statistically significant but clinically irrelevant dentoskeletal changes. Their potential occurrence should be thoroughly discussed with patients; regular follow up visits by a specialist experienced in dental sleep medicine are also mandatory during treatment in addition to polysomnographic examinations. PMID- 27932406 TI - Diagnostic concordance between skeletal cephalometrics, radiograph-based soft tissue cephalometrics, and photograph-based soft-tissue cephalometrics. AB - Objective: This study aims to investigate the diagnostic concordance between skeletal cephalometrics and soft-tissue cephalometrics in identifying facial lower third characteristics. Materials and methods: We compared a skeletal cephalometric analysis (SCA) to a soft-tissue analysis performed on cephalometric radiographs (rSTCA) and to one performed on profile photograph (pSTCA). Ninety six pre-treatment digital lateral cephalometric radiographs and 96 digital profile photographs were randomly selected for this study (patients' mean age: 18.33, SD: 3.38, age range: 14-29). Inclusion criteria were as follows: no skeletal asymmetry, well-aligned upper and lower dental arches, no history of orthodontic treatment, prosthodontic treatment, facial surgery and trauma, patient's age between 14 and 30 years, high-resolution images, exams taken with natural head position. Kruskas-Wallis and post hoc pairwise comparisons tests were used to find differences among the considered cephalometric methods. The diagnostic performance of the three methods was also assessed using the receiver operating characteristic (ROC) curve analysis. Results: Significant differences were found between SCA and rSTCA and between SCA and pSTCA in defining sagittal and vertical facial lower third characteristics (P < 0.05). No differences were found between rSTCA and pSTCA (P > 0.05) for the same facial characteristics. For each parameters investigated, pSTCA showed an area under the curve much closer to the perfect value of 1.00. Conclusion: Poor diagnostic concordance was found between SCA and rSTCA and between SCA and pSTCA. pSTCA is a reliable method for evaluating the soft-tissue profile characteristics compared to that performed on cephalograms. PMID- 27932407 TI - Torque differences according to tooth morphology and bracket placement: a finite element study. AB - Introduction: Torque of the maxillary incisors is essential in esthetics and proper occlusion, while torque expression is influenced by many factors. The aim of this finite element study was to assess the relative effect of tooth morphology, bracket prescription, and bracket positioning on tooth displacement and developed stresses/strains after torque application. Methods: A three dimensional upper right central incisor with its periodontal ligament (PDL) and alveolus was modelled. The tooth varied in the crown-root angle (CRA) between 156 degrees , 170 degrees , and 184 degrees . An 0.018-inch slot discovery(r) (Dentaurum, Ispringen, Germany) bracket with a rectangular 0.018 * 0.025-inch beta-titanium wire was modelled. Bracket torque prescription varied between 0 degrees , 12 degrees , and 22 degrees , with bracket placement at the centre of the middle, gingival or incisal third of the crown. A total of 27 models were generated and a buccal root torque of 30 degrees was applied. Afterwards, crown and apex displacement, strains in the PDL, and stresses in the bracket were calculated and analysed statistically. Results: The palatal crown displacement was significantly affected by bracket positioning (up to 94 per cent), while the buccal apex displacement was significantly affected by bracket prescription (up to 42 per cent) and bracket positioning (up to 23 per cent). Strains in the PDL were affected mainly by CRA (up to 54 per cent), followed by bracket positioning (up to 45 per cent). Finally, bracket prescription considerably affected the stresses in the bracket (up to 144 per cent). Limitations: These in silico results need to be validated in vivo before they can be clinically extrapolated. Conclusion: Tooth anatomy and the characteristics of the orthodontic appliance should be considered during torque application. PMID- 27932408 TI - Early responses of human periodontal ligament fibroblasts to cyclic and static mechanical stretching. AB - Objective: To compare the mechanotransduction caused by cyclic and static mechanical strains in human periodontal ligament fibroblasts (hPDLFs) cultured under identical conditions. Materials and methods: hPDLFs, originating from the same donors, were exposed either to cyclic or to static tensile strain using specially designed devices and under identical culture conditions. Activation of all members of mitogen-activated protein kinases (MAPKs) was monitored by western immunoblot analysis. Expression levels of immediate/early genes c-fos and c-jun were assessed with quantitative real-time polymerase chain reaction. Results: Time course experiments revealed that both types of stresses activate the three members of MAPK, that is ERK, p38, and JNK, with cyclic stress exhibiting a slightly more extended activation. Further downstream, both stresses upregulate the immediate/early genes c-fos and c-jun, encoding components of the activator protein-1 (AP-1), a key transcription factor in osteoblastic differentiation; again cyclic strain provokes a more intense upregulation. Six hours after the application of both strains, MAPK activation and gene expression return to basal levels. Finally, cells exposed to cyclic stress for longer periods are distributed approximately perpendicular to the axis of the applied strain, whereas cells exposed to static loading remain in a random orientation in culture. Conclusion: The findings of the present study indicate similar, although not identical, immediate/early responses of hPDLs to cyclic and static stretching, with cyclic strain provoking a more intense adaptive response of these cells to mechanical deformation. PMID- 27932409 TI - Increased prevalence of obstructive sleep apnea in patients with Cushing's syndrome compared with weight- and age-matched controls. AB - OBJECTIVE: Diabetes mellitus and obesity are well-known risk factors associated with obstructive sleep apnea (OSA). Cushing's syndrome (CS) is also characterized by obesity and diabetes mellitus. However, the association between CS and OSA remains unclear. Therefore, we investigated the possible associations between CS and OSA in this study. PATIENTS AND METHODS: Thirty female patients with newly diagnosed active CS and 30 age-, gender- and body mass index (BMI)-matched controls were included in this study. All participants were evaluated by overnight polysomnography. OSA was defined as having an apnea-hypopnea index (AHI) score of >=5 events/h. Insulin resistance was calculated by homeostasis model assessment (HOMA) scores. Fasting serum cortisol was also determined. RESULTS: The prevalence of OSA was higher (50% vs 23%, P = 0.003) in patients with CS compared with the control subjects. The mean HOMA (P = 0.046) and AHI (P = 0.028) scores were higher in patients with CS compared with the control subjects. AHI was positively correlated with the HOMA scores (r = 0.281, P = 0.046) in both groups. Linear regression analysis showed that serum cortisol remained as an independent predictor for AHI after controlling for BMI and HOMA score (P < 0.001). CONCLUSIONS: The prevalence of OSA increased in patients with CS compared with control subjects with similar ages and BMI levels. Hypercortisolemia is an independent risk factor for developing OSA. The presence of OSA needs to be considered in patients with CS. PMID- 27932410 TI - Anthropometric factors have significant influence on the outcome of the GHRH arginine test: establishment of normative data for an automated immunoassay specifically measuring 22 kDa human growth hormone. AB - CONTEXT: Adult growth hormone (GH) deficiency (GHD) is diagnosed by provocative testing of GH secretion. OBJECTIVE: To improve the diagnostic accuracy of GH releasing hormone (GHRH) plus arginine (GARG) testing, we evaluated the influence of age, BMI and sex and established normative data for an automatic immunoassay specifically measuring 22 kDa human GH. DESIGN/SETTING: Prospective multicenter study. PARTICIPANTS: Eighty-seven patients with hypothalamic-pituitary disease and 200 healthy controls. Patients were classified according to the number of pituitary hormone deficiencies (PHD). GHD was assumed when >=2 PHD (in addition to GH) were present (n = 51); 36 patients with <2 PHD were considered GH sufficient (GHS). ROC analysis identified cutoffs with >=95% specificity for GHD. Controls were prospectively stratified for sex, age and BMI. INTERVENTIONS: All participants received GHRH and l-arginine. MAIN OUTCOME MEASURES: GH was measured by immunoassay (iSYS, IDS). RESULTS: In controls, multiple stepwise regression analysis showed that BMI (21%, P < 0.0001), sex (20%, P < 0.0001) and age (5%, P < 0.001), accounted for 46% of GH peak level variability during GARG. Comparison of peak GH during GARG (GHD vs GHS + controls) revealed an overall cutoff of 3.9 ng/mL (sensitivity 86%, specificity 95%). After adjustment for BMI and sex, optimal cutoffs (male vs female) were 6.5 vs 9.7 ng/mL in lean, 3.5 vs 8.5 ng/mL in overweight and 2.2 vs 4.4 ng/mL in obese subjects respectively. CONCLUSION: BMI and sex account for most of the variability of peak GH levels during GARG. Consequently, diagnostic accuracy of the GARG test is significantly improved by use of adjusted cutoffs. PMID- 27932411 TI - MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults. AB - OBJECTIVE: Growth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP) modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This study's objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once-weekly in GHD adults. DESIGN: 54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose. The study included 2 stages: Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023. Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A. RESULTS: Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH related side effects. CONCLUSIONS: Once-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing. PMID- 27932412 TI - Universal Haplotype-Based Noninvasive Prenatal Testing for Single Gene Diseases. AB - BACKGROUND: Researchers have developed approaches for the noninvasive prenatal testing of single gene diseases. One approach that allows for the noninvasive assessment of both maternally and paternally inherited mutations involves the analysis of single nucleotide polymorphisms (SNPs) in maternal plasma DNA with reference to parental haplotype information. In the past, parental haplotypes were resolved by complex experimental methods or inferential approaches, such as through the analysis of DNA from other affected family members. Recently, microfluidics-based linked-read sequencing technology has become available and allows the direct haplotype phasing of the whole genome rapidly. We explored the feasibility of applying this direct haplotyping technology in noninvasive prenatal testing. METHODS: We first resolved the haplotypes of parental genomes with the use of linked-read sequencing technology. Then, we identified SNPs within and flanking the genes of interest in maternal plasma DNA by targeted sequencing. Finally, we applied relative haplotype dosage analysis to deduce the mutation inheritance status of the fetus. RESULTS: Haplotype phasing and relative haplotype dosage analysis of 12 out of 13 families were successfully achieved. The mutational status of these 12 fetuses was correctly classified. CONCLUSIONS: High-throughput linked-read sequencing followed by maternal plasma-based relative haplotype dosage analysis represents a streamlined approach for noninvasive prenatal testing of inherited single gene diseases. The approach bypasses the need for mutation-specific assays and is not dependent on the availability of DNA from other affected family members. Thus, the approach is universally applicable to pregnancies at risk for the inheritance of a single gene disease. PMID- 27932413 TI - Biomarkers and Coronary Lesions Predict Outcomes after Revascularization in Non ST-Elevation Acute Coronary Syndrome. AB - BACKGROUND: Risk stratification in non-ST-elevation acute coronary syndrome (NSTE ACS) is currently mainly based on clinical characteristics. With routine invasive management, angiography findings and biomarkers are available and may improve prognostication. We aimed to assess if adding biomarkers [high-sensitivity cardiac troponin T (cTnT-hs), N-terminal probrain-type natriuretic peptide (NT proBNP), growth differentiation factor 15 (GDF-15)] and extent of coronary artery disease (CAD) might improve prognostication in revascularized patients with NSTE ACS. METHODS: In the PLATO (Platelet Inhibition and Patient Outcomes) trial, 5174 NSTE-ACS patients underwent initial angiography and revascularization and had cTnT-hs, NT-proBNP, and GDF-15 measured. Cox models were developed adding extent of CAD and biomarker levels to established clinical risk variables for the composite of cardiovascular death (CVD)/spontaneous myocardial infarction (MI), and CVD alone. Models were compared using c-statistic and net reclassification improvement (NRI). RESULTS: For the composite end point and CVD, prognostication improved when adding extent of CAD, NT-proBNP, and GDF-15 to clinical variables (c-statistic 0.685 and 0.805, respectively, for full model vs 0.649 and 0.760 for clinical model). cTnT-hs did not contribute to prognostication. In the full model (clinical variables, extent of CAD, all biomarkers), hazard ratios (95% CI) per standard deviation increase were for cTnT-hs 0.93(0.81-1.05), NT-proBNP 1.32(1.13 1.53), GDF-15 1.20(1.07-1.36) for the composite end point, driven by prediction of CVD by NT-proBNP and GDF-15. For spontaneous MI, there was an association with NT-proBNP or GDF-15, but not with cTnT-hs. CONCLUSIONS: In revascularized patients with NSTE-ACS, the extent of CAD and concentrations of NT-proBNP and GDF 15 independently improve prognostication of CVD/spontaneous MI and CVD alone. This information may be useful for selection of patients who might benefit from more intense and/or prolonged antithrombotic treatment. ClinicalTrials.gov Identifier: NCT00391872. PMID- 27932415 TI - Targeted Next-Generation Sequencing for Diagnostics and Forensics. PMID- 27932414 TI - Serial Sampling of High-Sensitivity Cardiac Troponin T May Not Be Required for Prediction of Acute Myocardial Infarction Diagnosis in Chest Pain Patients with Highly Abnormal Concentrations at Presentation. AB - BACKGROUND: Guidelines for diagnosing acute myocardial infarction (AMI) recommend adding kinetic changes to the initial cardiac troponin (cTn) blood concentration to improve AMI diagnosis. We hypothesized that kinetic changes may not be required in patients presenting with highly abnormal cTn. METHODS: Patients presenting with suspected AMI to the emergency department were enrolled in a prospective diagnostic study. We assessed the positive predictive value (PPV) of initial high-sensitivity cardiac troponin T (hs-cTnT) blood concentrations alone and in combination with kinetic changes for AMI. Predefined relative changes (delta change of >=20%) and absolute changes (Delta change >=9.2 ng/L) within different time intervals (1 h, 2 h, and 4-14 h after presentation) were assessed. The final diagnosis was adjudicated by 2 independent cardiologists. RESULTS: Among 1282 patients, 213 (16.6%) patients had a final diagnosis of AMI. For AMI prediction, PPVs increased from 48.8% for an initial hs-cTnT >14 ng/L to 87.2% for >60 ng/L, whereas PPVs remained unchanged for higher hs-cTnT concentrations at baseline (87.1% for both >80 ng/L and >100 ng/L). With addition of 20% relative Delta change, PPVs were not further improved in patients with baseline hs-cTnT >80 ng/L using the 1-h (84.0%) and 2-h (88.9%) intervals, and only minimally when extending the interval to 4-14 h (91.2% for >80 ng/L and 90.4% for >100 ng/L, respectively). Similar findings were observed when applying absolute changes. CONCLUSIONS: In chest pain patients with highly abnormal hs-cTnT concentrations at presentation, subsequent blood draws may not be required, as they do not provide incremental diagnostic value for prediction of AMI diagnosis. PMID- 27932418 TI - In Memoriam: Donald Ainslie Henderson, 1928-2016. PMID- 27932416 TI - A Phase II Trial of Dovitinib in BCG-Unresponsive Urothelial Carcinoma with FGFR3 Mutations or Overexpression: Hoosier Cancer Research Network Trial HCRN 12-157. AB - Purpose: To assess the clinical and pharmacodynamic activity of dovitinib in a treatment-resistant, molecularly enriched non-muscle-invasive urothelial carcinoma of the bladder (NMIUC) population.Experimental Design: A multi-site pilot phase II trial was conducted. Key eligibility criteria included the following: Bacillus Calmette-Guerin (BCG)-unresponsive NMIUC (>2 prior intravesical regimens) with increased phosphorylated FGFR3 (pFGFR3) expression by centrally analyzed immunohistochemistry (IHC+) or FGFR3 mutations (Mut+) assessed in a CLIA-licensed laboratory. Patients received oral dovitinib 500 mg daily (5 days on/2 days off). The primary endpoint was 6-month TURBT-confirmed complete response (CR) rate.Results: Between 11/2013 and 10/2014, 13 patients enrolled (10 IHC+ Mut-, 3 IHC+ Mut+). Accrual ended prematurely due to cessation of dovitinib clinical development. Demographics included the following: median age 70 years; 85% male; carcinoma in situ (CIS; 3 patients), Ta/T1 (8 patients), and Ta/T1 + CIS (2 patients); median prior regimens 3. Toxicity was frequent with all patients experiencing at least one grade 3-4 event. Six-month CR rate was 8% (0% in IHC+ Mut-; 33% in IHC+ Mut+). The primary endpoint was not met. Pharmacodynamically active (94-5,812 nmol/L) dovitinib concentrations in urothelial tissue were observed in all evaluable patients. Reductions in pFGFR3 IHC staining were observed post-dovitinib treatment.Conclusions: Dovitinib consistently achieved biologically active concentrations within the urothelium and demonstrated pharmacodynamic pFGFR3 inhibition. These results support systemic administration as a viable approach to clinical trials in patients with NMIUC. Long-term dovitinib administration was not feasible due to frequent toxicity. Absent clinical activity suggests that patient selection by pFGFR3 IHC alone does not enrich for response to FGFR3 kinase inhibitors in urothelial carcinoma. Clin Cancer Res; 23(12); 3003-11. (c)2016 AACR. PMID- 27932417 TI - Molecular Pathways: The Necrosome-A Target for Cancer Therapy. AB - Necroptosis is a caspase-8-independent cell death that requires coactivation of receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3) kinases. The necrosome is a complex consisting of RIP1, RIP3, and Fas-associated protein with death domain leading to activation of the pseudokinase mixed lineage kinase like followed by a rapid plasma membrane rupture and inflammatory response through the release of damage-associated molecular patterns and cytokines. The necrosome has been shown to be relevant in multiple tumor types, including pancreatic adenocarcinoma, melanoma, and several hematologic malignancies. Preclinical data suggest that targeting this complex can have differential impact on tumor progression and that the effect of necroptosis on oncogenesis is cell type and context dependent. The emerging data suggest that targeting the necrosome may lead to immunogenic reprogramming in the tumor microenvironment in multiple tumors and that combining therapies targeting the necrosome with either conventional chemotherapy or immunotherapy may have beneficial effects. Thus, understanding the interplay of necroptotic cell death, transformed cells, and the immune system may enable the development of novel therapeutic approaches. Clin Cancer Res; 23(5); 1132-6. (c)2016 AACR. PMID- 27932419 TI - Jasmonic Acid Enhances Al-Induced Root Growth Inhibition. AB - Phytohormones such as ethylene and auxin are involved in the regulation of the aluminum (Al)-induced root growth inhibition. Although jasmonate (JA) has been reported to play a crucial role in the regulation of root growth and development in response to environmental stresses through interplay with ethylene and auxin, its role in the regulation of root growth response to Al stress is not yet known. In an attempt to elucidate the role of JA, we found that exogenous application of JA enhanced the Al-induced root growth inhibition. Furthermore, phenotype analysis with mutants defective in either JA biosynthesis or signaling suggests that JA is involved in the regulation of Al-induced root growth inhibition. The expression of the JA receptor CORONATINE INSENSITIVE1 (COI1) and the key JA signaling regulator MYC2 was up-regulated in response to Al stress in the root tips. This process together with COI1-mediated Al-induced root growth inhibition under Al stress was controlled by ethylene but not auxin. Transcriptomic analysis revealed that many responsive genes under Al stress were regulated by JA signaling. The differential responsive of microtubule organization-related genes between the wild-type and coi1-2 mutant is consistent with the changed depolymerization of cortical microtubules in coi1 under Al stress. In addition, ALMT-mediated malate exudation and thus Al exclusion from roots in response to Al stress was also regulated by COI1-mediated JA signaling. Together, this study suggests that root growth inhibition is regulated by COI1-mediated JA signaling independent from auxin signaling and provides novel insights into the phytohormone-mediated root growth inhibition in response to Al stress. PMID- 27932420 TI - The Plastid Genome of Polytoma uvella Is the Largest Known among Colorless Algae and Plants and Reflects Contrasting Evolutionary Paths to Nonphotosynthetic Lifestyles. AB - The loss of photosynthesis is frequently associated with parasitic or pathogenic lifestyles, but it also can occur in free-living, plastid-bearing lineages. A common consequence of becoming nonphotosynthetic is the reduction in size and gene content of the plastid genome. In exceptional circumstances, it can even result in the complete loss of the plastid DNA (ptDNA) and its associated gene expression system, as reported recently in several lineages, including the nonphotosynthetic green algal genus Polytomella Closely related to Polytomella is the polyphyletic genus Polytoma, the members of which lost photosynthesis independently of Polytomella Species from both genera are free-living organisms that contain nonphotosynthetic plastids, but unlike Polytomella, Polytoma members have retained a genome in their colorless plastid. Here, we present the plastid genome of Polytoma uvella: to our knowledge, the first report of ptDNA from a nonphotosynthetic chlamydomonadalean alga. The P. uvella ptDNA contains 25 protein-coding genes, most of which are related to gene expression and none are connected to photosynthesis. However, despite its reduced coding capacity, the P. uvella ptDNA is inflated with short repeats and is tens of kilobases larger than the ptDNAs of its closest known photosynthetic relatives, Chlamydomonas leiostraca and Chlamydomonas applanata In fact, at approximately 230 kb, the ptDNA of P. uvella represents the largest plastid genome currently reported from a nonphotosynthetic alga or plant. Overall, the P. uvella and Polytomella plastid genomes reveal two very different evolutionary paths following the loss of photosynthesis: expansion and complete deletion, respectively. We hypothesize that recombination-based DNA-repair mechanisms are at least partially responsible for the different evolutionary outcomes observed in such closely related nonphotosynthetic algae. PMID- 27932424 TI - Correction. PMID- 27932423 TI - Integrated genomic analysis of survival outliers in glioblastoma. AB - Background: To elucidate molecular features associated with disproportionate survival of glioblastoma (GB) patients, we conducted deep genomic comparative analysis of a cohort of patients receiving standard therapy (surgery plus concurrent radiation and temozolomide); "GB outliers" were identified: long-term survivor of 33 months (LTS; n = 8) versus short-term survivor of 7 months (STS; n = 10). Methods: We implemented exome, RNA, whole genome sequencing, and DNA methylation for collection of deep genomic data from STS and LTS GB patients. Results: LTS GB showed frequent chromosomal gains in 4q12 (platelet derived growth factor receptor alpha and KIT) and 12q14.1 (cyclin-dependent kinase 4), and deletion in 19q13.33 (BAX, branched chain amino-acid transaminase 2, and cluster of differentiation 33). STS GB showed frequent deletion in 9p11.2 (forkhead box D4-like 2 and aquaporin 7 pseudogene 3) and 22q11.21 (Hypermethylated In Cancer 2). LTS GB showed 2-fold more frequent copy number deletions compared with STS GB. Gene expression differences showed the STS cohort with altered transcriptional regulators: activation of signal transducer and activator of transcription (STAT)5a/b, nuclear factor-kappaB (NF-kappaB), and interferon-gamma (IFNG), and inhibition of mitogen-activated protein kinase (MAPK1), extracellular signal-regulated kinase (ERK)1/2, and estrogen receptor (ESR)1. Expression-based biological concepts prominent in the STS cohort include metabolic processes, anaphase-promoting complex degradation, and immune processes associated with major histocompatibility complex class I antigen presentation; the LTS cohort features genes related to development, morphogenesis, and the mammalian target of rapamycin signaling pathway. Whole genome methylation analyses showed that a methylation signature of 89 probes distinctly separates LTS from STS GB tumors. Conclusion: We posit that genomic instability is associated with longer survival of GB (possibly with vulnerability to standard therapy); conversely, genomic and epigenetic signatures may identify patients where up-front entry into alternative, targeted regimens would be a preferred, more efficacious management. PMID- 27932421 TI - MYB89 Transcription Factor Represses Seed Oil Accumulation. AB - In many higher plants, seed oil accumulation is precisely controlled by intricate multilevel regulatory networks, among which transcriptional regulation mainly influences oil biosynthesis. In Arabidopsis (Arabidopsis thaliana), the master positive transcription factors, WRINKLED1 (WRI1) and LEAFY COTYLEDON1-LIKE (L1L), are important for seed oil accumulation. We found that an R2R3-MYB transcription factor, MYB89, was expressed predominantly in developing seeds during maturation. Oil and major fatty acid biosynthesis in seeds was significantly promoted by myb89-1 mutation and MYB89 knockdown; thus, MYB89 was an important repressor during seed oil accumulation. RNA sequencing revealed remarkable up-regulation of numerous genes involved in seed oil accumulation in myb89 seeds at 12 d after pollination. Posttranslational activation of a MYB89-glucocorticoid receptor fusion protein and chromatin immunoprecipitation assays demonstrated that MYB89 inhibited seed oil accumulation by directly repressing WRI1 and five key genes and by indirectly suppressing L1L and 11 key genes involved in oil biosynthesis during seed maturation. These results help us to understand the novel function of MYB89 and provide new insights into the regulatory network of transcriptional factors controlling seed oil accumulation in Arabidopsis. PMID- 27932426 TI - Extracorporeal Membrane Oxygenation for Hemodynamic Support of Ventricular Tachycardia Ablation. AB - BACKGROUND: We report the experience in a cohort of consecutive patients receiving extracorporeal membrane oxygenation during catheter ablation of unstable ventricular tachycardia (VT) at our center. METHODS AND RESULTS: From 2010 to 2015, extracorporeal membrane oxygenation was initiated in 64 patients (average age: 63+/-15 years; left ventricular ejection fraction in 27+/-9%; cardiogenic shock in 23%, and electrical storm in 62% of patients) undergoing 74 unstable VT catheter ablation procedures. At least one VT was terminated in 81% of procedures with baseline inducible VT, and VT noninducibility was achieved in 69%. Acute heart failure occurred in 5 patients: 3 underwent emergency heart transplantation, 1 had left ventricular assist device (LVAD) implantation, and 1 patient eventually died because of subsequent mesenteric ischemia. All other patients were discharged alive. After a median follow-up of 21 months (13-28 months), VT recurrence was 33%; overall survival was 56 out of 64 patients (88%). Extracorporeal membrane oxygenation-supported ablation was the bridge to LVAD in 6.9% and to heart transplantation in 3.5% of patients. VT recurrence was related to ablation success (after 180 days of follow up: 19% when VT was noninducible, 42% if nonclinical VT was inducible, 75% when clinical VT was inducible, and 75% in untested patients, P<0.001). Incidence of all-cause death, heart transplantation, and LVAD was independently related to ablation outcome (at 180 days of follow-up: 9% when noninducibility was achieved, 50% in case of inducible VT, and 75% in untested patients, P<0.001). At multivariable analyses, noninducibility (hazard ratio 0.198; P=0.001) and left ventricular ejection fraction (hazard ratio 0.916; P=0.008) correlated with all-cause death, LVAD, and heart transplantation. CONCLUSIONS: Ablation of unstable VTs can be safely supported by extracorporeal membrane oxygenation, which allows rhythm stabilization with low procedure mortality, bridging decompensated patients to permanent LVAD or heart transplantation. Successful ablation is associated with better outcomes than unsuccessful ablation. PMID- 27932425 TI - Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias. AB - BACKGROUND: Mutations in SCN2B, encoding voltage-gated sodium channel beta2 subunits, are associated with human cardiac arrhythmias, including atrial fibrillation and Brugada syndrome. Because of this, we propose that beta2 subunits play critical roles in the establishment or maintenance of normal cardiac electric activity in vivo. METHODS AND RESULTS: To understand the pathophysiological roles of beta2 in the heart, we investigated the cardiac phenotype of Scn2b null mice. We observed reduced sodium and potassium current densities in ventricular myocytes, as well as conduction slowing in the right ventricular outflow tract region. Functional reentry, resulting from the interplay between slowed conduction, prolonged repolarization, and increased incidence of premature ventricular complexes, was found to underlie the mechanism of spontaneous polymorphic ventricular tachycardia. Scn5a transcript levels were similar in Scn2b null and wild-type ventricles, as were levels of Nav1.5 protein, suggesting that similar to the previous work in neurons, the major function of beta2-subunits in the ventricle is to chaperone voltage-gated sodium channel alpha-subunits to the plasma membrane. Interestingly, Scn2b deletion resulted in region-specific effects in the heart. Scn2b null atria had normal levels of sodium current density compared with wild type. Scn2b null hearts were more susceptible to atrial fibrillation, had increased levels of fibrosis, and higher repolarization dispersion than wild-type littermates. CONCLUSIONS: Genetic deletion of Scn2b in mice results in ventricular and atrial arrhythmias, consistent with reported SCN2B mutations in human patients. PMID- 27932428 TI - Delayed ventricular septal rupture complicating anterior wall myocardial infarction. AB - A 59-year-old woman was admitted to our hospital with acute pulmonary oedema and cardiogenic shock 35 days after anterior ST elevation myocardial infarction. She developed a new loud pan systolic murmur. Echocardiography revealed a ventricular septal rupture with a significant left to right shunt. She was immediately transferred to the local cardiothoracic unit where she underwent a successful ventricular septal defect (VSD) repair. Ventricular septal rupture often presents within the first 24 hours of acute myocardial infarction and is rare thereafter. It carries a poor mortality (41-80%) even when recognised. Timely recognition of this life-threatening complication can help reduce the resultant morbidity and mortality. Doctors should be aware that this well-recognised complication may present unusually late as in this case. PMID- 27932427 TI - Retrieval of the Leadless Cardiac Pacemaker: A Multicenter Experience. AB - BACKGROUND: Leadless cardiac pacemakers have emerged as a safe and effective alternative to conventional transvenous single-chamber ventricular pacemakers. Herein, we report a multicenter experience on the feasibility and safety of acute retrieval (<6 weeks) and chronic retrieval (>6 weeks) of the leadless cardiac pacemaker in humans. METHODS AND RESULTS: This study included patients enrolled in 3 multicenter trials, who received a leadless cardiac pacemaker implant and who subsequently underwent a device removal attempt. The overall leadless pacemaker retrieval success rate was 94%: for patients whose leadless cardiac pacemaker had been implanted for <6 weeks (acute retrieval cohort), complete retrieval was achieved in 100% (n=5/5); for those implanted for >= 6 weeks (chronic retrieval cohort), retrieval was achieved in 91% (n=10/11) of patients. The mean duration of time from implant to retrieval attempt was 346 days (range, 88-1188 days) in the chronic retrieval cohort, and nearly two thirds (n=7; 63%) had been implanted for >6 months before the retrieval attempt. There were no procedure-related adverse events at 30 days post retrieval procedure. CONCLUSIONS: This multicenter experience demonstrated the feasibility and safety of retrieving a chronically implanted single-chamber (right ventricle) active fixation leadless pacemaker. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT02051972, NCT02030418, and NCT01700244. PMID- 27932429 TI - IgG4-related disease presenting with headache and papilloedema. PMID- 27932430 TI - Bladder agenesis, ectopic ureters and a multicystic dysplastic horseshoe kidney in one twin newborn with normal amniotic fluid index in utero. AB - A monochorionic-diamniotic twin baby presented with intrauterine growth restriction and anuria. The baby was found to have bladder agenesis, a pelvic dysplastic horseshoe kidney, vertebral anomalies, a ventricular septal defect and facial dysmorphisms. It was surprising to find no abnormalities in amniotic fluid indices prenatally, suggesting the possibility of urine output that declined as the pregnancy proceeded. Some degree of twin-to-twin transfusion of amniotic fluid was also possible, which could have rescued the oligohydramnios known to be associated with kidney and urinary tract abnormalities. It was also notable that there was no abnormality in respiratory function, especially since further investigations revealed close to no kidney function. The intrauterine growth restriction (IUGR) along with the multiple anomalies found made the baby unsuitable for dialysis and transplant, and the decision of transition to palliative care was made. PMID- 27932431 TI - Effect of CPAP on acute aortic dissection with recanalisation. PMID- 27932432 TI - Fungal mobile mass on echocardiogram: native mitral valve Aspergillus fumigatus endocarditis. AB - The most common type of infective endocarditis is bacterial endocarditis. However, fungal infections have been seen more frequently, mostly in the immunocompromised population. We report a case of invasive Aspergillus fumigatus native mitral valve endocarditis. The patient received appropriate empiric antifungal treatment with a combination of liposomal amphotericin B and flucytosine, associated with surgical debridement, valve replacement and chordae tendineae repair. Despite receiving the standard treatment of Aspergillus endocarditis, and susceptibility of the microorganism to the antifungal regimen, the patient, unexpectedly, developed early-onset septic emboli. It is surprising to see that the patient had developed such complications early, despite attempts to eliminate the source of infection with surgical intervention. PMID- 27932433 TI - Acute hypertensive encephalopathy presenting with a partial third nerve palsy: image findings. PMID- 27932434 TI - Rapidly progressing dual infection with Aspergillus and Rhizopus: when soil inhabitants become deadly invaders. AB - We present a case report of a 61-year-old patient with acute pulmonary and cerebral infections with Aspergillus and Rhizopus. The only risk factor for invasive fungal disease was high-dose corticosteroids used to treat her chronic obstructive pulmonary disease exacerbation. She had rapid progression and succumbed to her infections within 2 weeks of diagnosis in spite of aggressive antifungal therapy and surgery. To the best of our knowledge, this is the first reported case of rapidly fatal dual infection with Aspergillus and Rhizopus Our case highlights the role of high-dose corticosteroids as a risk factor for invasive fungal disease in patients without traditional risk factors like haematological malignancies, solid organ transplantation or uncontrolled diabetes. PMID- 27932435 TI - Radical resection and improvised surgical reconstruction for a rare malignant triton tumour of intercostal nerve in a patient with neurofibromatosis type 1. AB - A man aged 28 years, with neurofibromatosis type 1, presented with abdominal pain and visible right lower chest swelling. He had cutaneous neurofibromas and several cafe-au-lait spots. CT scan of the chest and abdomen revealed a giant mass most likely originating from the right 7th intercostal nerve, extending downwards into the abdomen causing massive hepatic compression. A Trucut biopsy showed malignant peripheral nerve sheath tumour. Radical surgical resection with wide margins was performed. The chest wall and diaphragm were reconstructed with improvised surgical technique with excellent results. Final histopathology report revealed a triton tumour of the intercostal nerve. PMID- 27932436 TI - Multifactorial pathological hip subluxation in neurofibromatosis type-1 (NF1) due to intra-articular plexiform neurofibroma, lumbar radiculopathy and neurofibromatous polyneuropathy. AB - Neurofibromatosis type-1 (NF1) is a multisystem disorder with very rare descriptions of hip instability. We report a case of a 37-year-old man with known NF1 and childhood-onset of left foot drop, who developed persistent left hip pain following a minor trauma. Physical examination revealed left-sided mild foot drop, hip abductor weakness, bilateral sensory loss in feet and an antalgic gait. Work-up revealed anterolateral subluxation of the left femoral head along with left hip plexiform neurofibroma (PN), dysplastic and degenerative changes, neurofibromatous neuropathy and chronic left L5 radiculopathy. Initial improvement after surgical resection of the PN was unsustained and followed by increasing pain and recurrent hip subluxation, prompting a total hip arthroplasty which resulted in marked improvement of symptoms. Our patient, unlike those in other reports, illustrates multiple aetiologies of hip dislocation in NF1 including local factors, lumbar radiculopathy and polyneuropathy, reinforcing the importance of a multidisciplinary approach in the management of such cases. PMID- 27932437 TI - Reverse fluorescein cap sign of cavernous haemangioma of optic nerve on OCT angiography. PMID- 27932438 TI - Squamous cell carcinoma of the extrahepatic bile duct with metachronous para aortic lymph node metastasis successfully treated with S-1 plus cisplatin. AB - The most common histological classification of bile duct cancer is adenocarcinoma and squamous cell carcinoma (SCC) is relatively rare. We report a case of a 78 year-old man with SCC of the extrahepatic bile duct associated with metachronous para-aortic lymph node metastasis. He had undergone subtotal stomach-preserving pancreatoduodenectomy. The pathological findings demonstrated moderately differentiated SCC of the distal extrahepatic bile duct (T1N1M0, stage IIB). 6 months after surgery, recurrence of the para-aortic lymph node was shown in abdominal CT. 5 courses of tegafur/gimeracil/oteracil (S-1) plus cisplatin therapy was performed and the para-aortic lymph node disappeared, confirmed as complete response by imaging findings. The patient is alive without recurrence, 10 months after recurrence and chemotherapy. PMID- 27932439 TI - Management of splenic ectopic pregnancy presenting with massive haemoperitoneum. AB - Abdominal ectopic pregnancy (EP) accounts for only 1.3% of EPs and occurs when a fertilised ovum implants in an extrapelvic peritoneal location. Primary splenic pregnancy is a rare type of abdominal EP, with only 16 cases previously reported in the literature. Early diagnosis is essential as delay in treatment carries significant potential for morbidity and mortality. We present the case of a 27 year-old woman presenting with left upper quadrant abdominal pain, elevated human chorionic gonadotropin levels, absence of intrauterine gestational sac and massive haemoperitoneum on transvaginal ultrasound. The patient underwent emergent surgical exploration for high suspicion of ruptured abdominal EP. An open splenectomy was performed when the source of bleeding was confirmed to originate from the left upper quadrant. Final pathology confirmed subcapsular gestational sac implantation within the spleen. While two cases of medical management have been reported, splenectomy remains the current definitive management of rare cases of primary splenic pregnancy. PMID- 27932440 TI - Loss of pleural fluid level postpneumonectomy. PMID- 27932441 TI - Trophoblast cells inhibit neutrophil extracellular trap formation and enhance apoptosis through vasoactive intestinal peptide-mediated pathways. AB - STUDY QUESTION: Do human trophoblast cells modulate neutrophil extracellular trap (NET) formation, reactive oxygen species (ROS) synthesis and neutrophil apoptosis through mechanisms involving vasoactive intestinal peptide (VIP)? SUMMARY ANSWER: Trophoblast cells inhibited NET formation and ROS synthesis and enhanced neutrophil apoptosis through VIP-mediated pathways in a model of maternal placental interaction. WHAT IS KNOWN ALREADY: Immune homeostasis maintenance at the maternal-placental interface is mostly coordinated by trophoblast cells. Neutrophil activation and NET formation increases in pregnancies complicated by exacerbated pro-inflammatory responses. VIP has anti-inflammatory and immunosuppressant effects and is synthesized by trophoblast cells. STUDY DESIGN, SIZE, DURATION: This is a laboratory-based observational study that sampled circulating neutrophils from 50 healthy volunteers to explore their response in vitro to factors derived from human trophoblast cells. PARTICIPANTS/MATERIALS, SETTING, METHODS: Peripheral blood neutrophils were isolated from healthy volunteers and tested in vitro with first trimester trophoblast cell line (Swan 71 and HTR8) conditioned media (CM) or with VIP. The effect of VIP and trophoblast CM on NET formation was assessed by co-localization of elastase and DNA by confocal microscopy, DNA release and elastase activity measurement. Neutrophil apoptosis was determined by flow cytometry or fluorescence microscopy. ROS formation was assessed by flow cytometry with a fluorescent probe. VIP silencing was performed by siRNA transfection. For phagocytosis of apoptotic neutrophils, autologous monocytes were sampled, and engulfment and cytokines were assessed by flow cytometry and ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: Trophoblast CM and 10 nM VIP promoted neutrophil deactivation by preventing phorbol myristate acetate-induced NET formation and ROS synthesis while they increased neutrophil spontaneous apoptosis and reversed the anti-apoptotic effect of lipopolysaccharide (all P < 0.05 versus control). The effects of trophoblast CM were prevented by a VIP antagonist or when VIP knocked-down trophoblast cells were used (P < 0.05 versus control). Neutrophils driven to apoptosis by trophoblast CM could be rapidly engulfed by monocytes without increasing IL-12 production. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: The mechanisms of neutrophil deactivation by trophoblast VIP are based on the results obtained with neutrophils drawn from peripheral blood of healthy individuals interacting with trophoblast cell lines in vitro. These studies were designed to investigate biological processes at the cellular and molecular level; therefore, they have the limitations of studies in vitro and it is not possible to ascertain if these mechanisms operate similarly in vivo. We tested 50 neutrophil samples from healthy volunteers that have a normal variability in their responses. Cell lines derived from human trophoblast were used, and we cannot rule out a differential behavior of trophoblast cells in contact with neutrophils in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Results presented here are consistent with an active mechanism through which neutrophils in contact with trophoblast cells would be deactivated and silently cleared by decidual macrophages throughout pregnancy. They support a novel immunomodulatory role of trophoblast VIP on neutrophils at the placenta, providing new clues for pharmacological targeting of immune and trophoblast cells in pregnancy complications associated with exacerbated inflammation. STUDY FUNDING/COMPETING INTERESTS: This work was funded by the National Agency of Sciences and Technology (PICT 2011-0144, 2014-0657 and 2013-2177) and University of Buenos Aires (UBACyT 20020130100040BA, 20020150100161BA and 20020130100744BA). The authors declare no competing interests. PMID- 27932442 TI - Contraceptive sales in the setting of the Zika virus epidemic. AB - STUDY QUESTION: Has there been any influence of the Zika virus (ZIKV) outbreak on the sales of contraceptive methods in Brazil? SUMMARY ANSWER: Contraceptive sales in the 24 months of evaluation showed little variation and no significant change has been observed since the ZIKV outbreak. WHAT IS KNOWN ALREADY: Transmission of ZIKV is primarily by Aedes aegypti mosquitoes; however, sexual transmission has also been described. The association of several birth defects and the ZIKV infection during pregnancy has been established, and it was estimated in Bahia, Brazil that the infection rate could range from 10% to 80%. The World Health Organisation (WHO) declared the cluster of microcephaly cases and other neurological disorders a health emergency on 1 February 2016. The Brazilian government also made recommendations for women who were planning to become pregnant and who reside in ZIKV-affected areas to reconsider or postpone pregnancy. STUDY DESIGN, SIZE, DURATION: The objective of this study was to assess the sales of contraceptive methods in Brazil, tracking it from before and through the ZIKV outbreak. We obtained information from all pharmaceutical companies based in Brazil and from the manufacturers of long-acting reversible contraceptives (LARCs), including the copper-intrauterine device (IUD), the levonorgestrel-releasing intrauterine system (LNG-IUS) and implants, about contraceptives sales in the public and private sectors between September 2014 and August 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed the data for: (i) oral contraceptives, i.e. combined oral contraceptives (COC) and progestin only pills (POP), and vaginal and transdermal contraceptives, (ii) injectable contraceptives, i.e. once-a-month and depot-medroxyprogesterone acetate, (iii) LARCs and (iv) emergency contraceptive (EC) pills. MAIN RESULTS AND THE ROLE OF CHANCE: Monthly sales of COC, POP, patches and vaginal rings represent the major sales segment of the market, i.e. 12.7-13.8 million cycles/units per month (90%). The second largest group of sales was injectables, representing 0.8-1.5 million ampoules per month (9.5%). Following this, are LARC methods with sales of 37 000 41 000 devices per month (0.5%). It is important to note that although the peak months of sales were different for each group of contraceptives, there were no significant differences overall between the months of observation. The EC pill sales were between 1.0 million and 1.3 million of pills per month. LIMITATIONS, REASONS FOR CAUTION: Although the use of contraceptive methods was already high and no change was noted, the ZIKV outbreak may have changed the pregnancy intentions of Brazilian women. Consequently, the number of women planning pregnancy may be lower than that recorded. The contraceptive sales figures did not include condoms. Since condoms might not only prevent pregnancies, but also sexual transmission of ZIKV, this lack of information is a limitation. WIDER IMPLICATIONS OF THE FINDINGS: The results from this assessment showed that the sales of contraceptives presented little variation during the ZIKV outbreak in Brazil. Furthermore, it is possible that access to LARC methods was limited. Although we did not investigate the reason for low LARC uptake, we suspect that it is due to lack of availability of LARC in the public sector, the high cost of the methods and the incomplete insurance coverage on contraception for women. Projections estimate millions of additional cases of ZIKV transmission. Thus, a coordinated response is needed to ensure access to a wide range of contraceptive methods for women during the ZIKV outbreak. In conclusion, this assessment of contraceptive sales in Brazil identifies challenges in contraceptive access, especially for LARC methods, and represents an alternative source of data to help us understand the trends in demand for contraception in ZIKV-affected areas. STUDY FUNDING/COMPETING INTERESTS: This study received partial financial support from Fundacao de Apoio a Pesquisa do Estado de Sao Paulo (FAPESP) award # 2015/20504-9 and from an anonymous donor. The funding sources did not play a role in the study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication. The authors declare no conflict of interest associated with this study. TRIAL REGISTRATION NUMBER: N/A. PMID- 27932443 TI - PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. AB - Pancreatic ductal adenocarcinoma (PDAC) is considered a non-immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregulated PD-L1 expression in a JAK/Stat1-dependent manner. In vitro, PD-L1 inhibition did not alter radio- and chemosensitivity. In vivo, addition of anti-PD-L1 to high (12, 5 * 3, 20 Gy) but not low (6, 5 * 2 Gy) RT doses significantly improved tumor response in KPC and Pan02 allografts. Radiosensitization after PD-L1 blockade was associated with reduced CD11b+Gr1+ myeloid cell infiltration and enhanced CD45+CD8+ T-cell infiltration with concomitant upregulation of T-cell activation markers including CD69, CD44, and FasL, and increased CD8:Treg ratio. Depletion of CD8+ T cells abrogated radiosensitization by anti-PD-L1. Blockade of PD-L1 further augmented the effect of high RT doses (12 Gy) in preventing development of liver metastases. Exploring multiple mathematical models reveals a mechanism able to explain the observed synergy between RT and anti-PD-L1 therapy. Our findings provide a rationale for testing the use of immune checkpoint inhibitors with RT in PDAC. PMID- 27932445 TI - The Wae to repair: prostaglandin E2 (PGE2) triggers intestinal wound repair. PMID- 27932444 TI - Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages. AB - Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes. This was accompanied by depletion of epidermal gammadelta T cells and accumulation of regulatory T cells. Most importantly, activin increased the number of skin macrophages via attraction of blood monocytes, which was prevented by depletion of CCR2-positive monocytes. Gene expression profiling of macrophages from pre-tumorigenic skin and bioinformatics analysis demonstrated that activin induces a gene expression pattern in skin macrophages that resembles the phenotype of tumor-associated macrophages in different malignancies, thereby promoting angiogenesis, cell migration and proteolysis. The functional relevance of this finding was demonstrated by antibody-mediated depletion of macrophages, which strongly suppressed activin-induced skin tumor formation. These results demonstrate that activin induces skin carcinogenesis via attraction and reprogramming of macrophages and identify novel activin targets involved in tumor formation. PMID- 27932446 TI - Topoisomerase I-mediated cleavage at unrepaired ribonucleotides generates DNA double-strand breaks. AB - Ribonuclease activity of topoisomerase I (Top1) causes DNA nicks bearing 2',3' cyclic phosphates at ribonucleotide sites. Here, we provide genetic and biochemical evidence that DNA double-strand breaks (DSBs) can be directly generated by Top1 at sites of genomic ribonucleotides. We show that RNase H2 deficient yeast cells displayed elevated frequency of Rad52 foci, inactivation of RNase H2 and RAD52 led to synthetic lethality, and combined loss of RNase H2 and RAD51 induced slow growth and replication stress. Importantly, these phenotypes were rescued upon additional deletion of TOP1, implicating homologous recombination for the repair of Top1-induced damage at ribonuclelotide sites. We demonstrate biochemically that irreversible DSBs are generated by subsequent Top1 cleavage on the opposite strand from the Top1-induced DNA nicks at ribonucleotide sites. Analysis of Top1-linked DNA from pull-down experiments revealed that Top1 is covalently linked to the end of DNA in RNase H2-deficient yeast cells, supporting this model. Taken together, these results define Top1 as a source of DSBs and genome instability when ribonucleotides incorporated by the replicative polymerases are not removed by RNase H2. PMID- 27932447 TI - Unloading of homologous recombination factors is required for restoring double stranded DNA at damage repair loci. AB - Cells use homology-dependent DNA repair to mend chromosome breaks and restore broken replication forks, thereby ensuring genome stability and cell survival. DNA break repair via homology-based mechanisms involves nuclease-dependent DNA end resection, which generates long tracts of single-stranded DNA required for checkpoint activation and loading of homologous recombination proteins Rad52/51/55/57. While recruitment of the homologous recombination machinery is well characterized, it is not known how its presence at repair loci is coordinated with downstream re-synthesis of resected DNA We show that Rad51 inhibits recruitment of proliferating cell nuclear antigen (PCNA), the platform for assembly of the DNA replication machinery, and that unloading of Rad51 by Srs2 helicase is required for efficient PCNA loading and restoration of resected DNA As a result, srs2Delta mutants are deficient in DNA repair correlating with extensive DNA processing, but this defect in srs2Delta mutants can be suppressed by inactivation of the resection nuclease Exo1. We propose a model in which during re-synthesis of resected DNA, the replication machinery must catch up with the preceding processing nucleases, in order to close the single-stranded gap and terminate further resection. PMID- 27932450 TI - Accuracy of Diffusion-weighted Magnetic Resonance Colonography in Assessing Mucosal Healing and the Treatment Response in Patients with Ulcerative Colitis. AB - Background and Aims: Using sigmoidoscopy as the gold standard, we assessed the accuracy, and the responsiveness to change, of diffusion-weighted magnetic resonance colonography in ulcerative colitis, using the Nancy score. Methods: A total of 29 ulcerative colitis patients, having undergone at least two diffusion weighted magnetic resonance colonographies, were included. Disease activity was evaluated using the Mayo endoscopic subscore and the Nancy score. We determined the accuracy of the Nancy score in the diagnosis of mucosal healing. We also assessed its responsiveness to change in 17 patients with a Mayo endoscopic subscore of 2 or 3 at treatment initiation. Results: A total Nancy score < 7 had a sensitivity of 0.75 and a specificity of 0.67 (area under the curve: 0.72; 95% confidence interval: [0.56-0.88]; p = 0.0063) in the diagnosis of mucosal healing. The total Nancy score was sensitive to change in ulcerative colitis [Guyatt's responsiveness index: 1.8; standardised effect size ratio: 1.36]. The Nancy score was reliable [intra-class correlation coefficient: 0.63; p = 0.01]. The mean Mayo endoscopic subscore and the mean Nancy score both fell significantly in patients who achieved mucosal healing (mean +/- standard deviation [SD] Mayo endoscopic subscore: 2.4 +/- 0.55 at baseline and 0.6 +/- 0.55 at reassessment, p = 0.02; mean Nancy score: 18.2 +/- 9.1 at baseline and 3 +/- 1.6 at reassessment, p = 0.006). No significant changes in Nancy score were observed in active patients at reassessment. Conclusions: The Nancy score is a highly responsive, reliable tool for assessing treatment response in patients with ulcerative colitis. The Nancy score accurately detects mucosal healing. PMID- 27932451 TI - Extra-pulmonary Reactivation of Latent Tuberculosis After Initiation of Anti tumour Necrosis Factor Therapy for Inflammatory Bowel Disease-Are Current Screening Strategies Adequate? PMID- 27932449 TI - Oral Iron Treatment Response and Predictors in Anaemic Adolescents and Adults with IBD: A Prospective Controlled Open-Label Trial. AB - Background: Because of previous concerns about the efficacy and safety of oral iron for treating iron deficiency anaemia in inflammatory bowel disease [IBD], particularly in young people, we compared the effects of ferrous sulphate on haemoglobin response, disease activity and psychometric scores in adolescents and adults with IBD. We also assessed the relation of baseline serum hepcidin to haemoglobin response. Methods: We undertook a prospective, open-label, 6-week non inferiority trial of the effects of ferrous sulphate 200 mg twice daily on haemoglobin, iron status, hepcidin, disease activity (Harvey-Bradshaw Index, Simple Colitis Clinical Activity Index, C-reactive protein [CRP]), faecal calprotectin and psychometric scores in 45 adolescents [age 13-18 years] and 43 adults [>18 years]. Results: On intention-to-treat analysis, ferrous sulphate produced similar rises in haemoglobin in adolescents {before treatment 10.3 g/dl [0.18] (mean [SEM]), after 11.7 [0.23]: p < 0.0001} and adults (10.9 g/dl [0.14], 11.9 [0.19]: p < 0.0001); transferrin saturation, ferritin [in adolescents] and hepcidin [in adults] also increased significantly. On per-protocol univariate analysis, the haemoglobin response was inversely related to baseline haemoglobin, CRP and hepcidin. Oral iron did not alter disease activity; it improved Short IBDQ and Perceived Stress Questionnaire scores in adults. Conclusion: Oral ferrous sulphate was no less effective or well-tolerated in adolescents than adults, and did not increase disease activity in this short-term study. The inverse relation between baseline CRP and hepcidin levels and the haemoglobin response suggests that CRP or hepcidin measurements could influence decisions on whether iron should be given orally or intravenously. [ClinTrials.gov registration number NCT01991314]. PMID- 27932452 TI - Patients' Beliefs and Concerns About the Necessity of Long-Term Therapies Are Crucial for Medication Adherence for Inflammatory Bowel Disease. PMID- 27932448 TI - Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy. AB - Autophagy is a process delivering cytoplasmic components to lysosomes for degradation. Autophagy may, however, play a role in unconventional secretion of leaderless cytosolic proteins. How secretory autophagy diverges from degradative autophagy remains unclear. Here we show that in response to lysosomal damage, the prototypical cytosolic secretory autophagy cargo IL-1beta is recognized by specialized secretory autophagy cargo receptor TRIM16 and that this receptor interacts with the R-SNARE Sec22b to recruit cargo to the LC3-II+ sequestration membranes. Cargo secretion is unaffected by downregulation of syntaxin 17, a SNARE promoting autophagosome-lysosome fusion and cargo degradation. Instead, Sec22b in combination with plasma membrane syntaxin 3 and syntaxin 4 as well as SNAP-23 and SNAP-29 completes cargo secretion. Thus, secretory autophagy utilizes a specialized cytosolic cargo receptor and a dedicated SNARE system. Other unconventionally secreted cargo, such as ferritin, is secreted via the same pathway. PMID- 27932454 TI - Inducible Colonic M Cells Are Dependent on TNFR2 but Not Ltbetar, Identifying Distinct Signalling Requirements for Constitutive Versus Inducible M Cells. AB - Background and Aims: M cells associated with organised lymphoid tissues such as intestinal Peyer's patches provide surveillance of the intestinal lumen. Inflammation or infection in the colon can induce an M cell population associated with lymphoid infiltrates; paradoxically, induction is dependent on the inflammatory cytokine tumour necrosis factor [TNF]-alpha. Anti-TNFalpha blockade is an important therapeutic in inflammatory bowel disease, so understanding the effects of TNFalpha signalling is important in refining therapeutics. Methods: To dissect pro-inflammatory signals from M cell inductive signals, we used confocal microscopy image analysis to assess requirements for specific cytokine receptor signals using TNF receptor 1 [TNFR1] and 2 [TNFR2] knockouts [ko] back-crossed to the PGRP-S-dsRed transgene; separate groups were treated with soluble lymphotoxin beta receptor [sLTbetaR] to block LTbetaR signalling. All groups were treated with dextran sodium sulphate [DSS] to induce colitis. Results: Deficiency of TNFR1 or TNFR2 did not prevent DSS-induced inflammation nor induction of stromal cell expression of receptor activator of nuclear factor kappa-B ligand [RANKL], but absence of TNFR2 prevented M cell induction. LTbetaR blockade had no effect on M cell induction, but it appeared to reduce RANKL induction below adjacent M cells. Conclusions: TNFR2 is required for inflammation-inducible M cells, indicating that constitutive versus inflammation-inducible M cells depend on different triggers. The inducible M cell dependence on TNFR2 suggests that this specific subset is dependent on TNFalpha in addition to a presumed requirement for RANKL. Since inducible M cell function will influence immune responses, selective blockade of TNFalpha may affect colonic inflammation. PMID- 27932455 TI - Single-cell profiling reveals that eRNA accumulation at enhancer-promoter loops is not required to sustain transcription. AB - Enhancers are intergenic DNA elements that regulate the transcription of target genes in response to signaling pathways by interacting with promoters over large genomic distances. Recent studies have revealed that enhancers are bi directionally transcribed into enhancer RNAs (eRNAs). Using single-molecule fluorescence in situ hybridization (smFISH), we investigated the eRNA-mediated regulation of transcription during estrogen induction in MCF-7 cells. We demonstrate that eRNAs are localized exclusively in the nucleus and are induced with similar kinetics as target mRNAs. However, eRNAs are mostly nascent at enhancers and their steady-state levels remain lower than those of their cognate mRNAs. Surprisingly, at the single-allele level, eRNAs are rarely co-expressed with their target loci, demonstrating that active gene transcription does not require the continuous transcription of eRNAs or their accumulation at enhancers. When co-expressed, sub-diffraction distance measurements between nascent mRNA and eRNA signals reveal that co-transcription of eRNAs and mRNAs rarely occurs within closed enhancer-promoter loops. Lastly, basal eRNA transcription at enhancers, but not E2-induced transcription, is maintained upon depletion of MLL1 and ERalpha, suggesting some degree of chromatin accessibility prior to signal dependent activation of transcription. Together, our findings suggest that eRNA accumulation at enhancer-promoter loops is not required to sustain target gene transcription. PMID- 27932456 TI - Physico-chemical fingerprinting of RNA genes. AB - We advance here a novel concept for characterizing different classes of RNA genes on the basis of physico-chemical properties of DNA sequences. As knowledge-based approaches could yield unsatisfactory outcomes due to limitations of training on available experimental data sets, alternative approaches that utilize properties intrinsic to DNA are needed to supplement training based methods and to eventually provide molecular insights into genome organization. Based on a comprehensive series of molecular dynamics simulations of Ascona B-DNA consortium, we extracted hydrogen bonding, stacking and solvation energies of all combinations of DNA sequences at the dinucleotide level and calculated these properties for different types of RNA genes. Considering ~7.3 million mRNA, 255 524 tRNA, 40 649 rRNA (different subunits) and 5250 miRNA, 3747 snRNA, gene sequences from 9282 complete genome chromosomes of all prokaryotes and eukaryotes available at NCBI, we observed that physico-chemical properties of different functional units on genomic DNA differ in their signatures. PMID- 27932459 TI - The Basophil-specific Protease mMCP-8 Provokes an Inflammatory Response in the Skin with Microvascular Hyperpermeability and Leukocyte Infiltration. AB - Basophils have often been erroneously considered to be minor relatives or blood circulating precursors of tissue-resident mast cells because of some phenotypic similarity between them, including basophilic secretory granules in the cytoplasm. However, recent studies revealed that the repertoire of serine proteases stored in secretory granules is distinct in them. Particularly, mouse mast cell protease 8 (mMCP-8) is specifically expressed by basophils but not mast cells despite its name. Therefore, mMCP-8 is commonly used as a basophil-specific marker, but its functional property remains uncertain. Here we prepared recombinant mMCP-8 and examined its activity in vitro and in vivo Purified recombinant mMCP-8 showed heat-sensitive proteolytic activity when alpha-tubulin was used as a substrate. One intradermal shot of mMCP-8, not heat-inactivated, induced cutaneous swelling with increased microvascular permeability in a cyclooxygenase-dependent manner. Moreover, repeated intradermal injection of mMCP 8 promoted skin infiltration of leukocytes, predominantly neutrophils and, to a lesser extent, monocytes and eosinophils, in conjunction with up-regulation of chemokine expression in the skin lesion. These results suggest that mMCP-8 is an important effector molecule in basophil-elicited inflammation, providing novel insights into how basophils exert a crucial and non-redundant role, distinct from that played by mast cells, in immune responses. PMID- 27932460 TI - Protein O-Linked Mannose beta-1,4-N-Acetylglucosaminyl-transferase 2 (POMGNT2) Is a Gatekeeper Enzyme for Functional Glycosylation of alpha-Dystroglycan. AB - Disruption of the O-mannosylation pathway involved in functional glycosylation of alpha-dystroglycan gives rise to congenital muscular dystrophies. Protein O linked mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2) catalyzes the first step toward the functional matriglycan structure on alpha-dystroglycan that is responsible for binding extracellular matrix proteins and certain arenaviruses. Alternatively, protein O-linked mannose beta-1,2-N acetylglucosaminyltransferase 1 (POMGNT1) catalyzes the first step toward other various glycan structures present on alpha-dystroglycan of unknown function. Here, we demonstrate that POMGNT1 is promiscuous for O-mannosylated peptides, whereas POMGNT2 displays significant primary amino acid selectivity near the site of O-mannosylation. We define a POMGNT2 acceptor motif, conserved among 59 vertebrate species, in alpha-dystroglycan that when engineered into a POMGNT1 only site is sufficient to convert the O-mannosylated peptide to a substrate for POMGNT2. Additionally, an acceptor glycopeptide is a less efficient substrate for POMGNT2 when two of the conserved amino acids are replaced. These findings begin to define the selectivity of POMGNT2 and suggest that this enzyme functions as a gatekeeper enzyme to prevent the vast majority of O-mannosylated sites on proteins from becoming modified with glycan structures functional for binding laminin globular domain-containing proteins. PMID- 27932461 TI - Structural Characterization and Ligand/Inhibitor Identification Provide Functional Insights into the Mycobacterium tuberculosis Cytochrome P450 CYP126A1. AB - The Mycobacterium tuberculosis H37Rv genome encodes 20 cytochromes P450, including P450s crucial to infection and bacterial viability. Many M. tuberculosis P450s remain uncharacterized, suggesting that their further analysis may provide new insights into M. tuberculosis metabolic processes and new targets for drug discovery. CYP126A1 is representative of a P450 family widely distributed in mycobacteria and other bacteria. Here we explore the biochemical and structural properties of CYP126A1, including its interactions with new chemical ligands. A survey of azole antifungal drugs showed that CYP126A1 is inhibited strongly by azoles containing an imidazole ring but not by those tested containing a triazole ring. To further explore the molecular preferences of CYP126A1 and search for probes of enzyme function, we conducted a high throughput screen. Compounds containing three or more ring structures dominated the screening hits, including nitroaromatic compounds that induce substrate-like shifts in the heme spectrum of CYP126A1. Spectroelectrochemical measurements revealed a 155-mV increase in heme iron potential when bound to one of the newly identified nitroaromatic drugs. CYP126A1 dimers were observed in crystal structures of ligand-free CYP126A1 and for CYP126A1 bound to compounds discovered in the screen. However, ketoconazole binds in an orientation that disrupts the BC loop regions at the P450 dimer interface and results in a CYP126A1 monomeric crystal form. Structural data also reveal that nitroaromatic ligands "moonlight" as substrates by displacing the CYP126A1 distal water but inhibit enzyme activity. The relatively polar active site of CYP126A1 distinguishes it from its most closely related sterol-binding P450s in M. tuberculosis, suggesting that further investigations will reveal its diverse substrate selectivity. PMID- 27932464 TI - Role of Inflammation in Modulating Thrombotic-Fibrinolytic Balance in Venous Thrombosis. PMID- 27932462 TI - Salmonella Co-opts Host Cell Chaperone-mediated Autophagy for Intracellular Growth. AB - Salmonella enterica are invasive intracellular pathogens that replicate within a membrane-bound compartment inside infected host cells known as the Salmonella containing vacuole. How Salmonella obtains nutrients for growth within this intracellular niche despite the apparent isolation is currently not known. Recent studies have indicated the importance of glucose and related carbon sources for tissue colonization and intracellular proliferation within host cells during Salmonella infections, although none have been found to be essential. We found that wild-type Salmonella are capable of replicating within infected host cells in the absence of both exogenous sugars and/or amino acids. Furthermore, mutants defective in glucose uptake or dependent upon peptides for growth also showed no significant loss in intracellular replication, suggesting host-derived peptides can supply both carbon units and amino acids. Here, we show that intracellular Salmonella recruit the host proteins LAMP-2A and Hsc73, key components of the host protein turnover pathway known as chaperone-mediated autophagy involved in transport of cytosolic proteins to the lysosome for degradation. Host-derived peptides are shown to provide a significant contribution toward the intracellular growth of Salmonella The results reveal a means whereby intracellular Salmonella gain access to the host cell cytosol from within its membrane-bound compartment to acquire nutrients. Furthermore, this study provides an explanation as to how Salmonella evades activation of autophagy mechanisms as part of the innate immune response. PMID- 27932465 TI - Modulating Oxysterol Sensing to Control Macrophage Apoptosis and Atherosclerosis. PMID- 27932466 TI - Reconciling Smooth Muscle Cell Oligoclonality and Proliferative Capacity in Experimental Atherosclerosis. PMID- 27932467 TI - Reprogramming of Cardiac Repolarization: Notch Signals a Potential Role for Epigenetic Transcriptional Events. PMID- 27932468 TI - Cerebrovascular Variants in Posterior Circulation: A Potential Cause of Essential Hypertension. PMID- 27932469 TI - Alejandra San Martin: Academic Romantic. PMID- 27932470 TI - Quantifying Scientific Merit: Is it Time to Transform the Impact Factor? PMID- 27932471 TI - A Paradigm Shift Is Needed in the Field of Pulmonary Arterial Hypertension for Its Entrance Into the Precision Medicine Era. PMID- 27932472 TI - Exosomes: What Do We Love So Much About Them? PMID- 27932473 TI - The Peter Principle in Cardiovascular Cell Therapy: The Decline of a Theory or the Theory of a Decline. PMID- 27932474 TI - Recent Developments in Stem and Progenitor Cell Therapy for Cardiac Repair. PMID- 27932475 TI - Intercalated Cell Depletion and Vacuolar H+-ATPase Mistargeting in an Ae1 R607H Knockin Model. AB - Distal nephron acid secretion is mediated by highly specialized type A intercalated cells (A-ICs), which contain vacuolar H+-ATPase (V-type ATPase)-rich vesicles that fuse with the apical plasma membrane on demand. Intracellular bicarbonate generated by luminal H+ secretion is removed by the basolateral anion exchanger AE1. Chronically reduced renal acid excretion in distal renal tubular acidosis (dRTA) may lead to nephrocalcinosis and renal failure. Studies in MDCK monolayers led to the proposal of a dominant-negative trafficking mechanism to explain AE1-associated dominant dRTA. To test this hypothesis in vivo, we generated an Ae1 R607H knockin mouse, which corresponds to the most common dominant dRTA mutation in human AE1, R589H. Compared with wild-type mice, heterozygous and homozygous R607H knockin mice displayed incomplete dRTA characterized by compensatory upregulation of the Na+/HCO3- cotransporter NBCn1. Red blood cell Ae1-mediated anion-exchange activity and surface polypeptide expression did not change. Mutant mice expressed far less Ae1 in A-ICs, but basolateral targeting of the mutant protein was preserved. Notably, mutant mice also exhibited reduced expression of V-type ATPase and compromised targeting of this proton pump to the plasma membrane upon acid challenge. Accumulation of p62- and ubiquitin-positive material in A-ICs of knockin mice suggested a defect in the degradative pathway, which may explain the observed loss of A-ICs. R607H knockin did not affect type B intercalated cells. We propose that reduced basolateral anion-exchange activity in A-ICs inhibits trafficking and regulation of V-type ATPase, compromising luminal H+ secretion and possibly lysosomal acidification. PMID- 27932476 TI - High-Fat Diet-Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney. AB - Excessive fat intake contributes to the progression of metabolic diseases via cellular injury and inflammation, a process termed lipotoxicity. Here, we investigated the role of lysosomal dysfunction and impaired autophagic flux in the pathogenesis of lipotoxicity in the kidney. In mice, a high-fat diet (HFD) resulted in an accumulation of phospholipids in enlarged lysosomes within kidney proximal tubular cells (PTCs). In isolated PTCs treated with palmitic acid, autophagic degradation activity progressively stagnated in association with impaired lysosomal acidification and excessive lipid accumulation. Pulse-chase experiments revealed that the accumulated lipids originated from cellular membranes. In mice with induced PTC-specific ablation of autophagy, PTCs of HFD mice exhibited greater accumulation of ubiquitin-positive protein aggregates normally removed by autophagy than did PTCs of mice fed a normal diet. Furthermore, HFD-mice had no capacity to augment autophagic activity upon another pathologic stress. Autophagy ablation also exaggerated HFD-induced mitochondrial dysfunction and inflammasome activation. Moreover, renal ischemia-reperfusion induced greater injury in HFD-mice than in mice fed a normal diet, and ablation of autophagy further exacerbated this effect. Finally, we detected similarly enhanced phospholipid accumulation in enlarged lysosomes and impaired autophagic flux in the kidneys of obese patients compared with nonobese patients. These findings provide key insights regarding the pathophysiology of lipotoxicity in the kidney and clues to a novel treatment for obesity-related kidney diseases. PMID- 27932477 TI - Moss-Produced, Glycosylation-Optimized Human Factor H for Therapeutic Application in Complement Disorders. AB - Genetic defects in complement regulatory proteins can lead to severe renal diseases, including atypical hemolytic uremic syndrome and C3 glomerulopathies, and age-related macular degeneration. The majority of the mutations found in patients with these diseases affect the glycoprotein complement factor H, the main regulator of the alternative pathway of complement activation. Therapeutic options are limited, and novel treatments, specifically those targeting alternative pathway activation, are highly desirable. Substitution with biologically active factor H could potentially treat a variety of diseases that involve increased alternative pathway activation, but no therapeutic factor H is commercially available. We recently reported the expression of full-length recombinant factor H in moss (Physcomitrella patens). Here, we present the production of an improved moss-derived recombinant human factor H devoid of potentially immunogenic plant-specific sugar residues on protein N-glycans, yielding approximately 1 mg purified moss-derived human factor H per liter of initial P. patens culture after a multistep purification process. This glycosylation-optimized factor H showed full in vitro complement regulatory activity similar to that of plasma-derived factor H and efficiently blocked LPS induced alternative pathway activation and hemolysis induced by sera from patients with atypical hemolytic uremic syndrome. Furthermore, injection of moss derived factor H reduced C3 deposition and increased serum C3 levels in a murine model of C3 glomerulopathy. Thus, we consider moss-produced recombinant human factor H a promising pharmaceutical product for therapeutic intervention in patients suffering from complement dysregulation. PMID- 27932478 TI - Most ApoL1 Is Secreted by the Liver. AB - Two coding sequence variants in the APOL1 gene (G1 and G2) explain much of the increased risk for FSGS, HIV-associated nephropathy, and hypertension-attributed ESRD among people of recent African ancestry. The ApoL1 protein is expressed in a wide variety of cell tissues. It has been assumed that the majority of circulating ApoL1 is produced by the liver, but this has not been shown. Using mass spectrometry, we genotyped and quantified the circulating ApoL1 in two liver transplant recipients whose native APOL1 genotype differed from the genotype of the deceased donors, allowing us to differentiate liver- from nonliver-produced ApoL1. Our findings confirm that the liver is indeed the main source of circulating ApoL1. However, the liver is not the sole source of circulating ApoL1, because we found that residual amounts of native ApoL1 continued to circulate in the blood, even after the liver transplant. PMID- 27932479 TI - Progress in Understanding the Genetics of Calcium-Containing Nephrolithiasis. AB - Renal stone disease is a frequent condition, causing a huge burden on health care systems globally. Calcium-based calculi account for around 75% of renal stone disease and the incidence of these calculi is increasing, suggesting environmental and dietary factors are acting upon a preexisting genetic background. The familial nature and significant heritability of stone disease is known, and recent genetic studies have successfully identified genes that may be involved in renal stone formation. The detection of monogenic causes of renal stone disease has been made more feasible by the use of high-throughput sequencing technologies and has also facilitated the discovery of novel monogenic causes of stone disease. However, the majority of calcium stone formers remain of undetermined genotype. Genome-wide association studies and candidate gene studies implicate a series of genes involved in renal tubular handling of lithogenic substrates, such as calcium, oxalate, and phosphate, and of inhibitors of crystallization, such as citrate and magnesium. Additionally, expression profiling of renal tissues from stone formers provides a novel way to explore disease pathways. New animal models to explore these recently-identified mechanisms and therapeutic interventions are being tested, which hopefully will provide translational insights to stop the growing incidence of nephrolithiasis. PMID- 27932480 TI - MAGI2 Mutations Cause Congenital Nephrotic Syndrome. AB - Steroid-resistant nephrotic syndrome (SRNS), a heterogeneous disorder of the renal glomerular filtration barrier, results in impairment of glomerular permselectivity. Inheritance of genetic SRNS may be autosomal dominant or recessive, with a subset of autosomal recessive SRNS presenting as congenital nephrotic syndrome (CNS). Mutations in 53 genes are associated with human SRNS, but these mutations explain <=30% of patients with hereditary cases and only 20% of patients with sporadic cases. The proteins encoded by these genes are expressed in podocytes, and malfunction of these proteins leads to a universal end point of podocyte injury, glomerular filtration barrier disruption, and SRNS. Here, we identified novel disease-causing mutations in membrane-associated guanylate kinase, WW, and PDZ domain-containing 2 (MAGI2) through whole-exome sequencing of a deeply phenotyped cohort of patients with congenital, childhood onset SRNS. Although MAGI2 has been shown to interact with nephrin and regulate podocyte cytoskeleton and slit diaphragm dynamics, MAGI2 mutations have not been described in human SRNS. We detected two unique frameshift mutations and one duplication in three patients (two families); two siblings shared the same homozygous frameshift mutation, whereas one individual with sporadic SRNS exhibited compound heterozygosity. Two mutations were predicted to introduce premature stop codons, and one was predicted to result in read through of the normal translational termination codon. Immunohistochemistry in kidney sections from these patients revealed that mutations resulted in lack of or diminished podocyte MAGI2 expression. Our data support the finding that mutations in the MAGI2 gene are causal for congenital SRNS. PMID- 27932481 TI - Modeling Monogenic Human Nephrotic Syndrome in the Drosophila Garland Cell Nephrocyte. AB - Steroid-resistant nephrotic syndrome is characterized by podocyte dysfunction. Drosophila garland cell nephrocytes are podocyte-like cells and thus provide a potential in vivo model in which to study the pathogenesis of nephrotic syndrome. However, relevant pathomechanisms of nephrotic syndrome have not been studied in nephrocytes. Here, we discovered that two Drosophila slit diaphragm proteins, orthologs of the human genes encoding nephrin and nephrin-like protein 1, colocalize within a fingerprint-like staining pattern that correlates with ultrastructural morphology. Using RNAi and conditional CRISPR/Cas9 in nephrocytes, we found this pattern depends on the expression of both orthologs. Tracer endocytosis by nephrocytes required Cubilin and reflected size selectivity analogous to that of glomerular function. Using RNAi and tracer endocytosis as a functional read-out, we screened Drosophila orthologs of human monogenic causes of nephrotic syndrome and observed conservation of the central pathogenetic alterations. We focused on the coenzyme Q10 (CoQ10) biosynthesis gene Coq2, the silencing of which disrupted slit diaphragm morphology. Restoration of CoQ10 synthesis by vanillic acid partially rescued the phenotypic and functional alterations induced by Coq2-RNAi. Notably, Coq2 colocalized with mitochondria, and Coq2 silencing increased the formation of reactive oxygen species (ROS). Silencing of ND75, a subunit of the mitochondrial respiratory chain that controls ROS formation independently of CoQ10, phenocopied the effect of Coq2-RNAi. Moreover, the ROS scavenger glutathione partially rescued the effects of Coq2 RNAi. In conclusion, Drosophila garland cell nephrocytes provide a model with which to study the pathogenesis of nephrotic syndrome, and ROS formation may be a pathomechanism of COQ2-nephropathy. PMID- 27932482 TI - PATZ1 down-regulates FADS1 by binding to rs174557 and is opposed by SP1/SREBP1c. AB - The FADS1 and FADS2 genes in the FADS cluster encode the rate-limiting enzymes in the synthesis of long-chain polyunsaturated fatty acids (LC-PUFAs). Genetic variation in this region has been associated with a large number of diseases and traits many of them correlated to differences in metabolism of PUFAs. However, the causative variants leading to these associations have not been identified. Here we find that the multiallelic rs174557 located in an AluYe5 element in intron 1 of FADS1 is functional and lies within a PATZ1 binding site. The derived allele of rs174557, which is the common variant in most populations, diminishes binding of PATZ1, a transcription factor conferring allele-specific downregulation of FADS1. The PATZ1 binding site overlaps with a SP1 site. The competitive binding between the suppressive PATZ1 and the activating complex of SP1 and SREBP1c determines the enhancer activity of this region, which regulates expression of FADS1. PMID- 27932483 TI - Roles and regulations of the ETS transcription factor ELF4/MEF. AB - Most E26 transformation-specific (ETS) transcription factors are involved in the pathogenesis and progression of cancer. This is in part due to the roles of ETS transcription factors in basic biological processes such as growth, proliferation, and differentiation, and also because of their regulatory functions that have physiological relevance in tumorigenesis, immunity, and basal cellular homoeostasis. A member of the E74-like factor (ELF) subfamily of the ETS transcription factor family-myeloid elf-1-like factor (MEF), designated as ELF4 has been shown to be critically involved in immune response and signalling, osteogenesis, adipogenesis, cancer, and stem cell quiescence. ELF4 carries out these functions as a transcriptional activator or through interactions with its partner proteins. Mutations in ELF4 cause aberrant interactions and induce downstream processes that may lead to diseased cells. Knowing how ELF4 impinges on certain cellular processes and how it is regulated in the cells can lead to a better understanding of the physiological and pathological consequences of modulated ELF4 activity. PMID- 27932486 TI - The new junior doctors' contract: an occupational health and safety perspective. PMID- 27932485 TI - Axonal microRNAs: localization, function and regulatory mechanism during axon development. AB - Subcellular localization and translation of messenger RNAs are essential for the regulation of neuronal development and synaptic function. As post-transcriptional regulators, microRNAs (miRNAs) have been emerging as central players in the development and maturation of the nervous system. Recent discoveries reveal the critical functions of miRNAs in the axon of neurons via multiple pathways of molecular regulation. Here, we introduce methods for isolating axonal miRNAs and review recent findings on the localization and function as well as regulatory mechanism of axonal miRNAs during axon development. PMID- 27932484 TI - Role of Mdm2 and Mdmx in DNA repair. AB - Mdm2 and Mdmx are critical regulators of the p53 tumour suppressor and are overexpressed in many human malignancies. However, in recent years, their impact on genome instability was shown to be at least, in part, independent of p53. Both Mdm2 and Mdmx inhibit DNA break repair through their association with the Mre11/Rad50/Nbs1 DNA repair complex. Recent evidence indicates that harnessing Mdm2 and/or Mdmx-mediated inhibition of DNA break repair in cancer cells could provide a therapeutic opportunity, particularly for those malignancies that have lost functional p53. PMID- 27932488 TI - Examining age differences in duration of wage replacement by injury characteristics. AB - BACKGROUND: One explanation for why older age is associated with greater duration of wage replacement following a work-related injury may be that older workers sustain more severe injuries and different types of injury compared with their younger counterparts. AIMS: To examine the role of injury-related characteristics in explaining the impact of age on wage replacement duration, and whether the relationship between age and wage replacement duration is consistent across injury types and levels of severity. METHODS: A secondary analysis of workers' compensation claims in the Australian state of Victoria. In Victoria, only injuries which have accumulated >10 days of wage replacement, or have health care expenditures above a financial threshold, are eligible for compensation. Nested regression models were used to examine the relative contribution of injury related characteristics to age differences in wage replacement duration. RESULTS: Older age was associated with greater days of wage replacement among men and women, even after adjusting for injury characteristics. Adjustment for differences in injury types and compensation reporting practices resulted in moderate attenuation of the age-duration relationship among men and small attenuation among women. The age-duration relationship was consistent across injury types/severity. CONCLUSIONS: The relationship between older age and greater duration of wage replacement is ubiquitous across injuries of different types and severity. Future research is required to understand better why older age is consistently associated with worse compensation outcomes following work related injury. PMID- 27932487 TI - Mortality risk among workers with exposure to dioxins. AB - BACKGROUND: In several studies, dioxin exposure has been associated with increased risk from several causes of death. AIMS: To compare the mortality experience of workers exposed to dioxins during trichlorophenol (TCP) and pentachlorophenol (PCP) production to that of the general population and to examine mortality risk by estimated exposure levels. METHODS: A retrospective cohort study which followed up workers' vital status from 1940 to 2011, with serum surveys to support estimation of historical dioxin exposure levels. RESULTS: Among the 2192 study subjects, there were nine deaths in TCP workers from acute non-lymphatic leukaemia [standardized mortality ratio (SMR) = 2.88, 95% confidence interval (CI) 1.32-5.47], four mesothelioma deaths (SMR = 5.12, 95% CI 1.39-13.10) and four soft tissue sarcoma (STS) deaths (SMR = 3.08, 95% CI 0.84-7.87). In PCP workers, there were eight deaths from non-Hodgkin's lymphoma (SMR = 1.92, 95% CI 0.83-3.79), 150 from ischaemic heart disease (SMR = 1.20, 95% CI 1.01-7.89) and five from stomach ulcers (SMR = 3.38, 95% CI 1.10-7.89). There were no trends of increased mortality with increased dioxin exposure except for STS and 2,3,7,8-tetrachlorodibenzo-p-dioxin levels. This finding for STS should be interpreted with caution due to the small number of deaths and the uncertainty in diagnosis and nosology. CONCLUSIONS: While some causes of death were greater than expected, this study provides little evidence of increased risk when dioxin exposures are considered. PMID- 27932489 TI - Psychometric properties of the Irish Management Standards Indicator Tool. AB - BACKGROUND: Work Positive is Ireland's national policy initiative to control work related stress. Since the introduction of the UK Health and Safety Executive's Management Standards (MS) in 2004, a number of studies have been undertaken to assess the potential adaptation of the MS framework within Ireland. AIMS: To investigate the dimensionality, reliability and validity of the Irish version of the MS Indicator Tool (ROI-MSIT). METHODS: Between February 2011 and June 2014, we collected data from a wide range of public and private sector organizations that used the ROI-MSIT. In addition to the ROI-MSIT, respondents completed the WHO-Five Well-being Index (WHO-5). Exploratory factor analysis (EFA) was used to determine whether the ROI-MSIT maintained the structure of the UK instrument. The internal consistency of the ROI-MSIT was also assessed to determine its reliability, while its criterion-related validity was explored through correlation analysis with the WHO-5. RESULTS: Data were collected from 7377 participants. The factor structure of the ROI-MSIT consisted of six factors; the Demands, Control, Peer Support, Relationships and Role factors were equivalent to the original UK factors. Like the Italian version, a principal factor emerged that combined the Manager Support and Change domains. Cronbach's alpha scores ranged from 0.75 to 0.91. Finally, the ROI-MSIT's subscales and WHO-5 were positively correlated (r = 0.42-0.59, P < 0.001). CONCLUSIONS: The ROI-MSIT is reliable and valid, with a factor structure similar to the original UK instrument and the Italian MSIT. Further psychometric evaluation of the ROI-MSIT is recommended. PMID- 27932490 TI - C-terminus of the P4-ATPase ATP8A2 functions in protein folding and regulation of phospholipid flippase activity. AB - ATP8A2 is a P4-ATPase that flips phosphatidylserine and phosphatidylethanolamine across cell membranes. This generates membrane phospholipid asymmetry, a property important in many cellular processes, including vesicle trafficking. ATP8A2 deficiency causes severe neurodegenerative diseases. We investigated the role of the C-terminus of ATP8A2 in its expression, subcellular localization, interaction with its subunit CDC50A, and function as a phosphatidylserine flippase. C terminal deletion mutants exhibited a reduced tendency to solubilize in mild detergent and exit the endoplasmic reticulum. The solubilized protein, however, assembled with CDC50A and displayed phosphatidylserine flippase activity. Deletion of the C-terminal 33 residues resulted in reduced phosphatidylserine dependent ATPase activity, phosphatidylserine flippase activity, and neurite extension in PC12 cells. These reduced activities were reversed with 60- and 80 residue C-terminal deletions. Unlike the yeast P4-ATPase Drs2, ATP8A2 is not regulated by phosphoinositides but undergoes phosphorylation on the serine residue within a CaMKII target motif. We propose a model in which the C-terminus of ATP8A2 consists of an autoinhibitor domain upstream of the C-terminal 33 residues and an anti-autoinhibitor domain at the extreme C-terminus. The latter blocks the inhibitory activity of the autoinhibitor domain. We conclude that the C-terminus plays an important role in the efficient folding and regulation of ATP8A2. PMID- 27932491 TI - Lipid droplets are central organelles for meiosis II progression during yeast sporulation. AB - Neutral lipids, predominantly triacylglycerol (TAG) and sterol ester, are stored within the cellular organelles termed lipid droplets (LDs). Although it is believed that the major function of LDs is to supply the cell with energy and membranes, little is known about the cellular events directly involving LDs and their contents. In this study, we provide cytological evidence that LDs form direct contacts with the prospore membrane (PSM) that is synthesized de novo during meiosis II to sequester the dividing nuclei in sporulating yeast. Lipidomic analyses indicate that TAG lipolysis releases free fatty acids at a time that correlates well with meiosis II progression, concomitant with phospholipid remodeling. Mutants lacking TAG or impaired of TAG hydrolysis show spore wall assembly defects, supporting a role for TAG and/or its metabolites in spore wall morphogenesis. Not only does LD integrity influence spore wall assembly, LDs are also essential for other aspects of spore development. Yeast cells lacking LDs are severely defective in PSM growth and organization and display disrupted spindles, producing dead spores or even failing to form spores. Together these results link LD physiology directly to a unique membrane morphogenesis process critical for development. PMID- 27932492 TI - Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5-dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics. AB - MARCH5, an OMM-associated E3 ubiquitin ligase, controls mitochondrial function. Despite its importance, the mechanism and factors controlling MARCH5 activity are largely unknown. Here we report that the MARCH5 C-terminal domain plays a critical role in degradation of MARCH5 substrates, likely by facilitating release of ubiquitinated proteins from the OMM. We also found that the mitochondrial fission proteins Drp1 and Mff negatively regulate MARCH5's activity toward MiD49 and Mcl1. Knockouts of either Drp1 or Mff led to reduced expression, shorter half lives, and increased ubiquitination of MiD49 and Mcl1. Effects of Mff and Drp1 depletion on degradation rates and ubiquitination of Mcl1 and MiD49 were eliminated in Drp1-/-/MARCH5-/- and Mff-/-/MARCH5-/- cells. Our data show that it is not mitochondrial morphology per se but rather Mff and Drp1 that directly control MARCH5. Consistently, we find that Mff is an integral component of the MARCH5/p97/Npl4 complex, which is also controlled by MARCH5's C-terminal domain. Furthermore, not only mitochondrial fission but also fusion is regulated through Mff and Drp1 protein activities. Thus, in addition to their canonical roles in mitochondrial fission, Mff and Drp1 also act as regulatory factors that control mitochondrial fission and fusion. PMID- 27932493 TI - PRDM9 interactions with other proteins provide a link between recombination hotspots and the chromosomal axis in meiosis. AB - In mammals, meiotic recombination occurs at 1- to 2-kb genomic regions termed hotspots, whose positions and activities are determined by PRDM9, a DNA-binding histone methyltransferase. We show that the KRAB domain of PRDM9 forms complexes with additional proteins to allow hotspots to proceed into the next phase of recombination. By a combination of yeast-two hybrid assay, in vitro binding, and coimmunoprecipitation from mouse spermatocytes, we identified four proteins that directly interact with PRDM9's KRAB domain, namely CXXC1, EWSR1, EHMT2, and CDYL. These proteins are coexpressed in spermatocytes at the early stages of meiotic prophase I, the limited period when PRDM9 is expressed. We also detected association of PRDM9-bound complexes with the meiotic cohesin REC8 and the synaptonemal complex proteins SYCP3 and SYCP1. Our results suggest a model in which PRDM9-bound hotspot DNA is brought to the chromosomal axis by the action of these proteins, ensuring the proper chromatin and spatial environment for subsequent recombination events. PMID- 27932494 TI - Loss of a doublecortin (DCX)-domain protein causes structural defects in a tubulin-based organelle of Toxoplasma gondii and impairs host-cell invasion. AB - The ~6000 species in phylum Apicomplexa are single-celled obligate intracellular parasites. Their defining characteristic is the apical complex-membranous and cytoskeletal elements at the apical end of the cell that participate in host-cell invasion. The apical complex of Toxoplasma gondii and some other apicomplexans includes a cone-shaped assembly, the conoid, which in T. gondii comprises 14 spirally arranged fibers that are nontubular polymers of tubulin. The tubulin dimers of the conoid fibers make canonical microtubules elsewhere in the same cell, suggesting that nontubulin protein dictates their special arrangement in the conoid fibers. One candidate for this role is TgDCX, which has a doublecortin (DCX) domain and a TPPP/P25-alpha domain, both of which are known modulators of tubulin polymer structure. Loss of TgDCX radically disrupts the structure of the conoid, severely impairs host-cell invasion, and slows growth. Both the conoid structural defects and the impaired invasion of TgDCX-null parasites are corrected by reintroduction of a TgDCX coding sequence. The nontubular polymeric form of tubulin found in the conoid is not found in the host cell, suggesting that TgDCX may be an attractive target for new parasite-specific chemotherapeutic agents. PMID- 27932495 TI - Modulations of SIR-nucleosome interactions of reconstructed yeast silent pre heterochromatin by O-acetyl-ADP-ribose and magnesium. AB - Yeast silent heterochromatin provides an excellent model with which to study epigenetic inheritance. Previously we developed an in vitro assembly system to demonstrate the formation of filament structures with requirements that mirror yeast epigenetic gene silencing in vivo. However, the properties of these filaments were not investigated in detail. Here we show that the assembly system requires Sir2, Sir3, Sir4, nucleosomes, and O-acetyl-ADP-ribose. We also demonstrate that all Sir proteins and nucleosomes are components of these filaments to prove that they are SIR-nucleosome filaments. Furthermore, we show that the individual localization patterns of Sir proteins on the SIR-nucleosome filament reflect those patterns on telomeres in vivo. In addition, we reveal that magnesium exists in the SIR-nucleosome filament, with a role similar to that for chromatin condensation. These results suggest that a small number of proteins and molecules are sufficient to mediate the formation of a minimal yeast silent pre heterochromatin in vitro. PMID- 27932496 TI - Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons. AB - Mitochondria are essential organelles whose biogenesis, structure, and function are regulated by many signaling pathways. We present evidence that, in hippocampal neurons, activation of the Sonic hedgehog (Shh) signaling pathway affects multiple aspects of mitochondria. Mitochondrial mass was increased significantly in neurons treated with Shh. Using biochemical and fluorescence imaging analyses, we show that Shh signaling activity reduces mitochondrial fission and promotes mitochondrial elongation, at least in part, via suppression of the mitochondrial fission protein dynamin-like GTPase Drp1. Mitochondria from Shh-treated neurons were more electron-dense, as revealed by electron microscopy, and had higher membrane potential and respiratory activity. We further show that Shh protects neurons against a variety of stresses, including the mitochondrial poison rotenone, amyloid beta-peptide, hydrogen peroxide, and high levels of glutamate. Collectively our data suggest a link between Shh pathway activity and the physiological properties of mitochondria in hippocampal neurons. PMID- 27932497 TI - Intraflagellar transport-A complex mediates ciliary entry and retrograde trafficking of ciliary G protein-coupled receptors. AB - Cilia serve as cellular antennae where proteins involved in sensory and developmental signaling, including G protein-coupled receptors (GPCRs), are specifically localized. Intraflagellar transport (IFT)-A and -B complexes mediate retrograde and anterograde ciliary protein trafficking, respectively. Using a visible immunoprecipitation assay to detect protein-protein interactions, we show that the IFT-A complex is divided into a core subcomplex, composed of IFT122/IFT140/IFT144, which is associated with TULP3, and a peripheral subcomplex, composed of IFT43/IFT121/IFT139, where IFT139 is most distally located. IFT139-knockout (KO) and IFT144-KO cells demonstrated distinct phenotypes: IFT139-KO cells showed the accumulation of IFT-A, IFT-B, and GPCRs, including Smoothened and GPR161, at the bulged ciliary tips; IFT144-KO cells showed failed ciliary entry of IFT-A and GPCRs and IFT-B accumulation at the bulged tips. These observations demonstrate the distinct roles of the core and peripheral IFT-A subunits: IFT139 is dispensable for IFT-A assembly but essential for retrograde trafficking of IFT-A, IFT-B, and GPCRs; in contrast, IFT144 is essential for functional IFT-A assembly and ciliary entry of GPCRs but dispensable for anterograde IFT-B trafficking. Thus the data presented here demonstrate that the IFT-A complex mediates not only retrograde trafficking but also entry into cilia of GPCRs. PMID- 27932498 TI - Harnessing molecular motors for nanoscale pulldown in live cells. AB - Protein-protein interactions (PPIs) regulate assembly of macromolecular complexes, yet remain challenging to study within the native cytoplasm where they normally exert their biological effect. Here we miniaturize the concept of affinity pulldown, a gold-standard in vitro PPI interrogation technique, to perform nanoscale pulldowns (NanoSPDs) within living cells. NanoSPD hijacks the normal process of intracellular trafficking by myosin motors to forcibly pull fluorescently tagged protein complexes along filopodial actin filaments. Using dual-color total internal reflection fluorescence microscopy, we demonstrate complex formation by showing that bait and prey molecules are simultaneously trafficked and actively concentrated into a nanoscopic volume at the tips of filopodia. The resulting molecular traffic jams at filopodial tips amplify fluorescence intensities and allow PPIs to be interrogated using standard epifluorescence microscopy. A rigorous quantification framework and software tool are provided to statistically evaluate NanoSPD data sets. We demonstrate the capabilities of NanoSPD for a range of nuclear and cytoplasmic PPIs implicated in human deafness, in addition to dissecting these interactions using domain mapping and mutagenesis experiments. The NanoSPD methodology is extensible for use with other fluorescent molecules, in addition to proteins, and the platform can be easily scaled for high-throughput applications. PMID- 27932499 TI - Genetic Variation in One-Carbon Metabolism and Changes in Metabolic Parameters in First-Episode Schizophrenia Patients. AB - Background: In this study, we aimed to investigate the effects of polymorphisms in genes encoding 1-carbon metabolism enzymes on differential development of metabolic parameters during 12 weeks of treatment with second-generation antipsychotics in first-episode schizophrenia patients. Methods: The following polymorphisms in 1-carbon metabolism genes were genotyped: MTHFR (C677T and A1298C), MTHFD1 (G1958A), MTRR (A66G), and BHMT (G742A). A broad panel of metabolic parameters including body mass index, waist circumference, total cholesterol low and high density lipoproteins, triglycerides, homocysteine, folate, and vitamin B12 was determined. Results: There was a significant effect of the interaction between the MTHFR C677T polymorphism and time on body mass index and waist circumference in the allelic and genotype analyses. Indeed, patients with the MTHFR 677CC genotype had higher increase in body mass index and waist circumference compared with other corresponding genotypes or the MTHFR 677T allele carriers (CT and TT genotypes). In addition, patients with the MTHFR 677TT genotype had higher waist circumference in all time points. Similarly, patients with the MTHFR 677TT genotype had higher body mass index in all time points, but this effect was not significant after correction for multiple testing. Conclusions: Our results indicate that the MTHFR C677T polymorphism may predict antipsychotic-induced weight gain. Effects of the MTHFR C677T polymorphism might be different in initial exposure to antipsychotics compared with long-term perspective. PMID- 27932500 TI - NOTCH1 and NOTCH2 regulate epithelial cell proliferation in mouse and human gastric corpus. AB - : The Notch signaling pathway is known to regulate stem cells and epithelial cell homeostasis in gastrointestinal tissues; however, Notch function in the corpus region of the stomach is poorly understood. In this study we examined the consequences of Notch inhibition and activation on cellular proliferation and differentiation and defined the specific Notch receptors functioning in the mouse and human corpus. Notch pathway activity was observed in the mouse corpus epithelium, and gene expression analysis revealed NOTCH1 and NOTCH2 to be the predominant Notch receptors in both mouse and human. Global Notch inhibition for 5 days reduced progenitor cell proliferation in the mouse corpus, as well as in organoids derived from mouse and human corpus tissue. Proliferation effects were mediated through both NOTCH1 and NOTCH2 receptors, as demonstrated by targeting each receptor alone or in combination with Notch receptor inhibitory antibodies. Analysis of differentiation by marker expression showed no change to the major cell lineages; however, there was a modest increase in the number of transitional cells coexpressing markers of mucous neck and chief cells. In contrast to reduced proliferation after pathway inhibition, Notch activation in the adult stomach resulted in increased proliferation coupled with reduced differentiation. These findings suggest that NOTCH1 and NOTCH2 signaling promotes progenitor cell proliferation in the mouse and human gastric corpus, which is consistent with previously defined roles for Notch in promoting stem and progenitor cell proliferation in the intestine and antral stomach. NEW & NOTEWORTHY: Here we demonstrate that the Notch signaling pathway is essential for proliferation of stem cells in the mouse and human gastric corpus. We identify NOTCH1 and NOTCH2 as the predominant Notch receptors expressed in both mouse and human corpus and show that both receptors are required for corpus stem cell proliferation. We show that chronic Notch activation in corpus stem cells induces hyperproliferation and tissue hypertrophy, suggesting that Notch may drive gastric tumorigenesis. PMID- 27932501 TI - Molecular mechanism(s) involved in differential expression of vitamin C transporters along the intestinal tract. AB - Mammalian cells utilize two transporters for the uptake of ascorbic acid (AA), Na+-dependent vitamin C transporter SVCT-1 and SVCT-2. In the intestine, these transporters are involved in AA absorption and are expressed at the apical and basolateral membrane domains of the polarized epithelia, respectively. Little is known about the differential expression of these two transporters along the anterior-posterior axis of the intestinal tract and the molecular mechanism(s) that dictate this pattern of expression. We used mouse and human intestinal cDNAs to address these issues. The results showed a significantly lower rate of carrier mediated AA uptake by mouse colon than jejunum. This was associated with a significantly lower level of expression of SVCT-1 and SVCT-2 at the protein, mRNA, and heterogeneous nuclear RNA (hnRNA) levels in the colon than the jejunum, implying the involvement of transcriptional mechanism(s). Similarly, expression levels of SVCT-1 and SVCT-2 mRNA and hnRNA were significantly lower in human colon. We also examined the levels of expression of hepatocyte nuclear factor 1alpha and specificity protein 1, which drive transcription of the Slc23a1 and Slc23a2 promoters, respectively, and found them to be markedly lower in the colon. Furthermore, significantly lower levels of the activating markers for histone (H3) modifications [H3 trimethylation of lysine 4 (H3K4me3) and H3 triacetylation of lysine 9 (H3K9ac)] were observed in the Slc23a1 and Slc23a2 promoters in the colon. These findings show, for the first time, that SVCT-1 and SVCT-2 are differentially expressed along the intestinal tract and that this pattern of expression is, at least in part, mediated via transcriptional/epigenetic mechanisms.NEW & NOTEWORTHY Our findings show, for the first time, that transporters of the water-soluble vitamin ascorbic acid (i.e., the vitamin C transporters SVCT-1 and SVCT-2) are differentially expressed along the length of the intestinal tract and that the pattern of expression is mediated, at least in part, by transcriptional and epigenetic mechanism(s) affecting both Slc23a1 and Slc23a2 genes. PMID- 27932502 TI - Ca2+/calmodulin/MLCK pathway initiates, and RhoA/ROCK maintains, the internal anal sphincter smooth muscle tone. PMID- 27932503 TI - Computational modeling of epithelial fluid and ion transport in the parotid duct after transfection of human aquaporin-1. AB - : Previous studies have shown that localized delivery of the aquaporin-1 (AQP1) gene to the parotid duct can restore saliva flow in minipigs following irradiation-induced salivary hypofunction. The resulting flow rate and electrochemistry of secreted saliva contradicts current understanding of ductal fluid transport. We hypothesized that changes in expression of ion transport proteins have occurred following AQP1 transfection. We use a mathematical model of ion and fluid transport across the parotid duct epithelial cells to predict the expression profile of ion transporters that are consistent with the experimental measurements of saliva composition and secretion rates. Using a baseline set of parameters, the model reproduces the data for the irradiated, non AQP1-transfected case. We propose three scenarios which may have occurred after transfection, which differ in the location of the AQP1 gene. The first scenario places AQP1 within nonsecretory cells, and requires that epithelial sodium channel (ENaC) expression is greatly reduced (1.3% of baseline), and ductal bicarbonate concentration is increased from 40.6 to 137.0 mM, to drive water secretion into the duct. The second scenario introduces the AQP1 gene into all ductal cells. The final scenario has AQP1 primarily in the proximal duct cells which secrete water under baseline conditions. We find the change in the remaining cells includes a 95.8% reduction in ENaC expression, enabling us to reproduce all experimental ionic concentrations within 9 mM. These findings provide a mechanistic basis for the observations and will guide the further development of gene transfer therapy for salivary hypofunction. NEW & NOTEWORTHY: Following transfection of aquaporin into the parotid ducts of minipigs with salivary hypofunction, the resulting increase in salivary flow rates contradicts current understanding of ductal fluid transport. We show that the change in saliva electrochemistry and flow rate can be explained by changes in expression of ion transporters in the ductal cell membranes, using a mathematical model replicating a single parotid duct. PMID- 27932504 TI - Expression of Cav1.3 calcium channel in the human and mouse colon: posttranscriptional inhibition by IFNgamma. AB - It has been hypothesized that apically expressed L-type Ca2+ channel Cav1.3 (encoded by CACNA1D gene) contributes toward an alternative TRPV6-independent route of intestinal epithelial Ca2+ absorption, especially during digestion when high luminal concentration of Ca2+ and other nutrients limit TRPV6 contribution. We and others have implicated altered expression and activity of key mediators of intestinal and renal Ca2+ (re)absorption as contributors to negative systemic Ca2+ balance and bone loss in intestinal inflammation. Here, we investigated the effects of experimental colitis and related inflammatory mediators on colonic Cav1.3 expression. We confirmed Cav1.3 expression within the segments of the mouse and human gastrointestinal tract. Consistent with available microarray data (GEO database) from inflammatory bowel disease (IBD) patients, mouse colonic expression of Cav1.3 was significantly reduced in trinitrobenzene sulfonic acid (TNBS) colitis. In vitro, IFNgamma most potently reduced Cav1.3 expression. We reproduced these findings in vivo with wild-type and Stat1-/- mice injected with IFNgamma. The observed effect in Stat1-/- suggested a noncanonical transcriptional repression or a posttranscriptional mechanism. In support of the latter, we observed no effect on the cloned Cav1.3 gene promoter activity and accelerated Cav1.3 mRNA decay rate in IFNgamma-treated HCT116 cells. While the relative contribution of Cav1.3 to intestinal Ca2+ absorption and its value as a therapeutic target remain to be established, we postulate that Cav1.3 downregulation in IBD may contribute to the negative systemic Ca2+ balance, to increased bone resorption, and to reduced bone mineral density in IBD patients. PMID- 27932505 TI - Diagnostic Accuracy of T1-Weighted Dynamic Contrast-Enhanced-MRI and DWI-ADC for Differentiation of Glioblastoma and Primary CNS Lymphoma. AB - BACKGROUND AND PURPOSE: Glioblastoma and primary CNS lymphoma dictate different neurosurgical strategies; it is critical to distinguish them preoperatively. However, current imaging modalities do not effectively differentiate them. We aimed to examine the use of DWI and T1-weighted dynamic contrast-enhanced-MR imaging as potential discriminative tools. MATERIALS AND METHODS: We retrospectively reviewed 18 patients with primary CNS lymphoma and 36 matched patients with glioblastoma with pretreatment DWI and dynamic contrast-enhanced-MR imaging. VOIs were drawn around the tumor on contrast-enhanced T1WI and FLAIR images; these images were transferred onto coregistered ADC maps to obtain the ADC and onto dynamic contrast-enhanced perfusion maps to obtain the plasma volume and permeability transfer constant. Histogram analysis was performed to determine the mean and relative ADCmean and relative 90th percentile values for plasma volume and the permeability transfer constant. Nonparametric tests were used to assess differences, and receiver operating characteristic analysis was performed for optimal threshold calculations. RESULTS: The enhancing component of primary CNS lymphoma was found to have significantly lower ADCmean (1.1 * 10-3 versus 1.4 * 10-3; P < .001) and relative ADCmean (1.5 versus 1.9; P < .001) and relative 90th percentile values for plasma volume (3.7 versus 5.0; P < .05) than the enhancing component of glioblastoma, but not significantly different relative 90th percentile values for the permeability transfer constant (5.4 versus 4.4; P = .83). The nonenhancing portions of glioblastoma and primary CNS lymphoma did not differ in these parameters. On the basis of receiver operating characteristic analysis, mean ADC provided the best threshold (area under the curve = 0.83) to distinguish primary CNS lymphoma from glioblastoma, which was not improved with normalized ADC or the addition of perfusion parameters. CONCLUSIONS: ADC was superior to dynamic contrast-enhanced-MR imaging perfusion, alone or in combination, in differentiating primary CNS lymphoma from glioblastoma. PMID- 27932506 TI - Synthetic MRI in the Detection of Multiple Sclerosis Plaques. AB - BACKGROUND AND PURPOSE: Synthetic MR imaging enables the creation of various contrast-weighted images including double inversion recovery and phase-sensitive inversion recovery from a single MR imaging quantification scan. Here, we assessed whether synthetic MR imaging is suitable for detecting MS plaques. MATERIALS AND METHODS: Quantitative and conventional MR imaging data on 12 patients with MS were retrospectively analyzed. Synthetic T2-weighted, FLAIR, double inversion recovery, and phase-sensitive inversion recovery images were produced after quantification of T1 and T2 values and proton density. Double inversion recovery images were optimized for each patient by adjusting the TI. The number of visible plaques was determined by a radiologist for a set of these 4 types of synthetic MR images and a set of conventional T1-weighted inversion recovery, T2-weighted, and FLAIR images. Conventional 3D double inversion recovery and other available images were used as the criterion standard. The total acquisition time of synthetic MR imaging was 7 minutes 12 seconds and that of conventional MR imaging was 6 minutes 29 seconds The lesion-to-WM contrast and lesion-to-WM contrast-to-noise ratio were calculated and compared between synthetic and conventional double inversion recovery images. RESULTS: The total plaques detected by synthetic and conventional MR images were 157 and 139, respectively (P = .014). The lesion-to-WM contrast and contrast-to-noise ratio on synthetic double inversion recovery images were superior to those on conventional double inversion recovery images (P = .001 and < 0.001, respectively). CONCLUSIONS: Synthetic MR imaging enabled detection of more MS plaques than conventional MR imaging in a comparable acquisition time. The contrast for MS plaques on synthetic double inversion recovery images was better than on conventional double inversion recovery images. PMID- 27932507 TI - The "White Gray Sign" Identifies the Central Sulcus on 3T High-Resolution T1 Weighted Images. AB - BACKGROUND AND PURPOSE: The central sulcus is an important anatomic landmark, but most methods of identifying it rely on variable gyral and sulcal patterns. We describe and assess the accuracy of reduced gray-white contrast along the central sulcus, an observation we term the "white gray sign." MATERIALS AND METHODS: We conducted a retrospective review of 51 fMRIs with a T1-weighted 3D inversion recovery fast-spoiled gradient-echo and concomitant hand-motor fMRI, which served as confirmation for the location of the central sulcus. To measure gray-white contrast across the central and adjacent sulci, we performed a quantitative analysis of 25 normal hemispheres along the anterior and posterior cortices and intervening white matter of the pre- and postcentral gyri. 3D inversion recovery fast-spoiled gradient-echo axial images from 51 fMRIs were then evaluated by 2 raters for the presence of the white gray sign as well as additional established signs of the central sulcus: the bracket, cortical thickness, omega, and T signs. RESULTS: The mean gray-white contrast along the central sulcus was 0.218 anteriorly and 0.237 posteriorly, compared with 0.320 and 0.295 along the posterior precentral and anterior postcentral sulci, respectively (P < .001). Both raters correctly identified the central sulcus in all 35 normal and 16 abnormal hemispheres. The white gray sign had the highest agreement of all signs between raters and was rated as present the most often among all the signs. CONCLUSIONS: Reduced gray-white contrast around the central sulcus is a reliable sign for identification of the central sulcus on 3D inversion recovery fast spoiled gradient-echo images. PMID- 27932508 TI - First-Line Use of Core Needle Biopsy for High-Yield Preliminary Diagnosis of Thyroid Nodules. AB - BACKGROUND AND PURPOSE: Although core needle biopsy was introduced as a diagnostic alternative to fine-needle aspiration, the utility and safety of core needle biopsy for thyroid nodules in a large population has yet to be studied comprehensively. We evaluate core needle biopsy yields on a large-scale basis to investigate its potential in the preliminary diagnosis of thyroid nodules. MATERIALS AND METHODS: Between March 2005 and December 2013, 2448 initially detected thyroid nodules from 2120 consecutive patients who underwent core needle biopsy were retrospectively evaluated. Of these, 72 thyroid nodules from 63 patients were excluded due to prior fine-needle aspiration attempts. The inconclusive and conclusive result rates, diagnostic accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and unnecessary surgery rate of core needle biopsy were evaluated. RESULTS: With core needle biopsy as the first-line method, the inconclusive result rate was 11.9% (283/2376) and the conclusive result rate was 88.1% (2093/2376). The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of core needle biopsy for the diagnosis of malignancy were 96.7% (1160/1200), 89.7% (347/387), 100% (813/813), 100% (347/347), and 95.3% (813/853), respectively. There were no major complications and 12 minor complications. CONCLUSIONS: We have demonstrated that first-line use of core needle biopsy may well improve diagnostic accuracy in thyroid nodules, reducing inconclusive or false-negative results and unnecessary operations. Such benefits underscore the promising role of core needle biopsy in managing thyroid nodules and optimizing related surgical decision-making. PMID- 27932509 TI - Use of Phase-Contrast MRA to Assess Intracranial Venous Sinus Resistance to Drainage in Healthy Individuals. AB - BACKGROUND AND PURPOSE: Resistance to blood flow in the cerebral drainage system may affect cerebral hemodynamics. The objective of the present study was to use phase-contrast MRA to quantify resistance to drainage of blood across branches of the venous sinus tree and to determine whether the resistance to drainage values correlated with internal jugular vein outflows. MATERIALS AND METHODS: We performed whole-head phase-contrast MRA and 2D phase-contrast MR imaging in 31 healthy volunteers. Vascular segmentation was applied to the angiograms, and the internal jugular vein velocities were quantified from the flow images. Resistance to drainage across branches of the venous sinus tree was calculated from the segmented angiograms, by using the Poiseuille equation for laminar flow. Correlations between the values of resistance to drainage and internal jugular vein outflow measurements were assessed by using the Spearman rho. RESULTS: The overall mean resistance to drainage of the venous sinus tree was 24 +/- 7 Pa s/cm3. The mean resistance to drainage of the right side of the venous sinus tree was 42% lower than that of the left side (P < .001). There were negative correlations between the values of resistance to drainage and internal jugular vein outflows on both the left side of the venous sinus tree (R = -0.551, P = .002) and the right side (R = -0.662, P < .001). CONCLUSIONS: Phase-contrast MRA is a noninvasive means of calculating the resistance to drainage of blood across the venous sinus tree. Our approach for resistance to drainage quantification may be of value in understanding alterations in the cerebral venous sinus drainage system. PMID- 27932511 TI - Ascending and Descending Thoracic Vertebral Arteries. AB - Thoracic vertebral arteries are anastomotic chains similar to cervical vertebral arteries but found at the thoracic level. Descending thoracic vertebral arteries originate from the pretransverse segment of the cervical vertebral artery and curve caudally to pass into the last transverse foramen or the first costotransverse space. Ascending thoracic vertebral arteries originate from the aorta, pass through at least 1 costotransverse space, and continue cranially as the cervical vertebral artery. This report describes the angiographic anatomy and clinical significance of 9 cases of descending and 2 cases of ascending thoracic vertebral arteries. Being located within the upper costotransverse spaces, ascending and descending thoracic vertebral arteries can have important implications during spine interventional or surgical procedures. Because they frequently provide radiculomedullary or bronchial branches, they can also be involved in spinal cord ischemia, supply vascular malformations, or be an elusive source of hemoptysis. PMID- 27932510 TI - Embolization of Intracranial Dural Arteriovenous Fistulas Using PHIL Liquid Embolic Agent in 26 Patients: A Multicenter Study. AB - BACKGROUND AND PURPOSE: The introduction of liquid embolic agents has revolutionized endovascular approach to cranial vascular malformations. The aim of the study was to retrospectively assess the efficacy and safety of Precipitating Hydrophobic Injectable Liquid (PHIL), a new nonadhesive liquid embolic agent, in the treatment of patients with cranial dural arteriovenous fistulas. The primary end point was the rate of complete occlusion of dural arteriovenous fistulas. Secondary end points included the incidence of adverse events and clinical status at 3-month follow-up. MATERIALS AND METHODS: This was a retrospective multicenter study. Twenty-six consecutive patients with dural arteriovenous fistulas (de novo or previously treated) treated by injection of PHIL only or with PHIL in combination with other embolization products (such as Onyx or detachable coils) were included in the study. Recruitment started in August 2014 and ended in September 2015. RESULTS: Twenty-two (85%) patients were treated with PHIL only, with 3 patients treated with both PHIL and Onyx, and 1, with both PHIL and coils. Immediate complete angiographic occlusion was achieved in 20 (77%) patients. Of the 6 patients with residual fistulas, 3 were retreated with PHIL and 1 achieved angiographic cure. An adverse event was seen in 1 patient who developed worsening of preexisting ataxia due to acute thrombosis of the draining vein. CONCLUSIONS: PHIL appears to be safe and effective for endovascular treatment of cranial dural arteriovenous fistulas. Short-term angiographic and clinical results are comparable with those of Onyx, with the added advantage of easier preparation and improved homogeneous cast visualization. The use of iodine as a radio-opacifier also produces considerably less artifacts on CT compared with tantalum-based embolic materials. PMID- 27932512 TI - ATF6 Decreases Myocardial Ischemia/Reperfusion Damage and Links ER Stress and Oxidative Stress Signaling Pathways in the Heart. AB - RATIONALE: Endoplasmic reticulum (ER) stress causes the accumulation of misfolded proteins in the ER, activating the transcription factor, ATF6 (activating transcription factor 6 alpha), which induces ER stress response genes. Myocardial ischemia induces the ER stress response; however, neither the function of this response nor whether it is mediated by ATF6 is known. OBJECTIVE: Here, we examined the effects of blocking the ATF6-mediated ER stress response on ischemia/reperfusion (I/R) in cardiac myocytes and mouse hearts. METHODS AND RESULTS: Knockdown of ATF6 in cardiac myocytes subjected to I/R increased reactive oxygen species and necrotic cell death, both of which were mitigated by ATF6 overexpression. Under nonstressed conditions, wild-type and ATF6 knockout mouse hearts were similar. However, compared with wild-type, ATF6 knockout hearts showed increased damage and decreased function after I/R. Mechanistically, gene array analysis showed that ATF6, which is known to induce genes encoding ER proteins that augment ER protein folding, induced numerous oxidative stress response genes not previously known to be ATF6-inducible. Many of the proteins encoded by the ATF6-induced oxidative stress genes identified here reside outside the ER, including catalase, which is known to decrease damaging reactive oxygen species in the heart. Catalase was induced by the canonical ER stressor, tunicamycin, and by I/R in cardiac myocytes from wild-type but not in cardiac myocytes from ATF6 knockout mice. ER stress response elements were identified in the catalase gene and were shown to bind ATF6 in cardiac myocytes, which increased catalase promoter activity. Overexpression of catalase, in vivo, restored ATF6 knockout mouse heart function to wild-type levels in a mouse model of I/R, as did adeno-associated virus 9-mediated ATF6 overexpression. CONCLUSIONS: ATF6 serves an important role as a previously unappreciated link between the ER stress and oxidative stress gene programs, supporting a novel mechanism by which ATF6 decreases myocardial I/R damage. PMID- 27932513 TI - Improving Incidence of Postoperative Atrial Fibrillation After Cardiac Surgery Using Simplified Clinical Practice Guidelines. AB - OBJECTIVES: Postoperative atrial fibrillation (POAF) remains a major risk after cardiac surgery. Twelve percent patients admitted to this unit postcardiac surgery experienced POAF, which led to hemodynamic instability, increased risk of stroke, and increased length of postoperative intensive care unit stay. Our aim was to decrease the incidence of POAF in the cardiothoracic intensive care unit by the end of April 2014. METHODS: Design-Retrospective data analysis. Settings Postcardiac surgery intensive care in a tertiary hospital. PARTICIPANTS: Postcardiac surgery patients. Intervention-A clinical practice guideline (CPG) was developed to promote early prevention and to improve adherence to POAF prophylaxis recommendations. Patient's charts were our key performance indicator. Primary outcome measure-Percentage of patients who developed episodes of POAF within the first 24 hours of cardiac surgery. Process measures-compliance with the newly developed CPG and early postoperative patient assessment. Balance measure-early administration of beta-blocker. RESULTS: We were able to decrease POAF to 8% after intervention. Compliance with early assessment improved from 25% to 87%. Compliance with adherence to the CPG was 80%. Adherence to the newly developed paper form was the major challenge that could be overcome by an electronic form. We hope to decrease the incidence of POAF to 6% and develop an electronic form by the end of December 2014. CONCLUSION: This quality improvement project changed the strategy and succeeded in decreasing the incidence of POAF after cardiac surgery. It also improved early assessment of risk factors. PMID- 27932514 TI - Long-Term Therapy With Wu-Ling-San, a Popular Antilithic Chinese Herbal Formula, Did Not Prevent Subsequent Stone Surgery: A Nationwide Population-Based Cohort Study. AB - Traditional Chinese herbal medicine (CHM), which is widely used to treat pain and urolithiasis, is a promising therapy for urinary stone prevention. This study investigated the clinical efficacy of a popular CHM, Wu-Ling-San (WLS), in Taiwan for the prophylaxis of recurrent nephrolithiasis as assessed by surgical stone treatment via a nationwide population-based cohort study. The National Health Insurance Research Database, 2000-2010, which included one million patient records. All patients diagnosed with stone disease at the beginning of the study. The matched controls (4-fold the number of WLS patients) were stone patients who did not take WLS. Data analysis included the stone surgeries following the first treatment. We enrolled 11 900 patients with stone disease, and the incidence of stone patients in this database was 1.19%. The prevalence of comorbidities such as benign prostate hyperplasia, chronic kidney disease, diabetes mellitus, and urinary tract infection, but not hypertension, was significantly higher in WLS users. Several patients in both groups were prescribed potassium citrate. The stone treatment rate was significantly higher in WLS users (17.85%) than in the non-WLS users (14.47%). WLS users with an associated comorbidity had a higher treatment rate than the non-WLS users: 21.05% versus 16.70%, respectively. The surgery rate for upper urinary tract stones was higher in WLS users than in the non-WLS users (adjusted hazard ratio, 1.28; 95% confidence interval, 1.08-1.52; P < .05). The stone treatment rate (52.79%) was significantly higher in patients who used a very high amount of WLS (adjusted hazard ratio, 3.02; 95% confidence interval, 2.30-3.98). Stone patients using a high amount of WLS use had a high stone surgical rate. Long-term therapy with WLS did not have a preventive effect on stone surgical treatment. Long-term potassium citrate therapy as a preventive measure appeared to be underutilized in this study. PMID- 27932515 TI - Genotoxic effect of iron overload and disease complications in transfused beta thalassaemic patients. AB - In previously reported studies, we observed significantly high genotoxicity biomarkers in regularly transfused thalassaemic patients, thus, in this study, we better investigated the genotoxic effect of iron overload and of thalassaemia complications, including their drug treatments. The assessment was performed in 64 regularly transfused thalassaemic patients using cytokinesis-block micronucleus and comet assays. All patients were splenectomised and undergoing iron chelation therapy. To reduce hypoxia-induced oxidative damage, the patients with haemoglobin levels <9.5 g/dL were excluded. Serum concentrations of ferritin, iron, transferrin and the percentage of transferrin saturation, as well as cardiac and hepatic T2* magnetic resonance imaging, were considered to evaluate serum and organ siderosis.All genotoxic biomarkers significantly differed between patients and healthy subjects. Iron intake via blood transfusions was inversely related to percentage of DNA in tail. The disease complications affecting endpoints were active Hepatitis C virus infection, drug therapy for osteoporosis (i.e. bisphosphonates) and hormone replacement therapy for hypogonadism.The results, highlighting the combined effect of iron overload and, mainly, disease complications, including their respective pharmacological treatments, confirmed the increased cancer risk in thalassaemic patients. PMID- 27932516 TI - Global analysis of regulatory divergence in the evolution of mouse alternative polyadenylation. AB - Alternative polyadenylation (APA), which is regulated by both cis-elements and trans-factors, plays an important role in post-transcriptional regulation of eukaryotic gene expression. However, comparing to the extensively studied transcription and alternative splicing, the extent of APA divergence during evolution and the relative cis- and trans-contribution remain largely unexplored. To directly address these questions for the first time in mammals, by using deep sequencing-based methods, we measured APA divergence between C57BL/6J and SPRET/EiJ mouse strains as well as allele-specific APA pattern in their F1 hybrids. Among the 24,721 polyadenylation sites (pAs) from 7,271 genes expressing multiple pAs, we identified 3,747 pAs showing significant divergence between the two strains. After integrating the allele-specific data from F1 hybrids, we demonstrated that these events could be predominately attributed to cis regulatory effects. Further systematic sequence analysis of the regions in proximity to cis-divergent pAs revealed that the local RNA secondary structure and a poly(U) tract in the upstream region could negatively modulate the pAs usage. PMID- 27932518 TI - Epoetin-beta induced pure red cell aplasia: an unintended consequence. AB - Pure red cell aplasia is a rare condition associated with the use of recombinant human erythropoietin preparations. It has predominantly been associated with the subcutaneous use of a particular epoetin-alpha product, Eprex, and is rarely associated with intravenous use or with other commercially available products. Only a few cases of pure red cell aplasia secondary to epoetin-beta have been reported. On account of its rarity, the condition can often be missed on initial presentation, leading to unnecessary investigations and delayed diagnosis. A high index of suspicion is required for timely diagnosis and proper management. We present a case of severe anaemia secondary to the subcutaneous use of epoetin beta (Recormon) and briefly discuss the pathogenesis, diagnosis and management. PMID- 27932517 TI - Allergin-1 inhibits TLR2-mediated mast cell activation and suppresses dermatitis. AB - TLR2 recognizes cell wall components of Staphylococcus aureus, which colonizes >90% of atopic eczematous skin lesions. The regulatory mechanisms of TLR2 signaling in the skin remain unclear. Allergin-1, an inhibitory immunoglobulin like receptor containing an ITIM, is expressed on mast cells (MCs) and inhibits IgE-mediated anaphylaxis in mice. Here, we show that Allergin-1 inhibits TLR2 mediated activation of, and inflammatory cytokine production by, MCs in vitro Compared with wild-type mice, Allergin-1-deficient mice showed enhanced ear swelling with enhanced collagen deposition and greater Ly6G+ neutrophil recruitment after intra-dermal injection of Pam2CSK4 into pinnae. Using Mas-TRECK mice, which is an MC deletion system based on il4 enhancer elements, we also demonstrated that Allergin-1 on MCs is responsible for the Pam2CSK4-induced ear swelling. These results suggest that Allergin-1 on skin MCs suppresses TLR2 induced dermatitis. PMID- 27932519 TI - Host Plants Indirectly Influence Plant Virus Transmission by Altering Gut Cysteine Protease Activity of Aphid Vectors. AB - The green peach aphid, Myzus persicae, is a vector of the Potato leafroll virus (PLRV, Luteoviridae), transmitted exclusively by aphids in a circulative manner. PLRV transmission efficiency was significantly reduced when a clonal lineage of M. persicae was reared on turnip as compared with the weed physalis, and this was a transient effect caused by a host-switch response. A trend of higher PLRV titer in physalis-reared aphids as compared with turnip-reared aphids was observed at 24 h and 72 h after virus acquisition. The major difference in the proteomes of these aphids was the up-regulation of predicted lysosomal enzymes, in particular the cysteine protease cathepsin B (cathB), in aphids reared on turnip. The aphid midgut is the site of PLRV acquisition, and cathB and PLRV localization were starkly different in midguts of the aphids reared on the two host plants. In viruliferous aphids that were reared on turnip, there was near complete colocalization of cathB and PLRV at the cell membranes, which was not observed in physalis-reared aphids. Chemical inhibition of cathB restored the ability of aphids reared on turnip to transmit PLRV in a dose-dependent manner, showing that the increased activity of cathB and other cysteine proteases at the cell membrane indirectly decreased virus transmission by aphids. Understanding how the host plant influences virus transmission by aphids is critical for growers to manage the spread of virus among field crops. PMID- 27932521 TI - Adapting an HIV Risk Reduction Curriculum: Processes and Outcomes. AB - Becoming a Responsible Teen (BART) is a community-based, HIV risk reduction curriculum shown to increase safer sex behaviors among African American adolescents. However, BART does not address common barriers to sexual health care access, which may limit program efficacy. We used a community-engaged adaptation process to maximize program relevance and health outcomes by incorporating a broad ecological perspective. Adolescent and staff advisory boards at a community based organization recommended modifications (e.g., delete references to Kwanzaa, update language, localize incentives) and supported inclusion of critical on-site health services, such as sexually transmitted infection testing and condom provision. We conducted a trial of adapted BART (one session/week for 8 weeks) with 36 adolescents at two community organizations (mean age = 15.5 years, 52% female; 61% reported previous sexual intercourse). Most received on-site sexually transmitted infection testing (61%) and condoms (70%). Adolescents demonstrated significant improvements in self-efficacy for safer sexual practices (p < .02), AIDS risk knowledge (p < .001), condom knowledge (p < .001), and condom attitudes (p < .04). Adolescents and staff were satisfied with the revised curriculum and found on-site services acceptable. Based on improvements in constructs influencing behavior and the successful delivery of services essential for optimal health, future studies to assess efficacy and sustainability of the adapted curriculum appear warranted. PMID- 27932522 TI - Comparative Evaluation of Triphala and Ela Decoction With 0.2% Chlorhexidine as Mouthwash in the Treatment of Plaque-Induced Gingivitis and Halitosis: A Randomized Controlled Clinical Trial. AB - : Present study evaluates efficacy of Trifala and Ela as plaque controlling agent and compares it with chlorhexidine. AIM: To evaluate Antigingivitis, Antiplaque and Antihalitosis effect of Triphala and Ela decoction. A randomized sample of 60 patients with plaque induced gingivitis was enrolled and equally divided into two groups group A and group B. Group A was given Trifala and Ela decoction and Group B Chlorehexidine mouthwash for 21 days twice daily. Gingival inflammation index, plaque index and Organoleptic scoring scale was recorded at baseline, 14th day and 21st day. Comparing the plaque index for Group A with group B the reduction in from baseline to 14 day was 42.59 % and 38.62% respectively while from baseline to 21 day was 56.20% and 68.57% respectively. On comparing Gingival index for group A with group B the reduction from baseline to 14 day was 31.95% and 38.62 % respectively while from baseline to 21 day was 69.95 % and 68.57% respectively. Halitosis Percentage reduction at 14th day from base line was 33.33% and 38.18%; at 21 day from baseline 66.66% and 72.72% respectively for group A and group B. No statistical significant difference for intergroup comparison was found using paired t test. Intra group analysis using unpaired t test was significant for all the indices at different time intervals. Triphala and Ela decoction is organic, easy to prepare economical and equally effective as compared to chlorhexidine mouthwash. PMID- 27932520 TI - Myeloid-derived NF-kappaB negative regulation of PU.1 and c/EBP-beta-driven pro inflammatory cytokine production restrains LPS-induced shock. AB - Sepsis is a life-threatening event predominantly caused by Gram-negative bacteria. Bacterial infection causes a pronounced macrophage (MPhi) and dendritic cell activation that leads to excessive pro-inflammatory cytokine IL-1beta, IL-6 and TNF-alpha production (cytokine storm), resulting in endotoxic shock. Previous experimental studies have revealed that inhibiting NF-kappaB signaling ameliorates disease symptoms; however, the contribution of myeloid p65 in endotoxic shock remains elusive. In this study, we demonstrate increased mortality in mice lacking p65 in the myeloid lineage (p65Deltamye) compared with wild type mice upon ultra-pure LPS challenge. We show that increased susceptibility to LPS-induced shock was associated with elevated serum level of IL-1beta and IL-6. Mechanistic analyses revealed that LPS-induced pro inflammatory cytokine production was ameliorated in p65-deficient bone marrow derived MPhis; however, p65-deficient 'activated' peritoneal MPhis exhibited elevated IL-1beta and IL-6. We show that the elevated pro-inflammatory cytokine secretion was due, in part, to increased accumulation of IL-1beta mRNA and protein in activated inflammatory MPhis. The increased IL-1beta was linked with heightened binding of PU.1 and CCAAT/enhancer binding protein-beta to Il1b and Il6 promoters in activated inflammatory MPhis. Our data provide insight into a role for NF-kappaB in the negative regulation of pro-inflammatory cytokines in myeloid cells. PMID- 27932524 TI - Partial Tonsillectomy. AB - OBJECTIVES: Evaluate the content and readability of health information regarding partial tonsillectomy. METHODS: A web search was performed using the term partial tonsillectomy in Google, Yahoo!, and Bing. The first 50 websites from each search were evaluated using HONcode standards for quality and content. Readability was assessed using the Flesch-Kincaid Grade Level (FKGL), Flesch Reading Ease, Gunning-Fog Index, Coleman-Liau Index, Automated Readability Index, and SMOG score. The Freeman-Halton extension of Fisher's exact test was used to compare categorical differences between engines. RESULTS: Less than half of the websites mentioned patient eligibility criteria (43.3%), referenced peer-reviewed literature (43.3%), or provided a procedure description (46.7%). Twenty-two websites (14.7%) were unrelated to partial tonsillectomy, and over half contained advertisements (52%). These finding were consistent across search engines and search terms. The mean FKGL was 11.6 +/- 0.11, Gunning-Fog Index was 15.1 +/- 0.13, Coleman-Liau Index was 14.6 +/- 0.11, ARI was 12.9 +/- 0.13, and SMOG grade was 14.0 +/- 0.1. All readability levels exceeded the abilities of the average American adult. CONCLUSIONS: Current online information regarding partial tonsillectomy may not provide adequate information and may be written at a level too difficult for the average adult reader. PMID- 27932523 TI - Treatment of Recurrent Ovarian Cysts and Primary Infertility by Iranian Traditional Medicine: A Case Report. AB - Infertility is a medical and psychosocial problem with a high prevalence. There are different treatments for this problem in Iranian traditional medicine. A 28 year-old woman presented with the complaints of 4 emergency operations of the left ovarian cyst during 4 years and infertility. Diagnostic laparoscopy showed an ovarian cyst, adhesion, and endometriosis. Hysteroscopy was unremarkable. After 2 months of letrozole administration, the ovarian cyst ruptured again. Considering the failure of conventional treatments, Iranian traditional medicine products were administered to the patient. After 3 months, the patient conceived and delivered a healthy boy through normal vaginal delivery. These compounds may help with pregnancy as a uterine tonic, vitalizer, and aphrodisiac with brain and cardiac tonic properties. PMID- 27932525 TI - The Pharyngoesophageal Segment After Total Laryngectomy. AB - OBJECTIVE: The aim of the present study was to characterize the pharyngoesophageal segment in laryngectomees who rated themselves as functional tracheoesophageal speakers. METHODS: Voice perceptual assessment, high-resolution videomanometry of swallowing and phonation, and high-speed camera recording during phonation provided information about the anatomy and function of the pharyngoesophageal segment. RESULTS: Fourteen patients were included in the study. The voice assessments presented high intra/inter-listener reliability. We found a significant correlation between roughness and poor voice quality, hyperfunction and poor intelligibility, and poor voice quality, long time since the operation, and old age. High-resolution videomanometry during phonation revealed decreasing mean pressures from the distal esophagus to the pharynx and confirmed low resting pressures at the pharyngoesophageal segment and low esophageal peristaltic contraction pressures after laryngectomy in comparison to normal subjects. The neoglottis shape was mainly circular and presented a strong mucosal wave in most of the patients on the high-speed camera recording. CONCLUSIONS: Perceptual voice assessment and high-speed camera recordings provided baseline information about voice characteristics and vibration regularity of the neoglottis. Additionally, the quantitative measures obtained with high-resolution videomanometry may have clinical applicability as reference data in voice rehabilitation after total laryngectomy. PMID- 27932528 TI - Comorbidities, treatment patterns and cost-of-illness of acromegaly in Sweden: a register-linkage population-based study. AB - OBJECTIVE: Acromegaly is a complex endocrine disease with multiple comorbidities. Treatment to obtain biochemical remission includes surgery, medical therapy and radiation. We aimed to describe comorbidities, treatment patterns and cost-of illness in patients with acromegaly in Sweden. DESIGN: A nationwide population based study. METHODS: Patients with acromegaly were identified and followed in national registers in Sweden. Longitudinal treatment patterns were assessed in patients diagnosed between July 2005 and December 2013. The cost-of-illness during 2013 was estimated from a societal perspective among patients diagnosed between 1987 and 2013. RESULTS: Among 358 patients with acromegaly (48% men, mean age at diagnosis 50.0 (s.d. 15.3) years) at least one comorbidity was reported in 81% (n = 290). The most common comorbidities were hypertension (40%, n = 142), neoplasms outside the pituitary (30%, n = 109), hypopituitarism (22%, n = 80) and diabetes mellitus (17%, n = 61). Acromegaly treatment was initiated on average 3.7 (s.d. 6.9) months after diagnosis. Among the 301 treated patients, the most common first-line treatments were surgery (60%, n = 180), somatostatin analogues (21%, n = 64) and dopamine agonists (14%, n = 41). After primary surgery, 24% (n = 44) received somatostatin analogues. The annual per-patient cost was ?12 000; this was ?8700 and ?16 000 if diagnosed before or after July 2005, respectively. The cost-of-illness for acromegaly and its comorbidities was 77% from direct costs and 23% from production loss. CONCLUSIONS: The prevalence of comorbidity is high in patients with acromegaly. The most common first-line treatment in acromegalic patients was surgery followed by somatostatin analogues. The annual per-patient cost of acromegaly and its comorbidities was ?12 000. PMID- 27932526 TI - Human Plasma N-glycosylation as Analyzed by Matrix-Assisted Laser Desorption/Ionization-Fourier Transform Ion Cyclotron Resonance-MS Associates with Markers of Inflammation and Metabolic Health. AB - Glycosylation is an abundant co- and post-translational protein modification of importance to protein processing and activity. Although not template-defined, glycosylation does reflect the biological state of an organism and is a high potential biomarker for disease and patient stratification. However, to interpret a complex but informative sample like the total plasma N-glycome, it is important to establish its baseline association with plasma protein levels and systemic processes. Thus far, large-scale studies (n >200) of the total plasma N-glycome have been performed with methods of chromatographic and electrophoretic separation, which, although being informative, are limited in resolving the structural complexity of plasma N-glycans. MS has the opportunity to contribute additional information on, among others, antennarity, sialylation, and the identity of high-mannose type species.Here, we have used matrix-assisted laser desorption/ionization (MALDI)-Fourier transform ion cyclotron resonance (FTICR) MS to study the total plasma N-glycome of 2144 healthy middle-aged individuals from the Leiden Longevity Study, to allow association analysis with markers of metabolic health and inflammation. To achieve this, N-glycans were enzymatically released from their protein backbones, labeled at the reducing end with 2 aminobenzoic acid, and following purification analyzed by negative ion mode intermediate pressure MALDI-FTICR-MS. In doing so, we achieved the relative quantification of 61 glycan compositions, ranging from Hex4HexNAc2 to Hex7HexNAc6dHex1Neu5Ac4, as well as that of 39 glycosylation traits derived thereof. Next to confirming known associations of glycosylation with age and sex by MALDI-FTICR-MS, we report novel associations with C-reactive protein (CRP), interleukin 6 (IL-6), body mass index (BMI), leptin, adiponectin, HDL cholesterol, triglycerides (TG), insulin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and smoking. Overall, the bisection, galactosylation, and sialylation of diantennary species, the sialylation of tetraantennary species, and the size of high-mannose species proved to be important plasma characteristics associated with inflammation and metabolic health. PMID- 27932527 TI - Mechanisms of In Vivo Ribosome Maintenance Change in Response to Nutrient Signals. AB - Control of protein homeostasis is fundamental to the health and longevity of all organisms. Because the rate of protein synthesis by ribosomes is a central control point in this process, regulation, and maintenance of ribosome function could have amplified importance in the overall regulatory circuit. Indeed, ribosomal defects are commonly associated with loss of protein homeostasis, aging, and disease (1-4), whereas improved protein homeostasis, implying optimal ribosomal function, is associated with disease resistance and increased lifespan (5-7). To maintain a high-quality ribosome population within the cell, dysfunctional ribosomes are targeted for autophagic degradation. It is not known if complete degradation is the only mechanism for eukaryotic ribosome maintenance or if they might also be repaired by replacement of defective components. We used stable-isotope feeding and protein mass spectrometry to measure the kinetics of turnover of ribosomal RNA (rRNA) and 71 ribosomal proteins (r-proteins) in mice. The results indicate that exchange of individual proteins and whole ribosome degradation both contribute to ribosome maintenance in vivo In general, peripheral r-proteins and those with more direct roles in peptide-bond formation are replaced multiple times during the lifespan of the assembled structure, presumably by exchange with a free cytoplasmic pool, whereas the majority of r proteins are stably incorporated for the lifetime of the ribosome. Dietary signals impact the rates of both new ribosome assembly and component exchange. Signal-specific modulation of ribosomal repair and degradation could provide a mechanistic link in the frequently observed associations among diminished rates of protein synthesis, increased autophagy, and greater longevity (5, 6, 8, 9). PMID- 27932529 TI - Effectiveness of first-line pegvisomant monotherapy in acromegaly: an ACROSTUDY analysis. AB - OBJECTIVE: To examine the effectiveness and safety of primary pegvisomant monotherapy. DESIGN: Retrospective analysis of data extracted from ACROSTUDY (global observational outcomes study of patients with acromegaly treated with pegvisomant). METHODS: The earliest time to insulin-like growth factor 1 (IGF-1) normalization on pegvisomant monotherapy was determined. Both the proportion of patients who achieved IGF-1 normalization and the time to IGF-1 normalization on pegvisomant monotherapy were assessed. RESULTS: Eligible patients included 28 subjects on primary medical therapy (PT) and 176 controls on adjunctive pegvisomant therapy treated postoperatively, including 43 who were naive to medical therapy (NMT) and 133 who were previously treated medically and were washed out (WASH). IGF-1 normalization occurred in 76.9% (PT), 85.2% (NMT) and 78.3% (WASH) patients (P = NS). Median times to IGF-1 normalization were 0.5 year (PT), 0.7 year (NMT) and 0.6 year (WASH), P = NS. On survival analysis, the fraction of patients controlled on pegvisomant monotherapy was not different between groups. Higher baseline IGF-1 levels, obtained at study entry, predicted a lower likelihood of IGF-1 normalization on monotherapy (P = 0.012). Safety data include low prevalence of skin rashes, injection site reactions and reversible transaminase elevations. There was one patient (NMT) with a verified increase in tumor size. CONCLUSIONS: Pegvisomant monotherapy, administered either as primary medical therapy or as adjunctive therapy according to local practice, led to IGF 1 normalization in >75% of patients. Pegvisomant monotherapy had a favorable safety profile, consistent with previous observations. Prospective data are needed to further evaluate the role of primary pegvisomant monotherapy in acromegaly. PMID- 27932530 TI - Affective alterations in patients with Cushing's syndrome in remission are associated with decreased BDNF and cortisone levels. AB - OBJECTIVE: Affective alterations and poorer quality of life often persist in patients with Cushing's syndrome (CS) in remission. Brain-derived neurotrophic factor (BDNF) regulates the hypothalamic-pituitary-adrenal axis (HPA) and is highly expressed in brain areas controlling mood and response to stress. Our aims were to assess affective alterations after long-term remission of CS and evaluate whether they are associated with serum BDNF, salivary cortisol (SalF) and/or cortisone (SalE) concentrations. SUBJECTS AND METHODS: Thirty-six CS patients in remission (32 females/4 males; mean age (+/-s.d.), 48.8 +/- 11.8 years; median duration of remission, 72 months) and 36 gender-, age- and BMI-matched controls were included. Beck Depression Inventory-II (BDI-II), Center for Epidemiological Studies Depression Scale (CES-D), Positive Affect Negative Affect Scale (PANAS), State-Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS) and EuroQoL and CushingQoL questionnaires were completed and measured to evaluate anxiety, depression, stress perception and quality of life (QoL) respectively. Salivary cortisol was measured using liquid chromatography/tandem mass spectrometry (LC/TMS). BDNF was measured in serum using an ELISA. RESULTS: Remitted CS patients showed worse scores in all questionnaires than controls: STAI (P < 0.001), BDI (P < 0.001), CES-D (P < 0.001), PANAS (P < 0.01), PSS (P < 0.01) and EuroQoL (P < 0.01). A decrease in BDNF was observed in CS vs controls (P = 0.038), and low BDNF was associated with more anxiety (r = -0.247, P = 0.037), depression (r = -0.249, P = 0.035), stress (r = -0.277, P = 0.019) and affective balance (r = 0.243, P = 0.04). Morning salivary cortisone was inversely associated with trait anxiety (r = -0.377, P = 0.040) and depressed affect (r = 0.392, P = 0.032) in CS patients. Delay to diagnosis was associated with depressive symptoms (BDI-II: r = 0.398, P = 0.036 and CES-D: r = 0.449, P = 0.017) and CushingQoL scoring (r = -0.460, P < 0.01). CONCLUSIONS: Low BDNF levels are associated with affective alterations in 'cured' CS patients, including depression, anxiety and impaired stress perception. Elevated levels of SalE might also be related to poor affective status in these patients. PMID- 27932531 TI - Development of Type 2 Diabetes Mellitus Phenotyping Framework Using Expert Knowledge and Machine Learning Approach. AB - BACKGROUND: Phenotyping is an automated technique that can be used to distinguish patients based on electronic health records. To improve the quality of medical care and advance type 2 diabetes mellitus (T2DM) research, the demand for T2DM phenotyping has been increasing. Some existing phenotyping algorithms are not sufficiently accurate for screening or identifying clinical research subjects. OBJECTIVE: We propose a practical phenotyping framework using both expert knowledge and a machine learning approach to develop 2 phenotyping algorithms: one is for screening; the other is for identifying research subjects. METHODS: We employ expert knowledge as rules to exclude obvious control patients and machine learning to increase accuracy for complicated patients. We developed phenotyping algorithms on the basis of our framework and performed binary classification to determine whether a patient has T2DM. To facilitate development of practical phenotyping algorithms, this study introduces new evaluation metrics: area under the precision-sensitivity curve (AUPS) with a high sensitivity and AUPS with a high positive predictive value. RESULTS: The proposed phenotyping algorithms based on our framework show higher performance than baseline algorithms. Our proposed framework can be used to develop 2 types of phenotyping algorithms depending on the tuning approach: one for screening, the other for identifying research subjects. CONCLUSIONS: We develop a novel phenotyping framework that can be easily implemented on the basis of proper evaluation metrics, which are in accordance with users' objectives. The phenotyping algorithms based on our framework are useful for extraction of T2DM patients in retrospective studies. PMID- 27932532 TI - Late Restenosis After Both First-Generation and Second-Generation Drug-Eluting Stent Implantations Occurs in Patients With Drug-Eluting Stent Restenosis. AB - BACKGROUND: There are currently inadequate data about whether late restenosis occurs after drug-eluting stent (DES) implantation in patients with DES restenosis. METHODS AND RESULTS: We collected data for 608 patients who received revascularization for DES restenosis between 2004 and 2012 and analyzed 688 lesions: 359 lesions treated with a first-generation DES (first DES) and 329 lesions treated with a second-generation DES (second DES). Two serial angiographic follow-ups were routinely planned for the patients (at 8 and 20 months after the procedure). Early follow-up angiography was performed for 620 lesions (90.1%), and recurrent restenosis occurred in 84 lesions (25.8%) in the first DES group and in 72 lesions (24.5%) in the second DES group (P=0.78). Target lesion revascularization was performed for 69 lesions (21.2%) in the first DES group and for 48 lesions (16.3%) in the second DES group (P=0.15). Late follow-up angiography was performed for 438 (87.1%) of the remaining 503 lesions (excluding target lesion revascularization lesions), and late restenosis was found in 35 lesions (15.8%) in the first DES group and in 28 lesions (14.7%) in the second DES group (P=0.79). Nonfocal-type restenosis, percentage diameter stenosis after the procedure, previous stent size <=2.5 mm, and right coronary artery ostial lesion were independent predictors of early restenosis. Nonfocal type restenosis, percentage diameter stenosis at early follow-up, and stent fracture were independent predictors of late restenosis. CONCLUSIONS: Late restenosis occurs after both first DES implantation and second DES implantation for DES restenosis. PMID- 27932533 TI - Preoperative Proteinuria and Reduced Glomerular Filtration Rate Predicts Renal Replacement Therapy in Patients Supported With Continuous-Flow Left Ventricular Assist Devices. AB - BACKGROUND: Renal failure requiring renal replacement therapy (RRT) has detrimental effects on quality of life and survival of patients with continuous flow left ventricular assist devices (CF-LVADs). Current guidelines do not offer a decision-making algorithm for CF-LVAD candidates with poor baseline renal function. Objective of this study was to identify risk factors associated with RRT after CF-LVAD implantation. METHODS AND RESULTS: Three hundred and eighty nine consecutive patients underwent contemporary CF-LVAD implantation at the Columbia University Medical Center between January 2004 and August 2015. Baseline demographics, comorbid conditions, clinical risk scores, and renal function were analyzed in patients with or without RRT after CF-LVAD implantation. Time dependent receiver-operating characteristic curve analysis was performed to define optimal cutoffs for continuous risk factors. Forty-four patients (11.6%) required RRT during a median follow-up of 9.9 months. Patients requiring RRT had significantly worse renal function, lower hemoglobin, and increased proteinuria at baseline. Low estimated glomerular filtration rate (<40 mL/min/1.73 m2) and proteinuria (urine protein to creatinine ratio >=0.55 mg/mg) were significant predictors of RRT after CF-LVAD support. Dipstick proteinuria was also a significant predictor of RRT after CF-LVAD implantation. Patients with both low estimated glomerular filtration rate and proteinuria had highest risk of RRT (63.6%) compared with those with either low estimated glomerular filtration rate or proteinuria (18.7%) and those with neither of these risk factors (2.7%) at 1 year follow-up (log-rank P<0.001). CONCLUSIONS: Estimated glomerular filtration rate and proteinuria are predictors RRT after CF-LVAD implantation and should be routinely assessed in CF-LVAD candidates to guide decision making. PMID- 27932534 TI - Perceptual and Motor Performance of Combat-Sport Athletes Differs According to Specific Demands of the Discipline. AB - The specific demands of a combat-sport discipline may be reflected in the perceptual-motor performance of its athletes. Taekwondo, which emphasizes kicking, might require faster perceptual processing to compensate for longer latencies to initiate lower-limb movements and to give rapid visual feedback for dynamic postural control, while Karate, which emphasizes both striking with the hands and kicking, might require exceptional eye-hand coordination and fast perceptual processing. In samples of 38 Taekwondo athletes (16 females, 22 males; mean age = 19.9 years, SD = 1.2), 24 Karate athletes (9 females, 15 males; mean age = 18.9 years, SD = 0.9), and 35 Nonathletes (20 females, 15 males; mean age = 20.6 years, SD = 1.5), we measured eye-hand coordination with the Finger-Nose Finger task, and both perceptual-processing speed and attentional control with the Covert Orienting of Visual Attention (COVAT) task. Eye-hand coordination was significantly better for Karate athletes than for Taekwondo athletes and Nonathletes, but reaction times for the upper extremities in the COVAT task indicative of perceptual-processing speed-were faster for Taekwondo athletes than for Karate athletes and Nonathletes. In addition, we found no significant difference among groups in attentional control, as indexed by the reaction-time cost of an invalid cue in the COVAT task. The results suggest that athletes in different combat sports exhibit distinct profiles of perceptual-motor performance. PMID- 27932535 TI - Session Perceived Exertion Following Traditional and Circuit Resistance Exercise Methods in Older Hypertensive Women. AB - This study compared session ratings of perceived exertion (SRPE) between traditional multiple-set (TR) and circuit (CI) resistance exercise methods in treated hypertensive women. Fourteen volunteers (69.9 +/- 5.6 years) performed two training sessions (TR and CI) in a random order, with the same number of sets, exercises, and loads. SRPE was obtained 30 minutes following each session using Foster's scale. OMNI-resistance exercise scale (OMNI-RES) measures were subsequently taken. Foster's SRPE was not significantly different between sessions (3.8 +/- 0.9 TR vs. 3.4 +/- 1.0 CI; p = .125), but OMNI-RES values were significantly higher following TR than following CI (5.2 +/- 1.3 vs. 4.6 +/- 1.5; p = .033). Total session duration was longer for TR (29.3 +/- 1.2 vs. 20.0 +/- 0.9 minutes; p < .001). Using moderate loads, the CI method did not elicit higher SRPE when compared with TR. Conversely, significantly lower OMNI-RES values follow CI. These results will be useful for prescribing exercise regimens for older hypertensive women. PMID- 27932536 TI - An Event-Related Potential Study on the Perception and the Recognition of Face, Facial Features, and Objects in Children With Autism Spectrum Disorders. AB - The study investigated whether children with autism spectrum disorders (ASD) showed atypical patterns of brain specialization for face processing, whether the response to familiar and unfamiliar faces, facial features, and objects were different from typically developing children. Event-related potentials were recorded in 5- to 8-year-old children (12 children with ASD, 12 typically developing children) using passive viewing paradigm. The fastest P1 latencies to faces and the largest P1 amplitudes to objects were observed in both participant groups. Both groups exhibited larger N170 response to faces and eyes, F(3, 66) = 46.94, p < .0001). However, earlier P1 and N170 latencies were found on left hemisphere in children with ASD, respectively, F(1, 83) = 4.32, p = .04; F(1, 83) = 6.73, p = .01, indicating an atypical face processing pattern. All children showed a significant effect of familiarity for objects and mouths, F(1, 71) = 33.97, p < .0001; F(1, 71 = 15.94, p = .0002. Children with ASD revealed smaller negative central to faces relative to typically developing children. Face processing abnormalities revealed in children with ASD very likely exist. PMID- 27932537 TI - In search of a good nanny. PMID- 27932538 TI - Investigation of solid particles in the mainstream aerosol of the Tobacco Heating System THS2.2 and mainstream smoke of a 3R4F reference cigarette. AB - Combustion of biomass produces solid carbon particles, whereas their generation is highly unlikely when a biomass is heated instead of being burnt. For instance, in the Tobacco Heating System (THS2.2), the tobacco is heated below 350 degrees C and no combustion takes place. Consequently, at this relatively low temperature, released compounds should form an aerosol consisting of suspended liquid droplets via a homogeneous nucleation process. To verify this assumption, mainstream aerosol generated by the heat-not-burn product, THS2.2, was assessed in comparison with mainstream smoke produced from the 3R4F reference cigarette for which solid particles are likely present. For this purpose, a methodology was developed based on the use of a commercial Dekati thermodenuder operating at 300 degrees C coupled with a two-stage impactor to trap solid particles. If any particles were collected, they were subsequently analyzed by a scanning electron microscope and an electron dispersive X-ray. The setup was first assessed using glycerine-based aerosol as a model system. The removal efficiency of glycerin was determined to be 86 +/- 2% using a Trust Science Innovation (TSI) scanning mobility particle sizer, meaning that quantification of solid particles can be achieved as long as their fraction is larger than 14% in number. From experiments conducted using the 3R4F reference cigarette, the methodology showed that approximately 80% in number of the total particulate matter was neither evaporated nor removed by the thermodenuder. This 80% in number was attributed to the presence of solid particles and/or low volatile liquid droplets. The particles collected on the impactor were mainly carbon based. Oxygen, potassium, and chloride traces were also noted. In comparison, solid particles were not detected in the aerosol of THS2.2 after passing through the thermodenuder operated at 300 degrees C. This result is consistent with the fact that no combustion process takes place in THS2.2 and no formation and subsequent transfer of solid carbon particles is expected to occur in the mainstream aerosol. PMID- 27932539 TI - Assessment of concomitant versus sequential trastuzumab on radiation-induced cardiovascular toxicity. AB - There are limited data regarding effect of trastuzumab on radiation-induced cardiovascular toxicity when used sequentially or concomitantly. This experimental study aims to investigate effect of trastuzumab on radiation-induced cardiovascular toxicity with respect to the treatment sequence. One hundred and eight female Wistar albino rats were divided into six groups (G): G1 was control, G2 was trastuzumab, and G3 was radiotherapy (RT); G4 and G6 were sequential RT and trastuzumab; and G5 was concomitant RT and trastuzumab groups, respectively. Rats were killed at 6th h, 21st and 70th days after RT; thoracic aorta and heart samples were obtained. Transthoracic echocardiography and functional studies evaluating relaxation of thoracic aorta were performed. Subendothelial edema scores of thoracic aorta samples at 21st and 70th days were higher in RT groups (G3, G4, G5, and G6) ( p < 0.001). There was a deterioration of relaxation responses of thoracic aorta samples in RT groups ( p < 0.001). Cardiac fibrosis (CF) scores revealed detrimental effect of RT beginning from 6th h and trastuzumab from 21st day. RT groups showed further deterioration of CF at 70th day. Ejection fraction, left ventricular mass, and fractional shortening were significantly decreased in G4, G5, and G6. Trastuzumab may increase pathological damage in cardiovascular structures when used with RT regardless of timing. PMID- 27932540 TI - Twelve month follow-up on a randomised controlled trial of relaxation training for post-stroke anxiety. AB - OBJECTIVE: To follow up participants in a randomised controlled trial of relaxation training for anxiety after stroke at 12 months. DESIGN: Twelve month follow-up to a randomised controlled trial, in which the control group also received treatment. SETTING: Community. PARTICIPANTS: Fifteen of twenty one original participants with post-stroke anxiety participated in a one year follow up study. INTERVENTIONS: A self-help autogenic relaxation CD listened to five times a week for one month, immediately in the intervention group and after three months in the control group. MAIN MEASURES: Hospital Anxiety and Depression Scale Anxiety subscale and the Telephone Interview of Cognitive Status for inclusion. Hospital Anxiety and Depression Scale-Anxiety subscale for outcome. All measures were administered by phone. RESULTS: Anxiety ratings reduced significantly between pre and post-intervention, and between pre-intervention and one year follow-up ( chi2(2) = 22.29, p < 0.001). CONCLUSIONS: Reductions in anxiety in stroke survivors who received a self-help autogenic relaxation CD appear to be maintained after one year. PMID- 27932541 TI - Cooperation Between Kinesin Motors Promotes Spindle Symmetry and Chromosome Organization in Oocytes. AB - The oocyte spindle in most animal species is assembled in the absence of the microtubule-organizing centers called centrosomes. Without the organization provided by centrosomes, acentrosomal meiotic spindle organization may rely heavily on the bundling of microtubules by kinesin motor proteins. Indeed, the minus-end directed kinesin-14 NCD, and the plus-end directed kinesin-6 Subito are known to be required for oocyte spindle organization in Drosophila melanogaster How multiple microtubule-bundling kinesins interact to produce a functional acentrosomal spindle is not known. In addition, there have been few studies on the meiotic function of one of the most important microtubule-bundlers in mitotic cells, the kinesin-5 KLP61F. We have found that the kinesin-5 KLP61F is required for spindle and centromere symmetry in oocytes. The asymmetry observed in the absence of KLP61F depends on NCD, the kinesin-12 KLP54D, and the microcephaly protein ASP. In contrast, KLP61F and Subito work together in maintaining a bipolar spindle. We propose that the prominent central spindle, stabilized by Subito, provides the framework for the coordination of multiple microtubule bundling activities. The activities of several proteins, including NCD, KLP54D, and ASP, generate asymmetries within the acentrosomal spindle, while KLP61F and Subito balance these forces, resulting in the capacity to accurately segregate chromosomes. PMID- 27932542 TI - H2O2-Sensitive Isoforms of Drosophila melanogaster TRPA1 Act in Bitter-Sensing Gustatory Neurons to Promote Avoidance of UV During Egg-Laying. AB - The evolutionarily conserved TRPA1 channel can sense various stimuli including temperatures and chemical irritants. Recent results have suggested that specific isoforms of Drosophila TRPA1 (dTRPA1) are UV-sensitive and that their UV sensitivity is due to H2O2 sensitivity. However, whether such UV sensitivity served any physiological purposes in animal behavior was unclear. Here, we demonstrate that H2O2-sensitive dTRPA1 isoforms promote avoidance of UV when adult Drosophila females are selecting sites for egg-laying. First, we show that blind/visionless females are still capable of sensing and avoiding UV during egg laying when intensity of UV is high yet within the range of natural sunlight. Second, we show that such vision-independent UV avoidance is mediated by a group of bitter-sensing neurons on the proboscis that express H2O2-sensitive dTRPA1 isoforms. We show that these bitter-sensing neurons exhibit dTRPA1-dependent UV sensitivity. Importantly, inhibiting activities of these bitter-sensing neurons, reducing their dTRPA1 expression, or reducing their H2O2-sensitivity all significantly reduced blind females' UV avoidance, whereas selectively restoring a H2O2-sensitive isoform of dTRPA1 in these neurons restored UV avoidance. Lastly, we show that specifically expressing the red-shifted channelrhodopsin CsChrimson in these bitter-sensing neurons promotes egg-laying avoidance of red light, an otherwise neutral cue for egg-laying females. Together, these results demonstrate a physiological role of the UV-sensitive dTRPA1 isoforms, reveal that adult Drosophila possess at least two sensory systems for detecting UV, and uncover an unexpected role of bitter-sensing taste neurons in UV sensing. PMID- 27932544 TI - Improving the Identification of Phenotypic Abnormalities and Sexual Dimorphism in Mice When Studying Rare Event Categorical Characteristics. AB - Biological research frequently involves the study of phenotyping data. Many of these studies focus on rare event categorical data, and functional genomics studies typically study the presence or absence of an abnormal phenotype. With the growing interest in the role of sex, there is a need to assess the phenotype for sexual dimorphism. The identification of abnormal phenotypes for downstream research is challenged by the small sample size, the rare event nature, and the multiple testing problem, as many variables are monitored simultaneously. Here, we develop a statistical pipeline to assess statistical and biological significance while managing the multiple testing problem. We propose a two-step pipeline to initially assess for a treatment effect, in our case example genotype, and then test for an interaction with sex. We compare multiple statistical methods and use simulations to investigate the control of the type one error rate and power. To maximize the power while addressing the multiple testing issue, we implement filters to remove data sets where the hypotheses to be tested cannot achieve significance. A motivating case study utilizing a large scale high-throughput mouse phenotyping data set from the Wellcome Trust Sanger Institute Mouse Genetics Project, where the treatment is a gene ablation, demonstrates the benefits of the new pipeline on the downstream biological calls. PMID- 27932543 TI - Zinc Cluster Transcription Factors Alter Virulence in Candida albicans. AB - Almost all humans are colonized with Candida albicans However, in immunocompromised individuals, this benign commensal organism becomes a serious, life-threatening pathogen. Here, we describe and analyze the regulatory networks that modulate innate responses in the host niches. We identified Zcf15 and Zcf29, two Zinc Cluster transcription Factors (ZCF) that are required for C. albicans virulence. Previous sequence analysis of clinical C. albicans isolates from immunocompromised patients indicates that both ZCF genes diverged during clonal evolution. Using in vivo animal models, ex vivo cell culture methods, and in vitro sensitivity assays, we demonstrate that knockout mutants of both ZCF15 and ZCF29 are hypersensitive to reactive oxygen species (ROS), suggesting they help neutralize the host-derived ROS produced by phagocytes, as well as establish a sustained infection in vivo Transcriptomic analysis of mutants under resting conditions where cells were not experiencing oxidative stress revealed a large network that control macro and micronutrient homeostasis, which likely contributes to overall pathogen fitness in host niches. Under oxidative stress, both transcription factors regulate a separate set of genes involved in detoxification of ROS and down-regulating ribosome biogenesis. ChIP-seq analysis, which reveals vastly different binding partners for each transcription factor (TF) before and after oxidative stress, further confirms these results. Furthermore, the absence of a dominant binding motif likely facilitates their mobility, and supports the notion that they represent a recent expansion of the ZCF family in the pathogenic Candida species. Our analyses provide a framework for understanding new aspects of the interface between C. albicans and host defense response, and extends our understanding of how complex cell behaviors are linked to the evolution of TFs. PMID- 27932546 TI - What can a participatory approach to evaluation contribute to the field of integrated care? AB - Better integration of care within the health sector and between health and social care is seen in many countries as an essential way of addressing the enduring problems of dwindling resources, changing demographics and unacceptable variation in quality of care. Current research evidence about the effectiveness of integration efforts supports neither the enthusiasm of those promoting and designing integrated care programmes nor the growing efforts of practitioners attempting to integrate care on the ground. In this paper we present a methodological approach, based on the principles of participatory research, that attempts to address this challenge. Participatory approaches are characterised by a desire to use social science methods to solve practical problems and a commitment on the part of researchers to substantive and sustained collaboration with relevant stakeholders. We describe how we applied an emerging practical model of participatory research, the researcher-in-residence model, to evaluate a large-scale integrated care programme in the UK. We propose that the approach added value to the programme in a number of ways: by engaging stakeholders in using established evidence and with the benefits of rigorously evaluating their work, by providing insights for local stakeholders that they were either not familiar with or had not fully considered in relation to the development and implementation of the programme and by challenging established mindsets and norms. While there is still much to learn about the benefits and challenges of applying participatory approaches in the health sector, we demonstrate how using such approaches have the potential to help practitioners integrate care more effectively in their daily practice and help progress the academic study of integrated care. PMID- 27932545 TI - Population Genomics of Daphnia pulex. AB - Using data from 83 isolates from a single population, the population genomics of the microcrustacean Daphnia pulex are described and compared to current knowledge for the only other well-studied invertebrate, Drosophila melanogaster These two species are quite similar with respect to effective population sizes and mutation rates, although some features of recombination appear to be different, with linkage disequilibrium being elevated at short ([Formula: see text] bp) distances in D. melanogaster and at long distances in D. pulex The study population adheres closely to the expectations under Hardy-Weinberg equilibrium, and reflects a past population history of no more than a twofold range of variation in effective population size. Fourfold redundant silent sites and a restricted region of intronic sites appear to evolve in a nearly neutral fashion, providing a powerful tool for population genetic analyses. Amino acid replacement sites are predominantly under strong purifying selection, as are a large fraction of sites in UTRs and intergenic regions, but the majority of SNPs at such sites that rise to frequencies [Formula: see text] appear to evolve in a nearly neutral fashion. All forms of genomic sites (including replacement sites within codons, and intergenic and UTR regions) appear to be experiencing an [Formula: see text] higher level of selection scaled to the power of drift in D. melanogaster, but this may in part be a consequence of recent demographic changes. These results establish D. pulex as an excellent system for future work on the evolutionary genomics of natural populations. PMID- 27932547 TI - Practice to Evidence: Using Evaluability Assessment to Generate Practice-Based Evidence in Rural South Georgia. AB - Evidence from formal evaluation of real-world practice can address gaps in the public health knowledge base and provide information about feasible, relevant strategies for varied settings. Interest in evaluability assessment (EA) as an approach for generating practice-based evidence has grown. EA has been central to several structured assessment processes that identify and select promising programs and evaluate those most likely to produce useful findings. The Emory Prevention Research Center used EA as part of an initiative to generate practice based evidence for cancer prevention in southwest Georgia. Our initiative consisted of five steps: (1) environmental scan to identify potential programs, (2) program selection, (3) EA, (4) evaluation, and (5) dissemination. We identified nine programs, four of which completed a formal application, and conducted two EAs. EAs consisted of document review, site visits, and literature reviews. The EA purpose was to assess the program model, data availability, stakeholder interest in evaluation, feasibility of an outcome evaluation, and potential contribution to the literature. We conducted one outcome evaluation and one descriptive qualitative study; both were published in peer-reviewed journals. The outcome evaluation addressed knowledge gaps about strategies to promote colorectal cancer screening. Results led to the program's inclusion in national resources for practitioners seeking evidence-based practices and helped the community organization expand and strengthen the program. As part of a structured assessment process, EA can identify programs most likely to produce useful results for dissemination and is a viable approach for local initiatives to generate practice-based evidence in rural or low-resource settings. PMID- 27932548 TI - Total control of chromium in tanneries - thermal decomposition of filtration cake from enzymatic hydrolysis of chrome shavings. AB - This paper deals with the problem of chromium recovery from chrome-tanned waste and thus with reducing the environmental impact of the leather industry. Chrome tanned waste was transformed by alkaline enzymatic hydrolysis promoted by magnesium oxide into practically chromium-free, commercially applicable collagen hydrolysate and filtration cake containing a high portion of chromium. The crude and magnesium-deprived chromium cakes were subjected to a process of thermal decomposition at 650 degrees C under oxygen-free conditions to reduce the amount of this waste and to study the effect of magnesium removal on the resulting products. Oxygen-free conditions were applied in order to prevent the oxidation of trivalent chromium into the hazardous hexavalent form. Thermal decomposition products from both crude and magnesium-deprived chrome cakes were characterized by high chromium content over 50%, which occurred as eskolaite (Cr2O3) and magnesiochromite (MgCr2O4) crystal phases, respectively. Thermal decomposition decreased the amount of chrome cake dry feed by 90%. Based on the performed experiments, a scheme for the total control of chromium in the leather industry was designed. PMID- 27932549 TI - Proteolytic degradation of heat shock protein A2 occurs in response to oxidative stress in male germ cells of the mouse. AB - STUDY QUESTION: Does oxidative stress compromise the protein expression of heat shock protein A2 (HSPA2) in the developing germ cells of the mouse testis? SUMMARY ANSWER: Oxidative stress leads to the modification of HSPA2 by the lipid aldehyde 4-hydroxynonenal (4HNE) and initiates its degradation via the ubiquitin proteasome system. WHAT IS KNOWN ALREADY: Previous work has revealed a deficiency in HSPA2 protein expression within the spermatozoa of infertile men that have failed fertilization in a clinical setting. While the biological basis of this reduction in HSPA2 remains to be established, we have recently shown that the HSPA2 expressed in the spermatozoa of normozoospermic individuals is highly susceptible to adduction, a form of post-translational modification, by the lipid aldehyde 4HNE that has been causally linked to the degradation of its substrates. This modification of HSPA2 by 4HNE adduction dramatically reduced human sperm-egg interaction in vitro. Moreover, studies in a mouse model offer compelling evidence that the co-chaperone BCL2-associated athanogene 6 (BAG6) plays a key role in regulating the stability of HSPA2 in the testis, by preventing its ubiquitination and subsequent proteolytic degradation. STUDY DESIGN, SIZE, DURATION: Dose-dependent studies were used to establish a 4HNE-treatment regime for primary culture(s) of male mouse germ cells. The influence of 4HNE on HSPA2 protein stability was subsequently assessed in treated germ cells. Additionally, sperm lysates from infertile patients with established zona pellucida recognition defects were examined for the presence of 4HNE and ubiquitin adducts. A minimum of three biological replicates were performed to test statistical significance. PARTICIPANTS/MATERIALS, SETTING, METHODS: Oxidative stress was induced in pachytene spermatocytes and round spermatids isolated from the mouse testis, as well as a GC-2 cell line, using 50-200 uM 4HNE or hydrogen peroxide (H2O2), and the expression of HSPA2 was monitored via immunocytochemistry and immunoblotting approaches. Using the GC-2 cell line as a model, the ubiquitination and degradation of HSPA2 was assessed using immunoprecipitation techniques and pharmacological inhibition of proteasomal and lysosomal degradation pathways. Finally, the interaction between BAG6 and HSPA2 was examined in response to 4HNE exposure via proximity ligation assays. MAIN RESULTS AND THE ROLE OF CHANCE: HSPA2 protein levels were significantly reduced compared with controls after 4HNE treatment of round spermatids (P < 0.01) and GC-2 cells (P < 0.001) but not pachytene spermatocytes. Using GC-2 cells as a model, HSPA2 was shown to be both adducted by 4HNE and targeted for ubiquitination in response to cellular oxidative stress. Inhibition of the proteasome with MG132 prevented HSPA2 degradation after 4HNE treatment indicating that the degradation of HSPA2 is likely to occur via a proteasomal pathway. Moreover, our assessment of proteasome activity provided evidence that 4HNE treatment can significantly increase the proteasome activity of GC-2 cells (P < 0.05 versus control). Finally, 4HNE exposure to GC-2 cells resulted in the dissociation of HSPA2 from its regulatory co-chaperone BAG6, a key mediator of HSPA2 stability in male germ cells. LIMITATIONS, REASONS FOR CAUTION: While these experiments were performed using a mouse germ cell-model system, our analyses of patient sperm lysate imply that these mechanisms are conserved between mouse and human germ cells. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests a causative link between non enzymatic post-translational modifications and the relative levels of HSPA2 in the spermatozoa of a specific sub-class of infertile males. In doing so, this work enhances our understanding of failed sperm-egg recognition and may assist in the development of targeted antioxidant-based approaches for ameliorating the production of cytotoxic lipid aldehydes in the testis in an attempt to prevent this form of infertility. LARGE SCALE DATA: Not applicable. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Health and Medical Research Council of Australia (APP1101953). The authors have no competing interests to declare. PMID- 27932550 TI - Spermaurin, an La1-like peptide from the venom of the scorpion Scorpio maurus palmatus, improves sperm motility and fertilization in different mammalian species. AB - STUDY QUESTION: Is it possible to identify original compounds that are able to enhance sperm motility from the venom of the scorpion Scorpio maurus palmatus? SUMMARY ANSWER: We identified a potent disulfide-rich peptide (DRP) of 73 amino acids that significantly improved the motility of fresh and frozen-thawed sperm in different mammalian species, including human, and improved fertilization outcome in mouse IVF experiments. WHAT IS KNOWN ALREADY: Any disturbance of sperm motility has a strong impact on fertilization and can lead to subfertility or infertility. Significant efforts have, therefore, been made to identify pharmacological drugs that might improve sperm motility. Such compounds are particularly useful in azoospermia to improve testicular sperm extraction and in the domain of cryopreservation because the motility of frozen-thawed sperm is reduced. STUDY DESIGN, SIZE, DURATION: This was a basic science/medical research study aimed at identifying original compounds from a library of venoms able to enhance mammalian sperm motility, including human. We first identified in the venom of a scorpion S. m. palmatus a fraction able to potently activate sperm motility. We next purified and characterized the compound by liquid chromatography, mass spectrometry and peptide synthesis. Finally, the potency and toxicity of both purified and synthetic versions of the identified compound on sperm motility were assessed using different in vitro tests in different mammalian species. PARTICIPANTS/MATERIALS, SETTING, METHODS: For human sperm, biological samples were collected from normozoospermic donors and subfertile patients attending a reproduction department for diagnostic semen analysis. Testicular sperm was collected from cynomolgus monkeys (Macaca fascicularis) euthanized for the needs of specific authorized research projects. The peptide was also tested on bovine and mouse epidydimal sperm. We measured different sperm motility parameters with a computer-assisted sperm analysis system in the presence or absence of the peptide. MAIN RESULTS AND THE ROLE OF CHANCE: Size exclusion chromatography enabled us to isolate a fraction of the venom of S. m. palmatus able to increase sperm motility. By liquid chromatography and mass spectrometry, a peptide comprising 73 amino acids with 4 disulfide bridges was identified as responsible for the biological activity and called 'spermaurin'. The identity of spermaurin was confirmed by chemical synthesis. We showed that the peptide increased the motility of fresh and frozen-thawed human sperm. We observed that the potency of the peptide was higher on fresh ejaculated spermatozoa with a low motility, achieving a 100% increase of curvilinear velocity in poorly performing sperm. We also demonstrated that peptide is effective on bovine and mouse fresh epididymal, bovine frozen-thawed ejaculated and fresh non-human primate testicular sperm. Finally, in mouse IVF, the production of 2-cell embryos was increased by 24% when sperm were treated with the peptide. LIMITATIONS, REASONS FOR CAUTION: This work is an in vitro evaluation of the ability of spermaurin to improve sperm motility parameters. Another limitation of this study is the small number of human sperm samples tested with the natural (n = 36) and synthetic (n = 12) peptides. Moreover, the effect of the peptide on IVF outcome was only tested in mouse and further tests with human and bovine gametes are required to confirm and extend this result in other mammalian species. WIDER IMPLICATIONS OF THE FINDINGS: This work confirms our initial study showing that venoms represent an interesting source of molecules that are able to modify sperm physiology. Moreover, this work presents the first demonstrated biological action of a venom peptide from the scorpion S. m. palmatus with sequence similarities to La1 peptide from Liocheles australasiae (Wood scorpion), a widespread family of DRPs. LARGE SCALE DATA: Not applicable. STUDY FUNDING/COMPETING INTEREST(S): This work is part of the project 'LAB COM-14 LAB7 0004 01-LIPAV', funded by the program LabCom 2014 from the French Research Agency (ANR). Dr Arnoult reports grants from IMV Technologies during the conduct of the study. In addition, Drs Arnoult, Martinez, Ray and Schmitt have a patent EP16305642.7 pending containing some of the information presented in this manuscript. PMID- 27932551 TI - Antigen unmasking enhances visualization efficacy of the oocyte activation factor, phospholipase C zeta, in mammalian sperm. AB - STUDY QUESTION: Is it possible to improve clinical visualization of phospholipase C zeta (PLCzeta) as a diagnostic marker of sperm oocyte activation capacity and male fertility? SUMMARY ANSWER: Poor PLCzeta visualization efficacy using current protocols may be due to steric or conformational occlusion of native PLCzeta, hindering antibody access, and is significantly enhanced using antigen unmasking/retrieval (AUM) protocols. WHAT IS KNOWN ALREADY: Mammalian oocyte activation is mediated via a series of intracellular calcium (Ca2+) oscillations induced by sperm-specific PLCzeta. PLCzeta represents not only a potential clinical therapeutic in cases of oocyte activation deficiency but also a diagnostic marker of sperm fertility. However, there are significant concerns surrounding PLCzeta antibody specificity and detection protocols. STUDY DESIGN, SIZE DURATION: Two PLCzeta polyclonal antibodies, with confirmed PLCzeta specificity, were employed in mouse, porcine and human sperm. Experiments evaluated PLCzeta visualization efficacy, and whether AUM improved this. Antibodies against two sperm-specific proteins [post-acrosomal WW-binding protein (PAWP) and acrosin] were used as controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: Aldehyde- and methanol-fixed sperm were subject to immunofluorescence analysis following HCl exposure (pH = 0.1-0.5), acid Tyrode's solution exposure (pH = 2.5) or heating in 10 mM sodium citrate solution (pH = 6.0). Fluorescence intensity of at least 300 cells was recorded for each treatment, with three independent repeats. MAIN RESULTS AND THE ROLE OF CHANCE: Despite high specificity for native PLCzeta following immunoblotting using epitope-specific polyclonal PLCzeta antibodies in mouse, porcine and human sperm, immunofluorescent visualization efficacy was poor. In contrast, sperm markers PAWP and acrosin exhibited relatively impressive results. All methods of AUM on aldehyde-fixed sperm enhanced visualization efficacy for PLCzeta compared to visualization efficacy before AUM (P < 0.05 for all AUM interventions), but exerted no significant change upon PAWP or acrosin immunofluorescence following AUM. All methods of AUM enhanced PLCzeta visualization efficacy in mouse and human methanol-fixed sperm compared to without AUM (P < 0.05 for all AUM interventions), while no significant change was observed in methanol-fixed porcine sperm before and after. In the absence of aldehyde-induced cross linkages, such results suggest that poor PLCzeta visualization efficacy may be due to steric or conformational occlusion of native PLCzeta, hindering antibody access. Importantly, examination of sperm from individual donors revealed that AUM differentially affects observable PLCzeta fluorescence, and the proportion of sperm exhibiting detectable PLCzeta fluorescence in sperm from different males. LIMITATIONS, REASONS FOR CAUTION: Direct correlation of fertility outcomes with the level of PLCzeta in the sperm samples studied was not available. Such analyses would be required in future to determine whether the improved methodology for PLCzeta visualization we propose would indeed reflect fertility status. WIDER IMPLICATIONS OF THE FINDINGS: We propose that AUM alters conformational interactions to enhance PLCzeta epitope availability and visualization efficacy, supporting prospective application of AUM to reduce misinterpretation in clinical diagnosis of PLCzeta-linked male infertility. Our current results suggest that it is perhaps prudent that previous studies investigating links between PLCzeta and fertility parameters are re-examined in the context of AUM, and may pave the way for future work to answer significant questions such as how PLCzeta appears to be kept in an inactive form in the sperm. LARGE SCALE DATA: Not applicable. STUDY FUNDING/COMPETING INTERESTS: J.K. is supported by a Health Fellowship award from the National Institute for Social Care and Health Research (NISCHR). M.N. is supported by a Marie Curie Intra European Research Fellowship award. This work was also partly funded by a research grant from Cook Medical Technologies LLC. There are no competing financial interests to declare. PMID- 27932553 TI - Normalization matters: tracking the best strategy for sperm miRNA quantification. AB - STUDY QUESTION: What is the most reliable normalization strategy for sperm microRNA (miRNA) quantitative Reverse Transcription Polymerase Chain Reactions (qRT-PCR) using singleplex assays? SUMMARY ANSWER: The use of the average expression of hsa-miR-100-5p and hsa-miR-30a-5p as sperm miRNA qRT-PCR data normalizer is suggested as an optimal strategy. WHAT IS KNOWN ALREADY: Mean centering methods are the most reliable normalization strategies for miRNA high throughput expression analyses. Nevertheless, specific trustworthy reference controls must be established in singleplex sperm miRNA qRT-PCRs. STUDY DESIGN, SIZE DURATION: Cycle threshold (Ct) values from previously published sperm miRNA expression profiles were normalized using four approaches: (i) Mean-Centering Restricted (MCR) method (taken as the reference strategy); (ii) expression of the small nuclear RNA RNU6B; (iii) expression of four miRNAs selected by the Concordance Correlation Restricted (CCR) algorithm: hsa-miR-100-5p, hsa-miR-146b 5p, hsa-miR-92a-3p and hsa-miR-30a-5p; (iv) the combination of two of these miRNAs that achieved the highest proximity to MCR. PARTICIPANTS/MATERIALS, SETTING, METHODS: Expression profile data from 736 sperm miRNAs were taken from previously published studies performed in fertile donors (n = 10) and infertile patients (n = 38). For each tested normalizer molecule, expression ubiquity and uniformity across the different samples and populations were assessed as indispensable requirements for being considered as valid candidates. The reliability of the different normalizing strategies was compared to MCR based on the set of differentially expressed miRNAs (DE-miRNAs) detected between populations, the corresponding predicted targets and the associated enriched biological processes. MAIN RESULTS AND THE ROLE OF CHANCE: All tested normalizers were found to be ubiquitous and non-differentially expressed between populations. RNU6B was the least uniformly expressed candidate across samples. Data normalization through RNU6B led to dramatically misguided results when compared to MCR outputs, with a null prediction of target genes and enriched biological processes. Hsa-miR-146b-5p and hsa-miR-92a-3p were more uniformly expressed than RNU6B, but their results still showed scant proximity to the reference method. The highest resemblance to MCR was achieved by hsa-miR-100-5p and hsa-miR-30a-5p. Normalization against the combination of both miRNAs reached the best proximity rank regarding the detected DE-miRNAs (Area Under the Curve = 0.8). This combination also exhibited the best performance in terms of the target genes predicted (72.3% of True Positives) and their corresponding enriched biological processes (70.4% of True Positives). LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: This study is focused on sperm miRNA qRT-PCR analysis. The use of the selected normalizers in other cell types or tissues would still require confirmation. WIDER IMPLICATIONS OF THE FINDINGS: The search for new fertility biomarkers based on sperm miRNA expression using high throughput assays is one of the upcoming challenges in the field of reproductive genetics. In this context, validation of the results using singleplex assays would be mandatory. The normalizer strategy suggested in this study would provide a universal option in this area, allowing for normalization of the validated data without causing meaningful variations of the results. Instead, qRT-PCR data normalization by RNU6B should be discarded in sperm-miRNA expression studies. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the 2014/SGR00524 project (Agencia de Gestio d'Ajuts Universitaris i de Recerca, Generalitat de Catalunya, Spain) and UAB CF-180034 grant (Universitat Autonoma de Barcelona). Celia Corral-Vazquez is a recipient of a Personal Investigador en Formacio grant UAB/PIF2015 (Universitat Autonoma de Barcelona). The authors report no conflict of interest. PMID- 27932552 TI - Microfluidic analysis of oocyte and embryo biomechanical properties to improve outcomes in assisted reproductive technologies. AB - Measurement of oocyte and embryo biomechanical properties has recently emerged as an exciting new approach to obtain a quantitative, objective estimate of developmental potential. However, many traditional methods for probing cell mechanical properties are time consuming, labor intensive and require expensive equipment. Microfluidic technology is currently making its way into many aspects of assisted reproductive technologies (ART), and is particularly well suited to measure embryo biomechanics due to the potential for robust, automated single cell analysis at a low cost. This review will highlight microfluidic approaches to measure oocyte and embryo mechanics along with their ability to predict developmental potential and find practical application in the clinic. Although these new devices must be extensively validated before they can be integrated into the existing clinical workflow, they could eventually be used to constantly monitor oocyte and embryo developmental progress and enable more optimal decision making in ART. PMID- 27932554 TI - Inflammatory Cytokine Levels After Endovascular Therapy in Patients With Peripheral Artery Disease. AB - We evaluated the impact of endovascular therapy (EVT) on inflammatory cytokine levels and its relationship with in-stent restenosis in patients with peripheral artery disease. The study prospectively enrolled 35 patients with intermittent claudication who underwent EVT of the iliofemoral artery. Levels of interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-alpha) were measured using enzyme-linked immunosorbent assay before and at 2 hours, 4 hours, and 3 months after EVT. All cytokine levels increased significantly after EVT (IL-6 [pg/mL]: from 1.51 [0.84-1.93] before EVT to 6.97 [4.05-20.41] at 2 hours and 13.29 [4.57-31.88] at 4 hours; MCP-1 [pg/mL]: from 326.65 [265.60-406.55] before EVT to 411.18 [341.21-566.27] at 2 hours and 519.36 [383.58-644.85] at 4 hours; TNF-alpha [pg/mL]: from 1.08 [0.77-1.29] before EVT to 1.25 [0.94-1.81] at 2 hours and 1.27 [0.95-1.59] at 4 hours, all P < .001). However, cytokine levels did not differ significantly between lesions with and without in-stent restenosis. Overall, our results suggest that EVT significantly increases IL-6, MCP-1, and TNF-alpha levels in the ischemic leg, but this effect is not associated with a higher rate of in-stent restenosis. PMID- 27932555 TI - Mouthpiece ventilation and complementary techniques in patients with neuromuscular disease: A brief clinical review and update. AB - Noninvasive ventilatory support (NVS) is sometimes reported as suboptimal in patients with neuromuscular disease (NMD). The reasons for this include inadequate ventilator settings and/or lack of interface tolerance. NVS has been used for many years in patients with NMD disorders as a viable alternative to continuous ventilatory support via a tracheostomy tube. The mouthpiece ventilation (MPV) is a ventilatory mode that is used as daytime ventilatory support in combination with other ventilatory modalities and interfaces for nocturnal NVS. However, there is still a poor understanding of this method's benefits compared with other modalities. This review aims to highlight the indications and advantages along with the disadvantages of MPV. PMID- 27932557 TI - Semiquantitative Parameters in PSMA-Targeted PET Imaging with 18F-DCFPyL: Variability in Normal-Organ Uptake. AB - 18F-DCFPyL is a small-molecule inhibitor of the prostate-specific membrane antigen that has shown promise for evaluation of primary and metastatic prostate cancer using PET. Measuring the variability in normal-organ uptake of 18F-DCFPyL is necessary to understand its biodistribution, aid image interpretation, judge the reliability of scan quantification, and provide a basis for therapeutic monitoring. Methods: Sixty-five consecutive 18F-DCFPyL PET/CT scans from 64 patients with a history of prostate cancer were analyzed. Volumes of interest were defined for the lacrimal glands, major salivary glands, liver, spleen, and both kidneys. The mean SUV normalized to body mass or to lean body mass (SUL) was calculated for each volume of interest. The average SUV across all scans, the SD, and the coefficient of variation (COV) for each organ were calculated. The same parameters were also derived for a 3-cm sphere drawn in the center of the right lobe of the liver. Results: The average SUVmean for all selected organs measured was 6.6 +/- 1.8 for the right lacrimal gland, 6.4 +/- 1.8 for the left lacrimal gland, 9.1 +/- 2.0 for the right parotid gland, 9.0 +/- 2.1 for the left parotid gland, 9.6 +/- 2.3 for the right submandibular gland, 9.4 +/- 2.2 for the left submandibular gland, 5.0 +/- 0.7 for the whole liver, 5.1 +/- 0.7 for a 3-cm sphere in the liver, 4.0 +/- 1.5 for the spleen, 20.1 +/- 4.6 for the right kidney, and 19.4 +/- 4.5 for the left kidney. SULmean was lower overall, although demonstrating similar trends. The COV of SUVmean and SULmean was lower in the liver (13.8% and 14.5%, respectively) than in any other organ and was less than the comparable COV for 18F-FDG PET. The COV of SUVmean and SULmean in the 3-cm sphere in the liver was also low and similar to the variability in the whole liver (14.2% and 14.7%, respectively). Conclusion:18F-DCFPyL uptake in normal liver demonstrates less variability than in other 18F-DCFPyL-avid organs, and its variability is less than the reported variability of 18F-FDG in liver. Variability was slightly less for SUVmean than for SULmean, suggesting that SUVmean may be the preferable parameter for quantification of images obtained with 18F-DCFPyL. PMID- 27932559 TI - Reply: 18F-Fluoroestradiol PET to Predict the Response to Neoadjuvant Treatment of Luminal Breast Cancer. PMID- 27932556 TI - Orally Administered Berberine Modulates Hepatic Lipid Metabolism by Altering Microbial Bile Acid Metabolism and the Intestinal FXR Signaling Pathway. AB - Previous studies suggest that the lipid-lowering effect of berberine (BBR) involves actions on the low-density lipoprotein receptor and the AMP-activated protein kinase signaling pathways. However, the implication of these mechanisms is unclear because of the low bioavailability of BBR. Because the main action site of BBR is the gut and intestinal farnesoid X receptor (FXR) plays a pivotal role in the regulation of lipid metabolism, we hypothesized that the effects of BBR on intestinal FXR signaling pathway might account for its pharmacological effectiveness. Using wild type (WT) and intestine-specific FXR knockout (FXRint-/ ) mice, we found that BBR prevented the development of high-fat-diet-induced obesity and ameliorated triglyceride accumulation in livers of WT, but not FXRint /- mice. BBR increased conjugated bile acids in serum and their excretion in feces. Furthermore, BBR inhibited bile salt hydrolase (BSH) activity in gut microbiota, and significantly increased the levels of tauro-conjugated bile acids, especially tauro-cholic acid(TCA), in the intestine. Both BBR and TCA treatment activated the intestinal FXR pathway and reduced the expression of fatty-acid translocase Cd36 in the liver. These results indicate that BBR may exert its lipid-lowering effect primarily in the gut by modulating the turnover of bile acids and subsequently the ileal FXR signaling pathway. In summary, we provide the first evidence to suggest a new mechanism of BBR action in the intestine that involves, sequentially, inhibiting BSH, elevating TCA, and activating FXR, which lead to the suppression of hepatic expression of Cd36 that results in reduced uptake of long-chain fatty acids in the liver. PMID- 27932558 TI - PET/CT Imaging of Unstable Carotid Plaque with 68Ga-Labeled Somatostatin Receptor Ligand. AB - 68Ga-labeled somatostatin receptor ligand PET imaging has recently been shown in preclinical and early human studies to have a potential role in the evaluation of vulnerable arterial plaques. We prospectively evaluated carotid plaque 68Ga DOTATATE uptake in patients with recent carotid events, assessed inter- and intraobserver variability of such measurements, and explored the mechanism of any plaque DOTATATE activity with immunohistochemistry in resected specimens. Methods: Twenty consecutively consenting patients with recent symptomatic carotid events (transient ischemic attack, stroke, or amaurosis fugax), due for carotid endarterectomy, were prospectively recruited. 68Ga-DOTATATE PET/CT of the neck was performed before surgery. 68Ga-DOTATATE uptake was measured by drawing regions of interest along the carotid plaques and contralateral plaques/carotid arteries by an experienced radionuclide radiologist and radiographer. Two PET quantification methods with inter- and intraobserver variability were assessed. Resected carotid plaques were retrieved for somatostatin receptor subtype-2 (sst2) immunohistochemical staining. Results: The median time delay between research PET and surgery was 2 d. SUVs and target-to-background ratios for the symptomatic plaques and the asymptomatic contralateral carotid arteries/plaques showed no significant difference (n = 19, P > 0.10), regardless of quantification method. The intraclass correlation coefficient was greater than 0.8 in all measures of carotid artery/plaque uptake (SUV) and greater than 0.6 in almost all measures of target-to-background ratio. None of the excised plaques was shown to contain cells (macrophages, lymphocytes, vessel-associated cells) expressing sst2 on their cell membrane. Conclusion:68Ga-DOTATATE activity on PET in recently symptomatic carotid plaques is not significantly different from contralateral carotids/plaques. Any activity seen on PET is not shown to be from specific sst2 receptor-mediated uptake in vitro. It is therefore unlikely that sst2 PET/CT imaging will have a role in the detection and characterization of symptomatic carotid plaques. PMID- 27932560 TI - Reply: Neither Posttreatment PET/CT Nor Interim PET/CT Using Deauville Criteria Predicts Outcome in Pediatric Hodgkin Lymphoma. PMID- 27932561 TI - Repeatability of Quantitative Whole-Body 18F-FDG PET/CT Uptake Measures in Patients with Non-Small Cell Lung Cancer: Dynamic Versus Test-Retest Design. PMID- 27932563 TI - The Enigma of p53. AB - This perspective will focus on the physiological impact of wild-type and mutant p53 activities. In particular, the tissue-specific nature of activation of p53 targets and their subsequent effects on cell behavior will be discussed. Because mutations in p53 are common in human cancers, the regulation and physiological consequences of mutant p53 proteins will also be discussed. PMID- 27932562 TI - Intraoperative Assessment of Tumor Resection Margins in Breast-Conserving Surgery Using 18F-FDG Cerenkov Luminescence Imaging: A First-in-Human Feasibility Study. AB - In early-stage breast cancer, the primary treatment option for most women is breast-conserving surgery (BCS). There is a clear need for more accurate techniques to assess resection margins intraoperatively, because on average 20% of patients require further surgery to achieve clear margins. Cerenkov luminescence imaging (CLI) combines optical and molecular imaging by detecting light emitted by 18F-FDG. Its high-resolution and small size imaging equipment make CLI a promising technology for intraoperative margin assessment. A first-in human study was conducted to evaluate the feasibility of 18F-FDG CLI for intraoperative assessment of tumor margins in BCS. Methods: Twenty-two patients with invasive breast cancer received 18F-FDG (5 MBq/kg) 45-60 min before surgery. Sentinel lymph node biopsy was performed using an increased 99mTc-nanocolloid activity of 150 MBq to facilitate nodal detection against the gamma-probe background signal (cross-talk) from 18F-FDG. The cross-talk and 99mTc dose required was evaluated in 2 lead-in studies. Immediately after excision, specimens were imaged intraoperatively in an investigational CLI system. The first 10 patients were used to optimize the imaging protocol; the remaining 12 patients were included in the analysis dataset. Cerenkov luminescence images from incised BCS specimens were analyzed postoperatively by 2 surgeons blinded to the histopathology results, and mean radiance and margin distance were measured. The agreement between margin distance on CLI and histopathology was assessed. Radiation doses to staff were measured. Results: Ten of the 12 patients had an elevated tumor radiance on CLI. Mean radiance and tumor-to-background ratio were 560 +/- 160 photons/s/cm2/sr and 2.41 +/- 0.54, respectively. All 15 assessable margins were clear on CLI and histopathology. The agreement in margin distance and interrater agreement was good (kappa = 0.81 and 0.912, respectively). Sentinel lymph nodes were successfully detected in all patients. The radiation dose to staff was low; surgeons received a mean dose of 34 +/- 15 MUSv per procedure. Conclusion: Intraoperative 18F-FDG CLI is a promising, low-risk technique for intraoperative assessment of tumor margins in BCS. A randomized controlled trial will evaluate the impact of this technique on reexcision rates. PMID- 27932564 TI - A Conversation with Benjamin Neel. PMID- 27932565 TI - A Conversation with Gerard Evan. PMID- 27932566 TI - A Conversation with Guillermina (Gigi) Lozano. PMID- 27932567 TI - A Conversation with David Tuveson. PMID- 27932568 TI - Targeting HIF2 in Clear Cell Renal Cell Carcinoma. AB - Inactivation of the von Hippel-Lindau tumor-suppressor protein (pVHL) is the signature "truncal" event in clear cell renal cell carcinoma, which is the most common form of kidney cancer. pVHL is part of a ubiquitin ligase the targets the alpha subunit of the hypoxia-inducible factor (HIF) transcription factor for destruction when oxygen is available. Preclinical studies strongly suggest that deregulation of HIF, and particularly HIF2, drives pVHL-defective renal carcinogenesis. Although HIF2alpha was classically considered undruggable, structural and chemical work by Rick Bruick and Kevin Gardner at University of Texas Southwestern laid the foundation for the development of small molecule direct HIF2alpha antagonists (PT2385 and the related tool compound PT2399) by Peloton Therapeutics that block the dimerization of HIF2alpha with its partner protein ARNT1. These compounds inhibit clear cell renal cell carcinoma growth in preclinical models, and PT2385 has now entered the clinic. Nonetheless, the availability of such compounds, together with clustered regularly interspaced short palindromic repeat (CRISPR)-based gene editing approaches, has revealed a previously unappreciated heterogeneity among clear cell renal carcinomas and patient-derived xenografts with respect to HIF2 dependence, suggesting that predictive biomarkers will be needed to optimize the use of such agents in the clinic. PMID- 27932569 TI - Needle breakage in acupuncture: a biomechanical study. PMID- 27932570 TI - Effect of losartan combined with amlodipine or with a thiazide on uric acid levels in hypertensive patients. AB - : Hyperuricemia leads to endothelial dysfunction and insulin resistance, and has been associated with diseases such as hypertension. Antihypertensive drugs modify serum uric acid levels, however, few data are available about their combinations on uricemia. In this study we evaluate the effect of two combinations of losartan, with amlodipine or with hydrochlorothiazide, on serum uric acid levels in hypertensive patients. METHODS: A total of 60 hypertensive patients were randomized in two groups; group LA received losartan/amlodipine (100/5 mg) once a day, whereas LH group received losartan hydrochlorothiazide (100/12.5 mg) once a day for 3 months. In both groups serum uric acid levels were measured at the beginning and end of the study. Patients were evaluated monthly for blood pressure (BP) and adverse events. Statistical analysis was performed with a two way analysis of variance (ANOVA) for repeated measures. RESULTS: All patients experienced a significant reduction of BP to the same extent (LA 155/94 to 123/79, LH 157/92 to 124/78 mmHg, p > 0.05). In the LA group, serum uric acid decreased from 6.5 +/- 1.6 to 4.6 +/- 1.3 mg/ml ( p = 0.0001), whereas in the LH group there was a nonsignificant increase from 5.82 +/- 1.4 to 5.85 +/- 1.5 mg/ml, ( p = 0.936). When both groups were compared, we found a significant reduction ( p < 0.00013) on serum uric acid levels in the LA group. CONCLUSIONS: Both combinations decrease BP values to the same extent, however, LA combination showed a reduction on serum uric acid levels, which may contribute to a reduction in the metabolic risk in hypertensive patients. PMID- 27932571 TI - Esmolol before cardioplegia and as cardioplegia adjuvant reduces cardiac troponin release after cardiac surgery. A randomized trial. AB - BACKGROUND: Cardioplegic solutions are the standard in myocardial protection during cardiac surgery, since they interrupt the electro-mechanical activity of the heart and protect it from ischemia during aortic cross-clamping. Nevertheless, myocardial damage has a strong clinical impact. We tested the hypothesis that the short-acting beta-blocker esmolol, given immediately before cardiopulmonary bypass and as a cardioplegia additive, would provide an extra protection to myocardial tissue during cardiopulmonary bypass by virtually reducing myocardial activity and, therefore, oxygen consumption to zero. MATERIALS AND METHODS: This was a single-centre, double-blind, placebo controlled, parallel-group phase IV trial. Adult patients undergoing elective valvular and non-valvular cardiac surgery with end diastolic diameter >60 mm and ejection fraction <50% were enrolled. Patients were randomly assigned to receive either esmolol, 1 mg/kg before aortic cross-clamping and 2 mg/kg with Custodiol(r) crystalloid cardioplegia or equivolume placebo. The primary end point was peak postoperative troponin T concentration. Troponin was measured at Intensive Care Unit arrival and at 4, 24 and 48 hours. Secondary endpoints included ventricular fibrillation after cardioplegic arrest, need for inotropic support and intensive care unit and hospital stay. RESULTS: We found a reduction in peak postoperative troponin T, from 1195 ng/l (690-2730) in the placebo group to 640 ng/l (544-1174) in the esmolol group (p=0.029) with no differences in Intensive Care Unit stay [3 days (1-6) in the placebo group and 3 days (2-5) in the esmolol group] and hospital stay [7 days (6-10) in the placebo group and 7 days (6-12) in the esmolol group]. Troponin peak occurred at 24 hours for 12 patients (26%) and at 4 hours for the others (74%). There were no differences in other secondary end-points. CONCLUSIONS: Adding esmolol to the cardioplegia in high-risk patients undergoing elective cardiac surgery reduces peak postoperative troponin levels. Further investigation is necessary to assess esmolol effects on major clinical outcomes. PMID- 27932572 TI - A mechanism for acetylcholine receptor gating based on structure, coupling, phi, and flip. AB - Nicotinic acetylcholine receptors are allosteric proteins that generate membrane currents by isomerizing ("gating") between resting and active conformations under the influence of neurotransmitters. Here, to explore the mechanisms that link the transmitter-binding sites (TBSs) with the distant gate, we use mutant cycle analyses to measure coupling between residue pairs, phi value analyses to sequence domain rearrangements, and current simulations to reproduce a microsecond shut component ("flip") apparent in single-channel recordings. Significant interactions between amino acids separated by >15 A are rare; an exception is between the alphaM2-M3 linkers and the TBSs that are ~30 A apart. Linker residues also make significant, local interactions within and between subunits. Phi value analyses indicate that without agonists, the linker is the first region in the protein to reach the gating transition state. Together, the phi pattern and flip component suggest that a complete, resting<->active allosteric transition involves passage through four brief intermediate states, with brief shut events arising from sojourns in all or a subset. We derive energy landscapes for gating with and without agonists, and propose a structure-based model in which resting->active starts with spontaneous rearrangements of the M2 M3 linkers and TBSs. These conformational changes stabilize a twisted extracellular domain to promote transmembrane helix tilting, gate dilation, and the formation of a "bubble" that collapses to initiate ion conduction. The energy landscapes suggest that twisting is the most energetically unfavorable step in the resting->active conformational change and that the rate-limiting step in the reverse process is bubble formation. PMID- 27932574 TI - ULK1 cycling: The ups and downs of the autophagy response. AB - The Ser/Thr kinase ULK1/Atg1 controls autophagy initiation under nutrient starvation conditions. In this issue, Nazio et al. (2016. J. Cell Biol. https://doi.org/10.1083/jcb.201605089) demonstrate that oscillatory modulation of NEDD4L-mediated proteasomal degradation and mTOR-dependent de novo protein synthesis of ULK1 ensures the proper amplitude and duration of the autophagy response during prolonged starvation, thus maintaining cellular homeostasis. PMID- 27932573 TI - Fine-tuning of ULK1 mRNA and protein levels is required for autophagy oscillation. AB - Autophagy is an intracellular degradation pathway whose levels are tightly controlled to secure cell homeostasis. Unc-51-like kinase 1 (ULK1) is a conserved serine-threonine kinase that plays a central role in the initiation of autophagy. Here, we report that upon autophagy progression, ULK1 protein levels are specifically down-regulated by the E3 ligase NEDD4L, which ubiquitylates ULK1 for degradation by the proteasome. However, whereas ULK1 protein is degraded, ULK1 mRNA is actively transcribed. Upon reactivation of mTOR-dependent protein synthesis, basal levels of ULK1 are promptly restored, but the activity of newly synthesized ULK1 is inhibited by mTOR. This prepares the cell for a new possible round of autophagy stimulation. Our results thus place NEDD4L and ULK1 in a key position to control oscillatory activation of autophagy during prolonged stress to keep the levels of this process under a safe and physiological threshold. PMID- 27932575 TI - Natural killer cell granules converge to avoid collateral damage. AB - To clear infection, cytotoxic lymphocytes must destroy target cells while avoiding nonspecific killing of surrounding healthy cells. In this issue, Hsu et al. (2016. J. Cell Biol. https://doi.org/10.1083/jcb.201604136) use live-cell imaging to show that lytic granule convergence protects bystander cells from unintended death by promoting polarized secretion of soluble cytolytic proteins toward the intended target. PMID- 27932577 TI - Association between abdominal wall hernia and abdominal aortic aneurysm. PMID- 27932579 TI - Incidence rate for liver cancer in Japanese in Japan and in the United States from the Cancer Incidence in Five Continents. PMID- 27932580 TI - JJCO Paper of the Year and Highly Commended Paper. PMID- 27932576 TI - Mammalian synthetic biology for studying the cell. AB - Synthetic biology is advancing the design of genetic devices that enable the study of cellular and molecular biology in mammalian cells. These genetic devices use diverse regulatory mechanisms to both examine cellular processes and achieve precise and dynamic control of cellular phenotype. Synthetic biology tools provide novel functionality to complement the examination of natural cell systems, including engineered molecules with specific activities and model systems that mimic complex regulatory processes. Continued development of quantitative standards and computational tools will expand capacities to probe cellular mechanisms with genetic devices to achieve a more comprehensive understanding of the cell. In this study, we review synthetic biology tools that are being applied to effectively investigate diverse cellular processes, regulatory networks, and multicellular interactions. We also discuss current challenges and future developments in the field that may transform the types of investigation possible in cell biology. PMID- 27932582 TI - Translational Safety Genetics. AB - The emerging field of translational safety genetics is providing new opportunities to enhance drug discovery and development. Genetic variation in therapeutic drug targets, off-target interactors and relevant drug metabolism/disposition pathways can contribute to diverse drug pharmacologic and toxicologic responses between different animal species, strains and geographic origins. Recent advances in the sequencing of rodent, canine, nonhuman primate, and minipig genomes have dramatically improved the ability to select the most appropriate animal species for preclinical drug toxicity studies based on genotypic characterization of drug targets/pathways and drug metabolism and/or disposition, thus avoiding inconclusive or misleading animal studies, consistent with the principles of the 3Rs (replacement, reduction and refinement). The genetic background of individual animals should also be taken into consideration when interpreting phenotypic outcomes from toxicity studies and susceptibilities to spontaneous safety-relevant background findings. PMID- 27932583 TI - Inhibition of HIV-1 Gag-membrane interactions by specific RNAs. AB - HIV-1 particle assembly, which occurs at the plasma membrane (PM) of cells, is driven by the viral polyprotein Gag. Gag recognizes phosphatidylinositol-(4,5) bisphosphate [PI(4,5)P2], a PM-specific phospholipid, via the highly basic region (HBR) in its N-terminal matrix (MA) domain. The HBR is also known to bind to RNA. We have previously shown, using an in vitro liposome binding assay, that RNA inhibits Gag binding to membranes that lack PI(4,5)P2 If this RNA block is removed by RNase treatment, Gag can bind nonspecifically to other negatively charged membranes. In an effort to identify the RNA species that confer this inhibition of Gag membrane binding, we have tested the impact of purified RNAs on Gag interactions with negatively charged liposomes lacking PI(4,5)P2 We found that some tRNA species and RNAs containing stem-loop 1 of the psi region in the 5' untranslated region of the HIV-1 genome impose inhibition of Gag binding to membranes lacking PI(4,5)P2 In contrast, a specific subset of tRNAs, as well as an RNA sequence previously selected in vitro for MA binding, failed to suppress Gag-membrane interactions. Furthermore, switching the identity of charged residues in the HBR did not diminish the susceptibility of Gag-liposome binding for each of the RNAs tested, while deletion of most of the NC domain abrogates the inhibition of membrane binding mediated by the RNAs that are inhibitory to WT Gag-liposome binding. These results support a model in which NC facilitates binding of RNA to MA and thereby promotes RNA-based inhibition of Gag-membrane binding. PMID- 27932584 TI - The eIF3 complex of Trypanosoma brucei: composition conservation does not imply the conservation of structural assembly and subunits function. AB - The multisubunit eukaryotic initiation factor 3 (eIF3) plays multiple roles in translation but is poorly understood in trypanosomes. The putative subunits eIF3a and eIF3f of Trypanosoma brucei (TbIF3a and TbIF3f) were overexpressed and purified, and 11 subunits were identified, TbIF3a through l minus j, which form a tight complex. Both TbIF3a and TbIF3f are essential for the viability of T. brucei RNAi knockdown of either of them severely reduced total translation and the ratio of the polysome/80S peak area. TbIF3f and TbIF3a RNAi cell lines were modified to express tagged-TbIF3a and -TbIF3f, respectively. RNAi in combination with affinity purification assays indicated that both subunits are variably required for TbIF3 stability and integrity. The relative abundance of other subunits in the TbIF3f-tag complex changed little upon TbIF3a depletion; while only subunits TbIF3b, i, and e copurified comparably with TbIF3a-tag upon TbIF3f depletion. A genome-wide UV-crosslinking assay showed that several TbIF3 subunits have direct RNA-binding activity, with TbIF3c showing the strongest signal. In addition, CrPV IRES, but neither EMCV IRES nor HCV IRES, was found to mediate translation in T. brucei These results together imply that the structure of TbIF3 and the subunits function have trypanosome-specific features, although the composition is evolutionarily conserved. PMID- 27932585 TI - Structural and functional characterization of the TYW3/Taw3 class of SAM dependent methyltransferases. AB - S-adenosylmethionine (SAM)-dependent methyltransferases regulate a wide range of biological processes through the modification of proteins, nucleic acids, polysaccharides, as well as various metabolites. TYW3/Taw3 is a SAM-dependent methyltransferase responsible for the formation of a tRNA modification known as wybutosine and its derivatives that are required for accurate decoding in protein synthesis. Here, we report the crystal structure of Taw3, a homolog of TYW3 from Sulfolobus solfataricus, which revealed a novel alpha/beta fold. The sequence motif (S/T)xSSCxGR and invariant aspartate and histidine, conserved in TYW3/Taw3, cluster to form the catalytic center. These structural and sequence features indicate that TYW3/Taw3 proteins constitute a distinct class of SAM-dependent methyltransferases. Using site-directed mutagenesis along with in vivo complementation assays combined with mass spectrometry as well as ligand docking and cofactor binding assays, we have identified the active site of TYW3 and residues essential for cofactor binding and methyltransferase activity. PMID- 27932586 TI - Nup100 regulates Saccharomyces cerevisiae replicative life span by mediating the nuclear export of specific tRNAs. AB - Nuclear pore complexes (NPCs), which are composed of nucleoporins (Nups) and regulate transport between the nucleus and cytoplasm, significantly impact the replicative life span (RLS) of Saccharomyces cerevisiae We previously reported that deletion of the nonessential gene NUP100 increases RLS, although the molecular basis for this effect was unknown. In this study, we find that nuclear tRNA accumulation contributes to increased longevity in nup100Delta cells. Fluorescence in situ hybridization (FISH) experiments demonstrate that several specific tRNAs accumulate in the nuclei of nup100Delta mutants. Protein levels of the transcription factor Gcn4 are increased when NUP100 is deleted, and GCN4 is required for the elevated life spans of nup100Delta mutants, similar to other previously described tRNA export and ribosomal mutants. Northern blots indicate that tRNA splicing and aminoacylation are not significantly affected in nup100Delta cells, suggesting that Nup100 is largely required for nuclear export of mature, processed tRNAs. Distinct tRNAs accumulate in the nuclei of nup100Delta and msn5Delta mutants, while Los1-GFP nucleocytoplasmic shuttling is unaffected by Nup100. Thus, we conclude that Nup100 regulates tRNA export in a manner distinct from Los1 or Msn5. Together, these experiments reveal a novel Nup100 role in the tRNA life cycle that impacts the S. cerevisiae life span. PMID- 27932587 TI - A divalent cation-dependent variant of the glmS ribozyme with stringent Ca2+ selectivity co-opts a preexisting nonspecific metal ion-binding site. AB - Ribozymes use divalent cations for structural stabilization, as catalytic cofactors, or both. Because of the prominent role of Ca2+ in intracellular signaling, engineered ribozymes with stringent Ca2+ selectivity would be important in biotechnology. The wild-type glmS ribozyme (glmSWT) requires glucosamine-6-phosphate (GlcN6P) as a catalytic cofactor. Previously, a glmS ribozyme variant with three adenosine mutations (glmSAAA) was identified, which dispenses with GlcN6P and instead uses, with little selectivity, divalent cations as cofactors for site-specific RNA cleavage. We now report a Ca2+-specific ribozyme (glmSCa) evolved from glmSAAA that is >10,000 times more active in Ca2+ than Mg2+, is inactive in even 100 mM Mg2+, and is not responsive to GlcN6P. This stringent selectivity, reminiscent of the protein nuclease from Staphylococcus, allows rapid and selective ribozyme inactivation using a Ca2+ chelator such as EGTA. Because glmSCa functions in physiologically relevant Ca2+ concentrations, it can form the basis for intracellular sensors that couple Ca2+ levels to RNA cleavage. Biochemical analysis of glmSCa reveals that it has co-opted for selective Ca2+ binding a nonspecific cation-binding site responsible for structural stabilization in glmSWT and glmSAAA Fine-tuning of the selectivity of the cation site allows repurposing of this preexisting molecular feature. PMID- 27932589 TI - Sex and Race/Ethnicity Differences in Following Dietary and Exercise Recommendations for U.S. Representative Sample of Adults With Type 2 Diabetes. AB - This study examined sex by race/ethnicity differences in medical advice received for diet and exercise with corresponding health behaviors of a U.S. representative sample of adults with type 2 diabetes ( N = 1,269). Data from the National Health and Nutrition Examination Surveys for 2011-2014 for 185 Mexican Americans, 123 Other Hispanics, 392 non-Hispanic Blacks, 140 non-Hispanic Asians, and 429 non-Hispanic Whites were analyzed using logistic regression analyses. Reporting being given dietary and exercise advice was positively associated with reporting following the behavior. There were differences in sex and sex by race/ethnicity for reporting receiving medical advice and performing the advised health behavior. These results suggest the importance of physicians having patient-centered communication skills and cultural competency when discussing diabetes management. PMID- 27932588 TI - Mental Health Among Jail and Prison Inmates. AB - Previous studies provide insight into the mental health of jail and prison inmates, but this research does not compare the two groups of inmates. Using data from the Fragile Families and Child Wellbeing Study, this article examines how the association between incarceration and self-reported mental health varies by facility type, net of an array of demographic and socioeconomic characteristics. Both jail and prison inmates report high rates of depression, life dissatisfaction, heavy drinking, and illicit drug use. In adjusted logistic regression models, those incarcerated in jails, compared with those not incarcerated, have higher odds of depression (odds ratio [ OR] = 5.06, 90% confidence interval [CI; 1.96, 13.11]), life dissatisfaction ( OR = 3.59, 90% CI [1.40, 9.24]), and recent illicit drug use ( OR = 4.03, 90% CI [1.49, 10.58]). Those incarcerated in prisons have higher odds of life dissatisfaction ( OR = 3.88, 90% CI [2.16, 6.94]) and lower odds of recent heavy drinking ( OR = 0.32, 90% CI [0.13, 0.81]) compared with those not incarcerated. Furthermore, jail inmates report significantly more depression, heavy drinking, and illicit drug use than prison inmates. These results suggest the association between incarceration and mental health may vary substantially across facilities and highlight the importance of expanding research in this area beyond studies of prisons. The results also indicate that public health professionals in the correctional system should be especially attuned to the disproportionately high levels of poor mental health outcomes among jail inmates. PMID- 27932590 TI - The Accuracy of Measurements of Nonmelanoma Skin Cancer Sizes Referred to the Mohs Surgery Clinic. AB - BACKGROUND: Tumour size is a crucial factor used to plan Mohs procedures. Larger tumours require more time and stages of excision, and they need to be triaged as a higher priority. Therefore, the accuracy in measurement of tumour size is critical. OBJECTIVE: To investigate if there is a significant difference in accuracy of tumour measurements in referrals between dermatologists and nondermatologists. METHODS AND MATERIALS: Performed a retrospective study of 180 referrals from dermatologists and 47 referrals from nondermatologists to The Ottawa Hospital Riverside Mohs Surgery Clinic. We compared the mean size difference of tumours between the preoperative size and the size reported on referral. RESULTS: Average reported size upon referral of nonmelanoma skin cancer (NMSC) was 1.39 cm2 and 1.35 cm2 from dermatologists and nondermatologists, respectively ( P = .881). During the preoperative assessment, tumour sizes were 0.65 cm2 and 1.45 cm2 larger than that reported from dermatologists and nondermatologists, respectively ( P < .05). The duration between referral and preoperative assessment was 3 to 4 months for both groups ( P = .26). CONCLUSION: The accuracy of tumour measurements between dermatologists and nondermatologists differed significantly, as nondermatologists underestimated the size of NMSCs. This directly affects triaging patients and operative management in Mohs surgery. To compensate for size underestimation, early and prompt referrals of NMSCs from nondermatologists are warranted. PMID- 27932591 TI - The Cellular Diversity of the Pedunculopontine Nucleus: Relevance to Behavior in Health and Aspects of Parkinson's Disease. AB - The pedunculopontine nucleus (PPN) is a rostral brainstem structure that has extensive connections with basal ganglia nuclei and the thalamus. Through these the PPN contributes to neural circuits that effect cortical and hippocampal activity. The PPN also has descending connections to nuclei of the pontine and medullary reticular formations, deep cerebellar nuclei, and the spinal cord. Interest in the PPN has increased dramatically since it was first suggested to be a novel target for treating patients with Parkinson's disease who are refractory to medication. However, application of frequency-specific electrical stimulation of the PPN has produced inconsistent results. A central reason for this is that the PPN is not a heterogeneous structure. In this article, we review current knowledge of the neurochemical identity and topographical distribution of neurons within the PPN of both humans and experimental animals, focusing on studies that used neuronally selective targeting strategies to ascertain how the neurochemical heterogeneity of the PPN relates to its diverse functions in relation to movement and cognitive processes. If the therapeutic potential of the PPN is to be realized, it is critical to understand the complex structure-function relationships that exist here. PMID- 27932593 TI - Dexamethasone-Induced Intrauterine Growth Restriction Is Associated With Altered Expressions of Metastasis Tumor Antigens and Cell Cycle Control Proteins in Rat Placentas. AB - Molecular mechanisms affecting placental formation in intrauterine growth restricted (IUGR) pregnancies are not clearly understood. Since metastasis tumor antigens (MTAs) MTA1 and MTA2 promote cell proliferation and MTA3 suppresses it, we hypothesized that IUGR alters cell survival/cell death programs driven by placental MTAs. To induce IUGR, pregnant Sprague Dawley rats were given daily intraperitoneal injections of either saline or dexamethasone (0.4 mg/kg) starting from 14 days of gestation (dg) to either 19 dg or 21 dg. Gene and protein expressions of MTA1-3 in the placental basal and labyrinth zones were investigated by real-time polymerase chain reaction, Western blotting, and immunohistochemistry. We also explored the expressions of proliferating cell nuclear antigen (PCNA), caspase-3, p53, p21, and beta-catenin. Dexamethasone induced IUGR resulted in decreased expression of MTA1 in the nuclei of cells in the basal zone. The expression of p21 was increased and that of PCNA was reduced in both placental zones of IUGR rats. Cytoplasmic expression of MTA1 and p53 increased in the labyrinth zone of IUGR placentas in association with an increase in cell death as indicated by an increased caspase-3 expression. The labyrinth zone of IUGR placentas showed a significant reduction in MTA2-MTA3 gene expression and an increase in p53 protein levels. Total MTA3 level increased and beta-catenin level decreased in the labyrinth zone of IUGR placentas associated with a reduction in cell proliferation. Taken together, these results strongly suggest that dexamethasone-induced IUGR is associated with changes in MTA expression, decreased cell proliferation, and increased cell death in placentas. PMID- 27932595 TI - The Relationship Between Acute Malnutrition, Hygiene Practices, Water and Livestock, and Their Program Implications in Eastern Chad. AB - BACKGROUND: The causes of acute malnutrition are complex and time and geography variant and need to be better understood in order to both design more effective nutrition programs and evaluate them. The findings reported here are part of an evaluation of a 4-year multisectoral nutrition program led by Concern Worldwide in the Sila Region of eastern Chad. OBJECTIVE: To present evidence and learning about the relationships between acute malnutrition and potential drivers in Sila, Chad. METHODS: Quantitative household-level data from a clustered randomized control trial were collected in November/December 2014. The survey was complemented with water quality testing and qualitative data collected in February and March 2013 and 2014. RESULTS: Households who reported not regularly cleaning the container used for transporting water for household consumption were almost twice as likely to have a malnourished child. Households living in villages with larger concentrations of cattle and having more livestock sharing the same water source as for human consumption were significantly more likely to have a malnourished child. However, cleaning the water container mediated the negative impact of living in a village with a large cattle concentration on wasting. CONCLUSION: These results demonstrate that hygiene practices and livestock water management are correlated with acute malnutrition in Sila, Chad. These findings provide a hypothesis for a possible pathogen driving acute malnutrition rates- Cryptosporidium-as part of a complex water chain, whereby the source of infection may be mitigated by hygiene behaviors with important implications for humanitarian programs. PMID- 27932592 TI - The role of adipose tissue in cancer-associated cachexia. AB - Adipose tissue (fat) is a heterogeneous organ, both in function and histology, distributed throughout the body. White adipose tissue, responsible for energy storage and more recently found to have endocrine and inflammation-modulatory activities, was historically thought to be the only type of fat present in adult humans. The recent demonstration of functional brown adipose tissue in adults, which is highly metabolic, shifted this paradigm. Additionally, recent studies demonstrate the ability of white adipose tissue to be induced toward the brown adipose phenotype - "beige" or "brite" adipose tissue - in a process referred to as "browning." While these adipose tissue depots are under investigation in the context of obesity, new evidence suggests a maladaptive role in other metabolic disturbances including cancer-associated cachexia, which is the topic of this review. This syndrome is multifactorial in nature and is an independent factor associated with poor prognosis. Here, we review the contributions of all three adipose depots - white, brown, and beige - to the development and progression of cancer-associated cachexia. Specifically, we focus on the local and systemic processes involving these adipose tissues that lead to increased energy expenditure and sustained negative energy balance. We highlight key findings from both animal and human studies and discuss areas within the field that need further exploration. Impact statement Cancer-associated cachexia (CAC) is a complex, multifactorial syndrome that negatively impacts patient quality of live and prognosis. This work reviews a component of CAC that lacks prior discussion: adipose tissue contributions. Uniquely, it discusses all three types of adipose tissue, white, beige, and brown, their interactions, and their contributions to the development and progression of CAC. Summarizing key bench and clinical studies, it provides information that will be useful to both basic and clinical researchers in designing experiments, studies, and clinical trials. PMID- 27932594 TI - The Interaction between Genetic Ancestry and Breast Cancer Risk Factors among Hispanic Women: The Breast Cancer Health Disparities Study. AB - Background: Hispanic women have lower breast cancer incidence rates than non Hispanic white (NHW) women. To what extent genetic versus nongenetic factors account for this difference is unknown.Methods: Using logistic regression, we evaluated the interactive influences of established risk factors and ethnicity (self-identified and identified by ancestral informative markers) on breast cancer risk among 2,326 Hispanic and 1,854 NHW postmenopausal women from the United States and Mexico in the Breast Cancer Health Disparities Study.Results: The inverse association between the percentage of Native American (NA) ancestry and breast cancer risk was only slightly attenuated after adjusting for known risk factors [lowest versus highest quartile: odds ratio (OR) =1.39, 95% confidence interval (CI) = 1.00-1.92 among U.S. Hispanics; OR = 1.92 (95% CI, 1.29-2.86) among Mexican women]. The prevalence of several risk factors, as well as the associations with certain factors and breast cancer risk, differed according to genetic admixture. For example, higher body mass index (BMI) was associated with reduced risk among women with lower NA ancestry only [BMI <25 versus >30: OR = 0.65 (95% CI, 0.44-0.98) among U.S. Hispanics; OR = 0.53 (95% CI, 0.29-0.97) among Mexicans]. The average number of risk factors among cases was inversely related to the percentage of NA ancestry.Conclusions: The lower NA ancestry groups were more likely to have the established risk factors, with the exception of BMI. Although the majority of factors were associated with risk in the expected directions among all women, BMI had an inverse association among Hispanics with lower NA ancestry.Impact: These data suggest that the established risk factors are less relevant for breast cancer development among women with more NA ancestry. Cancer Epidemiol Biomarkers Prev; 26(5); 692-701. (c)2016 AACR. PMID- 27932596 TI - Infantile Lhermitte-Duclos Disease Treated Successfully With Rapamycin. AB - Lhermitte-Duclos disease is a rare hamartomatous tumor of the cerebellum resulting from a mutation in the phosphatase and tensin homolog (PTEN) gene: it has been reported in fewer than 10 infants. Rapamycin treatment has not yet been described in Lhermitte-Duclos disease. The infant underwent shunt placement shortly after birth for aqueductal stenosis. Her clinical progression included failure to thrive, seizures, episodes of decerebrate posturing, loss of respiratory drive, and pituitary insufficiency from mass effect. The characteristic "tiger stripe" sign on imaging prompted diagnosis. Rapamycin therapy was initiated at 18 months. Within 5 months, our patient has become responsive to her surroundings and had return of spontaneous breathing. Repeat magnetic resonance imaging (MRI) reveals lack of brainstem compression or distortion of pituitary stalk. Rapamycin should be considered in cases of Lhermitte-Duclos disease where surgical removal may not be an option, as in our case where the cerebellum was entirely involved. PMID- 27932598 TI - How Much Cerebrospinal Fluid Should We Remove Prior to Measuring a Closing Pressure? AB - OBJECTIVE: The objective of this study was to identify a relationship between cerebrospinal fluid (CSF) volume removal and change in CSF pressure in children with suspected idiopathic intracranial hypertension (IIH). METHODS: We performed a cross-sectional study of children 22 years and younger who underwent a lumbar puncture (LP) and had a documented opening pressure, closing pressure, and volume removed. Relationship between volume removal and pressure change was determined using a fractional polynomial regression procedure. RESULTS: In the 297 patients who met the inclusion criteria, CSF pressure decreased by 1 cm H2O for every 0.91 mL of CSF removed if the maximum change in pressure was less than 15 cm H2O ( R2 = 0.38). CONCLUSION: A linear relationship exists between the volume of CSF removed and the amount of pressure relieved when the desired pressure change is less than 15 cm H2O. PMID- 27932597 TI - Parent Experience of Neonatal Encephalopathy. AB - We aimed to characterize the parent experience of caring for an infant with neonatal encephalopathy. In this mixed-methods study, we performed semistructured interviews with parents whose infants were enrolled in an existing longitudinal cohort study of therapeutic hypothermia between 2011 and 2014. Thematic saturation was achieved after 20 interviews. Parent experience of caring for a child with neonatal encephalopathy was characterized by 3 principal themes. Theme 1: Many families described cumulative loss and grief throughout the perinatal crisis, critical neonatal course, and subsequent missed developmental milestones. Theme 2: Families experienced entangled infant and broader family interests. Theme 3: Parents evolved into and found meaning in their role as an advocate. These data offer insight into the lived experience of parenting an infant with neonatal encephalopathy. Primary data from parents can serve as a useful framework to guide the development and interpretation of parent-centered outcomes. PMID- 27932599 TI - The role of digital interventions in sexual health. PMID- 27932600 TI - Delineating the fine line between the mad and the bad: Victorian prisons and insane asylums, 1856-1914. PMID- 27932601 TI - School Nurse Workload. AB - The purpose of this scoping review was to survey the most recent (5 years) acute care, community health, and mental health nursing workload literature to understand themes and research avenues that may be applicable to school nursing workload research. The search for empirical and nonempirical literature was conducted using search engines such as Google Scholar, PubMed, CINAHL, and Medline. Twenty-nine empirical studies and nine nonempirical articles were selected for inclusion. Themes that emerged consistent with school nurse practice include patient classification systems, environmental factors, assistive personnel, missed nursing care, and nurse satisfaction. School nursing is a public health discipline and population studies are an inherent research priority but may overlook workload variables at the clinical level. School nurses need a consistent method of population assessment, as well as evaluation of appropriate use of assistive personnel and school environment factors. Assessment of tasks not directly related to student care and professional development must also be considered in total workload. PMID- 27932602 TI - A Cross-Cultural Study of Punishment Beliefs and Decisions. AB - The current research examined cultural similarities and differences in punishment beliefs and decisions. Participants were European Americans ( N = 50), Chinese Americans ( N = 57), and Chinese in Mainland China ( N = 50). The Functions of Punishment Questionnaire was used to measure participants' beliefs about the retributive or deterrent functions of punishment and a scenario method was used to measure the extent to which punishment decisions were driven by individuals' concerns for retribution or deterrence. The results indicated that, contrary to the hypothesis that the retributive function would be emphasized by individualistic groups and the deterrent function by collectivistic groups, Mainland Chinese participants had a stronger belief in retribution and a weaker belief in deterrence than did European and Chinese Americans. The results also indicated that retribution played a bigger role in punishment decisions for Chinese than for the other two groups, but the importance of the deterrence function in punishment decisions did not differ across the three groups. Finally, the correlation between interdependence orientation and the belief in retribution was positive for Chinese but negative for European Americans. Taken together, the findings provided little evidence that collectivists are more deterrence-oriented and individualists more retribution-oriented. PMID- 27932603 TI - Poststroke Depression: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. AB - Poststroke depression (PSD) is common, affecting approximately one third of stroke survivors at any one time after stroke. Individuals with PSD are at a higher risk for suboptimal recovery, recurrent vascular events, poor quality of life, and mortality. Although PSD is prevalent, uncertainty remains regarding predisposing risk factors and optimal strategies for prevention and treatment. This is the first scientific statement from the American Heart Association on the topic of PSD. Members of the writing group were appointed by the American Heart Association Stroke Council's Scientific Statements Oversight Committee and the American Heart Association's Manuscript Oversight Committee. Members were assigned topics relevant to their areas of expertise and reviewed appropriate literature, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion. This multispecialty statement provides a comprehensive review of the current evidence and gaps in current knowledge of the epidemiology, pathophysiology, outcomes, management, and prevention of PSD, and provides implications for clinical practice. PMID- 27932605 TI - Henry J.M. Barnett: 1922-2016. PMID- 27932604 TI - Poststroke Post-Traumatic Stress Disorder: A Review. PMID- 27932606 TI - Development and Validation of a Grading Scale for Primary Pontine Hemorrhage. AB - BACKGROUND AND PURPOSE: We aimed to develop and validate a grading scale for predicting 30-day mortality and 90-day functional outcome in patients with primary pontine hemorrhage (PPH). METHODS: We retrospectively reviewed records of consecutive patients with first-ever pontine hemorrhage from 3 teaching hospitals between 2005 and 2012. Independent factors associated with 30-day mortality were identified by logistic regression to establish a risk stratification scale, named the new PPH score. For validation of the new PPH score, we prospectively recruited subjects from 10 units between December 2014 and November 2015. The performance of the new PPH score was presented as discrimination and calibration, measured by area under the curve of the receiver operating characteristic and Hosmer-Lemeshow goodness-of-fit, respectively. RESULTS: Data of 171 patients were available for scale development. The new PPH score consisted of 2 independent factors with individual points assigned as follows: Glasgow Coma Scale score 3 to 4 (=2 points), 5 to 7 (=1 point), and 8 to 15 (=0 point); PPH volume >10 mL (=2 points), 5 to 10 mL (=1 point), and <5 mL (=0 point). An independent cohort of 98 patients was applied as an external validation of the new PPH score. Results showed that the new PPH score was discriminative in predicting both 30-day mortality (area under the curve, 0.902) and 90-day good outcome (area under the curve, 0.927). Furthermore, the new PPH score revealed a good calibration (chi2=1.387; P=0.846) in 30-day mortality prediction. CONCLUSIONS: The new PPH score is simple and reliable in predicting short-term and long-term outcome for PPH patients. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org.cn. Unique identifier: ChiCTR-OOC-14005533. PMID- 27932607 TI - Randomized, Open-Label, Phase 1/2a Study to Determine the Maximum Tolerated Dose of Intraventricular Sustained Release Nimodipine for Subarachnoid Hemorrhage (NEWTON [Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage]). AB - BACKGROUND AND PURPOSE: We conducted a randomized, open-label, phase 1/2a, dose escalation study of intraventricular sustained-release nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage. METHODS: Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG 1962 or enteral nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose. RESULTS: Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG-1962 dose limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%-74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%-48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04-2.03; P=0.027) enteral nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]). CONCLUSIONS: EG 1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01893190. PMID- 27932608 TI - Antiviral Activity of Pocapavir in a Randomized, Blinded, Placebo-Controlled Human Oral Poliovirus Vaccine Challenge Model. AB - Background: Immunodeficient individuals who excrete vaccine-derived polioviruses threaten polio eradication. Antivirals address this threat. Methods: In a randomized, blinded, placebo-controlled study, adults were challenged with monovalent oral poliovirus type 1 vaccine (mOPV1) and subsequently treated with capsid inhibitor pocapavir or placebo. The time to virus negativity in stool was determined. Results: A total of 144 participants were enrolled; 98% became infected upon OPV challenge. Pocapavir-treated subjects (n = 93) cleared virus a median duration of 10 days after challenge, compared with 13 days for placebo recipients (n = 48; P = .0019). Fifty-two of 93 pocapavir-treated subjects (56%) cleared virus in 2-18 days with no evidence of drug resistance, while 41 of 93 (44%) treated subjects experienced infection with resistant virus while in the isolation facility, 3 (3%) of whom were infected at baseline, before treatment initiation. Resistant virus was also observed in 5 placebo recipients (10%). Excluding those with resistant virus, the median time to virus negativity was 5.5 days in pocapavir recipients, compared with 13 days in placebo recipients (P < .0001). There were no serious adverse events and no withdrawals from the study. Conclusions: Treatment with pocapavir was safe and significantly accelerated virus clearance. Emergence of resistant virus and transmission of virus were seen in the context of a clinical isolation facility. Clinical Trials Registration: EudraCT 2011-004804-38. PMID- 27932610 TI - Statins, Influenza Vaccination and Influenza. PMID- 27932609 TI - Completing Polio Eradication: The Case for Antiviral Drugs. PMID- 27932611 TI - Kaposi's Sarcoma-Associated Herpesvirus Infection of Neurons in HIV-Positive Patients. AB - Background: Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), one of the leading cancers in human immunodeficiency virus (HIV)-infected patients in Zambia. KSHV was detected in the human central nervous system (CNS) by polymerase chain reaction (PCR) analysis, but tissue location and cell tropism for KSHV infection has not been established. Given the neurotropism exhibited by other herpesviruses and the frequent coinfection of HIV positive individuals by KSHV, we sought to determine whether the central nervous system (CNS) can be infected by KSHV in HIV-positive Zambian individuals. Methods: Postmortem brain tissue specimens were collected from individuals coinfected with KSHV and HIV. PCR and Southern blots were performed on DNA extracted from the brain tissue specimens to verify KSHV infection. Immunohistochemical analysis and immunofluorescent microscopy were used to localize and identify KSHV-infected cells. Tropism was further established by in vitro infection of primary human neurons with rKSHV.219. Results: KSHV DNA was detected in the CNS from 4 of 11 HIV-positive individuals. Immunohistochemical analysis and immunofluorescent microscopy demonstrated that KSHV infected neurons and oligodendrocytes in parenchymal brain tissues. KSHV infection of neurons was confirmed by in vitro infection of primary human neurons with rKSHV.219. Conclusion: Our study showed that KSHV infects human CNS-resident cells, primarily neurons, in HIV-positive Zambian individuals. PMID- 27932612 TI - Legionella longbeachae Is Immunologically Silent and Highly Virulent In Vivo. AB - Background: Legionella longbeachae (Llo) and Legionella pneumophila (Lpn) are the most common pneumonia-causing agents of the genus. Although both species can be lethal to humans and are highly prevalent, little is known about the molecular pathogenesis of Llo infections. In murine models of infection, Lpn infection is self-limited, whereas Llo infection is lethal. Methods: We used mouse macrophages, human macrophages, human epithelial cells, and mouse infections in vivo to evaluate multiple parameters of the infection. Results: We determined that the Llo Dot/Icm secretion system is critical for virulence. Different than Lpn, Llo disseminates and the animals develop a severe pulmonary failure, as demonstrated by lung mechanics and blood oxygenation assays. As compared to Lpn, Llo is immunologically silent and fails to trigger the production of cytokines in human pulmonary epithelial cells and in mouse and human macrophages. Infections in Tnfr1-/-, Ifng-/-, and Il12p40-/- mice supported the participation of cytokines for the resistance phenotype. Conclusions: Both Lpn and Llo require the Dot/Icm system for pathogenesis, but the infection outcome is strikingly different. Llo is immunologically silent, highly virulent, and lethal. The differences reported herein may reflect unappreciated clinical differences in patients infected with Lpn or Llo. PMID- 27932613 TI - Type 1 Reaction in Patients With Leprosy Corresponds to a Decrease in Proresolving Lipid Mediators and an Increase in Proinflammatory Lipid Mediators. AB - Background: Type 1 reaction (T1R) is an acute T-helper type 1 (Th1) inflammatory episode in patients with leprosy. While immunological responses associated with T1R have been investigated, the corresponding metabolic responses that could contribute to T1R pathology have received little attention. Methods: Metabolomics based analyses of sera from 7 patients with and 9 without T1R were conducted via liquid chromatography-mass spectrometry. Serum metabolites present at levels that significantly differed (P < .05) with a log2 fold change of >= 1.0 between patient groups were interrogated against known metabolic pathways. The structural identification of targeted metabolites was confirmed and abundance changes validated by mass spectrometry and enzyme-linked immunoassay. Results: Forty metabolic pathways were perturbed in patients with T1R, with 71 dysregulated metabolites mapping to pathways for lipid mediators of inflammation. Of note was an increase in the abundance of the proinflammatory leukotriene B4 (LTB4) and a corresponding decrease in the level of proresolving resolvin D1 (RvD1). Also, levels of prostaglandin D2 (PGD2) and lipoxin A4 (LXA4) in patients with T1R were significantly increased, while the level of prostaglandin E2 (PGE2) was decreased. Conclusions: The dysregulation of metabolic pathways leading to abundance shifts between proinflammatory and proresolving lipid mediators provides a link between metabolic and cellular immune responses that result in the Th1-mediated pathology of T1R. PMID- 27932614 TI - Validation of the Cepheid GeneXpert for Detecting Ebola Virus in Semen. AB - Background: Ebola virus (EBOV) RNA persistence in semen, reported sexual transmission, and sporadic clusters at the end of the 2013-2016 epidemic have prompted recommendations that male survivors refrain from unprotected sex unless their semen is confirmed to be EBOV free. However, there is no fully validated assay for EBOV detection in fluids other than blood. Methods: The Cepheid Xpert Ebola assay for EBOV RNA detection was validated for whole semen and blood using samples obtained from uninfected donors and spiked with inactivated EBOV. The validation procedure incorporated standards from Clinical and Laboratory Standards Institute and Good Clinical Laboratory Practices guidelines for evaluating molecular devices for use in infectious disease testing. Results: The assay produced limits of detection of 1000 copies/mL in semen and 275 copies/mL in blood. Limits of detection for both semen and blood increased with longer intervals between collection and testing, with acceptable results obtained up to 72 hours after specimen collection. Conclusions: The Cepheid Xpert Ebola assay is accurate and precise for detecting EBOV in whole semen. A validated assay for EBOV RNA detection in semen informs the care of male survivors of Ebola, as well as recommendations for public health. PMID- 27932616 TI - Modified Profile of Matrix Metalloproteinase 2 and 9 Production by Human Fallopian Tube Epithelial Cells After Infection In Vitro With Neisseria gonorrhoeae. AB - Epithelial shedding and scarring of fallopian tube mucosa are the main consequences of sexually transmitted Neisseria gonorrhoeae infection and probably involve an imbalance of host extracellular matrix components and their regulators such as matrix metalloproteinases (MMPs). In the current study, primary human fallopian tube epithelial cells were infected with N. gonorrhoeae, and MMP patterns were examined. Gonococcal infection induced a significant increase in secreted MMP-9 and an accumulation of cytoplasmic MMP-2 over time, but no significant MMP-3 or MMP-8 production was observed. Thus, MMP-9 in particular could play a role in tubal scarring in response to gonococcal infection. PMID- 27932615 TI - Use of an Anopheles Salivary Biomarker to Assess Malaria Transmission Risk Along the Thailand-Myanmar Border. AB - Background: The modalities of malaria transmission along the Thailand-Myanmar border are poorly understood. Here we address the relevance of using a specific Anopheles salivary biomarker to measure the risk among humans of exposure to Anopheles bites. Methods: Serologic surveys were conducted from May 2013 to December 2014 in 4 sentinel villages. More than 9400 blood specimens were collected in filter papers from all inhabitants at baseline and then every 3 months thereafter, for up to 18 months, for analysis by enzyme-linked immunosorbent assay. The relationship between the intensity of the human antibody response and entomological indicators of transmission (human biting rates and entomological inoculation rates [EIRs]) was studied using a multivariate 3-level mixed model analysis. Heat maps for human immunoglobulin G (IgG) responses for each village and survey time point were created using QGIS 2.4. Results: The levels of IgG response among participants varied significantly according to village, season, and age (P<.001) and were positively associated with the abundance of total Anopheles species and primary malaria vectors and the EIR (P<.001). Spatial clusters of high-IgG responders were identified across space and time within study villages. Conclusions: The gSG6-P1 biomarker has great potential to address the risk of transmission along the Thailand-Myanmar border and represents a promising tool to guide malaria interventions. PMID- 27932617 TI - Reduced Transplacental Transfer of Group B Streptococcus Surface Protein Antibodies in HIV-infected Mother-Newborn Dyads. AB - We evaluated the effect of maternal HIV infection on transplacental antibody transfer specific to 8 group B Streptococcus (GBS) surface proteins among 81 HIV uninfected and 83 HIV-infected mother-newborn pairs using a multiplex immunoassay. Significantly lower antibody titers were detected in HIV-infected mothers and HIV-exposed uninfected newborns compared to HIV-uninfected mother newborn dyads. Maternal HIV infection was also associated with reduced transplacental transfer of antibodies for Sip (25.8%), Foldase (30.4%), gba0392 (36.5%), gbs0393 (32.9%), gbs1539 (39.2%), gbs2106 (35.7%), and BibA (19.4%); P < .003. This reduced transplacental antibody might contribute to increased susceptibility for invasive GBS disease in HIV-exposed uninfected infants. PMID- 27932618 TI - The Roles of Unfolded Protein Response Pathways in Chlamydia Pathogenesis. AB - Chlamydia is an obligate intracellular bacterium that relies on host cells for essential nutrients and adenosine triphosphate (ATP) for a productive infection. Although the unfolded protein response (UPR) plays a major role in certain microbial infectivity, its role in chlamydial pathogenesis is unknown. We hypothesized that Chlamydia induces UPR and exploits it to upregulate host cell uptake and metabolism of glucose, production of ATP, phospholipids, and other molecules required for its replicative development and host survival. Using a combination of biochemical and pathway inhibition assays, we showed that the 3 UPR pathway transducers-protein kinase RNA-activated (PKR)-like ER kinase (PERK), inositol-requiring enzyme-1alpha (IRE1alpha), and activating transcription factor 6alpha (ATF6alpha)-were activated during Chlamydia infection. The kinase activity of PERK and ribonuclease (RNase) of IRE1alpha mediated the upregulation of hexokinase II and production of ATP via substrate-level phosphorylation. In addition, the activation of PERK and IRE1alpha promoted autophagy formation and apoptosis resistance for host survival. Moreover, the activation of IRE1alpha resulted in the generation of spliced X-box binding protein 1 (sXBP1) and upregulation of lipid production. The vital role of UPR pathways in Chlamydia development and pathogenesis could lead to the identification of potential molecular targets for therapeutics against Chlamydia. PMID- 27932620 TI - Dissecting Antibodies Induced by a Chimeric Yellow Fever-Dengue, Live-Attenuated, Tetravalent Dengue Vaccine (CYD-TDV) in Naive and Dengue-Exposed Individuals. AB - Sanofi Pasteur has developed a chimeric yellow fever-dengue, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that is currently approved for use in several countries. In clinical trials, CYD-TDV was efficacious at reducing laboratory-confirmed cases of dengue disease. Efficacy varied by dengue virus (DENV) serotype and prevaccination dengue immune status. We compared the properties of antibodies in naive and DENV-exposed individuals who received CYD TDV. We depleted specific populations of DENV-reactive antibodies from immune serum samples to estimate the contribution of serotype-cross-reactive and type specific antibodies to neutralization. Subjects with no preexisting immunity to DENV developed neutralizing antibodies to all 4 serotypes of DENV. Further analysis demonstrated that DENV4 was mainly neutralized by type-specific antibodies whereas DENV1, DENV2, and DENV3 were mainly neutralized by serotype cross-reactive antibodies. When subjects with preexisting immunity to DENV were vaccinated, they developed higher levels of neutralizing antibodies than naive subjects who were vaccinated. In preimmune subjects, CYD-TDV boosted cross reactive neutralizing antibodies while maintaining type-specific neutralizing antibodies acquired before vaccination. Our results demonstrate that the quality of neutralizing antibodies induced by CYD-TDV varies depending on DENV serotype and previous immune status. We discuss the implications of these results for understanding vaccine efficacy. PMID- 27932619 TI - Ontogeny of CD4+ T Lymphocytes With Phenotypic Susceptibility to HIV-1 During Exclusive and Nonexclusive Breastfeeding in HIV-1-Exposed Ugandan Infants. AB - Background: Among infants exposed to human immunodeficiency virus (HIV) type 1, mixed breastfeeding is associated with higher postnatal HIV-1 transmission than exclusive breastfeeding, but the mechanisms of this differential risk are uncertain. Methods: HIV-1-exposed Ugandan infants were prospectively assessed during the first year of life for feeding practices and T-cell maturation, intestinal homing (beta7hi), activation, and HIV-1 coreceptor (CCR5) expression in peripheral blood. Infants receiving only breast milk and those with introduction of other foods before 6 months were categorized as exclusive and nonexclusive, respectively. Results: Among CD4+ and CD8+ T cells, the expression of memory, activation, and CCR5 markers increased rapidly from birth to week 2, peaking at week 6, whereas cells expressing the intestinal homing marker increased steadily in the central memory (CM) and effector memory T cells over 48 weeks. At 24 weeks, when feeding practices had diverged, nonexclusively breastfed infants showed increased frequencies and absolute counts of beta7hi CM CD4+ and CD8+ T cells, including the HIV-1-targeted cells with CD4+beta7hi/CCR5+ coexpression, as well as increased activation. Conclusions: The T-cell phenotype associated with susceptibility to HIV-1 infection (CCR5+, gut-homing, CM CD4+ T cells) was preferentially expressed in nonexclusively breastfed infants, a group of infants at increased risk for HIV-1 acquisition. PMID- 27932621 TI - Treatment-Associated Inflammatory Deterioration in Tuberculous Meningitis: Unpicking the Paradox. PMID- 27932623 TI - Association Notes. PMID- 27932622 TI - Inflammasome Activation Underlying Central Nervous System Deterioration in HIV Associated Tuberculosis. AB - Tuberculous meningitis (TBM) is a frequent cause of meningitis in individuals with human immunodeficiency virus (HIV) infection, resulting in death in approximately 40% of affected patients. A severe complication of antiretroviral therapy (ART) in these patients is neurological tuberculosis-immune reconstitution inflammatory syndrome (IRIS), but its underlying cause remains poorly understood. To investigate the pathogenesis of TBM-IRIS, we performed longitudinal whole-blood microarray analysis of HIV-infected patients with TBM and reflected the findings at the protein level. Patients in whom TBM-IRIS eventually developed had significantly more abundant neutrophil-associated transcripts, from before development of TBM-IRIS through IRIS symptom onset. After ART initiation, a significantly higher abundance of transcripts associated with canonical and noncanonical inflammasomes was detected in patients with TBM IRIS than in non-IRIS controls. Whole-blood transcriptome findings complement protein measurement from the site of disease, which together suggest a dominant role for the innate immune system in the pathogenesis of TBM-IRIS. PMID- 27932624 TI - Allele rs2010963 C of the VEGFA gene is associated with the decreased risk of primary varicose veins in ethnic Russians. AB - Objective To study the association of polymorphisms rs699947, rs2010963, rs3025039 in the VEGFA gene region and rs1870377, rs2305949, rs2071559 in the VEGFR2 gene region with the risk of primary varicose veins in ethnic Russians. Methods Genotypes were determined by real-time PCR allelic discrimination. The case group consisted of 448 patients with primary varicose veins and the control group comprised 609 individuals without a history of chronic venous disease. Association was studied by logistic regression analysis. Results Allele rs2010963 C was associated with the decreased risk of varicose veins (additive model of inheritance: odds ratio = 0.73, 95% confidence interval = 0.59-0.91, P = 0.004). Conclusions Our results provide evidence that polymorphism rs2010963 located in the 5' untranslated region of the VEGFA gene can influence genetic susceptibility to primary varicose veins in Russians. Otherwise, it can be in linkage disequilibrium with another functional single nucleotide polymorphism that can alter the level of vascular endothelial growth factor A protein. PMID- 27932625 TI - Advantages and disadvantages of graduated and inverse graduated compression hosiery in patients with chronic venous insufficiency and healthy volunteers: A prospective, mono-centric, blinded, open randomised, controlled and cross-over trial. AB - : Background The therapeutic effectiveness of compression therapy depends on the selection of compression hosiery. Objectives To assess efficacy and tolerability of graduated elastic compression stockings (GECS) and inverse graduated elastic compression stockings (PECS). Methods Thirty-two healthy volunteers and thirty two patients with chronic venous insufficiency were analysed; wear period: one week for each stocking type (randomised, blinded). PRIMARY OUTCOME: volume reduction of 'Lower leg' (Image3D(r)) and 'Distal leg and foot' (water plethysmography). SECONDARY OUTCOMES: clinical symptoms of chronic venous insufficiency assessed by the Venous Clinical Severity Score, side effects and wear comfort in both groups. Results Volume of 'Lower leg': significant reduction in healthy volunteers (mean GECS: -37.5 mL, mean PECS: -37.2 mL) and in patients (mean GECS: -55.6 mL, mean PECS: -41.6 mL). Volume of 'Distal lower leg and foot': significant reduction in healthy volunteers (mean GECS: -27 mL, mean PECS: -16.7 mL), significant reduction in patients by GECS (mean: -43.4 mL), but non significant reduction by PECS (mean: -22.6 mL). Clinical symptoms of chronic venous insufficiency were improved significantly better with GECS than with PECS, p < 0.001. GECS led to more painful constrictions, p = 0.047, PECS slipped down more often, p < 0.001. Conclusion GECS and PECS reduce volume of the segment 'Lower leg' in patients and healthy volunteers. Patients' volume of the 'Distal lower leg and foot', however, were diminished significantly only by GECS ( p = 0.0001). Patients' complaints were improved by both GECS and PECS, and GECS were superior to PECS. PMID- 27932626 TI - A Longitudinal Analysis of the Association Between Living Arrangements and Health Among Older Adults in China. AB - This article used the nationally representative Chinese Longitudinal Healthy Longevity Survey to explore the associations between living arrangements and health among older adults. Living arrangements were stratified into six categories. Health was measured by self-rated health, activities of daily living (ADL) disability, and cognitive impairment. Random-effects ordered probit regressions were applied. The results indicated that coresidence had a positive effect on self-rated health compared with living alone. After introducing psychological well-being, the health differences observed in living with a spouse and living with both spouse and children were not significant. Participants with each of the living arrangement were more likely to have a higher rate of cognitive impairment and ADL disability than those living alone. Living arrangements were associated with older adults' health. Psychological well-being was a key factor in this association, which may result from living with a spouse, and could contribute to the self-rated health of older adults. PMID- 27932627 TI - Next Steps Toward Understanding the Relationship Between Cigarette Smoking and Depression/Anxiety Disorders: A Lifecourse Perspective. PMID- 27932628 TI - Potential Effectiveness of Pictorial Warning Labels That Feature the Images and Personal Details of Real People. AB - Introduction: Pictorial warning labels (PWL) that use photographs and the personal details of real people whose health has been affected by smoking (testimonial PWL) provide factual information about the consequences of tobacco use. Methods: Nine hundred and twenty-four adult current smokers participated in an online experiment that tested responses to four types of warning labels: (1) non-testimonial text warning labels (currently on packs in the United States); (2) non-testimonial PWL (previously proposed by the United States Food and Drug Administration); (3) image only testimonial PWL (created for study); (4) image + personal details testimonial PWL (created for study). Participants were randomly assigned to condition and then exposed to up to five warning labels addressing different health effects. Differences between conditions were assessed using emotional responses and a set of intention measures immediately following exposure, and self-reported behavior change at 5-week follow-up. Results: Compared to the non-testimonial text warning labels, all PWL elicited stronger emotional responses and intentions to forgo cigarettes and avoid the warning labels. Non-testimonial PWL and image + personal details testimonial PWL elicited stronger intentions to quit, whereas image only testimonial PWL generated a greater amount of quitting activity in the weeks following exposure. There were no significant differences in responses when comparing the non-testimonial PWL with both types of testimonial PWL. Conclusions: PWL that use images of real people convey factual information about the health effects of tobacco use. These testimonial PWL may be a promising alternative to the images previously proposed for use on PWL in the United States. Implications: In the United States, the PWL developed by the Food and Drug Administration (FDA) in 2011 were found by the courts to be unconstitutional, in part because they were deemed to present an opinion rather than fact. Findings from this experimental study indicate that PWL that use the images and personal details of real people to convey factual information about the health effects of tobacco use may satisfy the FDA's requirement for a set of PWL that (1) have the potential to positively impact the determinants of smoking cessation behavior, (2) meet legislative requirements under the Family Smoking Prevention and Tobacco Control Act and (3) may be more acceptable to the courts than the previously proposed and now dismissed PWL that carried non-factual images. PMID- 27932629 TI - Breathlessness during daily activity: The psychometric properties of the London Chest Activity of Daily Living Scale in patients with advanced disease and refractory breathlessness. AB - BACKGROUND: The London Chest Activities of Daily Living Scale measures the impact of breathlessness on both activity and social functioning. However, the London Chest Activities of Daily Living Scale is not routinely used in patients with advanced disease. AIM: To assess the psychometric properties of the London Chest Activities of Daily Living Scale in patients with refractory breathlessness due to advanced disease. DESIGN: A cross-sectional secondary analysis of data from a randomised controlled parallel-group, pragmatic, single-blind fast-track trial (randomised controlled trial) investigating the effectiveness of an integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness, known as the Breathlessness Support Service (NCT01165034). All patients completed the following questionnaires: the London Chest Activities of Daily Living Scale, Chronic Respiratory Questionnaire, the Palliative care Outcome Scale, Palliative care Outcome Scale-symptoms, the Hospital Anxiety and Depression Scale and breathlessness measured on a numerical rating scale. Data quality, scaling assumptions, acceptability, internal consistency and construct validity of the London Chest Activities of Daily Living Scale were determined using standard psychometric approaches. SETTING/PARTICIPANTS: Breathless patients with advanced malignant and non malignant disease. RESULTS: A total of 88 patients were studied, primary diagnosis included; chronic obstructive pulmonary disease = 53, interstitial lung disease = 17, cancer = 18. Median (range) London Chest Activities of Daily Living Scale total score was 46.5 (14-67). No floor or ceiling effect was observed for the London Chest Activities of Daily Living Scale total score. Internal consistency was good, and Cronbach's alpha for the London Chest Activities of Daily Living Scale total score was 0.90. Construct validity was good with 13 out of 15 a priori hypotheses met. CONCLUSION: Psychometric analyses suggest that the London Chest Activities of Daily Living Scale is acceptable, reliable and valid in patients with advanced disease and refractory breathlessness. PMID- 27932630 TI - Hospital doctors' understanding of use and withdrawal of the Liverpool Care Pathway: A qualitative study of practice-based experiences during times of change. AB - BACKGROUND: The Liverpool Care Pathway was used in UK hospitals (late 1990s to July 2014) in an attempt to generate hospice-style high-quality end-of-life care in acute settings. Despite being widely established, there was limited research or contextual evidence regarding this approach or its impact. Growing criticism from the public, media, politicians and healthcare professionals culminated with a critical independent review (July 2013) and subsequent withdrawal of the Liverpool Care Pathway. AIM: This research explores experiences of doctors using the Liverpool Care Pathway, prior to and during its withdrawal, to better understand shortfallings and inform future initiatives in hospital end-of-life care. DESIGN: Individual semi-structured audio-recorded interviews were transcribed verbatim and concurrently analysed using thematic analysis. SETTING/PARTICIPANTS: Following ethical approval, volunteer participants from an acute UK hospital were sought ( n = 73). A total of 18 specialist doctors were purposively selected. RESULTS: Seven themes shaped doctors' experiences of using the Liverpool Care Pathway: (1) changing perceptions according to length of clinical practice, (2) individual interpretation and application of the Liverpool Care Pathway, (3) limitations arising from setting, speciality and basic end-of life care competence, (4) understanding and acceptance of medical uncertainty at the end-of-life, (5) centrality of communication and fear of discussing dying, (6) external challenges, including a culture to cure, role modelling and the media and (7) desire for reassurance in end-of-life care decisions. CONCLUSION: Future initiatives in hospital end-of-life care must address doctors' fears, (in)abilty to tolerate medical uncertainty, communication skills and understanding of the dying phase, in order to provide optimum care in the last days of life. PMID- 27932631 TI - Dying in the hospital setting: A meta-synthesis identifying the elements of end of-life care that patients and their families describe as being important. AB - BACKGROUND: Despite most expected deaths occurring in hospital, optimal end-of life care is not available for all in this setting. AIM: To gain a richer and deeper understanding of elements of end-of-life care that consumers consider most important within the hospital setting. DESIGN: A meta-synthesis. DATA SOURCES: A systematic search of Academic Search Complete, AMED, CINAHL, MEDLINE, EMBASE, PsycINFO, PubMed, Google, Google Scholar and CareSearch for qualitative studies published between 1990 and April 2015 reporting statements by consumers regarding important elements of end-of-life hospital care. Study quality was appraised by two independent researchers using an established checklist. A three-stage synthesis approach focusing on consumer quotes, rather than primary author themes, was adopted for this review. RESULTS: Of 1922 articles, 16 met the inclusion criteria providing patient and family data for analysis. Synthesis yielded 7 patient and 10 family themes including 6 common themes: (1) expert care, (2) effective communication and shared decision-making, (3) respectful and compassionate care, (4) adequate environment for care, (5) family involvement and (6) financial affairs. Maintenance of sense of self was the additional patient theme, while the four additional family themes were as follows: (1) maintenance of patient safety, (2) preparation for death, (3) care extending to the family after patient death and (4) enabling patient choice at the end of life. CONCLUSION: Consumer narratives help to provide a clearer direction as to what is important for hospital end-of-life care. Systems are needed to enable optimal end of-life care, in accordance with consumer priorities, and embedded into routine hospital care. PMID- 27932632 TI - Not By Success Alone: Role Models Provide Pathways to Communal Opportunities in STEM. AB - Because of stereotypes that science, technology, engineering, and mathematics (STEM) fields do not fulfill communal goals, communally oriented individuals may select out of STEM. One potential route to engaging and promoting communally oriented individuals in STEM fields is through interactions with advisors or role models in STEM. We first demonstrate the perceived difficulty of finding role models who enact communal behaviors in STEM relative to other fields (Preliminary Study). Communally oriented students reported higher likelihood of observing admired others in math or science (i.e., investigative vicarious learning) over time (Study 1). Individuals preferred hypothetical STEM advisors who enacted communal workplace behaviors (Studies 2a-2b). Finally, individuals' communal orientation predicted how important they found the communal behaviors of actual role models (Studies 3a-3b). These findings provide further support for the goal congruity prediction that contexts-whether relational or occupational-that offer the pursuit of valued goals will be preferred. PMID- 27932633 TI - Agents of Reconciliation: Agency-Affirmation Promotes Constructive Tendencies Following Transgressions in Low-Commitment Relationships. AB - Conflicting parties experience threats to both their agency and morality, but the experience of agency-threat exerts more influence on their behavior, leading to relationship-destructive tendencies. Whereas high-commitment relationships facilitate constructive tendencies despite the conflict, we theorized that in low commitment relationships, affirming the adversary's agency is a prerequisite for facilitating more constructive tendencies. Focusing on sibling conflicts, Study 1 found that when commitment was low (rather than high), agency-affirmation increased participants' constructive tendencies toward their brother/sister compared with a control/no-affirmation condition. A corresponding morality affirmation did not affect participants' tendencies. Study 2 replicated these results in workplace conflicts and further found that the positive effect of agency-affirmation in low-commitment relationships was mediated by participants' wish to restore their morality. Study 3 induced a conflict between lab participants and manipulated their commitment. Again, in the low- (rather than high-) commitment condition, agency-affirmation increased participants' wish to restore their morality, leading to constructive behavior. PMID- 27932634 TI - A narrative review of the literature about people with intellectual disability who identify as lesbian, gay, bisexual, transgender, intersex or questioning. AB - This narrative review of the research literature presents a summary about the key issues facing people with intellectual disability (ID) who identify as lesbian, gay, bisexual, transgender, intersex or questioning (LGBTIQ). The aim of this review was to consolidate research of the topic; to identify whether any pilot studies reporting social/sexual/educational interventions had been published; and to offer some perspective on the type of future research required to better inform policy, practice and theory that may lead to better outcomes for people with ID who identify as LGBTIQ. Almost all of the research literature on the topic is either exploratory or descriptive which serves to outline the range of issues faced by people with ID who identify as LGBTIQ. Urgently needed as the next step, however, is a concerted effort to conduct a range of innovative educational and social interventions with collection of targeted and appropriate outcomes data. PMID- 27932635 TI - Genome Sequence of Bacteriophage GG32, Which Can Infect both Salmonella enterica Serovar Typhimurium and Escherichia coli O157:H7. AB - We report here a new virulent Salmonella enterica serovar Typhimurium (S Typhimurium) bacteriophage, GG32, which was isolated from the Guem River in the Republic of Korea. The strain can infect both S Typhimurium and Escherichia coli (E. coli) O157:H7 and may be a good candidate for a bio-control agent. PMID- 27932636 TI - Complete Genome Sequence of Bacteriophage MA12, Which Infects both Campylobacter jejuni and Salmonella enterica Serovar Enteritidis. AB - Here, we announce the complete genome sequence of Salmonella enterica serovar Enteritidis (S Enteritidis) bacteriophage MA12, a 41-Kb chromosome. The strain can infect both Campylobacter jejuni (C. jejuni) and S Enteritidis and can be used in phage therapy experiments with poultry and poultry meat. PMID- 27932637 TI - Complete Genome Sequences of Two Isolates of Canis familiaris Oral Papillomavirus from South Africa. AB - Canis familiaris oral papillomavirus, formerly canine oral papillomavirus, is a causative agent of the self-resolving canine oral papillomatosis and was first described in 1994. This is the first report of two full-length genome sequences described in South Africa and indicates the highly conserved nature of Canis familiaris oral papillomavirus. PMID- 27932638 TI - Draft Genome Sequences of Three Hypervirulent Carbapenem-Resistant Klebsiella pneumoniae Isolates from Bacteremia. AB - Hypervirulent Klebsiella pneumoniae strains have been increasingly reported worldwide, and there is emergence of carbapenem resistance among them. Here, we report the genome sequences of three carbapenem-resistant hypervirulent K. pneumoniae isolates isolated from bacteremic patients at a tertiary-care center in South India. PMID- 27932639 TI - Complete Genome Sequences of Six Chrysodeixis includens Nucleopolyhedrovirus Isolates from Brazil and Guatemala. AB - The baculovirus, Chrysodeixis (formerly Pseudoplusia) includens nucleopolyhedrovirus (ChinNPV), is a new Alphabaculovirus pathogenic to Chrysodeixis includens Here, we report the complete genome sequences of six ChinNPV isolates. The availability of these genome sequences will provide information on ChinNPV molecular genetics, promoting understanding of its pathogenicity, diversity, and evolution. PMID- 27932640 TI - Complete Genome Sequence of a Genotype III Japanese Encephalitis Virus, Isolated from Pigs in Sichuan, China. AB - A complete genomic sequence of Japanese encephalitis virus (JEV) was detected by viral metagenome analysis on aborted piglets. A phylogenetic analysis of this genome reveals that it is highly similar to previously reported India JEV genomes. The complete JEV sequence is 10,718 nucleotides long. PMID- 27932641 TI - Mitochondrial Genome Sequences of Four Strains of the Bloom-Forming Raphidophyte Heterosigma akashiwo. AB - We report here the complete mitochondrial genome sequences of four strains of bloom-forming raphidophytes from Heterosigma akashiwo These 39-kb sequences contain 42 protein-, two rRNA-, and 26 tRNA-coding sequences. Notable sequence variations were observed among these four newly sequenced and three previously characterized strains, suggesting their potential usage as strain-specific markers. PMID- 27932642 TI - Complete Genome Sequence of vB_EcoM-UFV13, a New Bacteriophage Able To Disrupt Trueperella pyogenes Biofilm. AB - vB_EcoM-UFV13, a member of the T4virus genus, shows lytic activity against Escherichia coli and effectiveness in controlling the biofilm formed by Trueperella pyogenes, which qualifies it as a promising component of phage cocktails for mastitis and metritis control. PMID- 27932643 TI - Genome Sequence of Burkholderia plantarii ZJ171, a Tropolone-Producing Bacterial Pathogen Responsible for Rice Seedling Blight. AB - Burkholderia plantarii is the causal agent of rice seedling blight. Here, we report the draft genome sequence of B. plantarii, which contains 8,020,831 bp, with a G+C content of 68.66% and a predicted 7,688 coding sequences. The annotated genome sequence will provide further insight into its pathogenicity. PMID- 27932644 TI - Detection and Whole-Genome Characterization of a G8P[1] Group A Rotavirus Strain from Deer. AB - Rotavirus A strain 14-02218-2, with genome constellation G8P[1]-I2-R2-C2-M2-A3-N2 T6-E2-H3, was isolated from newborn fawns. The 14-02218-2 rotavirus strain is related to bovine and bovine-like rotavirus strains. To our knowledge, this is the first report on whole-genome-based characterization of a deer rotavirus G8P[1] strain. PMID- 27932645 TI - Complete Genome Sequences of the Endophytic Streptomyces Strains EN16, EN23, and EN27, Isolated from Wheat Plants. AB - The complete genome sequences of three endophytic Streptomyces species were compared. Strains EN16, EN23, and EN27 were isolated from surface-sterilized roots of wheat plants from South Australia. In field trials, these strains are effective in suppressing fungal root diseases of wheat when added as spore coatings to wheat seed. PMID- 27932646 TI - Genome Sequence of Airborne Acinetobacter sp. Strain 5-2Ac02 in the Hospital Environment, Close to the Species of Acinetobacter towneri. AB - Acinetobacter spp. are found in 53% of air colonization samples from the hospital environment. In this work, we sequenced all the genome of airborne Acinetobacter sp. strain 5-2Ac02. We found important features at the genomic level in regards to the rhizome. By phylogenetic analysis, A. towneri was the species most closely related to Acinetobacter sp. 5-2Ac02. PMID- 27932647 TI - Complete Genome Sequences of Two Subgenotype 1b Newcastle Disease Viruses Isolated from Sansui Sheldrake Ducks in Guizhou, China. AB - Here, we report the complete genome sequences of two Newcastle disease viruses, Sheldrake duck/China/Guizhou/01/2016 and Sheldrake duck/China/Guizhou/02/2016, isolated from Sansui Sheldrake ducks in Guizhou Province, China. The genome of the isolates is 15,198 nucleotides in length. Phylogenetic analysis revealed that the isolates are clustered into subgenotype 1b in class I. PMID- 27932648 TI - Complete Genome Sequences of Two Newcastle Disease Virus Strains Isolated from a Wild Duck and a Pigeon in Russia. AB - Here, we report the complete genome sequences of two Newcastle disease virus (NDV) isolates, Adygea/duck/12/2008, from a wild duck in Russia, and Altai/pigeon/777/2010, from a pigeon in Russia. Based on comparative sequence analysis of the F gene, these strains were classified as NDV class II, genotypes VIId and VIb/2, respectively. PMID- 27932649 TI - Detection and Genomic Characterization of Enterovirus D68 in Respiratory Samples Isolated in the United States in 2016. AB - The genomic sequences of three 2016 enterovirus D68 (EV-D68) strains were obtained from respiratory samples of patients from Florida, Texas, and New York. These EV-D68 sequences share highest nucleotide identities with strains that circulated in North America, Europe, and Asia in 2014-2015. PMID- 27932651 TI - Draft Genome Sequence of Probiotic Lactobacillus acidophilus Strain L-55 Isolated from a Healthy Human Gut. AB - Probiotic Lactobacillus acidophilus L-55 was isolated from a healthy human gut. Here, we report the draft genome sequence of this organism. PMID- 27932650 TI - Draft Genome Sequence of a Novel Marinobacter sp. Strain from Honolulu Harbor, Hawai'i. AB - Marinobacter sp. strain X15-166BT was cultivated from sediment in Honolulu Harbor, Hawai'i. The X15-166BT draft genome of 3,490,661 bp encodes 3,115 protein coding open reading frames. We anticipate that the genome will provide insights into the strain's lifestyle and the evolution of Marinobacter. PMID- 27932652 TI - Complete Genome Sequence of the Nonylphenol-Degrading Bacterium Sphingobium cloacae JCM 10874T. AB - Sphingobium cloacae JCM 10874T can degrade phenolic endocrine-disrupting chemicals, nonylphenol, and octylphenol. Here, we report the complete genome sequence of the JCM 10874T strain. PMID- 27932653 TI - Draft Genome Sequences of Two Fabibacter sp. Strains Isolated from Coastal Surface Water of Aburatsubo Inlet, Japan. AB - Here, we report the draft genome sequences of Fabibacter sp. strain 4D4 and F. misakiensis strain SK-8T, isolated from surface seawater of a semienclosed inlet. PMID- 27932654 TI - Draft Genome Sequence of Antarctic Methanogen Enriched from Dry Valley Permafrost. AB - A genomic reconstruction belonging to the genus Methanosarcina was assembled from metagenomic data from a methane-producing enrichment of Antarctic permafrost. This is the first methanogen genome reported from permafrost of the Dry Valleys and can help shed light on future climate-affected methane dynamics. PMID- 27932655 TI - Complete Genome Sequence of Nitrilotriacetate-Degrading Aminobacter aminovorans KCTC 2477T. AB - Aminobacter aminovorans is a Gram-negative, pleomorphic rod-shaped, flagellated, and obligately aerobic bacterium that was isolated from soil. Here, we report the complete genome sequence of A. aminovorans KCTC 2477T, which degrades nitrilotriacetate-metal complexes and iminodiacetate, a metabolic intermediate of nitrilotriacetate. PMID- 27932656 TI - Draft Genome Sequences of Two Historical Listeria monocytogenes Strains from Human Listeriosis Cases in 1933. AB - We report here the draft genome sequences of two Listeria monocytogenes strains from some of the earliest reported cases of human listeriosis in North America. The strains were isolated in 1933 from patients in Massachusetts and Connecticut, USA, and belong to the widely disseminated hypervirulent clonal complex 1 (CC1) and CC2. PMID- 27932657 TI - Draft Genome Sequence of Pseudomonas sp. Strain CCA1, Isolated from Leaf Soil. AB - Pseudomonas sp. strain CCA1 was isolated from leaf soil collected in Higashi Hiroshima City in Hiroshima Prefecture, Japan. Here, we present a draft genome sequence of this strain. The genome consists of 24 contigs for a total of 6,993,992 bp, 8,917 predicted coding sequences, and a GC content of 67.2%. PMID- 27932658 TI - Correction for Pradeep et al., Draft Genome Sequence of Elizabethkingia anopheles, Isolated from a Postoperative Endophthalmitis Patient. PMID- 27932659 TI - Genome Sequence of Pseudomonas citronellolis SJTE-3, an Estrogen- and Polycyclic Aromatic Hydrocarbon-Degrading Bacterium. AB - Pseudomonas citronellolis SJTE-3, isolated from the active sludge of a wastewater treatment plant in China, can utilize a series of environmental estrogens and estrogen-like toxicants. Here, we report its whole-genome sequence, containing one circular chromosome and one circular plasmid. Genes involved in estrogen biodegradation in this bacterium were predicted. PMID- 27932660 TI - Identification of Beak and Feather Disease Virus in an Unusual Novel Host (Merops ornatus) Using Nested PCR. AB - The complete genome sequence of beak and feather disease virus (BFDV) was discovered from a rainbow bee-eater (Merops ornatus), a species of Coraciiformes The genome consisted of 1,996 bp encoding two major bidirectional transcribed open reading frames. This is the first evidence of BFDV infection and complete genome characterization for this novel host species. PMID- 27932661 TI - Draft Genome Sequence of the Anaerobic Ammonium-Oxidizing Bacterium "Candidatus Brocadia sp. 40". AB - The anaerobic ammonium-oxidizing (anammox) bacterium "Candidatus Brocadia sp. 40" demonstrated the fastest growth rate compared to others in this taxon. Here, we report the 2.93-Mb draft genome sequence of this bacterium, which has 2,565 gene coding regions, 41 tRNAs, and a single rrn operon. PMID- 27932662 TI - Nearly Complete Genome Sequences of Two Mimivirus Strains Isolated from a Japanese Freshwater Pond and River Mouth. AB - Members of the Mimiviridae family are large DNA viruses that infect Acanthamoeba cells. Here, we report the genome sequences of two new Mimiviridae family members, isolated from water samples from Shirakoma Pond and the mouth of the Arakawa River in Japan, with nearly complete genome sizes of 1,182,849 and 1,182,801 bp, respectively. PMID- 27932663 TI - Genomic Sequence of Canine Papillomavirus 19. AB - It is generally assumed that individual papillomas (warts) are caused by infection with individual papillomavirus types. Deep sequencing of virions extracted from a canine oral papilloma revealed the presence of canine papillomavirus 1 (CPV1), CPV2, and a novel canine papillomavirus, CPV19. This suggests that papillomas sometimes harbor multiple viral species. PMID- 27932664 TI - Adjusting for bias in unblinded randomized controlled trials. AB - It may not always be possible to blind participants of a randomized controlled trial for treatment allocation. As a result, estimators of the actual treatment effect may be biased. In this paper, we will extend a novel method, originally introduced in genetic research, for instrumental variable meta-analysis, adjusting for bias due to unblinding of trial participants. Using simulation studies, this novel method, "Egger Correction for non-Adherence", is introduced and compared to the performance of the "intention-to-treat," "as-treated," and conventional "instrumental variable" estimators. Scenarios considered (time varying) non-adherence, confounding, and between-study heterogeneity. The effect of treatment on a binary endpoint was quantified by means of a risk difference. In all scenarios with unblinded treatment allocation, the Egger Correction for non-Adherence method was the least biased estimator. However, unless the variation in adherence was relatively large, precision was lacking, and power did not surpass 0.50. As a comparison, in a meta-analysis of blinded randomized controlled trials, power of the conventional IV estimator was 1.00 versus at most 0.14 for the Egger Correction for non-Adherence estimator. Due to this lack of precision and power, we suggest to use this method mainly as a sensitivity analysis. PMID- 27932665 TI - Statistical analysis of a low cost method for multiple disease prediction. AB - Early identification of individuals at risk for chronic diseases is of significant clinical value. Early detection provides the opportunity to slow the pace of a condition, and thus help individuals to improve or maintain their quality of life. Additionally, it can lessen the financial burden on health insurers and self-insured employers. As a solution to mitigate the rise in chronic conditions and related costs, an increasing number of employers have recently begun using wellness programs, which typically involve an annual health risk assessment. Unfortunately, these risk assessments have low detection capability, as they should be low-cost and hence rely on collecting relatively few basic biomarkers. Thus one may ask, how can we select a low-cost set of biomarkers that would be the most predictive of multiple chronic diseases? In this paper, we propose a statistical data-driven method to address this challenge by minimizing the number of biomarkers in the screening procedure while maximizing the predictive power over a broad spectrum of diseases. Our solution uses multi-task learning and group dimensionality reduction from machine learning and statistics. We provide empirical validation of the proposed solution using data from two different electronic medical records systems, with comparisons over a statistical benchmark. PMID- 27932666 TI - Interval estimation for a proportion using a double-sampling scheme with two fallible classifiers. AB - Double-sampling schemes using one classifier assessing the whole sample and another classifier assessing a subset of the sample have been introduced for reducing classification errors when an infallible or gold standard classifier is unavailable or impractical. Inference procedures have previously been proposed for situations where an infallible classifier is available for validating a subset of the sample that has already been classified by a fallible classifier. Here, we consider the case where both classifiers are fallible, proposing and evaluating several confidence interval procedures for a proportion under two models, distinguished by the assumption regarding ascertainment of two classifiers. Simulation results suggest that the modified Wald-based confidence interval, Score-based confidence interval, two Bayesian credible intervals, and the percentile Bootstrap confidence interval performed reasonably well even for small binomial proportions and small validated sample under the model with the conditional independent assumption, and the confidence interval derived from the Wald test with nuisance parameters appropriately evaluated, likelihood ratio based confidence interval, Score-based confidence interval, and the percentile Bootstrap confidence interval performed satisfactory in terms of coverage under the model without the conditional independent assumption. Moreover, confidence intervals based on log- and logit-transformations also performed well when the binomial proportion and the ratio of the validated sample are not very small under two models. Two examples were used to illustrate the procedures. PMID- 27932667 TI - Lymph node yield is an independent predictor of survival in rectal cancer regardless of receipt of neoadjuvant therapy. AB - AIMS: Lymph node yield (LNY) is used as a marker of adequate oncological resection. The American Joint Committee on Cancer (AJCC) currently recommends that at least 12 nodes are necessary to confirm node-negative disease for rectal cancer. A LNY of 12 is not always achieved, particularly in patients who have undergone neoadjuvant treatment. This study attempts to examine factors associated with LNY and its prognostic impact following neoadjuvant chemoradiation in rectal cancer. METHODS: The 2006-2011 National Cancer Data Base was queried for patients with clinical stage I-III rectal cancer who underwent a proctectomy. Suboptimal LNY was defined as <12 lymph nodes examined. A mixed effects multinomial logistic regression model was used to identify independent factors associated with LNY. Mixed-effects Cox proportional hazards models were used to estimate the adjusted effect of LNY on 5-year overall survival. RESULTS: 25 447 patients met inclusion criteria. Overall, 62% of the cohort received neoadjuvant chemoradiation and 32% had suboptimal LNY. The median LNY for patients who received neoadjuvant therapy was 13 (IQR: 9-18) and for patients who did not receive neoadjuvant therapy was 15 (IQR: 12-21). After risk adjustment, there was a 3.5-fold difference in the rate of suboptimal LNY among individual hospitals (27%-95%). Suboptimal LNY was independently associated with an 18% increased hazard of death among patients who did not receive neoadjuvant treatment and a 20% increased hazard of death among those who did receive neoadjuvant treatment when controlled for adjuvant treatment, staging, proximal/distal margins and other patient factors. CONCLUSIONS: Suboptimal LNY is independently associated with worse overall survival regardless of neoadjuvant therapy, pathological staging and patient factors in rectal cancer. This finding underlies the importance and challenge of an optimal lymph node evaluation for prognostication, especially for patients receiving neoadjuvant therapy. PMID- 27932668 TI - Quantitative flow measurement after placing a flow diverter for a distal internal carotid artery aneurysm. AB - OBJECTIVES: To evaluate the differences in arterial flow after flow diverter placement using quantitative flow measurements based on digital subtraction angiography (DSA). METHODS: Between November 2013 and November 2015, all patients who had flow diverters placed for distal internal carotid artery (ICA) aneurysms were reviewed. Patients in whom the stent was placed across the ostia of the ophthalmic artery (OphA) and anterior choroidal artery (AChA) were enrolled. Five regions of interest were selected: the proximal ICA (as a reference), terminal ICA, middle cerebral artery (MCA), anterior cerebral artery (ACA), OphA, and AChA. The values of the peak, time-to-peak (TTP), and area under the curve (AUC) were analyzed using a quantitative DSA technique. RESULTS: The study enrolled 13 patients. The quantitative flow analysis showed improved flow in the terminal ICA (peak and AUC, p=0.036 and p=0.04, respectively), MCA (AUC, p=0.023), and ACA (AUC, p=0.006), and decreased flow in the OphA (peak and AUC, p=0.013 and p=0.005, respectively) and AChA (peak and subtracted TTP, p=0.023 and p=0.050, respectively) after flow diverter placement. Larger aneurysm volume was significantly correlated with decreased OphA flow after the procedure (peak and AUC, p=0.049 and p=0.037, respectively). Larger aneurysm volume also had a marginal correlation with increased distal ICA flow after the procedure, but this did not reach significance (peak and AUC, p=0.195 and p=0.060, respectively). CONCLUSIONS: Without using extra contrast medium or radiation dosages, color coded DSA enables quantitative monitoring of the cerebral circulation after flow diverting treatment. PMID- 27932669 TI - Quantification of the steady-state plasma concentrations of clozapine and N desmethylclozapine in Japanese patients with schizophrenia using a novel HPLC method and the effects of CYPs and ABC transporters polymorphisms. AB - Background This study developed a novel high-performance liquid chromatography (HPLC) method for the simultaneous quantification of clozapine and its active metabolite, N-desmethylclozapine, in human plasma and investigated the effects of various factors, including genetic polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A5, ABCB1 and ABCG2, on the steady-state plasma trough concentrations (C0) of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia. Methods Forty-five patients had been receiving fixed doses of clozapine for at least four weeks. The CYP2D6 ( CYP2D6*2, CYP2D6*5, CYP2D6*10), CYP3A5 ( CYP3A5*3), ABCB1 (1236C > T, 2677G > T/A, 3435C > T) and ABCG2 (421 C > A) genotypes were identified by polymerase chain reaction. Results The within- and between-day coefficients of variation (CV) were less than 11.0%, and accuracy was within 9.0% over the linear range from 10 to 2500 ng/mL for both analytes, and their LOQs were each 10 ng/mL. The median C0/dose (C0/D) ratios of clozapine were significantly higher in patients with the ABCG2 421 A allele than in those with the 421 C/C genotype ( P = 0.010). However, there were no significant differences in C0/D ratios of clozapine and N-desmethylclozapine among ABCB1, CYP2D6 or CYP3A5 genotypes. In multiple regression analysis, including polymorphisms, age, body weight and biochemical data of patients, the ABCG2 polymorphism alone was correlated with the C0/D ratios of clozapine ( R2 = 0.139, P = 0.016). Conclusions Among the various CYPs and drug transporters, BCRP appeared to most strongly influence clozapine exposure. Knowledge of the patient's ABCG2 421 C > A genotype before initiating therapy may be useful when making dosing decisions aimed at achieving optimal clozapine exposure. PMID- 27932670 TI - Red blood cell distribution width and neutrophil to lymphocyte ratio are associated with outcomes of adult subarachnoid haemorrhage patients admitted to intensive care unit. AB - Background Red blood cell distribution width (RDW) and neutrophil to lymphocyte ratio (NLR) have been reported to be associated with outcomes of acute cerebral infarction. However, their prognostic value in patients with subarachnoid haemorrhage (SAH) remains largely unknown. The aim of this study was to investigate the prognostic value of RDW and NLR in SAH patients. Methods Medical records of adult SAH patients admitted to intensive care unit (ICU) were extracted from Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC II, version 2.6), a publicly accessible ICU database. Prognostic value of RDW and NLR was analysed using logistic regression model, Kaplan-Meier curve analysis and Cox regression model. Results A total of 274 SAH patients were included. Patients died in hospital had significantly higher RDW and NLR. RDW and NLR were significantly associated with hospital death, with adjusted odds ratios of 1.39 (95% CI, 1.06-1.82) and 1.04 (95% CI, 1.00-1.08), respectively. Furthermore, increased RDW and NLR were associated with higher one-year mortality, with an adjusted hazard ratio of 1.20 (95% CI, 1.02-1.41) for per 1% increased RDW and 1.03 (95% CI, 1.00-1.05) for per 1 increased NLR. Conclusion RDW and NLR are useful indices to evaluate the outcomes of ICU admitted patients with SAH. PMID- 27932671 TI - Coupling of EIT with computational lung modeling for predicting patient-specific ventilatory responses. AB - Providing optimal personalized mechanical ventilation for patients with acute or chronic respiratory failure is still a challenge within a clinical setting for each case anew. In this article, we integrate electrical impedance tomography (EIT) monitoring into a powerful patient-specific computational lung model to create an approach for personalizing protective ventilatory treatment. The underlying computational lung model is based on a single computed tomography scan and able to predict global airflow quantities, as well as local tissue aeration and strains for any ventilation maneuver. For validation, a novel "virtual EIT" module is added to our computational lung model, allowing to simulate EIT images based on the patient's thorax geometry and the results of our numerically predicted tissue aeration. Clinically measured EIT images are not used to calibrate the computational model. Thus they provide an independent method to validate the computational predictions at high temporal resolution. The performance of this coupling approach has been tested in an example patient with acute respiratory distress syndrome. The method shows good agreement between computationally predicted and clinically measured airflow data and EIT images. These results imply that the proposed framework can be used for numerical prediction of patient-specific responses to certain therapeutic measures before applying them to an actual patient. In the long run, definition of patient specific optimal ventilation protocols might be assisted by computational modeling.NEW & NOTEWORTHY In this work, we present a patient-specific computational lung model that is able to predict global and local ventilatory quantities for a given patient and any selected ventilation protocol. For the first time, such a predictive lung model is equipped with a virtual electrical impedance tomography module allowing real-time validation of the computed results with the patient measurements. First promising results obtained in an acute respiratory distress syndrome patient show the potential of this approach for personalized computationally guided optimization of mechanical ventilation in future. PMID- 27932672 TI - A LED-based phosphorimeter for measurement of microcirculatory oxygen pressure. AB - Quantitative measurements of microcirculatory and tissue oxygenation are of prime importance in experimental research. The noninvasive phosphorescence quenching method has given further insight into the fundamental mechanisms of oxygen transport to healthy tissues and in models of disease. Phosphorimeters are devices dedicated to the study of phosphorescence quenching. The experimental applications of phosphorimeters range from measuring a specific oxygen partial pressure (Po2) in cellular organelles such as mitochondria, finding values of Po2 distributed over an organ or capillaries, to measuring microcirculatory Po2 changes simultaneously in several organ systems. Most of the current phosphorimeters use flash lamps as a light excitation source. However, a major drawback of flash lamps is their inherent plasma glow that persists for tens of microseconds after the primary discharge. This complex distributed excitation pattern generated by the flash lamp can lead to inaccurate Po2 readings unless a deconvolution analysis is performed. Using light-emitting diode (LED), a rectangular shaped light pulse can be generated that provides a more uniformly distributed excitation signal. This study presents the design and calibration process of an LED-based phosphorimeter (LED-P). The in vitro calibration of the LED-P using palladium(II)-meso-tetra(4-carboxyphenyl)-porphyrin (Pd-TCCP) as a phosphorescent dye is presented. The pH and temperature were altered to assess whether the decay times of the Pd-TCCP measured by the LED-P were significantly influenced. An in vivo validation experiment was undertaken to measure renal cortical Po2 in a rat subjected to hypoxic ventilation conditions and ischemia/reperfusion. The benefits of using LEDs as a light excitation source are presented. PMID- 27932673 TI - Are there sex differences in the capillary blood volume and diffusing capacity response to exercise? AB - Previous work suggests that women may exhibit a greater respiratory limitation in exercise compared with height-matched men. Diffusion capacity (DlCO) increases with incremental exercise, and the smaller lungs of women may limit membrane diffusing capacity (Dm) and pulmonary capillary blood volume (Vc) in response to the increased oxygen demand. We hypothesized that women would have lower DlCO, DlCO relative to cardiac output (DlCO/Q), Dm, Vc, and pulmonary transit time, secondary to lower Vc at peak exercise. Sixteen women (112 +/- 12% predicted relative Vo2peak) and sixteen men (118 +/- 22% predicted relative Vo2peak) were matched for height and weight. Hemoglobin-corrected diffusing capacity (DlCO), Vc, and Dm were determined via the multiple-[Formula: see text] DlCO technique at rest and during incremental exercise up to 90% of Vo2peak Both groups increased DlCO, Vc, and Dm with exercise intensity, but women had 20% lower DlCO (P < 0.001), 18% lower Vc (P = 0.002), and 22% lower Dm (P < 0.001) compared with men across all workloads, and neither group exhibited a plateau in Vc. When expressed relative to alveolar volume (Va), the between-sex difference was eliminated. The drop in DlCO/Q was proportionally less in women than men, and mean pulmonary transit time did not drop below 0.3 s in either group. Women demonstrate consistently lower DlCO, Vc, and Dm compared with height-matched men during exercise; however, these differences disappear with correction for lung size. These results suggest that after differences in lung volume are accounted for there is no intrinsic sex difference in the DlCO, Vc, or Dm response to exercise.NEW & NOTEWORTHY Women demonstrate lower diffusing capacity-to-cardiac output ratio (DlCO/Q), pulmonary capillary blood volume (Vc), and membrane diffusing capacity (Dm) compared with height-matched men during exercise. However, these differences disappear after correction for lung size. The drop in DlCO/Q was proportionally less in women, and pulmonary transit time did not drop below 0.3 s in either group. After differences in lung volume are accounted for, there is no intrinsic sex difference in DlCO, Vc, or Dm response to exercise. PMID- 27932674 TI - Metabolic adaptations in skeletal muscle after 84 days of bed rest with and without concurrent flywheel resistance exercise. AB - As metabolic changes in human skeletal muscle after long-term (simulated) spaceflight are not well understood, this study examined the effects of long-term microgravity, with and without concurrent resistance exercise, on skeletal muscle oxidative and glycolytic capacity. Twenty-one men were subjected to 84 days head down tilt bed rest with (BRE; n = 9) or without (BR; n = 12) concurrent flywheel resistance exercise. Activity and gene expression of glycogen synthase, glycogen phosphorylase (GPh), hexokinase, phosphofructokinase-1 (PFK-1), and citrate synthase (CS), as well as gene expression of succinate dehydrogenase (SDH), vascular endothelial growth factor (VEFG), peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1alpha), and myostatin, were analyzed in samples from m. vastus lateralis collected before and after bed rest. Activity and gene expression of enzymes controlling oxidative metabolism (CS, SDH) decreased in BR but were partially maintained in BRE. Activity of enzymes regulating anaerobic glycolysis (GPh, PFK-1) was unchanged in BR. Resistance exercise increased the activity of GPh. PGC-1alpha and VEGF expression decreased in both BR and BRE. Myostatin increased in BR but decreased in BRE after bed rest. The analyses of these unique samples indicate that long-term microgravity induces marked alterations in the oxidative, but not the glycolytic, energy system. The proposed flywheel resistance exercise was effective in counteracting some of the metabolic alterations triggered by 84-day bed rest. Given the disparity between gene expression vs. enzyme activity in several key metabolic markers, posttranscriptional mechanisms should be explored to fully evaluate metabolic adaptations to long-term microgravity with/without exercise countermeasures in human skeletal muscle. PMID- 27932675 TI - The effects of voluntary exercise and prazosin on capillary rarefaction and metabolism in streptozotocin-induced diabetic male rats. AB - Type-1 diabetes mellitus (T1D) causes impairments within the skeletal muscle microvasculature. Both regular exercise and prazosin have been shown to improve skeletal muscle capillarization and metabolism in healthy rats through distinct angiogenic mechanisms. The aim of this study was to evaluate the independent and additive effects of voluntary exercise and prazosin treatment on capillary-to fiber ratio (C:F) in streptozotocin (STZ)-treated diabetic rats. STZ (65 mg/kg) was intraperitoneally administered to male Sprague-Dawley rats (n = 36) to induce diabetes, with healthy, nondiabetic, sedentary rats (n = 10) as controls. The STZ treated rats were then divided into sedentary (SED) or exercising (EX; 24-h access to running wheels) groups and then further subdivided into prazosin (Praz) or water (H2O) treatment groups: nondiabetic-SED-H2O, STZ-SED-H2O, STZ-EX-H2O, STZ-SED-Praz, and STZ-EX-Praz. After 3 wk, untreated diabetes significantly reduced the C:F in tibialis anterior (TA) and soleus muscles in the STZ-SED-H2O animals (both P < 0.05). Voluntary exercise and prazosin treatment independently resulted in a normalization of C:F within the TA (1.86 +/- 0.12 and 2.04 +/- 0.03 vs 1.71 +/- 0.09, P < 0.05) and the soleus (2.36 +/- 0.07 and 2.68 +/- 0.14 vs 2.13 +/- 0.12, P < 0.05). The combined STZ-EX-Praz group resulted in the highest C:F within the TA (2.26 +/- 0.07, P < 0.05). Voluntary exercise volume was negatively correlated with fed blood glucose levels (r2 = -0.7015, P < 0.01) and, when combined with prazosin, caused further enhanced nonfasted glucose (P < 0.01). Exercise and prazosin reduced circulating nonesterified fatty acids more than either stimulus alone (P < 0.05). These results suggest that the distinct stimulation of angiogenesis, with both regular exercise and prazosin treatment, causes a cooperative improvement in the microvascular complications associated with T1D.NEW & NOTEWORTHY It is currently well established that poorly controlled diabetes reduces both skeletal muscle mass and muscle capillarization. These muscle-specific features of diabetes may, in turn, compromise insulin sensitivity and glucose control. Using a model of streptozotocin-induced diabetes, we show the vascular complications linked with disease and how chronic exposure to exercise and prazosin (an alpha1-adrenergic antagonist) can reduce these complications and improve glycemic control. PMID- 27932676 TI - Recovery of central and peripheral neuromuscular fatigue after exercise. AB - Sustained physical exercise leads to a reduced capacity to produce voluntary force that typically outlasts the exercise bout. This "fatigue" can be due both to impaired muscle function, termed "peripheral fatigue," and a reduction in the capacity of the central nervous system to activate muscles, termed "central fatigue." In this review we consider the factors that determine the recovery of voluntary force generating capacity after various types of exercise. After brief, high-intensity exercise there is typically a rapid restitution of force that is due to recovery of central fatigue (typically within 2 min) and aspects of peripheral fatigue associated with excitation-contraction coupling and reperfusion of muscles (typically within 3-5 min). Complete recovery of muscle function may be incomplete for some hours, however, due to prolonged impairment in intracellular Ca2+ release or sensitivity. After low-intensity exercise of long duration, voluntary force typically shows rapid, partial, recovery within the first few minutes, due largely to recovery of the central, neural component. However, the ability to voluntarily activate muscles may not recover completely within 30 min after exercise. Recovery of peripheral fatigue contributes comparatively little to the fast initial force restitution and is typically incomplete for at least 20-30 min. Work remains to identify what factors underlie the prolonged central fatigue that usually accompanies long-duration single joint and locomotor exercise and to document how the time course of neuromuscular recovery is affected by exercise intensity and duration in locomotor exercise. Such information could be useful to enhance rehabilitation and sports performance. PMID- 27932678 TI - Adjustments with running speed reveal neuromuscular adaptations during landing associated with high mileage running training. AB - It remains to be determined whether running training influences the amplitude of lower limb muscle activations before and during the first half of stance and whether such changes are associated with joint stiffness regulation and usage of stored energy from tendons. Therefore, the aim of this study was to investigate neuromuscular and movement adaptations before and during landing in response to running training across a range of speeds. Two groups of high mileage (HM; >45 km/wk, n = 13) and low mileage (LM; <15 km/wk, n = 13) runners ran at four speeds (2.5-5.5 m/s) while lower limb mechanics and electromyography of the thigh muscles were collected. There were few differences in prelanding activation levels, but HM runners displayed lower activations of the rectus femoris, vastus medialis, and semitendinosus muscles postlanding, and these differences increased with running speed. HM runners also demonstrated higher initial knee stiffness during the impact phase compared with LM runners, which was associated with an earlier peak knee flexion velocity, and both were relatively unchanged by running speed. In contrast, LM runners had higher knee stiffness during the slightly later weight acceptance phase and the disparity was amplified with increases in speed. It was concluded that initial knee joint stiffness might predominantly be governed by tendon stiffness rather than muscular activations before landing. Estimated elastic work about the ankle was found to be higher in the HM runners, which might play a role in reducing weight acceptance phase muscle activation levels and improve muscle activation efficiency with running training.NEW & NOTEWORTHY Although neuromuscular factors play a key role during running, the influence of high mileage training on neuromuscular function has been poorly studied, especially in relation to running speed. This study is the first to demonstrate changes in neuromuscular conditioning with high mileage training, mainly characterized by lower thigh muscle activation after touch down, higher initial knee stiffness, and greater estimates of energy return, with adaptations being increasingly evident at faster running speeds. PMID- 27932677 TI - Suite of clinically relevant functional assays to address therapeutic efficacy and disease mechanism in the dystrophic mdx mouse. AB - Duchenne muscular dystrophy (DMD) is a progressive primary myodegenerative disease caused by a genetic deficiency of the 427-kDa cytoskeletal protein dystrophin. Despite its single-gene etiology, DMD's complex pathogenesis remains poorly understood, complicating the extrapolation from results of preclinical studies in genetic homologs to the design of informative clinical trials. Here we describe novel phenotypic assays which when applied to the mdx mouse resemble recently used primary end points for DMD clinical trials. By coupling force transduction, high-precision motion tracking, and respiratory measurements, we have achieved a suite of integrative physiological tests that provide novel insights regarding normal and pathological responses to muscular exertion. A common feature of these physiological assays is the precise tracking and analysis of volitional movement, thereby optimizing the relevance to clinical tests. Unexpectedly, the measurable biological distinction between dystrophic and control mice at early time points in the disease process is better resolved with these tests than with the majority of previously used, labor-intensive studies of individual muscle function performed ex vivo. For example, the dramatic loss of volitional movement following a novel, standardized grip test distinguishes control mice from mdx mice by a 17.4-fold difference of the means (3.5 +/- 2.2 vs. 60.9 +/- 12.1 units of activity, respectively; effect size 1.99). The findings have both mechanistic and translational implications of potential significance to the fields of basic myology and neuromuscular therapeutics.NEW & NOTEWORTHY This study uses novel phenotypic assays which when applied to the mdx mouse resemble recently used primary end points for DMD clinical trials. A measurable distinction between dystrophic and control mice was seen at early time points in vivo compared with invasive muscle studies performed ex vivo. These assays shed light on normal and pathological responses to muscular exertion and have significant mechanistic and translational implications for the fields of basic myology and neuromuscular therapeutics. PMID- 27932679 TI - Tendon collagen synthesis declines with immobilization in elderly humans: no effect of anti-inflammatory medication. AB - : Nonsteroidal anti-inflammatory drugs (NSAIDs) are used as pain killers during periods of unloading caused by traumatic occurrences or diseases. However, it is unknown how tendon protein turnover and mechanical properties respond to unloading and subsequent reloading in elderly humans, and whether NSAID treatment would affect the tendon adaptations during such periods. Thus we studied human patellar tendon protein synthesis and mechanical properties during immobilization and subsequent rehabilitating resistance training and the influence of NSAIDs upon these parameters. Nineteen men (range 60-80 yr) were randomly assigned to NSAIDs (ibuprofen 1,200 mg/day; Ibu) or placebo (Plc). One lower limb was immobilized in a cast for 2 wk and retrained for 6 wk. Tendon collagen protein synthesis, mechanical properties, size, expression of genes related to collagen turnover and remodeling, and signal intensity (from magnetic resonance imaging) were investigated. Tendon collagen synthesis decreased (P < 0.001), whereas tendon mechanical properties and size were generally unchanged with immobilization, and NSAIDs did not influence this. Matrix metalloproteinase-2 mRNA tended to increase (P < 0.1) after immobilization in both groups, whereas scleraxis mRNA decreased with inactivity in the Plc group only (P < 0.05). In elderly human tendons, collagen protein synthesis decreased after 2 wk of immobilization, whereas tendon stiffness and modulus were only marginally reduced, and NSAIDs had no influence upon this. This indicates an importance of mechanical loading for maintenance of tendon collagen turnover. However, reduced collagen production induced by short-term unloading may only marginally affect tendon mechanical properties in elderly individuals. NEW & NOTEWORTHY: In elderly humans, 2 wk of inactivity reduces tendon collagen protein synthesis, while tendon stiffness and modulus are only marginally reduced, and NSAID treatment does not affect this. This indicates that mechanical loading is important for maintenance of tendon collagen turnover and that changes in collagen turnover induced by short-term immobilization may only have minor impact on the internal structures that are essential for mechanical properties in elderly tendons. PMID- 27932680 TI - Transspinal direct current stimulation modulates migration and proliferation of adult newly born spinal cells in mice. AB - Direct current electrical fields have been shown to be a major factor in the regulation of cell proliferation, differentiation, migration, and survival, as well as in the maturation of dividing cells during development. During adulthood, spinal cord cells are continuously produced in both animals and humans, and they hold great potential for neural restoration following spinal cord injury. While the effects of direct current electrical fields on adult-born spinal cells cultured ex vivo have recently been reported, the effects of direct current electrical fields on adult-born spinal cells in vivo have not been characterized. Here, we provide convincing findings that a therapeutic form of transspinal direct current stimulation (tsDCS) affects the migration and proliferation of adult-born spinal cells in mice. Specifically, cathodal tsDCS attracted the adult born spinal cells, while anodal tsDCS repulsed them. In addition, both tsDCS polarities caused a significant increase in cell number. Regarding the potential mechanisms involved, both cathodal and anodal tsDCS caused significant increases in expression of brain-derived neurotrophic factor, while expression of nerve growth factor increased and decreased, respectively. In the spinal cord, both anodal and cathodal tsDCS increased blood flow. Since blood flow and angiogenesis are associated with the proliferation of neural stem cells, increased blood flow may represent a major factor in the modulation of newly born spinal cells by tsDCS. Consequently, we propose that the method and novel findings presented in the current study have the potential to facilitate cellular, molecular, and/or bioengineering strategies to repair injured spinal cords.NEW & NOTEWORTHY Our results indicate that transspinal direct current stimulation (tsDCS) affects the migratory pattern and proliferation of adult newly born spinal cells, a cell population which has been implicated in learning and memory. In addition, our results suggest a potential mechanism of action regarding the functional effects of applying direct current. Thus tsDCS may represent a novel method by which to manipulate the migration and cell number of adult newly born cells and restore functions following brain or spinal cord injury. PMID- 27932681 TI - Acute intermittent hypoxia in rats activates muscle proteolytic pathways through a gluccorticoid-dependent mechanism. AB - Although it is well known that chronic hypoxia induces muscle wasting, the effects of intermittent hypoxia on skeletal muscle protein metabolism remain unclear. We hypothesized that acute intermittent hypoxia (AIH), a challenge that activates the hypothalamic-pituitary-adrenal axis, would alter muscle protein homeostasis through a glucocorticoid-dependent mechanism. Three-week-old rats were submitted to adrenalectomy (ADX) and exposed to 8 h of AIH (6% O2 for 40 s at 9-min intervals). Animals were euthanized, and the soleus and extensor digitorum longus (EDL) muscles were harvested and incubated in vitro for measurements of protein turnover. AIH increased plasma levels of corticosterone and induced insulin resistance as estimated by the insulin tolerance test and lower rates of muscle glucose oxidation and the HOMA index. In both soleus and EDL muscles, rates of overall proteolysis increased after AIH. This rise was accompanied by an increased proteolytic activities of the ubiquitin(Ub) proteasome system (UPS) and lysosomal and Ca2+-dependent pathways. Furthermore, AIH increased Ub-protein conjugates and gene expression of atrogin-1 and MuRF-1, two key Ub-protein ligases involved in muscle atrophy. In parallel, AIH increased the mRNA expression of the autophagy-related genes LC3b and GABARAPl1. In vitro rates of protein synthesis in skeletal muscles did not differ between AIH and control rats. ADX completely blocked the insulin resistance in hypoxic rats and the AIH-induced activation of proteolytic pathways and atrogene expression in both soleus and EDL muscles. These results demonstrate that AIH induces insulin resistance in association with activation of the UPS, the autophagic-lysosomal process, and Ca2+-dependent proteolysis through a glucocorticoid-dependent mechanism.NEW & NOTEWORTHY Since hypoxia is a condition in which the body is deprived of adequate oxygen supply and muscle wasting is induced, the present work provides evidence linking hypoxia to proteolysis through a glucocorticoid dependent mechanism. We show that the activation of proteolytic pathways, atrophy related genes, and insulin resistance in rats exposed to acute intermittent hypoxia was abolished by surgical removal of adrenal gland. This finding will be helpful for understanding of the muscle wasting in hypoxemic conditions. PMID- 27932682 TI - Preliminary assessment of midazolam, fentanyl and fluanisone combination for the sedation of rhesus macaques ( Macaca mulatta). AB - This study was undertaken to assess the suitability of fentanyl/fluanisone ('Hypnorm', VetaPharma; 0.315 mg/mL of fentanyl citrate and 10 mg/mL of fluanisone) alone or combined with midazolam in rhesus macaques. Fifteen rhesus macaques requiring sedation for veterinary procedures received an intramuscular (IM) dose range of Hypnorm from 0.01 mL/kg to 0.3 mL/kg either alone or combined with 0.5 mg/kg of midazolam. To reverse the sedation, flumazenil in combination with either naloxone, buprenorphine or butorphanol was administered intravenously (IV) or IM. Rhesus macaques were successfully sedated with 0.1 mL/kg of Hypnorm and 0.5 mg/kg of midazolam, and sedation was partially reversed by the administration of flumazenil and either naloxone or buprenorphine. However the primates remained slightly sedated and were only released into their home cage several hours post recovery. Butorphanol failed to induce recovery and caused marked respiratory depression. The neuroleptanalgesic combination, Hypnorm and midazolam, effectively immobilized rhesus macaques and was reversible with a combination of flumazenil and either naloxone or buprenorphine. PMID- 27932683 TI - Survival of bacteria of laboratory animal origin on cage bedding and inactivation by hydrogen peroxide vapour. AB - This study aims to determine the ability of laboratory animal bacteria to resist desiccation and inactivation by hydrogen peroxide vapour (HPV) on paper bedding pieces. Bedding pieces were saturated with bacterial suspensions in water or 2% (w/v) bovine serum albumin (BSA) in water, and held in a mouse facility. Viable counts showed variable survival rates over time for the bacterial species used ([ Pasteurella] pneumotropica, Muribacter muris, Pseudomonas aeruginosa, Acinetobacter redioresistens, Escherichia coli, Klebsiella oxytoca, Bordetella bronchiseptica, Bordetella hinzii, Enterococcus faecalis, beta-haemolytic Streptococcus spp., Staphylococcus aureus and Staphylococcus xylosus). Overall, BSA increased bacterial survival in the bedding pieces. The survival rates of Bacillus safensis were not influenced by BSA but depended on sporulation. When bedding pieces and Petri dishes inoculated with E. coli, P. aeruginosa and S. aureus were subjected to HPV disinfection, all bacterial species on the bedding pieces inoculated with bacterial suspensions in water were readily inactivated. By contrast, S. aureus and P. aeruginosa, but not E. coli cells survived HPV treatment in high numbers when inoculated on bedding pieces as a BSA suspension. Notably, all three bacterial species were readily inactivated by HPV even in the presence of BSA when smeared on smooth surfaces. In conclusion, the suspension medium and the carrier can influence the environmental survival and susceptibility of bacterial species to HPV. Our results may help to develop standard protocols that can be used to ensure the microbiological quality of experimental rodent housing. PMID- 27932684 TI - Standardizing the microbiota of fish used in research. AB - Little attention has been paid to the effects of fish microbiotas on the reproducibility and comparability of fish studies so far. Extrinsic and intrinsic factors, such as water quality, environmental microbial populations, diet, host genetic profile, gender, age and stress status, affect fish microbiotas and create significant inter- and intra-species variations. Fish microbiotas play critical roles in many key aspects of host physiology, such as protection against pathogens, digestion and development of the digestive tract and the local immune system. Thus, greater effort should be invested in standardizing the microbiological profiles of research fish. In this context, issues requiring consideration include the establishment of isogenic and isobiotic fish lines, the standardization of rearing conditions and the development of appropriate tests to adequately describe microbial populations. There are many challenges involved in each of these issues, and the research community must decide which aspects should be standardized for each species and each type of research. For all studies in which microbiota is expected to exert an influence, thorough reporting is of paramount importance. Every step towards standardization increases study quality and simultaneously contributes to reducing the number of fish used in research, which is a legal and ethical obligation. PMID- 27932685 TI - Longitudinal micro-computed tomography monitoring of progressive liver regeneration in a mouse model of partial hepatectomy. AB - The partial hepatectomy (PH) model is widely used to study liver regeneration. Currently, the extent of regeneration is analyzed by measuring the weight of the liver post-mortem or by magnetic resonance imaging. In this study we aimed to determine whether liver volume gain can be accurately measured using micro computed tomography (microCT). Approximately 42% of the liver was removed by ligation in C57BL/6 N mice. Mice were divided into two study groups. In group 1 conventional characterization of liver hyperplasia was performed by weighing the liver post-mortem. In group 2, liver volume gain was determined by microCT volume estimation. MicroCT results showed equivalent regeneration rates compared with the conventional method without the need to mathematically determine initial liver weights before PH. This parameter is strongly influenced by the age, strain and sex of the mice. In addition non-invasive microCT determination of volume gain over multiple time-points using the same animal reduces the number of animals needing to be used (in line with the 3R principle of replacement, reduction and refinement). PMID- 27932689 TI - Hiatus hernia presenting as resistant iron deficiency anaemia in a child. PMID- 27932687 TI - Diabetes Distress Among Persons With Type 1 Diabetes. AB - Purpose The purpose of this study is to evaluate associations between diabetes distress and a range of psychological health behaviors and concerns among persons with type 1 diabetes for the benefit of enhancing early identification and intervention of at-risk individuals. Methods Persons with type 1 diabetes (n = 268; 57.1% female, 91.0% white, 76.8% <18 years of age, average A1C 8.4%) completed the 2-item Diabetes Distress Screening Scale (DDS2) and a battery of psychometrically sound instruments measuring satisfaction with life, self-esteem, self-efficacy, depression, perfectionism, body image satisfaction, dietary restraint and eating, and shape and weight concerns. Each subscale score was compared within age groups (<18 years vs >=18 years) between groups (diabetes distress level [low, moderate, high]) using analysis of variance (with Bonferroni correction or the Kruskal-Wallis test if the variables were not normally distributed). Results For both age groups, high diabetes distress was independently associated with greater A1C values, higher depression scores and eating, and shape and weight concerns than those with low or moderate distress. For patients <18 years of age, those with high diabetes distress scored lower on measures of satisfaction with life, self-esteem, and self-efficacy and higher on dietary restraint and several areas of perfectionism than those with low or moderate distress. Conclusions Individuals with type 1 diabetes who have high diabetes distress also report higher A1C values and poorer psychological health concerns. A brief diabetes distress questionnaire can help to identify those who need additional screening, education and support, and treatment for overall health and well-being. PMID- 27932686 TI - Computed tomography-based survey of the vascular anatomy of the juvenile Gottingen minipig. AB - Over the past 50 years, image-guided procedures have been established for a wide range of applications. The development and clinical translation of new treatment regimens necessitate the availability of suitable animal models. The juvenile Gottingen minipig presents a favourable profile as a model for human infants. However, no information can be found regarding the vascular system of juvenile minipigs in the literature. Such information is imperative for planning the accessibility of target structures by catheterization. We present here a complete mapping of the arterial system of the juvenile minipig based on contrast-enhanced computed tomography. Four female animals weighing 6.13 +/- 0.72 kg were used for the analyses. Imaging was performed under anaesthesia, and the measurement of the vascular structures was performed independently by four investigators. Our dataset forms a basis for future interventional studies in juvenile minipigs, and enables planning and refinement of future experiments according to the 3R (replacement, reduction and refinement) principles of animal research. PMID- 27932690 TI - Peripartum dengue haemorrhagic fever: a chameleon that changes its spots. A case requiring laparotomy. PMID- 27932691 TI - Implementation of a triage system in Pakistan: the need of the hour. AB - In today's world, an effective emergency department (ED) cannot function properly without having a triage system. Though available in various forms, this essentially categorises patients according to the seriousness of their condition and the priority of their need.Pakistan is yet to introduce this system and where it exists, it is in its infancy. A disaster-prone country such as ours, which is frequently faced with both man-made and natural calamities, could benefit tremendously from its introduction. The activity of EDs would be streamlined and precious lives would be saved. PMID- 27932692 TI - Functional reorganization is a maladaptive response to injury - Commentary. PMID- 27932693 TI - Functional reorganization is a maladaptive response to injury - NO. PMID- 27932694 TI - Functional reorganization is a maladaptive response to injury - YES. PMID- 27932695 TI - Posture-Dependent Corticomotor Excitability Differs Between the Transferred Biceps in Individuals With Tetraplegia and the Biceps of Nonimpaired Individuals. AB - BACKGROUND: Following biceps transfer to enable elbow extension in individuals with tetraplegia, motor re-education may be facilitated by greater corticomotor excitability. Arm posture modulates corticomotor excitability of the nonimpaired biceps. If arm posture also modulates excitability of the transferred biceps, posture may aid in motor re-education. OBJECTIVE: Our objective was to determine whether multi-joint arm posture affects corticomotor excitability of the transferred biceps similar to the nonimpaired biceps. We also aimed to determine whether corticomotor excitability of the transferred biceps is related to elbow extension strength and muscle length. METHODS: Corticomotor excitability was assessed in 7 arms of individuals with tetraplegia and biceps transfer using transcranial magnetic stimulation and compared to biceps excitability of nonimpaired individuals. Single-pulse transcranial magnetic stimulation was delivered to the motor cortex with the arm in functional postures at rest. Motor evoked potential amplitude was recorded via surface electromyography. Elbow moment was recorded during maximum isometric extension trials, and muscle length was estimated using a biomechanical model. RESULTS: Arm posture modulated corticomotor excitability of the transferred biceps differently than the nonimpaired biceps. Elbow extension strength was positively related and muscle length was unrelated, respectively, to motor-evoked potential amplitude across the arms with biceps transfer. CONCLUSIONS: Corticomotor excitability of the transferred biceps is modulated by arm posture and may contribute to strength outcomes after tendon transfer. Future work should determine whether modulating corticomotor excitability via posture promotes motor re-education during the rehabilitative period following surgery. PMID- 27932697 TI - HtrA3 Isoform-Specific ELISAs for Early Detection of Preeclampsia. AB - Preeclampsia is a serious disorder of human pregnancy occurring after 20 weeks of gestation. It can be divided into subtypes of early onset (<34 weeks of gestation) and late onset (>34 weeks). Presymptomatic detection to identify those at high risk is important for managing this disease. HtrA3, a serine protease with high expression in the developing placenta, exists in long (HtrA3-L) and short (HtrA3-S) isoforms. They are identical, except HtrA3-S lacks the C-terminal PDZ domain. We have previously shown by Western blot analysis that serum HtrA3 levels at the end of the first trimester are significantly higher in women who later develop preeclampsia than in controls. In this study, using highly specific HtrA3 monoclonal antibodies, we established and fully validated two enzyme-linked immunosorbent assays to detect both HtrA3 isoforms together (HtrA3-T) and HtrA3-L alone in the human serum. We then determined serum HtrA3 at 11 to 13 weeks of gestation in a cohort of singleton pregnancies that proceeded without complications or developed preeclampsia in the third trimester. Compared with controls, those who developed late-onset preeclampsia had significantly higher levels of HtrA3-L, whereas those who developed early-onset preeclampsia had significantly lower ratios of HtrA3-L/HtrA3-T. These data support a potential utility of these HtrA3 ELISAs for early detection of preeclampsia. PMID- 27932696 TI - Corpus Callosum Structural Integrity Is Associated With Postural Control Improvement in Persons With Multiple Sclerosis Who Have Minimal Disability. AB - BACKGROUND: Improvement of postural control in persons with multiple sclerosis (PwMS) is an important target for neurorehabilitation. Although PwMS are able to improve postural performance with training, the neural underpinnings of these improvements are poorly understood. OBJECTIVE: To understand the neural underpinnings of postural motor learning in PwMS. METHODS: Supraspinal white matter structural connectivity in PwMS was correlated with improvements in postural performance (balancing on an oscillating surface over 25 trials) and retention of improvements (24 hours later). RESULTS: Improvement in postural performance was directly correlated to microstructural integrity of white matter tracts, measured as radial diffusivity, in the corpus callosum, posterior parieto sensorimotor fibers and the brainstem in PwMS. Within the corpus callosum, the genu and midbody (fibers connecting the prefrontal and primary motor cortices, respectively) were most strongly correlated to improvements in postural control. Twenty-four-hour retention was not correlated to radial diffusivity. CONCLUSION: PwMS who exhibited poorer white matter tract integrity connecting the cortical hemispheres via the corpus callosum showed the most difficulty learning to control balance on an unstable surface. Prediction of improvements in postural control through training (ie, motor learning) via structural imaging of the brain may allow for identification of individuals who are particularly well suited for postural rehabilitation interventions. PMID- 27932698 TI - Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen. AB - ZAP-70 is a critical molecule in the transduction of T cell antigen receptor signaling and the activation of T cells. Upon activation of the T cell antigen receptor, ZAP-70 is recruited to the intracellular zeta-chains of the T cell receptor, where ZAP-70 is activated and colocalized with its substrates. Inhibitors of ZAP-70 could potentially function as treatments for autoimmune diseases or organ transplantation. In this work, we present the design, optimization, and implementation of a screen for inhibitors that would disrupt the interaction between ZAP-70 and the T cell antigen receptor. The screen is based on a fluorescence polarization assay for peptide binding to ZAP-70. PMID- 27932699 TI - A Systematic Investigation of the Best Buffers for Use in Screening by MALDI-Mass Spectrometry. AB - Matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) offers a label-free alternative for the screening of biochemical targets in both 1536- and 6144-assay formats, as well as potentially providing increased sensitivity, reproducibility, and the simultaneous detection of multiple assay components within a specified m/z range. Ion suppression effects are one of the principal limitations reported for MS analysis. Within MALDI-MS screening, it has been identified that certain biochemical components incorporated into the assay (e.g., the buffers used to preserve the physiological conditions of the enzyme, salts, and other additives) induce suppression of the analyte ion signals monitored. This poorly understood phenomenon of ion suppression is a key reason the screening community has been reluctant to shift their investigations toward MS methods with reduced sample cleanup. Using acetylcholine as an assay substrate mimic, we have generated robust data to quantify the degree to which the most highly used components (base buffers, additional components, detergents, cell culture media, and other additives) within current screening assays are compatible with MALDI-MS. Here, the most suitable buffers and components, along with their identified optimal concentrations in terms of limiting ion suppression effects, are proposed for use in screening assays measured by MALDI-MS. PMID- 27932701 TI - Synthesis and characterization of fluorescein-grafted polyurethane for potential application in biomedical tracing. AB - Redesigned multifunctional biopolymers represent a novel building bridge for interdisciplinary collaborations in biomaterials development. We prepared fluorescein-grafted polyurethane scaffolds (PU-C1, PU-C5, and PU-B1) to meet both clinical needs and biological safety evaluations, using different contents of calcein and different synthesis procedures for potential biomedical tracing. X ray diffraction, infrared, X-ray photoelectron spectroscopy, nuclear magnetic resonance, scanning electron microscopy, and light microscopy were used to analyze the composition and structure of polyurethanes, as well as to observe their morphology with and without biomarkers. Fluorescence spectrophotometer and fluorescence microscopy were used to detect the fluorescence characteristics. The results showed that the grafting of calcein significantly affected the chemical structure and fluorescence sensitivities of copolymers. When compared to calcein, which was added before synthesis (PU-C1), the marker that was added during the extender process (PU-B1) presented higher fluorescence efficiency. Both PU-C5 and PU-B1 exhibited strong fluorescent response and good cytocompatibility in vitro and in vivo, with no interference from the autofluorescence of tissues after 4 weeks of implantation. The fluorescence-marked material can be used to continuously and noninvasively monitor the dynamic changes in polymers, which provides a way to clearly trace the material or to distinguish between the material and tissue in vivo. PMID- 27932700 TI - Predictors of Enteral Tube Feeding in Hospitalized Older Adults. AB - BACKGROUND: Despite general recognition that enteral tube feeding (ETF) is frequently employed in long-term care facilities and patients with dementia, remarkably little research has determined which factors are associated with its use in acutely ill older adults. In this study, we aimed to investigate determinants of ETF introduction in hospitalized older adults. METHODS: We examined a retrospective cohort of acutely ill patients, aged 60 years and older, admitted to a university hospital's geriatric ward from 2014-2015, in Sao Paulo, Brazil. The main outcome was the introduction of ETF during hospitalization. Predictors of interest included age, sex, referring unit, comorbidity burden, functional status, malnutrition, depression, dementia severity, and delirium. Multivariate analysis was performed using backward stepwise logistic regression. RESULTS: A total of 214 cases were included. Mean age was 81 years, and 63% were women. Malnutrition was detected in 47% of the cases, dementia in 46%, and delirium in 36%. ETF was initiated in 44 (21%) admissions. Independent predictors of ETF were delirium (odds ratio [OR], 4.83; 95% CI, 2.12-11.01; P < .001) and total functional dependency (OR, 8.95; 95% CI, 2.87-27.88; P < .001). Malnutrition was not independently associated with ETF. CONCLUSION: One in five acutely ill older adults used ETF while hospitalized. Delirium and functional dependency were independent predictors of its introduction. Risks and benefits of enteral nutrition in this particular context need to be further explored. PMID- 27932702 TI - Incorporation of cerium oxide into hydroxyapatite coating regulates osteogenic activity of mesenchymal stem cell and macrophage polarization. AB - Biomedical coatings for orthopedic implants should facilitate osseointegration and mitigate implant-induced inflammatory reactions. Cerium oxide (CeO2) ceramics possess anti-oxidative properties and can be used to decrease mediators of inflammation, which makes them attractive for biomedical applications. In our work, two kinds of CeO2 incorporated hydroxyapatite coatings (HA-10Ce and HA 30Ce) were prepared via plasma spraying technique and the effects of CeO2 addition on the responses of bone mesenchymal stem cells (BMSCs) and RAW264.7 macrophages were investigated. An increase in CeO2 content in the HA coatings resulted in better osteogenic behaviors of BMSCs in terms of cell proliferation, alkaline phosphatase (ALP) activity and mineralized nodule formation. RT-PCR and western blot analysis suggested that the incorporation of CeO2 may promote the osteogenic differentiation of BMSCs through the Smad-dependent BMP signaling pathway, which activated Runx2 expression and subsequently enhanced the expression of ALP and OCN. The expression profiles of macrophages cultured on the CeO2 modified coating revealed a tendency toward a M2 phenotype, because of an upregulation of M2 surface markers (CD163 and CD206), anti-inflammatory cytokines (TNF-alpha and IL-6) and osteoblastogenesis-related genes (BMP2 and TGF-beta1) as well as a downregulation of M1 surface markers (CCR7 and CD11c), proinflammatory cytokines (IL-10 and IL-1ra) and reactive oxygen species production. The results suggested the regulation of BMSCs behaviors and macrophage-mediated responses at the coating's surface were associated with CeO2 incorporation. The incorporation of CeO2 in HA coatings can be a valuable strategy to promote osteogenic responses and reduce inflammatory reactions. PMID- 27932703 TI - An in vivo pilot study of a microporous thin film nitinol-covered stent to assess the effect of porosity and pore geometry on device interaction with the vessel wall. AB - Sputter-deposited thin film nitinol constructs with various micropatterns were fabricated to evaluate their effect on the vessel wall in vivo when used as a covering for commercially available stents. Thin film nitinol constructs were used to cover stents and deployed in non-diseased swine arteries. Swine were sacrificed after approximately four weeks and the thin film nitinol-covered stents were removed for histopathologic evaluation. Histopathology revealed differences in neointimal thickness that correlated with the thin film nitinol micropattern. Devices covered with thin film nitinol with a lateral * vertical length = 20 * 40 um diamond pattern had minimal neointimal growth with well organized cell architecture and little evidence of ongoing inflammation. Devices covered with thin film nitinol with smaller fenestrations exhibited a relatively thick neointimal layer with inflammation and larger fenestrations showed migration of inflammatory and smooth muscle cells through the micro fenestrations. This "proof-of-concept" study suggests that there may be an ideal thin film nitinol porosity and pore geometry to encourage endothelialization and incorporation of the device into the vessel wall. Future work will be needed to determine the optimal pore size and geometry to minimize neointimal proliferation and in-stent stenosis. PMID- 27932705 TI - Possible role for glomerular-derived angiotensinogen in nephrotic syndrome. AB - BACKGROUND AND OBJECTIVE: Renin-angiotensin system (RAS) inhibitors reduce glomerular injury and proteinuria, indicating that angiotensin II (Ang II) is involved in glomerular diseases. Although the local RAS is reported to play an essential role in maintaining local tissue functions, the role of the local RAS in regulating glomerular function is not well evaluated. In this study, we analyzed the glomerular expression of RAS components in nephrotic models and the effect of Ang II receptor blockers (ARB) on the expression of angiotensinogen (AGT). METHODS: The levels of glomerular expression of RAS components were analyzed in two nephrotic models: anti-nephrin antibody-induced nephropathy and PAN nephropathy, a mimic of human minimal change nephrotic syndrome. The effect of the ARB irbesartan on the expression of AGT in the nephrotic model was analyzed. RESULTS: Glomerular expression of AGT and the receptors for Ang II was clearly increased in the nephrotic models, while the expression levels of renin, ACE and ACE2 were decreased. ARB treatment suppressed the increase of glomerular expression of AGT in the nephrotic model. CONCLUSION: It is conceivable that the promoted local RAS action participated in the glomerular dysfunction, and that ARB treatment ameliorated slit diaphragm injury by inhibiting the positive feedback loop of the activated local Ang II action. PMID- 27932708 TI - Charity reveals the difficulties of enforcing animal welfare law. PMID- 27932711 TI - Veterinary concerns about European dog trade. PMID- 27932718 TI - Resilience training: does it work? AB - With concern about mental health and wellbeing issues among veterinary students being much to the fore, what can be done to help build resilience? And could there be a risk of over-reacting? These issues were discussed in a debate at the BVA Congress at the London Vet Show. Georgina Mills reports. PMID- 27932717 TI - 'Would you eat an alien?' AB - A novel way of exploring comparative cognition, animal welfare ethics and human animal relations formed the basis of this year's Wooldridge Memorial Lecture, held during the BVA Congress at the London Vet Show last month. Christine Nicol, of the University of Bristol, shared her experiences of making the BBC Radio 4 series 'Would you eat an alien?' and gave an insight into the ethical dilemmas that formed the basis of the programme. Laura Honey reports. PMID- 27932719 TI - When veterinary teams are faced with clients who can't afford to pay. PMID- 27932721 TI - Can you reduce the dose of meloxicam in dogs with osteoarthritis? AB - BestBETs for Vets are generated by the Centre for Evidence-based Veterinary Medicine at the University of Nottingham to help answer specific questions and assist in clinical decision making. Although evidence is often limited, they aim to find, present and draw conclusions from the best available evidence, using a standardised framework. A more detailed description of how BestBETs for Vets are produced was published in a previous issue of Veterinary Record (VR, April 4, 2015, pp 354-356). PMID- 27932722 TI - The use of PRID-Delta versus CIDR in dairy cattle and subsequent pregnancy rate with artificial insemination. PMID- 27932726 TI - Addressing disillusionment among young vets. PMID- 27932730 TI - Reptiles and the Animal Welfare Act. PMID- 27932731 TI - Outbreaks of bovine interstitial pneumonia. PMID- 27932732 TI - Disbudding goat kids. PMID- 27932740 TI - Encouraging tomorrow's vet students. AB - EdVet was set up by a group of six vet students at Liverpool vet school with the aim of promoting a career in veterinary medicine to school children of all ages. PMID- 27932741 TI - Third-year student diary. AB - The stress of finding somewhere to live and a couple of health issues have been occupying our diarist Rosie Perrett recently. However, she has also been fascinated by anaesthesia and animal behaviour. PMID- 27932743 TI - [Recent Progress in Cerebroprotective Therapy]. PMID- 27932742 TI - Differences in cancer characteristics of Chinese patients with prostate cancer who present with different symptoms. AB - INTRODUCTION: Currently there is no structured prostate cancer screening programme in Asia. Early diagnosis of prostate cancer in Asia is by an opportunistic case-finding approach, that is, offering prostate-specific antigen testing to an individual without obvious symptoms of prostate cancer. In this study, we investigated the relationship between the mode of presentation and the characteristics of prostate cancers diagnosed in our hospital. METHODS: We recruited 120 consecutive Chinese patients with prostate cancer newly diagnosed from September 2011 to February 2013 in a regional hospital in Hong Kong. Patient demographics, symptoms, presentation, staging, and risk profiles were collected and analysed. RESULTS: The number of subjects diagnosed during a health check (group 1), investigated for symptoms with no/low suspicion of prostate cancer (group 2), investigated for symptoms where prostate cancer was suspected (group 3), or who had undergone transurethral prostatectomy (group 4) were 12 (10.0%), 53 (44.2%), 46 (38.3%), and nine (7.5%), respectively. Overall mean age was 71.0 (range, 54-90) years, and patients in group 3 were significantly older than those in groups 1 and 2 (P<0.001). Patients in group 3 had a significantly higher level of serum prostate-specific antigen, higher incidence of abnormal digital rectal examination, and more metastatic disease at presentation than the other groups. Nonetheless, more than 50% of the prostate cancers in groups 1 and 2 were of intermediate risk or higher staging at presentation. After a median follow-up of 32 months, cancer-specific survival was 100% for each of groups 1, 2, and 4 but was only 76.8% for group 3 (P=0.006). CONCLUSIONS: Patients with prostate cancer who presented with prostate cancer-related symptoms had more metastatic disease and poorer survival than patients diagnosed by a case-finding approach. Moreover, more than half of those patients diagnosed by case finding belonged to intermediate- or higher-risk groups for which active treatment was recommended. PMID- 27932744 TI - [Preservation of Sinonasal Function in Endoscopic Endonasal Surgery]. PMID- 27932746 TI - [Distribution of Pain and Numbness in Patients with Cervical Spine Disorders]. AB - PURPOSE: To elucidate the distribution of improved pain and numbness after cervical decompression surgery in patients with cervical spine disorders. METHODS: This study included 4 men and 5 women aged 45 to 71 years(mean 58 years)presenting with radiculopathy and 50 men and 17 women aged 35 to 88 years(mean 66 years)presenting with myelopathy. RESULTS: All 9 patients with radiculopathy presented with neck pain, and 3 presented with cervical angina. Among the patients with myelopathy, 2 presented with headache, 2 with onion-skin facial pain, 29 with neck pain, 8 with truncal pain, 7 with low back pain, 4 with numbness below the T4 dermatomal area, 1 with penile pain, 61 with arm pain, 49 with leg pain, and 2 without pain or numbness. Patients with myelopathy presenting with preoperative neck and arm pain had significantly better recovery rates compared to patients without such pain. CONCLUSION: Patients with cervical spine disorders present with pain and numbness in various areas. Preoperative neck pain and arm pain are indicators for better recovery in patients with myelopathy. PMID- 27932745 TI - [Association of Deep Venous Thrombosis with D-dimer Values in Patients with Hemorrhagic Stroke]. AB - Pulmonary embolism(PE)in the early phase of stroke worsens the prognosis. It is necessary to detect deep venous thrombosis(DVT)to avoid PE. We conducted the D dimer screening in order to detect DVT at an earlier stage. We retrospectively analyzed the clinical data of patients with hemorrhagic stroke who were admitted to the local stroke center, and investigated the complication rates of DVT, PE, D dimer values, and risk factors of DVT. From October 2012 to August 2014, 261 patients were included. DVT was detected in 46 patients(17.6%)and anticoagulant therapy was started in 5 patients with central DVT. PE did not occur during this observation period. The D-dimer cutoff value for estimating the presence of the DVT was 8.9MUg/mL, and the risk factors for DVT were older age, severe neurological disability, prolonged hospital stays, and subarachnoid hemorrhage. D dimer screening is very useful to make earlier diagnosis and treatment of DVT. PMID- 27932747 TI - [A Rare Case of Metastatic Brain Tumors in the Bilateral Cerebellopontine Angles]. AB - We encountered a rare case of metastatic brain tumors in the bilateral cerebellopontine angles. The patient was a 61-year-old man, who visited an otorhinolaryngology clinic with complaints of rapidly progressing bilateral hearing impairment and facial palsy. The patient was referred to our hospital because tumorous lesions were suspected in the bilateral cerebellopontine angles on brain magnetic resonance imaging. Regarding tumor markers, the patient's cancer antigen 19-9 and carcinoembryonic antigen levels were high, which suggested metastasis. However, no abnormal findings other than abdominal lymph node enlargement were detected on whole-body examination, and no primary lesion was identified. The tumor in the right cerebellopontine angle was excised using the lateral suboccipital approach and subjected to pathological examination. It was diagnosed as an adenocarcinoma; thus, both lesions were considered brain metastases from a malignant abdominal tumor, and radiochemotherapy was administered to the patient. Unfortunately, the patient died after 89 days of treatment, and a pathological autopsy revealed that the primary lesion was a common bile duct tumor. No dural metastasis was noted in the brain or spinal cord; however, tumors were detected in the epiarachnoid space during surgery. Metastasis to the bilateral cerebellopontine angles occurred in the same period, which was indicative of ascending metastasis through the vertebrobasilar artery. Hence, we suggest that progressive bilateral hearing impairment and facial palsy were a consequence of brain tumors that had metastasized bilaterally to the cerebellopontine angles. PMID- 27932748 TI - [Hydrocephalus Associated with Small Clinoidal Meningioma that Resolved after Tumor Removal:A Case Report]. AB - PURPOSE: Small meningiomas causing hydrocephalus without obstruction of the ventricular system are rare. Herein, we report a case of small clinoidal meningioma with communicating hydrocephalus, which resolved after tumor removal. CASE PRESENTATION: A 70-year-old woman presented with a 1-month history of memory disturbance followed by gait disturbance. MR images revealed a right clinoidal meningioma, 2 cm in diameter, and dilatation of the ventricles suggesting communicating hydrocephalus. The cerebrospinal fluid(CSF)pressure was 130 mmH2O, as determined via a lumbar puncture. High concentrations of protein(65mg/dL)were detected in the lumbar CSF. The tumor was completely removed via a frontotemporal craniotomy. Higher protein concentrations(94mg/dL)were detected in the CSF obtained intraoperatively from the sylvian cistern. The histopathological diagnosis was meningothelial meningioma. The patient's symptoms improved markedly after surgery. Postoperative MR images revealed resolution of the hydrocephalus. The lumbar CSF protein concentration returned to normal(43mg/dL). Neither tumor recurrence nor progression of hydrocephalus has been observed for 4 years. DISCUSSION: Communicating hydrocephalus, associated with a small meningioma at the supratentorial region, has not been described. Previous studies have shown that patients with meningioma may develop communicating hydrocephalus after tumor removal or stereotactic radiosurgery. Thus, it is interesting that the small supratentorial meningioma in our case developed communicating hydrocephalus without any therapeutic intervention. Considering the CSF protein concentration, we speculate that the hydrocephalus was the result of CSF malabsorption associated with high CSF protein concentration and CSF pathway obstruction at the suprasellar cistern caused by the tumor. PMID- 27932749 TI - [Hemorrhage from an Angiographically Obliterated Arteriovenous Malformation after Gamma Knife Radiosurgery:An Immunohistochemistry Study]. AB - A 24-year-old woman was diagnosed with a cerebral arteriovenous malformation(AVM)in the right parietal lobe(Spetzler-Martin grade I). The AVM was treated with stereotactic radiosurgery and was observed to have completely disappeared 3 years after radiosurgery. At the age of 35 years, the patient complained of a headache, and was referred to our hospital. A plain CT scan demonstrated a large cyst with niveau formation in the right parietal lobe. Cerebral angiography identified no recurrence of AVM. However, contrast MRI revealed an enhanced lesion on the surface of the cyst. The patient underwent cyst fenestration and total removal of the obliterated nidus through a right parietal craniotomy. Residual blood flow was confirmed in the obliterated nidus during surgery. The postoperative course was uneventful, and the headache was completely resolved. The patient was discharged without any neurological deficits. On pathological examination, a large number of small vessels were observed within the obliterated nidus. Immunohistochemistry demonstrated that these vessels were positive for CD31, CD34, and VEGFR-2, suggesting that endothelial progenitor cells may be involved in occult recurrence, cyst formation, and late bleeding after stereotactic radiosurgery targeting cerebral AVMs. PMID- 27932750 TI - [A Case Report of Spontaneous Cerebrospinal Fluid Otorrhea]. AB - Spontaneous cerebrospinal fluid(CSF)otorrhea is less common than CSF leakage caused by trauma, and rarely occurs in adults. We report an adult case of CSF otorrhea. A 71-year-old woman with no traumatic or otologic history was hospitalized due to bacterial meningitis. After hospitalization, CSF leakage started suddenly from the left external ear canal. A high resolution CT scan with intrathecal administration of contrast material revealed CSF leakage in the left ear canal and multiple bone erosions in both the tegmen mastoideum and the posterior fossa aspect of the petrous bone. We performed closure and surgery via the middle fossa approach. We identified a bone defect in the tegmen mastoideum but could not detect any obvious abnormality in the dura mater. We placed both a pericranial flap and a free abdominal fat on the middle base of the skull as sealing materials. There was no recurrence of CSF otorrhea following surgery. In this surgery, the use of a multilayered closure technique is very important to avoid the recurrence of CSF leakage. PMID- 27932751 TI - [A Case of Subacute Combined Degeneration Caused by Vitamin B12 Deficiency in a Cervical Spondylosis Surgery Referral]. AB - A 62-year-old man with a 1-year history of numbness of the extremities, clumsiness, and gait disorder was diagnosed with cervical spondylotic myelopathy at a neighboring clinic and referred to our institution for surgery. The patient had undergone a total gastrectomy 6 years previously. Flattening of the cervical cord, associated with diffuse cervical spondylosis and intramedullary intensity change, was observed on magnetic resonance imaging of the cervical spine. Neurological examination revealed decreased vibratory and position sense in all limbs, with posterior funiculus-based neurological symptoms. Blood biochemistry revealed decreased vitamin B12(VB12)levels and megaloblastic anemia. On the basis of these findings, the patient was diagnosed with subacute combined degeneration(SCD). The patient was treated with VB12 for 3 months; the gait disorder resolved and the intramedullary intensity changes in the posterior column of the medulla oblongata, thoracicus, and spinal cord were no longer observed. SCD is a pathological condition in which recovery of neurological function may be achieved through early administration of VB12. In some cases, it is difficult to differentiate between this condition and cervical spondylotic myelopathy because both diseases exhibit progressive spinal symptoms. The medical history and results of neurological evaluations of the patient are important for an accurate diagnosis, and should therefore not be overlooked. PMID- 27932752 TI - [The Usefulness of Considering Preoperative CT Images for Surgical Clipping in a Patient with a Distal ACA Ruptured Aneurysm]. PMID- 27932753 TI - [Pre- and Intra-Operative Supporting Technology for Brain Tumors(2)Transcranial and Endoscopic Surgery for Lateral Ventricle Tumors]. PMID- 27932754 TI - [Overexpression of lentivirus RFX1 and its inhibitory effect on proliferation of glioblastoma cells]. AB - OBJECTIVE: To construct overexpression lentivirus vector for human regulatory factor X1 (RFX1) gene, and to explore its effect on proliferation of F98 cell line.? Methods: Huamn RFX1 gene was amplified by polymerase reaction. Gene amplification products were inserted into lentivirus vector pITA, and the lentivirus vector pITA-RFX1 was constructed. The constructed vector was verified by agarose gel electrophoresis and DNA sequencing. Lentivirus vector pITA-RFX1 and virus packaging plasmids were cotransfected into 293T cells, and then transfected into F98 cells. RFX1 protein expression were detected by Western blot and laser confocal before and after transfection. Flow cytometry and cell counting kit-8 were used to detect cellular proliferation.? Results: Agarose gel electrophoresis and DNA sequencing showed that recombinant lentivirus plasmids pITA-RFX1 were constructed successfully. After transfection of pITA-RFX1, the RFX1 protein were over-expressed, which significantly inhibited the proliferation of F98 cells.? Conclusion: The overexpression lentivirus vector for RFX1 was constrcted successfully, and the up-regulation of RFX1 can prevent the proliferation of glioblastoma cells. PMID- 27932755 TI - [Effects of apigenin on self-renewal and ?uPAR expression in NCI-H446 cell line]. AB - OBJECTIVE: To investigate the effect of apigenin on self-renewal for sphere forming cells in human small cell lung cancer cell line NCI-H446 and the underlying mechanisms.? Methods: Sphere-forming cells from NCI-H446 cell line were cultured in stem cell-conditioned culture medium with ultra-low attachment surface plates. The rate of sphere-forming cells in the second passage sphere forming cells was used to evaluate the inhibitory effects of apigenin on the self renewal for sphere-forming cells. The protein level of urokinase-type plasminogen activator receptor (uPAR) in spheroids was analyzed by Western blot.? Results: Apigenin signifcantly inhibited the self-renewal of the second passage sphere forming cells [0, 5.0, 10.0, 20.0 MUmol/L apigenin: (18.2+/-1.9)%, (13.6+/-1.7)%, (10.6+/-1.6)%, (6.9+/-1.3)%, respectively] and down-regulated uPAR expression in a concentration-dependent manner (P<0.05).? Conclusion: Apigenin inhibits the self-renewal capacity of sphere-forming cells in NCI-H446 cells, which may be associated with down-regulation of uPAR expression. PMID- 27932756 TI - [Inhibitory effect of jianpi-jiedu prescription-contained serum on colorectal cancer SW48 cell proliferation by mTOR-P53-P21 signalling pathway]. AB - OBJECTIVE: To investigate the effect of jianpi-jiedu (JPJD) prescription contained serum on colorectal cancer SW48 cell proliferation and the underlying mechanisms.? Methods: Crude extract from JPJD was made by water extract method and the main components of crude extract from JPJD were analyzed by ultra performance liquid phase high resolution time of flight mass spectrometry (UPLC-Q TOF/MS). The low, medium, and high-concentration of JPJD-contained serum were prepared by the serum pharmacological method. The effect of serum containing JPJD on SW48 cell proliferation was determined by MTT assay. The cell cycle was detected by flow cytometric method. The protein levels of mammalian target of rapamycin (mTOR), phospho-mTOR, P-P53, and -P21, and the mRNA level of mTOR were examined by Western blot and RT-PCR, respectively.? Results: Seven compounds including calycosin-7-glucoside, astragaloside, ginsenoside-Re, ginsenoside-Rb1, glycyrrhizinic acid, apigenin, atractylenolide-II were identified. MTT assays demonstrated that the SW48 cell proliferation was inhibited by medium and high concentration of JPJD-contained serum and the percentages of cells at G1 phase in SW48 cell cultured in the medium and high concentration of JPJD serum group were significantly higher than those in the control group (P<0.05). Meanwhile, the levels of mTOR mRNA and phospho-mTOR protein in the medium and high concentration of JPJD serum groups were substantially lower than those in the control group (P<0.05). Conversely, the expressions of phospho-P53 and P21 protein were significantly increased in the medium and high concentration of JPJD serum group compared with those in the control group.? Conclusion: JPJD prescription contained serum can inhibit SW48 cell proliferation, which may be related to mTOR P53-P21 signaling pathways. PMID- 27932757 TI - [Expressions of epithelial cell adhesion molecule, vimentin and N-cadherin in molecular subtypes of breast cancer and the correlation among them]. AB - OBJECTIVE: To examine the expressions of epithelial cell adhesion molecule (EpCAM), vimentin and N-cadherin in breast cancer and its molecular subtypes, and to explore the correlation among them.? Methods: The expressions of EpCAM, vimentin and N-cadherin were detected by immunohistochemistry in 835 patients with breast cancer, and their correlations with clinical pathological features and prognosis were analyzed.? Results: The expression rates of EpCAM, vimentin and N-cadherin in the patients were 53.4%, 11.4% and 9.7% respectively, which were increased with the increase in tumor size, histological grade, lymph node size, tumor node stage of metastases classification, estrogen receptor and progesterone receptor levels (all P<0.05). The positive expression rates for EpCAM protein in luminal A, luminal B (HER2-), luminal B (HER2+), HER2 overexpression and triple-negative subtypes were 19.2%, 73.0%, 48.9%, 72.2%, and 62.1% respectively; for vimentin were 3.9%, 11.4%, 14.1%, 11.1%, and 20.5% respectively; for N-cadherin were 7.0%, 5.7%, 12.0%, 12.2% and 17.4% respectively, with statistical difference (all P<0.05). EpCAM expression was positively correlated with vimentin and N-cadherin in patients with breast cancer and triple-negative breast cancer.? Conclusion: EpCAM is overexpressed in triple negative subtype of breast cancer and it is associated with epithelial mesenchymal transition markers, which might be related to breast cancer progression and metastasis. PMID- 27932758 TI - [Expressions of HER2 and Topo IIalpha in breast cancer and ?its clinical significance]. AB - OBJECTIVE: To detect the expressions of human epidermal growth factor receptor 2 (HER2) and Topo IIalpha in breast cancer, and to analyze the clinical significance of neoadjuvant chemotherapy for the anthracycline-based drugs.? Methods: The HER2 and Topo IIalpha gene and protein expressions in cancer tissues from 189 patients with breast cancer were detected by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). And the objective response rate (ORR) and pathological complete rate (pCR) were analyzed.? Results: The HER2 protein expression in 46 patients (24.3%) and Topo IIalpha protein expression in 55 patients (29.1%) was 3+ by IHC or they were 49 (25.9%) and 94 (49.0%) by FISH, respectively. The ORR and pCR in HER2 negative or positive patients were 47.4% and 20.3% or 32.7% and 16.3%, respectively, with significant differences (All P<0.05). The ORR and pCR in Topo IIalpha positive or negative patients were 69.1% and 36.0% or 28.4% and 2.2%, respectively, with significant differences (All P<0.05).? Conclusion: FISH and IHC were consistent in the determination of HER2 expression whereas they were inconsistent in the determination of Topo IIalpha expression. The amplification of Topo IIalpha can effectively improve the effect of the adjuvant treatment effect of the anthracyclines. PMID- 27932759 TI - [PRKAR1alpha expression in non-small cell lung cancer and ?its clinicopathologic significance]. AB - OBJECTIVE: To evaluate the expression of cAMP-dependent protein kinase type I alpha regulatory subunit (PRKAR1alpha) in non-small cell lung cancer (NSCLC) and its correlation with clinicopathological features.? Methods: PRKAR1alpha expressions in 79 NSCLC patients and matched adjacent non-carcinoma tissues were analyzed by using qRT-PCR and immunohistochemistry.? Results: The negative rates of PRKAR1alpha protein in NSCLC, lung squamous cell carcinoma (SCL) and lung adenocarcinoma (ACL) were 58.2%, 77.8%, 32.4%, respectively. Compared to the matched adjacent non-carcinoma tissues, there were significant differences in levels of PRKAR1alpha mRNA and protein in ACL (P<0.05), but not in SCL and overall NSCLC (P>0.05). The expression of PRKAR1alpha protein was positively correlated with histological type, TNM stage, and lymph node metastasis (P<0.05). Tumor size and histogenesis differentiation were not related to the decreased PRKAR1alpha (P>0.05).? Conclusion: Low expression of PRKAR1alpha in ACL might be involved in the pathogenesis, which might serve as a novel diagnostic candidate. PMID- 27932760 TI - [SATB1 promotes the malignant of human non-Hodgkin lymphoma by activating the ribonucleotide reductase ?small subunit M2]. AB - OBJECTIVE: To explore the role of the special AT rich sequence binding protein-1 (SATB1) and ribonucleotide reductase M2 (RRM2) in enhancing malignant progression of non-Hodgkin lymphoma (NHL). ? Methods: A total of 42 NHL and 42 chronic lymphadenitis patients were recruited. The protein expressions of SATB1 and RRM2 in cervical lymph nodes were determined by Western blot. After overexpression of SATB1, siSATB1 or siRRM2, the mRNA levels of SATB1 and RRM2 in cells were analyzed via RT-PCR, the cell proliferation was evaluated via MTT and EdU assays, while the migration and invasion of cells were assessed by transwell assays.? Results: Compared with chronic lymphadenitis, the expressions of SATB1 and RRM2 in NHL patients were up-regulated. There was positive correlation between SATB1 and RRM2 in NHL patients. RRM2 mRNA level was up-regulated after transfection of SATB1 and down-regulated after transfection of siSATB1. Overexpression of SATB1 increased tumor cell proliferation, migration and invasion, while knockdown of RRM2 reversed those phenomena.? Conclusion: SATB1 functions as an oncogene and promotes tumor cell proliferation, migration and invasion by up-regulation of RRM2 in NHL. PMID- 27932761 TI - [Long noncoding RNA MALAT1: a potential novel prognostic biomarkers in cancers based on Meta-analysis]. AB - OBJECTIVE: To systematically review the potential value of long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) as a potential novel prognostic biomarker in cancers.? Methods: Databases including Cochrane Library, Medline, Embase, PubMed databases were searched for all English studies, which explored the correlation between lncRNA MALAT1 expression and overall survival in tumors. The retrieval time was from inception to August 1, 2015. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data, and assessed methodological quality. Then, Meta-analysis was performed using RevMan 5.3 software.? Results: Ten studies covered a total of 1 016 patients. Meta-analysis showed that high expression of MALAT1 was significantly correlated to poor overall survival (OS) in patients with tumor (HR= 2.08, 95% CI 1.74 to 2.48, P<0.001). ? Conclusion: LncRNA MALAT1 might be a potential novel prognostic biomarker in tumor. PMID- 27932762 TI - [Correlations between lipid ratio/oxidative stress status in COPD patients and pulmonary hypertension ?as well as prognosis]. AB - OBJECTIVE: To investigate the correlations between lipid ratio/oxidative stress status in chronic obstructive pulmonary disease (COPD) patients and pulmonary hypertension as well as the prognosis.? Methods: A total of 120 patients with COPD were randomly selected and served as the COPD group and 30 healthy persons were selected as the control group. The ratios of low density lipoprotein (LDL)/high-density lipoprotein (HDL), triglyceride (TG)/HDL and total cholesterol (TC)/HDL were measured. The superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and total antioxidant capacity (T-AOC) level in the control group and COPD patients were detected. Pulmonary hypertension incidence and 3-year survival rate for COPD patients were statistically analyzed. Spearman rank correlation method was used to analyze relationship between lipid ratio /oxidative stress status and pulmonary hypertension.? Results: Compared with control group, the ratios of LDL/HDL, TG/HDL and TC/HDL, and the serum MDA level in the COPD group were increased, while the serum SOD and T-AOC level in the COPD group were decreased; compared with stable period, lipid ratios and MDA levels in the acute period were elevated, while serum SOD and T-AOC levels were reduced (P<0.05). Pulmonary hypertension incidence and 3-year survival rates in the COPD group were 56.67% and 81.67% respectively; the lipid ratios and serum MDA levels in COPD patients with pulmonary hypertension were elevated compared with that in COPD patients without pulmonary hypertension; the serum SOD and T-AOC levels in COPD patients with pulmonary hypertension were reduced compared with that in patients without pulmonary hypertension (P<0.05). Spearman rank correlation analysis showed that ratios of LDL/HDL, TG/HDL and TC/HDL, and the serum MDA levels in COPD patients were positively correlated with 3-years pulmonary hypertension incidence (r=0.752, 0.748, 0.752, 0.748; P<0.05), and negatively correlated with 3-years survival rate (r=-0.722, -0.751, -0.736, -0.748; P<0.05); serum SOD and T-AOC levels in COPD patients were negatively correlated with 3 years pulmonary hypertension (r=-0.711, -0.734; P<0.05), and positively correlated with 3-year survival rate (r=0.726, 0.733; P<0.05). ? Conclusion: Blood lipid ratio and oxidative stress levels in COPD patients are elevated while antioxidant abilities were attenuated. The lipid ratio and oxidative stress status in COPD patients is closely related to the prognosis of pulmonary hypertension. Therefore, blood lipid ratio and oxidative stress status may be used in evaluation of pulmonary hypertension and prognosis for COPD patients. PMID- 27932763 TI - [Effect of vasoactive intestinal peptide on defecation and VIP-cAMP-PKA-AQP3 signaling pathway ?in rats with constipation]. AB - OBJECTIVE: To observe the effect of vasoactive intestinal peptide (VIP) on the metabolism of intestinal fluid and cyclic AMP protein kinase A signaling pathway (cAMP-PKA) and water channel protein 3 (AQP3) in rats with constipation, and to explore the mechanism of VIP in the treatment of constipation.? Methods: A total of 45 healthy adult rats were randomly divided into a control group, a model group, a model +VIP group. After 4 weeks of VIP treatment, the first black stool time were examined with the ink gastric method; the water content in feces was calculated; the morphological changes in colonic tissues were observed by HE staining. The expression of VIP and AQP3 protein levels in colon tissues were detected by Western blot; and the cAMP, PKA, AQP3 mRNA expression levels were detected by quantitative real time polymerase chain reaction (qPCR). ? Results: Compared with the control group, the first black stool time was prolonged, the water content of fecal decreased significantly (both P<0.01); part of the colon mucosa epithelial cells were destructed; the goblet cell volume decreased and quantity was reduced; the contents of AQP3 and VIP in colon tissues were significantly decreased, and the cAMP, PKA and AQP3 mRNA levels were decreased in the model group (all P<0.05). Compared with the model group, the first black stool time in the model +VIP group was shortened, the fecal water content increased significantly (both P<0.05); the mucosal epithelium integrity improved, the number of goblet cells increased; the content of AQP3 and VIP in colon tissues was increased, and the cAMP, PKA, and AQP3 mRNA levels were elevated (all P<0.05).? Conclusion: Intravenous injection of VIP can regulate intestinal fluid metabolism and improve the symptoms of constipation in rats, which might be related to the regulation of VIP-cAMP-PKA-AQP3 signaling pathway. PMID- 27932764 TI - [Effect of prolonged propofol infusion on myocardial enzyme, mitochondrial cytochrome C and adenosine ?triphosphate in rabbits]. AB - OBJECTIVE: To explore the effect of long-time propofol infusion on myocardial enzymes, mitochondrial cytochrome C and ATP in rabbits. ? Methods: A total of 18 New Zealand rabbits were randomly divided into 3 groups: a control group, a propofol group and an intralipid group. The rabbits were continuously infused with 0.9% normal saline in the control group, 1% propofol in the propofol group, and 10% intralipid in the intralipid group, respectivey. The arterial blood was collected at 0, 8, 16 h and the end of experiment to examine creatine kinase (CK) and creatine kinase isoenzyme (CK-MB). In the end, the myocardial mitochondria from myocardial tissues was separated by differential centrifugation, and mitochondrial cytochrome C content and adenosine triphosphate (ATP) levels were examined by high performance liquid chromatography.? Results: Compared with the control group, the release of cytochrome C from mitochondria were increased in the propofol group and the intralipid group (both P<0.05), but there was no significant difference between them (P>0.05). There was also no significant difference in the ATP content of the mitochondria among the 3 groups (P>0.05). The levels of CK were increased at 8, 16 and 24 h after infusion in the propofol group and the intralipid group compared with that before the infusion (all P<0.05); compared with the control group, the levels of CK were increased at 8, 16 and 24 h after infusion in the propofol group and the intralipid group (all P<0.05); compared with the intralipid group, the levels of CK were increased at 8, 16 and 24 h after infusion in the propofol group (all P>0.05); compared with the control group, the levels of CK-MB were obviously increased in the infusion of propofol for 24 h in the propofol group (P<0.05).? Conclusion: The levels of serum CK increase after the infusion of propofol and intralipid for a long time, and the levels of CK-MB also elevate in the infusion of propofol. Propofol and intralipid can increase the release of myocardial mitochondrial cytochrome C, but they don't affect the ATP production in myocardial mitochondrial. PMID- 27932765 TI - [Influencial factors for in-hospital patients with ST segment elevation myocardial infarction after emergency percutaneous coronary intervention]. AB - OBJECTIVE: To analyze the clinical outcomes of emergency percutaneous intervention in acute myocardial infarction (AMI) during hospital, and to find the relevant risk factors for the prognosis and cardiac events. ? Methods: We retrospective analyzed the patient with acute ST segment elevation myocardial infarction, who was successfully performed emergency percutaneous coronary intervention (PCI) in the Cardiac Cath Lab of the Second Xiangya Hospital from January 2010 to December 2014. According to situation for cardiovascular events, patients were divided into 2 groups. The clinical factors were compared between the 2 groups.? Results: The incidence of adverse event was 22% (67/304). By using t test and chi2 analysis, we found that Cr, NT-proBNP, HCT, WBC, age>75, Killip grade>=2, TIMI flow after PCI<=2, arrhythmia, multi-vessel lesion, ST-segment resolution>=50%, long D2B time are statistically different between the 2 groups. Logistic analysis revealed that HCT, NT-proBNP, Killip grade>=2, TIMI flow after PCI<=2, ST-segment resolution>=50%, long D2B time were important predictors for cardiac events in-hospital.? Conclusion: HCT, NT-proBNP, Killip grade>=2, TIMI flow after PCI<=2, ST-segment resolution>=50%, long D2B time are important predictors for cardiac events in-hospital. The prognosis for AMI patient after emergency PCI could be improved and the incidence of cardiac event in hospital could be reduced if the high risk factors can be properly handled. PMID- 27932766 TI - [Microsurgical techniques for dorsal wall aneurysms ?in the internal carotid artery]. AB - OBJECTIVE: To seek a reasonable microsurgical technique for dorsal wall aneurysms in the internal carotid artery (ICA), and to evaluate its efficacy.? Methods: A total of 21 patients with dorsal wall aneurysms in the ICA who received microsurgical techniques were retrospectively analyzed. The directive surgical clapping was applied for saccular aneurysm, while the techniques of stitching and wrapping, simple wrapping, and trapping with extracranial-intracranial bypass were used for cystic and blood blister false aneurysms.? Results: One patient died after operation, 1 patient suffered rebleeding and gave up treatment, the remaining 19 patients achieved saticfactory outcomes.? Conclusion: According to types of aneurysm wall, the different microsurgical treatments should be applied, and good outcomes can be achieved for patients with dorsal wall aneurysms in the ICA. PMID- 27932767 TI - [Mid- and long-term result of celiac artery coverage in TEVAR treatment for aortic dissection]. AB - OBJECTIVE: To observe the mid- and long-term result of intentional coverage of celiac artery in thoracic endovascular aortic repair (TEVAR) surgery for aortic dissection.? Methods: We retrospectively analyzed 21 cases who received TEVAR with celiac artery coverage during the operation. The existence of collaterals between celiac artery (CA) and superior mesenteric artery (SMA) was confirmed by preoperative CT angiography (CTA) or digital substract angiography (DSA) for each patient. We used the stent-graft precisely above the orifice of SMA. Follow-ups were carried out at 2 weeks, 1 month, 3 months, 6 months, 1 year after the operation, and once per year thereafter.? Results: No signs of visceral artery ischemic syptoms such as liver dysfunction, abdominal pain or distention were observed after the operation. There was no signs of spinal cord ischemia (SCI). Seven cases showed type II endoleak upon completion DSA but stopped automatically within 3 months. CTA in follow-ups showed thrombosis formation in false lumen.? Conclusion: The intentional coverage of CA during the TEVAR for aortic dissection is safe and effective. The incidence of post-operative SCI or visceral artery ischemia is low. Type II endoleak is a major complication but it can be ceased automatically after medication. PMID- 27932768 TI - [Application of combination of xenoskin with delayed microskin graft in extensively burned patients]. AB - OBJECTIVE: To observe clinical effects of combination of acellular porcine skin with delayed microskin graft on extensively burned patients.? Methods: Forty extensively burned patients were assigned into a treatment group and a control group. In the treatment group, 20 patients were covered with acellular porcine skin after escharectomy, and the delayed microskin grafting was performed 5 days later. In the control group, 20 patients were covered with allograft skin combined with microskin graft after escharectomy. The cure rate, the graft survival rate, wound healing time and cost per 1% wound were observed.? Results: The cure rate for the 2 groups was the same (90%), and wound healing time was similar between the two groups (P>0.05). The graft survival rate in the treatment group was higher than that in the control group (P<0.05), and cost per 1% wound in the treatment group was less than that in the control group (P<0.05).? Conclusion: The combination of acellular porcine skin with delayed microskin graft is an effective method to treat extensively burned patients, and it provides an ideal substitute for allograft skin combined with microskin graft. PMID- 27932769 TI - [Correction of posttraumatic thoracolumbar kyphosis with modified pedicle subtraction osteotomy]. AB - OBJECTIVE: To evaluate the efficacy and safety of modified pedicle subtraction osteotomy for treatment of thoracolumbar old fracture with kyphosis.? Methods: From January 2003 to January 2013, 58 patients of thoracolumbar kyphosis, who underwent modified pedicle subtraction osteotomy, were reviewed. Among them, 45 cases underwent initial operation and 13 cases underwent revision surgery. Preoperative and postoperative kyphotic Cobb's angle, score of back pain, as well as the incidence of complication were accessed by using visual analogue scale (VAS) and Oswestry disability index (ODI).? Results: Mean follow-up duration was 42 months (range, 24-60 months). Average operative time was 258 min (range, 190 430 min), while average bleeding was 950 mL (range, 600-1 600 mL). All the patients were significantly improved in function and self-image, and achieved kyphosis correction with 17.9 degrees +/- 4.3 degrees . VAS of low back pain was decreased by 3.1+/-0.6; ODI was dropped by 25.3%+/-5.5%. 3 patients (5.2%) suffered anterior thigh numbness and got recovery after 3 months of follow-up. Complications happened in 19 patients, including 12 with cerebrospinal fluid leak, 4 with superficial wound infection, and 3 with urinary tract infection. All these complications were managed properly and none of them underwent reoperation.? Conclusion: Modified pedicle subtraction osteotomy is a safe and effective technique for the treatment of old fracture with kyphosis. PMID- 27932770 TI - [Contrast sensitivity analysis about fundus changes of hypertensive disorders complicating pregnancy]. AB - OBJECTIVE: To observe corrected visual acuity and contrast sensitivity (CS) in patients with hypertensive disorders complicating pregnancy accompanied by fundus changes.? Methods: Ninety-eight patients with hypertensive disorders complicating pregnancy and 50 healthy pregnant women underwent eye examination, including corrected visual acuity and fundus examination, and CS. Differences in corrected visual acuity and contrast sensitivity between the 2 groups were analyzed with two independent samples t-test analysis, while correlation between vision and contrast sensitivity in patients was evaluated by using spearman correlation test. Difference in CS was compared between the early and advanced stage of fundus diseases.? Results: Corrected visual acuity and contrast sensitivity in patient with hypertensive disorders complicating pregnancy were lower than that in the control group (P<0.01). Corrected visual acuity in patients was associated with contrast sensitivity at variously spatial frequencies (P<0.01), showing the most correlation in contrast sensitivity at 6 of spatial frequency (r=0.87). Compared with the early stage, the CS in the advanced patients with fundus diseases was decreased (P<0.01).? Conclusion: The visual acuity and contrast sensitivity in patient with hypertensive disorders complicating pregnancy are reduced. The CS (6.0 c/d) has the largest correlation with corrected visual acuity. Comparing with the visual acuity, contrast sensitivity can be more comprehensive in evaluation of retinal function damage in patients with hypertensive disorders complicating pregnancy. PMID- 27932771 TI - [Analysis of the status and influential factors for prenatal care and postpartum visit among pregnant women based on the First Health Service Survey in Hunan Province]. AB - OBJECTIVE: To evaluate the status and influential factors for prenatal care and postpartum visit among pregnant women in Hunan Province from 2008 to 2013 based on the data from the First Health Service Survey in Hunan Province.? Methods: Based on the data of prenatal care and postpartum visit among pregnant women from the First Health Service Survey of Hunan Province in 2013, proportion of pregnant women, who didn't meet the criteria for prenatal care and postpartum visit, were calculated (>=5 times for prenatal care and >=2 times for postpartum visit, according to the National Basic Public Health Service program, 2009 Edition). Multivariable logistic regression models were used to identify the influencial factors.? Results: A total of 1 035 eligible women were included in data analysis. The proportion of pregnant women who did not meet the criteria were 40.12% (95% CI 24.91%-55.33%) for prenatal care and 64.88% (95% CI 39.70%-90.06%) for postpartum visit. After adjusting other confounding factors, pregnant women with middle- and high-income had lower proportions of not meeting the criteria than those with low-income, with adjusted odds ratios of 0.41 and 0.39, respectively. Multiparae had higher proportion of not meeting the criteria than primiparas, with adjusted odds ratio of 1.54, and pregnant women with age 25-34 years and 35-64 years had lower proportions of not meeting the criteria than those with age 15-24 years. In term of postpartum visit, pregnant women with middle- to high-income had lower proportions of not meeting the criteria than those with low-income, with adjusted odds ratios of 0.50, 0.46 and 0.54, respectively; multiparae had higher proportion of not meeting the criteria than primiparas, with the adjusted odds ratio of 2.30.? Conclusion: Proportions of pregnant women of not meeting the criteria are high in Hunan Province. Local government should strengthen the management to decrease the proportions of pregnant women who do not meet the standard in prenatal care and postpartum visit, especially for those mulparae with low family income and young age. PMID- 27932772 TI - [Modification and evaluation of assessment of ?medication literacy]. AB - OBJECTIVE: To translate and revise the Medication Literacy Assessment in English (MedLitRxSE-English) and evaluate its validity and reliability.? Methods: We introduced MedLitRxSE-English from abroad. According to the principles of Brislin and culture adjustment, we revised it as a Chinese edition. Using random sampling method, from Oct, 2014 to Jan, 2015, 461 non-hospitalized patients from the outpatient departments of the top three hospitals in Changsha city were investigated. The reliability and validity of the scale was tested.? Results: The test-retest reliability of the Chinese version for medication literacy scale was 0.885; the split reliability was 0.840; K-R was 0.820; the correlations between the assessment of medication literacy and the corresponding items were 0.427 0.587; the confirmatory factor analysis revealed overall good fit. Root mean square error of approximation (RMSEA), chi2/df, goodness of fit index (GFI) and comparative fit index (CFI) was 0.08, 3.06, 0.91 and 0.94, respectively. ? Conclusion: The Chinese version for the assessment of medication literacy is in good reliability and validity, and it can be used to evaluate the medication literacy in our country. PMID- 27932773 TI - [Effect of NLRP3 inflammasome on vascular diseases]. AB - The NLRP3 inflammasome, a protein complex belonging to the family of nucleotide binding and oligomerization domain like receptors (NLRs), plays a vital role in the innate immune system. It promotes pro-caspase 1 cleavage into active caspase 1, which contributes to maturation and releases of IL-1beta and IL-18 in response to the harmful signals and participates in the host immune response and sterile inflammation. Recently a large number of studies have shown that NLRP3 inflammasome closely relates to the pathogenesis of the vascular diseases. NLRP3 inflammasome, which involves in the sterile inflammation of the vascular wall, plays an important role in the pathogenesis of main, middle and small arteries. PMID- 27932774 TI - [Five cases of interstitial heterotopic pregnancy after IVF-ET treated by laparoscopic surgery]. AB - To evaluate the efficency and safety of laparoscopic surgery in the treatment of interstitial heterotopic pregnancy (IHP) after IVF-ET, five patients with interstitial heterotopic pregnancy after IVF-ET treated by laparoscopy in our hospital from Jan. 2012 to Jan. 2015 were retrospectively analyzed. All operations were finished laparoscopically without any major complications and they successfully delivered. The results suggest that laparosccpic surgery is feasible and safe for IHP to maintain the trauterine pregnancy, and it can diagnose and treat IHP at early stage, which cause mininmal injuries and less disturbance to trauterine pregnancy and ensure rapid recovery. PMID- 27932775 TI - [Experience in transumbilical endoscopic surgery diagnosis for 3 cases of pseudomyxoma peritonei]. AB - Three patients of pseudomyxoma peritonei who were diagnozed by transumbilical endoscopic surgery (TUES) were reviewed retrospectively from September 2014 to November 2014. Three cases of ascites patients underwent TUES were diagnozed as pseudomyxoma peritonei. All operations were successful. No open surgery or laparoscopic surgery was required. The mean operative time was (45+/-16) min; the mean intraoperative blood loss was 510 mL; the mean hospital stay time was 3 days. During the follow up of 911 months, no obvious scar was observed. Cosmetic results appear to be excellent. All patients were treated with intraperitoneal hyperthermia and chemotherapy. The survival rate was 100%. As a novel scarless endoscopic invasive abdominal surgery, TUES has high clinical value with the advantages such as small trauma, no scars, small risk and low cost in the diagnosis of unexplained ascites. PMID- 27932776 TI - Nasal Type Extranodal Natural Killer/T (NK/T) Cell Lymphoma Presenting as Periorbital Cellulitis: A Case Report. AB - BACKGROUND Extranodal lymphoma of the paranasal sinuses is a rare clinical entity seen in only 5-8% of extranodal lymphomas of the head and neck. Nasal natural killer/T cell lymphoma (Nasal NKTCL), which is a subtype of peripheral T cell lymphoma, constitutes about 1.4% of all lymphomas. NKTCL is usually diagnosed at a late stage because it presents with nonspecific symptoms in the early stages. CASE REPORT We report the case of a 25-year-old male patient who presented with periorbital swelling treated as fungal sinusitis but proven to have NKTCL. We review the literature and discuss the clinical manifestations of the disease, its relation to EBV virus, the histological and radiological characteristics, the prognostic indicators, and treatment options. This case report shows physicians that NKTCL lymphoma can present as periorbital cellulitis, although few similar cases are found in the literature. CONCLUSIONS NKTCL is a destructive midline tumor that should be kept in mind as a differential diagnosis of paranasal sinus lesions to help in early diagnosis, which can improve the prognosis. PMID- 27932777 TI - Phototoxicity of Liposomal Zn- and Al-phthalocyanine Against Cervical and Oral Squamous Cell Carcinoma Cells In Vitro. AB - Background Material and Methods Results Conclusions. PMID- 27932779 TI - Erratum: Vol. 65, No. 44. AB - In the report, "Incidence of Zika Virus Disease by Age and Sex - Puerto Rico, November 1, 2015-October 20, 2016," on page 1219 the following person should have been included as an author: Luisa I. Alvarado, MD, Ponce Health Sciences University-Saint Luke's Episcopal Hospital Consortium, Puerto Rico. PMID- 27932780 TI - Consumption of Combustible and Smokeless Tobacco - United States, 2000-2015. AB - Combustible and smokeless tobacco use causes adverse health outcomes, including cardiovascular disease and multiple types of cancer (1,2). Standard approaches for measuring tobacco use include self-reported surveys of use and consumption estimates based on tobacco excise tax data (3,4). To provide the most recently available tobacco consumption estimates in the United States, CDC used federal excise tax data to estimate total and per capita consumption during 2000-2015 for combustible tobacco (cigarettes, roll-your-own tobacco, pipe tobacco, small cigars, and large cigars) and smokeless tobacco (chewing tobacco and dry snuff). During this period, total combustible tobacco consumption decreased 33.5%, or 43.7% per capita. Although total cigarette consumption decreased 38.7%, cigarettes remained the most commonly used combustible tobacco product. Total noncigarette combustible tobacco (i.e., cigars, roll-your-own, and pipe tobacco) consumption increased 117.1%, or 83.8% per capita during 2000-2015. Total consumption of smokeless tobacco increased 23.1%, or 4.2% per capita. Notably, total cigarette consumption was 267.0 billion cigarettes in 2015 compared with 262.7 billion in 2014. These findings indicate that although cigarette smoking declined overall during 2000-2015, and each year from 2000 to 2014, the number of cigarettes consumed in 2015 was higher than in 2014, and the first time annual cigarette consumption was higher than the previous year since 1973. Moreover, the consumption of other combustible and smokeless tobacco products remains substantial. Implementation of proven tobacco prevention interventions (5) is warranted to further reduce tobacco use in the United States. PMID- 27932778 TI - Expression of Long Non-Coding RNA (lncRNA) Small Nucleolar RNA Host Gene 1 (SNHG1) Exacerbates Hepatocellular Carcinoma Through Suppressing miR-195. AB - BACKGROUND Aberrant expression of lncRNA has been suggested to have an association with tumorigenesis. Our study was designed to reveal the underlying connection between lncRNA SNHG1 and hepatocellular carcinoma (HCC) pathogenesis. MATERIAL AND METHODS A total of 122 pairs of HCC tissues (case group) and matched adjacent non-tumor liver tissues (control group) were collected for this study. RT-PCR and in situ hybridization were conducted to investigate differences in lncRNA SNHG1 expression between the case and control group. The expression levels of lncRNA SNHG1 and miR-195 in HepG2 cells transfected with SNHG1-mimic and SNHG1 inhibitor were measured by RT-PCR. The proliferation, invasion, and migration status of HepG2 cells after transfection were assessed through MTT assay, wound healing assay, and Transwell assay, respectively. Whether miR-195 is a direct downstream target of lncRNA SNHG1 was verified by both bioinformatics target gene prediction and dual-luciferase report assay. RESULTS The expression level of lncRNA SNHG1 was remarkably upregulated in HCC tissues and cell lines compared with normal tissues and cell lines. High expression of lncRNA SNHG1 contributed to the downregulation of miR-195 in HepG2 cells. Also, lncRNA SNHG1 exacerbated HCC cell proliferation, invasion, and migration in vitro through the inhibition of miR-195. This suggests that miR-195 is a direct downstream target of lncRNA SNHG1. CONCLUSIONS lncRNA SNHG1 may contribute to the aggravation of HCC through the inhibition of miR-195. PMID- 27932782 TI - CDC Grand Rounds: Modeling and Public Health Decision-Making. AB - Mathematical models incorporate various data sources and advanced computational techniques to portray real-world disease transmission and translate the basic science of infectious diseases into decision-support tools for public health. Unlike standard epidemiologic methods that rely on complete data, modeling is needed when there are gaps in data. By combining diverse data sources, models can fill gaps when critical decisions must be made using incomplete or limited information. They can be used to assess the effect and feasibility of different scenarios and provide insight into the emergence, spread, and control of disease. During the past decade, models have been used to predict the likelihood and magnitude of infectious disease outbreaks, inform emergency response activities in real time (1), and develop plans and preparedness strategies for future events, the latter of which proved invaluable during outbreaks such as severe acute respiratory syndrome and pandemic influenza (2-6). Ideally, modeling is a multistep process that involves communication between modelers and decision makers, allowing them to gain a mutual understanding of the problem to be addressed, the type of estimates that can be reliably generated, and the limitations of the data. As models become more detailed and relevant to real-time threats, the importance of modeling in public health decision-making continues to grow. PMID- 27932781 TI - Influenza Vaccination Coverage During Pregnancy - Selected Sites, United States, 2005-06 Through 2013-14 Influenza Vaccine Seasons. AB - Seasonal influenza vaccine is recommended for all pregnant women because of their increased risk for influenza-associated complications. In addition, receipt of influenza vaccine by women during pregnancy has been shown to protect their infants for several months after birth (1). As part of its case-control surveillance study of medications and birth defects, the Birth Defects Study of the Slone Epidemiology Center at Boston University has recorded data on vaccinations received during pregnancy since the 2005-06 influenza vaccination season. Among the 5,318 mothers of infants without major structural birth defects (control newborns) in this population, seasonal influenza vaccination coverage was approximately 20% in the seasons preceding the 2009-10 pandemic H1N1 (pH1N1) influenza season. During the 2009-10 influenza vaccination season, influenza vaccination coverage among pregnant women increased to 33%, and has increased modestly since then, to 41% during the 2013-14 season. Among pregnant women who received influenza vaccine during the 2013-14 season, 80% reported receiving their vaccine in a traditional health care setting, (e.g., the office of their obstetrician or primary care physician or their prenatal clinic) and 20% received it in a work/school, pharmacy/supermarket, or government setting. Incorporating routine administration of seasonal influenza vaccination into the management of pregnant women by their health care providers might increase coverage with this important public health intervention. PMID- 27932783 TI - Notes from the Field: Plague in Domestic Cats - Idaho, 2016. PMID- 27932784 TI - Notes from the Field: Investigation of Elizabethkingia anophelis Cluster - Illinois, 2014-2016. PMID- 27932785 TI - QuickStats: Percentage Distribution* of Respondent-Assessed Health Status? Among Adults Aged >=25 Years, by Completed Education - National Health Interview Survey,S United States, 2015. AB - In 2015, health status improved as the level of education increased; 74% of adults with a bachelor's degree or higher were in excellent or very good health compared with almost 37% of adults with less than a high school diploma. Nearly 28% of adults with less than a high school diploma were in fair or poor health compared with 6% of adults with a bachelor's degree or higher. PMID- 27932786 TI - State Medicaid Expansion Tobacco Cessation Coverage and Number of Adult Smokers Enrolled in Expansion Coverage - United States, 2016. AB - In 2015, 27.8% of adult Medicaid enrollees were current cigarette smokers, compared with 11.1% of adults with private health insurance, placing Medicaid enrollees at increased risk for smoking-related disease and death (1). In addition, smoking-related diseases are a major contributor to Medicaid costs, accounting for about 15% (>$39 billion) of annual Medicaid spending during 2006 2010 (2). Individual, group, and telephone counseling and seven Food and Drug Administration (FDA)-approved medications are effective treatments for helping tobacco users quit (3). Insurance coverage for tobacco cessation treatments is associated with increased quit attempts, use of cessation treatments, and successful smoking cessation (3); this coverage has the potential to reduce Medicaid costs (4). However, barriers such as requiring copayments and prior authorization for treatment can impede access to cessation treatments (3,5). As of July 1, 2016, 32 states (including the District of Columbia) have expanded Medicaid eligibility through the Patient Protection and Affordable Care Act (ACA),*,? which has increased access to health care services, including cessation treatments (5). CDC used data from the Centers for Medicare and Medicaid Services (CMS) Medicaid Budget and Expenditure System (MBES) and the Behavioral Risk Factor Surveillance System (BRFSS) to estimate the number of adult smokers enrolled in Medicaid expansion coverage. To assess cessation coverage among Medicaid expansion enrollees, the American Lung Association collected data on coverage of, and barriers to accessing, evidence-based cessation treatments. As of December 2015, approximately 2.3 million adult smokers were newly enrolled in Medicaid because of Medicaid expansion. As of July 1, 2016, all 32 states that have expanded Medicaid eligibility under ACA covered some cessation treatments for all Medicaid expansion enrollees, with nine states covering all nine cessation treatments for all Medicaid expansion enrollees. All 32 states imposed one or more barriers on at least one cessation treatment for at least some enrollees. Providing barrier-free access to cessation treatments and promoting their use can increase use of these treatments and reduce smoking and smoking related disease, death, and health care costs among Medicaid enrollees (4,6-8). PMID- 27932787 TI - High incidence of Philadelphia chromosome-like acute lymphoblastic leukemia in older adults with B-ALL. PMID- 27932789 TI - The maintenance ability and Ca2+ availability of skeletal muscle are enhanced by sildenafil. AB - Sildenafil relaxes vascular smooth muscle cells and is used to treat pulmonary artery hypertension as well as erectile dysfunction. However, the effectiveness of sildenafil on skeletal muscle and the benefit of its clinical use have been controversial, and most studies focus primarily on tissues and organs from disease models without cellular examination. Here, the effects of sildenafil on skeletal muscle at the cellular level were examined using mouse primary skeletal myoblasts (the proliferative form of skeletal muscle stem cells) and myotubes, along with single-cell Ca2+ imaging experiments and cellular and biochemical studies. The proliferation of skeletal myoblasts was enhanced by sildenafil in a dose-independent manner. In skeletal myotubes, sildenafil enhanced the activity of ryanodine receptor 1, an internal Ca2+ channel, and Ca2+ movement that promotes skeletal muscle contraction, possibly due to an increase in the resting cytosolic Ca2+ level and a unique microscopic shape in the myotube membranes. Therefore, these results suggest that the maintenance ability of skeletal muscle mass and the contractility of skeletal muscle could be improved by sildenafil by enhancing the proliferation of skeletal myoblasts and increasing the Ca2+ availability of skeletal myotubes, respectively. PMID- 27932792 TI - Responses to pomalidomide and placebo in myelofibrosis-related anaemia. PMID- 27932790 TI - Motor neurons derived from ALS-related mouse iPS cells recapitulate pathological features of ALS. AB - Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disease characterized by the loss of motor neurons in the spinal cord and brain. Mutations in Cu/Zn superoxide dismutase 1 (SOD1) are known to induce ALS. Although many research models have been developed, the exact pathological mechanism of ALS remains unknown. The recently developed induced pluripotent stem (iPS) cell technology is expected to illuminate the pathological mechanisms and new means of treatment for neurodegenerative diseases. To determine the pathological mechanism of ALS, we generated mouse iPS (miPS) cells from experimental ALS transgenic mice and control mice and characterized the cells using molecular biological methods. The generated miPS cells expressed many pluripotent genes and differentiated into three germ layers in vitro and in vivo. Motor neurons derived from ALS-related miPS cells recapitulated the pathological features of ALS. The ALS-model motor neurons showed SOD1 aggregates, as well as decreased cell survival rate and neurite length compared with wild-type motor neurons. Our study will be helpful in revealing the mechanism of motor neuronal cell death in ALS. PMID- 27932793 TI - Microbiome: More fibre a day keeps the pathogens away. PMID- 27932791 TI - Migration and invasion of drug-resistant lung adenocarcinoma cells are dependent on mitochondrial activity. AB - A small proportion of cancer cells have stem-cell-like properties, are resistant to standard therapy and are associated with a poor prognosis. The metabolism of such drug-resistant cells differs from that of nearby non-resistant cells. In this study, the metabolism of drug-resistant lung adenocarcinoma cells was investigated. The expression of genes associated with oxidative phosphorylation in the mitochondrial membrane was negatively correlated with the prognosis of lung adenocarcinoma. Because the mitochondrial membrane potential (MMP) reflects the functional status of mitochondria and metastasis is the principal cause of death due to cancer, the relationship between MMP and metastasis was evaluated. Cells with a higher MMP exhibited greater migration and invasion than those with a lower MMP. Cells that survived treatment with cisplatin, a standard chemotherapeutic drug for lung adenocarcinoma, exhibited increased MMP and enhanced migration and invasion compared with parental cells. Consistent with these findings, inhibition of mitochondrial activity significantly impeded the migration and invasion of cisplatin-resistant cells. RNA-sequencing analysis indicated that the expression of mitochondrial complex genes was upregulated in cisplatin-resistant cells. These results suggested that drug-resistant cells have a greater MMP and that inhibition of mitochondrial activity could be used to prevent metastasis of drug-resistant lung adenocarcinoma cells. PMID- 27932795 TI - Marine microbiology: When a relationship turns ugly. PMID- 27932794 TI - Last parasite standing. AB - This month's Genome Watch describes how whole-genome sequencing used for surveillance purposes has enabled the identification of new drug resistance markers in the malaria parasite. PMID- 27932796 TI - Viral evolution: Uncovering the secrets of the RNA virosphere. PMID- 27932797 TI - Microbiome: Weight loss without the yo-yo effect. PMID- 27932798 TI - Viral infection: How histones go viral. PMID- 27932799 TI - Immunotherapy: Switching off immune suppression. PMID- 27932805 TI - We are not alone. PMID- 27932806 TI - What's the risk of dentists losing their hearing? AB - Hearing loss and its association with occupational noise exposure among Saudi dentists: a cross-sectional study. PMID- 27932808 TI - NOAC drugs. PMID- 27932810 TI - Evaluation of the Stop Smoking Wales NHS Dental Practice Incentive Scheme. AB - In December 2014, Public Health Wales introduced a proof-of-concept incentive scheme, aiming to encourage National Health Service (NHS) dental practitioners in Wales to provide brief intervention for smoking cessation and increase referrals to Stop Smoking Wales (SSW). The scheme ran for 11 weeks. Practitioners were advised to only refer patients who agreed with the referral. Practices were reimbursed L7 for every referral sent to SSW. Eighty-three dental practices signed up to participate, equating to 18% of NHS sites across Wales. SSW received 308 referrals, of which 297 (96%) were considered new contacts. One hundred and fifty-eight individuals (51%) accepted an assessment. Of these, 48 actually attended (30%). Thirty-two individuals became treated smokers (attending both an assessment and treatment session). Of these, 22 became self-reported quitters; 19 of these were validated through carbon monoxide (CO) monitoring. The cost to receive individuals into SSW via the dental incentive scheme was approximately L98 per self-reported quitter. The scheme greatly increased the number of referrals to SSW from dentists, compared to previous records and so fulfilled its aims. Amendments to the process could improve cost-effectiveness of a similar scheme. PMID- 27932801 TI - DNA-encoded chemistry: enabling the deeper sampling of chemical space. AB - DNA-encoded chemical library technologies are increasingly being adopted in drug discovery for hit and lead generation. DNA-encoded chemistry enables the exploration of chemical spaces four to five orders of magnitude more deeply than is achievable by traditional high-throughput screening methods. Operation of this technology requires developing a range of capabilities including aqueous synthetic chemistry, building block acquisition, oligonucleotide conjugation, large-scale molecular biological transformations, selection methodologies, PCR, sequencing, sequence data analysis and the analysis of large chemistry spaces. This Review provides an overview of the development and applications of DNA encoded chemistry, highlighting the challenges and future directions for the use of this technology. PMID- 27932800 TI - TIMPs: versatile extracellular regulators in cancer. AB - A compelling long-term goal of cancer biology is to understand the crucial players during tumorigenesis in order to develop new interventions. Here, we review how the four non-redundant tissue inhibitors of metalloproteinases (TIMPs) regulate the pericellular proteolysis of a vast range of matrix and cell surface proteins, generating simultaneous effects on tumour architecture and cell signalling. Experimental studies demonstrate the contribution of TIMPs to the majority of cancer hallmarks, and human cancers invariably show TIMP deregulation in the tumour or stroma. Of the four TIMPs, TIMP1 overexpression or TIMP3 silencing is consistently associated with cancer progression or poor patient prognosis. Future efforts will align mouse model systems with changes in TIMPs in patients, will delineate protease-independent TIMP function, will pinpoint therapeutic targets within the TIMP-metalloproteinase-substrate network and will use TIMPs in liquid biopsy samples as biomarkers for cancer prognosis. PMID- 27932813 TI - Cost-effectiveness of repairing versus replacing composite or amalgam restorations. AB - 'Repairing instead of complete replacement of partially defective restorations is likely to retain teeth for longer...' PMID- 27932811 TI - A pilot study of the gingival response when smokers switch from smoking to vaping. AB - Introduction Tobacco smoking is one of the most important risk factors for periodontitis as it alters the host response to plaque. Although the prevalence of tobacco smoking has declined in recent years, the use of electronic-cigarettes (vaping) has increased. The effect of vaping on the gingiva is unknown and an evidence-base needs to be established before providing dental advice about the use of these products.Objective To compare the gingival health of a group of established smokers before and after substituting vaping for smoking tobacco.Design Pilot.Setting Guy's Dental Hospital (England) from April-December 2015.Materials and methods Twenty established smokers (all staff members at Guy's Hospital) with mild periodontal disease replaced their regular smoking habits with the use of e-cigarettes for two weeks.Main outcome measure The primary outcome measure of gingival inflammation was bleeding on probing. Levels of selected pro-inflammatory cytokines in GCF, saliva and serum samples were also determined.Results and conclusions There was a statistically significant increase in gingival inflammation when tobacco smokers switched from smoking to vaping for two weeks. However, this result must be interpreted with extreme caution since this is only a pilot study. Nonetheless, this study should provide a stepping stone to encourage further investigation of the effects of vaping on periodontal health. PMID- 27932817 TI - Evaluation of the efficiency of denture cleaners for removing denture adhesives. AB - Cushion adhesives are the most tenacious whereas powder adhesives are removed most effectively by denture cleaners. PMID- 27932819 TI - Interview: Sandra White: 'Dentists need to get more political'. PMID- 27932820 TI - Fitness to practise: Not new. PMID- 27932822 TI - Feasibility study: assessing the efficacy and social acceptability of using dental hygienist-therapists as front-line clinicians. AB - Background The oral health of the adult population has been improving in the United Kingdom decade upon decade. Over half of dental service activity in the National Health Service (NHS) is limited to a check-up without any further treatment. This raises a question as to whether check-ups could be provided by dental hygienist-therapists, rather than general dental practitioners. The aim of this study was to assess the feasibility of a definitive trial to evaluate the costs and effects of using dental hygienist-therapists to undertake the check up.Methods/design Adult NHS patients were randomised into three arms in two dental practices: patients who only saw dental hygienist-therapists for a check up, those that saw the general dental practitioner and dental hygienist-therapist alternatively and a control, where patients only saw the general dental practitioner for their check-up. The study ran for 15 months. The primary outcome measures of the study were patient recruitment, retention and fidelity. A parallel and embedded qualitative study was undertaken which recorded the views of participating patients to determine the social acceptability of the intervention.Results Sixty patients participated in the study. The initial recruitment rate for the study was 33.7%. This figure increased to over 82.1% when telephone calls or face-to-face recruitment was utilised. The retention rates were 60% for both the dental hygienist-therapist only group and the alternate general dental practitioner and dental hygienist-therapist group, compared to 70% for the general dental practitioner only group. Fifteen patients were interviewed in the qualitative study and supported a team approach to the provision of check-ups in the NHS. Conclusion This study demonstrates the feasibility of a definitive trial to evaluate the costs and effects of using dental-hygienist-therapists to undertake the check-up. PMID- 27932823 TI - Hereditary dentine dysplasias: terminology in the context of osteogenesis imperfecta. AB - Hereditary dentine dysplasias (HDD) such as dentinogenesis imperfecta (DI) and dentine dysplasia (DD) are a group of genetic conditions characterised by an abnormal dentine structure due to disturbances in the formation, composition, or organisation of the dentine matrix. Either the primary or both primary and secondary dentition are affected to varying degrees. These disorders result from mutations in the genes encoding the major protein constituents of dentine, notably collagens and phosphoproteins. The clinical and radiological features of the hereditary dentine dysplasias (HDD) are relevant to clinical dentistry, in particular osteogenesis imperfecta (OI) which is a well-known heterogeneous genetic disorder. OI is currently the focus of considerable academic attention and involvement of the teeth is a frequent and variable manifestation. In this analysis, the literature related to the classification, clinical features, and molecular pathogenesis of heritable structural tooth diseases affecting dentine formation is reviewed. The definition, history of the terminology and the development of the current classification is outlined and discussed in detail with the aim to address semantic confusion that has arisen in the literature on HDD and to provide clarity on the use of appropriate terminology in the context of OI. PMID- 27932824 TI - NICE guidance delays mouth cancer diagnosis. PMID- 27932825 TI - Regulation: Is change impossible? PMID- 27932828 TI - A question of loyalties. PMID- 27932829 TI - Phil Holloway. PMID- 27932830 TI - Our hygienist will see you for your check-up now... AB - Feasibility study: Assessing the efficacy and social acceptability of using dental hygienist-therapists as front-line clinicians. PMID- 27932831 TI - Bernard Geoffrey Norman Smith. PMID- 27932834 TI - Pharmaceuticals: Antibiotics and vegetarians. PMID- 27932832 TI - Should implants be considered for patients with periodontal disease? AB - Dental implants are seen as a good option for replacing missing teeth. The success and survival rates for implants are very high. Concerns are developing about the problem of peri-implantitis. The reports of its prevalence vary but it is noted that the presence of periodontal disease is a risk factor. The issue of peri-implantitis was raised in the House of Lords in 2014. Complaints relating to implants is on the rise with the General Dental Council. Placement of implants in patients with periodontal disease is not a treatment that should be done without a full periodontal assessment and stabilisation of periodontal disease first. This review considers the risk of placing implants in patients with aggressive and chronic periodontitis. PMID- 27932835 TI - Evaluation of toothbrush disinfection via different methods. AB - Centers for Disease Control and Prevention state 'the likelihood of toothbrush cross-contamination in these environments (schools and group settings) is very high.' PMID- 27932836 TI - Mouth Cancer Action takes fight to Westminster. PMID- 27932837 TI - Genetic variation may explain why females are less susceptible to dental erosion. AB - No association between enamel-formation genes and enamel loss (erosion), but there were associations when analysing 'extreme values' for these factors. PMID- 27932838 TI - OMFS: Times are changing. PMID- 27932841 TI - Feature: Taking the stress out of dental recruitment. PMID- 27932840 TI - Should dental teams be doing more to make adolescents aware of the health risks of water pipe tobacco smoking (shisha)? AB - The prevalence of waterpipe tobacco smoking (also known as shisha, hookah, narghile or hubble bubble) is increasing worldwide and is especially popular among adolescents of all cultures, ethnicities and socio-economic backgrounds. This increased prevalence is thought to be due to a number of factors including the relationship between the social aspect of waterpipe smoking and a thriving cafe culture, lack of regulatory or policy framework specific to waterpipe use, the perception of reduced harm and the evolution of social media. This opinion paper discusses the prevalence of shisha use among adolescents, associated risks and oral health conditions and effective shisha cessation interventions. The implications for the dental team are also discussed. PMID- 27932842 TI - We need to talk about vaping. AB - A pilot study of the gingival response when smokers switch from smoking to vaping. PMID- 27932843 TI - Contract reform: Who's to blame? PMID- 27932845 TI - Women are catching up. PMID- 27932844 TI - What factors influence patient compliance with supportive periodontal therapy in a general practice setting? AB - Background The importance of supportive periodontal therapy following active treatment has been well documented but numerous studies have shown patient compliance to be poor. The aim of this study was to ascertain which factors affect patient compliance and whether this included routinely recorded periodontal indices.Methodology This was a five-year retrospective service evaluation study set within a private general dental practice. It utilised demographic and periodontal data from patients who attended the practice for chronic periodontal treatment in 2009 and ascertained whether there were links between this data and compliance with the supportive phase of periodontal treatment.Results Three hundred and ten patients satisfied the inclusion criteria of which 32.3% were categorised as compliant, 45.5% non-compliant and 22.3% erratic attenders. Patients who were statistically significantly more compliant were males (p = 0.03) and non-smokers (p = 0.01). There was a trend for older people to be more compliant; however this was not statistically significant. Plaque and bleeding scores were lower in the compliant group but only the bleeding scores were statistically significant (p = 0.03). The pocket probing depths were used as an indicator of disease severity and showed no significant relationship with compliance.Conclusion Although some of the periodontal parameters showed a statistically significant relationship with compliance, the difference between the parameters was clinically minimal suggesting that there is no definitive physical characteristic which is an indicator of patient compliance. PMID- 27932847 TI - Dental publishing: Peer review reviewed. PMID- 27932848 TI - Accelerating Translational Research through Open Science: The Neuro Experiment. AB - Translational research is often afflicted by a fundamental problem: a limited understanding of disease mechanisms prevents effective targeting of new treatments. Seeking to accelerate research advances and reimagine its role in the community, the Montreal Neurological Institute (Neuro) announced in the spring of 2016 that it is launching a five-year experiment during which it will adopt Open Science-open data, open materials, and no patenting-across the institution. The experiment seeks to examine two hypotheses. The first is whether the Neuro's Open Science initiative will attract new private partners. The second hypothesis is that the Neuro's institution-based approach will draw companies to the Montreal region, where the Neuro is based, leading to the creation of a local knowledge hub. This article explores why these hypotheses are likely to be true and describes the Neuro's approach to exploring them. PMID- 27932849 TI - Report from the 18th International Symposium on Advances in Extraction Technologies (ExTech'2016) and the 22nd International Symposium on Separation Science (ISSS'2016), Torun, 3-6 July 2016. PMID- 27932850 TI - Co-generation of hydrogen and power/current pulses from supercapacitive MFCs using novel HER iron-based catalysts. AB - In this work, four different supercapacitive microbial fuel cells (SC-MFCs) with carbon brush as the anode and an air-breathing cathode with Fe-Aminoantipyrine (Fe-AAPyr) as the catalyst have been investigated using galvanostatic discharges. The maximum power (Pmax) obtained was in the range from 1.7 mW to 1.9 mW for each SC-MFC. This in-series connection of four SC-MFCs almost quadrupled Pmax to an operating voltage of 3025 mV and a Pmax of 8.1 mW, one of the highest power outputs reported in the literature. An additional electrode (AdHER) connected to the anode of the first SC-MFC and placed in the fourth SC-MFC evolved hydrogen. The hydrogen evolution reaction (HER) taking place at the electrode was studied on Pt and two novel platinum group metal-free (PGM-free) catalysts: Fe Aminoantipyrine (Fe-AAPyr) and Fe-Mebendazole (Fe-MBZ). The amount of H2 produced was estimated using the Faraday law as 0.86 mMd-1cm-2 (0.132 L day-1) for Pt, 0.83 mMd-1cm-2 (0.127 L day-1) for Fe-AAPyr and 0.8 mMd-1cm-2 (0.123 L day-1) for Fe-MBZ. Hydrogen evolution was also detected using gas chromatography. While HER was taking place, galvanostatic discharges were also performed showing simultaneous H2 production and pulsed power generation with no need of external power sources. PMID- 27932851 TI - Computational fluid dynamic modeling of a medium-sized surface mine blasthole drill shroud. AB - The Pittsburgh Mining Research Division of the U.S. National Institute for Occupational Safety and Health (NIOSH) recently developed a series of models using computational fluid dynamics (CFD) to study airflows and respirable dust distribution associated with a medium-sized surface blasthole drill shroud with a dry dust collector system. Previously run experiments conducted in NIOSH's full scale drill shroud laboratory were used to validate the models. The setup values in the CFD models were calculated from experimental data obtained from the drill shroud laboratory and measurements of test material particle size. Subsequent simulation results were compared with the experimental data for several test scenarios, including 0.14 m3/s (300 cfm) and 0.24 m3/s (500 cfm) bailing airflow with 2:1, 3:1 and 4:1 dust collector-to-bailing airflow ratios. For the 2:1 and 3:1 ratios, the calculated dust concentrations from the CFD models were within the 95 percent confidence intervals of the experimental data. This paper describes the methodology used to develop the CFD models, to calculate the model input and to validate the models based on the experimental data. Problem regions were identified and revealed by the study. The simulation results could be used for future development of dust control methods for a surface mine blasthole drill shroud. PMID- 27932852 TI - Evolutionary Connectionism: Algorithmic Principles Underlying the Evolution of Biological Organisation in Evo-Devo, Evo-Eco and Evolutionary Transitions. AB - The mechanisms of variation, selection and inheritance, on which evolution by natural selection depends, are not fixed over evolutionary time. Current evolutionary biology is increasingly focussed on understanding how the evolution of developmental organisations modifies the distribution of phenotypic variation, the evolution of ecological relationships modifies the selective environment, and the evolution of reproductive relationships modifies the heritability of the evolutionary unit. The major transitions in evolution, in particular, involve radical changes in developmental, ecological and reproductive organisations that instantiate variation, selection and inheritance at a higher level of biological organisation. However, current evolutionary theory is poorly equipped to describe how these organisations change over evolutionary time and especially how that results in adaptive complexes at successive scales of organisation (the key problem is that evolution is self-referential, i.e. the products of evolution change the parameters of the evolutionary process). Here we first reinterpret the central open questions in these domains from a perspective that emphasises the common underlying themes. We then synthesise the findings from a developing body of work that is building a new theoretical approach to these questions by converting well-understood theory and results from models of cognitive learning. Specifically, connectionist models of memory and learning demonstrate how simple incremental mechanisms, adjusting the relationships between individually-simple components, can produce organisations that exhibit complex system-level behaviours and improve the adaptive capabilities of the system. We use the term "evolutionary connectionism" to recognise that, by functionally equivalent processes, natural selection acting on the relationships within and between evolutionary entities can result in organisations that produce complex system level behaviours in evolutionary systems and modify the adaptive capabilities of natural selection over time. We review the evidence supporting the functional equivalences between the domains of learning and of evolution, and discuss the potential for this to resolve conceptual problems in our understanding of the evolution of developmental, ecological and reproductive organisations and, in particular, the major evolutionary transitions. PMID- 27932853 TI - Variations in cognitive abilities across the life course: Cross-sectional evidence from Understanding Society: The UK Household Longitudinal Study. AB - BACKGROUND: Populations worldwide are aging. Cognitive decline is an important precursor of dementia, illness and death and, even within the normal range, is associated with poorer performance on everyday tasks. However, the impact of age on cognitive function does not always receive the attention it deserves. METHODS: We have explored cross-sectional associations of age with five cognitive tests (word recall, verbal fluency, subtraction, number sequence, and numerical problem solving) in a large representative sample of over 40,000 men and women aged 16 to 100 living in the UK. RESULTS: Women performed better on word recall tests and men had higher scores for subtraction, number sequence and numerical problem solving. However, age-cognition associations were generally similar in both genders. Mean word recall and number sequence scores decreased from early adulthood with steeper declines from the mid-60s onwards Verbal fluency, subtraction and numerical problem solving scores remained stable or increased from early to mid-adulthood, followed by approximately linear declines from around age 60. Performance on all tests was progressively lower in respondents with increasingly worse self-rated health and memory. Age-related declines in word recall, verbal fluency and number sequence started earlier in those with the worst self-rated health. There was no compelling evidence for age dedifferentiation (that the general factor of cognitive ability changes in strength with age). CONCLUSIONS: We have confirmed previously observed patterns of cognitive aging using a large representative population sample. PMID- 27932854 TI - Predictors of ageing-related decline across multiple cognitive functions. AB - It is critical to discover why some people's cognitive abilities age better than others'. We applied multivariate growth curve models to data from a narrow-age cohort measured on a multi-domain IQ measure at age 11 years and a comprehensive battery of thirteen measures of visuospatial, memory, crystallized, and processing speed abilities at ages 70, 73, and 76 years (n = 1091 at age 70). We found that 48% of the variance in change in performance on the thirteen cognitive measures was shared across all measures, an additional 26% was specific to the four ability domains, and 26% was test-specific. We tested the association of a wide variety of sociodemographic, fitness, health, and genetic variables with each of these cognitive change factors. Models that simultaneously included all covariates accounted for appreciable proportions of variance in the cognitive change factors (e.g. approximately one third of the variance in general cognitive change). However, beyond physical fitness and possession of the APOE e4 allele, very few predictors were incrementally associated with cognitive change at statistically significant levels. The results highlight a small number of factors that predict differences in cognitive ageing, and underscore that correlates of cognitive level are not necessarily predictors of decline. Even larger samples will likely be required to identify additional variables with more modest associations with normal-range heterogeneity in aging-related cognitive declines. PMID- 27932855 TI - The I/O transform of a chemical sensor. AB - A number of sensing technologies, using a variety of transduction principles, have been proposed for non-invasive chemical sensing. A fundamental problem common to all these sensing technologies is determining what features of the transducer's signal constitute a chemical fingerprint that allows for precise analyte recognition. Of particular importance is the need to extract features that are robust with respect to the sensor's age or stimulus intensity. Here, using pulsed stimulus delivery, we show that a sensor's operation can be modeled as a linear input-output (I/O) transform. The I/O transform is unique for each analyte and can be used to precisely predict a temperature-programmed chemiresistor's response to the analyte given the recent stimulus history (i.e. state of an analyte delivery valve being open or closed). We show that the analyte specific I/O transforms are to a certain degree stimulus intensity invariant and can remain consistent even when the sensor has undergone considerable aging. Significantly, the I/O transforms for a given analyte are highly conserved across sensors of equal manufacture, thereby allowing training data obtained from one sensor to be used for recognition of the same set of chemical species with another sensor. Hence, this proposed approach facilitates decoupling of the signal processing algorithms from the chemical transducer, a key advance necessary for achieving long-term, non-invasive chemical sensing. PMID- 27932856 TI - Three-dimensional soft tissue analysis of the hand: a novel method to investigate effects of acromegaly. AB - BACKGROUND: Acral overgrowth is a highly common clinical sign in patients with active acromegaly. To what extent this overgrowth persists after long-term remission of acromegaly is largely unknown. Using the new imaging technique of three-dimensional (3D) stereophotogrammetry, it is possible to accurately investigate soft tissue changes of the hand. The aim of the recent study was to compare the 3D soft tissue characteristics of the hands of patients in long-term remission of acromegaly to those of a healthy pair matched control group. METHODS: A case-control study was performed at a tertiary referral center. Twelve patients in remission of acromegaly (58 % male, mean age 58.3 years, mean BMI 29.6 kg/m2) were compared to twelve age-, gender-, ethnicity-, and BMI-matched control subjects. Of each individual, 3D photographs of both hands were acquired and analyzed using a 3D computer software program. RESULTS: The patients in long term remission of acromegaly have overgrowth of soft tissue of the hand compared to matched control subjects, with a larger length and width of the hand (p = 0.0025, p = 0.0017, respectively). Furthermore, the diameters measured at the proximal interphalangeal (PIP) joints of the individual fingers are larger in the acromegaly patients. CONCLUSIONS: Significant soft tissue overgrowth of the hand persists in former acromegaly patients, even after long-term remission. Analysis of 3D hand photographs is an accurate and easy tool to evaluate the acral soft tissue patterns in acromegaly. Level of Evidence: Level III, diagnostic study. PMID- 27932858 TI - One-stage bone strip reconstruction technique with balloon sinus dilatation surgery for chronic maxillary atelectasis. AB - PURPOSE: Chronic maxillary atelectasis is characterized by unilateral spontaneous enophthalmos and hypoglobus due to increased orbital volume secondary to maxillary sinus inward deformation. Reformation of the sinus architecture and reconstruction of the orbit are key to a successful outcome. Here, we introduce a one-staged surgery that addresses both these goals. PATIENTS AND METHODS: We retrospectively reviewed 11 patients treated with one-stage orbital and sinus surgery. A transconjunctival subperiosteal approach was used to create slats in the thinned orbital floor. A nasal endoscopic approach was utilized to access the maxillary sinus and place a modified Foley catheter balloon through the enlarged maxillary ostium. A bridge graft of nasal septal, ear cartilage, or LactSorb was placed on the reconstructed and balloon-supported orbital floor. The balloon was deflated and removed at 10-14 days. All patients underwent complete ophthalmic and orbital evaluation, including standardized photography and radiologic imaging. RESULTS: Eleven patients, mean age 39.5 years, presented with diplopia in upgaze, superior sulcus deformity, and at least 2 mm of relative enophthalmos. After initial overcorrection, enophthalmos improved in all cases. Symmetry within 1 mm was accomplished in 10 of 11 cases. Follow-up time was 259+/-320 days. Full motility was recovered in all patients. CONCLUSION: We describe a one-staged surgery consisting of cutting slats in the orbital floor, dilating the maxillary sinus with a balloon, and stabilizing the orbital floor with a cartilage graft placement. Our anecdotal experience suggests that this surgical approach can safely achieve normalization of the pathologic sinus outflow and restoration of the orbit anatomy. The balloon ensures orbital floor stability during the healing process, and it may act to stent open the sinus ostium during early mucosal healing. PMID- 27932859 TI - Central corneal thickness of Iraqi population in relation to age, gender, refractive errors, and corneal curvature: a hospital-based cross-sectional study. AB - BACKGROUND: Central corneal thickness (CCT) is an important indicator of corneal status. Its measurement provides valid information about corneal physiological condition and possible changes associated with diseases, traumas, and hypoxia. It is an integral part for interpretation of intraocular pressure and glaucoma patient management and in prerefractive procedure assessment. OBJECTIVE: The aim of this study is to determine the mean CCT among a normal Iraqi population and to correlate between CCT and age, gender, refraction, and corneal curvature. PATIENTS AND METHODS: This cross-sectional study was carried out at Ibn Al Haitham Teaching Eye Hospital. A total of 418 eyes from 209 healthy individuals with an age range from 20 to 75 years were studied. CCT was measured by ultrasound pachymeter. Refraction was measured using an auto-refractor and confirmed by trial lenses and retinoscopy to calculate the spherical equivalent. Corneal curvature was measured using an auto-refracto-keratometer to calculate the average corneal curvature (AVK). RESULTS: The mean CCT was 543.95+/-32.58 MUm with a range from 422 to 636 MUm. CCT was not affected by gender. CCT significantly negatively correlated with age and AVK. CCT significantly positively correlated with the spherical equivalence. CONCLUSION AND RECOMMENDATION: Among an Iraqi population, CCT significantly decreased with age. Myopics had significantly thinner corneas. There was weak but significant negative correlation between CCT and corneal curvature. We recommend further studies about the relationship between central corneal thickness and other ocular parameters in Iraqi population such as the axial length. PMID- 27932860 TI - Rebound macular edema following oral acetazolamide therapy for juvenile X-linked retinoschisis in an Italian family. AB - BACKGROUND: Juvenile X-linked retinoschisis (RS1, OMIM: 312700) is a hereditary vitreoretinal dystrophy characterized by bilateral foveal schisis and, in half of the patients, splitting through the nerve fiber layer in the peripheral retina. In the first decade of life, patients usually develop a decrease in visual acuity. Long-term visual outcomes can be poor due to the limited number of known successful treatments. PURPOSE: The purposes of this study were to present, for the first time, a p.Arg197Cys missense mutation in the RS1 gene (OMIM: 300839) in a four-generation Italian family with RS1 and to examine the clinical response to the treatment with acetazolamide tablets alone or in combination with dorzolamide eye drops as assessed by spectral-domain optical coherence tomography (SD-OCT). METHODS: Eleven individuals, including two brothers with RS1 (patients 1 and 2), underwent a full medical history examination and a comprehensive ocular assessment that involved SD-OCT, fluorescein angiography, electroretinography and DNA analysis. Each RS1 patient received oral acetazolamide (375 mg daily) during the first three months. Thereafter, patient 1 continued only with dorzolamide eyedrops three times a day for a period of three months, while patient 2 spontaneously stopped both medications. RESULTS: Sequence analysis of the RS1 gene identified a hemizygous c.589C>T (p.Arg197Cys) missense mutation in exon 6, which has not been previously reported in an Italian family. A different response to the medical therapy was observed in the four eyes of the two affected brothers hemizygous for this abnormality. Of note, after acetazolamide interruption, a rebound effect on cystoid macular edema reduced the beneficial effects of the initial therapy for RS1 from p.Arg197Cys mutation. Indeed, a minimal rebound effect on cystoid macular edema, and an improvement in visual acuity, was observed in patient 1 during the six months of treatment. Conversely, in patient 2, an initial improvement in cystoid macular edema was not associated with visual acuity changes, followed by a marked rebound effect. CONCLUSION: This study showed that the sequential use of acetazolamide tablets and dorzolamide eye drops should be considered and studied further as a possible treatment for macular edema and visual impairment in patients with RS1 from a hemizygous p.Arg197Cys mutation. PMID- 27932857 TI - Vogt-Koyanagi-Harada syndrome - current perspectives. AB - Vogt-Koyanagi-Harada syndrome is a cause of noninfectious panuveitis, leading to significant vision loss in many patients. It is an autoimmune disease occurring in genetically susceptible individuals and clinically presents as bilateral panuveitis with serous retinal detachments and hyperemic, swollen optic discs, which are associated with neurological and auditory manifestations. Early diagnosis and prompt and adequate treatment with immunosuppressive agents (corticosteroids and other immunosuppressive drugs) may halt disease progression and prevent recurrences and vision loss. This review summarizes the current knowledge on the variable clinical aspects of this disease, highlighting diagnostic and treatment strategies. PMID- 27932861 TI - Interactive navigation-guided ophthalmic plastic surgery: assessment of optical versus electromagnetic modes and role of dynamic reference frame location using navigation-enabled human skulls. AB - AIM: The aim of this study was to assess the anatomical accuracy of navigation technology in localizing defined anatomic landmarks within the orbit with respect to type of technology (optical versus electromagnetic systems) and position of the dynamic reference marker on the skull (vertex, temporal, parietal, and mastoid) using in vitro navigation-enabled human skulls. The role of this model as a possible learning tool for anatomicoradiological correlations was also assessed. METHODS: Computed tomography (CT) scans were performed on three cadaveric human skulls using the standard image-guidance acquisition protocols. Thirty-five anatomical landmarks were identified for stereotactic navigation using the image-guided StealthStation S7TM in both electromagnetic and optical modes. Three outcome measures studied were accuracy of anatomical localization and its repeatability, comparisons between the electromagnetic and optical modes in assessing radiological accuracy, and the efficacy of dynamic reference frame (DRF) at different locations on the skull. RESULTS: The geometric localization of all the identified anatomical landmarks could be achieved accurately. The Cohen's kappa agreements between the surgeons were found to be perfect (kappa =0.941) at all predetermined points. There was no difference in anatomical localization between the optical and electromagnetic modes (P<=0.001). Precision for radiological identification did not differ with various positions of the DRF. Skulls with intact anatomical details and careful CT image acquisitions were found to be stereotactically useful. CONCLUSION: Accuracy of anatomic localization within the orbit with navigation technology is equal with optical and electromagnetic system. The location of DRF does not affect the accuracy. Navigation-enabled skull models can be potentially useful as teaching tools for achieving the accurate radiological orientation of orbital and periorbital structures. PMID- 27932862 TI - Role of the treating surgeon in the consent process for elective refractive surgery. AB - PURPOSE: To compare patient's perception of consent quality, clinical and quality of-life outcomes after laser vision correction (LVC) and refractive lens exchange (RLE) between patients who met their treating surgeon prior to the day of surgery (PDOS) or on the day of surgery (DOS). DESIGN: Retrospective, comparative case series. SETTING: Optical Express, Glasgow, UK. METHODS: Patients treated between October 2015 and June 2016 (3972 LVC and 979 RLE patients) who attended 1-day and 1-month postoperative aftercare and answered a questionnaire were included in this study. All patients had a thorough preoperative discussion with an optometrist, watched a video consent, and were provided with written information. Patients then had a verbal discussion with their treating surgeon either PDOS or on the DOS, according to patient preference. Preoperative and 1-month postoperative visual acuity, refraction, preoperative, 1-day and 1-month postoperative questionnaire were compared between DOS and PDOS patients. Multivariate regression model was developed to find factors associated with patient's perception of consent quality. RESULTS: Preoperatively, 8.0% of LVC and 17.1% of RLE patients elected to meet their surgeon ahead of the surgery day. In the LVC group, 97.5% of DOS and 97.2% of PDOS patients indicated they were properly consented for surgery (P=0.77). In the RLE group, 97.0% of DOS and 97.0% of PDOS patients stated their consent process for surgery was adequate (P=0.98). There was no statistically significant difference between DOS and PDOS patients in most of the postoperative clinical or questionnaire outcomes. Factors predictive of patient's satisfaction with consent quality were postoperative satisfaction with vision (46.7% of explained variance), difficulties with night driving, close-up vision or outdoor/sports activities (25.4%), visual phenomena (12.2%), dry eyes (7.5%), and patient's satisfaction with surgeon's care (8.2%). CONCLUSION: Perception of quality of consent was comparable between patients that elected to meet the surgeon PDOS, and those who did not. PMID- 27932864 TI - Efficacy and tolerability of vilazodone for major depressive disorder: evidence from phase III/IV randomized controlled trials. AB - Vilazodone is a new molecule approved for major depressive disorder (MDD). This report focuses on the efficacy and tolerability of vilazodone for MDD. MEDLINE, EMBASE, and Cochrane Library were searched. A total of 1,930 patients from four trials were included. A significant improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) total score was seen as early as week 2 (P<0.01) in vilazodone-treated patients. The results showed a higher rate of MADRS response with vilazodone compared with placebo (P<0.001). There were also greater improvements in the Hamilton Rating Scale for Anxiety as well as the Clinical Global Impressions (severity of illness and improvement of illness) scores from baseline in vilazodone-treated patients compared to placebo patients (P<0.001). Discontinuation rates due to adverse events were higher with vilazodone than placebo (P=0.0002). The most common adverse events of vilazodone were vomiting, nausea, diarrhea, insomnia, somnolence, dizziness, and dry mouth (P<0.05). Treatment-related effects on sexual function were mild compared to placebo in men (P=0.03). In conclusion, 40 mg/day of vilazodone had a rapid onset of response and showed good improvement in anxiety symptoms as well as good tolerability during short-term treatment (8-10 weeks) for MDD. Further studies should focus on the efficacy and tolerability of vilazodone over a longer duration and should utilize active comparators. PMID- 27932865 TI - Statistical modeling methods to analyze the impacts of multiunit process variability on critical quality attributes of Chinese herbal medicine tablets. AB - The quality of Chinese herbal medicine tablets suffers from batch-to-batch variability due to a lack of manufacturing process understanding. In this paper, the Panax notoginseng saponins (PNS) immediate release tablet was taken as the research subject. By defining the dissolution of five active pharmaceutical ingredients and the tablet tensile strength as critical quality attributes (CQAs), influences of both the manipulated process parameters introduced by an orthogonal experiment design and the intermediate granules' properties on the CQAs were fully investigated by different chemometric methods, such as the partial least squares, the orthogonal projection to latent structures, and the multiblock partial least squares (MBPLS). By analyzing the loadings plots and variable importance in the projection indexes, the granule particle sizes and the minimal punch tip separation distance in tableting were identified as critical process parameters. Additionally, the MBPLS model suggested that the lubrication time in the final blending was also important in predicting tablet quality attributes. From the calculated block importance in the projection indexes, the tableting unit was confirmed to be the critical process unit of the manufacturing line. The results demonstrated that the combinatorial use of different multivariate modeling methods could help in understanding the complex process relationships as a whole. The output of this study can then be used to define a control strategy to improve the quality of the PNS immediate release tablet. PMID- 27932863 TI - Non-imidazole-based histamine H3 receptor antagonists with anticonvulsant activity in different seizure models in male adult rats. AB - A series of twelve novel non-imidazole-based ligands (3-14) was developed and evaluated for its in vitro binding properties at the human histamine H3 receptor (hH3R). The novel ligands were investigated for their in vivo protective effects in different seizure models in male adult rats. Among the H3R ligands (3-14) tested, ligand 14 showed significant and dose-dependent reduction in the duration of tonic hind limb extension in maximal electroshock (MES)-induced seizure model subsequent to acute systemic administration (5, 10, and 20 mg/kg, intraperitoneally), whereas ligands 4, 6, and 7 without appreciable protection in MES model were most promising in pentylenetetrazole (PTZ) model. Moreover, the protective effect observed for ligand 14 in MES model was lower than that observed for the reference drug phenytoin and was entirely abrogated when rats were co-administered with the brain-penetrant H1R antagonist pyrilamine (PYR) but not the brain-penetrant H2R antagonist zolantidine (ZOL), demonstrating that histaminergic neurotransmission by activation of postsynaptically located H1Rs seems to be involved in the protective action. On the contrary, PYR and ZOL failed to abrogate the full protection provided by 4 in PTZ model and the moderate protective effect by 14 in strychnine (STR) model. Moreover, the experimental and in silico estimation of properties such as metabolism was performed for five selected test compounds. Also, lipophilicity using planar reversed-phase thin-layer chromatography method was included for better understanding of the molecular properties of the tested compounds. Additionally, the absorption, distribution, metabolism, and elimination and toxicity parameters were evaluated for the most promising compounds 2, 4, 6, 7, and 14 utilizing in vitro methods. These interesting results highlight the potential of H3R ligands as new antiepileptic drugs or as adjuvants to available epilepsy medications. PMID- 27932867 TI - Clustering Algorithms: Their Application to Gene Expression Data. AB - Gene expression data hide vital information required to understand the biological process that takes place in a particular organism in relation to its environment. Deciphering the hidden patterns in gene expression data proffers a prodigious preference to strengthen the understanding of functional genomics. The complexity of biological networks and the volume of genes present increase the challenges of comprehending and interpretation of the resulting mass of data, which consists of millions of measurements; these data also inhibit vagueness, imprecision, and noise. Therefore, the use of clustering techniques is a first step toward addressing these challenges, which is essential in the data mining process to reveal natural structures and identify interesting patterns in the underlying data. The clustering of gene expression data has been proven to be useful in making known the natural structure inherent in gene expression data, understanding gene functions, cellular processes, and subtypes of cells, mining useful information from noisy data, and understanding gene regulation. The other benefit of clustering gene expression data is the identification of homology, which is very important in vaccine design. This review examines the various clustering algorithms applicable to the gene expression data in order to discover and provide useful knowledge of the appropriate clustering technique that will guarantee stability and high degree of accuracy in its analysis procedure. PMID- 27932868 TI - Analysis of Parallel Algorithms on SMP Node and Cluster of Workstations Using Parallel Programming Models with New Tile-based Method for Large Biological Datasets. AB - Sequence alignment is an important tool for describing the relationships between DNA sequences. Many sequence alignment algorithms exist, differing in efficiency, in their models of the sequences, and in the relationship between sequences. The focus of this study is to obtain an optimal alignment between two sequences of biological data, particularly DNA sequences. The algorithm is discussed with particular emphasis on time, speedup, and efficiency optimizations. Parallel programming presents a number of critical challenges to application developers. Today's supercomputer often consists of clusters of SMP nodes. Programming paradigms such as OpenMP and MPI are used to write parallel codes for such architectures. However, the OpenMP programs cannot be scaled for more than a single SMP node. However, programs written in MPI can have more than single SMP nodes. But such a programming paradigm has an overhead of internode communication. In this work, we explore the tradeoffs between using OpenMP and MPI. We demonstrate that the communication overhead incurs significantly even in OpenMP loop execution and increases with the number of cores participating. We also demonstrate a communication model to approximate the overhead from communication in OpenMP loops. Our results are astonishing and interesting to a large variety of input data files. We have developed our own load balancing and cache optimization technique for message passing model. Our experimental results show that our own developed techniques give optimum performance of our parallel algorithm for various sizes of input parameter, such as sequence size and tile size, on a wide variety of multicore architectures. PMID- 27932866 TI - Effect of peritoneal dialysis fluid containing osmo-metabolic agents on human endothelial cells. AB - BACKGROUND: The use of glucose as the only osmotic agent in peritoneal dialysis (PD) solutions (PDSs) is believed to exert local (peritoneal) and systemic detrimental actions, particularly in diabetic PD patients. To improve peritoneal biocompatibility, we have developed more biocompatible PDSs containing xylitol and carnitine along with significantly less amounts of glucose and have tested them in cultured Human Vein Endothelial Cells (HUVECs) obtained from the umbilical cords of healthy (C) and gestational diabetic (GD) mothers. METHODS: Primary C- and GD-HUVECs were treated for 72 hours with our PDSs (xylitol 0.7% and 1.5%, whereas carnitine and glucose were fixed at 0.02% and 0.5%, respectively) and two glucose-based PDSs (glucose 1.36% or 2.27%). We examined their effects on endothelial cell proliferation (cell count), viability (3-(4,5 dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay), intracellular nitro oxidative stress (peroxynitrite levels), Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 membrane exposure (flow cytometry), and HUVEC monocyte interactions (U937 adhesion assay). RESULTS: Compared to glucose-based PDSs, our in vitro studies demonstrated that the tested PDSs did not change the proliferative potential both in C- and GD-HUVECs. Moreover, our PDSs significantly improved endothelial cell viability, compared to glucose-based PDSs and basal condition. Notably, glucose-based PDSs significantly increased the intracellular peroxynitrite levels, Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 membrane exposure, and endothelial cell monocyte interactions in both C- and GD-HUVECs, as compared with our experimental PDSs. CONCLUSION: Present results show that in control and diabetic human endothelial cell models, xylitol-carnitine-based PDSs do not cause cytotoxicity, nitro-oxidative stress, and inflammation as caused by hypertonic glucose-based PDSs. Since xylitol and carnitine are also known to favorably affect glucose homeostasis, these findings suggest that our PDSs may represent a desirable hypertonic solution even for diabetic patients in PD. PMID- 27932869 TI - Person-centered dementia care: current perspectives. AB - Person-centered dementia care is widely accepted as a value-based commitment to supporting people with dementia and is a guiding principle in care services. Policy ambitions to put people at the center of their own care are being developed internationally. These may be seen as part of the evolution of person centered care which has its origins in critical perspectives on practice and social responses to people with dementia. In England, one further development of person-centered care has been personalization - a government policy to extend individuals' choice and control over their social care and, latterly, ways to meet their health care needs. This paper charts the evolution of the concept of person-centered care to the policy of personalization (which has international comparators) and summarizes emerging and conflicting evidence about the implications of personal budgets in England on older people with mental health problems such as dementia and their families. It focuses on the evidence base of personalization and on emerging lessons for practice, drawing from the implementation of personalization and the adoption of personal budgets by this group. While personalization may be one policy initiative, the values and practices of person-centered dementia care remain fundamental to practice and are inspiring new ideas related to rights and justice for people with dementia. PMID- 27932870 TI - Evaluation of quality of life in chronic, progressing rheumatic diseases based on the example of osteoarthritis and rheumatoid arthritis. AB - BACKGROUND: Rheumatic diseases, irrespective of etiology and clinical course, influence different areas of a patient's life. Adapting to disability and limitations caused by an illness is very difficult for many patients. The main goal of a therapeutic procedure should be improvement of health-related quality of life (QoL). OBJECTIVE: Evaluation of the factors that influence the QoL that are conditioned by the state of health of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). METHODS: The study group consisted of 198 patients diagnosed with OA, according to the American College of Rheumatology criteria (1988), and 100 patients diagnosed with RA, according to the American College of Rheumatology criteria (2010). A diagnostic survey using visual analog scale of pain, health assessment questionnaire disability index, and 36-item short form health survey were used in this study. RESULTS: The average age of patients with OA was 59.16 (+/-15.87) years and patients with RA was 55.22 (+/-14.87) years. The average duration of illness examined for OA was 5.5 (+/-4.32) years, whereas for RA, it was slightly more at 6.8 (+/-5.21) years. Overall the QoL in both study groups was of medium level. Among patients with OA and RA, lower evaluation of QoL was mainly affected by age (OA - physical sphere [PCS] rs =-0.177, P<0.012; MCS rs =-0.185, P=0.008; RA - PCS rs =-0.234, P=0.019; MCS rs =-0.208, P=0.038), the level of physical disability (OA - PCS rp =-0.532, P<0.001; MCS rs =-0.467, P<0.001; RA - PCS rp =-0.326, P<0.001; MCS rs =-0.229, P<0.001), and pain (OA - PCS rp =-0.425, P<0.001; mental sphere/mental functioning (MCS) rs = 0.359, P<0.001; RA - PCS rp =-0.313, P<0.001; MCS rp =-0.128, P<0.001). CONCLUSION: Patients with OA, despite their average older age, had a higher evaluated QoL than patients with RA. Overall QoL in terms of mental functioning in both rheumatic diseases was assessed at a higher level than in the area of physical functioning. PMID- 27932871 TI - Efficacy and safety outcomes of fractional flow reserve in guiding clinical therapy of non-ST-segment elevation myocardial infarction compared with angiography alone in elderly Chinese patients. AB - OBJECTIVE: Fractional flow reserve (FFR) is an innovative method for evaluating the physiological significance of a coronary stenosis, but its validity is less certain in patients with non-ST-segment elevation myocardial infarction (NSTEMI). It is important to assess whether FFR is effective and safe in patients, especially elderly Chinese patients, with NSTEMI. As the first one in China, the purpose of this study was to establish the efficacy and safety outcomes of FFR in guiding clinical therapy of NSTEMI compared with angiography alone in elderly Chinese patients. PATIENTS AND METHODS: This prospective randomized controlled study included 220 patients with NSTEMI older than 65 years. Patients were assigned in a ratio of 1:1 to the FFR-guided group and the angiography-guided group, and their outcomes were evaluated after 1 year of follow-up. RESULTS: The mean age of the patients was 70+/-3.6 years, and 69.6% were men. Baseline characteristics of the patients had no differences between the two groups (P>0.05 for all). No differences in adverse events, including major adverse cardiovascular event, major adverse cardiovascular and cerebrovascular event, cardiovascular death, nonfatal myocardial infarction, heart failure, stroke, transient ischemic attack, all-cause mortality, contrast nephropathy, and major bleeding, was observed between the two groups during the follow-up (P>0.05 for all). The number of patients receiving medical therapy alone in the FFR-guided group was significantly more than that in the angiography-guided group (P<0.05). CONCLUSION: Compared with angiography-guided standard therapy, FFR reduced the application of percutaneous coronary intervention and obtained similar outcomes, demonstrating that FFR was effective and safe in guiding clinical therapy of NSTEMI in elderly Chinese patients. PMID- 27932872 TI - Randomized controlled trials and real-world observational studies in evaluating cardiovascular safety of inhaled bronchodilator therapy in COPD. AB - Long-acting muscarinic antagonist (LAMA) or long-acting beta2-agonist (LABA) bronchodilators and their combination are recommended for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Although the efficacy of LAMAs and LABAs has been well established through randomized controlled trials (RCTs), questions remain regarding their cardiovascular (CV) safety. Furthermore, while the safety of LAMA and LABA monotherapy has been extensively studied, data are lacking for LAMA/LABA combination therapy, and the majority of the studies that have reported on the CV safety of LAMA/LABA combination therapy were not specifically designed to assess this. Evaluation of CV safety for COPD treatments is important because many patients with COPD have underlying CV comorbidities. However, severe CV and other comorbidities are often exclusion criteria for RCTs, contributing to a lack in external validity and generalizability. Real-world observational studies are another important tool to evaluate the effectiveness and safety of COPD therapies in a broader population of patients and can improve upon the external validity limitations of RCTs. We examine what is already known regarding the CV and cerebrovascular safety of LAMA/LABA combination therapy from RCTs and real-world observational studies, and explore the advantages and limitations of data derived from each study type. We also describe an ongoing prospective, observational, comparative post-authorization safety study of a LAMA/LABA combination therapy (umeclidinium/vilanterol) and LAMA monotherapy (umeclidinium) versus tiotropium, with a focus on the relative merits of the study design. PMID- 27932873 TI - Coherence between self-reported and objectively measured physical activity in patients with chronic obstructive lung disease: a systematic review. AB - The beneficial effects of physical activity (PA) in patients with COPD, as well as the methods of their assessment, are well known and described. As objective measures of PA, such as the use of motion sensors, video recordings, exercise capacity testing, and indirect calorimetry, are not easily obtained in the daily clinical life, the reliability of the more accessible self-reported measurements of PA is important. In this review, we systematically identified original studies involving COPD patients and at least one parameter of self-reported and objective exercise testing, and analyzed every article for coherence between the objectively and self-reported measured PA. The studies are few, small, and very diverse, both in their use of questionnaires and objective measurements. Self reported assessments were found to generally overestimate the level of PA compared to measurements made objectively by activity monitors; however, more studies are needed to rely solely on the use of PA questionnaires in COPD patients. The most accurate and valid questionnaires appear to be the self completed Physical Activity Scale for the Elderly and the interviewer-completed Stanford Seven-Day Physical Activity Recall Questionnaire, but the ideal questionnaire still awaits construction. The motion sensors are accurate and validated in this patient group, especially SenseWearTM, but not easily accessible in clinical practice, as they have various technical and adhesive difficulties. PMID- 27932874 TI - Bronchodilator response of advanced lung function parameters depending on COPD severity. AB - BACKGROUND: COPD is defined as partly irreversible airflow obstruction. The response pattern of bronchodilators has not been followed in advanced lung function parameters. PURPOSE: The aim of this study was to investigate bronchodilator response pattern in advanced lung function parameters in a continuous fashion along forced expiratory volume in 1 second (FEV1) percent predicted (%p) in COPD patients and controls. PATIENTS AND METHODS: Eighty-one smokers/ex-smokers (41 controls and 40 COPD) performed spirometry, body plethysmography, impulse oscillometry and single-breath helium dilution carbon monoxide diffusion at baseline, after salbutamol inhalation and then after an additional inhalation of ipratropium. RESULTS: Most pulmonary function parameters showed a linear increase in response to decreased FEV1%p. The subjects were divided into groups of FEV1%p <65 and >65, and the findings from continuous analysis were verified. The exceptions to this linear response were inspiratory capacity (IC), forced vital capacity (FVC), FEV1/FVC and expiratory resistance (Rex), which showed a segmented response relationship to FEV1%p. IC and FVC, with break points (BP) of 57 and 58 FEV1%p respectively, showed no response above, but an incresed slope below the BP. In addition, in patients with FEV1%p <65 and >65, response of FEV1%p did not correlate to response of volume parameters. CONCLUSION: Response of several advanced lung function parameters differs depending on patients' baseline FEV1%p, and specifically response of volume parameters is most pronounced in COPD patients with FEV1%p <65. Volume and resistance responses do not follow the flow response measured with FEV1 and may thus be used as a complement to FEV1 reversibility to identify flow, volume and resistance responders. PMID- 27932875 TI - Screening of long non-coding RNA and TUG1 inhibits proliferation with TGF-beta induction in patients with COPD. AB - OBJECTIVE: To evaluate differentially expressed long noncoding RNAs (lncRNAs) and the potential role of lncRNA TUG1 in patients with chronic obstructive pulmonary disease (COPD). METHODS: Total RNA was extracted from both COPD and non-COPD lung tissues, and microarray analysis was performed with 25,628 lncRNA probes and 20,106 mRNA probes. In addition, five up-regulated and five down-regulated lncRNAs were selected for identification using quantitative real-time polymerase chain reaction. COPD cell model was established by transforming growth factor beta (TGF-beta) treatment. Cell Counting Kit-8 assay was used to detect BEAS-2B and HFL1 cell proliferation after TUG-siRNA transfection with TGF-beta treatment. In addition, the expression levels of alpha-SMA and fibronectin proteins were determined using Western blot in BEAS-2B and HFL1 cells after TUG-siRNA transfection with TGF-beta treatment. RESULTS: There were 8,376 (32.7%) differentially expressed lncRNAs and 5,094 (25.3%) differentially expressed mRNAs in COPD lung tissues compared with non-COPD lung tissues. Five of the analyzed lncRNAs (BC038205, BC130595, TUG1, MEG3, and LOC646329) were markedly increased, while five lncRNAs (LOC729178, PLAC2, LOC339529, LINC00229, and SNHG5) were significantly decreased in COPD lung tissues compared with non-COPD lung tissues (n=20) (***P<0.001). Knockdown of lncRNA TUG1 promotes BEAS-2B and HFL1 cell proliferation after TGF-beta treatment through inhibiting the expression levels of alpha-SMA and fibronectin. CONCLUSION: Abundant, differentially expressed lncRNAs and mRNAs were identified by microarray analysis and these might play a partial or key role in the diagnosis of patients with COPD. LncRNA TUG1 may become a very important class of biomarker and may act as a potential diagnostic and therapeutic target for patients with COPD. PMID- 27932876 TI - Effectiveness of neuromuscular electrical stimulation for the rehabilitation of moderate-to-severe COPD: a meta-analysis. AB - PURPOSE: Patients with COPD often experience skeletal muscle dysfunction. For those who are unable or unwilling to undertake physical training, neuromuscular electrical stimulation (NMES) may provide an alternative method of rehabilitation. The purpose of this meta-analysis was to investigate the controversial topic of whether this therapy is effective in patients with moderate-to-severe COPD. PATIENTS AND METHODS: We pooled data from nine trials published between January 9, 2002 and January 4, 2016 across PubMed, Embase, Cochrane Central Register of Controlled Trials, Google Scholar, and relevant websites for randomized controlled trials. In these trials, patients with moderate-to-severe COPD were randomly allocated to receive NMES. Primary outcomes were quadricep strength and exercise capacity. The secondary outcome was health related quality of life. RESULTS: We extracted data from 276 patients. NMES contributed to statistically improved quadricep strength (standardized mean difference 1.12, 95% confidence interval [CI] 0.64-1.59, I2=54%; P<0.00001) and exercise capacity, including longer exercise distance (weighted mean difference 51.53, 95% CI 20.13-82.93, I2=90%; P=0.001), and longer exercise endurance (standardized mean difference 1.11, 95% CI 0.14-2.08, I2=85%; P=0.02). There was no significant difference in St George's Respiratory Questionnaire scores (weighted mean difference -0.07, 95% CI -2.44 to 2.30, I2=56%; P=0.95). CONCLUSION: NMES appears an effectual means of enhancing quadricep strength and exercise capacity in moderate-to-severe COPD patients. Further research is demanded to clarify its effect on other outcomes and determine the optimal parameters for an NMES program. PMID- 27932877 TI - Factors influencing exacerbation-related self-management in patients with COPD: a qualitative study. AB - BACKGROUND: In patients with COPD, self-management skills are important to reduce the impact of exacerbations. However, both detection and adequate response to exacerbations appear to be difficult for some patients. Little is known about the underlying process of exacerbation-related self-management. Therefore, the objective of this study was to identify and explain the underlying process of exacerbation-related self-management behavior. METHODS: A qualitative study using semi-structured in-depth interviews was performed according to the grounded theory approach, following a cyclic process in which data collection and data analysis alternated. Fifteen patients (male n=8; age range 59-88 years) with mild to very severe COPD were recruited from primary and secondary care settings in the Netherlands, in 2015. RESULTS: Several patterns in exacerbation-related self management behavior were identified, and a conceptual model describing factors influencing exacerbation-related self-management was developed. Acceptance, knowledge, experiences with exacerbations, perceived severity of symptoms and social support were important factors influencing exacerbation-related self management. Specific factors influencing recognition of exacerbations were heterogeneity of exacerbations and habituation to symptoms. Feelings of fear, perceived influence on exacerbation course, patient beliefs, ambivalence toward treatment, trust in health care providers and self-empowerment were identified as specific factors influencing self-management actions. CONCLUSION: This study provided insight into factors influencing exacerbation-related self-management behavior in COPD patients. The conceptual model can be used as a framework for health care professionals providing self-management support. In the development of future self-management interventions, factors influencing the process of exacerbation-related self-management should be taken into account. PMID- 27932878 TI - The effect of exposure to nanoparticles and nanomaterials on the mammalian epigenome. AB - Human exposure to nanomaterials and nanoparticles is increasing rapidly, but their effects on human health are still largely unknown. Epigenetic modifications are attracting ever more interest as possible underlying molecular mechanisms of gene-environment interactions, highlighting them as potential molecular targets following exposure to nanomaterials and nanoparticles. Interestingly, recent research has identified changes in DNA methylation, histone post-translational modifications, and noncoding RNAs in mammalian cells exposed to nanomaterials and nanoparticles. However, the challenge for the future will be to determine the molecular pathways driving these epigenetic alterations, the possible functional consequences, and the potential effects on health. PMID- 27932879 TI - Study of a new bone-targeting titanium implant-bone interface. AB - New strategies involving bone-targeting titanium (Ti) implant-bone interface are required to enhance bone regeneration and osseointegration for orthopedic and dental implants, especially in osteoporotic subjects. In this study, a new dual controlled, local, bone-targeting delivery system was successfully constructed by loading tetracycline-grafted simvastatin (SV)-loaded polymeric micelles in titania nanotube (TNT) arrays, and a bone-targeting Ti implant-bone interface was also successfully constructed by implanting the delivery system in vivo. The biological effects were evaluated both in vitro and in vivo. The results showed that Ti surfaces with TNT-bone-targeting micelles could promote cytoskeletal spreading, early adhesion, alkaline phosphatase activity, and extracellular osteocalcin concentrations of rat osteoblasts, with concomitant enhanced protein expression of bone morphogenetic protein (BMP)-2. A single-wall bone-defect implant model was established in normal and ovariectomized rats as postmenopausal osteoporosis models. Microcomputed tomography imaging and BMP-2 expression in vivo demonstrated that the implant with a TNT-targeting micelle surface was able to promote bone regeneration and osseointegration in both animal models. Therefore, beneficial biological effects were demonstrated both in vitro and in vivo, which indicated that the bone-targeting effects of micelles greatly enhance the bioavailability of SV on the implant-bone interface, and the provision of SV loaded targeting micelles alone exhibits the potential for extensive application in improving local bone regeneration and osseointegration, especially in osteoporotic subjects. PMID- 27932880 TI - Hydrothermal synthesis of nitrogen-doped carbon dots with real-time live-cell imaging and blood-brain barrier penetration capabilities. AB - Nitrogen-doped carbon dots (N-CDs) were synthesized using a one-pot hydrothermal treatment with citric acid in the presence of polyethylenimine. Transmission electron microscopy analysis revealed that the N-CDs were monodispersed and quasi spherical with an average size of ~2.6 nm. Under ultraviolet irradiation the N CDs emitted a strong blue luminescence with a quantum yield as high as 51%. Moreover, the N-CDs exhibited a negligible cytotoxicity and could be applied as efficient nanoprobes for real-time imaging of live cells. In addition, the ability of the N-CDs to cross the blood-brain barrier (BBB) in a concentration dependent manner was demonstrated using an in vitro BBB model. Therefore, these PEI-passivated N-CDs with real-time live-cell imaging and BBB-penetration capabilities hold promise for traceable drug delivery to the brain. PMID- 27932882 TI - Sustained-release liquisolid compact tablets containing artemether-lumefantrine as alternate-day regimen for malaria treatment to improve patient compliance. AB - The present study aimed to develop low-dose liquisolid tablets of two antimalarial drugs artemether-lumefantrine (AL) from a nanostructured lipid carrier (NLC) of lumefantrine (LUM) and estimate the potential of AL as an oral delivery system in malariogenic Wistar mice. LUM-NLCs were prepared by hot homogenization using Precirol(r) ATO 5/Transcutol(r) HP and tallow fat/Transcutol(r) HP optimized systems containing 3:1 ratios of the lipids, respectively, as the matrices. LUM-NLC characteristics, including morphology, particle size, zeta potential, encapsulation efficiency, yield, pH-dependent stability, and interaction studies, were investigated. Optimized LUM-NLCs were mixed with artemether powder and other dry ingredients and the resultant powder evaluated for micromeritics. Subsequent AL liquisolid tablets were tested for in vitro drug release and in vivo antiplasmodial activity in mice infected with Plasmodium berghei berghei (NK 65). Results showed that optimized LUM-NLC were stable, spherical, polydispersed but nanometric. Percentage yield and encapsulation efficiency were ~92% and 93% for Precirol(r) ATO 5/Transcutol(r) HP batch, then 81% and 95% for tallow fat/Transcutol(r) HP batch while LUM was amorphous in NLC matrix. In vitro AL release from liquisolid compacts revealed initial burst release and subsequent sustained release. Liquisolid tablet compacts formulated with Precirol(r) ATO 5/Transcutol(r) HP-AL4 achieved higher LUM release in simulated intestinal fluid (84.32%) than tallow fat/Transcutol(r) HP-BL3 (77.9%). Non-Fickian (anomalous) diffusion and super case II transport were the predominant mechanisms of drug release. Equal parasitemia reduction was observed for both batches of tablet compacts (~92%), superior to the reduction obtained with commercial antimalarial formulations: Coartem(r) tablets (86%) and chloroquine phosphate tablets (66%). No significant difference (P<0.05) in parasite reduction between double (4/24 mg/kg) and single (2/12 mg/kg) strength doses of AL compacts was observed. Our result highlights that AL could be formulated in much lower doses (4/24 mg/kg), for once-in-two days oral administration to improve patient compliance, which is currently not obtainable with conventional AL dosage forms. PMID- 27932883 TI - Functional cortical changes in relapsing-remitting multiple sclerosis at amplitude configuration: a resting-state fMRI study. AB - OBJECTIVE: The aim of this study was to explore the amplitude of spontaneous brain activity fluctuations in patients with relapsing-remitting multiple sclerosis (RRMS) using the amplitude of low-frequency fluctuation (ALFF) method. METHODS: ALFF and SPM8 were utilized to assess alterations in regional spontaneous brain activities in patients with RRMS in comparison with healthy controls (HCs). The beta values of altered brain regions between patients with RRMS and HCs were extracted, and a receiver operating characteristic (ROC) curve was generated to calculate the sensitivities and specificities of these different brain areas for distinguishing patients with RRMS from HCs. Pearson correlation analyses were applied to assess the relationships between the beta values of altered brain regions and disease duration and Expanded Disability Status Scale (EDSS) score. PATIENTS AND PARTICIPANTS: A total of 18 patients with RRMS (13 females; five males) and 18 sex-, age-, and education-matched HCs (14 females; four males) were recruited for this study. MEASUREMENTS AND RESULTS: Compared with HCs, patients with RRMS showed higher ALFF responses in the right fusiform gyrus (Brodmann area [BA] 37) and lower ALFF responses in the bilateral anterior cingulate cortices (BA 24 and 32), bilateral heads of the caudate nuclei, and bilateral brainstem. The ROC analysis revealed that the beta values of these abnormal brain areas showed high degrees of sensitivity and specificity for distinguishing patients with RRMS from HCs. The EDSS score showed a significant negative Pearson correlation with the beta value of the caudate head (r=-0.474, P=0.047). CONCLUSION: RRMS is associated with disturbances in spontaneous regional brain activity in specific areas, and these specific abnormalities may provide important information about the neural mechanisms underlying behavioral impairment in RRMS. PMID- 27932881 TI - Preparation and antitumor evaluation of self-assembling oleanolic acid-loaded Pluronic P105/d-alpha-tocopheryl polyethylene glycol succinate mixed micelles for non-small-cell lung cancer treatment. AB - Oleanolic acid (OA) is a triterpenoid found in various fruits and vegetables and used in traditional Chinese medicine. OA plays a crucial role in the treatment of several cancers, but poor water solubility, low permeability, and significant efflux have limited its widespread clinical use. Vitamin E-d-alpha-tocopheryl polyethylene glycol succinate (vitamin E-TPGS) and Pluronic P105 were used to improve the solubility and permeability and to decrease the efflux of OA. OA loaded mixed micelles were prepared by ethanol thin-film hydration. The physicochemical properties of the micelles, including zeta potential, morphology, particle size, solubility, drug loading, and drug entrapment efficiency were characterized. OA release from micelles was slower than that from the free drug system. OA uptake by A549 non-small-cell lung cancer (NSCLC) cells was enhanced by the micelles. A tumor model was established by injecting A549 cells into nude mice. In vivo imaging showed that OA-micelles could accumulate in the tumors of nude mice. Additionally, smaller tumor size and increased expression of pro apoptotic proteins were observed in OA-micelle-treated mice, indicating that OA micelles are more effective than free OA in treating cancer. In vitro experiments were performed using two NSCLC cell lines (A549 and PC-9). Cytotoxicity evaluations showed that the half-maximal inhibitory concentrations of free OA and OA-micelles were 36.8+/-4.8 and 20.9+/-3.7 MUM, respectively, in A549 cells and 82.7+/-7.8 and 56.7+/-4.7 MUM, respectively, in PC-9 cells. Apoptosis assays revealed that the apoptotic rate of OA-micelle-treated A549 and PC-9 cells was higher than that of cells treated with the same concentration of free OA. Wound healing and transwell assays showed that migration and invasion were significantly suppressed in OA-micelle-treated cells. Immunofluorescence and Western blot analyses confirmed that the epithelial-mesenchymal transition was reversed in OA-micelle-treated cells. Mixed micelles are a promising nano-drug delivery system for lung cancer treatment. PMID- 27932884 TI - A randomized trial of aripiprazole vs blonanserin for the treatment of acute schizophrenia and related disorders. AB - OBJECTIVE: There has been no direct comparison of aripiprazole and blonanserin for schizophrenia treatment. We conducted a 24-week, rater-masked, randomized trial of aripiprazole (6-30 mg/d) vs blonanserin (4-24 mg/d) in schizophrenia patients who were not taking any antipsychotic medication for more than 2 weeks before enrollment (UMIN000011194). METHODS: The primary outcome measure for efficacy was improvement of Positive and Negative Syndrome Scale (PANSS) total score at week 24. Secondary outcomes were PANSS subscale scores, 21-item Hamilton Rating Scale for Depression (HAMD-21) score, response rate, discontinuation rate, and individual adverse events. RESULTS: Forty-four patients were recruited. The discontinuation rate was 86.4% in the aripiprazole group and 68.2% in the blonanserin treatment group. There was no significant difference in mean time to discontinuation between the groups. Although both treatment groups showed significant reductions in the PANSS total score, PANSS subscale scores, and HAMD 21 scores at week 24, the magnitudes of the changes did not differ between the groups. There were no significant differences in the incidences of adverse events including somnolence, extrapyramidal symptoms, prolactin-related adverse events, and weight change between the groups. CONCLUSION: Our results suggest similar efficacy and safety profiles of aripiprazole and blonanserin in the patients with schizophrenia. Double-blind controlled studies are needed to further explore the efficacy and safety of aripiprazole and blonanserin in schizophrenia. PMID- 27932885 TI - Health behaviors of patients diagnosed with type 2 diabetes mellitus and their influence on the patients' satisfaction with life. AB - BACKGROUND: The diagnosis of type 2 diabetes mellitus (T2DM) carries with it a number of changes to the patient's lifestyle. A healthy lifestyle, health and preventive behaviors, as well as healthy nutrition habits play a key role in treating T2DM as well as limiting its complications. MATERIALS AND METHODS: The aim of this study was the analysis of the correlation of T2DM patients' health behaviors and their influence on the patients' quality of life. The study was performed on a group of 50 patients from the Kuyavian-Pomeranian Voivodeship. In this study, the Health Behavior Inventory and the Satisfaction with Life Scale were used. The results were statistically analyzed. The study was approved by the ethics committee. RESULTS: The intensity of severity of health behavior and satisfaction with life of T2DM patients depends on the gender of the patient (P<0.05). The analysis of the patients' behaviors in four categories, proper eating habits (consuming vegetables, fruit, whole meal bread), health practices (daily physical activity, recreation, sleeping habits), preventive behaviors (including keeping to health recommendations), and positive mental attitude, showed substantial correlation of the Health Behavior Inventory and the Satisfaction with Life Scale (P<0.05). CONCLUSION: The categorization of the prohealth behaviors shown by diabetics allowed us to measure the connection between the individual categories of satisfaction with life. Males with T2DM showed a higher satisfaction with life score than females with the same diagnosis. The analysis showed that patients with a higher intensity of health behaviors also had superior health behaviors. The resulting correlations prove a notable relationship. PMID- 27932886 TI - Comparative efficacy of bilastine, levocetirizine and desloratadine updosing in chronic urticaria. PMID- 27932887 TI - Role of anuria in the relationship between indoxyl sulfate and anemia in peritoneal dialysis patients. AB - BACKGROUND: Experimental evidence suggests that indoxyl sulfate (IS) is associated with chronic kidney disease-related anemia. However, clinical studies are limited, and few have explored the potential confounding effect of anuria. This study, thus, evaluated the association between IS and anemia in both non anuric and anuric peritoneal dialysis (PD) patients. METHODS: This cross sectional and observational study included 165 chronic PD patients aged 19-84 years. Their serum IS levels in total and free forms were measured by ultra performance liquid chromatography. Correlations between serum IS and hemoglobin (Hb) were performed in both non-anuric and anuric groups. RESULTS: Among the study subjects, 90 were non-anuric and 75 were anuric. As a whole, there was no correlation between IS and Hb. Nonetheless, subsequent analysis of the non-anuric patients showed that Hb is negatively correlated with IS levels (rs =-0.405, P<0.001 for total form and rs =-0.296, P=0.005 for free form). Factors that significantly affected Hb levels in the stepwise multiple regression analysis include total IS and iron saturation. In contrast for anuric patients, serum ferritin, albumin, iron saturation, use of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, but not serum IS, were predictors for anemia in the multiple regression model. CONCLUSIONS: Serum IS is associated with an increased severity of anemia in non-anuric PD patients and not in anuric ones, indicating anuria could be a confounding factor in such association. PMID- 27932888 TI - Preoperative risk factors in total thyroidectomy of substernal goiter. AB - The definition of substernal goiter (SG) is based on variable criteria leading to a considerable variation in the reported incidence (from 0.2% to 45%). The peri- and postoperative complications are higher in total thyroidectomy (TT) for SG than that for cervical goiter. The aim of this study was to evaluate the preoperative risk factors associated with postoperative complications. From 2002 to 2014, 142 (8.5%; 98 women and 44 men) of the 1690 patients who underwent TT had a SG. We retrospectively evaluated the following parameters: sex, age, histology, pre- and retrovascular position, recurrence, and extension beyond the carina. These parameters were then related to the postoperative complications: seroma/hematoma, transient and permanent hypocalcemia, transient and permanent laryngeal nerve palsy, and the length of surgery. The results were further compared with a control group of 120 patients operated on in the same period with TT for cervical goiter. All but two procedures were terminated via cervicotomy, where partial sternotomies were required. No perioperative mortality was observed. Results of the statistical analysis (Student's t-test and Fisher's exact test) indicated an association between recurrence and extension beyond the carina with all postoperative complications. The group that underwent TT of SG showed a statistically significant higher risk for transient hypocalcemia (relative risk =1.767 with 95% confidence interval: 1.131-2.7605, P=0.0124, and need to treat =7.1) and a trend toward significance for transient recurrent laryngeal nerve palsy (relative risk =6.7806 with 95% confidence interval: 0.8577 53.2898, P=0.0696, and need to treat =20.8) compared to the group that underwent TT of cervical goiter. TT is the procedure to perform in SG even if the incidence of complications is higher than for cervical goiters. The major risk factors associated with postoperative complications are recurrence and extension beyond the carina. In the presence of these factors, greater care should be taken. PMID- 27932889 TI - Alveolar rhabdomyosarcoma of the sphenoid sinus mimicking optic neuritis presenting with intermittent visual loss in an adult. AB - A 23-year-old male with intermittent visual loss in his left eye for 4 months was originally treated as optic neuritis elsewhere. Upon presentation to our hospital (Beijing Tongren Hospital), his left eye visual acuity was reduced to hand motion at face. The left eye ocular motility was limited in upgaze, downgaze, adduction, and abduction. Computed tomography and magnetic resonance imaging revealed lesions in the sphenoid and ethmoid sinuses, orbital apex and carvernous sinus invading adjacent extraocular muscles. Endoscopic ethmo-sphenoidostomy and debulking surgery was performed and histopathology of the specimen demonstrated alveolar rhabdomyosarcoma. Despite having treatment with a combination of orbital radiation therapy and systemic chemotherapy, the patient developed generalized metastasis with cachexia and the left eye became no light perception due to optic atrophy. PMID- 27932890 TI - High expression of HMGA2 predicts poor survival in patients with clear cell renal cell carcinoma. AB - High-mobility group AT-hook 2 (HMGA2) is involved in a wide spectrum of biological processes and is upregulated in several tumors, but its role in renal carcinoma remains unclear. The aim of this study was to examine the expression of HMGA2 and its relationship to the overall survival (OS) of patients with non metastatic clear cell renal cell carcinoma (ccRCC) following surgery. The expression of HMGA2 was evaluated retrospectively by immunohistochemistry (IHC) in 162 patients with ccRCC who underwent nephrectomy in 2003 and 2004. An IHC analysis revealed that HMGA2 was expressed in the nuclei of tumor cells in 146 (90.1%) patients with ccRCC. The level of HMGA2 was positively correlated with tumor size, lymph node metastasis, and Fuhrman Grade. A Kaplan-Meier analysis with log-rank test found that patients with high HMGA2 expression had a poor outcome and that patients with low HMGA2 expression had better survival. Cox regression analysis showed that HMGA2 expression could serve as an independent prognostic factor for ccRCC patients. The efficacy of the following prognostic models was improved when HMGA2 expression was added: tumor node metastasis stage, UCLA Integrated Scoring System, Mayo Clinic stage, size, grade, and necrosis score. In summary, this study showed that HMGA2 expression is an independent prognostic factor for OS in patients with ccRCC. HMGA2 was found to be a valuable biomarker for ccRCC progression. PMID- 27932891 TI - Trastuzumab in the management of gastroesophageal cancer: patient selection and perspectives. AB - The addition of trastuzumab to the treatment of a subset of patients with advanced gastric and gastroesophageal junction cancers showing HER2 positivity has been shown to confer clinical benefit; however, questions remain over the optimal methods for defining and selecting such patients. This review provides an overview of current standards for assessing HER2 positivity, the evolving treatment landscape for HER2-positive gastric and esophageal cancers and the challenges and potential future directions in optimal patient selection for HER2 targeted therapy. PMID- 27932892 TI - The evolution of the diminishing role of extrapleural pneumonectomy in the surgical management of malignant pleural mesothelioma. AB - Malignant pleural mesothelioma is an uncommon and aggressive thoracic malignancy that is rarely curable, even when multimodality therapy is used. Systemic chemotherapy is the primary treatment for the majority of patients with this disease; however, surgical resection may benefit a subset of patients with early stage disease. The surgical approach that offers the best outcomes remains an area of controversy, with data from retrospective comparisons being the only guide. Historically, extrapleural pneumonectomy (EPP) has been the standard procedure, carrying with it a cost of significant morbidity and impact on quality of life that has raised questions regarding its routine application. Over the past two decades as surgical techniques have been refined and survival data with EPP in large case series have been reported, the paradigm has evolved toward the use of lung-sparing pleural resections such as pleurectomy/decortication (P/D) and extended P/D. The identification of patients who may benefit from EPP over pleurectomy has proven problematic, and the larger question regarding the impact of any type of surgical intervention on outcomes for pleural mesothelioma patients is still an area of investigation. Uniform treatment approaches have been difficult to develop due to the relatively small numbers of patients with this disease, the use of a staging system that does not readily identify those who may benefit from more aggressive therapy, and the institutional biases that have resulted from the growth of multimodality centers of excellence. PMID- 27932893 TI - Let-7a enhances the sensitivity of hepatocellular carcinoma cells to cetuximab by regulating STAT3 expression. AB - BACKGROUND: Let-7 miRNAs are reported to play an inhibitory role in carcinogenesis, tumor progression, recurrence, and pluripotency of cancer. However, few studies have reported the relationship between let-7 and drug sensitivity, especially for let-7a (a subtype of let-7). This study aimed to investigate the function of let-7a in regulating the sensitivity of hepatocellular carcinoma (HCC) cell lines to cetuximab. METHODS: The cytotoxicity of cetuximab on HCC cell lines (Huh7, Hep3B, HepG2, SNU449, and SNU387) was evaluated using a cell viability assay (the Cell Counting Kit-8 assay) and a cell proliferation assay (the Click-iT EdU Imaging Kit) in the presence of a control, a let-7a mimic, and a let-7a inhibitor. Small interfering RNA to knockdown the expression of signal transducer and activator of transcription 3 (STAT3) were employed. Protein and mRNA expression levels were determined using quantitative polymerase chain reaction and Western blot analysis. RESULTS: It was found that let-7a enhances the sensitivity of HCC cells with an epithelial phenotype (Huh7, Hep3B, and HepG2) to cetuximab, but has no effect on cells with the mesenchymal phenotype (SNU449 and SNU387). It was determined that STAT3 was a target mRNA of let-7a using TargetScan. Expression of STAT3 and let-7a mRNA were negatively correlated in HCC cell lines. Moreover, let-7a altered the protein and mRNA expression of STAT3. Furthermore, STAT3 knockdown enhanced the function of cetuximab on HCC cell lines with epithelial phenotypes, but not on HCC cell lines with mesenchymal phenotypes. Finally, a rescue experiment confirmed that let-7a affected the sensitivity of HCC cell lines to cetuximab by interacting with STAT3. CONCLUSIONS: There is a functional link between let-7a and STAT3 in enhancing the sensitivity of HCC cells with an epithelial phenotype to cetuximab. Our results provide novel insight into new methodologies for combating HCC drug resistance. PMID- 27932894 TI - Effects of parecoxib on postoperative pain and opioid-related symptoms following gynecologic surgery. AB - OBJECTIVE: To examine the analgesic and opioid-sparing effects of parecoxib following major gynecologic surgery. METHODS: This is a large subset analysis of patients from a multicenter, randomized, double-blind, placebo-controlled study of parecoxib/valdecoxib (PAR/VAL) for postoperative pain. Pain severity, pain interference with function, opioid use, occurrence of opioid-related symptoms, and Patient/Physician Global Evaluation of Study Medication were compared between placebo and PAR/VAL treatment groups in the days following surgery. RESULTS: Pain scores were reduced in the PAR/VAL group (n=98), relative to placebo (n=97), on Day 2 (-21%, P<0.001) and Day 3 (-23%, P=0.004). Pain interference with function scores were also significantly lower in the PAR/VAL group, compared with placebo, on Day 2 (-29%, P<0.001) and Day 3 (-28%, P=0.013). Consumption of supplemental morphine was significantly lower in the PAR/VAL group relative to placebo at 24 hours (-37%, P=0.010) and trended lower at 48 (-28%) and 72 hours (-26%). Patients in the PAR/VAL group also had a reduced risk of experiencing specific opioid-related symptoms, including "inability to concentrate" (relative risk =0.53) and "nausea" (relative risk =0.60) on Day 2. Both Patient and Physician Global Evaluation of Study Medication scores were better in the PAR/VAL group than in the placebo group. CONCLUSION: The current study adds support for the use of parecoxib in patients following major gynecologic surgery. PMID- 27932896 TI - Involvement of spinal glutamate transporter-1 in the development of mechanical allodynia and hyperalgesia associated with type 2 diabetes. AB - Little is known about the effects of the development of type 2 diabetes on glutamate homeostasis in the spinal cord. Therefore, we quantified the extracellular levels of glutamate in the spinal cord of Zucker diabetic fatty (ZDF) rats using in vivo microdialysis. In addition, protein levels of glutamate transporter-1 (GLT-1) in the spinal cord of ZDF rats were measured using Western blot. Finally, the effects of repeated intrathecal injections of ceftriaxone, which was previously shown to enhance GLT-1 expression, on the development of mechanical allodynia and hyperalgesia as well as on basal extracellular level of glutamate and the expression of GLT-1 in the spinal cord of ZDF rats were evaluated. It was found that ZDF rats developed mechanical hyperalgesia and allodynia, which were associated with increased basal extracellular levels of glutamate and attenuated levels of GLT-1 expression in the spinal cord, particularly in the dorsal horn. Furthermore, repeated intrathecal administrations of ceftriaxone dose-dependently prevented the development of mechanical hyperalgesia and allodynia in ZDF rats, which were correlated with enhanced GLT-1 expression without altering the basal glutamate levels in the spinal cord of ZDF rats. Overall, the results suggested that impaired glutamate reuptake in the spinal cord may contribute to the development of neuropathic pains in type 2 diabetes. PMID- 27932895 TI - Are patients' and doctors' accounts of the first specialist consultation for chronic back pain in agreement? AB - INTRODUCTION: The first consultation at a specialist pain clinic is potentially a pivotal event in a patient's pain history, affecting treatment adherence and engagement with longer term self-management. What doctors communicate to patients about their chronic pain and how patients interpret doctors' messages and explanations in pain consultations are under-investigated, particularly in specialist care. Yet, patients value personalized information about their pain problem. PATIENTS AND METHODS: Sixteen patients in their first specialist pain clinic consultation and the doctors they consulted were interviewed shortly after the consultation. Framework analysis, using patient themes, was used to identify full match, partial match, or mismatch of patient-doctor dyads' understandings of the consultation messages. RESULTS: Patients and doctors agreed, mainly implicitly, that medical treatment aiming at pain relief was primary and little time was devoted to discussion of self-management. Clinically relevant areas of mismatch included the explanation of pain, the likelihood of medical treatments providing relief, the long-term treatment plan, and the extent to which patients were expected to be active in achieving treatment goals. DISCUSSION: Overall, there appears to be reasonable concordance between doctors and patients, and patients were generally satisfied with their first consultation with a specialist. Two topics showed substantial mismatch, the estimated likely outcome of the next planned intervention and, assuming (as doctors but not patients did) that this was unsuccessful, the long-term treatment plan. It appeared that more complex issues often generate divergence of understanding or agreement. Despite the widespread recommendations to medical practitioners to check patients' understanding directly, it does not appear to be routine practice. CONCLUSION: It is hoped that this research encourages more detailed examination of shared and divergent experiences of pain consultations and also their influence on the subsequent course of intervention and adherence to treatment (not addressed here). PMID- 27932897 TI - Effect of ovarian endometrioma on uterine and ovarian blood flow in infertile women. AB - BACKGROUND: Angiogenesis has been found to be among the most important factors in the pathogenesis of endometriosis. The formation of new blood vessels is critical for the survival of newly implanted endometriotic foci. The use of 3-D power Doppler allows for the demonstration of the dynamic vascular changes that occur during the process of in vitro fertilization (IVF). We aimed to evaluate the effect of ovarian endometrioma on uterine and ovarian blood flow in infertile women. MATERIALS AND METHODS: In a case-control study at a university teaching hospital, 138 women with unilateral ovarian endometrioma scheduled for IVF were compared to 138 women with male-factor or unexplained infertility. In the mid luteal (peri-implantation) phase of the cycle, endometrial thickness, uterine and ovarian artery pulsatility index and resistance index, endometrial and ovarian volume, 3-D power Doppler vascularization index (VI), flow index (FI), and vascularization FI (VFI) values were measured in both groups. RESULTS: There were no significant differences (P>0.05) in endometrial thickness, uterine ovarian artery pulsatility index and resistance index, endometrial and ovarian volume, or VI, FI, and VFI between the two groups. Furthermore, the endometrial and ovarian Doppler indices were not influenced by endometrioma size. No significant differences were observed in the ovarian Doppler indices between endometrioma containing ovaries and contralateral ovaries. CONCLUSION: Ovarian endometrioma is not associated with impaired endometrial and ovarian blood flows in infertile women scheduled for IVF, and it is not likely to affect endometrial receptivity or ovarian function through a vascular mechanism. PMID- 27932898 TI - Two cases of Vogt-Koyanagi-Harada's disease in sub-Saharan Africa. AB - Vogt-Koyanagi-Harada's (VKH) disease has been reported to be rare in sub-Saharan Africa. Two Nigerians with the disease are presented in this report. The first patient, a 32-year-old pregnant Nigerian woman presented with a 1-month history of bilateral blurring of vision, persistent headache, and alopecia. Presenting visual acuity was 1 m counting fingers in both eyes. Examination revealed vitiligo and poliosis with bilateral panuveitis as well as bilateral exudative retinal detachment. A clinical assessment of complete VKH disease was made. The patient commenced systemic and topical steroids that resulted in remarkable recovery of vision and control of inflammation. The second patient, a 56-year-old Nigerian woman presented with severe headache, tinnitus, and visual loss in both eyes of 2 weeks duration. There was associated redness of both eyes and photophobia. Examination showed visual acuity of Hand motion (HM) and counting fingers at 1 meter (CF). in the right and left eye, respectively, with bilateral panuveitis and bilateral exudative retinal detachment. Subsequent follow-up showed poliosis, vitiligo, and sunsetting fundus appearance. The patient improved with systemic and topical corticosteroids. Developing a high index of suspicion is necessary in diagnosing VKH disease, even in sub-Saharan Africa. Prompt institution of appropriate treatment prevents blindness. PMID- 27932899 TI - Sudden Cardiac Death of a Body Packer Due to Cocaine Cardiotoxicity. AB - This article presents a case of sudden cardiac death due to the effects of cocaine concealed in the body of a male drug smuggler in his 40s, a so-called body packer. A total of 57 body packets filled with cocaine powder were discovered in his body cavities. The detailed autopsy examination, including histopathology and toxicology findings, is discussed with the aim of describing the mechanism of cocaine intoxication in the body packer and an analysis of cocaine-induced cardiotoxicity and sudden death. PMID- 27932900 TI - A student's perspective: are medical students adequately trained in BLS? PMID- 27932901 TI - ReefMedMol: Mollusca from the infralittoral rocky shores - the biocoenosis of photophilic algae - in the Mediterranean Sea. AB - BACKGROUND: This paper describes two datasets on the molluscan fauna from the Mediterranean infralittoral reef ecosystem - the biocoenosis of photophilic algae. The first dataset is taken from the East Mediterranean node of the NAGISA project. The second one is a compilation based on the available published material in peer - reviewed journals as well as from the accessible grey literature. These datasets cover a time period of 43 years from 1969 to 2012 from several locations spanning the Mediterranean Sea. NEW INFORMATION: This dataset is the only one available from this important Mediterranean Habitat, coded as 1170 in the Habitats Directive (92/43/EEC) and can provide valuable information on the needs of ecosystems functions and services assessment, habitat and species conservation as well as marine spatial planning. PMID- 27932902 TI - Introduction to the Greek Taxon Information System (GTIS) in LifeWatchGreece: the construction of the Preliminary Checklists of Species of Greece. PMID- 27932903 TI - Porifera of Greece: an updated checklist. AB - BACKGROUND: The checklist of Porifera of Greece was created in the framework of the Greek Taxon Information System (GTIS), an initiative of the LifeWatchGreece Research Infrastructure (ESFRI) that has resumed efforts to compile a complete checklist of species recorded from Greece. An updated checklist of Porifera was created on the basis of a list of the Aegean Demospongiae and Homoscleromorpha published one decade ago. All records of species known to occur in Greek waters were taxonomically validated and cross-checked for possible inaccuracies and omissions. Then, all recent publications were reviewed and the species recorded from 2006 to date were added to the list. NEW INFORMATION: The updated checklist of Porifera of Greece comprises 215 species, classified to 111 genera, 65 families, 24 orders, and 4 classes. In total, 34 new additions were made to the previous species list (8 Calcarea, 17 Demospongiae, 1 Hexactinellida, and 6 Homoscleromorpha) with Calcarea being listed for the first time from the area. The demosponge orders Poecilosclerida, Dictyoceratida, Tetractinellida, Haplosclerida, and Suberitida have the highest number of species covering 62% of the known Greek sponge species richness. It is worth mentioning that 8 species have been first described from Greek waters, 7 of which are considered endemic to this area. Our bibliographic overview also revealed knowledge gaps with regard to specific habitats typically rich in sponge diversity, and marine sectors of Greece. PMID- 27932904 TI - Brachiopoda of Greece: an annotated checklist. AB - BACKGROUND: Until today, only scattered species records of Brachiopoda from Greece have been included in publications on the Mediterranean brachiopod fauna. These records were mostly based on material collected during marine expeditions in the eastern Mediterranean decades ago, while few recent additional records appear in ecological studies. The aim of this paper was to give the first checklist of brachiopod species of Greece, in the framework of the Greek Taxon Information System (GTIS) initiative of the LifeWatchGreece Research Infrastructure (ESFRI), by reviewing the existing literature. NEW INFORMATION: Twelve brachiopod species have been found in Greek waters so far. The nomenclature, distribution, fossil records, ecology, and literature sources are discussed for each species. PMID- 27932905 TI - Macrofaunal assemblages associated with the sponge Sarcotragus foetidus Schmidt, 1862 (Porifera: Demospongiae) at the coasts of Cyprus and Greece. AB - BACKGROUND: This paper describes a dataset of macrofaunal organisms associated with the sponge Sarcotragus foetidus Schmidt, 1862, collected by scuba diving from two sampling sites: one in Greece (North Aegean Sea) and one in Cyprus (Levantine Sea). NEW INFORMATION: This dataset includes macrofaunal taxa inhabiting the demosponge Sarcotragus foetidus and contributes to the ongoing efforts of the Ocean Biogeographic Information System (OBIS) which aims at filling the gaps in our current knowledge of the world's oceans. This is the first paper, to our knowledge, where the macrofauna associated with S. foetidus from the Levantine Basin is being recorded. In total, 90 taxa were recorded, from which 83 were identified to the species level. Eight of these species are new records for the Levantine Basin. The dataset contains 213 occurrence records, fully annotated with all required metadata. It is accessible at http://lifewww 00.her.hcmr.gr:8080/medobis/resource.do?r=organismic_assemblages_sarcotragus_foet dus_cyprus_greece. PMID- 27932906 TI - Environmental variability and heavy metal concentrations from five lagoons in the Ionian Sea (Amvrakikos Gulf, W Greece). AB - BACKGROUND: Coastal lagoons are ecosystems of major importance as they host a number of species tolerant to disturbances and they are highly productive. Therefore, these ecosystems should be protected to ensure stability and resilience. The lagoons of Amvrakikos Gulf form one of the most important lagoonal complexes in Greece. The optimal ecological status of these lagoons is crucial for the well-being of the biodiversity and the economic prosperity of the local communities. Thus, monitoring of the area is necessary to detect possible sources of disturbance and restore stability. NEW INFORMATION: The environmental variables and heavy metals concentrations, from five lagoons of Amvrakikos Gulf were measured from seasonal samplings and compared to the findings of previous studies in the area, in order to check for possible sources of disturbance. The analysis, showed that i) the values of the abiotic parameters vary with time (season), space (lagoon) and with space over time; ii) the variability of the environmental factors and enrichment in certain elements is naturally induced and no source of contamination is detected in the lagoons. PMID- 27932907 TI - Optimized R functions for analysis of ecological community data using the R virtual laboratory (RvLab). AB - BACKGROUND: Parallel data manipulation using R has previously been addressed by members of the R community, however most of these studies produce ad hoc solutions that are not readily available to the average R user. Our targeted users, ranging from the expert ecologist/microbiologists to computational biologists, often experience difficulties in finding optimal ways to exploit the full capacity of their computational resources. In addition, improving performance of commonly used R scripts becomes increasingly difficult especially with large datasets. Furthermore, the implementations described here can be of significant interest to expert bioinformaticians or R developers. Therefore, our goals can be summarized as: (i) description of a complete methodology for the analysis of large datasets by combining capabilities of diverse R packages, (ii) presentation of their application through a virtual R laboratory (RvLab) that makes execution of complex functions and visualization of results easy and readily available to the end-user. NEW INFORMATION: In this paper, the novelty stems from implementations of parallel methodologies which rely on the processing of data on different levels of abstraction and the availability of these processes through an integrated portal. Parallel implementation R packages, such as the pbdMPI (Programming with Big Data - Interface to MPI) package, are used to implement Single Program Multiple Data (SPMD) parallelization on primitive mathematical operations, allowing for interplay with functions of the vegan package. The dplyr and RPostgreSQL R packages are further integrated offering connections to dataframe like objects (databases) as secondary storage solutions whenever memory demands exceed available RAM resources. The RvLab is running on a PC cluster, using version 3.1.2 (2014-10-31) on a x86_64-pc-linux-gnu (64-bit) platform, and offers an intuitive virtual environmet interface enabling users to perform analysis of ecological and microbial communities based on optimized vegan functions. A beta version of the RvLab is available after registration at: https://portal.lifewatchgreece.eu/. PMID- 27932908 TI - LifeWatch Greece data-services: Discovering Biodiversity Data using Semantic Web Technologies. AB - BACKGROUND: Biodiversity data is characterized by its cross-disciplinary character, the extremely broad range of data types and structures, and the variety of semantic concepts that it encompasses. Furthermore there is a plethora of different data sources providing resources for the same piece of information in a heterogeneous way. Even if we restrict our attention to Greek biodiversity domain, it is easy to see that biodiversity data remains unconnected and widely distributed among different sources. NEW INFORMATION: To cope with these issues, in the context of the LifeWatch Greece project, i) we supported cataloguing and publishing of all the relevant metadata information of the Greek biodiversity domain, ii) we integrated data from heterogeneous sources by supporting the definitions of appropriate models, iii) we provided means for efficiently discovering biodiversity data of interest and iv) we enabled the answering of complex queries that could not be answered from the individual sources. This work has been exploited, evaluated and scientificaly confirmed by the biodiversity community through the services provided by the LifeWatch Greece portal. PMID- 27932910 TI - Ascidiacea (Chordata: Tunicata) of Greece: an updated checklist. AB - BACKGROUND: The checklist of the ascidian fauna (Tunicata: Ascidiacea) of Greece was compiled within the framework of the Greek Taxon Information System (GTIS), an application of the LifeWatchGreece Research Infrastructure (ESFRI) aiming to produce a complete checklist of species recorded from Greece. This checklist was constructed by updating an existing one with the inclusion of recently published records. All the reported species from Greek waters were taxonomically revised and cross-checked with the Ascidiacea World Database. NEW INFORMATION: The updated checklist of the class Ascidiacea of Greece comprises 75 species, classified in 33 genera, 12 families, and 3 orders. In total, 8 species have been added to the previous species list (4 Aplousobranchia, 2 Phlebobranchia, and 2 Stolidobranchia). Aplousobranchia was the most speciose order, followed by Stolidobranchia. Most species belonged to the families Didemnidae, Polyclinidae, Pyuridae, Ascidiidae, and Styelidae; these 4 families comprise 76% of the Greek ascidian species richness. The present effort revealed the limited taxonomic research effort devoted to the ascidian fauna of Greece, which is attributed to the lack of experts and low sampling effort. Therefore, major knowledge gaps on the ascidian diversity of Greece occur and further research in this field is needed. PMID- 27932911 TI - Cumacea of Greece: a preliminary checklist. AB - BACKGROUND: The first attempt to compile the checklist of Cumacea of Greece was made in the context of the "Greek Biodiversity Database" project (2005-2008) coordinated by the Aristotle University of Thessaloniki. Since then, only scattered information on new elements of the Greek cumacean fauna has been available. The objectives of the present study were to update and cross-check taxonomically all cumacean species records from Greek waters for inaccuracies and omissions according to the recent literature and current taxonomic status. NEW INFORMATION: The updated checklist of Cumacea of Greece, which was built within the framework of the LifeWatch Greece Research Infrastructure (ESFRI) project (2013-2015) coordinated by the Hellenic Centre for Marine Research, comprises 62 species, classified in 24 genera and 6 families. However, a few more records need further cross-checking with the current literature resources. PMID- 27932909 TI - CIGESMED for divers: Establishing a citizen science initiative for the mapping and monitoring of coralligenous assemblages in the Mediterranean Sea. AB - BACKGROUND: Over the last decade, inventorying and monitoring of marine biodiversity has significantly benefited from the active engagement of volunteers. Although several Citizen Science projects concern tropical reef ecosystems worldwide, none of the existing initiatives has yet specifically focused on their Mediterranean equivalents. Mediterranean coralline reefs, known as "coralligenous", are bioherms primarily built by calcifying rhodophytes on hard substrates under dim-light conditions; they are considered hotspots of biodiversity and are extremely popular among divers due to their complex structure, conspicuous biological wealth and high aesthetic value. Nevertheless, data on their distribution, structure and conservation status is lacking for several Mediterranean areas while they are vulnerable to an increasing number of threats. NEW INFORMATION: In the framework of CIGESMED SeasEra (ERAnet) project a specialized Citizen Science project was launched, aiming to engage enthusiast divers in the study and monitoring of Mediterranean coralligenous assemblages through the gathering of basic information regarding their spatial occurrence, assemblage structure and associated pressures or threats. For its active implementation, a data collection protocol and a multilingual website were developed, comprising an educational module and a data submission platform. Georeferenced data reporting focuses on: (a) basic topographic and abiotic features for the preliminary description of each site, and the creation of data series for sites receiving multiple visits; (b) presence and relative abundance of typical conspicuous species, as well as (c) existence of pressures and imminent threats, for the characterization and assessment of coralligenous assemblages. A variety of tools is provided to facilitate end users, while divers have the choice to report additional information and are encouraged to upload their photographs. The long-term goal is the development of an active community of amateur observers providing widespread and ecologically significant data on coralligenous assemblages. PMID- 27932912 TI - Mysida and Lophogastrida of Greece: a preliminary checklist. AB - BACKGROUND: The checklist of Mysida and Lophogastrida of Greece was created within the framework of the Greek Taxon Information System (GTIS), which is one of the applications of the LifeWatchGreece Research Infrastructure (ESFRI) resuming efforts to develop a complete checklist of species recorded and reported from Greek waters. The objectives of the present study were to update and cross check taxonomically all records of Mysida and Lophogastrida species known to occur in Greek waters in order to search for inaccuracies and omissions. NEW INFORMATION: The up-to-date checklist of Mysida and Lophogastrida of Greece comprises 49 species, classified to 25 genera. PMID- 27932913 TI - LifeWatchGreece Portal development: architecture, implementation and challenges for a biodiversity research e-infrastructure. AB - BACKGROUND: Biodiversity data is characterized by its cross-disciplinary character, the extremely broad range of data types and structures, and the plethora of different data sources providing resources for the same piece of information in a heterogeneous way. Since the web inception two decades ago, there are multiple initiatives to connect, aggregate, share, and publish biodiversity data, and to establish data and work flows in order to analyze them. The European program LifeWatch aims at establishing a distributed network of nodes implementing virtual research environment in Europe to facilitate the work of biodiversity researchers and managers. LifeWatchGreece is one of these nodes where a portal was developed offering access to a suite of virtual laboratories and e-services. NEW INFORMATION: Despite its strict definition in information technology, in practice "portal" is a fairly broad term that embraces many web architectures. In the biodiversity domain, the term "portal" is usually used to indicate either a web site that provides access to a single or an aggregation of data repositories (like: http://indiabiodiversity.org/, http://www.mountainbiodiversity.org/, http://data.freshwaterbiodiversity.eu), a web site that gathers information about various online biodiversity tools (like http://test-eubon.ebd.csic.es/, http://marine.lifewatch.eu/) or a web site that just gathers information and news about the biodiversity domain (like http://chm.moew.government.bg). LifeWatchGreece's portal takes the concept of a portal a step further. In strict IT terms, LifeWatchGreece's portal is partly a portal, partly a platform and partly an aggregator. It includes a number of biodiversity-related web tools integrated into a centrally-controlled software ecosystem. This ecosystem includes subsystems for access control, traffic monitoring, user notifications and web tool management. These subsystems are shared to all the web tools that have been integrated to the portal and thereby are part of this ecosystem. These web tools do not consist in external and completely independent web applications as it happens in most other portals. A quite obvious (to the user) indication of this is the Single-Sign-On (SSO) functionality for all tools and the common user interface wrapper that most of these tools use. Another example of a less obvious functionality is the common user profile that is shared and can be utilized by all tools (e.g user's timezone). PMID- 27932914 TI - Macrobenthic molluscs from a marine - lagoonal environmental transition in Lesvos Island (Greece). AB - BACKGROUND: This paper describes an occurence dataset, also including numerical abundance and biomass data, pertaining to the macrobenthic molluscan assemblages from a marine - lagoonal environmental transition. The study system was the soft substrate benthoscape of the area of the Kalloni solar saltworks (Lesvos Island, Greece). Specifically, the study area extended from the infralittoral zone of the inner Kalloni Gulf (marine habitat) to the bottoms of the first two evaporation ponds of the Kalloni solar saltworks (lagoonal habitat). Bottom sediment samples (3 replicates) were collected with a Van Veen grab sampler (0.1 m2) at four sampling sites, along a 1.5 km long line transect that spanned the marine - lagoonal environmental transition. A total of four surveys were carried out seasonally in 2004. A total of 39,345 molluscan individuals were sorted out of the sediment samples and were identified to 71 species, belonging to the Gastropoda (36), Bivalvia (34) and Scaphopoda (1) classes. Numerical abundance and wet biomass (with shells) data are included in the dataset. NEW INFORMATION: The dataset described in the present paper partially fills a significant gap in the scientific literature: Because ecological research of coastal lagoons has seldom explicitly considered the marine - lagoonal habitats interface, there are no openly accessible datasets pertaining to the particular structural component of the transitional waters benthoscapes of the Mediterranean Sea. Such datasets could prove valuable in the research of the structure and functioning of transitional waters benthoscapes. The present dataset is available as a supplementary file (Suppl. material 1) and can also be accessed at http://ipt.medobis.eu/resource?r=kalloni_saltworks_phd. PMID- 27932916 TI - Taxonaut: an application software for comparative display of multiple taxonomies with a use case of GBIF Species API. AB - BACKGROUND: The Species API of the Global Biodiversity Information Facility (GBIF) provides public access to taxonomic data aggregated from multiple data sources. Each data source follows its own classification which can be inconsistent with classifications from other sources. Even with a reference classification e.g. the GBIF Backbone taxonomy, a comprehensive method to compare classifications in the data aggregation is essential, especially for non-expert users. NEW INFORMATION: A Java application was developed to compare multiple taxonomies graphically using classification data acquired from GBIF's ChecklistBank via the GBIF Species API. It uses a table to display taxonomies where each column represents a taxonomy under comparison, with an aligner column to organise taxa by name. Each cell contains the name of a taxon if the classification in that column contains the name. Each column also has a cell showing the hierarchy of the taxonomy by a folder metaphor where taxa are aligned and synchronised in the aligner column. A set of those comparative tables shows taxa categorised by relationship between taxonomies. The result set is also available as tables in an Excel format file. PMID- 27932915 TI - iCollections - Digitising the British and Irish Butterflies in the Natural History Museum, London. AB - BACKGROUND: The Natural History Museum, London (NHMUK) has embarked on an ambitious programme to digitise its collections . The first phase of this programme has been to undertake a series of pilot projects that will develop the necessary workflows and infrastructure development needed to support mass digitisation of very large scientific collections. This paper presents the results of one of the pilot projects - iCollections. This project digitised all the lepidopteran specimens usually considered as butterflies, 181,545 specimens representing 89 species from the British Isles and Ireland. The data digitised includes, species name, georeferenced location, collector and collection date - the what, where, who and when of specimen data. In addition, a digital image of each specimen was taken. This paper explains the way the data were obtained and the background to the collections which made up the project. NEW INFORMATION: Specimen-level data associated with British and Irish butterfly specimens have not been available before and the iCollections project has released this valuable resource through the NHM data portal. PMID- 27932917 TI - A Bioacoustic Record of a Conservancy in the Mount Kenya Ecosystem. AB - BACKGROUND: Environmental degradation is a major threat facing ecosystems around the world. In order to determine ecosystems in need of conservation interventions, we must monitor the biodiversity of these ecosystems effectively. Bioacoustic approaches offer a means to monitor ecosystems of interest in a sustainable manner. In this work we show how a bioacoustic record from the Dedan Kimathi University wildlife conservancy, a conservancy in the Mount Kenya ecosystem, was obtained in a cost effective manner. A subset of the dataset was annotated with the identities of bird species present since they serve as useful indicator species. These data reveal the spatial distribution of species within the conservancy and also point to the effects of major highways on bird populations. This dataset will provide data to train automatic species recognition systems for birds found within the Mount Kenya ecosystem. Such systems are necessary if bioacoustic approaches are to be employed at the large scales necessary to influence wildlife conservation measures. NEW INFORMATION: We provide acoustic recordings from the Dedan Kimathi University wildlife conservancy, a conservancy in the Mount Kenya ecosystem, obtained using a low cost acoustic recorder. A total of 2701 minute long recordings are provided including both daytime and nighttime recordings. We present an annotation of a subset of the daytime recordings indicating the bird species present in the recordings. The dataset contains recordings of at least 36 bird species. In addition, the presence of a few nocturnal species within the conservancy is also confirmed. PMID- 27932918 TI - Salix transect of Europe: variation in ploidy and genome size in willow associated common nettle, Urtica dioica L. sens. lat., from Greece to arctic Norway. AB - BACKGROUND: The common stinging nettle, Urtica dioica L. sensu lato, is an invertebrate "superhost", its clonal patches maintaining large populations of insects and molluscs. It is extremely widespread in Europe and highly variable, and two ploidy levels (diploid and tetraploid) are known. However, geographical patterns in cytotype variation require further study. NEW INFORMATION: We assembled a collection of nettles in conjunction with a transect of Europe from the Aegean to Arctic Norway (primarily conducted to examine the diversity of Salix and Salix-associated insects). Using flow cytometry to measure genome size, our sample of 29 plants reveals 5 diploids and 24 tetraploids. Two diploids were found in SE Europe (Bulgaria and Romania) and three diploids in S. Finland. More detailed cytotype surveys in these regions are suggested. The tetraploid genome size (2C value) varied between accessions from 2.36 to 2.59 pg. The diploids varied from 1.31 to 1.35 pg per 2C nucleus, equivalent to a haploid genome size of c. 650 Mbp. Within the tetraploids, we find that the most northerly samples (from N. Finland and arctic Norway) have a generally higher genome size. This is possibly indicative of a distinct population in this region. PMID- 27932919 TI - Metabarcoding of marine nematodes - evaluation of reference datasets used in tree based taxonomy assignment approach. AB - BACKGROUND: Metabarcoding is becoming a common tool used to assess and compare diversity of organisms in environmental samples. Identification of OTUs is one of the critical steps in the process and several taxonomy assignment methods were proposed to accomplish this task. This publication evaluates the quality of reference datasets, alongside with several alignment and phylogeny inference methods used in one of the taxonomy assignment methods, called tree-based approach. This approach assigns anonymous OTUs to taxonomic categories based on relative placements of OTUs and reference sequences on the cladogram and support that these placements receive. NEW INFORMATION: In tree-based taxonomy assignment approach, reliable identification of anonymous OTUs is based on their placement in monophyletic and highly supported clades together with identified reference taxa. Therefore, it requires high quality reference dataset to be used. Resolution of phylogenetic trees is strongly affected by the presence of erroneous sequences as well as alignment and phylogeny inference methods used in the process. Two preparation steps are essential for the successful application of tree-based taxonomy assignment approach. Curated collections of genetic information do include erroneous sequences. These sequences have detrimental effect on the resolution of cladograms used in tree-based approach. They must be identified and excluded from the reference dataset beforehand.Various combinations of multiple sequence alignment and phylogeny inference methods provide cladograms with different topology and bootstrap support. These combinations of methods need to be tested in order to determine the one that gives highest resolution for the particular reference dataset.Completing the above mentioned preparation steps is expected to decrease the number of unassigned OTUs and thus improve the results of the tree-based taxonomy assignment approach. PMID- 27932920 TI - Dung beetle (Coleoptera: Scarabaeoidea) assemblages in the western Italian Alps: benchmark data for land use monitoring. AB - BACKGROUND: Traditional agro-pastoral practices are in decline over much of the Alps (MacDonald et al. 2000), leading to shrub and tree encroachment, and this represents one of the main threats for the conservation of alpine biodiversity, as many plant and animal species are dependent on the presence of semi-natural open habitats. However, quantifying this environmental change and assessing its impact on biodiversity may be difficult, especially in the context of sparse historical survey data. The accessibility of contemporary data about local biodiversity surveys in general, and indicator taxa in particular, is an essential consideration for planning future evaluations of conservation status in the Alps and for conservation plans that use ecological indicators to monitor temporal changes in biodiversity. Dung beetles are important ecosystem service providers (Nichols et al. 2008) that have been assessed as a good ecological indicator taxon in several studies (reviewed by Nichols and Gardner 2011), and although the Alps is perhaps one of the best-studied regions in respect of dung beetles, there are still only eight readily-accessible publications. We have augmented and comprehensively reviewed the data from these publications. NEW INFORMATION: We first provide data about changes on a temporal scale of seasons in a dung beetle community in the western Italian Alps, an issue that has to be addressed in the local assemblages because it would affect regional biomonitoring and conservation research. This survey of 12 099 individuals belonging to 22 species illustrates a distinct seasonal pattern at a single site. Second, we collate the results of 13 published surveys of the presence of 46 species of dung beetles in 11 valleys in the western Italian Alps in the period from 2005 to 2012, a period of accelerated change in land use that started around 1945 (MacDonald et al. 2000). Because ten of the surveys used baited pitfall traps and four more used manual collection of specimens, the abundance data were not strictly comparable and they were therefore transformed to binary data (presence or-absence records) with measures of sampling effort. The results illustrate both spatial variation and temporal variation at the scale of years.Because of the importance of dung beetles in agro-pastoral ecosystems and the high sensitivity of montane ecosystems to climate change, these spatially and temporally explicit data sets provide important baseline information about western Italian Alpine dung beetles for investigations of the effects of land use change under ongoing climate change scenarios. PMID- 27932922 TI - Discontinuous color variation in the assassin bug species Tiarodes miyamotoi (Hemiptera: Reduviidae: Reduviinae). AB - BACKGROUND: The reduviine assassin bug, Tiarodes miyamotoi Ishikawa, Cai and Tomokuni, 2005 (Hemiptera: Heteroptera: Reduviidae: Reduviinae), has so far been known only from the Yaeyama Islands of Japan and no major intraspecific variation has been reported in this species. NEW INFORMATION: This is the first record of this species from Okinawa-honto Island as the northernmost locality. Furthermore, an apparently discontinuous intraspecific variation in coloration has been confirmed between populations from the Yaeyama and Okinawa-honto Islands; this variation has been reported for the first time in the genus Tiarodes Burmeister, 1835, which comprises approximately 90 species. PMID- 27932921 TI - Digging for historical data on the occurrence of benthic macrofaunal species in the southeastern Mediterranean. AB - BACKGROUND: The benthic macrofaunal biodiversity of the southeastern Mediterranean is considerably understudied compared to other Mediterranean regions. Monitoring biodiversity in this area is crucial as this region is particularly susceptible to biological invasions and temperature alteration. Historical biodiversity data could provide a useful baseline for monitoring potential changes and provide informarion to support a better understanding of the possible effects of anthropogenic activities on marine benthic communities. NEW INFORMATION: In this study, performed under the LifeWatchGreece Research Infrastructure, we present historical benthic occurrence data obtained from the sampling expedition carried out in 1933 by Adolf Steuer in the coastal area around Alexandria, Egypt, eastern Mediterranean. The occurrences were geo referenced to more than 170 stations, mostly located in the area of Alexandria, and the nearby coasts and lakes. All records were digitized and species names were cross-checked and taxonomically updated using the World Register of Marine Species. The outcome clearly shows that such initiatives can reveal an unexpected amount of highly valuable biodiversity information for "data-poor" regions. PMID- 27932923 TI - India Biodiversity Portal: An integrated, interactive and participatory biodiversity informatics platform. AB - BACKGROUND: This paper describes a growing biodiversity platform, launched in 2008, which organizes knowledge on the biodiversity of India. The main objective and originality of the India Biodiversity Portal (IBP) is to aggregate curated biodiversity data of different kinds (e.g. distribution maps, temporal distribution or life history) in an integrated platform where amateurs and experts can easily interact. NEW INFORMATION: Since its launch, the platform has seen an exceptional increase in both user activity and biodiversity data. Currently the portal has descriptions of over 20,400 species, and has aggregated approximately 1,280,000 observations covering more than 30,000 species, which already constitutes a unique source of information for scientists and stakeholders in conservation. Over 8500 users have registered on the portal. The amount of data generated and to be generated in the next few years by this portal will certainly help the effective implementation of biodiversity conservation and management in one of the most ecologically diverse countries in the world. PMID- 27932924 TI - Species conservation profile of the alpine stenoendemic spider Vesubia jugorum (Araneae, Lycosidae) from the Maritime Alps. PMID- 27932925 TI - Discovery of a New World ladybird beetle Nephaspis indus Gordon, 1996 (Coleoptera: Coccinellidae: Scymnini) on the Island of Taiwan. AB - BACKGROUND: Nephaspis indus Gordon, 1996 was imported into Taiwan from Hawaii in 1990 as a biological control agent for the spiralling whitefly, Aleurodicus dispersus Russell, 1965 (Hemiptera: Aleyrodidae). However, its establishment was not known prior to this study. NEW INFORMATION: Nephaspis indus Gordon, 1996, a natural enemy of Aleurodicus dispersus Russell (Hemiptera: Aleyrodidae) native to the Neotropical region, is recorded as established in Taiwan for the first time. The present paper provides a detailed further description and illustrations of the adult. Diagnostic characters for the genus and species are given and the nomenclature of this species is also discussed. PMID- 27932927 TI - The Avian Collection of the Zoological Museum of the University of Athens (ZMUA). AB - BACKGROUND: The Zoological Museum of the University of Athens (ZMUA) was established in 1858. It is the oldest natural history museum of Greece. The museum began its operation with the acquisition of a core collection and has been expanding ever since. One of the most substantial parts of the museum's collection consists of the avian exhibits, originating from around the world. NEW INFORMATION: Today, the avian collection consists of 2,948 specimens, preserved mostly through taxidermy, along with a significant number of eggs. The birds have been collected from around the world. A substantial part of the collection consists of individuals originating from Greece, Brazil, Canada and Australia. Having this valuable source of biogeographic information and a potential reserve of historical genetic diversity, ZMUA presents here the contents of the avian collection. PMID- 27932926 TI - A dataset of fishes in and around Inle Lake, an ancient lake of Myanmar, with DNA barcoding, photo images and CT/3D models. AB - BACKGROUND: Inle (Inlay) Lake, an ancient lake of Southeast Asia, is located at the eastern part of Myanmar, surrounded by the Shan Mountains. Detailed information on fish fauna in and around the lake has long been unknown, although its outstanding endemism was reported a century ago. NEW INFORMATION: Based on the fish specimens collected from markets, rivers, swamps, ponds and ditches around Inle Lake as well as from the lake itself from 2014 to 2016, we recorded a total of 948 occurrence data (2120 individuals), belonging to 10 orders, 19 families, 39 genera and 49 species. Amongst them, 13 species of 12 genera are endemic or nearly endemic to the lake system and 17 species of 16 genera are suggested as non-native. The data are all accessible from the document "A dataset of Inle Lake fish fauna and its distribution (http://ipt.pensoft.net/resource.do?r=inle_fish_2014-16)", as well as DNA barcoding data (mitochondrial COI) for all species being available from the DDBJ/EMBL/GenBank (Accession numbers: LC189568-LC190411). Live photographs of almost all the individuals and CT/3D model data of several specimens are also available at the graphical fish biodiversity database (http://ffish.asia/INLE2016; http://ffish.asia/INLE2016-3D). The information can benefit the clarification, public concern and conservation of the fish biodiversity in the region. PMID- 27932928 TI - Metabarcoding of marine nematodes - evaluation of similarity scores used in alignment-based taxonomy assignment approach. AB - BACKGROUND: The diversity of organisms is being commonly accessed using metabarcoding of environmental samples. Reliable identification of barcodes is one of the critical steps in the process and several taxonomy assignment methods were proposed to accomplish this task, including alignment-based approach that uses Basic Local Alignment Search Tool (BLAST) algorithm. This publication evaluates the variability of 5' end of 18S rRNA barcoding region as expressed by similarity scores (alignment score and identity score) produced by BLAST, and its impact on barcode identification to family-level taxonomic categories. NEW INFORMATION: In alignment-based taxonomy assignment approach, reliable identification of anonymous OTUs to supraspecific taxa depends on the correct application of similarity thresholds. Since various taxa show different level of genetic variation, practical application of alignment-based approach requires the determination and use of taxon-specific similarity thresholds. PMID- 27932929 TI - A systematic florula of a disturbed urban habitat: Pavements of Sheffield, England. AB - BACKGROUND: Human settlements are of increasing interest to ecologists, a fact demonstrated by the recent cluster of book-length treatments of the topic (Forman 2008, McDonnell et al. 2009, Gaston 2010, Niemela et al. 2011, Wilson 2011, Forman 2014). The natural world as a fascinating feature of towns and cities has a much longer history (e.g. Fitter 1945), and has also played a strong part in local biological conservation in some countries over the late 20th Century (Goode 2014). Despite much existing information on urban plant and animal communities resulting from these trends, very little, easily accessible, systematic data on urban biodiversity is currently available. NEW INFORMATION: Few systematic, randomised surveys at fine spatial grain exist for urban habitats, and even fewer of these surveys are in the public domain. This study was designed as a systematic florula (i.e. a small flora) of a relatively discrete urban habitat in order to provide a baseline that would enable robust insights into future environmental change. In addition, the dataset is likely to be useful for comparative studies of plant traits, particularly those of highly disturbed habitats (Williams et al. 2009). The survey is an occupancy study of the vascular plants of pavements (i.e. sidewalks) within 16 500 x 500 m (0.25 km2) urban grid cells, stratified by quadrant at the scale of the focal city (Sheffield, England) in order to provide more even coverage. The final dataset comprises 862 records of 183 taxa. PMID- 27932930 TI - Testing the Global Malaise Trap Program - How well does the current barcode reference library identify flying insects in Germany? AB - BACKGROUND: Biodiversity patterns are inherently complex and difficult to comprehensively assess. Yet, deciphering shifts in species composition through time and space are crucial for efficient and successful management of ecosystem services, as well as for predicting change. To better understand species diversity patterns, Germany participated in the Global Malaise Trap Program, a world-wide collection program for arthropods using this sampling method followed by their DNA barcode analysis. Traps were deployed at two localities: "Nationalpark Bayerischer Wald" in Bavaria, the largest terrestrial Natura 2000 area in Germany, and the nature conservation area Landskrone, an EU habitats directive site in the Rhine Valley. Arthropods were collected from May to September to track shifts in the taxonomic composition and temporal succession at these locations. NEW INFORMATION: In total, 37,274 specimens were sorted and DNA barcoded, resulting in 5,301 different genetic clusters (BINs, Barcode Index Numbers, proxy for species) with just 7.6% of their BINs shared. Accumulation curves for the BIN count versus the number of specimens analyzed suggest that about 63% of the potential diversity at these sites was recovered with this single season of sampling. Diversity at both sites rose from May (496 & 565 BINs) to July (1,236 & 1,522 BINs) before decreasing in September (572 & 504 BINs). Unambiguous species names were assigned to 35% of the BINs (1,868) which represented 12,640 specimens. Another 7% of the BINs (386) with 1,988 specimens were assigned to genus, while 26% (1,390) with 12,092 specimens were only placed to a family. These results illustrate how a comprehensive DNA barcode reference library can identify unknown specimens, but also reveal how this potential is constrained by gaps in the quantity and quality of records in BOLD, especially for Hymenoptera and Diptera. As voucher specimens are available for morphological study, we invite taxonomic experts to assist in the identification of unnamed BINs. PMID- 27932931 TI - New distribution records of the savanna specialist fungus-farming ant Cyatta Sosa Calvo et al. (Hymenoptera: Formicidae: Myrmicinae). AB - BACKGROUND: The fungus-farming ant genus Cyatta (Formicidae: Myrmicinae) is represented by a single species, C. abscondita Sosa-Calvo et al., known from a few localities in Brazil (in the states of Ceara, Minas Gerais, Sao Paulo and the Distrito Federal), and a single locality in the Misiones province, Argentina. Cyatta is known to occur predominantly in savanna habitats and occasionally in the transition zones between the Atlantic Forest and Cerrado. NEW INFORMATION: The new records reported here significantly expand the previously known distribution of Cyatta abscondita and provide further support for the intimate relation between this species and the savannas of South America. We report the first occurrence of the genus in southern Brazil (Parana state) and the westernmost occurrence (Bolivia) of Cyatta abscondita, which extend its distribution approximately 1450 km to the west. Finally, we discuss the importance of mapping inconspicuous species in order to develop strategies for protecting endangered areas and to increase our understanding of the evolutionary history of organisms and biomes. PMID- 27932932 TI - Atlas of Ohio Aquatic Insects: Volume II, Plecoptera. AB - BACKGROUND: We provide volume II of a distributional atlas of aquatic insects for the eastern USA state of Ohio. This treatment of stoneflies (Plecoptera) is companion to Armitage et al. (2011) on caddisflies (Trichoptera). We build on a recent analysis of Ohio stonefly diversity patterns based on large drainages (DeWalt et al. 2012), but add 3717 new records to the data set. We base most analyses on the United States Geological Survey Hierarchical Unit Code eight (HUC8) drainage scale. In addition to distributional maps for each species, we provide analyses of species richness versus HUC8 drainage area and the number of unique locations in a HUC8 drainage, species richness versus Ohio counties, analyze adult presence phenology throughout the year, and demonstrate stream size range affiliation for each species. NEW INFORMATION: This work is based on a total of 7797 specimen records gathered from 21 regional museums, agency data, personal collections, and from the literature Table 1. To our knowledge this is the largest stonefly data set available for a similarly sized geopolitical area anywhere in the world. These data are made available as a Darwin Core Archive supported by the Pensoft Integrated Publishing Toolkit (DeWalt et al. 2016b). All known published papers reporting stoneflies from Ohio are detailed in Suppl. material 1. We recovered 102 species from Ohio, including all nine Nearctic families Table 2. Two species were removed from the DeWalt et al. (2012) list and two new state records added. Perlidae (32 spp.) was most speciose, compared to the low diversity Pteronarcyidae (2 spp.) and Peltoperlidae (1 sp.). The richest HUC8 drainages occurred in northeastern, south-central, and southern regions of the state where drainages were heavily forested, had the highest slopes, and were contained within or adjacent to the unglaciated Allegheny and Appalachian Plateaus. Species poor drainages occurred mainly in the northwestern region where Wisconsinan aged lake plains climaxed to an expansive wooded wetland, the Black Swamp. The unglaciated Lower Scioto drainage (72 spp.) in south-central Ohio supported the greatest species richness. There was no relationship between species richness and HUC8 drainage size, but the number of unique locations in a drainage strongly related to species richness. All Ohio counties were represented in the data set with Hocking County (59 spp.) of the Lower Scioto drainage being the richest and most heavily sampled. Adult presence phenology was influenced by phylogenetic relationships such that the superfamily Nemouroidea (Capniidae, Leuctridae, Nemouridae, and Taeniopterygidae) generally emerged in winter and spring while the superfamilies Pteronarcyoidea (Pteronarcyidae, Peltoperlidae) and Perloidea (Chloroperlidae, Perlidae, Perlodidae) emerged later, some species continuing emergence through summer months. Species often occupied specific stream size ranges, while others were generalists. Two species once histrorically abundant in the western Lake Erie Bass Islands no longer reside there. Each of the 102 species is discussed in detail, including several that require additional collecting efforts to confirm their identities, presence, and distribution in Ohio. PMID- 27932933 TI - LifeWatchGreece: Construction and operation of the National Research Infrastructure (ESFRI). PMID- 27932934 TI - Data Policy and Data Sharing Agreement in the LifeWatchGreece Research Infrastructure. PMID- 27932935 TI - "...they think we are conversing, so we don't care about them..." Examining the causes of workplace violence against nurses in Ghana. AB - BACKGROUND: This study is part of a larger project aimed at exploring the workplace experiences of nurses working in public general hospitals in Ghana. The current paper explores the causes of workplace violence against nurses in Ghana. METHODS: Twenty-four semi-structured in-depth interviews were conducted with professional nurses working in five regions of Ghana. They were selected through purposive and participant-to-participant snowball sampling techniques. Data was analysed through thematic analyses. RESULTS: The findings of the study suggest that nurses are not (always) passive recipients of violence. Workplace violence can be instigated by either of the parties to the nurse-patient/relative interaction. Nurses' accounts of the causes of violence suggest that violence could be instrumental or reactive. The study further suggests that the causes of violence may differ depending on which party instigated the violence. The main causes of violence identified include ineffective communication, long waiting times and perceived unresponsiveness, and enforcement of visiting hours. CONCLUSION: It is concluded that workplace violence could be reduced through the provision of adequate information to patients and their relatives. Nurses could also be trained in effective communication and interpersonal skills; and on how to identify and avoid potentially violent situations. It is also imperative that policies and measures aimed at addressing workplace violence are instituted to address the problem. Mass education may also be carried out to sensitise the general public on the adverse effects of violence against nurses. PMID- 27932936 TI - Riboflavin along with antibiotics balances reactive oxygen species and inflammatory cytokines and controls Staphylococcus aureus infection by boosting murine macrophage function and regulates inflammation. AB - BACKGROUND: Macrophages serve as intracellular reservoirs of S. aureus. Recent in vitro studies have confirmed high level resistance by S. aureus to macrophage mediated killing and the intracellular persistence of Staphylococci may play an important role in the pathogenesis. Since this localization protects them from both cell-mediated and humoral immune responses, therefore, a successful anti staphylococcal therapy should include the elimination of intracellular bacteria, further protecting the host cells from staphylococci-induced cell death. So, only antibiotic therapy may not be helpful, successful therapy needs combination of drugs not only for elimination of pathogen but also for rescuing the host cell for S. aureus induced cell death. METHODS: In keeping with this idea an in vitro study has been done to examine the effect of Riboflavin along with antibiotics on phagocytosis, hydorgen peroxide, superoxide production, antioxidant enzyme levels, and cytokine levels in mouse macrophages for amelioration of the Staphylococcus aureus burden. The immune boosting effects of Riboflavin have been validated through perturbations of redox homeostasis and pro-inflammatory cytokines measurements. RESULTS: It was observed that the supplementation of Vitamin B-2 (Riboflavin) not only enhances macrophage function as previously reported but also decreases pro-inflammatory responses in Staphylococcus aureus infected macrophages. The observed influence of Riboflavin on enhanced antimicrobial effects such as enhanced phagocytosis of macrophages exposed to S. aureus, hydrogen peroxide or superoxide production when combined with either ciprofloxacin (CIP) or Azithromycin (AZM) and decrease in pro-inflammatory responses of IFN-gamma, IL-6, IL-1beta. Riboflavin treatment also decreased NO and TNF-alpha level possibly by inhibiting the NF-kappabeta pathway. The increased antioxidant enzymes like glutathione reductase, SOD and GSH level helped in maintaining a stable redox state in the cell. CONCLUSION: Riboflavin plus antibiotic pretreatment not only enhances macrophage functions but also decreases proinflammatory responses in Staphylococcus aureus infected macrophages indicating better bacterial clearance and regulated inflammation which may be considered as a novel and important therapeutic intervention. PMID- 27932938 TI - Welfare-to-Work Programs in America, 1980 to 2005: Meta-Analytic Evidence of the Importance of Job and Child Care Availability. AB - This meta-analysis extended a Campbell Collaboration review of welfare-to-work programs. Its synthesis of 65 randomized trials in America over the past generation replicated a small overall intervention effect. Moreover, it found (1) there was no long-term employment effect of interventions in areas where jobs were relatively unavailable, and (2) programs that provided child care were more effective than those that did not in the short and long term, even in areas of high labor market withdrawal. The availability of jobs as well as such supports as child care that enable their access seem to be key elements of welfare-to-work programs that work. PMID- 27932937 TI - Effect of electrolyzed high-pH alkaline water on blood viscosity in healthy adults. AB - BACKGROUND: Previous research has shown fluid replacement beverages ingested after exercise can affect hydration biomarkers. No specific hydration marker is universally accepted as an ideal rehydration parameter following strenuous exercise. Currently, changes in body mass are used as a parameter during post exercise hydration. Additional parameters are needed to fully appreciate and better understand rehydration following strenuous exercise. This randomized, double-blind, parallel-arm trial assessed the effect of high-pH water on four biomarkers after exercise-induced dehydration. METHODS: One hundred healthy adults (50 M/50 F, 31 +/- 6 years of age) were enrolled at a single clinical research center in Camden, NJ and completed this study with no adverse events. All individuals exercised in a warm environment (30 degrees C, 70% relative humidity) until their weight was reduced by a normally accepted level of 2.0 +/- 0.2% due to perspiration, reflecting the effects of exercise in producing mild dehydration. Participants were randomized to rehydrate with an electrolyzed, high pH (alkaline) water or standard water of equal volume (2% body weight) and assessed for an additional 2-h recovery period following exercise in order to assess any potential variations in measured parameters. The following biomarkers were assessed at baseline and during their recovery period: blood viscosity at high and low shear rates, plasma osmolality, bioimpedance, and body mass, as well as monitoring vital signs. Furthermore, a mixed model analysis was performed for additional validation. RESULTS: After exercise-induced dehydration, consumption of the electrolyzed, high-pH water reduced high-shear viscosity by an average of 6.30% compared to 3.36% with standard purified water (p = 0.03). Other measured biomarkers (plasma osmolality, bioimpedance, and body mass change) revealed no significant difference between the two types of water for rehydration. However, a mixed model analysis validated the effect of high-pH water on high-shear viscosity when compared to standard purified water (p = 0.0213) after controlling for covariates such as age and baseline values. CONCLUSIONS: A significant difference in whole blood viscosity was detected in this study when assessing a high-pH, electrolyte water versus an acceptable standard purified water during the recovery phase following strenuous exercise-induced dehydration. PMID- 27932940 TI - Retraction: The improvement of large High-Density Lipoprotein (HDL) particle levels, and presumably HDL metabolism, depend on effects of low-carbohydrate diet and weight loss. AB - [This retracts the article DOI: 10.17179/excli2015-642.]. PMID- 27932939 TI - Plant defense and herbivore counter-defense: benzoxazinoids and insect herbivores. AB - Benzoxazinoids are a class of indole-derived plant chemical defenses comprising compounds with a 2-hydroxy-2H-1,4-benzoxazin-3(4H)-one skeleton and their derivatives. These phytochemicals are widespread in grasses, including important cereal crops such as maize, wheat and rye, as well as a few dicot species, and display a wide range of antifeedant, insecticidal, antimicrobial, and allelopathic activities. Although their overall effects against insect herbivores are frequently reported, much less is known about how their modes of action specifically influence insect physiology. The present review summarizes the biological activities of benzoxazinoids on chewing, piercing-sucking, and root insect herbivores. We show how within-plant distribution modulates the exposure of different herbivore feeding guilds to these defenses, and how benzoxazinoids may act as toxins, feeding deterrents and digestibility-reducing compounds under different conditions. In addition, recent results on the metabolism of benzoxazinoids by insects and their consequences for plant-herbivore interactions are addressed, as well as directions for future research. PMID- 27932941 TI - Long Term Memory for Noise: Evidence of Robust Encoding of Very Short Temporal Acoustic Patterns. AB - Recent research has demonstrated that humans are able to implicitly encode and retain repeating patterns in meaningless auditory noise. Our study aimed at testing the robustness of long-term implicit recognition memory for these learned patterns. Participants performed a cyclic/non-cyclic discrimination task, during which they were presented with either 1-s cyclic noises (CNs) (the two halves of the noise were identical) or 1-s plain random noises (Ns). Among CNs and Ns presented once, target CNs were implicitly presented multiple times within a block, and implicit recognition of these target CNs was tested 4 weeks later using a similar cyclic/non-cyclic discrimination task. Furthermore, robustness of implicit recognition memory was tested by presenting participants with looped (shifting the origin) and scrambled (chopping sounds into 10- and 20-ms bits before shuffling) versions of the target CNs. We found that participants had robust implicit recognition memory for learned noise patterns after 4 weeks, right from the first presentation. Additionally, this memory was remarkably resistant to acoustic transformations, such as looping and scrambling of the sounds. Finally, implicit recognition of sounds was dependent on participant's discrimination performance during learning. Our findings suggest that meaningless temporal features as short as 10 ms can be implicitly stored in long-term auditory memory. Moreover, successful encoding and storage of such fine features may vary between participants, possibly depending on individual attention and auditory discrimination abilities. Significance Statement Meaningless auditory patterns could be implicitly encoded and stored in long-term memory.Acoustic transformations of learned meaningless patterns could be implicitly recognized after 4 weeks.Implicit long-term memories can be formed for meaningless auditory features as short as 10 ms.Successful encoding and long-term implicit recognition of meaningless patterns may strongly depend on individual attention and auditory discrimination abilities. PMID- 27932942 TI - Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma. AB - Neurodegeneration in glaucoma results in decline and loss of retinal ganglion cells (RGCs), and is associated with activation of myeloid cells such as microglia and macrophages. The chemokine fractalkine (FKN or Cx3cl1) mediates communication from neurons to myeloid cells. Signaling through its receptor Cx3cr1 has been implicated in multiple neurodegenerative diseases, but the effects on neuronal pathology are variable. Since it is unknown how FKN-mediated crosstalk influences RGC degeneration in glaucoma, we assessed this in a chronic mouse model, DBA/2J. We analyzed a DBA/2J substrain deficient in Cx3cr1, and compared compartmentalized RGC degeneration and myeloid cell responses to those in standard DBA/2J mice. We found that loss of FKN signaling exacerbates axon transport dysfunction, an early event in neurodegeneration, with a significant increase in RGCs with somal accumulation of the axonal protein phosphorylated neurofilament, and reduced retinal expression of genes involved in axon transport, Kif1b, and Atp8a2. There was no change in the loss of Brn3-positive RGCs, and no difference in the extent of damage to the proximal optic nerve, suggesting that the loss of fractalkine signaling primarily affects axon transport. Since Cx3cr1 is specifically expressed in myeloid cells, we assessed changes in retinal microglial number and activation, changes in gene expression, and the extent of macrophage infiltration. We found that loss of fractalkine signaling led to innate immune changes within the retina, including increased infiltration of peripheral macrophages and upregulated nitric oxide synthase-2 (Nos-2) expression in myeloid cells, which contributes to the production of NO and can promote axon transport deficits. In contrast, resident retinal microglia appeared unchanged either in number, morphology, or expression of the myeloid activation marker ionized calcium binding adaptor molecule 1 (Iba1). There was also no significant increase in the proinflammatory gene interleukin 1 beta (Il1beta). We conclude that loss of fractalkine signaling causes a selective worsening of axon transport dysfunction in RGCs, which is linked to enhanced Nos 2 expression in myeloid cells. Our findings suggest that distinct mechanisms may contribute to different aspects of RGC decline in glaucoma, with axonal transport selectively altered after loss of Cx3cr1 in microglia and/or macrophages. PMID- 27932943 TI - Vacuolar Protein Sorting Genes in Parkinson's Disease: A Re-appraisal of Mutations Detection Rate and Neurobiology of Disease. AB - Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined. Understanding the specific prevalence of all VPS gene mutations is key to understand the relevance of retromers impairment in the onset of PD. A number of PD-related mutations despite affecting different biochemical systems (autophagy, mitophagy, proteasome, endosomes, protein folding), all converge in producing an impairment in cell clearance. This may explain how genetic predispositions to PD may derive from slightly deleterious VPS mutations when combined with environmental agents overwhelming the clearance of the cell. This manuscript reviews genetic data produced in the last 5 years to re-define the actual prevalence of VPS gene mutations in the onset of PD. The prevalence of p.Asp620Asn mutation in VPS35 is 0.286 of familial PD. This increases up to 0.548 when considering mutations affecting all VPS genes. This configures mutations in VPS genes as the second most frequent autosomal dominant PD genotype. This high prevalence, joined with increased awareness of the role played by retromers in the neurobiology of PD, suggests environmentally-induced VPS alterations as crucial in the genesis of PD. PMID- 27932944 TI - Role of Homocysteine in the Ischemic Stroke and Development of Ischemic Tolerance. AB - Homocysteine (Hcy) is a toxic, sulfur-containing intermediate of methionine metabolism. Hyperhomocysteinemia (hHcy), as a consequence of impaired Hcy metabolism or defects in crucial co-factors that participate in its recycling, is assumed as an independent human stroke risk factor. Neural cells are sensitive to prolonged hHcy treatment, because Hcy cannot be metabolized either by the transsulfuration pathway or by the folate/vitamin B12 independent remethylation pathway. Its detrimental effect after ischemia-induced damage includes accumulation of reactive oxygen species (ROS) and posttranslational modifications of proteins via homocysteinylation and thiolation. Ischemic preconditioning (IPC) is an adaptive response of the CNS to sub-lethal ischemia, which elevates tissues tolerance to subsequent ischemia. The main focus of this review is on the recent data on homocysteine metabolism and mechanisms of its neurotoxicity. In this context, the review documents an increased oxidative stress and functional modification of enzymes involved in redox balance in experimentally induced hyperhomocysteinemia. It also gives an interpretation whether hyperhomocysteinemia alone or in combination with IPC affects the ischemia induced neurodegenerative changes as well as intracellular signaling. Studies document that hHcy alone significantly increased Fluoro-Jade C- and TUNEL positive cell neurodegeneration in the rat hippocampus as well as in the cortex. IPC, even if combined with hHcy, could still preserve the neuronal tissue from the lethal ischemic effects. This review also describes the changes in the mitogen-activated protein kinase (MAPK) protein pathways following ischemic injury and IPC. These studies provide evidence for the interplay and tight integration between ERK and p38 MAPK signaling mechanisms in response to the hHcy and also in association of hHcy with ischemia/IPC challenge in the rat brain. Further investigations of the protective factors leading to ischemic tolerance and recognition of the co-morbid risk factors would result in development of new avenues for exploration of novel therapeutics against ischemia and stroke. PMID- 27932946 TI - Increased Brain Neurotensin and NTSR2 Lead to Weak Nociception in NTSR3/Sortilin Knockout Mice. AB - The neuropeptide neurotensin (NT) elicits numerous pharmacological effects through three different receptors (NTSR1, NTSR2, and NTSR3 also called sortilin). Pharmacological approaches and generation of NTSR1 and NTSR2-deficient mice allowed to determine the NT-induced antipsychotic like behavior, the inhibitory of weak fear memory and the nociceptive signaling in a rat formalin tonic pain model to NTSR1. Conversely, the effects of NT on thermal and tonic nociceptions were mediated by NTSR2. However, the role of NTSR3/sortilin on the neurotensinergic system was not investigated. Here, by using C57Bl/6J mouse model in which the gene coding for NTSR3/sortilin has been inactivated, we observed a modification of the expression of both NTSR2 and NT itself. Quantitative PCR and protein expression using Western blot analyses and AlphaLisaTM technology resulted in the observation that brain NTSR2 as well as brain and blood NT were 2 fold increased in KO mice leading to a resistance of these mice to thermal and chemical pain. These data confirm that NTSR3/sortilin interacts with other NT receptors (i.e., NTSR2) and that its deletion modifies also the affinity of this receptor to NT. PMID- 27932947 TI - Increased fMRI Sensitivity at Equal Data Burden Using Averaged Shifted Echo Acquisition. AB - There is growing evidence as to the benefits of collecting BOLD fMRI data with increased sampling rates. However, many of the newly developed acquisition techniques developed to collect BOLD data with ultra-short TRs require hardware, software, and non-standard analytic pipelines that may not be accessible to all researchers. We propose to incorporate the method of shifted echo into a standard multi-slice, gradient echo EPI sequence to achieve a higher sampling rate with a TR of <1 s with acceptable spatial resolution. We further propose to incorporate temporal averaging of consecutively acquired EPI volumes to both ameliorate the reduced temporal signal-to-noise inherent in ultra-fast EPI sequences and reduce the data burden. BOLD data were collected from 11 healthy subjects performing a simple, event-related visual-motor task with four different EPI sequences: (1) reference EPI sequence with TR = 1440 ms, (2) shifted echo EPI sequence with TR = 700 ms, (3) shifted echo EPI sequence with every two consecutively acquired EPI volumes averaged and effective TR = 1400 ms, and (4) shifted echo EPI sequence with every four consecutively acquired EPI volumes averaged and effective TR = 2800 ms. Both the temporally averaged sequences exhibited increased temporal signal-to-noise over the shifted echo EPI sequence. The shifted echo sequence with every two EPI volumes averaged also had significantly increased BOLD signal change compared with the other three sequences, while the shifted echo sequence with every four EPI volumes averaged had significantly decreased BOLD signal change compared with the other three sequences. The results indicated that incorporating the method of shifted echo into a standard multi-slice EPI sequence is a viable method for achieving increased sampling rate for collecting event related BOLD data. Further, consecutively averaging every two consecutively acquired EPI volumes significantly increased the measured BOLD signal change and the subsequently calculated activation map statistics. PMID- 27932949 TI - Muscle-Type Nicotinic Receptor Modulation by 2,6-Dimethylaniline, a Molecule Resembling the Hydrophobic Moiety of Lidocaine. AB - To identify the molecular determinants responsible for lidocaine blockade of muscle-type nAChRs, we have studied the effects on this receptor of 2,6 dimethylaniline (DMA), which resembles lidocaine's hydrophobic moiety. Torpedo marmorata nAChRs were microtransplanted to Xenopus oocytes and currents elicited by ACh (IACh), either alone or co-applied with DMA, were recorded. DMA reversibly blocked IACh and, similarly to lidocaine, exerted a closed-channel blockade, as evidenced by the enhancement of IACh blockade when DMA was pre-applied before its co-application with ACh, and hastened IACh decay. However, there were marked differences among its mechanisms of nAChR inhibition and those mediated by either the entire lidocaine molecule or diethylamine (DEA), a small amine resembling lidocaine's hydrophilic moiety. Thereby, the IC50 for DMA, estimated from the dose-inhibition curve, was in the millimolar range, which is one order of magnitude higher than that for either DEA or lidocaine. Besides, nAChR blockade by DMA was voltage-independent in contrast to the increase of IACh inhibition at negative potentials caused by the more polar lidocaine or DEA molecules. Accordingly, virtual docking assays of DMA on nAChRs showed that this molecule binds predominantly at intersubunit crevices of the transmembrane-spanning domain, but also at the extracellular domain. Furthermore, DMA interacted with residues inside the channel pore, although only in the open-channel conformation. Interestingly, co-application of ACh with DEA and DMA, at their IC50s, had additive inhibitory effects on IACh and the extent of blockade was similar to that predicted by the allotopic model of interaction, suggesting that DEA and DMA bind to nAChRs at different loci. These results indicate that DMA mainly mimics the low potency and non-competitive actions of lidocaine on nAChRs, as opposed to the high potency and voltage-dependent block by lidocaine, which is emulated by the hydrophilic DEA. Furthermore, it is pointed out that the hydrophobic (DMA) and hydrophilic (DEA) moieties of the lidocaine molecule act differently on nAChRs and that their separate actions taken together account for most of the inhibitory effects of the whole lidocaine molecule on nAChRs. PMID- 27932948 TI - RNA Editing-Systemic Relevance and Clue to Disease Mechanisms? AB - Recent advances in sequencing technologies led to the identification of a plethora of different genes and several hundreds of amino acid recoding edited positions. Changes in editing rates of some of these positions were associated with diseases such as atherosclerosis, myopathy, epilepsy, major depression disorder, schizophrenia and other mental disorders as well as cancer and brain tumors. This review article summarizes our current knowledge on that front and presents glycine receptor C-to-U RNA editing as a first example of disease associated increased RNA editing that includes assessment of disease mechanisms of the corresponding gene product in an animal model. PMID- 27932951 TI - High Pressure-Induced mtDNA Alterations in Retinal Ganglion Cells and Subsequent Apoptosis. AB - Purpose: Our previous study indicated that mitochondrial DNA (mtDNA) damage and mutations are crucial to the progressive loss of retinal ganglion cells (RGCs) in a glaucomatous rat model. In this study, we examined whether high pressure could directly cause mtDNA alterations and whether the latter could lead to mitochondrial dysfunction and RGC death. Methods: Primary cultured rat RGCs were exposed to 30 mm Hg of hydrostatic pressure (HP) for 12, 24, 48, 72, 96 and 120 h. mtDNA alterations and mtDNA repair/replication enzymes OGG1, MYH and polymerase gamma (POLG) expressions were also analyzed. The RGCs were then infected with a lentiviral small hairpin RNA (shRNA) expression vector targeting POLG (POLG-shRNA), and mtDNA alterations as well as mitochondrial function, including complex I/III activities and ATP production were subsequently studied at appropriate times. Finally, RGC apoptosis and the mitochondrial-apoptosis pathway-related protein cleaved caspase-3 were detected using a Terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay and western blotting, respectively. Results: mtDNA damage was observed as early as 48 h after the exposure of RGCs to HP. At 120 h after HP, mtDNA damage and mutations significantly increased, reaching >40% and 4.8 +/- 0.3-fold, respectively, compared with the control values. Twelve hours after HP, the expressions of OGG1, MYH and POLG mRNA in the RGCs were obviously increased 5.02 +/- 0.6-fold (p < 0.01), 4.3 +/- 0.2-fold (p < 0.05), and 0.8 +/- 0.09-fold (p < 0.05). Western blot analysis showed that the protein levels of the three enzymes decreased at 72 and 120 h after HP (p < 0.05). After interference with POLG-shRNA, the mtDNA damage and mutations were significantly increased (p < 0.01), while complex I/III activities gradually decreased (p < 0.05). Corresponding decreases in membrane potential and ATP production appeared at 5 and 6 days after POLG-shRNA transfection respectively (p < 0.05). Increases in the apoptosis of RGCs and cleaved caspase-3 protein expression were observed after mtDNA damage and mutations. Conclusions: High pressures could directly cause mtDNA alterations, leading to mitochondrial dysfunction and RGC death. PMID- 27932945 TI - Monoaminergic and Histaminergic Strategies and Treatments in Brain Diseases. AB - The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review. PMID- 27932952 TI - Evaluating Tools for Live Imaging of Structural Plasticity at the Axon Initial Segment. AB - The axon initial segment (AIS) is a specialized neuronal compartment involved in the maintenance of axo-dendritic polarity and in the generation of action potentials. It is also a site of significant structural plasticity-manipulations of neuronal activity in vitro and in vivo can produce changes in AIS position and/or size that are associated with alterations in intrinsic excitability. However, to date all activity-dependent AIS changes have been observed in experiments carried out on fixed samples, offering only a snapshot, population wide view of this form of plasticity. To extend these findings by following morphological changes at the AIS of individual neurons requires reliable means of labeling the structure in live preparations. Here, we assessed five different immunofluorescence-based and genetically-encoded tools for live-labeling the AIS of dentate granule cells (DGCs) in dissociated hippocampal cultures. We found that an antibody targeting the extracellular domain of neurofascin provided accurate live label of AIS structure at baseline, but could not follow rapid activity-dependent changes in AIS length. Three different fusion constructs of GFP with full-length AIS proteins also proved unsuitable: while neurofascin-186 GFP and NaVbeta4-GFP did not localize to the AIS in our experimental conditions, overexpressing 270kDa-AnkyrinG-GFP produced abnormally elongated AISs in mature neurons. In contrast, a genetically-encoded construct consisting of a voltage gated sodium channel intracellular domain fused to yellow fluorescent protein (YFP-NaVII-III) fulfilled all of our criteria for successful live AIS label: this construct specifically localized to the AIS, accurately revealed plastic changes at the structure within hours, and, crucially, did not alter normal cell firing properties. We therefore recommend this probe for future studies of live AIS plasticity in vitro and in vivo. PMID- 27932953 TI - Biotic/Abiotic Stress-Driven Alzheimer's Disease. PMID- 27932950 TI - Amyloid Precursor Proteins Are Dynamically Trafficked and Processed during Neuronal Development. AB - Proteolytic processing of the Amyloid Precursor Protein (APP) produces beta amyloid (Abeta) peptide fragments that accumulate in Alzheimer's Disease (AD), but APP may also regulate multiple aspects of neuronal development, albeit via mechanisms that are not well understood. APP is a member of a family of transmembrane glycoproteins expressed by all higher organisms, including two mammalian orthologs (APLP1 and APLP2) that have complicated investigations into the specific activities of APP. By comparison, insects express only a single APP related protein (APP-Like, or APPL) that contains the same protein interaction domains identified in APP. However, unlike its mammalian orthologs, APPL is only expressed by neurons, greatly simplifying an analysis of its functions in vivo. Like APP, APPL is processed by secretases to generate a similar array of extracellular and intracellular cleavage fragments, as well as an Abeta-like fragment that can induce neurotoxic responses in the brain. Exploiting the complementary advantages of two insect models (Drosophila melanogaster and Manduca sexta), we have investigated the regulation of APPL trafficking and processing with respect to different aspects of neuronal development. By comparing the behavior of endogenously expressed APPL with fluorescently tagged versions of APPL and APP, we have shown that some full-length protein is consistently trafficked into the most motile regions of developing neurons both in vitro and in vivo. Concurrently, much of the holoprotein is rapidly processed into N- and C-terminal fragments that undergo bi-directional transport within distinct vesicle populations. Unexpectedly, we also discovered that APPL can be transiently sequestered into an amphisome-like compartment in developing neurons, while manipulations targeting APPL cleavage altered their motile behavior in cultured embryos. These data suggest that multiple mechanisms restrict the bioavailability of the holoprotein to regulate APPL-dependent responses within the nervous system. Lastly, targeted expression of our double-tagged constructs (combined with time-lapse imaging) revealed that APP family proteins are subject to complex patterns of trafficking and processing that vary dramatically between different neuronal subtypes. In combination, our results provide a new perspective on how the regulation of APP family proteins can be modulated to accommodate a variety of cell type-specific responses within the embryonic and adult nervous system. PMID- 27932954 TI - Neuronal Release of Cytokine IL-3 Triggered by Mechanosensitive Autostimulation of the P2X7 Receptor Is Neuroprotective. AB - Mechanical strain due to increased pressure or swelling activates inflammatory responses in many neural systems. As cytokines and chemokine messengers lead to both pro-inflammatory and neuroprotective actions, understanding the signaling patterns triggered by mechanical stress may help improve overall outcomes. While cytokine signaling in neural systems is often associated with glial cells like astrocytes and microglia, the contribution of neurons themselves to the cytokine response is underappreciated and has bearing on any balanced response. Mechanical stretch of isolated neurons was previously shown to trigger ATP release through pannexin hemichannels and autostimulation of P2X7 receptors (P2X7Rs) on the neural membrane. Given that P2X7Rs are linked to cytokine activation in other cells, this study investigates the link between neuronal stretch and cytokine release through a P2X7-dependent pathway. Cytokine assays showed application of a 4% strain to isolated rat retinal ganglion cells (RGCs) released multiple cytokines. The P2X7R agonist BzATP also released multiple cytokines; Interleukin 3 (IL-3), TNF-alpha, CXCL9, VEGF, L-selectin, IL-4, GM-CSF, IL-10, IL-1Ralpha, MIP and CCL20 were released by both stimuli, with the release of IL-3 greatest with either stimuli. Stretch-dependent IL-3 release was confirmed with ELISA and blocked by P2X7R antagonists A438079 and Brilliant Blue G (BBG), implicating autostimulation of the P2X7R in stretch-dependent IL-3 release. Neuronal IL-3 release triggered by BzATP required extracellular calcium. The IL-3Ralpha receptor was expressed on RGCs but not astrocytes, and both IL-3Ralpha and IL-3 itself were predominantly expressed in the retinal ganglion cell layer of adult retinal sections, implying autostimulation of receptors by released IL-3. While the number of surviving ganglion cells decreased with time in culture, the addition of IL-3 protected against this loss of neurons. Expression of mRNA for IL-3 and IL-3Ralpha increased in rat retinas stretched with moderate intraocular pressure (IOP) elevation; BBG blocked the rise in IL-3, implicating a role for the P2X7R in transcriptional regulation in vivo. In summary, mechanical stretch triggers release of cytokines from neurons that can convey neuroprotection. The enhancement of these signals in vivo implicates P2X7R-mediated IL-3 signaling as an endogenous pathway that could minimize damage following neuronal exposure to chronic mechanical strain. PMID- 27932955 TI - What Do We Really Know About 5-HT1A Receptor Signaling in Neuronal Cells? AB - Serotonin (5-HT) is a neurotransmitter that plays an important role in neuronal plasticity. Variations in the levels of 5-HT at the synaptic cleft, expression or dysfunction of 5-HT receptors may alter brain development and predispose to various mental diseases. Here, we review the transduction pathways described in various cell types transfected with recombinant 5-HT1A receptor (5-HT1AR), specially contrasting with those findings obtained in neuronal cells. The 5-HT1AR is detected in early stages of neural development and is located in the soma, dendrites and spines of hippocampal neurons. The 5-HT1AR differs from other 5-HT receptors because it is coupled to different pathways, depending on the targeted cell. The signaling pathway associated with this receptor is determined by Galpha isoforms and some cascades involve betagamma signaling. The activity of 5-HT1AR usually promotes a reduction in neuronal excitability and firing, provokes a variation in cAMP and Ca2+, levels which may be linked to specific types of behavior and cognition. Furthermore, evidence indicates that 5-HT1AR induces neuritogesis and synapse formation, probably by modulation of the neuronal cytoskeleton through MAPK and phosphoinositide-3-kinase (PI3K)-Akt signaling pathways. Advances in understanding the actions of 5-HT1AR and its association with different signaling pathways in the central nervous system will reveal their pivotal role in health and disease. PMID- 27932956 TI - Hypothalamic Vasopressinergic Projections Innervate Central Amygdala GABAergic Neurons: Implications for Anxiety and Stress Coping. AB - The arginine-vasopressin (AVP)-containing hypothalamic magnocellular neurosecretory neurons (VPMNNs) are known for their role in hydro-electrolytic balance control via their projections to the neurohypophysis. Recently, projections from these same neurons to hippocampus, habenula and other brain regions in which vasopressin infusion modulates contingent social and emotionally affected behaviors, have been reported. Here, we present evidence that VPMNN collaterals also project to the amygdaloid complex, and establish synaptic connections with neurons in central amygdala (CeA). The density of AVP innervation in amygdala was substantially increased in adult rats that had experienced neonatal maternal separation (MS), consistent with our previous observations that MS enhances VPMNN number in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. In the CeA, V1a AVP receptor mRNA was only observed in GABAergic neurons, demonstrated by complete co-localization of V1a transcripts in neurons expressing Gad1 and Gad2 transcripts in CeA using the RNAscope method. V1b and V2 receptor mRNAs were not detected, using the same method. Water-deprivation (WD) for 24 h, which increased the metabolic activity of VPMNNs, also increased anxiety-like behavior measured using the elevated plus maze (EPM) test, and this effect was mimicked by bilateral microinfusion of AVP into the CeA. Anxious behavior induced by either WD or AVP infusion was reversed by CeA infusion of V1a antagonist. VPMNNs are thus a newly discovered source of CeA inhibitory circuit modulation, through which both early-life and adult stress coping signals are conveyed from the hypothalamus to the amygdala. PMID- 27932957 TI - Emergence of Selectivity to Looming Stimuli in a Spiking Network Model of the Optic Tectum. AB - The neural circuits in the optic tectum of Xenopus tadpoles are selectively responsive to looming visual stimuli that resemble objects approaching the animal at a collision trajectory. This selectivity is required for adaptive collision avoidance behavior in this species, but its underlying mechanisms are not known. In particular, it is still unclear how the balance between the recurrent spontaneous network activity and the newly arriving sensory flow is set in this structure, and to what degree this balance is important for collision detection. Also, despite the clear indication for the presence of strong recurrent excitation and spontaneous activity, the exact topology of recurrent feedback circuits in the tectum remains elusive. In this study we take advantage of recently published detailed cell-level data from tadpole tectum to build an informed computational model of it, and investigate whether dynamic activation in excitatory recurrent retinotopic networks may on its own underlie collision detection. We consider several possible recurrent connectivity configurations and compare their performance for collision detection under different levels of spontaneous neural activity. We show that even in the absence of inhibition, a retinotopic network of quickly inactivating spiking neurons is naturally selective for looming stimuli, but this selectivity is not robust to neuronal noise, and is sensitive to the balance between direct and recurrent inputs. We also describe how homeostatic modulation of intrinsic properties of individual tectal cells can change selectivity thresholds in this network, and qualitatively verify our predictions in a behavioral experiment in freely swimming tadpoles. PMID- 27932958 TI - The Shark Alar Hypothalamus: Molecular Characterization of Prosomeric Subdivisions and Evolutionary Trends. AB - The hypothalamus is an important physiologic center of the vertebrate brain involved in the elaboration of individual and species survival responses. To better understand the ancestral organization of the alar hypothalamus we revisit previous data on ScOtp, ScDlx2/5, ScTbr1, ScNkx2.1 expression and Pax6 immunoreactivity jointly with new data on ScNeurog2, ScLhx9, ScLhx5, and ScNkx2.8 expression, in addition to immunoreactivity to serotonin (5-HT) and doublecortin (DCX) in the catshark Scyliorhinus canicula, a key species for this purpose since cartilaginous fishes are basal representatives of gnathostomes (jawed vertebrates). Our study revealed a complex genoarchitecture for the chondrichthyan alar hypothalamus. We identified terminal (rostral) and peduncular (caudal) subdivisions in the prosomeric paraventricular and subparaventricular areas (TPa/PPa and TSPa/PSPa, respectively) evidenced by the expression pattern of developmental genes like ScLhx5 (TPa) and immunoreactivity against Pax6 (PSPa) and 5-HT (PPa and PSPa). Dorso-ventral subdivisions were only evidenced in the SPa (SPaD, SPaV; respectively) by means of Pax6 and ScNkx2.8 (respectively). Interestingly, ScNkx2.8 expression overlaps over the alar-basal boundary, as Nkx2.2 does in other vertebrates. Our results reveal evidences for the existence of different groups of tangentially migrated cells expressing ScOtp, Pax6, and ScDlx2. The genoarchitectonic comparative analysis suggests alternative interpretations of the rostral-most alar plate in prosomeric terms and reveals a conserved molecular background for the vertebrate alar hypothalamus likely acquired before/during the agnathan-gnathostome transition, on which Otp, Pax6, Lhx5, and Neurog2 are expressed in the Pa while Dlx and Nkx2.2/Nkx2.8 are expressed in the SPa. PMID- 27932959 TI - Exposure to Ketamine Anesthesia Affects Rat Impulsive Behavior. AB - Introduction: Ketamine is a general anesthetic (GA) that activates several neurotransmitter pathways in various part of the brain. The acute effects as GA are the most well-known and sought-after: to induce loss of responsiveness and to produce immobility during invasive procedures. However, there is a concern that repeated exposure might induce behavioral changes that could outlast their acute effect. Most research in this field describes how GA affects cognition and memory. Our work is to access if general anesthesia with ketamine can disrupt the motivational behavior trait, more specifically measuring impulsive behavior. Methods: Aiming to evaluate the effects of exposure to repeat anesthetic procedures with ketamine in motivational behavior, we tested animals in a paradigm of impulsive behavior, the variable delay-to-signal (VDS). In addition, accumbal and striatal medium spiny neurons morphology was assessed. Results: Our results demonstrated that previous exposure to ketamine deep-anesthesia affects inhibitory control (impulsive behavior). Specifically, ketamine exposed animals maintain a subnormal impulsive rate in the initial periods of the delays. However, in longer delays while control animals progressively refrain their premature unrewarded actions, ketamine-exposed animals show a different profile of response with higher premature unrewarded actions in the last seconds. Animals exposed to multiple ketamine anesthesia also failed to show an increase in premature unrewarded actions between the initial and final periods of 3 s delays. These behavioral alterations are paralleled by an increase in dendritic length of medium spiny neurons of the nucleus accumbens (NAc). Conclusions: This demonstrates that ketamine anesthesia acutely affects impulsive behavior. Interestingly, it also opens up the prospect of using ketamine as an agent with the ability to modulate impulsivity trait. PMID- 27932960 TI - Noise Improves Visual Motion Discrimination via a Stochastic Resonance-Like Phenomenon. AB - The stochastic resonance (SR) is a phenomenon in which adding a moderate amount of noise can improve the signal-to-noise ratio and performance of non-linear systems. SR occurs in all sensory modalities including the visual system in which noise can enhance contrast detection sensitivity and the perception of ambiguous figures embedded in static scenes. Here, we explored how adding background white pixel-noise to a random dot motion (RDM) stimulus produced changes in visual motion discrimination in healthy human adults. We found that, although the average reaction times (RTs) remained constant, an intermediate level of noise improved the subjects' ability to discriminate motion direction in the RDM task. The psychophysical responses followed an inverted U-like function of the input noise, whereas the incorrect responses with short RTs did not exhibit such modulation by external noise. Moreover, by applying stimulus and noisy signals to different eyes, we found that the SR phenomenon occurred presumably in the primary visual cortex, where these two signals first converge. Our results suggest that a SR-like phenomenon mediates the improvement of visual motion perception in the RDM task. PMID- 27932961 TI - Patient-Specific Electric Field Simulations and Acceleration Measurements for Objective Analysis of Intraoperative Stimulation Tests in the Thalamus. AB - Despite an increasing use of deep brain stimulation (DBS) the fundamental mechanisms of action remain largely unknown. Simulation of electric entities has previously been proposed for chronic DBS combined with subjective symptom evaluations, but not for intraoperative stimulation tests. The present paper introduces a method for an objective exploitation of intraoperative stimulation test data to identify the optimal implant position of the chronic DBS lead by relating the electric field (EF) simulations to the patient-specific anatomy and the clinical effects quantified by accelerometry. To illustrate the feasibility of this approach, it was applied to five patients with essential tremor bilaterally implanted in the ventral intermediate nucleus (VIM). The VIM and its neighborhood structures were preoperatively outlined in 3D on white matter attenuated inversion recovery MR images. Quantitative intraoperative clinical assessments were performed using accelerometry. EF simulations (n = 272) for intraoperative stimulation test data performed along two trajectories per side were set-up using the finite element method for 143 stimulation test positions. The resulting EF isosurface of 0.2 V/mm was superimposed to the outlined anatomical structures. The percentage of volume of each structure's overlap was calculated and related to the corresponding clinical improvement. The proposed concept has been successfully applied to the five patients. For higher clinical improvements, not only the VIM but as well other neighboring structures were covered by the EF isosurfaces. The percentage of the volumes of the VIM, of the nucleus intermediate lateral of the thalamus and the prelemniscal radiations within the prerubral field of Forel increased for clinical improvements higher than 50% compared to improvements lower than 50%. The presented new concept allows a detailed and objective analysis of a high amount of intraoperative data to identify the optimal stimulation target. First results indicate agreement with published data hypothesizing that the stimulation of other structures than the VIM might be responsible for good clinical effects in essential tremor. (Clinical trial reference number: Ref: 2011-A00774-37/AU905). PMID- 27932962 TI - Neural Differences between Covert and Overt Attention Studied using EEG with Simultaneous Remote Eye Tracking. AB - Research on neural mechanisms of attention has generally instructed subjects to direct attention covertly while maintaining a fixed gaze. This study combined simultaneous eye tracking and electroencephalogram (EEG) to measure neural attention responses during exogenous cueing in overt attention shifts (with saccadic eye movements to a target) and compared these with covert attention shifts (responding manually while maintaining central fixation). EEG analysis of the period preceding the saccade latency showed similar occipital response amplitudes for overt and covert shifts, although response latencies differed. However, a frontal positivity was greater during covert attention shifts, possibly reflecting saccade inhibition to maintain fixation. The results show that combined EEG and eye tracking can be successfully used to study natural overt shifts of attention (applicable to non-verbal infants) and that requiring inhibition of saccades can lead to additional frontal responses. Such data can be used to refine current neural models of attention that have been mainly based on covert shifts. PMID- 27932963 TI - Distinct Neural Substrates for Maintaining Locations and Spatial Relations in Working Memory. AB - Previous work has demonstrated a distinction between maintenance of two types of spatial information in working memory (WM): spatial locations and spatial relations. While a body of work has investigated the neural mechanisms of sensory based information like spatial locations, little is known about how spatial relations are maintained in WM. In two experiments, we used fMRI to investigate the involvement of early visual cortex in the maintenance of spatial relations in WM. In both experiments, we found less quadrant-specific BOLD activity in visual cortex when a single spatial relation, compared to a single spatial location, was held in WM. Also across both experiments, we found a consistent set of brain regions that were differentially activated during maintenance of locations vs. relations. Maintaining a location, compared to a relation, was associated with greater activity in typical spatial WM regions like posterior parietal cortex and prefrontal regions. Whereas maintaining a relation, compared to a location, was associated with greater activity in the parahippocampal gyrus and precuneus/retrosplenial cortex. Further, in Experiment 2 we manipulated WM load and included trials where participants had to maintain three spatial locations or relations. Under this high load condition, the regions sensitive to locations vs. relations were somewhat different than under low load. We also identified regions that were sensitive to load specifically for location or relation maintenance, as well as overlapping regions sensitive to load more generally. These results suggest that the neural substrates underlying WM maintenance of spatial locations and relations are distinct from one another and that the neural representations of these distinct types of spatial information change with load. PMID- 27932964 TI - Temporary Nerve Block at Selected Digits Revealed Hand Motor Deficits in Grasping Tasks. AB - Peripheral sensory feedback plays a crucial role in ensuring correct motor execution throughout hand grasp control. Previous studies utilized local anesthesia to deprive somatosensory feedback in the digits or hand, observations included sensorimotor deficits at both corticospinal and peripheral levels. However, the questions of how the disturbed and intact sensory input integrate and interact with each other to assist the motor program execution, and whether the motor coordination based on motor output variability between affected and non affected elements (e.g., digits) becomes interfered by the local sensory deficiency, have not been answered. The current study aims to investigate the effect of peripheral deafferentation through digital nerve blocks at selective digits on motor performance and motor coordination in grasp control. Our results suggested that the absence of somatosensory information induced motor deficits in hand grasp control, as evidenced by reduced maximal force production ability in both local and non-local digits, impairment of force and moment control during object lift and hold, and attenuated motor synergies in stabilizing task performance variables, namely the tangential force and moment of force. These findings implied that individual sensory input is shared across all the digits and the disturbed signal from local sensory channel(s) has a more comprehensive impact on the process of the motor output execution in the sensorimotor integration process. Additionally, a feedback control mechanism with a sensation based component resides in the formation process for the motor covariation structure. PMID- 27932965 TI - The Neural Correlates of Humor Creativity. AB - Unlike passive humor appreciation, the neural correlates of real-time humor creation have been unexplored. As a case study for creativity, humor generation uniquely affords a reliable assessment of a creative product's quality with a clear and relatively rapid beginning and end, rendering it amenable to neuroimaging that has the potential for reflecting individual differences in expertise. Professional and amateur "improv" comedians and controls viewed New Yorker cartoon drawings while being scanned. For each drawing, they were instructed to generate either a humorous or a mundane caption. Greater comedic experience was associated with decreased activation in the striatum and medial prefrontal cortex (mPFC), but increased activation in temporal association regions (TMP). Less experienced comedians manifested greater activation of mPFC, reflecting their deliberate search through TMP association space. Professionals, by contrast, tend to reap the fruits of their spontaneous associations with reduced reliance on top-down guided search. PMID- 27932966 TI - Combination of Static Magnetic Fields and Peripheral Nerve Stimulation Can Alter Focal Cortical Excitability. AB - For clinical application of transcranial static magnetic stimulation (tSMS), it is important to achieve a focal target cortical stimulation. Previous study suggested that the associative stimulation combining non-invasive stimulation of the motor cortex (M1) and the peripheral nerve stimulation (PNS) may be useful to produce cortical excitability change. To test this hypothesis, we measured the M1 excitability and intracortical circuits by using transcranial magnetic stimulation (TMS) before and after the tSMS of short duration (5 min) combined with PNS. Thirty-three normal volunteers were participated; tSMS+PNS (n = 11), sham+PNS (n = 11), and tSMS alone (n = 11). We found the transient suppression of the motor-evoked potential (MEP) of the right abductor pollicis brevis (APB) muscle, but not of the abductor digiti minimi (ADM) muscle, when combining tSMS with PNS over median nerve at the wrist. The lack of suppressive effect on APB in tSMS alone with short duration is in accord with the previous observation. In addition, the tendency of transient enhancement of the short-latency intracortical inhibition was observed immediately after intervention in the tSMS+/-PNS group. These findings show that the combination of tSMS and PNS can induce the cortical excitability change in target cortical motor area and potentiate the suppression effect. PMID- 27932967 TI - Better Not to Know? Emotion Regulation Fails to Benefit from Affective Cueing. AB - Often we know whether an upcoming event is going to be good or bad. But does that knowledge help us regulate ensuing emotions? To address this question, we exposed participants to alleged social feedback that was either positive or negative. On half the trials, a preceding cue indicated the feedback's affective quality. On the remaining trials, the cue was uninformative. In two different blocks, participants either appraised feedback spontaneously or down-regulated ensuing emotions using a controlled appraisal strategy. Event-related potentials (ERPs) recorded throughout both blocks revealed an increased late positive potential (LPP) during cue and feedback epochs when cues were affectively informative as compared to uninformative. Additionally, during feedback epochs only, informative, but not uninformative, cueing was associated with an appraisal effect whereby controlled appraisal reduced the LPP relative to spontaneous appraisal for negative feedback. There was an opposite trend for positive feedback. Together, these results suggest that informative cues allowed individuals to anticipate an emotional response and to adjust emotion regulation. Overall, however, informative cues seemed to have prolonged and intensified emotional responding when compared with uninformative cues. Thus, affective cueing appears to be contraindicated when individuals aim to reduce their emotions. PMID- 27932969 TI - Variability of Neuronal Responses: Types and Functional Significance in Neuroplasticity and Neural Darwinism. AB - HIGHLIGHTS We suggest classifying variability of neuronal responses as follows: false (associated with a lack of knowledge about the influential factors), "genuine harmful" (noise), "genuine neutral" (synonyms, repeats), and "genuine useful" (the basis of neuroplasticity and learning).The genuine neutral variability is considered in terms of the phenomenon of degeneracy.Of particular importance is the genuine useful variability that is considered as a potential basis for neuroplasticity and learning. This type of variability is considered in terms of the neural Darwinism theory. In many cases, neural signals detected under the same external experimental conditions significantly change from trial to trial. The variability phenomenon, which complicates extraction of reproducible results and is ignored in many studies by averaging, has attracted attention of researchers in recent years. In this paper, we classify possible types of variability based on its functional significance and describe features of each type. We describe the key adaptive significance of variability at the neural network level and the degeneracy phenomenon that may be important for learning processes in connection with the principle of neuronal group selection. PMID- 27932968 TI - Neurobiology of Anorexia Nervosa: Serotonin Dysfunctions Link Self-Starvation with Body Image Disturbances through an Impaired Body Memory. AB - The etiology of anorexia nervosa (AN) is still unclear, despite that it is a critical and potentially mortal illness. A recent neurobiological model considers AN as the outcome of dysfunctions in the neuronal processes related to appetite and emotionality (Kaye et al., 2009, 2013). However, this model still is not able to answer a critical question: What is behind body image disturbances (BIDs) in AN? The article starts its analysis from reviewing some of the studies exploring the effects of the serotonin systems in memory (episodic, working, and spatial) and its dysfunctions. The review suggests that serotonin disturbances may: (a) facilitate the encoding of third person (allocentric) episodic memories; (b) facilitate the consolidation of emotional episodic memories (e.g., teasing), if preceded by repeated stress; (c) reduce voluntary inhibition of mnestic contents; (d) impair allocentric spatial memory. If we discuss these results within the interpretative frame suggested by the "Allocentric Lock Hypothesis" (Riva, 2012, 2014), we can hypothesize that altered serotoninergic activity in AN patients: (i) improves their ability to store and consolidate negative autobiographical memories, including those of their body, in allocentric perspective; (ii) impairs their ability to trigger voluntary inhibition of the previously stored negative memory of the body; (iii) impairs their capacity to retrieve/update allocentric information. Taken together, these points suggest a possible link between serotonin dysfunctions, memory impairments and BIDs: the impossibility of updating a disturbed body memory using real time experiential data-I'm locked to a wrong body stored in long term memory-pushes AN patients to control body weight and shape even when underweight. PMID- 27932970 TI - Bayesian Inference of Synaptic Quantal Parameters from Correlated Vesicle Release. AB - Synaptic transmission is both history-dependent and stochastic, resulting in varying responses to presentations of the same presynaptic stimulus. This complicates attempts to infer synaptic parameters and has led to the proposal of a number of different strategies for their quantification. Recently Bayesian approaches have been applied to make more efficient use of the data collected in paired intracellular recordings. Methods have been developed that either provide a complete model of the distribution of amplitudes for isolated responses or approximate the amplitude distributions of a train of post-synaptic potentials, with correct short-term synaptic dynamics but neglecting correlations. In both cases the methods provided significantly improved inference of model parameters as compared to existing mean-variance fitting approaches. However, for synapses with high release probability, low vesicle number or relatively low restock rate and for data in which only one or few repeats of the same pattern are available, correlations between serial events can allow for the extraction of significantly more information from experiment: a more complete Bayesian approach would take this into account also. This has not been possible previously because of the technical difficulty in calculating the likelihood of amplitudes seen in correlated post-synaptic potential trains; however, recent theoretical advances have now rendered the likelihood calculation tractable for a broad class of synaptic dynamics models. Here we present a compact mathematical form for the likelihood in terms of a matrix product and demonstrate how marginals of the posterior provide information on covariance of parameter distributions. The associated computer code for Bayesian parameter inference for a variety of models of synaptic dynamics is provided in the Supplementary Material allowing for quantal and dynamical parameters to be readily inferred from experimental data sets. PMID- 27932971 TI - Evaluation of Phase-Amplitude Coupling in Resting State Magnetoencephalographic Signals: Effect of Surrogates and Evaluation Approach. AB - Phase-amplitude coupling (PAC) plays an important role in neural communication and computation. Interestingly, recent studies have indicated the presence of ubiquitous PAC phenomenon even during the resting state. Despite the importance of PAC phenomenon, estimation of significant physiological PAC is challenging because of the lack of appropriate surrogate measures to control false positives caused by non-physiological PAC. Therefore, in the present study, we evaluated PAC phenomenon during resting-state magnetoencephalography (MEG) signal and considered various surrogate measures and computational approaches widely used in the literature in addition to proposing new ones. We evaluated PAC phenomenon over the entire length of the MEG signal and for multiple shorter time segments. The results indicate that the extent of PAC phenomenon mainly depends on the surrogate measures and PAC computational methods used, as well as the evaluation approach. After a careful and critical evaluation, we found that resting-state MEG signals failed to exhibit ubiquitous PAC phenomenon, contrary to what has been suggested previously. PMID- 27932972 TI - The ACE Brain. PMID- 27932973 TI - Decline in Proliferation and Immature Neuron Markers in the Human Subependymal Zone during Aging: Relationship to EGF- and FGF-Related Transcripts. AB - Neuroblasts exist within the human subependymal zone (SEZ); however, it is debated to what extent neurogenesis changes during normal aging. It is also unknown how precursor proliferation may correlate with the generation of neuronal and glial cells or how expression of growth factors and receptors may change throughout the adult lifespan. We found evidence of dividing cells in the human SEZ (n D 50) in conjunction with a dramatic age-related decline (21-103 years) of mRNAs indicative of proliferating cells (Ki67) and immature neurons (doublecortin). Microglia mRNA (ionized calcium-binding adapter molecule 1) increased during aging, whereas transcript levels of stem/precursor cells (glial fibrillary acidic protein delta and achaete-scute homolog 1), astrocytes (vimentin and pan-glial fibrillary acidic protein), and oligodendrocytes (oligodendrocyte lineage transcription factor 2) remained stable. Epidermal growth factor receptor (EGFR) and fibroblast growth factor 2 (FGF2) mRNAs increased throughout adulthood, while transforming growth factor alpha (TGFalpha), EGF, Erb-B2 receptor tyrosine kinase 4 (ErbB4) and FGF receptor 1 (FGFR1) mRNAs were unchanged across adulthood. Cell proliferation mRNA positively correlated with FGFR1 transcripts. Immature neuron and oligodendrocyte marker expression positively correlated with TGFalpha and ErbB4 mRNAs, whilst astrocyte transcripts positively correlated with EGF, FGF2, and FGFR1 mRNAs. Microglia mRNA positively correlated with EGF and FGF2 expression. Our findings indicate that neurogenesis in the human SEZ continues well into adulthood, although proliferation and neuronal differentiation may decline across adulthood. We suggest that mRNA expression of EGF- and FGF-related family members do not become limited during aging and may modulate neuronal and glial fate determination in the SEZ throughout human life. PMID- 27932974 TI - Patterns of Longitudinal Neural Activity Linked to Different Cognitive Profiles in Parkinson's Disease. AB - Mild cognitive impairment in Parkinson's disease (PD) has been linked with functional brain changes. Previously, using functional magnetic resonance imaging (fMRI), we reported reduced cortico-striatal activity in patients with PD who also had mild cognitive impairment (MCI) vs. those who did not (non-MCI). We followed up these patients to investigate the longitudinal effect on the neural activity. Twenty-four non-demented patients with Parkinson's disease (non-MCI: 12, MCI: 12) were included in the study. Each participant underwent two fMRIs while performing the Wisconsin Card Sorting Task 20 months apart. The non-MCI patients recruited the usual cognitive corticostriatal loop at the first and second sessions (Time 1 and Time 2, respectively). However, decreased activity was observed in the cerebellum and occipital area and increased activity was observed in the medial prefrontal cortex and parietal lobe during planning set shift at Time 2. Increased activity in the precuneus was also demonstrated while executing set-shifts at Time 2. The MCI patients revealed more activity in the frontal, parietal and occipital lobes during planning set-shifts, and in the parietal and occipital lobes, precuneus, and cerebellum, during executing set shift at Time 2. Analysis regrouping of both groups of PD patients revealed that hippocampal and thalamic activity at Time 1 was associated with less cognitive decline over time. Our results reveal that functional alteration along the time points differed between the non-MCI and MCI patients. They also underline the importance of preserving thalamic and hippocampal function with respect to cognitive decline over time. PMID- 27932975 TI - Adaptations of Prefrontal Brain Activity, Executive Functions, and Gait in Healthy Elderly Following Exergame and Balance Training: A Randomized-Controlled Study. AB - During aging, the prefrontal cortex (PFC) undergoes age-dependent neuronal changes influencing cognitive and motor functions. Motor-learning interventions are hypothesized to ameliorate motor and cognitive deficits in older adults. Especially, video game-based physical exercise might have the potential to train motor in combination with cognitive abilities in older adults. The aim of this study was to compare conventional balance training with video game-based physical exercise, a so-called exergame, on the relative power (RP) of electroencephalographic (EEG) frequencies over the PFC, executive function (EF), and gait performance. Twenty-seven participants (mean age 79.2 +/- 7.3 years) were randomly assigned to one of two groups. All participants completed 24 trainings including three times a 30 min session/week. The EEG measurements showed that theta RP significantly decreased in favor of the exergame group [L(14) = 6.23, p = 0.007]. Comparing pre- vs. post-test, EFs improved both within the exergame (working memory: z = -2.28, p = 0.021; divided attention auditory: z = -2.51, p = 0.009; divided attention visual: z = -2.06, p = 0.040; go/no-go: z = -2.55, p = 0.008; set-shifting: z = -2.90, p = 0.002) and within the balance group (set-shifting: z = -2.04, p = 0.042). Moreover, spatio-temporal gait parameters primarily improved within the exergame group under dual-task conditions (speed normal walking: z = -2.90, p = 0.002; speed fast walking: z = 2.97, p = 0.001; cadence normal walking: z = -2.97, p = 0.001; stride length fast walking: z = -2.69, p = 0.005) and within the balance group under single-task conditions (speed normal walking: z = -2.54, p = 0.009; speed fast walking: z = 1.98, p = 0.049; cadence normal walking: z = -2.79, p = 0.003). These results indicate that exergame training as well as balance training positively influence prefrontal cortex activity and/or function in varying proportion. PMID- 27932977 TI - Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer's Disease by Enhancing Neuronal Connectivity and Metabolic Activity. AB - Alzheimer's disease (AD), the most frequent type of dementia, is featured by Abeta pathology, neural degeneration and cognitive decline. To date, there is no cure for this disease. Neural stem cell (NSC) transplantation provides new promise for treating AD. Many studies report that intra-hippocampal transplantation of murine NSCs improved cognition in rodents with AD by alleviating neurodegeneration via neuronal complement or replacement. However, few reports examined the potential of human NSC transplantation for AD. In this study, we implanted human brain-derived NSCs (hNSCs) into bilateral hippocampus of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mouse model of AD to test the effects of hNSC transplantation on Alzheimer's behavior and neuropathology. Six weeks later, transplanted hNSCs engrafted into the brains of AD mice, migrated dispersedly in broad brain regions, and some of them differentiated into neural cell types of central nervous system (CNS). The hNSC transplantation restored the recognition, learning and memory deficits but not anxiety tasks in AD mice. Although Abeta plaques were not significantly reduced, the neuronal, synaptic and nerve fiber density was significantly increased in the frontal cortex and hippocampus of hNSC-treated AD mice, suggesting of improved neuronal connectivity in AD brains after hNSC transplantation. Ultrastructural analysis confirmed that synapses and nerve fibers maintained relatively well structured shapes in these mice. Furthermore, in vivo magnetic resonance spectroscopy (MRS) showed that hNSC-treated mice had notably increased levels of N-acetylaspartate (NAA) and Glu in the frontal cortex and hippocampus, suggesting that neuronal metabolic activity was improved in AD brains after hNSC transplantation. These results suggest that transplanted hNSCs rescued Alzheimer's cognition by enhancing neuronal connectivity and metabolic activity through a compensation mechanism in APP/PS1 mice. This study provides preclinical evidence that hNSC transplantation can be a possible and feasible strategy for treating patients with AD. PMID- 27932976 TI - Melatonin and Nitrones As Potential Therapeutic Agents for Stroke. AB - Stroke is a disease of aging affecting millions of people worldwide, and recombinant tissue-type plasminogen activator (r-tPA) is the only treatment approved. However, r-tPA has a low therapeutic window and secondary effects which limit its beneficial outcome, urging thus the search for new more efficient therapies. Among them, neuroprotection based on melatonin or nitrones, as free radical traps, have arisen as drug candidates due to their strong antioxidant power. In this Perspective article, an update on the specific results of the melatonin and several new nitrones are presented. PMID- 27932978 TI - Gender Specific Re-organization of Resting-State Networks in Older Age. AB - Advancing age is commonly associated with changes in both brain structure and function. Recently, the suggestion that alterations in brain connectivity may drive disruption in cognitive abilities with age has been investigated. However, the interaction between the effects of age and gender on the re-organization of resting-state networks is not fully understood. This study sought to investigate the effect of both age and gender on intra- and inter-network functional connectivity (FC) and the extent to which resting-state network (RSN) node definition may alter with older age. We obtained resting-state functional magnetic resonance images from younger (n = 20) and older (n = 20) adults and assessed the FC of three main cortical networks: default mode (DMN), dorsal attention (DAN), and saliency (SN). Older adults exhibited reduced DMN intra network FC and increased inter-network FC between the anterior cingulate cortex (ACC) and nodes of the DAN, in comparison to younger participants. Furthermore, this increase in ACC-DAN inter-network FC with age was driven largely by male participants. However, further analyses suggested that the spatial location of ACC, bilateral anterior insula and orbitofrontal cortex RSN nodes changed with older age and that age-related gender differences in FC may reflect spatial re organization rather than increases or decreases in FC strength alone. These differences in both the FC and spatial distribution of RSNs between younger and older adults provide evidence of re-organization of fundamental brain networks with age, which is modulated by gender. These results highlight the need to further investigate changes in both intra- and inter-network FC with age, whilst also exploring the modifying effect of gender. They also emphasize the difficulties in directly comparing the FC of RSN nodes between groups and suggest that caution should be taken when using the same RSN node definitions for different age or patient groups to investigate FC. PMID- 27932979 TI - Madagascine Induces Vasodilatation via Activation of AMPK. AB - Madagascine (3-isopentenyloxyemodin) can be chemically synthesized or purified from several Rhamnus species, and it is found to have more potent biological activities than the parent compound emodin. The aim of this study is to characterize the vasodilatory effect of madagascine on vasoconstriction and sphingosylphosphorylcholine induced vasospasm in ex vivo and reveal the potential mechanisms in vitro. The effects of madagascine on vasoconstriction of rat mesenteric resistance arteries (MRAs) induced by K+, methoxamine, and endothelin 1 were, respectively, studied. The cholesterol-enriched porcine coronary vascular smooth muscle (VSM) strips were used to investigate the effects of madagascine on abnormal constriction induced by sphingosylphosphorylcholine (SPC) which has a pivotal role in vasospasm. The vasodilatory effect was induced by madagascine (0.3-100 MUM) in isolated rat MRAs and the vasodilatory effect was blocked by NO synthase inhibitor L-NAME and AMPK inhibitor compound C. Madagascine (10 MUM) also significantly relaxed the abnormal constriction in porcine VSM induced by SPC and the effect was abolished by compound C. Madagascine significantly increased the phosphorylation of endothelial nitric oxide synthase (eNOS) in endothelial cells while decreasing the phosphorylation of myosin phosphatase target subunit 1 (MYPT1) in VSM cells. Madagascine-induced vasodilatation was abrogated using small interfering RNA knockdown of AMPK. In summary, madagascine exerted vasodilatation through activating AMPK, leading to the activation of eNOS in endothelium and inhibition of ROCK/MYPT1 in VSM. This study suggests the potential value of madagascine in amelioration of vasospasm related cardiovascular diseases. PMID- 27932980 TI - TNF-alpha-Induced cPLA2 Expression via NADPH Oxidase/Reactive Oxygen Species Dependent NF-kappaB Cascade on Human Pulmonary Alveolar Epithelial Cells. AB - Tumor necrosis factor-alpha (TNF-alpha) triggers activation of cytosolic phospholipase A2 (cPLA2) and then enhancing the synthesis of prostaglandin (PG) in inflammatory diseases. However, the detailed mechanisms of TNF-alpha induced cPLA2 expression were not fully defined in human pulmonary alveolar epithelial cells (HPAEpiCs). We found that TNF-alpha-stimulated increases in cPLA2 mRNA (5.2 folds) and protein (3.9 folds) expression, promoter activity (4.3 folds), and PGE2 secretion (4.7 folds) in HPAEpiCs, determined by Western blot, real-time PCR, promoter activity assay and PGE2 ELISA kit. These TNF-alpha-mediated responses were abrogated by the inhibitors of NADPH oxidase [apocynin (APO) and diphenyleneiodonium chloride (DPI)], ROS [N-acetyl cysteine, (NAC)], NF-kappaB (Bay11-7082) and transfection with siRNA of ASK1, p47 phox , TRAF2, NIK, IKKalpha, IKKbeta, or p65. TNF-alpha markedly stimulated NADPH oxidase activation and ROS including superoxide and hydrogen peroxide production which were inhibited by pretreatment with a TNFR1 neutralizing antibody, APO, DPI or transfection with siRNA of TRAF2, ASK1, or p47 phox . In addition, TNF-alpha also stimulated p47 phox phosphorylation and translocation in a time-dependent manner. On the other hand, TNF-alpha induced TNFR1, TRAF2, ASK1, and p47 phox complex formation in HPAEpiCs, which were attenuated by a TNF-alpha neutralizing antibody. We found that pretreatment with NAC, DPI, or APO also attenuated the TNF-alpha-stimulated IKKalpha/beta and NF-kappaB p65 phosphorylation, NF-kappaB (p65) translocation, and NF-kappaB promoter activity in HPAEpiCs. Finally, we observed that TNF-alpha-stimulated NADPH oxidase activation and ROS generation activates NF-kappaB through the NIK/IKKalpha/beta pathway. Taken together, our results demonstrated that in HPAEpiCs, up-regulation of cPLA2 by TNF-alpha is, at least in part, mediated through the cooperation of TNFR1, TRAF2, ASK1, and NADPH oxidase leading to ROS generation and ultimately activates NF-kappaB pathway. PMID- 27932981 TI - Proton Pump Inhibitors Display Antitumor Effects in Barrett's Adenocarcinoma Cells. AB - Recent evidence has reported that proton pump inhibitors (PPIs) can exert antineoplastic effects through the disruption of pH homeostasis by inhibiting vacuolar ATPase (H+-VATPase), a proton pump overexpressed in several tumor cells, but this aspect has not been deeply investigated in EAC yet. In the present study, the expression of H+-VATPase was assessed through the metaplasia-dysplasia adenocarcinoma sequence in Barrett's esophagus (BE) and the antineoplastic effects of PPIs and cellular mechanisms involved were evaluated in vitro. H+ VATPase expression was assessed by immunohistochemistry in paraffined-embedded samples or by immunofluorescence in cultured BE and EAC cell lines. Cells were treated with different concentrations of PPIs and parameters of citotoxicity, oxidative stress, and autophagy were evaluated. H+-VATPase expression was found in all biopsies and cell lines evaluated, showing differences in the location of the pump between the cell lines. Esomeprazole inhibited proliferation and cell invasion and induced apoptosis of EAC cells. Production of reactive oxygen species (ROS) seemed to be involved in the cytotoxic effects observed since the addition of N-acetylcysteine significantly reduced esomeprazole-induced apoptosis in EAC cells. Esomeprazole also reduced intracellular pH of tumor cells, whereas only disturbed the mitochondrial membrane potential in OE33 cells. Esomeprazole induced autophagy in both EAC cells, but also triggered a blockade in autophagic flux in the metastatic cell line. These data provide in vitro evidence supporting the potential use of PPIs as novel antineoplastic drugs for EAC and also shed some light on the mechanisms that trigger PPIs cytotoxic effects, which differ upon the cell line evaluated. PMID- 27932982 TI - Impact of CYP2C19 Variants on Clinical Efficacy of Clopidogrel and 1-Year Clinical Outcomes in Coronary Heart Patients Undergoing Percutaneous Coronary Intervention. AB - The impact of pharmacogenetic variants of cytochrome P450 2C19 (CYP2C19) on clopidogrel-mediated effects on platelet inhibition, inflammatory response and endothelial function, as well as risk of major adverse cardiovascular events (MACE), in coronary heart patients undergoing percutaneous coronary intervention (PCI) was investigated. To this end, we assessed the residual platelet aggregation rate (RPA), maximal aggregation rate (MAR) and plasma levels of sCD40L, sP-selectin, MMP-9, sVCAM-1 and sE-selectin after 24 h of PCI in 559 patients treated with clopidogrel and followed up for 1 year for evidence of MACE. CYP2C19*2 and *3 variants were identified using a clopidogrel-sensitive gene detection kit. Our results showed higher RPA and MAR as well as increased sE selectin, sCD40L, sP-selectin, MMP-9, and sVCAM-1 levels in CYP2C19 intermediate metabolizer (IM, CYP2C19*1/*2, or *1/*3), poor metabolizer (PM, CYP2C19*2/*2, *2/*3, or *3/*3) and combined IM+PM groups, relative to those in extensive metabolizers (EM, CYP2C19*1/*1). In total, 519 patients completed 1 year of follow-up, among which 69 (13.3%) experienced MACE. The risk of MACE in CYP2C19 IM+PM patients was 2.664 times higher than that in CYP2C19 EM patients (OR = 2.664 (1.397-5.193), P = 0.004). The data suggest that CYP2C19*2 and *3 variants modulate the drug efficacy of clopidogrel in coronary heart patients undergoing PCI and further enhance the risk of MACE. Accordingly, CYP2C19 pharmacogenetic profiling may be beneficial for coronary heart patients undergoing PCI to predict the efficacy of treatment with clopidogrel. We propose that IM and PM patients should benefit from treatment with higher clopidogrel doses to improve efficacy and reduce the incidence of MACE. PMID- 27932983 TI - Cannabidiol Regulation of Learned Fear: Implications for Treating Anxiety-Related Disorders. AB - Anxiety and trauma-related disorders are psychiatric diseases with a lifetime prevalence of up to 25%. Phobias and post-traumatic stress disorder (PTSD) are characterized by abnormal and persistent memories of fear-related contexts and cues. The effects of psychological treatments such as exposure therapy are often only temporary and medications can be ineffective and have adverse side effects. Growing evidence from human and animal studies indicates that cannabidiol, the main non-psychotomimetic phytocannabinoid present in Cannabis sativa, alleviates anxiety in paradigms assessing innate fear. More recently, the effects of cannabidiol on learned fear have been investigated in preclinical studies with translational relevance for phobias and PTSD. Here we review the findings from these studies, with an emphasis on cannabidiol regulation of contextual fear. The evidence indicates that cannabidiol reduces learned fear in different ways: (1) cannabidiol decreases fear expression acutely, (2) cannabidiol disrupts memory reconsolidation, leading to sustained fear attenuation upon memory retrieval, and (3) cannabidiol enhances extinction, the psychological process by which exposure therapy inhibits learned fear. We also present novel data on cannabidiol regulation of learned fear related to explicit cues, which indicates that auditory fear expression is also reduced acutely by cannabidiol. We conclude by outlining future directions for research to elucidate the neural circuit, psychological, cellular, and molecular mechanisms underlying the regulation of fear memory processing by cannabidiol. This line of investigation may lead to the development of cannabidiol as a novel therapeutic approach for treating anxiety and trauma-related disorders such as phobias and PTSD in the future. PMID- 27932984 TI - Curcumin Suppressed Activation of Dendritic Cells via JAK/STAT/SOCS Signal in Mice with Experimental Colitis. AB - Dendritic cells (DCs) play a pivotal role as initiators in the pathogenesis of inflammatory bowel disease and are regulated by the JAK/STAT/SOCS signaling pathway. As a potent anti-inflammatory compound, curcumin represents a viable treatment alternative or adjunctive therapy in the management of chronic inflammatory bowel disease (IBD). The mechanism of curcumin treated IBD on DCs is not completely understood. In the present study, we explored the mechanism of curcumin treated experimental colitis by observing activation of DCs via JAK/STAT/SOCS signaling pathway in colitis mice. Experimental colitis was induced by 2, 4, 6-trinitrobenzene sulfonic acid. After 7 days treatment with curcumin, its therapeutic effect was verified by decreased colonic weight, histological scores, and remitting pathological injury. Meanwhile, the levels of major histocompatibility complex class II and DC costimulatory molecules (CD83, CD28, B7-DC, CD40, CD40 L, and TLR2) were inhibited and followed the up-regulated levels of IL-4, IL-10, and IFN-gamma, and down-regulated GM-CSF, IL-12p70, IL-15, IL-23, and TGF-beta1. A key finding was that the phosphorylation of the three members (JAK2, STAT3, and STAT6) of the JAK/STAT/SOCS signaling pathway was inhibited, and the three downstream proteins (SOCS1, SOCS3, and PIAS3) from this pathway were highly expressed. In conclusion, curcumin suppressed the activation of DCs by modulating the JAK/STAT/SOCS signaling pathway to restore immunologic balance to effectively treat experimental colitis. PMID- 27932985 TI - Pregnane X Receptor (PXR)-Mediated Gene Repression and Cross-Talk of PXR with Other Nuclear Receptors via Coactivator Interactions. AB - Pregnane X receptor is a ligand-activated nuclear receptor (NR) that mainly controls inducible expression of xenobiotics handling genes including biotransformation enzymes and drug transporters. Nowadays it is clear that PXR is also involved in regulation of intermediate metabolism through trans-activation and trans-repression of genes controlling glucose, lipid, cholesterol, bile acid, and bilirubin homeostasis. In these processes PXR cross-talks with other NRs. Accumulating evidence suggests that the cross-talk is often mediated by competing for common coactivators or by disruption of coactivation and activity of other transcription factors by the ligand-activated PXR. In this respect mainly PXR-CAR and PXR-HNF4alpha interference have been reported and several cytochrome P450 enzymes (such as CYP7A1 and CYP8B1), phase II enzymes (SULT1E1, Gsta2, Ugt1a1), drug and endobiotic transporters (OCT1, Mrp2, Mrp3, Oatp1a, and Oatp4) as well as intermediate metabolism enzymes (PEPCK1 and G6Pase) have been shown as down regulated genes after PXR activation. In this review, I summarize our current knowledge of PXR-mediated repression and coactivation interference in PXR controlled gene expression regulation. PMID- 27932986 TI - Role of Quercetin in Modulating Chloride Transport in the Intestine. AB - Epithelial chloride channels provide the pathways for fluid secretion in the intestine. Cystic fibrosis transmembrane conductance regulator (CFTR) and calcium activated chloride channels (CaCCs) are the main chloride channels in the luminal membrane of enterocytes. These transmembrane proteins play important roles in many physiological processes. In this study, we have identified a flavonoid quercetin as a modulator of CaCC chloride channel activity. Fluorescence quenching assay showed that quercetin activated Cl- transport in a dose-dependent manner, with EC50 ~37 MUM. Short-circuit current analysis confirmed that quercetin activated CaCC-mediated Cl- currents in HT-29 cells that can be abolished by CaCCinh-A01. Ex vivo studies indicated that application of quercetin to mouse ileum and colon on serosal side resulted in activation of CFTR and CaCC mediated Cl- currents. Notably, we found that quercetin exhibited inhibitory effect against ANO1 chloride channel activity in ANO1-expressing FRT cells and decreased mouse intestinal motility. Quercetin-stimulated short-circuit currents in mouse ileum was multi-component, which included elevation of Ca2+ concentration through L-type calcium channel and activation of basolateral NKCC, Na+/K+-ATPase, and K+ channels. In vivo studies further revealed that quercetin promoted fluid secretion in mouse ileum. The modulatory effect of quercetin on CaCC chloirde channels may therefore represent a potential therapeutic strategy for treating CaCC-related diseases like constipation, secretory diarrhea and hypertension. The inverse effects of quercetin on CaCCs provided evidence that ANO1 and intestinal epithelial CaCCs are different calcium-activated chloride channels. PMID- 27932987 TI - Limits of Applicability of the Voronoi Tessellation Determined by Centers of Cell Nuclei to Epithelium Morphology. AB - It is well accepted that cells in the tissue can be regarded as tiles tessellating space. A number of approaches were developed to find an appropriate mathematical description of such cell tiling. A particularly useful approach is the so called Voronoi tessellation, built from centers of mass of the cell nuclei (CMVT), which is commonly used for estimating the morphology of cells in epithelial tissues. However, a study providing a statistically sound analysis of this method's accuracy is not available in the literature. We addressed this issue here by comparing a number of morphological measures of the cells, including area, perimeter, and elongation obtained from such a tessellation with identical measures extracted from direct imaging acquired by staining the cell membranes. After analyzing the shapes of 15,000 MDCK II epithelial cells under several conditions, we find that CMVT reasonably well reproduces many of the morphological properties of the tissue with an error that is between 10 and 15%. Moreover, cross-correlations between different morphological measures are reproduced qualitatively correctly by this method. However, all of the properties including the cell perimeters, number of neighbors, and anisotropy measures often suffer from systematic or size dependent errors. These discrepancies originate from the polygonal nature of the tessellation which sets the limits of the applicability of CMVT. PMID- 27932988 TI - Editorial: The Impact of Systems Medicine on Human Health and Disease. PMID- 27932989 TI - Hypoxic Living and Exercise Training Alter Adipose Tissue Leptin/Leptin Receptor in Rats. AB - Background: Hypobaric hypoxia results in weight loss in obese individuals, and exercise training is advocated for the treatment of obesity and its related metabolic dysfunctions. The purpose of this study was to investigate the effects of hypoxic living and exercise training on obesity and adipose tissue leptin/leptin receptor in dietary-induced obese rats. Methods: One hundred and thirty high-fat diet fed Sprague-Dawley rats were assigned into one of the following groups (n = 10 each): control, sedentary hypoxic living for 1-4 weeks (SH1, SH2, SH3, and SH4), living, and exercise training in normoxic conditions for 1-4 weeks (TN1, TN2, TN3, and TN4), and living and exercise training in hypoxic conditions for 1-4 weeks (TN1, TN2, TN3, and TN4). Epididymal adipose tissue expression levels of leptin and leptin receptor were determined Results: Compared to hypoxic living and living and exercise training in normoxic conditions, living and exercise training in hypoxic conditions for 3-4 weeks resulted in lower Lee index (P < 0.05-0.01), and higher expression of leptin and leptin receptor (P < 0.05-0.01) in adipose tissue. Conclusion: In a rodent model of altitude training, living, and exercise training in hypoxic conditions resulted in greater alterations in obesity and adipose tissue leptin/leptin receptor than hypoxic living alone and living and exercise training in normoxic conditions. PMID- 27932990 TI - Regulation of Connexins Expression Levels by MicroRNAs, an Update. AB - Control of cell-cell coordination and communication is regulated by several factors, including paracrine and autocrine release of biomolecules, and direct exchange of soluble factors between cells through gap junction channels. Additionally, hemichannels also participate in cell-cell coordination through the release of signaling molecules, such as ATP and glutamate. A family of transmembrane proteins named connexins forms both gap junction channels and hemichannels. Because of their importance in cell and tissue coordination, connexins are controlled both by post-translational and post-transcriptional modifications. In recent years, non-coding RNAs have garnered research interest due to their ability to exert post-transcriptional regulation of gene expression. One of the most recent, well-documented control mechanisms of protein synthesis is found through the action of small, single-stranded RNA, called micro RNAs (miRNAs or miRs). Put simply, miRNAs are negative regulators of the expression of a myriad proteins involved in many physiological and pathological processes. This mini review will briefly summarize what is currently known about the action of miRNAs over Cxs expression/function in different organs under some relevant physiological and pathological conditions. PMID- 27932991 TI - Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. AB - Human Gingival Mesenchymal Stem Cells (hGMSCs) are multipotential cells that can expand and differentiate in culture under specific and standardized conditions. In the present study, we have investigated whether in vitro pre-treatment of hGMSCs with Cannabidiol (CBD) can influence their expression profile, improving the therapeutic potential of this cell culture. Following CBD treatment (5 MUM) for 24 h, gene expression analysis through Next Generation Sequencing (NGS) has revealed several genes differentially expressed between CBD-treated hGMSCs (CBD hGMSCs) and control cells (CTR-hGMSCs) that were linked to inflammation and apoptosis. In particular, we have demonstrated that CBD treatment in hGMSCs prevented the activation of the NALP3-inflammasome pathway by suppressing the levels of NALP3, CASP1, and IL18, and in parallel, inhibited apoptosis, as demonstrated by the suppression of Bax. CBD treatment was also able to modulate the expression of the well-known mesenchymal stem cell markers (CD13, CD29, CD73, CD44, CD90, and CD166), and other surface antigens. Specifically, CBD led to the downregulation of genes codifying for antigens involved in the activation of the immune system (CD109, CD151, CD40, CD46, CD59, CD68, CD81, CD82, CD99), while it led to the upregulation of those implicated in the inhibition of the immune responses (CD47, CD55, CD276). In conclusion, the present study will provide a new simple and reproducible method for preconditioning hGMSCs with CBD, before transplantation, as an interesting strategy for improving the hGMSCs molecular phenotype, reducing the risk of immune or inflammatory reactions in the host, and in parallel, for increasing their survival and thus, their long-term therapeutic efficacy. PMID- 27932992 TI - Patient Similarity: Emerging Concepts in Systems and Precision Medicine. PMID- 27932993 TI - Effect of Permissive Dehydration on Induction and Decay of Heat Acclimation, and Temperate Exercise Performance. AB - Purpose: It has been suggested that dehydration is an independent stimulus for heat acclimation (HA), possibly through influencing fluid-regulation mechanisms and increasing plasma volume (PV) expansion. There is also some evidence that HA may be ergogenic in temperate conditions and that this may be linked to PV expansion. We investigated: (i) the influence of dehydration on the time-course of acquisition and decay of HA; (ii) whether dehydration augmented any ergogenic benefits in temperate conditions, particularly those related to PV expansion. Methods: Eight males [VO2max: 56.9(7.2) mL.kg-1.min-1] undertook two HA programmes (balanced cross-over design), once drinking to maintain euhydration (HAEu) and once with restricted fluid-intake (HADe). Days 1, 6, 11, and 18 were 60 min exercise-heat stress tests [HST (40 degrees C; 50% RH)], days 2-5 and 7-10 were 90 min, isothermal-strain (Tre ~ 38.5 degrees C), exercise-heat sessions. Performance parameters [VO2max, lactate threshold, efficiency, peak power output (PPO)] were determined pre and post HA by graded exercise test (22 degrees C; 55%RH). Results: During isothermal-strain sessions hypohydration was achieved in HADe and euhydration maintained in HAEu [average body mass loss -2.71(0.82)% vs. 0.56(0.73)%, P < 0.001], but aldosterone concentration, power output, and cardiovascular strain were unaffected by dehydration. HA was evident on day 6 {reduced end-exercise Tre [-0.30(0.27) degrees C] and exercise heart rate [ 12(15) beats.min-1], increased PV [+7.2(6.4)%] and sweat-loss [+0.25(0.22) L.h 1], P < 0.05} with some further adaptations on day 11 {further reduced end exercise Tre [-0.25(0.19) degrees C] and exercise heart rate [-3(9) beats.min-1], P < 0.05}. These adaptations were not notably affected by dehydration and were generally maintained 7-days post HA. Performance parameters were unchanged, apart from increased PPO (+16(20) W, irrespective of condition). Conclusions: When thermal-strain is matched, permissive dehydration which induces a mild, transient, hypohydration does not affect the acquisition and decay of HA, or endurance performance parameters. Irrespective of hydration, trained individuals require >5 days to optimize HA. PMID- 27932994 TI - Comparative mRNA and MicroRNA Profiling during Acute Myocardial Infarction Induced by Coronary Occlusion and Ablation Radio-Frequency Currents. AB - The ligation of the left anterior descending coronary artery is the most commonly used experimental model to induce myocardial infarction (MI) in rodents. A high mortality in the acute phase and the heterogeneity of the size of the MI obtained are drawbacks recognized in this model. In an attempt to solve the problem, our group recently developed a new MI experimental model which is based on application of myocardial ablation radio-frequency currents (AB-RF) that yielded MI with homogeneous sizes and significantly reduce acute mortality. In addition, cardiac structural, and functional changes aroused by AB-RF were similar to those seen in animals with MI induced by coronary artery ligation. Herein, we compared mRNA expression of genes that govern post-MI milieu in occlusion and ablation models. We analyzed 48 mRNAs expressions of nine different signal transduction pathways (cell survival and metabolism signs, matrix extracellular, cell cycle, oxidative stress, apoptosis, calcium signaling, hypertrophy markers, angiogenesis, and inflammation) in rat left ventricle 1 week after MI generated by both coronary occlusion and AB-RF. Furthermore, high-throughput miRNA analysis was also assessed in both MI procedures. Interestingly, mRNA expression levels and miRNA expressions showed strong similarities between both models after MI, with few specificities in each model, activating similar signal transduction pathways. To our knowledge, this is the first comparison of genomic alterations of mRNA and miRNA contents after two different MI procedures and identifies key signaling regulators modulating the pathophysiology of these two models that might culminate in heart failure. Furthermore, these analyses may contribute with the current knowledge concerning transcriptional and post-transcriptional changes of AB-RF protocol, arising as an alternative and effective MI method that reproduces most changes seem in coronary occlusion. PMID- 27932995 TI - Genome Sizes of Nine Insect Species Determined by Flow Cytometry and k-mer Analysis. AB - The flow cytometry method was used to estimate the genome sizes of nine agriculturally important insects, including two coleopterans, five Hemipterans, and two hymenopterans. Among which, the coleopteran Lissorhoptrus oryzophilus (Kuschel) had the largest genome of 981 Mb. The average genome size was 504 Mb, suggesting that insects have a moderate-size genome. Compared with the insects in other orders, hymenopterans had small genomes, which were averagely about ~200 Mb. We found that the genome sizes of four insect species were different between male and female, showing the organismal complexity of insects. The largest difference occurred in the coconut leaf beetle Brontispa longissima (Gestro). The male coconut leaf beetle had a 111 Mb larger genome than females, which might be due to the chromosome number difference between the sexes. The results indicated that insect invasiveness was not related to genome size. We also determined the genome sizes of the small brown planthopper Laodelphax striatellus (Fallen) and the parasitic wasp Macrocentrus cingulum (Brischke) using k-mer analysis with Illunima Solexa sequencing data. There were slight differences in the results from the two methods. k-mer analysis indicated that the genome size of L. striatellus was 500-700 Mb and that of M. cingulum was ~150 Mb. In all, the genome sizes information presented here should be helpful for designing the genome sequencing strategy when necessary. PMID- 27932996 TI - Genetic Regulation of Endothelial Vasomotor Function. AB - The endothelium plays an important role in the regulation of vasomotor tone and the maintenance of vascular integrity. Endothelial dysfunction, i.e., impaired endothelial dependent dilation, is a fundamental component of the pathogenesis of cardiovascular disease. Although endothelial dysfunction is associated with a number of cardiovascular disease risk factors, those risk factors are not the only determinants of endothelial dysfunction. Despite knowing many molecules involved in endothelial signaling pathways, the genetic contribution to endothelial function has yet to be fully elucidated. This mini-review summarizes current evidence supporting the genetic contribution to endothelial vasomotor function. Findings from population-based studies, association studies for candidate genes, and unbiased large genomic scale studies in humans and rodent models are discussed. A brief synopsis of the current studies addressing the genetic regulation of endothelial responses to exercise training is also included. PMID- 27932997 TI - Characterization of Reproductive Dormancy in Male Drosophila melanogaster. AB - Insects are known to respond to seasonal and adverse environmental changes by entering dormancy, also known as diapause. In some insect species, including Drosophila melanogaster, dormancy occurs in the adult organism and postpones reproduction. This adult dormancy has been studied in female flies where it is characterized by arrested development of ovaries, altered nutrient stores, lowered metabolism, increased stress and immune resistance and drastically extended lifespan. Male dormancy, however, has not been investigated in D. melanogaster, and its physiology is poorly known in most insects. Here we show that unmated 3-6 h old male flies placed at low temperature (11 degrees C) and short photoperiod (10 Light:14 Dark) enter a state of dormancy with arrested spermatogenesis and development of testes and male accessory glands. Over 3 weeks of diapause we see a dynamic increase in stored carbohydrates and an initial increase and then a decrease in lipids. We also note an up-regulated expression of genes involved in metabolism, stress responses and innate immunity. Interestingly, we found that male flies that entered reproductive dormancy do not attempt to mate females kept under non-diapause conditions (25 degrees C, 12L:12D), and conversely non-diapausing males do not mate females in dormancy. In summary, our study shows that male D. melanogaster can enter reproductive dormancy. However, our data suggest that dormant male flies deplete stored nutrients faster than females, studied earlier, and that males take longer to recover reproductive capacity after reintroduction to non-diapause conditions. PMID- 27932999 TI - The Need for a Consensus on the Locution "Central Nuclei" in Striated Muscle Myopathies. PMID- 27932998 TI - Gene Expression Dynamics in Major Endocrine Regulatory Pathways along the Transition from Solitary to Social Life in a Bumblebee, Bombus terrestris. AB - Understanding the social evolution leading to insect eusociality requires, among other, a detailed insight into endocrine regulatory mechanisms that have been co opted from solitary ancestors to play new roles in the complex life histories of eusocial species. Bumblebees represent well-suited models of a relatively primitive social organization standing on the mid-way to highly advanced eusociality and their queens undergo both, a solitary and a social phase, separated by winter diapause. In the present paper, we characterize the gene expression levels of major endocrine regulatory pathways across tissues, sexes, and life-stages of the buff-tailed bumblebee, Bombus terrestris, with special emphasis on critical stages of the queen's transition from solitary to social life. We focused on fundamental genes of three pathways: (1) Forkhead box protein O and insulin/insulin-like signaling, (2) Juvenile hormone (JH) signaling, and (3) Adipokinetic hormone signaling. Virgin queens were distinguished by higher expression of forkhead box protein O and downregulated insulin-like peptides and JH signaling, indicated by low expression of methyl farnesoate epoxidase (MFE) and transcription factor Kruppel homolog 1 (Kr-h1). Diapausing queens showed the expected downregulation of JH signaling in terms of low MFE and vitellogenin (Vg) expressions, but an unexpectedly high expression of Kr-h1. By contrast, reproducing queens revealed an upregulation of MFE and Vg together with insulin signaling. Surprisingly, the insulin growth factor 1 (IGF-1) turned out to be a queen-specific hormone. Workers exhibited an expression pattern of MFE and Vg similar to that of reproducing queens. Males were characterized by high Kr-h1 expression and low Vg level. The tissue comparison unveiled an unexpected resemblance between the fat body and hypopharyngeal glands across all investigated genes, sexes, and life stages. PMID- 27933001 TI - Commentary: The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria. PMID- 27933000 TI - In-Depth Study of the Interaction, Sensitivity, and Gating Modulation by PUFAs on K+ Channels; Interaction and New Targets. AB - Voltage gated potassium channels (KV) are membrane proteins that allow selective flow of K+ ions in a voltage-dependent manner. These channels play an important role in several excitable cells as neurons, cardiomyocytes, and vascular smooth muscle. Over the last 20 years, it has been shown that omega-3 polyunsaturated fatty acids (PUFAs) enhance or decrease the activity of several cardiac KV channels. PUFAs-dependent modulation of potassium ion channels has been reported to be cardioprotective. However, the precise cellular mechanism underlying the cardiovascular benefits remained unclear in part because new PUFAs targets and signaling pathways continue being discovered. In this review, we will focus on recent data available concerning the following aspects of the KV channel modulation by PUFAs: (i) the exact residues involved in PUFAs-KV channels interaction; (ii) the structural PUFAs determinants important for their effects on KV channels; (iii) the mechanism of the gating modulation of KV channels and, finally, (iv) the PUFAs modulation of a few new targets present in smooth muscle cells (SMC), KCa1.1, K2P, and KATP channels, involved in vascular relaxation. PMID- 27933002 TI - Gender Differences in Demographic and Clinical Features of Physicians Admitted to a Program for Medical Professionals with Mental Disorders. AB - OBJECTIVE: To examine the demographic and clinical differences between men and women admitted to a Physicians' Health Programme (PHP). METHOD: Retrospective chart review of 778 medical records of physicians admitted to the Barcelona PHP from February 1, 1998 until December 31, 2015. RESULTS: Women admitted to the Barcelona PHP were younger than men, were more likely to be self-referred and to be admitted for a non-addictive mental disorder. Prevalence of unipolar affective disorders (60.1 vs. 37.6%), adjustment disorders (62.4 vs. 37.6%), and obsessive compulsive disorder (61.1 vs. 38.9%) was significantly higher among women, whereas prevalence of alcohol use disorders was lower (32.7 vs. 67.3%). Nevertheless, both groups were similar with regard to medical specialty, working status, length of their first treatment episode, and presence of hospitalization during that episode. After multivariate analysis, age, type of referral, and main diagnosis (addictive disorders vs. other mental disorders) discriminated the differences between groups. CONCLUSION: Women physicians seem to be more prone to voluntarily ask for help from PHPs and are more likely to suffer from mood and anxiety disorders compared to men. However, mental disorders' severity may be similar in both groups. More studies are needed to clarify the gender factors related to this behavior. PMID- 27933003 TI - Altered Insular Function during Aberrant Salience Processing in Relation to the Severity of Psychotic Symptoms. AB - There is strong evidence for abnormal salience processing in patients with psychotic experiences. In particular, there are indications that the degree of aberrant salience processing increases with the severity of positive symptoms. The aim of the present study was to elucidate this relationship by means of brain imaging. Functional magnetic resonance imaging was acquired to assess hemodynamic responses during the Salience Attribution Test, a paradigm for reaction time that measures aberrant salience to irrelevant stimulus features. We included 42 patients who were diagnosed as having a psychotic disorder and divided them into two groups according to the severity of their positive symptoms. Whole brain analysis was performed using Statistical Parametric Mapping. We found no significant behavioral differences with respect to task performance. Patients with more positive symptoms showed increased hemodynamic responses in the left insula corresponding to aberrant salience than in patients with less positive symptoms. In addition, left insula activation correlated negatively with cumulative antipsychotic medication. Aberrant salience processing in the insula may be increased in psychosis, depending on the severity of positive symptoms. This study indicates that clinically similar psychosis manifestations share the same functional characteristics. In addition, our results suggest that antipsychotic medication can modulate insular function. PMID- 27933004 TI - Policy Implications of Achievement Testing Using Multilevel Models: The Case of Brazilian Elementary Schools. AB - Large-scale educational assessment has been established as source of descriptive, evaluative and interpretative information that influence educational policies worldwide throughout the last third of the twentieth century. In the 1990s the Brazilian Ministry of Education developed the National Basic Education Assessment System (SAEB) that regularly measures management, resource and contextual school features and academic achievement in public and private institutions. In 2005, after significant piloting and review of the SAEB, a new sampling strategy was taken and Prova Brasil became the new instrument used by the Ministry to assess skills in Portuguese (reading comprehension) and Mathematics (problem solving), as well as collecting contextual information concerning the school, principal, teacher, and the students. This study aims to identify which variables are predictors of academic achievement of fifth grade students on Prova Brasil. Across a large sample of students, multilevel models tested a large number of variables relevant to student achievement. This approach uncovered critical variables not commonly seen as significant in light of other achievement determinants, including student habits, teacher ethnicity, and school technological resources. As such, this approach demonstrates the value of MLM to appropriately nuanced educational policies that reflect critical influences on student achievement. Its implications for wider application for psychology studies that may have relevant impacts for policy are also discussed. PMID- 27933006 TI - System to Detect Racial-Based Bullying through Gamification. AB - Prevention and detection of bullying due to racial stigma was studied in school contexts using a system designed following "gamification" principles and integrating less usual elements, such as social interaction, augmented reality and cell phones in educational scenarios. "Grounded Theory" and "User Centered Design" were employed to explore coexistence inside and outside the classroom in terms of preferences and distrust in several areas of action and social frameworks of activity, and to direct the development of a cell phone app for early detection of school bullying scenarios. One hundred and fifty-one interviews were given at five schools selected for their high multiracial percentage and conflict. The most outstanding results were structural, that is the distribution of the classroom group by type of activity and subject being dealt with. Furthermore, in groups over 12 years of age, the relational structures in the classroom in the digital settings in which they participated with their cell phones did not reoccur, because face-to-face and virtual interaction between students with the supervision and involvement of the teacher combined to detect bullying caused by racial discrimination. PMID- 27933005 TI - Social Brain Hypothesis: Vocal and Gesture Networks of Wild Chimpanzees. AB - A key driver of brain evolution in primates and humans is the cognitive demands arising from managing social relationships. In primates, grooming plays a key role in maintaining these relationships, but the time that can be devoted to grooming is inherently limited. Communication may act as an additional, more time efficient bonding mechanism to grooming, but how patterns of communication are related to patterns of sociality is still poorly understood. We used social network analysis to examine the associations between close proximity (duration of time spent within 10 m per hour spent in the same party), grooming, vocal communication, and gestural communication (duration of time and frequency of behavior per hour spent within 10 m) in wild chimpanzees. This study examined hypotheses formulated a priori and the results were not corrected for multiple testing. Chimpanzees had differentiated social relationships, with focal chimpanzees maintaining some level of proximity to almost all group members, but directing gestures at and grooming with a smaller number of preferred social partners. Pairs of chimpanzees that had high levels of close proximity had higher rates of grooming. Importantly, higher rates of gestural communication were also positively associated with levels of proximity, and specifically gestures associated with affiliation (greeting, gesture to mutually groom) were related to proximity. Synchronized low-intensity pant-hoots were also positively related to proximity in pairs of chimpanzees. Further, there were differences in the size of individual chimpanzees' proximity networks-the number of social relationships they maintained with others. Focal chimpanzees with larger proximity networks had a higher rate of both synchronized low- intensity pant-hoots and synchronized high-intensity pant-hoots. These results suggest that in addition to grooming, both gestures and synchronized vocalizations may play key roles in allowing chimpanzees to manage a large and differentiated set of social relationships. Gestures may be important in reducing the aggression arising from being in close proximity to others, allowing for proximity to be maintained for longer and facilitating grooming. Vocalizations may allow chimpanzees to communicate with a larger number of recipients than gestures and the synchronized nature of the pant hoot calls may facilitate social bonding of more numerous social relationships. As group sizes increased through human evolution, both gestures and synchronized vocalizations may have played important roles in bonding social relationships in a more time-efficient manner than grooming. PMID- 27933007 TI - What Is the Correct Answer about The Dress' Colors? Investigating the Relation between Optimism, Previous Experience, and Answerability. AB - The Dress photograph, first displayed on the internet in 2015, revealed stunning individual differences in color perception. The aim of this study was to investigate if lay-persons believed that the question about The Dress colors was answerable. Past research has found that optimism is related to judgments of how answerable knowledge questions with controversial answers are (Karlsson et al., 2016). Furthermore, familiarity with a question can create a feeling of knowing the answer (Reder and Ritter, 1992). Building on these findings, 186 participants saw the photo of The Dress and were asked about the correct answer to the question about The Dress' colors ("blue and black," "white and gold," "other, namely...," or "there is no correct answer"). Choice of the alternative "there is no correct answer" was interpreted as believing the question was not answerable. This answer was chosen more often by optimists and by people who reported they had not seen The Dress before. We also found that among participants who had seen The Dress photo before, 19%, perceived The Dress as "white and gold" but believed that the correct answer was "blue and black." This, in analogy to previous findings about non-believed memories (Scoboria and Pascal, 2016), shows that people sometimes do not believe the colors they have perceived are correct. Our results suggest that individual differences related to optimism and previous experience may contribute to if the judgment of the individual perception of a photograph is enough to serve as a decision basis for valid conclusions about colors. Further research about color judgments under ambiguous circumstances could benefit from separating individual perceptual experience from beliefs about the correct answer to the color question. Including the option "there is no correct answer" may also be beneficial. PMID- 27933008 TI - Healthcare Needs, Experiences and Satisfaction after Terrorism: A Longitudinal Study of Survivors from the Utoya Attack. AB - Background: Public health outreach programs have been developed in order to ensure that needs are met after disasters. However, little is known about survivors' experiences with post-terror healthcare. In the present study, our objectives were to (1) describe survivors' experiences with post-terror healthcare, (2) identify factors associated with reports of unmet healthcare needs, and (3) examine the relationship between socio-demographic characteristics, healthcare experiences and satisfaction. Methods: Our study comprised three waves of semi-structured interviews with 261/490 (53%) survivors of the Utoya mass shooting. We applied Pearson's chi-squared tests (categorical variables) and independent t-tests (continuous variables) to compare survivors by whether or not they reported higher perceived needs than received help for psychological reactions and physical health problems, respectively. Ordinal regression analyses were applied to examine whether socio-demographic characteristics and healthcare experiences were associated with dissatisfaction. Results: Altogether 127 (49%) survivors reported very high/high help needs for psychological reactions, and 43 (17%) for attack-related physical health problems. Unmet healthcare needs were associated with higher levels of posttraumatic stress, psychological distress, somatic symptoms and less social support. Survivors with immigrant backgrounds and injured survivors who were not admitted to hospital reported unmet needs for physical health problems more often. After adjustments for socio-demographic characteristics, immigrant origin was associated with dissatisfaction with post-terror healthcare. After additionally adjusting for healthcare experiences, poor rating of the overall organization and accessibility of healthcare remained significantly associated with dissatisfaction. Conclusions: Most survivors were satisfied with the post terror healthcare they received, yet our findings indicate that increased attention to the physical health of non-hospitalized terrorism survivors is required. Furthermore, in future outreach, particular attention should be paid to the healthcare needs of survivors with immigrant background. PMID- 27933009 TI - Effects of Embodied Learning and Digital Platform on the Retention of Physics Content: Centripetal Force. AB - Embodiment theory proposes that knowledge is grounded in sensorimotor systems, and that learning can be facilitated to the extent that lessons can be mapped to these systems. This study with 109 college-age participants addresses two overarching questions: (a) how are immediate and delayed learning gains affected by the degree to which a lesson is embodied, and (b) how do the affordances of three different educational platforms affect immediate and delayed learning? Six 50 min-long lessons on centripetal force were created. The first factor was the degree of embodiment with two levels: (1) low and (2) high. The second factor was platform with three levels: (1) a large scale "mixed reality" immersive environment containing both digital and hands-on components called SMALLab, (2) an interactive whiteboard system, and (3) a mouse-driven desktop computer. Pre tests, post-tests, and 1-week follow-up (retention or delayed learning gains) tests were administered resulting in a 2 * 3 * 3 design. Two knowledge subtests were analyzed, one that relied on more declarative knowledge and one that relied on more generative knowledge, e.g., hand-drawing vectors. Regardless of condition, participants made significant immediate learning gains from pre-test to post-test. There were no significant main effects or interactions due to platform or embodiment on immediate learning. However, from post-test to follow up the level of embodiment interacted significantly with time, such that participants in the high embodiment conditions performed better on the subtest devoted to generative knowledge questions. We posit that better retention of certain types of knowledge can be seen over time when more embodiment is present during the encoding phase. This sort of retention may not appear on more traditional factual/declarative tests. Educational technology designers should consider using more sensorimotor feedback and gestural congruency when designing and opportunities for instructor professional development need to be provided as well. PMID- 27933010 TI - Differential Recall Bias, Intermediate Confounding, and Mediation Analysis in Life Course Epidemiology: An Analytic Framework with Empirical Example. AB - The mechanisms by which childhood socioeconomic status (CSES) affects adult mental health, general health, and well-being are not clear. Moreover, the analytical assumptions employed when assessing mediation in social and psychiatric epidemiology are rarely explained. The aim of this paper was to explain the intermediate confounding assumption, and to quantify differential recall bias in the association between CSES, childhood abuse, and mental health (SCL-10), general health (EQ-5D), and subjective well-being (SWLS). Furthermore, we assessed the mediating role of psychological and physical abuse in the association between CSES and mental health, general health, and well-being; and the influence of differential recall bias in the estimation of total effects, direct effects, and proportion of mediated effects. The assumptions employed when assessing mediation are explained with reference to a causal diagram. Poisson regression models (relative risk, RR and 99% CIs) were used to assess the association between CSES and psychological and physical abuse in childhood. Mediation analysis (difference method) was used to assess the indirect effect of CSES (through psychological and physical abuse in childhood) on mental health, general health, and well-being. Exposure (CSES) was measured at two time points. Mediation was assessed with both cross-sectional and longitudinal data. Psychological abuse and physical abuse mediated the association between CSES and adult mental health, general health, and well-being (6-16% among men and 7-14% among women, p < 0.001). The results suggest that up to 27% of the association between CSES and childhood abuse, 23% of the association between childhood abuse, and adult mental health, general health, and well-being, and 44% of the association between CSES and adult mental health, general health, and well-being is driven by differential recall bias. Assessing mediation with cross-sectional data (exposure, mediator, and outcome measured at the same time) showed that the total effects and direct effects were vastly overestimated (biased upwards). Consequently, the proportion of mediated effects were underestimated (biased downwards). If there is a true (unobserved) direct or indirect effect, and the direction of the differential recall bias is predictable, then the results of cross-sectional analyses should be discussed in light of that. PMID- 27933011 TI - Psychological Restoration Can Depend on Stimulus-Source Attribution: A Challenge for the Evolutionary Account? AB - Visiting or viewing nature environments can have restorative psychological effects, while exposure to the built environment typically has less positive effects. A classic view is that this difference in restorative potential of nature and built environments depends on differences in the intrinsic characteristics of the stimuli. In addition, an evolutionary account is often assumed whereby restoration is believed to be a hardwired response to nature's stimulus-features. Here, we propose the novel hypothesis that the restorative effects of a stimulus do not entirely depend on the stimulus-features per se, but also on the meaning that people assign to the stimulus. Participants conducted cognitively demanding tests prior to and after a brief pause. During the pause, the participants were exposed to an ambiguous sound consisting of pink noise with white noise interspersed. Participants in the "nature sound-source condition" were told that the sound originated from a nature scene with a waterfall; participants in the "industrial sound-source condition" were told that the sound originated from an industrial environment with machinery; and participants in the "control condition" were told nothing about the sound origin. Self-reported mental exhaustion showed that participants in the nature sound-source condition were more psychologically restored after the pause than participants in the industrial sound-source condition. One potential interpretation of the results is that restoration from nature experiences depends on learned, positive associations with nature; not only on hardwired responses shaped by evolution. PMID- 27933012 TI - Degrees of Freedom in Planning, Running, Analyzing, and Reporting Psychological Studies: A Checklist to Avoid p-Hacking. AB - The designing, collecting, analyzing, and reporting of psychological studies entail many choices that are often arbitrary. The opportunistic use of these so called researcher degrees of freedom aimed at obtaining statistically significant results is problematic because it enhances the chances of false positive results and may inflate effect size estimates. In this review article, we present an extensive list of 34 degrees of freedom that researchers have in formulating hypotheses, and in designing, running, analyzing, and reporting of psychological research. The list can be used in research methods education, and as a checklist to assess the quality of preregistrations and to determine the potential for bias due to (arbitrary) choices in unregistered studies. PMID- 27933013 TI - On Elementary Affective Decisions: To Like Or Not to Like, That Is the Question. AB - Perhaps the most ubiquitous and basic affective decision of daily life is deciding whether we like or dislike something/somebody, or, in terms of psychological emotion theories, whether the object/subject has positive or negative valence. Indeed, people constantly make such liking decisions within a glimpse and, importantly, often without expecting any obvious benefit or knowing the exact reasons for their judgment. In this paper, we review research on such elementary affective decisions (EADs) that entail no direct overt reward with a special focus on Neurocognitive Poetics and discuss methods and models for investigating the neuronal and cognitive-affective bases of EADs to verbal materials with differing degrees of complexity. In line with evolutionary and appraisal theories of (aesthetic) emotions and data from recent neurocognitive studies, the results of a decision tree modeling approach simulating EADs to single words suggest that a main driving force behind EADs is the extent to which such high-dimensional stimuli are associated with the "basic" emotions joy/happiness and disgust. PMID- 27933014 TI - Validation of the Vanderbilt Holistic Face Processing Test. AB - The Vanderbilt Holistic Face Processing Test (VHPT-F) is a new measure of holistic face processing with better psychometric properties relative to prior measures developed for group studies (Richler et al., 2014). In fields where psychologists study individual differences, validation studies are commonplace and the concurrent validity of a new measure is established by comparing it to an older measure with established validity. We follow this approach and test whether the VHPT-F measures the same construct as the composite task, which is group based measure at the center of the large literature on holistic face processing. In Experiment 1, we found a significant correlation between holistic processing measured in the VHPT-F and the composite task. Although this correlation was small, it was comparable to the correlation between holistic processing measured in the composite task with the same faces, but different target parts (top or bottom), which represents a reasonable upper limit for correlations between the composite task and another measure of holistic processing. These results confirm the validity of the VHPT-F by demonstrating shared variance with another measure of holistic processing based on the same operational definition. These results were replicated in Experiment 2, but only when the demographic profile of our sample matched that of Experiment 1. PMID- 27933015 TI - High Entrepreneurship, Leadership, and Professionalism (HELP): Toward an Integrated, Empirically Based Perspective. AB - This article evaluates the psychometric properties of a new measure for assessing the constructs of entrepreneurship, leadership, and professionalism, from an integrated point of view, the High Entrepreneurship, Leadership and Professionalism Questionnaire (HELP-Q). Exploratory factor analysis indicated a factor structure with three principal dimensions, and confirmatory factor analysis and goodness of fit indices indicated a good fit of the model to the data. All the dimensions showed good values of internal consistency. The results of the study thus indicate that the HELP-Q is a short and easily administered instrument with good psychometric properties that can promote entrepreneurship, leadership, and professionalism in workers as well as in those who are preparing to enter the turbulent 21st century labor market. PMID- 27933016 TI - Task-Irrelevant Expectation Violations in Sequential Manual Actions: Evidence for a "Check-after-Surprise" Mode of Visual Attention and Eye-Hand Decoupling. AB - When performing sequential manual actions (e.g., cooking), visual information is prioritized according to the task determining where and when to attend, look, and act. In well-practiced sequential actions, long-term memory (LTM)-based expectations specify which action targets might be found where and when. We have previously demonstrated (Foerster and Schneider, 2015b) that violations of such expectations that are task-relevant (e.g., target location change) cause a regression from a memory-based mode of attentional selection to visual search. How might task-irrelevant expectation violations in such well-practiced sequential manual actions modify attentional selection? This question was investigated by a computerized version of the number-connection test. Participants clicked on nine spatially distributed numbered target circles in ascending order while eye movements were recorded as proxy for covert attention. Target's visual features and locations stayed constant for 65 prechange-trials, allowing practicing the manual action sequence. Consecutively, a task-irrelevant expectation violation occurred and stayed for 20 change-trials. Specifically, action target number 4 appeared in a different font. In 15 reversion-trials, number 4 returned to the original font. During the first task-irrelevant change trial, manual clicking was slower and eye scanpaths were larger and contained more fixations. The additional fixations were mainly checking fixations on the changed target while acting on later targets. Whereas the eyes repeatedly revisited the task-irrelevant change, cursor-paths remained completely unaffected. Effects lasted for 2-3 change trials and did not reappear during reversion. In conclusion, an unexpected task-irrelevant change on a task-defining feature of a well-practiced manual sequence leads to eye-hand decoupling and a "check-after-surprise" mode of attentional selection. PMID- 27933017 TI - Why Acting Environmentally-Friendly Feels Good: Exploring the Role of Self-Image. AB - Recent research suggests that engagement in environmentally-friendly behavior can feel good. Current explanations for such a link do not focus on the nature of environmentally-friendly behavior itself, but rather propose well-being is more or less a side-benefit; behaviors that benefit environmental quality (e.g., spending one's money on people rather than products) also tend to make us feel good. We propose that the moral nature of environmentally-friendly behavior itself may elicit positive emotions as well, because engaging in this behavior can signal one is an environmentally-friendly and thus a good person. Our results show that engagement in environmentally-friendly behavior can indeed affect how people see themselves: participants saw themselves as being more environmentally friendly when they engaged in more environmentally-friendly behavior (Study 1). Furthermore, environmentally-friendly behavior resulted in a more positive self image, more strongly when it was voluntarily engaged in, compared to when it was driven by situational constraints (Study 2). In turn, the more environmentally friendly (Study 1) and positive (Study 2) people saw themselves, the better they felt about acting environmentally-friendly. Together, these results suggest that the specific self-signal that ensues from engaging in environmentally-friendly behavior can explain why environmentally-friendly actions may elicit a good feeling. PMID- 27933018 TI - A Study of the Coupling of FET Temperament Traits with Major Depression. AB - Objective: Temperament and mental illness have been linked to the same systems of behavioral regulation. A temperament model, carefully structured to respond to subtle differences within systems of behavior regulation, should exhibit distinct temperament patterns in the presence of mental illness. Previous comparisons of temperament profiles in mental disorders used mostly emotionality-related traits. In contrast, the Functional Ensemble of Temperament (FET) model differentiates not only between emotionality traits, but also between traits related to physical, verbal, and mental aspects of behavior and maps 12 functional aspects of behavior to temperament traits as well as to symptoms of mental illnesses. This article reports on the coupling of sex, age, and temperament traits with Major Depression (MD) using the FET framework. Method: Intake records of 467 subjects, ages 17-24, 25-45, 46-65, 66-84 were examined, with temperament assessed by the Structure of Temperament Questionnaire (based on the FET). Results: The presence of MD was associated with changes in mean temperament scores on 9 of the 12 traits. The results were in line with the DSM-5 criteria of fatigue (patients with MD reported a significant decrease in three types of endurance - motor-physical, social-verbal, and mental), of psychomotor retardation (a significant decrease in physical and social-verbal tempo) and of worthlessness (as low Self-Confidence). The results also showed that three new symptoms, high Impulsivity, high Neuroticism, and diminished Plasticity, should be considered as depressive symptoms in future versions of the DSM. As a significant negative result, no interaction of age or sex (with the exception of the Self-Confidence scale) with MD was found for temperament traits. Conclusion: The value of differentiating between physical, social, and mental aspects of behavior is demonstrated in the differential effects of major depression and gender. The value of differentiating between endurance, dynamical and orientation related aspects of behavior is also demonstrated. The deleterious impact of MD on temperament scores appeared to be similar across all age groups. The appearance of high impulsivity, neuroticism, and low plasticity deserve further study as associated factors in future versions of the DSM/ICD. PMID- 27933019 TI - Reduced Working Memory Mediates the Link between Early Institutional Rearing and Symptoms of ADHD at 12 Years. AB - Children who are raised in institutions show severe delays across multiple domains of development and high levels of psychopathology, including attention deficit/hyperactivity disorder (ADHD). Low performance in executive functions (EFs) are also common in institutionally reared children and often do not remediate following improvements in the caregiving environment. ADHD symptomatology also remains elevated even after children are removed from institutional care and placed in families. We investigate whether poor EF is a mechanism explaining elevated rates of ADHD in children reared in institutional settings in the Bucharest Early Intervention Project (BEIP). In the current study, we examine the potentially mediating role of poor EF in the association between institutionalization and symptoms of ADHD at age 12 years. A total of 107 children were assessed with the Cambridge Neuropsychological Test Automated Battery (CANTAB) on working memory, set-shifting and planning. We also obtained concurrent teacher reports on their levels of ADHD symptoms (inattention and impulsivity separately). Institutionalization strongly predicted elevations in symptoms of inattention and impulsivity at age 12 years (ps < 0.01). Indices of working memory and planning were also associated with ADHD after controlling for potential confounders (ps < 0.03). Mediation analyses revealed that poor working memory performance mediated the link between exposure to early institutionalization and higher scores of both inattention and impulsivity. These results replicate and extend the findings that we reported in the BEIP sample at age 8 years. Together, they suggest that compromised working memory is a key mechanism that continues to explain the strikingly high levels of ADHD in late childhood among children institutionalized in early life. Interventions targeting working memory may help to prevent ADHD among children exposed to institutional care. PMID- 27933020 TI - Feasibility of Group Schema Therapy for Outpatients with Severe Borderline Personality Disorder in Germany: A Pilot Study with Three Year Follow-Up. AB - Borderline Personality Disorder (BPD) is a severe, challenging to treat mental disorder. Schema therapy (ST) as an individual therapy has been proven to be an effective psychological treatment for BPD. A group format of ST (GST) has been developed and evaluated in a randomized controlled trial in the United States and piloted in The Netherlands. These results suggest that GST speeds up and amplifies treatment effects of ST and might reduce delivery costs. However, feasibility in the German health care system and with BPD patients with high BPD severity and comorbidity, and frequent hospitalization, has not been tested to date. We investigated GST in 10 severely impaired, highly comorbid female patients with BPD, that needed frequent hospital admission. Patients received an outpatient ST-treatment program with weekly group and individual sessions for 1 year. Outcome measures including BPD severity, general psychopathology, psychosocial functioning, quality of life, happiness, schemas, and modes, and days of hospitalization were assessed at the start of treatment and 6, 12, and 36 months later with semi-structured interviews and self-report measures. We observed significant decreases in severity of BPD symptoms, general symptom severity, dysfunctional BPD-specific modes and schemas, and days of hospitalization. Functional modes, quality of live and happiness improved. The results of this feasibility study are promising and encourage further implementation of ST outpatient treatment programs even for patients with severe BPD and high hospitalization risk. However, small sample size and the missing of a control group do not allow the generalizability of these findings. PMID- 27933021 TI - Dimensions of Compulsive Exercise across Eating Disorder Diagnostic Subtypes and the Validation of the Spanish Version of the Compulsive Exercise Test. AB - Objectives: Compulsive exercise in eating disorders has been traditionally considered as a behavior that serves the purpose of weight/shape control. More recently, it has been postulated that there may be other factors that drive the compulsive need to exercise. This has led to the development of the Compulsive Exercise Test (CET); a self-reported questionnaire that aims to explore the cognitive-behavioral underpinnings of compulsive exercise from a multi-faceted perspective. The objectives of this study were threefold: (1) to validate the Spanish version of the CET; (2) to compare eating disorder diagnostic subtypes and a healthy control group in terms of the factors that drive compulsive exercise as defined by the CET; (3) to explore how the dimensions evaluated in the CET are associated with eating disorder symptoms and general psychopathology. Methods: The CET was administered to a total of 157 patients with an eating disorder [40 anorexia nervosa, 56 bulimia nervosa (BN), and 61 eating disorder not-otherwise-specified (EDNOS)] and 128 healthy weight/eating controls. Patients were assessed via a semi-structured interview to reach a DSM-IV-TR diagnosis. Additionally, all participants completed the Symptom Checklist-90-Revised (SCL 90R) and the Eating Disorders Inventory-2 (EDI-2). Results: Confirmatory factor analysis demonstrated adequate goodness-of-fit to the original five-factor model of the CET. BN and EDNOS patients scored higher in the avoidance and rule-driven behavior, weight control, and total CET scales in comparison to the healthy controls, and higher across all scales apart from the exercise rigidity scale compared to the anorexia nervosa patients. Mean scores of the anorexia nervosa patients did not differ to those of the control participants, except for the mood improvement scale where the anorexia nervosa patients obtained a lower mean score. Mean scores between the BN and EDNOS patients were equivalent. The CET scales avoidance and rule-driven behavior, weight of control and total CET scores were positively correlated with the clinical assessment measures of the SCL-90R and EDI-2. Conclusion: Compulsive exercise is a multidimensional construct and the factors driving compulsive exercise differ according to the eating disorder diagnostic subtype. This should be taken into account when addressing compulsive exercise during the treatment of eating disorders. PMID- 27933022 TI - Emotional Empathy and Facial Mimicry for Static and Dynamic Facial Expressions of Fear and Disgust. AB - Facial mimicry is the tendency to imitate the emotional facial expressions of others. Increasing evidence suggests that the perception of dynamic displays leads to enhanced facial mimicry, especially for happiness and anger. However, little is known about the impact of dynamic stimuli on facial mimicry for fear and disgust. To investigate this issue, facial EMG responses were recorded in the corrugator supercilii, levator labii, and lateral frontalis muscles, while participants viewed static (photos) and dynamic (videos) facial emotional expressions. Moreover, we tested whether emotional empathy modulated facial mimicry for emotional facial expressions. In accordance with our predictions, the highly empathic group responded with larger activity in the corrugator supercilii and levator labii muscles. Moreover, dynamic compared to static facial expressions of fear revealed enhanced mimicry in the high-empathic group in the frontalis and corrugator supercilii muscles. In the low-empathic group the facial reactions were not differentiated between fear and disgust for both dynamic and static facial expressions. We conclude that highly empathic subjects are more sensitive in their facial reactions to the facial expressions of fear and disgust compared to low empathetic counterparts. Our data confirms that personal characteristics, i.e., empathy traits as well as modality of the presented stimuli, modulate the strength of facial mimicry. In addition, measures of EMG activity of the levator labii and frontalis muscles may be a useful index of empathic responses of fear and disgust. PMID- 27933023 TI - Implicit Motives and Men's Perceived Constraint in Fatherhood. AB - Research shows that implicit motives influence social relationships. However, little is known about their role in fatherhood and, particularly, how men experience their paternal role. Therefore, this study examined the association of implicit motives and fathers' perceived constraint due to fatherhood. Furthermore, we explored their relation to fathers' life satisfaction. Participants were fathers with biological children (N = 276). They were asked to write picture stories, which were then coded for implicit affiliation and power motives. Perceived constraint and life satisfaction were assessed on a visual analog scale. A higher implicit need for affiliation was significantly associated with lower perceived constraint, whereas the implicit need for power had the opposite effect. Perceived constraint had a negative influence on life satisfaction. Structural equation modeling revealed significant indirect effects of implicit affiliation and power motives on life satisfaction mediated by perceived constraint. Our findings indicate that men with a higher implicit need for affiliation experience less constraint due to fatherhood, resulting in higher life satisfaction. The implicit need for power, however, results in more perceived constraint and is related to decreased life satisfaction. PMID- 27933024 TI - Confabulating, Misremembering, Relearning: The Simulation Theory of Memory and Unsuccessful Remembering. AB - This article develops a taxonomy of memory errors in terms of three conditions: the accuracy of the memory representation, the reliability of the memory process, and the internality (with respect to the remembering subject) of that process. Unlike previous taxonomies, which appeal to retention of information rather than reliability or internality, this taxonomy can accommodate not only misremembering (e.g., the DRM effect), falsidical confabulation, and veridical relearning but also veridical confabulation and falsidical relearning. Moreover, because it does not assume that successful remembering presupposes retention of information, the taxonomy is compatible with recent simulation theories of remembering. PMID- 27933025 TI - Implicit Detection of Poetic Harmony by the Naive Brain. AB - The power of poetry is universally acknowledged, but it is debatable whether its appreciation is reserved for experts. Here, we show that readers with no particular knowledge of a traditional form of Welsh poetry unconsciously distinguish phrases conforming to its complex poetic construction rules from those that violate them. We studied the brain response of native speakers of Welsh as they read meaningful sentences ending in a word that either complied with strict poetic construction rules, violated rules of consonantal repetition, violated stress pattern, or violated both these constraints. Upon reading the last word of each sentence, participants indicated sentence acceptability. As expected, our inexperienced participants did not explicitly distinguish between sentences that conformed to the poetic rules from those that violated them. However, in the case of orthodox sentences, the critical word elicited a distinctive brain response characteristic of target detection -the P3b- as compared to the other conditions, showing that speakers of Welsh with no expertise of this particular form of poetry implicitly detect poetic harmony. These results show for the first time that before we even consider literal meaning, the musical properties of poetry speak to the human mind in ways that escape consciousness. PMID- 27933026 TI - Fitness Costs Predict Emotional, Moral, and Attitudinal Inbreeding Aversion. AB - In terms of sexual intercourse, the very last people we think about are our kin. Imagining inbreeding intercourse, whether it involves our closest kin or not, induces aversion in most people who invoke inbreeding depression problems or cultural considerations. Research has focused on the disgust felt when facing inbreeding intercourse between close kin but little is known about other responses. In this study, we considered the influence of fitness costs on aversive reactions by including disgust and emotional reaction as well as moral judgment and attitudes toward inbreeding: higher costs should induce a stronger aversive reaction. The fitness costs were manipulated by two factors: (i) the degree of the participants' involvement in the story (themselves, a sib or an unknown individual), and (ii) the degree of relatedness between the two inbreeding people (brother/sister, uncle-aunt/niece-nephew, cousin). To test this hypothesis, 140 women read and assessed different inbreeding stories varying in the fitness costs incurred. Findings showed that the higher the fitness costs were, the greater the aversive reaction was in an overall way. First, our results fitted with previous studies that tested the influence of fitness costs on disgust. Second, and more interestingly, findings went further by examining overall aversion, showing that fitness costs could influence emotions felt as well as attitudes and behaviors toward inbreeding people. The higher the fitness costs were, the less inbreeding people were perceived as moral and the more they were considered as a nuisance. However, results regarding avoidance were more nuanced. PMID- 27933027 TI - Differences of Perceived Image Generated through the Web Site: Empirical Evidence Obtained in Spanish Destinations. AB - In this paper, a study of the perceived destination image created by promotional Web Pages is expounded in an attempt to identify their differences as generators of destination image in the consumers' mind. Specifically, it seeks to analyse whether the web sites of different Spanish regions improve the image that consumers have of the destination, identifying their main dimensions and analysing its effect on satisfaction and intentions of the future behavior of potential visitors. To achieve these objectives and verify the hypotheses, a laboratory experiment was performed, where it was determined what changes are produced in the tourist's previous image after browsing the tourist webs of three different regions. Moreover, it analyses the differences in the effect of the perceived image on satisfaction and potential visitors' future behavioral intentions. The results obtained enable us to identify differences in the composition of the perceived image according to the destination, while confirming the significant effect of different perceived image dimensions regarding satisfaction. The results allow managers to gain a better understanding of the effectiveness of their sites from a consumer perspective as well as suggestions to follow in order to achieve greater efficiency in their communication actions in order to improve the motivation of visitors to go to the destination. PMID- 27933028 TI - Autism in Action: Reduced Bodily Connectedness during Social Interactions? AB - Autism is a lifelong disorder, defined by deficits in social interactions and flexibility. To date, diagnostic markers for autism primarily include limitations in social behavior and cognition. However, such tests have often shown to be inadequate for individuals with autism who are either more cognitively able or intellectually disabled. The assessment of the social limitations of autism would benefit from new tests that capture the dynamics of social initiative and reciprocity in interaction processes, and that are not dependent on intellectual or verbal skills. New entry points for the development of such assessments may be found in 'bodily connectedness', the attunement of bodily movement between two individuals. In typical development, bodily connectedness is related to psychological connectedness, including social skills and relation quality. Limitations in bodily connectedness could be a central mechanism underlying the social impairment in autism. While bodily connectedness can be minutely assessed with advanced techniques, our understanding of these skills in autism is limited. This Perspective provides examples of how the potential relation between bodily connectedness and specific characteristics of autism can be examined using methods from the coordination dynamics approach. Uncovering this relation is particularly important for developing sensitive tools to assess the tendency to initiate social interactions and the dynamics of mutual adjustments during social interactions, as current assessments are not suited to grasp ongoing dynamics and reciprocity in behavior. The outcomes of such research may yield valuable openings for the development of diagnostic markers for autism that can be applied across the lifespan. PMID- 27933029 TI - Drifting through Basic Subprocesses of Reading: A Hierarchical Diffusion Model Analysis of Age Effects on Visual Word Recognition. AB - Reading is one of the most popular leisure activities and it is routinely performed by most individuals even in old age. Successful reading enables older people to master and actively participate in everyday life and maintain functional independence. Yet, reading comprises a multitude of subprocesses and it is undoubtedly one of the most complex accomplishments of the human brain. Not surprisingly, findings of age-related effects on word recognition and reading have been partly contradictory and are often confined to only one of four central reading subprocesses, i.e., sublexical, orthographic, phonological and lexico semantic processing. The aim of the present study was therefore to systematically investigate the impact of age on each of these subprocesses. A total of 1,807 participants (young, N = 384; old, N = 1,423) performed four decision tasks specifically designed to tap one of the subprocesses. To account for the behavioral heterogeneity in older adults, this subsample was split into high and low performing readers. Data were analyzed using a hierarchical diffusion modeling approach, which provides more information than standard response time/accuracy analyses. Taking into account incorrect and correct response times, their distributions and accuracy data, hierarchical diffusion modeling allowed us to differentiate between age-related changes in decision threshold, non-decision time and the speed of information uptake. We observed longer non-decision times for older adults and a more conservative decision threshold. More importantly, high-performing older readers outperformed younger adults at the speed of information uptake in orthographic and lexico-semantic processing, whereas a general age-disadvantage was observed at the sublexical and phonological levels. Low-performing older readers were slowest in information uptake in all four subprocesses. Discussing these results in terms of computational models of word recognition, we propose age-related disadvantages for older readers to be caused by inefficiencies in temporal sampling and activation and/or inhibition processes. PMID- 27933030 TI - The Association of DRD2 with Insight Problem Solving. AB - Although the insight phenomenon has attracted great attention from psychologists, it is still largely unknown whether its variation in well-functioning human adults has a genetic basis. Several lines of evidence suggest that genes involved in dopamine (DA) transmission might be potential candidates. The present study explored for the first time the association of dopamine D2 receptor gene (DRD2) with insight problem solving. Fifteen single-nucleotide polymorphisms (SNPs) covering DRD2 were genotyped in 425 unrelated healthy Chinese undergraduates, and were further tested for association with insight problem solving. Both single SNP and haplotype analysis revealed several associations of DRD2 SNPs and haplotypes with insight problem solving. In conclusion, the present study provides the first evidence for the involvement of DRD2 in insight problem solving, future studies are necessary to validate these findings. PMID- 27933031 TI - Exhaustion Experiences in Junior Athletes: The Importance of Motivation and Self Control Competencies. AB - Quality of motivation, self-control competencies, as well as past performance experience influence sport participation outcomes in developing athletes. Studies have shown that junior athletes high in self-determined motivation are less prone to experience burnout, while self-control competencies help developing athletes to be conscious and deliberate in their self-regulatory efforts toward elite sport performances and avoid negative sport participation outcomes. Combining the self-determination theory framework and psychosocial theories of self-regulation, the aim of this cross-sectional study was to examine how various types of motivation and self-control competencies together are associated with the development of burnout symptoms in junior athletes. High-level Norwegian winter sport athletes from elite sport academies (N = 199; female n = 72; 16-20 years of age) consented to participate. Associations between six types of motivational regulation, self-control, and indices of exhaustion were investigated. We hypothesized that athletes' self-control competencies are important to operate successfully, and influenced by different types of motivation, they are expected to help athletes avoid negative sport participation outcomes such as emotional and physical exhaustion. Structural equation modeling analyses were conducted to analyze these relationships, and results revealed some multifaceted associations. When identifying antecedents of sport participation exhaustion and burnout, there is a need to go beyond the unique framework of motivation theories, and explore what cognitive competencies ensure fulfillment of motivation desires. In the current study, differences in junior athletes' quality of motivation influenced self-control competencies when predicting exhaustion. Interestingly, young athletes driven by self-determined (intrinsic, integrated, and identified), and controlled (introjected and amotivation) regulations in association with self control offered the strongest negative and positive associations with exhaustion, respectively. Findings clearly indicate that motivation and self-control competencies are meaningfully interrelated when assessing burnout propensity in young developing athletes. PMID- 27933032 TI - Bifurcation Type and Larger Low Shear Area Are Associated with Rupture Status of Very Small Intracranial Aneurysms. AB - BACKGROUND: Characterization of the risk factors for rupture of very small intracranial aneurysm (VSIA, <=3 mm) is clinically valuable, since VSIAs are implicated in subarachnoid hemorrhage. The aim of this study was to identify morphological and hemodynamic parameters that independently characterize the rupture status of VSIAs. METHODS: We conducted a retrospective study of consecutive VSIAs between September 2010 and February 2014 in our institute. A series of morphologic and hemodynamic parameters were evaluated using computational fluid dynamics, based on patient-specific three-dimensional geometrical models. RESULTS: We identified 186 patients with 206 VSIAs (73 ruptured, 133 unruptured). Univariable logistic regression analysis showed that bifurcation type, parent artery diameter, size ratio, time-averaged wall shear stress (WSS), maximum WSS, minimum WSS, and low shear area (LSA) were related to rupture status. Bifurcation type and larger LSA were independently associated with rupture status in multivariable logistic regression (p = 0.002 and p = 0.003, respectively). CONCLUSION: Bifurcation type and larger LSA were independently associated with VSIA rupture status. Further studies are needed prospectively on patient-derived geometries prior to rupturing based on large multi-population data to confirm the present findings. PMID- 27933033 TI - Central Amino Acid Sensing in the Control of Feeding Behavior. AB - Dietary protein quantity and quality greatly impact metabolic health via evolutionary-conserved mechanisms that ensure avoidance of amino acid imbalanced food sources, promote hyperphagia when dietary protein density is low, and conversely produce satiety when dietary protein density is high. Growing evidence supports the emerging concept of protein homeostasis in mammals, where protein intake is maintained within a tight range independently of energy intake to reach a target protein intake. The behavioral and neuroendocrine mechanisms underlying these adaptations are unclear. While peripheral factors are able to signal amino acid deficiency and abundance to the brain, the brain itself is exposed to and can detect changes in amino acid concentrations, and subsequently engages acute and chronic responses modulating feeding behavior and food preferences. In this review, we will examine the literature describing the mechanisms by which the brain senses changes in amino acids concentrations, and how these changes modulate feeding behavior. PMID- 27933034 TI - A Novel, Molybdenum-Containing Methionine Sulfoxide Reductase Supports Survival of Haemophilus influenzae in an In vivo Model of Infection. AB - Haemophilus influenzae is a host adapted human mucosal pathogen involved in a variety of acute and chronic respiratory tract infections, including chronic obstructive pulmonary disease and asthma, all of which rely on its ability to efficiently establish continuing interactions with the host. Here we report the characterization of a novel molybdenum enzyme, TorZ/MtsZ that supports interactions of H. influenzae with host cells during growth in oxygen-limited environments. Strains lacking TorZ/MtsZ showed a reduced ability to survive in contact with epithelial cells as shown by immunofluorescence microscopy and adherence/invasion assays. This included a reduction in the ability of the strain to invade human epithelial cells, a trait that could be linked to the persistence of H. influenzae. The observation that in a murine model of H. influenzae infection, strains lacking TorZ/MtsZ were almost undetectable after 72 h of infection, while ~3.6 * 103 CFU/mL of the wild type strain were measured under the same conditions is consistent with this view. To understand how TorZ/MtsZ mediates this effect we purified and characterized the enzyme, and were able to show that it is an S- and N-oxide reductase with a stereospecificity for S sulfoxides. The enzyme converts two physiologically relevant sulfoxides, biotin sulfoxide and methionine sulfoxide (MetSO), with the kinetic parameters suggesting that MetSO is the natural substrate of this enzyme. TorZ/MtsZ was unable to repair sulfoxides in oxidized Calmodulin, suggesting that a role in cell metabolism/energy generation and not protein repair is the key function of this enzyme. Phylogenetic analyses showed that H. influenzae TorZ/MtsZ is only distantly related to the Escherichia coli TorZ TMAO reductase, but instead is a representative of a new, previously uncharacterized clade of molybdenum enzyme that is widely distributed within the Pasteurellaceae family of pathogenic bacteria. It is likely that MtsZ/TorZ has a similar role in supporting host/pathogen interactions in other members of the Pasteurellaceae, which includes both human and animal pathogens. PMID- 27933035 TI - Life without dUTPase. AB - Fine-tuned regulation of the cellular nucleotide pools is indispensable for faithful replication of Deoxyribonucleic Acid (DNA). The genetic information is also safeguarded by DNA damage recognition and repair processes. Uracil is one of the most frequently occurring erroneous bases in DNA; it can arise from cytosine deamination or thymine-replacing incorporation. Two enzyme activities are primarily involved in keeping DNA uracil-free: dUTPase (dUTP pyrophosphatase) activity that prevent thymine-replacing incorporation and uracil-DNA glycosylase activity that excise uracil from DNA and initiate uracil-excision repair. Both dUTPase and the most efficient uracil-DNA glycosylase (UNG) is thought to be ubiquitous in free-living organisms. In the present work, we have systematically investigated the genotype of deposited fully sequenced bacterial and Archaeal genomes. We have performed bioinformatic searches in these genomes using the already well described dUTPase and UNG gene sequences. For dUTPases, we have included the trimeric all-beta and the dimeric all-alpha families and also, the bifunctional dCTP (deoxycytidine triphosphate) deaminase-dUTPase sequences. Surprisingly, we have found that in contrast to the generally held opinion, a wide number of bacterial and Archaeal species lack all of the previously described dUTPase gene(s). The dut- genotype is present in diverse bacterial phyla indicating that loss of this (or these) gene(s) has occurred multiple times during evolution. We discuss potential survival strategies in lack of dUTPases, such as simultaneous lack or inhibition of UNG and possession of exogenous or alternate metabolic enzymes involved in uracil-DNA metabolism. The potential that genes previously not associated with dUTPase activity may still encode enzymes capable of hydrolyzing dUTP is also discussed. Our data indicate that several unicellular microorganisms may efficiently cope with a dut- genotype lacking all of the previously described dUTPase genes, and potentially leading to an unusual uracil-enrichment in their genomic DNA. PMID- 27933036 TI - Functional Analysis of the Nitrogen Metabolite Repression Regulator Gene nmrA in Aspergillus flavus. AB - In Aspergillus nidulans, the nitrogen metabolite repression (NMR) regulator NmrA plays a major role in regulating the activity of the GATA transcription factor AreA during nitrogen metabolism. However, the function of nmrA in A. flavus has not been previously studied. Here, we report the identification and functional analysis of nmrA in A. flavus. Our work showed that the amino acid sequences of NmrA are highly conserved among Aspergillus species and that A. flavus NmrA protein contains a canonical Rossmann fold motif. Deletion of nmrA slowed the growth of A. flavus but significantly increased conidiation and sclerotia production. Moreover, seed infection experiments indicated that nmrA is required for the invasive virulence of A. flavus. In addition, the DeltanmrA mutant showed increased sensitivity to rapamycin and methyl methanesulfonate, suggesting that nmrA could be responsive to target of rapamycin signaling and DNA damage. Furthermore, quantitative real-time reverse transcription polymerase chain reaction analysis suggested that nmrA might interact with other nitrogen regulatory and catabolic genes. Our study provides a better understanding of NMR and the nitrogen metabolism network in fungi. PMID- 27933037 TI - Blad-Containing Oligomer Fungicidal Activity on Human Pathogenic Yeasts. From the Outside to the Inside of the Target Cell. AB - Blad polypeptide comprises residues 109-281 of Lupinus albus beta-conglutin precursor. It occurs naturally as a major subunit of an edible, 210 kDa oligomer which accumulates to high levels, exclusively in the cotyledons of Lupinus seedlings between the 4th and 14th day after the onset of germination. Blad containing oligomer (BCO) exhibits a potent and broad spectrum fungicide activity toward plant pathogens and is now on sale in the US under the tradename FractureTM. In this work we demonstrate its antifungal activity toward human pathogens and provide some insights on its mode of action. BCO bioactivity was evaluated in eight yeast species and compared to that of amphotericin B (AMB). BCO behaved similarly to AMB in what concerns both cellular inhibition and cellular death. As a lectin, BCO binds strongly to chitin. In addition, BCO is known to possess 'exochitinase' and 'endochitosanase' activities. However, no clear disruption was visualized at the cell wall after exposure to a lethal BCO concentration, except in cell buds. Immunofluorescent and immunogold labeling clearly indicate that BCO enters the cell, and membrane destabilization was also demonstrated. The absence of haemolytic activity, its biological origin, and its extraordinary antifungal activity are the major outcomes of this work, and provide a solid background for a future application as a new antifungal therapeutic drug. Furthermore, its predictable multisite mode of action suggests a low risk of inducing resistance mechanisms, which are now a major problem with other currently available antifungal drugs. PMID- 27933038 TI - Computing and Applying Atomic Regulons to Understand Gene Expression and Regulation. AB - Understanding gene function and regulation is essential for the interpretation, prediction, and ultimate design of cell responses to changes in the environment. An important step toward meeting the challenge of understanding gene function and regulation is the identification of sets of genes that are always co-expressed. These gene sets, Atomic Regulons (ARs), represent fundamental units of function within a cell and could be used to associate genes of unknown function with cellular processes and to enable rational genetic engineering of cellular systems. Here, we describe an approach for inferring ARs that leverages large scale expression data sets, gene context, and functional relationships among genes. We computed ARs for Escherichia coli based on 907 gene expression experiments and compared our results with gene clusters produced by two prevalent data-driven methods: Hierarchical clustering and k-means clustering. We compared ARs and purely data-driven gene clusters to the curated set of regulatory interactions for E. coli found in RegulonDB, showing that ARs are more consistent with gold standard regulons than are data-driven gene clusters. We further examined the consistency of ARs and data-driven gene clusters in the context of gene interactions predicted by Context Likelihood of Relatedness (CLR) analysis, finding that the ARs show better agreement with CLR predicted interactions. We determined the impact of increasing amounts of expression data on AR construction and find that while more data improve ARs, it is not necessary to use the full set of gene expression experiments available for E. coli to produce high quality ARs. In order to explore the conservation of co-regulated gene sets across different organisms, we computed ARs for Shewanella oneidensis, Pseudomonas aeruginosa, Thermus thermophilus, and Staphylococcus aureus, each of which represents increasing degrees of phylogenetic distance from E. coli. Comparison of the organism-specific ARs showed that the consistency of AR gene membership correlates with phylogenetic distance, but there is clear variability in the regulatory networks of closely related organisms. As large scale expression data sets become increasingly common for model and non-model organisms, comparative analyses of atomic regulons will provide valuable insights into fundamental regulatory modules used across the bacterial domain. PMID- 27933039 TI - The Contribution of Mathematical Modeling to Understanding Dynamic Aspects of Rumen Metabolism. AB - All mechanistic rumen models cover the main drivers of variation in rumen function, which are feed intake, the differences between feedstuffs and feeds in their intrinsic rumen degradation characteristics, and fractional outflow rate of fluid and particulate matter. Dynamic modeling approaches are best suited to the prediction of more nuanced responses in rumen metabolism, and represent the dynamics of the interactions between substrates and micro-organisms and inter microbial interactions. The concepts of dynamics are discussed for the case of rumen starch digestion as influenced by starch intake rate and frequency of feed intake, and for the case of fermentation of fiber in the large intestine. Adding representations of new functional classes of micro-organisms (i.e., with new characteristics from the perspective of whole rumen function) in rumen models only delivers new insights if complemented by the dynamics of their interactions with other functional classes. Rumen fermentation conditions have to be represented due to their profound impact on the dynamics of substrate degradation and microbial metabolism. Although the importance of rumen pH is generally acknowledged, more emphasis is needed on predicting its variation as well as variation in the processes that underlie rumen fluid dynamics. The rumen wall has an important role in adapting to rapid changes in the rumen environment, clearing of volatile fatty acids (VFA), and maintaining rumen pH within limits. Dynamics of rumen wall epithelia and their role in VFA absorption needs to be better represented in models that aim to predict rumen responses across nutritional or physiological states. For a detailed prediction of rumen N balance there is merit in a dynamic modeling approach compared to the static approaches adopted in current protein evaluation systems. Improvement is needed on previous attempts to predict rumen VFA profiles, and this should be pursued by introducing factors that relate more to microbial metabolism. For rumen model construction, data on rumen microbiomes are preferably coupled with knowledge consolidated in rumen models instead of relying on correlations with rather general aspects of treatment or animal. This helps to prevent the disregard of basic principles and underlying mechanisms of whole rumen function. PMID- 27933040 TI - DNRA and Denitrification Coexist over a Broad Range of Acetate/N-NO3- Ratios, in a Chemostat Enrichment Culture. AB - Denitrification and dissimilatory nitrate reduction to ammonium (DNRA) compete for nitrate in natural and engineered environments. A known important factor in this microbial competition is the ratio of available electron donor and elector acceptor, here expressed as Ac/N ratio (acetate/nitrate-nitrogen). We studied the impact of the Ac/N ratio on the nitrate reduction pathways in chemostat enrichment cultures, grown on acetate mineral medium. Stepwise, conditions were changed from nitrate limitation to nitrate excess in the system by applying a variable Ac/N ratio in the feed. We observed a clear correlation between Ac/N ratio and DNRA activity and the DNRA population in our reactor. The DNRA bacteria dominated under nitrate limiting conditions in the reactor and were outcompeted by denitrifiers under limitation of acetate. Interestingly, in a broad range of Ac/N ratios a dual limitation of acetate and nitrate occurred with co-occurrence of DNRA bacteria and denitrifiers. To explain these observations, the system was described using a kinetic model. The model illustrates that the Ac/N effect and concomitant broad dual limitation range related to the difference in stoichiometry between both processes, as well as the differences in electron donor and acceptor affinities. Population analysis showed that the presumed DRNA performing bacteria were the same under nitrate limitation and under dual limiting conditions, whereas the presumed denitrifying population changed under single and dual limitation conditions. PMID- 27933041 TI - Production, Characterization, and Application of Bacillus licheniformis W16 Biosurfactant in Enhancing Oil Recovery. AB - The biosurfactant production by Bacillus licheniformis W16 and evaluation of biosurfactant based enhanced oil recovery (EOR) using core-flood under reservoir conditions were investigated. Previously reported nine different production media were screened for biosurfactant production, and two were further optimized with different carbon sources (glucose, sucrose, starch, cane molasses, or date molasses), as well as the strain was screened for biosurfactant production during the growth in different media. The biosurfactant reduced the surface tension and interfacial tension to 24.33 +/- 0.57 mN m-1 and 2.47 +/- 0.32 mN m-1 respectively within 72 h, at 40 degrees C, and also altered the wettability of a hydrophobic surface by changing the contact angle from 55.67 +/- 1.6 to 19.54 degrees +/- 0.96 degrees . The critical micelle dilution values of 4X were observed. The biosurfactants were characterized by different analytical techniques and identified as lipopeptide, similar to lichenysin-A. The biosurfactant was stable over wide range of extreme environmental conditions. The core flood experiments showed that the biosurfactant was able to enhance the oil recovery by 24-26% over residual oil saturation (Sor). The results highlight the potential application of lipopeptide biosurfactant in wettability alteration and microbial EOR processes. PMID- 27933043 TI - Antimicrobial Susceptibility of Flavobacterium psychrophilum from Chilean Salmon Farms and Their Epidemiological Cut-Off Values Using Agar Dilution and Disk Diffusion Methods. AB - Flavobacterium psychrophilum is the most important bacterial pathogen for freshwater farmed salmonids in Chile. The aims of this study were to determine the susceptibility to antimicrobials used in fish farming of Chilean isolates and to calculate their epidemiological cut-off (COWT) values. A number of 125 Chilean isolates of F. psychrophilum were isolated from reared salmonids presenting clinical symptoms indicative of flavobacteriosis and their identities were confirmed by 16S rRNA polymerase chain reaction. Susceptibility to antibacterials was tested on diluted Mueller-Hinton by using an agar dilution MIC method and a disk diffusion method. The COWT values calculated by Normalized Resistance Interpretation (NRI) analysis allow isolates to be categorized either as wild type fully susceptible (WT) or as manifesting reduced susceptibility (NWT). When MIC data was used, NRI analysis calculated a COWT of <=0.125, <=2, and <=0.5 MUg mL-1 for amoxicillin, florfenicol, and oxytetracycline, respectively. For the quinolones, the COWT were <=1, <=0.5, and <=0.125 MUg mL-1 for oxolinic acid, flumequine, and enrofloxacin, respectively. The disk diffusion data sets obtained in this work were extremely diverse and were spread over a wide range. For the quinolones there was a close agreement between the frequencies of NWT isolates calculated using MIC and disk data. For oxolinic acid, flumequine, and enrofloxacin the frequencies were 45, 39, and 38% using MIC data, and 42, 41, and 44%, when disk data were used. There was less agreement with the other antimicrobials, because NWT frequencies obtained using MIC and disk data, respectively, were 24 and 10% for amoxicillin, 8 and 2% for florfenicol, and 70 and 64% for oxytetracycline. Considering that the MIC data was more precise than the disk diffusion data, MIC determination would be the preferred method for susceptibility testing for this species and the NWT frequencies derived from the MIC data sets should be considered as the more authoritative. Despite the high frequency of isolates showing full susceptibility to florfenicol, the significant frequencies of isolates exhibiting reduced susceptibility to oxytetracycline and quinolones may result in treatment failures when these agents are used. PMID- 27933042 TI - The Role of Stress and Stress Adaptations in Determining the Fate of the Bacterial Pathogen Listeria monocytogenes in the Food Chain. AB - The foodborne pathogen Listeria monocytogenes is a highly adaptable organism that can persist in a wide range of environmental and food-related niches. The consumption of contaminated ready-to-eat foods can cause infections, termed listeriosis, in vulnerable humans, particularly those with weakened immune systems. Although these infections are comparatively rare they are associated with high mortality rates and therefore this pathogen has a significant impact on food safety. L. monocytogenes can adapt to and survive a wide range of stress conditions including low pH, low water activity, and low temperature, which makes it problematic for food producers who rely on these stresses for preservation. Stress tolerance in L. monocytogenes can be explained partially by the presence of the general stress response (GSR), a transcriptional response under the control of the alternative sigma factor sigma B (sigmaB) that reconfigures gene transcription to provide homeostatic and protective functions to cope with the stress. Within the host sigmaB also plays a key role in surviving the harsh conditions found in the gastrointestinal tract. As the infection progresses beyond the GI tract L. monocytogenes uses an intracellular infectious cycle to propagate, spread and remain protected from the host's humoral immunity. Many of the virulence genes that facilitate this infectious cycle are under the control of a master transcriptional regulator called PrfA. In this review we consider the environmental reservoirs that enable L. monocytogenes to gain access to the food chain and discuss the stresses that the pathogen must overcome to survive and grow in these environments. The overlap that exists between stress tolerance and virulence is described. We review the principal measures that are used to control the pathogen and point to exciting new approaches that might provide improved means of control in the future. PMID- 27933044 TI - Antibiotic Resistance in the Food Chain: A Developing Country-Perspective. AB - Antibiotics are now "endangered species" facing extinction due to the worldwide emergence of antibiotic resistance (ABR). Food animals are considered as key reservoirs of antibiotic-resistant bacteria with the use of antibiotics in the food production industry having contributed to the actual global challenge of ABR. There are no geographic boundaries to impede the worldwide spread of ABR. If preventive and containment measures are not applied locally, nationally and regionally, the limited interventions in one country, continent and for instance, in the developing world, could compromise the efficacy and endanger ABR containment policies implemented in other parts of the world, the best-managed high-resource countries included. Multifaceted, comprehensive, and integrated measures complying with the One Health approach are imperative to ensure food safety and security, effectively combat infectious diseases, curb the emergence and spread of ABR, and preserve the efficacy of antibiotics for future generations. Countries should follow the World Health Organization, World Organization for Animal Health, and the Food and Agriculture Organization of the United Nations recommendations to implement national action plans encompassing human, (food) animal, and environmental sectors to improve policies, interventions and activities that address the prevention and containment of ABR from farm-to-fork. This review covers (i) the origin of antibiotic resistance, (ii) pathways by which bacteria spread to humans from farm-to-fork, (iii) differences in levels of antibiotic resistance between developed and developing countries, and (iv) prevention and containment measures of antibiotic resistance in the food chain. PMID- 27933045 TI - What Is the Link between Stringent Response, Endoribonuclease Encoding Type II Toxin-Antitoxin Systems and Persistence? AB - Persistence is a transient and non-inheritable tolerance to antibiotics by a small fraction of a bacterial population. One of the proposed determinants of bacterial persistence is toxin-antitoxin systems (TASs) which are also implicated in a wide range of stress-related phenomena. Maisonneuve E, Castro-Camargo M, Gerdes K. 2013. Cell 154:1140-1150 reported an interesting link between ppGpp mediated stringent response, TAS, and persistence. It is proposed that accumulation of ppGpp enhances the accumulation of inorganic polyphosphate which modulates Lon protease to degrade antitoxins. The decrease in the concentration of antitoxins supposedly activated the toxin to increase in the number of persisters during antibiotic treatment. In this study, we show that inorganic polyphosphate is not required for transcriptional activation of yefM/yoeB TAS, which is an indirect indication of Lon-dependent degradation of YefM antitoxin. The Delta10 strain, an Escherichia coli MG1655 derivative in which the 10 TAS are deleted, is more sensitive to ciprofloxacin compared to wild type MG1655. Furthermore, we show that the Delta10 strain has relatively lower fitness compared to the wild type and hence, we argue that the persistence related implications based on Delta10 strain are void. We conclude that the transcriptional regulation and endoribonuclease activity of YefM/YoeB TAS is independent of ppGpp and inorganic polyphosphate. Therefore, we urge for thorough inspection and debate on the link between chromosomal endoribonuclease TAS and persistence. PMID- 27933046 TI - Phylogenetic Signals of Salinity and Season in Bacterial Community Composition Across the Salinity Gradient of the Baltic Sea. AB - Understanding the key processes that control bacterial community composition has enabled predictions of bacterial distribution and function within ecosystems. In this study, we used the Baltic Sea as a model system to quantify the phylogenetic signal of salinity and season with respect to bacterioplankton community composition. The abundances of 16S rRNA gene amplicon sequencing reads were analyzed from samples obtained from similar geographic locations in July and February along a brackish to marine salinity gradient in the Baltic Sea. While there was no distinct pattern of bacterial richness at different salinities, the number of bacterial phylotypes in winter was significantly higher than in summer. Bacterial community composition in brackish vs. marine conditions, and in July vs. February was significantly different. Non-metric multidimensional scaling showed that bacterial community composition was primarily separated according to salinity and secondly according to seasonal differences at all taxonomic ranks tested. Similarly, quantitative phylogenetic clustering implicated a phylogenetic signal for both salinity and seasonality. Our results suggest that global patterns of bacterial community composition with respect to salinity and season are the result of phylogenetically clustered ecological preferences with stronger imprints from salinity. PMID- 27933047 TI - Diazotroph Diversity in the Sea Ice, Melt Ponds, and Surface Waters of the Eurasian Basin of the Central Arctic Ocean. AB - The Eurasian basin of the Central Arctic Ocean is nitrogen limited, but little is known about the presence and role of nitrogen-fixing bacteria. Recent studies have indicated the occurrence of diazotrophs in Arctic coastal waters potentially of riverine origin. Here, we investigated the presence of diazotrophs in ice and surface waters of the Central Arctic Ocean in the summer of 2012. We identified diverse communities of putative diazotrophs through targeted analysis of the nifH gene, which encodes the iron protein of the nitrogenase enzyme. We amplified 529 nifH sequences from 26 samples of Arctic melt ponds, sea ice and surface waters. These sequences resolved into 43 clusters at 92% amino acid sequence identity, most of which were non-cyanobacterial phylotypes from sea ice and water samples. One cyanobacterial phylotype related to Nodularia sp. was retrieved from sea ice, suggesting that this important functional group is rare in the Central Arctic Ocean. The diazotrophic community in sea-ice environments appear distinct from other cold-adapted diazotrophic communities, such as those present in the coastal Canadian Arctic, the Arctic tundra and glacial Antarctic lakes. Molecular fingerprinting of nifH and the intergenic spacer region of the rRNA operon revealed differences between the communities from river-influenced Laptev Sea waters and those from ice-related environments pointing toward a marine origin for sea-ice diazotrophs. Our results provide the first record of diazotrophs in the Central Arctic and suggest that microbial nitrogen fixation may occur north of 77 degrees N. To assess the significance of nitrogen fixation for the nitrogen budget of the Arctic Ocean and to identify the active nitrogen fixers, further biogeochemical and molecular biological studies are needed. PMID- 27933048 TI - Clay Components in Soil Dictate Environmental Stability and Bioavailability of Cervid Prions in Mice. AB - Chronic wasting disease (CWD) affects cervids and is the only known prion disease to affect free-ranging wildlife populations. CWD spread continues unabated, and exact mechanisms of its seemingly facile spread among deer and elk across landscapes in North America remain elusive. Here we confirm that naturally contaminated soil contains infectious CWD prions that can be transmitted to susceptible model organisms. We show that smectite clay content of soil potentiates prion binding capacity of different soil types from CWD endemic and non-endemic areas, likely contributing to environmental stability of bound prions. The smectite clay montmorillonite (Mte) increased prion retention and bioavailability in vivo. Trafficking experiments in live animals fed bound and unbound prions showed that mice retained significantly more Mte-bound than unbound prions. Mte promoted rapid uptake of prions from the stomach to the intestines via enterocytes and M cells, and then to macrophages and eventually CD21+ B cells in Peyer's patches and spleens. These results confirm clay components in soil as an important vector in CWD transmission at both environmental and organismal levels. PMID- 27933049 TI - High Diversity of Genogroup I Picobirnaviruses in Mammals. AB - In a molecular epidemiology study using 791 fecal samples collected from different terrestrial and marine mammals in Hong Kong, genogroup I picobirnaviruses (PBVs) were positive by RT-PCR targeting the partial RdRp gene in specimens from five cattle, six monkeys, 17 horses, nine pigs, one rabbit, one dog, and 12 California sea lions, with 11, 9, 23, 17, 1, 1, and 15 sequence types in the positive specimens from the corresponding animals, respectively. Phylogenetic analysis showed that the PBV sequences from each kind of animal were widely distributed in the whole tree with high diversity, sharing 47.4-89.0% nucleotide identities with other genogroup I PBV strains based on the partial RdRp gene. Nine complete segment 1 (viral loads 1.7 * 104 to 5.9 * 106/ml) and 15 segment 2 (viral loads 4.1 * 103 to 1.3 * 106/ml) of otarine PBVs from fecal samples serially collected from California sea lions were sequenced. In the two phylogenetic trees constructed using ORF2 and ORF3 of segment 1, the nine segment 1 sequences were clustered into four distinct clades (C1-C4). In the tree constructed using RdRp gene of segment 2, the 15 segment 2 sequences were clustered into nine distinct clades (R1-R9). In four sea lions, PBVs were detected in two different years, with the same segment 1 clade (C3) present in two consecutive years from one sea lion and different clades present in different years from three sea lions. A high diversity of PBVs was observed in a variety of terrestrial and marine mammals. Multiple sequence types with significant differences, representing multiple strains of PBV, were present in the majority of PBV-positive samples from different kinds of animals. PMID- 27933050 TI - An Essential Factor for High Mg2+ Tolerance of Staphylococcus aureus. AB - Internal bacterial concentration of Mg2+, the most abundant divalent cation in living cells, is estimated to be in the single millimolar range. However, many bacteria will thrive in media with only micromolars of Mg2+, by using a range of intensely studied and highly efficient import mechanisms, as well as in media with very high magnesium concentration, presumably mediated by currently unknown export mechanisms. Staphylococcus aureus has a particularly high Mg2+ tolerance for a pathogen, growing unimpaired in up to 770 mM Mg2+, and we here identify SA0657, a key factor in this tolerance. The predicted domain structure of SA0657 is shared with a large number of proteins in bacteria, archaea and even eukarya, for example CorB from Salmonella and the human CNNM protein family. One of the shared domains, a CBS pair potentially involved in Mg2+ sensing, contains the conserved Glycine326 which we establish to be a key residue for SA0657 function. In light of our findings, we propose the name MpfA, Magnesium Protection Factor A, for SA0657. PMID- 27933051 TI - Short Interfering RNA Inhibits Rift Valley Fever Virus Replication and Degradation of Protein Kinase R in Human Cells. AB - Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen causing severe outbreaks in humans and livestock in sub-Saharan Africa and the Arabian Peninsula. Human infections are characterized by fever, sometimes leading to encephalitis, retinitis, hemorrhagic fever, and occasionally death. There are currently no fully licensed vaccines or effective therapies for human use. Gene silencing mediated by double-stranded short interfering RNA (siRNA) is a sequence specific, highly conserved mechanism in eukaryotes, which serves as an antiviral defense mechanism. Here, we demonstrate that siRNA duplexes directed against the RVFV nucleoprotein can effectively inhibit RVFV replication in human (MRC5 cells) and African green monkey cells (Vero E6 cells). Using these cells, we demonstrate that individual or complex siRNAs, targeting the RVFV nucleoprotein gene completely abrogate viral protein expression and prevent degradation of the host innate antiviral factor, protein kinase R (PKR). Importantly, pre-treatment of cells with the nucleoprotein-specific siRNAs markedly reduces the virus titer. The antiviral effect of the siRNAs was not attributable to interferon or the interferon response effector molecule, PKR. Thus, the antiviral activity of RVFV nucleoprotein-specific siRNAs may provide novel therapeutic strategy against RVFV infections in animals and humans. PMID- 27933052 TI - What Is the Essence of Microbial Electroactivity? PMID- 27933053 TI - Waste Conversion into n-Caprylate and n-Caproate: Resource Recovery from Wine Lees Using Anaerobic Reactor Microbiomes and In-line Extraction. AB - To convert wastes into sustainable liquid fuels and chemicals, new resource recovery technologies are required. Chain elongation is a carboxylate-platform bioprocess that converts short-chain carboxylates (SCCs) (e.g., acetate [C2] and n-butyrate [C4]) into medium-chain carboxylates (MCCs) (e.g., n-caprylate [C8] and n-caproate [C6]) with hydrogen gas as a side product. Ethanol or another electron donor (e.g., lactate, carbohydrate) is required. Competitive MCC productivities, yields (product vs. substrate fed), and specificities (product vs. all products) were only achieved previously from an organic waste material when exogenous ethanol had been added. Here, we converted a real organic waste, which inherently contains ethanol, into MCCs with n-caprylate as the target product. We used wine lees, which consisted primarily of settled yeast cells and ethanol from wine fermentation, and produced MCCs with a reactor microbiome. We operated the bioreactor at a pH of 5.2 and with continuous in-line extraction and achieved a MCC productivity of 3.9 g COD/L-d at an organic loading rate of 5.8 g COD/L-d, resulting in a promising MCC yield of 67% and specificities of 36% for each n-caprylate and n-caproate (72% for both). Compared to all other studies that used complex organic substrates, we achieved the highest n-caprylate-to ncaproate product ratio of 1.0 (COD basis), because we used increased broth recycle rates through the forward membrane contactor, which improved in-line extraction rates. Increased recycle rates also allowed us to achieve the highest reported MCC production flux per membrane surface area thus far (20.1 g COD/m2 d). Through microbial community analyses, we determined that an operational taxonomic unit (OTU) for Bacteroides spp. was dominant and was positively correlated with increased MCC productivities. Our data also suggested that the microbiome may have been shaped for improved MCC production by the high broth recycle rates. Comparable abiotic studies suggest that further increases in the broth-recycle rates could improve the overall mass transfer coefficient and its corresponding MCC production flux by almost 30 times beyond the maximum that we achieved. With improved in-line extraction, the chain-elongation biotechnology production platform offers new opportunities for resource recovery and sustainable production of liquid fuels and chemicals. PMID- 27933054 TI - NifH-Harboring Bacterial Community Composition across an Alaskan Permafrost Thaw Gradient. AB - Since nitrogen (N) is often limiting in permafrost soils, we investigated the N2 fixing genetic potential and the inferred taxa harboring those genes by sequencing nifH gene fragments in samples taken along a permafrost thaw gradient in an Alaskan boreal soil. Samples from minimally, moderately and extensively thawed sites were taken to a depth of 79 cm to encompass zones above and below the depth of the water table. NifH reads were translated with frameshift correction and 112,476 sequences were clustered at 5% amino acid dissimilarity resulting in 1,631 OTUs. Sample depth in relation to water table depth was correlated to differences in the NifH sequence classes with those most closely related to group I nifH-harboring Alpha- and Beta-Proteobacteria in higher abundance above water table depth while those related to group III nifH-harboring Delta Proteobacteria more abundant below. The most dominant below water table depth NifH sequences, comprising 1/3 of the total, were distantly related to Verrucomicrobia-Opitutaceae. Overall, these results suggest that permafrost thaw alters the class-level composition of N2-fixing communities in the thawed soil layers and that this distinction corresponds to the depth of the water table. These nifH data were also compared to nifH sequences obtained from a study at an Alaskan taiga site, and to those of other geographically distant, non-permafrost sites. The two Alaska sites were differentiated largely by changes in relative abundances of the same OTUs, whereas the non-Alaska sites were differentiated by the lack of many Alaskan OTUs, and the presence of unique halophilic, sulfate- and iron-reducing taxa in the Alaska sites. PMID- 27933055 TI - Responses of Methanogenic and Methanotrophic Communities to Elevated Atmospheric CO2 and Temperature in a Paddy Field. AB - Although climate change is predicted to affect methane (CH4) emissions in paddy soil, the dynamics of methanogens and methanotrophs in paddy fields under climate change have not yet been fully investigated. To address this issue, a multifactor climate change experiment was conducted in a Chinese paddy field using the following experimental treatments: (1) enrichment of atmospheric CO2 concentrations (500 ppm, CE), (2) canopy air warming (2 degrees C above the ambient, WA), (3) combined CO2 enrichment and warming (CW), and (4) ambient conditions (CK). We analyzed the abundance of methanogens and methanotrophs, community structures, CH4 production and oxidation potentials, in situ CH4 emissions using real-time PCR, T-RFLP, and clone library techniques, as well as biochemical assays. Compared to the control under CE and CW treatments, CH4 production potential, methanogenic gene abundance and soil microbial biomass carbon significantly increased; the methanogenic community, however, remained stable. The canopy air warming treatment only had an effect on CH4 oxidation potential at the ripening stage. Phylogenic analysis indicated that methanogens in the rhizosphere were dominated by Methanosarcina, Methanocellales, Methanobacteriales, and Methanomicrobiales, while methanotrophic sequences were classified as Methylococcus, Methylocaldum, Methylomonas, Methylosarcina (Type I) and Methylocystis (Type II). However, the relative abundance of Methylococcus (Type I) decreased under CE and CW treatments and the relative abundance of Methylocystis (Type II) increased. The in situ CH4 fluxes indicated similar seasonal patterns between treatments; both CE and CW increased CH4 emissions. In conclusion results suggest that methanogens and methanotrophs respond differently to elevated atmospheric CO2 concentrations and warming, thus adding insights into the effects of simulated global climate change on CH4 emissions in paddy fields. PMID- 27933056 TI - Characterization of Three Novel SXT/R391 Integrating Conjugative Elements ICEMfuInd1a and ICEMfuInd1b, and ICEMprChn1 Identified in the Genomes of Marinomonas fungiae JCM 18476T and Marinomonas profundimaris Strain D104. AB - The genus Marinomonas comprises Gram negative bacteria which are widespread in the marine environment and there is no report on the genomic analysis of SXT/R391 ICEs derived from this group of bacteria. This study describes the genomic features of three new SXT/R391 integrating conjugating elements (ICEs) identified in the genome of Marinomonas fungiae JCM 18476T (ICEMfuInd1a and ICEMfuInd1b) and in Marinomonas profundimaris strain D104 (ICEMprChn1). Structural organizations of the three ICEs were similar to the typical SXT/R391 family of ICEs and showed high degree of conservation in the core genes. Sequence analysis revealed ICEMfuInd1b and ICEMprChn1 were inserted into the genome at 5'-end of an typical host prfC gene, while ICEMfuInd1a was inserted at 5'-end of an atypical hipA-like gene. Despite their coexistence, the ICEMfuInd1a and ICEMfuInd1b were not present in a tandem fashion in the genome of M. fungiae. Phylogenetic analyses revealed the three ICEs either evolved independently or high degrees of recombination events had masked their evolution from a common SXT ancestor. Further, we found that the typical entry exclusion mechanism mediated by the TraG/EeX protein pair was likely defective in preventing the conjugative transfer of a second copy of the same S (SXT) group ICE into the M. fungiae genome due to mutations. Our analysis showed the presence of 16, 25, and 27 variable genes in the hotspots of ICEMfuInd1a, ICEMfuInd1b, and ICEMprChn1, respectively, many of which were not reported earlier for SXT/R391 ICEs. Sequence analysis predicted these hotspot regions were shaped by acquisition of genes through homologous recombination between the SXT and R391 related ICEs or mobile genetic elements present in disparate marine bacteria. Multidrug resistance genes which are hallmark feature of SXT/R391 ICEs were not present in either of the two ICEs from M. fungiae but were present within a transposon cassette in the HS-1 of the ICEMprChn1 from M. profundimaris. Finally, our data provided information on the genetic diversity and predicted functions encoded by variable genes present in the hotspot regions of these new ICEs. PMID- 27933057 TI - Glutamine-Induced Secretion of Intestinal Secretory Immunoglobulin A: A Mechanistic Perspective. AB - Secretory immunoglobulin A (SIgA) is one important line of defense in the intestinal mucosal surface to protect the intestinal epithelium from enteric toxins and pathogenic microorganisms. Multiple factors, such as intestinal microbiota, intestinal cytokines, and nutrients are highly involved in production of SIgA in the intestine. Recently, glutamine has been shown to affect intestinal SIgA production; however, the underlying mechanism by which glutamine stimulates secretion of intestinal SIgA is unknown. Here, we review current knowledge regarding glutamine in intestinal immunity and show that glutamine-enhanced secretion of SIgA in the intestine may involve intestinal microbiota, intestinal antigen sampling and presentation, induction pathways for SIgA production by plasma cells (both T-dependent and T-independent pathway), and even transport of SIgA. Altogether, the glutamine-intestinal SIgA axis has broad therapeutic implications for intestinal SIgA-associated diseases, such as celiac disease, allergies, and inflammatory bowel disease. PMID- 27933058 TI - Skewed Lung CCR4 to CCR6 CD4+ T Cell Ratio in Idiopathic Pulmonary Fibrosis Is Associated with Pulmonary Function. AB - RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease. While it has been suggested that T cells may contribute to IPF pathogenesis, these studies have focused primarily on T cells outside of the pulmonary interstitium. Thus, the role of T cells in the diseased lung tissue remains unclear. OBJECTIVE: To identify whether specific CD4+ T cell subsets are differentially represented in lung tissue from patients with IPF. METHODS: CD4+ T cell subsets were measured in lung tissue obtained from patients with IPF at the time of lung transplantation, and from age- and gender-matched organ donors with no known lung disease. Subsets were identified by their surface expression of CCR4, CCR6, and CXCR3 chemokine receptors. CD4+ T cell subsets were correlated with measurements of lung function obtained prior to transplantation. RESULTS: Compared to controls, IPF patients had a higher proportion of lung CD4+ T cells, a higher proportion of CCR4+ CD4+ T cells, and a lower proportion of CCR6+ CD4+ T cells. The increase in CCR4+ CD4+ T cells in IPF lung tissue was not due to increased Tregs. Intriguingly, the increase in the ratio of CCR4+ cells to CCR6+ cells correlated significantly with better lung function. CONCLUSION: Our findings suggest a new paradigm that not all T cell infiltrates in IPF lungs are detrimental, but instead, specialized subsets may actually be protective. Thus, augmentation of the chemokines that recruit protective T cells, while blocking chemokines that recruit detrimental T cells, may constitute a novel approach to IPF therapy. PMID- 27933059 TI - Formation of Neutrophil Extracellular Traps under Low Oxygen Level. AB - Since their discovery, neutrophil extracellular traps (NETs) have been characterized as a fundamental host innate immune defense mechanism. Conversely, excessive NET-release may have a variety of detrimental consequences for the host. A fine balance between NET formation and elimination is necessary to sustain a protective effect during an infectious challenge. Our own recently published data revealed that stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha) by the iron chelating HIF-1alpha-agonist desferoxamine or AKB-4924 enhanced the release of phagocyte extracellular traps. Since HIF-1alpha is a global regulator of the cellular response to low oxygen, we hypothesized that NET formation may be similarly increased under low oxygen conditions. Hypoxia occurs in tissues during infection or inflammation, mostly due to overconsumption of oxygen by pathogens and recruited immune cells. Therefore, experiments were performed to characterize the formation of NETs under hypoxic oxygen conditions compared to normoxia. Human blood-derived neutrophils were isolated and incubated under normoxic (21%) oxygen level and compared to hypoxic (1%) conditions. Dissolved oxygen levels were monitored in the primary cell culture using a Fibox4 PSt3 measurement system. The formation of NETs was quantified by fluorescence microscopy in response to the known NET-inducer phorbol 12-myristate 13-acetate (PMA) or Staphylococcus (S.) aureus wild-type and a nuclease-deficient mutant. In contrast to our hypothesis, spontaneous NET formation of neutrophils incubated under hypoxia was distinctly reduced compared to control neutrophils incubated under normoxia. Furthermore, neutrophils incubated under hypoxia showed significantly reduced formation of NETs in response to PMA. Gene expression analysis revealed that mRNA level of hif-1alpha as well as hif-1alpha target genes was not altered. However, in good correlation to the decreased NET formation under hypoxia, the cholesterol content of the neutrophils was significantly increased under hypoxia. Interestingly, NET formation in response to viable S. aureus wild-type or nuclease-deficient strain was retained under hypoxia. Our results lead to the conclusion that hypoxia is not the ideal tool to analyze HIF-1alpha in neutrophils. However, the data clearly suggest that neutrophils react differently under hypoxia compared to normoxia and thereby highlight the importance of the usage of physiological relevant oxygen level when studying neutrophil functions. PMID- 27933060 TI - Regulators of Tfh Cell Differentiation. AB - The follicular helper T (Tfh) cells help is critical for activation of B cells, antibody class switching, and germinal center (GC) formation. The Tfh cells are characterized by the expression of CXC chemokine receptor 5 (CXCR5), ICOS, programed death 1 (PD-1), B cell lymphoma 6 (BCL-6), and IL-21. They are involved in clearing infections and are adversely linked with autoimmune diseases and also have a role in viral replication as well as clearance. On the one hand, Tfh cells are generated from naive CD4+ T cells with sequential steps involving cytokine signaling (IL-21, IL-6, IL-12, activin A), migration, and positioning in the GC by CXCR5, surface receptors (ICOS/ICOSL, signaling lymphocyte activation molecule associated protein/signaling lymphocyte activation molecule) as well as transcription factor (BCL-6, c-Maf, and signal transducer and activator of transcription 3) signaling and repressor miR155. On the other hand, Tfh generation is negatively regulated at specific steps of Tfh generation by specific cytokine (IL-2, IL-7), surface receptor (PD-1, CTLA-4), transcription factors B lymphocyte maturation protein 1, signal transducer and activator of transcription 5, T-bet, KLF-2 signaling, and repressor miR 146a. Interestingly, miR-17-92 and FOXO1 act as a positive as well as a negative regulator of Tfh differentiation depending on the time of expression and disease specificity. Tfh cells are also generated from the conversion of other effector T cells as exemplified by Th1 cells converting into Tfh during viral infection. The mechanistic details of effector T cells conversion into Tfh are yet to be clear. To manipulate Tfh cells for therapeutic implication and or for effective vaccination strategies, it is important to know positive and negative regulators of Tfh generation. Hence, in this review, we have highlighted and interlinked molecular signaling from cytokines, surface receptors, transcription factors, ubiquitin ligase, and microRNA as positive and negative regulators for Tfh differentiation. PMID- 27933061 TI - NCR1 Expression Identifies Canine Natural Killer Cell Subsets with Phenotypic Similarity to Human Natural Killer Cells. AB - Canines spontaneously develop many cancers similar to humans - including osteosarcoma, leukemia, and lymphoma - offering the opportunity to study immune therapies in a genetically heterogeneous and immunocompetent environment. However, a lack of antibodies recognizing canine NK cell markers has resulted in suboptimal characterization and unknown purity of NK cell products, hindering the development of canine models of NK cell adoptive immunotherapy. To this end, we generated a novel antibody to canine NCR1 (NKp46), the putative species-wide marker of NK cells, enabling purification of NK cells for further characterization. We demonstrate that CD3-/NKp46+ cells in healthy and osteosarcoma-bearing canines have phenotypic similarity to human CD3-/NKp46+ NK cells, expressing mRNA for CD16 and the natural cytotoxicity receptors NKp30, NKp44, and NKp80. Functionally, we demonstrate with the calcein release assay that canine CD3-/NKp46+ cells kill canine tumor cell lines without prior sensitization and secrete IFN-gamma, TNF-alpha, IL-8, IL-10, and granulocyte macrophage colony-stimulating factor as measured by Luminex. Similar to human NK cells, CD3-/NKp46+ cells expand rapidly on feeder cells expressing 4-1BBL and membrane-bound IL-21 (median = 20,283-fold in 21 days). Furthermore, we identify a minor Null population (CD3-/CD21-/CD14-/NKp46-) with reduced cytotoxicity against osteosarcoma cells, but similar cytokine secretion as CD3-/NKp46+ cells. Null cells in canines and humans have reduced expression of NKG2D, NKp44, and CD16 compared to NKp46+ NK cells and can be induced to express NKp46 with further expansion on feeder cells. In conclusion, we have identified and characterized canine NK cells, including an NKp46- subset of canine and human NK cells, using a novel anti-canine NKp46 antibody, and report robust ex vivo expansion of canine NK cells sufficient for adoptive immunotherapy. PMID- 27933062 TI - No Role for Mast Cells in Obesity-Related Metabolic Dysregulation. AB - Obesity-related adipose tissue (AT) inflammation that promotes metabolic dysregulation is associated with increased AT mast cell numbers. Mast cells are potent inducers of inflammatory responses and could potentially contribute to obesity-induced AT inflammation and metabolic dysregulation. Conflicting findings were reported on obesity-related metabolic dysfunction in mast cell-deficient mice, thus creating a controversy that has not been resolved to date. Whereas traditional Kit hypomorphic mast cell-deficient strains featured reduced diet induced obesity and diabetes, a Kit-independent model of mast cell deficiency, Cpa3Cre/+ mice, displayed no alterations in obesity and insulin sensitivity. Herein, we analyzed diet-induced obesity in Mcpt5-Cre R-DTA mice, in which the lack of mast cells is caused by a principle different from mast cell deficiency in Cpa3Cre/+ mice or Kit mutations. We observed no difference between mast cell deficient and -proficient mice in diet-induced obesity with regards to weight gain, glucose tolerance, insulin resistance, metabolic parameters, hepatic steatosis, and AT or liver inflammation. We conclude that mast cells play no essential role in obesity and related pathologies. PMID- 27933063 TI - Aire Downregulation Is Associated with Changes in the Posttranscriptional Control of Peripheral Tissue Antigens in Medullary Thymic Epithelial Cells. AB - Autoimmune regulator (Aire) is a transcriptional regulator of peripheral tissue antigens (PTAs) and microRNAs (miRNAs) in medullary thymic epithelial cells (mTECs). In this study, we tested the hypothesis that Aire also played a role as an upstream posttranscriptional controller in these cells and that variation in its expression might be associated with changes in the interactions between miRNAs and the mRNAs encoding PTAs. We demonstrated that downregulation of Aire in vivo in the thymuses of BALB/c mice imbalanced the large-scale expression of these two RNA species and consequently their interactions. The expression profiles of a large set of mTEC miRNAs and mRNAs isolated from the thymuses of mice subjected (or not) to small-interfering-induced Aire gene knockdown revealed that 87 miRNAs and 4,558 mRNAs were differentially expressed. The reconstruction of the miRNA-mRNA interaction networks demonstrated that interactions between these RNAs were under Aire influence and therefore changed when this gene was downregulated. Prior to Aire-knockdown, only members of the miR-let-7 family interacted with a set of PTA mRNAs. Under Aire-knockdown conditions, a larger set of miRNA families and their members established this type of interaction. Notably, no previously described Aire-dependent PTA interacted with the miRNAs, indicating that these PTAs were somehow refractory. The miRNA-mRNA interactions were validated by calculating the minimal free energy of the pairings between the miRNA seed regions and the mRNA 3' UTRs and within the cellular milieu using the luciferase reporter gene assay. These results suggest the existence of a link between transcriptional and posttranscriptional control because Aire downregulation alters the miRNA-mRNA network controlling PTAs in mTEC cells. PMID- 27933064 TI - Systemic Expression of Notch Ligand Delta-Like 4 during Mycobacterial Infection Alters the T Cell Immune Response. AB - The Notch ligand delta-like 4 (DLL4) is known to fine-tune the CD4+ T cell cytokine response. DLL4 is expressed on the surface of antigen-presenting cells (APCs) in a MyD88-dependent manner. We found that DLL4 expression was upregulated on bone marrow progenitor cells and APCs in mice infected with BCG Mycobacterium. Transfer of DLL4+ progenitor cells from infected hosts resulted in an increase DLL4+ myeloid cells in the spleen, indicating that expression of the dll4 gene is propagated throughout hematopoiesis. We also found an increase in DLL4+ monocytes from individuals who were infected with Mycobacterium tuberculosis. In latent individuals, DLL4 expression correlated with increased cytokine production from T cells in response to PPD stimulation. Finally, antibody blockade of DLL4 reduced T cell cytokine production from naive T cells stimulated with antigen. These results demonstrate that the Notch ligand DLL4 can influence T cell cytokine production in both humans and mice, and further reveal that expression of DLL4 is upregulated on early hematopoietic progenitors in response to chronic mycobacterial infection. These data suggest that widespread DLL4 expression may occur as a result of mycobacterial infection, and that this expression may alter CD4+ T cell responses to both previously encountered and novel antigens. PMID- 27933065 TI - Current Challenges and Limitations in Antibody-Based Detection of Citrullinated Histones. AB - Studies on NETosis demand reliable and convenient markers to monitor the progress of this form of cell death. Because a determining step in the release of nuclear chromatin NETs requires the conversion of arginine residues to citrulline residues in histones by peptidylarginine deiminase, citrullinated histones can provide such a marker. Here, we evaluate antibody reagents for the detection of citrulline residues in histones and observe alarming differences between commercial antisera and mouse and rabbit monoclonal antibodies in their ability to detect their nominal target residues. Differences between antibodies that are currently used to detect citrulline residues in histones could jeopardize efforts to reach a scientific consensus and instead lead to inconsistent and even conflicting conclusions regarding the regulation of histone deimination. Our results will assist others in planning their initial or ongoing studies on peptidylarginine deiminase activity with the use of currently available antibodies. Furthermore, we argue that, along with the careful attention to experimental conditions and calcium concentrations, validated antibody reagents are urgently needed to avoid possible setbacks in the research on NETosis. PMID- 27933067 TI - Peptide IDR-1002 Inhibits NF-kappaB Nuclear Translocation by Inhibition of IkappaBalpha Degradation and Activates p38/ERK1/2-MSK1-Dependent CREB Phosphorylation in Macrophages Stimulated with Lipopolysaccharide. AB - The inflammatory response is a critical molecular defense mechanism of the innate immune system that mediates the elimination of disease-causing bacteria. Repair of the damaged tissue, and the reestablishment of homeostasis, must be accomplished after elimination of the pathogen. The innate defense regulators (IDRs) are short cationic peptides that mimic natural host defense peptides and are effective in eliminating pathogens by enhancing the activity of the immune system while controlling the inflammatory response. Although the role of different IDRs as modulators of inflammation has been reported, there have been only limited studies of the signaling molecules regulated by this type of peptide. The present study investigated the effect of IDR-1002 on nuclear factor kappaB (NF-kappaB) and cAMP-response element-binding protein (CREB) transcription factors that are responsible for triggering and controlling inflammation, respectively, in macrophages. We found that TNF-alpha and COX-2 expression, IkappaBalpha phosphorylation, and NF-kappaB nuclear translocation were strongly inhibited in macrophages pre-incubated with IDR-1002 and then stimulated with lipopolysaccharide (LPS). IDR-1002 also increased CREB phosphorylation at Ser133 via activation of the p38/ERK1/2-MSK1 signaling pathways without detectable expression of the cytokines IL-4, IL-10, and IL-13 involved is suppressing inflammation or alternative activation. Transcriptional activation of NF-kappaB and CREB is known to require interaction with the transcriptional coactivator CREB-binding protein (CBP). To test for CBP-NF-kappaB and CBP-CREB complex formation, we performed co-immunoprecipitation assays. These assays showed that IDR-1002 inhibited the interaction between CBP and NF-kappaB in macrophages stimulated with LPS, which might explain the inhibition of TNF-alpha and COX-2 expression. Furthermore, the complex between CBP and CREB in macrophages stimulated with IDR-1002 was also inhibited, which might explain why IDR-1002 did not lead to expression of IL-4, IL-10, and IL-13, even though it induced an increase in phospho-CREB relative abundance. In conclusion, our results indicated that IDR-1002 has a dual effect. On one hand, it inhibited NF-kappaB nuclear translocation through a mechanism that involved inhibition of IkappaBalpha phosphorylation, and on the other, it activated a protein kinase signaling cascade that phosphorylated CREB to selectively influence cytokine gene expression. Based on these results, we think IDR-1002 could be a potential good biopharmaceutical candidate to control inflammation. PMID- 27933066 TI - Functionally Diverse NK-Like T Cells Are Effectors and Predictors of Successful Aging. AB - The fundamental challenge of aging and long-term survivorship is maintenance of functional independence and compression of morbidity despite a life history of disease. Inasmuch as immunity is a determinant of individual health and fitness, unraveling novel mechanisms of immune homeostasis in late life is of paramount interest. Comparative studies of young and old persons have documented age related atrophy of the thymus, the contraction of diversity of the T cell receptor (TCR) repertoire, and the intrinsic inefficiency of classical TCR signaling in aged T cells. However, the elderly have highly heterogeneous health phenotypes. Studies of defined populations of persons aged 75 and older have led to the recognition of successful aging, a distinct physiologic construct characterized by high physical and cognitive functioning without measurable disability. Significantly, successful agers have a unique T cell repertoire; namely, the dominance of highly oligoclonal alphabetaT cells expressing a diverse array of receptors normally expressed by NK cells. Despite their properties of cell senescence, these unusual NK-like T cells are functionally active effectors that do not require engagement of their clonotypic TCR. Thus, NK-like T cells represent a beneficial remodeling of the immune repertoire with advancing age, consistent with the concept of immune plasticity. Significantly, certain subsets are predictors of physical/cognitive performance among older adults. Further understanding of the roles of these NK-like T cells to host defense, and how they integrate with other physiologic domains of function are new frontiers for investigation in Aging Biology. Such pursuits will require a research paradigm shift from the usual young-versus-old comparison to the analysis of defined elderly populations. These endeavors may also pave way to age-appropriate, group targeted immune interventions for the growing elderly population. PMID- 27933068 TI - Mapping Quantitative Trait Loci Controlling High Iron and Zinc Content in Self and Open Pollinated Grains of Pearl Millet [Pennisetum glaucum (L.) R. Br.]. AB - Pearl millet is a multipurpose grain/fodder crop of the semi-arid tropics, feeding many of the world's poorest and most undernourished people. Genetic variation among adapted pearl millet inbreds and hybrids suggests it will be possible to improve grain micronutrient concentrations by selective breeding. Using 305 loci, a linkage map was constructed to map QTLs for grain iron [Fe] and zinc [Zn] using replicated samples of 106 pearl millet RILs (F6) derived from ICMB 841-P3 * 863B-P2. The grains of the RIL population were evaluated for Fe and Zn content using atomic absorption spectrophotometer. Grain mineral concentrations ranged from 28.4 to 124.0 ppm for Fe and 28.7 to 119.8 ppm for Zn. Similarly, grain Fe and Zn in open pollinated seeds ranged between 22.4-77.4 and 21.9-73.7 ppm, respectively. Mapping with 305 (96 SSRs; 208 DArT) markers detected seven linkage groups covering 1749 cM (Haldane) with an average intermarker distance of 5.73 cM. On the basis of two environment phenotypic data, two co-localized QTLs for Fe and Zn content on linkage group (LG) 3 were identified by composite interval mapping (CIM). Fe QTL explained 19% phenotypic variation, whereas the Zn QTL explained 36% phenotypic variation. Likewise for open pollinated seeds, the QTL analysis led to the identification of two QTLs for grain Fe content on LG3 and 5, and two QTLs for grain Zn content on LG3 and 7. The total phenotypic variance for Fe and Zn QTLs in open pollinated seeds was 16 and 42%, respectively. Analysis of QTL * QTL and QTL * QTL * environment interactions indicated no major epistasis. PMID- 27933069 TI - Accumulation and Secretion of Coumarinolignans and other Coumarins in Arabidopsis thaliana Roots in Response to Iron Deficiency at High pH. AB - Root secretion of coumarin-phenolic type compounds has been recently shown to be related to Arabidopsis thaliana tolerance to Fe deficiency at high pH. Previous studies revealed the identity of a few simple coumarins occurring in roots and exudates of Fe-deficient A. thaliana plants, and left open the possible existence of other unknown phenolics. We used HPLC-UV/VIS/ESI-MS(TOF), HPLC/ESI-MS(ion trap) and HPLC/ESI-MS(Q-TOF) to characterize (identify and quantify) phenolic type compounds accumulated in roots or secreted into the nutrient solution of A. thaliana plants in response to Fe deficiency. Plants grown with or without Fe and using nutrient solutions buffered at pH 5.5 or 7.5 enabled to identify an array of phenolics. These include several coumarinolignans not previously reported in A. thaliana (cleomiscosins A, B, C, and D and the 5'-hydroxycleomiscosins A and/or B), as well as some coumarin precursors (ferulic acid and coniferyl and sinapyl aldehydes), and previously reported cathecol (fraxetin) and non-cathecol coumarins (scopoletin, isofraxidin and fraxinol), some of them in hexoside forms not previously characterized. The production and secretion of phenolics were more intense when the plant accessibility to Fe was diminished and the plant Fe status deteriorated, as it occurs when plants are grown in the absence of Fe at pH 7.5. Aglycones and hexosides of the four coumarins were abundant in roots, whereas only the aglycone forms could be quantified in the nutrient solution. A comprehensive quantification of coumarins, first carried out in this study, revealed that the catechol coumarin fraxetin was predominant in exudates (but not in roots) of Fe-deficient A. thaliana plants grown at pH 7.5. Also, fraxetin was able to mobilize efficiently Fe from a Fe(III)-oxide at pH 5.5 and pH 7.5. On the other hand, non-catechol coumarins were much less efficient in mobilizing Fe and were present in much lower concentrations, making unlikely that they could play a role in Fe mobilization. The structural features of the array of coumarin type compounds produced suggest some can mobilize Fe from the soil and others can be more efficient as allelochemicals. PMID- 27933070 TI - Transcriptional Responses in Root and Leaf of Prunus persica under Drought Stress Using RNA Sequencing. AB - Prunus persica L. Batsch, or peach, is one of the most important crops and it is widely established in irrigated arid and semi-arid regions. However, due to variations in the climate and the increased aridity, drought has become a major constraint, causing crop losses worldwide. The use of drought-tolerant rootstocks in modern fruit production appears to be a useful method of alleviating water deficit problems. However, the transcriptomic variation and the major molecular mechanisms that underlie the adaptation of drought-tolerant rootstocks to water shortage remain unclear. Hence, in this study, high-throughput sequencing (RNA seq) was performed to assess the transcriptomic changes and the key genes involved in the response to drought in root tissues (GF677 rootstock) and leaf tissues (graft, var. Catherina) subjected to 16 days of drought stress. In total, 12 RNA libraries were constructed and sequenced. This generated a total of 315 M raw reads from both tissues, which allowed the assembly of 22,079 and 17,854 genes associated with the root and leaf tissues, respectively. Subsets of 500 differentially expressed genes (DEGs) in roots and 236 in leaves were identified and functionally annotated with 56 gene ontology (GO) terms and 99 metabolic pathways, which were mostly associated with aminobenzoate degradation and phenylpropanoid biosynthesis. The GO analysis highlighted the biological functions that were exclusive to the root tissue, such as "locomotion," "hormone metabolic process," and "detection of stimulus," indicating the stress-buffering role of the GF677 rootstock. Furthermore, the complex regulatory network involved in the drought response was revealed, involving proteins that are associated with signaling transduction, transcription and hormone regulation, redox homeostasis, and frontline barriers. We identified two poorly characterized genes in P. persica: growth-regulating factor 5 (GRF5), which may be involved in cellular expansion, and AtHB12, which may be involved in root elongation. The reliability of the RNA-seq experiment was validated by analyzing the expression patterns of 34 DEGs potentially involved in drought tolerance using quantitative reverse transcription polymerase chain reaction. The transcriptomic resources generated in this study provide a broad characterization of the acclimation of P. persica to drought, shedding light on the major molecular responses to the most important environmental stressor. PMID- 27933073 TI - Mistletoe Berry Outline Mapping with a Path Curve Function and Recording the Circadian Rhythm of Their Phenotypic Shape Change. AB - This paper presents a discovery: the change of the outline shape of mistletoe (Viscum album ssp. album) berries in vivo and in situ during ripening. It was found that a plant organ that is usually considered to merely increase in size actually changes shape in a specific rhythmic fashion. We introduce a new approach to chronobiological research on a macro-phenotypic scale to trace changes over long periods of time (with a resolution from hours to months) by using a dynamic form-determining parameter called Lambda (lambda). lambda is known in projective geometry as a measure for pertinent features of the outline shapes of egg-like forms, so called path curves. Ascertained circadian changes of form were analyzed for their correlation with environmental factors such as light, temperature, and other weather influences. Certain weather conditions such as sky cover, i.e., sunshine minutes per hour, have an impact on the amplitude of the daily change in form. The present paper suggests a possible supplement to established methods in chronobiology, as in this case the dynamic of form-change becomes a measurable feature, displaying a convincing accordance between mathematical rule and plant shape. PMID- 27933072 TI - Development and Evaluation of Chromosome Segment Substitution Lines Carrying Overlapping Chromosome Segments of the Whole Wild Rice Genome. AB - Common wild rice (Oryza rufipogon Griff.) represents an important resource for rice improvement. Genetic populations provide the basis for a wide range of genetic and genomic studies. In particular, chromosome segment substitution lines (CSSLs) are most powerful tools for the detection and precise mapping of quantitative trait loci (QTLs). In this study, 146 CSSLs were produced; they were derived from the crossing and back-crossing of two rice cultivars: Dongnanihui 810 (Oryza sativa L.), an indica rice cultivar as the recipient, and ZhangPu wild rice, a wild rice cultivar as the donor. First, a physical map of the 146 CSSLs was constructed using 149 molecular markers. Based on this map, the total size of the 147 substituted segments in the population was 1145.65 Mb, or 3.04 times that of the rice genome. To further facilitate gene mapping, heterozygous chromosome segment substitution lines (HCSSLs) were also produced, which were heterozygous in the target regions. Second, a physical map of the 244 HCSSLs was produced using 149 molecular markers. Based on this map, the total length of substituted segments in the HCSSLs was 1683.75 Mb, or 4.47 times the total length of the rice genome. Third, using the 146 CSSLs, two QTLs for plant height, and one major QTL for apiculus coloration were identified. Using the two populations of HCSSLs, the qPa-6-2 gene was precisely mapped to an 88 kb region. These CSSLs and HCSSLs may, therefore, provide powerful tools for future whole genome large-scale gene discovery in wild rice, providing a foundation enabling the development of new rice varieties. This research will also facilitate fine mapping and cloning of quantitative trait genes, providing for the development of superior rice varieties. PMID- 27933071 TI - Stress-Mediated cis-Element Transcription Factor Interactions Interconnecting Primary and Specialized Metabolism in planta. AB - Plant specialized metabolites are being used worldwide as therapeutic agents against several diseases. Since the precursors for specialized metabolites come through primary metabolism, extensive investigations have been carried out to understand the detailed connection between primary and specialized metabolism at various levels. Stress regulates the expression of primary and specialized metabolism genes at the transcriptional level via transcription factors binding to specific cis-elements. The presence of varied cis-element signatures upstream to different stress-responsive genes and their transcription factor binding patterns provide a prospective molecular link among diverse metabolic pathways. The pattern of occurrence of these cis-elements (overrepresentation/common) decipher the mechanism of stress-responsive upregulation of downstream genes, simultaneously forming a molecular bridge between primary and specialized metabolisms. Though many studies have been conducted on the transcriptional regulation of stress-mediated primary or specialized metabolism genes, but not much data is available with regard to cis-element signatures and transcription factors that simultaneously modulate both pathway genes. Hence, our major focus would be to present a comprehensive analysis of the stress-mediated interconnection between primary and specialized metabolism genes via the interaction between different transcription factors and their corresponding cis elements. In future, this study could be further utilized for the overexpression of the specific transcription factors that upregulate both primary and specialized metabolism, thereby simultaneously improving the yield and therapeutic content of plants. PMID- 27933074 TI - Comparative Genomic Analysis of the GRF Genes in Chinese Pear (Pyrus bretschneideri Rehd), Poplar (Populous), Grape (Vitis vinifera), Arabidopsis and Rice (Oryza sativa). AB - Growth-regulating factors (GRFs) are plant-specific transcription factors that have important functions in regulating plant growth and development. Previous studies on GRF family members focused either on a single or a small set of genes. Here, a comparative genomic analysis of the GRF gene family was performed in poplar (a model tree species), Arabidopsis (a model plant for annual herbaceous dicots), grape (one model plant for perennial dicots), rice (a model plant for monocots) and Chinese pear (one of the economical fruit crops). In total, 58 GRF genes were identified, 12 genes in rice (Oryza sativa), 8 genes in grape (Vitis vinifera), 9 genes in Arabidopsis thaliana, 19 genes in poplar (Populus trichocarpa) and 10 genes in Chinese pear (Pyrus bretschneideri). The GRF genes were divided into five subfamilies based on the phylogenetic analysis, which was supported by their structural analysis. Furthermore, microsynteny analysis indicated that highly conserved regions of microsynteny were identified in all of the five species tested. And Ka/Ks analysis revealed that purifying selection plays an important role in the maintenance of GRF genes. Our results provide basic information on GRF genes in five plant species and lay the foundation for future research on the functions of these genes. PMID- 27933075 TI - A Non-specific Setaria italica Lipid Transfer Protein Gene Plays a Critical Role under Abiotic Stress. AB - Lipid transfer proteins (LTPs) are a class of cysteine-rich soluble proteins having small molecular weights. LTPs participate in flower and seed development, cuticular wax deposition, also play important roles in pathogen and abiotic stress responses. A non-specific LTP gene (SiLTP) was isolated from a foxtail millet (Setaria italica) suppression subtractive hybridization library enriched for differentially expressed genes after abiotic stress treatments. A semi quantitative reverse transcriptase PCR analysis showed that SiLTP was expressed in all foxtail millet tissues. Additionally, the SiLTP promoter drove GUS expression in root tips, stems, leaves, flowers, and siliques of transgenic Arabidopsis. Quantitative real-time PCR indicated that the SiLTP expression was induced by NaCl, polyethylene glycol, and abscisic acid (ABA). SiLTP was localized in the cytoplasm of tobacco leaf epidermal cells and maize protoplasts. The ectopic expression of SiLTP in tobacco resulted in higher levels of salt and drought tolerance than in the wild type (WT). To further assess the function of SiLTP, SiLTP overexpression (OE) and RNA interference (RNAi)-based transgenic foxtail millet were obtained. SiLTP-OE lines performed better under salt and drought stresses compared with WT plants. In contrast, the RNAi lines were much more sensitive to salt and drought compared than WT. Electrophoretic mobility shift assays and yeast one-hybrids indicated that the transcription factor ABA responsive DRE-binding protein (SiARDP) could bind to the dehydration-responsive element of SiLTP promoter in vitro and in vivo, respectively. Moreover, the SiLTP expression levels were higher in SiARDP-OE plants compared than the WT. These results confirmed that SiLTP plays important roles in improving salt and drought stress tolerance of foxtail millet, and may partly be upregulated by SiARDP. SiLTP may provide an effective genetic resource for molecular breeding in crops to enhance salt and drought tolerance levels. PMID- 27933076 TI - Overexpression of TaNAC2D Displays Opposite Responses to Abiotic Stresses between Seedling and Mature Stage of Transgenic Arabidopsis. AB - Environmental stresses frequently affect plant growth and development, and many genes have been found to be induced by unfavorable environmental conditions. Here, we reported the biological functions of TaNAC2D, a stress-related NAC (NAM, ATAF, and CUC) gene from wheat. TaNAC2D showed transcriptional activator activity in yeast. TaNAC2D-GFP fusion protein was localized in the nucleus of wheat mesophyll protoplasts. TaNAC2D transcript abundance was significantly induced by NaCl, PEG6000, and abscisic acid (ABA) at seedling stage, and repressed by NaCl and PEG6000 at mature plant stage. When TaNAC2D was introduced into Arabidopsis, the 35-day-old soil-grown TaNAC2D-overexpression (TaNAC2D-OX) plants displayed slower stomatal closure, higher water loss rate, and more sensitivity to salt and drought stresses compared with WT plants. In contrast, TaNAC2D-OX seedlings, grown on 1/2 MS medium supplemented with different concentrations of NaCl, Mannitol, and MV, had enhanced tolerances to salt, osmotic and oxidative stresses during seed germination and post-germination periods. The opposite stress responsive phenotypes of transgenic Arabidopsis were consistent with the expression patterns of TaNAC2D in wheat. Moreover, under high salinity and dehydration conditions, three marker genes, including NCED3, RD29A, and RD29B, were down-regulated in 35-day-old TaNAC2D-OX plants grown in soil and up regulated in 14-day-old TaNAC2D-OX seedlings grown on 1/2 MS medium. Our results suggest that the change in growth stages and environmental conditions may regulate TaNAC2D's function. PMID- 27933077 TI - Ethylene Is Not Responsible for Phytochrome-Mediated Apical Hook Exaggeration in Tomato. AB - The apical hook of tomato seedlings is exaggerated by phytochrome actions, while in other species such as bean, pea and Arabidopsis, the hook is exaggerated by ethylene and opens by phytochrome actions. The present study was aimed to clarify mainly whether ethylene is responsible for the phytochrome-mediated hook exaggeration of tomato seedlings. Dark-grown 5-day-old seedlings were subjected to various ways of ethylene application in the dark as well as under the actions of red (R) or far-red light (FR). The ethylene emitted by seedlings was also quantified relative to hook exaggeration. The results show: Ambient ethylene, up to about 1.0 MUL L-1, suppressed (opened) the hooks formed in the dark as well as the ones exaggerated by R or FR, while at 3.0-10 MUL L-1 it enhanced (closed) the hook only slightly as compared with the most-suppressed level at about 1.0 MUL L 1. Treatment with 1-aminocyclopropane-1-carboxylic acid (ACC), the immediate precursor of ethylene biosynthesis, did not enhance the hook, only mimicking the suppressive effects of ambient ethylene. The biosynthesis inhibitor, CoCl2 or aminoethoxyvinylglycine, enhanced hook curvature, and the enhancement was canceled by supplement of ethylene below 1.0 MUL L-1. Auxin transport inhibitor, N-1-naphthylphthalamic acid, by contrast, suppressed curvature markedly without altering ethylene emission. The effects of the above-stated treatments did not differentiate qualitatively among the R-, FR-irradiated seedlings and dark control so as to explain phytochrome-mediated hook exaggeration. In addition, ethylene emission by seedlings was affected neither by R nor FR at such fluences as to cause hook exaggeration. In conclusion, (1) ethylene suppresses not only the light-exaggerated hook, but also the dark-formed one; (2) ethylene emission is not affected by R or FR, and also not correlated with the hook exaggerations; thus ethylene is not responsible for the hook exaggeration in tomato; and (3) auxin is essential for the maintenance and development of the hook in tomato as is the case in other species lacking phytochrome-mediated hook exaggeration. A possible mechanism of phytochrome action for hook exaggeration is discussed. PMID- 27933078 TI - Citrus leprosis virus C Infection Results in Hypersensitive-Like Response, Suppression of the JA/ET Plant Defense Pathway and Promotion of the Colonization of Its Mite Vector. AB - Leprosis is a serious disease of citrus caused by Citrus leprosis virus C (CiLV C, genus Cilevirus) whose transmission is mediated by false spider mites of the genus Brevipalpus. CiLV-C infection does not systemically spread in any of its known host plants, thus remaining restricted to local lesions around the feeding sites of viruliferous mites. To get insight into this unusual pathosystem, we evaluated the expression profiles of genes involved in defense mechanisms of Arabidopsis thaliana and Citrus sinensis upon infestation with non-viruliferous and viruliferous mites by using reverse-transcription qPCR. These results were analyzed together with the production of reactive oxygen species (ROS) and the appearance of dead cells as assessed by histochemical assays. After interaction with non-viruliferous mites, plants locally accumulated ROS and triggered the salicylic acid (SA) and jasmonate/ethylene (JA/ET) pathways. ERF branch of the JA/ET pathways was highly activated. In contrast, JA pathway genes were markedly suppressed upon the CiLV-C infection mediated by viruliferous mites. Viral infection also intensified the ROS burst and cell death, and enhanced the expression of genes involved in the RNA silencing mechanism and SA pathway. After 13 days of infestation of two sets of Arabidopsis plants with non-viruliferous and viruliferous mites, the number of mites in the CiLV-C infected Arabidopsis plants was significantly higher than in those infested with the non-viruliferous ones. Oviposition of the viruliferous mites occurred preferentially in the CiLV-C infected leaves. Based on these results, we postulated the first model of plant/Brevipalpus mite/cilevirus interaction in which cells surrounding the feeding sites of viruliferous mites typify the outcome of a hypersensitive-like response, whereas viral infection induces changes in the behavior of its vector. PMID- 27933079 TI - Small RNAs from Bemisia tabaci Are Transferred to Solanum lycopersicum Phloem during Feeding. AB - The phloem-feeding whitefly Bemisia tabaci is a serious pest to a broad range of host plants, including many economically important crops such as tomato. These insects serve as a vector for various devastating plant viruses. It is known that whiteflies are capable of manipulating host-defense responses, potentially mediated by effector molecules in the whitefly saliva. We hypothesized that, beside putative effector proteins, small RNAs (sRNA) are delivered by B. tabaci into the phloem, where they may play a role in manipulating host plant defenses. There is already evidence to suggest that sRNAs can mediate the host-pathogen dialogue. It has been shown that Botrytis cinerea, the causal agent of gray mold disease, takes advantage of the plant sRNA machinery to selectively silence host genes involved in defense signaling. Here we identified sRNAs originating from B. tabaci in the phloem of tomato plants on which they are feeding. sRNAs were isolated and sequenced from tomato phloem of whitefly-infested and control plants as well as from the nymphs themselves, control leaflets, and from the infested leaflets. Using stem-loop RT-PCR, three whitefly sRNAs have been verified to be present in whitefly-infested leaflets that were also present in the whitefly infested phloem sample. Our results show that whitefly sRNAs are indeed present in tomato tissues upon feeding, and they appear to be mobile in the phloem. Their role in the host-insect interaction can now be investigated. PMID- 27933080 TI - Identification of a Dolabellane Type Diterpene Synthase and other Root-Expressed Diterpene Synthases in Arabidopsis. AB - Arabidopsis thaliana maintains a complex metabolism for the production of secondary or specialized metabolites. Such metabolites include volatile and semivolatile terpenes, which have been associated with direct and indirect defensive activities in flowers and leaves. In comparison, the structural diversity and function of terpenes in Arabidopsis roots has remained largely unexplored despite a substantial number of root-expressed genes in the Arabidopsis terpene synthase (TPS) gene family. We show that five root-expressed TPSs of an expanded subfamily-a type clade in the Arabidopsis TPS family function as class I diterpene synthases that predominantly convert geranylgeranyl diphosphate (GGPP) to different semi-volatile diterpene products, which are in part detectable at low levels in the ecotypes Columbia (Col) and Cape Verde Island (Cvi). The enzyme TPS20 produces a macrocyclic dolabellane diterpene alcohol and a dolabellane-related diterpene olefin named dolathaliatriene with a so far unknown C6-C11 bicyclic scaffold besides several minor olefin products. The TPS20 compounds occur in all tissues of Cvi but are absent in the Col ecotype because of deletion and substitution mutations in the Col TPS20 sequence. The primary TPS20 diterpene products retard the growth of the root rot pathogen Pythium irregulare but only at concentrations exceeding those in planta. Together, our results demonstrate that divergence and pseudogenization in the Arabidopsis TPS gene family allow for structural plasticity in diterpene profiles of above- and belowground tissues. PMID- 27933081 TI - The Density and Length of Root Hairs Are Enhanced in Response to Cadmium and Arsenic by Modulating Gene Expressions Involved in Fate Determination and Morphogenesis of Root Hairs in Arabidopsis. AB - Root hairs are tubular outgrowths that originate from epidermal cells. Exposure of Arabidopsis to cadmium (Cd) and arsenic [arsenite, As(III)] increases root hair density and length. To examine the underlying mechanism, we measured the expression of genes involved in fate determination and morphogenesis of root hairs. Cd and As(III) downregulated TTG1 and GL2 (negative regulators of fate determination) and upregulated GEM (positive regulator), suggesting that root hair fate determination is stimulated by Cd and As(III). Cd and As(III) increased the transcript levels of genes involved in root hair initiation (RHD6 and AXR2) and root hair elongation (AUX1, AXR1, ETR1, and EIN2) except CTR1. DR5::GUS transgenic Arabidopsis showed a higher DR5 expression in the root tip, suggesting that Cd and As(III) increased the auxin content in the root tip. Knockdown of TTG1 in Arabidopsis resulted in increased root hair density and decreased root hair length compared with the control (Col-0) on 1/2 MS media. This phenotype may be attributed to the downregulation of GL2 and CTR1 and upregulation of RHD6. By contrast, gem mutant plants displayed a decrease in root hair density and length with reduced expression of RHD6, AXR2, AUX1, AXR1, ETR1, CTR1, and EIN2. Taken together, our results indicate that fate determination, initiation, and elongation of root hairs are stimulated in response to Cd and As(III) through the modulation of the expression of genes involved in these processes in Arabidopsis. PMID- 27933083 TI - The Sclerophyllous Eucalyptus camaldulensis and Herbaceous Nicotiana tabacum Have Different Mechanisms to Maintain High Rates of Photosynthesis. AB - It is believed that high levels of mesophyll conductance (gm) largely contribute to the high rates of photosynthesis in herbaceous C3 plants. However, some sclerophyllous C3 plants that display low levels of gm have high rates of photosynthesis, and the underlying mechanisms responsible for high photosynthetic rates in sclerophyllous C3 plants are unclear. In the present study, we examined photosynthetic characteristics in two high-photosynthesis plants (the sclerophyllous Eucalyptus camaldulensis and the herbaceous Nicotiana tabacum) using measurements of gas exchange and chlorophyll fluorescence. Under saturating light intensities, both species had similar rates of CO2 assimilation at 400 MUmol mol-1 CO2 (A400). However, E. camaldulensis exhibited significantly lower gm and chloroplast CO2 concentration (Cc) than N. tabacum. A quantitative analysis revealed that, in E. camaldulensis, the gm limitation was the most constraining factor for photosynthesis. By comparison, in N. tabacum, the biochemical limitation was the strongest, followed by gm and gs limitations. In conjunction with a lower Cc, E. camaldulensis up-regulated the capacities of photorespiratory pathway and alternative electron flow. Furthermore, the rate of alternative electron flow was positively correlated with the rates of photorespiration and ATP supply from other flexible mechanisms, suggesting the important roles of photorespiratory pathway, and alternative electron flow in sustaining high rate of photosynthesis in E. camaldulensis. These results highlight the different mechanisms used to maintain high rates of photosynthesis in the sclerophyllous E. camaldulensis and the herbaceous N. tabacum. PMID- 27933082 TI - RNA-seq Transcriptome Response of Flax (Linum usitatissimum L.) to the Pathogenic Fungus Fusarium oxysporum f. sp. lini. AB - Fusarium oxysporum f. sp. lini is a hemibiotrophic fungus that causes wilt in flax. Along with rust, fusarium wilt has become an important factor in flax production worldwide. Resistant flax cultivars have been used to manage the disease, but the resistance varies, depending on the interactions between specific cultivars and isolates of the pathogen. This interaction has a strong molecular basis, but no genomic information is available on how the plant responds to attempted infection, to inform breeding programs on potential candidate genes to evaluate or improve resistance across cultivars. In the current study, disease progression in two flax cultivars [Crop Development Center (CDC) Bethune and Lutea], showed earlier disease symptoms and higher susceptibility in the later cultivar. Chitinase gene expression was also divergent and demonstrated and earlier molecular response in Lutea. The most resistant cultivar (CDC Bethune) was used for a full RNA-seq transcriptome study through a time course at 2, 4, 8, and 18 days post-inoculation (DPI). While over 100 genes were significantly differentially expressed at both 4 and 8 DPI, the broadest deployment of plant defense responses was evident at 18 DPI with transcripts of more than 1,000 genes responding to the treatment. These genes evidenced a reception and transduction of pathogen signals, a large transcriptional reprogramming, induction of hormone signaling, activation of pathogenesis-related genes, and changes in secondary metabolism. Among these, several key genes that consistently appear in studies of plant-pathogen interactions, had increased transcript abundance in our study, and constitute suitable candidates for resistance breeding programs. These included: an induced RPMI-induced protein kinase; transcription factors WRKY3, WRKY70, WRKY75, MYB113, and MYB108; the ethylene response factors ERF1 and ERF14; two genes involved in auxin/glucosinolate precursor synthesis (CYP79B2 and CYP79B3); the flavonoid related enzymes chalcone synthase, dihydroflavonol reductase and multiple anthocyanidin synthases; and a peroxidase implicated in lignin formation (PRX52). Additionally, regulation of some genes indicated potential pathogen manipulation to facilitate infection; these included four disease resistance proteins that were repressed, indole acetic acid amido/amino hydrolases which were upregulated, activated expansins and glucanases, amino acid transporters and aquaporins, and finally, repression of major latex proteins. PMID- 27933084 TI - Photosystem II Functionality in Barley Responds Dynamically to Changes in Leaf Manganese Status. AB - A catalytic manganese (Mn) cluster is required for the oxidation of water in the oxygen-evolving complex (OEC) of photosystem II (PSII) in plants. Despite this essential role of Mn in generating the electrons driving photosynthesis, limited information is available on how Mn deficiency affects PSII functionality. We have here used parameters derived from measurements of fluorescence induction kinetics (OJIP transients), non-photochemical quenching (NPQ) and PSII subunit composition to investigate how latent Mn deficiency changes the photochemistry in two barley genotypes differing in Mn efficiency. Mn deficiency caused dramatic reductions in the quantum yield of PSII and led to the appearance of two new inflection points, the K step and the D dip, in the OJIP fluorescence transients, indicating severe damage to the OEC. In addition, Mn deficiency decreased the ability to induce NPQ in the light, rendering the plants incapable of dissipating excess energy in a controlled way. Thus, the Mn deficient plants became severely affected in their ability to recover from high light-induced photoinhibition, especially under strong Mn deficiency. Interestingly, the Mn-efficient genotype was able to maintain a higher NPQ than the Mn-inefficient genotype when exposed to mild Mn deficiency. However, during severe Mn deficiency, there were no differences between the two genotypes, suggesting a general loss of the ability to disassemble and repair PSII. The pronounced defects of PSII activity were supported by a dramatic decrease in the abundance of the OEC protein subunits, PsbP and PsbQ in response to Mn deficiency for both genotypes. We conclude that regulation of photosynthetic performance by means of maintaining and inducing NPQ mechanisms contribute to genotypic differences in the Mn efficiency of barley genotypes growing under conditions with mild Mn deficiency. PMID- 27933085 TI - Plant Physiological, Morphological and Yield-Related Responses to Night Temperature Changes across Different Species and Plant Functional Types. AB - Land surface temperature over the past decades has shown a faster warming trend during the night than during the day. Extremely low night temperatures have occurred frequently due to the influence of land-sea thermal difference, topography and climate change. This asymmetric night temperature change is expected to affect plant ecophysiology and growth, as the plant carbon consumption processes could be affected more than the assimilation processes because photosynthesis in most plants occurs during the daytime whereas plant respiration occurs throughout the day. The effects of high night temperature (HNT) and low night temperature (LNT) on plant ecophysiological and growing processes and how the effects vary among different plant functional types (PFTs) have not been analyzed extensively. In this meta-analysis, we examined the effect of HNT and LNT on plant physiology and growth across different PFTs and experimental settings. Plant species were grouped according to their photosynthetic pathways (C3, C4, and CAM), growth forms (herbaceous, woody), and economic purposes (crop, non-crop). We found that HNT and LNT both had a negative effect on plant yield, but the effect of HNT on plant yield was primarily related to a reduction in biomass allocation to reproduction organs and the effect of LNT on plant yield was more related to a negative effect on total biomass. Leaf growth was stimulated at HNT and suppressed at LNT. HNT accelerated plants ecophysiological processes, including photosynthesis and dark respiration, while LNT slowed these processes. Overall, the results showed that the effects of night temperature on plant physiology and growth varied between HNT and LNT, among the response variables and PFTs, and depended on the magnitude of temperature change and experimental design. These findings suggest complexities and challenges in seeking general patterns of terrestrial plant growth in HNT and LNT. The PFT specific responses of plants are critical for obtaining credible predictions of the changes in crop production, plant community structure, vegetation dynamics, biodiversity, and ecosystem functioning of terrestrial biomes when asymmetric night temperature change continues. PMID- 27933086 TI - Genotypic Differences in Phosphorus Efficiency and the Performance of Physiological Characteristics in Response to Low Phosphorus Stress of Soybean in Southwest of China. AB - Southwest of China is one of the major soybean (Glycine max L.) production regions in China with low availability of soil phosphorus (P). Whereas little information is available on P-efficient soybean genotypes in this region, even though using P-efficient soybean genotypes is a sustainable P management strategy for enhancing yield and P use efficiency. To assess the genetic variation on P use efficiency, 274 soybean genotypes were employed to compare the yields and P acquisition potentials in the field. Additionally, 10 representational genotypes (5 P-efficient genotypes and 5 P-inefficient genotypes) were grown in hydroponic media containing low P treatment (0.05 mM L-1) and high P treatment (0.25 mM L-1) to further investigate P assimilation characteristics and the related mechanisms of P-efficient soybean genotypes. In the field trial, the models described the relationships between yield and seed P concentration (R2 = 0.85), shoot P accumulation (R2 = 0.84), HI (R2 = 0.82) well. The yield, seed P concentration and shoot P accumulation ranged from 5.5 to 36.0 g plant-1, from 0.045 to 0.93% and from 0.065 to 0.278 mg plant-1, respectively. In the hydroponic trial, P efficient genotypes under low P treatment showed significantly better plant growth, P accumulation and root: shoot ratio than P-inefficient genotypes. Simultaneously, total root length, specific root length, root surface area and root volume of P-efficient were significantly greater than P-inefficient under low P treatment. Higher rate of organic acid exudation and acid phosphatase activities was observed in the P-efficient soybean genotypes under low P condition when compared to the P-inefficient soybean genotypes. It indicated that significant genetic variation for P use efficiency existed in this region, and the P-efficient soybean genotypes, especially E311 and E141, demonstrated great tolerance to P deficiency, which could be potential materials using in improving production and P use efficiency in low availability of soil P region. PMID- 27933088 TI - Comparison of Ionomic and Metabolites Response under Alkali Stress in Old and Young Leaves of Cotton (Gossypium hirsutum L.) Seedlings. AB - Soil salinization is an important agriculture-related environmental problem. Alkali stress and salt stress strongly influence the metabolic balance in plants. Salt and alkali stresses exert varied effects on old and young tissues, which display different adaptive strategies. In this study, we used cotton (Gossypium hirsutum L.) plants as experimental material to investigate whether alkali stress induces ionic and metabolism changes in old and young leaves of cotton plants exposed to alkali stress. Results showed that alkali stress exerted a considerably stronger growth inhibition on old leaves than on young leaves. Under alkali stress, young leaves can maintain low Na and high K contents and retain relatively stable tricarboxylic acid cycle, resulting in greater accumulation of photosynthetic metabolites. In terms of metabolic response, the young and old leaves clearly displayed different mechanisms of osmotic regulation. The amounts of inositol and mannose significantly increased in both old and young leaves of cotton exposed to alkali stress, and the extent of increase was higher in young leaves than in old leaves. In old leaves, synthesis of amino acids, such as GABA, valine, and serine, was dramatically enhanced, and this phenomenon is favorable for osmotic adjustment and membrane stability. Organs at different developmental stages possibly display different mechanisms of metabolic regulation under stress condition. Thus, we propose that future investigations on alkali stress should use more organs obtained at different developmental stages. PMID- 27933087 TI - Revisiting Vitis vinifera Subtilase Gene Family: A Possible Role in Grapevine Resistance against Plasmopara viticola. AB - Subtilisin-like proteases, also known as subtilases, are a very diverse family of serine peptidases present in many organisms. In grapevine, there are hints of the involvement of subtilases in defense mechanisms, but their role is not yet understood. The first characterization of the subtilase gene family was performed in 2014. However, simultaneously, the grapevine genome was re-annotated and several sequences were re-annotated or retrieved. We have performed a re characterization of this family in grapevine and identified 82 genes coding for 97 putative proteins, as result of alternative splicing. All the subtilases identified present the characteristic S8 peptidase domain and the majority of them also have a pro-domain I9 inhibitor, a protease-associated (PA) domain, and a signal peptide for targeting to the secretory pathway. Phylogenetic studies revealed six subtilase groups denominated VvSBT1 to VvSBT6. As several evidences have highlighted the participation of plant subtilases in response to biotic stimulus, we have investigated subtilase participation in grapevine resistance to Plasmopara viticola, the causative agent of downy mildew. Fourteen grapevine subtilases presenting either high homology to P69C from tomato, SBT3.3 from Arabidopsis thaliana or located near the Resistance to P. viticola (RPV) locus were selected. Expression studies were conducted in the grapevine-P. viticola pathosystem with resistant and susceptible cultivars. Our results may indicate that some of grapevine subtilisins are potentially participating in the defense response against this biotrophic oomycete. PMID- 27933089 TI - A Rare Inherited 15q11.2-q13.1 Interstitial Duplication with Maternal Somatic Mosaicism, Renal Carcinoma, and Autism. AB - Chromosome 15q11-q13.1 duplication is a common copy number variant associated with autism spectrum disorder (ASD). Most cases are de novo, maternal in origin and fully penetrant for ASD. Here, we describe a unique family with an interstitial 15q11.2-q13.1 maternal duplication and the presence of somatic mosaicism in the mother. She is typically functioning, but formal autism testing showed mild ASD. She had several congenital anomalies, and she is the first 15q Duplication case reported in the literature to develop unilateral renal carcinoma. Her two affected children share some of these clinical characteristics, and have severe ASD. Several tissues in the mother, including blood, skin, a kidney tumor, and normal kidney margin tissues were studied for the presence of the 15q11-q13.1 duplication. We show the mother has somatic mosaicism for the duplication in several tissues to varying degrees. A growth competition assay in two types of stem cells from duplication 15q individuals was also performed. Our results suggest that the presence of this interstitial duplication 15q chromosome may confer a previously unknown growth advantage in this particular individual, but not in the general interstitial duplication 15q population. PMID- 27933090 TI - The Worldwide Spread of the Tiger Mosquito as Revealed by Mitogenome Haplogroup Diversity. AB - In the last 40 years, the Asian tiger mosquito Aedes albopictus, indigenous to East Asia, has colonized every continent except Antarctica. Its spread is a major public health concern, given that this species is a competent vector for numerous arboviruses, including those causing dengue, chikungunya, West Nile, and the recently emerged Zika fever. To acquire more information on the ancestral source(s) of adventive populations and the overall diffusion process from its native range, we analyzed the mitogenome variation of 27 individuals from representative populations of Asia, the Americas, and Europe. Phylogenetic analyses revealed five haplogroups in Asia, but population surveys appear to indicate that only three of these (A1a1, A1a2, and A1b) were involved in the recent worldwide spread. We also found out that a derived lineage (A1a1a1) within A1a1, which is now common in Italy, most likely arose in North America from an ancestral Japanese source. These different genetic sources now coexist in many of the recently colonized areas, thus probably creating novel genomic combinations which might be one of the causes of the apparently growing ability of A. albopictus to expand its geographical range. PMID- 27933091 TI - Spatially Heterogeneous Environmental Selection Strengthens Evolution of Reproductively Isolated Populations in a Dobzhansky-Muller System of Hybrid Incompatibility. AB - Within-species hybrid incompatibility can arise when combinations of alleles at more than one locus have low fitness but where possession of one of those alleles has little or no fitness consequence for the carriers. Limited dispersal with small numbers of mate potentials alone can lead to the evolution of clusters of reproductively isolated genotypes despite the absence of any geographical barriers or heterogeneous selection. In this paper, we explore how adding heterogeneous natural selection on the genotypes (e.g., gene environment associations) that are involved in reproductive incompatibility affects the frequency, size and duration of evolution of reproductively isolated clusters. We conducted a simulation experiment that varied landscape heterogeneity, dispersal ability, and strength of selection in a continuously distributed population. In our simulations involving spatially heterogeneous selection, strong patterns of adjacency of mutually incompatible genotypes emerged such that these clusters were truly reproductively isolated from each other, with no reproductively compatible "bridge" individuals in the intervening landscape to allow gene flow between the clusters. This pattern was strong across levels of gene flow and strength of selection, suggesting that even relatively weak selection acting in the context of strong gene flow may produce reproductively isolated clusters that are large and persistent, enabling incipient speciation in a continuous population without geographic isolation. PMID- 27933092 TI - Effects of purified anthocyanin supplementation on platelet chemokines in hypocholesterolemic individuals: a randomized controlled trial. AB - BACKGROUND: It is becoming increasingly evident that platelet chemokines are involved in distinct aspects of atherosclerosis. The aim of this study was to examine the effects of long-term supplementation with purified anthocyanins on platelet chemokines in hypercholesterolemic individuals and to identify correlations of decreased platelet chemokine levels with serum lipid and inflammatory marker levels. METHODS: A total of 146 hypercholesterolemic individuals were recruited and treated with 320 mg of purified anthocyanins (n = 73) or a placebo (n = 73) daily for 24 weeks in this randomized, double-blind, placebo-controlled trial. RESULTS: Anthocyanin supplementation for 24 weeks significantly decreased the plasma CXCL7 (-12.32% vs. 4.22%, P = 0.001), CXCL5 ( 9.95% vs. 1.93%, P = 0.011), CXCL8 (-6.07% vs. 0.66%, P = 0.004), CXCL12 (-8.11% vs. 5.43%, P = 0.023) and CCL2 levels (-11.63% vs. 12.84%, P = 0.001) compared with the placebo. Interestingly, the decreases in the CXCL7 and CCL2 levels were both positively correlated with the decreases in the serum low-density lipoprotein-cholesterol (LDL-C), high-sensitivity C-reactive protein (hsCRP) and interleukin-1beta (IL-1beta) levels after anthocyanin supplementation for 24 weeks. The decrease in the CXCL8 level was negatively correlated with the increase in the how-density lipoprotein-cholesterol (HDL-C) level and was positively correlated with the decrease in the soluble P-selectin (sP-selectin) level in the anthocyanin group. In addition, a positive correlation was observed between the decreases in the CXCL12 and tumornecrosis factor-alpha (TNF-alpha) levels after anthocyanin supplementation. However, the plasma CXCL4L1, CXCL1, macrophage migration inhibitory factor (MIF) and human plasminogen activator inhibitor 1 (PAI-1) levels did not significantly change following anthocyanin supplementation. CONCLUSIONS: The present study supports the notion that platelet chemokines are promising targets of anthocyanins in the prevention of atherosclerosis. TRIAL REGISTRATION: ChiCTR-TRC-08000240. Registered: 10 December 2008. PMID- 27933093 TI - Long-term consumption of an obesogenic high fat diet prior to ischemia reperfusion mediates cardioprotection via Epac1-dependent signaling. AB - BACKGROUND: Obesity is still considered a risk factor for cardiovascular disease, although more recent knowledge also suggests obesity to be associated with reduced morbidity and mortality - the "obesity paradox". This study explores if long-term feeding of an obesogenic high fat diet renders the myocardium less susceptible to ischemic-reperfusion induced injury via Epac-dependent signaling. METHODS: Wild type (wt), Epac1 (Epac1-/-) and Epac2 (Epac2-/-) deficient mice were fed a high fat (HFD) or normal chow diet (ND) for 33 +/- 1 weeks. Six experimental groups were included: (1) control wt ND (wt ND), (2) control wt HFD (wt HFD), (3) Epac1-/- mice on ND (Epac1-/-ND), (4) Epac1-/- mice on HFD (Epac1-/ HFD), (5) Epac2-/- mice on ND (Epac2-/-ND), and (6) Epac2-/- mice on HFD (Epac2-/ HFD). Isolated ex vivo mice hearts were perfused in a constant pressure Langendorff mode, and exposed to 30min of global ischemia (GI) and 60min of reperfusion. Endpoints were infarct size and functional recovery. RESULTS: All groups fed a HFD presented with significantly enhanced body weight, visceral fat content and reduced glucose clearance compared to corresponding ND groups. Although the HFD cohorts presented with an overall comparable systemic capability to clear glucose, the Epac1-/- HFD group presented with glucose levels slightly above the human diabetes criteria at the end of the intraperitoneal glucose tolerance test (ipGTT). Moreover, the HFD significantly reduced infarct size in both wild type (wt HFD 41.3 +/- 5.5% vs. wt ND 58.0 +/- 9.8%, p < 0.05) and Epac2 /- cohorts (Epac2-/-HFD 34.4 +/- 7.2% vs. Epac2-/-ND 56.5 +/- 3.8%, p < 0.05). Interestingly, however, the HFD did not reduce infarct size in Epac1-/- deficient mice hearts (Epac1-/-HFD 65.1 +/- 5.1% vs. Epac1-/-ND 56.1 +/- 3.5%, ns.). CONCLUSION: Epac1-dependent signaling is involved in mediating the cardioprotection afforded by long-term feeding of an obesogenic high fat diet in mice hearts. PMID- 27933094 TI - The newer Opioid Agonist Treatment with lower substitutive opiate doses is associated with better toxicology outcome than the older Harm Reduction Treatment. AB - BACKGROUND: Charge-free heroin use disorder treatment in Italy follows two main approaches, i.e., harm reduction treatment (HRT) strategy in community low threshold facilities for drug addiction and opioid agonist treatment (OAT) in high-threshold facilities for opioid addiction, focusing on pharmacological maintenance according to the Dole and Nyswander strategy. We aimed to compare the impact of HRT and OAT on patient outcome, as assessed through negativity for drugs on about 1-year urinalyses. METHODS: We examined retrospectively the urinalyses of HRT and OAT patients for which at least four randomly sampled urinalyses per month were available for about 1 year, during which patients were undergoing methadone or buprenorphine maintenance; urinalyses focused on heroin, cocaine, cannabinoids, and their metabolites. RESULTS: Included were 189 HRT and 58 OAT patients. The latter were observed for a significantly longer period. There was a higher proportion of heroin- and cocaine-clean urinalyses in OAT patients, with cocaine-clean urinalyses discriminating best between the two groups. OAT patients were older, with longer dependence duration, more severe addiction history, and received lower methadone doses. Buprenorphine maintenance was more often associated with heroin-clean urinalyses. The higher the methadone doses, the lower were the percentage of heroin-clean urinalyses in HRT patients (negative correlation). CONCLUSIONS: The OAT approach was related to higher recovery and polyabuse abstinence rates compared to the HRT approach, despite greater severity of substance use, psychiatric and physical comorbidities. Our results are consistent with the possibility to use lower maintenance opiate doses (after induction and stabilization in methadone treatment according to Dole and Nyswander methodology) in treating heroin addiction. This seemed to be impossible adopting the currently accepted HRT model. PMID- 27933095 TI - Direct derivation of maize plant and crop height from low-cost time-of-flight camera measurements. AB - BACKGROUND: In agriculture, information about the spatial distribution of crop height is valuable for applications such as biomass and yield estimation, or increasing field work efficiency in terms of fertilizing, applying pesticides, irrigation, etc. Established methods for capturing crop height often comprise restrictions in terms of cost and time efficiency, flexibility, and temporal and spatial resolution of measurements. Furthermore, crop height is mostly derived from a measurement of the bare terrain prior to plant growth and measurements of the crop surface when plants are growing, resulting in the need of multiple field campaigns. In our study, we examine a method to derive crop heights directly from data of a plot of full grown maize plants captured in a single field campaign. We assess continuous raster crop height models (CHMs) and individual plant heights derived from data collected with the low-cost 3D camera Microsoft(r) Kinect(r) for Xbox OneTM based on a comprehensive comparison to terrestrial laser scanning (TLS) reference data. RESULTS: We examine single measurements captured with the 3D camera and a combination of the single measurements, i.e. a combination of multiple perspectives. The quality of both CHMs, and individual plant heights is improved by combining the measurements. R2 of CHMs derived from single measurements range from 0.48 to 0.88, combining all measurements leads to an R2 of 0.89. In case of individual plant heights, an R2 of 0.98 is achieved for the combined measures (with R2 = 0.44 for the single measurements). The crop heights derived from the 3D camera measurements comprise an average underestimation of 0.06 m compared to TLS reference values. CONCLUSION: We recommend the combination of multiple low-cost 3D camera measurements, removal of measurement artefacts, and the inclusion of correction functions to improve the quality of crop height measurements. Operating low-cost 3D cameras under field conditions on agricultural machines or on autonomous platforms can offer time and cost efficient tools for capturing the spatial distribution of crop heights directly in the field and subsequently to advance agricultural efficiency and productivity. More general, all processes which include the 3D geometry of natural objects can profit from low-cost methods producing 3D geodata. PMID- 27933096 TI - Erratum to: A representation of a compressed de Bruijn graph for pan-genome analysis that enables search. AB - [This corrects the article DOI: 10.1186/s13015-016-0083-7.]. PMID- 27933098 TI - Psychosomatic problems among medical students: a myth or reality? AB - BACKGROUND: Medical students are exposed to stress and this can predispose them to psychological and behavioral consequences. METHODS: Psychosomatic disorders were investigated among 385 medical students from two teaching hospitals using a stratified random sampling. The Enugu somatization Scale (ESS) was used to evaluate for presence of somatization in the participants. Statistical analysis was done with the Statistical Package for Social Sciences (SPPS) version 19 (Chicago IL). RESULTS: A total of 385 medical students with a calculated mean age of 23.55 +/- 3.33 years were recruited in this study. The prevalence of psychosomatic disorder was 55 (14.3%) with prevalence among males 33 (14.2%) and among females 22 (14.4%). Based on features, 44 (11.4%) had head features while 30 (7.8%) had body features of psychosomatic disorder respectively. Similar proportion of both males and females (about 14% each) had psychosomatic disorder. There was no statistically significant difference ([Formula: see text] = 0.002, p = 0.966). Students aged 24 years and below had similar proportion of psychosomatic disorder 38 (14.3%) with those aged over 24 years 17 (14.2%). The difference was not statistically significant ([Formula: see text] = 0.002, p = 0.964). Students from lower social class had lower proportion of psychosomatic disorder (10.6%) when compared to middle (17.2%) and upper (15.2%). The difference was equally not statistically significant ([Formula: see text] = 1.759, p = 0.415). Male students had similar likelihood of psychosomatic disorder with females (OR 1.01, 95% CI 0.56-1.82). Those had belong to middle socio economic class were about 1.2 times (AOR 1.15, 95% CI 0.54-2.45) and lower socio economic class about 0.6 times (AOR 0.66, 95% CI 0.31-1.37) likely to have psychosomatic disorder than those from upper socio-economic class. CONCLUSIONS: Psychosomatic disorders constitute an emerging mental health problem among medical students in Nigerian Universities. This can pose a major mental health problem if neglected. PMID- 27933097 TI - Molecular mechanisms of HPV mediated neoplastic progression. AB - Human Papillomavirus is the major etiological agent in the development of cervical cancer but not a sufficient cause. Despite significant research, the underlying mechanisms of progression from a low-grade squamous intraepithelial lesion to high grade squamous intraepithelial lesion are yet to be understood. Deregulation of viral gene expression and host genomic instability play a central role in virus-mediated carcinogenesis. Key events such as viral integration and epigenetic modifications may lead to the deregulation of viral and host gene expression. This review has summarized the available literature to describe the possible mechanism and role of viral integration in mediating carcinogenesis. HPV integration begins with DNA damage or double strand break induced either by oxidative stress or HPV proteins and the subsequent steps are driven by the DNA damage responses. Inflammation and oxidative stress could be considered as cofactors in stimulating viral integration and deregulation of cellular and viral oncogenes during the progression of cervical carcinoma. All these events together with the host and viral genetic and epigenetic modifications in neoplastic progression have also been reviewed which may be relevant in identifying a new preventive therapeutic strategy. In the absence of therapeutic intervention for HPV-infected individuals, future research focus should be directed towards preventing and reversing of HPV integration. DNA damage response, knocking out integrated HPV sequences, siRNA approach, modulating the selection mechanism of cells harboring integrated genomes and epigenetic modifiers are the possible therapeutic targets. PMID- 27933099 TI - Treating nonsuicidal self-injury (NSSI) in adolescents: consensus based German guidelines. AB - BACKGROUND: Nonsuicidal self-injury (NSSI) is a frequent and clinically relevant phenomenon in adolescence. Within Europe, Germany has one of the highest prevalence rates in youth with lifetime prevalence ranging between 25 and 35%. However, treatment guidelines for NSSI are not yet available. METHODS: Consensus based clinical guidelines were created by a working group consisting of members of eleven medical, psychological or psychotherapeutic professional national associations, and two members of patient self-help and prevention groups. The guidelines were developed in consecutive expert meetings and literature searches and agreed on in a final consensus conference. RESULTS: Given that evidence on both the psychotherapeutic and psychopharmacological treatment of NSSI is limited, a consensus based approach was chosen. The consensus indicated that due to the accumulating evidence on the efficacy of psychotherapeutic approaches, core elements of psychotherapy should be provided in treatment of NSSI. A specific psychopharmacological therapy of NSSI cannot be recommended. In addition, the guidelines provide recommendations for surgical intervention of NSSI. CONCLUSIONS: In accordance with the heterogeneous level of evidence, recommendations for the clinical management of NSSI in adolescence were made during a consensus conference after reviewing available literature. There is still a lack of knowledge on prevention as well as clinical interventions, which needs to be addressed by further clinically relevant studies. PMID- 27933100 TI - Genome and methylome of the oleaginous diatom Cyclotella cryptica reveal genetic flexibility toward a high lipid phenotype. AB - BACKGROUND: Improvement in the performance of eukaryotic microalgae for biofuel and bioproduct production is largely dependent on characterization of metabolic mechanisms within the cell. The marine diatom Cyclotella cryptica, which was originally identified in the Aquatic Species Program, is a promising strain of microalgae for large-scale production of biofuel and bioproducts, such as omega-3 fatty acids. RESULTS: We sequenced the nuclear genome and methylome of this oleaginous diatom to identify the genetic traits that enable substantial accumulation of triacylglycerol. The genome is comprised of highly methylated repetitive sequence, which does not significantly change under silicon starved lipid induction, and data further suggests the primary role of DNA methylation is to suppress DNA transposition. Annotation of pivotal glycolytic, lipid metabolism, and carbohydrate degradation processes reveal an expanded enzyme repertoire in C. cryptica that would allow for an increased metabolic capacity toward triacylglycerol production. Identification of previously unidentified genes, including those involved in carbon transport and chitin metabolism, provide potential targets for genetic manipulation of carbon flux to further increase its lipid phenotype. New genetic tools were developed, bringing this organism on a par with other microalgae in terms of genetic manipulation and characterization approaches. CONCLUSIONS: Functional annotation and detailed cross-species comparison of key carbon rich processes in C. cryptica highlights the importance of enzymatic subcellular compartmentation for regulation of carbon flux, which is often overlooked in photosynthetic microeukaryotes. The availability of the genome sequence, as well as advanced genetic manipulation tools enable further development of this organism for deployment in large-scale production systems. PMID- 27933101 TI - Study of Holtermanniella wattica, Leucosporidium creatinivorum, Naganishia adeliensis, Solicoccozyma aeria, and Solicoccozyma terricola for their lipogenic aptitude from different carbon sources. AB - BACKGROUND: The ability of some microorganisms to accumulate lipids is well known; however, only recently the number of studies on microbial lipid biosynthesis for obtaining oleochemical products, namely biofuels and some building blocks for chemistry, is rapidly and spectacularly increased. Since 1990s, some oleaginous yeasts were studied for their ability to accumulate lipids up to 60-70% of their dry weight. Due to the vast array of engineering techniques currently available, the recombinant DNA technology was the main approach followed so far for obtaining lipid-overproducing yeasts, mainly belonging to the Yarrowia lipolytica. However, an alternative approach can be offered by worldwide diversity as source of novel oleaginous yeasts. Lipogenic aptitude of a number of yeast strains has been reviewed, but many of these studies utilized a limited number of species and/or different culture conditions that make impossible the comparison of different results. Accordingly, the lipogenic aptitude inside the yeast world is still far from being fully explored, and finding new oleaginous yeast species can acquire a strategic importance. RESULTS: Holtermanniella wattica, Leucosporidium creatinivorum, Naganishia adeliensis, Solicoccozyma aeria, and Solicoccozyma terricola strains were selected as a result of a large scale screening on 706 yeasts (both Ascomycota and Basidiomycota). Lipid yields and fatty acid profiles of selected strains were evaluated at 20 and 25 degrees C on glucose, and on glycerol, xylose, galactose, sucrose, maltose, and cellobiose. A variable fatty acid profile was observed in dependence of both temperature and different carbon sources. On the whole, L. creatinivorum exhibited the highest performances: total lipid yield (YL) >7 g/l on glucose and glycerol, % of intracellular lipids on cell biomass (YL/DW) >70% at 20 degrees C on glucose, lipid coefficient (YL/Glu) around 20% on glucose, and daily productivity (YL/d) on glucose and sucrose >1.6 g/(l*d). CONCLUSIONS: This study provides some meaningful information about the lipogenic ability of some yeast species. Variable lipid yields and fatty acid profiles were observed in dependence of both temperature and different carbon sources. L. creatinivorum exhibited the highest lipogenic performances. PMID- 27933102 TI - A polysaccharide utilization locus from Flavobacterium johnsoniae enables conversion of recalcitrant chitin. AB - BACKGROUND: Chitin is the second most abundant polysaccharide on earth and as such a great target for bioconversion applications. The phylum Bacteroidetes is one of nature's most ubiquitous bacterial lineages and is essential in the global carbon cycle with many members being highly efficient degraders of complex carbohydrates. However, despite their specialist reputation in carbohydrate conversion, mechanisms for degrading recalcitrant crystalline polysaccharides such as chitin and cellulose are hitherto unknown. RESULTS: Here we describe a complete functional analysis of a novel polysaccharide utilization locus (PUL) in the soil Bacteroidete Flavobacterium johnsoniae, tailored for conversion of chitin. The F. johnsoniae chitin utilization locus (ChiUL) consists of eleven contiguous genes encoding carbohydrate capture and transport proteins, enzymes, and a two-component sensor-regulator system. The key chitinase (ChiA) encoded by ChiUL is atypical in terms of known Bacteroidetes-affiliated PUL mechanisms as it is not anchored to the outer cell membrane and consists of multiple catalytic domains. We demonstrate how the extraordinary hydrolytic efficiency of ChiA derives from synergy between its multiple chitinolytic (endo- and exo-acting) and previously unidentified chitin-binding domains. Reverse genetics show that ChiA and PUL-encoded proteins involved in sugar binding, import, and chitin sensing are essential for efficient chitin utilization. Surprisingly, the ChiUL encodes two pairs of SusC/D-like outer membrane proteins. Ligand-binding and structural studies revealed functional differences between the two SusD-like proteins that enhance scavenging of chitin from the environment. The combined results from this study provide insight into the mechanisms employed by Bacteroidetes to degrade recalcitrant polysaccharides and reveal important novel aspects of the PUL paradigm. CONCLUSIONS: By combining reverse genetics to map essential PUL genes, structural studies on outer membrane chitin-binding proteins, and enzymology, we provide insight into the mechanisms employed by Bacteroidetes to degrade recalcitrant polysaccharides and introduce a new saccharolytic mechanism used by the phylum Bacteroidetes. The presented discovery and analysis of the ChiUL will greatly benefit future enzyme discovery efforts as well as studies regarding enzymatic intramolecular synergism. PMID- 27933103 TI - Programmatic conversion of crystal structures into 3D printable files using Jmol. AB - BACKGROUND: Three-dimensional (3D) printed crystal structures are useful for chemistry teaching and research. Current manual methods of converting crystal structures into 3D printable files are time-consuming and tedious. To overcome this limitation, we developed a programmatic method that allows for facile conversion of thousands of crystal structures directly into 3D printable files. RESULTS: A collection of over 30,000 crystal structures in crystallographic information file (CIF) format from the Crystallography Open Database (COD) were programmatically converted into 3D printable files (VRML format) using Jmol scripting. The resulting data file conversion of the 30,000 CIFs proceeded as expected, however some inconsistencies and unintended results were observed with co-crystallized structures, racemic mixtures, and structures with large counterions that led to 3D printable files not containing the desired chemical structure. Potential solutions to these challenges are considered and discussed. Further, a searchable Jmol 3D Print website was created that allows users to both discover the 3D file dataset created in this work and create custom 3D printable files for any structure in the COD. CONCLUSIONS: Over 30,000 crystal structures were programmatically converted into 3D printable files, allowing users to have quick access to a sizable collection of 3D printable crystal structures. Further, any crystal structure (>350,000) in the COD can now be conveniently converted into 3D printable file formats using the Jmol 3D Print website created in this work. The 3D Print website also allows users to convert their own CIFs into 3D printable files. 3D file data, scripts, and the Jmol 3D Print website are provided openly to the community in an effort to promote discovery and use of 3D printable crystal structures. The 3D file dataset and Jmol 3D Print website will find wide use with researchers and educators seeking to 3D print chemical structures, while the scripts will be useful for programmatically converting large database collections of crystal structures into 3D printable files. PMID- 27933104 TI - Cardiovascular disease in patients with chronic kidney disease: a neglected subgroup. AB - The burden of non-communicable diseases has increased exponentially over the past decade and they account for majority of the health-related morbidity and mortality worldwide. In line with this, the prevalence of chronic kidney disease (CKD) has been increasing over the years. CKD progresses through stages and it is well known that patients are more likely to die than to progress to end-stage renal disease. The presence of multiple classical and novel risk factors predisposes this group of patients to premature cardiovascular mortality. Though being a common entity, prevention, diagnosis and treatment of cardiovascular diseases in CKD are mired with controversies. This is due to the fact that many of the well-established diagnostic modalities and treatment strategies have not been studied in detail in patients with CKD. Moreover, most of the studies have excluded patients with renal dysfunction though they are at a higher risk for adverse outcomes and require specific dose modifications. This has limited the evidence base for optimal decision making. In this review, we aim to cover the risk factors, diagnosis and effectiveness of interventional strategies in patients with CKD. PMID- 27933105 TI - Prevalence of atrial fibrillation in the Malaysian communities. AB - BACKGROUND AND AIM: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. The REDISCOVER (Responding to Increasing Cardiovascular disease prevalence) study is an observational longitudinal community-based study that tracks changing lifestyles, risk factors and chronic disease in urban and rural areas of Malaysia. In this study, we aim to study the prevalence of AF and its associated risk factors. METHODS: The study was conducted between 2007 and 2014. Participants were required to complete questionnaires on cardiovascular risk factors and medical history, and undergo physical examinations, blood tests, ECG and echocardiography examinations. Demographic variables including weight, height, blood pressure, serum glucose and serum lipid were recorded. Participants with AF were identified from their baseline ECG and at 3-year follow up. RESULTS: A total of 10 805 subjects participated in the study. Mean age was 52.6(+/-11.6) years and 56% were female; 4.4% of subjects had a diagnosis of ischaemic heart disease, 1.3% had a previous stroke, 16.7% had diabetes mellitus and 45.6% had hypertension. There were 53 subjects diagnosed with AF at baseline, giving a prevalence of 0.49%, and 0.54% at 3 years. AF was more prevalent in males (58.5% in the AF group compared to 43.9% in sinus rhythm (SR) subjects; p=0.03) and the older age group. Ischaemic heart disease was more prevalent in AF subjects (22.6%) compared to SR subjects (4.4%) (p<0.001). In the AF group previous stroke had occurred in 1.9% of subjects compared to 1.3% in the SR population (p=0.51), and 24.5% of subjects in the AF group had diabetes compared to 16.6% in the SR group (p=0.12). There was a significant difference in the prevalence of hypertension between the AF group (59.6%) compared to the SR subjects (45.5%) (p=0.04). CONCLUSIONS: The prevalence of AF in the Malaysian population was low at 0.54% compared to the global average of 1%. We found that AF was associated with older age, male sex, hypertension, and ischaemic heart disease. PMID- 27933106 TI - Screening-detected rheumatic heart disease can progress to severe disease. AB - OBJECTIVES: Echocardiography is a sensitive test for rheumatic heart disease (RHD) screening; however the natural history of RHD detected on screening has not been established. We aimed to evaluate the progression of screening-detected RHD in Fiji. METHODS: All young people previously diagnosed with RHD through screening, with echocardiograms available for review, were eligible. All baseline echocardiograms were reported again. Participants underwent follow-up echocardiography. A paediatric cardiologist determined the diagnosis using the World Heart Federation criteria and assessed the severity of regurgitation and stenosis. RESULTS: Ninety-eight participants were recruited (mean age, 17 years; median duration of follow-up, 7.5 years). Two other children had died from severe RHD. Fourteen of 20 (70%) definite RHD cases persisted or progressed, including four (20%) requiring valve surgery. Four (20%) definite RHD cases improved to borderline RHD and two (10%) to normal. Four of 17 (24%) borderline cases progressed to definite RHD (moderate: 2; severe: 2) and two (12%) improved to normal. Four of the 55 cases reclassified as normal at baseline progressed to borderline RHD. Cases with a follow-up interval >5 years were more likely to improve (37% vs 6%, p=0.03). CONCLUSIONS: The natural history of screening detected RHD is not benign. Most definite RHD cases persist and others may require surgery or succumb. Progression of borderline cases to severe RHD demonstrates the need for monitoring and individualised consideration of prophylaxis. Robust health system structures are needed for follow-up and delivery of secondary prophylaxis if RHD screening is to be scaled up. PMID- 27933107 TI - Foreword: special issue on computational finance and economics. PMID- 27933108 TI - Postural orientation and equilibrium processes associated with increased postural sway in autism spectrum disorder (ASD). AB - BACKGROUND: Increased postural sway has been repeatedly documented in children with autism spectrum disorder (ASD). Characterizing the control processes underlying this deficit, including postural orientation and equilibrium, may provide key insights into neurophysiological mechanisms associated with ASD. Postural orientation refers to children's ability to actively align their trunk and head with respect to their base of support, while postural equilibrium is an active process whereby children coordinate ankle dorsi-/plantar-flexion and hip abduction/adduction movements to stabilize their upper body. Dynamic engagement of each of these control processes is important for maintaining postural stability, though neither postural orientation nor equilibrium has been studied in ASD. METHODS: Twenty-two children with ASD and 21 age and performance IQ matched typically developing (TD) controls completed three standing tests. During static stance, participants were instructed to stand as still as possible. During dynamic stances, participants swayed at a comfortable speed and magnitude in either anterior-posterior (AP) or mediolateral (ML) directions. The center of pressure (COP) standard deviation and trajectory length were examined to determine if children with ASD showed increased postural sway. Postural orientation was assessed using a novel virtual time-to-contact (VTC) approach that characterized spatiotemporal dimensions of children's postural sway (i.e., body alignment) relative to their postural limitation boundary, defined as the maximum extent to which each child could sway in each direction. Postural equilibrium was quantified by evaluating the amount of shared or mutual information of COP time series measured along the AP and ML directions. RESULTS: Consistent with prior studies, children with ASD showed increased postural sway during both static and dynamic stances relative to TD children. In regard to postural orientation processes, children with ASD demonstrated reduced spatial perception of their postural limitation boundary towards target directions and reduced time to correct this error during dynamic postural sways but not during static stance. Regarding postural equilibrium, they showed a compromised ability to decouple ankle dorsi-/plantar-flexion and hip abduction/adduction processes during dynamic stances. CONCLUSIONS: These results suggest that deficits in both postural orientation and equilibrium processes contribute to reduced postural stability in ASD. Specifically, increased postural sway in ASD appears to reflect patients' impaired perception of their body movement relative to their own postural limitation boundary as well as a reduced ability to decouple distinct ankle and hip movements to align their body during standing. Our findings that deficits in postural orientation and equilibrium are more pronounced during dynamic compared to static stances suggests that the increased demands of everyday activities in which children must dynamically shift their COP involve more severe postural control deficits in ASD relative to static stance conditions that often are studied. Systematic assessment of dynamic postural control processes in ASD may provide important insights into new treatment targets and neurodevelopmental mechanisms. PMID- 27933109 TI - Functional characterization of rare FOXP2 variants in neurodevelopmental disorder. AB - BACKGROUND: Heterozygous disruption of FOXP2 causes a rare form of speech and language impairment. Screens of the FOXP2 sequence in individuals with speech/language-related disorders have identified several rare protein-altering variants, but their phenotypic relevance is often unclear. FOXP2 encodes a transcription factor with a forkhead box DNA-binding domain, but little is known about the functions of protein regions outside this domain. METHODS: We performed detailed functional analyses of seven rare FOXP2 variants found in affected cases, including three which have not been previously characterized, testing intracellular localization, transcriptional regulation, dimerization, and interaction with other proteins. To shed further light on molecular functions of FOXP2, we characterized the interaction between this transcription factor and co repressor proteins of the C-terminal binding protein (CTBP) family. Finally, we analysed the functional significance of the polyglutamine tracts in FOXP2, since tract length variations have been reported in cases of neurodevelopmental disorder. RESULTS: We confirmed etiological roles of multiple FOXP2 variants. Of three variants that have been suggested to cause speech/language disorder, but never before been characterized, only one showed functional effects. For the other two, we found no effects on protein function in any assays, suggesting that they are incidental to the phenotype. We identified a CTBP-binding region within the N-terminal portion of FOXP2. This region includes two amino acid substitutions that occurred on the human lineage following the split from chimpanzees. However, we did not observe any effects of these amino acid changes on CTBP binding or other core aspects of FOXP2 function. Finally, we found that FOXP2 variants with reduced polyglutamine tracts did not exhibit altered behaviour in cellular assays, indicating that such tracts are non-essential for core aspects of FOXP2 function, and that tract variation is unlikely to be a highly penetrant cause of speech/language disorder. CONCLUSIONS: Our findings highlight the importance of functional characterization of novel rare variants in FOXP2 in assessing the contribution of such variants to speech/language disorder and provide further insights into the molecular function of the FOXP2 protein. PMID- 27933110 TI - Profiling lung adenocarcinoma by liquid biopsy: can one size fit all? AB - BACKGROUND: Cancer is first and foremost a disease of the genome. Specific genetic signatures within a tumour are prognostic of disease outcome, reflect subclonal architecture and intratumour heterogeneity, inform treatment choices and predict the emergence of resistance to targeted therapies. Minimally invasive liquid biopsies can give temporal resolution to a tumour's genetic profile and allow the monitoring of treatment response through levels of circulating tumour DNA (ctDNA). However, the detection of ctDNA in repeated liquid biopsies is currently limited by economic and time constraints associated with targeted sequencing. METHODS: Here we bioinformatically profile the mutational and copy number spectrum of The Cancer Genome Network's lung adenocarcinoma dataset to uncover recurrently mutated genomic loci. RESULTS: We build a panel of 400 hotspot mutations and show that the coverage extends to more than 80% of the dataset at a median depth of 8 mutations per patient. Additionally, we uncover several novel single-nucleotide variants present in more than 5% of patients, often in genes not commonly associated with lung adenocarcinoma. CONCLUSION: With further optimisation, this hotspot panel could allow molecular diagnostics laboratories to build curated primer banks for 'off-the-shelf' monitoring of ctDNA by droplet-based digital PCR or similar techniques, in a time- and cost effective manner. PMID- 27933111 TI - Aberrant DNA hypermethylation-silenced SOX21-AS1 gene expression and its clinical importance in oral cancer. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) are more than 200 nucleotides in length and lack transcriptional ability. The biological function of lncRNAs in oral squamous cell carcinoma (OSCC) remains unclear. The aim of this study was to identify the dysfunction of lncRNA in OSCC. RESULTS: We analyzed the transcriptome profiles of human OSCC tissues and paired adjacent normal tissues from two patients through a next-generation sequencing approach. A total of 14 lncRNAs were upregulated (fold change >=3) and 13 were downregulated (fold change <=-3) in OSCC tissues compared with the adjacent normal tissues. SOX21-AS1 was subjected to further analysis, revealing that the expression levels of SOX21-AS1 significantly decreased in OSCC compared with the adjacent normal tissue. The promoter activity of SOX21-AS1 was obviously suppressed by in vitro methylation. The DNA methylation status of the SOX21-AS1 promoter was analyzed using combined bisulfite restriction analysis, revealing that the aberrant promoter hypermethylation of SOX21-AS1 was observed frequently in OSCC tissues. The effects of SOX21-AS1 on cell proliferation and invasion were examined through transient transfection. Our data showed that SOX21-AS1 could significantly suppress oral cancer cell growth and invasion. Furthermore, the low expression level of SOX21-AS1 was significantly correlated with an advanced stage (P = 0.047), large tumor size (P = 0.033), and poor disease-specific survival in OSCC patients (P = 0.002). CONCLUSIONS: SOX21-AS1 was identified as susceptible dysfunction correlated with promoter hypermethylation in OSCC. Low SOX21-AS1 expression may be an adverse prognostic biomarker for OSCC. PMID- 27933112 TI - Osteoblast and stem cell response to nanoscale topographies: a review. AB - To understand how cells respond to the nanoscale extracellular environment in vivo, cells from various sources have been cultured on nanoscale patterns fabricated using bottom-up and top-down techniques. Human fetal osteoblasts (hFOBs) and stem cells are some of them and they are known to be overtly responsive to nanoscale topographies - allowing us to investigate the hows and whys of the response in vitro. Information gathered from these in vitro studies could be used to control the cells, i.e. make the stem cells differentiate or retain their characteristics without the use of medium supplements. In this review, hFOB and stem cell responses to nanotopographies are summarized and discussed to shed some light on the influence of patterns on the reactions. Although both types of cells are responsive to nanoscale topographies, the responses are found to be unique to topographical dimension, shape, orientation and the types of cells used. This implies that cellular responses are influenced by multitude of factors and that if done right, cheaper self-assembled nanotopographies can be tailored to control the cells. A new self-assembly, powder-based technique is also included to provide an insight into the future of nanofabrication. PMID- 27933113 TI - A study of the optical and polarisation properties of InGaN/GaN multiple quantum wells grown on a-plane and m-plane GaN substrates. AB - We report on a comparative study of the low temperature emission and polarisation properties of InGaN/GaN quantum wells grown on nonpolar ([Formula: see text]) a plane and ([Formula: see text]) m-plane free-standing bulk GaN substrates where the In content varied from 0.14 to 0.28 in the m-plane series and 0.08 to 0.21 for the a-plane series. The low temperature photoluminescence spectra from both sets of samples are broad with full width at half maximum height increasing from 81 to 330 meV as the In fraction increases. Photoluminescence excitation spectroscopy indicates that the recombination mainly involves strongly localised carriers. At 10 K the degree of linear polarisation of the a-plane samples is much smaller than of the m-plane counterparts and also varies across the spectrum. From polarisation-resolved photoluminescence excitation spectroscopy we measured the energy splitting between the lowest valence sub-bands to lie in the range of 23-54 meV for the a- and m-plane samples in which we could observe distinct exciton features. Thus the thermal occupation of a higher valence sub band cannot be responsible for the reduction of the degree of linear polarisation at 10 K. Time-resolved spectroscopy indicates that in a-plane samples there is an extra emission component which is at least partly responsible for the reduction in the degree of linear polarisation. PMID- 27933114 TI - Instantaneous formation of SiOx nanocomposite for high capacity lithium ion batteries by enhanced disproportionation reaction during plasma spray physical vapor deposition. AB - Nanocomposite SiOx particles have been produced by a single step plasma spray physical vapor deposition (PS-PVD) through rapid condensation of SiO vapors and the subsequent disproportionation reaction. Core-shell nanoparticles, in which 15 nm crystalline Si is embedded within the amorphous SiOx matrix, form under typical PS-PVD conditions, while 10 nm amorphous particles are formed when processed with an increased degree of non-equilibrium effect. Addition of CH4 promotes reduction in the oxygen content x of SiO x , and thereby increases the Si volume in a nanocomposite particle. As a result, core-shell nanoparticles with x = 0.46 as anode exhibit increased initial efficiency and the capacity of lithium ion batteries while maintaining cyclability. Furthermore, it is revealed that the disproportionation reaction of SiO is promoted in nanosized particles attaining increased Si diffusivity by two orders of magnitude compared to that in bulk, which facilitates instantaneous composite nanoparticle formation during PS PVD. PMID- 27933115 TI - Effects of trimethylamine N-oxide and urea on DNA duplex and G-quadruplex. AB - We systematically investigated effects of molecular crowding with trimethylamine N-oxide (TMAO) as a zwitterionic and protective osmolyte and urea as a nonionic denaturing osmolyte on conformation and thermodynamics of the canonical DNA duplex and the non-canonical DNA G-quadruplex. It was found that TMAO and urea stabilized and destabilized, respectively, the G-quadruplex. On the other hand, these osmolytes generally destabilize the duplex; however, it was observed that osmolytes having the trimethylamine group stabilized the duplex at the lower concentrations because of a direct binding to a groove of the duplex. These results are useful not only to predict DNA structures and their thermodynamics under physiological environments in living cells, but also design of polymers and materials to regulate structure and stability of DNA sequences. PMID- 27933116 TI - Phoenix dactylifera mediated green synthesis of Cu2O particles for arsenite uptake from water. AB - In this study, an environmentally friendly, cost-effective, and single-step procedure is used for the synthesis of polycrystalline Cu2O particles with controlled morphologies. Simple sugars are extracted from date fruit pulp (Phoenix dactylifera) and used as a reducing agent for the formation of Cu2O particles in aqueous medium. The feasibility of this solution is compared with the standard glucose solution. The Cu2O particles are characterized by electron microscopy, X-ray diffraction, optical absorption and Raman scattering techniques. It is concluded that the morphology of the particles is mainly influenced by the solvents. The obtained Cu2O particles are then used as an adsorbent to uptake As(III) ions from water. The maximum adsorption capacity (Qmax) is estimated by Langmuir and Freundlich isotherms and it is found that Qmax = 14.3 mg g-1. Adsorption kinetics study showed that the adsorption equilibrium could be achieved in 1 h and that the purified water meets the standards of World Health Organization (WHO) for acceptable amount of As(III) in drinking water. Adsorption kinetic models showed that the adsorption is chemisorption in nature. PMID- 27933117 TI - Understanding the peculiarities of the piezoelectric effect in macro-porous BaTiO3. AB - This work demonstrates the potential of porous BaTiO3 for piezoelectric sensor and energy-harvesting applications by manufacture of materials, detailed characterisation and application of new models. Ferroelectric macro-porous BaTiO3 ceramics for piezoelectric applications are manufactured for a range of relative densities, alpha = 0.30-0.95, using the burned out polymer spheres method. The piezoelectric activity and relevant parameters for specific applications are interpreted by developing two models: a model of a 3-0 composite and a 'composite in composite' model. The appropriate ranges of relative density for the application of these models to accurately predict piezoelectric properties are examined. The two models are extended to take into account the effect of 90 degrees domain-wall mobility within ceramic grains on the piezoelectric coefficients [Formula: see text]. It is shown that porous ferroelectrics provide a novel route to form materials with large piezoelectric anisotropy [Formula: see text] at 0.20 <= alpha <= 0.45 and achieve a high squared figure of merit [Formula: see text] [Formula: see text]. The modelling approach allows a detailed analysis of the relationships between the properties of the monolithic and porous materials for the design of porous structures with optimum properties. PMID- 27933118 TI - Dynamics of native oxide growth on CdTe and CdZnTe X-ray and gamma-ray detectors. AB - We studied the growth of the surface oxide layer on four different CdTe and CdZnTe X-ray and gamma-ray detector-grade samples using spectroscopic ellipsometry. We observed gradual oxidization of CdTe and CdZnTe after chemical etching in bromine solutions. From X-ray photoelectron spectroscopy measurements, we found that the oxide consists only of oxygen bound to tellurium. We applied a refined theoretical model of the surface layer to evaluate the spectroscopic ellipsometry measurements. In this way we studied the dynamics and growth rate of the oxide layer within a month after chemical etching of the samples. We observed two phases in the evolution of the oxide layer on all studied samples. A rapid growth was visible within five days after the chemical treatment followed by semi saturation and a decrease in the growth rate after the first week. After one month all the samples showed an oxide layer about 3 nm thick. The oxide thickness was correlated with leakage current degradation with time after surface preparation. PMID- 27933119 TI - Longitudinal conductivity of LaF3/SrF2 multilayer heterostructures. AB - LaF3/SrF2 multilayer heterostructures with thicknesses of individual layers in the range 5-100 nm have been grown on MgO(100) substrates using molecular beam epitaxy. The longitudinal conductivity of the films has been measured using impedance spectroscopy in the frequency range 10-1-106 Hz and a temperature range 300-570 K. The ionic DC conductivities have been determined from Nyquist impedance diagrams and activation energies from the Arrhenius-Frenkel equation. An increase of the DC conductivity has been observed to accompany decreased layer thickness for various thicknesses as small as 25 nm. The greatest conductivity has been shown for a multilayer heterostructure having thicknesses of 25 nm per layer. The structure has a conductivity two orders of magnitude greater than pure LaF3 bulk material. The increasing conductivity can be understood as a redistribution of charge carriers through the interface due to differing chemical potentials of the materials, by strong lattice-constant mismatch, and/or by formation of a solid La1-xSrxF3-x solution at the interface during the growth process. PMID- 27933120 TI - Fast and selective cell isolation from blood sample by microfiber fabric system with vacuum aspiration. AB - Since circulating tumor cells (CTCs) are tumor cells which are found in the blood of cancer patients, CTCs are potential tumor markers, so a rapid isolation of CTCs is desirable for clinical applications. In this paper, a three-dimensional polystyrene (PS) microfiber fabric with vacuum aspiration system was developed for capturing CTCs within a short time. Various microfiber fabrics with different diameters were prepared by the electrospinning method and optimized for contact frequency with cells. Vacuum aspiration utilizing these microfiber fabrics could filter all cells within seconds without mechanical damage. The microfiber fabric with immobilized anti-EpCAM antibodies was able to specifically capture MCF-7 cells that express EpCAM on their surfaces. The specificity of the system was confirmed by monitoring the ability to isolate MCF-7 cells from a mixture containing CCRF-CEM cells that do not express EpCAM. Furthermore, the selective capture ability of the microfiber was retained even when the microfiber was exposed to the whole blood of pigs spiked with MCF-7 cells. The specific cell capture ratio of the vacuum aspiration system utilizing microfiber fabric could be improved by increasing the thickness of the microfiber fabric through electrospinning time. PMID- 27933121 TI - Alcoholic Hepatitis and Intestinal Barrier Breakdown: A Theoretical Reappraisal Based on Pentoxifylline's Action. PMID- 27933122 TI - Molecular Markers in the Pathogenesis of Cholangiocarcinoma: Potential for Early Detection and Selection of Appropriate Treatment. AB - Cholangiocarcinoma (CC) is a primary malignancy that arises from cholangiocytes, the epithelial cells lining the bile duct livers. The worldwide incidence of CC is increasing and despite of combined therapeutic strategies, its prognosis remains poor. Till now surgery remains the only curative treatment modality. Over the past years, several important studies have yielded new insights into the molecular mechanisms of cholangiocarcinoma. This review focused on critical molecular player during the development from inflammation and cellular and molecular pathogenesis of this disease. The novel prophylactic and therapeutic approach deals especially the molecules involved in inflammation of cholangiocite or those related to promotion and progression of CC. The elucidation of their specific effects and interaction of this complex mechanism will accelerate the development of new biomarker for early detection and predictor factors outcome in CC. PMID- 27933123 TI - 125I Radioactive Seeds Implantation Therapy for Hepatocellular Carcinoma. AB - BACKGROUND: This study was to evaluate the outcome and the prognostic factors of unresectable hepatocellular carcinoma (HCC) patients with 125I radioactive seeds implantation, who had failed transcatheter arterial chemoembolization (TACE). METHODS: From September 2002 to March 2006, 48 patients with unresectable HCC underwent 125I permanent implantation brachytherapy. Thirty-eight patients were male and 10 were female. Mean age was 59 years, ranginging from 32 to 86. Karnofsky performance status(KPS) was 100 in 10 patients, 80 in 21 patients, and 60 in 17 patients. According to Child-Pugh classification of liver, 34 patients were in class A and 14 patients in class B. Twenty-two patients had alpha fetoprotein (AFP) level > 400 ng/ml. Tumor size was < 5cm in 17 patients, 5-10 cm in 18 patients, and > 10cm in 13 patients. Thirty-four patients had confluent tumors, 14 patients presented single hepatic tumor. Serum hepatitis antigen markers were positive for type B in 38 patients and type C in 10 patients. Twenty two patients had Okuda Stage I, 24 patients Stage II, and 2 patients Stage III. According to the AJCC staging system (6th edition), 10 patients were in Stage II (T2N0M0), 20 in Stage IIIa (T3N0M0) and 18 in Stage IIIb (T4N0M0). RESULTS: An objective response was observed in 34 of 48 patients, giving a response rate of 70.8%. The survival rates at 1, 2 and 3 years were75%, 45.8% and 27.1%, respectively. In the analysis of prognostic factors, tumor type, tumor size, Okuda stage, AJCC stage, Liver Child-Pugh, pretreatment AFP level, and matched peripheral dose (MPD) all had significant impact on survival. CONCLUSIONS: The 125I permanent implantation brachytherapy induced a substantial tumor response rate of 70.8% with survival rates at 1, 2 and 3 years of 75%, 45.8% and 27.1%, respectively, and a median survival time of 15.5 months in patients with unresectable HCC who had failed TACE. The complications are acceptable and can be managed with conservative treatment. Although we do not know whether there is a survival benefit through the use of this treatment, 125I permanent implantation brachytherapy seems to be a practical method of salvage for this subset of patients. Further study is warranted to evaluate the survival of such patients with controlled trial. PMID- 27933124 TI - Esophageal Cancers: A Clinicopathologic and Immunohistochemical Study of 223 Cases. AB - The author reviewed 950 cases of consecutive esophageal biopsies in the last 15 years in out pathology laboratory of our hospital. There were 223 malignant lesions (23.5%). The number and frequency (percentages) were as follows: 54 mild dysplasia (5.7%), 30 moderate dyplasia (3.2%), 32 severe dysplasia (3.4%), 13 carcinoma in situ (1.4%), 71 squamous cell carcinoma (7.5%), 7 primary adenocarcinoma (0.7%), 1 primary signet ring cell carcinoma (0.1%), 4 primary small cell carcinoma (0.4%), 2 primary amelanotic malignant melanoma (0.2%), 1 primary undifferentiated sarcoma (0.1%), 7 gastric cancer invasion (0.7%), and 1 primary adenoid cystic carcinoma (0.1%). In this article, the clinical, histopathologic and immunohistochemical features of these esophageal cancers were described. PMID- 27933125 TI - Gastroesophageal Reflux Disease: A Population Based Study. AB - BACKGROUND: The prevalence of gastroesophageal reflux disease varies in different parts of the world. There are no population based studies in Nigeria. The main objectives of this study were to determine the prevalence and risk factors for gastroesophageal reflux disease in a population of Nigerian medical students. METHODS: The Carlsson-Dent questionnaire was administered to medical students in the clinical phase of their training at the University of Nigeria, Enugu Campus. Some putative risk factors for gastroesophageal reflux disease were also included in the questionnaire. RESULTS: The prevalence of gastroesophageal reflux disease was 26.34%. There was an association between the use of caffeine-containing substances (coffee and kolanuts) and the prevalence of gastroesophageal reflux disease (odds ratio = 2.2 and 2.015, respectively). CONCLUSIONS: Gastroesophageal reflux disease is common among Nigerian medical students. The use of caffeine containing substances (coffee and kolanuts) by students may have a role in the high prevalence. PMID- 27933126 TI - Heartburn in Staff of Golestan Medical University, Northeast of Iran. AB - BACKGROUND: Gastro-esophageal reflux disease (GERD) is the most common gastrointestinal disease in the west that has shown increasing incidence in Iran and Asian countries. The main presentations, described for GERD, are heartburn and acid regurgitation. METHODS: In this cross-sectional study in 2006, all personnel of Golestan Medical University (Northeast of Iran) were enrolled. A questionnaire consisting of demographic data, symptoms and risk factors was completed for all volunteers. Height and weight were measured. Chi-square and Non parametric tests were used for analysis. RESULTS: Symptoms of heartburn were seen in 60% of all 155 studied subjects. No significant relationship was seen between symptoms and variables like age, gender, BMI and tribes. Symptoms were more common in married ones (P < 0.05). CONCLUSIONS: Heartburn prevalence was high in this study. Heartburn was seen more in women and in married. The probable underlying etiology and explanation for these results should be studied more. PMID- 27933127 TI - The Hepatoprotective Effect of Vitamin A against Gasoline Vapor Toxicity in Rats. AB - BACKGROUND: Changes in the activities of plasma alanine amino transferase (ALT), aspartate amino transferase (AST), gamma glutamyl transferase (GGT), and alkaline phosphatase (ALP) are used to assess the functional state of the liver. Significant increase in the activities of these enzymes commonly indicates the hepatotoxicity of chemical agent(s) in the body. Exposure of male and female rats to 17.8 cm3h-1m-3 of Premium Motor Spirit (PMS) blend unleaded gasoline (UG) vapors for 6 hr/day, 5 days/week for 20 weeks have been observed to cause hepatotoxicity. In this study, the potential hepatoprotective effect of vitamin A (retinol) against gasoline vapours-induced toxicity was investigated in male and female rats. METHODS: Retinol (400 IU/kg/day) was orally administered to the test rats concomitant with the gasoline vapor exposure in the last two weeks of the experiment. RESULTS: The results obtained from this study showed that exposure to gasoline vapors caused significant increase (P < 0.05) in the activities of serum ALT, AST, ALP, GGT and bilirubin in both male and female rats. The treatment of the male and female test rats with vitamin A produced a significant decrease (P < 0.05) in the activities of these parameters, compared with the test rats without treatment; but insignificant increase(P >= 0.05), compared with the control. CONCLUSIONS: The result of this study demonstrates the beneficial effects of retinol, at prophylactic dosage, against gasoline vapours hepatotoxicity in male and female rats, thereby suggesting that retinol may be used to prevent hepatotoxicity in individuals frequently exposed to gasoline vapours. PMID- 27933128 TI - Effect of Zinc Supplementation in Children with Acute Diarrhea: Randomized Double Blind Controlled Trial. AB - BACKGROUND: To test the hypothesis that daily supplementation of zinc has any effect on clinical course of acute diarrhea, i.e. frequency of stool, on stool amount and duration of acute diarrhea. METHODS: In a randomized double blind placebo controlled trial, 117 children aged 6 months to 59 months in a medical college hospital, with acute diarrhea of less than 14 days were assigned by permuted block design 1:1 to receive intervention of zinc supplemented syrup (n = 60) or placebo syrup (n = 57). RESULTS: Baseline characteristics were similar in both the groups. Mean age in zinc supplemented group was 22.14 +/- 16.68 months and in placebo group 25.66 +/- 17.02 months. Reduction in stool frequency per day was found 62% in zinc supplemented group and 26% reduction was found in placebo supplemented group with obvious difference of 36% between these two groups from day 1 to day 3 and day 5, which was found statistically highly significant. Similarly, significant difference was observed for reduction in amount of stool per day from day 1 to day 3 and day 5 with obvious difference of 45% between the study groups. CONCLUSIONS: Oral zinc administration in acute diarrhea reduces the frequency of diarrhea and output of stool by changing the natural course of acute diarrheal disease, causes early normalization of stool consistency, early recovery and decreases total duration of hospital stay. Zinc supplementation is simple, acceptable and affordable strategy which should be considered in management of acute diarrhea. PMID- 27933129 TI - Splenic Perforation Following Colonoscopy. AB - Splenic perforation represents a rare complication of colonoscopy. In our report we have reviewed the experience reported in the world literature, including proposed mechanisms, risk factors for splenic perforation and available management options. We have also discussed our concerns for under reporting. We had a total of 4 cases of splenic perforation following colonoscopies at our centre. One patient had a small splenic laceration repaired; two were observed closely and discharged without intervention. The patient mentioned below required a splenectomy. PMID- 27933130 TI - Serrated Adenoma of Gastric Antrum: Alteration of Mucin Expression Profile and its Role in Carcinogenesis. AB - Serrated adenomas usually occur in colon, the gastric localization is extremely rare. These polyps have their own carcinogenetic pathway with microsatellite instability. In this report, we present a serrated adenoma localized in gastric antrum with four control endoscopies and biopsies. Immunohistochemical panel of MUC1, MUC2, MUC5AC, and MUC6 was applied to the biopsies. Serrated component, MUC 2 expression increased but goblet cells and MUC5AC expression decreased in follow up biopsies. This lesion probably was originated from a stem cell that had the potential of differentiation in gastric and intestinal way. This might result an incomplete metaplasia for both colon and stomach. Such lesions which originate from either colon or gastric mucosa may be precancerous and their carcinogenetic pathway may not represent its original organ. PMID- 27933131 TI - Facing the Challenge of Acute Autoimmune Liver Disease: Report of a Case and Review of the Literature. AB - Autoimmune liver diseases (ALD) comprise two broad categories: those with a hepatic predominance, autoimmune hepatitis (AIH), and those with a predominance of cholestatic features including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). An overlap syndrome (OS) is thought to exist where a patient appears with clinical features of more than one immune-mediated liver disease. Based on one personal observation we report a case of histologically proven OS. The relevant literature is briefly reviewed. A 68-year-old male was admitted in our department with general malaise, anorexia and jaundice. Trans abdominal ultrasonography as well as computerized tomography showed a slightly enlarged liver with mild fatty deposition and the patient was submitted to transcutaneous liver biopsy. Histological features included inflammatory infiltration of intra-hepatic bile ducts with the presence of endoepithelial lymphocytes and plasma cells, degenerative distortions and even focal damage of relevant epithelial cellular structures, periductal fibrosis, portal inflammation, interface hepatitis, ductular proliferation and canalicular cholestasis. It is apparent that exact definitions pertaining the OS are limited and general consensus on the precise determinations of overlap/variant syndromes is warranted in order to enable more accurate future research and establish common guidelines in the management of the condition. PMID- 27933132 TI - The Klippel-Trenauny Weber Syndrome: An Unusual Presentation of Hematochezia and a Review of the Literature. PMID- 27933133 TI - Pre-operative clinical and instrumental factors as antireflux surgery outcome predictors. AB - Gastroesophageal reflux disease (GERD) is nowadays a highly prevalent, chronic condition, with 10% to 30% of Western populations affected by weekly symptoms. Many patients with mild reflux symptoms are treated adequately with lifestyle modifications, dietary changes, and low-dose proton pump inhibitors (PPIs). For those with refractory GERD poorly controlled with daily PPIs, numerous treatment options exist. Fundoplication is currently the most commonly performed antireflux operation for management of GERD. Outcomes described in current literature following laparoscopic fundoplication indicate that it is highly effective for treatment of GERD; early clinical studies demonstrate relief of symptoms in approximately 85%-90% of patients. However it is still unclear which factors, clinical or instrumental, are able to predict a good outcome after surgery. Virtually all demographic, esophagogastric junction anatomic conditions, as well as instrumental (such as presence of esophagitis at endoscopy, or motility patterns determined by esophageal high resolution manometry or reflux patterns determined by means of pH/impedance-pH monitoring) and clinical features (such as typical or atypical symptoms presence) of patients undergoing laparoscopic fundoplication for GERD can be factors associated with symptomatic relief. With this in mind, we sought to review studies that identified the factors that predict outcome after laparoscopic total fundoplication. PMID- 27933134 TI - Pitfalls in histoacryl glue injection therapy for oesophageal, gastric and ectopic varices: A review. AB - Histoacryl glue is used increasingly for the treatment of gastric and ectopic varices, and there is experience in its use for oesophageal varices. It is an effective treatment, yet numerous reports of complications have accumulated. This review of the literature describes the technique, explores circulatory and vascular consideration unique to portal hypertension and categorises the complications into: "Embolisation", "local venous thrombosis", "fistulisation and extravascular injection", "ulceration, erosion and extrusion", and "nidus of infection". A case is then made for standardisation of the technique and the consent process. PMID- 27933135 TI - Impact of laparoscopic surgery training laboratory on surgeon's performance. AB - Minimally invasive surgery has been replacing the open standard technique in several procedures. Similar or even better postoperative outcomes have been described in laparoscopic or robot-assisted procedures when compared to open surgery. Moreover, minimally invasive surgery has been providing less postoperative pain, shorter hospitalization, and thus a faster return to daily activities. However, the learning curve required to obtain laparoscopic expertise has been a barrier in laparoscopic spreading. Laparoscopic surgery training laboratory has been developed to aid surgeons to overcome the challenging learning curve. It may include tutorials, inanimate model skills training (box models and virtual reality simulators), animal laboratory, and operating room observation. Several different laparoscopic courses are available with specific characteristics and goals. Herein, we aim to describe the activities performed in a dry and animal-model training laboratory and to evaluate the impact of different kinds of laparoscopic surgery training courses on surgeon's performance. Several tasks are performed in dry and animal laboratory to reproduce a real surgery. A short period of training can improve laparoscopic surgical skills, although most of times it is not enough to confer laparoscopic expertise for participants. Nevertheless, this short period of training is able to increase the laparoscopic practice of surgeons in their communities. Full laparoscopic training in medical residence or fellowship programs is the best way of stimulating laparoscopic dissemination. PMID- 27933136 TI - Critical analysis of the literature investigating urogenital function preservation following robotic rectal cancer surgery. AB - AIM: To analyses the current literature regarding the urogenital functional outcomes of patients receiving robotic rectal cancer surgery. METHODS: A comprehensive literature search of electronic databases was performed in October 2015. The following search terms were applied: "rectal cancer" or "colorectal cancer" and robot* or "da Vinci" and sexual or urolog* or urinary or erect* or ejaculat* or impot* or incontinence. All original studies examining the urological and/or sexual outcomes of male and/or female patients receiving robotic rectal cancer surgery were included. Reference lists of all retrieved articles were manually searched for further relevant articles. Abstracts were independently searched by two authors. RESULTS: Fifteen original studies fulfilled the inclusion criteria. A total of 1338 patients were included; 818 received robotic, 498 laparoscopic and 22 open rectal cancer surgery. Only 726 (54%) patients had their urogenital function assessed via means of validated functional questionnaires. From the included studies, three found that robotic rectal cancer surgery leads to quicker recovery of male urological function and five of male sexual function as compared to laparoscopic surgery. It is unclear whether robotic surgery offers favourable urogenital outcomes in the long run for males. In female patients only two studies assessed urological and three sexual function independently to that of males. In these studies there was no difference identified between patients receiving robotic and laparoscopic rectal cancer surgery. However, in females the presented evidence was very limited making it impossible to draw any substantial conclusions. CONCLUSION: There seems to be a trend towards earlier recovery of male urogenital function following robotic surgery. To evaluate this further, larger well designed studies are required. PMID- 27933137 TI - Gallstone ileus associated with impaction at Meckel's diverticulum: Case report and literature review. AB - Gallstone ileus due to erosion of one or more gallstones into the gastrointestinal tract is an uncommon cause of small bowel obstruction. The site of impaction is usually distal ileum, and less commonly the jejunum, colon, duodenum, or stomach. We report a rare case of gallstone ileus with impaction at the proximal small bowel and at a Meckel's diverticulum (MD) in a 64-year-old woman managed with laparoscopic converted to open small bowel resections. Patient was discharged home in stable condition and remained asymptomatic at 6-mo follow up. We review the current literature on surgical approaches to MD and gallstone ileus. Diverticulectomy or segmental resection is preferred for complicated MD. For gallstone ileus, simple enterolithotomy or segmental resection are the most the most favored especially in older co-morbid patients due to lower mortality rates and the rarity of recurrent gallstone ileus. In addition, laparoscopy has been increasingly reported as a safe approach to manage gallstone ileus. PMID- 27933138 TI - Treatment options for spontaneous and postoperative sclerosing mesenteritis. AB - Sclerosing mesenteritis is a rare pathology with only a few described cases in the literature. The etiology is unclear; however, several potential triggers, including abdominal surgery and abdominal trauma, have been discussed. The pathology includes a benign acute or chronic inflammatory process affecting the adipose tissue of the mesenterium. Despite it being a rare disease, sclerosing mesenteritis is an important differential diagnosis in patients after abdominal surgery or patients presenting spontaneously with signs of acute inflammation and abdominal pain. We present here three cases with sclerosing mesenteritis. In two cases, sclerosing mesenteritis occurred postoperatively after abdominal surgery. One patient was treated because of abdominal pain and specific radiological signs revealing spontaneous manifestation of sclerosing mesenteritis. So far there are no distinct treatment algorithms, so the patients were treated differently, including steroids, antibiotics and watchful waiting. In addition, we reviewed the current literature on treatment options for this rare disease. PMID- 27933139 TI - The neuromuscular system of Pycnophyes kielensis (Kinorhyncha: Allomalorhagida) investigated by confocal laser scanning microscopy. AB - BACKGROUND: Kinorhynchs are ecdysozoan animals with a phylogenetic position close to priapulids and loriciferans. To understand the nature of segmentation within Kinorhyncha and to infer a probable ancestry of segmentation within the last common ancestor of Ecdysozoa, the musculature and the nervous system of the allomalorhagid kinorhynch Pycnophyes kielensis were investigated by use of immunohistochemistry, confocal laser scanning microscopy, and 3D reconstruction software. RESULTS: The kinorhynch body plan comprises 11 trunk segments. Trunk musculature consists of paired ventral and dorsal longitudinal muscles in segments 1-10 as well as dorsoventral muscles in segments 1-11. Dorsal and ventral longitudinal muscles insert on apodemes of the cuticle inside the animal within each segment. Strands of longitudinal musculature extend over segment borders in segments 1-6. In segments 7-10, the trunk musculature is confined to the segments. Musculature of the digestive system comprises a strong pharyngeal bulb with attached mouth cone muscles as well as pharyngeal bulb protractors and retractors. The musculature of the digestive system shows no sign of segmentation. Judged by the size of the pharyngeal bulb protractors and retractors, the pharyngeal bulb, as well as the introvert, is moved passively by internal pressure caused by concerted action of the dorsoventral muscles. The nervous system comprises a neuropil ring anterior to the pharyngeal bulb. Associated with the neuropil ring are flask-shaped serotonergic somata extending anteriorly and posteriorly. A ventral nerve cord is connected to the neuropil ring and runs toward the anterior until an attachment point in segment 1, and from there toward the posterior with one ganglion in segment 6. CONCLUSIONS: Segmentation within Kinorhyncha likely evolved from an unsegmented ancestor. This conclusion is supported by continuous trunk musculature in the anterior segments 1-6, continuous pharyngeal bulb protractors and retractors throughout the anterior segments, no sign of segmentation within the digestive system, and the absence of ganglia in most segments. The musculature shows evidence of segmentation that fit the definition of an anteroposteriorly repeated body unit only in segments 7-10. PMID- 27933140 TI - Mitigating pharmaceutical waste exposures: policy and program considerations. AB - Pharmaceutical disposal and the environmental fate of medication metabolites directly impacts the public's health in two significant ways: accidental medication ingestion of pharmaceuticals that were not disposed of properly results in inadvertent toxicity; and environmental health consequences of pharmaceuticals that were inappropriately disposed and which contaminate municipal water supply. In reviewing the effectiveness of medication disposal policy globally, it is crucial to not only determine which policies are effective but also to assess why they are effective. By assessing the root causes for a specific policy's effectiveness it can be determined if those successes could be translated to another country with a different health care system, unique culture and divergent policy ecosystem. Any intervention regarding pharmaceutical disposal would require a multifaceted approach beyond raising awareness and coordinating pharmaceutical disposal on a national level. While consumer participation is important, effective primary prevention would also include research on drug development that is designed to biodegrade in the environment as opposed to medications that persist and accumulate in the natural environment even when properly disposed. Countries that lack a nationalized disposal policy should leverage the resources and infrastructure already in place in the national health care system to implement a unified policy to address medication disposal in the short-term. In tandem, efforts should be made to recruit the biotechnology sector in high-tech and academia to develop new technologies in medication design and water filtration to decrease exposures in the long-term. PMID- 27933141 TI - Emergence of serotype K1 Klebsiella pneumoniae ST23 strains co-producing the plasmid-mediated AmpC beta-lactamase DHA-1 and an extended-spectrum beta lactamase in Korea. AB - BACKGROUND: Serotype K1 Klebsiella pneumoniae has emerged as an important community pathogen causing various infections, including liver abscesses. Although serotype K1 K. pneumoniae community isolates have been reported as susceptible to most classes of antimicrobial agents, a few cases of infection caused by extended-spectrum beta-lactamase (ESBL)-producing serotype K1 K. pneumoniae have recently been reported in Asian countries. We identified three ESBL-producing strains of serotype K1 K. pneumoniae and conducted a molecular characterization of their drug resistance. METHODS: Three ESBL-producing serotype K1 K. pneumoniae ST23 strains were identified from strains in the Asian Bacterial Bank. Antimicrobial susceptibility testing was performed using the broth microdilution method, and ESBL production was tested by the double-disk synergy test and a confirmatory test. PCR was performed to detect the genes for plasmid mediated ESBL and AmpC beta-lactamases. RESULTS: All three strains were resistant to cefotaxime, ceftazidime, and piperacillin/tazobactam, and all were determined to be ESBL-producers. No known ESBL genes, including blaSHV, blaTEM, blaCTX-M, blaGES, blaPER, and blaVEB, were detected among the three strains. Of all plasmid mediated AmpC beta-lactamase (PAB) genes, including blaDHA-1, blaCMY, blaFOX, and blaMOX, the blaDHA-1 gene was detected in two of the strains. The PFGE patterns revealed that the two isolates carrying blaDHA-1 were closely related (84% similarity). CONCLUSIONS: No ESBL genes were detected among three ESBL-producing serotype K1 K. pneumoniae ST23 strains. Two strains contained the PAB gene blaDHA 1. The emergence of resistant strains of community-origin serotype K1 K. pneumoniae has important implications for effective treatment and infection control practices. PMID- 27933142 TI - Salidroside reduces tau hyperphosphorylation via up-regulating GSK-3beta phosphorylation in a tau transgenic Drosophila model of Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disease that causes substantial public health care burdens. Intensive efforts have been made to find effective and safe treatment against AD. Salidroside (Sal) is the main effective component of Rhodiola rosea L., which has several pharmacological activities. The objective of this study was to investigate the efficacy of Sal in the treatment of AD transgenic Drosophila and the associated mechanisms. METHODS: We used tau transgenic Drosophila line (TAU) in which tau protein is expressed in the central nervous system and eyes by the Gal4/UAS system. After feeding flies with Sal, the lifespan and locomotor activity were recorded. We further examined the appearance of vacuoles in the mushroom body using immunohistochemistry, and detected the levels of total glycogen synthase kinase 3beta (t-GSK-3beta), phosphorylated GSK-3beta (p-GSK 3beta), t-tau and p-tau in the brain by western blot analysis. RESULTS: Our results showed that the longevity was improved in salidroside-fed Drosophila groups as well as the locomotor activity. We also observed less vacuoles in the mushroom body, upregulated level of p-GSK-3beta and downregulated p-tau following Sal treatment. CONCLUSION: Our data presented the evidence that Sal was capable of reducing the neurodegeneration in tau transgenic Drosophila and inhibiting neuronal loss. The neuroprotective effects of Sal were associated with its up regulation of the p-GSK-3beta and down-regulation of the p-tau. PMID- 27933143 TI - Research and lobbying conflicting on the issue of a front-of-pack nutrition labelling in France. AB - Front-of-pack nutrition labelling has been highlighted as a promising strategy to help consumers making healthier food choices at the point of purchase. In France, a simplified front-of-pack nutrition labelling system was proposed in 2014, the 5 Colour Nutrition Label (5-CNL). It is supported by studies evaluating the various dimensions of the validation of both its underlying classification algorithm and its format. Opposed by agro-industry and retailers, multiples lobbying strategies have been deployed to stop or at least delay the implementation of the 5-CNL. Various alternative nutrition labels were proposed, and a full-scale trial was successfully argued for. This paper retraces the various steps of the opposition between public health and agro-industry lobbies on the topic of front-of-pack nutrition labelling in France. PMID- 27933144 TI - A project to improve the management of patients on warfarin in a primary care setting through the introduction of a POC analysis. AB - When noticed that patients commonly misunderstood their warfarin prescriptions when they were given by telephone. We found that the average TIR (time in range) (the relative time period the patients PT-INR value was in the therapeutic range) for patients decreased, and we noticed that the numbers of incidents increased. We made several interventions over a period of close to three years (2010-2012) to improve the quality of care, increase patients' TIRs, and decrease incidents. The interventions included; taking extra care when speaking to patients about their warfarin prescriptions on the phone and using an express mail delivery system to make sure patients got their letters in time. However, these changes made little difference to the measured results. In 2012, we introduced a point of care analysis. Through these simple actions TIR figures increased from 55 % to 75 80 % and fewer non-conformance reports were filed. Medical incidents, leading to costly hospitalizations, after the introduction of POC (point of care analysis) fell from six to two to three instances a year. The number of patients undergoing treatment and included in the study increased from 200 in 2008 to 250 in 2015. We found that these changes improved the quality of the care given without causing extra work for the staff. Patients were satisfied and the method has spread to other primary care centres. PMID- 27933145 TI - Ensuring timely thromboprophylaxis on a Medical Assessment Unit. AB - The Department of Health has defined hospital acquired venous thromboembolism (VTE) as any VTE event occurring within 90 days of hospital admission or surgery. 1 Hospital acquired thrombosis (HAT) is common during and after hospital admission and is considered a major patient safety issue. Current NICE guideline (CG 92) 2010, recommends that medical patients assessed at risk of VTE should have pharmacological prophylaxis commenced as soon as possible after risk assessment has been completed and continued until the patient is no longer at increased risk of VTE. 2 This quality improvement project was carried out in the medical assessment unit in Derriford Hospital, Plymouth. We aimed to increase appropriate VTE pharmacological prophylaxis to 100% prescribed in 6 hours by the end of May 2016 using the Plan-Do-Study-Act (PDSA) methodology. The primary outcome measure was whether or not enoxaparin was given within 6 hours of admission. Analysis showed that a major contributing factor to the prolonged time interval was lack of awareness of the Trust VTE guidelines which had recently been updated in accordance with NICE recommendations. Baseline measurement demonstrated that 29% of patients had first dose of enoxaparin within the 6-hour target, with a mean delay of 12 hours 22 minutes. With implementation of an education programme and development of a local VTE prevention care pathway to raise awareness of the new guidelines, a significant improvement was achieved with 71% of patients meeting the 6-hour target in PDSA cycle 1 and 83% of patients in PDSA cycle 2. The average time interval also reduced to 5 hours 52 minutes in PDSA cycle 1 and 5 hours 7 minutes in PDSA cycle 2. In conclusion, through utilization of simple change methodology, enoxaparin prescribing practice significantly improved. Potentially this may reduce morbidity (and mortality) associated with HAT together with cost implications of its management. PMID- 27933146 TI - Operationalising the Lean principles in maternity service design using 3P methodology. AB - The last half century has seen significant changes to Maternity services in England. Though rates of maternal and infant mortality have fallen to very low levels, this has been achieved largely through hospital admission. It has been argued that maternity services may have become over-medicalised and service users have expressed a preference for more personalised care. NHS England's national strategy sets out a vision for a modern maternity service that continues to deliver safe care whilst also adopting the principles of personalisation. Therefore, there is a need to develop maternity services that balance safety with personal choice. To address this challenge, a maternity unit in North East England considered improving their service through refurbishment or building new facilities. Using a design process known as the production preparation process (or 3P), the Lean principles of understanding user value, mapping value-streams, creating flow, developing pull processes and continuous improvement were applied to the design of a new maternity department. Multiple stakeholders were engaged in the design through participation in a time-out (3P) workshop in which an innovative pathway and facility for maternity services were co-designed. The team created a hybrid model that they described as "wrap around care" in which the Lean concept of pull was applied to create a service and facility design in which expectant mothers were put at the centre of care with clinicians, skills, equipment and supplies drawn towards them in line with acuity changes as needed. Applying the Lean principles using the 3P method helped stakeholders to create an innovative design in line with the aspirations and objectives of the National Maternity Review. The case provides a practical example of stakeholders applying the Lean principles to maternity services and demonstrates the potential applicability of the Lean 3P approach to design healthcare services in line with policy requirements. PMID- 27933147 TI - Large scale implementation of a medicines reconciliation care bundle in NHS GGC GP practices. AB - Medicines reconciliation (MR) is an essential process for patient safety, promoting safer use of medicines with effective communication at the interface, particularly when patients are admitted and discharged from hospital. Much of the work on MR has been focussed in secondary care, however, the principles are equally important in primary care. The aim of the work was to test the Scottish Patient Safety in Primary Care (SPSP-PC) MR care bundle and consider scale up and spread across all NHS Greater Glasgow and Clyde (NHS GGC) GP practices. Care bundles are a quality improvement tool which can drive improvement by standardising processes to deliver optimum care. Pilot work and testing began with 5 GP practices in 2011 and was spread to over 200 practices by 2015/16. A care bundle compliance process measure was measured monthly, with practices sampling 10 patients per month. Practices could view their run charts in real time and identify which measures resulted in "non-compliance" and PDSA cycles were promoted to test and implement improvements. Data was collated at NHS GGC level with an aim of 95% compliance with the care bundle by March 2016. MR care bundle compliance started at 40% (5 practices reporting) in 2011 with final data in March 2016 demonstrating 92% compliance (192 practices reporting). A sustained "reliability" of 92-93% across >200 practices has been observed since January 2015. In conclusion, the bundle was implemented by 97% of NHS GGC GP practices and resulted in process improvements. PMID- 27933148 TI - Role of peer support workers in improving patient experience in Tower Hamlets Specialist Addiction Unit. AB - The aim of the project was to improve patient experience for people in Tower Hamlets Specialist Addictions Unit in order to increase satisfaction by 25% in 12 months starting in August 2014. The team used the model for improvement as part of ELFT's quality improvement programme to support iterative cycles of testing and learning. This involved support from the Trust's quality improvement team. The theory of change was visualised through a driver diagram. A number of outcomes were measured and plotted over time - patient satisfaction, staff satisfaction, and attendance to peer support groups. The impact of changes was then observed using the plan, do, study, act (PDSA) cycles. The changes that positively influenced the outcomes were continued and ones without such impact were discontinued. The most successful intervention to improve patient satisfaction so far was the introduction of peer support facilitation for the "Breakfast club" - recovery orientated meeting of patients with less emphasis on the medical aspects of treatment. Staff satisfaction is proven to be one of the best determinants of patient experience, so this is also measured and plotted over time together with patient's satisfaction and attendance. Service user satisfaction improves attendance and outcomes in this difficult-to-engage group of patients (people with both substance misuse and mental health problems). Patient perspectives and priorities might be quite different to that of the clinical team, further supporting the importance of involving and engaging them in any quality improvement work. Involving peer support workers in improving engagement of people with substance misuse related problems appears essential. PMID- 27933149 TI - Venous thromboembolism capture on electronic systems in obstetrics patients at St Thomas' Hospital. AB - Venous thromboembolism (VTE) is one of the leading causes of maternal mortality in the UK. Therefore, timely VTE risk assessment is essential in all obstetrics patients. The Commissioning for Quality and Innovation (CQUIN) payment framework set a target for trusts to complete a VTE risk assessment within 24 hours of admission for 95% of patients. A combination of factors, including lack of integration between multiple IT systems, means that this CQUIN target is currently not being met for obstetric patients in the Hospital Birth Centre at Guys and St Thomas' NHS Trust. This project aims to increase staff awareness of this issue and educate them regarding the correct procedure for VTE assessment. Trialled methods included reminders at staff handovers, use of magnets on the patient whiteboard, posters and stickers displayed around the unit and a loyalty card scheme as incentive to complete assessments. Initial average completion rate was 20.7%, which increased to 67.5% after the first plan, do, study, act (PDSA) cycle with a slight drop to 65.7% after the second cycle. Completion rates increased to 92.3% on the last day of the third PDSA cycle. Although we did not reach the 95% target, we have raised awareness of the importance of recording VTE assessment on electronic systems, and hope we have created sustainable change. PMID- 27933150 TI - Implementing mobile devices to reduce non-rostered workload for junior doctors. AB - There is a large body of evidence demonstrating the detrimental effect of long work hours on the performance, mood, and job satisfaction of junior doctors. By extension these effects carry over into the realm of patient safety, compromising the quality of care provision. House officers in the general surgery department of Tauranga Hospital, New Zealand are often required to arrive at work well before their rostered start time of 7.30am to hand write the results of clinical investigations on their patient lists. Baseline measurement demonstrated that each house officer was spending an average of 28 minutes a day of non-rostered time completing this task, increasing to 33 minutes on post-acute days. This quality improvement project trialed the use of a mobile device for accessing clinical results in real-time on surgical ward rounds with the ultimate aim of reducing non-rostered workload by one hour per house officer, per week. A sustainable reduction to a median of 15 minutes non-rostered work per day for each house officer was achieved, translating into 75 minutes less non-rostered work for each house officer every week. Importantly, this result was sustained for more than seven working weeks and spanned a changeover in house officer rotation. Furthermore, the use of the devices was associated with a perceived improvement in the accuracy and timeliness of access to clinical results with no perceived detriment to the speed or flow of the ward round. PMID- 27933151 TI - Improving asthma care in a pediatric resident clinic. AB - There is variation in pediatric asthma management in the outpatient setting. Adherence to national asthma guidelines provides a systematic standardized approach to asthma management. There is a gap between usual and guideline consistent asthma care in resident clinics. Practice improvement modules aimed at improving resident physician adherence to asthma care guidelines have not been consistently utilized and have not yet been studied. Our aim was to increase guideline consistent care in our pediatric resident clinic in a twelve-month period via increasing performance on the following measures to 75%: spirometry testing; influenza immunization recommendation; level of control assessed through the use of a standardized questionnaire; appropriate medications per national guideline; and use of written asthma action plans. A summarized pediatric specific version of the National Heart Lung and Blood Institute National Asthma Education and Prevention Program Expert Panel Report 3 (NHLBI EPR-3) guidelines was made readily available to increase provider education. Electronic health record (EHR) enhancements included adding templates to create standardized asthma action plan, asthma control test and a pediatric asthma controller medication order-set. We also addressed the education of patients by simplifying patient instructions. We monitored our progress through the use of an online practice improvement module. We found statistically significant increases in use of a standardized instrument to determine level of control (20% to 81%); recommendation of influenza immunization (56% to 97%); use of national medication treatment guidelines (28% to 98%); distribution of asthma action plans (29% to 65%); and provision of asthma self-management education (35% to 74%). Standardizing the implementation of national guidelines for pediatric asthma through the use of a practice improvement module and electronic health records improved adherence to guidelines. The module allowed us to identify goals for improvement, collect and analyze our group performance data over time, assess the impact of each change, and redesign our process. Improving adherence to national pediatric asthma care guidelines is especially important in settings such as resident teaching clinics which provide care to underserved populations at higher risk for complications related to asthma. PMID- 27933152 TI - Ensuring availability of in date and fit for purpose emergency guidelines in all anaesthetic areas throughout the South East Scotland deanery. AB - Our aim was to institute a system whereby emergency anaesthetic guidelines are available in >90% of appropriate clinical areas throughout each of the acute hospital sites in three health board administrative regions, and whereby >90% of available guidelines are deemed to be in date and fit for purpose. Our objective was to achieve these targets within 6 months. Using quality improvement methodology, we inventoried available emergency anaesthetic guidelines in 132 locations throughout seven acute care hospitals. Five guidelines were then randomly selected per site per month and assessed for three process markers: was the guideline available in all appropriate areas, was it in-date (i.e. within date of review as specified on guideline or on consultation with author) and was it fit for purpose. Fitness for purpose was assessed by asking a junior colleague to simulate the emergency in a table top exercise using the guideline to aid management. This project was also used as a surveillance system to highlight outdated, unfit or missing guidance. Interventions included iterative revision of the master guideline lists, removal of outdated or unfit guidelines and creation or updating of guideline folders. 30 guidelines were assessed pre-intervention and 203 post-intervention. 52% of guidelines were available in appropriate areas pre-intervention rising to 76% post intervention, 67% of guidelines were in date pre-intervention rising to 82% post-intervention and 87% of guidelines were deemed fit for purpose pre-intervention rising to 92% post-intervention. We have demonstrated that regular review of emergency guidelines to maintain their currency is achievable and also demonstrated the feasibility of recruiting over 20 trainees across a training deanery to complete a QI project. We believe that organisations should maximise the resource of highly motivated trainees to achieve their QI goals. PMID- 27933153 TI - Improving pneumococcal vaccination rates of medical inpatients in urban Nepal using quality improvement measures. AB - Streptococcus pneumoniae infection is associated with high morbidity and mortality in low income countries. In Nepal, there is a high lung disease burden and incidence of pneumonia due to multiple factors including indoor air pollution, dust exposure, recurrent infections, and cigarette smoking. Despite the ready availability of effective pneumococcal vaccines (PNV), vaccine coverage rates remain suboptimal globally. Quality Improvement (QI) principles could be applied to improve compliance, but it is a virtually new technology in Nepal. This QI study for Patan Hospital sought to introduce the concept of QI there, to measure the baseline pneumococcal vaccination rate of qualifying adult patients discharged from the medical wards and to assess reasons for non-vaccination. QI interventions were instituted to improve this rate, measuring the effectiveness of QI methods to produce the desired outcomes using the Model for Improvement, Plan-Do-Study-Change (PDSA) methodology. In the three week baseline assessment, 2 out of 81 (2%) eligible patients recalled ever receiving a prior pneumococcal vaccine; 68 (84%) unvaccinated patients responded that they were not asked or were unaware of the PNV. After the QI interventions, the pneumococcal vaccination rate significantly increased to 42% (23/56, p<0.001). Post-intervention, the leading reason for non-vaccination was cost (20%, 11/56). Only 5 (9%) unvaccinated patients were not asked or were unaware of the PNV, a significant change in that process outcome from baseline (p<0.001). Quality improvement measures were effective in increasing pneumococcal vaccination rates, despite the limited familiarity with QI methods at this major teaching hospital. QI techniques may be useful in this and other efforts to improve quality in resource limited settings, without great cost. PMID- 27933154 TI - Improving diagnosis for congenital cataract by introducing NGS genetic testing. AB - Childhood cataract (CC) has an incidence of 3.5 per 10,000 by age 15 years. Diagnosis of any underlying cause is important to ensure effective and prompt management of multisystem complications, to facilitate accurate genetic counselling and to streamline multidisciplinary care. Next generation sequencing (NGS) has been shown to be effective in providing an underlying diagnosis in 70% of patients with CC in a research setting. This project aimed to integrate NGS testing in CC within six months of presentation and increase the rate of diagnosis. A retrospective case note review was undertaken to define the baseline efficacy of current care in providing a precise diagnosis. Quality improvement methods were used to integrate and optimize NGS testing in clinical care and measure the improvements made. The percentage of children receiving an NGS result within six months increased from 26% to 71% during the project period. The mean time to NGS testing and receiving a report decreased and there was a reduction in variation over the study period. Several patients and families had a change in management or genetic counselling as a direct result of the diagnosis given by the NGS test. The current recommended investigation of patients with bilateral CC is ineffective in identifying a diagnosis. Quality Improvement methods have facilitated successful integration of NGS testing into clinical care, improving time to diagnosis and leading to development of a new care pathway. PMID- 27933155 TI - A quality improvement initiative on the management of osteoporosis in older people with Parkinsonism. AB - The risk of falls is higher in patients with people with Parkinsonism (PwP) compared to those without Parkinsonism, and leads to adverse outcomes including fragility fractures. Osteoporosis is under-recognised, and the prevalence of fragility fractures in not well studied. The primary aim of this project is for 100% of new patient referrals to, and 80% of follow up patients within the movement disorder (MD) service with osteoporosis to be treated in accordance with evidence based osteoporosis guidance. Routinely captured information regarding demographics and fragility fractures was retrospectively extracted from the clinical workstation, clinic letters, and clinical coding between July and November 2015. The prevalence of fragility fracture was 22.6% (68/300), and only 40% (27/68) were on appropriate treatment for osteoporosis. A quality improvement (QI) methodology based on the model of improvement, Plan-Do-Study-Act (PDSA) cycles were used, and a monthly multidisciplinary team (MDT) meeting was introduced. This QI initiative has shown that MDT input can reduce referrals to physiotherapists; and also 100% of new patients, and 91% of follow up patients received evidence based osteoporosis treatment. PMID- 27933156 TI - Improving the accuracy of electronic prescribing in West Bay Health Center in Qatar. AB - Primary healthcare in Qatar uses electronic prescribing to reduce the risk of medication errors. Electronic prescribing is supported by computerized Physician Order Entry systems through Cerner (electronic medical record system). There are still prescription errors, despite electronic prescribing being in place for one year at West Bay Health Center. West Bay Health Center is a famous primary healthcare center in Qatar. It is a training center for the family medicine residency program, which is accredited by the accreditation council of general medical education international (ACGME-I). It serves a population of about 98,000 in Qatar with 35 physicians and 12 pharmacists. The aim of this project was to decrease medication errors by 30% from baseline measurement (according to type of error) from October 2015 to March 2016. It was found that there was a discrepancy between the pharmacy medication list and the list within Cerner. A master drug index was created to eliminate the discrepancy. Training on the use of this index was provided through lectures and one to one education, with material also sent through email. We found that there was some resistance from the physician side and therefore introduced a second intervention. We sent out a survey to find out more about these difficulties and provided more training and education. Our results showed an decrease in the proportion of wrong dose errors from 11.8% to 10.6%, wrong name from 6.9% to 6.2%, wrong duration from 11.7% to 10.3%, and non formulary drug errors from 2.6% to 1.6%. PMID- 27933157 TI - Absconding: reducing failure to return in adult mental health wards. AB - Failing to return from leave from acute psychiatric wards can have a range of negative consequences for patients, relatives and staff. This study used quality improvement methodology to improve the processes around patient leave and time away from the ward. The aim of this study was to improve rates of on-time return from leave by detained and informal patients by 50%. Following a baseline period, four interventions were implemented and refined using PDSA cycles. The main outcome measure was the proportion of periods of leave where the patient returned on time. Late return was defined as failure to return to the ward within 10 minutes of the agreed time. At baseline, the rate for on-time return was 56.0%; this increased to 87.1% post-intervention, a statistically significant increase of 55.5%. SPC charts show that the interventions were associated with improvements. The improvements have been sustained and the interventions are fully embedded into daily practice. The project was refined to local context and trialled on six additional wards: four of the six wards have successfully implemented the interventions and have on-time return rates of over 90%. This project produced a marked and sustained improvement in patients returning on-time from leave, facilitating a more open discussion between staff and patients about the purpose and value of periods away from the ward. Quality improvement approaches can be effectively applied in mental health settings. PMID- 27933158 TI - Development and implementation of a standardized pathway in the Pediatric Intensive Care Unit for children with severe traumatic brain injuries. AB - Severe traumatic brain injury (TBI) is a leading cause of morbidity and mortality in children. In 2003 and 2012, the Brain Trauma Foundation established and refined evidence-based guidelines for management of severe TBI in children. A recent multicenter study demonstrated an association between TBI guideline adherence and improved discharge survival. However, this study also showed large variation in adherence to pediatric TBI management at our level 1 pediatric trauma center, where overall adherence to fourteen pediatric intensive care unit (PICU) TBI clinical indicators was 64%. The aim of this quality improvement project was to increase TBI guideline adherence by implementing a standard care pathway for PICU management of children with severe TBI. A multi-disciplinary approach was utilized to develop the Pediatric Guideline Adherence and Outcomes (PEGASUS) care pathway, and iterative PDCA cycles were performed. Over an 18 month period following pathway implementation, overall PICU clinical guideline adherence rate increased to 80%. PMID- 27933159 TI - Functional brain alterations in anorexia nervosa: a scoping review. AB - BACKGROUND: Neuroimaging allows for the identification of brain abnormalities and alterations that are associated with anorexia nervosa (AN). We performed a scoping review to map out the extent and nature of recent research activity on functional magnetic resonance imaging (fMRI) in individuals diagnosed with, or recovered from, AN (AN-REC). MAIN TEXT: A literature search of PubMed, Psychinfo and Embase was conducted using the search terms "anorexia nervosa" AND "functional magnetic resonance imaging." We included fMRI studies that involved a comparison between individuals with AN or AN-REC and healthy controls published in English language between 2010 and 2015. A total of 49 papers were included, regardless of the experimental stimuli or paradigm. CONCLUSIONS: Findings varied considerably across studies, reflecting methodological differences in study design, such as sample differences and experimental paradigms. Collectively, studies published during the past five years suggest altered activation in regions related to the fronto-striato and the limbic circuits, which are theorized to have an important role in the pathophysiology of AN. PMID- 27933160 TI - Post-sensitization administration of non-digestible oligosaccharides and Bifidobacterium breve M-16V reduces allergic symptoms in mice. AB - To support dietary management of severe cow's milk allergic infants, a synbiotic mixture of non-digestible oligosaccharides and Bifidobacterium breve M-16V (B. breve) was designed from source materials that are completely cow's milk-free. It was investigated whether this specific synbiotic concept can reduce an established food allergic response in a research model for hen's egg allergy. Mice were orally sensitized once a week for 5 weeks to ovalbumin (OVA) using cholera toxin (CT) as an adjuvant. Non-sensitized mice received CT in PBS only. Sensitized mice were fed a control diet or a diet enriched with short-chain- (scFOS) and long-chain fructo-oligosaccharides (lcFOS), B. breve or scFOSlcFOS + B. breve for 3 weeks starting after the last sensitization. Non-sensitized mice received the control diet. Anaphylactic shock symptoms, acute allergic skin responses and serum specific IgE, mMCP-1 and galectin-9 were measured upon OVA challenge. Activated Th2-, Th1-cells and regulatory T-cells were quantified in spleen and mesenteric lymph nodes (MLN) and cytokine profiles were analyzed. Short chain fatty acids (SCFA) were measured in ceacal samples. The acute allergic skin response was reduced in mice fed the scFOSlcFOS + B. breve diet compared to mice fed any of the other diets. A reduction in mast cell degranulation (mMCP-1) and anaphylactic shock symptoms was also observed in these mice. Unstimulated splenocyte cultures produced increased levels of IL10 and IFNg in mice fed the scFOSlcFOS + B. breve diet. Correspondingly, increased percentages of activated Th1 cells were observed in the spleen. Allergen-specific re-stimulation of splenocytes showed a decrease in IL5 production. In summary; post-sensitization administration of scFOSlcFOS + B. breve was effective in reducing allergic symptoms after allergen challenge. These effects coincided with changes in regulatory and effector T-cell subsets and increases in the SCFA propionic acid. These results suggest immune modulatory benefits of dietary intervention with a unique combination of scFOSlcFOS + B. breve in established food allergy. Whether these effects translate to human applications is subject for ongoing clinical studies. PMID- 27933162 TI - Photoexcited State Properties of Carbon Dots from Thermally Induced Functionalization of Carbon Nanoparticles. AB - Carbon dots are small carbon nanoparticles with various surface passivation schemes, in which more effective has been the deliberate chemical functionalization of the nanoparticles for brighter fluorescence emissions, though the synthesis method is more tedious and subject to some limitations in the selection of functionalization molecules. Another more popular synthesis method has been the carbonization of organic species, with the method being more efficient and versatile, but less controllable in the synthesis and for the desired dot structure and performance. In this work, a hybrid approach combining the advantageous characteristics of the two synthesis methods was applied to the preparation of carbon dots with polyethyleneimine (PEI) for surface passivation, where pre-processed and selected small carbon nanoparticles were functionalized with PEI in microwave-induced thermal reactions. The optical absorption and fluorescence emission properties were evaluated, and the results suggested that the carbon dots thus prepared shared the same photoexcited state characteristics with those from the deliberate chemical functionalization, including comparable fluorescence colors and other properties. A further demonstration on the similarity in photoexcited state properties was based on the same visible light activated bactericidal functions of the PEI-carbon dots as those found in carbon dots from the deliberate chemical functionalization. The advantages and potential limitations of the hybrid approach for more controllable yet versatile and efficient syntheses of carbon dots are highlighted and discussed. PMID- 27933161 TI - Parallel reductions of IgE and exhaled nitric oxide after optimized anti inflammatory asthma treatment. AB - Immunoglobulin E (IgE) is crucial for the development of airway inflammation in atopic asthma, and inhibition of IgE using monoclonal antibodies is now part of asthma therapy. However, the impact of ordinary anti-inflammatory treatment on IgE is unclear. The aim of this study was to investigate if optimization of treatment with inhaled corticosteroid (ICS) and leukotriene-receptor antagonist (LTRA) according to symptoms or exhaled nitric oxide (FENO) levels over a one year period affects IgE concentrations. Altogether, 158 relatively well controlled but multi-sensitized asthmatics (age 18-65 years), with ongoing ICS treatment at baseline, were included in this post hoc analysis of data from a randomized, controlled trial on FENO-guided asthma therapy. Asthma control and quality of life (Juniper ACQ and mAQLQ), FENO, and serum IgE were measured at baseline and after one year. Concentrations of IgE antibodies to six common perennial aeroallergens were summed up (perennial IgE). We found that perennial and total IgE decreased by 10.2% and 16.0% (P < .001 both comparisons). This was not related to allergen exposure, whereas the total use of ICS and LTRA during the year correlated with the reduction in perennial IgE (P = .030 and P = .013). The decrease in perennial and total IgE correlated significantly with the reduction in FENO (P < .003 and P < .001), and with improvements in ACQ and mAQLQ scores (P < 0.05, all comparisons). We conclude that one year of optimization of treatment with ICS and LTRA in patients with persistent atopic asthma resulted in significant decreases in total IgE and IgE antibodies; these decreases correlated with a reduction in FENO and improvements in asthma control and quality of life. Thus, IgE is reduced by ordinary asthma controller medications and the effect on IgE seems to be clinically important. PMID- 27933163 TI - Temporal overlap and repeatability of feather corticosterone levels: practical considerations for use as a biomarker. AB - The measurement of corticosterone (CORT) levels in feathers has recently become an appealing tool for the conservation toolbox, potentially providing a non invasive, integrated measure of stress activity throughout the time of feather growth. However, because the mechanism of CORT deposition, storage and stability in feathers is not fully understood, it is unclear how reliable this measure may be, especially when there is an extended interval between growth and feather collection. We compared CORT levels of naturally grown feathers from tree swallows (Tachycineta bicolor) that were moulted and regrown concurrently and therefore expected to have similar CORT levels. Specifically, we compared the same feather from the left and right wing (moulted symmetrically) and different types of feathers (wing, back and tail) expected to have been moulted within the same time period. We found that larger, heavier feathers held more CORT per unit length. In addition, we found a lack of concordance in CORT levels both within the same feather type and between different feather types, even after taking into account differences in feather density. Our results indicate that naturally grown feathers may not consistently provide an indication of stress status. Additionally, conflict in results may arise depending on the feather assayed, and total feather volume may be an important consideration when interpreting feather CORT levels. Future work is necessary to determine explicitly the mechanisms of CORT deposition, the effects of environmental exposure and feather wear on the permanence of the feather CORT signal, and the influence of responses to wild stressors on feather CORT levels, before feather CORT can be implemented effectively as a tool for ecological and conservation applications. PMID- 27933164 TI - Effect of elevated carbon dioxide on shoal familiarity and metabolism in a coral reef fish. AB - Atmospheric CO2 is expected to more than double by the end of the century. The resulting changes in ocean chemistry will affect the behaviour, sensory systems and physiology of a range of fish species. Although a number of past studies have examined effects of CO2 in gregarious fishes, most have assessed individuals in social isolation, which can alter individual behaviour and metabolism in social species. Within social groups, a learned familiarity can develop following a prolonged period of interaction between individuals, with fishes preferentially associating with familiar conspecifics because of benefits such as improved social learning and greater foraging opportunities. However, social recognition occurs through detection of shoal-mate cues; hence, it may be disrupted by near future CO2 conditions. In the present study, we examined the influence of elevated CO2 on shoal familiarity and the metabolic benefits of group living in the gregarious damselfish species the blue-green puller (Chromis viridis). Shoals were acclimated to one of three nominal CO2 treatments: control (450 uatm), mid CO2 (750 uatm) or high-CO2 (1000 uatm). After a 4-7 day acclimation period, familiarity was examined using a choice test, in which individuals were given the choice to associate with familiar shoal-mates or unfamiliar conspecifics. In control conditions, individuals preferentially associated with familiar shoal mates. However, this association was lost in both elevated-CO2 treatments. Elevated CO2 did not impact the calming effect of shoaling on metabolism, as measured using an intermittent-flow respirometry methodology for social species following a 17-20 day acclimation period to CO2 treatment. In all CO2 treatments, individuals exhibited a significantly lower metabolic rate when measured in a shoal vs. alone, highlighting the complexity of shoal dynamics and the processes that influence the benefits of shoaling. PMID- 27933165 TI - Interactions between rates of temperature change and acclimation affect latitudinal patterns of warming tolerance. AB - Critical thermal limits form an increasing component of the estimation of impacts of global change on ectotherms. Whether any consistent patterns exist in the interactive effects of rates of temperature change (or experimental ramping rates) and acclimation on critical thermal limits and warming tolerance (one way of assessing sensitivity to climate change) is, however, far from clear. Here, we examine the interacting effects of ramping rate and acclimation on the critical thermal maxima (CTmax) and minima (CTmin) and warming tolerance of six species of springtails from sub-tropical, temperate and polar regions. We also provide microhabitat temperatures from 26 sites spanning 5 years in order to benchmark environmentally relevant rates of temperature change. Ramping rate has larger effects than acclimation on CTmax, but the converse is true for CTmin. Responses to rate and acclimation effects are more consistent among species for CTmax than for CTmin. In the latter case, interactions among ramping rate and acclimation are typical of polar species, less marked for temperate ones, and reduced in species from the sub-tropics. Ramping rate and acclimation have substantial effects on estimates of warming tolerance, with the former being more marked. At the fastest ramping rates (>1.0 degrees C/min), tropical species have estimated warming tolerances similar to their temperate counterparts, whereas at slow ramping rates (<0.4 degrees C/min) the warming tolerance is much reduced in tropical species. Rates of temperate change in microhabitats relevant to the springtails are typically <0.05 degrees C/min, with rare maxima of 0.3-0.5 degrees C/min depending on the site. These findings emphasize the need to consider the environmental setting and experimental conditions when assessing species' vulnerability to climate change using a warming tolerance approach. PMID- 27933166 TI - Sex-specific ecophysiological responses to environmental fluctuations of free ranging Hermann's tortoises: implication for conservation. AB - Physiological parameters provide indicators to evaluate how organisms respond to conservation actions. For example, individuals translocated during reinforcement programmes may not adapt to their novel host environment and may exhibit elevated chronic levels of stress hormones and/or decreasing body condition. Conversely, successful conservation actions should be associated with a lack of detrimental physiological perturbation. However, physiological references fluctuate over time and are influenced by various factors (e.g. sex, age, reproductive status). It is therefore necessary to determine the range of natural variations of the selected physiological metrics to establish useful baselines. This study focuses on endangered free-ranging Hermann's tortoises (Testudo hermanni hermanni), where conservation actions have been preconized to prevent extinction of French mainland populations. The influence of sex and of environmental factors (site, year and season) on eight physiological parameters (e.g. body condition, corticosterone concentrations) was assessed in 82 individuals from two populations living in different habitats. Daily displacements were monitored by radio-tracking. Most parameters varied between years and seasons and exhibited contrasting sex patterns but with no or limited effect of site. By combining behavioural and physiological traits, this study provides sex-specific seasonal baselines that can be used to monitor the health status of Hermann's tortoises facing environmental threats (e.g. habitat changes) or during conservation actions (e.g. translocation). These results might also assist in selection of the appropriate season for translocation. PMID- 27933167 TI - Arctic grayling (Thymallus arcticus) in saltwater: a response to Blair et al. (2016). AB - Although not well known, Arctic grayling can move through saline waters and are captured regularly in nearshore coastal waters in Arctic Canada and Alaska with salinities up to 18 ppt. We highlight the implications this has for Blair et al. (2016), a paper recently published in Conservation Physiology. PMID- 27933168 TI - Thermal ecological physiology of native and invasive frog species: do invaders perform better? AB - Biological invasions are recognized as an important biotic component of global change that threatens the composition, structure and functioning of ecosystems, resulting in loss of biodiversity and displacement of native species. Although ecological characteristics facilitating the establishment and spread of non native species are widely recognized, little is known about organismal attributes underlying invasion success. In this study, we tested the effect of thermal acclimation on thermal tolerance and locomotor performance in the invasive Xenopus laevis and the Chilean native Calyptocephalella gayi. In particular, the maximal righting performance (MUMAX), optimal temperature (TO), lower (CTmin) and upper critical thermal limits (CTmax), thermal breadth (Tbr) and the area under the performance curve (AUC) were studied after 6 weeks acclimation to 10 and 20 degrees C. We observed higher values of MUmax and AUC in X. laevis in comparison to C. gayi. On the contrary, the invasive species showed lower values of CTmin in comparison to the native one. In contrast, CTmax, TO and Tbr showed no inter specific differences. Moreover, we found that both species have the ability to acclimate their locomotor performance and lower thermal tolerance limit at low temperatures. Our results demonstrate that X. laevis is a better performer than C. gayi. Although there were differences in CTmin, the invasive and native frogs did not differ in their thermal tolerance. Interestingly, in both species the lower and upper critical thermal limits are beyond the minimal and maximal temperatures encountered in nature during the coldest and hottest month, respectively. Overall, our findings suggest that both X. laevis and C. gayi would be resilient to climate warming expectations in Chile. PMID- 27933169 TI - Why is prone positioning so unpopular? AB - Recent studies have shown acute respiratory distress syndrome (ARDS) to be underdiagnosed and inadequately treated, as evidenced by underutilization of low tidal volume ventilation. Despite a proven survival benefit in patients with severe ARDS, studies have also shown underutilization of prone positioning. Many questions persist as to the reasons for prone positioning's unpopularity. Additional studies are required to uncover the causes of this prone positioning underutilization phenomenon. PMID- 27933170 TI - Growth of a progesterone receptor-positive meningioma in a female patient with congenital adrenal hyperplasia. AB - : Meningioma growth has been previously described in patients receiving oestrogen/progestogen therapy. We describe the clinical, radiological, biochemical and pathologic findings in a 45-year-old woman with congenital adrenal hyperplasia secondary to a defect in the 21-hydroxylase enzyme who had chronic poor adherence to glucocorticoid therapy with consequent virilisation. The patient presented with a frontal headache and marked right-sided proptosis. Laboratory findings demonstrated androgen excess with a testosterone of 18.1 nmol/L (0-1.5 nmol) and 17-Hydroxyprogesterone >180 nmol/L (<6.5 nmol/L). CT abdomen was performed as the patient complained of rapid-onset increasing abdominal girth and revealed bilateral large adrenal myelolipomata. MRI brain revealed a large meningioma involving the right sphenoid wing with anterior displacement of the right eye and associated bony destruction. Surgical debulking of the meningioma was performed and histology demonstrated a meningioma, which stained positive for the progesterone receptor. Growth of meningioma has been described in postmenopausal women receiving hormone replacement therapy, in women receiving contraceptive therapy and in transsexual patients undergoing therapy with high-dose oestrogen and progestogens. Progesterone receptor positivity has been described previously in meningiomas. 17-Hydroxyprogesterone is elevated in CAH and has affinity and biological activity at the progesterone receptor. Therefore, we hypothesise that patients who have long-standing increased adrenal androgen precursor concentrations may be at risk of meningioma growth. LEARNING POINTS: Patients with long-standing CAH (particularly if not optimally controlled) may present with other complications, which may be related to long standing elevated androgen or decreased glucocorticoid levels.Chronic poor control of CAH is associated with adrenal myelolipoma and adrenal rest tissue tumours.Meningiomas are sensitive to endocrine stimuli including progesterone, oestrogen and androgens as they express the relevant receptors. PMID- 27933171 TI - Active postoperative acromegaly: sustained remission after discontinuation of somatostatin analogues. AB - : In patients with active acromegaly after pituitary surgery, somatostatin analogues are effective in controlling the disease and can even be curative in some cases. After treatment discontinuation, the likelihood of disease recurrence is high. However, a small subset of patients remains symptom-free after discontinuation, with normalized growth hormone (GH) and insulin-like growth factor (IGF1) levels. The characteristics of patients most likely to achieve sustained remission after treatment discontinuation are not well understood, although limited evidence suggests that sustained remission is more likely in patients with lower GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on an MRI scan and/or in patients who receive long-term treatment. In this report, we describe the case of a 56-year-old female patient treated with lanreotide Autogel for 11 years. Treatment was successfully discontinued, and the patient is currently disease-free on all relevant parameters (clinical, biochemical and tumour status). The successful outcome in this case adds to the small body of literature suggesting that some well-selected patients who receive long-term treatment with somatostatin analogues may achieve sustained remission. LEARNING POINTS: The probability of disease recurrence is high after discontinuation of treatment with somatostatin analogues.Current data indicate that remission after treatment discontinuation may be more likely in patients with low GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on MRI, and/or in patients receiving prolonged treatment.This case report suggests that prolonged treatment with somatostatin analogues can be curative in carefully selected patients. PMID- 27933172 TI - Brown tumor of the jaw after pregnancy and lactation in a MEN1 patient. AB - : Skeletal manifestations of primary hyperparathyroidism (pHPT) include brown tumors (BT), which are osteoclastic focal lesions often localized in the jaws. Brown tumors are a rare manifestation of pHTP in Europe and USA; however, they are frequent in developing countries, probably related to vitamin D deficiency and longer duration and severity of disease. In the majority of cases, the removal of the parathyroid adenoma is enough for the bone to remineralize, but other cases require surgery. Hyperparathyroidism in MEN1 develops early, and is multiglandular and the timing of surgery remains questionable. To our knowledge, there are no reports of BT in MEN 1 patients. We present a 29-year-old woman with MEN 1 who developed a brown tumor of the jaw 24 months after getting pregnant, while breastfeeding. Serum corrected calcium remained under 2.7 during gestation, and at that point reached a maximum of 2.82 mmol/L. Concomitant PTH was 196 pg/mL, vitamin D 13.7 ng/mL and alkaline phosphatase 150 IU/L. Bone mineral density showed osteopenia on spine and femoral neck (both T-scores = -1.6). Total parathyroidectomy was performed within two weeks, with a failed glandular graft autotransplantation, leading to permanent hypoparathyroidism. Two months after removal of parathyroid glands, the jaw tumor did not shrink; thus, finally it was successfully excised. We hypothesize that higher vitamin D and mineral requirements during maternity may have triggered an accelerated bone resorption followed by appearance of the jaw BT. We suggest to treat pHPT before planning a pregnancy in MEN1 women or otherwise supplement with vitamin D, although this approach may precipitate severe hypercalcemia. LEARNING POINTS: Brown tumors of the jaw can develop in MEN 1 patients with primary hyperparathyroidism at a young age (less than 30 years).Pregnancy and lactation might trigger brown tumors by increasing mineral and vitamin D requirements.Early parathyroidectomy is advisable in MEN 1 patients with primary hyperparathyroidism, at least before planning a pregnancy.Standard bone mineral density does not correlate with the risk of appearance of a brown tumor.Removal of parathyroid glands does not always lead to the shrinkage of the brown tumor, and surgical excision may be necessary. PMID- 27933173 TI - A rare case of gestational thyrotoxicosis as a cause of acute myocardial infarction. AB - : Angina pectoris in pregnancy is unusual and Prinzmetal's angina is much rarer. It accounts for 2% of all cases of angina. It is caused by vasospasm, but the mechanism of spasm is unknown but has been linked with hyperthyroidism in some studies. Patients with thyrotoxicosis-induced acute myocardial infarction are unusual and almost all reported cases have been associated with Graves' disease. Human chorionic gonadotropin hormone-induced hyperthyroidism occurs in about 1.4% of pregnant women, mostly when hCG levels are above 70-80 000 IU/L. Gestational transient thyrotoxicosis is transient and generally resolves spontaneously in the latter half of pregnancy, and specific antithyroid treatment is not required. Treatment with calcium channel blockers or nitrates reduces spasm in most of these patients. Overall, the prognosis for hyperthyroidism-associated coronary vasospasm is good. We describe a very rare case of an acute myocardial infarction in a 27-year-old female, at 9 weeks of gestation due to right coronary artery spasm secondary to gestational hyperthyroidism with free thyroxine of 7.7 ng/dL and TSH <0.07 IU/L. LEARNING POINTS: AMI and cardiac arrest due to GTT despite optimal medical therapy is extremely rare.Gestational hyperthyroidism should be considered in pregnant patients presenting with ACS-like symptoms especially in the setting of hyperemesis gravidarum.Our case highlights the need for increased awareness of general medical community that GTT can lead to significant cardiac events. Novel methods of controlling GTT as well as medical interventions like ICD need further study. PMID- 27933174 TI - A case of hepatitis C-associated osteosclerosis: accelerated bone turnover controlled by pulse steroid therapy. AB - : Hepatitis C-associated osteosclerosis (HCAO), a very rare disorder in which an extremely rapid bone turnover occurs and results in osteosclerosis, was acknowledged in 1990s as a new clinical entity with the unique bone disorder and definite link to chronic type C hepatitis, although the pathogenesis still remains unknown. Affected patients suffer from excruciating deep bone pains. We report the 19th case of HCAO with diagnosis confirmed by bone biopsy, and treated initially with a bisphosphonate, next with corticosteroids and finally with direct acting antivirals (DAA: sofosbuvir and ribavirin) for HCV infection. Risedronate, 17.5 mg/day for 38 days, did not improve the patient's symptoms or extremely elevated levels of bone markers, which indicated hyper-bone-formation and coexisting hyper-bone-resorption in the patient. Next, intravenous methylprednisolone pulse therapy followed by high-dose oral administration of prednisolone evidently improved them. DAA therapy initiated after steroid therapy successfully achieved sustained virological response, but no additional therapeutic effect on them was observed. Our results strongly suggested that the underlying immunological alteration is the crucial key to clarify the pathogenesis of HCAO. Bone mineral density of lumbar vertebrae of the patient was increased by 14% in four-month period of observation. Clarification of the mechanisms that develop osteosclerosis in HCAO might lead to a new therapeutic perspective for osteoporosis. LEARNING POINTS: HCAO is an extremely rare bone disorder, which occurs exclusively in patients affected with HCV, of which only 18 cases have been reported since 1992 and pathogenesis still remains unclear.Pathophysiology of HCAO is highly accelerated rates of both bone formation and bone resorption, with higher rate of formation than that of resorption, which occur in general skeletal leading to the diffuse osteosclerosis with severe bone pains.Steroid therapy including intravenous pulse administration in our patient evidently ameliorated his bone pains and reduced elevated values of bone markers. This was the first successful treatment for HCAO among cases reported so far and seemed to propose a key to solve the question for its pathogenesis.The speed of increase in the bone mineral content of the patient was very high, suggesting that clarification of the mechanism(s) might lead to the development of a novel therapy for osteoporosis. PMID- 27933175 TI - Hyperinsulinemic hypoglycemia associated with insulin antibodies caused by exogenous insulin analog. AB - : Insulin antibodies (IA) associated with exogenous insulin administration seldom caused hypoglycemia and had different characteristics from insulin autoantibodies (IAA) found in insulin autoimmune syndrome (IAS), which was first described by Dr Hirata in 1970. The characteristic of IAS is the presence of insulin-binding autoantibodies and related fasting or late postprandial hypoglycemia. Here, we report a patient with type 1 diabetes mellitus under insulin glargine and insulin aspart treatment who developed recurrent spontaneous post-absorptive hyperinsulinemic hypoglycemia with the cause probably being insulin antibodies induced by exogenous injected insulin. Examinations of serial sera disclosed a high titre of insulin antibodies (33%, normal <5%), high insulin concentration (111.9 IU/mL) and undetectable C-peptide when hypoglycemia occurred. An oral glucose tolerance test revealed persistent high serum levels of total insulin and undetectable C-peptide. Image studies of the pancreas were unremarkable, which excluded the diagnosis of insulinoma. The patient does not take any of the medications containing sulfhydryl compounds, which had been reported to cause IAS. After administering oral prednisolone for 3 weeks, hypoglycemic episodes markedly improved, and he was discharged smoothly. LEARNING POINTS: Insulin autoimmune syndrome (IAS) or IAS-like situation should be one of the differential diagnosis in patients with hyperinsulinemic hypoglycemia.Although less reported, insulin antibodies (IA) caused by exogenous insulin analog should be considered as the cause of hypoglycemia.Patients with suspected insulin autoimmune syndrome (IAS) should be screened for drugs related to autoimmunity to endogenous insulin. PMID- 27933176 TI - Pancreatic alpha-cell hyperplasia and hyperglucagonemia due to a glucagon receptor splice mutation. AB - : Glucagon stimulates hepatic glucose production by activating specific glucagon receptors in the liver, which in turn increase hepatic glycogenolysis as well as gluconeogenesis and ureagenesis from amino acids. Conversely, glucagon secretion is regulated by concentrations of glucose and amino acids. Disruption of glucagon signaling in rodents results in grossly elevated circulating glucagon levels but no hypoglycemia. Here, we describe a patient carrying a homozygous G to A substitution in the invariant AG dinucleotide found in a 3' mRNA splice junction of the glucagon receptor gene. Loss of the splice site acceptor consensus sequence results in the deletion of 70 nucleotides encoded by exon 9, which introduces a frame shift and an early termination signal in the receptor mRNA sequence. The mutated receptor neither bound 125I-labeled glucagon nor induced cAMP production upon stimulation with up to 1 uM glucagon. Despite the mutation, the only obvious pathophysiological trait was hyperglucagonemia, hyperaminoacidemia and massive hyperplasia of the pancreatic alpha-cells assessed by histology. Our case supports the notion of a hepato-pancreatic feedback system, which upon disruption leads to hyperglucagonemia and alpha-cell hyperplasia, as well as elevated plasma amino acid levels. Together with the glucagon-induced hypoaminoacidemia in glucagonoma patients, our case supports recent suggestions that amino acids may provide the feedback link between the liver and the pancreatic alpha-cells. LEARNING POINTS: Loss of function of the glucagon receptor may not necessarily lead to the dysregulation of glucose homeostasis.Loss of function of the glucagon receptor causes hyperaminoacidemia, hyperglucagonemia and alpha-cell hyperplasia and sometimes other pancreatic abnormalities.A hepato-pancreatic feedback regulation of the alpha-cells, possibly involving amino acids, may exist in humans. PMID- 27933177 TI - Anaemia and its association with month and blood phenotype in blood donors in Fako division, Cameroon. AB - BACKGROUND: Anaemia is one of the main factors in the deferral (disqualification) of blood donors following haematological screening. There is paucity of data on the prevalence of anaemia in blood donors in Sub-Saharan Africa. This study was undertaken to determine the prevalence of anaemia and its association with month and blood phenotype in blood donors in Fako division of Cameroon. METHODS: Blood donors were recruited between the 1st of January and 31st of December 2014, and their haemoglobin concentration (Hb) was determined using a haemoglobinometer. Anaemia was considered as Hb < 12 g/dl for females and Hb < 13 g/dl for males. The ABO and Rhesus blood groups were determined using standard techniques with monoclonal antibodies and the Coombs' test. The Pearson's chi-square, Pearson's correlation, student T test, ANOVA, univariate and multivariable logistic regression analyses adjusting for gender and age as categorical variable were all performed as part of the statistical analysis. RESULTS: A total of 1896 blood donors predominantly males (91.35%) took part in the study. The mean age of the donors was 32 +/- 7.81 years. On average, donors had donated blood 5.07 +/- 3.54 times in their lifetime. The prevalence of anaemia observed in this study was 31.44% (95% CI: 29.35-33.58). The prevalence of anaemia was higher in females (p <= 0.0001) and in participants of age 20 years and below (p = 0.001). A marginal association was observed between prevalence of anaemia and season (p = 0.051). Furthermore, a significant association was observed between prevalence of anaemia and the blood group AB (p = 0.001). The risk of developing anaemia was higher in females compared to males (OR = 2.7, p < 0.0001). The mean Hb observed in this study was 13.42 +/- 1.65; the mean Hb was not observed to be associated with the month or season adjusting for age and gender. CONCLUSION: This study revealed a high prevalence of anaemia which translates to a high rate of donor deferral as a result of anaemia in the study area. The prevalence of anaemia was observed to be associated with the blood phenotype and the month, but not the season (dry or rainy). Further studies will be needed to ascertain the aetiology and associated factors for anaemia in blood donors in the study area. PMID- 27933178 TI - Assessing medication packaging and labelling appropriateness in Sri Lanka. AB - BACKGROUND: There is substantial evidence of poor dispensing practices with inadequate packaging and labelling of medicines, and limited advice on their usage in low and middle-income countries (LMICs). We examined the labelling and packaging of medicines identified during a survey of 1322 households in six regions of Sri Lanka between 2010 and 2013 conducted using the World Health Organization (WHO) methodology for household surveys. We compared medicines obtained from public and private sources and asked interviewees if they understood how to take the medicines. METHODS: Packaging was considered adequate when the primary package was an envelope or closable container holding only one medicine. Adequate labels were legible and included medicine name, dose and expiration date. Interviewers assessed whether respondents knew how to take the medicines. RESULTS: Of 1322 households, 1253 households (94.8%) had at least one medicine; 84% were classified as western medicines and 16% traditional medicines. Of 5756 western medicines identified, 82.1% were adequately packaged, 43.3% adequately labelled and 41.4% both adequately packaged and labelled. Participants stated that they understood the label and knew how to take 96% of the medicines. Private medicine sources had more adequately packaged medicines than public sources (87.7% vs 73.5%; OR 2.58, 95% CI 2.23, 2.99) and more adequately labelled medicines (52.2% vs 27.4%; OR 2.90, 95% CI 2.57, 3.26). CONCLUSIONS: Inadequate packaging and labelling of medicines remain a concern in Sri Lanka. Commitment to Good Pharmacy Practices, investments in staff education and training and adequate dispensing resources (containers and labels), particularly in the public sector, are needed to address sub-optimal dispensing practices. Ageing populations with more chronic diseases requiring polypharmacy and complex medicine regimens increase the need for appropriately packaged and labelled medicines. PMID- 27933179 TI - Associations between genetics, medical status, physical exercise and psychological well-being in adults with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) is the most common autosomal recessive, life shortening disease among people of European origin. Type of genetic mutation and regular physical exercise has an impact on clinical outcome. This cross-sectional study explores the associations between genetics, medical status, physical exercise and psychological well-being in adult patients with CF. METHODS: Adult patients with CF (N=68; mean age: 32.2; range 18-67 years; 46% women) completed the Cystic Fibrosis Questionnaire-Revised and Hospital Anxiety Depression Scale. Measures about lung function/forced expiratory volume in 1 s per cent predicted, body mass index, physical working capacity, immunoglobulin G, CF Transmembrane Conductance Regulator (CFTR) mutations, and physical exercise were obtained. structural equation modelling was used to fit models to data. RESULTS: A cftr gene mutation*age interaction effect indicates a psychological disadvantage increasing with age of having more severe CFTR mutations; >65% of the effect is mediated by medical status. Physical exercise has a positive effect on psychological well-being, but >75% of the effect is mediated by medical status. CONCLUSIONS: Psychological well-being decreases with age in patients with more severe cftr mutations, to a large extent due to a parallel deterioration of medical status. Physical exercise has a positive effect on psychological well being if resulting in better health only. To manage the complexity of these patients' needs, the CF-care should emphasise a holistic approach and offer individualised exercise/treatment programmes and psychological competence. PMID- 27933180 TI - Serum levels of immunoglobulins and severity of community-acquired pneumonia. AB - INSTRUCTION: There is evidence of a relationship between severity of infection and inflammatory response of the immune system. The objective is to assess serum levels of immunoglobulins and to establish its relationship with severity of community-acquired pneumonia (CAP) and clinical outcome. METHODS: This was an observational and cross-sectional study in which 3 groups of patients diagnosed with CAP were compared: patients treated in the outpatient setting (n=54), patients requiring in-patient care (hospital ward) (n=173), and patients requiring admission to the intensive care unit (ICU) (n=191). RESULTS: Serum total IgG (and IgG subclasses IgG1, IgG2, IgG3, IgG4), IgA and IgM were measured at the first clinical visit. Normal cutpoints were defined as the lowest value obtained in controls (<=680, <=323, <=154, <=10, <=5, <=30 and <=50 mg/dL for total IgG, IgG1, IgG2, IgG3, IgG4, IgM and IgA, respectively). Serum immunoglobulin levels decreased in relation to severity of CAP. Low serum levels of total IgG, IgG1 and IgG2 showed a relationship with ICU admission. Low serum level of total IgG was independently associated with ICU admission (OR=2.45, 95% CI 1.4 to 4.2, p=0.002), adjusted by the CURB-65 severity score and comorbidities (chronic respiratory and heart diseases). Low levels of total IgG, IgG1 and IgG2 were significantly associated with 30-day mortality. CONCLUSIONS: Patients with severe CAP admitted to the ICU showed lower levels of immunoglobulins than non ICU patients and this increased mortality. PMID- 27933181 TI - What are the pros and cons of electronically monitoring inhaler use in asthma? A multistakeholder perspective. AB - INTRODUCTION: Electronic monitoring devices (EMDs) are the optimal method for collecting objective data on inhaler use in asthma. Recent research has investigated the attitudes of patients with asthma towards these devices. However, no research to date has formally considered the opinions of stakeholders and decision-makers in asthma care. These individuals have important clinical requirements that need to be taken into account if EMDs are to be successfully provisioned, making collecting their opinions on the key barriers facing these devices a valuable process. METHODS: Three rounds of surveys in a Delphi format were used to assess the most important pros and cons of EMDs for asthma care in a sample of 31 stakeholders which included healthcare professionals and members of clinical commissioning groups. RESULTS: The respondents identified 29 pros and 32 cons. Pros that were rated as most important included new visual evidence to aid clinical discussions with a patient and an increase in patient involvement and motivation. The cons that were rated as most important included a need for more clinical evidence of the effectiveness of EMDs, as well as better clarity over who has responsibilities in managing, interpreting and discussing data with a patient. CONCLUSIONS: The research provides a guide for EMD developers by highlighting where these devices may provide the most benefit as well as prioritising the key issues that need addressing if they are to be used effectively in everyday asthma care. PMID- 27933182 TI - Angiopoietin-like protein 4 and cardiovascular function in COPD. AB - INTRODUCTION: The coexistence of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) is frequent and might be inter-related through inflammation-related processes reflected by specific markers. Here, we studied angiopoietin-like protein 4 (ANGPTL4), an upcoming cardiovascular marker, in stable COPD, and its relationship to cardiovascular function with respect to well known CVD risk factors. METHODS: In a prospective COPD cohort study, we investigated serum ANGPTL4 levels, vascular status (ankle-brachial index (ABI)) and cardiac function (N-terminal pro-B-type natriuretic peptide (NT-proBNP)) as well as airflow limitation, objectively measured physical activity, the metabolic syndrome, high-sensitive C reactive protein (hs-CRP) and other CVD risk factors at 2 time points. We initially studied 74 stable COPD patients and 18 controls. For internal validation, we additionally studied 160 COPD patients of a former visit. RESULTS: ANGPTL4 was significantly elevated in COPD patients compared with controls (p=0.026). After correction for traditional CVD risk factors, including hs-CRP, higher levels of ANGPTL4 were independently associated with lower ABI (p=0.023) and higher NT-proBNP (p<0.001). These findings were confirmed in the internal validation analysis, which included echocardiographic assessments. CONCLUSIONS: Serum ANGPTL4 is independently associated with cardiovascular function in COPD and might qualify as a biomarker reflecting a pathogenic link between COPD and CVD. PMID- 27933183 TI - Differential eligibility of African American and European American lung cancer cases using LDCT screening guidelines. AB - INTRODUCTION: Lung cancer incidence and mortality is higher among African Americans compared with European Americans in the USA where screening guidelines are currently in place and based on age at diagnosis and smoking history. Given the different smoking patterns observed in these populations and the earlier age at which African Americans are diagnosed, it is possible that African Americans will be disproportionally excluded from screening programmes. METHODS: We assessed the capture of African American and EA lung cancer cases using the National Lung Screening Trial, US Preventive Services Task Force and Centers for Medicare and Medicaid Services eligibility guidelines in a population of lung cancer cases diagnosed between 1998 and 2014 in the Baltimore region of Maryland (n=1658). RESULTS: We found an absolute increase of 3.8% (relative increase: 11.5%) of EA lung cancer cases that fell within the eligible screening guidelines when compared with African Americans. This difference in proportions was not statistically significant (p=0.134). However, differences were more pronounced among women, where an absolute and relative difference of 4.2% and 13.6%, respectively, was observed (p=0.083). As more EA are likely to successfully quit smoking compared with African Americans, the inclusion of the time since quitting variable decreased the relative differences in eligibility. CONCLUSIONS: Current screening guidelines are projected to capture a higher proportion of EA lung cancer cases than African American cases; however, the differences are not statistically significant. Further studies are needed, especially among high-risk populations, to determine if racial differences in eligibility criteria for lung screening will lead to a widening of cancer health disparities. PMID- 27933184 TI - Coxsackie-adenovirus receptor expression is enhanced in pancreas from patients with type 1 diabetes. AB - OBJECTIVES: One of the theories connecting enterovirus (EV) infection of human islets with type 1 diabetes (T1D) is the development of a fertile field in the islets. This implies induction of appropriate proteins for the viral replication such as the coxsackie-adenovirus receptor (CAR). The aim of this study was to investigate to what extent CAR is expressed in human islets of Langerhans, and what conditions that would change the expression. DESIGN: Immunohistochemistry for CAR was performed on paraffin-embedded pancreatic tissue from patients with T1D (n=9 recent onset T1D, n=4 long-standing T1D), islet autoantibody-positive individuals (n=14) and non-diabetic controls (n=24) individuals. The expression of CAR was also examined by reverse transcription PCR on microdissected islets (n=5), exocrine tissue (n=5) and on explanted islets infected with EV or exposed to chemokines produced by EV-infected islet cells. RESULTS: An increased frequency of patients with T1D and autoantibody-positive individuals expressed CAR in the pancreas (p<0.039). CAR staining was detected more frequently in pancreatic islets from patients with T1D and autoantibody-positive subjects (15/27) compared with (6/24) non-diabetic controls (p<0.033). Also in explanted islets cultured in UV-treated culture medium from coxsackievirus B (CBV)-1 infected islets, the expression of the CAR gene was increased compared with controls. Laser microdissection of pancreatic tissue revealed that CAR expression was 10-fold higher in endocrine compared with exocrine cells of the pancreas. CAR was also expressed in explanted islets and the expression level decreased with time in culture. CBV-1 infection of explanted islets clearly decreased the expression of CAR (p<0.05). In contrast, infection with echovirus 6 did not affect the expression of CAR. CONCLUSIONS: CAR is expressed in pancreatic islets of patients with T1D and the expression level of CAR is increased in explanted islets exposed to proinflammatory cytokines/chemokines produced by infected islets. T1D is associated with increased levels of certain chemokines/cytokines in the islets and this might be the mechanism behind the increased expression of CAR in TID islets. PMID- 27933185 TI - Circulating SerpinB1 levels and clinical features in patients with type 2 diabetes. AB - OBJECTIVE: The main purpose of this study was to investigate the association of serum SerpinB1 levels and various parameters in patients with type 2 diabetes. The effect of canagliflozin (a sodium glucose cotransporter 2 (SGLT2) inhibitor), which can decrease circulating insulin levels, on serum SerpinB1 levels was also investigated. A recent study suggests that the serum levels of SerpinB1, also known as monocyte neutrophil elastase inhibitor, increase with insulin resistance, may have a protective effect for pancreatic beta cells, and may decrease insulin resistance. RESEARCH DESIGN AND METHODS: The study included 30 patients with type 2 diabetes hospitalized for glycemic control and 10 control subjects. RESULTS: SerpinB1 levels were significantly higher in patients with type 2 diabetes, compared with that in heathy control subjects (10.01+/-3.59 vs 5.69+/-1.64 ng/mL, p<0.0001). Serum SerpinB1 levels had a significant negative correlation with low-density lipoprotein cholesterol (LDL-C) (p=0.0123). Serum SerpinB1 levels had a significant positive association or trend toward a positive association with age and with hemoglobin A1c (HbA1c), and significant negative association with LDL-C levels in some multiple regression analysis models. Patients treated with statins had a tendency toward higher serum SerpinB1 levels, compared with those patients not treated with statins. During a 3-day observation period both with and without canagliflozin treatment, the serum SerpinB1 levels did not change. CONCLUSIONS: Serum SerpinB1 levels are elevated in patients with type 2 diabetes compared with that in healthy subjects and are negatively correlated with serum LDL-C. PMID- 27933187 TI - Validation of the German Diabetes Risk Score among the general adult population: findings from the German Health Interview and Examination Surveys. AB - OBJECTIVE: To evaluate the German Diabetes Risk Score (GDRS) among the general adult German population for prediction of incident type 2 diabetes and detection of prevalent undiagnosed diabetes. METHODS: The longitudinal sample for prediction of incident diagnosed type 2 diabetes included 3625 persons who participated both in the examination survey in 1997-1999 and the examination survey in 2008-2011. Incident diagnosed type 2 diabetes was defined as first-time physician diagnosis or antidiabetic medication during 5 years of follow-up excluding potential incident type 1 and gestational diabetes. The cross-sectional sample for detection of prevalent undiagnosed diabetes included 6048 participants without diagnosed diabetes of the examination survey in 2008-2011. Prevalent undiagnosed diabetes was defined as glycated haemoglobin >=6.5% (48 mmol/mol). We assessed discrimination as area under the receiver operating characteristic curve (ROC-AUC (95% CI)) and calibration through calibration plots. RESULTS: In longitudinal analyses, 82 subjects with incident diagnosed type 2 diabetes were identified after 5 years of follow-up. For prediction of incident diagnosed diabetes, the GDRS yielded an ROC-AUC of 0.87 (0.83 to 0.90). Calibration plots indicated excellent prediction for low diabetes risk and overestimation for intermediate and high diabetes risk. When considering the entire follow-up period of 11.9 years (ROC-AUC: 0.84 (0.82 to 0.86)) and including incident undiagnosed diabetes (ROC-AUC: 0.81 (0.78 to 0.84)), discrimination decreased somewhat. A previously simplified paper version of the GDRS yielded a similar predictive ability (ROC-AUC: 0.86 (0.82 to 0.89)). In cross-sectional analyses, 128 subjects with undiagnosed diabetes were identified. For detection of prevalent undiagnosed diabetes, the ROC-AUC was 0.84 (0.81 to 0.86). Again, the simplified version yielded a similar result (ROC-AUC: 0.83 (0.80 to 0.86)). CONCLUSIONS: The GDRS might be applied for public health monitoring of diabetes risk in the German adult population. Future research needs to evaluate whether the GDRS is useful to improve diabetes risk awareness and prevention among the general population. PMID- 27933186 TI - Effect of type and amount of dietary carbohydrate on biomarkers of glucose homeostasis and C reactive protein in overweight or obese adults: results from the OmniCarb trial. AB - OBJECTIVE: The glycemic index (GI) of dietary carbohydrate is thought to affect glucose homeostasis. Recently, the Effect of Amount and Type of Dietary Carbohydrates on Risk for Cardiovascular Heart Disease and Diabetes Study (OmniCarb) trial reported that a low-GI diet did not improve insulin sensitivity. We conducted this ancillary study of the OmniCarb trial to determine the effects of GI and carbohydrate content on glucose homeostasis and inflammation. RESEARCH DESIGN AND METHODS: OmniCarb was a randomized cross-over feeding study conducted in overweight or obese adults without diabetes (N=163). Participants were fed each of 4 diets for 5 weeks with 2-week washout periods. Weight was held constant. Diets were: high GI (GI>=65) with high carbohydrate (58% kcal), low GI (GI<=45) with low carbohydrate (40% kcal), low GI with high carbohydrate, and high GI with low carbohydrate. We measured glycated albumin (GA), fructosamine, and high sensitivity C reactive protein (CRP) at baseline and following each dietary period. These biomarkers were compared within-person between diets. RESULTS: The study population was 52% female and 50% black. Mean age was 53 (SD, 11) years; mean body mass index was 32 (SD 6) kg/m2. Reducing GI had no effect on GA or fructosamine, but increased fasting glucose in the setting of a high carbohydrate diet (+2.2 mg/dL; p=0.02). Reducing carbohydrate content decreased GA in the setting of a high-GI diet (-0.2%; p=0.03) and decreased fructosamine in the setting of a low-GI diet (-4 umol/L; p=0.003). Reducing carbohydrate while simultaneously increasing GI significantly reduced both GA (-0.2%; p=0.04) and fructosamine (-4 umol/L; p=0.009). Neither reducing GI nor amount of carbohydrate affected insulin or CRP. CONCLUSIONS: Reducing carbohydrate, regardless of high or low GI, decreased GA and fructosamine. This suggests that reducing carbohydrate content, rather than GI, is a better strategy for lowering glycemia in adults at risk for diabetes. TRIAL REGISTRATION NUMBER: NCT00608049. PMID- 27933188 TI - Quality of care in rural youth with type 1 diabetes: a cross-sectional pilot assessment. AB - BACKGROUND: Type 1 diabetes mellitus (T1DM) presents a significant health burden for patients and families. The quality of care (QOC) among those living in rural communities is thought to be subpar compared with those in urban communities; however, little data exist to reflect this, especially in pediatric diabetes. OBJECTIVE: The purpose of this pilot study was to investigate diabetes QOC among families living in rural versus urban areas. 6 QOC markers were used to compare youth with T1DM: appointment adherence, patient-provider communication, diabetes education during clinic visit, congruency with diabetes standards of care, diabetes self-management behaviors, and diabetes-related hospitalizations. RESEARCH DESIGN AND METHODS: Participants were rural or urban adult caregivers of youth ages 2-18 with >=10-month history of T1DM receiving treatment at Seattle Children's Hospital, USA. Participants were from rural areas of central Washington, or urban areas of western Washington. Caregivers completed a 26-item survey pertaining to the 6 QOC markers. The 6 QOC markers were compared across 61 participants (34 rural, 27 urban), to determine how diabetes care quality and experiences differed. Data were collected over 12 months. Groups were compared using t-tests and chi2 tests, as appropriate. RESULTS: Compared with urban families, rural families reported significantly lower income and a 4-fold greater usage of public insurance. Among the QOC measures, rural participants were significantly worse off in the appointment adherence, patient-provider communication, and hospitalizations categories. Congruence with diabetes standards of care (foot care only) was also significantly poorer in rural participants. CONCLUSIONS: The burden of travel in conjunction with the lack of resources in this rural population of families with T1DM youth is cause for concern and warrants further research. PMID- 27933189 TI - Insulin resistance of protein anabolism accompanies that of glucose metabolism in lean, glucose-tolerant offspring of persons with type 2 diabetes. AB - OBJECTIVE: To test whether protein anabolic resistance is an early defect in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: Seven lean, normoglycemic T2D offspring (T2D-O) and eight matched participants without family history (controls; C) underwent a 3-hour hyperinsulinemic (40 mU/m2/min), euglycemic (5.5 mmol/L) and isoaminoacidemic clamp. Whole-body glucose and protein kinetics were measured with d-[3-3H]glucose and l-[l-13C]leucine, respectively. Plasma amino acids were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Fasting glycemia and glucose kinetic variables did not differ between groups. Clamp decreases in glucose rate of appearance were not different, but rate of disappearance increased 29% less in T2D-O, to a significantly lower rate. Fasting leucine was higher in T2D-O, but kinetics did not differ. Clamp increases in leucine oxidation and decreases in endogenous rate of appearance (protein breakdown) were equal, but in T2D-O, non-oxidative rate of disappearance (protein synthesis) did not increase and net balance (synthesis-breakdown) did not become positive as in C. CONCLUSIONS: Resistance of whole-body protein anabolism (synthesis and net balance) accompanies resistance of glucose uptake in T2D-O. Mechanisms responsible, possible roles in the increased risk of developing diabetes, and its potential impact on long-term protein balance require definition. PMID- 27933190 TI - Canine parvovirus (CPV-2) variants circulating in Nigerian dogs. AB - Canine parvovirus type 2 (CPV-2) is a highly contagious viral disease with three variants (CPV-2a, CPV-2b and CPV-2c) currently circulating in dogs worldwide. The main aim of this study was to determine the prevalent CPV-2 variant in faecal samples from 53 dogs presenting with acute gastroenteritis suspected to be and consistent with CPV-2 to Nigerian Veterinary Clinics in 2013-2014. Seventy-five per cent of these dogs tested positive for CPV-2 in a commercial antigen test and/or by PCR. Partial sequencing of the VP2 gene of six of these demonstrated them to be CPV-2a. Most of the dogs (60 per cent) were vaccinated, with 74 per cent of them puppies less than six months old. PMID- 27933191 TI - Genetics of inherited cardiocutaneous syndromes: a review. AB - The life of a human being originates as a single cell which, under the influence of certain factors, divides sequentially into multiple cells that subsequently become committed to develop and differentiate into the different structures and organs. Alterations occurring early on in the development process may lead to fetal demise in utero. Conversely, abnormalities at later stages may result in structural and/or functional abnormalities of varying severities. The cardiovascular system and skin share certain developmental and structural factors; therefore, it is not surprising to find several inherited syndromes with both cardiac and skin manifestations. Here, we will review the overlapping pathways in the development of the skin and heart, as well as the resulting syndromes. We will also highlight several cutaneous clues that may help physicians screen and uncover cardiac anomalies that may be otherwise hidden and result in sudden cardiac death. PMID- 27933192 TI - Randomised comparison of drug-eluting versus bare-metal stenting in patients with non-ST elevation myocardial infarction. AB - OBJECTIVE: The superiority of drug-eluting stents (DES) over bare-metal stents (BMS) in patients with ST elevation myocardial infarction (STEMI) is well studied; however, randomised data in patients with non-ST elevation myocardial infarction (NSTEMI) are lacking. The objective of this study was to investigate whether stenting with everolimus-eluting stents (EES) safely reduces restenosis in patients with NSTEMI as compared to BMS. METHODS: ELISA-3 patients were asked to participate in the angiographic substudy and were randomised to DE (Xience V) or BM (Vision) stenting (ELISA-3 group). The primary end point was minimal luminal diameter (MLD) at 9-month follow-up angiography. In addition, 296 patients with NSTEMI who were excluded or did not want to participate in the ELISA-3 trial (RELI group) were randomised to DE or BM stenting and underwent clinical follow-up only (major adverse cardiac events (MACE), stent thrombosis (ST)). A pooled analysis was performed to assess an effect on clinical outcome. RESULTS: 178 of 540 ELISA-3 patients participated in the angiographic substudy. MLD at 9 months angiography was 2.37+/-0.63 mm (DES) versus 1.84+/-0.62 mm (BMS), p<0.001. Binary restenosis occurred in 1.9% in the DES group versus 16.7% in the BMS group (RR 0.11, 95% CI 0.02 to 0.84, p=0.007). In the pooled analysis, the incidence of MACE, target vessel revascularisation and ST at 2 years follow-up in the DES versus BMS group was 12.5% versus 16.0% (p=0.28), 4.0% versus 10.4% (p=0.009) and 1.3% versus 3.0% (p=0.34), respectively. CONCLUSIONS: In patients with NSTEMI, use of EES is safe and decreases both angiographic and clinical restenosis as compared to BMS http://www.isrctn.com/search?q=39230163. TRIAL REGISTRATION NUMBER: 39230163; Post-results. PMID- 27933193 TI - Outcomes of ischaemic mitral regurgitation in anterior versus inferior ST elevation myocardial infarction. AB - BACKGROUND: Ischaemic mitral regurgitation (IMR) is a detrimental complication of ST elevation myocardial infarction (STEMI). OBJECTIVE: We sought to determine patient characteristics and outcomes of patients with IMR with focus on anterior or inferior location of STEMI. METHODS: All patients presenting with STEMI complicated by IMR to our centre who underwent primary percutaneous coronary intervention within the first 12 hours of presentation from 1995 to 2014 were included. IMR was graded from 1+ to 4+ within 3 days of index myocardial infarction by echocardiography, divided into 2 groups based on infarct location and outcomes were compared. RESULTS: Overall, 805 patients were included. There were 302 (17.8%) patients with mitral regurgitation (MR) out of the 1700 patients with anterior STEMI while 503 (21.8%) had MR out of the 2305 patients with inferior STEMI. There was no significant difference between both groups in comorbidities, clinical presentation or door-to-balloon time (DBT; median 104 vs 106 min, p=0.5). 30-day and 1-year mortality were higher in anterior STEMI compared with inferior STEMI (14.9% vs 6.8% and 26.4% vs 14.3%, respectively, p<0.001 both), as well as 5-year mortality (39.7% vs 24.8%, p<0.01). When analysis was performed for each grade of IMR, anterior was associated with worse outcomes in every grade. On multivariate cox survival analysis, after adjustment for age, gender, comorbidities, grade of IMR, ejection fraction and DBT, anterior STEMI was still associated with worse outcomes (HR 1.62 (95% CI 1.23 to 2.12), p<0.001). CONCLUSIONS: Although IMR occurs more frequently with inferior infarction, outcomes are worse following anterior infarction. PMID- 27933194 TI - Contribution of the long-term care insurance certificate for predicting 1-year all-cause readmission compared with validated risk scores in elderly patients with heart failure. AB - OBJECTIVES: Readmission is a common and serious problem associated with heart failure (HF). Unfortunately, conventional risk models have limited predictive value for predicting readmission. The recipients of long-term care insurance (LTCI) are frail and have mental and physical impairments. We hypothesised that adjustment of the conventional risk score with an LTCI certificate enables a more accurate appreciation of readmission for HF. METHODS: We investigated 452 patients with HF who were followed up for 1 year to determine all-cause readmission. We obtained their clinical and socioeconomic data, including LTCI. The three clinical risk scores used in our evaluation were Keenan (2008), Krumholz (2000) and Charlson (1994). We used net reclassification improvement (NRI) to assess the incremental benefit. RESULTS: Patients with LTCI were significantly older, and had a higher prevalence of cerebrovascular disease and dementia than those without LTCI. One-year all-cause readmission (n=193, 43%) was significantly associated with all risk scores, receiving LTCI and the category of LTCI. Receiving LTCI was associated with readmission independent of all risk scores (HR, 1.59 to 1.63; all p<0.01). Adding LTCI to all risk scores led to a significantly improved reclassification, which was observed in the subgroup of patients with HF with preserved ejection fraction (>=50%) but not in the subgroup with reduced ejection fraction (<50%). CONCLUSIONS: Possession of an LTCI certificate was independently associated with 1-year all-cause readmission after adjusting for validated clinical risk scores in patients with HF. Adding LTCI status significantly improved the model performance for readmission risk, particularly in patients with HF and preserved ejection fraction. PMID- 27933195 TI - CR1 exon variants are associated with lowered CR1 expression and increased susceptibility to SLE in a Plasmodium falciparum endemic population. AB - BACKGROUND: Complement receptor 1 (CR1) plays an important role in immune complex clearance by opsonisation and possibly protects subjects from development of autoantibodies. Lower CR1 expression has been associated with susceptibility to systemic lupus erythematosus (SLE). In contrast, subjects displaying lower CR1 expression are protected against severe manifestations of falciparum malaria. This study is the first of its kind to investigate the association of CR1 variants with development of SLE in a P. falciparum endemic population from Odisha, India. METHODS: CR1 polymorphisms (intron 27 (A>T), exon 22 (A>G) and exon 33 (G>C)) were typed by PCR and restriction length polymorphism in 297 cases of female patients with SLE and 300 age-matched and sex-matched healthy controls from malaria endemic areas in Odisha, India. CR1 expression on monocytes was quantified by flow cytometry. RESULTS: The homozygous mutants of CR1 exon 22 (GG) and exon 33 (GG) and their minor alleles were associated with susceptibility to SLE. Furthermore, patients with SLE who harboured the GG genotype of the exon 33 polymorphism had a 3.12-fold higher chance of developing lupus nephritis. CR1 exon (22 and 33) variants were associated with lowered CR1 expression on monocytes in patients with SLE and in healthy controls. Patients with lupus nephritis showed significantly diminished CR1 expression than those without renal involvement (p=0.01). CONCLUSIONS: The results of the present study demonstrate that common CR1 exon variants are associated with diminished CR1 expression on monocytes and increased susceptibility to development of SLE and lupus nephritis in a malaria endemic area. PMID- 27933196 TI - Independent association of glucocorticoids with damage accrual in SLE. AB - OBJECTIVES: To determine factors associated with damage accrual in a prospective cohort of patients with SLE. METHODS: Patients with SLE who attended the Lupus Clinic at Monash Health, Australia, between 2007 and 2013 were studied. Clinical variables included disease activity (Systemic Lupus Erythematosus Disease Activity Index-2K, SLEDAI-2K), time-adjusted mean SLEDAI, cumulative glucocorticoid dose and organ damage (Systemic Lupus International Collaborating Clinics Damage Index (SDI)). Multivariate logistic regression analyses were performed to identify factors associated with damage accrual. RESULTS: A total of 162 patients were observed over a median (IQR) 3.6 (2.0-4.7) years. Seventy-five per cent (n=121) of patients received glucocorticoids. Damage accrual was significantly more frequent in glucocorticoid-exposed patients (42% vs 15%, p<0.01). Higher glucocorticoid exposure was independently associated with overall damage accrual after controlling for factors including ethnicity and disease activity and was significant at time-adjusted mean doses above 4.42 mg prednisolone/day; the OR of damage accrual in patients in the highest quartile of cumulative glucocorticoid exposure was over 10. Glucocorticoid exposure was independently associated with damage accrual in glucocorticoid-related and non glucocorticoid related domains of the SDI. CONCLUSIONS: Glucocorticoid use is independently associated with the accrual of damage in SLE, including in non glucocorticoid related domains. PMID- 27933197 TI - Molecular signatures in systemic lupus erythematosus: distinction between disease flare and infection. PMID- 27933198 TI - Interferon (IFN)-lambda is a potential mediator in lupus nephritis. AB - OBJECTIVES: Interferon (IFN)-alpha is thought to be central in the pathogenesis for lupus nephritis (LN) and recent studies also indicate a role for IFNlambda. Little is known about these cytokines in the context of treatment response. We studied levels of IFNalpha and IFNlambda in patients with LN in association with clinical and histological response (HR) to treatment. METHODS: Fifty-six patients with active LN were included. Renal biopsies were performed at baseline and after immunosuppressive therapy. Serum levels of IFNalpha and IFNlambda were analysed at both biopsy occasions and in 163 controls. The biopsies were evaluated according to the International Society of Nephrology/Renal Pathology Society classification. Clinical response was defined according to recent definitions. HR was defined as class I, II or III/IV-C on repeat biopsies. The expression of IFNlambda in renal tissue was assessed by immunohistochemistry. RESULTS: At baseline, serum levels of both IFNalpha and IFNlambda were higher in patients versus controls (p=0.01 and p=0.03, respectively). There was no correlation between IFNalpha and IFNlambda. Overall, IFNalpha decreased after treatment (p=0.003) but IFNlambda remained unchanged. However in patients with HR, IFNlambda decreased (p=0.01). The highest levels of IFNlambda were seen in patients with poor HR. Immunostaining of renal tissue revealed expression of IFNlambda, particularly in crescent formations, inflammatory infiltrates and tubular cells. CONCLUSIONS: The study supports a role for IFNlambda in LN, both in circulation and at a tissue level. Levels of IFNalpha and IFNlambda did not correlate and were affected differently by immunosuppression, indicating that they are differently involved in subgroups of LN. Persistent increased levels of IFNlambda were associated to an unfavourable HR to treatment. PMID- 27933199 TI - Efficacy and tolerability of repository corticotropin injection in patients with persistently active SLE: results of a phase 4, randomised, controlled pilot study. AB - OBJECTIVE: To evaluate the efficacy of a prolonged-release formulation of a porcine adrenocorticotropic hormone analogue (repository corticotropin injection (RCI)) added to standard of care in patients requiring moderate-dose corticosteroids for symptomatic SLE. METHODS: This prospective, randomised, double-blind, phase 4, pilot study (NCT01753401) enrolled 38 patients with persistently active SLE involving skin and/or joints. Enrolled patients received RCI, 40 U daily or 80 U every other day, or volume-matched placebo gel, for 8 weeks, with dose tapering to twice weekly during weeks 5-8. Efficacy endpoints included proportion of responders at week 4 based on a novel composite measure that included resolution of rash or arthritis measured using the hybrid SLE Disease Activity Index (hSLEDAI) without worsening British Isles Lupus Assessment Group (BILAG) scores in other organ systems at week 4 (primary), as well as improvements in total hSLEDAI and BILAG scores and other measures of skin and joint disease activity over the 8-week treatment period. RESULTS: Response, as defined for the primary endpoint, did not differ significantly between the combined placebo and RCI-treated groups at week 4. At week 8, the proportion of responders was higher in RCI-treated patients but did not statistically differ between groups (RCI 40 U (53.8%), RCI 80 U (33.3%), combined placebo (27.3%)). However, RCI treatment was associated with statistically significant improvements in several secondary endpoints, including total hSLEDAI, total BILAG and Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity scores within 8 weeks. Treatment was well tolerated. CONCLUSIONS: Although the primary endpoint was not met in this pilot study, secondary and post hoc analyses suggested that RCI was associated with improvements in SLE disease activity in a select patient population with steroid-dependent persistent disease. TRIAL REGISTRATION NUMBER: NCT01753401; results. PMID- 27933200 TI - Age-specific and sex-specific incidence of systemic lupus erythematosus: an estimate from cross-sectional claims data of 2.3 million people in the German statutory health insurance 2002. AB - OBJECTIVE: To provide an estimate of age-specific incidence rate of physician diagnosed systemic lupus erythematosus (SLE) for German men and women. METHODS: The age-specific and sex-specific prevalence of diagnosed SLE in claims data is used to estimate the incidence in the German male and female population. The claims data set stems from a representative sample of the statutory health insurance in 2002 and comprises 2.3 million people. The statutory health insurance covers >85% of the German population. RESULTS: The estimated incidence rates are 0.9 (95% CI 0.7 to 1.1) per 100 000 person-years for men and 1.9 (95% CI 1.7 to 2.2) per 100 000 person-years for women. The age-specific incidence rate of SLE in the male population has a maximum of 2.2 (95% CI 1.0 to 3.4) per 100 000 person-years at the age of 65-70 years. In women, the incidence is peaking at the rate of 3.6 (95% CI 2.9 to 4.3) cases per 100 000 person-years at the age of 20-25 years, but has a second local maximum (2.6, 95% CI 1.5 to 3.8) at menopausal age. CONCLUSIONS: For the first time, representative data on the incidence of SLE in Germany are provided. The estimated incidence rates of SLE for men and women in Germany are at the lower end of other estimates from comparable European countries. PMID- 27933201 TI - Association between metabolic syndrome and liver histology among NAFLD patients without diabetes. AB - BACKGROUND: Metabolic syndrome (MetS) and obesity are associated with non alcoholic fatty liver disease (NAFLD). The aim of this observational study was to examine the relationship of MetS and a diagnosis of non-alcoholic steatohepatitis (NASH) in patients without diabetes in the NASH Clinical Research Network (CRN). METHODS: Clinical, demographic, histological, laboratory and anthropometric data were collected on 356 adult patients without diabetes with NAFLD. Obesity was defined as body mass index >=30.0. MetS was determined using the National Cholesterol Education Program-Adult Treatment Panel III (NCEP ATPIII) 2001 criteria to include 3 or more of the following: increased waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, hypertension and elevated fasting blood glucose. RESULTS: Most patients were obese (71%) and had MetS (67%). Obesity was more prevalent among patients with MetS (80% vs 52%; p<=0.001). Markers of insulin resistance such as homoeostasis model assessment of insulin resistance (6.5 vs 4.9, p<=0.001) were higher among those with MetS compared with those without MetS. Histologically, patients without MetS had higher hepatocellular (p=0.04) and reticuloendothelial system iron (p=0.04). Patients with MetS were more likely to have severe hepatic steatosis (p=0.04) and chronic portal inflammation (p=0.01). On multiple logistic regression analysis, patients with definite NASH were almost 2.5 times more likely to have MetS than those without definite NASH (OR=2.41, p=0.01). CONCLUSIONS: MetS is common in patients without diabetes with NAFLD and is associated with greater insulin resistance, hepatic steatosis and portal inflammation. While patients without MetS have greater iron overload, patients with MetS may have an increased propensity to have NASH. Therefore, presence of MetS in patients without diabetes with NAFLD may serve as a potential criterion for liver biopsy. TRIAL REGISTRATION NUMBER: NCT00063622; Pre-results. PMID- 27933202 TI - Screening and management of viral hepatitis and hepatocellular carcinoma in Mongolia: results from a survey of Mongolian physicians from all major provinces of Mongolia. AB - BACKGROUND: According to Globocan, Mongolia has the highest worldwide hepatocellular carcinoma (HCC) incidence (78.1/100 000, 3.5* higher than China). AIMS AND METHODS: We conducted an anonymous survey of physicians from major provinces who attended an educational liver symposium, analysing their demography, practice, knowledge, perceptions and proposed solutions. Multivariate logistic regression was used to estimate OR relating demography and practice factors with higher provider knowledge and improvement. RESULTS: Of the 121 attendees, 44-95 (36-79%) responded to each question. Most were female (87%), young (79% age <50), subspecialists (81%), university-affiliated (74%), and practised in urban areas (61%). The mean pretest and post-test scores per physician were 60.4+/-20.4 and 65.6+/-21.3, with no observed significant predictors for baseline knowledge or improvement. Most (>80%) noted that <50% of patients who need hepatitis or HCC screening receive it. The main perceived barriers to screening were inability to pay for tests, lack of guidelines and poor patient awareness. Hepatitis treatment rates were low; 83% treated hepatitis C virus in <10 patients in the past year, and 86% treated hepatitis B virus in <10 patients/month. Treatment barriers were multifactorial, with cost as a principal barrier. Proposed solutions were universal screening policies (46%), removal of financial barriers (28%) and provider education (20%). CONCLUSIONS: Physicians from major regions of Mongolia noted low screening for viral hepatitis, even lower treatment rates, financial barriers and the need for increased educational efforts. We advocate broad-based medical education tailored to local needs and based on needs assessment and outcome measurements. PMID- 27933203 TI - Maternal inflammatory bowel disease and hypospadias in male offspring: a population-based study in Denmark. AB - BACKGROUND: The occurrence of inflammatory bowel disease (IBD) and hypospadias has been concurrently increasing, possibly through shared environmental risk factors such as endocrine disrupting compounds. Also, maternal IBD may disturb the normal development of the fetal reproductive tract. However, whether maternal IBD increases the risk of hypospadias in male offspring is unknown. We compared hypospadias risk in sons of mothers with and without IBD. METHODS: We used Danish nationwide population-based registries to conduct a longitudinal prevalence study including all live-born boys from 1979 through 2009. We computed HRs, as estimates of prevalence ratios (PRs), with 95% CIs for hypospadias, using Cox proportional hazards regression, while adjusting for measured confounding. RESULTS: Among 966 038 live-born boys, 4688 (0.5%) had a mother with a history of IBD diagnosis before the relevant childbirth. Among the boys with maternal IBD, 36 (0.8%) were diagnosed with hypospadias any time after birth, whereas 6112 (0.6%) sons of mothers without IBD diagnosis had hypospadias (adjusted PR: 1.20, (95% CI 0.86 to 1.67). Adjusted PRs for maternal Crohn's disease and ulcerative colitis were 1.38 (95% CI 0.83 to 2.29) and 1.10 (95% CI 0.71 to 1.68), respectively. Analyses defining hypospadias diagnosis recorded <6 months postpartum showed similar results. CONCLUSIONS: We found no convincing evidence of an association between maternal IBD and hypospadias. PMID- 27933205 TI - Dermatomyositis flare on imiquimod therapy highlights a crucial role of aberrant TLR7 signalling. PMID- 27933204 TI - Risk factors for developing colorectal cancer in Japanese patients with ulcerative colitis: a retrospective observational study-CAPITAL (Cohort and Practice for IBD total management in Kyoto-Shiga Links) study I. AB - BACKGROUND AND AIMS: Patients with ulcerative colitis (UC) are at risk for developing colorectal cancer (CRC), despite the development of new therapeutic agents. Stratification of the individual UC-patient's risk would be helpful to validate the risk factors for CRC. The aim of this study was to evaluate the risk factors for the development of CRC in a large cohort of patients with UC. METHODS: Data were obtained from 12 hospitals in the Kyoto-Shiga region during 2003-2013. We performed a retrospective cohort study of 2137 patients with UC. RESULTS: In total, 60 lesions of CRC were detected in 43 (2.0%) of 2137 patients. 30 of the 43 patients were male. The median age was 53 years. The median duration of disease was 13 years, and 67.4% of these patients had a disease duration >10 years. Of the 43 patients, 34 (79.1%) had extensive colitis. Primary sclerosing cholangitis was detected in 2 patients (4.7%). The median corticosteroids (CS) dose was 6.4 g, and 4 patients were treated with a total of more than 10 g of CS. 18 of these patients underwent more than 1 year CS treatment. Of all 60 CRC lesions, 43 (71.7%) were located in the distal colon and 35 (58.3%) were of the superficial type. Moreover, the stage of CRC was stage 0 or I in 55.8% of the 43 patients with CRC. Multivariate analysis suggested that extensive colitis could be a risk factor for the development of advanced CRC in patients with UC. CONCLUSIONS: Our findings indicated that male, extensive colitis, long-term duration of UC and family history of CRC, but not concomitant primary sclerosing cholangitis, are important factors for predicting CRC in Japanese patients with UC. Moreover, long-standing extensive colitis might contribute to the progression of CRC. Further studies are required to establish CRC surveillance in Japanese patients with UC. PMID- 27933206 TI - Improving inflammatory arthritis management through tighter monitoring of patients and the use of innovative electronic tools. AB - Treating to target by monitoring disease activity and adjusting therapy to attain remission or low disease activity has been shown to lead to improved outcomes in chronic rheumatic diseases such as rheumatoid arthritis and spondyloarthritis. Patient-reported outcomes, used in conjunction with clinical measures, add an important perspective of disease activity as perceived by the patient. Several validated PROs are available for inflammatory arthritis, and advances in electronic patient monitoring tools are helping patients with chronic diseases to self-monitor and assess their symptoms and health. Frequent patient monitoring could potentially lead to the early identification of disease flares or adverse events, early intervention for patients who may require treatment adaptation, and possibly reduced appointment frequency for those with stable disease. A literature search was conducted to evaluate the potential role of patient self monitoring and innovative monitoring of tools in optimising disease control in inflammatory arthritis. Experience from the treatment of congestive heart failure, diabetes and hypertension shows improved outcomes with remote electronic self-monitoring by patients. In inflammatory arthritis, electronic self monitoring has been shown to be feasible in patients despite manual disability and to be acceptable to older patients. Patients' self-assessment of disease activity using such methods correlates well with disease activity assessed by rheumatologists. This review also describes several remote monitoring tools that are being developed and used in inflammatory arthritis, offering the potential to improve disease management and reduce pressure on specialists. PMID- 27933208 TI - Detection of antibodies to citrullinated tenascin-C in patients with early synovitis is associated with the development of rheumatoid arthritis. PMID- 27933207 TI - What is the reliability of non-trained investigators in recognising structural MRI lesions of sacroiliac joints in patients with recent inflammatory back pain? Results of the DESIR cohort. AB - OBJECTIVE: The objective of this study was to evaluate the reliability of recognising structural lesions on MRI (erosions, fatty lesions, ankylosis) of the sacroiliac joints (MRI-SIJ) in clinical practice compared to a central reading in patients with a possible recent axial spondyloarthritis (axSpA). METHODS: Patients aged 18-50 years, with recent (<3 years) and chronic (>=3 months) inflammatory back pain, suggestive of axSpA were included in the DEvenir des Spondyloarthrites Indifferenciees Recentes (DESIR) cohort. MRI-SIJ structural lesions were scored by non-trained local readers, and by two trained central readers. Local readers scored each SIJ as normal, doubtful or definite lesions. Central readers scored separately each type of lesion. The central reading (mean of the two central readers' scores) was the external standard. Agreement (kappa) was calculated first between local (3 definitions of a positive MRI-SIJ) and central readings (9 definitions), and then between the two central readers. RESULTS: 664/708 patients with complete available images were included. Agreements between local and central readings were overall 'fair', except when considering at least 2 or 3 fatty lesions and at least 3 erosions and/or fatty lesions where agreement was 'moderate'. Agreement between central readers was similar. MRI-SIJ was positive for 52.6% of patients according to central reading (at least 1 structural lesion) and for 35.4% of patients according to local reading (at least unilateral 'doubtful' or 'definite' structural lesions). CONCLUSIONS: Agreement on a positive structural MRI-SIJ was fair to moderate between local and central readings, as well as between central readers. The reliability improved when fatty lesions were considered. TRIAL REGISTRATION NUMBER: NCTO 164 8907. PMID- 27933209 TI - Prevalence and incidence of gout in southern Sweden from the socioeconomic perspective. AB - OBJECTIVES: To estimate the prevalence and cumulative incidence of gout in southern Sweden with respect to socioeconomic status. METHODS: Among residents of Skane region in the year 2013 (total population 1.3 million), adult persons (age 18 years +) who between 1998 and 2013 received a diagnosis of gout (International Classification of Disease 10th Edition (ICD-10) code M10) by any physician were identified using the Skane Healthcare Register. We calculated the point prevalence by end of 2013 and annual cumulative incidence in 2013 standardised to the whole Skane population according to sex, individual information on occupation (white collar/blue collar), income (low/middle/high) and level of education (primary school/high school/university). RESULTS: The crude 2013 point prevalence of gout and 2013 cumulative incidence (95% CI) were 1.69% (1.66% to 1.71%) and 24 cases per 10 000 persons (23-25), respectively. Compared to women, men had higher point prevalence (2.44% (2.40% to 2.49%) vs 0.96% (0.93% to 0.98%)) and higher annual cumulative incidence (33 cases per 10 000 (32-35)) versus 15 (14-16)). These figures increased with higher age but decreased with higher level of education, being the lowest in individuals with a university degree. Persons with middle income had highest point prevalence and cumulative incidence of gout, while those with white collar occupations had the lowest. CONCLUSIONS: Gout is the most common inflammatory arthritis in southern Sweden with a prevalence of ~1.7% in the adult population. There is a socioeconomic gradient with more gout present in the lower level of education and with more manual labour. PMID- 27933210 TI - Educational needs of health professionals working in rheumatology in Europe. AB - OBJECTIVE: To explore the availability of postgraduate education for health professionals (HPs) working in rheumatology in Europe, and their perceived educational needs and barriers for participation in current educational offerings. METHODS: Structured interviews were conducted with national representatives of rheumatology HPs' organisations and an online survey among individual HPs was disseminated through existing European League Against Rheumatism (EULAR) networks (10 languages including English). These comprised questions on: availability of postgraduate education, familiarity with EULAR and its educational offerings, unmet needs regarding the contents and mode of delivery and potential barriers to participate in education (0-10 scales). RESULTS: According to 17 national representatives, postgraduate rheumatology education was most common for nurses, physical and occupational therapists. There were 1041 individuals responding to the survey, of whom 48% completed all questions. More than half (56%) were familiar with EULAR as an organisation, whereas <25% had attended the EULAR congress or were familiar with EULAR online courses. Educational needs regarding contents were highest for 'inflammatory arthritis' and 'connective tissue diseases' and regarding modes of delivery for 'courses organised in own country' and 'online courses'. Important barriers to participation included lack of 'resources', 'time' and 'English language skills'. Overall, there was considerable variation in needs and barriers among countries. CONCLUSIONS: There is a lack of postgraduate rheumatology education for HPs in most countries. There are opportunities to raise awareness regarding EULAR educational offerings and to develop courses provided in HPs' own country, tailored to national needs and barriers and taking language barriers into consideration. PMID- 27933211 TI - Systematic review and quality analysis of emerging diagnostic measures for calcium pyrophosphate crystal deposition disease. AB - OBJECTIVES: Calcium pyrophosphate crystal deposition disease (CPPD) is common, yet prevalence and overall clinical impact remain unclear. Sensitivity and specificity of CPPD reference standards (conventional crystal analysis (CCA) and radiography (CR)) were meta-analysed by EULAR (published 2011). Since then, new diagnostic modalities are emerging. Hence, we updated 2009-2016 literature findings by systematic review and evidence grading, and assessed unmet needs. METHODS: We performed systematic search of full papers (PubMed, Scopus/EMBASE, Cochrane 2009-2016 databases). Search terms included CPPD, chondrocalcinosis, pseudogout, ultrasound, MRI, dual energy CT (DECT). Paper selection, data abstraction, EULAR evidence level, and Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 bias and applicability grading were performed independently by 3 authors. RESULTS: We included 26 of 111 eligible papers, which showed emergence in CPPD diagnosis of ultrasound (U/S), and to lesser degree, DECT and Raman spectroscopy. U/S detected CPPD crystals in peripheral joints with sensitivity >80%, superior to CR. However, most study designs, though analytical, yielded low EULAR evidence level. DECT was marginally explored for CPPD, compared with 35 published DECT studies in gout. QUADAS-2 grading indicated strong applicability of U/S, DECT and Raman spectroscopy, but high study bias risk (in ~30% of papers) due to non-controlled designs, and non-randomised subject selection. CONCLUSIONS: Though CCA and CR remain reference standards for CPPD diagnosis, U/S, DECT and Raman spectroscopy are emerging U/S sensitivity appears to be superior to CR. We identified major unmet needs, including for randomised, blinded, controlled studies of CPPD diagnostic performance and rigorous analyses of 4 T MRI and other emerging modalities. PMID- 27933212 TI - Spontaneous destructive periodontitis and skeletal bone damage in transgenic mice carrying a human shared epitope-coding HLA-DRB1 allele. AB - OBJECTIVE: Shared epitope (SE)-coding DRB1 alleles are associated with bone erosion in several diseases, including rheumatoid arthritis (RA) and periodontal disease (PD), but the underlying mechanism is unknown. We have recently identified the SE as an osteoclast-activating ligand. To better understand the biological effects of the SE in vivo, here we sought to determine whether it can facilitate spontaneous bone damage in naive mice. METHODS: 3-month old naive transgenic mice that carry the human SE-coding allele DRB1*04:01, or a SE negative allele DRB1*04:02 were studied. Bone tissues were analysed by micro-CT, and the tooth-supporting tissues were studied by histology, immunohistochemistry and immunofluorescence. Serum biomarkers were determined by ELISA. RESULTS: Transgenic mice expressing the SE-coding DRB1*04:01 allele, but not mice carrying the SE-negative allele DRB1*04:02, showed spontaneous PD associated with interleukin (IL)-17 overabundance and periostin disruption. Mandibular bone volumetric and mineralisation parameters were significantly lower in SE-positive mice, and alveolar bone resorption was significantly increased in these mice. SE positive mice also had more slender tibiae, and their marrow, cortical and total areas were lower than those of SE-negative mice. Additionally, significantly increased serum IL-17, tumour necrosis factor-alpha and osteoprotegrin levels were found in SE-positive mice, while their receptor activator of nuclear factor kappa-B ligand levels were significantly lower. CONCLUSIONS: A human SE-coding allele increases the propensity to spontaneous bone-destructive periodontal inflammation and skeletal bone damage in transgenic mice. These findings provide new insights into the previously documented but poorly understood association of the SE with accelerated bone erosion in RA and several other human diseases. PMID- 27933213 TI - Molecular pathology of cancer: how to communicate with disease. AB - : Recent technical advances have brought insights into the biology of cancer in human, establishing it as a disease driven by genetic mutations. Beside inherited family tumour syndromes caused by germline mutations, somatic genetic alterations occur early in tumourigenesis, which accumulate during the progression of the disease and its treatment. Based on these observations, medical oncology has started to enter an era of stratified medicine, where treatment selection is becoming tailored to drugable molecular pathways. As a pre-requisite of an individualised treatment concept, molecular and genetic characterisation of the individual tumour has to be performed to align the most appropriate therapies according to the patient's disease. Reading the individual molecular tumour profile and responding by a tailored treatment concept is the 'communication' required to fight this deadly disease. This way to communicate is currently changing the field of oncology dramatically, and fundamentally involves the discipline of molecular pathology. This review highlights the role of genetic characterisation of human malignancies by giving an overview on the basic methods of molecular pathology, the challenge of the instable tumour genome and its clinical consequences. TRIAL REGISTRATION NUMBER: EK1541/2012. PMID- 27933215 TI - Quality to rely on: meeting report of the 5th Meeting of External Quality Assessment, Naples 2016. PMID- 27933216 TI - CSCO joins ESMO Open-Cancer Horizons. PMID- 27933214 TI - Integrating next-generation sequencing into clinical oncology: strategies, promises and pitfalls. AB - We live in an era of genomic medicine. The past five years brought about many significant achievements in the field of cancer genetics, driven by rapidly evolving technologies and plummeting costs of next-generation sequencing (NGS). The official completion of the Cancer Genome Project in 2014 led many to envision the clinical implementation of cancer genomic data as the next logical step in cancer therapy. Stemming from this vision, the term 'precision oncology' was coined to illustrate the novelty of this individualised approach. The basic assumption of precision oncology is that molecular markers detected by NGS will predict response to targeted therapies independently from tumour histology. However, along with a ubiquitous availability of NGS, the complexity and heterogeneity at the individual patient level had to be acknowledged. Not only does the latter present challenges to clinical decision-making based on sequencing data, it is also an obstacle to the rational design of clinical trials. Novel tissue-agnostic trial designs were quickly developed to overcome these challenges. Results from some of these trials have recently demonstrated the feasibility and efficacy of this approach. On the other hand, there is an increasing amount of whole-exome and whole-genome NGS data which allows us to assess ever smaller differences between individual patients with cancer. In this review, we highlight different tumour sequencing strategies currently used for precision oncology, describe their individual strengths and weaknesses, and emphasise their feasibility in different clinical settings. Further, we evaluate the possibility of NGS implementation in current and future clinical trials, and point to the significance of NGS for translational research. PMID- 27933217 TI - Poly(isoprenecarboxylates) from Glucose via Anhydromevalonolactone. AB - A short and efficient synthesis of a series of isoprenecarboxylic acid esters (ICAEs) and their corresponding polymers is presented. The base-catalyzed eliminative ring-opening of anhydromevalonolactone (3) provides isoprenecarboxylic acid (6-H), which was further transformed to the ICAEs. Reversible addition-fragmentation chain-transfer (RAFT) polymerization was used to synthesize high molecular weight (>100 kg mol-1) poly(isoprenecarboxylates) with dispersities (D) of ca. 1.5. The glass transition temperatures (Tg) and entanglement molecular weights (Me) of the poly(isoprenecarboxylates) were determined and showed similar trends to the Tg and Me values for analogous poly(acrylate esters). These new glucose-derived materials could provide a sustainable alternative to poly(acrylates). PMID- 27933218 TI - Erratum. AB - [This corrects the article on p. 6 in vol. 5.]. PMID- 27933219 TI - Erratum. AB - [This corrects the article on p. 6 in vol. 5.]. PMID- 27933220 TI - A Novel Method for Quantitative Serial Autofluorescence Analysis in Retinitis Pigmentosa Using Image Characteristics. AB - PURPOSE: Identifying potential biomarkers for disease progression in retinitis pigmentosa (RP) is highly relevant now that gene therapy and other treatments are in clinical trial. Here we report a novel technique for analysis of short wavelength autofluorescence (AF) imaging to quantify defined regions of AF in RP patients. METHODS: Fifty-five-degree AF images were acquired from 12 participants with RP over a 12-month period. Of these, five were identified as having a hyperfluorescent annulus. A standard Cartesian coordinate system was superimposed on images with the fovea as the origin and eight bisecting lines traversing the center at 45 degrees to each other. Spatial extraction software was programmed to highlight pixels corresponding to varying degrees of percentile fluorescence such that the parafoveal AF ring was mapped. Distance between the fovea and midpoint of the AF ring was measured. Percentage of low luminance areas was utilized as a measure of atrophy. RESULTS: The hyperfluorescent ring was most accurately mapped using the 70th percentile of fluorescence. Both the AF ring and peripheral hypofluorescence showed robust repeatability at all time points noted (P = 0.93). CONCLUSIONS: Both a hypofluorescent ring and retinal pigment epithelium atrophy were present on a significant proportion of RP patients and were consistently mapped over a 12-month period. There is potential extrapolation of this methodology to wide-field imaging as well as other retinal dystrophies. This anatomical change may provide a useful anatomical biomarker for assessing treatment end points in RP. TRANSLATIONAL RELEVANCE: Spatial extraction software can be a valuable tool in the assessment of ophthalmic imaging data. PMID- 27933221 TI - Evaluating the Biostability of Yellow and Clear Intraocular Lenses with a System Simulating Natural Intraocular Environment. AB - PURPOSE: Blue light-filtering intraocular lenses (IOLs) are thought to protect the retina from blue light damage after cataract surgery, and the implantation of yellow-tinted IOLs has been commonly used in cataract surgery. To our knowledge, this is the first investigation measuring the long-term biostability of yellow tinted IOLs using an in vitro system simulating natural intraocular environment. METHODS: Six hydrophobic acrylic IOLs, three clear IOLs, and three yellow-tinted IOLs were included in the study. Each yellow-tinted IOL was a matching counterpart of a clear IOL, with the only difference being the lens color. The IOLs were kept in conditions replicating the intraocular environment using a perfusion culture system for 7 months. Resolution, light transmittance rate, and the modulation transfer function (MTF) were measured before and after culturing. Surface roughness of the anterior and posterior surfaces was also measured. RESULTS: After culturing for 7 months, there were no changes in the resolution, the light transmittance rate, and MTF. The surface roughness of the anterior and posterior surfaces increased after culturing; however, this increase was clinically insignificant. There were no differences in surface roughness between the clear and yellow-tinted IOLs, either before or after culturing. CONCLUSIONS: A novel in vitro system replicating intraocular environment was used to investigate the biostability of yellow-tinted IOLs. The surface roughness showed no clinically significant increase after culturing for 7 months. TRANSLATIONAL RELEVANCE: This system is useful for evaluating the biostability of IOLs. PMID- 27933222 TI - Endophthalmitis Prophylaxis Using a Single Drop of Thermoresponsive Controlled Release Microspheres Loaded with Moxifloxacin in a Rabbit Model. AB - PURPOSE: Postsurgical endophthalmitis is a sight-threatening problem. We introduce a simple approach by using a single application of thermoresponsive controlled-release microspheres, loaded with moxifloxacin, to prevent bacterial endophthalmitis in a rabbit endophthalmitis prevention model. METHODS: We separated 24 rabbits into 3 treatment groups in which topical drop treatment was placed onto the conjunctival cul-de-sac: (1) a single drop of controlled-release microspheres containing moxifloxacin, (2) a single drop of controlled-release microspheres without moxifloxacin, and (3) multiple topical treatment with moxifloxacin alone every 15 minutes for 1 hour. All rabbits were challenged, 1 hour after microspheres drop placement and immediately after the fifth topical dose of moxifloxacin, with anterior chamber injections of Staphylococcus aureus. Rabbits in the topical moxifloxacin group also were treated after challenge and four additional times over the next 24 hours. After 24 hours, the rabbits were clinically evaluated for endophthalmitis and the animals were euthanized to culture for intraocular S. aureus. The treatment groups were compared statistically for bacterial endophthalmitis. RESULTS: No eyes had endophthalmitis, based on clinical presentation and/or positive culture, in the groups with controlled-release microspheres loaded with moxifloxacin (0/8, 0%) or multiple drops of topical moxifloxacin (0/8, 0%). In contrast, 8 of 8 eyes (100%; P = 0.0001), had endophthalmitis among eyes treated with controlled-release microspheres drops without moxifloxacin. CONCLUSION: A single drop of controlled release microspheres loaded with moxifloxacin was successful in preventing endophthalmitis. Further clinical studies will be required to confirm the full potential of controlled-release anti-infective loaded microspheres to prevent endophthalmitis. TRANSLATIONAL RELEVANCE: This study presents a simple method of prophylaxis to prevent postsurgical endophthalmitis. PMID- 27933223 TI - Epigenetic Editing: On the Verge of Reprogramming Gene Expression at Will. AB - Genome targeting has quickly developed as one of the most promising fields in science. By using programmable DNA-binding platforms and nucleases, scientists are now able to accurately edit the genome. These DNA-binding tools have recently also been applied to engineer the epigenome for gene expression modulation. Such epigenetic editing constructs have firmly demonstrated the causal role of epigenetics in instructing gene expression. Another focus of epigenome engineering is to understand the order of events of chromatin remodeling in gene expression regulation. Groundbreaking approaches in this field are beginning to yield novel insights into the function of individual chromatin marks in the context of maintaining cellular phenotype and regulating transient gene expression changes. This review focuses on recent advances in the field of epigenetic editing and highlights its promise for sustained gene expression reprogramming. PMID- 27933224 TI - 2-Diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one: Another Utility for Electrophilic Trifluoromethylthiolation Reactions. AB - 2-Diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one (diazo-triflone) (2) is not only a building block but also a reagent. In this study, diazo-triflone, which was originally used for the synthesis of beta-lactam triflones as a trifluoromethanesulfonyl (SO2CF3) building block under catalyst-free thermal conditions, is redisclosed as an effective electrophilic trifluoromethylthiolation reagent under copper catalysis. A broad set of enamines, indoles, beta-keto esters, pyrroles, and anilines were nicely transformed into corresponding trifluoromethylthio (SCF3) compounds in good to high yields by diazo-triflone under copper catalysis via an electrophilic-type reaction. A coupling-type trifluoromethylthiolation reaction of aryl iodides was also realized by diazo-triflone in acceptable yields. PMID- 27933225 TI - Rational Design of Dual Active Sites in a Single Protein Scaffold: A Case Study of Heme Protein in Myoglobin. AB - Rational protein design has been proven to be a powerful tool for creating functional artificial proteins. Although many artificial metalloproteins with a single active site have been successfully created, those with dual active sites in a single protein scaffold are still relatively rare. In this study, we rationally designed dual active sites in a single heme protein scaffold, myoglobin (Mb), by retaining the native heme site and creating a copper-binding site remotely through a single mutation of Arg118 to His or Met. Isothermal titration calorimetry (ITC) and electron paramagnetic resonance (EPR) studies confirmed that a copper-binding site of [3-His] or [2-His-1-Met] motif was successfully created in the single mutant of R118H Mb and R118M Mb, respectively. UV/Vis kinetic spectroscopy and EPR studies further revealed that both the heme site and the designed copper site exhibited nitrite reductase activity. This study presents a new example for rational protein design with multiple active sites in a single protein scaffold, which also lays the groundwork for further investigation of the structure and function relationship of heme/non-heme proteins. PMID- 27933226 TI - Opposite Anisotropy Effects of Singlet and Triplet Exciton Diffusion in Tetracene Crystal. AB - We observe the diffusion anisotropy difference between singlet and triplet excitons in organic crystals; that is, singlet and triplet excitons may have completely different spatial direction preference for diffusion. This phenomenon can be ascribed to the distinct dependence of different excitonic couplings (Coulomb Forster vs. exchange Dexter) existing in singlet and triplet excitons on their intermolecular distance and intermolecular orientation. Such a discovery provides insights for understanding the fundamental photophysical process in a vast range of organic condensed-phase systems and optimizing the efficiency of organic optoelectronic materials. PMID- 27933227 TI - Extending the Study of the 6,8 Rearrangement in Flavylium Compounds to Higher pH Values: Interconversion between 6-Bromo and 8-Bromo-apigeninidin. AB - The rearrangement between isomers 6- and 8-bromo-apigeninidin (6 and 8) was studied by pH jumps using stopped flow, UV/Vis, NMR, and HPLC analysis. The system constitutes a pH-dependent network of chemical reactions involving up to 18 different species. The dynamic network is equivalent to a single diprotic acid exhibiting two pKas, 2.55 and 5.4. Similar to other flavylium derivatives, the mole fraction of the species hemiketal and cis-chalcone in both multistate isomers are negligible at the equilibrium. At pH 1, the pure isomers are slowly converted in a mixture containing about 50 % of isomers 6 and 8, while at pH 4, the system evolves to mixture of 10 % trans-chalcone and 90 % of quinoidal bases. A series of pH jumps from pure isomer 6 at pH 1 to pH 6 and back to pH 1 leads to the same initial absorption spectra of the pure isomer 6. The same occurs for pure isomer 8, showing the lack of communication between the cis-chalcones, at least in the time scale of few minutes. A pH jump from the equilibrated mixture of the isomers at pH 1.0 to 5.8 permits to follow a very slow isomerization. PMID- 27933228 TI - WHO/INRUD prescribing indicators and prescribing trends of antibiotics in the Accident and Emergency Department of Bahawal Victoria Hospital, Pakistan. AB - A descriptive, retrospective and cross sectional study was conducted to assess the prescribing practices and antibiotic use patterns in the Accident and Emergency department of the Bahawal Victoria Hospital, Bahawalpur, Pakistan. A sample of 4320 prescriptions (systematic random sampling) was drawn out of a total of 1,080,000 prescriptions written during the period 1st January-31st December 2014. The standard World Health Organization/International Network for Rational Use of Drugs prescribing indicators were used to determine the prescribing practices of physicians. Published ideal standards for each of the indicators were used to identify irrational drug use. We also utilized an additional indicator to report the percentage share of antibiotics prescribed. The average number of drugs prescribed per encounter was 2.3 (SD = 1.3) (optimal value 1.6-1.8). Drugs prescribed by generic name occurred 83.1% of the time (optimal value 100%). Antibiotics and injections were prescribed 52.4% (optimal value 20.0-26.8%) and 98.0% (optimal value 13.4-24.1%) of the time respectively. Drugs prescribed from the Essential Drugs List equated to 81.5% (optimal value 100%). Out of 52.4% (n = 2262) prescriptions with antibiotics prescribed, 77.7% (n = 1758) had one antibiotic, 22.1% (n = 499) included two antibiotics, and 0.2% (n = 5) had three antibiotics. Cephalosporins were the most commonly prescribed class of antibiotics (81.5%) followed by penicillins (6.4%) and fluoroquinolones (6.2%). Among the individual antibiotics, ceftriaxone contributed the highest percentage share at 71.8% followed by cefotaxime (5.6%) and metronidazole (4.7%). The most frequently prescribed antibiotic combination was ciprofloxacin with metronidazole (52.1%). Irrational prescribing practices were common. Continuous education and training of physicians is required to ensure rational prescribing at Bahawal Victoria Hospital in the future. PMID- 27933229 TI - Mid-term shoulder functional and quality of life outcomes after shoulder replacement in obese patients. AB - BACKGROUND: Shoulder pain and loss of function are directly associated with obesity. QUESTIONS/PURPOSES: We hypothesized that significant interactions would exist between total shoulder arthroplasty (TSA) and reverse total shoulder arthroplasty (RSA) and obesity status on functional and quality of life (QOL) outcomes over the long term. Clinical and QOL outcomes (American Shoulder and Elbow Surgeons Evaluation form, Shoulder Pain and Disability Index, University of California at Los Angeles Shoulder Rating scale, Medical Outcomes Short Form 12 (SF-12), range of motion (ROM), and strength) were longitudinally compared in patients with low and high body mass index (BMI) after a TSA or a RSA. Prospectively collected data of patients with a TSA or RSA were reviewed (N = 310). Preoperative, 2-year, and final follow-up visits were included (range 3-17 years; mean 5.0 +/- 2.5 years). Patient data were stratified for analysis using BMI. RESULTS: Morbidly obese patients had worse preoperative functional scores and QOL compared to the other groups. There were no significant interactions of BMI group by surgery type for any of the outcome variables except for active external rotation ROM. Morbidly obese patients attained lower SF-12 scores compared to the remaining groups at each time point. CONCLUSIONS: Both TSA and RSA can be expected to impart positive functional outcomes in patients irrespective of BMI. Morbidly obese patients do not attain the same gains in Medical Outcomes SF-12 scores as the non-morbidly obese patients. The lower improvements in active external ROM may be due to morphological limitations of excessive adiposity. LEVEL OF EVIDENCE: This is a level II study. PMID- 27933230 TI - Maximum likelihood based analysis of equally spaced longitudinal count data with first-order antedependence and overdispersion. AB - This manuscript implements a maximum likelihood based approach that is appropriate for equally spaced longitudinal count data with over-dispersion, so that the variance of the outcome variable is larger than expected for the assumed Poisson distribution. We implement the proposed method in the analysis of seizure data and a subset of German Socio-Economic Panel data. To demonstrate the importance of correctly modeling the over-dispersion, we make comparisons with the semi-parametric generalized estimating equations approach that incorrectly ignores any over-dispersion in the data. Our simulations demonstrate that accounting for over-dispersion results in improved small-sample efficiency and appropriate coverage probabilities. We also provide code in R so that readers can implement our approach in their own analyses. PMID- 27933231 TI - Intuitionistic fuzzy-based model for failure detection. AB - In identifying to-be-improved product component(s), the customer/user requirements which are mainly considered, and achieved through customer surveys using the quality function deployment (QFD) tool, often fail to guarantee or cover aspects of the product reliability. Even when they do, there are always many misunderstandings. To improve the product reliability and quality during product redesigning phase and to create that novel product(s) for the customers, the failure information of the existing product, and its component(s) should ordinarily be analyzed and converted to appropriate design knowledge for the design engineer. In this paper, a new intuitionistic fuzzy multi-criteria decision-making method has been proposed. The new approach which is based on an intuitionistic fuzzy TOPSIS model uses an exponential-related function for the computation of the separation measures from the intuitionistic fuzzy positive ideal solution (IFPIS) and intuitionistic fuzzy negative ideal solution (IFNIS) of alternatives. The proposed method has been applied to two practical case studies, and the result from the different cases has been compared with some similar computational approaches in the literature. PMID- 27933232 TI - Molecular characterization and phylogenetic analysis of dengue virus type 1 in Guangdong in 2014. AB - BACKGROUND: Dengue is one of the most important emerging diseases of humans, with no preventive vaccines or antiviral cures available currently. In 2014, the Southeast Asian region experienced an unprecedented outbreak of dengue, especially in Guangdong, China. RESULTS: The nucleotide sequences of the E gene from 23 patients sera of dengue virus type 1 (DENV-1) from Guangzhou, China, were determined. One isolate that was recovered from a patient with serious liver damage was designated GZ02. The whole genome sequence of GZ02 was amplified, and confocal microscopy and plaque reduction neutralization test were performed to investigate the replication kinetics in liver L02 cells. In the study, assembly and genetic comparisons showed 11 of those E gene nucleotide sequences were absolutely accordant, and the nucleic acid sequence divergence among the other strains had no marked difference. CONCLUSIONS: Phylogenetic analysis based on the E gene indicated that the 23 new strains were closely related to strains from Malaysia or Singapore. Two different genotypes (genotype I and III) of DENV-1 were co-circulating in Guangdong, Malaysia, and Singapore from 2013 to 2014. However, no recombination event was found after 2005 between DENV strains from Guangdong and Malaysia or Singapore. GZ02 had a significant replicative advantage over DG14 and the DV1 standard strain. Importation of DENV-1 from Southeast Asian countries may have been an important contributing factor to the 2014 outbreak in Guangdong. PMID- 27933233 TI - Isolation and characterisation of crude oil sludge degrading bacteria. AB - BACKGROUND: The use of microorganisms in remediating environmental contaminants such as crude oil sludge has become a promising technique owing to its economy and the fact it is environmentally friendly. Polycyclic aromatic hydrocarbons (PAHs), as the major components of oil sludge, are hydrophobic and recalcitrant. An important way of enhancing the rate of PAH desorption is to compost crude oil sludge by incorporating commercial surfactants, thereby making them available for microbial degradation. In this study, crude oil sludge was composted for 16 weeks during which surfactants were added in the form of a solution. RESULTS: Molecular characterisation of the 16S rRNA genes indicated that the isolates obtained on a mineral salts medium belonged to different genera, including Stenotrophmonas, Pseudomonas, Bordetella, Brucella, Bacillus, Achromobacter, Ochrobactrum, Advenella, Mycobacterium, Mesorhizobium, Klebsiella, Pusillimonas and Raoultella. The percentage degradation rates of these isolates were estimated by measuring the absorbance of the 2,6-dichlorophenol indophenol medium. Pseudomonas emerged as the top degrader with an estimated percentage degradation rate of 73.7% after 7 days of incubation at 28 degrees C. In addition, the presence of the catabolic gene, catechol-2,3-dioxygenase was detected in the bacteria isolates as well as in evolutionary classifications based on phylogeny. CONCLUSIONS: The bacteria isolated in this study are potential agents for the bioremediation of crude oil sludge. PMID- 27933234 TI - Simulation enhanced distributed lag models for mortality displacement. AB - Distributed lag models (DLM) are attractive methods for dealing with mortality displacement, however their estimates can have substantial bias when the data is generated by a multi-state model. In particular DLMs are not valid for mortality displacement. Alternative methods are scarce and lack feasibility and validation. We investigate the breakdown of DLM in three state models by means of simulation and propose simulation enhanced distributed lag models (SEDLM) to overcome the defects. The new method provides simultaneous estimates of the net effect (entry) and the displacement effect (exit). These have improved performance over the singular estimate from a regular DLM. SEDLM entry estimates have negligible bias and their variance is reduced. The exit estimates are unbiased and their variance is one order of magnitude lower with respect to the entry estimates. Applying SEDLM to the original Chicago data, the 95% highest posterior density intervals for both entry and exit contain 0, providing neither evidence for a 'displacement effect' nor for a 'net effect'. PMID- 27933235 TI - Thailand's universal coverage scheme and its impact on health-seeking behavior. AB - BACKGROUND: Thailand's Universal Coverage Scheme (UCS) has improved healthcare access and utilization since its initial introduction in 2002. However, a substantial proportion of beneficiaries has utilized care outside the UCS boundaries. Because low utilization may be an indication of a policy gap between people's health needs and the services available to them, we investigated the patterns of health-seeking behavior and their social/contextual determinants among UCS beneficiaries in the year 2013. RESULTS: The study findings from the outpatient analysis showed that the use of designated facilities for care was significantly higher in low-income, unemployed, and chronic status groups. The findings from the inpatient analysis showed that the use of designated facilities for care was significantly higher in the low-income, older, and female groups. Particularly, for the low-income group, we found that they (1) had greater health care needs, (2) received a larger number of services from designated facilities, and (3) paid the least for both inpatient and outpatient services. CONCLUSIONS: This pro-poor impact indicated that the UCS could adequately respond to beneficiaries' needs in terms of vertical equity. However, we also found that a considerable proportion of beneficiaries utilized out-of-network services, which implied a lack of universal access to policy services from a horizontal equity point of view. Thus, the policy should continue expanding and diversifying its service benefits to strengthen horizontal equity. Particularly, private sector involvement for those who are employed as well as the increased unmet health needs of those in rural areas may be important policy priorities for that. Lastly, methodological issues such as severity adjustment and a detailed categorization of health-seeking behaviors need to be further considered for a better understanding of the policy impact. PMID- 27933236 TI - Purification and antigenic detection of O-specific polysaccharides of Salmonella enterica serovar Paratyphi A isolate from Pakistan: an emerging threat. AB - BACKGROUND: Paratyphoid fever caused by Salmonella enterica serovar Paratyphi A is becoming a serious health problem in Asian countries particularly Pakistan, China and India and situation is aggravated by current unavailability of a licensed vaccine. This study was designed to purify the O-specific polysaccharides (OSP) produced by an isolate of Salmonella Paratyphi A from Pakistan and detect antigenicity of extracted lipopolysaccharide (LPS) and purified OSP pioneerly in South Asian region as candidate for conjugate vaccine preparation. RESULTS: S. Paratyphi A isolates were identified through PCR using primers of fliC-a gene (329 bp) and confirmed via nested PCR using fliC-nested primers (289 bp). Yield of the LPS of S. Paratyphi A isolate was 40 mg/L of the bacterial culture using hot phenol method. The purified LPS revealed the characteristic ladder like pattern of S. Paratyphi A LPS on SDS-PAGE with silver staining. Purified OSP obtained by acid hydrolysis yielded 23 mg/L of culture broth and was not detected by silver staining. Antigenic interaction of the purified LPS and OSP with hyper immune mice sera was confirmed by single precipitin line evaluated through immunodiffusion assay. The antigenicity was found well intact. CONCLUSIONS: The purified antigenic OSP from S. Paratyphi A may have the potential to be coupled with a carrier protein to develop low cost conjugate vaccine candidates against S. Paratyphi A in paratyphoid endemic regions. PMID- 27933237 TI - Pricing policy for declining demand using item preservation technology. AB - We have designed an inventory model for seasonal products in which deterioration can be controlled by item preservation technology investment. Demand for the product is considered price sensitive and decreases linearly. This study has shown that the profit is a concave function of optimal selling price, replenishment time and preservation cost parameter. We simultaneously determined the optimal selling price of the product, the replenishment cycle and the cost of item preservation technology. Additionally, this study has shown that there exists an optimal selling price and optimal preservation investment to maximize the profit for every business set-up. Finally, the model is illustrated by numerical examples and sensitive analysis of the optimal solution with respect to major parameters. PMID- 27933238 TI - High particulate matter emission from additive-free Natural American Spirit cigarettes. AB - BACKGROUND: Involuntary exposure to health-threatening environmental tobacco smoke (Combined Mainstream and Side-stream Smoke, CMSS) is a worldwide problem, causing premature death of thousands of people. CMSS consists of particulate matter (PM), one of the main sources of indoor air pollution. PM constitutes a considerable health risk for passive smokers. It is important to inform the public about brand-specific differences in CMSS-associated PM, especially in the case of brands without additives, which are therefore promoted as natural and less health-threatening. METHODS: Mean concentrations and the area under the curve of PM10, PM2.5 and PM1 generated by Natural American Spirit cigarettes without additives and the 3R4F standard research cigarette (University of Kentucky, USA) were measured, analyzed and compared with each other. An automatic environmental tobacco smoke emitter was used to smoke 100 cigarettes, 20 of each brand, according to a standardized smoking protocol. RESULTS: This study could show that CMSS-associated PM released from tobacco brands without additives, which are therefore promoted as natural and less harmful, are higher than expected. CONCLUSIONS: It is highly improbable that Natural American Spirit tobacco products are a less harmful choice-at least not for passive smokers as this study could show. We conclude, the CMSS-associated PM level of every single customized brand should be measured because the origin of the tobacco and not the amount of CO, tar and nicotine (given as product information) seem to be responsible for the brand-specific PM release. This data is urgently needed to adequately inform the public about CMSS-associated PM exposure and the related health risk especially for passive smokers. PMID- 27933239 TI - Impact of bowel resection margins in node negative colon cancer. AB - PURPOSE: Surgical intestinal resection margins in colon cancer are a longstanding debate in terms the optimal distance between the tumor and the colonic section line. The aim of this study is to define the oncological outcomes in relation to surgical margins, measured in terms or recurrence rate, time-to-recurrence, disease-free survival and overall survival in a population of node negative colon cancer patients. METHODS: We conducted a retrospective observational longitudinal single institution study. All patients submitted to colon cancer surgery between January 2006 and December 2010 were analyzed. Only node negative patients were included in the study, with analysis of 215 patient charts, divided in two groups (Intestinal margin lower than 5 cm-group 1; and 5 cm or higher-group 2). RESULTS: Mean age of patients was 70.4 years (+/-11.7), with a male predominance (57.7%). Group 2 more frequently corresponded to Stage II (83 vs 71%; p = 0.05). Global mean total lymph nodes harvested were 12, and were higher in group II than in group I (13.8 +/- 8.2 vs 10.4 +/- 5.7; p = 0.001). In terms of time-to-recurrence patients of group 2 had longer time than patients of group 1 (32.3 +/- 12.1 vs 21.8 +/- 13.8 months; p = 0.03), as well as a lower recurrence rate in group I (13.7 vs 17.2%), despite not statistically significant. CONCLUSIONS: This study has showed that patients with 5 cm or higher bowel resection margins had longer time-to-recurrence that was statistically significant. Recurrence rates were lower in the group of patients with longer surgical margins, however not statistically significant. PMID- 27933240 TI - Synthesis of 2-tetrafluoropyridyl-4,5-disubstituted 1,2,3-triazoles. AB - ABSTRACT: By cycloaddition reaction of sodium azide with chalcone in the presence of CuO as a catalyst in DMF a 1,2,3-triazole are prepared in reaction with pentafluoropyridine to give 2-(tetrafluoropyridin-4-yl)-1,2,3-triazole derivatives in good yields and high regioselectivity. The regioselectivity of the compounds are confirmed by 19F-NMR and other spectroscopy. GRAPHICAL ABSTRACT: PMID- 27933241 TI - Numerical solution of linear and nonlinear Fredholm integral equations by using weighted mean-value theorem. AB - Mean value theorems for both derivatives and integrals are very useful tools in mathematics. They can be used to obtain very important inequalities and to prove basic theorems of mathematical analysis. In this article, a semi-analytical method that is based on weighted mean-value theorem for obtaining solutions for a wide class of Fredholm integral equations of the second kind is introduced. Illustrative examples are provided to show the significant advantage of the proposed method over some existing techniques. PMID- 27933242 TI - Transtuzumab induced organizing pneumonia: a case report. AB - BACKGROUND: Patients with metastatic breast cancer often have pulmonary symptoms with varying aetiologies. Transtuzumab is an extremely important drug used in the treatment of Her 2 neu over-expressing breast cancers. In this report we describe a case of organizing pneumonia associated with use of transtuzumab in metastatic breast cancer. Only three such cases have previously been reported. CASE DESCRIPTION: A 43 year old lady with Her 2 neu 3+, estrogen and progesterone receptor positive, metastatic breast cancer was started on weekly transtuzumab and albumen bound paclitaxel. She was admitted with an episode of bilateral pneumonitis after her fourth dose of therapy. It was managed conservatively with antibiotics. Subsequently, single agent transtuzumab was administered resulting in an anaphylactoid reaction followed by worsening dyspnoea requiring hospitalization and oxygen support for 3 days. DISCUSSION AND EVALUATION: The pneumonitis warranted further investigations including bronchoscopy which were performed. Bronchoscopic biopsy was consistent with a diagnosis of organizing pneumonia. Transtuzumab was stopped and she was started on steroids (dexamethasone). She improved remarkably and was discharged home on hormonal therapy, lapatinib and tapering doses of steroids. CONCLUSION: Organizing pneumonia closely mimics infection or progressive disease and can be difficult to diagnose in the setting of malignancy. Correct diagnosis is of paramount importance since delay in treatment can result in significantly adverse patient outcomes. PMID- 27933243 TI - Model-based extended quaternion Kalman filter to inertial orientation tracking of arbitrary kinematic chains. AB - Inertial orientation tracking is still an area of active research, especially in the context of out-door, real-time, human motion capture. Existing systems either propose loosely coupled tracking approaches where each segment is considered independently, taking the resulting drawbacks into account, or tightly coupled solutions that are limited to a fixed chain with few segments. Such solutions have no flexibility to change the skeleton structure, are dedicated to a specific set of joints, and have high computational complexity. This paper describes the proposal of a new model-based extended quaternion Kalman filter that allows for estimation of orientation based on outputs from the inertial measurements unit sensors. The filter considers interdependencies resulting from the construction of the kinematic chain so that the orientation estimation is more accurate. The proposed solution is a universal filter that does not predetermine the degree of freedom at the connections between segments of the model. To validation the motion of 3-segments single link pendulum captured by optical motion capture system is used. The next step in the research will be to use this method for inertial motion capture with a human skeleton model. PMID- 27933244 TI - A study on biological activity of marine fungi from different habitats in coastal regions. AB - In recent years, marine fungi have become an important source of active marine natural products. Former researches are limited in habitats selection of fungi with bioactive compounds. In this paper were to measure antibacterial and antitumor cell activity for secondary metabolites of marine fungi, which were isolated from different habitats in coastal regions. 195 strains of marine fungi were isolated and purified from three different habitats. They biologically active experiment results showed that fungi isolation from the mangrove habitats had stronger antibacterial activity than others, and the stains isolated from the estuarial habitats had the least antibacterial activity. However, the strains separated from beach habitats strongly inhibited tumor cell proliferation in vitro, and fungi of mangrove forest habitats had the weakest activity of inhibiting tumor. Meanwhile, 195 fungal strains belonged to 46 families, 84 genera, 142 species and also showed 137 different types of activity combinations by analyzing the inhibitory activity of the metabolites fungi for 4 strains of pathogenic bacteria and B-16 cells. The study investigated the biological activity of marine fungi isolated from different habitats in Haikou coastal regions. The results help us to understand bioactive metabolites of marine fungi from different habitats, and how to selected biological activity fungi from various marine habitats effectively. PMID- 27933245 TI - An adaptive switching filter based on approximated variance for detection of impulse noise from color images. AB - A new adaptive switching algorithm is presented where two adaptive filters are switched correspondingly for lower and higher noise ratio of the image. An adaptive center weighted vector median filter is used for the lower noise ratio whereas for higher noise ratio the noisy pixels are detected based on the comparison of the difference between the mean of the vector pixels in the window and the approximated variance of the vector pixels in the window. Then the window comprising the detected noisy pixel is further considered where the pixels are given exponential weights according to their similarity to the other neighboring pixels, spatially and radio metrically. The noisy pixels are then replaced by the weighted average of the pixels within the window. The filter is able to preserve higher signal content in the higher noise ratio as compared to other robust filters in comparison. With a little high in computational complexity, this technique performs well both in lower and higher noise ratios. Simulation results on various RGB images show that the proposed algorithm outperforms many other existing nonlinear filters in terms of preservation of edges and fine details. PMID- 27933246 TI - A quantitative report on the impact of chloride on the kinetic coefficients of auxin-induced growth: a numerical contribution to the "acid growth hypothesis". AB - This work presents the application of several our own novel methods of analysing the kinetics of plant growth, which create, among others, a common platform for the comparison of experimental results. A relatively simple formula is used to parameterize the wide range of data that has been obtained for Zea mays L. in the literature, though it can also be used for different species. A biophysical/biochemical interpretation of the parameters was obtained from a theoretical model that is based on a modified Lockhart equation. The derived formula, which was extended for practical use in Zajdel et al. (Acta Physiol Plant 38:5, 2016), and which was implemented in the attached computer program (ibid.), allowed the data that was obtained from the growth-related problems to be parameterized in a simple way. As a working example that shows the robustness of our approach, we comment in detail on the qualitative assessments of the impact of chloride ions on auxin-induced growth. We note that calculated continuous curves (fits), which are rooted in the growth functional that was introduced by Pietruszka (J Theor Biol 315:119-127, 2012), were in a perfect agreement (R2 ~ 0.99998) with the raw experimental data that was published recently by Burdach et al. (Ann Bot 114:1023-1034, 2014). This fact justified the use of this strict technique, which allows for the determination of kinetic coefficients, to critically evaluate the results and suppositions (claims) therein. Moreover, we calculated the time-delay derivative of elongation growth pH cross-correlations, and validated the "acid growth hypothesis" in figures by considering, amongst others, the magnitude of the H+-activity of elongation growth (per MUm). An empirical constant (field strength), EH+ = Em/(log10 1/aH+ ? MUm) = 0.157 +/- 0.009 [V/mm] was obtained, where Em [mV] is the membrane potential in the perenchymal coleoptile cells of Zea mays L. When this relation is known, the membrane potential can not only be determined for intact growth, but also for different intervening substances exclusively from growth (or growth rate) and pH measurements, i.e. without performing electrophysiological measurements. However, the question of whether this constant is universal remains open. PMID- 27933247 TI - Fault tolerance in computational grids: perspectives, challenges, and issues. AB - Computational grids are established with the intention of providing shared access to hardware and software based resources with special reference to increased computational capabilities. Fault tolerance is one of the most important issues faced by the computational grids. The main contribution of this survey is the creation of an extended classification of problems that incur in the computational grid environments. The proposed classification will help researchers, developers, and maintainers of grids to understand the types of issues to be anticipated. Moreover, different types of problems, such as omission, interaction, and timing related have been identified that need to be handled on various layers of the computational grid. In this survey, an analysis and examination is also performed pertaining to the fault tolerance and fault detection mechanisms. Our conclusion is that a dependable and reliable grid can only be established when more emphasis is on fault identification. Moreover, our survey reveals that adaptive and intelligent fault identification, and tolerance techniques can improve the dependability of grid working environments. PMID- 27933248 TI - Convergence and norm estimates of Hermite interpolation at zeros of Chevyshev polynomials. AB - In this paper, we investigate the simultaneous approximation of a function f(x) and its derivative [Formula: see text] by Hermite interpolation operator [Formula: see text] based on Chevyshev polynomials. We also establish general theorem on extreme points for Hermite interpolation operator. Some results are considered to be an improvement over those obtained in Al-Khaled and Khalil (Numer Funct Anal Optim 21(5-6): 579-588, 2000), while others agrees with Pottinger's results (Pottinger in Z Agnew Math Mech 56: T310-T311, 1976). PMID- 27933249 TI - An enterogenous cyst with atypical pathological findings and chemical meningitis. AB - INTRODUCTION: Intracranial enterogenous cysts are rare and mainly occur in the posterior fossa. These cysts are usually extra-axial, midline, anterior to the brainstem, or at the cerebellopontine angle. We report a case of an enterogenous cyst in which diagnosis was difficult because the lesion showed atypical pathologic findings. CASE PRESENTATION: A healthy 41-year-old man complained of paroxysmal occipital headaches lasting over a week, with increased severity for 3 days accompanied by slight dizziness and mild nausea. Magnetic resonance imaging showed a cystic lesion between clivus and brainstem. The patient underwent surgery for removal of the lesion via the right-sided far-later approach, and the lesion was resected totally. Although pathologic examinations showed a cyst had a mono-to-multilayered squamous epithelium, which are not accord with typical enterogenous cyst, the diagnosis was finally made based on the presence of basement membrane and immunohistochemical results. DISCUSSION AND EVALUATION: To confirm the diagnosis of enterogenous cyst, further pathologic examinations were performed and immunohistochemical characters were summarized. Chemical meningitis, a rare complication of enterogenous cyst, happened in current case. Use a syringe and aspirate the contents before incision might be a procedure to prevent chemical meningitis. CONCLUSIONS: To our knowledge, this is the first report of an enterogenous cyst associated with mono-to-multilayered squamous epithelium. Although during the follow-up time, no recurrence happened, long-term follow-up is needed. PMID- 27933250 TI - Clinical analysis on 430 cases of infantile purulent meningitis. AB - BACKGROUND: Purulent meningitis (PM) usually caused by a variety of pyogenic infection, is a kind of central nervous system infectious disease mostly common in children. It is easily misdiagnosed and its symptoms are varied. Excessive application of broad-spectrum antibiotics results in increased sickness and death of infants and young children. In this study, clinical data of 430 cases of PM in infants were analyzed to summarize the clinical experiences so as to achieve early diagnosis and early treatment of PM. RESULTS: Male-to-female ratio was 1.61:1, and the median age of incidence was 0.42 years. May was the modal month of onset (11.7%). Main clinical manifestations were fever (89.3%), vomiting (67.2%), mental fatigue (62.1%), anterior fontanelle full/bulging/high tension (54.2%), convulsion (52.6%), and meningeal irritation sign (24.7%). Cerebrospinal fluid (CSF) bacterial culture was done for 420 cases, of which 1.2% cases were positive. Blood culture was done for 146 cases of which 15.1% were positive. 175 (40.7%) cases had complications, among which 133 cases (76.0%) were subdural effusion, 21 cases (12.0%) were epilepsy. CONCLUSION: Infantile PM is common in Spring, and May is the modal month of onset. The CSF/blood pathogen detection rate is very low and it is difficult to find evidence of cause. Fever, vomiting, mental fatigue and anterior fontanelle full/bulging/high tension, convulsion are the main clinical manifestations on which diagnosis depends. For those children diagnosed as PM and still having recurrent fever and prominent anterior fontanelle after treatment, clinicians should consider the probability of subdural effusion and treat them with brain imaging test on time. PMID- 27933251 TI - Robust image hashing using ring partition-PGNMF and local features. AB - BACKGROUND: Image authentication is one of the challenging research areas in the multimedia technology due to the availability of image editing tools. Image hash may be used for image authentication which should be invariant to perceptually similar image and sensitive to content changes. The challenging issue in image hashing is to design a system which simultaneously provides rotation robustness, desirable discrimination, sensitivity and localization of forged area with minimum hash length. METHODS: In this paper, a perceptually robust image hashing technique based on global and local features has been proposed. The Global feature was extracted using ring partition and projected gradient nonnegative matrix factorization (PGNMF). The ring partitioning technique converts a square image into a secondary image that makes the system rotation invariant. The PGNMF which is usually faster than the other NMFs has been used to reduce the dimension of the secondary image to generate the shorter hash sequence. The local features extracted from the salient regions of the image help to localize the forged region in the maliciously manipulated images. The image hashing techniques that use only global features are limited in discrimination. RESULTS: The experimental results reveal that the proposed image hashing method based on global and local features provides better discrimination capability. The proposed hashing method is tested on large image sets collected from the different standard database. It is observed from the experimental results that the proposed system is robust to content-preserving operations and is capable of localizing the counterfeit area. CONCLUSIONS: The combination of global and local features is robust against the content-preserving operations, which has a desirable discriminative capability. The proposed system may be used in image authentication, forensic evidence, and image retrieval, etc. PMID- 27933252 TI - Reaction of hydroxyl-quinoline with pentafluoropyridin. AB - Reaction of pentafluoropyridine with 2 or 8-hydroxyl-quinoline under basic conditions in acetonitrile gives 4-oxy quinoline 2,3,5,6-tetrafluoropyridine derivatives in good yields. All the compounds were characterized using 1H, 13C, 19F-NMR and MS spectroscopy. PMID- 27933253 TI - Primary intracerebral osteosarcoma: a rare case report and review. AB - BACKGROUND: Primary intracranial osteosarcoma is a extremely rare disease entity. We describe a case of primary intracerebral osteosarcoma in an adult brain. CASE DESCRIPTION: A patient who presented with a 1-week history of headaches, and MRI examination was performed. The immunohistochemical diagnosis confirmed primary intracerebral osteosarcoma. The patient was treated with a surgical resection of the tumor. CONCLUSION: Primary osteosarcomas occurring in the brain are extremely rare. The MRI images did not provide a specific pretreatment diagnosis, and the histopathology was the mainstay in establishing the diagnosis. PMID- 27933254 TI - Characterization of a novel hatching enzyme purified from starfish Asterina pectinifera. AB - Hatching enzyme is a protease which can degrade the membrane of egg. In this study, a hatching enzyme was purified from starfish (Asterina pectinifera) with 6.34 fold of purification rate, 5.04 % of yield, and 73.87 U/mg of specific activity. The molecular weight of starfish hatching enzyme was 86 kDa, which was reduced to 62 kDa after removal of N-linked oligosaccharides. The optimal pH and temperature of the hatching enzyme activity were pH 7.0 and 40 degrees C, respectively, while those of stability were pH 8 and 20 degrees C. The kinetic parameters, Vmax , Km , K cat and Kcat/Km values were 0.197 U/ml, 0.289 mg/ml, 112.57 s-1, and 389.52 ml/mg s, respectively. Zn2+ increased the enzyme activity by 167.28 %, while EDTA, TPCK, TGCK, leupeptin, PMSF, and TLCK decreased. In addition, Ca2+, Mg2+, and Cu2+ did not affect the enzyme activity. The starfish hatching enzyme activity pretreated with EDTA was recovered by Zn2+. Therefore, the starfish hatching enzyme was classified as a serine-zinc protease. PMID- 27933255 TI - Dynamic loading and kinematics analysis of vertical jump based on different forefoot morphology. AB - PURPOSE: This study examined differences in ankle motion and plantar pressure between habitually barefoot male (HBM) and habitually shod male (HSM) during vertical jump. METHODS: Eighteen habitually barefoot males and twenty habitually shod males volunteered to join the test. Distance between hallux and second toe was measured with Easy-Foot-Scan. Plantar pressure and ankle kinematics were measured with EMED force platform and Vicon motion analysis system respectively. T test was taken to analyse the significant differences using Stata 12.0 software. RESULTS: The distance between hallux and other toes in HBM was greater than it in HSM. HBM showed larger plantar loading under hallux and medial forefoot, while HSM showed lager plantar loading under medial and central forefoot. HBM had smaller ankle plantarflexion, eversion and external rotation than HSM. CONCLUSION: Findings of this study provide basic information for further studies on different hallux/toe function in motion control between habitually shod and barefoot populations. PMID- 27933256 TI - Explaining bioenergy: representations of jatropha in Kenya before and after disappointing results. AB - Proponents of Jatropha curcas portrayed the crop as a 'sustainable biofuel' that was less threatening to food security and forests than other energy crops, creating a reputation that helped jatropha projects to multiply quickly throughout the global South. However, many jatropha initiatives failed to thrive and ultimately collapsed. This paper investigates how actors involved with jatropha in Kenya explained their visions of bioenergy at two points in time. In 2009, when many activities were beginning, I interviewed small-scale farmers, NGO staff, researchers, donors, government officials and members of the private sector about their expectations of jatropha as an energy crop. In late 2013, after jatropha activities in the country had dwindled, I re-interviewed many of the same individuals about their current views and their explanations of the events that had transpired since the initial fieldwork. Synthesizing these two sets of representations provides insight into how biofuel projects have been constructed, negotiated and renegotiated. Early hopes for jatropha rested on the belief that it could achieve many goals simultaneously, but when it failed to meet expectations proponents chose between two strategies: (1) 'unbundling' these goals to pursue separately the various aspirations they had initially attached to jatropha; and (2) seeking a new means of achieving the same bundle of goals. Understanding the choices made by jatropha actors in Kenya contributes to knowledge on the political ecology of biofuels and responsible innovation, and may signal patterns to come as even greater expectations are attached to multi use feedstocks in pursuit of the bioeconomy. PMID- 27933257 TI - Assessment of the quality of groundwater for drinking purposes in the Upper West and Northern regions of Ghana. AB - BACKGROUND: Underground water is an important natural resource serving as a reliable source of drinking water for many people worldwide, especially in developing countries. Underground water quality needs to be given a primary research and quality control attention due to possible contamination. This study was therefore designed to determine the physico-chemical and bacteriological quality of borehole water in the Upper West and Northern regions of Ghana. METHODS: The study was conducted in seven districts in Ghana (including six in the Upper West region and one in the Northern region). The bacterial load of the water samples was determined using standard microbiological methods. Physico chemical properties including pH, total alkalinity, temperature, turbidity, true colour, total dissolved solids (TDS), electrical conductivity, total hardness, calcium hardness, magnesium hardness, total iron, calcium ion, magnesium ion, chloride ion, fluoride ion, aluminium ion, arsenic, ammonium ions, nitrate and nitrite concentrations were determined. The values obtained were compared with the World Health Organization (WHO) standards for drinking water. RESULTS: The recorded pH, total alkalinity and temperature ranges were 6.14-7.50, 48-240 mg/l and 28.8-32.8 degrees C, respectively. Furthermore, the mean concentrations of iron, calcium, magnesium, chloride, fluoride, aluminium, arsenic, ammonium, nitrate and nitrite were 0.06, 22.11, 29.84, 13.97, 0.00, 0.00, 0.00, 0.01, 2.09 and 0.26 mg/l, respectively. Turbidity, true colour, TDS and electrical conductivity of the water samples ranged from 0.13 to 105 NTU, 5 to 130 HU, 80.1 to 524 mg/l and 131 to 873 uS/cm, respectively. In addition, the mean total hardness value was found to be 178.07 mg/l whereas calcium hardness and magnesium hardness respectively were 55.28 and 122.79 mg/l. Only 14% of the water samples tested positive for faecal coliforms. CONCLUSION: The study revealed that only a few of the values for the bacteriological and physico-chemical parameters of the water samples were above the tolerable limits recommended by the WHO. This calls for regular monitoring and purification of boreholes to ensure good water quality. PMID- 27933258 TI - P-th moment and almost sure stability of stochastic switched nonlinear systems. AB - This paper mainly tends to utilize [Formula: see text]-type function to investigate p-th moment and almost sure stability for a class of stochastic switched nonlinear systems. Based on the multiple Lyapunov functions approach, some sufficient conditions are derived to check the stability criteria of stochastic switched nonlinear systems. One numerical example is provided to demonstrate the effectiveness of the proposed results. PMID- 27933259 TI - Deformity correction and extremity lengthening in the lower leg: comparison of clinical outcomes with two external surgical procedures. AB - OBJECTIVE: Distraction osteogenesis is a method of stimulating the growth of new bone tissue in order to lengthen the extremities or bridge resected bone defects. In addition to the now-established intramedullary procedures, two different fixator systems are in use. The present study investigated the classical Ilizarov ring fixator (IRF) and a hexapod to assess the precision of lower-leg lengthening and complications classified using the Paley criteria for problems, obstacles, and complications. The study also examined the follow-up results in functional tests to assess outcomes in terms of range of motion in adjacent joints, daily activities, and quality of life. PATIENTS AND METHODS: A total of 43 patients (53 segments) who were treated over a period of 16 years were re-assessed. In 33 segments, treatment was carried out with the hexapod Taylor Spatial Frame (TSF); the conventional IRF was used in 20 segments. The patients' mean age was 13.5 years (range 2-54 years). The follow-up examinations were carried out 2-15 years postoperatively and comprised measurement of a current leg axis view with the patient standing, calculation of a knee score, activity scores, ankle joint scores, and assessment of motor function and sensory function using appropriate scores in the lower leg and foot. The post-treatment health-related quality of life was assessed using the Short-Form Health Survey-36 questionnaire. RESULTS: Using the Paley criteria, far fewer problems occurred in the TSF group in comparison with the IRF (TSF 12.1%, IRF 50%). In the problems category, significant differences were observed with regard to axial deviation (TSF 0%, IRF 36.8%) and pin infections (TSF 9.1%, IRF 40%). Comparison of the obstacles and complications did not identify any significant differences between the two groups. Analysis of the scores for the knee, activity, and motor function/sensory function also did not show any marked discrepancies, apart from a major difference in mobility in the upper and lower ankle joints with poorer findings in the TSF group. CONCLUSIONS: During treatment, the TSF ring fixator leads to fewer problems, fewer secondary axial translations, and fewer pin infections. However, with temporary transfixation of the ankle joints, the TSF system is also associated with postoperative deterioration in mobility in the upper and lower ankle joint. PMID- 27933260 TI - Use of a 10.22 m diameter EPB shield: a case study in Beijing subway construction. AB - INTRODUCTION: Beijing subway line 14 includes four stations and approximately 2.8 km of tunnels between the Dongfengbeiqiao and Jingshunlu areas of the city. Due to the surface and underground space limitations of this section, a double-track running tunnel instead of two single-track running tunnels was adopted to connect the two stations. The double-track tunnels were excavated by a 10.22 m diameter earth pressure balance (EPB) shield. It was the first time that an EPB shield more than 10 m in diameter was used in Beijing subway construction. CASE DESCRIPTION: The shield, which passes underneath densely built-up areas of the city and is equipped with a spoke-type cutterhead, with balance between the ground pressure and the earth chamber pressure at the tunnel face, is of great importance. Referring to experiences gained in the EPB shield tunneling, attention was paid to the function of soil conditioning and simultaneous backfilling grouting of the shield, and some special designs were considered in manufacturing the machine. DISCUSSION AND EVALUATION: In addition to the agitating rods welded to the cutterhead, two independently driven agitators were added to fully mix everything in the earth chamber. Independent pipelines were arranged for injecting different conditioning agents. Indoor tests in combination with field tests were conducted to find suitable additives and injection ratios of the additives, and determine the mix ratio of the two-component grout for simultaneous backfilling grouting. A scheme was employed for simultaneously injecting the bentonite slurry at 8% concentration and the foam liquid at 5% concentration to condition the excavated soil. The cement-sodium silicate grout was adopted to fill the tail void and the injection volume per ring was 14.1-15.3 m3. CONCLUSIONS: The performance of the shield and evaluation of the corresponding tunneling technologies are introduced in terms of the shield tunneling induced ground surface settlements. The success of the project is of great significance to Beijing subway construction and underground space utilization. The findings serve as a useful reference for similar projects. PMID- 27933261 TI - Efficient regeneration system from rye leaf base segments. AB - Rye is second only to wheat among grains most widely used in the making of bread and is also a very important gene resource for breeding and improvement of wheat and other cereal crops owing to tolerance to abiotic stress factors such as low temperatures, drought and poor soil conditions. However, application of biotechnologies has been limited in rye breeding since it is one of the most recalcitrant species in tissue culture. A simple and fast regeneration system from leaf-base segment explant of rye was developed in this study. Basal media, carbohydrate source, combination of plant growth regulators and the leaf segment locations were evaluated for callus and shoot formation. The highest callus formation (10.39%) and shoot formation (4.53%) were achieved from first basal segments 3-4 days old seedlings. MS (Murashige and Skoog, in Physiol Plant 15:473 497, 1962) medium supplemented with 30 g/L sucrose and 2 mg/L 2,4-D (2-4 dichlorophenoxyacetic acid) + 1 mg/L TDZ (Thidiazuran) was the best medium for shoot formation (18.75%) in first leaf base segment culture. Regenerated plants were phenotypically normal and set seed after they were successfully transferred to soil. The results indicate that this regeneration method can be used for genetic transformation in rye. PMID- 27933262 TI - Software project management tools in global software development: a systematic mapping study. AB - Global software development (GSD) which is a growing trend in the software industry is characterized by a highly distributed environment. Performing software project management (SPM) in such conditions implies the need to overcome new limitations resulting from cultural, temporal and geographic separation. The aim of this research is to discover and classify the various tools mentioned in literature that provide GSD project managers with support and to identify in what way they support group interaction. A systematic mapping study has been performed by means of automatic searches in five sources. We have then synthesized the data extracted and presented the results of this study. A total of 102 tools were identified as being used in SPM activities in GSD. We have classified these tools, according to the software life cycle process on which they focus and how they support the 3C collaboration model (communication, coordination and cooperation). The majority of the tools found are standalone tools (77%). A small number of platforms (8%) also offer a set of interacting tools that cover the software development lifecycle. Results also indicate that SPM areas in GSD are not adequately supported by corresponding tools and deserve more attention from tool builders. PMID- 27933263 TI - Manifold regularization for sparse unmixing of hyperspectral images. AB - BACKGROUND: Recently, sparse unmixing has been successfully applied to spectral mixture analysis of remotely sensed hyperspectral images. Based on the assumption that the observed image signatures can be expressed in the form of linear combinations of a number of pure spectral signatures known in advance, unmixing of each mixed pixel in the scene is to find an optimal subset of signatures in a very large spectral library, which is cast into the framework of sparse regression. However, traditional sparse regression models, such as collaborative sparse regression, ignore the intrinsic geometric structure in the hyperspectral data. RESULTS: In this paper, we propose a novel model, called manifold regularized collaborative sparse regression, by introducing a manifold regularization to the collaborative sparse regression model. The manifold regularization utilizes a graph Laplacian to incorporate the locally geometrical structure of the hyperspectral data. An algorithm based on alternating direction method of multipliers has been developed for the manifold regularized collaborative sparse regression model. CONCLUSIONS: Experimental results on both the simulated and real hyperspectral data sets have demonstrated the effectiveness of our proposed model. PMID- 27933264 TI - Heterophonic speech recognition using composite phones. AB - Heterophones pose challenges during training of automatic speech recognition (ASR) systems because they involve ambiguity in the pronunciation of an orthographic representation of a word. Heterophones are words that have the same spelling but different pronunciations. This paper addresses the problem of heterophonic languages by developing the concept of a Composite Phoneme (CP) as a basic pronunciation unit for speech recognition. A CP is a set of alternative sequences of phonemes. CP's are developed specifically in the context of Arabic by defining phonetic units that are consonant centric and absorb phonemically contrastive short vowels and gemination, not represented in the Arabic Modern Orthography (MO). CPs alleviate the need to diacritize MO into Classical Orthography (CO), to represent short vowels and stress, before generating pronunciation in terms of Simple Phonemes (SP). We develop algorithms to generate CP pronunciation from MO, and SP pronunciation from CO to map a word into a single pronunciation. We investigate the performance of CP, SP, UG (Undiacritized Grapheme), and DG (Diacritized Grapheme) ASRs. The experimental results suggest that UG and DG are inferior to SP and CP. For the A-SpeechDB corpus with MO vocabulary of 8000, the WER for bigram and context dependent phone are: 11.78, 12.64, and 13.59 % for CP, SP_M (SP from manual diacritized CO), and SP_A (SP from automated diacritized MO) respectively. For vocabulary of 24,000 MO words, the corresponding WER's are 13.69, 15.08, and 16.86 %. For uniform statistical model, SP has a lower WER than CP. For context independent phone (CI), CP has lower WER than SP. PMID- 27933265 TI - Multidirectional hybrid algorithm for the split common fixed point problem and application to the split common null point problem. AB - In this article, a new multidirectional monotone hybrid iteration algorithm for finding a solution to the split common fixed point problem is presented for two countable families of quasi-nonexpansive mappings in Banach spaces. Strong convergence theorems are proved. The application of the result is to consider the split common null point problem of maximal monotone operators in Banach spaces. Strong convergence theorems for finding a solution of the split common null point problem are derived. This iteration algorithm can accelerate the convergence speed of iterative sequence. The results of this paper improve and extend the recent results of Takahashi and Yao (Fixed Point Theory Appl 2015:87, 2015) and many others . PMID- 27933266 TI - Nonstrict and individual enhanced recovery after surgery (ERAS) in partial hepatectomy. AB - BACKGROUND: We aimed to evaluate postoperative recovery and short-term outcomes of patients undergoing partial hepatectomy managed with a nonstrict and individual enhanced recovery after surgery (ERAS) program. METHODS: A retrospective analysis of 168 partial hepatectomy patients in our institution was included. The discharged day and the respective impact of element application throughout the duration were analyzed. RESULTS: When all the required elements of ERAS were fully implemented, the median discharge day was 6. The more deviation occurred, the more delayed the patient discharged (P < 0.01). Preoperative ASA score, basic conditions of patients and ages were revealed closely associated with discharge day (P < 0.001). Without or an early removal of tubes and early oral feeding reduced hospital stay statistically (P < 0.01). Early discharge of patients (<3 days) did not show an increased complication incidence or readmission (P > 0.05). CONCLUSION: Nonstrict and individual use of ERAS in partial hepatectomy reduced postoperative length of stay without increasing complication rate. Our study proposes a modulation of ERAS according to the needs and acceptance of patients. In a word, better optionally required rather than mandatorily meet. PMID- 27933268 TI - Autologous platelet lysates local injections for treatment of tibia non-union with breakage of the nickelclad: a case report. AB - BACKGROUND: Nonunions of the tibia represent challenging orthopedic problems, which require the surgeon to analyze numerous factors and choose an appropriate treatment. This article presents a case report of tibia and fibula fracture patient who failed the internal fixation surgery and successfully recovered after one course of percutaneous autologous platelet lysates injection. CASE DESCRIPTION: The patient received an internal nickelclad breakage at 9 months post-surgery but reluctant to accept a second surgery, then autologous platelet lysates (APL) injection which is a less invasive method was recommended. The injections were carried once a week for three times. Radiologic evaluation was conducted every month until recovery. DISCUSSION AND EVALUATION: To the best of our knowledge, this is the first reported case of tibia delayed union with breakage of the plate resolved with APL injection. Improved clinical evidence was observed at 4 and 6 months after injection. The patient got good bony union at 8 months post-injection. The patient didn't feel any discomfort postinjection, no complications such as infection, refracture etc. were observed. CONCLUSIONS: APL percutaneous injection could be a new therapeutic option for the treatment of nonunion or delayed healing fractures. PMID- 27933267 TI - A mixed-method study of the efficacy of physical activity consultation as an adjunct to standard smoking cessation treatment among male smokers in Malaysia. AB - BACKGROUND: This study examined the effectiveness of using Physical Activity Consultation (PAC) as an addition to the standard smoking cessation treatment in Malaysia. We explored participants' experiences in terms of physical activity and smoking abstinence with the combined PAC and smoking cessation intervention. METHODS: Walk-in smokers from a local smoking cessation clinic volunteered for the 8-week intervention program, while undergoing standard smoking cessation treatment. In Week 1, a facilitator conducted a face-to-face intervention to explore participants' involvement in physical activity and helped to set physical activity strategies and goals for participants to increase physical activity levels. Participants were provided with follow-up phone calls at Weeks 3 and 6. Participants answered questionnaires that measured smoking withdrawal (Shiffman Jarvik Withdrawal Scale), cessation self-efficacy (Cessation Self-efficacy Questionnaire), physical activity involvement (International Physical Activity Questionnaire), and mood (Brunel Mood Scale) upon recruitment, at post intervention and at follow-up 3 months after the intervention ended. Participants also responded to interviews about their experiences with the PAC and smoking cessation treatment at post-intervention and at 3-month follow-up. RESULTS: Seven participants completed the program until follow-up. All were successfully abstinent. Only two participants increased physical activity levels, whereas others maintained their physical activity levels or showed slight decreases. Several themes were identified in this study, including participants' experiences with withdrawal symptoms, smoking cessation self-efficacy, triggers to smoking cessation, thoughts on standard smoking cessation treatment in Malaysia, physical activity involvement, mood, and thoughts and beliefs on combining smoking cessation and physical activity. CONCLUSIONS: This study suggests PAC was helpful in maintaining or increasing the overall physical activity levels of participants and could assist with smoking abstinence. Findings showed that all participants who stayed in the program were successfully abstinent. In general, the findings in this study provided promising results for further research on PAC as an adjunct to smoking cessation treatments in Malaysia. Trial registration This intervention is registered with the Australian New Zealand Clinical Trials Registry (Trial registration number: ACTRN12616000269437). PMID- 27933269 TI - BLAS3 optimization for the Godson-3B1500. AB - This paper proposes a performance model for general matrix multiplication (GEMM) on decoupled access/execute (DAE) architecture platforms, in order to guide improvements of the GEMM performance in the Godson-3B1500. This model focuses on the features of access processors (APs) and execute processors (EPs). To reduce the synchronization overhead between APs and EPs, a synchronization module selection mechanism (SMSM) is presented. Furthermore, two optimized algorithms of GEMM for DAE platforms based on the performance model are proposed for ideal performance. In the proposed algorithms, the kernel functions are optimized with single instruction multiple data (SIMD) vector instructions, and the overhead of AP is almost overlapped with EP by taking full advantage of the features of the architecture. Moreover, the synchronization overhead can be reduced according to the SMSM. In the end, the proposed algorithms are tested on the Godson-3B1500. The experimental results demonstrate that the computing performance of dGEMM reaches 91.9% of the theoretical peak performance and that zGEMM can reach 93% of the theoretical peak performance. PMID- 27933270 TI - Compliance control based on PSO algorithm to improve the feeling during physical human-robot interaction. AB - Robots play more important roles in daily life and bring us a lot of convenience. But when people work with robots, there remain some significant differences in human-human interactions and human-robot interaction. It is our goal to make robots look even more human-like. We design a controller which can sense the force acting on any point of a robot and ensure the robot can move according to the force. First, a spring-mass-dashpot system was used to describe the physical model, and the second-order system is the kernel of the controller. Then, we can establish the state space equations of the system. In addition, the particle swarm optimization algorithm had been used to obtain the system parameters. In order to test the stability of system, the root-locus diagram had been shown in the paper. Ultimately, some experiments had been carried out on the robotic spinal surgery system, which is developed by our team, and the result shows that the new controller performs better during human-robot interaction. PMID- 27933271 TI - Functional Significance of Aurora Kinases-p53 Protein Family Interactions in Cancer. AB - Aurora kinases play critical roles in regulating spindle assembly, chromosome segregation, and cytokinesis to ensure faithful segregation of chromosomes during mitotic cell division cycle. Molecular and cell biological studies have revealed that Aurora kinases, at physiological levels, orchestrate complex sequential cellular processes at distinct subcellular locations through functional interactions with its various substrates. Aberrant expression of Aurora kinases, on the other hand, cause defects in mitotic spindle assembly, checkpoint response activation, and chromosome segregation leading to chromosomal instability. Elevated expression of Aurora kinases correlating with chromosomal instability is frequently detected in human cancers. Recent genomic profiling of about 3000 human cancer tissue specimens to identify various oncogenic signatures in The Cancer Genome Atlas project has reported that recurrent amplification and overexpression of Aurora kinase-A characterize distinct subsets of human tumors across multiple cancer types. Besides the well-characterized canonical pathway interactions of Aurora kinases in regulating assembly of the mitotic apparatus and chromosome segregation, growing evidence also supports the notion that deregulated expression of Aurora kinases in non-canonical pathways drive transformation and genomic instability by antagonizing tumor suppressor and exacerbating oncogenic signaling through direct interactions with critical proteins. Aberrant expression of the Aurora kinases-p53 protein family signaling axes appears to be critical in the abrogation of p53 protein family mediated tumor suppressor pathways frequently deregulated during oncogenic transformation process. Recent findings reveal the existence of feedback regulatory loops in mRNA expression and protein stability of these protein families and their consequences on downstream effectors involved in diverse physiological functions, such as mitotic progression, checkpoint response pathways, as well as self renewal and pluripotency in embryonic stem cells. While these investigations have focused on the functional consequences of Aurora kinase protein family interactions with wild-type p53 family proteins, those involving Aurora kinases and mutant p53 remain to be elucidated. This article presents a comprehensive review of studies on Aurora kinases-p53 protein family interactions along with a prospective view on the possible functional consequences of Aurora kinase-mutant p53 signaling pathways in tumor cells. Additionally, we also discuss therapeutic implications of these findings in Aurora kinases overexpressing subsets of human tumors. PMID- 27933272 TI - Autophagy-Dependent Secretion: Contribution to Tumor Progression. AB - Autophagy is best known as a lysosomal degradation and recycling pathway to maintain cellular homeostasis. During autophagy, cytoplasmic content is recognized and packed in autophagic vacuoles, or autophagosomes, and targeted for degradation. However, during the last years, it has become evident that the role of autophagy is not restricted to degradation alone but also mediates unconventional forms of secretion. Furthermore, cells with defects in autophagy apparently are able to reroute their cargo, like mitochondria, to the extracellular environment; effects that contribute to an array of pathologies. In this review, we discuss the current knowledge of the physiological roles of autophagy-dependent secretion, i.e., the effect on inflammation and insulin/hormone secretion. Finally, we focus on the effects of autophagy dependent secretion on the tumor microenvironment (TME) and tumor progression. The autophagy-mediated secreted factors may stimulate cellular proliferation via auto- and paracrine signaling. The autophagy-mediated release of immune modulating proteins changes the immunosuppresive TME and may promote an invasive phenotype. These effects may be either direct or indirect through facilitating formation of the mobilized vesicle, aid in anterograde trafficking, or alterations in homeostasis and/or autonomous cell signaling. PMID- 27933273 TI - Prognostic Value of Plasma and Urine Glycosaminoglycan Scores in Clear Cell Renal Cell Carcinoma. AB - BACKGROUND: The prognosis of metastatic clear cell renal cell carcinoma (ccRCC) vastly improved since the introduction of antiangiogenic-targeted therapy. However, it is still unclear which biological processes underlie ccRCC aggressiveness and affect prognosis. Here, we checked whether a recently discovered systems biomarker based on plasmatic or urinary measurements of glycosaminoglycans (GAGs) aggregated into diagnostic scores correlated with ccRCC prognosis. METHODS: Thirty-one patients with a diagnosis of ccRCC (23 metastatic) were prospectively enrolled, and their urine and plasma biomarker scores were correlated to progression-free survival (PFS) and overall survival (OS) as either a dichotomous ("Low" vs. "High") or a continuous variable in a multivariate survival analysis. RESULTS: The survival difference between "High"- vs. "Low" scored patients was significant in the case of urine scores (2-year PFS rate = 53.3 vs. 100%, p = 3 * 10-4 and 2-year OS rate = 73.3 vs. 100%, p = 0.0078) and in the case of OS for plasma scores (2-year PFS rate = 60 vs. 84%, p = 0.0591 and 2-year OS rate = 66.7 vs. 90%, p = 0.0206). In multivariate analysis, the urine biomarker score as a continuous variable was an independent predictor of PFS [hazard ratio (HR): 4.62, 95% CI: 1.66-12.83, p = 0.003] and OS (HR: 10.13, 95% CI: 1.80-57.04, p = 0.009). CONCLUSION: This is the first report on an association between plasma or urine GAG scores and the prognosis of ccRCC patients. Prospective trials validating the prognostic and predictive role of this novel systems biomarker are warranted. PMID- 27933274 TI - Screening and Identification of an H-2Kb-Restricted CTL Epitope within the Glycoprotein of Hantaan Virus. AB - The cytotoxic T lymphocyte (CTL) response plays a key role in controlling viral infection, but only a few epitopes within the HTNV glycoprotein (GP) that are recognized by CTLs have been reported. In this study, we identified one murine HTNV GP-derived H2-Kb-restricted CTL epitope in C57BL/6 mice, which could be used to design preclinical studies of vaccines for HTNV infection. First, 15 8-mer peptides were selected from the HTNV GP amino acid sequence based on a percentile rank of <=1% by IEDB which is the most comprehensive collection of epitope prediction and analysis tool. A lower percentile rank indicates higher affinity and higher immune response. In the case of the consensus method, we also evaluated the binding score of peptide-binding affinity by the BIMAS software to confirm that all peptides were able to bind H2-Kb. Second, one novel GP-derived CTL epitope, GP6 aa456-aa463 (ITSLFSLL), was identified in the splenocytes of HTNV-infected mice using the IFN-gamma ELISPOT assay. Third, a single peptide vaccine was administered to C57BL/6 mice to evaluate the immunogenic potential of the identified peptides. ELISPOT and cell-mediated cytotoxicity assays showed that this peptide vaccine induced a strong IFN-gamma response and potent cytotoxicity in immunized mice. Last, we demonstrated that the peptide-vaccinated mice had partial protection from challenge with HTNV. In conclusion, we identified an H2-Kb-restricted CTL epitope with involvement in the host immune response to HTNV infection. PMID- 27933275 TI - An In Vitro Co-culture Mouse Model Demonstrates Efficient Vaccine-Mediated Control of Francisella tularensis SCHU S4 and Identifies Nitric Oxide as a Predictor of Efficacy. AB - Francisella tularensis is a highly virulent intracellular bacterium and cell mediated immunity is critical for protection, but mechanisms of protection against highly virulent variants, such as the prototypic strain F. tularensis strain SCHU S4, are poorly understood. To this end, we established a co-culture system, based on splenocytes from naive, or immunized mice and in vitro infected bone marrow-derived macrophages that allowed assessment of mechanisms controlling infection with F. tularensis. We utilized the system to understand why the clpB gene deletion mutant, DeltaclpB, of SCHU S4 shows superior efficacy as a vaccine in the mouse model as compared to the existing human vaccine, the live vaccine strain (LVS). Compared to naive splenocytes, DeltaclpB-, or LVS-immune splenocytes conferred very significant control of a SCHU S4 infection and the DeltaclpB-immune splenocytes were superior to the LVS-immune splenocytes. Cultures with the DeltaclpB-immune splenocytes also contained higher levels of IFN-gamma, IL-17, and GM-CSF and nitric oxide, and T cells expressing combinations of IFN-gamma, TNF-alpha, and IL-17, than did cultures with LVS immune splenocytes. There was strong inverse correlation between bacterial replication and levels of nitrite, an end product of nitric oxide, and essentially no control was observed when BMDM from iNOS-/- mice were infected. Collectively, the co-culture model identified a critical role of nitric oxide for protection against a highly virulent strain of F. tularensis. PMID- 27933276 TI - Acinetobacter baumannii Isolated from Lebanese Patients: Phenotypes and Genotypes of Resistance, Clonality, and Determinants of Pathogenicity. AB - Introduction:Acinetobacter baumannii is a nosocomial pathogen that usually affects critically ill patients. High mortality rates have been associated with MDR A. baumannii infections. Carbapenem resistance among these isolates is increasing worldwide and is associated with certain International Clones (ICs) and oxacillinases (OXAs). Moreover, this organism possesses a wide range of virulence factors, whose expression is not yet fully understood. In this study, clinical A. baumannii isolates are characterized in terms of antibiotic resistance, mechanisms of carbapenem resistance, clonality, and virulence. Materials and Methods:A. baumannii clinical isolates (n = 90) where obtained from a tertiary care center in Beirut, Lebanon. API 20NE strips in addition to the amplification of blaOXA-51-like were used for identification. Antibiotic susceptibility testing by disk diffusion was then performed in addition to PCRs for the detection of the most commonly disseminated carbapenemases. Clonality was determined by tri-locus PCR typing and doubling times were determined for isolates with varying susceptibility profiles. Biofilm formation, hemolysis, siderophore production, proteolytic activity, and surface motility was then determined for all the isolates. Statistical analysis was then performed for the determination of associations. Results and Discussion: 81 (90%) of the isolates were resistant to carbapenems. These high rates are similar to other multi-center studies in the country suggesting the need of intervention on a national level. 74 (91.3%) of the carbapenem resistant isolates harbored blaOXA-23-like including two that also harbored blaOXA-24-like. 88.9% of the A. baumannii isolates pertained to ICII and three other international clones were detected, showing the wide dissemination of clones into geographically distinct locations. Virulence profiles were highly diverse and no specific pattern was observed. Nevertheless, an association between motility, siderophore production, and biofilm formation was detected (p < 0.05). Conclusions: A very high rate of carbapenem resistance was detected, showing the need for immediate intervention. IC II and OXA-23-like were the most disseminated, reflecting their international dissemination. No specific associations were made between virulence and resistance, but instead associations among certain virulence factors were found. Investigating a more clonally diverse pool of isolates could help in the determination of associations between virulence and resistance. PMID- 27933278 TI - A Simple Method for Closure of Urethrocutaneous Fistula after Tubularized Incised Plate Repair: Preliminary Results. AB - BACKGROUND: Urethrocutaneous fistula (UCF) is the most prevalent complication after hypospadias repair surgery. Many methods have been developed for UCF correction, and the best technique for UCF repair is determined based on the size, location, and number of fistulas, as well as the status of the surrounding skin. OBJECTIVES: In this study, we introduced and evaluated a simple method for UCF correction after tubularized incised plate (TIP) repair. METHODS: This clinical study was conducted on children with UCFs <= 4 mm that developed after TIP surgery for hypospadias repair. The skin was incised around the fistula and the tract was released from the surrounding tissues and the dartos fascia, then ligated with 5 - 0 polydioxanone (PDS) sutures. The dartos fascia, as the second layer, was covered on the fistula tract with PDS thread (gauge 5 - 0) by the continuous suture method. The skin was closed with 6 - 0 Vicryl sutures. After six months of follow-up, surgical outcomes were evaluated based on fistula relapse and other complications. RESULTS: After six months, relapse occurred in only one patient, a six-year-old boy with a single 4-mm distal opening, who had undergone no previous fistula repairs. Therefore, in 97.5% of the cases, relapse was non-existent. Other complications, such as urethral stenosis, intraurethral obstruction, and epidermal inclusion cysts, were not seen in the other patients during the six-month follow-up period. CONCLUSIONS: This repair method, which is simple, rapid, and easily learned, is highly applicable, with a high success rate for the closure of UCFs measuring up to 4 mm in any location. PMID- 27933277 TI - Lectins from Synadenium carinatum (ScLL) and Artocarpus heterophyllus (ArtinM) Are Able to Induce Beneficial Immunomodulatory Effects in a Murine Model for Treatment of Toxoplasma gondii Infection. AB - Infection by Toxoplasma gondii affects around one-third of world population and the treatment for patients presenting toxoplasmosis clinically manifested disease is mainly based by a combination of sulfadiazine, pyrimethamine, and folinic acid. However, this therapeutic protocol is significantly toxic, causing relevant dose-related bone marrow damage. Thus, it is necessary to improve new approaches to investigate the usefulness of more effective and non-toxic agents for treatment of patients with toxoplasmosis. It has been described that lectins from plants can control parasite infections, when used as immunological adjuvants in vaccination procedures. This type of lectins, such as ArtinM and ScLL is able to induce immunostimulatory activities, including efficient immune response against parasites. The present study aimed to evaluate the potential immunostimulatory effect of ScLL and ArtinM for treatment of T. gondii infection during acute phase, considering that there is no study in the literature accomplishing this issue. For this purpose, bone marrow-derived macrophages (BMDMs) were treated with different concentrations from each lectin to determine the maximum concentration without or with lowest cytotoxic effect. After, it was also measured the cytokine levels produced by these cells when stimulated by the selected concentrations of lectins. We found that ScLL showed high capacity to induce of pro-inflammatory cytokine production, while ArtinM was able to induce especially an anti-inflammatory cytokines production. Furthermore, both lectins were able to increase NO levels. Next, we evaluated the treatment effect of ScLL and ArtinM in C57BL/6 mice infected by ME49 strain from T. gondii. The animals were infected and treated with ScLL, ArtinM, ArtinM plus ScLL, or sulfadiazine, and the following parameters analyzed: Cytokines production, brain parasite burden and survival rates. Our results demonstrated that the ScLL or ScLL plus ArtinM treatment induced production of pro-inflammatory and anti-inflammatory cytokines, showing differential but complementary profiles. Moreover, when compared with non-treated mice, the parasite burden was significantly lower and survival rates higher in mice treated with ScLL or ScLL plus ArtinM, similarly with sulfadiazine treatment. In conclusion, the results demonstrated the suitable potential immunotherapeutic effect of ScLL and ArtinM lectins to control acute toxoplasmosis in this experimental murine model. PMID- 27933279 TI - Is There a Role for Genetic Information in Risk Assessment and Decision Making in Prostate Cancer? AB - OBJECTIVES: Prostate cancer is a neoplasm with a variable natural history and clinical behavior. There is much debate on the use of inherited genetic information in clinical application including risk assessment and treatment decisions. This study was performed to evaluate the relationship between clinical parameters of prostate cancer (PSA, Gleason score, and metastasis) and expression of NKX3.1, AMACR, TMPRSS2-ERG, ERG, and SPINK1 genes. METHODS: Newly diagnosed cases of prostate cancer were selected for this study. Thirty four tissue samples were obtained via open radical prostatectomy and 9 samples were obtained via needle biopsy. Each tissue sample was sectioned into two parts, one used for detection of malignant changes and Gleason score determination, and the other immersed in RNA later solution (Qiagen). The expression of NKX3.1, AMACR, TMPRSS2 ERG, ERG, and SPINK1 genes were assessed by real-time PCR assay. Correlation between expression of each gene and PSA level, Gleason score, and presence of metastasis were examined. RESULTS: A total number of 43 specimens were studied, from which 9 were obtained from patients with metastatic prostate cancer. The expression of five examined genes had no correlation with PSA level and Gleason score. The expression of AMACR decreased in metastatic prostate cancer (P = 0.02). The expression of other genes showed no difference between metastatic and non-metastatic tumors (P > 0.1). CONCLUSIONS: Genetic information combined with clinical data can be useful in risk assessment and treatment planning. Based on the results of the current study, the decreased expression of AMACR was a sign of poor prognosis. PMID- 27933281 TI - PET imaging of urokinase-type plasminogen activator receptor (uPAR) in prostate cancer: current status and future perspectives. AB - Overexpression of urokinase-type plasminogen activator receptors (uPAR) represents an important biomarker for aggressiveness in most common malignant diseases, including prostate cancer (PC). Accordingly, uPAR expression either assessed directly in malignant PC tissue or assessed directly in plasma (intact/cleaved forms)-provides independent additional clinical information to that contributed by PSA, Gleason score, and other relevant pathological and clinical parameters. In this respect, non-invasive molecular imaging by positron emission tomography (PET) offers a very attractive technology platform, which can provide the required quantitative information on the uPAR expression profile, without the need for invasive procedures and the risk of missing the target due to tumor heterogeneity. These observations support non-invasive PET imaging of uPAR in PC as a clinically relevant diagnostic and prognostic imaging method. In this review, we will focus on the recent development of uPAR PET and the relevance within prostate cancer imaging. Novel antibody and small-molecule radiotracers-targeting uPAR, including a series of uPAR-targeting PET ligands, based on the high affinity peptide ligand AE105, have been synthesized and tested in vitro and in vivo in preclinical murine xenograft models and, recently, in a first-ever clinical uPAR PET study in cancer patients, including patients with PC. In this phase I study, a high and specific uptake of the tracer 64Cu-DOTA AE105 was found in both primary tumors and lymph node metastases. The results are encouraging and support large-scale clinical trials to determine the utility of uPAR PET in the management of patients with PC with the goal of improving outcome. PMID- 27933280 TI - Bone imaging in prostate cancer: the evolving roles of nuclear medicine and radiology. AB - The bone scan continues to be recommended for both the staging and therapy response assessment of skeletal metastases from prostate cancer. However, it is widely recognised that bone scans have limited sensitivity for disease detection and is both insensitive and non-specific for determining treatment response, at an early enough time point to be clinically useful. We, therefore, review the evolving roles of nuclear medicine and radiology for this application. We have reviewed the published literature reporting recent developments in imaging bone metastases in prostate cancer, and provide a balanced synopsis of the state of the art. The development of single-photon emission computed tomography combined with computed tomography has improved detection sensitivity and specificity but has not yet been shown to lead to improvements in monitoring therapy. A number of bone-specific and tumour-specific tracers for positron emission tomography/computed tomography (PET/CT) are now available for advanced prostate cancer that show promise in both clinical settings. At the same time, the development of whole-body magnetic resonance imaging (WB-MRI) that incorporates diffusion-weighted imaging also offers significant improvements for detection and therapy response assessment. There are emerging data showing comparative SPECT/CT, PET/CT, and WB-MRI test performance for disease detection, but no compelling data on the usefulness of these technologies in response assessment have yet emerged. PMID- 27933282 TI - Myocardial perfusion scintigraphy dosimetry: optimal use of SPECT and SPECT/CT technologies in stress-first imaging protocol. AB - PURPOSE: Over the past decade, nuclear medicine experts have been seeking to minimize patient exposure to radiation in myocardial perfusion scintigraphy (MPS). This review describes the latest technological innovations in MPS, particularly with regard to dose reduction. METHODS: We searched in PubMed for original clinical papers in English, published after 2008, using the following research criteria: (dose) and ((reduction) or (reducing)) and ((myocardial) or (cardiac) or (heart)) and ((nuclear medicine) or (nuclear imaging) or (radionuclide) or (scintigraphy) or (SPET) or (SPECT)). Thereafter, recent reviews on the topic were considered and other relevant clinical papers were added to the results. RESULTS: Of 202 non-duplicate articles, 17 were included. To these, another eight papers cited in recent reviews were added. By optimizing the features of software, i.e., through algorithms for iterative reconstruction with resolution recovery (IRRs), and hardware, i.e., scanners and collimators, and by preferring, unless otherwise indicated, the use of stress-first imaging protocols, it has become possible to reduce the effective dose by at least 50% in stress/rest protocols, and by up to 89% in patients undergoing a diagnostic stress-only study with new technology. With today's SPECT/CT systems, the use of a stress-first protocol can conveniently be performed, resulting in an overall dose reduction of about 35% if two-thirds of stress-first examinations were considered definitively normal. CONCLUSION: Using innovative gamma cameras, collimators and software, as well as, unless otherwise indicated, stress-first imaging protocols, it has become possible to reduce significantly the effective dose in a high percentage of patients, even when X-ray CT scanning is performed for attenuation correction. PMID- 27933283 TI - Neonatal Diagnostics: Toward Dynamic Growth Charts of Neuromotor Control. AB - The current rise of neurodevelopmental disorders poses a critical need to detect risk early in order to rapidly intervene. One of the tools pediatricians use to track development is the standard growth chart. The growth charts are somewhat limited in predicting possible neurodevelopmental issues. They rely on linear models and assumptions of normality for physical growth data - obscuring key statistical information about possible neurodevelopmental risk in growth data that actually has accelerated, non-linear rates-of-change and variability encompassing skewed distributions. Here, we use new analytics to profile growth data from 36 newborn babies that were tracked longitudinally for 5 months. By switching to incremental (velocity-based) growth charts and combining these dynamic changes with underlying fluctuations in motor performance - as the transition from spontaneous random noise to a systematic signal - we demonstrate a method to detect very early stunting in the development of voluntary neuromotor control and to flag risk of neurodevelopmental derail. PMID- 27933284 TI - "We Sometimes Hold on to Ours" - Professionals' Views on Factors that both Delay and Facilitate Transition to Adult Care. AB - BACKGROUND: The transition from child to adult services is a crucial time in the health of young people who may potentially fall into a poorly managed "care gap." Health service provision, which fails to meet the needs of young people and families at this time of significant change, may result in deterioration in health or disengagement with services, which can have negative long-term consequences. Developing transitional care packages has become a focus of activity in the United Kingdom and elsewhere. Indeed, policy documents have been trying to guide practice for many years, with some variable success. There is much work still to be done, particularly around how guidance and the sharing of best practice, when combined can result in a change in practice. OBJECTIVE: This study aimed to explore the views of professionals involved in transitional care, the process of transition in their services, and the barriers and facilitators to transition. METHODS: This was a qualitative study using focus group methodology. Four focus groups were carried out, attended by 36 health professionals across child and adult services. They had expertise in working with young people with various health conditions and disabilities. Transcripts were analyzed using qualitative content analysis. RESULTS: Eight key factors that impact on transition emerged from the data. These included factors associated with the patient group (such as age, health condition, having complex needs) as well as factors associated with services (such as the availability of equivalent services within adult care and the links between child and adult team). CONCLUSION: It is imperative that health professionals consider the population they are working with when planning transitional care and take into account the factors which can lead to delayed transition, so that this can be avoided if possible. Numerous examples of initiatives to facilitate more timely transition were shared: these have been reflected in our "Benchmarks for Transition from Child to Adult Health Services." We offer these benchmarks to inform and guide the practice of others and illustrate their potential for use in the context of the findings shared here. PMID- 27933285 TI - Developmental Profile and Diagnoses in Children Presenting with Motor Stereotypies. AB - INTRODUCTION: Motor stereotypies represent a typical example of the difficulty in distinguishing non-clinical behaviors (physiological and transient) from symptoms or among different disorders ["primary stereotypies," associated with autistic spectrum disorder (ASD), intellectual disabilities, genetic syndromes, and sensory impairment]. The aim of this study was to obtain an accurate assessment on the relationship between stereotypies and neurodevelopmental disorders. METHODS: We studied 23 children (3 girls), aged 36-95 months, who requested a consultation due to the persistence or increased severity of motor stereotypies. None of the patients had a previous diagnosis of ASD. The assessment included the Motor Severity Stereotypy Scale (MSSS), the Repetitive Behavior Scale-Revised (RBS-R), the Raven's Colored Progressive Matrices, the Child Behavior CheckList for ages 11/2-5 or 4-18 (CBCL), the Social Responsiveness Scale (SRS), and the Autism Diagnostic Observation Schedule-second edition (ADOS 2). RESULTS: All patients were showing motor stereotypies for periods of time varying from 6 to 77 months. The MSSS showed that each child had a limited number of stereotypies; their frequency and intensity were mild. The interference of stereotypies was variable; the impairment in daily life was mild. The RBS-R scores were positive for the subscale of "stereotypic behaviors" in all children. Moreover, several children presented other repetitive behaviors, mainly "ritualistic behavior" and "sameness behavior." All patients showed a normal cognitive level. The CBCL evidenced behavioral problems in 22% of the children: internalizing problems, attention, and withdrawn were the main complaints. On the SRS, all but one of the tested patients obtained clinical scores in the clinical range for at least one area. On the ADOS 2, 4 patients obtained scores indicating a moderate level of ASD symptoms, 4 had a mild level, and 15 showed no or minimal signs of ASD. DISCUSSION: Motor stereotypies in children with normal cognitive level represent a challenging diagnostic issue for which a finely tailored assessment is mandatory in order to define a precise developmental profile. Thus, careful and cautious use of standardized tests is warranted to avoid misdiagnosis. Furthermore, it is hard to consider motor stereotypies, even the primary ones, exclusively as a movement disorder. PMID- 27933287 TI - The Generalized Relative Pairs IBD Distribution: Its Use in the Detection of Linkage. AB - I introduce a novel approach to derive the distribution of disease affectional status given alleles identical by descent (IBD) sharing through ITO method. My approach tremendously simplifies the calculation of the affectional status distribution compared to the conventional method, which requires the parental mating information, and could be applied to disease with both dichotomous trait and quantitative trait locus (QTL). This distribution is shown to be independent of relative relationship and be employed to develop the marker IBD distributions for relative relationship. In addition, three linkage tests: the proportion, the mean test, and the LOD score test are proposed for different relative pairs based on their marker IBD distributions. Among all three tests, the mean test for sib pair requires the least sample size, thus, has the highest power. Finally, I evaluate the significance of different relative relationships by a Monte-Carlo simulation approach. PMID- 27933286 TI - Viral Infection in the Development and Progression of Pediatric Acute Respiratory Distress Syndrome. AB - Viral infections are an important cause of pediatric acute respiratory distress syndrome (ARDS). Numerous viruses, including respiratory syncytial virus (RSV) and influenza A (H1N1) virus, have been implicated in the progression of pneumonia to ARDS; yet the incidence of progression is unknown. Despite acute and chronic morbidity associated with respiratory viral infections, particularly in "at risk" populations, treatment options are limited. Thus, with few exceptions, care is symptomatic. In addition, mortality rates for viral-related ARDS have yet to be determined. This review outlines what is known about ARDS secondary to viral infections including the epidemiology, the pathophysiology, and diagnosis. In addition, emerging treatment options to prevent infection, and to decrease disease burden will be outlined. We focused on RSV and influenza A (H1N1) viral induced ARDS, as these are the most common viruses leading to pediatric ARDS, and have specific prophylactic and definitive treatment options. PMID- 27933288 TI - Health Complaints Associated with Poor Rental Housing Conditions in Arkansas: The Only State without a Landlord's Implied Warranty of Habitability. AB - Arkansas is the only U.S. state that does not have a landlord's implied warranty of habitability, meaning tenants have a requirement for maintaining their rental properties at certain habitability standards, but landlords are not legally required to contribute to those minimum health and safety standards. This project assessed the possibility that this lack of landlord responsibility affects tenants' perceived health. Using surveys and interviews, we collected self reported data on the prevalence and description of problems faced by renters who needed household repairs from their landlords. Of almost 1,000 renters, one-third of them had experienced a problem with their landlord making needed repairs; and one-quarter of those had a health issue they attributed to their housing conditions. Common issues included problems with plumbing, heating, or cooling systems, and pest or rodent control. Reported health problems included elevated stress levels, breathing problems, headaches, high blood pressure, and bites or infections. Hispanic respondents and those with less than a high school education were both significantly more likely to report problems with their landlords not making repairs as requested. These data suggest that the lack of landlord requirements may negatively impact the condition of rental properties and, therefore, may negatively impact the health of Arkansas renters. PMID- 27933289 TI - The Association between Stress Measured by Allostatic Load Score and Physiologic Dysregulation in African Immigrants: The Africans in America Study. AB - INTRODUCTION: Allostatic load score (ALS) summarizes the physiological effect of stress on cardiovascular, metabolic and immune systems. As immigration is stressful, ALS could be affected. OBJECTIVE: Associations between age of immigration, reason for immigration, and unhealthy assimilation behavior and ALS were determined in 238 African immigrants to the United States (age 40 +/- 10, mean +/- SD, range 21-64 years). METHODS: ALS was calculated using 10 variables from three domains; cardiovascular (SBP, DBP, cholesterol, triglyceride, homocysteine), metabolic [BMI, A1C, albumin, estimated glomerular filtration rate (eGFR)], and immunological [high-sensitivity C-reactive protein (hsCRP)]. Variables were divided into sex-specific quartiles with high-risk defined by the highest quartile for each variable except for albumin and eGFR, which used the lowest quartile. One point was assigned if the variable was in the high-risk range and 0 if not. Unhealthy assimilation behavior was defined by a higher prevalence of smoking, alcohol consumption, or sedentary activity in immigrants who lived in the US for >=10 years compare to <10 years. RESULTS: Sixteen percent of the immigrants arrived in the US as children (age < 18 years); 84% arrived as adults (age >= 18 years). Compared to adulthood immigrants, childhood immigrants were younger (30 +/- 7 vs. 42 +/- 9, P < 0.01) but had lived in the US longer (20 +/- 8 vs. 12 +/- 9 years, P < 0.01). Age-adjusted ALS was similar in childhood and adulthood immigrants (2.78 +/- 1.83 vs. 2.73 +/- 1.69, P = 0.87). For adulthood immigrants, multiple regression analysis (adj R2 = 0.20) revealed older age at immigration and more years in the US were associated with higher ALS (both P < 0.05); whereas, current age, education, income, and gender had no significant influence (all P >= 0.4). The prevalence of smoking, alcohol intake, and physical activity did not differ in adulthood immigrants living in the US for >=10 years vs. <10 years (all P >= 0.2). Reason for immigration was available for 77 participants. The reasons included: family reunification, lottery, marriage, work, education, and asylum. Compared to all other reasons combined, immigration for family reunification was associated with the lowest ALS (1.94 +/- 1.51 vs. 3.03 +/- 1.86, P = 0.03). CONCLUSION: African immigrants do not appear to respond to the stress of immigration by developing unhealthy assimilation behaviors. However, older age at immigration and increased duration of stay in the US are associated with higher ALS; whereas, family reunification is associated with lower ALS. CLINICAL TRIALSGOV IDENTIFIER: NCT00001853. PMID- 27933290 TI - Validation of a Cochlear Implant Patient-Specific Model of the Voltage Distribution in a Clinical Setting. AB - Cochlear Implants (CIs) are medical implantable devices that can restore the sense of hearing in people with profound hearing loss. Clinical trials assessing speech intelligibility in CI users have found large intersubject variability. One possibility to explain the variability is the individual differences in the interface created between electrodes of the CI and the auditory nerve. In order to understand the variability, models of the voltage distribution of the electrically stimulated cochlea may be useful. With this purpose in mind, we developed a parametric model that can be adapted to each CI user based on landmarks from individual cone beam computed tomography (CBCT) scans of the cochlea before and after implantation. The conductivity values of each cochlea compartment as well as the weighting factors of different grounding modes have also been parameterized. Simulations were performed modeling the cochlea and electrode positions of 12 CI users. Three models were compared with different levels of detail: a homogeneous model (HM), a non-patient-specific model (NPSM), and a patient-specific model (PSM). The model simulations were compared with voltage distribution measurements obtained from the backward telemetry of the 12 CI users. Results show that the PSM produces the lowest error when predicting individual voltage distributions. Given a patient-specific geometry and electrode positions, we show an example on how to optimize the parameters of the model and how to couple it to an auditory nerve model. The model here presented may help to understand speech performance variability and support the development of new sound coding strategies for CIs. PMID- 27933291 TI - Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice. AB - Disabled-2 (Dab2) is a clathrin and cargo binding endocytic adaptor protein, and cell biology studies revealed that Dab2 plays a role in cellular trafficking of a number of transmembrane receptors and signaling proteins. A PTB/PID domain located in the N-terminus of Dab2 binds the NPXY motif(s) present at the cytoplasmic tails of certain transmembrane proteins/receptors. The membrane receptors reported to bind directly to Dab2 include LDL receptor and its family members LRP1 and LRP2 (megalin), growth factor receptors EGFR and FGFR, and the cell adhesion receptor beta1 integrin. Dab2 also serves as an adaptor in signaling pathways. Particularly, Dab2 facilitates the endocytosis of the Ras activating Grb2/Sos1 signaling complex, controls its disassembly, and thereby regulates the Ras/MAPK signaling pathway. Cellular analyses have suggested several diverse functions for the widely expressed proteins, and Dab2 is also considered a tumor suppressor, as loss or reduced expression is found in several cancer types. Dab2 null mutant mice were generated and investigated to determine if the findings from cellular studies might be important and relevant in intact animals. Dab2 conditional knockout mice mediated through a Sox2-Cre transgene have no obvious developmental defects and have a normal life span despite that the Dab2 protein is essentially absent in the mutant mice. The conditional knockout mice were grossly normal, though more recent investigation of the Dab2 deficient mice revealed several phenotypes, which can be accounted for by several previously suggested mechanisms. The studies of mutant mice established that Dab2 plays multiple physiological roles through its endocytic functions and modulation of signal pathways. PMID- 27933292 TI - Nitric Oxide Modulates Postnatal Bone Marrow-Derived Mesenchymal Stem Cell Migration. AB - Nitric oxide (NO) is a small free-radical gas molecule, which is highly diffusible and can activate a wide range of downstream effectors, with rapid and widespread cellular effects. NO is a versatile signaling mediator with a plethora of cellular functions. For example, NO has been shown to regulate actin, the microfilament, dependent cellular functions, and also acts as a putative stem cell differentiation-inducing agent. In this study, using a wound-healing model of cellular migration, we have explored the effect of exogenous NO on the kinetics of movement and morphological changes in postnatal bone marrow-derived mesenchymal stem cells (MSCs). Cellular migration kinetics and morphological changes of the migrating MSCs were measured in the presence of an NO donor (S Nitroso-N-Acetyl-D,L-Penicillamine, SNAP), especially, to track the dynamics of single-cell responses. Two experimental conditions were assessed, in which SNAP (200 MUM) was applied to the MSCs. In the first experimental group (SN-1), SNAP was applied immediately following wound formation, and migration kinetics were determined for 24 h. In the second experimental group (SN-2), MSCs were pretreated for 7 days with SNAP prior to wound formation and the determination of migration kinetics. The generated displacement curves were further analyzed by non-linear regression analysis. The migration displacement of the controls and NO treated MSCs (SN-1 and SN-2) was best described by a two parameter exponential functions expressing difference constant coefficients. Additionally, changes in the fractal dimension (D) of migrating MSCs were correlated with their displacement kinetics for all the three groups. Overall, these data suggest that NO may evidently function as a stop migration signal by disordering the cytoskeletal elements required for cell movement and proliferation of MSCs. PMID- 27933293 TI - Differences in the Mechanical Properties of the Developing Cerebral Cortical Proliferative Zone between Mice and Ferrets at both the Tissue and Single-Cell Levels. AB - Cell-producing events in developing tissues are mechanically dynamic throughout the cell cycle. In many epithelial systems, cells are apicobasally tall, with nuclei and somata that adopt different apicobasal positions because nuclei and somata move in a cell cycle-dependent manner. This movement is apical during G2 phase and basal during G1 phase, whereas mitosis occurs at the apical surface. These movements are collectively referred to as interkinetic nuclear migration, and such epithelia are called "pseudostratified." The embryonic mammalian cerebral cortical neuroepithelium is a good model for highly pseudostratified epithelia, and we previously found differences between mice and ferrets in both horizontal cellular density (greater in ferrets) and nuclear/somal movements (slower during G2 and faster during G1 in ferrets). These differences suggest that neuroepithelial cells alter their nucleokinetic behavior in response to physical factors that they encounter, which may form the basis for evolutionary transitions toward more abundant brain-cell production from mice to ferrets and primates. To address how mouse and ferret neuroepithelia may differ physically in a quantitative manner, we used atomic force microscopy to determine that the vertical stiffness of their apical surface is greater in ferrets (Young's modulus = 1700 Pa) than in mice (1400 Pa). We systematically analyzed factors underlying the apical-surface stiffness through experiments to pharmacologically inhibit actomyosin or microtubules and to examine recoiling behaviors of the apical surface upon laser ablation and also through electron microscopy to observe adherens junction. We found that although both actomyosin and microtubules are partly responsible for the apical-surface stiffness, the mouse= 0.4475) number of piglets born and nursed, and similar (P >= 0.3141) body condition traits (e.g., body weight and backfat thickness) post-farrowing, yet exhibited minimal or extreme loss (P <= 0.0094) in body weight (8.6 +/- 1.48 kg and 26.1 +/- 1.90 kg, respectively) and backfat thickness (1.3 +/- 0.67 mm and 4.7 +/- 0.86 mm, respectively) following lactation (weaning). Plasma samples from first-parity gilts at post-farrowing and weaning were investigated using UPLC-MS and GC-MS to generate a comprehensive metabolic profile. Each approach yielded approximately 700 detected features. An ANOVA was performed on each detected compound in R for time of collection, body condition change, and the interaction, followed by a false discovery correction. Two unknown features were different (P <= 0.05) for extreme vs. minimal body condition change. Several compound differences (P <= 0.05) were identified between post-farrowing and weaning. Thirty-two features detected by UPLC-MS had at least a log2 fold-change of +/-1.0 while only 18 features had a log2 fold change of +/-0.6 or more for the significant GC-MS features. Annotation implicated various metabolic pathways. Creatinine was greater at weaning (P = 0.0224) and others have reported increased serum concentrations of creatinine in response to body weight loss. Hippurate and caprolactam, associated with protein catabolism, were also greater (P <= 0.0166) at weaning. Phospholipid features (P <= 0.0347) and inositol-related features (P <= 0.0236) were also greater at weaning. Inositol features may exert insulin-like effects. The energetic demands of lactation in gilts nursing their first litter indicated a greater difference exists between early and late lactation regardless of body condition loss. PMID- 27933299 TI - Strategy to Prime the Host and Cells to Augment Therapeutic Efficacy of Progenitor Cells for Patients with Myocardial Infarction. AB - Cell therapy in myocardial infarction (MI) is an innovative strategy that is regarded as a rescue therapy to repair the damaged myocardium and to promote neovascularization for the ischemic border zone. Among several stem cell sources for this purpose, autologous progenitors from bone marrow or peripheral blood would be the most feasible and safest cell-source. Despite the theoretical benefit of cell therapy, this method is not widely adopted in the actual clinical practice due to its low therapeutic efficacy. Various methods have been used to augment the efficacy of cell therapy in MI, such as using different source of progenitors, genetic manipulation of cells, or priming of the cells or hosts (patients) with agents. Among these methods, the strategy to augment the therapeutic efficacy of the autologous peripheral blood mononuclear cells (PBMCs) by priming agents may be the most feasible and the safest method that can be applied directly to the clinic. In this review, we will discuss the current status and future directions of priming PBMCs or patients, as for cell therapy of MI. PMID- 27933300 TI - Head Tilting Elicited by Head Turning in Three Dogs with Hypoplastic Cerebellar Nodulus and Ventral Uvula. AB - The nodulus and ventral uvula (NU) of the cerebellum play a major role in vestibular function in humans and experimental animals; however, there is almost no information about NU function in the veterinary clinical literature. In this report, we describe three canine cases diagnosed with presumptive NU hypoplasia. Of them, one adult dog presented with cervical intervertebral disk disease, and two juvenile dogs presented with signs of central vestibular disease. Interestingly, an unusual and possibly overlooked neurological sign that we called "positioning head tilt" was observed in these dogs. The dogs were able to turn freely in any direction at will. The head was in a level position when static or when the dog walked in a straight line. However, the head was tilted to the opposite side when the dog turned. Veterinary clinicians should be aware of this neurological sign that has not been reported previously, and its application in lesion localization in dogs. PMID- 27933301 TI - The Three "Musketairs" - Lasker Prize 2016 goes to the protagonists of hypoxia research. PMID- 27933302 TI - Polybrominated Diphenyl Ethers and Other Persistent Organic Pollutants in Serum Pools from the National Health and Nutrition Examination Survey: 2001-2002. AB - Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), and persistent pesticides have been measured in serum pools from participants 3-5, 6 11, 12-19, 20-39, 40-59, and >=60 years of age from the 2001-2002 National Health and Nutrition Examination Survey. For 2,2',4,4'-tetrabromodiphenyl ether (PBDE 47), the unweighted (not adjusted for sampling weights) arithmetic mean concentration (+/-95% confidence interval) was 3.4 times higher in 3-5-year-olds (216 +/- 30 ng/g of lipid) than in 12-19-year-olds (64 +/- 11 ng/g of lipid), with no apparent change with increasing age for adults >=20 years of age. By contrast, unweighted arithmetic mean concentrations of traditional persistent organic pollutants (POPs) such as hexachlorobenzene (HCB) and 2,2',3,3',4,4',5,5' octachlorobiphenyl (PCB194) were 2- and 20-fold higher, respectively, in persons >=60 years than in 12-19-year-old adolescents. Findings suggest higher exposures to PBDEs but lower exposures to traditional POPs in 3-5-year-old children than in adults. PMID- 27933303 TI - Purification of baculovirus vectors using heparin affinity chromatography. AB - Baculoviruses are commonly used for recombinant protein and vaccine production. Baculoviruses are nonpathogenic to vertebrates, have a large packaging capacity, display broad host and cell type tropism, infect both dividing and nondividing cells, and do not elicit strong immune or allergic responses in vivo. Hence, their use as gene delivery vehicles has become increasingly popular in recent years. Moreover, baculovirus vectors carrying mammalian regulatory elements can efficiently transduce and express transgenes in mammalian cells. Based on the finding that heparan sulfate, which is structurally similar to heparin, is an attachment receptor for baculovirus, we developed a novel scalable baculovirus purification method using heparin-affinity chromatography. Baculovirus supernatants were loaded onto a POROS heparin column, washed to remove unbound materials, and eluted with 1.5 mol/l NaCl, which yielded a recovery of purified baculovirus of 85%. After ultracentrifugation, baculovirus titers increased from 200- to 700-fold with overall yields of 26-29%. We further show that baculovirus particles were infectious, normal in morphology and size, despite high-salt elution and shear forces used during purification and concentration. Our chromatography-based purification method is scalable and, together with ultracentrifugation and/or tangential flow filtration, will be suitable for large scale manufacturing of baculovirus stocks for protein and vaccine production and in gene therapy applications. PMID- 27933304 TI - Preclinical validation: LV/IL-12 transduction of patient leukemia cells for immunotherapy of AML. AB - Interleukin-12 (IL-12) is a potent cytokine that may be harnessed to treat cancer. To date, nearly 100 IL-12-based clinical trials have been initiated worldwide. Yet systemic administration of IL-12 is toxic. Different strategies are being developed to reduce such toxicities by restricting IL-12 distribution. Our previous studies employed lentivector-mediated expression of murine IL-12 in tumor cells and demonstrated effective protection in both mouse leukemia and solid tumor challenge models. In this study, we carried out preclinical validation studies using a novel lentivector to engineer expression of human IL 12 in acute myeloid leukemia blast cells isolated from 21 patients. Acute myeloid leukemia cells were transduced with a bicistronic lentivector that encodes the human IL-12 cDNA as a fusion, as well as a LNGFR (DeltaLNGFR)/mutant thymidylate kinase cassette as a marking and cell-fate control element. A range of 20-70% functional transduction efficiencies was achieved. Transduced acute myeloid leukemia cells produced bioactive IL-12 protein and displayed dose-dependent sensitivity to the prodrug 3'-azido-3'-deoxythymidine. In vitro immortalization assays using transduced mouse hematopoietic stem cells demonstrated minimal genotoxic risk from our IL-12 vector. Scale-up transduction and cell processing was subsequently validated in a GMP facility to support our (now approved) Clinical Trial Application (CTA). PMID- 27933305 TI - Robust generation of transgenic mice by simple hypotonic solution mediated delivery of transgene in testicular germ cells. AB - Our ability to decipher gene sequences has increased enormously with the advent of modern sequencing tools, but the ability to divulge functions of new genes have not increased correspondingly. This has caused a remarkable delay in functional interpretation of several newly found genes in tissue and age specific manner, limiting the pace of biological research. This is mainly due to lack of advancements in methodological tools for transgenesis. Predominantly practiced method of transgenesis by pronuclear DNA-microinjection is time consuming, tedious, and requires highly skilled persons for embryo-manipulation. Testicular electroporation mediated transgenesis requires use of electric current to testis. To this end, we have now developed an innovative technique for making transgenic mice by giving hypotonic shock to male germ cells for the gene delivery. Desired transgene was suspended in hypotonic Tris-HCl solution (pH 7.0) and simply injected in testis. This resulted in internalization of the transgene in dividing germ-cells residing at basal compartment of tubules leading to its integration in native genome of mice. Such males generated transgenic progeny by natural mating. Several transgenic animals can be generated with minimum skill within short span of time by this easily adaptable novel technique. PMID- 27933306 TI - Significant changes in endogenous retinal gene expression assessed 1 year after a single intraocular injection of AAV-CNTF or AAV-BDNF. AB - Use of viral vectors to deliver therapeutic genes to the central nervous system holds promise for the treatment of neurodegenerative diseases and neurotrauma. Adeno-associated viral (AAV) vectors encoding brain-derived neurotrophic factor (BDNF) or ciliary derived neurotrophic factor (CNTF) promote the viability and regeneration of injured adult rat retinal ganglion cells. However, these growth inducing transgenes are driven by a constitutively active promoter, thus we examined whether long-term AAV-mediated secretion of BDNF or CNTF affected endogenous retinal gene expression. One year after the intravitreal injection of AAV-green fluorescent protein (GFP), bi-cistronic AAV-BDNF-GFP or AAV-CNTF-GFP, mRNA was extracted and analyzed using custom 96 well polymerase chain reaction arrays. Of 93 test genes, 56% showed significantly altered expression in AAV-BDNF GFP and/or AAV-CNTF-GFP retinas compared with AAV-GFP controls. Of these genes, 73% showed differential expression in AAV-BDNF versus AAV-CNTF injected eyes. To focus on retinal ganglion cell changes, quantitative polymerase chain reaction was undertaken on mRNA (16 genes) obtained from fixed retinal sections in which the ganglion cell layer was enriched. The sign and extent of fold changes in ganglion cell layer gene expression differed markedly from whole retinal samples. Sustained and global alteration in endogenous mRNA expression after gene therapy should be factored into any interpretation of experimental/clinical outcomes, particularly when introducing factors into the central nervous system that require secretion to evoke functionality. PMID- 27933307 TI - Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques. AB - Systemically delivered adeno-associated viral (AAV) vectors are now in early phase clinical trials for a variety of diseases. While there is a general consensus on inclusion and exclusion criteria for each of these trials, the conditions under which vectors are infused vary significantly. In this study, we evaluated the impact of intravenous infusion rate of AAV8 vector in cynomolgus macaques on transgene expression, vector clearance from the circulation, and potential activation of the innate immune system. The dose of AAV8 vector in terms of genome copies per kilogram body weight and its concentration were fixed, while the rate of infusion varied to deliver the entire dose over different time periods, including 1, 10, or 90 minutes. Analyses during the in-life phase of the experiment included sequential evaluation of whole blood for vector genomes and appearance of proinflammatory cytokines. Liver tissues were analyzed at the time of necropsy for enhanced green fluorescent protein (eGFP) expression and vector genomes. The data were remarkable with a relative absence of any statistically significant effect of infusion time on vector transduction, safety, and clearance. However, some interesting and unexpected trends did emerge. PMID- 27933308 TI - Tailored transgene expression to specific cell types in the central nervous system after peripheral injection with AAV9. AB - The capacity of certain adeno-associated virus (AAV) vectors to cross the blood brain barrier after intravenous delivery offers a unique opportunity for noninvasive brain delivery. However, without a well-tailored system, the use of a peripheral route injection may lead to undesirable transgene expression in nontarget cells or organs. To refine this approach, the present study characterizes the transduction profiles of new self-complementary AAV9 (scAAV9) expressing the green fluorescent protein (GFP) either under an astrocyte (glial fibrillary acidic (GFA) protein) or neuronal (Synapsin (Syn)) promoter, after intravenous injection of adult mice (2 * 1013 vg/kg). ScAAV9-GFA-GFP and scAAV9 Syn-GFP robustly transduce astrocytes (11%) and neurons (17%), respectively, without aberrant expression leakage. Interestingly, while the percentages of GFP positive astrocytes with scAAV9-GFA-GFP are similar to the performances observed with scAAV9-CBA-GFP (broadly active promoter), significant higher percentages of neurons express GFP with scAAV9-Syn-GFP. GFP-positive excitatory as well as inhibitory neurons are observed, as well as motor neurons in the spinal cord. Additionally, both activated (GFAP-positive) and resting astrocytes (GFAP negative) express the reporter gene after scAAV9-GFA-GFP injection. These data thoroughly characterize the gene expression specificity of AAVs fitted with neuronal and astrocyte-selective promoters after intravenous delivery, which will prove useful for central nervous system (CNS) gene therapy approaches in which peripheral expression of transgene is a concern. PMID- 27933309 TI - Impact of age and vector construct on striatal and nigral transgene expression. AB - Therapeutic protein delivery using viral vectors has shown promise in preclinical models of Parkinson's disease (PD) but clinical trial success remains elusive. This may partially be due to a failure to include advanced age as a covariate despite aging being the primary risk factor for PD. We investigated transgene expression following intracerebral injections of recombinant adeno-associated virus pseudotypes 2/2 (rAAV2/2), 2/5 (rAAV2/5), 2/9 (rAAV2/9), and lentivirus (LV) expressing green fluorescent protein (GFP) in aged versus young adult rats. Both rAAV2/2 and rAAV2/5 yielded lower GFP expression following injection to either the aged substantia nigra or striatum. rAAV2/9-mediated GFP expression was deficient in the aged striatonigral system but displayed identical transgene expression between ages in the nigrostriatal system. Young and aged rats displayed equivalent GFP levels following LV injection to the striatonigral system but LV-delivered GFP was deficient in delivering GFP to the aged nigrostriatal system. Notably, age-related transgene expression deficiencies revealed by protein quantitation were poorly predicted by GFP-immunoreactive cell counts. Further, in situ hybridization for the viral CbetaA promoter revealed surprisingly limited tropism for astrocytes compared to neurons. Our results demonstrate that aging is a critical covariate to consider when designing gene therapy approaches for PD. PMID- 27933310 TI - Dynamics of antigen presentation to transgene product-specific CD4+ T cells and of Treg induction upon hepatic AAV gene transfer. AB - The tolerogenic hepatic microenvironment impedes clearance of viral infections but is an advantage in viral vector gene transfer, which often results in immune tolerance induction to transgene products. Although the underlying tolerance mechanism has been extensively studied, our understanding of antigen presentation to transgene product-specific CD4+ T cells remains limited. To address this, we administered hepatotropic adeno-associated virus (AAV8) vector expressing cytoplasmic ovalbumin (OVA) into wt mice followed by adoptive transfer of transgenic OVA-specific T cells. We find that that the liver-draining lymph nodes (celiac and portal) are the major sites of MHC II presentation of the virally encoded antigen, as judged by in vivo proliferation of DO11.10 CD4+ T cells (requiring professional antigen-presenting cells, e.g., macrophages) and CD4+CD25+FoxP3+ Treg induction. Antigen presentation in the liver itself contributes to activation of CD4+ T cells egressing from the liver. Hepatic induced Treg rapidly disseminate through the systemic circulation. By contrast, a secreted OVA transgene product is presented in multiple organs, and OVA-specific Treg emerge in both the thymus and periphery. In summary, liver draining lymph nodes play an integral role in hepatic antigen presentation and peripheral Treg induction, which results in systemic regulation of the response to viral gene products. PMID- 27933311 TI - Contribution of Cerebellar Loops to Action Timing. AB - Recent studies of sensorimotor processing have benefited from decision-making paradigms that emphasize the selection of appropriate movements. Selecting when to make those responses, or action timing, is important as well. Although the cerebellum is commonly viewed as a controller of movement dynamics, its role in action timing is also firmly supported. Several lines of research have now extended this idea. Anatomical findings have revealed connections between the cerebellum and broader timing circuits, neurophysiological results have suggested mechanisms for timing within its microcircuitry, and theoretical work has indicated how temporal signals are processed through it and decoded by its targets. These developments are inspiring renewed studies of the role of the cerebellar loops in action timing. PMID- 27933312 TI - The Genetics and Epigenetics of PTSD: Overview, Recent Advances, and Future Directions. AB - This paper provides a brief summary and commentary on the growing literature and current developments related to the genetic underpinnings of posttraumatic stress disorder (PTSD). We first briefly provide an overview of the behavioral genetic literature on PTSD, followed by a short synopsis of the substantial candidate gene literature with a focus on genes that have been meta-analyzed. We then discuss the genome-wide association studies (GWAS) that have been conducted, followed by an introduction to other molecular platforms used in PTSD genomic studies, such as epigenetic and expression approaches. We close with a discussion of developments in the field that include the creation of the PTSD workgroup of the Psychiatric Genomics Consortium, statistical advances that can be applied to GWAS data to answer questions of heritability and genetic overlap across phenotypes, and bioinformatics techniques such as gene pathway analyses which will further advance our understanding of the etiology of PTSD. PMID- 27933313 TI - Genetic engineering of chimeric antigen receptors using lamprey derived variable lymphocyte receptors. AB - Chimeric antigen receptors (CARs) are used to redirect effector cell specificity to selected cell surface antigens. Using CARs, antitumor activity can be initiated in patients with no prior tumor specific immunity. Although CARs have shown promising clinical results, the technology remains limited by the availability of specific cognate cell target antigens. To increase the repertoire of targetable tumor cell antigens we utilized the immune system of the sea lamprey to generate directed variable lymphocyte receptors (VLRs). VLRs serve as membrane bound and soluble immune effectors analogous but not homologous to immunoglobulins. They have a fundamentally different structure than immunoglobulin (Ig)-based antibodies while still demonstrating high degrees of specificity and affinity. To test the functionality of VLRs as the antigen recognition domain of CARs, two VLR-CARs were created. One contained a VLR specific for a murine B cell leukemia and the other contained a VLR specific for the human T cell surface antigen, CD5. The CAR design consisted of the VLR sequence, myc-epitope tag, CD28 transmembrane domain, and intracellular CD3zeta signaling domain. We demonstrate proof of concept, including gene transfer, biosynthesis, cell surface localization, and effector cell activation for multiple VLR-CAR designs. Therefore, VLRs provide an alternative means of CAR based cancer recognition. PMID- 27933314 TI - Tunneling nanotubes: an alternate route for propagation of the bystander effect following oncolytic viral infection. AB - Tunneling nanotubes (TNTs) are ultrafine, filamentous actin-based cytoplasmic extensions which form spontaneously to connect cells at short and long-range distances. We have previously described long-range intercellular communication via TNTs connecting mesothelioma cells in vitro and demonstrated TNTs in intact tumors from patients with mesothelioma. Here, we investigate the ability of TNTs to mediate a viral thymidine kinase based bystander effect after oncolytic viral infection and administration of the nucleoside analog ganciclovir. Using confocal microscopy we assessed the ability of TNTs to propagate enhanced green fluorescent protein (eGFP), which is encoded by the herpes simplex virus NV1066, from infected to uninfected recipient cells. Using time-lapse imaging, we observed eGFP expressed in infected cells being transferred via TNTs to noninfected cells; additionally, increasing fluorescent activity in recipient cells indicated cell-to-cell transmission of the eGFP-expressing NV1066 virus had also occurred. TNTs mediated cell death as a form of direct cell-to-cell transfer following viral thymidine kinase mediated activation of ganciclovir, inducing a unique long-range form of the bystander effect through transmission of activated ganciclovir to nonvirus-infected cells. Thus, we provide proof-of-principle demonstration of a previously unknown and alternative mechanism for inducing apoptosis in noninfected recipient cells. The conceptual advance of this work is that TNTs can be harnessed for delivery of oncolytic viruses and of viral thymidine kinase activated drugs to amplify the bystander effect between cancer cells over long distances in stroma-rich tumor microenvironments. PMID- 27933315 TI - Immunogenicity of self tumor associated proteins is enhanced through protein truncation. AB - We showed previously that therapy with Vesicular Stomatitis Virus (VSV) expressing tumor-associated proteins eradicates established tumors. We show here that when cellular cDNA were cloned into VSV which retained their own poly-A signal, viral species emerged in culture which had deleted the cellular poly-A signal and also contained a truncated form of the protein coding sequence. Typically, the truncation occurred such that a Tyrosine-encoding codon was converted into a STOP codon. We believe that the truncation of tumor-associated proteins expressed from VSV in this way occurred to preserve the ability of the virus to replicate efficiently. Truncated cDNA expressed from VSV were significantly more effective than full length cDNA in treating established tumors. Moreover, tumor therapy with truncated cDNA was completely abolished by depletion of CD4+ T cells, whereas therapy with full length cDNA was CD8+ T cell dependent. These data show that the type/potency of antitumor immune responses against self-tumor-associated proteins can be manipulated in vivo through the nature of the self protein (full length or truncated). Therefore, in addition to generation of neoantigens through sequence mutation, immunological tolerance against self-tumor-associated proteins can be broken through manipulation of protein integrity, allowing for rational design of better self-immunogens for cancer immunotherapy. PMID- 27933316 TI - Systemic therapy with oncolytic myxoma virus cures established residual multiple myeloma in mice. AB - Multiple myeloma is an incurable malignancy of plasma B-cells. Traditional chemotherapeutic regimes often induce initial tumor regression; however, virtually all patients eventually succumb to relapse caused by either reintroduction of disease during autologous transplant or expansion of chemotherapy resistant minimal residual disease. It has been previously demonstrated that an oncolytic virus known as myxoma can completely prevent myeloma relapse caused by reintroduction of malignant cells during autologous transplant. The ability of this virus to treat established residual disease in vivo, however, remained unknown. Here we demonstrate that intravenous administration of myxoma virus into mice bearing disseminated myeloma results in the elimination of 70-90% of malignant cells within 24 hours. This rapid debulking was dependent on direct contact of myxoma virus with residual myeloma and did not occur through destruction of the hematopoietic bone marrow niche. Importantly, systemic myxoma therapy also induced potent antimyeloma CD8+ T cell responses which localized to the bone marrow and were capable of completely eradicating established myeloma in some animals. These results demonstrate that oncolytic myxoma virus is not only effective at preventing relapse caused by reinfusion of tumor cells during stem cell transplant, but is also potentially curative for patients bearing established minimal residual disease. PMID- 27933317 TI - THE EFFECT OF LOW TO MODERATE PRENATAL ALCOHOL EXPOSURE AND BINGE DRINKING EPISODES ON DRAW-A-PERSON AT AGE 5 YEARS. AB - This study examined the effects of maternal alcohol consumption and binge drinking during pregnancy on children's Draw-A-Person (DAP) scores. Participants were 1,533 5-year-olds from the Danish National Birth Cohort. Regression analyses revealed an adverse effect of nine or more drinks per week. A drop in mean DAP score of 6.26 (95 % CI: -12.24; -0.39) was observed in the fully adjusted model. A significant interaction between average weekly consumption and binge episodes also was observed. Findings suggest that prenatal exposure to moderate weekly doses of alcohol and binge drinking episodes are associated with lowered scores on the DAP. PMID- 27933318 TI - Global Analysis and Comparison of the Transcriptomes and Proteomes of Group A Streptococcus Biofilms. AB - To gain a better understanding of the genes and proteins involved in group A Streptococcus (GAS; Streptococcus pyogenes) biofilm growth, we analyzed the transcriptome, cellular proteome, and cell wall proteome from biofilms at different stages and compared them to those of plankton-stage GAS. Using high throughput RNA sequencing (RNA-seq) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) shotgun proteomics, we found distinct expression profiles in the transcriptome and proteome. A total of 46 genes and 41 proteins showed expression across the majority of biofilm time points that was consistently higher or consistently lower than that seen across the majority of planktonic time points. However, there was little overlap between the genes and proteins on these two lists. In line with other studies comparing transcriptomic and proteomic data, the overall correlation between the two data sets was modest. Furthermore, correlation was poorest for biofilm samples. This suggests a high degree of regulation of protein expression by nontranscriptional mechanisms. This report illustrates the benefits and weaknesses of two different approaches to global expression profiling, and it also demonstrates the advantage of using proteomics in conjunction with transcriptomics to gain a more complete picture of global expression within biofilms. In addition, this report provides the fullest characterization of expression patterns in GAS biofilms currently available. IMPORTANCE Prokaryotes are thought to regulate their proteomes largely at the level of transcription. However, the results from this first set of global transcriptomic and proteomic analyses of paired microbial samples presented here show that this assumption is false for the majority of genes and their products in S. pyogenes. In addition, the tenuousness of the link between transcription and translation becomes even more pronounced when microbes exist in a biofilm or a stationary planktonic state. Since the transcriptome level does not usually equal the proteome level, the validity attributed to gene expression studies as well as proteomic studies in microbial analyses must be brought into question. Therefore, the results attained by either approach, whether RNA-seq or shotgun proteomics, must be taken in context and evaluated with particular care since they are by no means interchangeable. PMID- 27933319 TI - A Metabolic Widget Adjusts the Phosphoenolpyruvate-Dependent Fructose Influx in Pseudomonas putida. AB - Fructose uptake in the soil bacterium Pseudomonas putida occurs through a canonical phosphoenolpyruvate (PEP)-dependent sugar transport system (PTSFru). The logic of the genetic circuit that rules its functioning is puzzling: the transcription of the fruBKA operon, encoding all the components of PTSFru, can escape the repression exerted by the catabolite repressor/activator protein Cra solely in the presence of intracellular fructose-1-P, an agonist formed only when fructose has been already transported. To study this apparently incongruous regulatory architecture, the changes in the transcriptome brought about by a seamless Deltacra deletion in P. putida strain KT2440 were inspected under different culture conditions. The few genes found to be upregulated in the cra mutant unexpectedly included PP_3443, encoding a bona fide glyceraldehyde-3-P dehydrogenase. An in silico model was developed to explore emergent properties that could result from such connections between sugar uptake with Cra and PEP. Simulation of fructose transport revealed that sugar uptake called for an extra supply of PEP (obtained through the activity of PP_3443) that was kept (i.e., memorized) even when the carbohydrate disappeared from the medium. This feature was traced to the action of two sequential inverters that connect the availability of exogenous fructose to intracellular PEP levels via Cra/PP_3443. The loss of such memory caused a much longer lag phase in cells shifted from one growth condition to another. The term "metabolic widget" is proposed to describe a merged biochemical and regulatory patch that tailors a given node of the cell molecular network to suit species-specific physiological needs. IMPORTANCE The regulatory nodes that govern metabolic traffic in bacteria often show connectivities that could be deemed unnecessarily complex at a first glance. Being a soil dweller and plant colonizer, Pseudomonas putida frequently encounters fructose in the niches that it inhabits. As is the case with many other sugars, fructose is internalized by a dedicated phosphoenolpyruvate (PEP) dependent transport system (PTSFru), the expression of which is repressed by the fructose-1-P-responding Cra regulatory protein. However, Cra also controls a glyceraldehyde-3-P dehydrogenase that fosters accumulation of PEP (i.e., the metabolic fuel for PTSFru). A simple model representing this metabolic and regulatory device revealed that such an unexpected connectivity allows cells to shift smoothly between fructose-rich and fructose-poor conditions. Therefore, although the metabolic networks that handle sugar (i.e., fructose) consumption look very similar in most eubacteria, the way in which their components are intertwined endows given microorganisms with emergent properties for meeting species-specific and niche-specific needs. PMID- 27933321 TI - Introduction of Basic Dermatologic Ultrasound in Undergraduate Medical Education. AB - Purpose: Teaching ultrasound procedures to undergraduates has recently been proposed to improve the quality of medical education. We address the impact of applying standardized dermatologic ultrasound teaching to our undergraduates. Materials and Methods: Medical students were offered an additional theoretical and practical seminar involving hands-on ultrasound dermatologic ultrasound during their mandatory dermatology practical training. The students' theoretical knowledge and dermatologic ultrasoud skills were tested with a multiple choice questionnaire extracted from Level 1 Spanish Society of Ultrasound Dermatologic Ultrasound accreditation exam before and after the course. After the course, the students were asked to answer a course evaluation questionnaire Results: The multiple-choice question scores after the course showed statistically significant improvement (5.82 vs. 8.71%; P<0.001). The questionnaire revealed that students were satisfied with the course, felt that it increased both their dermatologic and ultrasound knowledge, and indicated that they wanted more sonographic hands on training in both dermatologic ultrasound and other medical fields. Conclusion: Using both objective and subjective methods, we showed that the introduction of standardized ultrasound training programs in undergraduate medical education can improve both students' understanding of the technique and the quality of medical education in dermatology. PMID- 27933320 TI - Genetics and pathogenesis of idiopathic scoliosis. AB - Idiopathic scoliosis (IS), the most common spinal deformity, affects otherwise healthy children and adolescents during growth. The aetiology is still unknown, although genetic factors are believed to be important. The present review corroborates the understanding of IS as a complex disease with a polygenic background. Presumably IS can be due to a spectrum of genetic risk variants, ranging from very rare or even private to very common. The most promising candidate genes are highlighted. PMID- 27933322 TI - Silicone Disclosing Material used after Ceramic Surface Treatment Reduces Bond Strength. AB - PURPOSE: To evaluate the effect of a silicone disclosing procedure performed at different timepoints on the shear bond strength (SBS) of cements (self-adhesive composite cement, self-etch composite cement, resin-reinforced glass-ionomer cement) to different substrates (zirconia, lithium disilicate, bovine dentin). MATERIALS AND METHODS: The substrate/cement combinations were assigned to two groups (n = 15) according to the timepoint, at which the vinyl polyether silicone disclosing agent was applied: after (experimental groups, EXP) or before (control groups, CTRL) specific micromechanical treatments of the substrate surface. To increase standardization, the cements were applied into rubber rings (2.2 mm diameter x 1.0 mm thickness) positioned on the substrate surface. After luting procedures, all specimens were stored in 37 degrees C distilled water for 24 h, then subjected to SBS testing using a wire loop of 0.2 mm diameter at a crosshead speed of 1 mm/min until failure. Failure analysis was performed for all tested specimens. SBS data were submitted to Weibull analysis. RESULTS: The silicone disclosing procedure performed after micromechanical surface treatment reduced the characteristic shear bond strength to zirconia and lithium disilicate when compared to CTRL. However, for dentin specimens, there was no significant difference between CTRL and EXP for any of the cements investigated. Failure analysis showed a predominance of interfacial failures. CONCLUSION: The silicone disclosing procedure performed after the micromechanical treatment of ceramic surfaces negatively affected the cement bond strength. Therefore, after using it to check the fit of a prosthesis, clinicians should carefully clean the ceramic surface. PMID- 27933323 TI - Assessing Collagen and Micro-permeability at the Proanthocyanidin-treated Resin Dentin Interface. AB - PURPOSE: To establish a fluorescence-based method to simultaneously assess micro permeability and collagen cross-linking induced by chemical agents at the resin dentin interface. MATERIALS AND METHODS: Three chemical agents were investigated (proanthocyanidin-rich grape seed extract: GSE; carbodiimide hydrochloride/N hydroxysuccinimide: EDC/NHS; glutaraldehyde: GD) along with a control (distilled water) as primers applied on flat occlusal dentin surfaces of 48 teeth and restored with two commercially available etch-and-rinse adhesives. Resin-dentin interfaces were polished and infiltrated with rhodamine-B solution for confocal laser scanning microscopy analysis. Parameters were chosen that would allow acquisition of a simultaneous appearance of collagen and interfacial micro permeability (rhodamine-B). Fluorescence emission intensity (FEI) was converted into numerals and values were calculated for each group. Data were statistically analyzed using one-way ANOVA and post-hoc Scheffe's and multiple comparisons tests (alpha = 0.05). T-tests with Pearson correlations were used to investigate correlations between collagen cross-linking and micro-permeability. RESULTS: The FEI of collagen was the highest for GD, followed by GSE, with no significant differences between EDC/ NHS and the control group (p > 0.05). Micro-permeability was significantly affected by the adhesives (p < 0.05). Micro- permeability was the lowest for GSE groups, regardless of the adhesives (p < 0.001). Weak correlations were found between micro-permeability and collagen auto fluorescence. CONCLUSIONS: Non-enzymatic collagen cross-linking induced by GSE and GD can be detected by increased collagen auto-fluorescence, and results in reduced interfacial micro-permeability. Increased collagen auto-fluorescence was correlated with fluorescent collagen cross-links and decreased micro-permeability at the resin-dentin interface. Collagen auto-fluorescence is a useful tool to detect auto-fluorescent exogenous cross links and their potential impact on the quality of the resin-dentin interface. PMID- 27933324 TI - Effect of Aqueous Storage on Original and Repair Bond Strength and Residual Monomer Release of Fiberreinforced Composites. AB - PURPOSE: To evaluate the effects of aqueous storage on shear bond strength (SBS) and monomer release of fiberreinforced composites (FRCs). MATERIALS AND METHODS: Four unidirectional FRCs were tested, including one semi-interpenetrating polymer network (IPN) (ES, everStick) and three cross-linked polymer (CLP) FRCs (GT, GrandTec; TF, TenderFiber; DP, Dentapreg). The SBS of samples of original resin to fresh FRC with an intact oxygen inhibition layer (n = 30/group) and repair resin to FRC after surface treatment (n = 30/group) was evaluated after 6 and 12 months of storage in artificial saliva. Monomer release of polymerized resin coated and uncoated FRCs was detected by high-performance liquid chromatography after immersion for 1 h, 1 day, and 7 days. RESULTS: After 6 months, a significant decrease in SBS was seen with ES-repair (p < 0.0001). After 12 months, significant decreases were seen with ES-original (p < 0.0001), ES-repair (p < 0.0001), and TF-repair (p = 0.0003). A significant reduction was also found for GT-original (p = 0.0254) and GT-repair (p = 0.0176). At 6 and 12 months, GT showed the highest SBS values, with DP-repair being statistically similar to GT at 12 months. For UDMA and bis- GMA, the greatest amounts of release were seen in uncoated specimens, followed by flowable resin-coated and viscous resin-coated specimens. CONCLUSION: Matrix composition, interfacial bonding, and resin coverage seem to account for differences in the aging behavior of FRCs. The semi IPN material is likely to suffer most from the challenging oral conditions. CLP FRCs might be more stable over the long term. Coverage of FRCs with viscous resin is highly recommended to reduce residual monomer release. PMID- 27933325 TI - Influence of Pre-etching Times on Fatigue Strength of Self-etch Adhesives to Enamel. AB - PURPOSE: To use shear bond strength (SBS) and shear fatigue strength (SFS) testing to determine the influence of phosphoric acid pre-etching times prior to application of self-etch adhesives on enamel bonding. MATERIALS AND METHODS: Two single-step self-etch universal adhesives (Prime&Bond Elect and Scotchbond Universal), a conventional single-step self-etch adhesive (G-aenial Bond), and a conventional two-step self-etch adhesive (OptiBond XTR) were used. The SBS and SFS were obtained with phosphoric acid pre-etching for 3, 10, or 15 s prior to application of the adhesives, and without pre-etching (0 s) as a control. A staircase method was used to determine the SFS with 10 Hz frequency for 50,000 cycles or until failure occurred. The mean demineralization depth for each treated enamel surface was also measured using a profilometer. RESULTS: For all the adhesives, the groups with pre-etching showed significantly higher SBS and SFS than groups without pre-etching. However, there was no significant difference in SBS and SFS among groups with > 3 s of preetching. In addition, although the groups with pre-etching showed significantly deeper demineralization depths than groups without pre-etching, there was no significant difference in depth among groups with > 3 s of pre-etching. CONCLUSION: Three seconds of phosphoric acid pre-etching prior to application of self-etch adhesive can enhance enamel bonding effectiveness. PMID- 27933326 TI - Correction: [{beta-SiNi2W10O36(OH)2(H2O)}4]24-: a new robust visible light-driven water oxidation catalyst based on nickel-containing polyoxometalate. AB - Correction for '[{beta-SiNi2W10O36(OH)2(H2O)}4]24-: a new robust visible light driven water oxidation catalyst based on nickel-containing polyoxometalate' by Li Yu et al., Chem. Commun., 2016, DOI: 10.1039/c6cc02728h. PMID- 27933327 TI - Traumatic diaphragmatic injuries: a retrospective review of a 12-year experience at a tertiary trauma centre. AB - INTRODUCTION: Traumatic diaphragmatic injuries (TDIs) are clinically challenging. We aimed to review TDIs treated at a tertiary trauma centre over a 12-year period. METHODS: This was a single-centre retrospective review of adult patients with TDIs treated between 1 January 2003 and 31 December 2014. Primary outcomes were mortality rates and Injury Severity Scores (ISS) associated with each TDI subtype. Secondary outcomes included proportions of TDIs diagnosed radiologically, operatively or during autopsy. We compared the TDI subtypes with respect to mechanism of injury, mortality rates and median ISS. Data was analysed using descriptive statistics. RESULTS: Among 46 patients studied, the TDI subtypes noted were acute diaphragmatic herniation (n = 14, 30.4%), tears (n = 22, 47.8%) and contusions (n = 10, 21.7%). Patients with these TDI subtypes had a mortality rate of 35.7%-100%, while the ISS ranges for survivors and deaths were 22.0-34.0 (interquartile range [IQR] 6.5-23.0) and 53.5-66.0 (IQR 16.0-28.5), respectively. TDIs were identified via chest radiography (n = 2/33, 6.1%) and computed tomography (n = 6/13, 46.2%). All survivors (n = 21) and deaths (n = 25) underwent open surgery or autopsy, respectively, which confirmed TDIs. Blunt traumas and penetrating traumas were more frequently associated with acute herniation/contusions and tears, respectively. There were statistically significant differences among the TDI subtypes in their mechanism of injury, mortality rate and median ISS of survivors. CONCLUSION: TDIs showed varying injury patterns with blunt versus penetrating mechanisms of injury, and were associated with significant mortality rates. Preoperative imaging had limited diagnostic use. PMID- 27933328 TI - Predictors of emesis in children undergoing procedural sedation with intramuscular ketamine in a paediatric emergency department. AB - INTRODUCTION: Emesis is one of the most common adverse events associated with ketamine sedation. However, its predictors have not been clearly studied among Asian children. This study aimed to determine the incidence and predictors of emesis in children undergoing intramuscular (IM) ketamine sedation in an emergency department (ED) in Singapore and to identify high-risk groups, so that antiemetics may be administered prophylactically. METHODS: In a prospective observational study, all children requiring procedural sedation with IM ketamine in the paediatric ED between 1 April 2013 and 31 January 2015 were included. All cases of emesis following ketamine sedation were prospectively documented. Univariate and multivariate logistic regression analyses were performed to identify the predictors of emesis. RESULTS: 2,502 sedations were performed using IM ketamine in the ED during the study period. Overall incidence of emesis associated with IM ketamine sedation was 8.4%. Children aged >= 8 years were significantly associated with increased risk of emesis (odds ratio 4.636, 95% confidence interval 3.271-6.570; p < 0.001), with an emesis rate of 19.6%. Other variables such as initial dose (3 mg/kg vs. 4 mg/kg), total dosage (including top ups), type and site of procedure, gender and ethnicity were not significant predictors. The number needed to treat for antiemetics in children aged >= 8 years was five. CONCLUSION: Age is a significant predictor of emesis. We recommend conducting a randomised controlled trial to compare the effects of prophylactic oral ondansetron in patients stratified into the age groups of >= 8 years and < 8 years. PMID- 27933329 TI - The Effects of Cadmium Exposure on Cadmium Fractionation and Enzyme Activities in the Rhizosphere of Two Radish Cultivars (Raphanus sativus L.). AB - The effects of increasing Cd additions on plant growth and Cd fractionation and enzyme activities in rhizosphere soil of two radish cultivars were investigated. The results showed that Cd concentrations in shoot and root of cultivar 4 were both higher than for cultivar 19 under different Cd levels. Compared with cultivar 19, the total, shoot and root biomasses of cultivar 4 were significantly reduced with increasing Cd levels. A decrease in soil pH was observed for cultivar 4. The exchangeable Cd concentration of soil from cultivar 4 was significantly higher than for soil from cultivar 19, while the carbonate-bound Cd concentration of soil from cultivar 4 was significantly lower than for cultivar 19. Enzyme activities, especially acid phosphatase activity, were more susceptible to Cd in soil from cultivar 4. These results indicated that cultivar 19 exhibits a stronger ability to adapt to Cd stress than cultivar 4. PMID- 27933330 TI - Concentrations of Arsenic and Boron in Water, Sediment and the Tissues of Fish in Emet Stream (Turkey). AB - In this study, the concentrations of arsenic and boron were determined in the water and the sediment, as well as in the muscle tissues of Squalius cephalus, Alburnoides bipunctatus, Barbus plebejus and Capoeta tinca from Emet Stream. The fish samples were caught in May 2011 and September 2012. The metal concentrations in the water samples were as follows: arsenic was 137.1-1002 ug L-1, and boron was 2421-14490 ug L-1. The metal concentrations in the sediment samples were as follows: arsenic was 14.51-3317.1 mg kg-1, and boron was 14.22-1014.01 mg kg-1. The mean tissue concentration of arsenic was lower than the TFC and WHO limits. Boron has been identified in fish tissues at concentrations between 0.26 and 2.96 mg kg-1. The bioaccumulation in the muscle tissues of all fish species caught from Emet Stream did not exceed the limit values. PMID- 27933331 TI - Characterization of Arsenic Biotransformation by a Typical Bryophyte Physcomitrella patens. AB - Arsenic (As) is a ubiquitous environmental toxin that has created catastrophic human health and environmental problems around world. Physcomitrella patens is a potential model plant for the study of environmental monitoring, which exists in all kinds of ecosystems. In this study, arsenic metabolism was investigated by this moss. When supplied with different levels of arsenate (50, 100, 200 umol/L) for a 4-week period, the total arsenic concentrations were up to 231.4-565.4 mg/kg DW in this moss. Arsenite concentration increased with increasing external arsenate concentrations, the proportion was up to 25.1-36.8% of the total As. An arsenate reductase, PpACR2, was identified and functionally characterized. Heterologous expression of PpACR2 in an As(V)-sensitive strain WC3110 (DeltaarsC) of Escherichia coli conferred As(V) resistance. Purified PpACR2 protein exhibited the arsenate reductase activity. Given its powerful As accumulation ability, the bryophyte could be exploited in bioremediation of As-contaminated environments. PMID- 27933332 TI - ["Come O death, you brother of sleep" : the end of life as an issue in medicines and society]. PMID- 27933333 TI - Discriminatory ability of simple OGTT-based beta cell function indices for prediction of prediabetes and type 2 diabetes: the CODAM study. AB - AIMS/HYPOTHESIS: The hyperglycaemic clamp technique and the frequently sampled IVGTT are unsuitable techniques to assess beta cell function (BCF) in large cohorts. Therefore, the aim of this study was to evaluate the discriminatory ability of simple OGTT-based BCF indices for prediction of prediabetes (meaning impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes. METHODS: Glucose metabolism status was assessed by 2 h 75 g OGTT at baseline (n = 476, mean age 59.2 years, 38.7% women) and after 7 years of follow-up (n = 416) in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study (1999 2009). Baseline plasma glucose, insulin and C-peptide values during OGTTs were used to calculate 21 simple indices of BCF. Disposition indices (BCF index * Matsuda index), to compensate for the prevailing level of insulin resistance, were calculated for the BCF indices with the best discriminatory abilities. The discriminatory ability of the BCF indices was estimated by the area under the receiver operating characteristics curve (ROC AUC) with an outcome of incident prediabetes (n = 73) or type 2 diabetes (n = 60 and n = 18 cases, respectively, in individuals who were non-diabetic or had normal glucose metabolism at baseline). RESULTS: For incident prediabetes (n = 73), all ROC AUCs were less than 70%, whereas for incident type 2 diabetes, I30/I0, CP30/CP0, DeltaI30/DeltaG30, DeltaCP30/DeltaG30 (where I, CP and G are the plasma concentrations of insulin, C-peptide and glucose, respectively, at the times indicated), and corrected insulin response at 30 min had ROC AUCs over 70%. In at baseline non-diabetic individuals, disposition indices DeltaI30/DeltaG30, DeltaCP30/DeltaG30 and corrected insulin response at 30 min had ROC AUCs of over 80% for incident type 2 diabetes. Moreover, these BCF disposition indices had significantly better discriminatory abilities for incident type 2 diabetes than the Matsuda index alone. CONCLUSIONS/INTERPRETATION: BCF indices reflecting early phase insulin secretion have the best ability to discriminate individuals who will develop prediabetes and type 2 diabetes. Of these, DeltaCP30/DeltaG30, often referred to as the C-peptidogenic index, performed consistently well. PMID- 27933334 TI - Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels. AB - AIM/HYPOTHESIS: Neprilysin, a widely expressed peptidase, is upregulated in metabolically altered states such as obesity and type 2 diabetes. Like dipeptidyl peptidase-4 (DPP-4), neprilysin can degrade and inactivate the insulinotropic peptide glucagon-like peptide-1 (GLP-1). Thus, we investigated whether neprilysin deficiency enhances active GLP-1 levels and improves glycaemia in a mouse model of high fat feeding. METHODS: Nep +/+ and Nep -/- mice were fed a 60% fat diet for 16 weeks, after which active GLP-1 and DPP-4 activity levels were measured, as were glucose, insulin and C-peptide levels during an OGTT. Insulin sensitivity was assessed using an insulin tolerance test. RESULTS: High-fat-fed Nep -/- mice exhibited elevated active GLP-1 levels (5.8 +/- 1.1 vs 3.5 +/- 0.8 pmol/l, p < 0.05) in association with improved glucose tolerance, insulin sensitivity and beta cell function compared with high-fat-fed Nep +/+ mice. In addition, plasma DPP-4 activity was lower in high-fat-fed Nep -/- mice (7.4 +/- 1.0 vs 10.7 +/- 1.3 nmol ml-1 min-1, p < 0.05). No difference in insulin:C-peptide ratio was observed between Nep -/- and Nep +/+ mice, suggesting that improved glycaemia does not result from changes in insulin clearance. CONCLUSIONS/INTERPRETATION: Under conditions of increased dietary fat, an improved glycaemic status in neprilysin-deficient mice is associated with elevated active GLP-1 levels, reduced plasma DPP-4 activity and improved beta cell function. Thus, neprilysin inhibition may be a novel treatment strategy for type 2 diabetes. PMID- 27933335 TI - Iron: how much is too much? AB - Gross iron overload has long been known to result in diabetes mellitus. However, it is now thought that milder levels of iron overload, possibly within the normal range, also increase the risk of diabetes mellitus. The article by Rawal et al in this issue (Diabetologia doi: 10.1007/s00125-016-4149-3 ) provides further support for the relationship between mild degrees of iron overload and the risk of gestational diabetes. The purpose of this commentary is to briefly discuss the background of this relationship and the implications it may have for routine pregnancy care. PMID- 27933336 TI - SHP-1 activation inhibits vascular smooth muscle cell proliferation and intimal hyperplasia in a rodent model of insulin resistance and diabetes. AB - AIMS/HYPOTHESIS: Accelerated migration and proliferation of vascular smooth muscle cells (VSMCs) enhances arterial restenosis after angioplasty in insulin resistance and diabetes. Elevation of Src homology 2-containing protein tyrosine phosphatase 1 (SHP-1) induces apoptosis in the microvasculature. However, the role of SHP-1 in intimal hyperplasia and restenosis has not been clarified in insulin resistance and diabetes. METHODS: We used a femoral artery wire injury mouse model, rodent models with insulin resistance and diabetes, and patients with type 2 diabetes. Further, we modulated SHP-1 expression using a transgenic mouse that overexpresses SHP-1 in VSMCs (Shp-1-Tg). SHP-1 agonists were also employed to study the molecular mechanisms underlying the regulation of SHP-1 by oxidised lipids. RESULTS: Mice fed a high-fat diet (HFD) exhibited increased femoral artery intimal hyperplasia and decreased arterial SHP-1 expression compared with mice fed a regular diet. Arterial SHP-1 expression was also decreased in Zucker fatty rats, Zucker diabetic fatty rats and in patients with type 2 diabetes. In primary cultured VSMCs, oxidised LDL suppressed SHP-1 expression by activating Mek-1 (also known as Map2k1) and increased DNA methylation of the Shp-1 promoter. VSMCs from Shp-1-Tg mice exhibited impaired platelet-derived growth factor (PDGF)-stimulated tyrosine phosphorylation with a concomitant decrease in PDGF-stimulated VSMC proliferation and migration. Similarly, HFD-fed Shp-1-Tg mice and mice treated with the SHP-1 inducer, Icariside II, were protected from the development of intimal hyperplasia following wire injury. CONCLUSIONS/INTERPRETATION: Suppression of SHP-1 by oxidised lipids may contribute to the excessive VSMC proliferation, inflammatory cytokine production and intimal hyperplasia observed in arteries from diabetes and insulin resistance. Augmenting SHP-1 levels is a potential therapeutic strategy to maintain stent patency in patients with insulin resistance and diabetes. PMID- 27933337 TI - Biodegradation of the Herbicide 2,4-Dichlorophenoxyacetic Acid by a New Isolated Strain of Achromobacter sp. LZ35. AB - In this study, a bacterial strain of Achromobacter sp. LZ35, which was capable of utilizing 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-methyl-4-chlorophenoxy acetic acid (MCPA) as the sole sources of carbon and energy for growth, was isolated from the soil in a disused pesticide factory in Suzhou, China. The optimal 2,4-D degradation by strain LZ35 occurred at 30 degrees C and pH 8.0 when the initial 2,4-D concentration was 200 mg L-1. Strain LZ35 harbored the conserved 2,4-D/alpha-ketoglutarate dioxygenase (96%) and 2,4-dichlorophenol hydroxylase (99%), and catabolized 2,4-D via the intermediate 2,4-dichlorophenol. The inoculation of 7.8 * 106 CFU g-1 soil of strain LZ35 cells to 2,4-D contaminated soil could efficiently remove over 75 and 90% of 100 and 50 mg L-1 2,4-D in 12 days and significantly released the phytotoxicity of maize caused by the 2,4-D residue. This is the first report of an Achromobacter sp. strain that was capable of mineralizing both 2,4-D and MCPA. This study provides us a promising candidate for its application in the bioremediation of 2,4-D- or MCPA contaminated sites. PMID- 27933338 TI - Progress in Research and Application of HIV-1 TAT-Derived Cell-Penetrating Peptide. AB - Human immunodeficiency virus type I (HIV-1) transactivator of transcription (TAT) is encoded by HIV-1. It is a peptide rich in basic amino acids and belongs to the protein transduction domain family. It has been found that HIV-1 TAT and its core peptide segment TAT47-57 play an important role in promoting the cellular uptake of coupled bioactive macromolecules, such as peptides, proteins, oligonucleotides, and drug molecules. HIV-1 TAT can also significantly increase the soluble expression of extrinsic proteins. However, the mechanism behind the cellular uptake of HIV-1 TAT-derived cell-penetrating peptide remains unclear. This review focuses on the research into HIV-1 TAT-derived cell-penetrating peptide over the last years. We briefly discuss TAT's structural features, functions and applications, the mechanism of its cellular internalization, current challenges, and their possible solutions. At the end of this review, we provide a summary and predict the future research directions and potential applications of HIV-1 TAT when it is used as a cell-penetrating peptide. PMID- 27933339 TI - Efficacy and safety of osteoporosis medications in a rat model of late-stage chronic kidney disease accompanied by secondary hyperparathyroidism and hyperphosphatemia. AB - : This study showed that bisphosphonate was safe and effective for the treatment of bone disorders in stage 4 chronic kidney disease (CKD) rats. Intermittent teriparatide therapy showed an anabolic action on bone even under secondary hyperparathyroidism conditions without having an adverse effect on mineral metabolism in late-stage CKD. INTRODUCTION: Patients with late-stage CKD are at high risk for fragility fractures. However, there are no consensus on the efficacy and safety of osteoporosis medications for patients with late-stage CKD. In the present study, we aimed to examine the efficacy and safety of alendronate (ALN) and teriparatide (TPD) for treating bone disorder in late-stage CKD with pre-existing secondary hyperparathyroidism using a rat model of CKD. METHODS: Male 10-week-old Sprague-Dawley rats were subjected to a 5/6 nephrectomy or sham surgery and randomized into the following four groups: sham, vehicle (saline subcutaneous (sc) daily), ALN (50 MUg/kg sc daily), and TPD (40 MUg/kg sc daily). Medications commenced at 24 weeks of age and continued for 4 weeks. Micro computed tomography, histological analysis, infrared spectroscopic imaging, and serum assays were performed. RESULTS: Nephrectomized rats developed hyperphosphatemia, secondary hyperparathyroidism (SHPT), and high creatinine, equivalent to CKD stage 4 in humans. ALN suppressed the bone turnover and increased the degree of mineralization in cortical bone, resulting in an improvement in the mechanical properties. TPD further increased the bone turnover and significantly increased the degree of mineralization, micro-geometry, and bone volume, resulting in a significant improvement in the mechanical properties. Both ALN and TPD had no adverse effect on renal function and mineral metabolism. CONCLUSIONS: BP is safe and effective for the treatment of bone disorders in stage 4 CKD rats. Intermittent TPD therapy showed an anabolic action on bone even under SHPT conditions without having an adverse effect on mineral metabolism in late-stage CKD. PMID- 27933340 TI - Enhancement of pharmacological effects of uricosuric agents by concomitant treatment with pyrazinamide in rats. AB - Our goal was to establish a model for the evaluation of the effects of uricosuric agents and to clarify the underlying mechanism(s). The effects of a uricosuric agent co-treated with pyrazinamide, an anti-tubercular agent, on urate handling were examined in rats. Furthermore, the effects of uricosuric agents on urate uptake were evaluated using the vesicles of rat renal brush-border membrane. Treatment with probenecid, at a dose of 100 mg/kg, significantly increased the urinary urate to creatinine ratio (UUA/UCRE) in pyrazinamide-treated rats although the same treatment did not produce any uricosuric effects in intact rats. In this model, the urinary excretion of pyrazinecarboxylic acid (PZA), an active metabolite of pyrazinamide, was decreased by probenecid and indicated an inverse correlation between urinary excretion of urate and PZA. Furthermore, in the examination using FYU-981, a potent uricosuric agent, a more than 10-fold leftward shift of the dose-response relationship of the uricosuric effect was observed in pyrazinamide-treated rats when compared with intact rats. In the in vitro study, the treatment of the vesicles of rat renal brush-border membrane with PZA produced an increased urate uptake, which was inhibited by uricosuric agents. The pyrazinamide-treated model used in the present study seems to be valuable for the evaluation of uricosurics because of its higher sensitivity to these drugs when compared to intact rats, and this is probably due to the enhanced urate reabsorption accompanied with trans-stimulated PZA transport at the renal brush-border membrane. PMID- 27933341 TI - Intragenic Variations in BTLA Gene Influence mRNA Expression of BTLA Gene in Chronic Lymphocytic Leukemia Patients and Confer Susceptibility to Chronic Lymphocytic Leukemia. AB - The aim of this study was to determine the association between polymorphisms in gene encoding B- and T-lymphocyte attenuator (BTLA) and susceptibility to chronic lymphocytic leukemia (CLL) and their influence on mRNA expression of BTLA gene in T and B cells from CLL patients (pts.). The following BTLA single-nucleotide polymorphisms (SNPs): rs2705511, rs1982809, rs9288952, rs76844316, rs16859633, rs9288953, rs2705535, rs1844089, rs2705565, rs2633580 were genotyped with use of TaqMan probes in 321 CLL pts. and in 470 controls. The mRNA levels of human BTLA were determined in subpopulations of T and B cells from 37 CLL patients with use of Applied Biosystems assays. Three SNPs: rs1982809, rs2705511 and rs9288953 were associated with susceptibility to CLL. The frequency of rs1982809[G] allele and rs2705511[C] allele carriers was higher in patients compared to the controls (0.51 vs. 0.41, OR 1.51, 95% CI 1.14-2.02, p = 0.004 and 0.56 vs. 0.44, OR 1.62, 95% CI 1.22-2.16, p = 0.0009, respectively). Furthermore, rs9288953[TT] genotype was overrepresented in CLL pts. compared to the controls (0.22 vs. 0.14, OR 1.74, 95% CI 1.20-2.53, p = 0.004). The evaluation of the influence of BTLA SNPs on BTLA mRNA expression in CLL pts. showed that the presence of rs1982809[G] allele was associated with lower median (+/-SD) BTLA mRNA expression in T cells (expressed as 2-delta Ct) in CLL pts. as compared to [AA] homozygotes (0.009 +/- 0.013 vs. 0.026 +/- 0.012, p = 0.03). Our results indicate that rs1982809 BTLA gene polymorphism is associated with mRNA expression level and that variations in the BTLA gene might be considered as potentially low-penetrating CLL risk factor. PMID- 27933342 TI - Prediction of NK Cell Licensing Level in Selection of Hematopoietic Stem Cell Donor, Initial Results. AB - Natural killer (NK) cell licensing status depends on clonal expression of inhibitory killer cell immunoglobulin-like receptors (iKIR) and short term HLA environment. Licensed NK cells are more efficient in tumor killing than unlicensed NK cells. Cognate KIR-HLA pairs in hematopoietic stem cell transplant (HSCT) donor and recipient are decisive for the possible change in the NK cell licensing status after HSCT. We assessed clinical outcomes in 297 patients with lymphoproliferative or myeloproliferative malignancies, or myelodysplastic syndrome in a model with upward licensing, downward resetting, and unchanged licensing genetics status after T cell replate HSCT from unrelated donors. We found extremely low (0%) relapse/progression incidence (RI), and better (59%) event-free survival (EFS) in recipients with upward licensing status and highly increased RI (37.5%), and reduced EFS (8%) among patients with the downward resetting status of repopulated donor NK cells after HSCT, as compared with unchanged NK cell licensing (RI 23%, EFS 47%). These trends were confirmed in adjusted multivariable models (for RI p = 6.66E-09, OR = 1.47, 95% CI 1.29-1.66 and for EFS p = 3.79E-13, OR = 1.67, 95% CI 1.50-1.84). Differences in the incidence of acute graft versus host disease (GvHD 62, 69, and 47%) and chronic GvHD (24, 44, and 15%, respectively) in three groups were insignificant. It would be rationale the preferential selection of the donors with upward licensing over downward resetting inhibitory KIR:HLA constellation and inclusion of the KIR genotyping in the donor selection algorithm for malignant patients. Further studies using enlarged cohorts of patients with more homogenous diagnosis are essential to reliably verify these preliminary data. PMID- 27933343 TI - [Conservative treatment of congenital patellar dislocation]. AB - This article presents the rare case of a boy who was born in our hospital with valgus deformity and external rotation of the right lower leg because of congenital patellar dislocation. In the case presented a stable repositioning of the patella could be achieved by redressment with a plaster cast and leg brace. During a 4-year follow-up there were no tendencies towards dislocation during the clinical examination and no dislocation events were documented. In selected cases an attempt at conservative repositioning and retention treatment appears to be worthwhile before surgical treatment is indicated. PMID- 27933344 TI - Do we have adequate tools and skills to manage uncertainty among patients and families in ICU? PMID- 27933345 TI - Combining high-flow nasal cannula oxygen and non-invasive ventilation for pre oxygenation in the critically ill: is a double-pronged approach warranted? : Discussion on article "Apnoeic oxygenation via high-flow nasal cannula oxygen combined with non-invasive ventilation preoxygenation for intubation in hypoxaemic patients in the intensive care unit: the single-centre, blinded, randomised controlled OPTINIV trial". PMID- 27933346 TI - Intensive Care Medicine in 2050: toward an intensive care unit without waste. PMID- 27933347 TI - [Appropriate application of speech audiometry]. PMID- 27933348 TI - [Acupuncture in posttonsillectomy pain : A prospective double-blind randomized controlled trial. German version]. AB - BACKGROUND: Postoperative swallowing pain is one of the most unpleasant after effects of tonsillectomy. During recent years, the demand for alternatives to drug-based pain therapy has continued to grow, although the topic has received little research attention until now. MATERIALS AND METHODS: A total of 46 patients were randomized into verum acupuncture, control acupuncture, and drug based treatment groups. All patients received nonsteroidal antirheumatic drugs (NSAIDs). One hour after drug intake, the verum group also received acupuncture according to classical acupuncture rules (S34, S44 and PC5). The control group had acupuncture needles placed at nonspecific acupuncture points in the midaxillary line. Acupuncture was performed by a blinded acupuncturist, who had learnt exclusively these techniques in the run up to the study. Patients were asked to evaluate their pain before, and at intervals of 20 min, 1 h, 2 h, and 3 h after drug intake/acupuncture treatment using a visual analog scale (VAS). RESULTS: The analgesic effect of acupuncture was significant up to 3 hours in the verum group (p < 0.05). The analgesic effect in the control acupuncture group was significant for up to 1 h after acupuncture (p < 0.05). With reference to the time point before acupuncture, the differences between both acupuncture groups and the drug group were significant (p < 0.01) over the whole time. CONCLUSION: Acupuncture is an effective complement to NSAIDs in the treatment of posttonsillectomy pain. Particularly patients with allergies, drug intolerance, or reduced response to the commonly administered drugs may benefit from acupuncture. PMID- 27933349 TI - [Speech audiometric outcome parameters in clinical trials on hearing improvement]. AB - BACKGROUND: When comparing clinical studies nationally and internationally, there is great heterogeneity in the applied audiometric outcome parameters. Beside different frequencies included in pure-tone audiometry and the resulting averages, the word recognition scores are measured at varying sound pressure levels, i.e., either with a fixed sound pressure level or with a fixed sensation level. However, a comparison of studies, e. g., in meta-analysis, requires comparable outcome parameters. OBJECTIVE: In this study, the influence of speech audiometric outcome parameters on the outcome reporting of hearing therapies is studied. PATIENTS AND METHODS: Before and after a conservative or a surgical treatment aimed at hearing improvement, 25 patients with hearing impairment were tested with the German Freiburg speech intelligibility test with monosyllables and numbers at various levels, and with the German Oldenburg sentence test in quiet. Additionally, 49 subjects with normal hearing were tested. RESULTS: In a comparison of measurement methods (outcome parameters), the hearing improvement measured using constant sound pressure levels for speech audiometry was significantly greater and therefore more sensitive than using constant sensation levels. CONCLUSION: To test changes in hearing in clinical studies, fixed sound pressure levels should be preferred to fixed sensation levels. For the development of standardized outcome parameters for measuring speech intelligibility in quiet, fixed sound pressure levels or measurement of speech reception thresholds should be selected. PMID- 27933350 TI - Endoscopic ear surgery - a complement to microscopic ear surgery. AB - Wullstein, the founder of modern microscopic ear surgery, already used an oto endoscope intraoperatively. However, it is only after the recent development of modern video-endoscopy with high-definition, 4K, and 3-dimensional imaging that endoscopically guided surgery of the middle ear is gaining some importance. Key ventilation routes like the isthmus tympani and the epitympanic diaphragm can be visualized far better using an endoscope than with a microscope. Going through the external meatus, surgery of middle ear pathologies is possible without external incision. This type of primary endoscopic ear surgery has to be distinguished from secondary endoscopic ear surgery, where standard microscopic ear surgery is supplemented by endoscopic surgery. Having to hold the endoscope in one hand, surgery has to be performed single-handedly, which is awkward. In cases of extensive bone removal or excessive bleeding, the view through the endoscope lens is obscured; therefore; the endoscope cannot fully substitute the microscope. It is, however, an interesting adjunct to microscopic ear surgery. PMID- 27933351 TI - [Modern modifications of uvulopalatopharyngoplasty]. AB - Uvulopalatopharyngoplasty (UPPP) was first described in 1964 with regard to surgical treatment of snoring and in 1981 with regard to treatment of obstructive sleep apnea (OSA). The initial surgical techniques for OSA were very invasive, frequently leading to significant morbidity and complications. Wolfgang Pirsig et al. were the first in Germany to recognize that a radical surgical technique increased only the complications, not the efficacy of UPPP. The less invasive surgical technique developed based on these findings is still established in Germany. A meta-analysis from 1996 described a success rate of UPPP of about 50%. High-quality randomized trials demonstrate significant superiority of UPPP plus tonsillectomy compared to untreated controls. However, the objective outcome measures of classic UPPP could not be improved even with additional patient selection criteria, and the effects of UPPP often deteriorate over time. To overcome these limitations, various modifications of UPPP have been developed. Due to limited data, evaluation of these new techniques and their comparison with conventional UPPP is difficult at present. In studies comparing a modification of UPPP with the standard approach, the tested modification was demonstrated to be superior. A relevant limitation of the available data results from the small number of institutions (usually not more than two) that investigated the respective modification and the follow-up periods of usually only 6 months. Data are also too sparse to reliably assess complication rates. For conventional UPPP there are considerably more data, wider experience with long-term outcome, and more robust studies examining treatment effects beyond basic respiratory parameters. At present, modifications of UPPP should be principally employed in clinical trials. PMID- 27933353 TI - [Medical examination: Preparation for ENT specialisation : Part 28]. PMID- 27933352 TI - Intracochlear drug delivery in combination with cochlear implants : Current aspects. AB - Local drug application to the inner ear offers a number of advantages over systemic delivery. Local drug therapy currently encompasses extracochlear administration (i. e., through intratympanic injection), intracochlear administration (particularly for gene and stem cell therapy), as well as various combinations with auditory neurosensory prostheses, either evaluated in preclinical or clinical studies, or off-label. To improve rehabilitation with cochlear implants (CI), one focus is the development of drug-releasing electrode carriers, e. g., for delivery of glucocorticosteroids, antiapoptotic substances, or neurotrophins to the inner ear. The performance of cochlear implants may thus be improved by protecting neuronal structures from insertion trauma, reducing fibrosis in the inner ear, and by stimulating growth of neuronal structures in the direction of the electrodes. Controlled drug release after extracochlear or intracochlear application in conjunction with a CI can also be achieved by use of a biocompatible, resorbable controlled-release drug-delivery system. Two case reports for intracochlear controlled release drug delivery in combination with cochlear implants are presented. In order to treat progressive reduction in speech discrimination and increased impedance, two cochlear implant patients successfully underwent intracochlear placement of a biocompatible, resorbable drug-delivery system for controlled release of dexamethasone. The drug levels reached in inner ear fluids after different types of local drug application strategies can be calculated using a computer model. The intracochlear drug concentrations calculated in this way were compared for different dexamethasone application strategies. PMID- 27933354 TI - [Pathophysiology, diagnosis and treatment of Zenker's diverticulum]. AB - Zenker's diverticulum occurs at the dorsal pharyngoesophageal junction through Killian's dehiscence and is caused by increased intrabolus pressure. Symptomatic disease most frequently affects male elderly patients. Primary symptom is oropharyngeal dysphagia, as well as regurgitation of undigested food, halitosis, and chronic aspiration. A barium swallow study is performed to confirm diagnosis. Treatment options for symptomatic patients include open surgery, as well as transoral rigid or flexible endoscopic procedures. Transoral procedures have become the main treatment approach over the past year thanks to reduced intraoperative complication rates compared to open surgery. The septum dividing the diverticulum from the esophagus is most commonly divided by a stapler device, papillotome, or laser. For high-risk patients who are poor candidates for general anesthesia, the procedure can be performed via flexible endoscopy in awake patients, albeit at an increased risk of recurrence. PMID- 27933355 TI - [Central myelination disorder in classical galactosemia : Case report of two sisters]. PMID- 27933356 TI - [Injury to the upper limbs and prevention in equestrian sports]. AB - The upper limb is one of the most frequently injured body regions in equestrian sports, but it is unclear which injuries are involved, and there are no data on the associated accident mechanism. The present study is aimed at evaluating the accident mechanisms, injuries of the upper limbs, and the circumstances of the accident in equestrian sports. We included 218 patients who were all treated between 2006 and 2014 at the level I trauma center at the Medical University in Hannover because of equestrian-related accidents. The most frequent injuries were fractures and bruising in the shoulder area, fingers and hands, and the distal area of the lower arm, which were mostly caused by the horse kicking. To prevent hand injuries it is recommended that gloves are worn; the potential introduction of strengthened materials could protect the bones from severe bumping. Training in falling techniques to prevent serious injury to the upper limb would be useful. In general, primary prevention in equestrian sports should be extended to counteract the increasing neglect of protective equipment. PMID- 27933357 TI - Bilateral increases in ERK activation at the spinomedullary junction region by acute masseter muscle injury during temporomandibular joint inflammation in the rats. AB - We determined the role of persistent monoarthritis of temporomandibular joint region (TMJ) on bilateral masseter muscle (MM) nociception in male rats using orofacial nocifensive behaviors, phosphorylated extracellular signal-regulated kinase and Fos induction at the trigeminal subnucleus caudalis/upper cervical spinal cord (Vc/C2) region in response to formalin injection to the MM region. TMJ inflammation was induced by local injection of CFA into the left TMJ region. Orofacial nocifensive behaviors evoked by formalin injection ipsilateral or contralateral to the TMJ inflammation appeared to be increased at 1-14 days or at 1, 10 and 14 days after induction of TMJ inflammation, respectively, while increases in behavioral duration were seen mainly in the late phase rather than the early phase. The number of pERK positive cells was investigated in superficial laminae at the Vc/C2 region at 3, 10, 20, 60 and 80 min after MM stimulation with formalin at 14 days after TMJ inflammation. TMJ-inflamed rats displayed greater responses of pERK expression by the ipsilateral MM stimulation at 3-60 min, while contralateral MM stimulation increased pERK expression at 3, 10 and 20 min compared to non-CFA rats. Fos expression by MM stimulation was increased at 14 days after induction of TMJ inflammation regardless of the affected side. These findings showed that persistent TMJ inflammation for 10 and 14 days is sufficient to enhance MM nociception indicated by behaviors and neural responses in superficial laminae at the Vc/C2 region. PMID- 27933358 TI - Embodiment and the origin of interval timing: kinematic and electromyographic data. AB - Recent evidence suggests that interval timing (the judgment of durations lasting from approximately 500 ms. to a few minutes) is closely coupled to the action control system. We used surface electromyography (EMG) and motion capture technology to explore the emergence of this coupling in 4-, 6-, and 8-month-olds. We engaged infants in an active and socially relevant arm-raising task with seven cycles and response period. In one condition, cycles were slow (every 4 s); in another, they were fast (every 2 s). In the slow condition, we found evidence of time-locked sub-threshold EMG activity even in the absence of any observed overt motor responses at all three ages. This study shows that EMGs can be a more sensitive measure of interval timing in early development than overt behavior. PMID- 27933359 TI - Raccoons (Procyon lotor) as Sentinels of Trace Element Contamination and Physiological Effects of Exposure to Coal Fly Ash. AB - Anthropogenic pollutants disrupt global biodiversity, and terrestrial sentinels of pollution can provide a warning system for ecosystem-wide contamination. This study sought to assess whether raccoons (Procyon lotor) are sentinels of local exposure to trace element contaminants at a coal fly ash site and whether exposure resulted in health impairment or changes in the intestinal helminth communities. We compared trace element accumulation and the impact on health responses and intestinal helminth communities of raccoons inhabiting contaminated and reference sites of the U.S. Department of Energy's Savannah River Site (South Carolina, USA). Data on morphometry, hematology, histopathology, helminth community and abundance, and liver trace element burdens were collected from 15 raccoons captured adjacent to a coal fly ash basin and 11 raccoons from a comparable uncontaminated site nearby. Of eight trace elements analyzed, Cu, As, Se, and Pb were elevated in raccoons from the contaminated site. Raccoons from the contaminated site harbored higher helminth abundance than animals from the reference site and that abundance was positively associated with increased Cu concentrations. While we found changes in hematology associated with increased Se exposure, we did not find physiological or histological changes associated with higher levels of contaminants. Our results suggest that raccoons and their intestinal helminths act as sentinels of trace elements in the environment associated with coal fly ash contamination. PMID- 27933360 TI - Recent advances in glycomics, glycoproteomics and allied topics. PMID- 27933361 TI - Biotransformation and detectability of the new psychoactive substances N,N diallyltryptamine (DALT) derivatives 5-fluoro-DALT, 7-methyl-DALT, and 5,6 methylenedioxy-DALT in urine using GC-MS, LC-MSn, and LC-HR-MS/MS. AB - Derivatives of N,N-diallyltryptamine (DALT) can be classified as new psychoactive substances. Biotransformation and detectability of 5-fluoro-DALT (5-F-DALT), 7 methyl-DALT (7-Me-DALT), and 5,6-methylenedioxy-DALT (5,6-MD-DALT) are described here. Their metabolites detected in rat urine and pooled human liver microsomes were identified by liquid chromatography (LC)-high resolution (HR)-tandem mass spectrometry (MS/MS). In addition, the human cytochrome-P450 (CYP) isoenzymes involved in the main metabolic steps were identified and detectability tested in urine by the authors' urine screening approaches using GC-MS, LC-MSn, or LC-HR MS/MS. Aromatic and aliphatic hydroxylations, N-dealkylation, N-oxidation, and combinations could be proposed for all compounds as main pathways. Carboxylation after initial hydroxylation of the methyl group could also be detected for 7-Me DALT and O-demethylenation was observed for 5,6-MD-DALT. All phase I metabolites were extensively glucuronidated or sulfated. Initial phase I reactions were catalyzed by CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5. Rat urine samples were analyzed following two different low-dose administrations. GC MS was not able to monitor consumption reliably, but all three compounds are predicted to be detectable in cases of overdose. The LC-MSn and LC-HR-MS/MS approaches were suitable for detecting an intake of all three compounds mainly via their metabolites. However, after the lowest dose, a reliable monitoring could only be achieved for 5-F-DALT via LC-MSn and LC-HR-MS/MS and for 7-Me-DALT via LC-HR-MS/MS. The most abundant targets in both LC-MS screenings were one of two hydroxy-aryl metabolites and both corresponding glucuronides for 5-F-DALT, one N-deallyl hydroxy-aryl, the carboxy, and one dihydroxy-aryl metabolite for 7 Me-DALT, and the demethylenyl metabolite, its oxo metabolite, and glucuronide for 5,6-MD-DALT. PMID- 27933362 TI - Coordination-induced decomposition of luminescent gold nanoparticles: sensitive detection of H2O2 and glucose. AB - The surface inert of luminescent gold nanoparticles (AuNPs) toward biomolecules set a challenge to further exploit their bioanalytical applications using the direct luminescence response. Herein, we report a novel approach to induce significant luminescence quenching of the AuNPs upon the interaction with a metal coordination ligand tris(2-carboxyethyl)phosphine (TCEP), providing a strategy for the detection of H2O2 with a limit of detection (LOD) of 14 nM through the reaction between H2O2 and TCEP to protect the luminescence quenching of the AuNPs. Furthermore, this strategy is also extended for sensitive and selective detection of glucose with a LOD of 1.1 MUM based on monitoring the production of H2O2 catalyzed from the oxidation of glucose. The highly extendable feature of this strategy can have great potential in the sensitive detection of other biomolecules. Graphical Abstract A facile and extendable strategy has been developed for the sensitive detection of H2O2 and glucose based on the interaction between luminescent gold nanoparticles and TCEP, a metal coordination ligand. PMID- 27933363 TI - Spatially resolved metabolic distribution for unraveling the physiological change and responses in tomato fruit using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). AB - Information on spatiotemporal metabolic behavior is indispensable for a precise understanding of physiological changes and responses, including those of ripening processes and wounding stress, in fruit, but such information is still limited. Here, we visualized the spatial distribution of metabolites within tissue sections of tomato (Solanum lycopersicum L.) fruit using a matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) technique combined with a matrix sublimation/recrystallization method. This technique elucidated the unique distribution patterns of more than 30 metabolite-derived ions, including primary and secondary metabolites, simultaneously. To investigate spatiotemporal metabolic alterations during physiological changes at the whole-tissue level, MALDI-MSI was performed using the different ripening phenotypes of mature green and mature red tomato fruits. Although apparent alterations in the localization and intensity of many detected metabolites were not observed between the two tomatoes, the amounts of glutamate and adenosine monophosphate, umami compounds, increased in both mesocarp and locule regions during the ripening process. In contrast, malate, a sour compound, decreased in both regions. MALDI-MSI was also applied to evaluate more local metabolic responses to wounding stress. Accumulations of a glycoalkaloid, tomatine, and a low level of its glycosylated metabolite, esculeoside A, were found in the wound region where cell death had been induced. Their inverse levels were observed in non-wounded regions. Furthermore, the amounts of both compounds differed in the developmental stages. Thus, our MALDI-MSI technique increased the understanding of the physiological changes and responses of tomato fruit through the determination of spatiotemporally resolved metabolic alterations. Graphical abstract ?. PMID- 27933364 TI - Behavioral alterations of zebrafish larvae after early embryonic exposure to ketamine. AB - RATIONALE: Ketamine has been associated with pediatric risks that include neurocognitive impairment and long-term behavioral disorders. However, the neurobehavioral effects of ketamine exposure in early development remain uncertain. OBJECTIVES: This study aimed to test stage- and dose-dependent effects of ketamine exposure on certain brain functions by evaluating alterations in locomotion, anxiety-like and avoidance behaviors, as well as socialization. METHODS: Embryos were exposed to different concentrations of ketamine (0, 0.2, 0.4, and 0.8 mg mL-1) for 20 min during the 256-cell (2.5 h post fertilization hpf), 50% epiboly (5.5 hpf), and 1-4 somites (10.5 hpf) stages. General exploratory activities, natural escape-like responses, and social interactions were analyzed under continuous light or under a moving light stimulus. RESULTS: A dose-dependent decrease in the overall mean speed was perceived in the embryos exposed during the 256-cell stage. These results were related to previously observed head and eye malformations, following ketamine exposure at this stage and may indicate possible neurobehavioral disorders when ketamine exposure is performed at this stage. Results also showed that ketamine exposure during the 50% epiboly and 1-4 somites stages induced a significant increment of the anxiety like behavior and a decrease in avoidance behavior in all exposed groups. CONCLUSIONS: Overall, the results validate the neurodevelopmental risks of early life exposure to ketamine. PMID- 27933365 TI - Ketamine decreases sensitivity of male rats to misleading negative feedback in a probabilistic reversal-learning task. AB - RATIONALE: Depression is characterized by an excessive attribution of value to negative feedback. This imbalance in feedback sensitivity can be measured using the probabilistic reversal-learning (PRL) task. This task was initially designed for clinical research, but introduction of its rodent version provides a new and much needed translational paradigm to evaluate potential novel antidepressants. OBJECTIVES: In the present study, we aimed at evaluating the effects of a compound showing clear antidepressant properties-ketamine (KET)-on the sensitivity of rats to positive and negative feedback in the PRL paradigm. METHODS: We trained healthy rats in an operant version of the PRL task. For successful completion of the task, subjects had to learn to ignore infrequent and misleading feedback, arising from the probabilistic (80:20) nature of the discrimination. Subsequently, we evaluated the effect of KET (5, 10, and 20 mg/kg) on feedback sensitivity 1, 24, and 48 h after administration. RESULTS: We report that acute administration of the highest dose of KET (20 mg/kg) rapidly and persistently decreases the proportion of lose-shift responses made by rats after receiving negative feedback. CONCLUSION: Present results suggest that KET decreases negative feedback sensitivity and that changes in this basic neurocognitive function might be one of the factors responsible for its antidepressant action. PMID- 27933366 TI - Deficits in autonomic indices of emotion regulation and reward processing associated with prescription opioid use and misuse. AB - RATIONALE: Prescription opioid misuse and high-dose opioid use may result in allostatic dysregulation of hedonic brain circuitry, leading to reduced emotion regulation capacity. In particular, opioid misuse may blunt the ability to experience and upregulate positive affect from natural rewards. OBJECTIVES: The purpose of this study was to examine associations between opioid use/misuse and autonomic indices of emotion regulation capability in a sample of chronic pain patients receiving prescription opioid pharmacotherapy. METHODS: Chronic pain patients taking long-term opioid analgesics (N = 40) completed an emotion regulation task while heart rate variability (HRV) was recorded, and also completed self-report measures of opioid misuse, craving, pain severity, and emotional distress. Based on a validated cut-point on the Current Opioid Misuse Measure, participants were grouped as opioid misusers or non-misusers. Opioid misuse status and morphine equivalent daily dose (MEDD) were examined as predictors of HRV and self-reports of emotion regulation. RESULTS: Opioid misusers exhibited significantly less HRV during positive and negative emotion regulation, and significantly less positive effect, than non-misusers, after controlling for confounders including pain severity and emotional distress. MEDD was inversely associated with positive emotion regulation efficacy. CONCLUSION: Findings implicate the presence of reward processing deficits among chronic pain patients with opioid-misusing behaviors, and opioid dosage was associated with deficient emotion regulation, suggesting the presence of compromised top-down cognitive control over bottom-up hedonic processes. Emotion regulation among opioid misusers may represent an important treatment target. PMID- 27933368 TI - Anatomical variations of the greater palatine canal in cone-beam computed tomography. AB - PURPOSE: To analyze anatomical variations of the greater palatine canal (GPC) using cone beam computed tomography (CBCT) images. METHODS: This study included 110 CBCTs. Axial slices were used to determine the shape of GPC and the number of lesser palatine foramina (LPF). Sagittal slices were used to assess the shape of the GPC and the number of lesser palatine canals (LPCs). RESULTS: The most prevalent axial and sagittal GPC shapes were oval (46.36%) and hourglass (23.64%). Most GPCs presented one LPF (47.27%) and one LPC (90.91%). CONCLUSIONS: GPC anatomy is highly variable. CBCT is a useful tool for evaluating the anatomical variations of GPC. PMID- 27933367 TI - Antipsychotic inductors of brain hypothermia and torpor-like states: perspectives of application. AB - Hypothermia and hypometabolism (hypometabothermia) normally observed during natural hibernation and torpor, allow animals to protect their body and brain against the damaging effects of adverse environment. A similar state of hypothermia can be achieved under artificial conditions through physical cooling or pharmacological effects directed at suppression of metabolism and the processes of thermoregulation. In these conditions called torpor-like states, the mammalian ability to recover from stroke, heart attack, and traumatic injuries greatly increases. Therefore, the development of therapeutic methods for different pathologies is a matter of great concern. With the discovery of the antipsychotic drug chlorpromazine in the 1950s of the last century, the first attempts to create a pharmacologically induced state of hibernation for therapeutic purposes were made. That was the beginning of numerous studies in animals and the broad use of therapeutic hypothermia in medicine. Over the last years, many new agents have been discovered which were capable of lowering the body temperature and inhibiting the metabolism. The psychotropic agents occupy a significant place among them, which, in our opinion, is not sufficiently recognized in the contemporary literature. In this review, we summarized the latest achievements related to the ability of modern antipsychotics to target specific receptors in the brain, responsible for the initiation of hypometabothermia. PMID- 27933369 TI - Imaging mass spectrometry in drug development and toxicology. AB - During the last decades, imaging mass spectrometry has gained significant relevance in biomedical research. Recent advances in imaging mass spectrometry have paved the way for in situ studies on drug development, metabolism and toxicology. In contrast to whole-body autoradiography that images the localization of radiolabeled compounds, imaging mass spectrometry provides the possibility to simultaneously determine the discrete tissue distribution of the parent compound and its metabolites. In addition, imaging mass spectrometry features high molecular specificity and allows comprehensive, multiplexed detection and localization of hundreds of proteins, peptides and lipids directly in tissues. Toxicologists traditionally screen for adverse findings by histopathological examination. However, studies of the molecular and cellular processes underpinning toxicological and pathologic findings induced by candidate drugs or toxins are important to reach a mechanistic understanding and an effective risk assessment strategy. One of IMS strengths is the ability to directly overlay the molecular information from the mass spectrometric analysis with the tissue section and allow correlative comparisons of molecular and histologic information. Imaging mass spectrometry could therefore be a powerful tool for omics profiling of pharmacological/toxicological effects of drug candidates and toxicants in discrete tissue regions. The aim of the present review is to provide an overview of imaging mass spectrometry, with particular focus on MALDI imaging mass spectrometry, and its use in drug development and toxicology in general. PMID- 27933370 TI - Doxorubicin-induced chronic dilated cardiomyopathy-the apoptosis hypothesis revisited. AB - The chemotherapeutic agent doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10% of pediatric cancer survivors will 10-20 years later develop severe dilated cardiomyopathy (DCM), whereby the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidence, we first argue why a dilated phenotype can occur when little apoptosis is detected. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream of mitochondrial outer membrane permeabilisation (MOMP). This lack of MOMP induction is proposed to alter the metabolic phenotype, induce hypertrophic remodeling, and lead to functional cardiac impairment even in the absence of cardiomyocyte apoptosis. We discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosis-primed cancer cells and propose computational system biology as a tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DCM. PMID- 27933371 TI - Phase I clinical and pharmacokinetic study of S-1 plus oral leucovorin in patients with metastatic colorectal cancer. AB - PURPOSE: S-1 has shown a response rate of 35% in chemonaive patients with metastatic colorectal cancer (mCRC). Leucovorin enhances the antitumor activity of 5-fluorouracil, and concurrent oral administration of S-1 and leucovorin may represent a more active treatment option for mCRC. METHODS: S-1 (35 mg/m2) and leucovorin (25 mg/body) were orally administered twice daily to chemonaive patients with mCRC. Predefined dose (schedule)-limiting toxicities (DLTs) during the first course and treatment continuity during the first two courses were evaluated during three periods of treatment with S-1 plus leucovorin (level 0, 2 weeks; level 1, 3 weeks; and level 2, 4 weeks), each followed by a 2-week rest. The pharmacokinetics (PK) of S-1 and leucovorin were studied on days 1 and 14 of the first course. RESULTS: Fifteen patients were enrolled. All three patients had DLTs at level 2, and this level was considered the maximum tolerated schedule. Level 0 was designated as the recommended schedule based on the incidences of DLTs and treatment continuity. The main toxic effects were gastrointestinal, such as diarrhea and stomatitis. There was no grade 4 adverse event or treatment related death. The overall response rate was 67% (95% confidence interval, 38 88%). The PK profiles of S-1 plus leucovorin were similar to those in previous studies. CONCLUSIONS: The recommended schedule was 2 weeks of S-1 plus leucovorin followed by a 2-week rest. The increased response and gastrointestinal toxicities of S-1 plus leucovorin as compared with S-1 monotherapy suggest that co administration of leucovorin enhanced the activity of S-1. PMID- 27933372 TI - Late isolated intraocular relapse of a systemic diffuse large B-cell lymphoma detected by flow cytometry. PMID- 27933373 TI - Outcomes of multiple myeloma patients receiving bortezomib, lenalidomide, and carfilzomib. AB - New classes of drugs including the proteasome inhibitors (PI) bortezomib and, more recently, carfilzomib and the immunomodulatory agent lenalidomide have shown improved outcomes for multiple myeloma (MM) patients during the past decade. However, most of the studies reporting outcomes for patients receiving these drugs have relied on older data sets derived from large institutions that included patients not receiving their treatment at those facilities and represented only those eligible for clinical trials or were from sites where treatment options were limited. We have analyzed data from 258 MM patients who have received treatment with at least one of three agents: bortezomib, carfilzomib, and lenalidomide in a single clinic specializing in MM with respect to their responses and other outcomes to treatment regimens including these agents. Response rates were similar between these three drugs when used for the first time and again during subsequent treatment regimens. As expected, the clinical benefit rates (CBRs) were better for patients receiving their first treatment when compared to their use in subsequent treatment regimens. The CBRs were similar during their 2nd, 3rd, and 4th treatments containing these agents. Many patients refractory to these agents showed responses to regimens containing these same drugs when used in different combinations. In addition, patients refractory to one PI often responded to the other PI. The results of this study demonstrate that novel agents can be used repeatedly in novel combinations with significant clinical benefit for patients with MM. PMID- 27933375 TI - A Novel Method of Adrenal Venous Sampling via an Antecubital Approach. AB - PURPOSE: Currently, almost all adrenal venous sampling (AVS) procedures are performed by femoral vein access. The purpose of this study was to establish the technique of AVS via an antecubital approach and evaluate its safety and feasibility. MATERIALS AND METHODS: From January 2012 to June 2015, 194 consecutive patients diagnosed as primary aldosteronism underwent AVS via an antecubital approach without ACTH simulation. Catheters used for bilateral adrenal cannulations were recorded. The success rate of bilateral adrenal sampling, operation time, fluoroscopy time, dosage of contrast, and incidence of complications were calculated. RESULTS: A 5F MPA1 catheter was first used to attempt right adrenal cannulation in all patients. Cannulation of the right adrenal vein was successfully performed in 164 (84.5%) patients. The 5F JR5, Cobra2, and TIG catheters were the ultimate catheters for right adrenal cannulation in 16 (8.2%), 5 (2.6%), and 9 (4.6%) patients, respectively. For left adrenal cannulation, JR5 and Cobra2 catheters were used in 19 (9.8%) and 10 (5.2%) patients, respectively, while only TIG catheters were used in the remaining 165 (85.1%) patients. The rate of successful adrenal sampling on the right, left, and bilateral sides was 91.8%, 93.3%, and 87.6%, respectively. The mean time of operation was (16.3 +/- 4.3) minutes, mean fluoroscopy time was (4.7 +/- 1.3) minutes, and the mean use of contrast was (14.3 +/- 4.7) ml. The incidence of adrenal hematoma was 1.0%. CONCLUSIONS: This study showed that AVS via an antecubital approach was safe and feasible, with a high rate of successful sampling. PMID- 27933374 TI - Polymorphisms of the TGF-beta1 gene and the risk of acquired aplastic anemia in a Chinese population. AB - Acquired aplastic anemia (AA) is a hematological disease characterized by failure of bone marrow hematopoiesis resulting in pancytopenia. While immune-mediated destruction of hematopoietic stem/progenitor cells (HSPCs) plays a central role in the pathophysiology of acquired AA, the transforming growth factor-beta1 (TGF beta1) is crucial in adjusting the immune system. The aim of our study was to investigate the role of TGF-beta1 gene polymorphisms rs1800469 and rs2317130 in susceptibility to acquired AA. Via the approach of SNaPshot, we genotyped rs1800469 and rs2317130 in 101 patients with acquired AA and 165 controls. It derived us to the conclusion that the genotype TT of rs1800469 (C/T) was significantly associated with decreased risk of acquired AA (adjusted OR = 0.39, 95% CI = 0.18-0.83, P = 0.014). Furthermore, this decreased risk was more pronounced among male patients (adjusted OR = 0.35, 95% CI = 0.13-0.95, P = 0.038) and SAA/vSAA (severe AA/very severe AA) patients (adjusted OR = 0.31, 95% CI = 0.12-0.77, P = 0.02) compared with controls in subgroup analysis. However, a significant increased risk was observed in the genotype distributions of rs2317130 for TT genotype (adjusted OR = 2.52, 95% CI = 1.03-6.19, P = 0.04) compared with the CC genotype among the SAA/vSAA patients and controls in the severity stratification analysis. Our results indicated that TGF-beta1 gene polymorphisms might be involved in the munity of acquired AA in a Chinese population. This initial analysis provides valuable clues for further study of TGF-beta1 pathway genes in acquired AA. PMID- 27933376 TI - Percutaneous Biopsy of Retrobulbar Masses: Anatomical Considerations and MRI Guidance. AB - PURPOSE: Obtaining adequate tissue from retrobulbar masses remains a challenge. To this end, a new method of retrobulbar mass biopsy using MRI guidance is presented. MATERIALS AND METHODS: Two patients (7- and 71-year-old male) with indeterminate retrobulbar masses underwent bioptic and cytological samplings using MR-compatible 18G and 20-22G needles, and multi-planar MR fluoroscopy. An inferior approach was taken to avoid injury to the optic nerve and ophthalmic arteries. RESULTS: The two biopsies were completed without complication. The core biopsy resulted in a final diagnosis, whereas the cytological sampling was non diagnostic. CONCLUSION: Percutaneous MR-guided retrobulbar mass biopsy proved to be feasible and safe in the two cases described in this report. PMID- 27933377 TI - Radiofrequency Ablation of Hepatocellular Carcinoma with a "Nodule-in-Nodule" Appearance: Long-Term Follow-up and Clinical Implications. AB - PURPOSE: Hepatocellular carcinoma (HCC) with a "nodule-in-nodule" (NIN) appearance has unique histological characteristics as an early HCC. We assessed long-term therapeutic outcomes of radiofrequency ablation (RFA) in HCC patients considering this appearance. MATERIALS AND METHODS: Our Institutional Review Board approved this retrospective study, and the requirement for written informed consent was waived. Between May 2006 and April 2012, a total of 572 patients underwent RFA for single HCC as a first-line treatment. Patients were divided into a NIN HCC group (n = 22) and a non-NIN HCC group (n = 550), according to the NIN feature on pretreatment imaging studies. Local tumor progression (LTP) and disease-free survival (DFS) were compared. Prognostic factors for LTP and DFS were assessed using a Cox proportional hazards model. RESULTS: The cumulative LTP rates were 4.6 and 4.6% at 3 and 5 years, respectively, in the NIN HCC group, and 15.9 and 20.5% in the non-NIN HCC group, with borderline statistical significance (p = 0.085). The corresponding DFS rates were 53.8 and 37.7% in the NIN HCC group and 44.0 and 31.7% in the non-NIN HCC group, with no significant difference (p = 0.318). Although on multivariate analysis only tumor size was a significant prognostic factor for LTP, there was a trend bordering on the significance for the NIN feature [hazard ratio (HR) = 0.19; p = 0.099]. However, it was not a significant factor for DFS (HR = 0.18; p = 0.682). CONCLUSIONS: The NIN appearance, a rare (4%, 22/550) but unique feature of early HCC, may be a favorable prognostic factor for RFA in terms of local tumor control. PMID- 27933378 TI - A "Train-Track" Technique in Anatomic Reconstruction of SVC Bifurcation Complicated by Cardiac Tamponade: An Introspection. AB - This report describes a stenting technique used to anatomically reconstruct superior vena cava (SVC) bifurcation in a patient with benign SVC syndrome. After recanalizing the SVC bifurcation, we exchanged two 0.035-in. wires for two 0.018 in. wires, deployed the SVC stent over these two wires ("train-track" technique), and stented each innominate vein over one wire. However, our decisions to recanalize both innominate veins, use the "buddy-wire" technique for SVC dilation, and dilate the SVC to 16 mm before stent deployment likely contributed to SVC tear, which was managed by resuscitation, SVC stent placement, and pericardial drainage. Here, we describe the steps of the train-track technique, which can be adopted to reconstruct other bifurcations; we also discuss the controversial aspects of this case. PMID- 27933379 TI - The role of receptor-like protein kinases (RLKs) in abiotic stress response in plants. AB - KEY MESSAGE: We review and introduce recent studies on RLK s involved in the abiotic stress response and provide insights into potential regulatory mechanisms for alleviating abiotic stress. Abiotic stresses are important factors affecting plant growth and development, resulting in crop production reduction and even plant death. To survive, plants utilize different mechanisms to respond and adapt to continuously changing environmental factors. Understanding of the molecular mechanisms of plant response to various stresses will aid in improving tolerance of plants to abiotic stress through genetic engineering, which would greatly promote the development of modern agriculture. RLKs, the largest gene family in plants, play critical roles in the regulation of plant developmental processes, signaling networks and disease resistance. Many RLKs have been shown to be involved in abiotic stress responses, including the abscisic acid response, calcium signaling and antioxidant defense. This review summarizes recent studies on RLKs involved in plant responses to abiotic stress, including drought, salt, cold, toxic metals/metalloids and other stresses, and emphasizes the upstream and downstream factors in RLK signal transduction pathways under abiotic stress. PMID- 27933380 TI - Reply to "How should we define the no. 3b lesser curvature lymph node?" PMID- 27933381 TI - Genome-wide identification and functional analysis of S-RNase involved in the self-incompatibility of citrus. AB - S-RNase-based self-incompatibility is found in Solanaceae, Rosaceae, and Scrophulariaceae, and is the most widespread mechanism that prevents self fertilization in plants. Although 'Shatian' pummelo (Citrus grandis), a traditional cultivated variety, possesses the self-incompatible trait, the role of S-RNases in the self-incompatibility of 'Shatian' pummelo is poorly understood. To identify genes associated with self-incompatibility in citrus, we identified 16 genes encoding homologs of ribonucleases in the genomes of sweet orange (Citrus sinensis) and clementine mandarin (Citrus clementine). We preliminarily distinguished S-RNases from S-like RNases with a phylogenetic analysis that classified these homologs into three groups, which is consistent with the previous reports. Expression analysis provided evidence that CsRNS1 and CsRNS6 are S-like RNase genes. The expression level of CsRNS1 was increased during fruit development. The expression of CsRNS6 was increased during the formation of embryogenic callus. In contrast, we found that CsRNS3 possessed several common characteristics of the pistil determinant of self-incompatibility: it has an alkaline isoelectric point (pI), harbors only one intron, and is specifically expressed in style. We obtained a cDNA encoding CgRNS3 from 'Shatian' pummelo and found that it is homolog to CsRNS3 and that CgRNS3 exhibited the same expression pattern as CsRNS3. In an in vitro culture system, the CgRNS3 protein significantly inhibited the growth of self-pollen tubes from 'Shatian' pummelo, but after a heat treatment, this protein did not significantly inhibit the elongation of self- or non-self-pollen tubes. In conclusion, an S RNase gene, CgRNS3, was obtained by searching the genomes of sweet orange and clementine for genes exhibiting sequence similarity to ribonucleases followed by expression analyses. Using this approach, we identified a protein that significantly inhibited the growth of self-pollen tubes, which is the defining property of an S-RNase. PMID- 27933382 TI - The impact of hereditary multiple exostoses on quality of life, satisfaction, global health status, and pain. AB - PURPOSE: The aim of the study was to evaluate quality of life (QOL), global health status, pain, and level of satisfaction in patients with hereditary multiple exostoses (HME), and to correlate the association between the severity of diseases and age, sex, number of surgical procedures, and number of exostoses. METHODS: The data of 50 patients with HME were retrospectively evaluated and recorded. QOL was evaluated with the Short-Form Health Survey (SF-12) questionnaire, the 12-Item General Health Questionnaire (GHQ-12), and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF); intensity of pain was measured using the visual analogue scale (VAS). The association of age, gender, pain, quality of life, number of exostoses, and number of surgical procedures were evaluated and correlated. RESULTS: Mean number of exostoses in our patient's cohort resulted 18.12 +/- 8.60, and every patient underwent to a mean of 5.62 +/- 5.74 surgical procedures for the exostoses. Mean VAS resulted 5.16 +/- 2.90. Considering SF-12, mental (MCS) and physical (PCS) component resulted, respectively, 45.36 +/- 10.76 and 38.73 +/- 11.09, while GHQ-12 and Q-LES-Q-SF were 15.48 +/- 4.70 and 45.28 +/- 9.55, respectively. We found a significant positive correlation between the number of exostoses and the number of surgical procedures (p < 0.001), a significant positive correlation between the number of surgical procedures and GHQ-12 (p = 0.422) and VAS (p = 0.0011), and a negative correlation between the number of surgical procedures and PCS (p = 0.0257) and between age and GHQ-12 (p = 0.0385). CONCLUSIONS: We can conclude that HME impact on patient quality of life as measured by the MCS and PCS scores similar to the disability associated with osteoarthritis in the mental component and tumors or diabetes as regards the physical component. Moreover, we found no difference in patients' quality of life as regards number of exostoses, age, and surgical procedure, but we found that women have a worse response as regards the psychological side than men. PMID- 27933383 TI - The burden of rotator cuff surgery in Italy: a nationwide registry study. AB - PURPOSE: This study aimed to estimate the yearly number of RC surgeries in Italy, a country with universal access to healthcare for its population, from 2001 to 2014, based on official information source as hospitalization records. A secondary aim was to explore geographical variation in equity in access to RC surgery between three macroregions of Italy (North, Center and South). A tertiary aim was to perform statistical projections of the number of RC procedure volumes and rates on the basis of data from 2001 to 2014. Finally, we aimed to perform a prediction of charges by 2025 to examine the economic impact of RC surgery. METHODS: The analysis of the National Hospital Discharge records (SDO) maintained at the Italian Ministry of Health, concerning the 14 years of our survey (2001 through 2014) was performed. These data are anonymous and include the patient's age (in aggregate for class of age), sex, domicile, region of hospitalization, length of the hospitalization, and type of reimbursement (public or private). RESULTS: During the 14-year study period, 390,001 RC repairs were performed in Italy, which represented an incidence of 62.1 RC procedures for every 100,000 Italian inhabitants over 25 years old. Approximately 65% of RC repair were performed annually in patients ages <65 years, thus affecting the working population. 246,810 patients (63.3%) from the North underwent RC repairs from 2001 through 2014, 78,540 patients (20.2%) from the Center, and 64,407 patients (16.5%) from the South. The projection model predicted substantial increases in the numbers of RC repairs. CONCLUSIONS: This study confirms that the socioeconomic burden of RC surgery is growing and heavily affecting the working population. According to the prediction model, hospital costs sustained by the national health care system for RC procedures are expected to be over 1 billion euros by 2025. LEVEL OF EVIDENCE: II. PMID- 27933384 TI - Thyroid autoimmunity: is really associated with papillary thyroid carcinoma? AB - The incidence of thyroid cancer has been greatly increasing. Several studies aimed to investigate biomarkers for prediction of thyroid cancer. Some of these studies have suggested that thyroid autoantibodies (TAb) could be used as predictors of thyroid cancer risk, but the correlation between TAb and PTC is still a matter of debate. The aim of this study is to evaluate thyroid autoimmunity and TAbs in patients with PTC and benign multinodular goiter (MNG) to investigate if TAbs and autoimmune thyroid disease (ATD) could predict thyroid malignancy. A total of 577 patients with thyroid papillary carcinoma (PTC) and 293 patients with benign MNG disease were enrolled postoperatively. Demographic features, thyroglobulin (TgAb) and thyroid peroxidase antibodies (TPOAb) and histologic outcome of the patients were evaluated. The prevalence of ATD and TgAb or TPOAb measurements was not statistically different in PTC and MNG groups. However, tumors were significantly smaller and tumor capsule invasion was seen less frequently in patients with PTC and ATD than without ATD. Patients without ATD had more advanced stage (TNM stage III/IV) tumors than with ATD. Only one of the 11 patients with distant organ metastasis had ATD. The present study demonstrated that the prevalence of ATD diagnosed even with histology or TAb positivity was not different in patients with PTC and MNG. However, having ATD might be associated with a better prognosis in PTC patients. PMID- 27933385 TI - Outcomes and prognostic factors for squamous cell carcinoma of the oral tongue in young adults: a single-institution case-matched analysis. AB - There is controversy regarding prognosis and treatment of young patients with oral cavity cancer compared to their older counterparts. We conducted a retrospective case-matched analysis of all adult patients younger than 40 years and treated at our institution for a squamous cell carcinoma of the oral cavity. Only non-metastatic adult patients (age >18) with oral tongue cancer were eventually included and matched 1:1 with patients over 40 years of age, at least 20 years older than the cases, with same T and N category and treatment period. Sixty-three patients younger than 40 had an oral cavity squamous cell cancer out of which 57 had an oral tongue primary during the period 1999-2012, and 50 could be matched with an older control. No difference could be seen between younger and older patients with regard to overall, cancer-specific, or progression-free survival. The patterns of failure were similar, although in young patients, almost all failures occurred during the first 2 years following treatment. Although overall survival shows a trend toward lower survival in older patients, cancer-specific survival and analysis of pattern failure suggest that disease prognosis is similar between young and older adults with oral tongue cancer. Further work is needed to identify the younger patients with poorer prognosis who overwhelmingly fail during the first year after treatment and could benefit from treatment intensification. Until then, young adults ought to be treated using standard guidelines. PMID- 27933386 TI - Endoscopic submucosal dissection specimens in early colorectal cancer: lateral margins, macroscopic techniques, and possible pitfalls. AB - Endoscopic submucosal dissection (ESD) allows en-bloc resection of superficial gastrointestinal tumors, providing specimens on which lateral margin analysis can be performed reliably. Positive lateral margins have been linked to higher rates of recurrence/residual tumor. There are no guidelines for macroscopic processing of lateral margins. Currently, most institutions use parallel lateral sections, which are difficult to interpret. We use perpendicular lateral sections, hypothesizing that it decreases potential artifactually positive lateral margins. We analyzed positive lateral margin rates in colorectal ESD specimens according to sectioning method. We also looked at morphological factors associated with margin positivity as a function of technique used. We studied 166 ESD specimens, on which parallel sectioning practiced from 2006 to 2011 (n = 75). Perpendicular sectioning was used from 2010 to 2015 (n = 91). We recorded the number of positive margins, along with grade of dysplasia/carcinoma. Other information such as histopathological type, specimen size, lesion location, and patient follow-up was also recorded for evaluation. Forty of seventy-five (63%) margins were positive for parallel sections. In contrast, perpendicularly cut margins were significantly less frequently positive: 22/91 (24%) (p = 0.0001). Positive margins were found significantly more frequently in tubulo-villous lesions compared to tubular lesions in both the parallel and perpendicular groups (p = 0.03 and p = 0.02, respectively). Specimen size was not significantly associated with positive margins. Using perpendicular sectioning of colorectal ESD specimens, the proportion of cases with a positive lateral margin was significantly lower than when parallel sectioning was used. We suggest perpendicular sectioning to improve accuracy in histopathological analysis. This method is particularly important to use in future studies, as it may prevent authors from making conjectures based on overestimation of positive lateral margins. PMID- 27933387 TI - Effect of vitamin D on biochemical parameters in polycystic ovary syndrome women: a meta-analysis. AB - AIM: To investigate the therapeutical effect of vitamin D supplementation on the metabolism and endocrine parameters of PCOS patients. MATERIALS AND METHODS: Clinical studies investigating the therapeutic effect of vitamin D supplementation on PCOS patients were selected by searching PubMed, Embase, The Cochrane library and Web of Science until April 2016. The included articles were selected according to the inclusion criteria. Serum HOMA-IR, QUICKI, LDL, DHEAS, free testosterone (FT), total testosterone (TT), PTH, 25-hydroxy-vitamin D, and triglyceride of PCOS patients were enrolled for evaluating the therapeutic effects of vitamin D. RESULTS: 16 studies were included in this study. There was no significant difference between the placebo group and vitamin D group in the concentration of serum 25-hydroxy-vitamin D in patients with PCOS (P = 0.06). After treated with vitamin D, the serum 25-hydroxy-vitamin D in PCOS patients was increased (P < 0.00001), while the serum PTH (P = 0.003) and triglyceride (P = 0.006) were decreased. In addition, the serum HOMA-IR, QUICKI, LDL, DHEAS, FT, and TT in PCOS patients did not change. Subgroup analysis showed that the serum triglyceride of PCOS patients was decreased by low dose of vitamin D supplementation (<50,000 IU) (P = 0.03), but no significantly changed by high dose vitamin D supplementation (>=50,000 IU) (P = 0.17). CONCLUSION: Vitamin D supplementation significantly attenuates serum PTH and triglyceride in PCOS patients except for serum HOMA-IR, QUICKI, LDL, DHEAS, FT, and TT. Furthermore, less than 50,000 IU vitamin D supplementation is sufficient for decreasing serum triglyceride. PMID- 27933388 TI - Digital tomosynthesis as a new diagnostic tool for evaluation of spine damage in patients with ankylosing spondylitis. AB - We aimed to compare digital tomosynthesis (DTS) with radiographs for the assessment of spinal bone damage in patients with ankylosing spondylitis (AS). The study comprised 68 patients with AS who underwent both DTS and radiographs of the cervical and lumbar spine on the same day. Spinal bone damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and the presence of facet joint damage. The Wilcoxon signed-rank test and McNemar's test were used to compare spinal bone damage between the two modalities. In 68 AS patients with mean 4.5 years of disease duration, the mean mSASSS was 11.7 +/- 11.3 with radiographs and 13.1 +/- 11.5 with DTS (p = 0.001). A grade 1 (erosion, sclerosis, or squaring) score in the mSASSS system was higher with DTS than with radiographs (p = 0.001), but grade 2 (syndesmophyte) and grade 3 (bridge) scores (p > 0.005 each) were not. In particular, the grade 1 score was higher with DTS than with radiographs at the cervicothoracic (p < 0.001) and thoracolumbar (p = 0.003) junctions. With regard to facet joint damage, erosion/sclerosis of facet joints was better depicted by DTS than by radiographs in the cervical (54.4 vs. 22.1%, p < 0.001) and lumbar spine (72.1 vs. 11.8%, p < 0.001). DTS depicted more subtle damage of spinal vertebrae in patients with AS than radiographs did. Moreover, erosion/sclerosis of facet joints was better detected with DTS than with radiographs. PMID- 27933389 TI - High volume is the key for improving in-hospital outcomes after radical prostatectomy: a total population analysis in Germany from 2006 to 2013. AB - PURPOSE: Outcomes of radical prostatectomy are prone to publication bias, because most of the data originated from highly specialized centers. We assessed in hospital outcomes of all radical prostatectomies in Germany from 2006 to 2013 focusing on caseload volume, surgical approach, and certification status. METHODS: We analyzed the nationwide German hospital billing data covering 221,331 radical prostatectomies from 2006 to 2013. Outcomes were in-hospital mortality, surgical revision, and transfusion rates and the length of stay. Multivariate models described the impact of these factors. RESULTS: The yearly number of radical prostatectomies declined from 28,374 to 21,850. While shares of all other approaches decreased, shares for robot-assisted prostatectomy increased from 0.6 to 25.2%. Hospitals with >=100 cases a year reported lower in-hospital mortality with 0.08 versus 0.17% for hospitals with <50 cases a year. On multivariate analysis, the odds for an individual death were doubled in hospitals with <50 cases a year. All other factors showed no significant impact on mortality. Concerning blood transfusion, the surgical approach was the strongest predictor with minimally invasive surgery (26% of the odds of conventional surgery) followed by caseload volume. Surgical revision was frequent in hospitals with lower rates of minimally invasive approaches (OR 1.6) and smaller caseloads (OR 1.4). Length of stay was reduced by 3 days for caseloads >=200 a year, 2 days with minimally invasive approaches, and 1 day in certified prostate cancer centers. Lacking clinical information is a major limitation. CONCLUSIONS: Annual caseload volume of hospitals is the most important factor for improved in hospital outcomes. PMID- 27933390 TI - [De-escalation of therapy in ANCA-associated vasculitides]. AB - Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) require a differentiated therapeutic approach depending on the degree of organ dysfunction and disease activity. In organ dysfunction and life-threatening AAV cyclophosphamide and rituximab are recommended for the induction of remission. For remission induction with a lack of organ dysfunction and non-life-threatening AAV, methotrexate or mycophenolate mofetil are recommended. For remission maintenance therapy azathioprine or methotrexate are used. In the case of contraindications, intolerance or previous failure of azathioprine and methotrexate treatment, rituximab, leflunomide or mycophenolate mofetil may be used as alternatives. Maintenance therapy is usually continued for at least 2 years. De-escalation of therapy requires continuous clinical monitoring while the glucocorticoid medication and immunosuppressive therapy is tapered; however, every de-escalation of therapy carries a risk of relapse. PMID- 27933391 TI - [Tapering and termination of immunosuppressive treatment in spondyloarthritides (including psoriatic arthritis)]. AB - BACKGROUND: Immunomodulatory long-term treatment has also become the standard treatment for spondyloarthritides (SpA), including psoriatic arthritis (PsA); however, uncertainty exists about dose reduction or termination of treatment after remission or low disease activity. OBJECTIVE: When is it possible to reduce medication or terminate treatment for SpA? MATERIAL AND METHODS: An extensive non systematic literature search was performed focusing on practice guidelines, systematic meta-analyses and clinical trials on medicinal long-term treatment and voluntary medication reduction in axial and peripheral SpA, including PsA. RESULTS: The chances of drug-free remission after treatment with biologics for axial SpA and in PsA are low; however, in remission or a state of low disease activity reduction of the cumulative dosage of biologics can be successful in 53 100% of cases without a significant increase in disease activity. The current state and duration of remission, with or without comedication with nonsteroidal anti-inflammatory drugs (NSAID), extra-articular disease manifestations and the results of previous treatment attempts have to be carefully taken into consideration before elective dose reduction. CONCLUSION: Reduction of long-term treatment is an individualized decision made jointly by patients and physicians. The risk of flares and especially of extra-articular disease manifestations needs to be weighed against the possible advantages of reduced medication. Maintainenance of mediction-free disease remission is too rare in SpA or PsA patients carefully selected for biologics treatment, to allow a later voluntary termination of therapy, without at least a prior cautious attempt at dose reduction. PMID- 27933392 TI - Leishmania infection: painful or painless? AB - The complex life cycle and immunopathological features underpinning the interaction of Leishmania parasites and their mammalian hosts poses frequent poorly explored and inconclusively resolved questions. The altered nociceptive signals over the course of leishmaniasis remain an intriguing issue for nociceptive and parasitology researchers. Experimental investigations have utilized behavioral, morphological, and neuro-immune approaches in the study of experimental cutaneous leishmaniasis (CL). The data generated indicates new venues for the study of the pathological characteristics of nociceptive processing in this parasitic disease. Leishmania-induced pain may be easily observed in mice and rats. However, nociceptive data is more complex in human investigations, including the occurrence of painless lesions in mucocutaneous and cutaneous leishmaniasis. Data from recent decades indicate that humans can also be affected by pain-related symptoms, often distinct from the region of body infection. The molecular and cellular mechanisms underlying such variable nociceptive states in humans during the course of leishmaniasis are an active area of research. The present article reviews nociception in leishmaniasis, including in experimental models of CL and clinical reports. PMID- 27933393 TI - Prevalence and prognostic impact of left-sided valve thickening in systemic light chain amyloidosis. AB - BACKGROUND: Left heart valve thickening (LVT) was described in patients with light-chain amyloidosis (AL). This phenomenon reflects likely infiltration of the valve by amyloid proteins. However, the prevalence of LVT and its prognostic value have not been investigated in patients with AL. METHODS AND RESULTS: Comprehensive transthoracic echocardiography was performed at baseline in 150 patients [median age 68 (33-87) years; 59% male] with confirmed AL. The presence of abnormal mitral and/or aortic valve thickening (>3 mm) was assessed in all included patients. Overall, 42% had LVT at the time of diagnosis. Compared to patients without LVT, those with LVT were older and had a more advanced NYHA functional class (63% in patients with NYHA III-IV vs. 33% in NYHA I-II, p < 0.001). They also had higher left ventricular (LV) wall thickness and mass, larger left atrium, higher mitral annulus E/E' ratio and systolic pulmonary artery pressures, and lower LV ejection fraction (all p < 0.05). Patients with more advanced Mayo Clinic stage had a higher incidence of LVT: 58% in stage III vs. 45% in stage II and 5% in stage I (p < 0.001). During a median follow-up of 2 years, 79 deaths occurred. The presence of LVT was significantly associated with reduced 5-year survival (32 +/- 7 vs. 64 +/- 6%). In multivariate analysis, after adjusting for age, gender, NYHA functional class, and LV ejection fraction, LVT remained significantly associated with higher all-cause mortality (hazard ratio 1.90, 95% CI 1.10-3.34, p = 0.02). CONCLUSION: Left heart valve thickening is common in patients with AL and is associated with worse functional class, LV systolic and diastolic function, and more advanced stage of the disease. In addition, LVT appears to be a powerful marker of all-cause mortality. PMID- 27933394 TI - Men and women show similar survival rates after breast cancer. AB - PURPOSE: To compare the disease-free survival (DFS) and overall survival (OS) rates of men and women undergoing treatment for breast cancer. METHODS: A retrospective cohort study of patients with breast cancer diagnosed and treated at the Cancer Hospital III of the National Cancer Institute of Brazil, Rio de Janeiro, Brazil, between 1999 and 2013. Male breast cancer cases were matched for age, year of diagnosis, and clinical staging to three female cases (1:3). Patient characteristics were abstracted from hospital records and medical charts. Cases were analyzed using descriptive statistics, and comparisons between the genders were performed using Kaplan-Meier curves and Cox regression analysis with 95% confidence intervals. RESULTS: The study population comprised 98 men and 294 women. There were significant differences (p < 0.05) between the genders for marital status, alcohol consumption, smoking, presence of hypertension and other comorbidities, histological type of tumor, expression of estrogen receptors, progesterone receptors, human epidermal growth factor receptor-type 2, type of breast surgery, neoadjuvant chemotherapy, adjuvant radiotherapy, and use of palliative bisphosphonate therapy. Five- and 10-year DFS rates were, respectively, 80.0 and 51.4% for men and 71.4 and 63.5% for women (p = 0.245), and 5- and 10-year OS rates were, respectively, 65.0 and 47.5% for men and 56.5 and 41.4% for women (p = 0.221). CONCLUSION: There was no significant difference in prognosis (DFS and OS rates) between the genders, but significant differences in sociodemographic and clinical characteristics were detected between male and female breast cancer cases. PMID- 27933396 TI - Totally laparoscopic total gastrectomy using the overlap method; early outcomes of 50 consecutive cases. AB - BACKGROUND: Construction of an esophagojejunostomy is still a challenging procedure in totally laparoscopic total gastrectomy (TLTG), and there is no standard anastomosing method. The aims of this study were to describe our TLTG with the overlap method using a linear stapler and report surgical outcomes. METHODS: From January 2015 to April 2016, 50 patients underwent TLTG using the overlap method for gastric cancer. The procedures were performed by a single surgeon, and the patients' medical records were reviewed. Their clinicopathologic characteristics, operation time, date of flatus, hospital stay, morbidity, and mortality were analyzed. RESULTS: The median age and body mass index were 56 years and 23.5, respectively. Stage 1A tumors were the most common. Mean operating time was 144.6 min, and no cases required changing to open laparotomy during surgery. On average, flatus occurred 3.5 days after surgery, and patients were discharged 6.8 days after surgery. No patient experienced anastomosis leakage, stricture, duodenal stump leakage, luminal bleeding, pancreatic fistula, or wound problems. There were two cases of intra-abdominal bleeding that required additional surgery. Intra-abdominal fluid collection and mechanical ileus occurred in two patients, respectively, and were successfully managed with conservative treatment. CONCLUSIONS: We reported favorable surgical outcomes of TLTG using the overlap method. It is a feasible and safe option for treatment of gastric cancer. PMID- 27933397 TI - Laparo-endoscopic versus open recurrent inguinal hernia repair: should we follow the guidelines? AB - INTRODUCTION: On the basis of six meta-analyses, the guidelines of the European Hernia Society (EHS) recommend laparo-endoscopic recurrent repair following previous open inguinal hernia operation and, likewise, open repair following previous laparo-endoscopic operation. So far no data are available on implementation of the guidelines or for comparison of outcomes. Besides, there are no studies for comparison of outcomes for compliance versus non-compliance with the guidelines. PATIENTS AND METHODS: In total, 4812 patients with elective unilateral recurrent inguinal hernia repair in men were enrolled between September 1, 2009, and September 17, 2014, in the Herniamed Registry. Only patients with 1-year follow-up were included. RESULTS: Out of the 2482 laparo endoscopic recurrent repair operations 90.5% of patients, and out of the 2330 open recurrent repair procedures only 38.5% of patients, were operated on in accordance with the guidelines of the EHS. Besides, on compliance with the guidelines multivariable analysis demonstrated for laparo-endoscopic recurrent repair a significantly lower risk of pain at rest (OR 0.643 [0.476; 0.868]; p = 0.004) and pain on exertion (OR 0.679 [0.537; 0.857]; p = 0.001). Comparison of laparo-endoscopic and open recurrent repair in settings of compliance versus non compliance with the guidelines showed a higher incidence of perioperative complications and re-recurrences for recurrent repairs that did not comply with the guidelines. CONCLUSION: The EHS guidelines for recurrent inguinal hernia repair are not yet being observed to the extent required. Non-compliance with the guidelines is associated with higher perioperative complication rates and higher risk of re-recurrence. Even on compliance with the guidelines, the risk of pain at rest and pain on exertion is higher after open recurrent repair than after laparo-endoscopic repair. PMID- 27933395 TI - Influence of the HER receptor ligand system on sensitivity to cetuximab and trastuzumab in gastric cancer cell lines. AB - PURPOSE: Gastric cancer remains a major health concern, and improvement of the therapeutic options is crucial. Treatment with targeted therapeutics such as the EGFR-targeting antibody cetuximab or the HER2-targeting antibody trastuzumab is either ineffective or moderately effective in this disease, respectively. In this study, we analysed the involvement of the HER receptor ligands amphiregulin (AREG), epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) in the responsiveness of gastric cancer cell lines to cetuximab and trastuzumab. METHODS: A panel of 11 gastric cancer cell lines was characterized for cetuximab and trastuzumab sensitivity, ligand secretion and expression and activation of the HER receptors using WST-1 cell proliferation assays, ELISAs and Western blot analyses. We further investigated the effects of an exogenous ligand application on the cetuximab and trastuzumab sensitivity. RESULTS: We found no correlation between TGFalpha secretion and the sensitivity to cetuximab or trastuzumab. For AREG, we confirmed previous results indicating that this ligand is a positive predictor of cetuximab sensitivity. Exogenous HB-EGF was effective in rescuing sensitive cell lines from inhibition of cell proliferation by both, cetuximab and trastuzumab. CONCLUSIONS: Our data indicate that HB-EGF may be a useful marker for the prediction of trastuzumab sensitivity in gastric cancer. PMID- 27933398 TI - ECMO for intractable status asthmaticus following atracurium. AB - Intraoperative allergic reactions are rare but serious events associated with increased morbidity and mortality. We report the salvage of intraoperative anaphylaxis leading to extreme hypercapnic respiratory failure by veno-venous extracorporeal membrane oxygenation (ECMO). A 38-year-old woman undergoing thyroidectomy developed intractable bronchospasm after administration of atracurium, leading to extreme hypercapnic respiratory failure (PaCO2 > 250 mmHg, pH 6.773). After the failure of conventional medical therapy and ventilatory optimization, the patient was connected to a veno-venous ECMO circuit. PaCO2 of 45.6 mmHg and pH of 7.25 were achieved in 1 h, by slowly increasing sweep gas flows up to 3.5 L/min and using continuous end-tidal CO2 monitoring to gauge the procedure. After extubation and disconnection from ECMO, the patient was discharged on the 6th day without sequelae. Rapid reversal of extreme hypercapnic acidosis by ECMO was feasible, without any neurologic sequelae. Veno-venous ECMO support may be a valuable option for the salvage of intraoperative anaphylaxis. PMID- 27933399 TI - Implementation of clinical decision support in young children with acute gastroenteritis: a randomized controlled trial at the emergency department. AB - : Acute gastroenteritis (AGE) is one of the most frequent reasons for young children to visit emergency departments (EDs). We aimed to evaluate (1) feasibility of a nurse-guided clinical decision support system for rehydration treatment in children with AGE and (2) the impact on diagnostics, treatment, and costs compared with usual care by attending physician. A randomized controlled trial was performed in 222 children, aged 1 month to 5 years at the ED of the Erasmus MC-Sophia Children's hospital in The Netherlands ( 2010-2012). Outcome included (1) feasibility, measured by compliance of the nurses, and (2) length of stay (LOS) at the ED, the number of diagnostic tests, treatment, follow-up, and costs. Due to failure of post-ED weight measurement, we could not evaluate weight difference as measure for dehydration. Patient characteristics were comparable between the intervention (N = 113) and the usual care group (N = 109). Implementation of the clinical decision support system proved a high compliance rate. The standardized use of oral ORS (oral rehydration solution) significantly increased from 52 to 65%(RR2.2, 95%CI 1.09-4.31 p < 0.05). We observed no differences in other outcome measures. CONCLUSION: Implementation of nurse-guided clinical decision support system on rehydration treatment in children with AGE showed high compliance and increase standardized use of ORS, without differences in other outcome measures. What is Known: * Acute gastroenteritis is one of the most frequently encountered problems in pediatric emergency departments. * Guidelines advocate standardized oral treatment in children with mild to moderate dehydration, but appear to be applied infrequently in clinical practice. What is New: * Implementation of a nurse-guided clinical decision support system on treatment of AGE in young children showed good feasibility, resulting in a more standardized ORS use in children with mild to moderate dehydration, compared to usual care. * Given the challenges to perform research in emergency care setting, the ED should be experienced and adequately equipped, especially during peak times. PMID- 27933400 TI - [Orbital cavity tumor with macular folds]. AB - A 40-year-old patient presented with an orbital tumor of the right eye accompanied by visual impairment and macular folds. The diagnosis of mucocele was made through clinical and radiological investigations. The excision of the mucocele was performed immediately. As early as 8 weeks after the operation, an obvious increase in visual acuity was noticed. At this time, the macular folds were no longer detectable. PMID- 27933401 TI - Improvement of abnormal vaginal flora in Ugandan women by self-testing and short use of intravaginal antimicrobials. AB - The vaginal composition of African women is more often lactobacillus-deficient compared to that of women from other areas around the world. Lactobacillus deficient microflora is a known risk factor for serious health problems, such as preterm birth, cervix cancer, and entrapment of human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). The aim of this study was to assess the effect of local vaginal antibiotic or antiseptic treatment on abnormal vaginal flora (AVF), aerobic vaginitis (AV), and bacterial vaginosis (BV) among women in rural, semi-urban, and urban areas in Uganda, as compared to placebo. In a double-blind, placebo-controlled, randomized trial, 300 women presenting for outpatient routine, follow-up, or medical care at Mulago Hospital in Kampala, Uganda, were enrolled to receive 6 days of treatment with vaginal rifaximin (RFX), dequalinium chloride (DQC), or placebo if they had an increased vaginal pH of >4.5 as determined by self-testing. At initial visit and at control visit after 4 weeks, a smear was taken for blinded wet mount microscopy to determine AVF, BV, AV, and Candida severity scores. As compared to placebo, both RFX or DQC treatments dramatically diminished BV prevalence and severity from the initial to follow-up visit: the BV score declined from 2.5 to 1.6 (p < 0.0001) and from 2.5 to 1.9 (p < 0.0001), respectively. Similarly, strong improvements in the AV score were seen in both treatment regimens: moderate and severe AV declined from AV scores of 6.3 to 3.6 (p = 0.003) and from 6.6 to 4.1 (p < 0.004), respectively. Also, women with AVF (deceased or absent lactobacilli) showed similar improvements when compared with placebo. Women with normal flora and Candida at the initial visit showed less Candida after 4 weeks in the group treated with DQC (p = 0.014). Even after a short duration of intravaginal treatment with local non-absorbable antiseptics or antibiotics produced significant, lasting improvements in the vaginal microbiome composition of women with disturbed vaginal microflora. As African women have high prevalences of BV, AV, and AVF, this approach could improve their odds to prevent health compromising complications. Further studies assessing direct health outcomes are needed to substantiate this. PMID- 27933402 TI - Quality-of-life evaluation during platinum-based neoadjuvant chemotherapies for urothelial carcinoma. AB - BACKGROUND: Although quality of life (QOL) is one of the most important considerations in patients treated with anticancer therapies, desirable regimens for neoadjuvant chemotherapy including QOL in locally advanced urothelial carcinoma remain unclear. The present study evaluated the influence of neoadjuvant platinum-based chemotherapy on QOL in patients with locally advanced urothelial carcinoma. METHODS: Between June 2013 and March 2016, 83 urothelial carcinoma patients who received two courses of neoadjuvant chemotherapy were enrolled in this prospective observational study. Neoadjuvant regimens included gemcitabine + cisplatin (GCis) or gemcitabine + carboplatin (GCb) therapies. As a primary endpoint, we assessed QOL changes in each group before and after chemotherapy using the Quality of Life questionnaire on days 1, 3, and 15 of each cycle. Secondary endpoints included toxicity, safety, weight loss, renal function decline, and tumor responses. RESULTS: QOL analyses were performed in 39 patients receiving GCis and in 44 patients receiving GCb. Appetite loss, role functioning, nausea/vomiting, physical, and fatigue deteriorated >10% from baseline in the GCis group but not in the GCb group. Constipation worsened, whereas scores for pain and emotional items improved in both groups. Objective response rates were 38.5 and 43.2% in the GCis and GCb groups, respectively. CONCLUSIONS: Both GCis and GCb regimens were feasible in terms of QOL. The GCb regimen may be associated with a better QOL status especially in regard to gastrointestinal symptoms. PMID- 27933403 TI - Copy number abnormalities in new or progressive 'neurocutaneous melanosis' confirm it to be primary CNS melanoma. PMID- 27933405 TI - Current challenges of metastatic breast cancer. AB - Metastasis is one of the most characteristic yet problematic behaviors of cancer cells. Stage IV breast cancer accounts for a large portion of breast cancer related morbidity and mortality. Despite early detection and improvement in survival owing to advancements in biomedical research and overall improvement of the health system, 6-10% of patients present with stage IV disease in the developed world, with a higher incidence noted elsewhere. Despite advances in biomedical research into cancer, up to 70-80% of patients with stage IV breast cancer die of cancer in 5 years, a disproportionally higher mortality compared with non-metastatic breast cancer. In this article, we review the incidence, survival, heterogeneity, current practice, and challenges in stage IV breast cancer, and we finish by noting new research initiatives to improve poor survival and suggesting future directions. By doing so, we hope to set the basis of future directions for both treating physicians and translational researchers to relieve the suffering of patients with stage IV breast cancer and improve the survival of patients with this dismal disease. PMID- 27933404 TI - Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism. AB - Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer's disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the "post-GWAS" era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a beta3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Abeta peptide levels in 2886 AD cases. Lastly, we showed that the under expression of FERMT2 increases Abeta peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Abeta peptide production. PMID- 27933406 TI - Differential Roles for the Coagulation Factors XI and XII in Regulating the Physical Biology of Fibrin. AB - In the contact activation pathway of the coagulation, zymogen factor XII (FXII) is converted to FXIIa, which triggers activation of FXI leading to the activation of FIX and subsequent thrombin generation and fibrin formation. Feedback activation of FXI by thrombin has been shown to promote thrombin generation in a FXII-independent manner and FXIIa can bypass FXI to directly activate FX and prothrombin in the presence of highly negatively charged molecules, such as long chain polyphosphates (LC polyP). We sought to determine whether activation of FXII or FXI differentially regulate the physical biology of fibrin formation. Fibrin formation was initiated with tissue factor, ellagic acid (EA), or LC polyP in the presence of inhibitors of FXI and FXII. Our data demonstrated that inhibition of FXI decreased the rate of fibrin formation and fiber network density, and increased the fibrin network strength and rate of fibrinolysis when gelation was initiated via the contact activation pathway with EA. FXII inhibition decreased the fibrin formation and fibrin density, and increased the fibrinolysis rate only when fibrin formation was initiated via the contact activation pathway with LC polyP. Overall, we demonstrate that inhibition of FXI and FXII distinctly alter the biophysical properties of fibrin. PMID- 27933407 TI - SimVascular: An Open Source Pipeline for Cardiovascular Simulation. AB - Patient-specific cardiovascular simulation has become a paradigm in cardiovascular research and is emerging as a powerful tool in basic, translational and clinical research. In this paper we discuss the recent development of a fully open-source SimVascular software package, which provides a complete pipeline from medical image data segmentation to patient-specific blood flow simulation and analysis. This package serves as a research tool for cardiovascular modeling and simulation, and has contributed to numerous advances in personalized medicine, surgical planning and medical device design. The SimVascular software has recently been refactored and expanded to enhance functionality, usability, efficiency and accuracy of image-based patient-specific modeling tools. Moreover, SimVascular previously required several licensed components that hindered new user adoption and code management and our recent developments have replaced these commercial components to create a fully open source pipeline. These developments foster advances in cardiovascular modeling research, increased collaboration, standardization of methods, and a growing developer community. PMID- 27933408 TI - Twelve weeks' progressive resistance training combined with protein supplementation beyond habitual intakes increases upper leg lean tissue mass, muscle strength and extended gait speed in healthy older women. AB - The age-related decline in functional capability is preceded by a reduction in muscle quality. The purpose of this study was to assess the combined effects of progressive resistance training (PRT) and protein supplementation beyond habitual intakes on upper leg lean tissue mass (LTM), muscle quality and functional capability in healthy 50-70 years women. In a single-blinded, randomized, controlled design, 57 healthy older women (age 61.1 +/- 5.1 years, 1.61 +/- 0.65 m, 65.3 +/- 15.3 kg) consumed 0.33 g/kg body mass of a milk-based protein matrix (PRO) for 12 weeks. Of the 57 women, 29 also engaged in a PRT intervention (PRO + PRT). In comparison to the PRO group (n = 28), those in the PRO + PRT group had an increase in upper leg LTM [0.04 (95% CI -0.07 to 0.01) kg vs. 0.13 (95% CI 0.08-0.18) kg, P = 0.027], as measured by Dual-energy X-ray absorptiometry; an increase in knee extensor (KE) torque [-1.6 (95% CI -7.3 to 4.4 N m) vs. 10.2 (95% CI 4.3-15.8 N m), P = 0.007], as measured from a maximal voluntary isometric contraction (Con-Trex MJ; CMV AG); and an increase in extended gait speed [-0.01 (95% CI -0.52-0.04) m s-1 vs. 0.10 (95% CI 0.05-0.22) m s-1, P = 0.001] as measured from a maximal 900 m effort. There was no difference between groups in the time taken to complete 5 chair rises or the number of chair rises performed in 30 s (P > 0.05). PRT in healthy older women ingesting a dietary protein supplement is an effective strategy to improve upper leg LTM, KE torque and extended gait speed in healthy older women. PMID- 27933409 TI - Imaging trends in suspected appendicitis-a Canadian perspective. AB - PURPOSE: The purpose of our study was to assess trends in the imaging of suspected appendicitis in adult patients in emergency departments of academic centers in Canada. METHODS: A questionnaire was sent to all 17 academic centers in Canada to be completed by a radiologist who works in emergency radiology. The questionnaires were sent and collected over a period of 4 months from October 2015 to February 2016. RESULTS: Sixteen centers (94%) responded to the questionnaire. Eleven respondents (73%) use IV contrast-enhanced computed tomography (CT) as the imaging modality of choice for all patients with suspected appendicitis. Thirteen respondents (81%) use ultrasound as the first modality of choice in imaging pregnant patients with suspected appendicitis. Eleven respondents (69%) use ultrasound (US) as the first modality of choice in patients younger than 40 years of age. Ten respondents (67%) use ultrasound as the first imaging modality in female patients younger than 40 years of age. When CT is used, 81% use non-focused CT of the abdomen and pelvis, and 44% of centers use oral contrast. Thirteen centers (81%) have ultrasound available 24 h a day/7 days a week. At 12 centers (75%), ultrasound is performed by ultrasound technologists. Four centers (40%) perform magnetic resonance imaging (MRI) in suspected appendicitis in adult patients at the discretion of the attending radiologist. Eleven centers (69%) have MRI available 24/7. All 16 centers (100%) use unenhanced MRI. CONCLUSIONS: Various imaging modalities are available for the work-up of suspected appendicitis. Although there are North American societal guidelines and recommendations regarding the appropriateness of the multiple imaging modalities, significant heterogeneity in the first-line modalities exist, which vary depending on the patient demographics and resource availability. Imaging trends in the use of the first-line modalities should be considered in order to plan for the availability of the imaging examinations and to consider plans for an imaging algorithm to permit standardization across multiple centers. While this study examined the imaging trends specifically in Canada, there are implications to other countries seeking to streamline imaging protocols and determining appropriateness of the first-line imaging modalities. PMID- 27933410 TI - Magnetic resonance imaging patterns of treatment-related toxicity in the pediatric brain: an update and review of the literature. AB - Treatment-related neurotoxicity is a potentially life-threatening clinical condition that can represent a diagnostic challenge. Differentiating diagnoses between therapy-associated brain injury and recurrent disease can be difficult, and the immediate recognition of neurotoxicity is crucial to providing correct therapeutic management, ensuring damage reversibility. For these purposes, the knowledge of clinical timing and specific treatment protocols is extremely important for interpreting MRI patterns. Neuroradiologic findings are heterogeneous and sometimes overlapping, representing the compounding effect of the different treatments. Moreover, MRI patterns can be acute, subacute or delayed and involve different brain regions, depending on (1) the mechanism of action of the specific medication and (2) which brain regions are selectively vulnerable to specific toxic effects. This review illustrates the most common radiologic appearance of radiotherapy, chemotherapy and medication-associated brain injury in children, with special focus on the application of advanced MRI techniques (diffusion, perfusion and proton spectroscopy) in the diagnosis of the underlying processes leading to brain toxicity. PMID- 27933411 TI - Society of Surgical Oncology Breast Disease Working Group Statement on Prophylactic (Risk-Reducing) Mastectomy. AB - Over the past several years, there has been an increasing rate of bilateral prophylactic mastectomy (BPM) and contralateral prophylactic mastectomy (CPM) surgeries. Since publication of the 2007 SSO position statement on the use of risk-reducing mastectomy, there have been significant advances in the understanding of breast cancer biology and treatment. The purpose of this manuscript is to review the current literature as a resource to facilitate a shared and informed decision-making process regarding the use of risk-reducing mastectomy. PMID- 27933412 TI - Genetic diversity study on 12 X-STR loci of investigator(r) Argus X STR kit in Bangladeshi population. AB - The X-chromosome short tandem repeat (STR) loci are of particular interest for solving complex kinship and paternity cases. Here, we report the genetic data from 209 unrelated Bangladeshi individuals (102 males and 107 females) that were genotyped using the 12 X-chromosomal STR markers included in the Investigator(r) Argus X-12 kit (Qiagen). The 12 X-STR markers are located in four linkage groups (linkage group I: DXS10135, DXS10148, and DXS8378; linkage group II: DXS7132, DXS10079, and DXS10074; linkage group III: DXS10103, HPRTB, and DXS10101; and linkage group IV: DXS10146, DXS10134, and DXS7423). Allelic frequencies of the 12 X-STR loci and haplotype frequencies of the four linkage groups were investigated. No significant difference was observed in the allele frequencies of males and females. Distributions of heterozygosity were observed from 64.5 to 92.5% among the studied 12 X STR loci. DXS10135 and DXS10101 loci were found to be most polymorphic. For all the four linkage groups, the haplotype diversity was found to be greater than 0.986. A total of 95, 73, 66, and 74 haplotypes were observed in linkage groups I, II, III, and IV, respectively. Hardy-Weinberg equilibrium tests showed no significant deviation from expected values for all 12 loci (p > 0.05). The exact test for pairwise linkage disequilibrium for the 12 loci in the male samples did not show any significant linkage disequilibrium except the DXS10103 and DXS10101 loci after the p values were corrected by Bonferroni's correction for multiple testing (p > 0.05/66). A combined power of discrimination in male and female individuals were 0.999999998159791 and 0.999999999999993, respectively. The combined mean exclusion chance were 0.999997635 in deficiency cases, 0.999999996 in normal trio cases, and 0.999999178 in duo cases. The currently investigated Bangladeshi population showed significant differences when compared with previously reported X-STR data from other 12 populations. The results of the data analysis indicated that all the loci in the Investigator(r) Argus X 12 kit were fairly informative and might be useful in forensic application and kinship analysis in Bangladeshi population. PMID- 27933414 TI - Re: Enigmatic morphological traits in human teeth from early bronze age. PMID- 27933413 TI - Investigation on genetic thrombophilic factors in FFPE autopsy tissue from subjects who died from pulmonary embolism. AB - Venous thromboembolism (VTE) is a multifactorial disease determined by a combination of inherited and acquired factors. Inherited factors include mutations in the genes coding for coagulation factors, some of which seem to exert a differential influence on the risk of developing deep vein thrombosis (DVT) and pulmonary embolism (PE). In post-mortem studies of subjects who have died from pulmonary embolism (PE), the analysis of the factors that may have augmented the VTE risk is often limited to acquired factors. This is due to the complexity-and sometimes the unfeasibility-of analyzing genetic factors and to insufficient knowledge of their individual roles in PE development. The present study used formalin-fixed paraffin-embedded (FFPE) tissue to investigate a panel of 12 polymorphisms-the largest ever studied-that affect the VTE risk. Tissue samples came from post-mortem examinations performed by the specialists of the Section of Legal Medicine of the Department of Pathology of Marche's Polytechnic University, and by the specialists of Health Care District Hospital of Imola, on 44 subjects who died from PE in the period 1997-2014. All individuals were found to have at least one mutation affecting the VTE risk. The present study demonstrates that genetic analysis can be performed post-mortem and the results are useful for forensic investigations, especially from MTHFR C677T and PAI-1 4G/5G polymorphisms. Broader studies using the techniques described herein are needed to determine the relative influence of the individual polymorphisms and their interaction in PE deaths. PMID- 27933415 TI - Association between gamma-glutamyltransferase and albuminuria in nondiabetic adults with normal renal function. AB - BACKGROUND: Serum gamma-glutamyltransferase (GGT) has been associated with albuminuria in diabetes patients, but it has not been investigated in the general population. We aimed to investigate the association between serum GGT and albuminuria in the nondiabetic Korean population with normal kidney function. METHODS: Study participants (3948; 1549 men and 2399 women) with an estimated glomerular filtration rate >=60 mL/min/1.73 m2 were analyzed from the fifth Korean National Health and Nutrition Examination Survey (2011). Albuminuria was defined as an albumin-creatinine ratio >30 mg/g. Serum GGT was analyzed by dividing into quartiles. Multiple logistic models were used to analyze the associations between GGT and albuminuria. RESULTS: The prevalence of albuminuria was 5.1% and increased linearly according to increasing GGT quartiles (P for trend = 0.005). A linear regression analysis revealed that GGT was positively related with albuminuria (P = 0.008). After adjusting for confounding factors, the odds ratio for albuminuria was 1.80 (95% CI 1.079-3.010, P for trend = 0.029) for the highest quartile group compared with those observed in the lowest quartile of GGT. In addition, this independent relationship did not change when the cut-off value of GGT (30 IU/L) was applied to this analysis. Compared with GGT value <=30 IU/L, the adjusted odds ratio of albuminuria in participants with GGT >30 IU/L was 1.96 (95% CI 1.319-2.906, P < 0.001). CONCLUSION: Higher serum GGT levels within the reference range were significantly associated with albuminuria in nondiabetic Koreans with preserved kidney function, independently of traditional cardio-renal risk factors. PMID- 27933417 TI - On the characterization of the heterogeneous mechanical response of human brain tissue. AB - The mechanical characterization of brain tissue is a complex task that scientists have tried to accomplish for over 50 years. The results in the literature often differ by orders of magnitude because of the lack of a standard testing protocol. Different testing conditions (including humidity, temperature, strain rate), the methodology adopted, and the variety of the species analysed are all potential sources of discrepancies in the measurements. In this work, we present a rigorous experimental investigation on the mechanical properties of human brain, covering both grey and white matter. The influence of testing conditions is also shown and thoroughly discussed. The material characterization performed is finally adopted to provide inputs to a mathematical formulation suitable for numerical simulations of brain deformation during surgical procedures. PMID- 27933418 TI - Temporal Characteristics of EEG Microstates Mediate Trial-by-Trial Risk Taking. AB - People seem to have difficulties when perceiving events whose outcome has no influence on the outcome of future events. This illusion that patterns exist where there are none may lead to adverse consequences, such as escalating losses in financial trading or gambling debt. Despite the enormous social consequences of these cognitive biases, however, their neural underpinnings are poorly understood. Attempts to investigate them have so far relied on evoked neural activity, whereas spontaneous brain activity has been treated as noise to be averaged out. Here, we focus on the spontaneous electroencephalographic (EEG) activity during inter-trial-intervals (ITI) in a sequential risky decision-making task. Using multilevel mediation analyses, our results show that the percentage of time covered by two EEG microstates (i.e., functional brain-states of coherent activity) mediate the influence of outcomes of prior decisions on subsequent risk taking on a trial-by-trial basis. The devised multilevel mediation analysis of the temporal characteristics of EEG microstates during ITI provides a new window into the neurobiology of decision making by bringing the spontaneous brain activity to the forefront of the analysis. PMID- 27933416 TI - Positron emission tomography in amyotrophic lateral sclerosis: Towards targeting of molecular pathological hallmarks. AB - During the past decades, extensive efforts have been made to expand the knowledge of amyotrophic lateral sclerosis (ALS). However, clinical translation of this research, in terms of earlier diagnosis and improved therapy, remains challenging. Since more than 30% of motor neurons are lost when symptoms become clinically apparent, techniques allowing non-invasive, in vivo detection of motor neuron degeneration are needed in the early, pre-symptomatic disease stage. Furthermore, it has become apparent that non-motor signs play an important role in the disease and there is an overlap with cognitive disorders, such as frontotemporal dementia (FTD). Radionuclide imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), form an attractive approach to quantitatively monitor the ongoing neurodegenerative processes. Although [18F]-FDG has been recently proposed as a potential biomarker for ALS, active targeting of the underlying pathologic molecular processes is likely to unravel further valuable disease information and may help to decipher the pathogenesis of ALS. In this review, we provide an overview of radiotracers that have already been applied in ALS and discuss possible novel targets for in vivo imaging of various pathogenic processes underlying ALS onset and progression. PMID- 27933419 TI - Evaluating frontier orbital energy and HOMO/LUMO gap with descriptors from density functional reactivity theory. AB - Wave function theory (WFT) and density functional theory (DFT)-the two most popular solutions to electronic structure problems of atoms and molecules-share the same origin, dealing with the same subject yet using distinct methodologies. For example, molecular orbitals are artifacts in WFT, whereas in DFT, electron density plays the dominant role. One question that needs to be addressed when using these approaches to appreciate properties related to molecular structure and reactivity is if there is any link between the two. In this work, we present a piece of strong evidence addressing that very question. Using five polymeric systems as illustrative examples, we reveal that using quantities from DFT such as Shannon entropy, Fisher information, Ghosh-Berkowitz-Parr entropy, Onicescu information energy, Renyi entropy, etc., one is able to accurately evaluate orbital-related properties in WFT like frontier orbital energies and the HOMO (highest occupied molecular orbital)/LUMO (lowest unoccupied molecular orbital) gap. We verified these results at both the whole molecule level and the atoms-in molecules level. These results provide compelling evidence suggesting that WFT and DFT are complementary to each other, both trying to comprehend the same properties of the electronic structure and molecular reactivity from different perspectives using their own characteristic vocabulary. Hence, there should be a bridge or bridges between the two approaches. PMID- 27933420 TI - Comparative simulation study of chemical synthesis of functional DADNE material. AB - Amorphous molecular simulation to model the reaction species in the synthesis of chemically inert and energetic 1,1-diamino-2,2-dinitroethene (DADNE) explosive material was performed in this work. Nitromethane was selected as the starting reactant to undergo halogenation, nitration, deprotonation, intermolecular condensation, and dehydration to produce the target DADNE product. The Materials Studio (MS) forcite program allowed fast energy calculations and reliable geometric optimization of all aqueous molecular reaction systems (0.1-0.5 M) at 283 K and 298 K. The MS forcite-computed and Gaussian polarizable continuum model (PCM)-computed results were analyzed and compared in order to explore feasible reaction pathways under suitable conditions for the synthesis of DADNE. Through theoretical simulation, the findings revealed that synthesis was possible, and a total energy barrier of 449.6 kJ mol-1 needed to be overcome in order to carry out the reaction according to MS calculation of the energy barriers at each stage at 283 K, as shown by the reaction profiles. Local analysis of intermolecular interaction, together with calculation of the stabilization energy of each reaction system, provided information that can be used as a reference regarding molecular integrated stability. Graphical Abstract Materials Studio software has been suggested for the computation and simulation of DADNE synthesis. PMID- 27933421 TI - Erratum to: An Experimental Framework for Generating Evolvable Chemical Systems in the Laboratory. PMID- 27933422 TI - Dual mobility cups in revision total hip arthroplasty. AB - AIM: The purpose of our study was to evaluate the dislocation and aseptic loosening rates of a dual mobility construct in revision total hip arthroplasty (THA). METHODS: Three hundred thirty-four revision THAs performed between 2006 and 2011, using a dual mobility cup, were included in this retrospective study. The indications for revision were aseptic loosening (70%), infection (21%) and recurrent instability (9%). The minimum follow-up was five years (mean 7 +/- 2 years, maximum 10 years). RESULTS: At the latest follow-up, 11 episodes of dislocation occurred, seven of which were recurrent (1.3% for aseptic loosening, 2.8% for infection and 3.4% for recurrent dislocation). Ten cases of aseptic loosening occurred; in seven of them, a cemented cup into a reinforcement ring had been used (OR = 14, p = 0.0001). CONCLUSION: This study provided evidence of the advantages of dual mobility cups in all revision THA indications. PMID- 27933423 TI - How effective is embolization with N-2-butyl-cyanoacrylate for aneurysmal bone cysts? AB - PURPOSE: To evaluate the outcome of selective arterial embolization with N-2 butyl-cyanoacrylate for aneurysmal bone cysts. METHODS: We retrospectively studied 102 patients (72 male, 30 female; mean age, 16 years; range, 3-60 years) with aneurysmal bone cysts treated with embolization with N-2-butyl cyanoacrylate. Mean follow-up was seven years (range, 3-13 years); no patient was lost to follow-up. We evaluated healing and recurrences of the lesions, complications and cost of the procedures, and recurrences with respect to age and gender of the patients, and size and location of the lesions. RESULTS: Embolization was feasible in 88 patients (86.3%), and not feasible in 14 patients (13.6%) because feeding arteries were not identified or the spinal artery of Adamkiewicz was recognized at the embolization field. Seventy two patients (81.8%) experienced complete healing of their lesions after a single (50 patients, 56.8%), a second (17 patients, 19.3%) or a third embolization (5 patients, 5.7%). Sixteen patients (18.2%) experienced recurrence within four months (range, 3-9 months) after embolization; these patients underwent surgical treatment. Recurrences were more common in patients younger than 15 years of age and cysts larger than 6 cm, without any difference with respect to gender and location. Four patients (4.5%) experienced a complication including skin necrosis, sciatic nerve paresthesias, and femoral artery pseudoaneurysm. The cost estimate was 3000 euro per procedure. CONCLUSION: Embolization of aneurysmal bone cysts with N-2-butyl-cyanoacrylate is associated with good results and low complication rates, however, experience, technical skills, and knowledge of the vascular anatomy of the area is necessary. PMID- 27933424 TI - "Home Practice Is the Program": Parents' Practice of Program Skills as Predictors of Outcomes in the New Beginnings Program Effectiveness Trial. AB - An examination of the content and processes of evidence-based programs is critical for empirically evaluating theories about how programs work, the "action theory" of the program (West et al. in American Journal of Community Psychology, 21, 571-605, 1993). The New Beginnings Program (NBP; Wolchik et al., 2007), a parenting-after-divorce preventive intervention, theorizes that program-induced improvements in parenting across three domains: positive relationship quality, effective discipline, and protecting children from interparental conflict, will reduce the negative outcomes that are common among children from divorced families. The process theory is that home practice of program skills related to these parenting domains is the primary mechanism leading to positive change in parenting. This theory was tested using multi-rater data from 477 parents in the intervention condition of an effectiveness trial of the NBP (Sandler et al. 2016a, 2016b). Four research questions were addressed: Does home practice of skills predict change in the associated parenting outcomes targeted by the program? Is the effect above and beyond the influence of attendance at program sessions? What indicators of home practice (i.e., attempts, fidelity, efficacy, and competence) are most predictive of improvements in parenting? Do these indicators predict parenting improvements in underserved subpopulations (i.e., fathers and Latinos)? Structural Equation Modeling analyses indicated that parent reported efficacy and provider-rated parent competence of home practice predicted improvements in the targeted parenting domains according to both parent and child reports. Moreover, indicators of home practice predicted improvements in parenting for fathers and Latinos, although patterns of effects varied by parenting outcome. PMID- 27933425 TI - Ethical Issues in Using Social Media to Deliver an HIV Prevention Intervention: Results from the HOPE Peru Study. AB - Social media technologies have become increasingly useful tools for research based interventions. However, participants and social media users have expressed ethical concerns with these studies, such as risks and benefits of participation, as well as privacy, confidentiality, and informed consent issues. This study was designed to follow up with and assess experiences and perceptions of ethics related issues among a sample of 211 men who have sex with men who participated in the Harnessing Online Peer Education (HOPE) Peru study, a randomized controlled HIV prevention intervention conducted in Peru. We found that after adjusting for age, highest educational attainment, race, sexual orientation, and prior HIV research experience, participants in the intervention group were more likely than those in the control group to have safe sex (p = 0.0051) and get tested for HIV regularly (p = 0.0051). As a result of their participation, those in the intervention group benefited more positively than participants in the control group in improving HIV care (p = 0.0077) and learning where to receive sexual health services (p = 0.0021). Participants in the intervention group expressed higher levels of comfort than those in the control group in joining and seeing other people in the Facebook group (p = 0.039), seeing other people's posts (p = 0.038) and having other group members talk to them online (p = 0.040). We discuss the implications of these results as they relate to social media-based HIV research. PMID- 27933426 TI - Characterization of the first fully human anti-TEM1 scFv in models of solid tumor imaging and immunotoxin-based therapy. AB - Tumor endothelial marker 1 (TEM1) has been identified as a novel surface marker upregulated on the blood vessels and stroma in many solid tumors. We previously isolated a novel single-chain variable fragment (scFv) 78 against TEM1 from a yeast display scFv library. Here, we evaluated the potential applications of scFv78 as a tool for tumor molecular imaging, immunotoxin-based therapy and nanotherapy. Epitope mapping, three-dimensional structure docking and affinity measurements indicated that scFv78 could bind to both human and murine TEM1, with equivalent affinity, at a well-conserved conformational epitope. The rapid internalization of scFv78 and scFv78-labeled nanoparticles was triggered after specific TEM1 binding. The scFv78-saporin immunoconjugate also exerted dose dependent cytotoxicity with high specificity to TEM1-positive cells in vitro. Finally, specific and sensitive tumor localization of scFv78 was confirmed with optical imaging in a tumor mouse model that has highly endogenous mTEM1 expression in the vasculature. Our data indicated that scFv78, the first fully human anti-TEM1 recombinant antibody, recognizes both human and mouse TEM1 and has unique and favorable features that are advantageous for the development of imaging probes or antibody-toxin conjugates for a large spectrum of human TEM1 positive solid tumors. PMID- 27933427 TI - Minimal impact of response shift for SF-12 mental and physical health status in homeless and vulnerably housed individuals: an item-level multi-group analysis. AB - PURPOSE: The purpose of this study was to examine whether homeless or vulnerably housed individuals experienced response shift over a 12-month time period in their self-reported physical and mental health status. METHODS: Data were obtained from the Health and Housing in Transition study, a longitudinal multi site cohort study in Canada (N = 1190 at baseline). Multi-group confirmatory factor analysis (MG-CFA) and methods for response shift detection at the item level, based on the approach by Oort, were used to test for reconceptualization, reprioritization, and recalibration response shift on the SF-12 in four groups of individuals who were homeless (n = 170), housed (n = 437), or who reported a change in their housing status [from homeless to housed (n = 285) or housed to homeless (n = 73)] over a 12-month time period. Mean and variance adjusted weighted-least squares estimation was used to accommodate the ordinal and binary distributions of the SF-12 items. RESULTS: Using MG-CFA, a strict invariance model showed that the measurement model was equivalent for the four groups at baseline. Although we found small but statistically significant response shift for several measurement model parameters, the impact on the predicted average mental and physical health scores within each of the groups was small. CONCLUSIONS: Response shift does not appear to be a significant concern when using the SF-12 to obtain change scores over a 12-month period in this population. PMID- 27933428 TI - In 6- to 8-year-old children, cardiorespiratory fitness moderates the relationship between severity of life events and health-related quality of life. AB - PURPOSE: In children, the pathways by which physical activity and fitness are associated with physical and psychological wellbeing are still not fully understood. The present study examines for the first time in young children whether high levels of cardiorespiratory fitness and physical activity moderate the relationship between severity of life events and health-related quality of life. METHODS: Three hundred and seventy-eight children (188 girls, 190 boys, M age = 7.27 years) participated in this cross-sectional study. Parental education, gender, age, severity of life events, health-related quality of life and physical activity were assessed via parental questionnaires. Cardiorespiratory fitness was assessed with the 20 m shuttle run test. Hierarchical regression analyses were used to test whether physical activity and fitness interacted with critical life events to explain health-related quality of life. RESULTS: When exposed to critical life events, children with higher fitness levels experienced higher levels of psychological wellbeing, relative to their less fit peers. On the other hand, children with higher fitness levels experienced higher physical wellbeing and more positive friendship relationships when severity of life events was low. A similar moderation effect was found for physical activity with overall quality of life as outcome. CONCLUSIONS: Recent stressful experiences alone were not sufficient to explain negative health outcomes in young children. Children with low cardiorespiratory fitness levels experienced lower psychological wellbeing when they were exposed to critical life events. More research is needed to find out whether similar findings emerge with objective physical activity measurements and when critical life events are assessed over longer periods of time. PMID- 27933429 TI - Establishing the values for patient engagement (PE) in health-related quality of life (HRQoL) research: an international, multiple-stakeholder perspective. AB - PURPOSE: Active patient engagement is increasingly viewed as essential to ensuring that patient-driven perspectives are considered throughout the research process. However, guidance for patient engagement (PE) in HRQoL research does not exist, the evidence-base for practice is limited, and we know relatively little about underpinning values that can impact on PE practice. This is the first study to explore the values that should underpin PE in contemporary HRQoL research to help inform future good practice guidance. METHODS: A modified 'World Cafe' was hosted as a collaborative activity between patient partners, clinicians and researchers: self-nominated conference delegates participated in group discussions to explore values associated with the conduct and consequences of PE. Values were captured via post-it notes and by nominated note-takers. Data were thematically analysed: emergent themes were coded and agreement checked. Association between emergent themes, values and the Public Involvement Impact Assessment Framework were explored. RESULTS: Eighty participants, including 12 patient partners, participated in the 90-min event. Three core values were defined: (1) building relationships; (2) improving research quality and impact; and (3) developing best practice. Participants valued the importance of building genuine, collaborative and deliberative relationships-underpinned by honesty, respect, co-learning and equity-and the impact of effective PE on research quality and relevance. CONCLUSIONS: An explicit statement of values seeks to align all stakeholders on the purpose, practice and credibility of PE activities. An innovative, flexible and transparent research environment was valued as essential to developing a trustworthy evidence-base with which to underpin future guidance for good PE practice. PMID- 27933430 TI - Structural dynamics of nucleosome mediated by acetylations at H3K56 and H3K115,122. AB - Post translational modifications have a profound role in the regulation of several biological processes such as transcription, replication, and DNA repair. Acetylation and phosphorylation form a major class of post translational modifications involved in nucleosomal regulation by modifying its structure. The effect of post translational modifications on nucleosome structure could be better explored when the molecular trajectories explaining the time dependent structural evolution over a period of time is examined at the atomic level. The present study attempts to highlight the importance of acetylation, especially at entry-exit (Lys56) and dyad (Lys115 and Lys122) regions in regulating the nucleosome accessibility and mobility using all atom simulations. It is evident from this study that acetylation at Lys56, Lys115, and Lys122 introduces local changes in the electrostatic nature of the lateral surface and thereby weakens the histone-DNA interactions. In addition, simulations also reveal significant changes in the dynamics of superhelical DNA. The acetylation at Lys56 promotes a high amplitude out-of-planar movement of entry-exit termini. Whereas, acetylation at Lys115 and Lys122 increases the flexibility of the superhelical DNA to facilitate the rolling of the superhelical DNA around the octameric histone. In essence, the present study highlights the role of acetylation at Lys56, Lys115, and Lys122 in transcriptional regulation by promoting high amplitude dynamics of superhelical DNA for a possible unwrapping as well as mobility of nucleosome. PMID- 27933431 TI - Effect of Remote Ischaemic Preconditioning on Liver Injury in Patients Undergoing Major Hepatectomy for Colorectal Liver Metastasis: A Pilot Randomised Controlled Feasibility Trial. AB - BACKGROUND: Liver resection produces excellent long-term survival for patients with colorectal liver metastases but is associated with significant morbidity and mortality from ischaemia reperfusion injury (IRI). Remote ischaemic preconditioning (RIPC) can reduce the effect of IRI. This pilot randomised controlled trial evaluated RIPC in patients undergoing major hepatectomy at the Royal Free Hospital, London. METHODS: Sixteen patients were randomised to RIPC or sham control. RIPC was induced through three 10-min cycles of alternate ischaemia and reperfusion to the leg. At baseline and immediately post-resection, transaminases and indocyanine green (ICG) clearance were measured. FINDINGS: The RIPC group had lower ALT and AST levels immediately post-resection (ALT: 43% lower 497 +/- 165 vs 889 +/- 170 IU/L; p = 0.019 AST: 54% lower 408 +/- 166 vs 836 +/- 167 IU/L; p = 0.001) and at 24 h (ALT: 41% lower 412 +/- 144 vs 698 +/- 137 IU/L; p = 0.026 AST: 50% lower 316 +/- 116 vs 668 +/- 115 IU/L; p = 0.02). ICG clearance was reduced in controls versus RIPC immediately after resection (ICG-PDR: 11.1 +/- 1.1 vs 16.5 +/- 1.4%/min; p = 0.035). CONCLUSIONS: This pilot study shows that RIPC has potential to reduce liver injury following hepatectomy justifying a prospective RCT powered to demonstrate clinical benefits. PMID- 27933433 TI - Full-length infectious clone of an Iranian isolate of chicken anemia virus. AB - An Iranian field strain of chicken anemia virus (CAV), designated IR CAV, was isolated in the Marek's disease virus-transformed lymphoblastoid cell line MDCC MSB1 (MSB1) culture for the first time. The full-length CAV DNA of this strain was cloned in the bacterial plasmid pTZ57R/T to create the molecular clone pTZ CAV. The nucleotide and deduced amino acid sequences of viral proteins of IR CAV were compared with those of representative CAV sequences including reference and commercial vaccine strains. IR CAV was not related to vaccine strains and also found to have glutamine at positions 139 and 144 confirming previous studies in which such mutations were associated with a slow rate of virus spread in cell culture. pTZ-CAV was digested with PstI to release IR CAV DNA and then transfected into MSB1 cell by electroporation. The transfected cells showed cytopathic effect similar to virion-initiated infection. One-day old specific pathogen-free chicks were inoculated with the regenerated virus, which had been obtained from transfected MSB1 cells, and compared with the chicks inoculated with IR CAV. Gross lesions in the birds inoculated with the regenerated virus illustrated the infectious nature of the regenerated virus from the cloned IR CAV DNA. PMID- 27933432 TI - Lupus pathobiology based on genomics. AB - Systemic lupus erythematosus (SLE) is an autoimmune disorder with complex genetic underpinnings. This review attempts to assemble the myriad of genomic findings to build a clearer picture of the pathobiology of SLE to serve as a guide for therapeutics. Over 100 genes are now known for SLE, and several more penetrant ones have led to the emergence of more defined lupus phenotypes. Also discussed here are the targeted therapies that have come up on the horizon and the specific biologic mechanisms of more traditional therapies which have only recently been explored. The diagnostic toolbox has been enhanced by the addition of new antibodies, gene expression signatures, and mutation panels. This provides an opportunity to piece together the lupus puzzle and even revisit the clinical classification of SLE. PMID- 27933434 TI - The Nimba Mountains in Guinea. PMID- 27933435 TI - Ranolazine promotes muscle differentiation and reduces oxidative stress in C2C12 skeletal muscle cells. AB - PURPOSE: The purpose of this study is to investigate Ranolazine action on skeletal muscle differentiation and mitochondrial oxidative phenomena. Ranolazine, an antianginal drug, which acts blocking the late INaL current, was shown to lower hemoglobin A1c in patients with diabetes. In the present study, we hypothesized an action of Ranolazine on skeletal muscle cells regeneration and oxidative process, leading to a reduction of insulin resistance. METHODS: 10 MUM Ranolazine was added to C2C12 murine myoblastic cells during proliferation, differentiation and newly formed myotubes. RESULTS: Ranolazine promoted the development of a specific myogenic phenotype: increasing the expression of myogenic regulator factors and inhibiting cell cycle progression factor (p21). Ranolazine stimulated calcium signaling (calmodulin-dependent kinases) and reduced reactive oxygen species levels. Furthermore, Ranolazine maintained mitochondrial homeostasis. During the differentiation phase, Ranolazine promoted myotubes formation. Ranolazine did not modify kinases involved in skeletal muscle differentiation and glucose uptake (extracellular signal-regulated kinases 1/2 and AKT pathways), but activated calcium signaling pathways. During proliferation, Ranolazine did not modify the number of mitochondria while decreasing osteopontin protein levels. Lastly, neo-formed myotubes treated with Ranolazine showed typical hypertrophic phenotype. CONCLUSION: In conclusion, our results indicate that Ranolazine stimulates myogenesis and reduces a pro-oxidant inflammation/oxidative condition, activating a calcium signaling pathway. These newly described mechanisms may partially explain the glucose lowering effect of the drug. PMID- 27933436 TI - Emerging biotechnologies for production of itaconic acid and its applications as a platform chemical. AB - Recently, itaconic acid (IA), an unsaturated C5-dicarboxylic acid, has attracted much attention as a biobased building block chemical. It is produced industrially (>80 g L-1) from glucose by fermentation with Aspergillus terreus. The titer is low compared with citric acid production (>200 g L-1). This review summarizes the latest progress on enhancing the yield and productivity of IA production. IA biosynthesis involves the decarboxylation of the TCA cycle intermediate cis aconitate through the action of cis-aconitate decarboxylase (CAD) enzyme encoded by the CadA gene in A. terreus. A number of recombinant microorganisms have been developed in an effort to overproduce it. IA is used as a monomer for production of superabsorbent polymer, resins, plastics, paints, and synthetic fibers. Its applications as a platform chemical are highlighted. It has a strong potential to replace petroleum-based methylacrylic acid in industry which will create a huge market for IA. PMID- 27933437 TI - Focal disruption in the wall of the porcelain gallbladder: a sign of gallbladder carcinoma. PMID- 27933438 TI - Acoustic radiation force impulse (ARFI) elastography in the evaluation of renal parenchymal stiffness in patients with ureteropelvic junction obstruction. AB - PURPOSE: To investigate the role of acoustic radiation force impulse (ARFI) elastography in the detection of renal parenchymal damage in kidneys with and without ureteropelvic junction obstruction (UPJO). METHODS: Twenty-five pediatric patients with a diagnosis of UPJO who underwent surgery and 15 pediatric patients with conservatively managed UPJO were prospectively evaluated with ARFI elastography. Sixteen healthy volunteers constituted the control group. Shear wave velocity (SWV) measurements in the upper, mid, and lower poles of the affected kidney were performed. SWV values of kidneys based on presence of UPJO and hydronephrosis grade were compared. The correlation of SWV values with residual renal function obtained from diethylenetriaminepentaacetic acid or mercaptoacetyltriglycine-3 renal scan was evaluated. RESULTS: Significantly, higher SWV values were found in control kidneys compared to kidneys affected by UPJO. The median SWVs were 2.82 (2.51-3.07) m/s for the control kidneys and 2.36 (2.09-2.53) m/s for the kidneys in the UPJO group (p < 0.001). When UPJO patients were grouped according to the grade of hydronephrosis, grade 0 hydronephrotic kidneys [2.35 (2.11-2.50) m/s] and grade 3-4 hydronephrotic kidneys [1.86 (1.96 2.25) m/s] had significantly lower SWV values compared to grade 1-2 hydronephrotic kidneys [2.62 (2.37-2.90) m/s] (p < 0.05). CONCLUSIONS: ARFI as a noninvasive, radiation-free procedure for evaluating parenchymal stiffness may prove useful in the diagnostic work-up and follow-up of children with UPJO induced renal disease. PMID- 27933440 TI - Modern role of clinical ultrasound in liver abscess and echinococcosis. AB - In the Western world, liver abscesses are predominantly of pyogenic origin and can present a wide range of ultrasonographic features, from a solid mass to a cystic cavity. Amoebic abscesses are endemic in tropical areas and typically round single lesions. Echinococcal cyst is diagnosed by ultrasound (US). Serology is particularly useful when pathognomonic US features are absent. Treatment is determined based on the WHO ultrasonographic classification, and puncture, aspiration, injection, re-aspiration (PAIR) is a US-guided therapeutic option. Hepatic alveolar echinococcosis presents on US as a pseudotumoral mass frequently with calcifications that may invade the biliary tree and portal and hepatic veins. PMID- 27933439 TI - Measurement of carotid pulse wave velocity using ultrafast ultrasound imaging in hypertensive patients. AB - PURPOSE: The study aimed to assess the utility of ultrafast ultrasound imaging for evaluation of carotid pulse wave velocity (PWV) in newly diagnosed hypertension patients. METHODS: This prospective non-randomized study enrolled 90 hypertensive patients in our hospital from September to December 2013 as a hypertension group. An age- and sex-matched cohort of 50 healthy adults in our hospital from September to December 2013 was also included in the study as a control group. Carotid PWV at the beginning and at the end of systole (PWV-BS and PWV-ES, respectively) and intima-media thickness (IMT) were measured by ultrafast ultrasound imaging technology. The associations of PWV-BS, PWV-ES, and IMT with hypertension stage were evaluated by Spearman correlation analysis. RESULTS: PWV BS and PWV-ES in the hypertension group were significantly elevated compared with those in control group. Different hypertension stages significantly differed in PWV-BS and PWV-ES. PWV-BS and PWV-ES appeared to increase with the hypertension stage. Moreover, IMT, PWV-BS, and PWV-ES were positively correlated with the hypertension stage in hypertensive patients. CONCLUSION: Ultrafast ultrasound imaging was a valid and convenient method for the measurement of carotid PWV in hypertensive patients. Ultrafast ultrasound imaging might be recommended as a promising alternative method for early detection of arterial abnormality in clinical practice. PMID- 27933441 TI - Multimodality imaging to assess immediate response following irreversible electroporation in patients with malignant hepatic tumors. AB - PURPOSE: To assess the diagnostic accuracy of contrast-enhanced ultrasound (CEUS), contrast-enhanced multiphase CT (CECT), and gadoxetic acid-enhanced MRI (EOB-MRI) in identifying residual tumor in the subacute follow-up of patients with malignant hepatic tumors treated by irreversible electroporation (IRE). METHODS: We enrolled 16 patients with 21 hepatic lesions treated by IRE and examined by CEUS and CECT at 1 day after IRE and by EOB-MRI at 7 days after IRE. Follow-up examinations by EOB-MRI or CECT and CEUS were performed at 3-month intervals. Two radiologists independently reviewed the images and assessed the probability of residual tumor using a five-point scale with receiver operating characteristic (ROC) curve analysis. The sensitivity and specificity were also evaluated. Verifiable local recurrence was assessed using follow-up imaging as the reference standard. RESULTS: The mean area under the ROC curve was significantly higher for CEUS (0.980) than for CECT (0.742, P < 0.01) and EOB-MRI (0.806, P < 0.01), as were the sensitivity and specificity (mean 85.7 and 85.7% for CEUS, respectively, vs 64.3 and 46.4% for CECT and 78.6 and 64.3% for EOB MRI). CONCLUSION: CEUS was found to be superior to CECT and EOB-MRI for the diagnosis of residual tumor in the subacute phase following IRE. PMID- 27933443 TI - Editorial: CORR (r) Will Change to Double-blind Peer Review-What Took Us So Long to Get There? PMID- 27933442 TI - Arterial pulse wave propagation velocity in healthy dogs by pulse wave Doppler ultrasound. AB - The aim of this study was to prospectively evaluate the carotid-femoral pulse wave velocity (PWV) values in healthy dogs using pulse wave Doppler ultrasound. A secondary aim was to determine the feasibility of this method and to report the intra- and interobserver reproducibilities of the PWV in conscious dogs. The data were studied in 30 healthy, adult, male (n = 15) and female (n = 15) dogs. The time interval marked between the R wave peak of the electrocardiogram and the intersection of the blood flow wave upstroke of the Doppler spectrum with the baseline of zero frequency was determined for the carotid (T1) and for the femoral (T2) arteries. The distance covered by the pulse wave (L) was determined. The PWV was then calculated using the following formula: L/T2 - T1. The mean values of PWV calculated from the total sample (n = 30) evaluated were 13.41 +/- 2.20 m/s. No significant statistical difference was observed for the PWV measurements between males (14.82 +/- 3.18 m/s) and females (12.64 +/- 2.45 m/s). The analysis revealed no intra nor interobserver differences. A reasonable reproducibility of the PWV measurements was showed by intraclass correlation coefficients (ICC), and the coefficients of variation (CV). These data demonstrate that noninvasive vascular Doppler analysis is a feasible and reproducible method to determine the carotid-femoral PWV in dogs. PMID- 27933444 TI - Clinical Faceoff: Physician Burnout-Fact, Fantasy, or the Fourth Component of the Triple Aim? PMID- 27933445 TI - Correlation of crevicular fluid and serum levels of retinol-binding protein 4 and leptin in chronic periodontitis and obesity. AB - OBJECTIVE: Retinol-binding protein 4 (RBP4) and leptin are both adipokines and involved in the pathophysiology of different vascular and inflammatory diseases and selectively elevated in patients with obesity. The aim of the present study was to determine and correlate the levels of RBP4 and leptin in gingival crevicular fluid (GCF) and serum in patients with chronic periodontitis (CP) and obesity. MATERIALS AND METHODS: A total of 70 patients with age group 25 to 45 years were divided into four groups based on gingival index (GI), probing depth (PD), clinical attachment level (CAL), body mass index (BMI) and radiographic evidence of bone loss. The groups were (1) group I (non-obese periodontally healthy), (2) group II (obese periodontally healthy), (3) group III (non-obese with chronic periodontitis) and (4) group IV (obese with chronic periodontitis). The GCF and serum levels of human RBP4 and leptin were quantified using ELISA. RESULTS: An increase in RBP4 levels from group I to group IV was found in both GCF and serum. However, GCF leptin levels was found to be greatest in group II, then group I, group IV and group III showing the least while an increase in serum levels from group I to group IV was found. The GCF and serum values of the inflammatory mediator correlated with the evaluated periodontal parameters and with each other (p < 0.05). CONCLUSION: RBP4 and leptin can be considered as possible GCF and serum markers of inflammatory activity in CP and obesity, which further longitudinal studies are needed. PMID- 27933446 TI - Permanent tooth agenesis in non-syndromic Robin sequence and cleft palate: prevalence and patterns. AB - OBJECTIVES: Partial tooth agenesis is frequently observed in Robin sequence. Tooth anomalies are increasingly considered as an extended phenotype of the cleft palate population. The study objective was to compare the prevalence and patterns of tooth agenesis in a group of patients with non-syndromic Robin sequence (ns RS) and a group with non-syndromic cleft palate (ns-CP). MATERIALS AND METHODS: The panoramic radiographs of 115 ns-RS and 191 ns-CP patients were assessed for agenesis of the permanent dentition (excluding third molars) and the patterns recorded using the Tooth Agenesis Code. RESULTS: Partial tooth agenesis was observed in 47.8% of ns-RS and 29.8% of ns-CP patients with a greater prevalence in the mandibula than in the maxilla, particularly in ns-RS. The teeth most frequently absent in both groups were the mandibular second premolars and maxillary lateral incisors. Tooth agenesis was bilateral in two-thirds of affected ns-RS patients and one-half of ns-CP patients. In ns-RS, bilateral agenesis of the mandibular second premolars was more frequently observed in female than that in male patients. Completely symmetrical patterns of hypodontia were found in around 45% of ns-RS patients with tooth agenesis compared to 35% in ns-CP. No association was found between the extent of the palatal cleft and the severity of hypodontia. CONCLUSION: Tooth agenesis is more prevalent in ns-RS than that in ns-CP, demonstrates a much greater predilection for the mandible in ns-RS, and bears no relation to the extent of the palatal cleft. CLINICAL RELEVANCE: When compared to ns-CP, additional developmental disturbances are likely involved in the etiology of tooth agenesis in ns-RS. Future research could help identify the underlying genetic traits and aid in classifying patients in those with and without expected tooth agenesis in order to facilitate orthodontic management strategies. PMID- 27933447 TI - Indian summer heat wave of 2015: a biometeorological analysis using half hourly automatic weather station data with special reference to Andhra Pradesh. AB - Heat wave is a hazardous weather-related extreme event that affects living beings. The 2015 summer heat wave affected many regions in India and caused the death of 2248 people across the country. An attempt has been made to quantify the intensity and duration of heat wave that resulted in high mortality across the country. Half hourly Physiologically Equivalent Temperature (PET), based on a complete heat budget of human body, was estimated using automatic weather station (AWS) data of four locations in Andhra Pradesh state, where the maximum number of deaths was reported. The heat wave characterization using PET revealed that extreme heat load conditions (PET >41) existed in all the four locations throughout May during 2012-2015, with varying intensity. The intensity and duration of heat waves characterized by "area under the curve" method showed good results for Srikakulam and Undi locations. Variations in PET during each half an hour were estimated. Such studies will help in fixing thresholds for defining heat waves, designing early warning systems, etc. PMID- 27933448 TI - Erratum to: Grapevine phenology and climate change in Georgia. PMID- 27933449 TI - Clearing the fog: a review of the effects of dietary omega-3 fatty acids and added sugars on chemotherapy-induced cognitive deficits. AB - Cancer treatments such as chemotherapy have been an important part of extending survival in women diagnosed with breast cancer. However, chemotherapy can cause potentially toxic side effects in the brain that impair memory, verbal fluency, and processing speed in up to 30% of women treated. Women report that post chemotherapy cognitive deficits negatively impact quality of life and may last up to ten years after treatment. Mechanisms underlying these cognitive impairments are not fully understood, but emerging evidence suggests that chemotherapy induces structural changes in the brain, produces neuroinflammation, and reduces adult hippocampal neurogenesis. Dietary approaches that modify inflammation and neurogenesis are promising strategies for reducing chemotherapy-induced cognitive deficits in breast cancer survivors. In this review, we describe the cognitive and neuronal side effects associated with commonly used chemotherapy treatments for breast cancer, and we focus on the often opposing actions of omega-3 fatty acids and added sugars on cognitive function, neuroinflammation, and adult hippocampal neurogenesis. Omega-3 fatty acids administered concurrently with doxorubicin chemotherapy have been shown to prevent depressive-like behaviors and reduce neuroinflammation, oxidative stress, and neural apoptosis in rodent models. In contrast, diets high in added sugars may interact with n-3 FAs to diminish their anti-inflammatory activity or act independently to increase neuroinflammation, reduce adult hippocampal neurogenesis, and promote cognitive deficits. We propose that a diet rich in long-chain, marine-derived omega-3 fatty acids and low in added sugars may be an ideal pattern for preventing or alleviating neuroinflammation and oxidative stress, thereby protecting neurons from the toxic effects of chemotherapy. Research testing this hypothesis could lead to the identification of modifiable dietary choices to reduce the long-term impact of chemotherapy on the cognitive functions that are important to quality of life in breast cancer survivors. PMID- 27933450 TI - Effects of exercise intervention in breast cancer patients: is mobile health (mHealth) with pedometer more effective than conventional program using brochure? AB - PURPOSE: To investigate and compare the effects of mobile health (mHealth) and pedometer with conventional exercise program using a brochure on physical function and quality of life (QOL). METHODS: The study was a prospective, quasi randomized multicenter trial where 356 patients whose cancer treatment had been terminated were enrolled. All patients were instructed to perform a 12-week regimen of aerobic and resistance exercise. The mHealth group received a pedometer and a newly developed smartphone application to provide information and monitor the prescribed exercises. Those in the conventional group received an exercise brochure. Physical measurements were conducted at baseline, 6 weeks, and 12 weeks. Self-reported physical activity (international physical activity questionnaire-short form), general QOL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30), and breast cancer specific QOL (Quality of Life Questionnaire Breast Cancer Module 23) were assessed at baseline and 12 weeks. A user satisfaction survey was assessed in the mHealth group. RESULTS: Basic characteristics were not different between the two groups except for age and previous radiotherapy. Physical function, physical activity, and QOL scores were significantly improved regardless of the intervention method, and changes were not significantly different between the two groups. Additionally, the mean Likert scale response for overall satisfaction with the service was 4.27/5 in the mHealth group. CONCLUSIONS: Overall, both the mHealth coupled with pedometer and conventional exercise education using a brochure were effective in improving physical function, physical activity, and QOL. This study provides a basis of mHealth research in breast cancer patients for progressing further developing field, although superiority of the mHealth over the conventional program was not definitely evident. PMID- 27933451 TI - Association between adjuvant chemotherapy and risk of acute kidney injury in elderly women diagnosed with early-stage breast cancer. AB - PURPOSE: We studied elderly Medicare enrollees newly diagnosed with early-stage breast cancer to examine the association between adjuvant chemotherapy and acute kidney injury (AKI). METHODS: Using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we conducted a retrospective cohort study including women diagnosed with stages I-III breast cancer at ages 66-89 years between 1992 and 2007. We performed one-to-one matching on time-dependent propensity score on the day of adjuvant chemotherapy initiation within 6 months after the first cancer-directed surgery based on the estimated probability of chemotherapy initiation at each day for each patient, using a Cox proportional hazards model. We estimated the cumulative incidence of AKI using Kaplan-Meier methods. We used Cox proportional hazards models to evaluate the association between chemotherapy and the risk of AKI, and compared the risk among major chemotherapy types. RESULTS: The study included 28,048 women. The 6-month cumulative incidence of AKI was 0.80% for chemotherapy-treated patients, compared with 0.30% for untreated patients (P < 0.001). Adjuvant chemotherapy was associated with a nearly threefold increased risk of AKI [hazard ratio (HR) 2.73; 95% CI 1.8-4.1]. Compared with anthracycline-based chemotherapy, the HRs (95% CIs) were 1.66 (0.94-2.91), 0.88 (0.53-1.47), and 1.15 (0.57-2.32) for taxane based, CMF, and other chemotherapy, respectively. CONCLUSION: Our findings showed that adjuvant chemotherapy was associated with increased risk of AKI in elderly women diagnosed with early-stage breast cancer. The risk seemed to vary by regimen type, but the differences were not statistically significant. PMID- 27933452 TI - Responses of tropical legumes from the Brazilian Atlantic Rainforest to simulated acid rain. AB - We investigated the morphological and anatomical effects of simulated acid rain on leaves of two species native to the Brazilian Atlantic Rainforest: Paubrasilia echinata and Libidibia ferrea var. leiostachya. Saplings were subjected to acid rain in a simulation chamber during 10 days for 15 min daily, using H2SO4 solution pH 3.0 and, in the control, deionized water. At the end of the experiment, fragments from young and expanding leaves were anatomically analyzed. Although L. ferrea var. leiostachya leaves are more hydrophobic, rain droplets remained in contact with them for a longer time, as in the hydrophilic P. echinata leaves, droplets coalesce and rapidly run off. Visual symptomatology consisted in interveinal and marginal necrotic dots. Microscopic damage found included epicuticular wax flaking, turgor loss and epidermal cell shape alteration, hypertrophy of parenchymatous cells, and epidermal and mesophyll cell collapse. Formation of a wound tissue was observed in P. echinata, and it isolated the necrosis to the adaxial leaf surface. Acid rain increased thickness of all leaf tissues except spongy parenchyma in young leaves of L. ferrea var. leiostachya, and such thickness was maintained throughout leaf expansion. To our knowledge, this is the first report of acidity causing increase in leaf tissue thickness. This could represent the beginning of cell hypertrophy, which was seen in visually affected leaf regions. Paubrasilia echinata was more sensitive, showing earlier symptoms, but the anatomical damage in L. ferrea var. leiostachya was more severe, probably due to the higher time of contact with acid solution in this species. PMID- 27933453 TI - Engineering of Escherichia coli to facilitate efficient utilization of isomaltose and panose in industrial glucose feedstock. AB - Industrial glucose feedstock prepared by enzymatic digestion of starch typically contains significant amounts of disaccharides such as maltose and isomaltose and trisaccharides such as maltotriose and panose. Maltose and maltosaccharides can be utilized in Escherichia coli fermentation using industrial glucose feedstock because there is an intrinsic assimilation pathway for these sugars. However, saccharides that contain alpha-1,6 bonds, such as isomaltose and panose, are still present after fermentation because there is no metabolic pathway for these sugars. To facilitate more efficient utilization of glucose feedstock, we introduced glvA, which encodes phospho-alpha-glucosidase, and glvC, which encodes a subunit of the phosphoenolpyruvate-dependent maltose phosphotransferase system (PTS) of Bacillus subtilis, into E. coli. The heterologous expression of glvA and glvC conferred upon the recombinant the ability to assimilate isomaltose and panose. The recombinant E. coli assimilated not only other disaccharides but also trisaccharides, including alcohol forms of these saccharides, such as isomaltitol. To the best of our knowledge, this is the first report to show the involvement of the microbial PTS in the assimilation of trisaccharides. Furthermore, we demonstrated that an L-lysine-producing E. coli harboring glvA and glvC converted isomaltose and panose to L-lysine efficiently. These findings are expected to be beneficial for industrial fermentation. PMID- 27933454 TI - Improved production of adipate with Escherichia coli by reversal of beta oxidation. AB - The linear C6 dicarboxylic acid adipic acid is an important bulk chemical in the petrochemical industry as precursor of the polymer nylon-6,6-polyamide. In recent years, efforts were made towards the biotechnological production of adipate from renewable carbon sources using microbial cells. One strategy is to produce adipate via a reversed beta-oxidation pathway. Hitherto, the adipate titers were very low due to limiting enzyme activities for this pathway. In most cases, the CoA intermediates are non-natural substrates for the tested enzymes and were therefore barely converted. We here tested heterologous enzymes in Escherichia coli to overcome these limitations and to improve the production of adipate via a reverse beta-oxidation pathway. We tested in vitro selected enzymes for the efficient reduction of the enoyl-CoA and in the final reaction for the thioester cleavage. The genes encoding the enzymes which showed in vitro the highest activity were then used to construct an expression plasmid for a synthetic adipate pathway. Expression of paaJ, paaH, paaF, dcaA, and tesB in E. coli BL21(DE3) resulted in the production of up to 36 mg/L of adipate after 30 h of cultivation. Beside the activities of the pathway enzymes, the availability of metabolic precursors may limit the synthesis of adipate, providing another key target for further strain engineering towards high-yield production of adipate with E. coli. PMID- 27933455 TI - Exploration of genetic and phenotypic diversity within Saccharomyces uvarum for driving strain improvement in winemaking. AB - The selection and genetic improvement of wine yeast is an ongoing process, since yeast strains should match new technologies in winemaking to satisfy evolving consumer preferences. A large genetic background is the necessary starting point for any genetic improvement programme. For this reason, we collected and characterized a large number of strains belonging to Saccharomyces uvarum. In particular, 70 strains were isolated from cold-stored must samples: they were identified and compared to S. uvarum strains originating from different collections, regarding fermentation profile, spore viability and stress response. The results demonstrate a large biodiversity among the new isolates, with particular emphasis to fermentation performances, genotypes and high spore viability, making the isolates suitable for further genetic improvement programmes. Furthermore, few of them are competitive with Saccharomyces cerevisiae and per se, suitable for wine fermentation, due to their resistance to stress, short lag phase and fermentation by-products. PMID- 27933456 TI - Penicillin V acylases from gram-negative bacteria degrade N-acylhomoserine lactones and attenuate virulence in Pseudomonas aeruginosa. AB - Virulence pathways in gram-negative pathogenic bacteria are regulated by quorum sensing mechanisms, through the production and sensing of N-acylhomoserine lactone (AHL) signal molecules. Enzymatic degradation of AHLs leading to attenuation of virulence (quorum quenching) could pave the way for the development of new antibacterials. Penicillin V acylases (PVAs) belong to the Ntn hydrolase superfamily, together with AHL acylases. PVAs are exploited widely in the pharmaceutical industry, but their role in the natural physiology of their native microbes is not clearly understood. This report details the characterization of AHL degradation activity by homotetrameric PVAs from two gram negative plant pathogenic bacteria, Pectobacterium atrosepticum (PaPVA) and Agrobacterium tumefaciens (AtPVA). Both the PVAs exhibited substrate specificity for degrading long-chain AHLs. Exogenous addition of these enzymes into Pseudomonas aeruginosa greatly diminished the production of elastase and pyocyanin and biofilm formation and increased the survival rate in an insect model of acute infection. Subtle structural differences in the PVA active site that regulate specificity for acyl chain length have been characterized, which could reflect the evolution of AHL-degrading acylases in relation to the environment of the bacteria that produce them and also provide strategies for enzyme engineering. The potential for using these enzymes as therapeutic agents in clinical applications and a few ideas about their possible significance in microbial physiology have also been discussed. PMID- 27933458 TI - Free hand proprioception is well calibrated to verbal estimates of slanted surfaces. AB - We investigate the relationship between verbal and hand proprioception of slant. In Experiment 1 we demonstrate that verbally estimating free hand orientation produces overestimates by a factor of 1.67. These values are similar to those seen for verbal overestimates of slanted surfaces. In Experiment 2, participants positioned their hand to a ramp at 1 of 4 different orientations, and then verbally estimated the orientation of either their hand or the ramp. We show that verbal estimates of the ramp are a product of the orientation of their hand and the perception of the orientation of their hand. We discuss how this work is consistent with the proprioception calibration hypothesis that proposes that similar biases exist in both verbal estimates of visually perceived slant and proprioceptively perceived hand orientation and how this may explain free hand estimates to outdoor hills that are greater than actual hill orientation by a factor of ~2, but are still less than verbal (over)estimates. PMID- 27933457 TI - Pristine but metal-rich Rio Sucio (Dirty River) is dominated by Gallionella and other iron-sulfur oxidizing microbes. AB - Whether the extreme conditions of acidity and heavy metal pollution of streams and rivers originating in pyritic formations are caused primarily by mining activities or by natural activities of metal-oxidizing microbes living within the geological formations is a subject of considerable controversy. Most microbiological studies of such waters have so far focused on acid mine drainage sites, which are heavily human-impacted environments, so it has been problematic to eliminate the human factor in the question of the origin of the key metal compounds. We have studied the physico-chemistry and microbiology of the Rio Sucio in the Braulio Carrillo National Park of Costa Rica, 22 km from its volcanic rock origin. Neither the remote origin, nor the length of the river to the sampling site, have experienced human activity and are thus pristine. The river water had a characteristic brownish-yellow color due to high iron-dominated minerals, was slightly acidic, and rich in chemolithoautotrophic iron- and sulfur oxidizing bacteria, dominated by Gallionella spp. Rio Sucio is thus a natural acid-rock drainage system whose metal-containing components are derived primarily from microbial activities. PMID- 27933459 TI - Four Reasons Why Assisted Dying Should Not Be Offered for Depression. AB - Recently, several authors have argued that assisted dying may be ethically appropriate when requested by a person who suffers from serious depression unresponsive to treatment. We here present four arguments to the contrary. First, the arguments made by proponents of assisted dying rely on notions of "treatment resistant depression" that are problematic. Second, an individual patient suffering from depression may not be justified in believing that chances of recovery are minimal. Third, the therapeutic significance of hope must be acknowledged; when mental healthcare opens up the door to admitting hopelessness, there is a danger of a self-fulfilling prophecy. Finally, proponents of assisted dying in mental healthcare overlook the dangers posed to mental-health services by the institutionalization of assisted dying. PMID- 27933460 TI - Assessing Colorectal Cancer Screening Barriers by Two Methods. AB - Colorectal cancer (CRC) is commonly diagnosed in the USA despite screening tests that have decreased CRC incidence and mortality. Finding the best method to identify patient-level screening barriers is important to improve CRC screening rates. A group-randomized trial was conducted among ten primary-care clinics. Clinics were randomized to a multi-level (clinic, provider, patient) CRC screening intervention or usual care (2007-2013). Subsequent to clinic- and provider-level interventions, a three-step, patient-level intervention was conducted. One step of the patient-level intervention was a CRC screening barriers counseling call conducted by a lay health advisor (LHA). During the call, two methods were used to identify CRC screening barriers. An open-ended question was used first to determine why participants had not completed screening (without probes). Subsequently, the LHA read a list of additional potential screening barriers and asked participants whether each barrier was applicable (with probes). A generalized estimating equation approach was used to compare the two methods. Participants (n = 109) were female (59%), had a mean age of 57.2 years, and were white (67%) or black (31%). Most participants had some college education or a college degree (79%), annual household income $30,000+ (60%), and health insurance (80%). The number of CRC screening barriers increased with probing compared to the open-ended question format (OR 2.10, 95% CI 1.92-2.31; p < 0.01). The ranking of reported CRC screening barriers did not vary by assessment method. However, the methodology used to document CRC screening barriers may influence the content of patient-directed interventions. PMID- 27933461 TI - Factors Associated with HIV Testing Among Participants from Substance Use Disorder Treatment Programs in the US: A Machine Learning Approach. AB - HIV testing is the foundation for consolidated HIV treatment and prevention. In this study, we aim to discover the most relevant variables for predicting HIV testing uptake among substance users in substance use disorder treatment programs by applying random forest (RF), a robust multivariate statistical learning method. We also provide a descriptive introduction to this method for those who are unfamiliar with it. We used data from the National Institute on Drug Abuse Clinical Trials Network HIV testing and counseling study (CTN-0032). A total of 1281 HIV-negative or status unknown participants from 12 US community-based substance use disorder treatment programs were included and were randomized into three HIV testing and counseling treatment groups. The a priori primary outcome was self-reported receipt of HIV test results. Classification accuracy of RF was compared to logistic regression, a standard statistical approach for binary outcomes. Variable importance measures for the RF model were used to select the most relevant variables. RF based models produced much higher classification accuracy than those based on logistic regression. Treatment group is the most important predictor among all covariates, with a variable importance index of 12.9%. RF variable importance revealed that several types of condomless sex behaviors, condom use self-efficacy and attitudes towards condom use, and level of depression are the most important predictors of receipt of HIV testing results. There is a non-linear negative relationship between count of condomless sex acts and the receipt of HIV testing. In conclusion, RF seems promising in discovering important factors related to HIV testing uptake among large numbers of predictors and should be encouraged in future HIV prevention and treatment research and intervention program evaluations. PMID- 27933462 TI - What do You Need to Get Male Partners of Pregnant Women Tested for HIV in Resource Limited Settings? The Baby Shower Cluster Randomized Trial. AB - Male partner involvement has the potential to increase uptake of interventions to prevent mother-to-child transmission of HIV (PMTCT). Finding cultural appropriate strategies to promote male partner involvement in PMTCT programs remains an abiding public health challenge. We assessed whether a congregation-based intervention, the Healthy Beginning Initiative (HBI), would lead to increased uptake of HIV testing among male partners of pregnant women during pregnancy. A cluster-randomized controlled trial of forty churches in Southeastern Nigeria randomly assigned to either the HBI (intervention group; IG) or standard of care referral to a health facility (control group; CG) was conducted. Participants in the IG received education and were offered onsite HIV testing. Overall, 2498 male partners enrolled and participated, a participation rate of 88.9%. Results showed that male partners in the IG were 12 times more likely to have had an HIV test compared to male partners of pregnant women in the CG (CG = 37.71% vs. IG = 84.00%; adjusted odds ratio = 11.9; p < .01). Culturally appropriate and community-based interventions can be effective in increasing HIV testing and counseling among male partners of pregnant women. PMID- 27933463 TI - Effect of tempol and tempol plus catalase on intra-renal haemodynamics in spontaneously hypertensive stroke-prone (SHSP) and Wistar rats. AB - Vasoconstriction within the renal medulla contributes to the development of hypertension. This study investigated the role of reactive oxygen species (ROS) in regulating renal medullary and cortical blood perfusion (MBP and CBP respectively) in both stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar rats. CBP and MBP were measured using a laser-Doppler flow meter before and after intra-renal infusion of tempol, the superoxide dismutase (SOD) mimetic or tempol plus catalase, the hydrogen peroxide-degrading enzyme. Tempol infusion significantly elevated blood perfusion within the renal medulla (MBP) in both SHRSP (by 43 +/- 7%, P < 0.001) and Wistar rats (by 17 +/- 2%, P < 0.05) but the magnitude of the increase was significantly greater in the SHRSP (P < 0.01). When the enzyme catalase and tempol were co-infused, MBP was again significantly increased in SHRSP (by 57 +/- 6%, P < 0.001) and Wistar rats (by 33 +/- 6%, P < 0.001), with a significantly greater increase in perfusion being induced in the SHRSP relative to the Wistar rats (P < 0.01). Notably, this increase was significantly greater than in those animals infused with tempol alone (P < 0.01). These results suggest that ROS plays a proportionally greater role in reducing renal vascular compliance, particularly within the renal medulla, in normotensive and hypertensive animals, with effects being greater in the hypertensive animals. This supports the hypothesis that SHRSP renal vasculature might be subjected to elevated level of oxidative stress relative to normotensive animals. PMID- 27933464 TI - Can body composition be used to optimize the dose of platinum chemotherapy in lung cancer? A feasibility study. AB - PURPOSE: Current methods of dosing platinum-based chemotherapy are suboptimal. Potentially, taking lean body mass into account may help. To inform the design of a future study, we first examined the feasibility and acceptability of such an approach using dual-energy X-ray absorptiometry (DEXA) and explored aspects suggestive of over- and under-dosing. METHODS: Patients with lung cancer offered platinum-based chemotherapy over 1 year were identified and, if eligible, invited to take part in a prospective feasibility study. Questionnaires examined acceptability of the DEXA scan and of a future study that randomized between traditional dosing and one adjusted according to body composition. Dose-limiting toxicity (DLT) and a lack of neutropenia explored potential over- and under dosing, respectively. RESULTS: Of the 173 patients offered chemotherapy, 123 (71%) were ineligible, mostly because of failing entry criteria (84, 49%). Of the 50 approached, 18 (36%) participated, most receiving carboplatin, with 17 providing data. All found a DEXA scan acceptable; other assessments were fully completed, except nadir and pre-chemotherapy blood counts. Most (94%) were prepared to take part in a future study, although the additional hospital visits for a nadir blood count were unpopular with some. Five (29%) patients experienced six episodes of DLT which resulted in discontinuation (3), dose reduction (2) or change to a less toxic regimen (1). Nine (60%) patients experienced either no (2) or inconsistent (7) neutropenia. CONCLUSIONS: A randomized trial appears acceptable and feasible in patients receiving carboplatin. Adjustment of our entry criteria and avoiding a hospital visit for a nadir blood count should aid recruitment. PMID- 27933465 TI - Nano-Mechanical Characterization of Ataxia Telangiectasia Cells Treated with Dexamethasone. AB - Ataxia telangiectasia is a rare genetic disease and no therapy is currently available. Glucocorticoid analogues have been shown to improve the neurological symptoms of treated patients. In the present study ataxia telangiectasia and wild type cells were used as a cellular model and treated with dexamethasone. The cells were subsequently investigated for membrane and whole cell mechanical properties by atomic force microscopy. In addition, cytoskeleton protein dynamics and nuclear shapes were assayed by fluorescence microscopy, while western blots were used to assess actin and tubulin content. At the macro level, dexamethasone directly modified the cell shape, Young's modulus and cytoskeleton protein dynamics. At the nano level, the roughness of the cell surface and the local nano mechanical proprieties were found to be affected by Dexa. Our results show that ataxia telangiectasia and wild type cells are affected by Dexa, although there are dissimilarities in some macro-level and nano-level features between the tested cell lines. The Young's modulus of the cells appears to depend mainly on nuclear shape, with a slight contribution from the tested cytoskeleton proteins. The current study proposes that dexamethasone influences ataxia telangiectasia cell membranes contents, cell components and cell shape. PMID- 27933466 TI - microRNA-145 modulates epithelial-mesenchymal transition and suppresses proliferation, migration and invasion by targeting SIP1 in human cervical cancer cells. AB - PURPOSE: Previously, it has been reported that microRNA-145 (miR-145) is lowly expressed in human cervical cancers and that its putative tumour suppressive role may be attributed to epithelial-mesenchymal transition (EMT) regulation. Here, we aimed to assess whether miR-145 may affect EMT-associated markers/genes and suppress cervical cancer growth and motility, and to provide a mechanistic basis for these phenomena. METHODS: The identification of the SMAD-interacting protein 1 (SIP1) mRNA as putative miR-145 target was investigated using a 3' untranslated region (3'UTR) luciferase assay and Western blotting, respectively. The functional effects of exogenous miR-145 expression, miR-145 suppression or siRNA mediated SIP1 expression down-regulation in cervical cancer-derived C33A and SiHa cells were analysed using Western blotting, BrdU incorporation (proliferation), transwell migration and invasion assays. In addition, the expression levels of miR-145 and SIP1 were determined in primary human cervical cancer and non-cancer tissue samples using qRT-PCR. RESULTS: We found that miR-145 binds to the wild type 3'UTR of SIP1, but not to its mutant counterpart, and that, through this binding, miR-145 can effectively down-regulate SIP1 expression. In addition, we found that exogenous miR-145 expression or siRNA-mediated down-regulation of SIP1 expression attenuates the proliferation, migration and invasion of C33A and SiHa cells and alters the expression of the EMT-associated markers CDH1, VIM and SNAI1, whereas inhibition of endogenous miR-145 expression elicited the opposite effects. The expression of miR-145 in cervical cancer tissue samples was found to be low, while that of SIP1 was found to be high compared to non-cancerous cervical tissues. An inverse expression correlation between the two was substantiated through the anlaysis of data deposited in the TCGA database. CONCLUSION: Our data indicate that low miR-145 expression levels in conjunction with elevated SIP1 expression levels may contribute to cervical cancer development. MiR-145-mediated regulation of SIP1 provides a novel mechanistic basis for its tumour suppressive mode of action in human cervical cancer cells. PMID- 27933468 TI - Conditional screening for ultra-high dimensional covariates with survival outcomes. AB - Identifying important biomarkers that are predictive for cancer patients' prognosis is key in gaining better insights into the biological influences on the disease and has become a critical component of precision medicine. The emergence of large-scale biomedical survival studies, which typically involve excessive number of biomarkers, has brought high demand in designing efficient screening tools for selecting predictive biomarkers. The vast amount of biomarkers defies any existing variable selection methods via regularization. The recently developed variable screening methods, though powerful in many practical setting, fail to incorporate prior information on the importance of each biomarker and are less powerful in detecting marginally weak while jointly important signals. We propose a new conditional screening method for survival outcome data by computing the marginal contribution of each biomarker given priorily known biological information. This is based on the premise that some biomarkers are known to be associated with disease outcomes a priori. Our method possesses sure screening properties and a vanishing false selection rate. The utility of the proposal is further confirmed with extensive simulation studies and analysis of a diffuse large B-cell lymphoma dataset. We are pleased to dedicate this work to Jack Kalbfleisch, who has made instrumental contributions to the development of modern methods of analyzing survival data. PMID- 27933470 TI - Erratum to: Identification of a Novel Binding Protein of FAT10: Eukaryotic Translation Elongation Factor 1A1. PMID- 27933469 TI - Telephone-Based Mindfulness Therapy Intervention for Patients with Chronic Pancreatitis. AB - BACKGROUND: Patients with chronic pancreatitis (CP) have substantially impaired quality of life (QOL) both physically and mentally. Mindfulness therapy is a form of treatment that has been shown to be beneficial in many medical conditions but has not been evaluated in the CP patient population. AIMS: The aims of this study were (1) to test the feasibility and usability of a novel telephone-based mindfulness therapy service for patients with CP and (2) to determine whether there was any effect on CP quality of life. METHODS: We recruited ten patients with suspected or confirmed CP and five controls who were asked to utilize our telephone-based mindfulness therapy service daily for 28 days. Feasibility of the service was defined as the fraction of subjects with a >=50% compliance rate. Usability was assessed using a System Usability Scale (SUS). QOL was evaluated using the SF-36 questionnaire and the Pancreatitis Quality of Life Instrument (PANQOLI). Paired t tests were used to compare the SF-36 and PANQOLI pre- and post-intervention. RESULTS: There was an overall compliance rate of 67%. The mean SUS score for all participants was 79.3, above the average published score of 68. Results showed a significant improvement in the SF-36 Mental Component Summary scores after 28 days of mindfulness therapy for patients with CP, t(9) = 2.48, p = 0.035. There was also a significant improvement in the mean total PANQOLI scores in CP patients, t(9) = 2.41, p = 0.04, most notably in the social domain. CONCLUSION: Our telephone-based mindfulness therapy service represents a feasible and easily usable treatment adjunct for patients with CP, which may provide benefit in QOL by improving mental health-related domains. PMID- 27933467 TI - Osteosarcoma Overview. AB - Osteosarcoma (OS) is the most common primary malignancy of bone and patients with metastatic disease or recurrences continue to have very poor outcomes. Unfortunately, little prognostic improvement has been generated from the last 20 years of research and a new perspective is warranted. OS is extremely heterogeneous in both its origins and manifestations. Although multiple associations have been made between the development of osteosarcoma and race, gender, age, various genomic alterations, and exposure situations among others, the etiology remains unclear and controversial. Noninvasive diagnostic methods include serum markers like alkaline phosphatase and a growing variety of imaging techniques including X-ray, computed tomography, magnetic resonance imaging, and positron emission as well as combinations thereof. Still, biopsy and microscopic examination are required to confirm the diagnosis and carry additional prognostic implications such as subtype classification and histological response to neoadjuvant chemotherapy. The current standard of care combines surgical and chemotherapeutic techniques, with a multitude of experimental biologics and small molecules currently in development and some in clinical trial phases. In this review, in addition to summarizing the current understanding of OS etiology, diagnostic methods, and the current standard of care, our group describes various experimental therapeutics and provides evidence to encourage a potential paradigm shift toward the introduction of immunomodulation, which may offer a more comprehensive approach to battling cancer pleomorphism. PMID- 27933471 TI - Factors Associated with Medication Non-adherence in Patients with End-Stage Liver Disease. AB - BACKGROUND: Low medication adherence is known to contribute to worse health outcomes in the general population. AIM: We aimed to evaluate the medication regimen and determine the adherence levels among patients with end-stage liver disease. METHODS: We measured adherence in patients awaiting liver transplantation at a single center using the 8-item Morisky Medication Adherence Scale (MMAS-8), with a score <8 classified as low adherence. Medication regimen complexity was assessed using the Medication Regimen Complexity Index (MRCI) tool. Factors associated with low adherence were identified by logistic regression. RESULTS: Of 181 patients, 33% were female, median age was 62, and model for end-stage liver disease (MELD) score was 13. The median (IQR) number of medications was 10 (7-13), and the MRCI was 19 (13-27). In total, 54 (30%) were high adherers, and 127 (70%) were low adherers. In total, 42% reported sometimes forgetting to take their medication and 22% reported intermittent adherence within the past 2 weeks. The most common reasons for low adherence were: forgetfulness (27%) and side effects (14%). Compared to high adherence, low adherence was associated with higher number of medications, medication complexity, and diabetes, but lower rates of hepatocellular carcinoma and self perceived health. In univariable logistic regression, total medication number (OR 1.08), MRCI (OR 1.04), diabetes (OR 2.38), HCC (OR 0.38), and lower self perceived health (OR 1.37), were statistically significant factors associated with non-adherence. In multivariate analysis, only medication number without supplements (OR 1.14) remained significantly associated with medication non adherence. CONCLUSION: A majority of patients awaiting liver transplantation demonstrated low medication adherence. Total number of medications and regimen complexity were strong correlates of low adherence. Our data underscores the need for chronic liver disease management programs to improve medication adherence in this vulnerable population. PMID- 27933472 TI - Tumor Necrosis Factor Alpha Inhibitors Did Not Influence Postoperative Morbidity After Elective Surgical Resections in Crohn's Disease. AB - BACKGROUND: The real impact of anti-tumor necrosis alpha (TNF) therapy in postoperative complications after intestinal resections in Crohn's disease (CD) still needs to be determined. AIMS: To compare the postoperative complication rates after elective intestinal resections in CD patients, with or without previous exposure to anti-TNF therapy. METHODS: This was a retrospective and observational study, with elective intestinal resections for CD (emergency procedures were excluded). Patients were allocated in two groups according to preoperative anti-TNF status. Surgical and medical complications were analyzed and subsequently compared between the groups. RESULTS: A total of 123 patients were included (71 with and 52 without preoperative anti-TNF). The groups were considered homogeneous, except for perianal CD, previous azathioprine, and stomas. There was no significant difference between the groups regarding overall surgical complications (32.69% in anti-TNF- vs. 39.44% in anti-TNF+ patients, p = 0.457) or overall medical complications (21.15 vs. 21.13%, respectively, p = 1.000). In univariate analysis, previous steroids, perianal CD, and stomas were considered risk factors for surgical complications, and previous steroids and hypoalbuminemia for medical complications. In multivariate analysis, previous steroids were associated with higher rates of surgical and medical complications, while hypoalbuminemia was associated with higher medical complication rates. CONCLUSIONS: There was no influence of the previous use of anti-TNF agents in postoperative surgical and medical complication rates in elective intestinal resections for CD. Previous steroids and hypoalbuminemia were associated with higher complication rates. This was the first case series of the literature describing outcomes in exclusively elective operations. PMID- 27933473 TI - High Percentage of IBD Patients with Indefinite Fecal Calprotectin Levels: Additional Value of a Combination Score. AB - BACKGROUND AND AIM: Monitoring mucosal inflammation in inflammatory bowel disease (IBD) is of major importance to prevent complications and improve long-term disease outcome. The correlation of clinical activity indices with endoscopic disease activity is, however, moderate. Fecal calprotectin (FC) is a better predictor of mucosal inflammation, but values between 100 and 250 ug/g are difficult to interpret in clinical practice. We aimed to evaluate the occurrence of indefinite FC levels in a real-life IBD cohort and study the additional value of a combination of biochemical markers and clinical activity indices. METHODS: In total, 148 Crohn's disease (CD) and 80 ulcerative colitis (UC) patients visiting the outpatient clinic were enrolled. FC, clinical disease activity scored by the Harvey-Bradshaw index or Simple Clinical Colitis Activity Index, and C-reactive protein (CRP) were assessed. In a subset of patients, endoscopic activity was scored by the simple endoscopic score-Crohn's disease and Mayo endoscopic subscore. Clinical activity index, CRP, and FC were integrated in a combination score and compared with endoscopy. RESULTS: Indefinite FC values were present in 24% of CD and 15% of UC. In the cohort of patients with endoscopy scores available, the combination score predicted endoscopic disease activity in CD with a sensitivity of 83% and specificity of 69% [positive predictive value (PPV) 58%, negative predictive value (NPV) 89%]. In UC, this was 88 and 75% (PPV 93%, NPV 60%). CONCLUSIONS: A combination of FC with clinical activity indices or CRP may aid in classifying patients with indefinite disease activity according to FC alone. PMID- 27933474 TI - Thinking ethical and regulatory frameworks in medicine from the perspective of solidarity on both sides of the Atlantic. AB - This article provides a concise overview of the history of scholarship on solidarity in Europe and North America. While recent decades have seen an increase in conceptual and scholarly interest in solidarity in North America and other parts of the Anglo-Saxon world, the concept is much more strongly anchored in Europe. Continental European politics in particular have given rise to two of the most influential traditions of solidarity, namely, socialism and Christian ethics. Solidarity has also guided important public instruments and institutions in Europe (e.g., welfare, healthcare, etc.). Despite the much stronger affinity of continental European societies to solidaristic thinking, we argue that solidarity has much to offer for addressing societal challenges on both sides of the Atlantic and beyond. After proposing a working definition of solidarity that highlights its utility for guiding policy and practice, we give an example of how a solidarity-based perspective can shape instruments for the governance of data use. PMID- 27933476 TI - Answer to the Letter to the Editor of S. Sabour concerning "Reliability and reproducibility analysis of the AOSpine thoracolumbar spine injury classification system by Chinese spinal surgeons" by J. Cheng et al. (Eur Spine J; 2016: DOI 10.1007/s00586-016-4842-4). PMID- 27933475 TI - How safe is minimally invasive pedicle screw placement for treatment of thoracolumbar spine fractures? AB - STUDY DESIGN: Prospective analysis of patients who underwent minimally invasive posterior instrumentation. OBJECTIVE: The purpose of this study was to evaluate the safety of minimally invasive pedicle screw placement in patients with unstable thoracic and lumbar spine fractures using the conventional fluoroscopy technique. Although wound infection, haematoma, and new neurological deficit due to screw malplacement remain a common source of morbidity, estimates of their rates of occurrence remain relatively limited. METHODS: 2052 percutaneous pedicle screws in 433 consecutive patients were evaluated. The accuracy of pedicle screw placement was based on evaluation of axial 3-mm slice computed tomography scans. Morbidity and mortality data were collected prospectively. RESULTS: A total of 2029 of 2052 screws (99%) had a good or excellent position. 5 screws (0.2%) showed a higher grade violation of the medial pedicle wall. Seven patients (1.8%) needed revision due to screw malposition (3 pat.), surgical site infection, postoperative haematoma, implant failure (2 pat.), and technical difficulties. CONCLUSIONS: Minimally invasive transpedicular instrumentation is an accurate, reliable, and safe procedure to treat thoracic and lumbar spine fractures. PMID- 27933477 TI - Impact of low-energy CT imaging on selection of positive oral contrast media concentration. AB - OBJECTIVES: To determine to what extent low-energy CT imaging affects attenuation of gastrointestinal tract (GIT) opacified with positive oral contrast media (OCM). Second, to establish optimal OCM concentrations for low-energy diagnostic CT exams. METHODS: One hundred patients (38 men and 62 women; age 62 +/- 11 years; BMI 26 +/- 5) with positive OCM-enhanced 120-kVp single-energy CT (SECT), and follow-up 100-kVp acquisitions (group A; n = 50), or 40-70-keV reconstructions from rapid kV switching-single-source dual-energy CT (ssDECT) (group B; n = 50) were included. Luminal attenuation from different GIT segments was compared between exams. Standard dose of three OCM and diluted solutions (75%, 50%, and 25% concentrations) were introduced serially in a gastrointestinal phantom and scanned using SECT (120, 100, and 80 kVp) and DECT (80/140 kVp) acquisitions on a ssDECT scanner. Luminal attenuation was obtained on SECT and DECT images (40-70 keV), and compared to 120-kVp scans with standard OCM concentrations. RESULTS: Luminal attenuation was higher on 100-kVp (328 HU) and on 40-60-keV images (410-924 HU) in comparison to 120-kVp scans (298 HU) in groups A and B (p < 0.05). Phantom: There was an inverse correlation between luminal attenuation and X-ray energy, increasing up to 527 HU on low-kVp and 999 HU on low-keV images (p < 0.05). 25% and 50% diluted OCM solutions provided similar or higher attenuation than 120 kVp, at low kVp and keV, respectively. CONCLUSIONS: Low-energy CT imaging increases the attenuation of GIT opacified with positive OCM, permitting reduction of 25%-75% OCM concentration. PMID- 27933478 TI - MRI in pelvic inflammatory disease: a pictorial review. AB - Pelvic inflammatory disease (PID) is an ascending infection of the female genital tract caused by the spread of bacteria from the vagina to the pelvic reproductive organs and occasionally the peritoneum. The most common causative organisms are sexually transmitted. PID is a significant source of morbidity among reproductive age women both as a cause of abdominal pain and as a common cause of infertility. Its clinical presentation is often nonspecific, and the correct diagnosis may first come to light based on the results of imaging studies. MRI is well suited for the evaluation of PID and its complications due to its superior soft tissue contrast and high sensitivity for inflammation. MRI findings in acute PID include cervicitis, endometritis, salpingitis/oophoritis, and inflammation in the pelvic soft tissues. Acute complications include pyosalpinx, tuboovarian abscess, peritonitis, and perihepatitis. Hydrosalpinx, pelvic inclusion cysts and ureteral obstruction may develop as chronic sequela of PID. The pathophysiology, classification, treatment, and prognosis of PID are reviewed, followed by case examples of the appearance of acute and subclinical PID on MR images. PMID- 27933479 TI - "Bunch of grapes" in complete hydatidiform mole. AB - Complete hydatidiform mole is a common cause of gestational bleeding of the first trimester, commonly assessed by ultrasound. It represents an abnormal proliferation of trophoblastic tissue, with no fetal formation, just hydropic villi. These abnormal villi seen in ultrasound are compared to a "bunch of grapes," a classic description of this disease. PMID- 27933480 TI - Alternatives to the baseline KUB for CTKUB-detected calculi: evaluation of CT scout and average and maximum intensity projection images. AB - PURPOSE: A CT of the kidneys, ureters, and bladder (CTKUB) is the investigation of choice in suspected renal colic. Plain kidney, ureter, and bladder radiographs (KUB) can be used to monitor the progress of a stone if radiographically visible on a baseline KUB. This study aims to determine if a low-dose CT Scout, thick slab average intensity projection (AIP), or maximum intensity projection (MIP) images are suitable as substitutes for a baseline KUB. METHOD: A retrospective review of patients from a tertiary adult institute that had a positive CTKUB and a KUB within 4 h of the CT was performed. Two consultant radiologists independently reviewed the KUB, CT Scout, AIP, and MIP for stone visibility and their sensitivities and agreement values were compared. Stone characteristics (size, location, and peak Hounsfield units) and patient thickness were recorded and examined for any association with discordant results. RESULTS: 74 stones were evaluated for the study. KUB had a sensitivity of 66.2% (95% CI 54.3-76.8), CT Scout 47.3% (95% CI 35.6-59.3), AIP 55.4% (95% CI 43.4-67.0), and MIP 83.8% (95% CI 73.4-91.3). Fair agreement was found between the KUB and both CT Scout (kappa=0.363, 95% CI 0.167-0.558) and AIP (kappa=0.384, 95% CI 0.175-0.592). Moderate agreement was found between the KUB and MIP (kappa=0.412, 95% CI 0.198 0.625). Neither any stone characteristic nor patient thickness had a significant association with discordant results. CONCLUSION: None of the possible substitutes for a baseline KUB showed strong agreement with the KUB. Low-dose CT Scouts have a similar sensitivity to the published literature for higher dose CT Scouts. PMID- 27933481 TI - Fixation preference test: reliability for the detection of amblyopia in patients with strabismus and interexaminer agreement. AB - PURPOSE: The purpose of this study was to analyze the reliability of the fixation preference test (FPT) in the detection of amblyopia, and to determine interexaminer agreement. METHODS: Eighty patients whose visual acuity could be tested objectively and had a horizontal misalignment of more than 10 prism diopters were enrolled. The best corrected visual acuity (BCVA) and orthoptic findings were all recorded. Non-preferred eye in primary position and fixation preference grade were assessed independently by two masked experienced examiners. The primary outcome measures were reliability of FPT in terms of its correlation with BCVA and interexaminer agreement. RESULTS: There was no significant correlation between fixation preference grades and interocular visual acuity difference as well as the type and amount of deviation, the presence of fusion, stereopsis, anisometropia, and previous strabismus surgery for none of the examiners (p > 0.05 for all). Sensitivity was 52.0% for examiner 1 and 54.0% for examiner 2 while specificity was 50.0 and 46.7%, respectively. Interexaminer agreement was 76.7% (p < 0.001) for all patients. CONCLUSIONS: FPT is widely used in children particularly when the visual acuity cannot be determined in an objective manner. The test may not be accurate and reliable in the detection of amblyopia and also in predicting the visual acuity difference between both eyes, even though it was found to show a high degree of agreement between examiners. In conclusion, it should be kept in mind that the reliability of FPT may be limited and the results should be interpreted with caution and be supported by other tests. PMID- 27933482 TI - Effect of Linker Length and Flexibility on the Clostridium thermocellum Esterase Displayed on Bacillus subtilis Spores. AB - In fusion protein design strategies, the flexibility and length of linkers are important parameters affecting the bioactivity of multifunctional proteins. A series of fusion proteins with different linkers were constructed. The effect of temperature, pH, and organic solvents was investigated on the enzymatic activity. Fusion proteins with P1(PTPTPT) and P2((PTPTPT)2) linkers remained highly active with wide temperature range. At pH 9.6, the relative activity of fusion proteins with (PTPTPT)2 and S2(EGKSSGSGSESKST) linkers was 70 and 62 % (1.75 and 1.5 times of that of non-linker ones). Fusion proteins with S3((GGGGS)4) linker retained 55 % activity after 5 h of incubation at 80 degrees C (1.2-fold of that of non linker fusion proteins and 1.9-fold of GGGGS-linker fusion proteins). Finally, the relative activity of fusion proteins having different linkers was increased with 20 % dimethyl sulfoxide (DMSO) and methanol; relative activity of fusion proteins with EGKSSGSGSESKST linkers was enhanced 1.5- and 2.2-fold, respectively. These results suggest that longer flexible linker can enhance the activity and stability of displayed esterase than shorter flexible linker. Optimizing peptide linkers with length, flexibility, and amino acid composition could improve the thermostability and activity of the displayed enzyme. PMID- 27933483 TI - Covalent Immobilization of Human Placental 17beta-Hydroxysteroid Dehydrogenase Type 1 onto Glutaraldehyde Activated Silica Coupled with LC-TOF/MS for Anti Cancer Drug Screening Applications. AB - Human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), a potential target in breast cancer prevention and therapy, was extracted from human placenta and immobilized on nonporous silica (~5 MUm) with a covalent method for the first time. The optimum initial enzyme concentration and immobilization time during the immobilization process were 0.42 mg mL-1 and 12 h, repectively. The binding was confirmed by scanning electron microscope (SEM) and infrared spectroscopy (FT IR). It could improve the pH, thermal and storage stability compared to free enzyme. Moreover, the immobilized enzyme could be reused at least four times. A screening method based on it coupled with liquid chromatography-time-of-flight mass spectrometer (LC-TOF/MS) was established, and the half-maximal inhibitory concentration (IC 50) of apigenin for the immobilized enzyme was 291 nM. Subsequently, 10 natural products were evaluated leading to inhibition of the activity of 17beta-HSD1 at the concentration of 25 MUM, and six of them inhibit the activity over 50%. PMID- 27933484 TI - DNA as a Target for Anticancer Phen-Imidazole Pd(II) Complexes. AB - Imidazole ring is a known structure in many natural or synthetic drug molecules and its metal complexes can interact with DNA and do the cleavage. Hence, to study the influence of the structure and size of the ligand on biological behavior of metal complexes, two water-soluble Pd(II) complexes of phen and FIP ligands (where phen is 1,10-phenanthroline and FIP is 2-(Furan-2-yl)-1H Imidazo[4,5-f][1, 10]phenanthroline) with the formula of [Pd(phen)(FIP)](NO3)2 and [Pd(FIP)2]Cl2, that were activated against chronic myelogenous leukemia cell line, K562, were selected. Also, the interaction of these anticancer Pd(II) complexes with highly polymerized calf thymus DNA was extensively studied by means of electronic absorption, fluorescence, and circular dichroism in Tris buffer. The results showed that the binding was positive cooperation and [Pd(phen)(FIP)](NO3)2 (K f = 127 M-1 G = 1.2) exhibited higher binding constant and number of binding sites than [Pd(FIP)2]Cl2 (K f = 13 M-1 G = 1.03) upon binding to DNA. The fluorescence data indicates that quenching effect for [Pd(phen)(FIP)](NO3)2 (K SV = 58 mM-1) was higher than [Pd(FIP)2]Cl2 (K SV = 12 mM-1). Also, [Pd(FIP)2]Cl2 interacts with ethidium bromide-DNA, as non competitive inhibition, and can bind to DNA via groove binding and [Pd(phen)(FIP)](NO3)2 can intercalate in DNA. These results were confirmed by circular dichroism spectra. Docking data revealed that longer complexes have higher interaction energy and bind to DNA via groove binding. Graphical Abstract Two anticancer Pd(II) complexes of imidazole derivative have been synthesized and interacted with calf thymus DNA. Modes of binding have been studied by electronic absorption, fluorescence, and CD measurements. [Pd(FIP)2]Cl2 can bind to DNA via groove binding while intercalation mode of binding is observed for [Pd(phen)(FIP)](NO3)2. PMID- 27933486 TI - An Appraisal of Novel Biomarkers for Evaluating and Monitoring Neurologic Diseases: Editorial Introduction. PMID- 27933487 TI - Evaluation of standardized triple intrathecal therapy toxicity in oncohematological pediatric patients. AB - Background The administration of triple intrathecal therapy with methotrexate, cytarabine and a corticosteroid for the prophylaxis and treatment of neoplastic cell infiltration in the central nervous system in hematological malignancies is a widespread practice. There is limited information available about its toxicity profile. Several factors related to intrathecal preparation can affect toxicity. Thus, it was decided to standardize intrathecal chemotherapy, trying to obtain the best toxicity profile. Objective To assess the toxicity of a standardized triple intrathecal chemotherapy in oncohematological pediatric patients and to establish risk factors of toxicity. Setting Oncohematological pediatric unit from a tertiary hospital in Spain. Methods Prospective, descriptive and observational study in which all the administrations of standardized triple intrathecal chemotherapy in pediatric patients were registered. Main outcome measure Toxicity of the intrathecal therapy was recorded and possible risk factors were assessed. Results A total of 269 administrations of triple intrathecal chemotherapy were registered in 41 patients (mean age = 6.6 +/- 3.9 years). In 16.7% of the procedures, an adverse event was reported (total number of adverse events = 61). 47.5% were grade 1, 47.5% grade 2 and 4.9% grade 3. The administration of intrathecal chemotherapy inpatient and patient age >=3 years were risk factors of toxicity in the multivariate analysis. Conclusions The administration of standardized triple intrathecal chemotherapy is related to a low frequency of toxicity and most of the adverse events registered were mild/moderate. The detection of adverse effects was significantly greater in children with age greater than or equal to three years and in hospitalized patients. PMID- 27933488 TI - Effects of economic recession on elderly patients' perceptions of access to health care and medicines in Portugal. AB - Background In view of the current financial and demographic situation in Portugal, accessibility to health care may be affected, including the ability to adhere to medication. Objective To evaluate the perceived effects of the crisis on elderly patient's access to medicines and medical care, and its implications on medicine-taking behaviour. Setting Community pharmacy. Method A cross sectional study was undertaken during April 2013, where elderly patients answered a self-administered questionnaire based on their health-related experiences in the current and previous year. Binary logistic regression was used to ascertain the effects of potential predictors on the likelihood of adherence. Main outcome measures self-reported adherence. Results A total of 1231 questionnaires were collected. 27.3% of patients had stopped using treatments or health services in the previous year for financial motives; mostly private medical appointments, followed by dentist appointments. Almost 30% of patients stopped purchasing prescribed medicines. Over 20% of patients reduced their use of public services. Out-of-pocket expenses with medicines were considered higher in the current year by 40.1% of patients. The most common strategy developed to cope with increasing costs of medicines was generic substitution, but around 15% of patients also stopped taking their medication or started saving by increasing the interdose interval. Conclusion Reports of decreasing costs with medicines was associated with a decreased likelihood of adherence (OR 0.42; 95% CI 0.27-0.65). Lower perceived health status and having 3 or more co-morbidities were associated with lower odds of adhering, whilst less frequent medical appointments was associated with a higher likelihood of exhibiting adherence. PMID- 27933485 TI - Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process. PMID- 27933489 TI - Patients' understanding and use of analgesia for postnatal pain following hospital discharge. AB - Background Postnatal pain is one of the limiting factors in the recovery of women from child birth. Despite the routine prescribing of analgesics for postnatal pain, limited research is available on the use of analgesics by the women in postnatal period. Objective To measure the utilisation and effectiveness of prescribed oral analgesics, the incidence and severity of pain, and factors associated with poor pain control on the fifth-day post-hospital discharge in postnatal women. Setting A tertiary referral women's hospital of Western Australia. Method Prospective cohort follow-up study of 400 postnatal women at a tertiary referral women's hospital during May and July 2014. All eligible subjects were contacted for a telephone survey 5 days after their discharge from the hospital. Additional clinical data was collected from the hospital medical records. Main outcome measure Pain at discharge, analgesics prescribed on discharge, patient understanding and adherence, and postnatal pain management. Results 197 of 400 recruited women completed the telephone survey yielding a response rate of around 50%. 131 Women (66%) reported to be in pain at the fifth day post-hospital discharge. Older women (p = 0.003) and women who reported to be in pain at hospital discharge were more likely to experience pain at home (p = 0.001). Women were more likely to seek consultation from a healthcare professional (p = 0.001) prior to their scheduled follow up visit, purchase over the counter analgesics from pharmacy (p = 0.012) and seek non-drug alternative (p = 0.019) if they experienced pain at home. Conclusion Pain at hospital discharge was found to be a strong predictor of pain at home among the postnatal women in this study. We propose pain at the time of hospital discharge as a useful clinical indicator to identify postnatal women who need additional support to manage their pain at home thus minimising potential harm related to inappropriate use of medications. PMID- 27933490 TI - Alterations in the Cerebral Microvascular Proteome Expression Profile After Transient Global Cerebral Ischemia in Rat. AB - This study aimed at obtaining an in-depth mapping of expressional changes of the cerebral microvasculature after transient global cerebral ischemia (GCI) and the impact on these GCI-induced expressional changes of post-GCI treatment with a mitogen-activated protein kinase kinase (MEK1/2) inhibitor. GCI was induced in male Wistar rats followed by treatment with either vehicle or the MEK1/2 inhibitor U0126 every 12 h post-GCI. Seventy-two hours after GCI or sham surgery, the cerebral microvasculature was isolated and the protein content analysed with state-of-the-art mass spectrometry. The proteomic profile of the isolated cerebral microvasculature 72 h after GCI (compared to sham) indicated that the main expressional changes could be divided into nine categories: (1) cellular respiration, (2) remodelling of the extracellular matrix, (3) decreased contractile phenotype, (4) clathrin-mediated endocytosis, (5) ribosomal activity, (6) expression of chromatin structure-related proteins, (7) altered synaptic activity, (8) altered G-protein signalling and (9) instability of the membrane potential. Treatment with U0126 partly normalized the expression of one or more of the proteins in all nine categories. Flow cytometry confirmed key findings from the proteome such as upregulation of the extracellular proteins lamininbeta2 and nidogen2 (p < 0.05) after GCI. These results provide valuable molecular insight into the broad and complex expressional changes in the cerebral microvasculature after GCI and the effect of early MEK1/2 inhibitor treatment on these changes. PMID- 27933491 TI - NLRP3 is Required for Complement-Mediated Caspase-1 and IL-1beta Activation in ICH. AB - Complement-mediated inflammation plays a vital role in intracerebral hemorrhage (ICH), implicating pro-inflammatory factor interleukin-1beta (IL-1beta) secretion. Brain samples and contralateral hemiencephalon were all collected and detected by Western blot. NLRP3 expression was located by dual immunofluorescence staining at 1, 3, and 5 days post-ICH. Brain water content was examined post-ICH. The neural deficit scores were evaluated by observers blindly. ILs were detected by ELISA. SiRNAs targeting NLRP3 (siNLRP3), siASC, and siControl were injected to inhibit NLRP3 function. To test the complement activation via Nod-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), normal rabbit complement (NRC) was injected with lipopolysaccharide (LPS) to facilitate the complement function. As a result, complement 3a (C3a) and complement 5a (C5a) were upregulated during the ICH-induced neuroinflammation, and ablation of C3 attenuates ICH-induced IL 1beta release. Though the LPS rescues the neuroinflammation in the ICH model, C3 deficiency attenuates the LPS-induced inflammatory effect. The NLRP3 inflammasome was activated after ICH and was located in the microglial cell of the mouse brain, which exhibits a time-dependent manner. However, the number of NLRP3/Iba-1 dual-labeled cells in the C3-/- group is less than that in the WT group in each time course, respectively. IL-1beta and IL-18 released in perihematoma tissue, caspase-1-p20, brain water content, and behavioral outcomes were attenuated in the siNLRP3 and siASC groups than in the siControl and ICH groups. We also found that 5% of complement supplement enhances ICH-induced IL-1beta release, while NLRP3 and ASC inhibition attenuates it. In conclusion, complement-induced ICH neuroinflammation depended on NLRP3 activation, which facilities LPS- and ICH induced neuroinflammation, and NLRP3 is required for ICH-induced inflammation. PMID- 27933492 TI - Comparative analysis of speech impairment and upper limb motor dysfunction in Parkinson's disease. AB - It is currently unknown whether speech and limb motor effectors in Parkinson's disease (PD) are controlled by similar underlying brain processes. Based on computerized objective analysis, the aim of this study was to evaluate potential correlation between speech and mechanical tests of upper limb motor function. Speech and upper limb motor tests were performed in 22 PD patients and 22 healthy controls. Quantitative acoustic analyses of eight key speech dimensions of hypokinetic dysarthria, including quality of voice, sequential motion rates, consonant articulation, vowel articulation, average loudness, loudness variability, pitch variability, and number of pauses, were performed. Upper limb movements were assessed using the motor part of the Unified Parkinson's Disease Rating Scale, contactless three-dimensional motion capture system, blinded expert evaluation, and the Purdue Pegboard Test. Significant relationships were observed between the quality of voice assessed by jitter and amplitude decrement of finger tapping (r = 0.61, p = 0.003), consonant articulation evaluated using voice onset time and expert rating of finger tapping (r = 0.60, p = 0.003), and number of pauses and Purdue Pegboard Test score (r = 0.60, p = 0.004). The current study supports the hypothesis that speech impairment in PD shares, at least partially, similar pathophysiological processes with limb motor dysfunction. Vocal fold vibration irregularities appeared to be influenced by mechanisms similar to amplitude decrement during repetitive limb movements. Consonant articulation deficits were associated with decreased manual dexterity and movement speed, likely reflecting fine motor control involvement in PD. PMID- 27933493 TI - Norovirus GII.Pe Genotype: Tracking a Foodborne Outbreak on a Cruise Ship Through Molecular Epidemiology, Brazil, 2014. AB - Norovirus (NoV) is recognized as the most common cause of foodborne outbreaks. In 2014, an outbreak of acute gastroenteritis occurred on a cruise ship in Brazil, and NoV became the suspected etiology. Here we present the molecular identification of the NoV strains and the use of sequence analysis to determine modes of virus transmission. Food (cream cheese, tuna salad, grilled fish, orange mousse, and vegetables soup) and clinical samples were analyzed by ELISA, conventional RT-PCR, qRT-PCR, and sequencing. Genogroup GII NoV was identified by ELISA and conventional RT-PCR in fecal samples from 5 of 12 patients tested (41.7%), and in the orange mousse food sample by conventional RT-PCR and qRT-PCR. Two fecal GII NoV samples and the orange mousse GII NoV sample were successfully genotyped as GII.Pe (ORF 1), revealed 98.0-98.8% identities among them, and shared phylogenetically distinct cluster. Establishing the source of a NoV outbreak can be a challenging task. In this report, the molecular analysis of the partial RdRp NoV gene provided a powerful tool for genotyping (GII.Pe) and tracking of outbreak-related samples. In addition, the same fast and simple extraction methods applied to clinical samples could be successfully used for complex food matrices, and have the potential to be introduced in routine laboratories for screening foods for presence of NoV. PMID- 27933494 TI - Long-term effects of increasing acidity on low-pH sulfate-reducing bioprocess and bacterial community. AB - An ethanol-fed, sulfate-reducing anaerobic baffled reactor was operated over a period of 260 days to assess the effects of sequentially more acidic conditions (pH 4.5-2.5) on sulfate reduction and bacterial community. Results showed that the reactor could reduce sulfate and generate alkalinity at progressively lower pH values of 4.5, 3.5, and 2.5 in a synthetic wastewater containing 2500 mg/L sulfate. About 93.9% of the influent sulfate was removed at a rate of 4691 mg/L/day, and the effluent pH was increased to 6.8 even when challenged with influent pH as low as 2.5. Illumina MiSeq sequencing revealed that a step decrease in influent pH from 4.5 to 2.5 resulted in noticeable decrease in the biodiversity inside the sulfidogenic reactor. Additionally, complete and incomplete organic oxidizers Desulfobacter and Desulfovibrio were observed to be the most dominant sulfate reducers at pH 2.5, sustaining the low-pH, high-rate sulfate removal and alkalinity generation. PMID- 27933495 TI - Photocatalysis of S-metolachlor in aqueous suspension of magnetic cerium-doped mTiO2 core-shell under simulated solar light. AB - Magnetic cerium-doped mesoporous titanium dioxide was synthesized by combining sol-gel method and calcination using tetrabutanate and ammonium cerium nitrate as precursors and Pluronic P123 as a template coating on iron oxide covered with carbon in ethanol. The magnetic Ce-doped catalyst showed only anatase structure with a slight increase in lattice parameters compared to the undoped catalyst. The Ce LIII-edge X-ray absorption near-edge spectroscopy (XANES) spectra showed Ce3+, and the cerium substitution doping into titanium dioxide was proposed. Degradation of S-metolachlor in aqueous magnetic photocatalyst suspension followed (pseudo) first-order kinetics in the presence of 0.5 g L-1 of gamma Fe2O3@C@0.16 mol% Ce-mTiO2 with a half-life of 55.18 +/- 1.63 min. Fifteen degradation products were identified, and their transformation routes of the photocatalytic degradation were then proposed. Complementary toxicity assessment of the treated S-metolachlor solution was undertaken with Environment Canada's algal microplate assay measuring growth inhibition (72-h IC50) in the freshwater chlorophyte Pseudokirchneriella subcapitata. This test method revealed a significant decrease in toxicity (1.7-fold reduction after 180 min of irradiation treatment), thereby confirming that the by-products formed following photocatalysis would be less harmful from an environmental point of view. Photocatalytic degradation of S-metolachlor thus appears to hold promise as a cost-effective treatment technology to diminish the presence of this herbicide in aquatic systems. PMID- 27933496 TI - Green synthesis of Pd/walnut shell nanocomposite using Equisetum arvense L. leaf extract and its application for the reduction of 4-nitrophenol and organic dyes in a very short time. AB - Palladium nanoparticles (PdNPs) have been immobilized on the surface of walnut shell powder using Equisetum arvense L. leaf extract as reducing and stabilizing agents in this work. FT-IR spectroscopy, UV-Vis spectroscopy, photoluminescence spectroscopy, X-ray diffraction (XRD) pattern, field emission scanning electron microscopy (FESEM), energy dispersive X-ray spectroscopy (EDS), and transmission electron microscopy (TEM) have been used in the characterization of the nanocomposites thus prepared. High catalytic activity was shown by these nanocomposites in the reduction of different dyes. The PdNPs' diameter on the walnut shell was predominantly found within the 5-12-nm range. The advantages of these catalysts include facile and clean synthesis, simple preparation procedure, excellent properties, alterable supports, and low cost, which make them applicable in reduction of 4-nitrophenol (4-NP), Congo red (CR), methylene blue (MB), and rhodamine B (RhB) in the presence of aqueous NaBH4 at room temperature. Pd/walnut shell nanocomposites were highly active catalysts for reduction of these dyes. Moreover, Pd/walnut shell nanocomposite can be recovered and recycled seven times without any appreciable loss of catalytic activity. Graphical abstract Waste walnut shell as a natural valuable resource support for green synthesis of Pd/walnut shell nanocomposite using Equisetum arvense L. leaf extract and its application for the reduction of 4-nitrophenol and organic dyes in a very short time. PMID- 27933497 TI - A review and investigation of the effect of nanophotocatalytic ozonation process for phenolic compound removal from real effluent of pulp and paper industry. AB - Phenol and its derivatives are the major environmental pollutants discharged from paper and pulp industries into water bodies. All these compounds and chlorinated phenolic compounds in particular are very toxic to fauna and flora, even at relatively low concentration. This study aimed to investigate the removal rate of phenolic compounds from the effluent of pulp and paper industries using a combination of ozonation and photocatalytic processes. Firstly, a certain volume from the effluent of paper and pulp industries containing certain phenol concentrations was obtained and fed into a prefabricated reactor at laboratory scale. Then, the combined and separate effects of zinc oxide dosage (ZnO), ozone flow rate (O3), and pH under ultra violet radiation for 30 min were evaluated. The concentration of phenolic compounds and the produced ozone gas flow rate were measured by a spectrophotometry and iodometric method, respectively. The results showed that the phenolic removal rate increased at acidic PHs compared with alkaline PHs; it was also decreased with the increase in ZnO dosages. Furthermore, the highest phenolic compound's removal rate was 99% at the optimal condition (pH 5, ZnO dosage of 0.1 g L-1 at the 30 min with UV-C illumination of 125 W). Finally, Daphnia toxicity test showed that treated effluent was safe and met the standards to the extent that it can be discharged into the receiving waters. Graphical abstract ?. PMID- 27933498 TI - Diazinon dissipation in pesticide-contaminated paddy soil: kinetic modeling and isolation of a degrading mixed bacterial culture. AB - Dissipation kinetics of diazinon was investigated in soils culled from a paddy field with a long history of the pesticide application. Goodness of fit statistical indices derived from several fitted mono- and bi-exponential kinetic models revealed a bi-phasic pattern of the diazinon dissipation curve at 15 and 150 mg kg-1 spiking levels, which could be described best by the first-order double exponential decay (FODED) model. Parameters obtained from this model were able to describe the enhanced dissipation of diazinon as the result of repeated soil applications, where a larger fraction of the pesticide readily available in the solution phase was dissipated with a fast rate. Cluster and principal component analysis (PCA) of denaturing gradient gel electrophoresis (DGGE) obtained from soil bacterial populations revealed that they were only affected at the 150 mg kg-1 diazinon concentration. This was also supported by the phylogenetic tree obtained from sequences of the main gel bands. Accordingly, bacterial populations belonging to Proteobacteria were enriched in the soil following three treatments with diazinon at 150 mg kg-1. The Shannon's index revealed a nonsignificant increase (P <= 0.05) in overall diversity of soil bacteria following diazinon application. Diazinon-degrading bacteria were isolated from the paddy soils in a mineral salt medium. Results showed that the isolated mixed culture was able to remove 90% of the pesticide at two concentrations of 50 and 100 mg L-1 by 16.81 and 19.60 days, respectively. Sequencing the DGGE bands confirmed the role of Betaproteobacteria as the main components of the isolated mixed culture in the degradation of diazinon. PMID- 27933499 TI - Assessment of molecularly imprinted polymers (MIPs) in the preconcentration of disperse red 73 dye prior to photoelectrocatalytic treatment. AB - Magnetic molecularly imprinted polymers (MMIPs) have become a research hotspot due to their two important characteristics: target recognition and magnetic separation. This paper presents the preparation, characterization, and optimization of an MMIP for the preconcentration of disperse red 73 dye (DR73) and its subsequent efficient degradation by photoelectrocatalytic treatment. The MMIPs were characterized by scanning electron microscopy (SEM), which revealed homogeneous distribution of the particles. Excellent encapsulation of magnetite was confirmed by transmission electron microscopy (TEM). A study of dye binding showed that the dye was retained more selectively in the MIP, compared to the NIP. The release of DR73 from the imprinted polymers into methanol and acetic acid was analyzed by UV-Vis spectrophotometry. The extracts showed higher absorbance values for MMIP, compared to MNIP, confirming greater adsorption of dye in the MMIP material. The extracts were then subjected to photoelectrocatalytic treatment. LC-MS/MS analysis following this treatment showed that the dye was almost completely degraded. Hence, the combination of MMIP extraction and photoelectrocatalysis offers an alternative way of selectively removing an organic contaminant, prior to proceeding with its complete degradation. PMID- 27933500 TI - Climate change mitigation: the potential of agriculture as a renewable energy source in Nigeria. AB - Energy is pivotal to the economic development of every nation. However, its production and utilization leads to undesirable carbon emissions that aggravate global warming which results in climate change. The agriculture sector is a significant user of energy. However, it has the potential to be a major contributor to Nigeria's energy supply mix in meeting its energy deficit. More so, in the light of current and impending adverse effects of climate change, there is a need to contain GHG's emissions. This paper focuses on bioenergy utilization as a climate change mitigation strategy and one that can, through effective waste management, enhance sustainable economic development in Nigeria. The paper employed a critical discourse analysis to examine the potential of the agricultural sector to provide biofuels from energy crops and other biomass sources. We conclude that Nigeria can reduce its GHG emissions and greatly contribute to global climate change mitigation while also alleviating its energy supply deficit if the agricultural and municipal wastes readily available in its towns and cities are converted to bioenergy. Such engagements will not only promote a clean and healthy environment but also create jobs for economic empowerment and a better standard of living for the people. PMID- 27933501 TI - Toxicity effect of graphene oxide on growth and photosynthetic pigment of the marine alga Picochlorum sp. during different growth stages. AB - Graphene oxide (GO), a recently discovered material, has been investigated for many applications in various fields. Thus, an immense awareness should be paid on the potential effects of the material on the environment as huge quantities of GO may get to the environment. Aquatic organisms, marine algae as an example, are exposed to such material when disposed to the environment. Accordingly, it is significant to assess the probable interactions of GO with algae in evaluating its possible environmental risks. In this study, we have examined the effect of different concentrations of GO on Picochlorum sp. during the different growth phases. The results showed that the toxicity of GO increases with increasing its concentration. The lowest concentration (0.5 mg L-1) was found to improve the algae growth and pigment content of Picochlorum sp. In contrast, higher GO concentrations had a negative consequence on the growth of algae and photosynthetic pigment concentration. PMID- 27933502 TI - Reply to "Reviews of One Anastomosis Gastric Bypass" by K. Mahawar. PMID- 27933503 TI - Response to the "Letter to the Editor Concerning the Publication: Efficacy of First-Time Intragastric Balloon in Weight Loss: a Systematic Review and Meta Analysis of Randomized Controlled Trials". PMID- 27933505 TI - Response to Comment on: Systematic Review and Meta-Analysis of Occupational Outcomes After Bariatric Surgery. PMID- 27933504 TI - Mental Health Support Provided Throughout the Bariatric Surgery Clinical Pathway in French Specialized Care Centers for Obesity. AB - OBJECTIVE: Pre-operative psychological assessment is recommended by international guidelines for bariatric surgery candidates. Thereby, service teams caring for bariatric patients should include at least one mental health provider (e.g., a psychologist or psychiatrist). The objective of this study was to evaluate the psychology and psychiatry resources and practices in the 37 specialized obesity centers (CSOs) created by the French Ministry of Health. MATERIALS AND METHODS: CSO coordinators were contacted by e-mail to collect general information on the centers (e.g., number of bariatric operations). Secondly, psychologists and psychiatrists of each center completed an anonymous questionnaire assessing their professional practices and their organization of care pathways. RESULTS: The vast majority of CSO coordinators (81%, n = 26/32) answered our survey. These results show significant differences and shortages in terms of the psychology/psychiatry resources available. Most of the psychologists (n = 26/31) and psychiatrists (n = 10/10) stated that they systematically meet new patients only before surgery (56%) or both before and after the operation (30%); however, some psychologists and psychiatrists (14%) do not systematically meet all the patients (before and/or after surgery). Nevertheless, all the professionals provide psychology assessments, and about 75% of them offer a psychological follow-up, indicating a similarity regarding the practices of psychologists and psychiatrists. CONCLUSION: Our results highlight the place of psychological/psychiatric evaluations in French CSOs and emphasize the absence of mental health providers in several of these services. Post-operative psychological follow-up is not usually provided. It would be appropriate to create clear recommendations for post-operative psychological or psychiatric long-term follow-up. PMID- 27933506 TI - Letter to the Editor: Vagal Blocking (vBloc) Therapy: a New Era of Clinical Therapy for Extreme Obesity : Re: Apovian et al. Two-Year Outcomes of Vagal Nerve Blocking (vBloc) for the Treatment of Obesity in the ReCharge Trial. Obesity Surgery. 2016. PMID- 27933507 TI - Determinants of maternal vitamin D concentrations in Slovenia : A prospective observational study. AB - OBJECTIVE: To analyze the vitamin D status of pregnant women in Slovenia and the factors influencing it. METHODS: The study was performed in Maribor University Medical Centre (location 46 degrees N). Maternal serum 25-hydroxy-vitamin D (25(OH)D) in 4 groups of 100 pregnant women in 4 different seasons of the year was measured at the time of delivery. Data on life style, eating habits, sunbathing and intake of vitamin D supplements during pregnancy were obtained using a questionnaire. Information on maternal outcome was acquired from medical records. Duration of sunlight and average temperature in the month preceding delivery were calculated from meteorological data. RESULTS: The average maternal 25(OH)D concentration ranged from 28.5 +/- 17.1 nmol/l in March to 54.8 +/- 24.1 nmol/l in June (p < 0.001). Severe vitamin D deficiency, i.e. <25 nmol/l 25(OH)D was present in 23.6% of women overall. In multiple regression analysis supplements containing vitamin D (beta = 0.225, p < 0.001) and duration of intentional exposure to sunlight (beta = 0.192, p = 0.026) were associated with maternal 25(OH)D status. Significantly lower vitamin D levels were observed in women who had a cesarean section (t = 2.053, p = 0.041) and those with premature delivery (t = 2.296, p = 0.022). Vitamin D levels were not associated with the occurrence of gestational diabetes, gestational hypertension or infections during pregnancy. CONCLUSION: A high prevalence of vitamin D deficiency was detected at the end of pregnancy, especially in the months following autumn and winter and in women who did not take supplements containing vitamin D. PMID- 27933508 TI - Patterns of diabetes care in Slovenia, Croatia, Serbia, Bulgaria and Romania : An observational, non-interventional, cross-sectional study. AB - BACKGROUND: National guidelines for treating type 2 diabetes in the Balkans generally follow European guidelines. The current study was undertaken to estimate the rate of glycated hemoglobin (HbA1c) measurements and level of HbA1c control in diabetic patients treated in regular clinical practice settings in the Balkans and to evaluate if providing HbA1c measurements improves adherence to treatment guidelines. METHODS: This cross-sectional study enrolled type 2 diabetic patients treated by 79 primary care physicians and 102 specialists. The participants were provided with HbA1c measuring devices to measure HbA1c during regular office visits and a physician survey evaluated HbA1c the results feedback. Relevant clinical, demographic, drug treatment and specialist referral data were extracted from patient charts. Descriptive statistics and stepwise multivariate regression analysis were used. RESULTS: Among 1853 patients included (average age 63.5 +/- 10.7 years, 51% male) the average diabetes duration was 8.9 +/- 7.1 years, 40% of patients had HbA1c measured every 6 months and 34% every 12 months (or less frequently). The rate of 6-month measurement was higher among specialists (43%) vs. primary care physicians (32%, p < 0.01). The average HbA1c was 7.3 +/- 1.5 and 35% of patients achieved the target HbA1c level of < 6.5%. Metformin monotherapy was prescribed to 28% of patients and metformin + sulphonylurea to 23%, 55% of patients on metformin monotherapy and 32% of patients on dual therapy metformin + sulphonylurea achieved the target HbA1c < 6.5%. Treatment remained unchanged in 91% and was stepped up in only 7.2% of patients. Physicians were not surprised (in 79% of patients) or were pleasantly surprised (in 11%) by the HbA1c results at the time of visit. Average diabetes duration and patient use of home glucometers were associated with the level of disease control. CONCLUSIONS: The rates of HbA1c measurements remain low in the Balkans, although higher among specialists. Over 60% of patients, mostly treated with traditional oral antidiabetics did not achieve disease control. Providing convenient HbA1c measurement devices was not associated with a marked change in diabetes management. Future research is needed to evaluate the impact of these treatment patterns on long-term outcomes and costs to society. PMID- 27933509 TI - Effect of Shuanghu Qinggan Granule () and Yigan Yiqi Jieyu Granule () plus lamivudine on chronic hepatitis B patients: A randomized double-blind placebo controlled trial. AB - OBJECTIVE: To observe the clinical efficacy and safety of Shuanghu Qinggan Granule ( , SQG) plus Yigan Yiqi Jieyu Granule (, YYJG) combined with lamivudine (LAM) on chronic hepatitis B (CHB) patients. METHODS: The study was a multicenter, randomized, double-blinded and parallel controlled trial. A total of 320 patients were randomly allocated into 2 groups equally: 160 patients (treatment group) were given SQG and YYJG combined with LAM; and 160 patients (control group) were given LAM plus Chinese herb placebo, respectively. Liver functions, hepatitis B envelop antigen (HBeAg) titer levels, and hepatitis B virus DNA (HBV-DNA) load were monitored. RESULTS: (1) In the 48th week, the treatment group showed superior HBeAg seroconversion rate than that in the control group (38.0% vs. 24.0%, P<0.05). (2) In the 48th week, the treatment group demonstrated lower HBeAg titer than that in the control group (P<0.05). (3) In the 12th, 24th, 48th week, there was no statistical significance in HBV-DNA response rate between the two groups. (4) In the 12th week, the level of glutamyl transpeptidase (GGT) was significantly decreased in the treatment group compared with the control group (P<0.05); in the 36th week, the levels of alanine aminotransferase and aspartate transaminase were significantly lower in the treatment group than those in the control group (P<0.05). CONCLUSION: The protocol of SQG and YYJG combined with LAM to treat CHB showed superior efficacy than LAM monotherapy. PMID- 27933510 TI - Anti-fibrotic effects of Salvia miltiorrhiza and Ligustrazine Injection on LX-2 cells involved with increased N-myc downstream-regulated gene 2 expression. AB - OBJECTIVE: To investigate the effects of Salvia miltiorrhiza and Ligustrazine Injection (SML) on proliferation and apoptosis of human hepatic stellate cell LX 2 and the expression of N-myc downstreamregulated gene 2 (NDRG2, a tumor suppressor gene). METHODS: HSCs from the LX-2 cell line were cultured in vitro. The proliferative state of different initial LX-2 cell numbers was measured using a 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. LX-2 cells were plated in 96-well plates at an approximate density of 2.50*104 cells/mL and cultured for 24 h followed by the application of different concentrations of SML (1, 2, 4 and 8 MUL/mL). Cell proliferation was measured using the MTT assay at 24 and 48 h. Apoptosis was detected by flow cytometry at 24 h. LX-2 cells were treated with different concentrations of SML and extracted with protein lysis buffer. The levels of NDRG2 and beta-catenin were measured by Western blot. RESULTS: With the exception of the 1 and 2 MUL/mL concentrations, 4 and 8 MUL/mL SML inhibited cell proliferation in a concentration-dependent manner at 24 and 48 h (P<0.05). With the exception of the 1 and 2 MUL/mL concentrations, the NDRG2 expression level was greatly increased in a concentration-dependent manner. However, the level of beta-catenin was unaffected. CONCLUSION: SML inhibit LX-2 cell proliferation in a concentration dependent manner, and the mechanism may be associated with NDRG2 over-expression. PMID- 27933511 TI - Appraisal of the Quality and Contents of Clinical Practice Guidelines for Hypertension Management in Chinese Medicine: A Systematic Review. AB - OBJECTIVE: To evaluate the quality and consistency of recommendations in the clinical practice guidelines (CPGs) for hypertension in Chinese medicine (CM). METHODS: CM CPGs were identified from 5 electronic databases and hand searches through related handbooks published from January 1990 to December 2013. Three reviewers independently appraised the CPGs based on the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument, and compared the CPGs' recommendations on CM syndrome pattern classification and treatment. RESULTS: Five CM CPGs for hypertension were included. The quality score of the evidence based (EB) guideline was higher than those of the consensus-based with no explicit consideration of evidence-based (CB-EB) and the consensus-based (CB) guidelines. Three out of five patterns in the CPGs were recommended by the EB guideline. Tianma Gouteng Formula () in the EB guideline was recommended mostly for hypertension patients with pattern of ascendant hyperactivity of Gan (Liver) yang and pattern of yin deficiency with yang hyperactivity in the CPGs. Acupuncture and massage were recommended for Grade I and Grade II hypertension with severe symptoms weakening the quality of life in the EB guideline. For Grade I and Grade II hypertension, CM could be used alone, while for Grade III hypertension, they should be used in combination with Western medicines. CONCLUSION: The quality of EB guideline was higher than those of CB and CB-EB CPGs in CM for hypertension and CM should be prescribed alone or combined with Western medicines based on the grade of hypertension. PMID- 27933512 TI - Effect of Chinese medicine treatment based on pattern identification on cellular immunophenotype of myelodysplastic syndrome. AB - OBJECTIVE: To observe the influence of treatment based on Chinese medicine pattern identification on cellular immunophenotype of the myelodysplastic syndrome (MDS). METHODS: Sixty patients with MDS were randomly and equally assigned to the treatment group and the control group using a randomized digital table. Thirty patients in each group included 3 risk levels (low, moderate and high risks) with each level 10 patients according to the international prognostic scoring system. The control group was given conventional therapy which was also used in the treatment group. While the treatment group was given Zuogui Pill () and Yougui Pill () for low risk patients; Qingwen Baidu Decoction () and Bazhen Decoction () for moderate risk patients; Gexia Zhuyu Decoction () and Qinghao Biejia Decoction () combined with Shiquan Dabu Decoction () for high risk patients. After the treatment, the differences of overall response rate and immunophenotype (CD13, CD14, CD15, CD33 and CD34) of each group were analyzed. RESULTS: The overall response rate of the treatment group was significantly higher than the control group in low risk and moderate risk patients (P=0.029), there was no statistical differences of overall response rate between the treatment group and the control group in high risk patients (P=0.089). The expressions of CD13, CD14, CD33 and CD34 in all three risk levels of the treatment group were obviously decreased after the treatment, while CD15 in all three risk levels of the treatment group was obviously increased after the treatment (P<0.05 or P<0.01). Meanwhile, the difference values of CD13 and CD33 in low risk level of the treatment group, CD33 and CD34 in moderate risk level of the treatment group as well as CD34 and CD15 in high risk level of the treatment group, were all greater than the control groups and they were statistically significant (P<0.05 or P<0.01). CONCLUSIONS: It shows a better therapeutic effect if the MDS patients treated with Chinese medicine pattern identification in addition to conventional therapy. Since the treatment may inhibit the malignant clones and improve the dysmaturity of granulocyte differentiation, it is a feasible option in clinical practice. PMID- 27933513 TI - Effect of Yiqi Tongyang Decoction () on blood T cell subsets in patients with chronic immune thrombocytopenia. AB - OBJECTIVE: To measure the proportions of blood T cell subsets, Th1, Th2, Th17, Th22, and Treg cells, and other parameters in patients with chronic immune thrombocytopenia (CITP) before and after treatment with Yiqi Tongyang Decoction (, YTD) to explore T cell status of patients with CITP, and to defifine the mechanism of action of YTD. METHODS: The changes in peripheral blood T lymphocyte subsets, and those of Th1, Th2, Th17, Th22, and Treg cells in 30 patients with CITP (22 females and 8 males) were analyzed using multiparametric flflow cytometry before and after treatment with YTD for 6 months, and 26 healthy volunteers (14 males and 12 females) acted as a control. T-box expressed in T cells (T-bet) and GATA binding protein 3 (GATA-3) mRNA levels in patients and controls were analyzed using real-time reverse transcription-polymerase chain reaction. RESULTS: The proportions of Th1, Th17, Th22, Th1/Th2, and Th17/Treg cells increased in the peripheral blood of patients with CITP compared to those in controls before YTD therapy (P<0.05). Th1 cell numbers and the Th1/Th2 ratio fell in the treated patients with CITP to approximate the values of the control group (P>0.05). Th17 cell numbers and the Th17/Treg ratio also decreased in the treatment group (P<0.05), but not to the levels of the controls. The number of Treg cells in the peripheral blood of patients with CITP before treatment was lower than that in the control group (P<0.05), but increased after YTD treatment P<0.05), but not to the level of controls. T-bet and GATA-3 mRNA levels in peripheral blood were initially higher in patients before treatment than controls (P<0.05), but decreased after YTD therapy (P<0.05). CONCLUSIONS: Imbalances in T lymphocyte levels, particularly those of Th1/Th2 and Th17/Treg cells, play important roles in the pathogenesis of CITP. YTD effificiently regulated the dynamics of Th1/Th2 and Th17/Treg equilibria. PMID- 27933514 TI - Changes in cardiac repolarisation during spontaneous nocturnal hypoglycaemia in subjects with type 1 diabetes: a preliminary report. AB - AIMS: Experimental studies have revealed that hypoglycaemia can result in morphological changes in electrocardiographic repolarisation in subjects with type 1 diabetes. However, the influence of spontaneous nocturnal hypoglycaemia on repolarisation morphology in a 'real life' situation is not clear. METHODS: Adults with type 1 diabetes (n = 11) underwent continuous glucose monitoring with a subcutaneous sensor and digital 12-lead ECG recording for three nights. T-wave morphology was analysed with custom-made software during both hypoglycaemia (glucose <3.5 mmol/l at least 20 min) from ten consecutive heart beats in the middle of the deepest hypoglycaemia and from a control nonhypoglycaemic period (glucose >=5.0 mmol/l) from the same recording. RESULTS: In the comparison of 10 hypoglycaemia-control pairs, heart rate (65 +/- 12 beats/min during normoglycaemia versus 85 +/- 19 beats/min during hypoglycaemia, p = 0.028) increased and the QTc interval (439 +/- 5 vs. 373 +/- 5 ms, respectively, p = 0.025) decreased significantly during hypoglycaemia. The spatial QRS-T angle (TCRT) was reduced, and the roughness of the T-wave loop (T-E) increased significantly (p = 0.037 for both) in the patients during hypoglycaemia. CONCLUSIONS: In adults with type 1 diabetes, spontaneous nocturnal hypoglycaemia results in morphological changes and increased heterogeneity of global cardiac repolarisation. These changes may contribute to the risk of 'dead in bed' syndrome encountered in young individuals with type 1 diabetes. PMID- 27933515 TI - Serum bilirubin concentrations and incident coronary heart disease risk among patients with type 2 diabetes: the Dongfeng-Tongji cohort. AB - AIMS: Elevated serum bilirubin levels are associated with decreased coronary heart disease (CHD) risk in cross-sectional studies among diabetic patients, but prospective evidence is limited. We investigated the relationship of serum bilirubin levels with incident CHD risk among type 2 diabetes patients. METHODS: In a prospective study of 2918 type 2 diabetes embedded in the Dongfeng-Tongji cohort, serum total bilirubin (TBil), direct bilirubin (DBil), and indirect bilirubin (IBil) were measured at baseline. Cox proportional hazards models were used to examine the association between serum bilirubin levels and CHD risk. RESULTS: A total of 440 CHD cases were identified during 12,017 person-years of follow-up. Compared with extreme quartiles, the adjusted hazard ratio and 95% confidence interval of incident CHD were 0.74 (0.56-0.99) with P trend = 0.08 in IBil, while in TBil and DBil, the bilirubin-CHD associations were not significant. Moreover, serum TBil and IBil levels were interacted with drinking status on the risk of incident CHD (P interaction = 0.021 and 0.037, respectively), and the associations were evident in ever drinkers. In drinkers, when serum TBil or IBil concentrations increased 1 MUmol/L, the CHD risk both decreased 6% (95% CIs 0.89-0.99 and 0.87-1.00, respectively). CONCLUSIONS: Serum IBil levels were marginally related to decreased incident CHD risk among type 2 diabetes. Drinking could potentially enhance the associations of serum TBil and DBil levels with incident CHD risk. PMID- 27933516 TI - Costs of diabetes medication among male former elite athletes in later life. AB - AIMS: Regular physical activity plays a major role, in both prevention and treatment of type 2 diabetes. Less is known whether vigorous physical activity during young adulthood is associated with costs of diabetes medication in later life. The aim of this study is to evaluate this question. METHODS: The study population consisted of 1314 former elite-class athletes and 860 matched controls. The former athletes were divided into three groups based on their active career sport: endurance, mixed and power sports. Information on purchases of diabetes medication between 1995 and 2009 was obtained from the drug purchase register of the Finnish Social Insurance Institution. RESULTS: The total cost of diabetes medication per person year was significantly lower among the former endurance (mean 81 ? [95% CI 33-151 ?]) and mixed group athletes (mean 272 ? [95% CI 181-388 ?]) compared with the controls (mean 376 ? [95% CI 284-485 ?]), (p < 0.001 and p = 0.045, respectively). Of the former endurance athletes, 0.4% used insulin, while 5.2% of the controls used insulin (p = 0.018). CONCLUSIONS: A career as former endurance, sprint, jumper or team game athlete seems to reduce the costs of diabetes medication in later life. PMID- 27933517 TI - A novel mutation in the fibrinogen Aalpha chain (Gly13Arg, fibrinogen Nanning) causes congenital dysfibrinogenemia associated with defective peptide A release. AB - Dysfibrinogenemia is characterized by blood coagulation dysfunction induced by an abnormal molecular structure of fibrinogen. Here, we describe a new case. A 32 year-old female was suspected of having dysfibrinogenemia during routine laboratory screening, based on her decreased functional fibrinogen level, normal fibrinogen antigen level, and prolonged thrombin time. We extracted DNA and performed polymerase chain reaction and DNA sequencing to identify genetic mutation. Fibrin polymerization, the kinetics of the fibrinopeptide release, scanning electron microscopy, mass spectrometric analysis, fibrin cross-linking, sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blot were conducted. DNA sequencing identified a heterozygous point mutation, Gly13Arg in Aalpha chain. Fibrin polymerization was markedly impaired (prolonged lag phase and decreased final turbidity). The rate and extent of fibrinopeptide A release from the patient were abnormal and reduced. The mass spectrometry analysis revealed the presence of mutant fibrinogen chains in the patient's circulation. Electron micrographs revealed abnormal fibrin clots. Fibrin cross-linking was normal. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blot showed no difference. We report a new case with a mutation in the fibrinopeptide A region, AalphaGly13Arg. These results indicated that the functional abnormalities were related to delayed and defective fibrinopeptide A cleavage and likely impaired thrombin binding. PMID- 27933518 TI - Resources for Systems Genetics. AB - A key characteristic of systems genetics is its reliance on populations that vary to a greater or lesser degree in genetic complexity-from highly admixed populations such as the Collaborative Cross and Diversity Outcross to relatively simple crosses such as sets of consomic strains and reduced complexity crosses. This protocol is intended to help investigators make more informed decisions about choices of resources given different types of questions. We consider factors such as costs, availability, and ease of breeding for common scenarios. In general, we recommend using complementary resources and minimizing depth of resampling of any given genome or strain. PMID- 27933519 TI - Heterogeneous Stock Populations for Analysis of Complex Traits. AB - Heterogeneous Stock (HS) populations allow for fine-resolution genetic mapping of a variety of complex traits. HS mice and rats were created from breeding together eight inbred strains, followed by maintaining the colony in a manner that minimizes inbreeding. After 50 or more generations of breeding, the resulting animals' chromosomes represent a genetic mosaic of the founders' haplotypes, with the average distance between recombination events in the centiMorgan range. This allows for genetic mapping to only a few Mb, a much smaller region than what can be identified using traditional F2 intercross or backcross mapping strategies. HS animals have been used to fine-map a variety of complex traits including anxiety and fear behaviors, diabetes, asthma, and heart disease, among others. Once a quantitative trait locus (QTL) has been identified, founder sequence and expression analysis can be used to identify underlying causal genes. In the following review, we provide an overview of how HS rats and mice have been used to identify genetic loci, and in some cases the causal genes, underlying complex traits. We discuss the creation and breeding strategies for both HS rats and mice. We then discuss the statistical analyses used to identify genetic loci, as well as strategies to identify causal genes underlying these loci. We end the chapter by discussing limitations faced when using HS populations, including several statistical challenges that have not been fully resolved. PMID- 27933520 TI - Mouse Genome Informatics (MGI): Resources for Mining Mouse Genetic, Genomic, and Biological Data in Support of Primary and Translational Research. AB - The Mouse Genome Informatics (MGI), resource ( www.informatics.jax.org ) has existed for over 25 years, and over this time its data content, informatics infrastructure, and user interfaces and tools have undergone dramatic changes (Eppig et al., Mamm Genome 26:272-284, 2015). Change has been driven by scientific methodological advances, rapid improvements in computational software, growth in computer hardware capacity, and the ongoing collaborative nature of the mouse genomics community in building resources and sharing data. Here we present an overview of the current data content of MGI, describe its general organization, and provide examples using simple and complex searches, and tools for mining and retrieving sets of data. PMID- 27933521 TI - GeneNetwork: A Toolbox for Systems Genetics. AB - The goal of systems genetics is to understand the impact of genetic variation across all levels of biological organization, from mRNAs, proteins, and metabolites, to higher-order physiological and behavioral traits. This approach requires the accumulation and integration of many types of data, and also requires the use of many types of statistical tools to extract relevant patterns of covariation and causal relations as a function of genetics, environment, stage, and treatment. In this protocol we explain how to use the GeneNetwork web service, a powerful and free online resource for systems genetics. We provide workflows and methods to navigate massive multiscalar data sets and we explain how to use an extensive systems genetics toolkit for analysis and synthesis. Finally, we provide two detailed case studies that take advantage of human and mouse cohorts to evaluate linkage between gene variants, addiction, and aging. PMID- 27933522 TI - Complex Trait Analyses of the Collaborative Cross: Tools and Databases. AB - The Collaborative cross (CC) is a powerful mouse resource for investigating complex genetic traits. Here we discuss various tools and techniques for gene mapping and identification using the CC. The data analyses procedures are illustrated with examples. PMID- 27933523 TI - Integrative Functional Genomics for Systems Genetics in GeneWeaver.org. AB - The abundance of existing functional genomics studies permits an integrative approach to interpreting and resolving the results of diverse systems genetics studies. However, a major challenge lies in assembling and harmonizing heterogeneous data sets across species for facile comparison to the positional candidate genes and coexpression networks that come from systems genetic studies. GeneWeaver is an online database and suite of tools at www.geneweaver.org that allows for fast aggregation and analysis of gene set-centric data. GeneWeaver contains curated experimental data together with resource-level data such as GO annotations, MP annotations, and KEGG pathways, along with persistent stores of user entered data sets. These can be entered directly into GeneWeaver or transferred from widely used resources such as GeneNetwork.org. Data are analyzed using statistical tools and advanced graph algorithms to discover new relations, prioritize candidate genes, and generate function hypotheses. Here we use GeneWeaver to find genes common to multiple gene sets, prioritize candidate genes from a quantitative trait locus, and characterize a set of differentially expressed genes. Coupling a large multispecies repository curated and empirical functional genomics data to fast computational tools allows for the rapid integrative analysis of heterogeneous data for interpreting and extrapolating systems genetics results. PMID- 27933524 TI - A Suite of Tools for Biologists That Improve Accessibility and Visualization of Large Systems Genetics Datasets: Applications to the Hybrid Mouse Diversity Panel. AB - In this chapter we address the recent explosion in large multilevel population studies such as the METSIM study in humans as well as large panels of animal models such as the Hybrid Mouse Diversity Panel or the BXD set of recombinant inbred strains. These studies have harnessed the increasing affordability of large-scale high-throughput profiling to gather massive quantities of data. These datasets, spread across different -omics levels (genome, transcriptome, etc.), different tissues (e.g. heart, plasma, bone) and different environmental factors (e.g. diet, drugs) each individually have led to a number of novel findings relevant to a variety of complex diseases and other phenotypes. The analysis of these results, however, is often limited to individuals with a comprehensive understanding of database languages such as SQL. In this chapter, we describe the development of a GUI-based database analysis suite, using the Hybrid Mouse Diversity Panel as an example to lay out a series of methods for visualization and integration of large systems genetics datasets. The database is based on the Shiny suite of tools in R, and is transferrable to other SQL-based datasets. PMID- 27933525 TI - Expression QTLs Mapping and Analysis: A Bayesian Perspective. AB - The aim of expression Quantitative Trait Locus (eQTL) mapping is the identification of DNA sequence variants that explain variation in gene expression. Given the recent yield of trait-associated genetic variants identified by large-scale genome-wide association analyses (GWAS), eQTL mapping has become a useful tool to understand the functional context where these variants operate and eventually narrow down functional gene targets for disease. Despite its extensive application to complex (polygenic) traits and disease, the majority of eQTL studies still rely on univariate data modeling strategies, i.e., testing for association of all transcript-marker pairs. However these "one at-a time" strategies are (1) unable to control the number of false-positives when an intricate Linkage Disequilibrium structure is present and (2) are often underpowered to detect the full spectrum of trans-acting regulatory effects. Here we present our viewpoint on the most recent advances on eQTL mapping approaches, with a focus on Bayesian methodology. We review the advantages of the Bayesian approach over frequentist methods and provide an empirical example of polygenic eQTL mapping to illustrate the different properties of frequentist and Bayesian methods. Finally, we discuss how multivariate eQTL mapping approaches have distinctive features with respect to detection of polygenic effects, accuracy, and interpretability of the results. PMID- 27933526 TI - Epigenetics and Control of RNAs. AB - Histone modifications are epigenetic marks that fundamentally impact the regulation of gene expression. Integrating histone modification information in the analysis of gene expression traits (eQTL mapping) has been shown to significantly enhance the prediction of eQTLs. In this chapter, we describe (1) how to perform quantitative trait locus (QTL) analysis using histone modification levels as traits and (2) how to integrate these data with information on RNA expression for the elucidation of the epigenetic control of transcript levels. We will provide a comprehensive introduction into the topic, describe in detail how ChIP-seq data are analyzed and elaborate on how to integrate ChIP-seq and RNA-seq data from a segregating disease animal model for the identification of the epigenetic control of RNA expression. PMID- 27933527 TI - Integrating Multidimensional Data Sources to Identify Genes Regulating Complex Phenotypes. AB - Phenotypes collected with a view to quantitative trait locus mapping can be augmented with compatible whole-transcriptome expression data and information from several other sources. These different data sources can be assembled into multidimensional network models which allow the identification of key genes potentially driving the phenotype of interest. The following chapter describes this approach using an example workflow. Several alternatives and potential limitations are discussed to aid the researcher when applying these techniques to their own work. PMID- 27933528 TI - RNA-Seq in the Collaborative Cross. AB - The Collaborative Cross (CC) is a large panel of inbred mouse strains currently being developed for multiple areas of research. Scientists are taking integrated omics-style approaches to collecting data in order to obtain a deeper understanding of the biological mechanisms underlying a number of diverse disease phenotypes. As the cost of the next generation sequencing (NGS) decreases, RNA sequencing (RNA-seq) has become the favored approach to transcriptomic analyses versus microarrays due to increases in sensitivity and resolution. This is particularly the case with newly defined genomes, where experimental annotation has not caught up to the new microarray platforms. Traditional RNA-seq approaches are not ideal when working with results from collaborative cross studies, as the genomes across individual strains differ considerably. In this chapter we will provide an overview of how to effectively perform RNA-seq analysis from data obtained from the CC mice. PMID- 27933529 TI - QTL Mapping and Identification of Candidate Genes in DO Mice: A Use Case Model Derived from a Benzene Toxicity Experiment. AB - Diversity Outbred (DO) mice are a multiparental advanced generation intercross population derived from eight inbred strains which are genetically very diverse. They are maintained as an outbred population using a randomized mating design. Thus DO mice represent an ideal population to map phenotypic traits. Here, we provide a case study in which male DO mice were exposed to benzene and phenotyped for the number of micronucleated reticulocytes. We provide step-by-step R scripts for the analysis of phenotypes, genotypes, mapping of resistance gene loci and identification of candidate genes. PMID- 27933530 TI - Visualization of Results from Systems Genetics Studies in Chromosomal Context. AB - This chapter describes methods currently available for visualizing results from systems genetics experiments. Here, we abstract from the statistical methods used for genetic mapping, which are dependent on the specific resource being used, i.e. F2, RILs, or outbred populations among others. We use a public dataset with results from a mouse eQTL experiment for three examples of visualization: genome wide dot plots of marker-by-gene association, karyotype-like plots, and circos plots. Dot plots give a first overview of the results from eQTL mapping, allowing detecting genome-wide patterns of cis- and trans-genetic association to transcription level. Karyotype-like plots provide chromosomal context and allow integrating multiple tracks of information in a single plot. Circos plots can, in addition, display long-range interactions to provide an overview of genetic connectivity at the genome level. All examples are developed and explained using R code, an open-source language with powerful statistical and graphical capabilities. The principles reviewed here, however, can be applied with other software options, organisms, and to any type of molecular phenotype that can be assigned to a genomic position. PMID- 27933531 TI - Using Baseline Transcriptional Connectomes in Rat to Identify Genetic Pathways Associated with Predisposition to Complex Traits. AB - Although rat is a critical model organism in preclinical medications development, its use in systems genetics studies remains sparse. The PhenoGen database and website contain detailed information on the qualitative and quantitative aspects of the rat brain, liver, heart, and brown adipose transcriptome. This database has been generated using the HXB/BXH recombinant inbred panel and is being expanded to a hybrid rat diversity panel that includes many common inbred strains as well. By using such a panel, the PhenoGen project has created a renewable and cumulative resource for the rat genomics community. The database has been used to reconstruct the brain transcriptome identifying both annotated and unannotated transcribed elements that range in size from 20 nucleotides to over 30,000 nucleotides and elements that have a wide variety of roles in the cell including generation of proteins and regulation of the transcription and translation processes. In all 4 tissues, baseline transcriptional connectomes have been generated to model the relationships among transcripts. These connectomes can be used to identify genetic pathways associated with complex traits and to gain insight into biological function of individual transcripts. The PhenoGen website contains tools that allow the user to explore qualitative features of individual genes and to see how the gene relates to other genes within a tissue. The PhenoGen database and website continue to grow and to make use of the latest statistical methods for systems genetics creating a national resource for the rat genomics community. PMID- 27933532 TI - Precise Network Modeling of Systems Genetics Data Using the Bayesian Network Webserver. AB - The Bayesian Network Webserver (BNW, http://compbio.uthsc.edu/BNW ) is an integrated platform for Bayesian network modeling of biological datasets. It provides a web-based network modeling environment that seamlessly integrates advanced algorithms for probabilistic causal modeling and reasoning with Bayesian networks. BNW is designed for precise modeling of relatively small networks that contain less than 20 nodes. The structure learning algorithms used by BNW guarantee the discovery of the best (most probable) network structure given the data. To facilitate network modeling across multiple biological levels, BNW provides a very flexible interface that allows users to assign network nodes into different tiers and define the relationships between and within the tiers. This function is particularly useful for modeling systems genetics datasets that often consist of multiscalar heterogeneous genotype-to-phenotype data. BNW enables users to, within seconds or minutes, go from having a simply formatted input file containing a dataset to using a network model to make predictions about the interactions between variables and the potential effects of experimental interventions. In this chapter, we will introduce the functions of BNW and show how to model systems genetics datasets with BNW. PMID- 27933533 TI - Systems Genetics as a Tool to Identify Master Genetic Regulators in Complex Disease. AB - Systems genetics stems from systems biology and similarly employs integrative modeling approaches to describe the perturbations and phenotypic effects observed in a complex system. However, in the case of systems genetics the main source of perturbation is naturally occurring genetic variation, which can be analyzed at the systems-level to explain the observed variation in phenotypic traits. In contrast with conventional single-variant association approaches, the success of systems genetics has been in the identification of gene networks and molecular pathways that underlie complex disease. In addition, systems genetics has proven useful in the discovery of master trans-acting genetic regulators of functional networks and pathways, which in many cases revealed unexpected gene targets for disease. Here we detail the central components of a fully integrated systems genetics approach to complex disease, starting from assessment of genetic and gene expression variation, linking DNA sequence variation to mRNA (expression QTL mapping), gene regulatory network analysis and mapping the genetic control of regulatory networks. By summarizing a few illustrative (and successful) examples, we highlight how different data-modeling strategies can be effectively integrated in a systems genetics study. PMID- 27933534 TI - Genomic Control of Retinal Cell Number: Challenges, Protocol, and Results. AB - This chapter considers some of the challenges in obtaining accurate and consistent estimates of neuronal population size in the mouse retina, in order to identify the genetic control of cell number through QTL mapping and candidate gene analysis. We first discuss a variety of best practices for analyzing large numbers of recombinant inbred strains of mice over the course of a year in order to amass a satisfactory dataset for QTL mapping. We then consider the relative merits of using average cell density versus estimated total cell number as the target trait to be assessed, and why estimates of heritability may differ for these two traits when studying the retina in whole-mount preparations. Using our dataset on cell number for 12 different retinal cell types across the AXB/BXA recombinant inbred strain set as an example, we briefly review the QTL identified and their relationship to one another. Finally, we discuss our strategies for parsing QTL in order to identify prospective candidate genes, and how those candidates may in turn be dissected to identify causal regulatory or coding variants. By identifying the genetic determinants of nerve cell number in this fashion, we can then explore their roles in modulating developmental processes that underlie the formation of the retinal architecture. PMID- 27933535 TI - Systems Genetics Analysis to Identify the Genetic Modulation of a Glaucoma Associated Gene. AB - Loss of retinal ganglion cells (RGCs) is one of the hallmarks of retinal neurodegenerative diseases, glaucoma being one of the most common. Recently, gamma-synuclein (SNCG) was shown to be highly expressed in the somas and axons of RGCs. In various mouse models of glaucoma, downregulation of Sncg gene expression correlates with RGC loss. To investigate the regulation of Sncg in RGCs, we used a systems genetics approach to identify a gene that modulates the expression of Sncg, followed by confirmatory studies in both healthy and diseased retinas. We found that chromosome 1 harbors an eQTL that modulates the expression of Sncg in the mouse retina and identified Pfdn2 as the candidate upstream modulator of Sncg expression. Downregulation of Pfdn2 in enriched RGCs causes a concomitant reduction in Sncg. In this chapter, we describe our strategy and methods for identifying and confirming a genetic modulation of a glaucoma-associated gene. A similar method can be applied to other genes expressed in other tissues. PMID- 27933536 TI - Genetic Dissection of Variation in Hippocampal Intra- and Infrapyramidal Mossy Fibers in the Mouse. AB - This chapter describes the genetic analysis of a morphometric neuroanatomic trait. We used the extended BXD family of recombinant inbred mouse strains with the intent to analyze the genetic bases of heritable differences in hippocampal neurocircuitry and to identify Quantitative Trait Loci that underlie these variations. A detailed description of a GeneNetwork analysis is provided using data for the intra- and infrapyramidal mossy fiber (IIPMF) terminal fields which are strongly correlated with spatial navigation/radial maze learning. PMID- 27933537 TI - Complex Genetics of Cardiovascular Traits in Mice: F2-Mapping of QTLs and Their Underlying Genes. AB - In this chapter, we will use the example of the identification of Tnni3k as a modulator of cardiac conduction to introduce you to the use of a murine F2 generation intercross as a powerful method for the identification of novel genes relevant for cardiovascular traits. Murine F2-progeny is a genetically diverse panel of mice with differences in phenotype manifestations, e.g. cardiovascular traits such as cardiomyopathy and ECG parameters. This chapter discusses the best strategies for using F2-mice for genetic mapping. Moreover, we provide an example of the feasibility of identification of new genes modulating cardiac function utilizing the technique of mapping quantitative trait loci (QTLs) and a systems genetics integration of available genetic, gene expression, and phenotypic data. PMID- 27933538 TI - Systems Genetics of Liver Fibrosis. AB - This systems genetics analysis comprises quantitative measurements of hepatic fibrogenesis in mouse models and mapping of quantitative traits in mouse genetic reference populations. It is part of a large mapping project of fibrogenic genes including the analyses of experimental crosses from different inbred mouse strains. Extensive quantitative trait loci (QTL) mapping of fibrosis phenotypes and liver expression profiling in combination with in silico mapping facilitated the identification of QTL regions and underlying candidate genes that confer fibrosis susceptibility also in humans. Moreover, the approach led to the identification of interacting QTLs and gene networks in liver fibrosis, providing a key experimental platform for the development of novel, more precise therapeutic interventions. Here, we provide a use case for the application of different analysis tools and the integration of multiple datasets determined in F2 intercrosses and BXD recombinant inbred lines to identify, finemap and affirm fibrosis susceptibility loci. PMID- 27933539 TI - Systems Genetics Analysis of Iron and Its Regulation in Brain and Periphery. AB - In this contribution, we demonstrate the utility of the systems genetics-systems biology approach to the study of iron regulation while employing a comprehensive database. We describe our work in iron regulation in the brain and periphery under normal iron and iron-restricted dietary conditions in the BXD family of recombinant inbred mouse strains. Using multiple measures, we showed wide variation among the strains in the effect of being fed an iron-restricted diet for 100 days in every measure from brain and from the periphery. All data were entered into GeneNetwork ( www.genenetwork.org ), a database that contains genotypic, phenotypic, and gene expression data (Rosen et al., Methods Mol Biol 401:287-303, 2007). Using this resource, we were able to ask the following four questions concerning possible candidate genes underlying our measures: (1) what is the range of response for each of the measures? (2) Does the pattern of variability show continuous (additive genetic) or discrete (Mendelian) distribution across strains? (3) Are there genetic markers that are associated with the variability in the measures? (4) Are there genes in near the markers that contain associated allelic differences, and whose expression is related to the variability in the measures? Other questions that we could address include: (5) what is the association among the measures between the sexes? (6) What is the association among the measures, e.g., is liver iron status under the diets related to brain iron? (7) What is the relationship between our measures and other phenotypic parameters-i.e., is there an association between our brain iron measures and neurochemical phenotypes extant in the database? And finally, (8) are there gene networks that underlie single or combined measures? PMID- 27933540 TI - Systems Genetics of Obesity. AB - Obesity is a complex trait, determined by many genes and influenced by environmental factors. Mapping genomic loci contributing to obesity helps to identify gene variants responsible for differences in the phenotype. However, measuring fat content alone is often not sufficient to identify the underlying gene or genes. Besides in-depth phenotyping, well-designed genetic populations and the combined analysis of data of different origins are necessary to detect one of several genetic determinants. Structured mouse populations and linking information from different experiments help to simplify the complexity in the search for direct genetic effects or factors that are hidden in the genome. In this chapter we present an example of how the physicochemical characterization of adipose tissue in BXD recombinant inbred lines contributes to enlighten the obese phenotype of mice. We describe the search for gene(s) contributing to collagen content in adipose tissue of BXD strains using the GeneNetwork platform. PMID- 27933541 TI - Social Interactions and Indirect Genetic Effects on Complex Juvenile and Adult Traits. AB - Most animal species are social in one form or another, yet many studies in rodent model systems use either individually housed animals or ignore potential confounds caused by group housing. While such social interaction effects on developmental and behavioral traits are well established, the genetic basis of social interactions has not been researched in as much detail. Specifically, the effects of genetic variation in social partners on the phenotype of a focal individual have mostly been studied at the phenotypic level. Such indirect genetic effects (IGEs), where the genotype of one individual influences the phenotype of a second individual, can have important evolutionary and medically relevant consequences. In this chapter, we give a brief outline of social interaction effects, and how systems genetics approaches using recombinant inbred populations can be used to investigate indirect genetic effects specifically, including maternal genetic effects. We discuss experimental designs for the study of IGEs and show how indirect genetic loci can be identified that underlie social interaction effects, their mechanisms, and consequences for trait variation in focal individuals. PMID- 27933542 TI - Complex Genetics of Behavior: BXDs in the Automated Home-Cage. AB - This chapter describes a use case for the genetic dissection and automated analysis of complex behavioral traits using the genetically diverse panel of BXD mouse recombinant inbred strains. Strains of the BXD resource differ widely in terms of gene and protein expression in the brain, as well as in their behavioral repertoire. A large mouse resource opens the possibility for gene finding studies underlying distinct behavioral phenotypes, however, such a resource poses a challenge in behavioral phenotyping. To address the specifics of large-scale screening we describe how to investigate: (1) how to assess mouse behavior systematically in addressing a large genetic cohort, (2) how to dissect automation-derived longitudinal mouse behavior into quantitative parameters, and (3) how to map these quantitative traits to the genome, deriving loci underlying aspects of behavior. PMID- 27933543 TI - Integrative Analysis of Genetic, Genomic, and Phenotypic Data for Ethanol Behaviors: A Network-Based Pipeline for Identifying Mechanisms and Potential Drug Targets. AB - Complex behavioral traits, such as alcohol abuse, are caused by an interplay of genetic and environmental factors, producing deleterious functional adaptations in the central nervous system. The long-term behavioral consequences of such changes are of substantial cost to both the individual and society. Substantial progress has been made in the last two decades in understanding elements of brain mechanisms underlying responses to ethanol in animal models and risk factors for alcohol use disorder (AUD) in humans. However, treatments for AUD remain largely ineffective and few medications for this disease state have been licensed. Genome wide genetic polymorphism analysis (GWAS) in humans, behavioral genetic studies in animal models and brain gene expression studies produced by microarrays or RNA seq have the potential to produce nonbiased and novel insight into the underlying neurobiology of AUD. However, the complexity of such information, both statistical and informational, has slowed progress toward identifying new targets for intervention in AUD. This chapter describes one approach for integrating behavioral, genetic, and genomic information across animal model and human studies. The goal of this approach is to identify networks of genes functioning in the brain that are most relevant to the underlying mechanisms of a complex disease such as AUD. We illustrate an example of how genomic studies in animal models can be used to produce robust gene networks that have functional implications, and to integrate such animal model genomic data with human genetic studies such as GWAS for AUD. We describe several useful analysis tools for such studies: ComBAT, WGCNA, and EW_dmGWAS. The end result of this analysis is a ranking of gene networks and identification of their cognate hub genes, which might provide eventual targets for future therapeutic development. Furthermore, this combined approach may also improve our understanding of basic mechanisms underlying gene x environmental interactions affecting brain functioning in health and disease. PMID- 27933544 TI - Dissection of Host Susceptibility to Bacterial Infections and Its Toxins. AB - Infection is one of the leading causes of human mortality and morbidity. Exposure to microbial agents is obviously required. However, also non-microbial environmental and host factors play a key role in the onset, development and outcome of infectious disease, resulting in large of clinical variability between individuals in a population infected with the same microbe. Controlled and standardized investigations of the genetics of susceptibility to infectious disease are almost impossible to perform in humans whereas mouse models allow application of powerful genomic techniques to identify and validate causative genes underlying human diseases with complex etiologies. Most of current animal models used in complex traits diseases genetic mapping have limited genetic diversity. This limitation impedes the ability to create incorporated network using genetic interactions, epigenetics, environmental factors, microbiota, and other phenotypes. A novel mouse genetic reference population for high-resolution mapping and subsequently identifying genes underlying the QTL, namely the Collaborative Cross (CC) mouse genetic reference population (GRP) was recently developed. In this chapter, we discuss a variety of approaches using CC mice for mapping genes underlying quantitative trait loci (QTL) to dissect the host response to polygenic traits, including infectious disease caused by bacterial agents and its toxins. PMID- 27933545 TI - The Collaborative Cross Resource for Systems Genetics Research of Infectious Diseases. AB - An increasing body of evidence highlights the role of host genetic variation in driving susceptibility to severe disease following pathogen infection. In order to fully appreciate the importance of host genetics on infection susceptibility and resulting disease, genetically variable experimental model systems should be employed. These systems allow for the identification, characterization, and mechanistic dissection of genetic variants that cause differential disease responses. Herein we discuss application of the Collaborative Cross (CC) panel of recombinant inbred strains to study viral pathogenesis, focusing on practical considerations for experimental design, assessment and analysis of disease responses within the CC, as well as some of the resources developed for the CC. Although the focus of this chapter is on viral pathogenesis, many of the methods presented within are applicable to studies of other pathogens, as well as to case control designs in genetically diverse populations. PMID- 27933546 TI - Using Systems Genetics to Understanding the Etiology of Complex Disease. AB - Here, we discuss Systems Genetics applications for systematic evaluation of candidate causal genes together with follow-up bioinformatics pathway analysis. The aim of this chapter is to illustrate analytic procedures and we provide examples in the context of Type 1 diabetes (T1day), the risk of which is conferred by over 60 loci. We also describe the Type 1 Diabetes Systems Genetics website and provide a guide for its use and application to other diseases. PMID- 27933547 TI - Anti-Neuroinflammatory Effects of Fucoxanthin via Inhibition of Akt/NF-kappaB and MAPKs/AP-1 Pathways and Activation of PKA/CREB Pathway in Lipopolysaccharide Activated BV-2 Microglial Cells. AB - Microglia play a critical role in controlling the homeostasis of the brain, but over-activated microglia secrete pro-inflammatory mediators and cytokines, which induce neuronal cell death. Fucoxanthin (Fx), a marine carotenoid, has demonstrated a variety of beneficial health effects. Despite accumulating evidence supporting the immune-modulating effects of Fx in vitro, the underlying signaling pathways remain unknown. In the present study, Fx dose-dependently inhibited the secretion of lipopolysaccharide (LPS)-induced pro-inflammatory mediators including interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, reactive oxygen species (ROS), prostaglandin (PG) E2, and nitric oxide (NO) productions, and also suppressed the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 enzymes. Further, the reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated IL-6, TNF-alpha, iNOS, and COX-2 mRNA expression were suppressed by treatment with Fx in a dose-dependently manner. The mechanism studies indicated that Fx blocks protein kinase B (Akt)/nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPKs)/transcription factor (AP)-1 pathways. In addition, we demonstrated that Fx increases nuclear factor erythroid 2-related factor (Nrf)-2 activation and heme oxygenase (HO)-1 expression in LPS-activated BV-2 microglia. Subsequently, we found that Fx also mediates the reactive oxygen species (ROS) by activating protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) pathway, and promotes the production of brain-derived neurotrophic factor (BDNF). These results indicate that Fx may be more effective and potential than other candidates via either decreasing the pro-inflammatory factors production or increasing the neuroprotective molecules expression for therapy of neurodegenerative diseases. PMID- 27933548 TI - Metabolic Characterization of Acutely Isolated Hippocampal and Cerebral Cortical Slices Using [U-13C]Glucose and [1,2-13C]Acetate as Substrates. AB - Brain slice preparations from rats, mice and guinea pigs have served as important tools for studies of neurotransmission and metabolism. While hippocampal slices routinely have been used for electrophysiology studies, metabolic processes have mostly been studied in cerebral cortical slices. Few comparative characterization studies exist for acute hippocampal and cerebral cortical slices, hence, the aim of the current study was to characterize and compare glucose and acetate metabolism in these slice preparations in a newly established incubation design. Cerebral cortical and hippocampal slices prepared from 16 to 18-week-old mice were incubated for 15-90 min with unlabeled glucose in combination with [U 13C]glucose or [1,2-13C]acetate. Our newly developed incubation apparatus allows accurate control of temperature and is designed to avoid evaporation of the incubation medium. Subsequent to incubation, slices were extracted and extracts analyzed for 13C-labeling (%) and total amino acid contents (umol/mg protein) using gas chromatography-mass spectrometry and high performance liquid chromatography, respectively. Release of lactate from the slices was quantified by analysis of the incubation media. Based on the measured 13C-labeling (%), total amino acid contents and relative activity of metabolic enzymes/pathways, we conclude that the slice preparations in the current incubation apparatus exhibited a high degree of metabolic integrity. Comparison of 13C-labeling observed with [U-13C]glucose in slices from cerebral cortex and hippocampus revealed no significant regional differences regarding glycolytic or total TCA cycle activities. On the contrary, results from the incubations with [1,2 13C]acetate suggest a higher capacity of the astrocytic TCA cycle in hippocampus compared to cerebral cortex. Finally, we propose a new approach for assessing compartmentation of metabolite pools between astrocytes and neurons using 13C labeling (%) data obtained from mass spectrometry. Based on this approach we suggest that cellular metabolic compartmentation in hippocampus and cerebral cortex is very similar. PMID- 27933549 TI - Demyelination Occurred as the Secondary Damage Following Diffuse Axonal Loss in a Rat Model of Radiation Myelopathy. AB - The main purpose of the present study was to examine the time and dose-dependent course of demyelination in the rat radiation myelopathy model in the first 180 days after irradiation of the spinal cord. An irradiated cervical spinal cord rat model (C2-T2 segment) was generated using a 60Co irradiator to deliver 50 Gy and 100 Gy, respectively. The behavioral dysfunction was observed by the forelimb paralysis scoring system. The histological damage in the irradiated spinal cord was examined by hematoxylin/eosin staining, luxol fast blue staining, immunohistochemical analysis, methylene blue/Azure II staining, and uranyl/lead salts staining. The gene expression of oligodendrocyte-related markers were also determined by quantitative real-time PCR. The complete loss of forelimb motor function in all animals was observed at 180 days 50 Gy post-irradiation and at 120 days 100 Gy post-irradiation. We demonstrated that a 50 and 100-Gy single dose irradiation of the C2-T2 spinal cord segment resulted in diffuse axonal loss and elicited secondary demyelination damage in the spinal cord. We further observed that 100-Gy irradiation reduced the gene expression of myelin oligodendrocyte glycoprotein in irradiated spinal cord. Taken together, our data not only define diffuse axonal loss as the main histological damage but also provide the first evidence that demyelination occurred as the secondary damage in irradiated spinal cord. PMID- 27933550 TI - Effect of Variable Doses of Zinc Oxide Nanoparticles on Male Albino Mice Behavior. AB - Zinc oxide nanoparticles (ZnO NPs) have diverse utility these days ranging from being part of nanosensors to be ingredient of cosmetics. Present study was designed to report the effect of variable doses of ZnO NPs on selected aspects of male albino mice behavior. Nano particles were synthesized by sol-gel auto combustion method (Data not shown here). 10 week old male albino mice were divided into four experimental groups; group A, B and C were orally supplemented with 50 (low dose), 300 (medium dose) and 600 mg/ml solvent/kg body weight (high dose) of ZnO NPs for 4 days. Group D (control) orally received 0.2 M sodium phosphate buffer (solvent for ZnO NPs) for the same duration. A series of neurological tests (Rota rod, open field, novel object and light-dark box test) were conducted in all groups and performance was compared between ZnO NPs treated and control group. Muscular functioning during rota rod test was significantly improved in all ZnO NPs treated mice as compared to control group. While no significant differences in open field, novel object and light-dark box test performance were observed when data from studied parameters of specific ZnO NPs treatment were compared with the control group indicating that applied doses of ZnO NPs did not affect the exploratory, anxiolytic behavior and object recognition capability of adult male albino mice. PMID- 27933551 TI - Pentoxifylline Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats: Possibly via Inhibiting TLR 4/NF-kappaB Signaling Pathway. AB - Early brain injury (EBI) after subarachnoid hemorrhage (SAH) generally causes significant and lasting damage. Pentoxifylline (PTX), a nonselective phosphodiesterase inhibitor, has shown anti-inflammatory and neuroprotective properties in several brain injury models, but the role of PTX with respect to EBI following SAH remains uncertain. The purpose of this study was to investigate the effects of PTX on EBI after SAH in rats. Adult male Sprauge-Dawley rats were randomly assigned to the sham and SAH groups. PTX (30 or 60 mg/kg) or an equal volume of the administration vehicle (normal saline) was administrated at 30 min intervals following SAH. Neurological scores, brain edema, and neural cell apoptosis were evaluated. In order to explore other mechanisms, changes in the toll-like receptor 4 (TLR4) and the nuclear factor-kappaB (NF-kappaB) signaling pathway, in terms of the levels of apoptosis-associated proteins, were also investigated. We found that administration of PTX (60 mg/kg) notably improved neurological function and decreased brain edema at both 24 and 72 h following SAH. Treatment with PTX (60 mg/kg) significantly inhibited the protein expressions of TLR4, NF-kappaB, MyD88 and the downstream pro-inflammatory cytokines, such as the tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta). PTX also significantly reduced neural cell death and BBB permeability. Our observations may be the first time that PTX has been shown to play a neuroprotective role in EBI after SAH, potentially by suppressing the TLR4/NF-kappaB inflammation-related pathway in the rat brain. PMID- 27933552 TI - Use of low density polyethylene membranes for assessment of genotoxicity of PAHs in the Seine River. AB - The genotoxicity of river water dissolved contaminants is usually estimated after grab sampling of river water. Water contamination can now be obtained with passive samplers that allow a time-integrated sampling of contaminants. Since it was verified that low density polyethylene membranes (LDPE) accumulate labile hydrophobic compounds, their use was proposed as a passive sampler. This study was designed to test the applicability of passive sampling for combined chemical and genotoxicity measurements. The LDPE extracts were tested with the umu test (TA1535/pSK1002 +/- S9) and the Ames assay (TA98, TA100 and YG1041 +/- S9). We describe here this new protocol and its application in two field studies on four sites of the Seine River. Field LDPE extracts were negative with the YG1041 and TA100 and weakly positive with the TA98 + S9 and Umu test. Concentrations of labile mutagenic PAHs were higher upstream of Paris than downstream of Paris. Improvement of the method is needed to determine the genotoxicity of low concentrations of labile dissolved organic contaminants. PMID- 27933554 TI - Use of anticoagulant rodenticides by pest management professionals in Massachusetts, USA. AB - Secondary exposure to chemical rodenticides, specifically second-generation anticoagulant rodenticides (SGARs), poses a threat to non-target wildlife including birds of prey. Federal regulations in the United States currently limit homeowner access to SGARs as a way of minimizing this threat. With legal access to SGARs, pest management professionals (PMPs) represent a potential linkage to non-target exposure. There is limited research focused on rodent control practices, chemical rodenticide preferences, level of concern and awareness, or opinions on rodenticide regulations as they relate to PMPs. An online survey was sent to PMP companies across Massachusetts, USA, between October and November 2015. Thirty-five responses were obtained, a 20 % response rate. The preferred rodent control method among responding PMP companies was chemical rodenticides, specifically the SGAR bromadiolone. Respondents varied in their level of concern regarding the impact of chemical rodenticides on non-target species and showed a low level of awareness regarding SGAR potency and half-life. All responding companies reported using integrated pest management (IPM) strategies, with nearly all utilizing chemical rodenticides at some point. Enhanced education focused on SGAR potency, bioaccumulation potential, exposure routes, and negative impacts on non-target wildlife may improve efforts made by PMPs to minimize risk to wildlife and decrease dependence on chemical rodenticide use. Future studies evaluating use of anticoagulant rodenticide (ARs) by PMPs and the association with AR residues found in non-target wildlife is necessary to determine if current EPA regulations need to be modified to effectively reduce the risk of SGARs to non target wildlife. PMID- 27933553 TI - Spontaneous honeybee behaviour is altered by persistent organic pollutants. AB - The effect of environmental pollutants on honeybee behaviour has focused mainly on currently used pesticides. However, honeybees are also exposed to persistent organic pollutants (POPs). The aim of this laboratory based study was to determine if exposure to sublethal field-relevant concentrations of POPs altered the spontaneous behaviour of foraging-age worker honeybees. Honeybees (Apis mellifera) were orally exposed to either a sublethal concentration of the polychlorinated biphenyl (PCB) mixture Aroclor 1254 (100 ng/ml), the organochlorine insecticide lindane (2.91 ng/ml) or vehicle (0.01% DMSO, 0.00015% ethanol in 1M sucrose) for 1-4 days. The frequency of single event behaviours and the time engaged in one of four behavioural states (walking, flying, upside down and stationary) were monitored for 15 min after 1, 2, 3 and 4 days exposure. Exposure to Aroclor 1254 but not lindane increased the frequency and time engaged in honeybee motor activity behaviours in comparison to vehicle. The Aroclor 1254 induced hyperactivity was evident after 1 day of exposure and persisted with repeated daily exposure. In contrast, 1 day of exposure to lindane elicited abdominal spasms and increased the frequency of grooming behaviours in comparison to vehicle exposure. After 4 days of exposure, abdominal spasms and increased grooming behaviours were also evident in honeybees exposed to Aroclor 1254. These data demonstrate that POPs can induce distinct behavioural patterns, indicating different toxicokinetic and toxicodynamic properties. The changes in spontaneous behaviour, particularly the PCB-induced chronic hyperactivity and the associated energy demands, may have implications for colony health. PMID- 27933555 TI - Pharmacist's Comprehensive Geriatric Assessment: Introduction and Evaluation at Elderly Patient Admission. AB - BACKGROUND: The role of the clinical pharmacist within the healthcare system remains unclear. OBJECTIVE: Our objective was to describe a pharmacist's comprehensive geriatric assessment (pCGA) at admission of elderly patients and to assess its relevance in terms of medication compliance and pharmacist interventions (PIs). METHODS: We conducted a prospective interventional study over 29 months in a 34-bed medical/rehabilitation geriatric ward in a French geriatric hospital. At admission, patients received pharmaceutical care through a consistent three-step process: (1) pharmacists met with the patient to undertake cognitive screening and assess their medication adherence (using the Girerd score) and medication history; (2) medication reconciliation was conducted at admission to detect intentional and unintentional discrepancies in treatment; and (3) clinical medication review was carried out throughout the patient's stay. The pharmacist conveyed proposed interventions to optimise treatment to the physician through the electronic health record. The number and type of PIs and their rate of implementation were recorded. RESULTS: In total, 539 patients aged >65 years were included; their mean age was 84 years. Cognitive screening showed that 45% of patients were confused at admission. Medication adherence assessment indicated that 50.2% had adherence problems. Medication reconciliation at admission detected discrepancies in 48%, with a mean of 1.09 unintended discrepancies per patient. Patients were taking an average of 7 +/- 3 drugs. In total, 828 PIs were reported to physicians; 520 were accepted and implemented (62.8% acceptance rate). CONCLUSION: This approach helps to avoid medication errors and enables the suggestion of relevant PIs, which were implemented by physicians in two-thirds of cases. PMID- 27933557 TI - Atypical Presentation and Treatment Response in a Child with Familial Hypercholesterolemia Having a Novel LDLR Mutation. AB - Familial hypercholesterolemia (FH) is an autosomal codominantly inherited disease. The severity of clinical presentation depends on the zygosity of the mutations in the LDLR, APOB, or PCSK9 genes. The homozygous form (HoFH) is associated with high mortality rate by third decade of life, while individuals with HeFH begin to suffer from premature cardiovascular disease in fourth or fifth decade of life. Statin drugs have helped to improve the biochemical profile and life expectancy in HeFH, while they are only minimally effective in HoFH. LDL apheresis remains an effective treatment option in HoFH, though limited by its availability and affordability issues. We present the case that highlights a few novel aspects of clinical and genetic heterogeneity in FH, wherein a child presented with features of both HeFH and HoFH. His clinical picture was that of HoFH; however he responded well clinically and biochemically to pharmacologic treatment only. DNA sequencing showed a novel heterozygous rare splicing variant in the LDLR gene in addition to a relatively high polygenic trait score comprised of LDL-C raising alleles from common polymorphic sites. Interestingly his normolipemic mother showed the same heterozygous mutation. Thus this novel splicing variant in LDLR showed nonclassical co-segregation with the disease phenotype and was associated with a high polygenic trait score comprised of common LDL-C raising polymorphic alleles in the affected proband. Thus it indicates the phenotypic heterogeneity of FH and suggests that secondary causes, such as polygenic factors and possibly as yet undetermined genetic or environmental factors, can exacerbate the metabolic phenotype in an individual who is genotypically heterozygous for FH. PMID- 27933558 TI - ? PMID- 27933559 TI - [Contribution of nested PCR in the diagnosis of imported malaria in southern Algeria]. AB - The nested PCR was used to estimate its inputs in malaria diagnosis and in the performance of the microscope operators involved in the surveillance of malaria in remote areas of South Algeria. For the period 2010 to 2015, 112 patients (93 febrile and 19 asymptomatic) coming from sub-Saharan Africa were tested for malaria in the hospital of Tamanrasset. One part of the blood taken from fingertip was used for blood smears and the second part was absorbed in filter paper for molecular diagnosis. Overall, the infection was detected by nested PCR in 63 samples versus 53 by direct examination. In addition, 11 mixed infections and 6 positive asymptomatic cases not detected by microscopy were diagnosed by PCR. Moreover, two negative samples in nested PCR were tested positive by direct examination. The molecular tool is more sensitive than the direct examination in detecting infra-microscopic parasitaemia and mixed infections... PMID- 27933560 TI - Familiarity increases the number of remembered Pokemon in visual short-term memory. AB - Long-term memory (LTM) can influence many aspects of short-term memory (STM), including increased STM span. However, it is unclear whether LTM enhances the quantitative or qualitative aspect of STM. That is, do we retain a larger number of representations or more precise representations in STM for familiar stimuli than unfamiliar stimuli? This study took advantage of participants' prior rich multimedia experience with Pokemon, without investing on laboratory training to examine how prior LTM influenced visual STM. In a Pokemon visual STM change detection task, participants remembered more first-generation Pokemon characters that they were more familiar with than recent-generation Pokemon characters that they were less familiar with. No significant difference in memory quality was found when quantitative and qualitative effects of LTM were isolated using receiver operating characteristic (ROC) analyses. Critically, these effects were absent in participants who were unfamiliar with first-generation Pokemon. Furthermore, several alternative interpretations were ruled out, including general video-gaming experience, subjective Pokemon preference, and verbal encoding. Together, these results demonstrated a strong link between prior stimulus familiarity in LTM and visual STM storage capacity. PMID- 27933561 TI - Comment on "Sub-anesthetic Xenon Increases Erythropoietin Levels in Humans: A Randomized Controlled Trial". PMID- 27933562 TI - Authors' Reply to Anoop Balachandran et al.: Comment on "Sub-Anesthetic Xenon Increases Erythropoietin Levels in Humans: A Randomized Controlled Trial". PMID- 27933563 TI - Sensitivity to Crossover Constraints During Native and Non-native Pronoun Resolution. AB - We report the results from two experiments examining native and non-native German speakers' sensitivity to crossover constraints on pronoun resolution. Our critical stimuli sentences contained personal pronouns in either strong (SCO) or weak crossover (WCO) configurations. Using eye-movement monitoring during reading and a gender-mismatch paradigm, Experiment 1 investigated whether a fronted wh phrase would be considered as a potential antecedent for a pronoun intervening between the wh-phrase and its canonical position. Both native and non-native readers initially attempted coreference in WCO but not in SCO configurations, as evidenced by early gender-mismatch effects in our WCO conditions. Experiment 2 was an offline antecedent judgement task whose results mirrored the SCO/WCO asymmetry observed in our reading-time data. Taken together, our results show that the SCO constraint immediately restricts pronoun interpretation in both native and non-native comprehension, and further suggest that SCO and WCO constraints derive from different sources. PMID- 27933564 TI - An improved reverse genetics system for Newcastle disease virus genotype VII. PMID- 27933566 TI - Fracture incidence rates in Norwegian children, The Tromso Study, Fit Futures. AB - : This study describes childhood fracture rates in Norway, a country known for high fracture rates in the adult population. Fracture rates correspond with other reports from Scandinavia, although with a slightly higher proportion in girls. Indications of increased vulnerability during stages of puberty require further exploration. INTRODUCTION: Fractures are common injuries during childhood. Incidence rates and patterns vary, but population-based data are scarce. The aim of this study was to describe the sex-, age- and maturation-specific incidence of fractures in a representative population-based sample from a region in Norway. METHODS: All fractures in the population based convenient cohort Fit Futures, comprising 961 adolescents under 18 years, were recorded retrospectively from the local hospital. Details on individual's age and fracture site were recorded. A radiologist confirmed all fractures. RESULTS: In the period from birth to cohort scanning, the register recorded 316 fractures in 253 individuals. Fractures were more common in boys (35%) than in girls (31%). The overall annual fracture incidence was 204 per 10,000 persons-year under the age of 18 and 205 under the age of 16. The majority of fractures involved the upper extremities and the most common site of fracture was the forearm with 24% of the fractures followed by phalanges with 23% of the fractures. Fractures peaked in girls at sexual maturation stage 3. Boys had a peak in stage 2. Timing of subsequent fractures was also consistent with stages of sexual maturation. CONCLUSIONS: The overall incidence of fractures in childhood in Northern Norway corresponds with other reports from Scandinavia, although the proportion of fractures in girls is higher than in other studies. Both sexes seem especially vulnerable at stages related to sexual maturation. Whether this reflects bone vulnerability or other changes related to puberty requires further investigation. PMID- 27933565 TI - KSHV strategies for host dsDNA sensing machinery. AB - The innate immune system utilizes pattern recognition receptors cyclic GMP-AMP synthase (cGAS) to sense cytosolic double-stranded (ds) DNA and initiate type 1 interferon signaling and autophagy pathway, which collaborate to limit pathogen infections as well as alarm the adaptive immune response. The genomes of herpesviruses are large dsDNA, which represent a major class of pathogen signatures recognized by cellular DNA sensor cGAS. However, to successfully establish the persistent infection, herpesviruses have evolved their viral genes to modulate different aspects of host immune signaling. This review summarizes the evasion strategies of host cGAS DNA sensing pathway by Kaposi's Sarcoma associated Herpesvirus (KSHV) and their contributions to KSHV life cycles. PMID- 27933567 TI - Impact of endoscopic ultrasound-guided fine-needle aspiration in prospective liver transplant recipients with hepatocellular carcinoma and lymphadenopathy. AB - BACKGROUND: Diagnosis of metastatic disease is important in patients with cirrhosis and hepatocellular carcinoma (HCC) to prevent futile liver transplantation. Some of these patients have metastatic lymphadenopathy; however, it is difficult to perform percutaneous fine-needle aspiration due to presence of collateral and anatomic location. Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) of lymph nodes offers several advantages like real-time vision, proximity to target, and avoidance of collaterals. AIM: The aim of this study was to look for metastatic lymphadenopathy by EUS-guided FNA (EUS-FNA) in prospective liver transplant recipients with HCC. METHODS: A prospective study was conducted from January 2013 to January 2016 at a tertiary care center. All prospective liver transplant recipients with HCC had PET-CT and bone scan to look for metastatic disease. EUS-FNA was done in patients with abdominal or mediastinal lymphadenopathy and no evidence of extrahepatic disease. Data is shown as median (25-75 interquartile range). RESULTS: EUS-guided FNA was done for 50 patients (42 abdominal and 8 mediastinal lymph nodes), age 57 (53-62) years, Child-Turcotte Pugh 7 (6-9), and model for end-stage liver disease 10 (7-16). FNA material was adequate in 92% patients, metastasis in 15 (30%), granulomatous lymphadenopathy in 4 (8%), and reactive change in 27 patients (54%). The material was inadequate for diagnosis in 4 (8%) patients. Thus, EUS-guided FNA precluded transplantation in 30% of patients with lymphadenopathy, and 4 (8%) patients received anti tubercular therapy before liver transplantation. CONCLUSION: In patients with HCC and lymphadenopathy, EUS-guided FNA detected metastatic disease and precluded liver transplantation in approximately one third of patients. PMID- 27933568 TI - Healthcare Costs Among Patients with Heart Failure: A Comparison of Costs between Matched Decedent and Survivor Cohorts. AB - INTRODUCTION: Prior research suggests increased costs during the final months of life, yet little is known about healthcare cost differences between patients with heart failure (HF) who die or survive. METHODS: A retrospective claims study from a large US health plan [commercial and Medicare Advantage with Part D (MAPD)] was conducted. Patients were >=18 years old with two non-inpatient or one inpatient claim(s) with HF diagnosis code(s). The earliest HF claim date during 1 January 2010-31 December 2011 was the index date. Cohort assignment was based on evidence of death within 1 year (decedents) or survival for >1 year (survivors) post index. Per-patient-per-month (PPPM) and 1-year (variable decedent follow-up) costs (all-cause and HF-related) were calculated up to 1 year post-index. Cohorts were matched on demographic and clinical characteristics. Independent samples t tests and Pearson's chi-square tests were used to examine cohort differences. RESULTS: Among patients with HF, 8344 survivors were 1:1 matched to decedents [mean age 75 years, 50% female, 88% MAPD; mean time to decedents' death: 150 (SD 105) days]. Compared to survivors, more decedents had no pharmacy claims for HF related outpatient pharmacotherapy within 60 days post-index (42.1% vs. 27.1%; p < 0.001). Decedents also incurred higher all-cause medical costs (PPPM: $21,400 vs. $2663; 1 year: $60,048 vs. $32,394; both p < 0.001) and higher HF-related medical costs (PPPM: $16,477 vs. $1358; 1 year: $39,052 vs. $16,519; both p < 0.001). Hospitalizations accounted for more than half of all-cause PPPM medical costs (54.6% for survivors, 84.3% for decedents). CONCLUSION: Patients with HF who died within 1 year after an index HF encounter incurred markedly higher costs within 1 year (despite the much shorter post-index period) and PPPM costs than those who survived, with the majority of costs attributable to hospitalizations for both patient cohorts. There may be opportunities for improving outcomes in HF, considering higher use of pharmacotherapy and lower costs were seen among survivors. PMID- 27933570 TI - Long bone deformity correction and bone lengthening procedures. PMID- 27933571 TI - Mastering the sentence. PMID- 27933569 TI - Decision-Making in Clinical Practice: Oral Anticoagulant Therapy in Patients with Non-valvular Atrial Fibrillation and a Single Additional Stroke Risk Factor. AB - Approximately 1 in 3-4 patients presenting with an ischemic stroke will also have atrial fibrillation (AF), and AF-related strokes can be effectively prevented using oral anticoagulant therapy (OAC), either with well-controlled vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs). In addition, OAC use (both VKAs and NOACs) is associated with a 26% reduction in all cause mortality (VKAs) or an additional 10% mortality reduction with NOACs relative to VKAs. The decision to use OAC in individual AF patient is based on the estimated balance of the benefit from ischemic stroke reduction against the risk of major OAC-related bleeding [essentially intracranial hemorrhage (ICH)]. Better appreciation of the importance of VKAs' anticoagulation quality [a target time in therapeutic range (TTR) of >=70%] and the availability of NOACs (which offer better safety compared to VKAs) have decreased the estimated threshold for OAC treatment in AF patients towards lower stroke risk levels. Still, contemporary registry-based data show that OAC is often underused in AF patients at increased risk of stroke. The uncertainty whether to use OAC may be particularly pronounced in AF patients with a single additional stroke risk factor, who are often (mis)perceived as having a "borderline" or insufficient stroke risk to trigger the use of OAC. However, observational data from real world AF cohorts show that the annual stroke rates in such patients are higher than in patients with no additional stroke risk factors, and OAC use has been associated with reduction in stroke, systemic embolism, or death in comparison to no therapy or aspirin, with no increase in the risk of bleeding relative to aspirin. In this review article, we summarize the basic principles of stroke risk stratification in AF patients and discuss contemporary real-world evidence on OAC use and outcomes of OAC treatment in AF patients with a single additional stroke risk factor in various real-world AF cohorts. PMID- 27933572 TI - Relation between the stability of dental implants and two biological markers during the healing period: a prospective clinical study. AB - OBJECTIVES: The purposes of this study were to examine the correlation between the stability of dental implants and bone formation markers during the healing period and to monitor the stability of dental implants using the resonance frequency analysis (RFA) method. The null hypothesis of the study is no correlation between the stability of dental implant and bone formation markers. METHODS: The study is a prospective clinical study during the 3-month healing period of implant. At implant placement (PW Plus, Nakhon Pathom, Thailand) and after 1, 2, 3, 4, 6, 8, 10, and 12 weeks, RFA assessments were performed and gingival (GCF)/peri-implant crevicular fluids (PICF) were collected from ten patients. The level of osteocalcin (OC) was measured by using ELISA kits, and the level of alkaline phosphatase (ALP) activity was measured by colorimetric analysis. Repeated measures analysis of variance, the Friedman test, the Mann Whitney U test, and the Pearson correlation were performed for data analysis. RESULTS: There was a statistical decrease in the mean implant stability quotient (ISQ) values between 1 and 3 weeks (P < 0.05). The ISQ values recovered to the initial values at 4 weeks. There was no statistical difference in the ALP level at each measurement, while there was a statistical increase in the OC level at 6, 8, 10, and 12 weeks when compared with 1 week (P < 0.05). There was a significant correlation between ALP levels and ISQ values (r = 0.226, P < 0.05). There was a statistically significant correlation between OC levels and ISQ values at 1-12 weeks (r = 0.245, P < 0.05). CONCLUSIONS: The ISQ values were weakly correlated with both ALP and OC. The three-thread-design implant showed a high stability through healing period. PMID- 27933573 TI - [Efficacy of an iron retard preparation in patients with iron deficiency anemia]. AB - OBJECTIVE: To study the therapeutic efficacy of an oral iron retard preparation in patients with iron deficiency anemia. METHODS: In an investigator-initiated open study, 28 patients with iron deficiency anemia were treated with an iron sulfate sustained-release preparation (80 mg iron ions per tablet). The bioavailability was determined from the increase in the haemoglobin value under therapy and the measured blood loss. For the quantification of individual blood losses, a 59Fe labeling method was used and the 59Fe whole body retention in the observation period was measured with a whole body counter. This established method provides reliable data on the bioavailability of an oral iron preparation used. RESULTS: In all patients the increased iron loss (average 6.6 +/- 5.9 mg/d) was easily compensated by the amount of iron (average 11.7 +/- 6.6 mg/d) taken with a daily dose of 80 mg of iron. During the observation period of 6-10 weeks there was a significant increase in haemoglobin (Hb) and ferritin concentration (mean increase of Hb from 10.2 +/- 1.6 to 12.5 +/- 1.5 g/dl and from ferritin from 9 +/- 11 to 31 +/- 23 MUg/L). CONCLUSIONS: Our results show that the iron sulfate retardant preparation used has a high bioavailability for iron. In all patients the anemia could be treated effectively. These findings seem to indicate that patients with chronic iron deficiency anemia can also receive therapeutically administered iron from the distal intestine sections. PMID- 27933574 TI - [Long-term HRV analysis shows stress reduction by magnesium intake]. AB - BACKGROUND: Mental pressure and stress represent an ever-increasing socio political challenge. The heart rate variability (HRV) measurement, which has its origin in the cardiac function diagnosis, gives information on the neurovegetative activity. A low HRV shows an imbalance of the sympathetic and parasympathetic efferents and thus is an indicator of stress. METHOD: A randomized, controlled, two-armed parallel study with 100 participants and a period of 90 days was performed. Main object of investigation was to what extent the mineral magnesium, which is also a high-quality natural calcium antagonist in cardiology, can influence the sympathovagal balance, when given in combination with a strength-endurance training. The effect on intracellular magnesium concentration was investigated as an additional parameter. RESULTS: In the group with daily supplementation of 400 mg of magnesium, HRV parameters clearly increased: pNN50 - an indicator of parasympathetic activity - increased. LF-HF ratio as well as stress index - low values for each represent a good balance of the vegetative nervous system - decreased. In the control group no positive changes in HRV parameters could be shown. Vagus activity, and thus the adaptive and regenerative capacity of the body, veritably increased by magnesium supplementation. No effect on the intracellular magnesium concentration could be shown in the study. CONCLUSIONS: The results of this study point out that persons with mental and physical stress can benefit from a daily intake of magnesium. This might lead to an improved physiological regulation of the sympathetic and parasympathetic efferents and, furthermore, prevent magnesium deficiency and diseases such as, for example, restlessness, irritability, lack of concentration, sleep disorder or depression. PMID- 27933575 TI - [Fast-acting insulin - new developments towards more flexibility for the patient]. AB - BACKGROUND: Post-prandial insulin secretion occurs under physiological conditions very fast and in adequate concentrations. This mechanism is impaired in patients with type 2 diabetes and severe increases of postprandial glucose levels may occur. In order to achieve physiological conditions and to avoid postprandial hyperglycemia, exogenous insulin and insulin analogues should be absorbed very fast and appropriate maximum concentrations should be reached very quickly. METHOD: Overview RESULTS AND CONCLUSIONS: The development of new bolus insulins is focused on improved pharmacokinetic and pharmacodynamic properties. Not only new pharmaceutical formulations, but also different application sites and systems have been investigated. The latest innovations resulted in even faster acting insulins, which may offer patients improved postprandial glucose control and greater flexibility regarding meal planning. PMID- 27933576 TI - [Medical certificates and examinations in family doctor's office. Indications, barriers and relevance of standardization]. AB - BACKGROUND: In view of medical care being required more and more, the doctors' tight time should be reserved for tasks which correspond to their qualification. A standardization of certificates might save time and improve quality. OBJECTIVE: This paper overviews the role of certificates and the required examinations in family doctor's everyday practice. Current practices, difficulties and suggestions for improvements were worked out in order to illuminate the potential for standardization. METHODS: In a questionnaire for family doctors data concerning expenditure of time and billing of diverse certificates were collected and quantitatively evaluated. By means of expert interviews difficulties were identified and suggestions for improvement were developed. RESULTS: The use of templates shows a significant saving of time compared to free wording. Also, billing could be enhanced if carried out more systematically. Difficulties are mainly caused by unclear and unrealistic requests. CONCLUSIONS: It's worth being proactive and developing a systematic approach in order to save time and to improve the quality of certificates. Templates facilitate modest certificates, while elaborate certificates need adjustable textmodules and checklists. Consistent information and billing promote patients' understanding. PMID- 27933577 TI - Environmental and health impacts of effluents from textile industries in Ethiopia: the case of Gelan and Dukem, Oromia Regional State. AB - This study focuses on four textile industries (DH-GEDA, NOYA, ALMHADI, and ALSAR) established between 2005 and 2008 in the peri-urban areas of Dukem and Gelan. The objectives of the study were to generate baseline information regarding the concentration levels of selected pollutants and to analyze their effects on biophysical environments. This study also attempts to explore the level of exposure that humans and livestock have to polluted effluents and the effects thereof. The findings of this study are based on data empirically collected from two sources: laboratory analysis of sample effluents from the four selected textile plants and quantitative as well as qualitative socioeconomic data collection. As part of the latter, a household survey and focus group discussions (FGDs) with elderly and other focal persons were employed in the towns of Dukem and Gelan. The results of the study show that large concentrations of biological oxygen demand (BOD5), chemical oxygen demand (COD), total suspended solids (TSS), and pH were found in all the observed textile industries, at levels beyond the permissible discharge limit set by the national Environmental Protection Authority (EPA). Furthermore, sulfide (S2), R-phosphate (R-PO43), and Zn were found in large concentrations in DH-GEDA and ALMHADI, while high concentrations were also identified in samples taken from ALSAR and ALMHADI. In spite of the clear-cut legal tools, this study shows that the local environment, people, and their livestock are exposed to highly contaminated effluents. We therefore recommend that the respective federal and regional government bodies should reexamine the compliance to and actual implementation of the existing legal procedures and regulations and respond appropriately. PMID- 27933578 TI - Inhibitory activity of Beauveria bassiana and Trichoderma spp. on the insect pests Xylotrechus arvicola (Coleoptera: Cerambycidae) and Acanthoscelides obtectus (Coleoptera: Chrisomelidae: Bruchinae). AB - Xylotrechus arvicola is an important pest in vineyards (Vitis vinifera) in the main Iberian wine-producing regions, and Acanthoscelides obtectus causes severe post-harvest losses in the common bean (Phaseolus vulgaris). Under laboratory conditions with a spray tower, the susceptibility of the immature stages of X. arvicola and A. obtectus against the entomopathogenic fungi Beauveria bassiana and four strains of Trichoderma spp. was evaluated. Both insect pests T. harzianum and B. bassiana showed a good inhibitory activity, accumulating an inhibition on the eggs of values above 85 and 82%, respectively. T. atroviride and T. citrinoviride had a lower inhibitory activity, with inhibition values of 74.1 and 73.3% respectively. These fungi can be considered a highly effective tool for the control during the immature stages of these species. PMID- 27933579 TI - Oligomerization and chaperone-like activity of Drosophila melanogaster small heat shock protein DmHsp27 and three arginine mutants in the alpha-crystallin domain. AB - The small Hsp DmHsp27 from Drosophila melanogaster is one of the few small heat shock proteins (sHsps) found within the nucleus. We report that its dimerization is independent of disulfide bond formation and seems to rely on salt bridges. Unlike metazoan sHsps, DmHsp27 forms two populations of oligomers not in equilibrium. Mutations at highly conserved arginine residues in mammalian sHsps have been reported to be associated with protein conformational defects and intracellular aggregation. Independent mutation of three highly conserved arginines (R122, R131, and R135) to glycine in DmHsp27 results in only one population of higher molecular weight form. In vitro, the chaperone-like activity of wild-type DmHsp27 was comparable with that of its two isolated populations and to the single population of the R122G, R131G, and R135G using luciferase as substrate. However, using insulin, the chaperone-like activity of wild-type DmHsp27 was lower than that of R122G and R131G mutants. Altogether, the results characterize wild-type DmHsp27 and its alpha-crystallin domain (ACD) arginine mutants and may give insight into protection mechanism of sHsps. PMID- 27933580 TI - Headache service quality: evaluation of quality indicators in 14 specialist-care centres. AB - BACKGROUND: The study was a collaboration between Lifting The Burden (LTB) and the European Headache Federation (EHF). Its aim was to evaluate the implementation of quality indicators for headache care Europe-wide in specialist headache centres (level-3 according to the EHF/LTB standard). METHODS: Employing previously-developed instruments in 14 such centres, we made enquiries, in each, of health-care providers (doctors, nurses, psychologists, physiotherapists) and 50 patients, and analysed the medical records of 50 other patients. Enquiries were in 9 domains: diagnostic accuracy, individualized management, referral pathways, patient's education and reassurance, convenience and comfort, patient's satisfaction, equity and efficiency of the headache care, outcome assessment and safety. RESULTS: Our study showed that highly experienced headache centres treated their patients in general very well. The centres were content with their work and their patients were content with their treatment. Including disability and quality-of-life evaluations in clinical assessments, and protocols regarding safety, proved problematic: better standards for these are needed. Some centres had problems with follow-up: many specialised centres operated in one-touch systems, without possibility of controlling long-term management or the success of treatments dependent on this. CONCLUSIONS: This first Europe-wide quality study showed that the quality indicators were workable in specialist care. They demonstrated common trends, producing evidence of what is majority practice. They also uncovered deficits that might be remedied in order to improve quality. They offer the means of setting benchmarks against which service quality may be judged. The next step is to take the evaluation process into non-specialist care (EHF/LTB levels 1 and 2). PMID- 27933583 TI - Looking Beyond the 5-HTTLPR Polymorphism: Genetic and Epigenetic Layers of Regulation Affecting the Serotonin Transporter Gene Expression. AB - Serotonin (5-HT) is a neurotransmitter that regulates fundamental aspects of brain development, physiology and behaviour. The serotonin transporter (5-HTT) is deputized to the reuptake of 5-HT from the intersynaptic space in the presynaptic neurons. 5-HTT governs duration and magnitude of 5-HT biological actions, acting as a master regulator of the fine-tuning of 5-HT signalling. Genetic variation at SLC6A4 gene locus, encoding 5-HTT, contributes to alteration in 5-HT reuptake. The 5-HTTLPR/rs25531/rs25532 polymorphisms located in the promoter region of SLC6A4 gene have been associated with stress-related psychopathology and functional brain phenotypes. Besides, further DNA variations in functional regulative elements located at 5' and 3' termini of the SLC6A4 gene influence transcriptional and post-transcriptional steps. Recently, epigenetic processes including SLC6A4 promoter methylation and transcript silencing by microRNA were shown to be involved in the aetiology of affective disorders. Furthermore, gene environment interactions such as early life stress often encompass epigenetic changes, which can stably mark the genome in response to environmental stimuli potentially altering gene expression across lifespan. Therefore, it seems well established that functional variations in the SLC6A4 gene expression can no longer be ascribed to the modulating 5-HTTLPR promoter polymorphism but need to be integrated with the contribution arising from other interactive elements and epigenetic mechanisms. In this review, we discuss genetic and epigenetic layers of regulation affecting SLC6A4 gene expression. An overview of human and cellular studies investigating the impact of these regulatory processes on SLC6A4 gene expression is provided. PMID- 27933582 TI - MicroRNA-181c Ameliorates Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats. AB - Chronic cerebral hypoperfusion (CCH) characterized by global cerebral ischemia is an important risk factor contributing to the development of dementia. MicroRNAs (miRNAs) play important roles in the cellular adaptation to long-term ischemia/hypoxia by turning off or on the expression of target genes. MiR-181c is widely expressed in the nervous system, and tripartite motif 2 (TRIM2) is one of its target genes. In this work, we had identified that progressive spatial memory deficiency was induced in the bilateral common carotid artery occlusion (2-VO) rat models. Meanwhile, inhibition of miR-181c expression and upregulation of TRIM2 in the hippocampus of 2-VO rats were found accompanying with reduction in the dendritic branching and dendrite spine density of the hippocampal neurons. Viral vector-mediated miR-181c delivery might improve the cognitive deficiency via TRIM2 on neurofilament light (NF-L) ubiquitination resulting in remodeling of the hippocampal neurons as well as increase in N-methyl-D-aspartate receptor 1 (NR1) subunit cell surface expression. Meanwhile, miR-181c might rescue the cellular activity from ischemia/hypoxia. These results indicated a novel miRNA mediated mechanism involving miR-181c and TRIM2 in the cognitive impairment induced by CCH and provided a rationale for the development of miRNA-based strategies for prevention of dementia. PMID- 27933585 TI - Effect of Rheology and Poloxamers Properties on Release of Drugs from Silicon Dioxide Gel-Filled Hard Gelatin Capsules-A Further Enhancement of Viability of Liquid Semisolid Matrix Technology. AB - The liquid and semisolid matrix technology, filling liquids, semi-solids and gels in hard gelatin capsule are promising, thus, there is a need of enhanced research interest in the technology. Therefore, the present study was aimed to investigate isoniazid (freely soluble) and metronidazole (slightly soluble) gels filled in hard gelatin capsules for the effect of poloxamers of different viscosities on release of the drugs. Gel of each drug (10% w/w, particle size 180-250 MUm), prepared by mixing poloxamer and 8% w/w hydrophilic silicon dioxide (Aerosil(r) A200), was assessed for rheology, dispersion stability and release profile. Both the drugs remained dispersed in majority of gels for more than 30 days, and dispersions were depended on gels' viscosity, which was further depended on viscosity of poloxamers. A small change in viscosity was noted in gels on storage. FTIR spectra indicated no interactions between components of the gels. The gels exhibited thixotropic and shear-thinning behaviour, which were suitable for filling in hard gelatin capsules without any leakage from the capsules. The release of both drugs from the phase-stable gels for 30 days followed first-order kinetics and was found to be correlated to drugs' solubility, poloxamers' viscosity, polyoxyethylene contents and proportion of block copolymer (poloxamers) in the gels. The findings of the present study indicated that release of drugs of different solubilities (isoniazid and metronidazole) might be modified from gels using different poloxamers and Aerosil(r) A200. PMID- 27933584 TI - Matrine Treatment Blocks NogoA-Induced Neural Inhibitory Signaling Pathway in Ongoing Experimental Autoimmune Encephalomyelitis. AB - Myelin-associated inhibitors, such as NogoA, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp), play a pivotal role in the lack of neuroregeneration in multiple sclerosis, an inflammatory demyelinating disease of the central nervous system (CNS). Matrine (MAT), a monomer that is used in traditional Chinese medicine as an anti-inflammatory agent, has shown beneficial effects in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, the underlying mechanisms of MAT-induced EAE amelioration are not fully understood. In the present study, we show that MAT treatment suppressed ongoing EAE, and this effect correlated with an increased expression of growth-associated protein 43, an established marker for axonal regeneration. MAT treatment significantly reduced the levels of NogoA, its receptor complex NgR/p75NTR/LINGO-1, and their downstream RhoA/ROCK signaling pathway in the CNS. In contrast, intracellular cyclic AMP (cAMP) levels and its protein kinase (protein kinase A (PKA)), which can promote axonal regrowth by inactivating the RhoA, were upregulated. Importantly, adding MAT in primary astrocytes in vitro largely induced cAMP/PKA expression, and blockade of cAMP significantly diminished MAT-induced expression of PKA and production of BDNF, a potent neurotrophic factor for neuroregeneration. Taken together, our findings demonstrate that the beneficial effects of MAT on EAE can be attributed not only to its capacity for immunomodulation, but also to its directly promoting regeneration of the injured CNS. PMID- 27933586 TI - Preparation and Optimization of Meropenem-Loaded Solid Lipid Nanoparticles: In Vitro Evaluation and Molecular Modeling. AB - Encapsulation of antibiotics into nanocarriers has the potential to overcome resistance and disadvantages associated with conventional dosage forms as well as increase half-life of an antibiotic. Encapsulation of meropenem (MRPN) into solid lipid nanoparticles (SLNs) remains unexplored among the limited work reported on nanoformulation incorporating MRPN. The study aimed to use an experimental design, to optimize MRPN-loaded SLNs, and to undertake in vitro and in silico evaluations. A Box-Behnken design (BBD) was used to optimize manufacturing conditions of glycerol monostearate (GMS) SLNs loaded with MRPN. The SLNs were prepared using hot homogenization and ultrasonication method. Optimized MRPN-SLNs showed particle size, zeta potential, and entrapment efficiency of 112.61 +/- 0.66 nm, -20.43 +/- 0.99 mV, and 89.94 +/- 1.26%, respectively. The morphology of the SLNs revealed nearly spherical shaped particles. Differential scanning calorimetry and X-ray diffraction analysis showed that meropenem was present in amorphous form in the SLNs. Controlled in vitro MRPN release from SLNs was achieved and followed the Korsmeyer-Peppas model (R 2 = 0.9679). Prolonged in vitro antibacterial activity against Escherichia coli was also observed. The molecular modeling showed that both hydrophobic interactions and hydrogen bonding led to a stable MRPN-GMS complex formation, which was confirmed by its low heat of formation (-5536.13 kcal/mol). This stable complex could have contributed to the controlled release of MRPN from the SLNs and subsequent sustained antibacterial activity. PMID- 27933587 TI - Development of a More Efficient Albumin-Based Delivery System for Gambogic Acid with Low Toxicity for Lung Cancer Therapy. AB - Gambogic acid (GA) has been proven to be a potent chemotherapeutic agent for the treatment of lung cancer in clinical trials. However, GA is limited in its therapeutic value by properties such as poor water solubility and low chemical stability. In clinical trials, cationic arginine (Arg) was added to solubilize GA, and this may also cause other side effects. Here, we have designed and developed a more efficient human serum albumin (HSA)-based delivery system for GA with low toxicity which helps improve its solubility, chemical stability and increases its antitumor efficacy. The GA-HSA nanoparticles (NPs) were prepared by albumin-bound (nabTM) technology, with a particle size of 135.2 +/- 35.03 nm, a zeta potential of -21.81 +/- 1.24 mV, and a high entrapment efficiency. Compared with GA-Arg solution, the physical and chemical stability of the NPs were improved when stored at pH 7.4 in PBS or freeze-dried. The in vitro drug release showed that GA-HSA NPs had a more sustained release than GA-Arg solution. Furthermore, HSA NPs improved the therapeutic efficacy of GA and were less toxic compared with GA-Arg solution in A549-bearing mice. Therefore, this delivery system is a promising polymeric carrier for GA when used for tumor therapy. PMID- 27933588 TI - MitraClip step by step; how to simplify the procedure. AB - The MitraClip system is a device for percutaneous edge-to-edge reconstruction of the mitral valve in patients with severe mitral regurgitation who are deemed at high risk for surgery. Studies have underlined the therapeutic benefit of the MitraClip system for patients at extreme and high risk for mitral valve surgery, suffering from either degenerative or functional mitral regurgitation. The MitraClip procedure shows low peri-procedural complication rates, and a significant reduction in mitral regurgitation, as well as an improvement in functional capacity and most importantly quality of life. It hereby widens the spectrum of mitral valve repair for the Heart Team. The current review underscores the efficacy of the procedure and describes the technique to simplify the procedure. PMID- 27933590 TI - Three dimensional rotational angiography for assessment of coronary arteries during melody valve implantation: introducing a technique that may improve outcomes. AB - BACKGROUND: Adverse events from Melody valve implantation may be catastrophic. To date a role for three dimensional rotational angiography of the aortic root (3DRAA) during Melody valve implantation has not been established. OBJECTIVES: To describe the role of 3DRAA in the assessment of Melody valve candidacy and to demonstrate that it may improve outcomes. METHODS: All patients who underwent cardiac catheterisation for Melody valve implantation and 3DRAA between August 2013 and February 2015 were reviewed. RESULTS: 31 patients had 3DRAA with balloon sizing. Ten were deemed not Melody candidates (5 coronary compression, 2 aortic root distortion with cusp flattening, 2 RVOT was too large, and 1 had complex branch stenosis and a short landing zone). Of the 21 patients who were Melody candidates, 12 had conduits, 6 prosthetic valves and 3 native RVOTs. In patients with conduits, the technique of stenting the conduit prior to dilation was used after measuring the distance between the conduit and the coronary arteries on 3DRAA. In the Melody patients, we had 100% procedural success and no serious adverse events (coronary compression, tears, stent fracture or endocarditis). CONCLUSION: As a tool for case selection, 3DRAA may facilitate higher procedural success and decreased risk of serious adverse events. Furthermore, 3D rotational angiography allows stenting of the conduit prior to dilation, which may prevent tears and possibly endocarditis. PMID- 27933591 TI - Charcoal hemoperfusion in the treatment of medically refractory pruritus in cholestatic liver disease. AB - BACKGROUND: Pruritus is a distressing symptom in a considerable proportion of cholestatic patients and a few of them do not respond to conventional treatment. Charcoal hemoperfusion (CH) is an extracorporeal technique that is effective in eliminating protein-bound substances which may have accumulated during cholestasis. Several case reports have shown significant reduction of bilirubin in mechanical jaundice and neonatal hemolytic jaundice. However, the published data of CH for the treatment of refractory pruritus in cholestatic patients are scarce. METHODS: Procedure code "Charcoal hemoperfusion" (90997) was used to identify patients who received CH at Mayo Clinic, Rochester, from 1 January 2000 to 5 January 2015. Patients who received CH for refractory cholestatic pruritus were retrospectively reviewed. RESULTS: Thirteen patients were identified. A median of 5 (range 1-18) sessions for a total of 20 (1-72) h were performed. CH resulted in a significant decrease of pruritus in nine patients (69%). Two patients did not have significant relief and two patients did not pursue further treatments after having adverse reactions during the first session. Median pruritus numerical rating scale significantly decreased from 9/10 (9-10) to 4/10 (0-9) post-treatment (p = 0.004). Duration of symptom-free periods ranged from 8 to 90 days (median 18 days) in six patients who returned for follow-up. Most common adverse reactions were pain, bleeding from the catheter site and fever. CONCLUSION: CH temporarily improves the severity of medically refractory cholestatic pruritus in some patients. However, the improvement is not sustained and the short duration of benefit should be balanced with the invasive nature of the therapy and the relatively common adverse reactions. PMID- 27933592 TI - Future challenges in understanding ROS in plant responses to abiotic stress. PMID- 27933593 TI - Inflammation-induced CD69+ Kupffer cell feedback inhibits T cell proliferation via membrane-bound TGF-beta1. AB - Kupffer cells, tissue-resident macrophage lineage cell, are enriched in vertebrate liver. The mouse F4/80+ Kupffer cells have been subclassified into two subpopulations according to their phenotype and function: CD68+ subpopulation with potent reactive oxygen species (ROS) production and phagocytic capacities, and CD11b+ subpopulation with a potent capacity to produce T helper 1 cytokines. In addition, CD11b+ Kupffer cells/macrophages may be migrated from the bone marrow or spleen, especially in inflammatory conditions of the liver. For analyzing diverse Kupffer cell subsets, we infected mice with Listeria monocytogenes and analyzed the phenotype variations of hepatic Kupffer cells. During L. monocytogenes infection, hepatic CD69+ Kupffer cells were significantly induced and expanded, and CD69+ Kupffer cells expressed higher level of CD11b, and particularly high level of membrane-bound TGF-beta1 (mTGF-beta1) but lower level of F4/80. We also found that clodronate liposome administration did not eliminate hepatic CD69+ Kupffer cell subset. We consider the hepatic CD69+ Kupffer cell population corresponds to CD11b+ Kupffer cells, the bone marrow derived population. Hepatic CD69+ Kupffer cells suppressed Ag-nonspecific and OVA specific CD4 T cell proliferation through mTGF-beta1 both in vitro and in vivo, meanwhile, they did not interfere with activation of CD4 T cells. Thus, we have identified a new subset of inflammation-induced CD69+ Kupffer cells which can feedback inhibit CD4 T cell response via cell surface TGF-beta1 at the late stage of immune response against infection. CD69+ Kupffer cells may contribute to protect host from pathological injure by preventing overactivation of immune response. PMID- 27933594 TI - Vegetable Peel Waste for the Production of ZnO Nanoparticles and its Toxicological Efficiency, Antifungal, Hemolytic, and Antibacterial Activities. AB - Zinc oxide (ZnO) nanoparticles (NPs) are important materials when making different products like sun screens, textiles, and paints. In the current study, the photocatalytic effect of prepared ZnO NPs from Moringa oleifera (M. oleifera) was evaluated on degradation of crystal violet (CV) dye, which is largely released from textile industries and is harmful to the environment. Preliminarily, ZnO NP formation was confirmed using a double beam ultraviolet visible (UV-Vis) spectrophotometer; further, the NP size was estimated using XRD analysis and the functional group analysis was determined using Fourier transform infrared (FT-IR) spectroscopy. The morphology of the synthesized NPs was found to be a hexagonal shape using SEM and TEM analysis and elemental screening was analyzed using EDX. ZnO NPs were shown sized 40-45 nm and spherical in shape. The degradation percentage of ZnO NPs was calculated as 94% at 70 min and the rate of the reaction -k = 0.0282. The synthesized ZnO NPs were determined for effectiveness on biological activities such as antifungal, hemolytic, and antibacterial activity. ZnO NPs showed good antifungal activity against Alternaria saloni and Sclerrotium rolfii strains. Further, we have determined the hemolytic and antibacterial activity of ZnO NPs and we got successive results in antibacterial and hemolytic activities. PMID- 27933595 TI - Potential New Approaches to Modifying Intestinal GLP-1 Secretion in Patients with Type 2 Diabetes Mellitus : Focus on Bile Acid Sequestrants. AB - Type 2 diabetes mellitus is associated with a progressive decline in insulinproducing pancreatic beta-cells, an increase in hepatic glucose production, and a decrease in insulin sensitivity. The incretin hormones glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) stimulate glucose-induced insulin secretion; however, in patients with type 2 diabetes, the incretin system is impaired by loss of the insulinotropic effects of GIP as well as a possible reduction in secretion of GLP-1. Agents that modify GLP-1 secretion may have a role in the management of type 2 diabetes. The currently available incretin-based therapies, GLP-1 receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 (DPP-4) inhibitors (CD26 antigen inhibitors) [incretin enhancers], are safe and effective in the treatment of type 2 diabetes. However, they may be unable to halt the progression of type 2 diabetes, perhaps because they do not increase secretion of endogenous GLP-1. Therapies that directly target intestinal L cells to stimulate secretion of endogenous GLP-1 could possibly prove more effective than treatment with GLP-1 receptor agonists and DPP-4 inhibitors. Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes include G-protein-coupled receptor (GPCR) agonists, alpha-glucosidase inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, metformin, bile acid mimetics and bile acid sequestrants. Both the GPCR agonist AR231453 and the novel bile acid mimetic INT 777 have been shown to stimulate GLP-1 release, leading to increased insulin secretion and improved glucose tolerance in mice. Similarly, a study in insulin resistant rats demonstrated that the bile acid sequestrant colesevelam increased GLP-1 secretion and improved glucose levels and insulin resistance. In addition, the bile acid sequestrant colestimide (colestilan) has been shown to increase GLP 1 secretion and decrease glucose levels in patients with type 2 diabetes; these results suggest that the glucose-lowering effects of bile acid sequestrants may be partly due to their ability to increase endogenous GLP-1 levels. Evidence suggests that GPCR agonists, alpha-glucosidase inhibitors, PPAR agonists, metformin, bile acid mimetics and bile acid sequestrants may represent a new approach to management of type 2 diabetes via modification of endogenous GLP-1 secretion. PMID- 27933596 TI - Reduction in Healthcare and Societal Resource Utilization Associated with Cladribine Tablets in Patients with Relapsing-Remitting Multiple Sclerosis : Analysis of Economic Data from the CLARITY Study. AB - BACKGROUND: Multiple sclerosis (MS) is a common, chronic, neurodegenerative condition associated with substantial healthcare and societal economic burden. Disease-modifying MS treatments have the potential to reduce health resource utilization (HRU), thereby reducing the attendant socioeconomic burden. OBJECTIVE: This study aimed to compare health and societal resource use and productivity in patients with relapsing-remitting MS (RRMS) receiving cladribine tablets versus placebo over 96 weeks in the CLARITY study. METHODS: The CLARITY study was a 96-week, randomized, double-blind, placebo-controlled study in patients with RRMS. HRU data, societal resource use and productivity data were collected at baseline and during scheduled patient visits, at 6-month intervals. The recall period for the HRU questionnaire was 3 months. The study was carried out at 155 sites across 32 countries worldwide. The intent-to-treat population comprised 1326 patients with RRMS randomized to cladribine 3.5 mg/kg (n = 433) or 5.25 mg/kg (n = 456) tablets or placebo (n = 437). Patient subgroups with high baseline disease activity were identified based on criteria of >=2 relapses in the previous year (n = 392); >=1 T1 gadolinium-enhancing (Gd+) lesion (n = 413); and >=2 relapses in the previous year plus >=1 T1 Gd+ lesion (n= 138). Cladribine tablets were administered in two (3.5 mg/kg group) or four (5.25 mg/kg group) short courses given at 4-week intervals at the start of a 48-week treatment period, followed by another two courses at the start of a subsequent 48-week re treatment period. Interferon-beta rescue therapy was permitted from week 24. Intravenous corticosteroids were available for the treatment of neurological relapses. HRU outcomes included mean number of hospital days and emergency room (ER), clinic and home visits during each study period. Societal resource use and productivity outcomes included mean number of hours and days of paid assistance, mean patient and carer work days missed, and self-reported productivity. RESULTS: The mean number of hospital days per patient over 96 weeks was lower in the cladribine tablets groups (3.5 mg/kg group: -3.19 days; 5.25 mg/kg group: -1.54 days [both p<0.01]) versus placebo. Likewise the mean number of ER visits was lower in both cladribine tablet groups compared with placebo (3.5 mg/kg group: 0.09 visits; 5.25 mg/kg group: -0.11 visits [both p<0.01]), and the mean number of clinic visits was also lower in both cladribine tablet groups (3.5 mg/kg group: -0.68 visits; 5.25 mg/kg group: -0.66 visits [both p = 0.01]). Furthermore, treatment with cladribine tablets was associated with reduced mean numbers of missed work days for patients (3.5 mg/kg group: -2.42 days [p < 0.01]; 5.25 mg/kg group: -0.60 days [p = 0.50]). Corticosteroid use was lower amongst patients in the cladribine tablet groups than in the placebo group. The reduction in hospital days following treatment with cladribine tablets was also observed in patients with high disease activity at study baseline. CONCLUSION: This study provides evidence that the efficacy of cladribine tablets observed during the CLARITY study was associated with a reduced consumption of healthcare resources and a decreased need for medical and societal support. PMID- 27933597 TI - Efficacy and Safety of Dutasteride in Chinese Adults with Symptomatic Benign Prostatic Hyperplasia : A Randomized, Double-Blind, Parallel-Group, Placebo Controlled Study with an Open-Label Extension. AB - BACKGROUND: Dutasteride is a dual inhibitor of type I and type II 5alpha reductases and provides nearly complete suppression of dihydrotestosterone, which plays a key role in the aetiology and development of benign prostatic hyperplasia (BPH). Most knowledge about the efficacy and safety of dutasteride in BPH derives from three pivotal phase III studies conducted primarily in Caucasian populations. OBJECTIVE: This study aimed to evaluate the efficacy and safety of dutasteride in Chinese adults with symptomatic BPH. METHODS: This was a randomized, double-blind, parallel-group, placebo-controlled study conducted over 6 months, followed by an open-label extension of 12 months. A total of 253 BPH subjects with a total prostate volume (TPV) of >=30 cm3, a maximal urinary flow rate (Qmax) between 5 and 15 mL/s, and an American Urology Association Symptom Index (AUA-SI) score of >=12 units were randomized to dutasteride 0.5 mg/day orally or matching placebo treatment in a 1 : 1 ratio. After 6 months, eligible subjects who volunteered to enter the open-label extension received dutasteride 0.5 mg/day orally. Changes in TPV, Qmax and AUA-SI as well as drug safety were evaluated. RESULTS: Dutasteride significantly reduced mean TPV compared with placebo at 3 and 6 months (both p<0.05). At 6 months, mean TPV decreased by 17.14% versus 3.71% in the dutasteride and placebo groups, respectively. Numerically higher improvements in Qmax and AUA-SI were observed in the dutasteride group at 3 and 6 months, but there was no statistically significant difference between treatment groups. However, ad hoc analysis indicated that, at 6 months, significantly higher proportions of subjects in the dutasteride group experienced a Qmax improvement of >=3 mL/s, or an AUA-SI improvement of >=1 unit, compared with the placebo group (both p<0.05). According to these criteria, the Qmax responder rates were 33.63% and 19.83% in the dutasteride- and placebo treated groups, respectively, and the AUA-SI responder rates were 87.61% and 76.92%, respectively. During the open-label extension, continuous improvements in TPV, Qmax and AUA-SI were noted in both groups. Dutasteride was well tolerated with a low incidence of treatment-related adverse events over 18 months. CONCLUSION: Dutasteride was effective compared with placebo in the treatment of symptomatic BPH among Chinese patients. The efficacy data from trials involving subjects of different ethnic origins showed some similarities. Dutasteride was generally well tolerated during the study period. PMID- 27933598 TI - Therapeutic Efficacy and Tolerability of the Topical Treatment of Inflammatory Conditions of the Oral Cavity with a Mouthwash Containing Diclofenac Epolamine : A Randomized, Investigator-Blind, Parallel-Group, Controlled, Phase III Study. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac, are the mainstay of analgesic and anti-inflammatory treatment in dentistry. Diclofenac epolamine [diclofenac N-(2-hydroxyethyl)pyrrolidine; DHEP] is a diclofenac salt with greater water solubility and better cutaneous absorption properties than other commonly used forms of the drug. IBSA has recently developed a mouthwash formulation of DHEP for the topical treatment of inflammatory conditions of the oral cavity. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of DHEP mouthwash (Osmal(r)) with that of a reference product (commercially available diclofenac mouthwash). METHODS: This was a randomized, investigator-blind, parallel-group, controlled, phase III study that enrolled 80 patients with conditions affecting the oral cavity, characterized by an inflammatory component, and eligible for analgesic and anti inflammatory treatment. Patients were randomized 1 : 1 to DHEP mouthwash (0.103% DHEP in aqueous solution) or to diclofenac mouthwash (0.074% free diclofenac in aqueous solution). The treatment regimen was the same in both groups: 1-minute rinse with 15 mL of mouthwash, twice daily for 7 days. Visits were scheduled at study inclusion (D0), and 3 days (D3) and 7 days (D7) after treatment initiation. During each visit assessments were made of pain severity (using a 5-point semi quantitative scale and a 100-mm visual analogue scale [VAS]) and inflammatory signs (using a 5-point scale). The primary study endpoint was the change in pain severity scores from D0 to D3 and D7. Secondary endpoints included effects of treatment on inflammation score, quality of sleep, compliance with treatment and the safety and tolerability of treatment. RESULTS: The two treatment arms were homogeneous in terms of patient characteristics. The most prevalent oral condition was gingivitis. Overall both topical treatments were effective in alleviating pain and inflammation, as evidenced by decreases in pain and inflammation scores within 3 days after treatment initiation. Notably, a significantly greater proportion of patients treated with DHEP were free of pain and inflammatory symptoms at D3 compared with those treated with the diclofenac mouthwash (40% vs 20% of patients; p<0.05). Also, DHEP was associated with more marked, but not statistically significant, decreases in VAS pain scores versus baseline after 3 days' treatment. Compliance with both treatments was good and both mouthwashes were well tolerated. CONCLUSION: DHEP mouthwash was at least as effective as diclofenac mouth-wash at alleviating pain and inflammation symptoms and is well tolerated in patients with painful inflammatory conditions of the oral cavity. The potential of DHEP mouthwash deserves to be investigated in a larger patient population. PMID- 27933599 TI - Safety and Tolerability of High-Dose Budesonide/Formoterol via Turbuhaler(r) in Japanese Patients with Asthma : A Randomized, Double-Blind, Crossover, Active Comparator-Controlled, Phase III Study. AB - BACKGROUND: The use of budesonide/formoterol as both maintenance and reliever therapy in asthma is recommended in many countries; however, there are limited data available for the Asian patient population. OBJECTIVE: This study aimed to evaluate the short-term safety and tolerability of a fixed high-dose combination of the inhaled corticosteroid budesonide and the long-acting beta2-adrenoceptor agonist formoterol with that of the beta2-agonist terbutaline for acute symptom relief in Japanese adults with persistent asthma who were already receiving a combination of budesonide/formoterol maintenance therapy. METHODS: This was a randomized, double-blind, crossover, active comparator-controlled, phase III study. Patients aged 16-65 years with persistent asthma received either budesonide/formoterol 160 mg/4.5 mg ten inhalations daily for 3 days via Turbuhaler(r) or terbutaline 0.4 mg ten inhalations daily for 3 days via Turbuhaler(r), in addition to budesonide/formoterol 160 MUg/4.5 mg one inhalation twice daily as maintenance treatment. After a 7- to 14-day washout period, patients crossed over to receive the other medication for a further 3 days. Adverse events (AEs), clinical laboratory variables, 12-lead electrocardiogram (ECG) and vital signs were assessed throughout. RESULTS: Twenty-five patients (mean age 44.3 years, 40% female) were randomized and received at least one dose of study medication. Overall, 14 AEs were reported in 12 out of 25 patients (48%) during high-dose budesonide/ formoterol therapy and 24 AEs were reported in 14 out of 23 patients (61%) during terbutaline therapy. The majority of AEs were mild in intensity and no serious AEs were reported. The most common AEs were tremor (12%) during budesonide/formoterol therapy and tremor (17%), palpitations (13%), tachycardia (13%) and decreased serum potassium (13%) during terbutaline therapy. There were no clinically significant differences from baseline or between groups in laboratory values, vital signs or ECG recordings. CONCLUSION: Budesonide/formoterol 160 MUg/4.5 mg ten inhalations daily for 3 days in addition to ongoing budesonide/formoterol 160 MUg/4.5 MUg one inhalation twice daily maintenance therapy was well tolerated in Japanese adults with persistent asthma. PMID- 27933600 TI - Dose Proportionality and Pharmacokinetics of Fentanyl Buccal Soluble Film in Healthy Subjects : A Phase I, Open-Label, Three-Period, Crossover Study. AB - BACKGROUND AND OBJECTIVES: Fentanyl buccal soluble film (FBSF) is a small, bilayered, water-soluble polymer film (BioErodible MucoAdhesive; BEMATM) that adheres to the buccal mucosa and rapidly delivers fentanyl into the systemic circulation. It is approved for the treatment of cancer breakthrough pain in adult opioid-tolerant patients. The objective of this study was to evaluate the dose proportionality of the pharmacokinetics of FBSF in healthy subjects across a range of doses. METHODS: This was a phase I, open-label, single-dose, three period, Latin-square crossover study in which 12 healthy subjects received single FBSF doses of 200, 600 and 1200 MUg with 72 hours between doses. Oral naltrexone was administered to each subject prior to and after each study dose. Serial venous blood samples were collected for 48 hours after study drug administration. Adverse events were recorded throughout the study. Dose linearity was examined using a power model (P=a*Doseb), where P represents the dependent variable (maximum plasma drug concentration [Cmax], area under the plasma concentration time curve [AUC] from time zero to time of the last measurable concentration [AUClast], or AUC from time zero to infinity [AUCinfinity]), and a and b are constants. A value of b ~ 1 indicated linearity. RESULTS: Following administration of FBSF doses of 200-1200 MUg, mean Cmax values increased in a linear manner with values ranging from 0.383 ng/mL to 2.19ng/mL, respectively. Mean AUClast values increased from 3.001 ng ./mL to 19.17 ng.h/mL and mean AUCinfinity increased in a linear manner from 3.456 ng.h/mL to 20.43 ng .h/mL. All reported adverse events were considered to be mild to moderate in severity. CONCLUSIONS: This study demonstrates that peak fentanyl plasma concentrations and overall exposure increase in a dose-proportional manner following administration of FBSF. PMID- 27933601 TI - Breast Cancer Outlook for 2017: Keeping the Accelerator to the Floor. PMID- 27933603 TI - 12th European Congress on Epileptology, Prague, Czech Republic, 11-15 September, 2016. PMID- 27933602 TI - Fish tales: The use of zebrafish xenograft human cancer cell models. AB - Advances in scientific techniques have provided researchers with exceptional new opportunities to identify and monitor changes between different cancer types, during different stages of progression, between individual tumor cells and in the surrounding stroma. The wealth of information that can be obtained from new scientific techniques places additional requirements on the conventional cancer models. New models that could be used to rapidly access the (potential) functional importance of newly identified (epi)genetic and proteomic changes and test the efficacy on emerging (combinatorial) therapies are desperately required. The distinctive characteristics of zebrafish are progressively being applied to create more relevant models of human diseases. Zebrafish embryos provide a powerful tool to develop functional cancer models. This is a tool that can be used from drug discovery and development to assessment of drug toxicity. This review will summarise the use of zebrafish xenograft models to study human cancers, and discuss the benefits and limitations of these models. PMID- 27933604 TI - Chemoresistant lung cancer stem cells display high DNA repair capability to remove cisplatin-induced DNA damage. AB - BACKGROUND AND PURPOSE: The persistence of lung cancer stem cells (LCSCs) has been proposed to be the main factor responsible for the recurrence of lung cancer as they are highly resistant to conventional chemotherapy. However, the underlying mechanisms are still unclear. EXPERIMENTAL APPROACH: We examined the cellular response of a human LCSC line to treatment with cisplatin, a DNA damaging anticancer drug that is used extensively in the clinic. We compared the response to cisplatin of LCSCs and differentiated LCSCs (dLCSCs) by determining the viability of these cells, and their ability to accumulate cisplatin and to implement genomic and transcription-coupled DNA repair. We also investigated the transcription profiles of genes related to drug transport and DNA repair. KEY RESULTS: LCSCs were found to be more stem-like, and more resistant to cisplatin induced cytotoxicity than dLCSCs, confirming their drug resistance properties. LCSCs accumulated less cisplatin intracellularly than dLCSCs and showed less DNA damage, potentially due to their ability to down-regulate AQP2 and CTR1. The results of the transcription-coupled repair of cisplatin-DNA cross-links indicated a higher level of repair of DNA damage in LCSCs than in dLCSCs. In addition, LCSCs showed a greater ability to repair cisplatin-DNA interstrand cross-links than dLCSCs; this involved the activation of various DNA repair pathways. CONCLUSIONS AND IMPLICATIONS: Our results further clarify the mechanism of cisplatin resistance in LCSCs in terms of reduced cisplatin uptake and enhanced ability to implement DNA repairs. These findings may aid in the design of the next-generation of platinum-based anticancer drugs. PMID- 27933605 TI - Barriers to spousal contribution to childbirth pain relief in Nigeria. AB - AIM: The aim of this study was to investigate the barriers inhibiting the use of spousal presence for childbirth pain relief in health facilities and recommendations from three perspectives: the midwife, the woman, and the spouse. BACKGROUND: Spousal presence is a non-invasive, participatory and inexpensive technique used in pain management during childbirth. Although it contributes to a large extent in relieving childbirth pain, it is underutilized in Nigerian hospitals. Overcoming the challenges impeding spousal presence and participation during childbirth will improve maternal outcome, satisfaction and midwifery care practices. METHOD: A cross-sectional survey conducted in four hospitals in Nigeria involving midwives (n = 100), women (n = 142) and their spouses (n = 142) from June to December 2014 using pretested questionnaires. RESULTS: Five themes were identified: poor infrastructural facility, lack of adequate pain management policy, lack of midwife pain management practices, midwives' attitudes towards spousal presence during childbirth and feelings about spousal presence during childbirth pain relief. CONCLUSION: Infrastructural defects in the health facilities resulting in the lack of privacy in maternity units for both spouses and partners negatively influence the presence of a spouse during childbirth and pain relief. Adopting effective strategies such as good infrastructural facilities, staff training and spouse-friendly hospital policies will encourage spouses to fully participate in and contribute to childbirth pain relief. IMPLICATIONS FOR NURSING AND HEALTH POLICY: This study identified poor staff attitudes towards pain relief and spousal presence during childbirth as barriers. Providing adequate policies on pain management, continuous staff education and orientation on spousal relationship will improve active spousal participation and maternal satisfaction during childbirth. PMID- 27933607 TI - Erratum. PMID- 27933606 TI - Relaxin-like peptides in male reproduction - a human perspective. AB - : The relaxin family of peptide hormones and their cognate GPCRs are becoming physiologically well-characterized in the cardiovascular system and particularly in female reproductive processes. Much less is known about the physiology and pharmacology of these peptides in male reproduction, particularly as regards humans. H2-relaxin is involved in prostate function and growth, while insulin like peptide 3 (INSL3) is a major product of the testicular Leydig cells and, in the adult, appears to modulate steroidogenesis and germ cell survival. In the fetus, INSL3 is a key hormone expressed shortly after sex determination and is responsible for the first transabdominal phase of testicular descent. Importantly, INSL3 is becoming a very useful constitutive biomarker reflecting both fetal and post-natal development. Nothing is known about roles for INSL4 in male reproduction and only very little about relaxin-3, which is mostly considered as a brain peptide, or INSL5. The former is expressed at very low levels in the testes, but has no known physiology there, whereas the INSL5 knockout mouse does exhibit a testicular phenotype with mild effects on spermatogenesis, probably due to a disruption of glucose homeostasis. INSL6 is a major product of male germ cells, although it is relatively unexplored with regard to its physiology or pharmacology, except that in mice disruption of the INSL6 gene leads to a disruption of spermatogenesis. Clinically, relaxin analogues may be useful in the control of prostate cancer, and both relaxin and INSL3 have been considered as sperm adjuvants for in vitro fertilization. LINKED ARTICLES: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc. PMID- 27933608 TI - Assessing fear learning via conditioned respiratory amplitude responses. AB - Respiratory physiology is influenced by cognitive processes. It has been suggested that some cognitive states may be inferred from respiration amplitude responses (RAR) after external events. Here, we investigate whether RAR allow assessment of fear memory in cued fear conditioning, an experimental model of aversive learning. To this end, we built on a previously developed psychophysiological model (PsPM) of RAR, which regards interpolated RAR time series as the output of a linear time invariant system. We first establish that average RAR after CS+ and CS- are different. We then develop the response function of fear-conditioned RAR, to be used in our PsPM. This PsPM is inverted to yield estimates of cognitive input into the respiratory system. We analyze five validation experiments involving fear acquisition and retention, delay and trace conditioning, short and medium CS-US intervals, and data acquired with bellows and MRI-compatible pressure chest belts. In all experiments, CS+ and CS- are distinguished by their estimated cognitive inputs, and the sensitivity of this distinction is higher for model-based estimates than for peak scoring of RAR. Comparing these data with skin conductance responses (SCR) and heart period responses (HPR), we find that, on average, RAR performs similar to SCR in distinguishing CS+ and CS-, but is less sensitive than HPR. Overall, our work provides a novel and robust tool to investigate fear memory in humans that may allow wide and straightforward application to diverse experimental contexts. PMID- 27933609 TI - The role of electrical and jasmonate signalling in the recognition of captured prey in the carnivorous sundew plant Drosera capensis. AB - The carnivorous sundew plant (Drosera capensis) captures prey using sticky tentacles. We investigated the tentacle and trap reactions in response to the electrical and jasmonate signalling evoked by different stimuli to reveal how carnivorous sundews recognize digestible captured prey in their traps. We measured the electrical signals, phytohormone concentration, enzyme activities and Chla fluorescence in response to mechanical stimulation, wounding or insect feeding in local and systemic traps. Seven new proteins in the digestive fluid were identified using mass spectrometry. Mechanical stimuli and live prey induced a fast, localized tentacle-bending reaction and enzyme secretion at the place of application. By contrast, repeated wounding induced a nonlocalized convulsive tentacle movement and enzyme secretion in local but also in distant systemic traps. These differences can be explained in terms of the electrical signal propagation and jasmonate accumulation, which also had a significant impact on the photosynthesis in the traps. The electrical signals generated in response to wounding could partially mimic a mechanical stimulation of struggling prey and might trigger a false alarm, confirming that the botanical carnivory and plant defence mechanisms are related. To trigger the full enzyme activity, the traps must detect chemical stimuli from the captured prey. PMID- 27933610 TI - Resilience Mediates Impact of Some Childhood Maltreatment on Post-Traumatic Stress Symptoms in Conscripted Marines in the Republic of Korea. AB - Although it is known that post-traumatic stress symptoms (PTSS) can result from military service, the variance in PTSS unexplained by military service warrants further investigation, and no researchers have investigated South Korean Marines' vulnerability during their 2-year conscripted service as the first line of national defense against threats from North Korea. This study was designed to examine whether resilience mediated the relationship between childhood maltreatment and PTSS in 169 Korean conscripts into the Marine Corps. In a cross sectional study design, the Childhood Trauma Questionnaire-Short Form was used to measure childhood maltreatment, including abuse and neglect. The Impact of Event Scale-Revised and the Connor-Davidson Resilience Scale were used to measure PTSS and resilience. Structural equation modeling was used for data analysis. Half the conscripts reported at least one type of childhood maltreatment, and 22.3% had high PTSS, even in a short period of service. Childhood abuse was significantly associated with PTSS during military service, a relationship that was not mediated by resilience. However, resilience mediated the relationship between childhood neglect and PTSS during military service. Assessment of childhood maltreatment and resilience prior to military service is crucial for identifying conscripts at increased risk for PTSS during even brief military service. In addition to direct interventions for abuse effects among all Marines, interventions enhancing resilience may benefit conscripts who experienced childhood neglect. (c) 2016 Wiley Periodicals, Inc. PMID- 27933611 TI - A Review of "Peripheral Nerve Blocks for the Treatment of Headache in Older Adults: A Retrospective Study". PMID- 27933612 TI - Discussion of "A risk-based measure of time-varying prognostic discrimination for survival models," by C. Jason Liang and Patrick J. Heagerty. PMID- 27933613 TI - Rejoinder to discussions on: A risk-based measure of time-varying prognostic discrimination for survival models. PMID- 27933614 TI - Antiviral agents for infectious mononucleosis (glandular fever). AB - BACKGROUND: Infectious mononucleosis (IM) is a clinical syndrome, usually caused by the Epstein Barr virus (EPV), characterised by lymphadenopathy, fever and sore throat. Most cases of symptomatic IM occur in older teenagers or young adults. Usually IM is a benign self-limiting illness and requires only symptomatic treatment. However, occasionally the disease course can be complicated or prolonged and lead to decreased productivity in terms of school or work. Antiviral medications have been used to treat IM, but the use of antivirals for IM is controversial. They may be effective by preventing viral replication which helps to keep the virus inactive. However, there are no guidelines for antivirals in IM. OBJECTIVES: To assess the effects of antiviral therapy for infectious mononucleosis (IM). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, March 2016), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (1946 to 15 April 2016), Embase (1974 to 15 April 2016), CINAHL (1981 to 15 April 2016), LILACS (1982 to 15 April 2016) and Web of Science (1955 to 15 April 2016). We searched the World Health Organization (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov for completed and ongoing trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing antivirals versus placebo or no treatment in IM. We included trials of immunocompetent participants of any age or sex with clinical and laboratory confirmed diagnosis of IM, who had symptoms for up to 14 days. Our primary outcomes were time to clinical recovery and adverse events and side effects of medication. Secondary outcomes included duration of abnormal clinical examination, complications, viral shedding, health-related quality of life, days missing from school or work and economic outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, assessed the included studies' risk of bias and extracted data using a customised data extraction sheet. We used the GRADE criteria to rate the quality of the evidence. We pooled heterogeneous data where possible, and presented the results narratively where we could not statistically combine data. MAIN RESULTS: We included seven RCTs with a total of 333 participants in our review. Three trials studied hospitalised patients, two trials were conducted in an outpatient setting, while the trial setting was unclear in two studies. Participants' ages ranged from two years to young adults. The type of antiviral, administration route, and treatment duration varied between the trials. The antivirals in the included studies were acyclovir, valomaciclovir and valacyclovir. Follow-up varied from 20 days to six months. The diagnosis of IM was based on clinical symptoms and laboratory parameters.The risk of bias for all included studies was either unclear or high risk of bias. The quality of evidence was graded as very low for all outcomes and so the results should be interpreted with caution. There were statistically significant improvements in the treatment group for two of the 12 outcomes. These improvements may be of limited clinical significance.There was a mean reduction in 'time to clinical recovery as assessed by physician' of five days in the treatment group but with wide confidence intervals (CIs) (95% CI 8.04 to -1.08; two studies, 87 participants). Prospective studies indicate that clinical signs and symptoms may take one month or more to resolve and that fatigue may be persistent in approximately 10% of patients at six-month follow up, so this may not be a clinically meaningful result.Trial results for the outcome 'adverse events and side effects of medication' were reported narratively in only five studies. In some reports authors were unsure whether an adverse event was related to medication or complication of disease. These results could not be pooled due to the potential for double counting results but overall, the majority of trials reporting this outcome did not find any significant difference between treatment and control groups.There was a mean reduction in 'duration of lymphadenopathy' of nine days (95% CI -11.75 to -6.14, two studies, 61 participants) in favour of the treatment group.In terms of viral shedding, the overall effect from six studies was that viral shedding was suppressed while on antiviral treatment, but this effect was not sustained when treatment stopped.For all other outcomes there was no statistically significant difference between antiviral treatment and control groups. AUTHORS' CONCLUSIONS: The effectiveness of antiviral agents (acyclovir, valomaciclovir and valacyclovir) in acute IM is uncertain. The quality of the evidence is very low. The majority of included studies were at unclear or high risk of bias and so questions remain about the effectiveness of this intervention. Although two of the 12 outcomes have results that favour treatment over control, the quality of the evidence of these results is very low and may not be clinically meaningful. Alongside the lack of evidence of effectiveness, decision makers need to consider the potential adverse events and possible associated costs, and antiviral resistance. Further research in this area is warranted. PMID- 27933615 TI - Immediate-release versus controlled-release carbamazepine in the treatment of epilepsy. AB - BACKGROUND: Carbamazepine (CBZ) is a commonly used drug for epilepsy that is associated with troublesome adverse events including dizziness, double vision, drowsiness, poor co-ordination and unsteadiness. These adverse events often occur during peaks in drug plasma concentration. These adverse events may limit the daily dose of CBZ that can be tolerated and reduce the chances of seizure control in patients who require high doses. A controlled-release formulation of CBZ delivers the same dose over a longer period of time when compared to a standard immediate-release formulation, thereby reducing post-dose peaks in CBZ plasma concentration and potentially reducing adverse events.This is an updated version of the original Cochrane review published in Issue 12, 2014. OBJECTIVES: To determine the efficacy of immediate-release CBZ (IR CBZ) versus controlled release CBZ (CR CBZ) in patients diagnosed with epilepsy.The following review questions were investigated.(1) For newly diagnosed patients commencing CBZ, how do IR and CR formulations compare for efficacy and tolerability?(2) For patients on established treatment with IR CBZ but experiencing unacceptable adverse events, what is the effect on seizure control and the tolerability of a switch to a CR formulation versus remaining on the IR formulation? SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register, CENTRAL, and MEDLINE (Ovid) from inception to 30 August 2016. SELECTION CRITERIA: Randomised controlled trials comparing IR CBZ to CR CBZ in patients commencing monotherapy and patients presently treated with IR CBZ but experiencing unacceptable adverse events.Primary outcome measures included measures of seizure frequency, incidence of adverse events, proportion of patients with treatment failure and quality of life measures. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted the data and recorded relevant information on a standardised data extraction form. We used the Cochrane risk of bias tool to assess the methodological quality of included studies.The heterogeneity of the included trials with respect to the reporting of outcomes resulted in only a narrative, descriptive analysis being possible for both the categorical and time-to-event data. MAIN RESULTS: Ten trials (296 participants) fulfilled the criteria for inclusion in this review. Only one study had a low risk of bias. Two studies had a high risk of bias and the rest of the studies were rated as unclear risk of bias. One trial included patients with newly diagnosed epilepsy and nine included patients on treatment with IR CBZ.Eight trials reported heterogeneous measures of seizure frequency with conflicting results. A statistically significant difference was observed in only one trial, with patients prescribed CR CBZ experiencing fewer seizures than patients prescribed IR CBZ.Nine trials reported measures of adverse events. There was a trend in favour of CR CBZ with four trials reporting a statistically significant reduction in adverse events compared to IR CBZ. A further two trials reported fewer adverse events with CR CBZ but the reduction was not statistically significant. One trial found no difference in adverse events, and another trial reported more adverse events in the CR CBZ group than the IR CBZ group, although the increase was not statistically significant. AUTHORS' CONCLUSIONS: For this update no new eligible studies were identified and the conclusions drawn from the initial review remain unchanged.At present, data from trials do not confirm or refute an advantage for CR CBZ over IR CBZ for seizure frequency or adverse events in patients with newly diagnosed epilepsy.For trials involving epilepsy patients already prescribed IR CBZ, no conclusions can be drawn concerning the superiority of CR CBZ with respect to seizure frequency.There is a trend for CR CBZ to be associated with fewer adverse events when compared to IR CBZ. A change to CR CBZ may therefore be a worthwhile strategy in patients with acceptable seizure control on IR CBZ but experiencing unacceptable adverse events. The included trials were of small size and of poor methodological quality limiting the validity of this conclusion.Randomised controlled trials comparing CR CBZ to IR CBZ and using clinically relevant outcomes are required to inform the choice of CBZ preparation for patients with newly diagnosed epilepsy. PMID- 27933616 TI - Efficacy of preoperative ibuprofen and meloxicam on the success rate of inferior alveolar nerve block for teeth with irreversible pulpitis. AB - OBJECTIVE: The purpose of this study was to determine whether premedication with ibuprofen or meloxicam increases the success rate of anaesthesia in teeth with irreversible pulpitis. MATERIALS AND METHODS: In this parallel, double-blind clinical trial, 92 patients diagnosed with irreversible pulpitis were randomly divided into four groups of 23 patients. The first group (the no-premedication group) received no premedication, the second group (the meloxicam group) received 7.5 mg of meloxicam, the third group (the ibuprofen group) received 600 mg of ibuprofen, and the fourth group (the placebo group) received placebo 1 hour before intervention. Before taking the medication, electrical pulp testing (EPT) and the Heft-Parker visual analogue scale (VAS) were used to evaluate sensitivity and pain at baseline. Then, local anaesthesia was injected, and after 15 minutes, EPT was used again to evaluate tooth sensitivity. The pain during access preparation was also recorded using the Heft-Parker VAS. RESULTS: Ninety-two patients were analysed. The success rates of local anaesthesia were 21.7%, 34.8%, 78.3% and 73.9% in the no-premedication, placebo, ibuprofen and meloxicam groups, respectively, according to the EPT values. Considering the Heft-Parker VAS values, no premedication gave a 21.7% success rate, placebo gave a 34.8% success rate, ibuprofen gave an 82.6% success rate and meloxicam gave a 65.2% success rate. The ibuprofen and meloxicam groups showed significantly better results than the placebo and no-premedication groups (P < 0.001). However, the difference between meloxicam and ibuprofen groups was not significant. CONCLUSIONS: Premedication with meloxicam and ibuprofen significantly increased the success rates of inferior alveolar nerve block anaesthesia for teeth with irreversible pulpitis; however, neither drug provided profound anaesthesia. PMID- 27933617 TI - Shining a light on AHG "blind" spot(s). PMID- 27933618 TI - Erratum. PMID- 27933619 TI - Monocyte-mediated activation of endothelial cells occurs only after binding to extracellular vesicles from red blood cell products, a process mediated by beta integrin. AB - BACKGROUND: Red blood cell (RBC) transfusion is associated with organ failure. The mechanism remains unknown, but may include adherence of blood cells to the microvasculature. We hypothesized that RBC-derived extracellular vesicles (EVs) interact with monocytes to activate endothelial cells. STUDY DESIGN AND METHODS: Human umbilical vein endothelial cells were incubated with supernatant from fresh and stored RBC units either containing EVs or depleted from EVs, with or without the addition of immune cells. We measured expression of adhesion markers by flow cytometry and markers of coagulation and inflammation in the culture medium. We studied phagocytosis of EVs by monocytes by using confocal microscopy and flow cytometry. RESULTS: Incubation of endothelial cells with monocytes alone did not induce up regulation of adhesion markers. The addition of both monocytes and supernatant from RBCs containing EVs resulted in up regulation of endothelial expression of intercellular adhesion molecule 1 and E-selectin when compared to baseline. Up regulation was absent when stimulated with RBC supernatant depleted from EVs. EVs are phagocytosed by monocytes, which was partly abrogated after coincubation with two different complement receptor 3 (CR3)-blocking antibodies. Addition of RBC-derived EVs also increased levels of von Willebrand factor (VWF). There were no differences between groups related to storage time. CONCLUSION: EVs from RBC transfusion bags activate monocytes with subsequent up regulation of endothelial cell adhesion markers. EVs are phagocytosed by monocytes through CR3. Furthermore, these EVs proved to be a source of VWF. These effects are unrelated to storage time. Thereby, EVs from RBC transfusion bags induce a proinflammatory and procoagulant endothelial cell response. PMID- 27933620 TI - Platelet transfusion reactions do not occur more often in recipients transfused with apheresis versus buffy coat platelet concentrates. PMID- 27933621 TI - Donor card. PMID- 27933622 TI - Erratum. PMID- 27933623 TI - Documentation of transfusion-transmitted arbovirus infections in endemic areas. PMID- 27933625 TI - Comment on transfusion management of Factor V deficiency. PMID- 27933626 TI - The power of collaboration. PMID- 27933627 TI - Response to Trans-2016-0405.R1. PMID- 27933628 TI - In reply. PMID- 27933629 TI - Accepting hereditary hemochromatosis blood donors: ask not why, ask why not. PMID- 27933630 TI - Comparison of cartilage with temporalis fascia tympanoplasty: A meta-analysis of comparative studies. AB - OBJECTIVE: To systematically review the results of type 1 tympanoplasty with temporalis fascia (TF) versus cartilage in patients with chronic otitis media (COM) for graft integration and hearing improvement. DATA SOURCES: The English language literature (until June 1, 2016) was searched, using Medline (via PubMed), Scopus, ProQuest, Ovid, Cochrane database, and Google Scholar. REVIEW METHODS: A comprehensive review of the literature was performed. Prospective and retrospective studies enrolling patients with COM were included. Relevance and validity of selected articles were evaluated. Heterogeneity was assessed using I2 statistics. For dichotomous variables, absolute rate differences, and number needed to treat (NNT) were calculated. For continuous variables, standard mean differences were calculated. RESULTS: A total of 11 prospective and 26 retrospective studies involving 3,606 patients were included. In general, the overall graft integration rates of cartilage and fascia tympanoplasty were 92% and 82%, respectively (NNT = 11.1, P < 0.001). Although there was no significant difference in the air-bone gap (ABG) closure of < 10 dB between the two groups, the subanalysis of prospective studies showed that patients in the TF group had less mean postoperative ABG (P = 0.02). Subgroup analysis of palisade grafts compared with that of TF graft revealed a significant difference in the graft integration rate favoring cartilage tympanoplasty (P = 0.01). CONCLUSION: Cartilage grafting seemed to show a higher graft integration rate compared with TF grafting. Both cartilage and fascia tympanoplasty provided similar improvements in the hearing outcome postoperatively. Large prospective trials are necessary to collect high-quality data. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2139-2148, 2017. PMID- 27933631 TI - Hemicrania Continua-Like Headache Related to Transdermal Nitroglycerine Therapy. AB - Several cases of symptomatic hemicrania continua (HC) have been reported. A 66 year-old man, suffering from migraine without aura, presented with a four month history of a new headache fulfilling the ICHD 3beta clinical criteria for HC. HC onset was strictly related to the use of transdermal nitroglycerine patch (TNP). In agreement with the cardiologist, TNP was discontinued and the headache promptly disappeared; symptoms reappeared within 6-12 hours after nitroglycerine reintroduction. After permanent discontinuation of TNP, headache disappeared at one year follow-up. To the best of our knowledge, this is the first report of the occurrence of an HC-like headache related to TNP. PMID- 27933632 TI - Association of alirocumab therapy with inflammatory lesions of the vocal folds: A case report. AB - Therapeutic monocolonal antibodies (MAbs) are a new, rapidly growing class of medications that frequently have poorly characterized side-effect profiles. We present a patient who developed inflammatory lesions of the vocal folds in temporal relation to the initiation of alirocumab. Lesions of the vocal folds represent a previously unreported adverse effect of alirocumab therapy, making it the second MAb documented with such a side effect. The potential laryngeal effects of alirocumab specifically, and of MAbs more broadly, warrant investigation. Laryngoscope, 127:1652-1654, 2017. PMID- 27933633 TI - Discussion of "A risk-based measure of time-varying prognostic discrimination for survival models," by C. Jason Liang and Patrick J. Heagerty. PMID- 27933634 TI - Middle cranial fossa approach to repair tegmen defects assisted by three dimensionally printed temporal bone models. AB - OBJECTIVES/HYPOTHESIS: To explore the perioperative utility of three dimensionally (3D)-printed temporal bone models of patients undergoing repair of lateral skull base defects and spontaneous cerebrospinal fluid leaks with the middle cranial fossa approach. STUDY DESIGN: Case series. METHODS: 3D-printed temporal bone models-based on patient-specific, high-resolution computed tomographic imaging-were constructed using inexpensive polymer materials. Preoperatively, the models demonstrated the extent of temporal lobe retraction necessary to visualize the proposed defects in the lateral skull base. Also preoperatively, Silastic sheeting was arranged across the modeled tegmen, marked, and cut to cover all of the proposed defect sites. The Silastic sheeting was then sterilized and subsequently served as a precise intraoperative template for a synthetic dural replacement graft. Of note, these grafts were customized without needing to retract the temporal lobe. RESULTS: Five patients underwent the middle cranial fossa approach assisted by 3D-printed temporal bone models to repair tegmen defects and spontaneous cerebrospinal fluid leaks. No complications were encountered. The prefabricated dural repair grafts were easily placed and fit precisely onto the middle fossa floor without any additional modifications. All defects were covered as predicted by the 3D temporal bone models. At their postoperative visits, all five patients maintained resolution of their spontaneous cerebrospinal fluid leaks. CONCLUSIONS: Inexpensive 3D-printed temporal bone models of tegmen defects can serve as beneficial adjuncts during lateral skull base repair. The models provide a panoramic preoperative view of all tegmen defects and allow for custom templating of dural grafts without temporal lobe retraction. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:2347-2351, 2017. PMID- 27933635 TI - Vietnamese Version of Diabetes Self-Management Instrument: Development and Psychometric Testing. AB - Self-management plays a vital role in diabetes management for adults with type 2 diabetes (T2DM). While there are many people with T2DM in Vietnam, clinical understanding of diabetes self-management (DSM) in this context is limited due to the lack of a valid measurement instrument. Translation and back-translation processes were used to translate the Diabetes Self-Management Instrument (DSMI) into Vietnamese. Then, translation equivalence, face validity, construct validity, and internal consistency were assessed in a sample of 198 Vietnamese adults with T2DM. The Cronbach's alpha of the V-DSMI was .92, with a number of significant inter-item correlations. The Vietnamese version of the Diabetes Self Management Instrument (V-DSMI) retained the meaning of the original English version, and the language of the V-DSMI was clearly understandable to adults with T2DM in Vietnam. Confirmatory factor analysis supported the goodness of fit between the data and the previously identified factor structure. These results indicated that the V-DSMI is acceptable for use with Vietnamese adults with T2DM in further practice and research. However, future studies would be beneficial to determine the test-retest reliability and criterion validity of the V-DSMI. (c) 2016 Wiley Periodicals, Inc. PMID- 27933636 TI - Primary Headaches in an Elderly Population Seeking Medical Care for Cognitive Decline. AB - OBJECTIVES: To assess the prevalence of specific headache disorders in a population older than 65 years seeking consultation due to memory problems or cognitive impairment. METHODS: We verified the occurrence of headache symptoms and the impact of headaches on daily life. Headaches were classified as per the International Classification of Headache Disorders, 2nd edition (ICHD-2). All patients were screened with the Mini-Mental State Examination (MMSE), followed by the Selective Reminding Test and neuroimaging. Participants with severe cognitive impairment or dementia were excluded. RESULTS: A total of 1,237 patients (51.6% women), with mean age of 75.6 years (SD = 6.9) were screened from January 2006 to December 2014. Of them, 302 (24.4%) patients suffered from headaches. Most common individual diagnoses were probable migraine (13.8%), episodic tension-type headache (3.4%), and episodic migraine (3.0%). Chronic migraine or probable chronic migraine happened in 3.5%, while chronic tension-type headache affected 0.6%. Most patients with headaches routinely used symptomatic medications (55.6%). Mean MMSE scores were similar in patients with or without headaches, or with different headache diagnoses. CONCLUSIONS: Headache disorders overall, frequent headaches, and headaches requiring treatment are commonly seen in the elderly seeking care for cognitive decline and should be properly assessed and managed. PMID- 27933637 TI - Association of Temporal Variations in Staffing With Hospital-Acquired Pressure Injury in Military Hospitals. AB - To more precisely evaluate the effects of nurse staffing on hospital-acquired pressure injury (HAPI) development, data on nursing care hours per patient day (NCHPPD), nursing skill mix, patient turnover (i.e., admissions, transfers, and discharges), and patient acuity were merged with patient information from pressure injury prevalence surveys that were collected annually for the Military Nursing Outcomes Database (MilNOD) project. The MilNOD included staffing and adverse events from 56 medical-surgical, stepdown, and critical care units in 13 military hospitals over a 4-year-period. Data on 1,643 patients were analyzed with Cox proportional hazards models and generalized estimating equations. Staffing was not associated with pressure injuries in stepdown or critical care patients. However, among the 1,104 medical-surgical patients, higher licensed practical nurse (LPN) nursing care hours per patient day (NCHPPD) 3 days and 1 week prior to the HAPI discovery date were associated with fewer HAPI (HR 0.27, p < .001), after controlling for patient age, Braden mobility score, and albumin level. Neither total staff number, nor RN NCHPPD, nor the proportion of staff who were RNs (RN skill mix) were associated with HAPI. These findings suggest that on military medical-surgical units, LPNs play a major role in HAPI prevention. Although the national trend in acute care is to staff hospital units with more RNs and patient care technicians, and fewer LPNs, hospitals should reconsider LPNs as valuable members of the nursing care team. (c) 2016 Wiley Periodicals, Inc. PMID- 27933638 TI - Nursing interventions for smoking cessation in hospitalized patients: a systematic review. AB - AIM: This study aimed to clarify the role of nurses in planning and implementation of nursing interventions related to smoking cessation. BACKGROUND AND INTRODUCTION: Nearly half of all smokers die from smoking-related illnesses. Quitting smoking can reduce these problems. Smoking cessation interventions include various types helping smokers successfully quit. Studies suggest that hospitalization can be a golden opportunity for nurses helping patients to quit smoking because of No Smoking regulations. METHOD: A systematic review of the literature was carried through Web of Knowledge, ProQuest, Medscape, MedlinePlus, Ovid SID, Magiran, PubMed, and Science Direct databases between 1990-2015 on the subject of interest by keywords: role of nursing in smoking cessation, nursing intervention in smoking cessation, smoking cessation, smoking quitting and interventions planned by nurse. RESULT: Nineteen papers were systematic examined, dealing with smoking cessation interventions by nurses. Totally, 17 studies used counselling for quitting smoking. Most studies involved other methods such as manuals, pamphlets, brochures training or printed educational materials, audio and video file. Some studies used nicotine replacement methods for patients such as nicotine skin tags, chewing nicotine or bupropion. Moreover, 17 studies were conducted by telephone at patients' follow-up after hospital discharge. CONCLUSION: Nurses' interventions for smoking cessation play an important role in helping patients quit smoking successfully. There are a variety of interventions that nurses can employ according to the patient's condition and diagnosis of different diseases. IMPLICATION FOR NURSING AND HEALTH POLICY: Quitting smoking can reduce lung cancers and other health problems. Nurses play an important role in helping patients to quit smoking. PMID- 27933639 TI - Assessment of left atrial volume and function by real time three-dimensional echocardiography in obese patients. AB - OBJECTIVE: To evaluate left atrial (LA) volume and functions in obese subjects using real time three-dimensional echocardiography (RT3DE) and also the relationship between LA mechanical functions and N-terminal pro-atrial natriuretic peptide (NT-proANP). METHODS: This study included 40 obese (26 females and 14 males, mean age 51.9 years) and 40 normal weight subjects (23 females and 16 males, mean age 53.5 years) with normal coronary angiograms. All the study participants underwent RT3DE to assess LA volume and mechanical function. Plasma NT-proANP was determined by ELISA method. RESULTS: There was no significant difference between groups in left ventricular (LV) diameters and ejection fraction, which reflect LV systolic function. However, transmitral deceleration time, isovolumetric relaxation time, and peak late diastolic tissue Doppler velocity values, which reflect LV diastolic function, were found to be significantly higher in obese subjects when compared with controls. LA maximum volume (LAVmax), LAVmax index (LAVI), LA minimal volume (LAVmin), before atrial contraction volume (LAVpreA), LA active emptying volume, LA total emptying volume, and LA active emptying fraction, which reflect LA reservoir and pump functions, were also higher in obese subjects when compared with controls. LA passive emptying fraction was significantly lower in obese subjects than in controls. NT-proANP levels were similar between groups. There were positive correlations between NT-proANP level and LAVI, LAVmax, LAVmin, LAVpreA, and LA total and active emptying volumes. CONCLUSIONS: Left atrial mechanical functions and volumes are impaired in obese subjects. These findings may be regarded as early markers of subclinical cardiac failure in obese subjects who have not yet exhibited any clinical evidence of cardiovascular disease. PMID- 27933640 TI - Tricuspid annular plane systolic excursion as a marker of right ventricular dysfunction in pediatric patients with dilated cardiomyopathy. AB - BACKGROUND: Right ventricular systolic dysfunction (RVSD) is a predictor of outcomes in dilated cardiomyopathy (DCM) in adults, but little is known in children. Tricuspid annular plane systolic excursion (TAPSE) has emerged as a reliable tool to assess RVSD. We sought to determine the prevalence and prognostic significance of RVSD using TAPSE in children with DCM. METHODS: The first echocardiogram at the time of diagnosis with DCM was analyzed to obtain left ventricular ejection fraction (LVEF) and 2D TAPSE. RVSD was defined as TAPSE age-based z-score <=-2. The association of a composite primary endpoint including death, mechanical support, or transplantation with RVSD was analyzed using LVEF and TAPSE. RESULTS: Of the 96 patients, RVSD was noted in 84 (88%). During a median follow-up of 17.5 months (IQR 1.4, 76.2), the primary endpoints were reached in 59%. There was a lower LVEF in patients with RVSD (P=.016). Moderate or severe RVSD showed a significant association with the composite primary endpoint (unadjusted OR 2.7 [95% CI: 1.15-6.33], P=.023). Kaplan-Meier analysis showed that the event-free survival was significantly lower in patients with LVEF <=30% and TAPSE z-score <=-4. CONCLUSION: Children with DCM have a high prevalence of RVSD based on reduced TAPSE, and those with moderate or severe RVSD have worse clinical outcomes. PMID- 27933641 TI - Method of B0 mapping with magnitude-based correction for bipolar two-point Dixon cardiac MRI. AB - PURPOSE: The conventional two-point (2pt) Dixon technique explicitly estimates B0 map by performing phase unwrapping. When signal loss, phase singularity, artifacts, or spatially isolated regions corrupt the measured phase images, this unwrapping-based technique will face difficulty. This work aims to improve the reliability of B0 mapping by performing unwrapping error correction. METHOD: To detect the unwrapping-caused phase errors, we determined a magnitude-based fat/water mask and used it as reference to identify pixels being mismatched by the phase-based mask, which was derived from the B0-corrected phase term of the Hermitian product between echoes. Then, we corrected the afore-determined phase error on a region-by-region basis. We tested the developed method with nine patients' data, and the results were compared with a well-established region growing technique. RESULTS: By adding the step to correct unwrapping-caused error, we improved the robustness of B0 mapping, resulting in better fat-water separation when compared with the conventional 2pt and the phasor-based region growing techniques. CONCLUSION: We showed the feasibility of B0 mapping with bipolar 2pt human cardiac data. The software is freely available to the scientific community. Magn Reson Med 78:1862-1869, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27933642 TI - Bilateral choanal atresia in an adult woman with pycnodysostosis. PMID- 27933643 TI - Syntaxin 4a Regulates Matrix Vesicle-Mediated Bone Matrix Production by Osteoblasts. AB - Osteoblasts secrete matrix vesicles and proteins to bone surfaces, but the molecular mechanisms of this secretion system remain unclear. The present findings reveal the roles of important genes in osteoblasts involved in regulation of extracellular matrix secretion. We especially focused on "soluble N ethylmaleimide-sensitive factor (NSF) attachment protein receptor" (SNARE) genes and identified notable Syntaxin 4a (Stx4a) expression on the basolateral side of the plasma membrane of osteoblasts. Furthermore, Stx4a overexpression was found to increase mineralization by osteoblastic cells, whereas Stx4a knockdown reduced levels of mineralization. Also, BMP-4 and IGF-1 induced the localization of Stx4a to the basolateral side of the cells. To examine the function of Stx4a in osteoblasts, we generated osteoblast-specific Stx4a conditional knockout mice, which demonstrated an osteopenic phenotype due to reduced matrix secretion. Bone mineral density, shown by peripheral quantitative computed tomography (pQCT), was reduced in the femur metaphyseal and diaphyseal regions of Stx4a osteoblast specific deficient mice, whereas bone parameters, shown by micro-computed tomography (MUCT) and bone histomorphometric analysis, were also decreased in trabecular bone. In addition, primary calvarial cells from those mice showed decreased mineralization and lower secretion of matrix vesicles. Our findings indicate that Stx4a plays a critical role in bone matrix production by osteoblasts. (c) 2016 American Society for Bone and Mineral Research. PMID- 27933644 TI - Quantitative determination and evaluation of Paris polyphylla var. yunnanensis with different harvesting times using UPLC-UV-MS and FT-IR spectroscopy in combination with partial least squares discriminant analysis. AB - A rapid method was developed and validated by ultra-performance liquid chromatography-triple quadrupole mass spectroscopy with ultraviolet detection (UPLC-UV-MS) for simultaneous determination of paris saponin I, paris saponin II, paris saponin VI and paris saponin VII. Partial least squares discriminant analysis (PLS-DA) based on UPLC and Fourier transform infrared (FT-IR) spectroscopy was employed to evaluate Paris polyphylla var. yunnanensis (PPY) at different harvesting times. Quantitative determination implied that the various contents of bioactive compounds with different harvesting times may lead to different pharmacological effects; the average content of total saponins for PPY harvested at 8 years was higher than that from other samples. The PLS-DA of FT-IR spectra had a better performance than that of UPLC for discrimination of PPY from different harvesting times. PMID- 27933645 TI - Aflatoxin biomarkers in hair may facilitate long-term exposure studies. AB - Aflatoxins are highly toxic fungal metabolites produced by some members of the Aspergillus species. They are low molecular weight lipophilic compounds that are easily absorbed from the gastrointestinal tract. They contaminate most staple foods, including maize, peanuts, peanut butter and sorghum mainly in the tropics where hot and humid conditions promote fungal growth. Absorbed aflatoxins are metabolized by the cytochrome P450 enzyme system in the liver into toxic metabolites. Aflatoxin B (AFB)1 is the most toxic, carcinogenic and mutagenic naturally occurring toxin. Aflatoxin exposure assessment has been traditionally achieved through food use frequency questionnaires and laboratory analysis of food samples. However, estimation of individual exposure to aflatoxins based on these methods may not be accurate. The use of aflatoxin biomarkers in urine and blood for use in exposure studies has emerged in more recent times. However, the current biomarkers (e.g., AFB-N7 -guanine and AFB1 -albumin adduct) in use have a short half-life and are only practically useful to indicate levels over 24 h-3 months post-exposure. There is therefore an immediate need to study and evaluate alternative biomarkers in non-conventional matrices such as hair and nails. Hair analysis revealed considerable interest in forensic analysis particularly in the detection of drugs of abuse where it has emerged as a sensitive and specific technique complementary to blood and urinalysis. This article provides an overview of aflatoxins, current aflatoxin biomarkers and proposes the use of hair as a potential matrix for biomarkers of long-term aflatoxin exposure. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27933646 TI - Antisperm antibodies in repeat-breeding cows: Frequency, detection and validation of threshold levels employing sperm immobilization, sperm agglutination and immunoperoxidase assay. AB - Antisperm antibodies have been found in repeat-breeding(RB) cows, and those causing agglutination and/or immobilization of sperm are considered to be closely related to unexplained infertility. However, a standard protocol for identifying antisperm antibodies (ASA) in cattle is not validated. Therefore, an investigation was undertaken to evaluate sperm immobilization (SIT), sperm agglutination (SAT) and immunoperoxidase (IPT)assays for detection of ASA in serum and their respective threshold levels for confirmation. Animals (heifers, normally breeding, repeat-breeding and pregnant animals) that were free from IBR, brucellosis and uterine infections (screened by clinical examination) were included in the study. Sperm agglutinating, sperm immobilizing and antisperm antibodies evaluated by respective assay were significantly higher (p < .05) in RB cows compared to other groups. The SIT assay was able to identify 61% of RB caused by ASA, more than those employing SAT and IPT. Furthermore, a dilution rate of 1:5 and 1:80 (confirms 59.0 and 57.0% RB+ve)were sufficient to diagnose ASA by SAT and IPT, respectively. Results indicate the presence of __12.6% clumped spermatozoa and __ 2.6%(cut-off value) peroxidase-positive spermatozoa at 1:5 and 1:80 dilutions diagnosed with SAT and IPT, respectively, may be considered as repeaters arising out of ASA. Furthermore, study also showed the presence of lower incidence of ASA positivity in other groups of animals (heifer=40 years with two consecutive DXA scans and who were not receiving osteoporosis treatment at baseline (baseline mean age 62 +/- 10 years). We examined BMD and TBS change, osteoporosis treatment, and incident major osteoporotic fractures (MOFs) for each individual. Over a mean of 7.7 years follow-up, 770 women developed an incident MOF. During the interval between the two DXA scans (mean, 4.1 years), 5083 women initiated osteoporosis treatment (bisphosphonate use 80%) whereas 3961 women did not receive any osteoporosis treatment. Larger gains in both BMD and TBS were seen in women with greater adherence to osteoporosis medication (p for trend <0.001), and the magnitude of the increase was consistently greater for BMD than for TBS. Among treated women there was greater antifracture effect for each SD increase in total hip BMD change (fracture decrease 20%; 95% CI, 13% to 26%; p < 0.001), femoral neck BMD change (19%; 95% CI, 12% to 26%; p < 0.001), and lumbar spine BMD change (9%; 95% CI, 0% to 17%; p = 0.049). In contrast, change in TBS did not predict fractures in women who initiated osteoporosis treatment (p = 0.10). Among untreated women neither change in BMD or TBS predicted fractures. We conclude that, unlike antiresorptive treatment-related changes in BMD, change in lumbar spine TBS is not a useful indicator of fracture risk irrespective of osteoporosis treatment. (c) 2016 American Society for Bone and Mineral Research. PMID- 27933659 TI - Reviewers List 2016. PMID- 27933657 TI - Analysis of temozolomide resistance in low-grade gliomas using a mechanistic mathematical model. AB - Understanding how tumors develop resistance to chemotherapy is a major issue in oncology. When treated with temozolomide (TMZ), an oral alkylating chemotherapy drug, most low-grade gliomas (LGG) show an initial volume decrease but this effect is rarely long lasting. In addition, it has been suggested that TMZ may drive tumor progression in a subset of patients as a result of acquired resistance. Using longitudinal tumor size measurements from 121 patients, the aim of this study was to develop a semi-mechanistic mathematical model to determine whether resistance of LGG to TMZ was more likely to result from primary and/or from chemotherapy-induced acquired resistance that may contribute to tumor progression. We applied the model to a series of patients treated upfront with TMZ (n = 109) or PCV (procarbazine, CCNU, vincristine) chemotherapy (n = 12) and used a population mixture approach to classify patients according to the mechanism of resistance most likely to explain individual tumor growth dynamics. Our modeling results predicted acquired resistance in 51% of LGG treated with TMZ. In agreement with the different biological effects of nitrosoureas, none of the patients treated with PCV were classified in the acquired resistance group. Consistent with the mutational analysis of recurrent LGG, analysis of growth dynamics using mathematical modeling suggested that in a subset of patients, TMZ might paradoxically contribute to tumor progression as a result of chemotherapy induced resistance. Identification of patients at risk of developing acquired resistance is warranted to better define the role of TMZ in LGG. PMID- 27933660 TI - Are nutraceuticals the modern panacea? From myth to science. PMID- 27933661 TI - Mutations in the NEB gene cause fetal akinesia/arthrogryposis multiplex congenita. AB - OBJECTIVE: We studied a series of patients with fetal akinesia deformation sequence (FADS)/arthrogryposis multiplex congenita (AMC), with nemaline bodies on muscle specimens, which revealed mutations in the NEB gene. METHOD: We pathologically assessed seven cases from three families, who presented with AMC/FADS. Targeted genetic analysis for Ashkenazi Jewish mutation (in relevant patients) was followed by next-generation sequencing and multiplex ligation dependent probe amplification. RESULTS: All cases were detected on prenatal ultrasound. Characteristic nemaline bodies on muscle specimens were demonstrated in at least one case in each of the nuclear families. In the Ashkenazi Jewish family, the known founder mutation was compounded by one recurrent novel splice site. The other two families were of Chinese and Korean origins, and only one pathogenic heterozygous mutation was detected in each. CONCLUSIONS: Nemaline myopathy due to NEB mutation(s) leads to FADS/AMC. Currently, mutated NEB is under-recognized as a cause for AMC/FADS. Our study attempts to raise recognition of this gene as a cause, suggesting the NEB gene should be included in genetic panels used for FADS/AMC cases and be fully covered when EXOME sequencing is utilized. A heterozygous mutation may suggest either compounding undetected one or digenic interaction that requires further genetic analyses. (c) 2016 John Wiley & Sons, Ltd. PMID- 27933662 TI - Evidence of Staphylococcus Aureus Deformation, Proliferation, and Migration in Canaliculi of Live Cortical Bone in Murine Models of Osteomyelitis. AB - Although Staphylococcus aureus osteomyelitis is considered to be incurable, the major bacterial reservoir in live cortical bone has remained unknown. In addition to biofilm bacteria on necrotic tissue and implants, studies have implicated intracellular infection of osteoblasts and osteocytes as a mechanism of chronic osteomyelitis. Thus, we performed the first systematic transmission electron microscopy (TEM) studies to formally define major reservoirs of S. aureus in chronically infected mouse (Balb/c J) long bone tissue. Although rare, evidence of colonized osteoblasts was found. In contrast, we readily observed S. aureus within canaliculi of live cortical bone, which existed as chains of individual cocci and submicron rod-shaped bacteria leading to biofilm formation in osteocyte lacunae. As these observations do not conform to the expectations of S. aureus as non-motile cocci 1.0 to 1.5 MUm in diameter, we also performed immunoelectron microscopy (IEM) following in vivo BrdU labeling to assess the role of bacterial proliferation in canalicular invasion. The results suggest that the deformed bacteria: (1) enter canaliculi via asymmetric binary fission; and (2) migrate toward osteocyte lacunae via proliferation at the leading edge. Additional in vitro studies confirmed S. aureus migration through a 0.5-MUm porous membrane. Collectively, these findings define a novel mechanism of bone infection, and provide possible new insight as to why S. aureus implant-related infections of bone tissue are so challenging to treat. (c) 2016 American Society for Bone and Mineral Research. PMID- 27933663 TI - 3p26.3 terminal deletions: a challenge for prenatal genetic counseling. PMID- 27933664 TI - Left ventricular rotational mechanics in infants with hypoxic ischemic encephalopathy and preterm infants at 36 weeks postmenstrual age: A comparison with healthy term controls. AB - BACKGROUND AND AIMS: There is a paucity of data on left ventricle (LV) rotational physiology in neonates. We aimed to assess rotational mechanics in infants with hypoxic ischemic encephalopathy (HIE) and premature infants (<32 weeks) at 36 weeks postmenstrual age (PMA) (preterm group) and compare them with healthy term controls (term controls). We also compared the parameters in preterm infants with and without chronic lung disease (CLD). METHODS: Echocardiography was performed within 48 hours of birth or at 36 weeks PMA. LV basal and apical rotation, twist (and torsion=twist/LV length), twist rate (LVTR), and untwist rate (LVUTR) were measured. One-way ANOVA was used to compare values. RESULTS: There was no difference in gestation (40.0 [39.1-40.3] vs 39.9 [39.0-40.9], P>.05) or birthweight (3.7 [3.4-4.1] vs 3.5 [3.2-3.9], P>.05) between the HIE group (n=16) and term controls (n=30). The preterm group (n=35) had a gestation and weight of 36.0 [34.6-36.3] weeks and 2.3 [2.0-2.4] kg. The HIE group had lower twist, torsion, LVTR, and LVUTR than the other two groups. The preterm group had a more negative (clockwise) basal rotation while the term group had a more positive (counterclockwise) apical rotation. Preterm infants with CLD had higher apical rotation, twist, and torsion when compared to infants without CLD. CONCLUSION: Infants with HIE have reduced rotational mechanics. Preterm infants at 36 weeks PMA have comparable measurements of twist to term infants. This is achieved by predominant basal rather than apical rotation. Infants with CLD have increased apical rotation. PMID- 27933665 TI - Detection of DNA sequences from a novel papillomavirus in a feline basal cell carcinoma. AB - BACKGROUND: Basal cell carcinomas (BCCs) are uncommon feline skin neoplasms of uncertain cause. CASE: A 14-year-old Abyssinian cat developed a soft dermal nodule on the dorsal thorax. This mass grew slowly over a six month period before being surgically excised. METHODS AND RESULTS: Histology revealed a BCC. Additionally, changes suggestive of an early Bowenoid in situ carcinoma (BISC) were present in the overlying epidermis. Both the BCC and the BISC contained papillomavirus-induced cell changes and prominent basophilic intracytoplasmic bodies. PCR using consensus primers and primers specific for Felis catus papillomavirus types 2 and 3 (FcaPV-2 and -3) was used to amplify papillomaviral DNA. The same papillomaviral DNA sequence was present in the BCC and the BISC. This sequence was most similar to FcaPV-3, but with just 70.5% similarity, was from a novel papillomavirus type. No recurrence or further masses developed. CONCLUSIONS: This case is unusual due to the presence of a large dermal BCC associated with minimal BISC changes in the overlying epidermis. Additionally, papillomavirus-induced cell changes have not been described previously in a BCC. Furthermore, both the BCC and the BISC contained sequences from a novel papillomavirus type. These observations suggest that the development of some BCCs could be influenced by papillomavirus infection. The novel papillomavirus type detected is the third papillomavirus type to be associated with skin cancer in cats. PMID- 27933666 TI - Risk of Stroke and Recurrence After AF Ablation in Patients With an Initial Event Free Period of 12 Months. AB - INTRODUCTION: Because of the unclear prognostic effects of ablation of atrial fibrillation (AF), oral anticoagulation (OAC) is often continued after ablation even in asymptomatic patients. We sought to determine the frequency of stroke and AF recurrence in patients on and off therapeutic OAC 1 year after a successful AF ablation. METHODS AND RESULTS: Patients that underwent AF ablation and were free of AF 12 months after ablation were selected from our AF database. During follow up (FU), patients were screened for recurrence of AF, changes in OAC or antiarrhythmic medication, and the occurrence of stroke or transient ischemic attack (TIA). A total of 398 patients (median age 60.7 years [50.8, 66.8], 25% female) were investigated. The median duration of FU was 529 (373, 111,3.5) days. OAC was discontinued in 276 patients (69.3%). During FU, 4 patients (1%) suffered from stroke and 55 patients (13.8%) experienced a recurrence of AF. Persistent AF was significantly associated with a greater chance of AF recurrence (49.1% vs. 26.8%; P = 0.001). Neither CHADS2 nor CHA2DS2-VASc-Score nor recurrence of AF were significantly different in patients with or without stroke. There was a trend toward a higher percentage of coronary artery disease among patients that experienced stroke (50% vs. 10%; P = 0.057). CONCLUSION: The overall risk of stroke and AF recurrence is low in patients with a recurrence free interval of at least 12 months after AF ablation. Of note, recurrence of AF was not associated with a higher risk of stroke in our study population. PMID- 27933667 TI - A mobile, web-based system can improve positive airway pressure adherence. AB - SleepMapper is a mobile, web-based system that allows patients to self-monitor their positive airway pressure therapy, and provides feedback and education in real time. In addition to the usual, comprehensive support provided at our clinic, we gave the SleepMapper to 30 patients initiating positive airway pressure. They were compared with patients initiating positive airway pressure at our clinic without SleepMapper (controls) to determine whether SleepMapper affected adherence. A total of 61 patients had polysomnographic and adherence data analysed, 30 were given SleepMapper and 31 received our standard of care. The two groups were well matched at baseline to include no significant differences in age, apnea-hypopnea index, percentage receiving split-night polysomnographs and starting pressures. Patients in the control group received significantly more non-benzodiazepine sedative hypnotics the night of their polysomnography and during positive airway pressure initiation. At 11 weeks, patients in the SleepMapper group had a greater percentage of nights with any use (78.0 +/- 22.0 versus 55.5 +/- 24.0%; P < 0.001) and >4 h positive airway pressure use (78.0 +/- 22.0 versus 55.5 +/- 24.0%; P = 0.02). There was a trend toward more patients in the SleepMapper group achieving >4 h of use for at least 70% of nights [9/30 (30%) versus 3/31 (9.7%); P = 0.06]. In multivariate linear regression, the SleepMapper remained significantly associated with percentage of nights >4 h positive airway pressure use (beta coefficient = 0.18; P = 0.02). Added to our usual, comprehensive programme to maximize positive airway pressure adherence in new users, the SleepMapper was independently associated with an 18% increase in nights >4 h of use. PMID- 27933669 TI - Characterization of nitrated sugar alcohols by atmospheric-pressure chemical ionization mass spectrometry. AB - RATIONALE: The nitrated sugar alcohols mannitol hexanitrate (MHN), sorbitol hexanitrate (SHN) and xylitol pentanitrate (XPN) are in the same class of compounds as the powerful military-grade explosive pentaerythritol tetranitrate (PETN) and the homemade explosive erythritol tetranitrate (ETN) but, unlike for PETN and ETN, ways to detect MHN, SHN and XPN by mass spectrometry (MS) have not been fully investigated. METHODS: Atmospheric-pressure chemical-ionization mass spectrometry (APCI-MS) was used to detect ions characteristic of nitrated sugar alcohols. APCI time-of-flight mass spectrometry (APCI-TOF MS) and collision induced dissociation tandem mass spectrometry (CID MS/MS) were used for confirmation of each ion assignment. In addition, the use of the chemical ionization reagent dichloromethane was investigated to improve sensitivity and selectivity for detection of MHN, SHN and XPN. RESULTS: All the nitrated sugar alcohols studied followed similar fragmentation pathways in the APCI source. MHN, SHN and XPN were detectable as fragment ions formed by the loss of NO2 , HNO2 , NO3 , and CH2 NO2 groups, and in the presence of dichloromethane chlorinated adduct ions were observed. It was determined that in MS/MS mode, chlorinated adducts of MHN and SHN had the lowest limits of detection (LODs), while for XPN the lowest LOD was for the [XPN-NO2 ]- fragment ion. Partially nitrated analogs of each of the three compounds were also present in the starting materials, and ions attributable to these compounds versus those formed from in-source fragmentation of MHN, SHN, and XPN were distinguished and assigned using liquid chromatography APCI-MS and ESI-MS. CONCLUSIONS: The APCI-MS technique provides a selective and sensitive method for the detection of nitrated sugar alcohols. The methods disclosed here will benefit the area of explosives trace detection for counterterrorism and forensics. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27933668 TI - The role of the hippocampus in generalizing configural relationships. AB - The hippocampus has been implicated in integrating information across separate events in support of mnemonic generalizations. These generalizations may be underpinned by processes at both encoding (linking similar information across events) and retrieval ("on-the-fly" generalization). However, the relative contribution of the hippocampus to encoding- and retrieval-based generalizations is poorly understood. Using fMRI in humans, we investigated the hippocampal role in gradually learning a set of spatial discriminations and subsequently generalizing them in an acquired equivalence task. We found a highly significant correlation between individuals' performance on a generalization test and hippocampal activity during the test, providing evidence that hippocampal processes support on-the-fly generalizations at retrieval. Within the same hippocampal region there was also a correlation between activity during the final stage of learning (when all associations had been learnt but no generalization was required) and subsequent generalization performance. We suggest that the hippocampus spontaneously retrieves prior events that share overlapping features with the current event. This process may also support the creation of generalized representations during encoding. These findings are supportive of the view that the hippocampus contributes to both encoding- and retrieval-based generalization via the same basic mechanism; retrieval of similar events sharing common features. (c) 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID- 27933670 TI - Gold(I) Fluorohalides: Theory and Experiment. AB - The anionic trifluoromethylgold(I) derivatives [CF3 AuX]- , which have been prepared and isolated as their [PPh4 ]+ salts in good yield, undergo thermally induced difluorocarbene extrusion in the gas phase, giving rise to the mixed gold(I) fluorohalide complexes [F-Au-X]- (X=Cl, Br, I). These triatomic species have been detected by tandem mass spectrometry (MS2) experiments and their properties have been analyzed by DFT methods. The CF2 extrusion mechanism from the Au-CF3 moiety serves as a model for the CF2 insertion into the Au-F bond, since both reactivity channels are connected by the microreversibility principle. PMID- 27933671 TI - Causal inference in obesity research. AB - Obesity is a risk factor for a plethora of severe morbidities and premature death. Most supporting evidence comes from observational studies that are prone to chance, bias and confounding. Even data on the protective effects of weight loss from randomized controlled trials will be susceptible to confounding and bias if treatment assignment cannot be masked, which is usually the case with lifestyle and surgical interventions. Thus, whilst obesity is widely considered the major modifiable risk factor for many chronic diseases, its causes and consequences are often difficult to determine. Addressing this is important, as the prevention and treatment of any disease requires that interventions focus on causal risk factors. Disease prediction, although not dependent on knowing the causes, is nevertheless enhanced by such knowledge. Here, we provide an overview of some of the barriers to causal inference in obesity research and discuss analytical approaches, such as Mendelian randomization, that can help to overcome these obstacles. In a systematic review of the literature in this field, we found: (i) probable causal relationships between adiposity and bone health/disease, cancers (colorectal, lung and kidney cancers), cardiometabolic traits (blood pressure, fasting insulin, inflammatory markers and lipids), uric acid concentrations, coronary heart disease and venous thrombosis (in the presence of pulmonary embolism), (ii) possible causal relationships between adiposity and gray matter volume, depression and common mental disorders, oesophageal cancer, macroalbuminuria, end-stage renal disease, diabetic kidney disease, nuclear cataract and gall stone disease, and (iii) no evidence for causal relationships between adiposity and Alzheimer's disease, pancreatic cancer, venous thrombosis (in the absence of pulmonary embolism), liver function and periodontitis. PMID- 27933672 TI - Single neuron activity and theta modulation in the posterior parietal cortex in a visuospatial attention task. AB - The posterior parietal cortex (PPC) is implicated in directing and maintaining visual attention to locations in space. We hypothesized that the PPC also engages other cognitive processes in the transformation of behaviorally relevant visual inputs into appropriate actions, for example, monitoring of multiple locations, selection of responses to locations in space, and monitoring the outcome of response selections. We recorded single cells and local field potentials in the rat PPC during performance on a novel visuospatial attention (VSA) task that requires visually monitoring locations in space in order to make appropriate stimulus-guided locomotor responses. In each trial, rats attended to four locations on the floor of a maze. A randomly chosen location was briefly illuminated. Approach to the correct target location was followed by food reward. We observed that PPC activity correlated with multiple phases of the VSA task, including monitoring for stimulus onset, detection of a target, spatial location of the target, and target choice. A substantial proportion of cells with behavioral correlates were also modulated by outcome of the trial. Our analyses of local field potentials revealed strong oscillatory rhythms in the theta frequency band, and more than a third of PPC neurons were phase locked to theta oscillations. As in other brain regions, theta power correlated with running speed. Peak theta power was higher in superficial layers than deep layers providing evidence against volume conduction from the hippocampus. In addition, theta power was sensitive to the outcome of a choice. Theta power was significantly higher following incorrect choices compared with correct choices, possibly providing a prediction error signal. Our study provides evidence that the rat PPC has multiple roles in the translation of visual information into appropriate behavioral actions. (c) 2016 Wiley Periodicals, Inc. PMID- 27933673 TI - A biophysical and computational study unraveling the molecular interaction mechanism of a new Janus kinase inhibitor Tofacitinib with bovine serum albumin. AB - The interaction of a recently certified kinase inhibitor Tofacitinib (TFB) with bovine serum albumin (BSA) has been studied, by spectroscopic and molecular docking studies. Spectrofluorimetric measurements at 3 different temperatures (288, 298, and 310 K) showed that TFB quench the intrinsic fluorescence of BSA upon forming a nonfluorescent complex. The intrinsic fluorescence data showed that TFB binds to BSA with binding constant (Kb ) of approximately 104 M-1 , affirming a significant affinity of TFB with BSA. The decrease in Stern-Volmer quenching constant with increasing temperature exhibited the static mechanism of quenching. Negative value of DeltaG (-6.94 +/- 0.32 kcal.mol-1 ), DeltaH (-7.87 +/- 0.52 kcal.mol-1 ), and DeltaS (-3.14 +/- 0.42 cal.mol-1 .K-1 ) at all 3 temperatures declared the reaction between BSA and TFB to be spontaneous and exothermic. Far-UV circular dichroism spectroscopy results demonstrated an increase in helical content of BSA in the presence of TFB. Moreover, dynamic light scattering measurements showed that TFB resulted into a decrease in the hydrodynamic radii (from 3.6 +/- 0.053 to 2.9 +/- 0.02 nm) of BSA. Molecular docking studies confirmed that TFB binds near site II on BSA, hydrogen bonding, and hydrophobic interaction were involved in the BSA-TFB complex formation. The present study characterizing the BSA-TFB interaction could be significant towards gaining an insight into the drug pharmacokinetics and pharmacodynamics and also in the direction of rational drug designing with better competence, against emerging immune-mediated diseases, ie, alopecia and rheumatoid arthritis. PMID- 27933674 TI - Heterosis in hybrids within and between yeast species. AB - The performance of hybrids relative to their parents is an important factor in speciation research. We measured the growth of 46 Saccharomyces yeast F1 interspecific and intraspecific hybrids, relative to the growth of each of their parents, in pairwise competition assays. We found that the growth of a hybrid relative to the average of its parents, a measure of mid-parent heterosis, correlated with the difference in parental growth relative to their hybrid, a measure of phenotypic divergence, which is consistent with simple complementation of low fitness alleles in one parent by high fitness alleles in the other. Interspecific hybrids showed stronger heterosis than intraspecific hybrids. To manipulate parental phenotypic divergence independently of genotype, we also measured the competitive growth of a single interspecific hybrid relative to its parents in 12 different environments. In these assays, we not only identified a strong relationship between parental phenotypic divergence and mid-parent heterosis as before, but, more tentatively, a weak relationship between phenotypic divergence and best-parent heterosis, suggesting that complementation of deleterious mutations was not the sole cause of interspecific heterosis. Our results show that mating between different species can be beneficial, and demonstrate that competition assays between parents and offspring are a useful way to study the evolutionary consequences of hybridization. PMID- 27933675 TI - C3 -Symmetric Boron Lewis Acid with a Cage-Shape for Chiral Molecular Recognition and Asymmetric Catalysis. AB - Chiral Lewis acids play an important role in the precise construction of various types of chiral molecules. Here, a cage-shaped borate 2 was designed and synthesized as a chiral Lewis acid that possesses a unique C3 -symmetric structure composed of three homochiral binaphthyl moieties. The highly symmetrical structure of 2 with homochirality was clearly elucidated by X-ray crystallographic analysis. The peculiar chiral environment of 2?THF exhibited chiral recognition of some simple amines and a sulfoxide. Moreover, the application of 2?THF to hetero-Diels-Alder reactions as a chiral Lewis-acid catalyst afforded the enantioselective products, which were obtained through an entropy-controlled pathway according to the analysis of the relationship between optical yield and reaction temperature. In particular, the robust chiral reaction field of 2?THF allowed the first example of an asymmetric hetero-Diels-Alder reaction with a simple diene despite the requirement of high temperature. PMID- 27933677 TI - The effect of slow-paced breathing on stress management in adolescents with intellectual disability. AB - BACKGROUND: Intellectual disabilities often create a state of chronic stress for both the person concerned and their significant others (family, caregivers). The development of stress management methods is therefore important for the reduction of stress in persons with intellectual disability. The aim of this experiment was to investigate the effect of slow-paced breathing on stress symptoms experienced by adolescents with intellectual disabilities during a cognitive task under time pressure. METHOD: Fourteen adolescents with intellectual disabilities (Mage = 17.39 years, range 15-19 years) took part in two laboratory sessions - a slow paced breathing session (experimental condition) and an audiobook session (control condition) - the order of which was counterbalanced across participants. Vagal tone was measured through heart rate variability to index stress management. RESULTS: No difference in vagal tone was observed at baseline between experimental and control conditions. Compared with the control condition, vagal tone was significantly higher during the experimental condition. CONCLUSIONS: The slow-paced breathing task enhanced stress management to a greater extent than did listening to an audiobook. Slow-paced breathing seems to be an easy to learn stress management technique that appears as an effective auxiliary method of lowering stress in adolescents with intellectual disabilities. PMID- 27933676 TI - White matter hyperintensities are associated with disproportionate progressive hippocampal atrophy. AB - This study investigates relationships between white matter hyperintensity (WMH) volume, cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathology markers, and brain and hippocampal volume loss. Subjects included 198 controls, 345 mild cognitive impairment (MCI), and 154 AD subjects with serial volumetric 1.5-T MRI. CSF Abeta42 and total tau were measured (n = 353). Brain and hippocampal loss were quantified from serial MRI using the boundary shift integral (BSI). Multiple linear regression models assessed the relationships between WMHs and hippocampal and brain atrophy rates. Models were refitted adjusting for (a) concurrent brain/hippocampal atrophy rates and (b) CSF Abeta42 and tau in subjects with CSF data. WMH burden was positively associated with hippocampal atrophy rate in controls (P = 0.002) and MCI subjects (P = 0.03), and with brain atrophy rate in controls (P = 0.03). The associations with hippocampal atrophy rate remained following adjustment for concurrent brain atrophy rate in controls and MCIs, and for CSF biomarkers in controls (P = 0.007). These novel results suggest that vascular damage alongside AD pathology is associated with disproportionately greater hippocampal atrophy in nondemented older adults. (c) 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID- 27933678 TI - Trends in serious quit attempts in the United States, 2009-14. AB - BACKGROUND AND AIMS: Quitting smoking is the most potent way to reduce the health risks associated with smoking cigarettes, and public health objectives in the United States include dramatic increases in the proportion of smokers making a serious quit attempt each year. The US Centers for Disease Control and Prevention (CDC) has, since 2000, set as its Healthy People 2020 objective to encourage 80% of smokers to make a serious quit attempt per year. This study assessed the trend in quit attempts from 2009 to 2014. DESIGN: We examined the percentage of US smokers making a serious quit attempt each year from 2009 to 2014 from the repeating cross-sectional National Health Interview Survey (NHIS). SETTING: United States. PARTICIPANTS: The number of qualifying respondents per year ranged from 5748 in 2010 to 7219 in 2012, with a total of 40 362 respondents included in the analysis. MEASUREMENTS: Respondents were deemed to have made a serious quit attempt if they were either current smokers who reported that they stopped smoking for more than 1 day in the past 12 months because they were trying to quit smoking, or reported being former smokers (smoked 100+ cigarettes life-time, but now not smoking) who quit in the past year. FINDINGS: Analyses of trends from 2009 to 2014 showed an overall linear increase in quit attempts [odds ratio (OR) = 1.02, 95% confidence interval (CI) = 1.01-1.04, P = 0.0075], but also a quadratic trend (OR = 1.01, 95% CI = 1.00-1.02, P = 0.0189). CONCLUSIONS: The proportion of US smokers making a serious quit attempt has increased since 2009, due to an upward trend since 2011. The 2014 serious quit attempt rate was 55.0%. These rates are still below the Healthy People 2020 objective of 80% of smokers making a serious quit attempt per year. PMID- 27933679 TI - Supplementation with nutrients modulating insulin-like growth factor-1 negatively correlated with changes in the levels of pro-inflammatory cytokines in community dwelling elderly people at risk of undernutrition. AB - BACKGROUND: Suboptimal nutrition accompanied by chronic low-grade increases in circulating cytokine levels is more common in elderly people. We explored the improvement in nutritional status, especially in the level of insulin-like growth factor-1 (IGF-1) and its relationship with changes in circulating cytokine levels, after providing extra protein and energy content to community-dwelling older adults at risk of undernutrition. METHODS: Sixty nondiabetic subjects, aged >=65 years and living independently in a community for elderly people, with a serum pre-albumin level <=30 mg dL-1 and a body mass index <25 kg m-2 , were recruited. The subjects were followed for a 2-week pre-intervention period, during which they maintained routine dietary habits. This was followed by an intervention period, during which they received oral nutritional supplementation for 2 weeks. RESULTS: Following 2 weeks of intervention, there were significant increases in total lymphocyte count (TLC) and insulin-like growth factor (IGF)-1, pre-albumin and transferrin compared to baseline. Body weight and mid-arm circumference significantly increased without alteration of tricep skinfold thickness at the end of the intervention. There was a significant reduction in interleukin (IL)-6 levels and a trend toward a decrease in the tumor necrosis factor (TNF)-alpha levels. At baseline, age was negatively correlated with IGF-1 levels and positively correlated with IL-6 and TNF-alpha levels. The change (?, from baseline) in IGF-1 level was positively correlated with age and negatively correlated with ?IL-6 and ?TNF-alpha. CONCLUSIONS: A 2-week intervention with oral nutritional supplementation improved nutritional status and decreased circulating cytokine levels. Specifically, ?IGF-1 was negatively correlated with changes in pro-inflammatory cytokine levels in community-dwelling elderly people at risk of undernutrition. (Clinicaltrials.gov: NCT02656186). PMID- 27933680 TI - Primary Breast Angiosarcoma: A Retrospective Study of 36 Cases from a Single Chinese Medical Institute with Clinicopathologic and Radiologic Correlations. AB - The aim of this study was to present our experience with primary breast angiosarcoma (PBA) by describing a large series of cases with an emphasis on clinicopathologic and radiologic correlations. Thirty-six cases of PBA diagnosed at our institution between 2006 and 2014 were retrospectively evaluated. All but one case occurred in women with a median age of 35.5 years. The majority of patients presented with a deeply located painless mass, whereas a minority manifested as diffuse enlargement or swelling of the breast. Magnetic resonance imaging showed poorly demarcated lesions with low signal intensity on T1-weighted images, markedly high intensity on T2-weighted images, and prolongation of enhancement upon dynamic study. Histologically, 19 cases (52.8%) were low grade, 12 cases (33.3%) were intermediate grade, and 5 cases (13.9%) were high grade. Follow-up information was available for 27 patients and revealed local recurrence and/or metastasis in 16 patients (59.3%). Five patients (18.5%) died of the disease at a median interval of 20 months. Univariate analysis showed that tumor differentiation had effect on disease-free survival (DFS) (p = 0.005) but failed to predict overall survival (OS) (p = 0.645). The treatment modality was related to OS (p = 0.042) but not DFS (p = 0.131). The Cox proportional hazards regression model suggested that tumor differentiation was an independent predictor of DFS (p = 0.015). We hypothesize that tumor differentiation may be used as a prognostic factor for this rare malignancy. Clinicopathologic and radiologic correlation may help pathologists to arrive at the correct diagnosis of PBA. PMID- 27933681 TI - Evaluating a primary care psychology service in Ireland: a survey of stakeholders and psychologists. AB - Primary care psychology services (PCPS) represent an important resource in meeting the various health needs of our communities. This study evaluated the PCPS in a two-county area within the Republic of Ireland. The objectives were to (i) examine the viewpoints of the service for both psychologists and stakeholders (healthcare professionals only) and (ii) examine the enactment of the stepped care model of service provision. Separate surveys were sent to primary care psychologists (n = 8), general practitioners (GPs; n = 69) and other stakeholders in the two counties. GPs and stakeholders were required to rate the current PCPS. The GP survey specifically examined referrals to the PCPS and service configuration, while the stakeholder survey also requested suggestions for future service provision. Psychologists were required to provide information regarding their workload, time spent on certain tasks and productivity ideas. Referral numbers, waiting lists and waiting times were also obtained. All 8 psychologists, 23 GPs (33% response rate) and 37 stakeholders (unknown response rate) responded. GPs and stakeholders reported access to the PCPS as a primary concern, with waiting times of up to 80 weeks in some areas. Service provision to children and adults was uneven between counties. A stepped care model of service provision was not observed. Access can be improved by further implementation of a stepped care service, developing a high-throughput service for adults (based on a stepped care model), and employing a single waiting list for each county to ensure equal access. PMID- 27933682 TI - Highly Efficient Intramolecular Electrochemiluminescence Energy Transfer for Ultrasensitive Bioanalysis of Aflatoxin M1. AB - The intermolecular electrochemiluminescence resonance energy transfer (ECL-RET) between luminol and Ru(bpy)32+ was studied extensively to achieve the sensitive bioanalysis owing to the perfect spectral overlap of the donor and acceptor, but it still suffers from the challenging issue of low energy-transfer efficiency. The intramolecular ECL-RET towards the novel ECL compound containing the donor of luminol and the acceptor of Ru(bpy)2 (mcpbpy)2+ (Lum-Ru) was designed and investigated. With the high-efficient ECL-RET in one molecule, the highly intense ECL signal of Lum-Ru was obtained owing to the short path of energy transmission and less energy loss between luminol and Ru(bpy)2 (mcpbpy)2+ . Lum-Ru was further applied to construct a signal-off electrochemiluminescence (ECL) aptasensor for ultrasensitive detection of a harsh carcinogen of Aflatoxin M1 (AFM1). This sensing platform also provides a significant boost for the trace detection of other biomolecules in clinical analysis. PMID- 27933683 TI - Genetics and the conservation of natural populations: allozymes to genomes. AB - I consider how the study of genetic variation has influenced efforts to conserve natural populations over the last 50 years. Studies with allozymes in the 1970s provided the first estimates of the amount of genetic variation within and between natural populations at multiple loci. These early studies played an important role in developing plans to conserve species. The description of genetic variation in mitochondrial DNA in the early 1980s laid the foundation for the field of phylogeography, which provided a deeper look in time of the relationships and connectivity among populations. The development of microsatellites in the 1990s provided much more powerful means to describe genetic variation at nuclear loci, including the ability to detect past bottlenecks and estimate current effective population size with a single temporal sample. In the 2000s, single nucleotide polymorphisms presented a cornucopia of loci that has greatly improved power to estimate genetic and population demographic parameters important for conservation. Today, population genomics presents the ability to detect regions of the genome that are affected by natural selection (e.g. local adaptation or inbreeding depression). In addition, the ability to genotype historical samples has provided power to understand how climate change and other anthropogenic phenomena have affected populations. Modern molecular techniques provide unprecedented power to understand genetic variation in natural populations. Nevertheless, application of this information requires sound understanding of population genetics theory. I believe that current training in conservation genetics focuses too much on the latest techniques and too little on understanding the conceptual basis which is needed to interpret these data and ask good questions. PMID- 27933684 TI - Enhancement of Ag-Based Plasmonic Photocatalysis in Hydrogen Production from Ammonia Borane by the Assistance of Single-Site Ti-Oxide Moieties within a Silica Framework. AB - Ag nanoparticles (NPs) have gained great attention owing to their interesting plasmonic properties and efficient catalysis under visible-light irradiation. In this study, an Ag-based plasmonic catalyst supported on mesoporous silica with isolated and tetrahedrally coordinated single-site Ti-oxide moieties, namely, Ag/Ti-SBA-15, was designed with the purpose of utilizing the broad spectral range of solar energy. The Ti-SBA-15 support allows the deposition of small Ag NPs with a narrow size distribution. The chemical structure, morphology, and optical properties of the prepared catalyst were characterized by techniques such as UV/Vis, FT extended X-ray absorption fine structure, and X-ray photoelectron spectroscopy, field-emission SEM, TEM, and N2 physisorption studies. The catalytic activity of Ag/Ti-SBA-15 in hydrogen production from ammonia borane by hydrolysis was significantly enhanced in comparison with Ag/SBA-15 without Ti oxide moieties and Ag/TiO2 /SBA-15 involving agglomerated TiO2 , both in the dark and under light irradiation. Improved electron transfer under light irradiation caused by the creation of heterojunctions between Ag NPs and Ti-oxide moieties explains the results obtained in the present study. PMID- 27933685 TI - The STOP-ACEi Trial - Apt timing for this long awaited randomised controlled trial - Validation of the syndrome of late-onset renal failure from angiotensin blockade (LORFFAB)? PMID- 27933686 TI - Risk of incident Mycobacterium tuberculosis infection in patients with inflammatory bowel disease: a nationwide population-based study in South Korea. AB - BACKGROUND: The low incidence of Mycobacterium tuberculosis infection and lack of adequate controls have prevented researchers from estimating tuberculosis (TB) risk in inflammatory bowel disease (IBD) patients. AIM: To evaluate the risk of incident TB among IBD patients. METHODS: Using the 2011-2013 data of the South Korean National Health Insurance (NHI) system, we calculated the incidence rates (IRs), standardised incidence ratio (SIR) and number needed to screen (NNS) for incident TB in IBD patients compared to the general population in terms of subtype, age, gender and IBD medications. RESULTS: The IR, SIR and NNS for TB in IBD patients were 223.9/100 000 person-years, 2.64 (2.30-3.01) and 446.6 (392.8 517.6), respectively. The TB IR in Crohn's disease (CD) patients was significantly higher than that in ulcerative colitis (UC) patients (340.1/100 000 person-years vs. 165.5/100 000 person-years, respectively; P < 0.001). The SIR and NNS for TB among CD patients were 4.00 (3.59-4.45) and 604.2 (506.1-749.6), respectively; those among UC patients were 1.95 (1.66-2.27) and 294.0 (246.9 363.4). The TB IRs in IBD patients did not differ significantly by age or gender (Ptrend = 0.505 and P = 0.861, respectively). The TB IRs among IBD patients prescribed 5-ASA, corticosteroids, immunomodulators and anti-TNF-alpha were 143.5, 208.5, 284.6 and 554.1 per 100 000 person-years, respectively. Among IBD patients treated using anti-TNF-alpha, the TB IR was significantly higher than that among all IBD patients (P < 0.001); the SIR and NNS for TB were 6.53 (5.99 7.09) and 180.5 (144.6-240.1) respectively. CONCLUSION: Clinicians should be aware of the increased risk of active tuberculosis in patients with IBD who are receiving anti-TNF-alpha therapy. PMID- 27933687 TI - Letter: proton pump inhibitors and prognosis of cirrhosis - searching for the balance point. PMID- 27933688 TI - Letter: vedolizumab for the management of inflammatory bowel disease in patients after liver transplantation for primary sclerosing cholangitis. PMID- 27933689 TI - Letter: years of life that could be saved by preventing HCC. PMID- 27933690 TI - On the Reactions of Thiols, Sulfenic Acids, and Sulfinic Acids with Hydrogen Peroxide. AB - The reaction of thiols with H2 O2 is central to many processes essential to life, from protein folding to redox signaling. The initial products are assumed to be sulfenic acids, but their observation, and the kinetic and mechanistic characterization of their subsequent reactions, has proven challenging. The introduction of a 9-fluorotriptycene substituent enabled the use of 19 F NMR to directly monitor the reaction of a thiol with H2 O2 to yield a sulfenic acid, and its subsequent oxidation to sulfinic and sulfonic acids. The oxidations are specific base catalyzed, as revealed by the lack of isotope effects and the dependence of the kinetics on pH but not buffer concentration. PMID- 27933691 TI - Single Fusion Events at Polarized Liquid-Liquid Interfaces. AB - A new electrochemical framework for tracking individual soft particles in solution and monitoring their fusion with polarized liquid-liquid interfaces is reported. The physicochemical principle lies in the interfacial transfer of an ionic probe confined in the particles dispersed in solution and that is released upon their collision and fusion with the fluid interface. As a proof-of-concept, spike-like transients of a stochastic nature are reported in the current-time response of 1,2-dichloroethane(DCE)|water(W) submilli-interfaces after injection of DCE-in-W emulsions. The sign and potential dependence of the spikes reflect the charge and lipophilicity of the ionic load of the droplets. A comparison with dynamic light scattering measurements indicates that each spike is associated with the collision of a single sub-picoliter droplet. This opens a new framework for the study of single fusion events at the micro- and nanoscale and of ion transport across biomimetic soft interfaces. PMID- 27933692 TI - Preferential changes of skeletal muscle echogenicity in myotonic dystrophy type 1. AB - BACKGROUND AND PURPOSE: In myotonic dystrophy type 1 (DM1), weakness of distal limb muscles affects quality of life. Non-invasive evaluation of muscular involvement by muscle sonography could be useful for characterizing muscle specific involvement. METHODS: Sonography of the lower leg and forearm was performed in 19 patients with DM1 and 10 control subjects. The mean echo intensities (EIs) of seven limb muscles were obtained by computer-assisted histogram analysis and compared within DM1 according to the overall clinical severity. RESULTS: The EIs of the muscles were significantly higher in DM1 than in the controls (P < 0.01), except for the soleus (P = 0.4). Comparison of adjacent muscles showed the following: (i) greater EIs in flexor digitorum profundus than flexor carpi ulnaris (P < 0.01) and flexor digitorum superficialis (P = 0.02), and (ii) greater EIs in the medial head of the gastrocnemius than the soleus (P < 0.00001). In a subgroup analysis of DM1 according to the modified Rankin Scale (mRS), the more severe subgroup (mRS = 4-5) had lower mean EIs than the less severe subgroup (mRS from 1-3) (P = 0.01) in the flexor digitorum superficialis but not in other muscles. CONCLUSIONS: Preferential high echogenicity in the medial gastrocnemius and deep finger flexors is suggestive of DM1. Muscle echogenicity is not generally related to functional dysfunction in DM1. PMID- 27933693 TI - Heart transplantation in children with intellectual disability: An analysis of the UNOS database. AB - Heart transplantation in children with intellectual disability (ID) is an issue of debate due to the shortage of available donor organs. We sought to perform the first large-scale retrospective cohort study describing the prevalence and outcomes of heart transplantation in this population. The United Network of Organ Sharing database was queried from 2008 to 2015 for pediatric patients (age <19 years) receiving first, isolated heart transplant. Recipients were divided into three subgroups: definite ID, probable ID, and no ID. The chi-square test was used to compare patients' baseline characteristics. Kaplan-Meier and Cox proportional hazard regression analyses were used to estimate the association between ID and death-censored graft failure and patient survival. Over the study period, 565 pediatric patients with definite (131) or probable (434) ID received first heart transplant, accounting for 22.4% of all first pediatric heart transplants (n=2524). Recipients with definite ID did not significantly differ from those without ID in terms of gender, ethnicity, ischemia time, severity of pretransplant condition (waitlist status, mechanical ventilation, inotrope dependence, ECMO, VAD, PVRI, infection prior to transplant), or incidents of acute rejection within the first year. ID was associated with prolonged waitlist time (P<.001). Graft and patient survival at 3 years was equivalent between children with and without ID (P=.811 and .578, respectively). We conclude that intellectual disability is prevalent in children receiving heart transplants, with 22.4% of recipients over the study period having definite or probable ID. ID does not appear to negatively affect transplantation outcomes. Future studies are needed to assess long-term outcomes of transplantation in this population. PMID- 27933694 TI - Association of coffee consumption and chronic kidney disease: A meta-analysis. AB - BACKGROUND/OBJECTIVES: The risk of chronic kidney disease (CKD) in individuals who regularly drink coffee is controversial. The aim of this meta-analysis was to evaluate the association between coffee consumption and CKD. METHODS: A literature search was performed using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from inception until April 2016. We included studies that reported odd ratios or hazard ratios comparing the risk of CKD in individuals consuming significant amount of coffee vs. those who did not consume coffee. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Four observational studies with 14 898 individuals were included in our analysis to assess the association between coffee consumption and CKD. Coffee consumption was defined as one cup of coffee per day or greater. The pooled RR of CKD in individuals consuming coffee was 0.71 (95% CI, 0.47-1.08). The subgroup analysis showed the pooled RRs of CKD of 1.10 (95% CI, 0.94-1.29) in males and 0.81 (95% CI, 0.58 1.13) in females, respectively. CONCLUSIONS: Our study demonstrates no significant association between coffee consumption and CKD in males. However, future studies are required to assess a potential inverse association between coffee consumption and risk for developing CKD in females. PMID- 27933695 TI - Multiconfigurational Effects in Theoretical Resonance Raman Spectra. AB - We analyze resonance Raman spectra of the nucleobase uracil in the short-time approximation calculated with multiconfigurational methods. We discuss the importance of static electron correlation by means of density-matrix renormalization group self-consistent field (DMRG-SCF) calculations. Our DMRG-SCF results reveal that a minimal active orbital space that leads to a qualitatively correct description of the resonance Raman spectrum of uracil should encompass parts of the sigma/sigma* bonding/anti-bonding orbitals of the pyrimidine ring. We trace these findings back to the considerable entanglement between the sigma/sigma* bonding/anti-bonding as well as valence pi/pi* orbitals in the excited-state electronic structure of uracil, which indicates non-negligible non dynamical correlation effects that are less pronounced in the electronic ground state. PMID- 27933696 TI - Commentary on 'Blue-blocking glasses as additive treatment for mania: A randomized placebo-controlled trial'. PMID- 27933697 TI - Total magnetic resonance imaging burden of cerebral small-vessel disease is associated with post-stroke depression in patients with acute lacunar stroke. AB - BACKGROUND AND PURPOSE: Despite extensive studies on post-stroke depression (PSD), the role of the total burden of cerebral small-vessel disease (cSVD) in its pathogenesis remains unclear. METHODS: We conducted a magnetic resonance imaging (MRI)-based cohort study to investigate the relationship between total MRI burden of cSVD and PSD among patients with first-ever lacunar stroke. From June 2013 to January 2016, 374 patients were consecutively recruited. PSD was identified using the Chinese version of the Structured Clinical Interview for DSM IV. Brain MRI presence of silent lacunar infarcts, white-matter lesions, cerebral microbleeds and enlarged perivascular spaces was summed to an ordinal score between 0 and 4. Multivariable logistic regression analysis was performed to determine the contribution of total MRI cSVD burden in the prediction of PSD. RESULTS: Ninety patients (24.1%) were diagnosed with PSD at 3 months after stroke. Only two MRI markers of cSVD, asymptomatic lacunar infarcts and white matter lesions, were related to PSD [odds ratio (OR), 3.167; 95% confidence interval (CI), 1.879-5.338; P = 0.001 and OR, 2.284; 95% CI, 1.403-3.713; P = 0.001, respectively]. Moreover, higher total MRI cSVD burden was an independent predictor for PSD (high tertile OR, 4.577; 95% CI, 2.400-8.728; P = 0.001) after adjusting for individual cSVD MRI marker and other potential confounders. CONCLUSIONS: This study demonstrated that greater total MRI burden of cSVD may predict the presence of PSD in patients with acute lacunar stroke. PMID- 27933698 TI - Sofosbuvir plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 or 3 infection in India. AB - Until 2014, pegylated interferon plus ribavirin was the recommended standard of care for the treatment of chronic hepatitis C virus (HCV) infection in India. This open-label phase 3b study, conducted across 14 sites in India between 31 March 2014 and 30 November 2015, evaluated the efficacy and safety of sofosbuvir plus ribavirin therapy among treatment-naive patients with chronic genotype 1 or 3 HCV infection. A total of 117 patients with genotype 1 or 3 HCV infection were randomized 1:1 to receive sofosbuvir 400 mg and weight-based ribavirin (1000 or 1200 mg) daily for 16 or 24 weeks. Among those with genotype 1 infection, the primary efficacy endpoint of sustained virologic response at 12 weeks post treatment (SVR12) was reported in 90% (95% confidence intervals [CI], 73-98) and 96% (95% CI, 82-100) of patients following 16 and 24 weeks of treatment, respectively. For patients with genotype 3 infection, SVR12 rates were 100% (95% CI, 88-100) and 93% (95% CI, 78-99) after 16 and 24 weeks of therapy, respectively. Adverse events, most of which were mild or moderate in severity, occurred in 69% and 57% of patients receiving 16 and 24 weeks of treatment, respectively. The most common treatment-emergent adverse events were asthenia, headache and cough. Only one patient in the 24-week group discontinued treatment with sofosbuvir during this study. Overall, sofosbuvir plus ribavirin therapy achieved SVR12 rates >=90% and was well tolerated among treatment-naive patients with chronic genotype 1 or 3 HCV infection in India. PMID- 27933699 TI - Room-Temperature Arylation of Thiols: Breakthrough with Aryl Chlorides. AB - The formation of aryl C-S bonds is an important chemical transformation because aryl sulfides are valuable building blocks for the synthesis of biologically and pharmaceutically active molecules and organic materials. Aryl sulfides have traditionally been synthesized through the transition-metal-catalyzed cross coupling of aryl halides with thiols. However, the aryl halides used are usually bromides and iodides; readily available, low-cost aryl chlorides often not reactive enough. Furthermore, the deactivation of transition-metal catalysts by thiols has forced chemists to use high catalyst loadings, specially designed ligands, high temperatures, and/or strong bases, thus leading to high costs and the incompatibility of some functional groups. Herein, we describe a simple and efficient visible-light photoredox arylation of thiols with aryl halides at room temperature. More importantly, various aryl chlorides are also effective arylation reagents under the present conditions. PMID- 27933700 TI - Calcineurin inhibitor-free immunosuppression. PMID- 27933701 TI - CCR2 mediates Helicobacter pylori-induced immune tolerance and contributes to mucosal homeostasis. AB - BACKGROUND: We previously demonstrated that H. pylori infection leads to increased induction of regulatory T cells in local and systemic immune compartments. Here, we investigate the role of CCR2 in the tolerogenic programing of dendritic cells in a mouse model of H. pylori infection. MATERIALS AND METHODS: CCR2 deficient (CCR2KO) mice and wild-type (Wt) mice infected with H. pylori SS1 strain were analyzed by qPCR and FACS analysis. In vitro, bone marrow derived DC on day 6 from CCR2KO and Wt mice cocultured with or without H. pylori were examined to determine the impact of CCR2 signaling on dendritic cells function by qPCR, ELISA, and FACS analyses. RESULTS: Acute H. pylori infection was associated with a threefold increase in CCR2 mRNA expression in the gastric mucosa. H. pylori-infected CCR2KO mice exhibited a higher degree of mucosal inflammation, that is, increased gastritis scores and pro-inflammatory cytokine mRNA levels, but lower degree of H. pylori gastric colonization compared to infected Wt mice. Peripheral H. pylori-specific immune response measured in the CCR2KO spleen was characterized by a higher Th17 response and a lower Treg response. In vitro, CCR2KO bone marrow-derived DC was less mature and shown a lower Treg/Th17 ratio. Moreover, blockade of CCR2 signaling by MCP-1 neutralizing antibody inhibited H. pylori-stimulated bone marrow-derived DC maturation. CONCLUSIONS: Our results indicate that CCR2 plays an essential role in H. pylori induced immune tolerance and shed light on a novel mechanism of CCR2-dependent DC Treg induction, which appears to be important in maintaining mucosal homeostasis during H. pylori infection. PMID- 27933702 TI - Multiparameter Particle Display (MPPD): A Quantitative Screening Method for the Discovery of Highly Specific Aptamers. AB - Aptamers are a promising class of affinity reagents because they are chemically synthesized, thus making them highly reproducible and distributable as sequence information rather than a physical entity. Although many high-quality aptamers have been previously reported, it is difficult to routinely generate aptamers that possess both high affinity and specificity. One of the reasons is that conventional aptamer selection can only be performed either for affinity (positive selection) or for specificity (negative selection), but not both simultaneously. In this work, we harness the capacity of fluorescence activated cell sorting (FACS) for multicolor sorting to simultaneously screen for affinity and specificity at a throughput of 107 aptamers per hour. As a proof of principle, we generated DNA aptamers that exhibit picomolar to low nanomolar affinity in human serum for three diverse proteins, and show that these aptamers are capable of outperforming high-quality monoclonal antibodies in a standard ELISA detection assay. PMID- 27933703 TI - Effects of CPAP therapy on visceral fat thickness, carotid intima-media thickness and adipokines in patients with obstructive sleep apnoea. AB - BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is associated with an increased prevalence of metabolic syndrome. This study explores the effects of continuous positive airway pressure (CPAP) for patients with OSA on visceral and mesenteric fat thickness, carotid intima-media thickness (IMT) and adipokines. METHODS: A randomized controlled study was conducted at a teaching hospital on 90 patients newly diagnosed with OSA to receive either therapeutic CPAP or subtherapeutic CPAP for 3 months. Visceral fat thickness and carotid IMT were measured with B-mode ultrasound; adipokine levels were assessed at baseline and 3 months. RESULTS: Altogether, 45 patients received therapeutic CPAP and 45 received subtherapeutic CPAP without significant differences in age 50.3 (10.1) versus 48.7 (9.0) years, BMI 28.2 (3.9) versus 28.2 (4.5) kg/m2 , Epworth Sleepiness Scale (ESS) 12.4 (5.9) versus 11.3 (4.7), apnoea-hypopnoea index (AHI) 30.6 (21.4) versus 35.2 (25.5) /h, minimum SaO2 79.6 (10.8) versus 76.7 (12.4) % and existing co-morbidities. CPAP usage was therapeutic 4.2 (2.1) versus subtherapeutic 4.1 (2.0) h/night over 3 months. Adiponectin and irisin levels changed significantly following therapeutic CPAP for 3 months versus subtherapeutic CPAP (-1.6 vs 7.3, P = 0.042; 0.1 vs -0.1, P = 0.028 respectively) while only serum level of monocyte chemotactic protein 1 (MCP-1) at baseline was positively correlated with AHI (r = 0.278). No significant changes were observed in other adipokines, visceral fat thickness and IMT. CONCLUSION: Short-term therapeutic CPAP versus subtherapeutic CPAP does not significantly reduce visceral fat thickness and IMT, although it reduces adiponectin and increases irisin. PMID- 27933704 TI - What's in a name? Everything. PMID- 27933705 TI - Reply. PMID- 27933706 TI - Re: Fetoscopic repair of spina bifida: safer and better? PMID- 27933707 TI - Re: Ultrasound-based gestational-age estimation in late pregnancy. A. T. Papageorghiou, B. Kemp, W. Stones, E. O. Ohuma, S. H. Kennedy, M. Purwar, L. J. Salomon, D. G. Altman, J. A. Noble, E. Bertino, M. G. Gravett, R. Pang, L. Cheikh Ismail, F. C. Barros, A. Lambert, Y. A. Jaffer, C. G. Victora, Z. A. Bhutta and J. Villar, for the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st). Ultrasound Obstet Gynecol 2016; 48: 719-726. PMID- 27933708 TI - Reply. PMID- 27933709 TI - 26th World Congress on Ultrasound in Obstetrics and Gynecology, 25-28 September 2016, Rome, Italy: presentations and awards. PMID- 27933710 TI - Re: Relationship between general movements in neonates who were growth restricted in utero and prenatal Doppler flow patterns. J. C. Tanis, D. M. Schmitz, M. R. Boelen, L. Casarella, P. P. van den Berg, C. M. Bilardo and A. F. Bos. Ultrasound Obstet Gynecol 2016; 48: 772-778. PMID- 27933711 TI - Using a co-production prioritization exercise involving South Asian children, young people and their families to identify health priorities requiring further research and public awareness. AB - OBJECTIVES: To facilitate South Asian (SA) families and health-care professionals (HCPs) participation in a prioritization exercise to co-produce child health research and public awareness agendas. DESIGN: A three-stage process was adopted involving the following: (i) systematic literature review, (ii) HCP scoping survey and (iii) focus groups of SA adolescents and families. A Punjabi- and Urdu speaking community facilitator moderated focus groups. A British Sign Language interpreter assisted in the hard of hearing group. Concordant and discordant themes between HCPs and SAs were identified. SETTING: National survey of HCPs. Leicestershire for SA families. PARTICIPANTS: A total of 27 HCPs and 35 SAs. SAs varied by descent, age (16-74), UK stay length (3-57 years) religion and disability. RESULTS: Ranked by submission frequency in the survey, HCPs prioritized (i) public awareness on obesity, mental health, health-care access, vitamin D and routine health checks and (ii) research on nutrition, diabetes, health education and parenting methods. DISCUSSION: South Asians prioritized research into the effectiveness of alternative medicines, a theme not identified by HCPs. Both HCPs and SAs prioritized increased research or public awareness on mental health illness, blood and organ donation, obesity and diet. Whilst HCPs identified diabetes, vitamin D and rickets together with parenting methods were important priorities requiring increased public awareness, and these views were not shared by SAs. CONCLUSIONS: Minority groups are not always included in priority setting exercises due to concerns about language and perceived difficulty with accessing communities. Through this co-production exercise, we showed that it is possible and essential. PMID- 27933712 TI - The importance of mRNA structure in determining the pathogenicity of synonymous and non-synonymous mutations in haemophilia. AB - INTRODUCTION: Mutational analysis is commonly used to support the diagnosis and management of haemophilia. This has allowed for the generation of large mutation databases which provide unparalleled insight into genotype-phenotype relationships. Haemophilia is associated with inversions, deletions, insertions, nonsense and missense mutations. Both synonymous and non-synonymous mutations influence the base pairing of messenger RNA (mRNA), which can alter mRNA structure, cellular half-life and ribosome processivity/elongation. However, the role of mRNA structure in determining the pathogenicity of point mutations in haemophilia has not been evaluated. AIM: To evaluate mRNA thermodynamic stability and associated RNA prediction software as a means to distinguish between neutral and disease-associated mutations in haemophilia. METHODS: Five mRNA structure prediction software programs were used to assess the thermodynamic stability of mRNA fragments carrying neutral vs. disease-associated and synonymous vs. non synonymous point mutations in F8, F9 and a third X-linked gene, DMD (dystrophin). RESULTS: In F8 and DMD, disease-associated mutations tend to occur in more structurally stable mRNA regions, represented by lower MFE (minimum free energy) levels. In comparing multiple software packages for mRNA structure prediction, a 101-151 nucleotide fragment length appears to be a feasible range for structuring future studies. CONCLUSION: mRNA thermodynamic stability is one predictive characteristic, which when combined with other RNA and protein features, may offer significant insight when screening sequencing data for novel disease associated mutations. Our results also suggest potential utility in evaluating the mRNA thermodynamic stability profile of a gene when determining the viability of interchanging codons for biological and therapeutic applications. PMID- 27933713 TI - Antipsychotic adjunctive therapy to mood stabilizers and 1-year rehospitalization rates in bipolar disorder: A cohort study. AB - OBJECTIVES: Antipsychotic adjunctive therapy to mood stabilizers (MSs) may improve relapse prevention; however, only a few naturalistic studies, reflecting more generalizable bipolar disorder (BD) samples, support this notion. We compared the 1-year rehospitalization rates of manic patients with bipolar I disorder (BD-I) who were discharged with MS (lithium or valproate) monotherapy or with adjunctive atypical or typical antipsychotic therapy. METHODS: A total of 201 patients with BD-I who were hospitalized with manic episodes between 2005 and 2013 were retrospectively followed for 1-year rehospitalization rates according to treatment at discharge: MS monotherapy, MS with atypical antipsychotics, and MS with typical antipsychotics. Additionally, time to rehospitalization during the 1-year period after discharge was compared between treatment groups. Multivariable survival analyses adjusted for covariates known to influence rehospitalization were conducted. RESULTS: Rehospitalization rates within 1 year were significantly lower in the MS with atypical antipsychotics group (6.3%) compared to the MS monotherapy group (24.3%, P=.008) and to the MS with typical antipsychotics group (20.6%, P=.02). Time to rehospitalization was significantly longer for the MS with atypical antipsychotics group (345.5 days) compared to the MS monotherapy group (315.1 days, P=.006) and to the MS with typical antipsychotics group (334.1 days, P=.02). The MS with atypical antipsychotics group had a significantly reduced adjusted risk of rehospitalization (hazard ratio=0.17, 95% confidence interval: 0.05-0.61, P=.007) compared to the MS monotherapy group. CONCLUSIONS: Atypical antipsychotic adjunctive therapy to MSs may be more effective than MS monotherapy in preventing rehospitalization during the 1-year period after a BD manic episode. PMID- 27933714 TI - Development of Chemical Tools to Monitor and Control Isoaspartyl Peptide Methyltransferase Activity. AB - We have established a coupled assay system targeting protein l-isoaspartyl methyltransferase (PIMT), a key enzyme in the metabolism of isoaspartyl peptides and proteins. The system utilizes a fluorogenic peptide probe containing an isoaspartyl residue at the P1' position of the caspase-3 recognition sequence. Following PIMT-catalyzed methyl transfer reaction, the methylated probe is specifically cleaved by caspase-3 to give fluorescence activation. High throughput screening of our chemical library with this assay system identified PIMT inhibitors that may be useful as leads in the design of chemical probes for controlling PIMT activity. PMID- 27933715 TI - Efficacy of self-monitoring of blood glucose versus retrospective continuous glucose monitoring in improving glycaemic control in diabetic kidney disease patients. AB - AIMS: Patients with diabetic kidney disease (DKD) on anti-diabetic agents, are at greater risk of glycemic variations, both hypoglycemia and hyperglycemia. We aimed to compare glycemic control (using HbA1c) and hypoglycemia incidence in patients with Stage 3 DKD (eGFR 30-60 mL/min per 1.73 m2 ), receiving retrospective CGM-guided anti-diabetic therapy versus self-monitoring of blood glucose (SMBG) over 3 months. METHODS: Thirty patients with HbA1c >8% were randomized to 6-day retrospective CGM or SMBG. In the CGM group, CGM was worn at the beginning and 6 weeks. HbA1c, assessment of hypoglycaemia events (self reported and BG < 4 mmol/L from CGM/SMBG data) and medication adjustment were performed at baseline and 3 months. All patients received education on hypoglycaemia avoidance. RESULTS: Fourteen patients were allocated to CGM and 16 to SMBG. Mean (+/-SD) eGFR was 42.9 +/- 10.3 mL/min. Majority (86.7%) of patients had diabetes duration >10 years and on insulin therapy (90%). HbA1c improved significantly from baseline 9.9 +/- 1.2 to 9.0 +/- 1.5% (P < 0.001) at 3 months, with no difference between CGM (9.8 +/- 1.2 to 8.8 +/- 1.8%, P = 0.009) or SMBG (9.9 +/- 1.3 to 9.1 +/- 1.1%, P = 0.007) groups (P = 0.869 between groups). In the CGM group, percentage duration in hyperglycaemia (BG > 10 mmol/L) reduced from baseline 65.4 +/- 22.4% to 54.6 +/- 23.6% (P = 0.033) at 6 weeks, with a non significant rise in percentage duration in hypoglycaemia from 1.2 +/- 2.2% to 4.0 +/- 7.0% (P = 0.176). There was no difference in self-reported and documented hypoglycaemia events. CONCLUSION: In a pilot study of DKD patients, short-term episodic use of CGM reduced time spent in hyperglycaemia range without significantly increasing time-exposure to hypoglycaemia. However, both CGM and SMBG were equally effective in improving glycaemic control. PMID- 27933716 TI - Risks and treatment strategies for de novo hepatitis B virus infection from anti HBc-positive donors in pediatric living donor liver transplantation. AB - The aim of this study was to analyze the incidence and risk factors of de novo HBV infection in pediatric patients receiving living donor liver transplants (LDLT) from HBcAb-positive donors, and to explore its treatment strategies. The data of 101 pediatric recipients receiving LDLT in Tianjin First Central Hospital between September 2006 and December 2012 were retrospectively analyzed. The HBV markers were regularly tested before and after the surgery, including HBsAb, HBsAg, HBeAg, HBeAb, and HBcAb. The median follow-up period was 25.6 months, during which eight cases (7.92%) were diagnosed with de novo HBV infection. Forty four (43.6%) of the children received HBcAb-positive allografts. The rate of de novo HBV in the children that received HBcAb+ livers vs those received HBcAb- livers was 15.9% (7/44) vs 1.7% (1/57) (P=.037). The rates of de novo HBV in the children who received HBcAb-positive allografts were significantly less than in those that received preventative therapy with HBIG and lamivudine treatment (2/31, 6.4%) vs those that did not (5/13, 38.5%) (P<.01). HBcAb-positive liver donors are strongly associated with de novo HBV in HBsAg-negative pediatric patients receiving LDLT. However, the incidence of de novo HBV infection is significantly less with the use of prophylactic treatment strategies. PMID- 27933717 TI - Mass Cytometry Analytical Approaches Reveal Cytokine-Induced Changes in Natural Killer Cells. AB - BACKGROUND: Natural killer (NK) cells have antiviral and antitumor activity that could be harnessed for the treatment of infections and malignancies. To maintain cell viability and enhance antiviral and antitumor effects, NK cells are frequently treated with cytokines. Here they performed an extensive assessment of the effects of cytokines on the phenotype and function of human NK cells. METHODS: They used cytometry by time-of-flight (CyTOF) to evaluate NK cell repertoire changes after stimulation with interleukin (IL)-2, IL-15 or a combination of IL-12/IL-15/IL-18. To analyze the high dimensional CyTOF data, they used several statistical and visualization tools, including viSNE (Visualization of t-Distributed Stochastic Neighbor Embedding), Citrus (Cluster identification, characterization, and regression), correspondence analysis, and the Friedman-Rafsky test. RESULTS: All three treatments (IL-2, IL-15, and IL 12/IL-15/IL-18) increase expression of CD56 and CD69. The effects of treatment with IL-2 and IL-15 are nearly indistinguishable and characterized principally by increased expression of surface markers including CD56, NKp30, NKp44, and increased expression of functional markers, such as perforin, granzyme B, and MIP 1beta. The combination of IL-12/IL-15/IL-18 induces a profound shift in the repertoire structure, decreasing expression of CD16, CD57, CD8, NKp30, NKp46, and NKG2D, and dramatically increasing expression of IFN-gamma. CONCLUSIONS: CyTOF provides insights into the effects of cytokines on the phenotype and function of NK cells, which could inform future research efforts and approaches to NK cell immunotherapy. There are several analytical approaches to CyTOF data, and the appropriate method should be carefully selected based on which aspect of the dataset is being explored. (c) 2016 International Clinical Cytometry Society. PMID- 27933718 TI - Constipation in older people: A consensus statement. AB - BACKGROUND AND AIMS: Chronic constipation is a serious medical condition that affects 30%-40% of people over 60 years old. Although not normally life threatening, constipation reduces quality of life by the same extent as diabetes and osteoarthritis. There are currently no Europe-wide guidelines for treating constipation in older people, although there is some country-level guidance for the general population. We have evaluated the existing guidance and best clinical practice to improve the care of older people with constipation. METHOD: European healthcare professionals working in gastroenterology, geriatrics, nursing and pharmacology discussed the treatment of constipation in older people and reviewed existing guidance on the treatment of constipation in the general population. This manuscript represents the consensus of all authors. DISCUSSION: Most general guidance for constipation treatment recommends increased dietary fibre, fluid intake and exercise; however, this is not always possible in older patients. Although a common first-line treatment, bulk-forming laxatives are unsuitable for older people because of an associated need to increase fluid intake, osmotic laxatives are likely to be the most suitable laxative type for older patients. Treatment is often hampered by reluctance to talk about bowel problems so healthcare providers should proactively identify older constipated patients who are self-medicating or not receiving treatment. CONCLUSIONS: With certain modifications, general treatment guidelines can be applied to older people with constipation, although specific guidelines are still required for this age group. Awareness of constipation, its complications and treatment options need to be increased among healthcare providers, patients and carers. PMID- 27933719 TI - Depth profiling cross-linked poly(methyl methacrylate) films: a time-of-flight secondary ion mass spectrometry approach. AB - RATIONALE: In order to determine the degree of cross-linking on the surface and its variations in a nanometer-scale depth of organic materials, we developed an approach based on time-of-flight secondary ion mass spectrometry (TOF-SIMS), which provides rich chemical information in the form of fragment ions. TOF-SIMS is extremely surface-sensitive and capable of depth profiling with the use of a sputter ion beam to remove controllable amounts of substance. METHODS: Poly(methyl methacrylate) (PMMA) films spin-coated on a Si substrate were cross linked using a recently developed, surface sensitive, hyperthermal hydrogen projectile bombardment technique. The ion intensity ratio between two ubiquitous hydrocarbon ions, C6 H- and C4 H- , detected in TOF-SIMS, denoted as rho, was used to assess the degree of cross-linking of the PMMA films. The cross-linking depth of the PMMA films was revealed by depth profiling rho into the polymer films using a C60+ sputter beam. RESULTS: The control PMMA film spin-coated on a Si substrate was characterized by rho = 32% on its surface when using a 25 keV Bi3+ primary ion beam. This parameter on the PMMA films subjected to HHIC treatment for 10, 100 and 500 s increased to 45%, 56% and 65%, respectively. The depth profiles of rho obtained using a 10 keV C60+ ion beam resembled an exponential decay, from which the cross-linking depth was estimated to be 3, 15 and 39 nm, respectively, for the three cross-linked PMMA films. CONCLUSIONS: We demonstrated that the ion intensity ratio of C6 H- to C4 H- detected in TOF-SIMS provides a unique and simple means to assess the degree of cross-linking of the surface of PMMA films cross-linked by the surface sensitive hyperthermal hydrogen projectile bombardment technique. With a C60+ sputter beam, we were able to depth profile the PMMA films and determine cross-linking depths of the cross-linked polymer films at nanometer resolutions. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 27933720 TI - Autogenous bone grafting for treatment of osseous defect after impacted mandibular third molar extraction: A randomized controlled trial. AB - BACKGROUND: Extraction of impacted mandibular third molar (M3) has been cited as causing osseous defect at the distal aspect of the adjacent second molar (M2). PURPOSE: This randomized controlled trial was aimed to evaluate the effect of autogenous bone grafting in situ for regeneration of periodontal osseous defect distal to the M2 compared with non-grafting after impacted M3 removal. MATERIALS AND METHODS: A total of 60 sites in 51 adult patients were enrolled and randomly assigned to the control group or the test group. In both groups, the M3 was extracted using a piezosurgical device, and the distal root surface of M2 was scaled and root planned. In addition, the removed alveolar bone was grinded to particles and grafted to the distal osseous defect of M2 in the test group. The primary outcome variable was the osseous defect depth (ODD), the secondary outcome variables were probing pocket depth (PD) and clinical attachment level (CAL) on the disto-buccal aspect of the M2 during a 12-month follow-up period. Postoperative symptom at 7-day postoperatively and adverse events were also recorded and analyzed. RESULTS: The patient characteristics were homogeneous between the 2 groups. Six and 12 months after surgery, there were statistically significant bone fill in both groups (P < .01). Moreover, the ODD and CAL in the test group were significantly lower than the control group at every postoperative re-entry (P < .01). The postoperative symptom was more severe in the test group than the control group, but the difference was not significant (P > .05). CONCLUSIONS: The result of this study demonstrated that scaling and root planning was beneficial to periodontal healing of M2 after impacted M3 extraction. Addition of autogenous bone grafting for the treatment of osseous defects distal to M2 was safe and more effective than periodontal treatment alone. (Registry Number: ChiCTR-IOC-15006561). PMID- 27933721 TI - Shared molecular networks in orofacial and neural tube development. AB - BACKGROUND: Single genetic variants can affect multiple tissues during development. Thus it is possible that disruption of shared gene regulatory networks might underlie syndromic presentations. In this study, we explore this idea through examination of two critical developmental programs that control orofacial and neural tube development and identify shared regulatory factors and networks. Identification of these networks has the potential to yield additional candidate genes for poorly understood developmental disorders and assist in modeling and perhaps managing risk factors to prevent morbidly and mortality. METHODS: We reviewed the literature to identify genes common between orofacial and neural tube defects and development. We then conducted a bioinformatic analysis to identify shared molecular targets and pathways in the development of these tissues. Finally, we examine publicly available RNA-Seq data to identify which of these genes are expressed in both tissues during development. RESULTS: We identify common regulatory factors in orofacial and neural tube development. Pathway enrichment analysis shows that folate, cancer and hedgehog signaling pathways are shared in neural tube and orofacial development. Developing neural tissues differentially express mouse exencephaly and cleft palate genes, whereas developing orofacial tissues were enriched for both clefting and neural tube defect genes. CONCLUSION: These data suggest that key developmental factors and pathways are shared between orofacial and neural tube defects. We conclude that it might be most beneficial to focus on common regulatory factors and pathways to better understand pathology and develop preventative measures for these birth defects. Birth Defects Research 109:169-179, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27933722 TI - Management of Bladder Pain Syndrome: Green-top Guideline No. 70. PMID- 27933723 TI - Comparative molecular field analysis (CoMFA), topomer CoMFA, and hologram QSAR studies on a series of novel HIV-1 protease inhibitors. AB - Comparative molecular field analysis (CoMFA), topomer CoMFA, and hologram QSAR as three efficient methods of QSAR have been performed on 40 newly synthesized inhibitors against HIV-1 protease. Molecular alignment was performed by aid of crystallographic structure of template inhibitor (indirect alignment) and also by the molecular mechanic (MM)-minimized structure. Both alignment methods produced satisfactory statistics for training set, but indirect alignment had more predictive power. Generated counter maps, especially by topomer CoMFA, give comprehensive information about structural features affecting the inhibitory activities of studied chemicals. Based on the obtained information, some new inhibitors were suggested. PMID- 27933724 TI - Comparative analysis reveals amino acids critical for anticancer activity of peptide CIGB-552. AB - Because of resistance development by cancer cells against current anticancer drugs, there is a considerable interest in developing novel antitumor agents. We have previously demonstrated that CIGB-552, a novel cell-penetrating synthetic peptide, was effective in reducing tumor size and increasing lifespan in tumor bearing mice. Studies of protein-peptide interactions have shown that COMMD1 protein is a major mediator of CIGB-552 antitumor activity. Furthermore, a typical serine-protease degradation pattern for CIGB-552 in BALB/c mice serum was identified, yielding peptides which differ from CIGB-552 in size and physical properties. In the present study, we show the results obtained from a comparative analysis between CIGB-552 and its main metabolites regarding physicochemical properties, cellular internalization, and their capability to elicit apoptosis in MCF-7 cells. None of the analyzed metabolites proved to be as effective as CIGB 552 in promoting apoptosis in MCF-7. Taking into account these results, it seemed important to examine their cell-penetrating capacity and interaction with COMMD1. We show that internalization, a lipid binding-dependent process, is impaired as well as metabolite-COMMD1 interaction, key component of the apoptotic mechanism. Altogether, our results suggest that features conferred by the amino acid sequence are decisive for CIGB-552 biological activity, turning it into the minimal functional unit. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27933725 TI - Cellular engineering for therapeutic protein production: product quality, host modification, and process improvement. AB - Recombinant proteins offer many therapeutic advantages unavailable in traditional small molecule drugs, but the need for cellular versus chemical synthesis complicates production. Avenues for producing therapeutic biologics are continuously expanding, and developments in biochemistry, cell biology, and bioengineering fuel new discoveries that promise safer, more efficient, and cheaper drugs for consumers. Numerous approaches to express recombinant proteins exist, but Escherichia coli, Saccharomyces cerevisiae, and mammalian systems (e.g. Chinese hamster ovary cells, CHO) are the most widely utilized. Improvements to production in these hosts have focused on novel expression cassettes, cell line modifications, engineering secretion pathways, and media design. Here, we describe recent developments for improving protein production in E. coli, S. cerevisiae, and CHO systems and compare recent advancements to previous knowledge in the field. With the expanding importance and prevalence of protein therapeutics, these improvements will serve as the framework for future discoveries. PMID- 27933726 TI - Inheritance of evolved clethodim resistance in Lolium rigidum populations from Australia. AB - BACKGROUND: In Australia, the extensive use of clethodim for the control of Lolium rigidum has resulted in the evolution of many clethodim-resistant L. rigidum populations. Five clethodim-resistant populations of L. rigidum were analysed for the inheritance of clethodim resistance. RESULTS: Reciprocal crosses were made between resistant (R) and susceptible (S) populations. Within crosses, dose-responses of reciprocal F1 families of all populations except A61 were similar to each other, indicating that clethodim resistance in these populations is encoded on the nuclear genome. The level of dominance observed in the dose response experiments ranged from partial to complete within the herbicide rate used. In the A61 population, within each cross, the response of F1 from the maternal and paternal parent was different, indicating that resistance is inherited through the female parent. All backcross populations segregated in a different manner. Only one population, FP, fitted a single-gene model (1:1). Two populations fitted two-gene models: a 3:1 inheritance model for F4 and a 1:3 inheritance model for A91. For population E2, no clear pattern of inheritance was determined, suggesting more complex inheritance. CONCLUSION: The results of this study indicate that different patterns of clethodim resistance in L. rigidum exist. (c) 2016 Society of Chemical Industry. PMID- 27933727 TI - Mapping of inhibitors and activity data to the human kinome and exploring promiscuity from a ligand and target perspective. AB - An up-to-date collection of publicly available kinase inhibitors and activity data was mapped to the human kinome to comprehensively analyze current small molecule-kinase interactions. Compound distributions across the kinome were explored, structural relationships between inhibitors determined, and the tendency to form activity cliffs assessed. Furthermore, promiscuity was analyzed at the level of inhibitors and kinases, and a number of kinase targets with distinct preferences for single- or multitarget inhibitors were identified. Taken together, the results of current analysis provide a detailed view of kinase inhibitor interaction characteristics across the human kinome. PMID- 27933729 TI - Corrigendum to Morrison (2016), "ALE meta-analysis reveals dissociable networks for affective and discriminative aspects of touch." PMID- 27933728 TI - Sequential change detection and monitoring of temporal trends in random-effects meta-analysis. AB - Temporal changes in magnitude of effect sizes reported in many areas of research are a threat to the credibility of the results and conclusions of meta-analysis. Numerous sequential methods for meta-analysis have been proposed to detect changes and monitor trends in effect sizes so that meta-analysis can be updated when necessary and interpreted based on the time it was conducted. The difficulties of sequential meta-analysis under the random-effects model are caused by dependencies in increments introduced by the estimation of the heterogeneity parameter tau2 . In this paper, we propose the use of a retrospective cumulative sum (CUSUM)-type test with bootstrap critical values. This method allows retrospective analysis of the past trajectory of cumulative effects in random-effects meta-analysis and its visualization on a chart similar to CUSUM chart. Simulation results show that the new method demonstrates good control of Type I error regardless of the number or size of the studies and the amount of heterogeneity. Application of the new method is illustrated on two examples of medical meta-analyses. (c) 2016 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd. PMID- 27933730 TI - Reactivity of 9-aminoacridine drug quinacrine with glutathione limits its antiprion activity. AB - Quinacrine-the drug based on 9-aminoacridine-failed in clinical trials for prion diseases, whereas it was active in in vitro studies. We hypothesize that aromatic nucleophilic substitution at C9 could be contributing factor responsible for this failure because of the transfer of acridine moiety from quinacrine to abundant glutathione. Here, we described the semi-large-scale synthesis of the acridinylated glutathione and the consequences of its formation on biological and biophysical activities. The acridinylated glutathione is one order of magnitude weaker prion protein binder than the parent quinacrine. Moreover, according to log DpH 7.4 , the glutathione conjugate is two orders of magnitude more hydrophilic than quinacrine. Its higher hydrophilicity and higher dsDNA binding potency will significantly decrease its bioavailability in membrane-like environment. The glutathione deactivates quinacrine not only directly but also decreases its bioavailability. Furthermore, the conjugate can spontaneously decompose to practically insoluble acridone, which is precipitated out from the living systems. PMID- 27933731 TI - Independent risk factors for the development of skin erosion due to incontinence (incontinence-associated dermatitis category 2) in nursing home residents: results from a multivariate binary regression analysis. AB - The aim of this study was to identify characteristics independently associated with a higher risk of developing skin damage because of incontinence [incontinence-associated dermatitis (IAD) category 2] in nursing home residents. As part of a larger randomised controlled trial, IAD incidence was monitored for 1 month in a sample of 381 incontinent residents using a validated IAD Severity Categorisation Tool. Data on demographical, physical, functional and psychological characteristics were collected. The overall IAD incidence (category 1-2) was 30.0%, and 6% of the participants developed skin damage (IAD category 2). Residents who developed IAD category 2 were less mobile [odds ratio (OR) 2.72, 95% confidence interval (CI) 1.06-6.94], had more friction and shear issues (OR 2.54; 95% CI 1.02-6.33) and had more erythema due to incontinence (OR 3.02; 95% CI 1.04-8.73) before IAD category 2 occurrence. Care providers should give full attention to risk factors to both detect residents at risk for IAD development and to start prevention in time. PMID- 27933732 TI - Hypothesis-driven physical examination curriculum. AB - BACKGROUND: Medical students traditionally learn physical examination skills as a rote list of manoeuvres. Alternatives like hypothesis-driven physical examination (HDPE) may promote students' understanding of the contribution of physical examination to diagnostic reasoning. We sought to determine whether first-year medical students can effectively learn to perform a physical examination using an HDPE approach, and then tailor the examination to specific clinical scenarios. Medical students traditionally learn physical examination skills as a rote list of manoeuvres CONTEXT: First-year medical students at the University of Minnesota were taught both traditional and HDPE approaches during a required 17-week clinical skills course in their first semester. The end-of-course evaluation assessed HDPE skills: students were assigned one of two cardiopulmonary cases. Each case included two diagnostic hypotheses. During an interaction with a standardised patient, students were asked to select physical examination manoeuvres in order to make a final diagnosis. Items were weighted and selection order was recorded. INNOVATION: First-year students with minimal pathophysiology performed well. All students selected the correct diagnosis. Importantly, students varied the order when selecting examination manoeuvres depending on the diagnoses under consideration, demonstrating early clinical decision-making skills. IMPLICATIONS: An early introduction to HDPE may reinforce physical examination skills for hypothesis generation and testing, and can foster early clinical decision-making skills. This has important implications for further research in physical examination instruction. PMID- 27933733 TI - Mannich bases of 1,2,4-triazole-3-thione containing adamantane moiety: Synthesis, preliminary anticancer evaluation, and molecular modeling studies. AB - A series of 18 novel N-Mannich bases derived from 5-adamantyl-1,2,4-triazole-3 thione was synthesized and characterized using NMR spectroscopy and X-ray diffraction technique. All derivatives were evaluated for their anticancer potential against four human cancer cell lines. Several tested compounds exerted good cytotoxic activities on K562 and HL-60 cell lines, along with pronounced selectivity, showing lower cytotoxicity against normal fibroblasts MRC-5 compared to cancer cells. The effects of compounds 5b, 5e, and 5j on the cell cycle were investigated by flow cytometric analysis. It was found that these compounds cause the accumulation of cells in the subG1 and G1 phases of the cell cycle and induce caspase-dependent apoptosis, while the anti-angiogenic effects of 5b, 5e, and 5j have been confirmed in EA.hy926 cells using a tube formation assay. Further, the interaction of Bax protein with compound 5b was investigated by means of molecular modeling, applying the combined molecular docking/molecular dynamics approach. PMID- 27933734 TI - Improved quality of life in asthma patients under long-term therapy: Assessed by AHQ-Japan. AB - BACKGROUND AND OBJECTIVES: Assessment of the effects of long-term management on patient quality of life (QOL) would be extremely useful for determining asthma treatment strategies. However, no studies have evaluated QOL over an extended period of time. This study evaluated the changes in QOL, drug management and disease severity in the same asthma patients at an interval of approximately 9 years. METHODS: We re-surveyed asthma patients enrolled in a survey conducted in 2004 to evaluate the effects of approximately a decade of treatment on disease severity and QOL assessed by the Japanese Asthma Health Questionnaire (AHQ JAPAN). RESULTS: A total of 2179 patients were enrolled in the study from 93 centres, and 1332 patients were included in the per-protocol analysis. Usage rates of inhaled corticosteroids (ICS) for treatment of stable asthma were over 90% at both time points. The AHQ-JAPAN total score improved significantly from 22.2+/-19.7 in 2004 to 19.7+/-19.9 in 2013 (P<.001). Significant improvements were also observed in 5 of 6 subscales of AHQ-JAPAN, with Social Activity constituting the sole exception. CONCLUSIONS: Asthma severity declined and QOL assessed by AHQ-JAPAN improved, which is considered as a reflection of improved asthma control at least partly attributable to widespread use of anti inflammatory drugs as represented by ICS. The study also revealed the presence of those with poor QOL, especially in patients with concomitant respiratory diseases, and an increase in severe persistent asthma cases, warranting further long-term efforts at improving QOL. TRIAL REGISTRATION NUMBER: UMIN 000010483. PMID- 27933735 TI - Danazol has potential to cause PKC translocation, cell cycle dysregulation, and apoptosis in breast cancer cells. AB - Danazol, the established clinical drug, has given promising therapeutic results in a series of clinical trials with breast cancer patients. Danazol shares structural similarities with several known PKC agonists and fits well into the C1 domain. Danazol binds to the C1b domain of PKC with Kd of 5.64 +/- 1.27 MUm. MD simulation studies further support that the PKC-danazol molecular model is stable and showing minimum distortion to the structure during the simulation period. Immunofluorescence and Western blotting studies indicate that MDAMB-231 cells stimulated with danazol exhibit translocation of PKCalpha to the plasma membrane. Cells stimulated with danazol causes appearance of several phosphorylated proteins in lysate and plasma membrane. In addition, danazol affects carcinogenic molecule (PMA)-induced intracellular signaling in cancer cells. It halted the cancer cells in the G1 phase of the cell cycle and reduced the viability of ER+ve and triple-negative breast cancer cells with an IC50 of 31 +/- 2.63 and 65 +/- 4.27 MUg/ml, respectively. DNA fragmentation and flow cytometry experiments revealed that the cell death follows the apoptotic pathway. It affects mitochondrial membrane potentials and releases cytochrome-C from mitochondria to induce downstream apoptosis in breast cancer cells. Hence, the current study may help clinicians to re-design their treatment strategy to optimize therapeutic potentials of the molecule. PMID- 27933736 TI - Structural insight into the antiprion compound inhibition mechanism of native prion folding over misfolding. AB - Transition of a physiological folded prion (PrPC ) into a pathogenic misfolded prion (PrPSc ) causes lethal neurodegenerative disorders and prion diseases. Antiprion compounds have been developed to prevent this conversion; however, their mechanism of action remains unclear. Recently, we reported two antiprion compounds, BMD29 and BMD35, identified by in silico and in vitro screening. In this study, we used extensive explicit-solvent molecular dynamics simulations to investigate ligand-binding inhibition by antiprion compounds in prion folding over misfolding behavior at acidic pH. The two antiprion compounds and the previously reported GN8 compound resulted in a remarkably stabilized intermediate by binding to the hotspot region of PrPC , whereas free PrPC and the inactive compound BMD01 destabilized the structure of PrPC leading to the misfolded form. The results uncovered a secondary structural transition of free PrPC and transition suppression by the antiprion compounds. One of the major misfolding processes in PrPC , alternation of hydrophobic core residues, disruption of intramolecular interactions, and the increase in residue solvent exposure were significantly inhibited by both antiprion compounds. These findings provide insights into prion misfolding and inhibition by antiprion compounds. PMID- 27933737 TI - Testing the influence of surfactant-based wound dressings on proteinase activity. AB - Proteinases are enzymes that can digest other proteins. In chronic wounds, a sub class of these enzymes with the ability to degrade the extracellular matrix (matrix metalloproteinases, MMPs) have been found to both inhibit healing and to be able to aid in enzymatically debriding a wound. Enzymatic debridement using the enzymes present in a wound is generally called autolytic debridement. Clinicians seeking to employ autolytic debridement typically use occlusive materials such as medical honey, alginate dressings and other occlusive dressings. A relatively new class of gel dressings comprised of surfactants are now available for clinical use. A variety of surfactants are used in the study of MMP biochemistry. Surfactants can deactivate MMPs or can enhance their activity, depending on the surfactant. In order to begin to understand how the MMPs found in chronic wounds would respond to these new dressings, we tested a serial dilution series of two of the currently available surfactant-based dressings to determine their effects on four separate MMPs. The dose-response versus MMP activity of bacterial collagenase, host-derived MMP-8 and MMPs-2 and -9 was assessed using a simple mix-and-read fluorescent peptide activity assay. The enzyme's native activity in the absence of the gel was used to compare against the surfactant-treated samples. We found that the surfactant affected the proteinase activity differently for each enzyme. The activity of the bacterial collagenase was increased at low concentrations but slightly inhibited as the concentrations increased. The host MMP-8 collagenase responded similarly in that it was inhibited at higher concentrations. Interestingly, both MMP gelatinases presented with substantially increased activities, with MMP-2 increased to 200% of native activity, while MMP-9 presented with an increase of 300% activity over the same concentration range. MMPs appear to respond to a surfactant-based gel dressing differentially, with the MMP most commonly elevated in chronic wounds having the highest boost to activity. In wounds with elevated MMPs, our data suggest that the use of these surfactant-based dressings would be expected to enhance the activity of MMPs 2 and 9 gelatinases while simultaneously inhibiting MMP-8 collagenase. Hypothetically, this imbalanced effect would support a protection of the native dermal collagen and removal of denatured materials. However, the demonstration of these anticipated consequences is still being investigated. PMID- 27933738 TI - Exploratory analysis of textual data from the Mother and Child Handbook using a text mining method (II): Monthly changes in the words recorded by mothers. AB - AIM: The aim of the study was to examine the possibility of converting subjective textual data written in the free column space of the Mother and Child Handbook (MCH) into objective information using text mining and to compare any monthly changes in the words written by the mothers. METHODS: Pregnant women without complications (n = 60) were divided into two groups according to State-Trait Anxiety Inventory grade: low trait anxiety (group I, n = 39) and high trait anxiety (group II, n = 21). Exploratory analysis of the textual data from the MCH was conducted by text mining using the Word Miner software program. Using 1203 structural elements extracted after processing, a comparison of monthly changes in the words used in the mothers' comments was made between the two groups. The data was mainly analyzed by a correspondence analysis. RESULTS: The structural elements in groups I and II were divided into seven and six clusters, respectively, by cluster analysis. Correspondence analysis revealed clear monthly changes in the words used in the mothers' comments as the pregnancy progressed in group I, whereas the association was not clear in group II. CONCLUSION: The text mining method was useful for exploratory analysis of the textual data obtained from pregnant women, and the monthly change in the words used in the mothers' comments as pregnancy progressed differed according to their degree of unease. PMID- 27933739 TI - Light asymmetry explains the effect of nutrient enrichment on grassland diversity. AB - One of the most ubiquitous patterns in plant ecology is species loss following nutrient enrichment. A common explanation for this universal pattern is an increase in the size asymmetry of light partitioning (the degree to which large plants receive more light per unit biomass than smaller plants), which accelerates the rates of competitive exclusions. This 'light asymmetry hypothesis' has been confirmed by mathematical models, but has never been tested in natural communities due to the lack of appropriate methodology for measuring the size asymmetry of light partitioning in natural communities. Here, we use a novel approach for quantifying the asymmetry of light competition which is based on measurements of the vertical distribution of light below the canopy. Using our approach, we demonstrate that an increase in light asymmetry is the main mechanism behind the negative effect of nutrient enrichment on species richness. Our results provide a possible explanation for one of the main sources of contemporary species loss in terrestrial plant communities. PMID- 27933740 TI - Fine needle aspiration in the diagnosis and classification of hepatoblastoma: Analysis of 21 New Cases. AB - BACKGROUND: Diagnosis of hepatoblastoma (HBL) is based on characteristic clinical and radiological presentation, young age and marked elevation of serum alpha fetoprotein (aFP). Fine needle aspiration (FNA) technique is successfully used in the diagnosis of hepatoblastoma. To evaluate the value of FNA in the diagnosis and subtyping of HBL, we report our experience correlated to histological sections (core needle biopsy, CNB). METHODS: From 1991 to 2015, 21 cases from 20 patients were cytologically diagnosed as HBL. The patients were 15 males and 5 females, mean age being 3 years, and median age being 2 years and 4 months. Serum aFP levels ranged from negative to 1,285,000 ng/ml. We defined cytological criteria to diagnose fetal, embryonal, mesenchymal, and small cell undifferentiated components. RESULTS: The accurate cytological diagnosis of HBL was made in all cases; 8 cases exhibited a single component and 13 cases exhibited two or more components. Fetal and embryonal components were seen in 18 and 13 cases, respectively, and small cell undifferentiated component was seen in one case. Mesenchymal component was seen in 12 cases. Comparing cytology and histology, identical components were identified on both, FNA and CNB in 14 cases. When analyzing only the presence of epithelial components, 17 cases were concordant in both techniques. CONCLUSION: FNA allows to accurately diagnose HBL and recognize its histological subtypes. On the basis of high concordance between cytological and histological diagnosis, FNA is validated as an alternative diagnostic method to CNB. Diagn. Cytopathol. 2017;45:91-100. (c) 2016 Wiley Periodicals, Inc. PMID- 27933741 TI - Freezing-Facilitated Dehydration Allowing Deposition of ZnO from Aqueous Electrolyte. AB - When an aqueous NaCl solution with low concentrations of transition metal ions is frozen, most of the solutes are concentrated in the freeze concentrated solutions (FCS). However, Zn2+ is often accumulated at sites where other elements are not detected. X-ray absorption near-edge structure spectroscopy at the Zn K-edge indicates the formation of ZnO. A possible mechanism for the ZnO formation is discussed. PMID- 27933742 TI - Ethics of care in technology design. PMID- 27933743 TI - Where is Australasian Journal on Ageing being read? PMID- 27933744 TI - Neurolaw and Banks v Goodfellow (1870): Guidance for the assessment of testamentary capacity today. PMID- 27933745 TI - Corrigendum. PMID- 27933747 TI - Butler's three constructs of ageism in Australasian Journal on Ageing [corrected]. PMID- 27933748 TI - Exploring Glucocorticoid Receptor Agonists Mechanism of Action Through Mass Cytometry and Radial Visualizations. AB - Recent advances in combining flow cytometry and mass spectrometry have led to the development of mass cytometry, allowing for the interrogation of complex cell populations on an unprecedented scale. The volumes and high dimensionality of mass cytometry data pose significant challenges in terms of analysis and visualization. We implement a method called Radviz, where multidimensional single cell data can be visualized as a projection that maintains the original dimensions and data complexity whilst facilitating analysis and visualization. This enables identification of changes in populations, focusing the analysis on the most relevant aspect of large multidimensional datasets. To highlight the potential of Radviz, we profiled peripheral mononuclear blood cells (PBMCs) from three healthy donors and showed donor-specific differences in the number and composition of cell populations. In a second study, we explored the anti inflammatory effects of two glucocorticoid receptor (GR) ligands (cpd6 and cpd11) compared to dexamethasone (Dex) on human primary macrophages. Standard analysis at the population level showed that cpd6 and cpd11 have an overall anti inflammatory profile similar to that of Dex. CyTOF profiling and Radviz-driven analysis at the single cell level confirmed this observation, and identified a concentration-dependent effect of cpd6 that was not detected at the population level. Altogether, Radviz combines the strengths of a projection method, reducing the dimensionality of datasets, with that of a scatter plot, where the identity of each point can be inferred from the distance to the axis. This enables the visual exploration, analysis, and interpretation of complex, high dimensional data. (c) 2016 International Clinical Cytometry Society. PMID- 27933749 TI - Black Magic in Gray Titania: Noble-Metal-Free Photocatalytic H2 Evolution from Hydrogenated Anatase. AB - 'Black' TiO2 -in the widest sense, TiO2 reduced by various treatments-has attracted tremendous scientific interest in recent years because of some outstanding properties; most remarkably in photocatalysis. While the material effects visible light absorption (the blacker, the better), black titania produced by high pressure hydrogenation was recently reported to show another highly interesting feature; noble-metal-free photocatalytic H2 generation. In a systematic investigation of high-temperature hydrogen treatments of anatase nanoparticles, TEM, XRD, EPR, XPS, and photoelectrochemistry are used to characterize different degrees of surface hydrogenation, surface termination, electrical conductivity, and structural defects in the differently treated materials. The materials' intrinsic activity for photocatalytic hydrogen evolution is coupled neither with their visible light absorption behavior nor the formation of amorphous material, but rather must be ascribed to optimized and specific defect formation (gray is better than black). This finding is further confirmed by using a mesoporous anatase matrix as a hydrogenation precursor, which, after conversion to the gray state, even further enhances the overall photocatalytic hydrogen evolution activity. PMID- 27933750 TI - Comparing glucose and hemoglobin A1c diagnostic tests among a high metabolic risk Hispanic population. AB - BACKGROUND: Compare glycated hemoglobin (HbA1c ) diagnostic tests for prediabetes and diabetes with plasma glucose criteria and compare the metabolic profiles of people classified by HbA1c versus by glucose levels. METHODS: Participants were recruited for the San Juan Overweight Adults Longitudinal Study. The participants were primarily Hispanic (98%), without previously diagnosed diabetes, and aged 40 to 65 years. Participants classified as normal glycemic, prediabetes, or diabetes on the basis of baseline HbA1c and plasma glucose criteria were compared with respect to baseline cardiometabolic factors. RESULTS: The 1342 participants had a mean age of 50.5 +/- 6.8 years and 28% were men. Thirty-one percent were diagnosed with prediabetes by plasma glucose criteria and 53.4% by HbA1c , and 8.1% were diagnosed with diabetes by plasma glucose criteria and 6.3% by HbA1c ; overall concordance rate was 55.1%. The area under the receiver operating characteristic curve of HbA1c compared to plasma glucose criteria was 0.62 for impaired glucose and 0.76 for diabetes. A worse cardiometabolic profile was seen within subgroups that met HbA1c and plasma glucose criteria for diabetes or prediabetes. Those diagnosed with prediabetes by plasma glucose criteria had significantly higher systolic blood pressure and higher homeostatic model assessment than those diagnosed using HbA1c . Participants diagnosed with diabetes by plasma glucose criteria had lower body mass index, smaller waist circumference, and lower insulinogenic and disposition indices, but higher homeostatic model assessment of insulin resistance, than those diagnosed by HbA1c . CONCLUSIONS: Low concordance was seen between HbA1c and glucose measurements. The HbA1c is not a good test for prediabetes but shows reasonable validity for diabetes in this high-risk predominantly female Hispanic population. People classified by HbA1c , plasma glucose criteria, or both show different metabolic profiles; a combined test may be ideal. PMID- 27933751 TI - Synthesis of Acetone-Derived C6 , C9 , and C12 Carbon Scaffolds for Chemical and Fuel Applications. AB - A simple, inexpensive catalyst system (Amberlyst 15 and Ni/SiO2 -Al2 O3 ) is described for the upgrading of acetone to a range of chemicals and potential fuels. Stepwise hydrodeoxygenation of the produced ketones can yield branched alcohols, alkenes, and alkanes. An analysis of these products is provided, which demonstrates that this approach can provide a product profile of valuable bioproducts and potential biofuels. PMID- 27933754 TI - Tandem Thorpe Reaction/Palladium Catalyzed Asymmetric Allylic Alkylation: Access to Chiral beta-enaminonitriles with Excellent Enantioselectivity. AB - A new type of nucleophile, a 3-imino nitrile carbanion generated in situ by Thorpe reaction of acetonitrile with a base, was developed successfully and applied in a Pd-catalyzed asymmetric allylic alkylation with mono-substituted allyl reagents under Pd/SIOCPhox catalysis, affording beta-enaminonitrile products in high yields with excellent regio- and enantioselectivities. PMID- 27933753 TI - Mass Cytometry of Follicular Lymphoma Tumors Reveals Intrinsic Heterogeneity in Proteins Including HLA-DR and a Deficit in Nonmalignant Plasmablast and Germinal Center B-Cell Populations. AB - BACKGROUND: Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma that has a risk of transformation to more aggressive lymphoma. Relatively little is known about the nonmalignant B-cell and T-cell subset composition within the tumor microenvironment and whether altered phenotypes are associated with patterns of lymphoma B-cell heterogeneity. METHODS: Two mass cytometry (CyTOF) panels were designed to immunophenotype B and T cells in FL tumors. Populations of malignant B cells, nonmalignant B cells, and T cells from each FL tumor were identified and their phenotypes compared to B and T cells from healthy human tonsillar tissue. RESULTS: Diversity in cellular phenotype between tumors was greater for the malignant B cells than for nonmalignant B or T cells. The malignant B-cell population bore little phenotypic similarity to any healthy B-cell subset, and unexpectedly clustered closer to naive B-cell populations than GC B-cell populations. Among the nonmalignant B cells within FL tumors, a significant lack of GC and plasmablast B cells was observed relative to tonsil controls. In contrast, nonmalignant T cells in FL tumors were present at levels similar to their cognate tonsillar T-cell subsets. CONCLUSION: Mass cytometry revealed that diverse HLA-DR expression on FL cells within individual tumors contributed greatly to tumor heterogeneity. Both malignant and nonmalignant B cells in the tumor bore little phenotypic resemblance to healthy GC B cells despite the presence of T follicular helper cells in the tumor. These findings suggest that ongoing signaling interactions between malignant B cells and intra-tumor T cells shape the tumor microenvironment. (c) 2016 International Clinical Cytometry Society. PMID- 27933756 TI - Corrigendum. PMID- 27933755 TI - Maternal pre-pregnancy BMI downregulates neonatal cord blood LEP methylation. AB - BACKGROUND: Neonatal adiposity has many determinants and may be a risk factor for future obesity. Epigenetic regulation of metabolically important genes is a potential contributor. OBJECTIVES: The objective of the study is to determine whether methylation changes in the LEP gene in cord blood DNA are impacted by the maternal environment or affect neonatal adiposity measures. METHODS: A cross sectional study of 114 full-term neonates born to healthy mothers with normal glucose tolerance was performed. Cord blood was assayed for leptin and genome wide DNA methylation profiles via the Illumina 450K platform. Neonatal body composition was measured by air displacement plethysmography. Multivariate linear regression models and semi-partial correlation coefficients were used to analyze associations. False discovery rate was estimated to account for multiple comparisons. RESULTS: Maternal pre-pregnancy BMI was associated with decreased methylation at five CpG sites near the LEP transcription start site in an adjusted model (false discovery rate <0.022 for each site). The association between maternal BMI and cord blood leptin approached significance (r = 0.18, p = 0.054). Cord blood leptin was positively correlated with neonatal adiposity measures including birth weight (r = 0.45, p < 0.001), fat mass (r = 0.47, p < 0.001) and percent body fat (r = 0.44, p < 0.001). CONCLUSIONS: Maternal pre pregnancy BMI is strongly associated with decreased cord blood LEP gene methylation and may mediate the well-known association between maternal pre pregnancy BMI and neonatal adiposity. PMID- 27933758 TI - Solid Solution Quantum Dots with Tunable Dual or Ultrabroadband Emission for LEDs. AB - Quantum dots that efficiently emit white light directly or feature a "candle like" orange photoluminescence with a high Stokes shift are presented. The key to obtaining these unique emission properties is through controlled annealing of the core Cu-In-Ga-S quantum dots in the presence of zinc ions, thus forming Zn-Cu-In Ga-S solid solutions with different distributions of the substitution and dopant elements. The as-obtained nanocrystals feature excellent quantum yields of up to 82% with limited or even eliminated reabsorption and a color rendering index of bare particles of up to 88, enabling the production of high-quality white LEDs using a single color converter layer. Furthermore, the color properties can be tuned by changing the experimental conditions as well as by varying the excitation wavelength. The multicomponent luminescence mechanism is discussed in detail based on similar literature reports. White LEDs with unparalleled color quality and competitive luminous efficacies are presented herein. PMID- 27933757 TI - Structure and Dynamics of DNA and RNA Double Helices Obtained from the GGGGCC and CCCCGG Hexanucleotide Repeats That Are the Hallmark of C9FTD/ALS Diseases. AB - A (GGGGCC) hexanucleotide repeat (HR) expansion in the C9ORF72 gene, and its associated antisense (CCCCGG) expansion, are considered the major cause behind frontotemporal dementia and amyotrophic lateral sclerosis. We have performed molecular dynamics simulations to characterize the conformation and dynamics of the 12 duplexes that result from the three different reading frames in sense and antisense HRs for both DNA and RNA. These duplexes display atypical structures relevant not only for a molecular level understanding of these diseases but also for enlarging the repertoire of nucleic-acid structural motifs. G-rich helices share common features. The inner G-G mismatches stay inside the helix in Gsyn Ganti conformations and form two hydrogen bonds (HBs) between the Watson-Crick edge of Ganti and the Hoogsteen edge of Gsyn. In addition, Gsyn in RNA forms a base-phosphate HB. Inner G-G mismatches cause local unwinding of the helix. G rich double helices are more stable than C-rich helices due to better stacking and HBs of G-G mismatches. C-rich helix conformations vary wildly. C mismatches flip out of the helix in DNA but not in RNA. Least (most) stable C-rich RNA and DNA helices have single (double) mismatches separated by two (four) Watson-Crick basepairs. The most stable DNA structure displays an "e-motif" where mismatched bases flip toward the minor groove and point in the 5' direction. There are two RNA conformations, where the orientation and HB pattern of the mismatches is coupled to bending of the helix. PMID- 27933759 TI - Up to 100% Formation Ratio of Doublet Exciton in Deep-Red Organic Light-Emitting Diodes Based on Neutral pi-Radical. AB - In a neutral pi-radical-based organic light-emitting diode (OLED), although the emission comes from the doublet excitons and their transition to the ground state is spin-allowed, the upper limit of internal quantum efficiency (IQE) is not clear, 50% or 100%? In this work, the deep-red OLEDs based on a neutral pi radical were fabricated. Up to 100% doublet exciton formation ratio was obtained through rational designing device structure and host-guest doping system. This indicates the IQE of neutral pi-radical-based OLEDs will reach 100% if the nonradiative pathways of radicals can be suppressed. The maximum external quantum efficiency of the optimized device is as high as 4.3%, which is among the highest values of deep-red/near-infrared OLEDs with nonphosphorescent materials as emitters. Our results also indicate that using partially reduced radical mixture as emitter may be a way to solve aggregation-caused quenching in radical-based OLEDs. PMID- 27933761 TI - Multiphase Media Antiadhesive Coatings: Hierarchical Self-Assembled Porous Materials Generated Using Breath Figure Patterns. AB - The cleaning of interface pollutants typically consumes a large amount of energy. Therefore, the development of multiphase media antiadhesive materials is urgently required to meet the demand of energy savings and environmental protection. In this study, the antiadhesive properties toward several liquid droplets and bubbles in multiple media are demonstrated on a porous Fe2O3 coating, which is prepared via a facile spin-coating-assisted breath figure approach and a phase separation strategy. The prominent antiadhesive characteristic of these porous surfaces lies in their high-surface-energy hierarchical micro/nanoscale structure, which easily entraps one medium (oil or water) in the pore and repels other unmixable liquids and air bubbles. In addition, we successfully demonstrate an antifouling application of the coating, which shows excellent antiadhesive and super-antiwetting characteristics under multiple liquids. Our work extends relevant antiadhesion research from a single medium to multiple media and promises to broaden the applications of antiadhesive materials in sophisticated activities performed under complicated liquid environments, such as marine antifouling or pipeline transportation. PMID- 27933760 TI - Structural and Electrical Characterization of SiO2 Gate Dielectrics Deposited from Solutions at Moderate Temperatures in Air. AB - Silicon dioxide (SiO2) is the most widely used dielectric for electronic applications. It is usually produced by thermal oxidation of silicon or by using a wide range of vacuum-based techniques. By default, the growth of SiO2 by thermal oxidation of silicon requires the use of Si substrates whereas the other deposition techniques either produce low quality or poor interface material and mostly require high deposition or annealing temperatures. Recent investigations therefore have focused on the development of alternative deposition paradigms based on solutions. Here, we report the deposition of SiO2 thin film dielectrics deposited by spray pyrolysis in air at moderate temperatures of ~350 degrees C from pentane-2,4-dione solutions of SiCl4. SiO2 dielectrics were investigated by means of UV-vis absorption spectroscopy, spectroscopic ellipsometry, XPS, XRD, UFM/AFM, admittance spectroscopy, and field-effect measurements. Data analysis reveals smooth (RRMS < 1 nm) amorphous films with a dielectric constant of about 3.8, an optical band gap of ~8.1 eV, leakage current densities in the order of ~10-7 A/cm2 at 1 MV/cm, and high dielectric strength in excess of 5 MV/cm. XPS measurements confirm the SiO2 stoichiometry and FTIR spectra reveal features related to SiO2 only. Thin film transistors implementing spray-coated SiO2 gate dielectrics and C60 and pentacene semiconducting channels exhibit excellent transport characteristics, i.e., negligible hysteresis, low leakage currents, high on/off current modulation ratio on the order of 106, and high carrier mobility. PMID- 27933762 TI - Nanocomputed Tomography Imaging of Bacterial Alkaline Phosphatase Activity with an Iodinated Hydrogelator. AB - Alkaline phosphatase (ALP) is an important enzyme, but direct imaging of ALP activity with high spatiotemporal resolution remains challenging. In this work, we rationally designed an iodinated hydrogelator precursor Nap-Phe-Phe(I) Tyr(H2PO3)-OH (1P) which self-assembles into nanofibers to form hydrogel under the catalysis of ALP. With this property of concentrating iodine atoms at the locations of ALP, 1P was successfully applied for direct nanocomputed tomography (nano-CT) imaging of ALP activity in bacteria for the first time. We envision that, on the basis of this pioneering work, new hydrogelators containing more iodine atoms (e.g., five iodine atoms in 1P) will be designed for better nano-CT imaging of ALP activity with higher CT contrast in the near future. PMID- 27933763 TI - Interfacial Self-Assembly of Atomically Precise Graphene Nanoribbons into Uniform Thin Films for Electronics Applications. AB - Because of their intriguing electronic and optical properties, atomically precise graphene nanoribbons (GNRs) are considered to be promising materials for electronics and photovoltaics. However, significant aggregation and low solubility of GNRs in conventional solvents result in their poor processability for materials characterization and device studies. In this paper, we demonstrate a new fabrication approach for large-scale uniform thin films of nonfunctionalized atomically precise chevron-type GNRs. The method is based on (1) the exceptional solubility of graphitic materials in chlorosulfonic acid and (2) the original interfacial self-assembly approach by which uniform films that are single-GNR (~2 nm) thick can be routinely prepared. These films can be transferred to various substrates including Si/SiO2 and used for the streamlined fabrication of arrays of GNR-based devices. The described self-assembly approach should be applicable to other types of solution-synthesized atomically precise GNRs as well as large polyaromatic hydrocarbon (PAH) molecules and therefore should facilitate and streamline their device characterization. PMID- 27933764 TI - Effect of Thermal Annealing on the Electrical Conductivity of Copper-Tin Polymer Composites. AB - Polyvinylidene fluoride (PVDF) copolymer conductive composites containing 40 vol % copper (Cu) and tin (Sn) fillers are prepared by injection molding. Postmolding thermal annealing is found to increase the electrical conductivity of the composites by an order of magnitude. The volume ratio between Cu and Sn is found to have a significant effect on filler distribution but a weaker effect on electrical conductivity compared to the annealing conditions. Synchrotron X-ray tomography is used to visualize and quantitatively analyze the morphology and distribution of the filler particles, indicating that higher conductivity can be attributed to better dispersion of the low-melting-point Sn filler, which provides better interparticle contact in the Cu network. PMID- 27933767 TI - ACS Editors' Choice: Providing Recognition to Authors and Open Access to the Community. PMID- 27933765 TI - 3D Printing of Hierarchical Silk Fibroin Structures. AB - Like many other natural materials, silk is hierarchically structured from the amino acid level up to the cocoon or spider web macroscopic structures. Despite being used industrially in a number of applications, hierarchically structured silk fibroin objects with a similar degree of architectural control as in natural structures have not been produced yet due to limitations in fabrication processes. In a combined top-down and bottom-up approach, we exploit the freedom in macroscopic design offered by 3D printing and the template-guided assembly of ink building blocks at the meso- and nanolevel to fabricate hierarchical silk porous materials with unprecedented structural control. Pores with tunable sizes in the range 40-350 MUm are generated by adding sacrificial organic microparticles as templates to a silk fibroin-based ink. Commercially available wax particles or monodisperse polycaprolactone made by microfluidics can be used as microparticle templates. Since closed pores are generated after template removal, an ultrasonication treatment can optionally be used to achieve open porosity. Such pore templating particles can be further modified with nanoparticles to create a hierarchical template that results in porous structures with a defined nanotopography on the pore walls. The hierarchically porous silk structures obtained with this processing technique can potentially be utilized in various application fields from structural materials to thermal insulation to tissue engineering scaffolds. PMID- 27933768 TI - Nonlinear Optical Materials for the Smart Filtering of Optical Radiation. AB - The control of luminous radiation has extremely important implications for modern and future technologies as well as in medicine. In this Review, we detail chemical structures and their relevant photophysical features for various groups of materials, including organic dyes such as metalloporphyrins and metallophthalocyanines (and derivatives), other common organic materials, mixed metal complexes and clusters, fullerenes, dendrimeric nanocomposites, polymeric materials (organic and/or inorganic), inorganic semiconductors, and other nanoscopic materials, utilized or potentially useful for the realization of devices able to filter in a smart way an external radiation. The concept of smart is referred to the characteristic of those materials that are capable to filter the radiation in a dynamic way without the need of an ancillary system for the activation of the required transmission change. In particular, this Review gives emphasis to the nonlinear optical properties of photoactive materials for the function of optical power limiting. All known mechanisms of optical limiting have been analyzed and discussed for the different types of materials. PMID- 27933769 TI - Strategies for Carbon and Sulfur Tolerant Solid Oxide Fuel Cell Materials, Incorporating Lessons from Heterogeneous Catalysis. AB - Solid oxide fuel cells (SOFCs) are a rapidly emerging energy technology for a low carbon world, providing high efficiency, potential to use carbonaceous fuels, and compatibility with carbon capture and storage. However, current state-of-the-art materials have low tolerance to sulfur, a common contaminant of many fuels, and are vulnerable to deactivation due to carbon deposition when using carbon containing compounds. In this review, we first study the theoretical basis behind carbon and sulfur poisoning, before examining the strategies toward carbon and sulfur tolerance used so far in the SOFC literature. We then study the more extensive relevant heterogeneous catalysis literature for strategies and materials which could be incorporated into carbon and sulfur tolerant fuel cells. PMID- 27933770 TI - Structural Conversions of Synthetic and Protein-Bound Iron-Sulfur Clusters. AB - Synthetic iron-sulfur clusters of general formulation [FemSqLl]z with core atoms Fe and S and terminal ligands L constitute a family of molecular clusters with remarkably diverse geometrical and electronic structures. Several structure types are also found in proteins. The large majority of research on these clusters has involved elucidation of physical properties. Here, we direct attention to reactivity in the form of cluster conversions in which the FemSq cores of reactants are transformed to new structures, usually of different nuclearity, in overall reactions such as self-assembly and fragment condensation and dissociation. An extensive body of core conversions, many of which have not been recognized as such, are presented including those in biological systems. All structural core types are depicted, and all core conversions are diagrammatically summarized. Clusters containing the cubane-type Fe4S4 core play a central role in conversion chemistry. The core conversion concept tends to reinforce the description of iron-sulfur cores as modular units subject to various covalent bond interactions that lead to different structures. PMID- 27933772 TI - Synthetic Biology in Asia: New Kids on the Block. PMID- 27933774 TI - Comparative Analysis of the Interaction of the Primary Quinone QA in Intact and Mn-Depleted Photosystem II Membranes Using Light-Induced ATR-FTIR Spectroscopy. AB - In photosystem II, redox potential Em of primary quinone QA shifts by approximately +150 mV upon inactivation of the Mn4CaO5 cluster. Although this phenomenon is important in photoprotection, the molecular mechanism of the positive Em(QA-/QA) shift remains unclear. Here, we investigated the effect of Mn depletion on the interaction of QA using light-induced ATR-FTIR spectroscopy. It was shown that Mn depletion hardly changed a QA-/QA FTIR difference spectrum, indicating that the H-bond interaction of QA and its immediate surroundings were virtually unchanged by Mn4CaO5 cluster inactivation. On the basis of this result, a possible mechanism of the Em(QA-/QA) shift is discussed. PMID- 27933775 TI - Role of the Tryptophan Residues in the Specific Interaction of the Sea Anemone Stichodactyla helianthus's Actinoporin Sticholysin II with Biological Membranes. AB - Actinoporins are pore-forming toxins from sea anemones. Upon interaction with sphingomyelin-containing bilayers, they become integral oligomeric membrane structures that form a pore. Sticholysin II from Stichodactyla helianthus contains five tryptophans located at strategic positions; its role has now been studied using different mutants. Results show that W43 and W115 play a determinant role in maintaining the high thermostability of the protein, while W146 provides specific interactions for protomer-protomer assembly. W110 and W114 sustain the hydrophobic effect, which is one of the major driving forces for membrane binding in the presence of Chol. However, in its absence, additional interactions with sphingomyelin are required. These conclusions were confirmed with two sphingomyelin analogues, one of which had impaired hydrogen bonding properties. The results obtained support actinoporins' Trp residues playing a major role in membrane recognition and binding, but their residues have an only minor influence on the diffusion and oligomerization steps needed to assemble a functional pore. PMID- 27933777 TI - Introduction: Electronic Materials. PMID- 27933778 TI - Thermodynamic Additivity for Impacts of Base-Pair Substitutions on Association of the Egr-1 Zinc-Finger Protein with DNA. AB - The transcription factor Egr-1 specifically binds as a monomer to its 9 bp target DNA sequence, GCGTGGGCG, via three zinc fingers and plays important roles in the brain and cardiovascular systems. Using fluorescence-based competitive binding assays, we systematically analyzed the impacts of all possible single-nucleotide substitutions in the target DNA sequence and determined the change in binding free energy for each. Then, we measured the changes in binding free energy for sequences with multiple substitutions and compared them with the sum of the changes in binding free energy for each constituent single substitution. For the DNA variants with two or three nucleotide substitutions in the target sequence, we found excellent agreement between the measured and predicted changes in binding free energy. Interestingly, however, we found that this thermodynamic additivity broke down with a larger number of substitutions. For DNA sequences with four or more substitutions, the measured changes in binding free energy were significantly larger than predicted. On the basis of these results, we analyzed the occurrences of high-affinity sequences in the genome and found that the genome contains millions of such sequences that might functionally sequester Egr 1. PMID- 27933779 TI - Structural Basis for the Unusual Qy Red-Shift and Enhanced Thermostability of the LH1 Complex from Thermochromatium tepidum. AB - While the majority of the core light-harvesting complexes (LH1) in purple photosynthetic bacteria exhibit a Qy absorption band in the range of 870-890 nm, LH1 from the thermophilic bacterium Thermochromatium tepidum displays the Qy band at 915 nm with an enhanced thermostability. These properties are regulated by Ca2+ ions. Substitution of the Ca2+ with other divalent metal ions results in a complex with the Qy band blue-shifted to 880-890 nm and a reduced thermostability. Following the recent publication of the structure of the Ca bound LH1-reaction center (RC) complex [Niwa, S., et al. (2014) Nature 508, 228], we have determined the crystal structures of the Sr- and Ba-substituted LH1-RC complexes with the LH1 Qy band at 888 nm. Sixteen Sr2+ and Ba2+ ions are identified in the LH1 complexes. Both Sr2+ and Ba2+ are located at the same positions, and these are clearly different from, though close to, the Ca2+ binding sites. Conformational rearrangement induced by the substitution is limited to the metal-binding sites. Unlike the Ca-LH1-RC complex, only the alpha polypeptides are involved in the Sr and Ba coordinations in LH1. The difference in the thermostability between these complexes can be attributed to the different patterns of the network formed by metal binding. The Sr- and Ba-LH1-RC complexes form a single-ring network by the LH1 alpha-polypeptides only, in contrast to the double-ring network composed of both alpha- and beta-polypeptides in the Ca-LH1 RC complex. On the basis of the structural information, a combined effect of hydrogen bonding, structural integrity, and charge distribution is considered to influence the spectral properties of the core antenna complex. PMID- 27933780 TI - Volumetrically Derived Thermodynamic Profile of Interactions of Urea with a Native Protein. AB - We report the first experimental characterization of the full thermodynamic profile for binding of urea to a native protein. We measured the volumetric parameters of lysozyme at pH 7.0 as a function of urea within a temperature range of 18-45 degrees C. At neutral pH, lysozyme retains its native conformation between 0 and 8 M urea over the entire range of temperatures studied. Consequently, our measured volumetric properties reflect solely the interactions of urea with the native protein and do not involve contributions from urea induced conformational transitions. We analyzed our data within the framework of a statistical thermodynamic analytical model in which urea-protein interactions are viewed as solvent exchange in the vicinity of the protein. The analysis produced the equilibrium constant, k, for an elementary reaction of urea-protein binding with a change in standard state free energy (DeltaG degrees = -RT ln k) at each experimental temperature. We used the van't Hoff equation to compute from the temperature dependence of the equilibrium constant, k, changes in enthalpy, DeltaH degrees , and entropy, DeltaS degrees , accompanying binding. The thermodynamic profile of urea-protein interactions, in conjunction with published molecular dynamics simulation results, is consistent with the picture in which urea molecules, being underhydrated in the bulk, form strong, enthalpically favorable interactions with the surface protein groups while paying a high entropic price. We discuss ramifications of our results for providing insights into the combined effects of urea, temperature, and pressure on the conformational preferences of proteins. PMID- 27933776 TI - Regulation of a Coupled MARCKS-PI3K Lipid Kinase Circuit by Calmodulin: Single Molecule Analysis of a Membrane-Bound Signaling Module. AB - Amoeboid cells that employ chemotaxis to travel up an attractant gradient possess a signaling network assembled on the leading edge of the plasma membrane that senses the gradient and remodels the actin mesh and cell membrane to drive movement in the appropriate direction. In leukocytes such as macrophages and neutrophils, and perhaps in other amoeboid cells as well, the leading edge network includes a positive feedback loop in which the signaling of multiple pathway components is cooperatively coupled. Cytoplasmic Ca2+ is a recently recognized component of the feedback loop at the leading edge where it stimulates phosphoinositide-3-kinase (PI3K) and the production of its product signaling lipid phosphatidylinositol 3,4,5-trisphosphate (PIP3). A previous study implicated Ca2+-activated protein kinase C (PKC) and the phosphatidylinositol 4,5 bisphosphate (PIP2) binding protein MARCKS as two important players in this signaling, because PKC phosphorylation of MARCKS releases free PIP2 that serves as the membrane binding target and substrate for PI3K. This study asks whether calmodulin (CaM), which is known to directly bind MARCKS, also stimulates PIP3 production by releasing free PIP2. Single-molecule fluorescence microscopy is used to quantify the surface density and enzyme activity of key protein components of the hypothesized Ca2+-CaM-MARCKS-PIP2-PI3K-PIP3 circuit. The findings show that CaM does stimulate PI3K lipid kinase activity by binding MARCKS and displacing it from PIP2 headgroups, thereby releasing free PIP2 that recruits active PI3K to the membrane and serves as the substrate for the generation of PIP3. The resulting CaM-triggered activation of PI3K is complete in seconds and is much faster than PKC-triggered activation, which takes minutes. Overall, the available evidence implicates both PKC and CaM in the coupling of Ca2+ and PIP3 signals and suggests these two different pathways have slow and fast activation kinetics, respectively. PMID- 27933781 TI - Structure and Function of the Hepatitis C Virus Envelope Glycoproteins E1 and E2: Antiviral and Vaccine Targets. AB - The hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are critical in viral attachment and cell fusion, and studies of these proteins may provide valuable insights into their potential uses in vaccines and antiviral strategies. Progress has included elucidating the crystal structures of portions of their ectodomains, as well as many other studies of hypervariable regions, stem regions, glycosylation sites, and the participation of E1/E2 in viral fusion with the endosomal membrane. The available structural data have shed light on the binding sites of cross-neutralizing antibodies. A large amount of information has been discovered concerning heterodimerization, including the roles of transmembrane domains, disulfide bonding, and heptad repeat regions. The possible organization of higher order oligomers within the HCV virion has also been evaluated on the basis of experimental data. In this review, E1/E2 structure and function is discussed, and some important issues requiring further study are highlighted. PMID- 27933782 TI - Integration of Global Analyses of Host Molecular Responses with Clinical Data To Evaluate Pathogenesis and Advance Therapies for Emerging and Re-emerging Viral Infections. AB - Outbreaks associated with emerging and re-emerging viral pathogens continue to increase in frequency and are associated with an increasing burden to global health. In light of this, there is a need to integrate basic and clinical research for investigating the connections between molecular and clinical pathogenesis and for therapeutic development strategies. Here, we will discuss this approach with a focus on the emerging viral pathogens Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola virus (EBOV), and monkeypox virus (MPXV) from the context of clinical presentation, immunological and molecular features of the diseases, and OMICS-based analyses of pathogenesis. Furthermore, we will highlight the role of global investigations of host kinases, the kinome, for investigating emerging and re-emerging viral pathogens from the context of characterizing cellular responses and identifying novel therapeutic targets. Lastly, we will address how increased integration of clinical and basic research will assist treatment and prevention efforts for emerging pathogens. PMID- 27933783 TI - A Comprehensive Computational Analysis for the Binding Modes of Hepatitis C Virus NS5A Inhibitors: The Question of Symmetry. AB - Direct-acting antivirals (DAAs) form the current standard of care (SOC) against hepatitis C virus (HCV). These drugs selectively target the viral proteins, offering a unique mechanism to avoid toxicity, to increase their efficacy, and to evolve from decades of interferon- and ribavirin-based therapy. Among the promising HCV targets for DAAs is the NS5A protein, and daclatasvir (DCV) forms a first-in-class compound that selectively targets this protein. Despite the exceptional potency of DCV (~picomolar IC50) and although several DCV derivatives have been approved for human use or are close to approval, the exact mode of action of these drugs is still incomplete. This is simply due to the vast complexity of cocrystallizing DCV with NS5A in the absence of two amphipathic helices that are required for DCV binding. In this context, computational modeling provides a unique alternative to solve this problem. Here, we build upon our recent discovery of a completely symmetrical interaction between DCV and NS5A and investigate the mode of binding of six other structures similar to DCV. The selected compounds include both symmetric and asymmetric molecules. In addition, we show that our model correlates very well with mutations that can confer resistance to DCV. The current study enhances our understanding of the mode of action of this class of HCV inhibitors and helps in defining the origin of resistance to these drugs. PMID- 27933784 TI - Biosynthesis and Regulation of Sulfomenaquinone, a Metabolite Associated with Virulence in Mycobacterium tuberculosis. AB - Sulfomenaquinone (SMK) is a recently identified metabolite that is unique to the Mycobacterium tuberculosis (M. tuberculosis) complex and is shown to modulate its virulence. Here, we report the identification of the SMK biosynthetic operon that, in addition to a previously identified sulfotransferase stf3, includes a putative cytochrome P450 gene (cyp128) and a gene of unknown function, rv2269c. We demonstrate that cyp128 and stf3 are sufficient for the biosynthesis of SMK from menaquinone and rv2269c exhibits promoter activity in M. tuberculosis. Loss of Stf3 expression, but not that of Cyp128, is correlated with elevated levels of menaquinone-9, an essential component in the electron-transport chain in M. tuberculosis. Finally, we showed in a mouse model of infection that the loss of cyp128 exhibits a hypervirulent phenotype similar to that in previous studies of the stf3 mutant. These findings provide a platform for defining the molecular basis of SMK's role in M. tuberculosis pathogenesis. PMID- 27933785 TI - Chemical Methods for Probing Virus-Host Proteomic Interactions. AB - Interactions between host and pathogen proteins constitute an important aspect of both infectivity and the host immune response. Different viruses have evolved complex mechanisms to hijack host-cell machinery and metabolic pathways to redirect resources and energy flow toward viral propagation. These interactions are often critical to the virus, and thus understanding these interactions at a molecular level gives rise to opportunities to develop novel antiviral strategies for therapeutic intervention. This review summarizes current advances in chemoproteomic methods for studying these molecular altercations between different viruses and their hosts. PMID- 27933787 TI - Taking Aim at Host-Pathogen Interactions. PMID- 27933786 TI - Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL), a Resistance Mechanism for Two Distinct Compound Classes. AB - MMV007564 is a novel antimalarial benzimidazolyl piperidine chemotype identified in cellular screens. To identify the genetic determinant of MMV007564 resistance, parasites were cultured in the presence of the compound to generate resistant lines. Whole genome sequencing revealed distinct mutations in the gene named Plasmodium falciparum cyclic amine resistance locus (pfcarl), encoding a conserved protein of unknown function. Mutations in pfcarl are strongly associated with resistance to a structurally unrelated class of compounds, the imidazolopiperazines, including KAF156, currently in clinical trials. Our data demonstrate that pfcarl mutations confer resistance to two distinct compound classes, benzimidazolyl piperidines and imidazolopiperazines. However, MMV007564 and the imidazolopiperazines, KAF156 and GNF179, have different timings of action in the asexual blood stage and different potencies against the liver and sexual blood stages. These data suggest that pfcarl is a multidrug-resistance gene rather than a common target for benzimidazolyl piperidines and imidazolopiperazines. PMID- 27933788 TI - Desmosterol Increases Lipid Bilayer Fluidity during Hepatitis C Virus Infection. AB - Hepatitis C virus (HCV) uniquely affects desmosterol homeostasis by increasing its intracellular abundance and affecting its localization. These effects are important for productive viral replication because the inhibition of desmosterol synthesis has an antiviral effect that can be rescued by the addition of exogenous desmosterol. Here, we use subgenomic replicons to show that desmosterol has a major effect on the replication of HCV JFH1 RNA. Fluorescence recovery after photobleaching (FRAP) experiments performed with synthetic supported lipid bilayers demonstrate that the substitution of desmosterol for cholesterol significantly increases the lipid bilayer fluidity, especially in the presence of saturated phospholipids and ceramides. We demonstrate using LC-MS that desmosterol is abundant in the membranes upon which genome replication takes place and that supported lipid bilayers derived from these specialized membranes also exhibit significantly higher fluidity compared to that of negative control membranes isolated from cells lacking HCV. Together, these data suggest a model in which the fluidity-promoting effects of desmosterol on lipid bilayers play a crucial role in the extensive membrane remodeling that takes place in the endoplasmic reticulum during HCV infection. We anticipate that the supported lipid bilayer system described can provide a useful model system in which to interrogate the effects of lipid structure and composition on the biophysical properties of lipid membranes as well as their function in viral processes such as genome replication. PMID- 27933789 TI - The T296V Mutant of Amorpha-4,11-diene Synthase Is Defective in Allylic Diphosphate Isomerization but Retains the Ability To Cyclize the Intermediate (3R)-Nerolidyl Diphosphate to Amorpha-4,11-diene. AB - The T296V mutant of amorpha-4,11-diene synthase catalyzes the abortive conversion of the natural substrate (E,E)-farnesyl diphosphate mainly into the acyclic product (E)-beta-farnesene (88%) instead of the natural bicyclic sesquiterpene amorphadiene (7%). Incubation of the T296V mutant with (3R,6E)-nerolidyl diphosphate resulted in cyclization to amorphadiene. Analysis of additional mutants of amino acid residue 296 and in vitro assays with the intermediate analogue (2Z,6E)-farnesyl diphosphate as well as (3S,6E)-nerolidyl diphosphate demonstrated that the T296V mutant can no longer catalyze the allylic rearrangement of farnesyl diphosphate to the normal intermediate (3R,6E) nerolidyl diphosphate, while retaining the ability to cyclize (3R,6E)-nerolidyl diphosphate to amorphadiene. The T296A mutant predominantly retained amorphadiene synthase activity, indicating that neither the hydroxyl nor the methyl group of the Thr296 side chain is required for cyclase activity. PMID- 27933791 TI - Mechanistic Insights from the Crystal Structure of Bacillus subtilis o Succinylbenzoyl-CoA Synthetase Complexed with the Adenylate Intermediate. AB - o-Succinylbenzoyl-CoA (OSB-CoA) synthetase, or MenE, catalyzes an essential step in vitamin K biosynthesis and is a valuable drug target. Like many other adenylating enzymes, it changes its structure to accommodate substrate binding, catalysis, and product release along the path of a domain alternation catalytic mechanism. We have determined the crystal structure of its complex with the adenylation product, o-succinylbenzoyl-adenosine monophosphate (OSB-AMP), and captured a new postadenylation state. This structure presents unique features such as a strained conformation for the bound adenylate intermediate to indicate that it represents the enzyme state after completion of the adenylation reaction but before release of the C domain in its transition to the thioesterification conformation. By comparison to the ATP-bound preadenylation conformation, structural changes are identified in both the reactants and the active site to allow inference about how these changes accommodate and facilitate the adenylation reaction and to directly support an in-line backside attack nucleophilic substitution mechanism for the first half-reaction. Mutational analysis suggests that the conserved His196 plays an important role in desolvation of the active site rather than stabilizing the transition state of the adenylation reaction. In addition, comparison of the new structure with a previously determined OSB-AMP-bound structure of the same enzyme allows us to propose a release mechanism of the C domain in its alteration to form the thioesterification conformation. These findings allow us to better understand the domain alternation catalytic mechanism of MenE as well as many other adenylating enzymes. PMID- 27933790 TI - Structural Analysis Provides Mechanistic Insight into Nicotine Oxidoreductase from Pseudomonas putida. AB - The first structure of nicotine oxidoreductase (NicA2) was determined by X-ray crystallography. Pseudomonas putida has evolved nicotine-degrading activity to provide a source of carbon and nitrogen. The structure establishes NicA2 as a member of the monoamine oxidase family. Residues 1-50 are disordered and may play a role in localization. The nicotine-binding site proximal to the isoalloxazine ring of flavin shows an unusual composition of the classical aromatic cage (W427 and N462). The active site architecture is consistent with the proposed binding of the deprotonated form of the substrate and the flavin-dependent oxidation of the pyrrolidone C-N bond followed by nonenzymatic hydrolysis. PMID- 27933792 TI - Oxygen and Bis(3',5')-cyclic Dimeric Guanosine Monophosphate Binding Control Oligomerization State Equilibria of Diguanylate Cyclase-Containing Globin Coupled Sensors. AB - Bacteria sense their environment to alter phenotypes, including biofilm formation, to survive changing conditions. Heme proteins play important roles in sensing the bacterial gaseous environment and controlling the switch between motile and sessile (biofilm) states. Globin coupled sensors (GCS), a family of heme proteins consisting of a globin domain linked by a central domain to an output domain, are often found with diguanylate cyclase output domains that synthesize c-di-GMP, a major regulator of biofilm formation. Characterization of diguanylate cyclase-containing GCS proteins from Bordetella pertussis and Pectobacterium carotovorum demonstrated that cyclase activity is controlled by ligand binding to the heme within the globin domain. Both O2 binding to the heme within the globin domain and c-di-GMP binding to a product-binding inhibitory site (I-site) within the cyclase domain control oligomerization states of the enzymes. Changes in oligomerization state caused by c-di-GMP binding to the I site also affect O2 kinetics within the globin domain, suggesting that shifting the oligomer equilibrium leads to broad rearrangements throughout the protein. In addition, mutations within the I-site that eliminate product inhibition result in changes to the accessible oligomerization states and decreased catalytic activity. These studies provide insight into the mechanism by which ligand binding to the heme and I-site controls activity of GCS proteins and suggests a role for oligomerization-dependent activity in vivo. PMID- 27933793 TI - Differential Effect of Membrane Composition on the Pore-Forming Ability of Four Different Sea Anemone Actinoporins. AB - Sea anemone actinoporins constitute a protein family of multigene pore-forming toxins (PFT). Equinatoxin II (EqtII), fragaceatoxin C (FraC), and sticholysins I and II (StnI and StnII, respectively), produced by three different sea anemone species, are the only actinoporins whose molecular structures have been studied in depth. These four proteins show high sequence identities and practically coincident three-dimensional structures. However, their pore-forming activity can be quite different depending on the model lipid system employed, a feature that has not been systematically studied before. Therefore, the aim of this work was to evaluate and compare the influence of several distinct membrane conditions on their particular pore-forming behavior. Using a complex model membrane system, such as sheep erythrocytes, StnII showed hemolytic activity much higher than those of the other three actinoporins studied. In lipid model systems, pore forming ability when assayed against 4:1 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/sphingomyelin (SM) vesicles, with the membrane binding being the rate limiting step, decreased in the following order: StnI > StnII > EqtII > FraC. When using 1:1:1 DOPC/SM/cholesterol LUVs, the presence of Chol not only enhanced membrane binding affinities by ~2 orders of magnitude but also revealed how StnII was much faster than the other three actinoporins in producing calcein release. This ability agrees with the proposal that explains this behavior in terms of their high sequence variability along their first 30 N-terminal residues. The influence of interfacial hydrogen bonding in SM- or dihydro-SM-containing bilayers was also shown to be a generalized feature of the four actinoporins studied. It is finally hypothesized that this observed variable ability could be explained as a consequence of their distinct specificities and/or membrane binding affinities. Eventually, this behavior can be modulated by the nature of their natural target membranes or the interaction with not yet characterized isotoxin forms from the same sea anemone species. PMID- 27933795 TI - Potent Inhibition of 3-Deoxy-d-arabinoheptulosonate-7-phosphate (DAHP) Synthase by DAHP Oxime, a Phosphate Group Mimic. AB - 3-Deoxy-d-arabinoheptulosonate-7-phosphate (DAHP) synthase catalyzes the first step in the shikimate pathway. It catalyzes an aldol-like reaction of phosphoenolpyruvate (PEP) with erythrose 4-phosphate (E4P) to form DAHP. The kinetic mechanism was rapid equilibrium sequential ordered ter ter, with the essential divalent metal ion, Mn2+, binding first, followed by PEP and E4P. DAHP oxime, in which an oxime group replaces the keto oxygen, was a potent inhibitor, with Ki = 1.5 +/- 0.4 MUM, though with residual activity at high inhibitor concentrations. It displayed slow-binding inhibition with a residence time, tR, of 83 min. The crystal structure revealed that the oxime functional group, combined with two crystallographic waters, bound at the same location in the catalytic center as the phosphate group of the tetrahedral intermediate. DAHP synthase has a dimer-of-dimers homotetrameric structure, and DAHP oxime bound to only one subunit of each tight dimer. Inhibitor binding was competitive with respect to all three substrates in the subunits to which it bound. DAHP oxime did not overlap with the metal binding site, so the cause of their mutually exclusive binding was not clear. Similarly, there was no obvious structural reason for inhibitor binding in only two subunits; however, changes in global hydrogen/deuterium exchange showed large scale changes in protein dynamics upon inhibitor binding. The kcat value for the residual activity at high inhibitor concentrations was 3-fold lower, and the apparent KM,E4P value decreased at least 10-fold. This positive cooperativity of binding between DAHP oxime in subunits B and C, and E4P in subunits A and D appears to be the dominant cause for incomplete inhibition at high inhibitor concentrations. In spite of its lack of obvious structural similarity to phosphate, the oxime and crystallographic waters acted as a small, neutral phosphate mimic. PMID- 27933794 TI - Structural and Functional Influence of the Glycine-Rich Loop G302GGGY on the Catalytic Tyrosine of Histone Deacetylase 8. AB - Histone deacetylase 8 (HDAC8) catalyzes the hydrolysis of acetyl-l-lysine to yield products l-lysine and acetate through a mechanism in which a nucleophilic water molecule is activated by a histidine general base and a catalytic metal ion (Zn2+ or Fe2+). Acetyl-l-lysine also requires activation by metal coordination and a hydrogen bond with catalytic tyrosine Y306, which also functions in transition state stabilization. Interestingly, Y306 is located in the conserved glycine-rich loop G302GGGY. The potential flexibility afforded by the tetraglycine segment may facilitate induced-fit conformational changes in Y306 between "in" and "out" positions, as observed in related deacetylases. To probe the catalytic importance of the glycine-rich loop in HDAC8, we rigidified this loop by preparing the G302A, G303A, G304A, and G305A mutants and measured their steady state kinetics and determined their X-ray crystal structures. Substantial losses of catalytic efficiency are observed (10-500-fold based on kcat/KM), particularly for G304A HDAC8 and G305A HDAC8. These mutants also exhibit the greatest structural changes for catalytic tyrosine Y306 (1.3-1.7 A shifts of the phenolic hydroxyl group). Molecular dynamics simulations further indicate that G304 and G305 undergo pronounced structural changes as residue 306 undergoes a transition between "in" and "out" conformations. Thus, the G304A and G305A substitutions likely compromise the position and conformational changes of Y306 required for substrate activation and transition state stabilization. The G302A and G303A substitutions have less severe catalytic consequences, and these substitutions may influence an internal channel through which product acetate is believed to exit. PMID- 27933796 TI - Structural Dynamics of the Heterodimeric ABC Transporter TM287/288 Induced by ATP and Substrate Binding. AB - TM287/288 is a heterodimeric ATP-binding cassette (ABC) transporter, which harnesses the energy of ATP binding and hydrolysis at the nucleotide-binding domains (NBDs) to transport a wide variety of molecules through the transmembrane domains (TMDs) by alternating inward- and outward-facing conformations. Here, we conducted multiple 100 ns molecular dynamics simulations of TM287/288 in different ATP- and substrate-bound states to elucidate the effects of ATP and substrate binding. As a result, the binding of two ATP molecules to the NBDs induced the formation of the consensus ATP-binding pocket (ABP2) or the NBD dimerization, whereas these processes did not occur in the presence of a single ATP molecule or when the protein was in its apo state. Moreover, binding of the substrate to the TMDs enhanced the formation of ABP2 through allosteric TMD-NBD communication. Furthermore, in the apo state, alpha-helical subdomains of the NBDs approached each other, acquiring a conformation with core half-pockets exposed to the solvent, appropriate for ATP binding. We propose a "core-exposed" model for this novel conformation found in the apo state of ABC transporters. These findings provide important insights into the structural dynamics of ABC transporters. PMID- 27933797 TI - Nuclear Magnetic Resonance and Molecular Dynamics Simulation of the Interaction between Recognition Protein H7 of the Novel Influenza Virus H7N9 and Glycan Cell Surface Receptors. AB - Avian influenza A viruses, which can also propagate between humans, present serious pandemic threats, particularly in Asia. The specificity (selectivity) of interactions between the recognition protein hemagglutinin (HA) of the virus capsid and the glycoconjugates of host cells also contributes to the efficient spread of the virus by aerosol between humans. Some avian origin viruses, such as H1N1 (South Carolina 1918), have improved their selectivity for human receptors by mutation in the HA receptor binding site, to generate pandemic viruses. Molecular details and dynamics of glycan-HA interactions are of interest, both in predicting the pandemic potential of a new emerging strain and in searching for new antiviral drugs. Two complementary techniques, 1H saturation transfer difference (1H STD) nuclear magnetic resonance and molecular dynamics (MD) simulation, were applied to analyze the interaction of the new H7 (A/Anhui/1/13 H7N9) with LSTa [Neu5Ac alpha(2->3) Gal beta(1->3) GlcNAc beta(1->3) Gal beta(1 >4) Glc] and LSTc [Neu5Ac alpha(2->6) Gal beta(1->4) GlcNAc beta(1->3) Gal beta(1 >4) Glc] pentasaccharides, models of avian and human receptor glycans. Their interactions with H7 were analyzed for the first time using 1H STD and MD, revealing structural and dynamic behavior that could not be obtained from crystal structures, and contributing to glycan-HA specificity. This highlighted aspects that could affect glycan-HA recognition, including the mutation H7 G228S, which increases H2 and H3 specificity for the human receptor. Finally, interactions between LSTc and H7 were compared with those between LSTc and H1 of H1N1 (South Carolina 1918), contributing to our understanding of the recognition ability of HAs. PMID- 27933798 TI - High-Affinity Binding of Monomeric but Not Oligomeric Amyloid-beta to Ganglioside GM1 Containing Nanodiscs. AB - The interaction of the amyloid-beta protein (Abeta) with neuronal cell membranes plays a crucial role in Alzheimer's disease. Abeta undergoes structural changes upon binding to ganglioside GM1 containing membranes leading to altered molecular characteristics of the protein. The physiological role of the Abeta interaction with the ganglioside GM1 is still unclear. In order to further elucidate the molecular requirements of Abeta membrane binding, we tested different nanodiscs varying in their lipid composition, regarding the charge of the headgroups as well as ganglioside GM1 concentration. Nanodiscs are excellent model membrane systems for studying protein membrane interactions, and we show here their suitability to investigate the membrane interaction of Abeta. In particular, we set out to investigate whether the binding activity of GM1 to Abeta is specific for the assembly state of Abeta and compared the binding affinities of monomeric with oligomeric Abeta. Using fluorescence titration experiments, we demonstrate high-affinity binding of Abeta(1-40) to GM1 containing nanodiscs, with dissociation constants, KD, in the range from 25 to 41 nM, in a GM1 concentration dependent manner. Biolayer interferometry experiments confirmed the high-affinity binding of monomeric Abeta(1-40) (KD of 24 nM to 49 nM) as well as of Abeta(1-42) (KD of 30 nM) to GM1 containing nanodiscs, and no binding to phospholipid containing nanodiscs. Interestingly, and in contrast to monomeric Abeta, neither oligomeric Abeta(1-40) nor oligomeric Abeta(1-42) binds to GM1 nanodiscs. To the best of our knowledge, this is the first report of a loss of function for monomeric Abeta upon aggregation. PMID- 27933802 TI - ChemRXiv: A Chemistry Preprint Server. PMID- 27933800 TI - Substrate-Induced Carbon Monoxide Reactivity Suggests Multiple Enzyme Conformations at the Catalytic Copper M-Center of Peptidylglycine Monooxygenase. AB - The present study uses CO as a surrogate for oxygen to probe how substrate binding triggers oxygen activation in peptidylglycine monooygenase (PHM). Infrared stretching frequencies (nu(C = O)) of the carbonyl (CO) adducts of copper proteins are sensitive markers of Cu(I) coordination and are useful in probing oxygen reactivity because the electronic properties of O2 and CO are similar. The carbonyl chemistry has been explored using PHM WT and a number of active site variants in the absence and presence of peptidyl substrates. We have determined that upon carbonylation (i) a major CO band at 2092 cm-1 and a second minor CO band at 2063 cm-1 are observed in the absence of peptide substrate Ac YVG; (ii) the presence of peptide substrate amplifies the minor CO band and causes it to partially interconvert with the CO band at 2092 cm-1; (iii) the substrate-induced CO band is associated with a second conformer at CuM; and (iv) the CuH-site mutants, which are inactive, fail to generate any substrate-induced CO bands. The total intensity of both bands is constant, suggesting that the Cu(I)M-site partitions between the two carbonylated enzyme states. Together, these data provide evidence for two conformers at CuM, one of which is induced by binding of the peptide substrate with the implication that this represents the conformation that also allows binding and activation of O2. PMID- 27933801 TI - An Atypical alpha/beta-Hydrolase Fold Revealed in the Crystal Structure of Pimeloyl-Acyl Carrier Protein Methyl Esterase BioG from Haemophilus influenzae. AB - Pimeloyl-acyl carrier protein (ACP) methyl esterase is an alpha/beta-hydrolase that catalyzes the last biosynthetic step of pimeloyl-ACP, a key intermediate in biotin biosynthesis. Intriguingly, multiple nonhomologous isofunctional forms of this enzyme that lack significant sequence identity are present in diverse bacteria. One such esterase, Escherichia coli BioH, has been shown to be a typical alpha/beta-hydrolase fold enzyme. To gain further insights into the role of this step in biotin biosynthesis, we have determined the crystal structure of another widely distributed pimeloyl-ACP methyl esterase, Haemophilus influenzae BioG, at 1.26 A. The BioG structure is similar to the BioH structure and is composed of an alpha-helical lid domain and a core domain that contains a central seven-stranded beta-pleated sheet. However, four of the six alpha-helices that flank both sides of the BioH core beta-sheet are replaced with long loops in BioG, thus forming an unusual alpha/beta-hydrolase fold. This structural variation results in a significantly decreased thermal stability of the enzyme. Nevertheless, the lid domain and the residues at the lid-core interface are well conserved between BioH and BioG, in which an analogous hydrophobic pocket for pimelate binding as well as similar ionic interactions with the ACP moiety are retained. Biochemical characterization of site-directed mutants of the residues hypothesized to interact with the ACP moiety supports a similar substrate interaction mode for the two enzymes. Consequently, these enzymes package the identical catalytic function under a considerably different protein surface. PMID- 27933806 TI - Influence of Ship Emissions on Urban Air Quality: A Comprehensive Study Using Highly Time-Resolved Online Measurements and Numerical Simulation in Shanghai. AB - Shanghai has become an international shipping center in the world. In this study, the multiyear measurements and the high resolution air quality model with hourly ship emission inventory were combined to determine the influence of ship emissions on urban Shanghai. The aerosol time-of-flight mass spectrometer (ATOFMS) measurements were carried out at an urban site from April 2009 to January 2013. During the entire sampling time, most of the half-hourly averaged number fractions of primary ship emitted particles varied between 1.0-10.0%. However, the number fraction could reach up to 50% during the ship plume cases. Ship-plume-influenced periods usually occurred in spring and summer. The simulation of Weather Research and Forecasting/Community Multiscale Air Quality model (WRF/CMAQ) with hourly ship emission inventory provided the highly time resolved concentrations of ship-related air pollutants during a ship plume case. It showed ships could contribute 20-30% (2-7 MUg/m3) of the total PM2.5 within tens of kilometers of coastal and riverside Shanghai during ship-plume-influenced periods. Our results showed that ship emissions have substantial contribution to the air pollution in urban Shanghai. The control measures of ship emission should be taken considering its negative environment and human health effects. PMID- 27933799 TI - Substitution of a Single Amino Acid Reverses the Regiospecificity of the Baeyer Villiger Monooxygenase PntE in the Biosynthesis of the Antibiotic Pentalenolactone. AB - In the biosynthesis of pentalenolactone (1), PenE and PntE, orthologous proteins from Streptomyces exfoliatus and S. arenae, respectively, catalyze the flavin dependent Baeyer-Villiger oxidation of 1-deoxy-11-oxopentalenic acid (4) to the lactone pentalenolactone D (5), in which the less-substituted methylene carbon has migrated. By contrast, the paralogous PtlE enzyme from S. avermitilis catalyzes the oxidation of 4 to neopentalenolactone D (6), in which the more substituted methane substitution has undergone migration. We report the design and analysis of 13 single and multiple mutants of PntE mutants to identify the key amino acids that contribute to the regiospecificity of these two classes of Baeyer-Villiger monooxygenases. The L185S mutation in PntE reversed the observed regiospecificity of PntE such that all recombinant PntE mutants harboring this L185S mutation acquired the characteristic regiospecificity of PtlE, catalyzing the conversion of 4 to 6 as the major product. The recombinant PntE mutant harboring R484L exhibited reduced regiospecificity, generating a mixture of lactones containing more than 17% of 6. These in vitro results were corroborated by analysis of the complementation of the S. avermitilis DeltaptlED double deletion mutant with pntE mutants, such that pntE mutants harboring L185S produced 6 as the major product, whereas complemention of the DeltaptlED deletion mutant with pntE mutants carrying the R484L mutation gave 6 as more than 33% of the total lactone product mixture. PMID- 27933807 TI - Asymmetric Synthesis of gamma-Lactones through Koga Amine-Controlled Addition of Enediolates to alpha,beta-Unsaturated Sulfoxonium Salts. AB - A chiral Koga amine-controlled asymmetric synthesis of cis-gamma-lactones through a formal [3 + 2] cycloaddition of enediolates with alpha,beta-unsaturated sulfoxonium salts is described. The desired structural motif was formed in moderate to good yields (50-71% for 13 examples), with good to very good diastereoselectivity (dr 5:1 to 10:1 for 20 examples), favoring the cis-isomer, and good to excellent enantioselectivity (70-91% ee for 13 examples). PMID- 27933808 TI - Accurate Modeling of Scaffold Hopping Transformations in Drug Discovery. AB - The accurate prediction of protein-ligand binding free energies remains a significant challenge of central importance in computational biophysics and structure-based drug design. Multiple recent advances including the development of greatly improved protein and ligand molecular mechanics force fields, more efficient enhanced sampling methods, and low-cost powerful GPU computing clusters have enabled accurate and reliable predictions of relative protein-ligand binding free energies through the free energy perturbation (FEP) methods. However, the existing FEP methods can only be used to calculate the relative binding free energies for R-group modifications or single-atom modifications and cannot be used to efficiently evaluate scaffold hopping modifications to a lead molecule. Scaffold hopping or core hopping, a very common design strategy in drug discovery projects, is critical not only in the early stages of a discovery campaign where novel active matter must be identified but also in lead optimization where the resolution of a variety of ADME/Tox problems may require identification of a novel core structure. In this paper, we introduce a method that enables theoretically rigorous, yet computationally tractable, relative protein-ligand binding free energy calculations to be pursued for scaffold hopping modifications. We apply the method to six pharmaceutically interesting cases where diverse types of scaffold hopping modifications were required to identify the drug molecules ultimately sent into the clinic. For these six diverse cases, the predicted binding affinities were in close agreement with experiment, demonstrating the wide applicability and the significant impact Core Hopping FEP may provide in drug discovery projects. PMID- 27933809 TI - Development and Validation of a Computational Model for Androgen Receptor Activity. AB - Testing thousands of chemicals to identify potential androgen receptor (AR) agonists or antagonists would cost millions of dollars and take decades to complete using current validated methods. High-throughput in vitro screening (HTS) and computational toxicology approaches can more rapidly and inexpensively identify potential androgen-active chemicals. We integrated 11 HTS ToxCast/Tox21 in vitro assays into a computational network model to distinguish true AR pathway activity from technology-specific assay interference. The in vitro HTS assays probed perturbations of the AR pathway at multiple points (receptor binding, coregulator recruitment, gene transcription, and protein production) and multiple cell types. Confirmatory in vitro antagonist assay data and cytotoxicity information were used as additional flags for potential nonspecific activity. Validating such alternative testing strategies requires high-quality reference data. We compiled 158 putative androgen-active and -inactive chemicals from a combination of international test method validation efforts and semiautomated systematic literature reviews. Detailed in vitro assay information and results were compiled into a single database using a standardized ontology. Reference chemical concentrations that activated or inhibited AR pathway activity were identified to establish a range of potencies with reproducible reference chemical results. Comparison with existing Tier 1 AR binding data from the U.S. EPA Endocrine Disruptor Screening Program revealed that the model identified binders at relevant test concentrations (<100 MUM) and was more sensitive to antagonist activity. The AR pathway model based on the ToxCast/Tox21 assays had balanced accuracies of 95.2% for agonist (n = 29) and 97.5% for antagonist (n = 28) reference chemicals. Out of 1855 chemicals screened in the AR pathway model, 220 chemicals demonstrated AR agonist or antagonist activity and an additional 174 chemicals were predicted to have potential weak AR pathway activity. PMID- 27933811 TI - Fabrication of Highly Porous Nonspherical Particles Using Stop-Flow Lithography and the Study of Their Optical Properties. AB - A microfluidic flow lithography approach was investigated to synthesize highly porous nonspherical particles and Janus particles in a one-step and high throughput fashion. In this study, using common solvents as porogens, we were able to synthesize highly porous particles with different shapes using ultraviolet (UV) polymerization-induced phase separation in a microfluidic channel. We also studied the pore-forming process using operating parameters such as porogen type, porogen concentration, and UV intensity to tune the pore size and increase the pore size to submicron levels. By simply coflowing multiple streams in the microfluidic channel, we were able to create porous Janus particles; we showed that their anisotropic swelling/deswelling exhibit a unique optical shifting. The distinctive optical properties and the enlarged surface area of the highly porous particles can improve their performance in various applications such as optical sensors and drug loading. PMID- 27933812 TI - Ring-Opening Reactions of the N-4-Nosyl Hough-Richardson Aziridine with Nitrogen Nucleophiles. AB - Dinosylated alpha-d-glucopyranoside was directly transformed into alpha-d altropyranosides via in situ formed N-4-nosyl Hough-Richardson aziridine with nitrogen nucleophiles under mild conditions in fair to excellent yields. The scope of the aziridine ring-opening reaction was substantially broadened contrary to the conventional methods introducing solely the azide anion at high temperatures. If necessary, the N-4-nosyl Hough-Richardson aziridine can be isolated by filtration in a very good yield and high purity. PMID- 27933810 TI - Structure-Based Scaffold Repurposing for G Protein-Coupled Receptors: Transformation of Adenosine Derivatives into 5HT2B/5HT2C Serotonin Receptor Antagonists. AB - Adenosine derivatives developed to activate adenosine receptors (ARs) revealed micromolar activity at serotonin 5HT2B and 5HT2C receptors (5HTRs). We explored the structure-activity relationship at 5HT2Rs and modeled receptor interactions in order to optimize affinity and simultaneously reduce AR affinity. Depending on N6 substitution, small 5'-alkylamide modification maintained 5HT2BR affinity, which was enhanced upon ribose substitution with rigid bicyclo[3.1.0]hexane (North (N)-methanocarba), e.g., N6-dicyclopropylmethyl 4'-CH2OH derivative 14 (Ki 11 nM). 5'-Methylamide 23 was 170-fold selective as antagonist for 5HT2BR vs 5HT2CR. 5'-Methyl 25 and ethyl 26 esters potently antagonized 5HT2Rs with moderate selectivity in comparison to ARs; related 6-N,N-dimethylamino analogue 30 was 5HT2R-selective. 5' position flexibility of substitution was indicated in 5HT2BR docking. Both 5'-ester and 5'-amide derivatives displayed in vivo t1/2 of 3-4 h. Thus, we used G protein-coupled receptor modeling to repurpose nucleoside scaffolds in favor of binding at nonpurine receptors as novel 5HT2R antagonists, with potential for cardioprotection, liver protection, or central nervous system activity. PMID- 27933813 TI - "Atomic Force Masking" Induced Formation of Effective Hot Spots along Grain Boundaries of Metal Thin Films. AB - We present an interesting phenomenon, "atomic force masking", which is the deposition of a few-nanometer-thick gold film on ultrathin low-molecular-weight (LMW) polydimethylsiloxane (PDMS) engineered on a polycrystalline gold thin film, and demonstrated the formation of hot spot based on SERS. The essential principle of this atomic force masking phenomenon is that an LMW PDMS layer on a single crystalline grain of gold thin film would repel gold atoms approaching this region during a second cycle of evaporation, whereas new nucleation and growth of gold atoms would occur on LMW PDMS deposited on grain boundary regions. The nanostructure formed by the atomic force masking, denoted here as "hot spots on grain boundaries" (HOGs), which is consistent with finite-difference time-domain (FDTD) simulation, and the mechanism of atomic force masking were investigated by carrying out systematic experiments, and density functional theory (DFT) calculations were made to carefully explain the related fundamental physics. Also, to highlight the manufacturing advantages of the proposed method, we demonstrated the simple synthesis of a flexible HOG SERS, and we used this substrate in a swabbing test to detect a common pesticide placed on the surface of an apple. PMID- 27933814 TI - La2O3 Promoted Pd/rGO Electro-catalysts for Formic Acid Oxidation. AB - High activity, a low rate of CO poisoning, and long-term stability of Pd electro catalysts are necessary for practical use as an anode material in direct formic acid fuel cells. Achieving a high degree of Pd nanoparticle dispersion on a carbon support, without agglomeration, while maintaining a facile electron transfer through the catalyst surface are two challenging tasks to be overcome in fulfilling this aim. Herein, we report the effect of addition of La/La-oxides on the efficiency of Pd nanoparticles supported on reduced graphene oxide (rGO) for formic acid electro-oxidation reaction. A series of electro-catalysts with different Pd-La molar ratios were successfully synthesized and characterized using a range of techniques including PXRD, XPS, TEM, FTIR, and Raman spectroscopy and then tested as anode materials for direct formic acid fuel cells. We explore that the lanthanum species (La/La-oxide) significantly promote the activity and stability of Pd catalyst toward electrocatalytic oxidation of formic acid. The metallic ratio is found to be critical, and the activity order of various catalysts is observed as follows; Pd30La70/rGO > Pd80La20/rGO > Pd70La30 rGO. The obtained mass specific activity for Pd30La70/rGO (986.42 A/g) is 2.18 times higher than that for Pd/rGO (451 A/g) and 16 times higher than that for Pd/C (61.5 A/g) at given onset peak potentials. The high activity and stability of the electro-catalysts are attributed to the uniform dispersion of Pd nanoparticles over the rGO support, as evidenced from TEM images. It is believed that the role of La species in promoting the catalyst activity is to disperse the catalyst particles during synthesis and to facilitate the electron transfer via providing a suitable pathway during electrochemical testing. PMID- 27933815 TI - Gold Nanoparticles as a Potential Cellular Probe for Tracking of Stem Cells in Bone Regeneration Using Dual-Energy Computed Tomography. AB - Transplant of bone marrow mesenchymal stem cells (BMSCs) has attracted considerable interest for bone regeneration. However, noninvasive and real-time tracking of location and concentration of the implanted BMSCs remains a big challenge. Herein we designed a novel approach involving the surface modification of gold nanoparticles (AuNPs) with silica layers and DNA Transfectin 3000 (TS) to improve biocompatibility and to enhance the uptake by BMSCs, hence rendering the ability of tracking BMSCs with dual-energy computer tomography (DECT). Results showed that the endocytosis of AuNPs@SiO2-TS by BMSCs was as high as ~255 pg/cell after one-day incubation and did not obviously decrease after 14 days. Meanwhile, the AuNPs@SiO2-TS had no influence on the viability, cell cycle, and capabilities on osteogenic, chondrogenic, and adipogenic differentiation of BMSCs. Under a bone-defect rabbit model, the DECT images showed the migration of BMSCs toward a cortical bone defect without variation in volume. This study demonstrated that AuNPs@SiO2-TS could be a potential cellular probe for noninvasive and real-time tracking of BMSCs in bone tissue repairs using clinical CT or DECT techniques. It provided a novel and intuitive methodology for observing and investigating the bone regeneration in clinic. PMID- 27933816 TI - Improved Cycling Performance of Lithium-Oxygen Cells by Use of a Lithium Electrode Protected with Conductive Polymer and Aluminum Fluoride. AB - Lithium-oxygen batteries have attracted great attention for advanced energy storage systems because of their high specific energy. The enhancement of the interfacial stability of lithium negative electrodes is one of the many technical challenges toward high safety and long life lithium-oxygen batteries due to their high reactivity toward organic electrolytes and the lithium dendrite growth during the repeated cycling. Herein, we demonstrate that the protective layer comprising conductive polymer and AlF3 particles on lithium metal stabilized the lithium electrode by effectively reducing the reductive decomposition of the liquid electrolyte and suppressing the growth of lithium dendrite. As a result, the cycling performance of a lithium-oxygen cell assembled with a surface modified lithium electrode was remarkably improved as compared to a cell with a pristine lithium electrode. PMID- 27933817 TI - Peptide-Mediated Platelet Capture at Gold Micropore Arrays. AB - Ordered spherical cap gold cavity arrays with 5.4, 1.6, and 0.98 MUm diameter apertures were explored as capture surfaces for human blood platelets to investigate the impact of surface geometry and chemical modification on platelet capture efficiency and their potential as platforms for surface enhanced Raman spectroscopy of single platelets. The substrates were chemically modified with single-constituent self-assembled monolayers (SAM) or mixed SAMs comprised of thiol-functionalized arginine-glycine-aspartic acid (RGD, a platelet integrin target) with or without 1-octanethiol (adhesion inhibitor). As expected, platelet adhesion was promoted and inhibited at RGD and alkanethiol modified surfaces, respectively. Platelet adhesion was reversible, and binding efficiency at the peptide modified substrates correlated inversely with pore diameter. Captured platelets underwent morphological change on capture, the extent of which depended on the topology of the underlying substrate. Regioselective capture of the platelets enabled study for the first time of the surface enhanced Raman spectroscopy of single blood platelets, yielding high quality Raman spectroscopy of individual platelets at 1.6 MUm diameter pore arrays. Given the medical importance of blood platelets across a range of diseases from cancer to psychiatric illness, such approaches to platelet capture may provide a useful route to Raman spectroscopy for platelet related diagnostics. PMID- 27933818 TI - Atomic Layer Deposited Coatings on Nanowires for High Temperature Water Corrosion Protection. AB - Two-phase liquid-cooling technologies incorporating micro/nanostructured copper or silicon surfaces have been established as a promising thermal management solution to keep up with the increasing power demands of high power electronics. However, the reliability of nanometer-scale features of copper and silicon in these devices has not been well investigated. In this work, accelerated corrosion testing reveals that copper nanowires are not immune to corrosion in deaerated pure hot water. To solve this problem, we investigate atomic layer deposition (ALD) TiO2 coatings grown at 150 and 175 degrees C. We measured no difference in coating thickness for a duration of 12 days. Using a core/shell approach, we grow ALD TiO2/Al2O3 protective coatings on copper nanowires and demonstrate a preservation of nanoengineered copper features. These studies have identified a critical reliability problem of nanoscale copper and silicon surfaces in deaerated, pure, hot water and have successfully demonstrated a reliable solution using ALD TiO2/Al2O3 protective coatings. PMID- 27933819 TI - Thermal Stability of NaxCrO2 for Rechargeable Sodium Batteries; Studies by High Temperature Synchrotron X-ray Diffraction. AB - Thermal stability and phase transition processes of NaCrO2 and Na0.5CrO2 are carefully examined by high-temperature synchrotron X-ray diffraction method. O3 type NaCrO2 shows anisotropic thermal expansion on heating, which is a common character as layered materials, without phase transition in the temperature range of 27-527 degrees C. In contrast, for the desodiated phase, in-plane distorted P3-type layered oxide (P'3 Na0.5CrO2), phase transition occurs in the following order. Monoclinic distortion associated with Na/vacancy ordering is gradually lost on heating, and its symmetry increases and changes to a rhombohedral lattice at 207 degrees C. On further heating, phase segregation to two P3 layered metastable phases, which have different interlayer distances (17.0 and 13.5 A, presumably sodium-rich and sodium-free P3 phases, respectively) are observed on heating to 287-477 degrees C, but oxygen loss is not observed. Oxygen loss is observed at temperatures only above 500 degrees C, resulting in the formation of corundum-type Cr2O3 and O3 NaCrO2 as thermodynamically stable phases. From these results, possibility of NaxCrO2 as a positive electrode material for safe rechargeable sodium batteries is also discussed. PMID- 27933820 TI - Hyaluronate-Gold Nanorod/DR5 Antibody Complex for Noninvasive Theranosis of Skin Cancer. AB - Noninvasive transdermal delivery is a promising method with distinct advantages including patient compliance over other delivery routes. Here, hyaluronate-gold nanorod/death receptor 5 antibody (HA-AuNR/DR5 Ab) complex was developed for transdermal theranosis of skin cancer. The successful formation of the complex was corroborated by 1H nuclear magnetic resonance, UV-vis spectroscopy, dynamic light scattering, zeta potential, and transmission electron microscopy. In vitro biological activity of the complex was verified by ELISA and MTT assay using HCT116 cancer cells. In addition, in vivo photoacoustic imaging and two-photon microscopy clearly visualized the transdermal delivery of HA-AuNR/DR5 Ab complex through the inevitable barrier of stratum corneum in the skin. Furthermore, in vivo antitumor effect on skin cancer model mice was confirmed from statistically significant decrease of tumor-reflecting luciferase expression levels and apoptotic signals in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Taken together, we could confirm the feasibility of HA-AuNR/DR5 Ab complex as a novel theranostic platform for noninvasive transdermal treatment of skin cancers. PMID- 27933821 TI - Direct in Situ Conversion of Metals into Metal-Organic Frameworks: A Strategy for the Rapid Growth of MOF Films on Metal Substrates. AB - The fabrication of metal-organic framework (MOF) films on conducting substrates has demonstrated great potential in applications such as electronic conduction and sensing. For these applications, direct contact of the film to the conducting substrate without a self-assembled monolayer (SAM) is a desired step that must be achieved prior to the use of MOF films. In this report, we propose an in situ strategy for the rapid one-step conversion of Cu metal into HKUST-1 films on conducting Cu substrates. The Cu substrate acts both as a conducting substrate and a source of Cu2+ ions during the synthesis of HKUST-1. This synthesis is possible because of the simultaneous reaction of an oxidizing agent and a deprotonating agent, in which the former agent dissolves the metal substrate to form Cu2+ ions while the latter agent deprotonates the ligand. Using this strategy, the HKUST-1 film could not only be rapidly synthesized within 5 min but also be directly attached to the Cu substrate. Based on microscopic studies, we propose a plausible mechanism for the growth reaction. Furthermore, we show the versatility of this in situ conversion methodology, applying it to ZIF-8, which comprises Zn2+ ions and imidazole-based ligands. Using an I2-filled HKUST-1 film, we further demonstrate that the direct contact of the MOF film to the conducting substrate makes the material more suitable for use as a sensor or electronic conductor. PMID- 27933822 TI - Amplified Fluorescence from Polyfluorene Nanoparticles with Dual State Emission and Aggregation Caused Red Shifted Emission for Live Cell Imaging and Cancer Theranostics. AB - A newly synthesized polyfluorene derivative with pendant di(2-picolyl)amine (PF DPA) shows dual state emission and aggregation caused red shifted emission that was utilized for cell imaging and cancer theranostics. PF-DPA was nontoxic to normal cells but showed cytotoxicity against cancer cells, suggesting its utility for cancer therapy. PF-DPA exhibits a large and unique red shifted emission at 556 nm at higher water ratio of THF:H2O (10:90) due to the formation of polymer nanoparticles or PDots spontaneously by intra- and intermolecular self-assembly induced aggregation. Dual state emission and aggregation caused red shifted emission (>100 nm) in PF-DPA homopolymer nanoparticles is very unique and attributed to the combined effect of intramolecular planarization and J-type aggregate formation in the PDots (25 +/- 5 nm). The PF-DPA PDots exhibit bright green and orange fluorescence with exceptional live cell imaging properties and potential applications in cancer theranostics due to their selective cytotoxic nature toward cancer cells. PMID- 27933823 TI - Graphene Oxide Directed One-Step Synthesis of Flowerlike Graphene@HKUST-1 for Enzyme-Free Detection of Hydrogen Peroxide in Biological Samples. AB - A novel metal-organic framework (MOF)-based electroactive nanocomposite containing graphene fragments and HKUST-1 was synthesized via a facile one-step solvothermal method using graphene oxide (GO), benzene-1,3,5-tricarboxylic acid (BTC), and copper nitrate (Cu(NO3)2) as the raw materials. The morphology and structure characterization revealed that the GO could induce the transformation of HKUST-1 from octahedral structure to the hierarchical flower shape as an effective structure-directing agent. Also, it is interesting to find out that the GO was torn into small fragments to participate in the formation of HKUST-1 and then transformed into the reduction form during the solvothermal reaction process, which dramatically increased the surface area, electronic conductivity, and redox-activity of the material. Electrochemical assays showed that the synergy of graphene and HKUST-1 in the nanocomposite leaded to high electrocatalysis, fast response, and excellent selectivity toward the reduction of hydrogen peroxide (H2O2). Based on these remarkable advantages, satisfactory results were obtained when the nanocomposite was used as a sensing material for electrochemical determination of H2O2 in the complex biological samples such as human serum and living Raw 264.7 cell fluids. PMID- 27933824 TI - Spent Tea Leaf Templating of Cobalt-Based Mixed Oxide Nanocrystals for Water Oxidation. AB - The facile synthesis of nanostructured cobalt oxides using spent tea leaves as a hard template is reported. Following an impregnation-calcination and template removal pathway, sheetlike structures containing nanosized crystallites of Co3O4 are obtained. Co3O4 incorporated with Cu, Ni, Fe, and Mn (M/Co = 1/8 atomic ratio) are also prepared, and the materials are thoroughly characterized using X ray diffraction, electron microscopy, and N2 sorption. The method is applicable to several commercial tea leaves and is successfully scaled up to prepare over 7 g of Co3O4 with the same nanostructure. The oxides are then tested for electrochemical water oxidation, and Cu, Ni, and Fe incorporations show beneficial effect on the catalytic activity of Co3O4, achieving performance comparable to levels from benchmark electrocatalysts. These data suggest that tea leaf templating can be utilized as a facile and promising approach to prepare nanostructured functional catalyst. PMID- 27933825 TI - Plasmon-Enhanced Photodynamic Cancer Therapy by Upconversion Nanoparticles Conjugated with Au Nanorods. AB - Photodynamic therapy (PDT) based on photosensitizers (PSs) constructed with nanomaterials has been widely applied to treat cancer. This therapy is characterized by an improved PS accumulation in tumor regions. However, challenges, such as short penetration depth of light and low extinction coefficient of PSs, limit PDT applications. In this study, a nanocomposite consisting of NaYF4:Yb/Er upconversion nanoparticles (UCPs) conjugated with gold nanorods (Au NRs) was developed to improve the therapeutic efficiency of PDT. Methylene blue (MB) was embedded in a silica shell for plasmon-enhanced PDT. UCPs served as a light converter from near-infrared (NIR) to visible light to excite MB to generate reactive oxygen species (ROS). Au NRs could effectively enhance upconversion efficiency and ROS content through a localized surface plasmon resonance (SPR) effect. Silica shell thickness was adjusted to investigate the optimized MB loading amount, ROS production capability, and efficient distance for plasmon-enhanced ROS production. The mechanism of plasmon-enhanced PDT was verified by enhancing UC luminescence intensity through the plasmonic field and by increasing the light-harvesting capability and absorption cross section of the system. This process improved the ROS generation by comparing the exchange of Au NRs to Au nanoparticles with different SPR bands. NIR-triggered nanocomposites of UCP@SiO2:MB-NRs were significantly confirmed by improving ROS generation and further modifying folic acid (FA) to develop an active component targeting OECM-1 oral cancer cells. Consequently, UCP@SiO2:MB-NRs-FA could highly produce ROS and undergo efficient PDT in vitro and in vivo. The mechanism of PDT treatment by UCP@SiO2:MB-NRs-FA was evaluated via the cell apoptosis pathway. The proposed process is a promising strategy to enhance ROS production through plasmonic field enhancement and thus achieve high PDT therapeutic efficacy. PMID- 27933826 TI - Soluble, Exfoliated Two-Dimensional Nanosheets as Excellent Aqueous Lubricants. AB - Dispersion in water of two-dimensional (2D) nanosheets is conducive to their practical applications in fundamental science communities due to their abundance, low cost, and ecofriendliness. However, it is difficult to achieve stable aqueous 2D material suspensions because of the intrinsic hydrophobic properties of the layered materials. Here, we report an effective and economic way of producing various 2D nanosheets (h-BN, MoS2, MoSe2, WS2, and graphene) as aqueous dispersions using carbon quantum dots (CQDs) as exfoliation agents and stabilizers. The dispersion was prepared through a liquid phase exfoliation. The as-synthesized stable 2D nanosheets based dispersions were characterized by UV vis, HRTEM, AFM, Raman, XPS, and XRD. The solutions based on CQD decorated 2D nanosheets were utilized as aqueous lubricants, which realized a friction coefficient as low as 0.02 and even achieved a superlubricity under certain working conditions. The excellent lubricating properties were attributed to the synergetic effects of the 2D nanosheets and CQDs, such as good dispersion stability and easy-sliding interlayer structure. This work thus proposes a novel strategy for the design and preparation of high-performance water based green lubricants. PMID- 27933827 TI - Electrochemical in Situ Tracking of Volumetric Changes in Two-Dimensional Metal Carbides (MXenes) in Ionic Liquids. AB - We report the volumetric changes of MXenes in contact with different ionic liquids and the swelling/contraction during electrochemical voltage cycling by complementing electrochemical dilatometry with in situ X-ray diffraction measurements. A drastic, initial, and irreversible volume expansion of MXenes occurs during first contact to ionic liquids (wetting). Voltage cycling evidenced a highly reversible expansion and contraction of electrodes at a very large amplitude of strain (corresponding with max. 12 vol %), which may allow the use of MXene as a high-performance electrochemical actuator. PMID- 27933828 TI - Turn-on and Ratiometric Luminescent Sensing of Hydrogen Sulfide Based on Metal Organic Frameworks. AB - The sensing of hydrogen sulfide (H2S) has become a long-time challenging task. In this work, we developed a general strategy for sensing of H2S utilizing postsynthetic modification of a nano metal-organic frameworks (MOF) UiO-66 (COOH)2 with Eu3+ and Cu2+ ions. The nano MOF Eu3+/Cu2+@UiO-66-(COOH)2 displays the characteristic Eu3+ sharp emissions and the broad ligand-centered (LC) emission simultaneously. Because H2S can strongly increase the fluorescence of Eu3+ and quench the broad LC emission through its superior affinity for Cu2+ ions, the MOF Eu3+/Cu2+@UiO-66-(COOH)2 exhibits highly sensitive turn-on sensing of H2S over other environmentally and biologically relevant species under physiological conditions. Furthermore, this approach for fluorescent turn-on sensing of H2S is expected to extend to other water-stable MOFs containing uncoordinated -COOH. PMID- 27933829 TI - Effect of Polymer Gate Dielectrics on Charge Transport in Carbon Nanotube Network Transistors: Low-k Insulator for Favorable Active Interface. AB - Charge transport in carbon nanotube network transistors strongly depends on the properties of the gate dielectric that is in direct contact with the semiconducting carbon nanotubes. In this work, we investigate the dielectric effects on charge transport in polymer-sorted semiconducting single-walled carbon nanotube field-effect transistors (s-SWNT-FETs) by using three different polymer insulators: A low-permittivity (epsilonr) fluoropolymer (CYTOP, epsilonr = 1.8), poly(methyl methacrylate) (PMMA, epsilonr = 3.3), and a high-epsilonr ferroelectric relaxor [P(VDF-TrFE-CTFE), epsilonr = 14.2]. The s-SWNT-FETs with polymer dielectrics show typical ambipolar charge transport with high ON/OFF ratios (up to ~105) and mobilities (hole mobility up to 6.77 cm2 V-1 s-1 for CYTOP). The s-SWNT-FET with the lowest-k dielectric, CYTOP, exhibits the highest mobility owing to formation of a favorable interface for charge transport, which is confirmed by the lowest activation energies, evaluated by the fluctuation induced tunneling model (FIT) and the traditional Arrhenius model (EaFIT = 60.2 meV and EaArr = 10 meV). The operational stability of the devices showed a good agreement with the activation energies trend (drain current decay ~14%, threshold voltage shift ~0.26 V in p-type regime of CYTOP devices). The poor performance in high-epsilonr devices is accounted for by a large energetic disorder caused by the randomly oriented dipoles in high-k dielectrics. In conclusion, the low-k dielectric forms a favorable interface with s-SWNTs for efficient charge transport in s-SWNT-FETs. PMID- 27933830 TI - THz Pulse Detection by Multilayered GeTe/Sb2Te3. AB - We proposed and demonstrated terahertz (THz) pulse detection by means of multilayered GeTe/Sb2Te3 phase-change memory materials that are also known as a multilayer topological insulator-normal insulator (MTN) system. THz time-domain spectroscopy measurement was performed for MTN films with different multilayer repetitions as well as a conventional as-grown Ge-Te-Sb (GST) alloy film. It was found that MTNs absorb THz waves and that the absorption coefficient depends on the number of layers, while the as-grown GST alloy film was almost transparent for THz waves. Simple MTN-based THz detection devices were fabricated, and the THz-induced change in the current signal was measured when a DC bias voltage was applied between the electrodes. We confirmed that irradiation of THz pulse causes a decrease in the resistance of the MTNs. This result indicates that our devices are capable of THz detection. PMID- 27933831 TI - Improved Cycling Stability and Fast Charge-Discharge Performance of Cobalt-Free Lithium-Rich Oxides by Magnesium-Doping. AB - Layered Li-rich, Co-free, and Mn-based cathode material, Li1.17Ni0.25 xMn0.58MgxO2 (0 <= x <= 0.05), was successfully synthesized by a coprecipitation method. All prepared samples have typical Li-rich layered structure, and Mg has been doped in the Li1.17Ni0.25Mn0.58O2 material successfully and homogeneously. The morphology and the grain size of all material are not changed by Mg doping. All materials have a estimated size of about 200 nm with a narrow particle size distribution. The electrochemical property results show that Li1.17Ni0.25 xMn0.58MgxO2 (x = 0.01 and 0.02) electrodes exhibit higher rate capability than that of the pristine one. Li1.17Ni0.25-xMn0.58MgxO2 (x = 0.02) indicates the largest reversible capacity of 148.3 mAh g-1 and best cycling stability (capacity retention of 95.1%) after 100 cycles at 2C charge-discharge rate. Li1.17Ni0.25 xMn0.58MgxO2 (x = 0.02) also shows the largest discharge capacity of 149.2 mAh g 1 discharged at 1C rate at elevated temperature (55 degrees C) after 50 cycles. The improved electrochemical performances may be attributed to the decreased polarization, reduced charge transfer resistance, enhanced the reversibility of Li+ ion insertion/extraction, and increased lithium ion diffusion coefficient. This promising result gives a new understanding for designing the structure and improving the electrochemical performance of Li-rich cathode materials for the next-generation lithium-ion battery with high rate cycling performance. PMID- 27933832 TI - Annealing-Based Electrical Tuning of Cobalt-Carbon Deposits Grown by Focused Electron-Beam-Induced Deposition. AB - An effective postgrowth electrical tuning, via an oxygen releasing method, to enhance the content of non-noble metals in deposits directly written with gas assisted focused-electron-beam-induced deposition (FEBID) is presented. It represents a novel and reproducible method for improving the electrical transport properties of Co-C deposits. The metal content and electrical properties of Co-C O nanodeposits obtained by electron-induced dissociation of volatile Co2(CO)8 precursor adsorbate molecules were reproducibly tuned by applying postgrowth annealing processes at 100 degrees C, 200 degrees C, and 300 degrees C under high-vacuum for 10 min. Advanced thin film EDX analysis showed that during the annealing process predominantly oxygen is released from the Co-C-O deposits, yielding an atomic ratio of Co:C:O = 100:16:1 (85:14:1) with respect to the atomic composition of as-written Co:C:O = 100:21:28 (67:14:19). In-depth Raman analysis suggests that the amorphous carbon contained in the as-written deposit turns into graphite nanocrystals with size of about 22.4 nm with annealing temperature. Remarkably, these microstructural changes allow for tuning of the electrical resistivity of the deposits over 3 orders of magnitude from 26 mOmega cm down to 26 MUOmega cm, achieving a residual resistivity of rho2K/rho300 K = 0.56, close to the value of 0.53 for pure Co films with similar dimensions, making it especially interesting and advantageous over the numerous works already published for applications such as advanced scanning-probe systems, magnetic memory, storage, and ferroelectric tunnel junction memristors, as the graphitic matrix protects the cobalt from being oxidized under an ambient atmosphere. PMID- 27933833 TI - Tunable Pickering Emulsions with Environmentally Responsive Hairy Silica Nanoparticles. AB - Surface modification of the nanoparticles using surface anchoring of amphiphilic polymers offers considerable scope for the design of a wide range of brush-coated hybrid nanoparticles with tunable surface wettability that may serve as new class of efficient Pickering emulsifiers. In the present study, we prepared mixed polymer brush-coated nanoparticles by grafting ABC miktoarm star terpolymers consisting of poly(ethylene glycol), polystyrene, and poly[(3 triisopropyloxysilyl)propyl methacrylate] (MU-PEG-b-PS-b-PIPSMA) on the surface of silica nanoparticles. The wettability of the as-prepared nanoparticles can be precisely tuned by a change of solvent or host-guest complexation. 1H NMR result confirmed that such wettability change is due to the reorganization of the polymer chain at the grafted layer. We show that this behavior can be used for stabilization and switching between water-in-oil (W/O) and oil-in-water (O/W) emulsions. For hairy particles initially dispersed in oil, W/O emulsions were always obtained with collapsed PEG chains and mobile PS chains at the grafted layer. However, initially dispersing the hairy particles in water resulted in O/W emulsions with collapsed PS chains and mobile PEG chains. When a good solvent for both PS and PEG blocks such as toluene was used, W/O emulsions were always obtained no matter where the hairy particles were dispersed. The wettability of the mixed polymer brush-coated silica particles can also be tuned by host-guest complexation between PEG block and alpha-CD. More importantly, our result showed that surprisingly the resultant mixed brush-coated hairy nanoparticles can be employed for the one-step production of O/W/O multiple emulsions that are not attainable from conventional Pickering emulsifiers. The functionalized hairy silica nanoparticles at the oil-water interface can be further linked together utilizing poly(acrylic acid) as the reversible linker to form supramolecular colloidosomes, which show pH-dependent release of cargo. PMID- 27933834 TI - Alginate Bead Based Hexagonal Close Packed 3D Implant for Bone Tissue Engineering. AB - Success of bone tissue engineering (BTE) relies on the osteogenic microarchitecture of the biopolymeric scaffold and appropriate spatiotemporal distribution of therapeutic molecules (growth factors and drugs) inside it. However, the existing technologies have failed to address both the issues together. Keeping this perspective in mind, we have developed a novel three dimensional (3D) implant prototype by stacking hexagonal close packed (HCP) layers of calcium alginate beads. The HCP arrangement of the beads lead to a patterned array of interconnected tetrahedral and octahedral pores of average diameter of 142.9 and 262.9 MUm, respectively, inside the implant. The swelling pattern of the implants changed from isotropic to anisotropic in the z-direction in the absence of bivalent calcium ions (Ca2+) in the swelling buffer. Incubation of the implant in simulated body fluid (SBF) resulted in a 2.7-fold increase in the compressive modulus. The variation in the relaxation times as derived from the Weichert viscoelasticity model predicted a gradual increase in the interactions among the alginate molecules in the matrix. We demonstrated the tunability of the spatiotemporal drug release from the implant in a tissue mimicking porous semisolid matrix as well as in conventional drug release set up by changing the spatial coordinates of the "drug loaded depot layer" inside the implant. The therapeutic potential of the implant was confirmed against Escherichia coli using metronidazole as the model drug. Detailed analysis of cell viability, cell cycle progression, and cytoskeletal reorganization using osteoblast cells (MG-63) proved the osteoconductive nature of the implant. Expression of differentiation markers such as alkaline phosphatase, runx2, and collagen type 1 in human mesenchymal stem cell in vitro confirmed the osteogenic nature of the implant. When tested in vivo, VEGF loaded implant was found capable of inducing angiogenesis in a mice model. In conclusion, the bead based implant may find its utility in non-load-bearing BTE. PMID- 27933835 TI - Fully Printed Ultraflexible Supercapacitor Supported by a Single-Textile Substrate. AB - Textile-based supercapacitors have recently attracted much attention owing to their great potential as energy storage components in wearable electronics. However, fabrication of a high-performance, fully printed, and ultraflexible supercapacitor based on a single textile still remains a great challenge. Herein, a facile, low-cost, and textile-compatible method involving screen printing and transfer printing is developed to construct all-solid-state supercapacitors on a single silk fabric. The system exhibits a high specific capacitance of 19.23 mF cm-2 at a current density of 1 mA cm-2 and excellent cycling stability with capacitance retention of 84% after 2000 charging/discharging cycles. In addition, the device possesses superior mechanical stability with stable performance and structures after 100 times of bending and twisting. A butterfly-patterned supercapacitor was manufactured to demonstrate the compatibility of the printing approaches to textile aesthetics. This work may provide a facile and versatile approach for fabricating rationally designed ultraflexible textile-based power storage elements for potential applications in smart textiles and stretchable/flexible electronics. PMID- 27933836 TI - Fabrication, Testing, and Simulation of All-Solid-State Three-Dimensional Li-Ion Batteries. AB - Demonstration of three-dimensional all-solid-state Li-ion batteries (3D SSLIBs) has been a long-standing goal for numerous researchers in the battery community interested in developing high power and high areal energy density storage solutions for a variety of applications. Ideally, the 3D geometry maximizes the volume of active material per unit area, while keeping its thickness small to allow for fast Li diffusion. In this paper, we describe experimental testing and simulation of 3D SSLIBs fabricated using materials and thin-film deposition methods compatible with semiconductor device processing. These 3D SSLIBs consist of Si microcolumns onto which the battery layers are sequentially deposited using physical vapor deposition. The power performance of the 3D SSLIBs lags significantly behind that of similarly prepared planar SSLIBs. Analysis of the experimental results using finite element modeling indicates that the origin of the poor power performance is the structural inhomogeneity of the 3D SSLIB, coupled with low electrolyte ionic conductivity and diffusion rate in the cathode, which lead to highly nonuniform internal current density distribution and poor cathode utilization. PMID- 27933838 TI - Preparation of Interconnected Biomimetic Poly(vinylidene fluoride-co chlorotrifluoroethylene) Hydrophobic Membrane by Tuning the Two-Stage Phase Inversion Process. AB - A facile strategy was applied for poly(vinylidene fluoride-co chlorotrifluoroethylene) (PVDF-CTFE) hydrophobic membrane preparation by tuning the two-stage phase inversion process. The exposure stage was found to benefit the solid-liquid demixing process (gelation/crystallization) induced by the solvent evaporation and the subsequent phase inversion induced by immersion benefit the liquid-liquid demixing. It was confirmed that the electrospun nanostructure-like biomimetic surface and interconnected pore structure can be expected by controlling the exposure duration, and 300 s was considered as the inflection point of exposure duration for PVDF-CTFE membrane through which a tremendous variation would show. The micro/nanohierarchical structure in the membrane surface owing to the crystallization of PVDF-CTFE copolymer was responsible for the improvement of membrane roughness and hydrophobicity. Meanwhile, the interconnected pore structure in both the surface and the cross section, which were formed because of the crystallization process, offers more mass transfer passages and enhances the permeate flux. The membrane then showed excellent MD performance with high permeate flux, high salt rejection, and relatively high stability during a 48 h continuous DCMD operation, according to the morphology, pore structure, and properties, which can be a substitute for hydrophobic membrane application. PMID- 27933837 TI - Observation of Nanoscale Morphological and Structural Degradation in Perovskite Solar Cells by in Situ TEM. AB - High-resolution in situ transmission electron microscopy (TEM) and electron energy loss spectroscopy were applied to systematically investigate morphological and structural degradation behaviors in perovskite films during different environmental exposure treatments. In situ TEM experiment indicates that vacuum itself is not likely to cause degradation in perovskites. In addition, these materials were found to degrade significantly when they were heated to ~50-60 degrees C (i.e., a solar cell's field operating temperature) under illumination. This observation thus conveys a critically important message that the instability of perovskite solar cells at such a low temperature may limit their real field commercial applications. It was further unveiled that oxygen most likely attacks the CH3NH3+ organic moiety rather than the PbI6 component of perovskites during ambient air exposure at room temperature. This finding grants a deeper understanding of the perovskite degradation mechanism and suggests a way to prevent degradation of perovskites by tailoring the organic moiety component. PMID- 27933839 TI - Novel Application of Cellulose Paper As a Platform for the Macromolecular Self Assembly of Biomimetic Giant Liposomes. AB - We report a facile and scalable method to fabricate biomimetic giant liposomes by using a cellulose paper-based materials platform. Termed PAPYRUS for Paper Abetted liPid hYdRation in aqUeous Solutions, the method is general and can produce liposomes in various aqueous media and at elevated temperatures. Encapsulation of macromolecules and production of liposomes with membranes of complex compositions is straightforward. The ease of manipulation of paper makes practical massive parallelization and scale-up of the fabrication of giant liposomes, demonstrating for the first time the surprising usefulness of paper as a platform for macromolecular self-assembly. PMID- 27933840 TI - Low-Temperature Treated Lignin as Both Binder and Conductive Additive for Silicon Nanoparticle Composite Electrodes in Lithium-Ion Batteries. AB - This work demonstrates a high-performance and durable silicon nanoparticle-based negative electrode in which conventional polymer binder and carbon black additive are replaced with lignin. The mixture of silicon nanoparticles and lignin, a low cost, renewable, and widely available biopolymer, was coated on a copper substrate using the conventional slurry mixing and coating method and subsequently heat-treated to form the composite electrode. The composite electrode showed excellent electrochemical performance with an initial discharge capacity of up to 3086 mAh g-1 and retaining 2378 mAh g-1 after 100 cycles at 1 A g-1. Even at a relatively high areal loading of ~1 mg cm-2, an areal capacity of ~2 mAh cm-2 was achieved. The composite electrode also displayed excellent rate capability and performance in a full-cell setup. Through synergistic analysis of X-ray photoelectron spectroscopy, Raman, and nanoindentation experiment results, we attribute the amazing properties of Si/lignin electrodes to the judicious choice of heat treatment temperature at 600 degrees C. At this temperature, lignin undergoes complex compositional change during which a balance between development of conductivity and retaining of polymer flexibility is realized. We hope this work could lead to practicable silicon-based negative electrodes and stimulate the interest in the utilization of biorenewable resources in advanced energy applications. PMID- 27933841 TI - Oxide Heteroepitaxy for Flexible Optoelectronics. AB - The emerging technological demands for flexible and transparent electronic devices have compelled researchers to look beyond the current silicon-based electronics. However, fabrication of devices on conventional flexible substrates with superior performance are constrained by the trade-off between processing temperature and device performance. Here, we propose an alternative strategy to circumvent this issue via the heteroepitaxial growth of transparent conducting oxides (TCO) on the flexible mica substrate with performance comparable to that of their rigid counterparts. With the examples of ITO and AZO as a case study, a strong emphasis is laid upon the growth of flexible yet epitaxial TCO relying muscovite's superior properties compared to those of conventional flexible substrates and its compatibility with the present fabrication methods. Besides excellent optoelectro-mechanical properties, an additional functionality of high temperature stability, normally lacking in the current state-of-the-art transparent flexitronics, is provided by these heterostructures. These epitaxial TCO electrodes with good chemical and thermal stabilities as well as mechanical durability can significantly contribute to the field of flexible, light-weight, and portable smart electronics. PMID- 27933842 TI - Biomass-Derived Porous Fe3C/Tungsten Carbide/Graphitic Carbon Nanocomposite for Efficient Electrocatalysis of Oxygen Reduction. AB - The oxygen-reduction reaction (ORR) draws an extensive attention in many applications, and there is a growing interest to develop effective ORR electrocatalysts. Iron carbide (Fe3C) is a promising alternative to noble metals (e.g., platinum), but its performances need further improvement, and the real role of the Fe3C phase remains unclear. In this study, we synthesize Fe3C/tungsten carbide/graphitic carbon (Fe3C/WC/GC) nanocomposites, with waste biomass (i.e., pomelo peel) serving as carbon source, using a facile, one-step carbon thermal-reduction method. The nanocomposite is characterized by a porous structure consisting of uniform Fe3C nanoparticles encased by graphitic carbon (GC) layers with highly dispersed nanosized WC. The Fe3C provides the active sites for ORR, while the graphitic layers and WC nanoparticles can stibilize the Fe3C surface, preventing it from dissociation in the electrolyte. The Fe3C/WC/GC nanocomposite is highly active, selective, and stable toward four-electron ORR in pH-neutral electrolyte, which results in a 67.82% higher power density than that of commercial Pt/C and negligible voltage decay during a long-term phase of a 33 cycle (2200 h) operation of a microbial fuel cell (MFC). The density functional theory (DFT) calculations suggest high activity for splitting the O-O bond of molecular oxygen on the surface of Fe3C. PMID- 27933843 TI - Strategy to Achieve Highly Porous/Biocompatible Macroscale Cell Blocks, Using a Collagen/Genipin-bioink and an Optimal 3D Printing Process. AB - Recently, a three-dimensional (3D) bioprinting process for obtaining a cell-laden structure has been widely applied because of its ability to fabricate biomimetic complex structures embedded with and without cells. To successfully obtain a cell laden porous block, the cell-delivering vehicle, bioink, is one of the significant factors. Until now, various biocompatible hydrogels (synthetic and natural biopolymers) have been utilized in the cell-printing process, but a bioink satisfying both biocompatibility and print-ability requirements to achieve a porous structure with reasonable mechanical strength has not been issued. Here, we propose a printing strategy with optimal conditions including a safe cross linking procedure for obtaining a 3D porous cell block composed of a biocompatible collagen-bioink and genipin, a cross-linking agent. To obtain the optimal processing conditions, we modified the 3D printing machine and selected an optimal cross-linking condition (~1 mM and 1 h) of genipin solution. To show the feasibility of the process, 3D pore-interconnected cell-laden constructs were manufactured using osteoblast-like cells (MG63) and human adipose stem cells (hASCs). Under these processing conditions, a macroscale 3D collagen-based cell block of 21 * 21 * 12 mm3 and over 95% cell viability was obtained. In vitro biological testing of the cell-laden 3D porous structure showed that the embedded cells were sufficiently viable, and their proliferation was significantly higher; the cells also exhibited increased osteogenic activities compared to the conventional alginate-based bioink (control). The results indicated the fabrication process using the collagen-bioink would be an innovative platform to design highly biocompatible and mechanically stable cell blocks. PMID- 27933844 TI - Cellulose Nanocrystal/Poly(ethylene glycol) Composite as an Iridescent Coating on Polymer Substrates: Structure-Color and Interface Adhesion. AB - The broad utility as an environmentally friendly and colorful coating of cellulose nanocrystal (CNC) was limited by its instability of coloration, brittleness, and lack of adhesion to a hydrophobic surface. In the present work, a neutral polymer, poly(ethylene glycol) (PEG) was introduced into CNC coatings through evaporation-induced self-assembly (EISA) on polymer matrices. The structure-color and mechanical properties of the composite coating or coating film were characterized by UV-vis spectroscopy, polarized light microscopy (PLM), scanning electron microscopy (SEM), wide-angle X-ray diffraction (WXRD), and tensile tests. Results showed that the reflective wavelength of the iridescent CNCs could be finely tuned by incorporation of PEG with varied loadings from 2.5 to 50 wt %, although the high loading content of PEG would produce some side effects because of the severe microphase separation. Second, PEG played an effective plasticizer to improve the ductility or flexibility of the CNC coating or coating film. Furthermore, as a compatibilizer, PEG could effectively and tremendously enhance the adhesion strength between CNCs and neutral polymer matrices without destroying the chiral nematic mesophases of CNCs. Environmentally friendly CNC/PEG composites with tunable iridescence, good flexibility, and high bonding strength to hydrophobic polymer matrices are expected to be promising candidates in the modern green paint industry. PMID- 27933845 TI - Manganese Oxide Based Catalytic Micromotors: Effect of Polymorphism on Motion. AB - Manganese oxide (MnO2) has recently emerged as a promising alternate material for the fabrication of self-propelled micromotors. Platinum (Pt) has been traditionally used as a catalytic material for this purpose. However, the high cost associated with Pt restricts its widespread use toward practical applications where large amounts of material are required. MnO2 exists in different crystalline forms (polymorphs), which govern its catalytic behavior. In spite of this, the recent reports on MnO2 based micromotors have seldom reported on the polymorphic form involved. In the present work, we synthesized six different types of MnO2 based micromotors, which represent different geometrical designs (i.e., spherical, rod-like, and tube-like microparticles) and polymorphs, and characterized their motion behavior in different chemical environments. Out of all micromotors tested, the hollow spherical MnO2 microparticles reached the maximum velocity of ~1600 MUm s-1, which represents the fastest MnO2 based catalytic micromotor reported until date. The findings of this study will have a profound impact on the design and application of the next-generation synthetic micro- and nanomotors based on MnO2 as a low-cost and environment friendly material. PMID- 27933846 TI - Enhanced Cellular Internalization and On-Demand Intracellular Release of Doxorubicin by Stepwise pH-/Reduction-Responsive Nanoparticles. AB - The efficient delivery of antitumor agents to tumor sites faces numerous obstacles, such as poor cellular uptake and slow intracellular drug release. In this regard, smart nanoparticles (NPs) that respond to the unique microenvironment of tumor tissues have been widely used for drug delivery. In this study, novel charge-reversal and reduction-responsive histidine-grafted chitosan-lipoic acid NPs (HCSL-NPs) were selected for efficient therapy of breast cancer by enhancing cell internalization and intracellular pH- and reduction triggered doxorubicin (DOX) release. The surface charge of HCSL-NPs presented as negative at physiological pH and reversed to positive at the extracellular and intracellular pH of the tumor. In vitro release investigation revealed that DOX/HCSL-NPs demonstrated a sustained drug release under the physiological condition, whereas rapid DOX release was triggered by both endolysosome pH and high-concentration reducing glutathione (GSH). These NPs exhibited enhanced internalization at extracellular pH, rapid intracellular drug release, and improved cytotoxicity against 4T1 cells in vitro. Excellent tumor penetrating efficacy was also found in 4T1 tumor spheroids and solid tumor slices. In vivo experiments demonstrated that HCSL-NPs exhibited excellent tumor-targeting ability in tumor tissues as well as excellent antitumor efficacy and low systemic toxicity in breast tumor-bearing BALB/c mice. These results indicated that the novel charge-reversal and reduction-responsive HCSL-NPs have great potential for targeted and efficient delivery of chemotherapeutic drugs in cancer treatments. PMID- 27933847 TI - Hybrid Hairy Janus Particles as Building Blocks for Antibiofouling Surfaces. AB - Herein, we report a new strategy for the design of antifouling surfaces by using hybrid hairy Janus particles. The amphiphilic Janus particles possess either a spherical or a plateletlike shape and have core-shell structures with an inorganic core and hydrophilic/hydrophobic polymeric shells. Subsequently, these bifunctional Janus particles enable the fabrication of surfaces with modularity in chemical composition and final surface topography, which possess antifouling properties. The antifouling and fouling-release capability of the composite Janus particle-based surfaces is investigated using the marine biofilm-forming bacteria Cobetia marina. The Janus particle-based coatings are robust and significantly reduce bacterial retention under both static and dynamic conditions independent of the particle geometry. The plateletlike (kaolinite-based) Janus particles represent a scalable system for the rational design of antifouling coatings as well as their large-scale production and application in the future. PMID- 27933848 TI - Polyphenol Coating as an Interlayer for Thin-Film Composite Membranes with Enhanced Nanofiltration Performance. AB - Thin-film composite (TFC) nanofiltration membranes are prepared via interfacial polymerization with a polyphenol coating as an interlayer for the thin and smooth polyamide selective layer. The polyphenol interlayer is simply fabricated by the codeposition of tannic acid and diethylenetriamine without changing the surface morphology of the polysulfone ultrafiltration substrate. An interfacial polymerization is conducted from piperazidine and trimesoyl chloride on the polyphenol interlayer to construct the polyamide selective layer. The as-prepared TFC nanofiltration membranes show nearly tripled fold of water permeation flux as compared with those prepared at the same condition without an interlayer. They also exhibit a high rejection to Na2SO4 (>98%) because the thin and defect-free polyamide selective layer is formed on the polyphenol interlayer. These nanofiltration properties have high reproducibility, which means the TFC nanofiltration membranes are suitable for scale-up industrial applications. PMID- 27933849 TI - Carbon-Stabilized Interlayer-Expanded Few-Layer MoSe2 Nanosheets for Sodium Ion Batteries with Enhanced Rate Capability and Cycling Performance. AB - Sodium ion batteries (SIBs) have been considered as a promising alternative to lithium ion batteries, owing to the abundant reserve and low-cost accessibility of the sodium source. To date, the pursuit of high-performance anode materials remains a great challenge for the SIBs. In this work, carbon-stabilized interlayer-expanded few-layer MoSe2 nanosheets (MoSe2@C) have been fabricated by an oleic acid (OA) functionalized synthesis-polydopamine (PDA) stabilization carbonization strategy, and their structural, morphological, and electrochemical properties have been carefully characterized and compared with the carbon-free MoSe2. When evaluated as anode for sodium ion half batteries, the MoSe2@C exhibits a remarkably enhanced rate capability of 367 mA h g-1 at 5 A g-1, a high reversible discharge capacity of 445 mA h g-1 at 1 A g-1, and a long-term cycling stability over 100 cycles. To further explore the potential applications, the MoSe2@C is assembled into sodium ion full batteries with Na3V2(PO4)3 (NVP) as cathode materials, showing an impressively high reversible capacity of 421 mA h g 1 at 0.2 A g-1 after 100 cycles. Such results are primarily attributed to the unique carbon-stabilized interlayer-expanded few-layer MoSe2 nanosheets structure, which facilitates the permeation of electrolyte into the inner of MoSe2 nanosheets, promoting charge transfer efficiency among MoSe2 nanosheets, and accommodating the volume change from discharge-charge cycling. PMID- 27933850 TI - A 3D Nanostructure Based on Transition-Metal Phosphide Decorated Heteroatom-Doped Mesoporous Nanospheres Interconnected with Graphene: Synthesis and Applications. AB - A novel three-dimensional nanostructure based on cobalt phosphide nanoparticles (Co2P NPs) and heteroatom-doped mesoporous carbon spheres interconnected with graphene (3D PZM@Co2P@RGO) was facilely synthesized for the first time, and it was used for enhancing the flame retardancy and toxicity suppression of epoxy resins (EP) via a synergistic effect. Herein, the cross-linked polyphosphazene hollow spheres (PZM) were used as templates for the fabrication of 3D architecture. The 3D architecture based on Co2P-decorated heteroatom-doped carbon sphere and reduced graphene oxide was prepared via a carbonization procedure followed by a hydrothermal self-assembly strategy. The as-prepared material exhibits excellent catalytic activity with regard to the combustion process. Notably, inclusion of incorporating PZM@Co2P@RGO resulted in a dramatic reduction of the fire hazards of EP, such as a 47.9% maximum decrease in peak heat release rate and a 29.2% maximum decrease in total heat release, lower toxic CO yield, and formation of high-graphitized protective char layer. In addition, the mechanism for flame retardancy and toxicity suppression was proposed. It is reasonable to know that the improved flame-retardant performance for EP nanocomposites is attributed to tripartite cooperative effect from respective components (Co2P NPs and RGO) plus the heteroatom-doped carbon spheres. PMID- 27933851 TI - Synthesis of Polyethylenimine Functionalized Mesoporous Silica for In-Pipet-Tip Phosphopeptide Enrichment. AB - Synthesis of functionalized mesoporous silica material with large particle size remains a chanllenge. In this work, polyethylenimine (PEI) functionalized mesoporous silica (PFMS) with particle size as large as 100 MUm was successfully synthesized by a facile method. In the synthesis process, PEI served as four roles simultaneously, including functionalized reagent, alkaline catalyst, template for particle formation, and pore-structure-directing agent. The surface areas of the products were higher than 260 m2/g. Benefiting from the large particle size and high surface area, PFMS was packed in a pipet tip to fabricate a convenient and miniaturized solid phase extraction apparatus for sample preparation. Additionally, based on the extremely abundant basic sites in the organic units of PFMS, the in-pipet-tip system was used as an anion-exchanger for phosphopeptide enrichment. The specificity of the developed method was investigated by capture of phosphopeptides from tryptic digests of standard protein mixtures, tryptic digests of nonfat milk, and human serum. Furthermore, the method was utilized to analyze phosphopeptides in tryptic digests of rat brain lysate, and 2251 unique phosphopeptides were successfully detected. PMID- 27933852 TI - Facet-Dependent Property of Sequentially Deposited Perovskite Thin Films: Chemical Origin and Self-Annihilation. AB - Quantification of intergrain length scale properties of CH3NH3PbI3 (MAPbI3) can provide further understanding of material physics, leading to improved device performance. In this work, we noticed that two typical types of facets appear in sequential deposited perovskite (SDP) films: smooth and steplike morphologies. By mapping the surface potential as well as the photoluminescence (PL) peak position, we revealed the heterogeneity of SDP thin films that smooth facets are almost intrinsic with a PL peak at 775 nm, while the steplike facets are p-type doped with 5-nm blue-shifted PL peak. Considering the reaction process, we propose that the smooth facets have well-defined crystal lattices that resulted from the interfacial reaction between MAI and PbI2 domains containing low trap states density. The steplike facets are MAI-rich originated from the grain boundaries of PbI2 film and own more trap states. Conversion of steplike facets to smooth facets can be controlled by increasing the reaction time through Ostwald ripening. The improved stability, photoresponsivity up to 0.3 A/W, on/off ratio up to 3900, and decreased photo response time to ~160 MUs show that the trap states can be annihilated effectively to improve the photoelectrical conversion with prolonged reaction time and elimination of steplike facets. Our findings demonstrate the relationship between the facet heterogeneity of SDP films and crystal growth process for the first time, and imply that the systematic control of crystal grain modification will enable amelioration of crystallinity for more-efficient perovskite photoelectrical applications. PMID- 27933853 TI - Highly Efficient Flame Retardant Polyurethane Foam with Alginate/Clay Aerogel Coating. AB - Highly efficient flame retardant polyurethane foams with alginate/clay aerogel coatings were fabricated using a freeze-drying method. The microstructure and the interaction of the samples were characterized with scanning electron and optical microscopy (SEM) and (OM). The results show that PU foam has a porous structure with pore sizes of several hundred microns, and that of aerogel ranges from 10 to 30 MUm. The PU foam matrix and the aerogel coatings have strong interactions, due to the infusion of aerogel into the porous structure of the foam and the tension generated during the freeze-drying process. Both the PU foam and the aerogel exhibit good thermal stabilities, with onset decomposition temperatures above 240 degrees C. Combustion parameters, including LOI, TTI, HRR, TSR, FIGRA, CO, and CO2, all indicate significantly reduced fire risk. Total heat release of all but one of the samples was maintained, indicating that the flame retardant mechanism is to decrease flame spread rate by forming a heat, oxygen, and smoke barrier, rather than by reducing fuel content. This facile and inexpensive post-treatment of PU foam could expand its fire safe applications. PMID- 27933854 TI - Thermal Cycling Behavior of Thermal Barrier Coatings with MCrAlY Bond Coat Irradiated by High-Current Pulsed Electron Beam. AB - Microstructural modifications of a thermally sprayed MCrAlY bond coat subjected to high-current pulsed electron beam (HCPEB) and their relationships with thermal cycling behavior of thermal barrier coatings (TBCs) were investigated. Microstructural observations revealed that the rough surface of air plasma spraying (APS) samples was significantly remelted and replaced by many interconnected bulged nodules after HCPEB irradiation. Meanwhile, the parallel columnar grains with growth direction perpendicular to the coating surface were observed inside these bulged nodules. Substantial Y-rich Al2O3 bubbles and varieties of nanocrystallines were distributed evenly on the top of the modified layer. A physical model was proposed to describe the evaporation-condensation mechanism taking place at the irradiated surface for generating such surface morphologies. The results of thermal cycling test showed that HCPEB-TBCs presented higher thermal cycling resistance, the spalling area of which after 200 cycles accounted for only 1% of its total area, while it was about 34% for APS TBCs. The resulting failure mode, i.e., in particular, a mixed delamination crack path, was shown and discussed. The irradiated effects including compact remelted surface, abundant nanoparticles, refined columnar grains, Y-rich alumina bubbles, and deformation structures contributed to the formation of a stable, continuous, slow-growing, and uniform thermally grown oxide with strong adherent ability. It appeared to be responsible for releasing stress and changing the cracking paths, and ultimately greatly improving the thermal cycling behavior of HCPEB-TBCs. PMID- 27933855 TI - Mesoporous Silica Nanoparticles with Large Pores for the Encapsulation and Release of Proteins. AB - Mesoporous silica nanoparticles (MSNs) have been explored extensively as solid supports for proteins in biological and medical applications. Small (<200 nm) MSNs with ordered large pores (>5 nm), capable of encapsulating therapeutic small molecules suitable for delivery applications in vivo, are rare however. Here we present small, elongated, cuboidal, MSNs with average dimensions of 90 * 43 nm that possess disk-shaped cavities, stacked on top of each other, which run parallel to the short axis of the particle. Amine functionalization was achieved by modifying the MSN surface with 3-aminopropyltriethoxysilane or 3-[2-(2 aminoethylamino)ethylamino]propyltrimethoxysilane (AP-MSNs and AEP-MSNs) and were shown to have similar dimensions to the nonfunctionalized MSNs. The dimensions of these particles, and their large surface areas as measured by nitrogen adsorption desorption isotherms, make them ideal scaffolds for protein encapsulation and delivery. We therefore investigated the encapsulation and release behavior for seven model proteins (alpha-lactalbumin, ovalbumin, bovine serum albumin, catalase, hemoglobin, lysozyme, and cytochrome c). It was discovered that all types of MSNs used in this study allow rapid encapsulation, with a high loading capacity, for all proteins studied. Furthermore, the release profiles of the proteins were tunable. The variation in both rate and amount of protein uptake and release was found to be determined by the surface chemistry of the MSNs, together with the isoelectric point (pI), and molecular weight of the proteins, as well as by the ionic strength of the buffer. These MSNs with their large surface area and optimal dimensions provide a scaffold with a high encapsulation efficiency and controllable release profiles for a variety of proteins, enabling potential applications in fields such as drug delivery and protein therapy. PMID- 27933856 TI - Enabling Design of Advanced Elastomer with Bioinspired Metal-Oxygen Coordination. AB - It poses a huge challenge to expand the application gallery of rubbers into advanced smart materials and achieve the reinforcement simultaneously. In the present work, inspired by the metal-ligand complexations of mussel byssus, ferric ion was introduced into an oxygen-abundant rubber network to create additional metal-oxygen coordination cross-links. Such complexation has been revealed to be highly efficient in enhancing the strength and toughness of the rubbers. Significantly, such complexation also enables the functionalization of the rubber into highly damping or excellent multishape memory materials. We envision that the present work offers an efficient yet facile way of creating advanced elastomers based on industrially available diene-based rubber. PMID- 27933857 TI - Chloride Transport through Supramolecular Barrel-Rosette Ion Channels: Lipophilic Control and Apoptosis-Inducing Activity. AB - Despite the great interest in artificial ion channel design, only a small number of channel-forming molecules are currently available for addressing challenging problems, particularly in the biological systems. Recent advances in chloride mediated cell death, aided by synthetic ion carriers, encouraged us to develop chloride selective supramolecular ion channels. The present work describes vicinal diols, tethered to a rigid 1,3-diethynylbenzene core, as pivotal moieties for the barrel-rosette ion channel formation, and the activity of such channels was tuned by controlling the lipophilicity of designed monomers. Selective transport of chloride ions via an antiport mechanism and channel formation in the lipid bilayer membranes were confirmed for the most active molecule. A theoretical model of the supramolecular barrel-rosette, favored by a network of intermolecular hydrogen bonding, has been proposed. The artificial ion-channel mediated transport of chloride into cells and subsequent disruption of cellular ionic homeostasis were evident. Perturbation of chloride homeostasis in cells instigates cell death by inducing the caspase-mediated intrinsic pathway of apoptosis. PMID- 27933860 TI - Pathway-Based Approaches for Environmental Monitoring and Risk Assessment. PMID- 27933858 TI - Stereocontrolled Formation of a [4.4]Heterospiro Ring System with Unexpected Inversion of Configuration at the Spirocenter. AB - Stereoselective construction of the 1,3-diazaspiro[4.4]nonane core skeleton of massadine and related dimeric pyrrole-imidazole alkaloids is a synthetic challenge. We describe herein the synthesis of all C13/14 diastereomers of this spiro molecule through controlled oxidation and epimerization of the C13 spirocenter under mild acidic conditions. PMID- 27933861 TI - Detection of Drug-Responsive T-Lymphocytes in a Case of Fatal Antituberculosis Drug-Related Liver Injury. AB - Antituberculosis (TB) drug exposure is associated with a mild elevation of liver enzymes that occasionally develops into severe liver injury. Herein, we identify ethambutol- and rifampicin-specific CD4+ and CD8+ T-cell clones in a patient with fatal anti TB-related liver injury. The clones were activated to proliferate and secrete IFN-gamma, Il-13, and granzyme B following drug treatment. Drug responsive T-cells may contribute to the pathogenesis of antituberculosis-related liver failure. PMID- 27933862 TI - Copper(0)/Selectfluor System-Promoted Oxidative Carbon-Carbon Bond Cleavage/Annulation of o-Aryl Chalcones: An Unexpected Synthesis of 9,10 Phenanthraquinone Derivatives. AB - A general and efficient protocol for the synthesis of 9,10-phenanthraquinone derivatives has been successfully developed involving a copper(0)/Selectfluor system-promoted oxidative carbon-carbon bond cleavage/annulation of o-aryl chalcones. A variety of substituted 9,10-phenanthraquinones were synthesized in moderate to good yields under mild reaction conditions. PMID- 27933863 TI - Electrochemistry at the Nanoscale: Tackling Old Questions, Posing New Ones. PMID- 27933864 TI - Sequential Vapor Infiltration Treatment Enhances the Ionic Current Rectification Performance of Composite Membranes Based on Mesoporous Silica Confined in Anodic Alumina. AB - Ionic current rectification of nanofluidic diode membranes has been studied widely in recent years because it is analogous to the functionality of biological ion channels in principle. We report a new method to fabricate ionic current rectification membranes based on mesoporous silica confined in anodic aluminum oxide (AAO) membranes. Two types of mesostructured silica nanocomposites, hexagonal structure and nanoparticle stacked structure, were used to asymmetrically fill nanochannels of AAO membranes by a vapor-phase synthesis (VPS) method with aspiration approach and were further modified via sequence vapor infiltration (SVI) treatment. The ionic current measurements indicated that SVI treatment can modulate the asymmetric ionic transport in prepared membranes, which exhibited clear ionic current rectification phenomenon under optimal conditions. The ionic current rectifying behavior is derived from the asymmetry of surface conformations, silica species components, and hydrophobic wettability, which are created by the asymmetrical filling type, silica depositions on the heterogeneous membranes, and the condensation of silanol groups. This article provides a considerable strategy to fabricate composite membranes with obvious ionic current rectification performance via the cooperation of the VPS method and SVI treatment and opens up the potential of mesoporous silica confined in AAO membranes to mimic fluid transport in biological processes. PMID- 27933865 TI - Dimericbiscognienyne A: A Meroterpenoid Dimer from Biscogniauxia sp. with New Skeleton and Its Activity. AB - Dimericbiscognienyne A (1), an unusual diisoprenyl-cyclohexene-type meroterpenoid dimer, was isolated from Biscogniauxia sp. together with three new monomeric diisoprenyl-cyclohexene-type meroterpenoids (2-4) and one new isoprenyl-benzoic acid-type meroterpenoid (5). All structures were determined by extensive NMR spectroscopic methods, quantum chemical calculations, chemical derivatization, and X-ray crystallography. The formation of 1 is related to a unique intermolecular redox coupling Diels-Alder adduct reaction. Their cytotoxicities and short-term memory enhancement activities against Alzheimer's disease were assessed. PMID- 27933866 TI - Identification of Hydrogen Disulfanes and Hydrogen Trisulfanes in H2S Bottle, in Flint, and in Dry Mineral White Wine. AB - Through the accidental contamination of a gas cylinder of H2S, the importance of polysulfanes for flint, gun powder, and match odors was discovered. The hydrogen disulfane was prepared from disulfanediylbis[methyl(diphenyl)silane], and its odor descriptor was evaluated in the gas phase from a gas chromatograph coupled to an olfaction port. The occurrence of this compound in flint and pebbles was confirmed by analyses after derivatization with pentafluorobromobenzene. The occurrence of this sulfane was also confirmed in two dry white Swiss Chasselas wines, sorted by a large-scale sensory analysis from 80 bottles and evaluated by 62 wine professionals. The occurrence of disulfane was confirmed for the two wines described as the most mineral. Polysulfane comprises a class of compounds contributing to the flint odor and that may contribute to the wine mineral odor descriptor. Due to the high volatility and instability pure HSSH was not isolated but kept in solution and its odor profile was described by gas chromatography coupled to an olfaction port as flint, matches, and fireworks with a higher odor intensity compared to H2S. PMID- 27933867 TI - Peptidomic Approach to Developing ELISAs for the Determination of Bovine and Porcine Processed Animal Proteins in Feed for Farmed Animals. AB - The European Commission (EC) wants to reintroduce nonruminant processed animal proteins (PAPs) safely into the feed chain. This would involve replacing the current ban in feed with a species-to-species ban which, in the case of nonruminants, would only prohibit feeding them with proteins from the same species. To enforce such a provision, there is an urgent need for species specific methods for detecting PAPs from several species in animal feed and in PAPs from other species. Currently, optical microscopy and the polymerase chain reaction are the officially accepted methods, but they have limitations, and alternative methods are needed. We have developed immunoassays using antibodies raised against targets which are not influenced by high temperature and pressure. These targets were identified in a previous study based on an experimental approach. One optimized competitive ELISA detects bovine PAPs at 2% in plant derived feed. The detection capability demonstrated on blind samples shows a good correlation with mass spectrometry results. PMID- 27933869 TI - Changes in trans-S-1-Propenyl-l-cysteine Sulfoxide and Related Sulfur-Containing Amino Acids during Onion Storage. AB - trans-S-1-Propenyl-l-cysteine sulfoxide (PRENCSO) is the most abundant flavor precursor in onions. The changes in PRENCSO, its biosynthetic precursors, and cycloalliin contents in bulbs stored at 0 degrees C [i.e., recommended by the Food and Agriculture Organization of the United Nations (FAO)] are investigated. Ion-exchange high-performance liquid chromatography analysis revealed larger amounts of PRENCSO and cycloalliin, which were stoichiometrically balanced by the decrease in the combined amounts of the three biosynthetic precursors. The molar balance of the PRENCSO biosynthesis process during onion storage was explained well by the changes of these five compounds. High-throughput integrated liquid chromatography-tandem mass spectrometry analysis was employed to analyze multiple samples at 5 and 20 degrees C. The molar concentration data, converted using linear regression equations, showed a similar molar balance for the PRENCSO biosynthesis process comprising these five compounds during storage at all temperatures tested. Furthermore, the content of cycloalliin significantly increased at the expense of that of PRENCSO during storage at 20 degrees C. PMID- 27933868 TI - Residual Behaviors of Six Pesticides in Shiitake from Cultivation to Postharvest Drying Process and Risk Assessment. AB - The dissipation of six pesticides (carbendazim, thiabendazole, procymidone, bifenthrin, lambda-cyhalothrin, and beta-cyfluthrin) in shiitakes from cultivation to postharvest drying process was investigated, and the dietary exposure risk was estimated thereafter. The field trial study indicates that the half-lives of carbendazim, thiabendazole, and procymidone were much shorter than those of bifenthrin, lambda-cyhalothrin, and beta-cyfluthrin. Furthermore, the effects of two drying processes on the residues and processing factors (PFs) were investigated. The results showed that hot-air drying resulted in higher residues than sunlight exposure drying. Both drying processes led to pesticide residue concentration (with PF > 1), except for thiabendazole upon sunlight exposure treatment. The estimated daily intakes (EDIs) ranged from 0.06% of the acceptable daily intake (ADI) for thiabendazole to 42.43% of the ADI for procymidone. The results show that the six pesticide residues in dried shiitakes are still within acceptable levels for human consumption on the basis of a dietary risk assessment. PMID- 27933870 TI - Tools for Defusing a Major Global Food and Feed Safety Risk: Nonbiological Postharvest Procedures To Decontaminate Mycotoxins in Foods and Feeds. AB - Mycotoxin contamination of foods and animal feeds is a worldwide problem for human and animal health. Controlling mycotoxin contamination has drawn the attention of scientists and other food and feed stakeholders all over the world. Despite best efforts targeting field and storage preventive measures, environmental conditions can still lead to mycotoxin contamination. This raises a need for developing decontamination methods to inactivate or remove the toxins from contaminated products. At present, decontamination methods applied include an array of both biological and nonbiological methods. The targeted use of nonbiological methods spans from the latter half of last century, when ammoniation and ozonation were first used to inactivate mycotoxins in animal feeds, to the novel techniques being developed today such as photosensitization. Effectiveness and drawbacks of different nonbiological methods have been reported in the literature, and this review examines the utility of these methods in addressing food safety. Particular consideration is given to the application of such methods in the developing world, where mycotoxin contamination is a serious food safety issue in staple crops such as maize and rice. PMID- 27933871 TI - Food Polyphenol Apigenin Inhibits the Cytochrome P450 Monoxygenase Branch of the Arachidonic Acid Cascade. AB - The product of cytochrome P450 monooxygenase (P450) omega-hydroxylation of arachidonic acid (AA), 20- hydroxyeicosatetraenoic acid (HETE), is a potent vasoconstrictor. Utilizing microsomes as well as individual CYP4 isoforms we demonstrate here that flavonoids can block 20-HETE formation. Apigenin inhibits CYP4F2 with an IC50 value of 4.6 MUM and 20-HETE formation in human liver and kidney microsomes at 2.4-9.8 MUM. Interestingly, the structurally similar naringenin shows no relevant effect on the formation of 20-HETE. Based on these in vitro data, it is impossible to evaluate if a relevant blockade of 20-HETE formation can result in humans from intake of polyphenols with the diet. However, the potency of apigenin is comparable to those of P450 inhibitors such as ketoconazole. Moreover, an IC50 value in the micromolar range is also described for the inhibition of CYP-mediated drug metabolism leading to food-drug interactions. The modulation of the arachidonic acid cascade by food polyphenols therefore warrants further investigation. PMID- 27933872 TI - An Efficient One-Pot Synthesis of 2-(Aryloxyacetyl)cyclohexane-1,3-diones as Herbicidal 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors. AB - 4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is an important target for new bleaching herbicides discovery. As a continuous work to discover novel crop selective HPPD inhibitor, a series of 2-(aryloxyacetyl)cyclohexane-1,3 diones were rationally designed and synthesized by an efficient one-pot procedure using N,N'-carbonyldiimidazole (CDI), triethylamine, and acetone cyanohydrin in CH2Cl2. A total of 58 triketone compounds were synthesized in good to excellent yields. Some of the triketones displayed potent in vitro Arabidopsis thaliana HPPD (AtHPPD) inhibitory activity. 2-(2-((1-Bromonaphthalen-2-yl)oxy)acetyl)-3 hydroxycyclohex-2-en-1-one, II-13, displayed high, broad-spectrum, and postemergent herbicidal activity at the dosage of 37.5-150 g ai/ha, nearly as potent as mesotrione against some weeds. Furthermore, II-13 showed good crop safety against maize and canola at the rate of 150 g ai/ha, indicating that II-13 might have potential as a herbicide for weed control in maize and canola fields. II-13 is the first HPPD inhibitor showing good crop safety toward canola. PMID- 27933874 TI - Detection of Maillard Reaction Product [5-(5,6-Dihydro-4H-pyridin-3 ylidenemethyl)furan-2-yl]methanol (F3-A) in Breads and Demonstration of Bioavailability in Caco-2 Intestinal Cells. AB - [5-(5,6-Dihydro-4H-pyridin-3-ylidenemethyl)furan-2-yl]methanol, also called F3-A, has been isolated from hexose-lysine Maillard reaction (MR) models. Here we report on optimized conditions for the recovery of F3-A and concentrations found in bread. Recovery of F3-A was best achieved when samples were extracted with dichloromethane (DCM) at a solvent to sample ratio of 2:1 (v/v) after adjustment of the pH to 12. The amount of F3-A in whole wheat bread was significantly (P < 0.05) higher than that in white bread; bread crust contained a significantly (P < 0.05) higher amount of F3-A (0.9-7.8 MUg/100 g) than the bread crumb (not detectable-3.5 MUg/100 g); and toasting increased F3-A concentration with a range of not detectable to 6.0 MUg/100 g in the control bread and 4.0 and 17.7 MUg/100 g in the dark-toasted white sandwich bread and 100% whole wheat sandwich bread, respectively. The in vitro permeability of F3-A was measured using Caco-2 cell monolayer. The apparent permeability coefficient (Papp) of F3-A is (6.01 +/- 0.35) * 10-5 cm/s, which is similar to that of propranolol, a highly passive transcellular absorbed drug. In conclusion, the concentration of F3-A recovered in bread varies with the type of bread and degree of toasting, and F3-A is bioavailable. PMID- 27933873 TI - Amelioration of Experimental Autoimmune Encephalomyelitis by Isogarcinol Extracted from Garcinia mangostana L. Mangosteen. AB - Isogarcinol is a new natural immunosuppressant that was extracted from Garcinia mangostana L. in our laboratory. Knowledge of its effects on treatable diseases and its mechanism of action is still very limited. In this study, we explored the therapeutic effect of isogarcinol in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). Treatment with oral 100 mg/kg isogarcinol markedly ameliorated clinical scores, alleviated inflammation and demyelination of the spinal cord, and reduced intracranial lesions in EAE mice. The percentages of Th cells and macrophages were also strongly reduced. Isogarcinol appeared to act by inhibiting T helper (Th) 1 and Th17 cell differentiation via the janus kinase/signal transducers and activators of transcription pathway and by impairing macrophage function. Our data suggest that isogarcinol has the potential to be an effective therapeutic agent of low toxicity for treating MS and other autoimmune diseases. PMID- 27933875 TI - Protein Selectivity Controlled by Polymer Charge Density and Protein Yield: Carboxylated Polysaccharides versus Sulfated Polysaccharides. AB - The effect of polymer charge density on protein selectivity in the presence of carboxylated polysaccharides (CPS) and sulfated polysaccharides (SPS) was investigated for Kunitz trypsin inhibitor/Bowman-Birk protease inhibitor (KTI/BBI, KBM). To determine the conditions for coacervation or precipitation as a function of polymer charge densities, turbidimetric titrations and Tricine-SDS PAGE were used. Polymer charge density as well as chain flexibility greatly influenced the strength of interactions and protein recovery. Although charge compensation must occur for CPS-KBM complexes, SPS-KBM systems did not require conservation of charge neutrality. Despite their similar isoelectric points, KTI bound preferentially to CPS and SPS due to its higher affinity compared to BBI. Complexation of KBM with the polysaccharide with the lowest charge density, arabic gum, expectedly cannot realize the purification of BBI under conditions where binding to more highly charged polysaccharides occurs. This work will be beneficial to selective purification of target proteins through control of protein-polysaccharide complexation. PMID- 27933876 TI - Inhibition of Human Monoamine Oxidase: Biological and Molecular Modeling Studies on Selected Natural Flavonoids. AB - Naturally occurring flavonoids display a plethora of different biological activities, but emerging evidence suggests that this class of compounds may also act as antidepressant agents endowed with multiple mechanisms of action in the central nervous system, increasing central neurotransmission, limiting the reabsorption of bioamines by synaptosomes, and modulating the neuroendocrine and GABAA systems. Due to their presence in foods, food-derived products, and nutraceuticals, we established their role and structure-activity relationships as reversible and competitive human monoamine oxidase (MAO) inhibitors. In addition, molecular modeling studies, which evaluated their modes of MAO inhibition, are presented. These findings could provide pivotal implications in the quest of novel drug-like compounds and for the establishment of harmful drug-dietary supplement interactions commonly reported in the therapy with antidepressant agents. PMID- 27933877 TI - Nanoscale Polydopamine (PDA) Meets pi-pi Interactions: An Interface-Directed Coassembly Approach for Mesoporous Nanoparticles. AB - Well known for the adhesive property, mussel-inspired polydopamine (PDA) has been shown to enhance performance in a wide range of adsorption-based applications. However, imparting porous nanostructures to PDA materials for enhanced loading capacities has not been demonstrated even when surfactants were present in the synthesis. Herein, we report on the preparation of mesoporous PDA particles (MPDA) based on the assembly of primary PDA particles and Pluronic F127 stabilized emulsion droplets on water/1,3,5-trimethylbenzene (TMB) interfaces. The key to the formation of this new type of the MPDA structure is the full utilization of the pi-pi stacking interactions between PDA structures and the pi electron-rich TMB molecules. Remarkably, this method presents a facile approach for MPDA particles with an average diameter of ~90 nm, slit-like pores with a peak size of ~5.0 nm as well as hollow cavities. When used as the adsorbent for a model dye RhB, the MPDA particles achieved an ultrahigh RhB adsorption capacity of 1100 MUg mg-1, which is significantly higher than that for the PDA-reactive dyes with Eschenmoser structure. Moreover, it was demonstrated that the cavity space in MPDA can facilitate high volumetric uptake in a capillary filling/stacking manner via the pi-pi interactions. These developments pave a new avenue on the mechanism and the designed synthesis of functional PDA materials by organic-organic composite assembly for advanced adsorption applications. PMID- 27933878 TI - Atomic Layer Deposition of Ultrathin Nickel Sulfide Films and Preliminary Assessment of Their Performance as Hydrogen Evolution Catalysts. AB - Transition metal sulfides show great promise for applications ranging from catalysis to electrocatalysis to photovoltaics due to their high stability and conductivity. Nickel sulfide, particularly known for its ability to electrochemically reduce protons to hydrogen gas nearly as efficiently as expensive noble metals, can be challenging to produce with certain surface site compositions or morphologies, e.g., conformal thin films. To this end, we employed atomic layer deposition (ALD), a preeminent method to fabricate uniform and conformal films, to construct thin films of nickel sulfide (NiSx) using bis(N,N'-di-tert-butylacetamidinato)nickel(II) (Ni(amd)2) vapor and hydrogen sulfide gas. Effects of experimental conditions such as pulse and purge times and temperature on the growth of NiSx were investigated. These revealed a wide temperature range, 125-225 degrees C, over which self-limiting NiSx growth can be observed. In situ quartz crystal microbalance (QCM) studies revealed conventional linear growth behavior for NiSx films, with a growth rate of 9.3 ng/cm2 per cycle being obtained. The ALD-synthesized films were characterized using X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD) methods. To assess the electrocatalyitic activity of NiSx for evolution of molecular hydrogen, films were grown on conductive-glass supports. Overpotentials at a current density of 10 mA/cm2 were recorded in both acidic and pH 7 phosphate buffer aqueous reaction media and found to be 440 and 576 mV, respectively, with very low NiSx loading. These results hint at the promise of ALD-grown NiSx materials as water-compatible electrocatalysts. PMID- 27933879 TI - Short- and Long-Range Attractive Forces That Influence the Structure of Montmorillonite Osmotic Hydrates. AB - Clay swelling is a colloidal phenomenon that has a large influence on flow and solute migration in soils and sediments. While models for clay swelling have been proposed over many years, debate remains as to the interaction forces that combine to produce the observed swelling behavior. Using cryogenic transmission electron microscopy (cryo-TEM) and small-angle X-ray scattering, we study the influence of salinity, in combination with layer charge, interlayer cation, and particle size, on montmorillonite swelling. We observe a decrease in swelling with increased layer charge, increased cation charge, and decreased cation hydration, each indicative of the critical influence of Coulombic attraction between the negatively charged layers and interlayer cations. Cryo-TEM images of individual montmorillonite particles also reveal that swelling is dependent upon the number of layers in a particle. Calculations of the van der Waals (vdW) interaction based on new measurements of Hamaker coefficients confirm that long range vdW interactions extend beyond near-neighbor layer interactions and result in a decrease in layer spacing with a larger number of layers. This work clarifies the short- and long-range attractive interactions that govern clay structure and ultimately the stability and permeability of hydrated clays in the environment. PMID- 27933880 TI - Paired Electrolysis in the Simultaneous Production of Synthetic Intermediates and Substrates. AB - In electrochemical processes, an oxidation half-reaction is always paired with a reduction half-reaction. Although systems for reactions such as the reduction of CO2 can be coupled to water oxidation to produce O2 at the anode, large-scale O2 production is of limited value. One may replace a low-value half-reaction with a compatible half-reaction that can produce a valuable chemical compound and operate at a lower potential. In doing so, both the anodic and cathodic half reactions yield desirable products with a decreased energy demand. Here we demonstrate a paired electrolysis in the case of the oxidative condensation of syringaldehyde and o-phenylenediamine to give 2-(3,5-dimethoxy-4 hydroxyphenyl)benzimidazole coupled with the reduction of CO2 to CO mediated by molecular electrocatalysts. We also present general principles for evaluating current-voltage characteristics and power demands in paired electrolyzers. PMID- 27933881 TI - Neutral Aminyl Radicals Derived from Azoimidazolium Dyes. AB - The synthesis and characterization of a new class of neutral aminyl radicals is reported. Monoradicals were obtained by reduction of azoimidazolium dyes with potassium. Structural, spectroscopic, and computational data suggest that the spin density is centered on one of the nitrogen atoms of the former azo group. The reduction of a dimeric dye with an octamethylbiphenylene bridge between the azo groups resulted in the formation of a biradical with largely independent unpaired electrons. Both the monoradicals and the biradical were found to display high stability in solution as well as in the solid state. PMID- 27933882 TI - Alleviating Luminescence Concentration Quenching in Upconversion Nanoparticles through Organic Dye Sensitization. AB - The phenomenon of luminescence concentration quenching exists widely in lanthanide-based luminescent materials, setting a limit on the content of lanthanide emitter that can be used to hold the brightness. Here, we introduce a concept involving energy harvesting by a strong absorber and subsequent energy transfer to a lanthanide that largely alleviates concentration quenching. We apply this concept to Nd3+ emitters, and we show both experimentally and theoretically that the optimal doping concentration of Nd3+ in colloidal NaYF4:Nd upconverting nanoparticles is increased from 2 to 20 mol% when an energy harvestor organic dye (indocyanine green, ICG) is anchored onto the nanoparticle surface, resulting in ~10 times upconversion brightness. Theoretical analysis indicated that a combination of efficient photon harvesting due to the large absorption cross section of ICG (~30 000 times higher than that of Nd3+), non radiative energy transfer (efficiency ~57%) from ICG to the surface bound Nd3+ ions, and energy migration among the Nd3+ ions was able to activate Nd3+ ions inside the nanoparticle at a rate comparable with that of the pronounced short range quenching interaction at elevated Nd3+ concentrations. This resulted in the optimal concentration increase to produce significantly enhanced brightness. Theoretical modeling shows a good agreement with the experimental observation. This strategy can be utilized for a wide range of other lanthanide-doped nanomaterials being utilized for bioimaging and solar cell applications. PMID- 27933883 TI - Multivariable Modular Design of Pore Space Partition. AB - Pore space partition, especially the one using C3-symmetric 2,4,6-tri(4-pyridyl) 1,3,5-triazine as pore-partition agent in MIL-88 type (the acs net), has been shown to dramatically enhance CO2 uptake to near-record values. The continued advance in property engineering via pore space partition would depend on intelligent design of both framework components and pore-partition agent. Here, we report a new advance in the design of pore-partition agent by demonstrating a symmetry-guided pathway to develop a large variety of di- and trinuclear 1,2,4 triazolate-based clusters for use as pore-partition agent. The use of metal organic clusters (instead of organic ligands) as pore-partition agent gives rise to many new pore-partitioned materials with huge compositional variety. The full assembly involves the simultaneous formation of two separate coordination architectures (i.e., the 3-D acs framework and 0-D triazolate clusters) and the eventual welding between the acs framework and triazolate clusters. The wide range of new compositions and structures provides a high degree of tunability in gas sorption properties. PMID- 27933884 TI - Facile Surface Modification of Hydroxylated Silicon Nanostructures Using Heterocyclic Silanes. AB - Heterocyclic silanes containing Si-N or Si-S bonds in the ring undergo a ring opening reaction with -OH groups at the surface of porous Si nanostructures to generate -SH or -NH functional surfaces, grafted via O-Si bonds. The reaction is substantially faster (0.5-2 h at 25 degrees C) and more efficient than hydrolytic condensation of trialkoxysilanes on similar hydroxy-terminated surfaces, and the reaction retains the open pore structure and photoluminescence of the quantum-confined silicon nanostructures. The chemistry is sufficiently mild to allow trapping of the test protein lysozyme, which retains its enzymatic activity upon release from the modified porous nanostructure. PMID- 27933885 TI - The Limit of Intramolecular H-Bonding. AB - Hydrogen bonds are ubiquitous interactions in molecular recognition. The energetics of such processes are governed by the competing influences of pre organization and flexibility that are often hard to predict. Here we have measured the strength of intramolecular interactions between H-bond donor and acceptor sites separated by a variable linker. A striking distance-dependent threshold was observed in the intramolecular interaction energies. H-bonds were worth less than -1 kJ mol-1 when the interacting groups were separated by >=6 rotating bonds, but ranged between -5 and -9 kJ mol-1 for <=5 rotors. Thus, only very strong external H-bond acceptors were able to compete with the stronger internal H-bonds. In addition, a constant energetic penalty per rotor of ~5-6 kJ mol-1 was observed in less strained situations where the molecule contained >=4 rotatable bonds. PMID- 27933886 TI - Chemoenzymatic Labeling of Proteins for Imaging in Bacterial Cells. AB - Reliable methods to determine the subcellular localization of bacterial proteins are needed for the study of prokaryotic cell biology. We describe here a simple and general technique for imaging of bacterial proteins in situ by fluorescence microscopy. The method uses the eukaryotic enzyme N-myristoyltransferase to modify the N-terminus of the protein of interest with an azido fatty acid. Subsequent strain-promoted azide-alkyne cycloaddition allows conjugation of dyes and imaging of tagged proteins by confocal fluorescence microscopy. We demonstrate the method by labeling the chemotaxis proteins Tar and CheA and the cell division proteins FtsZ and FtsA in Escherichia coli. We observe distinct spatial patterns for each of these proteins in both fixed and live cells. The method should prove broadly useful for protein imaging in bacteria. PMID- 27933887 TI - Hydrazone Switch-Based Negative Feedback Loop. AB - A negative feedback loop that relies on the coordination-coupled deprotonation (CCD) of a hydrazone switch has been developed. Above a particular threshold of zinc(II), CCD releases enough protons to the environment to trigger a cascade of reactions that yield an imine. This imine sequesters the excess of zinc(II) from the hydrazone switch, hence lowering the effective amount of protons, and switching the cascade reactions "OFF", thus establishing the negative feedback loop. PMID- 27933889 TI - Next-Generation Reduction Sensitive Lipid Conjugates of Tenofovir: Antiviral Activity and Mechanism of Release. AB - The pharmacokinetic properties of tenofovir (TFV) and other charged nucleoside analogues are dramatically improved upon conjugation to a lipid prodrug. We previously prepared reduction-sensitive lipid conjugates of TFV that demonstrate superior antiviral activity compared to other lipid conjugates including the clinically approved formulation, tenofovir disoproxil fumarate (TDF). In continuation of that work, we have synthesized next-generation conjugates with reduced cytotoxicity that retain potent antiviral activity against HIV-1 and HBV with a therapeutic index >100000 for our most potent conjugate. We also show that disulfide reduction is not responsible for prodrug cleavage unless 3-exo-tet intramolecular cyclization can occur, suggesting that enzymatic hydrolysis is predominantly responsible for activity of our prodrugs in vitro. PMID- 27933890 TI - Discovery of Leucyladenylate Sulfamates as Novel Leucyl-tRNA Synthetase (LRS) Targeted Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitors. AB - Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. In this study, we developed leucyladenylate sulfamate derivatives as LRS-targeted mTORC1 inhibitors. Compound 18 selectively inhibited LRS-mediated mTORC1 activation and exerted specific cytotoxicity against colon cancer cells with a hyperactive mTORC1, suggesting that 18 may offer a novel treatment option for human colorectal cancer. PMID- 27933891 TI - An N,N-Bis(benzimidazolylpicolinoyl)piperazine (BT-11): A Novel Lanthionine Synthetase C-Like 2-Based Therapeutic for Inflammatory Bowel Disease. AB - Lanthionine synthetase C-like 2 (LANCL2), a novel therapeutic target for inflammatory and autoimmune diseases and diabetes, exerts anti-inflammatory and insulin-sensitizing effects. This study reports the first LANCL2-based therapeutics for inflammatory bowel disease (IBD). Analogues of 1 (ABA) and 2 (NSC61610) were screened by molecular docking, then synthesized and analyzed for binding to LANCL2 by surface plasmon resonance. Piperazine-1,4-diylbis(6 benzo[d]imidazole-2-yl)pyridine-2-yl)methanone, 7, was identified as the lead LANCL2-binding compound for treating IBD. The oral treatment with 7 (8 mg/kg/d) in a mouse model of IBD resulted in lowering the disease activity index, decreasing colonic inflammatory lesions by 4-fold, and suppressing inflammatory markers (e.g., TNF-alpha, and interferon-gamma) in the gut. Furthermore, studies in LANCL2-/- mice demonstrated that loss of LANCL2 abrogated beneficial actions of 7, suggesting high selectivity for the target. In conclusion, 7 merits continued development as a LANCL2-based, first-in-class orally active therapeutic for IBD. PMID- 27933892 TI - alpha-Glucosidase Inhibitors from the Marine-Derived Fungus Aspergillus flavipes HN4-13. AB - Three new butenolide derivatives, flavipesolides A-C (1-3), along with 13 known compounds (4-13, aspulvinone Q, monochlorosulochrin, and dihydrogeodin), were isolated from the marine-derived Aspergillus flavipes HN4-13 from a Lianyungang coastal sediment sample. The structures were elucidated by spectroscopic evidence. Compounds 4-6 and 9 were noncompetitive alpha-glucosidase inhibitors with Ki/IC50 values of 0.43/34, 2.1/37, 0.79/19, and 2.8/90 MUM, respectively. Compounds 1-3, 8, 10, and 13 are mixed alpha-glucosidase inhibitors with Ki/IC50 values of (2.5, 19)/44, (3.4, 14)/57, (9.2, 4.7)/95, (6.3, 5.5)/55, (1.4, 0.60)/9.9, and (2.5, 7.2)/33 MUM, respectively (IC50 101 MUM for acarbose and 79 MUM for 1-deoxynojirimycin). PMID- 27933893 TI - Isolation and Structure Elucidation by LC-DAD-MS and LC-DAD-SPE-NMR of Cyclopeptide Alkaloids from the Roots of Ziziphus oxyphylla and Evaluation of Their Antiplasmodial Activity. AB - Nine cyclopeptide alkaloids (1-9), of which five (compounds 2, 3, 5, 8, and 9) are described herein for the first time, were isolated from roots of Ziziphus oxyphylla by means of conventional separation methods as well as semipreparative HPLC with DAD and ESIMS detection and LC-DAD-SPE-NMR. Structure elucidation was done by spectroscopic means. Nummularine-R (1), a previously known constituent from this species, was isolated along with its new derivatives O desmethylnummularine-R (2) and O-desmethylnummularine-R N-oxide (3). In addition, the known compounds hemsine-A (4) and ramosine-A (6), as well as hemsine-A N oxide (5), were isolated. Moreover, oxyphylline-C (7), a known constituent of Z. oxyphylla stems, was obtained, and two new compounds were identified, oxyphyllines-E (8) and -F (9). Just like oxyphylline-C, oxyphyllines-E and -F belong to the relatively rare class of neutral cyclopeptide alkaloids. The antiplasmodial activity and cytotoxicity of compounds 1, 2, 4, 6, and 9 were evaluated, and the most promising activity was found for O-desmethylnummularine-R (2), which exhibited an IC50 value of 3.2 +/- 2.6 MUM against Plasmodium falciparum K1, whereas an IC50 value of >64.0 MUM was evident for its cytotoxicity against MRC-5 cells. PMID- 27933894 TI - Chloromethylhalicyclamine B, a Marine-Derived Protein Kinase CK1delta/epsilon Inhibitor. AB - The halogenated alkaloid chloromethylhalicyclamine B (1), together with the known natural compound halicyclamine B (2), was isolated from the extract of the sponge Acanthostrongylophora ingens. The structure of compound 1 was determined by spectroscopic means, and it was shown that 1 is produced by reaction of 2 with CH2Cl2 used for extraction. Compound 1 was a selective CK1delta/epsilon inhibitor with an IC50 of 6 MUM, while the natural compound 2 was inactive. The absolute configuration of 1 was determined by quantum mechanical calculation of its ECD spectrum, and this also determined the previously unknown absolute configuration of the parent halicyclamine B (2). Computational studies, validated by NOESY data, showed that compound 1 can efficiently interact with the ATP-binding site of CK1delta in spite of its globular structure, very different from the planar structure of known inhibitors of CK1delta. This opens the way to the design of a new structural type of CK1delta/epsilon inhibitors. PMID- 27933895 TI - Total Synthesis of Tetraketide and Cryptorigidifoliol I via a Sequential Allylation Strategy. AB - A unified and efficient synthetic route for both tetraketide (1) and cryptorigidifoliol I (2) has been devised successfully from commercially available starting materials in 11 and 17 steps, with 16% and 11% overall yields, respectively. Highlights of the syntheses involved sequential Lewis acid catalyzed highly regio- and diastereoselective allylations and intramolecular Mitsunobu lactonization. PMID- 27933896 TI - Total Synthesis and in Vitro Anti-Tumor-Promoting Activities of Racemic Acetophenone Monomers from Acronychia trifoliolata. AB - Six acetophenone derivatives, acronyculatins I (1), J (2), K (3), L (4), N (5), and O (6), were recently isolated from Acronychia trifoliolata, and the structure of the known acronyculatin B (7) was revised. Because of the limited quantities of isolated products as well as their structure similarity, racemic acronyculatins I-L, N, O, and B (1-7) were synthesized to confirm their structures and to obtain sufficient material for biological evaluation. Trihydroxyacetophenone was converted to the target compounds by various sequences of hydroxy group protection, allylation or prenylation, and epoxidation followed by cyclization. C-Prenylations were carried out by direct addition of a prenyl group or through 1,3- or 3,3-sigmatropic rearrangement. The synthesized racemic compounds were evaluated in an anti-tumor-promoting assay using the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13 acetate in Raji cells. All tested compounds significantly inhibited EBV-EA activation. Especially, racemic acronyculatin I (1) displayed the most potent inhibitory effects, with an IC50 value of 7.3 MUM. PMID- 27933897 TI - Tyrosyl-DNA Phosphodiesterase 1 Inhibitors: Usnic Acid Enamines Enhance the Cytotoxic Effect of Camptothecin. AB - Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a repair enzyme for stalled DNA topoisomerase 1 (Top1) cleavage complexes and other 3'-end DNA lesions. TDP1 is a perspective target for anticancer therapy based on Top1-poison-mediated DNA damage. Several novel usnic acid derivatives with an enamine moiety have been synthesized and tested as inhibitors of TDP1. The enamines of usnic acid showed IC50 values in the range of 0.16 to 2.0 MUM. These compounds revealed moderate cytotoxicity against human tumor MCF-7 cells. These new compounds enhanced the cytotoxicity of the established Top1 poison camptothecin by an order of magnitude. PMID- 27933898 TI - Versiquinazolines A-K, Fumiquinazoline-Type Alkaloids from the Gorgonian-Derived Fungus Aspergillus versicolor LZD-14-1. AB - Eleven fumiquinazoline-type alkaloids, namely, versiquinazolines A-K (1-11), along with cottoquinazolines B-D, were isolated from the gorgonian-derived fungus Aspergillus versicolor LZD-14-1. Their structures were determined by extensive analyses of the spectroscopic data (1D and 2D NMR, HRESIMS), in addition to the experimental and calculated ECD data and X-ray single-crystal diffraction analysis for the assignments of the absolute configurations. Versiquinazolines A, B, and F (1, 2, and 6), bearing a methanediamine or an aminomethanol unit and representing a unique subtype of fumiquinazolines, were found from nature for the first time. Possible biogenetic relationships of the versiquinazolines are postulated. In addition, the structures of cottoquinazolines B (12), D (13), and C (14) should be revised to the enantiomers. Compounds 1, 2, 7, and 11 exhibited inhibitory activities against thioredoxin reductase (IC50 values ranging from 12 to 20 MUM). PMID- 27933899 TI - Bioactive Terpenoids from Salvia plebeia: Structures, NO Inhibitory Activities, and Interactions with iNOS. AB - A phytochemical investigation to obtain new NO inhibitors resulted in the identification of six new (1-6) and four known (7-10) terpenoids from Salvia plebeia. Compounds 1 and 2 are new diterpenoids, 3-5 are new meroditerpenoids, 6 9 are sesquiterpenoids, and 10 is a known meroditerpenoid. The structures of these isolates were determined by routine NMR experiments and X-ray diffraction, as well as the electronic circular dichroism spectra. Compounds 1-4 are diterpenoids carrying an oxygen bridge, and 6 is a rare copane-type sesquiterpenoid with a bridged tricyclic framework. The isolates inhibited NO generation induced by lipopolysaccharide in BV-2 cells. The possible mechanism of NO inhibition of some bioactive compounds was also investigated using molecular docking, which revealed interactions of bioactive compounds with the iNOS protein. PMID- 27933900 TI - 13C NMR and LC-MS Profiling of Stilbenes from Elicited Grapevine Hairy Root Cultures. AB - Resveratrol and related oligostilbenes are defense molecules produced by grapevine in response to stresses including various elicitors or signal molecules. Together with their prominent role in planta, these compounds have been the center of much attention in recent decades due to their pharmacological properties. The cost-effective production of resveratrol derivatives such as viniferins or more structurally complex stilbene oligomers remains a challenging task. In this study, the chemical diversity of stilbenes produced by Vitis vinifera Pinot Noir hairy roots was investigated after elicitation for 4 days with a mixture of methyl jasmonate (100 MUM) and cyclodextrins (50 mM). Two crude extracts obtained from the culture medium and from the hairy roots were fractionated by centrifugal partition chromatography. The fractions were chemically investigated by two complementary identification approaches involving a 13C NMR-based dereplication method and liquid chromatography coupled to mass spectrometry (LC-MS). In total, groups of 21 and 18 molecules, including flavonoids and stilbenes, were detected in the culture medium and root extracts, respectively. These included resveratrol monomers, dimers, trimers, and a tetramer, thus highlighting the ability of elicited hairy root culture systems to synthesize a wide diversity of secondary metabolites of pharmaceutical significance. The main compounds were unambiguously identified as trans resveratrol, epsilon-viniferin, trans-piceatannol, pallidol, scirpusin A, eriodictyol, naringenin, vitisin B, and maackin. PMID- 27933902 TI - 3-Sulfanyl-4-methylpentan-1-ol in Dry-Hopped Beers: First Evidence of Glutathione S-Conjugates in Hop (Humulus lupulus L.). AB - Monovarietal dry-hopped beers were produced with the dual-purpose hop cultivars Amarillo, Hallertau Blanc, and Mosaic. The grapefruit-like 3-sulfanyl-4 methylpentan-1-ol was found in all three beers at concentrations much higher than expected on the basis of the free thiol content in hop. Even cysteinylated precursors proved unable to explain our results. As observed in wine, the occurrence of S-glutathione precursors was therefore suspected in hop. The analytical standards of S-3-(4-methyl-1-hydroxypentyl)glutathione, never described before, and of S-3-(1-hydroxyhexyl)glutathione, previously evidenced in grapes, were chemically synthesized. An optimized extraction of glutathionylated precursors was then applied to Amarillo, Hallertau Blanc, and Mosaic hop samples. HPLC-ESI(+)MS/MS revealed, for the first time, the occurrence of S-3-(1 hydroxyhexyl)glutathione and S-3-(4-methyl-1-hydroxypentyl)glutathione in hop, at levels well above those reported for their cysteinylated counterparts. S-3-(1 Hydroxyhexyl)glutathione emerged in all cases as the major adduct in hop. Yet, although 3-sulfanylhexan-1-ol seems relatively ubiquitous in free, cysteinylated, and glutathionylated forms, the glutathione adduct of 3-sulfanyl-4-methylpentan-1 ol, never evidenced in other plants up to now, was found only in the Hallertau Blanc variety. PMID- 27933903 TI - Proteomic Identification and Analysis of Arginine-Methylated Proteins of Plasmodium falciparum at Asexual Blood Stages. AB - Plasmodium falciparum undergoes a tightly regulated developmental process in human erythrocytes, and recent studies suggest an important regulatory role of post-translational modifications (PTMs). As compared with Plasmodium phosphoproteome, little is known about other PTMs in the parasite. In the present study, we performed a global analysis of asexual blood stages of Plasmodium falciparum to identify arginine-methylated proteins. Using two different methyl arginine-specific antibodies, we immunoprecipitated the arginine-methylated proteins from the stage-specific parasite lysates and identified 843 putative arginine-methylated proteins by LC-MS/MS. Motif analysis of the protein sequences unveiled that the methylation sites are associated with the previously known methylation motifs such as GRx/RGx, RxG, GxxR, or WxxxR. We identified Plasmodium homologues of known arginine-methylated proteins in trypanosomes, yeast, and human. Hydrophilic interaction liquid chromatography (HILIC) was performed on the immunoprecipitates from the trophozoite stage to enrich arginine-methylated peptides. Mass spectrometry analysis of immunoprecipitated and HILIC fractions identified 55 arginine-methylated peptides having 62 methylated arginine sites. Functional classification revealed that the arginine-methylated proteins are involved in RNA metabolism, protein synthesis, intracellular protein trafficking, proteolysis, protein folding, chromatin organization, hemoglobin metabolic process, and several other functions. Summarily, the findings suggest that protein methylation of arginine residues is a widespread phenomenon in Plasmodium, and the PTM may play an important regulatory role in a diverse set of biological pathways, including host-pathogen interactions. PMID- 27933904 TI - Global Analysis of Secreted Proteins and Glycoproteins in Saccharomyces cerevisiae. AB - Protein secretion is essential for numerous cellular activities, and secreted proteins in bodily fluids are a promising and noninvasive source of biomarkers for disease detection. Systematic analysis of secreted proteins and glycoproteins will provide insight into protein function and cellular activities. Yeast (Saccharomyces cerevisiae) is an excellent model system for eukaryotic cells, but global analysis of secreted proteins and glycoproteins in yeast is challenging due to the low abundances of secreted proteins and contamination from high abundance intracellular proteins. Here, by using mild separation of secreted proteins from cells, we comprehensively identified and quantified secreted proteins and glycoproteins through inhibition of glycosylation and mass spectrometry-based proteomics. In biological triplicate experiments, 245 secreted proteins were identified, and comparison with previous experimental and computational results demonstrated that many identified proteins were located in the extracellular space. Most quantified secreted proteins were down-regulated from cells treated with an N-glycosylation inhibitor (tunicamycin). The quantitative results strongly suggest that the secretion of these down-regulated proteins was regulated by glycosylation, while the secretion of proteins with minimal abundance changes was contrarily irrelevant to protein glycosylation, likely being secreted through nonclassical pathways. Glycoproteins in the yeast secretome were globally analyzed for the first time. A total of 27 proteins were quantified in at least two protein and glycosylation triplicate experiments, and all except one were down-regulated under N-glycosylation inhibition, which is solid experimental evidence to further demonstrate that the secretion of these proteins is regulated by their glycosylation. These results provide valuable insight into protein secretion, which will further advance protein secretion and disease studies. PMID- 27933905 TI - Nearsightedness of Oxygen-Containing Functional Groups. AB - Matter is nearsighted, that is, for a fixed chemical potential, the charge density is only sensitive to perturbations within a radius R. While it is known that the resultant change in the density at point r0 from some perturbation at some other point R (Deltan(r0,R)) is a monotonically decreasing function, a plausible range of a chemically significant Deltan(r0,R) and the value of R needed to cause these perturbations has not been well studied. Using the functional group, which upon satisfying the necessary atoms/bonds specific to that functional group retains a characteristic chemistry, this paper provides an initial study into the magnitude of both Deltan and R, the radius beyond which to affect a given property. Values for Deltan are shown to be robust across a variety of DFT functionals and provide a framework for the transfer of the functional group concept to other disciplines, such as metallurgy. PMID- 27933906 TI - Heterogeneous Reactions of Limonene on Mineral Dust: Impacts of Adsorbed Water and Nitric Acid. AB - Biogenic volatile organic compounds (BVOCs), including the monoterpene limonene, are a major source of secondary organic aerosol (SOA). While gas-phase oxidation initiates the dominant pathway for BVOC conversion to SOA, recent studies have demonstrated that biogenic hydrocarbons can also directly react with acidic droplets. To investigate whether mineral dust may facilitate similar reactive uptake of biogenic hydrocarbons, we studied the heterogeneous reaction of limonene with mineral substrates using condensed-phase infrared spectroscopy and identified the formation of irreversibly adsorbed organic products. For kaolinite, Arizona Test Dust, and silica at 30% relative humidity, GC-MS identified limonene-1,2-diol as the dominant product with total organic surface concentrations on the order of (3-5) * 1018 molecules m-2. Experiments with 18O labeled water support a mechanism initiated by oxidation of limonene by surface redox sites forming limonene oxide followed by water addition to the epoxide to form limonenediol. Limonene uptake on alpha-alumina, gamma-alumina, and montmorillonite formed additional products in high yield, including carveol, carvone, limonene oxide, and alpha-terpineol. To model tropospheric processing of mineral aerosol, we also exposed each mineral substrate to gaseous nitric acid prior to limonene uptake and identified similar surface adsorbed products that were formed at rates 2 to 5 times faster than without nitrate coatings. The initial rate of reaction was linearly dependent on gaseous limonene concentration between 5 * 1012 and 5 * 1014 molecules cm-3 (0.22-20.5 ppm) consistent with an Eley-Rideal-type mechanism in which gaseous limonene reacts directly with reactive surface sites. Increasing relative humidity decreased the amount of surface adsorbed products indicating competitive adsorption of surface adsorbed water. Using a laminar flow tube reactor we measured the uptake coefficient for limonene on kaolinite at 25% RH to range from gamma = 5.1 * 10-6 to 9.7 * 10-7. After adjusting for reactive surface areas, we estimate uptake coefficients for limonene on HNO3-processed mineral aerosol on the order of (1-6) * 10-6. Although this heterogeneous reaction will not impact the atmospheric lifetime of gaseous limonene, it does provide a new pathway for mineral aerosol to acquire secondary organic matter from biogenic hydrocarbons, which in turn will alter the physical properties of mineral dust. PMID- 27933907 TI - Origin of Acid-Base Catalytic Effects on Formaldehyde Hydration. AB - The mechanisms of hydronium- and hydroxide-catalyzed formaldehyde hydrations were investigated by quantum mechanical/molecular mechanical molecular dynamics in combination with flexible coordinates. A stepwise bimolecular and a concerted termolecular mechanism were found with a hydronium catalyst. The latter is more favorable and better consistent with experiment. Structurally, a dipole-bound species initially arranges the nucleophile in a favorable configuration for both routes, significantly enhancing the reactive collisions. On the one hand, the hydronium catalyst also plays a role of a reactant in the bimolecular path. On the other hand, only a stepwise mechanism was found with a hydroxide catalyst. Overall, hydroxide is a stronger catalyst than a hydronium when it is in contact distance with formaldehyde. PMID- 27933908 TI - Can a Topological Approach Predict Spin-Symmetry Breaking in Conjugated Hydrocarbons? AB - The closed-shell mean-field single determinants of large alternant hydrocarbons are frequently unstable with respect to a possible spin-symmetry breaking which produces different orbitals for the alpha and beta electrons, either in Hartree Fock or in Kohn-Sham DFT calculations. The present work shows that one may easily predict whether such a symmetry breaking will take place from the elementary topological Huckel Hamiltonian which introduces a simple hopping integral t. The demonstration makes use of the simplest representation of the bielectronic repulsion, namely, the Hubbard bielectronic operator, reduced to an on-site repulsion U, and takes benefit of the mirror theorem. A recipe is proposed to determine the relevant t/U ratio for a given exchange-correlation potential. The symmetry-breaking phenomenon first concerns the mixing between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), but it may eventually run on other pairs of mirror orbitals. These symmetry breakings may take place while the other molecular orbitals keep a closed-shell character. The spin polarization of these MOs, appearing in typical unrestricted mean-field calculations, is an induced and amplifying effect, which has to be distinguished from the symmetry breaking itself. Special attention is paid to the possible appearance of multiple symmetry breakings, leading to a polyradical character. The model is tested on six series of polycyclic hydrocarbons. This elementary approach sheds new arguments on the debate concerning the di- or polyradical character of polyacenes. PMID- 27933909 TI - Theoretical Study on the Photoelectron Spectra of Ln(COT)2-: Lanthanide Dependence of the Metal-Ligand Interaction. AB - We have performed a theoretical analysis of the recently reported photoelectron (PE) spectra of the series of sandwich complex anions Ln(COT)2- (Ln = La-Lu, COT = 1,3,5,7-cyclooctatetraene), focusing on the Ln dependence of the vertical detachment energies. For most Ln, the pi molecular orbitals, largely localized on the COT ligands, have the energy order of e1g < e1u < e2g < e2u as in the actinide analogues, reflecting the substantial orbital interaction with the Ln 5d and 5p orbitals. Thus, it would be expected that the lanthanide contraction would increase the orbital interaction so that the overlaps between the COT pi and Ln atomic orbitals tend to increase across the series. However, the PE spectra and theoretical calculations were not consistent with this expectation, and the details have been clarified in this study. Furthermore, the energy level splitting patterns of the anion and neutral complexes have been studied by multireference ab initio methods, and the X peak splittings observed in the PE spectra only for the middle-range Ln complexes were found to be due to the specific interaction between the Ln 4f and ligand pi orbitals of the neutral complexes in e2u symmetry. Because the magnitude of this 4f-ligand interaction depends critically on the final state 4f electron configuration and the spin state, a significant Ln dependence in the PE spectra is explained. PMID- 27933910 TI - Fundamental Aspects of Recoupled Pair Bonds. III. The Frustrated Recoupled Pair Bond in Oxygen Monofluoride. AB - In a previous paper in this series, we discussed the formation of recoupled pair bonds in the a4Sigma- states of CF and SF in which the recoupling process was essentially complete at the equilibrium geometry of the molecule. In this paper, we examine the a4Sigma- state of oxygen monofluoride (OF), which could also have a recoupled pair bond. Unlike the other two molecules, generalized valence bond calculations predict that the recoupling in OF is woefully incomplete at Re and the resulting potential energy curve for the OF(a4Sigma-) state is purely repulsive; the binding energy, ~11 kcal/mol, is entirely due to dynamical correlation. A number of factors account for these differences, but the nature of the dominant correlation effect in the oxygen 2p lone pair as well as the spatial extent of the 2p orbital are paramount. PMID- 27933911 TI - A Benefit of Using the IDSCRF- over UFF-Radii Cavities and Why Joint Correlations of NMR Chemical Shifts Can Be Advantageous: Condensed Pyridines as an IEF PCM/GIAO/DFT Case Study. AB - Herein, an advantage of the use of IDSCRF- over UFF-radii-based solute cavities in GIAO/DFT calculations is presented for the 13C and especially 15N NMR chemical shifts made for several bicyclic aromatic nitrogen heterocycles in CDCl3 solution treated within the classical IEF-PCM solvation scheme. Successful application of the IDSCRF-radii in the non 1:1 joint multinuclear 1H/13C and particularly 1H/13C/15N correlations of the measured deltaH,C(,N) values to those obtained theoretically is also documented for a series of test systems (-268 <= deltaN <= 72 ppm). The experimentally yet unknown deltaN's were found in this way for the title compounds via a trinuclear eq 1 determined for an optimally chosen value of the multiplication factor of initial raw deltaH data (mH = 10). Such a simultaneous analysis of the deltaH,C(,N) data is proposed as a novel method to study the solution structure of the other similar conformationally homogeneous (bio)organic compounds. The issue of small spurious imaginary vibrational frequencies computed for a few molecular systems using the Gaussian 09 default UFF-radii is briefly considered as well. PMID- 27933912 TI - Generalized Energy-Based Fragmentation Approach for Localized Excited States of Large Systems. AB - We have extended the generalized energy-based fragmentation (GEBF) approach to localized excited states of large systems. In this approach, the excited-state energy of a large system could be expressed as the combination of the excited state energies of "active subsystems", which contains the chromophore center, and the ground-state energies of "inactive subsystems". The GEBF approach has been implemented at the levels of time-dependent density functional theory (TDDFT) and approximate coupled cluster singles and doubles (CC2) method. Our results show that GEBF-TDDFT can reproduce the TDDFT excitation energies and solvatochromic shifts for large systems and that GEBF-CC2 could be used to validate GEBF-TDDFT result (with different functionals). The GEBF-TDDFT method is found to be able to provide satisfactory or reasonable descriptions on the experimental solvatochromic shifts for the n -> pi* transitions of acetone in various solutions, and the lowest pi -> pi* transitions of pyridine and uracil in aqueous solutions. PMID- 27933913 TI - DFT Study on the Interaction of Tris(benzene-1,2-dithiolato)molybdenum Complex with Water. A Hydrolysis Mechanism Involving a Feasible Seven-Coordinate Aquomolybdenum Intermediate. AB - In the present work, the reactivity of the tris(benzene-1,2-dithiolato)molybdenum complex ([Mo(bdt)3]) toward water is studied by means of the density functional theory (DFT). DFT calculations were performed using the M06, B3P86, and B3PW91 hybrid functionals for comparison purposes. The M06 method was employed to elucidate the reaction pathway, relative stability of the intermediate products, nature of the Mo-S bond cleavage, and electronic structure of the involved molybdenum species. This functional was also used to study the transference of electrons from the molybdenum center toward the ligands. The reaction pathway confirms that [Mo(bdt)3] undergoes hydrolysis, yielding dihydroxo-bis(benzene-1,2 dithiolato)molybdenum complex ([Mo(OH)2(bdt)2]) and benzenedithiol. The reaction takes place through seven transition structures, one of them involving an aquo seven-coordinate molybdenum intermediate stabilized by a lone pair (LP) LPO->LPMo hyperconjugative interaction. This heptacoordinate species allows understanding of the observed oxygen atom exchange between water and tertiary phosphines mediated by these complexes. Calculations also show that [Mo(C2H4S2)3] and [Mo(OH)2(C2H4S2)2] have d2 and d0 electronic configuration, and hence an electron pair must be transferred during the course of the hydrolysis. The frontier molecular orbital (FMO) analysis concludes that the electron pair is transferred in the rupture of the second Mo-S bond, from the occupied donating Mo dx2-y2 orbital to the unoccupied C2H4(SH)2 S-C sigma* ligand orbital. This result is supported by the bond dissociation energy calculations, which demonstrate that the neutral dissociation of the second Mo-S bond is energetically the more favorable. PMID- 27933914 TI - Spin Inversion Phenomenon and Two-State Reactivity Mechanism for Direct Benzene Hydroxylation by V4O10 Cluster. AB - The direct and selective introduction of hydroxyl group into aromatic compounds remains one of the challenging problems in oxidation chemistry. Keeping in view the reported reactivity of vanadium oxide in C-H activation of saturated hydrocarbons, the study explores the reactivity of neutral V4O10 cluster with benzene through rigorous computations performed within the formalism of density functional theory. Three possible reaction channels for the reactivity of V4O10 cluster with benzene have been deciphered, and comprehensive understanding of all possible mechanistic pathways has been obtained by analysis of all the intermediates and transition states encountered en route. The study provides promising evidence of direct abstraction of hydrogen by terminal oxygen of the cluster via three-centered transition state. The scan of potential energy surfaces for the reactivity of the cluster in its ground (singlet) and first excited (triplet) spin multiplicity states establishes two-state reactivity mechanisms. The spin crossover point has been identified through geometric and thermodynamic parameters, partial charges, and intrinsic reaction coordinate calculations. The study establishes the efficacy of V4O10 cluster species in direct hydroxylation of benzene to phenol. PMID- 27933915 TI - Atmospheric Chemistry of 1H-Heptafluorocyclopentene (cyc-CF2CF2CF2CF?CH-): Rate Constant, Products, and Mechanism of Gas-Phase Reactions with OH Radicals, IR Absorption Spectrum, Photochemical Ozone Creation Potential, and Global Warming Potential. AB - The rate constant for gas-phase reactions of OH radicals with 1H heptafluorocyclopentene (cyc-CF2CF2CF2CF?CH-) was measured using a relative rate method at 298 K: (5.20 +/- 0.09) * 10-14 cm3 molecule-1 s-1. The quoted uncertainty includes two standard deviations from the least-squares regression, the systematic error from the GC analysis, and the uncertainties of the rate constants of the reference compounds. The OH-radical-initiated oxidation of cyc CF2CF2CF2CF?CH- gives the main products COF2, CO, and CO2, leading to negligible environmental impact. For consumptions of cyc-CF2CF2CF2CF?CH- of less than 54%, the yield of the formation of ([COF2] + [CO] + [CO2])/5 (based on the conservation of carbon) was 0.99 +/- 0.02, which is very close to 100%. A possible degradation mechanism was proposed. The radiative efficiency (RE) of cyc CF2CF2CF2CF?CH- measured at room temperature was 0.215 W m-2 ppb-1. The atmospheric lifetime of cyc-CF2CF2CF2CF?CH- was calculated as 0.61 year, and the photochemical ozone creation potential (POCP) was negligible. The 20-, 100-, and 500-year time horizon global warming potentials (GWPs) were estimated as 153, 42, and 12, respectively. PMID- 27933917 TI - Exponential Relationships Capturing Atomistic Short-Range Repulsion from the Interacting Quantum Atoms (IQA) Method. AB - A topological atom is a quantum object with a well-defined intra-atomic energy, which includes kinetic energy, Coulomb energy, and exchange energy. In the context of intermolecular interactions, this intra-atomic energy is calculated from supermolecular wave functions, by using the topological partitioning. This partitioning is parameter-free and invokes only the electron density to obtain the topological atoms. In this work, no perturbation theory is used; instead, a single wave function describes the behavior of all van der Waals complexes studied. As the monomers approach each other, frontier atoms deform, which can be monitored through a change in their shape and volume. Here we show that the corresponding atomic deformation energy is very well described by an exponential function, which matches the well-known Buckingham repulsive potential. Moreover, we recover a combination rule that enables the interatomic repulsion energy between topological atoms A and B to be expressed as a function of the interatomic repulsion energy between A and A on one hand, and between B and B on the other hand. As a result a link is established between quantum topological atomic energies and classical well-known interatomic repulsive potentials. PMID- 27933916 TI - Theoretical ab Initio Study of the Series of N2X+ Cations with X = F, Cl, Br, and I. New Insights on the "Unusual" N2F+ Species. AB - The series of cations N2X+(X1Sigma+), with X = F, Cl, Br, I, has been theoretically studied by variational multireference CI and coupled-cluster techniques in conjunction with basis sets of quintuple-zeta quality. We report electronic and geometric structure data and harmonic frequencies as well as binding energies and potential energy curves. A new rationalization is provided for the bonding mode in N2F+, which provides an explanation for the unusually short N-F bond. PMID- 27933918 TI - Dissociation Dynamics and Electronic Structures of Highly Excited Ferrocenium Ions Studied by Femtosecond XUV Absorption Spectroscopy. AB - The dissociation dynamics of ferrocene are explored following strong field ionization using femtosecond time-resolved extreme ultraviolet (XUV) transient absorption spectroscopy. Employing transitions in the vicinity of the iron 3p (M2,3) edge, the dissociation is monitored from the point of view of the iron atom. With low strong field pump intensities (~2 * 1013 W cm-2), only ferrocenium cations are produced, and their iron 3p absorption spectrum is reported. It very closely resembles the 3p spectrum of atomic Fe+ ions but is red-shifted by 0.8 eV. With the aid of time-dependent density functional theory calculations, the spectrum is assigned to a combination of doublet and quartet spin states of ferrocenium ions. Ionization with more intense strong field pump pulses (>=6 * 1013 W cm-2) leads predominantly to the prompt production of ferrocenium ions that dissociate to give the spectral signature of bare Fe+ ions within 240 +/- 80 fs. Within the temporal resolution of the experiment (~40 fs), no spectral intermediates are observed, suggesting that the dissociation process occurs directly from the excited ferrocenium ion and that the bonds between the iron center and both cyclopentadienyl rings are broken almost simultaneously in an asynchronous concerted decay process. No evidence of slower dissociation channels is observed at a pump-probe delay of 250 ps, suggesting that all energy is very rapidly routed into dissociative states. PMID- 27933920 TI - Time Dependent Density Functional Theory Study of Magnetic Circular Dichroism Spectra of Gold Clusters Au9(PH3)83+ and Au9(PPh3)83. AB - Magnetic circular dichroism (MCD) spectroscopy is a source of important data about the electronic structure and optical properties of different chemical systems. Theoretical simulation of the MCD spectra can be used to assist in the understanding of empirically measured MCD spectra. In the present paper, a theoretical investigation of electronic and optical properties of phosphine protected gold clusters with a Au93+ core with D2h symmetry was performed with time-dependent density functional theory. The influence of ligands on the optical properties of the gold core was investigated. Simulations of the optical absorption and MCD spectra were performed for the bare gold Au93+ cluster as well as for ligand-protected Au9(PH3)83+ and Au9(PPh3)83+ species. MCD spectra were calculated at a temperature of 298 K and a magnetic field of 7 T. A comparative analysis of theoretical and experimental data was also performed. The obtained results show that the theoretically simulated MCD spectrum for the Au9(PPh3)83+ ion in gas phase exhibits a reasonable agreement with experimental results for the [Au9(PPh3)8](NO3)3 system, although with a red shift of up to 0.5 MUm-1. Overall, MCD provides significant additional details about the electronic structure of the considered systems compared to the absorption spectra. PMID- 27933919 TI - Theoretical Study of Cu/Mg Core-shell Nanocluster Formation. AB - In a recently reported helium droplet-mediated deposition experiment to produce copper-coated magnesium core-shell nanoclusters, structural inversion was observed, which resulted in copper in the nanocluster interior, surrounded by oxidized magnesium on the copper surface. This study utilizes density functional theory methods to model the migration of copper atoms into the interior of a magnesium nanocluster to probe the energetics of this process and to compare it to the complementary process of magnesium atom migration into the interior of a copper nanocluster. Potential energy surfaces describing the forced migration of copper (magnesium) atoms into the interior of a 30-atom magnesium (copper) cluster were generated using the B3PW91 hybrid generalized gradient approximation functional with the augmented correlation consistent core-valence polarized triple-zeta basis set for magnesium and a pseudopotential plus valence-only basis set for copper. The estimated barrier for atomic copper to penetrate the surface of Mg30 is 0.6 kcal mol-1. In contrast, the migration of atomic magnesium into the interior of Cu30 crosses an estimated barrier of 6 kcal mol-1. These results are qualitatively consistent with the observed structural inversion of copper coated magnesium nanoclusters and also suggest that inversion of a magnesium coated copper cluster is less likely to occur. PMID- 27933921 TI - Hemibonding between Water Cation and Water. AB - The hemibonding interaction in the water dimer cation is studied using coupled cluster electronic structure methods. The hemibonded dimer cation geometry is a local minimum structure characterized by the two participating monomers having both a very short separation and a near parallel relative orientation. It is shown that the vertically ionized dimer at its optimum neutral geometry can convert to the hemibonded dimer cation structure with essentially no energetic hindrance. Direct conversion to the hemibonded structure is therefore an energetically facile alternative to the minimum energy path that connects the vertically ionized neutral water dimer to the global minimum proton-transferred structure. A substantial barrier must be surmounted to convert the hemibonded dimer cation to the proton-transferred structure. The optical absorption spectrum of the hemibonded dimer cation is characterized by three excited near-UV states, two of which have very large oscillator strengths. Relative resonance Raman intensities are estimated for the hemibonded dimer cation vibrational modes, finding the intermolecular stretching mode to be the most strongly enhanced when in near resonance with each of the near-UV excited states, and the anharmonicity and overtones of this mode are estimated. These results provide guidance for the possible observation of hemibonded cations in irradiated liquid water. PMID- 27933923 TI - Enantioselective Rhodium-Catalyzed Allylic Alkylation of Prochiral alpha,alpha Disubstituted Aldehyde Enolates for the Construction of Acyclic Quaternary Stereogenic Centers. AB - A highly enantioselective rhodium-catalyzed allylic alkylation of prochiral alpha,alpha-disubstituted aldehyde enolates with allyl benzoate is described. This protocol provides a novel approach for the synthesis of acyclic quaternary carbon stereogenic centers and it represents the first example of the direct enantioselective alkylation of an aldehyde enolate per se. The versatility of the alpha-quaternary aldehyde products is demonstrated through their conversion to a variety of useful motifs applicable to target-directed synthesis. Finally, mechanistic studies indicate that high levels of asymmetric induction are achieved from a mixture of prochiral (E)- and (Z)-enolates, which provides an exciting development for this type of transformation. PMID- 27933922 TI - Synthesis of Graphene Nanoribbons by Ambient-Pressure Chemical Vapor Deposition and Device Integration. AB - Graphene nanoribbons (GNRs), quasi-one-dimensional graphene strips, have shown great potential for nanoscale electronics, optoelectronics, and photonics. Atomically precise GNRs can be "bottom-up" synthesized by surface-assisted assembly of molecular building blocks under ultra-high-vacuum conditions. However, large-scale and efficient synthesis of such GNRs at low cost remains a significant challenge. Here we report an efficient "bottom-up" chemical vapor deposition (CVD) process for inexpensive and high-throughput growth of structurally defined GNRs with varying structures under ambient-pressure conditions. The high quality of our CVD-grown GNRs is validated by a combination of different spectroscopic and microscopic characterizations. Facile, large-area transfer of GNRs onto insulating substrates and subsequent device fabrication demonstrate their promising potential as semiconducting materials, exhibiting high current on/off ratios up to 6000 in field-effect transistor devices. This value is 3 orders of magnitude higher than values reported so far for other thin film transistors of structurally defined GNRs. Notably, on-surface mass spectrometry analyses of polymer precursors provide unprecedented evidence for the chemical structures of the resulting GNRs, especially the heteroatom doping and heterojunctions. These results pave the way toward the scalable and controllable growth of GNRs for future applications. PMID- 27933925 TI - Giant Piezoelectricity and High Curie Temperature in Nanostructured Alkali Niobate Lead-Free Piezoceramics through Phase Coexistence. AB - Because of growing environmental concerns, the development of lead-free piezoelectric materials with enhanced properties has become of great interest. Here, we report a giant piezoelectric coefficient (d33) of 550 pC/N and a high Curie temperature (TC) of 237 degrees C in (1-x-y)K1-wNawNb1-zSbzO3-xBiFeO3 yBi0.5Na0.5ZrO3 (KNwNSz-xBF-yBNZ) ceramics by optimizing x, y, z, and w. Atomic resolution polarization mapping by Z-contrast imaging reveals the intimate coexistence of rhombohedral (R) and tetragonal (T) phases inside nanodomains, that is, a structural origin for the R-T phase boundary in the present KNN system. Hence, the physical origin of high piezoelectric performance can be attributed to a nearly vanishing polarization anisotropy and thus low domain wall energy, facilitating easy polarization rotation between different states under an external field. PMID- 27933924 TI - Structural and Spectroscopic Characterization of Reaction Intermediates Involved in a Dinuclear Co-Hbpp Water Oxidation Catalyst. AB - An end-on superoxido complex with the formula {[CoIII(OH2)(trpy)][CoIII(OO*)(trpy)](MU-bpp)}4+ (34+) (bpp- = bis(2-pyridyl)-3,5 pyrazolate; trpy = 2,2';6':2"-terpyridine) has been characterized by resonance Raman, electron paramagnetic resonance, and X-ray absorption spectroscopies. These results together with online mass spectrometry experiments using 17O and 18O isotopically labeled compounds prove that this compound is a key intermediate of the water oxidation reaction catalyzed by the peroxido-bridged complex {[CoIII(trpy)]2(MU-bpp)(MU-OO)}3+ (13+). DFT calculations agree with and complement the experimental data, offering a complete description of the transition states and intermediates involved in the catalytic cycle. PMID- 27933926 TI - Near-Quantitative Aqueous Synthesis of Rotaxanes via Bioconjugation to Oligopeptides and Proteins. AB - In spite of widespread interest in rotaxane-based molecular machines and materials, rotaxanes have not been attached covalently to proteins. We describe the near-quantitative aqueous synthesis of [2]rotaxanes based on neutral and charged aqueous hosts-cucurbit[7]uril (CB7) and cyclobis(paraquat-p-phenylene) (CBPQT4+), respectively-using the thiol-ene addition of cysteine and maleimide as a stoppering protocol. After verifying the high efficiency of the reaction using glutathione (GSH) as an oligopeptide stopper, we have employed cytochrome C (CytC) as a protein stopper to produce the first well-characterized protein rotaxane bioconjugates. We anticipate that this methodology will enable the preparation of novel materials that combine the unique properties of proteins and mechanical bonds. PMID- 27933929 TI - Porphyrins as Photoredox Catalysts: Experimental and Theoretical Studies. AB - Metalloporphyrins not only are vital in biological systems but also are valuable catalysts in organic synthesis. On the other hand, catalytic properties of free base porphyrins have been less explored. They are mostly known as efficient photosensitizers for the generation of singlet oxygen via photoinduced energy transfer processes, but under light irradiation, they can also participate in electron transfer processes. Indeed, we have found that free base tetraphenylporphyrin (H2TPP) is an efficient photoredox catalyst for the reaction of aldehydes with diazo compounds leading to alpha-alkylated derivatives. The performance of a porphyrin catalyst can be optimized by tailoring various substituents at the periphery of the macrocycle at both the beta and meso positions. This allows for the fine tuning of their optical and electrochemical properties and hence their catalytic activity. PMID- 27933927 TI - Three-Dimensionally Functionalized Reverse Phase Glycoprotein Array for Cancer Biomarker Discovery and Validation. AB - Glycoproteins have vast structural diversity that plays an important role in many biological processes and have great potential as disease biomarkers. Here, we report a novel functionalized reverse phase protein array (RPPA), termed polymer based reverse phase glycoprotein array (polyGPA), to capture and profile glycoproteomes specifically, and validate glycoproteins. Nitrocellulose membrane functionalized with globular hydroxyaminodendrimers was used to covalently capture preoxidized glycans on glycoproteins from complex protein samples such as biofluids. The captured glycoproteins were subsequently detected using the same validated antibodies as in RPPA. We demonstrated the outstanding specificity, sensitivity, and quantitative capabilities of polyGPA by capturing and detecting purified as well as endogenous alpha-1-acid glycoprotein (AGP) in human plasma. We further applied quantitative N-glycoproteomics and the strategy to validate a panel of glycoproteins identified as potential biomarkers for bladder cancer by analyzing urine glycoproteins from bladder cancer patients or matched healthy individuals. PMID- 27933930 TI - Nickel-Catalyzed Boron Insertion into the C2-O Bond of Benzofurans. AB - Treatment of benzofurans with bis(pinacolato)diboron and Cs2CO3 under nickel-NHC catalysis resulted in the insertion of a boron atom into the C2-O bond of benzofurans to afford the corresponding oxaborins. The scope of benzofuran substrates is wide, and the reactions proceeded without loss of functional groups such as fluoro, methoxy, and ester that are potentially reactive under nickel catalysis. The boron-inserted products proved to be useful building blocks and subsequently underwent a series of transformations, one of which led to the synthesis of fluorescent pi-expanded oxaborins. PMID- 27933931 TI - Imaging and Quantitation of a Succession of Transient Intermediates Reveal the Reversible Self-Assembly Pathway of a Simple Icosahedral Virus Capsid. AB - Understanding the fundamental principles underlying supramolecular self-assembly may facilitate many developments, from novel antivirals to self-organized nanodevices. Icosahedral virus particles constitute paradigms to study self assembly using a combination of theory and experiment. Unfortunately, assembly pathways of the structurally simplest virus capsids, those more accessible to detailed theoretical studies, have been difficult to study experimentally. We have enabled the in vitro self-assembly under close to physiological conditions of one of the simplest virus particles known, the minute virus of mice (MVM) capsid, and experimentally analyzed its pathways of assembly and disassembly. A combination of electron microscopy and high-resolution atomic force microscopy was used to structurally characterize and quantify a succession of transient assembly and disassembly intermediates. The results provided an experiment-based model for the reversible self-assembly pathway of a most simple (T = 1) icosahedral protein shell. During assembly, trimeric capsid building blocks are sequentially added to the growing capsid, with pentamers of building blocks and incomplete capsids missing one building block as conspicuous intermediates. This study provided experimental verification of many features of self-assembly of a simple T = 1 capsid predicted by molecular dynamics simulations. It also demonstrated atomic force microscopy imaging and automated analysis, in combination with electron microscopy, as a powerful single-particle approach to characterize at high resolution and quantify transient intermediates during supramolecular self-assembly/disassembly reactions. Finally, the efficient in vitro self-assembly achieved for the oncotropic, cell nucleus-targeted MVM capsid may facilitate its development as a drug-encapsidating nanoparticle for anticancer targeted drug delivery. PMID- 27933932 TI - Mechanism of the Pseudoirreversible Binding of Amantadine to the M2 Proton Channel. AB - The M2 proton channel of influenza A virus is an integral membrane protein involved in the acidification of the viral interior, a step necessary for the release of the viral genetic material and replication of new virions. The aim of this study is to explore the mechanism of drug (un)binding to the M2 channel in order to gain insight into the structural and energetic features relevant for the development of novel inhibitors. To this end, we have investigated the binding of amantadine (Amt) to the wild type (wt) M2 channel and its V27A variant using multiple independent molecular dynamics simulations, exploratory conventional metadynamics, and multiple-walkers well-tempered metadynamics calculations. The results allow us to propose a sequential mechanism for the (un)binding of Amt to the wt M2 channel, which involves the adoption of a transiently populated intermediate (up state) leading to the thermodynamically favored down binding mode in the channel pore. Furthermore, they suggest that chloride anions play a relevant role in stabilizing the down binding mode of Amt to the wt channel, giving rise to a kinetic trapping that explains the experimentally observed pseudoirreversible inhibition of the wt channel by Amt. We propose that this trapping mechanism underlies the inhibitory activity of potent M2 channel blockers, as supported by the experimental confirmation of the irreversible binding of a pyrrolidine analogue from electrophysiological current assays. Finally, the results reveal that the thermodynamics and kinetics of Amt (un)binding is very sensitive to the V27A mutation, providing a quantitative rationale to the drastic decrease in inhibitory potency against the V27A variant. Overall, these findings pave the way to explore the inhibitory activity of Amt related analogues in mutated M2 channel variants, providing guidelines for the design of novel inhibitors against resistant virus strains. PMID- 27933933 TI - Enzyme-Responsive Procarriers Capable of Transporting Chloride Ions across Lipid and Cellular Membranes. AB - Adopting the concept of procarrier for the first time, we demonstrated the controlled transport of chloride ions across lipid and cellular membranes. Procarriers containing highly hydrophilic appendages were initially inactive due to the lack of their partitioning into lipophilic membranes but were activated to transport chloride ions in the presence of specific enzymes that were able to hydrolyze off the appendages to generate an active carrier under specific conditions. Namely, the procarrier with an ester-bond-linked appendage was most activated by an esterase (PLE) at pH = 7.4, whereas the procarrier with a glycosyl-bond-linked appendage was activated only by a glycosylase (AOG) under slightly acidic conditions (pH = 5.5-6). In addition to controlling chloride transport, hydrophilic appendages greatly increase the water solubility of the procarrier, which may improve the deliverability of a hydrophobic active carrier into a plasma membrane. PMID- 27933934 TI - Tuning Electronic Structure To Control Manganese Nitride Activation. AB - Investigation of a series of oxidized nitridomanganese(V) salen complexes with different para ring substituents (R = CF3, tBu, and NMe2) demonstrates that nitride activation is dictated by remote ligand electronics. For R = CF3 and tBu, oxidation affords a Mn(VI) species and nitride activation, with dinitrogen homocoupling accelerated by the more electron-withdrawing CF3 substituent. Employing an electron-donating substituent (R = NMe2) results in a localized ligand radical species that is resistant to N coupling of the nitrides and is stable in solution at both 195 and 298 K. PMID- 27933935 TI - Anisotropic Conjugated Polymer Chain Conformation Tailors the Energy Migration in Nanofibers. AB - Conjugated polymers are complex multichromophore systems, with emission properties strongly dependent on the electronic energy transfer through active subunits. Although the packing of the conjugated chains in the solid state is known to be a key factor to tailor the electronic energy transfer and the resulting optical properties, most of the current solution-based processing methods do not allow for effectively controlling the molecular order, thus making the full unveiling of energy transfer mechanisms very complex. Here we report on conjugated polymer fibers with tailored internal molecular order, leading to a significant enhancement of the emission quantum yield. Steady state and femtosecond time-resolved polarized spectroscopies evidence that excitation is directed toward those chromophores oriented along the fiber axis, on a typical time scale of picoseconds. These aligned and more extended chromophores, resulting from the high stretching rate and electric field applied during the fiber spinning process, lead to improved emission properties. Conjugated polymer fibers are relevant to develop optoelectronic plastic devices with enhanced and anisotropic properties. PMID- 27933936 TI - Mechanism-Based Development of a Low-Potential, Soluble, and Cyclable Multielectron Anolyte for Nonaqueous Redox Flow Batteries. AB - The development of nonaqueous redox flow batteries (NRFBs) has been impeded by a lack of electroactive compounds (anolytes and catholytes) with the necessary combination of (1) redox potentials that exceed the potential limits of water, (2) high solubility in nonaqueous media, and (3) high stability toward electrochemical cycling. In addition, ideal materials would maintain all three of these properties over multiple electron transfer events, thereby providing a proportional increase in storage capacity. This paper describes the mechanism based design of a new class of metal-coordination complexes (MCCs) as anolytes for NRFBs. The tridentate bipyridylimino isoindoline (BPI) ligands of these complexes were designed to enable multielectron redox events. These molecules were optimized using a combination of systematic variation of the BPI ligand and the metal center along with mechanistic investigations of the decomposition pathways that occur during electrochemical cycling. Ultimately, these studies led to the identification of nickel BPI complexes that could undergo stable charge discharge cycling (<5% capacity loss over 200 cycles) as well as a derivative that possesses the previously unprecedented combination of high solubility (>700 mM in CH3CN), multiple electron transfers at low redox potentials (-1.7 and -1.9 V versus Ag/Ag+), and high stability in the charged state for days at high concentration. Overall, the studies described herein have enabled the identification of a promising anolyte candidate for NRFBs and have also provided key insights into chemical design principles for future classes of MCC-based anolytes. PMID- 27933937 TI - Hydrophobic Polymer Chain in Water That Undergoes a Coil-to-Globule Transition Near Room Temperature. AB - A simple model of a hydrophobic polymer in water is studied. The model polymer, a chain of Lennard-Jones particles with a fixed bond length, is designed in such a way that it undergoes a coil-to-globule conformational change near room temperature upon heating in liquid water. At low temperatures (?270 K), the polymer chain under vacuum takes a globular conformation, whereas in water, it adopts an extended form. At higher temperatures (?320 K), the polymer has a more compact conformation in water than under vacuum. The same polymer chain in a nonpolar solvent is always extended and shows no sign of a coil-to-globule transformation up to 360 K. The heat-induced collapse of the polymer uniquely observed in water is not attributed to the hydrophobic effect on individual monomers, but it is correlated with the temperature dependence of the potential of mean force between two monomers at contact distance. PMID- 27933938 TI - Single-Molecule Tracking Study of the Permeability and Transverse Width of Individual Cylindrical Microdomains in Solvent-Swollen Polystyrene-block poly(ethylene oxide) Films. AB - Understanding the properties of solvent-swollen block copolymer (BCP) microdomains is important for better solvent-based control of microdomain morphology, orientation, and permeability. In this study, single-molecule tracking (SMT) was explored to assess the permeability and transverse width of individual cylindrical microdomains in solvent-swollen polystyrene-block poly(ethylene oxide) (PS-b-PEO) films. PS-b-PEO films comprising shear-elongated cylindrical PEO microdomains were prepared by sandwiching its benzene or tetrahydrofuran (THF) solution between two glass substrates. SMT measurements were performed at different drying times to investigate the effects of solvent evaporation on the microdomain properties. SMT data showed one-dimensional (1D) motions of single fluorescent molecules (sulforhodamine B) based on their diffusion within the cylindrical microdomains. Microdomain permeability and transverse width were assessed from the single-molecule diffusion coefficients (DSMT) and transverse variance of the 1D trajectories (sigmadelta2), respectively. The DSMT and sigmadelta2 values from individual 1D trajectories were widely distributed with no evidence of correlation on a single molecule basis, possibly because the individual microdomains in a film were swollen to different extents. On average, microdomain permeability (D) and effective radius (r) gradually decreased within the first 3 days of drying due to solvent evaporation, and changed negligibly thereafter. PS-b-PEO films prepared from THF solutions exhibited larger changes in D and r as compared with those from benzene solutions due to the better swelling of the PEO microdomains by THF. Importantly, changes in D were more prominent than those in r, suggesting that the permeability of the PEO microdomains is very susceptible to the presence of solvent. These results reveal the unique capability of SMT to assess the properties of individual cylindrical microdomains in a solvent-swollen BCP film. PMID- 27933939 TI - Role of Hydration Layer in Dynamical Transition in Proteins: Insights from Translational Self-Diffusivity. AB - Elucidation of the role of hydration water underpinning dynamical crossover in proteins has proven challenging. Indeed, many contradictory findings in the literature seek to establish either causal or correlative links between water and protein behavior. Here, via molecular dynamics, we compute the temperature dependence of mean-square displacement and translational self-diffusivities for both hen egg white lysozyme and its hydration layer from 190 to 300 K. We find that the protein's mobility increases sharply at ~230 K, indicating dynamical onset; concerted motion with hydration-water molecules is evident up to ~285 K, confirming dynamical correlation between them. Exploring underlying mechanisms of such concerted motion, we scrutinize the water-protein hydrogen-bonding network as a function of temperature, noting sharp deviation from linearity of the hydrogen bond number's profile with temperature originating near the protein dynamical transition. Our studies reveal a common temperature profile/dependence of self-diffusivity values of the protein, hydration water, and the bulk solvent, originating from a common dependence on the bulk solvent viscosity, etaS. The key mechanistic role adopted by the protein-water hydrogen bond network in relation to the onset of proteins' dynamical transition is also discussed. PMID- 27933940 TI - Dimerization Mechanism of Alzheimer Abeta40 Peptides: The High Content of Intrapeptide-Stabilized Conformations in A2V and A2T Heterozygous Dimers Retards Amyloid Fibril Formation. AB - Amyloid beta (Abeta) oligomerization is associated with the origin and progression of Alzheimer's disease (AD). While the A2V mutation enhances aggregation kinetics and toxicity, mixtures of wild-type (WT) and A2V, and also WT and A2T, peptides retard fibril formation and protect against AD. In this study, we simulate the equilibrium ensemble of WT:A2T Abeta40 dimer by means of extensive atomistic replica exchange molecular dynamics and compare our results with previous equivalent simulations of A2V:A2V, WT:WT, and WT:A2V Abeta40 dimers for a total time scale of nearly 0.1 ms. Qualitative comparison of the resulting thermodynamic properties, such as the relative binding free energies, with the reported experimental kinetic and thermodynamic data affords us important insight into the conversion from slow-pathway to fast-pathway dimer conformations. The crucial reaction coordinate or driving force of such transformation turns out to be related to hydrophobic interpeptide interactions. Analysis of the equilibrium ensembles shows that the fast-pathway conformations contain interpeptide out-of register antiparallel beta-sheet structures at short interpeptide distances. In contrast, the slow-pathway conformations are formed by the association of peptides at large interpeptide distances and high intrapeptide compactness, such as conformations containing intramolecular three-stranded beta-sheets which sharply distinguish fast (A2V:A2V and WT:WT) and slow (WT:A2T and WT:A2V) amyloid forming sequences. Also, this analysis leads us to predict that a molecule stabilizing the intramolecular three-stranded beta-sheet or inhibiting the formation of an interpeptide beta-sheet spanning residues 17-20 and 31-37 would further reduce fibril formation and probably the cytotoxicity of Abeta species. PMID- 27933941 TI - Micelles of Gradient vs Diblock Copolymers: Difference in the Internal Structure and Properties. AB - We performed computer simulations to reveal a difference in internal structures of micelles formed by AB gradient copolymers and equivalent diblock copolymers in a selective solvent. In contrast to distinct core-shell structure of the diblock copolymer micelles (DCM), the soluble and insoluble monomer units are less segregated in the gradient copolymer micelles (GCM). Furthermore, the concentration of the soluble units in the GCM has a maximum at the core-corona interface. The maximum is a consequence of loop formation near the interface due to the broad distribution of the insoluble units along the chain and their assembly into the core of the micelle. As a result, the interfacial area per one gradient copolymer chain is larger than the area of the diblock copolymer, and the aggregation number of the GCM is smaller. Worsening of the solvent quality (increase of attraction between the insoluble groups) enlarges the aggregation number of the DCM. On the contrary, the aggregation number of the GCM practically does not change. Furthermore, the corona of the GCM becomes less swollen because more and more insoluble units join to the core and aggregate in the corona upon solvent worsening. In other words, the GCM become smaller. Such behavior is known as a "reel in" effect detected for gradient copolymer micelles at temperature elevation.39. PMID- 27933942 TI - Strong Impact of an Axial Ligand on the Absorption by Chlorophyll a and b Pigments Determined by Gas-Phase Ion Spectroscopy Experiments. AB - The microenvironments in photosynthetic proteins affect the absorption by chlorophyll (Chl) pigments. It is, however, a challenge to disentangle the impact on the transition energies of different perturbations, for example, the global electrostatics of the protein (nonbonded environmental effects), exciton coupling between Chl's, conformational variations, and binding of an axial ligand to the magnesium center. This is needed to distinguish between the two most commonly proposed mechanisms for energy transport in photosynthetic proteins, relying on either weakly or strongly coupled pigments. Here, on the basis of photodissociation action spectroscopy, we establish that the redshift of the Soret absorption band due to binding of a negatively charged carboxylate (as present in aspartic acid and glutamic acid residues) is 0.1-0.2 eV for Chl a and b. This effect is almost enough to reproduce the well-known green color of plants and can account for the strong spectral variation between Chl's. The experimental data serve to benchmark future high-level calculations of excited-state energies. Finally, we demonstrate that complexes between Chl a and histidine, tagged by a quaternary ammonium ion, can be made in the gas phase by electrospray ionization, but more work is needed to produce enough ions for gas-phase spectroscopy. PMID- 27933943 TI - Long-Lived Intermediates in a Cooperative Two-State Folding Transition. AB - Biomolecular folding often occurs through a cooperative two-state reactant <-> product transition; the term cooperative does not convey that intermediate structures are nonexistent but rather that these states are not observable by existing experimental techniques. Because of this, few intermediates have been studied and characterized. Recently, ion mobility spectrometry (IMS) measurements revealed that the oligomer polyproline-13 (Pro13, which in propanol (PrOH) favors the right-handed helical PPI structure having adjacent pyrrolidine rings in a cis configuration) folds through six sequential long-lived intermediates as it converts to the all-trans-configured PPII structure that is favored in aqueous solutions. Here, we examine the PPIPrOH -> PPIIaq folding transition for a HisPro13 sequence, i.e., Pro13 having a single histidine residue added to the N terminus. Remarkably, the IMS measurements show that, upon addition of histidine, all of the IMS peaks associated with intermediate structures disappear. Instead, HisPro13 folds via a cooperative two-state transition, delayed by a significant induction period. The induction period is temperature dependent-shifting the transition to longer times at lower temperatures. Equilibrium studies show that the HisPro13 PPIPrOH -> PPIIaq transition is endothermic but favored entropically. From these clues, we propose a sequential folding mechanism and develop a model that suggests that ~13-17 long-lived intermediates are likely responsible for the induction period. In this model, intermediates are separated by average individual activation barriers of ~90 kJ.mol-1, and are entropically favorable. PMID- 27933944 TI - Diffusion in Multicomponent Liquids: From Microscopic to Macroscopic Scales. AB - In spite of considerable research on the nature of aqueous alcohol mixtures that are characterized by microscopic inhomogeneity or incomplete mixing at the molecular level, transport properties have received little attention. We report the results of a study on diffusion in the ternary mixture of water with two alcohols, that is, water + methanol + ethanol, which is investigated on microscopic and macroscopic scales by means of molecular simulation and Taylor dispersion experiments. A novel protocol is developed for the comparison of mutual diffusion coefficients sampled by two fundamentally different approaches, which allows for their critical analysis. Because of complex intermolecular interactions, given by the presence of hydrogen bonding, the analysis of transport processes in this mixture is challenging for not only on the microscopic scale for simulation techniques but also on the macroscopic scale due to unfavorable optical properties. Binary limits of the Fick diffusion matrix are used for validation of the experimental ternary mixture results together with the verification of the validity of the phenomenological Onsager reciprocal relations. The Maxwell-Stefan diffusion coefficients and the thermodynamic factor are sampled by molecular simulation consistently on the basis of given force field models. The protocol for the comparison of the results from both approaches is also challenging because Fick diffusion coefficients of ternary mixtures depend on the frame of reference. Accordingly, the measured coefficients are transformed from the volume-averaged to the molar-averaged frame of reference, and it is demonstrated that both approaches provide not only similar qualitative behavior along two concentration paths but also strong quantitative agreement. This coordinated work using different approaches to study diffusion in multicomponent mixtures is expected to be a significant step forward for the accurate assessment of cross-diffusion. PMID- 27933945 TI - Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2). AB - Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile. PMID- 27933946 TI - Measurement of Ligand-Target Residence Times by 1H Relaxation Dispersion NMR Spectroscopy. AB - A ligand-observed 1H NMR relaxation experiment is introduced for measuring the binding kinetics of low-molecular-weight compounds to their biomolecular targets. We show that this approach, which does not require any isotope labeling, is applicable to ligand-target systems involving proteins and nucleic acids of variable molecular size. The experiment is particularly useful for the systematic investigation of low affinity molecules with residence times in the micro- to millisecond time regime. PMID- 27933947 TI - In Silico Discovery and Validation of Amide Based Small Molecule Targeting the Enzymatic Site of Shiga Toxin. AB - Shiga toxin (Stx), a category B biothreat agent, is a ribosome inactivating protein and toxic to human and animals. Here, we designed and synthesized small molecules that block the active site of the Stx A subunit. On the basis of binding energy, 20 molecules were selected for synthesis and evaluation. These molecules were primarily screened using fluorescence-based thermal shift assay and in vitro in Vero cells. Among 32 molecules (including 12 reported), six molecules offered protection with IC50 of 2.60-23.90 MUM. 4-Nitro-N-[2-(2 phenylsulfanylethylamino)ethyl]benzamide hydrochloride is the most potent inhibitor with IC50 at 7.96 MUM and selectivity index of 22.23 and is better than any known small molecule inhibitor of Stx. Preincubation with Stx offered full protection against Shiga toxin in mice. Surface plasmon resonance assay further confirmed that these molecules bind specifically to Stx A subunit. Further optimization is continued to identify a potential candidate which will be in vivo effective. PMID- 27933948 TI - Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease. AB - Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Abeta levels in rats and nonhuman primates and CSF Abeta levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization. PMID- 27933949 TI - Sulfonamide-Based Inhibitors of Aminoglycoside Acetyltransferase Eis Abolish Resistance to Kanamycin in Mycobacterium tuberculosis. AB - A two-drug combination therapy where one drug targets an offending cell and the other targets a resistance mechanism to the first drug is a time-tested, yet underexploited approach to combat or prevent drug resistance. By high-throughput screening, we identified a sulfonamide scaffold that served as a pharmacophore to generate inhibitors of Mycobacterium tuberculosis acetyltransferase Eis, whose upregulation causes resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN) in Mycobacterium tuberculosis. Rational systematic derivatization of this scaffold to maximize Eis inhibition and abolish the Eis-mediated KAN resistance of M. tuberculosis yielded several highly potent agents. A crystal structure of Eis in complex with one of the most potent inhibitors revealed that the inhibitor bound Eis in the AG-binding pocket held by a conformationally malleable region of Eis (residues 28-37) bearing key hydrophobic residues. These Eis inhibitors are promising leads for preclinical development of innovative AG combination therapies against resistant TB. PMID- 27933950 TI - Structure-Activity Relationship, Drug Metabolism and Pharmacokinetics Properties Optimization, and in Vivo Studies of New Brain Penetrant Triple T-Type Calcium Channel Blockers. AB - Despite the availability of numerous antiepileptic drugs, 20-30% of epileptic patients are pharmacoresistant with seizures not appropriately controlled. Consequently, new strategies to address this unmet medical need are required. T type calcium channels play a key role in neuronal excitability and burst firing, and selective triple T-type calcium channel blockers could offer a new way to treat various CNS disorders, in particular epilepsy. Herein we describe the identification of new 1,4-benzodiazepines as brain penetrant and selective triple T-type calcium channel blockers. From racemic hit 4, optimization work led to the preparation of pyridodiazepine 31c with improved physicochemical properties, solubility, and metabolic stability. The racemic mixture was separated by chiral preparative HPLC, and the resulting lead compound (3R,5S)-31c showed promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive absence-like epilepsy. PMID- 27933951 TI - Identification of the Binding Site of Chroman-4-one-Based Sirtuin 2-Selective Inhibitors using Photoaffinity Labeling in Combination with Tandem Mass Spectrometry. AB - Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4 one-based SIRT2-selective inhibitors. The photoactive diazirine 4, a potent SIRT2 inhibitor, was subjected to detailed photochemical characterization. In PAL experiments with SIRT2, a tryptic peptide originating from the covalent attachment of photoactivated 4 was identified. The peptide covers both the active site of SIRT2 and the proposed binding site of chroman-4-one-based inhibitors. A high-power LED was used as source for the monochromatic UV light enabling rapid photoactivation. PMID- 27933952 TI - End-Site-Specific Conjugation of Enoxaparin and Tetradeoxycholic Acid Using Nonenzymatic Glycosylation for Oral Delivery. AB - Heparin and low molecular weight heparins (LMWHs) have been the drug of choice for the treatment or the prevention of thromboembolic disease. Different methods are employed to prepare the LMWHs that are clinically approved for the market currently. In particular, enoxaparin, which has a reducing sugar moiety at the end-site of polysaccharide, is prepared by alkaline depolymerization. Focusing on this end-site-specific activity of LMWHs, we conjugated the tetraoligomer of deoxycholic acid (TetraDOCA; TD) at the end-site of enoxaparin via nonenzymatic glycosylation reaction. The end-site-specific conjugation is important for polysaccharide drug development because of the heterogeneity of polysaccharides. This study also showed that orally active enoxaparin and tetraDOCA conjugate (EnoxaTD) had therapeutic effect on deep vein thrombosis (DVT) without bleeding in animal models. Considering the importance of end-specific conjugation, these results suggest that EnoxaTD could be a drug candidate for oral heparin development. PMID- 27933954 TI - Discovery of [5-Amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2 yl)methanone (CH5183284/Debio 1347), An Orally Available and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor. AB - The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases regulates multiple biological processes, such as cell proliferation, migration, apoptosis, and differentiation. Various genetic alterations that drive activation of the receptors and the pathway are associated with tumor growth and survival; therefore, the FGFR family represents an attractive therapeutic target for treating cancer. Here, we report the discovery and the pharmacological profiles of 8 (CH5183284/Debio 1347), an orally available and selective inhibitor of FGFR1, FGFR2, and FGFR3. The chemical modifications, which were guided by 3D modeling analyses of the inhibitor and FGFRs, led to identifying an inhibitor that is selective to FGFR1, FGFR2, and FGFR3. In in vitro studies and xenograft models in mice, 8 shows antitumor activity against cancer cell lines that harbor genetically altered FGFRs. These results support the potential therapeutic use of 8 as a new anticancer agent. PMID- 27933953 TI - Synthesis and Characterization of a Novel gamma-Aminobutyric Acid Type A (GABAA) Receptor Ligand That Combines Outstanding Metabolic Stability, Pharmacokinetics, and Anxiolytic Efficacy. AB - 1,4-Benzodiazepines are used in the treatment of anxiety disorders but have limited long-term use due to adverse effects. HZ-166 (2) has been shown to have anxiolytic-like effects with reduced sedative/ataxic liabilities. A 1,3-oxazole KRM-II-81 (9) was discovered from a series of six bioisosteres with significantly improved pharmacokinetic and pharmacodynamic properties as compared to 2. Oxazole 9 was further characterized and exhibited improved anxiolytic-like effects in a mouse marble burying assay and a rat Vogel conflict test. PMID- 27933956 TI - Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound Ligands. AB - A previously studied congeneric series of thermolysin inhibitors addressing the solvent-accessible S2' pocket with different hydrophobic substituents showed modulations of the surface water layers coating the protein-bound inhibitors. Increasing stabilization of water molecules resulted in an enthalpically more favorable binding signature, overall enhancing affinity. Based on this observation, we optimized the series by designing tailored P2' substituents to improve and further stabilize the surface water network. MD simulations were applied to predict the putative water pattern around the bound ligands. Subsequently, the inhibitors were synthesized and characterized by high resolution crystallography, microcalorimetry, and surface plasmon resonance. One of the designed inhibitors established the most pronounced water network of all inhibitors tested so far, composed of several fused water polygons, and showed 50 fold affinity enhancement with respect to the original methylated parent ligand. Notably, the inhibitor forming the most perfect water network also showed significantly prolonged residence time compared to the other tested inhibitors. PMID- 27933955 TI - Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure-Activity Relationships. AB - Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer. PMID- 27933957 TI - Synthesis and Antiviral Evaluation of Octadecyloxyethyl Benzyl 9-[(2 Phosphonomethoxy)ethyl]guanine (ODE-Bn-PMEG), a Potent Inhibitor of Transient HPV DNA Amplification. AB - Human papillomavirus (HPV) high-risk genotypes such as HPV-16 and HPV-18 cause the majority of anogenital tract carcinomas, including cervical cancer, the second most common malignancy in women worldwide. Currently there are no approved antiviral agents that reduce or eliminate HPV and reverse virus-associated pathology. We synthesized and evaluated several alkoxyalkyl acyclic nucleoside phosphonate diesters and identified octadecyloxyethyl benzyl 9-[(2 phosphonomethoxy)ethyl]guanine (ODE-Bn-PMEG) as an active compound which strongly inhibited transient amplification of HPV-11, -16, and -18 origin-containing plasmid DNA in transfected cells at concentrations well below its cytotoxic concentrations. ODE-Bn-PMEG demonstrated increased uptake in human foreskin fibroblast cells and was readily converted in vitro to the active antiviral metabolite, PMEG diphosphate. The P-chiral enantiomers of ODE-Bn-PMEG were obtained and appeared to have equivalent antiviral activities against HPV. ODE-Bn PMEG is a promising candidate for the local treatment of HPV-16 and HPV-18 and other high-risk types, an important unmet medical need. PMID- 27933958 TI - 18F-Labeled Benzyldiamine Derivatives as Novel Flexible Probes for Positron Emission Tomography of Cerebral beta-Amyloid Plaques. AB - Early noninvasive visualization of cerebral beta-amyloid (Abeta) plaques with positron emission tomography (PET) is the most feasible way to diagnose Alzheimer's disease (AD). In this study, a series of flexible benzyldiamine derivatives (BDA) were proposed for binding to aggregated beta-amyloid 1-42 (Abeta1-42) with high adaptability, high binding affinity (6.8 +/- 0.6 nM), and rapid body excretion. The methylthio (12) and ethoxyl (10) derivatives were further labeled with 18F directly on their benzene ring and examined as PET probes for Abeta plaque imaging. [18F]12 displayed 4.87 +/- 0.52% ID/g initial uptake and prompt washout from normal brain in biodistribution studies. MicroPET CT imaging indicated sufficient retention of [18F]12 but lower white matter uptake in the brain of an AD transgenic mouse model compared with that of commercial [18F]AV-45. Our experimental results provide new insights for developing targeting ligands possessing a flexible framework for use as efficient Abeta probes for PET imaging of AD brain. PMID- 27933959 TI - Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90. AB - Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation. PMID- 27933961 TI - Substituent Effects on Drug-Receptor H-bond Interactions: Correlations Useful for the Design of Kinase Inhibitors. AB - Investigation of troponin I-interacting kinase (TNNI3K) as a potential target for the treatment of heart failure has produced a series of substituted N-methyl-3 (pyrimidin-4-ylamino)benzenesulfonamide inhibitors that display excellent potency and selectivity against a broad spectrum of protein kinases. Crystal structures of prototypical members bound to the ATP-binding site of TNNI3K reveal two anchoring hydrogen bond contacts: (1) from the hinge region amide N-H to the pyrimidine nitrogen and (2) from the sulfonamide N-H to the gatekeeper threonine. Evaluation of various para-substituted benzenesulfonamides defined a substituent effect on binding affinity resulting from modulation of the sulfonamide H-bond donor strength. An opposite electronic effect emerged for the hinge NH-pyrimidine H-bond interaction, which is further illuminated in the correlation of calculated H-bond acceptor strength and TNNI3K affinity for a variety of hinge binding heterocycles. These fundamental correlations on drug-receptor H-bond interactions may be generally useful tools for the optimization of potency and selectivity in the design of kinase inhibitors. PMID- 27933960 TI - Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors. AB - The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl rings, and/or functionalizing the terminal nitrogen with substituted piperazines, resulting in several novel leads such as 11b, which demonstrated high DAT affinity (Ki = 2.5 nM) and selectivity without producing concomitant locomotor stimulation in mice, as compared to cocaine. These results are consistent with an atypical DAT inhibitor profile and suggest that 11b may be a potential lead for development as a psychostimulant abuse medication. PMID- 27933962 TI - Design, Synthesis, and Pharmacological Characterization of 2-(2 Furanyl)thiazolo[5,4-d]pyrimidine-5,7-diamine Derivatives: New Highly Potent A2A Adenosine Receptor Inverse Agonists with Antinociceptive Activity. AB - In this study, we describe the design and synthesis of new N5-substituted-2-(2 furanyl) thiazolo[5,4-d]pyrimidine-5,7-diamines (2-18) and their pharmacological characterization as A2A adenosine receptor (AR) antagonists by using in vitro and in vivo assays. In competition binding experiments two derivatives (13 and 14) emerged as outstanding ligands showing two different affinity values (KH and KL) for the hA2A receptor with the high affinity KH value in the femtomolar range. The in vitro functional activity assays, performed by using cyclic AMP experiments, assessed that they behave as potent inverse agonists at the hA2A AR. Compounds 13 and 14 were evaluated for their antinociceptive activity in acute experimental models of pain showing an effect equal to or greater than that of morphine. Overall, these novel inverse agonists might represent potential drug candidates for an alternative approach to the management of pain. PMID- 27933963 TI - Benzenesulfonamides Incorporating Flexible Triazole Moieties Are Highly Effective Carbonic Anhydrase Inhibitors: Synthesis and Kinetic, Crystallographic, Computational, and Intraocular Pressure Lowering Investigations. AB - Herein we report the synthesis of two series of benzenesulfonamide containing compounds that incorporate the phenyl-1,2,3-triazole moieties. We explored the insertion of appropriate linkers, such as ether, thioether, and amino type, into the inner section of the molecules with the intent to confer additional flexibility. All obtained compounds were screened in vitro as inhibitors of the physiologically relevant human (h) isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Many of them were low nanomolar or subnanomolar hCA II, IX, and XII inhibitors, whereas they did not potently inhibit hCA I. Computational and X-ray crystallographic studies of the enzyme-inhibitor adducts helped us to rationalize the obtained results. Some of the sulfonamides reported here showed significant intraocular pressure lowering activity in an animal model of glaucoma. PMID- 27933964 TI - Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978). AB - The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand-androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimization of antischistosomal hydantoins. PMID- 27933966 TI - Hydrogen Oxidation-Mediated Current Discharge in Mesoporous Pt/TiO2 Nanocomposite. AB - Here we report on direct evidence of a correlation between hydrogen-to-water oxidation on mesoporous Pt/TiO2 nanocomposites at room temperature and the conversion of surface-released chemical energy into a stationary electrical current. The Pt phase of this heterojunction device is an electrically continuous 15 nm thick mesh deposited onto a mesoporous TiO2 substrate fabricated with a plasma electrolytic oxidation process. The H2O turnover frequency approaches an asymptotic value associated with the saturation of the Pt/TiO2 interface as the concentration of hydrogen gas is increased. In situ measurements of the reaction induced current concurrently with mass spectrometry measurements illuminate the polarity switch of the reaction current (from thermionic emission to a reverse steady-state flow) simultaneously with the production of water. Furthermore, a concentration-dependent value of 5 min is measured as the time constant for the adsorption of the initial addition of H2 and H2O formation and desorption. PMID- 27933965 TI - First Structure-Activity Relationship of 17beta-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme. AB - 17beta-HSD14 belongs to the SDR family and oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD+ as cofactor. The goal of this study was to identify and optimize 17beta-HSD14 nonsteroidal inhibitors as well as to disclose their structure-activity relationship. In a first screen, a library of 17beta-HSD1 and 17beta-HSD2 inhibitors, selected with respect to scaffold diversity, was tested for 17beta-HSD14 inhibition. The most interesting hit was taken as starting point for chemical modification applying a ligand-based approach. The designed compounds were synthesized and tested for 17beta-HSD14 inhibitory activity. The two best inhibitors identified in this study have a very high affinity to the enzyme with a Ki equal to 7 nM. The strong affinity of these inhibitors to the enzyme active site could be explained by crystallographic structure analysis, which highlighted the role of an extended H-bonding network in the stabilization process. The selectivity of the most potent compounds with respect to 17beta-HSD1 and 17beta-HSD2 is also addressed. PMID- 27933967 TI - Ionic Liquids as the MOFs/Polymer Interfacial Binder for Efficient Membrane Separation. AB - Obtaining strong interfacial affinity between filler and polymer is critical to the preparation of mixed matrix membranes (MMMs) with high separation efficiency. However, it is still a challenge for micron-sized metal organic frameworks (MOFs) to achieve excellent compatibility and defect-free interface with polymer matrix. Thin layer of ionic liquid (IL) was immobilized on micron-sized HKUST-1 to eliminate the interfacial nonselective voids in MMMs with minimized free ionic liquid (IL) in polymer matrix, and then the obtained IL decorated HKUST-1 was incorporated into 4,4'-(hexafluoroisopropylidene)diphthalic anhydride-2,3,5,6 tetramethyl-1,3-phenyldiamine (6FDA-Durene) to fabricate MMMs. Acting as a filler/polymer interfacial binder, the favorable MOF/IL and IL/polymer interaction can facilitate the enhancement of MOF/polymer affinity. Compared to MMM with only HKUST-1 incorporation, MMM with IL decorated HKUST-1 succeeded in restricting the formation of nonselective interfacial voids, leading to an increment in CO2 selectivity. The IL decoration method can be an effective approach to eliminate interfacial voids in MMMs, extending the filler selection to a wide range of large-sized fillers. PMID- 27933968 TI - Emissive H-Aggregates of an Ultrafast Molecular Rotor: A Promising Platform for Sensing Heparin. AB - Constructing "turn on" fluorescent probes for heparin, a most widely used anticoagulant in clinics, from commercially available materials is of great importance, but remains challenging. Here, we report the formation of a rarely observed emissive H-aggregate of an ultrafast molecular rotor dye, Thioflavin-T, in the presence of heparin, which provides an excellent platform for simple, economic and rapid fluorescence turn-on sensing of heparin. Generally, H aggregates are considered as serious problem in the field of biomolecular sensing, owing to their poorly emissive nature resulting from excitonic interaction. To the best of our knowledge, this is the first report, where contrastingly, the turn-on emission from the H-aggregates has been utilized in the biomolecule sensing scheme, and enables a very efficient and selective detection of a vital biomolecule and a drug with its extensive medical applications, i.e., heparin. Our sensor system offers several advantages including, emission in the biologically advantageous red-region, dual sensing, i.e., both by fluorimetry and colorimetry, and most importantly constructed from in-expensive commercially available dye molecule, which is expected to impart a large impact on the sensing field of heparin. Our system displays good performance in complex biological media of serum samples. The novel Thioflavin-T aggregate emission could be also used to probe the interaction of heparin with its only clinically approved antidote, Protamine. PMID- 27933969 TI - Laser-Scanned Programmable Color Temperature of Electroluminescence from White Light-Emitting Electrochemical Cells. AB - Recently, the control of correlated color temperature (CCT) of artificial solid state white-light sources starts to attract more attention since CTs affect human physiology and health profoundly. In this work, we proposed and demonstrated a method that can widely tune the CCTs of electroluminescence (EL) from white-light emitting electrochemical cells (LECs) by employing plasmonic filters. These integrated on-chip plasmonic filters are composed of semicontinuous thin Ag film or Ag nanoparticles (NPs) both included in the indium tin oxide anode contact, which have different characteristics of plasmonic resonant absorptions that can tune the EL spectra of white LECs. The CCTs of EL from white LECs integrated with semicontinuous thin Ag film and randomly distributed Ag NPs are 5778 and 2350 K, respectively. A commercially available laser scanning system was used to locally thermal anneal the semicontinuous thin Ag film to form the randomly distributed Ag NPs on the scanned areas. Hence, these two kinds of filters can be integrated on the same chip of white LEC, giving more freedom to control the CCTs of white EL and more potential applications. In addition, the laser scanning system used here is quite often used in display manufactures so that our proposed method can be immediately adopted by the light-emitting diode industry. PMID- 27933970 TI - Real-Time X-ray Imaging Reveals Interfacial Growth, Suppression, and Dissolution of Zinc Dendrites Dependent on Anions of Ionic Liquid Additives for Rechargeable Battery Applications. AB - The dynamic interfacial growth, suppression, and dissolution of zinc dendrites have been studied with the imidazolium ionic liquids (ILs) as additives on the basis of in situ synchrotron radiation X-ray imaging. The phase contrast difference of real-time images indicates that zinc dendrites are preferentially developed on the substrate surface in the ammoniacal electrolytes. After adding imidazolium ILs, both nucleation overpotential and polarization extent increase in the order of additive-free < EMI-Cl < EMI-PF6 < EMI-TFSA < EMI-DCA. The real time X-ray images show that the EMI-Cl can suppress zinc dendrites, but result in the formation of the loose deposits. The EMI-PF6 and EMI-TFSA additives can smooth the deposit morphology through suppressing the initiation and growth of dendritic zinc. The addition of EMI-DCA increases the number of dendrite initiation sites, whereas it decreases the growth rate of dendrites. Furthermore, the dissolution behaviors of zinc deposits are compared. The zinc dendrites show a slow dissolution process in the additive-free electrolyte, whereas zinc deposits are easily detached from the substrate in the presence of EMI-Cl, EMI PF6, or EMI-TFSA due to the formation of the loose structure. Hence, the dependence of zinc dendrites on anions of imidazolium IL additives during both electrodeposition and dissolution processes has been elucidated. These results could provide the valuable information in perfecting the performance of zinc based rechargeable batteries. PMID- 27933971 TI - Microwave Exfoliation of Graphite Oxides in H2S Plasma for the Synthesis of Sulfur-Doped Graphenes as Oxygen Reduction Catalysts. AB - Tuning the electronic and chemical properties of graphene can be carried out through heteroatomic doping, enabling its use as an electrocatalyst. Sulfur-doped graphene has been suggested to be a viable alternative to traditional Pt-based catalysts for oxygen reduction under alkaline conditions. Herein we present a fast and efficient route to synthesize S-doped graphenes through the microwave assisted exfoliation and reduction of three different graphite oxides in the presence of hydrogen sulfide. The materials obtained were characterized using scanning electron microscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, combustion elemental analysis, and voltammetry. These S-doped graphenes were found to have good electrochemical performance and were active in the catalysis of the oxygen reduction reaction. PMID- 27933972 TI - Lactoferrin-Immobilized Surfaces onto Functionalized PLA Assisted by the Gamma Rays and Nitrogen Plasma to Create Materials with Multifunctional Properties. AB - Both cold nitrogen radiofrequency plasma and gamma irradiation have been applied to activate and functionalize the polylactic acid (PLA) surface and the subsequent lactoferrin immobilization. Modified films were comparatively characterized with respect to the procedure of activation and also with unmodified sample by water contact angle measurements, mass loss, X-ray photoelectron spectroscopy (XPS), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), atomic force microscopy (AFM), and chemiluminescence measurements. All modified samples exhibit enhanced surface properties mainly those concerning biocompatibility, antimicrobial, and antioxidant properties, and furthermore, they are biodegradable and environmentally friendly. Lactoferrin deposited layer by covalent coupling using carbodiimide chemistry showed a good stability. It was found that the lactoferrin modified PLA materials present significantly increased oxidative stability. Gamma irradiated samples and lactoferrin-functionalized samples show higher antioxidant, antimicrobial, and cell proliferation activity than plasma-activated and lactoferrin-functionalized ones. The multifunctional materials thus obtained could find application as biomaterials or as bioactive packaging films. PMID- 27933973 TI - 3D-Array of Au-TiO2 Yolk-Shell as Plasmonic Photocatalyst Boosting Multi Scattering with Enhanced Hydrogen Evolution. AB - Nowadays, how to convert solar energy efficiently to other energies, such as chemical energy, is an important subject. In the present work, gold nanosphere (AuNS) monoencapsulated in TiO2 hollow nanosphere (Au-TiO2) and three-dimensional assembled array of Au-TiO2 (3D-array) were fabricated to carefully explore the multiscattering effect on the photocatalytic activity of H2 generation under simulated solar light and visible light irradiation, respectively. Au-TiO2 with the inner cavity diameter of 176 nm was uniformly synthesized via SiO2 protection method and then was used as building blocks for construction of 3D-array. The 3D array exhibited a much higher photocatalytic activity of H2 generation (3.5 folds under visible light irradiation, 1.4 folds under solar light irradiation) than Au TiO2. Single-particle plasmonic photoluminescence measurement and computational simulation of finite difference time domain (FDTD) were performed to elucidate the detailed mechanisms of photocatalysis. It was suggested that the hot electrons generated by AuNS under visible light irradiation play a significant role during the photocatalysis process. The higher activity of 3D-array is due to the elongation of light path length because of the multiscattering in-between Au TiO2 and the reflection inside of the TiO2 shell. Therefore, the AuNS has more opportunity to absorb light and more hot electrons are expected to be generated through the electron transfer from AuNS to TiO2 shell, leading to an increment in the H2 generation. This result gives us a new perspective of constructing structures for efficient light utilization. PMID- 27933974 TI - High-Work-Function Molybdenum Oxide Hole Extraction Contacts in Hybrid Organic Inorganic Perovskite Solar Cells. AB - We investigate the effect of high work function contacts in halide perovskite absorber-based photovoltaic devices. Photoemission spectroscopy measurements reveal that band bending is induced in the absorber by the deposition of the high work function molybdenum trioxide (MoO3). We find that direct contact between MoO3 and the perovskite leads to a chemical reaction, which diminishes device functionality. Introducing an ultrathin spiro-MeOTAD buffer layer prevents the reaction, yet the altered evolution of the energy levels in the methylammonium lead iodide (MAPbI3) layer at the interface still negatively impacts device performance. PMID- 27933976 TI - New rht-Type Metal-Organic Frameworks Decorated with Acylamide Groups for Efficient Carbon Dioxide Capture and Chemical Fixation from Raw Power Plant Flue Gas. AB - The combination of carbon dioxide capture and chemical fixation in a one-pot process is attractive for both chemists and governments. The cycloaddition of carbon dioxide with epoxides to produce cyclic carbonates is an atomic economical reaction without any side products. By incorporating acylamide to enhance the binding affinity toward CO2, new rht-type metal-organic frameworks (MOFs) with (3, 28) and (3, 24) connected units were constructed. Zn-NTTA with two types of dinuclear paddlewheel building blocks-{Zn2(OOC-)4} and {Zn2(OOC-)3}. The high uptake of CO2 (115.6 cm3.g-1) and selectivity over N2 (30:1) at 273 K indicated that these MOFs are excellent candidates for postcombustion CO2 isolation and capture. The MOFs feature high catalytic activity, rapid dynamics of transformation and excellent stability with turnover number (TON) values up to 110 000 per paddlewheel unit after 5 * 6 rounds of recyclability, demonstrating that they are promising heterogeneous catalysts for CO2 cyclo-addition to value added cyclic carbonates. The cycloaddition of epoxides with wet gases demonstrated that the catalyst activity was not affected by moisture, and the indices of the PXRD patterns of the bulk samples filtered from the catalytic reaction revealed that the crystallinities were maintained. The combination of the selective capture and catalytic transformation in one-pot enables the use of a negative-cost feedstock-raw power plant flue gas without any separation and purification-revealing the broad prospects of such MOFs for practical CO2 fixation in industry. PMID- 27933975 TI - High Antibacterial Activity of Functionalized Chemically Exfoliated MoS2. AB - In view of the implications of inherent resistance of pathogenic bacteria, especially ESKAPE pathogens toward most of the commercially available antibiotics and the importance of these bacteria-induced biofilm formation leading to chronic infection, it is important to develop new-generation synthetic materials with greater efficacy toward antibacterial property. In addressing this issue, this paper reports a proof-of-principle study to evaluate the potential of functionalized two-dimensional chemically exfoliated MoS2 (ce-MoS2) toward inhibitory and bactericidal property against two representative ESKAPE pathogenic strain-a Gram-positive Staphylococcus aureus (MRSA) and a Gram-negative Pseudomonas aeruginosa. More significantly, the mechanistic study establishes a different extent of oxidative stress together with rapid membrane depolarization in contact with ce-MoS2 having ligands of varied charge and hydrophobicity. The implication of our results is discussed in the light of the lack of survivability of planktonic bacteria and biofilm destruction in vitro. A comparison with widely used small molecules and other nanomaterial-based therapeutics conclusively establishes a better efficacy of 2D ce-MoS2 as a new class of antibiotics. PMID- 27933977 TI - Enhanced Ultraviolet Random Lasing from Au/MgO/ZnO Heterostructure by Introducing p-Cu2O Hole-Injection Layer. AB - Ultraviolet light-emitting devices (LEDs) were fabricated on the basis of Au/MgO/ZnO metal/insulator/semiconductor (MIS) heterostructures. By introducing a thermally oxidized p-type Cu2O hole-injection layer into this MIS structure, enhanced ultraviolet electroluminescence (EL) and random lasing with reduced threshold injection current are achieved. The enhancement mechanism is attributed to effective hole transfer from p-Cu2O to i-MgO under forward bias, which increases the initial carrier concentration of MgO dielectric layer and further promotes "impact-ionization" effect induced carrier generation and injection. The current study proposes a new and effective route to improve the EL performance of MIS junction LEDs via introducing extrinsic hole suppliers. PMID- 27933978 TI - Strong and Stiff: High-Performance Cellulose Nanocrystal/Poly(vinyl alcohol) Composite Fibers. AB - The mechanical properties of rodlike cellulose nanocrystals (CNCs) suggest great potential as bioderived reinforcement in (nano)composites. Poly(vinyl alcohol) (PVOH) is a useful industrial material and very compatible with CNC chemistry. High performance CNC/PVOH composite fibers were produced coaxial coagulation spinning, followed by hot-drawing. We showed that CNCs increase the alignment and crystallinity of PVOH, as well as providing direct reinforcement, leading to enhanced fiber strength and stiffness. At 40 wt % CNC loading, the strength and stiffness reached 880 MPa and 29.9 GPa, exceeding the properties of most other nanocellulose based composite fibers previously reported. PMID- 27933979 TI - Dual Core-Shell Structured Si@SiOx@C Nanocomposite Synthesized via a One-Step Pyrolysis Method as a Highly Stable Anode Material for Lithium-Ion Batteries. AB - Silicon (Si) has been regarded as a promising high-capacity anode material for developing advanced lithium-ion batteries (LIBs), but the practical application of Si anodes is still unsuccessful mainly due to the insufficient cyclability. To deal with this issue, we propose a new route to construct a dual core-shell structured Si@SiOx@C nanocomposite by direct pyrolysis of poly(methyl methacrylate) (PMMA) polymer on the surface of Si nanoparticles. Since the PMMA polymers can be chemically bonded on the nano-Si surface through the interaction between ester group and Si surface group, and thermally decomposed in the subsequent pyrolysis process with their alkyl chains converted to carbon and the residue oxygen recombining with Si to form SiOx, the dual core-shell structure can be conveniently formed in a one-step procedure. Benefiting from the strong buffering effect of the SiOx interlayer and the efficient blocking action of dense outer carbon layer in preventing electrolyte permeation, the obtained nanocomposite demonstrates a high capacity of 1972 mA h g-1, a stable cycling performance with a capacity retention of >1030 mA h g-1 over 500 cycles, and particularly a superiorly high Coulombic efficiency of >99.5% upon extended cycling, exhibiting a great promise for practical uses. More importantly, the synthetic method proposed in this work is facile and low cost, making it more suitable for large-scale production of high capacity anode for advanced LIBs. PMID- 27933980 TI - Nanoceria-Mediated Drug Delivery for Targeted Photodynamic Therapy on Drug Resistant Breast Cancer. AB - Photodynamic therapy (PDT) has shown great potential for overcoming drug resistant cancers. Here, we report a multifunctional drug delivery system based on chlorin e6 (Ce6)/folic acid (FA)-loaded branched polyethylenimine-PEGylation ceria nanoparticles (PPCNPs-Ce6/FA), which was developed for targeted PDT to overcome drug-resistant breast cancers. Nanocarrier delivery and FA targeting significantly promoted the cellular uptake of photosensitizers (PSs), followed by their accumulation in lysosomes. PPCNPs-Ce6/FA generated reactive oxygen species (ROS) after near-infrared irradiation (NIR, 660 nm), leading to reduced P glycoprotein (P-gp) expression, lysosomal membrane permeabilization (LMP), and excellent phototoxicity toward resistant MCF-7/ADR cells, even at ultralow doses. Moreover, we identified NIR-triggered lysosomal-PDT using the higher dose of PPCNPs-Ce6/FA, which stimulated cell death by plasma membrane blebbing, cell swelling, and energy depletion, indicating an oncosis-like cell death pathway, despite the occurrence of apoptotic or autophagic mechanisms at lower drug doses. In vivo studies showed prolonged blood circulation times, low toxicity in mice, and high tumor accumulation of PPCNPs-Ce6/FA. In addition, using NIR-triggered PDT, PPCNPs-Ce6/FA displayed excellent potency for tumor regression in the MCF 7/ADR xenograft murine model. This study suggested that multifunctional PPCNPs Ce6/FA nanocomposites are a versatile and effective drug delivery system that may potentially be exploited for phototherapy to overcome drug-resistant cancers, and the mechanisms of cell death induced by PDT should be considered in the design of clinical protocols. PMID- 27933981 TI - Hydrolytic Glycosidic Bond Cleavage in RNA Nucleosides: Effects of the 2'-Hydroxy Group and Acid-Base Catalysis. AB - Despite the inherent stability of glycosidic linkages in nucleic acids that connect the nucleobases to sugar-phosphate backbones, cleavage of these bonds is often essential for organism survival. The current study uses DFT (B3LYP) to provide a fundamental understanding of the hydrolytic deglycosylation of the natural RNA nucleosides (A, C, G, and U), offers a comparison to DNA hydrolysis, and examines the effects of acid, base, or simultaneous acid-base catalysis on RNA deglycosylation. By initially examining HCOO-...H2O mediated deglycosylation, the barriers for RNA hydrolysis were determined to be 30-38 kJ mol-1 higher than the corresponding DNA barriers, indicating that the 2'-OH group stabilizes the glycosidic bond. Although the presence of HCOO- as the base (i.e., to activate the water nucleophile) reduces the barrier for uncatalyzed RNA hydrolysis (i.e., unactivated H2O nucleophile) by ~15-20 kJ mol-1, the extreme of base catalysis as modeled using a fully deprotonated water molecule (i.e., OH- nucleophile) decreases the uncatalyzed barriers by up to 65 kJ mol-1. Acid catalysis was subsequently examined by selectively protonating the hydrogen-bond acceptor sites of the RNA nucleobases, which results in an up to ~80 kJ mol-1 barrier reduction relative to the corresponding uncatalyzed pathway. Interestingly, the nucleobase proton acceptor sites that result in the greatest barrier reductions match sites typically targeted in enzyme-catalyzed reactions. Nevertheless, simultaneous acid and base catalysis is the most beneficial way to enhance the reactivity of the glycosidic bonds in RNA, with the individual effects of each catalytic approach being weakened, additive, or synergistic depending on the strength of the base (i.e., degree of water nucleophile activation), the nucleobase, and the hydrogen bonding acceptor site on the nucleobase. Together, the current contribution provides a greater understanding of the reactivity of the glycosidic bond in natural RNA nucleosides, and has fundamental implications for the function of RNA targeting enzymes. PMID- 27933983 TI - Diols, alpha-Ketols, and Diones as 22pi Components in [2+2+2] Cycloadditions of 1,6-Diynes via Ruthenium(0)-Catalyzed Transfer Hydrogenation. AB - The first use of vicinal diols, ketols, or diones as 22pi components in metal catalyzed [2+2+2] cycloaddition is described. Using ruthenium(0) catalysts, 1,6 diynes form ruthenacyclopentadienes that engage transient diones in successive carbonyl addition. Transfer hydrogenolysis of the resulting ruthenium(II) diolate mediated by the diol or ketol reactant releases the cycloadduct with regeneration of ruthenium(0) and the requisite dione. PMID- 27933982 TI - Metabolic Effects of Cobalt Ferrite Nanoparticles on Cervical Carcinoma Cells and Nontumorigenic Keratinocytes. AB - The cytotoxic response, cellular uptake, and metabolomic profile of HeLa and HaCaT cell lines treated with cobalt ferrite nanoparticles (CoFe2O4 NPs) were investigated in this study. Cell viability assays showed low cytotoxicity caused by the uptake of the nanoparticles at 2 mg/mL. However, metabolomics revealed that these nanoparticles impacted cell metabolism even when tested at a concentration that presented low cytotoxicity according to the cell viability assay. The two cell lines shared stress-related metabolic changes such as increase in alanine and creatine levels. A reduced level of fumarate was also observed in HeLa cells after treatment with the nanoparticles, and this alteration can inhibit tumorigenesis. Fumarate is considered to be an oncometabolite that can inhibit prolyl hydroxylase, and this inhibition stabilizes HIF1alpha, one of the master regulators of tumorigenesis that promotes tumor growth and development. In summary, this study showed that nanoparticle treated HeLa cells demonstrated decreased concentrations of metabolites associated with cell proliferation and tumor growth. The results clearly indicated that treatment with these nanoparticles might cause a perturbation in cellular metabolism. PMID- 27933984 TI - Statistical Thermodynamic Model for Surface Tension of Organic and Inorganic Aqueous Mixtures. AB - The surface composition and tensions of aqueous aerosols govern a set of processes that largely determine the fate of particles in the atmosphere. Predictive modeling of surface tension can provide significant contributions to studies of atmospheric aerosol effects on climate and human health. A previously derived surface tension model for single solute aqueous solutions used adsorption isotherms and statistical mechanics to enable surface tension predictions across the entire concentration range as a function of solute activity. Here, we extend the model derivation to address multicomponent solutions and demonstrate its accuracy with systems containing mixtures of electrolytes and organic solutes. Binary model parameters are applied to the multicomponent model, requiring no further parametrization for mixtures. Five ternary systems are studied here and represent three types of solute combinations: organic-organic (glycerol-ethanol), electrolyte-organic (NaCl-succinic acid, NaCl-glutaric acid), and electrolyte electrolyte (NaCl-KCl and NH4NO3-(NH4)2SO4). For the NaCl-glutaric acid system, experimental measurements of picoliter droplet surface tension using aerosol optical tweezers show excellent agreement with the model predictions. PMID- 27933985 TI - Discovery of Topsentin Alkaloids and Their Derivatives as Novel Antiviral and Anti-phytopathogenic Fungus Agents. AB - Topsentin alkaloids and their derivatives were designed, synthesized, and characterized on the basis of NMR and mass spectroscopy. The antiviral activities against tobacco mosaic virus (TMV) and anti-phytopathogenic fungus activities of these alkaloids were evaluated for the first time. Alkaloids 1c, 1e, 2b, and 2d displayed significantly higher antiviral activities against TMV than Ribavirin, emerging as new lead compounds for anti-TMV research. Further fungicidal activity tests against 14 kinds of phytopathogenic fungi revealed that these alkaloids displayed broad-spectrum fungicidal activities. Topsentin derivative 2d with 4-5 mg/kg EC50 values against Sclerotinia sclerotiorum (Lib.), Rhizoctonia solani (Kuhn), and Botrytis cinerea (Pers.) emerged as a new lead compound for fungicidal research. Current studies provide support for the application of topsentin alkaloids as novel agrochemicals. PMID- 27933986 TI - Red Cabbage Microgreens Lower Circulating Low-Density Lipoprotein (LDL), Liver Cholesterol, and Inflammatory Cytokines in Mice Fed a High-Fat Diet. AB - Cardiovascular disease (CVD) is the leading cause of death in the United States, and hypercholesterolemia is a major risk factor. Population studies, as well as animal and intervention studies, support the consumption of a variety of vegetables as a means to reduce CVD risk through modulation of hypercholesterolemia. Microgreens of a variety of vegetables and herbs have been reported to be more nutrient dense compared to their mature counterparts. However, little is known about the effectiveness of microgreens in affecting lipid and cholesterol levels. The present study used a rodent diet-induced obesity (DIO) model to address this question. C57BL/6NCr mice (n = 60, male, 5 weeks old) were randomly assigned to six feeding groups: (1) low-fat diet; (2) high-fat diet; (3) low-fat diet + 1.09% red cabbage microgreens; (4) low-fat diet + 1.66% mature red cabbage; (5) high-fat diet + 1.09% red cabbage microgreens; (6) high-fat diet + 1.66% mature red cabbage. The animals were on their respective diets for 8 weeks. We found microgreen supplementation attenuated high fat diet induced weight gain. Moreover, supplementation with microgreens significantly lowered circulating LDL levels in animals fed the high-fat diet and reduced hepatic cholesterol ester, triacylglycerol levels, and expression of inflammatory cytokines in the liver. These data suggest that microgreens can modulate weight gain and cholesterol metabolism and may protect against CVD by preventing hypercholesterolemia. PMID- 27933987 TI - Influence of Geographical Location of Orchards on Green Kiwifruit Bioactive Components. AB - Italy is one of the world's major kiwifruit producers and exporters with orchards located in different areas from the north to the south of the peninsula. This study sought to investigate for the first time the possible influence of the geographical location of kiwifruit orchards on some fruit components, selected because of their involvement in beneficial or negative effects on human health. The fruits harvested in 16 Italian areas were analyzed, and the results obtained show that the observed variations of the relative amounts of total proteins, kiwellin, the major allergen actinidin, ascorbate, polyphenols, and superoxide dismutase (SOD)-like activity seem not to be related to the geographical location of the orchards. In contrast, the high concentration of the nutraceutical peptide kissper seems to have some relationship with the cultivation area. In fact, its amount is much higher in the fruits from the Lazio region, thus providing added value to these kiwifruits. PMID- 27933988 TI - Niosomes Consisting of Tween-60 and Cholesterol Improve the Chemical Stability and Antioxidant Activity of (-)-Epigallocatechin Gallate under Intestinal Tract Conditions. AB - In order to improve the chemical stability and antioxidant activity of (-) epigallocatechin gallate (EGCG) in the gastrointestinal tract, niosomes composed of Tween-60 and cholesterol were developed to encapsulate EGCG in this investigation. EGCG loaded niosomes with encapsulation efficiency around 76% exhibited a small Z-average diameter about 60 nm. Compared to free EGCG, the EGCG remaining in dialysis tubes was significantly improved for niosomes at pH 2 and 7.4. Meanwhile, the residual EGCG for niosomes increased from 3% to 49% after 2 h incubation in simulated intestinal fluid (SIF). Pancreatin was found to impact the stability of niosomes in SIF mainly. Furthermore, the results from ferric reducing antioxidant power and cellular antioxidant activity tests indicated that EGCG loaded niosomes exhibited stronger antioxidant ability than free EGCG during intestinal digestion. Thus, we can infer that niosomal encapsulation might be a promising approach to improve the oral bioavailability of EGCG in the body. PMID- 27933989 TI - Old Apple (Malus domestica L. Borkh) Varieties with Hypoallergenic Properties: An Integrated Approach for Studying Apple Allergenicity. AB - Freshly consumed apples (Malus domestica L. Borkh) can cause allergic reactions because of the presence of four classes of allergens. Knowledge of the genetic factors affecting the allergenic potential of apples would provide important information for the selection of hypoallergenic genotypes, which can be combined with the adoption of new agronomical practices to produce fruits with a reduced amount of allergens. In the present research, a multiple analytical approach was adopted to characterize the allergenic potential of 24 apple varieties released at different ages (pre- and post-green revolution). A specific workflow was set up including protein quantification by means of polyclonal antibodies, immunological analyses with sera of allergic subjects, enzymatic assays, clinical assessments on allergic patients, and gene expression assays on fruit samples. Taken as a whole, the results indicate that most of the less allergenic genotypes were found among those deriving from selection processes carried out prior to the so-called "green revolution". PMID- 27933990 TI - Automated Enrichment of Sulfanilamide in Milk Matrices by Utilization of Aptamer Linked Magnetic Particles. AB - The present work demonstrates the first automated enrichment approach for antibiotics in milk using specific DNA aptamers. First, aptamers toward the antibiotic sulfanilamide were selected and characterized regarding their dissociation constants and specificity toward relevant antibiotics via fluorescence assay and LC-MS/MS detection. The performed enrichment was automated using the KingFisherDuo and compared to a manual approach. Verifying the functionality, trapping was realized in different milk matrices: (i) 0.3% fat milk, (ii) 1.5% fat milk, (iii) 3.5% fat milk, and (iv) 0.3% fat cocoa milk drink. Enrichment factors up to 8-fold could be achieved. Furthermore, it could be shown that novel implementation of a magnetic separator increases the reproducibility and reduces the hands-on time from approximately half a day to 30 min. PMID- 27933991 TI - Identification of Acyl Chain Oxidation Products upon Thermal Treatment of a Mixture of Phytosteryl/-stanyl Linoleates. AB - A mixture of phytosterols/-stanols, consisting of 75% beta-sitosterol, 12% sitostanol, 10% campesterol, 2% campestanol, and 1% others, was esterified with linoleic acid. The resulting mixture of phytosteryl/-stanyl linoleates was subjected to thermal oxidation at 180 degrees C for 40 min. A silica solid-phase extraction was applied to separate a fraction containing the nonoxidized linoleates and nonpolar degradation products (heptanoates, octanoates) from polar oxidation products (oxo- and hydroxyalkanoates). In total, 15 sitosteryl, sitostanyl, and campesteryl esters, resulting from oxidation of the acyl chain, could be identified by GC-FID/MS. Synthetic routes were described for authentic reference compounds of phytosteryl/-stanyl 7-hydroxyheptanoates, 8 hydroxyoctanoates, 7-oxoheptanoates, 8-oxooctanoates, and 9-oxononanoates, which were characterized by GC-MS and two-dimensional NMR spectroscopy. The study provides data on the formation and identities of previously unreported classes of acyl chain oxidation products upon thermal treatment of phytosteryl/-stanyl fatty acid esters. PMID- 27933992 TI - Hydrothermal Degradation of Rutin: Identification of Degradation Products and Kinetics Study. AB - The model glycoside compound quercetin-3-O-rutinoside (rutin) was subjected to subcritical water within the temperature range of 120-220 degrees C, and the hydrothermal degradation products were analyzed. Two kinetic models describing the degradation of this compound in two different atmospheres (N2 and CO2), used for pressure establishment in the reactor, have been developed and compared. Reaction was considered a successive one with three irreversible steps. We confirmed that rutin degradation to quercetin follows first-order kinetics. At higher temperatures quercetin is further degraded in two degradation steps. Formations of 3,4-dihydroxybenzoic acid and catechol were described with the zero order kinetic models. Reaction rate constants for hydrolysis of glycoside to aglycone in a CO2 atmosphere are higher compared to those in a N2 atmosphere, whereas at higher temperatures reaction rate constants for further two successive reactions of aglycone degradation are slightly lower in the presence of CO2. The difference in reaction activation energies is practically negligible for both gases. Furthermore, degradation products of sugar moieties, that is, 5 hydroxymethylfurfural and 5-methylfurfural, were also detected and analyzed. PMID- 27933993 TI - Food Fingerprinting: Metabolomic Approaches for Geographical Origin Discrimination of Hazelnuts (Corylus avellana) by UPLC-QTOF-MS. AB - Ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used for geographical origin discrimination of hazelnuts (Corylus avellana L.). Four different LC-MS methods for polar and nonpolar metabolites were evaluated with regard to best discrimination abilities. The most suitable method was used for analysis of 196 authentic samples from harvest years 2014 and 2015 (Germany, France, Italy, Turkey, Georgia), selecting and identifying 20 key metabolites with significant differences in abundancy (5 phosphatidylcholines, 3 phosphatidylethanolamines, 4 diacylglycerols, 7 triacylglycerols, and gamma-tocopherol). Classification models using soft independent modeling of class analogy (SIMCA), linear discriminant analysis based on principal component analysis (PCA-LDA), support vector machine classification (SVM), and a customized statistical model based on confidence intervals of selected metabolite levels were created, yielding 99.5% training accuracy at its best by combining SVM and SIMCA. Forty nonauthentic hazelnut samples were subsequently used to estimate as realistically as possible the prediction capacity of the models. PMID- 27933994 TI - Serum Metabolomics Analysis of Quercetin against Acrylamide-Induced Toxicity in Rats. AB - The current study aimed to investigate whether quercetin plays a protective role in acrylamide (AA)-induced toxicity using a metabolomics approach. Rats were randomly divided into groups as follows: control, treated with AA [5 mg/kg body weight (bw)], treated with different dosages of quercetin (10 and 50 mg/kg bw, respectively), and treated with two dosages of quercetin plus AA. After a 16 week treatment, rat serum was collected for metabolomics analysis. Biochemical tests and examination of liver histopathology were further conducted to verify metabolic alterations. Twelve metabolites were identified for which intensities were significantly changed (increased or reduced) as a result of the treatment. These metabolites included isorhamnetin, citric acid, pantothenic acid, isobutyryl-l-carnitine, eicosapentaenoic acid, docosahexaenoic acid, sphingosine 1-phosphate, lysoPC(20:4), lysoPC(22:6), lysoPE(20:3), undecanedioic acid, and dodecanedioic acid. The results indicate that quercetin (50 mg/kg bw) exerts partial protective effects on AA-induced toxicity by reducing oxidative stress, protecting the mitochondria, and regulating lipid metabolism. PMID- 27933995 TI - Effects of Stable Degradation Products of Curcumin on Cancer Cell Proliferation and Inflammation. AB - Curcumin is among the most promising dietary compounds for cancer prevention. However, curcumin rapidly degrades in aqueous buffer at physiological pH, making it difficult to understand whether the effects of curcumin are from curcumin itself or its degradation products. Here we studied the antiproliferative and anti-inflammatory effects of curcumin degradation products, including its total degradation products (a mixture containing all stable degradation products of curcumin) and bicyclopentadione (a dominant stable degradation compound of curcumin). Curcumin potently modulated cell proliferation, progression of cell cycle, and apoptosis in MC38 colon cancer cells and inhibited lipopolysaccharide (LPS)-induced inflammatory responses and NF-kappaB signaling in RAW 264.7 macrophage cells. In contrast, neither the total degradation products of curcumin nor bicyclopentadione had such effects. For example, after 24 h of treatment in MC38 colon cancer cells, 5 MUg/mL curcumin inhibited 39.2 +/- 1.8% of cell proliferation, whereas its degradation products were inactive. Together, these results suggest that the stable chemical degradation products of curcumin are not likely to play a major role in mediating the biological activities of curcumin. PMID- 27933996 TI - Functional Properties of Novel Epigallocatechin Gallate Glucosides Synthesized by Using Dextransucrase from Leuconostoc mesenteroides B-1299CB4. AB - Epigallocatechin gallate (EGCG) is the most abundant catechin found in the leaves of green tea, Camellia sinensis. In this study, novel epigallocatechin gallate glucocides (EGCG-Gs) were synthesized by using dextransucrase from Leuconostoc mesenteroides B-1299CB4. Response surface methodology was adopted to optimize the conversion of EGCG to EGCG-Gs, resulting in a 91.43% conversion rate of EGCG. Each EGCG-G was purified using a C18 column. Of nine EGCG-Gs identified by nuclear magnetic resonance analysis, five EGCG-Gs (2 and 4-7) were novel compounds with yields of 2.2-22.6%. The water solubility of the five novel compounds ranged from 229.7 to 1878.5 mM. The 5'-OH group of EGCG-Gs expressed higher antioxidant activities than the 4'-OH group of EGCG-Gs. Furthermore, glucosylation at 7-OH group of EGCG-Gs was found to be responsible for maintaining tyrosinase inhibitory activity and increasing browning-resistant activities. PMID- 27933997 TI - Pod Mildew on Soybeans Can Mitigate the Damage to the Seed Arising from Field Mold at Harvest Time. AB - Seedpods are the outermost barrier of legume plants encountered by pests and pathogens, but research on this tissue, especially regarding their chemical constituents, is limited. In the present study, a mildew-index-model-based cluster analysis was used to evaluate and identify groups of soybean genotypes with different organ-specific resistance against field mold. The constituents of soybean pods, including proteins, carbohydrates, fatty acids, and isoflavones, were analyzed. Linear regression and correlation analyses were also conducted between these main pod constituents and the organ-specific mildew indexes of seed (MIS) and pod (MIP). With increases in the contents of infection constituents, such as proteins, carbohydrates, and fatty acids, the MIP increased and the MIS decreased. The MIS decreased with increases in the contents of glycitein (GLE) type isoflavonoids, which act as antibiotic constituents. Although the infection constituents in the soybean pods caused pod mildew, they also helped mitigate the corresponding seed mildew to a certain extent. PMID- 27933998 TI - Metal-Semiconductor Heteronanocrystals with Desired Configurations for Plasmonic Photocatalysis. AB - Precise control over the topology of plasmonic metal-semiconductor heteronanostructures is essential for fully harnessing their plasmonic function and hence for designing innovative solar energy conversion platforms. Here, we present a rational synthesis strategy for the realization of plasmonic metal semiconductor heteronanocrystals with intended configurations through the site selective overgrowth of semiconductor Cu2O on desired sites of anisotropic Au nanocrystals. Both the exploitation of structural characteristics of Au nanocrystals and the selective stabilization of their surfaces are keys to the construction of heteronanocrystals with a specific configuration. Our approach can provide an opportunity to precisely explore the link between the solar energy conversion efficiency and the structure of heteronanocrystals as well as to obtain important insights into the underpinning mechanism. Heteronanocrystals produced by Cu2O overgrowth preferentially on the multiple high-curvature sites of Au nanocrystals exhibited prominent photocatalytic hydrogen production activity due to efficient charge separation by strong plasmon excitation at the Au-Cu2O interface and subsequent sustainable hot electron transfer from Au to Cu2O. PMID- 27933999 TI - Tin-Free Direct C-H Arylation Polymerization for High Photovoltaic Efficiency Conjugated Copolymers. AB - A new and highly regioselective direct C-H arylation polymerization (DARP) methodology enables the reproducible and sustainable synthesis of high performance pi-conjugated photovoltaic copolymers. Unlike traditional Stille polycondensation methods for producing photovoltaic copolymers, this DARP protocol eliminates the need for environmentally harmful, toxic organotin compounds. This DARP protocol employs low loadings of commercially available catalyst components, Pd2(dba)3.CHCl3 (0.5 mol%) and P(2-MeOPh)3 (2 mol%), sterically tuned carboxylic acid additives, and an environmentally friendly solvent, 2-methyltetrahydrofuran. Using this DARP protocol, several representative copolymers are synthesized in excellent yields and high molecular masses. The DARP-derived copolymers are benchmarked versus Stille-derived counterparts by close comparison of optical, NMR spectroscopic, and electrochemical properties, all of which indicate great chemical similarity and no significant detectable structural defects in the DARP copolymers. The DARP- and Stille-derived copolymer and fullerene blend microstructural properties and morphologies are characterized with AFM, TEM, and XRD and are found to be virtually indistinguishable. Likewise, the charge generation, recombination, and transport characteristics of the fullerene blend films are found to be identical. For the first time, polymer solar cells fabricated using DARP-derived copolymers exhibit solar cell performances rivalling or exceeding those achieved with Stille derived materials. For the DARP copolymer PBDTT-FTTE, the power conversion efficiency of 8.4% is a record for a DARP copolymer. PMID- 27934000 TI - A Shape-Persistent Polyphenylene Spoked Wheel. AB - A shape-persistent polyphenylene with a "spoked wheel" structure was synthesized as a subunit of an unprecedented two-dimensional polyphenylene that we name graphenylene. The synthesis was carried out through a sixfold intramolecular Yamamoto coupling of a dodecabromo-substituted dendritic polyphenylene precursor, which had a central hexaphenylbenzene unit as a template. Characterizations by NMR spectroscopy and matrix-assisted laser ionization time-of-flight mass spectrometry provided an unambiguous structural proof for the wheel-like molecule with a molar mass of 3815.4 g/mol. Remarkably, scanning tunneling microscopy visualization clearly revealed the defined spoked wheel structure of the molecule with six internal pores. PMID- 27934001 TI - Enantioselective Copper-Catalyzed Intermolecular Cyanotrifluoromethylation of Alkenes via Radical Process. AB - A novel enantioselective copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes has been developed, in which a variety of CF3-containing alkylnitriles are furnished with excellent enantiomeric excess. Preliminary mechanistic studies revealed (1) the reaction was initiated by a SET process between activated Togni's CF3+ reagent and a Cu(I) catalyst; (2) the released CF3 radical readily added to styrene to provide a benzylic radical, which was then trapped by a chiral Cu(II) cyanide species to deliver the desired alkylnitriles; (3) a low concentration of the CN anion was crucial to obtain high enantioselectivity. PMID- 27934002 TI - Reversible Transformation of Pt Nanoparticles into Single Atoms inside High Silica Chabazite Zeolite. AB - We report the encapsulation of platinum species in highly siliceous chabazite (CHA) crystallized in the presence of N,N,N-trimethyl-1-adamantammonium and a thiol-stabilized Pt complex. When compared to Pt/SiO2 or Pt-containing Al-rich zeolites, the materials in this work show enhanced stability toward metal sintering in a variety of industrial conditions, including H2, O2, and H2O. Remarkably, temperatures in the range 650-750 degrees C can be reached without significant sintering of the noble metal. Detailed structural determinations by X ray absorption spectroscopy and aberration-corrected high-angle annular dark field scanning transmission electron microscopy demonstrate subtle control of the supported metal structures from ~1 nm nanoparticles to site-isolated single Pt atoms via reversible interconversion of one species into another in reducing and oxidizing atmospheres. The combined used of microscopy and spectroscopy is critical to understand these surface-mediated transformations. When tested in hydrogenation reactions, Pt/CHA converts ethylene (~80%) but not propylene under identical conditions, in contrast to Pt/SiO2, which converts both at similar rates. These differences are attributed to the negligible diffusivity of propylene through the small-pore zeolite and provide final evidence of the metal encapsulation. PMID- 27934003 TI - Ultrafast Polarization Switching in a Biaxial Molecular Ferroelectric Thin Film: [Hdabco]ClO4. AB - Molecular ferroelectrics are attracting much attention as valuable complements to conventional ceramic ferroelectrics owing to their solution processability and nontoxicity. Encouragingly, the recent discovery of a multiaxial molecular ferroelectric, tetraethylammonium perchlorate, is expected to be able to solve the problem that in the technologically relevant thin-film form uniaxial molecular ferroelectrics have been found to perform considerably more poorly than in bulk. However, it can show good polarization-electric field (P-E) hysteresis loops only at very low frequency, severely hampering practical applications such as ferroelectric random access memory. Here, we present a biaxial molecular ferroelectric thin film of [Hdabco]ClO4 (dabco = 1,4-diazabicyclo[2.2.2]octane) (1), where a perfect ferroelectric hysteresis loop can be observed even at 10 kHz. It is the first example of a molecular ferroelectric thin film whose polarization can be switched at such a high frequency. Moreover, using piezoresponse force microscopy, we clearly observed the coexistence of 180 degrees and non-180 degrees ferroelectric domains and provided direct experimental proof that 180 degrees ferroelectric switching and non-180 degrees ferroelastic switching are both realized; that is, a flexible alteration of the polarization axis direction can occur in the thin film by applying an electric field. These results open a new avenue for applications of molecular ferroelectrics and will inspire further exploration of high-performance multiaxial molecular ferroelectric thin films. PMID- 27934004 TI - Sustainable Synthesis of Quinolines and Pyrimidines Catalyzed by Manganese PNP Pincer Complexes. AB - This study represents the first example an environmentally benign, sustainable, and practical synthesis of substituted quinolines and pyrimidines using combinations of 2-aminobenzyl alcohols and alcohols as well as benzamidine and two different alcohols, respectively. These reactions proceed with high atom efficiency via a sequence of dehydrogenation and condensation steps that give rise to selective C-C and C-N bond formations, thereby releasing 2 equiv of hydrogen and water. A hydride Mn(I) PNP pincer complex recently developed in our laboratory catalyzes this process in a very efficient way. A total of 15 different quinolines and 14 different pyrimidines were synthesized in isolated yields of up to 91 and 90%, respectively. PMID- 27934005 TI - Morphology Evolution of High Efficiency Perovskite Solar Cells via Vapor Induced Intermediate Phases. AB - Morphology is critical component to achieve high device performance hybrid perovskite solar cells. Here, we develop a vapor induced intermediate phase (VIP) strategy to manipulate the morphology of perovskite films. By exposing the perovskite precursor films to different saturated solvent vapor atmospheres, e.g., dimethylformamide and dimethylsufoxide, dramatic film morphological evolution occurs, associated with the formation of different intermediate phases. We observe that the crystallization kinetics is significantly altered due to the formation of these intermediate phases, yielding highly crystalline perovskite films with less defect states and high carrier lifetimes. The perovskite solar cells with the reconstructed films exhibits the highest power conversion efficiency (PCE) up to 19.2% under 1 sun AM 1.5G irradiance, which is among the highest planar heterojunction perovskite solar cells. Also, the perovskite solar cells with VIP processing shows less hysteresis behavior and a stabilized power output over 18%. Our work opens up a new direction for morphology control through intermediate phase formation, and paves the way toward further enhancing the device performances of perovskite solar cells. PMID- 27934006 TI - Alkyl Bromides as Mild Hydride Sources in Ni-Catalyzed Hydroamidation of Alkynes with Isocyanates. AB - A catalytic hydroamidation of alkynes with isocyanates using alkyl bromides as hydride sources has been developed. The method turns parasitic beta-hydride elimination into a strategic advantage, rapidly affording acrylamides with excellent chemo- and regioselectivity. PMID- 27934007 TI - Flexibility Matters: Cooperative Active Sites in Covalent Organic Framework and Threaded Ionic Polymer. AB - The combination of two or more reactive centers working in concert on a substrate to facilitate the reaction is now considered state of the art in catalysis, yet there still remains a tremendous challenge. Few heterogeneous systems of this sort have been exploited, as the active sites spatially separated within the rigid framework are usually difficult to cooperate. It is now shown that this roadblock can be surpassed. The underlying principle of the strategy presented here is the integration of catalytic components with excellent flexibility and porous heterogeneous catalysts, as demonstrated by the placement of linear ionic polymers in close proximity to surface Lewis acid active sites anchored on the walls of a covalent organic framework (COF). Using the cycloaddition of the epoxides and CO2 as a model reaction, dramatic activity improvements have been achieved for the composite catalysts in relation to the individual catalytic component. Furthermore, they also clearly outperform the benchmark catalytic systems formed by the combination of the molecular organocatalysts and heterogeneous Lewis acid catalysts, while affording additional recyclability. The extraordinary flexibility and enriched concentration of the catalytically active moieties on linear polymers facilitate the concerted catalysis, thus leading to superior catalytic performance. This work therefore uncovers an entirely new strategy for designing bifunctional catalysts with double-activation behavior and opens a new avenue in the design of multicapable systems that mimic biocatalysis. PMID- 27934008 TI - Orbital Crossings Activated through Electron Injection: Opening Communication between Orthogonal Orbitals in Anionic C1-C5 Cyclizations of Enediynes. AB - Generally, the long-range electronic communication between spatially orthogonal orbitals is inefficient and limited to field and inductive effects. In this work, we provide experimental evidence that such communication can be achieved via intramolecular electron transfer between two degenerate and mutually orthogonal frontier molecular orbitals (MOs) at the transition state. Interaction between orthogonal orbitals is amplified when the energy gap between these orbitals approaches zero, or at an "orbital crossing". The crossing between two empty or two fully occupied MOs, which do not lead to stabilization, can be "activated" when one of the empty MOs is populated (i.e., electron injection) or one of the filled MOs is depopulated (i.e., hole injection). In reductive cycloaromatization reactions, such crossings define transition states with energies defined by both the in-plane and out-of-plane pi-systems. Herein, we provide experimental evidence for the utility of this concept using orbital crossings in reductive C1 C5 cycloaromatization reactions of enediynes. Communication with remote substituents via orbital crossings greatly enhances regioselectivity of the ring closure step in comparison to the analogous radical cyclizations. We also present photophysical data pertaining to the efficiency of electron injection into the benzannelated enediynes. PMID- 27934009 TI - Chemical Conversion of Linkages in Covalent Organic Frameworks. AB - The imine linkages of two layered, porous covalent organic frameworks (COFs), TPB TP-COF ([C6H3(C6H4N)3]2[C6H4(CH)2]3, 1) and 4PE-1P-COF ([C2(C6H4N)4][C6H4(CH)2]2, 2), have been transformed into amide linkages to make the respective isostructural amide COFs 1' and 2' by direct oxidation with retention of crystallinity and permanent porosity. Remarkably, the oxidation of both imine COFs is complete, as assessed by FT-IR and 13C CP-MAS NMR spectroscopy and demonstrates (a) the first chemical conversion of a COF linkage and (b) how the usual "crystallization problem" encountered in COF chemistry can be bypassed to access COFs, such as these amides, that are typically thought to be difficult to obtain by the usual de novo methods. The amide COFs show improved chemical stability relative to their imine progenitors. PMID- 27934010 TI - Ribosomal Peptide Syntheses from Activated Substrates Reveal Rate Limitation by an Unexpected Step at the Peptidyl Site. AB - Protein synthesis (translation) is central to cellular function and antibiotic development. Interestingly, the key chemical step of translation, peptide bond formation, is among the slower enzymatic reactions. The reason for this remains controversial because of reliance on studies using highly modified, severely minimized, or unreactive substrate analogues. Here, we investigated this problem by fast kinetics using full-length aminoacyl-tRNA substrates with atomic substitutions that activated the ester electrophile. While trifluoro substitution of hydrogens in nonconserved positions of the peptidyl-site substrate dramatically increased the ester reactivity in solution assays, a large hastening of the combined rates of ribosomal accommodation and peptidyl transfer was observed only with a slowly reacting aminoacyl-site nucleophile, proline. With a fast-reacting A-site nucleophile, phenylalanine, effects did not correlate at all with electrophilicities. As effects were observed using the same, natural, aminoacyl-tRNA at the A site and all rates of accommodation/peptidyl transfer were pH dependent, we concluded that rate limitation was not by A-site accommodation but rather by peptidyl transfer and a hitherto unexpected step at the P site. This new slow step, which we term P-site accommodation, has implications for the activation or inhibition of ribosome function in vitro and in vivo. PMID- 27934012 TI - Synthesis of Phosphorodiamidate Morpholino Oligonucleotides and Their Chimeras Using Phosphoramidite Chemistry. AB - Phosphorodiamidate morpholinos (PMOs) and PMO-DNA chimeras have been prepared on DNA synthesizers using phosphoramidite chemistry. This was possible by first generating boranephosphoroamidate morpholino internucleotide linkages followed by oxidative substitution with four different amines: N,N-dimethylamine, N methylamine, ammonia, and morpholine. When compared to a natural DNA duplex, the amino modified PMO was found to have a higher melting temperature with either complementary DNA or RNA, whereas the remaining PMO analogues having morpholino, dimethylamino, or N-methylamino phosphorodiamidate linkages had melting temperatures that were either comparable or reduced. Additionally the N,N dimethylamino PMO-DNA chimeras were found to stimulate RNaseH1 activity. Treatment of HeLa cells with fluorescently labeled PMO chimeras demonstrated that these analogues were efficiently taken up by cells in the presence of a lipid transfection reagent. Because of the simplistic synthesis procedures, various PMO analogues are now readily available and should therefore open new pathways for research into the antisense, diagnostic, and nanotechnology oligonucleotide fields. PMID- 27934011 TI - A Mechanistic Model for Colibactin-Induced Genotoxicity. AB - Precolibactins and colibactins represent a family of natural products that are encoded by the clb gene cluster and are produced by certain commensal, extraintestinal, and probiotic E. coli. clb+ E. coli induce megalocytosis and DNA double-strand breaks in eukaryotic cells, but paradoxically, this gene cluster is found in the probiotic Nissle 1917. Evidence suggests precolibactins are converted to genotoxic colibactins by colibactin peptidase (ClbP)-mediated cleavage of an N-acyl-d-Asn side chain, and all isolation efforts have employed DeltaclbP strains to facilitate accumulation of precolibactins. It was hypothesized that colibactins form unsaturated imines that alkylate DNA by cyclopropane ring opening (2 -> 3). However, as no colibactins have been isolated, this hypothesis has not been tested experimentally. Additionally, precolibactins A-C (7-9) contain a pyridone that cannot generate the unsaturated imines that form the basis of this hypothesis. To resolve this, we prepared 13 synthetic colibactin derivatives and evaluated their DNA binding and alkylation activity. We show that unsaturated imines, but not the corresponding pyridone derivatives, potently alkylate DNA. The imine, unsaturated lactam, and cyclopropane are essential for efficient DNA alkylation. A cationic residue enhances activity. These studies suggest that precolibactins containing a pyridone are not responsible for the genotoxicity of the clb cluster. Instead, we propose that these are off-pathway fermentation products produced by a facile double cyclodehydration route that manifests in the absence of viable ClbP. The results presented herein provide a foundation to begin to connect metabolite structure with the disparate phenotypes associated with clb+ E. coli. PMID- 27934013 TI - Blue Phosphorescent Zwitterionic Iridium(III) Complexes Featuring Weakly Coordinating nido-Carborane-Based Ligands. AB - We report the development of a new class of phosphorescent zwitterionic bis(heteroleptic) Ir(III) compounds containing pyridyl ligands with weakly coordinating nido-carboranyl substituents. Treatment of phenylpyridine-based Ir(III) precursors with C-substituted ortho-carboranylpyridines in 2 ethoxyethanol results in a facile carborane deboronation and the formation of robust and highly luminescent metal complexes. The resulting nido-carboranyl fragments associate with the cationic Ir(III) center through primarily electrostatic interactions. These compounds phosphoresce at blue wavelengths (450 470 nm) both in a poly(methyl methacrylate) (PMMA) matrix and in solution at 77 K. These complexes display structural stability at temperatures beyond 300 degrees C and quantum yields greater than 40%. Importantly, the observed quantum yields correspond to a dramatic 10-fold enhancement over the previously reported Ir(III) congeners featuring carboranyl-containing ligands in which the boron cluster is covalently attached to the metal. Ultimately, this work suggests that the use of a ligand framework containing a weakly coordinating anionic component can provide a new avenue for designing efficient Ir(III)-based phosphorescent emitters. PMID- 27934014 TI - Mechanism of Nucleophilic Activation of (-)-Lomaiviticin A. AB - (-)-Lomaiviticin A (1) is a C2-symmetric cytotoxin that contains two diazofluorene functional groups and which induces double-strand breaks (DSBs) in DNA. Evidence suggests DNA cleavage is initiated by hydrogen atom abstraction from the deoxyribose backbone. Here we demonstrate the formation of the vinyl radicals 1. and 2. from 1 by 1,7-addition of thiols to the diazofluorenes. These radicals can affect hydrogen atom abstraction from methanol and acetone. The first addition of thiol to 1 proceeds at a much greater rate than the second. The diazosulfide 5 formed en route to 1. has been detected at -50 degrees C and undergoes decomposition to 1. with a half-life of 110 min at -20 degrees C under air. These data, which constitute the first direct evidence for the generation of 1. and 2. from 1, provide insights into the mechanism of DNA cleavage by 1. PMID- 27934016 TI - Reticular Chemistry-Construction, Properties, and Precision Reactions of Frameworks. PMID- 27934015 TI - The B12-Radical SAM Enzyme PoyC Catalyzes Valine Cbeta-Methylation during Polytheonamide Biosynthesis. AB - Genomic and metagenomic investigations have recently led to the delineation of a novel class of natural products called ribosomally synthesized and post translationally modified peptides (RiPPs). RiPPs are ubiquitous among living organisms and include pharmaceutically relevant compounds such as antibiotics and toxins. A prominent example is polytheonamide A, which exhibits numerous post translational modifications, some of which were unknown in ribosomal peptides until recently. Among these post-translational modifications, C-methylations have been proposed to be catalyzed by two putative radical S-adenosylmethionine (rSAM) enzymes, PoyB and PoyC. Here we report the in vitro activity of PoyC, the first B12-dependent rSAM enzyme catalyzing peptide Cbeta-methylation. We show that PoyC catalyzes the formation of S-adenosylhomocysteine and 5'-deoxyadenosine and the transfer of a methyl group to l-valine residue. In addition, we demonstrate for the first time that B12-rSAM enzymes have a tightly bound MeCbl cofactor that during catalysis transfers a methyl group originating from S-adenosyl-l methionine. Collectively, our results shed new light on polytheonamide biosynthesis and the large and emerging family of B12-rSAM enzymes. PMID- 27934017 TI - Helix-Dependent Spin Filtering through the DNA Duplex. AB - Recent work suggests that electrons can travel through DNA and other chiral molecules in a spin-selective manner, but little is known about the origin of this spin selectivity. Here we describe experiments on magnetized DNA-modified electrodes to explore spin-selective electron transport through hydrated duplex DNA. Our results show that the two spins migrate through duplex DNA with a different yield and that spin selectivity requires charge transport through the DNA duplex. Significantly, shifting the same duplex DNA between right-handed B- and left-handed Z-forms leads to a diode-like switch in spin selectivity; which spin moves more efficiently through the duplex depends upon the DNA helicity. With DNA, the supramolecular organization of chiral moieties, rather than the chirality of the individual monomers, determines the selectivity in spin, and thus a conformational change can switch the spin selectivity. PMID- 27934018 TI - Self-Assembled Single-Walled Metal-Helical Nanotube (M-HN): Creation of Efficient Supramolecular Catalysts for Asymmetric Reaction. AB - Ever since the axial chiral catalysts were developed for asymmetric reactions with excellent chiral discrimination and high efficiencies, the interest in the supramolecular catalyst has also been extensively investigated. Here, with a hint from the typical molecular catalyst, we developed a series of metal-coordinated nanotube (M-helical nanotube, M-HN) catalysts for asymmetric reactions. The M-HN catalyst was fabricated on the basis of the self-assembly of an l-glutamic acid terminated bolaamphiphile, which formed a single-walled nanotube. On one hand, through the coordination of transition metal ions with the carboxylic acid groups on the nanotube surface, a wide variety of single-walled M-HN catalysts could be fabricated, in which the coordination sites could serve as the catalytic sites. On the other hand, using a slight amount of these catalysts, significant reactivity and enantioselectivity were realized for certain asymmetric reactions under mild conditions. Remarkably, Bi(III)-HN could catalyze the asymmetric Mukaiyama aldol reaction with high enantioselectivity (up to 97% ee) in an aqueous system; Cu(II)-HN catalyzed the asymmetric Diels-Alder reaction with up to 91% ee within 60 min. It was suggested that a synergetic effect of the aligned multicatalytic sites and stereochemical selectivity of the M-HN lead to an excellent catalytic performance. Through this work, we proposed a new concept of a single-walled nanotube as catalyst and showed the first example of nanotube catalysts presenting high reactivity and enantioselectivity that rivaled a chiral molecular catalyst. PMID- 27934020 TI - A Thieno[3,4-b]thiophene-Based Non-fullerene Electron Acceptor for High Performance Bulk-Heterojunction Organic Solar Cells. AB - A thieno[3,4-b]thiophene-based electron acceptor, ATT-1, is designed and synthesized. ATT-1 exhibits a planar conjugated framework, broad absorption with a large absorption coefficient, and a slightly high LUMO energy level. Bulk heterojunction (BHJ) solar cells based on PTB7-Th electron donor and ATT-1 electron acceptor delivered power conversion efficiencies of up to 10.07%, which is among the best performances reported for non-fullerene BHJ solar cells using PTB7-Th as the electron donor. PMID- 27934022 TI - Cationic Polymerization of Vinyl Ethers Controlled by Visible Light. AB - Photoinitiated cationic polymerizations are widely used in industrial processes; however, gaining photocontrol over chain growth would expand the utility of these methods and facilitate the design of novel complex architectures. We report herein a cationic polymerization regulated by visible light. This polymerization proceeds under mild conditions: a combination of a metal-free photocatalyst, a chain-transfer agent, and light irradiation enables the synthesis of various poly(vinyl ether)s with good control over molecular weight and dispersity as well as excellent chain-end fidelity. Significantly, photoreversible cation formation in this system enables efficient control over polymer chain growth with light. PMID- 27934023 TI - Diphosphine-Stabilized Small Gold Nanoclusters: From Crystal Structure Determination to Ligation-Driven Symmetry Breaking and Anion Exchange Properties. AB - A new class of small gold nanoclusters with molecular characteristics has been constructed using 1,1'-bis(diphenylphosphino)ferrocene (dppf) as the stabilizing ligand. The identities of the small gold nanoclusters have been fully characterized by NMR, electrospray ionization mass spectrometry, elemental analysis, and single-crystal X-ray diffraction analysis. Octa- and undecagold clusters are found to display different UV-vis absorption behavior. The ligation of the bidentate ligands and halides or pseudohalides has resulted in the symmetry breaking of these nanoclusters with C1 symmetry. The small gold nanoclusters with different coordinating halides or pseudohalides show distinct reactivities and stabilities in ligand/anion exchange experiments. The current research has provided insights into the origin of chirality in the diphosphine stabilized small gold nanoclusters. PMID- 27934019 TI - Experimental and Computational Analysis of Protein Stabilization by Gly-to-d-Ala Substitution: A Convolution of Native State and Unfolded State Effects. AB - The rational and predictable enhancement of protein stability is an important goal in protein design. Most efforts target the folded state, however stability is the free energy difference between the folded and unfolded states thus both are suitable targets. Strategies directed at the unfolded state usually seek to decrease chain entropy by introducing cross-links or by replacing glycines. Cross linking has led to mixed results. Replacement of glycine with an l-amino acid, while reducing the entropy of the unfolded state, can introduce unfavorable steric interactions in the folded state, since glycine is often found in conformations that require a positive phi angle such as helical C-capping motifs or type I' and II" beta-turns. l-Amino acids are strongly disfavored in these conformations, but d-amino acids are not. However, there are few reported examples and conflicting results have been obtained when glycines are replaced with d-Ala. We critically examine the effect of Gly-to-d-Ala substitutions on protein stability using experimental approaches together with molecular dynamics simulations and free energy calculations. The data, together with a survey of high resolution structures, show that the vast majority of proteins can be stabilized by substitution of C-capping glycines with d-Ala. Sites suitable for substitutions can be identified via sequence alignment with a high degree of success. Steric clashes in the native state due to the new side chain are rarely observed, but are likely responsible for the destabilizing or null effect observed for the small subset of Gly-to-d-Ala substitutions which are not stabilizing. Changes in backbone solvation play less of a role. Favorable candidates for d-Ala substitution can be identified using a rapid algorithm based on molecular mechanics. PMID- 27934024 TI - Persistent Energetic Electrons in Methylammonium Lead Iodide Perovskite Thin Films. AB - In conventional semiconductor solar cells, carriers are extracted at the band edges and the excess electronic energy (E*) is lost as heat. If E* is harvested, power conversion efficiency can be as high as twice the Shockley-Queisser limit. To date, materials suitable for hot carrier solar cells have not been found due to efficient electron/optical-phonon scattering in most semiconductors, but our recent experiments revealed long-lived hot carriers in single-crystal hybrid lead bromide perovskites. Here we turn to polycrystalline methylammonium lead iodide perovskite, which has emerged as the material for highly efficient solar cells. We observe energetic electrons with excess energy ?E*? ~ 0.25 eV above the conduction band minimum and with lifetime as long as ~100 ps, which is 2-3 orders of magnitude longer than those in conventional semiconductors. The energetic carriers also give rise to hot fluorescence emission with pseudo-electronic temperatures as high as 1900 K. These findings point to a suppression of hot carrier scattering with optical phonons in methylammonium lead iodide perovskite. We address mechanistic origins of this suppression and, in particular, the correlation of this suppression with dynamic disorder. We discuss potential harvesting of energetic carriers for solar energy conversion. PMID- 27934025 TI - Pressure-Driven Cooperative Spin-Crossover, Large-Volume Collapse, and Semiconductor-to-Metal Transition in Manganese(II) Honeycomb Lattices. AB - Spin-crossover (SCO) is generally regarded as a spectacular molecular magnetism in 3d4-3d7 metal complexes and holds great promise for various applications such as memory, displays, and sensors. In particular, SCO materials can be multifunctional when a classical light- or temperature-induced SCO occurs along with other cooperative structural and/or electrical transport alterations. However, such a cooperative SCO has rarely been observed in condensed matter under hydrostatic pressure (an alternative external stimulus to light or temperature), probably due to the lack of synergy between metal neighbors under compression. Here, we report the observation of a pressure-driven, cooperative SCO in the two-dimensional (2D) honeycomb antiferromagnets MnPS3 and MnPSe3 at room temperature. Applying pressure to this confined 2D system leads to a dramatic magnetic moment collapse of Mn2+ (d5) from S = 5/2 to S = 1/2. Significantly, a number of collective phenomena were observed along with the SCO, including a large lattice collapse (~20% in volume), the formation of metallic bonding, and a semiconductor-to-metal transition. Experimental evidence shows that all of these events occur in the honeycomb lattice, indicating a strongly cooperative mechanism that facilitates the occurrence of the abrupt pressure driven SCO. We believe that the observation of this cooperative pressure-driven SCO in a 2D system can provide a rare model for theoretical investigations and lead to the discovery of more pressure-responsive multifunctional materials. PMID- 27934027 TI - Visible Light-Gated Cobalt Catalysis for a Spatially and Temporally Resolved [2+2+2] Cycloaddition. AB - The ability to exert spatial and temporal control over a transition-metal catalyst offers diverse opportunities for the fabrication of functional materials. Using an external stimulus such as visible light to toggle a catalyst between an active and dormant state has proven to be an effective approach for controlled, radical methodologies. Outside of radical bond formation, there is a dearth of evidence that suggests traditional transition metal catalysis can similarly be controlled with visible light energy. Many cobalt complexes that catalyze the [2+2+2] cycloaddition are assisted by UV photolysis, but strict photocontrolled methods are unattainable due to high levels of thermally driven reactivity. Herein, we disclose the first light-controlled, cobalt-catalyzed [2+2+2] cycloaddition via a dual cobalt and photoredox catalyst manifold. We demonstrate the power of this method with a spatially and temporally resolved technique for arene formation using photolithography. PMID- 27934026 TI - Two-Photon Absorbing Phosphorescent Metalloporphyrins: Effects of pi-Extension and Peripheral Substitution. AB - The ability to form triplet excited states upon two-photon excitation is important for several applications of metalloporphyrins, including two-photon phosphorescence lifetime microscopy (2PLM) and two-photon photodynamic therapy (PDT). Here we analyzed one-photon (1P) and degenerate two-photon (2P) absorption properties of several phosphorescent Pt (II) porphyrins, focusing on the effects of aromatic pi-extension and peripheral substitution on triplet emissivity and two-photon absorption (2PA). Our 2PA measurements for the first time made use of direct time-resolved detection of phosphorescence, having the ability to efficiently reject laser background through microsecond time gating. pi-Extension of the porphyrin macrocycle by way of syn-fusion with two external aromatic fragments, such as in syn-dibenzo- (DBP) and syn-dinaphthoporphyrins (DNP), lowers the symmetry of the porphyrin skeleton. As a result, DBPs and DNPs exhibit stronger 2PA into the one-photon-allowed B (Soret) and Q states than fully symmetric (D4h) nonextended porphyrins. However, much more 2P-active states lie above the B state and cannot be accessed due to the interfering linear absorption. Alkoxycarbonyl groups (CO2R) in the benzo-rings dramatically enhance 2PA near the B state level. Time-dependent density functional theory (TDDFT) calculations in combinations with the sum-over-states (SOS) formalism revealed that the enhancement is due to the stabilization of higher-lying 2P-active states, which are dominated by the excitations involving orbitals extending onto the carbonyl groups. Furthermore, calculations predicted even stronger stabilization of the 2P-allowed gerade-states in symmetric Pt octaalkoxycarbonyl tetrabenzoporphyrins. Experiments confirmed that the 2PA cross-section of PtTBP(CO2Bu)8 near 810 nm reaches above 500 GM in spite of its completely centrosymmetric structure. Combined with exceptionally bright phosphorescence (phiphos = 0.45), strong 2PA makes Pt(II) complexes of pi-extended porphyrins a valuable class of chromophores for 2P applications. Another important advantage of these porphyrinoids is their compact size and easily scalable synthesis. PMID- 27934028 TI - Co-reactant-on-Demand ECL: Electrogenerated Chemiluminescence by the in Situ Production of S2O82- at Boron-Doped Diamond Electrodes. AB - A novel co-reactant-free electrogenerated chemiluminescence (ECL) system is developed where Ru(bpy)32+ emission is obtained on boron-doped diamond (BDD) electrodes. The method exploits the unique ability of BDD to operate at very high oxidation potential in aqueous solutions and to promote the conversion of inert SO42- into the reactive co-reactant S2O82-. This novel procedure is rather straightforward, not requiring any particular electrode geometry, and since the co-reactant is only generated in situ, the interference with biological samples is minimized. The underlying mechanism is similar to that of the Ru(bpy)32+/S2O82 system; however, the intensity of the emitted signal increases linearly with [SO42-] up to ~0.6 M, with possible implications for analytical uses of the proposed procedure. PMID- 27934029 TI - Design and Synthesis of Antiblinking and Antibleaching Quantum Dots in Multiple Colors via Wave Function Confinement. AB - Single-molecular spectroscopy reveals that photoluminescence (PL) of a single quantum dot blinks, randomly switching between bright and dim/dark states under constant photoexcitation, and quantum dots photobleach readily. These facts cast great doubts on potential applications of these promising emitters. After ~20 years of efforts, synthesis of nonblinking quantum dots is still challenging, with nonblinking quantum dots only available in red-emitting window. Here we report synthesis of nonblinking quantum dots covering most part of the visible window using a new synthetic strategy, i.e., confining the excited-state wave functions of the core/shell quantum dots within the core quantum dot and its inner shells (<= ~5 monolayers). For the red-emitting ones, the new synthetic strategy yields nonblinking quantum dots with small sizes (~8 nm in diameter) and improved nonblinking properties. These new nonblinking quantum dots are found to be antibleaching. Results further imply that the PL blinking and photobleaching of quantum dots are likely related to each other. PMID- 27934030 TI - Enhanced Photocurrents with ZnS Passivated Cu(In,Ga)(Se,S)2 Photocathodes Synthesized Using a Nonvacuum Process for Solar Water Splitting. AB - Chalcopyrite Cu(In,Ga)(Se,S)2 (CIGS) semiconductors are potential candidates for use in photoelectrochemical (PEC) hydrogen generation due to their excellent optical absorption properties and high conduction band edge position. In the present research, CIGS thin film was successfully prepared on a transparent substrate (F:SnO2 glass) using a solution-based process and applied for a photocathode in solar water splitting, which shows control of the surface state associated with sulfurization/selenization process significantly influences on the PEC activity. A ZnS passivation surface layer was introduced, which effectively suppresses charge recombination by surface states of CIGS. The CIGS/ZnS/Pt photocathode exhibited highly enhanced PEC activity (~24 mA.cm-2 at 0.3 V vs RHE). The performances of our CIGS photocathode on the transparent substrate were also characterized under front/back light illumination, and the incident photon to current conversion efficiency (IPCE) drastically changed depending on the illumination directions showing decreased IPCE especially under UV region with back illumination. The slow minority carrier (electron) transportation is suggested as a limiting factor for the PEC activity of the CIGS photocathode. PMID- 27934032 TI - Total Syntheses of Aflavazole and 14-Hydroxyaflavinine. AB - The first total syntheses of aflavazole (6) and 14-hydroxyaflavinine (8), two sterically congested indole diterpenoids, were accomplished. AlI3-promoted alkyne Prins cyclization was exploited to construct their key structural motifs. An electrocyclization-aromatization sequence assembled the pentasubstituted arene of 6, and a Stille-Migita coupling furnished the tetrasubstituted olefin of 8. The benzylic and allylic C-O bonds were reductively cleaved at the late stage of the syntheses, respectively. PMID- 27934031 TI - A Trojan-Horse Peptide-Carboxymethyl-Cytidine Antibiotic from Bacillus amyloliquefaciens. AB - Microcin C and related antibiotics are Trojan-horse peptide-adenylates. The peptide part is responsible for facilitated transport inside the sensitive cell, where it gets processed to release a toxic warhead-a nonhydrolyzable aspartyl adenylate, which inhibits aspartyl-tRNA synthetase. Adenylation of peptide precursors is carried out by MccB THIF-type NAD/FAD adenylyltransferases. Here, we describe a novel microcin C-like compound from Bacillus amyloliquefaciens. The B. amyloliquefaciens MccB demonstrates an unprecedented ability to attach a terminal cytidine monophosphate to cognate precursor peptide in cellular and cell free systems. The cytosine moiety undergoes an additional modification carboxymethylation-that is carried out by the C-terminal domain of MccB and the MccS enzyme that produces carboxy-SAM, which serves as a donor of the carboxymethyl group. We show that microcin C-like compounds carrying terminal cytosines are biologically active and target aspartyl-tRNA synthetase, and that the carboxymethyl group prevents resistance that can occur due to modification of the warhead. The results expand the repertoire of known enzymatic modifications of peptides that can be used to obtain new biological activities while avoiding or limiting bacterial resistance. PMID- 27934033 TI - Hexagons to Ribbons: Flipping Cyanide on Au{111}. AB - Cyanide monolayers on Au{111} restructure from a hexagonal close-packed lattice to a mixed-orientation "ribbon" structure through thermal annealing. The new surface structure loses most of the observed surface features characterizing the initial as-adsorbed system with "ribbon" domain boundaries isolating rotationally offset surface regions where the orientation is guided by the underlying gold lattice. A blue shift to higher frequencies of the CN vibration to 2235 cm-1 with respect to the as-adsorbed CN/Au{111} vibration at 2146 cm-1 is observed. In addition, a new low-frequency mode is observed at 145 cm-1, suggesting a chemical environment change similar to gold-cyanide crystallization. We discuss this new structure with respect to a mixed cyanide/isocyanide monolayer and propose a bonding scheme consisting of Au-CN and Au-NC bound molecules that are oriented normal to the Au{111} surface. PMID- 27934034 TI - Synthesis and Evaluation of Molybdenum and Tungsten Monoaryloxide Halide Alkylidene Complexes for Z-Selective Cross-Metathesis of Cyclooctene and Z-1,2 Dichloroethylene. AB - Molybdenum complexes with the general formula Mo(NR)(CHR')(OR")(Cl)(MeCN) (R = t Bu or 1-adamantyl; OR" = a 2,6-terphenoxide) recently have been found to be highly active catalysts for cross-metathesis reactions between Z-internal olefins and Z-1,2-dichloroethylene or Z-(CF3)CH?CH(CF3). In this paper we report methods of synthesizing new potential catalysts with the general formula M(NR)(CHR')(OR")(Cl)(L) in which M = Mo or W, NR = N-2,6-diisopropylphenyl or NC6F5, and L is a phosphine, a pyridine, or a nitrile. We also test and compare all catalysts in the cross-metathesis of Z-1,2-dichloroethylene and cyclooctene. Our investigations indicate that tungsten complexes are inactive in the test reaction either because the donor is bound too strongly or because acetonitrile inserts into a W?C bond. The acetonitrile or pivalonitrile Mo(NR)(CHR')(OR")(Cl)(L) complexes are found to be especially reactive because the 14e Mo(NR)(CHR')(OR")Cl core is accessible through dissociation of the nitrile to a significant extent. Pivalonitrile can be removed (>95%) from Mo(NAr)(CHCMe2Ph)(OHMT)(Cl)(t-BuCN) (Ar = 2,6-diisopropylphenyl; OHMT = 2,6 dimesitylphenoxide) to give 14e Mo(NAr)(CHCMe2Ph)(OHMT)Cl in solution as a mixture of syn and anti (60:40 at 0.015 M) nitrile-free isomers, but these 14e complexes have not yet been isolated in pure form. The syn isomer of Mo(NAr)(CHCMe2Ph)(OHMT)Cl binds pivalonitrile most strongly. Other Mo(NR)(CHR')(OR")(Cl)(L) complexes can be activated through addition of B(C6F5)3. High stereoselectivities (>98% Z,Z) of ClCH?CH(CH2)6CH?CHCl are not restricted to tert-butylimido or adamantylimido complexes; 96.2% Z selectivity is observed with boron-activated Mo(NC6F5)(CHR')(OHIPT)(Cl)(PPhMe2). So far no Mo?CHCl complexes, which are required intermediates in the test reaction, have been observed in NMR studies at room temperature. PMID- 27934035 TI - Mechanistic Insights into the Challenges of Cycling a Nonaqueous Na-O2 Battery. AB - Superoxide-based nonaqueous metal-oxygen batteries have received considerable research attention as they exhibit high energy densities and round-trip efficiencies. The cycling performance, however, is still poor. Here we study the cycling characteristic of a Na-O2 battery using solid-state nuclear magnetic resonance, Raman spectroscopy, and scanning electron microscopy. We find that the poor cycling performance is primarily caused by the considerable side reactions stemming from the chemical aggressiveness of NaO2 as both a solid-phase and dissolved species in the electrolyte. The side reaction products cover electrode surfaces and hinder electron transfer across the electrode-electrolyte interface, being a major reason for cell failure. In addition, the available electrode surface and porosity change considerably during cell discharging and charging, affecting the diffusion of soluble species (superoxide and water) and resulting in inhomogeneous reactions across the electrode. This study provides insights into the challenges associated with achieving long-lived superoxide-based metal O2 batteries. PMID- 27934036 TI - Using Paramagnetism to Slow Down Nuclear Relaxation in Protein NMR. AB - Paramagnetic metal ions accelerate nuclear spin relaxation; this effect is widely used for distance measurement and called paramagnetic relaxation enhancement (PRE). Theoretical predictions established that, under special circumstances, it is also possible to achieve a reduction in nuclear relaxation rates (negative PRE). This situation would occur if the mechanism of nuclear relaxation in the diamagnetic state is counterbalanced by a paramagnetic relaxation mechanism caused by the metal ion. Here we report the first experimental evidence for such a cross-correlation effect. Using a uniformly 15N-labeled mutant of calbindin D9k loaded with either Tm3+ or Tb3+, reduced R1 and R2 relaxation rates of backbone 15N spins were observed compared with the diamagnetic reference (the same protein loaded with Y3+). The effect arises from the compensation of the chemical shift anisotropy tensor by the anisotropic dipolar shielding generated by the unpaired electron spin. PMID- 27934037 TI - Spotlights: Volume 7, Issue 23. PMID- 27934038 TI - In Situ Spectroscopic Identification of MU-OO Bridging on Spinel Co3O4 Water Oxidation Electrocatalyst. AB - The formation of MU-OO peroxide (Co-OO-Co) moieties on spinel Co3O4 electrocatalyst prior to the rise of the electrochemical oxygen evolution reaction (OER) current was identified by in situ spectroscopic methods. Through a combination of independent in situ X-ray absorption, grazing-angle X-ray diffraction, and Raman analysis, we observed a clear coincidence between the formation of MU-OO peroxide moieties and the rise of the anodic peak during OER. This finding implies that a chemical reaction step could be generally ignored before the onset of OER current. More importantly, the tetrahedral Co2+ ions in the spinel Co3O4 could be the vital species to initiate the formation of the MU OO peroxide moieties. PMID- 27934039 TI - CO Separation from H2 via Hydrate Formation in Single-Walled Carbon Nanotubes. AB - Hydrogen is an alternative fuel without generating greenhouse gas or other harmful emissions. Industrial hydrogen production, however, always contains a small fraction of carbon monoxide (CO) (~0.5-2%) that must be removed for use in fuel cells. Here, we present molecular dynamics simulation evidence on facile separation of CO from H2 at ambient pressure via the formation of quasi-one dimensional (Q1D) clathrate hydrates within single-walled carbon nanotubes (SW CNTs). At ambient pressure, Q1D CO (or H2) clathrates in SW-CNTs are formed spontaneously when the SW-CNTs are immersed in CO (or H2) aqueous solution. More interestingly, for the CO/H2 aqueous solution, highly preferential adsorption of CO over H2 occurs within the octagonal or nonagonal ice nanotubes inside of SW CNTs. These results suggest that the formation of Q1D hydrates within SW-CNTs can be a viable and safe method for the separation of CO from H2, which can be exploited for hydrogen purification in fuel cells. PMID- 27934040 TI - Amplifying Excitation-Power Sensitivity of Photon Upconversion in a NaYbF4:Ho Nanostructure for Direct Visualization of Electromagnetic Hotspots. AB - Controlling excitation power is the most convenient approach to dynamically tuning upconversion that is essential for a variety of studies. However, this approach suffers from a significant constraint due to insensitive response of most upconversion systems to excitation power. Here we present a study of amplifying excitation power-sensitivity of upconversion in Ho3+ ions through the use of a NaYbF4 host. Mechanistic investigation reveals that the sensitive response of Ho3+ upconversion to excitation power stems from maximal use of the incident energy enabled by concentrated Yb3+ sensitizers. This allows us to sensitively tune the red-to-green emission intensity ratio from 0.37 to 5.19 by increasing the excitation power from 1.25 to 46.25 W cm-2, which represents a 5.6 fold amplification of the tunability (from 0.19 to 0.49) offered by Yb/Ho (19/1 mol %) codoped NaYF4. Our results highlight that the excitation-power sensitive upconversion emission can be exploited to experimentally visualize electromagnetic hotspots. PMID- 27934041 TI - To Photoredox or Not in Neutral Aqueous Solutions for Selected Benzophenone and Anthraquinone Derivatives. AB - The experimental and theoretical results in neutral aqueous solutions reported here indicate that a proton-coupled electron transfer (PCET) from an alcohol C-H bond to the para-carbonyl is the initial and crucial process for the photoredox reaction of 2-(1-hydroxyethyl)-anthraquinone (HEAQ) to occur while the counterpart 3-(hydroxymethyl)-benzophenone (3-BPOH) compound displays a different PCET from an alcohol O-H bond to the carbonyl as the first step, followed by an intersystem crossing process that does not lead to the analogous photoredox, which is caused by a subtle charge-radical coupled effect between HEAQ and 3 BPOH. This can account for experimental results in the literature that HEAQ can undergo efficient photoredox but 3-BPOH does not under neutral aqueous conditions. These results have implications for the pH-dependent photochemical behavior of aromatic carbonyl compounds in aqueous media. PMID- 27934042 TI - Free Excitons and Exciton-Phonon Coupling in CH3NH3PbI3 Single Crystals Revealed by Photocurrent and Photoluminescence Measurements at Low Temperatures. AB - We investigated the exciton-phonon couplings and exciton binding energy in CH3NH3PbI3 (MAPbI3) single crystals using temperature-dependent photocurrent (PC) and photoluminescence (PL) spectroscopy. The PC and PL data provide clear evidence of the existence of excitons in orthorhombic-phase MAPbI3. The temperature-dependent PC data were found to be less influenced by the bound excitons than the PL data, and thus the PC data reflect the intrinsic scatterings of excitons. We observed that the exciton-phonon couplings were strong in MAPbI3 and determined the longitudinal optical phonon energy to be 16.1 meV. Moreover, on the basis of the temperature dependences of the PC and PL data, we evaluated the exciton binding energy to be 12.4 meV for orthorhombic-phase MAPbI3 single crystals. Our findings pave a way for using simultaneous PC and PL measurements to determine precisely fundamental properties of perovskites. PMID- 27934043 TI - Slow Singlet Fission Observed in a Polycrystalline Perylenediimide Thin Film. AB - Singlet exciton fission (SF) is a process wherein an exciton in an organic semiconductor divides its energy to form two excitations. This process can offset thermalization losses in light harvesting technologies, but requires photostable materials with high SF efficiency. We report ultrafast kinetics of polycrystalline films of N-N'-dioctyl-3,4,9,10-perylenedicarboximide (C8-PDI), a chromophore predicted to undergo SF on picosecond time scales. While transient absorption measurements display picosecond dynamics, such kinetics are absent from low-fluence time-resolved emission experiments, indicating they result from singlet-singlet exciton annihilation. A model that accounts for annihilation can reproduce both measurements and highlights that care must be taken when extracting SF rates from time-resolved data. Our model also reveals SF proceeds in C8-PDI over 3.8 ns. Despite this slow rate, SF occurs in high yield (51%) due to a lack of competing singlet deactivation pathways. Our results show perylenediimides are a promising class of SF materials that merit further study. PMID- 27934044 TI - Carbon Nanotubes Immersed in Superfluid Helium: The Impact of Quantum Confinement on Wetting and Capillary Action. AB - A recent experimental study [ Ohba, Sci. Rep. 2016, 6, 28992 ] of gas adsorption on single-walled carbon nanotubes at temperatures between 2 and 5 K reported a quenched propagation of helium through carbon nanotubes with diameters below 7 A despite the small kinetic diameter of helium atoms. After assessing the performance of a potential model for the He-nanotube interaction via ab initio calculations with density functional theory-based symmetry adapted perturbation theory, we apply orbital-free helium density functional theory to show that the counterintuitive experimental result is a consequence of the exceptionally high zero-point energy of helium and its tendency to form spatially separated layers of helium upon adsorption at the lowest temperatures. Helium filling factors are derived for a series of carbon nanotubes and compared to the available experimental data. PMID- 27934045 TI - Accurate Long-Time Mixed Quantum-Classical Liouville Dynamics via the Transfer Tensor Method. AB - In this Letter, we combine the recently introduced transfer tensor method with the mixed quantum-classical Liouville method. The resulting protocol provides an accurate, general, flexible and robust new route for simulating the reduced dynamics of the quantum subsystem for arbitrarily long times, starting with computationally feasible short-time mixed quantum-classical Liouville dynamical maps. The accuracy and feasibility of the methodology are demonstrated on a spin boson benchmark model. PMID- 27934046 TI - Correction to "Solid-Liquid Thermal Transport and Its Relationship with Wettability and the Interfacial Liquid Structure". PMID- 27934047 TI - Dynamics of the Hydration Water of Antifreeze Glycoproteins. AB - Antifreeze glycoproteins (AFGPs) are unique proteins that inhibit the growth of ice by a mechanism that is still unclear. We study the dynamics of water in aqueous solutions of small and large isoforms of AFGPs using polarization resolved femtosecond infrared spectroscopy. We find that a fraction of the water molecules is strongly slowed down by the interaction with the antifreeze glycoprotein surface. The fraction of slow water molecules scales with the size and concentration of AFGP, and is similar to the fraction of slow water observed for nonantifreeze proteins, both at room temperature and close to biologically relevant working temperatures. We observe that inhibiting AFGP antifreeze activity using borate buffer induces no changes in the dynamics of water hydrating the AFGP. Our findings support a mechanism in which the sugar unit of AFGP forms the active ice-binding site. PMID- 27934048 TI - Quantum-Classical Calculation of Vibronic Spectra along a Reaction Path: The Case of the ECD of Easily Interconvertible Conformers with Opposite Chiral Responses. AB - We present a novel mixed method suitable for computing the low-to-middle resolution spectra of systems characterized by a large-amplitude motion s (defined by either a reaction or an internal path) coupled to a bath of harmonic oscillators r, which change with s. The method is based on an adiabatic approximation whereby s is considered much slower than r degrees of freedom and is treated classically. We show that the spectrum can be obtained by a suitable average of quantum vibronic spectra of the fast coordinates computed at representative values of the slow coordinate along the path. By our method we calculate the electronic circular dichroism (ECD) of 2,2,2-trifluoro-anthryl ethanol, which possesses two conformers with opposite chirality separated by a low-energy barrier. Path-averaged spectra are significantly different from those obtained only at the stable minima: Agreement with experiment is improved. The method represents a generalization of those currently based on harmonic approximation. PMID- 27934049 TI - Protein Immobilization Capabilities of Sucrose and Trehalose Glasses: The Effect of Protein/Sugar Concentration Unraveled by High-Field EPR. AB - Disaccharide glasses are increasingly used to immobilize proteins at room temperature for structural/functional studies and long-term preservation. To unravel the molecular basis of protein immobilization, we studied the effect of sugar/protein concentration ratios in trehalose or sucrose matrixes, in which the bacterial photosynthetic reaction center (RC) was embedded as a model protein. The structural, dynamical, and H-bonding characteristics of the sugar-protein systems were probed by high-field W-band EPR of a matrix-dissolved nitroxide radical. We discovered that RC immobilization and thermal stabilization, being independent of the protein concentration in trehalose, occur in sucrose only at sufficiently low sugar/protein ratios. EPR reveals that only under such conditions does sucrose form a microscopically homogeneous matrix that immobilizes, via H-bonds, the nitroxide probe. We conclude that the protein immobilization capability depends critically on the propensity of the glass forming sugar to create intermolecular H-bond networks, thus establishing long range, homogeneous connectivity within the matrix. PMID- 27934050 TI - Electrostatic Deflection of a Molecular Beam of Massive Neutral Particles: Fully Field-Oriented Polar Molecules within Superfluid Nanodroplets. AB - Electric deflection measurements on liquid helium nanodroplets doped with individual polar molecules demonstrate that the cold superfluid matrix enables full orientation of the molecular dipole along the external field. This translates into a deflection force that is increased enormously by comparison with typical deflection experiments, and it becomes possible to measurably deflect neutral doped droplets with masses of tens to hundreds of thousands of Daltons. By using continuous fluxes of fully oriented polar molecules and measuring the deflection of the doped nanodroplet beam, this approach makes it possible to directly determine the dipole moments of internally cryogenically cold molecules. The technique is broadly and generally applicable, including to complex and biological molecules. PMID- 27934051 TI - Ultrafast Long-Range Charge Separation in Organic Photovoltaics: Promotion by Off Diagonal Vibronic Couplings and Entropy Increase. AB - The exciton dissociation in a model donor/acceptor heterojunction with electron phonon couplings is simulated by a full quantum dynamical method, in which ultrafast long-range charge separation is observed. Such a novel scenario does not undergo short-range interfacial (pinned) charge transfer states, but can be mainly ascribed to the quantum resonance between local Frenkel excited states and a broad array of long-range charge transfer (LRCT) states assisted by the moderate off-diagonal vibronic couplings. The entropy-increasing effect associated with the very dense density of states for LRCT states is also found to be beneficial for lowering the free energy barrier for charge generation in organic solar cells. PMID- 27934052 TI - Probing the Conductance of the sigma-System of Bipyridine Using Destructive Interference. AB - Guidelines to predict trends in the electrical conductance of molecules have been developed for the pi-system of conjugated systems. Little is known, however, about the conductance of the underlying sigma-systems because the pi-system usually dominates the transport. Here we study a family of bipyridine-based molecules using STM-break junction experiments and density functional theory transport calculations. We use different lengths and substitution patterns to probe the role of both the sigma-system and the pi-system in controlling conductance. By exploiting the destructive interference feature found in the pi system of the meta-coupled six-membered aromatic rings, we show that the conductance of the sigma-system of a meta-coupled molecule can be probed directly and can even exceed that of its para-coupled analog. These results add to the understanding of the conductance through the chemically hidden sigma-electrons. PMID- 27934053 TI - Mass Transport in Surface Diffusion of van der Waals Bonded Systems: Boosted by Rotations? AB - Mass transport at a surface is a key factor in heterogeneous catalysis. The rate is determined by excitation across a translational barrier and depends on the energy landscape and the coupling to the thermal bath of the surface. Here we use helium spin-echo spectroscopy to track the microscopic motion of benzene adsorbed on Cu(001) at low coverage (theta ~ 0.07 ML). Specifically, our combined experimental and computational data determine both the absolute rate and mechanism of the molecular motion. The observed rate is significantly higher by a factor of 3.0 +/- 0.1 than is possible in a conventional, point-particle model and can be understood only by including additional molecular (rotational) coordinates. We argue that the effect can be described as an entropic contribution that enhances the population of molecules in the transition state. The process is generally relevant to molecular systems and illustrates the importance of the pre-exponential factor alongside the activation barrier in studies of surface kinetics. PMID- 27934054 TI - Gold Nanorods as Plasmonic Sensors for Particle Diffusion. AB - Plasmonic gold nanoparticles are normally used as sensor to detect analytes permanently bound to their surface. If the interaction between the analyte and the nanosensor surface is negligible, it only diffuses through the sensor's sensing volume, causing a small temporal shift of the plasmon resonance position. By using a very sensitive and fast detection scheme, we are able to detect these small fluctuations in the plasmon resonance. With the help of a theoretical model consistent with our detection geometry, we determine the analyte's diffusion coefficient. The method is verified by observing the trends upon changing diffusor size and medium viscosity, and the diffusion coefficients obtained were found to reflect reduced diffusion close to a solid interface. Our method, which we refer to as NanoPCS (for nanoscale plasmon correlation spectroscopy), is of practical importance for any application involving the diffusion of analytes close to nanoparticles. PMID- 27934056 TI - Liquid-Phase Exfoliation of MoS2 Nanosheets: The Critical Role of Trace Water. AB - Sonication-assisted liquid-phase exfoliation of layered materials in suitable organic solvents offers a simple scalable route for the production of 2D nanomaterials. N-methyl-2-pyrrolidone (NMP) is one of the most efficient solvents for liquid-phase exfoliation of a variety of layered solids, including MoS2. We show here that trace water present in NMP is crucial for the stability of MoS2 nanosheets in NMP dispersions. In the absence of water, the sheets are fragmented and chemically unstable. Using solution NMR techniques, 2D nuclear Overhauser effect and spin-lattice relaxation measurements, supported by classical molecular dynamics simulations, we are able to establish the role of water molecules in stabilizing the dispersion. We show that water molecules are localized at the Mo terminated edges of the MoS2 sheets, thereby inhibiting chemical erosion of the sheets, and they also exhibit enhanced interactions with the solvent NMP molecules, leading to the stability of the dispersion. PMID- 27934057 TI - High-Throughput Two-Dimensional Infrared (2D IR) Spectroscopy Achieved by Interfacing Microfluidic Technology with a High Repetition Rate 2D IR Spectrometer. AB - The precision control of microfluidic technology was successfully interfaced with a 100 kHz two-dimensional infrared (2D IR) spectrometer to observe the sensitivity of the anion cyanate (OCN-) to the surrounding solvent environment in a high-throughput manner. Producing high-throughput 2D IR spectroscopy measurements allows us to observe the vibrational response of cyanate in mixed solvent environments. Changes in solvation environment around the cyanate ion yield frequency shifts from 2150 to 2165 cm-1 when moving from a pure dimethylformamide solvent environment to a pure methanol environment. 2D IR spectra were captured laterally across microfluidic devices tailored to produce a tunable gradient to observe the OCN- vibrational response to mixed solvent environments. These experiments reveal that there is no preferential solvation of cyanate in this system; instead, a more complex local solvent environment is observed. PMID- 27934055 TI - Sub-10 fs Time-Resolved Vibronic Optical Microscopy. AB - We introduce femtosecond wide-field transient absorption microscopy combining sub 10 fs pump and probe pulses covering the complete visible (500-650 nm) and near infrared (650-950 nm) spectrum with diffraction-limited optical resolution. We demonstrate the capabilities of our system by reporting the spatially- and spectrally-resolved transient electronic response of MAPbI3-xClx perovskite films and reveal significant quenching of the transient bleach signal at grain boundaries. The unprecedented temporal resolution enables us to directly observe the formation of band-gap renormalization, completed in 25 fs after photoexcitation. In addition, we acquire hyperspectral Raman maps of TIPS pentacene films with sub-400 nm spatial and sub-15 cm-1 spectral resolution covering the 100-2000 cm-1 window. Our approach opens up the possibility of studying ultrafast dynamics on nanometer length and femtosecond time scales in a variety of two-dimensional and nanoscopic systems. PMID- 27934058 TI - Interference of Interchromophoric Energy-Transfer Pathways in pi-Conjugated Macrocycles. AB - The interchromophoric energy-transfer pathways between weakly coupled units in a pi-conjugated phenylene-ethynylene macrocycle and its half-ring analogue have been investigated using the nonadiabatic excited-state molecular dynamics approach. To track the flow of electronic transition density between macrocycle units, we formulate a transition density flux analysis adapted from the statistical minimum flow method previously developed to investigate vibrational energy flow. Following photoexcitation, transition density is primarily delocalized on two chromophore units and the system undergoes ultrafast energy transfer, creating a localized excited state on a single unit. In the macrocycle, distinct chromophore units donate transition density to a single acceptor unit but do not interchange transition density among each other. We find that energy transfer in the macrocycle is slower than in the corresponding half ring because of the presence of multiple interfering energy-transfer pathways. Simulation results are validated by modeling the fluorescence anisotropy decay. PMID- 27934059 TI - Understanding Atomic-Scale Features of Low Temperature-Relaxation Dynamics in Metallic Glasses. AB - Being a key feature of a glassy state, low temperature relaxation has important implications on the mechanical behavior of glasses; however, the mechanism of low temperature relaxation is still an open issue, which has been debated for decades. By systematically investigating the influences of cooling rate and pressure on low temperature relaxation in the Zr50Cu50 metallic glasses, it is found that even though pressure does induce pronounced local structural change, the low temperature-relaxation behavior of the metallic glass is affected mainly by cooling rate, not by pressure. According to the atomic displacement and connection mode analysis, we further demonstrate that the low temperature relaxation is dominated by the dispersion degree of fast dynamic atoms rather than the most probable atomic nonaffine displacement. Our finding provides the direct atomic-level evidence that the intrinsic heterogeneity is the key factor that determines the low temperature-relaxation behavior of the metallic glasses. PMID- 27934060 TI - Coexistence of Superconductivity and Superhardness in Beryllium Hexaboride Driven by Inherent Multicenter Bonding. AB - Unique multicenter bonding in boron-rich materials leads to the formation of complex structures and intriguing properties. Here global structural searches are performed to unearth the structure of beryllium hexaboride (BeB6) synthesized decades ago. Three BeB6 phases (alpha, beta, and gamma) were predicted to be stable at ambient and high pressures. The ground state at ambient pressure, alpha BeB6, consists of a strong and uniformly distributed covalent B-B network, which results in exceptional elastic properties and a hardness of 46 GPa comparable to gamma-B. Even more surprisingly, alpha-BeB6 retains credible electron phonon coupling in the boron sublattice, and is predicted to be superconducting at 9 K. Above 4 GPa, beta-BeB6 is stabilized with alternating boron slabs and triangular beryllium layers analogous to the structure of MgB2. The beta-BeB6 is predicted to be superconducting at 24 K, similar to Nb3(Al,Ge). The gamma-BeB6 is stable above 340 GPa. The understanding of intrinsic multicenter-bonding mechanism and related properties demonstrated in the very example of BeB6 provides new insights for the design of tunable multifunctional materials. PMID- 27934062 TI - Step-Controlled Povarov-Type Reaction with 1,2-Dihydroquinolines as Precursors of Dienophiles: Direct Synthesis of Spirocyclic Bi-tetrahydroquinolines and Functionalized 1,2-Dihydroquinolines. AB - A novel Povarov-type reaction for straightforward synthesis of novel spiro bi tetrahydroquinolines with readily available 1,2-DHQs (1,2-dihydroquinolines) and aromatic imines was developed. The reaction could be selectively stopped at the first stage under a Bronsted acid catalyst to afford the corresponding functionalized 1,2-DHQs conveniently. PMID- 27934063 TI - Uncovering the Binding and Specificity of beta-Wrapins for Amyloid-beta and alpha Synuclein. AB - Amyloidogenic proteins amyloid-beta peptide (Abeta) and alpha-synuclein (alpha syn) self-assemble into fibrillar amyloid deposits, senile plaques and Lewy bodies, pathological features of Alzheimer's and Parkinson's diseases, respectively. Interestingly, a portion of Alzheimer's disease cases also exhibit aggregation of alpha-syn into Lewy bodies, and growing evidence also suggests that Abeta and alpha-syn oligomers are toxic. Therefore, the simultaneous inhibition through sequestration of the two amyloidogenic proteins may constitute a promising therapeutic strategy. Recently discovered beta-wrapin proteins pave the way toward this direction as they can inhibit the aggregation and toxicity of both Abeta and alpha-syn. Here, we used computational methods, primarily molecular dynamics simulations and free energy calculations, to shed light into the key interaction-based commonalities leading to the dual binding properties of beta-wrapins for both amyloidogenic proteins, to identify which interactions potentially act as switches diminishing beta-wrapins' binding activity for Abeta/alpha-syn, and to examine the binding properties of the current most potent beta-wrapin for Abeta. Our analysis provides insights into the distinct role of the key determinants leading to beta-wrapin binding to Abeta and alpha-syn, and suggests that the Abeta 18VFFAED23 and alpha-syn 38LYVGSK43 are key domains determining the binding specificity of a beta-wrapin. Our findings can potentially lead to the discovery of novel therapeutics for Alzheimer's and Parkinson's diseases. PMID- 27934064 TI - Correction to "Effect of Interparticle Interactions on Agglomeration and Sedimentation Rates of Colloidal Silica Microspheres". PMID- 27934065 TI - Sugar Surfactant Based Microemulsions at Solid Surfaces: Influence of the Oil Type and Surface Polarity. AB - The structure of sugar-surfactant-based bicontinuous microemulsions in the bulk and at hydrophilic and hydrophobic solid planar surfaces was studied by means of neutron scattering techniques (SANS, NR, and GISANS). In particular, the influence of the type of oil (tetradecane and methyl oleate) on the structural properties in the vicinity of surfaces was investigated at different oil-to-water ratios. In the case of hydrophilic surfaces, the analysis of the scattering length density profiles reveals an induced ordering of the oil and water domains perpendicular to the solid-liquid interface in both sets of microemulsions. At hydrophobic surfaces, differences in the near-surface ordering between microemulsions containing polar and nonpolar oils are observed. PMID- 27934066 TI - Nanopores and Nanochannels: From Gene Sequencing to Genome Mapping. AB - DNA strands can be analyzed at the single-molecule level by isolating them inside nanoscale holes. The strategy is used for the label-free and portable sequencing with nanopores. Nanochannels can also be applied to map genomes with high resolution, as shown by Jeffet et al. in this issue of ACS Nano. Here, we compare the two strategies in terms of biophysical similarities and differences and describe that both are complementary and can improve the DNA analysis for genomic research and diagnostics. PMID- 27934067 TI - Architectural Engineering of Nanowire Network Fine Pattern for 30 MUm Wide Flexible Quantum Dot Light-Emitting Diode Application. AB - Replacing rigid metal oxides with flexible alternatives as a next-generation transparent conductor is important for flexible optoelectronic devices. Recently, nanowire networks have emerged as a new type of transparent conductor and have attracted wide attention because of their all-solution-based process manufacturing and excellent flexibility. However, the intrinsic percolation characteristics of the network determine that its fine pattern behavior is very different from that of continuous films, which is a critical issue for their practical application in high-resolution devices. Herein, a simple optimization approach is proposed to address this issue through the architectural engineering of the nanowire network. The aligned and random silver nanowire networks are fabricated and compared in theory and experimentally. Remarkably, network performance can be notably improved with an aligned structure, which is helpful for external quantum efficiency and the luminance of quantum dot light-emitting diodes (QLEDs) when the network is applied as the bottom-transparent electrode. More importantly, the advantage introduced by network alignment is also of benefit to fine pattern performance, even when the pattern width is narrowed to 30 MUm, which leads to improved luminescent properties and lower failure rates in fine QLED strip applications. This paradigm illuminates a strategy to optimize nanowire network based transparent conductors and can promote their practical application in high-definition flexible optoelectronic devices. PMID- 27934068 TI - Increased Gold Nanoparticle Retention in Brain Tumors by in Situ Enzyme-Induced Aggregation. AB - The treatment of brain tumors remains a challenge due to the limited accumulation of drugs and nanoparticles. Here, we triggered the aggregation of gold nanoparticles (AuNPs) using legumain to enhance the retention of chemotherapeutics in brain tumors. This nanoplatform, AuNPs-A&C, is comprised of Ala-Ala-Asn-Cys-Lys modified AuNPs (AuNPs-AK) and 2-cyano-6-aminobenzothiazole modified AuNPs (AuNPs-CABT). AuNPs-AK could be hydrolyzed to expose the 1,2 thiolamino groups on AuNPs-AK in the presence of legumain, which occurs by a click cycloaddition with the contiguous cyano group on AuNPs-CABT, resulting in formation of AuNPs aggregates. This strategy led to an enhanced retention of the AuNPs in glioma cells both in vitro and in vivo due to the blocking of nanoparticle exocytosis and minimizing nanoparticle backflow to the bloodstream. After conjugation of doxorubicin (DOX) via a pH-sensitive linker to AuNPs-A&C, the efficiency for treating glioma was improved. The median survival time for the DOX-linked AuNPs-A&C increased to 288% in comparison to the saline group. We further show the use of the AuNPs-A&C for optical imaging applications. In conclusion, we provide a strategy to increase nanoparticle tumor accumulation with the potential to improve therapeutic outcome. PMID- 27934069 TI - Blood-Brain-Barrier-Penetrating Albumin Nanoparticles for Biomimetic Drug Delivery via Albumin-Binding Protein Pathways for Antiglioma Therapy. AB - Nutrient transporters have been explored for biomimetic delivery targeting the brain. The albumin-binding proteins (e.g., SPARC and gp60) are overexpressed in many tumors for transport of albumin as an amino acid and an energy source for fast-growing cancer cells. However, their application in brain delivery has rarely been investigated. In this work, SPARC and gp60 overexpression was found on glioma and tumor vessel endothelium; therefore, such pathways were explored for use in brain-targeting biomimetic delivery. We developed a green method for blood-brain barrier (BBB)-penetrating albumin nanoparticle synthesis, with the capacity to coencapsulate different drugs and no need for cross-linkers. The hydrophobic drugs (i.e., paclitaxel and fenretinide) yield synergistic effects to induce albumin self-assembly, forming dual drug-loaded nanoparticles. The albumin nanoparticles can penetrate the BBB and target glioma cells via the mechanisms of SPARC- and gp60-mediated biomimetic transport. Importantly, by modification with the cell-penetrating peptide LMWP, the albumin nanoparticles display enhanced BBB penetration, intratumoral infiltration, and cellular uptake. The LMWP-modified nanoparticles exhibited improved treatment outcomes in both subcutaneous and intracranial glioma models, with reduced toxic side effects. The therapeutic mechanisms were associated with induction of apoptosis, antiangiogenesis, and tumor immune microenvironment regulation. It provides a facile method for dual drug-loaded albumin nanoparticle preparation and a promising avenue for biomimetic delivery targeting the brain tumor based on combination therapy. PMID- 27934070 TI - All-in-One Shape-Adaptive Self-Charging Power Package for Wearable Electronics. AB - Recently, a self-charging power unit consisting of an energy harvesting device and an energy storage device set the foundation for building a self-powered wearable system. However, the flexibility of the power unit working under extremely complex deformations (e.g., stretching, twisting, and bending) becomes a key issue. Here, we present a prototype of an all-in-one shape-adaptive self charging power unit that can be used for scavenging random body motion energy under complex mechanical deformations and then directly storing it in a supercapacitor unit to build up a self-powered system for wearable electronics. A kirigami paper based supercapacitor (KP-SC) was designed to work as the flexible energy storage device (stretchability up to 215%). An ultrastretchable and shape adaptive silicone rubber triboelectric nanogenerator (SR-TENG) was utilized as the flexible energy harvesting device. By combining them with a rectifier, a stretchable, twistable, and bendable, self-charging power package was achieved for sustainably driving wearable electronics. This work provides a potential platform for the flexible self-powered systems. PMID- 27934072 TI - Walking the Walk: A Giant Step toward Sustainable Plasmonics. AB - The use of earth-abundant materials is at the frontier of nanoplasmonics research, where their availability and low cost can enable practical mainstream applications and commercial viability. Aluminum is of specific interest in this regard, due to its ability to support plasmon resonances throughout the ultraviolet (UV), visible, and infrared regions of the spectrum. However, the lack of accurate dielectric data has critically limited the agreement between theoretical predictions and experimental measurements of the optical properties of Al nanostructures compared, for example, to the agreement enjoyed by the noble/coinage metals. As reported in this issue of ACS Nano, efforts by Cheng et al. to determine the dielectric function of pristine Al show that Al has substantially lower loss than was indicated by previously reported dielectric data for Al, including a 2-fold lower loss for the UV region compared to that in previous studies. These results provide data that are essential for accurate agreement between theory and experiment for Al plasmonic nanostructures, placing this earth-abundant metal on sound footing as a new and highly promising material for sustainable plasmonics by design. PMID- 27934071 TI - Complex Arrangement of Orthogonal Nanoscale Columns via a Supramolecular Orientational Memory Effect. AB - Memory effects, including shape, chirality, and liquid-crystallinity, have enabled macroscopic materials with novel functions. However, the generation of complex supramolecular nanosystems via memory effects has not yet been investigated. Here, we report a cyclotriveratrylene-crown (CTV) compound that self-assembles into supramolecular columns and spheres forming, respectively, hexagonal and cubic mesophases. Upon transition from one phase to the other, an epitaxial relationship holds, via an unprecedented supramolecular orientational memory effect. Specifically, the molecular orientation and columnar character of supramolecular packing is preserved in the cubic phase, providing an otherwise inaccessible structure comprising orthogonally oriented domains of supramolecular columns. The continuous columnar character of tetrahedrally distorted supramolecular spheres self-organized from the CTV derivative in the faces of the Pm3n lattice is the basis of this supramolecular orientational memory, which holds throughout cycling in temperature between the two phases. This concept is expected to be general for other combinations of periodic and quasiperiodic arrays generated from supramolecular spheres upon transition to supramolecular columns. PMID- 27934073 TI - Growth of Highly Strained CeO2 Ultrathin Films. AB - Large biaxial strain is a promising route to tune the functionalities of oxide thin films. However, large strain is often not fully realized due to the formation of misfit dislocations at the film/substrate interface. In this work, we examine the growth of strained ceria (CeO2) thin films on (001)-oriented single crystal yttria-stabilized zirconia (YSZ) via pulsed-laser deposition. By varying the film thickness systematically between 1 and 430 nm, we demonstrate that ultrathin ceria films are coherently strained to the YSZ substrate for thicknesses up to 2.7 nm, despite the large lattice mismatch (~5%). The coherency is confirmed by both X-ray diffraction and high-resolution transmission electron microscopy. This thickness is several times greater than the predicted equilibrium critical thickness. Partial strain relaxation is achieved by forming semirelaxed surface islands rather than by directly nucleating dislocations. In situ reflective high-energy electron diffraction during growth confirms the transition from 2-D (layer-by-layer) to 3-D (island) at a film thickness of ~1 nm, which is further supported by atomic force microscopy. We propose that dislocations likely nucleate near the surface islands and glide to the film/substrate interface, as evidenced by the presence of 60 degrees dislocations. An improved understanding of growing oxide thin films with a large misfit lays the foundation to systematically explore the impact of strain and dislocations on properties such as ionic transport and redox chemistry. PMID- 27934074 TI - Cancer Cell Membrane-Biomimetic Nanoparticles for Homologous-Targeting Dual-Modal Imaging and Photothermal Therapy. AB - An active cell membrane-camouflaged nanoparticle, owning to membrane antigens and membrane structure, can achieve special properties such as specific recognition, long blood circulation, and immune escaping. Herein, we reported a cancer cell membrane-cloaked nanoparticle system as a theranostic nanoplatform. The biomimetic nanoparticles (indocyanine green (ICG)-loaded and cancer cell membrane coated nanoparticles, ICNPs) exhibit a core-shell nanostructure consisting of an ICG-polymeric core and cancer cell membrane shell. ICNPs demonstrated specific homologous targeting to cancer cells with good monodispersity, preferable photothermal response, and excellent fluorescence/photoacoustic (FL/PA) imaging properties. Benefited from the functionalization of the homologous binding adhesion molecules from cancer cell membranes, ICNPs significantly promoted cell endocytosis and homologous-targeting tumor accumulation in vivo. Moreover, ICNPs were also good at disguising as cells to decrease interception by the liver and kidney. Through near-infrared (NIR)-FL/PA dual-modal imaging, ICNPs could realize real-time monitored in vivo dynamic distribution with high spatial resolution and deep penetration. Under NIR laser irradiation, ICNPs exhibited highly efficient photothermal therapy to eradicate xenografted tumor. The robust ICNPs with homologous properties of cancer cell membranes can serve as a bionic nanoplatform for cancer-targeted imaging and phototherapy. PMID- 27934076 TI - "Silent" Amino Acid Residues at Key Subunit Interfaces Regulate the Geometry of Protein Nanocages. AB - Rendering the geometry of protein-based assemblies controllable remains challenging. Protein shell-like nanocages represent particularly interesting targets for designed assembly. Here, we introduce an engineering strategy-key subunit interface redesign (KSIR)-that alters a natural subunit-subunit interface by selective deletion of a small number of "silent" amino acid residues (no participation in interfacial interactions) into one that triggers the generation of a non-native protein cage. We have applied KSIR to construct a non-native 48 mer nanocage from its native 24-mer recombinant human H-chain ferritin (rHuHF). This protein is a heteropolymer composed of equal numbers of two different subunits which are derived from one polypeptide. This strategy has allowed the study of conversion between protein nanocages with different geometries by re engineering key subunit interfaces and the demonstration of the important role of the above-mentioned specific residues in providing geometric specificity for protein assembly. PMID- 27934077 TI - Molding Inkjetted Silver on Nanostructured Surfaces for High-Throughput Structural Color Printing. AB - Inkjet printing of silver ink has been widely used to print conductive patterns in flexible electronic devices, and the printed patterns are commonly known to be colorless. We demonstrate that by printing a single type of ordinary silver nanoparticle ink on top of a substrate patterned with polymer nanostructures, the printed silver is molded by the nanostructures and gains robust structural colors. The colors are tunable by varying the geometries of nanostructures, and a broad range of visual colors can be achieved by mixing the red, green, and blue colors displayed from silver dots printed on different nanostructures. Such mechanism can enable full-color, scalable, high-throughput, versatile, and cost effective printing of structural color images for regular publishing and displaying purposes. In experiments, we implemented a transparent polymer substrate patterned with diffractive nanostructure arrays to print full-color images. The printed images display color-shifting optically variable effects useful for security and authentication applications that demand customizable anticounterfeiting features. PMID- 27934078 TI - Multiscale Hyperporous Silicon Flake Anodes for High Initial Coulombic Efficiency and Cycle Stability. AB - Three-dimensional (3D) hyperporous silicon flakes (HPSFs) are prepared via the chemical reduction of natural clay minerals bearing metal oxides. Natural clays generally have 2D flake-like structures with broad size distributions in the lateral dimension and varied thicknesses depending on the first processing condition from nature. They have repeating layers of silicate and metal oxides in various ratios. When the clay mineral is subjected to a reduction reaction, metal oxide layers can perform a negative catalyst for absorbing large amounts of exothermic heat from the reduction reaction of the silicate layers with metal reductant. Selectively etching out metal oxides shows a hyperporous nanoflake structure containing 100 nm macropores and meso-/micropores on its framework. The resultant HPSFs are demonstrated as anode materials for lithium-ion batteries. Compared to conventional micro-Si anodes, HPSFs exhibit exceptionally high initial Coulombic efficiency over 92%. Furthermore, HPSF anodes show outstanding cycling performance (reversible capacity of 1619 mAh g-1 at a rate of 0.5 C after 200 cycles, 95.2% retention) and rate performance (~580 mAh g-1 at a rate of 10 C) owing to their distinctive structure. PMID- 27934079 TI - Atomic Structure and Dynamics of Epitaxial 2D Crystalline Gold on Graphene at Elevated Temperatures. AB - The atomic level dynamics of gold on graphene is studied at temperatures up to 800 degrees C using an in situ heating holder within an aberration-corrected transmission electron microscope. At this high temperature, individual gold atoms and nanoclusters are mobile across the surface of graphene and attach to defect sites and migrate along the edges of holes in graphene. Gold nanoclusters on clean graphene show crystallinity at temperatures above their predicted melting point for equivalent sized clusters due to strong epitaxial interactions with the underlying graphene lattice. Gold nanoclusters anchored to defect sites in graphene exhibit discrete rotations between fixed orientations while maintaining epitaxial correlations to the graphene. We show that gold nanoclusters can be two dimensional with monolayer thickness and switch their crystal structure between two different phases. These results have important implications on the use of gold nanoclusters on graphene at elevated temperatures for applications, such as catalysis and plasmonics. PMID- 27934080 TI - Remote Control of Light-Triggered Virotherapy. AB - Clinical virotherapy has been successfully approved for use in cancer treatment by the U.S. Food and Drug Administration; however, a number of improvements are still sought to more broadly develop virotherapy. A particular challenge is to administer viral therapy systemically and overcome limitations in intratumoral injection, especially for complex tumors within sensitive organs. To achieve this, however, a technique is required that delivers the virus to the tumor before the body's natural self-defense eradicates the virus prematurely. Here we show that recombinant adeno-associated virus serotype 2 (AAV2) chemically conjugated with iron oxide nanoparticles (~5 nm) has a remarkable ability to be remotely guided under a magnetic field. Transduction is achieved with microscale precision. Furthermore, a gene for production of the photosensitive protein KillerRed was introduced into the AAV2 genome to enable photodynamic therapy (PDT), or light-triggered virotherapy. In vivo experiments revealed that magnetic guidance of "ironized" AAV2-KillerRed injected by tail vein in conjunction with PDT significantly decreases the tumor growth via apoptosis. This proof-of principle demonstrates guided and highly localized microscale, light-triggered virotherapy. PMID- 27934081 TI - Nanoscale Direct Mapping of Noise Source Activities on Graphene Domains. AB - An electrical noise is one of the key parameters determining the performance of modern electronic devices. However, it has been extremely difficult, if not impossible, to image localized noise sources or their activities in such devices. We report a "noise spectral imaging" strategy to map the activities of localized noise sources in graphene domains. Using this method, we could quantitatively estimate sheet resistances and noise source densities inside graphene domains, on domain boundaries and on the edge of graphene. The results show high activities of noise sources and large sheet resistance values at the domain boundary and edge of graphene. Additionally, we showed that the top layer in double-layer graphene had lower noises than single-layer graphene. This work provides valuable insights about the electrical noises of graphene. Furthermore, the capability to directly map noise sources in electronic channels can be a major breakthrough in electrical noise research in general. PMID- 27934082 TI - Redox-Mediated Disassembly to Build Activatable Trimodal Probe for Molecular Imaging of Biothiols. AB - Activatable multimodal probes that show enhancement of multiplex imaging signals upon interaction with their specific molecular target have become powerful tools for rapid and precise imaging of biological processes. Herein, we report a stimuli-responsive disassembly approach to construct a redox-activatable fluorescence/19F-MRS/1H-MRI triple-functional probe 1. The small molecule probe 1 itself has a high propensity to self-assemble into nanoparticles with quenched fluorescence, attenuated 19F-MRS signal, and high 1H-MRI contrast. Biothiols that are abundant in reducing biological environment were able to cleave the disulfide bond in probe 1 to induce disassembly of the nanoparticles and lead to fluorescence activation (~70-fold), 19F-MRS signal amplification (~30-fold) and significant r1 relaxivity reduction (~68% at 0.5 T). Molecular imaging of reducing environment in live cells and in vivo was realized using probe 1. This approach could facilitate the development of other stimuli-responsive trimodal probes for molecular imaging. PMID- 27934083 TI - Self-Assembled, Nanostructured, Tunable Metamaterials via Spinodal Decomposition. AB - Self-assembly via nanoscale phase separation offers an elegant route to fabricate nanocomposites with physical properties unattainable in single-component systems. One important class of nanocomposites are optical metamaterials which exhibit exotic properties and lead to opportunities for agile control of light propagation. Such metamaterials are typically fabricated via expensive and hard to-scale top-down processes requiring precise integration of dissimilar materials. In turn, there is a need for alternative, more efficient routes to fabricate large-scale metamaterials for practical applications with deep subwavelength resolution. Here, we demonstrate a bottom-up approach to fabricate scalable nanostructured metamaterials via spinodal decomposition. To demonstrate the potential of such an approach, we leverage the innate spinodal decomposition of the VO2-TiO2 system, the metal-to-insulator transition in VO2, and thin-film epitaxy, to produce self-organized nanostructures with coherent interfaces and a structural unit cell down to 15 nm (tunable between horizontally and vertically aligned lamellae) wherein the iso-frequency surface is temperature-tunable from elliptic to hyperbolic dispersion producing metamaterial behavior. These results provide an efficient route for the fabrication of nanostructured metamaterials and other nanocomposites for desired functionalities. PMID- 27934085 TI - Standardizing Nanomaterials. PMID- 27934084 TI - Highly Sensitive and Quick Detection of Acute Myocardial Infarction Biomarkers Using In2O3 Nanoribbon Biosensors Fabricated Using Shadow Masks. AB - We demonstrate a scalable and facile lithography-free method for fabricating highly uniform and sensitive In2O3 nanoribbon biosensor arrays. Fabrication with shadow masks as the patterning method instead of conventional lithography provides low-cost, time-efficient, and high-throughput In2O3 nanoribbon biosensors without photoresist contamination. Combined with electronic enzyme linked immunosorbent assay for signal amplification, the In2O3 nanoribbon biosensor arrays are optimized for early, quick, and quantitative detection of cardiac biomarkers in diagnosis of acute myocardial infarction (AMI). Cardiac troponin I (cTnI), creatine kinase MB (CK-MB), and B-type natriuretic peptide (BNP) are commonly associated with heart attack and heart failure and have been selected as the target biomarkers here. Our approach can detect label-free biomarkers for concentrations down to 1 pg/mL (cTnI), 0.1 ng/mL (CK-MB), and 10 pg/mL (BNP), all of which are much lower than clinically relevant cutoff concentrations. The sample collection to result time is only 45 min, and we have further demonstrated the reusability of the sensors. With the demonstrated sensitivity, quick turnaround time, and reusability, the In2O3 nanoribbon biosensors have shown great potential toward clinical tests for early and quick diagnosis of AMI. PMID- 27934086 TI - Multimodal Photodiode and Phototransistor Device Based on Two-Dimensional Materials. AB - With strong light-matter interaction in their atomically thin layered structures, two-dimensional (2D) materials have been widely investigated for optoelectronic applications such as photodetectors and photovoltaic devices. Depending on the aim of optoelectronic applications, different device structures have been employed. Lateral phototransistor structures have been employed for high optical gain, while vertical photodiode structures have been employed for fast response and low power operation. Herein, we demonstrate a multimodal photodetector platform based on 2D materials, combining both a phototransistor and a photodiode and taking the corresponding desirable characteristics from each structure within a single device. In this platform, a multilayered transition-metal dichalcogenide flake is transferred on top of metal electrodes, and a transparent gate electrode is employed. The channel region of the flake between electrodes operates as a phototransistor providing a high gain mode, while the electrode region in the same flake operates as a vertical Schottky photodiode providing a fast response mode. These modes can be dynamically selected by controlling the drain voltage and gate voltage. PMID- 27934087 TI - A Multifunctional Platform for Tumor Angiogenesis-Targeted Chemo-Thermal Therapy Using Polydopamine-Coated Gold Nanorods. AB - Image-guided combined chemo-thermal therapy assists in optimizing treatment time, enhancing therapeutic efficiency, and circumventing side effects. In the present study, we developed a chemo-photothermal theranostic platform based on polydopamine (PDA)-coated gold nanorods (GNRs). The PDA coating was thin; however, it significantly suppressed the cytotoxicity of the cetyltrimethylammonium bromide template and allowed high cisplatin loading efficiency, arginine-glycine-aspartic acid (RGD) peptide (c(RGDyC)) conjugation, and chelator-free iodine-125 labeling (RGD-125IPt-PDA@GNRs). While loaded cisplatin was released in a pH-sensitive manner, labeled 125I was outstandingly stable under biological conditions. RGD-125IPt-PDA@GNRs had a high specificity for alphavbeta3 integrin, and consequently, they could selectively accumulate in tumors, as revealed by single photon emission computed tomography/CT imaging, and in target tumor angiogenic vessels, as shown by high-resolution photoacoustic imaging. As RGD-125IPt-PDA@GNRs targets tumor angiogenesis, it is a highly potent tumor therapy. Combined chemo-photothermal therapy with probes could thoroughly ablate tumors and inhibit tumor relapse via a synergistic antitumor effect. Our studies demonstrated that RGD-125IPt-PDA@GNRs is a robust platform for image guided, chemo-thermal tumor therapy with outstanding synergistic tumor killing and relapse inhibition effects. PMID- 27934088 TI - Biomimetic Light-Harvesting Antenna Based on the Self-Assembly of Conjugated Polyelectrolytes Embedded within Lipid Membranes. AB - Here we report a biomimetic light-harvesting antenna based on negatively charged poly(phenylene ethynylene) conjugated polyelectrolytes assembled within a positively charged lipid membrane scaffold constructed by the lipid 1,2-dioleoyl 3-trimethylammonium-propane (DOTAP). Light harvested by the polymers was transferred via through-space mechanisms to a lipophilic energy acceptor (the cyanine dye DiI) whose effective molar absorption was enhanced by up to 18-fold due to the antenna effect. Absorption amplification of DiI was found to be due primarily to direct energy transfer from polymers. The efficiency of homoenergy transfer among polymers was next probed by the membrane embedding fullerene derivative phenyl-C61-butryic acid methyl ester (PCBM) acting as an electron acceptor. PCBM was able to quench the emission of up to five polymers, consistent with a modest amount of homotransfer. The ability of the membrane to accommodate a high density of polymer donors without self-quenching was crucial to the success of electronic energy harvesting achieved. This work highlights the potential of lipid membranes as a platform to organize light-harvesting molecules on the nanoscale toward achieving efficient energy transfer to a target chromophore/trap. PMID- 27934089 TI - Facet Energy versus Enzyme-like Activities: The Unexpected Protection of Palladium Nanocrystals against Oxidative Damage. AB - To develop nanomaterials as artificial enzymes, it is necessary to better understand how their physicochemical properties affect their enzyme-like activities. Although prior research has demonstrated that nanomaterials exhibit tunable enzyme-like activities depending on their size, structure, and composition, few studies have examined the effect of surface facets, which determine surface energy or surface reactivity. Here, we use electron spin resonance spectroscopy to report that lower surface energy {111}-faceted Pd octahedrons have greater intrinsic antioxidant enzyme-like activity than higher surface energy {100}-faceted Pd nanocubes. Our in vitro experiments found that those same Pd octahedrons are more effective than Pd nanocubes at scavenging reactive oxygen species (ROS). Those reductions in ROS preserve the homogeneity of mitochondrial membrane potential and attenuate damage to important biomolecules, thereby allowing a substantially higher number of cells to survive oxidative challenges. Our computations of molecular mechanisms for the antioxidant activities of {111}- and {100}-faceted Pd nanocrystals, as well as their activity order, agree well with experimental observations. These findings can guide the design of antioxidant-mimicking nanomaterials, which could have therapeutic or preventative potential against oxidative stress related diseases. PMID- 27934091 TI - Ultrafast Charge Transfer and Enhanced Absorption in MoS2-Organic van der Waals Heterojunctions Using Plasmonic Metasurfaces. AB - Hybrid organic-inorganic heterostructures are attracting tremendous attention for optoelectronic applications due to their low-cost processing and high performance in devices. In particular, van der Waals p-n heterojunctions formed between inorganic two-dimensional (2D) materials and organic semiconductors are of interest due to the quantum confinement effects of 2D materials and the synthetic control of the physical properties of organic semiconductors, enabling a high degree of tunable optoelectronic properties for the heterostructure. However, for photovoltaic applications, hybrid 2D-organic heterojunctions have demonstrated low power conversion efficiencies due to the limited absorption from constraints on the physical thickness of each layer. Here, we investigate the ultrafast charge transfer dynamics between an organic polymer:fullerene blend and 2D n-type MoS2 using transient pump-probe reflectometry. We employ plasmonic metasurfaces to enhance the absorption and charge photogeneration within the physically thin hybrid MoS2-organic heterojunction. For the hybrid MoS2-organic heterojunction in the presence of the plasmonic metasurface, the charge generation within the polymer is enhanced 6-fold, and the total active layer absorption bandwidth is increased by 90 nm relative to the polymer:fullerene blend alone. We demonstrate that MoS2-organic heterojunctions can serve as hybrid solar cells, and their efficiencies can be improved using plasmonic metasurfaces. PMID- 27934090 TI - Atomic Structure and Spectroscopy of Single Metal (Cr, V) Substitutional Dopants in Monolayer MoS2. AB - Dopants in two-dimensional dichalcogenides have a significant role in affecting electronic, mechanical, and interfacial properties. Controllable doping is desired for the intentional modification of such properties to enhance performance; however, unwanted defects and impurity dopants also have a detrimental impact, as often found for chemical vapor deposition (CVD) grown films. The reliable identification, and subsequent characterization, of dopants is therefore of significant importance. Here, we show that Cr and V impurity atoms are found in CVD grown MoS2 monolayer 2D crystals as single atom substitutional dopants in place of Mo. We attribute these impurities to trace elements present in the MoO3 CVD precursor. Simultaneous annular dark field scanning transmission electron microscopy (ADF-STEM) and electron energy loss spectroscopy (EELS) is used to map the location of metal atom substitutions of Cr and V in MoS2 monolayers with single atom precision. The Cr and V are stable under electron irradiation at 60 to 80 kV, when incorporated into line defects, and when heated to elevated temperatures. The combined ADF-STEM and EELS differentiates these Cr and V dopants from other similar contrast defect structures, such as 2S self-interstitials at the Mo site, preventing misidentification. Density functional theory calculations reveal that the presence of Cr or V causes changes to the density of states, indicating doping of the MoS2 material. These transferred impurities could help explain the presence of trapped charges in CVD prepared MoS2. PMID- 27934092 TI - Photoprompted Hot Electrons from Bulk Cross-Linked Graphene Materials and Their Efficient Catalysis for Atmospheric Ammonia Synthesis. AB - Ammonia synthesis is the single most important chemical process in industry and has used the successful heterogeneous Haber-Bosch catalyst for over 100 years and requires processing under both high temperature (300-500 degrees C) and pressure (200-300 atm); thus, it has huge energy costs accounting for about 1-3% of human's energy consumption. Therefore, there has been a long and vigorous exploration to find a milder alternative process. Here, we demonstrate that by using an iron- and graphene-based catalyst, Fe@3DGraphene, hot (ejected) electrons from this composite catalyst induced by visible light in a wide range of wavelength up to red could efficiently facilitate the activation of N2 and generate ammonia with H2 directly at ambient pressure using light (including simulated sun light) illumination directly. No external voltage or electrochemical or any other agent is needed. The production rate increases with increasing light frequency under the same power and with increasing power under the same frequency. The mechanism is confirmed by the detection of the intermediate N2H4 and also with a measured apparent activation energy only ~1/4 of the iron based Haber-Bosch catalyst. Combined with the morphology control using alumina as the structural promoter, the catalyst retains its activity in a 50 h test. PMID- 27934093 TI - Visualization of Stepwise Drug-Micelle Aggregate Formation and Correlation with Spectroscopic and Calorimetric Results. AB - Palmatine and berberine, imperative isoquinoline alkaloids, have many potential therapeutic uses. We visualized the stepwise complex formation between these alkaloids and sodium dodecyl sulfate (SDS), a known anionic surfactant characterizing alkaloid-induced SDS micelle formation at different stages. UV visible spectra directly divulged the complex formation at different stages, and this was supported by the fluorescence emission spectral and fluorescence anisotropy data. Fluorescence quenching experiments precisely located the alkaloid molecules in the micellar environment above the critical micelle concentration (CMC). The thermodynamics of the alkaloid binding and micelle formation suggested an exothermic enthalpy-driven initial electrostatic binding followed by an endothermic entropy-driven binding in the micellar core, both being spontaneous in nature. The atomic force microscopy results clearly visualized the shape and size of the alkaloid-induced micelles. This study presents stepwise characterization of alkaloid-SDS interaction below and above the CMC. PMID- 27934094 TI - Fixation and Permeabilization Approaches for Scanning Electrochemical Microscopy of Living Cells. AB - Scanning electrochemical microscopy (SECM) has been widely used for the electrochemical imaging of dynamic topographical and metabolic changes in alive adherent mammalian cells. However, extracting intracellular information by SECM is challenging, since it requires redox species to travel in and out the lipid cell membrane. Herein, we present cell fixation and permeabilization approaches as an alternative tool for visualizing cell properties by SECM. With this aim, adherent cells were analyzed in the SECM feedback mode in three different conditions: (i) alive; (ii) fixed, and (iii) fixed and permeabilized. The fixation was carried out with formaldehyde and does not damage lipid membranes. Therefore, this strategy can be used for the SECM investigation of cell topography or the passive transport of the redox mediator into the cells. Additional permeabilization of the cell membrane after fixation enables the analysis of the intracellular content through the coupling of SECM with immunoassay strategies for the detection of specific biomarkers. The latter was successfully applied as an easy and fast screening approach to detect the expression of the melanoma-associated marker tyrosinase in adherent melanoma cell lines corresponding to different cancer progression stages using the SECM substrate generation-tip collection mode. The present approach is simple, fast, and reliable and can open new ways to analyze cell cultures with electrochemically based scanning probe techniques. PMID- 27934095 TI - Biomimetic Optical-Filter Detection System for Discrimination of Infrared Chemical Signatures. AB - Optical-filter-based chemical sensors have the potential to dramatically alter the field of hazardous materials sensing. Such devices could be constructed using inexpensive components, in a small and lightweight package, for sensing hazardous chemicals in defense, industrial, and environmental applications. Filter-based sensors can be designed to mimic human color vision. Recent developments in this field have used this approach to discriminate between strongly overlapping chemical signatures in the mid-infrared. Reported work relied on using numerically filtered FTIR spectra to model the infrared biomimetic detection methodology. While these findings are encouraging, further advancement of this technique requires the collection and evaluation of directly filtered data, using an optical system without extensive numerical spectral analysis. The present work describes the design and testing of an infrared optical breadboard system that uses the biomimetic mammalian color-detection approach to chemical sensing. The set of chemicals tested includes one target chemical, fuel oil, along with two strongly overlapping interferents, acetone and hexane. The collected experimental results are compared with numerically filtered FTIR spectral data. The results show good agreement between the numerically filtered data model and the data collected using the optical breadboard system. It is shown that the optical breadboard system is operating as expected based on modeling and can be used for sensing and discriminating between chemicals with strongly overlapping absorption bands in the mid-infrared. PMID- 27934096 TI - Microfluidic Air Sampler for Highly Efficient Bacterial Aerosol Collection and Identification. AB - The early warning capability of the presence of biological aerosol threats is an urgent demand in ensuing civilian and military safety. Efficient and rapid air sample collection in relevant indoor or outdoor environment is a key step for subsequent analysis of airborne microorganisms. Herein, we report a portable battery-powered sampler that is capable of highly efficient bioaerosol collection. The essential module of the sampler is a polydimethylsiloxane (PDMS) microfluidic chip, which consisted of a 3-loop double-spiral microchannel featuring embedded herringbone and sawtooth wave-shaped structures. Vibrio parahemolyticus (V. parahemolyticus) as a model microorganism, was initially employed to validate the bioaerosol collection performance of the device. Results showed that the sampling efficacy reached as high as >99.9%. The microfluidic sampler showed greatly improved capturing efficiency compared with traditional plate sedimentation methods. The high performance of our device was attributed to the horizontal inertial centrifugal force and the vertical turbulence applied to airflow during sampling. The centrifugation field and turbulence were generated by the specially designed herringbone structures when air circulated in the double-spiral microchannel. The sawtooth wave-shaped microstructure created larger specific surface area for accommodating more aerosols. Furthermore, a mixture of bacterial aerosols formed by V. parahemolyticus, Listeria monocytogenes, and Escherichia coli was extracted by the microfluidic sampler. Subsequent integration with mass spectrometry conveniently identified the multiple bacterial species captured by the sampler. Our developed stand-alone and cable-free sampler shows clear advantages comparing with conventional strategies, including portability, easy-to-use, and low cost, indicating great potential in future field applications. PMID- 27934097 TI - Squeezing of Ion Populations and Peaks in Traveling Wave Ion Mobility Separations and Structures for Lossless Ion Manipulations Using Compression Ratio Ion Mobility Programming. AB - In this work we report an approach for spatial and temporal gas-phase ion population manipulation, wherein we collapse ion distributions in ion mobility (IM) separations into tighter packets providing higher sensitivity measurements in conjunction with mass spectrometry (MS). We do this for ions moving from a conventional traveling wave (TW)-driven region to a region where the TW is intermittently halted or "stuttered". This approach causes the ion packets spanning a number of TW-created traveling traps (TT) to be redistributed into fewer TT, resulting in spatial compression. The degree of spatial compression is controllable and determined by the ratio of stationary time of the TW in the second region to its moving time. This compression ratio ion mobility programming (CRIMP) approach has been implemented using "structures for lossless ion manipulations" (SLIM) in conjunction with MS. CRIMP with the SLIM-MS platform is shown to provide increased peak intensities, reduced peak widths, and improved signal-to-noise (S/N) ratios with MS detection. CRIMP also provides a foundation for extremely long path length and multipass IM separations in SLIM providing greatly enhanced IM resolution by reducing the detrimental effects of diffusional peak broadening and increasing peak widths. PMID- 27934098 TI - PlantMAT: A Metabolomics Tool for Predicting the Specialized Metabolic Potential of a System and for Large-Scale Metabolite Identifications. AB - Custom software entitled Plant Metabolite Annotation Toolbox (PlantMAT) has been developed to address the number one grand challenge in metabolomics, which is the large-scale and confident identification of metabolites. PlantMAT uses informed phytochemical knowledge for the prediction of plant natural products such as saponins and glycosylated flavonoids through combinatorial enumeration of aglycone, glycosyl, and acyl subunits. Many of the predicted structures have yet to be characterized and are absent from traditional chemical databases, but have a higher probability of being present in planta. PlantMAT allows users to operate an automated and streamlined workflow for metabolite annotation from a user friendly interface within Microsoft Excel, a familiar, easily accessed program for chemists and biologists. The usefulness of PlantMAT is exemplified using ultrahigh-performance liquid chromatography-electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-QTOF-MS/MS) metabolite profiling data of saponins and glycosylated flavonoids from the model legume Medicago truncatula. The results demonstrate PlantMAT substantially increases the chemical/metabolic space of traditional chemical databases. Ten of the PlantMAT predicted identifications were validated and confirmed through the isolation of the compounds using ultrahigh-performance liquid chromatography-mass spectrometry solid-phase extraction (UHPLC-MS-SPE) followed by de novo structural elucidation using 1D/2D nuclear magnetic resonance (NMR). It is further demonstrated that PlantMAT enables the dereplication of previously identified metabolites and is also a powerful tool for the discovery of structurally novel metabolites. PMID- 27934099 TI - Correction to Liquid Scintillation Counting Methodology for 99Tc Analysis: A Remedy for Radiopharmaceutical Waste. PMID- 27934100 TI - Toward More Reliable Measurements of Electron-Transfer Kinetics at Nanoelectrodes: Next Approximation. AB - Steady-state voltammetry at nanoelectrodes and scanning electrochemical microscopy (SECM) have recently been used to measure kinetics of several rapid heterogeneous electron transfer (ET) reactions. One problem with those experiments was that the dependence of the shape of the steady-state voltammogram on kinetic parameters becomes weak when the reaction rate approaches the diffusion limit. The possibility to fit the same experimental voltammogram using different combinations of the standard rate constant, transfer coefficient, and standard potential results in significant uncertainties in extracted parameter values. In this article, the reliability of the kinetic analysis was improved by obtaining steady-state voltammograms with both oxidized and reduced forms of redox species initially present in solution. Additional improvements were attained by characterizing the nanoelectrode geometry with the atomic force microscope and using water with a very low level of organic contaminants (TOC <= 1 ppb). This approach was used to re-evaluate the ET rate constants measured for several electroactive species, including ferrocene, ferrocenemethanol, 7,7,8,8 tetracyanoquinodimethane (TCNQ), and ferrocyanide at Pt electrodes. The obtained standard rate constants are higher than the values measured earlier at Pt and Au nanoelectrodes but comparable to those obtained in recent nanogap/SECM experiments. PMID- 27934101 TI - Exploiting Surface-Plasmon-Enhanced Light Scattering for the Design of Ultrasensitive Biosensing Modality. AB - Development of new detection methodologies and amplification schemes is indispensable for plasmonic biosensors to improve the sensitivity for the detection of trace amounts of analytes. Herein, an ultrasensitive scheme for signal enhancement based on the concept of surface-plasmon-resonance-enhanced light scattering (SP-LS) was validated experimentally and theoretically. The SP LS of gold nanoparticles' (AuNPs) tags was employed in a sandwich assay for the detection of cardiac troponin I and provided up to 2 orders of magnitude improved sensitivity over conventional AuNPs-enhanced refractometric measurements and 3 orders of magnitude improvement over label-free SPR. Simulations were also performed to provide insights into the physical mechanisms. PMID- 27934102 TI - Fluorescent Kinase Probes Enabling Identification and Dynamic Imaging of HER2(+) Cells. AB - The human epidermal growth factor receptor, EGFR/ERBB/HER, family of receptor tyrosine kinases is central to many signaling pathways and a validated chemotherapy target in multiple cancers. While EGFR/ERBB-targeted therapies, including monoclonal antibodies, e.g., trastuzumab, and small molecule kinase inhibitors, such as lapatinib, have been developed, rapid identification and classification of cancer cells is key to identifying the best treatment regime. We report ERBB2 (also HER2) targeting kinase probes that exhibit a "turn-on" emission response upon binding. These live cell compatible probes differentiate ERBB2(+) cells from low-level, ERBB2(-) cells by targeting the intracellular ATP binding pocket of ERBB2 with therapeutic inhibitor-like specificity. Beyond kinase expression levels, probe signal is linked to the phosphotyrosine correlated activation state of the ERBB2 population. Additionally, the rapid signaling capability of the probes can report changes in activation state in live cells providing a unique type of complementary information to immunohistochemical assays of receptor kinase populations. PMID- 27934103 TI - Simultaneous Identification and Antimicrobial Susceptibility Testing of Multiple Uropathogens on a Microfluidic Chip with Paper-Supported Cell Culture Arrays. AB - A microfluidic chip was developed for one-step identification and antimicrobial susceptibility testing (AST) of multiple uropathogens. The polydimethylsiloxane (PDMS) microchip used had features of cell culture chamber arrays connected through a sample introduction channel. At the bottom of each chamber, a paper substrate preloaded with chromogenic media and antimicrobial agents was embedded. By integrating a hydrophobic membrane valve on the microchip, the urine sample can be equally distributed into and confined in individual chambers. The identification and AST assays on multiple uropathogens were performed by combining the spatial resolution of the cell culture arrays and the color resolution from the chromogenic reaction. The composite microbial testing assay was based on dynamic changes in color in a serial of chambers. The bacterial antimicrobial susceptibility was determined by the lowest concentration of an antimicrobial agent that is capable of inhibiting the chromogenic reaction. Using three common uropathogenic bacteria as test models, the developed microfluidic approach was demonstrated to be able to complete the multiple colorimetric assays in 15 h. The accuracy of the microchip method, in comparison with that of the conventional approach, showed a coincidence of 94.1%. Our data suggest this microfluidic approach will be a promising tool for simple and fast uropathogen testing in resource-limited settings. PMID- 27934104 TI - Ratiometric Two-Photon Fluorescent Probe for in Vivo Hydrogen Polysulfides Detection and Imaging during Lipopolysaccharide-Induced Acute Organs Injury. AB - Acute organ injury observed during sepsis, caused by an uncontrolled release of inflammatory mediators, such as lipopolysaccharide (LPS), is quite fatal. The development of efficient methods for early diagnosis of sepsis and LPS-induced acute organ injury in living systems is of great biomedical importance. In living systems, cystathionine gamma-lyase (CSE) can be overexpressed due to LPS, and H2Sn can be formed by CSE-mediated cysteine metabolism. Thus, acute organ injury during sepsis may be correlated with H2Sn levels, making accurate detection of H2Sn in living systems of great physiological and pathological significance. In this work, our previously reported fluorescent platform was employed to design and synthesize a FRET-based ratiometric two-photon (TP) fluorescent probe TPR-S, producing a large emission shift in the presence of H2Sn. In this work, a naphthalene derivative two-photon fluorophore was chosen as the energy donor; a rhodol derivative fluorophore served as the acceptor. The 2-fluoro-5 nitrobenzoate group of probe TPR-S reacted with H2Sn and was selectively removed to release the fluorophore, resulting in a fluorescent signal decrease at 448 nm and enhancement at 541 nm. The ratio value of the fluorescence intensity between 541 and 448 nm (I541 nm/I448 nm) varied from 0.13 to 8.12 (~62-fold), with the H2Sn concentration changing from 0 to 1 mM. The detection limit of the probe was 0.7 MUM. Moreover, the probe was applied for imaging H2Sn in living cells, tissues, and organs of LPS-induced acute organ injury, which demonstrated its practical application in complex biosystems as a potential method to achieve early diagnosis of LPS-induced acute organ injury. PMID- 27934105 TI - Simultaneous Analysis of Free and Sulfated Steroids by Liquid Chromatography/Mass Spectrometry with Selective Mass Spectrometric Scan Modes and Polarity Switching. AB - Sulfated steroids can act as a latent form of active free steroids, coexisting with them in biological specimens. To evaluate the metabolic significance of free and sulfated steroid species, a simultaneous analysis of eight free steroids [cholesterol, pregnenolone, 17alpha-hydroxypregnenolone, progesterone, 17alpha hydroxyprogesterone, dehydroepiandrosterone (DHEA), testosterone, and 17beta estradiol] and four biologically relevant sulfated steroids was developed and validated, using selected-ion and multiple-reaction monitoring modes coupled to polarity-switching liquid chromatography/mass spectrometry (LC/MS). All steroids were separated on a reversed-phase phenyl column (50 mm * 2 mm, 3 MUm) at a flow rate of 0.5 mL/min. The limits of quantification ranged from 0.1 to 50 ng/mL at extraction recoveries of 94.1-105.5%, while the precision and accuracy were 2.5 9.3% and 92.4-105.9%, respectively. Quantitative results obtained for samples from obese girls showed that the serum levels of DHEA sulfate were significantly increased (P = 0.004), along with the metabolic ratio representing DHEA sulfotransferase (P < 0.02). The developed novel LC/MS method can quantitatively profile both free and sulfated steroids in a single analytical run. PMID- 27934107 TI - Detection of Prostate Specific Membrane Antigen at Picomolar Levels Using Biocatalysis Coupled to Assisted Ion Transfer Voltammetry at a Liquid-Organogel Microinterface Array. AB - A label-free electrochemical strategy for the detection of a cancer biomarker, prostate specific membrane antigen (PSMA), at picomolar concentrations without the use of antibodies, was investigated. The approach is based on the assisted ion transfer of protons, generated by a series of enzymatic reactions, at an array of microinterfaces between two immiscible electrolyte solutions (MU-ITIES). This nonredox electrochemical approach based on biocatalysis-coupled proton transfer at the MU-ITIES array opens a new way to detect the prostate cancer biomarker, with detection capability achieved at concentrations below those indicative of disease presence. The strategy is expected to contribute to cancer diagnostics, recurrence monitoring, and therapeutic treatment efficacy. PMID- 27934106 TI - Single-Stranded DNA Assisted Cell Penetrating Peptide-DNA Conjugation Strategy for Intracellular Imaging of Nucleases. AB - Cell penetrating peptides (CPPs) are very useful tools for delivery of DNA molecules into living cells without damaging the cell membranes. However, covalent conjugation of DNAs to CPPs is technically difficult, and the reactions between DNA and target nucleases are also liable to be affected by the cationic CPP molecules. In this work, we demonstrate that the electrostatic interactions between CPPs and single-stranded DNA (ssDNA) were stronger than those between CPP and double-stranded DNA (dsDNA). Taking advantage of this property, we developed an ssDNA protected CPP-DNA fluorescent probe which allowed for noninvasive and efficient cellular uptake and rapid imaging of target nucleases in living cells. The probe is highly sensitive and selective. This work represents the first example of using CPP-DNA conjugate to deliver DNA fluorescent probes for in situ imaging of nucleases within cells. The developed approach also holds great potential for the cellular delivery of other nucleic acid molecules for diagnosis or therapeutics purposes. PMID- 27934108 TI - Multianalytical Study of the Binding between a Small Chiral Molecule and a DNA Aptamer: Evidence for Asymmetric Steric Effect upon 3'- versus 5'-End Sequence Modification. AB - Nucleic acid aptamers are involved in a broad field of applications ranging from therapeutics to analytics. Deciphering the binding mechanisms between aptamers and small ligands is therefore crucial to improve and optimize existing applications and to develop new ones. Particularly interesting is the enantiospecific binding mechanism involving small molecules with nonprestructured aptamers. One archetypal example is the chiral binding between l-tyrosinamide and its 49-mer aptamer for which neither structural nor mechanistic information is available. In the present work, we have taken advantage of a multiple analytical characterization strategy (i.e., using electroanalytical techniques such as kinetic rotating droplet electrochemistry, fluorescence polarization, isothermal titration calorimetry, and quartz crystal microbalance) for interpreting the nature of binding process. Screening of the binding thermodynamics and kinetics with a wide range of aptamer sequences revealed the lack of symmetry between the two ends of the 23-mer minimal binding sequence, showing an unprecedented influence of the 5' aptamer modification on the bimolecular binding rate constant kon and no significant effect on the dissociation rate constant koff. The results we have obtained lead us to conclude that the enantiospecific binding reaction occurs through an induced-fit mechanism, wherein the ligand promotes a primary nucleation binding step near the 5'-end of the aptamer followed by a directional folding of the aptamer around its target from 5'-end to 3'-end. Functionalization of the 5'-end position by a chemical label, a polydA tail, a protein, or a surface influences the kinetic/thermodynamic constants up to 2 orders of magnitude in the extreme case of a surface immobilized aptamer, while significantly weaker effect is observed for a 3'-end modification. The reason is that steric hindrance must be overcome to nucleate the binding complex in the presence of a modification near the nucleation site. PMID- 27934109 TI - In Vivo Biotransformation of the Fusion Protein Tetranectin-Apolipoprotein A1 Analyzed by Ligand-Binding Mass Spectrometry Combined with Quantitation by ELISA. AB - The in vivo biotransformation of a novel fusion protein tetranectin/apolipoprotein A1 (TN-ApoA1) was investigated by ligand-binding mass spectrometry (LB-MS) in support of enzyme-linked immunosorbent assays (ELISA). The main focus was on catabolites formed by proteolysis of the fusion protein in rabbit following intravenous administration of lipidated TN-ApoA1. The drug and its catabolites were isolated from rabbit plasma by immunocapture with a monoclonal antibody (mAb) binding to the fusion region of TN-ApoA1. The captured drug and catabolites were released from the streptavidin-coated magnetic beads, separated by monolithic RP capillary HPLC, and online detected by high-resolution mass spectrometry. In addition, the same extract was digested with LysN to confirm or further narrow down the structure of the found catabolites. Two pharmacologically active catabolites were identified with conserved fusion region. The major catabolite [3-285] was formed by truncation of AP at the N terminus and the minor catabolite [29-270] by truncations of either side of the TN-ApoA1 sequence. Since the ELISA determined the sum of TN-ApoA1, along with its two main catabolites, the individual PK profiles of all three components could be derived by applying their mass peak composition for each sampling point. Parent drug accounted for 25% of drug-related material, whereas that of the catabolites [3-285] and [29-270] accounted for 66% and 9%, respectively. This result could be obtained without catabolite specific ELISAs or quantitative LC-MS assays. It was also confirmed that all relevant functional molecules of TN-ApoA1 in the plasma samples were quantified by the ELISA, which provided a good relationship for pharmacokinetic/pharmacodynamic evaluations. PMID- 27934110 TI - Molecular Imaging Biosensor Monitors p53 Sumoylation in Cells and Living Mice. AB - Small molecule mediated stabilization of p53 tumor suppressor protein through sumoylation is a promising new strategy for improving cancer chemotherapy. A molecular tool that monitors p53 sumoylation status and expedites screening for drugs that enhance p53 sumoylation would be beneficial. We report a molecularly engineered reporter fragment complementation biosensor based on optical imaging of Firefly luciferase (FLuc), to quantitatively image p53 sumoylation and desumoylation in cells and living mice. We initially characterized this biosensor by successfully imaging sumoylation of several target proteins, achieving significant FLuc complementation for ERalpha (p < 0.01), p53 (p < 0.005), FKBP12 (p < 0.03), ID (p < 0.03), and HDAC1 (p < 0.002). We then rigorously tested the sensitivity and specificity of the biosensor using several variants of p53 and SUMO1, including deletion mutants, and those with modified sequences containing the SUMO-acceptor site of target proteins. Next we evaluated the performance of the biosensor in HepG2 cells by treatment with ginkgolic acid, a drug that reduces p53 sumoylation, as well as trichostatin A, a potential inducer of p53 sumoylation by enhancement of its nuclear export. Lastly, we demonstrated the in vivo utility of this biosensor in monitoring and quantifying the effects of these drugs on p53 sumoylation in living mice using bioluminescence imaging. Adoption of this biosensor in future high throughput drug screening has the important potential to help identify new and repurposed small molecules that alter p53 sumoylation, and to preclinically evaluate candidate anticancer drugs in living animals. PMID- 27934111 TI - Gold-Coated Nanoelectrospray Emitters Fabricated by Gravity-Assisted Etching Self Termination and Electroless Deposition. AB - To improve the stability and sensitivity of nanoelectrospray for liquid chromatography-mass spectroscopy (LC-MS) analysis, we present a new method to fabricate gold-coated emitters. Via gravity-assisted etching self-termination, the emitter with a tapered outer surface and a straight inner surface is prepared with good reproducibility, without the need of fluid introduced to protect internal surface during etching. Followed by electroless deposition, the emitter is further coated with gold film homogeneously, by which the relative standard deviation (RSD) value of total ion current in 160 h is <5%, showing good stability. Compared to that obtained by a commercial emitter, the identified protein number from 2 MUg HeLa cell digests is increased over 10%, contributed by the stable electrospray and improved signal intensity of peptides. Furthermore, the integrated gold-coated emitter is prepared at the end of the ultranarrow-bore packed column (inner diameter of 25 MUm), and 218 proteins are identified from 2 ng HeLa cell digests. All of these results demonstrate the great promise of such emitters for use in ultrasensitive proteome analysis. PMID- 27934112 TI - Bioelectronic Nose Using Odorant Binding Protein-Derived Peptide and Carbon Nanotube Field-Effect Transistor for the Assessment of Salmonella Contamination in Food. AB - Salmonella infection is the one of the major causes of food borne illnesses including fever, abdominal pain, diarrhea, and nausea. Thus, early detection of Salmonella contamination is important for our healthy life. Conventional detection methods for the food contamination have limitations in sensitivity and rapidity; thus, the early detection has been difficult. Herein, we developed a bioelectronic nose using a carbon nanotube (CNT) field-effect transistor (FET) functionalized with Drosophila odorant binding protein (OBP)-derived peptide for easy and rapid detection of Salmonella contamination in ham. 3-Methyl-1-butanol is known as a specific volatile organic compound, generated from the ham contaminated with Salmonella. We designed and synthesized the peptide based on the sequence of the Drosophila OBP, LUSH, which specifically binds to alcohols. The C-terminus of the synthetic peptide was modified with three phenylalanine residues and directly immobilized onto CNT channels using the pi-pi interaction. The p-type properties of FET were clearly maintained after the functionalization using the peptide. The biosensor detected 1 fM of 3-methyl-1-butanol with high selectivity and successfully assessed Salmonella contamination in ham. These results indicate that the bioelectronic nose can be used for the rapid detection of Salmonella contamination in food. PMID- 27934113 TI - Ligating Dopamine as Signal Trigger onto the Substrate via Metal-Catalyst-Free Click Chemistry for "Signal-On" Photoelectrochemical Sensing of Ultralow MicroRNA Levels. AB - The efficiency of photon-to-electron conversion is extremely restricted by the electron-hole recombinant. Here, a new photoelectrochemical (PEC) sensing platform has been established based on the signal amplification of click chemistry (CC) via hybridization chain reaction (HCR) for highly sensitive microRNA (miRNA) assay. In this proposal, a preferred electron donor dopamine (DA) was first assembled with designed ligation probe (probe-N3) via amidation reaction to achieve DA-coordinated signal probe (PDA-N3). The PDA-N3 served as a flexible trigger to signal amplification through efficiently suppressing the electron-hole recombinant. Specifically, the PDA-N3 can be successfully ligated into the trapped hairpins (H1 and H2) via the superior ligation method of metal catalyst-free CC, in which the electron donor DA was introduced into the assay system. Moreover, the enzyme-free HCR, employed as a versatile amplification way, ensures that lots of PDA-N3 can be attached to the substrate. This PEC sensing for miRNA-141 detection illustrated the outstanding linear response to a concentration variation from 0.1 fM to 0.5 nM and a detection limit down to 27 aM, without additional electron donors. The sensor is further employed to monitor miRNA-141 from prostate carcinoma cell (22Rv1), showing good quantitative detection capability. This strategy exquisitely influences the analytical performance and offers a new PEC route to highly selective and sensitive detection of biological molecules. PMID- 27934115 TI - Determination of Halogenated Flame Retardants Using Gas Chromatography with Atmospheric Pressure Chemical Ionization (APCI) and a High-Resolution Quadrupole Time-of-Flight Mass Spectrometer (HRqTOFMS). AB - A method to determine halogenated flame retardants was developed that utilizes gas chromatography with atmospheric chemical ionization (APCI) high-resolution quadrupole time-of-flight mass spectrometry (HRqTOFMS). The new GC-APCI-HRqTOFMS method was used to determine the presence of 65 halogenated flame retardants (HFRs) in the United Sates National Institute of Standards and Technology (NIST) organic contaminants in house dust standard reference material (SRM). The accuracy of the measurements was compared to the certified NIST value for polybrominated diphenyl ethers (PBDEs) and had an average accuracy for the 14 certified PBDEs of 109% with subpicogram detection limits (on column) from a single 1 MUL injection with a run time of 18 min. SRM2585 extracts were also analyzed by GC electron ionization (EI) high-resolution mass spectrometry (HRMS), and there was an excellent correlation between the two data sets (R2 value of 0.996). The presence of 25 additional HFRs were also screened in the dust standard, and 10 were detected in concentrations above the limits of detection; these were p-TBX, PBBZ, PBT, PBEB, TDCPP, HBBZ, EHTBB, TBBPA, BEHTBP, and BTBPE. The results presented show that the proposed APCI-HRqTOFMS method was comparable and in many cases an improvement on the existing EI-HRMS method. PMID- 27934114 TI - Hybrid Synthetic Receptors on MOSFET Devices for Detection of Prostate Specific Antigen in Human Plasma. AB - The study reports the use of extended gate field-effect transistors (FET) for the label-free and sensitive detection of prostate cancer (PCa) biomarkers in human plasma. The approach integrates for the first time hybrid synthetic receptors comprising of highly selective aptamer-lined pockets (apta-MIP) with FETs for sensitive detection of prostate specific antigen (PSA) at clinically relevant concentrations. The hybrid synthetic receptors were constructed by immobilizing an aptamer-PSA complex on gold and subjecting it to 13 cycles of dopamine electropolymerization. The polymerization resulted in the creation of highly selective polymeric cavities that retained the ability to recognize PSA post removal of the protein. The hybrid synthetic receptors were subsequently used in an extended gate FET setup for electrochemical detection of PSA. The sensor was reported to have a limit of detection of 0.1 pg/mL with a linear detection range from 0.1 pg/mL to 1 ng/mL PSA. Detection of 1-10 pg/mL PSA was also achieved in diluted human plasma. The present apta-MIP sensor developed in conjunction with FET devices demonstrates the potential for clinical application of synthetic hybrid receptors for the detection of clinically relevant biomarkers in complex samples. PMID- 27934116 TI - Sensitive Surface Enhanced Raman Scattering-Based Detection of a BIGH3 Point Mutation Associated with Avellino Corneal Dystrophy. AB - Surface enhanced Raman scattering (SERS) is highly useful for sensitive analytical sensing; however, its practical availability for detecting a point mutation associated with disease in clinical sample was rarely proved. Herein, we present a toehold-mediated, DNA displacement-based, SERS sensor for detecting point mutations in the BIGH3 gene associated with the most common corneal dystrophies (CDs) in a clinical setting. To diagnose Avellino corneal dystrophy (ACD), selectivity was ensured by exploring optimal DNA displacement conditions such as length of toehold and hybridization temperature. A SERS-efficient Ag@Au bimetallic nanodendrite was employed to ensure sensitivity. Optimization for a clinical setting showed that discrimination was maximized when toehold length was 6-mer (T6), and hybridization temperature was 36 degrees C. On the basis of tests that used clinical homozygous and heterozygous CD samples, a single-base mismatched DNA sequence was identifiable within 30 min with a limit of detection (LOD) of 400 fM. From the results, we conclude that our toehold-mediated, DNA displacement-based, SERS sensor allows a rapid and sensitive detection of a BIGH3 gene point mutation associated with Avellino corneal dystrophy, indicating the practical ability of the method to diagnose genetic diseases caused by point mutations. PMID- 27934117 TI - Influx and Production Rates in Peak-Mode Isotachophoresis. AB - We present an analytical model useful in the design of peak-mode isotachophoresis (ITP) experiments. The model quantifies sample influx and production rates, the latter in applications where ITP is used to accelerate chemical reactions. We include analysis of the effect of initial sample placement location. We derive and identify key nondimensional parameters for the general case of weak electrolyte buffer ions in terms of sample placement (injection mode), initial concentrations, fully ionized mobilities, and reaction kinetic constants. We then discuss how to use these parameters in the optimal design of peak-mode ITP assays and highlight regimes of particular interest. We clearly identify a quasi equilibrium regime wherein production rates increase until they equal the influx rate of the low abundance sample species. The model and analysis are generally applicable to both cationic and anionic ITP assays and likely to a wide range of sample species. PMID- 27934118 TI - Unexpected Electrophoretic Behavior of Complexes between Rod-like Virions and Bivalent Antibodies. AB - Here we report on the unexpected electrophoretic behavior of complexes between rod-like virus particles (virions) and bivalent antibodies. The multiple complexes formed by the virions and antibodies migrated with electrophoretic mobilities of much greater absolute values than those of the unbound virions or antibodies while typically complexes have mobilities intermediate to those of their components. We hypothesized that the mobilities of unusually high absolute values are caused by the cross-linking of virions by bivalent antibodies into aggregates with prominent side-to-side binding. Theoretically, the mobility of such aggregates should be proportional to the square root of the number of cross linked virions. The formation of virion aggregates with prominent side-to-side binding was confirmed by atomic force microscopy. The dependence of the aggregate mobility on the number of cross-linked virions can be used to estimate this number. PMID- 27934119 TI - Mechanical Properties Based Particle Separation via Traveling Surface Acoustic Wave. AB - Most microfluidics-based sorting methodologies utilize size differences between suspended micro-objects as the defining characteristic by which they are sorted. Sorting based on mechanical properties, however, would provide a new avenue for sample preparation, detection and diagnosis for a number of emerging biological and medical analyses. In this study, we demonstrate separation of polystyrene (PS) and poly(methyl methacrylate) (PMMA) microspheres based entirely on their difference in mechanical properties using traveling surface acoustic waves (TSAWs). We theoretically examine the correlation of the applied TSAW frequency, particle density and sound speed with respect to the resultant acoustic radiation force (ARF) that acts to translate particles, and experimentally corroborate these predictions by translating PS and PMMA particles simultaneously in a stationary flow. Even when PS and PMMA particles have the same diameters, they exhibit strongly nonlinear and distinct acoustophoretic responses as a function of their mechanical properties and the applied TSAW frequency. By specifically matching the appropriate acoustic frequency to the desired particle size, each particle population can be selectively translated and sorted. We demonstrate that this mechanical property based sorting can continuously separate these particle populations with at least 95% efficiency in the mixed 10/15 MUm diameter PS and PMMA particle solutions tested. PMID- 27934121 TI - Safety: Declare the Hidden Risks and Hazards of Your Research. PMID- 27934120 TI - Accurate Drift Time Determination by Traveling Wave Ion Mobility Spectrometry: The Concept of the Diffusion Calibration. AB - Ion mobility spectrometry (IMS) is a gas phase separation technique, which relies on differences in collision cross section (CCS) of ions. Ionic clouds of unresolved conformers overlap if the CCS difference is below the instrumental resolution expressed as CCS/DeltaCCS. The experimental arrival time distribution (ATD) peak is then a superimposition of the various contributions weighted by their relative intensities. This paper introduces a strategy for accurate drift time determination using traveling wave ion mobility spectrometry (TWIMS) of poorly resolved or unresolved conformers. This method implements through a calibration procedure the link between the peak full width at half-maximum (fwhm) and the drift time of model compounds for wide range of settings for wave heights and velocities. We modified a Gaussian equation, which achieves the deconvolution of ATD peaks where the fwhm is fixed according to our calibration procedure. The new fitting Gaussian equation only depends on two parameters: The apex of the peak (A) and the mean drift time value (MU). The standard deviation parameter (correlated to fwhm) becomes a function of the drift time. This correlation function between MU and fwhm is obtained using the TWIMS calibration procedure which determines the maximum instrumental ion beam diffusion under limited and controlled space charge effect using ionic compounds which are detected as single conformers in the gas phase. This deconvolution process has been used to highlight the presence of poorly resolved conformers of crown ether complexes and peptides leading to more accurate CCS determinations in better agreement with quantum chemistry predictions. PMID- 27934122 TI - Application of LC-MS-Based Global Metabolomic Profiling Methods to Human Mental Fatigue. AB - Mental fatigue is characterized by a reduced capacity for work and a loss of capacity to respond to stimulation and is usually accompanied by a feeling of tiredness and drowsiness. Mental fatigue at work is a serious problem and can raise safety concerns especially in the transportation system. It is believed that mental fatigue is a direct or contributing cause of road and air related accidents and incidents. Psychological studies indicate that fatigue results in reduced work efficiency, alertness, and impaired mental performance. However, its underlying biochemical mechanisms are poorly understood. We hypothesized that the human body is an integrated system, and mental fatigue results in changes not only in psychology but also in biochemistry of the human body. These biochemical changes are detectable in metabolites. We employed global metabolomic profiling methods to screen biochemical changes that occur with mental fatigue in air traffic controllers (ATCs) in civil aviation. A total of 45, all male, ATCs (two batches) were recruited as two mental fatigue groups and 23 executive staff acted as a control group for this study. The volunteers' urine samples were collected before and after their work. The samples were analyzed with liquid chromatography/mass spectrometry equipped with a polar, a weak polar, and a nonpolar column, respectively. Three candidate biomarkers were selected on the basis of statistical significance, coefficient of variance, and compared with data of the three groups. The results suggest that urine metabolites may provide a complete new clue from biochemistry to understand, monitor, and manage human mental fatigue. PMID- 27934123 TI - Aspects of Quantitation in Mass Spectrometry Imaging Investigated on Cryo Sections of Spiked Tissue Homogenates. AB - Internal standards have been introduced in quantitative mass spectrometry imaging in order to compensate for differences in intensities throughout an image caused by, for example, difference in ion suppression or analyte extraction efficiency. To test how well the internal standards compensate for differences in tissue types in, for example, whole-body imaging, a set of tissue homogenates of different tissue types (lung, liver, kidney, heart, and brain) from rabbit was spiked to the same concentration with the drug amitriptyline and imaged in the same experiment using isotope labeled amitriptyline as internal standard. The results showed, even after correction with internal standard, significantly lower intensities from brain and to some extent also lung tissue, differences which may be ascribed to binding of the drug to proteins or lipids as known from traditional bioanalysis. The differences, which for these results range approximately within a factor of 3 (but for other compounds in other tissues could be higher), underscore the importance of preparing the standard curve in the same matrix as the unknown sample whenever possible. In, for example, whole body imaging where a diversity of tissue types are present, this variation across tissue types will therefore add to the overall uncertainty in quantitation. The tissue homogenates were also used in a characterization of various phenomena in quantitative MSI, such as to study how the signal depends of the thickness of the cryo-section, and to assess the accuracy of calibration by droplet deposition. For experiments on liver tissue, calibration by spiked tissue homogenates and droplet deposition was found to provide highly similar results and in both cases linearity with R2 values of 0.99. In the process, a new method was developed for preparation of standard curves of spiked tissue homogenates, based on the drilling of holes in a block of frozen liver homogenate, providing easy cryo slicing and good quantitative performance. PMID- 27934124 TI - Detection of Moisture by Fluorescent OFF-ON Sensor in Organic Solvents and Raw Food Products. AB - Copper complex based on a new class of fluorescence OFF-ON sensor 1.Cu has been reported for the detection of trace amounts of water in various organic solvents such as CH3OH, THF, CH3CN, and acetone by means of fluorescence emission intensity. The probe is highly responsive to water in THF (DL = 0.003 wt %). The dissociation of copper from probe 1.Cu in the presence of water is responsible for the fluorescence change and it was confirmed by electrospray ionization-mass spectrometry (ESI-MS), proton nuclear magnetic resonance (1H-NMR), and fluorescence lifetime studies. Real application of the probe was successfully applied for the detection of moisture content in commercial products such as salt, sugar, wheat, and washing powder. PMID- 27934125 TI - Quantitatively Monitoring the Size-Focusing of Au Nanoclusters and Revealing What Promotes the Size Transformation from Au44(TBBT)28 to Au36(TBBT)24. AB - "Size-focusing" is a well-recognized process and widely employed for the synthesis of atomically monodisperse metal nanoclusters. However, quantitatively monitoring the size-focusing of Au nanoclusters has not been achieved yet, and the in-depth understanding of the size focusing is far from completed. Herein, we introduce a facile, cheap, and powerful tool, preparative thin-layer chromatography (PTLC), to quantitatively track the size-focusing process, to reveal that mainly ~3 nm nanoparticles promote the transformation from Au44(TBBT)28 to Au36(TBBT)24 (where TBBT is 4-tert-butylbenzenethiolate) and to improve the syntheses of Au44(TBBT)28 and Au36(TBBT)24. Our work further demonstrates the usefulness of PTLC in nanocluster research and advances one step toward understanding the "size-focusing" process of nanoclusters. PMID- 27934126 TI - Selective and Sensitive Monitoring of Cerebral Antioxidants Based on the Dye Labeled DNA/Polydopamine Conjugates. AB - A simple and novel method for evaluating antioxidants in complex biological fluids has been developed based on the interaction of dye-labeled single-strand DNA (ssDNA) and polydopamine (PDA). Due to the interaction between ssDNA and PDA, the fluorescence of dye-labeled ssDNA (e.g., FITC-ssDNA, as donor) can be quenched by PDA (as acceptor) to the fluorescence "off" state through Forster resonance energy transfer (FRET). However, in the presence of various antioxidants, such as glutathione (GSH), ascorbic acid (AA), cysteine (Cys), and homocysteine (Hcys), the spontaneous oxidative polymerization reaction from DA to PDA would be blocked, resulting in the freedom of FITC-ssDNA and leading to the fluorescence "on" state. The sensing system shows great sensitivity for the monitoring of antioxidants in a fluorescent "turn on" format. The new strategy also exhibits great selectivity and is free from the interferences of amino acids, metal ions and the biological species commonly existing in brain systems. Moreover, by combining the microdialysis technique, the present method has been successfully applied to monitor the dynamic changes of the striatum antioxidants in rat cerebrospinal microdialysates during the normal/ischemia/reperfusion process. This work establishes an effective platform for in vivo monitoring antioxidants in cerebral ischemia model, and promises new opportunities for the research of brain chemistry, neuroprotection, physiological, and pathological events. PMID- 27934127 TI - Halochromic Isoquinoline with Mechanochromic Triphenylamine: Smart Fluorescent Material for Rewritable and Self-Erasable Fluorescent Platform. AB - Halochromic isoquinoline attached mechanochromic triphenylamine, N-phenyl-N-(4 (quinolin-2-yl)phenyl)benzenamine (PQPBA) and tris(4-(quinolin-2-yl)phenyl)amine (TQPA), smart fluorescent materials exhibit thermo/mechanochromism and tunable solid state fluorescence and their unusual halochromic response in PMMA matrix have been used for fabricating rewritable and self-erasable fluorescent platforms. PQPBA and TQPA showed strong fluorescence in solution (Phif = 0.9290 (PQPBA) and 0.9160 (TQPA)) and moderate solid state fluorescence (Phif = 20 (PQPBA) and 17% (TQPA). Interestingly, they exhibited a rare temperature (0-100 degrees C) dependent positive fluorescence enhancement via activating radiative vibrational transition. The deaggregation of PQPBA and TQPA in PMMA polymer matrix lead to the enhancement of fluorescence intensity strongly and fabricated strong blue fluorescent thin films (Phif = 58% (PQPBA) and 54% (TQPA). The halochromic isoquinoline has been exploited for demonstrating reversible off-on fluorescence switching by acid (TFA (trifluoroacetic acid)/HCl) and base (NH3) treatment in both solids as well as PMMA thin films. Importantly, rewritable and self-erasable fluorescent platform has been achieved by make use of unusual fluorescence responses of PQPBA/TQPA with TFA/HCl after exposing NH3. Single crystal and powder X-ray diffraction (PXRD) studies provided the insight on the solid-state fluorescence and external stimuli-induced fluorescence changes. PMID- 27934128 TI - Metal-Particle-Decorated ZnO Nanocrystals: Photocatalysis and Charge Dynamics. AB - Understanding of charge transfer processes is determinant to the performance optimization for semiconductor photocatalysts. As a representative model of composite photocatalysts, metal-particle-decorated ZnO has been widely employed for a great deal of photocatalytic applications; however, the dependence of charge carrier dynamics on the metal content and metal composition and their correlation with the photocatalytic properties have seldom been reported. Here, the interfacial charge dynamics for metal-decorated ZnO nanocrystals were investigated and their correspondence with the photocatalytic properties was evaluated. The samples were prepared with a delicate antisolvent approach, in which ZnO nanocrystals were grown along with metal particle decoration in a deep eutectic solvent. By modulating the experimental conditions, the metal content (from 0.6 to 2.3 at%) and metal composition (including Ag, Au, and Pd) in the resulting metal-decorated ZnO could be readily controlled. Time-resolved photoluminescence spectra showed that an optimal Au content of 1.3 at% could effectuate the largest electron transfer rate constant for Au-decorated ZnO nanocrystals, in conformity with the highest photocatalytic efficiency observed. The relevance of charge carrier dynamics to the metal composition was also inspected and realized in terms of the energy level difference between ZnO and metal. Among the three metal-decorated ZnO samples tested, ZnO-Pd displayed the highest photocatalytic activity, fundamentally according with the largest electron transfer rate constant deduced in carrier dynamics measurements. The current work was the first study to present the correlations among charge carrier dynamics, metal content, metal composition, and the resultant photocatalytic properties for semiconductor/metal heterostructures. The findings not only helped to resolve the standing issues regarding the mechanistic foundation of photocatalysis but also shed light on the intelligent design of semiconductor/metal composite systems to consolidate their utility in photocatalytic fields. PMID- 27934129 TI - Interfacial Transformation of an Amorphous Carbon Nanofilm upon Fe@Ag@Si Nanoparticle Landing and its Colloidal Nanoscrolls: Enhanced Nanocompositing Based Performance for Bioapplications. AB - We report a novel method for generating magneto-plasmonic carbon nanofilms and nanoscrolls using a combination of two gas-phase synthetic techniques. Ternary Fe@Ag@Si "onion-like" nanoparticles (NPs) are produced by a magnetron sputtering inert gas condensation source and are in situ landed onto the surface of carbon nanofilms, which were previously deposited by a DC arc discharge technique. Subsequently, a polyethylenimine-mediated chemical exfoliation process is performed to obtain carbon nanoscrolls (CNS) with embedded NPs (CNS-NPs). Of note, the carbon nanofilms undergo an interfacial transition upon addition of NPs and become rich in the sp2 phase. This transformation endows and enhances multiple functions, such as thermal conductivity and the plasmonic properties of the nanocomposites. The obtained two-dimentional (2D) nanocomposites not only exhibit a highly efficient surface-enhanced Raman scattering property, allowing sensitive detection of malachite green isothiocyanate (MGIT) and adenosine triphosphate (ATP) molecules at concentrations as low as 1 * 10-10 M, but also show enhanced near-infrared-responsive photothermal activity when forming stable colloidal 1D CNS-NPs. In addition, the CNS-NPs present an enhanced single- and two-photon fluorescence in comparison with pristine CNS and NPs. These results make them suitable for the rational fabrication of "all-in-one" multifunctional nanocomposites with tubular structures toward a wide range of biomedical solutions. PMID- 27934130 TI - Catalyst Interface Engineering for Improved 2D Film Lift-Off and Transfer. AB - The mechanisms by which chemical vapor deposited (CVD) graphene and hexagonal boron nitride (h-BN) films can be released from a growth catalyst, such as widely used copper (Cu) foil, are systematically explored as a basis for an improved lift-off transfer. We show how intercalation processes allow the local Cu oxidation at the interface followed by selective oxide dissolution, which gently releases the 2D material (2DM) film. Interfacial composition change and selective dissolution can thereby be achieved in a single step or split into two individual process steps. We demonstrate that this method is not only highly versatile but also yields graphene and h-BN films of high quality regarding surface contamination, layer coherence, defects, and electronic properties, without requiring additional post-transfer annealing. We highlight how such transfers rely on targeted corrosion at the catalyst interface and discuss this in context of the wider CVD growth and 2DM transfer literature, thereby fostering an improved general understanding of widely used transfer processes, which is essential to numerous other applications. PMID- 27934131 TI - Thermally Annealed Anisotropic Graphene Aerogels and Their Electrically Conductive Epoxy Composites with Excellent Electromagnetic Interference Shielding Efficiencies. AB - Dispersion and spatial distribution of graphene sheets play crucial roles in tailoring mechanical and functional properties of their polymer composites. Anisotropic graphene aerogels (AGAs) with highly aligned graphene networks are prepared by a directional-freezing followed by freeze-drying process and exhibit different microstructures and performances along the axial (freezing direction) and radial (perpendicular to the axial direction) directions. Thermal annealing at 1300 degrees C significantly enhances the quality of both AGAs and conventional graphene aerogels (GAs). The aligned graphene/epoxy composites show highly anisotropic mechanical and electrical properties and excellent electromagnetic interference (EMI) shielding efficiencies at very low graphene loadings. Compared to the epoxy composite with 0.8 wt % thermally annealed GAs (TGAs) with an EMI shielding effectiveness of 27 dB, the aligned graphene/epoxy composite with 0.8 wt % thermally treated AGAs (TAGAs) has an enhanced EMI shielding effectiveness of 32 dB along the radial direction with a slightly decreased shielding effectiveness of 25 dB along the axial direction. With 0.2 wt % TAGA, its epoxy composite exhibits a shielding effectiveness of 25 dB along the radial direction, which meets the requirement of ~20 dB for practical EMI shielding applications. PMID- 27934132 TI - Investigating the CVD Synthesis of Graphene on Ge(100): toward Layer-by-Layer Growth. AB - Germanium is emerging as the substrate of choice for the growth of graphene in CMOS-compatible processes. For future application in next generation devices the accurate control over the properties of high-quality graphene synthesized on Ge surfaces, such as number of layers and domain size, is of paramount importance. Here we investigate the role of the process gas flows on the CVD growth of graphene on Ge(100). The quality and morphology of the deposited material is assessed by using MU-Raman spectroscopy, X-ray photoemission spectroscopy, scanning electron microscopy, and atomic force microscopy. We find that by simply varying the carbon precursor flow different growth regimes yielding to graphene nanoribbons, graphene monolayer, and graphene multilayer are established. We identify the growth conditions yielding to a layer-by-layer growth regime and report on the achievement of homogeneous monolayer graphene with an average intensity ratio of 2D and G bands in the Raman map larger than 3. PMID- 27934133 TI - Simple Approach to Improving the Amplified Spontaneous Emission Properties of Perovskite Films. AB - Organo-lead halide perovskite has emerged as a promising optical gain media. However, continuous efforts are needed to improve the amplified spontaneous emission (ASE) even lasing properties to evade the poor photostability and thermal instability of the perovskites. Herein, we report that simply through the coating of polymer layer, the CH3NH3PbBr3 polycrystalline films prepared by a modified sequential deposition process show remarkably enhanced photoluminescence and prolonged decay lifetime. As a result, under nanosecond pulse pumping, the ASE threshold of the perovskite films is significantly reduced from 303 to 140 MUJ/cm2. Furthermore, the light exposure stability is improved greatly after the polymer coating. We confirmed that the polymer layer plays the roles of both surface passivation and symmetric waveguides. Our results may shed light upon the stable and sustained output of laser from perovskite materials. PMID- 27934134 TI - A Protein-Polymer Bioconjugate-Coated Upconversion Nanosystem for Simultaneous Tumor Cell Imaging, Photodynamic Therapy, and Chemotherapy. AB - Combined cancer therapy possesses many advantages including improved tumoricidal efficacy, reduced side effects, and retarded drug resistance. Herein, a protein polymer bioconjugate-coated multifunctional upconversion nanosystem, consisting of upconversion nanoparticles (UCNs) core, tailored amphiphilic protein-polymer bioconjugate shell, and photosensitizer zinc phthalocyanine (ZnPc) and antitumor drug doxorubicin coloaded inside, was elaborately developed for combined photodynamic therapy (PDT) and chemotherapy. In this system, UCNs core could convert deep penetrating near-infrared light to visible light for simultaneous cell fluorescence imaging and photodynamic therapy by activating ZnPc to generate cytotoxic ROS, while the protective shell of bovine serum albumin-poly(epsilon caprolactone) (BSA-PCL) offered excellent water solubility, good stability, and low cytotoxicity. The ROS production test showed that this nanosystem could successfully generate singlet oxygen under NIR irradiation. A cellular uptake study demonstrated that intense fluorescence emission of the UCNs could be observed in HeLa cells, indicating their outstanding real-time imaging capability. More importantly, compared with single PDT or chemotherapy systems, the constructed combined therapy UCNs system demonstrated significantly enhanced tumor cell killing efficiency. On the basis of our findings, this multifunctional UCNs nanosystem could be a promising versatile theranostic nanoplatform for image guided combined cancer therapy. PMID- 27934135 TI - Cancer Cell Hyperactivity and Membrane Dipolarity Monitoring via Raman Mapping of Interfaced Graphene: Toward Non-Invasive Cancer Diagnostics. AB - Ultrasensitive detection, mapping, and monitoring of the activity of cancer cells is critical for treatment evaluation and patient care. Here, we demonstrate that a cancer cell's glycolysis-induced hyperactivity and enhanced electronegative membrane (from sialic acid) can sensitively modify the second-order overtone of in-plane phonon vibration energies (2D) of interfaced graphene via a hole-doping mechanism. By leveraging ultrathin graphene's high quantum capacitance and responsive phononics, we sensitively differentiated the activity of interfaced Glioblastoma Multiforme (GBM) cells, a malignant brain tumor, from that of human astrocytes at a single-cell resolution. GBM cell's high surface electronegativity (potential ~310 mV) and hyperacidic-release induces hole-doping in graphene with a 3-fold higher 2D vibration energy shift of approximately 6 +/- 0.5 cm-1 than astrocytes. From molecular dipole-induced quantum coupling, we estimate that the sialic acid density on the cell membrane increases from one molecule per ~17 nm2 to one molecule per ~7 nm2. Furthermore, graphene phononic response also identified enhanced acidity of cancer cell's growth medium. Graphene's phonon sensitive platform to determine interfaced cell's activity/chemistry will potentially open avenues for studying activity of other cancer cell types, including metastatic tumors, and characterizing different grades of their malignancy. PMID- 27934136 TI - Enhanced Photocatalytic Degradation of Tetracycline by AgI/BiVO4 Heterojunction under Visible-Light Irradiation: Mineralization Efficiency and Mechanism. AB - Recently, visible-light-driven photocatalysis is of great interest in the environmental pollutant remediation. In the present study, a novel heterostructured photocatalyst AgI/BiVO4 was synthesized by an in situ precipitation procedure. The AgI/BiVO4 heterojunctions exhibited excellent photoactivity for the refractory pollutant (tetracycline (TC), a typical antibiotic) decomposition under visible light illumination. The synthetic sample with 1:4 mass ratio of AgI:BiVO4 possessed the highest photocatalytic performance in all of the as-prepared catalysts. The TC molecules were substantially eliminated (94.91%) within 60 min, and degradation efficiency was considerably better than those of bare BiVO4 (62.68%) and AgI (75.43%) under identical conditions. Simultaneously, 90.46% of TOC removal was also achieved within 120 min, suggesting that the mineralization was superior and further confirmed by three-dimensional excitation-emission matrix fluorescence spectroscopy (3D EEMs). The XRD, XPS, DRS, and PL measurements revealed that a small amount of Ag nanoparticles was produced at the early photodegradation process. The structure transformation from AgI/BiVO4 (double-type) to AgI/Ag/BiVO4 (sandwich-like) improved the corresponding visible-light absorption performance. The self assembly Z-scheme heterojunction that consisted of AgI, Ag, and BiVO4 also efficiently accelerated photoinduced electron-hole pairs' separation and ultimately improved the efficiency of TC degradation. The responsible photocatalytic mechanism was discussed in detail on the basis of the reactive species capturing tests and ESR analysis, and the experimental results had been validated that superoxide radicals and holes played a vital role during the photocatalytic process. Furthermore, TC degradation efficiency was not of significant loss after four consecutive cycles, suggesting the excellent photostability of AgI/BiVO4 nanocomposite. These features demonstrate that the AgI/BiVO4 heterojunction has great application potential for refractory pollutants' removal from wastewater. PMID- 27934137 TI - Gated Molecular Transport in Highly Ordered Heterogeneous Nanochannel Array Electrode. AB - In biology, all protein channels share a common feature of containing narrow pore regions with hydrophobic functional groups and selectivity filter regions abundant with charged residues, which work together to account for fast and selective mass transport in and out of cells. In this work, an ultrathin layer of polydimethylsiloxane (PDMS) was evaporated on the top orifices of charged silica nanochannels (2-3 nm in diameter and 60 nm in length) vertically attached to the electrode surface, and the resulting structure is designated as heterogeneous silica nanochannels (HSNs). As evidenced by voltammetric studies, the transport of ionic species in these HSNs was controlled by both hydrophobic rejection and electrostatic force arising from the top PDMS layer and from the bottom silica nanochannels, respectively. Anionic species encountered both hydrophobic rejection and electrostatic repulsion forces, and thus, their transport was strongly prohibited, while the transport of cationic species was permitted once the electrostatic attraction exceeded the hydrophobic rejection. Moreover, the magnitude of hydrophobic force could be regulated by the PDMS layer thickness, and that of the electrostatic force can be modulated by the salt concentration, solution pH, or applied voltage. It was demonstrated that the HSNs could be activated from an OFF state (no ion can transport) to an ON state (only cation transport occurs) by decreasing the salt concentration, increasing the solution pH, or applying negative voltages. PMID- 27934138 TI - New D-A1-D-A2-Type Regular Terpolymers Containing Benzothiadiazole and Benzotrithiophene Acceptor Units for Photovoltaic Application. AB - Two novel regular terpolymers that are of D-A1-D-A2 type and contain benzothiadiazole and 2,5-dibromo-8-dodecanoylbenzo[1,2-b:3,4-b':5,6 d"]trithiophene (P1) or 2,8-dibromo-5-dodecanoylbenzene[1,2-b:3,4-b':5,6 d"]trithiophene (P2) acceptor units with the same thiophene donor were synthesized through Stille coupling, and their optical and electrochemical properties were investigated. The highest occupied molecular orbital (HOMO) and lowest unoccupied (LUMO) molecular orbital energy levels of these terpolymers indicate that there is sufficient LUMO offset with PCBM for efficient exciton dissociation, and their deeper HOMO levels ensure the high open-circuit voltage for the resultant bulk heterojunction solar cells. Measurements on the solar cell devices also confirm that compared to those based on P2 the devices based on P1 possess a higher short-circuit photocurrent (Jsc) as well as a higher fill factor (FF), which is attributed to the lower bandgap and higher hole mobility for P1, whereas the Voc is higher for the devices that are based on P2, which may be a result of P2 having a lower HOMO energy level than P1. The optimized polymer solar cells fabricated using P1:PC71BM (DIO/CF) and P2:PC71BM (CF/DIO) for the active layers showed a PCE of 7.19% and 6.34%, respectively. Atomic force microscopy (AFM) images of P1:PC71BM blend films show that they exhibit more suitable morphology with favorable interpenetrating networks, which favors high Jsc and FF. Moreover, P1 exhibits a more crystalline nature than P2 that also favors the charge transport. This may be a result of better molecular packing, more distinct phase separation of the blended films, as well as a reduction of charge recombination. PMID- 27934139 TI - Synthesis, Structural Characterization, and Field-Effect Transistor Properties of n-Channel Semiconducting Polymers Containing Five-Membered Heterocyclic Acceptors: Superiority of Thiadiazole Compared with Oxadiazole. AB - Five-membered 1,3,4-oxadiazole (OZ) and 1,3,4-thiadiazole (TZ) heterocycle-based copolymers as active layer have long been ignored in solution-processable n channel polymer field-effect transistors (PFETs) despite the long history of using OZ or TZ derivatives as the electron-injecting materials in organic light emitting devices and their favorable electron affinities. Herein, we first report the synthesis and PFETs performance of two n-channel conjugated polymers bearing OZ- or TZ-based acceptor moieties, i.e., PNOZ and PNTZ, where simple thiophene units are utilized as the weak donors and additional alkylated naphthalenediimides units are used as the second acceptors. A comparative study has been performed to reveal the effect of different heterocyclic acceptors on thermal properties, electronic properties, ordering structures, and carrier transport performance of the target polymers. It is found that both polymers possess low-lying LUMO values below -4.0 eV, indicating high electron affinity for both heterocycle-based polymers. Because of strong polarizable ability of sulfur atom in TZ heterocycle, PNTZ exhibits a red shift in maximal absorption and stronger molecular aggregation even in the diluted chlorobenzene solution as compared to the OZ-containing PNOZ. Surface morphological study reveals that a nodule-like surface with a rough surface morphology is observed clearly for PNOZ films, whereas PNTZ films display highly uniform surface morphology with well interconnected fiber-like polycrystalline grains. Investigation of PFETs performance indicates that both polymers afford air-stable n-channel transport characteristics. The uniform morphological structure and compact pi-pi stacking endow PNTZ with a high electron mobility of 0.36 cm2 V-1 s-1, much higher than that of PNOZ (0.026 cm2 V-1 s-1). These results manifest the feasibility in improving electron-transporting property simply by tuning heteroatom substitutes in n-channel polymers; further demostrate that TZ derivatives possess much superior potential for developing high-performance n-channel polymers compared to OZ derivatives. PMID- 27934140 TI - A54 Peptide Modified and Redox-Responsive Glucolipid Conjugate Micelles for Intracellular Delivery of Doxorubicin in Hepatocarcinoma Therapy. AB - Redox-responsive nanomaterials applied in drug delivery systems (DDS) have attracted an increasing attention in pharmaceutical research as a carrier for antitumor therapy. However, there would be unwanted drug release from a redox responsive DDS with no selection at nontarget sites, leading to undesirable toxicities in normal tissues and cells. Here, an A54 peptide modified and PEGylated reduction cleavable glucolipid conjugate (A54-PEG-CSO-ss-SA, abbreviated to APCssA) was designed for intracellular delivery of doxorubicin (DOX). The synthesized APCssA could be assembled via micellization self-assembly in aqueous water above the critical micelle concentration (54.9 MUg/mL) and exhibited a high drug encapsulation efficiency (77.92%). The APCssA micelles showed an enhanced redox sensitivity in that the disulfide bond could be degraded quickly and the drug would be released from micelles in 10 mM levels of glutathione (GSH). The cellular uptake studies highlighted the affinity of APCssA micelles toward the hepatoma cells (BEL-7402) compared to that toward HepG2 cells. In contrast with the nonresponsive conjugate, the drug was released from APCssA micelles more quickly in 10 mM level of GSH concentration (tumor cells). Moreover, the DOX-loaded APCssA micelles displayed an increased cytotoxicity which was 1.6- to 2.0-fold that of unmodified and nonresponsive micelles. In vivo, the APCssA micelles had stronger distribution to liver and hepatoma tissue and prolonged the circulation and retention time, while the drug release only occurred in the tumor tissue. The APCssA/DOX showed the tumor inhibition rate equal to that of commercial doxorubicin hydrochloric without negative consequence. This study suggested that the APCssA/DOX showed promising potential to treat the tumor for its special tumor targeting, selective intracellular drug release, enhanced antitumor activity, and reduced toxicity on normal tissues. PMID- 27934142 TI - Bilayer Heterostructured PThTPTI/WS2 Photodetectors with High Thermal Stability in Ambient Environment. AB - Organic-based photodetectors (PDs) have great potential applications in next generation portable, low-cost, large-area displays and optical communications. However, for practical applications, they are facing big challenges due to their instabilities in ambient environments, especially under high temperatures. Robust materials and device architectures are highly demanded to overcome the problem. In this report, we employed a donor conjugated polymer PThTPTI and realized thin film PDs which can stably operate in ambient air under temperatures as high as 300 degrees C. By adding a discontinuous thin layer of WS2 beneath the PThTPTI film, the device photosensitivity is significantly enhanced without loss of the high thermal stability. This work provides new insights in designing novel and stable organic-based devices for future optoelectronic applications. PMID- 27934141 TI - Encaging Palladium Nanoparticles in Chitosan Modified Montmorillonite for Efficient, Recyclable Catalysts. AB - Metal nanoparticles, once supported by a suitable scaffolding material, can be used as highly efficient heterogeneous catalysts for numerous organic reactions. The challenge, though, is to mitigate the continuous loss of metals from the supporting materials as reactions proceed, so that the catalysts can be recycled multiple times. Herein, we combine the excellent chelating property of chitosan (CS) and remarkable stability of montmorillonite (MMT) into a composite material to support metal catalysts such as palladium (Pd). The in situ reduction of Pd2+ into Pd0 in the interstices of MMT/CS composites effectively encages the Pd0 nanoparticles in the porous matrices, while still allowing for reactant and product molecules of relatively small sizes to diffuse in and out the matrices. The prepared Pd0@MMT/CS catalysts are highly active for the Heck reactions of aromatic halides and alkenes, and can be recycled 30 times without significant loss of activities. Positron annihilation lifetime analysis and other structural characterization methods are implemented to elucidate the unique compartmentalization of metal catalysts in the composite matrices. As both CS and MMT are economical and abundant materials in nature, this approach may facilitate a versatile platform for developing highly recyclable, heterogeneous catalysts containing metal nanoparticles. PMID- 27934143 TI - Improving Ionic Conductivity and Lithium-Ion Transference Number in Lithium-Ion Battery Separators. AB - The microstructure of lithium-ion battery separators plays an important role in separator performance; however, here we show that a geometrical analysis falls short in predicting the lithium-ion transport in the electrolyte-filled pore space. By systematically modifying the surface chemistry of a commercial polyethylene separator while keeping its microstructure unchanged, we demonstrate that surface chemistry, which alters separator-electrolyte interactions, influences ionic conductivity and lithium-ion transference number. Changes in separator surface chemistry, particularly those that increase lithium-ion transference numbers can reduce voltage drops across the separator and improve C rate capability. PMID- 27934144 TI - Toothpaste-like Electrode: A Novel Approach to Optimize the Interface for Solid State Sodium-Ion Batteries with Ultralong Cycle Life. AB - A non-sintered method with toothpaste electrode for improving electrode ionic conductivity and reducing interface impedance is introduced in solid-state rechargeable batteries. At 70 degrees C, this novel solid-state battery can deliver a capacity of 80 mAh g-1 in a voltage range of 2.5-3.8 V at 0.1C rate using layered oxide Na0.66Ni0.33Mn0.67O2, Na-beta"-Al2O3 and sodium metal as cathode, electrolyte and anode, respectively. Moreover, the battery shows a superior stability and high reversibility, with a capacity retention of 90% after 10 000 cycles at 6C rate and a capacity of 79 mAh g-1 is recovered when the current rate is returned to 0.1C. Furthermore, a very thick electrode with active material mass loading of 6 mg cm-2 also presents a reasonable electrochemical performance. These results demonstrate that this is a promising approach to solve the interface problem and would open a new route in designing the next generation solid-state battery. PMID- 27934145 TI - Highly Conductive Cu-Cu Joint Formation by Low-Temperature Sintering of Formic Acid-Treated Cu Nanoparticles. AB - Highly conductive Cu-Cu interconnections of SiC die with Ti/Ni/Cu metallization and direct bonded copper substrate for high-power semiconductor devices are achieved by the low-temperature sintering of Cu nanoparticles with a formic acid treatment. The Cu-Cu joints formed via a long-range sintering process exhibited good electrical conductivity and high strength. When sintered at 260 degrees C, the Cu nanoparticle layer exhibited a low resistivity of 5.65 MUOmega.cm and the joints displayed a high shear strength of 43.4 MPa. When sintered at 320 degrees C, the resistivity decreased to 3.16 MUOmega.cm and the shear strength increased to 51.7 MPa. The microstructure analysis demonstrated that the formation of Cu-Cu joints was realized by metallurgical bonding at the contact interface between the Cu pad and the sintered Cu nanoparticle layer, and the densely sintered layer was composed of polycrystals with a size of hundreds of nanometers. In addition, high density twins were found in the interior of the sintered layer, which contributed to the improvement of the performance of the Cu-Cu joints. This bonding technology is suitable for high-power devices operating under high temperatures. PMID- 27934146 TI - Highly Flexible Indium Tin Oxide Nanofiber Transparent Electrodes by Blow Spinning. AB - Transparent conductive film (TCF) has found wide applications. Indium tin oxide (ITO) is currently the most widely used transparent electrode. However, major problem of ITO is the lacking of flexibility, which totally limits its applications. Here, we report a highly flexible transparent electrode consisting of freestanding ITO nanofiber network fabricated by blow spinning, the advantage of which is its high-efficiency, low cost and safety. When the bending radius decreased to 0.5 mm, the resistance of the transparent electrodes only increased by 18.4%. Furthermore, the resistance was almost unchanged after thousands of bending cycles at 3.5 mm bending radius. PMID- 27934147 TI - Resistive Switching and Modulation of Pb(Zr0.4Ti0.6)O3/Nb:SrTiO3 Heterostructures. AB - In this work, epitaxial Pb(Zr0.4Ti0.6)O3 (PZT) thin films with different thicknesses were deposited on Nb-doped SrTiO3 (NSTO) single-crystal substrates by chemical solution deposition (CSD), and their ferroelectric resistive switching behaviors were investigated. The results showed that the maximum ON/OFF ratio up to 850 could be obtained in the PZT/NSTO heterostructure with the 150 nm thick PZT film. On the basis of the Schottky-Simmons model and the modified semiconductor theory, we also evaluated the interfacial built-in field and the depletion layer at the PZT/NSTO interface, which can be modulated strongly by the ferroelectric polarization, but are independent of the thickness of the PZT thin films. It is clear that the ferroelectric resistive switching is related to the ferroelectric polarization and modulated by the thickness of ferroelectric films. Therefore, there is an optimal thickness of the PZT film for the maximum ON/OFF ratio due to the ferroelectricity and conductivity mutually restricting. It can be expected that by adjusting the ferroelectricity and conductivity of the ferroelectric thin film and its thickness, the maximum switching ratio can be further improved. PMID- 27934148 TI - Biomass-Derived Porous Carbonaceous Aerogel as Sorbent for Oil-Spill Remediation. AB - We prepared a cost-effective, environmentally friendly carbonaceuous oil sorbent with a lotus effect structure using a simple one-pot hydrothermal reaction and a mild modification process. The carbonaceous oil sorbent can rapidly, efficiently, and continuously collect oil in situ from a water surface. This sorbent was unlike traditional sorbents because it was not dependent on the weight and volume of the sorption material. The sorbent was also successfully used to separate and collect crude oil from the water surface and can collect organic solvents underwater. This novel oil sorbent and oil-collection device can be used in case of emergency for organic solvent leakages, as well as leakages in tankers and offshore drilling platforms. PMID- 27934149 TI - Rational Integration of Inbuilt Aperture with Mesoporous Framework in Unusual Asymmetrical Yolk-Shell Structures for Energy Storage and Conversion. AB - Despite the attractive benefits of hollow structures as electrodes for advanced energy storage-conversion capabilities, one prevailing shortcoming is their compromised structural integrity and volumetric energy density due to the introduction of an ultrathin shell with an excessively underutilized large hollow cavity. Herein, we report a facile and template-free synthetic route to realize unusual asymmetrical yolk-shell (AYs) structures composed of mixed-valence NiCo2O4 material. Explicitly, this work highlights the unusual off-central core, an AYs structure that encompasses a hemispherical hollow interior, and a mesoporous solid counterpart. As such, it retains desirable hollow structural characteristics while favorably precludes the excessive unexploited hollow interior space for increased active material packing. Unlike the conventional symmetrical yolk-shell (SYs) which is composed of a porous shell framework radially throughout the structure, the mesoporous solid constitution of the AYs structure offers an inbuilt reinforced framework to support the partial porous shell and concurrently leaves sufficient void for volumetric buffering. Another unique structural feature of the AYs structure is the formation of a submicron aperture or opening on the shell that enhances accessibility of electrolyte diffusion. All of these synergistic structural features of NiCo2O4 AYs structures enhance the pseudocapacitive and electrocatalytic properties. PMID- 27934150 TI - A Metal-Organic Framework Derived Porous Cobalt Manganese Oxide Bifunctional Electrocatalyst for Hybrid Na-Air/Seawater Batteries. AB - Spinel-structured transition metal oxides are promising non-precious-metal electrocatalysts for oxygen electrocatalysis in rechargeable metal-air batteries. We applied porous cobalt manganese oxide (CMO) nanocubes as the cathode electrocatalyst in rechargeable seawater batteries, which are a hybrid-type Na air battery with an open-structured cathode and a seawater catholyte. The porous CMO nanocubes were synthesized by the pyrolysis of a Prussian blue analogue, Mn3[Co(CN)6]2.nH2O, during air-annealing, which generated numerous pores between the final spinel-type CMO nanoparticles. The porous CMO electrocatalyst improved the redox reactions, such as the oxygen evolution/reduction reactions, at the cathode in the seawater batteries. The battery that used CMO displayed a voltage gap of ~0.53 V, relatively small compared to that of the batteries employing commercial Pt/C (~0.64 V) and Ir/C (~0.73 V) nanoparticles and without any catalyst (~1.05 V) at the initial cycle. This improved performance was due to the large surface area (catalytically active sites) and the high oxidation states of the randomly distributed Co and Mn cations in the CMO. Using a hard carbon anode, the Na-metal-free seawater battery exhibited a good cycle performance with an average discharge voltage of ~2.7 V and a discharge capacity of ~190 mAh g-1hard carbon during 100 cycles (energy efficiencies of 74-79%). PMID- 27934151 TI - Mechanical Response of Thermally Annealed Nafion Thin Films. AB - Perfluorinated ionomers, in particular, Nafion, are a critical component in hydrogen fuel cells as the ion conducting binder within the catalyst layer in which it can be confined to thicknesses on the order of 10 nm or less. It is well reported that many physical properties, such as the Young's modulus, are thickness dependent when the film thickness is less than 100 nm. Here we utilize a cantilever bending methodology to quantify the swelling-induced stresses and relevant mechanical properties of Nafion films as a function of film thickness exposed to cyclic humidity. We observe a factor of 5 increase in the Young's modulus in films thinner than 50 nm and show how this increased stiffness translates to reduced swelling or hydration. The swelling stress was found to increase by a factor of 2 for films approximately 40 nm thick. We demonstrate that thermal annealing enhances the modulus at all film thicknesses and correlate these mechanical changes to chemical changes in the infrared absorption spectra. PMID- 27934152 TI - Combined Effect of Chain Extension and Supramolecular Interactions on Rheological and Adhesive Properties of Acrylic Pressure-Sensitive Adhesives. AB - A new approach for the elaboration of low molecular weight pressure-sensitive adhesives based on supramolecular chemistry is explored. The synthesis of model systems coupled with probe-tack tests and rheological experiments highlights the influence of the transient network formed by supramolecular bonds on the adhesion energy. The first step of our approach consists of synthesizing poly(butyl acrylate-co-glycidyl methacrylate) copolymers from a difunctional initiator able to self-associate by four hydrogen bonds between urea groups. Linear copolymers with a low dispersity (Mn = 10 kg/mol, Ip < 1.4) have been synthesized via atom transfer radical polymerization. Films of the copolymers were then partially cross-linked through reaction of the epoxy functions with a diamine. The systematic variation of the average ratio of glycidyl methacrylate and diamine per copolymer shed light on the respective role played by the supramolecular interactions (between bis-urea groups and with the side chains) and by the chain extension and branching induced by the diamine/epoxy reaction. In this strategy, the adhesive performance can be optimized by modifying the strength of "stickers" (via the structure of the supramolecular initiator, for instance) and the polymer network (e.g., via the length and level of branching of the copolymer chains) in order to approach commercial PSA-like properties (high debonding energy and clean removal). PMID- 27934153 TI - Self-Powered Ultrabroadband Photodetector Monolithically Integrated on a PMN-PT Ferroelectric Single Crystal. AB - Photodetectors capable of detecting two or more bands simultaneously with a single system have attracted extensive attentions because of their critical applications in image sensing, communication, and so on. Here, we demonstrate a self-powered ultrabroadband photodetector monolithically integrated on a 0.72Pb(Mg1/3Nb2/3)O3-0.28PbTiO3 (PMN-28PT) single crystal. By combining the optothermal and pyroelectric effect, the multifunctional PMN-28PT single crystal can response to a wide wavelength range from UV to terahertz (THz). At room temperature, the photodetector could generate a pyroelectric current under the intermittent illumination of incident light in absence of external bias. A systematic study of the photoresponse was investigated. The pyroelectric current shows an almost linear relationship to illumination intensity. Benefiting from the excellent pyroelectric property of PMN-28PT single crystal and the optimized device architecture, the device exhibited a dramatic improvement in operation frequency up to 3 kHz without any obvious degradation in sensitivity. Such a self powered photodetector with ultrabroadband response may open a window for the novel application of ferroelectric materials in optoelectronics. PMID- 27934154 TI - High Performance Small-Molecule Cathode Interlayer Materials with D-A-D Conjugated Central Skeletons and Side Flexible Alcohol/Water-Soluble Groups for Polymer Solar Cells. AB - A new class of organic cathode interfacial layer (CIL) materials based on isoindigo derivatives (IID) substituted with pyridinium or sulfonate zwitterion groups were designed, synthesized, and applied in polymer solar cells (PSCs) with PTB7:PC71BM (PTB7: polythieno[3,4-b]-thiophene-co-benzodithiophene and PC71BM: [6,6]-phenyl C71-butyric acidmethyl ester) as an active layer. Compared with the control device, PSCs with an IID-based CIL show simultaneous enhancement of open circuit voltage (Voc), short-circuit current (Jsc), and fill factor (FF). Systematic optimizations of the central conjugated core and side flexible alcohol soluble groups demonstrated that isoindigo-based CIL material with thiophene and sulfonate zwitterion substituent groups can efficiently enhance the PSC performance. The highest power conversion efficiency (PCE) of 9.12%, which is 1.75 times that of the control device without CIL, was achieved for the PSC having an isoindigo-based CIL. For the PSCs with an isoindigo-based CIL, the molecule-dependent performance property studies revealed that the central conjugated core with D-A-D characteristics and the side chains with sulfonate zwitterions groups represents an efficient strategy for constructing high performance CILs. Our study results may open a new avenue toward high performance PSCs. PMID- 27934155 TI - Active Site Structures in Nitrogen-Doped Carbon-Supported Cobalt Catalysts for the Oxygen Reduction Reaction. AB - The catalytic mechanism and the nature of active sites are revealed for the oxygen reduction reaction (ORR) with new non-noble-metal nitrogen-doped carbon supported transition-metal catalysts (metal-N-C catalyst). Specifically, new nitrogen-doped carbon-supported cobalt catalysts (Co-N-C catalysts) are made by pyrolyzing various ratios of the nitrogen-atom rich heterocycle compound, 1-ethyl 3-methyl imidazolium dicyanamide (EMIM-dca) and cobalt salt (Co(NO3)2). The ORR activity (JK at 0.8 V vs RHE, in 0.1 M KOH solution) of a typical catalyst in this family, Co15-N-C800, is 8.25 mA/mg, which is much higher than the ORR activity values of N-C catalysts (0.41 mA/mg). The active site in the catalyst is found to be the Co-N species, which is most likely in the form of Co2N. Metallic cobalt (Co) particles, Co3C species, and N-C species are not catalytically active sites, nor do these moieties interact with the Co-N active sites during the catalysis of the ORR. Increasing the Co salt content during the synthesis favors the formation of Co-N active sites in the final catalyst. Higher pyrolysis temperatures (e.g., a temperature higher than 800 degrees C) do not favor the formation of the Co-N active sites, but cause the formed Co-N active sites to decompose, which, therefore, leads to a lower catalytic activity. This reveals that the control of the parameters that affect the final structure is critical to catalyst performance and, therefore, the effective development of high performance heteroatom-doped non-noble-metal ORR catalysts. PMID- 27934156 TI - Haptotatic Plasma Polymerized Surfaces for Rapid Tissue Regeneration and Wound Healing. AB - Skin has a remarkable capacity for regeneration; however, with an ever aging population, there is a growing burden to the healthcare system from chronic wounds. Novel therapies are required to address the problems associated with nonhealing chronic wounds. Novel wound dressings that can encourage increased reepithelialization could help to reduce the burden of chronic wounds. A suite of chemically defined surfaces have been produced using plasma polymerization, and the ability of these surfaces to support the growth of primary human skin cells has been assessed. Additionally, the ability of these surfaces to modulate cell migration and morphology has also been investigated. Keratinocytes and endothelial cells were extremely sensitive to surface chemistry showing increased viability and migration with an increased number of carboxylic acid functional groups. Fibroblasts proved to be more tolerant to changes in surface chemistry; however, these cells migrated fastest over amine-functionalized surfaces. The novel combination of comprehensive chemical characterization coupled with the focus on cell migration provides a unique insight into how a material's physicochemical properties affect cell migration. PMID- 27934157 TI - Photopolymerization of Diacetylene on Aligned Multiwall Carbon Nanotube Microfibers for High-Performance Energy Devices. AB - Linear two-dimensional materials have recently attracted an intense interest for supercapacitors because of their potential uses as electrodes in next-generation wearable electronics. However, enhancing the electrochemical properties of these materials without complicated structural modifications remains a challenge. Herein, we present the preparation of a hybrid electrode system via polydiacetylene (PDA) cloaking on the surface of aligned multiwall carbon nanotubes (MWCNTs) through self-assembly based in situ photopolymerization. This strategy eliminates the need for initiators and binders that hinder electrochemical performance in conventional conducting polymer based composite electrodes. As noncovalent PDA cloaking did not alter the chemical structure of MWCNTs, high inherent conductivity from sp2 hybridized carbon was preserved. The resulting hybrid microfiber (MWCNT@PDA) exhibited a significant increase in specific capacitance (1111 F g-1) when compared to bare MWCNTs (500 F g-1) and PDA (666.7 F g-1) in a voltage window of 0-1.2 V at a current density of 3 A g-1 in 0.5 M K2SO4 electrolyte. The specific capacitance was retained (ca. 95%) after 7000 charge/discharge cycles. The present results suggest that aligned MWCNTs cloaked with conjugated polymers could meet the demands for future flexible electronics. PMID- 27934158 TI - Soft X-ray Spectroscopy of a Complex Heterojunction in High-Efficiency Thin-Film Photovoltaics: Intermixing and Zn Speciation at the Zn(O,S)/Cu(In,Ga)Se2 Interface. AB - The chemical structure of the Zn(O,S)/Cu(In,Ga)Se2 interface in high-efficiency photovoltaic devices is investigated using X-ray photoelectron and Auger electron spectroscopy, as well as soft X-ray emission spectroscopy. We find that the Ga/(Ga+In) ratio at the absorber surface does not change with the formation of the Zn(O,S)/Cu(In,Ga)Se2 interface. Furthermore, we find evidence for Zn in multiple bonding environments, including ZnS, ZnO, Zn(OH)2, and ZnSe. We also observe dehydrogenation of the Zn(O,S) buffer layer after Ar+ ion treatment. Similar to high-efficiency CdS/Cu(In,Ga)Se2 devices, intermixing occurs at the interface, with diffusion of Se into the buffer, and the formation of S-In and/or S-Ga bonds at or close to the interface. PMID- 27934159 TI - Tailored Dual PEGylation of Inorganic Porous Nanocarriers for Extremely Long Blood Circulation in Vivo. AB - Drug carrier systems based on mesoporous inorganic nanoparticles generally face the problem of fast clearance from bloodstream thus failing in passive and active targeting to cancer tissue. To address this problem, a specific dual PEGylation (DPEG) method for mesoporous silicon (PSi) was developed and studied in vitro and in vivo. The DPEG coating changed significantly the behavior of the nanoparticles in vivo, increasing the circulation half-life from 1 to 241 min. Furthermore, accumulation of the coated particles was mainly taking place in the spleen whereas uncoated nanoparticles were rapidly deposited in the liver. The protein coronas of the particles differed considerably from each other. The uncoated particles had substantially more proteins adsorbed including liver and immune active proteins, whereas the coated particles had proteins capable of suppressing cellular uptake. These reasons along with agglomeration observed in blood circulation were concluded to cause the differences in the behavior in vivo. The biofate of the particles was monitored with magnetic resonance imaging by incorporating superparamagnetic iron oxide nanocrystals inside the pores of the particles making dynamic imaging of the particles feasible. The results of the present study pave the way for further development of the porous inorganic delivery system in the sense of active targeting as the carriers can be easily chemically modified allowing also magnetically targeted delivery and diagnostics. PMID- 27934160 TI - Ecofriendly Fabrication of Modified Graphene Oxide Latex Nanocomposites with High Oxygen Barrier Performance. AB - Large-scale industrial applications of barrier films and coatings that prevent permeation of degradative gases and moisture call for the development of cost efficient and ecofriendly polymer nanocomposites. Herein, we report the facile fabrication of latex nanocomposites (LNCs) by incorporating surface-modified graphene oxide (mGO) at various loadings (0.025-1.2 wt %) into a styrene-acrylic latex using water as the processing solvent. LNCs fabricated with mGO exhibited significant reductions (up to 67%) in water vapor sorption, resulting in greater environmental stability when compared to LNCs fabricated with equivalent loading of hydrophilic, unmodified GO. The assembly and coalescence of the exfoliated latex/mGO dispersions during the film formation process produced highly dispersed and well-ordered mGO domains with high aspect ratios, where alignment and overlap of the mGO domains improved with increasing mGO content. The addition of only 0.7 vol % (1.2 wt %) mGO led to an 84% decrease (relative to the neat polymer latex film) in oxygen permeability of the LNC films, an excellent barrier performance attributed to the observed LNC film morphologies. This work enables ecofriendly development of mechanically flexible mGO/LNC films with superior barrier properties for many industrial applications including protective coatings, food packaging, and biomedical products. PMID- 27934161 TI - Triple-Confined Well-Dispersed Biactive NiCo2S4/Ni0.96S on Graphene Aerogel for High-Efficiency Lithium Storage. AB - Layered double hydroxides (LDHs), also known as hydrotalcite-like anionic clay compounds, have attracted increasing interest in electrochemical energy storage, in the main form of LDH precursor-derived transition metal oxides (TMOs). One typical approach to improve cycling stability of the LDH-derived TMOs is to introduce one- and two-dimensional conductive carbonaceous supports, such as carbon nanotubes and graphene. We herein demonstrate an effective approach to improve the electrochemical performances of well-dispersed biactive NiCo2S4/Ni0.96S as anode nanomaterials for lithium-ion batteries (LIBs), by introducing a three-dimensional graphene aerogel (3DGA) support. The resultant 3DGA supported NiCo2S4/Ni0.96S (3DGA/NCS) composite, obtained by sulfuration of NiCo-layered double hydroxide (NiCo-LDH) precursor in situ grown on the 3DGA support (3DGA/NiCo-LDH). Electrochemical tests show that the 3DGA/NCS composite indeed delivers the greatly enhanced electrochemical performances compared with the NiCo2S4/Ni0.96S counterpart on two-dimensional graphene aerogel, i.e., a high reversible capacity of 965 mA h g-1 after 200 cycles at 100 mA g-1 and especially a superlong cycling stability of 620 mA h g-1 after 800 cycles at 1 A g-1. The enhancements could be ascribed to the compositional and structural advantages of boosting electrochemical performances: (i) well-dispersed NiCo2S4/Ni0.96S nanoparticles with interfacial nanodomains resulting from both the dual surface confinements of the 3DGA support and the crystallographic confinement of NiCo well-arranged LDH crystalline layer, (ii) an appropriate specific surface area and a wide pore size distribution of mesopores and macropores, and (iii) highly conductive 3DGA support that is measured experimentally by using electrochemical impedance spectra to underlie the enhancement. Our results demonstrate that the tunable LDH precursor-derived synthesis route may be extended to prepare various transition metal sulfides and even transition metal phosphides for energy storage with the aid of tunable cationic type and molar ratio. PMID- 27934162 TI - One-Pot UV-Triggered o-Nitrobenzyl Dopamine Polymerization and Coating for Surface Antibacterial Application. AB - Dopamine (DA) protected by an o-nitrobenzyl functionality on its phenolic group was synthesized as a photolabile catecholamine derivative. This compound, o nitrobenzyl dopamine (NBDA), was more stable than DA in basic solution at pH 8.5 and will not self-polymerize when protected from light. UV irradiation of a methanolic solution of NBDA at 365 nm for 40 min induced ca. 85% deprotection. Taking advantage of the stability of NBDA, a one-pot spray coating technique for modifying surfaces with polydopamine (PDA) was developed. Using ethylene glycol with Tris buffer (pH 8.5) as the solvent for this technique, stainless steel substrates can be coated with a robust PDA layer. Silver was deposited on the PDA coated surface after treatment with silver nitrate solution, and >80% of the deposited silver remained on the surface after 1 week immersion in water. The NBDA-Ag surface was highly effective in inhibiting Staphylococcus aureus (S. aureus) biofilm formation. PMID- 27934163 TI - Formation of Perovskite Heterostructures by Ion Exchange. AB - Thin-film optoelectronic devices based on polycrystalline organolead-halide perovskites have recently become a topic of intense research. Single crystals of these materials have been grown from solution with electrical properties superior to those of polycrystalline films. In order to enable the development of more complex device architectures based on organolead-halide perovskite single crystals, we developed a process to form epitaxial layers of methylammonium lead iodide (MAPbI3) on methylammonium lead bromide (MAPbBr3) single crystals. The formation of the MAPbI3 layer is found to be dominated by the diffusion of halide ions, leading to a shift in the photoluminescence and absorption spectra. X-ray diffraction measurements confirm the single-crystal nature of the MAPbI3 layer, while carrier transport measurements show that the converted layer retains the high carrier mobility typical of single-crystal perovskite materials. Such heterostructures on perovskite single crystals open possibilities for new types of devices. PMID- 27934164 TI - Self-Powered, Wireless, Remote Meteorologic Monitoring Based on Triboelectric Nanogenerator Operated by Scavenging Wind Energy. AB - Meteorologic monitoring plays a key role on weather forecast and disaster warning and deeply relies on various sensor networks. It is an optimal choice that grabbing the environmental energy around sensors for driving sensor network. Here, we demonstrate a self-powered, wireless, remote meteorologic monitoring system based on an innovative TENG. The TENG has been proved capable of scavenging wind energy and can be employed for self-powered, wireless meteorologic sounding. This work not only promotes the development of renewable energy harvesting, but also exploits and enriches promising applications based on TENGs for self-powered, wireless, remote sensing. PMID- 27934165 TI - Aspirin-Based Carbon Dots, a Good Biocompatibility of Material Applied for Bioimaging and Anti-Inflammation. AB - The emerging photoluminescent carbon-based nanomaterials are promising in various fields besides cell imaging and carrier transport. Carbon nanomaterials with specific biological functions, however, are rarely investigated. Aspirin is a very common anti-inflammatory medication to relieve aches and pains. In this study, we have tried to create a carbon nanoparticle with aspirin, and we expect that this new carbon nanoparticle will have both anti-inflammatory and fluorescent biomarker functions. Fluorescent aspirin-based carbon dots (FACDs) were synthesized by condensing aspirin and hydrazine through a one-step microwave assisted method. Imaging data demonstrated that FACDs efficiently entered into human cervical carcinoma and mouse monocyte macrophage cells in vitro with low cell toxicity. Results from quantitative polymerase chain reaction and histological analysis indicated that FACDs possessed effective anti-inflammatory effects in vitro and in vivo compared to aspirin only. Hematology, serum biochemistry, and histology results suggested that FACDs also had no significant toxicity in vivo. Our results clearly demonstrate that FACDs have dual functions, cellular imaging/bioimaging and anti-inflammation, and suggest that FACDs have great potential in future clinical applications. PMID- 27934167 TI - Conductive Boron-Doped Graphene as an Ideal Material for Electrocatalytically Switchable and High-Capacity Hydrogen Storage. AB - Electrocatalytic, switchable hydrogen storage promises both tunable kinetics and facile reversibility without the need for specific catalysts. The feasibility of this approach relies on having materials that are easy to synthesize, possessing good electrical conductivities. Graphitic carbon nitride (g-C4N3) has been predicted to display charge-responsive binding with molecular hydrogen-the only such conductive sorbent material that has been discovered to date. As yet, however, this conductive variant of graphitic carbon nitride is not readily synthesized by scalable methods. Here, we examine the possibility of conductive and easily synthesized boron-doped graphene nanosheets (B-doped graphene) as sorbent materials for practical applications of electrocatalytically switchable hydrogen storage. Using first-principle calculations, we find that the adsorption energy of H2 molecules on B-doped graphene can be dramatically enhanced by removing electrons from and thereby positively charging the adsorbent. Thus, by controlling charge injected or depleted from the adsorbent, one can effectively tune the storage/release processes which occur spontaneously without any energy barriers. At full hydrogen coverage, the positively charged BC5 achieves high storage capacities up to 5.3 wt %. Importantly, B-doped graphene, such as BC49, BC7, and BC5, have good electrical conductivity and can be easily synthesized by scalable methods, which positions this class of material as a very good candidate for charge injection/release. These predictions pave the route for practical implementation of electrocatalytic systems with switchable storage/release capacities that offer high capacity for hydrogen storage. PMID- 27934166 TI - Selective Deposition of Dielectrics: Limits and Advantages of Alkanethiol Blocking Agents on Metal-Dielectric Patterns. AB - Area selective atomic layer deposition has the potential to significantly improve current fabrication approaches by introducing a bottom-up process in which robust and conformal thin films are selectively deposited onto patterned substrates. In this paper, we demonstrate selective deposition of dielectrics on metal/dielectric patterns by protecting metal surfaces using alkanethiol blocking layers. We examine alkanethiol self-assembled monolayers (SAMs) with two different chain lengths deposited both in vapor and in solution and show that in both systems, thiols have the ability to block surfaces against dielectric deposition. We show that thiol molecules can displace Cu oxide, opening possibilities for easier sample preparation. A vapor-deposited alkanethiol SAM is shown to be more effective than a solution-deposited SAM in blocking ALD, even after only 30 s of exposure. The vapor deposition also results in a much better thiol regeneration process and may facilitate deposition of the SAMs on porous or three-dimensional structures, allowing for the fabrication of next generation electronic devices. PMID- 27934168 TI - Highly Efficient Silver-Cobalt Composite Nanotube Electrocatalysts for Favorable Oxygen Reduction Reaction. AB - This paper reports the synthesis and characterization of silver-cobalt (AgCo) bimetallic composite nanotubes. Cobalt oxide (Co3O4) nanotubes were fabricated by electrospinning and subsequent calcination in air and then reduced to cobalt (Co) metal nanotubes via further calcination under a H2/Ar atmosphere. As-prepared Co nanotubes were then employed as templates for the following galvanic replacement reaction (GRR) with silver (Ag) precursor (AgNO3), which produced AgCo composite nanotubes. Various AgCo nanotubes were readily synthesized with applying different reaction times for the reduction of Co3O4 nanotubes and GRR. One hour reduction was sufficiently long to convert Co3O4 to Co metal, and 3 h GRR was enough to deposit Ag layer on Co nanotubes. The tube morphology and copresence of Ag and Co in AgCo composite nanotubes were confirmed with SEM, HRTEM, XPS, and XRD analyses. Electroactivity of as-prepared AgCo composite nanotubes was characterized for ORR with rotating disk electrode (RDE) voltammetry. Among differently synthesized AgCo composite nanotubes, the one synthesized via 1 h reduction and 3 h GRR showed the best ORR activity (the most positive onset potential, greatest limiting current density, and highest number of electrons transferred). Furthermore, the ORR performance of the optimized AgCo composite nanotubes was superior compared to pure Co nanotubes, pure Ag nanowires, and bare platinum (Pt). High ethanol tolerance of AgCo composite nanotubes was also compared with the commercial Pt/C and then verified its excellent resistance to ethanol contamination. PMID- 27934169 TI - Scalable Nanoporous (Pt1-xNix)3Al Intermetallic Compounds as Highly Active and Stable Catalysts for Oxygen Electroreduction. AB - Author: Bimetallic platinum-nickel (Pt-Ni) alloys as oxygen reduction reaction (ORR) electrocatalysts show genuine potential to boost widespread use of low temperature fuel cells in vehicles by virtue of their high catalytic activity. However, their practical implementation encounters primary challenges in structural and catalytic durability caused by the low formation heat of Pt-Ni alloys. Here, we report nanoporous (NP) (Pt1-xNix)3Al intermetallic nanoparticles as oxygen electroreduction catalyst NP (Pt1-xNix)3Al, which circumvents this problem by making use of the extraordinarily negative formation heats of Pt-Al and Ni-Al bonds. The NP (Pt1-xNix)3Al nanocatalyst, which is mass-produced by alloying/dealloying and mechanical crushing technologies, exhibits specific activity of 3.6 mA cm-2Pt and mass activity of 2.4 A mg-1Pt at 0.90 V as a result of both ligand and compressive strain effects, while strong Ni-Al and Pt-Al bonds ensure their exceptional durability by alleviating evolution of Pt, Ni, and Al components and dissolutions of Ni and Al atoms. PMID- 27934170 TI - Role of Hydrogen Bonds in Thermal Transport across Hard/Soft Material Interfaces. AB - The nature of the bond is a dominant factor in determining the thermal transport across interfaces. In this paper, we study the role of the hydrogen bond in thermal transport across interfaces between hard and soft materials with different surface functionalizations around room temperature using molecular dynamics simulations. Gold (Au) is studied as the hard material, and four different types of organic liquids with different polarizations, including hexane (C5H11CH3), hexanamine (C6H13NH2), hexanol (C6H13OH), and hexanoic acid (C5H11COOH), are used to represent the soft materials. To study the hydrogen bonds at the Au/organic liquid interface, three types of thiol-terminated self assembled monolayer (SAM) molecules, including 1-hexanethiol [HS(CH2)5CH3], 6 mercapto-1-hexanol [HS(CH2)6OH], and 6-mercaptohexanoic acid [HS(CH2)5COOH], are used to functionalize the Au surface. These SAM molecules form hydrogen bonds with the studied organic liquids with varying strengths, which are found to significantly improve efficient interfacial thermal transport. Detailed analyses on the molecular-level details reveal that such efficient thermal transport originates from the collaborative effects of the electrostatic and van der Waals portions in the hydrogen bonds. It is found that stronger hydrogen bonds will pull the organic molecules closer to the interface. This shorter intermolecular distance leads to increased interatomic forces across the interfaces, which result in larger interfacial heat flux and thus higher thermal conductance. These results can provide important insight into the design of hard/soft materials or structures for a wide range of applications. PMID- 27934171 TI - ZnO Rods with Exposed {100} Facets Grown via a Self-Catalyzed Vapor-Solid Mechanism and Their Photocatalytic and Gas Sensing Properties. AB - We present a new method for vapor deposition of columnar ZnO structures in the form of rods on various substrates without the need for substrate modification with catalyst seed particles and at relatively low temperatures compared to other vapor deposition methods. These structures are used for the photodegradation of stearic acid (C18H36O2) and the photoactivated detection of gases such as carbon monoxide (CO), ethanol (C2H6O), toluene (C7H8), and nitrogen dioxide (NO2) at room temperature, showing improved selectivity compared to tests performed in themoactivated mode. PMID- 27934172 TI - Crystal Engineering for Low Defect Density and High Efficiency Hybrid Chemical Vapor Deposition Grown Perovskite Solar Cells. AB - Synthesis of high quality perovskite absorber is a key factor in determining the performance of the solar cells. We demonstrate that hybrid chemical vapor deposition (HCVD) growth technique can provide high level of versatility and repeatability to ensure the optimal conditions for the growth of the perovskite films as well as potential for batch processing. It is found that the growth ambient and degree of crystallization of CH3NH3PbI3 (MAPI) have strong impact on the defect density of MAPI. We demonstrate that HCVD process with slow postdeposition cooling rate can significantly reduce the density of shallow and deep traps in the MAPI due to enhanced material crystallization, while a mixed O2/N2 carrier gas is effective in passivating both shallow and deep traps. By careful control of the perovskite growth process, a champion device with power conversion efficiency of 17.6% is achieved. Our work complements the existing theoretical studies on different types of trap states in MAPI and fills the gap on the theoretical analysis of the interaction between deep levels and oxygen. The experimental results are consistent with the theoretical predictions. PMID- 27934173 TI - Mixed 1T-2H Phase MoS2/Reduced Graphene Oxide as Active Electrode for Enhanced Supercapacitive Performance. AB - A hybrid aerogel, composed of MoS2 sheets of 1T (distorted octahedral) and 2H (trigonal prismatic) phases, finely mixed with few layers of reduced graphene oxide (rGO) and obtained by means of a facile environment-friendly hydrothermal cosynthesis, is proposed as electrode material for supercapacitors. By electrochemical characterizations in three- and two-electrode configurations and symmetric planar devices, unique results have been obtained, with specific capacitance values up to 416 F g-1 and a highly stable capacitance behavior over 50000 charge-discharge cycles. The in-depth morphological and structural characterizations through field emission scanning electron microscopy, Raman, X ray photoelectron spectroscopy, X-ray diffraction, Brunauer-Emmett-Teller, and transmission electron microscopy analysis provides the proofs of the unique assembly of such 3D structured matrix. The unpacked MoS2 structure exhibits an excellent distribution of 1T and 2H phase sheets that are highly exposed to interaction with the electrolyte, and so available for surface/near-surface redox reactions, notwithstanding the quite low overall content of MoS2 embedded in the reduced graphene oxide (rGO) matrix. A comparison with other "more conventional" hybrid rGO-MoX2 electrochemically active materials, synthesized in the same conditions, is provided to support the outstanding behavior of the cosynthesized rGO-MoS2. PMID- 27934174 TI - Live Templates of a Supramolecular Block Copolymer for the Synthesis of Ordered Nanostructured TiO2 Films via Guest Exchange. AB - In this work, we introduce a facile method based on host-guest chemistry to synthesize a range of nanostructured TiO2 materials using supramolecular templates of a dendron-jacketed block copolymer (DJBCP). The DJBCP is composed of amphiphilic dendrons (4'-(3,4,5-tridodecyloxybenzoyloxy)benzoic acid, TDB) selectively incorporated into a P4VP block of polystyrene-block-poly(4 vinylpyridine) (PS-b-P4VP) via hydrogen bonding. The PS-b-P4VP host acts as a structure-directing template, while the guest molecules (TDB) assist the self assembly nanostructures and zone-axis alignment, resulting in the nanostructured template of vertically oriented cylinders formed via successive phase transformations from Im3m to R3m to P6mm upon thermal annealing in the doctor blade-cast film. The guest molecules subsequently direct the titania precursors into the P4VP domains of the templates via supramolecular guest exchange during immersion of the film in a designated precursor solution containing a P4VP selective solvent. The subsequent UV irradiation step leads to the formation of PS-b-P4VP/TiO2 hybrids. Finally, removal of the host template by calcination leaves behind mesoporous channels and makes sacrifices to be a carbon source for carbon-doping TiO2 materials. Various TiO2 nanoarchitectures, namely, vertical and wiggly micrometer-length channels, inverse opals, fingerprint-like channels, heterogeneous multilayers, and nanotubes, have been fabricated by highly tunable DJBCP nanostructures. PMID- 27934175 TI - One-Pot Solvothermal in Situ Growth of 1D Single-Crystalline NiSe on Ni Foil as Efficient and Stable Transparent Conductive Oxide Free Counter Electrodes for Dye Sensitized Solar Cells. AB - One-dimensional single-crystal nanostructural nickel selenides were successfully in situ grown on metal nickel foils by two simple one-step solvothermal methods, which formed NiSe/Ni counter electrodes (CEs) for dye-sensitized solar cells (DSSCs). The nickel foil acted as the nickel source in the reaction process, a supporting substrate, and an electron transport "speedway". Electrochemical testing indicated that the top 1D single-crystal NiSe exhibited prominent electrocatalytic activity for I3- reduction. Due to the metallic conductivity of Ni substrate and the outstanding electrocatalytic activity of single-crystal NiSe, the DSSC based on a NiSe/Ni CE exhibited higher fill factor (FF) and larger short-circuit current density (Jsc) than the DSSC based on Pt/FTO CE. The corresponding power conversion efficiency (6.75%) outperformed that of the latter (6.18%). Moreover, the NiSe/Ni CEs also showed excellent electrochemical stability in the I-/I3- redox electrolyte. These findings indicated that single crystal NiSe in situ grown on Ni substrate was a potential candidate to replace Pt/TCO as a cheap and highly efficient counter electrode of DSSC. PMID- 27934176 TI - Study of Microstructure Change of Carbon Nanofibers as Binder-Free Anode for High Performance Lithium-Ion Batteries. AB - Flexible and binder-free film of N, O-doped carbon nanofibers (CNFs) is the ideal anode for high-energy-density batteries. Here, CNFs flexible films which the N, O dopant give defect in graphite structure results in high specific surface area more than 500 m2 g-1. A flexible film of CNF800 carbonized at 800 degrees C delivers initial capacities of 2000 and 755 mAh g-1 at the current densities of 5 and 10 A g-1, respectively. After 500 cycles, CNF800 remains the capacities of 1251, 865, 702, and 305 mAh g-1 at 0.5, 1, 5, and 10 A g-1, respectively. The microstructures of CNFs under various state of charge are studied by HRTEM, XPS, 13C NMR, and so forth. The lithiation/delithiation mainly happens to the interlayer of graphite domain of CNFs. The dopants of nitrogen and oxygen involve in lithiation, but much of Li-N is irreversible. The excellent performances of CNFs film can be attributed to the N, O doped structure of graphite domain that has increased the conductivity and lithium storage ability. Further development of N, O doped CNFs may enable practical applications as flexible anode in high performance lithium-ion batteries. PMID- 27934177 TI - Metal-Organic Framework with Aromatic Rings Tentacles: High Sulfur Storage in Li S Batteries and Efficient Benzene Homologues Distinction. AB - We designed and fabricated a fluorophore-containing tetradentate carboxylate ligand-based metal-organic framework (MOF) material with open and semiopen channels, which acted as the host for sulfur trapped in Li-S batteries and sensor of benzene homologues. These channels efficiently provide a pi-pi* conjugated matrix for the charge transfer and guest molecule trapping. The open channel ensured a much higher loading quantitative of sulfur (S content-active material, 72 wt %; electrode, 50.4 wt %) than most of the MOF/sulfur composites, while the semiopen channel possessing aromatic rings tentacles guaranteed an outstanding specific discharge capacity (1092 mA h g-1 at 0.1 C) accompanied by good cycling stability. To our surprise, benefiting from special pi-pi* conjugated conditions, compound 1 could be a chemical sensor for benzene homologues, especially for 1,2,4-trimethylbenzene (1,2,4-TMB). This is the first example of MOFs materials serving as a sensor of 1,2,4-TMB among benzene homologues. Our works may be worthy of use for references in other porous materials systems to manufacture more long-acting Li-S batteries and sensitive chemical sensors. PMID- 27934179 TI - Role of Near Substrate and Bulk Polymer Morphology on Out-of-Plane Space-Charge Limited Hole Mobility. AB - Charge transport is a central issue in all types of organic electronic devices. In organic films, charge transport is crucially limited by film microstructure and the nature of the substrate/organic interface interactions. In this report, we discuss the influence of active layer thickness on space-charge limited hole transport in pristine polymer and polymer/fullerene bulk heterojunction thin films (~15-300 nm) in a diode structure. According to the results, the out-of plane hole mobility in pristine polymers is sensitive to the degree of polymer chain aggregation. Blending the polymers with a fullerene molecule does not change the trend of hole mobility if the polymer tends to make an amorphous structure. However, employing an aggregating polymer in a bulk heterojunction blend gives rise to a marked difference in charge carrier transport behavior compared to the pristine polymer and this difference is sensitive to active layer thickness. In aggregating polymer films, the thickness-dependent interchain interaction was found to have direct impact on hole mobility. The thickness dependent mobility trend was found to correspond well with the trend of fill factors of corresponding bulk heterojunction solar cells. This investigation has a vital implication for material design and the development of efficient organic electronic devices, including solar cells and light-emitting diodes. PMID- 27934178 TI - Zinc Oxide Flower-Like Nanostructures That Exhibit Enhanced Toxicology Effects in Cancer Cells. AB - Nanostructured zinc oxide (ZnO) materials have been intensively studied because of their potential applications in cancer therapies. However, a better comprehension of the toxicity of the flower-like ZnO nanostructures toward cancer cells is still needed. In this study, we investigate the cytotoxicity of a ZnO flower-like nanostructure produced at low temperature via aqueous solution in human cervical carcinoma (HeLa) cells and noncancerous cell-line murine fibroblast (L929) cells. Nanotoxicology effects were analyzed to study apoptosis and necrosis processes, reactive oxygen species production, and cellular uptake. Cells remained incubated for 24 h in concentrations of 0.1, 1.0, and 10.0 MUg mL 1 ZnO nanoparticles (NPs), with the estimated rods length varying from 1.7 +/- 0.4 to 2.3 +/- 0.4 MUm, synthesized at different times (4, 2, and 0.5 h) by an aqueous solution method. The cytotoxic response observed in noncancerous and cancer cells showed that all of the ZnO NPs synthesized by an aqueous solution exhibited enhanced toxicology effects in cancer cells. ZnO flower-nanostructures exhibited a higher cytotoxic against cancer HeLa cells, in comparison to the noncancerous cell line L929. The cytotoxic response of ZnO NPs at 0.5, 2, and 4 h in L929 cells was not statistically significant. This ability may be of clinical interest because of the effectiveness of ZnO NPs to distinguish between normal and cancer cells in cancer therapy. PMID- 27934180 TI - Infrared Response and Optoelectronic Memory Device Fabrication Based on Epitaxial VO2 Film. AB - In this work, high-quality VO2 epitaxial films were prepared on high-conductivity n-GaN (0001) crystal substrates via an oxide molecular beam epitaxy method. By fabricating a two-terminal VO2/GaN film device, we observed that the infrared transmittance and resistance of VO2 films could be dynamically controlled by an external bias voltage. Based on the hysteretic switching effect of VO2 in infrared range, an optoelectronic memory device was achieved. This memory device was operated under the "electrical writing-optical reading" mode, which shows promising applications in VO2-based optoelectronic device in the future. PMID- 27934181 TI - The Role of Interfacial Electronic Properties on Phonon Transport in Two Dimensional MoS2 on Metal Substrates. AB - We investigate the role of interfacial electronic properties on the phonon transport in two-dimensional MoS2 adsorbed on metal substrates (Au and Sc) using first-principles density functional theory and the atomistic Green's function method. Our study reveals that the different degree of orbital hybridization and electronic charge distribution between MoS2 and metal substrates play a significant role in determining the overall phonon-phonon coupling and phonon transmission. The charge transfer caused by the adsorption of MoS2 on Sc substrate can significantly weaken the Mo-S bond strength and change the phonon properties of MoS2, which result in a significant change in thermal boundary conductance (TBC) from one lattice-stacking configuration to another for same metallic substrate. In a lattice-stacking configuration of MoS2/Sc, weakening of the Mo-S bond strength due to charge redistribution results in decrease in the force constant between Mo and S atoms and substantial redistribution of phonon density of states to low-frequency region which affects overall phonon transmission leading to 60% decrease in TBC compared to another configuration of MoS2/Sc. Strong chemical coupling between MoS2 and the Sc substrate leads to a significantly (~19 times) higher TBC than that of the weakly bound MoS2/Au system. Our findings demonstrate the inherent connection among the interfacial electronic structure, the phonon distribution, and TBC, which helps us understand the mechanism of phonon transport at the MoS2/metal interfaces. The results provide insights for the future design of MoS2-based electronics and a way of enhancing heat dissipation at the interfaces of MoS2-based nanoelectronic devices. PMID- 27934182 TI - Wireless, Room Temperature Volatile Organic Compound Sensor Based on Polypyrrole Nanoparticle Immobilized Ultrahigh Frequency Radio Frequency Identification Tag. AB - Due to rapid advances in technology which have contributed to the development of portable equipment, highly sensitive and selective sensor technology is in demand. In particular, many approaches to the modification of wireless sensor systems have been studied. Wireless systems have many advantages, including unobtrusive installation, high nodal densities, low cost, and potential commercial applications. In this study, we fabricated radio frequency identification (RFID)-based wireless sensor systems using carboxyl group functionalized polypyrrole (C-PPy) nanoparticles (NPs). The C-PPy NPs were synthesized via chemical oxidation copolymerization, and then their electrical and chemical properties were characterized by a variety of methods. The sensor system was composed of an RFID reader antenna and a sensor tag made from a commercially available ultrahigh frequency RFID tag coated with C-PPy NPs. The C PPy NPs were covalently bonded to the tag to form a passive sensor. This type of sensor can be produced at a very low cost and exhibits ultrahigh sensitivity to ammonia, detecting concentrations as low as 0.1 ppm. These sensors operated wirelessly and maintained their sensing performance as they were deformed by bending and twisting. Due to their flexibility, these sensors may be used in wearable technologies for sensing gases. PMID- 27934183 TI - Coral-like Janus Porous Spheres. AB - A Janus porous sphere with a coral-like microstructure is prepared by stepwise dealloying a metallic alloy sphere and sequential modification (for example, using silanes and polymers). Nanoscale coral-like microstructure of the internal skeleton gives remarkable capillary force, thus accelerating the mass transportation. Starting from the outer layer of the sphere, stepwise dealloying can achieve different layers inwardly, thus introducing different composition and performance. As an example, poly(ethylene glycol)-poly(N-isopropylacrylamide) (PEG-PNIPAM)- and poly(ethylene glycol)-poly(N,N-diethylamino-2 ethylmethacrylate) (PEG-PDEAEMA)-responsive Janus porous spheres can quickly capture oil by simply changing temperature or pH. Similarly, release is also triggered. PMID- 27934184 TI - Two-Dimensional SiO2/VO2 Photonic Crystals with Statically Visible and Dynamically Infrared Modulated for Smart Window Deployment. AB - Two-dimensional (2D) photonic structures, widely used for generating photonic band gaps (PBG) in a variety of materials, are for the first time integrated with the temperature-dependent phase change of vanadium dioxide (VO2). VO2 possesses thermochromic properties, whose potential remains unrealized due to an undesirable yellow-brown color. Here, a SiO2/VO2 core/shell 2D photonic crystal is demonstrated to exhibit static visible light tunability and dynamic near infrared (NIR) modulation. Three-dimensional (3D) finite difference time domain (FDTD) simulations predict that the transmittance can be tuned across the visible spectrum, while maintaining good solar regulation efficiency (DeltaTsol = 11.0%) and high solar transmittance (Tlum = 49.6%). Experiments show that the color changes of VO2 films are accompanied by NIR modulation. This work presents a novel way to manipulate VO2 photonic structures to modulate light transmission as a function of wavelength at different temperatures. PMID- 27934185 TI - One-Step Synthesis of Cagelike Hollow Silica Spheres with Large Through-Holes for Macromolecule Delivery. AB - A facile, one-step method to prepare cagelike hollow silica nanospheres with large through-holes (HSNLs) using a lysozyme-assisted O/W miniemulsion technique is presented. The tetraethoxysilane (TEOS)-xylene mixture forms oil droplets which are stabilized by the cationic surfactant cetyltrimethylammonium bromide (CTAB), cosurfactant hexadecane (HD), and protein lysozyme. HSNLs (with diameter of 300-460 nm) with large through-holes (10-30 nm) were obtained directly after ultrasonic treatment and aging. Lysozyme can not only stabilize the oil/water interface, assist the hydrolysis of TEOS, and interact with silica particles to assemble into silica-lysozyme clusters but also contribute to the formation of through-holes due to its hydrophilicity variation at different pH conditions. A possible new mechanism called the interface desorption method is proposed to explain the formation of the through-holes. To confirm the effectiveness of large through-holes in delivering large molecules, bovine serum albumin (BSA, 21 * 4 * 14 nm3) was chosen as a model guest molecule; HSNLs showed much higher loading capacity compared with common hollow mesoporous silica nanospheres (HMSNs). The release of BSA can be well controlled by wrapping HSNLs with a heat-sensitive phase change material (1-tetradecanol). Cell toxicity was also conducted with a Cell Counting Kit-8 (CCK-8) assay to roughly evaluate the feasibility of HSNLs in biomedical applications. PMID- 27934187 TI - 3D Printed Microfluidic Device with Microporous Mn2O3-Modified Screen Printed Electrode for Real-Time Determination of Heavy Metal Ions. AB - Fabricating portable devices for the determination of heavy metal ions is an ongoing challenge. Here, a 3D printing approach was adopted to fabricate a microfluidic electrochemical sensor with the desired shape in which the model for velocity profiles in microfluidic cells was built and optimized by the finite element method (FEM). The electrode in the microfluidic cell was a flexible screen-printed electrode (SPE) modified with porous Mn2O3 derived from manganese containing metal-organic framework (Mn-MOF). The microfluidic device presented superior electrochemical detection properties toward heavy metal ions. The calibration curves at the modified SPE for Cd(II) and Pb(II) covered two linear ranges varying from 0.5 to 8 and 10 to 100 MUg L-1, respectively. The limits of detection were estimated to be 0.5 MUg L-1 for Cd(II) and 0.2 MUg L-1 for Pb(II), which were accordingly about 6 and 50 times lower than the guideline values proposed by the World Health Organization. Furthermore, the microfluidic device was connected to iPad via a USB to enable real-time household applications. Additionally, the sensing system exhibited a better stability and reproducibility compared with traditional detecting system which offered a promising prospect for the detection of heavy metal ions especially in household and resource-limited occasions. PMID- 27934186 TI - High Performance All Fluorescence White Organic Light Emitting Devices with a Highly Simplified Structure Based on Thermally Activated Delayed Fluorescence Dopants and Host. AB - Thermally activated delayed fluorescence (TADF) emitters of different colors commonly need different hosts, which cause the complexed device structure and low efficiency of all fluorescence white organic light-emitting devices (F-WOLEDs). To solve this, novel concept of employing TADF exciplex as universal host of TADF emitters with different colors was proposed. All blue, green, and orange devices based on the TADF exciplex host show much lower turn-on voltages, and comparable and even higher efficiencies than corresponding devices based on conventional hosts. The two color F-WOLED with extremely simplified device structure was finally fabricated, achieving a white emission with the maximum current efficiency (CE), power efficiency (PE), and external quantum efficiency (EQE) respectively of 50.1 cd A-1, 63.0 lm W-1, and 19.0% in the forward-viewing direction without any light out-coupling technology, which is the best performance among reported F-WOLEDs, demonstrating the superiority of the novel concept. PMID- 27934188 TI - Nanostructured Montmorillonite Clay for Controlling the Lipase-Mediated Digestion of Medium Chain Triglycerides. AB - Biocompatible lipid hybrid particles composed of montmorillonite and medium chain triglycerides were engineered for the first time by spray drying oil-in-water emulsions stabilized by montmorillonite platelets to form montmorillonite-lipid hybrid (MLH) microparticles containing up to 75% w/w lipid. In vitro lipolysis studies under simulated intestinal conditions indicated that the specific porous nanoarchitecture and surface chemistry of MLH particles significantly increased the rate (>10-fold) and extent of lipase-mediated digestion compared to that of coarse and homogenized submicrometer triglyceride emulsions. Proton nuclear magnetic resonance studies verified the rapid and enhanced production of fatty acids for MLH particles; these are electrostatically repelled by the negatively charged montmorillonite platelet faces and avoid the "interfacial poisoning" caused by incomplete digestion that retards lipid droplet digestion. MLH particles are a novel biomaterial and encapsulation system that optimize lipase enzyme efficiency and have excellent potential as a smart delivery system for lipophilic biomolecules owing to their exceptional physicochemical and biologically active properties. These particles can be readily fabricated with varying lipid loads and thus may be tailored to optimize the solubilization of specific bioactive molecules requiring reformulation. PMID- 27934189 TI - Activatable Multifunctional Persistent Luminescence Nanoparticle/Copper Sulfide Nanoprobe for in Vivo Luminescence Imaging-Guided Photothermal Therapy. AB - Multifunctional nanoprobes that provide diagnosis and treatment features have attracted great interest in precision medicine. Near-infrared (NIR) persistent luminescence nanoparticles (PLNPs) are optimal materials due to no in situ excitation needed, deep tissue penetration, and high signal-to-noise ratio, while activatable optical probes can further enhance signal-to-noise ratio for the signal turn-on nature. Here, we show the design of an activatable multifunctional PLNP/copper sulfide (CuS)-based nanoprobe for luminescence imaging-guided photothermal therapy in vivo. Matrix metalloproteinases (MMPs)-specific peptide substrate (H2N-GPLGVRGC-SH) was used to connect PLNP and CuS to build a MMP activatable system. The nanoprobe not only possesses ultralow-background for in vivo luminescence imaging due to the absence of autofluorescence and optical activatable nature but also offers effective photothermal therapy from CuS nanoparticles. Further bioconjugation of c(RGDyK) enables the nanoprobe for cancer-targeted luminescence imaging-guided photothermal therapy. The good biocompatibility and the multiple functions of highly sensitive tumor-targeting luminescence imaging and effective photothermal therapy make the nanoprobe promising for theranostic application. PMID- 27934190 TI - A Simple Approach to Fabricate an Efficient Inverted Polymer Solar Cell with a Novel Small Molecular Electrolyte as the Cathode Buffer Layer. AB - A novel small-molecule electrolyte, 1,1'-bis(4-hydroxypropyl)-[4,4'-bipyridine] 1,1'-diium bromide (V-OH), containing a mixture of PTB7:PC71BM has been designed and synthesized as a cathode buffer layer for inverted polymer solar cells (iPSCs). The molecular structure of this new compound comprises a viologen skeleton with hydroxyl group terminals. While the viologen unit is responsible for generating a favorable interface dipole, the two terminal hydroxyl groups of V-OH may generate a synergy effect in the magnitude of the interface dipole. Consequently, the devices containing the V-OH interlayer exhibited a power conversion efficiency (PCE) of 9.13% (short circuit current = 17.13 mA/cm2, open circuit voltage = 0.75 V, fill factor = 71.1%). The PCE of the devices with V-OH exhibited better long-term stability compared to that of the devices without V OH. Thus, we found that it is possible to enhance the efficiency of PSCs by a simple approach without the need for complicated methods of device fabrication. PMID- 27934191 TI - Plasma-Induced Nonvolatile Resistive Switching with Extremely Low SET Voltage in TiOxFy with AgF Nanoparticles. AB - Low power consumption is crucial for the application of resistive random access memory. In this work, we present the bipolar resistive switching in an Ag/TiOxFy/Ti/Pt stack with extremely low switch-on voltage of 0.07 V. Operating current as low as 10 nA was also obtained by conductive atomic force microscopy. The highly defective TiOxFy layer was fabricated by plasma treatment using helium, oxygen, and carbon tetrafluoride orderly. During the electroforming process, AgF nanoparticles were formed due to the diffusion of Ag+ which reacted with the adsorbed F- in the TiOxFy layer. These nanoparticles are of great importance to resistive switching performance because they are believed to be conductive phases and become part of the conducting path when the sample is switched to a low-resistance state. PMID- 27934192 TI - Biobased Nanoparticles for Broadband UV Protection with Photostabilized UV Filters. AB - Sunscreens rely on multiple compounds to provide effective and safe protection against UV radiation. UV filters in sunscreens, in particular, provide broadband UV protection but are heavily linked to adverse health effects due to the generation of carcinogenic skin-damaging reactive oxygen species (ROS) upon solar irradiation. Herein, we demonstrate significant reduction in the ROS concentration by encapsulating an antioxidant photostabilizer with multiple UV filters into biobased ethyl cellulose nanoparticles. The developed nanoparticles display complete broadband UV protection and can form transparent and flexible films. This system therefore shows significant potential toward effective and safe nanoparticle-based UV protective coatings. PMID- 27934193 TI - Systematic Investigation of Benzodithiophene-Benzothiadiazole Isomers for Organic Photovoltaics. AB - Two new donor-acceptor small molecules based on benzo[1,2-b:4,5-b']dithiophene (BDT) and benzo[c][1,2,5]thiadiazole (BT) were designed and synthesized. Small molecules 4,4'-[(4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5 b']dithiophene-2,6-diyl)bis(2,2'-bithiophene)-5,5' diyl]bis(benzo[c][1,2,5]thiadiazole) (BDT-TT-BT) and 4,4'-(4,8-bis(5-(2 ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene-2,6-diyl)bis[7-(2,2' bithiophene-5-yl)benzo[c][1,2,5]thiadiazole] (BDT-BT-TT) are structural isomers with the 2,2-bithiophene unit placed either between the BDT and BT units or at the end of the BT units. This work is targeted toward finding the effect of structural variation on optoelectronic properties, morphology, and photovoltaic performance. On the basis of theoretical calculations, the molecular geometry and energy levels are different for these two molecules when the position of the 2,2 bithiophene unit is changed. Optical and electrochemical properties of these two small molecules were characterized using UV-vis and cyclic voltammetry. The results showed that BDT-BT-TT has broader absorption and an elevated HOMO energy level when compared with those of BDT-TT-BT. The performance of these two isomers in solar cell devices was tested by blending with [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM). Power conversion efficiencies as high as 3.22 and 3.71% were obtained in conventional solar cell structures for BDT-TT-BT and BDT-BT-TT, respectively. The morphology was studied using grazing incident wide-angle X-ray scattering and transmission electron microscopy, which revealed different phase separations of these two molecules when blended with PC71BM. PMID- 27934195 TI - Negative Electro-conductance in Suspended 2D WS2 Nanoscale Devices. AB - We study the in situ electro-conductance in nanoscale electronic devices composed of suspended monolayer WS2 with metal electrodes inside an aberration-corrected transmission electron microscope. Monitoring the conductance changes when the device is exposed to the electron beam of 80 keV energy reveals a reversible decrease in conductivity with increasing beam current density. The response time of the electro-conductance when exposed to the electron beam is substantially faster than the recovery time when the beam is turned off. We propose a charge trap model that accounts for excitation of electrons into the conduction band and localized trap states from energy supplied by inelastic scattering of incident 80 keV electrons. These results show how monolayer transition metal dichalcogenide 2D semiconductors can be used as transparent direct electron detectors in ultrathin nanoscale devices. PMID- 27934194 TI - Design of Electrodeposited Bilayer Structures for Reliable Resistive Switching with Self-Compliance. AB - Programmable memory characteristics of electrodeposited CuOx-based resistive random access memory (ReRAM) can be significantly improved by adopting a bilayer structure with a built-in current limiter. To control the on-current and enhance the device uniformity, the bilayer structure of Pt/CuOx (switching layer)/CuOx (current limiter)/Pt is proposed. This structure is synthesized by controlling solution pH during electrochemical deposition (ECD). The bilayer structure of Pt/CuOx (synthesized at pH 9)/CuOx (synthesized at pH 11.5)/Pt exhibits reliable and uniform self-compliant resistive switching behavior. The origin of resistive switching is attributed to formation and rupture of conductive filaments in the CuOx (pH 9) layer. However, the CuOx (pH 11.5) layer acts as the resistor without resistive switching to control the overall resistance in ReRAM. Reversible "on" and "off" switching occurs with a switching time of 100 ns. Devices based on the bilayer structure showed long data retention and good endurance. This simple use of ECD to improve the memory characteristics of electrodeposited ReRAM offers the opportunity to realize reliable and self-compliant memory devices with low-cost solution processes. PMID- 27934196 TI - A Facile Approach for Constructing Conductive Polymer Patterns for Application in Electrochromic Devices and Flexible Microelectrodes. AB - We developed a novel strategy for fabricating poly(3,4-ethylenedioxythiophene) (PEDOT) patterns on various substrates, including hydrogels, via sequential solution procedure without multistep chemical etching or lift-off processes. First, PEDOT nanothin films were prepared on a glass substrate by solution phase monomer casting and oxidative polymerization. As a second step, after UV-induced poly(ethylene glycol) (PEG) photolithography at the PEDOT/PEG interface through a photomask, the hydrogel was peeled away from the PEDOT-coated glass substrate to detach the UV-exposed PEDOT region, which left the UV nonexposed PEDOT region intact on the glass substrate, resulting in PEDOT patterns. In a final step, the PEDOT patterns were cleanly transferred from the glass to a flexible hydrogel substrate by a direct-transfer process based on a second round of gelation process. Using this strategy, PEDOT patterns on ITO glass or ITO film were used to successfully fabricate an electrochromic (EC) device that exhibited stable electrochromic switching as a function of applied potential. Furthermore, PEDOT patterns on hydrogel were used to fabricate all organic, flexible microelectrodes with good electrical properties and excellent mechanical flexibility. Importantly, the conductivity of PEDOT patterns on hydrogel (ca. 235 S cm-1) described here is significantly higher than that previously reported (ca. 20-70 S cm-1). This approach can be easily integrated into various technological fabrication steps for the development of next-generation bioelectronics systems. PMID- 27934197 TI - Multifunctional Wearable Device Based on Flexible and Conductive Carbon Sponge/Polydimethylsiloxane Composite. AB - Wearable devices that can be used to monitor personal health, track human motions, and provide thermotherapy, etc., are highly desired in personalized healthcare. In this work, a multifunctional wearable "wrist band" which works as both heater for thermotherapy and sensor for personal health and motion monitoring is fabricated from a flexible and conductive carbon sponge/polydimethylsiloxane (CS/PDMS) composite. The key functional material of the wrist band, namely, the conductive CS, is synthesized from waste paper by a freeze-drying and high-temperature pyrolysis process. When the wrist band works as a heater under 15 V, a stable temperature difference of 20 degrees C is achieved between the wrist band and the ambient. When the wrist band serves as a wearable strain sensor, the wrist band exhibits fast and repeatable response and excellent durability within the strain range of 0-20% and the working frequency of 0.01-10 Hz. Finally, the typical applications of the multifunctional wearable wrist band, as a heater for thermotherapy and a sensor for blood pulse, breathe, and walk monitoring, are demonstrated. Due to its low cost, high flexibility, moderate conductivity, and excellent strain sensibility, the as-prepared wearable device based on the CS/PDMS composite is promising to be applied for the provision of personal healthcare. PMID- 27934198 TI - Yellow-Emitting Carbon Nanodots and Their Flexible and Transparent Films for White LEDs. AB - We report carbon nanodots that can be utilized as effective color converting phosphors for the production of white light-emitting diodes (LEDs). Blue excitable and yellow-emitting carbon nanodots, functionalized with 3 (imidazolidin-2-on-1-yl)propylmethyldimethoxysilane (IPMDS)-derived moieties (IS CDs), are synthesized by a novel one-pot reaction in which the products from the initial reaction occurring between urea and 3-(2-aminoethylamino)propylmethyl dimethoxysilane (AEPMDS) are further treated with citric acid. Distinctive from the majority of carbon nanodots reported previously, IS-CDs emit at 560 nm, under 460 nm excitation, with a quantum yield of 44%. Preliminary toxicity studies, assessed by the Artemia franciscana nauplii (brine shrimp larvae) bioassay, indicate that IS-CDs are largely nontoxic. Furthermore, the IS-CDs form flexible and transparent films without the need of encapsulating agents, and the solid films retain the optical properties of solvated IS-CDs. These features indicate an immense potential for the IS-CDs as an environmental-friendly, blue-excitable carbon nanodot-based phosphor in solid-state lighting devices. PMID- 27934200 TI - A Low-Energy Electron Beam Does Not Damage Single-Walled Carbon Nanotubes and Graphene. AB - Scanning electron microscopy (SEM) is a principal tool for studying nanomaterials, including carbon nanotubes and graphene. Imaging carbon nanomaterials by SEM, however, increases the disorder mode (D-mode) in their Raman spectra. Early studies, which relied on ambiguous ensemble measurements, claimed that the D-mode indicates damage to the specimens by a low-energy electron beam (e-beam). This claim has been accepted by the nanomaterials community for more than a decade without thorough examination. Here we demonstrate that a low-energy e-beam does not damage carbon nanomaterials. By performing measurements on single nanotubes, we independently examined the following factors: (1) the e-beam irradiation itself, (2) the e-beam-deposited hydrocarbon, and (3) the amorphous carbon deposited during synthesis of the material. We concluded that the e-beam-induced D-mode of both carbon nanotubes and graphene originates solely from the irradiated amorphous carbon and not from the e-beam itself or the hydrocarbon. The results of this study should help minimize potential ambiguities for researchers imaging a broad range of nanomaterials by electron microscopy. PMID- 27934201 TI - Relation between Natural and Practical Ligand Binding Constants: Strong Implications for Extraction of Molecular-Level Information from the Temperature Dependence of Ligand Binding Equilibria. PMID- 27934199 TI - Graphene Oxide Inhibits Antibiotic Uptake and Antibiotic Resistance Gene Propagation. AB - Antibiotics and antibiotic resistance genes (ARGs) in the natural environment have become substantial threats to the ecosystem and public health. Effective strategies to control antibiotics and ARG contaminations are emergent. A novel carbon nanomaterial, graphene oxide (GO), has attracted a substantial amount of attention in environmental fields. This study discovered the inhibition effects of GO on sulfamethoxazole (SMZ) uptake for bacteria and ARG transfer among microorganisms. GO promoted the penetration of SMZ from intracellular to extracellular environments by increasing the cell membrane permeability. In addition, the formation of a GO-SMZ complex reduced the uptake of SMZ in bacteria. Moreover, GO decreased the abundance of the sulI and intI genes by approximately 2-3 orders of magnitude, but the global bacterial activity was not obviously inhibited. A class I integron transfer experiment showed that the transfer frequency was up to 55-fold higher in the control than that of the GO treated groups. Genetic methylation levels were not significant while sulI gene replication was inhibited. The biological properties of ARGs were altered due to the GO-ARG noncovalent combination, which was confirmed using multiple spectral analyses. This work suggests that GO can potentially be applied for controlling ARG contamination via inhibiting antibiotic uptake and ARG propagation. PMID- 27934202 TI - CH3NH3Pb(BF4)3 and (C4H9NH3)2Pb(BF4)4 Family of 3D and 2D Perovskites without and with Iodide and Bromide Ions Substitution. AB - We report the synthesis of fully molecular ion (BF4-)-based organic-inorganic hybrid perovskite CH3NH3Pb(BF4)3, which is a wide band gap semiconductor, and the same can be easily tuned toward the visible by the incorporation of bromide or iodide ions in the crystal framework simply by changing lead precursors. We have also successfully transformed the distorted 3D molecular-ion-induced perovskite to 2D (C4H9NH3)2Pb(BF4)4, (C4H9NH3)2PbBr(4-x)(BF4)x, and (C4H9NH3)2PbI(4-x)(BF4)x perovskites that exhibit the optical absorption over the UV to visible region. The thin films of molecular-ion-containing 2D perovskites with Br- and I- anions show blue and green luminescence, respectively, under UV illumination. PMID- 27934204 TI - Magneto-Optical Response of Cobalt Interacting with Plasmonic Nanoparticle Superlattices. AB - The magneto-optical Kerr effect is a striking phenomenon whereby the optical properties of a material change under an applied magnetic field. Though promising for sensing and data storage technology, these properties are typically weak in magnitude and are inherently limited by the bulk properties of the active magnetic material. In this work, we theoretically demonstrate that plasmonic thin film assemblies on a cobalt substrate can achieve tunable transverse magneto optical (TMOKE) responses throughout the visible and near-infrared (300-900 nm). In addition to exhibiting wide spectral tunability, this response can be varied in sign and magnitude by changing the plasmonic volume fraction (1-20%), the composition and arrangement of the assembly, and the shape of the nanoparticle inclusions. Of particular interest is the newly discovered sensitivity of the sign and intensity of the TMOKE spectrum to collective metallic plasmonic behavior in silver, mixed silver-gold, and anisotropic superlattices. PMID- 27934203 TI - Transition from SAMO to Rydberg State Ionization in C60 in Femtosecond Laser Fields. AB - The transition between two distinct ionization mechanisms in femtosecond laser fields at 785 nm is observed for C60 molecules. The transition occurs in the investigated intensity range from 3 to 20 TW/cm2 and is visualized in electron kinetic energy spectra below the one-photon energy (1.5 eV) obtained via velocity map imaging. Assignment of several observed broad spectral peaks to ionization from superatom molecular orbitals (SAMOs) and Rydberg states is based on time dependent density functional theory simulations. We find that ionization from SAMOs dominates the spectra for intensities below 5 TW/cm2. As the intensity increases, Rydberg state ionization exceeds the prominence of SAMOs. Using short laser pulses (20 fs) allowed uncovering of distinct six-lobe photoelectron angular distributions with kinetic energies just above the threshold (below 0.2 eV), which we interpret as over-the-barrier ionization of shallow f-Rydberg states in C60. PMID- 27934205 TI - Spotlights: Volume 7, Issue 22. PMID- 27934206 TI - Broad-Band Pump-Probe Spectroscopy Quantifies Ultrafast Solvation Dynamics of Proteins and Molecules. AB - In this work, we demonstrate the use of broad-band pump-probe spectroscopy to measure femtosecond solvation dynamics. We report studies of a rhodamine dye in methanol and cryptophyte algae light-harvesting proteins in aqueous suspension. Broad-band impulsive excitation generates a vibrational wavepacket that oscillates on the excited-state potential energy surface, destructively interfering with itself at the minimum of the surface. This destructive interference gives rise to a node at a certain probe wavelength that varies with time. This reveals the Gibbs free-energy changes of the excited-state potential energy surface, which equates to the solvation time correlation function. This method captures the inertial solvent response of water (~40 fs) and the bimodal inertial response of methanol (~40 and ~150 fs) and reveals how protein-buried chromophores are sensitive to the solvent dynamics inside and outside of the protein environment. PMID- 27934207 TI - Unusual Li-Ion Transfer Mechanism in Liquid Electrolytes: A First-Principles Study. AB - Liquid electrolytes play an important role in commercial lithium-ion (Li-ion) batteries as a conduit for Li-ion transfer between anodes and cathodes. It is generally believed that the Li-ions move along with the salt ions; thus, Li-ion diffusion is only affected by the viscosity and salt concentration in the liquid electrolytes based on the Stokes-Einstein equation. In this study, a novel and faster Li-ion diffusion mechanism in electrolytes containing a cyanogen group is identified from first-principles molecular dynamics (FPMD) simulations. In this mechanism, the Li-ions are first detached from the Li-salt and then diffuse along with the solvent molecules, and the Li-ion diffusion does not obey the traditional Stokes-Einstein equation. The ionic conductivity of the electrolyte systems with this "solvent-assisted Li-ion diffusion" mechanism is further enhanced through Li-ion hopping. This novel Li-ion diffusion process explains recent findings of high Li-ion conductivity in electrolytes with cyanogen groups and furnishes a new paradigm for the design of fast-charging liquid electrolyte for Li-ion batteries. PMID- 27934208 TI - Prolonged Charge Separated States in Twisted Stacks of All-Carbon Donor and Acceptor Chromophores. AB - Twisted donor-on-donor and acceptor-on-acceptor bicontinuous assembly in all carbon pyren-1-ylaceanthrylene (PA) dyad extends the survival time of the photoinduced radical ion-pair intermediates. Aceanthrylene, a functional analog of C70, acts as a versatile electron acceptor owing to its high electron affinity and visible light absorption. Antithetical trajectories of the excitons in the nonparallel pi-ways led to persistent radical ion-pair intermediates in aggregated (taucrA ~ 1.28 ns) vs monomeric (taucrM <= 110 fs) PA dyad as observed using femtosecond transient absorption spectroscopy. Marcus theory of charge transfer rates predicts an ambipolar transport characteristic in crystalline PA, thereby endorsing PA as an all-carbon DA hybrid for nonfullerene photovoltaic applications. PMID- 27934209 TI - Significant Transient Mobility of Platinum Clusters via a Hot Precursor State on the Alumina Surface. AB - Relaxation dynamics of hot metal clusters on oxide surfaces play a crucial role in a variety of physical and chemical processes. However, their transient mobility has not been investigated as much as other systems such as atoms and molecules on metal surfaces due to experimental difficulties. To study the role of the transient mobility of clusters on the oxide surface, we investigated the initial adsorption process of size-selected Pt clusters on a thin Al2O3 film. Soft-landing the size-selected clusters while suppressing the thermal migration resulted in the transient migration controlling the initial adsorption states as an isolated and aggregated cluster, as revealed using scanning tunneling microscopy. We demonstrate that transient migration significantly contributes to the initial cluster adsorption process; the cross section for aggregation is seven times larger than the expected value from geometrical considerations, indicating that metal clusters are highly mobile during a energy dissipation process on the oxide surface. PMID- 27934210 TI - Ruthenium-Sulfonamide-Catalyzed Direct Dehydrative Condensation of Benzylic C-H Bonds with Aromatic Aldehydes. AB - The first catalytic dehydrative condensation of the benzylic C-H bonds of toluene and p-xylene with aromatic aldehydes is reported herein. This protocol provides highly atom-economical access to stilbene and p-distyrylbenzene derivatives, whereby water is the sole byproduct. The reaction is based on the deprotonation functionalization of benzylic C-H bonds through eta6-complexation of the arenes, which is realized for the first time using a catalytic amount of a transition metal activator. The key to the success of this method is the use of a sulfonamide anion as a catalyst component, which appears to facilitate not only the deprotonation of the benzylic C-H bonds but also the formation of a C-C bonds via an electrophilic tosylimine intermediate. PMID- 27934211 TI - Extreme Stabilization and Redox Switching of Organic Anions and Radical Anions by Large-Cavity, CH Hydrogen-Bonding Cyanostar Macrocycles. AB - Encapsulation of unstable guests is a powerful way to enhance their stability. The lifetimes of organic anions and their radicals produced by reduction are typically short on account of reactivity with oxygen while their larger sizes preclude use of traditional anion receptors. Here we demonstrate the encapsulation and noncovalent stabilization of organic radical anions by C-H hydrogen bonding in pi-stacked pairs of cyanostar macrocycles having large cavities. Using electrogenerated tetrazine radical anions, we observe significant extension of their lifetimes, facile molecular switching, and extremely large stabilization energies. The guests form threaded pseudorotaxanes. Complexation extends the radical lifetimes from 2 h to over 20 days without altering its electronic structure. Electrochemical studies show tetrazines thread inside a pair of cyanostar macrocycles following voltage-driven reduction (+e-) of the tetrazine at -1.00 V and that the complex disassembles after reoxidation (-e-) at -0.05 V. This reoxidation is shifted 830 mV relative to the free tetrazine radical indicating it is stabilized by an unexpectedly large -80 kJ mol-1. The stabilization is general as shown using a dithiadiazolyl anion. This finding opens up a new approach to capturing and studying unstable anions and a radical anions when encapsulated by size-complementary anion receptors. PMID- 27934213 TI - Development of Correlative Cryo-soft X-ray Tomography and Stochastic Reconstruction Microscopy. A Study of Cholesterol Crystal Early Formation in Cells. AB - We have developed a high resolution correlative method involving cryo-soft X-ray tomography (cryo-SXT) and stochastic optical reconstruction microscopy (STORM), which provides information in three dimensions on large cellular volumes at 70 nm resolution. Cryo-SXT morphologically identified and localized aggregations of carbon-rich materials. STORM identified specific markers on the desired epitopes, enabling colocalization between the identified objects, in this case cholesterol crystals, and the cellular environment. The samples were studied under ambient and cryogenic conditions without dehydration or heavy metal staining. The early events of cholesterol crystal development were investigated in relation to atherosclerosis, using as model macrophage cell cultures enriched with LDL particles. Atherosclerotic plaques build up in arteries in a slow process involving cholesterol crystal accumulation. Cholesterol crystal deposition is a crucial stage in the pathological cascade. Our results show that cholesterol crystals can be identified and imaged at a very early stage on the cell plasma membrane and in intracellular locations. This technique can in principle be applied to other biological samples where specific molecular identification is required in conjunction with high resolution 3D-imaging. PMID- 27934214 TI - Birch-Type Hydrogenation of Few-Layer Graphenes: Products and Mechanistic Implications. AB - Few-layer graphenes, supported on Si with a superficial oxide layer, were subjected to a Birch-type reduction using Li and H2O as the electron and proton donors, respectively. The extent of hydrogenation for bilayer graphene was estimated at 1.6-24.1% according to Raman and X-ray photoelectron spectroscopic data. While single-layer graphene reacts uniformly, few-layer graphenes were hydrogenated inward from the edges and/or defects. The role of these reactive sites was reflected in the inertness of pristine few-layer graphenes whose edges were sealed. Hydrogenation of labeled bilayer (12C/13C) and trilayer (12C/13C/12C) graphenes afforded products whose sheets were hydrogenated to the same extent, implicating passage of reagents between the graphene layers and equal decoration of each graphene face. The reduction of few-layer graphenes introduces strain, allows tuning of optical transmission and fluorescence, and opens synthetic routes to long sought-after films containing sp3-hybridized carbon. PMID- 27934215 TI - Correction to "Fluorescein: A Photo-CIDNP Sensitizer Enabling Hypersensitive NMR Data Collection in Liquids at Low Micromolar Concentration". PMID- 27934216 TI - Ctr1 Intracellular Loop Is Involved in the Copper Transfer Mechanism to the Atox1 Metallochaperone. AB - Understanding the human copper cycle is essential to understand the role of metals in promoting neurological diseases and disorders. One of the cycles controlling the cellular concentration and distribution of copper involves the copper transporter, Ctr1; the metallochaperone, Atox1; and the ATP7B transporter. It has been shown that the C-terminus of Ctr1, specifically the last three amino acids, HCH, is involved in both copper coordination and the transfer mechanism to Atox1. In contrast, the role of the intracellular loop of Ctr1, which is an additional intracellular segment of Ctr1, in facilitating the copper transfer mechanism has not been investigated yet. Here, we combine various biophysical methods to explore the interaction between this Ctr1 segment and metallochaperone Atox1 and clearly demonstrate that the Ctr1 intracellular loop (1) can coordinate Cu(I) via interactions with the side chains of one histidine and two methionine residues and (2) closely interacts with the Atox1 metallochaperone. Our findings are another important step in elucidating the mechanistic details of the eukaryotic copper cycle. PMID- 27934217 TI - Fluorescence and Energy Transfer in Dye-Labeled DNA Crystals. AB - DNA crystals make it possible to organize guest molecules into specific periodic 3D patterns at the nanoscale, and thereby to create novel macroscopic objects with potentially useful functionality. Here, we describe the fluorescence and energy transfer properties of DNA crystals that are self-assembled from DNA tensegrity triangles with covalently attached Cy3 and Cy5 dyes. When compared to reference DNA strands in solution, the fluorescence measurements indicate that the dyes in the crystal experience a more homogeneous environment, resulting in a 2-fold increase in Cy3 quantum yield and single-exponential Cy3 fluorescence decays. Energy transfer in a network of coupled Cy3 and Cy5 dyes in the DNA crystal is demonstrated experimentally. Numerical simulation finds the experiments to be consistent with a Forster model of the dyes in the periodic crystalline environment, and particularly if the transition dipoles are assumed random in orientation but static on the time scale of the excitation decay. PMID- 27934218 TI - Mechanical Insight into Resistance of Betaine to Urea-Induced Protein Denaturation. AB - It is known that urea can induce protein denaturation that can be inhibited by osmolytes. Yet, experimental explorations on this mechanism at the molecular level are still lacking. We have investigated the resistance of betaine to the urea-induced denaturation of lysozyme in aqueous solutions using low-field NMR. Our study demonstrates that urea molecules directly interact with lysozyme, leading to denaturation. However, betaine molecules interacting with urea more strongly than lysozyme can pull the bound urea molecules from lysozyme so that the protein is protected from denaturation. The number of urea molecules bound to a betaine molecule is given under different conditions. Proton NMR spectroscopy (1H-NMR) and Fourier transform infrared spectroscopy reveal that the interaction between betaine and urea is through hydrogen bonding. PMID- 27934219 TI - Resonance Raman in Vitro Detection and Differentiation of the Nitrite-Induced Hemoglobin Adducts in Functional Human Red Blood Cells. AB - This work presents in vitro studies of the functional, isolated human red blood cells (RBCs) treated with various concentrations of Na14NO2 and Na15NO2 with the use of resonance Raman spectroscopy (RRS) at two different laser excitations supported by absorption spectrophotometry (UV-vis). The products of the reaction between oxyhemoglobin (oxyHb) in isolated RBCs with NaNO2 were analyzed and identified in situ. The metHb-H2O was found to be the major product of this reaction; however, additional adducts were also clearly observed. Vibrational analysis allowed identification of various Hb3+NO2 species (Fe3+-O-N=O with O binding mode of nitrite ion to the Fe3+ core and nitrovinyl adducts with 2-vinyl nitration favored over 4-vinyl nitration) as well as the Fe3+-NO adduct. In addition, we were able to visualize in situ the Hb-NO2 species inside functional RBCs with the use of Raman imaging. PMID- 27934220 TI - Photophysical Characterization of Enhanced 6-Methylisoxanthopterin Fluorescence in Duplex DNA. AB - The structure and dynamic motions of bases in DNA duplexes and other constructs are important for understanding mechanisms of selectivity and recognition of DNA binding proteins. The fluorescent guanine analogue, 6-methylisoxanthopterin 6-MI, is well suited to this purpose as it exhibits an unexpected 3- to 4-fold increase in relative quantum yield upon duplex formation when incorporated into the following sequences: ATFAA, AAFTA, or ATFTA (where F represents 6-MI). To better understand some of the factors leading to the 6-MI fluorescence increase upon duplex formation, we characterized the effect of local sequence and structural perturbations on 6-MI photophysics through temperature melts, quantum yield measurements, fluorescence quenching assays, and fluorescence lifetime measurements. By examining 21 sequences we have determined that the duplex enhanced fluorescence (DEF) depends on the composition of bases adjacent to 6-MI and the presence of adenines at locations n +/- 2 from the probe. Investigation of duplex stability and local solvent accessibility measurements support a model in which the DEF arises from a constrained geometry of 6-MI in the duplex, which remains H-bonded to cytosine, stacked with adjacent bases and inaccessible to quenchers. Perturbation of DNA structure through the introduction of an unpaired base 3' to 6-MI or a mismatched basepair increases 6-MI dynamic motion leading to fluorescence quenching and a reduction in quantum yield. Molecular dynamics simulations suggest the enhanced fluorescence results from a greater degree of twist at the X-F step relative to the quenched duplexes examined. These results point to a model where adenine residues located at n +/- 2 from 6-MI induce a structural geometry with greater twist in the duplex that hinders local motion reducing dynamic quenching and producing an increase in 6-MI fluorescence. PMID- 27934221 TI - Enhancement of Cell Adhesion on a Phosphorylcholine-Based Surface through the Interaction with DNA Mediated by Ca2+ Ions. AB - 2-Methacryloyloxyethyl phosphorylcholine (MPC) has a PC group and is one of the most well-known bioinert polymers. In this study, we evaluated the interaction between MPC and DNA, which specifically interacts with the phospholipid head group via Ca2+ ions. A MPC monolayer and poly(MPC) brush were fabricated to observe the effect of the structure on the interaction between MPC and DNA via Ca2+ ions. The poly(MPC) brush, which shows higher MPC unit density, more efficiently interacted with DNA via Ca2+ ions. Also, serum protein could interact with the poly(MPC) brush via DNA, although the brush itself hardly interacted with serum proteins. Cell adhesion was significantly provoked on poly(MPC)/DNA compared with poly(MPC) because serum protein adsorption was induced on poly(MPC)/DNA. PMID- 27934222 TI - Probing the Local Secondary Structure of Human Vimentin with Electron Spin Echo Envelope Modulation (ESEEM) Spectroscopy. AB - Previously, an electron spin echo envelope modulation (ESEEM) spectroscopic approach was established to probe the local secondary structure of membrane proteins and peptides utilizing site-directed spin-labeling (SDSL). In this method, the side chain of one amino acid residue is selectively 2H-labeled and a nitroxide spin label is strategically placed 1, 2, 3, or 4 amino acids away from the 2H-labeled amino acid (denoted as i +/- 1 to i +/- 4, i represents the 2H labeled amino acid). ESEEM can detect the dipolar coupling between the nitroxide spin label and 2H atoms on the amino acid side chain. Due to the periodicity of different secondary structures, different ESEEM patterns can be revealed to probe the structure. For an alpha-helical structural component, a 2H ESEEM signal can be detected for i +/- 3 and i +/- 4 samples, but not for i +/- 1 or i +/- 2 samples. Several 2H-labeled hydrophobic amino acids have been demonstrated in model system that can be utilized to identify local secondary structures via this ESEEM approach in an extremely efficient fashion. In this study, the ESEEM approach was used to investigate the rod 2B region of the full-length intermediate filament protein human vimentin. Consistent with previous EPR and X ray crystallography results, our ESEEM results indicated helical structural components within this region. Thus, this ESEEM approach is able to identify alpha-helical structural components despite the coiled-coil nature of the vimentin structure. The data show that the human vimentin rod 2B adapted a typical alpha-helical structure around residue Leu309. This result is consistent with the X-ray data from fragmented protein segments and continuous wave EPR data on the full-length vimentin. Finally, the ESEEM data suggested that a local secondary structure slightly different from a typical alpha-helix was adopted around residue 340. PMID- 27934223 TI - Ultrafast Charge Recombination Dynamics in Ternary Electron Donor-Acceptor Complexes: (Benzene)2-Tetracyanoethylene Complexes. AB - The charge-transfer (CT) state relaxation dynamics of the binary (1:1) and ternary (2:1) benzene/tetracyanoethylene (BZ/TCNE) complexes are reported. Steady state and ultrafast time-resolved broadband fluorescence (TRFL) spectra of TCNE dissolved in a series of BZ/CCl4 mixed solvents are measured to elucidate the spectroscopic properties of the BZ/TCNE complexes and their CT-state relaxation dynamics. Both steady-state and TRFL spectra exhibit marked BZ concentration dependences, which can be attributed to the formation of two types of 2:1 complexes in the ground and excited states. By combining with the density functional theory (DFT) calculations, it was concluded that the BZ concentration dependence of the absorption spectra is mainly due to the formation and excitation of the sandwich-type 2:1 ternary complexes, whereas the changes in fluorescence spectra at high BZ concentrations are due to the formation of the asymmetric-type 2:1 ternary complex CT1 state. A unified mechanism involving both direct excitation and secondary formation of the 2:1 complexes CT states are proposed to account for the observations. The equilibrium charge recombination (CR) time constant of the 1:1 CT1 state is determined to be ~150 ps in CCl4, whereas that of the 2:1 DDA-type CT1 state becomes ~70 ps in 10% BZ/CCl4 and ~34 ps in pure BZ. The CR rates and the CT1-S0 energy gap of these complexes in different solvents exhibit a correlation conforming to the Marcus inverted region. It is concluded that partial charge resonance occurring between the two adjacent BZs in the asymmetric-type 2:1 CT1-state reduces the CR reaction exothermicity and increases the CR rate. PMID- 27934224 TI - Heterogeneity during Plasticization of Poly(vinylpyrrolidone): Insights from Reorientational Mobility of Single Fluorescent Probes. AB - While dynamics of single-molecule (SM) fluorescent probes have been used to investigate the structure and relaxation processes in polymers near the glass transition temperature (Tg), it is difficult to perform SM imaging at elevated temperatures which restricts such studies to a limited number of polymers for which Tg is close to room temperature (RT). Plasticization, solvent (or additive) induced lowering of Tg, offers an alternate avenue to access various effective temperatures in the glassy and rubbery phases of polymers under ambient conditions. By investigation of the reorientational propensity of individual Rhodamine 6G (Rh6G) probes, which is governed by rigidity/dynamics of the polymer cavities, we have explored the extent of spatiotemporal heterogeneity during moisture induced plasticization of poly(vinylpyrrolidone) (PVP), far below and near (below and above) bulk Tg. Lack of any probe reorientation suggests that the matrix remains extremely rigid up to a certain level of hydration, as expected for probes buried deep within the glassy state. At intermediate levels of hydration, SMs undergo a wide variety of rotational dynamics ranging from being static/wobbling motion to slow, hindered large-angle reorientation, as well as facile, intermittently hindered fast rotation, which reflects that swelling/softening of network cavities is spatiotemporally extremely diverse as the effective Tg approaches RT. SM probes exhibit temporally nonuniform rotational mobility even at relatively high moisture contents of the matrix beyond which probes can undergo translational motion, which indicates that relatively slow time scale polymer segmental motion can be operational for plasticized PVP (in the rubbery state). Our inferences are supported by the non Gaussian nature of angular jump distributions for dipolar reorientation, similar to those reported for translational diffusion of SM tracers in polymers and cellular media, suggesting the existence of slow time-varying local environmental changes around individual probe molecules during plasticization. PMID- 27934225 TI - Adsorption of Dimethyldodecylamine Oxide and Its Mixtures with Triton X-100 at the Hydrophilic Silica/Water Interface Studied Using Total Internal Reflection Raman Spectroscopy. AB - Adsorption of dimethyldodecylamine oxide (DDAO) and its mixtures with Triton X 100 (TX-100) at the hydrophilic silica/water interface has been studied using total internal reflection (TIR) Raman spectroscopy and target factor analysis (TFA). The use of a linear vibrational spectroscopic technique helps obtain information on molecular behavior, adsorbed amount, and conformational order of surfactant molecules at the interface. The results obtained from polarized Raman measurements of pure DDAO show insignificant changes in the orientation and conformational order of surface molecules as a function of DDAO bulk concentrations. The adsorption isotherm of pure DDAO shows a change in the structure of the adsorbed layer at concentrations close to the critical micelle concentration (cmc). TFA reveals that, for a low concentration of DDAO (0.30 mM in this study), adsorption of both DDAO and TX-100 in the mixed surfactants was enhanced at low TX-100 concentrations. The synergistic effect is dominant at low concentrations of TX-100, with enhanced adsorption of both surfactants. Although competitive adsorption is effective at high concentrations of TX-100, the presence of a small amount of DDAO at the interface still enhances TX-100 adsorption. When DDAO concentrations are increased to 1.00 mM, TX-100 replaces DDAO molecules on the surface when TX-100 concentration is increased. PMID- 27934226 TI - beta-Galactosidase Langmuir Monolayer at Air/X-gal Subphase Interface. AB - This article investigates the surface chemistry properties of the beta galactosidase monolayer at the air-subphase interface at the vicinity of its substrate, X-gal. We have demonstrated that the beta-galactosidase in the monolayer form remained active and performed hydrolysis of the X-gal in the subphase. We investigated the beta-galactosidase Langmuir monolayer in absence and presence of X-gal in the subphase of varying concentration of X-gal with the sodium chloride solution. It was found that the limiting molecular area as well as the collapse surface pressure kept on decreasing with the increasing concentration of X-gal. In accordance to the data obtained from the isotherm it was also found that beta-galactosidase forms a stable monolayer that does not aggregate at the air-subphase interface. The stability of the monolayer at the air-subphase interface was studied by using compression-decompression cycles with and without X-gal at varying concentration and different surface pressures. The infrared reflection-absorption spectroscopy (IRRAS) and Brewster angle microscopy (BAM) of beta-galactosidase Langmuir monolayer was also investigated for pure and mixed beta-galactosidase at the air-subphase. PMID- 27934227 TI - Many-Body Potentials for Aqueous Be2+ Derived from ab Initio Calculations. AB - An effective three-body potential for the aqueous Be2+ ion has been constructed from a large number of high-level ab initio cluster calculations. The new potential was validated in subsequent molecular dynamics simulations of both gas phase ion-water clusters and bulk liquid. The structures of the first and second solvation shells were studied using radial distribution functions and angular distribution functions. The vibrational spectrum of Be2+ and first shell waters was examined by computing power spectra from the molecular dynamics simulations. The observed bands showed reasonable agreement with experimental spectroscopic frequencies. The potential of mean force for water exchange between the first and second solvation shells was calculated and the energy barrier for exchange was found to have improved agreement with experiment relative to two-body force fields. Examination of the solvation structure near the transition state yielded results consistent with an associative mechanism. PMID- 27934228 TI - Structural Response of Human Serum Albumin to Oxidation: Biological Buffer to Local Formation of Hypochlorite. AB - The most abundant plasma protein, human serum albumin (HSA), plays a key part in the body's antioxidant defense against reactive species. This study was aimed at correlating oxidant-induced chemical and structural effects on HSA. Despite the chemical modification induced by the oxidant hypochlorite, the native shape is preserved up to oxidant/HSA molar ratio <80, above which a structural transition occurs in the critical range 80-120. This conformational variation involves the drifting of one of the end-domains from the rest of the protein and corresponds to the loss of one-third of the alpha-helix and a net increase of the protein negative charge. The transition is highly reproducible suggesting that it represents a well-defined structural response typical of this multidomain protein. The ability to tolerate high levels of chemical modification in a folded or only partially unfolded state, as well as the stability to aggregation, provides albumin with optimal features as a biological buffer for the local formation of oxidants. PMID- 27934229 TI - The Effect of Alkali Halides on the Critical Exponents of the 2,6 Dimethylpyridine-Water System. AB - The diffusion coefficients and shear viscosities of 2,6-dimethylpyridine-water mixtures of critical composition have been measured without and with small amounts of alkali halides added. The data have been analyzed in terms of power law behavior. Deviations from power law behavior indicate a coupling between the critical fluctuations in the local concentrations and the formation of mesoscopic molecular aggregates. The critical exponent of the fluctuation correlation length, the shear viscosity exponent, and the critical exponent of the relaxation rate of fluctuations have been evaluated to show noticeable influences from the salts. The correlation length exponent indicates a suppression of the critical fluctuations, whereas the viscosity exponent rather points at the activation of some extra fluctuations. No clear evidence has been obtained that the added salts affect the critical behavior, and thus cause the opposed effects in the exponents, directly by the long-range ionic fields. Alternatively, the ions may have an influence on the aggregate formation which in turn could modify the critical fluctuations either by reducing the region of true critical exponents or by affecting the critical behavior due to the presence as well as the formation and disintegration kinetics of the multimolecular structures. PMID- 27934230 TI - Autoxidation of Reduced Horse Heart Cytochrome c Catalyzed by Cardiolipin Containing Membranes. AB - Visible circular dichroism, absorption, and fluorescence spectroscopy were used to probe the binding of horse heart ferrocytochrome c to anionic cardiolipin (CL) head groups on the surface of 1,1',2,2'-tetraoleoyl cardiolipin (TOCL)/1,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC) (20%:80%) liposomes in an aerobic environment. We found that ferrocytochrome c undergoes a conformational transition upon binding that leads to complete oxidation of the protein at intermediate and high CL concentrations. At low lipid concentrations, the protein maintains a structure that is only slightly different from its native one, whereas an ensemble of misligated predominantly hexacoordinated low-spin states become increasingly populated at high lipid concentrations. A minor fraction of conformations with either high- or quantum-mixed-spin states were detected at a CL to protein ratio of 200 (the largest one investigated). The population of the non-native state is less pronounced than that found for cytochrome c-CL interactions initiated with oxidized cytochrome c. Under anaerobic conditions, the protein maintains its reduced state but still undergoes some conformational change upon binding to CL head groups on the liposome surface. Our data suggest that CL-containing liposomes function as catalysts by reducing the activation barrier for a Fe2+ -> O2 electron transfer. Adding NaCl to the existing cytochrome-liposome mixtures under aerobic conditions inhibits protein autoxidation of ferrocytochrome c and stabilizes the reduced state of the membrane-bound protein. PMID- 27934231 TI - Hydrogen Abstraction of Camphor Catalyzed by Cytochrome P450cam: A QM/MM Study. AB - A combined quantum mechanics and molecular mechanics (QM/MM, QM = UB3LYP-D3, MM = AMBER) method is used to study the hydrogen abstraction reaction in P450cam catalyzed hydroxylation of camphor in the quartet state. Compared to QM/MM calculations in the literature, this study uses larger basis sets for the most important atoms at the active site and QM/MM Hessian harmonic frequency calculations to determine the standard Gibbs free energy of activation and kinetic isotope effect. The QM/MM covalent boundary is treated with a capping hydrogen atom method, which is simple and robust. An energy barrier of 21.3 kcal/mol and a standard free energy of activation of 16.8 kcal/mol are obtained for this hydrogen abstraction reaction. These values are similar to those reported in the literature, suggesting that when a general protocol is followed, QM/MM results are reproducible. It is found that using a sufficiently large basis set is important to minimize basis set errors. PMID- 27934232 TI - Reversible-Switch Mechanism of the SAM-III Riboswitch. AB - Riboswitches are self-regulatory elements located at the 5' untranslated region of certain mRNAs. The Enterococcus faecalis SAM-III (SMK) riboswitch regulates downstream gene expression through conformational change by sensing S adenosylmethionine (SAM) at the translation level. Using the recently developed systematic helix-based computational method, we studied the co-transcriptional folding behavior of the SMK riboswitch and its shortened construct lacking the first six nucleotides. We find that there are no obvious misfolded structures formed during the transcription and refolding processes for this riboswitch. The full-length riboswitch quickly folds into the ON-state in the absence of SAM, and the coupling between transcription and translation is not required for the riboswitch to function. The potential to form helix P0 is necessary for the riboswitch to function as a switch. For this thermodynamically controlled reversible riboswitch, the fast helix-exchanging transition pathway between the two functional structures guaranteed that this riboswitch can act as a reversible riboswitch. PMID- 27934234 TI - Heteronuclear Cross-Relaxation under Solid-State Dynamic Nuclear Polarization. AB - We report on the spontaneous polarization transfer from dynamically hyperpolarized 1H to 13C during magic-angle spinning dynamic nuclear polarization (DNP) at temperatures around 100 K. The transfer is mediated by 1H-13C cross relaxation within methyl groups due to reorientation dynamics, and results in an inverted 13C NMR signal of enhanced amplitude. Further spreading of transferred polarization can then occur via 13C-13C spin-diffusion. The resulting process is equal to the nuclear Overhauser effect (NOE) where typically continuous saturation of 1H by radio frequency irradiation is employed. Here, hyperpolarization by irradiation with microwaves in the presence of typical bis nitroxide polarizing agents is utilized for steady-state displacement of 1H polarization from thermal equilibrium and perpetual spin-lattice relaxation. An effective 13C enhancement factor of up to -15 has been measured. Presence of Gd(III) furthermore amplifies the effect likely by accelerated relaxation of 1H. We provide experimental evidence for the proposed mechanism and show that DNP induced cross-relaxation is a robust feature within proteins and single amino acids and discuss potential applications. PMID- 27934235 TI - Multiple Roles of Cu(II) in Catalyzing Hydrolysis and Oxidation of beta-Lactam Antibiotics. AB - The widely used beta-lactam antibiotics such as penicillins and cephalosporins are known to be susceptible to CuII-catalyzed hydrolysis at their four-membered beta-lactam ring. However, this study elucidates that CuII can in fact play multiple roles in promoting the hydrolysis and/or oxidation of beta-lactam antibiotics under environmental aquatic conditions (pH 5.0-9.0 and 22 degrees C), depending on beta-lactams' structural characteristics and solution pH. Most significantly, the beta-lactam antibiotics that contain a phenylglycine primary amine group on the side chain can undergo direct oxidation by CuII via this functional group. On the other hand, the beta-lactam ring of penicillins is susceptible to CuII-catalyzed hydrolysis, followed by oxidation of the hydrolysis product by CuII. In contrast, the beta-lactam ring of cephalosporins is susceptible to CuII-catalyzed hydrolysis only. Solution pH influences the CuII promoted transformation by affecting the beta-lactam and CuII complexation through protonation/deprotonation of critical organic functional groups. When CuII acts as an oxidant to promote the transformation of beta-lactam antibiotics to yield CuI, the overall role of CuII appears catalytic if the reaction occurs under ambient atmospheric condition, due to quick oxidation of CuI by oxygen to regenerate CuII. Compared to earlier literature that largely assumed only the hydrolytic catalyst role of CuII in promoting degradation of beta-lactam antibiotics, the oxidative roles of CuII identified by this study mark important contributions to a more accurate mechanistic understanding. PMID- 27934236 TI - We Helped Flint Residents Save Themselves and Are Proud of It-Staying in Our Ivory Tower Would Have Perpetuated Injustice. PMID- 27934233 TI - Modeling Membrane Protein-Ligand Binding Interactions: The Human Purinergic Platelet Receptor. AB - Membrane proteins, due to their roles as cell receptors and signaling mediators, make prime candidates for drug targets. The computational analysis of protein ligand binding affinities has been widely employed as a tool in rational drug design efforts. Although efficient implicit solvent-based methods for modeling globular protein-ligand binding have been around for many years, the extension of such methods to membrane protein-ligand binding is still in its infancy. In this study, we extended the widely used Amber/MMPBSA method to model membrane protein ligand systems, and we used it to analyze protein-ligand binding for the human purinergic platelet receptor (P2Y12R), a prominent drug target in the inhibition of platelet aggregation for the prevention of myocardial infarction and stroke. The binding affinities, computed by the Amber/MMPBSA method using standard parameters, correlate well with experiment. A detailed investigation of these parameters was conducted to assess their impact on the accuracy of the method. These analyses show the importance of properly treating the nonpolar solvation interactions and the electrostatic polarization in the binding of nucleotide agonists and non-nucleotide antagonists to P2Y12R. On the basis of the crystal structures and the experimental conditions in the binding assay, we further hypothesized that the nucleotide agonists lose their bound magnesium ion upon binding to P2Y12R, and our computational study supports this hypothesis. Ultimately, this work illustrates the value of computational analysis in the interpretation of experimental binding reactions. PMID- 27934237 TI - Highly Selective Screening of Estrogenic Compounds in Consumer-Electronics Plastics by Liquid Chromatography in Parallel Combined with Nanofractionation Bioactivity Detection and Mass Spectrometry. AB - The chemical safety of consumer products is an issue of emerging concern. Plastics are widely used, e.g. as casings of consumer electronics (TVs, computers, routers, etc.), which are present in houses and offices in continuously increasing numbers. In this study, we investigate the estrogenic activity of components of plastics coming from electronics' casings. A recently developed fractionation platform for effect-directed analysis (EDA) was used. This platform combines reversed-phase liquid chromatography in parallel with bioassay detection via nanofractionation and with online high-resolution time-of flight mass spectrometry (TOFMS) for the identification of bioactives. Four out of eight of the analyzed plastics samples showed the presence of estrogenic compounds. Based on the MS results these were assigned to bisphenol A (BPA), 2,4 di-tert-butylphenol, and a possible bisphenol A analog. All samples contained flame retardants, but these did not show any estrogenicity. The observed BPA, however, could be an impurity of tetrabromo-BPA (TBBPA) or TBBPA-based flame retardants. Due to the plausible migration of additives from plastics into the environment, plastics from consumer electronics likely constitute a source of estrogenic compound contamination in the indoor environment. PMID- 27934238 TI - On Listening, Science, and Justice: A Call for Exercising Care in What Lessons We Draw from Flint. PMID- 27934239 TI - Correction to Stability and Aggregation Kinetics of Titania Nanomaterials under Environmentally Realistic Conditions. PMID- 27934240 TI - Modeling the Endogenous Sunlight Inactivation Rates of Laboratory Strain and Wastewater E. coli and Enterococci Using Biological Weighting Functions. AB - Models that predict sunlight inactivation rates of bacteria are valuable tools for predicting the fate of pathogens in recreational waters and designing natural wastewater treatment systems to meet disinfection goals. We developed biological weighting function (BWF)-based numerical models to estimate the endogenous sunlight inactivation rates of E. coli and enterococci. BWF-based models allow the prediction of inactivation rates under a range of environmental conditions that shift the magnitude or spectral distribution of sunlight irradiance (e.g., different times, latitudes, water absorbances, depth). Separate models were developed for laboratory strain bacteria cultured in the laboratory and indigenous organisms concentrated directly from wastewater. Wastewater bacteria were found to be 5-7 times less susceptible to full-spectrum simulated sunlight than the laboratory bacteria, highlighting the importance of conducting experiments with bacteria sourced directly from wastewater. The inactivation rate models fit experimental data well and were successful in predicting the inactivation rates of wastewater E. coli and enterococci measured in clear marine water by researchers from a different laboratory. Additional research is recommended to develop strategies to account for the effects of elevated water pH on predicted inactivation rates. PMID- 27934241 TI - LIF Spectroscopy of p-Fluorophenol...Water Complex: Hydrogen Bond Vibrations, Fermi Resonance, and Vibrational Relaxation in the Excited State. AB - Laser-induced fluorescence (FE) and vibrationally resolved dispersed fluorescence (DF) spectra of a 1:1 water complex of p-fluorophenol (pFP) have been measured in a supersonic jet expansion. The hydrogen bond stretching fundamental (sigma01) of the complex appears in the FE spectrum as a doublet with band maxima at 155 and 161 cm-1. Emission spectra recorded upon excitations of the two components reveal that a Fermi resonance between sigma1 and a combination involving a low-frequency intramolecular mode of pFP (mode 11) and a bending mode of water at the hydrogen bonded interface (mode rho1) is responsible for the observed splitting. The DF spectra of the Franck-Condon active 6a01 band (000 + 427 cm-1) of pFP reveals signatures of hydrogen bond induced vibrational energy relaxation (VER) predominantly from the bright (6a01) to a dark (9b1) level in S1. The relative intensities of the emission bands from the locally excited and relaxed levels indicate that VER for excitation up to this level occurs at a time scale similar to the fluorescence decay time of the complex. However, complete VER at a much faster time scale occurs for excitation beyond 822 cm-1 above S1 origin. PMID- 27934242 TI - Stepwise Internal Energy Change of Protonated Methanol Clusters By Using the Inert Gas Tagging. AB - Structural isomer population of a hydrogen-bonded cluster generally depends on temperature. Therefore, determination of an isomer population profile in a wide temperature range is important to understand the nature of hydrogen bond networks of the cluster. To explore an isomer population profile, stepwise changes of internal vibrational energy of a protonated hydrogen-bonded cluster are performed by inert gas tagging. We observe infrared spectra of the protonated methanol pentamer with various tag species. The bare protonated methanol pentamer practically has only two possible isomer types. With the tagging, the relative population of the two isomer types changes according to the binding energy with the tag species. The observed relative population follows its theoretically predicted temperature dependence. PMID- 27934243 TI - Strategies for Evaluation of Rys Roots and Weights. AB - The Rys quadrature method for evaluating molecular integrals requires accurate numerical values of the nodes of a Rys polynomial and associated weight factors. The numerical value of a Rys polynomial for a specified value of its argument can be evaluated by three-term recursion using alpha and beta coefficients. We review existing integration schemes for computing these recurrence parameters, discuss issues related to computational efficiency and numerical precision, and propose a slightly new integration method using Gauss-Rys quadrature. We discuss the advantages and disadvantages of using Golub's matrix method for the computation of roots and weights. PMID- 27934244 TI - Uncommon and Emissive {[Au2(C3H6NS2)2][Au(C3H6NS2)2]2(PF6)2} Mixed Au+ and Au3+ Pseudotetranuclear Crystalline Compound: Synthesis, Structural Characterization, and Optical Properties. AB - An uncommon emissive pseudotetranuclear compound, {[Au2(C3H6NS2)2][Au(C3H6NS2)2]2(PF6)2}, was synthesized and characterized in terms of its structure and optical properties. The synthesis produced a crystalline compound composed of four gold atoms with two different oxidation states (Au+ and Au3+) in the same crystalline structure. The title complex belonged to a triclinic crystalline system involving the centrosymmetric P1 space group. X-ray diffractometry and vibrational spectroscopy (infrared, Raman, and SERS) were used for structural characterization of the new crystal. The vibrational spectroscopy techniques supported the X-ray diffraction results and confirmed the presence of bonds including Au-Au and Au-S. Optical characterization performed using UV-vis spectroscopy showed that under ultraviolet excitation, the emissive crystalline complex presented characteristic broad luminescent bands centered at 420 and 670 nm. PMID- 27934245 TI - Second-Order Nonlinear Optical Properties of Carboranylated Square-Planar Pt(II) Zwitterionic Complexes: One-/Two-Dimensional Difference and Substituent Effect. AB - Zwitterionic complexes have been the subject of great interest in the past several decades due to their multifunctional application in supramolecular chemistry. Herein, a series of internally stable charge-compensated carboranylated square-planar Pt(II) zwitterionic complexes have been explored by density functional theory aim to assessing their structures, the first hyperpolarizabilities, first hyperpolarizability densities, and electronic absorption spectra. It is found that the first hyperpolarizabilities of two dimensional (2D) structure complexes are much larger with respect to the one dimensional complex. It is ascribed to the lower transition energy and more obvious charge transfer, which can be further illustrated by their large amplitude and separate distribution of first hyperpolarizability density. In addition, the first hyperpolarizabilities of 2D complexes can be further significantly modified by introducing electron-donating/withdrawing groups on the carborane cage. As a consequence, we believe that these 2D zwitterionic complexes can behave as novel second-order nonlinear optical chromophore with a promising future. PMID- 27934246 TI - Restricted-Open-Shell G4(MP2)-Type Procedures. AB - In the present study, we have reformulated the G4(MP2) and G4(MP2)-6X procedures for use with a restricted-open-shell (RO) formalism. We find that the resulting ROG4(MP2) and ROG4(MP2)-6X procedures generally perform comparably to the original unrestricted (U) variants, including their performance on radicals. Our analysis suggests that this is due mainly to the inclusion of empirical parameters that overcome the slightly less good performance of the U variants. However, a major practical advantage of ROG4(MP2) and ROG4(MP2)-6X is that they can be used in a wider range of computational chemistry software packages than the U analogs. We have demonstrated the importance of this aspect with a large scale ROG4(MP2)-6X computation for the dissociation of the dodecahedryl dimer (C20H19)2. PMID- 27934247 TI - Dissociative Photoionization of 1-Halogenated Silacyclohexanes: Silicon Traps the Halogen. AB - The threshold photoelectron spectra and threshold photoionization mass spectra of 1-halogenated-1-silacyclohexanes, for the halogens X = F, Cl, Br, and I, have been obtained using synchrotron vacuum ultraviolet radiation and photoelectron photoion coincidence spectroscopy. As confirmed by a similar ionization onset and density functional theory molecular orbitals, the ionization to the ground state is dominated by electron removal from the silacyclohexane ring for X = F, Cl, and Br, and from the halogen lone pair for X = I. The breakdown diagrams show that the dissociative photoionization mechanism is also different for X = I. Whereas the parent ions decay by ethylene loss for X = F to Br in the low-energy regime, the iodine atom is lost for X = I. The first step is followed by a sequential ethylene loss at higher internal energies in each of the compounds. It is argued that the tendency of silicon to lower bond angles stabilizes the complex cation in which C2H4 is eta2-coordinated to it, and which precedes ethylene loss. Together with the relatively strong silicon-halogen bonds and the increased inductive effect of the silacyclohexane ring in stabilizing the cation, this explains the main differences observed in the fragmentation of the halogenated silacyclohexane and halogenated cyclohexane ions. The breakdown diagrams have been modeled taking into account slow dissociations at threshold and the resulting kinetic shift. The 0 K appearance energies have been obtained to within 0.08 eV for the ethylene loss for X = F to Br (10.56, 10.51, and 10.51 eV, respectively), the iodine atom loss for X = I (10.11 eV), the sequential ethylene loss for X = F to I (12.29, 12.01, 11.94, and 11.86 eV, respectively), and the minor channels of H loss for X = F (10.56 eV) and propylene loss in X = Cl (also at 10.56 eV). The appearance energies for the major channels likely correspond to the dissociative photoionization reaction energy. PMID- 27934248 TI - Correction to "Optimization of Surface Coating on Small Pd Nanosheets for in Vivo near-Infrared Photothermal Therapy of Tumor". PMID- 27934249 TI - Synthesis of Phenanthro[1,10,9,8-cdefg]carbazole-Based Conjugated Polymers for Green-Selective Organic Photodiodes. AB - A push-pull-type donor copolymer, named PP-TPD, was synthesized with the Suzuki coupling reaction using 6H-phenanthro[1,10,9,8-cdefg]carbazole (PCZ) as the donor unit and 1,3-bis(5-bromothiophen-2-yl)-5-octyl-4H-thieno[3,4-c]pyrrole-4,6(5H) dione (TPD) as the acceptor unit. The synthesized PP-TPD was systematically investigated in terms of crystallinity and thermal, electrical, electrochemical, and optical properties. PP-TPD revealed green-selective absorption with a narrow full width at half-maximum of 138 nm. Green-selective organic photodiodes (OPDs) were constructed using PP-TPD as the green-absorbing donor and ZnO as the nonabsorbing acceptor material. The fabricated OPDs exhibited an extremely low dark current of 0.68 nA/cm2 at -5 V and a high detectivity above 1012 Jones at 550 nm. Moreover, they showed a sufficiently high 3-dB frequency and a linear dynamic range, similar to those of ideal-operating OPDs. The origin and physics background of the observed low dark current and high detectivity are discussed in detail. PMID- 27934250 TI - Fabrication of Carbohydrate-Conjugated Fingerprintlike Mesoporous Silica Net for the Targeted Capture of Bacteria. AB - Herein, a rapid, straightforward, reliable, and low-cost strategy for targeted capture and detection of bacteria using carbohydrate-conjugated mesoporous silica structure was developed. Fingerprint-like mesoporous silica net (FMSN) with well defined three-dimensional architecture and ordered morphology was first facilely synthesized by the aid of tetrabutylammonium iodine (TBAI) as cotemplates with cetyltrimethylammonium bromide (CTAB). When conjugated with maltoheptaose as targeting moiety, FMSN showed efficient and selective capturing capability of Staphylococcus epidermidis. This new and unique platform for capturing S. epidermidis is fast (within 18 min), high efficiency (greater than 98.6% from 1 * 103 CFU/mL to 1 * 108 CFU/mL), specific (compared to M. smegmatis mc2 155), and reusable (6 cycles). PMID- 27934252 TI - Breaking out of the Box: India and Climate Action on Short-Lived Climate Pollutants. PMID- 27934251 TI - Bacteria Inactivation during the Drying of Struvite Fertilizers Produced from Stored Urine. AB - Human urine can be processed into market-attractive fertilizers like struvite; however, concerns regarding the microbial safety of such products remain. The present study evaluated the inactivation of in situ heterotrophs, total bacteria as observed by flow cytometry, and inoculated Enterococcus spp. and Salmonella typhimurium during the drying of struvite under controlled temperature (from 5 to 35 degrees C) and relative humidity (approximately 40 and 80%) as well as dynamic field conditions. Bacteria accumulated in the struvite cake during struvite filtration. Despite the use of sublethal temperatures, all bacteria types were subsequently inactivated to some degree during struvite drying, and the inactivation typically increased with increasing drying temperature for a given relative humidity. Heterotrophic bacteria inactivation mirrored the trend in total bacteria during struvite drying. A linear relationship was observed between inactivation and sample moisture content. However, bacteria survivor curves were typically nonlinear when struvite was dried at low relative humidity, indicating bacterial persistence. Weibull model survivor curve fits indicated that a shift in the mechanism of inactivation may occur with changing humidity. For increased efficiency of bacterial inactivation during the production of struvite, initial heating under moist conditions is recommended followed by desiccation. PMID- 27934253 TI - Response to Comment on "Aquatic Exposure Predictions of Insecticide Field Concentrations Using a Multimedia Mass Balance Model". PMID- 27934254 TI - Correction to Contaminated Marine Sediments as a Source of Cesium Radioisotopes for Benthic Fauna near Fukushima. PMID- 27934255 TI - Correction to Polyethylenimine-Magadiite Layered Silicate Sorbent for CO2 Capture. PMID- 27934256 TI - Black Carbon Facilitated Dechlorination of DDT and its Metabolites by Sulfide. AB - 1,1-trichloro-2,2-di(4-chlorophenyl)ethane (DDT) and its metabolites 1,1-dichloro 2,2-bis(4-chlorophenyl)ethane (DDD) and 1,1-dichloro-2,2-bis(4 chlorophenyl)ethylene (DDE), are often detected in soils and sediments containing high concentrations of black carbon. Sulfide (~5 mM) from biological sulfate reduction often coexists with black carbon and serves as both a strong reductant and a nucleophile for the abiotic transformation of contaminants. In this study, we found that the abiotic transformation of DDT, DDD, and DDE (collectively referred to as DDX) require both sulfide and black carbon. 89.3 +/- 1.8% of DDT, 63.2 +/- 1.9% of DDD, and 50.9 +/- 1.6% of DDE were degraded by sulfide (5 mM) in the presence of graphite powder (21 g/L) after 28 days at pH 7. Chloride was a product of DDX degradation. To better understand the reaction pathways, electrochemical cells and batch reactor experiments with sulfide-pretreated graphite powder were used to differentiate the involvement of black carbon materials in DDX transformation by sulfide. Our results suggest that DDT and DDD are transformed by surface intermediates formed from the reaction between sulfide and black carbon, while DDE degradation involves reductive dechlorination. This research lays the groundwork for developing an alternative in situ remediation technique for rapidly decontaminating soils and sediments to lower toxic products under environmentally relevant conditions. PMID- 27934257 TI - Comment on "Aquatic Exposure Predictions of Insecticide Field Concentrations Using a Multimedia Mass-Balance Model". PMID- 27934258 TI - Capturing Lithium from Wastewater Using a Fixed Bed Packed with 3-D MnO2 Ion Cages. AB - 3-D MnO2 ion cages (CMO) were fabricated and shown to have a high capacity for lithium removal from wastewater. CMO had a maximum Li(I) adsorption capacity of 56.87 mg/g, which is 1.38 times greater than the highest reported value (41.36 mg/g). X-ray photoelectron spectroscopy indicated that the stability of the -Mn-O Mn-O- skeleton played an essential role in Li adsorption. The lattice clearance had a high charge density, forming a strong electrostatic field. The Dubinin Ashtakhov (DA) site energy distribution model based on Polanyi theory described the linear increase of Li adsorption capacity (Q0) with increasing temperature (Q0 = k3 * Em + d3 = k3 * (a * T) + d3). Furthermore, the pore diffusion model (PDM) accurately predicted the lithium breakthrough (R2 ~ 0.99). The maximum number of bed volumes (BVs) treated was 1374, 1972, and 2493 for 200 MUg/L at 20, 30, and 40 degrees C, respectively. Higher temperatures increased the number of BVs that may be treated, which implies that CMO will be useful in treating industrial Li(I) wastewater in regions with different climates (e.g., Northern or Southern China). PMID- 27934259 TI - Impacts of Large-Scale Land-Use Change on the Uptake of Polycyclic Aromatic Hydrocarbons in the Artificial Three Northern Regions Shelter Forest Across Northern China. AB - This study quantifies the influence of large-scale land-use change induced by the artificial Three-Northern Regions Shelter Forest (TNRSF) across northern China on the environmental cycling of organic chemicals. Atmospheric removal and long-term trends of two polycyclic aromatic hydrocarbon (PAH) species, phenanthrene (PHE) and benzo[a]pyrene (BaP), resulting from increasing vegetation coverage and soil organic carbon in the TNRSF over the last two decades were examined. Field sampling data and modeling result showed that the total atmospheric removal of PHE by TNRSF increased from 36.4 tons in 1990 to 76.8 tons in 2010, increasing at a rate of 5.6% yr-1, and BaP from 2.2 to 4.5 tons, increasing at a rate of 5.2% yr-1. Three model scenarios were designed to distinguish the effects of atmospheric emissions, and with and without TNRSF on the environmental fate of PAHs. Approximately 1-4% of PHE and BaP emitted in northern China were removed by the TNRSF during 1990-2010. Model simulations revealed that the TNRSF enhanced atmospheric removal of PHE by 29% and BaP by 53% compared with the simulation without the TNRSF, manifesting marked contributions of land-use change by the artificial TNRSF, the largest afforestation activity in human history, to the atmospheric removal of organic chemicals. PMID- 27934260 TI - Long-Term Impact of Field Applications of Sewage Sludge on Soil Antibiotic Resistome. AB - Land applications of municipal sewage sludge may pose a risk of introducing antibiotic resistance genes (ARGs) from urban environments into agricultural systems. However, how the sewage sludge recycling and application method influence soil resistome and mobile genetic elements (MGEs) remains unclear. In the present study, high through-put quantitative PCR was conducted on the resistome of soils from a field experiment with past (between 1994 and 1997) and annual (since 1994) applications of five different sewage sludges. Total inputs of organic carbon were similar between the two modes of sludge applications. Intrinsic soil resistome, defined as the ARGs shared by the soils in the control and sludge-amended plots, consisted of genes conferring resistance to multidrug, beta-lactam, Macrolide-Lincosamide-Streptogramin B (MLSB), tetracycline, vancomycin, and aminoglycoside, with multidrug resistance genes as the most abundant members. There was a strong correlation between the abundance of ARGs and MGE marker genes in soils. The composition and diversity of ARGs in the five sludges were substantially different from those in soils. Considerable proportions of ARGs and MGE marker genes in the sludges attenuated following the application, especially aminoglycoside and tetracycline resistance genes. Annual applications posed a more significant impact on the soil resistome, through both continued introduction and stimulation of the soil intrinsic ARGs. In addition, direct introduction of sludge-specific ARGs into soil was observed especially from ARG-rich sludge. These results provide a better insight into the characteristics of ARG dissemination from urban environment to the agricultural system through sewage sludge applications. PMID- 27934261 TI - Effects of Flow Regime on Metal Concentrations and the Attainment of Water Quality Standards in a Remediated Stream Reach, Butte, Montana. AB - Low-flow synoptic sampling campaigns are often used as the primary tool to characterize watersheds affected by mining. Although such campaigns are an invaluable part of site characterization, investigations which focus solely on low-flow conditions may yield misleading results. The objective of this paper is to demonstrate this point and elucidate the mechanisms responsible for the release of metals during rainfall runoff. This objective is addressed using data from diel and synoptic sampling campaigns conducted over a two-day period. Low flow synoptic sampling results indicate that concentrations of most constituents meet aquatic standards. This finding is in contrast to findings from a diel sampling campaign that captured dramatic increases in concentrations during rainfall runoff. Concentrations during the rising limb of the hydrograph were 2 23 times concentrations observed during synoptic sampling (most increases were >10-fold), remaining elevated during the receding limb of the hydrograph to produce a clockwise hysteresis loop. Hydrologic mechanisms responsible for the release of metals include increased transport due to resuspension of streambed solids, erosion of alluvial tailings, and overland flow. Rainfall also elevated the alluvial groundwater table and increased infiltration through the vadose zone, likely resulting in dissolution from alluvial tailings that were dry prior to the event. PMID- 27934262 TI - Long-Term Trends in Acid Neutralizing Capacity under Increasing Acidic Deposition: A Special Example of Eutrophic Taihu Lake, China. AB - While North America and Europe have been recovering from acidification, China is experiencing impacts of acid deposition. The Taihu region is a seriously impacted area by acid rain in China, with the average rainfall pH < 5. However, the acid neutralizing capacity (ANC) and pH of Taihu Lake have significantly increased over the past 60 years (p < 0.05). Analyses showed that watershed neutralization by carbonates and in-lake alkalinization by algae activities were the two major reactions responsible for the increase. In the Taihu basin, the dominant carbonate bedrocks are the major source of base cations (particularly Ca2+ and Mg2+) and act as the acidification buffer. In addition, our field measurements across the lake showed that the pH values were significantly higher in algal bloom waters than in areas without blooms. This observation was further supported by our statistical analysis showing that the Taihu ANC and pH were significantly correlated with the chlorophyll increase (p < 0.05; 1985-2015). However, our regression analysis indicated that the base cations in the watershed would be depleted by the early 2040s if the acid deposition continues at the current rate. Our results suggest that interactions between human accelerated weathering, watershed geochemistry, and in-lake algae activities significantly impact the water chemistry of the lake. We urgently recommend an "integrated and balanced" recovery plan for the lake ecosystem. PMID- 27934263 TI - Power of Plankton: Effects of Algal Biodiversity on Biocrude Production and Stability. AB - Algae-derived biocrude oil is a possible renewable energy alternative to fossil fuel based crude oil. Outdoor cultivation in raceway ponds is estimated to provide a better return on energy invested than closed photobioreactor systems. However, in these open systems, algal crops are subjected to environmental variation in temperature and irradiance, as well as biotic invasions which can cause costly crop instabilities. In this paper, we used an experimental approach to investigate the ability of species richness to maximize and stabilize biocrude production in the face of weekly temperature fluctuations between 17 and 27 degrees C, relative to a constant-temperature control. We hypothesized that species richness would lead to higher mean biocrude production and greater stability of biocrude production over time in the variable temperature environment. Counter to our hypothesis, species richness tended to cause a decline in mean biocrude production, regardless of environmental temperature variation. However, biodiversity did have stabilizing effects on biocrude production over time in the variable temperature environment and not in the constant temperature environment. Altogether, our results suggest that when the most productive and stable monoculture is unknown, inoculating raceway ponds with a diverse mixture of algae will tend to ensure stable harvests over time. PMID- 27934264 TI - Reductive Dechlorination of Trichloroethene by Zero-valent Iron Nanoparticles: Reactivity Enhancement through Sulfidation Treatment. AB - Zero-valent iron nanoparticles (nZVI) synthesized in the presence of reduced sulfur compounds have been shown to degrade trichloroethene (TCE) at significantly higher rates. However, the applicability of sulfidation as a general means to enhance nZVI reactivity under different particle preparation conditions and the underlying cause for this enhancement effect are not well understood. In this study, the effects of sulfidation reagent, time point of sulfidation, and sulfur loading on the resultant particles were assessed through TCE degradation experiments. Up to 60-fold increase in TCE reaction rates was observed upon sulfidation treatment, with products being fully dechlorinated hydrocarbons. While the reactivity of these sulfur-treated nZVI (S-nZVI) was relatively unaffected by the sulfidation reagent (viz., sodium sulfide, dithionite, or thiosulfate) or the sequence of sulfidation relative to iron reduction, TCE reaction rates were found to depend strongly on sulfur to iron ratio. At a low sulfur loading, TCE degradation was accelerated with increasing sulfur dose. The rate constant reached a limiting value, however, as the sulfur to iron mole ratio was greater than 0.025. Different from previous propositions that iron sulfidation leads to more efficient TCE or tetrachloroethene (PCE) degradation by enabling depassivation of iron surface, affording catalytic pathways, or facilitating electron transfer, we show that the role of sulfur in nZVI lies essentially in its ability to poison hydrogen recombination, which drives surface reactions to favor reduction by atomic hydrogen. This implies that the reactivity of S-nZVI is contaminant-specific and is selective against the background reaction of water reduction. As the effect of sulfur manifests through surface processes, sulfidation represents a broadly applicable surface modification approach to modulate or increase the reactivity of nZVI for treating TCE and other related contaminants. PMID- 27934265 TI - Cosolvent Effects on Dechlorination of Soil-Sorbed Polychlorinated Biphenyls Using Bentonite Clay-Templated Nanoscale Zero Valent Iron. AB - Zero-valent iron synthesized using bentonite clay as a template (CZVI) was tested for its reactivity toward polychlorinated biphenyl (PCB) dechlorination in soil slurries. Aqueous-phase decachlorobiphenyl (PCB209) was rapidly dechlorinated by CZVI with a reaction rate 10 times greater than that by conventional nanoscale zerovalent iron. This superior reactivity was due largely to the nanoscale size (~0.5 nm) of the ZVI particles located in the clay galleries. In soil slurries where PCB209 was strongly soil-bound, adding ethanol as an organic cosolvent led to increased PCB209 desorption into the liquid phase, thereby enhancing the PCB209 dechlorination with CZVI. The more effective PCB209 dechlorination in such a cosolvent system also promoted the subsequent stepwise dechlorinative process, leading to a relatively more removal of chlorine in the product mixture. The dechlorination became more rapid as the ethanol fraction increased from 10% to 50%, due apparently to the increasingly greater PCB209 desorption and thus facilitated contact with CZVI. Further increase in ethanol fraction above 50% led to an insignificant enhancement in degradation rate, due partially to attenuated contact of PCB209 with CZVI and reduced proton source from limited water content in the liquid. It is suggested that addition of organic cosolvents may make CZVI potentially useful for remediation of soils containing halogenated organic contaminants. PMID- 27934266 TI - Automated Calibration of Atmospheric Oxidized Mercury Measurements. AB - The atmosphere is an important reservoir for mercury pollution, and understanding of oxidation processes is essential to elucidating the fate of atmospheric mercury. Several recent studies have shown that a low bias exists in a widely applied method for atmospheric oxidized mercury measurements. We developed an automated, permeation tube-based calibrator for elemental and oxidized mercury, and we integrated this calibrator with atmospheric mercury instrumentation (Tekran 2537/1130/1135 speciation systems) in Reno, Nevada and at Mauna Loa Observatory, Hawaii, U.S.A. While the calibrator has limitations, it was able to routinely inject stable amounts of HgCl2 and HgBr2 into atmospheric mercury measurement systems over periods of several months. In Reno, recovery of injected mercury compounds as gaseous oxidized mercury (as opposed to elemental mercury) decreased with increasing specific humidity, as has been shown in other studies, although this trend was not observed at Mauna Loa, likely due to differences in atmospheric chemistry at the two locations. Recovery of injected mercury compounds as oxidized mercury was greater in Mauna Loa than in Reno, and greater still for a cation-exchange membrane-based measurement system. These results show that routine calibration of atmospheric oxidized mercury measurements is both feasible and necessary. PMID- 27934267 TI - Stochastic Technology Choice Model for Consequential Life Cycle Assessment. AB - Discussions on Consequential Life Cycle Assessment (CLCA) have relied largely on partial or general equilibrium models. Such models are useful for integrating market effects into CLCA, but also have well-recognized limitations such as the poor granularity of the sectoral definition and the assumption of perfect oversight by all economic agents. Building on the Rectangular-Choice-of Technology (RCOT) model, this study proposes a new modeling approach for CLCA, the Technology Choice Model (TCM). In this approach, the RCOT model is adapted for its use in CLCA and extended to incorporate parameter uncertainties and suboptimal decisions due to market imperfections and information asymmetry in a stochastic setting. In a case study on rice production, we demonstrate that the proposed approach allows modeling of complex production technology mixes and their expected environmental outcomes under uncertainty, at a high level of detail. Incorporating the effect of production constraints, uncertainty, and suboptimal decisions by economic agents significantly affects technology mixes and associated greenhouse gas (GHG) emissions of the system under study. The case study also shows the model's ability to determine both the average and marginal environmental impacts of a product in response to changes in the quantity of final demand. PMID- 27934268 TI - Volatile Organic Compound Emissions from Humans Indoors. AB - Research on the sources of indoor airborne chemicals has traditionally focused on outdoor air, building materials, furnishings, and activities such as smoking, cooking, and cleaning. Relatively little research has examined the direct role of occupant emissions, even though this source clearly contributes to indoor volatile organic compounds (VOCs) and influences indoor chemistry. In this work, we quantify occupant-related gaseous VOC emissions in a university classroom using a proton-transfer-reaction time-of-flight mass spectrometer. Time-resolved concentrations of VOCs in room air and supply air were measured continuously during occupied and unoccupied periods. The emission factor for each human emitted VOC was determined by dividing the occupant-associated source rate by the corresponding occupancy. Among the most abundant species detected were compounds associated with personal care products. Also prominent were human metabolic emissions, such as isoprene, methanol, acetone, and acetic acid. Additional sources included human skin oil oxidation by ozone, producing compounds such as 4 oxopentanal (4-OPA) and 6-methyl-5-hepten-2-one (6-MHO). By mass, human-emitted VOCs were the dominant source (57%) during occupied periods in a well-ventilated classroom, with ventilation supply air the second most important (35%), and indoor nonoccupant emissions the least (8%). The total occupant-associated VOC emission factor was 6.3 mg h-1 per person. PMID- 27934269 TI - Can Chemical Class Approaches Replace Chemical-by-Chemical Strategies? Lessons from Recent U.S. FDA Regulatory Action on Per- And Polyfluoroalkyl Substances. AB - Concern about the toxicity and exposure of per- and polyfluoroalkyl substances (PFASs) is growing among scientists, regulators, and residents of contaminated communities. In 2016, the United States Food and Drug Administration (FDA) removed three food contact substances (FCSs) containing perfluorinated chemicals from the list of approved FCSs due to concerns regarding chemical safety. To investigate the significance and limitations of the FDA's regulatory action for environmental health research, advocacy, and regulation, we conducted a media analysis and qualitative interviews with a range of involved stakeholders. We find that the FDA's regulatory action represents a potential shift from chemical by-chemical regulation toward class-based regulation, where groups of chemicals can be identified as sharing properties and risks, and are thus evaluated and regulated together. The FDA decision sets an important precedent of using a petition process to delist chemicals based on a safety standard. However, the narrow reach of this action also highlights the need for more comprehensive, precautionary chemical regulation capable of thoroughly evaluating classes of chemicals, and raises important questions about how classes of chemicals are delimited in environmental health science and regulation. PMID- 27934270 TI - Correction to Real-Time Ultrafine Aerosol Measurements from Wastewater Treatment Facilities. PMID- 27934272 TI - Correction to Size-resolved Identification, Characterization and Quantification of Primary Biological Organic Aerosol at a European Rural Site. PMID- 27934271 TI - Declining Mercury Concentrations in Bluefin Tuna Reflect Reduced Emissions to the North Atlantic Ocean. AB - Tunas are apex predators in marine food webs that can accumulate mercury (Hg) to high concentrations and provide more Hg (~40%) to the U.S population than any other source. We measured Hg concentrations in 1292 Atlantic bluefin tuna (ABFT, Thunnus thynnus) captured in the Northwest Atlantic from 2004 to 2012. ABFT Hg concentrations and variability increased nonlinearly with length, weight, and age, ranging from 0.25 to 3.15 mg kg-1, and declined significantly at a rate of 0.018 +/- 0.003 mg kg-1 per year or 19% over an 8-year period from the 1990s to the early 2000s. Notably, this decrease parallels comparably reduced anthropogenic Hg emission rates in North America and North Atlantic atmospheric Hg0 concentrations during this period, suggesting that recent efforts to decrease atmospheric Hg loading have rapidly propagated up marine food webs to a commercially important species. This is the first evidence to suggest that emission reduction efforts have resulted in lower Hg concentrations in large, long-lived fish. PMID- 27934273 TI - Aqueous Aggregation Behavior of Engineered Superparamagnetic Iron Oxide Nanoparticles: Effects of Oxidative Surface Aging. AB - For successful aqueous-based applications, it is necessary to fundamentally understand and control nanoparticle dispersivity and stability over a range of dynamic conditions, including variable ionic strengths/types, redox chemistries, and surface ligand reactivity/degradation states (i.e., surface aging). Here, we quantitatively describe the behavior of artificially aged, oleic acid (OA) bilayer coated iron oxide nanoparticles (IONPs) under different scenarios. Hydrogen peroxide (H2O2), used here as a model oxidant under both dark and light ultraviolet (UVA) conditions, was employed to "age" materials, to varying degrees, without increasing ionic strength. Short-term stability experiments indicate that OA-IONPs, while stable in the dark, are effectively destabilized when exposed to UVA/H2O2/*OH based oxidation processes. Compared to bicarbonate, phosphate (1.0 mM) has a net stabilizing effect on OA-IONPs under oxidative conditions, which can be attributed to (surface-based) functional adsorption. Corresponding aggregation kinetics in the presence of monovalent (Na+) and divalent cations (Ca2+) show that attachment efficiencies (alpha) are strongly dependent on the cation concentrations/types and degree of surface aging. Taken together, our findings directly highlight the need to understand the critical role of particle surface transformation(s), via oxidative aging, among other routes, with regard to the ultimate stability and environmental fate of surface functionalized engineered nanoparticles. PMID- 27934274 TI - Incorporation of Technetium into Spinel Ferrites. AB - Technetium (99Tc) is a problematic fission product for the long-term disposal of nuclear waste due to its long half-life, high fission yield, and to the environmental mobility of pertechnetate, the stable species in aerobic environments. One approach to preventing 99Tc contamination is using sufficiently durable waste forms. We report the incorporation of technetium into a family of synthetic spinel ferrites that have environmentally durable natural analogs. A combination of X-ray diffraction, X-ray absorption fine structure spectroscopy, and chemical analysis reveals that Tc(IV) replaces Fe(III) in octahedral sites and illustrates how the resulting charge mismatch is balanced. When a large excess of divalent metal ions is present, the charge is predominantly balanced by substitution of Fe(III) by M(II). When a large excess of divalent metal ions is absent, the charge is largely balanced by creation of vacancies among the Fe(III) sites (maghemitization). In most samples, Tc is present in Tc-rich regions rather than being homogeneously distributed. PMID- 27934275 TI - Flavoring Compounds Dominate Toxic Aldehyde Production during E-Cigarette Vaping. AB - The growing popularity of electronic cigarettes (e-cigarettes) raises concerns about the possibility of adverse health effects to primary users and people exposed to e-cigarette vapors. E-Cigarettes offer a very wide variety of flavors, which is one of the main factors that attract new, especially young, users. How flavoring compounds in e-cigarette liquids affect the chemical composition and toxicity of e-cigarette vapors is practically unknown. Although e-cigarettes are marketed as safer alternatives to traditional cigarettes, several studies have demonstrated formation of toxic aldehydes in e-cigarette vapors during vaping. So far, aldehyde formation has been attributed to thermal decomposition of the main components of e-cigarette e-liquids (propylene glycol and glycerol), while the role of flavoring compounds has been ignored. In this study, we have measured several toxic aldehydes produced by three popular brands of e-cigarettes with flavored and unflavored e-liquids. We show that, within the tested e-cigarette brands, thermal decomposition of flavoring compounds dominates formation of aldehydes during vaping, producing levels that exceed occupational safety standards. Production of aldehydes was found to be exponentially dependent on concentration of flavoring compounds. These findings stress the need for a further, thorough investigation of the effect of flavoring compounds on the toxicity of e-cigarettes. PMID- 27934276 TI - Correction to Acute Toxicity Prediction to Threatened and Endangered Species Using Interspecies Correlation Estimation (ICE) Models. PMID- 27934277 TI - Visible-Light-Responsive Graphitic Carbon Nitride: Rational Design and Photocatalytic Applications for Water Treatment. AB - Graphitic carbon nitride (g-C3N4) has recently emerged as a promising visible light-responsive polymeric photocatalyst; however, a molecular-level understanding of material properties and its application for water purification were underexplored. In this study, we rationally designed nonmetal doped, supramolecule-based g-C3N4 with improved surface area and charge separation. Density functional theory (DFT) simulations indicated that carbon-doped g-C3N4 showed a thermodynamically stable structure, promoted charge separation, and had suitable energy levels of conduction and valence bands for photocatalytic oxidation compared to phosphorus-doped g-C3N4. The optimized carbon-doped, supramolecule-based g-C3N4 showed a reaction rate enhancement of 2.3-10.5-fold for the degradation of phenol and persistent organic micropollutants compared to that of conventional, melamine-based g-C3N4 in a model buffer system under the irradiation of simulated visible sunlight. Carbon-doping but not phosphorus doping improved reactivity for contaminant degradation in agreement with DFT simulation results. Selective contaminant degradation was observed on g-C3N4, likely due to differences in reactive oxygen species production and/or contaminant-photocatalyst interfacial interactions on different g-C3N4 samples. Moreover, g-C3N4 is a robust photocatalyst for contaminant degradation in raw natural water and (partially) treated water and wastewater. In summary, DFT simulations are a viable tool to predict photocatalyst properties and oxidation performance for contaminant removal, and they guide the rational design, fabrication, and implementation of visible-light-responsive g-C3N4 for efficient, robust, and sustainable water treatment. PMID- 27934279 TI - Amending the Inadequacy of a Single Indicator for Climate Impact Analyses. PMID- 27934278 TI - Gridded National Inventory of U.S. Methane Emissions. AB - We present a gridded inventory of US anthropogenic methane emissions with 0.1 degrees * 0.1 degrees spatial resolution, monthly temporal resolution, and detailed scale-dependent error characterization. The inventory is designed to be consistent with the 2016 US Environmental Protection Agency (EPA) Inventory of US Greenhouse Gas Emissions and Sinks (GHGI) for 2012. The EPA inventory is available only as national totals for different source types. We use a wide range of databases at the state, county, local, and point source level to disaggregate the inventory and allocate the spatial and temporal distribution of emissions for individual source types. Results show large differences with the EDGAR v4.2 global gridded inventory commonly used as a priori estimate in inversions of atmospheric methane observations. We derive grid-dependent error statistics for individual source types from comparison with the Environmental Defense Fund (EDF) regional inventory for Northeast Texas. These error statistics are independently verified by comparison with the California Greenhouse Gas Emissions Measurement (CALGEM) grid-resolved emission inventory. Our gridded, time-resolved inventory provides an improved basis for inversion of atmospheric methane observations to estimate US methane emissions and interpret the results in terms of the underlying processes. PMID- 27934280 TI - Predictive Capabilities of in Vitro Assays for Estimating Pb Relative Bioavailability in Phosphate Amended Soils. AB - In this study, the in vitro bioaccessibility (IVBA) of lead (Pb) in phosphate amended Pb-contaminated soil was assessed using a variety of IVBA assays with an overarching aim of determining whether changes in Pb IVBA were congruent to those observed for Pb relative bioavailability (RBA) determined using an in vivo mouse assay. Amending soil with phosphoric acid or rock phosphate resulted in changes in Pb speciation, however, varying Pb IVBA results were obtained depending on the methodology utilized. In addition, IVBA assays influenced Pb speciation as a consequence of interactions between dissolved Pb and unreacted phosphate arising from the amendment or from assay constituents. When the relationship between Pb RBA and IVBA was assessed, a comparison of treatment effect ratios (Pb RBA or IVBA in treated soil divided by Pb RBA or IVBA for untreated soil) provided the best in vivo-in vitro correlation particular for SBRC (r2 = 0.83) and IVG (r2 = 0.89) intestinal extraction. For these assays, the slope of the lines of best fit were close to 1 (1.12, 0.82; SBRC, IVG intestinal extraction respectively) with small y-intercepts (0.09, 0.08 respectively) indicating that the efficacy of phosphate amendments for reducing Pb RBA may be predicted using IVBA assays. PMID- 27934281 TI - The Estimated Six-Year Mercury Dry Deposition Across North America. AB - Dry deposition of atmospheric mercury (Hg) to various land covers surrounding 24 sites in North America was estimated for the years 2009 to 2014. Depending on location, multiyear mean annual Hg dry deposition was estimated to range from 5.1 to 23.8 MUg m-2 yr-1 to forested canopies, 2.6 to 20.8 MUg m-2 yr-1 to nonforest vegetated canopies, 2.4 to 11.2 MUg m-2 yr-1 to urban and built up land covers, and 1.0 to 3.2 MUg m-2 yr-1 to water surfaces. In the rural or remote environment in North America, annual Hg dry deposition to vegetated surfaces is dominated by leaf uptake of gaseous elemental mercury (GEM), contrary to what was commonly assumed in earlier studies which frequently omitted GEM dry deposition as an important process. Dry deposition exceeded wet deposition by a large margin in all of the seasons except in the summer at the majority of the sites. GEM dry deposition over vegetated surfaces will not decrease at the same pace, and sometimes may even increase with decreasing anthropogenic emissions, suggesting that Hg emission reductions should be a long-term policy sustained by global cooperation. PMID- 27934282 TI - Future Impacts of Hydroelectric Power Development on Methylmercury Exposures of Canadian Indigenous Communities. AB - Developing Canadian hydroelectric resources is a key component of North American plans for meeting future energy demands. Microbial production of the bioaccumulative neurotoxin methylmercury (MeHg) is stimulated in newly flooded soils by degradation of labile organic carbon and associated changes in geochemical conditions. We find all 22 Canadian hydroelectric facilities being considered for near-term development are located within 100 km of indigenous communities. For a facility in Labrador, Canada (Muskrat Falls) with planned completion in 2017, we probabilistically modeled peak MeHg enrichment relative to measured baseline conditions in the river to be impounded, downstream estuary, locally harvested fish, birds and seals, and three Inuit communities. Results show a projected 10-fold increase in riverine MeHg levels and a 2.6-fold increase in estuarine surface waters. MeHg concentrations in locally caught species increase 1.3 to 10-fold depending on time spent foraging in different environments. Mean Inuit MeHg exposure is forecasted to double following flooding and over half of the women of childbearing age and young children in the most northern community are projected to exceed the U.S. EPA's reference dose. Equal or greater aqueous MeHg concentrations relative to Muskrat Falls are forecasted for 11 sites across Canada, suggesting the need for mitigation measures prior to flooding. PMID- 27934283 TI - A Method for Seawater Desalination via Squeezing Ionic Hydrogels. AB - In this study, mechanical force applied to squeeze poly(sodium acrylate-co-2 hydroxyethyl methacrylate) hydrogels that contained seawater in order to obtain fresh water. By incorporating ionic monomer sodium acrylate (SA) into hydrogels, the salt rejection was significantly enhanced from 27.62% to 64.57% (feed concentration 35.00g/L NaCl solution). As SA's concentration continuously increased, salt rejection declined due to the change in hydrogel's matrix structure. Therefore, water recovery raised as the current swelling degree increased. We also measured pore size distribution by applying mercury intrusion porosimetry on each hydrogel sample in the interest of finding out whether the sample SA5/HEMA15 owned multi pore structure, since the result could be good for the desalination performance. After 4 times reused, the hydrogel remained good desalination performance. Although compared to reverse osmosis (RO) and multistage flash distillation (MSF) & multiple effect distillation (MED) the salt rejection of this hydrogel (roughly 64%) seemed low, the hydrogels can be used for forward osmosis and reverse osmosis, as pretreatment of seawater to reduce the energy consumption for the downstream. PMID- 27934284 TI - Which Molecular Features Affect the Intrinsic Hepatic Clearance Rate of Ionizable Organic Chemicals in Fish? AB - Greater knowledge of biotransformation rates for ionizable organic compounds (IOCs) in fish is required to properly assess the bioaccumulation potential of many environmentally relevant contaminants. In this study, we measured in vitro hepatic clearance rates for 50 IOCs using a pooled batch of liver S9 fractions isolated from rainbow trout (Oncorhynchus mykiss). The IOCs included four types of strongly ionized acids (carboxylates, phenolates, sulfonates, and sulfates), three types of strongly ionized bases (primary, secondary, tertiary amines), and a pair of quaternary ammonium compounds (QACs). Included in this test set were several surfactants and a series of beta-blockers. For linear alkyl chain IOC analogues, biotransformation enzymes appeared to act directly on the charged terminal group, with the highest clearance rates for tertiary amines and sulfates and no clearance of QACs. Clearance rates for C12-IOCs were higher than those for C8-IOC analogues. Several analogue series with multiple alkyl chains, branched alkyl chains, aromatic rings, and nonaromatic rings were evaluated. The likelihood of multiple reaction pathways made it difficult to relate all differences in clearance to specific molecular features the tested IOCs. Future analysis of primary metabolites in the S9 assay is recommended to further elucidate biotransformation pathways for IOCs in fish. PMID- 27934285 TI - In Situ Nanoscale Imaging of Struvite Formation during the Dissolution of Natural Brucite: Implications for Phosphorus Recovery from Wastewaters. AB - As phosphorus (P) resources are diminishing, the recovery of this essential nutrient from wastewaters becomes an increasingly interesting option. P-recovery through the controlled crystallization of struvite (MgNH4PO4.6H2O), a potential slow-release fertilizer, is highly attractive, but costly if large amounts of Mg have to be added. In this context, natural Mg-minerals like brucite (Mg(OH)2) could provide more cost-effective Mg-sources compared to high-grade Mg-compounds such as MgCl2. Here we used in situ atomic force microscopy (AFM) to study the interactions of ammonium phosphate solutions with brucite (001) cleavage surfaces. Brucite dissolution was strongly enhanced in the presence of H2PO4- ions, most likely due to the formation of negatively charged surface complexes. Simultaneously with brucite dissolution, we directly observed the formation of a new phase that was identified as struvite by Raman spectroscopy. Our results suggest that brucite dissolution and struvite precipitation were coupled at the mineral-fluid interface within a thin fluid boundary layer. An interpretation is proposed where the heterogeneous nucleation and growth of struvite occurs via a particle-mediated process involving the formation of primary nanoparticles, followed by their continuous aggregation, fusion and possible transformation to crystalline struvite. These observations have implications for the feasibility of using brucite in phosphorus recovery processes. PMID- 27934286 TI - Selection and Application of Sulfide Oxidizing Microorganisms Able to Withstand Thiols in Gas Biodesulfurization Systems. AB - After the first commercial applications of a new biological process for the removal of hydrogen sulfide (H2S) from low pressure biogas, the need arose to broaden the operating window to also enable the removal of organosulfur compounds from high pressure sour gases. In this study we have selected microorganisms from a full-scale biodesulfurization system that are capable of withstanding the presence of thiols. This full-scale unit has been in stable operation for more than 10 years. We investigated the microbial community by using high-throughput sequencing of 16S rRNA gene amplicons which showed that methanethiol gave a competitive advantage to bacteria belonging to the genera Thioalkalibacter (Halothiobacillaceae family) and Alkalilimnicola (Ectothiorhosdospiraceae family). The sulfide-oxidizing potential of the acclimatized population was investigated under elevated thiol loading rates (4.5-9.1 mM d-1), consisting of a mix of methanethiol, ethanethiol, and propanethiol. With this biomass, it was possible to achieve a stable bioreactor operation at which 80% of the supplied H2S (61 mM d-1) was biologically oxidized to elemental sulfur. The remainder was chemically produced thiosulfate. Moreover, we found that a conventionally applied method for controlling the oxygen supply to the bioreactor, that is, by maintaining a redox potential set-point value, appeared to be ineffective in the presence of thiols. PMID- 27934287 TI - Mutagenic Azo Dyes, Rather Than Flame Retardants, Are the Predominant Brominated Compounds in House Dust. AB - Characterization of toxicological profiles by use of traditional targeted strategies might underestimate the risk of environmental mixtures. Unbiased identification of prioritized compounds provides a promising strategy for meeting regulatory needs. In this study, untargeted screening of brominated compounds in house dust was conducted using a data-independent precursor isolation and characteristic fragment (DIPIC-Frag) approach, which used data-independent acquisition (DIA) and a chemometric strategy to detect peaks and align precursor ions. A total of 1008 brominated compound peaks were identified in 23 house dust samples. Precursor ions and formulas were identified for 738 (73%) of the brominated compounds. A correlation matrix was used to cluster brominated compounds; three large groups were found for the 140 high-abundance brominated compounds, and only 24 (17%) of these compounds were previously known flame retardants. The predominant class of unknown brominated compounds was predicted to consist of nitrogen-containing compounds. Following further validation by authentic standards, these compounds (56%) were determined to be novel brominated azo dyes. The mutagenicity of one major component was investigated, and mutagenicity was observed at environmentally relevant concentrations. Results of this study demonstrated the existence of numerous unknown brominated compounds in house dust, with mutagenic azo dyes unexpectedly being identified as the predominant compounds. PMID- 27934288 TI - Development of an Enzyme-Linked Immunosorbent Assay for the Detection of Tyramine as an Index of Freshness in Meat and Seafood. AB - A competitive indirect enzyme-linked immunosorbent assay (ciELISA) using a polyclonal antibody was developed to detect tyramine in meat and seafood. This ciELISA had a 50% inhibition concentration (IC50) of 0.20 mg/L and a limit of detection (LOD) of 0.02 mg/L and showed no cross-reactivity with tyrosine or other biogenic amines. The average recoveries of tyramine from spiked samples for this ciELISA ranged from 85.6 to 102.6%, and the results exhibited good correlation with high-performance liquid chromatography (HPLC) results. The LOD of this assay for tyramine in meat and seafood samples was 1.20 mg/kg. The ciELISA was successfully applied to detect tyramine in positive fish samples, and the results were validated by HPLC to be reliable. The developed ciELISA allows for the rapid, specific, and accurate detection of tyramine in meat and seafood samples, and it could be a potentially useful tool for the evaluation of the freshness of protein-rich foods. PMID- 27934290 TI - Correction to 2-Furoylglycine as a Candidate Biomarker of Coffee Consumption. PMID- 27934289 TI - Schistosomicidal Activity of Alkyl-phenols from the Cashew Anacardium occidentale against Schistosoma mansoni Adult Worms. AB - Bioassay-guided study of the ethanol extract from the cashew Anacardium occidentale furnished cardol triene (1), cardol diene (2), anacardic acid triene (3), cardol monoene (4), anacardic acid diene (5), 2-methylcardol triene (6), and 2-methylcardol diene (7). 1D- and 2D-NMR experiments and HRMS analysis confirmed the structures of compounds 1-7. Compounds 2 and 7 were active against Schistosoma mansoni adult worms in vitro, with LC50 values of 32.2 and 14.5 MUM and selectivity indices of 6.1 and 21.2, respectively. Scanning electron microscopy of the tegument of male worms in the presence of compound 7 at 25 MUM after 24 h of incubation showed severe damage as well as peeling and reduction in the number of spine tubercles. Transmission electron microscopy analyses revealed swollen mitochondrial membrane, vacuoles, and altered tegument in worms incubated with compound 2 (25 MUM after 24 h). Worms incubated with compound 7 (25 MUM after 24 h) had lysed interstitial tissue, degenerated mitochondria, and drastically altered tegument. Together, the results indicated that compound 7 presents promising in vitro schistosomicidal activity. PMID- 27934291 TI - Antiprotozoal Effects of the Tomato Tetrasaccharide Glycoalkaloid Tomatine and the Aglycone Tomatidine on Mucosal Trichomonads. AB - The present study investigated the inhibitory effects of the commercial tetrasaccharide tomato glycoalkaloid tomatine and the aglycone tomatidine on three mucosal pathogenic protozoa that are reported to infect humans, cattle, and cats, respectively: Trichomonas vaginalis strain G3, Tritrichomonas foetus strain D1, and Tritrichomonas foetus strain C1. A preliminary screen showed that tomatine at 100 MUM concentration completely inhibited the growth of all three trichomonads. In contrast, the inhibition of all three pathogens by tomatidine was much lower, suggesting the involvement of the lycotetraose carbohydrate side chain in the mechanism of inhibition. Midpoints of concentration-response sigmoid plots of tomatine on the three strains correspond to IC50 values, the concentration that inhibits 50% of growth of the pathogenic protozoa. The concentration data were used to calculate the IC50 values for G3, D1, and C1 of 7.9, 1.9, and 2.2 MUM, respectively. The results show an approximately 4-fold variation from the lowest to the highest value (lowest activity). Although the inhibition by tomatine was not as effective as that of the medicinal drug metronidazole, the relatively low IC50 values for both T. vaginalis and T. foetus indicated tomatine as a possible natural alternative therapeutic for trichomoniasis in humans and food-producing (cattle and pigs) and domestic (cats) animals. Because tomatine has the potential to serve as a new antiprotozoan functional (medical) food, the distribution of this glycoalkaloid in tomatoes and suggestions for further research are discussed. PMID- 27934292 TI - Rice Koji Extract Enhances Lipid Metabolism through Proliferator-Activated Receptor Alpha (PPARalpha) Activation in Mouse Liver. AB - Koji is made from grains fermented with Aspergillus oryzae and is essential for the production of many traditional Japanese foods. Many previous studies have shown that koji contributes to the improvement of dyslipidemia. However, little is known regarding the underlying mechanism of this effect. Furthermore, the compound contributing to the activation of lipid metabolism is unknown. We demonstrated that rice koji extract (RKE) induces the mRNA expression of peroxisome proliferator-activated receptor alpha (PPARalpha) target genes, which promotes lipid metabolism in murine hepatocytes. This effect was not observed in PPARalpha-KO hepatocytes. We also demonstrated that RKE contained linolenic acid (LIA), oleic acid (OA), and hydroxyoctadecadienoic acids (HODEs), which activate PPARalpha, using LC-MS analysis. Our findings suggest that RKE, containing LIA, OA, and HODEs, could be valuable in improving dyslipidemia via PPARalpha activation. PMID- 27934293 TI - Fate of Anthocyanins through Cocoa Fermentation. Emergence of New Polyphenolic Dimers. AB - Fresh, ripe cocoa beans from Cameroon (German cocoa/Amelonado group and ICS 40/Trinitario group) were subjected to fermentation-like incubations in acetic acid, lactic acid, or both and to natural fermentation. Two naturally fermented samples from Cuba (UF 654/Trinitario group and C 411/Criollo group) were also investigated. Both cyanidin-3-galactoside and cyanidin-3-arabinoside (found as major anthocyanins in colored beans only) were drastically degraded through fermentation, especially in small beans and in the presence of acetic acid. On the other hand, emergence of a cyanidin-rhamnose isomer was evidenced, even in Criollo beans. In addition to the recently described structures F1 and F2 [m/z = 575 in ESI(-)], three additional polyphenolic structures [F3, F4, and F5; m/z = 557 in ESI(+)] were found after fermentation, the two former ones resulting from epicatechin oxidation. Synthesis of F5 requires an interclass reaction between cyani(di)n and epicatechin, which explains its absence in fermented Criollo beans. PMID- 27934294 TI - Label-free Proteomic Reveals that Cowpea Severe Mosaic Virus Transiently Suppresses the Host Leaf Protein Accumulation During the Compatible Interaction with Cowpea (Vigna unguiculata [L.] Walp.). AB - Viruses are important plant pathogens that threaten diverse crops worldwide. Diseases caused by Cowpea severe mosaic virus (CPSMV) have drawn attention because of the serious damages they cause to economically important crops including cowpea. This work was undertaken to quantify and identify the responsive proteins of a susceptible cowpea genotype infected with CPSMV, in comparison with mock-inoculated controls, using label-free quantitative proteomics and databanks, aiming at providing insights on the molecular basis of this compatible interaction. Cowpea leaves were mock- or CPSMV-inoculated and 2 and 6 days later proteins were extracted and analyzed. More than 3000 proteins were identified (data available via ProteomeXchange, identifier PXD005025) and 75 and 55 of them differentially accumulated in response to CPSMV, at 2 and 6 DAI, respectively. At 2 DAI, 76% of the proteins decreased in amount and 24% increased. However, at 6 DAI, 100% of the identified proteins increased. Thus, CPSMV transiently suppresses the synthesis of proteins involved particularly in the redox homeostasis, protein synthesis, defense, stress, RNA/DNA metabolism, signaling, and other functions, allowing viral invasion and spread in cowpea tissues. PMID- 27934296 TI - Identification of Candidate Host Cell Factors Required for Actin-Based Motility of Burkholderia pseudomallei. AB - Intracellular actin-based motility of the melioidosis pathogen Burkholderia pseudomallei requires the bacterial factor BimA. Located at one pole of the bacterium, BimA recruits and polymerizes cellular actin to promote bacterial motility within and between cells. Here, we describe an affinity approach coupled with mass spectrometry to identify cellular proteins recruited to BimA-expressing bacteria under conditions that promote actin polymerization. We identified a group of cellular proteins that are recruited to the B. pseudomallei surface in a BimA-dependent manner, a subset of which were independently validated with specific antisera including the ubiquitous scaffold protein Ras GTPase-activating like protein (IQGAP1). IQGAP1 integrates several key cellular signaling pathways including those involved in actin dynamics and has been shown to be involved in the adhesion of attaching and effacing Escherichia coli to infected cells and invasion of host cells by Salmonella enterica serovar Typhimurium. Although a direct interaction between BimA and IQGAP1 could not be detected using either conventional pulldown or yeast two hybrid techniques, confocal microscopy revealed that IQGAP1 is recruited to B. pseudomallei actin tails in infected cells, and siRNA-mediated knockdown highlighted a role for this protein in controlling the length and actin density of B. pseudomallei actin tails. PMID- 27934295 TI - Activity-Based Protein Profiling Shows Heterogeneous Signaling Adaptations to BRAF Inhibition. AB - Patients with BRAF V600E mutant melanoma are typically treated with targeted BRAF kinase inhibitors, such as vemurafenib and dabrafenib. Although these drugs are initially effective, they are not curative. Most of the focus to date has been upon genetic mechanisms of acquired resistance; therefore, we must better understand the global signaling adaptations that mediate escape from BRAF inhibition. In the current study, we have used activity-based protein profiling (ABPP) with ATP-analogue probes to enrich kinases and other enzyme classes that contribute to BRAF inhibitor (BRAFi) resistance in four paired isogenic BRAFi naive/resistant cell line models. Our analysis showed these cell line models, which also differ in their PTEN status, have considerable heterogeneity in their kinase ATP probe uptake in comparing both naive cells and adaptations to chronic drug exposure. A number of kinases including FAK1, SLK, and TAOK2 had increased ATP probe uptake in BRAFi resistant cells, while KHS1 (M4K5) and BRAF had decreased ATP probe uptake in the BRAFi-resistant cells. Gene ontology (GO) enrichment analysis revealed BRAFi resistance is associated with a significant enhancement in ATP probe uptake in proteins implicated in cytoskeletal organization and adhesion, and decreases in ATP probe uptake in proteins associated with cell metabolic processes. The ABPP approach was able to identify key phenotypic mediators critical for each BRAFi resistant cell line. Together, these data show that common phenotypic adaptations to BRAF inhibition can be mediated through very different signaling networks, suggesting considerable redundancy within the signaling of BRAF mutant melanoma cells. PMID- 27934297 TI - Schistosomiasis and soil-transmitted helminthiases: number of people treated in 2015. PMID- 27934298 TI - The Way Forward in Molecular Electrocatalysis. PMID- 27934300 TI - Tuning the Photophysics and Reverse Saturable Absorption of Heteroleptic Cationic Iridium(III) Complexes via Substituents on the 6,6'-Bis(fluoren-2-yl)-2,2' biquinoline Ligand. AB - To understand the effects of the terminal substituent at the diimine ligand on the photophysics of heteroleptic cationic Ir(III) complexes and to obtain Ir(III) complexes with extended ground-state absorption to the near-IR region while retaining the long-lived and broadly absorbing triplet excited state, we synthesized three heteroleptic cationic iridium(III) complexes bearing cyclometalating 1-phenylisoquinoline (C^N) ligands and substituted 6,6'-bis(7-R fluoren-2-yl)-2,2'-biquinoline (N^N) ligand (R = H, NO2, or NPh2). The photophysics of these complexes was systematically investigated via spectroscopic methods and time-dependent density functional theory. All complexes possess strong ligand-localized 1pi,pi* transitions mixed with ligand-to-ligand charge transfer (1LLCT)/metal-to-ligand charge transfer (1MLCT) transitions below 400 nm, and a broad and featureless absorption band above 400 nm that arises from the N^N ligand-localized 1pi,pi*/1ILCT (intraligand charge transfer) transitions as well as the very weak 1,3LLCT/1,3MLCT transitions at longer wavelengths. The electron-withdrawing NO2 substituent on the N^N ligand leads to a blue-shift of the 1pi,pi*/1ILCT absorption band, while the electron-donating NPh2 substituent causes a pronounced red-shift of this band. The unsubstituted and NO2-substituted complexes (complexes 1 and 2, respectively) are moderately emissive at room temperature (RT) in solution as well as at 77 K in the glassy matrix, while the NPh2-substituted complex (3) is weakly emissive at RT, but the emission becomes much brighter at 77 K. Complexes 1 and 2 show very broad and strong triplet excited-state absorption from 460 to 800 nm with moderately long lifetimes, while complex 3 exhibits weak but broad absorption bands from 384 to 800 nm with a longer lifetime than those of 1 and 2. The nonlinear transmission experiment manifests that complexes 1 and 2 are strong reverse saturable absorbers (RSA) at 532 nm, while 3 shows weaker RSA at this wavelength. These results clearly demonstrate that it is feasible to tune the ground-state and excited-state properties of the Ir(III) complexes via the terminal substituents at the diimine ligand. By introducing the fluoren-2-yl groups to the 2,2'-biquinoline ligand to extend the diimine ligand pi-conjugation, we can obtain Ir(III) complexes with reasonably long-lived and strongly absorbing triplet excited state while red shifting their 1,3LLCT/1,3MLCT absorption band into the near-IR region. These features are critical in developing visible to near-IR broadband reverse saturable absorbers. PMID- 27934299 TI - Interaction of the HIV NCp7 Protein with Platinum(II) and Gold(III) Complexes Containing Tridentate Ligands. AB - The human immunodeficiency virus (HIV) nucleocapsid protein (NCp7) plays significant roles in the virus life cycle and has been targeted by compounds that could lead to its denaturation or block its interaction with viral RNA. Herein, we describe the interactions of platinum(II) and gold(III) complexes with NCp7 and how the reactivity/affinity of potential inhibitors can be modulated by judicious choice of ligands. The interactions of [MCl(N3)]n+ (M = Pt2+ (n = 1) and Au3+ (n = 2); N3 = tridentate chelate ligands: bis(2 pyridylmethyl)methylamine (Mebpma, L1) and bis(2-pyridylmethyl)amine (bpma, L2) with the C-terminal zinc finger of NCp7 (ZF2) were investigated by electrospray ionization-mass spectroscopy (ESI-MS). Mass spectra from the incubation of [MCl(Mebpma)]n+ complexes (PtL1 and AuL1) with ZF2 indicated that they were more reactive than the previously studied diethylenetriamine-containing analogues [MCl(dien)]n+. The initial product of reaction of PtL1 with ZF2 results in loss of all ligands and release of zinc to give the platinated apopeptide {PtF} (F = apopeptide). This is in contrast to the incubation with [PtCl(dien)]+, in which {Pt(dien)}-peptide adducts are observed. Incubation of the Au3+ complex AuL1 with ZF2 gave AuxFn+ species (x = 1, 2, 4, F = apopeptide) again with loss of all ligands. Furthermore, the formally substitution-inert analogues [Pt(N3)L]2+ (L = 4-methylpyridine (4-pic), 4-dimethylaminopyridine (dmap), and 9-ethylguanine (9 EtGua)) were prepared to examine stacking interactions with N-acetyltryptophan (N AcTrp), the Trp-containing ZF2, and the "full" two-finger NCp7 itself using fluorescence quenching titration. Use of bpma and Mebpma gave slightly higher affinity than analogous [Pt(dien)L)]2+ complexes. The dmap-containing complexes (PtL1a and PtL2a) had the greatest association constants (Ka) for N-AcTrp and ZF2 peptide. The complex PtL1a had the highest Ka when compared with other known Pt2+ analogues: [Pt(dien)(9-EtGua)]2+ < [Pt(bpma)(9-EtGua)]2+ < [Pt(dien)(dmap)]2+< PtL2a < PtL1a. A Ka value of ca. 40.6 +/- 1.0 * 103 M-1 was obtained for the full NCp7 peptide with PtL1a. In addition, the mass spectrum of the interaction between ZF2 and PtL1a confirms formation of a 1:1 PtL1a/ZF2 adduct. The reactivity of selected complexes with sulfur-containing amino acid N acetylcysteine (N-AcCys) was also investigated by 195Pt and 1H NMR spectroscopy and ESI-MS. The precursor compounds [PtCl(N3)]+ PtL1 and PtL2 reacted readily, whereas their [Pt(N3)L]2+ analogues PtL1a and PtL2a were inert to substitution. PMID- 27934301 TI - Coordination-Induced Molecular Tweezing: Ruthenium Clusters Docked at Azuliporphyrinogens. AB - The reaction of [Ru3(CO)12] with a series of conformationally flexible thiaazuliporphyrinogens, namely, dithiadiazuli-, thiatriazuli- and tetraazuliporphyrinogen, yielded a series of complexes with two azulene rings coordinated by either Ru2(CO)5 and Ru4(CO)9 or two Ru4(CO)9 clusters. For dithiadiazuliporphyrinogen, three fundamental arrangements were detected, with two clusters being located at the same side or different sides of the meso plane. Coordination altered the electron density on the rings, allowing for dispersion promoted interactions between coordinated azulenes. To create this face-to-face arrangement, the ligand framework performs a tweezing movement with coordinated azulenes approaching each other. The tweezer-like arrangement of the coordinated azulene rings assists the formation of azulene inclusion complexes as determined by 1H NMR titration. PMID- 27934302 TI - Multifunctional Metal-Organic Frameworks with Fluorescent Sensing and Selective Adsorption Properties. AB - Metal-organic frameworks (MOFs) have attracted great attention in the past years due to their diverse structures as well as interesting properties. However, MOFs with multifunctionality are still challenging. Under solvothermal conditions, reactions of 1,3,5-tris(1-imidazolyl)benzene (tib) and 4,4',4"-benzene-1,3,5 triyl-tribenzoic acid (H3BTB) with Cd(II) salt give rise to two novel MOFs [Cd3(tib)2(BTB)2].3DEF.4.5H2O (1) and [Cd3(tib)2(BTB)2(DMA)2(H2O)2].2DMA.8H2O (2) (DEF = N,N-diethylformamide, DMA = N,N-dimethylacetamide) with three-dimensional framework structures. It is fascinating that 1 and 2 not only show unique selectivity for detection of acetone through fluorescence quenching mechanism but also exhibit selective adsorption of gas (CO2 over N2 at 298 K) and dye (methyl orange) molecules. PMID- 27934303 TI - Solvent-Dependent Thermochemistry of an Iridium/Ruthenium H2 Evolution Catalyst. AB - The hydricity of the heterobimetallic iridium/ruthenium catalyst [Cp*Ir(H)(MU bpm)Ru(bpy)2]3+ (1, where Cp* = eta5-pentamethylcyclopentadienyl, bpm = 2,2' bipyrimidine, and bpy = 2,2'-bipyridine) has been determined in both acetonitrile (63.1 kcal mol-1) and water (29.7 kcal mol-1). Hydride 1 features a large increase in the hydride donor ability when the solvent is changed from acetonitrile to water. The acidity of 1, in contrast, is essentially solvent independent because 1 remains strongly acidic in both solvents. On the basis of an X-ray crystallographic study, spectroscopic analysis, and time-dependent density functional theory calculations, the disparate reactivity trends are ascribed to substantial delocalization of the electron density onto both the bpm and bpy ligands in the conjugate base of 1, [Cp*Ir(MU-bpm)Ru(bpy)2]2+ (3). The H2 evolution tendencies of 1 are considered in the context of thermodynamic parameters. PMID- 27934304 TI - Regulation of NO Uptake in Flexible Ru Dimer Chain Compounds with Highly Electron Donating Dopants. AB - On-demand design of porous frameworks for selective capture of specific gas molecules, including toxic gas molecules such as nitric oxide (NO), is a very important theme in the research field of molecular porous materials. Herein, we report the achievement of highly selective NO adsorption through chemical doping in a framework (i.e., solid solution approach): the highly electron donating unit [Ru2(o-OMePhCO2)4] (o-OMePhCO2- = o-anisate) was transplanted into the structurally flexible chain framework [Ru2(4-Cl-2-OMePhCO2)4(phz)] (0; 4-Cl-2 OMePhCO2- = 4-chloro-o-anisate and phz = phenazine) to obtain a series of doped compounds, [{Ru2(4-Cl-2-OMePhCO2)4}1-x{Ru2(o-OMePhCO2)4}x(phz)] (x = 0.34, 0.44, 0.52, 0.70, 0.81, 0.87), with [Ru2(o-OMePhCO2)4(phz)] (1) as x = 1. The original compound 1 was made purely from a "highly electron donating unit" but had no adsorption capability for gases because of its nonporosity. Meanwhile, the partial transplant of the electronically advantageous [Ru2(o-OMePhCO2)4] unit with x = 0.34-0.52 in 0 successfully enhanced the selective adsorption capability of NO in an identical structurally flexible framework; an uptake at 95 kPa that was 1.7-3 mol/[Ru2] unit higher than that of the original 0 compound was achieved (121 K). The solid solution approach is an efficient means of designing purposeful porous frameworks. PMID- 27934306 TI - A Polar Titanium-Organic Chain with a Very Large Second-Harmonic-Generation Response. AB - A noncentrosymmetric (NCS) titanium-organic compound, [H2N(CH3)2]TiO{[NC5H3(CO2)2][NC5H4(CO2)]} (CAUMOF-18), has been synthesized by a solvothermal reaction. The aligned unidimensional polar chain structure of CAUMOF 18 consisting of corner-shared distorted TiO5N2 pentagonal bipyramids is attributed to strong hydrogen-bonding and pi-pi interactions. CAUMOF-18 reveals a very strong second-harmonic-generation efficiency of 400 times that of alpha-SiO2 and is phase-matchable (type I). Water-molecule-driven reversible centricity conversion and topotactic transformation to TiO2 microrods for CAUMOF-18 are also presented. PMID- 27934305 TI - Gear Up for a pH Shift: A Responsive Iron(II) 2-Amino-6-picolyl-Appended Macrocyclic paraCEST Agent That Protonates at a Pendent Group. AB - Two high-spin Fe(II) and Co(II) complexes of 1,4,7,10-tetraazacyclododecane (CYCLEN) appended with four 2-amino-6-picolyl groups, denoted as [Fe(TAPC)]2+ and [Co(TAPC)]2+, are reported. These complexes demonstrate C2-symmetrical geometry from coordination of two pendents, and they are present in a single diastereomeric form in aqueous solution as shown by 1H NMR spectroscopy and by a single-crystal X-ray structure for the Co(II) complex. A highly shifted but low intensity CEST (chemical exchange saturation transfer) signal from NH groups is observed at -118 ppm for [Co(TAPC)]2+ at pH 6.0 and 37 degrees C. A higher intensity CEST peak is observed for [Fe(TAPC)]2+, which demonstrates a pH dependent frequency shift from -72 to -79 ppm at pH 7.7 to 4.8, respectively, at 37 degrees C. This shift in the CEST peak correlates with the protonation of the unbound 2-amino-6-picolyl pendents, as suggested by UV-vis and 1H NMR spectroscopy studies at different pH values. Phantom imaging demonstrates the challenges and feasibility of using the [Fe(TAPC)]2+ agent on a low-field MRI scanner. The [Fe(TAPC)]2+ complex is the first transition-metal-based paraCEST agent that produces a pH-induced CEST frequency change toward the development of probes for concentration-independent imaging of pH. PMID- 27934307 TI - A Postsynthetic Modified MOF Hybrid as Heterogeneous Photocatalyst for alpha Phenethyl Alcohol and Reusable Fluorescence Sensor. AB - The recent discovery of lanthanide-based metal-organic frameworks (Ln-MOFs) offers the potential to extend the chemical sensing and catalysis capabilities of metal-organic frameworks (MOFs). Herein, a new europium functionalized material based on MIL-125(Ti)-NH2 is synthesized by covalent postsynthetic modification and shows photocatalytic oxidation properties of alpha-phenethyl alcohol, and their fluorescence quenching behaviors are investigated. The catalytic efficiency is tested by monitoring the photocatalytic oxidation of alpha-phenethyl alcohol under ultraviolet light irradiation. Furthermore, MIL-125(Ti)-AM-Eu is developed as a fluorescence sensor integrated with its photocatalytic and luminescent properties. The MIL-125(Ti)-AM-Eu is used for detecting alpha-phenethyl alcohol, which could be successfully oxidized to acetophenone by the catalyst, and the fluorescence of MIL-125(Ti)-AM-Eu has changed accordingly. PMID- 27934308 TI - Structural Stability and Anharmonicity of Pr2Ti2O7: Raman Spectroscopic and XRD Studies. AB - Herein we report results of pressure- and temperature-dependent Raman scattering studies on Pr2Ti2O7. Pressure-dependent studies performed up to 23 GPa suggest a reversible phase transition above 15 GPa with subtle changes. Temperature dependent investigations performed in the range of 77-1073 K showed anomalous temperature dependence of some of the Raman modes. Temperature-dependent X-ray diffraction data indicated no structural transition but nonlinear expansion of unit-cell parameters with increasing temperature. With increasing temperature, the structure dilates anisotropically, and volume of coordination polyhedra around all the atoms expands. Also with increasing temperature the distortions in coordination polyhedra around all the atoms decrease, and appreciable decrease is observed in Pr(1)O10 and Pr(3)O9 units. The pressure evolution of Raman-mode frequencies was analyzed for both ambient as well as high-pressure phases, and mode Gruneisen parameters for ambient pressure phase were obtained. The temperature evolution of Raman-mode frequencies was analyzed to obtain the explicit and implicit anharmonic components, and it was found that some of the modes attributable to TiO6 octahedra and PrOn polyhedra have dominating explicit anharmonic component. Comparison of the structural data with the temperature dependence of Raman modes suggests that the anomalous behavior in Raman modes is due to phonon-phonon interaction. PMID- 27934309 TI - Redox-Active Metallacarborane-Decorated Octasilsesquioxanes. Electrochemical and Thermal Properties. AB - Polyanionic and electroactive hybrids based on octasilsesquioxanes bearing metallacarborane units are developed. They show remarkable solubility in organic solvents and outstanding thermal stability. The metallacarboranes act as independent units simultaneously undergoing the reversible redox process. PMID- 27934310 TI - Cyclic Trinuclear Gold(I) Clusters with N,N and Unusual C,C Mixed-Ligand Bridges. AB - Three crystalline trinuclear gold(I) clusters, [Au3f2y] (1), [Au3fy2] (2), and [Au3y3] (3), where f = N,N'-bis(2,6-dimethylphenyl)methanimidamidate and y = dimethylendiphenylphosphinate, exhibit bridges from the N,N-formamidinate and/or from the ylide anion ligand whose P-methylene groups chelate in an unusual fashion, where the chelate CPC unit is perpendicular to the trigonal plane of the metal atoms. Assemblies 1 and 2 are the first gold(I) trinuclear clusters featuring mixed-ligand bridges from different N,N and C,C donors; 3 is a previously unknown homoleptic ylide anion cyclic trinuclear assembly. Formamidinate bridges in 1 and 2 connect gold(I) atoms at aurophilic distances of 3.084(2) and 3.0543(4) A, whereas an out-of-plane (perpendicular) P-ylide anion bite produces AuI-AuI distances of as large as 3.900(2) A in 3. The crystal space groups for 1 and 2 are triclinic P1 and that for 3 is monoclinic P21/c, with Z = 2 for 1 and 2 and Z = 4 for 3. Compounds are synthesized under Schlenk conditions at -20 degrees C in toluene by reacting the proper ratios of the gold(I) formamidinate [Au2f2] with the phosphorus ylide [Hy] under basic conditions (KOH), followed by extraction with ether. This synthesis also produces a dinuclear cation, [Au2f(Hy)2]+, previously reported by our group. A neutral mixed ligand dinuclear complex, [Au2fy], was not observed. Under UV light, 1 and 2 display a bright-green luminescence at room temperature and in frozen methyltetrahydrofuran solutions under liquid nitrogen, with microsecond lifetimes. All three complexes 1-3 are characterized by their X-ray crystal structures, 1H NMR, IR, UV-visible, and luminescence spectroscopies, and elemental analysis. PMID- 27934311 TI - A Switch-On NIR Probe for Specific Detection of Hg2+ Ion in Aqueous Medium and in Mitochondria. AB - A new 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based probe molecule (L) is synthesized for specific binding to Hg2+ ion in physiological condition with an associated luminescence ON response in the near-IR region of the spectrum. Appropriate functionalization in the 5-position of each of two pyrrole moieties with styryl functionality in a BODIPY core helped us in achieving the extended conjugation and a facile intramolecular charge transfer transition with a narrow energy gap for frontier orbitals. This accounted for a poor emission quantum yield for the probe molecule L. Binding to Hg2+ helped in interrupting the facile intramolecular charge transfer (ICT) process that was initially operational for L. This resulted in a hypsochromic shift of absorption band and a turn-on luminescence response with lambdaMaxEms of 650 nm on specific binding to Hg2+. Observed spectral changes are rationalized based on quantum chemical calculations. Interestingly, this reagent is found to be localized preferentially in the mitochondria of the live human colon cancer (Hct116) cells. Mitochondria is one of the major targets for localization of Hg2+, which actually decreases the mitochondrial membrane potential and modifies various proteins having sulfudryl functionality(ies) to cause cell apoptosis. Considering these, ability of the present reagent to specifically recognize Hg2+ in the mitochondrial region of the live Hct116 cells has significance. PMID- 27934312 TI - Structures, Phase Transformations, and Dielectric Properties of BiTaO4 Ceramics. AB - Low (alpha)- and high-temperature (beta) forms of BiTaO4 have attracted much attention due to their dielectric and photocatalytic properties. In the present work, a third form, the so-called HP-BiTaO4, was synthesized at high temperature and pressure. The phase evolution, phase transformations, and dielectric properties of alpha- and beta-BiTaO4 and HP-BiTaO4 ceramics are studied in detail. beta-BiTaO4 ceramics densified at 1300 degrees C with the microwave permittivity epsilonr ~ 53, the microwave quality factor Qf ~ 12070 GHz, and the temperature coefficient of resonant frequency tauf ~ -200 ppm/ degrees C. HP BiTaO4 ceramics were synthesized at 5 GPa and 1300 degrees C followed by annealing at 600 degrees C. In contrast with the alpha phase, HP-BiTaO4 exhibited epsilonr ~ 195 at 1 kHz to 10 MHz, accompanied by a low dielectric loss of ~0.004. The relation between structure and dielectric properties is discussed in the context of Shannon's additive rule and bond theory. PMID- 27934313 TI - Unusual Colorimetric Change for Alkane Solvents with a Porous Coordination Framework. AB - Alkane-selective colorimetric change from white to pink was observed with the simple system consisting of UiO-66 and 7-azaindole. The colorimetric change was strongly enhanced with increasing amounts of defects inside the UiO-66 framework, which indicates that interaction between the defects and 7-azaindole plays a pivotal role for this phenomenon. PMID- 27934314 TI - Iridium Cyclooctene Complex That Forms a Hyperpolarization Transfer Catalyst before Converting to a Binuclear C-H Bond Activation Product Responsible for Hydrogen Isotope Exchange. AB - [IrCl(COE)2]2 (1) reacts with pyridine (py) and H2 to form crystallographically characterized IrCl(H)2(COE)(py)2 (2). 2 undergoes py loss to form 16-electron IrCl(H)2(COE)(py) (3), with equivalent hydride ligands. When this reaction is studied with parahydrogen, 1 efficiently achieves hyperpolarization of free py (and nicotinamide, nicotine, 5-aminopyrimidine, and 3,5-lutudine) via signal amplification by reversible exchange (SABRE) and hence reflects a simple and readily available precatayst for this process. 2 reacts further over 48 h at 298 K to form crystallographically characterized (Cl)(H)(py)(MU-Cl)(MU-H)(kappa-MU NC5H4)Ir(H)(py)2 (4). This dimer is active in the hydrogen isotope exchange process that is used in radiopharmaceutical preparations. Furthermore, while [Ir(H)2(COE)(py)3]PF6 (6) forms upon the addition of AgPF6 to 2, its stability precludes its efficient involvement in SABRE. PMID- 27934315 TI - An Unprecedented M-O Cluster Constructed from Nanosized {[C5NH5]9[H31MoV12O24CoII12(PO4)23(H2O)4]}2- Anions Exhibiting Interesting Nonlinear-Optical Properties. AB - A novel high-nuclear nanosized cluster modified by conjugated organic ligands (pyridine and imidazole), [C5NH5]8[C3H5N2]2{[C5NH5]9[H31Mo12O24Co12(PO4)23(H2O)4]}.12H2O (1), has been successfully isolated under hydrothermal conditions and structurally characterized. Compound 1 consists of 12 CoII and 12 MoV ions linked by 23 {PO4} groups, exhibiting unprecedented nanosized ship-shaped clusters. The magnetic measurements reveal that compound 1 exhibits dominant antiferromagnetic interactions. Additionally, pyridine and imidazole ligands enhance the delocalized electron effects of clusters, and the third-order nonlinear-optical response of compound 1 is excellent. PMID- 27934316 TI - Multiple Bistability in Quinonoid-Bridged Diiron(II) Complexes: Influence of Bridge Symmetry on Bistable Properties. AB - Quinonoid bridges are well-suited for generating dinuclear assemblies that might display various bistable properties. In this contribution we present two diiron(II) complexes where the iron(II) centers are either bridged by the doubly deprotonated form of a symmetrically substituted quinonoid bridge, 2,5-bis[4 (isopropyl)anilino]-1,4-benzoquinone (H2L2') with a [O,N,O,N] donor set, or with the doubly deprotonated form of an unsymmetrically substituted quinonoid bridge, 2-[4-(isopropyl)anilino]-5-hydroxy-1,4-benzoquinone (H2L5') with a [O,O,O,N] donor set. Both complexes display temperature-induced spin crossover (SCO). The nature of the SCO is strongly dependent on the bridging ligand, with only the complex with the [O,O,O,N] donor set displaying a prominent hysteresis loop of about 55 K. Importantly, only the latter complex also shows a pronounced light induced spin state change. Furthermore, both complexes can be oxidized to the mixed-valent iron(II)-iron(III) form, and the nature of the bridge determines the Robin and Day classification of these forms. Both complexes have been probed by a battery of electrochemical, spectroscopic, and magnetic methods, and this combined approach is used to shed light on the electronic structures of the complexes and on bistability. The results presented here thus show the potential of using the relatively new class of unsymmetrically substituted bridging quinonoid ligands for generating intriguing bistable properties and for performing site-specific magnetic switching. PMID- 27934317 TI - Weak DyIII-DyIII Interactions in DyIII-Phthalocyaninato Multiple-Decker Single Molecule Magnets Effectively Suppress Magnetic Relaxation. AB - The DyIII quintuple-decker complex DyCdCdDy and hetero quadruple-decker complex DyCdY were synthesized, and their magnetic properties were compared with those of the quadruple-decker complex DyCdDy. Single-crystal X-ray analysis revealed that the coordination geometries around the DyIII ions of DyCdCdDy, DyCdY, and DyCdDy were similar. dc (direct current) magnetic measurements indicated that DyCdCdDy had very weak ferromagnetic DyIII-DyIII interactions but DyCdY did not. From a comparison of the magnetic relaxation times (tau) of the three complexes, the tau values of DyCdCdDy and DyCdDy, which have weak DyIII-DyIII interactions, are longer than that of DyCdY. In other words, weak DyIII-DyIII interactions effectively suppress magnetic relaxation. PMID- 27934318 TI - Cd3(MoO4)(TeO3)2: A Polar 3D Compound Containing d10-d0 SCALP-Effect Cations. AB - The new polar 3D cadmium molybdotellurite Cd3(MoO4)(TeO3)2 was obtained by means of a high-temperature solid-state method. Cd3(MoO4)(TeO3)2 is a monoclinic crystal system, and it exhibits the polar space group P21 (No. 4). The structure of Cd3(MoO4)(TeO3)2 can be viewed as a complicated 3D architecture that is composed of distorted CdOn (n = 6, 7) polyhedra, TeO3 trigonal pyramids, and MoO4 polyhedra. The compound features the first 3D NCS cadmium molybdotellurite with 1D 4- and 6-MR channels and a polar structure originating from the TeO3 groups, MoO4 groups, and displacements of d10 Cd2+ cations. The results were further confirmed by calculations of the net polarization. The UV-vis spectrum and thermal properties indicate that Cd3(MoO4)(TeO3)2 exhibits a broad transparent region and excellent thermal stability. SHG tests of Cd3(MoO4)(TeO3)2 revealed that its response is approximately the same as that of KH2PO4 at the same grain size between 105 and 150 MUm and that it is phase-matchable. PMID- 27934319 TI - Synthesis, Structure, and Anticancer Activity of Arene-Ruthenium(II) Complexes with Acylpyrazolones Bearing Aliphatic Groups in the Acyl Moiety. AB - A series of neutral ruthenium(II) arene complexes [(arene)Ru(QR)Cl] (arene = p cymene (cym) or hexamethylbenzene (hmb)) containing 4-acyl-5-pyrazolonate QR ligands with different electronic and steric substituents (R = 4-cyclohexyl, 4 stearoyl, or 4-adamantyl) and related ionic complexes [(arene)Ru(QR)(PTA)][PF6] (PTA = 1,3,5-triaza-7-phosphaadamantane) were synthesized and characterized by spectroscopy (IR, UV-vis, ESI-MS, and 1H and 13C NMR), elemental analysis, X-ray crystallography, and density functional theory studies. The cytotoxicity of the proligands and metal complexes was evaluated in vitro against human ovarian carcinoma cells (A2780 and A2780cisR), as well as against nontumorous human embryonic kidney (HEK293) cells. In general the cationic PTA-containing complexes are more cytotoxic than their neutral precursors with a chloride ligand in place of the PTA. Moreover, the complexes do not show cross-resistance and are essentially equally cytotoxic to both the A2780 and A2780cisR cell lines, although they only show limited selectivity toward the cancer cell lines. PMID- 27934320 TI - Oxygen Atom Transfer and Intramolecular Nitrene Transfer in a Rhenium beta Diketiminate Complex. AB - We present two routes to the oxo rhenium complex OReCl2(BDI) (1) (BDI = N,N' bis(2,6-diisopropylphenyl)-beta-diketiminate) and discuss the properties and reactivity of this material. Several adducts of 1 with DMAP (1-DMAP; DMAP = 4 dimethylaminopyridine), isonitriles (1-XylNC; XylNC = 2,6-dimethylphenyl isocyanide), and phosphines (1-PEt3; PEt3 = triethylphosphine) were isolated and characterized. Additionally, to probe the ancillary limitations of the BDI framework in high-valent rhenium complexes, oxygen atom transfer (OAT) reactivity with 1 was pursued. It was found that under thermolysis conditions OAT between 1 and PEt3 was observed by NMR spectroscopy, which indicated the formation of a new species, (ArN)ReCl2(MAD)(PEt3) (2; Ar = 2,6-diisopropylphenyl, MAD = 4-((2,6 diisopropylphenyl)imino)pent-2-enide). A mechanism for the generation of 2 involving nitrene transfer to rhenium from the BDI ligand is proposed. X-ray crystal structures of complexes 1, 1-PEt3, 1-DMAP, and 2 were determined and are discussed in detail. PMID- 27934321 TI - Copper(II) Complexes of Phenanthroline and Histidine Containing Ligands: Synthesis, Characterization and Evaluation of their DNA Cleavage and Cytotoxic Activity. AB - Copper(II) complexes have been intensely investigated in a variety of diseases and pathological conditions due to their therapeutic potential. The development of these complexes requires a good knowledge of metal coordination chemistry and ligand design to control species distribution in solution and tailor the copper(II) centers in the right environment for the desired biological activity. Herein we present the synthesis and characterization of two ligands HL1 and H2L2 containing a phenanthroline unit (phen) attached to the amino group of histidine (His). Their copper(II) coordination properties were studied using potentiometry, spectroscopy techniques (UV-vis and EPR), mass spectrometry (ESI-MS) and DFT calculations. The data showed the formation of single copper complexes, [CuL1]+ and [CuL2], with high stability within a large pH range (from 3.0 to 9.0 for [CuL1]+ and from 4.5 to 10.0 for [CuL2]). In both complexes the Cu2+ ion is bound to the phen unit, the imidazole ring and the deprotonated amide group, and displays a distorted square pyramidal geometry as confirmed by single crystal X ray crystallography. Interestingly, despite having similar structures, these copper complexes show different redox potentials, DNA cleavage properties and cytotoxic activity against different cancer cell lines (human ovarian (A2780), its cisplatin-resistant variant (A2780cisR) and human breast (MCF7) cancer cell lines). The [CuL2] complex has lower reduction potential (Epc= -0.722 V vs -0.452 V for [CuL1]+) but higher biological activity. These results highlight the effect of different pendant functional groups (carboxylate vs amide), placed out of the coordination sphere, in the properties of these copper complexes. PMID- 27934322 TI - Crystal Structure and Ferroelectric Properties of epsilon-Ga2O3 Films Grown on (0001)-Sapphire. AB - The crystal structure and ferroelectric properties of epsilon-Ga2O3 deposited by low-temperature MOCVD on (0001)-sapphire were investigated by single-crystal X ray diffraction and the dynamic hysteresis measurement technique. A thorough investigation of this relatively unknown polymorph of Ga2O3 showed that it is composed of layers of both octahedrally and tetrahedrally coordinated Ga3+ sites, which appear to be occupied with a 66% probability. The refinement of the crystal structure in the noncentrosymmetric space group P63mc pointed out the presence of uncompensated electrical dipoles suggesting ferroelectric properties, which were finally demonstrated by independent measurements of the ferroelectric hysteresis. A clear epitaxial relation is observed with respect to the c-oriented sapphire substrate, with the Ga2O3 [10-10] direction being parallel to the Al2O3 direction [11-20], yielding a lattice mismatch of about 4.1%. PMID- 27934323 TI - Combined Experimental and Theoretical Study of the Transient IR Spectroscopy of 7 Hydroxyquinoline in the First Electronically Excited Singlet State. AB - The photophysics of 7-hydroxyquinoline (7HQ) in protic media results from an interplay of acid-base chemistry, prompted by the effects of photoacidity of the hydroxyl group and photobasicity of the nitrogen atom in the quinoline aromatic system. With ultrafast IR spectroscopic measurements, we follow the proton transfer dynamics of 7HQ in its four possible charged forms in methanol solution. Using deuterated methanol as solvent, we determine deuteron transfer rates from the neutral to the zwitterionic form to be 330 ps, those from the cationic form to the zwitterionic form to be 170 ps, and those from the anionic form to the zwitterionic form to be 600 ps. We compare the observed IR-active fingerprint marker patterns in the electronic ground state and the first electronically excited 1Lb-state with those calculated using density functional theory and time dependent density functional theory, respectively, and find good correspondence between experimental and calculated transitions. The calculations provide insight into the nature of electronic excitation of these four different charged forms of 7HQ, suggesting the key role of electronic charge distribution changes upon electronic excitation of 7HQ and hydrogen bond changes at the donor hydroxyl and acceptor nitrogen moieties. PMID- 27934324 TI - Dynamics of Excited States for Fluorescent Emitters with Hybridized Local and Charge-Transfer Excited State in Solid Phase: A QM/MM Study. AB - The highly efficient organic light-emitting diodes (OLEDS) based on fluorescent emitters with hybridized local and charge-transfer (HLCT) excited state have attracted great attention recently. The excited-state dynamics of the fluorescent molecule with consideration of molecular interaction are studied using the hybrid quantum mechanics/molecular mechanics method. The results show that, in solid state, the internal conversion rate (KIC) between the first singlet excited state (S1) and the ground state (S0) is smaller than the fluorescent rate (Kr), while in gas phase KIC is much larger than Kr. By analyzing the Huang-Rhys (HR) factor and reorganization energy (lambda), we find that these two parameters in solid state are much smaller than those in gas phase due to the suppression of the vibration modes in low-frequency regions (<200 cm-1) related with dihedral angles between donor and acceptor groups. This is further demonstrated by the geometrical analysis that variation of the dihedral angle between geometries of S1 and S0 is smaller in solid state than that in gas phase. Moreover, combining the dynamics of the excited states and the adiabatic energy structures calculated in solid state, we illustrate the suggested "hot-exciton" mechanism of the HLCT emitters in OLEDs. Our work presents a rational explanation for the experimental results and demonstrates the importance of molecular interaction for theoretical simulation of the working principle of OLEDs. PMID- 27934325 TI - Ab Initio Study of Ionized Water Radical Cation (H2O)8+ in Combination with the Particle Swarm Optimization Method. AB - The structures of cationic water clusters (H2O)8+ have been globally explored by the particle swarm optimization method in combination with quantum chemical calculations. Geometry optimization and vibrational analysis for the 15 most interesting clusters were computed at the MP2/aug-cc-pVDZ level and infrared spectrum calculation at MPW1K/6-311++G** level. Special attention was paid to the relationships between their configurations and energies. Both MP2 and B3LYP-D3 calculations revealed that the cage-like structure is the most stable, which is different from a five-membered ring lowest energy structure but agrees well with a cage-like structure in the literature. Furthermore, our obtained cage-like structure is more stable by 0.87 and 1.23 kcal/mol than the previously reported structures at MP2 and B3LYP-D3 levels, respectively. Interestingly, on the basis of their relative Gibbs free energies and the temperature dependence of populations, the cage-like structure predominates only at very low temperatures, and the most dominating species transforms into a newfound four-membered ring structure from 100 to 400 K, which can contribute greatly to the experimental infrared spectrum. By topological analysis and reduced density gradient analysis, we also investigated the structural characteristics and bonding strengths of these water cluster radical cations. PMID- 27934326 TI - 4th International Conference on Chemical Bonding. PMID- 27934327 TI - Size and Site Dependence of the Catalytic Activity of Iridium Clusters toward Ethane Dehydrogenation. AB - This research focuses on optimizing transition metal nanocatalyst immobilization and activity to enhance ethane dehydrogenation. Ethane dehydrogenation, catalyzed by thermally stable Irn (n = 8, 12, 18) atomic clusters that exhibit a cuboid structure, was studied using the B3LYP method with triple-zeta basis sets. Relativistic effects and dispersion corrections were included in the calculations. In the dehydrogenation reaction Irn + C2H6 -> H-Irn-C2H5 -> (H)2 Irn-C2H4, the first H-elimination is the rate-limiting step, primarily because the reaction releases sufficient heat to facilitate the second H-elimination. The catalytic activity of the Ir clusters strongly depends on the Ir cluster size and the specific catalytic site. Cubic Ir8 is the least reactive toward H-elimination in ethane: Ir8 + C2H6 -> H-Ir8-C2H5 has a large (65 kJ/mol) energy barrier, whereas Ir12 (3 * 2 * 2 cuboid) and Ir18 (3 * 3 * 2 cuboid) lower this energy barrier to 22 and 3 kJ/mol, respectively. The site dependence is as prominent as the size effect. For example, the energy barrier for the Ir18 + C2H6 -> H-Ir18 C2H5 reaction is 3, 48, and 71 kJ/mol at the corner, edge, or face-center sites of the Ir18 cuboid, respectively. Energy release due to Ir cluster insertion into an ethane C-H bond facilitates hydrogen migration on the Ir cluster surface, and the second H-elimination of ethane. In an oxygen-rich environment, oxygen molecules may be absorbed on the Ir cluster surface. The oxygen atoms bonded to the Ir cluster surface may slightly increase the energy barrier for H-elimination in ethane. However, the adsorption of oxygen and its reaction with H atoms on the Ir cluster releases sufficient heat to yield an overall thermodynamically favored reaction: Irn + C2H6 + 1/2O2 -> Irn + C2H4 + H2O. These results will be useful toward reducing the energy cost of ethane dehydrogenation in industry. PMID- 27934328 TI - Influence of N-Oxide Introduction on the Stability of Nitrogen-Rich Heteroaromatic Rings: A Quantum Chemical Study. AB - N-Oxidization is an important strategy for enhancing the density and energy of energetic materials. Nevertheless, the influence of N+-O- introduction on molecular stability remains relatively unknown. Thus, the present work comprehensively studied 102 basic N-rich ring structures, including azoles, furazans, and azines, as well as their N-oxides by quantum chemical calculations. The introduction of N+-O- weakens molecular stability in most cases because the process elongates chemical bonds, decreases ring aromaticity, narrows the gaps between the highest occupied and lowest unoccupied molecular orbitals, and increases the photochemical reactivity. Besides, the easy H transfer to the neighboring O atom, which forms a N-OH isomer in azoles, renders the stabilization by N-oxide introduction ineffective. However, N-oxide introduction can enhance the molecular stability of 1,2,3,4-tetrazine-1,3-dioxide and tetrazino-tetrazine 1,3,6,8-tetraoxide by promoting sigma-pi separation and relieving lone-pair repulsion. Moreover, the alternate arrangement of positive and negative charges is another factor stabilizing the 1,2,3,4-tetrazine ring by 1,3-dioxidation. Finally, we assess the accessibility of N-oxidized azoles and azines by regarding N2O and H2O2 as oxidizers. We find that all the oxidations were exothermic, thermodynamically spontaneous, and kinetically feasible. After an overall evaluation, we propose 19 N-oxides as basic structures for high-energy materials with considerable stability. PMID- 27934329 TI - Electronic Structure of Neutral and Anionic Scandium Disilicon ScSi2-/0 Clusters and the Related Anion Photoelectron Spectrum. AB - Several quantum chemical methods including DFT (B3LYP, BP86 functional), coupled cluster theory (RCCSD(T)), and complete active space multiconfigurational methods (CASSCF/CASPT2) were used to study the geometric and electronic structures of the scandium disilicon cluster in both neutral and anionic states, ScSi2-/0. On the basis of the computed ground and lower-lying electronic states, and ionization energies of the anion, all the experimental bands in the anion photoelectron spectrum of ScSi2- can now fully be elucidated. The 3B2 and 2B2 states are determined to be the ground states of the anionic and the neutral triatomic species, respectively. The transition 3B2 -> 2B2 is thus assigned to be responsible for the X band in the photoelectron spectrum. The 2A1 neutral state is the final state corresponding to the A band. Although the first two bands arise from ionizations of scandium's 4s and 3d orbitals, all three remaining bands with higher ionization energies are the results of one-electron removals from the Si2 moiety orbitals of the anionic ground state 3B2. Two electronic states of the same representations 14B2 and 24B2 are ascribed to be the carriers of the B and C bands, whereas the excited state 4A2 is attributed to the last band D of the experimental photoelectron spectrum of ScSi2-. From all accessible vibrations of the ground and excited states computed at the B3LYP level, a simulation of band progressions in the photoelectron spectrum was also carried out and used to provide more insights into the experimental bands. PMID- 27934330 TI - Matrix Isolation Infrared and Ab Initio Study of the Interaction of N Heterocyclic Carbene with Water and Methanol: A Case Study of a Strong Hydrogen Bond. AB - This study reports, for the first time, the experimental study of the hydrogen bonded complexes of H2O and MeOH with 1,3-dimethylimidazol-2-ylidene, which is a dimethyl-substituted N-heterocyclic carbene, using matrix isolation infrared spectroscopy. The hydrogen bond was found to be established between the carbene carbon and the hydrogen in the O-H group of H2O or MeOH. The hydrogen-bonded complexes of N-heterocyclic carbenes are significantly stronger than many conventional hydrogen-bonded systems, as is evidenced by the large red shifts observed in the infrared frequencies of complexed H2O and MeOH. The experimental results were corroborated by computations performed at MP2 and M06-2X levels of theory, using 6-311++G(d,p) and aug-cc-pVDZ basis sets, which indicated large interaction energies (~9 kcal mol-1) for these complexes. Single-point calculations at the CCSD level of theory were also performed. Atoms-in-molecules (AIM), NBO, and LMOEDA analyses were also performed to understand the nature of the intermolecular interactions in these complexes. The dominant interaction was the electron delocalization from the carbene carbon to the sigma* orbital of O-H of H2O or MeOH. PMID- 27934331 TI - Contributions of Nearly-Degenerate States to the Photoelectron Spectra of the Vanadium Dicarbide Anion. AB - A theoretical study by using a wide variety of quantum chemical methods has been carried out to investigate the nature of the ionization processes that are responsible for the experimental observed photoelectron spectra of the anionic VC2- stoichiometry. In agreement with previous studies, the most stable structures for the anionic and neutral vanadium dicarbide species were unambiguously found to be cyclic isomers. However, concerning the nature of the ground state of the anionic cluster there appear to be two candidates that are nearly degenerate. Only by considering both these anionic states as initial states could a substantial novel and complete assignment for the observed anion photoelectron spectra be proposed. A thorough analysis of the electronic structures not only allows us to distinguish the one-electron processes but also enables to disclose their natures. All the lower binding energy bands involve ionizations out of a dominant V+ orbital. Opposed, the higher positioned bands are the outcome of an electron detachment out of the C22- ligand 3sigmag orbital. Finally, the experimentally observed vibrational progressions in the photoelectron spectra of VC2- were simulated on the basis of harmonic frequency analyses at the B3LYP level and the derived Franck-Condon factors. PMID- 27934332 TI - Toward the Full Quantum Dynamical Description of Photon Induced Processes in D2. AB - The dissociative ionization (multiphoton regime) of the D2+ ion by ultrashort laser pulses has been studied theoretically using ab initio calculations. The combined ionization and dissociation spectrum was explored for fixed molecular axis orientations. In accordance with previous investigations, the dominant features in the obtained joint energy spectrum were multiphoton peaks. In addition to this, in the present work, photoelectron angular distributions were analyzed as well. By performing a partial wave analysis for each multiphoton peak, we have identified the number of absorbed photons. Moreover, we also found that the angular distribution can significantly change inside a multiphoton peak as a function of electron and nuclear kinetic energy. PMID- 27934333 TI - Thermal Rate Coefficients for the Astrochemical Process C + CH+ -> C2+ + H by Ring Polymer Molecular Dynamics. AB - Thermal rate coefficients for the astrochemical reaction C + CH+ -> C2+ + H were computed in the temperature range 20-300 K by using novel rate theory based on ring polymer molecular dynamics (RPMD) on a recently published bond-order based potential energy surface and compared with previous Langevin capture model (LCM) and quasi-classical trajectory (QCT) calculations. Results show that there is a significant discrepancy between the RPMD rate coefficients and the previous theoretical results that can lead to overestimation of the rate coefficients for the title reaction by several orders of magnitude at very low temperatures. We argue that this can be attributed to a very challenging energy profile along the reaction coordinate for the title reaction, not taken into account in extenso by either the LCM or QCT approximation. In the absence of any rigorous quantum mechanical or experimental results, the computed RPMD rate coefficients represent state-of-the-art estimates to be included in astrochemical databases and kinetic networks. PMID- 27934334 TI - Effect of the Number of Methyl Groups on the Cation Affinity of Oxygen, Nitrogen, and Phosphorus Sites of Lewis Bases. AB - The effect of number of CH3 groups (n) on the cation (H+, Li+, Na+, Al+, CH3+) affinity, polarizability, and dipole moment of 14 simple molecules was investigated. Linear correlations were observed between the polarizabilities and the number of methyl groups. The variations of the cation affinities and dipole moments with the number of methyl groups (n) were not linear, and a quadratic function was proposed for obtaining a good fit of the experimental data. Also, because the proton affinities (PA), lithium cation affinities (LCA), sodium cation affinities (SCA), aluminum cation affinity (AlCA), and methyl cation affinity (MCA) varied quadratically with polarizabilities (alpha), a formula of the form [cation affinities] = a + balpha + calpha2 was proposed. After correction of the PAs, LCAs, SCAs, AlCA, and MCA for the dipole/charge interaction (EMU), linear relationships were observed between the corrected cation affinities and n or alpha. The contribution of EMU to PA and MCA was small (less than 20%), and its contribution to LCA and SCA was large (>50%). The electrostatic contribution to AlCA was considerable (20-50%); however, it was smaller than the electrostatic contribution to LCA and SCA. PMID- 27934335 TI - Enantioselective Synthesis of alpha-Mercapto-beta-amino Esters via Rh(II)/Chiral Phosphoric Acid-Cocatalyzed Three-Component Reaction of Diazo Compounds, Thiols, and Imines. AB - An enantioselective method for the synthesis of alpha-mercapto-beta-amino esters has been developed via a rhodium(II)/chiral phosphoric acid-cocatalyzed three component reaction of diazo compounds, thiols, and imines. This transformation is proposed to proceed through enantioselective trapping of the sulfonium ylide intermediate generated in situ from the diazo compound and thiol by the phosphoric acid-activated imine. With this method, a series of alpha-mercapto beta-amino esters were obtained in good yields with moderate to good stereoselectivities. PMID- 27934336 TI - Catalytic Diverse Radical-Mediated 1,2-Cyanofunctionalization of Unactivated Alkenes via Synergistic Remote Cyano Migration and Protected Strategies. AB - A catalytic radical protocol for 1,2-cyanofunctionalization of unactivated alkenes involving remote cyano migration triggered by addition of diverse carbon- and heteroatom-centered radicals to alkenes has been developed. This powerful strategy provides a diverse platform for the collection of a variety of synthetically important beta-functionalized alkyl nitriles bearing densely functionalized carbonyl, cyano, and other various functional groups within the same molecules. The substrates TMS (trimethylsilyl)-protected alkenyl cyanohydrins are straightforwardly accessible via simple cyanosilylation of the corresponding ketones. PMID- 27934337 TI - Synthesis of Multifunctionalized 2-Carbonylpyrrole by Rhodium-Catalyzed Transannulation of 1-Sulfonyl-1,2,3-triazole with beta-Diketone. AB - A facile rhodium-catalyzed transannulation of 1-sulfonyl-1,2,3-triazoles with beta-diketones was realized, and a series of multisubstituted 2-carbonylpyrroles were synthesized efficiently (up to 94% yield). The protocol features several advantages, such as readily available materials, mild reaction conditions, a concise operating procedure, a broad reaction scope, and excellent regioselectivity when benzoylacetone derivatives were used. PMID- 27934338 TI - Copper-Catalyzed Asymmetric Propargylation of Cyclic Aldimines. AB - The copper-catalyzed asymmetric propargylation of cyclic aldimines is reported. The influence of the imine trimer to inhibit the reaction was identified, and equilibrium constants between the monomer and trimer were determined for general classes of imines. Asymmetric propargylation of a diverse series of N-alkyl and N aryl aldimines was achieved with good to high asymmetric induction. The utility was demonstrated by a titanium catalyzed hydroamination and reduction to generate the chiral indolizidines (-)-crispine A and (-)-harmicine. PMID- 27934339 TI - Total Synthesis of Selaginpulvilin C and D Relying on in Situ Formation of Arynes and Their Hydrogenation. AB - The total syntheses of selaginpulvilins C and D is described. The key strategy for the construction of the core fluorene moiety involves in situ formation of an aryne intermediate followed by its formal hydrogenation. The precursor tetraynes that undergo aromatization via hexadehydro Diels-Alder reaction were prepared from readily available building blocks through typical alkyne-coupling reactions. PMID- 27934340 TI - Direct ortho-Arylation of Pyridinecarboxylic Acids: Overcoming the Deactivating Effect of sp2-Nitrogen. AB - Direct arylations of pyridines are challenging transformations due to the high Lewis basicity of the sp2-nitrogen. The use of carboxylates as directing groups is reported, facilitating the Pd-catalyzed C-H arylation of this difficult class of substrates. This methodology allows regioselective C3/C4 arylation, without the need to use solvent quantities of the pyridine, and using low-cost chloro- and bromoarenes as coupling partners. Furthermore, carboxylates could be employed as traceless directing groups through a one-pot C-H arylation/Cu(I)-mediated decarboxylation sequence, thereby accessing directing-group-free pyridine biaryls. PMID- 27934341 TI - AlkylFluor: Deoxyfluorination of Alcohols. AB - A practical, high-yielding method for the deoxyfluorination of alcohols is presented using AlkylFluor, a novel salt analogue of PhenoFluor. AlkylFluor is readily prepared on multigram scale and is stable to long-term storage in air and exposure to water. The practicality and applicability of this method is demonstrated with a variety of primary and secondary alcohol substrates. PMID- 27934342 TI - Access to Cyclopropyl-Fused Azacycles via a Palladium-Catalyzed Direct Alkenylation Strategy. AB - Palladium-catalyzed direct alkenylation of cyclopropyl C-H bonds proceeds in high efficiency. This transformation provides access to novel cyclopropyl-fused azacycles. Ligand studies suggest that bisphosphine monoxide analogues of dppf and rac-BINAP are the active ligand species. Preliminary results support that both BozPhos and IPrMonophos ligands can achieve high enantioinduction for this novel direct alkenylation reaction. To date, this represents the first example of enantioselective C-H functionalization employing a bisphosphine monoxide ligand. PMID- 27934343 TI - Synthesis of Polycarbonyl Pyrroles via K2S2O8-Mediated Oxidative Cyclization of Enamines. AB - A novel K2S2O8-promoted oxidative cyclization of enamines is described. A variety of enamines having diverse functional groups and substitution patterns react well using K2S2O8 as the oxidant in the absence of catalyst. This protocol provides a very simple route for the synthesis of polycarbonyl pyrroles and has the advantages of readily available starting materials, mild reaction conditions, and a wide scope of substrates. PMID- 27934344 TI - Copper-Catalyzed Oxidative Dearomatization/Spirocyclization of Indole-2 Carboxamides: Synthesis of 2-Spiro-pseudoindoxyls. AB - A copper-catalyzed oxidative dearomatization/spirocyclization of indole-2 carboxamides using tert-butyl hydroperoxide (TBHP) as the oxidant has been developed that provides rapid and efficient access to C2-spiro-pseudoindoxyls. Two of the sp2 C-H bonds are functionalized during the reaction process, and the reaction likely proceeds via the formation of a highly reactive 3H-indol-3-one intermediate followed by aromatic electrophilic substitution with the N-aryl ring of the amide moiety. PMID- 27934345 TI - Stereoinversion of Stereocongested Carbocyclic Alcohols via Triflylation and Subsequent Treatment with Aqueous N,N-Dimethylformamide. AB - A convenient method for the stereoinversion of secondary alcohols, applicable to stereocongested carbocyclic substrates, is reported. A simple three-step procedure, including triflylation of the hydroxy group, nucleophilic oxygenative displacement by the treatment with aqueous N,N-dimethylformamide (DMF), and methanolysis, allowed for efficient stereoinversion of various substrates, including sugar derivatives, in one pot. PMID- 27934346 TI - Correction to "Copper-Mediated C-N Coupling of Arylsilanes with Nitrogen Nucleophiles". PMID- 27934347 TI - 9-Ethynylfluoroenyl Radicals: Regioselective Dimerization and Post Ring Cyclization Reactions. AB - 9-Ethynylfluorenyl radical derivatives were readily prepared in situ and underwent simultaneous intermolecular coupling reactions. Interestingly, the dimerization process took place in either a head-to-tail or a head-to-head mode between the acetylenic or the allenic resonance forms dependent on the terminal substituents, which could be well explained by their different spin distribution and steric hindrance effects. The structures of the products were confirmed by X ray crystallographic and other spectroscopic analyses. It was also found that the newly generated dipropinyl dimers underwent a rearrangement and ring-cyclization reaction at room temperature, eventually giving unique difluorenylidene cyclobutene derivatives. PMID- 27934348 TI - Rh(III)- and Zn(II)-Catalyzed Synthesis of Quinazoline N-Oxides via C-H Amidation Cyclization of Oximes. AB - Quinazoline N-oxides have been prepared from simple ketoximes and 1,4,2-dioxazol 5-ones via Rh(III)-catalyzed C-H activation-amidation of the ketoximes and subsequent Zn(II)-catalyzed cyclization. The substrate scope and functional group compatibility were examined. The reaction features relay catalysis by Rh(III) and Zn(II). PMID- 27934349 TI - Enantioselective Conversion of Achiral Cyclohexadienones to Chiral Cyclohexenones by Desymmetrization. AB - The enantioselective reduction of prochiral 4,4-disubstituted 2,5 cyclohexadienones to chiral 2-cyclohexenones has been accomplished by the use of a carefully selected chiral bisphosphine-CuI complex and diisobutylaluminum hydride-hexamethylphosphoric triamide complex. This reagent has provided access to a key bicyclic intermediate for the total synthesis of the natural enantiomer of the pentacyclic sesterterpene retigeranic acid that involves spatial discrimination between CH3 and CH2CH2R substituents, an operation that has been elusive previously. In addition, a second method for desymmetrization is described using catalytic enantioselective [4 + 2]-cycloaddition of cyclopentadiene to prochiral 4,4-disubstituted 2,5-cyclohexadienones. PMID- 27934351 TI - Thermally Induced [3 + 2] Cycloaddition of Alkynyl-Tethered Diazoamides: Synthetic and Mechanistic Insights. AB - A general and unprecedented thermally induced formal [3 + 2] cycloaddition has been developed that provides a general access to fused lactam derivatives in high to excellent yields with broad substrate scope. In comparison with the reported metal-catalyzed carbene/alkynyl metathesis, this is the only example in this area under catalyst-free conditions with excellent selectivity. Mechanistic studies indicate that the 3H-pyrazole is the key intermediate in this cascade reaction, which is confirmed spectroscopically for the first time. PMID- 27934350 TI - Synthesis and Bioactivity of Diastereomers of the Virulence Lanthipeptide Cytolysin. AB - Cytolysin, a two-component lanthipeptide comprising cytolysin S (CylLS") and cytolysin L (CylLL"), is the only family member to exhibit lytic activity against mammalian cells in addition to synergistic antimicrobial activity. A subset of the thioether cross-links of CylLS" and CylLL" have ll stereochemistry instead of the canonical dl stereochemistry in all previously characterized lanthipeptides. The synthesis of a CylLS" variant with dl stereochemistry is reported. Its antimicrobial activity was found to be decreased, but not its lytic activity against red blood cells. Hence, the unusual ll stereochemistry is not responsible for the lytic activity. PMID- 27934352 TI - Selective Synthesis of Partially Protected d-Talopyranosides and d Gulopyranosides via Catalytic Asymmetric Dihydroxylation: Multiplier Effects of Substrate Control and Catalyst Control. AB - Highly selective syntheses of d-talopyranosides and d-gulopyranosides have been achieved by utilizing the multiplier effects of substrate control and catalyst control. Through the combination of an O-benzoyl-protected substrate and the AD mix-beta system, the d-talopyranoside was obtained in a ratio of 96:4. In contrast, the d-gulopyranoside was obtained in a ratio of 3:97 through the use of an O-tert-butyldimethylsilyl-protected substrate and AD-mix-alpha. PMID- 27934353 TI - Palladium-Catalyzed Stereoselective Formation of Substituted Allylic Thioethers and Sulfones. AB - A general method is reported for the stereoselective preparation of highly functionalized allylic thioethers. This protocol is based on a Pd-catalyzed thiolation of modular vinyl cyclic carbonate substrates and features high (Z) selectivity, good yields, minimal waste, ample product scope, and operational simplicity. A one-pot strategy was used for the stereoselective formation of pharma-relevant allylic sulfones derived from their in situ prepared thioether precursors. PMID- 27934354 TI - A General, One-Pot Method for the Synthesis of Sulfinic Acids from Methyl Sulfones. AB - A simple and efficient method for converting methyl sulfones to sulfinic acids is described. The process involves alkylation with a benzylic halide, followed by in situ elimination of the resulting styrene in the presence of excess base to yield a sulfinic acid in a single reaction process. The usefulness of the alkylation elimination sequence is demonstrated by generating a variety of sulfinic acids from methyl sulfones. Late stage functionalization and 14C-labeling of several biologically active methyl sulfones were accessed via sulfinate intermediates. PMID- 27934355 TI - Mechanism of Ru(II)-Catalyzed Rearrangements of Allenyl- and Alkynylcyclopropanols to Cyclopentenones. AB - A comparison study of the Ru(II)-catalyzed rearrangements of allenyl- and alkynylcyclopropanols to the corresponding cyclopentenones has been undertaken with the aid of an alkyl substituent on the three-membered ring. These ring expansion reactions proceed with exceptional regioselectivity irrespective of the cis/trans stereochemistry of the substituents on the three-membered ring. beta Carbon elimination is the common feature in the absence of a chelating group at the 4'-position in the alkyne chain. PMID- 27934356 TI - Improvements to the Practical Usability of the "Crystalline Sponge" Method for Organic Structure Determination. AB - A microwell droplet approach provided high-quality samples in >=90% yield of the "crystalline sponge", which was exhibited previously as a revolutionary organic structure determination method. The new protocol, from crystal growth to guest soaking, was conducted in 1-7 days (depending on the guest) and was robust toward user errors, marking improvements over existing protocols. Unit cell determination was used as a practical crystal screening metric. These advances improve the practicality of the crystalline sponge technique for characterizing unknown organic molecules. PMID- 27934357 TI - Access to 4-Oxazolidinones: A (3 + 2) Cycloaddition Approach. AB - The novel reactivity of in situ generated aza-oxyallyl cation intermediates with a variety of carbonyl compounds is reported to construct 4-oxazolidinones motifs with good yields and diastereoselectivities. This simple and efficient (3 + 2) cycloaddition method provides direct access to potential bioactive compounds. PMID- 27934358 TI - Synthesis of Cycloalkyl Substituted 7-Azaindoles via Photoredox Nickel Dual Catalytic Cross-Coupling in Batch and Continuous Flow. AB - An efficient photoredox/Ni dual catalytic Csp2-Csp3 cross-coupling protocol in a continuous-flow regime to synthesize a variety of regioisomeric cycloalkyl substituted 7-azaindoles has been developed. These transformations proceed efficiently under mild conditions (blue LED light irradiation at 30 degrees C over 40 min residence time in mixed solvent systems). Reactions are easy to perform and afford most of the desired 2-, 3-, 4-, 5-, and 6-cycloalkyl substituted 7-azaindoles in moderate-to-good yield. PMID- 27934360 TI - Base-Promoted Synthesis of N-Substituted 1,2,3-Triazoles via Enaminone-Azide Cycloaddition Involving Regitz Diazo Transfer. AB - The domino reactions between NH-based secondary enaminones and tosyl azide have been developed for the synthesis of various N-substituted 1,2,3-triazoles by employing t-BuONa as the base promoter. Through a key Regitz diazo-transfer process with tosyl azide, the reactions proceed efficiently at room temperature with good substrate tolerance. PMID- 27934359 TI - Synthesis of Non-natural, Frame-Shifted Isoprenoid Diphosphate Analogues. AB - A set of synthetic approaches was developed and applied to the synthesis of eight frame-shifted isoprenoid diphosphate analogues. These analogues were designed to increase or decrease the methylene units between the double bonds and/or the pyrophosphate moieties of the isoprenoid structure. Evaluation of mammalian GGTase-I and FTase revealed that small structural changes can result in substantial changes in substrate activity. PMID- 27934362 TI - Access to Diosgenyl Glycoconjugates via Gold(I)-Catalyzed Etherification of Diosgen-3-yl ortho-Hexynylbenzoate. AB - An efficient protocol for the synthesis of diverse diosgen-3-yl glycoconjugates, a class of novel synthetic analogs of natural saponins of biological significance, has been developed. The method relies on gold(I)-catalyzed etherification of diosgen-3-yl ortho-hexynylbenzoate with stoichiometric sugar alcohols to afford the corresponding glycoconjugates in 38%-99% yields. The reaction involves the preferential attack of hydroxyl groups to the C3 position of homoallylic carbocation intermediate and displays a broad substrate scope and a good functional group tolerance. PMID- 27934361 TI - Labeling Studies Clarify the Committed Step in Bacterial Gibberellin Biosynthesis. AB - Bacteria have evolved gibberellin phytohormone biosynthesis independently of plants and fungi. Through 13C-labeling and NMR analysis, the mechanistically unusual "B" ring contraction catalyzed by a cytochrome P450 (CYP114), which is the committed step in gibberellin biosynthesis, was shown to occur via oxidative extrusion of carbon-7 from ent-kaurenoic acid in bacteria. This is identical to the convergently evolved chemical transformation in plants and fungi, suggesting a common semipinacol rearrangement mechanism potentially guided by carbon-4alpha carboxylate proximity. PMID- 27934363 TI - Rhodium(III)-Catalyzed Oxidative C-H/C-H Cross-Coupling of Heteroarenes and Masked Benzylamines. AB - The first example of oxidative C-H/C-H cross-coupling of oxalyl amide-protected benzylamines and various heteroarenes in the presence of a rhodium(III) catalyst has been developed. The route provides a means of synthesizing ortho heteroarylated benzylamines. The methodology presents broad substrate scope, great functional group tolerance, and good to excellent yields in the synthesis of substituted benzylamines. The study also reveals that the thienoisoquinoline derivatives can be accessed through the intramolecular amination of thiophenyl substituted benzylamines with palladium(II). PMID- 27934364 TI - Unactivated C(sp3)-H Bond Functionalization of Alkyl Nitriles with Vinylarenes and Mechanistic Studies. AB - The first example of a metal-free unactivated C(sp3)-H bond functionalization of alkyl nitriles with terminal vinylarenes to provide gamma-ketonitrile derivatives is described. This protocol features simple operations, a broad substrate scope, and atom and step economy. In addition, Cu-catalyzed C(sp3)-H bond functionalization of azodiisobutyronitrile (AIBN) and analogues with terminal vinylarenes to generate gamma-ketonitriles was also studied. A preliminary free radical pathway was confirmed by capturing an alkyl radical, and a conjugate system was found that can stabilize radical intermediates and be in favor of this transformation. Density functional theory (DFT) calculations also provide important evidence of the free-radical pathway. PMID- 27934365 TI - Palladium-Catalyzed Arylation of Ketones and Acetonitrile with Ortho Alkylation of Aryl Rings: De Novo Synthesis of Tetralines and Benzocycloheptenes. AB - Palladium-catalyzed alpha-arylation reactions of ketones with simultaneous ortho alkylation offer 1,2,3-substituted arenes. The reactions of 1,omega-dihaloalkanes also allow facile construction of medicinally important tetralines and benzocycloheptenes. PMID- 27934366 TI - Recyclable Hypervalent-Iodine-Mediated Dehydrogenative Cyclopropanation under Metal-Free Conditions. AB - A method is developed for the synthesis of cyclopropanes from the C(sp2)-C(sp3) single bonds of beta-keto esters with activated methylene compounds under metal free conditions in the presence of 5-trimethylammonio-1,3-dioxo-1,3-dihydro 1lambda5-benzo[d][1,2]iodoxol-1-ol anion (AIBX), a recyclable water-soluble hypervalent iodine(V) reagent developed by our group. This mild, efficient method has a wide substrate scope and good functional group tolerance and is complementary to existing cyclopropanation strategies. The method can be used to construct polysubstituted ring-fused cyclopropanes and is amenable to further synthetic transformations for construction of complex biologically active molecules as well as asymmetric cyclopropanes (90% de) when a chiral ester auxiliary is used. PMID- 27934367 TI - Intramolecular Csp2-Csp2 Friedel-Crafts Arylation: Substrate- and Condition Controlled Divergent Synthesis of Fused-beta-carbolines. AB - A triple cooperative catalysis-mediated multicomponent reaction between 1-formyl N-substituted-beta-carbolines, a terminal alkyne, and a secondary amine allows access to unprecedented polycyclic beta-carbolines via sequential A3-coupling and an intramolecular Csp2-Csp2 Friedel-Crafts arylation reaction. The reaction is successful in a dry inert atmosphere only with substrates bearing a methoxy substituted benzyl group at the indole nitrogen. Conversely, treating 3 aminoindolizino[8,7-b]indoles (obtained after A3-coupling) with acid in the presence of H2O in air offers a general route to natural-alkaloid-like products. PMID- 27934368 TI - Catalytic Enantioselective Desymmetrization of Norbornenoquinones via C(sp2)-H Alkylation. AB - The enantioselective Diels-Alder (DA) reaction with monosubstituted p benzoquinones is an unmet challenge. A new approach for the enantioselective synthesis of monosubstituted quinone-DA adducts is presented based on C(sp2)-H alkylative desymmetrization of meso-DA adducts. Catalyzed by a tertiary amino thiourea derivative, this reaction utilizes nitroalkanes as the alkylating agents and generates densely functionalized products bearing at least four contiguous stereogenic centers remote from the reaction site with excellent enantioselectivities. PMID- 27934369 TI - Insertion of Arynes into P-O Bonds: One-Step Simultaneous Construction of C-P and C-O Bonds. AB - The insertion of arynes into P-O bonds for the preparation of o-hydroxy substituted arylphosphine oxides, -phosphinates, and -phosphonates is described. This novel reaction leads to the simultaneous formation of C-P and C-O bonds in one step with good yields and regioselectivities under mild and transition-metal free conditions. The easy follow-up transformations of the resulting o-hydroxyl group extend these reactions to the facile construction of other ortho substituted arylphosphorus compounds. PMID- 27934370 TI - Synthetic Approach to the Core Structure of Oleandrin and Related Cardiac Glycosides with Highly Functionalized Ring D. AB - The first synthetic approach to the core structure of cardiac glycoside oleandrin exhibiting a potent cytotoxic activity, starting from a common androstane derivative, has been accomplished. The synthesis is focused on stereoselective transformations in the densely substituted and sterically shielded five-membered ring (steroid ring D). The developed synthesis paves a route to the synthesis of related bufadienolides, i.e., constituents of traditional drug Ch'an Su, bufotalin, and cinobufagin. PMID- 27934371 TI - Pd(II)/Ag(I)-Promoted One-Pot Synthesis of Cyclic Ureas from (Hetero)Aromatic Amines and Isocyanates. AB - A simple and facile one-pot reaction has been developed to afford a diverse range of N,N'-disubstituted benzimidazolones and imidazopyridinones containing two differently substituted N atoms. A cooperative Pd(II)/Ag(I) system promotes the sequential addition/intramolecular C-H amidation reaction of (hetero)aromatic amines and isocyanates, leading to the formation of two C-N bonds. A mechanism involving radical intermediates generated by single-electron transfer (SET) in the presence of a Ag2CO3 oxidant and Pd(OAc)2 Lewis acid is proposed. This protocol offers an operationally easy, simple, and robust approach with the use of readily available starting materials, good functional group tolerance, and high efficiency. PMID- 27934372 TI - Pd-Catalyzed Site-Selective p-Hydroxyphenyloxylation of Benzylic alpha-C(sp3)-H Bonds with 1,4-Benzoquinone. AB - A Pd-catalyzed, site-selective p-hydroxyphenyloxylation of benzylic alpha-C(sp3) H bonds with 1,4-benzoquinone using thioamide as a directing group is reported. 1,4-Benzoquinone is employed as the p-hydroxyphenyloxy source without extra oxidants. This method exclusively gives site selectivity at alpha-C(sp3)-H bonds rather than the usual beta-C(sp3)-H bonds through C-H activation mode. The reactions proceed with high functional group tolerance in yields of 42-93%. PMID- 27934373 TI - Copper-Catalyzed Direct Coupling of Unprotected Propargylic Alcohols with P(O)H Compounds: Access to Allenylphosphoryl Compounds under Ligand- and Base-Free Conditions. AB - The first facile and efficient copper-catalyzed direct C-P cross-coupling of unprotected propargylic alcohols with P(O)H compounds has been developed, providing a general, one-step approach to construct valuable allenylphosphoryl frameworks with operational simplicity and high step- and atom-economy under ligand-, base-, and additive-free conditions. PMID- 27934374 TI - Procedure for the Synthesis of Polysubstituted Carbazoles from 3-Vinyl Indoles. AB - A simple Bronsted acid catalyzed tandem reaction, including intermolecular nucleophilic addition, substitution and intramolecular cyclization, in a one-pot manner is described. Thirty two 2-indolyl substituted carbazoles are generated in good to excellent yields. Based on this tandem reaction strategy, the poly(1,4 carbazole) is prepared for the first time. Preliminary studies indicate that the poly(1,4-carbazole) has good thermostability and optical properties. PMID- 27934375 TI - E- and Z-Selective Transfer Semihydrogenation of Alkynes Catalyzed by Standard Ruthenium Olefin Metathesis Catalysts. AB - Selective transfer semihydrogenation of alkynes to yield alkenes was achieved with commercial first and second generation Hoveyda-Grubbs catalysts and formic acid as a hydrogen donor. This catalytic system is distinguished by its selectivity and compatibility with many functional groups (halogens, cyano, nitro, sulfide, alkenes). The metathetic activity of the ruthenium catalysts may be utilized in tandem sequences of olefin metathesis plus alkyne reduction. PMID- 27934376 TI - Microwave-Assisted Synthesis of 2-Aryl-2-oxazolines, 5,6-Dihydro-4H-1,3-oxazines, and 4,5,6,7-Tetrahydro-1,3-oxazepines. AB - The first general procedure for the synthesis of 5- to 7-membered cyclic iminoethers by microwave-assisted cyclization of omega-amido alcohols promoted by polyphosphoric acid (PPA) esters is presented. 2-Aryl-2-oxazolines and 5,6 dihydro-4H-1,3-oxazines were efficiently prepared using ethyl polyphosphate/CHCl3. Trimethylsilyl polyphosphate in solvent-free conditions allowed for the synthesis of hitherto-unreported 4,5,6,7-tetrahydro-1,3 oxazepines. The method involves good to excellent yields and short reaction times.The reaction mechanism and the role of PPA esters were investigated in a chiral substrate. PMID- 27934377 TI - Multiple Aryne Insertions into Oxindoles: Synthesis of Bioactive 3,3-Diarylated Oxindoles and Dibenzo[b,e]azepin-6-ones. AB - An aryne insertion cascade reaction on oxindoles has been observed and constitutes a convenient "one pot" preparation of bioactive di- and triarylated oxindoles in good yields under mild conditions. A temperature controlled "reaction switch" enables ready access to dibenzo[b,e]azepin-6-one derivatives employing the same reaction regime. This tactic has been extended to a short synthesis of potent antiulcer agent darenzepine. PMID- 27934378 TI - Pd Catalysis in Cyanide-Free Synthesis of Nitriles from Haloarenes via Isoxazolines. AB - A method to obtain aryl nitriles from the corresponding halides by Pd catalysis, in the absence of any cyanide source, is reported. The reaction of an aryl halide, ethyl nitroacetate, and an olefin readily delivers an aromatic nitrile. A variety of aryl iodides/bromides have been converted into the corresponding cyanoarenes in fair to excellent yields. The reaction likely involves the following steps: (a) Pd-catalyzed alpha-arylation of ethyl nitroacetate; (b) nitrile oxide formation; PMID- 27934379 TI - Synthesis and Electrical Properties of Derivatives of 1,4 bis(trialkylsilylethynyl)benzo[2,3-b:5,6-b']diindolizines. AB - A new class of nitrogen-containing arene organic semiconductors incorporating fused indolizine units is described. This system, though having a zigzag shape, mimics the electronic properties of its linear analogue pentacene as a result of nitrogen lone pair incorporation into the pi-electron system. Solubilizing trialkylsilylethynyl groups were employed to target crystal packing motifs appropriate for field-effect transistor devices. The triethylsilylethynyl derivative yielded hole mobilities of 0.1 cm2 V-1 s-1 and on/off current ratios of 105. PMID- 27934380 TI - Free-Radical Carbocyanation of Cyclopropenes: Stereocontrolled Access to All Carbon Quaternary Stereocenters in Acyclic Systems. AB - Free-radical carbocyanation of cyclopropenes offers straightforward access to tetrasubstituted cyclopropanes in satisfying yields with moderate diastereoselectivity. The incorporation of various functional groups on the cyclopropane ring allows a subsequent base-mediated ring-opening reaction leading to functionalized acyclic systems having an all-carbon quaternary stereocenter. PMID- 27934381 TI - Ester Formation via Nickel-Catalyzed Reductive Coupling of Alkyl Halides with Chloroformates. AB - The synthesis of alkyl esters from readily available alkyl halides and chloroformates was achieved for the first time using a mild Ni-catalyzed reductive coupling protocol. Unactivated primary and secondary alkyl iodides as well as glycosyl, benzyl, and aminomethyl halides were successfully employed to yield products in moderate to excellent yields with high functional group tolerance. PMID- 27934383 TI - Intramolecular Electronic Coupling in the Thiophene-Bridged Carbazole-Based Diporphyrin. AB - The Glaser coupling reaction of ethynyl-substituted carbazole-based isophlorins provided butadiyne-bridged dimers, which were transformed into the thiophene bridged dimers via the annulation reaction. Oxidation of these isophlorin dimers afforded carbazole-based diporphyrins. Notable electronic interactions in the diporphyrins have been confirmed by means of UV/vis-near-infrared (NIR) absorption spectroscopy, cyclic voltammetry (CV) measurements, and density functional theory (DFT) calculations. PMID- 27934382 TI - Enantioselective, Copper-Catalyzed Alkynylation of Ketimines To Deliver Isoquinolines with alpha-Diaryl Tetrasubstituted Stereocenters. AB - An enantioselective, copper-catalyzed alkynylation of cyclic alpha,alpha-diaryl ketiminium ions has been developed to deliver isoquinoline products with diaryl, tetrasubstituted stereocenters. The success of this reaction relied on identification of Ph-PyBox as the optimal ligand, i-Pr2NEt as the base, and CHCl3 as the solvent. A broad scope and functional group tolerance were observed. Notably, the use of both aryl and silyl acetylenes results in high yields and enantioselectivities. Mechanistic experiments are consistent with a dimeric or higher order catalyst. PMID- 27934384 TI - Aryne Relay Chemistry en Route to Aminoarenes: Synthesis of 3-Aminoaryne Precursors via Regioselective Silylamination of 3-(Triflyloxy)arynes. AB - A facile synthetic method for preparing 3-amino-2-silylaryl triflates via regioselective silylamination of 3-(triflyloxy)arynes with N-silylamines is described. Fluoride-mediated generation of 3-aminobenzyne from 3-amino-2 silylphenyl triflate, easily prepared by this method, in the presence of various arynophiles efficiently afforded diverse aniline derivatives, including a 5 aminocoumarin derivative, demonstrating the utility of aryne relay approach. PMID- 27934385 TI - A Scalable Total Synthesis of (-)-Nakadomarin A. AB - The convergent total synthesis of the manzamine alkaloid (-)-nakadomarin A (1) is described. The retrosynthetic analysis recognized spirocycle 3, assembled via an organocatalyst-promoted Michael addition/cyclization between bicyclic lactam 4 and furan aldehyde 5, both accessible from achiral starting materials and on a multigram scale. Lactam 4 is assembled through an SN2'/reduction/Staudinger/retro aza-Claisen sequence on scale. After spirocyclization, the synthesis of nakadomarin is completed in only six steps. PMID- 27934386 TI - Ruthenium-Catalyzed Synthesis of beta-Hydroxyamides from beta-Ketonitriles in Water. AB - An unprecedented hydration/transfer hydrogenation tandem process for the catalytic conversion of beta-ketonitriles into synthetically useful beta hydroxyamides in water has been developed, making use of the ruthenium(II) complex [RuCl2(eta6-p-cymene){P(4-C6H4F)2Cl}] in combination with sodium formate. PMID- 27934387 TI - Stereoselective Synthesis of alpha-Fluoro-gamma-nitro Thioesters under Organocatalytic Conditions. AB - Fluorinated monothiomalonates (F-MTMs) were used as building blocks for the stereoselective synthesis of organofluorine compounds. We present conjugate addition reactions between F-MTMs with nitroolefins that proceed under mild organocatalytic conditions and provide access to alpha-fluoro-gamma-nitro thioesters with adjacent tetrasubstituted and tertiary stereogenic centers. Only 1 mol % of a cinchona alkaloid-urea catalyst is necessary to obtain the addition products in excellent yields and stereoselectivities. The methodology allowed for the straightforward synthesis of a fluorinated analogue of the PAR-2 agonist AC 264613. PMID- 27934388 TI - Iodine Promoted Regioselective alpha-Sulfenylation of Carbonyl Compounds using Dimethyl Sulfoxide as an Oxidant. AB - A metal-free regioselective sulfenylation of the alpha-CH3 group of ketones has been achieved in the presence of the alpha-CH2 or alpha-CH group using the cross dehydrogenative (CDC) strategy. Aldehydes also exhibit good selectivity forming the corresponding alpha-sulfenylated products. This efficient sulfenylation of ketones or aldehydes with thiones or heterocyclic thiols utilizes dimethyl sulfoxide (DMSO) as an oxidant in the presence of iodine. This eco-friendly method uses readily available and inexpensive I2 and DMSO. The application of this methodology has been demonstrated by synthesizing precursors for Julia- Kocienski olefination intermediates. PMID- 27934389 TI - Practical Cross-Coupling between O-Based Electrophiles and Aryl Bromides via Ni Catalysis. AB - Cross-coupling of various O-based electrophiles with aryl bromides was developed through Ni-catalyzed C-O activation in the presence of magnesium. Beside carboxylates, carbamates, and ethers, phenols exhibited excellent reactivity under modified conditions. This chemistry was featured as a simple and environmentally benign process with low catalyst loading and easy manipulations. The method exhibited broad substrate scopes. PMID- 27934390 TI - Catalytic Enantioselective Synthesis of Tetrahydocarbazoles and Exocyclic Pictet Spengler-Type Reactions. AB - A synthetic strategy for the synthesis of chiral tetrahydrocarbazoles (THCAs) has been developed. The strategy relies on two types of 6-exo-trig cyclization of 3 substituted indole substrates. Enantioselective domino Friedel-Crafts-type reactions leading to THCAs can be catalyzed by chiral phosphoric acid derivatives (with up to >99% ee), and the first examples of exocyclic Pictet-Spengler reactions to form THCAs are reported. PMID- 27934391 TI - Regio- and Chemoselective Mono- and Bisnitration of 8-Amino quinoline Amides with Fe(NO3)3.9H2O as Promoter and Nitro Source. AB - An efficient and regioselective remote C(5)-H nitration of 8-aminoquinoline amides by using the economical and nontoxic Fe(NO3)3.9H2O as promoter and nitro source has been developed. Furthermore, when CuCl2.2H2O was used as a catalyst, 8 aminoquinoline amides dominantly underwent bisnitration to give 5,7-dinitro-8 aminoquinoline amides. Notably, this is the first example in which Fe(NO3)3.9H2O plays a dual role as both chelating promoter and nitration reagent, and CuCl2.2H2O acts as an efficient catalyst for the bisnitration of quinolines. PMID- 27934393 TI - Transmetal-Catalyzed Enantioselective Cross-Coupling Reaction of Racemic Secondary Benzylic Bromides with Organoaluminum Reagents. AB - The transmetal-catalyzed enantioselective cross-coupling reaction of secondary benzylic electrophiles with organoaluminum reagents has been developed. The reaction of secondary benzylic electrophiles with alkynylaluminum reagents provides a mild way for the chiral propargyl compounds bearing aromatic group in high yields with good enantioselectivities using NiBr2.diglyme and (R)-iPr-Pybox as the catalytic system. The reaction of secondary benzylic electrophiles with alkenylaluminum reagents affords the corresponding chiral aryl alkenes in moderate yields with excellent stereoselectivities using commercially available PdCl2 and (R)-BINAP as the catalytic system. PMID- 27934392 TI - (+/-)-Ganoapplanin, a Pair of Polycyclic Meroterpenoid Enantiomers from Ganoderma applanatum. AB - (+/-)-Ganoapplanin (1), a pair of novel meroterpenoid enantiomers featuring an unprecedented dioxaspirocyclic skeleton constructed from a 6/6/6/6 tetracyclic system and an unusual tricyclo[4.3.3.03',7']dodecane motif, were isolated from Ganoderma applanatum. Its structure and absolute configurations were determined by spectroscopic analyses, X-ray crystallography, and ECD (electronic circular dichroism calculations). A plausible biogenetic pathway, involving a key Gomberg Bachmann reaction, was also proposed for (+/-)-1. Biological studies showed that (+/-)-1 and its enantiomers exhibited different inhibitory activities on T-type voltage-gated calcium channels. PMID- 27934395 TI - Mechanism of Silver-Mediated Geminal Difluorination of Styrenes with a Fluoroiodane Reagent: Insights into Lewis-Acid-Activation Model. AB - Fluorination mediated by the cyclic hypervalent fluoroiodane reagent (1) often requires an exogenous Lewis acid. The widely accepted Lewis-acid-activation model is that a given Lewis acid binds to the oxygen atom of 1 (O-coordination) to polarize the I-O bond. Computational studies of silver-mediated geminal difluorination of styrenes with 1 reveal a new "F-coordination" model that is energetically much preferred over the commonly accepted "O-coordination" model. The calculations rationalize the regioselective formation of the geminal difluorination product. PMID- 27934396 TI - Diethylenetriamine-Mediated Direct Cleavage of Unactivated Carbamates and Ureas. AB - Diethylenetriamine is effective for the direct cleavage of unactivated carbamates and ureas without additional reagents and catalysts. Various carbamates and ureas were cleaved to afford products in good yield, and the reactions were not affected by air or moisture. Unique chemoselective cleavage of carbamate and urea in the presence of amides was also achieved. PMID- 27934394 TI - Euphomilones A and B, ent-Rosane Diterpenoids with 7/5/6 and 5/7/6 Skeletons from Euphorbia milii. AB - Three highly modified ent-rosane diterpenoids, euphomilones A (1) and B (2) and euphomianol A (3), were isolated from the aerial parts of Euphorbia milii. The structures were elucidated from physical, spectroscopic, and X-ray diffraction data, as well as experimental and calculated electronic circular dichroism (ECD) analysis. Plausible biogenetic pathways to 1-3 are proposed. Also, compound 1 exhibited inhibition of receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast formation (IC50 = 12.6 MUM). PMID- 27934397 TI - Nanoscale Disassembly and Free Radical Reorganization of Polydopamine in Ionic Liquids. AB - Despite the growing scientific and technological relevance of polydopamine (PDA), a eumelanin-like adhesive material widely used for surface functionalization and coating, knowledge of its structural and physicochemical properties, including in particular the origin of paramagnetic behavior, is still far from being complete. Herein, we disclose the unique ability of ionic liquids (ILs) to disassemble PDA, either as a suspension or as a thin film, up to the nanoscale, and to establish specific interactions with the free radical centers exposed by deaggregation of potential investigative value. Immersion of PDA-coated glasses into four different ILs ([C1C1im][(CH3O)HPO2], [C1C1im][(CH3O)CH3PO2], [C1C1im][(CH3O)2PO2], [N1888][C18:1]) at room temperature caused the fast and virtually complete removal of the coating as determined by UV-visible spectroscopy and scanning electron microscopy (SEM). Transmission electron microscopy (TEM) analysis of the colored supernatants from PDA suspensions in ILs revealed the presence of nanostructures not exceeding 50 nm in diameter. Electron paramagnetic resonance (EPR) analysis indicated profound IL-dependent modifications in signal intensity, line-width, and g-factor values of PDA. These differences were interpreted in terms of a partial conversion of C-centered radicals into O-centered semiquinone-type components following destacking and interaction with the anion component in ILs. The discovery of ILs as a powerful tool to disassemble PDA under mild conditions provides a new entry both to detailed investigations of this biopolymer on the nanoscale and to mild removal of coatings from functionalized surfaces, greatly expanding the scope of PDA based surface functionalization strategies. PMID- 27934398 TI - Energetic and Dynamic Analysis of Transport of Na+ and K+ through a Cyclic Peptide Nanotube in Water and in Lipid Bilayers. AB - Potential of mean force (PMF) profiles and position-dependent diffusion coefficients of Na+ and K+ are calculated to elucidate the translocation of ions through a cyclic peptide nanotube, composed of 8 * cyclo[-(d-Leu-Trp)4-] rings, in water and in hydrated DMPC bilayers. The PMF profiles and PMF decomposition analysis for the monovalent cations show that favorable interactions of the cations with the CPN as well as the lipid bilayer and dehydration free energy penalties are two major competing factors which determine the free energy surface for ion transport through CPNs both in water and in lipid bilayers, and that the selectivity of CPNs to cations mainly arises from favorable interaction energies of cations with CPNs and lipid bilayers that are more dominant than the dehydration penalties. Calculations of the position-dependent diffusion coefficients and dynamic friction kernels of the cations indicate that the dehydration process along with the molecular rearrangements occurring outside the channel and the coupling of the ion motions with the chain-structured water movements inside the channel lead to a decrease of the diffusion coefficients far away from the channel entrance and also reduced coefficients inside the channel. The PMF and diffusivity profiles for Na+ and K+ reveal that the energetics of ion transport through the CPN are governed by global interactions of ions with all the components in the system, while the diffusivity of ions through the channel is mostly determined by local interactions of ions with the confined water molecules inside the channel. Comparison of Na+ and K+ ion distributions based on overdamped Brownian dynamics simulations based on the PMF and diffusivity profiles with the corresponding results from molecular dynamics shows good agreement, indicating accuracy of the Bayesian inference method for determining diffusion coefficients in this application. In addition, this work shows that position-dependent diffusion coefficients of ions are required to explain the dynamics and conductance of ions through the CPN properly. PMID- 27934399 TI - Nanoscopic Structural Investigation of Physically Cross-Linked Nanogels Formed from Self-Associating Polymers. AB - The detailed structure of a nanogel formed by self-association of cholesterol bearing pullulans (CHPs) was determined by contrast variation small-angle neutron scattering. The decomposition of scattering intensities into partial scattering functions of each CHP nanogel component, i.e., pullulan, cholesterol, and the cross-term between the pullulan and the cholesterol, allows us to investigate the internal structure of the nanogel. The effective spherical radius of the skeleton formed by pullulan chains was found to be 8.1 +/- 0.3 nm. In the CHP nanogel, there are about 19 cross-linking points where a cross-linking point is formed by aggregation of trimer cholesterol molecules, and the spatially inhomogeneous distribution of the cross-linking points in the nanogel can be represented by the mass fractal dimension of 2.6. The average radius of gyration of the partial chains can also be determined to be 1.7 +/- 0.1 nm by analyzing the extracted cross-correlation between the cross-linker and the tethered polymer chain quantitatively, and the size agrees with the value assuming random distribution of the cross-linkers on the chains. As the result, the complex structure of the nanogels is coherently revealed at the nanoscopic level. PMID- 27934400 TI - Organic-Inorganic Nanocomposites via Self-Assembly of an Amphiphilic Triblock Copolymer Bearing a Poly(butadiene-g-POSS) Subchain in Epoxy Thermosets: Morphologies, Surface Hydrophobicity, and Dielectric Properties. AB - Organic-inorganic nanocomposites composed of polyhedral oligomeric silsesquioxane (POSS) and epoxy resin were prepared via self-assembly of an amphiphilic triblock copolymer bearing a poly(POSS) midblock in epoxy thermosets. First, this organic inorganic amphiphilic triblock copolymer was synthesized via hydrosilylation of heptaphenylhydro POSS with an existing triblock copolymer containing a short polybutadiene midblock. It was found that this novel amphiphilic block copolymer can self-assemble into nanophases in epoxy thermosets. In the presence of preformed nanophases, the curing reaction was performed, and the organic inorganic nanocomposites containing poly(POSS) microdomains were thus obtained. Compared with plain epoxy, the as-obtained thermosets exhibited enhanced surface hydrophobicity; the enhanced surface hydrophobicity is attributed to enrichment of the POSS component at the surface of the materials. Owing to the formation of poly(POSS) microdomains, the dielectric constants of the materials significantly reduced, whereas the dielectric loss remained almost unchanged. PMID- 27934401 TI - Tuning the Phosphorescence and Solid State Luminescence of Triarylborane Functionalized Acetylacetonato Platinum Complexes. AB - A new series of luminescent cyclometalated platinum complexes with triarylborane functionalized acetylacetonate ligands is reported. The complexes exhibit solid state luminescence and phosphorescence under ambient conditions. The luminescence color can be tuned from green to red by varying the cyclometalating ligand [2 phenylpyridine (for 1 and 2), 2-thiophenylpyridine (for 3 and 4), 2 thianapthenylpyridine (for 5 and 6)]. The luminescence originates from mixed 3MLCT/3IL [MLCT, metal to ligand charge transfer; IL, intraligand] states of square planar platinum and borane moieties. The pi spacer (phenyl or duryl) which connects the boryl and platinum entities has a significant role in determining the photoluminescence efficiency. The bulky duryl spacer in 2, 4, and 6 significantly reduces pi-pi stacking of the square planar platinum moiety in the solid state and provides a rigid backbone, thereby increasing their quantum yield significantly. The role of Lewis-acidic borane on the photoluminescence features is evaluated by fluoride binding experiments. PMID- 27934402 TI - Solid-State 27Al NMR Spectroscopy of the gamma-Al13 Keggin Containing Al Coordinated by a Terminal Hydroxyl Ligand. AB - We report solid-state 27Al NMR spectroscopic results for the sulfate salt of the gamma-Al13 Keggin cluster, gamma-[AlO4Al12(OH)25(OH2)11][SO4]3.[H2O]14, that provide a spectroscopic signature for partial hydrolysis of this Keggin-type cluster. In 27Al multiple-quantum magic-angle spinning NMR spectra, all 13 Al positions of the cluster are at least partially resolved and assigned with the aid of density functional theory (DFT) calculations of the 27Al electric field gradients. The isotropic chemical shift of the single tetrahedral site, 75.7 ppm, is nearly identical to that reported for solutions from which the cluster crystallizes. Reflecting broadly similar coordination environments, the octahedral Al show mostly small variations in isotropic chemical shift (+7 to +11 ppm) and quadrupolar coupling constant (CQ; 6-7.5 MHz), except for one resonance that exhibits a much smaller CQ and another site with a larger value. DFT calculations show that deprotonation of a terminal water ligand, to form an eta OH group, causes a large reduction in the 27Al CQ, allowing assignment of a distinct, narrow peak for octahedral Al to this hydroxyl-terminated site. This result suggests a relationship between octahedral 27Al NMR line width and hydrolysis for solids prepared from Keggin-type clusters. PMID- 27934403 TI - Transition-Metal-Complex Cationic Dyes Photosensitive to Two Types of 2D Layered Silver Bromides with Visible-Light-Driven Photocatalytic Properties. AB - With mixed transition-metal (TM) complex, alkali-metal cations, or halogen anions as structure-directing agents, two types of two-dimensional (2D) layered inorganic-organic hybrid silver bromides were prepared and structurally characterized as K[TM(2,2-bipy)3]2Ag6Br11 (TM = Ni (1), Co (2), Zn (3), Fe (4)) and [TM(2,2-bipy)3]2Ag13Br17 (TM = Ni (5), Co (6), Zn (7), Fe (8)). Compounds 1-4 feature 2D microporous anionic [Ag6Br11]5- layers composed of [Ag3Br7] secondary building units based on AgBr4 tetrahedral units, and compounds 5-8 contain 2D [Ag13Br16]3- layers built from the one-dimensional complex [Ag8Br12] and [Ag5Br8] chains. The photosensitization of TM complex dyes led to the narrow semiconducting behaviors with tunable band gaps of 1.73-2.71 eV for the title compounds, which result in excellent and stable photocatalytic degradation activities over organic pollutants under visible-light irradiation. The studies of photocatalytic mechanism based on radical-trapping experiments and electronic band structural calculation show that the TM complex cations play important roles in the photocatalytical activities and photochemical stabilities due to their excellent separating abilities for photogenerated carriers. This technique affords one new type of visible-light-driven photocatalyst and facilitates the integration of 2D layered materials and semiconducting photocatalytic properties into one hybrid d10 TM halogenide. PMID- 27934404 TI - Boron Trifluoride Gas Adsorption in Metal-Organic Frameworks. AB - Coordinatively unsaturated metal-organic frameworks (MOFs) were studied for boron trifluoride (BF3) sorption. MOF-74-Mg, MOF-74-Mn, and MOF-74-Co show high initial uptake (below 6.7 * 10-3 bar) with negligible deliverable capacity. The BF3 isotherm of MOF-74-Cu exhibits gradual uptake up to 0.9 bar and has a deliverable gravimetric capacity that is more than 100% higher than activated carbon. Two other Cu2+ MOFs, MOF-505 and HKUST-1, have slightly lower deliverable capacities compared to MOF-74-Cu. PMID- 27934405 TI - Evaluating NaREMgWO6 (RE = La, Gd, Y) Doubly Ordered Double Perovskites as Eu3+ Phosphor Hosts. AB - Three doubly ordered double perovskites NaREMgWO6 (RE = La, Gd, Y) have been synthesized via traditional solid-state methods, doped with Eu3+, and characterized to evaluate their promise as Eu3+ phosphor hosts. NaYMgWO6, a new member of the family, was found to crystallize in the P21 space group and is isostructural with NaGdMgWO6. Emissions characteristic of Eu3+ ions (5D0 -> 7F4,3,2,1,0) were observed, with the most intense transition being the 5D0 -> 7F2 transition near 615 nm. Substitution of Eu3+ onto a more compressed RE site in the NaY1-xEuxMgWO6 and NaGd1-xEuxMgWO6 hosts results in a blue shift of the charge-transfer excitation band and an increase in the intensity of the 5D0 -> 7F2 transition compared to NaLa1-xEuxMgWO6. All of the hosts can incorporate high concentrations of Eu3+ before concentration quenching is observed. When the rare earth ion is either Gd3+ or Y3+, good energetic overlap between the Eu3+ charge transfer band and the absorption of the host lattice results in sensitization and energy transfer from the perovskite host lattice to the Eu3+ activator sites. These hosts display comparable if not better luminescence than Y2O3:Eu3+, a commonly used commercial standard, demonstrating their promise as red phosphors. PMID- 27934406 TI - Structures of M2(SO2)6B12F12 (M = Ag or K) and Ag2(H2O)4B12F12: Comparison of the Coordination of SO2 versus H2O and of B12F122- versus Other Weakly Coordinating Anions to Metal Ions in the Solid State. AB - The structures of three solvated monovalent cation salts of the superweak anion B12F122- (Y2-), K2(SO2)6Y, Ag2(SO2)6Y, and Ag2(H2O)4Y, are reported and discussed with respect to previously reported structures of Ag+ and K+ with other weakly coordinating anions. The structures of K2(SO2)6Y and Ag2(SO2)6Y are isomorphous and are based on expanded cubic close-packed arrays of Y2- anions with M(OSO)6+ complexes centered in the trigonal holes of one expanded close-packed layer of B12 centroids (?). The K+ and Ag+ ions have virtually identical bicapped trigonal prism MO6F2 coordination spheres, with M-O distances of 2.735(1)-3.032(2) A for the potassium salt and 2.526(5)-2.790(5) A for the silver salt. Each M(OSO)6+ complex is connected to three other cationic complexes through their six MU-SO2 kappa1O,kappa2O' ligands. The structure of Ag2(H2O)4Y is unique [different from that of K2(H2O)4Y]. Planes of close-packed arrays of anions are offset from neighboring planes along only one of the linear ?...?...? directions of the close packed arrays, with [Ag(MU-H2O)2Ag(MU-H2O)2)]infinity infinite chains between the planes of anions. There are two nearly identical AgO4F2 coordination spheres, with Ag-O distances of 2.371(5)-2.524(5) A and Ag-F distances of 2.734(4) 2.751(4) A. This is only the second structurally characterized compound with four H2O molecules coordinated to a Ag+ ion in the solid state. Comparisons with crystalline H2O and SO2 solvates of other Ag+ and K+ salts of weakly coordinating anions show that (i) N[(SO2)2(1,2-C6H4)]-, BF4-, SbF6-, and Al(OC(CF3)3)4- coordinate much more strongly to Ag+ than does Y2-, (ii) SnF62- coordinates somewhat more strongly to K+ than does Y2-, and (iii) B12Cl122- coordinates to K+ about the same as, if not slightly weaker than, Y2-. PMID- 27934407 TI - Synthesis and Characterization of Adducts between SF4 and Oxygen Bases: Examples of O...S(IV) Chalcogen Bonding. AB - Lewis acid-base adducts between SF4 and the oxygen bases tetrahydrofuran, cyclopentanone, and 1,2-dimethoxyethane were synthesized and characterized by Raman spectroscopy and X-ray crystallography. Crystal structures of (SF4.OC4H8)2, SF4.(OC4H8)2, SF4.CH3OC2H4OCH3, and SF4.(O?C5H8)2 show weak S...O chalcogen bonding interactions ranging from 2.662(2) to 2.8692(9) A. Caffeine, which has three Lewis basic sites, was reacted with SF4 and one aliquot of HF forming C8H10N4O2.2SF4.HF, which was also characterized by X-ray crystallography. Density functional theory calculations aided in the assignment of the vibrational spectra of (SF4.OC4H8)2, SF4.(OC4H8)2, SF4.CH3OC2H4OCH3, and SF4.(O?C5H8)2. Bonding was studied by natural bond order and the quantum theory of atoms in molecules analyses. PMID- 27934408 TI - Variation of the Molecular Conformation, Shape, and Cavity Size in Dinuclear Metalla-Macrocycles Containing Hetero-Ditopic Dithiocarbamate-Carboxylate Ligands from a Homologous Series of N-Substituted Amino Acids. AB - A homologous series of dithiocarbamate ligands derived from N-substituted amino acids was reacted with different diorganotin dichlorides to give 18 diorganotin complexes. Spectroscopic and mass spectrometric analysis evidenced the formation of assemblies with six-coordinate tin atoms embedded in skewed-trapezoidal bipyramidal coordination environments of composition C2SnS2O2. Single-crystal X ray diffraction analysis for three of the compounds revealed a one-dimensional polymeric structure for the complex with the ligand derived from 5-aminopentanoic acid, which through further intermolecular Sn...O interactions generated an overall two-dimensional coordination polymer containing 40-membered hexanuclear tin macrocycles. On the contrary, the ligands derived from 6-aminohexanoic and 8 aminooctanoic acid provided the expected 22- and 26-membered dinuclear macrocyclic structures. Density functional theory calculations for a representative series of macrocyclic complexes of composition [Me2SnLx]2 with Lx = -S2CN(Me)-(CH2)x-COO- (x = 3-12) enabled a detailed analysis of the variations in the molecular conformation, shape, and cavity size of the macrocycles in dependence of the aliphatic spacer. Because of odd-even effects, the difunctional ligands can adopt either a curved or a twisted-pincer shape, while the SnSxO4-x (x = 0-4) moieties can act either as linear or angular tectons with varying connectivity angles. PMID- 27934409 TI - Kinetically Inert Lanthanide Complexes as Reporter Groups for Binding of Potassium by 18-crown-6. AB - The barcode-like spectrum of lanthanide-centered emission has been used in imaging and to make responsive luminescent reporters. The intensities and the shapes of each line in the luminescence spectrum can also report on the coordination environment of the lanthanide ion. Here, we used lanthanide-centered emission to report on the binding of potassium in an 18-crown-6 binding pocket. The responsive systems were made by linking a crown ether to a kinetically inert lanthanide binding pocket using a molecular building block approach. Specifically, an alkyne-appended Ln.DO3A was used as a building block in a copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) "click" reaction with azide-functionalized crown ethers. The resulting complexes were investigated using NMR and optical methods. Titrations with potassium chloride in methanol observing the sensititzed europium- and terbium-centered emissions were used to investigate the response of the systems. The molecular reporters based on aliphatic crown ethers were found to have strongly inhibited binding of potassium, while the benzo-18-crown-6 derived systems had essentially the same association constants as the native crown ethers. The shape of the lanthanide emission spectra was shown to be unperturbed by the binding of potassium, while the binding was reported by an overall increased intensity of the lanthanide centered emission. This observation was contrasted to the change in spectral shape between propargyl-Ln.DO3A and the triazolyl-Ln.DO3A complexes. The solution structure of the lanthanide complexes was found to be determining for the observed physical chemical properties of these systems. PMID- 27934410 TI - Isomeric Diruthenium Complexes of a Heterocyclic and Quinonoid Bridging Ligand: Valence and Spin Alternatives for the Metal/Ligand/Metal Arrangement. AB - 5,7,12,14-Tetraazapentacene-6,13-quinone (L) reacts with 2 equiv of [Ru(acac)2(CH3CN)2] to form two linkage isomeric bis(chelate) compounds, [{RuII(acac)2}2(MU-L)], blue 1, with 5,6;12,13 coordination and violet 2 with 5,6;13,14 coordination. The linkage isomers could be separated, structurally characterized in crystals as rac diastereomers (DeltaDelta/LambdaLambda), and studied by voltammetry (CV, DPV), EPR, and UV-vis-NIR spectroelectrochemistry (meso-1, rac-2). DFT and TD-DFT calculations support the structural and spectroscopic results and suggest a slight energy preference (DeltaE = 263 cm-1) for the rac-isomer 1 as compared to 2. Starting from the RuII-(MU-L0)-RuII configurations of 1 and 2 with low-lying metal-to-ligand charge transfer (MLCT) absorptions, the compounds undergo two reversible one-electron oxidation steps with open-shell intermediates 1+ (Kc = 4 * 104) and 2+ (Kc = 6 * 105). Both monocations display metal-centered spin according to EPR, but the DFT-calculated spin densities suggest a RuIII(MU-L*-)RuIII three-spin situation with opposite spin density at the bridging ligand for the meso form of 1+, estimated to lie 1887 cm-1 lower in energy than rac-1+, which is calculated with a Class II mixed valent situation RuIII-(MU-L0)-RuII. A three-spin arrangement RuIII-(MU-L*-) RuIII with negative spin density at one metal site is suggested by DFT for rac-2+ which is more stable by DeltaE = 890 cm-1 than rac-1+. Reduction of 1 or 2 (Kc = 107-108) occurs mainly at the central bridging ligand with notable contributions (30%) from the metals in 1- and 2-. The mixed-valent RuIII(MU-L)RuII versus radical-bridged RuIII(MU-L*-)RuIII alternative is discussed comprehensively in comparison with related valence-ambiguous cases. PMID- 27934411 TI - Cadmium Compounds with an [N3C] Atrane Motif: Evidence for the Generation of a Cadmium Hydride Species. AB - Tris(2-pyridylthio)methane ([Tptm]H) has been employed to synthesize a series of cadmium carbatrane compounds that feature an [N3C] coordination environment. Specifically, [Tptm]H reacts with Cd[N(SiMe3)2]2 to afford [Tptm]CdN(SiMe3)2, which thereby provides access to other derivatives. For example, [Tptm]CdN(SiMe3)2 reacts with (i) CO2 to form {[Tptm]Cd(MU-NCO)}2 and (ii) Me3SiOH and Ph3SiOH to form {[kappa3-Tptm]Cd(MU-OSiMe3)}2 and [Tptm]CdOSiPh3, respectively. The siloxide compound {[kappa3-Tptm]Cd(MU-OSiMe3)}2 reacts with Me3SiX (X = Cl, Br, O2CMe) to give [Tptm]CdX, while the reaction with PhSiH3 in the presence of CO2 generates the formate complex, [Tptm]CdO2CH, thereby providing evidence for the generation of a proposed cadmium hydride intermediate, {[Tptm]CdH}. PMID- 27934412 TI - Computational Gas-Phase Formation Enthalpy and Electron Affinity for Platinum Hexafluoride: Is Gaseous PtF6 Diamagnetic because of a Relativistic Effect? AB - In the present work, a computational thermochemistry study (semiempirical, PM6 method) for platinum hexafluoride (PtF6) is performed. The gas-phase formation enthalpy (DeltafH degrees ) and electron affinity are calculated and the results compared with the experimental data. A calculated DeltafH degrees (g) value of 669.47 kJ mol-1, in very good agreement with the experimental data from the literature, was obtained by Knudsen cell mass spectrometry. However, such a value was obtained when a PtF6 molecule with no unpaired electrons (diamagnetic) was modeled. Such a fact is in contrast with the four-unpaired-electron configuration (t2g3eg1) generally accepted for gaseous (and solid) PtF6 but is in agreement with the fact (based on quantum relativistic calculations) that the triplet state t2g is split in the tetragonal field into a singlet and a lower-lying doublet, with four 5d4 electrons occupying the 5dxz and 5dyz atomic orbitals in the spin paired state. The modeled compound exhibits a distorted structure and a dipole moment of 0.30 D. The calculated electron affinity is 7.6 eV, in very good agreement with the experimental and calculated data. The computed zero-point energy, G degrees , H degrees , and S degrees values for such a structure are 34.71 kJ mol-1, -725.59 kJ mol-1, -612.11 kJ mol-1, and 380.31 J K-1 mol-1. The positive S degrees and negative G degrees and H degrees values show that, from a thermodynamic point of view, the structure it stable. A working hypothesis is proposed in which the coordination number in PtF6 is 8 and the fluoride has a polymeric nature. PMID- 27934413 TI - Synthesis, Characterization, and Low Temperature Transport Properties of Eu11 xYbxCd6Sb12 Solid-Solution Zintl Phases. AB - Eu11-xYbxCd6Sb12 Zintl solid solutions have been prepared by tin flux reaction by employing the elements Eu/Yb/Cd/Sb/Sn in the ratio 11 - xp:xp:6:12:30, where xp is an integer less than 11 representing the preparative amount of Eu (11 - xp) and Yb (xp). Efforts to make the Yb compositions for x exceeding ~3 resulted in structures other than the Sr11Cd6Sb12 structure type. The crystal structures and compositions were determined by single-crystal and powder X-ray diffraction and wavelength-dispersive X-ray analysis measurements. The title solid-solution Zintl compounds crystallize in the centrosymmetric monoclinic space group C2/m (no. 12, Z = 2) as the Sr11Cd6Sb12 structure type (Pearson symbol mC58), and the lattice parameters decrease with increasing ytterbium content. Single crystal X-ray diffraction shows that Yb atoms are not randomly distributed in the Eu sites but have a site preference which can be attributed to size effects. The influence of the rare earth (RE) metal sites on thermal and electronic properties of RE11Cd6Sb12 solid solutions has been studied by measuring their thermoelectric properties from 5 to 300 K after consolidation by either spark plasma sintering (SPS) or hot pressing (HP). Electron microprobe analysis reveals that some of the rare earth metal is lost during SPS; as a result pellets formed through SPS have lower electrical resistivity by an order of magnitude due to increased hole charge carrier concentrations. While the carrier concentration increases, the mobility decreases due to deficiencies in Eu content. Refinement of powder X-ray diffraction shows that Eu loss is mainly from the Eu1 crystallographic site, which has a unique coordination suggesting that this site plays a key role in the transport properties of RE11Cd6Sb12. PMID- 27934414 TI - Computational Design of Cobalt Catalysts for Hydrogenation of Carbon Dioxide and Dehydrogenation of Formic Acid. AB - A series of cobalt complexes with acylmethylpyridinol and aliphatic PNP pincer ligands are proposed based on the active site structure of [Fe]-hydrogenase. Density functional theory calculations indicate that the total free energy barriers of the hydrogenation of CO2 and dehydrogenation of formic acid catalyzed by these Co complexes are as low as 23.1 kcal/mol in water. The acylmethylpyridinol ligand plays a significant role in the cleavage of H2 by forming a strong Co-Hdelta-...Hdelta+-O dihydrogen bond in a fashion of frustrated Lewis pairs. PMID- 27934416 TI - Solid Solutions between BiMnO3 and BiCrO3. AB - Solid solutions BiMn1-xCrxO3 (0 <= x <= 1) have been prepared at 6 GPa and 1370 1620 K. Their structural properties have been studied with synchrotron X-ray powder diffraction, and their physical properties have been investigated by dc/ac magnetic, specific heat, dielectric, and differential scanning calorimetry measurements. A magnetic phase diagram of BiMn1-xCrxO3 is established. A phase with orbital ordering observed in BiMnO3 is suppressed at x > 0.1, accompanied by a drop in the ferromagnetic Curie temperature TC from 101 K for x = 0 to 76 K for x = 0.15 and sharp changes in the lattice parameters. The TC value monotonically decreases up to x = 0.3 (with TC = 53 K). For intermediate compositions with x = 0.4, 0.5, spin-glass magnetic properties are found at 28 and 24 K, respectively. The Neel temperature TN linearly increases from 36 K for x = 0.6 to 111 K for x = 1.0. A spin-reorientation transition is observed at 61 K for x = 0.9 and 72 K for x = 1.0. Re-entrant spin-glass transitions are also observed for samples with x = 0.3, 0.6, 0.7 by ac susceptibility at low temperatures. At high temperatures, a structural phase transition from C2/c to Pnma symmetry is observed for all compositions with a monotonic change of the phase transition temperature. The magnetic phase diagram from the BiMnO3-rich side (x <= 0.5) resembles a phase diagram of BiMn1-xScxO3 solid solutions, indicating that the nature of substituting cations (magnetic or nonmagnetic) is not crucial for doped BiMnO3. PMID- 27934415 TI - Effect of Perylene Photosensitizer Attachment to [Pd(triphosphine)L]2+ on CO2 Electrocatalysis. AB - Two new covalently linked chromophore-CO2 reduction catalyst systems were prepared using a perylene chromophore and a bis[(dicyclohexylphosphino)ethyl]phenylphosphinopalladium(II) catalyst. The primary goal of this study is to probe the influence of photosensitizer attachment on the electrocatalytic performance. The position either para or meta to the phosphorus on the phenyl group of the palladium complex was linked via a 2,5-xylyl group to the 3 position of perylene. The electrocatalytic CO2 reduction activity of the palladium complex is maintained in the meta-linked system, but is lost in the para-linked system, possibly because of unfavorable interactions of the perylene chromophore with the glassy carbon electrode used. Following selective photoexcitation of the perylene, an enhanced perylene excited-state decay rate was observed in the palladium complexes compared to perylene attached to the free ligands. This decrease is accompanied by formation of the perylene cation radical, showing that electron transfer from perylene to the palladium catalyst occurs. Electron transfer and charge recombination were both found to be faster in the para-linked system than in the meta-linked one, which is attributed to stronger electronic coupling in the former. These results illustrate the need to carefully tune the electronic coupling between a photosensitizer chromophore and the catalyst to promote photodriven electron transfer yet inhibit adverse electronic effects of the chromophore on electrocatalysis. PMID- 27934417 TI - Hybridization Gap in the Semiconducting Compound SrIr4In2Ge4. AB - Large single crystals of SrIr4In2Ge4 were synthesized using the In flux method. This compound is a hybridization gap semiconductor with an experimental optical band gap of Eg = 0.25(3) eV. It crystallizes in the tetragonal EuIr4In2Ge4 structure type with space group I42m and unit cell parameters a = 6.9004(5) A and c = 8.7120(9) A. The electronic structure is very similar to both EuIr4In2Ge4 and the parent structure Ca3Ir4Ge4, suggesting that these compounds comprise a new family of hybridization gap materials that exhibit indirect gap, semiconducting behavior at a valence electron count of 60 per formula unit, similar to the Heusler alloys. PMID- 27934418 TI - Synthesis, Crystal Structures, Magnetic Properties, and Theoretical Investigation of a New Series of NiII-LnIII-WV Heterotrimetallics: Understanding the SMM Behavior of Mixed Polynuclear Complexes. AB - The polynuclear compounds containing anisotropic metal ions often exhibit efficient barriers for blocking of magnetization at fairly arbitrary geometries. However, at variance with mononuclear complexes, which usually become single molecule magnets (SMM) under the sole requirement of a highly axial crystal field at the metal ion, the factors influencing the SMM behavior in polynuclear complexes, especially, with weakly axial magnetic ions, still remain largely unrevealed. As an attempt to clarify these conditions, we present here the synthesis, crystal structures, magnetic behavior, and ab initio calculations for a new series of NiII-LnIII-WV trimetallics, [(CN)7W(CN)Ni(H2O)(valpn)Ln(H2O)4].H2O (Ln = Y 1, Eu 2, Gd 3, Tb 4, Dy 5, Lu 6). The surprising finding is the absence of the magnetic blockage even for compounds involving strongly anisotropic DyIII and TbIII metal ions. This is well explained by ab initio calculations showing relatively large transversal components of the g-tensor in the ground exchange Kramers doublets of 1 and 4 and large intrinsic tunneling gaps in the ground exchange doublets of 3 and 5. In order to get more insight into this behavior, another series of earlier reported compounds with the same trinuclear [WVNiIILnIII] core structure, [(CN)7W(CN)Ni(dmf)(valdmpn)Ln(dmf)4].H2O (Ln = GdIII 7, TbIII 8a, DyIII 9, HoIII 10), [(CN)7W(CN)Ni(H2O)(valdmpn)Tb(dmf)2.5(H2O)1.5].H2O.0.5dmf 8b, and [(CN)7W(CN)Ni(H2O)(valdmpn)Er(dmf)3(H2O)1].H2O.0.5dmf 11, has been also investigated theoretically. In this series, only 8b exhibits SMM behavior which is confirmed by the present ab initio calculations. An important feature for the entire series is the strong ferromagnetic coupling between Ni(II) and W(V), which is due to an almost perfect trigonal dodecahedron geometry of the octacyano wolframate fragment. The reason why only 8b is an SMM is explained by positive zero-field splitting on the nickel site, precluding magnetization blocking in complexes with fewer axial Ln ions. Further analysis has shown that, in the absence of ZFS on Ni ion, all compounds in the two series (except those containing Y and Gd) would be SMMs. The same situation arises for perfectly axial ZFS on Ni(II) with the main anisotropy axis parallel to the main magnetic axis of Ln(III) ions. In all other cases the ZFS on Ni(II) will worsen the SMM properties. The general conclusion is that the design of efficient SMMs on the basis of such complexes should involve isotropic or weekly anisotropic metal ions, such as Mn(II), Fe(III), etc., along with strongly axial lanthanides. PMID- 27934419 TI - Paramagnetism of Aqueous Actinide Cations. Part II: Theoretical Aspects and New Measurements on An(IV). AB - The magnetic properties of actinide(IV) (An(IV)) cations are investigated in various solutions (HClO4, HCl, and HNO3) by the Evans NMR method. The magnetic susceptibilities measured in noncomplexing medium are compared with the previous studies, and the influence of the medium is verified with new measurements in complexing solutions. To rationalize these results, spin-orbit complete active space perturbation theory at second order calculations are performed on the free ions and on the aquo complexes to determine the nature of electronic states, the magnetic susceptibility, and the UV-visible-near-IR spectra. The different factors contributing to the An(IV) magnetic properties were identified. The ligand field effect on the magnetic behavior (Curie constant and temperature independent susceptibilities) was analyzed by considering different solvation environments. These results indicate a significant effect of the zero-field splitting of the ground J manifold on the An(IV) magnetic susceptibility. PMID- 27934420 TI - A Cyanide-Bridged Magnetically Switchable Cage with Encapsulated Water Molecules. AB - A cage complex, H2O@[Co5Fe4], was found to encapsulate two water molecules during its self-assembly. The complex exhibited remarkable multifunctionality, combining magnetic switching from the thermal electron-transfer-coupled spin transition of the cage host and dipolar reorientational motion of the confined water, as evidenced by permittivity measurements, density functional theory calculations, and solid-state 2H NMR spectra. PMID- 27934421 TI - Correction to Synthesis and Coordination Chemistry of a Phosphine-Decorated Fluorescein: "Double Turn-On" Sensing of Gold(III) Ions in Water. PMID- 27934422 TI - Excited States of Triphenylamine-Substituted 2-Pyridyl-1,2,3-triazole Complexes. AB - A new 2-pyridyl-1,2,3-triazole (pytri) ligand, TPA-pytri, substituted with a triphenylamine (TPA) donor group on the 5 position of the pyridyl unit was synthesized and characterized. Dichloroplatinum(II), bis(phenylacetylide)platinum(II), bromotricarbonylrhenium(I), and bis(bipyridyl)ruthenium(II) complexes of this ligand were synthesized and compared to complexes of pytri ligands without the TPA substituent. The complexes of unsubstituted pytri ligands show metal-to-ligand charge-transfer (MLCT) absorption bands involving the pytri ligand in the near-UV region. These transitions are complemented by intraligand charge-transfer (ILCT) bands in the TPA-pytri complexes, resulting in greatly improved visible absorption (lambdamax = 421 nm and epsilon = 19800 M-1 cm-1 for [Pt(TPA-pytri)Cl2]). The resonance Raman enhancement patterns allow for assignment of these absorption bands. The [Re(TPA-pytri)(CO)3Br] and [Pt(TPA-pytri)(CCPh)2] complexes were examined with time-resolved infrared spectroscopy. Shifts in the C=C and C=O stretching bands revealed that the complexes form states with increased electron density about their metal centers. [Pt(TPA-pytri)Cl2] is unusual in that it is emissive despite the presence of deactivating d-d states, which prevents emission from the unsubstituted pytri complex. PMID- 27934423 TI - Metal-Ligand Exchange in a Cyclic Array: The Stepwise Advancement of Supramolecular Complexity. AB - Herein, we demonstrate how the supramolecular complexity (evaluated by the degree of self-sorting M) evolves in a chemical cycle of cascaded metallosupramolecular transformations, using abiological self-assembled entities as input signals. Specifically, the successive addition of the supramolecular self-assembled structures S1 and (T2 + S2) to the starting supramolecular two-component equilateral triangle T1 (M = 1) first induced a fusion into the three-component quadrilateral R1 (M = 6) and then to the five-component scalene triangle T3 (M = 16). Upon the addition of the supramolecular input M1 to T3, a notable self sorting event occurred, leading to regeneration of the triangle T1 along with formation of the scalene triangle T4 (M = 25). This last step closed the cycle of the supramolecular transformations. PMID- 27934424 TI - Tetranuclear Lanthanide Complexes Containing a Hydrazone-type Ligand. Dysprosium [2 * 2] Gridlike Single-Molecule Magnet and Toroic. AB - A multidentate hydrazone-type ligand (Z,Z)-bis(1-(pyridin-2-yl)-1-amino methylidene)oxalohydrazide (H2L) was utilized in the synthesis of three new isomorphous tetranuclear complexes of the general formula [Ln4(HL)4(H2L)2(NO3)4](NO3)4.4CH3OH (Ln = GdIII, 1, TbIII, 2, DyIII, 3) with the gridlike [2 * 2] topology. The analysis of the static magnetic data revealed weak anti-ferromagnetic interaction among lanthanide(III) atoms, whereas dynamic magnetic data led to the observation of the single-molecule magnet behavior in zero static magnetic field for the Dy4 compound 3 with Ueff = 42.6 K and tau0 = 1.50 * 10-5 s. The theoretical CASSCF calculations supported also the presence of the net toroidal magnetic moment, which classifies compound 3 also as a single molecule toroic. PMID- 27934425 TI - Multiple Fluorine-Substituted Phosphate Germanium Fluorides and Their Thermal Stabilities. AB - Anhydrous compounds are crucially important for many technological applications, such as achieving high performance in lithium/sodium cells, but are often challenging to synthesize under hydrothermal conditions. Herein we report that a modified solvo-/hydro-fluorothermal method with fluoride-rich and water-deficient condition is highly effective for synthesizing anhydrous compounds by the replacement of hydroxyl groups and water molecules with fluorine. Two anhydrous phosphate germanium fluorides, namely, Na3[GeF4(PO4)] and K4[Ge2F9(PO4)], with chainlike structures involving multiple fluorine substitutions, were synthesized using the modified solvo-/hydro-fluorothermal method. The crystal structure of Na3[GeF4(PO4)] is constructed by the common single chains infinity1{[GeF4(PO4)]3 } built from alternating GeO2F4 octahedra and PO4 tetrahedra. For K4[Ge2F9(PO4)], it takes the same single chain in Na3[GeF4(PO4)] as the backbone but has additional flanking GeOF5 octahedra via an O-corner of the PO4 groups, resulting in a dendrite zigzag single chain infinity1{[Ge2F9(PO4)]4-}. The multiple fluorine substitutions in these compounds not only force them to adopt the low dimensional structures because of the "tailor effect" but also improve their thermal stabilities. The thermal behavior of Na3[GeF4(PO4)] was investigated by an in situ powder X-ray diffraction experiment from room temperature to 700 degrees C. The modified solvo-/hydro-fluorothermal method is also shown to be effective in producing the most germanium-rich compounds in the germanophosphate system. PMID- 27934426 TI - A "Beheaded" TAML Activator: A Compromised Catalyst that Emphasizes the Linearity between Catalytic Activity and pKa. AB - Studies of the new tetra-amido macrocyclic ligand (TAML) activator [FeIII{(Me2CNCOCMe2NCO)2CMe2}OH2]- (4) in water in the pH range of 2-13 suggest its pseudo-octahedral geometry with two nonequivalent axial H2O ligands and revealed (i) the anticipated basic drift of the first pKa of water to 11.38 due to four electron-donating methyl groups alongside (ii) its counterintuitive enhanced resistance to acid-induced iron(III) ejection from the macrocycle. The catalytic activity of 4 in the oxidation of Orange II (S) by H2O2 in the pH range of 7-12 is significantly lower than that of previously reported TAML activators, though it follows the common rate law (v/[FeIII] = kIkII[H2O2][S]/(kI[H2O2] + kII[S]) and typical pH profiles for kI and kII. At pH 7 and 25 degrees C the rate constants kI and kII equal 0.63 +/- 0.02 and 1.19 +/- 0.03 M-1 s-1, respectively. With these new values for pKa, kI and kII establishing new high and low limits, respectively, the rate constants kI and kII were correlated with pKa values of all TAML activators. The relations log k = log k0 + alpha * pKa were established with log k0 = 13 +/- 2 and 20 +/- 4 and alpha = -1.1 +/- 0.2 and -1.8 +/- 0.4 for kI and kII, respectively. Thus, the reactivity of TAML activators across four generations of catalysts is predictable through their pKa values. PMID- 27934427 TI - Spin-Lattice Coupling in [Ni(HF2)(pyrazine)2]SbF6 Involving the HF2- Superexchange Pathway. AB - Magnetoelastic coupling in the quantum magnet [Ni(HF2)(pyrazine)2]SbF6 has been investigated via vibrational spectroscopy using temperature, magnetic field, and pressure as tuning parameters. While pyrazine is known to be a malleable magnetic superexchange ligand, we find that HF2- is surprisingly sensitive to external stimuli and is actively involved in both the magnetic quantum phase transition and the series of pressure-induced structural distortions. The amplified spin lattice interactions involving the bifluoride ligand can be understood in terms of the relative importance of the intra- and interplanar magnetic energy scales. PMID- 27934428 TI - Characterization and Subsequent Reactivity of an Fe-Peroxo Porphyrin Generated by Electrochemical Reductive Activation of O2. AB - Reductive activation of O2 is achieved by using the [FeIII(F20TPP)Cl] (F20TPP = 5,10,15,20-tetrakis(pentafluorophenyl) porphyrinate) porphyrin through electrochemical reduction of the [FeIII(F20TPP)(O2*-)] superoxo complex. Formation of the [FeIII(F20TPP)(OO)]- peroxo species is monitored by using low temperature electronic absorption spectroscopy, electron paramagnetic resonance, and cyclic voltammetry. Its subsequent protonation to yield the [FeIII(F20TPP)(OOH)] hydroperoxo intermediate is probed using low-temperature electronic absorption spectroscopy and electron paramagnetic resonance. PMID- 27934430 TI - Stabilization of LnB12 (Ln = Gd, Sm, Nd, and Pr) in Zr1-xLnxB12 under Ambient Pressure. AB - We report ambient pressure stabilization of a previously synthesized high pressure (6.5 GPa) phase, GdB12, in a Zr1-xGdxB12 solid solution (with ~54 at. % Gd solubility, as determined by both powder X-ray diffraction and energy dispersive spectroscopy). Limited solubilities of Sm (~15 at. % Sm), Nd (~7 at. % Nd), and Pr (~4 at. % Pr), in ZrB12 were also achieved. Previous attempts at preparing these rare-earth borides were unsuccessful even under high pressure. On the basis of insights provided from the unit cell sizes observed via solid solutions, at least 6.5 GPa of pressure would be needed to synthesize these rare earth borides since Sm, Nd, and Pr atomic radii are larger than that of Gd. The solid-solution formation for Zr1-xGdxB12 and Zr1-xSmxB12 can be seen in the change of the unit cell of each of the solid solutions relative to their pure parent compounds as well as in the change of color of the respective alloys. For Zr0.45Gd0.55B12 and Zr0.70Sm0.30B12, the cubic unit cell parameter (a) reached a value of 7.453 and 7.428 A, respectively, compared to 7.412 A for pure ZrB12. PMID- 27934429 TI - "Molecular Nanoclusters": A 2-nm-Sized {Mn29} Cluster with a Spherical Structure. AB - The comproportionation reaction between MnII and MnVII sources in the presence of 3,3-dimethylacrylic acid and azides has led to a new {Mn29} molecular cluster with a spherical structure and dimensions of ~2.2 nm, comparable in size to the smallest classical and magnetic nanoparticles. PMID- 27934431 TI - Synthesis, Characterization, and Reactivity of the Group 11 Hydrido Clusters [Ag6H4(dppm)4(OAc)2] and [Cu3H(dppm)3(OAc)2]. AB - The group 11 hydride clusters [Ag6H4(dppm)4(OAc)2] (1) and [Cu3H(dppm)3(OAc)2] (2) (dppm = 1,1-bis(diphenylphosphino)methane) were synthesized in moderate yields from the reaction of M(OAc) (M = Ag, Cu) with Ph2SiH2, in the presence of dppm. Complex 1 is the first structurally characterized homometallic polyhydrido silver cluster to be isolated. Both 1 and 2 catalyze the hydrosilylation of (alpha,beta-unsaturated) ketones. Notably, this represents the first example of hydrosilylation with an authentic silver hydride complex. PMID- 27934433 TI - Cyanido Antimonate(III) and Bismuthate(III) Anions. AB - The reaction of in situ generated E(CN)3 (E = Sb, Bi) with different amounts of [Ph4P]CN and [PPN]CN ([PPN]+ = [Ph3P-N-PPh3]+) was studied, affording salts bearing the novel ions [E(CN)5]2-, [Bi2(CN)11]5-, and [Bi(CN)6]3-. The valence lone pair of electrons on the central atom of antimony and bismuth(III) compounds can be either sterically active in an unsymmetric fashion (three shorter bonds + x longer bonds) or symmetric (with rather long averaged bonds). In the presence of weakly coordinating cations (e.g., [Ph4P]+ and [PPN]+), the solid-state structures of salts with [E(CN)5]2- anions contain well-separated cations and monomeric anions, which display a sterically active lone pair and a monomeric square-based pyramidal (pseudo-octahedral) structure. The [Bi(CN)5.MeCN]2- acetonitrile adduct ion exhibits a strongly distorted octahedral structure, which is better understood as a [5 + 1] coordination. The intriguing [Ph4P]6[Bi2(CN)11]CN salt consists of separated cations and anions as well as well-separated [Bi2(CN)11]5- and CN- ions. The structure of the molecular [Bi2(CN)11]5- ion can be described as two square-based-pyramidal [Bi(CN)5]2- fragments connected by a disordered bridging CN- ion, thereby leading to a distorted-octahedral environment around the two Bi centers. Here the steric effect of the lone pair is much less pronounced but still present. PMID- 27934432 TI - Reactivity of a Cobalt(III)-Hydroperoxo Complex in Electrophilic Reactions. AB - The reactivity of mononuclear metal-hydroperoxo adducts has fascinated researchers in many areas due to their diverse biological and catalytic processes. In this study, a mononuclear cobalt(III)-peroxo complex bearing a tetradentate macrocyclic ligand, [CoIII(Me3-TPADP)(O2)]+ (Me3-TPADP = 3,6,9 trimethyl-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane), was prepared by reacting [CoII(Me3-TPADP)(CH3CN)2]2+ with H2O2 in the presence of triethylamine. Upon protonation, the cobalt(III)-peroxo intermediate was converted into a cobalt(III) hydroperoxo complex, [CoIII(Me3-TPADP)(O2H)(CH3CN)]2+. The mononuclear cobalt(III)-peroxo and -hydroperoxo intermediates were characterized by a variety of physicochemical methods. Results of electrospray ionization mass spectrometry clearly show the transformation of the intermediates: the peak at m/z 339.2 assignable to the cobalt(III)-peroxo species disappears with concomitant growth of the peak at m/z 190.7 corresponding to the cobalt(III)-hydroperoxo complex (with bound CH3CN). Isotope labeling experiments further support the existence of the cobalt(III)-peroxo and -hydroperoxo complexes. In particular, the O-O bond stretching frequency of the cobalt(III)-hydroperoxo complex was determined to be 851 cm-1 for 16O2H samples (803 cm-1 for 18O2H samples), and its Co-O vibrational energy was observed at 571 cm-1 for 16O2H samples (551 cm-1 for 18O2H samples; 568 cm-1 for 16O22H samples) by resonance Raman spectroscopy. Reactivity studies performed with the cobalt(III)-peroxo and -hydroperoxo complexes in organic functionalizations reveal that the latter is capable of conducting oxygen atom transfer with an electrophilic character, whereas the former exhibits no oxygen atom transfer reactivity under the same reaction conditions. Alternatively, the cobalt(III)-hydroperoxo complex does not perform hydrogen atom transfer reactions, while analogous low-spin Fe(III)-hydroperoxo complexes are capable of this reactivity. Density functional theory calculations indicate that this lack of reactivity is due to the high free energy cost of O-O bond homolysis that would be required to produce the hypothetical Co(IV)-oxo product. PMID- 27934434 TI - Characterization of Ground State Electron Configurations of High-Spin Quintet Ferrous Heme Iron in Deoxy Myoglobin Reconstituted with Trifluoromethyl Group Substituted Heme Cofactors. AB - We introduced trifluoromethyl (CF3) group(s) as heme side chain(s) of sperm whale myoglobin (Mb) in order to characterize the electronic nature of heme Fe(II) in deoxy Mb using 19F NMR spectroscopy. On the basis of the anti-Curie behavior of CF3 signals, we found that the deoxy Mb is in thermal equilibrium between the 5B2, (dxy)2(dxz)(dyz)(dz2)(dx2-y2), and 5E, (dxy)(dxz)2(dyz)(dz2)(dx2-y2), states of the heme Fe(II), i.e., 5B2 ? 5E. Analysis of the curvature in Curie plots has yielded for the first time DeltaH and DeltaS values of ~-20 kJ mol-1 and ~-60 J K 1 mol-1, respectively, for the thermal equilibrium. Thus, the 5E state is slightly dominant over the 5B2 one at 25 degrees C. These findings provide not only valuable information about the ground state electronic structure of the high spin heme Fe(II) in deoxy native Mb but also an important clue for elucidating the mechanism responsible for acceleration of the spin-forbidden oxygenation of the protein. PMID- 27934435 TI - Structural and Thermodynamic Stability of the "1111" Structure Type: A Case Study of the EuFZnPn Series. AB - Two new compounds with the LaOAgS structure, EuFZnAs (1) and EuFZnSb (2), were obtained via solid state reaction. Both compounds are tetragonal (P4/nmm) with the cell parameters a = 4.1000(1) A and c = 9.0811(1) A for 1 and a = 4.2852(1)A and c = 9.4238(1)A for 2. The absence of their phosphide analog can be explained based on crystal chemical considerations as well as on quantum-chemical estimates of their thermodynamic stability with respect to EuF2 and EuZn2Pn2. The magnetic response of 1 and 2 is ascribed to the presence of Eu2+ ions. Both compounds are paramagnetic down to low temperatures, where they order antiferromagnetically at ~5 K and ~3 K, respectively. They are narrow-gap semiconductors, and EuFZnSb demonstrates a relatively high value of the Seebeck coefficient. PMID- 27934436 TI - Verdazyl Radical, a Building Block for a Six-Spin-Center 2p-3d-4f Single-Molecule Magnet. AB - The versatile verdazyl family provides a new member as its reduced form 1,5 dimethyl-3-[3'-(hydroxymethyl)-2'-pyridine]-6-oxotetrazane (H3vdpyCH2OH). Upon oxidation and deprotonation in the presence of the acetate salts of CoII and DyIII, the vdpyCH2OH radical is able to self-assemble [(vdpyCH2O)2Co2Dy2ac8] (Hac = HO2CCH3), a 2p-3d-4f cluster displaying single-molecule-magnet properties. PMID- 27934437 TI - Insight into the Uranyl Oxyfluoride Topologies through the Synthesis, Crystal Structure, and Evidence of a New Oxyfluoride Layer in [(UO2)4F13][Sr3(H2O)8](NO3).H2O. AB - A new strontium uranyl oxyfluoride, [(UO2)4F13][Sr3(H2O)8](NO3).H2O, was synthesized under hydrothermal conditions. The single-crystal X-ray structure was determined. This compound crystallizes in the triclinic space group P1 (No. 2), with unit cell parameters a = 10.7925(16) A, b = 10.9183(16) A, c = 13.231(2) A, alpha = 92.570(8) degrees , beta = 109.147(8) degrees , gamma = 92.778(8) degrees , V = 1468.1(4) A3, and Z = 2. The structure is built from uranyl-containing [Formula: see text] chains of tetrameric units of corner-sharing UO2F5 pentagonal bipyramids. These chains are linked through trimeric strontium units to form strontium-uranyl oxyfluoride layers further assembled by nitrate groups. The interlayer space is occupied by free water molecules. This compound was characterized by spectroscopic methods, especially 19F NMR highlighting the many different fluoride sites. Structural relationships with other uranyl oxyfluorides were investigated through the different F/O ratios, the structural building unit, and the structural arrangement. PMID- 27934438 TI - Electrochemical Properties and CO2-Reduction Ability of m-Terphenyl Isocyanide Supported Manganese Tricarbonyl Complexes. AB - To circumvent complications with redox-active ligands commonly encountered in the study of manganese electrocatalysts for CO2 reduction, we have studied the electrochemistry of the manganese mixed carbonyl/isocyanide complexes XMn(CO)3(CNArDipp2)2 (X = counteranion), to evaluate the pairing effects of the counteranion and their influence over the potential necessary for metal-based reduction. The complexes described herein have been shown to act as functional analogues to the known homoleptic carbonyl manganese complexes [Mn(CO)5]n (n = 1 , 0, 1+). The m-terphenyl isocyanide ligand CNArDipp2 improves the kinetic stability of the resulting mixed carbonyl/isocyanide systems, such that conversion among all three oxidation states is easily effected by chemical reagents. Here, we have utilized an electrochemical study to fully understand the redox chemistry of this system and its ability to facilitate CO2 reduction and to provide comparison to known manganese-based CO2 electrocatalysts. Two complexes, BrMn(CO)3(CNArDipp2)2 and [Mn(THF)(CO)3(CNArDipp2)2]OTf, have been studied using infrared spectroelectrochemistry (IR-SEC) to spectroscopically characterize the redox states of these complexes during the course of electrochemical reactions. A striking difference in the necessary potential leading to the first one-electron reduction has been found for the halide and triflate species, respectively. Complete selectivity for the formation of CO and CO32- is observed in the reactivity of [Mn(CO)3(CNArDipp2)2]- with CO2, which is deduced via the trapping and incorporation of liberated CO into the zerovalent species Mn(CO)3(CNArDipp2)2 to form the dimers Mn2(CO)7(CNArDipp2)3 and Mn2(CO)8(CNArDipp2)2. PMID- 27934439 TI - Cp*-Substituted Boron Cations: The Effect of NHC, NHO, and CAAC Ligands. AB - The effect of a ligand on the electron deficiency and Lewis acidity of the Cp* substituted boron dication has been investigated experimentally and theoretically. In addition to the reported IMes- and N-heterocyclic olefin (NHO) stabilized boron dications, the related cyclic alkylamino carbene (CAAC) coordinated boron mono- and dications have also been synthesized and structurally characterized. An electrochemical study of dications [3a-3c]2+ confirms the higher electron deficiency of the dicationic system than the related boron monocations. Moreover, the presence of a pi-acidic CAAC ligand is critical for realizing stable radical species generated from the chemical reduction of boron cations. The nature of the axial ligand also significantly affects the selectivity of the hydride addition reaction of boron dications. While bulky superhydride reacts with [3a-3c]2+ in the same manner to give the cyclic boreniums, [BH4]- attacks three different electrophilic sites of boron dications: the sp2 carbon of Cp* of the IMes-coordinated system ([3a]2+), the central boron atom of the NHO-stabilized analogue ([3b]2+), and the ylidene carbon of the CAAC containing boron dication ([3c]2+). PMID- 27934440 TI - Introduction of a Biphenyl Moiety for a Solvent-Responsive Aryl Gold(I) Isocyanide Complex with Mechanical Reactivation. AB - Luminescent compounds that are sensitive to volatile organic solvents are useful for detection of harmful gases. Although such compounds have been reported, discrimination of various types of volatile organic compounds using one compound remains challenging. We reported a series of gold isocyanide complexes that form various crystalline structures with distinct emission properties, which can be interconverted by mechanical stimulation and solvent addition. Here, we report that introduction of a biphenyl unit into a gold isocyanide scaffold (denoted complex 3) enables discrimination of various volatile organic compounds by forming 11 solvent-containing crystal structures 3/solvent [solvent can be CHCl3, pyridine (Py), CH2Cl2, CH2Br2, dimethylacetamide (DMA), acetaldehyde (AcH), CH3CN, DMF, (S)-propylene oxide (SPO), rac-propylene oxide (racPO), or acetone] with different emission properties (emission maxima of 490-580 nm). Mechanical stimulation of 3/solvent affords amorphous 3ground without solvent inclusion. The resulting 3ground can again detect volatile compounds by forming 3/solvent with concomitant emission color changes. We also afforded a dozen single crystals of 3, which include 11 solvated 3/solvent and one solvent-free 3/none. The molecular arrangements of 3 in 3/solvent and 3/none are all different. Comparison of various crystallographic parameters of 3/solvent and 3/none with their corresponding optical properties indicates that a combination of various structural properties of 3 affects the optical properties of 3. This study reveals that the introduction of a biphenyl moiety could be a useful design to develop versatile indicators for solvents through the formation of multiple luminescent crystal structure. PMID- 27934441 TI - Th(H2O)(IVO3)2[IVII0.6V1.76O7(OH)]: A Mixed-Valent Iodine Compound Containing Periodate Stabilized by Crystallographically Compatible Lattice Sites. AB - Periodate is a strong oxidant and is often reduced to IO3- or I2 under hydrothermal conditions. Here, we present a rare case of a mixed-valent iodate(V)/periodate(VII) compound, Th(H2O)(IVO3)2[IVII0.6V1.76O7(OH)], prepared with a hydrothermal method starting from periodic acid. Crystallographic results demonstrate that heptavalent iodine adopts IVIIO6 distorted octahedral geometries, which are stabilized on the crystallographically compatible crystal lattice sites of VO6 octahedra through an aliovalent substitutional disorder mechanism. X-ray photoelectron and synchrotron radiation X-ray absorption spectroscopes both quantitatively confirm the presence of mixed valent iodine oxoanions with a molar ratio (IV/IVII) of 4:1, consistent with the single crystal X-ray analysis. The crystallization of mixed-valent products with compatible lattice site can be fancily utilized for stabilizing the uncommon oxidation states of other elements in general. PMID- 27934442 TI - Paracrystalline Disorder from Phosphate Ion Orientation and Substitution in Synthetic Bone Mineral. AB - Hydroxyapatite is an inorganic mineral closely resembling the mineral phase in bone. However, as a biological mineral, it is highly disordered, and its composition and atomistic structure remain poorly understood. Here, synchrotron X ray total scattering and pair distribution function analysis methods provide insight into the nature of atomistic disorder in a synthetic bone mineral analogue, chemically substituted hydroxyapatite. By varying the effective hydrolysis rate and/or carbonate concentration during growth of the mineral, compounds with varied degrees of paracrystallinity are prepared. From advanced simulations constrained by the experimental pair distribution function and density functional theory, the paracrystalline disorder prevalent in these materials appears to result from accommodation of carbonate in the lattice through random displacement of the phosphate groups. Though many substitution modalities are likely to occur in concert, the most predominant substitution places carbonate into the mirror plane of an ideal phosphate site. Understanding the mineralogical imperfections of a biologically analogous hydroxyapatite is important not only to potential bone grafting applications but also to biological mineralization processes themselves. PMID- 27934444 TI - Mixed-Metal Hybrid Polyoxometalates with Amino Acid Ligands: Electronic Versatility and Solution Properties. AB - Eight new members of a family of mixed-metal (Mo,W) polyoxometalates (POMs) with amino acid ligands have been synthesized and investigated in the solid state and solution using multiple physical techniques. While the peripheral POM structural framework is conserved, the different analogues vary in nuclearity of the central metal-oxo core, overall redox state, metal composition, and identity of the zwitterionic alpha-amino acid ligands. Structural investigations reveal site selective substitution of Mo for W, with a strong preference for Mo to occupy the central metal-oxo core. This core structural unit is a closed tetrametallic loop in the blue reduced species and an open trimetallic loop in the colorless oxidized analogues. Density functional theory calculations suggest the core as the favored site of reduction and reveal that the corresponding molecular orbital is much lower in energy for a tetra- versus trimetallic core. The reduced species are diamagnetic, each with a pair of strongly antiferromagnetically coupled MoV centers in the tetrametallic core, while in the oxidized complexes all Mo is hexavalent. Solution small-angle X-ray scattering and circular dichroism (CD) studies indicate that the hybrid POM is stable in aqueous solution on a time scale of days within defined concentration and pH ranges, with the stability enhanced by the presence of excess amino acid. The CD experiments also reveal that the amino acid ligands readily exchange with other alpha-amino acids, and it is possible to isolate the products of amino acid exchange, confirming retention of the POM framework. Cyclic voltammograms of the reduced species exhibit an irreversible oxidation process at relatively low potential, but an equivalent reductive process is not evident for the oxidized analogues. Despite their overall structural similarity, the oxidized and 2e-reduced hybrid POMs are not interconvertible because of the respective open- versus closed-loop arrangement in the central metal-oxo cores. PMID- 27934443 TI - Synthesis, Crystal Structure, and Stability of Cubic Li7-xLa3Zr2-xBixO12. AB - Li oxide garnets are among the most promising candidates for solid-state electrolytes in novel Li ion and Li metal based battery concepts. Cubic Li7La3Zr2O12 stabilized by a partial substitution of Zr4+ by Bi5+ has not been the focus of research yet, despite the fact that Bi5+ would be a cost-effective alternative to other stabilizing cations such as Nb5+ and Ta5+. In this study, Li7-xLa3Zr2-xBixO12 (x = 0.10, 0.20, ..., 1.00) was prepared by a low-temperature solid-state synthesis route. The samples have been characterized by a rich portfolio of techniques, including scanning electron microscopy, X-ray powder diffraction, neutron powder diffraction, Raman spectroscopy, and 7Li NMR spectroscopy. Pure-phase cubic garnet samples were obtained for x >= 0.20. The introduction of Bi5+ leads to an increase in the unit-cell parameters. Samples are sensitive to air, which causes the formation of LiOH and Li2CO3 and the protonation of the garnet phase, leading to a further increase in the unit-cell parameters. The incorporation of Bi5+ on the octahedral 16a site was confirmed by Raman spectroscopy. 7Li NMR spectroscopy shows that fast Li ion dynamics are only observed for samples with high Bi5+ contents. PMID- 27934445 TI - Synthesis of Polyfunctional Pyridines via Copper-Catalyzed Oxidative Coupling Reactions. AB - An efficient and concise approach for the synthesis of polysubstituted pyridines has been achieved through copper-catalyzed oxidative sp3 C-H coupling of oxime acetates with toluene derivatives. Besides, benzylamine and p toluenesulfonylhydrazone were also introduced to react with oxime acetates to enrich the diversity of this synthetic method. These transformations provide highly flexible and facile preparation of substituted pyridines and thus are useful in practical synthesis. PMID- 27934446 TI - Stereoselective Peptide Modifications via beta-C(sp3)-H Arylations. AB - Palladium-catalyzed stereoselective beta-arylations of phenylalanine, proline- and pipecolinic acid-containing peptides are a versatile tool for peptide modifications. The reactions proceed without epimerization of stereogenic centers in the peptide chain. If suitable functionalized aryl iodides are introduced, subsequent cross coupling reactions can be used for further modifications. The 8 amino quinoline (AQ) directing group can easily be removed, allowing the prolongation of the peptide chain at the C-terminus. PMID- 27934447 TI - Design and Performance Validation of a Conductively Heated Sealed-Vessel Reactor for Organic Synthesis. AB - A newly designed robust and safe laboratory scale reactor for syntheses under sealed-vessel conditions at 250 degrees C maximum temperature and 20 bar maximum pressure is presented. The reactor employs conductive heating of a sealed glass vessel via a stainless steel heating jacket and implements both online temperature and pressure monitoring in addition to magnetic stirring. Reactions are performed in 10 mL borosilicate vials that are sealed with a silicone cap and Teflon septum and allow syntheses to be performed on a 2-6 mL scale. This conductively heated reactor is compared to a standard single-mode sealed-vessel microwave instrument with respect to heating and cooling performance, stirring efficiency, and temperature and pressure control. Importantly, comparison of the reaction outcome for a number of different synthetic transformations performed side by side in the new device and a standard microwave reactor suggest that results obtained using microwave conditions can be readily mimicked in the operationally much simpler and smaller conventionally heated device. PMID- 27934448 TI - N-Acylsaccharins as Amide-Based Arylating Reagents via Chemoselective N-C Cleavage: Pd-Catalyzed Decarbonylative Heck Reaction. AB - Palladium-catalyzed decarbonylative Heck reaction of amides by chemoselective N-C activation using N-acylsaccharins as coupling partners has been accomplished. These studies represent only the second example of amide-Heck reactions reported to date. A broad range of electronically diverse amide and olefin coupling partners is amenable to this transformation. Orthogonal site-selective Heck cross couplings by C-Br/N-C cleavage and mechanistic studies are reported. This report introduces readily available, bench-stable, cheap, and benign N-acylsaccharins as aryl transfer reagents to access versatile aryl-metal intermediates. PMID- 27934449 TI - Synthesis and Stereochemical Analysis of Planar-Chiral (E)-4-[7]Orthocyclophene. AB - An efficient synthesis of (E)-4-[7]orthocyclophene (E)-1 via photochemical isomerization of (Z)-1 has been achieved. The key intermediate (Z)-1 was synthesized from commercially available 2-(hydroxymethyl)benzenepropanol (3) in five steps: (i) group-selective Mitsunobu reaction with CH2?CHCH2CH(SO2Ph)2, (ii) oxidation of alcohol, (iii) olefination, (iv) RCM, and (v) removal of sulfones in an overall yield of 73%. The photochemical isomerization of (Z)-1 was efficiently performed in the presence of AgNO3-impregnated silica gel (AgNO3/SiO2). The resulting (E)-1 shows dynamic planar chirality at rt. Enantioenriched (E)-1 was prepared by the HPLC separation of enantiomers using a chiral stationary phase, and the absolute stereochemistry was determined by X-ray diffraction analysis of the Pt-coordinated crystalline derivative. The planar chirality of (E)-1 can be converted into the central chirality of carbon; e.g., the oxidation of (R)-(E)-1 using DMDO provided epoxide (8S,9S)-9 in a stereospecific manner. Furthermore, the Lewis acid-promoted reaction of (8S,9S)-9 afforded a unique tricyclic compound (8S,9S)-10 in an excellent yield and in a stereospecific manner. PMID- 27934450 TI - General Method for the Synthesis of Functionalized Tetrabenzo[8]circulenes. AB - Functionalized derivatives of the saddle-shaped molecule tetrabenzo[8]circulene were successfully synthesized through a Diels-Alder/oxidative cyclodehydrogenation approach. This methodology improves on our previously reported synthesis, affording products containing both electron-rich and electron poor functional groups from readily available starting materials in a more efficient manner. The optoelectronic effects that result from the introduction of this functionality are presented and briefly discussed. PMID- 27934451 TI - Dipeptide-Based Chiral Tertiary Amine-Catalyzed Asymmetric Conjugate Addition Reactions of 5H-Thiazol/Oxazol-4-Ones. AB - Highly enantio- and chemo-selective 1,4-conjugate addition process of 5H-thiazol 4-ones with maleimides or 1,4-naphthoquinones, and 5H-oxazol-4-ones with maleimides were performed under a dipeptide-based tertiary amine (DP-UAA) catalyst. A series of valuable N,S- and N,O-containing heterocyclic compounds with excellent enantio- and disastereo-selectivities (up to >99% ee, > 20:1 dr) were attained. PMID- 27934452 TI - N-Heterocyclic Carbene/Lewis Acid Dual Catalysis for the Divergent Construction of Enantiopure Bridged Lactones and Fused Indenes. AB - The chiral triazole carbene and Ti(OPr-i)4 cocatalyzed reaction between alpha,beta-unsaturated aldehydes and 2-(aroylvinyl)benzaldehydes was systematically studied. A divergence in reaction pathways was observed under different reaction conditions. In benzene solvent and at ambient temperature, the reaction produced 4,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones, the bridged caprolactones, as the major products in moderate yields with excellent enantioselectivity. The same reaction in dichloroethane and at 50 degrees C, however, gave 2,8-dihydrocyclopenta[a]indenes as the major products in most cases. The application of the method developed was demonstrated by the transformation of the bridged lactone products into enantiopure 4-hydroxy-1,2,3,4 tetrahydronaphthalene-2-carboxylic acids. PMID- 27934453 TI - Total Synthesis of Clerobungin A via a Cascade Cyclization Reaction. AB - The first total synthesis of the novel cyclohexylethanoid natural product clerobungin A has been achieved in six steps and 14% overall yield starting from commercially available tyrosol. Key steps in this sequence include a bioinspired oxidative dearomatization of a phenol and a hemiacetalization/oxa-Michael cascade to form the tricyclic ring system. Resolution of a late-stage intermediate via chiral HPLC allowed for the measurement of the chiroptical properties of both enantiomers of clerobungin A, supporting the scalemic nature of the natural product. PMID- 27934454 TI - A Reagent-Controlled Phospha-Michael Addition Reaction of Nitroalkenes with Bifunctional N-Heterocyclic Phosphine (NHP)-Thioureas. AB - Bifunctional N-heterocyclic phosphine (NHP)-thioureas have been successfully applied for phospha-Michael addition reaction of nitroalkenes to afford diversely substituted beta-nitrodiazaphosphonates. This transformation takes place at room temperature under catalyst-free conditions and exhibits broad functional group tolerance. The key to success in catalyst, additive-free reaction conditions is the suitable hydrogen-bond activation of the nitro group by a Bronsted acid (thiourea), which artfully combined with the highly nucleophilic NHP motif for a synergetic effect. Importantly, this transformation enables a two-step synthesis of pharmaceutically, biologically significant beta-amino phosphonic acids. PMID- 27934455 TI - Kinetics and Thermodynamics of Reversible Thiol Additions to Mono- and Diactivated Michael Acceptors: Implications for the Design of Drugs That Bind Covalently to Cysteines. AB - Additions of cysteine thiols to Michael acceptors underpin the mechanism of action of several covalent drugs (e.g., afatinib, osimertinib, ibrutinib, neratinib, and CC-292). Reversible Michael acceptors have been reported in which an additional electron-withdrawing group was added at the alpha-carbon of a Michael acceptor. We have performed density functional theory calculations to determine why thiol additions to these Michael acceptors are reversible. The alpha-EWG group stabilizes the anionic transition state and intermediate of the Michael addition, but less intuitively, it destabilizes the neutral adduct. This makes the reverse reaction (elimination) both faster and more thermodynamically favorable. For thiol addition to be reversible, the Michael acceptor must also contain a suitable substituent on the beta-carbon, such as an aryl or branched alkyl group. Computations explain how these structural elements contribute to reversibility and the ability to tune the binding affinities and the residence times of covalent inhibitors. PMID- 27934456 TI - Divergent Synthesis of Polymethoxylated 4-Aryl-2-quinolones. AB - Polymethoxylated 4-aryl-2-quinolones were synthesized from the corresponding (o aminophenyl)propiolates via Cu-catalyzed hydroarylation and subsequent deprotection/lactam formation. Selective iodination of the C3 position of the product followed by coupling reactions of the resulting 3-iodinated 4-aryl-2 quinolone afforded 3-substituted-4-aryl-2-quinolones. Moreover, the N-benzyl protecting group was successfully replaced with other polyoxygenated benzyl groups. PMID- 27934457 TI - Stereoselective Synthesis of a Dipyridyl Transient Receptor Potential Vanilloid-3 (TRPV3) Antagonist. AB - An efficient asymmetric synthesis of dipyridyl TRPV3 antagonist 1 is reported. The four-step route involves two C-C bond-forming steps, a highly diastereoselective alkene hydration, and asymmetric ketone hydrosilylation in 97% ee. PMID- 27934458 TI - A Green Light-Triggerable RGD Peptide for Photocontrolled Targeted Drug Delivery: Synthesis and Photolysis Studies. AB - We describe for the first time the synthesis and photochemical properties of a coumarin-caged cyclic RGD peptide and demonstrate that uncaging can be efficiently performed with biologically compatible green light. This was accomplished by using a new dicyanocoumarin derivative (DEAdcCE) for the protection of the carboxyl function at the side chain of the aspartic acid residue, which was selected on the basis of Fmoc-tBu SPPS compatibility and photolysis efficiency. The shielding effect of a methyl group incorporated in the coumarin derivative near the ester bond linking both moieties in combination with the use of acidic additives such as HOBt or Oxyma during the basic Fmoc-removal treatment were found to be very effective for minimizing aspartimide-related side reactions. In addition, a conjugate between the dicyanocoumarin-caged cyclic RGD peptide and ruthenocene, which was selected as a metallodrug model cargo, has been synthesized and characterized. The fact that green-light triggered photoactivation can be efficiently performed both with the caged peptide and with its ruthenocenoyl bioconjugate reveals great potential for DEAdcCE-caged peptide sequences as selective drug carriers in the context of photocontrolled targeted anticancer strategies. PMID- 27934459 TI - Electrochemically Oxidative alpha-C-H Functionalization of Ketones: A Cascade Synthesis of alpha-Amino Ketones Mediated by NH4I. AB - An efficient electrochemical protocol for the synthesis of alpha-amino ketones via the oxidative cross-dehydrogenative coupling of ketones and secondary amines has been developed. The electrochemistry performs in a simple undivided cell using NH4I as a redox catalyst and a cheap graphite plate as electrodes under constant current conditions. Gram-scale reaction demonstrates the practicality of the protocol. The reaction is proposed to procced through an initial alpha iodination of ketone, followed by a nucleophilic substitution of amines. PMID- 27934460 TI - Kinetic Study of the Reaction of the Phthalimide-N-oxyl Radical with Amides: Structural and Medium Effects on the Hydrogen Atom Transfer Reactivity and Selectivity. AB - A kinetic study of the hydrogen atom transfer (HAT) reactions from a series of secondary N-(4-X-benzyl)acetamides and tertiary amides to the phthalimide-N-oxyl radical (PINO) has been carried out. The results indicate that HAT is strongly influenced by structural and medium effects; in particular, the addition of Bronsted and Lewis acids determines a significant deactivation of C-H bonds alpha to the amide nitrogen of these substrates. Thus, by changing the reaction medium, it is possible to carefully control the regioselectivity of the aerobic oxidation of amides catalyzed by N-hydroxyphthalimide, widening the synthetic versatility of this process. PMID- 27934461 TI - Cp*Rh(III)-Catalyzed Low Temperature C-H Allylation of N-Aryl-trichloro Acetimidamide. AB - The readily synthesized trichloro acetimidamide was found to be an excellent directing group for the directed C-H-allylation reactions. Depending on the allylating agent used, selectively either mono- or diallylated products were readily synthesized. Moreover, the trichloro acetimidamide directing group was found to be highly efficient even at lower temperature for the C-H-allylation reaction. Due to mildness of the reaction conditions, double bond isomerization or cyclization to indole side product was not observed. PMID- 27934462 TI - Correction to [4 + 3] Cycloaddition of Phthalazinium Dicyanomethanides with Azoalkenes Formed in Situ: Synthesis of Triazepine Derivatives. PMID- 27934463 TI - Exotic Chemistry and Rational Organic Syntheses at 1000 degrees C. AB - Subliming organic compounds into a stream of nitrogen gas and passing the vapors rapidly through a very hot oven (flash vacuum pyrolysis) promotes high temperature thermal reactions in the gas phase that are generally difficult to achieve in solution under ordinary laboratory conditions. Exploring, exposing, and exploiting gas-phase organic chemistry at temperatures of 1000 degrees C and above has uncovered some extraordinary reactions and led to some landmark syntheses. PMID- 27934464 TI - Catalyst-Controlled Straightforward Synthesis of Highly Substituted Pyrroles/Furans via Propargylation/Cycloisomerization of alpha-Oxoketene-N,S acetals. AB - A facile and efficient InCl3 catalyzed one-pot synthesis of highly substituted pyrroles has been developed via a tandem propargylation/cycloisomerization reaction of alpha-oxoketene-N,S-acetals with propargyl alcohols. Notably, in the presence of Bronsted acid p-TSA.H2O, the reaction afforded the hydrolyzed product propargylated-1,3-dicarbonyl compounds, which upon treatment with Cs2CO3 underwent regioselective intramolecular cyclization furnishing tetrasubstituted furan derivatives. PMID- 27934465 TI - Recent Developments in Amide Synthesis Using Nonactivated Starting Materials. AB - Amides are unquestionably one of the most important functional groups in organic chemistry because of their presence in numerous interesting molecules such as peptides, pharmaceutical agents, naturally occurring molecules, proteins and alkaloids, among others. This synopsis surveys the diverse recent approaches to amide synthesis from nonactivated carboxylic acids and derivatives as well as noncarboxylic compounds, highlighting the most innovative methodologies and those that are more eco-friendly compared to traditional methods while focusing on recent developments during the past two years. PMID- 27934466 TI - Palladium(II)-Catalyzed C-H Bond Activation/C-C and C-O Bond Formation Reaction Cascade: Direct Synthesis of Coumestans. AB - A palladium catalyzed cascade reaction of 4-hydroxycoumarins and in situ generated arynes has been developed for the direct synthesis of coumestans. This cascade strategy proceeds via C-H bond activation/C-O and C-C bond formations in a single reaction vessel. This methodology affords moderate to good yields of coumestans and is tolerant of a variety of functional groups including halide. The methodology was applied to the synthesis of natural product flemichapparin C. PMID- 27934467 TI - Rhodium-Catalyzed Oxidative Synthesis of Quinoline-Fused Sydnones via 2-fold C-H Bond Activation. AB - Rh(III)-catalyzed synthesis of mesoionic heterocycles has been achieved via C-H activation of sydnones and oxidative coupling with internal alkynes. This reaction occurred under mild conditions with high efficiency, broad substrate scope, and low catalyst loading. Moreover, synthetic applications of a coupled product have been demonstrated in the late-stage derivatization into a variety of highly functionalized scaffolds. PMID- 27934468 TI - alpha-Azido Esters in Depsipeptide Synthesis: C-O Bond Cleavage during Azido Group Reduction. AB - alpha-Azido esters, when treated with dithiothreitol (DTT)/diisopropylethylamine (DIPEA), undergo both azido group reduction to give alpha-amino esters and C-O bond cleavage to give triazoles. The extent of triazole formation depends upon leaving group ability. Some C-O bond cleavage via triazole formation was also found to occur when a resin-bound peptide, which contained a terminal alpha-azido ester group, was treated with DTT/DIPEA. C-O bond cleavage also took place when this peptide was treated with PPh3, PBu3, or PMe3; however, in these cases, C-O bond cleavage occurred via either triazole formation and/or hydrolysis of the ester bond in the iminophosphorane intermediate to give betaines. The mechanism that dominated for C-O bond cleavage depended upon the phosphine that was used for azido group reduction. C-O bond cleavage during reduction of the azido group in the peptide was minimized by performing the reduction with PBu3 in the presence of a symmetric anhydride derived from an amino acid in dry THF followed by the addition of water. Surprisingly, these conditions provided the amine as the major product, while the expected amide was formed as a minor product. These conditions were employed in an improved synthesis of an analogue of the cyclic lipodepsipeptide antibiotic daptomycin. PMID- 27934469 TI - Metal-Free Cascade Oxidative Decarbonylative Alkylation/Arylation of Alkynoates with Alphatic Aldehydes. AB - The oxidative difunctionalization of aryl alkynoates with alphatic aldehydes as a cheap and abundant alkyl radical source was developed, providing a variety of trisubstituted alkenes in moderate to good yields. In this reaction, radical decarbonylative alkylation of C-C triple bond, 1,4-aryl migration, and decarboxylation were involved under metal-free conditions. PMID- 27934470 TI - Northern-Southern Route to Synthetic Bacteriochlorins. AB - A new route to bacteriochlorins via Northern-Southern (N-S) self-condensation of a dihydrodipyrrin-acetal complements a prior Eastern-Western (E-W) route. Each bacteriochlorin was prepared in five steps from an alpha-halopyrrole and a 2,2 dimethylpent-4-ynoic acid. The first three steps follow Jacobi's synthesis of dihydrodipyrrins: Pd-mediated coupling to form a lactone-pyrrole, Petasis reagent treatment for methenylation, and Paal-Knorr type ring closure to form the 1,2,2 trimethyl-substituted dihydrodipyrrin. Subsequent steps entail conversion of the 1-methyl group to the 1-(dimethoxymethyl) unit and acid-catalyzed self condensation of the resulting dihydrodipyrrin-acetal. The essential differences between the N-S and E-W routes lie in (1) the location of the gem-dimethyl group (with respect to the 1-acetal unit) at the 2- versus 3-position in the dihydrodipyrrin-acetals, respectively, (2) the method of synthesis of the dihydrodipyrrins, and consequently (3) access to diverse substituted bacteriochlorins including those with substituents at the meso-positions. Ten new bacteriochlorins bearing 0-6 total aryl, alkyl, and carboethoxy substituents at the beta-pyrrole and/or meso-positions have been prepared, with yields of macrocycle formation of up to 39%. Four single-crystal X-ray structures (two intermediates, two bacteriochlorins) were determined. The bacteriochlorins exhibit characteristic bacteriochlorophyll-like absorption spectra, including a Qy band in the region 713-760 nm. PMID- 27934471 TI - Ruthenium-Catalyzed [3 + 2] Cycloaddition of 2H-Azirines with Alkynes: Access to Polysubstituted Pyrroles. AB - A ruthenium-catalyzed intermolecular [3 + 2] cycloaddition of 2H-azirines and activated alkynes is reported, which provides polysubstituted pyrroles in moderate to good yields. This approach features a C-N bond cleavage of 2H azirines by a ruthenium catalyst. The results of this study would provide a complementary method to synthesize polysubstituted pyrroles from the known 2H azirine approaches and advance 2H-azirine chemistry. PMID- 27934472 TI - Application of Pd-Catalyzed Cross-Coupling Reactions in the Synthesis of 5,5 Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles that Inhibit ALK5 Kinase. AB - C-H activation of position 3 of a substituted pyrazole ring catalyzed by palladium(II) was straightforward and convenient for arylated or heteroarylated 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles. Moreover, we introduced simple protection of the nitrogen in the pyridin-2-yl directing group, which otherwise does not allow a cross-coupling reaction, by transformation to the N oxide. Selected final products were reasonably selective ALK5 kinase inhibitors. PMID- 27934473 TI - Correction to Mechanochemical Preparation of 3,5-Disubstituted Hydantoins from Dipeptides and Unsymmetrical Ureas of Amino Acid Derivatives. PMID- 27934474 TI - Diastereoselective Trifluoroacetylation of Highly Substituted Pyrrolidines by a Dakin-West Process. AB - A robust approach allowing for the efficient trifluoroacetylation of a series of highly substituted pyrrolidines in a diastereoselective manner is reported. The transformation is based on a Dakin-West reaction of advanced pyrrolidine 2 carboxylic acid derivatives that can be assembled stereoselectively in four synthetic steps. Importantly, this work demonstrates how the introduction of lateral substituents on the pyrrolidine scaffold enables the generation of the desired trifluoroacetylation products, which was not possible previously due to the exclusive formation of trifluoromethylated oxazoles (vide infra). In the course of this work we succeeded for the first time in isolating and characterizing (HRMS, IR, 1H, 13C and 19F NMR, X-ray) different intermediates of the Dakin-West reaction allowing us to probe its mechanism. PMID- 27934475 TI - Proximity-Induced H-Aggregation of Cyanine Dyes on DNA-Duplexes. AB - A wide variety of organic dyes form, under certain conditions, clusters know as J and H-aggregates. Cyanine dyes are such a class of molecules where the spatial proximity of several dyes leads to overlapping electron orbitals and thus to the creation of a new energy landscape compared to that of the individual units. In this work, we create artificial H-aggregates of exactly two Cyanine 3 (Cy3) dyes by covalently linking them to a DNA molecule with controlled subnanometer distances. The absorption spectra of these coupled systems exhibit a blue-shifted peak, whose intensity varies depending on the distance between the dyes and the rigidity of the DNA template. Simulated vibrational resolved spectra, based on molecular orbital theory, excellently reproduce the experimentally observed features. Circular dichroism spectroscopy additionally reveals distinct signals, which indicates a chiral arrangement of the dye molecules. Molecular dynamic simulations of a Cy3-Cy3 construct including a 14-base pair DNA sequence verified chiral stacking of the dye molecules. PMID- 27934477 TI - Regio- and Stereoselective Hydrosulfonation of Alkynylcarbonyl Compounds with Sulfinic Acid in Water. AB - We report the atom-economic and environmentally friendly synthesis of Z-beta sulfonyl-a,beta-unsaturated carbonyl compounds in water. The mechanism study reveals that the hydrosulfonylation of alkynylcarbonyl compounds with sulfinic acids proceeds via a mechanism that features a sulfinic acid molecule protonating an alkynyl motif to form the ethenium intermediate, which subsequently reacted with a sulfonyl anion to afford the desired products. The ethenium intermediate differentiated electronic and steric demands between the two substituents on the C=C triple bond of the alkyne substrates to exhibit high regio- and stereoselectivity from a wide range of Z-beta-sulfonyl-a,beta-unsaturated carbonyl compounds. PMID- 27934476 TI - Characterization and Synthesis of Eudistidine C, a Bioactive Marine Alkaloid with an Intriguing Molecular Scaffold. AB - An extract of Eudistoma sp. provided eudistidine C (1), a heterocyclic alkaloid with a novel molecular framework. Eudistidine C (1) is a racemic natural product composed of a tetracyclic core structure further elaborated with a p methoxyphenyl group and a phenol-substituted aminoimidazole moiety. This compound presented significant structure elucidation challenges due to the large number of heteroatoms and fully substituted carbons. These issues were mitigated by application of a new NMR pulse sequence (LR-HSQMBC) optimized to detect four- and five-bond heteronuclear correlations and the use of computer-assisted structure elucidation software. Synthesis of eudistidine C (1) was accomplished in high yield by treating eudistidine A (2) with 4(2-amino-1H-imidazol-5-yl)phenol (4) in DMSO. Synthesis of eudistidine C (1) confirmed the proposed structure and provided material for further biological characterization. Treatment of 2 with various nitrogen heterocycles and electron-rich arenes provided a series of analogues (5-10) of eudistidine C. Chiral-phase HPLC resolution of epimeric eudistidine C provided (+)-(R)-eudistidine C (1a) and (-)-(S)-eudistidine C (1b). The absolute configuration of these enantiomers was assigned by ECD analysis. (-) (S)-Eudistidine C (1b) modestly inhibited interaction between the protein binding domains of HIF-1alpha and p300. Compounds 1, 2, and 6-10 exhibited significant antimalarial activity against Plasmodium falciparum. PMID- 27934478 TI - Pulmonary Surfactant Protein A-Mediated Enrichment of Surface-Decorated Polymeric Nanoparticles in Alveolar Macrophages. AB - Surfactant protein A (SP-A), a lung anti-infective protein, is a lectin with affinity for sugars found on fungal and micrococcal surfaces such as mannose. We synthesized a mannosylated poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) copolymer and used it to produce nanoparticles with a polyester (PLGA/PLA) core and a PEG shell decorated with mannose residues, designed to be strongly associated with SP-A for an increased uptake by alveolar macrophages. Nanoparticles made of the copolymers were obtained by nanoprecipitation and displayed a size of around 140 nm. The presence of mannose on the surface was demonstrated by zeta potential changes according to pH and by a strong aggregation in the presence of concanavalin A. Mannosylated nanoparticles bound to SP-A as demonstrated by dynamic light scattering and transmission electron microscopy. The association with SP-A increased nanoparticle uptake by THP-1 macrophages in vitro. In vivo experiments demonstrated that after intratracheal administration of nanoparticles with or without SP-A, SP-A-coated mannosylated nanoparticles were internalized by alveolar macrophages in greater proportion than SP-A-coated nonmannosylated nanoparticles. The data demonstrate for the first time that the pool of nanoparticles available to lung cells can be changed after surface modification, using a biomimetic approach. PMID- 27934479 TI - Doxorubicin and siRNA Codelivery via Chitosan-Coated pH-Responsive Mixed Micellar Polyplexes for Enhanced Cancer Therapy in Multidrug-Resistant Tumors. AB - This study investigated the potential of chitosan-coated mixed micellar nanocarriers (polyplexes) for codelivery of siRNA and doxorubicin (DOX). DOX loaded mixed micelles (serving as cores) were prepared by thin film hydration method and coated with chitosan (CS, serving as outer shell), and complexed with multidrug resistance (MDR) inhibiting siRNA. Selective targeting was achieved by folic acid conjugation. The polyplexes showed pH-responsive enhanced DOX release in acidic tumor pH, resulting in higher intracellular accumulation, which was further augmented by downregulation of mdr-1 gene after treatment with siRNA complexed polyplexes. In vitro cytotoxicity assay demonstrated an enhanced cytotoxicity in native 4T1 and multidrug-resistant 4T1-mdr cell lines, compared to free DOX. Furthermore, in vivo, polyplexes codelivery resulted in highest DOX accumulation and significantly reduced the tumor volume in mice with 4T1 and 4T1 mdr tumors as compared to the free DOX groups, leading to improved survival times in mice. In conclusion, codelivery of siRNA and DOX via polyplexes has excellent potential as targeted drug nanocarriers for treatment of MDR cancers. PMID- 27934481 TI - Minimum Transendothelial Electrical Resistance Thresholds for the Study of Small and Large Molecule Drug Transport in a Human in Vitro Blood-Brain Barrier Model. AB - A human cell-based in vitro model that can accurately predict drug penetration into the brain as well as metrics to assess these in vitro models are valuable for the development of new therapeutics. Here, human induced pluripotent stem cells (hPSCs) are differentiated into a polarized monolayer that express blood brain barrier (BBB)-specific proteins and have transendothelial electrical resistance (TEER) values greater than 2500 Omega.cm2. By assessing the permeabilities of several known drugs, a benchmarking system to evaluate brain permeability of drugs was established. Furthermore, relationships between TEER and permeability to both small and large molecules were established, demonstrating that different minimum TEER thresholds must be achieved to study the brain transport of these two classes of drugs. This work demonstrates that this hPSC-derived BBB model exhibits an in vivo-like phenotype, and the benchmarks established here are useful for assessing functionality of other in vitro BBB models. PMID- 27934482 TI - Pronounced Cellular Uptake of Pirarubicin versus That of Other Anthracyclines: Comparison of HPMA Copolymer Conjugates of Pirarubicin and Doxorubicin. AB - Many conjugates of water-soluble polymers with biologically active molecules were developed during the last two decades. Although, therapeutic effects of these conjugates are affected by the properties of carriers, the properties of the attached drugs appear more important than the same carrier polymer in this case. Pirarubicin (THP), a tetrahydropyranyl derivative of doxorubicin (DOX), demonstrated more rapid cellular internalization and potent cytotoxicity than DOX. Here, we conjugated the THP or DOX to N-(2-hydroxypropyl)methacrylamide copolymer via a hydrazone bond. The polymeric prodrug conjugates, P-THP and P DOX, respectively, had comparable hydrodynamic sizes and drug loading. Compared with P-DOX, P-THP showed approximately 10 times greater cellular uptake during a 240 min incubation and a cytotoxicity that was more than 10 times higher during a 72-h incubation. A marginal difference was seen in P-THP and P-DOX accumulation in the liver and kidney at 6 h after drug administration, but no significant difference occurred in the tumor drug concentration during 6-24 h after drug administration. Antitumor activity against xenograft human pancreatic tumor (SUIT2) in mice was greater for P-THP than for P-DOX. To sum up, the present study compared the biological behavior of two different drugs, each attached to an N-(2-hydroxypropyl)methacrylamide copolymer carrier, with regard to their uptake by tumor cells, body distribution, accumulation in tumors, cytotoxicity, and antitumor activity in vitro and in vivo. No differences in the tumor cell uptake of the polymer-drug conjugates, P-THP and P-DOX, were observed. In contrast, the intracellular uptake of free THP liberated from the P-THP was 25-30 times higher than that of DOX liberated from P-DOX. This finding indicates that proper selection of the carrier, and especially conjugated active pharmaceutical ingredient (API) are most critical for anticancer activity of the polymer-drug conjugates. THP, in this respect, was found to be a more preferable API for polymer conjugation than DOX. Hence the treatment based on enhanced permeability and retention (EPR) effect that targets more selectively to solid tumors can be best achieved with THP, although both polymer conjugates of DOX and THP exhibited the EPR effects and drug release profiles in acidic pH similarly. PMID- 27934480 TI - A Mechanistic Study on Nanoparticle-Mediated Glucagon-Like Peptide-1 (GLP-1) Secretion from Enteroendocrine L Cells. AB - L cells have attracted particular interest because of the pleiotropic effects of their secreted peptides (i.e., glucagon-like peptide (GLP) 1 and 2, peptide YY (PYY)). L cells express different G-protein-coupled receptors (GPCRs) that can be activated by endogenous ligands found in the gut lumen. We herein hypothesized that lipid-based nanoparticles could mimic endogenous ligands and thus activate GLP-1 secretion in type 2 diabetes mellitus treatment. To assess this hypothesis, lipid-based nanoparticles (nanostructured lipid carriers (NLC), lipid nanocapsules (LNC), and liposomes) and PLGA nanoparticles were added to the L cells and GLP-1 secretion was quantified. Among these nanoparticles, only NLC resulted effective at inducing GLP-1 secretion in both murine and human L cells in vitro. The mRNA expression of proglucagon showed that this effect was due to an increased GLP-1 secretion and not to an increased GLP-1 synthesis. The mechanism by which NLC triggered GLP-1 secretion by L cells revealed an extracellular interaction of NLC, exerting a physiological GLP-1 secretion. We herein demonstrate that nanomedicine can be used to induce GLP-1 secretion from murine and human L cells. PMID- 27934484 TI - Palladium-Catalyzed Multicomponent Reaction (MCR) of Propargylic Carbonates with Isocyanides. AB - A palladium-catalyzed multicomponent reaction (MCR) of propargylic carbonates with isocyanides is reported. Remarkably, the orderly insertion of isocyanides affords two types of valuable N-heterocyclic products (Z)-6-imino-4,6-dihydro-1H furo[3,4-b]pyrrol-2-amines and (E)-5-iminopyrrolones in high yields. Systematic analysis of the reaction conditions indicates that the selectivity of these N heterocyclic products can be controlled by ligands and temperature. PMID- 27934483 TI - Short Route to Cassane-Type Diterpenoids: Synthesis of the Supposed Structure of Benthaminin 1. AB - A short route toward aromatic cassane diterpenes from labdane terpenoids has been developed. In the key step, the aromatic ring with the oxygenated function at C 12 and the characteristic carbon group at C-14 of the target compounds is elaborated via a Diels-Alder/aromatization sequence of a furanosesquiterpene and methyl propiolate. On this basis, the synthesis of the proposed structure of benthaminin 1 from trans-communic acid has been achieved. The physical properties of the synthetic compound are somewhat different from those reported for the natural product. PMID- 27934485 TI - A Hydrogenation/Oxidative Fragmentation Cascade for Synthesis of Chiral 4,5 Dihydro-1H-benzo[d]azepin-1-ones. AB - An iridium-catalyzed asymmetric hydrogenation/oxidative fragmentation of 6 substituted 5H-benzo[d] benzofuro[3,2-b]azepines has been developed, providing an efficient access to optically active 4-substituted 4,5-dihydro-1H-benzo[d]azepin 1-ones with up to 91% ee. A possible reaction pathway includes the asymmetric hydrogenation to furnish chiral cyclic amines and oxidative fragmentation under an air atmosphere. PMID- 27934486 TI - Preparation of Protein Conjugates via Homobifunctional Diselenoester Cross Linker. AB - Adipic acid diselenoester was developed as an efficient cross-linker for covalent protein conjugation with a variety of small molecular haptens, including mono- and disaccharides, peptide, fluorescence dye, and nicotine. Compared to the counterparts of N-hydroxysuccinimide (NHS) and p-nitrophenyl (PNP) linkers, the diselenoester linker demonstrates improved balance between reactivity and stability and coupling of haptens to proteins under mild conditions with high incorporation efficiency. PMID- 27934487 TI - Nickel-Catalyzed Diaryl Ketone Synthesis by N-C Cleavage: Direct Negishi Cross Coupling of Primary Amides by Site-Selective N,N-Di-Boc Activation. AB - A general Negishi acylation of primary amides enabled by a combination of site selective N,N-di-Boc activation and nickel catalysis is reported for the first time. The reaction is promoted by a bench-stable, inexpensive Ni catalyst. The reaction shows excellent functional group compatibility, affording functionalized diaryl ketones by selective N-C cleavage. Most notably, this protocol represents the first amide cross-coupling by direct metal insertion of simple and readily available primary amides. The overall strategy by N,N-di-Boc activation/metal insertion is suitable for a broad range of coupling protocols via acylmetals. Mechanistic experiments suggest high reactivity of N,N-di-Boc activated 1 degrees amides in direct amide C-N cross-couplings. PMID- 27934488 TI - Sodium Hydroxide Catalyzed Dehydrocoupling of Alcohols with Hydrosilanes. AB - An O-Si bond construction protocol employing abundantly available and inexpensive NaOH as the catalyst is described. The method enables the cross-dehydrogenative coupling of an alcohol and hydrosilane to directly generate the corresponding silyl ether under mild conditions and without the production of stoichiometric salt byproducts. The scope of both coupling partners is excellent, positioning the method for use in complex molecule and materials science applications. A novel Si-based cross-coupling reagent is also reported. PMID- 27934489 TI - Metal-Free Synthesis of 6-Phosphorylated Phenanthridines: Synthetic and Mechanistic Insights. AB - A novel and efficient method for the generation of phosphinoyl radicals from the combination of diphenyliodonium salt (Ph2I+,-OTf) with triethylamine (Et3N) in the presence of secondary phosphine oxides is reported. By employing this practical and simple approach, a large variety of 6-phosphorylated phenanthridines have been synthesized through the addition of phosphinoyl radicals to isonitriles as radical acceptors. The reaction works smoothly in the absence of any transition metal or photocatalyst. On the basis of electron paramagnetic resonance (EPR) and density functional theory (DFT) calculations, the mechanism of this reaction is discussed. PMID- 27934490 TI - Mechanism and Stereoselectivity in an Asymmetric N-Heterocyclic Carbene-Catalyzed Carbon-Carbon Bond Activation Reaction. AB - The mechanism and origin of stereoinduction in a chiral N-heterocyclic carbene (NHC) catalyzed C-C bond activation of cyclobutenone has been established using B3LYP-D3 density functional theory computations. The activation of cyclobutenone as an NHC-bound vinyl enolate and subsequent reaction with the electrophilic sulfonyl imine leads to the lactam product. The most preferred stereocontrolling transition state exhibits a number of noncovalent interactions rendering additional stabilization. The computed enantio- and diastereoselectivities are in good agreement with the previous experimental observations. PMID- 27934491 TI - Cobalt-Catalyzed Carbonylation of C(sp2)-H Bonds with Azodicarboxylate as the Carbonyl Source. AB - A novel and efficient approach for the C(sp2)-H bond carbonylation of benzamides has been developed using stable and inexpensive Co(OAc)2.4H2O as the catalyst and the commercially available and easily handling azodicarboxylates as the nontoxic carbonyl source. A broad range of substrates bearing diverse functional groups were tolerated. This is the first example where cobalt-catalyzed C(sp2)-H bond carbonylation occurs with azodicarboxylate as the carbonyl source. PMID- 27934492 TI - Aminofluorene-Mediated Biomimetic Domino Amination-Oxygenation of Aldehydes to Amides. AB - A conceptually novel biomimetic strategy based on a domino amination-oxygenation reaction was developed for direct amidation of aldehydes under metal-free conditions employing molecular oxygen as the oxidant. 9-Aminofluorene derivatives acted as pyridoxamine-5'-phosphate equivalents for efficient, chemoselective, and operationally simple amine-transfer oxygenation reaction. Unprecedented RNH transfer involving secondary amine to produce secondary amides was achieved. In the presence of 18O2, 18O-amide was formed with excellent (95%) isotopic purity. PMID- 27934493 TI - Visible-Light-Mediated Oxidative Dimerization of Arylalkynes in the Open Air: Stereoselective Synthesis of (Z)-1,4-Enediones. AB - An organic photoredox catalytic one-pot protocol is developed for the highly stereoselective synthesis of (Z)-1,4-enediones. The reaction starts directly from alkyne precursors, using 4-(4-cyanophenyl)-2,6-diphenylpyrylium tetrafluoroborate (CN-TPT) as an efficient photosensitizer and dioxygen in the air as a green oxidant. A Csp-Csp oxidative coupling/[4 + 2] cyclization (with dioxygen)/fragmentive isomerization cascade mechanism was proposed. The predominant formation of (Z)-1,4-enediones is attributed to the efficient visible light illumination from blue LEDs, along with possible energy transfer from the photosensitizer CN-TPT to the E-isomers. PMID- 27934494 TI - Monoterpene Indole Alkaloid-Like Compounds Based on Diversity-Enhanced Extracts of Iridoid-Containing Plants and Their Immune Checkpoint Inhibitory Activity. AB - A library of iridoid-conjugated indole alkaloid-like compounds was constructed from diversity-enhanced extracts, which constitutes an approach for increasing the chemical diversity of natural-product-like compounds by combining natural product chemistry and diversity-oriented synthesis. Pharmacological screening of the library revealed a seed compound that can be used for the development of small molecular immune checkpoint inhibitors. PMID- 27934495 TI - Construction of 1,2,4-Triazole Derivatives via Cyclocondensation of Alkylidene Dihydropyridines and Aryldiazonium Salts. AB - Alkylidene dihydropyridines (anhydrobases) prepared via dearomatization of N acylated 4-(aminomethyl)pyridines participate in [3 + 2] cyclocondensation reactions with aryldiazonium cations to afford substituted 1,2,4-triazolium salts or neutral 1,2,4-triazoles in high isolated yield. The reaction proceeds in the presence of a variety of N-acyl groups and aryl-susbtituted diazonium salts and offers a general route to pyridyl-substituted 1,2,4-triazoles. PMID- 27934496 TI - Chemical Synthesis of HMGA1a Proteins with Post-translational Modifications via Ser/Thr Ligation. AB - The first chemical synthesis of nuclear protein HMGA1a via Ser/Thr ligation is reported. Notably, Hmb (2-hydroxy-4-methoxybenzyl) exhibits crucial improvement of both the difficult coupling during solid phase peptide synthesis and the poor ligation encountered in protein synthesis. These efforts led to preparation of HMGA1a analogs with well-defined phosphorylation and methylation patterns (9 synthetic proteins in total), thus overcoming the heterogeneous and combinatory problems inherent to protein post-translational modifications (PTMs), and facilitating the study of the regulatory roles of such PTMs. PMID- 27934497 TI - Radical (Phenylsulfonyl)difluoromethylation of Isocyanides with PhSO2CF2H under Transition-Metal-Free Conditions. AB - An atom-economical method for radical (phenylsulfonyl)difluoromethylation of isocyanides with PhSO2CF2H under transition-metal-free conditions has been developed. A PhSO2CF2 radical is generated through the oxidation of PhSO2CF2- after the deprotonation of PhSO2CF2H in one pot. The reaction exhibits excellent functional-group tolerance and the resulting products can be further modified with the removal of a PhSO2 group to give other CF2-containing compounds. PMID- 27934499 TI - 2,5,8,11-Tetraalkenyl Perylene Bisimides: Direct Regioselective Synthesis and Enhanced pi-pi Stacking Interaction. AB - A series of 2,5,8,11-tetraalkenyl perylene bisimide (PBI) derivatives were synthesized through Ru(II)- or Rh(III)-catalyzed regio- and steroselective oxidative C-H olefination in one step. The optical electronic and self-assembly of the 2,5,8,11-substituted PBIs were investigated, which showed great potential in optoelectronic applications. PMID- 27934500 TI - Catalytic Undirected Intermolecular C-H Functionalization of Arenes with 3 Diazofuran-2,4-dione: Synthesis of 3-Aryl Tetronic Acids, Vulpinic Acid, Pinastric Acid, and Methyl Isoxerocomate. AB - A variety of 3-aryl tetronic acids have been synthesized by an undirected, intermolecular C-H functionalization of arenes with 3-diazofuran-2,4-dione. This methodology featured as a key step in the synthesis of a series of naturally occurring 3-aryl-5-arylidene tetronic acids (pulvinates) from commercially available tetronic acid. Salient features of the pulvinic acid synthesis include a one-step, stereoselective synthesis of the C5 arylidene group and a single step introduction of the C3 aryl substituent. PMID- 27934498 TI - Naphthoquinone-Oxindole Alkaloids, Coprisidins A and B, from a Gut-Associated Bacterium in the Dung Beetle, Copris tripartitus. AB - Coprisidins A and B (1 and 2) were isolated from a gut-associated Streptomyces sp. in the dung beetle Copris tripartitus. Using a combination of spectroscopic techniques, the structures of the compounds were determined to be the first examples of natural naphthoquinone-oxindole alkaloids. Coprisidin A was found to inhibit the action of Na+/K+-ATPase, and coprisidin B showed activity for the induction of NAD(P)H:quinone oxidoreductase 1. PMID- 27934501 TI - Orthogonally Protected 1,2-Diols from Electron-Rich Alkenes Using Metal-Free Olefin syn-Dihydroxylation. AB - A new method for the stereoselective metal-free syn-dihydroxylation of electron rich olefins is reported, involving reaction with TEMPO/IBX in trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP) and the addition of a suitable nucleophile. Orthogonally protected syn 1,2-diols were obtained with high levels of diastereocontrol, and these products were selectively deprotected and selectively functionalized into synthetically useful compounds. PMID- 27934502 TI - Metal-Free, Site-Selective Addition to Ynones: An Approach to Synthesize Substituted Quinoline Derivatives. AB - An efficient two component cycloaddition reaction to synthesize various substituted quinoline derivatives was developed. Ynone 1 was functionalizated by N-oxide attacking the C3-oxetium site and C3-site regioselectively to give 3 and 4. Analogues 3k and 4v have a high binding constant with Hg2+ in CH3CN. PMID- 27934503 TI - Syntheses of Tetrahydropyridazine and Tetrahydro-1,2-diazepine Scaffolds through Cycloaddition Reactions of Azoalkenes with Enol Diazoacetates. AB - Catalyst-dependent [4 + 2]-cycloaddition reactions of azoalkenes from alpha halohydrazones with enol diazoacetates have been developed. A [4 + 2] cycloaddition of enol diazoacetates with in situ formed azoalkenes produces tetrahydropyridazinyl-substituted diazoacetates promoted by only Cs2CO3. In contrast, donor-acceptor cyclopropenes, which are formed in situ from enol diazoacetates by Rh2(OAc)4-catalyzed dinitrogen extrusion, undergo [4 + 2] cycloaddition with azoalkenes to yield bicyclo[4.1.0]tetrahydropyridazines. These stable cycloaddition products undergo subsequent one-step transformations to form 6-alkylidenetetrahydropyridazines and 4,5,6,7-tetrahydro-1,2-diazepine derivatives in good yields. PMID- 27934504 TI - One-Pot Conversion of Fluorophores to Phosphorophores. AB - Facile, one-pot conversion of free base 5,10,15-tris(pentafluorophenyl)corrole, (H3)tpfc, into the coinage metal complexes of 2,3,17,18-tetraiodo-5,10,15 tris(pentafluorophenyl)corrole, (I4-tpfc)M (M = Cu, Ag, Au), is reported. The iodination/metalation procedures provide much higher yields and larger selectivity than both conceivable stepwise syntheses. Photophysical analysis shows that the gold(III) complex (I4-tpfc)Au displays phosphorescence at room temperature and a substantial quantum yield for singlet oxygen formation. PMID- 27934505 TI - Copper-Catalyzed Oxidative ipso-Annulation of Activated Alkynes with Silanes: An Approach to 3-Silyl Azaspiro[4,5]trienones. AB - A novel strategy of silylation and dearomatization of activated alkynes with silanes to synthesize azaspiro[4,5]trienones is developed, which could be facilely achieved through a tandem difunctionalization of alkyne, dearomatization, and oxidation and provided a facile approach to produce useful 3 silyl azaspiro[4,5]trienones in an efficient manner. PMID- 27934506 TI - Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer's Disease. AB - Verubecestat is an inhibitor of beta-secretase being evaluated for the treatment of Alzheimer's disease. The first-generation route relies on an amide coupling with a functionalized aniline, the preparation of which introduces synthetic inefficiencies. The second-generation route replaces this with a copper-catalyzed C-N coupling, allowing for more direct access to the target. Other features of the new route include a diastereoselective Mannich-type addition into an Ellman sulfinyl ketimine and a late-stage guanidinylation. PMID- 27934507 TI - Garmultins A-G, Biogenetically Related Polycyclic Acylphloroglucinols from Garcinia multiflora. AB - Garmultins A and B (1 and 2), two polycyclic polyprenylated acylphloroglucinols characterized by the coupling of two novel cages, 2,11 dioxatricyclo[4.4.1.03,9]undecane and tricyclo[4.3.1.03,7]decane, along with five biogenetically related analogues (3-7), were isolated from Garcinia multiflora. Their structures and absolute configurations were determined by extensive NMR analysis, X-ray crystallography, and electronic circular dichroism calculations. Three compounds were capable of inhibiting oncogene expression and inducing apoptosis in human erythroleukemia cells. PMID- 27934508 TI - Bis- and Tris-fused Tetrathiafulvalenes Extended with Anthracene-9,10-diylidene. AB - Bis- and tris-fused pi-electron donors composed of extended tetrathiafulvalene with anthraquinoid spacers (4 and 5) were successfully synthesized. X-ray structure analysis of tetrakis(methylthio)-5 (5a) revealed that the molecule adopted a transoid-cisoid conformation. The cyclic voltammogram of 4a is composed of two pairs of two-electron redox waves, while the cyclic voltammogram of tetrakis(hexylthio) derivative 5b consists of one pair of four-electron redox waves and one pair of two-electron redox waves, respectively. Spectroelectrochemistry of 4a and 1H NMR spectrum of a 4b salt revealed that two positive charges in 42+ are distributed mainly on one TTFAQ (9,10-bis(1,3-dithiol 2-ylidene)-9,10-dihydroanthracene) moiety. PMID- 27934509 TI - Tribute to Toyoki Kunitake. PMID- 27934510 TI - Conserved Molecular Superlattices in a Series of Homologous Synthetic Mycobacterial Cell-Wall Lipids Forming Interdigitated Bilayers. AB - Synthetic analogues of the cell-wall lipid monomycoloyl glycerol (MMG) are promising as next-generation vaccine adjuvants. In the present study, the thermotropic phase behavior of an array of synthetic MMG analogues was examined by using simultaneous small- and wide-angle X-ray scattering under excess water conditions. The MMG analogues differed in the alkyl chain lengths and in the stereochemistry of the polar glycerol headgroup or of the lipid tails (native like versus alternative compounds). All MMG analogues formed poorly hydrated lamellar phases at low temperatures and inverse hexagonal (H2) phases at higher temperatures prior to melting. MMG analogues with a native-like lipid acid configuration self-assembled into noninterdigitated bilayers whereas the analogues displaying an alternative lipid acid configuration formed interdigitated bilayers in a subgel (Lc') state. This is in contrast to previously described interdigitated phases for other lipids, which are usually in a gel (Lbeta) state. All investigated MMG analogues displayed an abrupt direct temperature-induced phase transition from Lc' to H2. This transition is ultimately driven by the lipid chain melting and the accompanying change in molecular shape. No intermediate structures were found, but the entire array of MMG analogues displayed phase coexistence during the lamellar to H2 transition. The structural data also showed that the headgroups of the MMG analogues adopting the alternative lipid acid configuration were ordered and formed a two dimensional molecular superlattice, which was conserved regardless of the lipid tail length. To our knowledge, the MMG analogues with an alternative lipid acid configuration represent the first example of a lipid system showing both interdigitation and superlattice formation, and as such could serve as an interesting model system for future studies. The MMG analogues are also relevant from a subunit vaccine perspective because they are well-tolerated and display promising immunopotentiating activity. The structural characterization described here will serve as a prerequisite for the rational design of nanoparticulate adjuvants with specific and tailored structural features. PMID- 27934511 TI - Oxide-Free Actuation of Gallium Liquid Metal Alloys Enabled by Novel Acidified Siloxane Oils. AB - Electrowetting and electrocapillarity of liquid metals have a long history, and a recent explosion of renewed interest. Liquid metals have electromagnetic properties and surface tensions (>500 mN/m) that enable new forms of reconfigurable devices. However, the only nontoxic option, gallium alloys, suffer from immediate formation of a semirigid surface oxide. Although acids or electrochemical reduction can remove this oxide, these approaches surround the gallium alloy in a fluid that is also electrically conducting, diminishing electromagnetic effectiveness and precluding electrowetting actuation. Reported here are acidified siloxanes that remove and prevent oxide formation. Importantly, the siloxane oil associatively incorporates hydrochloric or hydrobromic acids, is electrically insulating, is chemically stable, removes etching byproducts (including water), and allows robust electrowetting. This work opens up new opportunities for liquid metal reconfiguration, and is of fundamental interest due to the unexpected chemical stability of the acidified siloxanes and their application to other materials and surfaces. PMID- 27934512 TI - Effects of Chain-Chain Associations on Hybridization in DNA Brushes. AB - Hybridization of solution nucleic acids to DNA brushes is widely encountered in diagnostic and materials science applications. Typically, brush chain lengths of ten or more nucleotides are used to provide the needed sequence specificity and binding affinity. At these lengths, coincidental occurrence of complementary regions is expected to lead to associations between the nominally single-stranded brush chains due to intra- or interchain base pairing. This report investigates how these associations impact the brushes' hybridization activity toward complementary "target" sequences. Brushes were prepared from 20-mer chains with four-nucleotide-long "adhesive regions" through which neighboring chains could interact. The affinity and position of the adhesive region along the chain backbone were varied. DNA brushes were exposed to complementary solution targets, and the corresponding melting transitions were measured to estimate free energies of the brush-target hybridization. These results revealed that higher affinity adhesive regions more extensively suppressed brush hybridization relative to hybridization in solution. Associations near the middle of the chains were found to be more penalizing than those at the immobilized or the free end of the chains. Provided that the brush chains were close enough to associate, changes in brush density did not exert a significant effect on hybridization thermodynamics within the investigated coverage window. Comparison of the DNA brush results with those from commercial Affymetrix single-nucleotide-polymorphism (SNP) microarrays revealed agreement in the impact of chain associations on hybridization. PMID- 27934513 TI - Assessing the Surface Area of Porous Solids: Limitations, Probe Molecules, and Methods. AB - In this modeling study, the uses of nitrogen (77.3 K), probe molecule of choice for decades, and argon, opted as alternative in the 2015 IUPAC report on adsorptive characterization, as probe molecules for geometric surface area determination are compared. Graphene sheets possessing slit-shaped pores with varying size (width) are chosen as model porous solids, and different methods for the determination of specific surface areas are investigated. The BET method, which is the most commonly applied analysis, is compared to the Langmuir and relatively recently proposed ESW (excess sorption work) method. We show that either using argon or nitrogen as adsorptive, the physical meaningfulness of adsorption-derived surface areas highly depends on the pore size. When less than two full layers of adsorbate molecules can be formed within slitlike pores of a graphitic material (Dpore < 5.8 A for Ar/N2), adsorption-derived surface areas are about half that of the geometric surface area. Between two and four layers (6.8 < Dpore < 12.8 A), adsorption surface areas can be significantly larger (up to 75%) than the geometric surface area because monolayer-multilayer formation and pore filling cannot be distinguished. For four or more layers of adsorbate molecules (Dpore > 12.8 A), adsorption-derived surface areas are comparable to their geometrically accessible counterparts. Note that for the Langmuir method this only holds if pore-filling effects are excluded during determination. This occurs in activated carbon materials as well. In the literature, this indistinguishability issue has been largely overlooked, and erroneous claims of materials with extremely large surface areas have been made. Both the BET and Langmuir areas, for Dpore > 12.8 A, correspond to geometric surface areas, whereas the ESW method yields significantly lower values. For the 6.8 A < Dpore < 12.8 A range, all methods erroneously overestimate the specific surface area. For the energetically homogeneous graphene sheets, differences between argon and nitrogen for the assessment of surface areas are minor. PMID- 27934514 TI - Septin Interferes with the Temperature-Dependent Domain Formation and Disappearance of Lipid Bilayer Membranes. AB - Domain formation or compartmentalization in a lipid bilayer membrane has been thought to take place dynamically in cell membranes and play important roles in the spatiotemporal regulation of their physiological functions. In addition, the membrane skeleton, which is a protein assembly beneath the cell membrane, also regulates the properties as well as the morphology of membranes because of its role as a diffusion barrier against constitutive molecules of the membrane or as a scaffold for physiological reactions. Therefore, it is important to study the relationship between lipid bilayer membranes and proteins that form the membrane skeleton. Among cytoskeletal systems, septin is unique because it forms arrays on liposomes that contain phosphoinositides, and this property is thought to contribute to the formation of the annulus in sperm flagellum. In this study, a supported lipid bilayer (SLB) was used to investigate the effect of septin on lipid bilayers because SLBs rather than liposomes are suitable for observation of the membrane domains formed. We found that SLBs containing phosphatidylinositol (PI) reversibly form domains by decreasing the temperature and that septin affects both the formation and the disappearance of the cooling-induced domain. Septin inhibits the growth of cooling-induced domains during decreases in temperature and inhibits the dispersion and the disappearance of those domains during increases in temperature. These results indicate that septin complexes, i.e., filaments or oligomers assembling on the surface of lipid bilayer membranes, can regulate the dynamics of domain formation via their behavior as an anchor for PI molecules. PMID- 27934515 TI - Biobased Wrinkled Surfaces Induced by Wood Mimetic Skins upon Drying: Effect of Mechanical Properties on Wrinkle Morphology. AB - We previously developed biobased wrinkled surfaces based on wood mimetic skins in which microscopic wrinkles were fabricated on a chitosan film by immersion in a phenolic acid solution, horseradish peroxidase-catalyzed surface reaction, and drying. Here, we prepared a diverse range of wrinkled films by immersion treatment at 30, 40, 50, and 60 degrees C in p-coumaric acid and then investigated the correlation between wrinkle morphology and mechanical properties. Wrinkle wavelengths gradually decreased as the immersion temperature increased as well as the previous report. In order to clarify the mechanisms responsible for the different wrinkle morphologies, the films were subjected to elastic moduli measurement and GPC analysis after immersion treatment. These experiments provided evidence that the chitosan around the film surface decomposed along with the immersion process. The decomposition was accelerated by higher immersion temperature, suggesting that higher temperatures led to the formation of softer skins, inducing smaller wrinkles. In fact, wrinkle morphologies with this system were predominately determined by the hardness of the wood mimetic skins. This phenomenon is consistent with the fundamentals of surface wrinkling in nature. This study is the first to demonstrate that artificial wrinkling triggered by water evaporation can be controlled by precise control of the surface hardness of soft material. PMID- 27934516 TI - Impact of Spatial Distribution of Charged Groups in Core Poly(N isopropylacrylamide)-Based Microgels on the Resultant Composite Structures Prepared by Seeded Emulsion Polymerization of Styrene. AB - A series of raspberry-shaped composite microgels were synthesized by seeded emulsion polymerization of styrene in the presence of hydrogel particles with different distributions of charged groups. Unlike microgels whose charged groups are localized in their center,29 polystyrene nanoparticles were formed inside the core microgels when the microgels whose charged groups were localized on their surface were used as cores for seeded emulsion polymerization. The effects of the surface charge densities of the core microgels and the concentration of styrene monomer during the polymerization on the resultant structures of composite microgels were investigated. The surface structures of obtained composite microgels were mainly evaluated by electron microscopy, and their stimuli responsiveness was evaluated by dynamic light scattering and laser Doppler velocimetry. The internal structures of the composite microgels were visualized from ultrathin cross sections observed by transmission electron microscopy (TEM). Cryo-TEM was used to clarify the microscopic structures of composite microgels when they were in hydrated states. Through a series of characterizations, we summarize the effects of structures of core microgels on the resultant composite structures. PMID- 27934517 TI - Dynamics of Hydrogel-Assisted Giant Unilamellar Vesicle Formation from Unsaturated Lipid Systems. AB - While current research is centered on observing biophysical properties and phenomena in giant unilamellar vesicles (GUVs), little is known about fabrication parameters that control GUV formation. Using different lipids and rehydration buffers, we directly observe varying dynamics of hydrogel-assisted GUV formation via fluorescence microscopy. We observe the effects of buffer ionic strength, osmolarity, agarose density, and pH on the formation of GUVs using neutral and charged lipids. We find that increasing rehydration buffer ionic strength correlates with increased vesicle size and rate of GUV formation. Increasing buffer acidity increased the rate of GUV formation, while more basic environments slowed the rate. For buffers containing 500 mM sucrose, GUV formation was overall inhibited and only tubules formed. Observations of GUV formation dynamics elucidate parametric effects of charge, ionic strength, pH, and osmolarity, demonstrating the versatility of this biomimetic platform. PMID- 27934518 TI - Imidazolium-Based Lipid Analogues and Their Interaction with Phosphatidylcholine Membranes. AB - 4,5-Dialkylated imidazolium lipid salts are a new class of lipid analogues showing distinct biological activities. The potential effects of the imidazolium lipids on artificial lipid membranes and the corresponding membrane interactions was analyzed. Therefore, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was employed to create an established lipid monolayer model and a bilayer membrane. Mixed monolayers of DPPC and 4,5-dialkylimidazolium lipids differing by their alkyl chain length (C7, C11, and C15) were characterized by surface pressure-area (pi-A) isotherms using a Wilhelmy film balance in combination with epifluorescence microscopy. Monolayer hysteresis for binary mixtures was examined by recording triplicate consecutive compression-expansion cycles. The lipid miscibility and membrane stability of DPPC/imidazolium lipids were subsequently evaluated by the excess mean molecular area (DeltaAex) and the excess Gibbs free energy (DeltaGex) of mixing. Furthermore, the thermotropic behavior of mixed liposomes of DPPC/imidazolium lipids was investigated by differential scanning calorimetry (DSC). The C15-imidazolium lipid (C15-IMe.HI) forms a thermodynamically favored and kinetically reversible Langmuir monolayer with DPPC and exhibits a rigidification effect on both DPPC monolayer and bilayer structures at low molar fractions (X <= 0.3). However, the incorporation of the C11-imidazolium lipid (C11-IMe.HI) causes the formation of an unstable and irreversible Langmuir-Gibbs monolayer with DPPC and disordered DPPC liposomes. The C7-imidazolium lipid (C7-IMe.HI) displays negligible membrane activity. To better understand these results on a molecular level, all-atom molecular dynamics (MD) simulations were performed. The simulations yield two opposing molecular mechanisms governing the different behavior of the three imidazolium lipids: a lateral ordering effect and a free volume/stretching effect. Overall, our study provides the first evidence that the membrane interaction of the C15 and C11 derivatives modulates the structural organization of lipid membranes. On the contrary, for the C7 derivative its membrane activity is too low to contribute to its earlier reported potent cytotoxicity. PMID- 27934519 TI - Ionic Nature of a Gemini Surfactant at the Air/Water Interface. AB - The ionic state of an adsorbed gemini surfactant at the air/water interface was investigated using a combination of surface potential and surface tension data. The combined model was developed and successfully described the experimental data. The results verified the existence of three ionic states of the gemini surfactant in the interfacial zone. Furthermore, the model can quantify the adsorbed concentrations of these species. At low concentrations, the fully dissociated state dominates the adsorption. At high concentrations, the fully associated state dominates, accounting for up to 80% of the total adsorption. In the middle range, the adsorption is dominated by the partially associated state, which has a maximum percentage of 80% at a critical micelle concentration of 0.5. The variation in the ionic state is a unique characteristic of gemini surfactants, which can be the underlying mechanism for their advantages over conventional surfactants. PMID- 27934520 TI - Two-Step Membrane Binding of NDPK-B Induces Membrane Fluidity Decrease and Changes in Lipid Lateral Organization and Protein Cluster Formation. AB - Nucleoside diphosphate kinases (NDPKs) are crucial elements in a wide array of cellular physiological or pathophysiological processes such as apoptosis, proliferation, or metastasis formation. Among the NDPK isoenzymes, NDPK-B, a cytoplasmic protein, was reported to be associated with several biological membranes such as plasma or endoplasmic reticulum membranes. Using several membrane models (liposomes, lipid monolayers, and supported lipid bilayers) associated with biophysical approaches, we show that lipid membrane binding occurs in a two-step process: first, initiation by a strong electrostatic adsorption process and followed by shallow penetration of the protein within the membrane. The NDPK-B binding leads to a decrease in membrane fluidity and formation of protein patches. The ability of NDPK-B to form microdomains at the membrane level may be related to protein-protein interactions triggered by its association with anionic phospholipids. Such accumulation of NDPK-B would amplify its effects in functional platform formation and protein recruitment at the membrane. PMID- 27934522 TI - Graphene Oxide Monolayer as a Compatibilizer at the Polymer-Polymer Interface for Stabilizing Polymer Bilayer Films against Dewetting. AB - We investigate the effect of adding graphene oxide (GO) sheets at the polymer polymer interface on the dewetting dynamics and compatibility of immiscible polymer bilayer films. GO monolayers are deposited at the poly(methyl methacrylate) (PMMA)-polystyrene (PS) interface by the Langmuir-Schaefer technique. GO monolayers are found to significantly inhibit the dewetting behavior of both PMMA films (on PS substrates) and PS films (on PMMA substrates). This can be interpreted in terms of an interfacial interaction between the GO sheets and these polymers, which is evidenced by the reduced contact angle of the dewet droplets. The favorable interaction of GO with both PS and PMMA facilitates compatibilization of the immiscible polymer bilayer films, thereby stabilizing their bilayer films against dewetting. This compatibilization effect is verified by neutron reflectivity measurements, which reveal that the addition of GO monolayers broadens the interface between PS and the deuterated PMMA films by 2.2 times over that of the bilayer in the absence of GO. PMID- 27934521 TI - Controlling the Photocorrosion of Zinc Sulfide Nanoparticles in Water by Doping with Chloride and Cobalt Ions. AB - Photodegradation under UV light irradiation is a major drawback in photocatalytic applications of sulfide semiconductors. ZnS nanoparticles were doped with very low amounts of chloride or cobalt ions in the ppm range and codoped with chloride and cobalt ions during their synthesis by precipitation in aqueous solution followed by calcination. The high-temperature wurtzite phase annealed at 800 degrees C had a high susceptibility to UV irradiation in water, while the low temperature zincblende phase annealed at 400 degrees C was found to be stable. Chlorine doping increased the rate of photocorrosion in water, whereas cobalt doping led to a stabilization of the ZnS nanoparticles. Based on photochemical and spectroscopic investigations applying UV/vis, X-ray photoelectron, and photoluminescence spectroscopy, the increased susceptibility of Cl-doped ZnS is ascribed to a higher number of surface point defects, whereas the stabilization by Co2+ is caused by additional recombination pathways for the charge carriers in the bulk, thus avoiding photocorrosion processes at the surface. Additional doping of Cl-doped ZnS with cobalt ions was found to counteract the detrimental effect of the chloride ions efficiently. PMID- 27934523 TI - Synergistic Growth of Giant Wormlike Micelles in Ternary Mixed Surfactant Solutions: Effect of Octanoic Acid. AB - The synergistic growth of giant wormlike micelles in ternary mixed solutions composed of an anionic surfactant (sodium laurylethersulfate, SLES), a zwitterionic surfactant (cocamidopropyl betaine, CAPB), and octanoic acid (HC8) is studied. Rheological data and their analysis in terms of Cole-Cole plots and micellar characteristic times are presented, and the micellar structures behind the observed rheological behavior are revealed by cryo-TEM micrographs. The surfactant composition is fixed near the maximal micelle size of the binary SLES + CAPB system, whereas the concentration of HC8 is varied. At a given HC8 concentration, the viscosity of the ternary micellar solutions exhibits a very high and sharp peak. Polarized-light optical microscopy indicates that all investigated solutions are isotropic rather than liquid-crystalline. The cryo-TEM imaging shows complex phase behavior: wormlike micelles to the left of the peak, giant entangled wormlike micelles at the peak, and long wormlike micelles coexisting with multiconnected micellar aggregates to the right of the peak. The formation of multiconnected micelles leads to a drop in viscosity at the higher concentrations. The results contribute to a better understanding of the structure rheology relations in micellar surfactant solutions and could be useful for controlling the properties of formulations in personal-care and house-hold detergency. PMID- 27934524 TI - Self-Assembled Hierarchical Arrays for Colored Retroreflective Coatings. AB - This study reports a self-assembly technology for fabricating retroreflection coatings with hierarchical nano-/microstructures, which are inspired by the binary periodic structures found in the compound eyes of insects. Silica colloidal crystals of adjustable thicknesses are assembled on encountering glass microbeads using a Langmuir-Blodgett-like approach in a layer-by-layer manner. The as-assembled hierarchical structures exhibit a brilliant color caused by Bragg diffraction from the crystalline lattice of silica colloidal crystals on glass microbeads. The resultant coating is capable of reflecting light in the opposite direction of the incident light. Moreover, the dependence of the silica particle size, the colloidal crystal thickness, and the incident angle on the retroreflective properties are investigated in this study. PMID- 27934525 TI - Dynamic Chemically Driven Dewetting, Spreading, and Self-Running of Sessile Droplets on Crystalline Silicon. AB - A chemically driven dewetting effect is demonstrated using sessile droplets of dilute hydrofluoric acid on chemically oxidized silicon wafers. The dewetting occurs as the thin oxide is slowly etched by the droplet and replaced by a hydrogen-terminated surface; the result of this is a gradual increase in the contact angle of the droplet with time. The time-varying work of adhesion is calculated from the time-varying contact angle; this corresponds to the changing chemical nature of the surface during dewetting and can be modeled by the well known logistic (sigmoid) function often used for the modeling of restricted growth, in this case, the transition from an oxidized surface to a hydrogen terminated silicon surface. The observation of the time-varying contact angle allows one to both measure the etch rate of the silicon oxide and estimate the hydrogenation rate as a function of HF concentration and wafer type. In addition to this, at a certain HF concentration, a self-running droplet effect is observed. In contrast, on hydrogen-terminated silicon wafers, a chemically induced spreading effect is observed using sessile droplets of nitric acid. The droplet spreading can also be modeled using a logistical function, where the restricted growth is the transition from hydrogen-terminated to a chemically induced oxidized silicon surface. The chemically driven dewetting and spreading observed here add to the methods available to study dynamic wetting (e.g., the moving three-phase contact line) of sessile droplets on surfaces. By slowing down chemical kinetics of the wetting, one is able to record the changing profile of the sessile droplet with time and gather information concerning the time-varying surface chemistry. The data also indicates a chemical interface hysteresis (CIH) that is compared to contact angle hysteresis (CAH). The approach can also be used to study the chemical etching and deposition behavior of thin films using liquids by monitoring the macroscopic droplet profile and relating this to the time varying physical and chemical interface phenomena. PMID- 27934526 TI - Self-Assembly of Polyoxovanadate-Containing Fluorosurfactants. AB - Two novel polyoxovanadate (POV)-containing fluorosurfactants, each with two hydrophobic fluorinated "tails" and one nanosized, hydrophilic, rigid POV "head group", are synthesized for the first time. They self-assemble into spherical, bilayer vesicles in acetonitrile/water mixed solvents, as evidenced by systemic studies using laser light scattering (LLS) and electron microscopy techniques. The vesicle sizes demonstrate dynamic change over different solvent compositions mainly as a result of the solvent swelling of the fluorocarbon chains, although the charge number on the POVs changes over the solvent polarity as well. PMID- 27934527 TI - Facile Assembly of Large-Area 2D Microgel Colloidal Crystals Using Charge Reversible Substrates. AB - 2D colloidal crystals (CCs) have important applications; however, the fabrication of large-area, high-quality 2D CCs is still far from being trivial, and the fabrication of 2D microgel CCs is even harder. Here, we have demonstrated that they can be facilely fabricated using charge-reversible substrates. The charge reversible substrates were prepared by modification with amino groups. The amino groups were then protected by amidation with 2,2-dimethylsuccinic anhydride. At acidic pH, the surface charge of the modified substrate will change from negative to positive as a result of the hydrolysis of the amide bonds and the regeneration of the amino groups. 2D microgel CCs can be simply fabricated by applying a concentrated microgel dispersion on the modified substrate. The negatively charged surface of the substrate allows the negatively charged microgel spheres, especially those close to the substrate, to self-assemble into 3D CCs. With the gradual hydrolysis of the amide bonds and the charge reversal of the substrate, the first 111 plane of the 3D assembly is fixed in situ on the substrate. The resulting 2D CC has a high degree of ordering because of the high quality of the parent 3D microgel CC. Because large-area 3D microgel CCs can be facilely fabricated, this method allows for the fabrication of 2D CCs of any size. Nonplanar substrates can also be used. In addition, the interparticle distance of the 2D array can be tuned by the concentration of the microgel dispersion. Besides rigid substrates (such as glass slides, quartz slides, and silicon wafers), flexible polymer films, including polyethylene terephthalate and poly(vinyl chloride) films, were also successfully used as substrates for the fabrication of 2D microgel CCs. PMID- 27934528 TI - Equilibrium Grain Boundary Segregation and Clustering of Impurities in Colloidal Polycrystalline Monolayers. AB - We investigate the segregation of impurities to grain boundaries in colloidal polycrystalline monolayers using video microscopy. A model colloidal alloy is prepared by embedding large spherical impurities in a polycrystalline monolayer of small host colloidal hard spheres, which stops grain growth at a finite grain size. The size ratio between the impurities and the host particles determines whether they behave as interstitial or substitutional impurities in the bulk crystal, akin to those in real alloys. We find that the partitioning of impurities between the grains and the grain boundaries is in very good agreement with the Langmuir-McLean adsorption model for equilibrium grain boundary segregation. This enables the direct measurement of the free energy of adsorption for the two types of impurities. Near saturation, we characterize the spatial distribution of the adsorbed impurities and find that it strongly depends on their interstitial or substitutional nature. This is because the relative importance of clustering and mixing due to nonadditivity is determined by geometrical constraints imposed by the crystalline host lattice. PMID- 27934529 TI - Omega-O-Acylceramides in Skin Lipid Membranes: Effects of Concentration, Sphingoid Base, and Model Complexity on Microstructure and Permeability. AB - Omega-O-acylceramides (acylCer), a subclass of sphingolipids with an ultralong N acyl chain (from 20 to 38 carbons, most usually 30 and 32 carbons), are crucial components of the skin permeability barrier. AcylCer are involved in the formation of the long periodicity lamellar phase (LPP, 12-13 nm), which is essential for preventing water loss from the body. Lower levels of acylCer and LPP accompany skin diseases, such as atopic dermatitis, lamellar ichthyosis, and psoriasis. We studied how the concentration and structure of acylCer influence the organization and permeability barrier properties of model lipid membranes. For simple model membranes composed of the sphingosine-containing acylCer (EOS), N-lignoceroyl sphingosine, lignoceric acid, cholesterol (Chol), and cholesteryl sulfate (CholS), the LPP formed at 10% Cer EOS (of the total Cer) and the short periodicity phase disappeared at 30% Cer EOS. Surprisingly, membranes with the LPP had higher permeabilities than the control membrane without acylCer. In the complex models consisting of acylCer (EOS, phytosphingosine EOP, dihydrosphingosine EOdS, or their mixture; at 10% of the total Cer), a six component Cer mixture, a free fatty acid mixture, cholesterol (Chol), and cholesteryl sulfate (CholS), acylCer decreased the membrane permeability to model permeants (with the strongest effects for acylCer EOP and EOdS) when compared with the permeability of the control membrane without acylCer. However, in the complex model, only a mixture of acylCer EOS, EOdS, and EOP and not the individual acylCer formed both the LPP and orthorhombic chain packing at the 10% level. Thus, the relationships between acylCer, LPP formation, and permeability barrier function are not trivial. Lipid heterogeneity is essential-only the most complex model with nine Cer subclasses mimicked both the organization and permeability of stratum corneum lipid membranes. PMID- 27934530 TI - Noncontact Synergistic Effect between Au Nanoparticles and the Fe2O3 Spindle Inside a Mesoporous Silica Shell as Studied by the Fenton-like Reaction. AB - An Au-Fe2O3@mesoporous SiO2 nanoreactor with a multiyolks/shell structure was synthesized through a multistep method. In this nanoreactor, the spindle Fe2O3 and Au nanoparticles were inside the same mesoporous SiO2 shell as the yolks but in a noncontact manner. The noncontact synergistic effect between Au nanoparticles and the Fe2O3 spindle was studied with a Fenton-like reaction. The catalytic activity of the Au-Fe2O3@mesoporous SiO2 nanoreactor to the Fenton-like reaction for the degradation of organic dyes was dramatically enhanced by the noncontact synergistic effect. PMID- 27934531 TI - Liquid Imbibition in Ceramic-Coated Carbon Nanotube Films. AB - Understanding of the liquid imbibition dynamics in nanoporous materials is important to advances in chemical separations, phase change heat transfer, electrochemical energy storage, and diagnostic assays. We study the liquid imbibition behavior in films of ceramic-coated vertically aligned carbon nanotubes (CNTs). The nanoscale porosity of the films is tuned by conformal ceramic coating via atomic layer deposition (ALD), enabling stable liquid imbibition and precise measurement of the imbibition dynamics without capillary densification of the CNTs. We show that the imbibition rate decreases as the ceramic coating thickness increases, which effectively changes the CNT-CNT spacing and therefore decreases the permeability. We derive a model, based on Darcy's law, that incorporates an expression for the permeability of nanoscale post arrays, and we show that the model fits the experimental results with high accuracy. The tailorable porosity, along with controllable surface wettability and mechanical stability of coated CNTs, suggest their suitability for application-guided engineering, and for further investigation of imbibition behavior at finer length scales. PMID- 27934532 TI - Investigation of Controllable Nanoscale Heat-Denatured Bovine Serum Albumin Films on Graphene. AB - Two-dimensional graphene devices are widely used for biomolecule detection. Nevertheless, the surface modification of graphene is critical to achieve the high sensitivity and specificity required for biological detection. Herein, native bovine serum albumin (BSA) in inorganic solution is denatured on the graphene surface by heating, leading to the formation of nanoscale BSA protein films adsorbed on the graphene substrate via pi-stacking interactions. This technique yields a controllable, scalable, uniform, and high-coverage method for graphene biosensors. Further, the application of such nanoscale heat-denatured BSA films on graphene as a universal graphene biosensor platform is explored. The thickness of heat-denatured BSA films increased with heating time and BSA concentration but decreased with solvent concentration as confirmed by atomic force microscopy. The noncovalent interaction between denatured BSA films and graphene was investigated by Raman spectroscopy. BSA can act as a p-type and n type dopant by modulating pH-dependent net charges on the layered BSA-graphene surface, as assessed by current-voltage measurements. Chemical groups of denatured BSA films, including amino and carboxyl groups, were verified by X-ray photoelectron microscopy, attenuated total reflectance-Fourier transform infrared spectra, and fluorescent labeling. The tailoring of the BSA-graphene surfaces through chemical modification, controlled thickness, and doping type via noncovalent interactions provides a controllable, multifunctional biosensor platform for molecular diagnosis without the possibility of nonspecific adsorption on graphene. PMID- 27934533 TI - Effects of Structural Flexibility on the Kinetics of DNA Y-Junction Assembly and Gelation. AB - The kinetics of DNA assembly is determined not only by temperature but also by the flexibility of the DNA tiles. In this work, the flexibility effect was studied with a model system of Y-junctions, which contain single-stranded thymine (T) loops in the center. It was demonstrated that the incorporation of a loop with only one thymine prominently improved the assembly rate and tuned the final structure of the assembly, whereas the incorporation of a loop of two thymines exhibited the opposite effect. These observations could be explained by the conformation adjustment rate and the intermotif binding strength. Increasing DNA concentration hindered the conformational adjustment rate of DNA strands, leading to the formation of hydrogels in which the network was connected by ribbons. Therefore, the gel can be treated as a metastable state during the phase transition. PMID- 27934535 TI - Covalent Surface Functionalization of Semiconducting Polymer Dots with beta Cyclodextrin for Fluorescent Ratiometric Assay of Cholesterol through Host-Guest Inclusion and FRET. AB - Special functionalization of semiconducting polymer dots (Pdots) is highly desired to expand their applications in chemo/biosening. Herein, carboxyl functionalized poly[(9,9-dioctylfluorenyl-2,7-diyl)-co-(1,4-benzo-{2,1',3} thiadiazole)] dots covalently tagged with aminated beta-cyclodextrin (NH2-CD) have been designed to construct a ratiometric sensor for cholesterol (Cho). Using CD-Pdots as energy donors with rhodamine B (RB) as energy acceptors, a fluorescence resonance energy transfer (FRET) pair has been built because the host-guest interaction between RB and CD attached to Pdots brings donors and acceptors into close proximity. In the presence of Cho, the acceptors will depart from the donors because of the competitive inclusion interaction between Cho and RB with CD, resulting in the hindering of the FRET process between CD-Pdots and RB. On the basis of the turn-on fluorescence of CD-Pdots and turn-off fluorescence of RB, a sensitive ratiometric method for the determination of Cho in the concentration range from 25 to 350 nM with a detection limit of 4.9 nM was achieved. The proposed method was validated to determine free Cho in human serum samples with satisfactory results. PMID- 27934534 TI - Partitioning into Colloidal Structures of Fasted State Intestinal Fluid Studied by Molecular Dynamics Simulations. AB - We performed molecular dynamics (MD) simulations to obtain insights into the structure and molecular interactions of colloidal structures present in fasted state intestinal fluid. Drug partitioning and interaction were studied with a mixed system of the bile salt taurocholate (TCH) and 1,2-dilinoleoyl-sn-glycero-3 phosphocholine (DLiPC). Spontaneous aggregation of TCH and DLiPC from unconstrained MD simulations at the united-atom level using the Berger/Gromos54A7 force fields demonstrated that intermolecular hydrogen bonding between TCH molecules was an important factor in determining the overall TCH and DLiPC configuration. In bilayered systems, these intermolecular hydrogen bonds resulted in embedded transmembrane TCH clusters. Free energy simulations using the umbrella sampling technique revealed that the stability of these transmembrane TCH clusters was superior when they consisted of 3 or 4 TCH per bilayer leaflet. All-atom simulations using the Slipids/GAFF force fields showed that the TCH embedded in the bilayer decreased the energy barrier to penetrate the bilayer (DeltaGpen) for water, ethanol, and carbamazepine, but not for the more lipophilic felodipine and danazol. This suggests that diffusion of hydrophilic to moderately lipophilic molecules through the bilayer is facilitated by the embedded TCH molecules. However, the effect of embedded TCH on the overall lipid/water partitioning was significant for danazol, indicating that the incorporation of TCH plays a crucial role for the partitioning of lipophilic solutes into e.g. lipidic vesicles existing in fasted state intestinal fluids. To conclude, the MD simulations revealed important intermolecular interactions in lipidic bilayers, both between the bile components themselves and with the drug molecules. PMID- 27934536 TI - Microfluidic Manufacturing of Polymeric Nanoparticles: Comparing Flow Control of Multiscale Structure in Single-Phase Staggered Herringbone and Two-Phase Reactors. AB - We compare the microfluidic manufacturing of polycaprolactone-block-poly(ethylene oxide) (PCL-b-PEO) nanoparticles (NPs) in a single-phase staggered herringbone (SHB) mixer and in a two-phase gas-liquid segmented mixer. NPs generated from two different copolymer compositions in both reactors and at three different flow rates, along with NPs generated using a conventional bulk method, are compared with respect to morphologies, dimensions, and internal crystallinities. Our work, the first direct comparison between alternate microfluidic NP synthesis methods, shows three key findings: (i) NP morphologies and dimensions produced in the bulk are different from those produced in a microfluidic mixer, whereas NP crystallinities produced in the bulk and in the SHB mixer are similar; (ii) NP morphologies, dimensions, and crystallinities produced in the single-phase SHB and two-phase mixers at the lowest flow rate are similar; and (iii) NP morphologies, dimensions, and crystallinities change with flow rate in the two phase mixer but not in the single-phase SHB mixer. These findings provide new insights into the relative roles of mixing and shear in the formation and flow directed processing of polymeric NPs in microfluidics, informing future reactor designs for manufacturing NPs of low polydispersity and controlled multiscale structure and function. PMID- 27934537 TI - A study of sociocultural factors on depression in Chinese infertile women from Hunan Province. AB - OBJECTIVE: To explore the sociocultural factors influencing depression in Chinese infertile women in Hunan Province. METHODS: A cross-sectional study was carried out. A total of 211 Chinese infertile women completed demographic details, a disease-related information questionnaire, a self-rating depression scale (SDS) and a social support rating scale (SSRS). RESULTS: One hundred and seven (50.71%) of the participants were classified as depressed according to the self-rating depression scale. The average SDS index score was 50.06 +/- 10.59. Using analysis of variance (ANOVA), Pearson correlation and a multivariable regression analysis, the results showed family type, feelings of discrimination, social support, feelings of shame and reproductive pressures were influential factors in depression among Chinese infertile women. CONCLUSION: Sociocultural factors influence depression levels in Chinese female infertile patients. The unique aspects of Chinese culture may have a negative mental impact on the patients, and cultural factors should be taken into consideration in the development of coping strategies for Chinese infertile women. PMID- 27934538 TI - Plateletcrit in patients with gestational diabetes mellitus. PMID- 27934539 TI - Healthcare reform in the Middle East and the USA. AB - Mustafa Z Younis speaks to Laura Dormer, Commissioning Editor: Dr Mustafa Z Younis is an internationally recognized scholar and was a member of the Executive Committee of the International Society for Research of Healthcare Financial Management. Dr Younis has authored and published over 200 articles, abstracts and presentations in refereed journals and meetings, and has presented at national and international conferences. Dr Younis has administrative experience as Senior Adviser for the President at Zirve University, Turkey and as Chair of the Department of Health Policy and Management at Florida International University (FL, USA) where he led the accreditation efforts for the Healthcare Management Program. Dr Younis has a history of playing visible roles on the editorial boards of journals as Chief Editor, Guest Editor and Editorial board member of leading journals such as Journal of International Medical Research, Journal of Health Care Finance, Inquiry, Journal of Health and Human Services Administration, Journal of Public Budgeting, Accounting and Financial Management. Dr Younis is a frequent speaker for both academic and professional audiences. His talks often feature his latest research and work in progress as well as cross-industry trends and strategy implications. He has provided workshops and presentation for wide organizations. His research and findings applied to for-profit, non-profit settings, and government. Dr Younis has consulted with several organizations on healthcare finance, and economics. Dr Younis is often invited to speak about the challenges in the healthcare industry and other related topics to health economics, finance, and research. He has presented topics such as, healthcare reform, ownership structure, profitability, unit cost, payment system and efficiency in management, at a variety of forums and conferences in Europe, Asia and Middle East. PMID- 27934540 TI - Correlation between functional mobility and cognitive performance in older adults with cognitive impairment. AB - Association between cognitive impairment and gait performance occurs in mild cognitive impairment (MCI) and Alzheimer's disease (AD), particularly under "divided attention" conditions, leading to a greater risk of falls. We studied 36 controls, 42 MCI, and 26 mild AD patients, using the Timed Up-and-Go test (TUG) under four conditions: TUG single - TUG1; TUG cognitive - TUG2; TUG manual -TUG3; TUG cognitive and manual - TUG4. Cognition was assessed using the MMSE, SKT, Exit25, and TMT (A and B). We found significant correlations between cognitive scores and TUG2 [r values (MMSE: -0.383, TMT-A: 0.430, TMT-B: 0.386, Exit25: 0.455, SKT: 0.563)] and TUG4 [(MMSE: -0.398, TMT-A: 0.384, TMT-B: 0.352,Exit25: 0.466, SKT: 0.525)] in the AD group, and between all TUG modalities and SKT in MCI and AD. Our results revealed that functional mobility impairment in cognitive dual tasks correlated to cognitive decline in AD patients and to attention and memory impairment in MCI. PMID- 27934541 TI - Association between endothelial dysfunction and otoneurological symptoms in children with sickle cell disease. AB - OBJECTIVE: To evaluate the association between endothelial dysfunction and otoneurological symptoms and vaso-occlusive phenomena in children with sickle cell disease (SCD). METHODS: Cross-sectional study with 54 children, aged between 6 and19 years of age, of whom 28 had genotype SS and 26 apparently healthy (AA genotype) whose parents or guardians, or the children themselves, filled out a questionnaire designed to assess their otoneurological symptoms. All the individuals were submitted assessment of endothelial function by flow-mediated dilation (FMD) percentage with reactive hyperemia of brachial artery Doppler. RESULTS: Otoneurological symptoms (tinnitus and/or vertigo) predominated in the SCD group (46.4 vs. 15.4%; p = 0.006). A negative correlation was observed between FMD percentage and time of evolution of vertigo SCD (r = -0.432; p = 0.022) and the linear regression analysis demonstrated that for every reduction in FMD percentage there was an increase in time of evolution of vertigo of 1.79 months (beta = -1.79; p = 0.022). The positive correlation between episodes of painful crisis and time of evolution of vertigo (r = 0.3; p = 0.04). DISCUSSION: The presence of vascular endothelial damage in the labyrinthine artery in patients with SCD is capable of compromising the semicircular canals, shown by clinical expression of otoneurological symptoms, such as vertigo. In the present study, an association was observed between endothelial dysfunction with otoneurological symptoms and otoneurological symptoms and vaso-occlusive phenomena in SCD. PMID- 27934542 TI - The impact of aging on associative memory for preexisting unitized associations. AB - Aging is accompanied by a decline in associative memory that can, however, be attenuated when associations are unitized at encoding, that is, when they form an integrated entity. Unitization is thought to promote familiarity-based recognition memory, which is preserved in aging. We examined whether preexperimentally unitized associations (compound words (CWs)) do indeed reduce age differences in memory, and whether preexperimental unitization promotes familiarity. In Experiment 1, we assessed the memory of 20 young and 20 older participants for compound versus unrelated word pairs using a yes/no recognition test with Remember/Know/Guess judgments. In Experiment 2, we tested 20 young and 20 older participants using the same procedure, except for the use of a two alternative forced-choice recognition paradigm, which is thought to enhance the contribution of familiarity. The results of both experiments corroborated the greater contribution of familiarity to recognition of unitized associations. In Experiment 1, however, the use of CWs did not attenuate the age-related associative decline. We suggest that preexisting knowledge associated with recombined compounds induced high absolute familiarity and illusory recollection, leading to high false-recognition rates for the older adults. By contrast, the two groups performed similarly across both conditions in Experiment 2. Thus, the forced-choice procedure facilitates the use of familiarity in such a way that it improves older adults' associative memory to the level of young participants. These results suggest that the modulation of associative memory in aging by preexisting unitization varies according to methodological parameters, such as the nature of the lures and the test format. PMID- 27934543 TI - Five radiographic methods for assessing skeletal maturity in a Spanish population: is there a correlation? AB - OBJECTIVES: The need for accurate techniques of estimating age has sharply increased in line with the rise in illegal migration and the political, economic and socio-demographic problems that this poses in developed countries today. The methods routinely employed for determining chronological age are mainly based on determining skeletal maturation using radiological techniques. The objective of this study was to correlate five different methods for assessing skeletal maturation. MATERIALS AND METHODS: 606 radiographs of growing patients were analyzed, and each patient was classified according to two cervical vertebral based methods, two hand-wrist-based methods and one tooth-based method. Spearman's rank-order correlation coefficient was applied to assess the relationship between chronological age and the five methods of assessing maturation, as well as correlations between the five methods (p < 0.05). RESULTS: Spearman's rank correlation coefficients for chronological age and cervical vertebral maturation stage using both methods were 0.656/0.693 (p < 0.001), respectively, for males. For females, the correlation was stronger for both methods. The correlation coefficients for chronological age against the two hand wrist assessment methods were statistically significant only for Fishman's method, 0.722 (p < 0.001) and 0.839 (p < 0.001), respectively for males and females. CONCLUSIONS: The cervical vertebral, hand-wrist and dental maturation methods of assessment were all found to correlate strongly with each other, irrespective of gender, except for Grave and Brown's method. The results found the strongest correlation between the second molars and females, and the second premolar and males. CLINICAL RELEVANCE: This study sheds light on and correlates with the five radiographic methods most commonly used for assessing skeletal maturation in a Spanish population in southern Europe. PMID- 27934544 TI - A rehabilitation program based on music practice for patients with unilateral spatial neglect: a single-case study. AB - Two major limitations of unilateral spatial neglect (USN) rehabilitation methods are actually reported: a lack of long-term efficiency and a lack of generalization to daily life. The aim of our case study was to underline how a multisensory method-music practice-could avoid these limitations. Mrs BV suffered from a chronic severe USN. She had rehabilitation sessions of music practice over 8 weeks. An improvement of her USN was found on paper-pencil tests but also in daily activities. Benefits subsisted 4 months after rehabilitation. Music practice seemed to avoid the major limitations of USN rehabilitations and could represent a promising tool. PMID- 27934545 TI - Victor's justice: atrocities in postwar Nigeria. AB - The Nigerian Government's declaration of 'no victor, no vanquished' after the capitulation of Biafra on 12 January 1970, was applauded as the right step towards reconciliation and transition from war to peace. Despite this declaration and assurance of amnesty, the Nigerian Government and its soldiers still engaged in acts that amounted to retributive justice. They starved and killed innocent Biafran civilians, looted their property and raped their women. Surprisingly, these postwar atrocities committed against former Biafrans have been largely ignored in the historiography of the Nigeria-Biafra War. This paper seeks to fill the gap in the war literature by interrogating Nigerian Government's attitude towards the postwar humanitarian crisis and crimes against humanity in former Biafra. The paper argues that former Biafrans were not fully reintegrated into the Nigerian society and that the Nigerian Government deliberately neglected them to die in large numbers, thereby making it difficult for the war victims to recover from the hardships of the conflict. PMID- 27934546 TI - Sodium bicarbonate ingestion and individual variability in time-to-peak pH. AB - This study determined variability in time-to-peak pH after consumption of 300 mg kg-1 of sodium bicarbonate. Seventeen participants (mean +/- SD: age 21.38 +/- 1.5 years; mass 75.8 +/- 5.8 kg; height 176.8 +/- 7.6 cm) reported to the laboratory where a resting capillary sample was taken. Then, 300 mg kg-1 of NaHCO3 in 450 ml of flavoured water was ingested. Participants rested for 90 min and repeated blood samples were procured at 10 min intervals for 60 min and then every 5 min until 90 min. Blood pH concentrations were measured. Results suggested that time-to-peak pH (64.41 +/- 18.78 min) was variable with a range of 10-85 min and a coefficient of variation of 29.16%. A bimodal distribution occurred, at 65 and 75 min. In conclusion, athletes, when using NaHCO3 as an ergogenic aid, should determine their time-to-peak pH to best utilize the added buffering capacity this substance allows. PMID- 27934547 TI - Nurse confidence in gynaecological oncology practice and the evaluation of a professional development module. AB - BACKGROUND: A tertiary-based education program on gynaecological oncology was attended by 62 registered nurses (RN). AIMS: The program aimed to update nurses' knowledge, improve skills and ability to manage common situations and to assess program efficacy. DESIGN: Evaluation framework with specifically designed pre post questionnaire about program content and nurse confidence. METHOD: RN interested in gynaecological oncology were invited to attend. Nurses rated their confidence about gynaecological oncology skills one week prior to the program, immediately post-course, 3 months post and 12 months post. Speaker presentations were evaluated immediately post-course. RESULTS: Participants indicated improved confidence immediately after participating in the course (z = -6.515, p < .001); whilst confidence subsequently declined and stabilised up to 12 months post course, it still remained significantly higher than before the course: 3 months post- (z = -5.284, p < .001) and 12 months post- (z = -4.155, p < .001). CONCLUSIONS: Results support the value of continuing professional education for improving nurse confidence in the gynaecological oncology setting. PMID- 27934548 TI - ARHGEF10 gene polymorphism is closely associated with the risk of ischemic stroke in Northern Han Chinese population. AB - Stroke is a common disease with high mortality and morbidity. It is of high importance to identify biomarkers of stroke. Rho guanine nucleotide-exchange factor(GEF) 10 (ARHGEF10) gene polymorphism has been found to be associated with various human diseases, but its correlation with stroke remains unknown. This study aims to evaluate the potential association of the single nucleotide polymorphisms (SNPs) of ARHGEF10 with ischemic stroke (IS) in northern Han Chinese population. Three SNPs of ARHGEF10 gene were analyzed in 385 IS patients and 362 hypertension control patients using the ligase detection reaction (LDR) method. Logistic regression analysis demonstrated that GG genotypes of SNP rs2280887 were associated with an increased risk of IS in dominant, recessive, and additive models. Moreover, SNP rs9657362 and SNP rs4480162 were significantly associated with IS in dominant and additive models. These results indicate that ARHGEF10 gene polymorphisms may affect IS risk in northern Han Chinese. PMID- 27934549 TI - Burden of illness and research investments in translational sciences for pharmaceuticals in metastatic cancers. AB - AIM: To explore whether investments in translational sciences for six metastatic cancers follow idiosyncratic returns to those investments rather than levels of burden of illness (BI). METHODS: Associate the number of translational clinical trials in the USA involving oncolytic drugs approved during 2008-2013 and the level (in 2008) and changes (2002-2008 and 2008-2014) in cancer-specific years of life lost. RESULTS: Investments in trials were positively associated only with contemporary changes in BI (2008-2014). The relationship was stronger for government-sponsored comparative-effectiveness trials than for industry. CONCLUSION: Translational research investments follow anticipated changes to BI levels. Systematic quantification of these expected returns from specific investments can help guide investment decisions in translational health sciences and generate productive dialogue across stakeholders. PMID- 27934550 TI - Healthcare resource allocation decisions affecting uninsured services. AB - Purpose Using the example of community access programs (CAPs), the purpose of this paper is to describe resource allocation and policy decisions related to providing health services for the uninsured in the USA and the organizational values affecting these decisions. Design/methodology/approach The study used comparative case study methodology at two geographically diverse sites. Researchers collected data from program documents, meeting observations, and interviews with program stakeholders. Findings Five resource allocation or policy decisions relevant to providing healthcare services were described at each site across three categories: designing the health plan, reacting to funding changes, and revising policies. Organizational values of access to care and stewardship most frequently affected resource allocation and policy decisions, while economic and political pressures affect the relative prioritization of values. Research limitations/implications Small sample size, the potential for social desirability or recall bias, and the exclusion of provider, member or community perspectives beyond those represented among participating board members. Practical implications Program directors or researchers can use this study to assess the extent to which resource allocation and policy decisions align with organizational values and mission statements. Social implications The description of how healthcare decisions are actually made can be matched with literature that describes how healthcare resource decisions ought to be made, in order to provide a normative grounding for future decisions. Originality/value This study addresses a gap in literature regarding how CAPs actually make resource allocation decisions that affect access to healthcare services. PMID- 27934551 TI - Relationship between geriatric nutritional risk index and subpopulation lymphocyte counts in patients undergoing hemodialysis and peritoneal dialysis. AB - We investigated the relationship between geriatric nutritional risk index (GNRI) and subpopulation lymphocyte counts (SLCs) in hemodialysis (HD) and peritoneal dialysis (PD) patients and evaluated whether they can be helpful in the diagnosis of malnutrition in these patients. We examined the GNRI and SLCs of 50 HD patients (mean: 55.8 +/- 12.7 years; 28 men and 22 women) and 16 Continuous Ambulatory Peritoneal Dialysis (CAPD) patients (mean: 49.8 +/- 14.5 years; 10 men and six women). The GNRI is calculated based on the serum albumin level, dry weight, and ideal body weight and uses the following equation: GNRI = [14.89 * albumin (g/dL)] + [41.7 * (weight/ideal body weight)]. SLCs were evaluated using flow cytometry. T-tests and chi2 tests were performed to compare the two groups. Logistic regression analysis was performed for predicting malnutrition in dialysis patients. The average GNRI value was 100.1 +/- 8.4 in HD patients and 99.2 +/- 8.1 in PD patients, and no significant differences in GNRI or SLC were observed between the two groups. SLCs were higher in patients with higher GNRI (GNRI >= 100) although there was no statistical difference. Logistic regression for predicting malnutrition according to GNRI revealed that age, female sex, and CD19 counts predicted malnutrition in HD and PD patients. These results suggest that GNRI and SLCs (especially CD19 count) may be significant nutritional markers in these patients. PMID- 27934553 TI - Sustainable Healthcare in Dermatology: From management of diseases to empathy for well-being. PMID- 27934552 TI - Correction to: Successful treatment of ulcerated hemangiomas with a dual wavelength 595- and 1064-nm laser system. PMID- 27934554 TI - Empathy in medicine: Neuroscience, education and challenges. AB - Empathy is a multifaceted skill and asset for health care providers. This paper uses current neuroscience literature of empathy to generate nuanced theory of how empathy can be blocked by personal stress and aversion among health care professionals. Current training approaches for educating sustainable empathy are reviewed in depth. The final part of the paper provides suggestions on how to spread empathy education farther and wider across medical education. PMID- 27934555 TI - Does installation of the backstroke start device reduce 15-m start time in swimming? AB - The purpose of this study was to determine the installation of the backstroke start device reduces 15-m time. Thirteen college swimmers participated in this study. The aerial start and underwater motions were recorded with two digital video cameras. The center of mass (CM) of the swimmer, angular displacements and velocities of the shoulder, hip and knee joints were calculated. As an indicator of performance, the 5- and 15-m times were measured. The 5- and 15-m times in the backstroke start device condition were significantly shorter than in the non backstroke start device condition. The vertical velocities of the CM at hand-off and toe-off in the backstroke start device condition were significantly greater than in the non-backstroke start device condition, while there was no significant difference in the CM horizontal velocity at toe-off. As a result, the height of the great trochanter at entry of the fingertips, with the backstroke start device, was 15 cm higher than in the non-backstroke start device condition. In addition, the CM horizontal velocities at 5 m in the backstroke start device condition were significantly greater than those of the non-backstroke start device. Thus, the use of the backstroke start device may reduce the 15-m time by diminution of the entry area. PMID- 27934556 TI - Room for improvement: Palliating the ego in feedback-resistant medical students. AB - Feedback in medical education provides the impetus for growth in a field pressured to demonstrate continuous progress. Unfortunately, as it always incorporates some level of judgment, certain students appear more resistant than receptive to receiving feedback. Coupled with the ubiquitous stressors of medicine-examinations, perpetual knowledge acquisition, competition for employment-there subtly emerges a learning environment in which the mindset of medical trainees morphs from collegiality to outperformance of one's peers. As the unconscious mind is ultimately focused on self-protection, the cognitive response of reflecting upon received feedback is overcome by an emotional response to safeguard one's self-image against criticism in a culture of comparison. Although self-confidence plays a critical role in mitigating burnout, the relationship between resiliency and ego-armoring is rarely discussed in the literature. Consequently, despite the best intentions of educators in fostering clinical maturity among their trainees, the fact remains that insecurity, inadequacy and invulnerability continue to drive feedback-resistance among medical students. PMID- 27934557 TI - Surgical Complications After Kidney Transplantation. AB - Since the first successful organ transplant conducted between twins in 1954, kidney transplant has evolved considerably over the past 50 years. Kidney transplant plays an important role in the treatment of end-stage kidney disease to improve the quality of life and prolong the life of patients. Despite significant advances, postoperative medical and surgical complications still represent important causes of morbidity and mortality. Many problems can be avoided through prophylactic correction of abnormalities detected during the preoperative evaluation; however, it is critical that technical mishaps at all stages of the transplant process (donor nephrectomy, benchwork preparation, and implant) be prevented and that careful postoperative monitoring be carried out, including thorough examination by attending physicians. However, despite these advances, surgical complications still present serious problems in kidney transplant recipients. PMID- 27934558 TI - Fibroblast Growth Factor 23 in Postrenal Transplant: An Often Forgotten Hormone. AB - Fibroblast growth factor 23 is likely to be the most important regulator of phosphate homeostasis, which mediates its functions through fibroblast growth factor receptors and the coreceptor Klotho. In addition to reducing expression of the sodium-phosphate cotransporters NPT2a and NPT2c in the proximal tubules, fibroblast growth factor 23 inhibits renal 1alpha-hydroxylase and stimulates 24 hydroxylase and appears to reduce parathyroid hormone secretion in short-term studies. Fibroblast growth factor 23 synthesis and secretion by osteocytes and osteoblasts are upregulated through 1,25-dihydroxyvitamin D3 and through an increased dietary phosphate intake. Recent studies have indicated that a low protein diet and calcium deficiency reduce circulating fibroblast growth factor 23 levels, but magnesium deficiency increases fibroblast growth factor levels. Drugs such as phosphate binders, bisphosphonate, and estrogens have various effects on circulating fibroblast growth factor 23 levels. The high cardiovascular disease event rates and mortality associated with elevated levels of this hormone may be due to various effects on the cardiovascular system, including left ventricular hypertrophy, arterial stiffness, vascular calcifications, endothelial dysfunction, and increased levels of inflammatory markers. In addition, elevated levels of this hormone may contribute to mineral bone metabolism disorders and to patient and allograft survival after renal transplant. Here, we discuss the effects of fibroblast growth factor 23 on adverse renal, bone, and cardiovascular outcomes after kidney transplant. PMID- 27934560 TI - Low-Activity Kidney Transplant Center, A Single-Center Experience: Early Care as a Major Challenge. AB - OBJECTIVES: In many countries, some kidney transplants are performed in small centers, from which clinical data are rarely specifically reported. The aim of this study was to describe patient and graft survival rates and their correlates in a low-activity kidney transplant center. MATERIALS AND METHODS: We performed a retrospective cohort study of all patients who underwent transplant between January 2002 and May 2012 at a university hospital. Patient, graft, and death censored graft survival rates were assessed with Kaplan-Meier analyses and compared by log-rank test, with associated factors analyzed by Cox proportional hazards modeling. RESULTS: Among a total of 162 patients, the mean age was 41.8 +/- 13.5 years, and 92% received a living-donor graft. At 1, 3, and 5 years, patient survival was 88.6%, 86%, and 82.9%. Graft survival was 86.9%, 83%, and 77%, and death-censored graft survival was 98.1%, 96.6%, and 92.9% at the same time points. Most graft losses were due to patient death from infection and occurred within the first year after transplant. After adjustment, age over 42 years (hazard ratio of 3.94; 95% confidence interval, 1.39-11.13), deceased donor graft (hazard ratio of 11.41; 95% confidence interval, 1.2-108.35), and higher average education (hazard ratio of 4.96; 95% confidence interval, 1.01-24.32) were independently associated with graft loss. CONCLUSIONS: The observed patient and graft survival rates were similar to those described in large databases; however, early mortality remains a major challenge. Improving posttransplant care is a key issue to increasing survival in small transplant centers. PMID- 27934559 TI - Recurrent Nephrotic Syndrome After Renal Transplant in Children. AB - OBJECTIVES: Recurrent disease occurs in around 30% of children transplanted for steroid-resistant nephrotic syndrome. Its precipitating risk factors have rarely been studied in the Middle East. The aim of our study was to determine what characterizes posttransplant recurrence of nephrotic syndrome in Syrian children. MATERIALS AND METHODS: We performed a retrospective analysis of 12 nephrotic children who received 1 renal allograft at the Kidney Hospital in Damascus from 2002 to 2013. RESULTS: Native kidney biopsy results showed focal segmental glomerulosclerosis in 9 of 10 patients. Four patients had 1 or more sibling affected with nephrotic syndrome, and the remaining patients were labeled as having sporadic disease. Genetic screening for NPHS2, NPHS1, and Wilms tumor gene (WT1) mutations were done for 6 patients, and 1 novel homozygous NPHS2 mutation was identified in 1 patient. All patients received transplants from living donors. Four patients had recurrence of initial disease after transplant (overall recurrence rate of 33%). However, 1 patient showed complete and spontaneous remission 20 months after transplant; As expected, the patient with NPSH2 mutation had no recurrence. Patients with sporadic disease showed risk of recurrence 5 times higher than patients with familial disease (P = .24). Interestingly, all recurrent cases had received a kidney from a related donor and were initially classified as having sporadic disease. Although not statistically significant, the risk of recurrence from related donor grafts was 6.75 times higher than from unrelated donors (P = .16). To the best of our knowledge, this observation, the first of its kind, has never been investigated or pointed out in the literature. CONCLUSIONS: Further research is needed to confidently determine whether living related donor grafts are associated with increased incidence of recurrence of nephrotic syndrome. PMID- 27934561 TI - Various Regimens of Total Body Irradiation for Hematopoietic Stem Cell Transplant. AB - OBJECTIVES: We aimed to evaluate the safety of total body irradiation before bone marrow transplant. MATERIALS AND METHODS: We analyzed 110 patients (65 male, 45 female) who underwent total body irradiation for hematopoietic stem cell transplant between May 1998 and March 2013. Median age at total body irradiation was 17 years (range, 1-62 y). Median observation time was 777 days (range, 31 5494 d). Initial diagnoses were acute lymphoblastic leukemia (24 patients), acute myeloid leukemia (26 patients), chronic myeloid leukemia (7 patients), myelodysplastic syndrome (8 patients), malignant lymphoma (13 patients), mucopolysaccharidosis (12 patients), neuroblastoma (10 patients), and other diseases (10 patients). The total fractionated dose used for total body irradiation was 12 Gy in 69 patients and 6.0-10.8 Gy in 29 patients. Single-dose total body irradiation was administered to 12 patients. Most patients (63 of 110) received chemotherapy consisting of cyclophosphamide alone. RESULTS: Ocular complications were observed in 29.5% of the patients. Hypothyroidism, interstitial pneumonia, obliterative bronchiolitis, and veno-occlusive disease developed in 8.2%, 1.8%, 0.9%, and 2.7% of patients. Growth abnormality was observed in 10 (20%) of the 50 pediatric patients. The use of a lower dose (< 12 Gy vs 12 Gy) of fractionated total body irradiation did not decrease the incidence of adverse events; however, nonmyeloablative conditioning with low-dose singlefraction total body irradiation reduced the incidence of adverse events. Three patients who underwent total body irradiation as reirradiation therapy achieved long-term survival without adverse events. CONCLUSIONS: Fractionated total body irradiation given at a lower dose (<12 Gy vs 12 Gy) did not decrease the incidence of adverse events. PMID- 27934562 TI - First Domino Liver Transplant in Saudi Arabia. PMID- 27934564 TI - Conscientious Objection in Healthcare and Moral Integrity. AB - There are several reasons for accommodating health professionals' conscientious objections. However, several authors have argued that among the most important and compelling reasons is to enable health professionals to maintain their moral integrity. Accommodation is said to provide "moral space" in which health professionals can practice without compromising their moral integrity. There are, however, alternative conceptions of moral integrity and corresponding different criteria for moral-integrity-based claims. It is argued that one conception of moral integrity, the identity conception, is sound and suitable in the specific context of responding to health professionals' conscientious objections and their requests for accommodation. According to the identity conception, one maintains one's moral integrity if and only if one's actions are consistent with one's core moral convictions. The identity conception has been subject to a number of criticisms that might call into question its suitability as a standard for determining whether health professionals have genuine moral-integrity-based accommodation claims. The following five objections to the identity conception are critically examined: (1) it does not include a social component, (2) it is a conception of subjective rather than objective integrity, (3) it does not include a reasonableness condition, (4) it does not include any substantive moral constraints, and (5) it does not include any intellectual integrity requirement. In response to these objections, it is argued that none establishes the unsuitability of the identity conception in the specific context of responding to health professionals' conscientious objections and their requests for accommodation. PMID- 27934563 TI - Cerebrospinal-fluid Alzheimer's Disease Biomarkers and Blood-Brain Barrier Integrity in a Natural Population of Cognitive Intact Parkinson's Disease Patients. AB - BACKGROUND: Cerebrospinal-fluid (CSF) Alzheimer's Disease (AD) biomarkers have been extensively studied in Parkinson's Disease (PD). Although reduced CSF beta amyloid1-42 (Abeta42) levels have been associated with cognitive decline in PD, the alteration of CSF tau proteins remains controversial. In addition, the impairment of the blood-brain barrier (BBB) has been previously demonstrated along the PD progression. OBJECTIVE: The aim of the present study was to assess CSF AD biomarkers and BBB integrity in a natural cohort of cognitive intact PD patients compared to matched controls. METHOD: We measured and correlated CSF AD biomarkers and CSF/serum albumin ratio (expression of BBB integrity) in 124 PD patients and 46 controls. We distributed PD patients in three subgroups based on the Hoehn and Yahr (H&Y) staging: mild PD (1-1.5, n=40); moderate PD (2-2.5, n=58); advanced PD (3-5, n=26). PD patients were also distinguished as tremor dominant (TD, n=44) and non-tremor dominant (NTD, n=80). RESULTS: PD patients showed lower CSF Abeta42 levels and higher CSF/serum albumin ratio compared to controls. CSF total tau (t-tau) concentrations as well as the CSF/serum albumin ratio gradually increased among H&Y stages. Conversely, we did not find differences between TD and NTD patients. Significantly, we documented the positive correlation between CSF t-tau levels and both CSF/serum albumin ratio and motor impairment in PD patients. CONCLUSION: This study performed in cognitive intact PD patients confirms the progressive increase of CSF tau proteins levels and BBB impairment along with the evolution of PD pathology. Since the BBB ensures the clearance of tau proteins from brain, we hypothesize that the dysfunction of the BBB throughout the disease progression may possibly cause the concurrent increase of CSF tau proteins levels in PD, which could be irrespective of cognitive decline. PMID- 27934565 TI - Conscientious Objection and "Effective Referral". AB - Complicity in an immoral, and even criminal, activity, such as robbery or murder, is itself regarded as involving responsibility for those acts. What should the position be of health professionals who are expected to participate in actions that they believe are morally wrong? Professional responsibilities may clash with private conscience. Even referring a patient to someone else, when what is in question may be assisted suicide, or euthanasia, seems to involve some complicity. This is a live issue in Canada, but similar dilemmas occur elsewhere. Physicians and others should not be coerced into involvement of any kind in what they regard as wrong. Such coercion goes against the very principles of liberal democracy. Conscience matters. Reasonable accommodation should be given to those whose moral judgment may be at variance with prevailing professional norms. Moral questions should still be given weight within medicine, and disagreements respected. Dedication to the promotion of human welfare should be paramount, but it should be recognized that there may be different visions of what such welfare consists of. PMID- 27934566 TI - The Legal Ethical Backbone of Conscientious Refusal. AB - This article analyzes the idea of a legal right to conscientious refusal for healthcare professionals from a basic legal ethical standpoint, using refusal to perform tasks related to legal abortion (in cases of voluntary employment) as a case in point. The idea of a legal right to conscientious refusal is distinguished from ideas regarding moral rights or reasons related to conscientious refusal, and none of the latter are found to support the notion of a legal right. Reasons for allowing some sort of room for conscientious refusal for healthcare professionals based on the importance of cultural identity and the fostering of a critical atmosphere might provide some support, if no countervailing factors apply. One such factor is that a legal right to healthcare professionals' conscientious refusal must comply with basic legal ethical tenets regarding the rule of law and equal treatment, and this requirement is found to create serious problems for those wishing to defend the idea under consideration. We conclude that the notion of a legal right to conscientious refusal for any profession is either fundamentally incompatible with elementary legal ethical requirements, or implausible because it undermines the functioning of a related professional sector (healthcare) or even of society as a whole. PMID- 27934567 TI - Tolerance, Professional Judgment, and the Discretionary Space of the Physician. AB - Arguments against physicians' claims of a right to refuse to provide tests or treatments to patients based on conscientious objection often depend on two premises that are rarely made explicit. The first is that the protection of religious liberty (broadly construed) should be limited to freedom of worship, assembly, and belief. The second is that because professions are licensed by the state, any citizen who practices a licensed profession is required to provide all the goods and services determined by the profession to fall within the scope of practice of that professional specialty and permitted by the state, regardless of any personal religious, philosophical, or moral objection. In this article, I argue that these premises ought to be rejected, and therefore the arguments that depend on them ought also to be rejected. The first premise is incompatible with Locke's conception of tolerance, which recognizes that fundamental, self identifying beliefs affect public as well as private acts and deserve a broad measure of tolerance. The second premise unduly (and unrealistically) narrows the discretionary space of professional practice to an extent that undermines the contributions professions ought to be permitted to make to the common good. Tolerance for conscientious objection in the public sphere of professional practice should not be unlimited, however, and the article proposes several commonsense, Lockean limits to tolerance for physician claims of conscientious objection. PMID- 27934568 TI - The Inevitability of Assessing Reasons in Debates about Conscientious Objection in Medicine. AB - This article first critically reviews the major philosophical positions in the literature on conscientious objection and finds that they possess significant flaws. A substantial number of these problems stem from the fact that these views fail to assess the reasons offered by medical professionals in support of their objections. This observation is used to motivate the reasonability view, one part of which states: A practitioner who lodges a conscientious refusal must publicly state his or her objection as well as the reasoned basis for the objection and have these subjected to critical evaluation before a conscientious exemption can be granted (the reason-giving requirement). It is then argued that when defenders of the other philosophical views attempt to avoid granting an accommodation to spurious objections based on discrimination, empirically mistaken beliefs, or other unjustified biases, they are implicitly committed to the reason-giving requirement. This article concludes that based on these considerations, a reason giving position such as the reasonability view possesses a decisive advantage in this debate. PMID- 27934569 TI - Two Concepts of Conscience and their Implications for Conscience-Based Refusal in Healthcare. AB - Healthcare professionals are not currently obliged to justify conscientious objections. As a consequence, there are currently no practical limits on the scope of conscience-based refusals in healthcare. Recently, a number of bioethicists, including Christopher Meyers, Robert D. Woods, Robert Card, Lori Kantymir, and Carolyn McLeod, have raised concerns about this situation and have offered proposals to place principled limits on the scope of conscience-based refusals in healthcare. Here, I seek to adjudicate among their proposals. I argue that to adjudicate among them properly it is important to consider the theoretical bases for conscientious objection. I further argue that there are two such bases to be considered. Some conscientious objections are justified by appeal to all-things-considered moral judgments, and some are justified by appeal to the "dictates of conscience." I argue that both of these bases are legitimate and that both should be accommodated in any principled scheme to limit the scope of conscientious refusals in healthcare. PMID- 27934570 TI - How to Allow Conscientious Objection in Medicine While Protecting Patient Rights. AB - Paradigmatic cases of conscientious objection in medicine are those in which a physician refuses to provide a medical service or good because doing so would conflict with that physician's personal moral or religious beliefs. Should such refusals be allowed in medicine? We argue that (1) many conscientious objections to providing certain services must be allowed because they fall within the range of freedom that physicians have to determine which services to offer in their practices; (2) at least some conscientious objections to serving particular groups of patients should be allowed because they are not invidiously discriminatory; and (3) even in cases of invidiously discriminatory conscientious objections, legally prohibiting individual physicians from refusing to serve patients on the basis of such objections is not always the best solution. PMID- 27934571 TI - The Cost of Conscience. AB - The spread of demands by physicians and allied health professionals for accommodation of their private ethical, usually religiously based, objections to providing care of a particular type, or to a particular class of persons, suggests the need for a re-evaluation of conscientious objection in healthcare and how it should be regulated. I argue on Kantian grounds that respect for conscience and protection of freedom of conscience is consistent with fairly stringent limitations and regulations governing refusal of service in healthcare settings. Respect for conscience does not entail that refusal of service should be cost free to the objector. I suggest that conscientious objection in medicine should be conceptualized and treated analogously to civil disobedience. PMID- 27934572 TI - Conscientious Objection, Complicity in Wrongdoing, and a Not-So-Moderate Approach. AB - This article analyzes the problem of complicity in wrongdoing in the case of healthcare practitioners (and in particular Roman Catholic ones) who refuse to perform abortions, but who are nonetheless required to facilitate abortions by informing their patients about this option and by referring them to a willing colleague. Although this solution is widely supported in the literature and is also widely represented in much legislation, the argument here is that it fails to both (1) safeguard the well-being of the patients, and (2) protect the moral integrity of healthcare practitioners. Finally, the article proposes a new solution to this problem that is based on a desirable ratio of conscientious objectors to non-conscientious objectors in a hospital or in a given geographic area. PMID- 27934574 TI - How To Welcome New Technologies. PMID- 27934573 TI - Conscientious Non-objection in Intensive Care. AB - Discussions of conscientious objection (CO) in healthcare often concentrate on objections to interventions that relate to reproduction, such as termination of pregnancy or contraception. Nevertheless, questions of conscience can arise in other areas of medicine. For example, the intensive care unit is a locus of ethically complex and contested decisions. Ethical debate about CO usually concentrates on the issue of whether physicians should be permitted to object to particular courses of treatment; whether CO should be accommodated. In this article, I focus on the question of how clinicians ought to act: should they provide or support a course of action that is contrary to their deeply held moral beliefs? I discuss two secular examples of potential CO in intensive care, and propose that clinicians should adopt a norm of conscientious non-objection (CNO). In the face of divergent values and practice, physicians should set aside their personal moral beliefs and not object to treatment that is legally and professionally accepted and provided by their peers. Although there may be reason to permit conscientious objections in healthcare, conscientious non-objection should be encouraged, taught, and supported. PMID- 27934575 TI - Refusing to Treat Sexual Dysfunction in Sex Offenders. AB - This article examines one kind of conscientious refusal: the refusal of healthcare professionals to treat sexual dysfunction in individuals with a history of sexual offending. According to what I call the orthodoxy, such refusal is invariably impermissible, whereas at least one other kind of conscientious refusal-refusal to offer abortion services-is not. I seek to put pressure on the orthodoxy by (1) motivating the view that either both kinds of conscientious refusal are permissible or neither is, and (2) critiquing two attempts to buttress it. PMID- 27934576 TI - When the Milk of Human Kindness Becomes a Luxury (and Untested) Good. PMID- 27934577 TI - The Effects of Closed-Loop Medical Devices on the Autonomy and Accountability of Persons and Systems-CORRIGENDUM. PMID- 27934578 TI - Principles of Ethical Leadership Illustrated by Institutional Management of Prion Contamination of Neurosurgical Instruments. PMID- 27934579 TI - Guest Editorial: Conscientious Objection in Healthcare: Problems and Perspectives. PMID- 27934580 TI - 20 years of communicating facts and figures. PMID- 27934581 TI - Severe acute respiratory infection caused by swine influenza virus in a child necessitating extracorporeal membrane oxygenation (ECMO), the Netherlands, October 2016. AB - In October 2016, a severe infection with swine influenza A(H1N1) virus of the Eurasian avian lineage occurred in a child with a previous history of eczema in the Netherlands, following contact to pigs. The patient's condition deteriorated rapidly and required life support through extracorporeal membrane oxygenation. After start of oseltamivir treatment and removal of mucus plugs, the patient fully recovered. Monitoring of more than 80 close unprotected contacts revealed no secondary cases. PMID- 27934582 TI - More than 20 years after re-emerging in the 1990s, diphtheria remains a public health problem in Latvia. AB - In 1994, the World Health Organization (WHO) declared the goal of eliminating diphtheria within the WHO European Region by the year 2000. However, in 1990 an epidemic emerged within the Russian Federation and spread to other countries, including Latvia, by 1994. We describe national surveillance and immunisation coverage data in Latvia from 1994 to 2014 and present historical data from 1946. We defined a laboratory-confirmed case as a clinical case in which toxin producing Corynebacterium diphtheriae, C. ulcerans or C. pseudotuberculosis was isolated. From 1994 to 2014, 1,515 cases were reported, giving an average annual incidence of 3.2 cases per 100,000 inhabitants (range 0.1-14.8), with the highest incidence in age groups 5-19 and 40-49 years (4.4 and 4.3/100,000, respectively); 111 deaths were reported, 83.8% cases were laboratory-confirmed. Most cases occurred in unvaccinated adults. To improve disease control a supplementary immunisation campaign for adults was initiated in 1995, and by the end of 1998 national coverage among adults reached 70%, and reached 77% in 2003, but declined to 59% by 2014. Diphtheria remains a problem in Latvia with continued circulation of toxin-producing strains of C. diphtheriae. We recommend to strengthen immunisation to cover adults, as well as the education of health professionals and a serological survey. PMID- 27934584 TI - Monitoring of HIV testing services in the EU/EEA. PMID- 27934583 TI - Bacillus cereus-induced food-borne outbreaks in France, 2007 to 2014: epidemiology and genetic characterisation. AB - The aim of this study was to identify and characterise Bacillus cereus from a unique national collection of 564 strains associated with 140 strong-evidence food-borne outbreaks (FBOs) occurring in France during 2007 to 2014. Starchy food and vegetables were the most frequent food vehicles identified; 747 of 911 human cases occurred in institutional catering contexts. Incubation period was significantly shorter for emetic strains compared with diarrhoeal strains A sub panel of 149 strains strictly associated to 74 FBOs and selected on Coliphage M13 PCR pattern, was studied for detection of the genes encoding cereulide, diarrhoeic toxins (Nhe, Hbl, CytK1 and CytK2) and haemolysin (HlyII), as well as panC phylogenetic classification. This clustered the strains into 12 genetic signatures (GSs) highlighting the virulence potential of each strain. GS1 (nhe genes only) and GS2 (nhe, hbl and cytK2), were the most prevalent GS and may have a large impact on human health as they were present in 28% and 31% of FBOs, respectively. Our study provides a convenient molecular scheme for characterisation of B. cereus strains responsible for FBOs in order to improve the monitoring and investigation of B. cereus-induced FBOs, assess emerging clusters and diversity of strains. PMID- 27934586 TI - Generation of an isogenic, gene-corrected iPSC line from a symptomatic 59-year old female patient with frontotemporal dementia caused by an R406W mutation in the microtubule associated protein tau (MAPT) gene. AB - Frontotemporal dementia with parkinsonism linked to chromosome 17q21.2 (FTDP-17) is an autosomal-dominant neurodegenerative disorder. Mutations in the MAPT (microtubule-associated protein tau) gene can cause FTDP-17, but the underlying pathomechanisms of the disease are still unknown. Induced pluripotent stem cells (iPSCs) hold great promise to model FTDP-17 as such cells can be differentiated in vitro to the required cell type. Furthermore, gene-editing approaches allow generating isogenic gene-corrected controls that can be used as a very specific control. Here, we report the generation of genetically corrected iPSCs from a 59 year-old female FTD-17 patient carrying an R406W mutation in the MAPT-gene. PMID- 27934587 TI - Generation of an iPSC line from a patient with tyrosine hydroxylase (TH) deficiency: TH-1 iPSC. AB - Fibroblasts from a male patient with compound heterozygous variants in the tyrosine hydroxylase gene (TH; OMIM: 191290; c.[385-C>T]; [692-G>C]/p.[R129*]; [R231P]), the rate-limiting enzyme for dopamine synthesis, were reprogrammed to iPSCs using episomal reprogramming delivering the reprogramming factors Oct3/4, Sox2, L-Myc, Lin28, Klf4 and p53 shRNA Okita et al. (2011). Pluripotency of TH-1 iPSC was verified by immunohistochemistry and RT-PCR analysis. Cells exhibited a normal karyotype and differentiated spontaneously into the 3 germ layers in vitro. TH-1 iPSC represents the first model system to study the pathomechanism of this rare metabolic disease and provides a useful tool for drug testing. PMID- 27934585 TI - Estimating HIV incidence and number of undiagnosed individuals living with HIV in the European Union/European Economic Area, 2015. AB - Since 2011, human immunodeficiency virus (HIV) incidence appears unchanged in the European Union/European Economic Area with between 29,000 and 33,000 new cases reported annually up to 2015. Despite evidence that HIV diagnosis is occurring earlier post-infection, the estimated number of people living with HIV (PLHIV) who were unaware of being infected in 2015 was 122,000, or 15% of all PLHIV (n=810,000). This is concerning as such individuals cannot benefit from highly effective treatment and may unknowingly sustain transmission. PMID- 27934588 TI - Generation of human embryonic stem cell line chHES-472 from abnormal embryos diagnosed with Spinocerebellar ataxia type 3. AB - Spinocerebellar ataxia type3 (SCA3) is an autosomal dominant neurodegenerative disorder. Human embryonic stem cell line chHES-472 was derived from abnormal embryo donated by SCA3 patient after preimplantation genetic diagnosis (PGD) treatment. This cell line had a normal karyotype and retained the disease-causing mutant in ATXN3 gene. Characteristic tests proved that the embryonic stem cell line presented typical markers of pluripotency and had the capability to form the three germlayers in vivo. PMID- 27934589 TI - Characterization of iPSCs derived from dermal fibroblasts from a healthy 19year old female. AB - Primary fibroblasts from a healthy 19years old female were reprogrammed by transduction of retroviruses OCT4, SOX2, c-MYC and KLF4. iPSCs were characterized by immunocytochemistry, embryonic body-formation, DNA-fingerprint and karyotype analysis and comparative transcriptome analyses with the human embryonic stem cell line H1 revealed a Pearsons correlation coefficient of 0.8952. PMID- 27934590 TI - Generation of an isogenic, gene-corrected iPSC line from a pre-symptomatic 28 year-old woman with an R406W mutation in the microtubule associated protein tau (MAPT) gene. AB - Frontotemporal dementia with parkinsonism linked to chromosome 17q21.2 (FTDP-17) is an autosomal-dominant neurodegenerative disorder. Mutations in the MAPT (microtubule-associated protein tau) gene can cause FTDP-17, but the underlying pathomechanisms of the disease are still unknown. Induced pluripotent stem cells (iPSCs) hold great promise to model FTDP-17 as such cells can be differentiated in vitro to the required cell type. Furthermore, gene-editing approaches allow generating isogenic gene-corrected controls that can be used as a very specific control. Here, we report the generation of genetically corrected iPSCs from a pre symptomatic carrier of the R406W mutation in the MAPT-gene. PMID- 27934591 TI - Generation of a human induced pluripotent stem cell (iPSC) line from a Bernard Soulier syndrome patient with the mutation p.Asn45Ser in the GPIX gene. AB - Bernard Soulier Syndrome (BSS) is an inherited rare platelet disorder characterized by mutations in the platelet glycoprotein complex GPIb-IX-V. We generated an induced pluripotent stem cell (iPSC) line from a BSS patient with a mutation p.Asn45Ser in the GPIX locus (BSS2-PBMC-iPS4F24). Peripheral blood mononuclear cells were reprogrammed using non-integrative viral transduction. Characterization of BSS2-PBMC-iPS4F24 included mutational analysis of GPIX locus, analysis of conventional pluripotency-associated factors at mRNA and protein level and in vitro and in vivo differentiation studies. This iPSC line will provide a powerful tool to study the biology of BSS disease. PMID- 27934592 TI - Generation of MERRF patient-derived induced pluripotent stem cell line iMERRF-C7. AB - Human iPSC line iMERRF-C7 was generated from PBMCs of a patient with mitochondrial disorder MERRF. Using Sendai virus, the reprogramming factors Oct3/4, Sox2, Klf4, and cMyc were delivered non-integratively. The resulting iPSCs expressed pluripotency markers, could differentiate into the three germ layers in vivo, had normal genomic structure, and retained the disease-causing m.8344 mutation with similar heteroplasmic level. PMID- 27934593 TI - Establishment of induced pluripotent stem cell (iPSC) line from an 8-year old female patient with ischemic Moyamoya disease. AB - Peripheral blood mononuclear cells (PBMCs) were collected from an 8-year old female patient affected by ischemic Moyamoya disease (MMD). Patient's PBMCs were reprogrammed using Sendai virus particles delivering the four Yamanaka factors. The footprint free hiPSC line expressed the major pluripotency markers and exhibited a normal karyotype. Cells were competent to give rise to progeny of differentiated cells belonging to the 3 germ layers. This hiPSC line represents a good tool to in vitro model MMD in order to shed light on the cellular and molecular mechanisms responsible for the occurrence of this syndrome. PMID- 27934594 TI - Establishment of induced pluripotent stem cell (iPSC) line from 55-year old male patient with hemorrhagic Moyamoya disease. AB - Peripheral blood mononuclear cells (PBMCs) were collected from 55-year old male patient with a confirmed diagnosis of hemorrhagic Moyamoya disease (MMD). PBMCs were reprogrammed using Sendai virus particles delivering the four Yamanaka factors. A footprint-free hiPSC line was characterized by the expression of pluripotency markers and a normal karyotype. These cells were able to give rise to Embryoid Bodies and to a progeny of differentiated cells belonging to the 3 germ layers. This hiPSC line represents a suitable tool for modelling in vitro MMD disease to investigate the cellular mechanisms underlying the occurrence of this pathology. PMID- 27934595 TI - Generation of human embryonic stem cell line chHES-458 from abnormal embryos with HTT gene mutation. AB - The human embryonic stem cell (hESC) line chHES-458 was derived from a abnormal blastocyst carrying the expanded CAG repeat mutation of the HTT gene that would lead to Huntington disease. This cell line maintained a normal karyotype 46, XX during long-term culture and displayed pluripotent characteristics, including expression of pluripotency-related transcription factors and capacity of forming well-differentiated three germ layers after being injected into the SCID mice. PMID- 27934596 TI - Establishment of an induced pluripotent stem cell (iPSC) line from a patient with Clozapine-responder Schizophrenia. AB - Peripheral blood mononuclear cells (PBMCs) were collected from a patient with treatment-refractory Schizophrenia who presented an exceptional clinical response to Clozapine. iPSC lines were established with a non-integrating reprogramming system based on Sendai virus. A footprint-free hiPSC line was characterized to confirm the expression of the main endogenous pluripotency markers and have a regular karyotype. Pluripotency was confirmed by differentiation into cells belonging to the three germ layers. This hiPSC line represents a valuable tool to study the molecular, biochemical and electrophysiological properties of mature neuronal populations belonging to Clozapine responder patients with a severe form of Schizophrenia. PMID- 27934597 TI - Generation of human embryonic stem cells from abnormal blastocyst diagnosed with adrenoleukodystrophy. AB - Human embryonic stem cell (hESC) line chHES-480 was derived from abnormal blastocyst diagnosed with adrenoleukodystrophy (ALD) after preimplantation genetic diagnosis (PGD) treatment. DNA sequencing analysis confirmed that chHES 480 cell line carried a hemizygous missense mutation c.1825G>A(p.Glu609Lys) of ABCD1 gene. Characteristic tests proved that the chHES-480 cell line presented typical markers of pluripotency and had the capability to form the three germ layers both in vitro and in vivo. PMID- 27934598 TI - Human embryonic stem cells derived from abnormal blastocyst donated by polycystic kidney syndrome patient. AB - Human embryonic stem cell (hESC) line chHES-468 was derived from abnormal blastocyst donated by polycystic kidney syndrome (PKD) patient after preimplantation genetic diagnosis (PGD) treatment. DNA sequencing analysis confirmed that chHES-468 cell line carried a heterozygous mutation, c.10526_10527delAG, of PKD1. Characteristic tests proved that the chHES-468 cell line presented typical markers of pluripotency and had the capability to form the three germ layers both in vitro and in vivo. PMID- 27934599 TI - Generation of an Abcc8 homozygous mutation human embryonic stem cell line using CRISPR/Cas9. AB - The gene of ATP-binding cassette subfamily C member 8 (Abcc8) is cytogenetically located at 11p15.1 and encodes the sulfonylurea receptor (SUR1). SUR1 is a subunit of ATP-sensitive potassium channel (KAPT) in the beta-cell regulating insulin secretion. Mutations of ABCC8 are responsible for congenital hyperinsulinism (CHI). Here we generated an Abcc8 homozygous mutant cell line by CRISPR/Cas9 technique with 22bp deletion resulting in abnormal splicing on human embryonic stem cell line H1. The phenotypic characteristics of this cell line reveal defective KATP channel and diazoxide-unresponsive that provides an ideal model for molecular pathology research and drug screening for CHI. PMID- 27934600 TI - Generation of human embryonic stem cells from abnormal blastocyst diagnosed with albinism. AB - Human embryonic stem cell (hESC) line chHES-478 was derived from abnormal blastocyst diagnosed with albinism after preimplantation genetic diagnosis (PGD) treatment. DNA sequencing analysis confirmed that chHES-478 cell line carried a compound heterozygous mutation, c.896G>A(p.Arg299His) and c.929_930insC(p.Pro310Glnfs*9), of TYR gene. Characteristic tests proved that the chHES-478 cell line presented typical markers of pluripotency and had the capability to form the three germ layers both in vitro and in vivo. PMID- 27934601 TI - Establishment of human embryonic stem cell line with a complex abnormal karyotype and the stable XIST expression. AB - The embryonic stem cell line chHES-3XISTa was derived from heterogeneous chHES-3 cells. chHES-3XISTa showed a new abnormal karyotype of 46,XX with 8 derivation chromosomes and expressed X inactive specific transcript (XIST) in continual culture. Tri-methylation of H3 Lys-27 (H3K27me3) punctate enrichment located in RNA Polymerase II hole was also found in all chHES-3XISTa cells. Pluripotent markers and differentiate capability in vitro were confirmed by immunochemistry staining. PMID- 27934602 TI - Generation of human iPSCs from urine derived cells of a patient with a novel homozygous PAI-1 mutation. AB - We have generated a human induced pluripotent stem cell (iPSC) line under feeder free culture conditions using the urine derived cells (UCs) collected from subject with a novel homozygous Plasminogen Activator Inhibitor-1 (PAI-1 null) mutation. The Sendai virus (SeV) vector encoding pluripotent Yamanaka transcription factors was used at a low multiplicity of infection to reprogram the PAI-1 UCs. PMID- 27934603 TI - Generation and characterization of an induced pluripotent stem cell (iPSC) line from a patient with clozapine-resistant Schizophrenia. AB - Peripheral Blood Mononuclear Cells (PBMCs) were collected from a patient with clozapine-resistant (also known as "super-refractory") Schizophrenia. iPSCs were established with a non-integrating Sendai virus-based reprogramming system. A footprint-free hiPSC line was characterized to express the main endogenous pluripotency markers and to retain a normal karyotype. Cells showed pluripotency competency by giving rise to progeny of differentiated cells belonging to the three germ layers. This hiPSC line represents a valuable tool to obtain mature, pathology-relevant neuronal populations in vitro that are suitable to investigate the molecular background of the schizophrenic disorder and the resultant patients' response to treatments. PMID- 27934604 TI - Generation of induced pluripotent stem cells (iPSCs) stably expressing CRISPR based synergistic activation mediator (SAM). AB - Human fibroblasts were engineered to express the CRISPR-based synergistic activation mediator (SAM) complex: dCas9-VP64 and MS2-P65-HSF1. Two induced pluripotent stem cells (iPSCs) clones expressing SAM were established by transducing these fibroblasts with lentivirus expressing OCT4, SOX2, KLF4 and C MYC. We have validated that the reprogramming cassette is silenced in the SAM iPSC clones. Expression of pluripotency genes (OCT4, SOX2, LIN28A, NANOG, GDF3, SSEA4, and TRA-1-60), differentiation potential to all three germ layers, and normal karyotypes are validated. These SAM-iPSCs provide a novel, useful tool to investigate genetic regulation of stem cell proliferation and differentiation through CRISPR-mediated activation of endogenous genes. PMID- 27934605 TI - Generation of an Abcc8 heterozygous mutation human embryonic stem cell line using CRISPR/Cas9. AB - The gene of ATP-binding cassette subfamily C member 8 (Abcc8) is cytogenetically located at 11p15.1 and encodes the sulfonylurea receptor (SUR1). SUR1 is a subunit of ATP-sensitive potassium channel (KAPT) in the beta-cell regulating insulin secretion. Mutations of ABCC8 are responsible for congenital hyperinsulinism (CHI). Here we reported that an Abcc8 heterozygous mutant cell line was generated by CRISPR/Cas9 technique with 1bp insertion resulting in abnormal splicing on human embryonic stem cell line H1. The phenotypic characteristics of this cell line reveal defective KATP channel and diazoxide responsive that provides ideal model for molecular pathology research and drug screening for CHI. PMID- 27934606 TI - Radial access for acute coronary syndromes: case closed? PMID- 27934607 TI - Conquering CTO revascularisation: the summit is near with 90% of the ascent behind us. PMID- 27934608 TI - FFR in daily clinical practice: from "Pret-a-Porter" to "Haute Couture". PMID- 27934610 TI - In vivo validation of mathematically derived fractional flow reserve for assessing haemodynamics of coronary tandem lesions. AB - AIMS: Our aim was to propose a prediction model for the post-stenting fractional flow reserve (FFR'd,pred) at a position distal to the tandem lesion. METHODS AND RESULTS: Using the FFR at a position proximal to the tandem lesion (FFRp), and the FFR gradients across proximal (DeltaFFRp) and distal (DeltaFFRd) stenoses, FFR'd,pred after treating either the distal or proximal lesion was predicted as FFRp-DeltaFFRp/(1-1.33kDeltaFFRd) or FFRp-DeltaFFRd/(1-1.33DeltaFFRp), respectively. The flow fraction of the distal main branch (k) was estimated using the diameter ratio of side to distal main branches. For in vivo validation, 50 patients with a tandem lesion (diameter stenosis >50%) were evaluated. Compared to the conventional model that did not consider side branch flow, our predicted FFR showed closer correlation with the measured FFR (R2=0.83 vs. 0.57) and significant reduction in mean absolute errors (0.034+/-0.028 vs. 0.053+/-0.049, p<0.001). In particular, with a large side branch and low baseline FFR, decision making using the current model had greater predictive ability than with the conventional model. CONCLUSIONS: By predicting which stenosis is more severe and/or whether the remaining lesion after the first treatment is functionally significant, a tandem prediction model can help to plan optimised stent implantation. PMID- 27934609 TI - Approaches to percutaneous coronary intervention of right coronary artery chronic total occlusions: insights from a multicentre US registry. AB - AIMS: The goal of this study was to describe the procedural characteristics, strategy selection and associated technical and efficiency outcomes for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) of the right coronary artery (RCA). METHODS AND RESULTS: We examined the clinical and angiographic characteristics of patients who underwent RCA CTO PCI between 2012 and 2015 at 11 centres in the USA. The RCA was the CTO target vessel in 739 of 1,308 CTO PCIs (56%). Overall technical and procedural success rates were 90% and 88%, respectively. A major adverse cardiovascular event (MACE) occurred in 19 patients (2.6%). Technical success was most frequently achieved using antegrade wire escalation (38% of successful procedures) followed by retrograde (36%) and antegrade dissection/re-entry (26%). Technical success was similar between various locations of RCA CTOs (p=0.11). Compared with antegrade-only procedures, utilisation of any retrograde approach was associated with lower technical (85% vs. 95%, p<0.001) and procedural (82% vs. 94%, p<0.001) success and a higher MACE rate (3.8% vs. 1.4%, p=0.037). CONCLUSIONS: RCA CTOs represent the majority of CTO target lesions, can be treated with high success and acceptable complication rates, and require frequent use of the retrograde approach and antegrade dissection/re-entry. PMID- 27934611 TI - A multicentre European registry to evaluate the Direct Flow Medical transcatheter aortic valve system for the treatment of patients with severe aortic stenosis. AB - AIMS: Our aim was to assess the clinical outcomes of the Direct Flow Medical Transcatheter Aortic Valve System (DFM-TAVS), when used in routine clinical practice. METHODS AND RESULTS: This is a prospective, open-label, multicentre, post-market registry of patients treated with DFM-TAVS according to approved commercial indications. Echocardiographic and angiographic data were evaluated by an independent core laboratory and adverse events were adjudicated and classified according to VARC-2 criteria by an independent clinical events committee. The primary endpoint was freedom from all-cause mortality at 30 days post procedure. Secondary endpoints included procedural, early safety and efficacy endpoints at 30 days. Two hundred and fifty patients with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI) with the DFM-TAVS were enrolled in 21 European centres. The primary endpoint, freedom from all-cause mortality at 30 days, was met in 98% (245/250) of patients. Device success was 83.8%. Moderate or severe aortic regurgitation was reported in 3% of patients, and none/trace regurgitation in 73% of patients. Post-procedural permanent pacemaker implantation was performed in 30 patients (12.0%). CONCLUSIONS: The DFM-TAVS was associated with good short-term outcomes in this real-world registry. The low pacemaker and aortic regurgitation rates confirm the advantages of this next generation transcatheter heart valve (THV). PMID- 27934612 TI - Spontaneous enlargement of pulmonary artery after successful balloon pulmonary angioplasty in a patient with chronic thromboembolic pulmonary hypertension. PMID- 27934613 TI - Complete blood flow obstruction due to a distally embolised Edwards SAPIEN valve prosthesis. PMID- 27934614 TI - High-risk left main percutaneous coronary intervention supported by pressure controlled intermittent coronary sinus occlusion. PMID- 27934615 TI - Usefulness of three-dimensional optical frequency domain imaging for diagnosing in-stent restenosis due to a stent fracture. PMID- 27934617 TI - WITHDRAWN: Multimedia teaching material. PMID- 27934616 TI - Pregnancy and cirrhosis: four cases at the Lome campus university teaching hospital (Togo). AB - To evaluate the hepatic and obstetric complications in pregnant women with cirrhosis. We report the cases of four pregnant women with cirrhosis treated in the gastroenterology and obstetrics-gynecology departments of the Lome Campus University Teaching Hospital between 2013 and 2015. The women's mean age was 32 years. Three were in the first trimester of pregnancy. Almost all had signs of advanced cirrhosis, including ascites (50%), lower-limb edema (75%), and jaundice (25%). All (100%) had liver failure and anemia. Cirrhosis was due to hepatitis virus B infection for 3 women. All had singleton pregnancies. Two mothers died; fetal outcome included one fetal loss and one stillbirth. This study shows the high risk associated with the combination of pregnancy and cirrhosis. Prognosis is poor for both mother and fetus. PMID- 27934618 TI - Cross-reactivity of cephalosporins: allergic immediate hypersensitivity to ceftriaxone in a cefcapene pivoxil-sensitized patient. PMID- 27934620 TI - Diagnostic performance parameters for melanocytic lesions before and during the dermoscopy era. PMID- 27934619 TI - A case of fulminant type 1 diabetes mellitus, with a precipitous decrease in pancreatic volume, induced by nivolumab for malignant melanoma: analysis of HLA and CTLA-4 polymorphisms. PMID- 27934621 TI - Drug-resistant epilepsy after treatment for childhood acute lymphocytic leukaemia: from focal epilepsy to Lennox-Gastaut syndrome. AB - Drug-resistant epilepsy, not associated with acute brain complications or central nervous system leukaemic involvement, can develop in patients treated for acute lymphocytic leukaemia during childhood. It has been postulated that this rare complication may be due to CNS oncological treatment neurotoxicity, related to intrathecal drugs, such as methotrexate, and brain radiotherapy. We report four patients who developed drug-resistant epilepsy sometime after receiving treatment for acute lymphocytic leukaemia. All patients were female and received intrathecal methotrexate. One received additional intrathecal cytarabine, and two concomitant brain radiotherapy. Two developed Lennox-Gastaut type syndrome, one multifocal epilepsy, and one focal epilepsy related to a radiotherapy-induced cavernous angioma. The development of drug-resistant epilepsy after treatment for acute lymphocytic leukaemia is a rare complication that may vary, from focal epilepsy to an epileptic encephalopathy. This may appear even years after the treatment has finished and is most likely associated with treatment-related neurotoxicity. PMID- 27934622 TI - [AntibioticScout: Online tool for antimicrobial stewardship in veterinary medicine]. AB - INTRODUCTION: Resistances to antimicrobials pose serious public health challenges. This issue concerns both human and veterinary medicine and can only be solved by a multidisciplinary approach. A comprehensive concept is, therefore, being worked out within the StAR (strategy antibiotic resistance) program in order to preserve the effectiveness of antibiotics for humans as well as animals. In this context, the AntibioticScout (www.AntibioticScout. ch) offers a new online tool for the prudent use of antibiotics in veterinary medicine. By involving all stakeholders, the guidelines included in the AntibioticScout will result in a nationwide accepted standard for the treatment of bacterial infections in animals. An additional system for the rapid reporting of cases of suspected lack of efficacy of antimicrobials is integrated to allow early detection of emerging resistance and the immediate launch of risk mitigation measures. A first version of the AntibioticScout for the treatment of dogs, cats and horses is available by the end of 2016. All stakeholders are now invited to contribute to the development of the AntibioticScout decision support. PMID- 27934624 TI - Safety profile of 1,25-dihydroxyvitamin D3 of herbal origin in broiler chicken. AB - INTRODUCTION: The safety of supplementing broiler feed with a standardised herbal extract, Solanum Glaucophyllum Standardised Leaves (SGSL) containing glycosylated 1a,25-dihydroxyvitamin D3 (1,25(OH)2D3) and standardised to contain 10 ug/g 1,25(OH)2D3 equivalent, was examined in two studies. In a first study, we examined the potential of SGSL to substitute vitamin D3 (VD3) and the tolerated dose range of SGSL when applied without concomitant VD3 by analyzing performance and blood chemical parameters after 14, 25 and 38 days on diets containing two doses of SGSL (1 and 10 g/kg feed) as source of 1,25(OH)2D3. In the second study, the no adverse effect level of SGSL was determined by analyzing the same parameters after 35 days on diets containing basic VD3 supply and in addition 0.2, 1.0, 2.0 and 4.0 g of SGSL/kg feed. We showed that SGSL was able to substitute VD3 in broilers as far as the performance parameters were concerned. Also, we found that the no adverse effect level is at least 4 g SGSL/kg feed when used with moderate doses of VD3. This is 20 times higher than the upper limit of the commercially recommended dose. We concluded that SGSL is a safe feed additive to use in broiler chicken. PMID- 27934623 TI - Investigation of coagulation and serum biochemistry profiles in dairy cattle with different degrees of fatty liver. AB - INTRODUCTION: Das Ziel der vorliegenden Arbeit war es, Blutgerinnungsprofile, biochemische und hamatologische Parameter bei Kuhen mit unterschiedlichen Schweregraden der Leberverfettung zu untersuchen. Der Schweregrad der Leberverfettung wurde mittels histologischer Untersuchung von Leberbiopsien ermittelt. Funfzig Kuhe, die wegen linksseitiger Labmagenverlagerung uberwiesen wurden und verschiedene Schweregrade einer Leberverfettung aufwiesen wurden untersucht. Ein Gerinnungsprofil einschliesslich Prothrombinzeit, Thrombinzeit, partieller Thromboplastinzeit und Fibrinogen konnte nicht zwischen Kuhen mit oder ohne Leberverfettung unterscheiden. Die Aspartat Aminotransferase (ASAT) war der einzige Parameter, der bei Kuhen mit Leberverfettung signifikant verandert war, jedoch nicht verschiedene Schweregrade der Leberverfettung unterscheiden konnte. Die Ergebnisse zeigen, dass Gerinnungsfaktoren durch eine Leberverfettung nicht beeinflusst werden. Die routinemassig gemessenen biochemischen Parameter sind nicht geeignet um den Schweregrad einer Leberverfettung bestimmen zu konnen. PMID- 27934625 TI - Ultrasonographic findings in two sheep with enzootic calcinosis. AB - INTRODUCTION: This report describes 2 sheep with enzootic calcinosis characterized by abnormal cardiovascular and respiratory findings and ascites causing abdominal distension. Both sheep were anorexic and listless and had increased heart and respiratory rates. Auscultation of the heart revealed a gallop rhythm in sheep 1 and a loud systolic heart murmur in sheep 2. The activities of liver enzymes were severely increased in both sheep. Abdominal ultrasonography showed severe ascites and congestion of the liver and caudal vena cava. Echocardiography in sheep 2 showed hyperechoic and markedly thickened mitral and aortic valves with moderate-severe mitral insufficiency and generalized cardiomegaly. Both sheep were euthanized and examined postmortem. In addition to ascites and pleural effusion, the principal lesions were nodular thickening of the heart valves and calcification of the aorta and other arteries. Nutrition of the sheep did not include hay pellets, but the sheep were kept together with alpacas and lamas and had access to the hay pellets of these animals. In addition visitors were allowed to feed the sheep with hay pellets offered by the zoo in a dispenser. The two types of hay pellets had Vit D concentrations of 9'900 IU VitD3/kg and 7'000 IU Vit D2/kg, respectively. The definitive diagnosis was enzootic calcinosis. PMID- 27934626 TI - Management of a growing dog with renal failure fed a homemade diet. PMID- 27934628 TI - Inadvertent transfer of surgical skin marking could potentiate wrong site surgery. PMID- 27934627 TI - Characterization and Prediction of Cardiovascular Effects of Fingolimod and Siponimod Using a Systems Pharmacology Modeling Approach. AB - Sphingosine 1-phosphate (S1P) receptor agonists are associated with cardiovascular effects in humans. This study aims to develop a systems pharmacology model to identify the site of action (i.e., primary hemodynamic response variable) of S1P receptor agonists, and to predict, in a quantitative manner, the cardiovascular effects of novel S1P receptor agonists in vivo. The cardiovascular effects of once-daily fingolimod (0, 0.1, 0.3, 1, 3, and 10 mg/kg) and siponimod (3 and 15 mg/kg) were continuously recorded in spontaneously hypertensive rats and Wistar-Kyoto rats. The results were analyzed using a recently developed systems cardiovascular pharmacology model, i.e. the CVS model; total peripheral resistance and heart rate were identified as the site of action for fingolimod. Next, the CVS model was interfaced with an S1P agonist pharmacokinetic-pharmacodynamic (PKPD) model. This combined model adequately predicted, in a quantitative manner, the cardiovascular effects of siponimod using in vitro binding assays. In conclusion, the combined CVS and S1P agonist PKPD model adequately describes the hemodynamic effects of S1P receptor agonists in rats and constitutes a basis for the prediction, in a strictly quantitative manner, of the cardiovascular effects of novel S1P receptor agonists. PMID- 27934629 TI - The work environment of junior doctors: their perspectives and coping strategies. AB - OBJECTIVE: This study explores the associations between psychological distress in junior doctors and their work environment and how they cope with work stressors. METHODS: A cross-sectional survey designed by Health Education and Training Institute was delivered in 2014 to over 1900 junior doctors across 15 hospital networks through Australian Capital Territory and New South Wales. Psychological distress was evaluated using the Kessler Psychological Distress Scale-10 (K10). Numerous variables were assessed for associations with psychological distress to identify the strongest relationships and the coping strategies used. Potential associations between work demands, coping strategies and psychological distress were explored. RESULTS: 540 responses were analysed. 414 (81%) thought their workload was reasonable, 376 (75%) were enjoying their current job and 446 (82.6%) were content with their work life. However, 85 (15.7%) reported that they would not study medicine if given their time again, and 146 (27%) reported workplace bullying. The mean K10 score was 17.2 (sigma=6.3) and the prevalence of elevated psychological distress was between 63% and 80% higher than the general community. Variables most strongly associated with distress were: being discontented with workload, lack of enjoyment from current job, taking time off work and having experienced workplace bullying. There was a preference to use social activities as a method of coping but at higher levels of psychological distress there is a greater proportion who took time off work. CONCLUSIONS: Psychologically distressed junior doctors need recognition, support and treatment. Future interventions should focus on improving work environment, job satisfaction, provision of supports, use of healthy coping strategies and improving work-related relationships. This could potentially reduce levels of psychological distress in junior doctors, optimise delivery of healthcare to patients and maximise workforce potential. PMID- 27934630 TI - Does place of death vary by deprivation for patients known to specialist palliative care services? AB - OBJECTIVES: Referral to, and usage of, specialist palliative care (SPC) services are not equitable and social deprivation may be a contributory factor in this. Deprivation may also affect the place of death of patients with cancer. No study, however, has investigated whether inequalities persist following referral to SPC services. This study investigates whether place of death varies by deprivation for patients known to SPC services. METHODS: Place of death and postcode were obtained for 485 consecutive patients known to SPC services within NHS Lothian who died in 2014-2015. From this information, deprivation quintile (DQ) was derived using the Scottish Index of Multiple Deprivation (SIMD) database and place of death compared between DQs and analysed statistically. RESULTS: Across all DQs, patients known to SPC services were more likely to die in the hospice than at home or in hospital. There was, however, a small but statistically significant difference in the ratio of hospital deaths compared to hospice deaths between the DQs, with higher death rates in hospital for the most deprived compared to the least deprived and higher death rates in the hospice for the least deprived compared to the most deprived. CONCLUSIONS: This study suggests that even after referral to specialist palliative care services variation in place of death by deprivation persists. Greater deprivation is associated with increased likelihood of dying in hospital and decreased likelihood of dying in a hospice, although no difference was noted for home deaths. PMID- 27934631 TI - Cardiac involvement in ankylosing spondylitis. Can new magnetic resonance indices interpret cardiac pathophysiology beyond echocardiography? PMID- 27934632 TI - QRS fragmentation in tetralogy of Fallot: clinical utility and risk prediction. PMID- 27934634 TI - The episode, the PTAC, cost, and the neurointerventionalist. AB - Episodic care forms a payment methodology of increasing relevance to neurointerventional specialists and other providers. Episodic care payment models are currently recognized in both payment paths described by the Medicare Access and Children's Health Insurance Program (CHIP) Reauthorization Act (MACRA): the Merit-Based Incentive Payment System and Advanced Alternative Payment Models. Understanding the cost of care, as well as how such costs are shaped in the context of episodic care, will be critical to success in both of these paths. PMID- 27934633 TI - c-Myc co-ordinates mRNA cap methylation and ribosomal RNA production. AB - The mRNA cap is a structure added to RNA pol II transcripts in eukaryotes, which recruits factors involved in RNA processing, nuclear export and translation initiation. RNA guanine-7 methyltransferase (RNMT)-RNA-activating miniprotein (RAM), the mRNA cap methyltransferase complex, completes the basic functional mRNA cap structure, cap 0, by methylating the cap guanosine. Here, we report that RNMT-RAM co-ordinates mRNA processing with ribosome production. Suppression of RNMT-RAM reduces synthesis of the 45S ribosomal RNA (rRNA) precursor. RNMT-RAM is required for c-Myc expression, a major regulator of RNA pol I, which synthesises 45S rRNA. Constitutive expression of c-Myc restores rRNA synthesis when RNMT-RAM is suppressed, indicating that RNMT-RAM controls rRNA production predominantly by controlling c-Myc expression. We report that RNMT-RAM is recruited to the ribosomal DNA locus, which may contribute to rRNA synthesis in certain contexts. PMID- 27934635 TI - Metabolism of the MEK1/2 Inhibitor Pimasertib Involves a Novel Conjugation with Phosphoethanolamine in Patients with Solid Tumors. AB - Pimasertib (AS703026 or MSC1936369B) is a selective inhibitor of MEK1/2, the mitogen-activated protein kinase (MAPK) signaling pathway, which is often dysregulated in cancer cells. Pimasertib has shown potent preclinical antitumor activity and its clinical activity is being investigated in various tumor types. In this phase I study, the disposition and biotransformation of 14C-radiolabeled pimasertib was investigated in six patients with locally advanced or metastatic solid tumors (NCT01713036). Ultra-performance liquid chromatography-mass spectrometry and radiodetection techniques were used to investigate the profiles and structures of metabolites in plasma, urine, and feces after a single oral dose of 14C-pimasertib. A total of 14 different phase I and II metabolites of 14C pimasertib were detected, which were principally generated through oxidations and conjugations (direct and indirect); but other reactions included isomerization, N dealkylation, deamination, and deiodination to form minor metabolites. Two major metabolites (>10% of total drug-related material), M554 and M445, were identified in plasma and urine. In feces, M445 was the primary metabolite with only trace amounts of M554 excreted. All other metabolites, including enantiomers of M445 and pimasertib, were detected to a lesser extent (<5%) in these matrices. M445 was identified as a carboxylic acid of pimasertib. M554 was identified as a novel phosphoethanolamine conjugate on the propanediol moiety of pimasertib by high resolution mass spectrometry and multiple nuclear magnetic resonance spectroscopy techniques. To our knowledge, a phosphoethanolamine conjugate is a novel metabolite not previously described for a pharmaceutical agent and requires detailed further investigations to understand any implications. PMID- 27934636 TI - Impact of Probe Substrate Selection on Cytochrome P450 Reaction Phenotyping Using the Relative Activity Factor. AB - Accurately assessing the contribution of cytochrome P450 (P450) isoforms to overall metabolic clearance is important for prediction of clinical drug-drug interactions (DDIs). The relative activity factor (RAF) approach in P450 reaction phenotyping assumes that the interaction between P450-selective probes and testing systems is the same as the interaction of drug candidate with those systems. To test this assumption, an intersystem clearance ratio (ICR) was created to evaluate the difference in values between RAF-scaled intrinsic clearance (CLint) and measured CLint in human liver microsomes (HLMs). The RAF value for CYP3A4 or CYP2C9 derived from a particular P450-selective probe reaction was applied to calculate RAF-scaled CLint for other probe reactions of the same P450 isoform in a crossover manner and compared with the measured HLM CLint When RAF derived from midazolam or nifedipine was used for CYP3A4, the ICR for testosterone 6beta-hydroxylation was 31 and 25, respectively, suggesting significantly diverse interactions of CYP3A4 probes with the testing systems. Such ICR differences were less profound among probes for CYP2C9. In addition, these RAF values were applied to losartan and meloxicam, whose metabolism is mostly CYP2C9 mediated. Only using the RAF derived from testosterone for CYP3A4 produced the expected CYP2C9 contribution of 72%-87% and 47%-69% for metabolism of losartan and meloxicam, respectively. RAF derived from other CYP3A4 probes would have attributed predominantly to CYP3A4 and led to incorrect prediction of DDIs. Our study demonstrates a significant impact of probe substrate selection on P450 phenotyping using the RAF approach, and the ICR may provide a potential solution. PMID- 27934637 TI - Management of Rodent Populations by Anticoagulant Rodenticides: Toward Third Generation Anticoagulant Rodenticides. AB - Second-generation anticoagulant rodenticides (SGARs) have been used since the 1980s for pest management. They are highly efficient even in warfarin-resistant rodents. Nevertheless, because of their tissue persistence, nontarget poisoning by SGARs is commonly described in wildlife. Due to this major problem, a new generation of anticoagulants must be developed to limit this risk. This study proposes a method of developing a new generation of anticoagulant rodenticides by revisiting the old SGARs based on the concept of stereochemistry. Each current SGAR is a mixture of diastereomers. Diastereomers of each compound were purified, and their biologic properties were compared by determining their ability to inhibit vitamin K epoxide reductase (VKOR) activity involved in the activation of vitamin K-dependent clotting factors and their toxicokinetic properties. Systematically, for each SGAR, both diastereomers are as effective in inhibiting VKOR activity. However, their toxicokinetic properties are very different, with one of the two diastereomers always more rapidly cleared than the other one. For all SGARs except flocoumafen, the less persistent diastereomer is always the less predominant isomer present in the current mixture. Therefore, the development of baits containing only the less persistent diastereomer would avoid the ecotoxicological risk associated with their use without decreasing their efficacy. PMID- 27934638 TI - Comparative Evaluation of Dehydroepiandrosterone Sulfate Potential to Predict Hepatic Organic Anion Transporting Polypeptide Transporter-Based Drug-Drug Interactions. AB - Pharmacokinetic drug-drug interactions (DDIs) on hepatic organic anion transporting polypeptides (OATPs) are important clinical issues. Previously, we reported that plasma dehydroepiandrosterone sulfate (DHEAS) could serve as an endogenous probe to predict OATP-based DDIs in monkeys using rifampicin as an OATP inhibitor. Since the contribution of hepatic OATPs to the changes in plasma DHEAS by rifampicin remains unclear, however, we performed an in vivo pharmacokinetic study to explore this issue. Since plasma DHEAS concentrations were low in our rat model, the disposition of externally administered DHEAS was evaluated. Intravenously administered DHEAS was recovered mainly in bile (29.1%) and less in urine (2.95%). The liver tissue-to-plasma concentration ratio (Kpliver) decreased from 41.8 to 5.07 by rifampicin, and this decrement was consistent with the decrease in distribution volume from 247 to 59 ml/rat. Comparison of the in vitro IC50 of rifampicin for DHEAS uptake by isolated rat hepatocytes and in vivo plasma rifampicin concentration suggested that the effect of rifampicin on the plasma DHEAS concentration was explained mostly by the inhibition of hepatic OATPs, demonstrating that DHEAS could be a biomarker of hepatic OATP activity. Next, previously reported rifampicin-induced changes in plasma concentrations evaluated as an AUC ratio (AUCR) of possible probe compounds were compared on the basis of rifampicin dose/body surface area. The AUCR values of endogenous compounds and i.v. administered statins, for which possible DDIs in the intestinal absorption process can be excluded, increased proportionally to the rifampicin dose. Simultaneous measurement of these endogenous compounds could be effective biomarkers for the prediction of OATP based DDIs. PMID- 27934639 TI - Pregnancy-specific telephone support helps reduce maternal smoking. PMID- 27934640 TI - Nursing home residents prefer fewer interventions and the nursing home instead of hospital for place of death. PMID- 27934641 TI - Psychological treatment is one of the several important components to the effective management of postpartum depression. PMID- 27934642 TI - DemDel, a nursing-led practice-based delirium intervention, improves certain outcomes for older cognitively impaired inpatients. PMID- 27934643 TI - Self-management programme for people with dementia and their spouses demonstrates some benefits, but the model has limitations. PMID- 27934647 TI - Preface. PMID- 27934648 TI - Arginine Metabolism Revisited. AB - Mammalian arginine metabolism is complex due to the expression of multiple enzymes that utilize arginine as substrate and to interactions or competition between specific enzymes involved in arginine metabolism. Moreover, cells may contain multiple intracellular arginine pools that are not equally accessible to all arginine metabolic enzymes, thus presenting additional challenges to more fully understanding arginine metabolism. At the whole-body level, arginine metabolism ultimately results in the production of a biochemically diverse range of products, including nitric oxide, urea, creatine, polyamines, proline, glutamate, agmatine, and homoarginine. Included in this group of compounds are the methylated arginines (e.g., asymmetric dimethylarginine), which are released upon degradation of proteins containing methylated arginine residues. Changes in arginine concentration also can regulate cellular metabolism and function via a variety of arginine sensors. Although much is known about arginine metabolism, elucidation of the physiologic or pathophysiologic roles for all of the pathways and their metabolites remains an active area of investigation, as exemplified by current findings highlighted in this review. PMID- 27934644 TI - Sugar-Sweetened Beverage but Not Diet Soda Consumption Is Positively Associated with Progression of Insulin Resistance and Prediabetes. AB - BACKGROUND: Previous studies have shown an inconsistent relation between habitual beverage consumption and insulin resistance and prediabetes. OBJECTIVE: The objective of the present study was to test the hypothesis that the consumption of sugar-sweetened beverages (SSBs), rather than diet soda, is associated with long term progression of insulin resistance and the development of prediabetes. METHODS: We analyzed the prospective association between cumulative mean consumption of SSBs or diet soda and incident prediabetes (n = 1685) identified across a median of 14 y of follow-up in participants [mean +/- SD age: 51.9 +/- 9.2 y; 59.6% women; mean +/- SD body mass index (BMI; kg/m2): 26.3 +/- 4.4] of the Framingham Offspring cohort. The prospective association between beverage consumption and change in homeostasis model assessment of insulin resistance (HOMA-IR; n = 2076) over ~7 y was also analyzed. The cumulative mean consumption of SSBs and diet soda was estimated by using food-frequency questionnaires. Multivariable Cox proportional hazards models and linear regression models were implemented to estimate the HRs of incident prediabetes and change in HOMA-IR, respectively. RESULTS: After adjustment for multiple potential confounders, including baseline BMI, we observed that SSB intake was positively associated with incident prediabetes (P-trend < 0.001); the highest SSB consumers (>3 servings/wk; median: 6 servings/wk) had a 46% higher risk of developing prediabetes than did the SSB nonconsumers (HR: 1.46; 95% CI: 1.16, 1.83). Higher SSB intake was also associated with a greater increase in HOMA-IR (P-trend = 0.006). No prospective associations were observed between diet soda intake and risk of prediabetes (P-trend = 0.24) or changes in HOMA-IR (P-trend = 0.25). These associations were similar after additional adjustment for change in BMI. CONCLUSION: Regular SSB intake, but not diet soda intake, is associated with a greater increase in insulin resistance and a higher risk of developing prediabetes in a group of middle-aged adults. PMID- 27934649 TI - Safety and Effectiveness of Arginine in Adults. AB - l-Arginine (Arg) appears to have a beneficial effect on the regulation of nutrient metabolism to enhance lean tissue deposition and on insulin resistance in humans. The observed safe level for oral administration of Arg is ~20 g/d, but higher levels have been tested in short-term studies without serious adverse effects; however, more data are needed in both animal models and humans to fully evaluate safety as well as efficacy. The primary objective of this review is to summarize the current knowledge of the safety, pharmacokinetics, and effectiveness of oral Arg in adults. Arg supplementation has been used safely in vulnerable populations, such as pregnant women, preterm infants, and individuals with cystic fibrosis. Several recent studies have shown beneficial effects of Arg in individuals with obesity, insulin resistance, and diabetes. Collectively, the data suggest that Arg supplementation is a safe and generally well-tolerated nutriceutical that may improve metabolic profiles in humans. PMID- 27934651 TI - A Perspective on the Safety of Supplemental Tryptophan Based on Its Metabolic Fates. AB - Over the past 50 y, tryptophan has been ingested in amounts well in excess of its dietary requirement. This use is based on extensive findings that ingesting tryptophan increases brain tryptophan concentrations, which stimulates the synthesis and release of the neurotransmitter serotonin, from which it is derived. Such increases in serotonin function may improve mood and sleep. However, tryptophan ingestion has other effects, such as increasing serotonin production in the gut, increasing serotonin concentrations in blood, stimulating the production of the hormone melatonin (a tryptophan metabolite), stimulating tryptophan metabolism via the kynurenine pathway, and possibly stimulating the production of tryptophan metabolites in the gut microbiome. Several of the kynurenine metabolites have actions on excitatory glutamate receptors in the gut and brain and on cells of the immune system. In addition, metabolites of tryptophan produced by colonic bacteria are reported to cause adverse effects in some species. This review examines each of these tryptophan pathways to determine if any of the metabolites increase after tryptophan ingestion, and if so, whether effects are seen on target body functions. In this regard, recent research suggests that it may be useful to examine kynurenine pathway metabolites and some microbial tryptophan metabolites to determine whether supplemental tryptophan consumption increases their concentrations in the body and amplifies their actions. PMID- 27934650 TI - Parenteral or Enteral Arginine Supplementation Safety and Efficacy. AB - Arginine supplementation has the potential to improve the health of patients. Its use in hospitalized patients has been a controversial topic in the nutrition literature, especially concerning supplementation of septic patients. In this article, we review the relevant literature both for and against the use of arginine in critically ill, surgical, and hospitalized patients. The effect of critical illness on arginine metabolism is reviewed, as is its use in septic and critically ill patients. Although mounting evidence supports immunonutrition, there are only a few studies that suggest that this is safe in patients with severe sepsis. The use of arginine has been shown to benefit a variety of critically ill patients. It should be considered for inclusion in combinations of immunonutrients or commercial formulations for groups in whom its benefit has been reported consistently, such as those who have suffered trauma and those in acute surgical settings. The aims of this review are to discuss the role of arginine in health, the controversy surrounding arginine supplementation of septic patients, and the use of arginine in critically ill patients. PMID- 27934652 TI - Tryptophan Intake in the US Adult Population Is Not Related to Liver or Kidney Function but Is Associated with Depression and Sleep Outcomes. AB - BACKGROUND: Tryptophan is an indispensable amino acid and is a precursor of the neurotransmitter serotonin. Tryptophan metabolites, such as serotonin and melatonin, are thought to participate in the regulation of mood and sleep and tryptophan is used to treat insomnia, sleep apnea, and depression. OBJECTIVE: This study examined the intake of tryptophan and its associations with biochemical, behavioral, sleep, and health and safety outcomes in adults in a secondary analysis of a large, publicly available database of the US population. METHODS: Data from the NHANES 2001-2012 (n = 29,687) were used to determine daily intakes of tryptophan and its associations with biochemical markers of health- and safety-related outcomes, self-reported depression, and sleep-related variables. Data were adjusted for demographic factors and protein intake. Linear trends were computed across deciles of intake for each outcome variable, and P trends were determined. RESULTS: The usual tryptophan intake by US adults was 826 mg/d, severalfold higher than the Estimated Average Requirement for adults of 4 mg/(kg ? d) (~280 mg/d for a 70-kg adult). Most health- and safety-related biochemical markers of liver function, kidney function, and carbohydrate metabolism were not significantly (P-trend > 0.05) associated with deciles of tryptophan intake and were well within normal ranges, even for individuals in the 99th percentile of intake. Usual intake deciles of tryptophan were inversely associated with self-reported depression measured by the Patient Health Questionnaire raw score (0-27; P-trend < 0.01) and calculated level (1 = no depression, 5 = severe depression; P-trend < 0.01) and were positively associated with self-reported sleep duration (P-trend = 0.02). CONCLUSIONS: Tryptophan intake was not related to most markers of liver function, kidney function or carbohydrate metabolism. Levels of tryptophan intake in the US population appear to be safe as shown by the absence of abnormal laboratory findings. Tryptophan intake was inversely associated with self-reported level of depression and positively associated with sleep duration. PMID- 27934653 TI - Leucine and Mammalian Target of Rapamycin-Dependent Activation of Muscle Protein Synthesis in Aging. AB - The preservation or restoration of muscle mass is of prime importance for healthy aging. However, aging has been repeatedly shown to be associated with resistance of muscle to the anabolic effects of feeding. Leucine supplementation has been proposed as a possible strategy because of its regulatory role on protein homeostasis. Indeed, it acts independently of growth factors and leads to enhanced cap-dependent mRNA translation initiation and increased protein synthesis. Leucine acts as a signaling molecule directly at the muscle level via the activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1). However, in aged muscle, mTORC1 activation seems to be impaired, with decreased sensitivity and responsiveness of muscle protein synthesis to amino acids, whereas the phosphorylation state of several components of this signaling pathway appears to be higher in the basal state. This may stem from specific age-related impairment of muscle signaling and from decreased nutrient and growth factor delivery to the muscle. Whether aging per se affects mTORC1 signaling remains to be established, because aging is frequently associated with inadequate protein intake, decreased insulin sensitivity, inactivity, inflammatory processes, etc. Whatever its origin, this anabolic resistance to feeding can be mitigated by quantitative and qualitative manipulation of protein supply, such as leucine supplementation; however, there remains the question of possible adverse effects of long-term, high-dose leucine supplementation in terms of insulin resistance and tumorigenesis. PMID- 27934655 TI - Safety and Tolerability of Leucine Supplementation in Elderly Men. AB - Leucine, a branched-chain amino acid, has been shown to stimulate muscle protein synthesis and has been suggested to play a role in the prevention of age-related muscle atrophy (sarcopenia). Although leucine supplementation may be beneficial, the efficacious dose of leucine is unknown. Before conducting studies with increased doses of leucine, the Tolerable Upper Intake Level (UL) for leucine needs to be determined. The objective of this review is to describe 2 current studies to determine the UL for leucine in young and elderly men. Initially, in young men we tested the conceptual model of determining the maximum oxidative capacity of an amino acid to be an ideal marker for identifying the UL. Leucine oxidation, measured with the use of l-[1-13C]leucine, increased with increasing leucine intakes and reached a plateau at higher intakes. Two-phase linear regression analysis identified a breakpoint of 550 mg ? kg-1 ? d-1 (95% CI: 454, 646 mg ? kg-1 ? d-1), with a simultaneous increase in blood ammonia concentrations above normal values (35 MUmol/L). Recently, a similar study was conducted in elderly men (~72 y old). A breakpoint in leucine oxidation was observed at 431 mg ? kg-1 ? d-1 (95% CI: 351, 511 mg ? kg-1 ? d-1), with blood ammonia concentrations above normal (35 MUmol/L) at leucine intakes >550 mg ? kg 1 ? d-1 Taking the data together, the UL for leucine intake in healthy elderly men could be set at a value similar to young men, at 500 mg ? kg-1 ? d-1, or ~35 g/d for an individual weighing 70 kg; or, as a cautious estimate, the leucine UL could also be considered as 351 mg ? kg-1 ? d-1 (the lower 95% CI), which would be ~24.5 g/d for an elderly individual weighing 70 kg. These studies to determine the UL for leucine in humans are acute diet studies, and future studies with additional biomarkers and long-term supplementation of leucine will be necessary. PMID- 27934654 TI - Efficacy and Safety of Leucine Supplementation in the Elderly. AB - Leucine supplementation has grown in popularity due to the discovery of its anabolic effects on cell signaling and protein synthesis in muscle. The current recommendation is a minimum intake of 55 mg ? kg-1. d-1 Leucine acutely stimulates skeletal muscle anabolism and can overcome the anabolic resistance of aging. The value of chronic leucine ingestion for muscle growth is still unclear. Most of the research into leucine consumption has focused on efficacy. To our knowledge, very few studies have sought to determine the maximum safe level of intake. Limited evidence suggests that intakes of <=1250 mg ? kg-1. d-1 do not appear to have any health consequences other than short-term elevated plasma ammonia concentrations. Similarly, no adverse events have been reported for the leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB), although no studies have tested HMB toxicity in humans. Therefore, future research is needed to evaluate leucine and HMB toxicity in the elderly and in specific health conditions. PMID- 27934656 TI - The Safety and Regulatory Process for Amino Acids in Europe and the United States. AB - The safety of long-term, high-dose amino acid consumption marketed as dietary supplements or functional or medical foods requires regulatory clearance in the European Union through the novel food process or through the Dietary Supplement Health and Education Act or the GRAS (Generally Recognized As Safe) route in the United States. The safety assessment of high daily doses of amino acids for bodybuilding or other health benefits is expected to require human studies to support tolerability and safety. The need for human studies is based on the fact that there is little or no evidence of toxicity from the conduct of animal toxicity studies and because standard animal testing would be inappropriate because of the large dosages required to provide a suitable margin of safety when extrapolating from animals to humans. Furthermore, the large dosages in animals required to provide a substantial margin of safety could lead to nutritional and physiologic imbalances, potentially confounding an amino acid safety assessment. PMID- 27934657 TI - The Importance of Quality Specifications in Safety Assessments of Amino Acids: The Cases of l-Tryptophan and l-Citrulline. AB - The increasing consumption of amino acids from a wide variety of sources, including dietary supplements, natural health products, medical foods, infant formulas, athletic and work-out products, herbal medicines, and other national and international categories of nutritional and functional food products, increases the exposure to amino acids to amounts far beyond those normally obtained from the diet, thereby necessitating appropriate and robust safety assessments of these ingredients. Safety assessments of amino acids, similar to all food constituents, largely rely on the establishment of an upper limit [Tolerable Upper Intake Level (UL)] considered to be a guide for avoiding high intake, above which adverse or toxic effects might occur. However, reliable ULs have been difficult or impossible to define for amino acids because of inadequate toxicity studies in animals and scarce or missing clinical data, as well as a paucity or absence of adverse event reporting data. This review examines 2 amino acids that have been associated with in-market adverse events to show how quality specifications might have helped prevent the adverse clinical outcomes. We further highlight the importance of various factors that should be incorporated into an overall safety assessment of these and other amino acids. In addition to the traditional reliance on the established UL, well-defined quality specifications, review of synthesis and production strategies, potential interactions with drugs, contraindications with certain disease states, and cautionary use within certain age groups should all be taken into consideration. PMID- 27934659 TI - Either side of the door. PMID- 27934658 TI - Proposals for Upper Limits of Safe Intake for Arginine and Tryptophan in Young Adults and an Upper Limit of Safe Intake for Leucine in the Elderly. AB - On the basis of research presented during the 9th Amino Acid Assessment Workshop, a No Observed Adverse Effect Level (NOAEL) for diet-added arginine (added mostly in the form of dietary supplements) of 30 g/d and an upper limit of safe intake (ULSI) for diet-added tryptophan (added mostly in the form of dietary supplements) of 4.5 g/d have been proposed. Both recommendations apply to healthy young adults. The total dietary leucine ULSI proposed for elderly individuals is 500 mg . kg-1 . d-1 All 3 recommendations are relevant only to high-quality amino acid-containing products with specifications corresponding to those listed in the US Pharmacopeia Because the above amino acids are extensively utilized as dietary supplements for various real or perceived benefits, such as vasodilation, spermatogenesis, sleep, mood regulation, or muscle recovery, the above safety recommendations will have an important impact on regulatory and nutritional practices. PMID- 27934660 TI - EZH2 deletion in early mesenchyme compromises postnatal bone microarchitecture and structural integrity and accelerates remodeling. AB - In this study, we examined the functional importance of EZH2 during skeletal development and homeostasis using the conditional deletion of Ezh2 (Ezh2fl/fl ) in early mesenchyme with the use of a Prrx-1-cre driver mouse (Ezh2+/+). Heterozygous (Ezh2+/-) newborn and 4-wk-old mice exhibited increased skeletal size, growth plate size, and weight when compared to the wild-type control (Ezh2+/+), whereas homozygous deletion of Ezh2 (Ezh2-/-) resulted in skeletal deformities and reduced skeletal size, growth plate size, and weight in newborn and 4-wk-old mice. Ezh2-/- mice exhibited enhanced trabecular patterning. Osteogenic cortical and trabecular bone formation was enhanced in Ezh2+/- and Ezh2-/- animals. Ezh2+/- and Ezh2-/- mice displayed thinner cortical bone and decreased mechanical strength compared to the wild-type control. Differences in cortical bone thickness were attributed to an increased number of osteoclasts, corresponding with elevated levels of the bone turnover markers cross-linked C telopeptide-1 and tartrate-resistant acid phosphatase, detected within serum. Moreover, Ezh2+/- mice displayed increased osteoclastogenic potential coinciding with an upregulation of Rankl and M-csf expression by mesenchymal stem cells (MSCs). MSCs isolated from Ezh2+/- mice also exhibited increased trilineage potential compared with wild-type bone marrow stromal/stem cells (BMSCs). Gene expression studies confirmed the upregulation of known Ezh2 target genes in Ezh2 /- bone tissue, many of which are involved in Wnt/BMP signaling as promoters of osteogenesis and inhibitors of adipogenesis. In summary, EZH2 appears to be an important orchestrator of skeletal development, postnatal bone remodelling and BMSC fate determination in vitro and in vivo-Hemming, S., Cakouros, D., Codrington, J., Vandyke, K., Arthur, A., Zannettino, A., Gronthos, S. EZH2 deletion in early mesenchyme compromises postnatal bone microarchitecture and structural integrity and accelerates remodeling. PMID- 27934661 TI - Chicken muscle mitochondrial content appears co-ordinately regulated and is associated with performance phenotypes. AB - Mitochondrial content is a fundamental cellular bioenergetic phenotype. Previous work has hypothesised possible links between variation in muscle mitochondrial content and animal performance. However, no population screens have been performed in any production species. Here, we have designed a high throughput molecular approach to estimate mitochondrial content in commercial broilers. Technical validity was established using several approaches, including its performance in monoclonal DF-1 cells, cross-tissue comparisons in tissues with differing metabolic demands (white fat=80% within four minutes for six tooth measurements in this model could be considered a skilled examiner. PMID- 27934669 TI - LGBT Coverage in U.S. Dental Schools and Dental Hygiene Programs: Results of a National Survey. AB - The aims of this study were to assess curricular coverage of lesbian, gay, bisexual, and transgender (LGBT) content in U.S. and Canadian dental schools and U.S. dental hygiene programs, including hours of LGBT content, pedagogy used, and assessment methods, and to determine whether respondents perceived their institution's coverage as adequate. Data were collected from academic deans at 32 U.S. and two Canadian dental schools and from program directors at 71 U.S. dental hygiene programs (response rates 49%, 20%, 23%, respectively). The results showed that 29% of responding dental schools and 48% of responding dental hygiene programs did not cover LGBT content. Among the respondents, dental schools dedicated on average 3.68 hours and dental hygiene programs 1.25 hours in required settings to LGBT content. Lectures (dental schools 68%, dental hygiene programs 45%) and small group instruction (43%, 25%) were reported as the most common methodology used in teaching this content. Most of the responding dental schools and dental hygiene programs covered HIV (85%, 53%), oral disease risk (63%, 54%), and barriers to accessing health care for LGBT people (58%, 38%). Up to a third reported no need for coverage of topics such as sexual orientation (21%, 32%), coming out (29%, 37%), transitioning (29%, 38%), and sex reassignment surgery (32%, 35%). Assessment was through written examinations (41%, 30%) and faculty-observed patient interactions (21%, 23%); some respondents (20%, 33%) reported no assessment of learning outcomes. The most frequently endorsed strategies for increasing LGBT content were receiving curricular material focusing on LGBT-related health issues and health disparities and having trained faculty to teach LGBT content. PMID- 27934670 TI - Assessment of Diagnosed Temporomandibular Disorders and Orofacial Pain Conditions by Predoctoral Dental Students: A Pilot Study. AB - Temporomandibular disorders and orofacial pain (TMD/OFP) conditions are challenging to diagnose for predoctoral dental students due to the multifactorial etiology, complexity, and controversial issues surrounding these conditions. The aim of this study was to determine if patients in the clinic of one U.S. dental school reported existing signs and symptoms of TMD/OFP, whether the dental students diagnosed the condition based on the reported signs and symptoms, and if the condition was then treated. The study was based on a retrospective analysis of electronic health record data over a three-year period. The results showed that, during the study period, 21,352 patients were treated by student providers. Of those patients, 5.33% reported signs or symptoms associated with TMD/OFP; 5.99% received a TMD/OFP diagnosis; and 0.26% received at least one form of TMD/OFP treatment that had either a diagnosis or signs/symptoms of TMD/OFP. In addition, a small percentage (0.24%) of patients with no documented diagnosis received some sort of TMD/OFP-related treatment. A randomly selected sample of 90 patient charts found that no diagnoses of TMD/OFP were recorded in any of them. The results suggested that students had only marginally diagnosed the problems. Training for students including comprehensive didactic courses and clinical experiences to gain knowledge, context, and skill may be required to ensure they reach the required level of competence and prepare them to face the diagnostic challenges of TMD/OFP after graduation. PMID- 27934671 TI - Does the Sequence of Preclinical Dental Crown Type Preparations Affect Evaluation Scores? AB - Preclinical dental students must demonstrate aptitude in the preparation of teeth for treatment with several types of fixed dental prostheses. The optimal sequence of instruction and examination of these crown preparations in preclinical fixed prosthodontics is unknown. The aim of this study was to determine if grading scores by faculty and students were affected by changing the sequence of crown type preparations. Practical exams of two successive student cohorts (n=89 in 2014; n=92 in 2015) at one U.S. dental school using three crown preparations (full cast, porcelain fused to metal, and all-ceramic) in different order were analyzed by faculty grades and student self-assessment. All of the models indicated that the sequence in which the crown type preparations were taught did have an effect on the grades. The 2014 cohort had overall higher grades and particularly higher grades for the all-ceramic crown preparations. Evaluation scores were affected by the sequence in which the different crown type preparations were taught and tested. Although the overall results suggested that students may perform better if the all-ceramic crown preparation is taught last, this tendency may differ between years. PMID- 27934672 TI - The Global Footprint of Oral Medicine Specialists: The University of Pennsylvania Experience. AB - The aim of this study was to analyze the global footprint of oral medicine specialists who graduated from the University of Pennsylvania oral medicine residency program. In 2016, a cross-sectional electronic survey was distributed to 53 graduates of that program, asking about their current geographical location and professional status. Of those 53 graduates, 23 (43%) completed the survey with 22 reporting their current location and 21 reporting their current professional status. The results showed that 17 graduates were located within the U.S., and five were located internationally. Twelve graduates were in full-time academic positions, three were in part-time academic positions/part-time private practice, three were in full-time private practice, two were in postdoctoral training programs, and one was not employed. This study found that oral medicine specialists trained at the University of Pennsylvania were located both domestically and internationally. The majority held faculty positions at academic institutions with fewer involved in private practice. This program may thus be considered a source of future dental academicians. PMID- 27934673 TI - Should Lecture Recordings Be Mandated in Dental Schools? Two Viewpoints: Viewpoint 1: Lecture Recordings Should Be Mandatory in U.S. Dental Schools and Viewpoint 2: Lecture Recordings Should Not Be Mandatory in U.S. Dental Schools. AB - Transcription or recording of lectures has been in use for many years, and with the availability of high-fidelity recording, the practice is now ubiquitous in higher education. Since technology has permeated education and today's tech-savvy students have expectations for on-demand learning, dental schools are motivated to record lectures, albeit with positive and negative implications. This Point/Counterpoint article addresses the question of whether lecture recording should be mandatory in U.S. dental schools. Viewpoint 1 supports the statement that lecture recording should be mandatory. Proponents of this viewpoint argue that the benefits-notably, student satisfaction and potential for improvement in student performance-outweigh concerns. Viewpoint 2 takes the opposite position, arguing that lecture recording decreases students' classroom attendance and adversely affects the morale of educators. Additional arguments against mandatory lecture recordings involve the expense of incorporating technology that requires ongoing support. PMID- 27934674 TI - Should Attendance Be Required in Lecture Classrooms in Dental Education? Two Viewpoints: Viewpoint 1: Attendance in the Lecture Classroom Should Be Required and Viewpoint 2: Attendance Should Not Be Required in the Lecture Classroom. AB - This Point/Counterpoint discusses the long-argued debate over whether lecture attendance in dental school at the predoctoral level should be required. Current educational practice relies heavily on the delivery of content in a traditional lecture style. Viewpoint 1 asserts that attendance should be required for many reasons, including the positive impact that direct contact of students with faculty members and with each other has on learning outcomes. In lectures, students can more easily focus on subject matter that is often difficult to understand. A counter viewpoint argues that required attendance is not necessary and that student engagement is more important than physical classroom attendance. This viewpoint notes that recent technologies support active learning strategies that better engage student participation, fostering independent learning that is not supported in the traditional large lecture classroom and argues that dental education requires assimilation of complex concepts and applying them to patient care, which passing a test does not ensure. The two positions agree that attendance does not guarantee learning and that, with the surge of information technologies, it is more important than ever to teach students how to learn. At this time, research does not show conclusively if attendance in any type of setting equals improved learning or ability to apply knowledge. PMID- 27934677 TI - Response to: 'Does the risk of lymphoma in patients with RA treated with TNF inhibitors differ according to the histological subtype and the type of TNF inhibitor?' by Nocturne et al. PMID- 27934679 TI - Response to: 'Let's not fool ourselves. In RA, the ACR/EULAR remission criteria are not perfect!' by Baker et al. PMID- 27934680 TI - Let's not fool ourselves. In RA, the ACR/EULAR remission criteria are not perfect! PMID- 27934678 TI - Incidence of hepatitis B virus reactivation in patients with resolved infection on immunosuppressive therapy for rheumatic disease: a multicentre, prospective, observational study in Japan. AB - BACKGROUND: Although the reactivation of hepatitis B virus (HBV) is recognised as a serious complication in patients with rheumatic disease (RD) receiving immunosuppressive drugs (ISDs), the incidence and risk factors for reactivation remain controversial. OBJECTIVES: To investigate the incidence and risk factors for HBV reactivation in patients with RD. METHODS: We performed a multicentre, observational, prospective study over 2 years in patients with resolved HBV infection. Patients with RD treated with a dose of >=5 mg/day prednisolone and/or synthetic or biological ISDs with negative HB virus surface antigen and positive anti-HB virus surface antibody (HBsAb) and/or anti-HB virus core antibody (HBcAb) were enrolled. Quantitative HBV DNA results and related data were regularly recorded. RESULTS: Among 1042 patients, including 959 with rheumatoid arthritis, HBV DNA was detected in 35 (1.93/100 person-years), with >2.1 log copies/mL observed in 10 patients (0.55/100 person-years). None of the reactivated patients, including seven treated with a nucleic acid analogue, showed overt hepatitis. Low HBsAb titres and advanced age seemed to be risk factors for HBV reactivation; however, reactivation was observed in three patients with positive HBsAb and negative HBcAb test results. The risk of reactivation was lower with methotrexate but higher with prednisolone among the different types of ISDs. The intervals from the start of ISD to reactivation were relatively long (3-182 months; median, 66 months). CONCLUSIONS: The incidence of HBV reactivation with ISD use was 1.93/100 person-years in patients with RD with resolved HBV infection. No overt hepatitis was observed in the reactivated patients. PMID- 27934681 TI - Analysis of Cytochrome c Release by Immunocytochemistry. AB - Cytochrome c is normally localized between the inner and outer membranes of mitochondria in healthy cells. However, during apoptosis, it is released into the cytoplasm, where it binds to apoptotic protease activating factor. Caspase-9 is then recruited and activated by this complex in a process known as the induced proximity model. Release of cytochrome c from mitochondria is therefore a critical event in apoptosis and various protocols are available for its measurement. Cytochrome c in mitochondria has a punctate localization pattern in the cell and its translocation to the cytoplasm results in a diffuse distribution. This is visually striking and easily observed by immunocytochemistry. This protocol describes the use of immunocytochemistry to assay cytochrome c release during apoptosis. PMID- 27934682 TI - Measuring Mitochondrial Transmembrane Potential by TMRE Staining. AB - Adenosine triphosphate (ATP) is the main source of energy for metabolism. Mitochondria provide the majority of this ATP by a process known as oxidative phosphorylation. This process involves active transfer of positively charged protons across the mitochondrial inner membrane resulting in a net internal negative charge, known as the mitochondrial transmembrane potential (DeltaPsim). The proton gradient is then used by ATP synthase to produce ATP by fusing adenosine diphosphate and free phosphate. The net negative charge across a healthy mitochondrion is maintained at approximately -180 mV, which can be detected by staining cells with positively charged dyes such as tetramethylrhodamine ethyl ester (TMRE). TMRE emits a red fluorescence that can be detected by flow cytometry or fluorescence microscopy and the level of TMRE fluorescence in stained cells can be used to determine whether mitochondria in a cell have high or low DeltaPsim. Cytochrome c is essential for producing DeltaPsim because it promotes the pumping the protons into the mitochondrial intermembrane space as it shuttles electrons from Complex III to Complex IV along the electron transport chain. Cytochrome c is released from the mitochondrial intermembrane space into the cytosol during apoptosis. This impairs its ability to shuttle electrons between Complex III and Complex IV and results in rapid dissipation of DeltaPsim. Loss of DeltaPsim is therefore closely associated with cytochrome c release during apoptosis and is often used as a surrogate marker for cytochrome c release in cells. PMID- 27934683 TI - Generating Bait Strains for Yeast One-Hybrid Assays. AB - Yeast one-hybrid (Y1H) assays are used to identify which transcription factor (TF) "preys" can bind a DNA fragment of interest that is used as the "bait." Undertaking Y1H assays requires the generation of a yeast "bait strain" for each DNA fragment of interest that features the DNA bait coupled to a reporter(s). Plasmids encoding TFs fused to the Gal4 activation domain (AD) are then introduced into the bait strain, and activation of the reporter(s) indicates that a TF-DNA interaction has occurred. Here, we present a protocol for the first part of the strategy-the generation of a bait strain for Y1H assays. We assume that the DNA bait has already been cloned into two different reporter constructs: One places the fragment of interest upstream of HIS3, an auxotrophic growth marker, whereas the other places the DNA bait upstream of LacZ, a colorimetric marker that changes colorless X-gal into a blue compound. Briefly, generation of the bait strain involves using homologous recombination to integrate the two reporters into the genome of the yeast strain, screening individual integrants for background reporter expression (i.e., expression in the absence of a TF), and using polymerase chain reaction (PCR) and sequencing to confirm the DNA bait identity from both integrated reporter cassettes. PMID- 27934684 TI - Performing Yeast One-Hybrid Library Screens. AB - Yeast one-hybrid (Y1H) assays are used to identify which transcription factor (TF) "prey" molecules can bind a DNA fragment of interest that is used as "bait". Y1H assays involve introducing plasmids that encode TFs into a yeast "bait strain" in which the DNA fragment of interest is integrated upstream of one or more reporters, and activation of these reporters indicates that a TF-DNA interaction has occurred. These plasmids express each TF as a hybrid protein (hence the "one-hybrid" name) fused to the activation domain (AD) of the yeast TF Gal4. The AD moiety activates reporter expression even if the TF to which it is fused typically functions as a repressor. Here, we describe how to perform a Y1H screen of a library of cDNA fragments cloned into a pPC86 plasmid expressing the protein encoded by the cDNA as an AD fusion. The method assumes availability of either commercially available libraries or libraries generated in house using mRNA extracted from a tissue of interest. We also assume that users have access to a yeast bait strain that possesses the DNA fragment of interest integrated upstream of two different reporters-HIS3, an auxotrophic marker, and LacZ, a colorimetric marker that changes colorless X-gal into a blue compound. Briefly, the screen involves transforming the AD-cDNA library into the yeast bait strain, identifying colonies that show activation of both reporters, retesting the interaction in a freshly grown bait strain, and sequencing the cDNA insert to identify the interacting TF. PMID- 27934685 TI - Colony Lift Colorimetric Assay for beta-Galactosidase Activity. AB - In this protocol, we present a qualitative assay for monitoring the level of expression of beta-galactosidase, an enzyme encoded by the LacZ gene, in yeast. This is useful both for determining autoactivity of LacZ expression in yeast DNA "bait" strains and for assessing LacZ reporter gene activation mediated by a transcription factor "prey" interaction with a DNA bait of interest in yeast one hybrid (Y1H) assays. In this colorimetric assay, yeast are lysed in liquid nitrogen and then assayed for beta-galactosidase expression using the colorless compound X-gal, which turns blue in the presence of this enzyme. PMID- 27934686 TI - Zymolyase-Treatment and Polymerase Chain Reaction Amplification from Genomic and Plasmid Templates from Yeast. AB - Here, we present a protocol for amplifying DNA fragments from the genome of, or plasmids transformed into, yeast strains that require the use of the lytic enzyme zymolyase to break open the yeast cells by digesting the cell wall. Yeast strains requiring such treatment include YM4271 and Y1HaS2, whereas other yeast strains (e.g., MaV103) might not require treatment with Zymolyase. PMID- 27934687 TI - Preparation of Intracellular Metabolite Extracts from Liquid Schizosaccharomyces pombe Cultures. AB - The success of metabolomic analysis relies heavily on the sample preparation protocol. Here we present a protocol for intracellular metabolite extraction from liquid fission yeast cultures based on rapid quenching in pure methanol at -40 degrees C, bead-beating in 50% methanol for cell disruption, and 10 kDa cutoff ultrafiltration for removal of proteins. Samples are concentrated by vacuum evaporation and resuspended in 50% acetonitrile for mass spectrometric analysis. This protocol is optimal for extraction of polar metabolites such as amino acids, organic acids, nucleotides, sugars, or sugar-phosphates. Its implementation requires <6 h and allows preparation of multiple samples in parallel. PMID- 27934688 TI - Measurement of Metabolome Samples Using Liquid Chromatography-Mass Spectrometry, Data Acquisition, and Processing. AB - We present a protocol for metabolomic sample measurement using hydrophilic interaction chromatography (HILIC) combined with high-resolution Orbitrap mass spectrometry (MS). We also introduce a raw data processing method using MZmine 2 software, and include a list of 111 metabolite peaks (with their m/z values and retention times) previously identified in metabolome samples using this method. PMID- 27934689 TI - Differentiating Mouse Embryonic Stem Cells into Embryoid Bodies by Hanging-Drop Cultures. AB - Embryonic stem (ES) cells can develop into many types of differentiated tissues if they are placed into a differentiating environment. This can occur in vivo when the ES cells are injected into or aggregated with an embryo, or in vitro if their culture conditions are modified to induce differentiation. There are an increasing number of differentiating culture conditions that can bias the differentiation of ES cells into desired cell types. Determining the mechanisms that control ES cell differentiation into therapeutically important cell types is a quickly growing area of research. Knowledge gained from these studies may eventually lead to the use of stem cells to repair specific damaged tissues. Many times ES cell differentiation proceeds through an intermediate stage called the embryoid body (EB). EBs are round structures composed of ES cells that have undergone some of the initial stages of differentiation. EBs can then be manipulated further to generate more specific cell types. This protocol describes a method to differentiate ES cells into EBs. It produces EBs of comparable size. This aspect is important because the differentiation processes taking place inside an EB are influenced by its size. PMID- 27934690 TI - Precipitation of DNA with Ethanol. AB - DNA can be precipitated out of solution for the removal of salts and/or for resuspension in an alternative buffer. Either ethanol or isopropanol can be used to achieve this purpose; however, the use of ethanol is generally preferred. Cations, provided as salts, are typically included to neutralize the negative charge of the DNA phosphate backbone. This method describes ethanol precipitation of DNA in microcentrifuge tubes. PMID- 27934691 TI - Dead Cert: Measuring Cell Death. AB - Many cells in the body die at specific times to facilitate healthy development or because they have become old, damaged, or infected. Defects in cells that result in their inappropriate survival or untimely death can negatively impact development or contribute to a variety of human pathologies, including cancer, AIDS, autoimmune disorders, and chronic infection. Cell death may also occur following exposure to environmental toxins or cytotoxic chemicals. Although this is often harmful, it can be beneficial in some cases, such as in the treatment of cancer. The ability to objectively measure cell death in a laboratory setting is therefore essential to understanding and investigating the causes and treatments of many human diseases and disorders. Often, it is sufficient to know the extent of cell death in a sample; however, the mechanism of death may also have implications for disease progression, treatment, and the outcomes of experimental investigations. There are a myriad of assays available for measuring the known forms of cell death, including apoptosis, necrosis, autophagy, necroptosis, anoikis, and pyroptosis. Here, we introduce a range of assays for measuring cell death in cultured cells, and we outline basic techniques for distinguishing healthy cells from apoptotic or necrotic cells-the two most common forms of cell death. We also provide personal insight into where these assays may be useful and how they may or may not be used to distinguish apoptotic cell death from other death modalities. PMID- 27934692 TI - In the Midst of Life-Cell Death: What Is It, What Is It Good for, and How to Study It. AB - Cell death, one of the most fundamental biological processes, has not made it into the public consciousness in the same way that genetic inheritance, cell division, or DNA replication has. Everyone knows they get their genes from their parents, but few would be aware that even before they were born a lot of essential cell death has shaped their development. The greater population, for the most part, is blissfully unaware that every day millions of their own cells die in a programmed way and that this is essential for normal human physiology their well-being, in fact. Nowhere is the burial liturgy, "In the midst of life we are in death," more apt. Despite this public underappreciation, cell death research is a major industry. A search in PubMed for "apoptosis," a special form of cell death that is caused by caspases, returns approximately 280,000 hits. The intense research interest arises from the realization that abnormal cell death responses play an important role in two of the biggest killers in the western world: cancer and cardio/cerebrovascular disease. Furthermore, the manner in which cells die can also influence the development of autoimmune and autoinflammatory diseases. It is therefore of paramount importance to ensure that experiments accurately quantitate and correctly identify cell death in all its guises. That is the goal of this protocol collection. PMID- 27934693 TI - Gene-Centered Yeast One-Hybrid Assays. AB - An important question when studying gene regulation is which transcription factors (TFs) interact with which cis-regulatory elements, such as promoters and enhancers. Addressing this issue in complex multicellular organisms is challenging as several hundreds of TFs and thousands of regulatory elements must be considered in the context of different tissues and physiological conditions. Yeast one-hybrid (Y1H) assays provide a powerful "gene-centered" method to identify the TFs that can bind a DNA sequence of interest. In this introduction, we describe the basic principles of the Y1H assay and its advantages and disadvantages and briefly discuss how it is complementary to "TF-centered" methods that identify protein-DNA interactions for a known protein of interest. PMID- 27934694 TI - Metabolomic Analysis of Schizosaccharomyces pombe: Sample Preparation, Detection, and Data Interpretation. AB - Metabolomics is a modern field of chemical biology that strives to simultaneously quantify hundreds of cellular metabolites. Techniques for metabolomic analysis in Schizosaccharomyces pombe have only recently been developed. Here we introduce methods that provide a complete workflow for metabolomic analysis in S. pombe Based on available literature, we estimate the yeast metabolome to comprise on the order of several thousand different metabolites. We discuss the feasibility of extraction and detection of such a large number of metabolites, and the influences of various parameters on the results. Among the parameters addressed are cell cultivation conditions, metabolite extraction techniques, and detection and quantification methods. Further, we provide recommendations on data management and data processing for metabolomic experiments, and describe possible pitfalls regarding the interpretation of metabolomic data. Finally, we briefly discuss potential future developments of this technique. PMID- 27934696 TI - High-throughput allele-specific expression across 250 environmental conditions. AB - Gene-by-environment (GxE) interactions determine common disease risk factors and biomedically relevant complex traits. However, quantifying how the environment modulates genetic effects on human quantitative phenotypes presents unique challenges. Environmental covariates are complex and difficult to measure and control at the organismal level, as found in GWAS and epidemiological studies. An alternative approach focuses on the cellular environment using in vitro treatments as a proxy for the organismal environment. These cellular environments simplify the organism-level environmental exposures to provide a tractable influence on subcellular phenotypes, such as gene expression. Expression quantitative trait loci (eQTL) mapping studies identified GxE interactions in response to drug treatment and pathogen exposure. However, eQTL mapping approaches are infeasible for large-scale analysis of multiple cellular environments. Recently, allele-specific expression (ASE) analysis emerged as a powerful tool to identify GxE interactions in gene expression patterns by exploiting naturally occurring environmental exposures. Here we characterized genetic effects on the transcriptional response to 50 treatments in five cell types. We discovered 1455 genes with ASE (FDR < 10%) and 215 genes with GxE interactions. We demonstrated a major role for GxE interactions in complex traits. Genes with a transcriptional response to environmental perturbations showed sevenfold higher odds of being found in GWAS. Additionally, 105 genes that indicated GxE interactions (49%) were identified by GWAS as associated with complex traits. Examples include GIPR-caffeine interaction and obesity and include LAMP3-selenium interaction and Parkinson disease. Our results demonstrate that comprehensive catalogs of GxE interactions are indispensable to thoroughly annotate genes and bridge epidemiological and genome-wide association studies. PMID- 27934695 TI - Overview of CRISPR-Cas9 Biology. AB - Prokaryotes use diverse strategies to improve fitness in the face of different environmental threats and stresses, including those posed by mobile genetic elements (e.g., bacteriophages and plasmids). To defend against these elements, many bacteria and archaea use elegant, RNA-directed, nucleic acid-targeting adaptive restriction machineries called CRISPR -: Cas (CRISPR-associated) systems. While providing an effective defense against foreign genetic elements, these systems have also been observed to play critical roles in regulating bacterial physiology during environmental stress. Increasingly, CRISPR-Cas systems, in particular the Type II systems containing the Cas9 endonuclease, have been exploited for their ability to bind desired nucleic acid sequences, as well as direct sequence-specific cleavage of their targets. Cas9-mediated genome engineering is transcending biological research as a versatile and portable platform for manipulating genetic content in myriad systems. Here, we present a systematic overview of CRISPR-Cas history and biology, highlighting the revolutionary tools derived from these systems, which greatly expand the molecular biologists' toolkit. PMID- 27934699 TI - Corrigendum: Replication timing is regulated by the number of MCMs loaded at origins. PMID- 27934697 TI - The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences. AB - Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research, have the largest natural geographic distribution of any nonhuman primate, and have been the focus of much evolutionary and behavioral investigation. Consequently, rhesus macaques are one of the most thoroughly studied nonhuman primate species. However, little is known about genome-wide genetic variation in this species. A detailed understanding of extant genomic variation among rhesus macaques has implications for the use of this species as a model for studies of human health and disease, as well as for evolutionary population genomics. Whole-genome sequencing analysis of 133 rhesus macaques revealed more than 43.7 million single-nucleotide variants, including thousands predicted to alter protein sequences, transcript splicing, and transcription factor binding sites. Rhesus macaques exhibit 2.5-fold higher overall nucleotide diversity and slightly elevated putative functional variation compared with humans. This functional variation in macaques provides opportunities for analyses of coding and noncoding variation, and its cellular consequences. Despite modestly higher levels of nonsynonymous variation in the macaques, the estimated distribution of fitness effects and the ratio of nonsynonymous to synonymous variants suggest that purifying selection has had stronger effects in rhesus macaques than in humans. Demographic reconstructions indicate this species has experienced a consistently large but fluctuating population size. Overall, the results presented here provide new insights into the population genomics of nonhuman primates and expand genomic information directly relevant to primate models of human disease. PMID- 27934698 TI - LTR-mediated retroposition as a mechanism of RNA-based duplication in metazoans. AB - In a broad range of taxa, genes can duplicate through an RNA intermediate in a process mediated by retrotransposons (retroposition). In mammals, L1 retrotransposons drive retroposition, but the elements responsible for retroposition in other animals have yet to be identified. Here, we examined young retrocopies from various animals that still retain the sequence features indicative of the underlying retroposition mechanism. In Drosophila melanogaster, we identified and de novo assembled 15 polymorphic retrocopies and found that all retroposed loci are chimeras of internal retrocopies flanked by discontinuous LTR retrotransposons. At the fusion points between the mRNAs and the LTR retrotransposons, we identified shared short similar sequences that suggest the involvement of microsimilarity-dependent template switches. By expanding our approach to mosquito, zebrafish, chicken, and mammals, we identified in all these species recently originated retrocopies with a similar chimeric structure and shared microsimilarities at the fusion points. We also identified several retrocopies that combine the sequences of two or more parental genes, demonstrating LTR-retroposition as a novel mechanism of exon shuffling. Finally, we found that LTR-mediated retrocopies are immediately cotranscribed with their flanking LTR retrotransposons. Transcriptional profiling coupled with sequence analyses revealed that the sense-strand transcription of the retrocopies often lead to the origination of in-frame proteins relative to the parental genes. Overall, our data show that LTR-mediated retroposition is highly conserved across a wide range of animal taxa; combined with previous work from plants and yeast, it represents an ancient and ongoing mechanism continuously shaping gene content evolution in eukaryotes. PMID- 27934701 TI - Translational termination without a stop codon. AB - Ribosomes stall when they encounter the end of messenger RNA (mRNA) without an in frame stop codon. In bacteria, these "nonstop" complexes can be rescued by alternative ribosome-rescue factor A (ArfA). We used electron cryomicroscopy to determine structures of ArfA bound to the ribosome with 3'-truncated mRNA, at resolutions ranging from 3.0 to 3.4 angstroms. ArfA binds within the ribosomal mRNA channel and substitutes for the absent stop codon in the A site by specifically recruiting release factor 2 (RF2), initially in a compact preaccommodated state. A similar conformation of RF2 may occur on stop codons, suggesting a general mechanism for release-factor-mediated translational termination in which a conformational switch leads to peptide release only when the appropriate signal is present in the A site. PMID- 27934702 TI - Selective oxidative dehydrogenation of propane to propene using boron nitride catalysts. AB - The exothermic oxidative dehydrogenation of propane reaction to generate propene has the potential to be a game-changing technology in the chemical industry. However, even after decades of research, selectivity to propene remains too low to be commercially attractive because of overoxidation of propene to thermodynamically favored CO2 Here, we report that hexagonal boron nitride and boron nitride nanotubes exhibit unique and hitherto unanticipated catalytic properties, resulting in great selectivity to olefins. As an example, at 14% propane conversion, we obtain selectivity of 79% propene and 12% ethene, another desired alkene. Based on catalytic experiments, spectroscopic insights, and ab initio modeling, we put forward a mechanistic hypothesis in which oxygen terminated armchair boron nitride edges are proposed to be the catalytic active sites. PMID- 27934703 TI - Evidence for bulk superconductivity in pure bismuth single crystals at ambient pressure. AB - At ambient pressure, bulk rhombohedral bismuth is a semimetal that remains in the normal state down to at least 10 millikelvin. Superconductivity in bulk bismuth is thought to be unlikely because of the extremely low carrier density. We observed bulk superconductivity in pure bismuth single crystals below 0.53 millikelvin at ambient pressure, with an estimated critical magnetic field of 5.2 microteslas at 0 kelvin. Superconductivity in bismuth cannot be explained by the conventional Bardeen-Cooper-Schrieffer theory because its adiabatic approximation does not hold true for bismuth. Future theoretical work will be needed to understand superconductivity in the nonadiabatic limit in systems with low carrier densities and unusual band structures, such as bismuth. PMID- 27934704 TI - Editorial expression of concern. PMID- 27934705 TI - More tornadoes in the most extreme U.S. tornado outbreaks. AB - Tornadoes and severe thunderstorms kill people and damage property every year. Estimated U.S. insured losses due to severe thunderstorms in the first half of 2016 were $8.5 billion (US). The largest U.S. effects of tornadoes result from tornado outbreaks, which are sequences of tornadoes that occur in close succession. Here, using extreme value analysis, we find that the frequency of U.S. outbreaks with many tornadoes is increasing and that it is increasing faster for more extreme outbreaks. We model this behavior by extreme value distributions with parameters that are linear functions of time or of some indicators of multidecadal climatic variability. Extreme meteorological environments associated with severe thunderstorms show consistent upward trends, but the trends do not resemble those currently expected to result from global warming. PMID- 27934706 TI - Erratum for the Report "Large wind ripples on Mars: A record of atmospheric evolution" by M. G. A. Lapotre, R. C. Ewing, M. P. Lamb, W. W. Fischer, J. P. Grotzinger, D. M. Rubin, K. W. Lewis, M. J. Ballard, M. Day, S. Gupta, S. G. Banham, N. T. Bridges, D. J. Des Marais, A. A. Fraeman, J. A. Grant, K. E. Herkenhoff, D. W. Ming, M. A. Mischna, M. S. Rice, D. Y. Sumner, A. R. Vasavada, R. A. Yingst. PMID- 27934707 TI - Erratum for the Report "Self-organization of river channels as a critical filter on climate signals" by C. B. Phillips and D. J. Jerolmack. PMID- 27934708 TI - Intracellular innate immune surveillance devices in plants and animals. AB - Multicellular eukaryotes coevolve with microbial pathogens, which exert strong selective pressure on the immune systems of their hosts. Plants and animals use intracellular proteins of the nucleotide-binding domain, leucine-rich repeat (NLR) superfamily to detect many types of microbial pathogens. The NLR domain architecture likely evolved independently and convergently in each kingdom, and the molecular mechanisms of pathogen detection by plant and animal NLRs have long been considered to be distinct. However, microbial recognition mechanisms overlap, and it is now possible to discern important key trans-kingdom principles of NLR-dependent immune function. Here, we attempt to articulate these principles. We propose that the NLR architecture has evolved for pathogen-sensing in diverse organisms because of its utility as a tightly folded "hair trigger" device into which a virtually limitless number of microbial detection platforms can be integrated. Recent findings suggest means to rationally design novel recognition capabilities to counter disease. PMID- 27934709 TI - Crystal structures of a group II intron lariat primed for reverse splicing. AB - The 2'-5' branch of nuclear premessenger introns is believed to have been inherited from self-splicing group II introns, which are retrotransposons of bacterial origin. Our crystal structures at 3.4 and 3.5 angstrom of an excised group II intron in branched ("lariat") form show that the 2'-5' branch organizes a network of active-site tertiary interactions that position the intron terminal 3'-hydroxyl group into a configuration poised to initiate reverse splicing, the first step in retrotransposition. Moreover, the branchpoint and flanking helices must undergo a base-pairing switch after branch formation. A group II-based model of the active site of the nuclear splicing machinery (the spliceosome) is proposed. The crucial role of the lariat conformation in active-site assembly and catalysis explains its prevalence in modern splicing. PMID- 27934710 TI - News at a glance. PMID- 27934711 TI - Dam-building threatens Mekong fisheries. PMID- 27934712 TI - Congress votes on sweeping biomedical bill. PMID- 27934713 TI - Hubble uses galactic lens to study universe's first stars. PMID- 27934714 TI - One year later, Zika scientists prepare for a long war. PMID- 27934716 TI - Quest for qubits. PMID- 27934715 TI - Energy pulses reveal possible new state of memory. PMID- 27934717 TI - Bringing legends to life. PMID- 27934718 TI - Reforming the U.S. coal leasing program. PMID- 27934719 TI - As the bat flies. PMID- 27934720 TI - Spying on the neighbors' pool. PMID- 27934721 TI - Galaxy formation through cosmic recycling. PMID- 27934722 TI - Metabolic cues for hematopoietic stem cells. PMID- 27934723 TI - Can T cells be too exhausted to fight back? PMID- 27934724 TI - When stop makes sense. PMID- 27934725 TI - Ralph J. Cicerone (1943-2016). PMID- 27934726 TI - Trial and error. PMID- 27934727 TI - The future of bionic dynamos. PMID- 27934728 TI - Retracing embryological fate. PMID- 27934729 TI - Passing the point of no return. PMID- 27934730 TI - The intelligent invertebrate. PMID- 27934731 TI - Arrested development. PMID- 27934733 TI - Nuclear power: Deployment speed. PMID- 27934732 TI - Nuclear power: Serious risks. PMID- 27934735 TI - How new particles form. PMID- 27934734 TI - Nuclear power: Deployment speed-Response. PMID- 27934736 TI - A massive galaxy forming from molecular gas. PMID- 27934737 TI - Running interference. PMID- 27934738 TI - Shining light on a peculiar coupling. PMID- 27934739 TI - Glial cells contribute to pain. PMID- 27934740 TI - Zika virus is fit to be tied. PMID- 27934741 TI - How to maintain hematopoietic stem cells. PMID- 27934742 TI - Protecting by changing the code. PMID- 27934743 TI - Overactive antiviral responses in lupus. PMID- 27934744 TI - Shared logic in diverse immune systems. PMID- 27934745 TI - Tie me up, cut me down. PMID- 27934746 TI - Frame-by-frame view of acidic transport. PMID- 27934747 TI - Attention changes local brain activity. PMID- 27934748 TI - How to reactivate forgotten memories. PMID- 27934749 TI - The epigenetics of exhaustion. PMID- 27934750 TI - How bats spread viruses. PMID- 27934751 TI - Letting SLE-Ping plaques lie. PMID- 27934752 TI - Acquiring the genes to digest wood. PMID- 27934753 TI - Targeting tip growth. PMID- 27934755 TI - Neuron development in human embryos. PMID- 27934754 TI - Getting an UPR hand on recovERy. PMID- 27934756 TI - Keeping tissue layers separate. PMID- 27934757 TI - Autonomously eat, digest, move, repeat. PMID- 27934758 TI - Side effects for placebo poppers. PMID- 27934759 TI - Quantized Faraday and Kerr rotation and axion electrodynamics of a 3D topological insulator. AB - Topological insulators have been proposed to be best characterized as bulk magnetoelectric materials that show response functions quantized in terms of fundamental physical constants. Here, we lower the chemical potential of three dimensional (3D) Bi2Se3 films to ~30 meV above the Dirac point and probe their low-energy electrodynamic response in the presence of magnetic fields with high precision time-domain terahertz polarimetry. For fields higher than 5 tesla, we observed quantized Faraday and Kerr rotations, whereas the dc transport is still semiclassical. A nontrivial Berry's phase offset to these values gives evidence for axion electrodynamics and the topological magnetoelectric effect. The time structure used in these measurements allows a direct measure of the fine structure constant based on a topological invariant of a solid-state system. PMID- 27934760 TI - Molecular gas in the halo fuels the growth of a massive cluster galaxy at high redshift. AB - The largest galaxies in the universe reside in galaxy clusters. Using sensitive observations of carbon monoxide, we show that the Spiderweb galaxy-a massive galaxy in a distant protocluster-is forming from a large reservoir of molecular gas. Most of this molecular gas lies between the protocluster galaxies and has low velocity dispersion, indicating that it is part of an enriched intergalactic medium. This may constitute the reservoir of gas that fuels the widespread star formation seen in earlier ultraviolet observations of the Spiderweb galaxy. Our results support the notion that giant galaxies in clusters formed from extended regions of recycled gas at high redshift. PMID- 27934761 TI - Spectroscopic snapshots of the proton-transfer mechanism in water. AB - The Grotthuss mechanism explains the anomalously high proton mobility in water as a sequence of proton transfers along a hydrogen-bonded (H-bonded) network. However, the vibrational spectroscopic signatures of this process are masked by the diffuse nature of the key bands in bulk water. Here we report how the much simpler vibrational spectra of cold, composition-selected heavy water clusters, D+(D2O)n, can be exploited to capture clear markers that encode the collective reaction coordinate along the proton-transfer event. By complexing the solvated hydronium "Eigen" cluster [D3O+(D2O)3] with increasingly strong H-bond acceptor molecules (D2, N2, CO, and D2O), we are able to track the frequency of every O-D stretch vibration in the complex as the transferring hydron is incrementally pulled from the central hydronium to a neighboring water molecule. PMID- 27934762 TI - Reactivation of latent working memories with transcranial magnetic stimulation. AB - The ability to hold information in working memory is fundamental for cognition. Contrary to the long-standing view that working memory depends on sustained, elevated activity, we present evidence suggesting that humans can hold information in working memory via "activity-silent" synaptic mechanisms. Using multivariate pattern analyses to decode brain activity patterns, we found that the active representation of an item in working memory drops to baseline when attention shifts away. A targeted pulse of transcranial magnetic stimulation produced a brief reemergence of the item in concurrently measured brain activity. This reactivation effect occurred and influenced memory performance only when the item was potentially relevant later in the trial, which suggests that the representation is dynamic and modifiable via cognitive control. The results support a synaptic theory of working memory. PMID- 27934763 TI - Selective modulation of cortical state during spatial attention. AB - Neocortical activity is permeated with endogenously generated fluctuations, but how these dynamics affect goal-directed behavior remains a mystery. We found that ensemble neural activity in primate visual cortex spontaneously fluctuated between phases of vigorous (On) and faint (Off) spiking synchronously across cortical layers. These On-Off dynamics, reflecting global changes in cortical state, were also modulated at a local scale during selective attention. Moreover, the momentary phase of local ensemble activity predicted behavioral performance. Our results show that cortical state is controlled locally within a cortical map according to cognitive demands and reveal the impact of these local changes in cortical state on goal-directed behavior. PMID- 27934764 TI - Gliogenic LTP spreads widely in nociceptive pathways. AB - Learning and memory formation involve long-term potentiation (LTP) of synaptic strength. A fundamental feature of LTP induction in the brain is the need for coincident pre- and postsynaptic activity. This restricts LTP expression to activated synapses only (homosynaptic LTP) and leads to its input specificity. In the spinal cord, we discovered a fundamentally different form of LTP that is induced by glial cell activation and mediated by diffusible, extracellular messengers, including d-serine and tumor necrosis factor (TNF), and that travel long distances via the cerebrospinal fluid, thereby affecting susceptible synapses at remote sites. The properties of this gliogenic LTP resolve unexplained findings of memory traces in nociceptive pathways and may underlie forms of widespread pain hypersensitivity. PMID- 27934765 TI - Zika virus produces noncoding RNAs using a multi-pseudoknot structure that confounds a cellular exonuclease. AB - The outbreak of Zika virus (ZIKV) and associated fetal microcephaly mandates efforts to understand the molecular processes of infection. Related flaviviruses produce noncoding subgenomic flaviviral RNAs (sfRNAs) that are linked to pathogenicity in fetal mice. These viruses make sfRNAs by co-opting a cellular exonuclease via structured RNAs called xrRNAs. We found that ZIKV-infected monkey and human epithelial cells, mouse neurons, and mosquito cells produce sfRNAs. The RNA structure that is responsible for ZIKV sfRNA production forms a complex fold that is likely found in many pathogenic flaviviruses. Mutations that disrupt the structure affect exonuclease resistance in vitro and sfRNA formation during infection. The complete ZIKV xrRNA structure clarifies the mechanism of exonuclease resistance and identifies features that may modulate function in diverse flaviviruses. PMID- 27934766 TI - Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation. AB - A specialized bone marrow microenvironment (niche) regulates hematopoietic stem cell (HSC) self-renewal and commitment. For successful donor-HSC engraftment, the niche must be emptied via myeloablative irradiation or chemotherapy. However, myeloablation can cause severe complications and even mortality. Here we report that the essential amino acid valine is indispensable for the proliferation and maintenance of HSCs. Both mouse and human HSCs failed to proliferate when cultured in valine-depleted conditions. In mice fed a valine-restricted diet, HSC frequency fell dramatically within 1 week. Furthermore, dietary valine restriction emptied the mouse bone marrow niche and afforded donor-HSC engraftment without chemoirradiative myeloablation. These findings indicate a critical role for valine in HSC maintenance and suggest that dietary valine restriction may reduce iatrogenic complications in HSC transplantation. PMID- 27934767 TI - Generation of influenza A viruses as live but replication-incompetent virus vaccines. AB - The conversion of life-threatening viruses into live but avirulent vaccines represents a revolution in vaccinology. In a proof-of-principle study, we expanded the genetic code of the genome of influenza A virus via a transgenic cell line containing orthogonal translation machinery. This generated premature termination codon (PTC)-harboring viruses that exerted full infectivity but were replication-incompetent in conventional cells. Genome-wide optimization of the sites for incorporation of multiple PTCs resulted in highly reproductive and genetically stable progeny viruses in transgenic cells. In mouse, ferret, and guinea pig models, vaccination with PTC viruses elicited robust humoral, mucosal, and T cell-mediated immunity against antigenically distinct influenza viruses and even neutralized existing infecting strains. The methods presented here may become a general approach for generating live virus vaccines that can be adapted to almost any virus. PMID- 27934769 TI - Making a difference, differently. PMID- 27934771 TI - Correction: Questioning the significance of the non-identity problem in applied ethics: a reply to Tony Hope. PMID- 27934770 TI - To stop or not to stop: dissent and undue burden as reasons to stop participation in paediatric research. AB - Children participating in clinical research may show signs of discomfort, discontent, dissent and so on, that cannot be solved by comforting the child. When, and on what ground, should such signs lead to the decision to withdraw the child from the trial? In order to adequately protect children participating in clinical research, it is important to know how to determine during the course of a trial whether participation is still justified. Yet to date, legislation, ethical guidelines and medical ethical literature do not provide sufficient guidance. Therefore, in this paper we aim to provide the required clarity. We identify two types of reasons for taking signs of discomfort, discontent, dissent and so on, very seriously: (1) the principle of respect for the growing autonomy of the child, in those cases where a child expresses a clear, explicit and persistent wish to be withdrawn from the study; and (2) the principle of non maleficence, in those cases where for an individual child, the research burden appears to be higher than acceptable. We recommend to closely monitor each child during the course of the study, thereby being vigilant to whether the child still wants to continue and to whether the actual burden the child experiences is still acceptable in relation to the permitted levels of burden. PMID- 27934772 TI - The Ethics Liaison Program: building a moral community. AB - Ethicists often struggle to maintain institution-wide awareness of and commitment to medical ethics. At Beth Israel Deaconess Medical Center (BIDMC), we created the Ethics Liaison Program to address that challenge by making ethics part of the moral culture of the institution. Liaisons represent clinical and non-clinical areas throughout the medical centre. The liaison has a four-part role: to spread awareness and understanding of Ethics Programs among their coworkers; share information regarding ethical dilemmas in their work area with the members of the Ethics Support Service; review ethics activities and needs within their area; and undertake ethics-related projects. This paper lists the notable attributes of the Ethics Liaison Program, and describes the purpose and structure of the programme, its advantages and the challenges to implementing it. The Ethics Liaison Program has helped to make ethics part of the everyday culture at BIDMC, and other medical centres might benefit from the establishment of similar programmes. PMID- 27934773 TI - Are positive experiences of children in non-therapeutic research justifiable research benefits? AB - BACKGROUND: Conducting non-therapeutic research is ethically challenging because participation conveys risks and burden and no health benefit. In this paper, we report the positive experiences of a diverse group of healthy and ill children (6 18 years) who participated in non-therapeutic research studies and discuss whether these positive experiences can justifiably be viewed as benefits. METHODS: We used semistructured interviews from an earlier study about children's experiences in clinical research and did a secondary analysis on the positive experiences of the children in the non-therapeutic studies (N=30). Interviews were analysed using 'thematic' analysis. RESULTS: The interviewed children most frequently mentioned as positive experiences of non-therapeutic research participation helping others and the gratification that comes with it, possible health benefits in the future, having fun and new/increased knowledge about the human body, hospitals and doing research. Less frequently mentioned were getting a present, not having to go to school and getting extra attention from healthcare staff. CONCLUSIONS: Our study shows that children participating in non therapeutic research have various positive experiences while taking part. We argue that some of these justifiably could be taken into the risk-benefit analysis in certain situations or maybe even as a standard part of this analysis. This may help to increase the number of (crucial) non-therapeutic studies with children. PMID- 27934774 TI - The moral agency of institutions: effectively using expert nurses to support patient autonomy. AB - Patient autonomy-with an emphasis on informed consent and the right to refuse treatment-is a cornerstone of modern bioethics. Within discussions about patient autonomy, feminist bioethicists have argued for a relational approach to autonomy. Under a relational framework, we must look beyond the individual moment of choice to include the role relationships and specific contexts can play in supporting or undermining autonomy. Given the day-to-day interactions they have with patients, nurses play a significant role in helping patients understand the nature of their illnesses and make truly informed decisions. However, the skills of expert nurses also support patient autonomy in more subtle ways. Specifically, nurses develop skills of attunement that help them to find subtle ways to support patient autonomy. However, in order to effectively do this, nurses need institutions that support their professional autonomy. In this paper, I look at the ways nurses have been inhibited in their professional autonomy both as a profession and as individual practitioners. I argue that turning our attention to institutions and the role they play in supporting or undermining nurses' autonomy can help promote nurses' professional autonomy and thereby enhance patient autonomy. PMID- 27934775 TI - Real-world effectiveness and predictors of sustained virological response with all-oral therapy in 21,242 hepatitis C genotype-1 patients. AB - BACKGROUND: Predictors of sustained virological response (SVR) to all-oral HCV regimens can inform nuanced treatment decisions. We evaluated effectiveness and identified predictors of SVR for ledipasvir/sofosbuvir +/- ribavirin (LDV/SOF +/ RBV) and ombitasvir/paritaprevir/ritonavir + dasabuvir (OPrD) +/-RBV in patients treated in routine practice. METHODS: Observational, intent-to-treat cohort of 21,142 genotype-1 patients initiating 8 or 12 weeks of LDV/SOF +/-RBV or 12 weeks of OPrD +/-RBV at any Veterans Affairs facility. Multivariate logistic regression models were constructed to model SVR and identify predictors. RESULTS: SVR was 91.2% (9,781/10,720) for LDV/SOF, 89.6% (3,266/3,646) for LDV/SOF+RBV, 91.7% (1,197/1,306) for OPrD and 87.8% (3,365/3,832) for OPrD+RBV. For LDV/SOF +/-RBV, reduced odds of SVR occurred in African-Americans (0.80, 95% CI 0.70, 0.92, P<0.001), body mass index (BMI)<25 (0.77, 95% CI 0.66, 0.90, P<0.001), BMI>=30 (0.77, 95% CI 0.67, 0.89, P<0.001), proton pump inhibitors (PPIs; 0.81, 95% CI 0.71, 0.92, P<0.001), decompensated liver disease (0.58, 95% CI 0.45, 0.74, P<0.001) and FIB4>3.25 (0.60, 95% CI 0.53, 0.69, P<0.001). For OPrD +/-RBV, FIB 4>3.25 negatively predicted SVR (0.72, 95% CI 0.59, 0.88, P<0.001). Detectable 4 week on-treatment HCV RNA>=15 IU/ml reduced SVR odds for both regimens (LDV/SOF +/-RBV OR 0.49, 95% CI 0.41, 0.58, P<0.001; OPrD +/-RBV OR 0.38, 95% CI 0.29, 0.50, P<0.001). Receipt of OPrD+RBV compared to LDV/SOF reduced odds of SVR (OR 0.70, 95% CI 0.62, 0.80, P<0.001). Mental health diagnosis did not impact likelihood of SVR. CONCLUSIONS: The diversity and size of this cohort allowed for extensive examination of regimen-specific predictors of SVR. FIB-4>3.25 and detectable 4-week on-treatment HCV RNA had the greatest negative impact. African American race, low or high BMI, and PPIs negatively impacted odds of SVR for LDV/SOF +/-RBV. Mental health diagnoses did not. PMID- 27934776 TI - Prediction of subjective ratings of emotional pictures by EEG features. AB - OBJECTIVE: Emotion dysregulation is an important aspect of many psychiatric disorders. Brain-computer interface (BCI) technology could be a powerful new approach to facilitating therapeutic self-regulation of emotions. One possible BCI method would be to provide stimulus-specific feedback based on subject specific electroencephalographic (EEG) responses to emotion-eliciting stimuli. APPROACH: To assess the feasibility of this approach, we studied the relationships between emotional valence/arousal and three EEG features: amplitude of alpha activity over frontal cortex; amplitude of theta activity over frontal midline cortex; and the late positive potential over central and posterior mid line areas. For each feature, we evaluated its ability to predict emotional valence/arousal on both an individual and a group basis. Twenty healthy participants (9 men, 11 women; ages 22-68) rated each of 192 pictures from the IAPS collection in terms of valence and arousal twice (96 pictures on each of 4 d over 2 weeks). EEG was collected simultaneously and used to develop models based on canonical correlation to predict subject-specific single-trial ratings. Separate models were evaluated for the three EEG features: frontal alpha activity; frontal midline theta; and the late positive potential. In each case, these features were used to simultaneously predict both the normed ratings and the subject-specific ratings. MAIN RESULTS: Models using each of the three EEG features with data from individual subjects were generally successful at predicting subjective ratings on training data, but generalization to test data was less successful. Sparse models performed better than models without regularization. SIGNIFICANCE: The results suggest that the frontal midline theta is a better candidate than frontal alpha activity or the late positive potential for use in a BCI-based paradigm designed to modify emotional reactions. PMID- 27934778 TI - Self-assembly behaviors of molecular designer functional RADA16-I peptides: influence of motifs, pH, and assembly time. AB - In the current study, we present three designer self-assembling peptides (SAPs) by appending RADA 16-I with epitopes IKVAV, RGD, and YIGSR, which have different net charges and amphiphilic properties at neutral pH. The self-assembly of the designer SAPs is intensively investigated as a function of pH, canion type, and assembly time. The morphologies of the designer SAPs were studied by atomic force microscope. The secondary structure was investigated by circular dichroism. The dynamic viscoelasticity of designer SAP solutions was examined during titration with different alkaline reagents. Our study indicated that both electrostatic and hydrophilic/hydrophobic interactions of the motifs exhibited influences on the self-assembly, consequentially affecting the fiber morphologies and rheological properties. Moreover, NaOH induced a quicker assembly/reassembly of the designer SAPs than Tris because of its strong ionic strength. Therefore, our study gained comprehensive insight into the self-assembling mechanism as references for developing RADA 16-I-based functional SAPs. PMID- 27934779 TI - Formation of p-type ZnO thin film through co-implantation. AB - We present a study on the formation of p-type ZnO thin film through ion implantation. Group V dopants (N, P) with different ionic radii are implanted into chemical vapor deposition grown ZnO thin film on GaN/sapphire substrates prior to thermal activation. It is found that mono-doped ZnO by N+ implantation results in n-type conductivity under thermal activation. Dual-doped ZnO film with a N:P ion implantation dose ratio of 4:1 is found to be p-type under certain thermal activation conditions. Higher p-type activation levels (1019 cm-3) under a wider thermal activation range are found for the N/P dual-doped ZnO film co implanted by additional oxygen ions. From high resolution x-ray diffraction and x ray photoelectron spectroscopy it is concluded that the observed p-type conductivities are a result of the promoted formation of PZn-4NO complex defects via the concurrent substitution of nitrogen at oxygen sites and phosphorus at zinc sites. The enhanced solubility and stability of acceptor defects in oxygen co-implanted dual-doped ZnO film are related to the reduction of oxygen vacancy defects at the surface. Our study demonstrates the prospect of the formation of stable p-type ZnO film through co-implantation. PMID- 27934777 TI - Rodent model for assessing the long term safety and performance of peripheral nerve recording electrodes. AB - OBJECTIVE: In the US alone, there are approximately 185 000 cases of limb amputation annually, which can reduce the quality of life for those individuals. Current prosthesis technology could be improved by access to signals from the nervous system for intuitive prosthesis control. After amputation, residual peripheral nerves continue to convey motor signals and electrical stimulation of these nerves can elicit sensory percepts. However, current technology for extracting information directly from peripheral nerves has limited chronic reliability, and novel approaches must be vetted to ensure safe long-term use. The present study aims to optimize methods to establish a test platform using rodent model to assess the long term safety and performance of electrode interfaces implanted in the peripheral nerves. APPROACH: Floating Microelectrode Arrays (FMA, Microprobes for Life Sciences) were implanted into the rodent sciatic nerve. Weekly in vivo recordings and impedance measurements were performed in animals to assess performance and physical integrity of electrodes. Motor (walking track analysis) and sensory (Von Frey) function tests were used to assess change in nerve function due to the implant. Following the terminal recording session, the nerve was explanted and the health of axons, myelin and surrounding tissues were assessed using immunohistochemistry (IHC). The explanted electrodes were visualized under high magnification using scanning electrode microscopy (SEM) to observe any physical damage. MAIN RESULTS: Recordings of axonal action potentials demonstrated notable session-to-session variability. Impedance of the electrodes increased upon implantation and displayed relative stability until electrode failure. Initial deficits in motor function recovered by 2 weeks, while sensory deficits persisted through 6 weeks of assessment. The primary cause of failure was identified as lead wire breakage in all of animals. IHC indicated myelinated and unmyelinated axons near the implanted electrode shanks, along with dense cellular accumulations near the implant site. Scanning electron microscopy (SEM) showed alterations of the electrode insulation and deformation of electrode shanks. SIGNIFICANCE: We describe a comprehensive testing platform with applicability to electrodes that record from the peripheral nerves. This study assesses the long term safety and performance of electrodes in the peripheral nerves using a rodent model. Under this animal test platform, FMA electrodes record single unit action potentials but have limited chronic reliability due to structural weaknesses. Future work will apply these methods to other commercially-available and novel peripheral electrode technologies. PMID- 27934780 TI - Quantum transport localization through graphene. AB - Localization of atomic defect-induced electronic transport through a single graphene layer is calculated using a full-valence electronic structure description as a function of the defect density and taking into account the atomic-scale deformations of the layer. The elementary electronic destructive interferences leading to Anderson localization are analyzed. The low-voltage current intensity decreases with increasing length and defect density, with a calculated localization length zeta = 3.5 nm for a defect density of 5%. The difference from the experimental defect density of 0.5% required for an oxide surface-supported graphene to obtain the same zeta is discussed, pointing out how interactions of the graphene supporting surface and surface chemical modifications also control electronic transport localization. PMID- 27934781 TI - Ultraviolet responses of a heterojunction Si quantum dot solar cell. AB - We investigated the ultraviolet (UV) responses of a heterojunction Si quantum dot (QD) solar cell consisting of p-type Si-QDs fabricated on a n-type crystalline Si (p-Si-QD/n-c-Si HJSC). The UV responses were compared with a conventional n-type crystalline Si solar cell (n-c-Si SC). The external and internal quantum efficiency results of the p-Si-QD/n-c-Si HJSC exhibited a clear enhancement in the UV responses (300-400 nm), which was not observed in the n-c-Si SC. Based on the results of the cell reflectance and bias-dependent responses, we expect that almost all UV responses occur in the p-Si-QD layer, and the generated carriers can be transported via the Si-QD layer due to the formation of a sufficient electric filed. As a result, a high power conversion efficiency of 14.5% was achieved from the p-Si-QD/n-c-Si HJSC. By reducing the thickness of the n-Si substrate from 650 MUm to 300 MUm, more enhanced power conversion efficiency of 14.8% was obtained which is the highest value among the reported Si-QD based solar cells to date. PMID- 27934782 TI - Can conventional phase-change memory devices be scaled down to single-nanometre dimensions? AB - The scaling potential of 'mushroom-type' phase-change memory devices is evaluated, down to single-nanometre dimensions, using physically realistic simulations that combine electro-thermal modelling with a Gillespie Cellular Automata phase-transformation approach. We found that cells with heater contact sizes as small as 6 nm could be successfully amorphized and re-crystallized (RESET and SET) using moderate excitation voltages. However, to enable the efficient formation of amorphous domes during RESET in small cells (heater contact diameters of 10 nm or less), it was necessary to improve the thermal confinement of the cell to reduce heat loss via the electrodes. The resistance window between the SET and RESET states decreased as the cell size reduced, but it was still more than an order of magnitude even for the smallest cells. As expected, the RESET current reduced as the cells got smaller; indeed, RESET current scaled with the inverse of the heater contact diameter and ultra-small RESET currents of only 19 MUA were achieved for the smallest cells. Our results show that the conventional mushroom-type phase-change cell architecture is scalable and operable in the sub-10nm region. PMID- 27934783 TI - Injectable PAMAM/ODex double-crosslinked hydrogels with high mechanical strength. AB - In situ injectable double-crosslinked hydrogels containing thiol functionalized poly(amido-amine) dendrimers (Gn-PAMAM-NH2-X) and oxidized dextrans (ODex) were prepared under physiological conditions without using potentially cytotoxic cross linkers. The double-crosslinked structure was created by Schiff's base reaction and the formation of disulfide bonds. The morphology of the hydrogels was characterized by scanning electron microscopy. The gelation time, swelling and rheological behaviors of the hydrogels were investigated. We also studied the adhesive strength and cytocompatibility of the hydrogels. The surface amino density, concentration and generation of PAMAM are the main factors affecting the gelation. Relatively high surface amino density contributes to quick gelation, whereas too great a surface amino may lead to the brittleness of the hydrogel. A moderate concentration of PAMAM (10% wt) is suitable for gelation considering its appropriate gelation time. Where surface amino density and the mass concentration of PAMAM-NH2 were identical, PAMAM with less generation was prone to gelation. The injectable PAMAM/ODex hydrogels have double-crosslinked structures and a high crosslinking density which lead to their high storage modulus. The adhesive strength of the hydrogels is about 2.4 times of commercial available fibrin glue and these hydrogels are nontoxic to L929 mouse fibroblast cells. The L929 cells can attach easily to the surface of hydrogels and proliferate on them, which demonstrates these novel injectable hydrogels are biocompatible and have potential uses in tissue engineering. PMID- 27934784 TI - Photoinitiator-free 3D scaffolds fabricated by excimer laser photocuring. AB - Photoinitiator-free fabrication of poly(ethylene glycol) diacrylate (PEGDA) scaffolds is achieved using a novel three-dimensional (3D) printing method called mask projected excimer laser stereolithography (MPExSL). The spatial resolution of photoinitiator-free curing is suitable for 3D layer-by-layer fabrication with a single layer thickness well controllable at tens to hundreds of microns using 248 nm wavelength for the irradiation. The photoinitiator-free scaffolds are superior compared to their counterparts fabricated by using photoinitiator molecules, showing a higher level of biocompatibility. A release of toxic chemicals from the photoinitiator containing scaffolds is proven by cell proliferation tests. In contrast, no toxic release is found from the photoinitiator-free scaffolds, resulting in the very same level of cell proliferation as the control sample. The demonstration of photoinitiator-free PEGDA scaffolds enables the fabrication of 3D scaffolds with the highest level of biocompatibility for both in vitro and in vivo applications. PMID- 27934785 TI - Influence of hydroxyl-terminated polydimethylsiloxane on high-strength biocompatible polycarbonate urethane films. AB - The present study describes a series of novel polycarbonate urethane films that were fabricated via the solution-casting method from 4,4'-methylenebis(cyclohexyl isocyanate) (H12MDI) and 1,4-butanediol (BDO) chain extender as hard segments, poly(1,6-hexanediol)carbonate diols (PCDL) and hydroxyl-terminated polydimethylsiloxane (PDMS) as soft segments, with dibutyltin dilaurate as the catalyst. Varied molar ratios of PDMS (less than 30%) were utilized to enhance the mechanical properties and biocompatibilities. The microstructure and degrees of phase separation were characterized using atomic force microscopy. The chemical structure and surface morphology of the materials were further confirmed by attenuated total reflectance Fourier transform infrared spectroscopy, 1H NMR and 13C NMR, water droplet contact angle and scanning electron microscopy. Thermal properties were measured by differential scanning calorimetry. MTT assay and hemolytic tests were studied for evaluating cellular viability and hemocompatibility of fabricated films using L929 fibroblast cells and adult rabbit blood. The results demonstrated polyurethane films with soft segments partially replaced by PDMS could remarkably improve the biocompatibility while maintaining relatively stable mechanical behavior, making them exciting potential candidates for artificial vessels or other tissue engineering applications. PMID- 27934786 TI - Electrospun polycaprolactone/chitosan scaffolds for nerve tissue engineering: physicochemical characterization and Schwann cell biocompatibility. AB - Electrospun polycaprolactone (PCL)/chitosan (CH) blend scaffolds with different CH weight ratios were prepared to study the effect of scaffold composition on its physicochemical and biological properties. Scanning electron microscopy showed bead-free homogeneous randomly arranged nanofibers whose average diameter decreased from 240 to 110 nm with increasing CH content. The infrared spectra of the PCL/CH blends were very similar to the neat PCL scaffold. Energy-dispersive x ray spectroscopy analysis confirmed the presence of carbon, oxygen and nitrogen in the scaffolds, although fluorine-from chemicals used as solvent-was also detected. The water contact angle decreased from 113 degrees (for PCL) to 52 degrees with increasing chitosan content. The biocompatibility was evaluated using fibroblasts and Schwann cell (SC) cultures. Cytotoxicity assays using fibroblasts demonstrated that electrospun scaffolds could be considered as non cytotoxic material. Biocompatibility tests also revealed that the SCs adhered to scaffolds with different CH content, although the formulation containing CH at 5 wt% exhibited the highest proliferation on days 1 and 3. A better cell distribution was observed in the CH/PCL blends than in the neat PCL or CH scaffolds, where the cells were clustered. Immunochemistry analysis confirmed that SCs expressed the specific p75 cell marker on the scaffolds, suggesting that PCL/CH scaffolds would be good candidates for peripheral nerve tissue engineering. PMID- 27934787 TI - Long-term biological performance of injectable and degradable calcium phosphate cement. AB - Enhancing degradation of poorly degrading injectable calcium phosphate (CaP) cements (CPCs) can be achieved by adding poly(lactic-co-glycolic acid) (PLGA) microparticles, generating porosity after polymer degradation. CPC-PLGA has proven to be biodegradable, although its long-term biological performance is still unknown. Optimization of injectability could be achieved via addition of carboxymethyl cellulose (CMC). Here, we evaluated the long-term in vivo performance of CPC-PLGA with or without the lubricant CMC in comparison to the devitalized bovine bone mineral (DBBM) predicate device Bio-Oss(r). Rabbit femoral bone defects were injected with a CPC-formulation or filled with Bio Oss(r) granules. Samples were retrieved at 6 and 26 weeks. Material degradation for Bio-Oss(r) was marginal, starting with 57% material remnants at implantation, 49% at 6 weeks, and 35% at 26 weeks, respectively. In contrast, CPC-PLGA and CPC PLGA-CMC showed significant material degradation, starting with 100% material remnants at implantation, 56 and 78% at 6 weeks, and 8 and 21% at 26 weeks. Bone formation showed to be rapid for Bio-Oss(r), with 24% at 6 weeks, and a similar value (27%) at 26 weeks. Both CPC-PLGA and CPC-PLGA-CMC showed a continuous temporal increase in bone formation, with 13 and 6% at 6 weeks, and 44 and 32% at 26 weeks. This study showed that CPC-PLGA induces favorable bone responses with >90% degradation and >40% new bone formation after an implantation period of 26 weeks. PMID- 27934788 TI - Reduced antibacterial property of metallic magnesium in vivo. AB - Magnesium and its alloys have drawn interest as antibacterial biomaterials, owing to their ability to alkalize the surrounding medium during degradation. The antibacterial effect of pure Mg and Mg alloys in vitro has previously been reported. However, the antibacterial property of Mg in vivo might be different because of the apparently dissimilar corrosion characteristics. In this study, pure Mg rods were implanted and bacterial suspension were injected into rat femurs to investigate the antibacterial property of Mg in vivo. The results showed that contrary to the high antibacterial rate in vitro, Mg exhibited a dramatic drop in antibacterial effect in vivo. Bacteria proliferated on the surface of the Mg rods as well as in the femur. Inflammatory cells filled cavities in the cortical bone of the femur, which was demonstrated by histological and micro-CT examination after 2 and 4 weeks of implantation. It is suggested that a reduced corrosion rate in vivo would result in insufficient pH value. In addition, the deposition layer would prevent further corrosion of Mg and provide a favorite site for bacteria adhesion. Hence, the dramatically reduced antibacterial property of Mg needs to be noticed when it is used as a biomaterial. PMID- 27934790 TI - Abdomino-endoscopic perineal excision of the rectum for benign and malignant pathology: Technique considerations for true transperineal verus transanal total mesorectal excision endoscopic proctectomy. AB - PURPOSE: Transanal minimally invasive surgery using single port instrumentation is now well described for the performance of total mesorectal excision with restorative colorectal/anal anastomosis most-often in conjunction with transabdominal multiport assistance. While non-restorative abdomino-endoscopic perineal excision of the anorectum is conceptually similar, it has been less detailed in the literature. METHODS: Consecutive patients undergoing non restorative ano-proctectomy including a transperineal endoscopic component were analysed. All cases commenced laparoscopically with initial medial to lateral mobilisation of any left colon and upper rectum. The lower anorectal dissection started via an intersphincteric or extrasphincteric incision for benign and malignant pathology, respectively, and following suture closure and circumferential mobilisation of the anorectum, a single port (GelPOINT Path, Applied Medical) was positioned allowing the procedure progress endoscopically in all quadrants up to the cephalad dissection level. Standard laparoscopic instrumentation was used. Specimens were removed perineally. RESULTS: Of the 13 patients (median age 55 years, median BMI 28.75 kg/m2, median follow-up 17 months, 6 males), ten needed completion proctectomy for ulcerative colitis following prior total colectomy (three with concomitant parastomal hernia repair) while three required abdominoperineal resection for locally advanced rectal cancer following neoadjuvant chemoradiotherapy. Median operative time was 190 min, median post-operative discharge day was 7. Eleven specimens were of high quality. Four patients developed perineal wound complications (one chronic sinus, two abscesses needing drainage) within median 17-month follow-up. CONCLUSION: Convergence of transabdominal and transanal technology and technique allows accuracy in combination operative performance. Nuanced appreciation of transperineal operative access should allow specified standardisation and innovation. PMID- 27934789 TI - A 3D map of the hindlimb motor representation in the lumbar spinal cord in Sprague Dawley rats. AB - OBJECTIVE: Spinal cord injury (SCI) is a devastating neurological trauma with a prevalence of about 282 000 people living with an SCI in the United States in 2016. Advances in neuromodulatory devices hold promise for restoring function by incorporating the delivery of electrical current directly into the spinal cord grey matter via intraspinal microstimulation (ISMS). In such designs, detailed topographic maps of spinal cord outputs are needed to determine ISMS locations for eliciting hindlimb movements. The primary goal of the present study was to derive a topographic map of functional motor outputs in the lumbar spinal cord to hindlimb skeletal muscles as defined by ISMS in a rat model. APPROACH: Experiments were carried out in nine healthy, adult, male, Sprague Dawley rats. After a laminectomy of the T13-L1 vertebrae and removal of the dura mater, a four shank, 16-channel microelectrode array was inserted along a 3D (200 um) stimulation grid. Trains of three biphasic current pulses were used to determine evoked movements and electromyographic (EMG) activity. Via fine wire EMG electrodes, stimulus-triggered averaging (StTA) was used on rectified EMG data to determine response latency. MAIN RESULTS: Hindlimb movements were elicited at a median current intensity of 6 uA, and thresholds were significantly lower in ventrolateral sites. Movements typically consisted of whole leg, hip, knee, ankle, toe, and trunk movements. Hip movements dominated rostral to the T13 vertebral segment, knee movements were evoked at the T13-L1 vertebral junction, while ankle and digit movements were found near the rostral L1 vertebra. Whole leg movements spanned the entire rostrocaudal region explored, while trunk movements dominated medially. StTAs of EMG activity demonstrated a latency of ~4 ms. SIGNIFICANCE: The derived motor map provides insight into the parameters needed for future neuromodulatory devices. PMID- 27934791 TI - Comparison of single incision and multi incision diagnostic laparoscopy on evaluation of diaphragmatic status after left thoracoabdominal penetrating stab wounds. AB - AIM: Single incision diagnostic laparoscopy (SIDL) may be an alternative procedure to multi-incision diagnostic laparoscopy (MDL) for penetrating thoracoabdominal stab wounds. The purpose of this study is sharing our experience and comparing two techniques for diaphragmatic status. MATERIALS AND METHODS: Medical records of 102 patients with left thoracoabdominal penetrating stab injuries who admitted to Istanbul School of Medicine, Trauma and Emergency Surgery Clinic between February 2012 and April 2016 were examined. The patients were grouped according to operation technique. Patient records were retrospectively reviewed for data including, age, sex, length of hospital stay, diaphragm injury rate, surgical procedure, operation time and operation time with wound repair, post-operative complications and accompanying injuries. RESULTS: The most common injury location was the left anterior thoracoabdomen. SIDL was performed on 26 patients. Nine (34.6%) of the 26 patients had a diaphragm injury. Seventy-six patients underwent MDL. Diaphragmatic injury was detected in 20 (26.3%) of 76 patients. The average operation time and post-operative complications were similar; there was no statistically significant difference between MDL and SIDL groups. CONCLUSION: SIDL can be used as a safe and feasible procedure in the repair of a diaphragm wounds. SIDL may be an alternative method in the diagnosis and treatment of these patients. PMID- 27934792 TI - The opportunities & challenges in delivering oral cholera vaccines. PMID- 27934793 TI - Altered cord blood lipid profile, insulin resistance & growth restriction during the perinatal period & its potential role in the risk of developing cardiovascular disease later in life. PMID- 27934794 TI - Angiotensin receptor blockers & endothelial dysfunction: Possible correlation & therapeutic implications. AB - The endothelium is one of the most important constituents of vascular homeostasis, which is achieved through continual and balanced production of different relaxing and contractile factors. When there is a pathological disturbance in release of these products, endothelial dysfunction (ED) will probably occur. ED is considered to be the initial step in the development of atherosclerosis. This pathological activation and inadequate functioning of endothelial cells was shown to be to some extent a reversible process, which all together resulted in increased interest in investigation of different beneficial treatment options. To this point, the pharmacological approach, including for example, the use of angiotensin-converting enzyme inhibitors or statins, was clearly shown to be effective in the improvement of ED. One of many critical issues underlying ED represents instability in the balance between nitric oxide and angiotensin II (Ang II) production. Considering that Ang II was confirmed to be important for the development of ED, the aim of this review article was to summarize the findings of up to date clinical studies associated with therapeutic application of angiotensin receptor blockers and improvement in ED. In addition, it was of interest to review the pleiotropic actions of angiotensin receptor blockers linked to the improvement of ED. The prospective, randomized, double blind, placebo or active-controlled clinical trials were identified and selected for the final evaluation. PMID- 27934795 TI - Current global status & impact of human papillomavirus vaccination: Implications for India. AB - This review addresses the effectiveness and safety of human papillomavirus (HPV) vaccines, the current status of its introduction in the National Immunization Programmes (NIPs) and its relevance to India, which contributes a fifth of the global burden of cervical cancer. The vast literature on efficacy, acceptability and safety of HPV vaccination and its impact after population level introduction was reviewed and discussed. The efficacy of HPV vaccines in preventing high-grade precancerous lesions caused by vaccine-targeted HPV infections was 90 per cent or higher in HPV naomicronve women in randomized clinical trials. Two doses at 6 or 12 months apart are recommended for 9-14 yr old girls and three doses over six months to one year period for those aged above 15 yr. More than 80 countries or territories have introduced HPV vaccination in their NIPs, of which 33 are low- and middle-income countries (LMICs); in addition, 25 LMICs have introduced pilot programmes before a phased national expansion. Significant reductions in the frequency of HPV 16 and 18 infections, genital warts and cervical premalignant lesions in vaccinated cohorts and herd immunity in general populations have been reported from countries that introduced vaccination in NIPs as early as 2007. More than 280 million doses of HPV vaccines have been administered worldwide with the excellent safety profile with no serious adverse events linked to it. The high burden of cervical cancer and the high efficacy and safety of HPV vaccination justify its introduction in the Indian NIP at the earliest possibility to substantially reduce the cervical cancer burden in future. PMID- 27934796 TI - PLGA-loaded nanomedicines in melanoma treatment: Future prospect for efficient drug delivery. AB - Current treatment methods for melanoma have some limitations such as less target specific action, severe side effects and resistance to drugs. Significant progress has been made in exploring novel drug delivery systems based on suitable biochemical mechanisms using nanoparticles ranging from 10 to 400 nm for drug delivery and imaging, utilizing their enhanced penetration and retention properties. Poly-lactide-co-glycolide (PLGA), a copolymer of poly-lactic acid and poly-glycolic acid, provides an ideally suited performance-based design for better penetration into skin cells, thereby having a greater potential for the treatment of melanoma. Moreover, encapsulation protects the drug from deactivation by biological reactions and interactions with biomolecules, ensuring successful delivery and bioavailability for effective treatment. Controlled and sustained delivery of drugs across the skin barrier that otherwise prohibits entry of larger molecules can be successfully made with adequately stable biocompatible nanocarriers such as PLGA for taking drugs through the small cutaneous pores permitting targeted deposition and prolonged drug action. PLGA is now being extensively used in photodynamic therapy and targeted therapy through modulation of signal proteins and drug-DNA interactions. Recent advances made on these nanomedicines and their advantages in the treatment of skin melanoma are highlighted and discussed in this review. PMID- 27934797 TI - Small-for-gestational-age versus appropriate-for-gestational-age: Comparison of cord blood lipid profile & insulin levels in term newborns (SAGA-ACT study). AB - BACKGROUND & OBJECTIVES: The genesis of atherosclerotic lesions, a major cardiovascular risk factor starts in the early stage of life. If the premature development of cardiovascular risk factors can be anticipated during childhood, cardiovascular events can be prevented effectively by taking appropriate measures. This study was carried out to assess the role of in utero malnutrition in cardiovascular disease development by comparing cord blood lipid profiles and serum insulin levels between small-for-gestational-age (SGA) and appropriate-for gestational-age (AGA) term newborns. METHODS: Consecutive full-term infants who were born between June 20 and August 19, 2013, at the Obstetric Unit of a Hospital at Secunderabad, India, were enrolled in this study. Participating newborns were divided into SGA group (n = 51; test group) and AGA group (n = 52; control group) based on their gestational age and body weight. Cord blood lipid profile and insulin levels were compared between these two groups. RESULTS: As compared to the newborns in AGA group, SGA group of newborns had significantly (P<0.01) higher levels of cholesterol, triglyceride and low-density lipoprotein. No difference was observed between the groups for high-density lipoprotein and insulin levels. Mild and moderate anaemia was observed among mothers of both groups, while severe anaemia was seen in mothers of SGA group only. INTERPRETATION & CONCLUSIONS: SGA newborns exhibited elevated lipid profiles as compared to AGA newborns. Hence, SGA newborns should be closely monitored for cardiovascular morbidities during childhood, adolescence and early adult life. PMID- 27934798 TI - Identification of a novel collagen type IV alpha-4 (COL4A4) mutation in a Chinese family with autosomal dominant Alport syndrome using exome sequencing. AB - BACKGROUND & OBJECTIVES: Alport syndrome (AS) is an inherited disorder characterized by glomerulonephritis and end-stage renal disease (ESRD). The aim of this study was to identify the gene responsible for the glomerulopathy in a Chinese family with autosomal dominant AS using exome sequencing. METHODS: A 4 generation, 30-member Chinese Han family was enrolled in this study. Exome sequencing was conducted in the proband of the family, and then direct sequencing was performed in family members of the pedigree and 100 normal controls. RESULTS: A novel frameshift mutation, c.3213delA (p.Gly1072GlufsFNx0169), in the collagen type IV alpha-4 gene (COL4A4) was found to be the genetic cause. Neither sensorineural hearing loss nor ocular abnormalities were present in the patients of this family. Other clinical features, such as age of onset, age of ESRD occurring and disease severity, varied among the patients of this family. INTERPRETATION & CONCLUSIONS: A novel frameshift mutation, c.3213delA (p.Gly1072GlufsFNx0169) in the COL4A4 gene, was identified in the Chinese pedigree with autosomal dominant AS. Our findings may provide new insights into the cause and diagnosis of AS and also have implications for genetic counselling. PMID- 27934799 TI - Subtelomeric rearrangements in Indian children with idiopathic intellectual disability/developmental delay: Frequency estimation & clinical correlation using fluorescence in situ hybridization (FISH). AB - BACKGROUND & OBJECTIVES: Subtelomeres are prone to deleterious rearrangements owing to their proximity to unique sequences on the one end and telomeric repetitive sequences, which increase their tendency to recombine, on the other end. These subtelomeric rearrangements resulting in segmental aneusomy are reported to contribute to the aetiology of idiopathic intellectual disability/developmental delay (ID/DD). We undertook this study to estimate the frequency of subtelomeric rearrangements in children with ID/DD. METHODS: One hundred and twenty seven children with idiopathic ID/DD were tested for subtelomeric rearrangements using karyotyping and FISH. Blood samples were cultured, harvested, fixed and GTG-banded using the standard protocols. RESULTS: Rearrangements involving the subtelomeres were observed in 7.8 per cent of the tested samples. Detection of rearrangements visible at the resolution of the karyotype constituted 2.3 per cent, while those rearrangements detected only with FISH constituted 5.5 per cent. Five deletions and five unbalanced translocations were detected. Analysis of parental samples wherever possible was informative regarding the inheritance of the rearrangement. INTERPRETATION & CONCLUSIONS: The frequency of subtelomeric rearrangements observed in this study was within the reported range of 0-35 per cent. All abnormal genotypes were clinically correlated. Further analysis with array technologies presents a future prospect. Our results suggest the need to test individuals with ID/DD for subtelomeric rearrangements using sensitive methods such as FISH. PMID- 27934800 TI - Effect of a polyherbal formulation cream on diabetic neuropathic pain among patients with type 2 diabetes - A pilot study. AB - BACKGROUND & OBJECTIVES: Painful diabetic neuropathy is a common complication of diabetes and can severely limit patients' daily functions. The aim of this pilot study was to evaluate the safety and effect of using a polyherbal formulation in reducing the symptoms of diabetic neuropathic pain in comparison with placebo among patients with type 2 diabetes. METHODS: A total of 50 (M:F = 33:17) consecutive type 2 diabetes patients with painful diabetic neuropathy were enrolled in this study. All these patients had either two or more symptoms of diabetic neuropathy such as pain, burning and pricking sensations and numbness in their feet. They were randomly assigned to two groups: group 1 (n = 26) patients were treated with polyherbal formulation cream and group 2 (n = 24) patients were administered placebo. The patients were followed up for six months. Changes in the symptoms of painful diabetic neuropathy of each patient were recorded at baseline, third and sixth month using the Diabetic Neuropathic Score. RESULTS: The mean age of the patients, duration of diabetes and glycated haemoglobin (HbA 1c ) were similar in both groups at baseline. During follow up visits, there was a decrease in the HbA 1c levels in the study and control groups. The symptoms of painful diabetic neuropathy were also similar in both groups at baseline. A significant decrease in symptoms of neuropathic pain was observed among the group of patients treated with polyherbal formulation cream (76.9 per cent) compared to the placebo-treated group (12.5 per cent) (P<0.001), at the end of the final follow up. INTERPRETATION & CONCLUSIONS: In this pilot study polyherbal formulation cream was found to be effective as well as safe to treat painful diabetic neuropathy. However, its long term use needs to be evaluated for any further effectiveness and side effects. PMID- 27934801 TI - Derivation & validation of glycosylated haemoglobin (HbA 1c ) cut-off value as a diagnostic test for type 2 diabetes in south Indian population. AB - BACKGROUND & OBJECTIVES: Glycosylated haemoglobin (HbA 1c ) has been in use for more than a decade, as a diagnostic test for type 2 diabetes. Validity of HbA 1c needs to be established in the ethnic population in which it is intended to be used. The objective of this study was to derive and validate a HbA 1c cut-off value for the diagnosis of type 2 diabetes in the ethnic population of Rayalaseema area of south India. METHODS: In this cross-sectional study, consecutive patients suspected to have type 2 diabetes underwent fasting plasma glucose (FPG) and 2 h post-load plasma glucose (2 h-PG) measurements after a 75 g glucose load and HbA 1c estimation. They were classified as having diabetes as per the American Diabetes Association criteria [(FPG >=7 mmol/l (>=126 mg/dl) and/or 2 h-PG >=11.1 mmol/l (>=200 mg/dl)]. In the training data set (n = 342), optimum cut-off value of HbA 1c for defining type 2 diabetes was derived by receiver-operator characteristic (ROC) curve method using oral glucose tolerance test results as gold standard. This cut-off was validated in a validation data set (n = 341). RESULTS: On applying HbA 1c cut-off value of >6.3 per cent (45 mmol/mol) to the training data set,sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for diagnosing type 2 diabetes were calculated to be 90.6, 85.2, 80.8 and 93.0 per cent, respectively. When the same cut-off value was applied to the validation data set, sensitivity, specificity, PPV and NPV were 88.8 , 81.9, 74.0 and 92.7 per cent, respectively, although the latter were consistently smaller than the proportions for the training data set, the differences being not significant. INTERPRETATION & CONCLUSIONS: HbA 1c >6.3 per cent (45 mmol/mol) appears to be the optimal cut-off value for the diagnosis of type 2 diabetes applicable to the ethnic population of Rayalaseema area of Andhra Pradesh state in south India. PMID- 27934802 TI - Circulating heat shock protein mRNA profile in gestational hypertension, pre eclampsia & foetal growth restriction. AB - BACKGROUND & OBJECTIVES: Heat shock proteins (Hsp) are ubiquitously distributed phylogenetically conserved molecules that regulate cellular homeostasis and maintain the integrity and function of cellular proteins. Increased levels of Hsp in maternal circulation have been shown to be associated with increased risk of pregnancy related complications. The objective of this study was to explore extracellular Hsp mRNA levels in maternal circulation and quantified Hsp27, Hsp60, Hsp70, Hsp90 and Hsp70 binding protein 1 (HspBP1) mRNAs in maternal plasma samples using real-time reverse-transcriptase polymerase chain reaction. METHODS: Pregnancies with gestational hypertension (GH) (n = 33), pre-eclampsia (PE) with or without foetal growth restriction (FGR) (n = 78) and FGR (n = 25) were involved in the study. Hsp gene expression was analysed in relation to the severity of the disease with respect to the degree of clinical signs, requirements for the delivery and Doppler ultrasound parameters. RESULTS: Upregulation of Hsp70 was observed in patients with mild and severe PE (P = 0.004 and P = 0.005, respectively) and in pregnancies complicated with PE delivering before and after 34 wk of gestation regardless of the degree of clinical signs (P = 0.015 and P = 0.009, respectively). No difference in the expression of other Hsp genes among the studied groups was observed. No association between Hsp gene expression and Doppler ultrasonography parameters was found. INTERPRETATION & CONCLUSIONS: These data support that maternal circulation can reflect both maternal and foetal pathologic conditions. Hsp70 represents the sole plasmatic marker, and increased Hsp70 mRNA levels reflect maternal and placental stress response to pregnancy-related complications such as GH and PE, irrespective of the severity of the disease. PMID- 27934803 TI - Chronic vitamin A-enriched diet feeding regulates hypercholesterolaemia through transcriptional regulation of reverse cholesterol transport pathway genes in obese rat model of WNIN/GR-Ob strain. AB - BACKGROUND & OBJECTIVES: Hepatic scavenger receptor class B1 (SR-B1), a high density lipoprotein (HDL) receptor, is involved in the selective uptake of HDL associated esterified cholesterol (EC), thereby regulates cholesterol homoeostasis and improves reverse cholesterol transport. Previously, we reported in euglycaemic obese rats (WNIN/Ob strain) that feeding of vitamin A-enriched diet normalized hypercholesterolaemia, possibly through hepatic SR-B1-mediated pathway. This study was aimed to test whether it would be possible to normalize hypercholesterolaemia in glucose-intolerant obese rat model (WNIN/GR/Ob) through similar mechanism by feeding identical vitamin A-enriched diet. METHODS: In this study, 30 wk old male lean and obese rats of WNIN/GR-Ob strain were divided into two groups and received either stock diet or vitamin A-enriched diet (2.6 mg or 129 mg vitamin A/kg diet) for 14 wk. Blood and other tissues were collected for various biochemical analyses. RESULTS: Chronic vitamin A-enriched diet feeding decreased hypercholesterolaemia and normalized abnormally elevated plasma HDL cholesterol (HDL-C) levels in obese rats as compared to stock diet-fed obese groups. Further, decreased free cholesterol (FC) and increased esterified cholesterol (EC) contents of plasma cholesterol were observed, which were reflected in higher EC to FC ratio of vitamin A-enriched diet-fed obese rats. However, neither lecithin-cholesterol acyltransferase (LCAT) activity of plasma nor its expression (both gene and protein) in the liver were altered. On the contrary, hepatic cholesterol levels significantly increased in vitamin A enriched diet fed obese rats. Hepatic SR-B1 expression (both mRNA and protein) remained unaltered among groups. Vitamin A-enriched diet fed obese rats showed a significant increase in hepatic low-density lipoprotein receptor mRNA levels, while the expression of genes involved in HDL synthesis, namely, ATP-binding cassette protein 1 (ABCA1) and apolipoprotein A-I, were downregulated. No such response was seen in vitamin A-supplemented lean rats as compared with their stock diet-fed lean counterparts. INTERPRETATION & CONCLUSIONS: Chronic vitamin A enriched diet feeding decreased hypercholesterolaemia and normalized HDL-C levels, possibly by regulating pathways involved in HDL synthesis and degradation, independent of hepatic SR-B1 in this glucose-intolerant obese rat model. PMID- 27934804 TI - Use of hydrogen peroxide vapour & plasma irradiation in combination for quick decontamination of closed chambers. AB - BACKGROUND & OBJECTIVES: Various conventional methods such as gaseous, vapour and misting systems, fogging, manual spray and wipe techniques employing a number of chemical agents are used for decontamination of enclosed spaces. Among all these methods, use of aerosolized formaldehyde is the most preferred method due to cost effectiveness and practical aspects. However, being extremely corrosive in nature generating very irritating fumes and difficulty in maintaining a high level of gas concentration, many laboratories prefer the vaporization of hydrogen peroxide (H 2 O 2 ) as an alternative. We present here the results of using H 2 O 2 vapour in combination with plasma irradiation for quick decontamination of closed chambers. METHODS: The present study describes a decontamination method, using plasma irradiation in combination with H 2 O 2 (5%). Effect of plasma irradiation and H 2 O 2 on the viability of bacterial spores (Bacillus subtilis), Chikungunya and Kyasanur Forest Disease viruses was assessed. RESULTS: Data suggest that with the combination of H 2 O 2 vapour and plasma irradiation, within short time (three minutes), decontamination of surfaces and space volume could be achieved. Although it showed damage of spores present on the strips, it did not show any penetration power. INTERPRETATION & CONCLUSIONS: The results were encouraging, and this method was found to be efficient for achieving surface sterilization in a short time. This application may be useful in laboratories and industries particularly, those working on clean facility concept following good laboratory and manufacturing practices. PMID- 27934805 TI - Comparison of clinical effects of beclomethasone dipropionate & budesonide in treatment of children with mild persistent asthma: A double-blind, randomized, controlled study. AB - BACKGROUND & OBJECTIVES: Various inhaled corticosteroids (ICSs) are available to control the symptoms of asthma. Although beclomethasone dipropionate (BDP) and budesonide (BUD) are one of the oldest ICSs, their wide availability and low cost make them attractive options in developing countries. Due to lack of consensus on which of the two drugs is better for controlling mild persistent asthma, we undertook this study to compare the efficacy of these two drugs by measuring the change in percentage predicted forced expiratory volume in one second (FEV 1 ) from baseline in children with mild persistent asthma. METHODS: A double-blind, randomized, parallel group study was conducted in children 7-15 yr of age with newly diagnosed asthma. Of the 85 cases of mild persistent asthma, 42 received BUD while 43 received BDP at a dose of 400 ug/day using pressurized metered-dose inhaler with valved spacer for two months. The outcomes measured were change in FEV 1 , symptom scores and side effects. RESULTS: There was a significant (P < 0.05) improvement in FEV 1 in BUD group (98.43 +/- 4.63%) than in BDP group (95.65 +/- 5.66%) at the end of two months of treatment. The mean symptom scores in BUD group (0.28 +/- 1.22) and BDP group (0.43 +/- 1.52) were comparable after two months. No side effects were seen in either group. INTERPRETATION & CONCLUSIONS: FEV 1 was significantly greater in BUD group than BDP group. Improvement in symptoms and incidence of side effects were similar. Our findings indicate that both BDP and BUD can be used effectively in the management of children with mild persistent asthma. [CTRI No: CTRI/2013/03/003495]. PMID- 27934806 TI - Molecular appraisal of intestinal parasitic infection in transplant recipients. AB - BACKGROUND & OBJECTIVES: Diarrhoea is the main clinical manifestation caused by intestinal parasitic infections in patients, with special reference to transplant recipients who require careful consideration to reduce morbidity and mortality. Further, molecular characterization of some important parasites is necessary to delineate the different modes of transmission to consider appropriate management strategies. We undertook this study to investigate the intestinal parasitic infections in transplant recipients with or without diarrhoea, and the genotypes of the isolated parasites were also determined. METHODS: Stool samples from 38 transplant recipients comprising 29 post-renal, two liver and seven bone marrow transplant (BMT) recipients presenting with diarrhoea and 50 transplant recipients (42 post-renal transplant, eight BMT) without diarrhoea were examined for the presence of intestinal parasites by light microscopy using wet mount, modified Ziehl-Neelsen staining for intestinal coccidia and modified trichrome staining for microsporidia. Genotypes of Cryptosporidium species were determined by multilocus genotyping using small subunit ribosomal (SSUrRNA), Cryptosporidium oocyst wall protein (COWP) and dihydrofolate reductase (DHFR) as the target genes. Assemblage study for Giardia lamblia was performed using triose phosphate isomerase (TPI) as the target gene. Samples were also screened for bacterial, fungal and viral pathogens. RESULTS: The parasites that were detected included Cryptosporidium species (21%, 8/38), Cystoisospora (Isospora) belli (8%, 3), Cyclospora cayetanensis (5%, 2), G. lamblia (11%, 4), Hymenolepis nana (11%, 4), Strongyloides stercoralis (3%, 1) and Blastocystis hominis (3%, 1). Multilocus genotyping of Cryptosporidium species at SSUrRNA, COWP and DHFR loci could detect four isolates of C. hominis; two of C. parvum, one of mixed genotype and one could not be genotyped. All the C. hominis isolates were detected in adult post renal transplant (PRT) recipients, whereas the C. parvum isolates included a child with BMT and an adult with PRT. Clostridium difficle, cytomegalovirus and Candida albicans were found in 2, 3 and 2 patients, respectively. INTERPRETATION & CONCLUSIONS: In the present study, C. hominis was observed as an important parasite causing intestinal infections in transplant recipients. Multilocus genotyping of Cryptosporidium species could detect four isolates of C. hominis; two of C. parvum, one of mixed genotype and one could not be genotyped. Genotyping of G. lamblia revealed that assemblage B was most common. PMID- 27934807 TI - Transmission of mutans streptococci in mother-child pairs. AB - BACKGROUND & OBJECTIVES: Dental caries is an infectious, transmissible disease. Maternal transfer of mutans streptococci (MS) has been a subject of research. The aim of this study was to evaluate the transmission of MS from mother to children through genetic analysis. METHODS: Thirty mother-child pairs were included and divided into three groups according to the age of the children. Saliva samples were collected and MS colonies from each mother-child pair were isolated. After inoculation and incubation, MS colonies were submitted to amplification technique by polymerase chain reaction (PCR) for identification and arbitrarily primed PCRs (AP-PCRs) to determine various MS genotypes. RESULTS: From birth to six months of age, 30 per cent of children exhibited MS colonization, and by the age of 30 months, 100 per cent harboured the bacteria (P < 0.001). Factors associated with MS colonization were eruption of teeth (P < 0.001), feeding habits with mean colony count being significantly lower in breast-fed as compared to bottle-fed children (P < 0.001) and a significant association between mean MS count of child and mother's practice of sharing spoon with child (P < 0.001). The AP-PCR fingerprinting profile analysis showed 17 MS groups (clusters) containing identical or highly related isolates in mother-child pairs with a high level of similarity (77.27 %). INTERPRETATION & CONCLUSIONS: The presence of matching MS genotypes suggested vertical transmission from mothers to children. Feeding habits, gum cleaning and number of erupted teeth in children had significant effect on MS colonization. There is a need to develop strategies to present MS colonization in children. PMID- 27934808 TI - Presence of metallo-beta-lactamases (MBL), extended-spectrum beta-lactamase (ESBL) & AmpC positive non-fermenting Gram-negative bacilli among Intensive Care Unit patients with special reference to molecular detection of blaCTX-M & blaAmpC genes. AB - BACKGROUND & OBJECTIVES: Non-fermenting Gram-negative bacilli (NFGNB) including Pseudomonas aeruginosa and Acinetobacter baumannii have been implicated in a variety of infections, particularly in the Intensive Care Units (ICUs). This study was aimed to overview the burden of multidrug-resistant NFGNB causing infections in ICU and also to assess the occurrence of extended-spectrum beta lactamases (ESBLs), AmpC and metallo-beta-lactamases (MBLs) among these isolates. METHODS: Bacterial culture, identification and antibiotic susceptibility were carried out. ESBLs and AmpC were detected both phenotypically and genotypically. MBL was detected by modified Hodge and imipenem-ethylenediaminetetraacetic acid double-disc synergy test. RESULTS: NFGNB represented 45 (37%) of total 121 Gram negative isolates. Multidrug resistance was observed in 66.9 per cent and 72.5 per cent isolates of P. aeruginosa and A. baumannii, respectively. Detection by phenotypic methods showed presence of ESBL, AmpC and MBL in 21.4, 51.1 and 21.4 per cent isolates, respectively. When detected genotypically by polymerase chain reaction, ESBL and AmpC were detected in 21.4 and 41.4 per cent of NFGNB isolates, respectively. BlaCTX-M (21.4%) was the most prevalent gene responsible for ESBL production. INTERPRETATION & CONCLUSIONS: Most of the NFGNB isolated from ICU patients were multidrug-resistant and producers of ESBL, AmpC and MBL. A regular surveillance is required to detect ESBL, AmpC and MBL producers, especially in ICU patients. PMID- 27934809 TI - Wilms' tumour 1 gene mutations in south Indian children with steroid-resistant nephrotic syndrome. AB - BACKGROUND & OBJECTIVES: Clinically, nephrotic syndrome (NS) is a diverse group of symptoms; about 20 per cent of NS cases are resistant to steroid treatment, and within ten years they progress to end-stage renal disease. The present study was undertaken to identify the mutations of Wilms' tumour 1 (WT1) gene in steroid resistant NS (SRNS) children. METHODS: A total of 173 children with SRNS and 100 children in the control group were enrolled in the study. DNA extraction was done, screened for WT1 (exons 8 and 9) gene amplified by polymerase chain reaction and direct sequencing. Karyotype analyses were done for WT1 mutation cases. RESULTS: WT1 mutations were found in three of 173 SRNS cases (2 girls, 1 boy). All of them had intron 9 (IVS 9 + 4 C>T, 2; IVS + 5 G>A, 1) mutation. Of these three cases, one had familial and another two had sporadic history. Renal histology analysis showed two cases with focal segmental glomerulosclerosis (FSGS) and they had external female genitalia but 46,XY karyotype. Both of them had streak gonads. Of the three cases, one expired. INTERPRETATION & CONCLUSIONS: The findings of the present study indicate that all females with SRNS-FSGS should be screened for WT1 gene mutation to diagnose whether they have FS for possible gonadectomy. PMID- 27934810 TI - Effect of hypertension at presentation on prognosis in patients with dilated cardiomyopathy presenting with normal renal angiogram. AB - BACKGROUND & OBJECTIVES: Dilated cardiomyopathy (DCM) is a progressive disease of heart with systolic and diastolic dysfunction carrying a poor long-term prognosis. The prognostic index and predictors of mortality are considered to be useful in guiding the treatment. This study was undertaken to evaluate the effects of hypertension at presentation on prognosis in patients with DCM presenting with normal renal and coronary angiogram. METHODS: An observational, analytical, non-interventional and a combination of retrospective and prospective study was conducted in patients between 15 and 75 yr of age with DCM having on and off symptoms while receiving treatment in a cardiology outpatient department for more than a year. Sixty patients who fulfilled the inclusion criteria were enrolled in the study. Left ventricular systolic and diastolic functions were assessed by echocardiography along with New York Heart Association (NYHA) functional class prospectively and at baseline retrospectively. Patients were grouped into two categories: DCM with hypertension at presentation (HTNAP, Category 1) and DCM without hypertension at presentation (NHTNAP, Category 2). The primary end-points were the number and dose of parenteral drugs at hospitalization, duration of hospital stay and change in the left ventricular (LV) systolic function expressed as LV ejection fraction, and the secondary end points included overall mortality, change in LV and right ventricular systolic and diastolic functions and change in the NYHA functional class between baseline and three month follow up in patients. RESULTS: Thirty five and 25 patients presented with HTNAP and NHTNAP, respectively (total 60). The overall mortality was 10 per cent (6/60). The number of hospitalizations was less in HTNAP category and of days of hospital stay was 6.3 in HTNAP and 9.8 in NHTNAP, the difference being significant (P < 0.001). The HTNAP category required less parenteral diuretics and inotropes compared with the NHTNAP category. The echocardiographic parameters showed better improvements in the HTNAP group as compared to the NHTNAP group. Overall, the patients in the <35 yr of age showed the best prognosis (P < 0.001). INTERPRETATION & CONCLUSIONS: Normal or high blood pressure response at acute presentation of DCM leads to better prognosis which may be due to an intact renovascular and an active sympathetic system and can depict the stage of DCM. PMID- 27934811 TI - Performance of the 2010 American College of Rheumatology/European League against Rheumatism (ACR/EULAR) criteria for classification of rheumatoid arthritis in an Indian population: An observational study in a single centre. AB - BACKGROUND & OBJECTIVES: The 1987 American College of Rheumatology (ACR) criteria were criticised for classifying patients only in the late stage. The 2010 ACR/European League against Rheumatism (ACR/EULAR) classification criteria for rheumatoid arthritis (RA) were thus formulated to recognize the early stage of disease with high sensitivity. This pilot study was designed to estimate and compare the sensitivities of the 1987 ACR and 2010 ACR/EULAR classification criteria for RA. METHODS: In a tertiary care hospital, the medical records of 97 patients diagnosed with RA were reviewed. Case study forms were filled with relevant clinical data and investigation results after reviewing each medical record. The radiographs of hands were also reviewed. To each case, both the 1987 ACR and the 2010 ACR/EULAR criteria were applied and the results of the classification were noted. RESULTS: The sensitivity of the 2010 ACR/EULAR criteria was found to be 79.38 per cent [95% confidence interval (CI) = 71.33 87.43%] and the sensitivity of the 1987 ACR criteria was found to be 63.92 per cent (95% CI = 54.36-73.48%). The difference in the sensitivities was significant (P< 0.01). There was a significant rise in sensitivity of the 2010 ACR/EULAR criteria when patients having anti-cyclic citrullinated peptide (CCP) titres were analysed. INTERPRETATION & CONCLUSIONS: The 2010 ACR/EULAR criteria were found to be more sensitive than the 1987 ACR criteria possibly owing to features of the criteria. Anti-CCP titres were found to increase the sensitivity of the 2010 ACR/EULAR criteria. PMID- 27934812 TI - Haitian variant tcpA in Vibrio cholerae O1 El Tor strains in National Capital Region (India). PMID- 27934813 TI - Revisiting tuberculids - Five year experience in a tertiary care teaching hospital. PMID- 27934814 TI - Giant cutaneous horns. PMID- 27934815 TI - Hypopituitarism following rifle cleaning accident. PMID- 27934816 TI - Strengthening surveillance key to addressing antimicrobial resistance. PMID- 27934817 TI - Exploring the hidden potential of fosfomycin for the fight against severe Gram negative infections. AB - Gram-negative resistance is a serious global crisis putting the world on the cusp of 'pre-antibiotic era'. This serious crisis has been catalysed by the rapid increase in carbapenem-resistant Enterobacteriaceae (CRE). Spurge in colistin usage to combat CRE infections leads to the reports of (colistin and carbapenem resistant enterobacteriaceae) CCRE (resistance to colistin in isolates of CRE) infections further jeopardising our last defence. The antibacterial apocalypse imposed by global resistance crisis requires urgent alternative therapeutic options. Interest in the use of fosfomycin renewed recently for serious systemic infections caused by multidrug-resistant Enterobacteriaceae. This review aimed at analysing the recent evidence on intravenous fosfomycin to explore its hidden potential, especially when fosfomycin disodium is going to be available in India. Although a number of promising evidence are coming up for fosfomycin, there are still areas where more work is required to establish intravenous fosfomycin as the last resort antibacterial for severe Gram-negative infections. PMID- 27934818 TI - Understanding the viridians group streptococci: Are we there yet? AB - The viridans group streptococci are a heterogeneous group of organisms which exist as commensals in the oropharynx and the gut. They cause serious infections when they gain entry into sterile sites particularly in patients with predisposing conditions. Classification and species differentiation of these organisms has always been a challenge because of phenotypic differences between strains of the same species. Facklam's typing scheme based on six metabolic properties has been the most widely used and many commercial identification systems are based on it. Due to the ambiguity in species differentiation based on phenotypic tests, nucleic acid-based methods have been developed to improve the identification of these organisms. Results using genotypic methods such as 16S rRNA and sodA gene sequencing have been promising. Multilocus sequence analysis of seven house-keeping genes map, pfl, pyk, ppaC, rpoB, soda and tuf amplified by polymerase chain reaction was found to be an accurate alternative to other methods and could be useful in the characterisation of larger collections of isolates. PMID- 27934819 TI - Trend of human brucellosis over a decade at tertiary care centre in North Karnataka. AB - BACKGROUND: Brucellosis is an important zoonotic disease. India having a major agrarian population is expected to have a higher prevalence. However, due to lack of laboratory facility or awareness among clinicians, the disease is largely underreported. The aim of this study was to know the prevalence and trend of human brucellosis over a decade, in patients attending a teaching hospital in North Karnataka, and to understand their geographical distribution. MATERIALS AND METHODS: The study was conducted from January 2006 to December 2015 at a tertiary care teaching hospital in North Karnataka. A total of 3610 serum samples were evaluated from suspected cases of brucellosis. All serum samples were initially screened by Rose Bengal plate test, and positive samples were further analysed by Serum agglutination test (SAT) using standard Brucella abortus antigen from Indian Veterinary Research Institute, Izatnagar, Uttar Pradesh, India. A titre above or equal to 1:80 IU/ml was considered as positive. Demographic data such as age, sex and native place of these patients were also analysed. RESULTS: We observed that human brucellosis is present in North Karnataka. The overall seropositivity of brucellosis in suspected cases was 5.1%. The positive titres ranged from 1:80 to 163,840 IU/ml. The majority of the patients were from Gadag, Koppal and Haveri districts of North Karnataka. CONCLUSION: Our study confirms the presence of human brucellosis in the northern part of Karnataka. Further studies to understand the prevalence of animal brucellosis in these areas will help in implementing prevention measures. PMID- 27934820 TI - Molecular characterisation of antimicrobial resistance in Pseudomonas aeruginosa and Acinetobacter baumannii during 2014 and 2015 collected across India. AB - BACKGROUND: Surveillance of antimicrobial resistance (AMR) is of great importance. Pseudomonas aeruginosa and Acinetobacter baumannii are important pathogens and emergence of resistance in these have increased the morbidity and mortality rates. This surveillance study was initiated by the Government of India - Indian Council of Medical Research. The aim of this study is to determine the antimicrobial susceptibility profile and to characterise the enzyme mediated antimicrobial resistance such as extended spectrum beta-lactamases (ESBLs) and carbapenemases among multidrug-resistant (MDR) P. aeruginosa and A. baumannii. MATERIALS AND METHODS: A multi-centric study was conducted from January 2014 to December 2015 with a total number of 240 MDR P. aeruginosa and 312 MDR A. baumannii isolated from blood, cerebrospinal fluid, respiratory, pus, urine and intra-abdominal infections. Kirby-Bauer disc diffusion was done to determine the antimicrobial susceptibility profile. Further, MDR isolates were characterised by multiplex polymerase chain reaction to determine the resistance genes for ESBLs and carbapenemases. RESULTS: Among the ESBLs, blaVEB (23%), blaTEM (5%) and blaSHV (0.4%) in P. aeruginosa and blaPER (54%), blaTEM (16%) and blaSHV (1%) in A. baumannii were the most prevalent. Likewise, blaVIM (37%), blaNDM (14%), blaGES (8%) and blaIMP (2%) in P. aeruginosa and blaOXA-23like (98%), blaOXA 58like (2%), blaNDM (22%) and blaVIM (3%) in A. baumannii were found to be the most prevalent carbapenemases. blaOXA-51like gene, intrinsic to A. baumannii was present in all the isolates tested. CONCLUSION: The data shown highlight the wide difference in the molecular mechanisms of AMR profile between P. aeruginosa and A. baumannii. In P. aeruginosa, plasmid-mediated mechanisms are much lesser than the chromosomal mediated mechanisms. In A. baumannii, class D oxacillinases are more common than other mechanisms. Continuous surveillance to monitor the trends in AMR among MDR pathogens is important for implementation of infection control and to guide appropriate empirical antimicrobial therapy. PMID- 27934821 TI - Drug susceptibility of rapid and slow growing non-tuberculous mycobacteria isolated from symptomatics for pulmonary tuberculosis, Central India. AB - BACKGROUND: Non-tuberculous mycobacteria (NTM) are emerging as important pathogens. Their treatment also differs from that of Mycobacterium tuberculosis. In India, any datum on them is scarce as species identification and drug susceptibility are not performed in most laboratories. Susceptibility also differs from one geographic area to another, and in our country, there are no data even to guide the clinicians to start treatment empirically. METHODOLOGY: The present study endeavours to generate drug susceptibility data on NTM isolated from sputum samples collected and stored from 6445 symptomatics for pulmonary tuberculosis during a prevalence survey and from specimens received from the hospital. Isolates were not necessarily associated with the disease. Species were identified and antibiotic susceptibility was performed using micro-broth dilution technique as per the standard Clinical and Laboratory Standards Institute guidelines. RESULTS: A total of 65 NTM with 11 species were identified, of which 27 belonged to Mycobacterium fortuitum complex, 14 Mycobacterium gordonae, 9 Mycobacterium avium, 7 Mycobacterium flavescens, 4 Mycobacterium scrofulaceum and one each of others. Sensitivity to amikacin for M. fortuitum was 95.22% (20 out of 21), followed by ciprofloxacin (76.19%) and clarithromycin (71.42%). All the 9 M. avium isolates, 11 of M. gordonae (78.57%), 5 of M. flavescens and 2 of M. scrofulaceum were sensitive to clarithromycin. All NTM were resistant to first line antitubercular drugs except 8, which were sensitive to streptomycin. CONCLUSIONS: Drug sensitivity of NTM varies from species to species. While amikacin was the best for rapidly growing mycobacteria, clarithromycin was the most active drug against M. avium and other slow growers. PMID- 27934822 TI - Distribution of virulence determinants among antimicrobial-resistant and antimicrobial-susceptible Escherichia coli implicated in urinary tract infections. AB - INTRODUCTION: Uropathogenic Escherichia coli (UPEC) rely on the correlation of virulence expression with antimicrobial resistance to persist and cause severe urinary tract infections (UTIs). OBJECTIVES: We assessed the virulence pattern and prevalence among UPEC strains susceptible and resistant to multiple antimicrobial classes. METHODS: A total of 174 non-duplicate UPEC strains from patients with clinically significant UTIs were analysed for susceptibility to aminoglycoside, antifolate, cephalosporin, nitrofuran and quinolone antibiotics for the production of extended-spectrum beta-lactamases and for the presence of six virulence determinants encoding adhesins (afimbrial, Type 1 fimbriae, P and S fimbriae) and toxins (cytotoxic necrotising factor and haemolysin). RESULTS: Relatively high resistance rates to nalidixic acid, ciprofloxacin, cephalothin and trimethoprim-sulfamethoxazole (82%, 78%, 62% and 59%, respectively) were observed. Fourteen distinct patterns were identified for the virulence determinants such as afaBC, cnfI, fimH, hylA, papEF and sfaDE. The toxin gene, cnfI (75.3%), was the second most prevalent marker to the adhesin, fimH (97.1%). The significant association of sfaDE/hylA (P < 0.01) among antimicrobial resistant and susceptible strains was also observed notwithstanding an overall greater occurrence of virulence factors among the latter. CONCLUSIONS: This study provides a snapshot of UPEC complexity in Jamaica and highlights the significant clonal heterogeneity among strains. Such outcomes emphasise the need for evidence based strategies in the effective management and control of UTIs. PMID- 27934823 TI - Banana peel culture as an indigenous medium for easy identification of late sporulation human fungal pathogens. AB - AIM: Fungi are increasing in incidence as human pathogens and newer and rarer species are continuously being encountered. Identifying these species from growth on regular culture media may be challenging due to the absence of typical features. An indigenous and cheap medium, similar to the natural substrate of these fungi, was standardised in our laboratory as an aid to species identification in a conventional laboratory setting. MATERIALS AND METHODS: Ripe banana peel pieces, sterilised in an autoclave at 121 degrees C temperature and 15 lbs pressure for 15 min promoted good growth of hyphae and pycnidia or acervuli in coelomycetes, flabelliform and medusoid fruiting bodies of basidiomycetes and fruit bodies such as cleistothecium in ascomycetes. The growth from the primary isolation medium was taken and inoculated onto the pieces of double-autoclaved ripe banana peel pieces in a sterile glass Petri dish with some moisture (sprinkles of sterile distilled water). A few sterile coverslips were placed randomly inside the Petri dish for the growing fungus to stick on to it. The plates were kept at room temperature and left undisturbed for 15-20 days. At a time, one coverslip was taken out and placed on a slide with lactophenol cotton blue and focused under the microscope to look for fruit bodies. RESULTS: Lasiodiplodia theobromae, Macrophomina phaseolina, Nigrospora sphaerica, Chaetomium murorum, Nattrassia mangiferae and Schizophyllum commune were identified by characteristic features from growth on banana peel culture. CONCLUSIONS: Banana peel culture is a cheap and effective medium resembling the natural substrate of fungi and is useful for promoting characteristic reproductive structures that aid identification. PMID- 27934824 TI - Genomic profile of antibiotic resistant, classical ctxB positive Vibrio cholerae O1 biotype El Tor isolated in 2003 and 2005 from Puri, India: A retrospective study. AB - OBJECTIVES: To examine eight strains of Vibrio cholerae O1 isolated in 2003 and 2005 from Puri, India, for antibiotic susceptibility, presence of virulence and regulatory genes, cholera toxin (CT) production, CTX arrangement and genomic profiles. MATERIALS AND METHODS: Bacterial strains were tested for antibiotic susceptibility using disc diffusion assay. Polymerase chain reaction determined the presence of antibiotic resistance, virulence and regulatory genes. To determine the type of cholera toxin subunit B (ctxB), nucleotide sequencing was performed. Southern hybridisation determined the number and arrangement of CTXPhi. Ribotyping and pulsed-field gel electrophoresis (PFGE) were used to determine the genomic profile of isolates. RESULTS: All the eight strains, except one strain, showed resistant to nalidixic acid, sulphamethoxazole, streptomycin and trimethoprim and possessed the sullI, strB, dfrA1 and int SXT genes. All the strains carried the toxin-co-regulated pilus pathogenicity island, the CTX genetic element, the repeat in toxin and produced CT. Restriction fragment length polymorphism (RFLP) analysis showed that V. cholerae O1 possess a single copy of the CTX element flanked by tandemly arranged RS element. Nucleotide sequencing of the ctxB gene showed the presence of classical ctxB. RFLP analysis of conserved rRNA gene showed two ribotype patterns. PFGE analysis also showed at least three PFGE patterns, irrespective of year of isolations, indicating the genomic relatedness among them. CONCLUSION: Overall, these data suggest that classical ctxB-positive V. cholerae O1 El Tor strains that appeared in 2003 continue to cause infection in 2005 in Puri, India, and belong to identical ribotype(s) and/or pulsotype(s). There is need to continuous monitor the emergence of variant of El Tor because it will improve our understanding of the evolution of new clones of variant of V. cholerae. PMID- 27934825 TI - Molecular analysis of Rv0679c and Rv0180c genes of Mycobacterium tuberculosis from clinical isolates of pulmonary tuberculosis. AB - CONTEXT: Two novel proteins/genes Rv0679c and Rv0180c of Mycobacterium tuberculosis (MTB) H37Rv were classified as a hypothetical membrane and transmembrane proteins which might have a role in the invasion. Molecular analysis of these genes in human clinical isolates of pulmonary tuberculosis (PTB) patients was not well characterised. AIMS: To assess the molecular diversity of Rv0679c and Rv0180c genes of MTB from clinical isolates of PTB patients. SETTINGS AND DESIGN: DNA from 97 clinical isolates was extracted and subjected to amplification using selective primers by polymerase chain reaction (PCR). The PCR product obtained was sequenced commercially. PATIENTS AND METHODS: Clinical isolates obtained from tuberculosis patients were investigated for polymorphisms in the Rv0679c and Rv0180c genes by PCR and DNA sequencing. Genomic DNA isolated by cetyltrimethylammonium bromide method was used for amplification of genes. RESULTS: Rv0679c gene was highly conserved in 61 out of 65 clinical isolates assessed for sequence homology with wild-type H37Rv gene and was identical using ClustalW. Fifty-five out of 78 (70.5%) clinical isolates assessed for Rv0180c were positive for single nucleotide polymorphism (SNP) at 258th position where the nucleotide G was replaced with T (G to T). In clinical isolates of untreated cases, the frequency was 54.5% for SNP at 258th position which is low compared to cases undergoing treatment where the frequency was 73.1%. CONCLUSIONS: Molecular analysis of Rv0180c in clinical isolates of PTB assessed in this study was the first report, where an SNP at 258th position G to T was identified within the gene. Rv0679c gene was highly conserved (94%), within Indian clinical isolates as compared to reports from other nations. PMID- 27934826 TI - Molecular characterisation of Panton-Valentine leucocidin-producing methicillin resistant Staphylococcus aureus clones isolated from the main hospitals in Taif, KSA. AB - INTRODUCTION: Panton-Valentine leucocidin (PVL) is a bicomponent pore-forming cytolytic toxin encoded by the lukF-PV and lukS-PV genes. Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) may carry the pvl genes which may be related to increased disease severity. This study aimed to characterise the PVL-producing MRSA recovered from different Taif Hospitals, Saudi Arabia. METHODS: The study included 45 hospital-acquired-MRSA (HA-MRSA) and 26 CA-MRSA strains which were identified from 445 S. aureus strains isolated from different clinical samples. MRSA strains were identified by standard oxacillin salt agar screening procedure and by the detection of the mecA gene by the polymerase chain reaction (PCR). Detection of the S. aureus-specific femA, mecA and pvl genes was performed by multiplex PCR. PCR-restriction fragment length polymorphism (PCR-RFLP) analysis was done for coagulase (coa) gene. RESULTS: The staphylococcal cassette chromosome mec types of the 45 HA-MRSA strains were Type I (n = 24), Type II (n = 7) and Type III (n = 14) whereas the 26 CA-MRSA strains were Type IV (n = 14), Type V (n = 11) and one isolate was non-typeable. All the HA-MRSA and six CA-MRSA strains were PVL-negative PCR-RFLP analysis of coa gene showed that PVL-positive MRSA (n = 20) isolates showed six different patterns, and five patterns were shared by PVL-positive methicillin-susceptible S. aureus (MSSA). The eighth pattern was the most frequent in both MRSA and MSSA. CONCLUSION: PVL is more frequent among CA-MRSA than MSSA. All the HA-MRSA and 25% of CA-MRSA strains were negative for PVL. The pvl gene was related to the severity of infection but not related to coa gene RFLP pattern. PMID- 27934827 TI - Flooding adds pathogenic Escherichia coli strains to the water sources in southern Khyber Pakhtunkhwa, Pakistan. AB - PURPOSE: Seasonal rains in Pakistan result in heavy floods across the country, whereby faecal contaminants will be added to the water bodies and cause numerous food-borne outbreaks. The present study was aimed to determine the prevalence of diarrheagenic Escherichia coli (DEC) strains in the water sources. MATERIALS AND METHODS: Two hundred water samples collected during (2011-2012) were processed for the isolation of E. coli (EC) strains. EC strains were further analysed for antibiotic susceptibility patterns, and pathogroups-specific virulence factors stx1, stx2, stx2c, eae, tir, hlyA, bfpA, estA and eltA were detected using multiplex polymerase chain reaction. RESULTS: Thirty-three percent of the water samples were contaminated with EC pathotypes. Fifty percent (33/66) of the DEC pathotypes were identified as enterotoxigenic EC (ETEC). Seventy-two percent (13/18) of the enteropathogenic EC (EPEC) strains were identified as typical EPEC and 28% (5/18) as atypical EPEC. Eleven percent (7/66) of the Shiga toxin EC (STEC) isolates carried a combination of stx1 and stx2 genes. Summer was found as a peak season with 47% (31/66) for EC pathogroups' activities. Eighty-nine percent of the strains showed resistance against tetracycline. CONCLUSION: ETEC and EPEC are the primary causes of water contamination in southern regions of Khyber Pakhtunkhwa province, Pakistan. Firm adherence to the prescribed drugs can decrease trends in antibiotic resistance. PMID- 27934828 TI - Generation and characterisation of monoclonal antibodies specific to avian influenza H7N9 haemagglutinin protein. AB - INTRODUCTION: Emerging virulent strains of influenza virus pose a serious public health threat with potential pandemic consequences. A novel avian influenza virus, H7N9, breached the species barrier from infected domestic poultry to humans in 2013 in China. Since then, it has caused numerous infections in humans with a close contact to poultry. MATERIALS AND METHODS: In this study, we describe the preliminary characterisation of five murine monoclonal antibodies (MAbs) developed against recombinant haemagglutinin (rHA) protein of avian H7N9 A/Anhui/1/2013 virus by their Western blot and enzyme-linked immunosorbent assay (ELISA) reactivity and binding affinity. RESULTS: Of the five MAbs, four were highly specific to H7N9 HA and did not show any cross-reactivity in ELISA with rHA protein from pandemic as well as seasonal H1N1, H2N2, H3N2, H5N1 and influenza virus B (B/Brisbane/60/2008). However, one of the MAbs, MA-24, in addition to HA protein of H7N9 also reacted strongly with HA protein of H3N2 and weakly with HA of pandemic and seasonal H1N1 and H2N2. All the five MAbs also reacted with H7N9 rHA in Western blot. The MAbs bound H7N9 rHA with an equilibrium dissociation constant (KD) ranging between 0.14 and 25.20 nM, indicating their high affinity to HA. CONCLUSIONS: These antibodies may be useful in developing diagnostic tools for the detection of influenza H7N9 virus infections. PMID- 27934829 TI - Does the presence of Klebsiella pneumoniae carbapenemase and New Delhi metallo beta-lactamase-1 genes in pathogens lead to fatal outcome? AB - INTRODUCTION: Infections due to multidrug-resistant (MDR) pathogens are a medical challenge. There is considerable apprehension among clinicians regarding pathogens reported as carrying New Delhi metallo-beta-lactamase-1 (NDM) and Klebsiella pneumoniae carbapenemase (KPC) genes from their patients. In the face of extremely high rates of antimicrobial resistance, it is essential to gauge the clinical significance of isolation of pathogens carrying these genes from clinical samples. This study compares the outcome of patients infected with pathogens carrying NDM/KPC genes versus those without these genes. METHODS: The study was conducted over a 1-year period at a Level-1 trauma centre. Hospital acquired infections were diagnosed on the basis of CDC's criteria. The correlation of isolation of a multi-resistant pathogen carrying KPC or NDM genes with the clinical outcome was ascertained. RESULTS: A total of 276 consecutive patients admitted to the Intensive Care Units/wards of the JPNA Trauma Centre were included in this study. Of the 371 isolates recovered from these patients, 116 were from patients who had a fatal outcome. The difference in prevalence of blaNDMand blaKPCwas not significant in any genera of Gram-negative pathogens isolated from patients who survived versus those who had a fatal outcome. CONCLUSION: Isolation of MDR pathogens carrying NDM/KPC genes from clinical samples is not always a harbinger of a fatal outcome. Efforts should be made to prevent cross-transmission of these pathogens. PMID- 27934830 TI - Coagulase-negative staphylococci causing blood stream infection at an Indian tertiary care hospital: Prevalence, antimicrobial resistance and molecular characterisation. AB - INTRODUCTION: Recent years have seen a rise of coagulase-negative staphylococci (CoNS) from common contaminants to agents of nosocomial blood stream infections (BSI's). Molecular typing and establishing a correlation with antibiotic resistance is essential particularly in countries like India where genotyping studies for drug-resistant CoNS are sparse. METHODS: A prospective study was done over 18 months, wherein 42,693 blood samples were received, and 59 patients with BSI due to CoNS were evaluated. The isolates recovered were identified by a biochemical test panel and matrix-assisted laser desorption ionization - time of flight mass spectrometry followed by antimicrobial susceptibility testing by Kirby-Baur disc diffusion method and E-test strips. Staphylococcal chromosomal cassette mec (SCCmec) element was characterised by multiplex polymerase chain reaction for all methicillin-resistant (MR) isolates. RESULTS: The majority of CoNS isolated were constituted by Staphylococcus haemolyticus (47.5%) followed by Staphylococcus epidermidis (33.9%), Staphylococcus hominis (11.86%), Staphylococcus cohnii (5.08%) and Staphylococcus warneri (1.69%). Among all isolates 57.6% were MR with statistically significant higher resistance versus methicillin sensitive-CoNS. This difference was significant for erythromycin (76% vs. 44%, P = 0.011), rifampicin (50% vs. 12%,P= 0.002) and amikacin (26.5% vs. 4%, P = 0.023), ciprofloxacin (64.7% vs. 20%, P = 0.001) and cotrimoxazole (55.9% vs. 20%, P = 0.006). SCCmec type I was predominant (61.8%, P = 0.028) and exhibited multidrug resistance (76.2%). Coexistence of SCCmec type I and III was seen in 8.82% MR isolates. CONCLUSION: CoNS exhibit high antimicrobial resistance thereby limiting treatment options. The presence of new variants of SCCmec type in hospital-acquired CoNS may predict the antibiotic resistance pattern. This is the first evaluation of the molecular epidemiology of CoNS causing BSI from India and can serve as a guide in the formulation of hospital infection control and treatment guidelines. PMID- 27934831 TI - Synergism between fluconazole and methylene blue-photodynamic therapy against fluconazole-resistant Candida strains. AB - Photodynamic therapy (PDT) has been proved to be effective against fungi and it may be employed as a coadjutant to conventional antifungal agents, leading to a more effective microbial control minimising side effects. This work evaluates the combined effect of PDT and fluconazole against resistant Candida albicans, Candida glabrata and Candida krusei. The yeasts were submitted to methylene blue PDT (MB-PDT) in sub-inhibitory concentrations. In the present work, MB-PDT combined with fluconazole was more efficient in the inhibition of the C. albicans and C. glabrata than each treatment alone, being possible to infer that the treatments are synergic. PMID- 27934833 TI - Can minocycline be a carbapenem sparing antibiotic? Current evidence. AB - With the increasing incidence of multidrug-resistant organisms, there is a need for newer antibiotics. However, due to the lack of new antimicrobial agents, it is necessary to re-evaluate the older agents like minocycline which is a second line antimicrobial agent. In this study, minocycline susceptibility testing was performed for 693 Escherichia coli, 316 Klebsiella spp. and 89 Acinetobacter spp. Among extended spectrum beta-lactamase producing E. coli and Klebsiella spp. percentage susceptibility to minocycline were 76 and 85, respectively. Among the carbapenem resistant E. coli, Klebsiella spp. and Acinetobacter spp. minocycline susceptibility were 52%, 55% and 42%, respectively. Based on the susceptibility profile, minocycline can be considered for treatment of infections by multidrug resistant organisms. PMID- 27934832 TI - In vitro sensitivity pattern of chloroquine and artemisinin in Plasmodium falciparum. AB - Artemisinin (ART) and its derivatives form the mainstay of antimalarial therapy. Emergence of resistance to them poses a potential threat to future malaria control and elimination on a global level. It is important to know the mechanism of action of drug and development of drug resistance. We put forwards probable correlation between the mode of action of chloroquine (CQ) and ART. Modified trophozoite maturation inhibition assay, WHO Mark III assay and molecular marker study for CQ resistance at K76T codon in Plasmodium falciparum CQ-resistant transporter gene were carried out on cultured P. falciparum. On comparing trophozoite and schizont growth for both CQ-sensitive (MRC-2) and CQ-resistant (RKL-9) culture isolates, it was observed that the clearance of trophozoites and schizonts was similar with both drugs. The experiment supports that CQ interferes with heme detoxification pathway in food vacuoles of parasite, and this may be correlated as one of the plausible mechanisms of ART. PMID- 27934834 TI - Pulmonary Mycobacterium kansasii disease in immunocompetent host: Treatment outcomes with short-course chemotherapy. AB - Mycobacterium kansasii, most virulent of all atypical mycobacteria, causes pulmonary disease identical to the disease caused by Mycobacterium tuberculosis. Early identification of the species and prompt initiation of treatment for M. kansasii is necessary to prevent morbidity and mortality due to this disease. This case series highlights the similarity in the clinical presentation of both M. tuberculosis and M. kansasii and response to direct observation of short course chemotherapy with rifampicin, in the management of pulmonary M. kansasii disease. Larger studies are required to evaluate the long-term effect of short course chemotherapy, especially use of moxifloxacin, in the management of pulmonary M. kansasii disease. PMID- 27934835 TI - Six-year susceptibility trends and effect of revised Clinical Laboratory Standards Institute breakpoints on ciprofloxacin susceptibility reporting in typhoidal Salmonellae in a tertiary care paediatric hospital in Northern India. AB - The antimicrobial trends over 6 years were studied, and the effect of revised Clinical Laboratory Standards Institute (CLSI) breakpoints (2012) for ciprofloxacin susceptibility reporting in typhoidal Salmonellae was determined. A total of 874 (95.4%) isolates were nalidixic acid-resistant (NAR). Using the CLSI 2011 guidelines (M100-S21), 585 (66.9%) isolates were ciprofloxacin susceptible. The susceptibility reduced to 11 (1.25%) isolates when interpreted using 2012 guidelines (M100-S22). Among the forty nalidixic acid susceptible (NAS) Salmonellae, susceptibility to ciprofloxacin decreased from 37 isolates (M100 S21) to 12 isolates (M100-S22). The 25 cases which appeared resistant with newer guidelines had a minimum inhibitory concentration (MIC) range between 0.125 and 0.5 MUg/ml. MIC50 for the third generation cephalosporins varied between 0.125 and 0.5 MUg/ml over 6 years whereas MIC90 varied with a broader range of 0.19-1 MUg/ml. The gap between NAR and ciprofloxacin-resistant strains identified using 2011 guidelines has been reduced; however, it remains to be seen whether additional NAS, ciprofloxacin-resistant isolates are truly resistant to ciprofloxacin by other mechanisms of resistance. PMID- 27934836 TI - Improved detection of Shigella using Escherichia coli medium enrichment: Polymerase chain reaction from stool samples. AB - Laboratory diagnosis of shigellosis using conventional culture technique is limited by lower sensitivity and higher turnaround time. Here, we have evaluated the role of polymerase chain reaction from stool samples after enrichment in Escherichia coli medium for detection of Shigellae. The technique not only increased the sensitivity but also decreased the turnaround time. PMID- 27934837 TI - High fungal spore burden with predominance of Aspergillus in hospital air of a tertiary care hospital in Chandigarh. AB - The prevalence of fungal spores in the hospital air is essential to understand the hospital-acquired fungal infections. Air conditioners (ACs) used in hospitals may either reduce spores in air or be colonised by fungi and aid in its dissemination. The present study was conducted to assess the fungal spore burden in AC and non-AC areas. We found a high fungal spore count in air irrespective of whether the area was AC or non-AC. The most predominant species isolated were Aspergillus flavus and Aspergillus fumigatus. Such high concentrations of pathogenic fungi in air may predispose individuals to develop disease. PMID- 27934838 TI - A high yield DNA extraction method for medically important Candida species: A comparison of manual versus QIAcube-based automated system. AB - The prognosis of infected individuals with candidemia depends on rapid and precise diagnosis which enables optimising treatment. Three fungal DNA extraction protocols have been compared in this study for medically important Candida species. The quality and quantity of the DNA extracted by physical, chemical and automated protocols was compared using NanoDrop ND-2000 spectrophotometer. It was found that the yield and purity (260/230) ratio of extracted DNA was significantly high in the physical treatment-based protocol as compared to chemical based or automated protocol. Extracted DNA-based real time-polymerase chain reaction showed an analytical sensitivity of 103 cfu/mL. The result of this study suggests physical treatment is the most successful extraction technique compared to other two protocols. PMID- 27934839 TI - Internalisation of hepatitis C virus core protein by human conjunctival fibroblasts. AB - Recent studies indicate that hepatitis C virus (HCV) proteins can mediate innate immune response and inflammation in conjunctival fibroblasts which contributes to the pathology of dry eye condition associated with chronic HCV infection. The present study investigates the phagocytic potential of human conjunctival fibroblasts (HCFj) for HCV core protein. HCFj cells were incubated with HCV core antigen for different periods of time, and fluorescent micrographs were taken to observe protein internalisation. HCFj cells were capable of internalising HCV core antigen within 1 h; this gives an insight into another molecular mechanism which may contribute towards HCV-associated conjunctival inflammation. PMID- 27934840 TI - Application of real-time quantitative polymerase chain reaction assay to detect Legionella pneumophila in patients of community-acquired pneumonia in a tertiary care hospital. AB - Legionella pneumophila is one of the important pathogen responsible for community -acquired pneumonia attributing for 1-5% of cases. Since early and accurate therapy reduces mortality, rapid and reliable diagnostic methods are needed. A total of 134 samples of blood, urine and respiratory tract fluids were collected. Blood was tested for IgG, IgM and IgA antibodies using commercially available kits. A total of 8 (6%) samples were found to be positive for L. pneumophila by quantitative reverse transcription polymerase chain reaction (qRT-PCR), compared to conventional PCR where 6 (4.4%) samples were positive. Serology was positive in a total of 32 (23%) cases though only 3 (2.2%) of the PCR-positive cases were positive by serology as well. These results suggest that real-time PCR can detect Legionella infection early in the course of the disease before serological response develops. PMID- 27934841 TI - Aeromonas hydrophila meningitis and fulminant sepsis in preterm newborn: A case report and review of literature. AB - Neonatal meningitis is a lethal infection occurring in the 1st month of life. The risk of developing permanent neurological sequels is high among the neonates who survive. Bacterial pathogens are commonly associated with this condition. Aeromonas is a Gram-negative bacteria of aquatic habitat. Although isolation of Aeromonas species from neonates with blood stream infection is infrequently reported, neonatal meningitis caused by Aeromonas is exceedingly rare. We present a case of fulminant sepsis and meningitis caused by Aeromonas hydrophila in a preterm newborn male. The bacteria was isolated in culture from blood and cerebrospinal fluid. In spite of targeted antibiotics and supportive therapy, the baby failed to respond and died on the 12th day of life. PMID- 27934842 TI - Infections related to Granulicatella adiacens: Report of two cases and review of literature. AB - Infections due to nutritionally variant streptococci are diagnosed rarely due to difficulties encountered during identification and isolation. Mortality rate in these infections is high therefore appropriate supplemented media and reliable detection systems should be implemented to isolate these fastidious organisms. Here, we describe two cases of Granulicatella adiacens infections. All microbiologic identifications were made with MALDI-TOF Vitek MS (BioMerieux, France), and the results confirmed by 16S ribotyping. PMID- 27934843 TI - Successful treatment of primary cerebral mucormycosis: Role of microbiologist. AB - Fungal brain abscess is rare with a rapidly progressive disease with fulminant course and invariably fatal outcome, unless diagnosed early and treated rapidly. We report a 56-year-old woman diagnosed to have fungal abscess who recovered completely following amphotericin B treatment. She presented with weakness of the right hand, deviation of mouth to left and aphasia for 2 days. Computed tomography of the brain revealed a left frontal capsuloganglionic hypodense lesion. Stereotactic biopsy was performed, and microbiological confirmation of non-septate fungal hyphae from pus from aspirate within 2 h helped initiate timely and appropriate treatment leading to cure. Histopathology and culture later confirmed mucormycosis. PMID- 27934844 TI - Severe unresolving Plasmodium falciparum malaria following artemisinin combination therapy: Emergence of drug resistance in Saudi Arabia. AB - A 5-year-old female child presented with fever of 1-week duration after visiting a malaria endemic zone without antimalarial prophylaxis. The patient presented with respiratory distress, decreased level of consciousness and high-grade fever. An elevated parasitaemia reaching 800,000/MUl was observed. Antimalarial therapy was initiated with artesunate being administered intravenous (IV) along with IV clindamycin. Contrary to the expectations, there was no resolution of fever. Following a week of unresolved fever, the drug therapy was revised and altered to IV quinine dihydrochloride and IV clindamycin. Emergence of non-responsiveness to artesunate in Saudi Arabia is an alarming sign and requires revision of management protocols. PMID- 27934845 TI - In vitro susceptibility of carbapenem-resistant Enterobacteriaceae to colistin: A hope at present. PMID- 27934846 TI - Gonococcal opa gene as a diagnostic target for nucleic acid amplification tests in Indian Population. PMID- 27934847 TI - Stamp's modified Ziehl-Neelsen staining for Brucella: Beware of the first impressions. PMID- 27934848 TI - Medical Council of India circular on research publications: Flaring up the fire. PMID- 27934849 TI - Polymyxin Nordmann/Poirel test for rapid detection of polymyxin resistance in Enterobacteriaceae: Indian experience. PMID- 27934850 TI - Erratum: Endemic Indian clones of Klebsiella pneumoniae harbouring New Delhi metallo beta lactamase 1 on a hybrid plasmid replicon type: A case of changing New Delhi metallo beta lactamase plasmid landscapes in India? AB - [This corrects the article DOI: 10.4103/0255-0857.188314.]. PMID- 27934851 TI - Corrigendum: Using rare earth elements to constrain particulate organic carbon flux in the East China Sea. PMID- 27934852 TI - Erratum: Myc overexpression enhances epicardial contribution to the developing heart and promotes extensive expansion of the cardiomyocyte population. PMID- 27934855 TI - Alzheimer disease: Sex-specific inflammatory link to early Alzheimer pathology. PMID- 27934853 TI - Clinical and biological progress over 50 years in Rett syndrome. AB - In the 50 years since Andreas Rett first described the syndrome that came to bear his name, and is now known to be caused by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, a compelling blend of astute clinical observations and clinical and laboratory research has substantially enhanced our understanding of this rare disorder. Here, we document the contributions of the early pioneers in Rett syndrome (RTT) research, and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation, and the interplay with other Rett related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, considering the lessons learned from both cell and animal models, and how they might inform future clinical trials. With a focus on the core criteria, we examine the relationships between genotype and clinical severity. We review current knowledge about the many comorbidities that occur in RTT, and how genotype may modify their presentation. We also acknowledge the important drivers that are accelerating this research programme, including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we highlight the major milestones since 1966, and what they mean for the day-to-day lives of individuals with RTT and their families. PMID- 27934857 TI - In-plane topological p-n junction in the three-dimensional topological insulator Bi2-xSbxTe3-ySey. AB - A topological p-n junction (TPNJ) is an important concept to control spin and charge transport on a surface of three-dimensional topological insulators (3D TIs). Here we report successful fabrication of such TPNJ on a surface of 3D-TI Bi2-xSbxTe3-ySey thin films and experimental observation of the electrical transport. By tuning the chemical potential of n-type topological Dirac surface of Bi2-xSbxTe3-ySey on its top half by using tetrafluoro-7,7,8,8 tetracyanoquinodimethane as an organic acceptor molecule, a half surface can be converted to p-type with leaving the other half side as the opposite n-type, and consequently TPNJ can be created. By sweeping the back-gate voltage in the field effect transistor structure, the TPNJ was controlled both on the bottom and the top surfaces. A dramatic change in electrical transport observed at the TPNJ on 3D-TI thin films promises novel spin and charge transport of 3D-TIs for future spintronics. PMID- 27934858 TI - Multiple signal classification algorithm for super-resolution fluorescence microscopy. AB - Single-molecule localization techniques are restricted by long acquisition and computational times, or the need of special fluorophores or biologically toxic photochemical environments. Here we propose a statistical super-resolution technique of wide-field fluorescence microscopy we call the multiple signal classification algorithm which has several advantages. It provides resolution down to at least 50 nm, requires fewer frames and lower excitation power and works even at high fluorophore concentrations. Further, it works with any fluorophore that exhibits blinking on the timescale of the recording. The multiple signal classification algorithm shows comparable or better performance in comparison with single-molecule localization techniques and four contemporary statistical super-resolution methods for experiments of in vitro actin filaments and other independently acquired experimental data sets. We also demonstrate super-resolution at timescales of 245 ms (using 49 frames acquired at 200 frames per second) in samples of live-cell microtubules and live-cell actin filaments imaged without imaging buffers. PMID- 27934854 TI - Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. AB - Genetic predisposition to multiple sclerosis (MS) only explains a fraction of the disease risk; lifestyle and environmental factors are key contributors to the risk of MS. Importantly, these nongenetic factors can influence pathogenetic pathways, and some of them can be modified. Besides established MS-associated risk factors - high latitude, female sex, smoking, low vitamin D levels caused by insufficient sun exposure and/or dietary intake, and Epstein-Barr virus (EBV) infection - strong evidence now supports obesity during adolescence as a factor increasing MS risk. Organic solvents and shift work have also been reported to confer increased risk of the disease, whereas factors such as use of nicotine or alcohol, cytomegalovirus infection and a high coffee consumption are associated with a reduced risk. Certain factors - smoking, EBV infection and obesity - interact with HLA risk genes, pointing at a pathogenetic pathway involving adaptive immunity. All of the described risk factors for MS can influence adaptive and/or innate immunity, which is thought to be the main pathway modulated by MS risk alleles. Unlike genetic risk factors, many environmental and lifestyle factors can be modified, with potential for prevention, particularly for people at the greatest risk, such as relatives of individuals with MS. Here, we review recent data on environmental and lifestyle factors, with a focus on gene-environment interactions. PMID- 27934856 TI - Bulk cell density and Wnt/TGFbeta signalling regulate mesendodermal patterning of human pluripotent stem cells. AB - In vitro differentiation of human pluripotent stem cells (hPSCs) recapitulates early aspects of human embryogenesis, but the underlying processes are poorly understood and controlled. Here we show that modulating the bulk cell density (BCD: cell number per culture volume) deterministically alters anteroposterior patterning of primitive streak (PS)-like priming. The BCD in conjunction with the chemical WNT pathway activator CHIR99021 results in distinct paracrine microenvironments codifying hPSCs towards definitive endoderm, precardiac or presomitic mesoderm within the first 24 h of differentiation, respectively. Global gene expression and secretome analysis reveals that TGFbeta superfamily members, antagonist of Nodal signalling LEFTY1 and CER1, are paracrine determinants restricting PS progression. These data result in a tangible model disclosing how hPSC-released factors deflect CHIR99021-induced lineage commitment over time. By demonstrating a decisive, functional role of the BCD, we show its utility as a method to control lineage-specific differentiation. Furthermore, these findings have profound consequences for inter-experimental comparability, reproducibility, bioprocess optimization and scale-up. PMID- 27934859 TI - TRBP ensures efficient Dicer processing of precursor microRNA in RNA-crowded environments. AB - The RNA-binding protein TRBP is a central component of the Dicer complex. Despite a decade of biochemical and structural studies, the essential functionality of TRBP in microRNA (miRNA) biogenesis remains unknown. Here we show that TRBP is an integral cofactor for time-efficient Dicer processing in RNA-crowded environments. We competed for Dicer processing of pre-miRNA with a large amount of cellular RNA species and found that Dicer-TRBP, but not Dicer alone, remains resilient. To apprehend the mechanism of this substrate selectivity, we use single-molecule fluorescence. The real-time observation reveals that TRBP acts as a gatekeeper, precluding Dicer from engaging with pre-miRNA-like substrates. TRBP acquires the selectivity using the PAZ domain of Dicer, whereas Dicer moderates the RNA-binding affinity of TRBP for fast turnover. This coordinated action between TRBP and Dicer accomplishes an efficient way of discarding pre-miRNA-like substrates. PMID- 27934860 TI - Scanning superlens microscopy for non-invasive large field-of-view visible light nanoscale imaging. AB - Nanoscale correlation of structural information acquisition with specific molecule identification provides new insight for studying rare subcellular events. To achieve this correlation, scanning electron microscopy has been combined with super-resolution fluorescent microscopy, despite its destructivity when acquiring biological structure information. Here we propose time-efficient non-invasive microsphere-based scanning superlens microscopy that enables the large-area observation of live-cell morphology or sub-membrane structures with sub-diffraction-limited resolution and is demonstrated by observing biological and non-biological objects. This microscopy operates in both non-invasive and contact modes with ~200 times the acquisition efficiency of atomic force microscopy, which is achieved by replacing the point of an atomic force microscope tip with an imaging area of microspheres and stitching the areas recorded during scanning, enabling sub-diffraction-limited resolution. Our method marks a possible path to non-invasive cell imaging and simultaneous tracking of specific molecules with nanoscale resolution, facilitating the study of subcellular events over a total cell period. PMID- 27934861 TI - Bond selectivity in electron-induced reaction due to directed recoil on an anisotropic substrate. AB - Bond-selective reaction is central to heterogeneous catalysis. In heterogeneous catalysis, selectivity is found to depend on the chemical nature and morphology of the substrate. Here, however, we show a high degree of bond selectivity dependent only on adsorbate bond alignment. The system studied is the electron induced reaction of meta-diiodobenzene physisorbed on Cu(110). Of the adsorbate's C-I bonds, C-I aligned 'Along' the copper row dissociates in 99.3% of the cases giving surface reaction, whereas C-I bond aligned 'Across' the rows dissociates in only 0.7% of the cases. A two-electronic-state molecular dynamics model attributes reaction to an initial transition to a repulsive state of an Along C I, followed by directed recoil of C towards a Cu atom of the same row, forming C Cu. A similar impulse on an Across C-I gives directed C that, moving across rows, does not encounter a Cu atom and hence exhibits markedly less reaction. PMID- 27934862 TI - Corrigendum: Modulation of expression of genes involved in glycosaminoglycan metabolism and lysosome biogenesis by flavonoids. PMID- 27934863 TI - Metabolism: Intestinal microbiota affects host physiology. PMID- 27934864 TI - An updated view of hypothalamic-vascular-pituitary unit function and plasticity. AB - The discoveries of novel functional adaptations of the hypothalamus and anterior pituitary gland for physiological regulation have transformed our understanding of their interaction. The activity of a small proportion of hypothalamic neurons can control complex hormonal signalling, which is disconnected from a simple stimulus and the subsequent hormone secretion relationship and is dependent on physiological status. The interrelationship of the terminals of hypothalamic neurons and pituitary cells with the vasculature has an important role in determining the pattern of neurohormone exposure. Cells in the pituitary gland form networks with distinct organizational motifs that are related to the duration and pattern of output, and modifications of these networks occur in different physiological states, can persist after cessation of demand and result in enhanced function. Consequently, the hypothalamus and pituitary can no longer be considered as having a simple stratified relationship: with the vasculature they form a tripartite system, which must function in concert for appropriate hypothalamic regulation of physiological processes, such as reproduction. An improved understanding of the mechanisms underlying these regulatory features has implications for current and future therapies that correct defects in hypothalamic-pituitary axes. In addition, recapitulating proper network organization will be an important challenge for regenerative stem cell treatment. PMID- 27934865 TI - Adipose tissue: Reversing age-related decline in beiging. PMID- 27934866 TI - Chickpea transcription factor CaTLP1 interacts with protein kinases, modulates ROS accumulation and promotes ABA-mediated stomatal closure. AB - Tubby and Tubby-like proteins (TLPs), in mammals, play critical roles in neural development, while its function in plants is largely unknown. We previously demonstrated that the chickpea TLP, CaTLP1, participates in osmotic stress response and might be associated with ABA-dependent network. However, how CaTLP1 is connected to ABA signaling remains unclear. The CaTLP1 was found to be engaged in ABA-mediated gene expression and stomatal closure. Complementation of the yeast yap1 mutant with CaTLP1 revealed its role in ROS scavenging. Furthermore, complementation of Arabidopsis attlp2 mutant displayed enhanced stress tolerance, indicating the functional conservation of TLPs across the species. The presence of ABA-responsive element along with other motifs in the proximal promoter regions of TLPs firmly established their involvement in stress signalling pathways. The CaTLP1 promoter driven GUS expression was restricted to the vegetative organs, especially stem and rosette leaves. Global protein expression profiling of wild-type, attlp2 and complemented Arabidopsis plants revealed 95 differentially expressed proteins, presumably involved in maintaining physiological and biological processes under dehydration. Immunoprecipitation assay revealed that protein kinases are most likely to interact with CaTLP1. This study provides the first demonstration that the TLPs act as module for ABA mediated stomatal closure possibly via interaction with protein kinase. PMID- 27934867 TI - Heritable expansion of the genetic code in mouse and zebrafish. PMID- 27934868 TI - Regulation of mATG9 trafficking by Src- and ULK1-mediated phosphorylation in basal and starvation-induced autophagy. AB - Autophagy requires diverse membrane sources and involves membrane trafficking of mATG9, the only membrane protein in the ATG family. However, the molecular regulation of mATG9 trafficking for autophagy initiation remains unclear. Here we identified two conserved classic adaptor protein sorting signals within the cytosolic N-terminus of mATG9, which mediate trafficking of mATG9 from the plasma membrane and trans-Golgi network (TGN) via interaction with the AP1/2 complex. Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation. Our findings uncover novel mechanisms of mATG9 trafficking and suggest a coordination of basal and stress-induced autophagy. PMID- 27934870 TI - Erratum: Weighted and directed interactions in evolving large-scale epileptic brain networks. PMID- 27934871 TI - Solving the second-order free rider problem in a public goods game: An experiment using a leader support system. AB - Punishment of non-cooperators-free riders-can lead to high cooperation in public goods games (PGG). However, second-order free riders, who do not pay punishment costs, reduce the effectiveness of punishment. Here we introduce a "leader support system," in which one group leader can freely punish group followers using capital pooled through the support of group followers. In our experiment, participants engage in three stages repeatedly: a PGG stage in which followers decide to cooperate for their group; a support stage in which followers decide whether to support the leader; and a punishment stage in which the leader can punish any follower. We compare a support-present condition with a no-support condition, in which there is an external source for the leader's punishment. The results show that punishment occurs more frequently in the support-present condition than the no-support condition. Within the former, both higher cooperation and higher support for a leader are achieved under linkage-type leaders-who punish both non-cooperators and non-supporters. In addition, linkage type leaders themselves earn higher profits than other leader types because they withdraw more support. This means that leaders who effectively punish followers could increase their own benefits and the second-order free rider problem would be solved. PMID- 27934869 TI - A pair of transposon-derived proteins function in a histone acetyltransferase complex for active DNA demethylation. AB - Transposons are generally kept silent by epigenetic mechanisms including DNA methylation. Here, we identified a pair of Harbinger transposon-derived proteins (HDPs), HDP1 and HDP2, as anti-silencing factors in Arabidopsis. hdp1 and hdp2 mutants displayed an enhanced silencing of transgenes and some transposons. Phylogenetic analyses revealed that HDP1 and HDP2 were co-domesticated from the Harbinger transposon-encoded transposase and DNA-binding protein, respectively. HDP1 interacts with HDP2 in the nucleus, analogous to their transposon counterparts. Moreover, HDP1 and HDP2 are associated with IDM1, IDM2, IDM3 and MBD7 that constitute a histone acetyltransferase complex functioning in DNA demethylation. HDP2 and the methyl-DNA-binding protein MBD7 share a large set of common genomic binding sites, indicating that they jointly determine the target specificity of the histone acetyltransferase complex. Thus, our data revealed that HDP1 and HDP2 constitute a functional module that has been recruited to a histone acetyltransferase complex to prevent DNA hypermethylation and epigenetic silencing. PMID- 27934872 TI - Structural Analysis of Glycine Sarcosine N-methyltransferase from Methanohalophilus portucalensis Reveals Mechanistic Insights into the Regulation of Methyltransferase Activity. AB - Methyltransferases play crucial roles in many cellular processes, and various regulatory mechanisms have evolved to control their activities. For methyltransferases involved in biosynthetic pathways, regulation via feedback inhibition is a commonly employed strategy to prevent excessive accumulation of the pathways' end products. To date, no biosynthetic methyltransferases have been characterized by X-ray crystallography in complex with their corresponding end product. Here, we report the crystal structures of the glycine sarcosine N methyltransferase from the halophilic archaeon Methanohalophilus portucalensis (MpGSMT), which represents the first structural elucidation of the GSMT methyltransferase family. As the first enzyme in the biosynthetic pathway of the osmoprotectant betaine, MpGSMT catalyzes N-methylation of glycine and sarcosine, and its activity is feedback-inhibited by the end product betaine. A structural analysis revealed that, despite the simultaneous presence of both substrate (sarcosine) and cofactor (S-adenosyl-L-homocysteine; SAH), the enzyme was likely crystallized in an inactive conformation, as additional structural changes are required to complete the active site assembly. Consistent with this interpretation, the bound SAH can be replaced by the methyl donor S-adenosyl-L methionine without triggering the methylation reaction. Furthermore, the observed conformational state was found to harbor a betaine-binding site, suggesting that betaine may inhibit MpGSMT activity by trapping the enzyme in an inactive form. This work implicates a structural basis by which feedback inhibition of biosynthetic methyltransferases may be achieved. PMID- 27934873 TI - High-density Association Mapping and Interaction Analysis of PLA2R1 and HLA Regions with Idiopathic Membranous Nephropathy in Japanese. AB - Although recent studies showed anti-PLA2R antibody plays a crucial role in idiopathic membranous nephropathy (IMN), detailed HLA mapping and interaction between the HLA genes and PLA2R1 have not been investigated in IMN. We genotyped across the PLA2R1 gene and the HLA region, using 183 IMN patients and 811 healthy controls. Five SNPs around the PLA2R1 gene were significantly associated with IMN. In addition to the two SNPs previously reported to be strongly associated with IMN, rs3749119 and rs35771982 (OR 3.02 and 2.93, P = 3.24E-14 and 4.64E-14, respectively), two novel intronic SNPs (rs2715928 and rs16844715) were also identified as IMN-associated SNPs (OR = 2.30 and 2.51, P = 3.15E-10 and 5.66E-13, respectively). In the HLA gene analysis, DRB1*1501 and DQB1*0602 were strongly associated with IMN (P = 1.14E-11 and 1.25E-11, respectively). The interaction was strongest between HLA-DRB1*15:01 - HLA-DQB1*06:02 and the intronic SNP rs2715928 (OR = 17.53, P = 4.26E-26). Furthermore, positive interaction was also observed between HLA-DRB1*15:01 - HLA-DQB1*06:02 and the missense SNP rs35771982 (OR = 15.91, P = 2.76E-29), which is in strong linkage disequilibrium with 5'UTR SNP rs3749119, and intronic SNP rs16844715 (OR = 15.91, P = 2.30E-26) for IMN. Neither HLA-DRB1*15:01 nor HLA-DQB1*06:02 was associated with steroid responsiveness, overall survival and renal survival during the observation period of mean 11 years though limited number of analysis. PMID- 27934874 TI - Raman signatures of inversion symmetry breaking and structural phase transition in type-II Weyl semimetal MoTe2. AB - Transition metal dichalcogenide MoTe2 is an important candidate for realizing the newly predicted type-II Weyl fermions, for which the breaking of the inversion symmetry is a prerequisite. Here we present direct spectroscopic evidence for the inversion symmetry breaking in the low-temperature phase of MoTe2 by systematic Raman experiments and first-principles calculations. We identify five lattice vibrational modes that are Raman-active only in the low-temperature noncentrosymmetric structure. A hysteresis is also observed in the peak intensity of inversion symmetry-activated Raman modes, confirming a temperature-induced structural phase transition with a concomitant change in the inversion symmetry. Our results provide definitive evidence for the low-temperature noncentrosymmetric Td phase from vibrational spectroscopy, and suggest MoTe2 as an ideal candidate for investigating the temperature-induced topological phase transition. PMID- 27934876 TI - Immunohistochemistry for p53 is a useful tool to identify cases of acute myeloid leukemia with myelodysplasia-related changes that are TP53 mutated, have complex karyotype, and have poor prognosis. AB - In this study, we evaluate the expression of p53 in core biopsies with acute myeloid leukemia and correlate the level of expression with acute myeloid leukemia subtype, TP53 mutation status, karyotype, and survival. Of the 143 cases evaluated, 71 fulfilled the WHO 2016 criteria for acute myeloid leukemia with myelodysplasia-related changes, 40 were acute myeloid leukemia-not otherwise specified, 25 were acute myeloid leukemia with recurrent genetic abnormalities, and 7 were therapy-related acute myeloid leukemia. By immunohistochemistry, 17% showed p53 expression in >5% of the cells. Of the 24 cases with >5% p53-positive cells, 17 were acute myeloid leukemia with myelodysplasia-related changes, 5 were acute myeloid leukemia-not otherwise specified, 1 was acute myeloid leukemia with recurrent genetic abormalities, and 1 was therapy-related acute myeloid leukemia. In cases for which data was available, expression of >5% p53-positive cells was significantly associated with genotype (n=67) and/or karyotype (n=130). Among the 115 cases for which clinical follow up was available, the overall survival of cases with p53 expression >15% (Median=102 days) was significantly shorter compared with cases with p53 expression <=15% (Median=435 days). Within the acute myeloid leukemia with myelodysplasia-related changes group, this association remained significant, with cases with <=15% p53-positive cells having a median overall survival of 405 days versus 102 days for cases with >15% p53-positive cells. Among acute myeloid leukemia with myelodysplasia-related changes cases with a complex karyotype, the finding of >15% p53-positive cells was significantly associated with worse overall survival. The poor prognosis associated with more than 15% p53-positive cells was independent of age and karyotype. In acute myeloid leukemia with myelodysplasia-related changes, p53 expression may be useful to infer TP53 mutation status, complex karyotype, and/or poor prognosis in situations where other modalities are not readily available. PMID- 27934875 TI - Functional and structural characterization of a novel putative cysteine protease cell wall-modifying multi-domain enzyme selected from a microbial metagenome. AB - A current metagenomics focus is to interpret and transform collected genomic data into biological information. By combining structural, functional and genomic data we have assessed a novel bacterial protein selected from a carbohydrate-related activity screen in a microbial metagenomic library from Capra hircus (domestic goat) gut. This uncharacterized protein was predicted as a bacterial cell wall modifying enzyme (CWME) and shown to contain four domains: an N-terminal, a cysteine protease, a peptidoglycan-binding and an SH3 bacterial domain. We successfully cloned, expressed and purified this putative cysteine protease (PCP), which presented autoproteolytic activity and inhibition by protease inhibitors. We observed cell wall hydrolytic activity and ampicillin binding capacity, a characteristic of most bacterial CWME. Fluorimetric binding analysis yielded a Kb of 1.8 * 105 M-1 for ampicillin. Small-angle X-ray scattering (SAXS) showed a maximum particle dimension of 95 A with a real-space Rg of 28.35 A. The elongated molecular envelope corroborates the dynamic light scattering (DLS) estimated size. Furthermore, homology modeling and SAXS allowed the construction of a model that explains the stability and secondary structural changes observed by circular dichroism (CD). In short, we report a novel cell wall-modifying autoproteolytic PCP with insight into its biochemical, biophysical and structural features. PMID- 27934877 TI - Overexpression and gene amplification of PD-L1 in cancer cells and PD-L1+ immune cells in Epstein-Barr virus-associated gastric cancer: the prognostic implications. AB - Cancer cells use PD-L1 to evade antitumor immunity through interaction with programmed cell death protein 1 (PD-1) on T cells. Recent whole-genome sequence studies revealed frequent gene amplification of PD-L1 in Epstein-Barr virus associated gastric cancer (EBVaGC). To investigate the significance of PD-L1 in cancer cells and their microenvironment in EBVaGC, we studied PD-L1 expression by analysis of the public database and immunohistochemistry with fluorescent in situ hybridization (FISH) of the PD-L1 gene. Analysis of the database from The Cancer Genome Atlas also disclosed high expression of PD-L1 in EBVaGC compared with other molecular subtypes of GC. Expression of PD-L1 was frequently detected in cancer cells of EBVaGC (33/96; 34%), with infiltration of PD-L1+ immune cells in its stroma (43/96; 45%). Both expression of PD-L1 in cancer cells and PD-L1+ immune cell infiltration in EBVaGC were significantly correlated with diffuse histology according to Lauren's classification and tumor invasion (pT1b or more). As a prognostic indicator, PD-L1 expression in cancer cells correlated with poor outcomes in both overall survival and disease-specific survival (P=0.0498, 0.007). PD-L1-positive cancers had dense infiltration of PD-L1+ immune cells as well as CD8+ and PD-1+ cells in EBVaGC. FISH analysis of representative samples of the tumor demonstrated gene amplification of PD-L1 in 11% of cases. PD-L1 amplified cells corresponded to PD-L1-positive cells showing high-intensity immunohistochemical staining among cancer cells showing weak or moderate intensities. Taken together, PD-L1 expression in cancer cells and their microenvironment may contribute to the progression of EBVaGC, and gene amplification occurs as clonal evolution during progression. This specific subtype of GC infected with EBV is potentially a good candidate for immunotherapy targeting of the PD-L1/PD-1 axis. PMID- 27934878 TI - Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi. AB - Blue nevi are common melanocytic tumors arising in the dermal layer of the skin. Similar to uveal melanomas, blue nevi frequently harbor GNAQ and GNA11 mutations. Recently, recurrent CYSLTR2 and PLCB4 mutations were identified in uveal melanomas not harboring GNAQ or GNA11 mutations. All four genes (GNAQ, GNA11, CYSLTR2, and PLCB4) code for proteins involved in the same signaling pathway, which is activated by mutations in these genes. Given the related functional consequences of these mutations and the known genetic similarities between uveal melanoma and blue nevi, we analyzed a cohort of blue nevi to investigate whether CYSLTR2 and PLCB4 mutations occur in tumors lacking GNAQ or GNA11 mutations (as in uveal melanoma). A targeted next-generation sequencing assay covering known activating mutations in GNAQ, GNA11, CYSLTR2, PLCB4, KIT, NRAS, and BRAF was applied to 103 blue nevi. As previously reported, most blue nevi were found to harbor activating mutations in GNAQ (59%, n=61), followed by less frequent mutations in GNA11 (16%, n=17). Additionally, one BRAF (1%) and three NRAS (3%) mutations were detected. In three tumors (3%) harboring none of the aforementioned gene alterations, CYSLTR2 mutations were identified. All three CYSLTR2 mutations were the same c.386T>A, L129Q mutation previously identified in uveal melanoma that has been shown to lead to increased receptor activation and signaling. In summary, our study identifies CYSLTR2 L129Q alterations as a previously unrecognized activating mutation in blue nevi, occuring in a mutually exclusive fashion with known GNAQ and GNA11 mutations. Similar to GNAQ and GNA11 mutations, CYSLTR2 mutations, when present, are likely defining pathogenetic events in blue nevi. PMID- 27934880 TI - Carbon monoxide in an extremely metal-poor galaxy. AB - Extremely metal-poor galaxies with metallicity below 10% of the solar value in the local universe are the best analogues to investigating the interstellar medium at a quasi-primitive environment in the early universe. In spite of the ongoing formation of stars in these galaxies, the presence of molecular gas (which is known to provide the material reservoir for star formation in galaxies such as our Milky Way) remains unclear. Here we report the detection of carbon monoxide (CO), the primary tracer of molecular gas, in a galaxy with 7% solar metallicity, with additional detections in two galaxies at higher metallicities. Such detections offer direct evidence for the existence of molecular gas in these galaxies that contain few metals. Using archived infrared data, it is shown that the molecular gas mass per CO luminosity at extremely low metallicity is approximately one-thousand times the Milky Way value. PMID- 27934879 TI - Xp11.2 translocation renal cell carcinoma with NONO-TFE3 gene fusion: morphology, prognosis, and potential pitfall in detecting TFE3 gene rearrangement. AB - Xp11 translocation renal cell carcinomas are characterized by several different translocations involving the TFE3 gene. Tumors with different specific gene fusions may have different clinicopathological manifestations. Fewer than 10 renal cell carcinoma cases with NONO-TFE3 have been described. Here we examined eight additional cases of this rare tumor using clinicopathological, immunohistochemical, and molecular analyses. The male-to-female ratio of our study cohort was 1:1, and the median age was 30 years. The most distinctive feature of the tumors was that they exhibited glandular/tubular or papillary architecture that was lined with small-to-medium cuboidal to high columnar cells with indistinct cell borders and an abundantly clear or flocculent eosinophilic cytoplasm. The nuclei were oriented toward the luminal surface and were round and uniform in shape, which resulted in the appearance of secretory endometrioid subnuclear vacuolization. The distinct glandular/tubular or papillary architecture was often accompanied by sheets of epithelial cells that presented a biphasic pattern. Immunohistochemically, all eight cases demonstrated moderate (2+) or strong (3+) positive staining for TFE3, CD10, RCC marker, and PAX-8. None of the tumors were immunoreactive for CK7, Cathepsin K, Melan-A, HMB45, Ksp cadherin, Vimentin, CA9, 34betaE12 or CD117. NONO-TFE3 fusion transcripts were identified in six cases by RT-PCR. All eight cases showed equivocal split signals with a distance of nearly 2 signal diameters and sometimes had false-negative results. Furthermore, we developed a fluorescence in situ hybridization (FISH) assay to serve as an adjunct diagnostic tool for the detection of the NONO-TFE3 fusion gene and used this method to detect the fusion gene in all eight cases. Long-term follow-up (range, 10-102 months) was available for 7 patients. All 7 patients were alive with no evidence of recurrent disease or disease progression after their initial resection. This report adds to the known data regarding NONO TFE3 renal cell carcinoma. PMID- 27934881 TI - The Relationship Between Cortical Inhibition and Electroconvulsive Therapy in the Treatment of Major Depressive Disorder. AB - Dysfunctional cortical inhibition (CI) is postulated as a key neurophysiological mechanism in major depressive disorder. Electroconvulsive therapy (ECT) is the treatment of choice for resistant depression and ECT has been associated with enhanced CI. The objective of this study was to evaluate the relationship between CI and ECT response in resistant depression. Twenty-five patients with treatment resistant depression underwent an acute course of ECT. CI was indexed by the cortical silent period (CSP) and short-interval cortical inhibition (SICI), through TMS-EMG. CI and clinical response was measured prior to beginning an acute ECT course and within 48 hours of the last ECT treatment in the course. Clinical response to ECT was assessed by HDRS-17 before and after an acute course of ECT. We found that there was a significant difference in CSP at baseline between responder and non-responder groups (p = 0.044). Baseline CSP predicted therapeutic response to ECT with sensitivity of 80% and specificity of 60%. There were no changes in CSP or SICI after administration of the ECT course. Our findings suggest that duration of pre-treatment CSP may be a useful predictor of therapeutic response to ECT in patients with TRD. PMID- 27934882 TI - Stable knockdown of CREB, HIF-1 and HIF-2 by replication-competent retroviruses abrogates the responses to hypoxia in hepatocellular carcinoma. AB - The fast proliferation of tumor cells develops faster than the vasculature, resulting, in most malignant tumors, in generation of hypoxic regions. Hypoxia renders solid tumors resistant to radiation and chemotherapeutics while providing opportunities for tumor-selective therapies targeting tumor hypoxia. Here we exploit two properties of tumors: propagation of tumor cells and ongoing generation of hypoxic regions to construct a system that preferentially leads to the death of tumor cells and thus hinders tumor growth. We constructed murine leukemia virus replication-competent (RCR) viruses that infect only propagating cells. These viruses express small hairpin RNAs (shRNAs) targeting cyclic AMP response-element binding protein (CREB), hypoxia-inducible factors 1 (HIF)-1 or HIF-2 individually or all three together (X3). These viruses efficiently infected in vitro human hepatocellular carcinoma (HepG2 and FLC4) cells and established persistence of the virus and knocked down the expression of the regulators of the hypoxia-responding genes. Knockdown of either HIF-1 or CREB or both in hypoxia reduced the expression of hypoxia-response elements- and CRE-mediated gene expression, diminished cell proliferation and increased caspase-3 activity. We did not detect any significant effect of the efficiently knocked down HIF-2 on any of the functions tested in vitro. Moreover, severe combined immunodeficiency mice implanted subcutaneously with HepG2 stably infected with recombinant RCRs showed reduction of tumor growth and vascular endothelial growth factor expression, and no hypoxia-guided neovascularization. Combined treatment (RCRs+doxorubicin) improved efficacy in the context of in vitro hypoxia and in vivo (with either vACE-CREB or vACE-X3). This synergistic effect may lead to an improved efficacy and safety profile of the treatment that may result in fewer side effects. PMID- 27934883 TI - Preclinical evaluation of radiation and systemic, RGD-targeted, adeno-associated virus phage-TNF gene therapy in a mouse model of spontaneously metastatic melanoma. AB - The incidence of melanoma in the United States continues to rise, with metastatic lesions notoriously recalcitrant to therapy. There are limited effective treatment options available and a great need for more effective therapies that can be rapidly integrated in the clinic. In this study, we demonstrate that the combination of RGD-targeted adeno-associated virus phage (RGD-AAVP-TNF) with hypofractionated radiation therapy results in synergistic inhibition of primary syngeneic B16 melanoma in a C57 mouse model. Furthermore, this combination appeared to modify the tumor microenvironment, resulting in decreased Tregs in the draining LN and increased tumor-associated macrophages within the primary tumor. Finally, there appeared to be a reduction in metastatic potential and a prolongation of overall survival in the combined treatment group. These results indicate the use of targeted TNF gene therapy vector with radiation treatment could be a valuable treatment option for patients with metastatic melanoma. PMID- 27934884 TI - Rapid, Affordable and Portable Medium-Throughput Molecular Device for Zika Virus. AB - Zika virus (ZIKV) has gained global attention as an etiologic agent of fetal microcephaly and Guillain-Barre syndrome. Existing immuno-based rapid tests often fail to distinguish between Zika and related flaviviruses that are common in affected regions of Central and South Americas and the Caribbean. The US CDC and qualified state health department laboratories can perform the reverse transcription polymerase chain reaction (RT-PCR) ZIKV test using highly sophisticated instruments with long turnaround times. The preliminary results of a portable and low-cost molecular diagnostics system for ZIKV infection are reported here. In less than 15 minutes, this low-cost platform can automatically perform high quality RNA extraction from up to 12 ZIKV-spiked urine samples simultaneously. It can also perform reverse transcription recombinase polymerase amplification reaction (RT-RPA) in <=15 minutes. The fluorescent signal produced from probe-based RT-RPA or RT-PCR assays can be monitored using LEDs and a smartphone camera. In addition, the RT-RPA and RT-PCR assays do not cross-react with dengue and chikungunya viral RNA. This low-cost system lacks complicated, sensitive and high cost components, making it suitable for resource-limited settings. It has the potential to offer simple sample-to-answer molecular diagnostics and can inform healthcare workers of patients' diagnosis promptly. PMID- 27934885 TI - Quantitative analysis of nonadiabatic effects in dense H3S and PH3 superconductors. AB - The comparison study of high pressure superconducting state of recently synthesized H3S and PH3 compounds are conducted within the framework of the strong-coupling theory. By generalization of the standard Eliashberg equations to include the lowest-order vertex correction, we have investigated the influence of the nonadiabatic effects on the Coulomb pseudopotential, electron effective mass, energy gap function and on the 2Delta(0)/TC ratio. We found that, for a fixed value of critical temperature (178 K for H3S and 81 K for PH3), the nonadiabatic corrections reduce the Coulomb pseudopotential for H3S from 0.204 to 0.185 and for PH3 from 0.088 to 0.083, however, the electron effective mass and ratio 2Delta(0)/TC remain unaffected. Independently of the assumed method of analysis, the thermodynamic parameters of superconducting H3S and PH3 strongly deviate from the prediction of BCS theory due to the strong-coupling and retardation effects. PMID- 27934886 TI - Foxa1 is essential for development and functional integrity of the subthalamic nucleus. AB - Inactivation of transcription factor Foxa1 in mice results in neonatal mortality of unknown cause. Here, we report that ablation of Foxa1 causes impaired development and loss of the subthalamic nucleus (STN). Functional deficits in the STN have been implicated in the etiology of Huntington's and Parkinson's disease. We show that neuronal ablation by Synapsin1-Cre-mediated Foxa1 deletion is sufficient to induce hyperlocomotion in mice. Transcriptome profiling of STN neurons in conditional Foxa1 knockout mice revealed changes in gene expression reminiscent of those in neurodegenerative diseases. We identified Ppargc1a, a transcriptional co-activator that is implicated in neurodegeneration, as a Foxa1 target. These findings were substantiated by the observation of Foxa1-dependent demise of STN neurons in conditional models of Foxa1 mutant mice. Finally, we show that the spontaneous firing activity of Foxa1-deficient STN neurons is profoundly impaired. Our data reveal so far elusive roles of Foxa1 in the development and maintenance of STN function. PMID- 27934888 TI - The world's road to water scarcity: shortage and stress in the 20th century and pathways towards sustainability. AB - Water scarcity is a rapidly growing concern around the globe, but little is known about how it has developed over time. This study provides a first assessment of continuous sub-national trajectories of blue water consumption, renewable freshwater availability, and water scarcity for the entire 20th century. Water scarcity is analysed using the fundamental concepts of shortage (impacts due to low availability per capita) and stress (impacts due to high consumption relative to availability) which indicate difficulties in satisfying the needs of a population and overuse of resources respectively. While water consumption increased fourfold within the study period, the population under water scarcity increased from 0.24 billion (14% of global population) in the 1900s to 3.8 billion (58%) in the 2000s. Nearly all sub-national trajectories show an increasing trend in water scarcity. The concept of scarcity trajectory archetypes and shapes is introduced to characterize the historical development of water scarcity and suggest measures for alleviating water scarcity and increasing sustainability. Linking the scarcity trajectories to other datasets may help further deepen understanding of how trajectories relate to historical and future drivers, and hence help tackle these evolving challenges. PMID- 27934887 TI - Aldosterone induces rapid sodium intake by a nongenomic mechanism in the nucleus tractus solitarius. AB - The purpose of this study was to determine whether aldosterone has a rapid action in the nucleus tractus solitarius (NTS) that increases sodium intake, and to examine whether this effect of aldosterone, if present, is mediated by G protein coupled estrogen receptor (GPER). Adult male Sprague-Dawley rats with a stainless steel cannula in the NTS were used. Aldosterone was injected into the NTS at the doses of 1, 5, 10 and 20 ng 0.1 MUl-1. A rapid dose-related increase of 0.3 M NaCl intake was induced within 30 min and this increase was not suppressed by the mineralocorticoid receptor (MR) antagonist spironolactone (10 ng 0.1 MUl-1). Water intake was not affected by aldosterone. The GPER agonist G-1 produced a parallel and significant increase in sodium intake, while pre-treatment with GPER antagonist G15 (10 ng 0.1 MUl-1) blocked the G-1 or aldosterone-induced rapid sodium intake. In addition, sodium intake induced by sodium depletion or low sodium diet fell within 30 min after injection into the NTS of the MR antagonist spironolactone, while G15 had no effect. Our results confirm previous reports, and support the hypothesis that aldosterone evokes rapid sodium intake through a non-genomic mechanism involving GPER in NTS. PMID- 27934890 TI - Plasmonic efficiencies of nanoparticles made of metal nitrides (TiN, ZrN) compared with gold. AB - Metal nitrides have been proposed to replace noble metals in plasmonics for some specific applications. In particular, while titanium nitride (TiN) and zirconium nitride (ZrN) possess localized plasmon resonances very similar to gold in magnitude and wavelength, they benefit from a much higher sustainability to temperature. For this reason, they are foreseen as ideal candidates for applications in nanoplasmonics that require high material temperature under operation, such as heat assisted magnetic recording (HAMR) or thermophotovoltaics. This article presents a detailed investigation of the plasmonic properties of TiN and ZrN nanoparticles in comparison with gold nanoparticles, as a function of the nanoparticle morphology. As a main result, metal nitrides are shown to be poor near-field enhancers compared to gold, no matter the nanoparticle morphology and wavelength. The best efficiencies of metal nitrides as compared to gold in term of near-field enhancement are obtained for small and spherical nanoparticles, and they do not exceed 60%. Nanoparticle enlargements or asymmetries are detrimental. These results mitigate the utility of metal nitrides for high-temperature applications such as HAMR, despite their high temperature sustainability. Nevertheless, at resonance, metal nitrides behave as efficient nanosources of heat and could be relevant for applications in thermoplasmonics, where heat generation is not detrimental but desired. PMID- 27934889 TI - Accurate Quantitative Sensing of Intracellular pH based on Self-ratiometric Upconversion Luminescent Nanoprobe. AB - Accurate quantitation of intracellular pH (pHi) is of great importance in revealing the cellular activities and early warning of diseases. A series of fluorescence-based nano-bioprobes composed of different nanoparticles or/and dye pairs have already been developed for pHi sensing. Till now, biological auto fluorescence background upon UV-Vis excitation and severe photo-bleaching of dyes are the two main factors impeding the accurate quantitative detection of pHi. Herein, we have developed a self-ratiometric luminescence nanoprobe based on forster resonant energy transfer (FRET) for probing pHi, in which pH-sensitive fluorescein isothiocyanate (FITC) and upconversion nanoparticles (UCNPs) were served as energy acceptor and donor, respectively. Under 980 nm excitation, upconversion emission bands at 475 nm and 645 nm of NaYF4:Yb3+, Tm3+ UCNPs were used as pHi response and self-ratiometric reference signal, respectively. This direct quantitative sensing approach has circumvented the traditional software based subsequent processing of images which may lead to relatively large uncertainty of the results. Due to efficient FRET and fluorescence background free, a highly-sensitive and accurate sensing has been achieved, featured by 3.56 per unit change in pHi value 3.0-7.0 with deviation less than 0.43. This approach shall facilitate the researches in pHi related areas and development of the intracellular drug delivery systems. PMID- 27934891 TI - Structure determination of molecules in an alignment laser field by femtosecond photoelectron diffraction using an X-ray free-electron laser. AB - We have successfully determined the internuclear distance of I2 molecules in an alignment laser field by applying our molecular structure determination methodology to an I 2p X-ray photoelectron diffraction profile observed with femtosecond X-ray free electron laser pulses. Using this methodology, we have found that the internuclear distance of the sample I2 molecules in an alignment Nd:YAG laser field of 6 * 1011 W/cm2 is elongated by from 0.18 to 0.30 A "in average" relatively to the equilibrium internuclear distance of 2.666 A. Thus, the present experiment constitutes a critical step towards the goal of femtosecond imaging of chemical reactions and opens a new direction for the study of ultrafast chemical reaction in the gas phase. PMID- 27934894 TI - Corrigendum: Abrupt switch to migratory night flight in a wild migratory songbird. PMID- 27934893 TI - Structural and fluctuational difference between two ends of Abeta amyloid fibril: MD simulations predict only one end has open conformations. AB - Abeta amyloid fibrils, which are related to Alzheimer's disease, have a cross beta structure consisting of two beta-sheets: beta1 and beta2. The Abeta peptides are thought to be serially arranged in the same molecular conformation along the fibril axis. However, to understand the amyloid extension mechanism, we must understand the amyloid fibril structure and fluctuation at the fibril end, which has not been revealed to date. Here, we reveal these features by all-atom molecular dynamics (MD) simulations of Abeta42 and Abeta40 fibrils in explicit water. The structure and fluctuation were observed to differ between the two ends. At the even end, the Abeta peptide always took a closed form wherein beta1 and beta2 were closely spaced. The Abeta peptide fluctuated more at the odd end and took an open form wherein the two beta-sheets were well separated. The differences are attributed to the stronger beta-sheet formation by the beta1 exposed at the even end than the beta2 exposed at the odd end. Along with the small fluctuations at the even end, these results explain why the fibril extends from one end only, as observed in experiments. Our MD results agree well with recent observations by high-speed atomic force microscopy. PMID- 27934892 TI - Genome maintenance and bioenergetics of the long-lived hypoxia-tolerant and cancer-resistant blind mole rat, Spalax: a cross-species analysis of brain transcriptome. AB - The subterranean blind mole rat, Spalax, experiences acute hypoxia-reoxygenation cycles in its natural subterranean habitat. At the cellular level, these conditions are known to promote genomic instability, which underlies both cancer and aging. However, Spalax is a long-lived animal and is resistant to both spontaneous and induced cancers. To study this apparent paradox we utilized a computational procedure that allows detecting differences in transcript abundance between Spalax and the closely related above-ground Rattus norvegicus in individuals of different ages. Functional enrichment analysis showed that Spalax whole brain tissues maintain significantly higher normoxic mRNA levels of genes associated with DNA damage repair and DNA metabolism, yet keep significantly lower mRNA levels of genes involved in bioenergetics. Many of the genes that showed higher transcript abundance in Spalax are involved in DNA repair and metabolic pathways that, in other species, were shown to be downregulated under hypoxia, yet are required for overcoming replication- and oxidative-stress during the subsequent reoxygenation. We suggest that these differentially expressed genes may prevent the accumulation of DNA damage in mitotic and post-mitotic cells and defective resumption of replication in mitotic cells, thus maintaining genome integrity as an adaptation to acute hypoxia-reoxygenation cycles. PMID- 27934895 TI - Corrigendum: The bacterial toxin CNF1 as a tool to induce retinal degeneration reminiscent of retinitis pigmentosa. PMID- 27934896 TI - Transient appearance of circulating tumor DNA associated with de novo treatment. AB - The limitation of circulating tumor DNA (ctDNA) is its inability to detect cancer cell subpopulations with few or no dying cells. Lung cancer patients subjected to the EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment were prospectively collected, and ctDNA levels represented by the activating and T790M mutations were measured. The first data set (21 patients) consisting of samples collected in the period from before initiation of EGFR-TKI to at least 2 weeks after initiation: the ctDNA dynamics generally exhibited a rapid decrease and/or a transient increase. In 4 patients, we detected a transient increase of ctDNA bearing activating mutations not identified in biopsy samples. ctDNA with the same genotypical pattern was identified in 7 out of the 39 patients of the second data set intended to include samples until the onset of disease progression. In 6 of the 7 patients, this unique ctDNA appeared in the early period after treatment initiation, and did not reappear even after disease progression or chemotherapy. In another patient, similar ctDNA appeared upon radiation therapy. The identification of ctDNA with a unique genotype indicates the presence of cancer cell subpopulations that normally contain few or no dying cells, but generate dead cells because of the treatment. PMID- 27934897 TI - Experimental and theoretical study on the driving force and glass flow by laser induced metal sphere migration in glass. AB - Light is able to remotely move matter. Among various driving forces, laser induced metal sphere migration in glass has been reported. The temperature on the laser-illuminated side of the sphere was higher than that on the non-illuminated side. This temperature gradient caused non-uniformity in the interfacial tension between the glass and the melted metal as the tension decreased with increasing temperature. In the present study, we investigated laser-induced metal sphere migration in different glasses using thermal flow calculations, considering the temperature dependence of the material parameters. In addition, the velocity of the glass flow generated by the metal sphere migration was measured and compared with thermal flow calculations. The migration velocity of the stainless steel sphere increased with increasing laser power density; the maximum velocity was 104 MUm/s in borosilicate glass and 47 MUm/s in silica glass. The sphere was heated to more than 2000 K. The temperature gradient of the interfacial tension between the stainless steel sphere and the glass was calculated to be -2.29 * 10 5 N/m/K for borosilicate glass and -2.06 * 10-5 N/m/K for silica glass. Glass flowed in the region 15-30 MUm from the surface of the sphere, and the 80-MUm sphere migrated in a narrow softened channel. PMID- 27934899 TI - Erratum: Novel amperometric glucose biosensor based on MXene nanocomposite. PMID- 27934898 TI - Observation of superconducting vortex clusters in S/F hybrids. AB - While Abrikosov vortices repel each other and form a uniform vortex lattice in bulk type-II superconductors, strong confinement potential profoundly affects their spatial distribution eventually leading to vortex cluster formation. The confinement could be induced by the geometric boundaries in mesoscopic-size superconductors or by the spatial modulation of the magnetic field in superconductor/ferromagnet (S/F) hybrids. Here we study the vortex confinement in S/F thin film heterostructures and we observe that vortex clusters appear near magnetization inhomogeneities in the ferromagnet, called bifurcations. We use magnetic force microscopy to image magnetic bifurcations and superconducting vortices, while high resolution scanning tunneling microscopy is used to obtain detailed information of the local electronic density of states outside and inside the vortex cluster. We find an intervortex spacing at the bifurcation shorter than the one predicted for the same superconductor in a uniform magnetic field equal to the thermodynamical upper critical field Hc2. This result is due to a local enhanced stray field and a competition between vortex-vortex repulsion and Lorentz force. Our findings suggest that special magnetic topologies could result in S/F hybrids that support superconductivity even when locally the vortex density exceeds the thermodynamic critical threshold value beyond which the superconductivity is destroyed. PMID- 27934900 TI - Corrigendum: PAK1 confers chemoresistance and poor outcome in non-small cell lung cancer via beta-catenin-mediated stemness. PMID- 27934901 TI - Towards peptide vaccines against Zika virus: Immunoinformatics combined with molecular dynamics simulations to predict antigenic epitopes of Zika viral proteins. AB - The recent outbreak of Zika virus (ZIKV) infection in Brazil has developed to a global health concern due to its likely association with birth defects (primary microcephaly) and neurological complications. Consequently, there is an urgent need to develop a vaccine to prevent or a medicine to treat the infection. In this study, immunoinformatics approach was employed to predict antigenic epitopes of Zika viral proteins to aid in development of a peptide vaccine against ZIKV. Both linear and conformational B-cell epitopes as well as cytotoxic T-lymphocyte (CTL) epitopes were predicted for ZIKV Envelope (E), NS3 and NS5 proteins. We further investigated the binding interactions of altogether 15 antigenic CTL epitopes with three class I major histocompatibility complex (MHC I) proteins after docking the peptides to the binding groove of the MHC I proteins. The stability of the resulting peptide-MHC I complexes was further studied by molecular dynamics simulations. The simulation results highlight the limits of rigid-body docking methods. Some of the antigenic epitopes predicted and analyzed in this work might present a preliminary set of peptides for future vaccine development against ZIKV. PMID- 27934902 TI - Effects of dose reduction on bone strength prediction using finite element analysis. AB - This study aimed to evaluate the effect of dose reduction, by means of tube exposure reduction, on bone strength prediction from finite-element (FE) analysis. Fresh thoracic mid-vertebrae specimens (n = 11) were imaged, using multi-detector computed tomography (MDCT), at different intensities of X-ray tube exposures (80, 150, 220 and 500 mAs). Bone mineral density (BMD) was estimated from the mid-slice of each specimen from MDCT images. Differences in image quality and geometry of each specimen were measured. FE analysis was performed on all specimens to predict fracture load. Paired t-tests were used to compare the results obtained, using the highest CT dose (500 mAs) as reference. Dose reduction had no significant impact on FE-predicted fracture loads, with significant correlations obtained with reference to 500 mAs, for 80 mAs (R2 = 0.997, p < 0.001), 150 mAs (R2 = 0.998, p < 0.001) and 220 mAs (R2 = 0.987, p < 0.001). There were no significant differences in volume quantification between the different doses examined. CT imaging radiation dose could be reduced substantially to 64% with no impact on strength estimates obtained from FE analysis. Reduced CT dose will enable early diagnosis and advanced monitoring of osteoporosis and associated fracture risk. PMID- 27934904 TI - Reevaluation of Performance of Electric Double-layer Capacitors from Constant current Charge/Discharge and Cyclic Voltammetry. AB - The electric characteristics of electric-double layer capacitors (EDLCs) are determined by their capacitance which is usually measured in the time domain from constant-current charging/discharging and cyclic voltammetry tests, and from the frequency domain using nonlinear least-squares fitting of spectral impedance. The time-voltage and current-voltage profiles from the first two techniques are commonly treated by assuming ideal RsC behavior in spite of the nonlinear response of the device, which in turn provides inaccurate values for its characteristic metrics [corrected]. In this paper we revisit the calculation of capacitance, power and energy of EDLCs from the time domain constant-current step response and linear voltage waveform, under the assumption that the device behaves as an equivalent fractional-order circuit consisting of a resistance Rs in series with a constant phase element (CPE(Q, alpha), with Q being a pseudocapacitance and alpha a dispersion coefficient). In particular, we show with the derived (Rs, Q, alpha)-based expressions, that the corresponding nonlinear effects in voltage-time and current-voltage can be encompassed through nonlinear terms function of the coefficient alpha, which is not possible with the classical RsC model. We validate our formulae with the experimental measurements of different EDLCs. PMID- 27934903 TI - Unlocking bat immunology: establishment of Pteropus alecto bone marrow-derived dendritic cells and macrophages. AB - Bats carry and shed many emerging infectious disease agents including Ebola virus and SARS-like Coronaviruses, yet they rarely display clinical symptoms of infection. Bat epithelial or fibroblast cell lines were previously established to study the bat immune response against viral infection. However, the lack of professional immune cells such as dendritic cells (DC) and macrophages has greatly limited the significance of current investigations. Using Pteropus alecto (P. alecto) GM-CSF plus IL4, FLT3L and CSF-1, we successfully generated bat bone marrow-derived DC and macrophages. Cells with the phenotype, morphology and functional features of monocyte-derived DC, bona fide DC or macrophages were obtained in GM-CSF/IL4, FLT3L or CSF-1 cultures, respectively. The successful generation of the first bat bone marrow-derived immune cells paves the way to unlocking the immune mechanisms that confer host resilience to pathogens in bats. PMID- 27934905 TI - Contributions of rational soil tillage to compaction stress in main peanut producing areas of China. AB - Tillage intensities largely affect soil compaction dynamics in agro-ecosystems. However, the contribution of tillage intensities on compaction changes in underground peanut (Arachis hypogaea) fields has not been quantified. We thus aimed to better understand the role of soil tillage intensities in mitigation of compaction stress for peanuts. Using three field tillage experiments in major Chinese peanut producing areas, we quantified the effects of (1) no tillage, (2) shallow (20 cm) plowing, (3) deep (30 cm) plowing and (4) deep (30 cm) loosening on changes in soil bulk density at 0-10 cm, 10-20 cm and 20-30 cm depths, roots and pods growth, and nutrient accumulation. Results showed that tillage management effectively mitigated soil compaction stress for peanut growth and production. Greater beneficial improvement for the underground growth of roots and pods, and N accumulation ranked as deep plowing > shallow plowing and deep loosening. Respective increases of 7.5% and 4.6% in root biomass productions and peanut yields were obtained when soil bulk density was decreased by 0.1 g cm-3. Our results suggest that the mitigation of soil compaction stress by deep plowing could be a key tillage strategy for increasing peanut yields in the field. PMID- 27934906 TI - Two-dimensional Fibonacci grating for far-field super-resolution imaging. AB - A two-dimensional (2D) Fibonacci grating is used to transform evanescent waves into propagating waves for far-field super-resolution imaging. By detecting far field intensity distributions of light field through objects in front of the 2D Fibonacci grating in free space at once, we can retrieve the image of objects with beyond lambda/7 spatial resolution. We also find that the coherent illumination case can give a better resolution than incoherent illumination case by such 2D grating-assisted imaging system. The analytical results are verified by numerical simulation. PMID- 27934907 TI - High-speed swept source optical coherence Doppler tomography for deep brain microvascular imaging. AB - Noninvasive microvascular imaging using optical coherence Doppler tomography (ODT) has shown great promise in brain studies; however, high-speed microcirculatory imaging in deep brain remains an open quest. A high-speed 1.3 MUm swept-source ODT (SS-ODT) system is reported which was based on a 200 kHz vertical-cavity-surface-emitting laser. Phase errors induced by sweep-trigger desynchronization were effectively reduced by spectral phase encoding and instantaneous correlation among the A-scans. Phantom studies have revealed a significant reduction in phase noise, thus an enhancement of minimally detectable flow down to 268.2 MUm/s. Further in vivo validation was performed, in which 3D cerebral-blood-flow (CBF) networks in mouse brain over a large field-of-view (FOV: 8.5 * 5 * 3.2 mm3) was scanned through thinned skull. Results showed that fast flows up to 3 cm/s in pial vessels and minute flows down to 0.3 mm/s in arterioles or venules were readily detectable at depths down to 3.2 mm. Moreover, the dynamic changes of the CBF networks elicited by acute cocaine such as heterogeneous responses in various vessel compartments and at different cortical layers as well as transient ischemic events were tracked, suggesting the potential of SS-ODT for brain functional imaging that requires high flow sensitivity and dynamic range, fast frame rate and a large FOV to cover different brain regions. PMID- 27934908 TI - TREM-2 promotes acquired cholesteatoma-induced bone destruction by modulating TLR4 signaling pathway and osteoclasts activation. AB - Triggering receptor expressed on myeloid cells (TREM) has been broadly studied in inflammatory disease. However, the expression and function of TREM-2 remain undiscovered in acquired cholesteatoma. The expression of TREM-2 was significantly higher in human acquired cholesteatoma than in normal skin from the external auditory canal, and its expression level was positively correlated with the severity of bone destruction. Furthermore, TREM-2 was mainly expressed on dendritic cells (DCs). In human acquired cholesteatoma, the expression of proinflammatory cytokines (IL-1beta, TNF-alpha and IL-6) and matrix metalloproteinases (MMP-2, MMP-8 and MMP-9) were up-regulated, and their expression levels were positively correlated with TREM-2 expression. Osteoclasts were activated in human acquired cholesteatoma. In an animal model, TREM-2 was up regulated in mice with experimentally acquired cholesteatoma. TREM-2 deficiency impaired the maturation of experimentally acquired cholesteatoma and protected against bone destruction induced by experimentally acquired cholesteatoma. Additional data showed that TREM-2 up-regulated IL-1beta and IL-6 expression via TLR4 instead of the TLR2 signaling pathway and promoted MMP-2 and MMP-8 secretion and osteoclast activation in experimentally acquired cholesteatoma. Therefore, TREM-2 might enhance acquired cholesteatoma-induced bone destruction by amplifying the inflammatory response via TLR4 signaling pathways and promoting MMP secretion and osteoclast activation. PMID- 27934909 TI - Characterization of the first double-stranded RNA bacteriophage infecting Pseudomonas aeruginosa. AB - Bacteriophages (phages) are widely distributed in the biosphere and play a key role in modulating microbial ecology in the soil, ocean, and humans. Although the role of DNA bacteriophages is well described, the biology of RNA bacteriophages is poorly understood. More than 1900 phage genomes are currently deposited in NCBI, but only 6 dsRNA bacteriophages and 12 ssRNA bacteriophages genome sequences are reported. The 6 dsRNA bacteriophages were isolated from legume samples or lakes with Pseudomonas syringae as the host. Here, we report the first Pseudomonas aeruginosa phage phiYY with a three-segmented dsRNA genome. phiYY was isolated from hospital sewage in China with the clinical P. aeruginosa strain, PAO38, as a host. Moreover, the dsRNA phage phiYY has a broad host range, which infects 99 out of 233 clinical P. aeruginosa strains isolated from four provinces in China. This work presented a detailed characterization of the dsRNA bacteriophage infecting P. aeruginosa. PMID- 27934911 TI - Effect of Kelp Waste Extracts on the Growth and Development of Pakchoi (Brassica chinensis L.). AB - To explore the effects of kelp waste extracts (KWE) on the growth and development of Brassia chinensis L., germination and greenhouse experiments were carried out under different concentrations of KWE. The results showed that a higher germination percentage (95%), associated with high germination index (8.70), germination energy (71.67%) and seedling vigor index (734.67), was obtained under a lower KWE concentration (2%) compared with the control. The radicle length (4.97 cm), fresh weight (0.32 g/10 seedlings) and dry weight (0.015 g/10 seedlings) were significantly increased in the treatment of 2% KWE. KWE also could enhance the root growth, the maximum leaf length * width and the fresh weight of plants, the optimal value of which increased by 8.37 cm, 58.14 cm2 and 7.76 g under the treatment of 10% KWE compared with the control respectively. Meanwhile, the contents of vitamin C and soluble sugars in pakchoi leaf were improved by 19.6 mg/100 g and 1.44 mg/g compared with the control, and the nitrate content was decreased by 212.27 mg/kg. Briefly, KWE could markedly stimulate the pakchoi seeds germination at a lower concentration (2%) and enhance the plant growth and quality at a higher concentration (10%). PMID- 27934913 TI - Erratum: Charge density waves in disordered media circumventing the Imry-Ma argument. PMID- 27934910 TI - Extensive genetic diversity of Rickettsiales bacteria in multiple mosquito species. AB - Rickettsiales are important zoonotic pathogens, causing severe disease in humans globally. Although mosquitoes are an important vector for diverse pathogens, with the exception of members of the genus Wolbachia little is known about their role in the transmission of Rickettsiales. Herein, Rickettsiales were identified by PCR in five species of mosquitoes (Anopheles sinensis, Armigeres subalbatus, Aedes albopictus, Culex quinquefasciatus and Cu. tritaeniorhynchus) collected from three Chinese provinces during 2014-2015. Subsequent phylogenetic analyses of the rrs, groEL and gltA genes revealed the presence of Anaplasma, Ehrlichia, Candidatus Neoehrlichia, and Rickettsia bacteria in mosquitoes, comprising nine documented and five tentative species bacteria, as well as three symbionts/endosybionts. In addition, bacteria were identified in mosquito eggs, larvae, and pupae sampled from aquatic environments. Hence, these data suggest that Rickettsiales circulate widely in mosquitoes in nature. Also of note was that Ehrlichia and Rickettsia bacteria were detected in each life stage of laboratory cultured mosquitoes, suggesting that Rickettsiales may be maintained in mosquitoes through both transstadial and transovarial transmission. In sum, these data indicate that mosquitoes may have played an important role in the transmission and evolution of Rickettsiales in nature. PMID- 27934912 TI - BIX01294, an inhibitor of histone methyltransferase, induces autophagy-dependent differentiation of glioma stem-like cells. AB - Glioblastoma (GBM) contains rare glioma stem-like cells (GSCs) with capacities of self-renewal, multi-lineage differentiation, and resistance to conventional therapy. Drug-induced differentiation of GSCs is recognized as a promising approach of anti-glioma therapy. Accumulating evidence suggests that unique properties of stem cells depend on autophagy. Here we demonstrate that BIX01294, an inhibitor of a G9a histone methyltransferase (introducing H3K9me2 and H3K27me3 repressive marks) triggers autophagy in human glioma cells. Pharmacological or genetic inhibition of autophagy decreased LC3-II accumulation and GFP-LC3 punctation in BIX01294-treated cells. GSCs-enriched spheres originating from glioma cells and GBM patient-derived cultures express lower levels of autophagy related (ATG) genes than the parental glioma cell cultures. Typical differentiation inducers that upregulate neuronal and astrocytic markers in sphere cultures, increase the level of ATG mRNAs. G9a binds to the promoters of autophagy (LC3B, WIPI1) and differentiation-related (GFAP, TUBB3) genes in GSCs. Higher H3K4me3 (an activation mark) and lower H3K9me2 (the repressive mark) levels at the promoters of studied genes were detected in serum-differentiated cells than in sphere cultures. BIX01294 treatment upregulates the expression of autophagy and differentiation-related genes in GSCs. Pharmacological inhibition of autophagy decreases GFAP and TUBB3 expression in BIX01294-treated GSCs suggesting that BIX01294-induced differentiation of GSCs is autophagy-dependent. PMID- 27934914 TI - Gestational age-dependency of height and body mass index trajectories during the first 3 years in Japanese small-for-gestational age children. AB - Gestational age (GA) is thought to affect height growth in small-for-gestational age (SGA) children. However, the GA-specific trajectories in body mass index (BMI) and early appearances of adiposity rebound (AR) have not been fully investigated in a cohort of Japanese SGA children. A longitudinal cohort study was conducted with 1063 SGA children born in Kobe, Japan, with sufficient records from birth to 3 years of age. Subjects were divided into subgroups based on GA: 39-41 weeks GA (n = 723), 37-38 weeks GA (n = 256), 34-36 weeks GA (n = 62), and <34 weeks GA (n = 22). Height and BMI were assessed at 4 months, 9 months, 1.5 years, and 3 years of age. The catch-up rate for height was GA-dependent. Most children with 39-41 weeks GA (91%) caught up by 4 months of age; however, lower GA was associated with a slower elevation in the catch-up rate. The BMI trajectory during the first 3 years was also GA-dependent, with a change in GA dependency at a boundary of 37 weeks GA. Approximately 7% of SGA children had already developed AR before 3 years of age. In conclusion, growth patterns during infancy and early childhood in SGA children differ depending on GA. PMID- 27934916 TI - Plant-derived cis-beta-ocimene as a precursor for biocompatible, transparent, thermally-stable dielectric and encapsulating layers for organic electronics. AB - This article presents low-temperature, one-step dry synthesis of optically transparent thermally-stable, biocompatible cis-beta-ocimene-based thin films for applications as interlayer dielectric and encapsulating layer for flexible electronic devices, e.g. OLEDs. Morphological analysis of thin films shows uniform, very smooth (Rq < 1 nm) and defect-free moderately hydrophilic surfaces. The films are optically transparent, with a refractive index of ~1.58 at 600 nm, an optical band gap of ~2.85 eV, and dielectric constant of 3.5-3.6 at 1 kHz. Upon heating, thin films are chemically and optically stable up to at least 200 degrees C, where thermal stability increases for films manufactured at higher RF power as well as for films deposited away from the plasma glow. Heating of the sample increases the dielectric constant, from 3.7 (25 degrees C) to 4.7 (120 degrees C) at 1 kHz for polymer fabricated at 25 W. Polymers are biocompatible with non-adherent THP-1 cells and adherent mouse macrophage cells, including LPS stimulated macrophages, and maintain their material properties after 48 h of immersion into simulated body fluid. The versatile nature of the films fabricated in this study may be exploited in next-generation consumer electronics and energy technologies. PMID- 27934915 TI - The defining DNA methylation signature of Floating-Harbor Syndrome. AB - Floating-Harbor syndrome (FHS) is an autosomal dominant genetic condition characterized by short stature, delayed osseous maturation, expressive language impairment, and unique facial dysmorphology. We previously identified mutations in the chromatin remodeling protein SRCAP (SNF2-related CBP Activator Protein) as the cause of FHS. SRCAP has multiple roles in chromatin and transcriptional regulation; however, specific epigenetic consequences of SRCAP mutations remain to be described. Using high resolution genome-wide DNA methylation analysis, we identified a unique and highly specific DNA methylation "epi-signature" in the peripheral blood of individuals with FHS. Both hyper and hypomethylated loci are distributed across the genome, preferentially occurring in CpG islands. Clonal bisulfite sequencing of two hypermethylated (FIGN and STPG2) and two hypomethylated (MYO1F and RASIP1) genes confirmed these findings. The identification of a unique methylation signature in FHS provides further insight into the biological function of SRCAP and provides a unique biomarker for this disorder. PMID- 27934917 TI - Co-delivery of docetaxel and palmitoyl ascorbate by liposome for enhanced synergistic antitumor efficacy. AB - Palmitoyl ascorbate (PA) as an antioxidant has the potential for the treatment of cancer. In the present study, a nanocarrier system was developed for co-delivery of docetaxel (DOC) with palmitoyl ascorbate and the therapeutic efficacy of a combination drug regimen was investigated. For this purpose, different ratios of docetaxel and palmitoyl ascorbate were co-encapsulated in a liposome and they all showed high encapsulation efficiency. The average diameters of the liposomes ranged from 140 to 170 nm. Negative zeta potential values were observed for all systems, ranged from -40 mV to -56 mV. Studies on drug release and cellular uptake of the co-delivery system demonstrated that both drugs were effectively taken up by the cells and released slowly. Moreover, the liposome loading drugs with DOC/PA concentration ratio of 1:200 showed the highest anti-tumor activity to three different types of tumor cells. The higher in vivo therapeutic efficacy with lower systemic toxicity of the DOC-PA200-LPs was also verified by the H22 tumor bearing mice model. Our results showed that such co-loaded delivery systems could serve as a promising therapeutic approach to improve clinical outcomes against hepatic carcinoma. PMID- 27934918 TI - Targeting ASC in NLRP3 inflammasome by caffeic acid phenethyl ester: a novel strategy to treat acute gout. AB - Gouty arthritis is caused by the deposition of uric acid crystals, which induce the activation of NOD-like receptor family, pyrin domain containing 3(NLRP3) inflammasome. The NLRP3 inflammasome, composed of NLRP3, the adaptor protein ASC, and caspase-1, is closely linked to the pathogenesis of various metabolic diseases including gouty arthritis. We investigated whether an orally administrable inhibitor of NLRP3 inflammasome was effective for alleviating the pathological symptoms of gouty arthritis and what was the underlying mechanism. In primary mouse macrophages, caffeic acid phenethyl ester(CAPE) blocked caspase 1 activation and IL-1beta production induced by MSU crystals, showing that CAPE suppresses NLRP3 inflammasome activation. In mouse gouty arthritis models, oral administration of CAPE suppressed MSU crystals-induced caspase-1 activation and IL-1beta production in the air pouch exudates and the foot tissues, correlating with attenuation of inflammatory symptoms. CAPE directly associated with ASC as shown by SPR analysis and co-precipitation, resulting in blockade of NLRP3-ASC interaction induced by MSU crystals. Our findings provide a novel regulatory mechanism by which small molecules harness the activation of NLRP3 inflammasome by presenting ASC as a new target. Furthermore, the results suggest the preventive or therapeutic strategy for NLRP3-related inflammatory diseases such as gouty arthritis using orally available small molecules. PMID- 27934919 TI - Chiral Sulfoxide-Induced Single Turn Peptide alpha-Helicity. AB - Inducing alpha-helicity through side-chain cross-linking is a strategy that has been pursued to improve peptide conformational rigidity and bio-availability. Here we describe the preparation of small peptides tethered to chiral sulfoxide containing macrocyclic rings. Furthermore, a study of structure-activity relationships (SARs) disclosed properties with respect to ring size, sulfur position, oxidation state, and stereochemistry that show a propensity to induce alpha-helicity. Supporting data include circular dichroism spectroscopy (CD), NMR spectroscopy, and a single crystal X-ray structure for one such stabilized peptide. Finally, theoretical studies are presented to elucidate the effect of chiral sulfoxides in inducing backbone alpha-helicity. PMID- 27934920 TI - Functional human induced hepatocytes (hiHeps) with bile acid synthesis and transport capacities: A novel in vitro cholestatic model. AB - Drug-induced cholestasis is a leading cause of drug withdrawal. However, the use of primary human hepatocytes (PHHs), the gold standard for predicting cholestasis in vitro, is limited by their high cost and batch-to-batch variability. Mature hepatocyte characteristics have been observed in human induced hepatocytes (hiHeps) derived from human fibroblast transdifferentiation. Here, we evaluated whether hiHeps could biosynthesize and excrete bile acids (BAs) and their potential as PHH alternatives for cholestasis investigations. Quantitative real time PCR (qRT-PCR) and western blotting indicated that hiHeps highly expressed BA synthases and functional transporters. Liquid chromatography tandem mass spectrometry (LC-MS/MS) showed that hiHeps produced normal intercellular unconjugated BAs but fewer conjugated BAs than human hepatocytes. When incubated with representative cholestatic agents, hiHeps exhibited sensitive drug-induced bile salt export pump (BSEP) dysfunction, and their response to cholestatic agent mediated cytotoxicity correlated well with that of PHHs (r2 = 0.8032). Deoxycholic acid (DCA)-induced hepatotoxicity in hiHeps was verified by elevated aspartate aminotransferase (AST) and gamma-glutamyl-transferase (gamma-GT) levels. Mitochondrial damage and cell death suggested DCA-induced toxicity in hiHeps, which were attenuated by hepatoprotective drugs, as in PHHs. For the first time, hiHeps were reported to biosynthesize and excrete BAs, which could facilitate predicting cholestatic hepatotoxicity and screening potential therapeutic drugs against cholestasis. PMID- 27934921 TI - Acid-sensing ion channels are expressed in the ventrolateral medulla and contribute to central chemoreception. AB - The role of acid-sensing ion channels (ASICs) in the ventrolateral medulla (VLM) remains uncertain. Here, we found that ASIC1a and ASIC2 are widely expressed in rat medulla, and the expression level is higher at neonatal stage as compared to adult stage. The two ASIC subunits co-localized in medualla neurons. Furthermore, pH reduction triggered typical ASIC-type currents in the medulla, including the VLM. These currents showed a pH50 value of 6.6 and were blocked by amiloride. Based on their sensitivity to psalmotoxin 1 (PcTx1) and zinc, homomeric ASIC1a and heteromeric ASIC1a/2 channels were likely responsible for acid-mediated currents in the mouse medulla. ASIC currents triggered by pH 5 disappeared in the VLM neurons from ASIC1-/-, but not ASIC2-/- mice. Activation of ASICs in the medulla also triggered neuronal excitation. Moreover, microinjection of artificial cerebrospinal fluid at a pH of 6.5 into the VLM increased integrated phrenic nerve discharge, inspiratory time and respiratory drive in rats. Both amiloride and PcTx1 inhibited the acid-induced stimulating effect on respiration. Collectively, our data suggest that ASICs are highly expressed in the medulla including the VLM, and activation of ASICs in the VLM contributes to central chemoreception. PMID- 27934922 TI - Extreme Activity of Drug Nanocrystals Coated with A Layer of Non-Covalent Polymers from Self-Assembled Boric Acid. AB - Non-covalent polymers have remarkable advantages over synthetic polymers for wide biomedical applications. In this study, non-covalent polymers from self-assembled boric acid were used as the capping reagent to replace synthetic polymers in drug crystallization. Under acidic pH, boric acid self-assembled on the surface of drug nanocrystals to form polymers with network-like structures held together by hydrogen bonds. Coating driven by boric acid self-assembly had negligible effects on drug crystallinity and structure but resulted in drug nanocrystals with excellent dispersion properties that aided in the formation of a more stable suspension. Boric acid coating improved drug stability dramatically by preventing drug molecules from undergoing water hydrolysis in a neutral environment. More importantly, the specific reactivity of orthoboric groups to diols in cell glycocalyx facilitated a rapid cross-membrane translocation of drug nanocrystals, leading to efficient intracellular drug delivery, especially on cancer cells with highly expressed sialic acids. Boric acid coated nanocrystals of camptothecin, an anticancer drug with poor aqueous solubility and stability, demonstrated extreme cytotoxic activity (IC50 < 5.0 MUg/mL) to cancer cells compared to synthetic polymer coated CPT nanocrystals and free CPT. Surface coating using non-covalent polymers from self-assembled boric acid will have wide biomedical applications especially in biomaterials and drug delivery field. PMID- 27934923 TI - Timosaponin AIII induces antiplatelet and antithrombotic activity via Gq-mediated signaling by the thromboxane A2 receptor. AB - The thromboxane (Tx) A2 pathway is a major contributor to the amplification of initial platelet activation and is therefore a key drug target. To identify potent small-molecule inhibitors of the thromboxane prostaglandin (TP) receptor, we screened a small steroidal saponin library using U46619-induced rat platelet aggregation assays. Timosaponin AIII (TAIII) was identified as a potent inhibitor of U46619-induced rat platelet aggregation and exhibited superior selectivity for the TP receptor versus other G protein-coupled receptors and a PKC activator. TAIII inhibited U46619-induced rat platelet aggregation independent of increases in cAMP and cGMP and the inhibition of TxA2 production. Both PKC and PLC activators restored TAIII-inhibited platelet aggregation, whereas TAIII did not inhibit platelet aggregation induced by co-activation of the G12/13 and Gz pathways. Furthermore, TAIII did not affect the platelet shape change or ROCK2 phosphorylation evoked by low-dose U46619. In vivo, TAIII prolonged tail bleeding time, reduced the mortality of animals with acute pulmonary thromboembolism and significantly reduced venous thrombus weight. Our study suggests that TAIII, by preferentially targeting Gq-mediated PLC/PKC signaling from the TP receptor, induces stronger in vitro antiplatelet activity and in vivo antithrombotic effects and may be an excellent candidate for the treatment of thrombotic disorders. PMID- 27934924 TI - Improving the photovoltaic performance of perovskite solar cells with acetate. AB - In an all-solid-state perovskite solar cell, methylammonium lead halide film is in charge of generating photo-excited electrons, thus its quality can directly influence the final photovoltaic performance of the solar cell. This paper accentuates a very simple chemical approach to improving the quality of a perovskite film with a suitable amount of acetic acid. With introduction of acetate ions, a homogeneous, continual and hole-free perovskite film comprised of high-crystallinity grains is obtained. UV-visible spectra, steady-state and time resolved photoluminescence (PL) spectra reveal that the obtained perovskite film under the optimized conditions shows a higher light absorption, more efficient electron transport, and faster electron extraction to the adjoining electron transport layer. The features result in the optimized perovskite film can provide an improved short-circuit current. The corresponding solar cells with a planar configuration achieves an improved power conversion efficiency of 13.80%, and the highest power conversion efficiency in the photovoltaic measurements is up to 14.71%. The results not only provide a simple approach to optimizing perovskite films but also present a novel angle of view on fabricating high-performance perovskite solar cells. PMID- 27934926 TI - Ultrahigh-speed Si-integrated on-chip laser with tailored dynamic characteristics. AB - For on-chip interconnects, an ideal light source should have an ultralow energy consumption per bandwidth (operating en-ergy) as well as sufficient output power for error-free detection. Nanocavity lasers have been considered the most ideal for smaller operating energy. However, they have a challenge in obtaining a sufficient output power. Here, as an alternative, we propose an ultrahigh-speed microcavity laser structure, based on a vertical cavity with a high-contrast grating (HCG) mirror for transverse magnetic (TM) polarisation. By using the TM HCG, a very small mode volume and an un-pumped compact optical feedback structure can be realised, which together tailor the frequency response function for achieving a very high speed at low injection currents. Furthermore, light can be emitted laterally into a Si waveguide. From an 1.54-MUm optically-pumped laser, a 3-dB frequency of 27 GHz was obtained at a pumping level corresponding to sub-mA. Using measured 3-dB frequen-cies and calculated equivalent currents, the modulation current efficiency factor (MCEF) is estimated to be 42.1 GHz/mA1/2, which is superior among microcavity lasers. This shows a high potential for a very high speed at low injection currents or avery small heat generation at high bitrates, which are highly desirable for both on-chip and off-chip applications. PMID- 27934925 TI - Set anode potentials affect the electron fluxes and microbial community structure in propionate-fed microbial electrolysis cells. AB - Anode potential has been shown to be a critical factor in the rate of acetate removal in microbial electrolysis cells (MECs), but studies with fermentable substrates and set potentials are lacking. Here, we examined the impact of three different set anode potentials (SAPs; -0.25, 0, and 0.25 V vs. standard hydrogen electrode) on the electrochemical performance, electron flux to various sinks, and anodic microbial community structure in two-chambered MECs fed with propionate. Electrical current (49-71%) and CH4 (22.9-41%) were the largest electron sinks regardless of the potentials tested. Among the three SAPs tested, 0 V showed the highest electron flux to electrical current (71 +/- 5%) and the lowest flux to CH4 (22.9 +/- 1.2%). In contrast, the SAP of -0.25 V had the lowest electron flux to current (49 +/- 6%) and the highest flux to CH4 (41.1 +/- 2%). The most dominant genera detected on the anode of all three SAPs based on 16S rRNA gene sequencing were Geobacter, Smithella and Syntrophobacter, but their relative abundance varied among the tested SAPs. Microbial community analysis implies that complete degradation of propionate in all the tested SAPs was facilitated by syntrophic interactions between fermenters and Geobacter at the anode and ferementers and hydrogenotrophic methanogens in suspension. PMID- 27934927 TI - Sensitisation of an Azole-Resistant Aspergillus fumigatus Strain containing the Cyp51A-Related Mutation by Deleting the SrbA Gene. AB - Azoles are widely used for controlling fungal growth in both agricultural and medical settings. The target protein of azoles is CYP51, a lanosterol 14-alpha demethylase involved in the biosynthesis of ergosterol. Recently, a novel azole resistance mechanism has arisen in pathogenic fungal species Aspergillus fumigatus. Resistant strains contain a 34-bp or 46-bp tandem repeat (TR) in the promoter of cyp51A, and have disseminated globally in a short period of time. In this study, we investigated whether an azole-resistant strain with a 46-bp TR (TR46/Y121F/T289A) could be sensitised to azoles by deletion of srbA, encoding a direct regulator of cyp51A. The loss of SrbA did not affect colony growth or conidia production, but decreased expression of cyp51A. The srbA deletion strain showed hyper-susceptibility to medical azoles as well as azole fungicides, while its sensitivity to non-azole fungicides was unchanged. This is the first demonstration that deletion of a regulator of cyp51A can sensitise an azole resistant A. fumigatus strain. This finding may assist in the development of new drugs to help combat life-threatening azole-resistant fungal pathogens. PMID- 27934930 TI - Tailoring thermal conductivity via three-dimensional porous alumina. AB - Three-dimensional anodic alumina templates (3D-AAO) are an astonishing framework with open highly ordered three-dimensional skeleton structures. Since these templates are architecturally different from conventional solids or porous templates, they teem with opportunities for engineering thermal properties. By establishing the mechanisms of heat transfer in these frameworks, we aim to create materials with tailored thermal properties. The effective thermal conductivity of an empty 3D-AAO membrane was measured. As the effective medium theory was not valid to extract the skeletal thermal conductivity of 3D-AAO, a simple 3D thermal conduction model was developed, based on a mixed series and parallel thermal resistor circuit, giving a skeletal thermal conductivity value of approximately 1.25 W.m-1.K-1, which matches the value of the ordinary AAO membranes prepared from the same acid solution. The effect of different filler materials as well as the variation of the number of transversal nanochannels and the length of the 3D-AAO membrane in the effective thermal conductivity of the composite was studied. Finally, the thermal conductivity of two 3D-AAO membranes filled with cobalt and bismuth telluride was also measured, which was in good agreement with the thermal model predictions. Therefore, this work proved this structure as a powerful approach to tailor thermal properties. PMID- 27934928 TI - Comparison of non-Gaussian and Gaussian diffusion models of diffusion weighted imaging of rectal cancer at 3.0 T MRI. AB - Water molecular diffusion in vivo tissue is much more complicated. We aimed to compare non-Gaussian diffusion models of diffusion-weighted imaging (DWI) including intra-voxel incoherent motion (IVIM), stretched-exponential model (SEM) and Gaussian diffusion model at 3.0 T MRI in patients with rectal cancer, and to determine the optimal model for investigating the water diffusion properties and characterization of rectal carcinoma. Fifty-nine consecutive patients with pathologically confirmed rectal adenocarcinoma underwent DWI with 16 b-values at a 3.0 T MRI system. DWI signals were fitted to the mono-exponential and non Gaussian diffusion models (IVIM-mono, IVIM-bi and SEM) on primary tumor and adjacent normal rectal tissue. Parameters of standard apparent diffusion coefficient (ADC), slow- and fast-ADC, fraction of fast ADC (f), alpha value and distributed diffusion coefficient (DDC) were generated and compared between the tumor and normal tissues. The SEM exhibited the best fitting results of actual DWI signal in rectal cancer and the normal rectal wall (R2 = 0.998, 0.999 respectively). The DDC achieved relatively high area under the curve (AUC = 0.980) in differentiating tumor from normal rectal wall. Non-Gaussian diffusion models could assess tissue properties more accurately than the ADC derived Gaussian diffusion model. SEM may be used as a potential optimal model for characterization of rectal cancer. PMID- 27934929 TI - Use of polyvinylpyrrolidone-iodine solution for sterilisation and preservation improves mechanical properties and osteogenesis of allografts. AB - Allografts eliminate the disadvantages associated with autografts and synthetic scaffolds but are associated with a disease-transmission risk. Therefore, allograft sterilisation is crucial. We aimed to determine whether polyvinylpyrrolidone-iodine (PVP-I) can be used for sterilisation and as a new wet-preservation method. PVP-I-sterilised and preserved allografts demonstrated improved mechanical property, osteogenesis, and excellent microbial inhibition. A thigh muscle pouch model of nude mice showed that PVP-I-preserved allografts demonstrated better ectopic formation than Co60-sterilised allografts (control) in vivo (P < 0.05). Furthermore, the PVP-I-preserved group showed no difference between 24 h and 12 weeks of allograft preservation (P > 0.05). PVP-I-preserved allografts showed more hydrophilic surfaces and PVP-I-sterilised tendons showed higher mechanical strength than Co60-sterilised tendons (P < 0.05). The level of residual PVP-I was higher without washing and with prolonged preservation (P < 0.05). In vitro cellular tests showed that appropriate PVP-I concentration was nontoxic to preosteoblast cells, and cellular differentiation measured by alkaline phosphatase activity and osteogenic gene markers was enhanced (P < 0.05). Therefore, the improved biological performance of implanted allografts may be attributable to better surface properties and residual PVP-I, and PVP-I immersion can be a simple, easy method for allograft sterilisation and preservation. PMID- 27934931 TI - The impact of environmental parameters on microcystin production in dialysis bag experiments. AB - It is important to understand what environmental parameters may regulate microcystin (MC) production and congener type. To determine if environmental conditions in two hydraulically connected lakes can influence MC production and congener ratios, we incubated dialysis bags containing phytoplankton from mesotrophic/eutrophic Muskegon Lake into hypereutrophic Bear Lake (Michigan, USA) and vice versa. Strong cyanobacteria growth was observed in all dialysis bags with Bear Lake phytoplankton in July and August. Phytoplankton communities were dominated by Aphanizomenon aphanizomenoides, Microcystis wesenbergii, Limnothrix redekei. MC concentrations were correlated with M. wesenbergii and A. aphanizomenoides biovolume. MC concentrations in bags incubated in the Muskegon Lake with Bear Lake water were significantly higher than the other bags. The higher light intensity and total nitrogen concentration may have caused the increase of MC production. The MC-LR/MC-RR ratios varied with sample origin but not with lake of incubation, indicating that physical environmental factors (water temperature and turbidity) were not the reasons for different toxin production ratios. Differences in total phosphorus concentrations might be one reason for the dissimilarity of the MC-LR/MC-RR ratio between the two lakes. The higher light intensity and NO3-N concentration in Muskegon Lake are two factors contributing to an increase of MC production. PMID- 27934932 TI - Expression profiling and functional annotation of noncoding genes across 11 distinct organs in rat development. AB - Accumulating evidence suggests that noncoding RNAs (ncRNAs) have important regulatory functions. However, lacking of functional annotations for ncRNAs hampered us from carrying out the subsequent functional or predictive research. Here we dissected the expression profiles of 3,458 rat noncoding genes using rat bodymap RNA-sequencing data consisting of 11 solid organs over four developmental stages (juvenile, adolescent, adult and aged) from both sexes, and conducted a comprehensive analysis of differentially expressed noncoding genes (DEnGs) between various conditions. We then constructed a co-expression network between protein-coding and noncoding genes to infer biological functions of noncoding genes. Modules of interest were linked to online databases including DAVID for functional annotation and pathway analysis. Our results indicated that noncoding genes are functionally enriched through pathways similar to those of protein coding genes. Terms about development of the immune system were enriched with genes from age-related modules, whereas terms about sexual reproduction were enriched with genes in sex-related modules. We also built connection networks on some significant modules to visualize the interactions and regulatory relationship between protein-coding and noncoding genes. Our study could improve our understanding and facilitate a deeper investigation on organ/age/sex-related regulatory events of noncoding genes, which may lead to a superior preclinical model for drug development and translational medicine. PMID- 27934933 TI - Decadal shifts of East Asian summer monsoon in a climate model free of explicit GHGs and aerosols. AB - The East Asian summer monsoon (EASM) experienced decadal transitions over the past few decades, and the associated "wetter-South-drier-North" shifts in rainfall patterns in China significantly affected the social and economic development in China. Two viewpoints stand out to explain these decadal shifts, regarding the shifts either a result of internal variability of climate system or that of external forcings (e.g. greenhouse gases (GHGs) and anthropogenic aerosols). However, most climate models, for example, the Atmospheric Model Intercomparison Project (AMIP)-type simulations and the Coupled Model Intercomparison Project (CMIP)-type simulations, fail to simulate the variation patterns, leaving the mechanisms responsible for these shifts still open to dispute. In this study, we conducted a successful simulation of these decadal transitions in a coupled model where we applied ocean data assimilation in the model free of explicit aerosols and GHGs forcing. The associated decadal shifts of the three-dimensional spatial structure in the 1990s, including the eastward retreat, the northward shift of the western Pacific subtropical high (WPSH), and the south-cool-north-warm pattern of the upper-level tropospheric temperature, were all well captured. Our simulation supports the argument that the variations of the oceanic fields are the dominant factor responsible for the EASM decadal transitions. PMID- 27934934 TI - Long Duration of Ground Motion in the Paradigmatic Valley of Mexico. AB - Built-up on top of ancient lake deposits, Mexico City experiences some of the largest seismic site effects worldwide. Besides the extreme amplification of seismic waves, duration of intense ground motion from large subduction earthquakes exceeds three minutes in the lake-bed zone of the basin, where hundreds of buildings collapsed or were seriously damaged during the magnitude 8.0 Michoacan earthquake in 1985. Different mechanisms contribute to the long lasting motions, such as the regional dispersion and multiple-scattering of the incoming wavefield from the coast, more than 300 km away the city. By means of high performance computational modeling we show that, despite the highly dissipative basin deposits, seismic energy can propagate long distances in the deep structure of the valley, promoting also a large elongation of motion. Our simulations reveal that the seismic response of the basin is dominated by surface waves overtones, and that this mechanism increases the duration of ground motion by more than 170% and 290% of the incoming wavefield duration at 0.5 and 0.3 Hz, respectively, which are two frequencies with the largest observed amplification. This conclusion contradicts what has been previously stated from observational and modeling investigations, where the basin itself has been discarded as a preponderant factor promoting long and devastating shaking in Mexico City. PMID- 27934935 TI - Modulation of thermal noise and spectral sensitivity in Lake Baikal cottoid fish rhodopsins. AB - Lake Baikal is the deepest and one of the most ancient lakes in the world. Its unique ecology has resulted in the colonization of a diversity of depth habitats by a unique fauna that includes a group of teleost fish of the sub-order Cottoidei. This relatively recent radiation of cottoid fishes shows a gradual blue-shift in the wavelength of the absorption maximum of their visual pigments with increasing habitat depth. Here we combine homology modeling and quantum chemical calculations with experimental in vitro measurements of rhodopsins to investigate dim-light adaptation. The calculations, which were able to reproduce the trend of observed absorption maxima in both A1 and A2 rhodopsins, reveal a Barlow-type relationship between the absorption maxima and the thermal isomerization rate suggesting a link between the observed blue-shift and a thermal noise decrease. A Nakanishi point-charge analysis of the electrostatic effects of non-conserved and conserved amino acid residues surrounding the rhodopsin chromophore identified both close and distant sites affecting simultaneously spectral tuning and visual sensitivity. We propose that natural variation at these sites modulate both the thermal noise and spectral shifting in Baikal cottoid visual pigments resulting in adaptations that enable vision in deep water light environments. PMID- 27934936 TI - Polymer translocation through nano-pores in vibrating thin membranes. AB - Polymer translocation is a promising strategy for the next-generation DNA sequencing technologies. The use of biological and synthetic nano-pores, however, still suffers from serious drawbacks. In particular, the width of the membrane layer can accommodate several bases at the same time, making difficult accurate sequencing applications. More recently, the use of graphene membranes has paved the way to new sequencing capabilities, with the possibility to measure transverse currents, among other advances. The reduced thickness of these new membranes poses new questions on the effect of deformability and vibrations of the membrane on the translocation process, two features which are not taken into account in the well established theoretical frameworks. Here, we make a first step forward in this direction. We report numerical simulation work on a model system simple enough to allow gathering significant insight on the effect of these features on the average translocation time, with appropriate statistical significance. We have found that the interplay between thermal fluctuations and the deformability properties of the nano-pore play a crucial role in determining the process. We conclude by discussing new directions for further work. PMID- 27934937 TI - Spatiotemporal processing of somatosensory stimuli in schizotypy. AB - Unusual interaction behaviors and perceptual aberrations, like those occurring in schizotypy and schizophrenia, may in part originate from impaired remapping of environmental stimuli in the body space. Such remapping is contributed by the integration of tactile and proprioceptive information about current body posture with other exteroceptive spatial information. Surprisingly, no study has investigated whether alterations in such remapping occur in psychosis-prone individuals. Four hundred eleven students were screened with respect to schizotypal traits using the Schizotypal Personality Questionnaire. A subgroup of them, classified as low, moderate, and high schizotypes were to perform a temporal order judgment task of tactile stimuli delivered on their hands, with both uncrossed and crossed arms. Results revealed marked differences in touch remapping in the high schizotypes as compared to low and moderate schizotypes. For the first time here we reveal that the remapping of environmental stimuli in the body space, an essential function to demarcate the boundaries between self and external world, is altered in schizotypy. Results are discussed in relation to recent models of 'self-disorders' as due to perceptual incoherence. PMID- 27934938 TI - Changes in hippocampal AMPA receptors and cognitive impairments in chronic ketamine addiction models: another understanding of ketamine CNS toxicity. AB - Ketamine has been reported to impair human cognitive function as a recreational drug of abuse. However, chronic effects of ketamine on central nervous system need to be further explored. We set out to establish chronic ketamine addiction models by giving mice a three or six month course of daily intraperitoneal injections of ketamine, then examined whether long-term ketamine administration induced cognition deficits and changed hippocampal post-synaptic protein expression in adult mice. Behavior tests results showed that mice exhibited dose- and time-dependent learning and memory deficits after long-term ketamine administration. Western blot results showed levels of GluA1, p-S845 and p-S831 proteins demonstrated significant decline with ketamine 60 mg/kg until six months administration paradigm. But levels of p-S845 and p-S831 proteins exhibited obvious increase with ketamine 60 mg/kg three months administration paradigm. NR1 protein levels significantly decrease with ketamine 60 mg/kg three and six months administration paradigm. Our results indicate that reduced expression levels and decreased phosphorylation levels of hippocampal post-synaptic membrane GluA1- containing AMPA receptors maybe involved in cognition impairment after long-term ketamine administration. These findings provide further evidence for the cognitive damage of chronic ketamine addiction as a recreational drug. PMID- 27934939 TI - High-throughput compound evaluation on 3D networks of neurons and glia in a microfluidic platform. AB - With great advances in the field of in vitro brain modelling, the challenge is now to implement these technologies for development and evaluation of new drug candidates. Here we demonstrate a method for culturing three-dimensional networks of spontaneously active neurons and supporting glial cells in a microfluidic platform. The high-throughput nature of the platform in combination with its compatibility with all standard laboratory equipment allows for parallel evaluation of compound effects. PMID- 27934940 TI - Accelerated craniofacial bone regeneration through dense collagen gel scaffolds seeded with dental pulp stem cells. AB - Therapies using mesenchymal stem cell (MSC) seeded scaffolds may be applicable to various fields of regenerative medicine, including craniomaxillofacial surgery. Plastic compression of collagen scaffolds seeded with MSC has been shown to enhance the osteogenic differentiation of MSC as it increases the collagen fibrillary density. The aim of the present study was to evaluate the osteogenic effects of dense collagen gel scaffolds seeded with mesenchymal dental pulp stem cells (DPSC) on bone regeneration in a rat critical-size calvarial defect model. Two symmetrical full-thickness defects were created (5 mm diameter) and filled with either a rat DPSC-containing dense collagen gel scaffold (n = 15), or an acellular scaffold (n = 15). Animals were imaged in vivo by microcomputer tomography (Micro-CT) once a week during 5 weeks, whereas some animals were sacrificed each week for histology and histomorphometry analysis. Bone mineral density and bone micro-architectural parameters were significantly increased when DPSC-seeded scaffolds were used. Histological and histomorphometrical data also revealed significant increases in fibrous connective and mineralized tissue volume when DPSC-seeded scaffolds were used, associated with expression of type I collagen, osteoblast-associated alkaline phosphatase and osteoclastic-related tartrate-resistant acid phosphatase. Results demonstrate the potential of DPSC loaded-dense collagen gel scaffolds to benefit of bone healing process. PMID- 27934943 TI - Stable C &N isotopes in 2100 Year-B.P. human bone collagen indicate rare dietary dominance of C4 plants in NE-Italy. AB - C4 plants (e.g. maize, millet), part of our current diet, are only endemic of reduced areas in South-Europe due to their need of warm climates. Since the first vestiges of agriculture in Europe remains of C4 plants were recorded but their overall proportion in the human diet remains unknown. Therefore, isotopic (delta13C and delta15N) composition of bone collagen from the skeletal remains (human and animals) of a Celtic population, Cenomani Gauls, from Verona (3rd to 1st century BC) in the NE Italy provide a new perspective on this matter. The delta13C collagen values of 90 human skeletal individuals range between -20.20/00 and -9.70/00 (V-PDB) with a mean value of -15.30/00. As present day C4 plants have delta13C values around -110/00, which is equivalent to -9.50/00 for samples of preindustrial age, the less negative delta13C values in these individuals indicate a diet dominated by C4 plants. This palaeodietary study indicates that some European populations predominantly consumed cultivated C4 plants 2100 year B.P. This is supported by the paleobotanical records and ancient Roman sources (e.g. Pliny the Elder), which indicate that millet was a staple food in South Europe. PMID- 27934941 TI - Oral Cnm-positive Streptococcus Mutans Expressing Collagen Binding Activity is a Risk Factor for Cerebral Microbleeds and Cognitive Impairment. AB - Cerebral microbleeds (CMBs) are an important risk factor for stroke and dementia. We have shown that the collagen binding surface Cnm protein expressed on cnm positive Streptococcus mutans is involved in the development of CMBs. However, whether the collagen binding activity of cnm-positive S. mutans is related to the nature of the CMBs or to cognitive impairment is unclear. Two-hundred seventy nine community residents (70.0 years) were examined for the presence or absence of cnm-positive S. mutans in the saliva by PCR and collagen binding activity, CMBs, and cognitive function were evaluated. Cnm-positive S. mutans was detected more often among subjects with CMBs (p < 0.01) than those without. The risk of CMBs was significantly higher (odds ratio = 14.3) in the group with S. mutans expressing collagen binding activity, as compared to the group without that finding. Deep CMBs were more frequent (67%) and cognitive function was lower among subjects with cnm-positive S. mutans expressing collagen binding activity. This work supports the role of oral health in stroke and dementia and proposes a molecular mechanism for the interaction. PMID- 27934942 TI - Defective Acetylcholine Receptor Subunit Switch Precedes Atrophy of Slow-Twitch Skeletal Muscle Fibers Lacking ERK1/2 Kinases in Soleus Muscle. AB - To test the role of extracellular-signal regulated kinases 1 and 2 (ERK1/2) in slow-twitch, type 1 skeletal muscle fibers, we studied the soleus muscle in mice genetically deficient for myofiber ERK1/2. Young adult mutant soleus was drastically wasted, with highly atrophied type 1 fibers, denervation at most synaptic sites, induction of "fetal" acetylcholine receptor gamma subunit (AChRgamma), reduction of "adult" AChRepsilon, and impaired mitochondrial biogenesis and function. In weanlings, fiber morphology and mitochondrial markers were mostly normal, yet AChRgamma upregulation and AChRepsilon downregulation were observed. Synaptic sites with fetal AChRs in weanling muscle were ~3% in control and ~40% in mutants, with most of the latter on type 1 fibers. These results suggest that: (1) ERK1/2 are critical for slow-twitch fiber growth; (2) a defective gamma/epsilon-AChR subunit switch, preferentially at synapses on slow fibers, precedes wasting of mutant soleus; (3) denervation is likely to drive this wasting, and (4) the neuromuscular synapse is a primary subcellular target for muscle ERK1/2 function in vivo. PMID- 27934945 TI - Real-Time Optical Monitoring of Pt Catalyst Under the Potentiodynamic Conditions. AB - In situ monitoring of electrode materials reveals detailed physicochemical transition in electrochemical device. The key challenge is to explore the localized features of electrode surfaces, since the performance of an electrochemical device is determined by the summation of local architecture of the electrode material. Adaptive in situ techniques have been developed for numerous investigations; however, they require restricted measurement environments and provide limited information, which has impeded their widespread application. In this study, we realised an optics-based electrochemical in situ monitoring system by combining a dark-field micro/spectroscopy with an electrochemical workstation to investigate the physicochemical behaviours of Pt catalyst. We found that the localized plasmonic trait of a Pt-decorated Au nanoparticle as a model system varied in terms of its intensity and wavelength during the iterations of a cyclic voltammetry test. Furthermore, we show that morphological and compositional changes of the Pt catalyst can be traced in real time using changes in quantified plasmonic characteristics, which is a distinct advantage over the conventional electrochemistry-based in situ monitoring systems. These results indicate the substantial promise of online operando observation in a wide range of electrical energy conversion systems and electrochemical sensing areas. PMID- 27934944 TI - Overexpression of Glucocorticoid-induced Leucine Zipper (GILZ) increases susceptibility to Imiquimod-induced psoriasis and involves cutaneous activation of TGF-beta1. AB - Psoriasis vulgaris is a chronic inflammatory skin disease affecting millions of people. Its pathophysiology is complex and involves a skin compartment with epidermal and immune cells which produce cytokines, e.g. belonging to the IL-23 Th17-cell axis. Glucocorticoids (GCs) are the most common therapeutics used in cutaneous inflammatory disorders and GC-induced leucine zipper (GILZ) has emerged as a mediator of GCs due to its anti-inflammatory actions, theoretically lacking GC side-effects. We evaluated whether GILZ may provide a better therapeutic index in comparison to GCs during the onset and progression of psoriasis by generating and characterizing a mouse model with generalized overexpression of this protein (GILZ-Tg mice) and the imiquimod (IMQ) psoriasis model. Unexpectedly, in GILZ-Tg mice, the severity of IMQ-induced psoriasis-like skin lesions as well as induction of cytokines commonly up-regulated in human psoriasis (Il-17, Il-22, Il 23, Il-6, S100a8/a9, and Stat3) was significantly more pronounced relative to GILZ-Wt mice. The increased susceptibility to IMQ-induced psoriasis of GILZ-Tg mice was significantly associated with skin-specific over-activation of TGF-beta1 mediated signaling via SMAD2/3. Our findings demonstrate that GILZ may behave as pro-inflammatory protein in certain tissues and that, similar to prolonged GC therapy, GILZ as an alternative treatment for psoriasis may also have adverse effects. PMID- 27934946 TI - Global water cycle amplifying at less than the Clausius-Clapeyron rate. AB - A change in the cycle of water from dry to wet regions of the globe would have far reaching impact on humanity. As air warms, its capacity to hold water increases at the Clausius-Clapeyron rate (CC, approximately 7% degrees C-1). Surface ocean salinity observations have suggested the water cycle has amplified at close to CC following recent global warming, a result that was found to be at odds with state-of the art climate models. Here we employ a method based on water mass transformation theory for inferring changes in the water cycle from changes in three-dimensional salinity. Using full depth salinity observations we infer a water cycle amplification of 3.0 +/- 1.6% degrees C-1 over 1950-2010. Climate models agree with observations in terms of a water cycle amplification (4.3 +/- 2.0% degrees C-1) substantially less than CC adding confidence to projections of total water cycle change under greenhouse gas emission scenarios. PMID- 27934947 TI - Opposite effects of high- and low-frequency transcranial random noise stimulation probed with visual motion adaptation. AB - Transcranial random noise stimulation (tRNS) is a recent neuro-modulation technique whose effects at both behavioural and neural level are still debated. Here we employed the well-known phenomenon of motion after-effect (MAE) in order to investigate the effects of high- vs. low-frequency tRNS on motion adaptation and recovery. Participants were asked to estimate the MAE duration following prolonged adaptation (20 s) to a complex moving pattern, while being stimulated with either sham or tRNS across different blocks. Different groups were administered with either high- or low-frequency tRNS. Stimulation sites were either bilateral human MT complex (hMT+) or frontal areas. The results showed that, whereas no effects on MAE duration were induced by stimulating frontal areas, when applied to the bilateral hMT+, high-frequency tRNS caused a significant decrease in MAE duration whereas low-frequency tRNS caused a significant corresponding increase in MAE duration. These findings indicate that high- and low-frequency tRNS have opposed effects on the adaptation-dependent unbalance between neurons tuned to opposite motion directions, and thus on neuronal excitability. PMID- 27934949 TI - Giant magnetoresistance, three-dimensional Fermi surface and origin of resistivity plateau in YSb semimetal. AB - Very strong magnetoresistance and a resistivity plateau impeding low temperature divergence due to insulating bulk are hallmarks of topological insulators and are also present in topological semimetals where the plateau is induced by magnetic field, when time-reversal symmetry (protecting surface states in topological insulators) is broken. Similar features were observed in a simple rock-salt structure LaSb, leading to a suggestion of the possible non-trivial topology of 2D states in this compound. We show that its sister compound YSb is also characterized by giant magnetoresistance exceeding one thousand percent and low temperature plateau of resistivity. We thus performed in-depth analysis of YSb Fermi surface by band calculations, magnetoresistance, and Shubnikov-de Haas effect measurements, which reveals only three-dimensional Fermi sheets. Kohler scaling applied to magnetoresistance data accounts very well for its low temperature upturn behavior. The field-angle-dependent magnetoresistance demonstrates a 3D-scaling yielding effective mass anisotropy perfectly agreeing with electronic structure and quantum oscillations analysis, thus providing further support for 3D-Fermi surface scenario of magnetotransport, without necessity of invoking topologically non-trivial 2D states. We discuss data implying that analogous field-induced properties of LaSb can also be well understood in the framework of 3D multiband model. PMID- 27934948 TI - Thyroid hormone suppresses expression of stathmin and associated tumor growth in hepatocellular carcinoma. AB - Stathmin (STMN1), a recognized oncoprotein upregulated in various solid tumors, promotes microtubule disassembly and modulates tumor growth and migration activity. However, the mechanisms underlying the genetic regulation of STMN1 have yet to be elucidated. In the current study, we report that thyroid hormone receptor (THR) expression is negatively correlated with STMN1 expression in a subset of clinical hepatocellular carcinoma (HCC) specimens. We further identified the STMN1 gene as a target of thyroid hormone (T3) in the HepG2 hepatoma cell line. An analysis of STMN1 expression profile and mechanism of transcriptional regulation revealed that T3 significantly suppressed STMN1 mRNA and protein expression, and further showed that THR directly targeted the STMN1 upstream element to regulate STMN1 transcriptional activity. Specific knockdown of STMN1 suppressed cell proliferation and xenograft tumor growth in mice. In addition, T3 regulation of cell growth arrest and cell cycle distribution were attenuated by overexpression of STMN1. Our results suggest that the oncogene STMN1 is transcriptionally downregulated by T3 in the liver. This T3-mediated suppression of STMN1 supports the theory that T3 plays an inhibitory role in HCC tumor growth, and suggests that the lack of normal THR function leads to elevated STMN1 expression and malignant growth. PMID- 27934950 TI - A Predictive Model for Toxicity Effects Assessment of Biotransformed Hepatic Drugs Using Iterative Sampling Method. AB - Measuring toxicity is one of the main steps in drug development. Hence, there is a high demand for computational models to predict the toxicity effects of the potential drugs. In this study, we used a dataset, which consists of four toxicity effects:mutagenic, tumorigenic, irritant and reproductive effects. The proposed model consists of three phases. In the first phase, rough set-based methods are used to select the most discriminative features for reducing the classification time and improving the classification performance. Due to the imbalanced class distribution, in the second phase, different sampling methods such as Random Under-Sampling, Random Over-Sampling and Synthetic Minority Oversampling Technique are used to solve the problem of imbalanced datasets. ITerative Sampling (ITS) method is proposed to avoid the limitations of those methods. ITS method has two steps. The first step (sampling step) iteratively modifies the prior distribution of the minority and majority classes. In the second step, a data cleaning method is used to remove the overlapping that is produced from the first step. In the third phase, Bagging classifier is used to classify an unknown drug into toxic or non-toxic. The experimental results proved that the proposed model performed well in classifying the unknown samples according to all toxic effects in the imbalanced datasets. PMID- 27934951 TI - Biological marks of early-life socioeconomic experience is detected in the adult inflammatory transcriptome. AB - Consistent evidence is accumulating to link lower socioeconomic position (SEP) and poorer health, and the inflammatory system stands out as a potential pathway through which socioeconomic environment is biologically embedded. Using bloodderived genome-wide transcriptional profiles from 268 Italian participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we evaluated the association between early life, young and later adulthood SEP and the expression of 845 genes involved in human inflammatory responses. These were examined individually and jointly using several inflammatory scores. Our results consistently show that participants whose father had a manual (as compared to nonmanual) occupation exhibit, later in life, a higher inflammatory score, hence indicating an overall increased level of expression for the selected inflammatory-related genes. Adopting a life course approach, these associations remained statistically significant upon adjustment for later-in-life socioeconomic experiences. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated, and were replicated in an independent study. Our study provides additional evidence that childhood SEP is associated with a sustainable upregulation of the inflammatory transcriptome, independently of subsequent socioeconomic experiences. Our results support the hypothesis that early social inequalities impacts adult physiology. PMID- 27934953 TI - An analytical toolkit for polyploid willow discrimination. AB - Polyploid breeding is an important means for creating elite willow cultivars, and therefore provokes an active demand for discriminating the ploidy levels of natural willow stands. In this study, we established an analytical toolkit for polyploid willow identification by combining molecular markers and flow cytometry (FCM). A total of 10 single-copy fully informative SSRs were chosen for marker aided selection based on a segregation test with a full-sib willow pedigree and a mutability test with a collection of natural willow stands. Aided by these molecular markers, we performed polyploid selection in two tree species and two shrub species of the genus Salix. The ploidy levels of the investigated samples were further examined using a flow cytometer. It was previously shown that results from marker-aided selection were consistent with those from FCM measurements. Based on ploidy level assessment in different willow species, it was found that tree willows were dominantly tetraploid, whereas shrub willows were most frequently diploid. With this analytical toolkit, polyploids can be rapidly screened from a large number of natural stands; thereafter, the exact ploidy levels of the polyploid candidates can be efficiently confirmed by FCM. This analytical toolkit will greatly enhance polyploid breeding programs for willows. PMID- 27934952 TI - Effect of arginine on oligomerization and stability of N-acetylglutamate synthase. AB - N-acetylglutamate synthase (NAGS; E.C.2.3.1.1) catalyzes the formation of N acetylglutamate (NAG) from acetyl coenzyme A and glutamate. In microorganisms and plants, NAG is the first intermediate of the L-arginine biosynthesis; in animals, NAG is an allosteric activator of carbamylphosphate synthetase I and III. In some bacteria bifunctional N-acetylglutamate synthase-kinase (NAGS-K) catalyzes the first two steps of L-arginine biosynthesis. L-arginine inhibits NAGS in bacteria, fungi, and plants and activates NAGS in mammals. L-arginine increased thermal stability of the NAGS-K from Maricaulis maris (MmNAGS-K) while it destabilized the NAGS-K from Xanthomonas campestris (XcNAGS-K). Analytical gel chromatography and ultracentrifugation indicated tetrameric structure of the MmMNAGS-K in the presence and absence of L-arginine and a tetramer-octamer equilibrium that shifted towards tetramers upon binding of L-arginine for the XcNAGS-K. Analytical gel chromatography of mouse NAGS (mNAGS) indicated either different oligomerization states that are in moderate to slow exchange with each other or deviation from the spherical shape of the mNAGS protein. The partition coefficient of the mNAGS increased in the presence of L-arginine suggesting smaller hydrodynamic radius due to change in either conformation or oligomerization. Different effects of L-arginine on oligomerization of NAGS may have implications for efforts to determine the three-dimensional structure of mammalian NAGS. PMID- 27934954 TI - STRAP Acts as a Scaffolding Protein in Controlling the TLR2/4 Signaling Pathway. AB - The WD40-repeat protein serine/threonine kinase receptor-associated protein (STRAP) is involved in the regulation of several biological processes, including cell proliferation and apoptosis, in response to various stresses. Here, we show that STRAP is a new scaffold protein that functions in Toll-like receptor (TLR) mediated immune responses. STRAP specifically binds transforming growth factor beta-activated kinase 1 (TAK1) and IkappaB kinase alpha (IKKalpha) along with nuclear factor-kappaB (NF-kappaB) subunit p65, leading to enhanced association between TAK1, IKKalpha, and p65, and subsequent facilitation of p65 phosphorylation and nuclear translocation. Consequently, the depletion of STRAP severely impairs interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and IL-1beta production, whereas its overexpression causes a significant increase in the secretion of these pro-inflammatory cytokines by TLR2 or TLR4 agonist stimulated macrophages. Notably, STRAP translocates to the nucleus and subsequently binds to NF-kappaB at later times after lipopolysaccharide (LPS) stimulation, resulting in prolonged IL-6 mRNA production. Moreover, the C terminal region of STRAP is essential for its functional activity in facilitating IL-6 production. Collectively, these observations suggest that STRAP acts as a scaffold protein that positively contributes to innate host defenses against pathogen infections. PMID- 27934955 TI - Objective breast tissue image classification using Quantitative Transmission ultrasound tomography. AB - Quantitative Transmission Ultrasound (QT) is a powerful and emerging imaging paradigm which has the potential to perform true three-dimensional image reconstruction of biological tissue. Breast imaging is an important application of QT and allows non-invasive, non-ionizing imaging of whole breasts in vivo. Here, we report the first demonstration of breast tissue image classification in QT imaging. We systematically assess the ability of the QT images' features to differentiate between normal breast tissue types. The three QT features were used in Support Vector Machines (SVM) classifiers, and classification of breast tissue as either skin, fat, glands, ducts or connective tissue was demonstrated with an overall accuracy of greater than 90%. Finally, the classifier was validated on whole breast image volumes to provide a color-coded breast tissue volume. This study serves as a first step towards a computer-aided detection/diagnosis platform for QT. PMID- 27934956 TI - Placental antibody transfer efficiency and maternal levels: specific for measles, coxsackievirus A16, enterovirus 71, poliomyelitis I-III and HIV-1 antibodies. AB - Maternal antibodies transported across the placenta can provide vital immunity against infectious pathogens for infants. We here examine maternal antibody (MA) levels and their association with neonatal antibody levels. Pregnant women of gestational age >=35 weeks were enrolled at a Guangzhou China hospital and mother infant paired sera were collected. Measles IgG antibody was detected using ELISA assay, neutralizing antibodies titers against coxsackievirus A16 (CA16), enterovirus 71 (EV71), PV I-III and HIV-1 were performed. 711 mother-infant pairs were enrolled and positive relationships for paired serums were found (r: 0.683 0.918). 81.6%, 87.0%, and 82.3% of mothers, and 87.3%, 72.7%, and 72.2% of newborns were positive for measles, CA16 and EV71 antibodies respectively. The highest Neonatal: maternal ratio (NMR) was found in measles (1.042) and the ratios for the other pathogens ranged from 0.84 to 1.00. Linear regressions showed that log(NMR) decreased by a factor of 0.04-15.43 as log(MA) levels increased. A second analysis restricted to maternal positive measles sera revealed that MA measles of was still inversely associated with NMR. Low NMR was found in high MA HIV + serums among 22 paired sera. MA levels appear to play a role determining transplacental antibody transfer; further study is needed to reveal the mechanism. PMID- 27934957 TI - Urban-development-induced Changes in the Diversity and Composition of the Soil Bacterial Community in Beijing. AB - Numerous studies have implicated urbanization as a major cause of loss of biodiversity. Most of them have focused on plants and animals, even though soil microorganisms make up a large proportion of that biodiversity. However, it is unclear how the soil bacterial community is affected by urban development. Here, paired-end Illumina sequencing of the 16 S rRNA gene at V4 region was performed to study the soil microbial community across Beijing's built-up area. Proteobacteria, Acidobacteria, Bacteroidetes, Actinobacteria, Gemmatimonadetes, Verrucomicrobia, Planctomycetes, and Chloroflexi were the dominant phyla in all samples, but the relative abundance of these phyla differed significantly across these concentric zones. The diversity and composition of the soil bacterial community were found to be closely correlated with soil pH. Variance partitioning analysis suggested that urban ring roads contributed 5.95% of the bacterial community variation, and soil environmental factors explained 17.65% of the variation. The results of the current work indicate that urban development can alter the composition and diversity of the soil microbial community, and showed pH to be a key factor in the shaping of the composition of the soil bacterial community. Urban development did have a strong impact on the bacterial community of urban soil in Beijing. PMID- 27934958 TI - Gram positive and Gram negative bacteria differ in their sensitivity to cold plasma. AB - Cold atmospheric-pressure plasma (CAP) is a relatively new method being investigated for antimicrobial activity. However, the exact mode of action is still being explored. Here we report that CAP efficacy is directly correlated to bacterial cell wall thickness in several species. Biofilms of Gram positive Bacillus subtilis, possessing a 55.4 nm cell wall, showed the highest resistance to CAP, with less than one log10 reduction after 10 min treatment. In contrast, biofilms of Gram negative Pseudomonas aeruginosa, possessing only a 2.4 nm cell wall, were almost completely eradicated using the same treatment conditions. Planktonic cultures of Gram negative Pseudomonas libanensis also had a higher log10 reduction than Gram positive Staphylococcus epidermidis. Mixed species biofilms of P. aeruginosa and S. epidermidis showed a similar trend of Gram positive bacteria being more resistant to CAP treatment. However, when grown in co-culture, Gram negative P. aeruginosa was more resistant to CAP overall than as a mono-species biofilm. Emission spectra indicated OH and O, capable of structural cell wall bond breakage, were present in the plasma. This study indicates that cell wall thickness correlates with CAP inactivation times of bacteria, but cell membranes and biofilm matrix are also likely to play a role. PMID- 27934960 TI - Nanoscale assembly of superconducting vortices with scanning tunnelling microscope tip. AB - Vortices play a crucial role in determining the properties of superconductors as well as their applications. Therefore, characterization and manipulation of vortices, especially at the single-vortex level, is of great importance. Among many techniques to study single vortices, scanning tunnelling microscopy (STM) stands out as a powerful tool, due to its ability to detect the local electronic states and high spatial resolution. However, local control of superconductivity as well as the manipulation of individual vortices with the STM tip is still lacking. Here we report a new function of the STM, namely to control the local pinning in a superconductor through the heating effect. Such effect allows us to quench the superconducting state at nanoscale, and leads to the growth of vortex clusters whose size can be controlled by the bias voltage. We also demonstrate the use of an STM tip to assemble single-quantum vortices into desired nanoscale configurations. PMID- 27934959 TI - HOPX functions as a tumour suppressor in head and neck cancer. AB - Head and neck squamous cell carcinoma (HNSCC) is generalized term that encompasses a diverse group of cancers that includes tumours of the oral cavity (OSCC), oropharynx (OPSCC) and nasopharynx (NPC). Genetic alterations that are common to all HNSCC types are likely to be important for squamous carcinogenesis. In this study, we have investigated the role of the homeodomain-only homeobox gene, HOPX, in the pathogenesis of HNSCC. We show that HOPX mRNA levels are reduced in OSCC and NPC cell lines and tissues and there is a general reduction of HOPX protein expression in these tumours and OPSCCs. HOPX promoter methylation was observed in a subset of HNSCCs and was associated with a worse overall survival in HPV negative tumours. RNAseq analysis of OSCC cells transfected with HOPX revealed a widespread deregulation of the transcription of genes related to epithelial homeostasis and ectopic over-expression of HOPX in OSCC and NPC cells inhibited cell proliferation, plating efficiency and migration, and enhanced sensitivity to UVA-induced apoptosis. Our results demonstrate that HOPX functions as a tumour suppressor in HNSCC and suggest a central role for HOPX in suppressing epithelial carcinogenesis. PMID- 27934961 TI - Minimum Electric Field Exposure for Seizure Induction with Electroconvulsive Therapy and Magnetic Seizure Therapy. AB - Lowering and individualizing the current amplitude in electroconvulsive therapy (ECT) has been proposed as a means to produce stimulation closer to the neural activation threshold and more focal seizure induction, which could potentially reduce cognitive side effects. However, the effect of current amplitude on the electric field (E-field) in the brain has not been previously linked to the current amplitude threshold for seizure induction. We coupled MRI-based E-field models with amplitude titrations of motor threshold (MT) and seizure threshold (ST) in four nonhuman primates (NHPs) to determine the strength, distribution, and focality of stimulation in the brain for four ECT electrode configurations (bilateral, bifrontal, right-unilateral, and frontomedial) and magnetic seizure therapy (MST) with cap coil on vertex. At the amplitude-titrated ST, the stimulated brain subvolume (23-63%) was significantly less than for conventional ECT with high, fixed current (94-99%). The focality of amplitude-titrated right unilateral ECT (25%) was comparable to cap coil MST (23%), demonstrating that ECT with a low current amplitude and focal electrode placement can induce seizures with E-field as focal as MST, although these electrode and coil configurations affect differently specific brain regions. Individualizing the current amplitude reduced interindividual variation in the stimulation focality by 40-53% for ECT and 26% for MST, supporting amplitude individualization as a means of dosing especially for ECT. There was an overall significant correlation between the measured amplitude-titrated ST and the prediction of the E-field models, supporting a potential role of these models in dosing of ECT and MST. These findings may guide the development of seizure therapy dosing paradigms with improved risk/benefit ratio. PMID- 27934962 TI - Artificial high birefringence in all-dielectric gradient grating for broadband terahertz waves. AB - Subwavelength dielectric gratings are widely applied in the phase and polarization manipulation of light. However, the dispersion of the normal dielectric gratings is not flat while their birefringences are not enough in the THz regime. In this paper, we have fabricated two all-dielectric gratings with gradient grids in the THz regime, of which artificial birefringence is much larger than that of the equal-grid dielectric grating demonstrated by both experiments and simulations. The transmission and dispersion characteristics are also improved since the gradient grids break the periodicity of grating lattices as a chirp feature. From 0.6-1.4 THz, a broadband birefringence reaches 0.35 with a low dispersion and good linearity of phase shift, and the maximum phase shift is 1.4pi. Furthermore, these gradient gratings are applied as half-wave plates and realize a linear polarization conversion with a conversion rate over 99%, also much higher than the equal-grid gratings. These gradient gratings show great advantages compared to the periodic gratings and provide a new way in the designing of artificial birefringence material. PMID- 27934963 TI - Experimental evidence for chemical mate guarding in a moth. AB - In polyandrous species, males seek to maximize their reproductive output by monopolizing their mate. Often the male transfers substances to the female that suppress her sexual receptivity or antagonize the behavior of competing males; both are usually transferred in seminal fluids and represent forms of chemical mate guarding. In moths, more long-range female sex pheromones have been identified than in any other animal group, and males often display with close range sex pheromones, yet odor-based post-copulatory mate guarding has not been described in moths so far. We tested the hypothesis that the male sex pheromone in the noctuid moth Heliothis virescens perfumes the female and functions as an anti-aphrodisiac. Indeed, virgin females perfumed with male pheromone extract, or with its main component, mated significantly less than control virgin females, and this effect persisted for two successive nights. This chemical mate guarding strategy was disadvantageous for H. virescens females, because the reproductive output of twice-mated females was significantly higher than that of once-mated females. Since the female and male sex pheromones are biosynthetically related in this and other moth species, chemical mate guarding may also impose selection pressure on the long-range female sex pheromone channel and consequently affect the evolution of sexual communication. PMID- 27934964 TI - Mitigate Cascading Failures on Networks using a Memetic Algorithm. AB - Research concerning cascading failures in complex networks has become a hot topic. However, most of the existing studies have focused on modelling the cascading phenomenon on networks and analysing network robustness from a theoretical point of view, which considers only the damage incurred by the failure of one or several nodes. However, such a theoretical approach may not be useful in practical situation. Thus, we first design a much more practical measure to evaluate the robustness of networks against cascading failures, termed Rcf. Then, adopting Rcf as the objective function, we propose a new memetic algorithm (MA) named MA-Rcf to enhance network the robustness against cascading failures. Moreover, we design a new local search operator that considers the characteristics of cascading failures and operates by connecting nodes with a high probability of having similar loads. In experiments, both synthetic scale free networks and real-world networks are used to test the efficiency and effectiveness of the MA-Rcf. We systematically investigate the effects of parameters on the performance of the MA-Rcf and validate the performance of the newly designed local search operator. The results show that the local search operator is effective, that MA-Rcf can enhance network robustness against cascading failures efficiently, and that it outperforms existing algorithms. PMID- 27934965 TI - Role and mechanism of the AMPK pathway in waterborne Zn exposure influencing the hepatic energy metabolism of Synechogobius hasta. AB - Previous studies have investigated the physiological responses in the liver of Synechogobius hasta exposed to waterborne zinc (Zn). However, at present, very little is known about the underlying molecular mechanisms of these responses. In this study, RNA sequencing (RNA-seq) was performed to analyse the differences in the hepatic transcriptomes between control and Zn-exposed S. hasta. A total of 36,339 unigenes and 1,615 bp of unigene N50 were detected. These genes were further annotated to the Nonredundant protein (NR), Nonredundant nucleotide (Nt), Swiss-Prot, Kyoto Encyclopedia of Genes and Genomes (KEGG), Clusters of Orthologous Groups (COG) and Gene Ontology (GO) databases. After 60 days of Zn exposure, 708 and 237 genes were significantly up- and down-regulated, respectively. Many differentially expressed genes (DEGs) involved in energy metabolic pathways were identified, and their expression profiles suggested increased catabolic processes and reduced biosynthetic processes. These changes indicated that waterborne Zn exposure increased the energy production and requirement, which was related to the activation of the AMPK signalling pathway. Furthermore, using the primary hepatocytes of S. hasta, we identified the role of the AMPK signalling pathway in Zn-influenced energy metabolism. PMID- 27934967 TI - Association between gut microbiota and diapause preparation in the cabbage beetle: a new perspective for studying insect diapause. AB - Gut microbiota mediate the nutritional metabolism and play important roles in human obesity. Diapausing insects accumulate large fat reserves and develop obese phenotypes in order to survive unfavorable conditions. However, the possibility of an association between gut microbiota and insect diapause has not been investigated. We used the Illumina MiSeq platform to compare gut bacterial community composition in nondiapause- (i.e. reproductive) and diapause-destined female cabbage beetles, Colaphellus bowringi, a serious pest of vegetables in Asia. Based on variation in the V3-V4 hypervariable region of 16S ribosomal RNA gene, we identified 99 operational taxonomic units and 17 core microbiota at the genus level. The relative abundance of the bacterial community differed between reproductive and diapause-destined female adults. Gut microbiota associated with human obesity, including Bacteroidetes, Firmicutes, and Proteobacteria, showed a good correlation with diapause. This association between gut microbiota and diapause in the cabbage beetle may open a new avenue for studying insect diapause, as well as developing a natural insect obesity model with which to explore the mechanisms responsible for human obesity. PMID- 27934966 TI - The mechanism of a formaldehyde-sensing transcriptional regulator. AB - Most organisms are exposed to the genotoxic chemical formaldehyde, either from endogenous or environmental sources. Therefore, biology has evolved systems to perceive and detoxify formaldehyde. The frmRA(B) operon that is present in many bacteria represents one such system. The FrmR protein is a transcriptional repressor that is specifically inactivated in the presence of formaldehyde, permitting expression of the formaldehyde detoxification machinery (FrmA and FrmB, when the latter is present). The X-ray structure of the formaldehyde treated Escherichia coli FrmR (EcFrmR) protein reveals the formation of methylene bridges that link adjacent Pro2 and Cys35 residues in the EcFrmR tetramer. Methylene bridge formation has profound effects on the pattern of surface charge of EcFrmR and combined with biochemical/biophysical data suggests a mechanistic model for formaldehyde-sensing and derepression of frmRA(B) expression in numerous bacterial species. PMID- 27934970 TI - Surface Characteristics of Silicon Nanowires/Nanowalls Subjected to Octadecyltrichlorosilane Deposition and n-octadecane Coating. AB - In this study, nanowires/nanowalls were generated on a silicon wafer through a chemical etching method. Octadecyltrichlorosilane (OTS) was deposited onto the nanowire/nanowall surfaces to alter their hydrophobicity. The hydrophobic characteristics of the surfaces were further modified via a 1.5-MUm-thick layer of n-octadecane coating on the OTS-deposited surface. The hydrophobic characteristics of the resulting surfaces were assessed using the sessile water droplet method. Scratch and ultraviolet (UV)-visible reflectivity tests were conducted to measure the friction coefficient and reflectivity of the surfaces. The nanowires formed were normal to the surface and uniformly extended 10.5 MUm to the wafer surface. The OTS coating enhanced the hydrophobic state of the surface, and the water contact angle increased from 27 degrees to 165 degrees . The n-octadecane coating formed on the OTS-deposited nanowires/nanowalls altered the hydrophobic state of the surface. This study provides the first demonstration that the surface wetting characteristics change from hydrophobic to hydrophilic after melting of the n-octadecane coating. In addition, this change is reversible; i.e., the hydrophilic surface becomes hydrophobic after the n octadecane coating solidifies at the surface, and the process again occurs in the opposite direction after the n-octadecane coating melts. PMID- 27934968 TI - K63-polyubiquitinated HAUSP deubiquitinates HIF-1alpha and dictates H3K56 acetylation promoting hypoxia-induced tumour progression. AB - Intratumoural hypoxia induces HIF-1alpha and promotes tumour progression, metastasis and treatment resistance. HIF-1alpha stability is regulated by VHL-E3 ligase-mediated ubiquitin-dependent degradation; however, the hypoxia-regulated deubiquitinase that stabilizes HIF-1alpha has not been identified. Here we report that HAUSP (USP7) deubiquitinase deubiquitinates HIF-1alpha to increase its stability, induce epithelial-mesenchymal transition and promote metastasis. Hypoxia induces K63-linked polyubiquitinated HAUSP at lysine 443 to enhance its functions. Knockdown of HAUSP decreases acetylation of histone 3 lysine 56 (H3K56Ac). K63-polyubiquitinated HAUSP interacts with a ubiquitin receptor CBP to specifically mediate H3K56 acetylation. ChIP-seq analysis of HAUSP and HIF-1alpha binding reveals two motifs responsive to hypoxia. HectH9 is the E3 ligase for HAUSP and a prognostic marker together with HIF-1alpha. This report demonstrates that hypoxia-induced K63-polyubiquitinated HAUSP deubiquitinates HIF-1alpha and causes CBP-mediated H3K56 acetylation on HIF-1alpha target gene promoters to promote EMT/metastasis, further defining HAUSP as a therapeutic target in hypoxia induced tumour progression. PMID- 27934972 TI - Molecular dynamics simulation of the structure and interfacial free energy barriers of mixtures of ionic liquids and divalent salts near a graphene wall. AB - A molecular dynamics study of mixtures of 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIm][BF4]) with magnesium tetrafluoroborate (Mg[BF4]2) confined between two parallel graphene walls is reported. The structure of the system is analyzed by means of ionic density profiles, lateral structure of the first layer close to the graphene surface and angular orientations of imidazolium cations. Free energy profiles for divalent magnesium cations are calculated using two different methods in order to evaluate the height of the potential barriers near the walls, and the results are compared with those of mixtures of the same ionic liquid and a lithium salt (Li[BF4]). Preferential adsorption of magnesium cations is analyzed using a simple model and compared to that of lithium cations, and vibrational densities of states are calculated for the cations close to the walls analyzing the influence of the graphene surface charge. Our results indicate that magnesium cations next to the graphene wall have a roughly similar environment to that in the bulk. Moreover, they face higher potential barriers and are less adsorbed on the charged graphene walls than lithium cations. In other words, magnesium cations have a more stable solvation shell than lithium ones. PMID- 27934969 TI - Quantitative HDL Proteomics Identifies Peroxiredoxin-6 as a Biomarker of Human Abdominal Aortic Aneurysm. AB - High-density lipoproteins (HDLs) are complex protein and lipid assemblies whose composition is known to change in diverse pathological situations. Analysis of the HDL proteome can thus provide insight into the main mechanisms underlying abdominal aortic aneurysm (AAA) and potentially detect novel systemic biomarkers. We performed a multiplexed quantitative proteomics analysis of HDLs isolated from plasma of AAA patients (N = 14) and control study participants (N = 7). Validation was performed by western-blot (HDL), immunohistochemistry (tissue), and ELISA (plasma). HDL from AAA patients showed elevated expression of peroxiredoxin-6 (PRDX6), HLA class I histocompatibility antigen (HLA-I), retinol binding protein 4, and paraoxonase/arylesterase 1 (PON1), whereas alpha-2 macroglobulin and C4b-binding protein were decreased. The main pathways associated with HDL alterations in AAA were oxidative stress and immune inflammatory responses. In AAA tissue, PRDX6 colocalized with neutrophils, vascular smooth muscle cells, and lipid oxidation. Moreover, plasma PRDX6 was higher in AAA (N = 47) than in controls (N = 27), reflecting increased systemic oxidative stress. Finally, a positive correlation was recorded between PRDX6 and AAA diameter. The analysis of the HDL proteome demonstrates that redox imbalance is a major mechanism in AAA, identifying the antioxidant PRDX6 as a novel systemic biomarker of AAA. PMID- 27934971 TI - Cognitions about bodily purity attenuate stress perception. AB - Based on the assumption that physical purity is associated with a clean slate impression, we examined how cognitions about bodily cleanliness modulate stress perception. Participants visualized themselves in a clean or dirty state before reporting the frequency of stress-related situations experienced in the past. In Study 1 (n = 519) and Study 2 (n = 647) cleanliness versus dirtiness cognitions reliably reduced stress perception. Further results and a mediation analysis revealed that this novel effect was not simply driven by participants' cognitive engagement in stress recall. Moreover, we found that participants' temporal engagement in the recall of past stressful events negatively correlated with the amount of perceived stress, indicating an ease-of-retrieval phenomenon. However, a direct manipulation of the number of recalled stressful events in Study 3 (n = 792) showed the opposite effect: few versus many recalled events increased the perceived frequency of past stress-related situations. Overall, these novel results indicate an interesting avenue for future research on cognitively oriented stress reduction interventions, add to the literature on purity-related clean slate effects, and may help to better understand washing rituals in patients with obsessive-compulsive disorders. PMID- 27934973 TI - Non-collinear ferromagnetic short range order in MgO decked multi-layered graphene. AB - A careful magnetic study of MgO decked multi-layered graphene (MDMLG), synthesized by a combustion process that does not involve the use of graphite (which can be a source of magnetic impurities) was conducted and an elaborate analysis of high-precision magnetization data permits us to completely rule out the presence of a long-range ferromagnetic (FM) ordering at temperatures T >= 2.5 K. Instead, a non-collinear FM short-range order persists up to temperatures as high as 300 K and a concomitant paramagnetic component is present at all the temperatures. The observed exponential temperature variations of the 'field cooled' and 'zero-field-cooled' magnetizations, remanent magnetization, saturation magnetization, coercive field, exchange field and random anisotropy field are shown to basically reflect the exponential growth of the correlation length for the spins at the zigzag edges of graphene as the temperature falls below the temperature, Tx ? 10 K where a crossover from extremely weak to moderately weak magnetic anisotropy occurs. In sharp contrast, a paramagnetic response is induced by the defects in nanometer-sized MgO crystallites in MDMLG. PMID- 27934974 TI - Electron spin resonance and fluorescence imaging assisted electrochemical approach for accurate and comprehensive monitoring of cellular hydrogen peroxide dynamics. AB - Dynamic alteration in the levels of cellular hydrogen peroxide (H2O2) is closely related to a variety of human diseases, as well as signal transduction pathways that regulate cell survival and death. Although qualitative or quantitative methods are available for measuring either intra- or extra-cellular H2O2 levels, accurate and comprehensive in situ detection of the real-time H2O2 dynamics of living cells remains a significant challenge. To solve this problem, a novel multi-dimensional in situ cell assay platform combining electrochemistry, electron spin resonance (ESR) and optical imaging is designed. In this platform, the real-time concentration of extracellular H2O2 released from stimulated cells can be accurately detected by ESR assisted chronoamperometry, while the level of intracellular H2O2 is simultaneously monitored via the incorporated fluorescence imaging. Accurately and simultaneously analyzing the level variations of extra- and intra-cellular reactive oxygen species based on our assay platform can complement each other for further precise and in-depth investigation of their membrane transport and related cellular signaling, which will benefit disease diagnosis and treatment. PMID- 27934975 TI - Xurography for microfluidics on a reactive solid. AB - In this paper, we propose a simple method to embed transparent reactive materials in a microfluidic cell, and to observe in situ the dissolution of the material. As an example, we show how to obtain the dissolution rate of a calcite window of optical quality, dissolved in water and hydrochloric acid (HCl). These fluids circulate at controlled flowrates in a channel which is obtained by xurography: double sided tape is cut out with a cutter plotter and placed between the calcite window and a non-reactive support. While the calcite window reacts in contact with the acid, its topography is measured in situ every 10 s using an interference microscope, with a pixel resolution of 4.9 MUm and a vertical resolution of 50 nm. In order to avoid inlet influence on the reaction, a thin layer of photoresist is added on the calcite surface at the inlet and outlet. This layer is also used as a non reactive reference surface. PMID- 27934976 TI - Influence of double (w1/o/w2) emulsion composition on lubrication properties. AB - Double (w1/o/w2) emulsions are potential fat replacers in foods. Fats are known for their lubricating properties, which contribute to texture perception. It is therefore of interest to understand how the composition of double emulsions influences lubrication properties. This study focuses on the understanding of the influence of the fraction of inner dispersed aqueous phase w1 and the gelation of the w1 droplets on the lubrication properties of double emulsions. The addition of an inner water phase w1 to the oil droplets decreased friction at low entrainment speeds due to adsorption of the lipophilic emulsifier polyglycerol polyricinoleate (PGPR) at the hydrophobic tribo-surface. At higher entrainment speeds, double emulsions with w1 fractions of up to 6% (corresponding to fat reduction of 20%) displayed comparable tribological behavior as full-fat single (o/w2) emulsions. For double emulsions with gelled w1 droplets at higher w1 fractions of up to 15% (corresponding to fat reduction of 50%), an increase in friction was observed compared to full-fat single (o/w2) emulsions. The increase in friction is probably related to the presence of gelled droplets expelled from the inner w1 into the outer w2 phase, and to the deformability of (w1/o) droplets. Lubrication decreased when gelled particles were expelled from the inner w1 phase to the outer w2 phase. Lubrication also decreased when the deformability of (w1/o) droplets decreased, since less deformable (w1/o) droplets spread less easily on the tribo-pair surface. Knowledge about lubrication properties of double emulsions can be used in future studies to relate composition to sensory perception and develop double emulsions further as fat replacers. PMID- 27934977 TI - Real-time observation of protein aggregates in pharmaceutical formulations using liquid cell electron microscopy. AB - Understanding the properties of protein-based therapeutics is a common goal of biologists and physicians. Technical barriers in the direct observation of small proteins or therapeutic agents can limit our knowledge of how they function in solution and in the body. Electron microscopy (EM) imaging performed in a liquid environment permits us to peer into the active world of cells and molecules at the nanoscale. Here, we employ liquid cell EM to directly visualize a protein based therapeutic in its native conformation and aggregate state in a time resolved manner. In combination with quantitative analyses, information from this work contributes new molecular insights toward understanding the behaviours of immunotherapies in a solution state that mimics the human body. PMID- 27934978 TI - 3D printed metal molds for hot embossing plastic microfluidic devices. AB - Plastics are one of the most commonly used materials for fabricating microfluidic devices. While various methods exist for fabricating plastic microdevices, hot embossing offers several unique advantages including high throughput, excellent compatibility with most thermoplastics and low start-up costs. However, hot embossing requires metal or silicon molds that are fabricated using CNC milling or microfabrication techniques which are time consuming, expensive and required skilled technicians. Here, we demonstrate for the first time the fabrication of plastic microchannels using 3D printed metal molds. Through optimization of the powder composition and processing parameters, we were able to generate stainless steel molds with superior material properties (density and surface finish) than previously reported 3D printed metal parts. Molds were used to fabricate poly(methyl methacrylate) (PMMA) replicas which exhibited good feature integrity and replication quality. Microchannels fabricated using these replicas exhibited leak-free operation and comparable flow performance as those fabricated from CNC milled molds. The speed and simplicity of this approach can greatly facilitate the development (i.e. prototyping) and manufacture of plastic microfluidic devices for research and commercial applications. PMID- 27934979 TI - Conformational adjustment for high-pressure glass formation of 1-alkyl-3 methylimidazolium tetrafluoroborate. AB - The conformational stability of 1-alkyl-3-methylimidazolium tetrafluoroborate ([Cnmim][BF4], n = 3-8) under high pressure was investigated using Raman spectroscopy to reveal the preferential role of the alkyl-chain length (n) in high-pressure glass transition. To evaluate this, we determined the intensity ratio (r) and differences in the partial molar volume (DeltaVtrans->gauche) between the whole trans and gauche conformers of the [Cnmim] cation using Raman intensities. Interestingly, both values were classified into a two alkyl-chain length region at the border of n = 5. The coulombic interaction (cation-anion interaction) for the conformational stability is the predominant factor below n = 5 (the cation-head portion: alkyl carbon number C < 5), and the alkyl-chain packing effect (cation-cation interaction) is the predominant factor above n = 5 (the cation-tail portion: C > 5). In combination with the conformational preference of the [Cnmim] cation under a high-pressure glassy state, the alkyl chain displays a preferential role, i.e., an increase in the gauche conformer of [Cnmim][BF4] adjusts to avoid crystallization (the conformational adjustment effect). In the presence of the coulombic interaction, the preferential role of the flexible alkyl chain is an important key to elucidate the mechanism of the complicated high-pressure phase transition behavior of ionic liquids. PMID- 27934980 TI - A novel micromixer based on the alternating current-flow field effect transistor. AB - Induced-charge electroosmosis (ICEO) phenomena have been attracting considerable attention as a means for pumping and mixing in microfluidic systems with the advantage of simple structures and low-energy consumption. We propose the first effort to exploit a fixed-potential ICEO flow around a floating electrode for microfluidic mixing. In analogy with the field effect transistor (FET) in microelectronics, the floating electrode act as a "gate" electrode for generating asymmetric ICEO flow and thus the device is called an AC-flow FET (AC-FFET). We take advantage of a tandem electrode configuration containing two biased center metal strips arranged in sequence at the bottom of the channel to generate asymmetric vortexes. The current device is manufactured on low-cost glass substrates via an easy and reliable process. Mixing experiments were conducted in the proposed device and the comparison between simulation and experimental results was also carried out, which indicates that the micromixer permits an efficient mixing effect. The mixing performance can be further enhanced by the application of a suitable phase difference between the driving electrode and the gate electrode or a square wave signal. Finally, we performed a critical analysis of the proposed micromixer in comparison with different mixer designs using a comparative mixing index (CMI). The novel methods put forward here offer a simple solution to mixing issues in microfluidic systems. PMID- 27934982 TI - Shape, electronic structure and steric effects of organometallic nanocatalysts: relevant tools to improve the synergy between theory and experiment. AB - Working closely with experimentalists on the comprehension of the surface properties of catalytically active organometallic nanoparticles (NPs) requires the development of several computational strategies which significantly differ from the cluster domain where a precise knowledge of their optimal geometry is a mandatory prerequisite to computational modeling. Theoretical simulations can address several properties of organometallic nanoparticles: the morphology of the metal core, the surface composition under realistic thermodynamic conditions, the relationship between adsorption energies and predictive descriptors of reactivity. It is in such context that an integrated package has been developed or adapted in our group: (i) one tool aims at building a wide variety of the typical shapes exhibited by nanoparticles. Using Reverse Monte Carlo modeling, a given shape can be optimized in order to fit pair distribution function data obtained from X-ray diffraction measurements; (ii) trends in density functional theory (DFT) adsorption energies of surface species can be rationalized and predicted by making use of simple descriptors. This is why we have proposed an extension of the d-band center model, that leads to the formulation of a generalized ligand-field theory. A comparison between cobalt and ruthenium is proposed in the case of a 55-atoms nanocluster. The accuracy of the generalized coordination number [Angew. Chem., Int. Ed., 2014, 53, 8316], a very simple coordination-activity criterion, is also assessed; (iii) the builder package is completed by the steric-driven grafting of ligands on the surface of metal NPs. It easily generates structures with adjustable surface composition values and coordination modes; (iv) after a local optimization at the DFT level of theory, DFT energies and normal modes of vibration can feed a general tool based on the ab initio thermodynamics method. This method aims at easily calculating an optimal surface composition under realistic temperature and pressure conditions. In addition to that, we also show to what extent knowledge of the density of states (DOS) and of the crystal overlap Hamilton population (COHP), both projected from a plane-wave basis set to a local basis set, sheds light on metal core-ligand chemical bonding. PMID- 27934981 TI - Novel DNA sensor system for highly sensitive and quantitative retrovirus detection using virus encoded integrase as a biomarker. AB - In the current study we describe a novel DNA sensor system that allows the detection of single catalytic DNA integration events mediated by retrovirus encoded integrase (IN) present in viral particles. This is achieved by rolling circle amplification mediated conversion of enzymatic reactions happening within nanometer dimensions to directly detectable micrometer sized DNA products. The system utilizes the unique integration reaction of IN to generate a surface anchored nicked DNA circle that serves as a substrate for rolling circle amplification and allows for specific, quantitative and sensitive detection of purified recombinant IN or virus particles with a detection limit of less than 30 virus particles per MUL of sample. Moreover, by modifying the nucleotide sequences of the utilized DNA it was possible to tailor the system to distinguish between the highly pathogenic lentivirus HIV and the gammaretrovirus murine leukemia virus present in a given sample. Infections with HIV remain a major threat to global health with more than 2 million new infections and 1 million deaths each year. The sensitive and specific detection of HIV particles based on IN activity holds promise for the development of a new type of diagnostic tools suitable for early (within hours of infection) detection of HIV, which would be valuable for prevention strategies as well as for efficient treatment. PMID- 27934983 TI - Syntheses, structures and magnetic properties of nine coordination polymers based on terphenyl-tetracarboxylic acid ligands. AB - Nine coordination polymers (CPs) [Mn(H3L)(H2L)0.5(phen)]n (1), [Ni2L(phen)2(MU2 H2O)]n (2), {[Mn2L(phen)2].(DMA)(H2O)}n (3), {[Co2L(MU2-H2O)(MU2-DMA)].DMF}n (4), [CoL0.5(H2O)(phen)]n (5), {[Ni2L(MU2-H2O)(MU2-DMA)].DMA}n (6), {[Co2L(MU2 H2O)(MU2-DMA)].DMA}n (7), {[Ni2L(MU2-H2O)(H2O)2(DMF)2].(H2O)2(DMF)}n (8), and {[Ni4L2(MU2-H2O)4(H2O)2].(H2O)2(NMP)}n (9) (H4L = 1,1':4',1''-terphenyl 2',4,4'',5'-tetracarboxylic acid, DMA = N,N-dimethylacetamine, DMF = N,N dimethylformamide, NMP = N-methyl-2-pyrrolidone, phen = 1,10-phenanthroline) have been synthesized and structurally characterized. Crystal structural analyses reveal that 1 features the uninodal 2D (4,4) network with the dinuclear Mn2(COO)2 units as 4-connected nodes. 3 and 5 possess the binodal 2D (4,4) network with dinuclear Mn2(COO)4/Co2O2 units and L4- ligands as 4-connected nodes, respectively. In 2 and 8, each dinuclear Ni2(COO)2(MU2-H2O) unit links to four L4 ligands and each L4- ligand bridges four dinuclear Ni2(COO)2(MU2-H2O) units to generate the 3D framework, which can also be rationalized as a binodal 4,4 connected (42.84)(42.84) topological network by considering the dinuclear Ni2(COO)2(MU2-H2O) units as non-planar 4-connected nodes and L4- ligands as planar 4-connected nodes, respectively. In 4, 6-7 and 9, there exist a series of parallel-aligned metal-carboxylate chains, which are linked along two directions by para-terphenyl moieties of L4- ligands to generate the 3D frameworks. Moreover, direct current magnetic susceptibility measurements were carried out to study their magnetic properties. In complexes 2 and 9, weak ferromagnetic interactions between the magnetic centers were observed. In addition, the other compounds show weak antiferromagnetic exchange interactions between the adjacent metal ions. PMID- 27934984 TI - Control of apoptosis by SMAR1. AB - The nuclear matrix associated protein SMAR1 is sensitive to p53 and acts as a stress inducer as well as a regulator in the p53 regulatory network. Depending on the amount of stress SMAR1 stimulates, it can drive the p53 dynamics in the system to various dynamical states which correspond to various cellular states. The behavior of p53 in these dynamical states is found to be multifractal, due to the mostly long range correlations and large scale fluctuations imparted by stress. This fractal behavior is exhibited in the topological properties of the networks constructed from these dynamical states, and is a signature of self organization to optimize information flow in the dynamics. The assortativity found in these networks is due to perturbation induced by stress, and indicates that the hubs in the time series play a significant role in stress management. SMAR1 can also regulate apoptosis in the presence of HDAC1, depending on the stress induced by it. PMID- 27934985 TI - Importance of specimen pretreatment for the low-level detection of mycobacterial lipoarabinomannan in human serum. AB - Patient care and prevention of disease outbreaks rely heavily on the performance of diagnostic tests. These tests are typically carried out in serum, urine, and other complex sample matrices, but are often plagued by a number of matrix effects such as nonspecific adsorption and complexation with circulating proteins. This paper demonstrates the importance of sample pretreatment to overcome matrix effects, enabling the low-level detection of a disease marker for tuberculosis (TB). The impact of pretreatment is illustrated by detecting a cell wall component unique to mycobacteria, lipoarabinomannan (LAM). LAM is a major virulence factor in the infectious pathology of Mycobacterium tuberculosis (Mtb) and has been successfully detected in the body fluids of TB-infected individuals; however, its clinical sensitivity - identifying patients with active infection - remains problematic. This and the companion paper show that the detection of LAM in an immunoassay is plagued by its complexation with proteins and other components in serum. Herein, we present the procedures and results from an investigation of several different pretreatment schemes designed to disrupt complexation and thereby improve detection. These sample pretreatment studies, aimed at determining the optimal conditions for complex disruption, were carried out by using a LAM simulant derived from the nonpathogenic M. smegmatis, a mycobacterium often used as a model for Mtb. We have found that a perchloric acid based pretreatment step improves the ability to detect this simulant by ~1500* with respect to that in untreated serum. This paper describes the approach to pretreatment, how pretreatment improves the detection of the LAM simulant in human serum, and the results from a preliminary investigation to identify possible contributors to complexation by fractionating serum according to molecular weight. The companion paper applies this pretreatment approach to assays of TB patient samples. PMID- 27934986 TI - A unique copper(ii)-assisted transformation of acetylacetone dioxime in acetone that leads to one-dimensional, quinoxaline-bridged coordination polymers. AB - The reactions of copper(ii) carboxylate sources with acetylacetone dioxime (acacdoH2) in Me2CO have been studied and a novel, metal ion-assisted ligand transformation has been discovered. The reaction of [Cu2(diba)4(dibaH)2] and acacdoH2 (1 : 1.5) in Me2CO has provided access to the complex {[Cu2(diba)4(qunx)]}n (1) in low yield (25-30%), where dibaH is 3,3 dimethylbutyric acid and qunx is quinoxaline. The [Cu2(piv)4(pivH)2]/acacdoH2 (1 : 1.5) reaction system in warm Me2CO, where pivH is pivalic acid, gave the analogous complex {[Cu2(piv)4(qunx)]}n (2) in moderate yield (~50%). Complexes 1 and 2 can be easily prepared by the direct 1 : 1 reactions between the corresponding copper(ii) carboxylate starting materials and qunx in Me2CO and MeOH, respectively. The formation of coordinated qunx in 1 and 2 is CuII-promoted (assisted) as suggested by the failure to synthesize the free qunx by a variety of reactions of acacdoH2 and Me2CO under aerobic conditions in the absence or even the presence of dibaH and pivH, respectively. The observed acacdoH2 -> qunx transformation is catalytic and new in the chemistry of the dioximes of beta diketones, and a mechanism has been proposed based on well-established reactions of organic chemistry. The mechanism is based on a double Beckmann rearrangement type transformation and the overall scheme is represented by the 1 : 1 : 1 reaction between acacdoH2, Me2CO and O2. Complexes 1 and 2 have similar molecular structures consisting of paddle-wheel {Cu2(eta1:eta1:MU-O2CR)4} units bridged by qunx ligands in a zigzag 1D chain arrangement. The geometry of the CuII ions is square pyramidal with a quinoxaline nitrogen atom occupying the apical position at each metal ion. Weak H bonds are present within the chains, the donors being qunx carbon atoms and the acceptors being coordinated carboxylate oxygen atoms. Neighbouring chains interact through C-Hpi interactions between diba-/piv- methyl groups and the "pyrazine" part of qunx forming layers which are stacked along the b (1) or a (2) axis through weak van der Waals interactions. The packing of the layers is different in the two structures, due to the different nature of the carboxylate ligands. Hirshfeld surface analysis of the two structures reveals the similarity of the interchain (intralayer) interactions. The IR and Raman data of 1 and 2 are discussed in terms of the coordination mode of the carboxylate groups and permit assignments of some characteristic bands/peaks of coordinated qunx. Dc magnetic susceptibility studies in the 1.8-310 K range reveal very strong antiferromagnetic CuIICuII exchange interactions within the carboxylate-bridged Cu2 units (J = -479 K for 1 and -532 K for 2 using the H = - J?S1.S2 spin Hamiltonian) and weaker antiferromagnetic interactions between the Cu2 units via the qunx superexchange pathways, with the latter being ~10% in strength compared to the former. A critical discussion of the acacdoH2 -> qunx transformation in 1 and 2 is provided in the light of other impressive, recently discovered CuII assisted transformations of acacdoH2, pointing out the key role of the solvent in the processes known to date. PMID- 27934987 TI - Electric field controlled CO2 capture and CO2/N2 separation on MoS2 monolayers. AB - Developing new materials and technologies for efficient CO2 capture, particularly for separation of CO2 post-combustion, will significantly reduce the CO2 concentration and its impacts on the environment. A challenge for CO2 capture is to obtain high performance adsorbents with both high selectivity and easy regeneration. Here, CO2 capture/regeneration on MoS2 monolayers controlled by turning on/off external electric fields is comprehensively investigated through a density functional theory calculation. The calculated results indicate that CO2 forms a weak interaction with MoS2 monolayers in the absence of an electric field, but strongly interacts with MoS2 monolayers when an electric field of 0.004 a.u. is applied. Moreover, the adsorbed CO2 can be released from the surface of MoS2 without any energy barrier once the electric field is turned off. Compared with the adsorption of CO2, the interactions between N2 and MoS2 are not affected significantly by the external electric fields, which indicates that MoS2 monolayers can be used as a robust absorbent for controllable capture of CO2 by applying an electric field, especially to separate CO2 from the post-combustion gas mixture where CO2 and N2 are the main components. PMID- 27934988 TI - Precise regulation of tilt angle of Si nanostructures via metal-assisted chemical etching. AB - The ability to regulate the tilt angle of Si nanostructures is important for their applications in photoelectric devices. Herein we demonstrate a facile method to precisely regulate the tilt angle of nanocones with metal-assisted chemical etching (MaCE) in a one-step process based on the systematic investigation of the formation mechanism of the tilt angle. With Au nanohole arrays as templates, the tilt angles of Si nanocone arrays can be tuned from 69.2 degrees to 88.6 degrees by varying the composition of the etchant. When the Si nanocone arrays are the same height (2.2 MUm), the reflectivity decreases with the decreasing of the tilt angle. When the tilt angle is 83.0 degrees , the average reflectivity is lowered to 1.37% in the 250-1000 nm range. This method can be applied for fabrication over a large area (as large as 2 cm * 2 cm). This chemical method should be applicable to other Si nanostructures, which may promote the applications of MaCE in semiconductor manufacturing. PMID- 27934990 TI - Kinetics of receptor-mediated endocytosis of elastic nanoparticles. AB - It is now widely recognized that mechanical properties play critical roles in the cell uptake of nanomaterials. Here we conduct a theoretical study on the kinetics of receptor-mediated endocytosis of elastic nanoparticles that is limited by receptor diffusion, specifically focusing on how the uptake rate depends on the nanoparticle stiffness and size, membrane tension and binding strength between membrane receptors and ligands grafted on the nanoparticle surface. It is shown that, while soft nanoparticles are energetically less prone to full wrapping than stiff ones, the wrapping of the former is kinetically faster than that of the latter. Spherical and cylindrical elastic nanoparticles show dramatic differences in the effect of stiffness on the uptake rate. Additional theoretical analysis is performed to investigate the role of the stochastic receptor-ligand binding in the endocytosis of elastic nanoparticles. The relation between the uptake efficiency and uptake proneness is discussed. This study provides new insight into the elasticity effects on cell uptake and may serve as a design guideline for the controlled endocytosis and diagnostics delivery. PMID- 27934989 TI - 2D analysis of polydisperse core-shell nanoparticles using analytical ultracentrifugation. AB - Accurate knowledge of the size, density and composition of nanoparticles (NPs) is of major importance for their applications. In this work the hydrodynamic characterization of polydisperse core-shell NPs by means of analytical ultracentrifugation (AUC) is addressed. AUC is one of the most accurate techniques for the characterization of NPs in the liquid phase because it can resolve particle size distributions (PSDs) with unrivaled resolution and detail. Small NPs have to be considered as core-shell systems when dispersed in a liquid since a solvation layer and a stabilizer shell will significantly contribute to the particle's hydrodynamic diameter and effective density. AUC measures the sedimentation and diffusion transport of the analytes, which are affected by the core-shell compositional properties. This work demonstrates that polydisperse and thus widely distributed NPs pose significant challenges for current state-of-the art data evaluation methods. The existing methods either have insufficient resolution or do not correctly reproduce the core-shell properties. First, we investigate the performance of different data evaluation models by means of simulated data. Then, we propose a new methodology to address the core-shell properties of NPs. This method is based on the parametrically constrained spectrum analysis and offers complete access to the size and effective density of polydisperse NPs. Our study is complemented using experimental data derived for ZnO and CuInS2 NPs, which do not have a monodisperse PSD. For the first time, the size and effective density of such structures could be resolved with high resolution by means of a two-dimensional AUC analysis approach. PMID- 27934991 TI - A homogeneous atomic layer MoS2(1-x)Se2x alloy prepared by low-pressure chemical vapor deposition, and its properties. AB - We report the growth of large-area monolayer MoS2(1-x)Se2x alloys with controlled morphologies using a low-pressure chemical vapor deposition (CVD) method. MoS2(1 x)Se2x alloys with different morphologies, created using the same growth time, have been observed by controlling the gaseous MoO3 precursor on substrates placed in regions with different temperatures. TEM observations clearly reveal that the as-synthesized monolayer MoS2(1-x)Se2x alloy is crystalline, with a hexagonal structure. XPS, Raman mapping, and EDS mapping clearly show the homogeneous substitution of ~2 atomic weight % Se through the whole crystal. Compared with a pristine CVD-grown monolayer of MoS2, the optical band gap differs by 4.52%, from 1.77 eV to 1.69 eV. Additionally, back-gated transistors fabricated on the monolayer MoS2(1-x)Se2x alloy exhibit n-type behavior at a current on/off ratio of ~104 and a high mobility value of 8.4 cm2 V-1 s-1. PMID- 27934993 TI - Atomically thin cesium lead bromide perovskite quantum wires with high luminescence. AB - We report a room-temperature colloidal synthesis of few-unit-cell-thick CsPbBr3 QWs with lengths over a hundred nanometers. The surfactant-directed oriented attachment growth mechanism was proposed to explain the formation of such CsPbBr3 QWs. Owing to the strong quantum confinement effect, the photoluminescence (PL) emission peak of few-unit-cell-thick CsPbBr3 QWs blue-shifted to 430 nm. The ensemble PL quantum yield (PLQY) of the few-unit-cell-thick CsPbBr3 QWs increased to 21.13% through a simple heat-treatment process. The improvement of PLQY was ascribed to the reduction of the density of surface trap states and defect states induced by the heat-treatment process. Notably, the dependence of the bandgap on the diameter with different numbers of unit cells was presented for the first time in 1-D CsPbBr3 QWs on the basis of the produced few-unit-cell-thick CsPbBr3 QWs. PMID- 27934992 TI - Highly efficient redox-driven reversible color switching of dye molecules via hydrogenation/oxygenation. AB - We report a novel reversible color switching system based on one-pot hydrogenation/oxygenation reactions over Pd/CeO2-x catalysts and fast interconversion of thionine (TH+) and leuco thionine (LTH). Oxygen vacancies produced by Pd-catalyzed instant hydrogenation of CeO2 and strong metal-support interaction (SMSI) could lead to fast color switching. PMID- 27934994 TI - Determination of the thermal, oxidative and photochemical degradation rates of scintillator liquid by fluorescence EEM spectroscopy. AB - The thermal, oxidative and photochemical stability of the scintillator liquid proposed for the SNO+ experiment has been tested experimentally using accelerated aging methods. The stability of the scintillator constituents was determined through fluorescence excitation emission matrix (EEM) spectroscopy and absorption spectroscopy, using parallel factor analysis (PARAFAC) as an multivariate analysis tool. By exposing the scintillator liquid to a well-known photon flux at 365 nm and by measuring the decay rate of the fluorescence shifters and the formation rate of their photochemical degradation products, we can place an upper limit on the acceptable photon flux as 1.38 +/- 0.09 * 10-11 photon mol L-1. Similarly, the oxidative stability of the scintillator liquid was determined by exposure to air at several elevated temperatures. Through measurement of the corresponding activation energy it was determined that the average oxygen concentration would have to be kept below 4.3-7.1 ppbw (headspace partial pressure below 24 ppmv). On the other hand, the thermal stability of the scintillator cocktail in the absence of light and oxygen was remarkable and poses no concern to the SNO+ experiment. PMID- 27934995 TI - The wetting behavior of aqueous surfactant solutions on wheat (Triticum aestivum) leaf surfaces. AB - In this research the wetting behavior of agro-surfactant solutions (Triton X-100, SDS, DTAB) on wheat leaf surfaces have been investigated based on the surface free energy, surface tension, and the contact angle. The results show that the contact angle of those surfactant solutions keeps constant with low adsorption at interfaces below 1 * 10-5 mol L-1. With the increase in concentration, the contact angles of Triton X-100 decrease sharply because the adsorption of molecules at solid-liquid interfaces (GammaSL') is several times greater than that at liquid-air interfaces (GammaLV). With regards to SDS and DTAB, the contact angle also decreases but is even larger than 90 degrees above the CMC, while the ratio of GammaSL' to GammaLV is about 1.20, demonstrating that the Gibbs surface excess is related to the structure of surfactant molecules. Obviously, besides the properties of wheat leaf surfaces and surfactant solutions, the wetting behavior mainly depends on their noncovalent interactions. Among these, the hydrophobic interaction is the main force promoting molecules to adsorb on the surface, with the assistance of the Lifshitz-van der Waals interactions and the electrostatic interactions. According to the mechanism of their wetting behavior on plant surfaces, the recipe of pesticide formulation can be adjusted with better wettability to reduce its loss, consequently improving pesticide utilization and decreasing environmental contamination. PMID- 27934996 TI - Large photoacoustic effect enhancement for ICG confined inside MCM-41 mesoporous silica nanoparticles. AB - Indocyanine green was encapsulated inside the pores of pegylated amino functionalized MCM-41 Mesoporous Silica Nanoparticles (ICG-MSNs). In addition to a greater stability and a decrease of toxicity, the photoacoustic effect of ICG MSNs increases by nearly 400% compared to free ICG due to fluorescence quenching and high photothermal conversion of the encapsulated dyes. Upon i.v. administration in tumor-bearing mice, an overall photoacoustic enhancement of ca. 25% was measured in the tumor region. PMID- 27934997 TI - Lead (Pb) exposure reduces global DNA methylation level by non-competitive inhibition and alteration of dnmt expression. AB - Low-dose exposure to lead (Pb) is connected to developmental neurological alterations by inducing molecular changes, such as aberrant gene expression patterns. The attributing molecular mechanism, however, is not well-elucidated. In this study, we revealed epigenetic features and mechanisms that can alter gene expression patterns by identifying changes in DNA methyltransferase (DNMT) activity, expression pattern and DNA methylation level using moelcular studies and a zebrafish animal model. We characterized the effects of Pb on the activities of various DNMTs in vitro and determined the molecular role of Pb in modulating DNMT activity via kinetic experiments. An exposure of 100 or 500 ppb of Pb was found to significantly lower the activity of maintenance DNMTs. The inhibition mechanism can be described using non-competitive Michaelis-Menten kinetics. A zebrafish animal model was then used to assess the biological significance of our findings. An embryonic exposure to 100 or 500 ppb Pb resulted in a significant change in global methylation levels consistent with previous studies using human and rodent model. Our study also suggests that Pb exposure in zebrafish alters the expression patterns of dnmt3 and dnmt4 which are human DNMT3b orthologs. The knowledge from this study suggests that Pb exposure can affect the activity of maintenance DNMTs via non-competitive inhibition, which has not been reported previously. Meanwhile, the expression pattern of de novo methyltransferases can also be altered. Collectively, they result in a reduction in global DNA methylation level in Pb-exposed zebrafish model, which can be compared to findings in human and rodent studies. PMID- 27934998 TI - Shear-driven segregation of dry granular materials with different friction coefficients. AB - We report the first experimental demonstration of bulk segregation in a shear driven dry granular mixture, where the particles only differ in their surface friction coefficients. We found that the smoother particles tend to sink to the bottom of the shear zone, while rough particles migrate to the top of the sample. This phenomenon is similar to the well known kinetic sieving in particle mixtures with size heterogeneity. In the present case the smooth particles have a higher probability to penetrate into voids created by the shearing than the rough ones. Discrete element simulations were carried out and reproduced the experimentally observed segregation patterns. Moreover, simulations performed in the absence of gravity revealed that rough particles tend to remain in the shear zone, while the smooth particles are being expelled from it. We propose a mechanism in which the smooth particles are driven towards regions of lower shear rate. PMID- 27934999 TI - Metal- and base-free reductive coupling reaction of P(O)-H with aryl/alkyl sulfonyl chlorides: a novel protocol for the construction of P-S-C bonds. AB - Novel and efficient synthesis of S-aryl/alkyl phosphinothioates from P(O)-H and aryl/alkyl sulfonyl chlorides under metal- and base-free conditions is described. This reaction provides an alternative strategy for the construction of P-S-C bonds in moderate to excellent yields. Moreover, this method can be readily applied to gram-scale preparation. PMID- 27935000 TI - Sheet-like and truncated-dodecahedron-like AgI structures via a surfactant assisted protocol and their morphology-dependent photocatalytic performance. AB - Silver halide-based structures have been attracting great interest as efficient visible-light-driven photocatalysts towards the photodegradation of organic pollutants, and those studies focusing on their morphology-dependent catalytic performances have received particular attention. While great advancements in this regard have been witnessed in the past few years with respect to AgCl- and AgBr based photocatalysts, relevant explorations concerning AgI-based species are relatively rare, even though the excellent durability of AgI-based structures renders them attractive candidates for potential photocatalytic uses. By means of chemical reactions between AgNO3 and tetramethylammonium iodide (TMAI), and AgNO3 and tetrabutylammonium iodide (TBAI), we herein report that AgI structures with a sheet-like and a truncated-dodecahedron-like morphology, respectively, could be controllably synthesized via a surfactant-assisted fabrication protocol. In our synthesis systems, AgNO3 works as the silver source, while the TMAI and TBAI surfactants serve not only as an iodine source but also as a directing reagent for controllable fabrication. It has been demonstrated that our AgI structures could work as visible-light-energized photocatalysts towards the photodegradation of methyl orange. We find that compared to their sheet-like counterparts, the truncated-dodecahedron-like AgI architectures exhibit substantially boosted catalytic performances. Moreover, we disclose that our truncated-dodecahedron like AgI-based species could display excellent photocatalytic stability, wherein their catalytic reactivity displays only trivial fluctuations under visible-light irradiation even after the photoreactions have been repeated 22 times continuously. Our work might not only introduce a facile protocol for the controllable synthesis of AgI structures but also pave an avenue for facile enhancement of their catalytic performances via morphology alterations. PMID- 27935001 TI - Elastocapillary bending of microfibers around liquid droplets. AB - We report on the elastocapillary deformation of flexible microfibers in contact with liquid droplets. A fiber is observed to bend more as the size of the contacting droplet is increased. At a critical droplet size, proportional to the bending elastocapillary length, the fiber is seen to spontaneously wind around the droplet. To rationalize these observations, we invoke a minimal model based on elastic beam theory, and find agreement with experimental data. Further energetic considerations provide a consistent prediction for the winding criterion. PMID- 27935002 TI - Connectivity, dynamics, and structure in a tetrahedral network liquid. AB - We report a detailed computational study by Brownian dynamics simulations of the structure and dynamics of a liquid of patchy particles which forms an amorphous tetrahedral network upon decreasing the temperature. The highly directional particle interactions allow us to investigate the system connectivity by discriminating the total set of particles into different populations according to a penta-modal distribution of bonds per particle. With this methodology we show how the particle bonding process is not randomly independent but it manifests clear bond correlations at low temperatures. We further explore the dynamics of the system in real space and establish a clear relation between particle mobility and particle connectivity. In particular, we provide evidence of anomalous diffusion at low temperatures and reveal how the dynamics is affected by the short-time hopping motion of the weakly bounded particles. Finally we widely investigate the dynamics and structure of the system in Fourier space and identify two quantitatively similar length scales, one dynamic and the other static, which increase upon cooling the system and reach distances of the order of few particle diameters. We summarize our findings in a qualitative picture where the low temperature regime of the viscoelastic liquid is understood in terms of an evolving network of long time metastable cooperative domains of particles. PMID- 27935003 TI - A temperature, pH and sugar triple-stimuli-responsive nanofluidic diode. AB - In this article, we have demonstrated for the first time a triple stimuli responsive nanofluidic diode that can rectify ionic current under multiple external stimuli including temperature, pH, and sugar. This diode was fabricated by immobilizing poly[2-(dimethylamino)ethyl methacrylate]-co-[4-vinyl phenylboronic acid] (P(DMAEMA-co-VPBA)) onto the wall of a single glass conical nanopore channel via surface-initiator atom transfer radical polymerization (SI ATRP). The copolymer brushes contain functional groups sensitive to pH, temperature and sugar that can induce charge and configuration change to affect the status of the pore wall. The experimental results confirmed that the P(DMAEMA co-VPBA) brush modified nanochannel regulated the ionic current rectification successfully under three different external stimuli. This biomimetically inspired research simulates the complex biological multi-functions of ion channels and promotes the development of "smart" biomimetic nanochannel systems for actuating and sensing applications. PMID- 27935004 TI - Elasto-electro-capillarity: drop equilibrium on a charged, elastic solid. AB - We present a study here on elasto-electro-capillarity - for the first time, the matter of drop equilibrium on a soft (elastic and incompressible) and charged solid has been studied. Charges on the elastic solid induce an electric double layer or EDL at the solid-drop interface. Our analysis accounts for the electrostatic wetting contribution of the EDL in the overall energy balance. Our results reveal that (a) with an increase in "softness", the equilibrium solid liquid contact angles show transition from the EDL-modified Young's law (rigid limit) to the EDL-modified Neumann's law (soft limit); (b) the EDL effects invariably enhance solid deformation and lower the apparent contact angle made by the drop with the undeformed solid; (c) the solid contact angles increase and the cusp made by the deformed solid undergoes enhanced rotation due to the EDL effects; and (d) the EDL effects are more prominent for the case where the solid vapor surface energy exceeds the solid-liquid surface energy. The fact that the EDL effects invariably decrease the overall wetting energy of the system, thereby supporting a larger increase in the elastic energy associated with a larger solid deformation, explains all these findings and establishes that surface charges enhance the "softness" of a soft surface in the context of elastocapillarity. PMID- 27935005 TI - Preoperative low level laser therapy in dogs undergoing tibial plateau levelling osteotomy: A blinded, prospective, randomized clinical trial. AB - OBJECTIVES: To evaluate the influence of preoperative low-level laser therapy (LLLT) on therapeutic outcomes of dogs undergoing tibial plateau levelling osteotomy (TPLO). METHODS: Healthy dogs undergoing TPLO were randomly assigned to receive either a single preoperative LLLT treatment (800-900 nm dual wavelength, 6 W, 3.5 J/cm2, 100 cm2 area) or a sham treatment. Lameness assessment and response to manipulation, as well as force plate analysis, were performed preoperatively, then again at 24 hours, two weeks, and eight weeks postoperatively. Radiographic signs of healing of the osteo-tomy were assessed at eight weeks postoperatively. RESULTS: Twenty-seven dogs (27 stifles) were included and no major complications occurred. At eight weeks postoperatively, a significant difference in peak vertical force analysis was noted between the LLLT (39.6% +/- 4.7%) and sham groups (28.9% +/- 2.6%), (p <0.01 Time, p <0.01 L). There were no significant differences noted between groups for all other parameters. The age of dogs in the LLLT group (6.6 +/- 1.6 years) was greater than that for the sham group (4.5 +/- 2.0, p <0.01). Although not significant, a greater proportion of LLLT dogs (5/8) had healed at the eight-week time point than in the sham group (3/12) despite the age difference (p = 0.11) Clinical significance: The results of this study demonstrate that improved peak vertical force could be related to the preoperative use of LLLT for dogs undergoing TPLO at eight weeks postoperatively. The use of LLLT may improve postoperative return to function following canine osteotomies and its use is recommended. PMID- 27935006 TI - Comparison of osteotomy technique and jig type in completion of distal femoral osteotomies for correction of medial patellar luxation. An in vitro study. AB - OBJECTIVES: Femoral osteotomies are frequently completed to correct malalignment associated with patellar luxation. The objectives of this study were to compare the use of: 1) two different types of jig; and 2) different types of osteotomy in the realignment of canine femoral bone models which possessed various iterations of angular deformity. METHODS: Models of canine femora possessing distal varus, external torsion and a combination of varus and torsion underwent correction utilizing two alignment jigs (Slocum jig and Deformity Reduction Device) and either a closing wedge ostectomy (CWO) or an opening wedge osteotomy (OWO). Post correctional alignment was evaluated by radiographic assessment and compared between groups. RESULTS: The use of the Slocum jig resulted in frontal plane overcorrection when used with CWO in models of femoral varus, and when used with OWO in models of femoral varus and external torsion when compared to other techniques. The Deformity Reduction Device tended to realign the frontal plane closer to the post-correction target value in all angulation types. The use of both jigs resulted in undercorrection in the transverse plane in models with varus and torsion. CLINICAL SIGNIFICANCE: Jig selection and osteotomy type may lead to different post-correctional alignment results when performing distal femoral osteotomies. Whereas OWO allows accurate correction when used with either jig to address frontal plane deformities, the Deformity Reduction Device can be utilized with both CWO and OWO to correct torsion-angulation femoral deformities to optimize frontal plane alignment. PMID- 27935007 TI - A response to: Traumatic fracture of the medial coronoid process in 24 dogs. PMID- 27935008 TI - Distal femoral lateral closing wedge osteotomy as a component of comprehensive treatment of medial patellar luxation and distal femoral varus in dogs. AB - OBJECTIVE: To describe a cohort of dogs with medial patellar luxation managed with a distal femoral lateral closing wedge ostectomy (DFO) as a component of comprehensive treatment, and to report radiographic and long-term clinical outcome of this technique. METHODS: Medical records of dogs that had a lateral closing wedge DFO as part of management of medial patellar luxation at three veterinary teaching hospitals were reviewed. Surgical reports as well as the preoperative, postoperative, and follow-up radiographs were reviewed. The anatomical lateral distal femoral angle (aLDFA) was determined. Long-term clinical outcome was assessed by telephone interview with the owner. RESULTS: A lateral closing wedge DFO was performed on 66 limbs. The mean pre- and postoperative aLDFA was 107.6 degrees +/- 5.8 degrees and 94.1 degrees +/- 4.2 degrees , respectively. Cranial cruciate ligament disease was identified in 28/66 affected limbs. Tibial angular deformity, torsional deformity, or both was identified in nine of the 66 limbs. Ostectomy healing was confirmed radiographically in 51/66 limbs. The mean time to union was 73 +/- 37 days. All patellae were in the normal position and stable. Complications included infection (2/51), fixation failure (1/51), delayed healing (2/51), and persistent lameness (1/51). CLINICAL SIGNIFICANCE: In this cohort of cases, DFO was a highly successful and repeatable component of surgical treatment for dogs with medial patellar luxation associated with femoral varus. This study also provides more evidence of the high rate of concurrent cranial cruciate ligament disease in cases of medial patellar luxation complicated by femoral varus, and supports an association between stifle instability and medial patellar luxation. PMID- 27935009 TI - Intracranial Pressure Influences the Behavior of the Optic Nerve Head. AB - In this work, the biomechanical responses of the optic nerve head (ONH) to acute elevations in intracranial pressure (ICP) were systematically investigated through numerical modeling. An orthogonal experimental design was developed to quantify the influence of ten input factors that govern the anatomy and material properties of the ONH on the peak maximum principal strain (MPS) in the lamina cribrosa (LC) and postlaminar neural tissue (PLNT). Results showed that the sensitivity of ONH responses to various input factors was region-specific. In the LC, the peak MPS was most strongly dependent on the sclera thickness, LC modulus, and scleral canal size, whereas in the PLNT, the peak MPS was more sensitive to the scleral canal size, neural tissue modulus, and pia mater modulus. The enforcement of clinically relevant ICP in the retro-orbital subarachnoid space influenced the sensitivity analysis. It also induced much larger strains in the PLNT than in the LC. Moreover, acute elevation of ICP leads to dramatic strain distribution changes in the PLNT, but had minimal impact on the LC. This work could help to better understand patient-specific responses, to provide guidance on biomechanical factors resulting in optic nerve diseases, such as glaucoma, papilledema, and ischemic optic neuropathy, and to illuminate the possibilities for exploiting their potential to treat and prevent ONH diseases. PMID- 27935010 TI - Australian dermatologists' perspective on skin of colour: Results of a national survey. AB - BACKGROUND/OBJECTIVES: This study documents the perspectives of Australian dermatologists on the adequacy of teaching and training in skin of colour (SOC), and their confidence in diagnosing and treating common medical, surgical and cosmetic issues in SOC and to gauge their desire for further training in this area. METHODS: Surveys were distributed to Australasian Dermatologists during their annual scientific meeting in Melbourne, Australia in 2014. Completed surveys from dermatologists nationwide were collected and evaluated. Altogether 270 surveys were distributed. RESULTS: In total, 140 surveys were completed and returned. Four surveys were excluded as they were completed by dermatologists who were not practicing in Australia. Thus, 136 surveys were deemed appropriate for analysis. While 75% of participants were confident in managing common medical issues in SOC 85% were not confident in managing common cosmetic issues in SOC and 75% were not confident performing procedures on SOC. Over 80% stated they would have liked more teaching in SOC during their training and over 50% of those surveyed believe they had enough time to undertake further training in this area. CONCLUSION: We propose here the first analysis of issues relating to SOC dermatology among Australian dermatologists in the context of the changing patient demographic in the country. The findings of this survey clearly demonstrate there is a need and desire for more training in medical, cosmetic and procedural aspects of SOC dermatology and that most of the Australian dermatologists surveyed have the desire and time to undertake such training. PMID- 27935011 TI - Electrical stimulation with non-implanted electrodes for overactive bladder in adults. AB - BACKGROUND: Several options exist for managing overactive bladder (OAB), including electrical stimulation (ES) with non-implanted devices, conservative treatment and drugs. Electrical stimulation with non-implanted devices aims to inhibit contractions of the detrusor muscle, potentially reducing urinary frequency and urgency. OBJECTIVES: To assess the effects of ES with non-implanted electrodes for OAB, with or without urgency urinary incontinence, compared with: placebo or any other active treatment; ES added to another intervention compared with the other intervention alone; different methods of ES compared with each other. SEARCH METHODS: We searched the Cochrane Incontinence Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 10 December 2015). We searched the reference lists of relevant articles and contacted specialists in the field. We imposed no language restrictions. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials of ES with non-implanted devices compared with any other treatment for OAB in adults. Eligible trials included adults with OAB with or without urgency urinary incontinence (UUI). Trials whose participants had stress urinary incontinence (SUI) were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, extracted data from eligible trials and assessed risk of bias, using the Cochrane 'Risk of bias' tool. MAIN RESULTS: We identified 63 eligible trials (4424 randomised participants). Forty-four trials did not report the primary outcomes of perception of cure or improvement in OAB. The majority of trials were deemed to be at low or unclear risk of selection and attrition bias and unclear risk of performance and detection bias. Lack of clarity with regard to risk of bias was largely due to poor reporting.For perception of improvement in OAB symptoms, moderate-quality evidence indicated that ES was better than pelvic floor muscle training (PFMT) (risk ratio (RR) 1.60, 95% confidence interval (CI) 1.19 to 2.14; n = 195), drug treatment (RR 1.20, 95% 1.04 to 1.38; n = 439). and placebo or sham treatment (RR 2.26, 95% CI 1.85 to 2.77, n = 677) but it was unclear if ES was more effective than placebo/sham for urgency urinary incontinence (UUI) (RR 5.03, 95% CI 0.28 to 89.88; n = 242). Drug treatments included in the trials were oestrogen cream, oxybutynin, propantheline bromide, probanthine, solifenacin succinate, terodiline, tolterodine and trospium chloride.Low- or very low-quality evidence suggested no evidence of a difference in perception of improvement of UUI when ES was compared to PFMT with or without biofeedback.Low- quality evidence indicated that OAB symptoms were more likely to improve with ES than with no active treatment (RR 1.85, 95% CI 1.34 to 2.55; n = 121).Low- quality evidence suggested participants receiving ES plus PFMT, compared to those receiving PFMT only, were more than twice as likely to report improvement in UUI (RR 2.82, 95% CI 1.44 to 5.52; n = 51).There was inconclusive evidence, which was either low- or very low quality, for OAB-related quality of life when ES was compared to no active treatment, placebo/sham or biofeedback-assisted PFMT, or when ES was added to PFMT compared to PFMT-only. There was very low-quality evidence from a single trial to suggest that ES may be better than PFMT in terms of OAB-related quality of life.There was a lower risk of adverse effects with ES than tolterodine (RR 0.12, 95% CI 0.05 to 0.27; n = 200) (moderate-quality evidence) and oxybutynin (RR 0.11, 95% CI 0.01 to 0.84; n = 79) (low-quality evidence).Due to the very low quality evidence available, we could not be certain whether there were fewer adverse effects with ES compared to placebo/sham treatment, magnetic stimulation or solifenacin succinate. We were also very uncertain whether adding ES to PFMT or to drug therapy resulted in fewer adverse effects than PFMT or drug therapy alone Nor could we tell if there was any difference in risk of adverse effects between different types of ES.There was insufficient evidence to determine if one type of ES was more effective than another or if the benefits of ES persisted after the active treatment period stopped. AUTHORS' CONCLUSIONS: Electrical stimulation shows promise in treating OAB, compared to no active treatment, placebo/sham treatment, PFMT and drug treatment. It is possible that adding ES to other treatments such as PFMT may be beneficial. However, the low quality of the evidence base overall means that we cannot have full confidence in these conclusions until adequately powered trials have been carried out, measuring subjective outcomes and adverse effects. PMID- 27935012 TI - Mutational Analysis of Agxt in Tunisian Population with Primary Hyperoxaluria Type 1. AB - BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive metabolic disorder caused by inherited mutations in the AGXT gene encoding liver peroxisomal alanine:glyoxylate aminotransferase (AGT). PH1 is a clinically and genetically heterogeneous disorder. The aim of our study was to analyze and characterize the mutational spectrum of PH1 in Tunisian patients. MATERIALS AND METHODS: Molecular studies of 146 Tunisian patients suspected with PH were performed by PCR/Restriction fragment length polymorphism (RFLP) to detect seven mutations described as the most common. Direct sequencing for the 11 exons was performed in patients in whom any mutation was not identified. RESULTS: The genetic diagnosis of PH1 was confirmed in 62.3% of patients. The first molecular approach based on PCR/restriction enzyme test was positive in 37.6% of patients, whereas the second molecular approach based on whole gene sequencing was successful in 24% of cases. Twelve pathogenic mutations were detected in our cohort. Two mutations were novel, and five were detected for the first time in Tunisians. The three most frequent mutations were p.Ile244Thr, p.Gly190Arg, and c.33dupC, with a frequency of 43.4%, 21.4%, and 13.1%, respectively. CONCLUSION: The two novel mutations detected in our study extend the spectrum of known AGXT gene mutations. The screen for the mutations identified in this study can provide a useful, cost-effective, and first-line investigation in Tunisian PH1 patients. PMID- 27935013 TI - The Ghost in the Touchscreen: Social Scaffolds Promote Learning by Toddlers. AB - This study examined the effect of a "ghost" demonstration on toddlers' imitation. In the ghost condition, virtual pieces moved to make a fish or boat puzzle. Fifty two 2.5- and 3-year-olds were tested on a touchscreen (no transfer) or with 3D pieces (transfer); children tested with 3D pieces scored above a no demonstration baseline, but children tested on the touchscreen did not. Practice on the touchscreen (n = 23) by 2.5- and 3-year-olds prior to the ghost demonstration did not improve performance. Finally, children who learned the puzzle task via a social demonstration and were tested on the touchscreen (n = 26) performed better than the ghost conditions. Taken together, these studies demonstrate that social demonstrations enhance learning from novel touchscreen tools during early childhood. PMID- 27935014 TI - Systematic review and qualitative evidence synthesis of patient-reported outcome measures for abdominal aortic aneurysm. AB - BACKGROUND: The aim was to identify and evaluate existing patient-reported outcome measures (PROMs) for use in patients with an abdominal aortic aneurysm (AAA) to inform the selection for use in surgical practice. METHODS: Two reviews were conducted: a systematic review to identify valid, reliable and acceptable PROMs for patients with an AAA, and a qualitative evidence synthesis to assess the relevance to patients of the identified PROM items. PROM studies were evaluated for their psychometric properties using established assessment criteria, and for their methodological quality using the COSMIN checklist. Qualitative studies were synthesized using framework analysis, and concepts identified were then triangulated using a protocol with the item concepts of the identified PROMs. RESULTS: Four PROMs from three studies were identified in the first review: Short Form 36, Australian Vascular Quality of Life Index, Aneurysm Dependent Quality of Life (AneurysmDQoL) and Aneurysm Symptoms Rating Questionnaire (AneurysmSRQ). None of the identified PROMs had undergone a rigorous psychometric evaluation within the AAA population. Four studies were included in the qualitative synthesis, from which 28 concepts important to patients with an AAA were identified. The AneurysmDQoL and AneurysmSRQ together provided the most comprehensive assessment of these concepts. Fear of rupture, control, ability to forget about the condition and size of aneurysm were all concepts identified in the qualitative studies but not covered by items in the identified PROMs. CONCLUSION: Further research is needed to develop PROMs for AAA that are reliable, valid and acceptable to patients. PMID- 27935015 TI - Extracorporeal cardiopulmonary resuscitation after out-of-hospital cardiac arrest in a Danish health region. AB - BACKGROUND: Extracorporeal Cardiopulmonary Resuscitation (ECPR) has emerged as a feasible rescue therapy for refractory, normothermic out-of-hospital cardiac arrest (OHCA). Reported survival rates vary and comparison between studies is hampered by heterogeneous study populations, differences in bystander intervention and in pre-hospital emergency service organisation. We aimed to describe the first experiences, treatment details, complications and outcome with ECPR for OHCA in a Danish health region. METHODS: Retrospective study of adult patients admitted at Aarhus University Hospital, Denmark between 1 January 2011 and 1 July 2015 with witnessed, refractory, normothermic OHCA treated with ECPR. OHCA was managed with pre-hospital advanced airway management and mechanical chest compression during transport. Relevant pre-hospital and in-hospital data were collected with special focus on low-flow time and ECPR duration. Survival to hospital discharge with Cerebral Performance Category (CPC) of 1 and 2 at hospital discharge was the primary endpoint. RESULTS: Twenty-one patients were included. Median pre-hospital low-flow time was 54 min [range 5-100] and median total low-flow time was 121 min [range 55-192]. Seven patients survived (33%). Survivors had a CPC score of 1 or 2 at hospital discharge. Five survivors had a shockable initial rhythm. In all survivors coronary occlusion was the presumed cause of cardiac arrest. CONCLUSION: Extracorporeal cardiopulmonary resuscitation is feasible as a rescue therapy in normothermic refractory OHCA in highly selected patients. Low-flow time was longer than previously reported. Survival with favourable neurological outcome is possible despite prolonged low-flow duration. PMID- 27935016 TI - Leveraging constraints and biotelemetry data to pinpoint repetitively used spatial features. AB - Satellite telemetry devices collect valuable information concerning the sites visited by animals, including the location of central places like dens, nests, rookeries, or haul-outs. Existing methods for estimating the location of central places from telemetry data require user-specified thresholds and ignore common nuances like measurement error. We present a fully model-based approach for locating central places from telemetry data that accounts for multiple sources of uncertainty and uses all of the available locational data. Our general framework consists of an observation model to account for large telemetry measurement error and animal movement, and a highly flexible mixture model specified using a Dirichlet process to identify the location of central places. We also quantify temporal patterns in central place use by incorporating ancillary behavioral data into the model; however, our framework is also suitable when no such behavioral data exist. We apply the model to a simulated data set as proof of concept. We then illustrate our framework by analyzing an Argos satellite telemetry data set on harbor seals (Phoca vitulina) in the Gulf of Alaska, a species that exhibits fidelity to terrestrial haul-out sites. PMID- 27935017 TI - EARLY-ESLI study: Long-term experience with eslicarbazepine acetate after first monotherapy failure. AB - PURPOSE: Evaluate real-life experience with eslicarbazepine acetate (ESL) after first monotherapy failure in a large series of patients with focal epilepsy. METHOD: Multicentre, retrospective, 1-year, observational study in patients older than 18 years, with focal epilepsy, who had failed first antiepileptic drug monotherapy and who received ESL. Data from clinical records were analysed at baseline, 3, 6 and 12 months to assess effectiveness and tolerability. RESULTS: Eslicarbazepine acetate was initiated in 253 patients. The 1-year retention rate was 92.9%, and the final median dose of ESL was 800 mg. At 12 months, 62.3% of patients had been seizure free for 6 months; 37.3% had been seizure free for 1 year. During follow-up, 31.6% of the patients reported ESL-related adverse events (AEs), most commonly somnolence (8.7%) and dizziness (5.1%), and 3.6% discontinued due to AEs. Hyponatraemia was observed in seven patients (2.8%). After starting ESL, 137 patients (54.2%) withdrew the prior monotherapy and converted to ESL monotherapy; 75.9% were seizure free, 87.6% were responders, 4.4% worsened, and 23.4% reported ESL-related AEs. CONCLUSION: Use of ESL after first monotherapy failure was associated with an optimal seizure control and tolerability profile. Over half of patients were converted to ESL monotherapy during follow-up. PMID- 27935018 TI - Tolerability and efficacy of perampanel in children with refractory epilepsy. AB - AIM: There are few reports on the tolerability and efficacy of perampanel, a new antiepileptic drug with a novel mechanism of action, in children and adolescents. We aimed to describe our experience with perampanel add-on and mono-therapy in children with refractory epilepsy. METHOD: Computerized medical records of children treated with perampanel in the paediatric neurology clinic from December 2012 to October 2015 were reviewed. RESULTS: Twenty-four children treated with perampanel (15 females, 9 males) aged 1 year 6 months to 17 years (mean 10y, standard deviation [SD] 4y 5mo) were identified. Adverse events were more common in children aged 12 years or older (89%) compared to younger children (53%), and were mainly behavioural. Ten (42%) children had 50 per cent or higher seizure reduction, two (8%) children had 33 per cent seizure reduction, and seizures were less severe in one (4%) child. Perampanel was discontinued in 13 (54%) children mostly due to adverse events. The mean duration of follow-up in the remaining 11 children was 8.1 months (SD 5.2) (range 1.3-17mo). INTERPRETATION: Perampanel is associated with a relatively high rate of behavioural adverse events mostly in adolescents with refractory epilepsy. PMID- 27935019 TI - Family Caregiver Factors Associated with Unmet Needs for Care of Older Adults. AB - OBJECTIVES: To examine caregiver factors associated with unmet needs for care of older adults. DESIGN: Population-based surveys of caregivers and older adult care recipients in the United States in 2011. SETTING: 2011 National Health and Aging Trends Study and National Study of Caregiving. PARTICIPANTS: Family caregivers (n = 1,996) of community-dwelling older adults with disabilities (n = 1,366). MEASUREMENTS: Disabled care recipient reports of unmet needs for care in the past month with activities of daily living (ADLs; e.g., wet or soiled clothing), mobility (e.g., have to stay inside), or instrumental activities of daily living (IADLs; e.g., medication errors). Caregiver reported sociodemographic characteristics, caregiving intensity and tasks performed, health, and psychosocial effects. RESULTS: Of the care recipients, 44.3% reported at least one unmet need for care in the past month (38.2% ADL related, 14.6% IADL related). Younger caregivers, caregiving sons, caregivers not living with care recipients, and having supplemental paid caregivers were associated with more unmet needs. Caregivers with recipients reporting two or more unmet needs were more likely to spend more than 100 hours per month caregiving, help with skin care and wounds, report caregiving as emotionally and physically difficult, and report restricted participation in valued activities (all P < .001). CONCLUSION: Unmet ADL needs are prevalent among older adults with family caregivers. Caregivers experiencing high levels of burden, stress, and negative physical and psychosocial impacts may provide substandard or poor care to older adults, which may be a risk factor for neglect. Clinicians caring for disabled older adults should assess their unmet needs and the capacity of caregivers to address them. PMID- 27935020 TI - Mycorrhizal status helps explain invasion success of alien plant species. AB - It is still debated whether alien plants benefit from being mycorrhizal, or if engaging in the symbiosis constrains their establishment and spread in new regions. We analyzed the association between mycorrhizal status of alien plant species in Germany and their invasion success. We compared whether the representation of species with different mycorrhizal status (obligate, facultative, or non-mycorrhizal) differed at several stages of the invasion process. We used generalized linear models to explain the occupied geographical range of alien plants, incorporating interactions of mycorrhizal status with plant traits related to morphology, reproduction, and life-history. Non naturalized aliens did not differ from naturalized aliens in the relative frequency of different mycorrhizal status categories. Mycorrhizal status significantly explained the occupied range of alien plants; with facultative mycorrhizal species inhabiting a larger range than non-mycorrhizal aliens and obligate mycorrhizal plant species taking an intermediate position. Aliens with storage organs, shoot metamorphoses, or specialized structures promoting vegetative dispersal occupied a larger range when being facultative mycorrhizal. We conclude that being mycorrhizal is important for the persistence of aliens in Germany and constitutes an advantage compared to being non-mycorrhizal. Being facultative mycorrhizal seems to be especially advantageous for successful spread, as the flexibility of this mycorrhizal status may enable plants to use a broader set of ecological strategies. PMID- 27935021 TI - Screening and evaluation tools of dysphagia in children with neuromuscular diseases: a systematic review. AB - AIM: Dysphagia is frequent in paediatric patients with neuromuscular diseases (pNMD). Its detection is important for initiating early diagnosis and treatment as well as for minimizing related complications. The aim of this study was to review the literature on dysphagia screening and evaluation tools in pNMD. METHOD: A systematic review was performed on the basis of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Three databases (PubMed, CINAHL, and ScienceDirect) were searched. Measurement properties of tools and the quality index developed by Downs and Black were considered. RESULTS: Our search yielded four studies and four different tools for paediatric patients with Duchenne muscular dystrophy (DMD). The Sydney Swallow Questionnaire, surface electromyography, Neuromuscular Disease Swallowing Status Scale, and videofluoroscopic swallow study showed interesting properties for DMD. No data were available for other NMD and children under 9 years. The mean total score for the quality index was 17.5. INTERPRETATION: We did not identify any superior validated tools, either for screening or for evaluation of dysphagia, and no widely accepted protocol. Further studies are needed to identify the simplest assessment with the best psychometric properties for pNMD. We recommend establishing a specific tool for pNMD. PMID- 27935023 TI - Causes of mortality in individuals with tuberous sclerosis complex. AB - AIM: The causes of death in patients with tuberous sclerosis complex (TSC) have rarely been studied, with only one published account, which was reported from the Mayo Clinic in 1991. We aimed to investigate mortality in a large cohort of patients with TSC from one of two national referral clinics in the UK. METHOD: We identified 284 patients who attended Bath TSC clinic between 1981 and 2015, and ascertained causes of death by reviewing medical records, death certificates, and postmortem reports. RESULTS: Sixteen patients died from complications of TSC: eight from TSC kidney diseases; four from sudden unexpected death in epilepsy (SUDEP); two from lymphangioleiomyomatosis; one from a subependymal giant cell astrocytoma; and one from a pancreatic malignancy. The median age of death was 33 years (interquartile range [IQR] 26-46). Mortality was significantly more common in patients with learning disabilities than in those without (13/135 [9%] vs 3/131 [2%]; two-tailed Fisher exact test p=0.020). INTERPRETATION: Renal disease is a major cause of mortality in TSC. Lifelong surveillance and early intervention is warranted. SUDEP is also an important cause of mortality. Patients with learning disabilities are at significantly greater risk of early mortality and this implies the need for greater vigilance for TSC-related complications in this group. Female patients are vulnerable to pulmonary and renal disease. Pancreatic lesions are a rare but potentially treatable cause of mortality. PMID- 27935022 TI - Anti-atherosclerotic effect of the angiotensin 1-7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis. AB - BACKGROUND AND PURPOSE: Inflammation plays a key role in atherosclerosis. The protective role of angiotensin 1-7 (Ang-(1-7)) in vascular pathologies suggested the therapeutic use of low MW, non-peptide Ang-(1-7) mimetics, such as AVE0991. The mechanisms underlying the vaso-protective effects of AVE0991, a Mas receptor agonist, remain to be explored. EXPERIMENTAL APPROACH: We investigated the effects of AVE0991 on the spontaneous atherosclerosis in apolipoprotein E (ApoE) /- mice, in the context of vascular inflammation and plaque stability. KEY RESULTS: AVE0991 has significant anti-atherosclerotic properties in ApoE-/- mice and increases plaque stability, by reducing plaque macrophage content, without effects on collagen. Using the descending aorta of chow-fed ApoE-/- mice, before significant atherosclerotic plaque develops, we gained insight to early events in atherosclerosis. Interestingly, perivascular adipose tissue (PVAT) and adventitial infiltration with macrophages and T-cells precedes atherosclerotic plaque or the impairment of endothelium-dependent NO bioavailability (a measure of endothelial function). AVE0991 inhibited perivascular inflammation, by reducing chemokine expression in PVAT and through direct actions on monocytes/macrophages inhibiting their activation, characterized by production of IL-1beta, TNF-alpha, CCL2 and CXCL10, and differentiation to M1 phenotype. Pretreatment with AVE0991 inhibited migration of THP-1 monocytes towards supernatants of activated adipocytes (SW872). Mas receptors were expressed in PVAT and in THP-1 cells in vitro, and the anti-inflammatory effects of AVE0991 were partly Mas dependent. CONCLUSIONS AND IMPLICATIONS: The selective Mas receptor agonist AVE0991 exhibited anti-atherosclerotic and anti-inflammatory actions, affecting monocyte/macrophage differentiation and recruitment to the perivascular space during early stages of atherosclerosis in ApoE-/- mice. LINKED ARTICLES: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc. PMID- 27935024 TI - Risk factors for dental caries among children with cerebral palsy in a low resource setting. AB - AIM: To describe the oral health status and investigate factors affecting dental caries experience among children with cerebral palsy (CP) in rural Bangladesh. METHOD: A cross-sectional study was conducted among children with CP who are part of the Bangladesh Cerebral Palsy Register (BCPR) study. Caries experience was measured by identifying decayed, missing, and filled teeth for deciduous and permanent teeth (dmft/DMFT). Clinical periodontal index, body mass index, oral hygiene behaviour, masticatory ability, and dietary habits were recorded. CP motor types and severity of functional mobility (Gross Motor Function Classification System [GMFCS]) were assessed. RESULTS: Of 90 children with CP (mean age 9y 7mo, range 2-17y, 37.8% female and 62.2% male), 35% of 2 to 6 year olds, and 70% of 7 to 11 year olds (p=0.014) experienced caries (dmft+DMFT>0). The mean values (standard deviation [SD]) of dmft and DMFT were 2.46 (3.75) and 0.72 (1.79) respectively. After adjusting for age and sex, binary logistic regression analysis showed a significant relationship with dental caries for children who had quadriplegia (odds ratio [OR] 5.56, p=0.035), tooth cleaning less than one time/day (OR 0.08, p=0.016), using toothpowder or charcoal for cleaning (OR 7.63, p=0.015), and snacking between meals more than one time/day (OR 6.93, p=0.012). INTERPRETATION: Early oral health preventive care is required for children with CP because dental caries is highly prevalent in these children. PMID- 27935025 TI - Warmth and Demand: The Relation Between Students' Perceptions of the Classroom Environment and Achievement Growth. AB - Theory suggests that African American students benefit from warm and demanding teachers. This study examines the relation between students' perceptions of 634 teachers' warm demander characteristics and achievement growth in fourth and fifth grades (Mstudent age = 9-11.5 years). Analyses explored whether relations were moderated by the proportion of African American students in the classroom or the ethnic match or mismatch between African American students and their teachers. Results indicated that students' perceptions of teachers' demand (challenge and control) related to student achievement growth. Findings showed a stronger relation between challenge and academic growth in classrooms with more African American students, but no significant findings were identified for ethnic match or mismatch. PMID- 27935026 TI - Genetically based latitudinal clines in Artemisia californica drive parallel clines in arthropod communities. AB - Intraspecific variation in plant traits has been clearly shown to drive the structure of associated arthropod communities at the spatial scale of individual plant populations. Nevertheless, it is largely unknown whether plant trait variation among populations drives landscape-scale variation in arthropod communities, and how the strength of such plant genetic effects compares to, and interacts with, those of environmental variation. We documented the structure of arthropod communities on Artemisia californica for two consecutive years in a common garden of plants sourced from five populations along a 5 degrees latitudinal gradient and grown under precipitation treatments approximating the four-fold difference between the north and south range margins for this species. Previous study of plant traits from this garden documented clinal genetic variation, suggesting local adaptation to this environmental gradient, as well as effects of precipitation manipulation that were consistent among populations (i.e., no genotype-by-environment interaction). Within the common garden, arthropod density, evenness, and diversity increased clinally with population source latitude, and arthropod community composition (i.e., species relative abundance) showed a north-south divide. The 2.6-fold cline of northward increase in arthropod density in the common garden was mirrored by a 6.4-fold increase in arthropod density on wild plants sampled along the species range. In contrast to the strong influence of plant genotype, the precipitation manipulation only influenced arthropod community composition, and plant genetic effects on arthropods operated independently of precipitation regime (no genotype-by environment interaction). Accordingly, we conclude that the strongest driver of landscape-level variation in arthropod communities in this foundational plant species is not variation in the abiotic environment itself, but rather variation in plant traits underlain by the evolutionary process of plant local adaptation. PMID- 27935027 TI - A whole-plant perspective reveals unexpected impacts of above- and belowground herbivores on plant growth and defense. AB - Trade-offs between plant growth and defense are central to theoretical frameworks used to study the ecology and evolution of plant defense against herbivores. However, these frameworks, as well as the experiments designed to test them, rarely include belowground herbivores. We experimentally challenged seedlings of the tropical shrub Solanum lycocarpum (Solanaceae) with either aboveground foliar herbivores (Spodoptera caterpillars) or belowground root herbivores (the nematode Meloidogyne incognita) and measured the resulting changes in plant growth rates, biomass allocation, and the concentration of defensive terpenoids in roots and leaves. We found that plants that suffered aboveground herbivory responded with aboveground growth but belowground defense. Similarly, belowground herbivory resulted in root growth but elevated defenses of leaves. These results underscore the importance of belowground plant-herbivore interactions, and suggest that, in contrast to theoretical predictions, plants can simultaneously invest in both growth and defense. Finally, they emphasize the need for a "whole-plant" perspective in theoretical and empirical evaluations of plant-herbivore interactions. PMID- 27935028 TI - Planktonic equatorial diversity troughs: fact or artifact? Latitudinal diversity gradients in Radiolaria. AB - In contrast to the classical notion of an increasing biodiversity from the poles to the equator, a number of studies concluded that the diversity of marine species is highest at the middle latitudes, and decreases at the equator. Using a worldwide database critically compiled from 72 surveys (307 species, 4,807 water column and surface sediment samples), we analyzed the latitudinal gradients in species richness (LGSR) of a highly diversified group of marine holoplanktonic protists, the polycystine Radiolaria. Species richness values were corrected for uneven sample coverage and sample size, and contrasted with gradients in 11 environmental variables. Radiolarian species richness decreases from the equator to the poles both in the water column and in the surface sediments and is tightly coupled with temperature throughout the entire thermal range of marine waters. In the tropical Pacific Ocean, a conspicuous east-west gradient in diversity is also associated with temperature. Globally, diversity is negatively correlated with mean annual concentrations of nutrients (N, P, Si) and chlorophyll a. Disagreements with results reported for many other oceanic plankton may stem from the reduction of 3D distributional patterns onto 2D or 1D spaces, to the intermittent mixing of Subtropical and Subpolar species at the middle latitudes, and to a Mid-Domain Effect. The fact that radiolarian LGSR do not show this drop at the equator is partly due to methodological and database-related differences, and probably also in part a reflection of taxon-specific traits. PMID- 27935029 TI - Mangrove expansion and contraction at a poleward range limit: climate extremes and land-ocean temperature gradients. AB - Within the context of climate change, there is a pressing need to better understand the ecological implications of changes in the frequency and intensity of climate extremes. Along subtropical coasts, less frequent and warmer freeze events are expected to permit freeze-sensitive mangrove forests to expand poleward and displace freeze-tolerant salt marshes. Here, our aim was to better understand the drivers of poleward mangrove migration by quantifying spatiotemporal patterns in mangrove range expansion and contraction across land ocean temperature gradients. Our work was conducted in a freeze-sensitive mangrove-marsh transition zone that spans a land-ocean temperature gradient in one of the world's most wetland-rich regions (Mississippi River Deltaic Plain; Louisiana, USA). We used historical air temperature data (1893-2014), alternative future climate scenarios, and coastal wetland coverage data (1978-2011) to investigate spatiotemporal fluctuations and climate-wetland linkages. Our analyses indicate that changes in mangrove coverage have been controlled primarily by extreme freeze events (i.e., air temperatures below a threshold zone of -6.3 to -7.6 degrees C). We expect that in the past 121 yr, mangrove range expansion and contraction has occurred across land-ocean temperature gradients. Mangrove resistance, resilience, and dominance were all highest in areas closer to the ocean where temperature extremes were buffered by large expanses of water and saturated soil. Under climate change, these areas will likely serve as local hotspots for mangrove dispersal, growth, range expansion, and displacement of salt marsh. Collectively, our results show that the frequency and intensity of freeze events across land-ocean temperature gradients greatly influences spatiotemporal patterns of range expansion and contraction of freeze-sensitive mangroves. We expect that, along subtropical coasts, similar processes govern the distribution and abundance of other freeze-sensitive organisms. In broad terms, our findings can be used to better understand and anticipate the ecological effects of changing winter climate extremes, especially within the transition zone between tropical and temperate climates. PMID- 27935030 TI - Temperature effects on mass-scaling exponents in colonial animals: a manipulative test. AB - Body size and temperature are fundamental drivers of ecological processes because they determine metabolic rates at the individual level. Whether these drivers act independently on individual-level metabolic rates remains uncertain. Most studies of intraspecific scaling of unitary organisms must rely on preexisting differences in size to examine its relationship with metabolic rate, thereby potentially confounding size-correlated traits (e.g., age, nutrition) with size, which can affect metabolic rate. Here, we use a size manipulation approach to test whether metabolic mass scaling and temperature dependence interact in four species (two phyla) of colonial marine invertebrates. Size manipulation in colonial organisms allows tests of how ecological processes (e.g., predation) affect individual physiology and consequently population- and community-level energy flux. Body mass and temperature interacted in two species, with one species exhibiting decreased and the other increased mass-scaling exponents with increasing temperature. The allometric scaling of metabolic rate that we observe in three species contrasts with the isometric scaling of ingestion rates observed in some colonial marine invertebrates. Thus, we suggest that the often observed competitive superiority of colonial over unitary organisms may arise because the difference between energy intake and expenditure increases more strongly with size in colonial organisms. PMID- 27935032 TI - Prognostic analysis of patients with epilepsy according to time of relapse after withdrawal of antiepileptic drugs following four seizure-free years. AB - OBJECTIVE: We performed a retrospective, prognostic analysis of a cohort of patients with epilepsy according to time of relapse after four seizure-free years. METHODS: Planned withdrawal of antiepileptic drugs (AEDs) and at least 3 years of follow-up after AED discontinuation were performed. The following two groups were assessed: (1) an early relapse (ER) group of patients who experienced recurrence during AED withdrawal and (2) a late relapse (LR) group of patients who experienced recurrence after completion of the AED discontinuation process. After dichotomization, the relapse rate, prognostic factors, and their impacts for each group were compared with those of a group of patients who continued to be seizure-free after AED withdrawal (SF group) using multiple logistic regression analysis. The AED intake mode was also analyzed. RESULTS: Two hundred seventeen (64.6%) of the 336 total patients experienced relapse. One hundred thirty-nine patients (41.4%) and 78 patients (23.2%) were included in the LR and ER groups, respectively. Symptom duration >120 months showed the strongest negative prognostic impact as demonstrated by the 4.7-fold higher risk of recurrence in the ER group compared with the SF group. Additional factors with a negative prognostic impact included an age at epilepsy onset of <=20 years and the presence of localization-related epilepsy. No reliable predictor between the SF and LR groups was revealed. After exclusion of the SF group, post hoc analysis according to age at epilepsy onset and symptom duration showed that the above mentioned negative prognostic factors significantly affected the relapse patterns of the LR and ER groups. SIGNIFICANCE: The results suggest that longer symptom duration, which could be associated with intrinsic reactivation of epilepsy, is the strongest negative prognostic factor for relapse. Relapse after AED withdrawal in prolonged follow-up of seizure-free patients is one aspect of the natural history of epilepsy. PMID- 27935031 TI - Interictal epileptiform discharges impair word recall in multiple brain areas. AB - OBJECTIVES: Interictal epileptiform discharges (IEDs) have been linked to memory impairment, but the spatial and temporal dynamics of this relationship remain elusive. In the present study, we aim to systematically characterize the brain areas and times at which IEDs affect memory. METHODS: Eighty epilepsy patients participated in a delayed free recall task while undergoing intracranial electroencephalography (EEG) monitoring. We analyzed the locations and timing of IEDs relative to the behavioral data in order to measure their effects on memory. RESULTS: Overall IED rates did not correlate with task performance across subjects (r = 0.03, p = 0.8). However, at a finer temporal scale, within-subject memory was negatively affected by IEDs during the encoding and recall periods of the task but not during the rest and distractor periods (p < 0.01, p < 0.001, p = 0.3, and p = 0.8, respectively). The effects of IEDs during encoding and recall were stronger in the left hemisphere than in the right (p < 0.05). Of six brain areas analyzed, IEDs in the inferior-temporal, medial-temporal, and parietal areas significantly affected memory (false discovery rate < 0.05). SIGNIFICANCE: These findings reveal a network of brain areas sensitive to IEDs with key nodes in temporal as well as parietal lobes. They also demonstrate the time-dependent effects of IEDs in this network on memory. PMID- 27935033 TI - Detection of colorectal neoplasia: Combination of eight blood-based, cancer associated protein biomarkers. AB - Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed eight cancer-associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia. Plasma AFP, CA19-9, CEA, hs-CRP, CyFra21-1, Ferritin, Galectin-3 and TIMP-1 were determined in EDTA-plasma using the Abbott ARCHITECT(r) automated immunoassay platform. Primary endpoints were detection of (i) CRC and high-risk adenoma and (ii) CRC. Logistic regression was performed. Final reduced models were constructed selecting the four biomarkers with the highest likelihood scores. Subjects (N = 4,698) were consecutively included during 2010-2012. Colonoscopy detected 512 CRC patients, 319 colonic cancer and 193 rectal cancer. Extra colonic malignancies were detected in 177 patients, 689 had adenomas of which 399 were high-risk, 1,342 had nonneoplastic bowell disease and 1,978 subjects had 'clean' colorectum. Univariable analysis demonstrated that all biomarkers were statistically significant. Multivariate logistic regression demonstrated that the blood-based biomarkers in combination significantly predicted the endpoints. The reduced model resulted in the selection of CEA, hs CRP, CyFra21-1 and Ferritin for the two endpoints; AUCs were 0.76 and 0.84, respectively. The postive predictive value at 90% sensitivity was 25% for endpoint 1 and the negative predictive value was 93%. For endpoint 2, the postive predictive value was 18% and the negative predictive value was 97%. Combinations of serological protein biomarkers provided a significant identification of subjects with high risk of the presence of colorectal neoplasia. The present set of biomarkers could become important adjunct in early detection of CRC. PMID- 27935034 TI - Integrated Analysis and MicroRNA Expression Profiling Identified Seven miRNAs Associated With Progression of Oral Squamous Cell Carcinoma. AB - MicroRNAs have been used as diagnostic and prognostic biomarkers for many cancers including oral squamous cell carcinoma (OSCC). Several studies have been shown that microRNA (miRNA) play important roles during the progression of OSCC. However, the results vary largely in different studies due to different platforms and sample sizes. In this study, we systematically evaluated a large scale of miRNA profiles from current qualified OSCC samples, and further investigated the functions of genes regulated by these key miRNAs as well as the signaling pathways through which these miRNA effect carcinogenesis. Seven key miRNAs were identified, and of which three were significantly upregulated, including hsa-miR 21, hsa-miR-31, hsa-miR-338, and four were downregulated, namely hsa-miR-125b, hsa-miR-133a, hsa-miR-133b, and hsa-miR-139. The function enrichment analysis revealed that target genes of upregulated miRNAs were associated with cellular protein metabolic process, macromolecule metabolic process, and TGF-beta pathway, while the targets of downregulated were enriched in negative regulation of macromolecule biosynthetic process and gene expression, and p53, long-term potentiation and adherens junction pathways. Transcription factor analysis revealed that there were 67 (51.1%) transcription factors influenced by both up and downregulated miRNAs. In summary, seven key miRNAs were found to play essential role in progression of OSCC, as well as the target genes and transcription factors of these miRNAs. The potential functions of these target genes identified in our study may be profitable to diagnosis and prognostic prediction of OSCC as biomarkers. J. Cell. Physiol. 232: 2178-2185, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27935035 TI - Micro-CT versus synchrotron radiation phase contrast imaging of human cochlea. AB - High-resolution images of the cochlea are used to develop atlases to extract anatomical features from low-resolution clinical computed tomography (CT) images. We compare visualization and contrast of conventional absorption-based micro-CT to synchrotron radiation phase contrast imaging (SR-PCI) images of whole unstained, nondecalcified human cochleae. Three cadaveric cochleae were imaged using SR-PCI and micro-CT. Images were visually compared and contrast-to-noise ratios (CNRs) were computed from n = 27 regions-of-interest (enclosing soft tissue) for quantitative comparisons. Three-dimensional (3D) models of cochlear internal structures were constructed from SR-PCI images using a semiautomatic segmentation method. SR-PCI images provided superior visualization of soft tissue microstructures over conventional micro-CT images. CNR improved from 7.5 +/- 2.5 in micro-CT images to 18.0 +/- 4.3 in SR-PCI images (p < 0.0001). The semiautomatic segmentations yielded accurate reconstructions of 3D models of the intracochlear anatomy. The improved visualization, contrast and modelling achieved using SR-PCI images are very promising for developing atlas-based segmentation methods for postoperative evaluation of cochlear implant surgery. PMID- 27935036 TI - Sentinel node metastasis mitotic rate (SN-MMR) as a prognostic indicator of rapidly progressing disease in patients with sentinel node-positive melanomas. AB - Risk stratification of sentinel lymph node biopsy (SNB)-positive patients with malignant melanoma differs among current classification systems. To improve classification of patients with rapidly progressive disease who may profit from adjuvant therapy with novel immune or targeted treatment modalities, a single center retrospective analysis was performed including all melanoma patients diagnosed with a positive SN at a university-based skin cancer center over a 10 year period (2002-2012) (96 of 419 patients). Sentinel node metastasis mitotic rate (SN-MMR) and further histologic parameters were determined by blinded histological re-evaluation and correlated with clinical follow-up (overall [OS], melanoma-specific [MSS], and disease-free survival [DFS]). Median follow-up was 53 months. In univariate analyses, SN tumor penetrative depth (TPD), maximum tumor diameter (MTD), number of positive SN, SN-MMR and the S-, Rotterdam, RDC, Hannover I and II classification systems correlated with OS, MSS and DFS. Multivariate Cox regression analyses showed that a binary classification system based only on the SN-MMR (<1 vs. >=1 mitoses/mm2 ) was the strongest independent prognostic indicator for all endpoints analyzed. Kaplan-Meier analyses confirmed binary SN-MMR to be superior to stratify patients into high- and low-risk groups (45.45% vs. 87.92% 5-yr MSS). The general prognostic validity of the published SN classification systems was confirmed. The novel SN-MMR classification system may improve discrimination of patients with slowly and rapidly progressive disease. We therefore propose its implementation into clinical practice as the SN-MMR can be easily and reliably determined in routine pathology reports. Its prognostic value for the selection of patients amenable to adjuvant therapies should be studied in clinical trials. PMID- 27935037 TI - An isogenic blood-brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells. AB - The blood-brain barrier (BBB) is critical in maintaining a physical and metabolic barrier between the blood and the brain. The BBB consists of brain microvascular endothelial cells (BMECs) that line the brain vasculature and combine with astrocytes, neurons and pericytes to form the neurovascular unit. We hypothesized that astrocytes and neurons generated from human-induced pluripotent stem cells (iPSCs) could induce BBB phenotypes in iPSC-derived BMECs, creating a robust multicellular human BBB model. To this end, iPSCs were used to form neural progenitor-like EZ-spheres, which were in turn differentiated to neurons and astrocytes, enabling facile neural cell generation. The iPSC-derived astrocytes and neurons induced barrier tightening in primary rat BMECs indicating their BBB inductive capacity. When co-cultured with human iPSC-derived BMECs, the iPSC derived neurons and astrocytes significantly elevated trans-endothelial electrical resistance, reduced passive permeability, and improved tight junction continuity in the BMEC cell population, while p-glycoprotein efflux transporter activity was unchanged. A physiologically relevant neural cell mixture of one neuron: three astrocytes yielded optimal BMEC induction properties. Finally, an isogenic multicellular BBB model was successfully demonstrated employing BMECs, astrocytes, and neurons from the same donor iPSC source. It is anticipated that such an isogenic facsimile of the human BBB could have applications in furthering understanding the cellular interplay of the neurovascular unit in both healthy and diseased humans. Read the Editorial Highlight for this article on page 843. PMID- 27935039 TI - The Sabotaging Role of Myeloid Cells in Anti-Angiogenic Therapy: Coordination of Angiogenesis and Immune Suppression by Hypoxia. AB - Tumor angiogenesis has become a promising target for anti-tumor therapy. Unfortunately, the somewhat inevitable occurrence of resistance has limited the efficacy of anti-angiogenic therapy. In addition to their well-established role in immune suppression, bone marrow-derived myeloid cells actively contribute to tumor angiogenesis. More importantly, myeloid cells constitute one of the major mechanisms of resistance to angiogenesis inhibition. As the most pervasive feature in tumor microenvironment, hypoxia is able to initiate both pro angiogenic and immunosuppressive capacities of myeloid cells. Tumor adapts to hypoxic stress primarily through signaling mediated by hypoxic inducible factors (HIFs) and consequently utilizes hypoxia to its own advantage. In this regard, hypoxia orchestrates both angiogenesis and immune evasion to support tumor growth. In this article, we will review available information on the sabotaging role of myeloid cells in anti-angiogenic therapy. We will also discuss how hypoxia coordinates the dual-role cellular and molecular participants in microenvironment to maximize the efficiency of angiogenesis and immunosuppression to promote tumor progression. J. Cell. Physiol. 232: 2312-2322, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27935038 TI - Extensive translational regulation during seed germination revealed by polysomal profiling. AB - This work investigates the extent of translational regulation during seed germination. The polysome occupancy of each gene is determined by genome-wide profiling of total mRNA and polysome-associated mRNA. This reveals extensive translational regulation during Arabidopsis thaliana seed germination. The polysome occupancy of thousands of individual mRNAs changes to a large extent during the germination process. Intriguingly, these changes are restricted to two temporal phases (shifts) during germination, seed hydration and germination. Sequence features, such as upstream open reading frame number, transcript length, mRNA stability, secondary structures, and the presence and location of specific motifs correlated with this translational regulation. These features differed significantly between the two shifts, indicating that independent mechanisms regulate translation during seed germination. This study reveals substantial translational dynamics during seed germination and identifies development dependent sequence features and cis elements that correlate with the translation control, uncovering a novel and important layer of gene regulation during seed germination. PMID- 27935040 TI - Network-based characterization of the synaptic proteome reveals that removal of epigenetic regulator Prmt8 restricts proteins associated with synaptic maturation. AB - The brain adapts to dynamic environmental conditions by altering its epigenetic state, thereby influencing neuronal transcriptional programs. An example of an epigenetic modification is protein methylation, catalyzed by protein arginine methyltransferases (PRMT). One member, Prmt8, is selectively expressed in the central nervous system during a crucial phase of early development, but little else is known regarding its function. We hypothesize Prmt8 plays a role in synaptic maturation during development. To evaluate this, we used a proteome-wide approach to characterize the synaptic proteome of Prmt8 knockout versus wild-type mice. Through comparative network-based analyses, proteins and functional clusters related to neurite development were identified to be differentially regulated between the two genotypes. One interesting protein that was differentially regulated was tenascin-R (TNR). Chromatin immunoprecipitation demonstrated binding of PRMT8 to the tenascin-r (Tnr) promoter. TNR, a component of perineuronal nets, preserves structural integrity of synaptic connections within neuronal networks during the development of visual-somatosensory cortices. On closer inspection, Prmt8 removal increased net formation and decreased inhibitory parvalbumin-positive (PV+) puncta on pyramidal neurons, thereby hindering the maturation of circuits. Consequently, visual acuity of the knockout mice was reduced. Our results demonstrated Prmt8's involvement in synaptic maturation and its prospect as an epigenetic modulator of developmental neuroplasticity by regulating structural elements such as the perineuronal nets. PMID- 27935043 TI - Differences in utilization of dental procedures by children enrolled in Wisconsin Medicaid and Delta Dental insurance plans. AB - BACKGROUND: Few studies have directly compared dental procedures provided in public and private insurance plans for enrollees living in dental health professional shortage areas (DHPSAs). We examined the rates for the different types of dental procedures received by 0-18-year-old children living in DHPSAs and non-DHPSAs who were enrolled in Medicaid and those enrolled under Delta Dental of Wisconsin (DDW) for years 2002 to 2008. METHODS: Medicaid and DDW dental claims data for 2002 to 2008 was analyzed. Enrollees were divided into DDW DHPSA and non-DHPSA and Medicaid-DHPSA and non-DHPSA groups. Descriptive and multivariable analyses using over-dispersed Poisson regression were performed to examine the effect of living in DHPSAs and insurance type in relation to the number of procedures received. RESULTS: Approximately 49 and 65 percent of children living in non-DHPSAs that were enrolled in Medicaid and DDW received at least one preventive dental procedure annually, respectively. Children in DDW non DHPSA group had 1.79 times as many preventive, 0.27 times fewer complex restorative and 0.51 times fewer endodontic procedures respectively, compared to those in Medicaid non-DHPSA group. Children enrolled in DDW-DHPSA group had 1.53 times as many preventive and 0.25 times fewer complex restorative procedures, compared to children in Medicaid-DHPSA group. CONCLUSIONS: DDW enrollees had significantly higher utilization rates for preventive procedures than children in Medicaid. There were significant differences across Medicaid and DDW between non DHPSA and DHPSA for most dental procedures received by enrollees. PMID- 27935042 TI - Insight in DNA Repair of UV-induced Pyrimidine Dimers by Chromatographic Methods. AB - UV-induced formation of pyrimidine dimers in DNA is a major deleterious event in both eukaryotic and prokaryotic cells. Accumulation of cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts can lead to cell death or be at the origin of mutations. In skin, UV induction of DNA damage is a major initiating event in tumorigenesis. To counteract these deleterious effects, all cell types possess DNA repair machinery, such as nucleotide excision repair and, in some cell types, direct reversion. Different analytical approaches were used to assess the efficiency of repair and decipher the enzymatic mechanisms. We presently review the information provided by chromatographic methods, which are complementary to biochemical assays, such as immunological detection and electrophoresis-based techniques. Chromatographic assays are interesting in their ability to provide quantitative data on a wide range of damage and are also valuable tools for the identification of repair intermediates. PMID- 27935041 TI - AvrPm2 encodes an RNase-like avirulence effector which is conserved in the two different specialized forms of wheat and rye powdery mildew fungus. AB - There is a large diversity of genetically defined resistance genes in bread wheat against the powdery mildew pathogen Blumeria graminis (B. g.) f. sp. tritici. Many confer race-specific resistance to this pathogen, but until now only the mildew avirulence gene AvrPm3a2/f2 that is recognized by Pm3a/f was known molecularly. We performed map-based cloning and genome-wide association studies to isolate a candidate for the mildew avirulence gene AvrPm2. We then used transient expression assays in Nicotiana benthamiana to demonstrate specific and strong recognition of AvrPm2 by Pm2. The virulent AvrPm2 allele arose from a conserved 12 kb deletion, while there is no protein sequence diversity in the gene pool of avirulent B. g. tritici isolates. We found one polymorphic AvrPm2 allele in B. g. triticale and one orthologue in B. g. secalis and both are recognized by Pm2. AvrPm2 belongs to a small gene family encoding structurally conserved RNase-like effectors, including Avra13 from B. g. hordei, the cognate Avr of the barley resistance gene Mla13. These results demonstrate the conservation of functional avirulence genes in two cereal powdery mildews specialized on different hosts, thus providing a possible explanation for successful introgression of resistance genes from rye or other grass relatives to wheat. PMID- 27935044 TI - The Relationship of Trust and Intent to Stay Among Registered Nurses at Jordanian Hospitals. AB - AIMS: This study examined the relationship between the level of trust with immediate supervisor and the level of intent to stay at work among registered nurses (RNs) in Jordan and explored if there is a significant difference between RNs working in governmental- and university-affiliated teaching hospitals. BACKGROUND: Financial retention strategies are not feasible in low- and middle income countries. This study investigated if the level of trust that RNs hold toward their immediate supervisors could affect their intent to stay at work, so as to be used as a nonfinancial strategy. METHODS: A descriptive correlational design was used to examine this relationship among a convenience sample of 260 hospital nurses in Jordan. Descriptive and inferential statistics were used to analyze the data. RESULTS: When the level of trust increased, the level of intent to stay at work also increased. RNs working in governmental-affiliated teaching hospitals reported higher levels of trust and intent to stay at work than those working in university-affiliated teaching hospitals. CONCLUSION: The findings emphasized the positive effect of trust with immediate supervisor on the level of RNs' intent to stay. IMPLICATIONS FOR NURSING MANAGEMENT: Building trust between RNs and their immediate supervisors could be an important retention strategy. PMID- 27935046 TI - Test Anxiety in the Nursing Skills Laboratory: A Concept Analysis. AB - BACKGROUND: The concept of test anxiety has been well documented within the health education literature, with much of the literature addressing the clinical environment and simulation laboratories. Minimal exploration of test anxiety has been conducted within the context of a nursing skills laboratory. AIM: This concept analysis of test anxiety will provide clarity to the meaning and use of this concept within the nursing educational setting of a controlled skills laboratory. METHOD: Walker and Avant's (2005) framework was used to identify the defining attributes, antecedents, and consequences of test anxiety and applied in model, borderline, and contrary cases, and empirical referents. CONCLUSIONS: Understanding the concept of test anxiety will enable nurse educators to develop strategies to reduce student anxiety during testing in the skill laboratory. These insights can lead to positive changes within the nursing curricula and may benefit those students who experience testing anxiety. PMID- 27935047 TI - Team-Based Care: A Concept Analysis. AB - AIM: The purpose of this concept analysis is to clarify and analyze the concept of team-based care in clinical practice. BACKGROUND: Team-based care has garnered attention as a way to enhance healthcare delivery and patient care related to quality and safety. However, there is no consensus on the concept of team-based care; as a result, the lack of common definition impedes further studies on team based care. METHODS: This analysis was conducted using Walker and Avant's strategy. Literature searches were conducted using PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and PsycINFO, with a timeline from January 1985 to December 2015. RESULTS: The analysis demonstrates that the concept of team-based care has three core attributes: (a) interprofessional collaboration, (b) patient-centered approach, and (c) integrated care process. This is accomplished through understanding other team members' roles and responsibilities, a climate of mutual respect, and organizational support. Consequences of team-based care are identified with three aspects: (a) patient, (b) healthcare professional, and (c) healthcare organization. CONCLUSION: This concept analysis helps better understand the characteristics of team-based care in the clinical practice as well as promote the development of a theoretical definition of team-based care. PMID- 27935045 TI - Patient-derived xenografts of gastrointestinal cancers are susceptible to rapid and delayed B-lymphoproliferation. AB - Patient-derived cancer xenografts (PDX) are widely used to identify and evaluate novel therapeutic targets, and to test therapeutic approaches in preclinical mouse avatar trials. Despite their widespread use, potential caveats of PDX models remain considerably underappreciated. Here, we demonstrate that EBV associated B-lymphoproliferations frequently develop following xenotransplantation of human colorectal and pancreatic carcinomas in highly immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ (NSG) mice (18/47 and 4/37 mice, respectively), and in derived cell cultures in vitro. Strikingly, even PDX with carcinoma histology can host scarce EBV-infected B-lymphocytes that can fully overgrow carcinoma cells during serial passaging in vitro and in vivo. As serial xenografting is crucial to expand primary tumor tissue for biobanks and cohorts for preclinical mouse avatar trials, the emerging dominance of B lymphoproliferations in serial PDX represents a serious confounding factor in these models. Consequently, repeated phenotypic assessments of serial PDX are mandatory at each expansion step to verify "bona fide" carcinoma xenografts. PMID- 27935048 TI - Height-related scaling of phloem anatomy and the evolution of sieve element end wall types in woody plants. AB - In the sieve elements (SEs) of the phloem, carbohydrates are transported throughout the whole plant from their site of production to sites of consumption or storage. SE structure, especially of the pore-rich end walls, has a direct effect on translocation efficiency. Differences in pore size and other features were interpreted as an evolutionary trend towards reduced hydraulic resistance. However, this has never been confirmed. Anatomical data of 447 species of woody angiosperms and gymnosperms were used for a phylogenetic analysis of end wall types, calculation of hydraulic resistance and correlation analysis with morphological and physiological variables. end wall types were defined according to pore arrangement: either grouped into a single area (simple) or into multiple areas along the end wall (compound). Convergent evolution of end wall types was demonstrated in woody angiosperms. In addition, an optimization of end wall resistance with plant height was discovered, but found to be independent of end wall type. While physiological factors also showed no correlation with end wall types, the number of sieve areas per end wall was found to scale with SE length. The results exclude the minimization of hydraulic resistance as evolutionary driver of different end wall types, contradicting this long-standing assumption. Instead, end wall type might depend on SE length. PMID- 27935049 TI - Engineering chloroplasts to improve Rubisco catalysis: prospects for translating improvements into food and fiber crops. AB - 494 I. 495 II. 496 III. 496 IV. 499 V. 499 VI. 501 VII. 501 VIII. 502 IX. 505 X. 506 507 References 507 SUMMARY: The uncertainty of future climate change is placing pressure on cropping systems to continue to provide stable increases in productive yields. To mitigate future climates and the increasing threats against global food security, new solutions to manipulate photosynthesis are required. This review explores the current efforts available to improve carbon assimilation within plant chloroplasts by engineering Rubisco, which catalyzes the rate limiting step of CO2 fixation. Fixation of CO2 and subsequent cycling of 3 phosphoglycerate through the Calvin cycle provides the necessary carbohydrate building blocks for maintaining plant growth and yield, but has to compete with Rubisco oxygenation, which results in photorespiration that is energetically wasteful for plants. Engineering improvements in Rubisco is a complex challenge and requires an understanding of chloroplast gene regulatory pathways, and the intricate nature of Rubisco catalysis and biogenesis, to transplant more efficient forms of Rubisco into crops. In recent times, major advances in Rubisco engineering have been achieved through improvement of our knowledge of Rubisco synthesis and assembly, and identifying amino acid catalytic switches in the L subunit responsible for improvements in catalysis. Improving the capacity of CO2 fixation in crops such as rice will require further advances in chloroplast bioengineering and Rubisco biogenesis. PMID- 27935050 TI - The Anthocyanins, Oenin and Callistephin, Protect RPE Cells Against Oxidative Stress. AB - The retinal pigment epithelium (RPE) is a highly metabolic layer of postmitotic cells lining Bruch's membrane in the retina. While these cells contain endogenous photosensitizers that mediate blue light-induced damage, it has also been shown that blue light exposure damages mitochondrial DNA in RPE cells resulting in mitochondrial dysfunction and unregulated generation of reactive oxygen species (ROS). As RPE cells are postmitotic, it is imperative to decrease oxidative stress to these cells and preserve function. Dietary plant-derived antioxidants such as anthocyanins offer a simple and accessible solution for decreasing oxidative stress. The anthocyanins malvidin-3-O-glucoside (oenin) and pelargonidin-3-O-glucoside (callistephin) were tested for their ability and efficacy in decreasing ROS generation and preserving mitochondrial redox activity in blue light-irradiated ARPE-19 cells. A significant decrease in intracellular ROS with concurrent increase in mitochondrial redox activity was observed for tested concentrations of oenin, while callistephin was beneficial to stressed cells at higher concentrations. These findings suggest anthocyanins are effective antioxidants in blue light-stressed RPE cells in vitro. Additionally, oxidation products of these anthocyanins were examined using LC/MS and findings suggest the possibility of multiple oxidation sites for these compounds. PMID- 27935051 TI - The survival impact of delayed surgery and adjuvant chemotherapy on stage II/III rectal cancer with pathological complete response after neoadjuvant chemoradiation. AB - Neoadjuvant concurrent chemoradiation (CCRT) is standard treatment for clinical stage II/III rectal cancers. However, whether patients with pathological complete response (pT0N0, pCR) should receive adjuvant chemotherapy and whether delayed surgery will influence the pCR rate remains controversial. A nationwide population study was conducted using the Taiwan Cancer Registry Database from January 2007 to December 2013. Kaplan-Meier survival analysis was performed. Cox proportional hazards models were used to estimate multivariate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI). Of the 1,914 patients who received neoadjuvant CCRT, 259 (13.6%) achieved pCR and had better survival (adjusted HR: 0.37, 95% CI: 0.24-0.58; p < 0.001). The cumulative rate of pCR rose up to 83.4% in the 9th week and slowly reached a plateau after the 11th week. Among the patients with pCR, those who received adjuvant chemotherapy had no survival benefits compared to those without adjuvant chemotherapy (adjusted HR: 0.72, 95 CI: 0.27-1.93; p = 0.52). By subgroup analysis, those younger than 70-year old and received adjuvant chemotherapy had better survival benefit than those without adjuvant chemotherapy (adjusted HR: 0.19, 95% CI: 0.04-0.97; p = 0.046). Delayed surgery by 9-12 weeks after the end of neoadjuvant CCRT can maximize the pCR rate, which is correlated with better survival. Adjuvant chemotherapy may be considered in patients with pCR and aged <70-year old, but further prospectively randomized controlled trials are warranted to validate these findings. PMID- 27935052 TI - An Ethenoadenine FAD Analog Accelerates UV Dimer Repair by DNA Photolyase. AB - Reduced anionic flavin adenine dinucleotide (FADH- ) is the critical cofactor in DNA photolyase (PL) for the repair of cyclobutane pyrimidine dimers (CPD) in UV damaged DNA. The initial step involves photoinduced electron transfer from *FADH- to the CPD. The adenine (Ade) moiety is nearly stacked with the flavin ring, an unusual conformation compared to other FAD-dependent proteins. The role of this proximity has not been unequivocally elucidated. Some studies suggest that Ade is a radical intermediate, but others conclude that Ade modulates the electron transfer rate constant (kET ) through superexchange. No study has succeeded in removing or modifying this Ade to test these hypotheses. Here, FAD analogs containing either an ethano- or etheno-bridged Ade between the AN1 and AN6 atoms (e-FAD and epsilon-FAD, respectively) were used to reconstitute apo-PL, giving e PL and epsilon-PL respectively. The reconstitution yield of e-PL was very poor, suggesting that the hydrophobicity of the ethano group prevented its uptake, while epsilon-PL showed 50% reconstitution yield. The substrate binding constants for epsilon-PL and rPL were identical. epsilon-PL showed a 15% higher steady state repair yield compared to FAD-reconstituted photolyase (rPL). The acceleration of repair in epsilon-PL is discussed in terms of an epsilon-Ade radical intermediate vs superexchange mechanism. PMID- 27935053 TI - Effects of arbuscular mycorrhizal fungi inoculation on carbon and nitrogen distribution and grain yield and nutritional quality in rice (Oryza sativa L.). AB - BACKGROUND: The importance of arbuscular mycorrhizal fungi (AMF) for nutrient uptake and growth in rice has been widely recognized. However, little is known about the distribution of carbon (C) and nitrogen (N) in rice under AMF inoculation, which can affect grain yield and quality. This study was conducted to investigate the distribution of C and N within rice plants under AMF inoculation and the effects on grain yield and quality. RESULTS: AMF inoculation significantly increased N accumulation and distribution in vegetative tissues at tillering, and N translocation into seeds from heading to maturity. Consequently, AMF inoculation more strongly impacted the distribution of N than that of C in seeds, with significantly reduced C:N ratios and increased protein content (by 7.4%). Additionally, AMF inoculation significantly increased grain yield by 28.2% through increasing the grain:straw ratio by 18.4%. In addition, the roots of inoculated rice exhibited greater change in C distribution, with significantly higher C concentrations, C accumulations, and C:N ratios at tillering and maturity. CONCLUSION: AMF inoculation affected the distribution of N in seeds and C in roots. As such, AMF inoculation may be a potential method for improving grain yield and quality. (c) 2016 Society of Chemical Industry. PMID- 27935054 TI - Damaging Effects of Ultraviolet Radiation on the Cornea. AB - The cornea sits at the anterior aspect of the eye and, like the skin, is highly exposed to ultraviolet radiation (UVR). The cornea blocks a significant proportion of UVB from reaching the posterior structures of the eye. However, UVA can penetrate the full thickness of the cornea, even reaching the anterior portion of the lens. Epidemiological data indicate that UVR is a contributing factor for a multitude of diseases of the cornea including pterygium, photokeratitis, climatic droplet keratopathy and ocular surface squamous neoplasia (OSSN), although the pathogenic mechanisms of each require further elucidation. UVR is a well-known genotoxic agent, and its effects have been well characterized in organs such as the skin. However, we are only beginning to identify its effects on the cornea, such as the UVR signature C -> T and CC -> TT transversions identified by sequencing and increased proliferative and shedding rates in response to UVR exposure. Alarmingly, a single low-dose exposure of UVR to the cornea is sufficient to elicit genetic, molecular and cellular changes, supporting the consideration of using protective measures, such as wearing sunglasses when outdoors. The aim of this review was to describe the adverse effects of UVR on the cornea. PMID- 27935055 TI - Subcellular Targeting as a Determinant of the Efficacy of Photodynamic Therapy. AB - In prior studies, we have identified the ability of low-level lysosomal photodamage to potentiate the phototoxic effect of subsequent photodamage to mitochondria. The mechanism involves calpain-mediated cleavage of the autophagy associated protein ATG5 to form a proapoptotic fragment (tATG5). In this report, we explore the permissible time lag between the two targeting procedures along with the effect of simultaneously targeting both lysosomes and mitochondria. This was found to be as effective as the sequential protocol with no gap between the irradiation steps. Inhibition of calpain reversed the enhanced efficacy of the "simultaneous" protocol. It appears that even a minor level of lysosomal photodamage can have a significant effect on the efficacy of subsequent mitochondrial photodamage. We propose that these results may explain the efficacy of Photofrin, a photosensitizing product that also targets both lysosomes and mitochondria for photodamage. PMID- 27935056 TI - Chemiluminescence of Cigarette Smoke: Salient Features of the Phenomenon. AB - The study disclosed herein provides for the first time a detailed experimental support for the general mechanism of the cigarette-smoke-derived chemiluminescence, as an example par excellence of the excited-state generation in a chemically complex aerosol medium. The mechanism involves chemiexcitation in a unimolecular transformation of the smoke-borne free radical species. However, the concentration of these radicals, [r?], obeys a bimolecular (second-order) kinetics and depends on a particulate-phase content (total particulate matter, TPM) of the cigarette smoke. The decrease in [r?] with increasing the TPM amount manifests radical-scavenging propensity of the smoke particulate phase. Astonishingly, no energy transfer takes place from the primary excited light emitting species to luminophoric molecules abundant in the smoke. The reported results build up fundamentals of a facile chemiluminescence assay for free radical properties of the smoke. The experimental approaches developed for this study are of general scope and may be used for mechanistic elucidation of the excited-state generation in chemical systems and environments of an arbitrary complexity. PMID- 27935057 TI - Crosstalk Among UV-Induced Inflammatory Mediators, DNA Damage and Epigenetic Regulators Facilitates Suppression of the Immune System. AB - The suppression of the immune system by overexposure to ultraviolet (UV) radiation has been implicated in the initiation and progression of photocarcinogenesis. Numerous changes occur in the skin on UVB exposure, including the generation of inflammatory mediators, DNA damage, epigenetic modifications, and migration and functional alterations in the antigen-presenting dendritic cells. Although each of these alterations can elicit a cascade of events that have the potential to modulate immune sensitivity alone, there is emerging evidence that there is considerable crosstalk between these cascades. The development of an understanding of UV-induced changes in the skin that culminate in UV-induced immunosuppression, which has been implicated in the risk of nonmelanoma skin cancer, as a network of events has implications for the development of more effective chemopreventive strategies. In the current review article, we discuss the evidence of interactions between the various molecular targets and signaling mechanisms associated with UV-induced immunosuppression. PMID- 27935059 TI - RNA Polymerase-I-Dependent Transcription-coupled Nucleotide Excision Repair of UV Induced DNA Lesions at Transcription Termination Sites, in Saccharomyces cerevisiae. AB - If not repaired, ultraviolet light-induced DNA damage can lead to genome instability. Nucleotide excision repair (NER) of UV photoproducts is generally fast in the coding region of genes, where RNA polymerase-II (RNAP2) arrest at damage sites and trigger transcription-coupled NER (TC-NER). In Saccharomyces cerevisiae, there is RNA polymerase-I (RNAP1)-dependent TC-NER, but this process remains elusive. Therefore, we wished to characterize TC-NER efficiency in different regions of the rDNA locus: where RNAP1 are present at high density and start transcription elongation, where the elongation rate is slow, and in the transcription terminator where RNAP1 pause, accumulate and then are released. The Rpa12 subunit of RNAP1 and the Nsi1 protein participate in transcription termination, and NER efficiency was compared between wild type and cells lacking Rpa12 or Nsi1. The presence of RNAP1 was determined by chromatin endogenous cleavage and chromatin immunoprecipitation, and repair was followed at nucleotide precision with an assay that is based on the blockage of Taq polymerase by UV photoproducts. We describe that TC-NER, which is modulated by the RNAP1 level and elongation rate, ends at the 35S rRNA gene transcription termination site. PMID- 27935058 TI - Bimodal Targeting Using Sulfonated, Mannosylated PEI for Combined Gene Delivery and Photodynamic Therapy. AB - Photodynamic therapy (PDT) and gene delivery have both been used to target both cancer cells and tumor-associated macrophages (TAMs). Given the complex nature of tumor tissue, there could be merit in combining these strategies simultaneously. In this study, we developed a bimodal targeting approach to both cancer cells and macrophages, employing materials conducive to both gene delivery and PDT. Polymers libraries were created that consisted of cationic polyethyleneimine (PEI) conjugated to the photosensitizer pyropheophorbide-a, with sulfonation (to target selectin-expressing cells) and mannosylation (to target TAMs). Polyplexes, consisting of these polymers electrostatically bound to DNA, were analyzed for transfection efficacy and cytotoxicity toward epithelial cells and macrophages to assess dual-targeting. This study provides preliminary proof of principle for using modified PEI for targeted gene delivery and PDT. PMID- 27935060 TI - MtMAPKK4 is an essential gene for growth and reproduction of Medicago truncatula. AB - Mitogen-activated protein kinase (MAPK) cascades are universal signaling modules in eukaryotes, including yeasts, animals and plants. They are involved in responses to various biotic and abiotic stresses, hormones, cell division and developmental processes. A MAPK cascade is composed of three functionally tiered protein kinases, namely MAPK, MAPK kinases (MAPKKs) and MAPK kinase kinases (MAPKKKs). These kinases have been intensively studied for their roles in developmental and physiological processes in various organisms. In this study, a Medicago truncatula MtMAPKK4 mutant with the tobacco retrotransposon Tnt1 insertion was identified using reverse genetics methods. No homozygous progeny could be produced by self-pollination of mapkk4/+ heterozygotes for 5 generations. Heterozygous mapkk4/+ mutant plants exhibited growth retardation, chlorosis symptoms and significantly reduced numbers of infection threads and nodules. The interaction between MtMAPKK4 and MtMAPK3/6 occurred both in yeast and in planta. Green fluorescent protein-tagged MtMAPKK4, MtMAPK3 and MtMAPK6 were all localized to membranes, cytoplasm and nuclei. Expression of MtMAPKK4, MtMAPK3 and MtMAPK6 was detected in various tissues of M. truncatula plants at the nodule maturation stage. Transcript levels of these genes were decreased in roots at the early symbiotic stage. PMID- 27935062 TI - What explains high life satisfaction in men living with Duchenne muscular dystrophy? A preliminary study to inform psychological intervention. AB - INTRODUCTION: There are increasing numbers of men with Duchenne muscular dystrophy (mDMD). For those who struggle to live with the condition, psychological interventions may be helpful. However, it is unclear how these should be tailored for mDMD. To inform intervention, this study assessed whether 2 well-validated psychological models (Leventhal's Self-Regulatory Model; Psychological Flexibility Model) could explain variation in life satisfaction (LS). METHODS: Sixteen mDMD, aged 18-43 years, completed an online survey comprised of questionnaire measures of LS, mood, and both psychological models: Illness Perceptions (Leventhal's Self-Regulatory Model); engagement in meaningful activity, and acceptance/awareness of difficult thoughts and feelings (Psychological Flexibility Model). A median split enabled comparison of high and low LS groups. RESULTS: Those with higher LS were characterized by the ability to undertake personally meaningful activity in acceptance of difficult thoughts and feelings. CONCLUSIONS: Results supported the Psychological Flexibility Model. However, methodological limitations mean that these findings should be considered preliminary. Muscle Nerve 56: 163-166, 2017. PMID- 27935063 TI - Human papillomavirus (HPV) infection in a case-control study of oral squamous cell carcinoma and its increasing trend in northeastern Thailand. AB - Human papillomavirus (HPV) is an independent risk factor for development of oral squamous cell carcinoma (OSCC). This study aimed to investigate the role of HPV infection and the trend in percentage of HPV-associated OSCC over a 5-year period in northeastern Thailand. In this case-control study, 91 exfoliated oral cell samples and 80 lesion cell samples from OSCC cases and exfoliated oral cells from 100 age/gender-matched controls were collected. HPV infection was investigated by PCR using GP5+/GP6+ primers followed by HPV genotyping using reverse line blot hybridization. Quantitative RT-PCR was used to evaluate HPV oncogene transcription. Temporal trends of HPV infection were evaluated in archived formalin-fixed paraffin-embedded (FFPE) OSCC tissues using in situ hybridization. HPV DNA was found in 17.5% (14/80) of lesion samples from OSCC cases and 29.7% (27/91) of exfoliated oral cell samples from the same cases. These values were significantly higher than in exfoliated oral cell samples from controls (13%, 13/100). HPV-16 was the genotype most frequently found in OSCC cases (92.8%, 13/14 infected cases). Interestingly, HPV oncogene mRNA expression was detected and correlated with OSCC cases (P < 0.005). Of 146 archived FFPE OSCC samples, 82 (56.2%) were positive for high-risk HPV DNA and 64 (43.8%) cases were positive for HPV E6/E7 mRNA expression. There was a trend of increasing percentage of HPV associated OSCC from 2005 to 2010. This was especially so for females with well differentiated tumors in specific tongue sub-sites. We suggest that HPV infection plays an important role in oral carcinogenesis in northeastern Thailand. PMID- 27935064 TI - Intersession reliability of the interpolated twitch technique applied during isometric, concentric, and eccentric actions of the human knee extensor muscles. AB - INTRODUCTION: Although it has been shown that voluntary activation (%VA) of the knee extensors during isometric contractions can be reliably assessed with the interpolated twitch technique, little is known about the reliability of %VA during concentric and eccentric muscle actions. Therefore, relative and absolute intersession reliability of quadriceps muscle's %VA during different contraction modes was determined. METHODS: After a familiarization session, 21 participants (17 males, 25 +/- 2 yrs) completed two testing sessions. Paired supramaximal electrical stimuli were administered to the femoral nerve during isometric, concentric, eccentric MVCs, and at rest to assess %VA (stimuli were applied at 70 degrees knee flexion). RESULTS AND DISCUSSION: Data indicate that %VA of the knee extensors can be reliably measured during isometric [intraclass correlation coefficient (ICC) = 0.89, coefficient of variation (CV) = 4.1%], concentric (ICC = 0.87, CV = 6.6%), and eccentric muscle actions (ICC = 0.86, CV = 7.0%). Muscle Nerve 56: 324-327, 2017. PMID- 27935065 TI - High risk of heterosexual transmission of human T-cell lymphotropic virus type 1 infection in Brazil. AB - Human T-cell lymphotropic virus type 1 is transmitted primarily either through sexual intercourse or from mother to child. The current study investigated sexual transmission and compared the HTLV-1 proviral load between seroconcordant and serodiscordant couples by examining both men and women among the index partners without using subjective criteria to establish the direction of sexual transmission. Between January 2013 and May 2015, 178 HTLV-1-positive patients had spouses, 107 of which had tested partners, thus increasing the initial sample size (46 men and 61 women). Individuals co-infected with HTLV-2 or human immunodeficiency virus were not included in the analysis. From among the included participants, 26 men and 26 women were paired with each other, resulting in 26 seroconcordant couples; 12 seroconcordant couples were formed from another four men and eight women. Forty-three serodiscordant couples were formed from 16 men and 27 women. The rate of seroconcordance was 46.9%. The HTLV-1 proviral load was compared between 19 and 37 seroconcordant and serodiscondant couples, respectively, and the concordant couples showed higher proviral loads (P = 0.03). There were no differences between the groups according to age, relationship length, having a mother or sibling with HTLV-1, race, ethnicity, nationality, education, history of blood transfusion, HAM/TSP, ALT, or hepatitis C virus status. In multivariate analysis, relationship time was shown associated with ocurrence of seroconcordance status. The apparent association between high circulating levels of provirus and seroconcordance rate among couples suggests that proviral loads contribute markedly to the risk of sexual transmission, regardless of gender index. PMID- 27935061 TI - Autophagy in UV Damage Response. AB - UV radiation exposure from sunlight and artificial tanning beds is the major risk factor for the development of skin cancer and skin photoaging. UV-induced skin damage can trigger a cascade of DNA damage response signaling pathways, including cell cycle arrest, DNA repair and, if damage is irreparable, apoptosis. Compensatory proliferation replaces the apoptotic cells to maintain skin barrier integrity. Disruption of these processes can be exploited to promote carcinogenesis by allowing the survival and proliferation of damaged cells. UV radiation also induces autophagy, a catabolic process that clears unwanted or damaged proteins, lipids and organelles. The mechanisms by which autophagy is activated following UV exposure, and the functions of autophagy in UV response, are only now being clarified. Here, we summarize the current understanding of the mechanisms governing autophagy regulation by UV, the roles of autophagy in regulating cellular response to UV-induced photodamage and the implications of autophagy modulation in the treatment and prevention of photoaging and skin cancer. PMID- 27935066 TI - Detection of HCV genotypes 1b and 2a by a reverse transcription loop-mediated isothermal amplification assay. AB - Hepatitis C virus (HCV) genotypes 1b and 2a are the major cause of liver disease in northern China; however, conventional detection tools are labor-consuming, technically demanding, and costly. Here, we assessed the specificity, sensitivity, and clinical utility of reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for detection of HCV genotypes 1b and 2a. Firstly, clinical samples were collected from HCV genotype 1b and 2a infected patients and the RNA were extracted. Secondly, specificity of RT-LAMP assay for detection HCV genotypes 1b and 2a were tested against viral genomes of other hepatitis viruses. Sensitivity of RT-LAMP assay was determined using serial dilutions of standard HCV genotypes 1b and 2a. The amplified products were detected by both electrophoresis and calcein/Mn2+ -dependent visual methods. Finally, we compared the clinical detection rate of RT-LAMP to that of real-time PCR. RT-LAMP assay showed high specificity to detect HCV genotypes 1b and 2b since there was no cross-reactivity with other hepatitis viruses. Sensitivity of RT-LAMP was 100 IU/mL for both genotypes detected by either electrophoresis or calcein/Mn2+ -dependent visual methods. The detection rate of RT-LAMP assay in clinical samples was also comparable to that of real-time PCR without significant difference between the both assays. This study proposes a newly developed RT-LAMP assay for detection of HCV genotypes 1b and 2a. RT-LAMP is highly specific, sensitive, and simple diagnostic tool which would be useful for screening and early diagnosis of HCV especially in resource-limited environments. PMID- 27935067 TI - Asymmetry of lower extremity force and muscle activation during knee extension and functional tasks. AB - INTRODUCTION: Strength and power asymmetries of >10% may negatively impact physical function. METHODS: Twenty-four healthy participants, 30-60 years of age, were assessed for muscle power asymmetry during isokinetic knee extension and ground reaction force asymmetry during chair-rise and vertical jump tasks. Neuromuscular activation asymmetry and coactivation of vastus lateralis (VL) and biceps femoris (BF) were assessed in each condition. Symmetric (SG) and asymmetric (AG) groups were identified using a 10% knee extension power asymmetry criterion. RESULTS: The AG had greater chair-rise rate of force development asymmetry (P = 0.003, d = 1.29), but a similar chair-rise and vertical jump peak force asymmetry as the SG. Large group effects were found for VL activation asymmetry during knee extension (P = 0.047, d = 0.87), BF activation asymmetry during vertical jump (P = 0.015, d = 1.12), and strong leg coactivation during vertical jump (P = 0.028, d = 0.96). CONCLUSIONS: Compensation for muscle power asymmetry may occur during functional tasks, potentially through differential activation of strong and weak leg muscles. Muscle Nerve 56: 495-504, 2017. PMID- 27935068 TI - Single-fiber EMG with concentric electrodes in lambert-eaton myasthenia. AB - INTRODUCTION: We analyzed jitter recordings made with concentric needle electrode (CNE) single-fiber electromyography (SFEMG) in Lambert-Eaton myasthenia (LEM). METHODS: Fifteen subjects diagnosed with LEM were studied using CNE-SFEMG in the extensor digitorum (ED) and tibialis anterior (TA) muscles. CNE-SFEMG in the ED and TA was also used to evaluate 12 and 10 healthy controls (HCs), respectively. RESULTS: Ten men and 5 women were diagnosed with LEM based on an increase of 100% in compound muscle action potential amplitude during 50 Hz repetitive nerve stimulation. All patients exhibited markedly greater jitter in the ED (88.8 +/- 23.2 us) and TA (92.2 +/- 30.2 us) than HCs (28.3 +/- 3.4 us and 30.9 +/- 5.1 us, respectively). CONCLUSIONS: CNE-SFEMG is sensitive for discovering abnormalities in neuromuscular transmission in LEM. Muscle Nerve 56: 253-257, 2017. PMID- 27935069 TI - Nerve ultrasound abnormalities mirror the course of varicella zoster virus sensory-motor radiculoplexopathy. PMID- 27935070 TI - Prevalence of genital, oral, and anal HPV infection among STI patients in Italy. AB - Human papillomavirus (HPV) is a carcinogenic agent responsible for tumor development in many sexually involved tissues. We present a survey on the prevalence of HPV infection in a risk population for sexually transmitted infections (STIs). The studied population was formed by 125 STI clinic attendees, who took part in a screening program on STIs. To be included in the study, the patients had to show no overt clinical signs of HPV infection. Genital (cervical in women, urethral in men), anal, and oral samples were collected with ThinPrep liquid based cytology preparation system. Overall, of the screened population, 56% proved positive for genital HPV, 37% for oral HPV, and 42% for anal HPV infection. Our data indicate that in STI patients, HPV infection is more prevalent, than previously estimated. Further studies are needed to better understand the epidemiological burden of HPV in sexually involved tissues, especially in the oral mucosa. PMID- 27935071 TI - Severe murine limb-girdle muscular dystrophy type 2C pathology is diminished by FTY720 treatment. AB - INTRODUCTION: Limb-girdle muscular dystrophy type 2C (LGMD-2C) is caused by mutations in gamma-sarcoglycan and is a devastating, progressive, and fully lethal human muscle-wasting disease that has no effective treatment. This study examined the efficacy of the sphingosine-1-phosphate receptor modulator FTY720 in treating Sgcg-/- DBA2/J, a severe mouse model of LGMD-2C. FTY720 treatment was expected to target LGMD-2C disease progression at 2 key positions by reducing chronic inflammation and fibrosis. METHODS: The treatment protocol was initiated at age 3 weeks and was continued with alternate-day injections for 3 weeks. RESULTS: The treatment produced significant functional benefit by plethysmography and significant reductions of membrane permeability and fibrosis. Furthermore, the protocol elevated protein levels of delta-sarcoglycan, a dystrophin glycoprotein family member. CONCLUSION: This study showed that FTY720 is an effective muscular dystrophy treatment when therapy is initiated early in the disease progression. Muscle Nerve 56: 486-494, 2017. PMID- 27935072 TI - Physical exercise in myasthenia gravis is safe and improves neuromuscular parameters and physical performance-based measures: A pilot study. AB - INTRODUCTION: Due to the shortage of exercise-related research in Myasthenia Gravis (MG), there are no consensus guidelines on physical exercise for MG patients. METHODS: In this prospective pilot study, 10 MG patients with mild disease performed supervised aerobic and resistance training twice weekly for 12 weeks. The Myasthenia Gravis Composite (MGC) score, compound motor action potential (CMAP), repetitive nerve stimulation, muscle force, physical performance-based measures, serum levels of interleukin-6, muscle enzymes, and immuno-microRNAs miR-150-5p and miR-21-5p were assessed before and after the training period. RESULTS: Physical exercise was well tolerated, and the MGC score was unchanged. Muscle resistance weights and CMAP amplitudes increased for biceps brachii and rectus femoris muscles, and physical performance-based measures improved. Muscle enzymes remained normal, whereas disease-specific microRNAs miR 150-5p and miR-21-5p were reduced after the training period. CONCLUSIONS: We propose that general recommendations regarding physical exercise can be applied safely to well-regulated MG patients. Muscle Nerve 56: 207-214, 2017. PMID- 27935073 TI - NO accumulation alleviates H2 O2 -dependent oxidative damage induced by Ca(NO3 )2 stress in the leaves of pumpkin-grafted cucumber seedlings. AB - Nitric oxide (NO) and hydrogen peroxide (H2 O2 ), two important signaling molecules, are stimulated in plants by abiotic stresses. In this study, we investigated the role of NO and its interplay with H2 O2 in the response of self grafted (S-G) and salt-tolerant pumpkin-grafted (Cucurbita maxima * C. moschata) cucumber seedlings to 80 mM Ca(NO3 )2 stress. Endogenous NO and H2 O2 production in S-G seedlings increased in a time-dependent manner, reaching maximum levels after 24 h of Ca(NO3 )2 stress. In contrast, a transient increase in NO production, accompanied by H2 O2 accumulation, was observed at 2 h in rootstock grafted plants. Nw -Nitro-l-Arg methyl ester hydrochloride (l-NAME), an inhibitor of nitric oxide synthase (NOS), tungstate, an inhibitor of nitrate reductase (NR), and 2-(4-carboxyphenyl)-4,4,5,5-tetramethy-limidazoline-1-oxyl-3-oxide (cPTIO), a scavenger of NO, were found to significantly inhibit NO accumulation induced by salt stress in rootstock-grafted seedlings. H2 O2 production was unaffected by these stress conditions. Ca(NO3 )2 stress-induced NO accumulation was blocked by pretreatment with an H2 O2 scavenger (dimethylthiourea, DMTU) and an inhibitor of NADPH oxidase (diphenyleneiodonium, DPI). In addition, maximum quantum yield of PSII (Fv/Fm), as well as the activities and transcript levels of antioxidant enzymes, were significantly decreased by salt stress in rootstock grafted seedlings after pretreatment with these above inhibitors; antioxidant enzyme transcript levels and activities were higher in rootstock-grafted seedlings compared with S-G seedlings. These results suggest that rootstock grafting could alleviate the oxidative damage induced by Ca(NO3 )2 stress in cucumber seedlings, an effect that may be attributable to the involvement of NO in H2 O2 -dependent antioxidative metabolism. PMID- 27935075 TI - Nerve conduction studies are safe in patients with central venous catheters. AB - INTRODUCTION: It is unknown if central venous catheters bypass the skin's electrical resistance and engender a risk of nerve conduction study-induced cardiac arrhythmia. The objective of this study is to determine if nerve conduction studies affect cardiac conduction and rhythm in patients with central venous catheters. METHODS: Under continuous 12-lead electrocardiogram monitoring, subjects with and without central venous catheters underwent a series of upper extremity nerve conduction studies. A cardiologist reviewed the electrocardiogram tracings for evidence of cardiac conduction abnormality or arrhythmia. RESULTS: Ten control subjects and 10 subjects with central venous catheters underwent the nerve conduction study protocol. No malignant arrhythmias or conduction abnormalities were noted in either group. CONCLUSIONS: Nerve conduction studies of the upper extremities, including both proximal stimulation and repetitive stimulation, do not appear to confer increased risk of cardiac conduction abnormality in those patients with central venous catheters who are not critically ill or have a prior history of arrhythmia. Muscle Nerve 56: 321-323, 2017. PMID- 27935074 TI - Neurite growth could be impaired by ETFDH mutation but restored by mitochondrial cofactors. AB - INTRODUCTION: c.250G>A (p.Ala84Thr) in ETFDH is the most common mutation that causes later-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD) in the southern Chinese population. No functional study has targeted this mutation. METHODS: Using cells expressing ETFDH-wild-type (WT) or ETFDH-mutant (p.Ala84Thr), reactive oxygen species (ROS) production and neurite length were analyzed, followed by pathomechanism exploration and drug screening. RESULTS: Increased ROS production and marked neurite shortening were observed in the cells expressing the ETFDH-mutant, compared with WT. Further studies demonstrated that suberic acid, an accumulated intermediate metabolite in MADD, could significantly impair neurite outgrowth of NSC34 cells, but neurite shortening could be restored by supplementation with carnitine, riboflavin, or Coenzyme Q10. CONCLUSIONS: Neurite shortening caused by the c.250G>A mutation in ETFDH suggests that neural defects could be underdiagnosed in human patients with MADD. This impairment might be treatable with mitochondrial cofactor supplementation. Muscle Nerve 56: 479-485, 2017. PMID- 27935076 TI - Electrophysiologically identified piriformis syndrome is successfully treated with incobotulinum toxin a and physical therapy. AB - INTRODUCTION: Piriformis syndrome is entrapment of the sciatic nerve by the piriformis muscle. METHODS: In this article we describe a 56-person randomized, double-blind, controlled study involving physical therapy and incobotulinum toxin A or placebo. Inclusion criteria were 3-SD delay of posterior tibial (PT) or fibular (FN) H-reflexes on flexion, adduction, and internal rotation (FAIR) testing, and normal paraspinal electromyographic findings. Outcome measures included adverse side effects, visual analog scale (VAS) findings, and H-reflex delay on the FAIR test. RESULTS: Mean intervention VAS score decreased significantly more compared with placebo at 2, 4, 6, 8, 10, and 12 weeks post injection (P < 0.0001). FAIR test scores for PT, but not FN, decreased significantly more compared with placebo at 2, 4, 6, and 8 weeks post-injection (PT: P = 0.038, 0.003, 0.003, and 0.046). Adverse effects were minimal. VAS slope and PT FAIR test results varied significantly (P < 0.0001). CONCLUSION: Incobotulinum toxin A chemodenervation may be useful for treating piriformis syndrome as identified by the FAIR test. Muscle Nerve 56: 258-263, 2017. PMID- 27935077 TI - Changes in electromechanical delay during fatiguing dynamic muscle actions. AB - INTRODUCTION: The onsets of the electromyographic (EMG) signal, mechanomyographic (MMG) signal, and force production were used to identify voluntary electromechanical delay (EMD) during maximal and submaximal leg extensions. METHODS: Twelve men performed 30% 1-repetition-maximum concentric, dynamic constant external resistance leg extensions to failure. The time periods for the onsets of EMG to MMG (EMDE-M ), MMG to force (EMDM-F ), and EMG to force (EMDE-F ) were assessed before, during, and after testing. RESULTS: Pretest vs. posttest assessments indicated approximately equal contributions from excitation contraction coupling (EMDE-M ) and series elastic component (EMDM-F ) to the overall EMDE-F . During the workbout, excitation-contraction coupling failure and increases in the compliance of the series elastic component began at 40% and 30% of the repetitions to failure, respectively, and continued to failure. CONCLUSIONS: Increases in the series elastic component (EMDM-F ) began to affect EMDE-F before excitation-contraction coupling failure (EMDE-M ), and both contributed to EMDE-F throughout the remainder of the fatiguing workbout. Muscle Nerve 56: 315-320, 2017. PMID- 27935078 TI - Ischemic myopathy revealing systemic calciphylaxis. AB - INTRODUCTION: Patients with renal failure who are being treated with dialysis frequently develop neuromuscular manifestations. Renal failure-associated calciphylaxis, also termed calcific uremic arteriolopathy (CUA), is a life threatening condition usually observed in patients with end-stage renal disease on chronic dialysis or after renal transplantation. METHODS: We describe a hemodialyzed patient who presented with rapidly progressive unexplained systemic vasculopathy, muscle atrophy, and proximal weakness, that unexpectedly proved to be caused by calciphylaxis. RESULTS: Quadriceps muscle biopsy disclosed diffuse vascular calcific deposits on medium- and small-sized vessels, characteristic of CUA. Other changes included ischemic myopathy, focal intracellular calcium accumulation within myofibers, and calcium deposits in endomysial capillaries associated with marked complement activation and C5b9 formation. CONCLUSION: There are only a few descriptions of muscle involvement in the context of CUA, a condition with a prognosis that depends on early diagnosis and treatment. This report underscores the usefulness of muscle biopsy in the diagnosis of systemic calciphylaxis. Muscle Nerve 56: 529-533, 2017. PMID- 27935079 TI - High-resolution manometry in patients with idiopathic inflammatory myopathy: Elevated prevalence of esophageal involvement and differences according to autoantibody status and clinical subset. AB - INTRODUCTION: In this study we assessed high-resolution manometry (HRM) findings in patients with dermatomyositis and polymyositis. METHODS: From 2008 to 2015, we performed a cross-sectional study of myositis patients. A survey of esophageal symptoms and HRM data were analyzed and compared among different clinical and serologic groups. RESULTS: Twenty-four (45%) of the 53 patients included in the study had manometric involvement that was not correlated with any esophageal symptom (P = 0.8). Failed waves (34% vs. 0%, P = 0.004) and decreased upper esophageal sphincter pressure (50 vs. 70 mm Hg, P = 0.03) were more common in polymyositis than in dermatomyositis patients. Jackhammer esophagus was more common in anti-TIF1-gamma patients (30% vs. 9%, P = 0.04), and lower esophageal sphincter involvement (47% vs. 25%, P = 0.03) was more prevalent in patients with the antisynthetase syndrome. CONCLUSIONS: Esophageal involvement is common in myositis patients, but it correlates poorly with esophageal symptoms. Specific clinical and serologic groups have different manometric features. Muscle Nerve 56: 386-392, 2017. PMID- 27935080 TI - A case of new-onset antibody-positive myasthenia gravis in a patient treated with pembrolizumab for melanoma. PMID- 27935081 TI - Hemodynamic function during finger force production tasks in healthy adults. AB - INTRODUCTION: Near-infrared spectroscopy (NIRS) is a noninvasive technique used to measure muscle hemodynamics. The focus of this study was to evaluate changes in muscle oxygenation during sustained maximal force production in young, healthy control individuals to establish baseline function in an ideal population. METHODS: NIRS was used to monitor reduced hemoglobin (HbR) and oxygenated hemoglobin (HbO) in forearm muscles. Hemodynamic responses during force production tasks were monitored in real time. RESULTS: During handgrip exercises, maximal force production declined significantly. Increased HbR was found while HbO remained constant. The correlation between force production and HbO was positive (r = 0.18), while the correlation between force and HbR was negative (r = -0.48). The application of NIRS to monitor the correlation between force production and hemodynamic measures in the forearm was successful. These data set the foundation for future use of NIRS as a diagnostic tool for individuals with peripheral vascular disease: Muscle Nerve 56: 472-478, 2017. PMID- 27935082 TI - Improved separation and size characterization of gold nanoparticles through a novel capillary zone electrophoresis method using poly(sodium4-styrenesulfonate) as stabiliser and a stepwise field strength gradient. AB - A novel capillary zone electrophoresis (CZE) method was developed for an improved separation and size characterization of pristine gold nanoparticles (AuNP) using uncoated fused-silica capillaries with UV-Vis detection at 520 nm. To avoid colloid aggregation and/or adsorption during runs, poly(sodium 4 styrenesulfonate) (PSS) was added (1%, w/v) in the running buffer (CAPS 10 mM, pH 11). This polyelectrolyte conferred an enhanced stabilization to AuNP, both steric and electrostatic, exalting at the same time their differences in electrophoretic mobility. Resolution was further and successfully improved through a stepwise field strength gradient by the application of 25 kV for the first 5 min and then 10 kV. Migration times varied linearly with particles diameters showing relative standard deviations better than 1% for daily experiments and 3% for interday experiments. A comparison with the size distribution obtained by transmission electron microscopy (TEM) allowed assessing that the electrophoretic profile can reasonably be considered as representative of the effective size heterogeneity of each colloid. Finally, the practical utility of the proposed method was demonstrated by measuring the core diameter of a gold colloid sample produced by chemical synthesis which was in good agreement with the value obtained by TEM measurements. PMID- 27935084 TI - A Physical Heart Failure Simulation System Utilizing the Total Artificial Heart and Modified Donovan Mock Circulation. AB - With the growth and diversity of mechanical circulatory support (MCS) systems entering clinical use, a need exists for a robust mock circulation system capable of reliably emulating and reproducing physiologic as well as pathophysiologic states for use in MCS training and inter-device comparison. We report on the development of such a platform utilizing the SynCardia Total Artificial Heart and a modified Donovan Mock Circulation System, capable of being driven at normal and reduced output. With this platform, clinically relevant heart failure hemodynamics could be reliably reproduced as evidenced by elevated left atrial pressure (+112%), reduced aortic flow (-12.6%), blunted Starling-like behavior, and increased afterload sensitivity when compared with normal function. Similarly, pressure-volume relationships demonstrated enhanced sensitivity to afterload and decreased Starling-like behavior in the heart failure model. Lastly, the platform was configured to allow the easy addition of a left ventricular assist device (HeartMate II at 9600 RPM), which upon insertion resulted in improvement of hemodynamics. The present configuration has the potential to serve as a viable system for training and research, aimed at fostering safe and effective MCS device use. PMID- 27935083 TI - Endometrial cancer risk prediction including serum-based biomarkers: results from the EPIC cohort. AB - Endometrial cancer risk prediction models including lifestyle, anthropometric and reproductive factors have limited discrimination. Adding biomarker data to these models may improve predictive capacity; to our knowledge, this has not been investigated for endometrial cancer. Using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the improvement in discrimination gained by adding serum biomarker concentrations to risk estimates derived from an existing risk prediction model based on epidemiologic factors. Serum concentrations of sex steroid hormones, metabolic markers, growth factors, adipokines and cytokines were evaluated in a step-wise backward selection process; biomarkers were retained at p < 0.157 indicating improvement in the Akaike information criterion (AIC). Improvement in discrimination was assessed using the C-statistic for all biomarkers alone, and change in C-statistic from addition of biomarkers to preexisting absolute risk estimates. We used internal validation with bootstrapping (1000-fold) to adjust for over-fitting. Adiponectin, estrone, interleukin-1 receptor antagonist, tumor necrosis factor-alpha and triglycerides were selected into the model. After accounting for over-fitting, discrimination was improved by 2.0 percentage points when all evaluated biomarkers were included and 1.7 percentage points in the model including the selected biomarkers. Models including etiologic markers on independent pathways and genetic markers may further improve discrimination. PMID- 27935085 TI - Muscle activation during resistance exercise at 70% and 90% 1-repetition maximum in resistance-trained men. AB - INTRODUCTION: Muscle activation was investigated during resistance exercise with 2 relatively high-intensity loads. METHODS: Ten resistance-trained men performed the leg press exercise to repetition failure: a set at 70% of 1-repetition maximum (1RM) and a set at 90% of 1RM. Surface electromyography (EMG) was used to assess peak and mean muscle activation of the vastus lateralis, rectus femoris, and vastus medialis. RESULTS: Peak and mean EMG remained greater at 90% than 70% 1RM across all repetitions (P = 0.03 and P = 0.02, respectively). Main effects for trial were also significant for mean EMG activity of the final common repetitions (P = 0.03) favoring 90% 1RM; however, peak EMG activity was similar during the final common repetitions of the 70% and 90% 1RM sets. CONCLUSIONS: Across all repetitions, 90% 1RM appears to produce greater muscle activation during the leg press exercise, but similar peak EMG was observed during the final common repetitions of each set. Muscle Nerve 56: 505-509, 2017. PMID- 27935086 TI - Exercise responses in patients with chronically high creatine kinase levels. AB - INTRODUCTION: Elevated serum creatine kinase (CK) is often taken to reflect muscle disease, but many individuals have elevated CK without a specific diagnosis. How elevated CK reflects muscle metabolism during exercise is not known. METHODS: Participants (46 men, 48 women) underwent incremental exercise testing to assess aerobic performance, cardiovascular response, and ventilatory response. Serum lactate, ammonia, and CK were measured at rest, 4 minutes into exercise, and 2 minutes into recovery. RESULTS: High-CK and control subjects demonstrated similar aerobic capacities and cardiovascular responses to incremental exercise. Those with CK >= 300 U/L exhibited significantly higher lactate and ammonia levels after maximal exercise, together with increased ventilatory responses, whereas those with CK >=200 U/L but <= 300 U/L did not. CONCLUSIONS: We recommend measurement of lactate and ammonia profiles during a maximal incremental exercise protocol to help identify patients who warrant muscle biopsy to rule out myopathy. Muscle Nerve 56: 264-270, 2017. PMID- 27935087 TI - A multi-module microfluidic platform for continuous pre-concentration of water soluble ions and separation of oil droplets from oil-in-water (O/W) emulsions using a DC-biased AC electrokinetic technique. AB - A novel continuous flow microfluidic platform specifically designed for environmental monitoring of O/W emulsions during an aftermath of oil spills is reported herein. Ionized polycyclic aromatic hydrocarbons which are toxic are readily released from crude oil to the surrounding water phase through the smaller oil droplets with enhanced surface area. Hence, a multi-module microfluidic device is fabricated to form ion enrichment zones in the water phase of O/W emulsions for the ease of detection and to separate micron-sized oil droplets from the O/W emulsions. Fluorescein ions in the water phase are used to simulate the presence of these toxic ions in the O/W emulsion. A DC-biased AC electric field is employed in both modules. In the first module, a nanoporous Nafion membrane is used for activating the concentration polarization effect on the fluorescein ions, resulting in the formation of stable ion enrichment zones in the water phase of the emulsion. A 35.6% amplification of the fluorescent signal is achieved in the ion enrichment zone; corresponding to 100% enrichment of the fluorescent dye concentration. In this module, the main inlet is split into two channels by using a Y-junction so that there are two outlets for the oil droplets. The second module located downstream of the first module consists of two oil droplet entrapment zones at two outlets. By switching on the appropriate electrodes, either one of the two oil droplet entrapment zones can be activated and the droplets can be blocked in the corresponding outlet. PMID- 27935088 TI - Shifts in the distribution of ixodid ticks parasitizing cattle in Zimbabwe. AB - In an attempt to update information on the ecological distribution of ixodid ticks (Ixodida: Ixodidae) in Zimbabwe, a cross-sectional survey was carried out between September 2013 and May 2015 at 322 dip tanks. A total of 15 tick species were collected, namely: Amblyomma hebraeum Koch (65.2%, n = 210/322), Amblyomma variegatum Fabricius (14.9%, n = 48/322), Hyalomma rufipes Koch (62.4%, n = 201/322), Hyalomma truncatum Koch (37.9%, n = 122/322), Rhipicephalus appendiculatus Neumann (60.6%, n = 195/322), Rhipicephalus compositus Neumann (0.3%, n = 1/322,), Rhipicephalus decoloratus Koch (61.8%, n = 199/322), Rhipicephalus evertsi evertsi Neumann (65.2%, n = 210/322), Rhipicephalus lunulatus Neumann (4%, n = 13/322), Rhipicephalus microplus Canestrini (32%, n = 103/322), Rhipicephalus near punctatus Walker and Horak (7.1%, n = 23/322), Rhipicephalus simus Koch (5.6%, n = 18/322) and Rhipicephalus cf. turanicus Pomerantsev (3.4%, n = 11/322). Compared with previous surveys, changes in the distribution of A. hebraeum, A. variegatum and R. microplus were recorded. The distributions of other tick species have largely remained unchanged. Factors which might have influenced these changes and the possible impacts on the epidemiology of tick-borne diseases are discussed. PMID- 27935089 TI - The mechanisms of nickel toxicity in aquatic environments: An adverse outcome pathway analysis. AB - Current ecological risk assessment and water quality regulations for nickel (Ni) use mechanistically based, predictive tools such as biotic ligand models (BLMs). However, despite many detailed studies, the precise mechanism(s) of Ni toxicity to aquatic organisms remains elusive. This uncertainty in the mechanism(s) of action for Ni has led to concern over the use of tools like the BLM in some regulatory settings. To address this knowledge gap, the authors used an adverse outcome pathway (AOP) analysis, the first AOP for a metal, to identify multiple potential mechanisms of Ni toxicity and their interactions with freshwater aquatic organisms. The analysis considered potential mechanisms of action based on data from a wide range of organisms in aquatic and terrestrial environments on the premise that molecular initiating events for an essential metal would potentially be conserved across taxa. Through this analysis the authors identified 5 potential molecular initiating events by which Ni may exert toxicity on aquatic organisms: disruption of Ca2+ homeostasis, disruption of Mg2+ homeostasis, disruption of Fe2+/3+ homeostasis, reactive oxygen species-induced oxidative damage, and an allergic-type response of respiratory epithelia. At the organ level of biological organization, these 5 potential molecular initiating events collapse into 3 potential pathways: reduced Ca2+ availability to support formation of exoskeleton, shell, and bone for growth; impaired respiration; and cytotoxicity and tumor formation. At the level of the whole organism, the organ level responses contribute to potential reductions in growth and reproduction and/or alterations in energy metabolism, with several potential feedback loops between each of the pathways. Overall, the present AOP analysis provides a robust framework for future directed studies on the mechanisms of Ni toxicity and for developing AOPs for other metals. Environ Toxicol Chem 2017;36:1128-1137. (c) 2016 SETAC. PMID- 27935090 TI - Clinical utility of closure times using the platelet function analyzer-100/200. AB - The "platelet function analyzer" (PFA)-100 was first introduced to us in 1995. Since then, the instrument has appeared in over 50 reviews and almost 1000 publications. Recently, the PFA-100 has been "upgraded" to the PFA-200, which has transformed the user interface and electronic management, but retained the fundamental mechanics, and essentially provides the same results. The PFA-100/200 has conceivable clinical utility to screen for von Willebrand Disease (VWD) and platelet disorders, and in monitoring desmopressin (DDAVP) therapy in both, and possibly anti-platelet therapy. Its great strengths are its usage simplicity and sensitivity to conditions affecting primary hemostasis. However, as a "global" test, its limitation is that closure time (CT) test results are neither predictive of, nor specific for, any individual disorder. However, utilized properly, the PFA-100/200 reflects a valuable addition to hemostasis laboratories involved in identification or therapeutic-monitoring of disorders of primary hemostasis. PMID- 27935091 TI - Fabrication of complete dentures in three visits using existing prosthesis-a simplified technique for geriatric patients. AB - Complete edentulism often limits patients' ability to masticate and perform other oral functions, resulting in a reduction of oral-health-related quality of life. Although the two-implant mandibular overdenture may be considered as a minimum standard of treatment of complete edentulism, patients often prefer conventional complete dentures due to cost and surgical procedures related to implant supported dentures. Many complete denture patients may have limited access to dental care due to socioeconomic or health issues, hence there is a need in simplification of complete denture fabrication. Researchers have proposed "simplified" techniques to fabricate complete dentures by eliminating two stage impression procedures facebow transfer, and articulator programming, with impressive initial results. However, long-term clinical data of these techniques is unavailable. A novel technique for fabricating simplified complete dentures in three visits, using patient's existing dentures is presented here. Unlike previously described techniques on "simplified" dentures, this technique does not eliminate vital steps such as border-molded impressions, facebow transfer, verification of centric relations during try-in, programming of the articulator, and balancing procedures. PMID- 27935092 TI - A Flap Endonuclease (TcFEN1) Is Involved in Trypanosoma cruzi Cell Proliferation, DNA Repair, and Parasite Survival. AB - FLAP endonucleases (FEN) are involved both in DNA replication and repair by processing DNA intermediaries presenting a nucleotide flap using its phosphodiesterase activity. In spite of these important functions in DNA metabolism, this enzyme was not yet studied in Trypanosomatids. Trypanosoma cruzi, the ethiological agent of Chagas disease, presents two dividing cellular forms (epimastigote and amastigote) and one non-proliferative, infective form (trypomastigote). The parasite survives DNA damage produced by reactive species generated in its hosts. The activity of a T. cruzi FLAP endonuclease (TcFEN1) was determined in the three cellular forms of the parasite using a DNA substrate generated by annealing three different oligonucleotides to form a double-stranded DNA with a 5' flap in the middle. This activity showed optimal pH and temperature similar to other known FENs. The substrate cut by the flap endonuclease activity could be ligated by the parasite generating a repaired DNA product. A DNA flap endonuclease coding sequence found in the T. cruzi genome (TcFEN1) was cloned, inserted in parasite expression vectors and transfected to epimastigotes. The purified native recombinant protein showed DNA flap endonuclease activity. This endonuclease was found located in the parasite nucleus of transfected epimastigotes and its over-expression increased both parasite proliferation and survival to H2 O2 . The presence of a flap endonuclease activity in T. cruzi and its nuclear location are indicative of the participation of this enzyme in DNA processing of flap fragments during DNA replication and repair in this parasite of ancient evolutive origin. J. Cell. Biochem. 118: 1722-1732, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27935094 TI - Cascading Delay Risk of Airline Workforce Deployments with Crew Pairing and Schedule Optimization. AB - This article concerns the assignment of buffer time between two connected flights and the number of reserve crews in crew pairing to mitigate flight disruption due to flight arrival delay. Insufficient crew members for a flight will lead to flight disruptions such as delays or cancellations. In reality, most of these disruption cases are due to arrival delays of the previous flights. To tackle this problem, many research studies have examined the assignment method based on the historical flight arrival delay data of the concerned flights. However, flight arrival delays can be triggered by numerous factors. Accordingly, this article proposes a new forecasting approach using a cascade neural network, which considers a massive amount of historical flight arrival and departure data. The approach also incorporates learning ability so that unknown relationships behind the data can be revealed. Based on the expected flight arrival delay, the buffer time can be determined and a new dynamic reserve crew strategy can then be used to determine the required number of reserve crews. Numerical experiments are carried out based on one year of flight data obtained from 112 airports around the world. The results demonstrate that by predicting the flight departure delay as the input for the prediction of the flight arrival delay, the prediction accuracy can be increased. Moreover, by using the new dynamic reserve crew strategy, the total crew cost can be reduced. This significantly benefits airlines in flight schedule stability and cost saving in the current big data era. PMID- 27935093 TI - Daughters of Mothers Who Smoke: A Population-based Cohort Study of Maternal Prenatal Tobacco use and Subsequent Prenatal Smoking in Offspring. AB - BACKGROUND: Prenatal exposure to tobacco is associated with adverse health outcomes for the mother and child, and has been associated with an increased risk of tobacco smoking and nicotine dependence in offspring. The objective of this study was to examine the risk of prenatal smoking, among daughters, associated with maternal prenatal smoking. METHODS: We used a population-based cohort study design, with linked vital records data of mothers and daughters delivering 1984 96 and 1996-2013, respectively, in Washington State. The exposure of interest was mothers' prenatal smoking (any vs. no smoking at any time during pregnancy), while the outcome was daughters' prenatal smoking (similarly assessed). We used multivariable log-binomial regression to obtain estimates of the relative risk (RR) and 95% confidence interval (CI). RESULTS: Daughters exposed to maternal prenatal smoking were more likely to smoke during their pregnancy, compared to unexposed daughters (RR 1.78, 95% CI 1.72, 1.84, adjusted for the year the daughter delivered, her marital status and educational attainment, and the mothers' race/ethnicity). CONCLUSIONS: In this relatively young population, we found that daughters exposed to maternal prenatal smoking have an increased risk of smoking later on during their own pregnancy, emphasizing the importance of exposures during the prenatal period. The mechanisms leading to prenatal smoking are multifactorial and likely include behavioural, genetic, epigenetic and environmental factors. An understanding of this risk factor for prenatal smoking may guide health care providers to better target smoking cessation interventions to at-risk populations. PMID- 27935095 TI - Alteration of Neurotrophic Factors After Transplantation of Bone Marrow Derived Lin-ve Stem Cell in NMDA-Induced Mouse Model of Retinal Degeneration. AB - Retinal ganglion cell layer (RGCs) is one of the important layers of retina, depleted in Glaucoma. Loss of RGC neurons is a major cellular mechanism involved in its pathogenesis resulting in severe vision loss. Stem cell therapy has emerged as a potential strategy to arrest the apoptotic loss of RGCs and also replace the degenerative cells in damaged retina. Here, we have investigated the incorporation and survival of mouse bone marrow derived Lin-ve stem cells in N methyl-d-aspartate (NMDA)-induced mouse model of retinal degeneration. Two days after intravitreal injection of NMDA (100 mM) showed significant decrease in ganglion cell number and increase in TUNEL positive apoptotic cells in retinal layers. The injury was further characterized by immunohistochemical expression of Brn3b, GFAP, Bcl2, pCREB, CNTF, GDNF, and BDNF in retinal layers. Lin-ve cells (100,000 dose) were intravitreally transplanted after 2 days of injury and evaluated after 7, 14, and 21 days of transplantation. Transplanted cells were found to have migrated from intravitreal space and incorporated into injured retina at 7, 14, and 21 days post-transplantation. At 21 days Brn3b, CNTF, and BDNF expression was found to be upregulated whereas GDNF was downregulated when compared to respective injury time points. Molecular data showed decrease in the expression of Brn3b, BDNF, CNTF, and GDNF post transplantation when compared with injury groups. This study reveals that Lin-ve stem cells may exert neuroprotective effect in damaged retina mediated by participation of neurotrophic factors induced by stem cell transplantation at the site of injury. J. Cell. Biochem. 118: 1699-1711, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27935096 TI - The heterozygote state for beta-thalassemia detrimentally affects health outcomes. PMID- 27935097 TI - Streaming potential of superhydrophobic microchannels. AB - For the purpose of gaining larger streaming potential, it has been suggested to employ superhydrophobic microchannels with a large velocity slip. There are two kinds of superhydrophobic surfaces, one having a smooth wall with a large Navier slip coefficient caused by the hydrophobicity of the wall material, and the other having a periodic array of no- shear slots of air pockets embedded in a nonslip wall. The electrokinetic flows over these two superhydrophobic surfaces are modelled using the Navier-Stokes equation and convection-diffusion equations of the ionic species. The Navier slip coefficient of the first kind surfaces and the no-shear slot ratio of the second kind surfaces are similar in the sense that the volumetric flow rate increases as these parameter values increase. However, although the streaming potential increases monotonically with respect to the Navier slip coefficient, it reaches a maximum and afterward decreases as the no shear ratio increases. The results of the present investigation imply that the characterization of superhydrophobic surfaces employing only the measurement of volumetric flow rate against pressure drop is not appropriate and the fine structure of the superhydrophobic surfaces must be verified before predicting the streaming potential and electrokinetic flows accurately. PMID- 27935098 TI - TRIAD1 Is a Novel Transcriptional Target of p53 and Regulates Nutlin-3a-Induced Cell Death. AB - Nutlin-3a is a non-genotoxic, p53-activating, MDM2 inhibitor being investigated as an anticancer agent. Although Nutlin-3a selectively antagonizes the ubiquitin E3 ligase activity of MDM2, its efficacy is not entirely regulated by MDM2 levels in cancer cells. Here, we report that the cytotoxic effects of Nutlin-3a are regulated by TRIAD1 via a positive feedback loop with p53. We found that Nutlin 3a enhanced TRIAD1 transcription in a p53-dependent manner. Using in silico analysis and promoter luciferase assays, we demonstrated that p53-mediated transcription of TRIAD1 is mediated by a p53 consensus sequence in the TRIAD1 promoter region. Silencing TRIAD1 expression in wild-type p53 (p53WT ) cancer cells suppressed Nutlin-3a-mediated p53 activation and p53 target gene expression. These effects were enhanced in TRIAD1-overexpressing p53WT cancer cells, but not in p53-deficient cancer cells. Furthermore, TRIAD1 knockdown significantly reduced the growth inhibitory and cytotoxic effects of Nutlin-3a in p53WT cancer cells, as demonstrated by cell viability assays, cell cycle analysis, clonogenic growth, and soft-agar colony forming assays. Together, these data indicate that TRIAD1 regulates Nutlin-3a-mediated p53 activation and the cytotoxic activity of Nutlin-3a. J. Cell. Biochem. 118: 1733-1740, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27935099 TI - MCPIP1 Exogenous Overexpression Inhibits Pathways Regulating MYCN Oncoprotein Stability in Neuroblastoma. AB - The main physiological function of MCPIP1 (regnase-1) is negative regulation of inflammation. Moreover, roles of regnase-1 in apoptosis and differentiation have also been described, but its involvement in cancer is yet to be fully recognized. Earlier, we showed a lack of expression of MCPIP1 in both primary tumors and several neuroblastoma cell lines. Additionally, we reported that levels of MCPIP1 and the key neuroblastoma oncoprotein-MYCN were inversely correlated in BE(2)-C clones overexpressing the MCPIP1 gene. Here, we show that exogenous expression of the MCPIP1 protein decreases MYCN mRNA and protein levels without changing the MYCN mRNA half-life. Furthermore, it was shown that MCPIP1-wt exogenous expression affects levels and phosphorylation of MYCN partners such as Aurora A (Thr288), CDC2 (Tyr15 and Thr161), GSK3beta (Ser9), and key cellular components of Akt/mTOR signaling, which regulate MYCN stability and activation. In accordance with the obtained results, we found increased phosphorylation of MYCN protein at Thr58 that causes destabilization of the oncoprotein. Moreover, it is shown that exogenous expression of MCPIP1 does not cause apoptosis. Our data extend knowledge on roles of MCPIP1 in our model and link the protein to regulation of expression and stability of MYCN through decrease of signaling via Akt/mTOR pathway. J. Cell. Biochem. 118: 1741-1755, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27935100 TI - Precise injection of human mesenchymal stromal cells in the urethral sphincter complex of Gottingen minipigs without unspecific bulking effects. AB - AIM: To investigate if injection of cells in the urethral sphincter complex causes unspecific bulking effects. METHODS: Human mesenchymal stromal cells were isolated, expanded, and characterized. For transurethral injection, cells were labeled with the fluorescent dye PKH26 and in magnetic resonance imaging associated experiments with superparamagnetic particles. Aliquots of cells in 250 uL solvent were injected under vision in the urethral sphincter of immuno suppressed Gottingen minipigs. Sphincteric closure pressure was recorded by standard and high-definition urethral pressure profilometry prior to and after cell injection. The animals were sacrificed after surgery or after 3 weeks, 3, 6, or 12 months of follow-up. The localisation of the injected cells was explored by histochemistry. Sham-treated animals served as controls. RESULTS: PKH26-labeled cells survive injections in sphincter tissue samples by Williams cystoscopic injection needle well. In our animal study, the cellular depots were detected in the submucosa or in deeper zones of the sphincter, depending of the length of the injection needle (4-8 mm). Adverse effects associated with injection of cells or solvent such as a noteworthy bleeding, incontinence, or obstruction, were not recorded (n = 96 minipigs). However, a transient infiltration of macrophages was detected 3 weeks after cell injection. Changes in the urethral pressure profiles were not observed in cell-treated (n = 72) compared to sham-treated animals (n = 24). CONCLUSIONS: Injection of small aliquots of cells to investigate cell therapies in minipigs is a feasible and safe procedure, and it does not bias the intrinsic urethral wall pressure. PMID- 27935101 TI - GPNMB ameliorates mutant TDP-43-induced motor neuron cell death. AB - Glycoprotein nonmetastatic melanoma protein B (GPNMB) aggregates are observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, but the detailed localization is still unclear. Mutations of transactive response DNA binding protein 43kDa (TDP-43) are associated with neurodegenerative diseases including ALS. In this study, we evaluated the localization of GPNMB aggregates in the spinal cord of ALS patients and the effect of GPNMB against mutant TDP-43 induced motor neuron cell death. GPNMB aggregates were not localized in the glial fibrillary acidic protein (GFAP)-positive astrocyte and ionized calcium binding adaptor molecule-1 (Iba1)-positive microglia. GPNMB aggregates were localized in the microtubule-associated protein 2 (MAP-2)-positive neuron and neurofilament H non-phosphorylated (SMI-32)-positive neuron, and these were co-localized with TDP 43 aggregates in the spinal cord of ALS patients. Mock or TDP-43 (WT, M337V, and A315T) plasmids were transfected into mouse motor neuron cells (NSC34). The expression level of GPNMB was increased by transfection of mutant TDP-43 plasmids. Recombinant GPNMB ameliorated motor neuron cell death induced by transfection of mutant TDP-43 plasmids and serum-free stress. Furthermore, the expression of phosphorylated ERK1/2 and phosphorylated Akt were decreased by this stress, and these expressions were increased by recombinant GPNMB. These results indicate that GPNMB has protective effects against mutant TDP-43 stress via activating the ERK1/2 and Akt pathways, and GPNMB may be a therapeutic target for TDP-43 proteinopathy in familial and sporadic ALS. (c) 2016 Wiley Periodicals, Inc. PMID- 27935102 TI - Differential Expression of Newly Identified Long Intergenic Non-Coding RNAs in Buffalo Oocytes Indicating Their Possible Role in Maturation and Embryonic Development. AB - Female germ cell and its intricate milieu regulate key processes of folliculogenesis and early embryonic development. However, the composition and dynamics of the oocyte transcriptome defines its future fertilizing ability which in turn depends on a number of oocyte specific genes whose identities are still unknown. In this context, the construction of buffalo oocyte specific subtracted cDNA library has raised fresh challenges of defining the importance of a battery of oocyte expressed transcripts in oocyte maturation. The present study tried to characterize these hitherto unknown transcripts and further to assess their expression dynamics in buffalo oocytes of different quality. For this purpose, three ESTs were selected from the library and subjected to 5' and 3' RACE for generating their full length sequences. These constructed full length sequences were validated by amplifying them in oocytes. Further these sequences were extensively analyzed for their coding potential and possible role using coding potential calculator and miRNA database. Besides, their expression was monitored during in vitro maturation in good (BCB+) and poor quality (BCB-) oocytes which was interestingly found to be differing significantly. All the three sequences under study were interpreted as long intergenic non-coding RNAs with the possibility of two of them acting as a miRNA precursors. Also, their differential expression trends in competitively diverse oocytes hints at their possible involvement in oocyte maturation and future embryonic development which needs to be explored further. J. Cell. Biochem. 118: 1712-1721, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27935103 TI - Concerns of Older Veteran Callers to the Veterans Crisis Line. AB - When the Veterans Crisis Line (VCL) was implemented, it was uncertain if veterans, and particularly older male veterans, would utilize the service. We examined VCL use by a growing group of veterans at increased risk for suicide: those aged 60 and older. Real-time clinical data were gathered from a weekly random sampling of calls. Approximately 25% of calls were from veterans aged 60 or older; over 80% reported benefit from the call. Several significant differences in presenting concerns between older and younger callers were found. Targeted outreach to encourage older veterans to use the VCL is suggested. PMID- 27935104 TI - Parents reported higher satisfaction rates when children recognised hospital staff from photographs placed in prominent locations. AB - AIM: Improved communication with staff during a child's hospitalisation is an important determinant of family satisfaction. We examined whether displaying staff photographs in prominent locations would help children and their parents or guardians to recognise staff and whether this enhanced identification would improve parental satisfaction with their child's hospitalisation. METHODS: No photographs were displayed during the first part of the study. During the second part of the study, staff photographs were placed in prominent locations throughout the paediatric ward. Parents filled in a satisfaction questionnaire on discharge, and the children and their parents were asked how many staff members they could name. RESULTS: The children named a significantly larger number of staff members in phase two than phase one, while the parents' score was unchanged. Overall parental satisfaction was significantly higher in phase two. The parent's age, the duration of the child's hospitalisation and taking part in phase two of the study were significant predictors of parental satisfaction. CONCLUSION: When children were more able to recognise and name hospital staff, this indirectly improved parental satisfaction, even if the number that parents could identify remained unchanged. Displaying staff photographs is a simple way of increasing parental satisfaction during a child's hospitalisation. PMID- 27935106 TI - Fate of abstracts presented at the annual meetings of the American association of clinical anatomists. AB - A recent study examined the rate of full-length research paper publication following abstract presentation at the British association of clinical anatomists (BACA) annual meetings. The accepted standard for research dissemination is peer reviewed publication following presentation at a national or international meeting. The study objectives were quantitative assessment of the abstracts presented at the American Association of Clinical Anatomists' (AACA) annual meetings with regards to the rate of subsequent full-length publication and comparison to BACA publication rates. All abstracts presented at the AACA annual meetings between 2003 and 2010 were analysed. MEDLINE was searched to identify peer-reviewed publications arising from each presented abstract. In total, 1,120 abstracts were presented with 22.9% (n = 257) subsequently published as full length research papers. The mean number of abstracts presented each year was 140.0 +/- 35.9. The median time to publication was 16 months. Chi-squared analysis showed the publication rate of abstracts presented at AACA (22.9%) was not statistically significantly different to BACA (20.4%) (P = 0.09). A total of 11.3% (n = 29) of the articles were published as full-length research articles before presentation as an abstract at an AACA meeting compared to 5.4% of abstracts presented at a BACA meeting. These rates are lower but comparable to those of surgical specialty meetings. Further work should try to identify any concerning reasons for the reduced rate of abstract publication in anatomical research. Clin. Anat. 30:140-144, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 27935105 TI - Identifying the optimum source of mesenchymal stem cells for use in knee surgery. AB - Single sitting procedures where the mononuclear cell fraction is extracted from bone marrow and implanted directly into cartilage and bone defects are becoming more popular as novel treatments for cartilage defects which have, until now had few treatment options. This is on the basis that the mesenchymal stem cells (MSCs) contained within will repair the damaged tissue. This study sought to determine if the femur and tibia could provide equivalent amounts of mesenchymal stem cells, with equivalent viability and proliferative capacity, to that obtained from the gold standard of the pelvis in order to potentially reduce the morbidity associated with these procedures. Bone marrow was extracted from the pelvis, femur, and tibia of human subjects. The mononuclear cell fraction was extracted and cultured in the laboratory. Mesenchymal stem cell populations were assessed using a colony forming unit count. Viability was assessed using a PrestoBlue viability assay. Population doubling number was calculated between the end of passage 0 and passage three to determine the proliferative abilities of the different populations. Finally, the cell surface phenotype of the cells was determined by flow cytometry. The results showed that the pelvis was superior to the femur and tibia in terms of the number of stem cells isolated. There was no statistically significant difference in the phenotype of the cells isolated from different locations. This work shows that when undertaking single sitting procedures, the pelvis remains the optimum source for obtaining MSCs, despite the morbidity associated with bone marrow collection from the pelvis. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1868-1875, 2017. PMID- 27935107 TI - Surgical findings during exploratory laparotomy are closely related to mortality in premature infants with necrotising enterocolitis. AB - AIM: This study investigated whether a correlation existed between surgical findings during the first laparotomy for necrotising enterocolitis (NEC) and death and, or, disease progression. METHODS: We included infants admitted within one day of birth to our tertiary neonatal department at Rigshospitalet, Denmark, from 2006 to 2015, who underwent a laparotomy for acute NEC. They were classified according to the locality and extent of intestinal necrosis by a paediatric surgeon, based on the surgical findings. We correlated the surgical findings with postoperative outcomes, namely death and, or, progression of NEC. RESULTS: The first laparotomy showed that 48 infants had NEC, including 21 who demonstrated postoperative progression. Of these, six died before undergoing another laparotomy and 14 of the 15 infants who underwent relaparotomy also died. There was a significant association between surgical findings and NEC-related mortality (p = 0.03). The association between surgical findings and the progression of NEC was also significant (p < 0.0001). CONCLUSION: Surgical findings during laparotomy for NEC were strongly correlated with mortality, which was close to 100% after relaparotomy. Considering the discouraging outcome, further studies should focus on alternative surgical approaches, such as proximal diverting jejunostomy and the clip and drop technique for the treatment of severe NEC. PMID- 27935108 TI - Abscisic acid and transpiration rate are involved in the response to boron toxicity in Arabidopsis plants. AB - Boron (B) is an essential microelement for vascular plant development, but its toxicity is a major problem affecting crop yields in arid and semi-arid areas of the world. In the literature, several genes involved in abscisic acid (ABA) signalling and responses are upregulated in Arabidopsis roots after treatment with excess B. It is known that the AtNCED3 gene, which encodes a crucial enzyme for ABA biosynthesis, plays a key role in the plant response to drought stress. In this study, root AtNCED3 expression and shoot ABA content were rapidly increased in wild-type plants upon B-toxicity treatment. The Arabidopsis ABA deficient nced3-2 mutant had higher transpiration rate, stomatal conductance and accumulated more B in their shoots than wild-type plants, facts that were associated with the lower levels of ABA in this mutant. However, in wild-type plants, B toxicity caused a significant reduction in stomatal conductance, resulting in a decreased transpiration rate. This response could be a mechanism to limit the transport of excess B from the roots to the leaves under B toxicity. In agreement with the higher transpiration rate of the nced3-2 mutant, this genotype showed an increased leaf B concentration and damage upon exposure to 5 mM B. Under B toxicity, ABA application decreased B accumulation in wild-type and nced3-2 plants. In summary, this work shows that excess B applied to the roots leads to rapid changes in AtNCED3 expression and gas exchange parameters that would contribute to restrain the B entry into the leaves, this effect being mediated by ABA. PMID- 27935109 TI - Transplantation of human skeletal muscle-derived progenitor cells ameliorates knee osteoarthritis in streptozotocin-induced diabetic mice. AB - The epidemiological and experimental evidence suggests that diabetes can be an independent risk factor for osteoarthritis. The osteoarthritis-like cartilage damage has been shown in streptozotocin-induced diabetic mice. The therapeutic effects of human skeletal muscle-derived progenitor cells (HSMPCs) on diabetic osteoarthritis still remain unclear. Here, we investigated the therapeutic potential of HSMPCs on diabetic knee osteoarthritis. The in vitro chondrogenic ability of HSMPCs was determined by pellet culture assay. Male mice were used to develop the model of streptozotocin-induced type 1 diabetes and its related osteoarthritis. HSMPCs were injected intra-articularly to rescue osteoarthritis. Protein expressions of advanced glycation end-products, cyclooxygenase-2, and type-2 collagen in tissues were determined by immunohistochemistry. The pellet culture assay showed that HSMPCs cultured in differentiation medium for chondrogenesis significantly produced larger pellets with an overproduction of extracellular matrix than in growth medium. In in vivo experiments, intra articular injection of HSMPCs for 4 weeks significantly prevented the progression of degenerative changes in the cartilage of streptozotocin-induced diabetic mice, including an obvious increase of total articular cartilage thickness and a decrease of fibrous cartilage thickness. HSMPCs transplantation also exerted the decline in advanced glycation end-products and cyclooxygenase-2 protein expression, but increased the type-2 collagen protein expression in streptozotocin-induced osteoarthritic cartilages. Moreover, HSMPCs transplantation also inhibited the increased serum interleukin-6 and matrix metalloproteinase-3 levels in diabetic mice. These results demonstrated for the first time that HSMPCs transplantation ameliorates cartilage degeneration in diabetes-related osteoarthritis mice. These findings suggest that HSMPCs transplantation may apply as a potential therapeutic use of diabetes-related osteoarthritis. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1886-1893, 2017. PMID- 27935110 TI - Involvement of opioid receptors in inhibition of bladder overactivity induced by sacral neuromodulation in pigs: A possible action mechanism. AB - AIMS: To determine the role of opioid receptors in the inhibition of bladder overactivity by sacral neuromodulation (SNM) in pigs, and explore the possible mechanism of SNM. METHODS: Both implant-driven stimulators of the S3 spinal nerve were implanted in seven pigs. Naloxone and tramadol were administered. Multiple cystometrograms were performed to determine the effects of SNM and opioid receptors on the micturition reflex by infusing normal saline (NS) or acetic acid (AA). RESULTS: AA-induced bladder overactivity significantly reduced the bladder capacity (BC) to 29.9 +/- 3.9% of the NS control level (413.1 +/- 55.4 mL) (P < 0.01). SNM significantly increased the BC to 39.4 +/- 5.5% of the NS control level (P < 0.03). In the absence of SNM, the cumulative dose of naloxone (0.02 and 0.2 mg/kg intravenously) did not significantly change the BC (25.1 +/- 3.1% and 20.2 +/- 3.1% of the NS control level, respectively) (P > 0.05). In the presence of SNM, both doses of naloxone significantly reduced the BC to 27.2 +/- 3.0% and 25.1 +/- 2.9% of the NS control level (P < 0.05), respectively. In the absence of SNM, tramadol did not significantly change the BC (31.5 +/- 3.9% of the NS control level) (P > 0.05). In the presence of SNM, tramadol significantly increased the BC to 49.1 +/- 6.1% of the NS control level (P < 0.01). CONCLUSIONS: Opioid receptors play a role in inhibition of bladder overactivity during SNM. Combining SNM with tramadol could be a novel treatment modality for overactive bladder. PMID- 27935111 TI - Degradation of elastic fiber and elevated elastase expression in long head of biceps tendinopathy. AB - Tendinopathy of the long head of the biceps (TLHB) involves various types of extracellular matrix degeneration, but previous studies have not evaluated elastic fibers. The purpose of this study was to investigate elastic fiber distribution in long head of the biceps (LHB). The TLHB tendons of 16 consecutive patients (eight men and eight women; average age of 55.75 years; age range of 40 71 years) were transected and harvested. Three cadaveric LHB tendons were used as the control group. The expression of collagen type I was decreased, but type III was increased in TLHB. Disruption of elastic fibers was particularly observed in grade II specimens where the level of elastase-positive staining was significantly higher than in grade I specimens. Elastic fibers were not observed in the grade III area, implying a higher expression of elastase than in the grade I area. Results of Western blotting showed that the expression of elastin was higher in the control group and the levels of elastin significantly decreased in grades II and III of TLHB. Levels of osteopontin and elastase were increased in primary culture of human tenocytes after experiencing elastic derived peptide treatment. These results suggested that elastase may be caused by the disruption of elastic fibers in the development of chronic tendinopathy and that elastic derived peptide may enhance elastase and osteopontin expression. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1919-1926, 2017. PMID- 27935112 TI - Cross-sectional, school-based study of 14-19 year olds showed that raised blood pressure was associated with obesity and abdominal obesity. AB - AIM: Gaining weight has been directly associated with an increased probability of developing high blood pressure (HBP) and metabolic abnormalities. We examined the independent and combined effects of overweight, obesity and abdominal obesity on blood pressure in adolescents. METHODS: This cross-sectional school-based study evaluated 869 adolescents (53.4% girls) from 14 to 19 years of age, and the data were collected in 2013 in the city of Imperatriz, Maranhao, Brazil. The outcome was HBP. The independent variables were overweight and obesity classified by body mass index, abdominal obesity classified by the waist-to-height ratio and the combination of obesity and overweight and abdominal obesity. The potential confounding variables were age, the socio-economic status of the family, parental education, type of school and physical activity levels. RESULTS: The prevalence ratios of HBP were higher when male and female adolescents were overweight (1.61 3.11), generally obese (3.20-4.70), had abdominal obesity (2.18-3.02) and were both generally obese and had abdominal obesity (3.28-5.16) compared with normal weight adolescents. CONCLUSION: Obesity or abdominal obesity increased the risk of HBP in adolescents aged 14-19. However, adolescents who were both generally obese and had abdominal obesity showed an even higher risk of having HBP. PMID- 27935113 TI - FAK is overexpressed in keratocystic odontogenic tumor: a preliminary study. AB - BACKGROUND: Focal adhesion kinase (FAK) is an important mediator of cell adhesion, growth proliferation, survival, angiogenesis, and migration. FAK is overexpressed in many locally invasive and malignant lesions including oral cancer. Looking at the tumorigenic nature of keratocystic odontogenic tumor (KCOT), which involves local invasion, proliferation, and recurrence, we hypothesized strong expression of FAK in the epithelial lining of KCOT. MATERIALS AND METHODS: 34 KCOTs, 11 orthokeratinized odontogenic cysts (OOCs), 25 radicular cysts (RCs), 17 dentigerous cysts (DCs), and 25 dental follicles (DFs) were retrieved from archives and subjected to the immunohistochemical analysis using FAK antibody. RESULTS: In KCOT, strong expression was observed in 22 (62.8%) cases followed by weak and negative expression in 9 (25.71%) and 4 (11.4%) cases, respectively. Negative expression was seen in 7 (63.63%) cases of OOC, while 4 (36.36%) showed weak expression. In case of RC, 20 (80%) cases displayed negative expression and 4 (16%) and 1 (4%) cases showed weak and strong expressions, respectively. In case of DC, negative expression was seen in 14 (82.35%) cases and weak expression in 3 (17.64%) cases. DF was characterized by negative [21 (84%)] and weak expression [4 (16%)]. Nuclear expression of FAK was seen only in KCOT (11 cases). There was statistically significant higher FAK expression in KCOT as compared to OOC, RC, DC, and DF (P < 0.00001). CONCLUSION: FAK molecule could be an important player in tumorigenesis of KCOT and thus is a potential target for future drug development. PMID- 27935114 TI - Sexism in the dissection room: A medical student perspective. PMID- 27935115 TI - Elongation of transverse aortic arch; not specific for Turner Syndrome. PMID- 27935117 TI - Long noncoding RNA MALAT1 affects the efficacy of radiotherapy for esophageal squamous cell carcinoma by regulating Cks1 expression. AB - OBJECTIVE: Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been well studied in the progression of many malignancies. However, its association with the radioresistance of tumors has not been well understood yet. This study tried to explore the role of MALAT1 in regulating the radiosensitivity of esophageal cancer (EC), especially esophageal squamous cell carcinoma (ESCC), involving its regulation on Cks1 expression. METHODS: KYSE150 cells were subcutaneously inoculated into nude mice to establish ESCC xenografts. Real-time PCR and Western blot analysis were performed to detect the expression of MALAT1 and Cks1 in irradiated xenografts and cells. Functional analysis was performed in both EC9706 and KYSE150 cells via the transfection of corresponding plasmids or small interfering RNAs (siRNAs). Irradiation-induced damage was examined by the detection of cell viability and apoptosis using MTT and TUNEL assays, respectively. RESULTS: Both MALAT1 and Cks1 were downregulated in irradiated xenografts and cells. Cks1FER1L4 showed significant downregulation. Overexpression of MALAT1 inhibited irradiation-induced decrease in cell viability, increase in apoptosis, and downregulation of Cks1. Cks1 expression was also downregulated by MALAT1 siRNA, while Cks1 siRNA strongly recovered MALAT1 induced radioresistance in vitro. Moreover, better tumor growth, accompanied by Cks1 upregulation, was observed in KYSE150 xenografts with MALAT1 overexpression, especially under radiation treatment. CONCLUSION: MALAT1 acted as one positive regulator of the radioresistance of ESCC, at least partly due to its promotion on Cks1 expression. Furthermore, MALAT1-targeted therapies showed great potential in enhancing the radiotherapeutic effect on ESCC. PMID- 27935118 TI - Sexism in the dissection room: A medical student perspective. PMID- 27935119 TI - Differences in survival outcome between oropharyngeal and oral cavity squamous cell carcinoma in relation to HPV status. AB - BACKGROUND: This study examined the prognostic significance of human papillomavirus (HPV) in patients with oropharyngeal and oral cavity squamous cell carcinoma (SCC). METHODS: Tissue microarrays were constructed from oropharyngeal and oral cavity SCC (n = 143). The presence of functional HPV in tumour was determined by combined assessments of p16 immunohistochemistry and HPV in situ hybridisation. RESULTS: Oropharyngeal SCC patients presented with more advanced disease in comparison with oral cavity SCC patients (P = 0.001). HPV is present in 60% and 61% of oropharyngeal and oral cavity SCC patients, respectively. HPV positive oropharyngeal SCC patients with advanced TNM stages displayed better overall and disease-free survival outcomes than HPV-negative patients (P = 0.022 and 0.046, respectively). Such survival differences were not observed in oral cavity SCC. CONCLUSIONS: HPV is common in both oropharyngeal and oral cavity SCC and is associated with better survival outcome in oropharyngeal SCC but not in oral cavity SCC patients. PMID- 27935121 TI - Urea is successful in treating inappropriate antidiuretic hormone secretion in an infant. PMID- 27935120 TI - Prevalence of high-risk human papillomavirus infection among women in Shaanxi province of China: A hospital-based investigation. AB - This study aimed to investigate the characteristics of female high-risk human papillomavirus (HR-HPV) infection in Shaanxi province of China. A total of 14 111 women were enrolled for HPV genotyping test, and a cytology, and/or cervix biopsy were performed in partial women. Of these women, the HPV infection rate was 30.21%, and 26.73% were caused by HR-HPV. The most common HR-HPV genotypes were HPV-16, HPV-58, HPV-52, HPV-18, and HPV-31. The prevalence of HR-HPV among women older than 50 years was significantly higher than the other groups (P < 0.05). The main carcinogenic genotypes were HPV-16, HPV-18, HPV-58, HPV-52, and HPV-31. HPV-16 and HPV-18 combined caused 80.79% of cervical cancer cases. The infection with multiple HR-HPVs was not a risk factor for cervical lesions. In conclusion, HPV infection was common among women in Shaanxi province. Women older than 50 years were a high-risk group for HR-HPV infection and cervical cancer. HPV-16 and HPV-18 were the main carcinogenic genotypes in this region. PMID- 27935122 TI - Outcome and cervical metastatic spread of squamous cell cancer of the buccal mucosa, a retrospective analysis of the past 25 years. AB - OBJECTIVES: Because of the low proportion of squamous cell carcinomas (SCCs) of the buccal mucosa within the carcinomas of the oral cavity in the Western population, data concerning metastatic pattern are sparse. Therefore, this retrospective study is focusing on the occurrence of cervical metastases (CM) and the overall outcome of this tumor entity. MATERIALS AND METHODS: From January 1988 to October 2013, 113 patients were treated in the Department of Oral and Maxillofacial Surgery, Mainz, for an oral SCC of the cheek. Metastatic pattern and clinical parameters that are possibly associated with an increased risk for CM as well as overall outcome were analyzed. RESULTS: The average follow-up was 48 months (range: 1-248 months). A total of 55 (49%) patients were female and 58 (51%) male, with an average age of 65 +/- 13 years (?68 +/- 14 years; ?63 +/- 11 years). In total, 55% of the patients either smoked and/or consumed alcohol. In total, 34% of the patients had a stage III or IV tumor, with overall 23% having CM at the time of diagnosis. During the follow-up, 50% (n = 56) of the patients developed a relapse after 12 months (median). Tumor size (P = 0.002*) and grading (P < 0.001*) are significantly associated with the occurrence of CM. Metastases (P = 0.008*) and advanced tumor size (P = 0.018) had an influence on the survival, whereas the relapse had no significant influence (P = 0.928). Five-year survival rate was 80%. CONCLUSIONS: SCC of the buccal mucosa shows aggressive behavior with a considerably high proportion of relapse. Since overall outcome is significantly decreased by the cervical metastatic pattern, a selective, ipsilateral neck dissection for this patient group is recommended as the primary management. PMID- 27935123 TI - Efficacy and safety of nucleoside antiviral drugs for treatment of recurrent herpes labialis: a systematic review and meta-analysis. AB - OBJECTIVES: To evaluate the effectiveness and safety of nucleoside antiviral drugs for the treatment of recurrent herpes labialis. METHODS: Randomized controlled trials that examined the effectiveness and/or safety of nucleoside antiviral drugs for recurrent herpes labialis were identified via a literature search. The parameters used to measure efficacy were time to healing of classic and all lesions, time to resolution of pain, and percentage of aborted lesions. Safety was assessed by evaluating the adverse events reported during treatment. Subgroup analyses based on the mode of application (topical/systemic) and type of nucleoside antiviral drugs were performed, as were sensitivity analyses of studies with a low risk of bias. RESULTS: Our analysis included 16 publications reporting 25 randomized controlled trials (8453 patients). Nucleoside antiviral drugs decreased the time to healing of all lesions (mean difference: -0.74 days; 95% confidence interval: -0.86, -0.62), especially classic lesions (mean difference: -1.09 days; 95% confidence interval: -1.27, -0.92). They also reduced the time to resolution of pain (mean difference: -0.38 days; 95% confidence interval: -0.58, -0.18) and increased the percentage of aborted lesions (rate ratio: 1.15; 95% confidence interval: 1.07, 1.23). Valaciclovir more effectively reduced the time to healing of all lesions and the time to resolution of pain than did aciclovir. Both nucleoside antiviral drugs increased the percentage of aborted lesions, whereas penciclovir and famciclovir did not. CONCLUSIONS: Nucleoside antiviral drugs are safe and beneficial for the treatment of recurrent herpes labialis; both systemic and topical formulations are recommended. Valaciclovir is more effective than aciclovir, especially in reducing the time to healing of lesions. PMID- 27935124 TI - Erythritol/chlorhexidine combination reduces microbial biofilm and prevents its formation on titanium surfaces in vitro. AB - BACKGROUND: The purpose of this in vitro study was to evaluate the antibiofilm activity of a novel air-polishing powder consisting of erythritol and chlorhexidine, assessing its ability to reduce previously grown microbial biofilm and to prevent biofilm formation on titanium surfaces. METHODS: Clinical strains of Staphylococcus aureus, Pseudomonas aeruginosa, Bacteroides fragilis and Candida albicans isolated from peri-implantitis lesions were used. Biofilm was grown on sandblasted titanium discs and treated with erythritol/chlorhexidine. The antimicrobial activity was evaluated by determining the minimum inhibitory concentration and the minimum microbicidal concentration. The antibiofilm activity was assessed by semiquantitative spectrophotometric assay and by confocal laser scanning microscopy. RESULTS: Erythritol/chlorhexidine displayed an inhibitory and a microbicidal activity against all the tested strains. The spectrophotometric analysis showed that the treatment was effective in both reducing the previously developed biofilm and decreasing biofilm formation on titanium surfaces. Confocal laser scanning microscopy analysis showed a significant reduction of the total biofilm volume, with an increase of the percentage of dead cells of all the microorganisms tested. CONCLUSIONS: Erythritol/chlorhexidine displayed significant antimicrobial and antibiofilm activity against microorganisms isolated from peri-implantitis lesions. Due to its properties, it might represent a promising approach for the prevention and treatment of peri-implant diseases associated to microbial biofilm infections. PMID- 27935125 TI - Clinical phenotype of recurrent aphthous stomatitis and interleukin-1beta genotype in a Polish cohort of patients. AB - BACKGROUND: The aim of this study was to evaluate the relation between a clinical profile and the interleukin-1beta (IL-1beta) genotype in a Polish cohort of patients with RAS. METHODS: One hundred and four patients with RAS were enrolled in the study and all were subject to an oral examination. The severity of RAS was assessed according to the clinical type of the disease, the number of lesions per flare-up and the length of intervals between the episodes. The genotyping of two SNPs of the IL-1beta gene, IL-1beta c.-511 T>C (rs16944) and IL-1beta c.+3954 C>T (rs1143634), was carried out by genomic DNA isolated from blood samples and by using the PCR-RFLP approach. The results were statistically analysed with chi square and Fisher's tests and Spearman's rank correlation, with P < 0.05 assumed to be a significance level (Statistica 10; StatSoft(r) , Krakow, Poland). RESULTS: No statistically significant associations or correlations were found between the presence of *2 allele and minor, major or herpetiform RAS nor after the stratification using the RAS severity score and the classification based on the number of lesions per one flare-up. A weak correlation was found between the number of lesions per one flare-up and heterozygosity promoting the A type of RAS, characterized by a low number of eruptions. CONCLUSIONS: The presence of IL 1 beta *2 allele within the c.+3954 and c.-511 SNPs was found to be neither a significant risk factor for a higher incidence of any type of RAS, nor did it influence the disease severity and mode of recurrences. PMID- 27935127 TI - Outer Surface Interactions of Cucurbit[6]uril That Trigger the Assembly of Supramolecular Three-Dimensional Polycatenanes. AB - A supramolecular polycatenane stabilized by outer surface interactions between cucurbit[6]uril (Q[6] or CB[6]) cations and [CdCl4 ]2- is reported. The arrangement of the poly-interlocked supramolecular framework is evidently constructed by a favorable combination of weak non-covalent interactions such as hydrophobic effects, hydrogen bonding, ion-dipole interactions, and C-H???Cl interactions in the solid state. Further study suggests that such 3D poly interlocked species could be rapidly precipitated from the mixture solution in high yield owing to electrostatic interaction of the [CdCl4 ]2- anion with the electropositive outer surface of Q[6] host. This work thus demonstrates a simple, low-cost, and efficient non-covalent approach for the construction of a infinite 3D interlocked structure in water besides through coordination or covalent bonds. PMID- 27935126 TI - Does cell phone use increase the chances of parotid gland tumor development? A systematic review and meta-analysis. AB - BACKGROUND: Prior epidemiological studies had examined the association between cell phone use and the development of tumors in the parotid glands. However, there is no consensus about the question of whether cell phone use is associated with increased risk of tumors in the parotid glands. We performed a meta-analysis to evaluate the existing literature about the mean question and to determine their statistical significance. METHODS: Primary association studies. Papers that associated cell phone use and parotid gland tumors development were included, with no restrictions regarding publication date, language, and place of publication. Systematic literature search using PubMed, SciELO and Embase followed by meta-analysis. RESULTS AND CONCLUSION: Initial screening included 37 articles, and three were included in meta-analysis. Using three independent samples including 5087 subjects from retrospective case-control studies, cell phone use seems to be associated with greater odds (1.28, 95%- confidence interval: 1.09-1.51) to develop salivary gland tumor. Results should be read with caution due to the limited number of studies available and their retrospective design. PMID- 27935128 TI - Nonlinear Frameworks for Reversible and Pluripotent Wetting on Topographic Surfaces. AB - Soft, ultrathin frameworks nonlinearly organized in tandem are presented to realize both reversible and pluripotent wetting on topographic surfaces. A design rule is introduced by establishing and proving the theoretical model upon hierarchical textures. Nonlinear frameworks can be conformally and reversibly wet upon complex topography in nature, thereby overcoming the wetting problems in previous conventional solid systems. PMID- 27935129 TI - Performance comparison of electrospray ionization and atmospheric pressure chemical ionization in untargeted and targeted liquid chromatography/mass spectrometry based metabolomics analysis of grapeberry metabolites. AB - RATIONALE: Electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) are both used to generate ions for the analysis of metabolites by liquid chromatography/mass spectrometry (LC/MS). We compared the performance of these methods for the analysis of Corvina grapevine berry methanolic extracts, which are complex mixtures of diverse metabolites. METHODS: Corvina berries representing three ripening stages (veraison, early-ripening and full-ripening) were collected during two growing seasons, powdered and extracted with methanol. Untargeted metabolomic analysis was carried out by LC/ESI-MS and LC/APCI-MS. Processed data files were assembled into a data matrix for multivariate statistical analysis. The limits of detection (LODs), limits of quantification (LOQs), linear ranges, and matrix effects were investigated for strongly polar metabolites such as sucrose and tartaric acid and for moderately polar metabolites such as caftaric acid, epicatechin and quercetin 3-O-glucoside. RESULTS: Multivariate statistical analysis of the 608 features revealed that APCI was particularly suitable for the ionization of strongly polar metabolites such as sugars and organic acids, whereas ESI was more suitable for moderately polar metabolites such as flavanols, flavones and both glycosylated and acylated anthocyanins. APCI generated more fragment ions whereas ESI generated more adducts. ESI achieved lower LODs and LOQs for sucrose and tartaric acid but featured narrower linear ranges and greater matrix effects. CONCLUSIONS: ESI and APCI are not complementary ion sources. Indeed, ESI can be exploited to analyze moderately polar metabolites, whereas APCI can be used to investigate weakly polar/non-polar metabolites and, as demonstrated by our results, also strongly polar metabolites. ESI and APCI can be used in parallel, exploiting their strengths to cover the plant metabolome more broadly than either method alone. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27935130 TI - Effect of FK-506 (tacrolimus) therapy on bone healing of titanium implants: a histometric and biomechanical study in mice. AB - Immunosuppressive agents have been recognized as a factor affecting bone metabolism. The aim of the present study was to evaluate the influence of FK-506 administration on the healing of bone around titanium implants. Thirty-two male mice were randomly allocated to two groups: the FK-506 group (n = 16 mice), which received subcutaneous administration of FK-506 (1 mg kg-1 d-1 ); and the control group (n = 16 mice), which received saline solution by the same route of administration. After 2 wk, one titanium implant with sandblasted/acid-etched surface was placed in the femur. The therapy continued until the mice were killed 2 and 4 wk after surgery. The femurs with implants were evaluated by biomechanical testing and histologic analysis. The bone-implant contact (BIC) and bone volume (BV/TV) within a 100-MUm-wide circumferential zone lateral to the implant surface were histomorphometrically analyzed. Compared with the control group, the FK-506 group showed significantly lower BIC and BV/TV at both 2 and 4 wk. Biomechanical tests showed that FK-506 significantly impaired the strength of bone-implant integration at both 2 and 4 wk postoperatively. Our data indicate that immunosuppressive therapy with FK-506 negatively affects the fixation of titanium implants. PMID- 27935131 TI - Evaluation of interactions between RAW264.7 macrophages and small molecules by capillary electrophoresis. AB - In this study, the affinity interactions between RAW 264.7 macrophages and three small molecules including naringin, oleuropein and paeoniflorin were evaluated by affinity capillary electrophoresis (ACE), partial filling affinity capillary electrophoresis (PFACE) and frontal analysis capillary electrophoresis (FACE), respectively. The result indicated that ACE (varying concentrations of cell suspension were filled in the capillary as receptor) may not be suitable for the evaluation of interactions between cell and small molecules due to the high viscosity of cell suspension; PFACE can qualitatively evaluate the interaction, but the difference in viscosity between RAW264.7 suspension and buffer effects on the liner relationship between filling length and injection time, which makes the calculation of binding constant difficult. Furthermore, based on the PFACE results, naringin showed stronger interaction with macrophages than the other two molecules; taking advantage of the aggregation phenomenon of cell induced by electric field, FACE was successfully used to determine the stoichiometry (n = 5*109 ) and binding constant (Kb = 1*104 L/mol) of the interaction between RAW264.7 and naringin. PMID- 27935132 TI - MoS2 /Carbon Nanotube Core-Shell Nanocomposites for Enhanced Nonlinear Optical Performance. AB - Nanocomposites of layered MoS2 and multi-walled carbon nanotubes (CNTs) with core shell structure were prepared by a simple solvothermal method. The formation of MoS2 nanosheets on the surface of coaxial CNTs has been confirmed by scanning electron microscopy, transmission electron microscopy, absorption spectrum, Raman spectroscopy, and X-ray photoelectron spectroscopy. Enhanced third-order nonlinear optical performances were observed for both femtosecond and nanosecond laser pulses over a broad wavelength range from the visible to the near infrared, compared to those of MoS2 and CNTs alone. The enhancement can be ascribed to the strong coupling effect and the photoinduced charge transfer between MoS2 and CNTs. This work affords an efficient way to fabricate novel CNTs based nanocomposites for enhanced nonlinear light-matter interaction. The versatile nonlinear properties imply a huge potential of the nanocomposites in the development of nanophotonic devices, such as mode-lockers, optical limiters, or optical switches. PMID- 27935133 TI - Modulation of brown adipocyte activity by milk by-products: Stimulation of brown adipogenesis by buttermilk. AB - Brown adipocytes dissipate chemical energy in the form of heat through the expression of mitochondrial uncoupling protein 1 (Ucp1); Ucp1 expression is further upregulated by the stimulation of beta-adrenergic receptors in brown adipocytes. An increase in energy expenditure by activated brown adipocytes potentially contributes to the prevention of or therapeutics for obesity. The present study examined the effects of milk by-products, buttermilk and butter oil, on brown adipogenesis and the function of brown adipocytes. The treatment with buttermilk modulated brown adipogenesis, depending on the product tested; during brown adipogenesis, buttermilk 1 inhibited the differentiation of HB2 brown preadipocytes. In contrast, buttermilk 3 and 5 increased the expression of Ucp1 in the absence of isoproterenol (Iso), a beta-adrenergic receptor agonist, suggesting the stimulation of brown adipogenesis. In addition, the Iso-induced expression of Ucp1 was enhanced by buttermilk 2 and 3. The treatment with buttermilk did not affect the basal or induced expression of Ucp1 by Iso in HB2 brown adipocytes, except for buttermilk 5, which increased the basal expression of Ucp1. Conversely, butter oil did not significantly affect the expression of Ucp1, irrespective of the cell phase of HB2 cells, ie, treatment during brown adipogenesis or of brown adipocytes. The results of the present study indicate that buttermilk is a regulator of brown adipogenesis and suggest its usefulness as a potential food material for antiobesity. PMID- 27935134 TI - Strain- and time-dependent alterations in hepatic iron metabolism in a murine model of nonalcoholic steatohepatitis. AB - : Nonalcoholic steatohepatitis is a common liver disease that is often accompanied by dysregulated iron metabolism. The aim of the study was to test the hypothesis that aberrant iron metabolism in nonalcoholic steatohepatitis is modulated by genetic susceptibility to inflammation and oxidative stress. Hepatic histology and iron content were assessed in 3 inbred strains of mice (C57BL/6, BALB/c, and C3H/HeJ) fed an atherogenic diet (AD). Hepatic expression of genes relevant to iron metabolism, inflammation, and oxidative stress were quantitated by real-time reverse transcription-polymerase chain reaction. At 6 weeks on the AD, histologic injury and induction of inflammatory and oxidative stress associated gene expression were most pronounced in C57BL/6. At 18 weeks on the AD, these parameters were similar in C57BL/6 and BALB/c. Atherogenic diet-fed C3H/HeJ showed milder responses at both time points. The AD was associated with decreased hepatic iron concentrations in all strains at 6 and 18 weeks. The decrease in hepatic iron concentrations did not correlate with changes in hepcidin expression and was not associated with altered expression of iron transporters. These findings are similar to those observed in models of obesity induced steatosis and indicate that hepatic steatosis can be associated with depletion of iron stores that is not explained by upregulation of hepcidin expression by inflammation. SIGNIFICANCE OF THE STUDY: Nonalcoholic steatohepatitis (NASH) is a common liver disease that often accompanies the metabolic syndrome. The latter condition has been linked to iron deficiency and diminished intestinal iron absorption, likely the result of hepcidin upregulation by chronic inflammation. Paradoxically, some NASH patients accumulate excess hepatic iron, which may increase fibrosis and cancer risk. Iron accumulation has been attributed to suppression of hepcidin by oxidative stress. The objective of this study was to investigate the contributions of inflammation and oxidative stress to altered hepatic iron metabolism in a murine model of NASH using inbred strains of mice with differing susceptibilities to injury. PMID- 27935135 TI - Micro RNA-550a interferes with vitamin D metabolism in peripheral B cells of patients with diabetes. AB - The pathogenesis of diabetes is to be further investigated. Vitamin D3 (VitD3) can improve diabetes. Micro RNAs (miR) are involved in regulating cell activities. This study tests a hypothesis that miR-550a interferes with the metabolism of VitD3 in peripheral B cells. In this study, blood samples were collected from patients with diabetes and healthy persons. The B cells were isolated from the blood samples to be treated with tumor necrosis factor (TNF) alpha. The B cells were then collected and analyzed for the expression of miR 550a and cyp27b1. The results showed that B cells from healthy subjects were capable of converting VitD metabolite calcidiol to calcitriol, which was impaired in B cells collected from diabetic patients. The diabetic patients showed lower bone mineral density than that in healthy subject. The miR-550a was negatively correlated with bone mineral density and the Levels of cyp27b1 in peripheral B cells of patients with diabetes. In vitro study showed that TNF-alpha increased miR-550a expression and inhibited the expression of cyp27b1 in B cells. miR-550a mediated the effects of TNF-alpha on inducing chromatin remodeling at the cyp27b1 gene locus. In conclusion, miR-550a mediates the TNF-alpha-induced suppression of cyp27b1 expression in peripheral B cells of patients with diabetes, which can be blocked by inhibition of miR-550a. PMID- 27935136 TI - A possible S-glutathionylation of specific proteins by glyoxalase II: An in vitro and in silico study. AB - : Glyoxalase II, the second of 2 enzymes in the glyoxalase system, is a hydroxyacylglutathione hydrolase that catalyses the hydrolysis of S-d lactoylglutathione to form d-lactic acid and glutathione, which is released from the active site. The tripeptide glutathione is the major sulfhydryl antioxidant and has been shown to control several functions, including S-glutathionylation of proteins. S-Glutathionylation is a way for the cells to store reduced glutathione during oxidative stress, or to protect protein thiol groups from irreversible oxidation, and few enzymes involved in protein S-glutathionylation have been found to date. In this work, the enzyme glyoxalase II and its substrate S-d lactoylglutathione were incubated with malate dehydrogenase or with actin, resulting in a glutathionylation reaction. Glyoxalase II was also submitted to docking studies. Computational data presented a high propensity of the enzyme to interact with malate dehydrogenase or actin through its catalytic site and further in silico investigation showed a high folding stability of glyoxalase II toward its own reaction product glutathione both protonated and unprotonated. This study suggests that glyoxalase II, through a specific interaction of its catalytic site with target proteins, could be able to perform a rapid and specific protein S-glutathionylation using its natural substrate S-d lactoylglutathione. SIGNIFICANCE: This article reports for the first time a possible additional role of Glo2 that, after interacting with a target protein, is able to promote S-glutathionylation using its natural substrate SLG, a glutathione derived compound. In this perspective, Glo2 can play a new important regulatory role inS-glutathionylation, acquiring further significance in cellular post-translational modifications of proteins. PMID- 27935137 TI - Regulation mechanism of PDK1 on macrophage metabolism and function. AB - PDK1 is a member of the atypical glandular cell kinases family that regulates the activities of most atypical glandular cell kinases during different development stages and treatment of cancers. PDK1 is also a critical glucose metabolism enzyme regulating glucolysis or glucose oxidase in cells, and more research is needed to further understand the underlying mechanism. The research of PDK1 presented by recent studies focuses much on cancer treatment and has helped researchers gain much insight in this regard. Given the close relationship between inflammation and cancer, it is of great significance to discover the function of PDK1 and its regulating mechanism on special immune cells macrophages. This review summarizes the recent findings regarding PDK1 in terms of regulating the function and metabolism of macrophage. The mechanism of PDK1 in regulating inflammatory secretion, migration, phagocytosis, and the energy metabolism of macrophage and a possible path to develop PDK1 related pharmaceutical products are discussed as well. PMID- 27935138 TI - Characteristics of Accredited Transcranial Doppler Ultrasound Laboratories in the United States. AB - PURPOSE: The aim of this study was to describe in detail the characteristics and accreditation compliance of laboratories in the United States applying for Intersocietal Accreditation Commission (IAC) transcranial Doppler (TCD) accreditation. METHODS: This was a retrospective study of all applicant laboratories from 2012 to 2015. We used the IAC database to extract laboratory characteristics and guideline compliance metrics. RESULTS: Evaluation of 97 laboratories demonstrated that 67% were hospital-based and located in the South (43.3%), corresponding to the location of "Stroke Belt" states. Cases from 186 interpreting physicians, of which 110 (59%) were neurologists, were evaluated during the accreditation process. Established practice was the most common training pathway (54.8%), and a majority had not obtained an additional vascular interpretation credential (72.6%). From 318 case studies, the most frequent indications were subarachnoid hemorrhage (31.0%), stroke (17.0%), and carotid stenosis (14.3%). Although most laboratories had been previously accredited, accreditation was delayed for 77.3% due to incomplete studies (33.0%), discrepant findings between the report and the laboratory's diagnostic criteria (23.7%), and discrepant findings between the report and the waveforms/images (17.5%). CONCLUSIONS: The results suggest that there are significant differences between IAC applicant laboratories and laboratories represented by Centers for Medicaid and Medicare Services (CMS) claims data. In addition, accurate study reporting, physician training, and ongoing quality improvement activities may not be optimized in laboratories applying for accreditation. With the information learned from this study, educational strategies by professional organizations, including the IAC, can be tailored to help improve TCD practice. PMID- 27935139 TI - NHC-Stabilised Acetylene-How Far Can the Analogy Be Pushed? AB - Experimental studies suggest that the compound (NHCbz )2 C2 H2 can be considered as a complex of a distorted acetylene fragment which is stabilised by benzoannelated N-heterocyclic carbene ligands (NHCbz )->(C2 H2 )<-(NHCbz ). A quantum chemical analysis of the electronic structures shows that the description with dative bonds is more favourable than with electron-sharing double bonds (NHCbz )=(C2 H2 )=(NHCbz ). PMID- 27935140 TI - Three-Dimensional Metal-Organic Framework as Super Heat-Resistant Explosive: Potassium 4-(5-Amino-3-Nitro-1H-1,2,4-Triazol-1-Yl)-3,5-Dinitropyrazole. AB - A new super heat-resistant explosive, potassium 4-(5-amino-3-nitro-1H-1,2,4 triazol-1-yl)-3,5-dinitropyrazole (KCPT, 1), featuring a three-dimensional (3D) energetic metal-organic framework (MOF) was synthesized and fully characterized. The new 3D MOF was found to be extremely heat-resistant, having a high decomposition temperature of 323 degrees C. In addition, KCPT exhibits the best calculated detonation performance (vD =8457 m s-1 , p=32.5 GPa) among the reported super heat-resistant explosives or energetic potassium salts while retaining a suitable impact sensitivity of 7.5 J, which makes it one of the most promising heat-resistant explosives. PMID- 27935142 TI - Sharing information about cancer with one's family is associated with improved quality of life. AB - OBJECTIVE: The aim of this study was to investigate the association between cancer patients' ability to share information about their illness with their social network and attachment style dimensions, alexithymia, and quality of life. We hypothesised that ability to share information about one's cancer with family, friends, and medical teams would be positively associated with quality of life and secure attachment and negatively associated with alexithymia. METHODS: Forty five cancer patients were recruited from the Psycho-oncology Unit of the San Camillo-Forlanini Hospital in Rome. We collected anamnestic data and self-report data on social sharing ability, quality of life, alexithymia, and attachment. RESULTS: Sharing with family (B = 4.66; SE = 1.82; beta = .52; SE = 0.20; t(41) = 2.6; P = .0143) was the only predictor of global health status, and attachment security was the only predictor of mean social sharing (B = 0.25; SE = 0.06; beta = .63; SE = 0.14; t(41) = 4.4; P < .0001). CONCLUSIONS: Encouraging patients to share information about their experience of cancer may help to improve their quality of life. Attachment security seems to promote social sharing. Psychological assessments of cancer patients should cover both ability to share information about one's cancer with family and attachment security. PMID- 27935141 TI - Evolution of a multi-step phosphorelay signal transduction system in Ensifer: recruitment of the sigma factor RpoN and a novel enhancer-binding protein triggers acid-activated gene expression. AB - Most Ensifer strains are comparatively acid sensitive, compromising their persistence in low pH soils. In the acid-tolerant strain Ensifer medicae WSM419, the acid-activated expression of lpiA is essential for enhancing survival in lethal acidic conditions. Here we characterise a multi-step phosphorelay signal transduction pathway consisting of TcsA, TcrA, FsrR, RpoN and its cognate enhancer-binding protein EbpA, which is required for the induction of lpiA and the downstream acvB gene. The fsrR, tcrA, tcsA and rpoN genes were constitutively expressed, whereas lpiA and acvB were strongly acid-induced. RACE mapping revealed that lpiA/acvB were co-transcribed as an operon from an RpoN promoter. In most Ensifer species, lpiA/acvB is located on the chromosome and the sequence upstream of lpiA lacks an RpoN-binding site. Nearly all Ensifer meliloti strains completely lack ebpA, tcrA, tcsA and fsrR regulatory loci. In contrast, E. medicae strains have lpiA/acvB and ebpA/tcrA/tcsA/fsrR co-located on the pSymA megaplasmid, with lpiA/acvB expression coupled to an RpoN promoter. Here we provide a model for the expression of lpiA/acvB in E. medicae. This unique acid activated regulatory system provides insights into an evolutionary process which may assist the adaptation of E. medicae to acidic environmental niches. PMID- 27935143 TI - The use of C57Bl/6 * CBA F1 hybrid cross as a model for human age-related oocyte aneuploidy. PMID- 27935146 TI - Resilience of Cyber Systems with Over- and Underregulation. AB - Recent cyber attacks provide evidence of increased threats to our critical systems and infrastructure. A common reaction to a new threat is to harden the system by adding new rules and regulations. As federal and state governments request new procedures to follow, each of their organizations implements their own cyber defense strategies. This unintentionally increases time and effort that employees spend on training and policy implementation and decreases the time and latitude to perform critical job functions, thus raising overall levels of stress. People's performance under stress, coupled with an overabundance of information, results in even more vulnerabilities for adversaries to exploit. In this article, we embed a simple regulatory model that accounts for cybersecurity human factors and an organization's regulatory environment in a model of a corporate cyber network under attack. The resulting model demonstrates the effect of under- and overregulation on an organization's resilience with respect to insider threats. Currently, there is a tendency to use ad-hoc approaches to account for human factors rather than to incorporate them into cyber resilience modeling. It is clear that using a systematic approach utilizing behavioral science, which already exists in cyber resilience assessment, would provide a more holistic view for decisionmakers. PMID- 27935144 TI - A Bio-Chemosynthetic Approach to Superparamagnetic Iron Oxide-Ansamitocin Conjugates for Use in Magnetic Drug Targeting. AB - A combination of mutasynthesis using a mutant strain of A. pretiosum blocked in the biosynthesis of amino-hydroxybenzoic acid (AHBA) and semisynthesis relying on a Stille cross-coupling step provided access to new ansamitocin derivatives of which one was attached by a thermolabile linker to nanostructured iron oxide particles. When exposed to an oscillating electromagnetic field the resulting iron oxide/ansamitocin conjugate 19 heats up in an aqueous suspension and the ansamitocin derivative 16 is released by means of a retro-Diels-Alder reaction. It exerts strong antiproliferative activity (IC50 =4.8 ng mg-1 ) in mouse fibroblasts. These new types of conjugates have the potential for combating cancer through hyperthermia and chemotherapy using an electromagnetic external trigger. PMID- 27935147 TI - Cycles of silence: First Nations women overcoming social and historical barriers in supportive cancer care. AB - BACKGROUND: First Nations people with cancer in Canada confront several critical inequities in physical and psychosocial domains. First Nations women are at a particular disadvantage as they are disproportionately affected by social determinants of health, but how they navigate these challenges within their communities is poorly understood. OBJECTIVE: Our study explores survivorship experiences of First Nations women with cancer and their caregivers. Drawing from a larger data set on survivorship, we identify several major barriers to cancer communication and support in First Nations communities. METHODS: Our team conducted a participatory, arts-based study using several data collection methods (interviews, sharing sessions, photovoice, and other creative activities) with 43 participants (24 cancer survivors and 19 caregivers) from four First Nations communities in Canada. RESULTS: Two major themes have emerged out of our data analyses: (1) suffering without support leads to cycles of silence and (2) community-based supports can disrupt these cycles. We identified several social, historical, and institutional barriers to speaking about cancer and finding/providing support; however, communities met the challenge of silence through voluntary and unsolicited provision of support. CONCLUSIONS: Widespread silence around cancer reflects both the limited access First Nations people have to formal, supportive programs and services, as well as the creative ways they provide emotional, social, and financial support within their informal networks. Beyond the support of their communities, they also required institutional provision of care that is culturally safe, addressing the colonial impacts on cancer communication and the disproportionate burdens of disease in First Nations communities. PMID- 27935148 TI - Customized vs population-based growth charts to identify neonates at risk of adverse outcome: systematic review and Bayesian meta-analysis of observational studies. AB - OBJECTIVE: To compare the effectiveness of customized vs population-based growth charts for the prediction of adverse pregnancy outcomes. METHODS: MEDLINE, ClinicalTrials.gov and The Cochrane Library were searched up to 31 May 2016 to identify interventional and observational studies comparing adverse outcomes among large- (LGA) and small- (SGA) for-gestational-age neonates, when classified according to customized vs population-based growth charts. Perinatal mortality and admission to the neonatal intensive care unit (NICU) of both SGA and LGA neonates, intrauterine fetal demise (IUFD) and neonatal mortality of SGA neonates, and neonatal shoulder dystocia and hypoglycemia as well as maternal third- and fourth-degree perineal lacerations in LGA pregnancies were evaluated. RESULTS: The electronic search identified 237 records that were examined based on title and abstract, of which 27 full-text articles were examined for eligibility. After excluding seven articles, 20 observational studies were included in a Bayesian meta-analysis. Neonates classified as SGA according to customized growth charts had higher risks of IUFD (odds ratio (OR), 7.8 (95% CI, 4.2-12.3)), neonatal death (OR, 3.5 (95% CI, 1.1-8.0)), perinatal death (OR, 5.8 (95% CI, 3.8 7.8)) and NICU admission (OR, 3.6 (95% CI, 2.0-5.5)) than did non-SGA cases. Neonates classified as SGA according to population-based growth charts also had increased risk for adverse outcomes, albeit the point estimates of the pooled ORs were smaller: IUFD (OR, 3.3 (95% CI, 1.9-5.0)), neonatal death (OR, 2.9 (95% CI, 1.2-4.5)), perinatal death (OR, 4.0 (95% CI, 2.8-5.1)) and NICU admission (OR, 2.4 (95% CI, 1.7-3.2)). For LGA vs non-LGA, there were no differences in pooled ORs for perinatal death, NICU admission, hypoglycemia and maternal third- and fourth-degree perineal lacerations when classified according to either the customized or the population-based approach. In contrast, both approaches indicated that LGA neonates are at increased risk for shoulder dystocia than are non-LGA ones (OR, 7.4 (95% CI, 4.9-9.8) using customized charts; OR, 8.0 (95% CI, 5.3-10.1) using population-based charts). CONCLUSIONS: Both customized and population-based growth charts can identify SGA neonates at risk for adverse outcomes. Although the point estimates of the pooled ORs may differ for some outcomes, the overlapping CIs and lack of direct comparisons prevent conclusions from being drawn on the superiority of one method. Future clinical trials should compare directly the two approaches in the management of fetuses of abnormal size. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27935149 TI - The sorting receptor SorCS3 is a stronger regulator of glutamate receptor functions compared to GABAergic mechanisms in the hippocampus. AB - Correct function of glutamate receptors in the postsynaptic density is crucial to synaptic function and plasticity. SorCS3 (sortilin-related receptor CNS expressed 3) is a sorting receptor which previously has been shown to interact with the key postsynaptic proteins; PSD-95 and PICK1. In this study, we employed electrophysiological analyses of acute brain slices combined with immunohistochemistry to define the role of SorCS3 in hippocampal synapses in CA1 and the dentate gyrus. We analyzed a juvenile (P17-21) and a young adult (P55-65) group of animals from a Sorcs3 knockout mouse model. We show that the basal synaptic transmission is severely affected in SorCS3-deficient neurons in CA1, while only slightly reduced in the dentate gyrus. Specifically, input/output curves of CA1 synapses revealed a 20% reduction of fEPSP (field excitatory postsynaptic potential) slopes at the highest stimulation intensity in knockouts of the juvenile group, which developed to a 33% decrease in young adult animals. These impairments may be a result of changes in the postsynaptic AMPA receptors. Interestingly, repetitive afferent stimulation demonstrated that SorCS3-deficient slices respond with an enhanced synaptic facilitation and reduced synaptic depression. These changes also developed with age. A molecular mechanism underlying this relative increase during repetitive stimulations is compatible with enhanced mobility of postsynaptic AMPA receptors resulting in faster exchange of desensitized receptors in the postsynaptic density. The altered response during repetitive stimulation was characteristic for CA1 but not the dentate gyrus. Immunohistochemical analyses of parvalbumin positive neurons combined with paired-pulse tests of network inhibition and patch-clamp recordings only showed minute inhibitory changes in SorCS3-deficient slices. Our results suggest that SorCS3 serves an important role in the postsynaptic protein network, which is more pronounced in CA1 compared to the dentate gyrus. These data support a role for SorCS3 in controlling proper positioning and mobility of glutamate receptors in the postsynaptic density. (c) 2016 Wiley Periodicals, Inc. PMID- 27935150 TI - Trends in potentially inappropriate medication prescribing to nursing home patients: comparison of three cross-sectional studies. AB - PURPOSE: The aim of this study was to examine trends in potentially inappropriate medication (PIM) prescribing in Norwegian nursing homes. METHODS: Patients aged >=70 years were included from three cross-sectional studies conducted in 1997, 2005 and 2011. PIMs were analyzed according to the Norwegian General Practice Nursing Home criteria (NORGEP-NH), use of single substances to avoid, combinations to avoid, and deprescribing items. Associations between sample and use of PIMs were examined by logistic regression, adjusted for age, gender, and ward. We established Pearsons r for correlations between numbers of drugs and PIMs. RESULTS: Altogether, 4373 patients (mean age 85.7 years, 73.5% women) were included. The mean overall number of drugs per patient increased from 4.7 in 1997 to 6.9 in 2011 (p < 0.001). Use of any single substances to avoid increased from 36.8% in 1997 to 39.5% in 2011 (p = 0.002), use of any combinations to avoid from 16.3% to 27.0% (p < 0.001), and use of any deprescribing items from 46.0% to 55.3% (p < 0.001). Use of codeine-analgesics, nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, long-acting benzodiazepines, and first generation antihistamines decreased significantly, while use of short-acting benzodiazepines, z-hypnotics, statins, and anti-dementia drugs increased significantly. A moderate strong correlation was detected between number of drugs and the three above-mentioned PIM categories, r = 0.34, r = 0.43, r = 0.37, respectively (all p < 0.001). CONCLUSIONS: Although several PIMs were less commonly prescribed in recent years, increased overall use of PIMs may suggests worsening of prescribing quality for nursing home patients in Norway. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27935151 TI - Patient-related characteristics associated with non-persistence with statin therapy in elderly patients following an ischemic stroke. AB - PURPOSE: This study was aimed at evaluating the extent of non-persistence with statin therapy in elderly patients after an ischemic stroke and identifying patient-related characteristics that are risk factors for non-persistence. METHODS: The evaluable study cohort (n = 2748) was derived from the database of the largest health insurance provider in the Slovak Republic. Patients aged >=65 years who were initiated on statin therapy following the diagnosis of an ischemic stroke during one full year (1 January 2010 to 31 December 2010) constituted this cohort. Each patient was followed for a period of 3 years from the date of the first statin prescription. Patients with a continuous treatment gap of 6 months without statin prescription were designated as non-persistent. The Cox proportional hazard model was applied to determine patient-associated characteristics that influenced the likelihood of non-persistence. RESULTS: During the 3-year follow-up period, 39.7% of patients in the study cohort became non-persistent. Factors associated with decreased probability of a patient becoming non-persistent were age >=75 years (hazard ratio (HR) 0.75), polypharmacy (concurrent use of >=6 drugs) (HR 0.79), diabetes mellitus (HR 0.80), dementia (HR 0.81) and hypercholesterolemia (HR 0.50). On the other hand, the presence of anxiety disorders (HR 1.33) predicted an increased likelihood of a patient being non-persistent. CONCLUSIONS: Our findings suggest that patients aged >=75 years or those with the presence of diabetes mellitus, dementia, hypercholesterolemia or polypharmacy were likely to be persistent with statin therapy, whereas those with anxiety disorders may need greater assistance with persistence of statin therapy. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27935152 TI - Intellectual outcomes of extremely preterm infants at school age. AB - BACKGROUND: The survival rate of extremely preterm (EP) infants (<28 weeks of gestation) has improved dramatically, and there is great interest in the long term prognosis. The aim of this study was to elucidate the influence of prenatal and postnatal care on long-term intellectual outcome in EP infants. METHODS: Subjects were EP infants admitted to the neonatal intensive care unit from 1982 to 2005. The survival rate and neurodevelopmental outcomes at 6 years of age were analyzed for the periods 1982-1991 (period 1) and 1992-2005 (period 2). Logistic regression analysis was performed to examine risk factors for intellectual impairment. RESULTS: Survival rate improved significantly from 84.5% (period 1) to 92.4% (period 2; P = 0.007). Follow-up data were obtained from 92 children in period 1 (69.7% of survivors) and from 245 in period 2 (72.3% of survivors). The incidence of intellectual impairment increased from 16.3% (period 1) to 31.0% (period 2). Significant factors associated with intellectual impairment were period 2 (OR, 3.53; P = 0.007), supplemental oxygen at 36 weeks' corrected age (OR, 2.22; P = 0.012), number of days in the hospital (OR, 1.01; P = 0.012), intraventricular hemorrhage (IVH; OR, 3.05; P = 0.024), and later tube-feeding commencement date (OR, 1.10; P = 0.032). CONCLUSIONS: Despite an increase in survival rate, the rate of intellectual impairment increased in period 2. According to risk factor analysis, reducing the incidence of chronic lung disease and/or apnea, IVH, and nutritional deprivation is a key factor in improving the intellectual outcomes of EP infants. PMID- 27935153 TI - Effect of storage on quality traits of the semimembranosus muscle of farmed fallow deer (Dama dama) bucks and does. AB - A total of 12 farmed fallow deer bucks and 12 does aged 31-32 months were included in a study on the effect of storage in vacuum packaging on the functionality of venison of the Semimembranosus muscle. All the analyzed meat quality traits were not affected by sex. The storage of meat in vacuum led to: an increase of pH (by 0.13 units; P = 0.001), L* (by 1.85 units; P = 0.002), a* (by 1.15 units; P = 0.013) and chroma (by 1.16 units; P = 0.016), a decrease of free water (by 6.62 percentage points (p.p.); P = 0.001) and water-holding capacity (cm2 ) (by 29.61%; P = 0.001), and the increase of dry matter content (by 0.67 p.p.; P = 0.001). The results indicate that the chilled storage of venison caused the stabilization of pH and color, improvement of water-holding capacity, with no negative effect on the proximate chemical composition. The quality of deer meat obtained from does and bucks was similar. PMID- 27935154 TI - Disruption of rich club organisation in cerebral small vessel disease. AB - Cerebral small vessel disease (SVD) is an important cause of vascular cognitive impairment. Recent studies have demonstrated that structural connectivity of brain networks in SVD is disrupted. However, little is known about the extent and location of the reduced connectivity in SVD. Here they investigate the rich club organisation-a set of highly connected and interconnected regions-and investigate whether there is preferential rich club disruption in SVD. Diffusion tensor imaging (DTI) and cognitive assessment were performed in a discovery sample of SVD patients (n = 115) and healthy control subjects (n = 50). Results were replicated in an independent dataset (49 SVD with confluent WMH cases and 108 SVD controls) with SVD patients having a similar SVD phenotype to that of the discovery cases. Rich club organisation was examined in structural networks derived from DTI followed by deterministic tractography. Structural networks in SVD patients were less dense with lower network strength and efficiency. Reduced connectivity was found in SVD, which was preferentially located in the connectivity between the rich club nodes rather than in the feeder and peripheral connections, a finding confirmed in both datasets. In discovery dataset, lower rich club connectivity was associated with lower scores on psychomotor speed (beta = 0.29, P < 0.001) and executive functions (beta = 0.20, P = 0.009). These results suggest that SVD is characterized by abnormal connectivity between rich club hubs in SVD and provide evidence that abnormal rich club organisation might contribute to the development of cognitive impairment in SVD. Hum Brain Mapp 38:1751-1766, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 27935155 TI - The hippocampus influences assimilation and accommodation of schemata that are not hippocampus-dependent. AB - Learning is facilitated when information can be incorporated into an already learned set of rules or 'mental schema'. The location of a new restaurant, for example, is learned more easily if the neighbourhood's general layout is already known. This type of information is processed by the hippocampus and stored as a schema in the cortex, but it is not known whether the hippocampus can also map new stimuli to cortical schemata that are hippocampus-independent, such as odour classification. Using a hippocampus-independent odour-rule task we found that animals without a functional hippocampus learnt which odours did not fit the rule faster than sham animals, which persistently applied the rule to all odours. Conversely, when non-fitting odours were linked to a new rule sham animals were faster to link these odours to the new rule. The hippocampus, thus, regulates the association of stimuli with existing schemata even when the schemata are hippocampus-independent. (c) 2016 Wiley Periodicals, Inc. PMID- 27935156 TI - CASP9 germline mutation in a family with multiple brain tumors. AB - We report a novel CASP9 germline mutation that may increase susceptibility to the development of brain tumors. We identified this mutation in a family in which three brain tumors had developed within three generations, including two anaplastic astrocytomas occurring in cousins. The cousins were diagnosed at similar ages (29 and 31 years), and their tumors showed similar histological features. Genetic analysis revealed somatic IDH1 and TP53 mutations in both tumors. However, no germline TP53 mutations were detected, despite the fact that this family fulfills the criteria of Li-Fraumeni-like syndrome. Whole exome sequencing revealed a germline stop-gain mutation (R65X) in the CASP9 gene, which encodes caspase-9, a key molecule for the p53-dependent mitochondrial death pathway. This mutation was also detected in DNA extracted from blood samples from the two siblings who were each a parent of one of the affected cousins. Caspase-9 immunohistochemistry showed the absence of caspase-9 immunoreactivity in the anaplastic astrocytomas and normal brain tissues of the cousins. These observations suggest that CASP9 germline mutations may have played a role at least in part to the susceptibility of development of gliomas in this Li-Fraumeni like family lacking a TP53 germline mutation. PMID- 27935157 TI - Coeliac patients detected during type 1 diabetes surveillance had similar issues to those diagnosed on a clinical basis. AB - AIM: Screening children with type 1 diabetes for coeliac disease is controversial, because they often appear asymptomatic. Our aim was to establish whether active screening should be recommended. METHODS: This study focused on 22 children whose coeliac disease was detected by serological screening during diabetes surveillance and 498 children diagnosed because of a clinical suspicion. We compared the clinical and histological data at diagnosis and the children's adherence and responses to a gluten-free diet. RESULTS: The serological screening group suffered less from decreased growth (p = 0.016) and clinical symptoms (p < 0.001) at diagnosis than the clinical group. The groups did not differ in terms of age at diagnosis (p = 0.903), gender (p = 0.353), anaemia (p = 0.886), endomysial antibody titres (p = 0.789) and the severity of small-bowel mucosal atrophy (p = 0.104). They also showed equal adherence (p = 0.086) and clinical responses (p = 0.542) to a gluten-free diet after a median follow-up of 13 months. CONCLUSION: Coeliac patients detected during diabetes surveillance had signs of malabsorption and advanced mucosal damage that was similar to those diagnosed on a clinical basis. They often suffered from unrecognised gluten dependent symptoms and showed excellent adherence and responses to a gluten-free diet. Our findings support active screening for coeliac disease in patients with type 1 diabetes. PMID- 27935158 TI - A machine learning approach for ranking clusters of docked protein-protein complexes by pairwise cluster comparison. AB - Reliable identification of near-native poses of docked protein-protein complexes is still an unsolved problem. The intrinsic heterogeneity of protein-protein interactions is challenging for traditional biophysical or knowledge based potentials and the identification of many false positive binding sites is not unusual. Often, ranking protocols are based on initial clustering of docked poses followed by the application of an energy function to rank each cluster according to its lowest energy member. Here, we present an approach of cluster ranking based not only on one molecular descriptor (e.g., an energy function) but also employing a large number of descriptors that are integrated in a machine learning model, whereby, an extremely randomized tree classifier based on 109 molecular descriptors is trained. The protocol is based on first locally enriching clusters with additional poses, the clusters are then characterized using features describing the distribution of molecular descriptors within the cluster, which are combined into a pairwise cluster comparison model to discriminate near-native from incorrect clusters. The results show that our approach is able to identify clusters containing near-native protein-protein complexes. In addition, we present an analysis of the descriptors with respect to their power to discriminate near native from incorrect clusters and how data transformations and recursive feature elimination can improve the ranking performance. Proteins 2017; 85:528-543. (c) 2016 Wiley Periodicals, Inc. PMID- 27935159 TI - De novo sequencing of highly modified therapeutic oligonucleotides by hydrophobic tag sequencing coupled with LC-MS. AB - Correct sequences are prerequisite for quality control of therapeutic oligonucleotides. However, there is no definitive method available for determining sequences of highly modified therapeutic RNAs, and thereby, most of the oligonucleotides have been used clinically without direct sequence determination. In this study, we developed a novel sequencing method called 'hydrophobic tag sequencing'. Highly modified oligonucleotides are sequenced by partially digesting oligonucleotides conjugated with a 5'-hydrophobic tag, followed by liquid chromatography-mass spectrometry analysis. 5'-Hydrophobic tag printed fragments (5'-tag degradates) can be separated in order of their molecular masses from tag-free oligonucleotides by reversed-phase liquid chromatography. As models for the sequencing, the anti-VEGF aptamer (Macugen) and the highly modified 38-mer RNA sequences were analyzed under blind conditions. Most nucleotides were identified from the molecular weight of hydrophobic 5'-tag degradates calculated from monoisotopic mass in simple full mass data. When monoisotopic mass could not be assigned, the nucleotide was estimated using the molecular weight of the most abundant mass. The sequences of Macugen and 38-mer RNA perfectly matched the theoretical sequences. The hydrophobic tag sequencing worked well to obtain simple full mass data, resulting in accurate and clear sequencing. The present study provides for the first time a de novo sequencing technology for highly modified RNAs and contributes to quality control of therapeutic oligonucleotides. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27935160 TI - Surgical treatment of mature cystic teratomas: A comparison of emergent and elective surgeries. AB - AIM: To compare patient characteristics, imaging and surgical management of mature cystic teratomas (MCTs) according to surgery type - elective versus emergent. METHODS: The study included surgeries performed between 1990 and 2016, during which histologically verified ovarian MCT material was obtained. The elective management group included surgeries performed at a pre-set date or incidental finding of MCT as part of a different surgery. Emergent surgeries were considered as such if performed as a result of suspected adnexal torsion. RESULTS: One hundred ninety two operations in which MCT was confirmed by histology were included: 136 elective, 56 emergent. The majority (88.5%) of study patients were of reproductive age. Patients in the emergent surgery group were significantly younger (27.5 +/- 10.2 vs 36 +/- 13.8 years, P < 0.001). Sensitivity for dermoid diagnosis was significantly increased among elective surgery patients (65.2% vs. 47.1%, P = 0.02). Laparoscopy was the preferred surgical mode in both study groups. Adnexal torsion was confirmed in 67.8% of emergent surgeries. Conservative surgery, including cystectomy with or without detorsion, was more commonly performed in emergent surgeries (91% vs. 72.7%, P = 0.006). Bilateral salpingo-oophorectomy with or without total abdominal hysterectomy was more commonly performed in elective surgery patients (22% vs. 3.5%, P = 0.001). Patient parity, mass size and white blood cell count were independently associated with adnexal torsion. CONCLUSIONS: Adnexal torsion is common among symptomatic patients with MCT and is related to mass size, patient age, past parity and white blood cell count. Most patients with MCT are of reproductive age and thus are treated with a minimally invasive approach. PMID- 27935161 TI - Effects of noise exposure on neonatal auditory brainstem response thresholds in pregnant guinea pigs at different gestational periods. AB - AIM: Noise exposure during pregnancy has been reported to cause fetal hearing impairment. However, little is known about the effects of noise exposure during various gestational stages on postnatal hearing. In the present study, we investigated the effects of noise exposure on auditory brainstem response (ABR) at the early, mid-, and late gestational periods in newborn guinea pigs. METHODS: Pregnant guinea pigs were exposed to 4-kHz pure tone at a 120-dB sound pressure level for 4 h. We divided the animals into four groups as follows: the control, early gestational exposure, mid-gestational exposure, and late gestational exposure groups. ABR thresholds and latencies in newborns were recorded using 1-, 2-, and 4-kHz tone burst on postnatal days 1, 7, 14, and 28. Changes in ABR thresholds and latencies were measured between the 4 * 4 and 4 * 3 factorial groups mentioned above (gestational periods * postnatal days, gestational periods * frequencies). RESULTS: The thresholds were low in the order of control group < early gestational exposure group < mid-gestational exposure group and late gestational exposure group. Noise exposure during pregnancy influenced ABR thresholds in neonatal guinea pigs. CONCLUSION: This is the first study to show that noise exposure during the early, mid-, and late gestational periods significantly elevated ABR thresholds in neonatal guinea pigs. PMID- 27935162 TI - Vulnerability of eastern US tree species to climate change. AB - Climate change is expected to alter the distribution of tree species because of critical environmental tolerances related to growth, mortality, reproduction, disturbances, and biotic interactions. How this is realized in 21st century remains uncertain, in large part due to limitations on plant migration and the impacts of landscape fragmentation. Understanding these changes is of particular concern for forest management, which requires information at an appropriately fine spatial resolution. Here we provide a framework and application for tree species vulnerability to climate change in the eastern United States that accounts for influential drivers of future distributions. We used species distribution models to project changes in habitat suitability at 800 m for 40 tree species that vary in physiology, range, and environmental niche. We then developed layers of adaptive capacity based on migration potential, forest fragmentation, and propagule pressure. These were combined into metrics of vulnerability, including an overall index and spatially explicit categories designed to inform management. Despite overall favorable changes in suitability, the majority of species and the landscape were considered vulnerable to climate change. Vulnerability was significantly exacerbated by projections of pests and pathogens for some species. Northern and high-elevation species tended to be the most vulnerable. There were, however, some notable areas of particular resilience, including most of West Virginia. Our approach combines some of the most important considerations for species vulnerability in a straightforward framework, and can be used as a tool for managers to prioritize species, areas, and actions. PMID- 27935163 TI - Manipulating tablets and capsules given to hospitalised children in Norway is common practice. AB - AIM: This study provided an overview of manipulating oral medicines given to hospitalised children and evaluated this practice in two hospitals. It focused on the type of manipulation and the dosage forms that were manipulated. METHOD: This was a cross-sectional, prospective study, carried out on the paediatric wards at two Norwegian hospitals for four weeks in 2013. A medicine was said to have been manipulated if it was not administered as described in the Norwegian summary of product characteristics. RESULTS: This study showed that 17% of the 3070 administrations of oral medicines to the hospitalised children involved manipulation. Tablets, including modified release preparations, were the most frequently manipulated medicines. In approximately half of these cases, only a segment of the unit dose was administered. No manipulation of oral liquids was seen. The bioavailability of as much as 44% of the most frequent given substances may be sensitive to such manipulations due to limited aqueous solubility. Various routines for splitting and handling the unit doses were observed. CONCLUSION: Manipulation of oral medication was regularly performed on paediatric wards. There is an urgent need for age-appropriate medicines, documented and standardised processes for manipulating medicines and staff training on the consequences of manipulation. PMID- 27935164 TI - Kaolin-activated thromboelastography and standard coagulation assays in cyanotic and acyanotic infants undergoing complex cardiac surgery: a prospective cohort study. AB - BACKGROUND AND AIMS: Several studies report the use of thromboelatography (TEG) to monitor coagulation in pediatric cardiac surgery. The aim of this study was to compare baseline and intraoperative TEG, TEG-functional fibrinogen, and standard coagulation assays in children with cyanotic and acyanotic congenital heart disease (CHD) undergoing cardiac surgery. METHODS: This is a prospective observational study of 63 children aged <24 months undergoing cardiac surgery with cardiopulmonary bypass (CPB). Exclusion criteria included preoperative anticoagulant therapy and hepatic failure. We collected blood at anesthesia induction (T1), at lowest temperature after CPB start (T2), and after heparin neutralization (T3). Coagulation was evaluated by TEG (reaction time [R]), k, alpha-angle, maximum amplitude (MA), MA-fibrinogen (MA-fib), and by standard coagulation assays (prothrombin time, activated partial thromboplastin time, fibrinogen level, platelet [PLT] count). RESULTS: Sixty-three patients were enrolled (38 cyanotic and 25 acyanotic). Median age was 4 [IQR 2-6] months and median weight was 5 [IQR 3.7-6.5] kg. Most common surgeries were: ventricular septal defect repair (n = 13), Fallot correction (n = 11), and arterial switch operation (n = 10). Cyanotic and acyanotic children were well matched: R, k, MA, and MA-fib at T1, T2, and T3 were not significantly different between cyanotic and acyanotic children. At T2, significant correlations were showed between MA and PLT count (r = 0.4; P = 0.0008) and k and plasma fibrinogen level (r = -0.54; P < 0.0001). At T3, significant correlations were showed between MA and PLT count (r = 0.5; P < 0.0001), G and PLT count (r = 0.6; P < 0.0001), and MA-fib and plasma fibrinogen level (r = 0.5; P = 0.002). CONCLUSIONS: According to our findings, cyanosis does not affect TEG parameters in children with CHD. PLT count and plasma fibrinogen significantly correlated (are significantly associated) with MA and MA-fib respectively, suggesting that use of TEG after protamine administration may be prompted for improved hemostatic monitoring in the perioperative phase. PMID- 27935165 TI - Long-term forest resilience to climate change indicated by mortality, regeneration, and growth in semiarid southern Siberia. AB - Several studies have documented that regional climate warming and the resulting increase in drought stress have triggered increased tree mortality in semiarid forests with unavoidable impacts on regional and global carbon sequestration. Although climate warming is projected to continue into the future, studies examining long-term resilience of semiarid forests against climate change are limited. In this study, long-term forest resilience was defined as the capacity of forest recruitment to compensate for losses from mortality. We observed an obvious change in long-term forest resilience along a local aridity gradient by reconstructing tree growth trend and disturbance history and investigating postdisturbance regeneration in semiarid forests in southern Siberia. In our study, with increased severity of local aridity, forests became vulnerable to drought stress, and regeneration first accelerated and then ceased. Radial growth of trees during 1900-2012 was also relatively stable on the moderately arid site. Furthermore, we found that smaller forest patches always have relatively weaker resilience under the same climatic conditions. Our results imply a relatively higher resilience in arid timberline forest patches than in continuous forests; however, further climate warming and increased drought could possibly cause the disappearance of small forest patches around the arid tree line. This study sheds light on climate change adaptation and provides insight into managing vulnerable semiarid forests. PMID- 27935166 TI - Time to viral suppression is not related to achievement of SVR12 in HCV GT1 infected patients treated with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin. AB - High rates of sustained virologic response at post-treatment week 12 (SVR12) were achieved in six phase 3 trials of ombitasvir (OBV, an NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor) co-dosed with ritonavir (PTV/r) + dasabuvir (DSV, an NS5B RNA polymerase inhibitor) (ie, 3D regimen) with or without ribavirin (RBV) in adults with chronic genotype (GT) 1 hepatitis C virus (HCV) infection. We assessed whether time to first HCV RNA value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of SVR12. Data were analysed from GT1-infected patients enrolled in six phase 3 studies of 3D +/- RBV. Patients who experienced non-virologic failure were excluded from analysis. HCV RNA was determined using the Roche COBAS TaqMan RT-PCR assay (lower limit of quantification, LLOQ =25 IU/mL). SVR12 was analysed by week of first HCV RNA suppression, defined as HCV RNA 10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count <75*10E9/mL (RR: 3.50, P=.019). In patients with MELD <10, type of NS5A inhibitor did not impact on SVR12 (94% vs 97%; adjusted RR: 0.49). Thirteen patients (6.3%) had serious adverse events, including three deaths (1.4%) and one therapy discontinuation (0.5%), higher in decompensated patients (16.7% vs 3.6%, P<.006). In patients with GT3 infection and cirrhosis, SVR12 rates were high with both SOF+DCV and SOF/LDV, with few serious adverse events. PMID- 27935172 TI - ACL injury reduces satellite cell abundance and promotes fibrogenic cell expansion within skeletal muscle. AB - Anterior cruciate ligament (ACL) injuries are associated with significant loss of strength in knee extensor muscles that persists despite physical therapy. The underlying mechanisms responsible for this protracted muscle weakness are poorly understood; however, we recently showed significant myofiber atrophy and altered muscle phenotype following ACL injury. We sought to further explore perturbations in skeletal muscle morphology and progenitor cell activity following an ACL injury. Muscle biopsies were obtained from the injured and non-injured vastus lateralis of young adults (n = 10) following ACL injury, and histochemical/immunohistochemical analyses were undertaken to determine collagen content, abundance of connective tissue fibroblasts, fibrogenic/adipogenic progenitor (FAP) cells, satellite cells, in addition to indices of muscle fiber denervation and myonuclear apoptosis. The injured limb showed elevated collagen content (p < 0.05), in addition to a greater abundance of fibroblasts and FAPs (p < 0.05) in the injured limb. Fibroblast content was correlated with increased accumulation of extracellular matrix in the injured limb as well. A higher frequency of interstitial nuclei were positive for phospho-SMAD3 in the injured limb (p < 0.05), providing some evidence for activation of a fibrogenic program through transforming growth factor beta following an ACL injury. The injured limb also displayed reduced satellite cell abundance, increased fiber denervation and DNA damage associated with apoptosis (p < 0.05), indicating alterations within the muscle itself after the ligament injury. Injury of the ACL induces a myriad of negative outcomes within knee extensor muscles, which likely compromise the restorative capacity and plasticity of skeletal muscle, impeding rehabilitative efforts. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1876-1885, 2017. PMID- 27935173 TI - Gastropancreatic ligament: Description, incidence, and involvement during laparoscopic sleeve gastrectomy. AB - During laparoscopic sleeve gastrectomy (LSG), adhesions between the stomach and the pancreas are sometimes found, forming a "gastropancreatic ligament" (GPL). However, the GPL has only been described once in the literature, in 1985. The objective of this study was to determine the incidence of the GPL during LSG, describe this structure and assess its effect on the surgical technique. All patients undergoing primary LSG in our institution (n = 240) and patients referred for gastric fistula (GF) after primary LSG (n = 18) between January 2015 and December 2015 were included. The primary endpoint was the incidence of a GPL during primary LSG. The secondary endpoints were the postoperative complication rate, the postoperative GF rate, and the presence of this ligament during reoperation for GF. Among the 240 patients, a GPL was visible in 49 cases (20.4%) and was described as thin in 34 of these (69.4%). Twelve postoperative complications (5%) were observed, including seven major (2.9%). The GF rate was 2% (n = 5), not requiring reoperation. The gastric stenosis rate was 0.4% (n = 1). The GPL had been previously sectioned in one of the five patients (20%) with postoperative GF. During the study period, 18 patients were referred for GF and 14 were reoperated. A non-sectioned GPL, not described in the operating report, was observed in four patients (28.5%). A GPL was identified in 20.4% of cases. Identification of a GPL could be important in the context of LSG, as section of the ligament allows tension-free stapling to be performed and can therefore possibly reduce the risk of postoperative complications, particularly GF. Clin. Anat. 30:336-341, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 27935174 TI - Going with the flow: the role of ocean circulation in global marine ecosystems under a changing climate. AB - Ocean warming, acidification, deoxygenation and reduced productivity are widely considered to be the major stressors to ocean ecosystems induced by emissions of CO2 . However, an overlooked stressor is the change in ocean circulation in response to climate change. Strong changes in the intensity and position of the western boundary currents have already been observed, and the consequences of such changes for ecosystems are beginning to emerge. In this study, we address climatically induced changes in ocean circulation on a global scale but relevant to propagule dispersal for species inhabiting global shelf ecosystems, using a high-resolution global ocean model run under the IPCC RCP 8.5 scenario. The 1/4 degree model resolution allows improved regional realism of the ocean circulation beyond that of available CMIP5-class models. We use a Lagrangian approach forced by modelled ocean circulation to simulate the circulation pathways that disperse planktonic life stages. Based on trajectory backtracking, we identify present-day coastal retention, dominant flow and dispersal range for coastal regions at the global scale. Projecting into the future, we identify areas of the strongest projected circulation change and present regional examples with the most significant modifications in their dominant pathways. Climatically induced changes in ocean circulation should be considered as an additional stressor of marine ecosystems in a similar way to ocean warming or acidification. PMID- 27935175 TI - Tree demography suggests multiple directions and drivers for species range shifts in mountains of Northeastern United States. AB - Climate change is expected to lead to upslope shifts in tree species distributions, but the evidence is mixed partly due to land-use effects and individualistic species responses to climate. We examined how individual tree species demography varies along elevational climatic gradients across four states in the northeastern United States to determine whether species elevational distributions and their potential upslope (or downslope) shifts were controlled by climate, land-use legacies (past logging), or soils. We characterized tree demography, microclimate, land-use legacies, and soils at 83 sites stratified by elevation (~500 to ~1200 m above sea level) across 12 mountains containing the transition from northern hardwood to spruce-fir forests. We modeled elevational distributions of tree species saplings and adults using logistic regression to test whether sapling distributions suggest ongoing species range expansion upslope (or contraction downslope) relative to adults, and we used linear mixed models to determine the extent to which climate, land use, and soil variables explain these distributions. Tree demography varied with elevation by species, suggesting a potential upslope shift only for American beech, downslope shifts for red spruce (more so in cool regions) and sugar maple, and no change with elevation for balsam fir. While soils had relatively minor effects, climate was the dominant predictor for most species and more so for saplings than adults of red spruce, sugar maple, yellow birch, cordate birch, and striped maple. On the other hand, logging legacies were positively associated with American beech, sugar maple, and yellow birch, and negatively with red spruce and balsam fir - generally more so for adults than saplings. All species exhibited individualistic rather than synchronous demographic responses to climate and land use, and the return of red spruce to lower elevations where past logging originally benefited northern hardwood species indicates that land use may mask species range shifts caused by changing climate. PMID- 27935177 TI - Physical Chemistry Is on a Roll. PMID- 27935176 TI - Effects of alpha-lipoic acid supplementation on growth performance, antioxidant capacity and biochemical parameters for ammonia-exposed broilers. AB - In order to estimate the effect of alpha-lipoic acid (LA) supplementation on relieving ammonia stress of broilers, 180 22-day-old male broilers were assigned to three groups, six replicates in each group and 10 birds per replicate. The three groups were: (1) a control group without ammonia stress; (2) exposure to 70 ppm atmospheric ammonia (AM); (3) exposure to 70 ppm atmospheric ammonia and administration of 300 mg/kg LA (AM + LA). The experimental period was 3 weeks. Results showed that average daily weight gain was increased and feed conversion ratio was decreased in the AM + LA group, compared with the AM group (P < 0.05). Total superoxide dismutase and glutathione peroxidase activities in serum, and glutathione content in liver were higher in the AM + LA group than that in the AM group (P < 0.05); however, serum malondialdehyde content was decreased by LA addition (P < 0.05). Additionally, serum glutamic-pyruvic transaminase, creatine kinase and lactate dehydrogenase activities were reduced and albumin level was increased by LA addition (P < 0.05). In conclusion, LA addition could relieve ammonia stress to restore broiler production performance to normal levels. PMID- 27935178 TI - Simple additive simulation overestimates real influence: altered nitrogen and rainfall modulate the effect of warming on soil carbon fluxes. AB - Experiments and models have led to a consensus that there is positive feedback between carbon (C) fluxes and climate warming. However, the effect of warming may be altered by regional and global changes in nitrogen (N) and rainfall levels, but the current understanding is limited. Through synthesizing global data on soil C pool, input and loss from experiments simulating N deposition, drought and increased precipitation, we quantified the responses of soil C fluxes and equilibrium to the three single factors and their interactions with warming. We found that warming slightly increased the soil C input and loss by 5% and 9%, respectively, but had no significant effect on the soil C pool. Nitrogen deposition alone increased the soil C input (+20%), but the interaction of warming and N deposition greatly increased the soil C input by 49%. Drought alone decreased the soil C input by 17%, while the interaction of warming and drought decreased the soil C input to a greater extent (-22%). Increased precipitation stimulated the soil C input by 15%, but the interaction of warming and increased precipitation had no significant effect on the soil C input. However, the soil C loss was not significantly affected by any of the interactions, although it was constrained by drought (-18%). These results implied that the positive C fluxes climate warming feedback was modulated by the changing N and rainfall regimes. Further, we found that the additive effects of [warming * N deposition] and [warming * drought] on the soil C input and of [warming * increased precipitation] on the soil C loss were greater than their interactions, suggesting that simple additive simulation using single-factor manipulations may overestimate the effects on soil C fluxes in the real world. Therefore, we propose that more multifactorial experiments should be considered in studying Earth systems. PMID- 27935179 TI - Association Between Confidence in Smiling and Esthetic Characteristics. AB - OBJECTIVE: This study aimed to analyze which facial, gingival and dental characteristics are associated with confidence in smiling among 75 subjects seeking treatment in a northern Brazilian public dental university. MATERIALS AND METHODS: Clinical examinations and three standardized photographs of each subject were taken by one trained examiner. In addition, a questionnaire was applied to assess confidence in smiling. The subjects were dichotomized into two groups, non confident (n = 36) and confident (n = 39) in smiling. Chi-square/Fischer exact test were used to associate the facial, gingival and dental characteristics between groups. RESULTS: The subjects that reported to be non-confident in smiling were statistically associated with smile type (p = 0.030) and wrongly positioned teeth (p = 0.047). On the other hand, gender (p = 0.491), marital status (p = 0.217), gum pigmentation (p = 0.930), midline (p = 0.176), volume of the upper (p = 0.380), and lower (p = 0.615) lips were not associated with self reported confidence in smiling. CONCLUSION: In patients seeking dental treatment in a public dental university, non-confidence in smiling was associated only with some oral and intraoral characteristics and not with demographic characteristics. CLINICAL SIGNIFICANCE: This study showed that only smile type and wrongly positioned teeth were statistically associated with confidence in smiling. Dentists should pay attention to those intraoral characteristics, but the clinical decision making should always include the patients' perception. (J Esthet Restor Dent 29:E56-E66, 2017). PMID- 27935180 TI - Management of early-onset neonatal sepsis differs in the north and south of Scandinavia. AB - AIM: This study compared the management and outcomes of early-onset neonatal sepsis (EONS) in two tertiary neonatal units in Denmark and Norway. METHODS: We retrospectively studied all infants diagnosed with EONS between April 2010 and March 2013 and managed at Odense University Hospital, Denmark, and the University Hospital of North Norway, Norway. Clinical and laboratory data were collected from patient records. RESULTS: We identified 137 EONS cases in Denmark and 101 in Norway. There were 35 culture-confirmed EONS cases: 16% of the Danish cases and 13% of the Norwegian cases. Staphylococcus aureus was the most frequently detected pathogen in 11 cases (31%), followed by Group B streptococci in nine (26%) and Escherichia coli in six (17%). In 85% of the 238 cases, the empiric therapy comprised gentamicin and a beta-lactam, namely ampicillin in Denmark and benzylpenicillin in Norway. Patients with positive blood cultures had higher C reactive protein levels than patients with negative blood cultures and higher sepsis-attributable mortality. Lumbar punctures were performed more frequently in Denmark. CONCLUSION: There were marginal differences in the management of EONS between units in Denmark and Norway, mainly in their choice of antibiotics and the use of lumbar punctures. Staphylococcus aureus was the most common pathogen. PMID- 27935181 TI - The Assembly of an All-Inorganic Porous Soft Framework from Metal Oxide Molecular Nanowires. AB - An all-inorganic soft framework is rare but interesting for both fundamental research and practical applications. Here, an all-inorganic soft framework based on a transition metal oxide is reported. The periodic connection of a one dimensional anionic tungstoselenate molecular wire building block with a CoII ion is used to construct the crystalline material. The crystal structure of the material was determined by high-angle annular dark-field scanning transmission electron microscopy combined with several characterization techniques. The soft framework of the material enables water adsorption/desorption with a change in its structure, leading to a high level of water adsorption. The framework of the material is flexible, and the structure of the molecular wire building block is stable during the water adsorption/desorption process. PMID- 27935182 TI - Pain management intervention targeting nursing staff and general practitioners: Pain intensity, consequences and clinical relevance for nursing home residents. AB - AIM: Although chronic pain is common in older adults, its treatment is frequently inappropriate. This problem is particularly prevalent in nursing home residents. We therefore developed an intervention to optimize pain management and evaluated its effects on pain intensity and pain interference with function in nursing home residents in Germany. METHODS: In a cluster-randomized controlled intervention, 195 residents of 12 Berlin nursing homes who were affected by pain were surveyed at three points of measurement. A modified German version of the Brief Pain Inventory was used to assess pain sites, pain intensity and pain interference with function in various domains of life. The intervention consisted of separate training measures for nursing staff and treating physicians. RESULTS: The primary objective of reducing the mean pain intensity by 2 points was not achieved, partly because the mean pain intensity at baseline was relatively low. However, marginal reductions in pain were observed in the longitudinal assessment at 6 month follow up. The intervention and control groups differed significantly in the intensity sum score and in the domain of walking. Furthermore, the proportion of respondents with pain scores >0 on three pain intensity items decreased significantly. CONCLUSIONS: Given the multifocal nature of the pain experienced by nursing home residents, improving the pain situation of this vulnerable group is a major challenge. To achieve meaningful effects not only in pain intensity, but especially in pain interference with function, training measures for nursing staff and physicians need to be intensified, and long-term implementation appears necessary. Geriatr Gerontol Int 2017; 17: 1534-1543. PMID- 27935184 TI - Impaired ecosystem process despite little effects on populations: modeling combined effects of warming and toxicants. AB - Freshwater ecosystems are exposed to many stressors, including toxic chemicals and global warming, which can impair, separately or in combination, important processes in organisms and hence higher levels of organization. Investigating combined effects of warming and toxicants has been a topic of little research, but neglecting their combined effects may seriously misguide management efforts. To explore how toxic chemicals and warming, alone and in combination, propagate across levels of biological organization, including a key ecosystem process, we developed an individual-based model (IBM) of a freshwater amphipod detritivore, Gammarus pseudolimnaeus, feeding on leaf litter. In this IBM, life history emerges from the individuals' energy budgets. We quantified, in different warming scenarios (+1-+4 degrees C), the effects of hypothetical toxicants on suborganismal processes, including feeding, somatic and maturity maintenance, growth, and reproduction. Warming reduced mean adult body sizes and population abundance and biomass, but only in the warmest scenarios. Leaf litter processing, a key contributor to ecosystem functioning and service delivery in streams, was consistently enhanced by warming, through strengthened interaction between the detritivorous consumer and its resource. Toxicant effects on feeding and maintenance resulted in initially small adverse effects on consumers, but ultimately led to population extinction and loss of ecosystem process. Warming in combination with toxicants had little effect at the individual and population levels, but ecosystem process was impaired in the warmer scenarios. Our results suggest that exposure to the same amount of toxicants can disproportionately compromise ecosystem processing depending on global warming scenarios; for example, reducing organismal feeding rates by 50% will reduce resource processing by 50% in current temperature conditions, but by up to 200% with warming of 4 degrees C. Our study has implications for assessing and monitoring impacts of chemicals on ecosystems facing global warming. We advise complementing existing monitoring approaches with directly quantifying ecosystem processes and services. PMID- 27935185 TI - Chemically Reduced Graphene Oxide for the Assessment of Food Quality: How the Electrochemical Platform Should Be Tailored to the Application. AB - Graphene platforms have been drawing considerable attention in electrochemistry for the detection of various electroactive probes. Depending on the chemical composition and properties of the probe, graphene materials with diverse structural features may be required to achieve an optimal electrochemical performance. This work comprises a comparative study on three chemically modified graphenes, obtained from the same starting material and with different oxygen functionalities and structural defects (graphene oxide (GO), chemically reduced graphene oxide (CRGO), and thermally reduced graphene oxide (TRGO)) towards the electrochemical detection of quinine, an important flavoring agent present in tonic-based beverages. In general, the reduced graphenes, namely CRGO and TRGO, showed enhanced performance in terms of calibration sensitivity and selectivity, due to the improved heterogeneous electron-transfer rates on their surfaces. In particular, CRGO provided the best overall electrochemical performance, which can be attributed to its higher density of structural defects and reduced amount of oxygen functionalities. For this reason, CRGO was employed for the electrochemical detection of quinine in commercial tonic drink samples, showing high sensitivity and selectivity, and therefore representing a valid low-cost alternative to more complicated and time consuming traditional analytical methods. PMID- 27935183 TI - Metformin in adults with type 1 diabetes: Design and methods of REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL): An international multicentre trial. AB - AIMS: Cardiovascular (CV) disease is a major cause of reduced life expectancy in type 1 diabetes (T1D). Intensive insulin therapy prevents CV complications but is constrained by hypoglycaemia and weight gain. Adjunct metformin reduces insulin dose requirement and stabilizes weight but there are no data on its cardiovascular effects. We have therefore initiated an international double blind, randomized, placebo-controlled trial (REMOVAL: REducing with MetfOrmin Vascular Adverse Lesions in type 1 diabetes) to examine whether metformin reduces progression of atherosclerosis in adults with T1D. Individuals >=40 years of age with T1D for >=5 years are eligible if they have >=3 of 10 specified CV risk factors. The enrolment target is 500 participants in 17 international centres. MATERIALS AND METHODS: After 12 weeks of single-blind placebo-controlled run-in, participants with >= 70% adherence are randomized to metformin or matching placebo for 3 years with insulin titrated towards HbA1c 7.0% (53 mmol/mol). The primary endpoint is progression of averaged mean far wall common carotid intima media thickness (cIMT) measured by ultrasonography at baseline, 12, 24 and 36 months. This design provides 90% power to detect a mean difference of 0.0167 mm in cIMT progression between treatment arms (alpha = 0.05), assuming that up to 20% withdraw or discontinue treatment. Other endpoints include HbA1c, weight, LDL cholesterol, insulin requirement, progression of retinopathy, endothelial function and frequency of hypoglycaemia. CONCLUSION: REMOVAL is the largest clinical trial of adjunct metformin therapy in T1D to date and will provide clinically meaningful information on its potential to impact CV disease and other complications. PMID- 27935187 TI - Holocene carbon dynamics at the forest-steppe ecotone of southern Siberia. AB - The forest-steppe ecotone in southern Siberia is highly sensitive to climate change; global warming is expected to push the ecotone northwards, at the same time resulting in degradation of the underlying permafrost. To gain a deeper understanding of long-term forest-steppe carbon dynamics, we use a highly resolved, multiproxy, palaeolimnological approach, based on sediment records from Lake Baikal. We reconstruct proxies that are relevant to understanding carbon dynamics including carbon mass accumulation rates (CMAR; g C m-2 yr-1 ) and isotope composition of organic matter (delta13 CTOC ). Forest-steppe dynamics were reconstructed using pollen, and diatom records provided measures of primary production from near- and off-shore communities. We used a generalized additive model (GAM) to identify significant change points in temporal series, and by applying generalized linear least-squares regression modelling to components of the multiproxy data, we address (1) What factors influence carbon dynamics during early Holocene warming and late Holocene cooling? (2) How did carbon dynamics respond to abrupt sub-Milankovitch scale events? and (3) What is the Holocene carbon storage budget for Lake Baikal. CMAR values range between 2.8 and 12.5 g C m-2 yr-1 . Peak burial rates (and greatest variability) occurred during the early Holocene, associated with melting permafrost and retreating glaciers, while lowest burial rates occurred during the neoglacial. Significant shifts in carbon dynamics at 10.3, 4.1 and 2.8 kyr bp provide compelling evidence for the sensitivity of the region to sub-Milankovitch drivers of climate change. We estimate that 1.03 Pg C was buried in Lake Baikal sediments during the Holocene, almost one-quarter of which was buried during the early Holocene alone. Combined, our results highlight the importance of understanding the close linkages between carbon cycling and hydrological processes, not just temperatures, in southern Siberian environments. PMID- 27935186 TI - Coupling of a voltage-gated Ca2+ channel homologue with a plasma membrane H+ ATPase in yeast. AB - Yeast has a homologue of mammalian voltage-gated Ca2+ channels (VGCCs), enabling the efficient uptake of Ca2+ . It comprises two indispensable subunits, Cch1 and Mid1, equivalent to the mammalian pore-forming alpha1 and auxiliary alpha2 /delta subunits, respectively. Unlike the physiological roles of Cch1/Mid1 channels, the regulatory mechanisms of the yeast VGCC homologue remain unclear. Therefore, we screened candidate proteins that interact with Mid1 by an unbiased proteomic approach and identified a plasma membrane H+ -ATPase, Pma1, as a candidate. Mid1 coimmunoprecipitated with Pma1, and Mid1-EGFP colocalized with Pma1-mCherry at the plasma membrane. The physiological relevance of their interaction was determined using the temperature-sensitive mutant, pma1-10. At the nonpermissive temperature, the membrane potential was less negative and Ca2+ uptake was lower in pma1-10 than in wild-type cells. Increased extracellular H+ increased the rate of Ca2+ uptake. Therefore, H+ extrusion by Pma1 may be important for Ca2+ influx through Cch1/Mid1. These results suggest that Pma1 interacts physically with Cch1/Mid1 Ca2+ channels to enhance their activity via its H+ -pumping activity. PMID- 27935188 TI - Characteristics of physical prefrailty among Japanese healthy older adults. AB - AIM: The purpose of the present study was to clarify the characteristics of frailty at an early stage (prefrailty) in a healthy elderly Japanese population. METHODS: The participants were 620 healthy older adults (age range 60-89 years) who were current students or graduates of a community college for older adults in Japan. All participants were evaluated using the Kihon Checklist, a tool developed to screen for frailty in Japan. The participants were categorized by the Fried criteria (lost weight, handgrip strength, walking speed, exhaustion, physical activity) into either a prefrailty (1-2 criteria) or a non-frailty (0 criterion) group. RESULTS: In the logistic regression model for the prevalence of prefrailty, significant and independent determinants were chronic constipation (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.15-3.90, P = 0.016), occurrence of incontinence (OR 2.0, 95% CI 1.39-2.82, P < 0.001), unable to climb stairs (OR 3.0, 95% CI 1.26-7.02, P = 0.013), dry mouth (OR 1.5, 95% CI 1.04 2.22, P = 0.029), a lack of fulfillment (OR 3.2, 95% CI 1.26-7.93, P = 0.015), found easy tasks difficult (OR 2.8, 95% CI 1.30-5.85, P = 0.008) and felt helpless (OR 2.1, 95% CI 1.02-4.39, P = 0.044). CONCLUSIONS: These results suggest that the appearance of autonomic failure, oral malfunction and some psychological factors in relation to depressed mood, but not anthropometric measurements, are characteristic of prefrailty. Geriatr Gerontol Int 2017; 17: 1568-1574. PMID- 27935190 TI - Computational Prediction and Rationalization, and Experimental Validation of Handedness Induction in Helical Aromatic Oligoamide Foldamers. AB - Metadynamics simulations were used to describe the conformational energy landscapes of several helically folded aromatic quinoline carboxamide oligomers bearing a single chiral group at either the C or N terminus. The calculations allowed the prediction of whether a helix handedness bias occurs under the influence of the chiral group and gave insight into the interactions (sterics, electrostatics, hydrogen bonds) responsible for a particular helix sense preference. In the case of camphanyl-based and morpholine-based chiral groups, experimental data confirming the validity of the calculations were already available. New chiral groups with a proline residue were also investigated and were predicted to induce handedness. This prediction was verified experimentally through the synthesis of proline-containing monomers, their incorporation into an oligoamide sequence by solid phase synthesis and the investigation of handedness induction by NMR spectroscopy and circular dichroism. PMID- 27935189 TI - Epigenetic regulation of the glucose transporter gene Slc2a1 by beta hydroxybutyrate underlies preferential glucose supply to the brain of fasted mice. AB - We carried out liquid chromatography-tandem mass spectrometry analysis of metabolites in mice. Those metabolome data showed that hepatic glucose content is reduced, but that brain glucose content is unaffected, during fasting, consistent with the priority given to brain glucose consumption during fasting. The molecular mechanisms for this preferential glucose supply to the brain are not fully understood. We also showed that the fasting-induced production of the ketone body beta-hydroxybutyrate (beta-OHB) enhances expression of the glucose transporter gene Slc2a1 (Glut1) via histone modification. Upon beta-OHB treatment, Slc2a1 expression was up-regulated, with a concomitant increase in H3K9 acetylation at the critical cis-regulatory region of the Slc2a1 gene in brain microvascular endothelial cells and NB2a neuronal cells, shown by quantitative PCR analysis and chromatin immunoprecipitation assay. CRISPR/Cas9 mediated disruption of the Hdac2 gene increased Slc2a1 expression, suggesting that it is one of the responsible histone deacetylases (HDACs). These results confirm that beta-OHB is a HDAC inhibitor and show that beta-OHB plays an important role in fasting-induced epigenetic activation of a glucose transporter gene in the brain. PMID- 27935191 TI - Double-Negative Mechanical Metamaterials Displaying Simultaneous Negative Stiffness and Negative Poisson's Ratio Properties. PMID- 27935192 TI - Osteoblast adhesion, migration, and proliferation variations on chemically patterned nanocrystalline diamond films evaluated by live-cell imaging. AB - Cell fate modulation by adapting the surface of a biocompatible material is nowadays a challenge in implantology, tissue engineering as well as in construction of biosensors. Nanocrystalline diamond (NCD) thin films are considered promising in these fields due to their extraordinary physical and chemical properties and diverse ways in which they can be modified structurally and chemically. The initial cell distribution, the rate of cell adhesion, distance of cell migration and also the cell proliferation are influenced by the NCD surface termination. Here, we use real-time live-cell imaging to investigate the above-mentioned processes on oxidized NCD (NCD-O) and hydrogenated NCD (NCD H) to elucidate cell preference to the NCD-O especially on surfaces with microscopic surface termination patterns. Cells adhere more slowly and migrate farther on NCD-H than on NCD-O. Cells seeded with a fetal bovine serum (FBS) supplement in the medium move across the surface prior to adhesion. In the absence of FBS, the cells adhere immediately, but still exhibit different migration and proliferation on NCD-O/H regions. We discuss the impact of these effects on the formation of cell arrays on micropatterned NCD. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1469-1478, 2017. PMID- 27935193 TI - Optimal bile duct division using real-time indocyanine green near-infrared fluorescence cholangiography during laparoscopic donor hepatectomy. PMID- 27935194 TI - Unconventional Reactivity of (Z)-Enoate Propargylic Alcohols in the Presence of Acids. AB - The unconventional reactivity of (Z)-enoate-attached propargylic alcohols in the presence of acids (nucleophilic and non-nucleophilic) was described. This study led to the discovery and development of a new strategy for the collective synthesis of the synthetically useful building blocks alpha-OMs-, alpha-OTs-, and alpha-Cl-enones, as well as 4,5-dioxonoates. The reaction proceeded under very mild conditions and showed a broad substrate scope. PMID- 27935195 TI - Ultrahigh molecular weight polyethylene/graphene oxide nanocomposites: Wear characterization and biological response to wear particles. AB - In the field of total joint replacements, polymer nanocomposites are being investigated as alternatives to ultrahigh molecular weight polyethylene (UHMWPE) for acetabular cup bearings. The objective of this study was to investigate the wear performance and biocompatibility of UHMWPE/graphene oxide (GO) nanocomposites. This study revealed that low concentrations of GO nanoparticles (0.5 wt %) do not significantly alter the wear performance of UHMWPE. In contrast, the addition of higher concentrations (2 wt %) led to a significant reduction in wear. In terms of biocompatibility, UHMWPE/GO wear particles did not show any adverse effects on L929 fibroblast and PBMNC viability at any of the concentrations tested over time. Moreover, the addition of GO to a UHMWPE matrix did not significantly affect the inflammatory response to wear particles. Further work is required to optimize the manufacturing processes to improve the mechanical properties of the nanocomposites and additional biocompatibility testing should be performed to understand the potential clinical application of these materials. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 183-190, 2018. PMID- 27935196 TI - An In Vitro Evaluation of Human Enamel Surfaces Subjected to Erosive Challenge After Bleaching. AB - OBJECTIVES: This study aimed to evaluate whether tooth enamel bleached with hydrogen peroxide (H2 O2 ) is more susceptible to erosion when compared with unbleached tooth enamel; and whether the presence of calcium (Ca) in the bleaching gel influenced this process. MATERIALS AND METHODS: Enamel blocks were prepared from human molars, and submitted to surface microhardness analysis (baseline). Blocks were prepared and randomly divided into four treatment groups (n = 20): G1 and G2-bleached with 7.5% H2 O2 , with and without Ca, respectively; G3 and G4-bleached with 35% H2 O2 , with and without Ca, respectively. After bleaching, these groups were submitted to an erosive challenge with 1% citric acid. G5 and G6 (n = 20, each) were the negative (without bleaching) and positive controls (without bleaching, but with erosion), respectively. The percentage of surface hardness loss (%SHL), the 3D non-contact profilometry and Scanning Electron Microscopy (SEM) analyses were performed. RESULTS: G2 showed the highest %SHL after bleaching. G1 presented the lowest %SHL in comparison with G2, G3, G4, and G6 after erosion (p < 0.05), which was confirmed only by the SEM analysis. CONCLUSION: It is suggested that low concentration of H2 O2 with calcium can be recommended for at-home bleaching agents, which may avoid the mineral loss of bleached enamel after an erosive challenge. CLINICAL SIGNIFICANCE: Low concentration of H2 02 with calcium can be recommended for at-home bleaching agents, which may avoid the mineral loss of bleached enamel after an erosive challenge. (J Esthet Restor Dent 29:128-136, 2017). PMID- 27935197 TI - Ring-Expansion Approach to Medium-Sized Lactams and Analysis of Their Medicinal Lead-Like Properties. AB - Medium-sized rings are widely considered to be under-represented in biological screening libraries for lead identification in medicinal chemistry. To help address this, a library of medium-sized lactams has been generated by using a simple, scalable and versatile ring-expansion protocol. Analysis of the library by using open-access computational tool LLAMA suggested that these lactams and their derivatives have highly promising physicochemical and 3D spatial properties and thus have much potential in drug discovery. PMID- 27935198 TI - Investigation of cell viability and morphology in 3D bio-printed alginate constructs with tunable stiffness. AB - In this article, mouse fibroblast cells (L929) were seeded on 2%, 5%, and 10% alginate hydrogels, and they were also bio-printed with 2%, 5%, and 10% alginate solutions individually to form constructs. The elastic and viscous moduli of alginate solutions, their interior structure and stiffness, interactions of cells and alginate, cell viability, migration and morphology were investigated by rheometer, MTT assay, scanning electron microscope (SEM), and fluorescent microscopy. The three types of bio-printed scaffolds of distinctive stiffness were prepared, and the seeded cells showed robust viability either on the alginate hydrogel surfaces or in the 3D bio-printed constructs. Majority of the proliferated cells in the 3D bio-printed constructs weakly attached to the surrounding alginate matrix. The concentration of alginate solution and hydrogel stiffness influenced cell migration and morphology, moreover the cells formed spheroids in the bio-printed 10% alginate hydrogel construct. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1009-1018, 2017. PMID- 27935199 TI - Model averaging for treatment effect estimation in subgroups. AB - In many clinical trials, biological, pharmacological, or clinical information is used to define candidate subgroups of patients that might have a differential treatment effect. Once the trial results are available, interest will focus on subgroups with an increased treatment effect. Estimating a treatment effect for these groups, together with an adequate uncertainty statement is challenging, owing to the resulting "random high" / selection bias. In this paper, we will investigate Bayesian model averaging to address this problem. The general motivation for the use of model averaging is to realize that subgroup selection can be viewed as model selection, so that methods to deal with model selection uncertainty, such as model averaging, can be used also in this setting. Simulations are used to evaluate the performance of the proposed approach. We illustrate it on an example early-phase clinical trial. PMID- 27935200 TI - Probing bacterial cell biology using image cytometry. AB - Advances in automated fluorescence microscopy have made snapshot and time-lapse imaging of bacterial cells commonplace, yet fundamental challenges remain in analysis. The vast quantity of data collected in high-throughput experiments requires a fast and reliable automated method to analyze fluorescence intensity and localization, cell morphology and proliferation as well as other descriptors. Inspired by effective yet tractable methods of population-level analysis using flow cytometry, we have developed a framework and tools for facilitating analogous analyses in image cytometry. These tools can both visualize and gate (generate subpopulations) more than 70 cell descriptors, including cell size, age and fluorescence. The method is well suited to multi-well imaging, analysis of bacterial cultures with high cell density (thousands of cells per frame) and complete cell cycle imaging. We give a brief description of the analysis of four distinct applications to emphasize the broad applicability of the tool. PMID- 27935202 TI - Corrigendum: Synthesis, Structure and Catalytic Activity of NHC-AgI Carboxylate Complexes. PMID- 27935201 TI - Probing Bilayer Grain Boundaries in Large-Area Graphene with Tip-Enhanced Raman Spectroscopy. AB - The bilayer grain boundaries (GBs) in chemical-vapor-deposition-grown large-area graphene are identified using multispectral tip-enhanced Raman imaging with 18 nm spatial resolution. The misorientation angle of the bilayer GBs is determined from a quantitative analysis of the phonon-scattering properties associated with the modified electronic structure. PMID- 27935203 TI - Solution Chemistry of N,N'-Disubstituted Amidines: Identification of Isomers and Evidence for Linear Dimer Formation. AB - Amidines have found widespread use, but their solution chemistry remains poorly understood. In this work, X-ray crystallographic and detailed 1D and 2D NMR spectroscopic studies have been performed to elucidate the preferred isomers and their interconversion mechanisms. Amidines are shown to exist as a mixture of E syn and Z-anti isomers in solution and to form dimeric H-bonded aggregates that are also observed in the solid state. Rapid proton exchange/tautomerization reactions occur within the dimers, allowing fast interconversion of E-syn and Z anti isomers even at very low temperatures. Three different exchange processes were identified in solution, and on this basis the unusual concentration and temperature dependence of the NMR spectra of these amidines could be explained. This work thus resolves some of the puzzles of the complex solution chemistry of this prominent class of compounds. PMID- 27935204 TI - Cross-Dehydrogenative-Coupling of Alkoxybenzenes with Toluenes: Copper(II) Halide Mediated Tandem Halo/Benzylation of Arenes. AB - A cross-dehydrogenative-coupling of alkoxybenzenes and toluenes with concomitant halogenation is reported. Conditions employed were the use of stoichiometric copper halide salts and dialkylperoxides to afford a range of bromoalkoxydi- and triarylmethanes. Preliminary mechanistic studies suggest that the in situ production of haloarenes (or dihaloarenes) followed by a copper-mediated coupling of a benzylic radical is operational. PMID- 27935205 TI - Corrigendum: One-Pot Sequential Propargylation/Cycloisomerization: A Facile [4+2] Benzannulation Approach to Carbazoles. PMID- 27935207 TI - Living donor liver transplantation with a left trisegmental graft from a donor with anomalous branching of the portal vein. PMID- 27935206 TI - Developmental transcriptional regulation by SUMOylation, an evolving field. AB - SUMOylation is a reversible post-translational protein modification that affects the intracellular localization, stability, activity, and interactions of its protein targets. The SUMOylation pathway influences several nuclear and cytoplasmic processes. The expression of many genes, in particular those involved in development is finely tuned in space and time by several groups of proteins. There is growing evidence that transcriptional regulation mechanisms involve direct SUMOylation of transcriptional-related proteins such as initiation and elongation factors, and subunits of chromatin modifier and remodeling complexes originally described as members of the trithorax and Polycomb groups in Drosophila. Therefore, it is being unveiled that SUMOylation has a role in both, gene silencing and gene activation mechanisms. The goal of this review is to discuss the information on how SUMO modification in components of these multi subunit complexes may have an effect in genome architecture and function and, therefore, in the regulation of gene expression in time and space. PMID- 27935208 TI - Antioxidant properties of coenzyme Q10-pretreated mouse pre-antral follicles derived from vitrified ovaries. AB - AIM: This study evaluated the antioxidant status of pre-antral follicles derived from vitrified ovaries pretreated with coenzyme Q10 (CoQ10). METHODS: Mouse pre antral follicles derived from fresh and vitrified warmed ovarian tissue were cultured with or without CoQ10 (50 MUmol/L). Follicular growth, total antioxidant capacity (TAC), malondialdehyde (MDA) level, and superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) activity during cultivation were assessed. RESULTS: The growth rate of the fresh pre-antral follicles was higher compared with the vitrified groups, especially in the CoQ10-treated than non treated groups. MDA increased while TAC decreased at 96 h of the cultivation period. TAC was higher while MDA was lower in the fresh pre-antral follicles than in the vitrified groups. These rates were higher in the CoQ10-treated than non treated groups. The vitrified and fresh CoQ10-pretreated groups had significantly higher SOD, GPX, and CAT activity compared with the CoQ10 non-treated groups. CONCLUSION: CoQ10-supplemented maturation medium can increase antioxidant enzyme activity and decrease lipid peroxidation in cultured pre-antral follicles derived from fresh and vitrified mouse ovaries. PMID- 27935209 TI - Tailoring the physicochemical and shape memory properties of the biodegradable polymer poly(glycerol dodecanoate) via curing conditions. AB - A major challenge in the repair and regeneration of soft tissue damage occurring as a result of aging, injury, or disease is recapitulating the biomechanical properties of the native tissue. Ideally, a candidate biomaterial for soft tissue engineering applications should be biocompatible, nonlinearly elastic to match soft tissue mechanical behavior, biodegradable to enable tissue remodeling, and tailorable to achieve a range of nonlinear elastic mechanical properties to match specific soft tissues. In addition, for cardiac and other applications, the biomaterial should have shape memory characteristics to facilitate minimally invasive and/or catheter-based delivery. Poly(glycerol dodecanoate) (PGD) is a shape memory material that has nonlinear elastic properties at body temperature and elastic-plastic behavior at room temperature. In this study, we investigated the effects of curing conditions on the nonlinear elastic, shape memory, and biocompatibility properties of PGD. Increased curing and crosslinking resulted in an increase in both the initial stiffness and the nonlinear strain stiffening behavior of PGD. After shape fixation at 60% strain, 100% shape recovery was achieved within 1 min at body temperature for all conditions tested. Polymer curing had no adverse effects on the cellular biocompatibility or non-hemolytic characteristics of PGD, indicating the potential suitability of these formulations for blood-contacting device applications. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1618-1623, 2017. PMID- 27935210 TI - Mechanistic Insight into the Oxidation of Organic Phenylselenides by H2 O2. AB - The oxidation of organic phenylselenides by H2 O2 is investigated in model compounds, namely, n-butyl phenyl selenide (PhSe(nBu)), bis(phenylselanyl)methane (PhSeMeSePh), diphenyl diselenide (PhSeSePh), and 1,2-bis(phenylselanyl)ethane (PhSeEtSePh). Through a combined experimental (1 H and 77 Se NMR) and computational approach, we characterize the direct oxidation of monoselenide to selenoxide, the stepwise double oxidation of PhSeMeSePh that leads to different diastereomeric diselenoxides, the complete oxidation of the diphenyldiselenide that leads to selenium-selenium bond cleavage, and the subsequent formation of the phenylseleninic product. The oxidation of PhSeEtSePh also results in the formation of phenylseleninic acid along with 1-(vinylseleninyl)benzene, which is derived from a side elimination reaction. The evidence of a direct mechanism, in addition to an autocatalytic mechanism that emerges from kinetic studies, is discussed. By considering our observations of diselenides with chalcogen atoms that are separated by alkyl spacers of different length, a rationale for the advantage of diselenide versus monoselenide catalysts is presented. PMID- 27935211 TI - Bioinspired Special Wettability Surfaces: From Fundamental Research to Water Harvesting Applications. AB - Nowadays, the pollution of water has become worse in many parts of the world, which causes a severe shortage of clean water and attracts widespread attention worldwide. Bioinspired from nature, i.e. spider silk, cactus, Namib desert beetle, Nepenthes alata, special wettability surfaces have attracted great interest from fundamental research to water-harvesting applications. Here, recently published literature about creatures possessing water-harvesting ability are reviewed, with a focus on the corresponding water-harvesting mechanisms of creatures in dry or arid regions, consisting of the theory of wetting and transporting. Then a detailed account of the innovative fabrication technologies and bionic water-harvesting materials with special wetting are summarized, i.e. bio-inspired artificial spider silk, bio-inspired artificial cactus-like structures, and bio-inspired artificial Namib desert beetle-like surfaces. Special attentions are paid to the discussion of the advantages and disadvantages of the technologies, as well as factors that affect the amount of water harvesting. Finally, conclusions, future outlooks and the current challenges for future development of the water-harvesting technology are presented and discussed. PMID- 27935212 TI - Hemophilia Liver Transplantation Observational Study. AB - Hepatitis C virus (HCV) infection is the leading cause of liver disease in hemophilia patients. In those with human immunodeficiency virus (HIV)/HCV coinfection, the rate of liver disease progression is greater than in HCV monoinfected individuals. Despite antiretroviral therapy, which slows HCV liver disease progression, some require transplantation. Whether transplant outcomes are worse in hemophilic (H) rather than nonhemophilic (NH) candidates is unknown. In order to determine rates and predictors of pretransplant and posttransplant survival, we conducted a retrospective observational study using United Network for Organ Sharing national transplant registry data, comparing HCV+ H and NH candidates. We identified 2502 HCV+ liver transplant candidates from 8 US university-based transplant centers, between January 1, 2004 to December 31, 2010, including 144 HIV+ (6%) and 2358 HIV-; 36 H (1%) and 2466 NH; 1213 (48%) transplanted and 1289 not transplanted. Other than male predominance and younger age, each were P < 0.001. Baseline data were comparable between H and NH. In univariate analysis, 90-day pretransplant mortality was associated with higher baseline Model for End-Stage Liver Disease (MELD; hazard ratio [HR] = 1.15; P < 0.001), lower baseline platelet count (HR = 0.9 per 25,000/uL; P = 0.04), and having HIV/HCV+ hemophilia (P = 0.003). In multivariate analysis, pretransplant mortality was associated with higher MELD (P < 0.001) and was significantly greater in HIV+ than HIV- groups (P = 0.001). However, it did not differ between HIV+ H and NH (HR = 1.7; P = 0.36). Among HIV/HCV+, posttransplant mortality was similar between H and NH, despite lower CD4 in H (P = 0.04). In conclusion, this observational study confirms that hemophilia per se does not have a specific influence on transplant outcomes and that HIV infection increases the risk of mortality in both H and NH patients. Liver Transplantation 23 762-768 2017 AASLD. PMID- 27935214 TI - Stabilized sulforaphane for clinical use: Phytochemical delivery efficiency. AB - SCOPE: The isothiocyanate sulforaphane (SF) from broccoli is one of the most potent known inducers of the cytoprotective phase 2 response. Its role in a host of biochemical pathways makes it a major component of plant-based protective strategies for enhancing healthspan. Many nutritional supplements are now marketed that purport to contain SF, which in plants exists as a stable precursor, a thioglucoside hydroxysulfate. However, SF in pure form must be stabilized for use in supplements. METHODS AND RESULTS: We evaluated the stability and bioavailability of two stabilized SF preparations-an alpha cyclodextrin inclusion (SF-alphaCD), and an SF-rich, commercial nutritional supplement. SF-alphaCD area-under-the-curve peak serum concentrations occurred at 2 h, but six of ten volunteers complained of mild stomach upset. After topical application it was not effective in upregulating cytoprotective enzymes in the skin of SKH1 mice whereas pure SF was effective in doing so. Both of these "stabilized" SF preparations were as potent as pure SF in inducing the cytoprotective response in cultured cells, and they were more stable and as bioavailable. CONCLUSION: Our studies of a stabilized phytochemical component of foods should encourage further examination of similar products for their utility in chronic disease prevention and therapy. PMID- 27935213 TI - UHPLC-Q-TOF-MS-based metabolomics approach to compare the saponin compositions of Xueshuantong injection and Xuesaitong injection. AB - Various traditional Chinese medicine preparations developed from Notoginseng total saponins, including Xueshuantong injection and Xuesaitong injection, are extensively used in China to treat cardiocerebrovascular diseases. However, the difference of their saponin compositions remains unknown. An ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry based metabolomics approach was developed to probe the saponin discrimination between Xueshuantong and Xuesaitong and the related factors by large sample analysis. A highly efficient chromatographic separation was achieved on an HSS T3 column within 20 min with the holistic metabolites information recorded in the negative MSE mode. A six-step data pretreatment procedure mainly based on Progenesis QI and mass defect filtering was established. Pattern recognition chemometrics was used to discover the potential saponin markers. The saponin composition of Wuzhou Xueshuantong showed distinct discrimination from the other products. Wuzhou Xueshuantong contains more abundant protopanaxatriol type noto-R1 , Rg1 , Re, and protopanaxadiol-type Rb1 , but less Rd and other low polarity protopanaxadiol-type ginsenosides. These differences could not directly correlate to the use of different parts of Panax notoginseng, but possibly to the different preparation techniques employed by different manufacturers. These results are beneficial to the establishment of pharmacopoeia standards and the assessment of the efficacy and adverse drug reactions for these homologous products. PMID- 27935215 TI - Donors With Immune Thrombocytopenia: Do They Pose a Risk to Transplant Recipients? AB - Transplant-mediated alloimmune thrombocytopenia (TMAT) from donors with immune thrombocytopenia (ITP) can result in significant bleeding complications in the recipient. The risk to a recipient of TMAT if they receive an organ from a donor with ITP is unknown. The outcomes of recipients of organs from deceased donors with ITP recorded in the UK Transplant Registry between 2000 and 2015 were reviewed. Twenty-one deceased organ donors had a predonation diagnosis of ITP. These donors were significantly more likely to have died from intracranial hemorrhage than were all other deceased organ donors (85% vs. 57%, p < 0.001). Organs from donors with ITP resulted in 49 organ transplants (31 kidney, 14 liver, four heart), with only one case of TMAT, which occurred in a liver transplant recipient and resulted in death from bleeding complications 18 days posttransplantation. The recipient of a kidney from the same organ donor was not affected. Unadjusted 5-year patient and graft survival was significantly worse for liver transplant recipients from donors with ITP compared with liver transplant recipients from donors without ITP (64% vs. 85%, p = 0.012). Organs from donors with ITP may be considered for transplantation, but livers should be used with caution. PMID- 27935217 TI - Takotsubo cardiomyopathy after cesarean section: A case report and literature review. AB - Takotsubo cardiomyopathy (TCM) is clinically identical to acute myocardial infarction. We report an unusual case of TCM and review similar cases in pregnant women. A young woman with no pre-existing cardiovascular risk factors suffered sudden dyspnea during a cesarean section. Electrocardiography (ECG) showed T-wave inversion. We observed acute lung edema and left ventricular systolic dysfunction on echocardiography. A cardiac catheterization diagnosed TCM. We reviewed 20 cases of TCM; 17 cases occurred during the post-partum period and three during pregnancy. Five of these cases had vaginal deliveries and the remaining cases had cesarean sections. Within the latter group, five cases appeared intraoperatively. With the exception of one patient with normal ECG results, all other patients progressed, with changes in ECG readings and elevation of cardiac enzyme serum levels. However, cardiac catheterization revealed that coronary arterial damage did not occur in any of the cases. After three months, each patient fully recovered. PMID- 27935216 TI - Modulation of diet-induced mechanical allodynia by metabolic parameters and inflammation. AB - Dietary-associated diseases have increased tremendously in our current population, yet key molecular changes associated with high-fat diets that cause clinical pre-diabetes, obesity, hyperglycemia, and peripheral neuropathy remain unclear. This study examines molecular and metabolic aspects altered by voluntary exercise and a high-fat diet in the mouse dorsal root ganglion. Mice were examined for changes in mRNA and proteins encoding anti-inflammatory mediators, metabolic-associated molecules, and pain-associated ion channels. Proteins involved in the synaptosomal complex and pain-associated TRP ion channels decrease in the dorsal root ganglion of high-fat exercise animals relative to their sedentary controls. Exercise reversed high-fat diet induced mechanical allodynia without affecting weight gain, elevated blood glucose, and utilization of fat as a fuel source. Independent of weight or fat mass changes, high-fat exercised mice display reduced inflammation-associated mRNAs. The benefits of exercise on abnormal peripheral nerve function appear to occur independent of systemic metabolic changes, suggesting that the utilization of fats and inflammation in the peripheral nervous system may be key for diet-induced peripheral nerve dysfunction and the response to exercise. PMID- 27935218 TI - Neonatal sepsis and simple minor neurological dysfunction. AB - BACKGROUND: This study examined potential risk factors for and consequences of simple minor neurological dysfunction (SMND), in a group of very low-birthweight newborns followed until preschool age. METHODS: This was a prospective longitudinal study. Children with birthweight <1500 g were assessed at 4-6 years of age. Twenty-eight children with normal neurological examination and 35 children with SMND were included in the final analysis. Risk factors for the development of SMND and its association with certain neuropsychiatric conditions were studied. RESULTS: Based on neonatal data, in children with SMND, Apgar score at 1 min (6.13 +/- 2.37 vs 7.66 +/- 1.04, P = 0.008) and at 5 min (8.63 +/- 1.29 vs 9.45 +/- 0.65, P = 0.019) was lower, duration of hospital stay was longer (45.8 +/- 21.8 vs 35.1 +/- 18.2 days, P = 0.037), and the frequency of sepsis was higher (73.5 vs 25%, P < 0.001). Sepsis was found to be an independent risk factor for SMND (OR, 7.6; 95% CI: 2.2-26.0; P = 0.001). The children with SMND had lower intelligence quotient and higher prevalence of hyperactivity and refraction error. CONCLUSION: Postnatal sepsis was the single most important risk factor for the development of SMND, and these children with SMND are at great risk for certain neuropsychiatric conditions. Preventive strategies, particularly for sepsis in the neonatal period, and early diagnosis and rehabilitation of future neuropsychiatric disorders are needed for better management of these cases. PMID- 27935219 TI - The influence of a chronic L-carnitine administration on the plasma metabolome of male Fischer 344 rats. AB - SCOPE: L-carnitine has been advertised as a fat-lowering and performance enhancing supplement, although scientific evidence for its effectiveness is lacking. The uptake of about 1-2 g of L-carnitine per day may result in the formation of metabolites like trimethylamine-N-oxide (TMAO), which in turn may be converted to potential carcinogens or promote the development of cardiovascular diseases. METHODS AND RESULTS: To assess whether an L-carnitine supplementation changes overall metabolism or causes the formation of previously unknown metabolites, we analyzed plasma samples from Fischer 344 rats originating from a previous study using a multi-platform metabolomics approach comprising LC-MS/MS and GC*GC-MS methods. Despite an intake of up to 352 mg L-carnitine/kg body weight/day for 1 year, plasma concentrations of only 29 out of 359 metabolites were significantly influenced, the induced concentration changes being often comparatively small. Nevertheless, a clear dose-response relationship and a substantial concentration increase were observed for TMAO, i.e. a tenfold higher TMAO level was measured in the high-dose group when compared to the control (2.5 versus 25.0 MUM). CONCLUSION: Although L-carnitine supplementation did not cause large changes in the plasma metabolome, a higher risk for cardiovascular disease due to chronically elevated TMAO plasma concentrations cannot be excluded. PMID- 27935221 TI - Hypoxia-induced redox signalling in Muller cells. PMID- 27935220 TI - Nuclear co-repressor (NCoR) is required to maintain insulin sensitivity in C2 C12 myotubes. AB - Nuclear co-repressor (NCoR) regulates peripheral insulin sensitivity; however, its role in modulating insulin sensitivity in skeletal muscle remains elusive. Present study investigated protein expression and effect of NCoR on insulin sensitivity in murine skeletal muscle cell line C2 C12 . Myotubes as compared to myoblasts of C2 C12 cells were found to be more sensitive in response to insulin as increase in insulin-stimulated phosphorylation of AKT at serine 473 residue (pAKTS473 ) was significantly higher in myotubes. Incidentally, reduced protein level of NCoR coincided with differentiation of myoblasts into myotubes of C2 C12 cells. However, insulin stimulation per se failed to affect protein level of NCoR either in myoblasts or myotubes of C2 C12 cells. To assess the role of NCoR on insulin sensitivity, NCoR was transiently knocked down using siRNA in myotubes of C2 C12 . In fact, transient silencing of NCoR led to significant reduction in insulin-stimulated pAKTS473 and impaired glucose uptake. This observation is in contrast to published studies where NCoR has been reported to negatively regulate insulin signaling cascade. Furthermore, transient silencing of NCoR failed to improve insulin sensitivity in chronic hyperinsulinemia-induced insulin-resistant model of C2 C12 cells. Importantly, inhibition of lysosomal protein degradation pathway using ammonium chloride restored protein level of NCoR but failed to increase glucose uptake in serum-starved C2 C12 myotubes. Collectively, data from present study show differential protein level of NCoR under different cell state (myoblast and myotubes) of C2 C12 cells and NCoR proves to be vital for maintaining insulin sensitivity in C2 C12 myotubes. PMID- 27935222 TI - Diverse manganese(II)-oxidizing bacteria are prevalent in drinking water systems. AB - Manganese (Mn) oxides are highly reactive minerals that influence the speciation, mobility, bioavailability and toxicity of a wide variety of organic and inorganic compounds. Although Mn(II)-oxidizing bacteria are known to catalyze the formation of Mn oxides, little is known about the organisms responsible for Mn oxidation in situ, especially in engineered environments. Mn(II)-oxidizing bacteria are important in drinking water systems, including in biofiltration and water distribution systems. Here, we used cultivation dependent and independent approaches to investigate Mn(II)-oxidizing bacteria in drinking water sources, a treatment plant and associated distribution system. We isolated 29 strains of Mn(II)-oxidizing bacteria and found that highly similar 16S rRNA gene sequences were present in all culture-independent datasets and dominant in the studied drinking water treatment plant. These results highlight a potentially important role for Mn(II)-oxidizing bacteria in drinking water systems, where biogenic Mn oxides may affect water quality in terms of aesthetic appearance, speciation of metals and oxidation of organic and inorganic compounds. Deciphering the ecology of these organisms and the factors that regulate their Mn(II)-oxidizing activity could yield important insights into how microbial communities influence the quality of drinking water. PMID- 27935223 TI - Response to and toxicity of gemcitabine for recurrent ovarian cancer according to number of previous chemotherapy regimens. AB - AIM: Gemcitabine is used not only as a second-line, but also as a third-line or higher regimen for taxane/platinum-resistant recurrent ovarian cancer. The purpose of this study was to clarify the response to and toxicity of gemcitabine for recurrent ovarian cancer according to the number of previous chemotherapy regimens. METHODS: The subjects were patients with taxane/platinum-resistant recurrent ovarian cancer on gemcitabine treatment at the present hospital between June 2007 and September 2013. We retrospectively reviewed the medical records. Response and adverse events were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. and the Common Terminology Criteria for Adverse Events v4.0, respectively. RESULTS: The subjects consisted of 65 patients. The median number of previous chemotherapy regimens was 3 (range, 1-7). Overall response rate was 4.6%, and disease control rate (DCR) was 40.0%. DCR versus one, two, three, and >=four previous chemotherapy regimens was 83.3%, 45.0%, 36.4%, and 23.5%, respectively. Grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 52.3%, 9.2%, and 9.2% of patients, respectively. Prevalence of grade 3/4 neutropenia according to one, two, three, and >=four previous chemotherapy regimens was 66.7%, 55.0%, 54.5%, and 41.2%, respectively. Prevalence of anemia, thrombocytopenia, and almost all the non-hematological toxicities also did not increase with an increase in the number of previous chemotherapy regimens. CONCLUSIONS: Although DCR decreased as the number of previous chemotherapy regimens increased, the toxicities did not increase. Gemcitabine may be relatively safe in heavily pretreated ovarian cancer patients. PMID- 27935224 TI - Tideless estuaries in brackish seas as possible freshwater-marine transition zones for bacteria: the case study of the Vistula river estuary. AB - Most bacteria are found either in marine or fresh waters and transitions between the two habitats are rare, even though freshwater and marine bacteria co-occur in brackish habitats. Estuaries in brackish, tideless seas could be habitats where the transition of freshwater phylotypes to marine conditions occurs. We tested this hypothesis in the Gulf of Gdansk (Baltic Sea) by comparing bacterial communities from different zones of the estuary, via pyrosequencing of 16S rRNA amplicons. We predicted the existence of a core microbiome (CM, a set of abundant OTUs present in all samples) comprising OTUs consisting of populations specific for particular zones of the estuary. The CMs for the entire studied period consisted of only eight OTUs, and this number was even lower for specific seasons: five in spring, two in summer, and one in autumn and winter. Six of the CM OTUs, and another 21 of the 50 most abundant OTUs consisted of zone-specific populations, plausibly representing micro-evolutionary forces. The presence of up to 15% of freshwater phylotypes from the Vistula River in the brackish Gulf of Gdansk supported our hypothesis, but high dissimilarity between the bacterial communities suggested that freshwater-marine transitions are rare even in tideless estuaries in brackish seas. PMID- 27935225 TI - Effect of long-term glycemic variability on estimated glomerular filtration rate decline among patients with type 2 diabetes mellitus: Insights from the Diabetic Nephropathy Cohort in Singapore. AB - BACKGROUND: In the present study, we examined the association between HbA1c variability and renal disease progression based on estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes mellitus (T2DM) in Singapore. METHODS: Glycemic burden and renal function were retrospectively assessed in 1628 patients in 2002-2014. Multivariable logistic regression was used to assess the relationships between HbA1c variability (expressed as HbA1c coefficient of variation [HbA1c-CV] in quartiles), HbA1c intrapersonal mean (HbA1c-IM), and eGFR decline, adjusted for baseline covariates. RESULTS: Among patients with relatively good glycemic control (i.e. HbA1c-IM below the median cohort value [8.0%]), HbA1c-CV Quartile 4 was associated with eGFR decline (odds ratio [OR] 1.88; 95% confidence interval [CI] 1.10-3.25). The OR for HbA1c-CV Quartile 4 was 2.20 (95% CI 1.24-3.89) after additional adjustment for HbA1c-IM. Where HbA1c-IM was above the median cohort value, HbA1c-CV Quartiles 3 and 4 were associated with eGFR decline, with ORs of 2.60 (95% CI 1.48-4.55) and 3.29 (95% CI 1.89-5.76) respectively. After further adjusting for HbA1c-IM, the ORs for Quartiles 3 and 4 were 2.69 (95% CI 1.53-4.74) and 3.51 (95% CI 1.98-6.21), respectively. CONCLUSIONS: Variability in HbA1c is strongly and independently associated with eGFR decline in patients with T2DM independent of mean HbA1c. The findings may highlight the importance of sustained stable glycemic control in management of diabetes mellitus. PMID- 27935226 TI - Clinical study on the factors affecting the post-partum recovery of patients with hypertensive pregnancy disorders at a Chinese hospital. AB - AIM: The aim of this study was to investigate the post-partum recovery of blood pressure (BP) in women with hypertensive disorders of pregnancy (HDP) and to evaluate HDP risk factors. METHODS: A total of 124 patients with gestational hypertension (n = 63) or pre-eclampsia (n = 61) who gave birth at Peking University People's Hospital between January and December 2013 were included in this study. The recorded clinical and laboratory parameters included the patients' general information, maternal pre-pregnancy body mass index, gestational weight gain, gestational age at onset and delivery, delivery mode and time taken for BP to return to normal level. Logistic regression analysis was performed to evaluate the influence of various risk factors on post-partum BP recovery. RESULTS: The mean interval for BP normalization was 24.1 +/- 22.8 days (median, 7 days). Forty-six percent of the patients recovered from hypertension within three days, and 75% recovered within six weeks of delivery. About 90% of the patients required 60 days for BP to normalize after delivery. After adjusting for confounding factors, post-partum recovery from hypertension was found to be influenced by hypertension severity, maternal serum albumin level, a family history of hypertension and gestational week at delivery. CONCLUSIONS: The BP of the majority of the patients with gestational hypertension or pre-eclampsia returned to normal within 60 days of delivery. Hypertension severity, maternal serum albumin level, a family history of family hypertension and gestational week at delivery influenced the time required for BP normalization. PMID- 27935227 TI - High-speed counter-current chromatography assisted preparative isolation of bioactive compounds from stem bark of Juglans mandshurica. AB - High-speed counter-current chromatography was applied for the first time for the separation and purification of bioactive compounds contained in the stem bark of Juglans mandshurica Maxim. Silica gel column chromatography was first used to obtain three composition-enriched target fractions from a crude J. mandshurica methanol extract. Three independent high-speed counter-current chromatography processes were then used to further isolate 13 bioactive compounds, namely, six galloyl glucose derivatives, three flavonones, three naphthoquinones, and ethyl gallate. The isolates were identified by ultrahigh-performance liquid chromatography with tandem mass spectrometry, and ultraviolet and NMR spectroscopy, and compared with literature data. Their purities were determined to be >94.6% by ultrahigh performance liquid chromatography. Furthermore, based on the total phenolic content and results of a 2,2-diphenyl-1-picrylhydrazyl test, the methanol extract and two of the three initial fractions were observed to be rich in phenolic compounds and exhibit good free radical scavenging abilities, while nine of the isolated compounds exhibited remarkable antioxidant activity, superior to that of butyrate hydroxy-toluene and comparable to that of gallic acid. The results of this research confirm the effectiveness of high-speed counter-current chromatography for the separation of compounds contained in extremely complex samples, and provide a basis for the further utilization of J. mandshurica. PMID- 27935228 TI - Second generation slit-based photoacoustic tomography system for vascular imaging in human. AB - Slit-based photoacoustic tomography is a newly developed technique that improves the elevation numerical aperture of a linear array through acoustic diffraction. The slit, placed at the acoustic focus of a linear array, effectively forms an array of virtual detectors with high receiving angle, which subsequently improves the elevation resolution. However, due to the complex implementation, our original system could only image phantoms and sacrificed animals. In this report, the system has been significantly improved. In particular, we designed a slit holder that can be directly mounted to the transducer array for easy adjustment of slit width and simultaneous scanning of both the array and the slit. To enlarge the imaging field of view, we replaced the single circular optical fiber bundle with a bifurcated line fiber bundle which moved simultaneously with the array and the slit. The data acquisition system has also been updated to double the imaging speed. With these improvements, the new system can image a 3.8 * 4 cm2 region within 40 seconds and the object only needs to be coupled through ultrasound gel. We successfully used the system to image vasculatures in the palm and forearm of human volunteers. 3D palm vascular image of human palm. PMID- 27935230 TI - Comment on Abd El Aziz et al., A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head to-head studies in type 2 diabetic patients. PMID- 27935229 TI - Cortico-limbic connectivity in MAOA-L carriers is vulnerable to acute tryptophan depletion. AB - INTRODUCTION: A gene-environment interaction between expression genotypes of the monoamine oxidase A (MAOA) and adverse childhood experience increases the risk of antisocial behavior. However, the neural underpinnings of this interaction remain uninvestigated. A cortico-limbic circuit involving the prefrontal cortex (PFC) and the amygdala is central to the suppression of aggressive impulses and is modulated by serotonin (5-HT). MAOA genotypes may modulate the vulnerability of this circuit and increase the risk for emotion regulation deficits after specific life events. Acute tryptophan depletion (ATD) challenges 5-HT regulation and may identify vulnerable neuronal circuits, contributing to the gene-environment interaction. METHODS: Functional magnetic resonance imaging measured the resting state state activity in 64 healthy males in a double-blind, placebo-controlled study. Cortical maps of amygdala correlation identified the impact of ATD and its interaction with low- (MAOA-L) and high-expression variants (MAOA-H) of MAOA on cortico-limbic connectivity. RESULTS: Across all Regions of Interest (ROIs) exhibiting an ATD effect on cortico-limbic connectivity, MAOA-L carriers were more susceptible to ATD than MAOA-H carriers. In particular, the MAOA-L group exhibited a larger reduction of amygdala connectivity with the right prefrontal cortex and a larger increase of amygdala connectivity with the insula and dorsal PCC. CONCLUSION: MAOA-L carriers were more susceptable to a central 5-HT challenge in cortico-limbic networks. Such vulnerability of the cortical serotonergic system may contribute to the emergence of antisocial behavior after systemic challenges, observed as gene-environment interaction. Hum Brain Mapp 38:1622-1635, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27935231 TI - Prolonged tacrolimus for pediatric gastrointestinal disorder: Double-edged sword? AB - BACKGROUND: Although tacrolimus (TAC) can induce remission in children with refractory inflammatory bowel disease (IBD) or autoimmune gastroenteropathy (AGE), its use in maintenance therapy remains controversial. The aim of this study was to investigate the potential nephrotoxic nature of prolonged TAC use. METHODS: This retrospective study reviewed children with gastrointestinal disorder who underwent kidney biopsy for the evaluation of renal damage during TAC therapy for >1 year. The clinical and histological features of renal damage were evaluated in this single-institution cohort. RESULTS: Eighteen of 121 children with IBD and two children with AGE followed at a national children hospital in Tokyo, Japan, received TAC between August 2006 and April 2013. Among them, five (Crohn's disease, n = 3; autoimmune gastropathy, n = 1; autoimmune enteropathy, n = 1) received TAC for >1 year, and underwent kidney biopsy. All five had achieved remission on TAC, but had histological evidence of chronic nephrotoxicity. Renal damage in one patient with relatively low TAC trough level remained mild. Estimated glomerular filtration rate (eGFR) at the time of kidney biopsy was lower than at the initiation of TAC in all four available patients. Among them, eGFR improved in one patient after the decrease or discontinuation of TAC. CONCLUSIONS: TAC appeared to be effective in children with refractory gastrointestinal disorder, but long-term use seems to cause irreversible renal damage. Rigorous monitoring of eGFR and kidney biopsy in selected cases should be considered for the proper adjustment of TAC. PMID- 27935232 TI - Prognostic Factors of Survival among Women with Metastatic Breast Cancer and Impact of Primary or Secondary Nature of Disease on Survival: A French Population Based Study. AB - We aim to determine whether differences in survival exist between two populations of women with metastatic breast cancer (MBC) and to identify prognostic factors of survival after metastasis diagnosis. Data on women with MBC diagnosed between 2000 and 2011 were provided by the Cote d'Or Breast cancer registry. Survival rates and median overall survival (OS) after metastasis diagnosis were determined using the Kaplan-Meier method and prognostic factors were determined in a Cox proportional hazard model. Overall, 282 women with primary MBC and 340 with secondary MBC were included. A 2-year survival rate was significantly better in women with primary MBC (50.8% [95% CI: 47.8-53.8%] versus 44.5% [95% CI: 41.8 47.2%]). However, median OS did not differ between the two groups (p = 0.1). The prognostic factors associated with worst survival were a triple-negative tumor type (p < 10-4 ), multiple metastases sites (p < 10-4 ), an older age at metastasis (p < 10-4 ), and a SBR grade G3 (p = 0.007). OS between women with primary MBC and women with secondary MBC does not seem to differ significantly. This population-based study provides original epidemiological data on French women without any selection bias inherent to hospital cohorts. PMID- 27935233 TI - Kinetic analysis of de novo centriole assembly in heat-shocked mammalian cells. AB - Mammalian cells are capable of de novo centriole formation after the removal of existing centrioles. This suggests that de novo centriole assembly is repressed in normally duplicating cells to maintain a constant number of centrioles in the cells. However, neither the mechanism of de novo centriole assembly nor that of its hypothesized repression is understood due to the lack of an experimental system. We found that the heat shock (HS; 42 degrees C, 2 h) of mouse embryonic fibroblasts caused the separation of centriole pairs, a transient increase in polo-like kinase (Plk) 4 expression, and the formation of a complex containing gamma-tubulin, pericentrin, HS protein (Hsp) 90, and Plk4, in approximately half of the cells. Subsequently, spindle-assembly abnormal protein (Sas) 6, centrosomal protein (Cep) 135, and centrin localized to the complex, and tubulin consequently became polyglutamylated, indicating de novo centriole assembly in the heat-shocked cells. These results suggested that HS-induced de novo centriole assembly could provide an experimental system for further elucidating the regulation of centrosome number in mammalian cells. (c) 2016 Wiley Periodicals, Inc. PMID- 27935234 TI - Analysis of antioxidative factors related to AMD risk development in the polish patients. AB - PURPOSE: Age-related macular degeneration (AMD) is a major cause of blindness in developed countries. Oxidative mechanisms may play a key role in the aetiology of AMD. The main aim of this study was to investigate antioxidative markers in the pathogenesis of AMD. METHODS: A total of 510 subjects including 240 patients with AMD (mean age 77.9 +/- 8.5 year) and 270 controls (mean age 74.0 +/- 10.4 year) were allowed in this study. We measured activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) and examined their association with the SNPs of respective genes (SOD1 + 35A/C, CAT C-262T and GPx Pro197Leu). Restriction fragment length polymorphism (RFLP) technique was used to determine the selected gene polymorphisms. Sixty subjects including 30 patients with AMD (mean age 69.4 +/- 9.3) and 30 controls (mean age 64.6 +/- 8.2) were enrolled to determine the activity of antioxidant enzymes by spectrometry method. RESULTS: A significant decrease in enzymes, SOD (p = 0.011), CAT (p = 0.002) and GPx (p <= 0.001) in AMD patients compared to controls, was indicated. The risk of susceptibility to AMD was significantly higher in patients with AMD who had Pro197Leu C/T genotype of GPx (OR = 2.78; 95% CI = 1.78-4.35). The A/C genotype and the C allele frequencies of A/C polymorphism of SOD1 gene significantly reduce the risk of AMD (OR=0.48; 95% CI 0.27; 0.85). CONCLUSION: In conclusion, our data showed that insufficient antioxidant capacity may have an important role in age-related macular degeneration. The polymorphism of GPx Pro197Leu may reduce the ability to scavenge free radicals in retina and contribute to the development of AMD. PMID- 27935235 TI - Bilateral tear film alterations in patients with unilateral quiescent herpes simplex keratitis. AB - PURPOSE: To evaluate bilateral tear function and corneal sensitivity in patients with unilateral quiescent herpes simplex keratitis (HSK) and determine the correlation between corneal sensitivity and tear secretion in both eyes. METHODS: Thirty-five patients diagnosed with unilateral quiescent HSK and 35 heathy controls were included in this study. Bilateral tear osmolarity, Schirmer's test, the tear break-up time (TBUT) and corneal sensitivity were measured in all participants. RESULTS: In the HSK group, both eyes demonstrated a significant increase in tear osmolarity, and a decrease in Schirmer's test and the TBUT compared with healthy controls (All p < 0.001). The bilateral tear osmolarity and Schirmer's test were similar, but the TBUT (4.9 +/- 2.1 versus 7.4 +/- 2.0 second; p < 0.001) and corneal sensitivity (35.1 +/- 1.9 versus 54.3 +/- 0.8 mm; p < 0.001) were significantly lower in the affected eyes. The bilateral tear osmolarity, Schirmer's test and the TBUT were significantly correlated with corneal sensitivity of the affected eye (All p < 0.001). When corneal sensitivity of the unaffected eye was treated as a control variable, tear osmolarity (R = 0.626, p < 0.001), Schirmer's test (R = 0.739, p < 0.001) and the TBUT (R = 0.691, p < 0.001) of the unaffected eyes were still significantly correlated with the corneal sensitivity of the affected eyes. CONCLUSIONS: Unilateral quiescent HSK causes bilateral tear impairment, which depends on the loss of corneal sensitivity in the affected eye. In the affected eye with severe corneal sensitivity loss, bilateral dry eye occurred. PMID- 27935236 TI - Ocular traumas in working age adults in Finland - Helsinki Ocular Trauma Study. AB - PURPOSE: To describe epidemiology, causes, treatments and outcomes of ocular injuries in adults aged 17 to 60 in southern Finland. METHODS: All new ocular trauma patients admitted to the Helsinki University Eye Hospital (HUEH), during 1 year in 2011-2012. The data were from hospital records and prospectively from patient questionnaires. The follow-up time was 3 months. RESULTS: The incidence for ocular injury was 88/100 000/year. From 831 trauma patients, 80% were men, 34% were work-related injuries, and 11% were assaults. Most of the injuries were minor traumas (54%). Contusions (22.5%) and chemical injuries and burns (13%) were common. Fractures (5%), lid wounds (3%), open globe injuries (OGI, 2%) and optic nerve injuries (0.5%) were rare. The main causes of ocular injury were superficial foreign bodies (33%), chemicals (13%), body parts (13%) and sports equipment (10%). The most dangerous objects were needles, stones, pellet guns, tools and guns. No patient with OGI used protective eyewear. All OGI and most of contusions needed a lifelong follow-up. Permanent impairment (73 patients, 9%) was caused most often by body parts, sports equipment and work tools. CONCLUSION: A typical ocular trauma patient was a man aged 31-45 with a minor trauma caused by a foreign body at work and a final visual acuity of 20/20. Most common serious injuries were contusion, OGI or fracture at home or at work and were caused by a body part, sport equipment or work tool. Factors causing common and serious eye injuries provide the targets for protective measures. PMID- 27935237 TI - Engineering Favorable Morphology and Structure of Fe-N-C Oxygen-Reduction Catalysts through Tuning of Nitrogen/Carbon Precursors. AB - Structures and morphologies of Fe-N-C catalysts are believed to be crucial because of the number of active sites and local bonding structures governing the overall catalyst performance for the oxygen reduction reaction (ORR). However, the knowledge how to rationally design catalysts is still lacking. By combining different nitrogen/carbon precursors, including polyaniline (PANI), dicyandiamide (DCDA), and melamine (MLMN), we aim to tune catalyst morphology and structure to facilitate the ORR. Instead of the commonly studied single precursors, multiple precursors were used during the synthesis; this provides a new opportunity to promote catalyst activity and stability through a likely synergistic effect. The best-performing Fe-N-C catalyst derived from PANI+DCDA is superior to the individual PANI or DCDA-derived ones. In particular, when compared to the extensively explored PANI-derived catalysts, the binary precursors have an increased half-wave potential of 0.83 V and an enhanced electrochemical stability in challenging acidic media, indicating a significantly increased number of active sites and strengthened local bonding structures. Multiple key factors associated with the observed promotion are elucidated, including the optimal pore size distribution, highest electrochemically active surface area, presence of dominant amorphous carbon, and thick graphitic carbon layers with more pyridinic nitrogen edge sites likely bonded with active atomic iron. PMID- 27935238 TI - Identification of novel disulfide adducts between the thiol containing leaving group of the nerve agent VX and cysteine containing tripeptides derived from human serum albumin. AB - Chemical warfare agents represent a continuous and considerable threat to military personnel and the civilian population. Such compounds are prohibited by the Chemical Weapons Convention, to which adherence by the member states is strictly controlled. Therefore, reliable analytical methods for verification of an alleged use of banned substances are required. Accordingly, current research focuses on long-term biomarkers derived from covalent adducts with biomolecules such as proteins. Recently, we have introduced a microbore liquid chromatography/electrospray ionization high-resolution tandem mass spectrometry method allowing for the investigation of two different classes of adducts of the nerve agent VX with human serum albumin (HSA). Phosphonylated tyrosine residues and novel disulfide adducts at cysteine residues of HSA were produced by enzymatic cleavage with pronase and detected simultaneously. Notably, the thiol containing leaving group of VX (2-(diisopropylamino)ethanethiol, DPAET) formed disulfide adducts that were released as cysteine and proline containing dipeptides originating from at least two different sites of HSA. Aim of this study was to identify assumed and novel adducts of DPAET with HSA using synthetic peptide reference compounds. Two novel tripeptides were identified representing disulfide adducts with DPAET (Met-Pro-Cys-DPAET, MPC-DPAET and Asp-Ile-Cys-DPAET, DIC-DPAET). MPC-DPAET was shown to undergo partial in-source decay during electrospray ionization for MS detection thereby losing the N-terminal Met residue. This results in the more stable Pro-Cys-DPAET (PC-DPAET) dipeptide detectable as protonated ion. The limit of detection for MPC-DPAET was evaluated, revealing toxicologically relevant VX plasma concentrations. The results provide novel insights into the reactivity of VX and its endogenous targets. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27935239 TI - Effect of galantamine on attention in patients with Alzheimer's disease combined with cerebrovascular disease. AB - AIM: Patients with Alzheimer's disease (AD) and cerebrovascular disease (CVD) show greater attentional deficits compared with AD patients without CVD. The aim of the present study was to investigate the effect of galantamine on attention in AD patients with CVD. METHODS: In this open trial, 1512 patients with AD and CVD were recruited from 71 nationwide hospitals. The patients were given galantamine for 16 weeks. The primary outcome measure was the score on the Attention Questionnaire Scale (AQS), which measures the patients' attention in their daily lives. The secondary outcome measures were the scores on the Korean Mini-Mental State Examination, the Clinical Dementia Rating scale and the Global Deterioration Scale. Efficacy measures were calculated both at baseline and at the end of the treatment (week 16). RESULTS: The responders rate on the AQS (change of the AQS from baseline >0) was 60.6% in AD patients with CVD. At the end of the treatment, both the AQS (15.0 +/- 5.7 vs 16.3 +/- 5.8, P < 0.001) and the Korean Mini-Mental State Examination scores (17.8 +/- 4.8 vs 18.1 +/- 5.1, P < 0.001) showed a significant improvement relative to the baseline performance. The Clinical Dementia Rating (1.25 +/- 0.59 vs 1.22 +/- 0.63 P = 0.025) and Global Deterioration Scale (3.82 +/- 0.94 vs 3.76 +/- 0.96, P = 0.002) scores also showed a significant decrease at the end of the treatment. CONCLUSIONS: Galantamine is effective in improving attention in the daily lives of AD patients with CVD. Geriatr Gerontol Int 2017; 17: 1661-1668. PMID- 27935241 TI - What training and skills will the ecotoxicologists of the future require? AB - Students and academic researchers conduct a diverse range of studies that add to the growing body of ecotoxicology research. Once an academic researcher entertains an applied research topic, there is potential for that research to be used in local, state, or federal regulatory decision or action. The ability of regulatory decision makers to use academic studies to inform decisions is dependent on: 1) the relevance of the experiment to regulatory decisions, 2) the reliability of the laboratory and the study itself, and 3) quality reporting of data such that study relevance and reliability are evident. The purpose of this brief communication is to highlight actions that can be taken by Society of Environmental Toxicology and Chemistry members to enhance the usability of academic research studies in regulatory decision making by promoting training, partnerships, and communication. Integr Environ Assess Manag 2017;13:580-584. (c) 2016 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC). PMID- 27935240 TI - Effects of liraglutide on cardiovascular risk factors in patients with type 1 diabetes. AB - We investigated the short-term effect of adding liraglutide 1.8 mg once daily to insulin treatment on cardiovascular risk factors in patients with type 1 diabetes. In total, 100 overweight (BMI >=25 kg/m2 ) adult patients (age >=18 years) with type 1 diabetes and HbA1c >= 8% (64 mmol/mol) were randomized to liraglutide 1.8 mg or placebo added to insulin treatment in a 24-week double blinded, placebo-controlled trial. At baseline and after 24 weeks of treatment, 24-hour blood pressure and heart rate, pulse pressure, pulse wave velocity and carotid intima-media thickness were evaluated. Compared with placebo, liraglutide increased 24-hour heart rate by 4.6 beats per minute (BPM); P = .0015, daytime heart rate by 3.7; P = .0240 and night-time heart rate by 7.5 BPM; P < .001 after 24 weeks. Diastolic nocturnal blood pressure increased by 4 mm Hg; P = .0362 in the liraglutide group compared with placebo. In conclusion, in patients with long standing type 1 diabetes, liraglutide as add-on to insulin increased heart rate and did not improve other cardiovascular risk factors after 24 weeks of treatment. PMID- 27935242 TI - Autonomic & Autacoid Pharmacology 2016: The year in review. PMID- 27935243 TI - MoCDC14 is important for septation during conidiation and appressorium formation in Magnaporthe oryzae. AB - As a typical foliar pathogen, appressorium formation and penetration are critical steps in the infection cycle of Magnaporthe oryzae. Because appressorium formation and penetration are closely co-regulated with the cell cycle, and Cdc14 phosphatases have an antagonistic relationship with cyclin-dependent kinases (CDKs) on proteins related to mitotic exit and cytokinesis, in this study, we functionally characterized the MoCDC14 gene in M. oryzae. The Mocdc14 deletion mutant showed significantly reduced growth rate and conidiation. It was also defective in septum formation and nuclear distribution. Septation was irregular in Mocdc14 hyphae and hyphal compartments became multi-nucleate. Mutant conidia often showed incomplete septa or lacked any septum. During appressorium formation, the septum delimiting appressoria from the rest of the germ tubes was often formed far away from the neck of the appressoria or not formed at all. Unlike the wild-type, some mutant appressoria had more than one nucleus at 24 h. In addition to appressoria, melanization occurred on parts of the germ tubes and conidia, depending on the irregular position of the appressorium-delimiting septum. The Mocdc14 mutant was also defective in glycogen degradation during appressorium formation and appressorial penetration of intact plant cells. Similar defects in septum formation, melanization and penetration were observed with appressorium-like structures formed at hyphal tips in the Mocdc14 mutant. Often a long fragment of mutant hyphae was melanized, together with the apical appressorium-like structures. These results indicate that MoCDC14 plays a critical role in septation, nuclear distribution and pathogenesis in M. oryzae, and correct septum formation during conidiogenesis and appressorium formation requires the MoCdc14 phosphatase. PMID- 27935244 TI - Different Enzymatic Processing of gamma-Phosphoramidate and gamma-Phosphoester Modified ATP Analogues. AB - Monitoring the activity of ATP-consuming enzymes provides the basis for elucidating their modes of action and regulation. Although a number of ATP analogues have been developed for this, their scope is restricted because of the limited acceptance by respective enzymes. In order to clarify which kind of phosphate-modified ATP analogues are accepted by the alpha-beta-phosphoanhydride cleaving ubiquitin-activating enzyme 1 (UBA1) and the beta-gamma-phosphoanhydride cleaving focal adhesion kinase (FAK), we tested phosphoramidate- and phosphoester modified ATP analogues. UBA1 and FAK were able to convert phosphoramidate modified ATP analogues, even with a bulky modification like biotin. In contrast, a phosphoester-modified analogue was poorly accepted. These results demonstrate that minor variations in the design of ATP analogues for monitoring ATP utilization have a significant impact on enzymatic acceptance. PMID- 27935245 TI - Modeling the effects of lattice defects on microtubule breaking and healing. AB - Microtubule reorganization often results from the loss of polymer induced through breakage or active destruction by energy-using enzymes. Pre-existing defects in the microtubule lattice likely lower structural integrity and aid filament destruction. Using large-scale molecular simulations, we model diverse microtubule fragments under forces generated at specific positions to locally crush the filament. We show that lattices with 2% defects are crushed and severed by forces three times smaller than defect-free ones. We validate our results with direct comparisons of microtubule kinking angles during severing. We find a high statistical correlation between the angle distributions from experiments and simulations indicating that they sample the same population of structures. Our simulations also indicate that the mechanical environment of the filament affects breaking: local mechanical support inhibits healing after severing, especially in the case of filaments with defects. These results recall reports of microtubule healing after flow-induced bending and corroborate prior experimental studies that show severing is more likely at locations where microtubules crossover in networks. Our results shed new light on mechanisms underlying the ability of microtubules to be destroyed and healed in the cell, either by external forces or by severing enzymes wedging dimers apart. (c) 2016 Wiley Periodicals, Inc. PMID- 27935246 TI - Determination of a metabolite of nifursol in foodstuffs of animal origin by liquid-liquid extraction and liquid chromatography with tandem mass spectrometry. AB - An analytical method has been developed for the detection of a metabolite of nifursol, 3,5-dinitrosalicylic acid hydrazide, in foodstuffs of animal origin (chicken liver, pork liver, lobster, shrimp, eel, sausage, and honey). The method combines liquid chromatography and tandem mass spectrometry with liquid-liquid extraction. Samples were hydrolyzed with hydrochloric acid and derivatized with 2 nitrobenzaldehyde at 37 degrees C for 16 h. The solutions of derivatives were adjusted to pH 7.0-7.5, and the metabolite was extracted with ethyl acetate. 3,5 Dinitrosalicylic acid hydrazide determination was performed in the negative electrospray ionization method. Both isotope-labeled internal standard and matrix matched calibration solutions were used to correct the matrix effects. Limits of quantification were 0.5 MUg/kg for all samples. The average recoveries, measured at three concentration levels (0.5, 2.0, and 10 MUg/kg) were in the range of 75.8 108.4% with relative standard deviations below 9.8%. The developed method exhibits a high sensitivity and selectivity for the routine determination and confirmation of the presence of a metabolite of nifursol in foodstuffs of animal origin. PMID- 27935247 TI - Focusing on situation-specific expectations in major depression as basis for behavioural experiments - Development of the Depressive Expectations Scale. AB - OBJECTIVES: Dysfunctional expectations are considered to be core features of various mental disorders. The aim of the study was to develop the Depressive Expectations Scale (DES) as a depression-specific measure for the assessment of dysfunctional expectations. Whereas previous research primarily focused on general cognitions and attitudes, the DES assesses 25 future-directed expectations (originally 75 items) which are situation-specific and falsifiable. DESIGN AND METHODS: To evaluate the psychometric properties of the DES, the scale was completed by 175 participants with and without severe depressive symptoms in an online survey. Participants additionally completed the Patient Health Questionnaire modules for depression (PHQ-9) and anxiety (GAD-7). People experiencing depressive symptoms were informed about the study with the help of self-help organizations. RESULTS: Reliability analyses indicated excellent internal consistency of the scale. An exploratory factor analyses revealed four factors: social rejection, social support, mood regulation, and ability to perform. The DES sum score strongly correlated with the severity of depressive symptoms. The DES sum score also significantly correlated with symptoms of generalized anxiety. CONCLUSION: The DES was shown to have excellent reliability; validity analyses were promising. As the DES items are situation-specific and falsifiable, they can be tested by the individual using behavioural experiments and may therefore facilitate cognitive restructuring. Thus, a structured assessment of patients' expectation with help of the DES can provide a basis for interventions within cognitive-behavioural treatment of depression. PRACTITIONER POINTS: Assessing situation-specific expectations in patients experiencing depressive symptoms can provide a basis for the conduction of behavioural experiments to test patients' expectations. For the use of behavioural experiments, therapists should choose those dysfunctional expectations which a patient strongly agrees on. To modify patients' expectations, they should be exposed to situations where the discrepancy between patients' expectations and actual situational outcomes can be maximized. The Depressive Expectations Scale can be completed repeatedly to monitor a patient's progress within cognitive behavioural treatment. PMID- 27935248 TI - Cisplatin Primary Complex with l-Histidine Target Revealed by IR Multiple Photon Dissociation (IRMPD) Spectroscopy. AB - The primary complex obtained from cisplatin and l-histidine in water has been detected and isolated by electrospray ionization. The so-obtained cis-[PtCl(NH3 )2 (histidine)]+ complex has been characterized in detail by high-resolution mass spectrometry (MS), tandem MS, IR multiple photon dissociation (IRMPD) spectroscopy, and by quantum chemical calculations. The structural features revealed by IRMPD spectroscopy indicate that platinum binds to the imidazole group, which presents tautomeric forms. Thus, depending on the position of the amino acid pendant on the imidazole ring, isomeric complexes are formed that are remarkably different with respect to the ease with which they undergo fragmentation when activated either by energetic collisions or by multiple IR photon absorption. It is shown here how IRMPD kinetics can allow their relative proportions to be estimated. PMID- 27935249 TI - In-capillary probing of quantum dots and fluorescent protein self-assembly and displacement using Forster resonance energy transfer. AB - Herein, a Forster resonance energy transfer system was designed, which consisted of CdSe/ZnS quantum dots donor and mCherry fluorescent protein acceptor. The quantum dots and the mCherry proteins were conjugated to permit Forster resonance energy transfer. Capillary electrophoresis with fluorescence detection was used for the analyses for the described system. The quantum dots and mCherry were sequentially injected into the capillary, while the real-time fluorescence signal of donor and acceptor was simultaneously monitored by two channels with fixed wavelength detectors. An effective separation of complexes from free donor and acceptor was achieved. Results showed quantum dots and hexahistidine tagged mCherry had high affinity and the assembly was affected by His6 -mCherry/quantum dot molar ratio. The kinetics of the self-assembly was calculated using the Hill equation. The microscopic dissociation constant values for out of- and in capillary assays were 10.49 and 23.39 MUM, respectively. The capillary electrophoresis with fluorescence detection that monitored ligands competition assay further delineated the different binding capacities of histidine containing peptide ligands for binding sites on quantum dots. This work demonstrated a novel approach for the improvement of Forster resonance energy transfer for higher efficiency, increased sensitivity, intuitionistic observation, and low sample requirements of the in-capillary probing system. PMID- 27935250 TI - Apolipoprotein E (epsilon) genotype has a greater impact on apoB-48 than apoB-100 responses to dietary fat manipulation-insights from the SATgenepsilon study. AB - SCOPE: To determine the contribution of intestinally and liver-derived lipoproteins to the postprandial plasma triacylglycerol (TAG) response in APOE3/E3 and E3/E4 individuals following chronic dietary fat manipulation. METHODS AND RESULTS: In sequential order, participants (n = 12 E3/E3, n = 11 E3/E4) followed low fat; high-fat, high-saturated fat (HSF); and HSF with 3.45 g/day docosahexaenoic acid (HSF-DHA) diets, each for 8 weeks. After each dietary period, an acute test meal with a macronutrient profile representative of the dietary intervention was consumed. Apolipoprotein (apo)B isoforms were determined in isolated TAG-rich lipoprotein fractions (Svedberg flotation rate (Sf ) > 400, Sf 60-400, and Sf 20-60) by specific ELISA. A genotype * meal/diet interaction for the Sf > 400 fraction apoB-48 response (p < 0.05) was observed, with higher concentrations reached after the low fat than HSF-DHA meal in E4 carriers. This finding was associated with a lower TAG content of the Sf > 400 particles. Fasting Sf 60-400 and 20-60 apoB-48 concentrations were also significantly higher in E4 carriers. No impact of genotype on the apoB-100 responses was evident. CONCLUSION: Our study revealed marked effects of dietary fat composition on the Sf > 400 apoB-48 response and particle TAG content in E4 carriers relative to the "wild-type" E3/E3 genotype, which suggest APOE genotype is a potential modulator of chylomicron particle synthesis. PMID- 27935251 TI - Simultaneous determination of 35 ultra-trace level organophosphorus pesticide residues in Sanjie Zhentong capsules of traditional Chinese medicine using ultra high performance liquid chromatography with tandem mass spectrometry. AB - The aim of this study was to develop an analytical method for the simultaneous determination of ultra-trace levels of 35 organophosphorus pesticide residues in Sanjie Zhentong capsules, a traditional Chinese medicine prescription. A method based on multiclass and multiresidue sample preparation was developed. First, samples were hydrated with water at 4 degrees C. A ratio of 1:3 sample/water was used for each of the sample amounts. Then, different extraction solvents were screened. This step was followed by a dispersive solid-phase extraction clean-up procedure using both primary secondary amine and polyamide. A comprehensive sensitive multiresidue liquid chromatography tandem mass spectrometry method was investigated and validated. Good linearity was achieved in the range of 10-500 MUg/kg for each analyte. The average recovery ranged from 70 to 120%, except for methamidophos, fonophos, diazinon, and chlorpyriphos-ethyl, the recoveries of which ranged from 60-70% at the lower concentration level. The precision values were lower than 10% for all the compounds in three concentration levels. The limits of detection and limits of quantification values were 0.01-2.1 and 0.05 3.4 MUg/kg, respectively. The matrix effects were determined, and most of the compounds showed signal suppression. Finally, this optimized procedure was applied for the analysis of real samples. PMID- 27935252 TI - Innovative method for the enrichment of high-polarity bioactive molecules present at low concentrations in complex matrices. AB - Ginsenoside Rg1 is a valuable bioactive molecule but its high polarity and low concentration in complex mixtures makes it a challenge to separate Ginsenoside Rg1 from other saponins with similar structures, resulting in low extraction efficiency. The successful development of effective Rg1 molecularly imprinted polymers that exhibit high selectivity and adsorption may offer an improved method for the enrichment of active compounds. In this work, molecularly imprinted polymers were prepared with two different methods, precipitation polymerization or surface imprinted polymerization. Comparison of the adsorption abilities showed higher adsorption of the surface molecularly imprinted polymers prepared by surface imprinted polymerization, 46.80 mg/g, compared to the 27.74 mg/g observed for the molecularly imprinted polymers prepared by precipitation polymerization. Therefore, for higher adsorption of the highly polar Rg1, surface imprinted polymerization is a superior technique to make Rg1 molecularly imprinted polymers. The prepared surface molecularly imprinted polymers were tested as a solid-phase extraction column to directionally enrich Rg1 and its analogues from ginseng tea and total ginseng extracts. The column with surface molecularly imprinted polymers showed higher enrichment efficiency and better selectivity than a C18 solid-phase extraction column. Overall, a new, innovative method was developed to efficiently enrich high-polarity bioactive molecules present at low concentrations in complex matrices. PMID- 27935253 TI - Shape Controlled Plasmonic Sn Doped CdO Colloidal Nanocrystals: A Synthetic Route to Maximize the Figure of Merit of Transparent Conducting Oxide. AB - The synthesis of different anisotropic shaped (eight different shapes) Sn4+ doped CdO (Sn:CdO) colloidal nanocrystals (NCs) by precise tuning of precursor reactivity and proper choice of capping agent is reported. In all these systems, formation of Sn:CdO quantum dots (QDs) of 2-3 nm is identified at very early stage of reaction. The colloidally stable QDs act as a continuous source for the formation of primary nanoparticles that can be transformed selectively into specific type of nanoparticle morphology. The specific facet stabilization of fcc (face centered cubic)CdO is predicted by particular choice of ligand. Fine tuning of plasmonic absorbance band can be achieved by variation of Sn4+ doping concentration. Different anisotropic Sn:CdO NCs exhibit interesting shape dependent plasmonic absorbance features in NIR region. High quality crack free uniform dense thin film has been deposited on glass substrate to make high quality transparent conducting oxide (TCO) coatings. figure of merit of TCO can be maximized as high as 0.523 Omega-1 with conductivity of 43 600 S cm-1 and visible transmittance of ~85% which is much higher than commercially available tin doped indium oxide and other transparent electrodes. PMID- 27935254 TI - Application of solid-phase microextraction with gas chromatography and mass spectrometry for the early detection of active moulds on historical woollen objects. AB - The goal of this work was to determine the microbial volatile organic compounds emitted by moulds growing on wool in search of particular volatiles mentioned in the literature as indicators of active mould growth. The keratinolytically active fungi were inoculated on two types of media: (1) samples of wool placed on broths, and (2) on broths containing amino acids that are elements of the structure of keratin. All samples were prepared inside 20 mL vials (closed system). In the first case (1) the broths did not contain any sources of organic carbon, nitrogen, or sulfur, i.e. wool was the only nutrient for the moulds. A third type of sample was historical wool prepared in a Petri dish without a broth and inoculated with a keratinolytically active mould (open system). The microbial volatiles emitted by moulds were sampled with the headspace solid-phase microextraction method. Volatiles extracted on solid-phase microextraction fibers were analyzed in a gas chromatography with mass spectrometry system. Qualitative and quantitative analyses of chromatograms were carried out in search of indicators of metabolic activity. The results showed that there are three groups of volatiles that can be used for the detection of active forms of moulds on woollen objects. PMID- 27935255 TI - Multiple actinic keratoses induced by occupational UV exposure in a patient with preexisting disseminated superficial actinic porokeratosis (Chernosky-Freeman). PMID- 27935256 TI - Pigment Translocation in Caridean Shrimp Chromatophores: Receptor Type, Signal Transduction, Second Messengers, and Cross Talk Among Multiple Signaling Cascades. AB - Pigment aggregation in shrimp chromatophores is triggered by red pigment concentrating hormone (RPCH), a neurosecretory peptide whose plasma membrane receptor may be a G-protein coupled receptor (GPCR). While RPCH binding activates the Ca2+ /cGMP signaling cascades, a role for cyclic AMP (cAMP) in pigment aggregation is obscure, as are the steps governing Ca2+ release from the smooth endoplasmic reticulum (SER). A role for the antagonistic neuropeptide, pigment dispersing homone (alpha-PDH) is also unclear. In red, ovarian chromatophores from the freshwater shrimp Macrobrachium olfersi, we show that a G-protein antagonist (AntPG) strongly inhibits RPCH-triggered pigment aggregation, suggesting that RPCH binds to a GPCR, activating an inhibitory G-protein. Decreasing cAMP levels may cue pigment aggregation, since cytosolic cAMP titers, when augmented by cholera toxin, forskolin or vinpocentine, completely or partially impair pigment aggregation. Triggering opposing Ca2+ /cGMP and cAMP cascades by simultaneous perfusion with lipid-soluble cyclic nucleotide analogs induces a "tug-of-war" response, pigments aggregating in some chromatosomes with unpredictable, oscillatory movements in others. Inhibition of cAMP-dependent protein kinase accelerates aggregation and reduces dispersion velocities, suggesting a role in phosphorylation events, possibly regulating SER Ca2+ release and pigment aggregation. The second messengers IP3 and cADPR do not stimulate SER Ca2+ release. alpha-PDH does not sustain pigment dispersion, suggesting that pigment translocation in caridean chromatophores may be regulated solely by RPCH, since PDH is not required. We propose a working hypothesis to further unravel key steps in the mechanisms of pigment translocation within crustacean chromatophores that have remained obscure for nearly a century. PMID- 27935257 TI - Simplified capillary isoelectric focusing with chemical mobilization for intact protein analysis. AB - We report a capillary isoelectric focusing system based on a sequential injection method for simplified chemical mobilization. This system was coupled to an ion trap mass spectrometer with an electrokinetically pumped nanoelectrospray interface. The nanoelectrospray emitter employed an acidic sheath electrolyte. To simplify focusing and mobilization, a plug of ammonium hydroxide was first injected into the capillary, followed by a section of mixed sample and ampholyte. During focusing, the NH3 H2 O section worked as catholyte. As focusing progressed, the NH3 H2 O section was titrated to lower pH by the acidic sheath electrolyte. Chemical mobilization started automatically once the ammonium hydroxide was consumed by the acidic sheath flow electrolyte, which then acted as the mobilization solution. In this report, the lengths of the NH3 H2 O section and sample were optimized. With a 1 m long capillary, a relative short plug of the NH3 H2 O section (3 cm) produced both fast migration and reasonable separation resolution. The simplified capillary isoelectric focusing mass spectrometry system produced base peak intensity relative standard deviation of 8.5% and migration time relative standard deviation <=0.6% for myoglobin and cytochrome C in triplicate runs. PMID- 27935258 TI - Polyphenols from Lonicera caerulea L. berry attenuate experimental nonalcoholic steatohepatitis by inhibiting proinflammatory cytokines productions and lipid peroxidation. AB - SCOPE: Nonalcoholic steatohepatitis (NASH) is a common disease, which is closely associated with inflammation and oxidative stress, and Lonicera caerulea L. polyphenols (LCP) are reported to possess both antioxidant and anti-inflammatory properties. This study aimed to investigate the protective effects and mechanisms of LCP on NASH in a high-fat diet plus carbon tetrachloride (CCL4 ) induced mouse model. METHODS AND RESULTS: Mice were fed with high-fat diet containing LCP (0.5 1%) or not, and then administrated with CCL4 to induce NASH. Liver sections were stained by hematoxylin-eosin stain, serum transaminases and lipids were measured by clinical analyzer, insulin was examined by ELISA, cytokines were determined by multiplex technology, and hepatic proteins were detected by Western blotting. LCP improved histopathological features of NASH with lower levels of lipid peroxidation and cytokines including granulocyte colony-stimulating factor, IL-3, IL-4, macrophage inflammatory protein-1beta, IL-6, IL-5, keratinocyte-derived cytokine, tumor necrosis factor-alpha, IL-2, IL-1beta, monocytes chemotactic protein-1, IL-13, IFN-gamma, IL-10, IL-12(p70), IL-1alpha, eotaxin, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein-1alpha, IL 17, and RANTES. Further molecular analysis revealed that LCP increased the expression of nuclear factor (erythroid-derived 2)-like 2 and manganese-dependent superoxide dismutase, but decreased forkhead box protein O1 and heme oxygenase-1 in the liver of NASH mice. CONCLUSION: Dietary supplementation of LCP ameliorates inflammation and lipid peroxidation by upregulating nuclear factor (erythroid derived 2)-like 2 and manganese-dependent superoxide dismutase, and downregulating forkhead box protein O1 and heme oxygenase-1 in NASH. PMID- 27935259 TI - Manuka honey sinus irrigation for the treatment of chronic rhinosinusitis: a randomized controlled trial. AB - BACKGROUND: Manuka honey (MH) has been shown in vitro to be effective against biofilm-producing bacteria. This study assessed the effectiveness of MH for patients with active chronic rhinosinusitis (CRS) and prior sinus surgery. METHODS: This prospective single-blinded (clinician only) randomized controlled trial recruited patients with active CRS and prior sinus surgery. Patients received either MH or saline (SAL) sinus irrigations twice daily for 30 days and were offered oral antibiotics and/or oral/topical steroids as indicated. Outcomes were 22-item Sino-Nasal Outcome Test (SNOT-22) change score (primary), culture negativity, and Lund-Kennedy endoscopic change score. RESULTS: Forty-two patients were analyzed (MH, n = 20; SAL, n = 22). The SNOT-22 change score achieved a clinically significant improvement in both groups but was similar between MH (median [interquartile range]: -12 [-20, -1]) and SAL (-12.5 [-22, -6]) (p = 0.57). Culture negativity was better on MH (8/19, 42%) compared to SAL (4/21, 19%), nearing statistical significance (p = 0.11). Lund-Kennedy endoscopic change score improved in both groups but was not statistically better on MH (-3 [-5, 0]) compared to SAL (-1 [-2, 0]) (p = 0.20). For patients not receiving oral antibiotics/steroids, culture negativity was statistically better on MH (5/10, 50%) compared to SAL (0/6, 0%) (p = 0.04). MH was well-tolerated. No adverse events were reported. CONCLUSION: In patients with active CRS and prior sinus surgery, both MH and SAL improved outcomes, but there was no statistically significant difference between these groups. However, in the subset that did not receive oral antibiotics/steroids, culture negativity was statistically better on MH, suggesting that MH alone may be effective for acute exacerbations of CRS. PMID- 27935260 TI - In vitro studies on flubromazolam metabolism and detection of its metabolites in authentic forensic samples. AB - Flubromazolam is a triazole benzodiazepine with high potency and long-lasting central nervous system depressant effects; however, limited data about its pharmacokinetics are available. Here, we report in vitro studies of the human flubromazolam metabolism analyzed by liquid chromatography high-resolution mass spectrometry (LC-HRMS). In vitro investigations were carried out in pooled human liver microsomes (pHLM) and recombinant cytochrome P450 (CYP)-enzymes. To confirm those metabolites detected in vitro, authentic samples obtained from two forensic cases were also analyzed by LC-HRMS. Additionally, determination of the unbound fraction of flubromazolam in pHLM and in plasma was performed by equilibrium dialysis with subsequent prediction of its hepatic clearance (CLH ) using well stirred and parallel-tube models. Additional findings obtained by routine screening methods of these forensic cases are also reported. Studies using incubations with nicotinamide adenine dinucleotide phosphate-fortified pHLM with or without uridine 5'-diphosphoglucuronic acid and incubations with CYP-enzymes identified the main metabolic pathway of flubromazolam as hydroxylation on the alpha- and/or 4-position mediated by CYP3A4 and CYP3A5, with subsequent glucuronidation of the hydroxylated metabolites as well as of the parent drug. Further, alpha-hydroxy-flubromazolam and its corresponding glucuronide were detected in vivo together with the N-glucuronide of flubromazolam. The predicted CLH of flubromazolam using the well-stirred and parallel-tube models were 0.42 and 0.43 mL/min/kg, respectively. Based on the data presented here, flubromazolam is primarily metabolized by CYP3A4/5 with a high protein-binding and a predicted low clearance. Analysis of authentic samples suggested that analytical targets for flubromazolam should be the compound itself and alpha-hydroxy-flubromazolam. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27935261 TI - Matrix rigidity regulates microtubule network polarization in migration. AB - The microtubule organizing center (MTOC) frequently polarizes to a position in front of the nucleus during cell migration, but recent work has shown conflicting evidence for MTOC location in migratory polarized cells. Here, we show that subcellular localization of the MTOC is modulated by extracellular matrix stiffness. In scratch wound assays as well as single cell migration of mesenchymal stem cells (MSCs) the MTOC appears randomly positioned when cells are migrating on soft matrix, whereas on stiff matrix the MTOC is in front of the nucleus. The bulk of the microtubule density is also equally likely to be in front of or behind the nucleus on soft matrix, but it is polarized in front of the nucleus on stiff matrix. This occurred during cell migration with cells in interphase. During cytokinesis, the centrosomes polarize on either side of the chromosomes even on soft matrix, with MIIB localized strongly in the cleavage furrow which depolarizes only on soft matrix as cells exit cytokinesis. When cells are immobilized on micro-patterns printed on the top of substrates of different stiffness, MIIB polarized if the matrix was sufficiently stiff similar to results with migrating cells. However, the MTOC was randomly positioned with respect to the nucleus independent of matrix stiffness. We deduce that cell migration is necessary to orient the MTOC in front of the nucleus and that matrix stiffness helps to drive cell polarization during migration. (c) 2016 Wiley Periodicals, Inc. PMID- 27935262 TI - Elastic tethers between separating anaphase chromosomes in crane-fly spermatocytes coordinate chromosome movements to the two poles. AB - Separating anaphase chromosomes in crane-fly spermatocytes are connected by elastic tethers, as originally described by LaFountain et al. (2002): telomere containing arm fragments severed from the arms move backwards to the partner telomeres. We have tested whether the tethers coordinate the movements of separating partner chromosomes. In other cell types anaphase chromosomes move faster, temporarily, when their kinetochore microtubules are severed. However, in crane-fly spermatocytes the chromosomes move at their usual speed when their kinetochore microtubules are severed. To test whether the absence of increased velocity is because tethers link the separating chromosomes and coordinate their movements, we cut tethers with a laser microbeam and then cut the kinetochore microtubules. After this procedure, the associated chromosome sped up, as in other cells. These results indicate that the movements of partner anaphase chromosomes in crane-fly spermatocytes are coordinated by elastic tethers connecting the two chromosomes and confirm that chromosomes speed up in anaphase when their kinetochore microtubules are severed. (c) 2016 Wiley Periodicals, Inc. PMID- 27935263 TI - New glycemic targets for patients with diabetes from the Japan Diabetes Society. AB - In the 'Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013', a new concept of the glycemic control in patients with diabetes in Japan has been declared from the Japan Diabetes Society. The main objective value of HbA1c was set to <7% from the perspective of preventing microvascular complications. On the other hand, the objective in cases where objectives can be attained by appropriate dietary or exercise therapy, or during pharmacotherapy without the occurrence of side effects such as hypoglycemia was set to <6%, and the objective in cases where intensification of treatment was considered difficult due to side effects such as hypoglycemia or for other reasons was set to <8%. Treatment objectives should be established individually, in consideration of age, duration of disease, organ damage, risk of hypoglycemia, support structure, and etc. PMID- 27935264 TI - Improved delivery of sinus irrigations after middle turbinate resection during endoscopic sinus surgery. AB - BACKGROUND: Improvement in topical delivery to nasal mucosa is a fundamental goal of endoscopic sinus surgery (ESS). This study compares the penetration of irrigation before and after middle turbinate resection (MTR) to assess the efficacy of topical delivery. METHODS: ESS was performed on 4 cadaver heads, followed by MTR. Each head was irrigated with fluorescein-dyed water using a squeeze bottle both before and after MTR. Videos were recorded by rigid nasal endoscopy. Four blinded raters reviewed videos and scored the extent of staining (0 to 3) for each site. RESULTS: The mean score for the extent of staining of all anatomical sites before and after MTR was 1.30 and 1.92, respectively (p = 0.035). The mean score for extent of staining before and after MTR was 2.56 and 2.81 (p = 0.134) for the maxillary sinus, 1.66 and 2.25 (p = 0.022) for the ethmoid sinus, 1.03 and 1.94 (p = 0.263) for the sphenoid sinus, 0.16 and 0.94 (p = 0.055) for the frontal sinus, and 1.09 and 1.66 (p = 0.340) for the olfactory cleft, respectively. When evaluating interrater reliability, Cronbach's alpha was 0.92, which is acceptable. When evaluating intrarater reliability, the Fleiss kappa statistic for each rater was excellent or good. CONCLUSION: Overall, MTR results in significant improvement in the penetration of nasal irrigations in the cadaver model. Each individual sinus displays a trend toward improvement; however, only the ethmoid sinus displays a statistically significant improvement. Further in vivo studies are needed to elucidate the role of MTR. PMID- 27935266 TI - Study of Electrochemical Reduction of CO2 for Future Use in Secondary Microbial Electrochemical Technologies. AB - The fluctuation and decentralization of renewable energy have triggered the search for respective energy storage and utilization. At the same time, a sustainable bioeconomy calls for the exploitation of CO2 as feedstock. Secondary microbial electrochemical technologies (METs) allow both challenges to be tackled because the electrochemical reduction of CO2 can be coupled with microbial synthesis. Because this combination creates special challenges, the electrochemical reduction of CO2 was investigated under conditions allowing microbial conversions, that is, for their future use in secondary METs. A reproducible electrodeposition procedure of In on a graphite backbone allowed a systematic study of formate production from CO2 with a high number of replicates. Coulomb efficiencies and formate production rates of up to 64.6+/-6.8 % and 0.013+/-0.002 mmolformate h-1 cm-2 , respectively, were achieved. Electrode redeposition, reusability, and long-term performance were investigated. Furthermore, the effect of components used in microbial media, that is, yeast extract, trace elements, and phosphate salts, on the electrode performance was addressed. The results demonstrate that the integration of electrochemical reduction of CO2 in secondary METs can become technologically relevant. PMID- 27935267 TI - Adipocyte size redux. PMID- 27935265 TI - Modelling mitral valvular dynamics-current trend and future directions. AB - Dysfunction of mitral valve causes morbidity and premature mortality and remains a leading medical problem worldwide. Computational modelling aims to understand the biomechanics of human mitral valve and could lead to the development of new treatment, prevention and diagnosis of mitral valve diseases. Compared with the aortic valve, the mitral valve has been much less studied owing to its highly complex structure and strong interaction with the blood flow and the ventricles. However, the interest in mitral valve modelling is growing, and the sophistication level is increasing with the advanced development of computational technology and imaging tools. This review summarises the state-of-the-art modelling of the mitral valve, including static and dynamics models, models with fluid-structure interaction, and models with the left ventricle interaction. Challenges and future directions are also discussed. PMID- 27935269 TI - From adolescent to elder rats: Motivation for palatable food and cannabinoids receptors. AB - To analyze motivation, food self-administration and decision-making were evaluated in adolescent, adult, and aged rats. Subjects were trained to press a lever (fixed ratio, FR1 and FR5) in an operant chamber, to obtain chocolate flavor pellets. They assessed the progressive ratio (PR), extinction, and reinstatement of the behavior. To estimate decision-making for food, rats were trained in the conditioned place preference (CPP) paradigm: (a) associating one compartment with lab chow (LCh) one day and the other compartment with rice krisspies (RK), the next day. (b) Training similar to (a) but on the day RK was the reinforcer, it was delivered with a progressive delay. In addition, CB1 and CB2 receptor expression in the nucleus accumbens (NAcc) and prefrontal cortex (PFC) was estimated by means of Western blot. Adolescent rats consumed higher amounts of RK/body weight than adult and aged rats during FR1, FR5, and PR. Extinction was more prolonged for adolescent rats than for adult and aged rats. First CPP condition, all three groups of rats preferred the RK-associated compartment. Second CPP condition, adolescent rats developed equal preference to both compartments, while adult and aged rats preferred the RK-associated compartment. Rats per group ate a similar amount of either reinforcer. Adolescent rats exhibited low expression of CB1R in the NAcc and low expression of both CB1R and CB2R in the PFC compared with adult and aged rats. Adolescent rats display higher motivation for palatable food and an indiscriminate seeking behavior suggesting involvement of both homeostatic and hedonic systems in their decision making processes. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 917-927, 2017. PMID- 27935270 TI - Visible-Light-Promoted Activation of Unactivated C(sp3)-H Bonds and Their Selective Trifluoromethylthiolation. AB - Selective functionalization of ubiquitous C(sp3)-H bonds using visible light is a highly challenging yet desirable goal in organic synthesis. The development of such processes relies on both rational design and serendipitous discoveries from innovative tools such as screening technologies. Applying a mechanism-based screening strategy, we herein report photoredox-mediated hydrogen atom transfer catalysis for the selective activation of otherwise unactivated C(sp3)-H bonds, followed by their trifluoromethylthiolation, which has high potential as a late stage functionalization tool. The generality of this method is exhibited through incorporation of the trifluoromethylthio group in a large number of C(sp3)-H bonds with high selectivity without the need for an excess of valuable substrate. PMID- 27935268 TI - Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter. AB - Morphine shows large interindividual variability in its pharmacokinetics; however, the cause of this has not been fully addressed. The variability in morphine disposition is considered to be due to a combination of pharmacogenetic and physiological determinants related to morphine disposition. We previously reported the effect of organic cation transporter (OCT1) genotype on morphine disposition in pediatric patients. To further explore the underlying mechanisms for variability arising from relevant determinants, including OCT1, a physiologically based pharmacokinetic (PBPK) model of morphine was developed. The PBPK model predicted morphine concentration-time profiles well, in both adults and children. Almost all of the observed morphine clearances in pediatric patients fell within a twofold range of median predicted values for each OCT1 genotype in each age group. This PBPK modeling approach quantitatively demonstrates that OCT1 genotype, age-related growth, and changes in blood flow as important contributors to morphine pharmacokinetic (PK) variability. PMID- 27935271 TI - Self-Powered Random Number Generator Based on Coupled Triboelectric and Electrostatic Induction Effects at the Liquid-Dielectric Interface. AB - Modern cryptography increasingly employs random numbers generated from physical sources in lieu of conventional software-based pseudorandom numbers, primarily owing to the great demand of unpredictable, indecipherable cryptographic keys from true random numbers for information security. Thus, far, the sole demonstration of true random numbers has been generated through thermal noise and/or quantum effects, which suffers from expensive and complex equipment. In this paper, we demonstrate a method for self-powered creation of true random numbers by using triboelectric technology to collect random signals from nature. This random number generator based on coupled triboelectric and electrostatic induction effects at the liquid-dielectric interface includes an elaborately designed triboelectric generator (TENG) with an irregular grating structure, an electronic-optical device, and an optical-electronic device. The random characteristics of raindrops are harvested through TENG and consequently transformed and converted by electronic-optical device and an optical-electronic device with a nonlinear characteristic. The cooperation of the mechanical, electrical, and optical signals ensures that the generator possesses complex nonlinear input-output behavior and contributes to increased randomness. The random number sequences are deduced from final electrical signals received by an optical-electronic device using a familiar algorithm. These obtained random number sequences exhibit good statistical characteristics, unpredictability, and unrepeatability. Our study supplies a simple, practical, and effective method to generate true random numbers, which can be widely used in cryptographic protocols, digital signatures, authentication, identification, and other information security fields. PMID- 27935272 TI - Precast Gelatin-Based Molds for Tissue Embedding Compatible with Mass Spectrometry Imaging. AB - Preparation of tissue for matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) generally involves embedding the tissue followed by freezing and cryosectioning, usually between 5 and 25 MUm thick, depending on the tissue type and the analyte(s) of interest. The brain is approximately 60% fat; it therefore lacks rigidity and poses structural preservation challenges during sample preparation. Histological sample preparation procedures are generally transferable to MALDI-MSI; however, there are various limitations. Optimal cutting temperature compound (OCT) is commonly used to embed and mount fixed tissue onto the chuck inside the cryostat during cryosectioning. However, OCT contains potential interferences that are detrimental to MALDI-MSI, while fixation is undesirable for the analysis of some analytes either due to extraction or chemical modification (i.e., polar metabolites). Therefore, a method for both fixed and fresh tissue compatible with MALDI-MSI and histology is desirable to increase the breadth of analyte(s), maintain the topographies of the brain, and provide rigidity to the fragile tissue while eliminating background interference. The method we introduce uses precast gelatin-based molds in which a whole mouse brain is embedded, flash frozen, and cryosectioned in preparation for mass spectrometry imaging (MSI). PMID- 27935273 TI - Are Graphitic Surfaces Hydrophobic? AB - Graphitic carbons are important solid materials with myriad applications including electrodes, adsorbents, catalyst support, and solid lubricants. Understanding the interaction between water and graphitic carbons is critically important for both fundamental material characterization and practical device fabrication because the water-graphitic interface is essential to many applications. Research interests in graphene and carbon nanotubes over the past decades have brought renewed interest to elucidate wettability of graphitic carbons and understand their interaction with the surrounding environment. Research on this topic can be traced back to the 1940s, and the prevailing notion has been that graphitic carbons are hydrophobic. Though there have been different voices, this conclusion is supported by many previous water contact angle tests and well accepted by the community since sp2 carbon is nonpolar in nature. However, recent results from our groups showed that graphitic surfaces are intrinsically mildly hydrophilic and adsorbed hydrocarbon contaminants from the ambient air render the surface hydrophobic. This unexpected finding challenges the long-lasting conception and could completely change the way graphitic materials are made, modeled, and modified. With several other research groups reporting similar findings, it is important for the community to realize the importance of airborne contamination on the surface-related properties of graphitic materials and revisit the intrinsic water-graphite interaction. This Account aims to summarize our recent work on water wettability of graphitic surfaces and discuss future research directions toward understanding the intrinsic water-graphite interaction. Historical perspective will first be provided highlighting the long accepted notion that graphite is hydrophobic along with a few reports suggesting otherwise. Next, our recent experimental data will be presented showing that pristine graphene and graphite are mildly hydrophilic; chemical analysis showed that hydrocarbons adsorb onto the clean surfaces thus rendering them hydrophobic. These results are further rationalized by analyzing the change in surface energy of the graphitic surfaces before and after hydrocarbon contamination. Facile methods to remove hydrocarbons from a contaminated surface will be discussed along with a convenient water treatment method that we developed to inhibit hydrocarbon adsorption onto a pristine graphitic surface. Implications of contamination will be illustrated through comparing the electrochemical activity of pristine and contaminated graphite. Lastly, consequences of these findings and future research directions to address a few important unanswered questions will be discussed. PMID- 27935274 TI - A Rapid and Facile Detection for Specific Small-Sized Amino Acids Based on Target Triggered Destruction of Metal Organic Frameworks. AB - Most of the reported metal organic frameworks (MOFs)-based DNA sensors were developed by utilizing the different adsorption capacities of MOFs to different structural DNAs (for example, single-stranded DNAs (ssDNAs) and double-stranded DNAs (dsDNAs)) or ssDNAs with different lengths. Herein, we introduced another strategy for the design of MOFs-based biosensing platforms. We found that specific small-sized amino acids (for example, glycine and serine) could lead to the destruction of the MOFs formed by [Cu(mal)(bpy)].2H2O], thus recovering the fluorescence of a fluorophore-labeled ssDNA that had been quenched by MOFs. The corresponding working mechanism was discussed. On the basis of this finding, a mix-and-detect fluorescence method was designed for the turn-on detection of specific small-sized amino acids. The feasibility of its use in real serum samples was also demonstrated. Besides biosensing applications, the discovery of amino acids-triggered destruction of MOFs can also enrich the building blocks of molecular logic gate. As an example, a biomolecular logic gate that performs OR logic operation was constructed using glycine and a DNA strand as inputs. PMID- 27935275 TI - New Magnetic Graphitized Carbon Black TiO2 Composite for Phosphopeptide Selective Enrichment in Shotgun Phosphoproteomics. AB - Graphitized carbon black (GCB) has been employed for extraction of several classes of analytes, due to the large surface area and the unique chemistry of its surface groups that allows for extracting a wide range of analytes, including polar, acidic compounds. Despite the fact that structurally related materials, such as graphene, found application as hybrid-components in phosphoproteomics, surprisingly, GCB has never been used for the selective enrichment of phosphopeptides. For this purpose, in the present work we used GCB to prepare a magnetic composite with TiO2 (mGCB@TiO2) that was then applied to yeast total extracts. We exploited the high surface area provided by nanostructures, the presence of nano-TiO2 for selective binding of phosphopeptides, and the magnetic responsiveness of magnetite for solid-phase separation. The material was extensively characterized at each modification step by transmission electron microscopy, Fourier-transformed infrared spectroscopy, thermogravimetric analysis, Raman spectroscopy, and porosimetry. Next, the new system was applied for the enrichment of casein phosphopeptides from a simulated tryptic digest with bovine serum albumin (BSA:casein, 100:1). Finally, after assessing the potential applicability, the composite was employed for enriching phosphopeptides from yeast protein digests. This allowed us not only to optimize the enrichment protocol but also to fully compare its performance to commercial TiO2 spin columns. To achieve this aim, the optimized enrichment protocol was included in a typical shotgun proteomics analytical workflow based on nanoHPLC-MS/MS analysis. PMID- 27935276 TI - Molecular Monolayers for Electrical Passivation and Functionalization of Silicon Based Solar Energy Devices. AB - Silicon-based solar fuel devices require passivation for optimal performance yet at the same time need functionalization with (photo)catalysts for efficient solar fuel production. Here, we use molecular monolayers to enable electrical passivation and simultaneous functionalization of silicon-based solar cells. Organic monolayers were coupled to silicon surfaces by hydrosilylation in order to avoid an insulating silicon oxide layer at the surface. Monolayers of 1 tetradecyne were shown to passivate silicon micropillar-based solar cells with radial junctions, by which the efficiency increased from 8.7% to 9.9% for n+/p junctions and from 7.8% to 8.8% for p+/n junctions. This electrical passivation of the surface, most likely by removal of dangling bonds, is reflected in a higher shunt resistance in the J-V measurements. Monolayers of 1,8-nonadiyne were still reactive for click chemistry with a model catalyst, thus enabling simultaneous passivation and future catalyst coupling. PMID- 27935278 TI - The GLO1 Gene Is Required for Full Activity of O-Acetyl Homoserine Sulfhydrylase Encoded by MET17. AB - During glycolysis, yeast generates methylglyoxal (MG), a toxic metabolite that affects growth. Detoxification can occur when glyoxylase I (GLO1) and glyoxylase II (GLO2) convert MG to lactic acid. We have identified an additional, previously unrecognized role for GLO1 in sulfur assimilation in the yeast Saccharomyces cerevisiae. During a screening for putative carbon-sulfur lyases, the glo1 deletion strain showed significant production of H2S during fermentation. The glo1 strain also assimilated sulfate inefficiently but grew normally on cysteine. These phenotypes are consistent with reduced activity of the O-acetyl homoserine sulfhydrylase, Met17p. Overexpression of Glo1p gave a dominant negative phenotype that mimicked the glo1 and met17 deletion strain phenotypes. Western analysis revealed reduced expression of Met17p in the glo1 deletion, but there was no indication of an altered conformation of Met17p or any direct interaction between the two proteins. Unravelling a novel function in sulfur assimilation and H2S generation in yeast for a gene never connected with this pathway provides new opportunities for the study of this molecule in cell signaling, as well as the potential regulation of its accumulation in the wine and beer industry. PMID- 27935277 TI - Structural Roles of Noncoding RNAs in the Heart of Enzymatic Complexes. AB - Over billions of years of evolution, nature has embraced proteins as the major workhorse molecules of the cell. However, nearly every aspect of metabolism is dependent upon how structured RNAs interact with proteins, ligands, and other nucleic acids. Key processes, including telomere maintenance, RNA processing, and protein synthesis, require large RNAs that assemble into elaborate three dimensional shapes. These RNAs can (i) act as flexible scaffolds for protein subunits, (ii) participate directly in substrate recognition, and (iii) serve as catalytic components. Here, we juxtapose the near atomic level interactions of three ribonucleoprotein complexes: ribonuclease P (involved in 5' pre-tRNA processing), the spliceosome (responsible for pre-mRNA splicing), and telomerase (an RNA-directed DNA polymerase that extends the ends of chromosomes). The focus of this perspective is profiling the structural and dynamic roles of RNAs at the core of these enzymes, highlighting how large RNAs contribute to molecular recognition and catalysis. PMID- 27935280 TI - High-Efficiency Silicon/Organic Heterojunction Solar Cells with Improved Junction Quality and Interface Passivation. AB - Silicon/organic heterojunction solar cells (HSCs) based on conjugated polymers, poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), and n-type silicon (n-Si) have attracted wide attention due to their potential advantages of high efficiency and low cost. However, the state-of-the-art efficiencies are still far from satisfactory due to the inferior junction quality. Here, facile treatments were applied by pretreating the n-Si wafer in tetramethylammonium hydroxide (TMAH) solution and using a capping copper iodide (CuI) layer on the PEDOT:PSS layer to achieve a high-quality Schottky junction. Detailed photoelectric characteristics indicated that the surface recombination was greatly suppressed after TMAH pretreatment, which increased the thickness of the interfacial oxide layer. Furthermore, the CuI capping layer induced a strong inversion layer near the n-Si surface, resulting in an excellent field effect passivation. With the collaborative improvements in the interface chemical and electrical passivation, a competitive open-circuit voltage of 0.656 V and a high fill factor of 78.1% were achieved, leading to a stable efficiency of over 14.3% for the planar n-Si/PEDOT:PSS HSCs. Our findings suggest promising strategies to further exploit the full voltage as well as efficiency potentials for Si/organic solar cells. PMID- 27935279 TI - Catalytic Promiscuity of O-GlcNAc Transferase Enables Unexpected Metabolic Engineering of Cytoplasmic Proteins with 2-Azido-2-deoxy-glucose. AB - O-GlcNAc transferase (OGT) catalyzes the installation of N-acetylglucosamine (GlcNAc) O-linked to nucleocytoplasmic proteins (O-GlcNAc) within multicellular eukaryotes. OGT shows surprising tolerance for structural changes in the sugar component of its nucleotide sugar donor substrate, uridine diphosphate N acetylglucosamine (UDP-GlcNAc). Here, we find that OGT uses UDP-glucose to install O-linked glucose (O-Glc) onto proteins only 25-fold less efficiently than O-GlcNAc. Spurred by this observation, we show that OGT transfers 2-azido-2-deoxy d-glucose (GlcAz) in vitro from UDP-GlcAz to proteins. Further, feeding cells with per-O-acetyl GlcAz (AcGlcAz), in combination with inhibition or inducible knockout of OGT, shows OGT-dependent modification of nuclear and cytoplasmic proteins with O-GlcAz as detected using microscopy, immunoblot, and proteomics. We find that O-GlcAz is reversible within cells, and an unidentified cellular enzyme exists to cleave O-Glc that can also process O-GlcAz. We anticipate that AcGlcAz will prove to be a useful tool to study the O-GlcNAc modification. We also speculate that, given the high concentration of UDP-Glc within certain mammalian tissues, O-Glc may exist within mammals and serve as a physiologically relevant modification. PMID- 27935281 TI - Engineering Cyclohexanone Monooxygenase for the Production of Methyl Propanoate. AB - A previous study showed that cyclohexanone monooxygenase from Acinetobacter calcoaceticus (AcCHMO) catalyzes the Baeyer-Villiger oxidation of 2-butanone, yielding ethyl acetate and methyl propanoate as products. Methyl propanoate is of industrial interest as a precursor of acrylic plastic. Here, various residues near the substrate and NADP+ binding sites in AcCHMO were subjected to saturation mutagenesis to enhance both the activity on 2-butanone and the regioselectivity toward methyl propanoate. The resulting libraries were screened using whole cell biotransformations, and headspace gas chromatography-mass spectrometry was used to identify improved AcCHMO variants. This revealed that the I491A AcCHMO mutant exhibits a significant improvement over the wild type enzyme in the desired regioselectivity using 2-butanone as a substrate (40% vs 26% methyl propanoate, respectively). Another interesting mutant is the T56S AcCHMO mutant, which exhibits a higher conversion yield (92%) and kcat (0.5 s-1) than wild type AcCHMO (52% and 0.3 s-1, respectively). Interestingly, the uncoupling rate for the T56S AcCHMO mutant is also significantly lower than that for the wild type enzyme. The T56S/I491A double mutant combined the beneficial effects of both mutations leading to higher conversion and improved regioselectivity. This study shows that even for a relatively small aliphatic substrate (2-butanone), catalytic efficiency and regioselectivity can be tuned by structure-inspired enzyme engineering. PMID- 27935282 TI - Effect of Natural Organic Matter on Plutonium Sorption to Goethite. AB - The effect of citric acid (CA), desferrioxamine B (DFOB), fulvic acid (FA), and humic acid (HA) on plutonium (Pu) sorption to goethite was studied as a function of organic carbon concentration and pH using batch sorption experiments at 5 mgC.L-1 and 50 mgC.L-1 natural organic matter (NOM), 10-9-10-10 M 238Pu, and 0.1 g.L-1 goethite concentrations, at pH 3, 5, 7, and 9. Low sorption of ligands coupled with strong Pu complexation decreased Pu sorption at pH 5 and 7, relative to a ligand-free system. Conversely, CA, FA, and HA increased Pu sorption to goethite at pH 3, suggesting ternary complex formation or, in the case of humic acid, incorporation into HA aggregates. Mechanisms for ternary complex formation were characterized by Fourier transform infrared spectroscopy in the absence of Pu. CA and FA demonstrated clear surface interactions at pH 3, HA appeared unchanged suggesting HA aggregates had formed, and no DFOB interactions were observed. Plutonium sorption decreased in the presence of DFOB (relative to a ligand free system) at all pH values examined. Thus, DFOB does not appear to facilitate formation of ternary Pu-DFOB-goethite complexes. At pH 9, Pu sorption in the presence of all NOM increased relative to pH 5 and 7; speciation models attributed this to Pu(IV) hydrolysis competing with ligand complexation, increasing sorption. The results indicate that in simple Pu-NOM-goethite ternary batch systems, NOM will decrease Pu sorption to goethite at all but particularly low pH conditions. PMID- 27935284 TI - Thiophene-Functionalized Hybrid Perovskite Microrods and their Application in Photodetector Devices for Investigating Charge Transport Through Interfaces in Particle-Based Materials. AB - Particle-based semiconductor materials are promising constituents of future technologies. They are described by unique features resulting from the combination of discrete nanoparticle characteristics and the emergence of cooperative phenomena based on long-range interaction within their superstructure. (Nano)particles of outstanding quality with regards to size and shape can be prepared via colloidal synthesis using appropriate capping agents. The classical capping agents are electrically insulating, which impedes particle particle electronic communication. Consequently, there exists a high demand for realizing charge transport through interfaces especially for semiconductors of relevance like hybrid perovskites (HYPEs), for example, CH3NH3PbI3 (MAPI) as one of the most prominent representatives. Of particular interest are crystals in the micrometer range, as they possess synergistic advantages of single crystalline bulk properties, shape control as well as the possibility of being functionalized. Here we provide a synthetic strategy toward thiophene functionalized single crystalline MAPI microrods originating from the single source precursor CH3NH3PbI3TEG2 (TEG = triethylene glycol). In the dark, the microrods show enhanced charge transport characteristics of holes over 2 orders of magnitude compared to microscale cuboids with insulating alkyl surface modifiers and nonfunctionalized random sized particles. In large-area prototype photodetector devices (2.21 cm2), the thiophene functionalization improves the response times because of the interparticle charge transport (tON = 190 ms, tOFF = 430 ms) compared to alkyl-functionalized particles (tON = 1055 ms, tOFF = 60 ms), at similar responsivities of 0.65 and 0.71 mA W-1, respectively. Further, the surface functionalization and crystal grains on the micrometer scale improve the device stability. Therefore, this study provides clear evidence for the interplay and importance of crystal size, shape and surface modification of MAPI crystals, which is of major importance in every optoelectronic device. PMID- 27935285 TI - Mechanical Testing of Engineered Spider Silk Filaments Provides Insights into Molecular Features on a Mesoscale. AB - Spider dragline silk shows the highest toughness in comparison to all other known natural or man-made fibers. Despite a broad experimental foundation concerning the macroscopic silk thread properties as well as a thorough simulation-based molecular understanding, the impact of the mesoscale building blocks, namely nano /submicrometer-sized filaments, on the mechanical properties of the threads remains the missing link. Here, we illustrate the function of these mesoscaled building blocks using electrospun fibers made of a recombinant spider silk protein and show the impact of beta-sheet content and fiber hydration on their mechanical performance. Specifically elucidating the interplay between beta-sheet cross-linking (fiber strength) and structural water (fiber extensibility), the results bridge the gap between the molecular and the macroscopic view on the mechanics of spider silk. It is demonstrated that the extensibility of the here used single (MaSp2-like) protein system is in good accordance with the simulated extensibilities published by other groups. Furthermore, sufficient hydration of the fibers is shown to be a prerequisite to obtain a toughness in the range of that of natural dragline silk. Preliminary studies on electrospun fibers of the MaSp2-based recombinant spider silk proteins used in this work have indicated their basic applicability in the technical field of filter systems as well as in regenerative medicine. The presented work provides a fundamental understanding of the mechanical performance of such fibers under different wetting conditions, a prerequisite to further specify their potential for such applications. PMID- 27935283 TI - A Single Deoxynucleoside Kinase Variant from Drosophila melanogaster Synthesizes Monophosphates of Nucleosides That Are Components of an Expanded Genetic System. AB - Deoxynucleoside kinase from D. melanogaster (DmdNK) has broad specificity; although it catalyzes the phosphorylation of natural pyrimidine more efficiently than natural purine nucleosides, it accepts all four 2'-deoxynucleosides and many analogues, using ATP as a phosphate donor to give the corresponding deoxynucleoside monophosphates. Here, we show that replacing a single amino acid (glutamine 81 by glutamate) in DmdNK creates a variant that also catalyzes the phosphorylation of nucleosides that form part of an artificially expanded genetic information system (AEGIS). By shuffling hydrogen bonding groups on the nucleobases, AEGIS adds potentially as many as four additional nucleobase pairs to the genetic "alphabet". Specifically, we show that DmdNK Q81E creates the monophosphates from the AEGIS nucleosides dP, dZ, dX, and dK (respectively 2 amino-8-(1'-beta-d-2'-deoxyribofuranosyl)-imidazo[1,2-a]-1,3,5-triazin-4(8H)-one, dP; 6-amino-3-(1'-beta-d-2'-deoxyribofuranosyl)-5-nitro-1H-pyridin-2-one, dZ; 8 (1'beta-d-2'-deoxy-ribofuranosyl)imidazo[1,2-a]-1,3,5-triazine-2(8H)-4(3H)-dione, dX; and 2,4-diamino-5-(1'-beta-d-2'-deoxyribofuranosyl)-pyrimidine, dK). Using a coupled enzyme assay, in vitro kinetic parameters were obtained for three of these nucleosides (dP, dX, and dK; the UV absorbance of dZ made it impossible to get its precise kinetic parameters). Thus, DmdNK Q81E appears to be a suitable enzyme to catalyze the first step in the biosynthesis of AEGIS 2'-deoxynucleoside triphosphates in vitro and, perhaps, in vivo, in a cell able to manage plasmids containing AEGIS DNA. PMID- 27935286 TI - Entrainment of a Bacterial Synthetic Gene Oscillator through Proteolytic Queueing. AB - Internal chemical oscillators (chemical clocks) direct the behavior of numerous biological systems, and maintenance of a given period and phase among many such oscillators may be important for their proper function. However, both environmental variability and fundamental molecular noise can cause biochemical oscillators to lose coherence. One solution to maintaining coherence is entrainment, where an external signal provides a cue that resets the phase of the oscillators. In this work, we study the entrainment of gene networks by a queueing interaction established by competition between proteins for a common proteolytic pathway. Principles of queueing entrainment are investigated for an established synthetic oscillator in Escherichia coli. We first explore this theoretically using a standard chemical reaction network model and a map-based model, both of which suggest that queueing entrainment can be achieved through pulsatile production of an additional protein competing for a common degradation pathway with the oscillator proteins. We then use a combination of microfluidics and fluorescence microscopy to verify that pulse trains modulating the production rate of a fluorescent protein targeted to the same protease (ClpXP) as the synthetic oscillator can entrain the oscillator. PMID- 27935287 TI - Self-Assembled Tb3+ Complex Probe for Quantitative Analysis of ATP during Its Enzymatic Hydrolysis via Time-Resolved Luminescence in Vitro and in Vivo. AB - To more accurately assess the pathways of biological systems, a probe is needed that may respond selectively to adenosine triphosphate (ATP) for both in vitro and in vivo detection modes. We have developed a luminescence probe that can provide real-time information on the extent of ATP, ADP, and AMP by virtue of the luminescence and luminescence lifetime observed from a supramolecular polymer based on a C3 symmetrical terpyridine complex with Tb3+ (S1-Tb). The probe shows remarkable selective luminescence enhancement in the presence of ATP compared to other phosphate-displaying nucleotides including adenosine diphosphate (ADP), adenosine monophosphate (AMP), guanosine triphosphate (GTP), thymidine triphosphate (TTP), H2PO4- (Pi), and pyrophosphate (PPi). In addition, the time resolved luminescence lifetime and luminescence spectrum of S1-Tb could facilitate the quantitative measurement of the exact amount of ATP and similarly ADP and AMP within living cells. The time-resolved luminescence lifetime of S1-Tb could also be used to quantitatively monitor the amount of ATP, ADP, and AMP in vitro following the enzymatic hydrolysis of ATP. The long luminescence lifetime, which was observed into the millisecond range, makes this S1-Tb-based probe particularly attractive for monitoring biological ATP levels in vivo, because any short lifetime background fluorescence arising from the complex molecular environment may be easily eliminated. PMID- 27935288 TI - Ion Accumulation Time Dependent Molecular Characterization of Natural Organic Matter Using Electrospray Ionization-Fourier Transform Ion Cyclotron Resonance Mass Spectrometry. AB - Natural organic matter (NOM) is a complex organic mixture and plays a crucial role in environmental processes. By using Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS), detailed molecular information on NOM could be achieved. In this paper, ion accumulation time (IAT), a key parameter of FTICR-MS for complex mixture detection, was the focus, and its effect on the molecular characterization of NOM by FTICR-MS was systematically investigated. A notable feature of selective detection of NOM molecules by FTICR-MS with different IAT was observed. Most of the polar molecules with high O/C ratio (O/C ratio >0.5) could be easily detected by FTICR-MS with a short IAT, but extending IAT led to the ion intensities of these molecules decreasing or even disappearing. Meanwhile, a large number of unsaturated and aromatic molecules with low O/C ratio (O/C ratio <0.6) and low polarity, all of which could not be observed with a short IAT, were remarkably detected by extending IAT. Results also revealed that the unsaturated and aromatic molecules, which could only be observed by extending the IAT, were not generated by the fragmentation of molecules in NOM or from the dissociation of NOM aggregations but originally existed in NOM samples. The selective detection of NOM molecules caused by IAT extension was possibly attributed to their different polarity and different stability in the collision cell. On the basis of these results, a novel strategy of combining mass spectrometric data of NOM obtained with different IAT by FTICR MS was proposed. With this strategy, more than 4715 CHO-molecular formulas were assigned, where about 2000 more formulas were obtained in comparison with using a short IAT (2733 CHO-molecular formulas identified) solely. The strategy is simple and robust and can be used as an alternative method to obtain more molecular information on NOM in the environment. PMID- 27935289 TI - Piezopotential-Programmed Multilevel Nonvolatile Memory As Triggered by Mechanical Stimuli. AB - We report the development of a piezopotential-programmed nonvolatile memory array using a combination of ion gel-gated field-effect transistors (FETs) and piezoelectric nanogenerators (NGs). Piezopotentials produced from the NGs under external strains were able to replace the gate voltage inputs associated with the programming/erasing operation of the memory, which reduced the power consumption compared with conventional memory devices. Multilevel data storage in the memory device could be achieved by varying the external bending strain applied to the piezoelectric NGs. The resulting devices exhibited good memory performance, including a large programming/erasing current ratio that exceeded 103, multilevel data storage of 2 bits (over 4 levels), performance stability over 100 cycles, and stable data retention over 3000 s. The piezopotential-programmed multilevel nonvolatile memory device described here is important for applications in data storable electronic skin and advanced human-robot interface operations. PMID- 27935291 TI - A Comparison between the Photoactivation Kinetics of Human and Bovine Rhodopsins. AB - Rhodopsin is a G-protein-coupled receptor important for vertebrate vision under dim light conditions. Many studies of the activation mechanism of bovine rhodopsin have been conducted, but there have been relatively few investigations of the human protein. A recent study of the late photointermediates of bovine rhodopsin studies at 15 degrees C and pH 7.3, 8.0, and 8.7 revealed a rather complex activation mechanism involving two metarhodopsin I480 and metarhodopsin II intermediates. Human rhodopsin was studied under these same conditions using time-resolved optical absorption spectroscopy with measurements from 10 MUs to 200 ms after photolysis. The results show that the two proteins follow the same photoactivation mechanism, although their kinetics differ significantly. The comparison of bovine and human rhodopsins shows that the initial Schiff base deprotonation equilibrium is more forward shifted in human rhodopsin, and more of the reaction flows through the metarhodopsin I380 intermediate in human rhodopsin than in the bovine protein. PMID- 27935290 TI - Aromatic Functionality of Target Proteins Influences Monomer Selection for Creating Artificial Antibodies on Plasmonic Biosensors. AB - Natural antibodies used as biorecognition elements suffer from numerous shortcomings, such as limited chemical and environmental stability and cost. Artificial antibodies based on molecular imprinting are an attractive alternative to natural antibodies. We investigated the role of aromatic interactions in target recognition capabilities of artificial antibodies. Three proteins with different aromatic amino acid content were employed as model targets. Artificial antibodies were formed on nanostructures using combinations of silane monomers of varying aromatic functionality. We employed refractive index sensitivity of plasmonic nanostructures as a transduction platform for monitoring various steps in the imprinting process and to quantify the target recognition capabilities of the artificial antibodies. The sensitivity of the artificial antibodies with aromatic interactions exhibited a protein-dependent enhancement. Selectivity and sensitivity enhancement due to the presence of aromatic groups in imprinted polymer matrix was found to be higher for target proteins with higher aromatic amino acid content. Our results indicate that tailoring the monomer composition based on the amino acid content of the target protein can improve the sensitivity of plasmonic biosensors based on artificial antibodies without affecting the selectivity. PMID- 27935292 TI - Introduction of Premature Stop Codons as an Evolutionary Strategy To Rescue Signaling Network Function. AB - The cellular concentrations of key components of signaling networks are tightly regulated, as deviations from their optimal ranges can have negative effects on signaling function. For example, overexpression of the yeast mating pathway mitogen-activated protein kinase (MAPK) Fus3 decreases pathway output, in part by sequestering individual components away from functional multiprotein complexes. Using a synthetic biology approach, we investigated potential mechanisms by which selection could compensate for a decrease in signaling activity caused by overexpression of Fus3. We overexpressed a library of random mutants of Fus3 and used cell sorting to select variants that rescued mating pathway activity. Our results uncovered that one remarkable way in which selection can compensate for protein overexpression is by introducing premature stop codons at permitted positions. Because of the low efficiency with which premature stop codons are read through, the resulting cellular concentration of active Fus3 returns to values within the range required for proper signaling. Our results underscore the importance of interpreting genotypic variation at the systems rather than at the individual gene level, as mutations can have opposite effects on protein and network function. PMID- 27935294 TI - Free-Standing Networks of Core-Shell Metal and Metal Oxide Nanotubes for Glucose Sensing. AB - Nanotube assemblies represent an emerging class of advanced functional materials, whose utility is however hampered by intricate production processes. In this work, three classes of nanotube networks (monometallic, bimetallic, and metal oxide) are synthesized solely using facile redox reactions and commercially available ion track membranes. First, the disordered pores of an ion track membrane are widened by chemical etching, resulting in the formation of a strongly interconnected pore network. Replicating this template structure with electroless copper plating yields a monolithic film composed of crossing metal nanotubes. We show that the parent material can be easily transformed into bimetallic or oxidic derivatives by applying a second electroless plating or thermal oxidation step. These treatments retain the monolithic network structure but result in the formation of core-shell nanotubes of altered composition (thermal oxidation: Cu2O-CuO; electroless nickel coating: Cu-Ni). The obtained nanomaterials are applied in the enzyme-free electrochemical detection of glucose, showing very high sensitivities between 2.27 and 2.83 A M-1 cm-2. Depending on the material composition, varying reactivities were observed: While copper oxidation reduces the response to glucose, it is increased in the case of nickel modification, albeit at the cost of decreased selectivity. The performance of the materials is explained by the network architecture, which combines the advantages of one-dimensional nano-objects (continuous conduction pathways, high surface area) with those of a self-supporting, open-porous superstructure (binder free catalyst layer, efficient diffusion). In summary, this novel synthetic approach provides a fast, scalable, and flexible route toward free-standing nanotube arrays of high compositional complexity. PMID- 27935293 TI - Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation. AB - Glycogen synthase (GS) is the rate limiting enzyme in the synthesis of glycogen. Eukaryotic GS is negatively regulated by covalent phosphorylation and allosterically activated by glucose-6-phosphate (G-6-P). To gain structural insights into the inhibited state of the enzyme, we solved the crystal structure of yGsy2-R589A/R592A to a resolution of 3.3 A. The double mutant has an activity ratio similar to the phosphorylated enzyme and also retains the ability to be activated by G-6-P. When compared to the 2.88 A structure of the wild-type G-6-P activated enzyme, the crystal structure of the low-activity mutant showed that the N-terminal domain of the inhibited state is tightly held against the dimer related interface thereby hindering acceptor access to the catalytic cleft. On the basis of these two structural observations, we developed a reversible redox regulatory feature in yeast GS by substituting cysteine residues for two highly conserved arginine residues. When oxidized, the cysteine mutant enzyme exhibits activity levels similar to the phosphorylated enzyme but cannot be activated by G 6-P. Upon reduction, the cysteine mutant enzyme regains normal activity levels and regulatory response to G-6-P activation. PMID- 27935295 TI - Metabolism-Based Click-Mediated Platform for Specific Imaging and Quantification of Cell Surface Sialic Acids. AB - Although we believe that the cell surface sialic acids (Sias) are playing an important role in cell-cell interactions and related tumor metastasis processes, acquisition of their quantitative information has yet been a challenge to date. Here, we reported the construction of a new analytical platform for Sias-specific imaging and quantification. We used N-azidoacetyl-mannosamine tetraacylated as a metabolic sugar substrate to bioassemble azido-Sias on the surface of cells via the metabolic pathway of Sias de novo synthesis. These azido-Sias allow us to perform a duplex Sias-specific analysis with various fluorescent and elemental reporters such as DIBO-Alexa Fluor 647, DBCO-DOTA-Eu, and DBCO-PEG4-BODIPY, which can be easily labeled and/or tagged through an effective copper-free bioorthogonal click reaction. Compared to the previous reported strategies, we quantified the cell surface Sias with the LODs (3sigma) down to 8.9 fmol and 0.24 pmol using 153Eu- and 10B-species unspecific isotope dilution ICPMS, in addition to their red- and green-CLSM profiling. Such a platform enables us to evaluate Sias regulation under the administration of paclitaxel, finding that 1 MUM paclitaxel induced a significant Sias decrease of 67% on the surface of hepatic tumor cell SMMC-7721, while had no obvious adverse effect to that of para carcinomatous liver cell LO2. Besides Sias, we believe that this metabolism-based click-mediated platform will provide opportunities to study other monosaccharides and their corresponding biological roles when more corresponding chemically modified sugar substrates and specific bioorthogonal reactions are developed. PMID- 27935297 TI - Probing the Soft and Nanoductile Mechanical Nature of Single and Polycrystalline Organic-Inorganic Hybrid Perovskites for Flexible Functional Devices. AB - Although organic-inorganic hybrid perovskites have been extensively investigated for promising applications in energy-related devices, their mechanical properties, which restrict their practical deployment as flexible and wearable devices, have been largely unexplored at the atomistic level. Toward this level of understanding, we predict the elastic constant matrix and various elastic properties of CH3NH3PbI3 (MAPbI3) using atomistic simulations. We find that single-crystalline MAPbI3 is much stiffer and exhibits higher ultimate tensile strength than polycrystalline samples, but the latter exhibit unexpected, greatly enhanced nanoductility and fracture toughness, resulting from the extensive amorphization during the yielding process. More interestingly, polycrystalline MAPbI3 exhibits inverse Hall-Petch grain-boundary strengthening effect, in which the yield stress is reduced when decreasing the grain size, due to amorphous grain boundaries. By monitoring the centro-symmetry parameter and local stress evolution, we confirm the soft and nanoductile nature of defective MAPbI3 with a crack. By conducting atomic stress decomposition, we attribute such fracture toughness primarily to the strong electrostatic interactions between the ionic components. The observed limited brittle fracture behavior is attributed to the transformation of partial edge dislocations to disordered atoms (nanovoid formation). A significant plastic deformation region is observed when nanovoids enlarge and coalesce with adjacent ones, which ultimately leads to crack propagations via ionic-chain breaking. After comparing with traditional inorganic energy-related materials, we find that hybrid perovskites are more compressible and can absorb more strain energy before fracture, which makes them well suited for wearable functional devices with high mechanical flexibility and robustness. PMID- 27935296 TI - Graphene-Montmorillonite Composite Sponge for Safe and Effective Hemostasis. AB - Montmorillonite (MMT) is considered to be the most effective hemostat among natural phyllosilicates. However, there is a barrier against using MMT for the commercial hemostatics because the invaded MMT powders might cause thrombosis in vessel. Until now, it is still a challenge to manage the release of MMT and eliminate its side effect. Herein, we present a graphene-MMT composite sponge (GMCS), synthesized under a hydrothermal reaction, fixing MMT powders into the cross-linked graphene sheets. We demonstrate that only a few embedded MMT can evoke remarkable platelet stimulation at the sponge interface, while maintaining fast plasma absorbency of the innate sponge. In the synergy of the above hemostatic mechanisms, the GMCS can rapidly stop bleeding in approximately 85 s in rabbit artery injury test. More importantly, computed tomography angiography certifies that the GMCS does not cause thrombus or blood clot in vessels. Cytotoxicity assay further highlights its biocompatibility. In-depth analysis proposes that two-dimensional graphene overmatches one-dimensional linear polymers in the composite construction, and dimension transformation of blood distribution plays a crucial role for reinforcing the hemostatic performance. This GMCS hemostat not only opens a new perspective for graphene composite, but also makes a new chance of using clays for trauma therapy. PMID- 27935298 TI - Magnetic Structures of Heterometallic M(II)-M(III) Formate Compounds. AB - A study of the magnetic structure of the [NH2(CH3)2]n[FeIIIMII(HCOO)6]n niccolite like compounds, with MII = CoII (2) and MnII (3) ions, has been carried out using neutron diffraction and compared with the previously reported FeII-containing compound (1). The inclusion of two different metallic atoms into the niccolite like structure framework leads to the formation of isostructural compounds with very different magnetic behaviors due to the compensation or not of the different spins involved in each lattice. Below TN, the magnetic order in these compounds varies from ferrimagnetic behavior for 1 and 2 to an antiferromagnetic behavior with a weak spin canting for 3. Structure refinements of 2 and 3 at low temperature (45 K) have been carried out combining synchrotron X-ray and high resolution neutron diffraction in a multipattern approach. The magnetic structures have been determined from the difference patterns between the neutron data in the paramagnetic and the magnetically ordered regions. These difference patterns have been analyzed using a simulated annealing protocol and symmetry analysis techniques. The obtained magnetic structures have been further rationalized by means of ab initio DFT calculations. The direction of the magnetic moment of each compound has been determined. The easy axis of the MII for compound 1 (FeII) is along the c axis; for compound 2 (CoII), the moments are mainly within the ab plane; finally, for compound 3 (MnII), the calculations show that the moments have components both in the ab plane and along the c axis. PMID- 27935300 TI - Interface Play between Perovskite and Hole Selective Layer on the Performance and Stability of Perovskite Solar Cells. AB - Perovskite solar cells with variety of hole selective contacts such as 2,2',7,7' tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene (Spiro-OMeTAD), poly(3 hexylthiophene-2,5-diyl), poly[bis(4-phenyl)(2,5,6-trimentlyphenyl)amine], 5,10,15-trihexyl-3,8,13-tris(4-methoxyphenyl)-10,15-dihydro-5H-diindolo[3,2 a:3',2'-c]carbazole (HMPDI), and 2',7'-bis(bis(4 methoxyphenyl)amino)spiro[cyclopenta[2,1-b:3,4-b']dithiophene-4,9'-fluorene] were employed to elucidate its role at the interface of perovskite and metallic cathode. Microscopy images revealed Spiro-OMeTAD and HMPDI produce smoother and intimate contact between perovskite/hole transporting materials (HTM) interfaces among others evaluated here. This morphological feature appears to be connected with three fundamental facts: (1) hole injection to the HTM is much more efficient as evidenced by photoluminescence measurements, (2) recombination losses are less important as evidenced by intensity-modulated photovoltage spectroscopy and impedance spectroscopy measurements, and (3) fabricated solar cells are much more robust against degradation by moisture. Devices with higher open-circuit photovoltages are characterized by higher values of the recombination resistance extracted from the impedance data. The variation in device hysteresis behavior can be ascribed mainly due to the molecular interaction and the core of HTM employed. In all cases, this fact is related with a larger value of the low-frequency capacitance, which indicates that the HTM can induce specific slow processes of ion accumulation at the interface. Notably, these processes tend to slowly relax in time, as hysteresis is substantially reduced for aged devices. PMID- 27935299 TI - Strongly Coupled FeNi Alloys/NiFe2O4@Carbonitride Layers-Assembled Microboxes for Enhanced Oxygen Evolution Reaction. AB - Hydrogen produced from electrocatalytic water splitting is a promising route due to the sustainable powers derived from the solar and wind energy. However, the sluggish kinetics at the anode for water splitting makes the highly effective and inexpensive electrocatalysts desirable in oxygen evolution reaction (OER) by structure and composition modulations. Metal-organic frameworks (MOFs) have been intensively used as the templates/precursors to synthesize complex hollow structures for various energy-related applications. Herein, an effective and facile template-engaged strategy originated from bimetal MOFs is developed to construct hollow microcubes assembled by interconnected nanopolyhedron, consisting of intimately dominant FeNi alloys coupled with a small NiFe2O4 oxide, which was confined within carbonitride outer shell (denoted as FeNi/NiFe2O4@NC) via one-step annealing treatment. The optimized FeNi/NiFe2O4@NC exhibits excellent electrocatalytic performances toward OER in alkaline media, showing 10 mA.cm-2 at eta = 316 mV, lower Tafel slope (60 mV.dec-1), and excellent durability without decay after 5000 CV cycles, which also surpasses the IrO2 catalyst and most of non-noble catalysts in the OER, demonstrating a great perspective. The superior OER performance is ascribed to the hollow interior for fast mass transport, in situ formed strong coupling between FeNi alloys and NiFe2O4 for electron transfer, and the protection of carbonitride layers for long stability. PMID- 27935301 TI - Supramolecular Self-Assembly Induced Adjustable Multiple Gating States of Nanofluidic Diodes. AB - Artificial nanochannels, inheriting smart gating functions of biological ion channels, promote the development of artificial functional nanofluidic devices for high-performance biosensing and electricity generation. However, gating states of the artificial nanochannels have been mainly realized through chemical modification of the channels with responsive molecules, and their gating states cannot be further regulated once the nanochannel is modified. In this work, we employed a new supramolecular layer-by-layer (LbL) self-assembly method to achieve reversible and adjustable multiple gating features in nanofluidic diodes. Initially, a self-assembly precursor was modified into a single conical nanochannel, then host molecule-cucurbit[8]uril (CB[8]) and guest molecule, a naphthalene derivative, were self-assembled onto the precursor through an LbL method driven by host-enhanced pi-pi interaction, forming supramolecular monolayer or multilayers on the inner surface of the channel. These self assemblies with different layer numbers possessed remarkable charge effects and steric effects, exhibiting a capability to regulate the surface charge density and polarity, the effective diameter, and the geometric asymmetry of the single nanochannel, realizing reversible gating of the single nanochannel among multiple rectification and ion-conduction states. As an example of self-assembly of supramolecular networks in nanoconfinements, this work provides a new approach for enhancing functionalities of artificial nanochannels by LbL supramolecular self-assemblies. Meanwhile, since the host molecule, CB[8], used in this work can interact with different kinds of biomolecules and stimuli-responsive chemical species, this work can be further extended to build a novel stable multiple-state research platform for a variety of uses such as sensing and controllable release. PMID- 27935302 TI - Accurate Dissociation of Chemical Bonds Using DFT-in-DFT Embedding Theory with External Orbital Orthogonality. AB - Our recent density functional theory (DFT)-in-DFT embedding protocol, which enforces intersubsystem (or external orbital) orthogonality, is used for the first time to investigate covalent bond dissociation and is shown to do so accurately. Full potential energy curves for the dissociation of a H-O bond in H2O and the C-C bond in H3C-CH3 have been constructed using the new embedding method, as have the challenging ionic bonds in LiH and LiF, and were found to match the reference Kohn-Sham (KS)-DFT curves to at least one part in 106. The added constraint of external orbital orthogonality allows for the formulation of an embedding protocol that does not rely on approximate kinetic energy functionals for the evaluation of the so-called nonadditive kinetic potential, does not introduce compensatory potentials, and does not require a total system calculation at any stage. The present work extends the demonstrated applicability of the external orthogonality variant of embedding theory by more than a factor of 2 to the interaction strength range of strong single bonds. In particular, it is demonstrated that homolytic cleavage of both covalent and ionic bonds into radicals can be accomplished. PMID- 27935303 TI - Detection of Neutral Species in the MALDI Plume Using Femtosecond Laser Ionization: Quantitative Analysis of MALDI-MS Signals Based on a Semiequilibrium Proton Transfer Model. AB - We investigated neutral species in the matrix-assisted laser desorption and ionization (MALDI) plume using femtosecond laser ionization spectrometry with simultaneous measurement of the standard MALDI spectrum of the identical MALDI event induced by pulsed UV laser irradiation. The ratio of neutral species in the plume [A]p/[M]p (A = phenylalanine (Phe) or alanine (Ala), M = 2,5 dihydroxybenzoic acid (DHB)) was confirmed to be the same as that of the sample mixture in the range of [A]0/[M]0 = 4 * 10-4-1, indicating the validity of the widely adopted approximation [A]p/[M]p = [A]0/[M]0 in the reaction quotient of the proton transfer reaction MH+ + A ? M + AH+. An effective parameter representing the extent of thermal equilibrium in the thermal proton transfer model is introduced for the first time. Numerical simulation based on this semiequilibrium model successfully reproduced variations of MALDI signal intensities AH+ and MH+ with two parameters: the fraction of ionized matrix a <= 10-5 and an effective temperature T = 1200 and 1100 K for Phe/DHB and Ala/DHB systems, respectively. These values show good agreement with those determined previously by different experimental approaches. The extent of thermal equilibrium was determined to be 95% and 98% for Phe/DHB and Ala/DHB systems, respectively, suggesting that the proton transfer reactions almost proceed to their thermal equilibrium. PMID- 27935304 TI - Pickering and Network Stabilization of Biocompatible Emulsions Using Chitosan Modified Silica Nanoparticles. AB - Edible solid particles constitute an attractive alternative to surfactants as stabilizers of food-grade emulsions for products requiring a long-term shelf life. Here, we report on a new approach to stabilize edible emulsions using silica nanoparticles modified by noncovalently bound chitosan oligomers. Electrostatic modification with chitosan increases the hydrophobicity of the silica nanoparticles and favors their adsorption at the oil-water interface. The interfacial adsorption of the chitosan-modified silica particles enables the preparation of oil-in-water emulsions with small droplet sizes of a few micrometers through high-pressure homogenization. This approach enables the stabilization of food-grade emulsions for more than 3 months. The emulsion structure and stability can be effectively tuned by controlling the extent of chitosan adsorption on the silica particles. Bulk and interfacial rheology are used to highlight the two stabilization mechanisms involved. Low chitosan concentration (1 wt % with respect to silica) leads to the formation of a viscoelastic film of particles adsorbed at the oil-water interface, enabling Pickering stabilization of the emulsion. By contrast, a network of agglomerated particles formed around the droplets is the predominant stabilization mechanism of the emulsions at higher chitosan content (5 wt % with respect to silica). These two pathways against droplet coalescence and coarsening open up different possibilities to engineer the long-term stabilization of emulsions for food applications. PMID- 27935305 TI - Conversion of Arylboronic Acids to Tetrazoles Catalyzed by ONO Pincer-Type Palladium Complex. AB - A convenient synthesis of a library of tetrazoles through a novel and operationally simple protocol effecting the direct conversion of arylboronic acids catalyzed by a new ONO pincer-type Pd(II) complex under mild reaction conditions using the readily available reagents is reported. The palladium complex was reused up to four cycles in an open-flask condition. PMID- 27935306 TI - Phosphoric Acid-Catalyzed Asymmetric Synthesis of SPINOL Derivatives. AB - Axially chiral 1,1'-spirobiindane-7,7'-diol (SPINOL) is the most fundamental and important privileged structure from which other chiral ligands containing a 1,1' spirobiindane backbone are synthesized. Driven by the development of enantioselective syntheses of axially chiral SPINOL derivatives, we have successfully developed the first phosphoric acid-catalyzed asymmetric approach. This approach is highly convergent and functional group tolerant, efficiently providing SPINOLs in good yield with excellent enantioselectivity, thus delivering a practical and straightforward access to this privileged structure. It should be emphasized that the catalyst loading could be decreased to only 0.1 mol% for the preparative-scale synthesis. Furthermore, 4,4'-dimethyl-SPINOL phosphoric acid was synthesized and applied to catalyze the model reaction for synthesis of enantioenriched SPINOL derivatives. PMID- 27935307 TI - Regulating Underwater Superoleophobicity to Superoleophilicity on Hierarchical Structured Copper Substrates through Assembling n-Alkanoic Acids. AB - In this paper, we report a simple method based on assembling n-alkanoic acids on hierarchical structured copper toward preparing surfaces with tunable oil wetting performance in water. Surface wettability from superoleophobicity to superoleophilicity in water can be regulated through tuning the chain length of n alkanoic acids. Importantly, even in strongly acid and basic water, such phenomena can still be observed. The cooperation between the hierarchical structures and the surface chemical composition variation is responsible for the controllability. Meanwhile, the tunable ability is universal and the controllability is suitable for various oils including silicon oil, n-hexane, and chloroform. Moreover, the method was also used on copper mesh substrates, and we reported the related application of selective oil/water separation. This paper provides a flexible strategy toward preparing surfaces with tunable oil wetting performances, which can also be suitable for other materials, and offers some fresh ideas in manipulating underwater oil wetting performances on surfaces. PMID- 27935308 TI - Combining Molecular Scaffolds from FDA Approved Drugs: Application to Drug Discovery. AB - We have enumerated all linear combinations of ring systems from FDA approved drugs, up to three rings in length and up to four bonds linkers to give an in silico database of approximately 14 million molecules. This virtual library was compared with molecular databases of published and commercially available compounds to assess the prevalence of drug ring combinations in modern medicinal chemistry and to identify areas of under-represented, but clinically validated, chemical space. From the 10 trillion molecular comparisons, we found that less than 1% of the possible combinations of drug ring systems appear in commercially available libraries. This key observation highlights significant opportunities to design new fragment-like and lead-like libraries aimed at improving success rates and reducing risk in small molecule drug discovery, as, based on our previous analysis ( Taylor J. Med. Chem. 2014 , 57 , 5845 - 5849 ), approximately 70% of all new drugs are made up of only ring systems that have been used in existing drugs. PMID- 27935309 TI - Pressurizing Field-Effect Transistors of Few-Layer MoS2 in a Diamond Anvil Cell. AB - Hydrostatic pressure applied using diamond anvil cells (DAC) has been widely explored to modulate physical properties of materials by tuning their lattice degree of freedom. Independently, electrical field is able to tune the electronic degree of freedom of functional materials via, for example, the field-effect transistor (FET) configuration. Combining these two orthogonal approaches would allow discovery of new physical properties and phases going beyond the known phase space. Such experiments are, however, technically challenging and have not been demonstrated. Herein, we report a feasible strategy to prepare and measure FETs in a DAC by lithographically patterning the nanodevices onto the diamond culet. Multiple-terminal FETs were fabricated in the DAC using few-layer MoS2 and BN as the channel semiconductor and dielectric layer, respectively. It is found that the mobility, conductance, carrier concentration, and contact conductance of MoS2 can all be significantly enhanced with pressure. We expect that the approach could enable unprecedented ways to explore new phases and properties of materials under coupled mechano-electrostatic modulation. PMID- 27935310 TI - Reduction of Selenoamides to Amines Using SmI2-H2O. AB - Selenoamides are selectively reduced to amines by SmI2 with H2O. The process is general for primary, secondary, and tertiary aryl and alkyl selenoamide substrates and selectively delivers amine products. The reduction proceeds under mild conditions using SmI2 activated by straightforward addition of H2O, and does not require an additional Lewis base additive. PMID- 27935311 TI - Palladium-Catalyzed Ortho-Alkoxylation of N-Benzoyl alpha-Amino Acid Derivatives at Room Temperature. AB - An efficient palladium-catalyzed ortho-alkoxylation of N-benzoyl alpha-amino acid derivatives at room temperature has been explored. This novel transformation, using amino acids as directing groups, Pd(OAc)2 as catalyst, alcohols as the alkoxylation reagents, and PhI(OAc)2 as the oxidant, showed wide generality, good functional tolerance, and high monoselectivity and regioselectivity. PMID- 27935312 TI - Guided Electro-Optical Switching of Small Graphene Oxide Particles by Larger Ones in Aqueous Dispersion. AB - Although the large Kerr coefficient of aqueous graphene oxide (GO) dispersions is quite attractive for electro-optical applications with low power consumption, the maximum birefringence of GO dispersions is not sufficiently high for actual display applications. Here we report that adding a small amount of larger GO particles (about 4 MUm) into a high-concentration dispersion of small GO (about 0.2 MUm) can improve the electro-optical sensitivity to an electric field and also the maximum birefringence. Large GOs induce the ordering of small particles and enhance the electro-optical switching. Large GOs have higher polarizability and are easily driven under an applied electric field, and the rotational motion of large GO particles leads to switching of surrounding small GO particles, improving the electro-optical performance. The binary mixture can overcome the limitations of pure dispersions of large GO or small GO particles; the former has high interparticle interaction, and the latter has low sensitivity to an electric field. PMID- 27935314 TI - A Versatile Method to Determine the Cellular Bioavailability of Small-Molecule Inhibitors. AB - The determination of the cellular bioavailability of small-molecule inhibitors is a critical step for interpreting cell-based data and guiding inhibitor optimization. Herein, a HPLC-MS based protocol was developed to determine inhibitor cellular bioavailability. This generalizable protocol allows determination of the accurate intracellular concentrations and characterization of various properties of inhibitors including the extra- and intracellular stability, the dose- and time-dependence of the intracellular concentrations, the cell permeability, and the nonspecific binding with the cell culture plates, the extracellular matrices, and the cell membrane. The inhibitors of the protein protein interactions, bromodomains, and the beta-catenin/B-cell lymphoma 9 (BCL9) interaction were used to examine the protocol, and the cellular bioavailability of the inhibitors in cancer cells was determined. High nonspecific binding and low cellular uptake were observed for two bromodomain inhibitors. The two beta catenin/BCL9 inhibitors had low nonspecific binding but different cellular uptake. These inhibitors exhibited different stability kinetics in cells. PMID- 27935313 TI - Energy Ordering of Molecular Orbitals. AB - Orbitals are invaluable in providing a model of bonding in molecules or between molecules and surfaces. Most present-day methods in computational chemistry begin by calculating the molecular orbitals of the system. To what extent have these mathematical objects analogues in the real world? To shed light on this intriguing question, we employ a photoemission tomography study on monolayers of 3,4,9,10-perylene-tetracarboxylic acid dianhydride (PTCDA) grown on three Ag surfaces. The characteristic photoelectron angular distribution enables us to assign individual molecular orbitals to the emission features. When comparing the resulting energy positions to density functional calculations, we observe deviations in the energy ordering. By performing complete active space calculations (CASSCF), we can explain the experimentally observed orbital ordering, suggesting the importance of static electron correlation beyond a (semi)local approximation. On the other hand, our results also show reality and robustness of the orbital concept, thereby making molecular orbitals accessible to experimental observations. PMID- 27935315 TI - Tribenzotriquinacene-Based Crown Ethers: Synthesis and Selective Complexation with Ammonium Salts. AB - Two tribenzotriquinacene-based crown ethers, TBTQ-dibenzo-24-crown-8 5 and TBTQ benzo-21-crown-7 6, were prepared from the key TBTQ intermediate, 2,3-dihydroxy 4b,8b,12b,12d-tetramethyltribenzotriquinacene (13), which in turn was synthesized in six steps using two variants of our cyclodehydration method on a multigram scale. The host-guest complexation properties of the TBTQ-based crown ethers 5 and 6 with a paraquat derivative, 16, and two secondary ammonium salts, 17 and 18, were studied by 1H NMR spectroscopy and mass spectrometry. It was found that host 5 binds to the paraquat derivative 16 as a 1:1 complex in CDCl3/CD3CN solution with an association constant of Ka = (9.2 +/- 1.8) * 102 M-1, whereas no complexation was found for 17 and 18. In contrast, the TBTQ-crown ether 6 assembles selectively with dibutylammonium hexafluorophosphate 18 as a 1:1 complex in CDCl3/CD3COCD3 [Ka = (5.0 +/- 1.4) * 102 M-1], for which a threaded [2]pseudorotaxane structure is assumed. PMID- 27935316 TI - Rapid Synthesis of Sub-5 nm Sized Cubic Boron Nitride Nanocrystals with High Piezoelectric Behavior via Electrochemical Shock. AB - A key challenge in current superhard materials research is the design of novel superhard nanocrystals (NCs) whereby new and unexpected properties may be predicted. Cubic boron nitride (c-BN) is a superhard material which ranks next to diamond; however, downsizing c-BN material below the 10 nm scale is rather challenging, and the interesting new properties of c-BN NCs remain unexplored and wide open. Herein we report an electrochemical shock method to prepare uniform c BN NCs with a lateral size of only 3.4 +/- 0.6 nm and a thickness of only 0.74 +/ 0.3 nm at ambient temperature and pressure. The fabrication process is simple and fast, with c-BN NCs produced in just a few minutes. Most interestingly, the NCs exhibit excellent piezoelectric performance with a large recordable piezoelectric coefficient of 25.7 pC/N, which is almost 6 times larger than that from bulk c-BN and even competitive to conventional piezoelectric materials. The phenomenon of enhancement in the piezoelectric properties of BN NCs might arise from the nanoscale surface effect and nanoscale shape effect of BN NCs. This work paves an interesting route for exploring new properties of superhard NCs. PMID- 27935317 TI - Interface Engineering of Domain Structures in BiFeO3 Thin Films. AB - A wealth of fascinating phenomena have been discovered at the BiFeO3 domain walls, examples such as domain wall conductivity, photovoltaic effects, and magnetoelectric coupling. Thus, the ability to precisely control the domain structures and accurately study their switching behaviors is critical to realize the next generation of novel devices based on domain wall functionalities. In this work, the introduction of a dielectric layer leads to the tunability of the depolarization field both in the multilayers and superlattices, which provides a novel approach to control the domain patterns of BiFeO3 films. Moreover, we are able to study the switching behavior of the first time obtained periodic 109 degrees stripe domains with a thick bottom electrode. Besides, the precise controlling of pure 71 degrees and 109 degrees periodic stripe domain walls enable us to make a clear demonstration that the exchange bias in the ferromagnet/BiFeO3 system originates from 109 degrees domain walls. Our findings provide future directions to study the room temperature electric field control of exchange bias and open a new pathway to explore the room temperature multiferroic vortices in the BiFeO3 system. PMID- 27935318 TI - Versatile Polarization Generation with an Aluminum Plasmonic Metasurface. AB - All forms of light manipulation rely on light-matter interaction, the primary mechanism of which is the modulation of its electromagnetic fields by the localized electromagnetic fields of atoms. One of the important factors that influence the strength of interaction is the polarization of the electromagnetic field. The generation and manipulation of light polarization have been traditionally accomplished with bulky optical components such as waveplates, polarizers, and polarization beam splitters that are optically thick. The miniaturization of these devices is highly desirable for the development of a new class of compact, flat, and broadband optical components that can be integrated together on a single photonics chip. Here we demonstrate, for the first time, a reflective metasurface polarization generator (MPG) capable of producing light beams of any polarizations all from a linearly polarized light source with a single optically thin chip. Six polarization light beams are achieved simultaneously including four linear polarizations along different directions and two circular polarizations, all conveniently separated into different reflection angles. With the Pancharatnam-Berry phase-modulation method, the MPG sample was fabricated with aluminum as the plasmonic metal instead of the conventional gold or silver, which allowed for its broadband operation covering the entire visible spectrum. The versatility and compactness of the MPG capable of transforming any incident wave into light beams of arbitrary polarizations over a broad spectral range are an important step forward in achieving a complete set of flat optics for integrated photonics with far-reaching applications. PMID- 27935319 TI - Haplotype association and synergistic effect of human aldosterone synthase (CYP11B2) gene polymorphisms causing susceptibility to essential hypertension in Indian patients. AB - BACKGROUND: Aldosterone synthase (CYP11B2) is a key enzyme involved in the terminal steps of aldosterone biosynthesis. Genetic variability in CYP11B2 gene has been associated with heterogeneous aldosterone production, which can affect sodium homeostasis and thereby regulation of blood pressure. Hence, the present study was aimed to explore the single-locus variations, haplotype and epistasis patterns of CYP11B2 (C-344T, intron-2 gene conversion and Lys173Arg) gene polymorphisms, and the risk contributed by them to the development of essential hypertension (EHT). METHODS: A total of 279 hypertensive patients and 200 normotensive controls were enrolled in this study. C-344T and Lys173Arg polymorphisms of CYP11B2 gene were genotyped by PCR-RFLP method and intron-2 gene conversion (IC) polymorphism by allele-specific PCR analysis. RESULTS: Single locus analysis revealed significant association of CYP11B2 C-344T and Lys173Arg polymorphisms with EHT (p < 0.05). Considering the sexes, Lys173 allele was found to be at risk for hypertension in males (OR 1.40; 95% CI = 1.01-1.96). Unphased haplotype analysis revealed H1 (T-Conv-Lys; p = 0.0017) to have significant risk for EHT, while haplotype H4 (T-Wt-Arg) had a significant protective effect. Multifactor dimensionality reduction (MDR) interaction analysis found the overall best model with C-344T and IC polymorphisms exhibiting strong synergistic effect. CONCLUSION: The present study revealed a strong synergistic effect of CYP11B2 C 344T and IC polymorphisms causing susceptibility to EHT and haplotype H1 (-344T Conv-Lys173) as the risk-conferring factor for hypertension predisposition. PMID- 27935320 TI - Missing laboratory results data in electronic health databases: implications for monitoring diabetes risk. AB - AIM: Laboratory test (lab) results may be useful to detect incident diabetes in electronic health record and claims-based studies. RESEARCH DESIGN & METHODS: Using the Mini-Sentinel distributed database, we assessed the value of lab results added to diagnosis codes and dispensing claims to identify incident diabetes. RESULTS: Inclusion of lab results increased the number of diabetes outcomes identified by 21%. In settings where capture of lab results was relatively complete, the absence of lab results was associated with implausibly low rates of the outcome. CONCLUSION: Lab results can increase sensitivity of algorithms for detecting diabetes, and missing lab results are associated with much lower rates of diabetes ascertainment regardless of algorithm. Patterns of missing lab results may identify ascertainment bias. PMID- 27935321 TI - Neighborhood Economic Deprivation and Social Fragmentation: Associations With Children's Sleep. AB - BACKGROUND & OBJECTIVE: A growing body of work indicates that experiences of neighborhood disadvantage place children at risk for poor sleep. This study aimed to examine how both neighborhood economic deprivation (a measure of poverty) and social fragmentation (an index of instability) are associated with objective measures of the length and quality of children's sleep. PARTICIPANTS: Participants were 210 children (54.3% boys) living predominantly in small towns and semirural communities in Alabama. On average children were 11.3 years old (SD = .63); 66.7% of the children were European American and 33.3% were African American. The sample was socioeconomically diverse with 67.9% of the participants living at or below the poverty line and 32.1% from lower-middle-class or middle class families. METHODS: Indicators of neighborhood characteristics were derived from the 2012 American Community Survey and composited to create two variables representing neighborhood economic deprivation and social fragmentation. Child sleep period, actual sleep minutes, and efficiency were examined using actigraphy. RESULTS: Higher levels of neighborhood economic deprivation were associated with fewer sleep minutes and poorer sleep efficiency. More neighborhood social fragmentation was also linked with poorer sleep efficiency. Analyses controlled for demographic characteristics, child health, and family socioeconomic status. CONCLUSIONS: Findings indicate that living in economically and socially disadvantaged neighborhoods predicts risk for shorter and lower quality sleep in children. Examination of community context in addition to family and individual characteristics may provide a more comprehensive understanding of the factors shaping child sleep. PMID- 27935323 TI - Changes in Subjective Sleep Quality Before a Competition and Their Relation to Competitive Anxiety. AB - OBJECTIVE/BACKGROUND: The aim of this study was to examine the effects of competitions on subjective sleep quality. Previous studies have been inconclusive and lack differentiated and standardized measurements of subjective sleep quality. Furthermore the temporal relation between precompetitive anxiety and sleep quality was investigated. Anxiety and nervousness associated with competitions are considered to cause sleep impairments. PARTICIPANTS: A convenience sample of N = 79 elite male athletes from various sports participated. METHODS: In a time-to-event paradigm, sleep quality and competitive anxiety were assessed via standardized self-report measurements 4 days before a competition and on the day of the competition. Univariate analyses were used to examine differences between time points. To examine cross-lagged effects between anxiety and sleep quality a latent change score model (LCSM) was specified that tested an effect of anxiety on changes in sleep quality. RESULTS: Evaluations of nocturnal sleep deteriorated significantly from 4 days before competition to the day of competition, but there were no differences regarding perceptions of the restorative value of sleep. LCSM revealed that athletes who reported more intense worry symptoms 4 days before competition also reported greater deterioration in evaluations of nocturnal sleep. CONCLUSIONS: The findings support earlier reports of impaired subjective sleep quality before competitions. Precompetitive sleep impairments appear also to be preceded by cognitive anxiety. Whereas interventions should thus address worry-cognitions associated with competition and sleep, research should address the practical importance of these perceptions of sleep impairments. PMID- 27935322 TI - Physical Activity and Cognition: A Mediating Role of Efficient Sleep. AB - OBJECTIVE: Physical activity benefits executive control, but the mechanism through which this benefit occurs is unclear. Sleep is a candidate mechanism given that it improves with exercise and has restorative effects on the prefrontal cortex. The present cross-sectional study examined the mediating role of sleep in the relationship between physical activity and executive control in young and older adults. PARTICIPANTS: Young (n = 59) and older (n = 53) community dwelling adults ages 21-30 and 55-80. METHODS: Participants wore an accelerometer for one week to assess sleep efficiency, total sleep time, and physical activity, operationalized as metabolic equivalent of task (METs) during time spent awake. Cognition was assessed in the laboratory across multiple measures of executive control, memory recall, and processing speed. Mediation analyses tested the role of sleep efficiency in the cross-sectional relationship between METs and cognitive performance accounting for age, sex, and education. RESULTS: METs were significantly associated with performance before, but not after accounting for covariates. METs were associated with sleep efficiency but not total sleep time. Sleep efficiency, but not total sleep time, mediated the relationship between METs and working memory, switching, verbal ability and fluency, and recall. Age group did not moderate the mediating role of sleep efficiency in the relationship between METs and performance. CONCLUSION: Sleep efficiency is one pathway by which physical activity may be associated with executive control across young and older adults. PMID- 27935324 TI - Outcomes of haploidentical transplant compared with matched donor allogeneic stem cell transplant. AB - The risk of acute and chronic graft-versus-host disease (GVHD) with haploidentical transplant with post-transplant high-dose cyclophosphamide may be lower compared with matched unrelated donor transplant and largely similar to matched related donor transplant. The lower probability of GVHD with the haploidentical donor may result in a risk of nonrelapse mortality that is at least similar to or even lower than the matched donor. The incidence of relapse and survival are also largely similar to different donor types. Haploidentical transplant may be associated with slower engraftment. Given a lower risk of GVHD, haploidentical transplant has gained popularity. Additionally, the use of post transplant high-dose cyclophosphamide has been extended to lower the risk of GVHD with matched donor and mismatched unrelated donor transplant. PMID- 27935325 TI - Decreased baroreflex sensitivity is linked to sympathovagal imbalance, low-grade inflammation, and oxidative stress in pregnancy-induced hypertension. AB - Pregnancy-induced hypertension (PIH) has been reported as a cardiovascular (CV) risk. We assessed the sympathovagal imbalance (SVI) and the association of inflammation and oxidative stress (OS) with CV risks in PIH. A total of 125 pregnant women having a risk factor for PIH were followed till term and the incidence of PIH was observed. Retrospectively, they were divided into two groups: Group I (those who did not develop PIH, n = 82) and Group II (those who developed PIH, n = 43). Blood pressure variability (BPV) parameters including baroreflex sensitivity (BRS), spectral heart rate variability (HRV), autonomic function tests (AFTs), inflammatory markers (interleukin-6, TNF-alpha, interferon gamma), and OS markers were measured in both the groups. Alterations in parasympathetic and sympathetic components of AFTs were analyzed. Link of various parameters to BRS was assessed by correlation and multiple regression analysis. Parasympathetic components of AFTs were decreased from the early part of pregnancy and sympathetic components were increased toward the later part of pregnancy. Decreased BRS, the marker of CV risk, was more prominent in Group II subjects. Independent contribution of interleukin-6 (beta = 0.276, P = 0.020), TNF-alpha (beta = 0.408, P = 0.002), interferon-gamma (beta = 0.355, P = 0.008), and thiobarbituric-acid reactive substance (beta = 0.287, P = 0.015) to BRS was found to be significant. It was concluded that sympathetic overactivity that develops more in the later part (third trimester) of pregnancy contributes to SVI and genesis of PIH. In PIH women, CV risks are present from the beginning of pregnancy that intensifies in the later part of pregnancy. Retrograde inflammation and oxidative stress contribute to the decreased BRS in PIH. PMID- 27935326 TI - Role of CD56 in Normal Kidney Development and Wilms Tumorigenesis. AB - The cell-surface glycoprotein CD56 has three major isoforms that play important roles in cell adhesion and signaling, which may promote cell proliferation, differentiation, survival, or migration. It is an important molecule in normal kidney development and acts as a key marker in Wilms tumor stem and progenitor cells. Here, we review the structural and genetic features of the CD56 glycoprotein, and summarize its roles in the normal versus diseased metanephric blastema. We discuss areas of CD56-related research that may complement or improve existing Wilms tumor treatment strategies, including the antibody-drug conjugate lorvotuzumab mertansine that binds to CD56. PMID- 27935327 TI - Activation induced cell death (AICD) of human melanoma antigen-specific TCR engineered CD8 T cells involves JNK, Bim and p53. AB - OBJECTIVES: Adoptive cancer immunotherapy (ACT) with transgenic T cell receptor (TCR) engineered (TCReng) anti-tumor T cells has produced encouraging results, however, efficacy of these approaches need improvement. Since premature activation induced cell death (AICD) of adoptively administered T cells could be a major impediment, we examined the mechanism(s) underlying AICD in TCReng CD8+ cytolytic T lymphocytes (CTL). METHODS: AICD in human tumor antigen-specific MHC class I restricted TCR engineered CD8+ CTL was induced by exposing them to cognate peptide epitope. RESULTS: We show that TCReng CD8+ human primary CTL undergo AICD even upon encountering their cognate peptide epitope for the very first time. AICD in TCReng CTL is a death-receptor-independent, JNK activation driven intrinsic processes, in which p53-mediated mitochondria-centric, non transcription-dependent pathway plays an essential role. Activated JNK modulates mitochondrial membrane integrity in CTL undergoing AICD by directly interacting with Bcl family protein, Bim, and the mitochondrial membrane pore complex, voltage dependent anion channel (VDAC), leading to the release of caspase independent death executioner, apoptosis inducing factor (AIF), accumulation of single strand DNA breaks and eventually to cell death. CONCLUSIONS: Our findings offer opportunities to interfere with AICD in TCReng CD8+ anti-tumor CTL for sustaining them longer for producing better clinical outcomes. PMID- 27935328 TI - Advances of the HUPO Human Proteome Project with broad applications for life sciences research. PMID- 27935329 TI - Update on bipolar disorder biomarker candidates: what about uric acid/adenosine hypothesis? PMID- 27935331 TI - Ciliated Foregut Cyst of Gallbladder: A First in Childhood and Review of Literature. AB - Ciliated foregut cyst (CFC) is a rare developmental anomaly. We report first case of CFC of gallbladder diagnosed in a 9-year-old child. CFCs are usually located above the diaphragm, commonly in a bronchus or oesophagus. A duplex gallbladder was originally suspected, but histology confirmed the CFC. gallbladder. PMID- 27935330 TI - Design and optimization of thermosensitive nanoemulsion hydrogel for sustained release of praziquantel. AB - OBJECTIVE: This work aimed to develop an alternative sustained-release thermosensitive praziquantel-loaded nanoemulsion (PZQ-NE) hydrogel for better schistosomiasis treatment. SIGNIFICANCE: PZQ-NE-dispersed chitosan/glycerol 2 phosphate disodium/HPMC (NE/CS/beta-GP/HMPC) hydrogel was successfully prepared to improve bioavailability of PZQ. METHODS: Solubility tests and pseudo-ternary phase diagrams were applied to screen optimal oils, surfactants and co surfactants of NE. The hydrogels were characterized for gelling time, surface exudates, rheological properties and in vitro drug release. Formulation optimization of NE/CS/beta-GP/HMPC hydrogel was conducted by Box-Behnken experimental design combined with response surface methodology. In vitro cytotoxicity of hydrogel was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide method. The sustained-release property of PZQ in NE and optimized hydrogel was evaluated by pharmacokinetic study in rabbits. RESULTS: The formulation of PZQ-NE consisted of mass ratio of 12.5% capryol 90 containing PZQ (160 mg/g), 40% cremophor RH 40/tween 20 and transcutol HP (S/CoS = 2:1), 47.5% deionized water. PZQ releasing from NE/CS/beta-GP/HMPC hydrogels was best fitted to Higuchi model and governed by diffusion. Rheological investigation evidenced the themosensitive gelation of different hydrogel systems and their gel like character at 37 degrees C. The optimized hydrogel formulation consisted of HPMC solution (103.69 mg/g), 3.03% (w/v) chitosan and 14.1% (w/v) beta-GP showed no cytotoxicity when the addition of NE was no more than 100 mg/g. Pharmacokinetic parameters indicated that NE/CS/beta-GP/HMPC hydrogel can significantly slow down drug elimination, prolong mean residence time and improve bioavailability of PZQ. CONCLUSIONS: NE/CS/beta-GP/HMPC hydrogel possessed sustained-release property and could be an alternative antischistosomal drug delivery system with improved therapeutic effect. PMID- 27935332 TI - Intraocular Pressure after Intravitreal Triesence Injection. AB - PURPOSE: Elevated intraocular pressure (IOP) is a frequent adverse event associated with intravitreal triamcinolone acetate injection. The incidence of elevated IOP with preserved forms of triamcinolone has been studied but the effect of preservative-free formulations has not been clinically evaluated. DESIGN: A retrospective, observational clinical study. METHODS: For patients undergoing intravitreal injections over the study period, age, sex, history of glaucoma or ocular hypertension were recorded. For each injection, preinjection IOP, maximum IOP (IOPmax), dose, and indication for injection were noted for both eyes. RESULTS: Fourteen patients received 72 injections in 18 eyes. The mean baseline IOP was 15.4 mm Hg; the mean IOPmax was 19.8 mm Hg (P<0.001), occurring 63 days after injection. Outcomes were not significantly different between patients receiving 2 or 4 mg doses. History of glaucoma did not significantly affect IOPmax. CONCLUSIONS: Eyes should be monitored for IOP rises after preservative-free triamcinolone acetonide injections. PMID- 27935333 TI - Cost-utility analysis of the insufflation of warmed humidified carbon dioxide during open and laparoscopic colorectal surgery. AB - BACKGROUND: An evaluation was conducted to estimate the cost-effectiveness of insufflation of warmed humidified CO2 during open and laparoscopic colorectal surgery compared with usual care from a UK NHS perspective. METHODS: Decision analytic models were developed for open and laparoscopic surgery. Incremental costs per quality-adjusted life year (QALY) were estimated. The open surgery model used data on the incidence of intra-operative hypothermia and applied risks of complications for hypothermia and normothermia. The laparoscopic surgery model utilised data describing complications directly. Sensitivity analyses were conducted. RESULTS: Compared with usual care, insufflation of warmed humidified CO2 dominated. For open surgery, savings of L20 and incremental QALYs of 0.013 were estimated per patient. For laparoscopic surgery, savings of L345 and incremental QALYs of 0.001 per patient were estimated. Results were robust to most sensitivity analyses. CONCLUSIONS: Considering the current evidence base, the intervention is likely to be cost-effective compared with usual care in patients undergoing colorectal surgery. PMID- 27935334 TI - Antiretroviral drug-loaded nanoparticles-in-films: a new option for developing vaginal microbicides? PMID- 27935335 TI - Pediatric Chondromyxoid Fibroma-Like Osteosarcoma. AB - Chondromyxoid fibroma-like osteosarcoma (CMF-OS) is a low-grade osteosarcoma, often misdiagnosed on initial biopsy as a benign lesion, with five cases previously described. We report a 13-year-old male with an intramedullary lytic CMF-OS of the right tibial proximal metaphysis with cortical destruction and soft tissue extension. Diagnosis was based on malignant new bone formation, increased mitotic figures, lamellar bone permeation with bony destruction, and correlation with imaging studies. There were no metastasis at presentation and the tumor showed good response to standard chemotherapy with >95% necrosis. PMID- 27935336 TI - RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials. AB - INTRODUCTION: According to Hanahan and Weinberg, cancer manifests as six essential physiologic hallmarks: (1) self-sufficiency in growth signals, (2) insensitivity to growth-inhibitory signals, (3) evasion of programmed cell death, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) invasion and metastasis. As a facilitator of these traits as well as immunosuppression and chemoresistance, the presence of tumor-associated macrophages (TAMs) may serve as the seventh hallmark of cancer. Anticancer agents that successfully reprogram TAMs to target rather than support tumor cells may hold the key to better therapeutic outcomes. Areas covered: This article summarizes the characteristics of the macrophage-stimulating agent RRx-001, a molecular iconoclast, sourced from the aerospace industry, with a particular emphasis on the cell-to-cell transfer mechanism of action (RBCs to TAMs) underlying its antitumor activity as well as its chemo and radioprotective properties, consolidated from various preclinical and clinical studies. Expert opinion: RRx-001 is macrophage-stimulating agent with the potential to synergize with chemotherapy, radiotherapy and immunotherapy while simultaneously protecting normal tissues from their cytotoxic effects. Given the promising indications of activity in multiple tumor types and these normal tissue protective properties, RRx-001 may be used to treat a broad spectrum of malignancies, if it is approved in the future. PMID- 27935337 TI - Induction of interleukin-1beta by mouse mammary tumor irradiation promotes triple negative breast cancer cells invasion and metastasis development. AB - PURPOSE: Radiotherapy increases the level of inflammatory cytokines, some of which are known to promote metastasis. In a mouse model of triple negative breast cancer (TNBC), we determined whether irradiation of the mammary tumor increases the level of key cytokines and favors the development of lung metastases. MATERIALS AND METHODS: D2A1 TNBC cells were implanted in the mammary glands of a Balb/c mouse and then 7 days old tumors were irradiated (4 * 6 Gy). The cytokines IL-1beta, IL-4, IL-6, IL-10, IL-17 and MIP-2 were quantified in plasma before, midway and after irradiation. The effect of tumor irradiation on the invasion of cancer cells, the number of circulating tumor cells (CTC) and lung metastases were also measured. RESULTS: TNBC tumor irradiation significantly increased the plasma level of IL-1beta, which was associated with a greater number of CTC (3.5 fold) and lung metastases (2.3-fold), compared to sham-irradiated animals. Enhancement of D2A1 cell invasion in mammary gland was associated with an increase of the matrix metalloproteinases-2 and -9 activity (MMP-2, -9). The ability of IL-1beta to stimulate the invasiveness of irradiated D2A1 cells was confirmed by in vitro invasion chamber assays. CONCLUSION: Irradiation targeting a D2A1 tumor and its microenvironment increased the level of the inflammatory cytokine IL-1beta and was associated with the promotion of cancer cell invasion and lung metastasis development. PMID- 27935338 TI - Pars Plana Vitrectomy for Vitreomacular Traction Syndrome: Analysing the Preoperative Prognostic Factors. AB - PURPOSE: To identify the prognostic factors affecting the surgical outcomes in patients with vitreomacular traction syndrome undergoing pars plana vitrectomy. METHODS: This was a retrospective clinical study of 67 eyes of 67 patients with vitreomacular traction syndrome who underwent pars plana vitrectomy. Demographic, clinical, and optical coherence tomography (OCT) characteristics were collected and analyzed. Univariate and multivariate linear regression analysis were used to examine the effect of parameters on change in best-corrected visual acuity (BCVA). RESULTS: At a mean follow-up period of 15.9+/-12 months (mean+/-SD), the BCVA improved from 0.7+/-0.3 LogMAR (mean+/-SD) to 0.5+/-0.3. Seven patients developed full-thickness macular hole intraoperatively and tamponade (air, 20% SF6 or 12% C3F8) was used in 41 patients. Retinal breaks were identified intraoperatively in four patients. Regression analysis demonstrated that the preoperative BCVA was the only parameter affecting the postoperative visual outcome. CONCLUSION: In the present study, the preoperative BCVA plays a predictive role in the surgical outcome of patients with VMT undergoing pars plana vitrectomy. No other preoperative OCT characteristics demonstrated prognostic potential. Further prospective studies are needed in order to examine the role of several factors that could potentially facilitate preoperative patient counselling. PMID- 27935340 TI - From staff nurse to nurse consultant. AB - John Fowler, Independent education consultant, continues to explore the importance of leadership for clinically based nurses. PMID- 27935339 TI - History taking and physical assessment in holistic palliative care. AB - In carrying out a holistic palliative care assessment the palliative care clinical nurse specialist needs to develop the knowledge and skill of history taking and health assessment to make safe and competent decisions with patients regarding the future management of their care. This article examines this process in making a differential diagnosis with particular reference to the respiratory physical examination of a patient with a history of lung cancer using the Calgary Cambridge Model. The model gives structure to the preparation, history taking, and physical examination (inspection, palpation, percussion and auscultation) before explaining, planning and closing the consultation, while considering the palliative patient's and family's individual wishes and goals. PMID- 27935341 TI - Dealing with our emotions-do we just bottle things up? PMID- 27935342 TI - Nursing history: from conformity to challenging practice. AB - Elizabeth Rosser, Deputy Dean (Education and Professional Practice) and Professor of Nursing at Bournemouth University, considers the lessons that the nursing profession has learned since its early days. PMID- 27935343 TI - Change is in the air. PMID- 27935344 TI - Safe management of ileostomates with high-output stomas. AB - An ileostomy is where the small bowel is diverted to the abdominal surface resulting in the formation of a stoma. An Ileostomy can be temporary or permanent and produces loose faeces. Some ileostomates can develop high output in the early postoperative stage. Most will resolve, some will require ongoing treatment and management. While patients are monitored closely according to protocol in hospital once discharged into the community, there appears to be little standardisation. A literature search revealed that existing guidelines are for management of patients in the acute care setting. However, if not adequately prepared and monitored, patients with prolonged high output are at risk of complications including dehydration, acute kidney injury and malnutrition. This article discusses the development of a guideline aimed at improving education, monitoring and ultimately improving outcomes for patients with high-output stomas in the community. PMID- 27935345 TI - Using health psychology techniques to manage chronic physical symptoms. AB - Chest pain and palpitations, non-malignant pain, breathlessness and fatigue often endure despite the receipt of appropriate nursing and medical care. This is distressing for patients, impacts on their quality of life and ability to function and is associated with high healthcare usage and costs. The cognitive behavioural approach offers nurses a model to understand how people's perceptions and beliefs and their emotional, behavioural and physiological reactions are linked. Common 'thinking errors' which can exacerbate symptom severity and impact are highlighted. Understanding of this model may help nurses to help patients cope better with their symptoms by helping them to come up with alternative more helpful beliefs and practices. Many Improving Access to Psychological Therapy services offer support to people with chronic physical symptoms and nurses are encouraged to sign post patients to them. PMID- 27935346 TI - Obtaining informed consent to treatment: new legal dimensions. AB - John Tingle, Reader in Health Law at Nottingham Trent University, discusses the guidance on consent to treatment issued by the Royal College of Surgeons, which takes the implications of a landmark legal case into account. PMID- 27935347 TI - Incontinence pad absorption and skin barrier creams: a non-patient study. AB - Exposure of the skin to excessive moisture, such as in cases of incontinence, can damage its natural barrier function and lead to tissue damage and breakdown. Common methods for managing incontinence and preventing related skin damage include the use of incontinence pads and the application of skin barrier creams to reduce exposure to moisture and irritants. Previous reports have indicated that barrier creams can transfer onto incontinence pads from the skin and reduce their absorbency, and thus the efficacy of both products. This study, using non patient volunteers, investigated the effect on incontinence pad absorbency of Medi Derma-S and Medi Derma-Pro; two products from the Medi Skin Protection range, in comparison with other market-leading products. Results indicated that, while there was a small degree of product transfer onto the incontinence pads, this did not have a major impact on the absorption of synthetic urine. Medi Derma S and Medi Derma-Pro performed consistently with other similar market-leading products. PMID- 27935348 TI - Caring for adults with severe mental illness and physical health problems. AB - Emeritus Professor Alan Glasper, from the University of Southampton, discusses a recent report that reveals discrepancies in the management of physical health problems among people with severe mental illness. PMID- 27935349 TI - Setting staffing levels: what to consider. AB - Sam Foster, Chief Nurse at Heart of England NHS Foundation Trust, was invited to a round table discussion to debate the role of the nursing associate. She continues to review available evidence to give an informed response. PMID- 27935350 TI - Ineligibility criteria and deprivation of liberty authorisations in the community. AB - Richard Griffith, Senior Lecturer in Health Law at Swansea University, discusses the circumstances in which a person can be subject to a deprivation of liberty safeguards authorisation in the community. PMID- 27935352 TI - Praise, not punishment. PMID- 27935351 TI - Childhood constipation: recognition, management and the role of the nurse. AB - Constipation is a common childhood condition that health professionals will encounter in many different settings. The majority of these cases of childhood constipation are idiopathic in nature. It is considered to exhibit the 'tip of the iceberg' phenomenon as a large number of cases remain undetected due to under recognition by families, embarrassment regarding the condition, fear of receiving a negative response from health professionals, or parental belief there is actually something more seriously wrong and failure to accept the diagnosis. Prompt evaluation and management is likely to be associated with better outcomes. To ensure this, fast recognition of symptoms, with care taken to exclude any 'red flag' symptoms that could indicate an organic cause and subsequently a different treatment pathway, is essential. Nurses, given their regular contact with families in different settings, are suitably placed to detect these symptoms early and can play a vital role in successful management of the condition. Laxatives are the first line in management of constipation. Polyethylene glycol 3350 is the laxative that evidence-based guidelines from the National Institute for Health and Care Excellence (2010) recommend as the initial pharmacological management. Advice should also be given about supportive measures, including diet and lifestyle changes. PMID- 27935353 TI - Stoma nursing in Iran: a less equal working relationship. PMID- 27935354 TI - Convex stoma appliances: an audit of stoma care nurses. AB - This article observes the complexities surrounding the use of convex appliances within the specialist sphere of stoma care. It highlights some of the results taken from a small audit carried out with 24 stoma care nurses examining the general use of convex appliances and how usage of convex products has evolved, along with specialist stoma care practice. PMID- 27935355 TI - A shift in working patterns. PMID- 27935356 TI - Evaluation of a new ostomy mouldable seal: an international product evaluation. AB - A new mouldable seal, Brava(r) Protective Seal, was evaluated by patients on aspects related to residue, durability, and preference. A total of 135 patients from four countries participated (Denmark, Germany, Japan and the USA) and the new product was compared to the patients' usual pouching systems. Less residue and easier skin cleansing was observed, which may benefit patient quality of life. The possible benefits of less residue for peristomal skin health need further investigation. PMID- 27935357 TI - Comparing ostomates' perceptions of hydrocolloid and silicone seals: a survey. AB - Most stoma flanges are made of hydrocolloid material. Hydrocolloid is a hydrophilic material that attracts water, potentially resulting in moisture becoming trapped between the flange and skin. Also, as hydrocolloids are absorbent, the material breaks down over time, and there is a risk that some of the adhesive can remain on the skin on removal. Unlike hydrocolloids, silicone comprises fully cross-linked silicone polymers whose properties have been engineered to manage moisture without breaking down (i.e. manage the transepidermal water loss (TEWL)). A questionnaire survey was undertaken to determine ostomates' perceptions of silicone versus hydrocolloid stoma care products (both flanges and seals). The survey was sent to 229 ostomates who had used silicone seals, of whom 78 returned it (a response rate of 34%). The results suggest that use of the silicone seals resulted in a improvement in the condition of the peristomal skin condition, reduced leakage and increased wear time. Further research into this area is required. PMID- 27935358 TI - Convergent lines of evidence support the role of uric acid levels as a potential biomarker in bipolar disorder. PMID- 27935359 TI - Microsurgical and endoscopic approaches to the pulvinar. AB - OBJECTIVE Approaches to the pulvinar remain challenging because of the depth of the target, surrounding critical neural structures, and complicated arterial and venous relationships. The purpose of this study was to compare the surgical approaches to different parts of the pulvinar and to examine the efficacy of the endoscope as an adjunct to the operating microscope in this area. METHODS The pulvinar was examined in 6 formalin-fixed human cadaveric heads through 5 approaches: 4 above and 1 below the tentorium. Each approach was performed using both the surgical microscope and 0 degrees or 45 degrees rigid endoscopes. RESULTS The pulvinar has a lateral ventricular and a medial cisternal surface that are separated by the fornix and the choroidal fissure, which wrap around the posterior surface of the pulvinar. The medial cisternal part of the pulvinar can be further divided into upper and lower parts. The superior parietal lobule approach is suitable for lesions in the upper ventricular and cisternal parts. Interhemispheric precuneus and posterior transcallosal approaches are suitable for lesions in the part of the pulvinar forming the anterior wall of the atrium and adjacent cisternal part. The posterior interhemispheric transtentorial approach is suitable for lesions in the lower cisternal part and the supracerebellar infratentorial approach is suitable for lesions in the inferior and medial cisternal parts. The microscope provided satisfactory views of the ventricular and cisternal surfaces of the pulvinar and adjacent neural and vascular structures. The endoscope provided multi-angled and wider views of the pulvinar and adjacent structures. CONCLUSIONS A combination of endoscopic and microsurgical techniques allows optimal exposure of the pulvinar. PMID- 27935360 TI - The effect of postoperative infection on survival in patients with glioblastoma. AB - OBJECTIVE Glioblastoma is a primary glial neoplasm with a median survival of approximately 1 year. There are anecdotal reports that postoperative infection may confer a survival advantage in patients with glioblastoma. However, only a few case reports in the literature, along with 2 retrospective cohort studies, show some potential link between infection and prolonged survival in patients with glioblastoma. The objective of this study was to evaluate the effect of postoperative infection in patients with glioblastoma using a large national database. METHODS The linked Surveillance, Epidemiology, and End Results (SEER) Medicare database was searched to identify patients 66 years of age and older with glioblastoma, with and without infection, from 1997 to 2010. The primary outcome was survival after diagnosis. The statistical analysis was performed with a graphical representation using Kaplan-Meier curves, univariate analysis with the log-rank test, and multivariate analysis with proportional hazards modeling. RESULTS A total of 3784 patients with glioblastoma were identified from the database, and from these, 369 (9.8%) had postoperative infection within 1 month of surgery. In patients with glioblastoma who had an infection within 1 month of surgery, there was no significant difference in survival (median 5 months) compared with patients with no infection (median 6 months; p = 0.17). The study also showed that older age, increased Gagne comorbidity score, and having diabetes may be negatively associated with survival. CONCLUSIONS Infection after craniotomy within 1 month was not associated with a survival benefit in patients with glioblastoma. PMID- 27935361 TI - Acute impairment of saccadic eye movements is associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE Delayed cerebral ischemia (DCI) causing cerebral infarction remains a significant cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH). Early brain injury in the first 72 hours following rupture is likely to play a key role in the pathophysiology underlying DCI but remains difficult to quantify objectively. Current diagnostic modalities are based on the concept of vasoconstriction causing cerebral ischemia and infarction and are either invasive or have a steep learning curve and user variability. The authors sought to determine whether saccadic eye movements are impaired following aSAH and whether this measurement in the acute period is associated with the likelihood of developing DCI. METHODS As part of a prospective, observational cohort study, 24 male and female patients (mean age 53 years old, range 31-70 years old) were recruited. Inclusion criteria included presentation with World Federation of Neurosurgical Societies (WFNS) Grades 1 or 2 ("good grade") aSAH on admission and endovascular treatment within 72 hours of aneurysmal rupture. DCI and DCI-related cerebral infarction were defined according to consensus guidelines. Saccadometry data were collected at 3 time points in patients: in the first 72 hours, between Days 5 and 10, and at 3 months after aSAH. Data from 10 healthy controls was collected on 1 occasion for comparison. RESULTS Age-adjusted saccadic latency in patients was significantly prolonged in the first 72 hours following aSAH when compared with controls (188.7 msec [95% CI 176.9-202.2 msec] vs 160.7 msec [95% CI 145.6-179.4 msec], respectively; p = 0.0054, t-test). By 3 months after aSAH, there was no significant difference in median saccadic latency compared with controls (188.7 msec [95% CI 176.9-202.2 msec] vs 180.0 msec [95% CI 165.1-197.8 msec], respectively; p = 0.4175, t-test). Patients diagnosed with cerebral infarction due to DCI had a significantly higher age-adjusted saccadic latency in the first 72 hours than those without infarction (240.6 msec [95% CI 216.7-270.3 msec] vs 204.1 msec [95% CI 190.7-219.5 msec], respectively; p = 0.0157, t-test). This difference was more pronounced during Days 5-10 following aSAH, the peak incidence for DCI (303.7 msec [95% CI 266.7-352.7 msec] vs 207.6 msec [95% CI 193.7-223.6 msec], respectively; p < 0.0001, t-test). A binary generalized linear model showed that latency in the first 72 hours was the only significant predictor of cerebral infarction (p = 0.0185). CONCLUSIONS This is the first study to use saccadometry to measure the saccadic latency of eye movements in patients with aSAH during the acute period following aneurysm rupture. The results showed that median saccadic latency is associated with the risk of developing cerebral infarction due to DCI and may act as a potential objective biomarker to guide the need for intensive care admission and treatment. Future studies will look to formally validate saccadic latency as a biomarker of DCI in a larger cohort and assess whether the addition of saccades improves current clinical models for predicting patients at risk. PMID- 27935362 TI - Dramatic radiographic response resulting in cerebrospinal fluid rhinorrhea associated with sunitinib therapy in recurrent atypical meningioma: case report. AB - Sunitinib is a multiple tyrosine kinase inhibitor with antiangiogenic, cytostatic, and antimigratory activity for meningiomas. A recent clinical trial of sunitinib for treatment of recurrent Grade II and III meningiomas suggested potential efficacy in this population, but only 2 patients exhibited significant radiographic response with tumor volume reduction. The authors illustrate another such case and discuss a complication related to this dramatic tumor volume reduction in aggressive skull base meningiomas. The authors describe the case of a 39-year-old woman who had undergone repeat surgical interventions and courses of radiotherapy over the previous 11 years for recurrent cranial and spinal meningiomas. Despite 4 operations over the course of 4 years on her right petroclival meningioma with cavernous sinus and jugular fossa extensions, she had progressive neurological deficits and tumor recurrences. The specimen histology progressed from WHO Grade I initially to Grade II at the time of the third recurrence. The lesion was then irradiated 3 times using stereotactic radiosurgery for further recurrences. More recently, the tumor size increased rapidly on imaging, in association with progressive neurological symptoms arising from brainstem compression and vasogenic edema. Institution of sunitinib therapy yielded a dramatic radiographic response, with marked reduction in the tumor volume and reduction of brainstem vasogenic edema within a few weeks of initiation of treatment. The significant radiographic response of tumor in the clival region was also associated with CSF rhinorrhea from a dural breach created by resolution of the invasive skull base meningioma, which necessitated withholding the sunitinib medication. To address the leak, the authors undertook surgical exploration and transsphenoidal packing using an autologous fat graft and a vascularized pedicled nasoseptal flap. The patient has done well during follow-up of 3 months after packing, with no evidence of recurrent CSF leak, and the medication was subsequently restarted. Prior clinical data and the dramatic radiographic response in this patient suggest that sunitinib holds promising therapeutic potential in carefully selected patients with recurrent atypical meningiomas where conventional strategies have been exhausted. There is a potential risk of associated CSF rhinorrhea, especially in more invasive skull base lesions showing dramatic radiographic response. PMID- 27935364 TI - Methicillin-resistant Staphylococcus aureus. AB - This article examines some of the issues involved in the management and control of MRSA colonisation and infection in wounds. PMID- 27935365 TI - Readers' Questions. AB - Q How can you accurately assess pressure damage on patients with darkly pigmented skins? A The identification of pressure damage in patients with darkly pigmented skin has always been difficult as it does not exhibit the characteristic erythematous changes normally associated with pressure damage in Caucasian skin. PMID- 27935374 TI - From the Journals. AB - TISSUE SEALANTS AIR-FLUIDISED BEDS TISSUE CONCENTRATIONS OF ANTIBIOTICS. PMID- 27935375 TI - Post-infectious Uveitis. PMID- 27935376 TI - Mesenchymal Stem Cells Modulate Light-induced Activation of Retinal Microglia Through CX3CL1/CX3CR1 Signaling. AB - PURPOSE: To evaluate the effect of CX3CL1/CX3CR1 signaling on the interaction between mesenchymal stem cells (MSCs) and retinal microglia. METHODS: Supernatants of homogenized retina were harvested from light-damaged SD rats (ISHR) to stimulated retinal microglia. Stimulated microglia were cocultured with MSCs, CX3CL1 over-expressing MSCs (CX3CL1-MSCs) or CX3CL1-blocked MSCs (anti CX3CL1-MSCs) for 24 hours, and their molecular and functional changes were examined. Moreover, soluble CX3CL1 was directly added to microglia cultures. RESULTS: ISHR stimulation activated retinal microglia. MSCs coculture inhibited the protein expression of pro-inflammatory factors by activated microglia, increased the protein expression of neurotrophic factors, and was accompanied with upregulation of CX3CR1. Meanwhile, MSCs suppressed proliferative and migratory function of activated microglia, but promoted the phagocytic capability. These effects were strengthened by CX3CL1- MSCs, and reversed by anti CX3CL1-MSCs. Soluble CX3CL1 could enhanced microglial migration. CONCLUSIONS: MSCs might restore homeostatic functions of retinal microglia responded to light damage mainly through CX3CL1/CX3CR1 signaling. PMID- 27935378 TI - From the Journals. AB - FINDING THE TRUE PREVALENCE OF LEG ULCERS WOUND CARE AND MRSA. PMID- 27935379 TI - Compression therapy for leg disorders: Critique 2. AB - This paper reviews compression therapy of the lower extremities and lays down guidelines for the levels of compression that are required to counteract different degrees of increased tissue pressure. PMID- 27935380 TI - Compression therapy for leg disorders. AB - Two critiques review the paper cited below and discuss its influence on compression therapy. PMID- 27935381 TI - Management of neuropathie ulceration. AB - Patients with diabetes who develop neuropathic foot ulcers are often managed with prolonged bed-rest or given a total contact cast. As these methods are not ideal for many patients, we examined a boot cast as an alternative approach to treating intractable neuropathic ulcers. PMID- 27935382 TI - The Norton score and pressure sore prevention: Critique II. AB - The prevention and management of pressure sores presents enormous challenges to health professionals, particularly those working in specialties such as elderly care or spinal Injuries. Bringing together the findings of three investigations and offering practical guidance to nursing colleagues, this frequently quoted study has become established as a key contribution to pressure area care. Certainly the work displays great foresight and conviction that something could, and indeed should, be done about pressure area care. Given the importance attached to this work, however, it is of concern that a number of methodological and analytical oversights cast doubt on the validity of the conclusions. PMID- 27935383 TI - Editorial. AB - Towards consensus Biosurgery in wound healing. PMID- 27935384 TI - From the Journals. AB - PSYCHOSOCIAL FACTORS AND LEG ULCER HEALING IN OLDER PATIENTSM THE USE OF NON ADHERENT DRESSINGS IN SKIN-GRAFT MANAGEMENT VIDEO TECHNIQUE FOR MEASURING WOUND SIZE COMPRESSION HOSIERY AND VENOUS LEG ULCERS VENOUS LEG ULCERS AND QUALITY OF LIFE PRESSURE SORE GRADING SCALES AND INTER-RATER RELIABILITY VITAMIN SUPPLEMENTS AND DIETARY INTAKE IN OLDER PEOPLE. PMID- 27935385 TI - Hydroactive dressings and serum proteins: an in vitro study. AB - An in vitro approach was used to obtain information about the compatibility of hydroactive dressing materials with the serum proteins which are thought to be relevant to wound healing. Artificial wound fluid was incubated with different hydroactive dressings (Cutinova hydro, Varihesive E, Comfeel Ulcer Dressing and Allevyn), and concentrations of total protein, albumin, immunoglobulin and growth factors were measured after one day of incubation. Cutinova hydro and Allevyn absorbed considerable amounts of fluid. Fluid uptake was lower for the hydrocolloid dressings. An unexpected finding was that Cutinova hydro showed an approximately two-fold increase over control values in the concentration of all proteins tested, indicating a selective absorption of water by this dressing. For the other dressings tested, zero or very low absorption of proteins was found, indicating a basically satisfactory protein compatibility. PMID- 27935386 TI - The Norton score and pressure sore prevention: Critique III. AB - Were you to ask any group of nurses to name the single piece of nursing research which has had most influence on clinical practice, it is likely that a significant number would answer: 'Norton'. The 'Norton score' has already been the subject of considerable comment1-4, and it is not the purpose here to provide a critique of the critics. PMID- 27935387 TI - Readers' Questions. AB - DIFFICULTIES WITH DOPPLER ABPI MEASUREMENTS MORHULIN CREAM NOT RECOMMENDED FOR SUPERFICIAL SORES. PMID- 27935388 TI - The Norton score and pressure sore prevention. AB - Three critiques review the classic paper cited below and discuss its influence on the prevention of pressure sores in patients at risk. PMID- 27935389 TI - The effect of Interaction Anxiousness Scale and Brief Social Phobia Scale for screening social anxiety disorder in college students: a study on discriminative validity. AB - BACKGROUND: Social anxiety disorder (SAD) is one of the most prevalent mental health problems, but there is little research concerning the effective screening instruments in practice. METHODS: This study was designed to examine the discriminative validity of Interaction Anxiousness Scale (IAS) and Brief Social Phobia Scale (BSPS) for the screening of SAD through the compared and combined analysis. Firstly, 421 Chinese undergraduates were screened by the IAS and BSPS. Secondly, in the follow-up stage, 248 students were interviewed by the Structured Clinical Interview for DSM-IV. Receiver operating characteristic (ROC) analysis was used, and the related psychometric characters were checked. RESULTS: The results indicated that the ROC in these two scales demonstrated discrimination is in satisfactory level (range: 0.7-0.8). However, the highest agreement (92.17%) was identified when a cut-off point of 50 measured by the IAS and a cut-off point of 34 by the BSPS were combined, also with higher PPV, SENS, SPEC and OA than that reached when BSPS was used individually, as well as PPV, SPEC and OA in IAS. CONCLUSION: The findings indicate that the combination of these two scales is valid as the general screening instrument for SAD in maximizing the discriminative validity. PMID- 27935390 TI - Highly Sensitive People in an Insensitive World: How to Create a Happy Life. PMID- 27935391 TI - Assessment of Mental Capacity: a Practical Guide for Doctors and Lawyers. PMID- 27935392 TI - Sleep disturbance among people with major depressive disorders (MDD) in Singapore. AB - BACKGROUND: Sleep problems are common with major depressive disorder (MDD), which has been identified as the most pervasive mental disorder in Singapore. AIMS: This study aimed to establish the prevalence of sleep disturbance among adults with lifetime and 12-month MDD, as well as its socio-demographic and clinical correlates. METHOD: Data were collected from the Singapore Mental Health Study, a cross-sectional epidemiological survey of the local residential population aged >=18 years. Using the CIDI 3.0, 417 and 181 respondents with lifetime and 12 month MDD were included in the analysis. RESULTS: The prevalence of insomnia related sleep disturbance among those with lifetime and 12-month MDD was 90.9% and 91.4%, respectively. Multiple logistic regression analyses revealed ethnicity, education and the number of depressive episodes as well as clinical comorbidities such as obsessive compulsive disorder, diabetes and hypertension to be significantly associated with sleep disturbance among those with lifetime MDD. However, only 28.6% of those with sleep disturbance sought help from a professional. CONCLUSIONS: The proportion of Singaporeans with MDD who have sleep disturbance is high, with increased risk for mental and physical health problems. Given the low rate of treatment contact, individuals with MDD must be screened and treated for sleep disturbance. PMID- 27935393 TI - Autonomy and Mental Disorder. PMID- 27935395 TI - The Journal of Mental Health would like to thank all our reviewers for 2016. PMID- 27935394 TI - Personality Disorders. PMID- 27935396 TI - The use of antiseptics in wound care. AB - Three critiques review the classic paper cited below and discuss its influence on developments in wound care. PMID- 27935397 TI - The use of antiseptics in wound care: Critique II. AB - This frequently referenced paper is a review of the use of antiseptics and antimicrobials in wound healing. It is often used in support of arguments for banning antiseptics. Careful reading suggests that this is a misinterpretation. The authors, while accepting the ritualistic approach of many clinicians in treating chronic wounds, state that there is a need to question procedure, particularly in relation to the use of antiseptics and antimicrobials. PMID- 27935398 TI - From the Journals. AB - THE EFFECT OF PSYCHOLOGICAL STRESS ON WOUND HEALING GRADING LEG ULCERS AGEING AND DISABILITY IN SPINAL CORD INJURY NURSE PRESCRIBING MRSA IN THE COMMUNITY. PMID- 27935399 TI - The use of antiseptics in wound care: Critique III. AB - Leaper and his colleagues were a seminal force in challenging and changing wound care practice. Three key issues emerge from their paper1, each of which warrants reconsideration today. First, the basis of their philosophy about the use of chemical agents in open wounds; second, the research evidence they used to support their case; and third, why the nursing profession reacted so positively to their message. PMID- 27935400 TI - Reviews. AB - TRACE ELEMENT MEDICINE AND CHELATION THERAPY WOUND CARE FOR HEALTH PROFESSIONALS. PMID- 27935402 TI - Editorial. AB - Journal of Wound Care awards Lies, damned lies and statistics. PMID- 27935401 TI - Letters. AB - COMMUNITY CLINICS FOR LEG ULCERS COMMUNITY CLINICS IMPROVE HEALING RATES AND QUALITY OF LIFE ABSORBENCY OF PERFORATED FILM WOUND DRESSINGS CORRECT TECHNIQUE FOR ABPI MEASUREMENT. PMID- 27935403 TI - Quality of life measurement tools. AB - The following three papers describe various measurement tools used to assess the effects of chronic wounds on patients' quality of life. PMID- 27935404 TI - The Nottingham Health Profile. AB - One hundred and twenty-five patients with chronic leg ulcers were involved in a study examining quality-of-life parameters1. The study aims were to investigate if leg ulcers influence quality of life and whether gender, age, present or previous profession and duration of the ulcer influence patients' perceptions of quality of life. PMID- 27935405 TI - Reviews. AB - THE DIABETIC FOOT: AN ILLUSTRATED GUIDE TO MANAGEMENT WOUND CARE MANUAL. PMID- 27935406 TI - Generic tools. AB - Health is a complex concept. In 1946, the World Health Organization (WHO) defined it as 'a state of complete physical, mental and social well-being, and not merely the absence of disease and infirmity'1. 'Ill' health could thus be defined as feelings of pain and discomfort or change in usual functioning and feeling. PMID- 27935407 TI - Letters. AB - MAGGOTS - A PERSONAL EXPERIENCE ABPI TECHNIQUES VAPOUR-PERMEABLE DRESSINGS PRESSURE SORES AND SPINAL CORD INJURY DANGERS OF TOWEL CLIPS. PMID- 27935408 TI - From the Journals. AB - RISK FACTORS IN THE HEALING OF VENOUS ULCERS THE ACTIVATION AND EFFECTS OF NEUTROPHILS AND MONOCYTES COMPRESSION STOCKINGS AND LEG ULCER RECURRENCE PRESSURE SORE PREVENTION AND TREATMENT. PMID- 27935409 TI - Thrombolysis and Varidase Dressing. AB - THROMBOLYSIS AND VARIDASE DRESSING. PMID- 27935410 TI - Establishment of a high-throughput detection system for DNA demethylating agents. AB - Epigenetic alterations underlie various human disorders, including cancer, and this has resulted in the development of drugs targeting epigenetic alterations. Although DNA demethylating agents are one of the major epigenetic drugs, only two compounds-5-azacytidine (5-aza-CR, azacitidine) and 5-aza-2'-deoxycytidine (5-aza dC, decitabine)-have obtained clinical approval. Here, we aimed to establish a detection system for DNA demethylating agents suitable for a high-throughput screening (HTS) in mammalian cells. We inserted luciferase and EGFP reporter genes under the UCHL1 promoter, which is methylation-silenced in human colon cancers and can be readily demethylated to drive strong expression. Methylated UCHL1 promoter was introduced into HCT116 colon cancer cells, and transfectants with methylated exogenous UCHL1 promoter were obtained. By screening subclones from each of the epigenetically heterogeneous transfectant clones, we finally obtained three optimal subclones that expressed luciferase and EGFP after 5-aza dC treatment with high signal-to-noise ratios. Nucleosomes with H3K9me2 were present around the exogenous UCHL1 promoter in all three subclones. Using one of the subclones (HML58-3), HTS was conducted using 19,840 small molecules. Two hit compounds were obtained, and these turned out to be 5-aza-dC and 5-aza-CR. The assay system constructed here demonstrates a robust response to DNA demethylating agents, along with high specificity, and will be useful for screening and biological assays in epigenetics. PMID- 27935411 TI - Climacteric ripening of apple fruit is regulated by transcriptional circuits stimulated by cross-talks between ethylene and auxin. AB - Apple is a fleshy fruit distinguished by a climacteric type of ripening, since most of the relevant physiological changes are triggered and governed by the action of ethylene. After its production, this hormone is perceived by a series of receptors to regulate, through a signaling cascade, downstream ethylene related genes. The possibility to control the effect of ethylene opened new horizons to the improvement of the postharvest fruit quality. To this end, 1 methylcyclopropene (1-MCP), an ethylene antagonist, is routinely used to modulate the ripening progression increasing storage life. In a recent work published in The Plant Journal, the whole transcriptome variation throughout fruit development and ripening, with the adjunct comparison between normal and impaired postharvest ripening, has been illustrated. In particular, besides the expected downregulation of ethylene-regulated genes, we shed light on a regulatory circuit leading to de-repressing the expression of a specific set of genes following 1 MCP treatment, such as AUX/IAA, NAC and MADS. These findings suggested the existence of a possible ethylene/auxin cross-talk in apple, regulated by a transcriptional circuit stimulated by the interference at the ethylene receptor level. PMID- 27935412 TI - Rice OsERF71-mediated root modification affects shoot drought tolerance. AB - Drought is the most serious problem that impedes crop development and productivity worldwide. Although several studies have documented the root architecture adaption for drought tolerance, little is known about the underlying molecular mechanisms. Our latest study demonstrated that overexpression of the OsERF71 in rice roots under drought conditions modifies root structure including larger aerenchyma and radial root growth, and thereby, protects the rice plants from drought stresses. The OsERF71-mediated root modifications are caused by combinatory overexpression of general stress-inducible, cell wall-associated and lignin biosynthesis genes that contribute to drought tolerance. Here we addressed that the OsERF71-mediated root modifications alter physiological capacity in shoots without evidence of developmental changes for drought tolerance. Thus, the OsERF71-mediated root modifications provide novel molecular insights into drought tolerance mechanisms. PMID- 27935415 TI - The management of chronic ulceration. AB - The following case report illustrates the long-term difficulties facing many patients with chronic wounds and the management options available. PMID- 27935413 TI - Stable core virome despite variable microbiome after fecal transfer. AB - We recently described the 4.5-year time course of the enteric bacterial microbiota and virome of a patient cured from recurrent Clostridium difficile infection (rCDI) by fecal microbiota transplantation (FMT). Here, we extended the virome analyses and found the patient's phage population to exhibit highly donor similar characteristics following FMT, which remained stable for the whole period tested (up to 7 months). Moreover, the detected viral populations of donor and patient exhibited comparable diversity and richness. These findings were unexpected since enteric viromes are normally highly variable, assumed to influence the bacterial host community and change with environmental conditions. In contrast to the virome, the bacterial microbiota varied indeed for more than 7 months with ongoing dysbiosis before it reached donor similarity. Our findings that are based on sequence information and protein domain analysis seem to suggest that stable phage properties correlate with successful FMT better than the changing bacterial communities. We speculate that we here preferentially detected a stable core virome, which dominated over a variable flexible virome that may have been too heterogeneous for experimental detection or was underrepresented in the databases. It will be interesting to analyze whether the enteric virome allows predictions for the clinical outcome of FMT for rCDI and other diseases such as inflammatory bowel disease or obesity. PMID- 27935414 TI - Blue light does not inhibit nodulation in Sesbania rostrata. AB - Earlier, we reported that root nodulation was inhibited by blue light irradiation of Lotus japonicus. Because some legumes do not establish nodules exclusively on underground roots, we investigated whether nodule formation in Sesbania rostrata, which forms both root and "stem" nodules following inoculation with Azorhizobium caulinodans, is inhibited by blue light as are L. japonicus nodules. We found that neither S. rostrata nodulation nor nitrogen fixation was inhibited by blue light exposure. Moreover, although A. caulinodans proliferation was not affected by blue light irradiation, bacterial survival was decreased. Therefore, blue light appears to impose different responses depending on the legume-rhizobial symbiosis. PMID- 27935416 TI - From the Journals. AB - THE DIAGNOSIS AND MANAGEMENT OF LEG ULCERS IN THE COMMUNITY NO STANDARD FOR SKIN CARE IN PATIENTS WITH INCONTINENCE PROBLEMS ASSESSING PRESSURE SORE RISK. PMID- 27935417 TI - Editorial. AB - Wound care awards Hand care. PMID- 27935418 TI - Evaluation of a hydrocolloid dressing. AB - A hydrocolloid dressing was compared to adhesive skin tapes on children's postoperative wounds. A total of 170 children of varying ages were randomised in two parallel groups, in nine centres of plastic, thoracic, gastrointestinal, urogenital and orthopaedic surgery. Skin closure was satisfactory in both groups, with 76 (89.4%) healthy closures without dehiscence in the hydrocolloid group and 81(95.3%) in the control group; a relationship was found between partial closures/dehiscence and the type of surgical procedure. No product-related maceration, infection or adverse event was reported during the study and both groups showed very satisfactory cosmetic results. PMID- 27935419 TI - Is there really an eccentric action of the hamstrings during the swing phase of high-speed running? Part II: Implications for exercise. AB - We have previously argued that there may actually be no significant eccentric, but rather predominantly an isometric action of the hamstring muscle fibres during the swing phase of high-speed running when the attachment points of the hamstrings are moving apart. Based on this we suggested that isometric rather than eccentric exercises are a more specific way of conditioning the hamstrings for high-speed running. In this review we argue that some of the presumed beneficial adaptations following eccentric training may actually not be related to the eccentric muscle fibre action, but to other factors such as exercise intensity. Furthermore, we discuss several disadvantages associated with commonly used eccentric hamstring exercises. Subsequently, we argue that high-intensity isometric exercises in which the series elastic element stretches and recoils may be equally or even more effective at conditioning the hamstrings for high-speed running, since they also avoid some of the negative side effects associated with eccentric training. We provide several criteria that exercises should fulfil to effectively condition the hamstrings for high-speed running. Adherence to these criteria will guarantee specificity with regards to hamstrings functioning during running. Practical examples of isometric exercises that likely meet several criteria are provided. PMID- 27935420 TI - The epigenetic regulation of Dicer and microRNA biogenesis by Panobinostat. AB - microRNAs (miRs) are small noncoding RNAs that regulate/fine tune many cellular protein networks by targeting mRNAs for either degradation or translational inhibition. Dicer, a type III endoribonuclease, is a critical component in miR biogenesis and is required for mature microRNA production. Abnormal Dicer expression occurs in numerous cancer types and correlates with poor patient prognosis. Recent reports have demonstrated that epigenetic agents, including histone deacetylase inhibitors (HDACi), may regulate Dicer and miR expression. HDACi are a class of epigenetic agents used to treat cancer, viral infections, and inflammatory disorders. However, little is known regarding the epigenetic regulation of miR biogenesis and function. We therefore investigated whether clinically successful HDACi modulated Dicer expression and found that Panobinostat, a clinically approved HDACi, enhanced Dicer expression via posttranscriptional mechanisms. Studies using proteasome inhibitors suggested that Panobinostat regulated the proteasomal degradation of Dicer. Further studies demonstrated that Panobinostat, despite increasing Dicer protein expression, decreased Dicer activity. This suggests that Dicer protein levels do not necessarily correlate with Dicer activity and mature miR levels. Taken together, we present evidence here that Panobinostat posttranscriptionally regulates Dicer/miR biogenesis and suggest Dicer as a potential therapeutic target in cancer. PMID- 27935421 TI - The effect of westward travel across five time zones on sleep and subjective jet lag ratings in athletes before and during the 2015's World Rowing Junior Championships. AB - This study examined sleep-wake habits and subjective jet-lag ratings of 55 German junior rowers (n = 30 male, 17.8 +/- 0.5 years) before and during the World Rowing Junior Championships 2015 in Rio de Janeiro, Brazil. Athletes answered sleep logs every morning, and Liverpool John Moore's University Jet-Lag Questionnaires each evening and morning. Following an 11-h westward flight with 5 h time shift, advanced bedtimes (-1 h, P < .001, etap2 = 0.68), reduced sleep onset latency (P = .002, etap2 = 0.53) and increased sleep duration (P < .001, etap2 = 0.60) were reported for the first two nights. Jet-lag symptoms peaked upon arrival but were still present after 6 days. Sleep quality improved (P < .001, etap2 = 0.31) as well as some scales of the Recovery-Stress Questionnaire for Athletes. Participation was successful as indicated by 11 of 13 top 3 placings. Overall, the initial desynchronisation did not indicate negative impacts on competition performance. As travel fatigue probably had a major effect on perceptual decrements, sleep during travel and time to recover upon arrival should be emphasised. Coaches and practitioners should consider higher sleep propensity in the early evening by scheduling training sessions and meetings until the late afternoon. PMID- 27935422 TI - A knock to the system: A new sociotechnical systems approach to sport-related concussion. AB - Broader contextual factors that influence concussion management have tended to be overlooked. To address this, the present study used a sociotechnical systems approach to identify perceived responsibilities and applied strategies for three domains of concussion management (i.e., prevention, identification and treatment). Participants were 118 members of the community rugby union system in Australia (69.2% male). Participants from throughout the rugby system (e.g., players, parents, coaches, club management) were asked open-ended questions about their perceived responsibilities and the strategies they use for concussion management. It was found that (a) proper training, technique correction and education were recurrent prevention themes; (b) the majority of key stakeholders felt that they could consistently identify concussion; however, medical aids (medics) were the only system actors who stated a responsibility to use standardised concussion assessment measures and (c) less than one third of the respondents indicated their involvement in treating concussion. This study identifies specific junctures in the system that prevents effective concussion management strategies. A sociotechnical systems approach improves the understanding of concussion prevention, and management beliefs and behaviours. PMID- 27935423 TI - The effect of unilateral balance training on postural control of the contralateral limb. AB - To investigate the impact of unilateral balance training on postural control of the trained and contralateral limb in healthy elderly. Fifty-one healthy old adults were randomly assigned into training group (TG) and control group (CG). Participants of the TG performed unilateral balance training (dominant (DOM) leg) over 4 weeks (4*/week). Centre of pressure analysis was performed at baseline, 5 weeks follow-up and 9 weeks follow-up under the following conditions: (1) one-leg stance without additional task, (2) one-leg stance with motor task and (3) one leg stance with cognitive task. From baseline to 5 weeks follow-up, a mixed analysis of variance detected a significant time * group interaction for the DOM leg (P < 0.05), indicating higher improvement of the TG in comparison to CG. No significant interaction effect was found for the non-DOM leg. Within the TG, the non-DOM leg significantly improved in mean velocity (P = 0.001) and anterior posterior range (P < 0.001). Unilateral balance training was effective to improve postural control of the trained leg. The effect on the contralateral leg was small and not significant within this study design. Improvements were retained after 4 weeks without training. A tendency is given that unilateral balance training might be beneficial to improve postural control of the contralateral leg. PMID- 27935424 TI - Structural dynamics and DNA interaction of human TFIID. AB - TFIID is a large protein complex required for the recognition and binding of eukaryotic gene core promoter sequences and for the recruitment of the rest of the general transcription factors involved in initiation of eukaryotic protein gene transcription. Cryo-electron microscopy studies have demonstrated the conformational complexity of human TFIID, where one-third of the mass of the complex can shift its position by well over 100 A. This conformational plasticity appears to be linked to the capacity of TFIID to bind DNA, and suggests how it would allow both the recognition of different core promoter elements and the tuning of its binding affinity by regulatory factors. PMID- 27935426 TI - Joint stiffness and running economy during imposed forefoot strike before and after a long run in rearfoot strike runners. AB - Research has focused on the effects of acute strike pattern modifications on lower extremity joint stiffness and running economy (RE). Strike pattern modifications on running biomechanics have mostly been studied while runners complete short running bouts. This study examined the effects of an imposed forefoot strike (FFS) on RE and ankle and knee joint stiffness before and after a long run in habitual rearfoot strike (RFS) runners. Joint kinetics and RE were collected before and after a long run. Sagittal joint kinetics were computed from kinematic and ground reaction force data that were collected during over-ground running trials in 13 male runners. RE was measured during treadmill running. Knee flexion range of motion, knee extensor moment and ankle joint stiffness were lower while plantarflexor moment and knee joint stiffness were greater during imposed FFS compared with RFS. The long run did not influence the difference in ankle and knee joint stiffness between strike patterns. Runners were more economical during RFS than imposed FFS and RE was not influenced by the long run. These findings suggest that using a FFS pattern towards the end of a long run may not be mechanically or metabolically beneficial for well-trained male RFS runners. PMID- 27935427 TI - Short-term heat acclimation prior to a multi-day desert ultra-marathon improves physiological and psychological responses without compromising immune status. AB - Multistage, ultra-endurance events in hot, humid conditions necessitate thermal adaptation, often achieved through short term heat acclimation (STHA), to improve performance by reducing thermoregulatory strain and perceptions of heat stress. This study investigated the physiological, perceptual and immunological responses to STHA prior to the Marathon des Sables. Eight athletes (age 42 +/- 4 years and body mass 81.9 +/- 15.0 kg) completed 4 days of controlled hyperthermia STHA (60 min.day-1, 45 degrees C and 30% relative humidity). Pre, during and post sessions, physiological and perceptual measures were recorded. Immunological measures were recorded pre-post sessions 1 and 4. STHA improved thermal comfort (P = 0.02), sensation (P = 0.03) and perceived exertion (P = 0.04). A dissociated relationship between perceptual fatigue and Tre was evident after STHA, with reductions in perceived Physical (P = 0.04) and General (P = 0.04) fatigue. Exercising Tre and HR did not change (P > 0.05) however, sweat rate increased 14% (P = 0.02). No changes were found in white blood cell counts or content (P > 0.05). Four days of STHA facilitates effective perceptual adaptations, without compromising immune status prior to an ultra-endurance race in heat stress. A greater physiological strain is required to confer optimal physiological adaptations. PMID- 27935425 TI - How is Herstatin, a tumor suppressor splice variant of the oncogene HER2, regulated? AB - The human epidermal growth factor receptor 2 (HER2)/receptor tyrosine-protein kinasebB-2 (ERBB2) is overexpressed in 20-30% of breast tumors leading to faster growing and more aggressive tumors. Alternative splicing generates a functionally distinct HER2 variant called Herstatin, which is produced by the inclusion of intron 8. Herstatin acts as a tumor suppressor by effectively blocking HER2 activity and cell proliferation, while promoting apoptosis. In the present study we investigated HER2 pre-mRNA regulatory sequences and splicing factors which regulate the alternative splicing of Herstatin. A Herstatin minigene, comprising exon 8/intron 8/exon 9 of HER2 was generated and subsequent in vitro splicing assays revealed that RNA secondary structure and somatic mutations did not impact on inclusion of intron 8. However, using RNase-assisted RNA chromatography, followed by mass spectrometry, we identified six RNA-binding proteins (splicing factors) that bind to RNA sequences surrounding exon 8/intron 8 and intron 8/exon 9 boundaries; these included hnRNP I, H1, D, A2/B1 and hnRNPA1 plus the SR protein SRSF1. Specifically, overexpression of hnRNP A1 significantly increased retention of intron 8 resulting in higher levels of Herstatin in SKBR3 breast cancer cells whereas SRSF1 only had a marginal effect in decreasing Herstatin but increased exogenous HER2 levels under these experimental conditions. In conclusion, we have identified the first splicing factors and regulatory sequences that are involved in the production of Herstatin. PMID- 27935428 TI - Prior immune exposure can protect or can enhance pathology in the enteroviruses: what predicts the outcome? PMID- 27935429 TI - Investigating the effect of charged amino acids on DNA conformation in EcoRI-DNA complex: a molecular dynamics simulation study. AB - Sequence-specific binding of proteins to DNA is essential for almost all the cellular processes like transcription, translation, replication, etc. One among the various mechanisms that has been identified so far that contributes to the specificity in protein-DNA interaction is the DNA conformational change. Electrostatic neutralization of the phosphate groups by the positively charged amino acid residues in proteins is thought to bring about such conformational changes in DNA. Here, we employ molecular dynamics simulations to examine the effect of charge on amino acids Lys113, Arg145, and Asp91 which are attached to the scissile phosphate on the conformation of DNA in EcoRI-DNA complex. The results indicate that the charge of these amino acids is essential for maintaining the local conformation of DNA in the EcoRI-bound form. Interestingly, we observe that the positively charged amino acids Lys113 and Arg145 have a long range influence on the DNA conformation, whereas the negatively charged amino acid Asp91 has only a localized effect on the DNA conformation. The charge on the amino acids also alters the collective dynamics of EcoRI. Collectively, the results shed light on the diversity of the effect of charges on DNA conformation as well as on protein dynamics. PMID- 27935430 TI - Human runners exhibit a least variable gait speed. AB - This study characterises the relationship between gait variability and speed in runners using data from trunk accelerations in each axis. Twelve participants of varying fitness ran on the treadmill with three sessions of six randomly ordered self-selected speeds. A VO2max test was conducted on the fourth session. Running gait was tracked with inertial sensors. The occurrence of a mid-range speed was analysed for the anterior-posterior, vertical and lateral directional coefficient of variation (CV) of root mean square (RMS) acceleration data. One participant with noisy gait signals was omitted. The results show all remaining participants consistently showed significant quadratic U-shaped relationships between vertical RMS CV acceleration and speed. Neither anterior-posterior nor lateral RMS CV acceleration were clearly related to speed. These least variable gait speeds were similar to estimates of optimal speed derived from minimum cost of transport with speed. In conclusion, there exists a mid-range speed for each runner with the least variable gait in the vertical direction, and this occurred significantly more often than would be expected by chance (P < 0.05). However, there are no prominent patterns for the anterior-posterior and lateral directions. This finding supports anecdotal evidence from runners and coaches concerning gait consistency. PMID- 27935431 TI - Moving a hospital: simulation - a way to co-produce safety healthcare facilities. AB - Moving a hospital is a critical period for quality and safety of healthcare. Change is very stressful for professionals. Workers who have experienced relocation of their place of work report deterioration in health status. Building a new hospital or restructuring a unit could provide an opportunity for improving safety and value in healthcare and for ensuring better quality of worklife for the staff. We used in situ simulation to promote experiential learning by training healthcare workers in the workplace in which they are expected to use their skills. In situ simulation was a way to design, plan, assess and implement a new healthcare environment before opening its doors for patient care. We can envisage that simulation will soon be used formally to identify potential problems in healthcare delivery and in staff quality of worklife in new healthcare facilities. Simulation is a way to co-produce a safe and valuable healthcare facility. PMID- 27935432 TI - To bend or not to bend? Rule adherence among staff at an eating disorder unit. AB - On inpatient eating disorder units, resolving under-nutrition and reestablishing normal eating behavior are key treatment aims. Consequently, the provision of support at mealtimes is a core work task for patients with severe eating disorders. The purpose of this study was to explore staff deliberations and actions, as observed during staff-patient interactions at mealtimes on an inpatient eating disorder unit (EDU). We specifically aimed to characterize how and why staff members intervene during staff-patient interactions in which a refeeding script is activated. This exploratory qualitative study combined non participant observation and in-depth interviews. Content analysis was used to categorize and abstract the data material. Through the described analysis, we identified two main types of patterns which were categorized as rule adherence and rule bending, describing how staff chose how to intervene in situations where refeeding scripts were activated. The current findings may contribute to enhanced insight and awareness regarding staff behavior and deliberations when providing meal support, and thus help staff members to better understand how meal time support is practiced on inpatient EDUs. PMID- 27935434 TI - Unilateral Fatigue Affects the Unipedal Postural Balance in Individuals With Intellectual Disability. AB - This study aimed to explore the effect of local muscle fatigue on the unipedal stance in men with intellectual disability (ID). The Centre of pressure (CoP) excursions and the isometric maximal voluntary contraction (MVC) were measured before and after a fatiguing exercise. Higher baseline values of CoP excursions and lower MVC values were recorded in the ID group. After the fatiguing exercise, this group showed higher MVC decrease and higher percentage of increase of the mean CoP velocity. In conclusion, men with ID are more vulnerable to the disturbing effects of fatigue during the unipedal stance compared to men without ID. PMID- 27935435 TI - Improving nursing students' assessment of fall risk in community-dwelling older adults. AB - Nationally, approximately one third of older adults fall each year. Falls and resulting injury result in decreased mobility, functional impairment, loss of independence, and increased mortality. Utilization of evidence-based protocols by health care providers to identify older adults at risk of falling is limited, and rates of participation by older adults in prevention activities is low. Because of nursing's increasing role in caring for older adults, development of fall prevention education for nursing students would result in increased awareness of the need for fall prevention in community-dwelling older adults and increased access of older adults to falls risk assessment. There is a need to extend research to inform teaching and learning strategies for fall prevention. After pretesting, a convenience sample of 52 undergraduate nursing students and 22 graduate nursing students completed an online education program and performed a falls risk assessment on an older adult. After completing the clinical assignment, students completed a posttest and self-efficacy survey. Data were analyzed using multivariate statistical tests. Results revealed an increase in knowledge and student self-reporting of efficacy of fall risk assessment skills for the older adult population. This study suggests that nursing students acquired the necessary knowledge and self-efficacy for assessing fall risk of older adults through the combination of an online learning module and participating in actual fall risk assessment of an older adult. PMID- 27935437 TI - Improving health care student attitudes toward older adults through educational interventions: A systematic review. AB - Educational institutions should aim to positively influence the attitudes of future health care practitioners toward older patients to ensure the provision of quality patient care. This systematic review of the literature aims to determine the effectiveness of educational interventions designed to improve health care student behaviors and/or attitudes toward older people. The 29 studies included in this review utilized a variety of interventions, methods, and measurement tools. The most common type of educational intervention incorporated interaction with real patients. Few studies evaluated the impact of interventions on behavior; therefore, more observational studies are required. Overall interventions incorporating interactions with real patients who are independently living had a positive impact on student attitudes toward older adults. Clinically focused placements with patients who are ill may still have a place in the development of the patient-centered interview and assessment skills, along with improving confidence and competence, despite not having a favorable impact on attitudes. PMID- 27935436 TI - Difference in Cortical Relay Time Between Intrinsic Muscles of Dominant and Nondominant Hands. AB - The authors aimed to calculate and compare cortical relay time (CRT) between intrinsic hand muscles and between homonymous muscles of dominant and nondominant hands. The participants comprised 22 healthy volunteers. The CRT for long-latency reflexes (LLRs) was calculated by subtracting the peak latency of somatosensory evoked potentials of component N20 and the onset latency of motor evoked potentials from the onset latency of LLRs. CRT was significantly shorter for the first dorsal interosseous muscle than for the abductor pollicis brevis muscle, regardless of hand dominance. CRT for the abductor pollicis brevis muscle was significantly shorter in the dominant hand than in the nondominant hand. Evaluation of CRT for intrinsic muscles might be beneficial in the understanding of individuated finger functions. PMID- 27935438 TI - Assessing Proprioception in Children: A Review. AB - Proprioception is the subconscious and conscious awareness of the spatial and mechanical status of the musculoskeletal framework. When working with children with motor delays and sensory integrative dysfunction, occupational therapists routinely assess the client's proprioceptive system. However, currently available assessments for occupational therapists are primarily observer-based and concerns have been raised about the reliability of observer-based assessments of sensation. The author's purpose was to review measures of proprioception currently available to occupational therapists and explore direct measures of proprioception from neuroscience and rehabilitation that can be adapted for pediatric clinical use. Observer-based and direct measurements of proprioception assessments complement each other in meeting clinical needs. A better understanding of both types of evaluation will improve proprioceptive evaluation. PMID- 27935440 TI - Money matters and so does autonomy when it comes to health. PMID- 27935441 TI - Foreword to special section of Gerontology & Geriatrics Education. PMID- 27935443 TI - Acceptability and tolerability of omega-3 fatty acids as adjunctive treatment for children and adolescents with eating disorders. AB - The objective of this study was to examine the acceptability and tolerability of omega-3 fatty acids as an adjunctive treatment for children and adolescents with eating disorders (EDs). Children and adolescents with EDs received omega-3 supplements (300 mg eicosapentaenoic acid [EPA] and 200 mg docosahexaenoic acid [DHA]/day) in addition to standard treatment for 8 weeks. Primary outcomes were dropout rate, compliance, and side effects. Secondary outcomes included percent ideal body weight, Eating Disorders Inventory-3 (EDI-3), Children's Depression Inventory-2 (CDI-2), and Multidimensional Anxiety Scale for Children (MASC). There were 21 participants with mean age of 15.29 +/- 2.0 years. There were no dropouts. Omega-3 was well tolerated by all participants. Compared to baseline, at week 8 there was a significant increase in mean percent ideal body weight but no significant difference in scores on the EDI-3, CDI-2, and MASC. We conclude that omega-3 supplements are acceptable and well tolerated in the pediatric ED population. PMID- 27935444 TI - Talk of Ages: Using intergenerational classroom modules to engage older and younger students across the curriculum. AB - Age-friendly college campuses offer opportunities for lifelong learning for students of all ages. University-based retirement communities are especially well aligned with this goal by allowing residents to enroll in college courses. Although this arrangement is a standard educational option for college-linked communities, it can have challenges. In particular, the semester-long schedule may be inconvenient for many older students. The Talk of Ages intergenerational module program described in this case study was designed to offer an alternative curricular format to bring older and younger students together for 1 to 2 weeks in focused course activities. To encourage participation across the curriculum, instructors were urged to draw on existing course content. Initial feedback about the program indicated that instructors as well as older and younger students found the program appealing. Useful suggestions for refining the program were also revealed. PMID- 27935442 TI - Psychosis After Switch in Opioid Maintenance Agonist and Risperidone-Induced Pisa Syndrome: Two Critical Incidents in Dual Diagnosis Treatment. AB - BACKGROUND AND AIMS: Dual diagnosis commonly occurs among patients with an opioid use disorder. Treatment is ideally performed in an integrated fashion. We present a case that illustrates the complex and challenging psychiatric and medical therapy of such patients in the light of the literature. CASE DESCRIPTION: We report on a 56-year-old patient with schizophrenia and opioid dependence who experienced both risperidone-induced Pisa syndrome and, 3 years later, acute psychosis after switching the opioid substitution medication from methadone to slow-release oral morphine due to QT prolongation. CONCLUSIONS: With the current availability of a diversity of substitution opioids in Switzerland (methadone, buprenorphine, diacetylmorphine, sustained-release oral morphine), studies on differential effectiveness of these agents in opioid-dependent subpopulations with selective comorbidity profiles are desirable. The same is true for further investigation of the involvement of the opioid receptor system in schizophrenia. In clinical practice, any alteration of opioid medication in patients with dual diagnosis and a history of schizophrenia should be accompanied by close observation for psychotic symptoms. PMID- 27935446 TI - Sample size requirement in analytical studies for similarity assessment. AB - For the assessment of biosimilar products, the FDA recommends a stepwise approach for obtaining the totality-of-the-evidence for assessing biosimilarity between a proposed biosimilar product and its corresponding innovative biologic product. The stepwise approach starts with analytical studies for assessing similarity in critical quality attributes (CQAs), which are relevant to clinical outcomes at various stages of the manufacturing process. For CQAs that are the most relevant to clinical outcomes, the FDA requires an equivalence test be performed for similarity assessment based on an equivalence acceptance criterion (EAC) that is obtained using a single test value of some selected reference lots. In practice, we often have extremely imbalanced numbers of reference and test lots available for the establishment of EAC. In this case, to assist the sponsors, the FDA proposed an idea for determining the number of reference lots and the number of test lots required in order not to have imbalanced sample sizes when establishing EAC for the equivalence test based on extensive simulation studies. Along this line, this article not only provides statistical justification of Dong, Tsong, and Weng's proposal, but also proposes an alternative method for sample size requirement for the Tier 1 equivalence test. PMID- 27935447 TI - Lateral mass screw stimulation thresholds in posterior cervical instrumentation surgery: a predictor of medial deviation. AB - OBJECTIVE Normative data exists for stimulus-evoked pedicle screw electromyography (EMG) current thresholds in the lumbar spine, and is routinely referenced during spine surgeries to detect a screw breach, prevent injury of neural elements, and ensure the most biomechanically sound instrumentation construct. To date, similar normative data for cervical lateral mass screws is limited, thus the utility of lateral mass screw testing remains unclear. To address this disparity, in this study the authors describe cumulative lateral mass screw stimulation threshold data in patients undergoing posterior cervical instrumentation with lateral mass screws. These data are correlated with screw placement on postoperative imaging, and a novel correlation is discovered with direct clinical implications. METHODS Using a ball-tip probe, 154 lateral mass screws in 21 patients were electrically tested intraoperatively. In each case, for each screw, the lowest (or threshold) current at which the first polyphasic stimulus-evoked EMG response was reproducibly observed by a neurophysiologist was recorded. All patients underwent postoperative CT. Screw position within the lateral mass was first measured in the axial and sagittal planes for each lateral mass screw using the CT images. Screw placement was also evaluated by 2 independent physicians, blinded to current threshold data, on a binary scale of acceptability. The predictive capacity of screw EMG threshold data was evaluated via multivariable regression analyses and receiver operating characteristic (ROC) analyses. Predictive capacity was examined with respect to screw position within the lateral mass, as well as screw acceptability. RESULTS Lateral mass screw EMG thresholds did not appear to differ significantly for screws considered "acceptable" versus "unacceptable" according to the radiographic criteria. Accordingly, ROC analysis confirmed that EMG current threshold data were of minimal utility in predicting screw radiographic acceptability. However, EMG threshold was significantly predictive of screw medial distance from the spinal canal. A screw stimulating below 7.5 mA correctly identified a screw as being within 2 mm of the spinal canal with 75% sensitivity and 92% specificity (positive predictive value 20%, negative predictive value 99.3%), independent of its distance relative to other lateral mass landmarks. EMG current threshold was not significantly predictive of screw deviation in the superior or inferior directions, and was inversely predictive of screw deviations in the lateral direction. CONCLUSIONS In the context of uncertainty regarding the utility of cervical lateral mass EMG current threshold data, this study found that EMG current thresholds correspond significantly, and exclusively, with screw distance from the spinal canal. This association appears independent of other criteria for screw misplacement. As such, the authors recommend that EMG current thresholds be referenced in the case of a suspected medial breach as an effective means to rule out screw placement too medial to the spinal canal. PMID- 27935445 TI - The Effects of Sensory Manipulations on Motor Behavior: From Basic Science to Clinical Rehabilitation. AB - Modifying sensory aspects of the learning environment can influence motor behavior. Although the effects of sensory manipulations on motor behavior have been widely studied, there still remains a great deal of variability across the field in terms of how sensory information has been manipulated or applied. Here, the authors briefly review and integrate the literature from each sensory modality to gain a better understanding of how sensory manipulations can best be used to enhance motor behavior. Then, they discuss 2 emerging themes from this literature that are important for translating sensory manipulation research into effective interventions. Finally, the authors provide future research directions that may lead to enhanced efficacy of sensory manipulations for motor learning and rehabilitation. PMID- 27935448 TI - Diagnostic accuracy of motor evoked potentials to detect neurological deficit during idiopathic scoliosis correction: a systematic review. AB - OBJECTIVE The goal of this study was to evaluate the efficacy of intraoperative transcranial motor evoked potential (TcMEP) monitoring in predicting an impending neurological deficit during corrective spinal surgery for patients with idiopathic scoliosis (IS). METHODS The authors searched the PubMed and Web of Science database for relevant lists of retrieved reports and/or experiments published from January 1950 through October 2014 for studies on TcMEP monitoring use during IS surgery. The primary analysis of this review fit the operating characteristic into a hierarchical summary receiver operating characteristic curve model to determine the efficacy of intraoperative TcMEP-predicted change. RESULTS Twelve studies, with a total of 2102 patients with IS were included. Analysis found an observed incidence of neurological deficits of 1.38% (29/2102) in the sample population. Of the patients who sustained a neurological deficit, 82.8% (24/29) also had irreversible TcMEP change, whereas 17.2% (5/29) did not. The pooled analysis using the bivariate model showed TcMEP change with sensitivity (mean 91% [95% CI 34%-100%]) and specificity (mean 96% [95% CI 92 98%]). The diagnostic odds ratio indicated that it is 250 times more likely to observe significant TcMEP changes in patients who experience a new-onset motor deficit immediately after IS correction surgery (95% CI 11-5767). TcMEP monitoring showed high discriminant ability with an area under the curve of 0.98. CONCLUSIONS A patient with a new neurological deficit resulting from IS surgery was 250 times more likely to have changes in TcMEPs than a patient without new deficit. The authors' findings from 2102 operations in patients with IS show that TcMEP monitoring is a highly sensitive and specific test for detecting new spinal cord injuries in patients undergoing corrective spinal surgery for IS. They could not assess the value of TcMEP monitoring as a therapeutic adjunct owing to the limited data available and their study design. PMID- 27935449 TI - Multiple-hook fixation in revision spinal deformity surgery for patients with a previous multilevel fusion mass: technical note and preliminary outcomes. AB - OBJECTIVE A previous multilevel fusion mass encountered during revision spinal deformity surgery may obscure anatomical landmarks, making instrumentation unworkable or incurring substantial blood loss and operative time. This study introduced a surgical technique of multiple-hook fixation for fixating previous multilevel fusion masses in revision spinal deformity surgeries and then evaluated its outcomes. METHODS Patients with a previous multilevel fusion mass who underwent revision corrective surgery down to the lumbosacral junction were retrospectively studied. Multiple hooks were used to fixate the fusion mass and linked to distal pedicle screws in the lumbosacral-pelvic complex. Radiological and clinical outcomes were evaluated. RESULTS The charts of 8 consecutive patients with spinal deformity were retrospectively reviewed (7 women, 1 man; mean age 56 years). The primary diagnoses included flat-back deformity (6 cases), thoracolumbar kyphoscoliosis (1 case), and lumbar spondylosis secondary to a previous scoliosis fusion (1 case). The mean follow-up duration was 30.1 months. Operations were performed at T3/4-ilium (4 cases), T7-ilium (1 case), T6-S1 (1 case), T12-S1 (1 case), and T9-L5 (1 case). Of 8 patients, 7 had sagittal imbalance preoperatively, and their mean C-7 plumb line improved from 10.8 +/- 2.9 cm preoperatively to 5.3 +/- 3.6 cm at final follow-up (p = 0.003). The mean lumbar lordosis of these patients at final follow-up was significantly greater than that preoperatively (35.2 degrees +/- 12.6 degrees vs 16.8 degrees +/- 11.8 degrees , respectively; p = 0.005). Two perioperative complications included osteotomy-related leg weakness in 1 patient and a stitch abscess in another. CONCLUSIONS The multiple-hook technique provides a viable alternative option for fixating a previous multilevel fusion mass in revision spinal deformity surgery. PMID- 27935450 TI - Postoperative wound infection: Critique II. AB - The surveillance of wound and other hospital-acquired infections has become of particular interest to the Department of Health, since infection rates are potentially useful as a measurement of the quality of care and are an important aspect of surgical outcome1. Infection rates might be used to compare the performance of hospitals or individual surgeons. PMID- 27935451 TI - Postoperative wound infection. AB - Three clinicians review the work of Cruse and Foord, cited below, and discuss its effect on current and future practice. PMID- 27935452 TI - Postoperative wound infection: Critique III. AB - There can be few single-centre studies that have a sample population of nearly 63 000 and few investigators who have the resilience to continue collecting data for 10 years. For these reasons alone, this work by Cruse and Foord1 demands attention; it has had considerable influence on our examination of the risk factors associated with surgical wound infections, and the way in which we have taught students about the aetiology of such infections. PMID- 27935453 TI - Appropriate use of dressings. AB - This issue includes an audit assessing the appropriate use of dressings in clinical practice (pages 305-308). The authors define appropriate use if the dressing chosen and the technique for application are based on a combination of relevant literature, expert opinion and manufacturer's advice. PMID- 27935454 TI - Letters. AB - CONSIDERATION OF BED-BASES PRESCRIBED GUIDE IS VALUE FOR MONEY DURABILITY OF HYDROGELS CHARCOAL DRESSINGS. PMID- 27935455 TI - Assessing the use of dressings in practice. AB - An audit was carried out in an NHS trust to identify the degree to which wound management products were being selected and used appropriately. Fifty patients with various types of wounds were involved; observers noted the condition of wounds at dressing changes and the procedures used, then studied each patient's hospital documentation (medical notes, nursing care plan and drug chart). Nursing staff were interviewed to ascertain the input of various disciplines in dressing choice. The 'correct' choice of dressing was made in only 48% of wounds, and correct choice and use were identified in just 20%, with wide variations between different products. A quarter of patients reported pain associated with their wounds, but none received analgesia before dressing changes. As a result of the audit, new guidelines on dressing choice and use have been produced, with others in preparation, and the hospital formulary has been amended. PMID- 27935456 TI - Erratum. PMID- 27935457 TI - Impact of a Hypnotically-Based Intervention on Pain and Fear in Women Undergoing Labor. AB - The purpose of this study was to evaluate the effects of a hypnotically-based intervention for pain and fear in women undergoing labor who are about to receive an epidural catheter. A group of 155 women received interventions that included either (a) patient rocking, gentle touching, and hypnotic communication or (b) patient rocking, gentle touching, and standard communication. The authors found that the hypnotic communication intervention was more effective than the standard communication intervention for reducing both pain intensity and fear. The results support the use of hypnotic communication just before and during epidural placement for women who are in labor and also indicate that additional research to evaluate the benefits and mechanism of this treatment is warranted. PMID- 27935458 TI - Group Hypnotizability Of Inpatient Adolescents. AB - This study investigated group hypnotizability in 167 adolescents (ages 13-17) in an inpatient behavioral healthcare setting through use of the Waterloo-Stanford Group Scale, Form C. It also investigated the influence of hypnotic inductions on group hypnotizability. Adolescents were randomly assigned to either a group session of hypnosis (n = 84) with a hypnotic induction or a comparison "no induction" group (n = 83) that received identical suggestions without a hypnotic induction. Adolescents' imaginative absorption and dissociation were measured to examine their influence on hypnotizability. A between-group comparison showed the induction condition had a significantly higher score than the no-induction group on both behavioral and subjective measures of hypnotizability. PMID- 27935459 TI - Hypnosis in the Treatment of Major Depression: An Analysis of Heart Rate Variability. AB - Hypnosis is an adjuvant treatment of major depression (MD). Heart rate variability (HRV) can assess the autonomic nervous system, which is associated with MD, and HRV is decreased in MD patients. There is a lack of research on HRV changes before, during, and after the use of hypnosis in MD patients. A total of 21 MD patients participated in this study, and 5-minute electrocardiograms were recorded before, during, and after hypnosis. Compared with the prehypnotic condition, HRV parameters significantly (p < .01) increased in the hypnotic and posthypnotic conditions. The results suggest that hypnosis treatment should bring some functional improvement to the autonomic nervous system. HRV is potentially a useful tool that quantifies the physiological impact of hypnosis treatment in MD patients. PMID- 27935460 TI - Sensory Experience Memory in Resource Therapy. AB - A sensory experience memory (SEM) is an emotional memory that may be either connected to an intellectual memory or it may have become dissociated from its corresponding intellectual memory. Sensory experience memories are the cause of a number of pathologies, including PTSD, panic disorder, and anxiety. When a personality state that holds a negative SEM assumes the conscious, the client may display negative emotional reactions that appear unwarranted. SEMs can also play a central role in therapy to resolve pathology. Resource therapy (RT) incorporates the understanding of SEMs in both diagnosis and treatment. RT will be used in this article to illustrate the importance of working with SEMs, but therapists can translate the use of SEMs to other therapeutic modalities. PMID- 27935461 TI - Forward Affect Bridge. AB - This article presents a modification of the affect bridge technique. The Forward Affect Bridge enables practitioners to create and maintain hope when it is missing. Hope is relevant for diminishing avoidance and being involved with necessary activities. The main idea is to build up a positive atmosphere in the here and now (relying on rapport), to amplify it, and to project it forward. By using clinical vignettes, the authors illustrate these techniques. PMID- 27935463 TI - Is Primary-Process Cognition a Feature of Hypnosis? AB - The division of cognition into primary and secondary processes is an important part of contemporary psychoanalytic metapsychology. Whereas primary processes are most characteristic of unconscious thought and loose associations, secondary processes generally govern conscious thought and logical reasoning. It has been theorized that an induction into hypnosis is accompanied by a predomination of primary-process cognition over secondary-process cognition. The authors hypothesized that highly hypnotizable individuals would demonstrate more primary process cognition as measured by a recently developed cognitive-perceptual task. This hypothesis was not supported. In fact, low hypnotizable participants demonstrated higher levels of primary-process cognition. Exploratory analyses suggested a more specific effect: felt connectedness to the hypnotist seemed to promote secondary-process cognition among low hypnotizable participants. PMID- 27935462 TI - Psychological Features of Hypnotizability: A First Step Towards Its Empirical Definition. AB - This study examined the relationship between the Hypnotic Induction Profile (HIP) and several psychological tests: Tellegen Absorption Scale (TAS), Spontaneity Assessment Inventory-Revised (SAI-R), Dissociative Experiences Scale (DES), Short Form Boundary Questionnaire (SFBQ), Mini Locus of Control (MLOC), Testoni Death Representation Scale (TDRS), and the Interpersonal Reactivity Index (IRI). Two hundred and forty volunteers were administered the above tests; 78 of them were also administered the HIP, and its scores were compared to those on the other tests. A significant correlation was found among the TAS, DES, SFBQ, and IRI. The HIP was significantly correlated to the DES (r = .19 p1tail = .045), and the IRI ec subscale (r = .19 p1tail = .044); 14 test items from DES, IRI, TAS, SAIR, and SFBQ were also significantly related to the HIP. The findings suggest that hypnotizability may relate to stronger perception of the inner world, decreased aptitude for managing memory processing, and increased sensitivity and empathy. PMID- 27935464 TI - Effects of Hypnosis on Regression to Primary-Process Thinking. AB - The authors tested the hypothesis that hypnotic age regression produces a shift from secondary- to primary-thought processing in hypnotizable participants. Thirty participants were tested for hypnotizability using the Elkins Scale of Hypnotizability (EHS). Participants were exposed to a tailored hypnotic arm levitation induction and a hypnotic suggestion to age regress to 5 years of age and to have a dream. Primary-process thinking was assessed using the Primary Process Thinking Scale. An independent t test with 2 levels of hypnotizability (middle and high) showed high hypnotizables demonstrated higher ratings of primary thought processing than those in the middle group. PMID- 27935465 TI - Efficacy of Self-Hypnosis in Pain Management in Female Patients with Multiple Sclerosis. AB - Pain is common in patients with multiple sclerosis. This study evaluated self hypnosis for pain control in that population. A randomized clinical trial was conducted on 60 patients, who were assigned to either a control group or to a self-hypnosis group, in which patients performed self-hypnosis at least 10 times a day. All patients were trained to score the perceived pain twice daily on a numerical rating scale and also reported the quality of pain with the McGill Pain questionnaire. Repeated-measures analysis showed a significant difference between the groups; pain was lower in the self-hypnosis group but was not maintained after 4 weeks. Self-hypnosis could effectively decrease the intensity and could modify quality of pain in female patients with multiple sclerosis. PMID- 27935467 TI - Possible toxicity following embolization of congenital giant vertex hemangioma: case report. AB - The authors describe the case of a 3-year-old boy with a giant congenital vertex hemangioma who underwent presurgical embolization with Onyx (ethylene-vinyl alcohol copolymer dissolved in dimethyl sulfoxide) and Glubran ( N-butyl-2 cyanoacrylate). This vascular tumor had no intracranial vascular communication as assessed by pre-embolization MRI and catheter angiography. All embolizations were performed by direct percutaneous injection. One week following the last embolization procedure the child presented with a 24-hour history of ataxia and extrapyramidal tremor. He was diagnosed with a possible immune-mediated reaction to Onyx or Glubran, which was treated with an urgent surgical excision of the hemangioma followed by intravenous administration of immunoglobulin and steroids. To the authors' knowledge, this is the first case of possible immune-mediated toxicity secondary to either Onyx or Glubran administration. This case highlights the need for awareness of potential toxic reactions to these embolic agents in the treatment of hemangiomas in the pediatric patient. PMID- 27935468 TI - Interdural cavernous sinus dermoid cyst in a child: case report. AB - Interdural dermoid cysts (DCs) of the cavernous sinus (CS), located between the outer (dural) and inner layer (membranous) of the CS lateral wall, are rare lesions in children. The authors report on a 5-year-old boy with third cranial nerve palsy and exophthalmos who underwent gross-total removal of an interdural DC of the right CS via a frontotemporal approach. The patient had a good outcome and no recurrence at the 12-month follow-up. To the best of the authors' knowledge this is the second pediatric case of interdural DC described in the literature. PMID- 27935469 TI - Preoperative transdural collateral vessels in moyamoya as radiographic biomarkers of disease. AB - OBJECTIVE The prevalence of angiographically evident preoperative transdural collateral vessels in moyamoya is not well documented. The authors hypothesized that transdural collaterals could be used as radiographic biomarkers of disease, and that their presence is associated with more advanced moyamoya arteriopathy at diagnosis, which is a harbinger of more frequent operative complications and a predictor of better long-term angiographic results following surgery. METHODS The study consists of a single-institution case series of patients with moyamoya who underwent pial synangiosis between 2005 and 2013. RESULTS Moyamoya was diagnosed in a total of 204 patients (n = 121 [59%] female, 83 [41%] male); the average age at surgery was 9.5 years (range 0.4-35 years). Radiographically, 154 (75%) had bilateral disease for a total of 308 affected hemispheres; 152 (75%) had radiographic stroke; and 190 (93%) had "ivy sign" on FLAIR MRI, indicating slow flow. Of the 358 hemispheres, 324 were treated operatively. On preoperative angiography, 107 patients (52%) had transdural collaterals in 176 affected hemispheres (49%). The Suzuki stage was higher in patients with collaterals (3.4 vs 3.0, p = 0.002). Of 324 treated hemispheres, 84 (26%) had collaterals within the surgical field. Complications included 12 strokes (3.7% stroke rate/hemisphere), with 5 (42%) directly attributable to interruption of transdural collaterals. On 1-year postoperative arteriograms available in 222 hemispheres, Matsushima grades trended better in patients with preoperative collaterals (1.5 vs 1.8 [A = 1, B = 2, C = 3]; p < 0.003). CONCLUSIONS Transdural collaterals are present in nearly half of all preoperative arteriograms in patients with moyamoya. These collaterals are more common in advanced disease, are associated with stroke as a perioperative complication, and may suggest increased capacity to produce surgical collaterals postoperatively. These data support the utility of preoperative arteriography. PMID- 27935470 TI - Alternating Adaptation of Eye and Hand Movements to Opposite Directed Double Steps. AB - Eye and hand movements can adapt to a variety of sensorimotor discordances. Studies on adaptation of movement directions suggest that the oculomotor and the hand motor system access the same adaptive mechanism related to the polarity of a discordance, because concurrent adaptations to opposite directed discordances strongly interfere. The authors scrutinized whether participants adapt their hand and eye movements to opposite directions (clockwise/counterclockwise) when both motor systems are alternatingly exposed to opposite directed double steps, and whether such adaptation is influenced by the allocation of effector to adaptation direction. The results showed that hand and eye movements adapted to opposite directions, but adaptation was biased to the counterclockwise direction. Aftereffects emerged nearly unbiased and independently for both motor systems. The authors conclude that the oculomotor and the hand motor system use independent mechanisms when they adapt to opposite polarities, although they interact during adaptation or concurrent performance. PMID- 27935471 TI - Oral Motor Abilities Are Task Dependent: A Factor Analytic Approach to Performance Rate. AB - Measures of performance rates in speech-like or volitional nonspeech oral motor tasks are frequently used to draw inferences about articulation rate abnormalities in patients with neurologic movement disorders. The study objective was to investigate the structural relationship between rate measures of speech and of oral motor behaviors different from speech. A total of 130 patients with neurologic movement disorders and 130 healthy subjects participated in the study. Rate data was collected for oral reading (speech), rapid syllable repetition (speech-like), and rapid single articulator movements (nonspeech). The authors used factor analysis to determine whether the different rate variables reflect the same or distinct constructs. The behavioral data were most appropriately captured by a measurement model in which the different task types loaded onto separate latent variables. The data on oral motor performance rates show that speech tasks and oral motor tasks such as rapid syllable repetition or repetitive single articulator movements measure separate traits. PMID- 27935472 TI - Trunk Compensation During Bimanual Reaching at Different Heights by Healthy and Hemiparetic Adults. AB - The authors explored how trunk compensation and hand symmetry in stroke survivors and healthy controls were affected by the distance and height of virtual targets during a bimanual reaching task. Participants were asked to reach to 4 different virtual targets set at: 90% of their arm length at shoulder, xiphoid process, and knee height, and 50% of their arm length at xiphoid process height. For the stroke group, for all targets, the hands' movements were more asymmetrical than those of the healthy group, with more asymmetry observed in the direction of gravity, and trunk forward displacement values were larger and more variable. The knee targets had the largest trunk displacement values; index of curvature and trunk displacement were strongly correlated with participants' impairment scores. A strong correlation was found between the hands' asymmetry in the anterior or posterior direction for the shoulder targets, and the impairment scores. The results suggest that target height influences the degree of trunk compensation and hand symmetry during bimanual reaching by hemiparetic participants. PMID- 27935473 TI - Correlates of the over-evaluation of weight and shape in binge eating disorder and mixed eating disorder samples: A meta-analytic review. AB - This meta-analysis assessed the strength of the association between correlates of shape and weight over-evaluation across binge eating disorder and mixed eating disorder samples. Across 32 studies, over-evaluation correlates were divided into demographic, eating pathology, or psychosocial. Shape and weight over-evaluation was associated with higher eating pathology and psychosocial impairment. The method of assessment (interview versus self-report questionnaire) moderated some of the relationships. Over-evaluation was unrelated to demographics and treatment outcome. These findings highlight the importance of addressing shape and weight over-evaluation during treatment, and support the idea of using shape and weight over-evaluation as a severity specifier for binge eating disorder. PMID- 27935474 TI - A pathology of progress? Locating the historiography of cancer. AB - Despite its prominent position in today's medical research, popular culture and everyday life, cancer's history is relatively unwritten. Compared to the other great 'plagues' - cholera, tuberculosis or tropical fevers, to name but a scant handful - cancer has few dedicated pages in the general surveys, and its specialists have largely failed to convince the broader community of medical historians - or indeed historians of anything at all - that histories of the disease can tell us fundamental things about the science and practice of medicine, both past and present. Moreover, cancer has a remarkably stable profile over time, at least in terms of its definition, language and terminology - a detail that only makes the disease's absence from historical literature more surprising. PMID- 27935475 TI - Thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons. AB - Neocortical GABAergic interneuron migration and thalamo-cortical axon (TCA) pathfinding follow similar trajectories and timing, suggesting they may be interdependent. The mechanisms that regulate the radial dispersion of neocortical interneurons are incompletely understood. Here we report that disruption of TCA innervation, or TCA-derived glutamate, affected the laminar distribution of GABAergic interneurons in mouse neocortex, resulting in abnormal accumulation in deep layers of interneurons that failed to switch from tangential to radial orientation. Expression of the KCC2 cotransporter was elevated in interneurons of denervated cortex, and KCC2 deletion restored normal interneuron lamination in the absence of TCAs. Disruption of interneuron NMDA receptors or pharmacological inhibition of calpain also led to increased KCC2 expression and defective radial dispersion of interneurons. Thus, although TCAs are not required to guide the tangential migration of GABAergic interneurons, they provide crucial signals that restrict interneuron KCC2 levels, allowing coordinated neocortical invasion of TCAs and interneurons. PMID- 27935476 TI - Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases. AB - Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors. PMID- 27935477 TI - Regulation of B cell fate by chronic activity of the IgE B cell receptor. AB - IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE+ B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE+ germinal center (GC) B cell but variably increased PC responses. We were unable to confirm reports that the IgE BCR directly promoted intrinsic apoptosis. Instead, IgE+ GC B cells exhibited poor antigen presentation and prolonged cell cycles, suggesting reduced competition for T cell help. We propose that chronic BCR activity and access to T cell help play critical roles in regulating IgE responses. PMID- 27935478 TI - Labeling proteins inside living cells using external fluorophores for microscopy. AB - Site-specific fluorescent labeling of proteins inside live mammalian cells has been achieved by employing Streptolysin O, a bacterial enzyme which forms temporary pores in the membrane and allows delivery of virtually any fluorescent probes, ranging from labeled IgG's to small ligands, with high efficiency (>85% of cells). The whole process, including recovery, takes 30 min, and the cell is ready to be imaged immediately. A variety of cell viability tests were performed after treatment with SLO to ensure that the cells have intact membranes, are able to divide, respond normally to signaling molecules, and maintains healthy organelle morphology. When combined with Oxyrase, a cell-friendly photostabilizer, a ~20x improvement in fluorescence photostability is achieved. By adding in glutathione, fluorophores are made to blink, enabling super resolution fluorescence with 20-30 nm resolution over a long time (~30 min) under continuous illumination. Example applications in conventional and super resolution imaging of native and transfected cells include p65 signal transduction activation, single molecule tracking of kinesin, and specific labeling of a series of nuclear and cytoplasmic protein complexes. PMID- 27935479 TI - Structural basis for subtype-specific inhibition of the P2X7 receptor. AB - The P2X7 receptor is a non-selective cation channel activated by extracellular adenosine triphosphate (ATP). Chronic activation of P2X7 underlies many health problems such as pathologic pain, yet we lack effective antagonists due to poorly understood mechanisms of inhibition. Here we present crystal structures of a mammalian P2X7 receptor complexed with five structurally-unrelated antagonists. Unexpectedly, these drugs all bind to an allosteric site distinct from the ATP binding pocket in a groove formed between two neighboring subunits. This novel drug-binding pocket accommodates a diversity of small molecules mainly through hydrophobic interactions. Functional assays propose that these compounds allosterically prevent narrowing of the drug-binding pocket and the turret-like architecture during channel opening, which is consistent with a site of action distal to the ATP-binding pocket. These novel mechanistic insights will facilitate the development of P2X7-specific drugs for treating human diseases. PMID- 27935480 TI - Optimal compensation for neuron loss. AB - The brain has an impressive ability to withstand neural damage. Diseases that kill neurons can go unnoticed for years, and incomplete brain lesions or silencing of neurons often fail to produce any behavioral effect. How does the brain compensate for such damage, and what are the limits of this compensation? We propose that neural circuits instantly compensate for neuron loss, thereby preserving their function as much as possible. We show that this compensation can explain changes in tuning curves induced by neuron silencing across a variety of systems, including the primary visual cortex. We find that compensatory mechanisms can be implemented through the dynamics of networks with a tight balance of excitation and inhibition, without requiring synaptic plasticity. The limits of this compensatory mechanism are reached when excitation and inhibition become unbalanced, thereby demarcating a recovery boundary, where signal representation fails and where diseases may become symptomatic. PMID- 27935482 TI - Dural sinus stenting for idiopathic intracranial hypertension: factors associated with hemodynamic failure and management with extended stenting. AB - BACKGROUND: Some patients undergoing dural sinus stenting for idiopathic intracranial hypertension (IIH) develop clinical and hemodynamic failure (recurrence of the pressure gradient) owing to stent-adjacent stenosis. OBJECTIVE: To characterize factors associated with hemodynamic failure, and to describe outcomes of patients after repeat stenting. MATERIALS AND METHODS: We reviewed the initial and follow-up clinical, venographic, and hemodynamic data in 39 patients with IIH treated over 17 years with stenting. Thirty-two had follow up angiographic and hemodynamic data at 1-99 months (mean 27.6, median 19.5 months). Eight patients were treated with 12 repeat stenting procedures, including extended stenting into the superior sagittal sinus (SSS). RESULTS: All patients had an initial successful hemodynamic result with the pressure gradient reduced from 10-43 to 0-7 mm Hg. 10/32 patients (31.3%), all women, developed new stenoses in the transverse sinus or posterior SSS above the stent with a recurrent pressure gradient. 7/9 patients with pure extrinsic stenosis of the transverse-sigmoid junction pre-stenting developed new stenoses and hemodynamic failure. All patients with hemodynamic failure who were restented had early and mid-term documented hemodynamic success at 1.7-50 months. They were free from papilledema at 3.8-50 months after the last restenting, and 11.5-99.5 months after initial stent placement (mean 45.3, median 38.5 months). CONCLUSIONS: Pure extrinsic compression of the transverse-sigmoid junction and female gender were strongly associated with hemodynamic failure. Eight patients with hemodynamic failure who were restented had successful control of papilledema, including 4/4 who had extended stenting into the SSS. PMID- 27935481 TI - Structure of the transporter associated with antigen processing trapped by herpes simplex virus. AB - The transporter associated with antigen processing (TAP) is an ATP-binding cassette (ABC) transporter essential to cellular immunity against viral infection. Some persistent viruses have evolved strategies to inhibit TAP so that they may go undetected by the immune system. The herpes simplex virus for example evades immune surveillance by blocking peptide transport with a small viral protein ICP47. In this study, we determined the structure of human TAP bound to ICP47 by electron cryo-microscopy (cryo-EM) to 4.0 A. The structure shows that ICP47 traps TAP in an inactive conformation distinct from the normal transport cycle. The specificity and potency of ICP47 inhibition result from contacts between the tip of the helical hairpin and the apex of the transmembrane cavity. This work provides a clear molecular description of immune evasion by a persistent virus. It also establishes the molecular structure of TAP to facilitate mechanistic studies of the antigen presentation process. PMID- 27935484 TI - Anatomical and morphological characteristics may explain why groin pain is more common in male than female athletes. PMID- 27935483 TI - Predicting sport and occupational lower extremity injury risk through movement quality screening: a systematic review. AB - BACKGROUND: Identification of risk factors for lower extremity (LE) injury in sport and military/first-responder occupations is required to inform injury prevention strategies. OBJECTIVE: To determine if poor movement quality is associated with LE injury in sport and military/first-responder occupations. MATERIALS AND METHODS: 5 electronic databases were systematically searched. Studies selected included original data; analytic design; movement quality outcome (qualitative rating of functional compensation, asymmetry, impairment or efficiency of movement control); LE injury sustained with sport or military/first responder occupation. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were followed. 2 independent authors assessed the quality (Downs and Black (DB) criteria) and level of evidence (Oxford Centre of Evidence-Based Medicine model). RESULTS: Of 4361 potential studies, 17 were included. The majority were low-quality cohort studies (level 4 evidence). Median DB score was 11/33 (range 3-15). Heterogeneity in methodology and injury definition precluded meta-analyses. The Functional Movement Screen was the most common outcome investigated (15/17 studies). 4 studies considered inter relationships between risk factors, 7 reported diagnostic accuracy and none tested an intervention programme targeting individuals identified as high risk. There is inconsistent evidence that poor movement quality is associated with increased risk of LE injury in sport and military/first-responder occupations. CONCLUSIONS: Future research should focus on high-quality cohort studies to identify the most relevant movement quality outcomes for predicting injury risk followed by developing and evaluating preparticipation screening and LE injury prevention programmes through high-quality randomised controlled trials targeting individuals at greater risk of injury based on screening tests with validated test properties. PMID- 27935485 TI - Preparticipation physical examination: Is it time to stop doing the sports physical? PMID- 27935486 TI - Infographic. General guidance for the prevention of illness in athletes. PMID- 27935488 TI - Psychological readiness to return to sport: three key elements to help the practitioner decide whether the athlete is REALLY ready? PMID- 27935487 TI - Copenhagen five-second squeeze: a valid indicator of sports-related hip and groin function. AB - BACKGROUND: No simple clinical measure exits to evaluate groin pain and its severity in athletes. The aim was to investigate the validity, reliability and responsiveness of a five-second hip-adduction squeeze test for football players designed to assess sports-related hip and groin function, pain and severity. METHODS: Construct validity was assessed in 667 subelite male football players with a mean age (+/-SD) of 24+/-4 in the beginning of the season. Responsiveness and reliability were evaluated during the season in 52 and 10 players, respectively. Players answered the Copenhagen Hip and Groin Outcome Score (HAGOS) and performed the Copenhagen five-second squeeze assessed on a Numerical Pain Rating Scale (NRS) ranging from 0 to 10. RESULTS: As hypothesised higher pain scores during the Copenhagen five-second squeeze correlated significantly (Spearman's rho=-0.61, p<0.01) with a lesser HAGOS (Sport) Score. The change scores in the Copenhagen five-second squeeze also correlated significantly (Spearman's rho=-0.51, p<0.01), with HAGOS (Sport) change scores in the responsiveness analysis, and test-retest reliability (concordance correlation coefficient) was 0.90. Moreover, significant (p<0.01) between-group differences existed for HAGOS (Sport) Scores in players reporting groin pain intensity at one of the 3 different pain levels: NRS (0-2), NRS (3-5) and NRS (6-10). The NRS (6 10) group had the lowest median (IQR) HAGOS (Sport) Score of 47 (31-61). CONCLUSIONS: The Copenhagen five-second squeeze is a valid indicator of sports related hip and groin function in football players. Players reporting groin pain intensity as 6 of 10 or more in the Copenhagen five-second squeeze experience substantially impaired sports-related hip and groin function. PMID- 27935491 TI - Charity offers advice on helping owners choose the right pet. PMID- 27935489 TI - Management of concussion in disability sport: a different ball game? PMID- 27935494 TI - Brexit at the forefront of BVA President's speech in Northern Ireland. PMID- 27935495 TI - Students help raise awareness of AMR. AB - Holly Hills, a veterinary student at the University of Nottingham, reports on events held by students at the university to mark European Antibiotic Awareness Day last month. PMID- 27935496 TI - Reducing error and blame in practice. AB - The value of checklists as a means of overcoming human error in both veterinary and medical practice was discussed during the BVA Congress at the London Vet Show last month. Speakers explained that, while checklists are not the answer to everything, there is good evidence to support their use. Kathryn Clark reports. PMID- 27935498 TI - Sustainability in an ever-changing world. AB - The world is always changing and, with Brexit on the horizon, what issues should the profession be focusing on? And is veterinary education doing enough to encourage interest in veterinary public health? These were among the topics discussed at a recent conference organised by the Veterinary Public Health Association (VPHA) and the Association of Government Veterinarians (AGV). Georgina Mills reports. PMID- 27935499 TI - Is cattle veterinary practice fit for the future? AB - This question was examined during a debate at this year's congress of the British Cattle Veterinary Association, Suzanne Jarvis reports. PMID- 27935500 TI - Veterinary medicines update. AB - The following information has been produced for Veterinary Record by the Veterinary Medicines Directorate (VMD) to provide an update for veterinary surgeons on recent changes to marketing authorisations for veterinary medicines in the UK and on other relevant issues. PMID- 27935502 TI - Disease surveillance in England and Wales, November 2016. AB - ?Current and emerging issues: recrudescence of Schmallenberg virus?Highlights from the scanning surveillance network?Update on international disease threats?Focus on avian influenza in EuropeThese are among matters discussed in the Animal and Plant Health Agency's (APHA's) November disease surveillance report. PMID- 27935503 TI - Update on avian influenza in Europe. AB - This article has been prepared by Helen Roberts and colleagues from Defra's International Disease Monitoring Team with Jane Clark, Richard Irvine and Ian Brown of the APHA. PMID- 27935504 TI - Gluten exposure and multisystem disease in dogs. PMID- 27935505 TI - Heightened risk of H5N8 highly pathogenic avian influenza. PMID- 27935506 TI - Assessment of the unnecessary suffering offence. PMID- 27935507 TI - Safe and secure storage of controlled drugs. PMID- 27935508 TI - In Practice CPD 2017 programme. AB - Zoe Davies describes what the BVA In Practice CPD programme has in store for the coming year. PMID- 27935509 TI - BVA Council regional vacancies. AB - Are you aware of BVA Council's role in ensuring that the Association fulfils its representational function? Do you care about issues affecting the profession and could you help ensure they are heard at the highest level? There are vacancies for seven regional representatives on Council and elections will take place early next year. PMID- 27935510 TI - New media guide to support members' PR. AB - Shirley Dent, BVA's media manager, announces the launch of a new media guide to help members promote their own and the profession's work in local media. PMID- 27935512 TI - BVA membership rates 2017. AB - BVA's head of membership, Tim Sainty, outlines the BVA membership rates for the year ahead, as agreed at the AGM in September. PMID- 27935513 TI - Playing our part in antibiotic awareness. AB - Nicky Mansell, one of the recent graduate representatives on BVA Council, discusses antimicrobial resistance and responsible use of antibiotics. PMID- 27935515 TI - Free CPD during pre-congress day at virtual congress. AB - As part of the International Webinar Vet Virtual Congress, BVA members can benefit from free CPD through BVA's pre-congress day. Zoe Davies, BVA's marketing manager, explains. PMID- 27935517 TI - Diary of a parliamentary intern. AB - Parliamentary veterinary intern Anthony Ridge considers the diverse group of people he has met over the past year and how this has changed his perspective on animal health and welfare and the values vets bring to society. PMID- 27935516 TI - Enhancing learning experiences. AB - Equine thermographer Elaine Hall wanted to improve her teaching skills so she enrolled on a course that could equip her with the skills she needed to improve her students' learning experience. PMID- 27935518 TI - The idea of uniform change: is it time to revisit a central tenet of Rose's "Strategy of Preventive Medicine"? AB - A mean-centric view of populations, whereby a change in the mean of a health variable at the population level is assumed to result in uniform change across the distribution, is a core component of Geoffrey Rose's concept of the "population strategy" to disease prevention. This idea also has a critical role in Rose's observation that individuals who are considered abnormal or sick (the rightward tail of the distribution) and those who are considered normal (the center) are very closely related, and that true preventive medicine must focus on shifting the normal or average. In this Perspective, we revisit these core tenets of Rose's concept of preventive medicine after providing an overview of the key concepts that he developed. We examine whether these assumptions apply to population changes in body mass index (BMI) and show that there is considerable evidence of a widening of the BMI distribution in populations over time. We argue that, with respect to BMI, the idea of using statistical measures of a population solely on the basis of means and the assumption that populations are coherent entities that change uniformly over time may not fully capture the true nature of changes in the population. These issues have important implications for how we assess and interpret the health of populations over time with implications for the balance between universal and targeted strategies aimed at improving health. PMID- 27935519 TI - The role of obesity in the relation between total water intake and urine osmolality in US adults, 2009-2012. AB - BACKGROUND: Adequate water intake is critical to physiologic and cognitive functioning. Although water requirements increase with body size, it remains unclear whether weight status modifies the relation between water intake and hydration status. OBJECTIVE: We examined how the association between water intake and urine osmolality, which is a hydration biomarker, varied by weight status. DESIGN: NHANES cross-sectional data (2009-2012) were analyzed in 9601 nonpregnant adults aged >=20 y who did not have kidney failure. Weight status was categorized with the use of body mass index on the basis of measured height and weight (underweight or normal weight, overweight, and obesity). Urine osmolality was determined with the use of freezing-point depression osmometry. Hypohydration was classified according to the following age-dependent formula: >=831 mOsm/kg - [3.4 * (age - 20 y)]. Total water intake was determined with the use of a 24-h dietary recall and was dichotomized as adequate or low on the basis of the Institute of Medicine's adequate intake recommendations for men and women (men: >=3.7 or <3.7 L; nonlactating women: >=2.7 or <2.7 L; lactating women: >=3.8 or <3.8 L for adequate or low intakes, respectively). We tested interactions and conducted linear and log-binomial regressions. RESULTS: Total water intake (P = 0.002), urine osmolality (P < 0.001), and hypohydration prevalence (P < 0.001) all increased with higher weight status. Interactions between weight status and water intake status were significant in linear (P = 0.005) and log-binomial (P = 0.015) models, which were then stratified. The prevalence ratio of hypohydration between subjects with adequate water intake and those with low water intake was 0.56 (95% CI: 0.43, 0.73) in adults who were underweight or normal weight, 0.67 (95% CI: 0.57, 0.79) in adults who were overweight, and 0.78 (95% CI: 0.70, 0.88) in adults who were obese. CONCLUSION: On a population level, obesity modifies the association between water intake and hydration status. PMID- 27935520 TI - Effect of fructose consumption on insulin sensitivity in nondiabetic subjects: a systematic review and meta-analysis of diet-intervention trials. AB - BACKGROUND: High fructose consumption has been suggested to contribute to several features of metabolic syndrome including insulin resistance, but to our knowledge, no previous meta-analyses have investigated the effect of fructose on insulin sensitivity in nondiabetic subjects. OBJECTIVE: We performed a systematic review and meta-analysis of controlled diet-intervention studies in nondiabetic subjects to determine the effect of fructose on insulin sensitivity. DESIGN: We searched MEDLINE, EMBASE, and the Cochrane Library for relevant trials on the basis of predetermined eligibility criteria. Two investigators independently performed the study selection, quality assessment, and data extraction. Results were pooled with the use of the generic inverse-variance method with random effects weighting and were expressed as mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs. RESULTS: Twenty-nine articles that described 46 comparisons in 1005 normal-weight and overweight or obese participants met the eligibility criteria. An energy-matched (isocaloric) exchange of dietary carbohydrates by fructose promoted hepatic insulin resistance (SMD: 0.47; 95% CI: 0.03, 0.91; P = 0.04) but had no effect on fasting plasma insulin concentrations (MD: -0.79 pmol/L; 95% CI: -6.41, 4.84 pmol/L; P = 0.78), the homeostasis model assessment of insulin resistance (HOMA-IR) (MD: 0.13; 95% CI: -0.07, 0.34; P = 0.21), or glucose disposal rates under euglycemic hyperinsulinemic clamp conditions (SMD: 0.00; 95% CI: 20.41, 0.41; P = 1.00). Hypercaloric fructose (~25% excess of energy compared with that of the weight maintenance control diet) raised fasting plasma insulin concentrations (MD: 3.38 pmol/L; 95% CI: 0.03, 6.73 pmol/L; P < 0.05) and induced hepatic insulin resistance (SMD: 0.77; 95% CI: 0.28, 1.26; P < 0.01) without affecting the HOMA IR (MD: 0.18; 95% CI: -0.02, 0.39; P = 0.08) or glucose disposal rates (SMD: 0.10; 95% CI: -0.21, 0.40; P = 0.54). Results may have been limited by the low quality, small sample size, and short duration (mostly <60 d) of included trials. CONCLUSIONS: Short-term fructose consumption, in isocaloric exchange or in hypercaloric supplementation, promotes the development of hepatic insulin resistance in nondiabetic adults without affecting peripheral or muscle insulin sensitivity. Larger and longer-term studies are needed to assess whether real world fructose consumption has adverse effects on insulin sensitivity and long term outcomes. PMID- 27935521 TI - Leucine supplementation enhances integrative myofibrillar protein synthesis in free-living older men consuming lower- and higher-protein diets: a parallel-group crossover study. AB - BACKGROUND: Leucine co-ingestion with lower-protein (LP)-containing meals may overcome the blunted muscle protein synthetic response to food intake in the elderly but may be effective only in individuals who consume LP diets. OBJECTIVE: We examined the impact of leucine co-ingestion with mixed macronutrient meals on integrated 3-d rates of myofibrillar protein synthesis (MyoPS) in free-living older men who consumed higher protein (HP) (1.2 g . kg-1 . d-1) or LP (0.8 g . kg 1 . d-1) in rested and resistance exercise (REX) conditions. DESIGN: In a crossover design, 20 healthy older men [aged 65-85 y] were randomly assigned to receive LP or HP diets while ingesting a placebo (days 0-2) and Leu supplement (5 g leucine/meal; days 3-5) with their 3 main daily meals. A bout of unilateral REX was performed during the placebo and Leu treatments. Ingested 2H2O and skeletal muscle biopsies were used to measure the 3-d integrated rate of MyoPS during the placebo and Leu treatments in the rested and REX legs. RESULTS: Leucinemia was higher with Leu treatment than with placebo treatment (P < 0.001). MyoPS was similar in LP and HP during both treatments (P = 0.39) but was higher with Leu treatment than with placebo treatment in the rested (pooled mean +/- SD: Leu, 1.57% +/- 0.11%/d; placebo, 1.48% +/- 0.08%/d; main effect of treatment: P < 0.001) and REX (pooled mean: Leu, 1.87% +/- 0.09%/d; placebo, 1.71 +/- 0.10%/d; main effect of treatment: P < 0.001) legs. CONCLUSIONS: Leu co-ingestion with daily meals enhances integrated MyoPS in free-living older men in rested and REX conditions and is equally effective in older men who consume daily protein intakes greater than or equal to the RDA. This trial was registered at clinicaltrials.gov as NCT02371278. PMID- 27935522 TI - Macro- and micronutrient intakes in picky eaters: a cause for concern? AB - BACKGROUND: Picky eating (PE) is characterized by an unwillingness to eat certain foods and by strong food preferences. PE may result in lower intakes of energy and nutrients, which may compromise health. OBJECTIVES: We quantified nutrient and food group intakes in children identified as picky eaters or nonpicky eaters and compared intakes between groups and with United Kingdom reference nutrient intakes. DESIGN: PE was identified in an observational cohort (Avon Longitudinal Study of Parents and Children) from questionnaires administered when children were aged 2, 3, 4.5, and 5.5 y. Dietary intake was assessed at 3.5 and 7.5 y with a 3-d food record. The dietary assessment at 3.5 y compared picky eaters with nonpicky eaters identified at age 3 y, and the assessment at 7.5 y compared longitudinally defined PE groups. RESULTS: Picky eaters aged 3 y had lower mean carotene, iron, and zinc intakes than nonpicky eaters. There were similar differences between the longitudinally defined PE groups. Iron and zinc intakes were most likely to be below recommended amounts, with free sugar intake much higher than recommended. There were no significant differences in energy intakes between the groups, and intakes were adequate relative to estimated average requirements. Nutrient differences were explained by lower intakes of meat, fish, vegetables, and fruits in picky eaters than in nonpicky eaters. There were higher intakes of sugary foods and drinks in older picky eaters. CONCLUSIONS: PE did not result in compromised macronutrient intakes, although intakes of zinc and iron were more likely to be below recommendations for picky eaters than for nonpicky eaters. Emphasis should be placed on allaying parental concerns about picky eaters being prone to inadequate nutrient intakes and on encouraging all parents to extend their child's diet to include more nutrient-rich items, especially fruits and vegetables, and less nutrient-poor sugary foods. PMID- 27935523 TI - Telehealth methods to deliver dietary interventions in adults with chronic disease: a systematic review and meta-analysis. AB - BACKGROUND: The long-term management of chronic disease requires the adoption of complex dietary recommendations, which can be facilitated by regular coaching to support behavioral changes. Telehealth interventions can overcome patient centered barriers to accessing face-to-face programs and provide feasible delivery methods, accessible regardless of geographic location. OBJECTIVE: This systematic review assessed the effectiveness of telehealth dietary interventions at facilitating dietary change in chronic disease. DESIGN: A structured systematic search was conducted for all randomized controlled trials evaluating multifactorial dietary interventions in adults with chronic disease that provided diet education in an intervention longer than 4 wk. Meta-analyses that used the random-effects model were performed on diet quality, dietary adherence, fruit and vegetables, sodium intake, energy, and dietary fat intake. RESULTS: A total of 25 studies were included, involving 7384 participants. The telehealth dietary intervention was effective at improving diet quality [standardized mean difference (SMD): 0.22 (95% CI: 0.09, 0.34), P = 0.0007], fruit and vegetable intake [mean difference (MD) 1.04 servings/d (95% CI: 0.46, 1.62 servings/d), P = 0.0004], and dietary sodium intake [SMD: -0.39 (-0.58, -0.20), P = 0.0001]. Single nutrients (total fat and energy consumption) were not improved by telehealth intervention; however, after a telehealth intervention, important clinical outcomes were improved, such as systolic blood pressure [MD: -2.97 mm Hg (95% CI: -5.72, -0.22 mm Hg), P = 0.05], total cholesterol [MD: -0.08 mmol/L (95% CI: -0.16, -0.00 mmol/L), P = 0.04], triglycerides [MD: -0.10 mmol/L (95% CI: 0.19, -0.01 mmol/L), P = 0.04], weight [MD: -0.80 kg (95% CI: -1.61, 0 kg), P = 0.05], and waist circumference [MD: -2.08 cm (95% CI: -3.97, -0.20 cm), P = 0.03]. CONCLUSIONS: Telehealth-delivered dietary interventions targeting whole foods and/or dietary patterns can improve diet quality, fruit and vegetable intake, and dietary sodium intake. When applicable, they should be incorporated into health care services for people with chronic conditions. This review was registered at http://www.crd.york.ac.uk/PROSPERO/ as CRD42015026398. PMID- 27935524 TI - Urinary potassium excretion, renal ammoniagenesis, and risk of graft failure and mortality in renal transplant recipients. AB - BACKGROUND: Renal transplant recipients (RTRs) have commonly been urged to limit their potassium intake during renal insufficiency and may adhere to this principle after transplantation. Importantly, in experimental animal models, low dietary potassium intake induces kidney injury through stimulation of ammoniagenesis. In humans, low potassium intake is an established risk factor for high blood pressure. OBJECTIVE: We hypothesized that low 24-h urinary potassium excretion [UKV; urinary potassium concentration * volume], the gold standard for assessment of dietary potassium intake, represents a risk factor for graft failure and mortality in RTRs. In secondary analyses, we aimed to investigate whether these associations could be explained by ammoniagenesis, plasma potassium, or blood pressure. DESIGN: In a prospective cohort of 705 RTRs, we assessed dietary potassium intake by a single 24-h UKV and food-frequency questionnaires. Cox regression analyses were used to investigate prospective associations with outcome. RESULTS: We included 705 stable RTRs (mean +/- SD age: 53 +/- 13 y; 57% men) at 5.4 y (IQR: 1.9-12.0 y) after transplantation and 253 kidney donors. Mean +/- SD UKV was 73 +/- 24 mmol/24 h in RTRs compared with 85 +/- 25 mmol/24 h in kidney donors. During follow-up for 3.1 y (IQR: 2.7-3.9 y), 45 RTRs developed graft failure and 83 died. RTRs in the lowest sex-specific tertile of UKV (women, <55 mmol/24 h; men, <65 mmol/24 h) had an increased risk of graft failure (HR: 3.70; 95% CI: 1.64, 8.34) and risk of mortality (HR; 2.66; 95% CI: 1.53, 4.61), independent of potential confounders. In causal path analyses, 24-h urinary ammonia excretion, plasma potassium, and blood pressure did not affect these associations. CONCLUSIONS: Our results indicate that low UKV is associated with a higher risk of graft failure and mortality in RTRs. Specific attention for adequate potassium intake after transplantation seems warranted. This trial was registered at clinicaltrials.gov as NCT02811835. PMID- 27935526 TI - Health economics and health insurance aspects of Mendelian randomization. PMID- 27935525 TI - Association of dietary protein and dairy intakes and change in renal function: results from the population-based longitudinal Doetinchem cohort study. AB - BACKGROUND: Evidence has suggested that protein from dairy may be less detrimental to renal health than protein from nondairy products. However, to our knowledge, no previous studies have used cystatin C-based measures of the estimated glomerular filtration rate (eGFR). OBJECTIVE: We investigated the associations of sources of protein and dairy with the change in the eGFR in persons with a normal or mildly decreased eGFR. DESIGN: We included 3798 participants, aged 26-65 y, from the Doetinchem Cohort study who were examined >=3 times 5 y apart. Intakes of protein and dairy and subtypes of protein and dairy were assessed at each round. With the use of the Chronic Kidney Disease Epidemiology Collaboration equation, the eGFR was estimated from cystatin C with all available samples per participant examined in one assay run. Generalized estimating equation models, which were adjusted for lifestyle, biological, and other dietary factors (monounsaturated fat, polyunsaturated fat, phosphorus, magnesium, calcium, and vitamin D) were performed. RESULTS: The mean baseline eGFR in the total cohort and in subjects with a mildly decreased eGFR (>=1 eGFR of 60-90 mL . min-1 . 1.73 m-2 during follow-up; n = 1326) was 108.6 and 95.2 mL . min-1 . 1.73 m-2, and the mean annual decline in both groups was 1.01 and 1.34 mL . min-1 . 1.73 m-2, respectively. Intakes of total, vegetable, animal, and nondairy protein, dairy protein, cheese, total dairy, high-fat dairy, and fermented dairy were not associated with eGFR changes. In individuals with a mildly decreased eGFR, higher consumption of milk, milk products, and low-fat dairy was associated with less annual decline in the eGFR (P-trend = 0.003). These associations were partially explained by dietary components of dairy (monounsaturated fat, polyunsaturated fat, phosphorus, magnesium, calcium, and vitamin D; P-trend < 0.04). CONCLUSIONS: Higher low-fat dairy consumption, but not sources of protein, is associated with less annual decline in the eGFR, particularly in individuals with a mildly decreased eGFR. These associations are partly attributable to other major components of dairy. Confirmation of these results will improve our ability to understand the role of dairy consumption in the prevention of renal dysfunction. PMID- 27935527 TI - Nutritional Evaluation and Optimisation in Neonates trial: is the protein-to energy ratio important? PMID- 27935528 TI - Reply to P Mainie. PMID- 27935529 TI - Whole-grain intake and risk of type 2 diabetes. PMID- 27935530 TI - Reply to J-B Qin et al. PMID- 27935531 TI - The role of nutritional biomarkers in prediction and understanding the etiology of type 2 diabetes. PMID- 27935532 TI - Reply to A Abbasi. PMID- 27935535 TI - Continuous Ambulatory Peritoneal Dialysis in Patients with HIV and End-Stage Renal Failure. AB - ? BACKGROUND: This study aimed to evaluate the differences in continuous ambulatory peritoneal dialysis (CAPD)-related outcomes according to human immunodeficiency virus (HIV) status of end-stage renal failure patients. ? METHODS: This prospective cohort study included 70 HIV-negative and 70 HIV positive consecutive patients with renal failure who underwent dialysis with newly inserted Tenckhoff catheters between September 2012 and February 2015. Patients were followed up monthly at a central renal clinic for 1 year or until the primary endpoints of technique failure or death. ? RESULTS: Technique failure rates were similar (HIV-negative: 0.270 episodes/person-year; HIV-positive: 0.298 episodes/person-year; hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.51 - 2.32; p = 0.822). However, there were fewer HIV-positive patients with complete 1-year follow-up with a patent catheter (42.9% vs 58.6% in the HIV-negative cohort; p = 0.063) owing to their higher all-cause mortality rate (0.55 vs 0.25 deaths/person-year, respectively; HR, 2.11; CI, 1.07 - 4.14; p = 0.031). Cluster of differentiation 4 count (CD4) < 200/MUL (HR, 5.39; CI, 2.20 - 13.21; p < 0.001) and unsuppressed viral load (HR, 3.63; CI 1.72 - 7.67; p = 0.001) were associated with increased mortality hazards. Rates of first peritonitis were 0.616 (HIV-negative) and 1.668 (HIV-positive) episodes/person-year (HR, 2.38; CI, 1.46 - 3.89; p = 0.001). All-cause admission rates were 1.52 (HIV-negative) and 2.97 (HIV-positive) hospital admissions/person-year (HR, 1.66; CI, 1.12 - 2.48; p = 0.013). ? CONCLUSION: Although HIV-seropositive status of patients on CAPD did not adversely influence technique failure rates or patency at 1 year, uncontrolled HIV infection may be associated with increased relative risk of mortality and morbidity. PMID- 27935534 TI - Representativeness of Honeypot Trial Participants to Australasian PD Patients. AB - BACKGROUND: The HONEYPOT trial failed to establish the superiority of exit-site application of Medihoney compared with nasal mupirocin prophylaxis for the prevention of peritonitis in peritoneal dialysis (PD) patients. This study aimed to assess the representativeness of the patients in the HONEYPOT trial to the Australian and New Zealand PD population. METHODS: This study compared baseline characteristics of the 371 PD patients in the HONEYPOT trial with those of 6,085 PD patients recorded on the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. RESULTS: Compared with the PD population, the HONEYPOT sample was older (standardized difference [d] = 0.19, p = 0.003), more likely to be treated with automated PD (d = 0.58, p < 0.001), had higher residual renal function (d = 0.26, p < 0.001) and a higher proportion of participants with end stage kidney disease due to polycystic kidney disease (d = 0.17) and lower proportion due to diabetes (d = -0.17) and glomerulonephritis (d = -0.18) (p < 0.001), and lower proportions of indigenous people (d = -0.17, p < 0.001), current smokers (d = -0.10, p < 0.001), and people with prior histories of hemodialysis (d = -0.16, p < 0.001), diabetes mellitus (d = -0.18, p < 0.001), and coronary artery disease (d = -0.15, p < 0.001). CONCLUSIONS: HONEYPOT trial participants tended to be healthier than the Australian and New Zealand PD patient population. Although the differences between the groups were generally modest, it is possible that their cumulative effect may have had some impact on external generalizability, which is not an uncommon occurrence in clinical trials. PMID- 27935536 TI - Evaluation of a 12-Month Pilot of Long-Term and Temporary Assisted Peritoneal Dialysis. AB - ? BACKGROUND: Peritoneal dialysis (PD) is challenging for patients with functional limitations, and assisted PD can support these patients, but previous reports of assisted PD have not examined the role of temporary assisted PD and had difficulty identifying adequate comparator cohorts. ? METHODS: Peritoneal Dialysis Assist (PDA), a 12-month pilot of long-term and temporary assisted PD was completed in multiple PD centers in British Columbia, Canada. Continuous cycler PD (CCPD) patients were identified for PDA by standardized criteria, and service could be long-term or temporary/respite. The PDA program provided daily assistance with cycler dismantle and setup, but patients remained responsible for cycler connections and treatment decisions. Outcomes were compared against both the general CCPD population and patients who met PDA criteria but were not enrolled (PDA-eligible). ? RESULTS: Fifty-three PDA patients had an 88% 1-year death- and transplant-censored technique survival that was similar to the general CCPD cohort (84%) and PDA-eligible cohort (86%). The PDA cohort had lower peritonitis rates (0.18 episodes/patient-year vs 0.22 and 0.36, respectively), but higher hospitalization (55% vs 34% and 35%, respectively). Long-term PDA cost approximately CDN$15,000/year in addition to existing dialysis costs. A total of 8/11 respite PDA patients (73%) returned to self-care PD after a median PDA use of 29 days, which costs $1,250/patient. ? CONCLUSIONS: Peritoneal Dialysis Assist provides effective support to functionally-limited CCPD patients and yields acceptable clinical outcomes. The program costs less than transfer to HD or long term care, which represents cost minimization for failing self-care PD patients. Respite PDA provides effective temporary support; most patients returned to self care PD and service was cost-effective compared with alternatives of hospitalization or transfer to HD. PMID- 27935537 TI - Predictors of Residual Renal Function Decline in Peritoneal Dialysis Patients: The balANZ Trial. AB - ? OBJECTIVE: Preservation of residual renal function (RRF) is associated with improved survival. The aim of the present study was to identify independent predictors of RRF and urine volume (UV) in incident peritoneal dialysis (PD) patients. ? METHODS: The study included incident PD patients who were balANZ trial participants. The primary and secondary outcomes were RRF and UV, respectively. Both outcomes were analyzed using mixed effects linear regression with demographic data in the first model and PD-related parameters included in a second model. ? RESULTS: The study included 161 patients (mean age 57.9 +/- 14.1 years, 44% female, 33% diabetic, mean follow-up 19.5 +/- 6.6 months). Residual renal function declined from 7.5 +/- 2.9 mL/min/1.73 m2 at baseline to 3.3 +/- 2.8 mL/min/1.73 m2 at 24 months. Better preservation of RRF was independently predicted by male gender, higher baseline RRF, higher time-varying systolic blood pressure (SBP), biocompatible (neutral pH, low glucose degradation product) PD solution, lower peritoneal ultrafiltration (UF) and lower dialysate glucose exposure. In particular, biocompatible solution resulted in 27% better RRF preservation. Each 1 L/day increase in UF was associated with 8% worse RRF preservation (p = 0.007) and each 10 g/day increase in dialysate glucose exposure was associated with 4% worse RRF preservation (p < 0.001). Residual renal function was not independently predicted by body mass index, diabetes mellitus, renin angiotensin system inhibitors, peritoneal solute transport rate, or PD modality. Similar results were observed for UV. ? CONCLUSIONS: Common modifiable risk factors which were consistently associated with preserved RRF and residual UV were use of biocompatible PD solutions and achievement of higher SBP, lower peritoneal UF, and lower dialysate glucose exposure over time. PMID- 27935538 TI - The correlation of TAS2R38 gene variants with higher risk for chronic rhinosinusitis in Polish patients. AB - BACKGROUND: Bitter taste receptors (T2Rs), especially T2R38s appear as innovative regulators of innate immunity in the respiratory system. The single nucleotide polymorphisms (SNPs) in TAS2R38 gene may contribute to individual differences in susceptibility to respiratory infections especially chronic rhinosinusitis (CRS). TAS2R38 genotypes distribution varies by geographic region, race and ethnicity. The aim of the preliminary study was the identification of SNPs in TAS2R38 encoding genes in Polish patients with CRS and finding potential correlation with CRS phenotypes. MATERIAL AND METHODS: The preliminary study contained 20 CRS patients undergoing functional endoscopic sinus surgery (FESS). Fresh sinus mucosa (SM) was obtained during FESS in CRS patients. Patients were genotyped for TAS2R38 using Sanger method and the genotype occurrences of the clinically recalcitrant CRS cohort was evaluated. Analysis of TAS2R38 expression in SM of CRS patients was performed using immunohistochemistry (IHC). RESULTS: T2R38 was highly expressed in SM of CRS patients. Patients with CRS demonstrated both common genotypes PAV, AVI. The heterozygotes frequency (AVI/PAV) was the highest. The protective genotype (PAV/PAV) was noticed in the lowest frequency and connected with lower average value of CT score compare to AVI/AVI genotypes (p=0.01). CONCLUSIONS: The work presented in this study provides the hypothesis that airway bitter T2Rs are an innovative sphere of human respiratory innate protection. TAS2R38 polymorphism may influence the susceptibility to CRS. The AVI haplotypes are an independent risk factors for CRS. Additionally, the bitter taste receptors and related signalling pathways might create an unique group of therapeutic targets to treat CRS. PMID- 27935539 TI - Role of Chlamydia pneumoniae in the pathogenesis of hypertrophy and adenoid tissue inflammation in children. AB - OBJECTIVE: A tropism to epithelial cells and lymphocytes, an inhibition of apoptosis in host cells, an ability to occurrence in persistent form resistant to antibiotic treatment are the features of Chlamydia pneumoniae, which can have connection with chronic inflammation of an adenoid tissue and adenoid hypertrophy. This study aimed to (1) detect the C. pneumoniae in an adenoid in children undergoing adenoidectomy, (2) estimate a connection between C. pneumoniae occurrence and the size of adenoid, (3) demonstration in which of adenoid cells C. pneumoniae occurs most often. MATERIAL AND METHODS: The examined group consisted of 200 children aged from 2 to 16 years (mean age 6,4) undergoing adenoidectomy. In all children during qualification for adenoidectomy a fiberoscopic examination of the nasopharynx was performed. A part of removed adenoid tissue was analysed by real-time PCR for C. pneumoniae. Adenoids from children with positive PCR examination and from 10 children with negative PCR examination were examined using immunohistochemistry (IHC). RESULTS: C. pneumoniae in the adenoid was present in 5,5% children. Positive results were obtained most frequently (24,14%, 7/29) in the eldest group (10-16 years). A statistical analysis demonstrated the correlation between C. pneumoniae occurrence in an adenoid tissue and the size of adenoid. In immunohistochemistry C. pneumoniae was found the most frequently in lymphocytes and in epithelial cells. CONCLUSIONS: A presence of C. pneumoniae in lymphocytes and epithelial cells of the adenoid first of all in older children with adenoid hypertrophy confirms the participation of this bacteria in adenoid pathology. PMID- 27935540 TI - Optical rhinometry - new challenges and possibilities of rhinitis diagnostics and not only. AB - Optical rhinometry is the only diagnostic tool in rhinitis for assessing real time changes in nasal occlusion. It illustrates lumen changes of nasal mucosa vessels in response nonspecific/specific factors and not only. The first attempts to standardize the method conducted by German researchers show the potential of optical rhinometry not only as regards challenge tests, but also vice versa, in respect of the anemization of the mucosa it evaluates the extent of the oedema which occurred in the pathomechanism of non-allergic rhinitis. The relatively small number of publications in the domain of interest demonstrates there is a need to conduct further research on the suitability of the above-mentioned technique for the evaluation of nasal patency in the field of rhinological diagnostics. PMID- 27935542 TI - Otolaryngological manifestations of leishmaniosis. AB - Travel to developing countries is associated with possibility to acquire different, also parasitic, diseases which have become a diagnostic and therapeutic problem. The ENT specialist is one of the medical officers who may make initial contact with a patient with a suspected parasitic disease. One of them is leishmaniosis: a parasitic disease classified as Neglected Tropical Diseases (NTD), which occurs in the tropics, subtropics and southern Europe. While asymptomatic invasion is observed in some cases, three forms of symptomatic leishmaniosis can be distinguished: cutaneous leishmaniosis (CL), visceral leishmaniosis (VL), and mucosal leishmaniosis (ML). Signs and symptoms of these forms, as well as the differential diagnosis, diagnostic procedures and treatment are presented in the paper. PMID- 27935541 TI - Is the Monocyte/HDL Ratio a Prognostic Marker of Idiopathic Sudden Hearing Loss? AB - OBJECTIVE: In this study, our aim was to investigate whether Monocyte/HDL ratio is a marker of the prognosis of the idiopathic sudden hearing loss (ISHL). STUDY DESIGN: Retrospective, case-control clinical trial. MATERIALS AND METHODS: 45 patients, who were diagnosed with idiopathic sudden hearing loss and were treated with the same therapy regime and 47 healthy volunteers, who applied to the hospital for routine controls and had audiological and laboratory examination between March 2014 and December 2015, were included in the study. Monocyte/HDL ratios of the patients in the study and control groups were calculated from the results of the blood counts and biochemical analysis. Additionally, the study group was divided into two sub-groups regarding their responses (responders and non-responders) to the treatment determined by the audiological examination, which was carried out after 3 months according to the Siegel criteria. The Monocyte/HDL ratios between the groups were statistically evaluated. RESULTS: There was no statistically significant difference between the MHRs of the study and control groups (p=0.574). However, the MHR was significantly higher in the non-responders? group compared with the responders? group, although they were treated with the same therapy regimen (p=0.005). CONCLUSION: There was no difference in MHRs between study and control groups. However, as MHR was higher in the patients with good prognosis compared with the patients with bad prognosis, we believe that regarding the ISHL, MHR is not a predictive value but might have prognostic marker. PMID- 27935543 TI - Acoustic neuroma as first sign of inner ear functional disorders. AB - INTRODUCTION: The aim of this work was to describe acoustic neuromas as the first signs of inner ear functional disorders. MATERIAL AND METHODS: The study covered 3,456 audiological and otoneurological patients, who were treated in the Department of Otolaryngology, Laryngological Oncology, Audiology and Phoniatrics Military Medical Academy University Teaching Hospital in Lodz within the period of 2011-2016. Among the studied subjects, an acoustic neuroma on the vestibulocochlear nerve was diagnosed in 13 cases (5,16%), including 9 women and 4 men. Each patient underwent a medical interview and an objective examination with static and dynamic tests, pure tone audiometry and speech audiometry tests, impedance audiometry tests, characteristics of tinnitus, videonystagmography and auditory brainstem evoked potentials (ABR) in crack. In each case of an incorrect ABR recording, contrast-enhanced MRI was performed. STUDY RESULTS: The conducted tests showed an incorrect ABR recording in 252 patients (7,29%, including 54,37% women and 45,63% men). In the performed contrast-enhanced MRI, 13 patients (5,16%), including 3,57% women and 1,59% men, had an image typical to neuroma of the vestibulocochlear nerve. Each one of the studied patients showed signs and symptoms typical to an acoustic neuroma such as hypoacusia and balance disorders, tinnitus in 12 subjects, headaches in the temporal and occipital area in 4 subjects, trigeminal neuralgia symptoms in 2 subjects and vision problems like scotoma and blurred vision reported by 1 patient. CONCLUSION: Each case of sensorineural hearing loss, particularly unilateral sensorineural hearing loss, requires expanded hearing tests and auditory brainstem evoked potentials tests. An incorrect brainstem evoked potentials recording such as: an elongated latency of the 5th wave, an elongated interlatency of 1-2-3 and 1-2-3-4 waves, requires a contract-enhanced magnetic resonance imaging to diagnose cerebellopontine angle tumours. PMID- 27935544 TI - Identification of early-stage lung adenocarcinoma prognostic signatures based on statistical modeling. AB - BACKGROUND: Current staging methods are lack of precision in predicting prognosis of early-stage lung adenocarcinomas. OBJECTIVE: We aimed to develop a gene expression signature to identify high- and low-risk groups of patients. METHODS: We used the Bayesian Model Averaging algorithm to analyze the DNA microarray data from 442 lung adenocarcinoma patients from three independent cohorts, one of which was used for training. RESULTS: The patients were assigned to either high- or low-risk groups based on the calculated risk scores based on the identified 25 gene signature. The prognostic power was evaluated using Kaplan-Meier analysis and the log-rank test. The testing sets were divided into two distinct groups with log-rank test p-values of 0.00601 and 0.0274 respectively. CONCLUSIONS: Our results show that the prognostic models could successfully predict patients' outcome and serve as biomarkers for early-stage lung adenocarcinoma overall survival analysis. PMID- 27935545 TI - Effects of different components of the extracellular matrix on endothelialization. AB - The endothelialization of cardiovascular prostheses is known to improve their haemocompatibility. As such body-foreign materials often do not endothelialize spontaneously. A lot of in vitro studies are ongoing how endothelialization of biomaterials can be improved. In this study the influence of different components of a tissue-typical extracellular matrix (ECM) like laminin, fibronectin or gelatin on the formation of an endothelial cell monolayer and on the shear resistance of adherent cells on these substrates was studied.The study revealed that the density of human venous endothelial cells (HUVEC) monolayers differed markedly between cells grown on a natural ECM and cells grown on singularized components of an ECM (p < 0.001). Only HUVEC grown on laminin showed similar densities and a stress fiber pattern comparable to HUVEC grown on the ECM. HUVEC grown on gelatin- or fibronectin-coated coverslips were less firmly attached to the substrate; frequently individual HUVEC and even groups of cells detached.Concluding it seems that coating of implants with laminin supports the formation of shear resistant endothelial cell (EC) monolayer - superior to other ECM components. PMID- 27935546 TI - Shear wave elastography of the testes in a healthy study collective - Differences in standard values between ARFI and VTIQ techniques. AB - INTRODUCTION: Shear wave elastography (SWE) is a recent technique in the assessment of tissue elasticity. Different elastography techniques have been described over the years.Acoustic Radiation Force Impulse Imaging (ARFI) uses mechanical excitation of tissue to create detectable shear waves, a higher shear wave velocity being associated with an increased tissue stiffness.The Virtual Touch Tissue Imaging Quantification (VTIQ) method uses a mechanical push pulse as well, additionally creating a colour-coded map, in which tissue stiffness can be measured within a stored map on the ultrasound device after measurement.ARFI has been used in determining standard values in testes of a healthy study collective, VTIQ has already been used in the evaluation of unclear scrotal masses.Both techniques allow an operator-independent examination without application of mechanical pressure. The aim of this study was to determine whether there is a statistically significant difference between shear wave velocity values of both techniques in a healthy collective. MATERIAL AND METHODS: Twenty patients without known testicular pathology underwent standard B-mode sonography and additional shear wave elastography in the ARFI mode as well as the VTIQ technique of both testes using the Siemens Acuson S2000TM and S3000TM ultrasound devices (Siemens HealthCare, Erlangen, Germany).Measurements of shear wave velocity were performed in the upper pole, the central portion and the lower pole separately for each testis. Values were described in m/s.Statistical evaluation was performed using paired t-test analysis. RESULTS: We measured a mean shear wave velocity of 0.81 m/s using ARFI and 1.07 m/s with VTIQ.Shear wave velocities determined by VTIQ were all significantly higher than values gained in the ARFI mode. (p < 0.001 to p = 0.007). Values were between 0.22 and 0.29 m/s higher, when the examination was performed using VTIQ. CONCLUSION: ARFI and VTIQ elastography modes both proved to be feasible techniques in the assessment of testicular tissue elasticity. Consideration of higher values for VTIQ is important, when different elastography measurement results are compared, especially for the application of devices in a clinical setting, e.g. in the work-up of scrotal masses.A calculable factor for a comparison between both devices is desirable, but to be further assessed in largerstudies. PMID- 27935547 TI - Flap design and perfusion are keys of success: Axial fasciocutaneous posterior thigh flaps for deep small pelvic defect reconstruction. AB - BACKGROUND AND OBJECTIVES: Radical excisions of the rectum often result in large perineal and intrapelvic defects. Compromised wound healing can delay adjuvant therapies and limit the patient's prognosis. With current treatment, integrity of the abdominal wall may be maintained. The defect geometry is unique and requires extensive volume for reconstruction. This study describes the surgical technique and reports clinical outcomes of fasciocutaneous posterior thigh flaps as preliminary data for this indication. METHODS: Thirteen posterior thigh flaps were used in eleven patients between 2013-2015. Patients were prospectively followed-up for the pursposes of this case series. Flap dimensions and volume were measured in two representative cases. The surgical technique is described in detail. RESULTS: Dead space occlusion was achieved in 100% of cases. No intestinal herniation was detected. Vaginal wall defects were concurrently reconstructed in two patients. Total flap volume was calculated as 315-360 cm3. The fasciocutaneous flaps were easy to harvest, versatile to manipulate and did not result in significant function deficits. CONCLUSIONS: In contrast to classic Vertical Rectus Abdominis Muscle (VRAM) flaps, the posterior thigh flaps preserve abdominal wall function and should be considered as a reliable alternative option in reconstruction of intrapelvic defects including neighboring organs. Future studies of larger patient series should be executed to verify our findings and determine the optimal point in time for reconstruction. PMID- 27935548 TI - Microwave ablation of large HCC lesions: Added value of CEUS examinations for ablation success control. AB - PURPOSE: To assess the value of dynamic contrast enhanced ultrasound (CEUS) for the detection of residual tumor tissue day 1 after microwave ablation (MWA) of large hepatocellular carcinoma (HCC) compared to MRI. MATERIAL AND METHODS: 30 consecutive patients (5 females, 25 males, mean age 64 years, age range 54-73 years) with an untreated HCC lesion larger than or equal to 3 cm underwent percutaneous MWA between 03/2014 and 04/2016. 1 patient was excluded because of an artificial pacemaker. All remaining 29 patients underwent 3-T MRI with liver specific contrast agent and CEUS 1 day after ablation to detect residual tumor tissue. The 6-week follow-up including CEUS and MRI was defined as the reference standard. RESULTS: Complete ablation was achieved in 23 of 29 treated lesions (79%). The sensitivities and specificities for the detection of residual tumor tissue on day 1 were 100% and 83% for CEUS and 87% and 67% for MRI resp. without the differences being statistically significant. CONCLUSION: CEUS allows a reliable assessment of therapeutic success of percutaneous ablation of large HCC lesions one day after the ablation. Its ability to visualize reactive periablation perfusion changes in real-time might be of advantage in the depiction of residual tumor tissue when compared to MRI imaging alone. PMID- 27935549 TI - Malignancies after liver transplantation: Value of contrast-enhanced ultrasound (CEUS). AB - PURPOSE: To evaluate the sensitivity and specificity of contrast-enhanced ultrasound (CEUS) and computed tomography (CT) in the diagnosis of malignancies after liver transplantation. MATERIALS AND METHODS: A total of 23 patients with suspicious liver masses after liver transplantation with initial imaging series between September 2006 and September 2015 were statistically analysed. CEUS and CT were compared in their diagnosis of malignancy with CT being the gold standard. Out of 23 patients 9 patients showed malignant masses in CT, which could also be detected in 7 out 9 of cases using CEUS. RESULTS: CEUS showed a sensitivity of 77.8%, a specificity of 100.0%, a positive predictive value (PPV) of 100.0% and a negative predictive value (NPV) of 87,5% in comparison with CT being the gold standard. In 2 cases CT showed a malignancy, contrary to the CEUS examination that was reported as normal. CONCLUSION: CEUS seems to be an alternative option for the evaluation of malignant masses in liver transplant patients. CEUS shows a high specificity and PPV in the detection of malignant liver masses. PMID- 27935550 TI - Vascular complications in liver transplantation: Beneficial role of contrast enhanced ultrasound (CEUS) in the postoperative phase. AB - PURPOSE: To compare the sensitivity and specificity of contrast-enhanced ultrasound (CEUS) and computed tomography (CT) in the diagnosis of vascular complications after liver transplantation in the postoperative phase. MATERIALS AND METHODS: A total of 60 patients with elevated liver function tests after liver transplantation with initial imaging studies between July 2005 and November 2015 were retrospectively analysed. CEUS and CT were compared in their diagnosis of vascular complications and CT was considered as the gold standard. Out of 60 patients 28 patients showed vascular complications in CT, which could also be detected in 25 out 28 of cases using CEUS. Diagnostic accuracy was tested by using the CT diagnosis as the gold standard. RESULTS: CEUS showed a sensitivity of 89.3%, a specificity of 100.0%, a positive predictive value (PPV) of 100.0% and a negative predictive value (NPV) of 91,4% compared to CT as the gold standard. In 3 cases CT showed a vascular complication, whereas the CEUS examination was reported as normal. CONCLUSION: CEUS is a fast, non-ionizing imaging modality for the initial exclusion of vascular complications after liver transplantation. CEUS shows a high specificity and PPV in the detection of vascular complications. In unclear cases CT still is considered as the gold standard. PMID- 27935551 TI - Organotypic soft-tissue co-cultures: Morphological changes in microvascular endothelial tubes after incubation with iodinated contrast media. AB - INTRODUCTION: Clinical complications like thrombosis or anaphylaxis have been described to go along with the intra-venous or intra-arterial injection of iodinated contrast media (CM). It has been suggested that the administration of CM affects rheological parameters and thereby causes reduced blood velocity in microvessels. In vitro studies revealed significant buckling of endothelial cells after exposure to CM reducing the lumen of vessels. The aim of this study was to test the influence of CM on three-dimensional microvascular tubules with open lumina within an organotypic soft-tissue co-culture assay in vitro. This model, which is based on the co-culture of endothelial cells and fibroblasts, allows the analysis and quantitation of different parameters of microvascular endothelial capillary structures. MATERIAL AND METHODS: Human dermal fibroblasts and human dermal microvascular endothelial cells were co-cultured for 10 days. Fibroblasts were adapted to the endothelial cell medium before co-culture and allowed to proliferate as well as produce extracellular matrix. The co-cultures were exposed to three different CM, i.e., Iomeprol (Imeron 400MCT), Iodixanol (Visipaque 320) or Iohexol (Accupaque 350) for 1.5 minutes or 5.0 minutes, respectively. For this, a mixture of CM and cell culture medium in a ratio of 30% CM by volume was prepared. After fixation in methanol/acetone, the endothelial cells were immunolabeled with the endothelial marker anti-CD31 and the tubular structures were assessed morphometrically. RESULTS: In the organotypic soft-tissue co cultures with fibroblasts, the endothelial cells developed three-dimensional capillary-like structures which expanded via sprouting branches. After incubation with the different CM, the numbers of endothelial tubes (p = 0.001) and their lengths (p = 0.003) were significantly lower after the 5 minutes incubation time, when compared to the 1.5 minutes incubation time. The tubular diameters were significantly reduced after 5 minutes (p < 0.001), when compared to the 1.5 minutes incubation duration. Interestingly, Iomeprol and Iodixanol induced an elongation of the tubular branches during incubation duration of 1.5 minutes (p = 0.015). However, after 5 minutes incubation, the tubular branches were drastically shorter in the presence of Iomeprol and Iodixanol than the tubular branches of the control (p = 0.007). SUMMARY AND CONCLUSION: All CM exerted a negative effect on the parameters of in vitro blood vessel development. PMID- 27935552 TI - Prefabrication and free transfer of a tissue engineered composite flap - An experimental model in the rat. AB - BACKGROUND: The technique of flap-prefabrication has been successfully established in tissue engineering: missing intrinsic vascularisation of engineered tissue can be generated in vivo by microsurgical vesselloop construction. It is possible to move engineered tissue into a defect with microsurgery. In the literature, the combination of engineered tissue covered with skin is not widely reported. OBJECTIVE: Aim of this study was to establish a model to investigate scaffold prefabrication with full thickness skin graft coverage with subsequent free tissue transfer. METHODS: 8 Wistar rats were operated in 2 separate steps: 1) after creating an arteriovenous loop with the femoral vessels, a porous scaffold was placed on the loop and covered with an inguinally based skin flap. A control was implanted without loop into the contralateral groin. 2) 6 weeks later the prefabricated composite flaps were microsurgically transferred to the cervical region. Skin-island monitoring was performed with Laser Doppler-scanner after the transfer. RESULTS: Continuous loss of the skin islands was observed within 72 hours. Complications included wound dehiscence, thrombosis and death from anaesthesia; in spite of consistent loop viability. CONCLUSION: Evaluation showed that modifications are necessary to maintain the skin-island cove. PMID- 27935553 TI - Percutaneous irreversible electroporation (IRE) of prostate cancer: Contrast enhanced ultrasound (CEUS) findings during follow up. AB - PURPOSE: Irreversible electroporation (IRE) is a focal non-thermal ablation technique that can be used to treat prostate cancer (Pca). The objective was to document the evolution of the volume of the prostate gland and the ablation zone after IRE of Pca. MATERIAL AND METHODS: A retrospective analysis of the image findings of CEUS 1 day, 6 weeks, 3 months and 6 months after IRE of 25 patients was conducted. The prostate gland volumes and the size of the ablation zones were documented. Changes in volume and size over time were calculated. RESULTS: There was a significant volume reduction of the prostate gland in the first 3 months after ablation. The mean percentage change after 6 weeks was 34.3% with another decrease of 35.0% after 3 months. Volume did not change between month 3 and 6. Size of ablation zone measured in short- and long-axis significantly diminished until 6 months after ablation. CONCLUSION: CEUS showed a significant involution of the prostate gland during the first 3 months and a significant decrease of the ablation zone during the first 6 months after IRE of prostate cancer. PMID- 27935554 TI - Risk of Mortality Associated with Antipsychotic Monotherapy and Polypharmacy Among Community-Dwelling Persons with Alzheimer's Disease. AB - We aimed to analyze the risk of non-cancer mortality according to duration of antipsychotic use and to compare the risk associated with polypharmacy and monotherapy among community-dwellers with Alzheimer's disease (AD). The risk of mortality between most frequently used antipsychotic drugs was compared. Data from a nationwide register-based MEDALZ study that included all 70,718 community dwellers newly diagnosed with AD during 2005-2011 in Finland was utilized. Death, excluding cancer as direct cause of death, was extracted from Causes of Death Register. Incident antipsychotic use was compared with time without antipsychotics with Cox proportional hazard models. Antipsychotic use was associated with an increased risk of mortality (adjusted hazard ratio [aHR] 1.61; 95% Confidence Interval [CI] 1.53-1.70). The absolute difference in mortality rate was 4.58 (95% CI 4.53-4.63) deaths per 100 person-years. The risk of mortality was increased from the first days of use and attenuated gradually but remained increased even after two years of use (aHR 1.30; 95% CI 1.16-1.46). Compared with nonuse, antipsychotic polypharmacy (aHR 2.88; 95% CI 2.38-3.49) was associated with an increased risk of mortality than monotherapy (aHR 1.57; 95% CI 1.49-1.66). Haloperidol was associated with higher risk of mortality (aHR 1.52; 95% CI 1.14-2.02) and quetiapine with lower risk (aHR 0.84; 95% CI 0.75-0.94) compared with risperidone. In conclusion, the findings support current treatment guidelines on having a high threshold for antipsychotic initiation among persons with AD. Antipsychotic polypharmacy and long-term use should be avoided and drug choice should be weighed against risk/benefit evidence. PMID- 27935555 TI - Algoplus(r) Scale in Older Patients with Dementia: A Reliable Real-World Pain Assessment Tool. AB - Pain is still a neglected clinical issue in elderly people with dementia and/or communicative disorders, with an unacceptable higher rate of under diagnosis and under treatment. Cognitive deficit and emotional and psychological disturbances entangle pain symptoms, affecting patient self-report. So far, observational pain tools do not have fully adequate clinimetric properties and quality requirements for easy-to-use daily rating. Older patients with dementia represent a clinical challenge. The assessment of pain is important for improving clinical outcomes, such as functional status, frailty trajectories, comorbidity, and quality of life. The PAINAID scale appears to be the most accurate pain tool in people with dementia along with the Algoplus(r) scale, a recently developed tool to rapidly assess acute pain in hospitals settings. The present study aimed to assess the clinimetric properties of the Algoplus(r), as compared to PAINAID, for detecting acute pain in a real-world cohort of hospitalized older patients with dementia. PMID- 27935556 TI - Elevation of Peripheral BDNF Promoter Methylation Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer's Disease: A 5-Year Longitudinal Study. AB - Epigenetic aberrations have been identified as biomarkers to predict the risk of Alzheimer's disease (AD). This study aimed to evaluate whether altered DNA methylation status of BDNF promoter could be used as potential epigenetic biomarkers for predicting the progression from amnestic mild cognitive impairment (aMCI) to AD. A total of 506 aMCI patients and 728 cognitively normal controls were recruited in the cross-sectional analyses. Patients (n = 458) from aMCI cohort were classified into two groups after 5-year follow-up: aMCI-stable group (n = 330) and AD-conversion group (n = 128). DNA methylation of BDNF promoter was detected by bisulfite-PCR amplification and pyrosequencing. The DNA methylation levels of CpG1 and CpG2 in promoter I and CpG5 and CpG6 in promoter IV of BDNF gene were significantly higher in the aMCI group than in the control group at baseline and also were increased in the conversion group compared with the non conversion group at 5-year follow up time point. CpG5 in BDNF promoter IV had the highest AUC of 0.910 (95% CI: 0.817-0.983, p < 0.05). Kaplan-Meier analysis showed a significant AD conversion propensity for aMCI patients with high methylation levels of CpG5 (HR = 1.96, 95% CI: 1.07-2.98, p < 0.001). Multivariate Cox regression analysis revealed elevated methylation status of CpG5 was a significant independent predictor for AD conversion (HR = 3.51, p = 0.013). These results suggest that elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to AD. PMID- 27935557 TI - Wearable tubing assistive walking device immediately enhances gait parameters in subjects with stroke: A randomized controlled study. AB - BACKGROUND: Stroke patients develop compensatory movements due to limitations of ankle dorsiflexion and knee flexion. To solve the limitations, there are many adjustable walking assistive devices such as robotic devices, ankle-foot orthoses, and functional electric stimulation in rehabilitation session. However, these assistive devices have some disadvantages, including expense and discomforts. Therefore, the development of a new assistive device for stroke patients is needed to assist ankle dorsiflexion and knee flexion. OBJECTIVE: This study investigated the effects of a wearable tubing assistive walking device (WTAWD) on gait parameters (gait speed, cadence, and step length and stride length on affected and less affected sides) in patients with stroke. METHODS: Gait parameters were measured using the GAITRite system. One-way repeated measures analysis of variance was used to determine gait differences under three conditions (WTAWD, barefoot, and conventional elastic band orthosis). RESULTS: Gait speed, cadence, and step length and stride length on both affected and less affected sides were significantly greater with WTAWD, compared to barefoot and conventional elastic band orthosis conditions. CONCLUSION: WTAWD could be effective for patients with stroke. PMID- 27935558 TI - Evaluation of body temperature in individuals with stroke. AB - BACKGROUND: A stroke can cause alterations in thermal sensitivity. OBJECTIVE: to verify the conditions of body temperature in hemiplegic patients after stroke as compared to healthy individuals, as well as establish relations between thermal sensitivity and gender, age, Body Mass Index (BMI), plegic side, time after stroke, reports of thermal alterations and the motricity of patients with stroke sequelae. METHODS: This cross-sectional study included 100 patients (55.6+/-13 years) with ischemic or hemorrhagic stroke sequelae with unilateral hemiparesis and thirty healthy subjects (55+/-12.9 years). Individuals with nervous peripheral lesions, diabetes, peripheral vascular diseases or tumors were not included in this study. The volunteers underwent axillary temperature evaluations with the use of a cutaneous thermometer and evaluations of cutaneous temperature of hands and feet as measured by infrared thermography captured by an infrared sensor (ThermaCAMTM SC 500-FLIR Systems). The mean temperature ( degrees C) was analyzed with the SigmaStat 3.5 statistical package. RESULTS: The results have shown that healthy individuals have similar temperatures on either side of the body. The hemiplegic subjects presented a lower temperature on the plegic side and compared to the healthy subjects, both feet of the hemiparetic individuals were colder. The results have also shown that age, body mass index, and the time after stroke have no influence on the alterations in temperature. Regarding the paretic side, individuals with hemiplegia on the right side (right foot) had a lower temperature than those affected on the left side. Motricity was not related to any difference in temperature between the limbs and the reports of temperature differences had no relation with the actual differences found in the study. CONCLUSIONS: Healthy individuals have temperature symmetry between between sides of the body, while individuals with stroke sequelae present lower temperature in the paretic side, especially on their feet. PMID- 27935559 TI - Application of a model to analyze shoulder biomechanics in adult patients with spinal cord injury when walking with crutches in two different gait patterns. AB - BACKGROUND: Specific biomechanical models have been developed to study gait using crutches. Clinical application of these models is needed in adult spinal cord injury (SCI) population walking with different patterns of gait with crutches to prevent overuse shoulder injuries. OBJECTIVE: To apply a biomechanical model in a clinical environment to analyze shoulder in adult SCI patients walking with two different patterns of gait with crutches: two point reciprocal gait (RG) and swing-through gait (SG). METHODS: Load cells were fixed to the distal ends and forearm cuffs of a pair of crutches. An active markers system was used for kinematics. Five cycles for each gait pattern were analyzed applying a biomechanical model of the upper limbs. Fifteen subjects with SCI were analyzed. RESULTS: The flexo-extension range of motion was significantly greater when using SG (p < 0.01). Similarly, the superior, posterior and medial forces were significantly stronger for SG in all 3 directions. Flexion, adduction and internal rotation torques were also greater in SG (p < 0.01). CONCLUSIONS: A biomechanical model was successfully applied to study shoulder biomechanics in adult patients with SCI walking with crutches in two different gait patterns. Greater loads exerted on the shoulder walking with SG were confirmed compared to RG. PMID- 27935560 TI - Mobility measures differentiate falls risk status in persons with multiple sclerosis: An exploratory study. AB - BACKGROUND: Falls are of great concern among persons with multiple sclerosis (MS). OBJECTIVE: To examine differences in metrics of mobility, postural control, and cognition in persons with MS with distinct fall risk status; and to investigate predictors of fall risk group membership using discriminant analysis. METHODS: Forty-seven persons with MS completed the Activities-Balance Confidence (ABC) Scale and underwent a battery of assessments of mobility, balance, and cognition. Participants further wore an accelerometer for 7 days as an assessment of steps/day. Participants were allocated into fall risk groups based on ABC scale scores (increased fall risk (IFR); and normal fall risk (NFR)). We examined univariate differences between groups using ANOVA, and discriminant function analysis (DFA) identified the significant multivariate predictors of FR status. RESULTS: After controlling for disability level, the IFR group had significantly (p < 0.05) worse scores on measures of mobility (i.e., MSWS-12, 6 MW, and steps/day) compared to the NFR group. DFA identified MSWS-12 and 6 MW scores as significant (p < 0.05) predictors of fall risk group membership. Those two variables collectively explained 55% of variance in fall risk grouping. CONCLUSIONS: The findings suggest that mobility should be the focus of rehabilitation programs in persons with MS, especially for those at IFR. PMID- 27935561 TI - Patterns of change and stability in caregiver burden and life satisfaction from 1 to 2 years after severe traumatic brain injury: A Norwegian longitudinal study. AB - OBJECTIVE: To assess burden and life satisfaction in family members of patients with severe traumatic brain injury (sTBI) at 1 and 2 years post-injury, examine if change in burden can be predicted by family member and patient demographics, patient's functional status, family members social network or level of burden at 1 year. METHODS: Prospective national multicenter study. Self-report from family members, patient data collected from a national cohort study on patients with sTBI. 80 family members participated. MAIN OUTCOME MEASURE: The Caregiver Burden Scale (CBS), life satisfaction. RESULTS: Total burden increased between years 1 and 2 post-injury (P = 0.04). Thirty percent of the family members reported an increased burden, 55% were stable, and 15% had a decrease in burden between the two follow-up times. Logistic regression analyses revealed that experiencing loneliness was an independent predictor of increased burden from 1 to 2 years post-injury (OR = 4.35, P < 0.05). Life Satisfaction was lower at the 2 year follow-up than at 1 year (p = 0.03). CONCLUSIONS: The results demonstrate a need for long-term follow-up of patients and family members that focuses on professional support to relieve burden and risk of loneliness or social isolation. This group may benefit from additional follow-up interventions tailored to their needs. PMID- 27935562 TI - Current conservative management and classification of club foot: A review. AB - Clubfoot, known as congenital talipes equinovarus, is one of the complex paediatric foot deformity with the incidence of 1 in every 1000 live births. It consists of four complex foot abnormalities such as forefoot adductus, midfoot cavus, and hindfoot varus and ankle equinus. There are a number of surgical techniques (soft tissue releases, arthrodesis) used to correct clubfoot. However currently the conservative management (manipulation, serial casting, and braces) of clubfoot is considered as the best choice and it is widely accepted among orthopaedists. Clubfoot treated with surgical techniques might suffer various complications such as soft tissues contractures, neurovascular complications, infections, and shortening of the limbs. Although conservative method is generally considered as an effective method, it is still challenging to cure clubfoot in advance stages. Also, the classification of the initial severity of clubfoot is essential to evaluate the outcome of the treatment. In this review, the aim is to review the different types of conservative method and the assessment of clubfoot severity. PMID- 27935563 TI - Physical activity and walking performance: Influence on quality of life in ambulatory children with cerebral palsy (CP). AB - PURPOSE: To examine the relationship of physical activity (PA) and walking performance to QOL in ambulatory children with CP, as function is not consistently associated with QOL in this population. METHODS: A secondary analysis of a cross-sectional cohort of 128 ambulatory children with CP, ages 2.2 9.9 years and GMFCS levels I-III, was employed. Individual multivariate regression models were developed for physical, psychosocial, and total domains of QOL as measured by the Pediatric Quality of Life Inventory (PedsQL) controlling for physical activity and walking performance, participation level and frequency, topography of CP, walking capacity, age, and satisfaction with participation. RESULTS: Physical, psychosocial and total QOL averaged 52.2, 60.9, and 56.5 respectively. PA was positively associated with physical (0.64, p < 0.01) and total QOL (0.54, p < 0.01). Walking performance was associated with physical QOL (0.16, p = 0.05), participation level was positively related to psychosocial (0.44, p < 0.01), and age negatively for all QOL domains (> -0.43, p < 0.01). CONCLUSIONS: Physical activity, walking performance, and level of participation in daily life are associated with varying domains of QOL. Future work should explore factors that influence the relationship of daily physical/walking activity and participation to QOL in children with ambulatory CP as they age. PMID- 27935564 TI - High prevalence of cranial asymmetry exists in infants with neonatal brachial plexus palsy. AB - PURPOSE: This study aimed to: 1) evaluate the prevalence of cranial asymmetry (positional plagiocephaly) in infants with neonatal brachial plexus palsy (NBPP); 2) examine the association of patient demographics, arm function, and NBPP related factors to positional plagiocephaly; and 3) determine percentage of spontaneous recovery from positional plagiocephaly and its association with arm function. METHODS: Infants < 1 year of age with NBPP and no previous exposure to plagiocephaly cranial remolding therapy or surgical intervention were recruited for this prospective cross-sectional study. Positional plagiocephaly (diagonal difference) measurements were captured using a fiberglass circumferential mold of the cranium. Included infants were divided into 2 groups: 1) those with positional plagiocephaly at most recent evaluation (plagio group), including infants with resolved positional plagiocephaly (plagio-resolved subgroup); and 2) those who never had positional plagiocephaly (non-plagio group). Standard statistics were applied. RESULTS: Eighteen of 28 infants (64%) had positional plagiocephaly. Delivery type might be predictive for plagiocephaly. Infants in the non-plagio group exhibited more active range of motion than infants in the plagio group. All other factors had no significant correlations. CONCLUSIONS: A high prevalence of positional plagiocephaly exists among the NBPP population examined. Parents and physicians should encourage infants to use their upper extremities to change position and reduce chance of cranial asymmetry. PMID- 27935565 TI - Traumatic amputations in children and adolescents: A demographic study from a tertiary care center in Northern India. AB - PURPOSE: To determine the demographic pattern, level, mechanism of traumatic amputation in children and adolescent age group and to compare findings with other studies. METHODS: Patients aged less than 18 years with traumatic amputation attending Department of Physical Medicine and Rehabilitation, King George's Medical University, Lucknow, India between July 2013 and January 2016 were enrolled and their demographic characteristics were analyzed. RESULTS: Fifty three patients were included aged less than 18 years when injured. Mean age of the population studied was 9.89 +/- 4.13 with male to females ratio of 3:2. Majority (69.81%) of traumatic amputations involved lower limb. Most common level was unilateral transtibial (35.85%), followed by transfemoral (16.98%). In upper limb, most common type was transradial. RTA followed by train accidents was most common mechanism of traumatic amputation. 8 patients needed revision surgery. 52.8% patients of acquired amputations complained of phantom sensation and 37.74% phantom pain. CONCLUSIONS: This study aims to visualize the current scenario and the data generated could be possibly helpful in planning policies and programs at institutional as well as at higher levels for prevention, treatment and distribution of resource to the young amputee population, to ensure their better health care and also opportunities in life. PMID- 27935566 TI - Factors associated with parent depressive symptoms and family quality of life in parents of adolescents and young adults with and without Spina Bifida. AB - PURPOSE: The purpose of this study was to explore factors related to parental depressive symptoms (PDS) and family quality of life (FQOL) in parents of adolescents and young adults (AYA) with and without a specific chronic health condition (CHC), spina bifida. METHODS: Two hundred and nine parents of AYA (112 with SB; and 97 without) and their AYA (46% males and 54% females) took part in a multi-site cross-sectional descriptive correlational study. In telephone interviews parents reported on measures of family satisfaction, resources, cohesion, stress, demographic and clinical data. RESULTS: In the multivariate analyses, 38% of the variance of PDS was explained by family income, family resources and parent stress. Having a child with SB was not predictive of PDS. However, having a child with SB, along with family satisfaction, parent stress and PDS explained 49% of the variance of FQOL. PDS partially mediate the relationship of family resources and FQOL. CONCLUSION: PDS, family stress, and resources should be evaluated routinely, especially for those with low income. Parents of AYA with SB who have elevated PDS are at increased risk of having lower reported FQOL. PMID- 27935569 TI - A quality of life model promotes enablement for children with medical complexity. PMID- 27935571 TI - Editorial. PMID- 27935570 TI - After a child's acquired brain injury (ABI): An ethnographic study of being a parent. AB - PURPOSE: To explore the meanings associated with being a parent of a child with an aquired brain injury (ABI). METHODS: An ethnographic study was conducted with parents of children aged 3 to 10 years who had acquired a severe brain injury. Purposeful sampling was used to recruit parents from the Glenrose Rehabilitation Hospital in Edmonton, Alberta. Data collection involved participant observation, fieldwork and semi-structured interviews. Field notes and interviews transcriptions were analysed using a thematic analysis framework and informed by symbolic interactionism theory. RESULTS: Six parent dyads (mothers and fathers) and 4 mothers participated in the study.Parents' meanings of 'parenting' a child with severe brain injury were shaped by the injury, wide range of familial dynamics, and interactions. Six main themes related to parental meanings emerged from our data: (1) Getting 'back to normal'; (2) Relying on a support system; (3) Worrying something bad may happen after the injury; (4) Going through a range of emotions following the injury; (5) Changing family dynamics after the injury; and (6) Ongoing performativity. CONCLUSION: Parents' meanings of 'parenting' a child are extensively impacted by their child's functioning after the ABI. Having a greater appreciation of these experiences may be beneficial for medical professionals. PMID- 27935574 TI - Europium doping of superparamagnetic iron oxide nanoparticles enables their detection by fluorescence microscopy and for quantitative analytics. AB - BACKGROUND: Pharmacokinetic studies and histological detection of superparamagnetic iron oxide nanoparticles (SPIO) in biomedical research are limited due to a high iron background especially in pathological tissues. OBJECTIVE: The suitability of doping the iron oxide cores of SPIO with europium (Eu) was tested for improved histologic detection and for quantitative analysis without changing their properties as probes for magnetic resonance imaging (MRI). A special variant of SPIO, so called very small superparamagnetic iron oxide nanoparticles (VSOP), was used for this approach. METHODS: VSOP, stabilized by a citrate coating, were synthesized with and without addition of Eu (Eu-VSOP and VSOP, respectively). MR signal enhancing effects of Eu-VSOP and VSOP were studied in vitro. Cellular uptake of Eu-VSOP and VSOP was examined in RAW264.7 cells. For Eu-VSOP, fluorescence microscopy and spectrophotometry were used. Eu fluorescence was enhanced by means of an antenna system. For VSOP, Prussian blue staining and photometry using the phenanthroline method were applied. Results for both VSOP variants were compared. RESULTS: Eu-VSOP and VSOP did not differ with respect to MR signal enhancing effects nor to uptake characteristics in the RAW264.7 cell experiments. Fluorescence microscopy detects Eu-VSOP with higher sensitivity compared to light microscopy using Prussian blue staining. In microscopy as well as in the analytical quantification using fluorescence, detection of Eu-VSOP is not contaminated by Fe background. CONCLUSIONS: Doping the VSOP with Eu allows for their improved detection by fluorescence microscopy and quantitative analysis without changing their cellular uptake characteristics or their MR signal enhancing effects and thus would allow for a multimodal approach for studying their pharmacokinetics and biodistribution in experimental research. PMID- 27935575 TI - Visual brain activity patterns classification with simultaneous EEG-fMRI: A multimodal approach. AB - BACKGROUND: Classification of the visual information from the brain activity data is a challenging task. Many studies reported in the literature are based on the brain activity patterns using either fMRI or EEG/MEG only. EEG and fMRI considered as two complementary neuroimaging modalities in terms of their temporal and spatial resolution to map the brain activity. For getting a high spatial and temporal resolution of the brain at the same time, simultaneous EEG fMRI seems to be fruitful. METHODS: In this article, we propose a new method based on simultaneous EEG-fMRI data and machine learning approach to classify the visual brain activity patterns. We acquired EEG-fMRI data simultaneously on the ten healthy human participants by showing them visual stimuli. Data fusion approach is used to merge EEG and fMRI data. Machine learning classifier is used for the classification purposes. RESULTS: Results showed that superior classification performance has been achieved with simultaneous EEG-fMRI data as compared to the EEG and fMRI data standalone. This shows that multimodal approach improved the classification accuracy results as compared with other approaches reported in the literature. CONCLUSIONS: The proposed simultaneous EEG-fMRI approach for classifying the brain activity patterns can be helpful to predict or fully decode the brain activity patterns. PMID- 27935576 TI - Acute lymphoblastic leukemia relapsing after first-line pediatric-inspired therapy: a retrospective GRAALL study. AB - The outcome of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) relapsing after pediatric-inspired front-line therapy is ill known. Here 229 relapsing Ph- ALL younger adults (18-63 years) treated within the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/-2005 trials were considered. Salvage regimens consisted of potentially curative therapies in 194 cases, low-intensity therapies in 21, allogeneic stem cell transplant (allo-SCT) in 6 and best supportive care in 8. Overall, 77 patients received allo-SCT after relapse. The median follow-up was 3.1 years. A second complete remission (CR2) was achieved in 121 patients (53%). In multivariate analysis, only younger age <45 years (P=0.008) and CR1 duration ?18 months (P=0.009) predicted CR2. Overall survival (OS) at 2 and 5 years was 19.3% (14-24%) and 13.3% (8-18%), respectively. In CR2 patients, disease-free survival (DFS) at 2 and 5 years was 29.0% (21-38%) and 25% (17-33%). In multivariate analysis, CR1 duration ?18 months and allo-SCT after relapse were associated with longer DFS (P<0.009 and P=0.004, respectively) and longer OS (P=0.004 and P<0.0001, respectively). In conclusion, although younger adults relapsing after pediatric-inspired ALL therapies retain a poor outcome, some of them may be cured if CR1 duration ?18 months and if allo-SCT can be performed in CR2. New therapies are definitely needed for these patients. PMID- 27935578 TI - Comment on 'Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia'. PMID- 27935577 TI - Bone marrow fibrosis grade is an independent risk factor for overall survival in patients with primary myelofibrosis. PMID- 27935579 TI - MiR-139-5p is a potent tumor suppressor in adult acute myeloid leukemia. PMID- 27935581 TI - Comprehensive study on ERG gene expression in normal karyotype acute myeloid leukemia: ERG expression is of limited prognostic value, whereas the accumulation of adverse prognostic markers stepwise worsens the prognosis. PMID- 27935583 TI - Depleting stabilized GOF mutant p53 proteins by inhibiting molecular folding chaperones: a new promise in cancer therapy. PMID- 27935580 TI - Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial. AB - We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9 4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk. PMID- 27935582 TI - Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to die. AB - The mammalian target of rapamycin (mTOR) is a key regulator of cell growth, autophagy, translation, and survival. Dysregulation of mTOR signaling is associated with cancer, diabetes, and autism. However, a role for mTOR signaling in neuronal death is not well delineated. Here we show that global ischemia triggers a transient increase in mTOR phosphorylation at S2448, whereas decreasing p-mTOR and functional activity in selectively vulnerable hippocampal CA1 neurons. The decrease in mTOR coincides with an increase in biochemical markers of autophagy, pS317-ULK-1, pS14-Beclin-1, and LC3-II, a decrease in the cargo adaptor p62, and an increase in autophagic flux, a functional readout of autophagy. This is significant in that autophagy, a catabolic process downstream of mTORC1, promotes the formation of autophagosomes that capture and target cytoplasmic components to lysosomes. Inhibitors of the lysosomal (but not proteasomal) pathway rescued the ischemia-induced decrease in mTOR, consistent with degradation of mTOR via the autophagy/lysosomal pathway. Administration of the mTORC1 inhibitor rapamycin or acute knockdown of mTOR promotes autophagy and attenuates ischemia-induced neuronal death, indicating an inverse causal relation between mTOR, autophagy, and neuronal death. Our findings identify a novel and previously unappreciated mechanism by which mTOR self-regulates its own levels in hippocampal neurons in a clinically relevant model of ischemic stroke. PMID- 27935585 TI - Tell me about your stemness. I'll give your cancer risk! PMID- 27935584 TI - Ketogenesis contributes to intestinal cell differentiation. AB - The intestinal epithelium undergoes a continual process of proliferation, differentiation and apoptosis. Previously, we have shown that the PI3K/Akt/mTOR pathway has a critical role in intestinal homeostasis. However, the downstream targets mediating the effects of mTOR in intestinal cells are not known. Here, we show that the ketone body beta-hydroxybutyrate (betaHB), an endogenous inhibitor of histone deacetylases (HDACs) induces intestinal cell differentiation as noted by the increased expression of differentiation markers (Mucin2 (MUC2), lysozyme, IAP, sucrase-isomaltase, KRT20, villin, Caudal-related homeobox transcription factor 2 (CDX2) and p21Waf1). Conversely, knockdown of the ketogenic mitochondrial enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) attenuated spontaneous differentiation in the human colon cancer cell line Caco-2. Overexpression of HMGCS2, which we found is localized specifically in the more differentiated portions of the intestinal mucosa, increased the expression of CDX2, thus further suggesting the contributory role of HMGCS2 in intestinal differentiation. In addition, mice fed a ketogenic diet demonstrated increased differentiation of intestinal cells as noted by an increase in the enterocyte, goblet and Paneth cell lineages. Moreover, we showed that either knockdown of mTOR or inhibition of mTORC1 with rapamycin increases the expression of HMGCS2 in intestinal cells in vitro and in vivo, suggesting a possible cross-talk between mTOR and HMGCS2/betaHB signaling in intestinal cells. In contrast, treatment of intestinal cells with betaHB or feeding mice with a ketogenic diet inhibits mTOR signaling in intestinal cells. Together, we provide evidence showing that HMGCS2/betaHB contributes to intestinal cell differentiation. Our results suggest that mTOR acts cooperatively with HMGCS2/betaHB to maintain intestinal homeostasis. PMID- 27935586 TI - Use of plankton-derived vitamin B1 precursors, especially thiazole-related precursor, by key marine picoeukaryotic phytoplankton. AB - Several cosmopolitan marine picoeukaryotic phytoplankton are B1 auxotrophs requiring exogenous vitamin B1 or precursor to survive. From genomic evidence, representatives of picoeukaryotic phytoplankton (Ostreococcus and Micromonas spp.) were predicted to use known thiazole and pyrimidine B1 precursors to meet their B1 demands, however, recent culture-based experiments could not confirm this assumption. We hypothesized these phytoplankton strains could grow on precursors alone, but required a thiazole-related precursor other the well-known and extensively tested 4-methyl-5-thiazoleethanol. This hypothesis was tested using bioassays and co-cultures of picoeukaryotic phytoplankton and bacteria. We found that specific B1-synthesizing proteobacteria and phytoplankton are sources of a yet-to-be chemically identified thiazole-related precursor(s) that, along with pyrimidine B1 precursor 4-amino-5-hydroxymethyl-2-methylpyrimidine, can support growth of Ostreococcus spp. (also Micromonas spp.) without B1. We additionally found that the B1-synthesizing plankton do not require contact with picoeukaryotic phytoplankton cells to produce thiazole-related precursor(s). Experiments with wild-type and genetically engineered Ostreococcus lines revealed that the thiazole kinase, ThiM, is required for growth on precursors, and that thiazole-related precursor(s) accumulate to appreciable levels in the euphotic ocean. Overall, our results point to thiazole-related B1 precursors as important micronutrients promoting the survival of abundant phytoplankton influencing surface ocean production and biogeochemical cycling. PMID- 27935587 TI - A family of interaction-adjusted indices of community similarity. AB - Interactions between taxa are essential drivers of ecological community structure and dynamics, but they are not taken into account by traditional indices of beta diversity. In this study, we propose a novel family of indices that quantify community similarity in the context of taxa interaction networks. Using publicly available datasets, we assessed the performance of two specific indices that are Taxa INteraction-Adjusted (TINA, based on taxa co-occurrence networks), and Phylogenetic INteraction-Adjusted (PINA, based on phylogenetic similarities). TINA and PINA outperformed traditional indices when partitioning human-associated microbial communities according to habitat, even for extremely downsampled datasets, and when organising ocean micro-eukaryotic plankton diversity according to geographical and physicochemical gradients. We argue that interaction-adjusted indices capture novel aspects of diversity outside the scope of traditional approaches, highlighting the biological significance of ecological association networks in the interpretation of community similarity. PMID- 27935588 TI - Single-cell mass spectrometry reveals the importance of genetic diversity and plasticity for phenotypic variation in nitrogen-limited Chlamydomonas. AB - Phenotypic variation is vital for microbial populations to survive environmental perturbations. Both genetic and non-genetic factors contribute to an organism's phenotypic variation and therefore its fitness. To investigate the correlation between genetic diversity and phenotypic variation, we applied our recently developed mass spectrometry method that allows for the simultaneous measurement of more than 25 different lipids and pigments with high throughput in the unicellular microalga Chlamydomonas reinhardtii. We monitored the impact of nitrogen limitation on a genetically diverse wild-type strain CC-1690 and two isoclonal isolates from CC-1690 named ANC3 and ANC5. Measuring molecular composition of thousands of single cells at different time points of the experiment allowed us to capture a dynamic picture of the phenotypic composition and adaptation of the populations over time. Although the genetically diverse population maintained phenotypic variation over the whole time course of the experiment, the isoclonal cultures showed higher synchronicity in their phenotypic response. Furthermore, the genetically diverse population showed equal or greater phenotypic variation over the whole time range in multidimensional trait space compared with isoclonal populations. However, along individual trait axes non-genetic variance was higher in isoclonal populations. PMID- 27935589 TI - Strategies to improve reference databases for soil microbiomes. PMID- 27935590 TI - Methylacidiphilum fumariolicum SolV, a thermoacidophilic 'Knallgas' methanotroph with both an oxygen-sensitive and -insensitive hydrogenase. AB - Methanotrophs play a key role in balancing the atmospheric methane concentration. Recently, the microbial methanotrophic diversity was extended by the discovery of thermoacidophilic methanotrophs belonging to the Verrucomicrobia phylum in geothermal areas. Here we show that a representative of this new group, Methylacidiphilum fumariolicum SolV, is able to grow as a real 'Knallgas' bacterium on hydrogen/carbon dioxide, without addition of methane. The full genome of strain SolV revealed the presence of two hydrogen uptake hydrogenases genes, encoding an oxygen-sensitive (hup-type) and an oxygen-insensitive enzyme (hhy-type). The hhy-type hydrogenase was constitutively expressed and active and supported growth on hydrogen alone up to a growth rate of 0.03 h-1, at O2 concentrations below 1.5%. The oxygen-sensitive hup-type hydrogenase was expressed when oxygen was reduced to below 0.2%. This resulted in an increase of the growth rate to a maximum of 0.047 h-1, that is 60% of the rate on methane. The results indicate that under natural conditions where both hydrogen and methane might be limiting strain SolV may operate primarily as a methanotrophic 'Knallgas' bacterium. These findings argue for a revision of the role of hydrogen in methanotrophic ecosystems, especially in soil and related to consumption of atmospheric methane. PMID- 27935591 TI - Coupled molecular and isotopic evidence for denitrifier controls over terrestrial nitrogen availability. AB - Denitrification removes ecologically available nitrogen (N) from the biosphere and influences both the pace and magnitude of global climate change. Disagreements exist over the degree to which this microbial process influences N availability patterns across Earth's ecosystems. We combine natural stable isotope methods with qPCR to investigate how denitrifier gene abundance is related to variations in nitrate (NO3-) pool sizes across diverse terrestrial biomes and conditions. We analyze NO3- isotope composition (15N/14N, 18O/16O) and denitrifier gene nirS in 52 soil samples from different California ecosystems, spanning desert, chaparral, oak-woodland/savanna and forest. delta15N-NO3- correlates positively with delta18O-NO3- (P?0.03) and nirS abundance (P=0.00002) across sites, revealing the widespread importance of isotopic discrimination by soil denitrifiers. Furthermore, NO3- concentrations correlate negatively to nirS (P=0.002) and delta15N-NO3- (P=0.003) across sites. We also observe these spatial relationships in short-term (7-day), in situ soil-incubation experiments; NO3- depletion strongly corresponds with increased nirS, nirS/16 rRNA, and enrichment of heavy NO3- isotopes over time. Overall, these findings suggest that microbial denitrification can consume plant-available NO3- to low levels at multiple time scales, contributing to N-limitation patterns across sites, particularly in moist, carbon-rich soils. Furthermore, our study provides a new approach for understanding the relationships between microbial gene abundance and terrestrial ecosystem functioning. PMID- 27935592 TI - Molecular insights into a dinoflagellate bloom. AB - In coastal waters worldwide, an increase in frequency and intensity of algal blooms has been attributed to eutrophication, with further increases predicted because of climate change. Yet, the cellular-level changes that occur in blooming algae remain largely unknown. Comparative metatranscriptomics was used to investigate the underlying molecular mechanisms associated with a dinoflagellate bloom in a eutrophied estuary. Here we show that under bloom conditions, there is increased expression of metabolic pathways indicative of rapidly growing cells, including energy production, carbon metabolism, transporters and synthesis of cellular membrane components. In addition, there is a prominence of highly expressed genes involved in the synthesis of membrane-associated molecules, including those for the production of glycosaminoglycans (GAGs), which may serve roles in nutrient acquisition and/or cell surface adhesion. Biotin and thiamine synthesis genes also increased expression along with several cobalamin biosynthesis-associated genes, suggesting processing of B12 intermediates by dinoflagellates. The patterns in gene expression observed are consistent with bloom-forming dinoflagellates eliciting a cellular response to elevated nutrient demands and to promote interactions with their surrounding bacterial consortia, possibly in an effort to cultivate for enhancement of vitamin and nutrient exchanges and/or direct consumption. Our findings provide potential molecular targets for bloom characterization and management efforts. PMID- 27935593 TI - Warming and nutrient enrichment in combination increase stochasticity and beta diversity of bacterioplankton assemblages across freshwater mesocosms. AB - The current climate warming and eutrophication are known to interactively threaten freshwater biodiversity; however, the interactive effects on lacustrine bacterioplankton diversity remain to be determined. Here, we analyzed the spring bacterioplankton community composition (BCC) in 24 outdoor, flow-through mesocosms (mimicking shallow lake environments) under 3 temperature scenarios and 2 nutrient regimes. Our results revealed that neither long-term warming (8.5 years) nor nutrient enrichment had significant effects on bacterioplankton alpha diversity, whereas long-term enhanced warming (elevated 50% above the IPCC A2 climate scenario) and nutrient enrichment in combination increased bacterioplankton beta diversity. We also found that BCC shifted significantly under enhanced warming and nutrient-enriched conditions towards decreased relative abundances of Actinobacteria, Bacteroidetes and Betaproteobacteria, whereas the percentages of Cyanobacteria, total rare phyla and unclassified phyla significantly increased. Null-model tests indicated that deterministic processes played a more important role than stochastic processes in determining BCC. However, the relative importance of stochasticity, primarily ecological drift, was enhanced and contributed to the increased beta diversity of BCC under enhanced warming and nutrient-enriched conditions. Overall, our study suggests that the synergetic effects of warming and nutrient enrichment may result in high variability in the composition of bacterioplankton communities in lacustrine water bodies. PMID- 27935595 TI - Identification of the fitness determinants of budding yeast on a natural substrate. AB - The budding yeasts are prime models in genomics and cell biology, but the ecological factors that determine their success in non-human-associated habitats is poorly understood. In North America Saccharomyces yeasts are present on the bark of deciduous trees, where they feed on bark and sap exudates. In the North East, Saccharomyces paradoxus is found on maples, which makes maple sap a natural substrate for this species. We measured growth rates of S. paradoxus natural isolates on maple sap and found variation along a geographical gradient not explained by the inherent variation observed under optimal laboratory conditions. We used a functional genomic screen to reveal the ecologically relevant genes and conditions required for optimal growth in this substrate. We found that the allantoin degradation pathway is required for optimal growth in maple sap, in particular genes necessary for allantoate utilization, which we demonstrate is the major nitrogen source available to yeast in this environment. Growth with allantoin or allantoate as the sole nitrogen source recapitulated the variation in growth rates in maple sap among strains. We also show that two lineages of S. paradoxus display different life-history traits on allantoin and allantoate media, highlighting the ecological relevance of this pathway. PMID- 27935594 TI - Plantmediated horizontal transmission of Wolbachia between whiteflies. AB - Maternal transmission is the main transmission pathway of facultative bacterial endosymbionts, but phylogenetically distant insect hosts harbor closely related endosymbionts, suggesting that horizontal transmission occurs in nature. Here we report the first case of plant-mediated horizontal transmission of Wolbachia between infected and uninfected Bemisia tabaci AsiaII7 whiteflies. After infected whiteflies fed on cotton leaves, Wolbachia was visualized, both in the phloem vessels and in some novel 'reservoir' spherules along the phloem by fluorescence in situ hybridization using Wolbachia-specific 16S rRNA probes and transmission electron microscopy. Wolbachia persisted in the plant leaves for at least 50 days. When the Wolbachia-free whiteflies fed on the infected plant leaves, the majority of them became infected with the symbiont and vertically transmitted it to their progeny. Multilocus sequence typing and sequencing of the wsp (Wolbachia surface protein) gene confirmed that the sequence type of Wolbachia in the donor whiteflies, cotton phloem and the recipient whiteflies are all identical (sequence type 388). These results were replicated using cowpea and cucumber plants, suggesting that horizontal transmission is also possible through other plant species. Our findings may help explain why Wolbachia bacteria are so abundant in arthropods, and suggest that in some species, Wolbachia may be maintained in populations by horizontal transmission. PMID- 27935596 TI - Environmental fluctuations and host skin bacteria shift survival advantage between frogs and their fungal pathogen. AB - Fluctuating environments can modulate host-pathogen interactions by providing a temporary advantage to one of the interacting organisms. However, we know very little about how environmental conditions facilitate beneficial interactions between hosts and their microbial communities, resulting in individual persistence with a particular pathogen. Here, we experimentally infected Eleutherodactylus coqui frogs with the fungal pathogen Batrachochytrium dendrobatidis (Bd) under environmental conditions known to confer the survival advantage to the host during the warm-wet season, or alternatively to the pathogen during the cool-dry season. We used 16S rRNA amplicon sequencing to quantify changes in bacterial richness and phylogenetic diversity, and identified operational taxonomic units (OTUs) that became overrepresented or suppressed as a consequence of Bd infection. During the warm-wet season, frogs limited Bd infections, recruited putatively beneficial bacteria and returned to pre infection levels of richness and phylogenetic diversity. In contrast, during the cool-dry season, Bd infections kept increasing through time, and bacterial diversity remained constant. Our findings confirm that infection outcome not only depends on abiotic factors, but also on biotic interactions between hosts and their associated bacterial communities. PMID- 27935598 TI - The gene polymorphisms of IL-8(-251T/A) and IP-10(-1596C/T) are associated with susceptibility and progression of type 2 diabetic retinopathy in northern Chinese population. AB - PurposeThe aim of the present study is to investigate the association of the polymorphism of two genes in CXC chemokine family, interleukin-8 (IL-8) and interferon-inducible protein 10 (IP-10), with both susceptibility and progression of DR in T2D population of northern China.Patients and methodsA total of 1043 eligible type 2 diabetic patients from Heilongjiang of northern China were recruited for this study. They were grouped into: with diabetic retinopathy (DR, 528 cases) and without diabetic retinopathy (DNR, 515 cases). Single nucleotide polymorphism (SNP) genotyping of IL-8(-251T/A) and IP-10(-1596C/T) was performed by polymerase chain reaction. Multivariate analysis and stepwise multiple logistic progression analysis were conducted to evaluate the association between gene SNP and DR susceptibility and progression. Pooled odds ratio (OR) with 95% confidence interval (CI) was applied to assess the strength of the association among study groups.ResultsThe occurring of IL-8(-251) AA genotype was correlated with susceptibility (OR: 2.286, 95% CI: 1.382-3.782, P=0.001) and progression of high-risk proliferative diabetic retinopathy (PDR) (OR: 0.354, 95% CI: 0.162 0.770, P=0.009). Reversely, T allele of IP-10 (-1596) C/T was correlated with a reduced risk of DR (OR: 0.341, 95% CI: 0.249-0.466, P<0.001). However, gene polymorphisms of IL-8-251T/A and IP-10-1596C/T were not associated with diabetic macular edema (DME)(P>0.05).ConclusionsAA genotype of IL-8-251T/A was closely correlated to DR and high-risk proliferative diabetic retinopathy (PDR). -1596T allele of the IP-10 is a beneficial genotype for DR. PMID- 27935599 TI - Magnetic resonance imaging of the functional anatomy of the superior oblique muscle in patients with primary superior oblique overaction. AB - PurposeTo quantitatively determine the size and contractility of the superior oblique (SO) muscle in primary SO overaction (PSOOA).Patients and methodsA prospective, observational study was conducted on 12 patients with PSOOA, and 10 healthy, orthotropic subjects. Sets of contiguous, 2 mm slice thickness, quasi coronal magnetic resonance imaging were obtained during different gazes, giving pixel resolution of 0.391 mm. Cross-sectional areas of the SO muscles were determined in primary position, supraduction, and infraduction to evaluate size and contractility. The cross-sectional areas of SO muscle were compared with those of controls in the primary position to detect hypertrophy or atrophy and changes in contractility could be detected during the vertical gaze. All statistical calculations were performed using PROC MIXED (SAS 9.4).ResultsThere was no difference between the ipsilesional (affected eye), contralesional (unaffected eye), and normal SO muscle cross-sections: 0.176+/-0.018 cm2, 0.175+/ 0.005 cm2, and 0.173+/-0.015 cm2, respectively (P=0.82). The maximum contractility of SO muscle on the ipsilesional (affected) side was 0.097+/-0.024 cm2, and was different than on the contralesional (unaffected) side: 0.067+/ 0.015 cm2 and in control subjects: 0.063+/-0.018 cm2 (P=0.0002).ConclusionsIn PSOOA, the ipsilesional SO is more contractile than the contralesional SO muscle and different than in controls, with no difference in SO muscle size in primary position, which suggests that excessive innervation rather than muscle hypertrophy underlies PSOOA. PMID- 27935600 TI - Pseudodacryocystitis: paediatric case series of infected atypical ethmoid air cells masquerading as recurrent dacryocystitis. AB - PurposeTo highlight the clinical and surgical considerations in treating patients with apparent recurrent acute dacryocystitis with a patent lacrimal system.MethodsThree children referred to a tertiary unit as recurrent acute dacryocystitis were reviewed retrospectively. Imaging and subsequent surgical intervention revealed the underlying diagnosis.ResultsAll three cases presented with recurrent abscesses in the region of the lacrimal sac that failed to respond to incision and drainage. The lesions were lower and more lateral to the usual location of a sac abscess and closer to the inferior orbital rim. All three cases were found to have patent lacrimal systems on syringing, and all were found to have infected, low-lying, anteriorly placed aberrant ethmoid air cells on computed tomography and magnetic resonance imaging. These were confirmed on subsequent surgical exploration.ConclusionsInfected low-lying ethmoid air cells can mimic dacryocystitis with recurrent abcesses. In cases where a patent nasolacrimal system is demonstrated and a more inferolateral location of the swelling than would be expected in dacryocystitis is seen, imaging is warranted to ensure the appropriate intervention is undertaken. Anterior ethmoidectomy as opposed to dacryocystorhinostomy is the appropriate treatment in these cases. PMID- 27935597 TI - The evidence informing the surgeon's selection of intraocular lens on the basis of light transmittance properties. AB - In recent years, manufacturers and distributors have promoted commercially available intraocular lenses (IOLs) with transmittance properties that filter visible short-wavelength (blue) light on the basis of a putative photoprotective effect. Systematic literature review. Out of 21 studies reporting on outcomes following implantation of blue-light-filtering IOLs (involving 8914 patients and 12 919 study eyes undergoing cataract surgery), the primary outcome was vision, sleep pattern, and photoprotection in 9 (42.9%), 9 (42.9%), and 3 (14.2%) respectively, and, of these, only 7 (33.3%) can be classed as high as level 2b (individual cohort study/low-quality randomized controlled trials), all other studies being classed as level 3b or lower. Of the level 2b studies, only one (14.3%) found in favor of blue-light-filtering IOLs vs ultraviolet (UV)-only filtering IOLs on the basis of an association between better post-operative contrast sensitivity (CS) at select frequencies with the former; however, that study did not measure or report CS preoperatively in either group, and the finding may simply reflect better preoperative CS in the eyes scheduled to be implanted with the blue-light-filtering IOL; moreover, that study failed to measure macular pigment, a natural preceptoral filter of blue-light, augmentation of which is now known to improve CS. In terms of photoprotection, there is no level 2b (or higher) evidence in support of blue filtering IOLs vs UV-only filtering IOLs. On the basis of currently available evidence, one cannot advocate for the use of blue-light-filtering IOLs over UV-only filtering IOLs. PMID- 27935601 TI - Incidence and risk factors for cystoid macular edema following scleral buckling. AB - PurposeTo investigate the incidence of cystoid macular edema (CME) after scleral buckling (SB) and verify the possible risk factors of CME.MethodsA retrospective, non-comparative, interventional case series study was conducted. Clinical charts of 130 consecutive patients who were underwent successful SB for primary retinal detachment (RD) from 2009 to 2013 were reviewed. Optical coherence tomography (OCT) was applied to detect CME. Data pertaining to patient demographics, pre- and postoperative visual acuity, surgical procedures, and postoperative OCT findings were recorded. Factors associated with CME were also analyzed.ResultsThe incidence of CME was 9/130 (6.9%). Risk factors for developing CME were older age (non-CME vs CME: 44.8+/-14.8 vs 57.3+/-5.3 years, P<0.05), more extensive RD (RD extent by clock hours; non-CME vs CME: 4.61+/-1.57 vs 5.78+/-1.39, P<0.05), macular detachment (non-CME vs CME: 51.2 vs 88.9%, P<0.05), and external drainage (non-CME vs CME: 38.8% vs 77.8%, P<0.05). There was no significant difference between patient with and without CME regarding the use of gas tamponade and the lens status. In patients with more extensive RD (macular detachment plus RD of more than 3 clock hours before surgery), 8 of 68 patients had CME after SB and only older age and external drainage factors were associated with CME.ConclusionsThe risk factors associated with CME after SB were older age, more extended RD, macular detachment, and external drainage. External drainage should be used with caution in older patients with more extensive RD. PMID- 27935602 TI - Effectiveness and safety of nutritional supplements in the treatment of hereditary retinal dystrophies: a systematic review. AB - The hereditary retinal dystrophies (HRDs) are a group of genetically determined disorders that result in loss of the visual function. There is a lack of standard pharmacological treatments or widely accepted nutritional recommendations. The objective of this review is to summarise the scientific evidence on the effectiveness and safety of nutritional supplements for the treatment of HRDs. We conducted a scientific literature search on Medline and PreMedline, EMBASE, SCI EXPANDED, SSCI, and The Cochrane Library up to August 2014. Experimental, quasi experimental and controlled observational studies were selected. Eight studies were ultimately included, seven on retinitis pigmentosa (RP) and one on Best disease. Vitamin A, vitamin E, docosahexaenoic acid (DHA), lutein and beta carotene were assessed. A 15 000 IU daily dose of vitamin A was reported to have shown a small protective effect on the progression of RP, as was the use of the carotenoids lutein and beta-carotene. Different DHA doses has no effect on RP or Best disease. No supplement showed severe adverse effects in the selected studies although strong evidence of toxicity exists for high doses of vitamin A and beta carotene in certain populations. The selected studies concluded that there may be a small beneficial effect of vitamin A, lutein and beta-carotene on the progression of RP. The limited evidence available indicates some well-designed additional studies on combined supplements strategies may achieve more robust conclusions. Moreover, the scarcity of evidence available on the treatment of HRD other than RP with nutritional supplements supports the need for further research efforts. PMID- 27935603 TI - Anterior segment imaging-based subdivision of subjects with primary angle-closure glaucoma. AB - PurposeThe purpose of this study was to identify whether it was possible to subdivide subjects with primary angle-closure glaucoma (PACG) based on anterior segment optical coherence tomography (ASOCT) imaging, and to determine the characteristics of such subgroups.MethodsWe evaluated 210 subjects with PACG. All subjects underwent gonioscopy and ASOCT imaging. Customized software was used to measure ASOCT parameters. An agglomerative hierarchical clustering method was first used to determine the optimum number of parameters to be included in the determination of subgroups. Then, the best number of subgroups was determined using Akaike Information Criterion (AIC) and Gaussian Mixture Model (GMM) methods.ResultsThe mean age of the subjects was 67.9 years, and 53.3% were female. Following the hierarchical clustering, four parameters (iris area, anterior chamber depth (ACD), anterior chamber width (ACW), and lens vault (LV)) were chosen to be representative of related parameters. The optimal number of subgroups using GMM analysis and AIC was 3. Subgroup 1 (N=89; 42.4%) was characterized by a large iris area, subgroup 2 (N=24; 11.4%) by a large LV and a shallow ACD, whereas subgroup 3 (N=97; 46.2%) displayed only intermediate values across iris area, LV, and ACD.ConclusionsWe identified three distinct subgroups of PACG subjects based on ASOCT imaging. PMID- 27935604 TI - Ocular characteristics associated with the location of focal lamina cribrosa defects in open-angle glaucoma patients. AB - PurposeTo investigate the clinical characteristics according to the location of focal lamina cribrosa (LC) defects and its associated ocular features.Patients and methodsA total of 139 open-angle glaucoma patients underwent Spectralis optical coherence tomography (OCT) with enhanced depth imaging. Alterations in the contour of the LC were investigated to find focal LC defects. The location of the visible LC defect from the neural canal wall (far-peripheral and mid peripheral) and clock-hour position (superotemporal, temporal and inferotemporal) were classified. Disc ovality ratio and disc-foveal angle were measured from disc and retinal nerve fiber layer (RNFL) photographs. The disc tilt degree was measured using a Heidelberg Retina Tomograph (HRT) III system. The en face OCT image of the disc scans was registered to the disc and RNFL photographs, to determine whether the focal LC defects corresponded spatially to the glaucomatous damage location.ResultsEyes with far-peripheral LC defects were significantly myopic and had a higher disc ovality ratio. The disc tilt degree obtained by HRT revealed significant temporal disc tilt in eyes with temporal LC defects (P<0.001). Eyes with inferotemporal LC defects had a significantly larger disc foveal angle (P=0.027). The inferotemporal LC defects corresponded to the location of glaucomatous damage in 81.6%; however, only 46.2% of eyes with a superotemporal LC defect and 3.2% of eyes with a temporal LC defect corresponded spatially with the glaucomatous damage location.ConclusionsThe clinical characteristics and association with glaucomatous damage location were different according to the location of focal LC defect. PMID- 27935605 TI - Evolution of the circuitry for conscious color vision in primates. AB - There are many ganglion cell types and subtypes in our retina that carry color information. These have appeared at different times over the history of the evolution of the vertebrate visual system. They project to several different places in the brain and serve a variety of purposes allowing wavelength information to contribute to diverse visual functions. These include circadian photoentrainment, regulation of sleep and mood, guidance of orienting movements, detection and segmentation of objects. Predecessors to some of the circuits serving these purposes presumably arose before mammals evolved and different functions are represented by distinct ganglion cell types. However, while other animals use color information to elicit motor movements and regulate activity rhythms, as do humans, using phylogenetically ancient circuitry, the ability to appreciate color appearance may have been refined in ancestors to primates, mediated by a special set of ganglion cells that serve only that purpose. Understanding the circuitry for color vision has implications for the possibility of treating color blindness using gene therapy by recapitulating evolution. In addition, understanding how color is encoded, including how chromatic and achromatic percepts are separated is a step toward developing a complete picture of the diversity of ganglion cell types and their functions. Such knowledge could be useful in developing therapeutic strategies for blinding eye disorders that rely on stimulating elements in the retina, where more than 50 different neuron types are organized into circuits that transform signals from photoreceptors into specialized detectors many of which are not directly involved in conscious vision. PMID- 27935606 TI - Structural and functional assessment of macula to diagnose glaucoma. AB - PurposeTo compare the diagnostic abilities of structural (ganglion cell-inner plexiform layer (GCIPL) thickness measured using spectral domain optical coherence tomography (SDOCT)) and functional (visual sensitivities measured using standard automated perimetry (SAP) and microperimetry (MP)) assessments of macula in glaucoma.MethodsIn a prospective study, 46 control eyes (28 subjects) and 61 glaucoma eyes (46 patients) underwent visual sensitivity estimation at macula (central 10 degrees ) by SAP and MP, and GCIPL thickness measurement at macula by SDOCT. Glaucoma was diagnosed by experts based on the optic disc and retinal nerve fiber layer changes. Area under the receiver-operating characteristic (AUC) curves and sensitivities at 95% specificity were used to assess the diagnostic ability of visual sensitivity and GCIPL measurements at various macular sectors.ResultsAUCs of GCIPL parameters ranged between 0.58 and 0.79. AUCs of SAP and MP sensitivities ranged between 0.59 and 0.71, and 0.59 and 0.72, respectively. There were no statistically significant differences between the AUCs of corresponding sector measurements (P>0.10 for all comparisons). Sensitivities at 95% specificities ranged from 31-59% for GCIPL parameters, 16 34% for SAP, and 8-38% for MP parameters. Sensitivities were significantly better with GCIPL compared with SAP and MP parameters in diagnosing glaucoma. Inferotemporal, inferior, and superotemporal sector measurements of GCIPL and visual sensitivity showed the best abilities to diagnose glaucoma.ConclusionsComparing the diagnostic abilities of structural and functional tests at macula in glaucoma, GCIPL thickness measurements with SDOCT performed better than the visual sensitivity measurements by SAP and MP. PMID- 27935607 TI - Microencapsulated cells of Lactobacillus paracasei subsp. paracasei in biopolymer complex coacervates and their function in a yogurt matrix. AB - L. paracasei subsp. paracasei E6 cells were encapsulated by complex coacervation using whey protein isolate (WPI) and gum arabic and introduced in stirred yogurts after fermentation. For comparison purposes, yogurts without addition of L. paracasei and yogurts with free cells of L. paracasei were produced. The survival of free and microencapsulated L. paracasei cells was evaluated during storage of the yogurts for 45 days at 4 degrees C. In addition, yogurts were exposed to simulated gastric juice and the reduction in viable numbers of L. paracasei cells was assessed. The effect of complex coacervates' addition on the rheological properties of yogurts was also evaluated. Yogurts containing encapsulated L. paracasei cells showed a slightly improved cell survival (<=0.22 log CFU g-1 reduction) during storage when compared to yogurts containing free cells (<=0.64 log CFU g-1 reduction). Moreover, the microencapsulated L. paracasei cells exhibited greater survival compared to free cells upon exposure of the yogurt samples to simulated gastric juice (pH 2.0) for 3 h. Finally, the incorporation of complex coacervates did not significantly affect the rheological properties of yogurts especially when added at concentrations less than 10% w/w. Consequently, the inclusion of microencapsulated bacteria by complex coacervation in yogurts, could become an effective vehicle for successful delivery of probiotics to the gut, and hence contributing to the improvement of the gastrointestinal tract health, without altering the texture of the product. PMID- 27935608 TI - A peptide-based synthetic transcription factor selectively down-regulates the proto-oncogene CFOS in tumour cells and inhibits proliferation. AB - Selectively regulating genes is an important goal in Chemical Biology. We report the development of a peptide-based synthetic transcription factor which binds the targeted DNA sequence with high affinity and single base-pair discrimination capability. When delivered inside a tumor cell, it regulated targeted genes selectively and inhibited cell proliferation. PMID- 27935609 TI - Interactions between circulating nanoengineered polymer particles and extracellular matrix components in vitro. AB - The extracellular matrix (ECM) that surrounds cells in vivo represents a biological barrier for nanomaterials in biomedicine. Herein, we present a system for investigating the interactions between circulating polymer particles and ECM components in vitro using a commercially available flow-based device. We use this system to show how material-dependent interactions of two different particle types-one assembled using poly(ethylene glycol) (PEG) and one prepared using poly(methacrylic acid) (PMA)-affect their interactions with basement membrane extracts during in vitro circulation, with PEG particles remaining in circulation longer than PMA particles. Further, by comparing macroporous hyaluronic acid gel constructs (typically used for tissue engineering) with basement membrane extracts, we show that scaffold-effects (porosity and surface chemistry) impact on circulation time in vitro. The presented system is simple and modular, and can be used to rapidly screen fundamental interactions of engineered particles with biologically relevant microenvironments under flow-conditions. PMID- 27935611 TI - Insight into the interactions between nanoparticles and cells. AB - Multifunctional nanoparticles (NPs) have been widely used in biomedical applications because of their versatile properties. The properties of NPs should be well designed and controlled according to various applications because they may directly affect the functions and performances of NPs in biological systems. Cellular uptake is a prerequisite for the success of NP-based biomedical applications. However, the internalized NPs inside cells may have some adverse effects. Therefore, the interactions between NPs and cells should be thoroughly investigated and elucidated. This review summarizes the latest advances in NP cell interactions. Especially the effects of NP properties including size, shape, shell structure, surface chemistry and protein corona formation on cellular uptake and cytotoxicity are highlighted in detail. Their effects on cell proliferation, differentiation and cellular mechanics are also discussed. These insights into NP-cell interactions should provide useful information for the preparation of highly functional NPs and their biomedical applications. PMID- 27935610 TI - Comparison of nanomedicine-based chemotherapy, photodynamic therapy and photothermal therapy using reduced graphene oxide for the model system. AB - Given the complexity of tumors, several nanomaterial-based treatment modalities like chemotherapy (CT), photodynamic therapy (PDT) and photothermal therapy (PTT) have been developed for combating cancers. However, it is still unclear which strategy is better or how to select optimal approaches for combination treatment since each strategy has been investigated under different conditions. Inspired by its good payload capacity and unique near-infrared absorption, reduced graphene oxide (rGO) was selected in this study as the carrier for loading of doxorubicin (DOX), a chemotherapy drug, and chlorin e6 (Ce6), a photosensitizer. The therapeutic efficacies of PTT, CT and PDT were systematically investigated in vitro using 2D culture and multicellular tumor spheroid (3D) models. Interestingly, while all three types of therapies delivered by rGO appeared to be effective in the conventional 2D cell culture model, only PTT but not CT and PDT showed great treatment efficacy in the 3D tumor spheroid model at the tested concentrations. Such a difference is due to the fact that heat diffusion is much more efficient than the diffusion of therapeutic molecules inside the tumor. Furthermore, in vivo evidence also confirmed the unique advantage of PTT compared to the other two treatment modalities using the TdT-mediated dUTP nick end labeling (TUNEL) staining assay. This study highlights the unique advantages of nanomedicine-based photothermal therapy among these three modalities in cancer treatment in terms of killing tumor cells located far from tumor blood vessels. PMID- 27935612 TI - Fabricating polyacrylamide microbeads by inverse emulsification to mimic the size and elasticity of living cells. AB - Inverse emulsification was used to fabricate polyacrylamide (PAAm) microbeads with size and elastic properties similar to typical, mammalian cells. These biomimicking microbeads could be fluorescently stained and functionalized with a collagen type-I coating, post-polymerization, for tracking bead locations and promoting cell recognition/binding, respectively. By occupying a previously unfilled range of sizes and mechanical properties, these microbeads may find unique use in both biomedical and materials applications. PMID- 27935613 TI - Site-selective installation of BASHY fluorescent dyes to Annexin V for targeted detection of apoptotic cells. AB - Fluorophores are indispensable for imaging biological processes. We report the design and synthesis of azide-tagged boronic acid salicylidenehydrazone (BASHY) dyes and their use for site-selective labelling of Annexin V. The Annexin V-BASHY conjugate maintained function and fluorescence as demonstrated by the targeted detection of apoptotic cells. PMID- 27935614 TI - Hybrid porous bamboo-like CNTs embedding ultrasmall LiCrTiO4 nanoparticles as high rate and long life anode materials for lithium ion batteries. AB - Compared with Li4Ti5O12, LiCrTiO4 with the same spinel structure exhibits superior conductivity and Li+ diffusion properties. However, there has been no extensive study on LiCrTiO4 as an anode material in lithium ion batteries, due to its pulverization, loss of electrical contact, and particle aggregation. A unique architecture based on hybrid porous CNTs embedding ultrasmall LiCrTiO4 nanoparticles (6 +/- 2 nm) was designed by using a facile sol-gel process combined with subsequent heat treatment. As an anode for lithium ion batteries, due to the absence of the aforementioned problems, the electrode exhibited high reversible capacity, excellent rate capability and superior long-term cycling stability at high current densities. Such nanocomposites should be competitive candidates to replace Li4Ti5O12-based anode materials. PMID- 27935615 TI - Aminoglycoside-based novel probes for bacterial diagnostic and therapeutic applications. AB - Specific detection of pathogens has long been recognized as a vital strategy in the control of infectious diseases. Two novel theranostic neomycin analogs exhibit efficient targeting, labelling and killing of broad spectrum bacteria while not damaging macrophage-like cells. Furthermore, lipidated probe 2 clearly showed antibacterial activity against methicillin-resistant S. aureus. PMID- 27935616 TI - One pot conversion of benzophenone imine into the relevant 2-aza-allenium. AB - Interaction of common imines with WCl6 in organic solvents revealed very unusual features in the context of imine chemistry. Ph2C[double bond, length as m-dash]NH was converted in one pot into the 2-aza-allenium species [Ph2C[double bond, length as m-dash]N[double bond, length as m-dash]CPh2]+via N2 release, with [Ph2C[double bond, length as m-dash]NH2]+ being a co-product. PhCH[double bond, length as m-dash]NtBu underwent C-H bond activation resulting in the formation of [C[triple bond, length as m-dash]N] containing derivatives, together with [PhCH[double bond, length as m-dash]NHtBu]+. PMID- 27935617 TI - Fenton's reagent for the rapid and efficient isolation of microplastics from wastewater. AB - Fenton's reagent was used to isolate microplastics from organic-rich wastewater. The catalytic reaction did not affect microplastic chemistry or size, enabling its use as a pre-treatment method for focal plane array-based micro-FT-IR imaging. Compared with previously described microplastic treatment methods, Fenton's reagent offers a considerable reduction in sample preparation times. PMID- 27935619 TI - A practical synthesis of benzothiophenes via visible-light-promoted cyclization of disulfides and alkynes. AB - Visible-light-promoted intermolecular radical cyclization of disulfides and alkynes has been developed. Benzothiophenes bearing ester, ketone, aldehyde and aryl substituents were synthesized in good yields. The reaction was carried out in the absence of transition-metal catalysts and extra additives. Oxygen was used as the sole oxidant. In addition, the irradiation of sunlight could also promote the reaction efficiently. PMID- 27935618 TI - Enhanced fluorescence of aqueous BODIPY by interaction with cavitand cucurbit[7]uril. AB - One cationic BODIPY chromophore was synthesized and its complexation behaviour with the macrocyclic host cucurbit[7]uril (CB[7]) was studied using different spectroscopy techniques such as UV-vis absorption, steady-state and time-resolved fluorescence, 1H NMR as well as DFT based quantum calculations. The dye showed formation of a 1 : 1 dye-CB[7] complex with improvement in the fluorescence intensity. These new results of the formation of moderate association of aqueous BODIPYs with the nontoxic host CB[7] may lead to promising applications of the dye molecule as a sensitive and efficient off-on mode fluorescent probe in chemical and biological studies. PMID- 27935620 TI - Drug governs the morphology of polyalkylated block copolymer aggregates. AB - Polyalkylated copolymers based on mPEG-b-(AGE-C6,12 or 18)25 have been used to formulate clinically relevant concentrations of doxorubicin (DOX) and the impact of drug incorporation on copolymer aggregation behaviour was examined. The copolymer aggregates were analyzed by various microscopy techniques (TEM, cryo TEM and AFM) and scattering methods (SANS, DLS). In the absence of the drug, the copolymers formed largely non-spherical aggregates (i.e. cylinders, vesicles). Drug incorporation during copolymer aggregate formation directed the formation of only spherical aggregates. As well, the nature of the core-forming block was found to influence drug release and cytotoxicity of the formulations. PMID- 27935621 TI - Letter in reference to: "Short-term effects of night shift work on breast cancer risk: a cohort study of payroll data". AB - There are major flaws with the analyses in the Vistisen et al (1) cohort study examining if night shift work is a short-term risk factor for breast cancer. The crucial problem is the potential for exposure misclassification, which is very high. The authors' definition of day shift is ">=3 hours of work between 06:00 20:00 hours". This means that a worker on an 8-hour shift that begins at 03:00 hours would be classified as a day rather than night shift worker because he/she worked only two hours between 24:00-05:00 hours. Similarly, a second shifter might start work at 17:00 but not get off until 01:00 and yet still be classified as a "day shift" worker. This does not make sense as a baseline comparison group "unexposed" to work during the night hours. A sensible classification system would be to define "day shift" as any shift that begins after 07:00 and ends before 18:00 hours. This is straightforward and avoids all of the ambiguities inherent in the definition used by the authors. In addition, the authors claim that the "inception population" is less likely to have had past prior non-day work hours. However, this group has an average age of >35 years. It is inconceivable that all of these women were new graduates who started a public health sector job for the first time. Rather, the majority must surely have worked elsewhere for many years but then started in the regions covered only after 2006. This topic is too important, and this cohort too valuable, not to carefully define the baseline comparison group of "day workers" in a sensible manner. All the inferences rely crucially on this definition. The authors have the data to define the day-working baseline group in a way that avoids these obvious biases. That is why it is so frustrating that the authors chose to conduct the analyses as they did, with a highly flawed definition of "day work", when they could have done so much better. A highly flawed epidemiological report is worse than no report at all because it misleads the scientific community and the public. Reference 1. Vistisen HT, Garde AH, Frydenberg M, Christiansen P, Hansen AM, Hansen J, Bonde JPE, Kolstad HA. Short-term effects of night shift work on breast cancer risk: a cohort study of payroll data. Scand J Work Environ Health - online first. http://dx.doi.org/10.5271/sjweh.3603. PMID- 27935622 TI - Response to Dr Stevens' letter ref. Visitisen et al: "Short-term effects of night shift work on breast cancer risk: a cohort study of payroll data". AB - We thank Dr Richard Stevens for his comments (1) on our recent article that showed no increased risk of breast cancer following recent night shift work when compared with recent day shift work (2). This finding was based on linkage of day by-day information on working hours and breast cancer incidence data. Results are thus less likely to have been biased by differential misclassification than findings from earlier studies relying on self-report (3). We defined a night shift as >=3 hours of work between 24:00-05:00 hours and a day shift as >=3 hours work between 6:00-20:00 hours. This day shift definition did not exclude shifts starting before 05:00 or ending after 24:00 hours. However, this affected only 0.02% and 0.3% of all day shifts, respectively. This diminutive misclassification, that is expected to be non-differential, can hardly explain our negative findings. It is suggested that shifts that begin after 07:00 and end before 18:00 would constitute a more sensible baseline comparison group. Since the biological mechanism is not certain, it is not obvious to us if this will be a more appropriate reference than the present. However, we agree that future studies should test how different definitions of shifts affect the risk of breast cancer, which will be possible using this type of data. We only had information on working hours from 2007 and onwards, and night shift work prior to 2007 could have confounded our analyses towards no effect but only if inversely associated with night shift work in 2007 or later. We find this unlikely. Left truncation could also have biased findings towards the null. We therefore supplemented analyses of the total study population with analyses of the one-third of the population with first recorded employment in 2008 or later (the inception population). Even if the mean age was 35.5 years - and many undoubtedly had been working (with and without night shifts) prior to 2008 - this population should be less affected by such selection bias, but we observed similar risk estimates as for the total study population. Taken together, we find that our study provides rather robust evidence of no short-term breast cancer risk following recent night shift work. It must, however, be stressed that data did not allow assessment of a possible long-term risk. Reference 1. Stevens R. Letter ref. Vitisen et al: "Short-term effects of night shift work on breast cancer risk: a cohort study of payroll data". Scand J Work Environ Health. 2017;43(1):95. http://dx.doi.org/10.5271/sjweh.3607 2. Vistisen HT, Garde AH, Frydenberg M, Christiansen P, Hansen AM, Hansen J, Bonde JP, Kolstad HA. Short-term effects of night shift work on breast cancer risk: A cohort study of payroll data. Scand J Work Environ Health. 2017;43(1):59-67. http://dx.doi.org/10.5271/sjweh.3603. 3. Ijaz S, Verbeek J, Seidler A, Lindbohm ML, Ojajarvi A, Orsini N, Costa G, Neuvonen K. Night-shift work and breast cancer--a systematic review and meta analysis. Scand J Work Environ Health. 2013 Sep 1;39(5):431-47. http://dx.doi.org/10.5271/sjweh.3371. PMID- 27935623 TI - Reducing blood volume requirements for clinical pathology testing in toxicologic studies-points to consider. AB - In preclinical safety assessment, blood volume requirements for various endpoints pose a major challenge. The goal of this working group was to review current practices for clinical pathology (CP) testing in preclinical toxicologic studies, and to discuss advantages and disadvantages of methods for reducing blood volume requirements. An industry-wide survey was conducted to gather information on CP instrumentation and blood collection practices for hematology, clinical biochemistry, and coagulation evaluation in laboratory animals involved in preclinical studies. Based on the survey results and collective experience of the authors, the working group proposes the following "points to consider" for CP testing: (1) For most commercial analyzers, 0.5 mL and 0.8 mL of whole blood are sufficient for hematology and biochemistry evaluation, respectively. (2) Small analyzers with low volume requirements and low throughput have limited utility in preclinical studies. (3) Sample pooling or dilution is inappropriate for many CP methods. (4) Appropriate collection sites should be determined based on blood volume requirements and technical expertise. (5) Microsampling does not provide sufficient volume given current analyzer and quality assurance requirements. (6) Study design considerations include: the use of older/larger animals (rodents), collection of CP samples before toxicokinetic samples, use of separate subsets of mice for hematology and clinical biochemistry testing, use of a priority list for clinical biochemistry, and when possible, eliminating coagulation testing. PMID- 27935624 TI - Multiple papules in a Chinese man. PMID- 27935625 TI - Comparison of established and novel methods for the detection and enumeration of microparticles in canine stored erythrocyte concentrates for transfusion. AB - BACKGROUND: Microparticles (MP) are submicron, phosphatidylserine (PS)-bearing lipid vesicles with physiologic and pathologic roles in coagulation and inflammation. Microparticles accumulate in packed RBC (pRBC) stored for transfusion, potentially increasing recipient morbidity. Historically, canine MP have been detected with the PS label annexin V in supernatant samples. Other detection methods are available but have not been evaluated in dogs. OBJECTIVES: The purpose of the study was to detect and enumerate MP in canine pRBC using annexin V, lactadherin, and bio-maleimide to compare label performance and assess microparticle accumulation under standard storage conditions. METHODS: Microparticles (0.5-1.0 MUm) in canine dog erythrocyte antigen 1.1 positive, nonleukoreduced pRBC were labeled with FITC-annexin V, FITC-lactadherin, and the fluorescent dye bio-maleimide, and were counted using flow cytometry at 3 time points (days 7, 21, and 35) of storage. Unprocessed pRBC, rather than supernatant, were used. RESULTS: Annexin V and bio-maleimide labeling produced comparable microparticle counts (P = .16), while lactadherin labeling resulted in higher microparticle counts than annexin V (P = .002) and bio-maleimide (P = .006), particularly on day 7. Bio-maleimide- and annexin V-based microparticle counts increased significantly from day 7 to 35 (P = .04), and increases from day 21 to 35 approached statistical significance (P = .05). CONCLUSIONS: Bio maleimide- and annexin V-mediated microparticle counts were comparable in unprocessed canine pRBC using flow cytometry. Whether the increased microparticle counts with lactadherin were due to increased sensitivity for small, PS-bearing MP or due to labeling of membrane fragments and debris requires further investigation. PMID- 27935626 TI - Assessment of radial torsion using computed tomography in dogs with and without antebrachial limb deformity. AB - OBJECTIVE: To evaluate the reliability of radial torsion assessment in dogs using computed tomography (CT). STUDY DESIGN: Cadaveric and retrospective observational clinical study. ANIMALS: Thoracic limbs (n = 40) from bilateral normal cadaveric canine specimens (10 pairs) and unilateral antebrachial angular limb deformity (ALD) dogs (10 uniapical and 10 biapical deformities). METHODS: Limbs were evaluated using CT. Frontal, sagittal, and axial plane (torsion) values were obtained using published guidelines and compared between groups and limbs. Radial torsion reliability was assessed among 3 observers using intraclass correlation coefficients (ICC). RESULTS: The mean (+/-SD) radial torsion of normal dogs was 3.6 degrees +/- 6.4 degrees and contained a significant right to left limb variation of 2.6 degrees . Mean radial torsion in uniapical ALD limbs (3.6 degrees +/- 18.7 degrees ) was not significantly different from biapical ALD limbs (8.9 degrees +/- 17.9 degrees ). There was a wide range of torsion values in normal and ALD limbs. The interobserver reliability was excellent (ICC > 0.8) for normal dogs, good (0.73) for uniapical, and excellent (0.89) for biapical ALD limbs. The intraobserver reliability was excellent (>0.8) for all groups. CONCLUSION: There was a small side-to-side variation of radial torsion in normal dogs. With directed training, torsion assessment using CT is reliable in dogs with and without antebrachial bone deformity. PMID- 27935627 TI - Clinical evaluation of Statstrip(r) Lactate for use in fetal scalp blood sampling. AB - INTRODUCTION: Point-of-care testing of fetal scalp blood lactate is used as an alternative to pH analysis in fetal scalp blood sampling (FBS) during labor. Lactate measurements are not standardized and values vary with each device used. The aim of this study was to evaluate StatStrip(r) Lactate (SSL) in the clinical setting in comparison with lactate (RLL) and pH (RLpH) using RapidLab(r) . MATERIAL AND METHODS: We obtained 323 FBS samples from 139 women. Parallel sampling of SSL and RLL/RLpH was performed in 247 samples. Outcome measures were the agreement and discrepancy rates between SSL, RLL and RLpH and the failure rate of all three methods. We constructed a Bland-Altman graph to assess the variability between the measurements across the range of values. The discrepancy rates between methods were compared using previously established cut-off values for SSL indicating reassurance (<5.7 mmol/L) and immediate delivery (>7.0 mmol/L) with those for RLpH (<7.20 and >7.25). RESULTS: SSL showed excellent agreement with RLL (R2 = 0.742) and poor agreement with RLpH (R2 = 0.204). Failure rates for SSL, RLL and RLpH were 7, 43 and 23%, respectively. Using the cut-off values for reassurance and immediate delivery, the discrepancy rates between SSL and RLpH were 14 and 5%, respectively. CONCLUSIONS: SSL is a reliable test to measure lactate in FBS with a low failure rate. As there are discrepancies between SSL and RLpH, and the cut-off values have not yet been evaluated prospectively regarding intervention rates and neonatal outcome, we recommend using SSL in addition to pH in FBS. PMID- 27935628 TI - An unusual cause for a psoriasiform dermatosis. PMID- 27935629 TI - Careful not to throw the baby out with the bath water! PMID- 27935630 TI - Appreciable uncertainty regarding benefits and risks in the treatment of bacterial vaginosis to prevent preterm birth. PMID- 27935631 TI - Painful cutaneous nodules. PMID- 27935632 TI - Ultrastructural abnormalities and loss of myelinated fibers in the corpus callosum of demyelinated mice induced by cuprizone. AB - It is now accepted that white matter abnormalities play an important role in demyelinating diseases and a wide range of psychiatric disorders. Experimental demyelination (especially induced by cuprizone) has been investigated extensively. However, details regarding demyelination and ultrastructural changes of myelinated fibers have not been previously reported. Therefore, we determined the extent of demyelination using quantitative stereology. Mice exposed to cuprizone in the current study showed abnormal anxiety-like behavior without impaired spatial learning or memory. The myelinated fibers in whole corpus callosum of mice exposed to cuprizone showed extensive myelin deficiencies and occasional axonal injuries. The total length of the myelinated fibers in whole corpus callosum of mice exposed to cuprizone was significantly decreased by 45% compared with control mice. The loss of myelinated fibers was mainly due to the marked loss of the fibers with a diameter of 0.4 to 0.8 MUm. The g-ratio of the myelinated fibers in the corpus callosum of mice exposed to cuprizone (0.69 +/- 0.02) was significantly decreased compared with control mice (0.76 +/- 0.02). These results might help us to further understand the role of white matter abnormalities in demyelinating diseases or a wide range of psychiatric disorders. (c) 2016 Wiley Periodicals, Inc. PMID- 27935633 TI - Nodular presentation of Dirofilaria repens infection in a cat mimicking a fibrosarcoma. AB - A cat with multiple subcutaneous nodules suggesting a soft tissue sarcoma by physical and computed tomographic examination was diagnosed as being affected by subcutaneous filariosis based on cytologic and ultrasonographic assessments. Nodules were surgically removed and extracted nematodes were identified by PCR as Dirofilaria repens. Furthermore, DNA of Dipetalonema dracunculoides (syn. Acantocheilonema dracunculoides) was detected by PCR, with no evidence of circulating microfilariae. To the best of the authors' knowledge, this represents the first report describing adults of D repens in multiple subcutaneous nodules in a cat. Cytopathologic examination allowed characterization of the parasitic nature of the nodules. Veterinary practitioners should be aware of the possible nodular presentation of D repens in cats and should include D repens in the differential diagnosis of subcutaneous neoformations in the cat. PMID- 27935634 TI - Delusional infestation may be caused by recreational drug usage in some patients, but they may not disclose their habit. AB - BACKGROUND: Patients with delusional infestation (DI) believe that their skin is infested with organisms or inanimate particles, despite objective evidence to the contrary. Previous studies indicate a higher rate of recreational drug use among patients with DI. It is known that symptoms of infestation such as formication can be secondary to use of recreational drugs and alcohol. We carried out a pilot study observing the prevalence of recreational drug use in patients with DI. AIM: To observe the prevalence of recreational drug use in patients with DI. METHODS: A retrospective review of 86 consecutive patient records was carried out over a 3 year period (1 March 2012 to 1 March 2015) to determine current or previous recreational drug use. Additionally, 24 consecutive patients with DI attending clinic between 1 December 2014 and 1 March 2015 were prospectively offered a urine test for recreational drugs. RESULTS: Of the 86 patients, 19 had recreational drug use documented in their medical notes (22.1%). Of the 24 patients offered a urine test, 18 accepted (75%); the remaining 6 patients agreed to provide a urine sample immediately after consultation, but did not do so. Of the 18 samples collected, 6 were positive (33.3% of completed tests) for recreational drugs. Cannabis was the most commonly used drug. CONCLUSIONS: This study indicates that the prevalence of recreational drug use in patients with DI is high, and that patients do not always disclose their habit. It is hoped that this pilot study will lead to further research into this finding. PMID- 27935636 TI - Nonhealing surgical wound due to cutaneous malakoplakia. PMID- 27935635 TI - Oleanolic acid rejuvenates testicular function through attenuating germ cell DNA damage and apoptosis via deactivation of NF-kappaB, p53 and p38 signalling pathways. AB - OBJECTIVES: Inflammation can cause degenerative changes of reproductive function. Oleanolic acid (OA), the effective component from Ligustrum lucidum Ait., exhibits significantly anti-inflammation and antiageing activity. However, whether OA restores testicular dysfunction via inhibition of inflammation with ageing is unclear. Here, in a natural ageing rat model, we investigated the protection effects of OA and its mechanism of action. METHODS: Eighteen-month-old Sprague Dawley (SD) rats were randomly divided into ageing control group and two OA-treated groups (5 and 25 mg/kg). Nine-month-old SD rats were used as adult controls. All rats were received either vehicle or OA for 6 months. Then, histomorphology, weight and index of testis, protein expression and immunohistochemistry were examined. KEY FINDINGS: Oleanolic acid significantly restored testicular morphology and improved testicular weight and index. Moreover, OA significantly inhibited phospho-NF-kappaB p65 and its downstream proinflammatory cytokines' expressions, including IL-1beta, COX-2 and TNF-alpha in testis tissues. Similarly, OA remarkably inhibited IL-1beta and TNF-alpha production. OA significantly attenuated germ cells' DNA damage and apoptosis. Such changes were accompanied by downregulation of gammaH2AX, p-P53 and Bax expressions, and upregulation of Bcl-2 and Bcl-2/Bax ratio. In addition, OA remarkably inhibited p38 signalling. CONCLUSIONS: Oleanolic acid effectively rejuvenates testicular function via attenuating germ cell DNA damage and apoptosis through deactivation of NF-kappaB, p53 and p38 signalling pathways. PMID- 27935638 TI - When can we infer mechanism from parasite aggregation? A constraint-based approach to disease ecology. AB - Few hosts have many parasites while many hosts have few parasites. This axiom of macroparasite aggregation is so pervasive it is considered a general law in disease ecology, with important implications for the dynamics of host-parasite systems. Because of these dynamical implications, a significant amount of work has explored both the various mechanisms leading to parasite aggregation patterns and how to infer mechanism from these patterns. However, as many disease mechanisms can produce similar aggregation patterns, it is not clear whether aggregation itself provides any additional information about mechanism. Here we apply a "constraint-based" approach developed in macroecology that allows us to explore whether parasite aggregation contains any additional information beyond what is provided by mean parasite load. We tested two constraint-based null models, both of which were constrained on the total number of parasites P and hosts H found in a sample, using data from 842 observed amphibian host-trematode parasite distributions. We found that constraint-based models captured ~85% of the observed variation in host-parasite distributions, suggesting that the constraints P and H contain much of the information about the shape of the host parasite distribution. However, we also found that extending the constraint-based null models can identify the potential role of known aggregating mechanisms (such as host heterogeneity) and disaggregating mechanisms (such as parasite-induced host mortality) in constraining host-parasite distributions. Thus, by providing robust null models, constraint-based approaches can help guide investigations aimed at detecting biological processes that directly affect parasite aggregation above and beyond those that indirectly affect aggregation through P and H. PMID- 27935637 TI - Functional and phenotypic heterogeneity of group 3 innate lymphoid cells. AB - Group 3 innate lymphoid cells (ILC3), defined by expression of the transcription factor retinoid-related orphan receptor gammat, play key roles in the regulation of inflammation and immunity in the gastrointestinal tract and associated lymphoid tissues. ILC3 consist largely of two major subsets, NCR+ ILC3 and LTi like ILC3, but also demonstrate significant plasticity and heterogeneity. Recent advances have begun to dissect the relationship between ILC3 subsets and to define distinct functional states within the intestinal tissue microenvironment. In this review we discuss the ever-expanding roles of ILC3 in the context of intestinal homeostasis, infection and inflammation - with a focus on comparing and contrasting the relative contributions of ILC3 subsets. PMID- 27935639 TI - Peroxisome proliferator-activated receptor-beta/delta modulates mast cell phenotype. AB - The peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) is known to have multiple anti-inflammatory effects, typically observed in endothelial cells, macrophages, T cells and B cells. Despite the fact that mast cells are important mediators of inflammation, to date, the role of PPARbeta/delta in mast cells has not been examined. Hence, the present study examined the hypothesis that PPARbeta/delta modulates mast cell phenotype. Bone marrow-derived mast cells (BMMCs) and peritoneal mast cells from Pparbeta/delta+/+ mice expressed higher levels of high-affinity IgE receptor (FcepsilonRI) compared with Pparbeta/delta-/- mice. BMMCs from Pparbeta/delta+/+ mice also exhibited dense granules, associated with higher expression of enzymes and proteases compared with Pparbeta/delta-/- mice. Resting BMMCs from Pparbeta/delta+/+ mice secreted lower levels of inflammatory cytokines, associated with the altered activation of phospholipase Cgamma1 and extracellular signal-regulated kinases compared with Pparbeta/delta-/- mice. Moreover, the production of cytokines by mast cells induced by various stimuli was highly dependent on PPARbeta/delta expression. This study demonstrates that PPARbeta/delta is an important regulator of mast cell phenotype. PMID- 27935640 TI - The basis function approach for modeling autocorrelation in ecological data. AB - Analyzing ecological data often requires modeling the autocorrelation created by spatial and temporal processes. Many seemingly disparate statistical methods used to account for autocorrelation can be expressed as regression models that include basis functions. Basis functions also enable ecologists to modify a wide range of existing ecological models in order to account for autocorrelation, which can improve inference and predictive accuracy. Furthermore, understanding the properties of basis functions is essential for evaluating the fit of spatial or time-series models, detecting a hidden form of collinearity, and analyzing large data sets. We present important concepts and properties related to basis functions and illustrate several tools and techniques ecologists can use when modeling autocorrelation in ecological data. PMID- 27935641 TI - Pinus contorta invasions increase wildfire fuel loads and may create a positive feedback with fire. AB - Invasive plant species that have the potential to alter fire regimes have significant impacts on native ecosystems. Concern that pine invasions in the Southern Hemisphere will increase fire activity and severity and subsequently promote further pine invasion prompted us to examine the potential for feedbacks between Pinus contorta invasions and fire in Patagonia and New Zealand. We determined how fuel loads and fire effects were altered by P. contorta invasion. We also examined post-fire plant communities across invasion gradients at a subset of sites to assess how invasion alters the post-fire vegetation trajectory. We found that fuel loads and soil heating during simulated fire increase with increasing P. contorta invasion age or density at all sites. However, P. contorta density did not always increase post-fire. In the largest fire, P. contorta density only increased significantly post-fire where the pre fire P. contorta density was above an invasion threshold. Below this threshold, P. contorta did not dominate after fire and plant communities responded to fire in a similar manner as uninvaded communities. The positive feedback observed at high densities is caused by the accumulation of fuel that in turn results in greater soil heating during fires and high P. contorta density post-fire. Therefore, a positive feedback may form between P. contorta invasions and fire, but only above an invasion density threshold. These results suggest that management of pine invasions before they reach the invasion density threshold is important for reducing fire risk and preventing a transition to an alternate ecosystem state dominated by pines and novel understory plant communities. PMID- 27935642 TI - Long-term health-related quality of life in living liver donors: A south Asian experience. AB - AIM: The aim of this study was to evaluate long-term health-related quality of life (HRQOL), changes in lifestyle, and complications in living liver donors at a single transplant center from southern India. METHODS: A total of 64 consecutive living liver donors from 2008 to 2011 were evaluated; 46 of 64 donors completed the short form 36 (SF-36) via telephonic interviews or clinic consultations. Mean follow-up was 48 months (range: 37-84 months). RESULTS: There was no mortality in the donors evaluated. Overall morbidity was 23%, which included wound infections (4.3%), incisional hernia (2.1%), biliary leak (4.3%), and nonspecific complaints regarding the incision site (15.2%). All 46 donors who completed the SF-36 had no change in career path or predonation lifestyle. A total of 40 of 46 (87%) donors had no limitations, decrements, or disability in any domain, while six of 46 (13%) had these in some domains of which general health (GH) was most severely affected. CONCLUSIONS: Living donor hepatectomy is safe with acceptable morbidity and excellent long-term HRQOL with no change in career path or significant alteration of lifestyle for donors. PMID- 27935643 TI - Plant-herbivore synchrony and selection on plant flowering phenology. AB - Temporal variation in natural selection has profound effects on the evolutionary trajectories of populations. One potential source of variation in selection is that differences in thermal reaction norms and temperature influence the relative phenology of interacting species. We manipulated the phenology of the butterfly herbivore Anthocharis cardamines relative to genetically identical populations of its host plant, Cardamine pratensis, and examined the effects on butterfly preferences and selection acting on the host plant. We found that butterflies preferred plants at an intermediate flowering stage, regardless of the timing of butterfly flight relative to flowering onset of the population. Consequently, the probability that plant genotypes differing in timing of flowering should experience a butterfly attack depended strongly on relative phenology. These results suggest that differences in spring temperature influence the direction of herbivore-mediated selection on flowering phenology, and that climatic conditions can influence natural selection also when phenotypic preferences remain constant. PMID- 27935644 TI - To reverse or not to reverse? A systematic review of autograft polarity on functional outcomes following peripheral nerve repair surgery. AB - BACKGROUND: The literature describing the best clinical practice for proximal distal autograft orientation, otherwise known as nerve graft polarity, is inconsistent. With existing disparities in the peripheral nerve literature, the clinical question remains whether reversing nerve autograft polarity bears an advantage for nerve regeneration. METHODS: A comprehensive review of the literature using Embase and PubMed databases (1940-June 2015) was performed to retrieve all original articles on the effects of nerve autograft polarity on nerve regeneration and functional recovery following primary repair of peripheral nerve defects. RESULTS: The initial database search yielded 318 titles. Duplicate exclusion, title review and full text review yielded six articles which directly compared nerve autograft polarity. Histological, morphometric, electrophysiological, and behavioral outcomes were reviewed. All retained articles were animal studies, of which none demonstrated significant differences in outcomes between the normal and reversed polarity groups. A reversed graft may ensure that regenerating nerve fibers are not lost at branching points, however this may not translate into improved function. CONCLUSION: There is insufficient data to suggest that nerve autograft polarity has an impact on nerve regeneration and functional outcomes. PMID- 27935645 TI - Small-for-size syndrome in live donor liver transplantation-Pathways of injury and therapeutic strategies. AB - Due to the severe organ shortage and the increasing gap between the supply and demand for donor grafts, live donor liver transplantation (LDLT) has become an accepted and alternative technique for the expansion of the donor pool. However, donor safety and good recipient outcomes must be balanced regarding risk stratification and decision-making within this patient population. Small-for-size syndrome (SFSS) is one of the complications encountered after LDLT, thus increasing the burden of optimizing donor graft selection and effective treatments during its occurrence. A graft-to-recipient weight ratio (GRWR) <0.8 predisposes the graft to SFSS. However, other factors may induce this complication even without a graft-to-patient size mismatch. Several strategies to prevent this complication include portal vein flow and liver outflow modulation, as well as pharmacological treatment. Also, as an entity with a multifactorial etiology, outcomes vary between right-lobe, left-lobe, and posterior-lobe donation among series encountered in the literature. In this review, we analyze the pathophysiology and classification of this complication, the state-of-the-art on management of SFSS, and the outcomes regarding the best treatment strategy on this patient population. PMID- 27935646 TI - Postactivation potentiation can counteract declines in force and power that occur after stretching. AB - Stretching can decrease a muscle's maximal force, whereas short but intense muscle contractions can increase it. We hypothesized that when combined, postactivation potentiation induced by reactive jumps would counteract stretch induced decrements in drop jump (DJ) performance. Moreover, we measured changes in muscle twitch forces and ankle joint stiffness (KAnkle ) to examine underlying mechanisms. Twenty subjects completed three DJs and 10 electrically evoked muscle twitches of the triceps surae subsequent to four different conditioning activities and control. The conditioning activities were 10 hops, 20s of static stretching of the triceps surae muscle, 20s of stretching followed by 10 hops, and vice versa. After 10 hops, twitch peak torque (TPT) was 20% and jump height 5% higher compared with control with no differences in KAnkle . After stretching, TPT and jump height were both 9% and KAnkle 6% lower. When hops and stretching were combined as conditioning activities, jump height was not different compared with control but significantly higher (11% and 8%) compared with stretching. TPTs were 16% higher compared with control when the hops were performed after stretching and 9% higher compared with the reverse order. KAnkle was significantly lower when stretching was performed after the hops (6%) compared with control, but no significant difference was observed when hops were performed after stretching. These results demonstrate that conditioning hops can counteract stretch-related declines in DJ performance. Furthermore, the differences in TPTs and KAnkle between combined conditioning protocols indicate that the order of conditioning tasks might play an important role at the muscle-tendon level. PMID- 27935647 TI - Shifts in intertidal zonation and refuge use by prey after mass mortalities of two predators. AB - Recent mass mortalities of two predatory sea star species provided an unprecedented opportunity to test the effect of predators on rocky intertidal prey. Mass mortalities provide insight that manipulative experiments cannot because they alter ecosystems on a larger scale, for longer time periods, and remove both organisms and their cues from the environment. We examined shifts in population size structure, vertical zonation, and use of emersed refuge habitats outside tidepools by the abundant herbivorous black turban snail Tegula funebralis, both before and after the successive mortalities of two predatory sea stars. The small cryptic predator Leptasterias spp. suffered a localized but extreme mortality event in November 2010, followed by two mass mortalities of the keystone predator Pisaster ochraceus in August 2011 and autumn 2013. After the local extinction of Leptasterias, the population size of Tegula more than doubled. Also, since Leptasterias primarily inhabited only mid to low intertidal tidepools at this site, small and medium sized snails (which are preferred by Leptasterias) shifted lower in the intertidal and into tidepools after the mortality of Leptasterias. After the mortality of Pisaster in August 2011, large snails did not shift lower in the intertidal zone despite being preferred by Pisaster. Small and medium sized snails became denser in the higher zone and outside tidepools, which was not likely due to Pisaster mortality. Previous studies concluded that Pisaster maintained vertical size gradients of snails, but our data implicate the overlooked predator Leptasterias as the primary cause. This natural experiment indicated that (1) predators exert top-down control over prey population sizes and lower limits, (2) vertical zonation of prey are dynamic and controlled in part by prey behavior, and (3) predators exert the strongest effects on more vulnerable individuals, which typically inhabit stressful habitats higher on the shore or outside tidepools to avoid predation. Because the mass mortalities of two predators drastically reduced both the predation pressure and the chemical cues of predators in the environment, we were able to investigate both the effects of predators on prey populations and the effects on mobile prey behavior. PMID- 27935648 TI - Cardiac allograft vasculopathy after heart transplantation: Is it really ominous? AB - OBJECTIVES: Cardiac allograft vasculopathy (CAV) remains a major impediment to long-term survival after heart transplantation (HT). We investigated the incidence, disease course, and risk factors for CAV. METHODS: Among 399 patients who underwent HT between November 1992 and July 2014, 297 survivors were reviewed. Endpoints were CAV development and the composite outcome of death or re HT. RESULTS: During 5.6+/-5.2 years, CAV was detected in 54 patients: 45 (83.3%), 8 (14.8%), and 1 (1.8%) patients for CAV 1, 2, and 3, respectively. At 1, 5, and 10 years, 99.0%, 82.4%, and 60.3% of patients were free of CAV, respectively. Only four patients (7.4%) showed progression over 4.8+/-2.1 years' follow-up. The presence of CAV did not affect the composite outcome (P=.89). Predictors of CAV included donor age (HR1.06, 95% CI: 1.03-1.10: P<.001), recipient age (1.03 [1.003-1.06]; P=.03), ischemic time >240 minutes (3.15 [1.36-7.28], P=.007), postoperative renal replacement therapy (RRT) (7.1 [2.3-21.8]; P=.001), and triglyceride level at 1 year post-HT (1.005 [1.002-1.008], P=.003). CONCLUSIONS: CAV incidence after HT appears acceptable, with most cases being stationary and inconsequential for survival. Development of CAV seems to be influenced by donor and recipient age, ischemic time, postoperative RRT, and high triglyceride level. PMID- 27935649 TI - Intense pre-admission carriage and further acquisition of ESBL-producing Enterobacteriaceae among patients and their caregivers in a tertiary hospital in Rwanda. AB - OBJECTIVES: To assess the presence and risk factors of intestinal carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) among patients admitted to the University Teaching Hospital of Butare and among their attending caregivers, and to analyse the acquisition of ESBL-PE carriage during hospital stay and associated factors. METHODS: We screened 392 patients and their attending caregivers at admission and discharge for ESBL-PE carriage. Bacterial species were determined using the API-20E system, and antimicrobial susceptibility testing was performed by agar disc diffusion. Data on socio economic status, diet, behaviour, household assets, livestock and hospital procedures were collected. RESULTS: At admission, 50% of the patients showed intestinal ESBL-PE carriage (Escherichia coli, 51%; Klebsiella pneumoniae, 39%; Enterobacter cloacae, 19%) as did 37% of their caregivers. Co-resistance was common but no carbapenem resistance was detected. At discharge, the proportion of ESBL-PE-colonised patients increased to 65% (caregivers, 47%) with almost complete carriage in paediatric patients (93%). The acquisition rate among initially non-colonised patients was 55% (or, 71/1000 patient days). Independent predictors of admission carriage included a colonised caregiver, prior antibiotic intake, egg consumption and neglecting to boil drinking water, whereas being a paediatric patient, undergoing surgery and male gender predicted acquisition during hospitalisation. CONCLUSIONS: Abundant admission carriage of ESBL-PE and a high acquisition rate in a Rwandan university hospital point to potential intrahospital transmission and community dissemination. Caregivers are an additional source of possible spread. Risk factors of colonisation such as diet and water source need to be tackled to prevent the further emergence and spread of ESBL-PE. PMID- 27935650 TI - Association between diabetes mellitus and active tuberculosis in Africa and the effect of HIV. AB - OBJECTIVE: To determine current evidence for the association between diabetes and active tuberculosis in Africa, and how HIV modifies, or not, any association between diabetes and active tuberculosis. METHODS: We conducted a systematic review by searching the EMBASE, Global Health and MEDLINE databases. Studies were eligible for inclusion if they explored the association between diabetes mellitus prevalence and active tuberculosis incidence or prevalence, used a comparison group, were conducted in an African population and adjusted the analysis for at least age. Study characteristics were compared, and risk of bias was assessed. The range of effect estimates was determined for the primary association and for effect modification by HIV. RESULTS: Three eligible studies were identified: two investigated the primary association and two investigated HIV as a potential effect modifier. All studies were case-control studies, including a combined total of 1958 tuberculosis cases and 2111 non-tuberculosis controls. Diabetes diagnostic methods and analysis strategies varied between studies. Individual study adjusted odds ratios of active tuberculosis for the effect of diabetes mellitus (unstratified) ranged from 0.88 (95% CI 0.17-4.58) to 10.7 (95% CI 4.5 26.0). Individual study P-values for HIV interaction ranged from 0.01 to 0.83. Quantitative synthesis of individual study data was not performed due to heterogeneity between studies. CONCLUSIONS: Few data currently exist on the association between diabetes and active tuberculosis in Africa, and on the effect of HIV on this association. Existing data are disparate. More regional research is needed to guide policy and practice on the care and control of tuberculosis and diabetes in Africa. PMID- 27935651 TI - Epidemiology of diabetic kidney disease in adult patients with type 1 diabetes in Italy: The AMD-Annals initiative. AB - BACKGROUND: Patients with type 1 diabetes mellitus are at increased risk of death. This risk appears to be modulated by kidney dysfunction. The aim of this study was to evaluate the prevalence of diabetic kidney disease (DKD), its traits, and clinical correlates in a large sample of patients with type 1 diabetes. METHODS: Clinical data of 20 464 patients with type 1 diabetes were extracted from electronic medical records. Estimated glomerular filtration rate (eGFR) and increased urinary albumin excretion were considered. RESULTS: Mean age of the patients was 46 +/- 16 years, 55.0% were males, and duration of diabetes 19 +/- 13 years. The frequency of diabetic kidney disease, low eGFR, and albuminuria was 23.5%, 8.1%, and 19.5%, respectively. In the multivariate analysis the presence of diabetic kidney disease was associated with age (odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.10-1.18), duration of diabetes (OR = 1.05, 95% CI: 1.03-1.07), and worse glycemic control (OR = 1.24, 95% CI: 1.21-1.28, for every 1% glycated hemoglobin increase). Diabetic kidney disease was also independently associated with an atherogenic lipid profile and increased systolic blood pressure. Glucose control, systolic blood pressure, triglycerides, and high density lipoprotein cholesterol were associated with both low eGFR and albuminuria. Male gender, retinopathy and smoke were related to albuminuria, being female was related to low eGFR, while SUA levels were associated with DKD, low eGFR and albuminuria. CONCLUSIONS: In our sample of patients with type 1 diabetes, diabetic kidney disease entails an unsafe cardiovascular risk profile. Hyperglycemia, arterial hypertension, and atherogenic lipid profile affected both low eGFR and albuminuria. Retinopathy and smoking were related only to albuminuria while being female and elevated serum uric acid were associated only with low eGFR. PMID- 27935652 TI - Facile Access to Unprecedented Electron-Precise Monohydrodiboranes(4), cis-1,2 Dihydrodiboranes(4), and a 1,1-Dihydrodiborane(5). AB - 2,3-Bis(dimethylamino)-substituted B2 N2 C2 heterocycles underwent selective dimethylamino/hydride exchange with either one or two equivalents of BH3 ?SMe2 to give the corresponding cyclic monohydrido- or (cis)1,2-dihydridodiboranes(4), respectively. Upon either heating or irradiation in solution, the latter underwent ring contraction to the corresponding five-membered BN2 C2 heterocycles, whereas irradiation of the 1,2-dimethylaminoethene-supported 1,2 dihydridodiborane(4) in the presence of PEt3 gave an unprecedented unsymmetrical 1,1-dihydrodiborane(5) phosphine adduct. PMID- 27935653 TI - Strong epidemiological evidence that alcohol causes cancer, but how might the public interpret this information? PMID- 27935654 TI - Research of bionic design on tools with rostrum of cyrtotrachelus bugueti guer (coleoptera: curculionidae). AB - To improve the torsional resistance capability of multilayered composite pipes, a bionic design was presented based on the rostrum of Cyrtotrachelus Bugueti Guer. Morphology and mechanical properties of the weevil's rostrum were studied. Scanning electron microscope (SEM) was employed to observe the macro /microstructure and inner structure. Nanoindentation was carried out to measure the elastic modulus and the hardness of the biological materials. Based on the structure of rostrum, a mathematical model of multilayered biomimetic pipe was established with the statistical methods. Then, the 3D biomimetic cylinder was built and the torsional resistance capability was analyzed using the finite element analysis. From the SEM and nanoindentation, it was found that the rostrum is a cylindrical hollow multilayered structure composed by three materials. In the transverse section of rostrum, the materials' moduli are 3.07, 3.15, and 8.64 GPa, the hardness are 172.71, 125.32, and 278.99 MPa, respectively. In the longitudinal section, the moduli are 3.01, 4.35, and 7.66 GPa, the hardness are157.46, 149.15, and 253.51 MPa, respectively. The results of simulation showed that the distributional type of lamination has a significant effect on the torsional resistance capability of multilayered structure. The biomimetic structure, which imitates the lamination of rostrum, is superior in the aspect of torsional resistance compared with the nonlaminated or uniform laminated structure. Additionally, the bionic method is feasible and efficient. PMID- 27935655 TI - Highly Flexible Multifunctional Biopaper Comprising Chitosan Reinforced by Ultralong Hydroxyapatite Nanowires. AB - Highly flexible multifunctional biopaper comprising ultralong hydroxyapatite nanowires and chitosan (UHANWs/CS), with high weight fractions of ultralong hydroxyapatite nanowires (UHANWs) up to 100 wt. %, is reported. The as-prepared UHANWs/CS composite biopaper has high flexibility and superior mechanical properties even when the weight fraction of UHANWs is as high as 90 wt. %. In contrast, the control samples consisting of hydroxyapatite nanorods and chitosan (HANRs/CS) with weight fractions of HANRs higher than 66.7 wt.% cannot be obtained in the form of the flexible membrane. The ultimate tensile strength and Young's modulus of the UHANWs/CS composite biopaper are about 3.2 times and 4.3 times those of the HANRs/CS membrane with the same weight fraction of HAP, respectively. In addition, the UHANWs/CS composite biopaper (90 wt. % UHANWs) can be used for color printing using a commercial ink-jet printer. The surface wettability, swelling ratio, and water vapor transmission rate of the UHANWs/CS composite biopaper are adjustable by changing the addition amount of UHANWs. In vitro experiments indicate that the UHANWs/CS composite biopaper has good degradability, high acellular bioactivity and high biocompatibility. The as prepared UHANWs/CS composite biopaper is therefore promising for various biomedical applications such as wound dressing, bone-fracture fixation, and bone defect repair. PMID- 27935656 TI - Patterns of metal distribution in hypersaline microbialites during early diagenesis: Implications for the fossil record. AB - The use of metals as biosignatures in the fossil stromatolite record requires understanding of the processes controlling the initial metal(loid) incorporation and diagenetic preservation in living microbialites. Here, we report the distribution of metals and the organic fraction within the lithifying microbialite of the hypersaline Big Pond Lake (Bahamas). Using synchrotron-based X-ray microfluorescence, confocal, and biphoton microscopies at different scales (cm-MUm) in combination with traditional geochemical analyses, we show that the initial cation sorption at the surface of an active microbialite is governed by passive binding to the organic matrix, resulting in a homogeneous metal distribution. During early diagenesis, the metabolic activity in deeper microbialite layers slows down and the distribution of the metals becomes progressively heterogeneous, resulting from remobilization and concentration as metal(loid)-enriched sulfides, which are aligned with the lamination of the microbialite. In addition, we were able to identify globules containing significant Mn, Cu, Zn, and As enrichments potentially produced through microbial activity. The similarity of the metal(loid) distributions observed in the Big Pond microbialite to those observed in the Archean stromatolites of Tumbiana provides the foundation for a conceptual model of the evolution of the metal distribution through initial growth, early diagenesis, and fossilization of a microbialite, with a potential application to the fossil record. PMID- 27935657 TI - Profile and reintegration experience of Ebola survivors in Guinea: a cross sectional study. AB - OBJECTIVE: To describe the experience of Guinean Ebola virus disease (EVD) survivors in Guinea, up to ten months after discharge from the Ebola treatment unit. METHODS: Cross-sectional study using a standardised semistructured questionnaire among survivors from Conakry and Coyah districts in 2015 in Guinea. We used proportions, mean (standard deviation) and median (interquartile range) to summarise the variables. The McNemar chi-square test was used to compare proportions. RESULTS: The 121 EVD survivors interviewed had a median reintegration time from discharge of 18 weeks (IQR: 14-32 weeks). Most survivors were aged 15-44 years (87.6%) with secondary to higher level of education (68.6%), and 25.6% were healthcare workers. The majority reported a lower socio economic status (90%), a less favourable work situation (79%) and psychological status (60%). About 31% reported physical health problems. Most survivors reported lower levels of reintegration with friends and at work place (72%) and lower acceptance by others in general (71%) in the period after the EVD as compared to the period before the EVD. Only 55 survivors (45.5%) were involved in one or more activities of the EVD response: participation in clinical studies on the EVD (44 survivors, 36.4%), community sensitisation (28 survivors, 23.1%) or work in Ebola treatment and/or transit centres (23 survivors, 21.7%). CONCLUSION: There is a need for a long-term follow-up of EVD survivors in Guinea and more efforts to support their social, professional and economic reintegration, especially in rural areas. PMID- 27935658 TI - Three New Iridoid Glycosides from the Aerial Parts of Asperula involucrata. AB - Three new iridoid glycosides, named involucratosides A - C (1 - 3), were isolated from the H2 O subextract of crude MeOH extract prepared from the aerial parts of Asperula involucrata along with a known iridoid glycoside (adoxoside), three flavone glycosides (apigenin 7-O-beta-glucopyranoside, luteolin 7-O-beta glucopyranoside, apigenin 7-O-rutinoside) as well as two phenolic acid derivatives (chlorogenic acid and ferulic acid 4-O-beta-glucopyranoside). Their chemical structures were established by UV, IR, 1D- (1 H, 13 C and JMOD) and 2D- (COSY, HSQC, HMBC and NOESY) NMR experiments and HR-ESI-MS. In addition, the crude extract, subextracts and isolates were evaluated for their xanthine oxidase inhibitory and antioxidant activities in in vitro tests. This is the first report on the chemical composition and bioactivities of A. involucrata. PMID- 27935659 TI - Exploring the Least Studied Australian Eucalypt Genera: Corymbia and Angophora for Phytochemicals with Anticancer Activity against Pancreatic Malignancies. AB - While the pharmacological and toxicological properties of eucalypts are well known in indigenous Australian medicinal practice, investigations of the bioactivity of eucalypt extracts against high mortality diseases such as pancreatic cancer in Western medicine have to date been limited, particularly amongst the genera Corymbia and Angophora. Four Angophora and Corymbia species were evaluated for their phytochemical profile and efficacy against both primary and secondary pancreatic cancer cell lines. The aqueous leaf extract of Angophora hispida exhibited statistically higher total phenolic content (107.85 +/- 1.46 mg of gallic acid equiv. per g) and total flavonoid content (57.96 +/- 1.93 mg rutin equiv. per g) and antioxidant capacity compared to the other tested eucalypts (P < 0.05). Both A. hispida and A. floribunda aqueous extracts showed statistically similar saponin contents. Angophora floribunda extract exerted significantly greater cell growth inhibition of 77.91 +/- 4.93% followed by A. hispida with 62.04 +/- 7.47% (P < 0.05) at 100 MUg/ml in MIA PaCa-2 cells with IC50 values of 75.58 and 87.28 MUg/ml, respectively. More studies are required to isolate and identify the bioactive compounds from these two Angophora species and to determine their mode of action against pancreatic malignancies. PMID- 27935660 TI - Biofilm formation in Haas palatal expanders with and without use of an antimicrobial agent: an in situ study. AB - Orthodontic appliances causes specific alterations in oral environment, including reduction of pH, increase of dental biofilm and elevation of salivary microbial levels, causing an increased risk for dental caries. This study evaluated, using microbial culture and scanning electron microscopy (SEM), the in situ contamination by mutans streptococci (MS) of different surfaces of Haas palatal expanders with and without use of chlorhexidine gluconate mouthrinses (CHX). Thirty-four patients were randomly assigned to two groups (n = 17/group), using placebo (Group I) and 0.12% CHX (Group II-Periogard(r) ) mouthrinses twice a week. After 4 months, appliances were submitted to microbiological processing and after fragments were analyzed by SEM. Mann-Whitney U test (alpha = 5%) was used to assess differences between groups on the appliances' different surfaces and to compare the contamination on the free and nonfree surfaces of these components. There was no difference (p = 0.999) between groups regarding the number of MS colonies/biofilms on the nonfree surfaces, which showed intense contamination. However, free surfaces of Group II presented less contamination (p < 0.001) than those of Group I in all appliances' components. Results of the microbial culture were confirmed by SEM. Use of 0.12% CHX was effective in reducing the formation of MS colonies/biofilms on free surfaces of Haas expanders, in situ. PMID- 27935661 TI - Bee communities along a prairie restoration chronosequence: similar abundance and diversity, distinct composition. AB - Recognition of the importance of bee conservation has grown in response to declines of managed honey bees and some wild bee species. Habitat loss has been implicated as a leading cause of declines, suggesting that ecological restoration is likely to play an increasing role in bee conservation efforts. In the midwestern United States, restoration of tallgrass prairie has traditionally targeted plant community objectives without explicit consideration for bees. However, restoration of prairie vegetation is likely to provide ancillary benefits to bees through increased foraging and nesting resources. We investigated community assembly of bees across a chronosequence of restored eastern tallgrass prairies and compared patterns to those in control and reference habitats (old fields and prairie remnants, respectively). We collected bees for 3 yr and measured diversity and abundance of in-bloom flowering plants, vegetation structure, ground cover, and surrounding land use as predictors of bee abundance and bee taxonomic and functional diversity. We found that site-level variables, but not site type or restoration age, were significant predictors of bee abundance (bloom diversity, P = 0.004; bare ground cover, P = 0.02) and bee diversity (bloom diversity, P = 0.01). There were significant correlations between overall composition of bee and blooming plant communities (Mantel test, P = 0.002), and both plant and bee assemblages in restorations were intermediate between those of old fields and remnant prairies. Restorations exhibited high bee beta diversity, i.e., restored sites' bee assemblages were taxonomically and functionally differentiated from each other. This pattern was strong in younger restorations (<20 yr old), but absent from older restorations (>20 yr), suggesting restored prairie bee communities become more similar to one another and more similar to remnant prairie bee communities over time with the arrival of more species and functional groups of bees. Our results indicate that old fields, restorations, and remnants provide habitat for diverse and abundant bee communities, but continued restoration of old fields will help support and conserve bee communities more similar to reference bee communities characteristic of remnant prairies. PMID- 27935662 TI - Antibacterial activity of glass ionomer cement modified by zinc oxide nanoparticles. AB - This study evaluated the antibacterial activity of zinc oxide nanoparticles incorporated into self-cured glass ionomer cement (GIC) and light-cured resin reinforced GIC on Streptococcus mutans biofilm. The GICs, Fuji II (GC America) and Fuji II LC (GC America), were incorporated with nanoparticles at concentrations of 0%, 1%, and 2% by weight, and the biofilm maturation time was one and seven days. Circular specimens of each GIC type were prepared. The antibacterial activity was evaluated by determining the number of colony forming units of S. mutans strain per milliliter. Morphology of the biofilm was analyzed by scanning electron microscopy (SEM). The data obtained for each GIC were analyzed by two-way ANOVA (alpha = 5%). For chemically activated GIC, no significant difference was observed in relation to the time of biofilm maturation (p = 0.744), concentration of nanoparticles (p = 0.966), and their interaction (p = 0.800). The results from analysis of GIC modified by light-polymerized resin showed that only of the maturing time significantly affected the number of adhered cells on the biofilm (p = 0.034, F = 4.778). The more mature the biofilm, higher the number of cells. SEM analysis showed no change in cell morphology in relation to the type of GIC, maturation time, and nanoparticles concentration. We conclude that the inclusion of zinc oxide nanoparticles at concentrations of 1% and 2% by weight into the GICs evaluated here, did not promote their antimicrobial activity against S. mutans. PMID- 27935663 TI - Relative importance of abiotic, biotic, and disturbance drivers of plant community structure in the sagebrush steppe. AB - Abiotic conditions, biotic factors, and disturbances can act as filters that control community structure and composition. Understanding the relative importance of these drivers would allow us to understand and predict the causes and consequences of changes in community structure. We used long-term data (1989 2002) from the sagebrush steppe in the state of Washington, USA, to ask three questions: (1) What are the key drivers of community-level metrics of community structure? (2) Do community-level metrics and functional groups differ in magnitude or direction of response to drivers of community structure? (3) What is the relative importance of drivers of community structure? The vegetation in 2002 was expressed as seven response variables: three community-level metrics (species richness, total cover, compositional change from 1989 to 2002) and the relative abundances of four functional groups. We used a multi-model inference framework to identify a set of top models for each response metric beginning from a global model that included two abiotic drivers, six disturbances, a biotic driver (initial plant community), and interactions between the disturbance and biotic drivers. We also used a permutational relative variable importance metric to rank the influence of drivers. Moisture availability was the most important driver of species richness and of native forb cover. Fire was the most important driver of shrub cover and training area usage was important for compositional change, but disturbances, including grazing, were of secondary importance for most other variables. Biotic drivers, as represented by the initial plant communities, were the most important driver for total cover and for the relative covers of exotics and native grasses. Our results indicate that the relative importance of drivers is dependent on the choice of metric, and that drivers such as disturbance and initial plant community can interact. PMID- 27935664 TI - Point-of-care assessment of C-reactive protein and white blood cell count to identify bacterial aetiologies in malaria-negative paediatric fevers in Tanzania. AB - OBJECTIVE: To assess the role of point-of-care (PoC) assessment of C-reactive protein (CRP) and white blood cell (WBC) count to identify bacterial illness in Tanzanian children with non-severe non-malarial fever. METHODS: From the outpatient department of a district hospital in Tanzania, 428 patients between 3 months and 5 years of age who presented with fever and a negative malaria test were enrolled. All had a physical examination and bacterial cultures from blood and urine. Haemoglobin, CRP and WBC were measured by PoC devices. RESULTS: Positive blood cultures were detected in 6/428 (1.4%) children and urine cultures were positive in 24/401 (6.0%). Mean WBC was similar in children with or without bacterial illness (14.0 * 109 , 95% CI 12.0-16.0 * 109 vs. 12.0 * 109 , 95% CI 11.4-12.7 * 109), while mean CRP was higher in children with bacterial illness (41.0 mg/l, 95% CI 28.3-53.6 vs. 23.8 mg/l, 95% CI 17.8-27.8). In ROC analysis, the optimum cut-off value for CRP to identify bacterial illness was 19 mg/l but with an area under the curve of only 0.62. Negative predictive values exceeded 80%, while positive predictive values were under 40%. CONCLUSION: WBC and CRP levels had limited value in identifying children with bacterial infections. The positive predictive values for both tests were too low to be used as single tools for treatment decisions. PMID- 27935665 TI - Chemical Composition of the Essential Oils from Different Morphological Parts of Pinus cembra L. AB - The essential oils from needles, twigs, bark, wood, and cones of Pinus cembra were analyzed by GC-FID, GC/MS, and 1 H-NMR spectroscopy. More than 130 compounds were identified. The oils differed in the quantitative composition. The principal components of the oil from twigs with needles were alpha-pinene (36.3%), limonene (22.7%) and beta-phellandrene (12.0%). The needle oil was dominated by alpha pinene (48.4%), whereas in the oil from bark and in the oil from twigs without needles there were limonene (36.2% and 33.6%, resp.) and beta-phellandrene (18.8% and 17.1%, resp.). The main constituents of the wood oil as well as cone oil were alpha-pinene (35.2% and 39.0%, resp.) and beta-pinene (10.4% and 18.9%, resp.). The wood oil and the cone oil contained large amounts of oxygenated diterpenes in comparison with needle, twig, and bark oils. PMID- 27935666 TI - COMPARISON OF TRANSVERSE COMPUTED TOMOGRAPHIC EXCRETORY UROGRAPHY IMAGES AND MAXIMUM INTENSITY PROJECTION IMAGES FOR DIAGNOSING ECTOPIC URETERS IN DOGS. AB - Computed tomographic maximum intensity projection (MIP) images have been shown to improve reader confidence in their diagnoses and to improve detection of vascular structures and pulmonary nodules. The objectives of this method comparison study were to compare transverse source computed tomographic excretory urography (CTEU) images to two, five, and 10 slab thick MIP images for diagnosing canine ectopic ureters, compare reader confidence, and evaluate interobserver agreement. Two board-certified veterinary radiologists and a board-certified small animal internist blindly reviewed transverse source CTEU and two, five, and 10 slab thick MIP images of 24 dogs enrolled in the study. Inclusion criteria included a diagnostic CTEU and either cystoscopic or surgical confirmation of the presence or absence of ureteral ectopia. Eleven dogs were confirmed to have 17 ectopic ureters at surgery and/or cystoscopically. There was no significant difference in reader diagnoses between viewing methods or between viewing methods and the surgical/cystoscopic findings (P < 0.001). Reader confidence was significantly greater on two (P = 0.0080) and five (P = 0.0009) slab thick MIP images with significant interobserver agreement between readers for all viewing methods (P values ranging between 0.0363 and <0.001). In addition, the diagnostic accuracy of MIP images was similar to or better than transverse source CTEU images, when assessed by a radiologist. The study results suggest that CTEU is a reliable imaging technique for diagnosing canine ectopic ureters among specialists of varied experience. In addition, thin slice reconstructed MIP images improve reader confidence and potentially diagnostic accuracy, and thus their use should be considered, especially in more challenging cases. PMID- 27935667 TI - Positive and negative affectivity as risk factors for heavy drinking in the second half of life: a prospective cohort study. AB - AIMS: To estimate the prospective relations between levels of propensity to experience positive affect (PA) and propensity to experience negative affect (NA) and risk of heavy drinking in a cohort of Norwegians aged 40-80 years. DESIGN: Clustered sampling was used to draw Norwegians aged 40-79 years in 2002/03 (t1). The relationship between PA and NA measured at t1 and heavy drinking measured in 2007/08 (t2) was estimated with random-intercept logistic regression. SETTING: Norway. PARTICIPANTS: A total of 2142 (44.0% men) who consumed mean = 3.07 [standard deviation (SD) = 3.15] UK units of alcohol on average per week and were intoxicated less than once per week at t1. MEASURES: The Brief Measure of Positive and Negative Affect, quantity-frequency measure of alcohol use and frequency of drinking to intoxication. Heavy drinking at t2 (> 14 units per week and/or intoxication >= once per week) was regressed on PA and NA at t1. FINDINGS: Controlling for alcohol consumption, gender, age, income and level of education (at t1) and change in PA and NA, there was little evidence for an association between level of PA and heavy drinking [odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.71, 1.29, Bayes factor = 0.15]. The level of NA at t1 was associated with greater risk of heavy drinking at t2 (OR = 1.40, 95% CI = 1.02, 1.93). CONCLUSION: There is little evidence for an association between the propensity to experience positive affect and heavy drinking among Norwegians aged 40-80 years. Norwegian adults in the second half of life with a high propensity to experience negative affect are at greater risk of heavy drinking approximately 5 years later than those with a low propensity to experience negative affect. PMID- 27935668 TI - Chemical Composition, Antimicrobial and Insecticidal Activities of Flowers Essential Oils of Alpinia zerumbet (Pers.) B.L.Burtt & R.M.Sm. from Martinique Island. AB - Alpinia species, used as ornamental plants and flavoring agents, are renowned for their therapeutic properties and their subsequent use in traditional medicines throughout the world. Alpinia zerumbet (Pers.) B.L.Burtt & R.M.Sm. is the most common Alpinia species encountered in Martinique. Several essential oils (EOs) obtained by hydrodistillation of A. zerumbet flowers collected in various locations on the island at different seasons were analysed to evaluate the influence of the collection period and area on the EOs' chemical compositions and to assess their bioactivity. A combination of GC-FID and GC/MS techniques was used to examine the volatile constituents, leading to the identification of a total of 71 components accounting for 97.8 - 99.3% of the respective total GC-FID areas: among them, nineteen compounds were characterized for the first time in A. zerumbet EOs. The antimicrobial activity of these EOs was assessed against eight bacterial, yeast and fungal strains and two multi-resistant strains: some significant bacteriostatic and fungistatic activities of A. zerumbet flower oils were evidenced. Finally, an interesting insecticidal activity of the flower EO was highlighted for the first time against Aedes aegypti. PMID- 27935669 TI - Influence of cattle on browsing and grazing wildlife varies with rainfall and presence of megaherbivores. AB - In many savanna ecosystems worldwide, livestock share the landscape and its resources with wildlife. The nature of interactions between livestock and wildlife is a subject of considerable interest and speculation, yet little controlled experimental research has been carried out. Since 1995, we have been manipulating the presence and absence of cattle and large mammalian herbivore wildlife in a Kenyan savanna in order to better understand how different herbivore guilds influence habitat use by specific wildlife species. Using dung counts as a relative assay of herbivore use of the different experimental plots, we found that cattle had a range of effects, mostly negative, on common mesoherbivore species, including both grazers and mixed feeders, but did not have significant effects on megaherbivores. The effect of cattle on most of the mesoherbivore species was contingent on both the presence of megaherbivores and rainfall. In the absence of megaherbivores, wild mesoherbivore dung density was 36% lower in plots that they shared with cattle than in plots they used exclusively, whereas in the presence of megaherbivores, wild mesoherbivore dung density was only 9% lower in plots shared with cattle than plots used exclusively. Cattle appeared to have a positive effect on habitat use by zebra (a grazer) and steinbuck (a browser) during wetter periods of the year but a negative effect during drier periods. Plots to which cattle had access had lower grass and forb cover than plots from which they were excluded, while plots to which megaherbivores had access had more grass cover but less forb cover. Grass cover was positively correlated with zebra and oryx dung density while forb cover was positively correlated with eland dung density. Overall these results suggest that interactions between livestock and wildlife are contingent on rainfall and herbivore assemblage and represent a more richly nuanced set of interactions than the longstanding assertion that cattle simply compete with (grazing) wildlife. Specifically, rainfall and megaherbivores seemed to moderate the negative effects of cattle on some mesoherbivore species. Even if cattle tend to reduce wildlife use of the landscape, managing simultaneously for livestock production (at moderate levels) and biodiversity conservation is possible. PMID- 27935671 TI - Two-Dimensional Liquid Chromatography: A State of the Art Tutorial. AB - In this tutorial, we discuss the motivations for doing two-dimensional liquid chromatography (2D-LC) and describe the commonly used implementations of the method. We review important guiding principles for method development, discuss the state of the art in 2D-LC performance as measured by peak capacity, and describe example applications from different fields that we hope will inspire new users to adopt 2D-LC for their analytical problems. PMID- 27935670 TI - Development of a pathway model to assess the exposure of European pine trees to pine wood nematode via the trade of wood. AB - Pine wood nematode (PWN), Bursaphelenchus xylophilus, is a threat for pine species (Pinus spp.) throughout the world. The nematode is native to North America, and invaded Japan, China, Korea, and Taiwan, and more recently Portugal and Spain. PWN enters new areas through trade in wood products. Once established, eradication is not practically feasible. Therefore, preventing entry of PWN into new areas is crucial. Entry risk analysis can assist in targeting management to reduce the probability of entry. Assessing the entry of PWN is challenging due to the complexity of the wood trade and the wood processing chain. In this paper, we develop a pathway model that describes the wood trade and wood processing chain to determine the structure of the entry process. We consider entry of PWN through imported coniferous wood from China, a possible origin of Portuguese populations, to Europe. We show that exposure increased over years due to an increase in imports of sawn wood. From 2000 to 2012, Europe received an estimated 84 PWN propagules from China, 88% of which arose from imported sawn wood and 12% from round wood. The region in Portugal where the PWN was first reported is among those with the highest PWN transfer per unit of imported wood due to a high host cover and vector activity. An estimated 62% of PWN is expected to enter in countries where PWN is not expected to cause the wilt of pine trees because of low summer temperatures (e.g., Belgium, Sweden, Norway). In these countries, PWN is not easily detected, and such countries can thus serve as potential reservoirs of PWN. The model identifies ports and regions with high exposure, which helps targeting monitoring and surveillance, even in areas where wilt disease is not expected to occur. In addition, we show that exposure is most efficiently reduced by additional treatments in the country of origin, and/or import wood from PWN free zones. Pathway modelling assists plant health managers in analyzing risks along the pathway and planning measures for enhancing biosecurity. PMID- 27935672 TI - Topotactic Transformation of Metal-Organic Frameworks to Graphene-Encapsulated Transition-Metal Nitrides as Efficient Fenton-like Catalysts. AB - Innovation in transition-metal nitride (TMN) preparation is highly desired for realization of various functionalities. Herein, series of graphene-encapsulated TMNs (FexMn6-xCo4-N@C) with well-controlled morphology have been synthesized through topotactic transformation of metal-organic frameworks in an N2 atmosphere. The as-synthesized FexMn6-xCo4-N@C nanodices were systematically characterized and functionalized as Fenton-like catalysts for catalytic bisphenol A (BPA) oxidation by activation of peroxymonosulfate (PMS). The catalytic performance of FexMn6-xCo4-N@C was found to be largely enhanced with increasing Mn content. Theoretical calculations illustrated that the dramatically reduced adsorption energy and facilitated electron transfer for PMS activation catalyzed by Mn4N are the main factors for the excellent activity. Both sulfate and hydroxyl radicals were identified during the PMS activation, and the BPA degradation pathway mainly through hydroxylation, oxidation, and decarboxylation was investigated. Based on the systematic characterization of the catalyst before and after the reaction, the overall PMS activation mechanism over FexMn6-xCo4-N@C was proposed. This study details the insights into versatile TMNs for sustainable remediation by activation of PMS. PMID- 27935674 TI - Multiplexed Imaging of Trace Residues in a Single Latent Fingerprint. AB - The development of highly sensitive, selective, nondestructive, and multiplexed imaging modalities is essential for latent fingerprint (LFP) identification and fingerprint residues detection. Herein, we present a versatile strategy to identify LFPs and to probe the multiple trace residues in a single LFP simultaneously. With the purpose of achieving high sensitivity, we for the first time introduced a polydopamine (PDA)-triggered Au growth method to prepare superbright and multiplex surface-enhanced Raman scattering (SERS) tags, which were endowed with high selectivity by conjugating with specific antibodies. In combination with a rapid Raman mapping technique, the sensitivity of the SERS probes was down to picogram scale and all the three levels of LFP features can be clearly seen. More significantly, the multiplexed imaging of diverse residues in a single LFP provides more accurate information than that using monochromatic imaging of individuals alone. The high analytical figures of merit enable this approach great promise for use in the fields ranging from chemical detection to molecular imaging. PMID- 27935675 TI - Encapsulation of Either Hydrophilic or Hydrophobic Substances in Spongy Cellulose Particles. AB - We have reported cellulose particles with a spongy structure that we prepared by the solvent releasing method (SRM) from cellulose droplets composed of cellulose, 1-butyl-3-methylimidazoliumchrolide ([Bmim]Cl), and N,N-dimethylformamide (DMF). The spongy structure collapsed as the medium evaporated, resulting in dense cellulose particles. In this study, we encapsulated the hydrophilic and hydrophobic fluorescent substances in these particles to investigate the use of such particles in potential applications that require encapsulating of substances (e.g., drug delivery). Wet cellulose particles retained their spongy structure in both hydrophobic and hydrophilic media. When the spongy cellulose particles were dispersed in a solution containing nonvolatile solutes, these solutes were driven into the cellulose particles as media evaporated. Subsequently, the cellulose particles collapsed and encapsulated the nonvolatile solutes. Regardless of whether the solute was hydrophilic or hydrophobic, the encapsulation efficiency exceeds 80%. The maximum loading reflected the saturated solubility of solute in solution that filled the cellulose beads. Moreover, the encapsulated solute was released by dispersing the cellulose beads in the solvent, and the rate of release of the encapsulated solute could be controlled by coating the cellulose beads with a conventional polymer. PMID- 27935673 TI - Cell-Density Dependence of Host-Defense Peptide Activity and Selectivity in the Presence of Host Cells. AB - Host-defense peptides (HDPs) are promising compounds against multidrug-resistant microbes. In vitro, their bactericidal and toxic concentrations are significantly different, but this might be due to the use of separate assays, with different cell densities. For experiments with a single cell type, the cell-density dependence of the active concentration of the DNS-PMAP23 HDP could be predicted based on the water/cell-membrane partition equilibrium and exhibited a lower bound at low cell counts. On the basis of these data, in the simultaneous presence of both bacteria and an excess of human cells, one would expect no significant toxicity, but also inhibition of the bactericidal activity due to peptide sequestration by host cells. However, this inhibition did not take place in assays with mixed cell populations, showing that for the HDP esculentin-1a(1 21)NH2, a range of bactericidal, nontoxic concentrations exists and confirming the effective selectivity of HDPs. Mixed-cell assays might be necessary to effectively asses HDP selectivity. PMID- 27935676 TI - Calibrant-Free Analyte Quantitation via a Variable Velocity Flow Cell. AB - In this paper, we describe a novel method for analyte quantitation that does not rely on calibrants, internal standards, or calibration curves but, rather, leverages the relationship between disparate and predictable surface-directed analyte flux to an array of sensing addresses and a measured resultant signal. To reduce this concept to practice, we fabricated two flow cells such that the mean linear fluid velocity, U, was varied systematically over an array of electrodes positioned along the flow axis. This resulted in a predictable variation of the address-directed flux of a redox analyte, ferrocenedimethanol (FDM). The resultant limiting currents measured at a series of these electrodes, and accurately described by a convective-diffusive transport model, provided a means to calculate an "unknown" concentration without the use of calibrants, internal standards, or a calibration curve. Furthermore, the experiment and concentration calculation only takes minutes to perform. Deviation in calculated FDM concentrations from true values was minimized to less than 0.5% when empirically derived values of U were employed. PMID- 27935678 TI - Ultrafine Pt Nanoclusters Confined in a Calixarene-Based {Ni24} Coordination Cage for High-Efficient Hydrogen Evolution Reaction. AB - To obtain stable and ultrafine Pt nanoclusters, a trigonal prismatic coordination cage with the sulfur atoms on the edges was solvothermally synthesized to confine them. In the structure of {Ni24(TC4A-SO2)6(TDC)12 (H2O)6} (H4TC4A-SO2 = p-tert butylsulfonylcalix[4]arene; H2TDC = 2,5-thiophenedicarboxylic acid), three Ni4 (TC4A-SO2) SBUs are bridged by three TDC ligands into a triangle and two such triangles are pillared by three pairs of TDC ligands to form a trigonal prism. The cage cavity has 12 sulfur atoms on the surface. Because of the porous structure and strong covalent interaction between metal and sulfur, ultrafine Pt nanoclusters composed of less than ~18 Pt atoms can be facilely confined in the present trigonal prismatic cage (Pt@CIAC-121). The as-synthesized Pt NCs exhibit higher electrocatalytic activity than commercial Pt/C toward hydrogen evolution reaction. PMID- 27935679 TI - A New Solution to an Old Problem: Synthesis of Unsubstituted Poly(para phenylene). AB - Unsubstituted and structurally well-defined poly(para-phenylene) (PPP) has been long-desired as an organic semiconductor prototype of conjugated polymers. To date, several attempts to synthesize unsubstituted, pristine, high-molecular weight PPP have failed. Here we solved this synthetic problem by a versatile precursor route. Suzuki polymerization of kinked disubstituted 1,4 dimethoxycyclohexadienylene monomers yielded a well-soluble, nonaromatic precursor polymer. Its solubility allowed processing by spin-coating into nanometer-thick films. Subsequent additive-free thermal treatment induced aromatization and led to exclusively para-connected, highly fluorescent PPP with a length of about 75 phenylene units. PMID- 27935677 TI - Tryptophan Synthase Uses an Atypical Mechanism To Achieve Substrate Specificity. AB - Tryptophan synthase (TrpS) catalyzes the final steps in the biosynthesis of l tryptophan from l-serine (Ser) and indole-3-glycerol phosphate (IGP). We report that native TrpS can also catalyze a productive reaction with l-threonine (Thr), leading to (2S,3S)-beta-methyltryptophan. Surprisingly, beta-substitution occurs in vitro with a 3.4-fold higher catalytic efficiency for Ser over Thr using saturating indole, despite a >82000-fold preference for Ser in direct competition using IGP. Structural data identify a novel product binding site, and kinetic experiments clarify the atypical mechanism of specificity: Thr binds efficiently but decreases the affinity for indole and disrupts the allosteric signaling that regulates the catalytic cycle. PMID- 27935680 TI - Self-Assembling Nanocomposite Tectons. AB - The physical characteristics of composite materials are dictated by both the chemical composition and spatial configuration of each constituent phase. A major challenge in nanoparticle-based composites is developing methods to precisely dictate particle positions at the nanometer length scale, as this would allow complete control over nanocomposite structure-property relationships. In this work, we present a new class of building blocks called nanocomposite tectons (NCTs), which consist of inorganic nanoparticles grafted with a dense layer of polymer chains that terminate in molecular recognition units capable of programmed supramolecular bonding. By tuning various design factors, including the particle size and polymer length, we can use the supramolecular interactions between NCTs to controllably alter their assembly behavior, enabling the formation of well-ordered body-centered cubic superlattices consisting of inorganic nanoparticles surrounded by polymer chains. NCTs therefore present a modular platform that enables the construction of composite materials where the composition and three-dimensional arrangement of different constituents within the composite can be independently controlled. PMID- 27935681 TI - Continuous Optical 3D Printing of Green Aliphatic Polyurethanes. AB - Photosensitive diurethanes were prepared from a green chemistry synthesis pathway based on methacrylate-functionalized six-membered cyclic carbonate and biogenic amines. A continuous optical 3D printing method for the diurethanes was developed to create user-defined gradient stiffness and smooth complex surface microstructures in seconds. The green chemistry-derived polyurethane (gPU) showed high optical transparency, and we demonstrate the ability to tune the material stiffness of the printed structure along a gradient by controlling the exposure time and selecting various amine compounds. High-resolution 3D biomimetic structures with smooth curves and complex contours were printed using our gPU. High cell viability (over 95%) was demonstrated during cytocompatibility testing using C3H 10T1/2 cells seeded directly on the printed structures. PMID- 27935682 TI - Electrochemical Polymerization of Iron(III) Polypyridyl Complexes through C-C Coupling of Redox Non-innocent Phenolato Ligands. AB - Phenolato moieties impart redox flexibility to metal complexes due their accessible (oxidative) redox chemistry and have been proposed as functional ligand moieties in redox non-innocent ligand based transition metal catalysis. Here, the electro- and spectroelectrochemistry of phenolato based MU-oxo diiron(III) complexes [(L1)Fe(MU-O)Fe(L1)]2+ (1) and [(L2)Fe(MU-O)Fe(L2)]2+ (2), where L1 = 2-(((di(pyridin-2-yl)methyl)(pyridin-2-ylmethyl)amino)methyl)phenol and L2 = 3,5-di-tert-butyl-2-(((di(pyridin-2-yl)methyl)(pyridin-2 ylmethyl)amino)methyl)phenol, is described. The electrochemical oxidation of 1 in dichloromethane results in aryl C-C coupling of phenoxyl radical ligand moieties to form tetra nuclear complexes, which undergo subsequent oxidation to form iron(III) phenolato based polymers (poly-1). The coupling is blocked by placing tert-butyl groups at para and ortho positions of phenol units (i.e., 2). Poly-1 shows two fully reversible redox processes in monomer free solution. Assignment of species observed during the electrochemical and chemical {(NH4)2[CeIV(NO3)6]} oxidation of 1 in acetonitrile is made by comparison with the UV-vis-NIR absorption and resonance micro-Raman spectroelectrochemistry of poly-1, and by DFT calculations, which confirms that oxidative coupling occurs in acetonitrile also. However, in contrast to that observed in dichloromethane, in acetonitrile, the oligomers formed are degraded in terms of a loss of the Fe(III)-O-Fe(III) bridge by protonation. The oxidative redox behavior of 1 and 2 is, therefore, dominated by the formation and reactivity of Fe(III) bound phenoxyl radicals, which considerably holds implications in regard to the design of phenolato based complexes for oxidation catalysis. PMID- 27935683 TI - Structural Regulation of PdCu2 Nanoparticles and Their Electrocatalytic Performance for Ethanol Oxidation. AB - Two types of PdCu2 nanoparticles were prepared through one-pot synthesis and a two-step reducing process, named as PdCu2-1 and PdCu2-2, respectively. The morphology and structure of as-prepared samples were investigated by transmission electron microscopy, high-resolution transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and inductively coupled plasma optical emission spectrometry. Results showed that more Pd atoms were buried in the inside of PdCu2-1, whereas more available Pd sites were distributed on the surface of PdCu2-2. The electrochemical measurements indicated that both PdCu2-1 and PdCu2-2 nanoparticles showed a higher electrocatalytic activity than that for pure Pd nanoparticles. In particular, PdCu2-2 predictably exhibited a better stability and durability as well as a lower onset potential and a higher catalytic current density than that of PdCu2-1 toward ethanol oxidation in alkaline media. On the basis of these studies, the formation mechanisms of both the PdCu2 catalysts and the relationship between their structure and properties were discussed in this paper. PMID- 27935684 TI - A Modified Approach for in Situ Chemical Oxidation Coupled to Biodegradation Enhances Light Nonaqueous Phase Liquid Source-Zone Remediation. AB - Field and batch experiments were conducted to assess whether a modified approach for in situ chemical oxidation (ISCO) (with MgO2 and Fe2O3 particles recovered from acid mine drainage treatment) can enhance LNAPL (light nonaqueous phase liquid) dissolution and produce bioavailable soluble compounds. This modified ISCO approach was coupled to biodegradation to further remove residual compounds by microbially mediated processes. Pure palm biodiesel (B100) was chosen to represent a poorly water-soluble compound that behaves like LNAPLs, and 100 L was released to a 2 m2 area excavated down to the water table. A past adjacent B100 field experiment under natural attenuation was conducted as a baseline control. Results demonstrated the enhancement of organic compound dissolution and production of soluble compounds due to the modified in situ chemical oxidation. The slow release of H2O2 by MgO2 decomposition (termed partial chemical oxidation) and production of soluble compounds allowed the stimulation of microbial growth and promoted a beneficial response in microbial communities involved in oxidized biodiesel compound biodegradation. This is the first field experiment to demonstrate that this modified ISCO approach coupled to biodegradation could be a feasible strategy for the removal of poorly water soluble compounds (e.g., biodiesel) and prevent the long-term effects generally posed in source zones. PMID- 27935685 TI - Determining Molecular Orientations in Disordered Materials from X-ray Linear Dichroism at the Iodine L1-Edge. AB - To demonstrate that measurements of X-ray linear dichroism are effective for determining bond orientations in disordered materials, we report the first observation of X-ray linear dichroism at the iodine L1-edge. The iodine containing molecular solid studied in this work was the inclusion compound containing 4,4'-diiodobiphenyl guest molecules in the perhydrotriphenylene host structure. In this material, the guest substructure does not exhibit three dimensional ordering, and thus diffraction-based techniques do not provide insights on the orientational properties of the guest molecules. Iodine L1-edge X ray absorption spectra, recorded as a function of orientation of a single crystal of the material, exhibit significant dichroism (whereas no dichroism is observed at the iodine L2- and L3-edges). From quantitative analysis of the X-ray dichroism, the orientational properties of the C-I bonds within this material are established. The results pave the way for applying X-ray dichroism to determine molecular orientational properties of other materials, especially for partially ordered materials such as liquid crystals, confined liquids, and disordered crystalline phases, for which diffraction techniques may not be applicable. PMID- 27935687 TI - Chemical Synthesis, Versatile Structures and Functions of Tailorable Adjuvants for Optimizing Oral Vaccination. AB - Oral vaccines have become a recent focus because of their potential significance in disease prevention and therapy. In the development of oral vaccine-based therapeutics, synthetic materials with tailorable structures and versatile functions can act as antigen conveyers with adjuvant effects, reduce the time cost for vaccine optimization, and provide high security and enhanced immunity. This review presents an overview of the current status of tailoring synthetic adjuvants for oral vaccination, modification strategies for producing effectors with specific structures and functions, enhancement of immune-associated efficiencies, including the barrier-crossing capability to protect antigens in the gastrointestinal tract, coordination of the antigens penetrating mucosa and cell barriers, targeting of concentrated antigens to immune-associated cells, and direct stimulation of immune cells. Finally, we focus on prospective synthetic adjuvants that facilitate the use of oral vaccines via two approaches, namely, in vivo antigen expression and cancer immunotherapy. PMID- 27935686 TI - Neuroprotection of Brain Cells by Lipoic Acid Treatment after Cellular Stress. AB - We have previously observed that in vivo lipoic acid (LA) treatment induced a protective effect onto primary cortical neurons after brain injury. In an effort to better understand LA action mechanism in the brain, in the present study, we stressed brain cells in vitro and ex vivo and then analyzed by inmmunocytochemistry and biochemical assays, the changes induced by LA on cell survival and on the concentration of oxidative stress markers, such as glutathione (GSH), oxidized glutathione (GSSG), and malondialdehyde (MDA). The stressors used were lipopolysaccharide (LPS), dopamine, and l-buthionine-S,R sulfoximine (BSO). Our results showed that LA decreased cell death and increased GSH/GSSG ratio in cells stressed by LPS + dopamine, suggesting that the mechanism underlying LA action is regeneration of GSSG to GSH. When cells were stressed by BSO, LA diminished cell death and decreased GSH/GSSG ratio. In this case, it could be concluded that, due to the low GSH basal levels, GSSG reduction is not possible and therefore it might be thought that cell death prevention might be mediated through other mechanisms. Finally, we induced chemical oxidative damage in brain homogenate. After LA treatment, GSH and GSH/GSSG ratio increased and MDA concentration decreased, demonstrating again that LA was not able to increase de novo GSH synthesis but is able to increase GSSG conversion to GSH. PMID- 27935688 TI - Quantifying Cr(VI) Production and Export from Serpentine Soil of the California Coast Range. AB - Hexavalent chromium (Cr(VI)) is generated in serpentine soils and exported to surface and groundwaters at levels above health-based drinking water standards. Although Cr(VI) concentrations are elevated in serpentine soil pore water, few studies have reported field evidence documenting Cr(VI) production rates and fluxes that govern Cr(VI) transport from soil to water sources. We report Cr speciation (i) in four serpentine soil depth profiles derived from the California Coast Range serpentinite belt and (ii) in local surface waters. Within soils, we detected Cr(VI) in the same horizons where Cr(III)-minerals are colocated with biogenic Mn(III/IV)-oxides, suggesting Cr(VI) generation through oxidation by Mn oxides. Water-extractable Cr(VI) concentrations increase with depth constituting a 7.8 to 12 kg/km2 reservoir of Cr(VI) in soil. Here, Cr(VI) is produced at a rate of 0.3 to 4.8 kg Cr(VI)/km2/yr and subsequently flushed from soil during water infiltration, exporting 0.01 to 3.9 kg Cr(VI)/km2/yr at concentrations ranging from 25 to 172 MUg/L. Although soil-derived Cr(VI) is leached from soil at concentrations exceeding 10 MUg/L, due to reduction and dilution during transport to streams, Cr(VI) levels measured in local surface waters largely remain below California's drinking water limit. PMID- 27935689 TI - DNA-Catalyzed DNA Cleavage by a Radical Pathway with Well-Defined Products. AB - We describe an unprecedented DNA-catalyzed DNA cleavage process in which a radical-based reaction pathway cleanly results in excision of most atoms of a specific guanosine nucleoside. Two new deoxyribozymes (DNA enzymes) were identified by in vitro selection from N40 or N100 random pools initially seeking amide bond hydrolysis, although they both cleave simple single-stranded DNA oligonucleotides. Each deoxyribozyme generates both superoxide (O2-* or HOO*) and hydrogen peroxide (H2O2) and leads to the same set of products (3' phosphoglycolate, 5'-phosphate, and base propenal) as formed by the natural product bleomycin, with product assignments by mass spectrometry and colorimetric assay. We infer the same mechanistic pathway, involving formation of the C4' radical of the guanosine nucleoside that is subsequently excised. Consistent with a radical pathway, glutathione fully suppresses catalysis. Conversely, adding either superoxide or H2O2 from the outset strongly enhances catalysis. The mechanism of generation and involvement of superoxide and H2O2 by the deoxyribozymes is not yet defined. The deoxyribozymes do not require redox-active metal ions and function with a combination of Zn2+ and Mg2+, although including Mn2+ increases the activity, and Mn2+ alone also supports catalysis. In contrast to all of these observations, unrelated DNA-catalyzed radical DNA cleavage reactions require redox-active metals and lead to mixtures of products. This study reports an intriguing example of a well-defined, DNA-catalyzed, radical reaction process that cleaves single-stranded DNA and requires only redox inactive metal ions. PMID- 27935690 TI - International Interlaboratory Digital PCR Study Demonstrating High Reproducibility for the Measurement of a Rare Sequence Variant. AB - This study tested the claim that digital PCR (dPCR) can offer highly reproducible quantitative measurements in disparate laboratories. Twenty-one laboratories measured four blinded samples containing different quantities of a KRAS fragment encoding G12D, an important genetic marker for guiding therapy of certain cancers. This marker is challenging to quantify reproducibly using quantitative PCR (qPCR) or next generation sequencing (NGS) due to the presence of competing wild type sequences and the need for calibration. Using dPCR, 18 laboratories were able to quantify the G12D marker within 12% of each other in all samples. Three laboratories appeared to measure consistently outlying results; however, proper application of a follow-up analysis recommendation rectified their data. Our findings show that dPCR has demonstrable reproducibility across a large number of laboratories without calibration. This could enable the reproducible application of molecular stratification to guide therapy and, potentially, for molecular diagnostics. PMID- 27935691 TI - DNA-Mediated Morphological Control of Pd-Au Bimetallic Nanoparticles. AB - Recent reports have shown that different DNA sequences can mediate the control of shapes and surface properties of nanoparticles. However, all previous studies have involved only monometallic particles, most of which were gold nanoparticles. Controlling the shape of bimetallic nanoparticles is more challenging, and there is little research into the use of DNA-based ligands for their morphological control. We report the DNA-templated synthesis of Pd-Au bimetallic nanoparticles starting from palladium nanocube seeds. The presence of different homo-oligomer DNA sequences containing 10 deoxy-ribonucleotides of thymine, adenine, cytosine, or guanine results in the growth of four distinct morphologies. Through detailed kinetic studies by absorption spectroscopy, scanning electron microscopy (SEM) and scanning transmission electron microscopy (STEM), we have determined the role of DNA in controlling Pd-Au nanoparticle growth morphologies. One major function of DNA is affecting various properties of the incoming metal atoms, including their diffusion and deposition on the Pd nanocube seed. Interestingly, nanoparticle growth in the presence of A10 follows an aggregative growth mechanism that is unique when compared to the other base oligomers. These findings demonstrate that DNA can allow for programmable control of bimetallic nanoparticle morphologies, resulting in more complex hybrid materials with different plasmonic properties. The capability to finely tune multimetallic nanoparticle morphology stems from the versatile structure that is unique to DNA in comparison to conventionally used capping agents in colloidal nanomaterial synthesis. PMID- 27935693 TI - Metastable Layered Cobalt Chalcogenides from Topochemical Deintercalation. AB - We present a general strategy to synthesize metastable layered materials via topochemical deintercalation of thermodynamically stable phases. Through kinetic control of the deintercalation reaction, we have prepared two hypothesized metastable compounds, CoSe and CoS, with the anti-PbO type structure from the starting compounds KCo2Se2 and KCo2S2, respectively. Thermal stability, crystal structure from X-ray and neutron diffraction, magnetic susceptibility, magnetization, and electrical resistivity are studied for these new layered chalcogenides; both CoSe and CoS are found to be weak itinerant ferromagnets with Curie temperatures close to 10 K. Due to the weak van der Waals forces between the layers, CoSe is found to be a suitable host for further intercalation of guest species such as Li-ethylenediamine. From first-principles calculations, we explain why the Co chalcogenides are ferromagnets instead of superconductors as in their iron analogues. Bonding analysis of the calculated electronic density of states both explains their phase stability and predicts the limits of our deintercalation technique. Our results have broad implications for the rational design of new two-dimensional building blocks for functional materials. PMID- 27935694 TI - Engendering Long-Term Air and Light Stability of a TiO2-Supported Porphyrinic Dye via Atomic Layer Deposition. AB - Organic and porphyrin-based chromophores are prevalent in liquid-junction photovoltaic and photocatalytic solar-cell chemistry; however, their long-term air and light instability may limit their practicality in real world technologies. Here, we describe the protection of a zinc porphyrin dye, adsorbed on nanoparticulate TiO2, from air and light degradation by a protective coating of alumina grown with a previously developed post-treatment atomic layer deposition (ALD) technique. The protective Al2O3 ALD layer is deposited using dimethylaluminum isopropoxide as an Al source; in contrast to the ubiquitous ALD precursor trimethylaluminum, dimethylaluminum isopropoxide does not degrade the zinc porphyrin dye, as confirmed by UV-vis measurements. The growth of this protective ALD layer around the dye can be monitored by an in-reactor quartz crystal microbalance (QCM). Furthermore, greater than 80% of porphyrin light absorption is retained over ~1 month of exposure to air and light when the protective coating is present, whereas almost complete loss of porphyrin absorption is observed in less than 2 days in the absence of the ALD protective layer. Applying the Al2O3 post-treatment technique to the TiO2-adsorbed dye allows the dye to remain in electronic contact with both the semiconductor surface and a surrounding electrolyte solution, the combination of which makes this technique promising for numerous other electrochemical photovoltaic and photocatalytic applications, especially those involving the dye-sensitized evolution of oxygen. PMID- 27935692 TI - Dynamic and Electrostatic Effects on the Reaction Catalyzed by HIV-1 Protease. AB - HIV-1 Protease (HIV-1 PR) is one of the three enzymes essential for the replication process of HIV-1 virus, which explains why it has been the main target for design of drugs against acquired immunodeficiency syndrome (AIDS). This work is focused on exploring the proteolysis reaction catalyzed by HIV-1 PR, with special attention to the dynamic and electrostatic effects governing its catalytic power. Free energy surfaces for all possible mechanisms have been computed in terms of potentials of mean force (PMFs) within hybrid QM/MM potentials, with the QM subset of atoms described at semiempirical (AM1) and DFT (M06-2X) level. The results suggest that the most favorable reaction mechanism involves formation of a gem-diol intermediate, whose decomposition into the product complex would correspond to the rate-limiting step. The agreement between the activation free energy of this step with experimental data, as well as kinetic isotope effects (KIEs), supports this prediction. The role of the protein dynamic was studied by protein isotope labeling in the framework of the Variational Transition State Theory. The predicted enzyme KIEs, also very close to the values measured experimentally, reveal a measurable but small dynamic effect. Our calculations show how the contribution of dynamic effects to the effective activation free energy appears to be below 1 kcal.mol-1. On the contrary, the electric field created by the protein in the active site of the enzyme emerges as being critical for the electronic reorganization required during the reaction. These electrostatic properties of the active site could be used as a mold for future drug design. PMID- 27935695 TI - Tunable Narrow Band Emissions from Dye-Sensitized Core/Shell/Shell Nanocrystals in the Second Near-Infrared Biological Window. AB - We introduce a hybrid organic-inorganic system consisting of epitaxial NaYF4:Yb3+/X3+@NaYbF4@NaYF4:Nd3+ (X = null, Er, Ho, Tm, or Pr) core/shell/shell (CSS) nanocrystal with organic dye, indocyanine green (ICG) on the nanocrystal surface. This system is able to produce a set of narrow band emissions with a large Stokes-shift (>200 nm) in the second biological window of optical transparency (NIR-II, 1000-1700 nm), by directional energy transfer from light harvesting surface ICG, via lanthanide ions in the shells, to the emitter X3+ in the core. Surface ICG not only increases the NIR-II emission intensity of inorganic CSS nanocrystals by ~4-fold but also provides a broadly excitable spectral range (700-860 nm) that facilitates their use in bioapplications. We show that the NIR-II emission from ICG-sensitized Er3+-doped CSS nanocrystals allows clear observation of a sharp image through 9 mm thick chicken breast tissue, and emission signal detection through 22 mm thick tissue yielding a better imaging profile than from typically used Yb/Tm-codoped upconverting nanocrystals imaged in the NIR-I region (700-950 nm). Our result on in vivo imaging suggests that these ICG-sensitized CSS nanocrystals are suitable for deep optical imaging in the NIR-II region. PMID- 27935696 TI - Cyanobacteriochrome Photoreceptors Lacking the Canonical Cys Residue. AB - Cyanobacteriochromes (CBCRs) are cyanobacterial photoreceptors that sense near ultraviolet to far-red light. Like the distantly related phytochromes, all CBCRs reported to date have a conserved Cys residue (the "canonical Cys" or "first Cys") that forms a thioether linkage to C31 of the linear tetrapyrrole (bilin) chromophore. Detection of ultraviolet, violet, and blue light is performed by at least three subfamilies of two-Cys CBCRs that require both the first Cys and a second Cys that forms a second covalent linkage to C10 of the bilin. In the well characterized DXCF subfamily, the second Cys is part of a conserved Asp-Xaa-Cys Phe motif. We here report novel CBCRs lacking the first Cys but retaining the DXCF Cys as part of a conserved Asp-Xaa-Cys-Ile-Pro (DXCIP) motif. Phylogenetic analysis demonstrates that DXCIP CBCRs are a sister to a lineage of DXCF CBCR domains from phototaxis sensors. Three such DXCIP CBCR domains (cce_4193g1, Cyan8802_2776g1, and JSC1_24240) were characterized after recombinant expression in Escherichia coli engineered to produce phycocyanobilin. All three covalently bound bilin and showed unidirectional photoconversion in response to green light. Spectra of acid-denatured proteins in the dark-adapted state do not correspond to those of known bilins. One DXCIP CBCR, cce_4193g1, exhibited very rapid dark reversion consistent with a function as a power sensor. However, Cyan8802_2776g1 exhibited slower dark reversion and would not have such a function. The full length cce_4193 protein also possesses a DXCF CBCR GAF domain (cce_4193g2) with a covalently bound phycoviolobilin chromophore and a blue/green photocycle. Our studies indicate that CBCRs need not contain the canonical Cys residue to function as photochromic light sensors and that phototaxis proteins containing DXCIP CBCRs may potentially perceive both light quality and light intensity. PMID- 27935697 TI - Tunable Wavelength Enhanced Photoelectrochemical Cells from Surface Plasmon Resonance. AB - Photocatalysis is a promising technology for renewable energy production. Many photocatalysis have realized the visible-light-driven catalytic activity. However, it is still difficult to achieve the enhanced photocatalytic activity with tunable wavelength. We have designed tunable wavelength enhanced photoelectrochemical cells by tuning the surface plasmon resonance (SPR) peaks, which can be controlled by the aspect ratios of the Au nanorods, for both the cathode with the hydrogen evolution reaction and the anode with the electrooxidation of methanol reaction. The optimal photocatalytic activity of the hydrogen evolution and electrooxidation of the methanol can be realized only when the illuminating wavelength matches with the SPR peaks, which is quite selective to the illuminating wavelength. The blue shift of the SPR peak increases the photoelectrocatalytic effect whereas the red shift enhances the photothermal effect. Such studies provide a useful way for improving the photocatalytic activity and the selectivity of the photocatalytic reactions by adjusting the illuminating wavelength. PMID- 27935699 TI - New Particle Formation from Methanesulfonic Acid and Amines/Ammonia as a Function of Temperature. AB - Previous studies have shown that methanesulfonic acid (MSA) reacts with amines and ammonia to form particles, which is expected to be particularly important in coastal and agricultural areas. We present the first systematic study of temperature dependence of particle formation from the reactions of MSA with trimethylamine (TMA), dimethylamine (DMA), methylamine (MA), and ammonia over the range of 21-28 degrees C and 0.4-5.9 s in a flow reactor under dry conditions and in the presence of 3 * 1017 cm-3 water vapor. Overall activation energies (Eoverall) for particle formation calculated from the dependence of rates of particle formation on temperature for all of these bases are negative. The negative Eoverall is interpreted in terms of reverse reactions that decompose intermediate clusters in competition with the forward reactions that grow the clusters into particles. The average values of Eoverall for the formation of detectable particles are: TMA, -(168 +/- 19) kcal mol-1; DMA, -(134 +/- 30) kcal mol-1; MA, -(68 +/- 23) kcal mol-1; NH3, -(110 +/- 16) kcal mol-1 (+/-1sigma). The strong inverse dependence of particle formation with temperature suggests that particle formation may not decline proportionally with concentrations of MSA and amines if temperature also decreases, for example at higher altitudes or in winter. PMID- 27935698 TI - Tailoring Nanostructure Morphology for Enhanced Targeting of Dendritic Cells in Atherosclerosis. AB - Atherosclerosis, a leading cause of heart disease, results from chronic vascular inflammation that is driven by diverse immune cell populations. Nanomaterials may function as powerful platforms for diagnostic imaging and controlled delivery of therapeutics to inflammatory cells in atherosclerosis, but efficacy is limited by nonspecific uptake by cells of the mononuclear phagocytes system (MPS). MPS cells located in the liver, spleen, blood, lymph nodes, and kidney remove from circulation the vast majority of intravenously administered nanomaterials regardless of surface functionalization or conjugation of targeting ligands. Here, we report that nanostructure morphology alone can be engineered for selective uptake by dendritic cells (DCs), which are critical mediators of atherosclerotic inflammation. Employing near-infrared fluorescence imaging and flow cytometry as a multimodal approach, we compared organ and cellular level biodistributions of micelles, vesicles (i.e., polymersomes), and filomicelles, all assembled from poly(ethylene glycol)-bl-poly(propylene sulfide) (PEG-bl-PPS) block copolymers with identical surface chemistries. While micelles and filomicelles were respectively found to associate with liver macrophages and blood-resident phagocytes, polymersomes were exceptionally efficient at targeting splenic DCs (up to 85% of plasmacytoid DCs) and demonstrated significantly lower uptake by other cells of the MPS. In a mouse model of atherosclerosis, polymersomes demonstrated superior specificity for DCs (p < 0.005) in atherosclerotic lesions. Furthermore, significant differences in polymersome cellular biodistributions were observed in atherosclerotic compared to naive mice, including impaired targeting of phagocytes in lymph nodes. These results present avenues for immunotherapies in cardiovascular disease and demonstrate that nanostructure morphology can be tailored to enhance targeting specificity. PMID- 27935701 TI - Cobalt-Catalyzed [6 + 2] Cycloaddition of Alkynes with 1,3,5,7-Cyclooctatetraene as a Key Element in the Direct Construction of Substituted Bicyclo[4.3.1]decanes. AB - A new, effective catalytic system based on Co(acac)2 has been developed for [6 + 2] cycloaddition of terminal alkynes to 1,3,5,7-cyclooctatetraene to give substituted bicyclo[4.2.2]deca-2,4,7,9-tetraenes in high yields (68-85%). The electrophilic activation of double bonds in the bicyclic products with m-CPBA is an efficient method for the synthesis of substituted bicyclo[4.3.1]deca-2,4,8 triene-7,10-diols, which form the key structural moieties of numerous natural biologically active compounds. The structures of the obtained compounds were reliably proven by modern spectral methods and X-ray diffraction. The mechanism of the discovered rearrangement was studied both using deuterium-labeled bicyclo[4.2.2]deca-2,4,7,9-tetraenes and utilizing quantum chemical calculations. The obtained substituted bicyclo[4.3.1]deca-2,4,8-triene-7,10-diols and their keto derivatives showed high antitumor activity in vitro against Hek293, Jurkat, K562, and A549 tumor cell lines. PMID- 27935700 TI - A Life Cycle Assessment Case Study of Coal-Fired Electricity Generation with Humidity Swing Direct Air Capture of CO2 versus MEA-Based Postcombustion Capture. AB - Most carbon capture and storage (CCS) envisions capturing CO2 from flue gas. Direct air capture (DAC) of CO2 has hitherto been deemed unviable because of the higher energy associated with capture at low atmospheric concentrations. We present a Life Cycle Assessment of coal-fired electricity generation that compares monoethanolamine (MEA)-based postcombustion capture (PCC) of CO2 with distributed, humidity-swing-based direct air capture (HS-DAC). Given suitable temperature, humidity, wind, and water availability, HS-DAC can be largely passive. Comparing energy requirements of HS-DAC and MEA-PCC, we find that the parasitic load of HS-DAC is less than twice that of MEA-PCC (60-72 kJ/mol versus 33-46 kJ/mol, respectively). We also compare other environmental impacts as a function of net greenhouse gas (GHG) mitigation: To achieve the same 73% mitigation as MEA-PCC, HS-DAC would increase nine other environmental impacts by on average 38%, whereas MEA-PCC would increase them by 31%. Powering distributed HS-DAC with photovoltaics (instead of coal) while including recapture of all background GHG, reduces this increase to 18%, hypothetically enabling coal-based electricity with net-zero life-cycle GHG. We conclude that, in suitable geographies, HS-DAC can complement MEA-PCC to enable CO2 capture independent of time and location of emissions and recapture background GHG from fossil-based electricity beyond flue stack emissions. PMID- 27935702 TI - Alternate "Drug" Delivery Utilizing beta-Lactam Cores: Syntheses and Biological Evaluation of beta-Lactams Bearing Isocyanate Precursors. AB - The synthesis of a small set of beta-lactams containing isocyanate precursors is described. The release of the isocyanate precursor in model hydrolysis experiments was substantiated by trapping experiments, thus confirming that beta lactams can be designed that are capable of releasing alternatively reactive species. Preliminary biological assessments are also briefly discussed. PMID- 27935703 TI - Absorption Cross Sections of 2-Nitrophenol in the 295-400 nm Region and Photolysis of 2-Nitrophenol at 308 and 351 nm. AB - 2-Nitrophenol is an important component of "brown carbon" in the atmosphere. Photolysis is its dominant gas phase removal process. We have determined the gas phase absorption cross sections of 2-nitrophenol in the 295-400 nm region by using cavity ring-down spectroscopy. 2-Nitrophenol exhibits a broad absorption band over the wavelength region studied, with the peak absorption located at 345 nm. Absorption cross section values range between (2.86 +/- 0.18) * 10-18 and (2.63 +/- 0.31) * 10-20 cm2/molecule over the 295-400 nm range. We have investigated the HONO, NO2, and OH formation channels following the gas phase photolysis of 2-nitrophenol at 308 and 351 nm. Direct NO2 formation was not observed. HONO and OH are direct products from 2-nitrophenol photolysis. The average OH quantum yields from the photolysis of 0.5, 1.0, and 2.0 mTorr of 2 nitrophenol are 0.69 +/- 0.07 and 0.70 +/- 0.07 at 308 and 351 nm. The average HONO quantum yields are 0.34 +/- 0.09 and 0.39 +/- 0.07 at 308 and 351 nm. The OH and HONO quantum yields are independent of nitrogen carrier gas pressure in the 20-600 Torr range. Oxidant formation rate constants from 2-nitrophenol photolysis have been calculated. Discussions have been made concerning the role of 2 nitrophenol gas phase photolysis in the formation of atmospheric oxidants in regions of high anthropogenic emissions. PMID- 27935704 TI - Simulating the Favorable Aggregation of Monolacunary Keggin Anions. AB - We here present a series of classical molecular dynamics simulations (MD) on aqueous solutions of the salts Li5AlW12O40 and Li9AlW11O39, providing us with valuable insight on their aggregative behavior. Analysis of relative dipole moment orientation in pairs of aggregated [AlW11O39]9- excludes that their large dipole moment is behind their greater propensity to aggregate. On the other hand, MD simulations of the aqueous Li+ salt of the fictitious [AlW12O40]9--as high in charge as [AlW11O39]9-, but lacking dipole moment and tetrahedral in shape like [AlW12O40]5--reveal that it is in fact the higher negative charge itself that promotes aggregation, by allowing to recruit a higher number of Li+ countercations, which then act as an electrostatic glue. The lower charge on [AlW12O40]5-, on the other hand, is not able to muster enough Li+ countercations for it to aggregate favorably. PMID- 27935705 TI - Aroma-Active Compounds in Bartlett Pears and Their Changes during the Manufacturing Process of Bartlett Pear Brandy. AB - Application of aroma extract dilution analysis to Bartlett pears and the fermented mash produced thereof revealed 24 and 34 aroma-active compounds in the flavor dilution (FD) factor range between 8 and 8192. Twenty-eight compounds, which have not been described before in Bartlett pears or in fermented pear mash, were identified. While ethyl (E,Z)-2,4-decadienoate (pear-like, metallic odor impression), hexyl acetate (green, fruity), and acetic acid (vinegar-like) showed the highest concentrations in Bartlett pears, ethanol (ethanolic), acetic acid, 3 methyl-1-butanol (malty), 1-hexanol (grassy, marzipan-like), (S)-2- and 3 methylbutanoic acid (sweaty), and 2-phenylethanol (flowery, honey-like) were present at the highest amounts in the fermented mash. The key aroma compounds were quantitated in each pear brandy production step (pears, fermented mash, distillate, and aged distillate) by stable isotope dilution analysis showing a clear influence of each step on the overall aroma of the spirit and, consequently, revealing clearly changing concentrations (e.g., of ethyl (S)-2 methylbutanoate, (E)-beta-damascenone, ethyl (E,Z)-2,4-decadienoate, and ethyl (E,E)-2,4-decadienoate) and different aroma perceptions during the manufacturing process. In addition, the concentrations of the so-called "pear esters" ethyl (E,Z)-2,4-decadienoate and ethyl (E,E)-2,4-decadienoate were determined in 6 different pear varieties (Abate Fetel, Anjou, Bartlett, Forelle, Kaiser Alexander, and Packham's Triumph) clearly demonstrating the aroma potential of the variety Bartlett, which is mostly used for brandy production due to the high amounts of both esters eliciting a typical pear-like odor impression. PMID- 27935706 TI - Phase-Transfer Catalyzed O-Silyl Ether Deprotection Mediated by a Cyclopropenium Cation. AB - The use of a cyclopropenium cation as a phase-transfer catalyst for O-silyl ether deprotection is reported. Mechanistic insight into this deprotection methodology derived by linear free-energy relationships (LFER), quantum theory of atoms in molecules (QTAIM), and density functional theory (DFT) calculations are also provided. PMID- 27935707 TI - On the Role of Nonspherical Cavities in Short Length-Scale Density Fluctuations in Water. AB - Density fluctuations in liquid water are at the heart of numerous phenomena associated with hydrophobic effects such as protein folding and the interaction between biomolecules. One of the most fundamental processes in this regard is the solvation of hydrophobic solutes in water. The vast majority of theoretical and numerical studies examine density fluctuations at the short length scale focusing exclusively on spherical cavities. In this work, we use both first-principles and classical molecular dynamics simulations to demonstrate that density fluctuations in liquid water can deviate significantly from the canonical spherical shapes. We show that regions of empty space are frequently characterized by exotic, highly asymmetric shapes that can be quite delocalized over the hydrogen bond network. Interestingly, density fluctuations of these shapes are characterized by Gaussian statistics with larger fluctuations. An important consequence of this is that the work required to create non spherical cavities can be substantially smaller than that of spheres. This feature is also qualitatively captured by the Lum-Chandler Weeks theory. The scaling behavior of the free energy as a function of the volume at short length scales is qualitatively different for the nonspherical entities. We also demonstrate that nonspherical density fluctuations are important for accommodating the hydrophobic amino acid alanine and are thus likely to have significant implications when it comes to solvating highly asymmetrical species such as alkanes, polymers, or biomolecules. PMID- 27935708 TI - Imidazolium Salts Mimicking the Structure of Natural Lipids Exploit Remarkable Properties Forming Lamellar Phases and Giant Vesicles. AB - Tailor-made ionic liquids based on imidazolium salts have recently attracted a large amount of attention because of their extraordinary properties and versatile functionality. An intriguing ability to interact with and stabilize membranes has already been reported for 1,3-dialkylimidazolium compounds. We now reveal further insights into the field by investigating 1,3-dimethyl-4,5-dialkylimidazolium (Cn IMe.HI, n = 7, 11, 15) and 1,3-dibenzyl-4,5-dialkylimidazolium (Cn-IBn.HBr, n = 7, 11, 15) salts. Diverse alkyl chain lengths and headgroups differing in their steric demand were employed for the membrane interface interaction with bilayer membranes imitating the cellular plasma membrane. Membrane hydration properties and domain fluidization were analyzed by fluorescent bilayer probes in direct comparison to established model membranes in a buffered aqueous environment, which resembles the salt content and pH of the cytosol of living cells. Membrane binding and insertion was analyzed via a quartz crystal microbalance and confocal laser scanning microscopy. We show that short-chain 4,5-dialkylimidazolium salts with a bulky headgroup were able to disintegrate membranes. Long-chain imidazolium salts form bilayer membrane vesicles spontaneously and autonomously without the addition of other lipids. These 4,5-dialkylimidazolium salts are highly eligible for further biochemical engineering and drug delivery. PMID- 27935709 TI - Physical and Chemical Stability of Curcumin in Aqueous Solutions and Emulsions: Impact of pH, Temperature, and Molecular Environment. AB - The utilization of curcumin as a nutraceutical in food and supplement products is often limited because of its low water solubility, poor chemical stability, and low oral bioavailability. This study examined the impact of pH, storage temperature, and molecular environment on the physical and chemical stability of pure curcumin in aqueous solutions and in oil-in-water emulsions. Unlike naturally occurring curcuminoid mixtures (that contain curcumin, demethoxy curcumin, and bisdemethoxy-curcumin), pure curcumin was highly unstable to chemical degradation in alkaline aqueous solutions (pH >=7.0) and tended to crystallize out of aqueous acidic solutions (pH <7). These effects were attributed to changes in the molecular structure of curcumin under different pH conditions. The curcumin crystals formed were relatively large (10-50 MUm), which made them prone to rapid sedimentation. The incorporation of curcumin into oil-in water emulsions (30% MCT, 1 mg curcumin/g MCT, d32 ~ 298 nm) improved its water dispersibility and chemical stability. After incubation at 37 degrees C for 1 month, >85% of curcumin was retained by emulsions stored under acidic conditions (pH <7), whereas 62, 60, and 53% was retained by emulsions stored at pH 7.0, 7.4, and 8.0, respectively. There was little change in the color of curcumin-loaded emulsions when stored under acidic conditions, but their yellow color faded when stored under alkaline conditions. There was no evidence of droplet aggregation or creaming in emulsions stored for 31 days at ambient temperature. These results suggest that emulsion-based delivery systems may be suitable for improving the water dispersibility and chemical stability of curcumin, which would facilitate its application in foods and supplements. PMID- 27935711 TI - Low-Cost Phase-Selective Organogelators for Rapid Gelation of Crude Oils at Room Temperature. AB - Frequent marine oil spills pose a significant threat to the environment and marine's ecosystem. We have recently reported a highly tunable molecular gelling scaffold, which enables us to identify a few first examples of phase-selective organogelators (PSOGs) that can instantly gel the crude oil of various types with room-temperature operation. In this study, we demonstrate the high robustness and reliability of this modular gelling scaffold in consistently and combinatorially producing high capacity PSOGs. Such a unique feature has allowed us to carry out a systematic study of 48 gelators via a two-step screening process and to discover another powerful carboxybenzyl-based gelator with comparable gelling properties but with a cost lowered by more than 300%, pointing to a good commercial potential for rapid cleanup of oil spills while effectively eliminating environmental pollution caused by the spilled oil. PMID- 27935712 TI - The Monomer Electron Density Force Field (MEDFF): A Physically Inspired Model for Noncovalent Interactions. AB - We propose a methodology to derive pairwise-additive noncovalent force fields from monomer electron densities without any empirical input. Energy expressions are based on the symmetry-adapted perturbation theory (SAPT) decomposition of interaction energies. This ensures a physically motivated force field featuring an electrostatic, exchange-repulsion, dispersion, and induction contribution, which contains two types of parameters. First, each contribution depends on several fixed atomic parameters, resulting from a partitioning of the monomer electron density. Second, each of the last three contributions (exchange repulsion, dispersion, and induction) contains exactly one linear fitting parameter. These three so-called interaction parameters in the model are initially estimated separately using SAPT reference calculations for the S66x8 database of noncovalent dimers. In a second step, the three interaction parameters are further refined simultaneously to reproduce CCSD(T)/CBS interaction energies for the same database. The limited number of parameters that are fitted to dimer interaction energies (only three) avoids ill-conditioned fits that plague conventional parameter optimizations. For the exchange-repulsion and dispersion component, good results are obtained for all dimers in the S66x8 database using one single value for the associated interaction parameters. The values of those parameters can be considered universal and can also be used for dimers not present in the original database used for fitting. For the induction component such an approach is only viable for the dispersion-dominated dimers in the S66x8 database. For other dimers (such as hydrogen-bonded complexes), we show that our methodology remains applicable. However, the interaction parameter needs to be determined on a case-specific basis. As an external validation, the force field predicts interaction energies in good agreement with CCSD(T)/CBS values for dispersion-dominated dimers extracted from an HIV-II protease crystal structure with a bound ligand (indinavir). Furthermore, experimental second virial coefficients of small alkanes and alkenes are well reproduced. PMID- 27935710 TI - Quantification of ATP7B Protein in Dried Blood Spots by Peptide Immuno-SRM as a Potential Screen for Wilson's Disease. AB - Wilson's Disease (WD), a copper transport disorder caused by a genetic defect in the ATP7B gene, has been a long time strong candidate for newborn screening (NBS), since early interventions can give better results by preventing irreversible neurological disability or liver cirrhosis. Several previous pilot studies measuring ceruloplasmin (CP) in infants or children showed that this marker alone was insufficient to meet the universal screening for WD. WD results from mutations that cause absent or markedly diminished levels of ATP7B. Therefore, ATP7B could serve as a marker for the screening of WD, if the protein can be detected from dried blood spots (DBS). This study demonstrates that the immuno-SRM platform can quantify ATP7B in DBS in the picomolar range, and that the assay readily distinguishes affected cases from normal controls (p < 0.0001). The assay precision was <10% CV, and the protein was stable for a week in DBS at room temperature. These promising proof-of-concept data open up the possibility of screening WD in newborns and the potential for a multiplexed assay for screening a variety of congenital disorders using proteins as biomarkers in DBS. PMID- 27935713 TI - Symmetry-Directed Self-Organization in Peptide Nanoassemblies through Aromatic pi pi Interactions. AB - Almost all biological systems are assemblies of one or more biomolecules from nano- to macrodimensions. Unlike inorganic molecules, peptide systems attune with the conceptual framework of aggregation models when forming nanoassemblies. Three significant recent theoretical models have indicated that nucleation, end-to-end association, and geometry of growth are determined primarily by the size and electrostatics of the individual basic building blocks. In this study, we tested six model systems, differentially modulating the prominence of three design variables, namely, aromatic pi-pi interactions, local electrostatics, and overall symmetry of the basic building unit. Our results indicate that the crucial design elements in a peptide-based nanoassembly are (a) a stable extended pi-pi interaction network, (b) size, and (c) overall symmetry of the basic building blocks. The six model systems represent all of the design variables in the best manner possible, considering the complexity of a biomolecule. The results provide important directives in deciding the morphology and crystallinity of peptide nanoassemblies. PMID- 27935714 TI - Palladium-Catalyzed Acylations: One-Pot Synthesis of Indenones. AB - An efficient, one-pot synthesis of substituted indenones was accomplished starting from simple o-iodoketones and aldehydes. [Pd]-catalyzed direct acylation of o-iodoketones with aldehydes was employed as the key step. Subsequent intramolecular aldol condensation afforded the indenones. Notably, a variety of indenones were achieved. Significantly, the natural product neolignan was accomplished in one pot. PMID- 27935715 TI - Self-Assembly, Dynamics, and Polymorphism of hIAPP(20-29) Aggregates at Solid Liquid Interfaces. AB - The misfolding and subsequent assembly of proteins and peptides into insoluble amyloid structures play important roles in the development of numerous diseases. The dynamics of self-assembly and the morphology of the resulting aggregates critically depend on various environmental factors and especially on the presence of interfaces. Here, we show in detail how the presence of surfaces with different physicochemical properties influences the assembly dynamics and especially the aggregate morphology of hIAPP(20-29), an amyloidogenic fragment of the peptide hormone human islet amyloid polypeptide (hIAPP), which is involved in the development of type 2 diabetes. Time-lapse atomic force microscopy is employed to study the assembly dynamics of hIAPP(20-29) and the morphology of the resulting aggregates in bulk solution as well as at hydrophilic and hydrophobic model surfaces. We find that the presence of hydrophilic mica surfaces promotes fibrillation when compared with the assembly in bulk solution and results in a more pronounced polymorphism. Three fibrillar species are found to coexist on the mica surface, that is, straight, coiled, and ribbon-like fibrils, whereas only the straight and coiled fibrils are observed in bulk solution after comparable incubation times. In addition, the straight and coiled fibrils assembled at the mica surface have significantly different dimensions compared with those assembled in bulk solution. The three fibrillar species found on the mica surface most likely form independently by lateral association of arbitrary numbers of protofibrils with about 2 nm height. On hydrophobic hydrocarbon surfaces, fibrillation is retarded but not completely suppressed, in contrast to previous observations for full-length hIAPP(1-37). Our results show that peptide-surface interactions may induce diverse, peptide-specific alterations of amyloid assembly dynamics and fibrillar polymorphism. They may therefore contribute to a deeper understanding of the molecular processes that govern amyloid aggregation at different surfaces. PMID- 27935716 TI - Fluctuation Spectroscopy Analysis of Glucose Capped Gold Nanoparticles. AB - In this work, we report the synthesis and biophysical studies carried out on a new kind of biocompatible and very stable gold nanoparticle (GNP) stabilized with glucose through a PEG linker (AuNP-PEG-Glu). The synthetic path was optimized to obtain nanoparticles of controlled sizes. zeta-potential and dynamic light scattering measurements allowed assessment of the nanodimension, dispersity, surface charge, and stability of our GNPs. Confocal microscopy demonstrated qualitatively that glucose molecules are successfully bonded to GNP surfaces. For our study, we selected nanoparticles with diameter in a range that maximizes the internalization efficiency in cells (40 nm). A detailed investigation about the biophysical proprieties of AuNP-PEG-Glu was carried out by means of fluorescence correlation spectroscopy (FCS) and orbital tracking techniques. This work gives new insights about the uptake mechanism of gold nanoparticles capped with glucose molecules. PMID- 27935717 TI - The Role of Unconventional Hydrogen Bonds in Determining BII Propensities in B DNA. AB - An accurate understanding of DNA backbone transitions is likely to be the key for elucidating the puzzle of the intricate sequence-dependent mechanical properties that govern most of the biologically relevant functions of the double helix. One factor believed to be important in indirect recognition within protein-DNA complexes is the combined effect of two DNA backbone torsions (epsilon and zeta) which give rise to the well-known BI/BII conformational equilibrium. In this work we explain the sequence-dependent BII propensity observed in RpY steps (R = purine; Y = pyrimidine) at the tetranucleotide level with the help of a previously undetected C-H...O contact between atoms belonging to adjacent bases. Our results are supported by extensive multimicrosecond molecular dynamics simulations from the Ascona B-DNA Consortium, high-level quantum mechanical calculations, and data mining of the experimental structures deposited in the Protein Data Bank. PMID- 27935718 TI - Emergence of Solvent-Separated Na+-Cl- Ion Pair in Salt Water: Photoelectron Spectroscopy and Theoretical Calculations. AB - Solvation of salts in water is a fundamental physical chemical process, but the underlying mechanism remains unclear. We investigated the contact ion pair (CIP) to solvent-separated ion pair (SSIP) transition in NaCl(H2O)n clusters with anion photoelectron spectroscopy and ab initio calculations. It is found that the SSIP type of structures show up at n = 2 for NaCl-(H2O)n anions. For neutral NaCl(H2O)n, the CIP structures are dominant at n < 9. At n = 9-12, the CIP structures and SSIP structures of NaCl(H2O)n are nearly degenerate in energy, coincident to the H2O:NaCl molar ratio of NaCl saturated solution and implying that the CIP and SSIP structures can coexist in concentrated solutions. These results are useful for understanding the solvation of salts at the molecular level. PMID- 27935719 TI - Natural Gas Evolution in a Gas Hydrate Melt: Effect of Thermodynamic Hydrate Inhibitors. AB - Natural gas extraction from gas hydrate sediments by injection of hydrate inhibitors involves the decomposition of hydrates. The evolution of dissolved gas from the hydrate melt is an important step in the extraction process. Using classical molecular dynamics simulations, we study the evolution of dissolved methane from its hydrate melt in the presence of two thermodynamic hydrate inhibitors, NaCl and CH3OH. An increase in the concentration of hydrate inhibitors is found to promote the nucleation of methane nanobubbles in the hydrate melt. Whereas NaCl promotes bubble formation by enhancing the hydrophobic interaction between aqueous CH4 molecules, CH3OH molecules assist bubble formation by stabilizing CH4 bubble nuclei formed in the solution. The CH3OH molecules accumulate around the nuclei leading to a decrease in the surface tension at their interface with water. The nanobubbles formed are found to be highly dynamic with frequent exchange of CH4 molecules between the bubble and the surrounding liquid. A quantitative analysis of the dynamic behavior of the bubble is performed by introducing a unit step function whose value depends on the location of CH4 molecules with respect to the bubble. It is observed that an increase in the concentration of thermodynamic hydrate inhibitors reduces the exchange process, making the bubble less dynamic. It is also found that for a given concentration of the inhibitor, larger bubbles are less dynamic compared to smaller ones. The dependence of the dynamic nature of nanobubbles on bubble size and inhibitor concentration is correlated with the solubility of CH4 and the Laplace pressure within the bubble. The effect of CO2 on the formation of nanobubble in the CH4-CO2 mixed gas hydrate melt in the presence of inhibitors is also examined. The simulations show that the presence of CO2 molecules significantly reduces the induction time for methane nanobubble nucleation. The role of CO2 in the early nucleation of bubble is explained based on the interaction between the bubble and the dissolved CO2 molecules. PMID- 27935721 TI - Rh-Mediated Enantioselective Synthesis, Crystal Structures, and Photophysical/Chiroptical Properties of Phenanthrenol-Based [9]Helicene-like Molecules. AB - The enantioselective synthesis of phenanthrenol-based [9]helicene-like molecules has been achieved via the rhodium-mediated intramolecular [2 + 2 + 2] cycloadditions of 3-phenanthrenol-linked triynes. Crystal structures and photophysical/chiroptical properties of these [9]helicene-like molecules were compared with the corresponding [7]helicene-like molecules. PMID- 27935720 TI - Theoretical Insights into the Reaction and Inhibition Mechanism of Metal Independent Retaining Glycosyltransferase Responsible for Mycothiol Biosynthesis. AB - Understanding enzymatic reactions with atomic resolution has proven in recent years to be of tremendous interest for biochemical research, and thus, the use of QM/MM methods for the study of reaction mechanisms is experiencing a continuous growth. Glycosyltransferases (GTs) catalyze the formation of glycosidic bonds, and are important for many biotechnological purposes, including drug targeting. Their reaction product may result with only one of the two possible stereochemical outcomes for the reacting anomeric center, and therefore, they are classified as either inverting or retaining GTs. While the inverting GT reaction mechanism has been widely studied, the retaining GT mechanism has always been controversial and several questions remain open to this day. In this work, we take advantage of our recent GPU implementation of a pure QM(DFT-PBE)/MM approach to explore the reaction and inhibition mechanism of MshA, a key retaining GT responsible for the first step of mycothiol biosynthesis, a low weight thiol compound found in pathogens like Mycobacterium tuberculosis that is essential for its survival under oxidative stress conditions. Our results show that the reaction proceeds via a front-side SNi-like concerted reaction mechanism (DNAN in IUPAC nomenclature) and has a 17.5 kcal/mol free energy barrier, which is in remarkable agreement with experimental data. Detailed analysis shows that the key reaction step is the diphosphate leaving group dissociation, leading to an oxocarbenium-ion-like transition state. In contrast, fluorinated substrate analogues increase the reaction barrier significantly, rendering the enzyme effectively inactive. Detailed analysis of the electronic structure along the reaction suggests that this particular inhibition mechanism is associated with fluorine's high electronegative nature, which hinders phosphate release and proper stabilization of the transition state. PMID- 27935722 TI - Nonlocal Spin Diffusion Driven by Giant Spin Hall Effect at Oxide Heterointerfaces. AB - A two-dimensional electron gas emerged at a LaAlO3/SrTiO3 interface is an ideal system for "spin-orbitronics" as the structure itself strongly couple the spin and orbital degree of freedom through the Rashba spin-orbit interaction. One of core experiments toward this direction is the nonlocal spin transport measurement, which has remained elusive due to the low spin injection efficiency to this system. Here we bypass the problem by generating a spin current not through the spin injection from outside but instead through the inherent spin Hall effect and demonstrate the nonlocal spin transport. The analysis on the nonlocal spin voltage, confirmed by the signature of a Larmor spin precession and its length dependence, displays that both D'yakonov-Perel' and Elliott-Yafet mechanisms involve in the spin relaxation at low temperature. Our results show that the oxide heterointerface is highly efficient in spin-charge conversion with exceptionally strong spin Hall coefficient gamma ~ 0.15 +/- 0.05 and could be an outstanding platform for the study of coupled charge and spin transport phenomena and their electronic applications. PMID- 27935723 TI - Remote Photoregulated Ring Gliding in a [2]Rotaxane via a Molecular Effector. AB - A molecular barbiturate messenger, which is reversibly released/captured by a photoswitchable artificial molecular receptor, is shown to act as an effector to control ring gliding on a distant hydrogen-bonding [2]rotaxane. Thus, light driven chemical communication governing the operation of a remote molecular machine is demonstrated using an information-rich neutral molecule. PMID- 27935724 TI - Reversibly Tunable Lower Critical Solution Temperature Behavior Induced by H Bonded Aromatic Amide Macrocycle and Imidazolium Host-Guest Complexation. AB - A new supramolecular host-guest motif comprising an H-bonded aromatic amide macrocycle and imidazolium cation based ionic liquids was developed, which allows tunable binding affinity via altering N-substitution or counterions. This host guest system exhibits lower critical solution temperature behavior that can be precisely controlled by adjusting concentration, competitive guest, and acid/base. The demonstrated separation of two organic dyes with the supramolecular complex holds promising applications in separation science. PMID- 27935725 TI - van der Waals Stacking-Induced Topological Phase Transition in Layered Ternary Transition Metal Chalcogenides. AB - Novel materials with nontrivial electronic and photonic band topology are crucial for realizing novel devices with low power consumption and heat dissipation and quantum computing free of decoherence. Here, we theoretically predict a novel class of ternary transition metal chalcogenides that exhibit dual topological characteristics, quantum spin Hall insulators (QSHIs) in their two-dimensional (2D) monolayers and topological Weyl semimetals in their 3D noncentrosymmetric crystals upon van der Waals (vdW) stacking. Remarkably, we find that one can create and annihilate Weyl fermions and realize the transition between Type-I and Type-II Weyl fermions by tuning vdW interlayer spacing, providing the missing physical picture of the evolution from 2D QSHIs to 3D Weyl semimetals. Our results also show that these materials possess excellent thermodynamic stability and weak interlayer binding; some of them were synthesized two decades ago, implying their great potentials for experimental synthesis, characterization, and vdW heterostacking. Moreover, their ternary nature will offer more tunability for electronic structure by controlling different stoichiometry and valence charges. Our findings provide an ideal materials platform for realizing QSH effect and exploring fundamental topological phase transition and will open up a variety of new opportunities for two-dimensional materials and topological materials research. PMID- 27935727 TI - How to write a health policy brief. AB - Although many health care professionals are interested in health policy, relatively few have training in how to utilize their clinical experience and scientific knowledge to impact policy. Developing a policy brief is one approach that health professionals may use to draw attention to important evidence that relates to policy. This article offers guidance on how to write a policy brief by outlining 4 steps: (a) define the problem, (b) state the policy, (c) make your case, and (d) discuss the impact. The steps and tips offer a starting point for health care professionals interested in health policy and translating research or clinical experience to impact policy. (PsycINFO Database Record PMID- 27935728 TI - On sanction-goal justifications: How and why deterrence justifications undermine rule compliance. AB - Authorities frequently justify their sanctions as attempts to deter people from rule breaking. Although providing a sanction justification seems appealing and harmless, we propose that a deterrence justification decreases the extent to which sanctions are effective in promoting rule compliance. We develop a theoretical model that specifies how and why this occurs. Consistent with our model, 5 experiments demonstrated that-compared with sanctions provided without a justification or sanctions provided with a just-deserts justification-sanction effectiveness decreased when sanctions were justified as attempts to deter people from rule breaking. This effect was mediated by people feeling distrusted by the authority. We further demonstrated that (a) the degree to which deterrence fostered distrust was attenuated when the sanction was targeted at others (instead of the participant) and (b) the degree to which distrust undermined rule compliance was attenuated when the authority was perceived as legitimate. We discuss the practical implications for authorities tasked with promoting rule compliance, and the theoretical implications for the literature on sanctions, distrust, and rule compliance. (PsycINFO Database Record PMID- 27935726 TI - Automatic avoidance tendencies for alcohol cues predict drinking after detoxification treatment in alcohol dependence. AB - Alcohol dependence is characterized by conflict between approach and avoidance motivational orientations for alcohol that operate in automatic and controlled processes. This article describes the first study to investigate the predictive validity of these motivational orientations for relapse to drinking after discharge from alcohol detoxification treatment in alcohol-dependent patients. One hundred twenty alcohol-dependent patients who were nearing the end of inpatient detoxification treatment completed measures of self-reported (Approach and Avoidance of Alcohol Questionnaire; AAAQ) and automatic (modified Stimulus Response Compatibility task) approach and avoidance motivational orientations for alcohol. Their drinking behavior was assessed via telephone follow-ups at 2, 4, and 6 months after discharge from treatment. Results indicated that, after controlling for the severity of alcohol dependence, strong automatic avoidance tendencies for alcohol cues were predictive of higher percentage of heavy drinking days (PHDD) at 4-month (beta = 0.22, 95% CI [0.07, 0.43]) and 6-month (beta = 0.22, 95% CI [0.01, 0.42]) follow-ups. We failed to replicate previous demonstrations of the predictive validity of approach subscales of the AAAQ for relapse to drinking, and there were no significant predictors of PHDD at 2-month follow-up. In conclusion, strong automatic avoidance tendencies predicted relapse to drinking after inpatient detoxification treatment, but automatic approach tendencies and self-reported approach and avoidance tendencies were not predictive in this study. Our results extend previous findings and help to resolve ambiguities with earlier studies that investigated the roles of automatic and controlled cognitive processes in recovery from alcohol dependence. (PsycINFO Database Record PMID- 27935730 TI - Patterns of pregnancy and postpartum depressive symptoms: Latent class trajectories and predictors. AB - Depressive symptoms among pregnant and postpartum women are common. However, recent studies indicate that depressive symptoms in the perinatal period do not follow a uniform course, and investigations of the heterogeneity of time courses and associated factors are needed. The aim of this study was to explore whether depressive symptoms in the perinatal period could be categorized into several distinct trajectories of symptom development among subgroups of perinatal women, and to identify predictors of these trajectory groups. The study used data from 1,036 Norwegian women participating in a community-based prospective study from midpregnancy until 12-months postpartum. Depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale at 7 time points (4 during pregnancy). Partner-related attachment, stress, childhood adversities, pregnancy-related anxiety, previous psychopathology, and socioeconomic conditions were assessed at enrollment. By means of growth mixture modeling based on piecewise growth curves, 4 classes of depressive symptom trajectories were identified, including (a) pregnancy only (4.4%); (b) postpartum only (2.2%); (c) moderate-persistent (10.5%); and (d) minimum symptoms (82.9%) classes. Multinomial logistic regression analyses showed that membership in the pregnancy only and postpartum only classes primarily was associated with pregnancy-related anxiety and previous psychopathology, respectively, whereas the moderate-persistent class was associated with diverse psychosocial adversity factors. Findings suggest heterogeneity in temporal patterns of elevated depressive mood, relating specific trajectories of time courses with distinct adversity factors. Researchers and clinicians should be aware of possible multiple courses of elevated perinatal depressive mood, and inquire about possible diverse adversity factors, aberrant pathways, and prognoses. (PsycINFO Database Record PMID- 27935729 TI - Abnormal neural responses to feedback in depressed adolescents. AB - Depression rates surge in adolescence, particularly among females. Recent findings suggest that depressed adolescents are characterized by hypersensitivity to negative outcomes and blunted responsiveness to rewards. However, our understanding of the pathophysiology and time course of these abnormalities remains limited. Due to their high temporal resolution, event-related potentials (ERPs) provide an ideal probe to investigate these processes. In the present study, healthy (n = 25) and depressed (n = 26) female adolescents (13-18 years) completed a gambling task during 128-channel ERP recording. Time-domain analyses focused on ERPs linked to initial processing of negative versus rewarding outcomes (feedback-related negativity; FRN), and later, elaborative processing (late positive potential; LPP). Additionally, time-frequency analyses were used to decompose the FRN into its 2 constituent neural signals: loss-related theta and reward-related delta activity, thereby allowing us to separately probe these 2 putative mechanisms underlying FRN abnormalities in depression. Relative to healthy adolescents, depressed youth showed potentiated FRN (loss vs. reward) responses. Time-frequency analyses revealed that this group difference in the FRN was driven by increased loss-related theta activity in depressed youth, and not by reward-related delta activity. For the LPP, healthy adolescents exhibited sustained positivity to rewards versus losses, whereas depressed adolescents showed the opposite pattern. Moreover, an enhanced LPP to losses was associated with rumination. In summary, the LPP may be a sensitive probe of depressive rumination, whereas FRN-linked theta activity may represent a neural marker of hypersensitivity to negative outcomes in depressed youth. Implications for treatment and future ERP research are discussed. (PsycINFO Database Record PMID- 27935731 TI - Two Bayesian tests of the GLOMOsys Model. AB - Priming is arguably one of the key phenomena in contemporary social psychology. Recent retractions and failed replication attempts have led to a division in the field between proponents and skeptics and have reinforced the importance of confirming certain priming effects through replication. In this study, we describe the results of 2 preregistered replication attempts of 1 experiment by Forster and Denzler (2012). In both experiments, participants first processed letters either globally or locally, then were tested using a typicality rating task. Bayes factor hypothesis tests were conducted for both experiments: Experiment 1 (N = 100) yielded an indecisive Bayes factor of 1.38, indicating that the in-lab data are 1.38 times more likely to have occurred under the null hypothesis than under the alternative. Experiment 2 (N = 908) yielded a Bayes factor of 10.84, indicating strong support for the null hypothesis that global priming does not affect participants' mean typicality ratings. The failure to replicate this priming effect challenges existing support for the GLOMOsys model. (PsycINFO Database Record PMID- 27935732 TI - Active perspective taking induces flexible use of self-knowledge during social inference. AB - Social life hinges on the ability to infer others' mental states. By default, people often recruit self-knowledge during social inference, particularly for others who are similar to oneself. How do people's active perspective-taking efforts-deliberately imagining another's perspective-affect self-knowledge use? In 2 experiments, we test the flexible self-application hypothesis: that the application of self-knowledge to a perspective-taking target differs based on that person's similarity to oneself. We found consistent evidence that, when making inferences about dissimilar others, perspective taking increased the projection of one's own traits and preferences to those targets, relative to a control condition. When making inferences about similar others, however, perspective taking decreased projection. These findings suggest that self-target similarity critically shapes the inferential processes triggered by active perspective-taking efforts. (PsycINFO Database Record PMID- 27935733 TI - Correction to Kane et al. (2016). AB - Reports an error in "Individual differences in the executive control of attention, memory, and thought, and their associations with schizotypy" by Michael J. Kane, Matt E. Meier, Bridget A. Smeekens, Georgina M. Gross, Charlotte A. Chun, Paul J. Silvia and Thomas R. Kwapil (Journal of Experimental Psychology: General, 2016[Aug], Vol 145[8], 1017-1048). There were errors in Table 3 and Table 7 (these transcription errors were limited to descriptive statistics in the Tables and did not affect any inferential statistics). In Table 3, the ARRO-TUT and LETT-TUT variables had incorrect values for Mean [95% CI], SD, Skew, Kurtosis, and N. In Table 7, the same values (plus Min and Max) were incorrect for the SEM-SART variable. The correct values for these measures are presented in the correction (the values for Min and Max were correct as set in Table 3, but are repeated below for clarity). (The following abstract of the original article appeared in record 2016-29680-001.) A large correlational study took a latent variable approach to the generality of executive control by testing the individual-differences structure of executive-attention capabilities and assessing their prediction of schizotypy, a multidimensional construct (with negative, positive, disorganized, and paranoid factors) conveying risk for schizophrenia. Although schizophrenia is convincingly linked to executive deficits, the schizotypy literature is equivocal. Subjects completed tasks of working memory capacity (WMC), attention restraint (inhibiting prepotent responses), and attention constraint (focusing visual attention amid distractors), the latter 2 in an effort to fractionate the "inhibition" construct. We also assessed mind-wandering propensity (via in-task thought probes) and coefficient of variation in response times (RT CoV) from several tasks as more novel indices of executive attention. WMC, attention restraint, attention constraint, mind wandering, and RT CoV were correlated but separable constructs, indicating some distinctions among "attention control" abilities; WMC correlated more strongly with attentional restraint than constraint, and mind wandering correlated more strongly with attentional restraint, attentional constraint, and RT CoV than with WMC. Across structural models, no executive construct predicted negative schizotypy and only mind wandering and RT CoV consistently (but modestly) predicted positive, disorganized, and paranoid schizotypy; stalwart executive constructs in the schizophrenia literature-WMC and attention restraint-showed little to no predictive power, beyond restraint's prediction of paranoia. Either executive deficits are consequences rather than risk factors for schizophrenia, or executive failures barely precede or precipitate diagnosable schizophrenia symptoms. (PsycINFO Database Record PMID- 27935734 TI - Exposure to justice diminishes moral perception. AB - Evidence suggests that people have a lower threshold for the conscious awareness of moral words. Given the potential motivational relevance of moral concerns, the authors hypothesized and found that motivational relevance of moral stimuli enhanced the detection of moral words. People who saw a CrimeStoppers advertisement in which a majority (vs. minority) of wanted murderers had been brought to justice exhibited reduced detection of moral words (Experiment 1). Similarly, people who read that an assailant was arrested (vs. escaped punishment) exhibited reduced detection of moral words (Experiment 2). In both experiments, the effect of justice motives on moral word detection was specific to words presented near (vs. distant) to the threshold for perceptual awareness. These findings suggest that satiating (vs. activating) justice motives can reduce the frequency with which moral (vs. non-moral) words reach perceptual awareness. Implications for models of moral psychology, particularly the role of perception in morality, are discussed. (PsycINFO Database Record PMID- 27935735 TI - Pharmacokinetic and Pharmacodynamic Properties of Lisdexamfetamine in Adults with Attention-Deficit/Hyperactivity Disorder. AB - BACKGROUND: Lisdexamfetamine (LDX) is a prodrug and consists of an active moiety, d-amphetamine, bound to lysine. Clinically, d-amphetamine becomes available postcleavage of the prodrug in the blood stream. Clinical effects of LDX in attention-deficit/hyperactivity disorder (ADHD) have been shown to persist up to 14 hours; however, pharmacokinetic (PK) data of LDX and amphetamine in ADHD adults are not currently available. OBJECTIVES: (1) To examine PK data of LDX and d-amphetamine in plasma and (2) to compare such PK data with Time-Sensitive ADHD Symptom Scale (TASS) ratings (PK vs. pharmacodynamic [PD]). METHODS: Plasma d amphetamine/LDX levels and TASS ratings were obtained immediately before morning dosing and then 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdosing in 21 adults with ADHD treated with 5 weeks of single-blind LDX up to 70 mg/day (after 1 week single-blind placebo). ADHD Rating Scale scores were obtained at the beginning of the visit, before morning dosing. RESULTS: LDX levels peaked at 1.5 hours after administration (Tmax) and then rapidly declined (levels were negligible at 6 hours and area under the plasma concentration versus time curve, AUC = 45.9, Cmax = 25.0, and half-life [t1/2] = 0.5 hours). Levels of d-amphetamine peaked at (Tmax) 4.4 hours and then slowly declined (AUC = 641.6, Cmax = 67.9, and t1/2 = 17.0 hours). No statistically significant correlations were seen between d amphetamine levels and TASS scores. CONCLUSIONS: (1) Prodrug LDX levels peaked fairly rapidly and declined, while d-amphetamine levels peaked 3 hours later than LDX levels and persisted throughout the day and (2) the absence of PK/PD correlations between PK data and TASS ratings may be due to the subjects being tested in a controlled nonattention demanding environment. PMID- 27935737 TI - Low-Level Laser Therapy for Reducing the Hip, Waist, and Upper Abdomen Circumference of Individuals with Obesity. AB - OBJECTIVE: To assess the effectiveness of low-level laser therapy (LLLT) for reducing hip, thigh, and abdomen circumference of individuals with body-mass index (BMI) between 30 and 40 kg/m2. BACKGROUND: Previous studies demonstrated the effectiveness of LLLT for reducing body circumference in the hips, thighs, and abdomen of nonobese individuals with a BMI <30 kg/m2. METHODS: In this randomized, double-blind sham-controlled study, obese, but otherwise healthy, individuals were randomized to undergo 30-min LLLT (n = 28) or sham treatments (n = 25) three times weekly for 4 weeks. Body measurements were obtained after 2 and 4 weeks of treatment and 2 weeks post-treatment ( ClinicalTrials.gov Identifier: NCT01821352). RESULTS: After 4 weeks, 20 LLLT-treated subjects (71.43%) achieved >=7.2 cm decrease in combined measurements versus three sham-treated subjects (12%; p < 0.00005). The mean (standard deviation) decrease in combined measurement for LLLT-treated subjects was 10.52 (7.59) cm (p < 0.0001 vs. baseline) versus 1.80 (3.20) cm for sham-treated subjects. Among subjects with a combined >=7.2 cm decrease, the mean total decrease 2 weeks post-treatment was 15.21 cm. There were no adverse events. CONCLUSIONS: Based on these results, the device was cleared by the U.S. Food and Drug Administration as a noninvasive esthetic treatment for reduction of circumference of hips, waist, and upper abdomen when applied to individuals with a BMI between 30 and 40 kg/m2. PMID- 27935736 TI - Pioglitazone and Risk for Bone Fracture: Safety Data From a Randomized Clinical Trial. AB - Context: Pioglitazone reduces cardiovascular risk in nondiabetic patients after an ischemic stroke or transient ischemic attack (TIA) but is associated with increased risk for bone fracture. Objective: To characterize fractures associated with pioglitazone by location, mechanism, severity, timing, and sex. Design, Setting, and Patients: Patients were 3876 nondiabetic participants in the Insulin Resistance Intervention after Stroke trial randomized to pioglitazone or placebo and followed for a median of 4.8 years. Fractures were identified through quarterly interviews. Results: At 5 years, the increment in fracture risk between pioglitazone and placebo groups was 4.9% [13.6% vs 8.8%; hazard ratio (HR), 1.53; 95% confidence interval (CI), 1.24 to 1.89). In each group, ~80% of fractures were low energy (i.e., resulted from fall) and 45% were serious (i.e., required surgery or hospitalization). For serious fractures most likely to be related to pioglitazone (low energy, nonpathological), the risk increment was 1.6% (4.7% vs 3.1%; HR, 1.47; 95% CI, 1.03 to 2.09). Increased risk for any fracture was observed in men (9.4% vs 5.2%; HR, 1.83; 95% CI, 1.36 to 2.48) and women (14.9% vs 11.6%; HR, 1.32; 95% CI, 0.98 to 1.78; interaction P = 0.13). Conclusions: Fractures affected 8.8% of placebo-treated patients within 5 years after an ischemic stroke or TIA. Pioglitazone increased the absolute fracture risk by 1.6% to 4.9% and the relative risk by 47% to 60%, depending on fracture classification. Our analysis suggests that treatments to improve bone health and prevent falls may help optimize the risk/benefit ratio for pioglitazone. PMID- 27935738 TI - The coronary sinus reducer: clinical evidence and technical aspects. AB - INTRODUCTION: Chronic refractory angina is often a disabling condition, predominantly due to severe obstructive coronary artery disease, that is inadequately controlled by optimal medical therapy and not amenable to further percutaneous or surgical revascularization. mortality rates associated with this condition are relatively low in clinically stable patients. however, it is associated with a high hospitalization rate and a reduction in both exercise capacity and quality of life. due to the paucity of available treatment options, there is an unmet need for new therapies for these patients and for a reduction in the associated economic healthcare burden. Areas covered: This review is focusing on the clinical evidence and technical aspects of this new therapeutic modality in refractory angina patients unsuitable for revascularization. Expert commentary: The Coronary Sinus Reducer (Neovasc Inc. Richmond B.C., Canada) is a new percutaneous device designed to achieve a controlled narrowing of the coronary sinus that may alleviate myocardial ischemia, possibly by redistributing blood from the less ischemic sub-epicardium to the more ischemic sub-endocardium, or by neoangiogenesis. Recently, a randomized, double-blind, multi-center clinical trial demonstrated a benefit in improving symptoms in 104 refractory angina patients, when compared to placebo. PMID- 27935739 TI - The Pregnancy-Breastfeeding Interface. PMID- 27935740 TI - Assessment of Port-Specific Pain After Gynecological Laparoscopy: A Prospective Cohort Clinical Trial. AB - OBJECTIVE: To determine the association between pain related to laparoscopic port sites and different incision sizes after gynecological laparoscopy. DESIGN: Prospective, cohort trial Canadian Task Force classification 2-II. SETTING: Zhejiang Provincial People's Hospital, China. PATIENTS: Two hundred patients who underwent three-port laparoscopic gynecological procedures for benign indications. INTERVENTIONS: In total, 200 patients underwent laparoscopic gynecological procedures. Each patient had three incisions, one in the left lower abdomen, measuring 5, 10, or 15 mm based on the type of surgery, another measuring 10 mm in the umbilical port, and the third one measuring 5 mm, in the right lower abdomen. Port-related pain was registered and measured by visual analogue score (VAS). MEASUREMENTS AND MAIN RESULTS: The VAS score showed statistically significant differences between 5-, 10-, and 15-mm port sites at each time point (24 and 72 hours) (P < .05); the score elevated as the size of the incision increased. Pain was significantly lower at the umbilical port sites at 24 hours than in the left lower abdominal port sites with incisions of the same (10 mm) size (P = .013) and also significantly lower in the right lower abdominal port sites than in the left lower abdominal port sites with incisions of the same (5 mm) size (P = .041). Specimen extraction port significantly affected the 24-hour pain intensity, while specimen extraction port, surgical time, and previous abdominal surgery affected the 72-hour pain intensity. CONCLUSIONS: The size of port sites is the most important factor related to port specific pain. PMID- 27935741 TI - Barriers to evidence-based physician decision-making at the point of care: a narrative literature review. AB - We conduct a narrative literature review using four real-world cases of clinical decisions to show how barriers to the use of evidence-based medicine affect physician decision-making at the point of care, and where adjustments could be made in the healthcare system to address these barriers. Our four cases constitute decisions typical of the types physicians make on a regular basis: diagnostic testing, initial treatment and treatment monitoring. To shed light on opportunities to improve patient care while reducing costs, we focus on barriers that could be addressed through changes to policy and/or practice at a particular level of the healthcare system. We conclude by relating our findings to the passage of the Medicare Access and Children's Health Insurance Program Reauthorization Act in April 2015. PMID- 27935743 TI - 2016 TERMIS - Americas Conference and Exhibition San Diego, CA December 11-14, 2016. PMID- 27935742 TI - Risk factors for premenstrual asthma: a systematic review and meta-analysis. AB - INTRODUCTION: Asthma in women can deteriorate in specific phases during the menstrual cycle. Deterioration in the premenstrual phase (increase in symptoms or deterioration in peak flow measurements) is known as premenstrual asthma. The etiology remains mostly unknown. Areas covered: This paper systematically reviews risk factors for premenstrual asthma. Medline, Embase, CINAHL, Scopus, Web of Science, LILACS and secondary sources were searched. The selection criteria were met by 20 articles. Expert commentary: Women with pre-menstrual asthma are older, have more severe asthma, a higher body-mass index, a longer duration of asthma and a greater likelihood of aspirin sensitive asthma. They more often have dysmenorrhea, premenstrual syndrome, shorter menstrual cycles, and longer menstrual bleeding. The role of hormone levels and systemic inflammation remains unclear. PMID- 27935745 TI - Does Abnormal Laboratory Results Notification with the Short Message Service Shorten Length of Stay in the Pediatric Emergency Department Observation Unit? AB - BACKGROUND: A new age in communications began with the entry into use of cell phones and their applications. Cell phones and their various applications must be actively used in patient monitoring in the healthcare system. INTRODUCTION: The purpose of this study was to determine the length of stay in the pediatric emergency department observation unit (PEDOU) based upon the notification of abnormal laboratory results (ALRs) via the short message service (SMS). MATERIALS AND METHODS: Patients with ALRs notified through the SMS (April-May-June 2015: study period) were evaluated retrospectively, and those admitted to hospital after such notification were enrolled as the study group (SG). Patients presenting to the pediatric emergency department (April-May-June 2014: control period), whose ALRs were not notified through the SMS, and who were hospitalized for treatment, were enrolled as the control group (CG). Age, sex, length of stay in the PEDOU (min), admission diagnosis, and receiving department were recorded for both groups. RESULTS: Number of patients monitored in the PEDOU was 8584 during the study period and 8507 during the control period (p = 0.27). Length of stay of patients monitored in the PEDOU during the control period (n = 8507) and study period (n = 8584) was 136.4 and 133.5 min, respectively (p = 0.92). One hundred forty-seven patients were enrolled as the SG and 154 as the CG. Length of stay in the PEDOU was 221.1 +/- 86.9 (65-542) min in the CG and 154.8 +/- 76.6 (15-442) min in the SG (p < 0.001, 95% confidence interval: 47.5-84.8). CONCLUSIONS: Notification of ALRs through the SMS does not affect length of stay in the PEDOU. Use of this method reduces length of stay of patients who require more rapid hospitalization. PMID- 27935746 TI - Effect of restaurant types on compensation claims for work-related musculoskeletal disorders in France. AB - OBJECTIVES: The economic burden of work-related musculoskeletal disorders (WMSDs) is industry specific. The objective was to analyse compensation claims for WMSDs among restaurant workers in France taking into account the type of restaurant. METHODS: Data for 2014 were obtained from the French National Health Insurance Fund for Salaried Workers. A chi-square test was used to compare claims, incapacity and lost work day rates in different types of restaurant. RESULTS: Prevalence for WMSDs differed significantly by the type of kitchen: collective restaurant (7.2/1000 workers), traditional restaurant (1.7/1000), and fast food restaurant (1.0/1000). There were more male claimants in traditional restaurant workers (51.0%) than in collective restaurant workers (40.1%) but more female claimants in collective restaurant workers (50.1%) than in traditional restaurant workers (39.4%). Permanent incapacity was significantly more prevalent in collective restaurant workers (49.6%), than in traditional (41.9%) and fast food (8.5%) restaurant workers. In collective restaurant workers, as a percentage, claims, permanent incapacity and lost work days increased with age range or work experience. CONCLUSIONS: Prevalence for WMSDs and therefore incapacity and lost work days are different according to the type of restaurant. Preventive strategies should take these differences into consideration. PMID- 27935747 TI - Treatment Decision-Making Capacity in Children and Adolescents Hospitalized for an Acute Mental Disorder: The Role of Cognitive Functioning and Psychiatric Symptoms. AB - OBJECTIVE: This study was conducted to assess treatment decision-making capacity (TDMC) in a child and adolescent psychiatric sample and to verify possible associations between TDMC, psychiatric symptom severity, and cognitive functioning. METHODS: Twenty-two consecutively recruited patients hospitalized for an acute mental disorder, aged 11-18 years, underwent measurement of TDMC by the MacArthur Competence Assessment Tool for Treatment (MacCAT-T). The MacCAT-T interview focused on patients' current treatment, which comprised second generation antipsychotics (45.5%), first-generation antipsychotics (13.6%), antiepileptic drugs used as mood stabilizers or lithium carbonate (45.5%), selective serotonin reuptake inhibitors (32%), and benzodiazepines (18%). We moreover measured cognitive functioning (Wechsler Intelligence Scale for Children III) and psychiatric symptom severity (Brief Psychiatric Rating Scale v 4.0). RESULTS: Patients' TDMC varied within the sample, but MacCAT-T scores were good in the sample overall, suggesting that children and adolescents with severe mental disorders could be competent to consent to treatment. The TDMC proved independent of psychiatric diagnosis while being positively associated with cognitive functioning and negatively with excitement. CONCLUSION: The MacCAT-T proved feasible for measuring TDMC in a child and adolescent psychiatric sample. TDMC in minors with severe mental disorders was not necessarily impaired. These results deserve reconsidering the interplay between minors and surrogate decision makers as concerning treatment decisions. PMID- 27935749 TI - From the Journals. AB - NOISE AND WOUND HEALING FOUR-LAYER BANDAGE STUDY MANAGEMENT SYSTEMS NECROTISING FASCIITIS DISFIGURING INJURIES. PMID- 27935750 TI - Wound infection: Managing wound infection. AB - Many dilemmas trouble clinicians working with infected and non-healing wounds and there is still considerable debate as to what the aim of treating such patients should be. Should it be to eradicate specific pathogenic organisms? Or should it be to reduce the bacterial burden present on open wounds? PMID- 27935752 TI - Editorial. AB - The management of wound infection Pressure sores. PMID- 27935751 TI - Clinical audit and effective change in leg ulcer services. AB - An audit of clinical leg ulcer services was undertaken in South Bedfordshire and was followed by a process of implementation using research-based methods; a re audit was conducted 18 months later. Using an adaptation of the Riverside model, patients were referred to community leg ulcer clinics. They were assessed using Doppler ultrasound; those with ABPI >0.8 were treated using a high-compression four-layer bandage system. Those with ABPI 0.6-0.8 were treated using reduced compression, and those with ABPI <0.6 were sent to their GP for referral for specialist opinion. In October 1993, the average cost of consumables for each patient was L8.53, and this rose to L10.14 in May 1995. However, patients treated in community clinics had a reduced cost of consumables of L7.91 compared with L10.78 for patients treated at home. There was also a corresponding reduction in weekly treatments and an overall reduction in nursing time to treat patients. In 111 patients (134 limbs) treated by high compression in the community clinics, cumulative percentage healing was 54% after 12 weeks and 68% after 24 weeks. Although these results were lower than those achieved in the Riverside project, much of the difference can be explained by the different patient populations and ulcer duration. The results support a system of care which offers rationalisation of service, staff training and research-based effective assessment and treatment. PMID- 27935748 TI - ATF4 Targets RET for Degradation and Is a Candidate Tumor Suppressor Gene in Medullary Thyroid Cancer. AB - Context: Medullary thyroid cancer (MTC) is an aggressive tumor that harbors activating mutations of the RET proto-oncogene. We previously reported that RET inhibits transcriptional activity of ATF4, the master regulator of the stress response pathway, to prevent cell death. Objective: We hypothesized that loss of function of ATF4 plays a role in initiation of MTC. Design: Targeted deletion of Atf4 in mice was used to assess ATF4 function in the thyroid gland. ATF4 overexpression was achieved by adenoviral and lentiviral vectors. We used immunohistochemical analysis and western blotting of MTC tumors to determine protein levels of RET and ATF4 and the Kaplan-Meier method to determine their association with clinical outcome. Results: Targeted deletion of Atf4 in mice causes C-cell hyperplasia, a precancerous lesion for MTC. Forced ATF4 expression decreased survival of MTC cells and blocked the activation of RET downstream signaling pathways (phosphorylated ERK, phosphorylated AKT, and p70S6K). ATF4 knockdown decreased sensitivity to tyrosine kinase inhibitor-induced apoptosis. Moreover, ATF4 expression decreased RET protein levels by promoting RET ubiquitination. We found decreased or loss of ATF4 in 52% of MTC tumors (n = 39) compared with normal thyroid follicle cells. A negative correlation was observed between RET and ATF4 protein levels in MTC tumors, and low ATF4 expression was associated with poor overall survival in patients with MTC. Conclusions: ATF4 was identified as a negative regulator of RET, a candidate tumor suppressor gene, and may be a molecular marker that distinguishes patients at high risk of MTC from those with a longer survival prognosis. PMID- 27935753 TI - Healing properties of calcium alginate dressings. AB - In a prospective, randomised, controlled trial of 92 patients with full-thickness pressure ulcers, the efficacy of an alginate wound dressing was compared to that of an established local treatment with dextranomer paste. During treatment, a minimal 40% reduction in wound area was obtained in 74% of the patients in the alginate group and in 42% of those in the dextranomer group. The median time taken to achieve this goal was four weeks with alginate and more than eight weeks in the control group. Mean surface area reduction per week was 2.39cm2 (sd 3.54) and 0.27cm2 (sd 3.21) in the alginate and dextranomer groups respectively (p=0.0001). This difference was still highly significant when the sub-groups of almost completely healed subjects at the end of the study were considered. This striking healing efficacy of an alginate dressing suggests it possesses pharmacological properties which require further investigation. PMID- 27935754 TI - Wound infection: MRSA. AB - The proportion of Staphylococcus aureus that is methicillin resistant (MRSA) has been rising in UK hospitals over the past 10 years. In some individual hospitals this increase has been explosive. The propensity for MRSA to spread arises mainly from the following reasons: Antimicrobial selection increases the biomass of MRSA in a particular patient or patient population The organism is located on exposed body surfaces(for example, the skin and nasal mucosa) MRSA is easily transferred from patient to patient, for example via the hands of staff. PMID- 27935755 TI - Wound infection. AB - The following papers were presented at a recent master class held In association with Smith and Nephew. The first is a review of the literature on sampling bacteria; the second examines the prevention and control of MRSA; the third describes the management of wound infection and includes a delegate poll on preferred treatments. PMID- 27935756 TI - Special foot clinics for patients with diabetes. AB - Three reviewers consider the paper cited below and discuss its influence on the care of patients with diabetes who develop foot ulceration. PMID- 27935757 TI - From the Journals. AB - VENOUS LEG ULCERS AND SQUAMOUS CELL CARCINOMA LEG ULCER MANAGEMENT IN THE COMMUNITY A REAWAKENING OF TRACE-ELEMENT WOUND RESEARCH. PMID- 27935758 TI - Reviews. AB - A PRESCRIBER'S GUIDE TO DRESSINGS AND WOUND MANAGEMENT MATERIALS CLAYTON'S ELECTROTHERAPY 10th edition. PMID- 27935760 TI - Special foot clinics for patients with diabetes: Critique III. AB - The article under review is essentially a report of clinical activity, introducing what was in 1986 still a novel concept - a multidisciplinary clinic in which different specialties were represented simultaneously, and orthopaedic and vascular consultants were available for consultation; all working together as a multidisciplinary team to manage the 'at-risk foot' in patients with diabetes. PMID- 27935759 TI - Special foot clinics for patients with diabetes: Critique II. AB - This paper reports the experiences and benefits of a specialist diabetic foot clinic established in the 1980s with a grant from the British Diabetic Association. A three-year prospective study was undertaken of 239 patients attending the clinic with foot ulcers. The introduction of the clinic resulted in a high rate of ulcer healing and a reduced number of major amputations. PMID- 27935761 TI - From the Journals. AB - PLASMINOGEN ACTIVITY IN WOUND HEALING ELDERLY PEOPLE AND ENERGY REQUIREMENTS ELDERLY PEOPLE AND MEAN DAILY PROTEIN REQUIREMENTS POSTOPERATIVE ENTERAL FEEDING ISSUES IN THE SELECTION OF WOUND-HEALING DRESSINGS. PMID- 27935763 TI - Reviews. AB - STATISTICS AT SQUARE ONE (9TH EDITION). PMID- 27935762 TI - Letters. AB - LIMITATIONS OF DOPPLER ASSESSMENT TOPICAL USE OF GENTAMICIN. PMID- 27935764 TI - Morphofunctional Renal Alterations in Progeny of Mice Fed Rhodiola kirilowii Extracts or Epigallocatechin During Pregnancy and Lactation. AB - Treating infections in pregnant patients is potentially dangerous even when herbal medicines are used. Many herbal medicines, among them extracts from plants of Rhodiola genus, have antimicrobial, anti-inflammatory, and immunostimulatory properties owing to their polyphenol content; they may, however, affect fetal development due to their antiangiogenic properties. The aim of this study was to explain whether daily feeding pregnant and lactating mice with 20 mg/kg Rhodiola kirilowii aqueous (RKW) or 50% hydro-alcoholic (RKW-A) extracts, or 0.2 mg/kg epigallocatechin (EGC, antiangiogenic compound of Rhodiola extracts), may lead to abnormalities in morphology and function of the kidneys of adult progeny. Such abnormalities were not observed in the kidneys of 6-week-old offspring, neither in RKW nor in the control group. However, the progeny of RKW-A- or EGC-fed mothers presented morphometric abnormalities in the kidney structure, with a significantly higher number of glomeruli/mm2 and a lower diameter of glomeruli (RKW-A group) or a significantly higher glomeruli diameter (EGC), than in the control and RKW groups. Abnormalities in serum vascular endothelial growth factor, tumor necrosis factor (TNF)-alpha, urea, creatinine, and cystatin C levels were also found. We recommend caution in long-term use of RKW-A extract and EGC-rich foods during pregnancy and lactation. PMID- 27935765 TI - Gb3-binding lectins as potential carriers for transcellular drug delivery. AB - OBJECTIVES: Epithelial cell layers as well as endothelia forming the blood-brain barrier can drastically reduce the efficiency of drug targeting. Our goal was to investigate lectins recognizing the glycosphingolipid globotriaosylceramide (Gb3) for their potential as carriers for transcytotic drug delivery. METHODS: We utilized an in vitro model based on Madin-Darby canine kidney cells transfected with Gb3 synthase to characterize transcytosis of the Gb3-binding lectins LecA from Pseudomonas aeruginosa and the B-subunit of Shiga toxin (StxB). RESULTS: Both lectins were rapidly transcytosed from the apical to the basolateral plasma membrane and vice versa. Whereas StxB proceeded on retrograde and transcytotic routes, LecA avoided retrograde transport. This differential trafficking could be explained by our observation that LecA and StxB segregated into different domains during endocytosis. Furthermore, inhibiting the small GTPase Rab11a, which organizes trafficking through apical recycling endosomes, blocked basolateral to apical transcytosis of both lectins. CONCLUSIONS: Gb3-binding lectins are promising candidates for transcytotic drug delivery. Our findings highlight that LecA and StxB, which both bind Gb3 but exhibit dissimilar valence and molecular structures of their carbohydrate binding sites and can take divergent intracellular trafficking routes. This opens up the possibility of developing tailor-made glycosphingolipid-binding carrier lectins, which take optimized trafficking pathways. PMID- 27935766 TI - Dual-Source Single-Energy Multidetector CT Used to Obtain Multiple Radiation Exposure Levels within the Same Patient: Phantom Development and Clinical Validation. AB - Purpose To develop, in a phantom environment, a method to obtain multidetector computed tomographic (CT) data sets at multiple radiation exposure levels within the same patient and to validate its use for potential dose reduction by using different image reconstruction algorithms for the detection of liver metastases. Materials and Methods The American College of Radiology CT accreditation phantom was scanned by using a dual-source multidetector CT platform. By adjusting the radiation output of each tube, data sets at six radiation exposure levels (100%, 75%, 50%, 37.5%, 25%, and 12.5%) were reconstructed from two consecutive dual source single-energy (DSSE) acquisitions, as well as a conventional single-source acquisition. A prospective, HIPAA-compliant, institutional review board-approved study was performed by using the same DSSE strategy in 19 patients who underwent multidetector CT of the liver for metastatic colorectal cancer. All images were reconstructed by using conventional weighted filtered back projection (FBP) and sinogram-affirmed iterative reconstruction with strength level of 3 (SAFIRE-3). Objective image quality metrics were compared in the phantom experiment by using multiple linear regression analysis. Generalized linear mixed-effects models were used to analyze image quality metrics and diagnostic performance for lesion detection by readers. Results The phantom experiment showed comparable image quality between DSSE and conventional single-source acquisition. In the patient study, the mean size-specific dose estimates for the six radiation exposure levels were 13.0, 9.8, 5.8, 4.4, 3.2, and 1.4 mGy. For each radiation exposure level, readers' perception of image quality and lesion conspicuity was consistently ranked superior with SAFIRE-3 when compared with FBP (P <= .05 for all comparisons). Reduction of up to 62.5% in radiation exposure by using SAFIRE 3 yielded similar reader rankings of image quality and lesion conspicuity when compared with routine-dose FBP. Conclusion A method was developed and validated to synthesize multidetector CT data sets at multiple radiation exposure levels within the same patient. This technique may provide a foundation for future clinical trials aimed at estimating potential radiation dose reduction by using iterative reconstructions. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27935768 TI - Hypertrophic Osteoarthropathy: Clinical and Imaging Features. AB - Hypertrophic osteoarthropathy (HOA) is a medical condition characterized by abnormal proliferation of skin and periosteal tissues involving the extremities and characterized by three clinical features: digital clubbing (also termed Hippocratic fingers), periostosis of tubular bones, and synovial effusions. HOA can be a primary entity, known as pachydermoperiostosis, or can be secondary to extraskeletal conditions, with different prognoses and management implications for each. There is a high association between secondary HOA and malignancy, especially non-small cell lung cancer. In such cases, it can be considered a form of paraneoplastic syndrome. The most prevalent secondary causes of HOA are pulmonary in origin, which is why this condition was formerly referred to as hypertrophic pulmonary osteoarthropathy. HOA can also be associated with pleural, mediastinal, and cardiovascular causes, as well as extrathoracic conditions such as gastrointestinal tumors and infections, cirrhosis, and inflammatory bowel disease. Although the skeletal manifestations of HOA are most commonly detected with radiography, abnormalities can also be identified with other modalities such as computed tomography, magnetic resonance imaging, and bone scintigraphy. The authors summarize the pathogenesis, classification, causes, and symptoms and signs of HOA, including the genetics underlying the primary form (pachydermoperiostosis); describe key findings of HOA found at various imaging modalities, with examples of underlying causative conditions; and discuss features differentiating HOA from other causes of multifocal periostitis, such as thyroid acropachy, hypervitaminosis A, chronic venous insufficiency, voriconazole induced periostitis, progressive diaphyseal dysplasia, and neoplastic causes such as lymphoma. (c)RSNA, 2016. PMID- 27935767 TI - Effect of Physical Activity and/or Healthy Eating on GDM Risk: The DALI Lifestyle Study. AB - Context: Lifestyle approaches for preventing gestational diabetes mellitus (GDM) have produced mixed results. Objective: The aim of the present study was to compare the effectiveness of 3 lifestyle interventions [healthy eating (HE), physical activity (PA), and both HE and PA (HE+PA)] with usual care (UC) in reducing GDM risk. Design: The present study was a multicenter randomized controlled trial conducted from 2012 to 2014 [the DALI (vitamin D and lifestyle intervention for GDM prevention) lifestyle study]. Setting: The study occurred at antenatal clinics across 11 centers in 9 European countries. Patients: Consecutive pregnant women at <20 weeks of gestation with a body mass index (BMI) of >=29 kg/m2 and without GDM using the International Association of Diabetes and Pregnancy Study Group criteria (n = 436). For the intervention, women were randomized, stratified by site, to UC, HE, PA, or HE+PA. The women received 5 face-to-face and <=4 telephone coaching sessions using the principles of motivational interviewing. A gestational weight gain (GWG) <5 kg was targeted. The coaches received standardized training and an intervention toolkit tailored to their culture and language. Main Outcome Measures: The endpoints were the GWG at 35 to 37 weeks and the fasting glucose and insulin sensitivity [homeostasis model assessment insulin resistance (HOMA-IR)] at 24 to 28 weeks. Results: We randomized 108 women to HE+PA, 113 to HE, 110 to PA, and 105 to UC. In the HE+PA group, but not HE or PA alone, women achieved substantially less GWG than did the controls (UC) by 35 to 37 weeks (-2.02; 95% confidence interval, -3.58 to -0.46 kg). Despite this reduction, no improvements were seen in fasting or postload glucose levels, insulin concentrations, or HOMA-IR. The birthweights and large and small for gestational age rates were similar. Conclusions: The combined HE+PA intervention was able to limit GWG but did not reduce fasting glycemia. Thus, lifestyle changes alone are unlikely to prevent GDM among women with a BMI of >=29 kg/m2. PMID- 27935769 TI - Fluoroscopically Guided Epidural Injections of the Cervical and Lumbar Spine. AB - Advances in imaging and the development of injection techniques have enabled spinal intervention to become an important tool in managing chronic spinal pain. Epidural steroid injection (ESI) is one of the most widely used spinal interventions; it directly delivers drugs into the epidural space to relieve pain originating from degenerative spine disorders-central canal stenoses and neural foraminal stenoses-or disk herniations. Knowledge of the normal anatomy of the epidural space is essential to perform an effective and safe ESI and to recognize possible complications. Although computed tomographic (CT) or combined CT fluoroscopic guidance has been increasingly used in ESI, conventional fluoroscopic guidance is generally performed. In ESI, drugs are delivered into the epidural space by interlaminar or transforaminal routes in the cervical spine or by interlaminar, transforaminal, or caudal routes in the lumbar spine. Epidurography is usually performed before drug delivery to verify the proper position of the needle in the epidural space. A small amount of contrast agent is injected with fluoroscopic guidance. Familiarity with the findings on a typical "true" epidurogram (demonstrating correct needle placement in the epidural space) permits proper performance of ESI. Findings on "false" epidurograms (demonstrating incorrect needle placement) include muscular staining and evidence of intravascular injection, inadvertent facet joint injection, dural puncture, subdural injection, and intraneural or intradiscal injection. (c)RSNA, 2016 An earlier incorrect version of this article appeared online. This article was corrected on December 22, 2016. PMID- 27935771 TI - Preparing Anesthetists to Manage Cannot Intubate/Cannot Ventilate Situations. AB - Cannot intubate/cannot ventilate (CICV) situations during anesthesia are rare, potentially catastrophic to the patient, and difficult to predict. Widely adopted practice guidelines advocate an algorithmic approach to CICV situations in which the anesthetist: (a) recognizes the CICV situation, (b) calls for help, (c) steadily progresses through a variety of methods to ventilate the patient and secure the airway, (d) restores ventilation via an infraglottic airway if the patient cannot be safely awakened prior to becoming moribund. Despite widespread consensus that rapid progression to placement of an infraglottic airway is critical to the survival of the patient in a CICV situation, the rarity of CICV is a substantial barrier for anesthetists attempting to gain and maintain skill at placing infraglottic airways. Peer-reviewed literature reveals a number of themes relevant to training anesthetists in infraglottic airway placement. Specific training in infraglottic airway access consistently decreased the time required for anesthetists to decide to place an infraglottic airway. No one approach or method for placing an infraglottic airway was consistently faster or more successful. Model fidelity (i.e., the use of low-fidelity task trainers vs. high-fidelity simulated patients) during teaching did not affect the performance of anesthetists at placing infraglottic airways, and performance rapidly plateaued after five repetitions during teaching. Finally, skill at placing an infraglottic airway was sustained for 6 to 12 months after training. These findings have implications for how nurse anesthetists should learn and sustain the skill of infraglottic airway placement. Nurse anesthetists should undergo initial training that requires the repetitive placement of infraglottic airways, and receive sustainment training every 6 to 12 months thereafter. Although rarely used, the skill of an anesthetist in infraglottic airway placement can mean the difference between life and death for the patient in a CICV situation. PMID- 27935770 TI - From Breast Cancer to Antimicrobial: Combating Extremely Resistant Gram-Negative "Superbugs" Using Novel Combinations of Polymyxin B with Selective Estrogen Receptor Modulators. AB - Novel therapeutic approaches are urgently needed to combat nosocomial infections caused by extremely drug-resistant (XDR) "superbugs." This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with selective estrogen receptor modulators (SERMs) against problematic Gram negative pathogens. In vitro synergistic antibacterial activity of polymyxin B and the SERMs tamoxifen, raloxifene, and toremifene was assessed using the microdilution checkerboard and static time-kill assays against a panel of Gram negative isolates. Polymyxin B and the SERMs were ineffective when used as monotherapy against polymyxin-resistant minimum inhibitory concentration ([MIC] >=8 mg/L) Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. However, when used in combination, clinically relevant concentrations of polymyxin B and SERMs displayed synergistic killing against the polymyxin resistant P. aeruginosa, K. pneumoniae, and A. baumannii isolates as demonstrated by a >=2-3 log10 decrease in bacterial count (CFU/ml) after 24 hours. The combination of polymyxin B with toremifene demonstrated very potent antibacterial activity against P. aeruginosa biofilms in an artificial sputum media assay. Moreover, polymyxin B combined with toremifene synergistically induced cytosolic green fluorescence protein release, cytoplasmic membrane depolarization, permeabilizing activity in a nitrocefin assay, and an increase of cellular reactive oxygen species from P. aeruginosa cells. In addition, scanning and transmission electron micrographs showed that polymyxin B in combination with toremifene causes distinctive damage to the outer membrane of P. aeruginosa cells, compared with treatments with each compound per se. In conclusion, the combination of polymyxin B and SERMs illustrated a synergistic activity against XDR Gram-negative pathogens, including highly polymyxin-resistant P. aeruginosa isolates, and represents a novel combination therapy strategy for the treatment of infections because of problematic XDR Gram-negative pathogens. PMID- 27935772 TI - Anesthetic Implications of Obesity and Obstructive Sleep Apnea. AB - The incidence of morbid obesity has tripled within the past 25 years in developed countries, with the highest rate of growth noted among people with body mass index (BMI) greater than 50. The physiologic derangements that accompany obesity affect almost every organ system leading to a vast array of comorbid conditions including obstructive sleep apnea (OSA). This review focuses on the unique perioperative management considerations that the nurse anesthetist must address when caring for these patients as well as the impact of obesity and OSA on postoperative complications and mortality rates. Current research is reviewed to highlight best practice recommendations for all phases of anesthetic management including implications for bariatric surgery and office-based practice. PMID- 27935773 TI - Lung-Protective Ventilation. AB - Historically, mechanical ventilation of the lungs utilizing relatively large tidal volumes was common practice in the operating room and intensive care unit (ICU). The rationale behind this treatment strategy was to yield better patient outcomes, that is, fewer pulmonary complications, and a reduction in morbidity and mortality. As evidence-based practice has evolved, potential harmful effects of traditional, nonphysiological mechanical ventilation (ventilation with larger tidal volumes and the tolerance of high airway pressures) even in shortterm treatment have been shown to correlate with systemic inflammation and the development of ventilator-associated lung injury. Lung-protective ventilation principles using more physiological tidal volumes, avoiding high inspiratory plateau pressures, along with appropriate levels of positive end-expiratory pressure have been shown to decrease pulmonary complications and improve outcomes in patients with acute respiratory distress syndrome requiring ongoing ventilatory support in the ICU. In addition, current research is beginning to validate the benefit of providing more physiologic ventilator support in the operating room, particularly for high-risk patients undergoing major abdominal surgery, in minimizing acute lung injury. A review of lung-protective ventilation measures including benefits and potential side effects is presented. Additional treatment modalities and therapeutic considerations are offered for inclusion in optimal patient management. PMID- 27935774 TI - Communication in the Operating Room Setting. AB - Ideal and effective communication consists of a clear, audible, and focused message from a transmitter that is delivered to an attentive, undistracted receiver, and consists of both verbal and nonverbal types. Communication in the health care setting is highly complex and dynamic, involving multiple settings, participants, and unique challenges. Effective communication in the perioperative environment is a requirement for safe patient care delivery and an important element of teamwork. A message must be accurately delivered in a uniquely high risk and time-sensitive location, beset with numerous distractions, barriers, and challenges. Surgical checklists and time-out procedures have promoted a standardized, "all-hands" approach to addressing some of the challenges to effective communication in the perioperative environment. Postoperative debriefing sessions have demonstrated effectiveness in improving team functioning in the simulated learning environment and hold promise as another strategy to address these challenges, but require further research and development. Other promising strategies to improve effective perioperative communication are focused on team building activities and minimizing distractions at critical time points within patient care delivery, but to date are not substantiated by evidence. Future research is necessary to examine these novel approaches to improving communication in the perioperative environment to influence the safety of patient care delivery in this highly challenging health care setting. Wise men speak because they have something to say; Fools because they have to say something. Plato. PMID- 27935775 TI - Anesthesia Information Management Systems. AB - Anesthesia information management systems (AIMS) are rapidly gaining widespread acceptance. Aggressively promoted as an improvement to manual-entry recordkeeping systems in the areas of accuracy, completeness, quality improvement, billing, and vigilance, these systems record all patient vital signs and parameters, providing a legible hard copy and permanent electronic record. With well-documented financial incentives, as well as government subsidies, AIMS are becoming adopted at an unprecedented rate. With the goals of the federal government to enhance the use of the electronic medical record, there is an emerging belief that AIMS may soon be mandated, with more limited choices than currently available. As assessed by, and often in spite of the published evidence, concerns of practitioners still reflect many of the same concerns expressed in the editorial comments of the past. PMID- 27935776 TI - Chronic Postsurgical Pain. AB - Chronic postsurgical pain (CPSP) is defined as a persistent pain state that exists more than 2 months postoperatively and cannot be explained by other causes such as recurrence of disease, apparent inflammation, or other nonsurgical related factors. CPSP is a type of persistent pain condition that often complicates recovery from surgical procedures. It is thought to be caused by surgical nerve injury, but the fact that an identifiable nerve injury can be found in only one-third of CPSP patients suggests that the problem may be far more complex than a simple surgically created nerve injury. Certain surgical procedures report a high incidence of CPSP, helping to isolate likely candidates for this problem, but instituting preventative measures and identifying a treatable source of pain continues to be elusive. Some progress has been made in the areas of prevention and treatment. PMID- 27935777 TI - Acupuncture and Chronic Pain Management. AB - According to National Institute of Health Pathways to Prevention Workshop (2014), chronic pain affects an estimated 100 million Americans, with approximately 25 million people experiencing moderate to severe chronic pain, which negatively impacts their ability to function leading to a diminished quality of life. Pain is the primary reason Americans are on disability, which adds to the economic and social burden of suffering for the nation. Chronic pain costs are estimated to be between 560 and 630 billion per year. An estimated 5 to 8 million Americans use opioids for long-term management of chronic pain, which can have deleterious effects on their lives including addiction. Recent evidence suggests that acupuncture, a treatment modality that has been used worldwide for over 2,000 years, may provide a useful pain management option for those who suffer from chronic pain. The investigation into its mechanism of action and efficacy remains elusive, but promising. PMID- 27935778 TI - Anesthesia Involvement in Palliative Care. AB - Palliative care teams require multidisciplinary support. While this is an emerging area in anesthesia practice, there are many avenues for certified registered nurse anesthetists (CRNAs) to share their unrivaled clinical knowledge. CRNAs may become involved with or consult on palliative sedation, medical management, interventional pain management, terminal wean/extubation, and organ donation. Additionally, CRNAs need to understand the unique needs of this patient population so that they can appropriately care for palliative care patients presenting to the operating room for palliative surgery. More research is needed to further explore CRNA involvement in palliative care. However, CRNAs have a specialized knowledge of pharmacology and physiology that perfectly complements the multidisciplinary palliative care team. Death is the wish of some, the relief of many, and the end of all. Lucius Annaeus Seneca (4 BCE65). PMID- 27935779 TI - Treatment and Prevention of Spinal-Induced Hypotension in the Cesarean Section Patient: What Does the Evidence Say? AB - Most anesthesia providers prefer to do a subarachnoid block (SAB) for cesarean section because of its rapid onset and reliability to provide adequate anesthesia. However an effect of the SAB is that it causes a spinal-induced hypotension (SIH) in up to 85% of the population. There have been multiple studies that assessed fluid administration, vasopressor administration, maternal positioning, or serotonin blockers given prophylactically to attenuate the SIH response. Despite these multiple studies, the method to prevent and treat SIH remains varied from one anesthesia practice to another. The purpose of this chapter is to review the evidence on the various methods used to prevent and treat SIH. PMID- 27935780 TI - Forced-Air Warmers and Surgical Site Infections in Patients Undergoing Knee or Hip Arthroplasty. AB - The majority of the evidence indicates preventing inadvertent perioperative hypothermia reduces the incidence of many perioperative complications. Among the results of inadvertent perioperative hypothermia are increased bleeding, myocardial events, impaired wound healing, and diminished renal function. Most researchers agree there is an increased incidence of surgical site infections in patients who experience inadvertent perioperative hypothermia. Forced-air warming is effective in preventing inadvertent perioperative hypothermia. Paradoxically, forced-air warmers have been implicated in causing surgical site infections in patients undergoing total knee or hip arthroplasty. The results of investigations suggest these devices harbor pathogens and cause unwanted airflow disturbances. However, no significant increases in bacterial counts were found when forced-air warmers were used according to the manufacturer's directions. The results of one study suggested the incidence of surgical site infections in patients undergoing total joint arthroplasty was increased when using a forced-air warmer. However these researchers did not control for other factors affecting the incidence of surgical site infections in these patients. Current evidence does not support forced-air warmers causing surgical site infections in patients undergoing total knee or hip arthroplasty. Clinicians must use and maintain these devices as per the manufacturer's directions. They may consider using alternative warming methods. Well-conducted studies are needed to help determine the role of forced air warmers in causing infections in these patients. PMID- 27935781 TI - The Neurotoxicity of General Anesthetic Drugs: Emphasis on the Extremes of Age. AB - A substantial body of research suggests that anesthetic exposure to patients who are very young or very old may impair cognitive, behavioral, and emotional development or recovery. In lower animal models of pre- and postnatal age, anesthetic exposure may impact inflammation, synaptogenesis, neuronal apoptosis, and glial cell development. To date, research in humans is inconclusive regarding the long-term cognitive and behavioral sequelae of general anesthesia in the young child. In older adults, postoperative cognitive dysfunction and cognitive delirium are identified as markers of anesthetic neurotoxicity. Existing neurological degenerative processes and other comorbidities in combination with the stress of surgery make evaluating the independent impact of anesthetic exposure difficult. Advances in research, imaging, and partnerships have enhanced the potential for understanding the impact of anesthetic exposure. In both populations, the resulting data and limitations faced in initial research efforts are catalysts for current prospective studies. PMID- 27935782 TI - Wet or Dry? A Review of Intravenous Fluid Administration in Anesthesia Practice. AB - Fluid therapy has dramatically changed since its early inception nearly 200 years ago. Administration of intravenous fluid (IVF) has evolved from a "drip" technique to the algorithmic approach of the anesthetic fluid plan, and is now moving toward Goal-Directed Fluid Therapy. As the science and culture of fluid management evolves, anesthetists must remain focused on "why" anesthetic fluid matters. The purpose of IVF administration is to support tissue perfusion and maintain euvolemia. As the evidence underlying perioperative practice matures and the science of anesthesia races to meet the evolving demands of surgery, anesthetists must align knowledge generation with the individualized needs of the patient. The future of perioperative IVF therapy will be patient centric. In the near future, anesthetists will know the patient's blood volume before, during, and after the surgery. They will no longer depend on inaccurate surrogates to estimate, but have the knowledge to titrate fluids to maintain a zero balance. Practice will move away from algorithms and toward individualized fluid administration based on reproducible end points. Decisions about fluid selection, timing, and volume will be driven by patient- and case-specific requirements as specific as when a patient is typed and crossed for blood transfusion. The greatest challenge for the anesthetist in perioperative fluid therapy is to move beyond the dogmatic practices of the past and toward fluid therapy guided by patient centric evidence. PMID- 27935783 TI - The Role of Pharmacogenomics in Anesthesia Pharmacology. AB - The field of pharmacogenomics seeks to identify the impact of genetic variants on drug dosing, response, metabolism, and safety outcomes. The narrow therapeutic indices for anesthesia drugs, variability of patient responses to anesthesia, and the risks associated with surgery make anesthetics and the perioperative period prime targets for pharmacogenetic research. Anesthesia providers strive to optimize anesthesia delivery and patient outcomes and to specifically reduce anesthesia-related risks and negative outcomes. Despite pharmacogenomics emerging from the field of anesthesia, the most significant advances to date in the understanding and application of genetics to pharmacology have occurred outside of anesthesiology. This chapter provides an overview of genetic concepts fundamental to understanding the pharmacogenetics of anesthesia practice and presents the current state of the science with respect to the genetic influence on the response to volatile and intravenous anesthetic agents and opioid receptor agonists commonly used in anesthesia practice. In addition, the chapter delineates U.S. Food and Drug Administration labeling tenets for pharmacogenetics, discusses clinical implications of pharmacogenomics for family members, and highlights the potential for future paradigm shifts in pharmacogenomics of anesthesia practice. PMID- 27935785 TI - Romantic Attachment and Physical Intimate Partner Violence Perpetration in a Chilean Sample: The Mediating Role of Emotion Regulation Difficulties. AB - Despite evidence that adult attachment insecurity has been linked to the perpetration of physical intimate violence, the mechanisms underlying this link need further exploration. The goal of this study was to evaluate the mediating role of emotion regulation difficulties in the association between romantic attachment and the use of physical intimate partner violence. To this end, 611 students recruited from Chilean universities completed the Experiences in Close Relationships questionnaire, the Difficulties in Emotion Regulation Scale, and the Revised Conflict Tactics Scales. Structural equation modeling (SEM) analyses revealed that emotion regulation difficulties mediated the relationship between dimensions of romantic attachment (anxiety over abandonment and avoidance of intimacy) and physical violence perpetration among both male and female participants. Implications for future research and clinical practice are presented herein. PMID- 27935786 TI - Beneficioso y Una Prioridad: Latina Women's Perceptions about HIV Testing. AB - OBJECTIVES: Studies indicate a higher rate of HIV infection among Latinos in the United States, and a pattern of later testing associated with poorer disease management, greater risk of spreading infection, and higher death rates. Thus, it is imperative to generate culturally holistic strategies to improve HIV testing among Latina women. METHODS: We surveyed 182 Latina women in the southeastern US. We cross-tabulated demographic, social, and experiential factors of women who have taken a previous HIV test with women who have not yet been tested. We examined key comparisons between these women in terms of socio-demographic characteristics, sources of information about HIV testing, and responses to questions that identify factors enabling women to take an HIV test. RESULTS: Our results indicate that Latina women perceive HIV testing as worthwhile, beneficial, and a priority for them. They demonstrate the importance of family networks, trusted and bilingual service providers, and known test locations associated with higher percentages of women taking the HIV test. CONCLUSIONS: The results provide input to community health advocates to identify women who need additional support to take an HIV test. PMID- 27935787 TI - E-cigarette Nicotine Delivery: Data and Learnings from Pharmacokinetic Studies. AB - OBJECTIVES: E-cigarettes could potentially play a major role in tobacco harm reduction by delivering nicotine in a vapor containing significantly fewer toxicants than cigarette smoke and may aid smoking behavior changes such as reduction or cessation. METHODS: We examined blood nicotine levels in smokers who were non-accustomed to e-cigarette use (Study 1) and accustomed e-cigarette users (Study 2). We compared nicotine levels when participants used a closed modular system e-cigarette to those when participants smoked a cigarette. RESULTS: In Study 1, Cmax (geometric mean (CV)) during a 5-minute puffing period (10 puffs, 30 seconds apart) was 13.4 (51.4) ng/ ml for a regular cigarette. The e-cigarette Cmax was significantly lower (p .05) at 2.5 (67.8) ng/ml. In Study 2, during a 5 minute ad libitum puffing period, cigarette Cmax was 7.2 (130.8) ng/mL, and it was 7.8 (108.2) ng/mL for the e-cigarette. CONCLUSIONS: Our data demonstrate heterogeneity of nicotine deliveries both between products and also with the same products used by different cohorts, eg, accustomed users versus smokers. Such differences must be taken into account when determining the likely behavioral impact, on smoking reduction and cessation, of nicotine delivery data and when planning e-cigarette nicotine pharmacokinetic studies. PMID- 27935788 TI - Evidence of Query Theory as a Tool to Assist Restrained Eaters. AB - OBJECTIVES: Using theories from decision-making and behavioral economics, we conducted a study to improve understanding of the decisions of Restrained Eaters. We identified Restrained Eaters via the Revised Restraint Questionnaire. METHODS: One hundred two (N = 102) participants were each randomly assigned to an endowment condition and asked to list their thoughts about 2 products. RESULTS: We found a significant interaction of endowment and thoughts on decisions. Research findings suggest the behavior of Restrained Eaters depends upon both endowment and thoughts, and that they exert self-control beyond food decisions. CONCLUSIONS: This work suggests decisions Restrained Eaters make can be manipulated via endowment and how they are instructed to structure their thoughts. PMID- 27935789 TI - The Development and Validation of the Mood-based Indoor Tanning Scale. AB - OBJECTIVES: Research indicates that mood-based motivations may be an important predictor of indoor tanning bed use and may be related to indoor tanning dependence. Problematically, little research has been conducted to develop a psychometric measure of mood-based tanning motivations. The current study seeks to develop and validate the moodbased indoor tanning scale (MITS). METHODS: Two studies were conducted to identify and verify the MITS factor structure as well as assess construct validity. Study 1 was conducted at 5 geographically diverse universities in the United States. Study 2 was conducted by using a national online sample in the United States. RESULTS: Results from study 1 specified the factor structure of the MITS. Results from study 2 suggest that a one-point increase in the MITS measure corresponds with using indoor tanning beds 11 more times in the past year. CONCLUSIONS: These findings demonstrate that moodbased tanning motivations are a strong predictor of indoor tanning intentions and behavior. Further, they suggest that health behavior researchers and healthcare practitioners can use the MITS to assess the extent to which mood-based motivations impact indoor tanning bed use. PMID- 27935790 TI - Spice and Herb Use with Vegetables: Liking, Frequency, and Self-efficacy among US Adults. AB - OBJECTIVES: To inform future initiatives to encourage vegetable intake, we explored how spice and herb (S/H) use with vegetables was related to consumer characteristics. METHODS: A questionnaire collected information on S/H liking and use frequency, whether S/Hs were used when cooking vegetables, and belief that consumers could use S/Hs when cooking vegetables. The questionnaire was distributed to members of an online panel of US consumers. RESULTS: Younger respondents (18-29 years) and respondents who identified as Asian/ Pacific Islander or other racial group used 19 of the 20 S/Hs more frequently than their older and white/Caucasian, African-American or Hispanic counterparts, respectively. S/H use when cooking vegetables at home was significantly higher for women. Self-efficacy was higher for women, 18-29 year-olds, and 30-49 year olds, and lower for respondents who identified as white/Caucasian race and those with annual incomes below 50,000. CONCLUSIONS: Low-income, male, older ( 50 years), and white/ Caucasian respondents were identified as target audiences that may benefit the most from interventions encouraging S/H use with vegetables to increase consumption. It is critical to account for socio-demographic characteristics of the audience when designing interventions. PMID- 27935791 TI - Lessons Learned From an Online Study with Dual-smoker Couples. AB - OBJECTIVE: In this paper we present lessons learned from an online study assessing couples' health behaviors. METHODS: We conducted an online cross sectional study to assess health behaviors of dual-smoker couples. Participants were recruited via passive and targeted methods. Data were collected from 77 (pre safeguard) and 197 (post-safeguard) participants. Safeguards included: (1) changing the incentive from prepaid card to raffle; (2) allowing only one IP address per response; (3) masking eligibility; (4) adding multiple questions to ensure consistency in responses; and (5) emphasizing data surveillance. We computed descriptive statistics using SAS 9.4 to compare enrollment rates and validity of data between the pre- and post-safeguard participants. RESULTS: Although 77 entries were collected within 24 hours (presafeguards), 5 responses were ineligible and excluded. Among the remaining 72 entries, 68.1 were fraudulent as either multiple data entries (24.5) and/or conflict in responses to similar survey items (83.7). Once safeguards were administered (post-safeguards), data collection took longer to obtain 297 participants, which included 27 ineligibles. Among the 270 eligible participants, 35.9 were fraudulent due to conflicting responses to similar survey items. CONCLUSION: Online data collection via surveys should use safeguards to capture valid data. Many safeguards exist, which researchers should consider when designing online survey projects. PMID- 27935793 TI - Co-occurring Risk Factors in Multiple Sclerosis. AB - OBJECTIVE: We examined individual and co-occurring risk factors as correlates of health outcomes in persons with multiple sclerosis (MS). METHODS: Sixty-nine participants with MS completed measures of nutrition, physical activity levels, comorbidity and neuroperformance. The data were analyzed using t-test analyses in SPSS Statistics 22.0. RESULTS: Total number of comorbidities (z = 2.36, p = .02), cardiovascular disease symptoms (z = 2.63, p = .01), Timed 25-Foot Walk (T25FW) speed (z = 2.53, p = .01), and 6 Minute Walk (6MW) distance (z = 2.61, p = .01) had significant differences in the cluster of co-occurring poor nutrition and insufficient levels of physical activity. There was a significant difference between those reporting two vs. one risk factor for number of comorbidities (z = 2.41, p = .02), cardiovascular disease symptoms (z = 2.40 p = .02), T25FW speed (z = 2.39, p = .02), and 6MW distance (z = 2.68, p = .01). CONCLUSIONS: These results suggest that: (1) the cluster of co-occurring poor diet and insufficient physical activity is associated with comorbidities and neuroperformance markers; and (2) that cluster is further synergistically associated with comorbidities and neuroperformance markers. PMID- 27935794 TI - Exploring Exclusive and Poly-tobacco Use among Adult Cigarette Smokers in Minnesota. AB - OBJECTIVES: In recent decades, the United States has seen dramatic reductions in cigarette smoking. In contrast, other tobacco products (OTPs) have increased in popularity, particularly electronic cigarettes. The availability of new OTPs also has led to the use of multiple tobacco products that includes combustible cigarettes (poly-use). This study examines patterns of exclusive cigarette and polyuse among adult smokers in Minnesota. METHODS: Data from 5 rounds of the Minnesota Adult Tobacco Survey (MATS) series 1999-2014 were analyzed. Weighted estimates of the prevalence of exclusive and poly-tobacco use were calculated. The use of multiple tobacco products was contrasted with past 30-day exclusive cigarette smoking. Poly-use was measured as the current use of combustible cigarettes plus past 30-day use of another tobacco product. RESULTS: The percentage of Minnesota adults who used at least 2 tobacco products increased from 3.2 in 1999 to 5.8 in 2014. The most common combination of products in 2014 was combustible cigarettes and electronic nicotine delivery systems (ENDS), a combination that increased significantly between 2010 and 2014. Compared to exclusive cigarette smoking, poly-users were more likely to be younger and male. CONCLUSIONS: In this state-based survey, the number of people using multiple tobacco products remains modest but nearly doubled from 1999 to 2014. Further surveillance should discern motivations and patterns of use among poly-users. PMID- 27935792 TI - Youth and Caregiver Physical Activity and Sedentary Time: HCHS/SOL Youth. AB - OBJECTIVES: We examined associations between youth and caregiver moderate/ vigorous physical activity (MVPA) and sedentary (SED) time, using accelerometery, in the Hispanic Community Health Study/Study of Latino Youth (HCHS/ SOL) Youth. METHODS: Participants were 623 caregivers and 877 youth 8-16 years old, enrolled in 2012-2014. Associations of youth and caregiver MVPA time, SED time, and meeting MVPA recommendations ( 150 min/week, adults; 420 min/week, youth) were examined in regression models that controlled for sample weights, design effects, and demographic and health covariates. RESULTS: Youth whose caregivers met MVPA recommendations were nearly twice as likely to meet these recommendations themselves when compared to youth whose caregivers did not meet MVPA recommendations (OR = 1.9, 95 CI 1.1, 3.3). Youth and caregiver SED time also were significantly related (p .05). A similar pattern of findings was observed in analyses limited to relationships in which the caregiver was a biological parent of the youth (N = 485 caregivers; N = 795 youth). CONCLUSIONS: MVPA and SED are correlated within Latino families as observed by statistically significant relationships of youth and caregiver activity. Additional research is needed to understand underlying genetic and environmental factors that explain these findings. PMID- 27935795 TI - Alcohol Use, Hooking-Up, Condom Use: Is There a Sexual Double Standard? AB - OBJECTIVES: The purposes of the study were to: (1) identify judgments college students make of peers based on descriptions of drinking, hooking-up, and condom use behaviors; and (2) determine whether participants' judgments differed based on the sex of the person described. METHODS: Participants (N = 574 college students) completed an online questionnaire that included one of 8 different vignettes (4 vignette types, female or male model). Participants evaluated statements, comprising 3 scales (likability, positive character, negative behavior) relative to the model depicted in the vignette. RESULTS: For female participants, significant effects for vignette type for all 3 scales and significant effects for model sex (negative behavior) were revealed. Male participants only showed significant effects for vignette type for positive character traits. CONCLUSIONS: Results should be of value to college level health educators and considered by those involved in drinking behavior and sexual health programming on college campuses. PMID- 27935797 TI - Abstracts of the 28th Annual Conference of the International Society for Environmental Epidemiology (ISEE), 1-4 September 2016, Rome, Italy. AB - The 28th annual conference of the International Society for Environmental Epidemiology was held 1 - 4 September 2016 in Rome, Italy. The conference theme was "Old and New Risks: Challenges for Environmental Epidemiology." The focus of this year's conference is current and future challenges in exposure assessment, study design, and data analyses. PMID- 27935796 TI - Correlation of West Nile Virus Incidence in Donated Blood with West Nile Neuroinvasive Disease Rates, United States, 2010-2012. AB - Over the past decade, West Nile virus (WNV) has spread across the United States. We aggregated blood donor data from 2010-2012 and then calculated the incidence of WNV RNA-positive donations and compared the incidence with neuroinvasive disease (NID) case data from the ArboNET surveillance system. Of 10,107,853 donations, 640 were confirmed positive. The seasonal WNV incidence rate per 100,000 persons was 33.4 (95% CI 22-45) in 2010, 25.7 (95% CI 15-34) in 2011, and 119.9 (95% CI 98-141) in 2012. NID to blood donor ratios were 1 in 164 (95% CI 152-178) in 2010, 1 in 158 (95% CI 145-174) in 2011, and 1 in 131 (95% CI 127 136) in 2012. We updated estimates of the ratio of NID to WNV infection rates, demonstrating stable disease penetrance over the study period. Blood donor WNV RNA screening is a valuable public health tool for WNV surveillance. PMID- 27935798 TI - Health Gains and Financial Protection Provided by the Ethiopian Mental Health Strategy: an Extended Cost-Effectiveness Analysis. AB - Background: Mental and neurological (MN) health care has long been neglected in low-income settings. This paper estimates health and non-health impacts of fully publicly financed care for selected key interventions in the National Mental Health Strategy in Ethiopia for depression, bipolar disorder, schizophrenia and epilepsy. Methods: A methodology of extended cost-effectiveness analysis (ECEA) is applied to MN health care in Ethiopia. The impact of providing a package of selected MN interventions free of charge in Ethiopia is estimated for: epilepsy (75% coverage, phenobarbital), depression (30% coverage, fluoxetine, cognitive therapy and proactive case management), bipolar affective disorder (50% coverage, valproate and psychosocial therapy) and schizophrenia (75% coverage, haloperidol plus psychosocial treatment). Multiple outcomes are estimated and disaggregated across wealth quintiles: (1) healthy-life-years (HALYs) gained; (2) household out of-pocket (OOP) expenditures averted; (3) expected financial risk protection (FRP); and (4) productivity impact. Results: The MN package is expected to cost US$177 million and gain 155,000 HALYs (epilepsy US$37m and 64,500 HALYs; depression US$65m and 61,300 HALYs; bipolar disorder US$44m and 20,300 HALYs; and schizophrenia US$31m and 8,900 HALYs) annually. The health benefits would be concentrated among the poorest groups for all interventions. Universal public finance averts little household OOP expenditures and provides minimal FRP because of the low current utilization of these MN services in Ethiopia. In addition, economic benefits of US$ 51 million annually are expected from depression treatment in Ethiopia as a result of productivity gains, equivalent to 78% of the investment cost. Conclusions: The total MN package in Ethiopia is estimated to cost equivalent to US$1.8 per capita and yields large progressive health benefits. The expected productivity gain is substantially higher than the expected FRP. The ECEA approach seems to fit well with the current policy challenges and captures important equity concerns of scaling up MN programmes. PMID- 27935799 TI - Strengthening health information systems for disability-related rehabilitation in LMICs. AB - The purpose of this study was to describe the state of rehabilitation health information systems (HIS) in different settings, and identify key processes and actions which contribute to the development of HIS which can effectively support low- and middle-income countries (LMICs) allocate resources to health-related rehabilitation to people with disabilities. Nine case studies were conducted across different disability and developmental settings using documentary review and semi-structured key informant interviews (N = 41). Results were analysed against the six building blocks of a HIS, based on the Health Metrics Network Framework and Standards for Country Health Information Systems and existing HIS capacity. Key barriers or enablers to good disability data collection and use, were documented for each HIS component. Research results suggest there is no gold standard HIS for rehabilitation. There was broad consensus however, that effective health related disability planning requires reliable data on disability prevalence, functional status, access to rehabilitation services and functional outcomes of rehabilitation. For low-resource settings, and where routine HIS are already challenged, planning to include disability and rehabilitation foci starting with a minimum dataset on functioning, and progressively improving the system for increased utility and harmonization, is likely to be most effective and minimize the potential for overburdening fragile systems. The recommendations from this study are based on the successes and challenges of countries with established information systems, and will assist LMICs to prioritize strategic measures to strengthen the collection and use of data for rehabilitation, and progressively realize the rights of people with disabilities. PMID- 27935801 TI - Maternal and neonatal health impact of obstetrical risk insurance scheme in Mauritania: a quasi experimental before-and-after study. AB - A variety of health financing schemes shaped on pre-payment scheme have been implemented across Sub-Saharan Africa (SSA) to address the Millennium Development Goals (MDGs). In Mauritania, the Obstetric Risk Insurance package (ORI) focusing on maternal and perinatal health has been progressively implemented at the health district level since 2002. Here, our main objective was to assess the effectiveness of the ORI in increasing facility-based delivery rates, as well as increases in family planning, antenatal and postnatal care, caesarean delivery and neonatal health, from demographic and health survey data between 2002 and 2011. We also examined whether the effects of the ORI varied between strata of the population. The study was based on a quasi-experimental before-and-after design to assess the causal link between availability of ORI and increase in use of maternal health services and neonatal mortality. In combination with geographical information system, difference-in-differences and odd ratio approaches were used to address our objectives. Indicators of access to care for pregnant women and neonatal health and improved in both non-intervention and intervention groups during the study period. There was no global effect of the availability of ORI on facility-based delivery rates, nor on the use of antenatal and postnatal care services, except for qualified antenatal services. However, delivery rates in local health centres with ORI increased more rapidly than in those with no ORI, the contrary was shown for hospitals. Caesarean delivery and family planning decreased with ORI. Although late neonatal mortality rates remained low in the country, a significant decrease was seen in districts without ORI. Except for some strata of the population, ORI has not really met its objective of attracting more pregnant women towards facility-based health care. PMID- 27935802 TI - Perceptions on diabetes care provision among health providers in rural Tanzania: a qualitative study. AB - Diabetes prevalence in Tanzania was estimated at 9.1% in 2012 among adults aged 24-65 years - higher than the HIV prevalence in the general population at that time. Health systems in lower- and middle-income countries are not designed for chronic health care, yet the rising burden of non-communicable diseases such as diabetes demands chronic care services. To inform policies on diabetes care, we conducted a study on the health services in place to diagnose, treat and care for diabetes patients in rural Tanzania. The study was an exploratory and descriptive study involving qualitative methods (in-depth interviews, observations and document reviews) and was conducted in a rural district in Tanzania. Fifteen health providers in four health facilities at different levels of the health care system were interviewed. The health care organization elements of the Innovative Care for Chronic Conditions (ICCC) framework were used to guide assessment of the diabetes services in the district. We found that diabetes care in this district was centralized at the referral and district facilities, with unreliable supply of necessary commodities for diabetes care and health providers who had some knowledge of what was expected of them but felt ill-prepared for diabetes care. Facility and district level guidance was lacking and the continuity of care was broken within and between facilities. The HMIS could not produce reliable data on diabetes. Support for self-management to patients and their families was weak at all levels. In conclusion, the rural district we studied did not provide diabetes care close to the patients. Guidance on diabetes service provision and human resource management need strengthening and policies related to task-shifting need adjustment to improve quality of service provision for diabetes patients in rural settings. PMID- 27935803 TI - Spatiotemporal mapping of cervical cancer incidence highlights need for targeted prevention in Songkhla province, Thailand. AB - Background: The national cervical cancer screening program in Thailand has been successful in reducing overall burden from this disease. However, evaluation on spatial and temporal scales is needed to assess the efficacy of this program in smaller regions. Here, we geographically assess incidence in a province with a uniquely heterogeneous distribution of lifestyle factors associated with religiosity. Methods: Cervical cancer cases were extracted from the provincial cancer registry from 1989 to 2013. Age-adjusted incidence rates were calculated using population statistics from the census bureau and adjusted to the Segi world standard population. Bayesian hierarchical modelling was employed to spatiotemporally map cervical cancer incidence trends in Songkhla province in 5 year period. Results: Overall, the incidence of cervical cancer decreased in Songkhla province. The three districts with a Muslim population of greater than 70% had consistently lower cervical cancer rates from 1989 to 2013 compared with the rest of the predominantly Buddhist districts. Hotspots of incidence were identified in Sadao, Hat Yai and the juncture of Mueang Songkhla and Singhanakhon in each 5-year period. Conclusions: Distinct cervical cancer incidence trends by religion over time indicate differences in sexual habits, lifestyle and religion associated culture between Muslims and Buddhists, and suggest divergent risk factor profiles for these groups. The high incidence rates in Sadao and Hat Yai is likely explained by the main road to Malaysia, which runs across these two areas and has frequent commercial sex trade. Female sex workers should be targeted as a vulnerable population for screening efforts to address this continuing burden of cervical cancer. PMID- 27935804 TI - Privilege and inclusivity in shaping Global Health agendas. PMID- 27935806 TI - Lessons learnt from outstanding mid-career women in endocrine cancer research. PMID- 27935805 TI - E2F1-mediated human POMC expression in ectopic Cushing's syndrome. AB - Cushing's syndrome is caused by excessive adrenocorticotropic hormone (ACTH) secretion derived from pituitary corticotroph tumors (Cushing disease) or from non-pituitary tumors (ectopic Cushing's syndrome). Hypercortisolemic features of ectopic Cushing's syndrome are severe, and no definitive treatment for paraneoplastic ACTH excess is available. We aimed to identify subcellular therapeutic targets by elucidating transcriptional regulation of the human ACTH precursor POMC (proopiomelanocortin) and ACTH production in non-pituitary tumor cells and in cell lines derived from patients with ectopic Cushing's syndrome. We show that ectopic hPOMC transcription proceeds independently of pituitary specific Tpit/Pitx1 and demonstrate a novel E2F1-mediated transcriptional mechanism regulating hPOMC We identify an E2F1 cluster binding to the proximal hPOMC promoter region (-42 to +68), with DNA-binding activity determined by the phosphorylation at Ser-337. hPOMC mRNA expression in cancer cells was upregulated (up to 40-fold) by the co-expression of E2F1 and its heterodimer partner DP1. Direct and indirect inhibitors of E2F1 activity suppressed hPOMC gene expression and ACTH by modifying E2F1 DNA-binding activity in ectopic Cushing's cell lines and primary tumor cells, and also suppressed paraneoplastic ACTH and cortisol levels in xenografted mice. E2F1-mediated hPOMC transcription is a potential target for suppressing ACTH production in ectopic Cushing's syndrome. PMID- 27935807 TI - Methylphenidate for ADHD in children and adolescents: throwing the baby out with the bathwater. AB - A recent Cochrane review assessed the efficacy of methylphenidate for attention deficit/hyperactivity disorder (ADHD) in children and adolescents. Notwithstanding the moderate-to-large effect sizes for ADHD symptom reduction found in the meta-analysis, the authors concluded that the quality of the evidence is low and therefore the true magnitude of these effects remains uncertain. We identified a number of major concerns with the review, in the domains of study inclusion, approaches to quality assessment and interpretation of data relating to serious adverse events as well as of the clinical implications of the reported effects. We also found errors in the extraction of data used to estimate the effect size of the primary outcome. Considering all the shortcomings, the conclusion in the Cochrane review that the status of the evidence is uncertain is misplaced. Professionals, parents and patients should refer to previous reviews and existing guidelines, which include methylphenidate as one of the safe and efficacious treatment strategies for ADHD. PMID- 27935808 TI - Evidence on methylphenidate in children and adolescents with ADHD is in fact of 'very low quality'. AB - Banaschewski and colleagues from the European Attention Deficit Hyperactivity Disorder (ADHD) guideline group make a number of critical comments regarding our systematic review on methylphenidate for children and adolescents with ADHD. In this article, we present our views, showing that our trial selection was not flawed and was undertaken with scientific justification. Similarly, our data collection and interpretation was systematic and correct. We have followed a sound methodology for assessing risk of bias and our conclusions are not misleading. We acknowledge that different researchers might make risk of bias judgments at higher or lower thresholds, but we have been consistent and transparent in applying our pre-defined and per reviewed protocol. Although we made minor errors, we demonstrate that the effects are negligible and not affecting our conclusions. We are happy to correct such errors and to engage in debate on methodological and ethical issues. In terms of clinical implications, we are advocating that clinicians, patients and their relatives should weight carefully risks and benefits of methylphenidate. Clinical experience seems to suggest that there are people who benefit from this medication. Our systematic review does, however, raise questions regarding the overall quality of the methylphenidate trials. PMID- 27935809 TI - Assessing and measuring cognitive function in major depressive disorder. AB - Cognitive dysfunction is a major component of major depressive disorder (MDD). No 'gold-standard' tool exists for the assessment of cognitive dysfunction for adults with MDD. The use of measurement-based care to improve treatment outcomes invites the need for a systematic screening, evaluation and measurement tool. The aim herein was to provide a succinct summary of literature documenting clinical implication of cognitive dysfunction in MDD, and a review of available screening, diagnostic and measurement tools for cognitive dysfunction in MDD is provided. We also take the opportunity to introduce a screening tool (ie, the THINC-it tool) targeted at addressing the unmet needs. We found that there are limitations to the current measurement scales; for example, many are not targeted for MDD and not all digitally available tests are free of charge. Furthermore, the spectrum of cognitive dysfunction in MDD is poorly represented by the existing tests and as such, there is a lack of sensitivity in the ability to screen a patient with MDD for a cognitive dysfunction. Recognising and addressing the limitations in the current screening techniques for cognitive dysfunction as well as being presented with the current tools available provides the ability to perform an educated cognitive screening for a patient with MDD. PMID- 27935810 TI - Designing and analysing clinical trials in mental health: an evidence synthesis approach. AB - OBJECTIVE: When planning a clinical study, evidence on the treatment effect is often available from previous studies. However, this evidence is mostly ignored for the analysis of the new study. This is unfortunate, since using it could lead to a smaller study without compromising power. We describe a design that addresses this issue. METHODS: We use a Bayesian meta-analytic model to incorporate the available evidence in the analysis of the new study. The shrinkage estimate for the new study integrates the evidence from the other studies. At the planning phase of the study, it allows a statistically justified reduction of the sample size. RESULTS: The design is illustrated using data from an Food and Drug Administration (FDA) review of lurasidone for the treatment of schizophrenia. Three studies inform the meta-analysis before the new study is conducted. Results from an additional phase III study, which were not available at the time of the FDA review, are then used for the actual analysis. CONCLUSIONS: In the presence of reliable and relevant evidence, the design offers a way to conduct a smaller study without compromising power. It therefore fills a gap between the assessment of evidence and its actual use in the design and analysis of studies. PMID- 27935811 TI - Which psychotherapy for PTSD? PMID- 27935812 TI - Society for Endocrinology endocrine emergency guidance. PMID- 27935813 TI - SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. PMID- 27935814 TI - SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency management of severe symptomatic hyponatraemia in adult patients. PMID- 27935815 TI - SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency management of acute hypocalcaemia in adult patients. PMID- 27935816 TI - SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency management of acute hypercalcaemia in adult patients. PMID- 27935817 TI - SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency management of pituitary apoplexy in adult patients. PMID- 27935818 TI - Prenatal ethanol exposure in mice phenocopies Cdon mutation by impeding Shh function in the etiology of optic nerve hypoplasia. AB - Septo-optic dysplasia (SOD) is a congenital disorder characterized by optic nerve, pituitary and midline brain malformations. The clinical presentation of SOD is highly variable with a poorly understood etiology. The majority of SOD cases are sporadic, but in rare instances inherited mutations have been identified in a small number of transcription factors, some of which regulate the expression of Sonic hedgehog (Shh) during mouse forebrain development. SOD is also associated with young maternal age, suggesting that environmental factors, including alcohol consumption at early stages of pregnancy, might increase the risk of developing this condition. Here, we address the hypothesis that SOD is a multifactorial disorder stemming from interactions between mutations in Shh pathway genes and prenatal ethanol exposure. Mouse embryos with mutations in the Shh co-receptor, Cdon, were treated in utero with ethanol or saline at embryonic day 8 (E8.0) and evaluated for optic nerve hypoplasia (ONH), a prominent feature of SOD. We show that both Cdon-/- mutation and prenatal ethanol exposure independently cause ONH through a similar pathogenic mechanism that involves selective inhibition of Shh signaling in retinal progenitor cells, resulting in their premature cell-cycle arrest, precocious differentiation and failure to properly extend axons to the optic nerve. The ONH phenotype was not exacerbated in Cdon-/- embryos treated with ethanol, suggesting that an intact Shh signaling pathway is required for ethanol to exert its teratogenic effects. These results support a model whereby mutations in Cdon and prenatal ethanol exposure increase SOD risk through spatiotemporal perturbations in Shh signaling activity. PMID- 27935820 TI - S113R mutation in SLC33A1 leads to neurodegeneration and augmented BMP signaling in a mouse model. AB - The S113R mutation (c.339T>G) (MIM #603690.0001) in SLC33A1 (MIM #603690), an ER membrane acetyl-CoA transporter, has been previously identified in individuals with hereditary spastic paraplegia type 42 (SPG42; MIM #612539). SLC33A1 has also been shown to inhibit the bone morphogenetic protein (BMP) signaling pathway in zebrafish. To better understand the function of SLC33A1, we generated and characterized Slc33a1S113R knock-in mice. Homozygous Slc33a1S113R mutant mice were embryonic lethal, whereas heterozygous Slc33a1 mutant mice (Slc33a1wt/mut) exhibited behavioral abnormalities and central neurodegeneration, which is consistent with hereditary spastic paraplegia (HSP) phenotypes. Importantly, we found an upregulation of BMP signaling in the nervous system and mouse embryonic fibroblasts of Slc33a1wt/mut mice. Using a sciatic nerve crush injury model in vivo and dorsal root ganglion (DRG) culture in vitro we showed that injury induced axonal regeneration in Slc33a1wt/mut mice was accelerated and mediated by upregulated BMP signaling. Exogenous addition of BMP signaling antagonist, noggin, could efficiently alleviate the accelerated injury-induced axonal regrowth. These results indicate that SLC33A1 can negatively regulate BMP signaling in mice, further supporting the notion that upregulation of BMP signaling is a common mechanism of a subset of hereditary spastic paraplegias. PMID- 27935822 TI - Adipose tissue in control of metabolism. AB - Adipose tissue plays a central role in regulating whole-body energy and glucose homeostasis through its subtle functions at both organ and systemic levels. On one hand, adipose tissue stores energy in the form of lipid and controls the lipid mobilization and distribution in the body. On the other hand, adipose tissue acts as an endocrine organ and produces numerous bioactive factors such as adipokines that communicate with other organs and modulate a range of metabolic pathways. Moreover, brown and beige adipose tissue burn lipid by dissipating energy in the form of heat to maintain euthermia, and have been considered as a new way to counteract obesity. Therefore, adipose tissue dysfunction plays a prominent role in the development of obesity and its related disorders such as insulin resistance, cardiovascular disease, diabetes, depression and cancer. In this review, we will summarize the recent findings of adipose tissue in the control of metabolism, focusing on its endocrine and thermogenic function. PMID- 27935819 TI - A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK- and PI3K-induced malignant growth. AB - Somatic mutations activating MAPK and PI3K signalling play a pivotal role in both tumours and brain developmental disorders. We developed a zebrafish model of brain tumours based on somatic expression of oncogenes that activate MAPK and PI3K signalling in neural progenitor cells and found that HRASV12 was the most effective in inducing both heterotopia and invasive tumours. Tumours, but not heterotopias, require persistent activation of phospho (p)-ERK and express a gene signature similar to the mesenchymal glioblastoma subtype, with a strong YAP component. Application of an eight-gene signature to human brain tumours establishes that YAP activation distinguishes between mesenchymal glioblastoma and low grade glioma in a wide The Cancer Genome Atlas (TCGA) sample set including gliomas and glioblastomas (GBMs). This suggests that the activation of YAP might be an important event in brain tumour development, promoting malignant versus benign brain lesions. Indeed, co-expression of dominant-active YAP (YAPS5A) and HRASV12 abolishes the development of heterotopias and leads to the sole development of aggressive tumours. Thus, we have developed a model proving that neurodevelopmental disorders and brain tumours might originate from the same activation of oncogenes through somatic mutations, and established that YAP activation is a hallmark of malignant brain tumours. PMID- 27935821 TI - Stromal hedgehog signaling maintains smooth muscle and hampers micro-invasive prostate cancer. AB - It is widely appreciated that reactive stroma or carcinoma-associated fibroblasts can influence epithelial tumor progression. In prostate cancer (PCa), the second most common male malignancy worldwide, the amount of reactive stroma is variable and has predictive value for tumor recurrence. By analyzing human PCa protein and RNA expression databases, we found smooth muscle cells (SMCs) are decreased in advanced tumors, whereas fibroblasts are maintained. In three mouse models of PCa, PB-MYC, ERG/PTEN and TRAMP, we found the composition of the stroma is distinct. SMCs are greatly depleted in advanced PB-MYC tumors and locally reduced in ERG/PTEN prostates, whereas in TRAMP tumors the SMC layers are increased. In addition, interductal fibroblast-like cells expand in PB-MYC and ERG/PTEN tumors, whereas in TRAMP PCa they expand little and stromal cells invade into intraductal adenomas. Fate mapping of SMCs showed that in PB-MYC tumors the cells are depleted, whereas they expand in TRAMP tumors and interestingly contribute to the stromal cells in intraductal adenomas. Hedgehog (HH) ligands secreted by epithelial cells are known to regulate prostate mesenchyme expansion differentially during development and regeneration. Any possible role of HH signaling in stromal cells during PCa progression is poorly understood. We found that HH signaling is high in SMCs and fibroblasts near tumor cells in all models, and epithelial Shh expression is decreased whereas Ihh and Dhh are increased. In human primary PCa, expression of IHH is the highest of the three HH genes, and elevated HH signaling correlates with high stromal gene expression. Moreover, increasing HH signaling in the stroma of PB-MYC PCa resulted in more intact SMC layers and decreased tumor progression (micro-invasive carcinoma). Thus, we propose HH signaling restrains tumor progression by maintaining the smooth muscle and preventing invasion by tumor cells. Our studies highlight the importance of understanding how HH signaling and stromal composition impact on PCa to optimize drug treatments. PMID- 27935826 TI - Retraction: The generation and characterization of novel Col1a1FRT-Cre-ER-T2-FRT and Col1a1FRT-STOP-FRT-Cre-ER-T2 mice for sequential mutagenesis. PMID- 27935824 TI - Helicobacter pylori VacA, acting through receptor protein tyrosine phosphatase alpha, is crucial for CagA phosphorylation in human duodenum carcinoma cell line AZ-521. AB - Helicobacter pylori, a major cause of gastroduodenal diseases, produces vacuolating cytotoxin (VacA) and cytotoxin-associated gene A (CagA), which seem to be involved in virulence. VacA exhibits pleiotropic actions in gastroduodenal disorders via its specific receptors. Recently, we found that VacA induced the phosphorylation of cellular Src kinase (Src) at Tyr418 in AZ-521 cells. Silencing of receptor protein tyrosine phosphatase (RPTP)alpha, a VacA receptor, reduced VacA-induced Src phosphorylation. Src is responsible for tyrosine phosphorylation of CagA at its Glu-Pro-Ile-Tyr-Ala (EPIYA) variant C (EPIYA-C) motif in Helicobacter pylori-infected gastric epithelial cells, resulting in binding of CagA to SHP-2 phosphatase. Challenging AZ-521 cells with wild-type H. pylori induced phosphorylation of CagA, but this did not occur when challenged with a vacA gene-disrupted mutant strain. CagA phosphorylation was observed in cells infected with a vacA gene-disrupted mutant strain after addition of purified VacA, suggesting that VacA is required for H. pylori-induced CagA phosphorylation. Following siRNA-mediated RPTPalpha knockdown in AZ-521 cells, infection with wild-type H. pylori and treatment with VacA did not induce CagA phosphorylation. Taken together, these results support our conclusion that VacA mediates CagA phosphorylation through RPTPalpha in AZ-521 cells. These data indicate the possibility that Src phosphorylation induced by VacA is mediated through RPTPalpha, resulting in activation of Src, leading to CagA phosphorylation at Tyr972 in AZ-521 cells. PMID- 27935828 TI - Resumes dans ce numero. PMID- 27935829 TI - Resumenes en esta edicion. PMID- 27935823 TI - Renal disease pathophysiology and treatment: contributions from the rat. AB - The rat has classically been the species of choice for pharmacological studies and disease modeling, providing a source of high-quality physiological data on cardiovascular and renal pathophysiology over many decades. Recent developments in genome engineering now allow us to capitalize on the wealth of knowledge acquired over the last century. Here, we review rat models of hypertension, diabetic nephropathy, and acute and chronic kidney disease. These models have made important contributions to our understanding of renal diseases and have revealed key genes, such as Ace and P2rx7, involved in renal pathogenic processes. By targeting these genes of interest, researchers are gaining a better understanding of the etiology of renal pathologies, with the promised potential of slowing disease progression or even reversing the damage caused. Some, but not all, of these target genes have proved to be of clinical relevance. However, it is now possible to generate more sophisticated and appropriate disease models in the rat, which can recapitulate key aspects of human renal pathology. These advances will ultimately be used to identify new treatments and therapeutic targets of much greater clinical relevance. PMID- 27935831 TI - The Brief Case: Probable Transfusion-Transmitted Babesiosis in a Transplant Recipient. PMID- 27935825 TI - Microglia activation in a pediatric rabbit model of tuberculous meningitis. AB - Central nervous system (CNS) tuberculosis (TB) is the most severe form of extra pulmonary TB and disproportionately affects young children where the developing brain has a unique host response. New Zealand white rabbits were infected with Mycobacterium tuberculosis via subarachnoid inoculation at postnatal day 4-8 and evaluated until 4-6 weeks post-infection. Control and infected rabbit kits were assessed for the development of neurological deficits, bacterial burden, and postmortem microbiologic and pathologic changes. The presence of meningitis and tuberculomas was demonstrated histologically and by in vivo magnetic resonance imaging (MRI). The extent of microglial activation was quantified by in vitro immunohistochemistry as well as non-invasive in vivo imaging of activated microglia/macrophages with positron emission tomography (PET). Subarachnoid infection induced characteristic leptomeningeal and perivascular inflammation and TB lesions with central necrosis, a cellular rim and numerous bacilli on pathologic examination. Meningeal and rim enhancement was visible on MRI. An intense microglial activation was noted in M. tuberculosis-infected animals in the white matter and around the TB lesions, as evidenced by a significant increase in uptake of the tracer 124I-DPA-713, which is specific for activated microglia/macrophages, and confirmed by quantification of Iba-1 immunohistochemistry. Neurobehavioral analyses demonstrated signs similar to those noted in children with delayed maturation and development of neurological deficits resulting in significantly worse composite behavior scores in M. tuberculosis-infected animals. We have established a rabbit model that mimics features of TB meningitis in young children. This model could provide a platform for evaluating novel therapies, including host-directed therapies, against TB meningitis relevant to a young child's developing brain. PMID- 27935830 TI - Photo Quiz: A Man with Lymphadenopathy and Lethargy. PMID- 27935832 TI - Closing the Brief Case: Probable Transfusion-Transmitted Babesiosis in a Transplant Recipient. PMID- 27935833 TI - Answer to November 2016 Photo Quiz. PMID- 27935834 TI - Viral DNA Sensors IFI16 and Cyclic GMP-AMP Synthase Possess Distinct Functions in Regulating Viral Gene Expression, Immune Defenses, and Apoptotic Responses during Herpesvirus Infection. AB - : The human interferon-inducible protein IFI16 is an important antiviral factor that binds nuclear viral DNA and promotes antiviral responses. Here, we define IFI16 dynamics in space and time and its distinct functions from the DNA sensor cyclic dinucleotide GMP-AMP synthase (cGAS). Live-cell imaging reveals a multiphasic IFI16 redistribution, first to viral entry sites at the nuclear periphery and then to nucleoplasmic puncta upon herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV) infections. Optogenetics and live-cell microscopy establish the IFI16 pyrin domain as required for nuclear periphery localization and oligomerization. Furthermore, using proteomics, we define the signature protein interactions of the IFI16 pyrin and HIN200 domains and demonstrate the necessity of pyrin for IFI16 interactions with antiviral proteins PML and cGAS. We probe signaling pathways engaged by IFI16, cGAS, and PML using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated knockouts in primary fibroblasts. While IFI16 induces cytokines, only cGAS activates STING/TBK-1/IRF3 and apoptotic responses upon HSV-1 and HCMV infections. cGAS-dependent apoptosis upon DNA stimulation requires both the enzymatic production of cyclic dinucleotides and STING. We show that IFI16, not cGAS or PML, represses HSV-1 gene expression, reducing virus titers. This indicates that regulation of viral gene expression may function as a greater barrier to viral replication than the induction of antiviral cytokines. Altogether, our findings establish coordinated and distinct antiviral functions for IFI16 and cGAS against herpesviruses. IMPORTANCE: How mammalian cells detect and respond to DNA viruses that replicate in the nucleus is poorly understood. Here, we decipher the distinct functions of two viral DNA sensors, IFI16 and cGAS, during active immune signaling upon infection with two herpesviruses, herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV). We show that IFI16 rapidly oligomerizes at incoming herpesvirus genomes at the nuclear periphery to transcriptionally repress viral gene expression and limit viral replicative capacity. We further demonstrate that IFI16 does not initiate upstream activation of the canonical STING/TBK-1/IRF3 signaling pathway but is required for downstream antiviral cytokine expression. In contrast, we find that, upon DNA sensing during herpesvirus infection, cGAS triggers apoptosis in a STING dependent manner. Our live-cell imaging, mass spectrometry-based proteomics, CRISPR-based cellular assays, and optogenetics underscore the value of integrative approaches to uncover complex cellular responses against pathogens. PMID- 27935835 TI - Robust Extracellular pH Modulation by Candida albicans during Growth in Carboxylic Acids. AB - : The opportunistic fungal pathogen Candida albicans thrives within diverse niches in the mammalian host. Among the adaptations that underlie this fitness is an ability to utilize a wide array of nutrients, especially sources of carbon that are disfavored by many other fungi; this contributes to its ability to survive interactions with the phagocytes that serve as key barriers against disseminated infections. We have reported that C. albicans generates ammonia as a byproduct of amino acid catabolism to neutralize the acidic phagolysosome and promote hyphal morphogenesis in a manner dependent on the Stp2 transcription factor. Here, we report that this species rapidly neutralizes acidic environments when utilizing carboxylic acids like pyruvate, alpha-ketoglutarate (alphaKG), or lactate as the primary carbon source. Unlike in cells growing in amino acid-rich medium, this does not result in ammonia release, does not induce hyphal differentiation, and is genetically distinct. While transcript profiling revealed significant similarities in gene expression in cells grown on either carboxylic or amino acids, genetic screens for mutants that fail to neutralize alphaKG medium identified a nonoverlapping set of genes, including CWT1, encoding a transcription factor responsive to cell wall and nitrosative stresses. Strains lacking CWT1 exhibit retarded alphaKG-mediated neutralization in vitro, exist in a more acidic phagolysosome, and are more susceptible to macrophage killing, while double cwt1Delta stp2Delta mutants are more impaired than either single mutant. Together, our observations indicate that C. albicans has evolved multiple ways to modulate the pH of host-relevant environments to promote its fitness as a pathogen. IMPORTANCE: The fungal pathogen Candida albicans is a ubiquitous and usually benign constituent of the human microbial ecosystem. In individuals with weakened immune systems, this organism can cause potentially life-threatening infections and is one of the most common causes of hospital-acquired infections. Understanding the interactions between C. albicans and immune phagocytic cells, such as macrophages and neutrophils, will define the mechanisms of pathogenesis in this species. One such adaptation is an ability to make use of nonstandard nutrients that we predict are plentiful in certain niches within the host, including within these phagocytic cells. We show here that the metabolism of certain organic acids enables C. albicans to neutralize acidic environments, such as those within macrophages. This phenomenon is distinct in several significant ways from previous reports of similar processes, indicating that C. albicans has evolved multiple mechanisms to combat the harmful acidity of phagocytic cells. PMID- 27935836 TI - The PAS Domain-Containing Protein HeuR Regulates Heme Uptake in Campylobacter jejuni. AB - Campylobacter jejuni is a leading cause of bacterially derived gastroenteritis. A previous mutant screen demonstrated that the heme uptake system (Chu) is required for full colonization of the chicken gastrointestinal tract. Subsequent work identified a PAS domain-containing regulator, termed HeuR, as being required for chicken colonization. Here we confirm that both the heme uptake system and HeuR are required for full chicken gastrointestinal tract colonization, with the heuR mutant being particularly affected during competition with wild-type C. jejuni Transcriptomic analysis identified the chu genes-and those encoding other iron uptake systems-as regulatory targets of HeuR. Purified HeuR bound the chuZA promoter region in electrophoretic mobility shift assays. Consistent with a role for HeuR in chu expression, heuR mutants were unable to efficiently use heme as a source of iron under iron-limiting conditions, and mutants exhibited decreased levels of cell-associated iron by mass spectrometry. Finally, we demonstrate that an heuR mutant of C. jejuni is resistant to hydrogen peroxide and that this resistance correlates to elevated levels of catalase activity. These results indicate that HeuR directly and positively regulates iron acquisition from heme and negatively impacts catalase activity by an as yet unidentified mechanism in C. jejuni IMPORTANCE: Annually, Campylobacter jejuni causes millions of gastrointestinal infections in the United States, due primarily to its ability to reside within the gastrointestinal tracts of poultry, where it can be released during processing and contaminate meat. In the developing world, humans are often infected by consuming contaminated water or by direct contact with livestock. Following consumption of contaminated food or water, humans develop disease that is characterized by mild to severe diarrhea. There is a need to understand both colonization of chickens, to make food safer, and colonization of humans, to better understand disease. Here we demonstrate that to efficiently colonize a host, C. jejuni requires iron from heme, which is regulated by the protein HeuR. Understanding how HeuR functions, we can develop ways to inhibit its function and reduce iron acquisition during colonization, potentially reducing C. jejuni in the avian host, which would make food safer, or limiting human colonization. PMID- 27935837 TI - Patient-Specific Bacteroides Genome Variants in Pouchitis. AB - : A 2-year longitudinal microbiome study of 22 patients who underwent colectomy with an ileal pouch anal anastomosis detected significant increases in distinct populations of Bacteroides during 9 of 11 patient visits that coincided with inflammation (pouchitis). Oligotyping and metagenomic short-read annotation identified Bacteroides populations that occurred in early samples, bloomed during inflammation, and reappeared after antibiotic treatment. Targeted cultivation of Bacteroides isolates from the same individual at multiple time points and from several patients detected subtle genomic changes, including the identification of rapidly evolving genomic elements that differentiate isogenic strains of Bacteroides fragilis from the mucosa versus lumen. Each patient harbored Bacteroides spp. that are closely related to commonly occurring clinical isolates, including Bacteroides ovatus, B. thetaiotaomicron, B. vulgatus, and B. fragilis, which contained unique loci in different patients for synthesis of capsular polysaccharides. The presence of unique Bacteroides capsular polysaccharide loci within different hosts and between the lumen and mucosa may represent adaptations to stimulate, suppress, and evade host-specific immune responses at different microsites of the ileal pouch. IMPORTANCE: This longitudinal study provides an opportunity to describe shifts in the microbiomes of individual patients who suffer from ulcerative colitis (UC) prior to and following inflammation. Pouchitis serves as a model for UC with a predictable incidence of disease onset and enables prospective longitudinal investigations of UC etiology prior to inflammation. Because of insufficient criteria for predicting which patients will develop UC or pouchitis, the interpretation of cross-sectional study designs suffers from lack of information about the microbiome structure and host gene expression patterns that directly correlate with the onset of disease. Our unique longitudinal study design allows each patient to serve as their own control, providing information about the state of the microbiome and host prior to and during the course of disease. Of significance to the broader community, this study identifies microbial strains that may have genetic elements that trigger the onset of disease in susceptible hosts. PMID- 27935838 TI - The Paralogous Histone Deacetylases Rpd3 and Rpd31 Play Opposing Roles in Regulating the White-Opaque Switch in the Fungal Pathogen Candida albicans. AB - : Chromatin modifications affect gene regulation in response to environmental stimuli in numerous biological processes. For example, N-acetyl-glucosamine and CO2 induce a morphogenetic conversion between white (W) and opaque (O) cells in MTL (mating-type locus) homozygous and heterozygous ( A: /alpha) strains of the human fungal pathogen Candida albicans Here, we identify 8 histone-modifying enzymes playing distinct roles in the regulation of W/O switching in MTL homozygous and heterozygous strains. Most strikingly, genetic removal of the paralogous genes RPD3 and RPD31, both of which encode almost identical orthologues of the yeast histone deacetylase (HDAC) Rpd3, reveals opposing roles in W/O switching of MTL A: /alpha strains. We show that Rpd3 and Rpd31 functions depend on MTL genotypes. Strikingly, we demonstrate that Rpd3 and Rpd31, which are almost identical except for a divergent C-terminal extension present in Rpd31, exert their functions in distinct regulatory complexes referred to as CaRpd3L and CaRpd31S complexes. Moreover, we identify the Candida orf19.7185 product Ume1, the orthologue of yeast Ume1, as a shared core subunit of CaRpd3L and CaRpd31S. Mechanistically, we show that the opposing roles of Rpd3 and Rpd31 require their deacetylase activities. Importantly, CaRpd3L interacts with the heterodimeric transcriptional repressor A: 1/alpha2, thus controlling expression of WOR1 encoding the master regulator of W/O switching. Thus, our work provides novel insight about regulation mechanisms of W/O switching in MTL A: /alpha strains. This is the first example of two highly conserved HDACs exerting opposing regulatory functions in the same process in a eukaryotic cell. IMPORTANCE: RPD3-like histone deacetylases (also called class I HDACs) are conserved from unicellular eukaryotes to mammals. Specifically, the genome of the human fungal pathogen Candida albicans, the most frequent cause of invasive fungal infections of high morbidity and mortality, harbors two almost identical paralogous HDACs, Rpd3 and Rpd31. We show here for the first time that Rpd3 and Rpd31 acquired functional divergence related to a distinct C-terminal domain. Rpd3 and Rpd31 associate with different complexes in the control regions of the master regulator gene WOR1, which is required for white-opaque (W/O) morphogenesis, respectively. The ability to switch is important for fungal pathogenesis, since it enables distinct host niche colonization. This work is to the best of our knowledge the first description of two paralogous HDACs playing opposing functional roles in the same developmental process. Our work adds a new angle concerning the molecular understanding of HDACs in the regulation of cell fate decisions. PMID- 27935839 TI - Capsular Polysaccharide Expression in Commensal Streptococcus Species: Genetic and Antigenic Similarities to Streptococcus pneumoniae. AB - : Expression of a capsular polysaccharide is considered a hallmark of most invasive species of bacteria, including Streptococcus pneumoniae, in which the capsule is among the principal virulence factors and is the basis for successful vaccines. Consequently, it was previously assumed that capsule production distinguishes S. pneumoniae from closely related commensals of the mitis group streptococci. Based on antigenic and genetic analyses of 187 mitis group streptococci, including 90 recognized serotypes of S. pneumoniae, we demonstrated capsule production by the Wzy/Wzx pathway in 74% of 66 S. mitis strains and in virtually all tested strains of S. oralis (subspecies oralis, dentisani, and tigurinus) and S. infantis Additional analyses of genomes of S. cristatus, S. parasanguinis, S. australis, S. sanguinis, S. gordonii, S. anginosus, S. intermedius, and S. constellatus revealed complete capsular biosynthesis (cps) loci in all strains tested. Truncated cps loci were detected in three strains of S. pseudopneumoniae, in 26% of S. mitis strains, and in a single S. oralis strain. The level of sequence identities of cps locus genes confirmed that the structural polymorphism of capsular polysaccharides in S. pneumoniae evolved by import of cps fragments from commensal Streptococcus species, resulting in a mosaic of genes of different origins. The demonstrated antigenic identity of at least eight of the numerous capsular polysaccharide structures expressed by commensal streptococci with recognized serotypes of S. pneumoniae raises concerns about potential misidentifications in addition to important questions concerning the consequences for vaccination and host-parasite relationships both for the commensals and for the pathogen. IMPORTANCE: Expression of a capsular polysaccharide is among the principal virulence factors of Streptococcus pneumoniae and is the basis for successful vaccines against infections caused by this important pathogen. Contrasting with previous assumptions, this study showed that expression of capsular polysaccharides by the same genetic mechanisms is a general property of closely related species of streptococci that form a significant part of our commensal microbiota. The demonstrated antigenic identity of many capsular polysaccharides expressed by commensal streptococci and S. pneumoniae raises important questions concerning the consequences for vaccination and host-parasite relationships both for the commensals and the pathogen. PMID- 27935840 TI - A Stress-Induced Bias in the Reading of the Genetic Code in Escherichia coli. AB - : Escherichia coli mazEF is an extensively studied stress-induced toxin-antitoxin (TA) system. The toxin MazF is an endoribonuclease that cleaves RNAs at ACA sites. Thereby, under stress, the induced MazF generates a stress-induced translation machinery (STM), composed of MazF-processed mRNAs and selective ribosomes that specifically translate the processed mRNAs. Here, we further characterized the STM system, finding that MazF cleaves only ACA sites located in the open reading frames of processed mRNAs, while out-of-frame ACAs are resistant. This in-frame ACA cleavage of MazF seems to depend on MazF binding to an extracellular-death-factor (EDF)-like element in ribosomal protein bS1 (bacterial S1), apparently causing MazF to be part of STM ribosomes. Furthermore, due to the in-frame MazF cleavage of ACAs under stress, a bias occurs in the reading of the genetic code causing the amino acid threonine to be encoded only by its synonym codon ACC, ACU, or ACG, instead of by ACA. IMPORTANCE: The genetic code is a universal characteristic of all living organisms. It defines the set of rules by which nucleotide triplets specify which amino acid will be incorporated into a protein. Our results represent the first existing report on a stress induced bias in the reading of the genetic code. We found that in E. coli, under stress, the amino acid threonine is encoded only by its synonym codon ACC, ACU, or ACG, instead of by ACA. This is because under stress, MazF generates a stress induced translation machinery (STM) in which MazF cleaves in-frame ACA sites of the processed mRNAs. PMID- 27935841 TI - The Cytoplasmic Tail Domain of Epstein-Barr Virus gH Regulates Membrane Fusion Activity through Altering gH Binding to gp42 and Epithelial Cell Attachment. AB - : Epstein-Barr virus (EBV) is associated with infectious mononucleosis and a variety of cancers as well as lymphoproliferative disorders in immunocompromised patients. EBV mediates viral entry into epithelial and B cells using fusion machinery composed of four glycoproteins: gB, the gH/gL complex, and gp42. gB and gH/gL are required for both epithelial and B cell fusion. The specific role of gH/gL in fusion has been the most elusive among the required herpesvirus entry glycoproteins. Previous mutational studies have focused on the ectodomain of EBV gH and not on the gH cytoplasmic tail domain (CTD). In this study, we chose to examine the function of the gH CTD by making serial gH truncation mutants as well as amino acid substitution mutants to determine the importance of the gH CTD in epithelial and B cell fusion. Truncation of 8 amino acids (aa 698 to 706) of the gH CTD resulted in diminished fusion activity using a virus-free syncytium formation assay and fusion assay. The importance of the amino acid composition of the gH CTD was also investigated by amino acid substitutions that altered the hydrophobicity or hydrophilicity of the CTD. These mutations also resulted in diminished fusion activity. Interestingly, some of the gH CTD truncation mutants and hydrophilic tail substitution mutants lost the ability to bind to gp42 and epithelial cells. In summary, our studies indicate that the gH CTD is an important functional domain. IMPORTANCE: Infection with Epstein-Barr virus (EBV) causes diseases ranging from the fairly benign infectious mononucleosis to life threatening cancer. Entry into target cells is the first step for viral infection and is important for EBV to cause disease. Understanding the EBV entry mechanism is useful for the development of infection inhibitors and developing EBV vaccine approaches. Epithelial and B cells are the main target cells for EBV infection. The essential glycoproteins for EBV entry include gB, gH/gL, and gp42. We characterized the function of the EBV gH C-terminal cytoplasmic tail domain (CTD) in fusion using a panel of gH CTD truncation or substitution mutants. We found that the gH CTD regulates fusion by altering gp42 and epithelial cell attachment. Our studies may lead to a better understanding of EBV fusion and entry, which may result in novel therapies that target the EBV entry step. PMID- 27935842 TI - When Obligate Partners Melt Down. AB - Insect hosts derive benefits from their obligate symbionts, including nutrient supplementation and the ability to colonize otherwise inhospitable niches. But long-term symbionts sometimes also limit the ecological range of their hosts; in particular, they are often more temperature sensitive than the hosts themselves. Even small increases in average temperature, comparable to those occurring under current conditions of climate change, can kill symbionts and, with them, their hosts. In some cases, limitations imposed by obligate symbionts may help to counter the spread of invasive pests, but they also contribute to contractions in populations and geographic ranges of invertebrate species. PMID- 27935843 TI - Siderophores: More than Stealing Iron. AB - Siderophores are small molecular iron chelators that are produced by microbes and whose most notable function is to sequester iron from the host and provide this essential metal nutrient to microbes. Recent studies have proposed additional, noncanonical roles for siderophores, including the acquisition of noniron metals and modulation of host functions. Recently, Holden et al. (V. I. Holden, P. Breen, S. Houle, C. M. Dozois, and M. A. Bachman, mBio 7:e01397-16, 2016, http://dx.doi.org/10.1128/mBio.01397-16) showed that siderophores secreted by Klebsiella pneumoniae during lung infection induce stabilization of the transcription factor HIF-1alpha, increase the expression of proinflammatory cytokines in the lung, and promote dissemination of K. pneumoniae to the spleen. Thus, their study demonstrated novel roles for siderophores in vivo, beyond iron sequestration. The interaction of siderophores with host cells further promotes the pathogenicity of K. pneumoniae and is likely relevant for other pathogens that also secrete siderophores in the host. PMID- 27935844 TI - Cooperative Evolutionary Strategy between the Bacteriome and Mycobiome. AB - Nonhealing chronic wounds are all unique in origin and circumstance, and attempting to isolate a single etiology for the failure of a wound to heal is daunting. Wounds represent complex systems of multispecies fungal and bacterial biofilms. The survival strategies of interactive microbial communities have led to cooperative evolutionary strategies that culminate in biofilm formation. In microbial dysbiosis, biofilms are beneficial to both bacterial and fungal communities but detrimental to the host. Fungi benefit by a surge in their virulence factors, while bacteria become tolerant to antibacterials as a consequence of living under the protective umbrella of the biofilm matrix. This interkingdom cooperation negatively impacts the host, as the fungi and bacteria produce extracellular enzymes that inflict tissue damage, leading to an increase in proinflammatory cytokines, which results in oxidative damage and apoptotic cell death. PMID- 27935845 TI - Stability and aggregation propensity do not fully account for the association of various germline variable domain gene segments with light chain amyloidosis. AB - Variable domain (VL) gene segments exhibit variable tendencies to be associated with light chain amyloidosis (AL). While few of them are very frequent in AL and give rise to most of the amyloidogenic light chains compiled at the sequence databases, other are rarely found among the AL cases. To analyze to which extent these tendencies depend on folding stability and aggregation propensity of the germline VL protein, we characterized VL proteins encoded by four AL-associated germline gene segments and one not associated to AL. We found that the AL associated germline rVL proteins differ widely in conformational stability and propensity to in vitro amyloid aggregation. While in vitro the amyloid formation kinetics of these proteins correlate well with their folding stabilities, the folding stability does not clearly correlate with their germline's frequencies in AL. We conclude that the association of the VL genes segments to amyloidosis is not determined solely by the folding stability and aggregation propensity of the germline VL protein. Other factors, such as the frequencies of destabilizing mutations and susceptibility to proteolysis, must play a role in determining the light chain amyloidogenicity. PMID- 27935846 TI - Guardians in a stressful world: the Opu family of compatible solute transporters from Bacillus subtilis. AB - The development of a semi-permeable cytoplasmic membrane was a key event in the evolution of microbial proto-cells. As a result, changes in the external osmolarity will inevitably trigger water fluxes along the osmotic gradient. The ensuing osmotic stress has consequences for the magnitude of turgor and will negatively impact cell growth and integrity. No microorganism can actively pump water across the cytoplasmic membrane; hence, microorganisms have to actively adjust the osmotic potential of their cytoplasm to scale and direct water fluxes in order to prevent dehydration or rupture. They will accumulate ions and physiologically compliant organic osmolytes, the compatible solutes, when they face hyperosmotic conditions to retain cell water, and they rapidly expel these compounds through the transient opening of mechanosensitive channels to curb water efflux when exposed to hypo-osmotic circumstances. Here, we provide an overview on the salient features of the osmostress response systems of the ubiquitously distributed bacterium Bacillus subtilis with a special emphasis on the transport systems and channels mediating regulation of cellular hydration and turgor under fluctuating osmotic conditions. The uptake of osmostress protectants via the Opu family of transporters, systems of central importance for the management of osmotic stress by B. subtilis, will be particularly highlighted. PMID- 27935847 TI - Structure-based development of PDEdelta inhibitors. AB - The prenyl binding protein PDEdelta enhances the diffusion of farnesylated Ras proteins in the cytosol, ultimately affecting their correct localization and signaling. This has turned PDEdelta into a promising target to prevent oncogenic KRas signaling. In this review we summarize and describe the structure-guided development of the three different PDEdelta inhibitor chemotypes that have been documented so far. We also compare both their potency for binding to the PDEdelta pocket and their in vivo efficiency in suppressing oncogenic KRas signaling, as a result of the inhibition of the PDEdelta/KRas interaction. PMID- 27935850 TI - Physical activity: start at a younger age. PMID- 27935848 TI - Plasmin(ogen) serves as a favorable biomarker for prediction of survival in advanced high-grade serous ovarian cancer. AB - In serous ovarian cancer, the clinical relevance of tumor cell-expressed plasmin(ogen) (PLG) has not yet been evaluated. Due to its proteolytic activity, plasmin supports tumorigenesis, however, angiostatin(-like) fragments, derived from PLG, can also function as potent anti-tumorigenic factors. In the present study, we assessed PLG protein expression in 103 cases of advanced high-grade serous ovarian cancer (FIGO III/IV) by immunohistochemistry (IHC). In 70/103 cases, positive staining of tumor cells was observed. In univariate Cox regression analysis, PLG staining was positively associated with prolonged overall survival (OS) [hazard ratio (HR)=0.59, p=0.026] of the patients. In multivariable analysis, PLG, together with residual tumor mass, remained a statistically significant independent prognostic marker (HR=0.49, p=0.009). In another small patient cohort (n=29), we assessed mRNA expression levels of PLG by quantitative PCR. Here, elevated PLG mRNA levels were also significantly associated with prolonged OS of patients (Kaplan-Meier analysis; p=0.001). This finding was validated by in silico analysis of a microarray data set (n=398) from The Cancer Genome Atlas (Kaplan-Meier analysis; p=0.031). In summary, these data indicate that elevated PLG expression represents a favorable prognostic biomarker in advanced (FIGO III/IV) high-grade serous ovarian cancer. PMID- 27935849 TI - The class III phosphatidylinositol 3-kinase Vps34 in Saccharomyces cerevisiae. AB - The class III phosphatidylinositol 3-kinase Vps34 (vacuolar protein sorting 34) catalyzes for the formation of the signaling lipid phosphatidylinositol-3 phopsphate, which is a central factor in the regulation of autophagy, endocytic trafficking and vesicular transport. In this article, we discuss the functional role of the lipid kinase Vps34 in Saccharomyces cerevisiae. PMID- 27935851 TI - An analysis of the sequence of the BAD gene among patients with maturity-onset diabetes of the young (MODY). AB - BACKGROUND: Monogenic diabetes is a rare disease caused by single gene mutations. Maturity onset diabetes of the young (MODY) is one of the major forms of monogenic diabetes recognised in the paediatric population. To date, 13 genes have been related to MODY development. The aim of the study was to analyse the sequence of the BCL2-associated agonist of cell death (BAD) gene in patients with clinical suspicion of GCK-MODY, but who were negative for glucokinase (GCK) gene mutations. METHODS: A group of 122 diabetic patients were recruited from the "Polish Registry for Paediatric and Adolescent Diabetes - nationwide genetic screening for monogenic diabetes" project. The molecular testing was performed by Sanger sequencing. RESULTS: A total of 10 sequence variants of the BAD gene were identified in 122 analysed diabetic patients. CONCLUSIONS: Among the analysed patients suspected of MODY, one possible pathogenic variant was identified in one patient; however, further confirmation is required for a certain identification. PMID- 27935852 TI - Three cases of Japanese acromicric/geleophysic dysplasia with FBN1 mutations: a comparison of clinical and radiological features. AB - Acromicric dysplasia (AD) and geleophysic dysplasia (GD) are rare skeletal dysplasias characterized by short stature, acromelia, joint contracture, hepatomegaly, hoarseness and respiratory distress. Compared with GD, AD presents with milder clinical and radiological features. Radiological findings of AD and GD consist of shortened tubular bones of the hands and feet, and deformed capital femoral epiphyses. The genetic cause of AD and some cases of GD was shown to be mutations in the transforming growth factor (TGF) beta-binding protein-like domain 5 of the fibrillin 1 gene (FBN1), which is also mutated in Marfan syndrome. In the present study, we report and compare the highly varied clinical and radiological features of three Japanese AD/GD children. Our patients, harboring FBN1 mutations p.Tyr1699Cys, p.Ser1750Arg, and p.Gly1762Ser, shared common clinical symptoms such as severe short stature, acromelia and hepatomegaly. Short tubular bones of hands and deformities of femur heads are common radiological features of our patients. PMID- 27935853 TI - Food exchange estimation by children with type 1 diabetes at summer camp. AB - BACKGROUND: As exchange counting poses difficulty for children with type 1 diabetes (T1D) attending diabetes camps, they often guesstimate food amount without performing an exchange calculation. The aim of the study was to compare the accuracy of estimation with exchange counting using the mobile food exchange calculator (MFEC). METHODS: During a summer camp, 25 children with T1D on pumps estimated the number of carbohydrate (CE) and fat/protein exchanges (FPE) appropriate for main meals. Afterwards, the number of exchanges was counted with MFEC and electronic scales. RESULTS: There was a difference between CE (p<0.0001) and FPE (p<0.0001) estimations and counting using MFEC. The youth miscalculated the true values of >=1 CE and >=1 FPE by 31% and 23%, respectively. They more often underestimated than overestimated CE and FPE (p<0.0001). The estimation error increased with younger age. CONCLUSIONS: Carbohydrate counting caused significant error in the exchange number. The use of MFEC facilitates correct exchange calculation. Patients should weigh food and calculate exchanges themselves using mobile applications. PMID- 27935854 TI - Second-trimester maternal serum markers in the prediction of preeclampsia. AB - AIM: To determine whether late second-trimester maternal serum biomarkers are useful for the prediction of preeclampsia during the third trimester, a case control study including 33 preeclamptic and 71 healthy pregnancies was conducted. Maternal serum concentrations of placental protein 13 (PP13), pregnancy associated plasma protein (PAPP-A), pentraxin3 (PTX3), soluble FMS-like tyrosine kinase-1 (sFlt-1), myostatin and follistatin-like-3 (FSLT-3) were measured at 24 28 weeks' gestation. All the concentrations of these markers were compared between the preeclamptic and control groups. Receiver operating characteristic (ROC) curve analysis was applied to assess sensitivity and specificity of serum markers with significant difference. RESULTS: The levels of PP13 and sFlt-1 were significantly increased and FSLT3 was significantly decreased in patients with preeclampsia. However, the concentration of PAPPA, PTX3 and myostatin did not differ significantly. In screening for preeclampsia during the third trimester by PP13, sFlt-1 and FSLT3, the detection rate was 61.3%, 48.1% and 39.1%, respectively, at 80% specificity, and the detection rate increased to 69.8% by combination of these three markers. CONCLUSION: Maternal serum levels of PP13, sFlt-1 and FSLT3 play an important role in predicting late-onset preeclampsia, and the combination of these three markers significantly increases the detection rate for prediction. PMID- 27935855 TI - Estimation of fetal weight by ultrasonography after preterm premature rupture of membranes: comparison of different formulas. AB - OBJECTIVE: To compare different ultrasonographic fetal weight estimation formulas in predicting the fetal birth weight of preterm premature rupture of membrane (PPROM) fetuses. METHODS: Based on the ultrasonographic measurements, the estimated fetal weight (EFW) was calculated according to the published formulas. The comparisons used estimated birth weight (EBW) and observed birth weight (OBW) to calculate the mean absolute percentage error [(EBW-OBW)/OBW*100], mean percentage error [(EBW-OBW)/OBW*100)] and their 95% confidence intervals. RESULTS: There were 234 PPROM patients in the study period. The mean gestational age at which PPROM occured was 31.2+/-3.7 weeks and the mean gestational age of delivery was 32.4+/-3.2 weeks. The mean birth weight was 1892+/-610 g. The median absolute percentage error for 33 formulas was 11.7%. 87.9% and 21.2% of the formulas yielded inaccurate results when the cut-off values for median absolute percentage error were 10% and 15%, respectively. The Vintzileos' formula was the only method which had less than or equal to 10% absolute percentage error in all age and weight groups. CONCLUSIONS: For PPROM patients, most of the formulas designed for sonographic fetal weight estimation had acceptable performance. The Vintzileos' method was the only formula having less than 10% absolute percentage error in all gestational age and weight groups; therefore, it may be the preferred method in this cohort. Amniotic fluid index (AFI) before delivery had no impact on the performance of the formulas in terms of mean percentage errors. PMID- 27935856 TI - Environmental PAH exposure and male idiopathic infertility: a review on early life exposures and adult diagnosis. AB - The male reproductive system is acutely and uniquely sensitive to a variety of toxicities, including those induced by environmental pollutants throughout the lifespan. Early life hormonal and morphological development results in several especially sensitive critical windows of toxicity risk associated with lifelong decreased reproductive health and fitness. Male factor infertility can account for over 40% of infertility in couples seeking treatment, and 44% of infertile men are diagnosed with idiopathic male infertility. Human environmental exposures are poorly understood due to limited available data. The latency between maternal and in utero exposure and a diagnosis in adulthood complicates the correlation between environmental exposures and infertility. The results from this review include recommendations for more and region specific monitoring of polycyclic aromatic hydrocarbon (PAH) exposure, longitudinal and clinical cohort considerations of exposure normalization, gene-environment interactions, in utero exposure studies, and controlled mechanistic animal experiments. Additionally, it is recommended that detailed semen analysis and male fertility data be included as endpoints in environmental exposure cohort studies due to the sensitivity of the male reproductive system to environmental pollutants, including PAHs. PMID- 27935857 TI - Potentiation of the anticancer effects of everolimus using a dual mTORC1/2 inhibitor in hepatocellular carcinoma cells. AB - There is lots of evidence to support the critical involvement of mTOR signaling in the carcinogenesis of hepatocellular carcinoma (HCC). However, it has not been determined how the roles of individual mTORC1 and mTORC2 inhibitors played in the HCC therapeutics. We thus compared the effects of everolimus, Ku0063794, and a combination of the two therapies on HCC cells, using various in vitro studies (HepG2, Hep3B, and Huh7 cells), ex vivo culturing of HCC tissues obtained from patients, and the in vivo mouse xenograft model of HCC cells. Our in vitro, ex vivo, and in vivo experiments consistently demonstrated that everolimus and Ku0063794 combination therapy was superior to individual monotherapies, as manifested by higher reduction of proliferation, migration, and invasion of HCC cells, and the higher inhibition of EMT process as well. Although individual monotherapies could not inhibit SIRT1 (positive regulator of EMT) expression, the combination therapy significantly inhibited SIRT1 expression. However, overexpression of SIRT1 mitigated the EMT-inhibiting effect of the combination therapy, suggesting that the combination therapy inhibits the EMT by way of suppressing SIRT1 expression. Therefore, when considering everolimus as an anti HCC agent, the improved anticancer effects provided by combining it with an inhibitor of both mTORC1 and mTORC2 should be recognized. PMID- 27935858 TI - Paradoxical induction of growth arrest and apoptosis by EGF via the up-regulation of PTEN by activating Redox factor-1/Egr-1 in human lung cancer cells. AB - Epidermal growth factor (EGF) signaling promotes cell proliferation and survival in several types of cancer. Here, however, we showed that EGF inhibits proliferation and promotes programmed cell death in non-small cell lung cancer (NSCLC) cells. In A549 cells, EGF increased redox factor-1 (Ref-1) expression and the association of Ref-1 with zinc finger-containing transcriptional regulator (EGR1) via activation of p22phox, RAC1, and an NADPH oxidase subunit. EGF increased p22phox and RAC1 expression through activation of purinergic receptors (P2Y). Elevated Ref-1/EGR1 levels increased phosphatase and tensin homolog (PTEN) levels, leading to inhibition of the Akt pathway. EGF-induced PTEN upregulation increased apoptosis and autophagy-induced damage in A549 cells, whereas Ref-1 knockdown blocked EGF-induced PTEN upregulation in an NADPH oxidase p22phox subunit-independent manner. In addition, p22phox knockdown restored EGF-induced effects, implying that changes in P2Y activity caused by EGF, which activates NADPH oxidase via RAC1, influenced Ref-1-mediated redox regulation. Finally, EGF similarly attenuated cell proliferation and promoted autophagy and apoptosis in vivo in a xenograft model using A549 cells. These findings reveal that EGF induced redox signaling is linked to Ref-1-induced death in NSCLC cells. PMID- 27935859 TI - Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma. AB - Tumor suppressive microRNA (miR)-150 inhibits metastasis by combining with the C C chemokine receptor 6 (CCR6) "seed sequence" mRNA of the 3'-untranslated region (3'-UTR) in advanced cutaneous T-cell lymphoma (CTCL). Because the histone deacetylase inhibitor (HDACI) vorinostat showed excellent outcomes for treating advanced CTCL, HDACIs may reduce the metastasis of CTCL by targeting miR-150 and/ or CCR6. To examine whether these candidate molecules are essential HDACI targets in advanced CTCL, we used the My-La, HH, and HUT78 CTCL cell lines for functional analysis because we previously demonstrated that their xenografts in NOD/Shi-scid IL-2gammanul mice (CTCL mice) induced multiple metastases. We found that pan- HDACIs (vorinostat and panobinostat) inhibited the migration of CTCL cells and downregulated CCR6. The miRNA microarray analysis against CTCL cell lines demonstrated that these pan-HDACIs commonly upregulated 161 miRNAs, including 34 known tumor suppressive miRNAs such as miR-150. Although 35 miRNAs possessing the CCR6 "seed sequence" were included in these 161 miRNAs, miR-150 and miR-185-5p were downregulated in CTCL cells compared to in normal CD4+ T-cells. The transduction of 12 candidate miRNAs against CTCL cells revealed that miR-150 most efficiently inhibited their migration capabilities and downregulated CCR6. Quantitative reverse transcriptase-polymerase chain reaction demonstrated that miR-150 was downregulated in advanced but not early CTCL primary cases. Finally, we injected miR-150 or siCCR6 into CTCL mice and found that mouse survival was significantly prolonged. These results indicate that miR-150 and its target, CCR6, are essential therapeutic targets of pan-HDACIs in advanced CTCL with metastatic potential. PMID- 27935860 TI - T lymphocyte SHP2-deficiency triggers anti-tumor immunity to inhibit colitis associated cancer in mice. AB - Nonresolving inflammation is involved in the initiation and progression process of tumorigenesis. Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is known to inhibit acute inflammation but its role in chronic inflammation associated cancer remains unclear. The role of SHP2 in T cells in dextran sulfate sodium (DSS)-induced colitis and azoxymethane-DSS-induced colitis-associated carcinogenesis was examined using SHP2CD4-/- conditional knockout mice. SHP2 deficiency in T cells aggravated colitis with increased level of pro-inflammatory cytokines including IFN-gamma and IL-17A. In contrast, the SHP2CD4-/- mice developed much fewer and smaller tumors than wild type mice with higher level of IFN-gamma and enhanced cytotoxicity of CD8+ T cells in the tumor and peritumoral areas. At the molecular level, STAT1 was hyper-phosphorylated in T cells lacking SHP2, which may account for the increased Th1 differentiation and IFN-gamma secretion. IFN-gamma neutralization or IFN-gamma receptor knockout but not IL-17A neutralization, abrogated the anti-tumor effect of SHP2 knockout with lowered levels of perforin 1, FasL and granzyme B. Finally, the expression of granzyme B was negatively correlated with the malignancy of colon cancer in human patients. In conclusion, these findings suggest a new strategy to treat colitis-associated cancer via targeting SHP2. PMID- 27935861 TI - MicroRNA-203 predicts human survival after resection of colorectal liver metastasis. AB - BACKGROUND: Resection of colorectal liver metastasis (CRLM) can be curative. Predicting which patients may benefit from resection, however, remains challenging. Some microRNAs (miRNAs) become deregulated in cancers and contribute to cancer progression. We hypothesized that miRNA expression can serve as a prognostic marker of survival after CRLM resection. RESULTS: MiR-203 was significantly overexpressed in tumors of short-term survivors compared to long term survivors. R1/R2 margin status and high clinical risk score (CRS) were also significantly associated with short-term survival (both p = 0.001). After adjusting for these variables, higher miR-203 expression remained an independent predictor of shorter survival (p = 0.010). In the serum cohort, high CRS and KRAS mutation were significantly associated with short-term survival (p = 0.005 and p = 0.026, respectively). After adjusting for CRS and KRAS status, short-term survivors were found to have significantly higher miR-203 levels (p = 0.016 and p = 0.033, respectively). MATERIALS AND METHODS: We employed next-generation sequencing of small-RNAs to profile miRNAs in solid tumors obtained from 38 patients who underwent hepatectomy for CRLM. To validate, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed on 91 tumor samples and 46 preoperative serum samples. CONCLUSIONS: After CRLM resection, short-term survivors exhibited significantly higher miR-203 levels relative to long-term survivors. MiR-203 may serve as a prognostic biomarker and its prognostic capacity warrants further investigation. PMID- 27935862 TI - Targeting of interleukin (IL)-17A inhibits PDL1 expression in tumor cells and induces anticancer immunity in an estrogen receptor-negative murine model of breast cancer. AB - The expression of IL-17A and programmed death ligand 1 (PDL1) is increased in estrogen receptor-negative breast cancer. IL-17A promotes tumor cell survival and invasiveness and inhibits the antitumor immune response. The PDL1-PD1 (programmed death protein 1) signaling pathway promotes escape from immune surveillance in tumor cells. The pro-tumor properties of IL-17A and PDL1 in various cancers have been previously examined; however, the relationship and roles of IL-17A and PDL1 in ER-negative breast cancer have not been evaluated. Therefore, we assessed whether IL-17A promotes PDL1 expression in tumor cells and whether targeting of IL-17A could inhibit ER-negative breast cancer progression in a murine model. Our study revealed that IL-17A promoted PDL1 expression in human and mouse cells. In the murine cancer model, targeting of IL-17A inhibited PDL1 expression in the tumor microenvironment, decreased the percentage of Treg cells in tumor infiltrating lymphocytes, and promoted CD4+ and CD8+ T cells to secrete interferon gamma. More importantly, treatment with combined anti-IL-17A and anti PDL1 antibodies enhanced antitumor effects in favor of tumor eradication. Thus, our study established a pro-tumor role of IL-17A in promoting tumor immune escape and supports the development of a novel cytokine immunotherapy against breast cancer. PMID- 27935863 TI - A ruthenium anticancer compound interacts with histones and impacts differently on epigenetic and death pathways compared to cisplatin. AB - Ruthenium complexes are considered as potential replacements for platinum compounds in oncotherapy. Their clinical development is handicapped by a lack of consensus on their mode of action. In this study, we identify three histones (H3.1, H2A, H2B) as possible targets for an anticancer redox organoruthenium compound (RDC11). Using purified histones, we confirmed an interaction between the ruthenium complex and histones that impacted on histone complex formation. A comparative study of the ruthenium complex versus cisplatin showed differential epigenetic modifications on histone H3 that correlated with differential expression of histone deacetylase (HDAC) genes. We then characterized the impact of these epigenetic modifications on signaling pathways employing a transcriptomic approach. Clustering analyses showed gene expression signatures specific for cisplatin (42%) and for the ruthenium complex (30%). Signaling pathway analyses pointed to specificities distinguishing the ruthenium complex from cisplatin. For instance, cisplatin triggered preferentially p53 and folate biosynthesis while the ruthenium complex induced endoplasmic reticulum stress and trans-sulfuration pathways. To further understand the role of HDACs in these regulations, we used suberanilohydroxamic acid (SAHA) and showed that it synergized with cisplatin cytotoxicity while antagonizing the ruthenium complex activity. This study provides critical information for the characterization of signaling pathways differentiating both compounds, in particular, by the identification of a non-DNA direct target for an organoruthenium complex. PMID- 27935864 TI - Prognostic value of combined preoperative fibrinogen and neutrophil-lymphocyte ratio in patients with hepatocellular carcinoma after liver transplantation. AB - OBJECTIVES: Elevated plasma fibrinogen (Fib) correlated with patient's prognosis in several solid tumors. However, few studies have illuminated the relationship between preoperative Fib and prognosis of HCC after liver transplantation. We aimed to clarify the prognostic value of Fib and whether the prognostic accuracy can be enhanced by the combination of Fib and neutrophil-lymphocyte ratio (NLR). RESULTS: Fib was correlated with Child-pugh stage, alpha-fetoprotein (AFP), size of largest tumor, macro- and micro-vascular invasion. Univariate analysis showed preoperative Fib, AFP, NLR, size of largest tumor, tumor number, macro- and micro vascular invasion were significantly associated with disease-free survival (DFS) and overall survival (OS) in HCC patients with liver transplantation. After multivariate analysis, only Fib and macro-vascular invasion were independently correlated with DFS and OS. Survival analysis showed that preoperative Fib > 2.345 g/L predicted poor prognosis of patients HCC after liver transplantation. Preoperative Fib showed prognostic value in various subgroups of HCC. Furthermore, the predictive range was expanded by the combination of Fib and NLR. MATERIALS AND METHODS: Data were collected retrospectively from 130 HCC patients who underwent liver transplantation. Preoperative Fib, NLR and clinicopathologic variables were analyzed. The survival analysis was performed by the Kaplan-Meier method, and compared by the log-rank test. Univariate and multivariate analyses were performed to identify the prognostic factors for DFS and OS. CONCLUSIONS: Preoperative Fib is an independent effective predictor of prognosis for HCC patients, higher levels of Fib predict poorer outcomes and the combination of Fib and NLR enlarges the prognostic accuracy of testing. PMID- 27935865 TI - Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents. AB - Due to exposure to environmental toxicants, a "field cancerization" effect occurs in the lung resulting in the development of a field of initiated but morphologically normal appearing cells in the damaged epithelium of bronchial airways with dysregulated gene expression patterns. Using a mouse model of lung squamous cell carcinoma (SCC), we performed transcriptome sequencing (RNA-Seq) to profile bronchial airway gene expression and found activation of the PI3K and Myc signaling networks in cytologically normal bronchial airway epithelial cells of mice with preneopastic lung SCC lesions, which was reversed by treatment with the PI3K Inhibitor XL-147 and pioglitazone, respectively. Activated MYC signaling was also present in premalignant and tumor tissues from human lung SCC patients. In addition, we identified a key microRNA, mmu-miR-449c-5p, whose suppression significantly up-regulated Myc expression in the normal bronchial airway epithelial cells of mice with early stage SCC lesions. We developed a novel bronchial genomic classifier in mice and validated it in humans. In the classifier, Ppbp (pro-platelet basic protein) was overexpressed 115 fold in the bronchial airways of mice with preneoplastic lung SCC lesions. This is the first report that demonstrates Ppbp as a novel biomarker in the bronchial airway for lung cancer diagnosis. PMID- 27935866 TI - HIC1 (hypermethylated in cancer 1) SUMOylation is dispensable for DNA repair but is essential for the apoptotic DNA damage response (DDR) to irreparable DNA double-strand breaks (DSBs). AB - The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor mediating the p53-dependent apoptotic response to irreparable DNA double-strand breaks (DSBs) through direct transcriptional repression of SIRT1. HIC1 is also essential for DSB repair as silencing of endogenous HIC1 in BJ-hTERT fibroblasts significantly delays DNA repair in functional Comet assays. HIC1 SUMOylation favours its interaction with MTA1, a component of NuRD complexes. In contrast with irreparable DSBs induced by 16 hours of etoposide treatment, we show that repairable DSBs induced by 1 h etoposide treatment do not increase HIC1 SUMOylation or its interaction with MTA1. Furthermore, HIC1 SUMOylation is dispensable for DNA repair since the non SUMOylatable E316A mutant is as efficient as wt HIC1 in Comet assays. Upon induction of irreparable DSBs, the ATM-mediated increase of HIC1 SUMOylation is independent of its effector kinase Chk2. Moreover, irreparable DSBs strongly increase both the interaction of HIC1 with MTA1 and MTA3 and their binding to the SIRT1 promoter. To characterize the molecular mechanisms sustained by this increased repression potential, we established global expression profiles of BJ hTERT fibroblasts transfected with HIC1-siRNA or control siRNA and treated or not with etoposide. We identified 475 genes potentially repressed by HIC1 with cell death and cell cycle as the main cellular functions identified by pathway analysis. Among them, CXCL12, EPHA4, TGFbetaR3 and TRIB2, also known as MTA1 target-genes, were validated by qRT-PCR analyses. Thus, our data demonstrate that HIC1 SUMOylation is important for the transcriptional response to non-repairable DSBs but dispensable for DNA repair. PMID- 27935868 TI - Analysis of progression-free survival of first-line tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring leu858Arg or exon 19 deletions. AB - BACKGROUND: Gefitinib, erlotinib and afatinib provide remarkable response rates and progression-free survival compared to platinum-based chemotherapy in patients with non-small cell lung cancer harboring epidermal growth factor receptor activating mutations, and are therefore standard first-line treatment in these patients. However, no study has compared these drugs regarding progression-free survival. MATERIALS AND METHODS: We conducted this retrospective study at a single medical center in Taiwan from February 16, 2011 to October 30, 2015. We used the Kaplan-Meier method to estimate survival, and multivariate Cox proportional hazard models to estimate adjusted hazard ratios and 95% confidence intervals. FINDINGS: Of the 1006 patients diagnosed with stage IIIb and IV non small cell lung cancer in the study period, 448 (44.5%) had EGFR-activating mutations and received first-line therapy with gefitinib (n = 304, 67.6%), erlotinib (n = 63, 14.3%), or afatinib (n = 81, 18.1%). The median duration of follow-up for progression-free survival was 12.1 months in the gefitinib arm (Interquartile range [IQR]: 5.5-16.5), 11.2 months in the erlotinib arm (IQR: 4.9 16.7), and 10.3 months in the afatinib arm (IQR: 7.0-14.2). Progression-free survival was significantly longer in the patients who received afatinib or erlotinib compared to those who received gefitinib (log-rank test, p < 0.001), and the median progression-free survival was 11.4 months in the gefitinib group. INTERPRETATION: Afatinib and erlotinib provide significant benefits in progression-free survival compared to gefitinib in first-line treatment of patients with non-small-cell lung cancers harboring EGFR-activating mutations. Further clinical trials are warranted to validate these findings. PMID- 27935867 TI - The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple negative breast cancer models as single agent and in combination with everolimus. AB - Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subgroup of breast tumors clinically defined by the lack of estrogen, progesterone and HER2 receptors, limiting the use of the targeted therapies employed in other breast malignancies. Recent evidence indicates that c-MYC is a key driver of TNBC. The BET-bromodomain inhibitor OTX015 (MK-8628) has potent antiproliferative activity accompanied by c-MYC down-regulation in several tumor types, and has demonstrated synergism with the mTOR inhibitor everolimus in different models. The aim of this study was to evaluate the anti-tumor activity of OTX015 as single agent and in combination with everolimus in TNBC models. OTX015 was assayed in three human TNBC-derived cell lines, HCC1937, MDA-MB-231 and MDA-MB-468, all showing antiproliferative activity after 72 h (GI50 = 75-650 nM). This was accompanied by cell cycle arrest and decreased expression of cancer stem cells markers. However, c-MYC protein and mRNA levels were only down-regulated in MDA MB-468 cells. Gene set enrichment analysis showed up-regulation of genes involved in epigenetic control of transcription, chromatin and the cell cycle, and down regulation of stemness-related genes. In vitro, combination with everolimus was additive in HCC1937 and MDA-MB-231 cells, but antagonistic in MDA-MB-468 cells. In MDA-MB-231 murine xenografts, tumor mass was significantly (p < 0.05) reduced by OTX015 with respect to vehicle-treated animals (best T/C = 40.7%). Although everolimus alone was not active, the combination was more effective than OTX015 alone (best T/C = 20.7%). This work supports current clinical trials with OTX015 in TNBC (NCT02259114). PMID- 27935869 TI - The involvement of Bcl-2 family proteins in AKT-regulated cell survival in cisplatin resistant epithelial ovarian cancer. AB - Many studies involving patients with cisplatin-resistant ovarian cancer have shown that AKT activation leads to inhibition of apoptosis. The aim of this study was to examine the potential involvement of the Bcl-2 family proteins in AKT regulated cell survival in response to cisplatin treatment. Cisplatin-sensitive (PEO1) and cisplatin-resistant (PEO4) cells were taken from ascites of patients with ovarian cancer before cisplatin treatment and after development of chemoresistance. It was found that cisplatin treatment activated the AKT signaling pathway and promoted cell proliferation in cisplatin-resistant EOC cells. When AKT was transfected into nucleus of cisplatin-resistant ovarian cancer cells, DNA-PK was phosphorylated at S473. The activated AKT (pAKT-S473) in these cells inhibited the death signal induced by cisplatin thereby inhibiting cisplatin-mediated apoptosis. Results from this study showed that the combination of cisplatin, DNA-PK inhibitor NU7441, and AKT inhibitor TCN can overcome drug resistance, increase apoptosis, and re-sensitize PEO4 cells to cisplatin treatment. A decrease in apoptotic activity was seen in PEO4 cells when Bad was downregulated by siRNA, which indicated that Bad promotes apoptosis in PEO4 cells. Use of the Bcl-2 inhibitor ABT-737 showed that ABT-737 binds to Bcl-2 but not Mcl-1 and releases Bax/Bak which leads to cell apoptosis. The combination of ABT-737 and cisplatin leads to a significant increase in the death of PEO1 and PEO4 cells. All together, these results indicate that Bcl-2 family proteins are regulators of drug resistance. The combination of cisplatin and Bcl-2 family protein inhibitor could be a strategy for the treatment of cisplatin-resistant ovarian cancer. PMID- 27935870 TI - Changes in the methylation status of the Oct3/4, Nanog, and Sox2 promoters in stem cells during regeneration of rat tracheal epithelium after injury. AB - We investigated the relationship between promoter methylation and tracheal stem cell activation. We developed a model of rat tracheal epithelium regeneration after 5-fluorouracil (5-FU)-induced injury. Using immunohistochemistry and Western blotting, the expression levels of the stem cell pluripotency regulator Oct3/4 and differentiation marker CK14 were measured after 5-FU treatment. The methylation status of the Oct3/4, Nanog, and Sox2 promoters was investigated using methylation-specific PCR. Additionally, the effects of 5-azacytidine (5 azaC), a demethylating agent, on Oct3/4, Nanog, and Sox2 mRNA and protein expression were evaluated. Finally, we measured the activity of the maintenance and de novo DNA methyltransferases DNMT1, DNMT3a, and DNMT3b. Our data indicate that Oct3/4, Sox2, and Nanog are transiently expressed in response to 5-FU induced injury, and then they are gradually silenced as the cells differentiate. DNA methylation can result in silencing of gene expression, and it can determine whether tracheal stem cells are in an active or dormant state. Treatment with 5 FU reversed the methylation of the Oct3/4, Nanog, and Sox2 promoters, which corresponded to increases in Oct3/4, Nanog, and Sox2 mRNA and protein. Thus, both maintenance and de novo methyltransferases are involved in regulating tracheal stem cell dormancy and activation. PMID- 27935871 TI - Decreased expression of protocadherin 20 is associated with poor prognosis in hepatocellular carcinoma. AB - Recently, protocadherin 20 has been reported as a tumor suppressor gene in hepatocellular carcinoma (HCC); however, the prognostic value of protocadherin 20 in HCC remains unclear. Hence, the purpose of this study was to investigate the clinical and prognostic values of protocadherin 20 in HCC patients. The expression of protocadherin 20 was assessed by quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry. Kaplan-Meier curves were created to calculate the overall survival of the patients, and Cox regression models were used to identify the risk factors associated with prognosis. Of 317 primary HCC patients, decreased expression of protocadherin 20 was observed in 184 (58.0%) patients (P < 0.001). Reduced protocadherin 20 protein expression correlated with portal hypertension, poor tumor differentiation, advanced Okuda stage, and Cancer of the Liver Italian Program score (all P < 0.05). Low protocadherin 20 expression was an independent risk factor for mortality (P = 0.018). Furthermore, in our newly developed simple risk score based on protocadherin 20, patients with total score > 1.11 showed significantly poorer outcome; and the predictive value of the score was better than the Barcelona Clinic Liver Cancer stage, Okuda stage, and Child-Pugh classification (Harrell's concordance index = 0.614). Taken together, these findings suggest that protocadherin 20 may represent a novel prognostic biomarker for HCC patients. PMID- 27935872 TI - Feasibility of a novel one-stop ISET device to capture CTCs and its clinical application. AB - INTRODUCTION: Circulating tumor cells (CTCs) play a crucial role in cancer metastasis. In this study, we introduced a novel isolation method by size of epithelial tumor cells (ISET) device with automatic isolation and staining procedure, named one-stop ISET (osISET) and validated its feasibility to capture CTCs from cancer patients. Moreover, we aim to investigate the correlation between clinicopathologic features and CTCs in colorectal cancer (CRC) in order to explore its clinical application. RESULTS: The capture efficiency ranged from 80.3% to 88% with tumor cells spiked into medium while 67% to 78.3% with tumor cells spiked into healthy donors' blood. In detection blood samples of 72 CRC patients, CTCs and clusters of circulating tumor cells (CTC-clusters) were detected with a positive rate of 52.8% (38/72) and 18.1% (13/72) respectively. Moreover, CTC positive rate was associated with factors of lymphatic or venous invasion, tumor depth, lymph node metastasis and TNM stage in CRC patients (p < 0.01). Lymphocyte count and neutrophil to lymphocyte ratio (NLR) were significantly different between CTC positive and negative groups (p < 0.01). MATERIALS AND METHODS: The capture efficiency of the device was tested by spiking cancer cells (MCF-7, A549, SW480, Hela) into medium or blood samples of healthy donors. Blood samples of 72 CRC patients were detected by osISET device. The clinicopathologic characteristics of 72 CRC patients were collected and the association with CTC positive rate or CTC count were analyzed. CONCLUSIONS: Our osISET device was feasible to capture and identify CTCs and CTC-clusters from cancer patients. In addition, our device holds a potential for application in cancer management. PMID- 27935873 TI - Comparison of Biocompatibility of Cemented vs. Cementless Hip Joint Endoprostheses Based on Postoperative Evaluation of Proinflammatory Cytokine Levels. AB - BACKGROUND The yearly increase in the number of procedures involving implantation of hip joint endoprostheses forces prosthetics manufacturers to search for biologically neutral implants. The goal of this study was to assess the concentration of Interleukin-6 (IL-6) and its correlation with C-reactive protein (CRP), depending on the type of hip joint endoprosthesis (cemented or cementless endoprosthesis) in order to determine implant biotolerance during the early postoperative period. MATERIAL AND METHODS The sample comprised 200 patients [mean age=64 (31-81) years] with coxarthrosis. All patients underwent hip joint arthroplasty using a cemented or cementless endoprosthesis. Blood samples were collected 3 times: before the procedure, on the first day after the procedure, and after 6 weeks. IL-6 and CRP levels were assayed using immunoenzymatic methods. The results were subjected to statistical analysis using the Shapiro Wilk test. RESULTS On the 1st day after the procedure, CRP and IL-6 concentration increased rapidly after implantation of both cemented and cementless endoprostheses. At 6 weeks postoperatively, the CRP value remained at a similar level in patients after cemented arthroplasty and was almost 2-fold lower in patients who underwent cementless arthroplasty. The IL-6 value returned to the baseline level in patients after cementless arthroplasty and showed an ongoing increasing tendency in patients after cemented arthroplasty. CONCLUSIONS 1. The measurement of C-reactive protein and Interleukin-6 is a high-sensitivity test, assessing implant biotolerance. 2. The implantation of a cemented endoprosthesis induces a higher increase in the level of proinflammatory cytokines as compared with a cementless endoprosthesis. 3. For a complete assessment of both early and later body responses to implantation and the related surgical procedure, further studies using available approaches and tools are recommended. PMID- 27935874 TI - [Ischaemic postconditioning of the heart. Analysis of experimental findings]. AB - The data of publications regarding the influence of experimental atherosclerosis on the infarct-limiting effect of ischaemic postconditioning (IPost) are controversial. The presented information is suggestive that ageing removes or attenuates the infarct-limiting effect of postconditioning but does not influence the antiarrhythmic effect of IPost. The majority of experimental data report that streptozotocin-induced diabetes removes the infarct-limiting effect of IPost. The data concerning type 2 diabetes mellitus are controversial: some authors state that such diabetes completely levels the cardioprotecting effect of IPost; others tell that it only attenuates but does not remove the infarct-limiting effect of IPost. Postconditioning in rats with elevated arterial pressure prevents the appearance of reperfusion cardiac contractility dysfunction and exerts an infarct limiting effect. Cardiac hypertrophy, postinfarction remodelling and dilatation cardiomyopathy do not influence the infarct-limiting and inotropic effect of postconditioning. According to the majority of publications, IPost enhances the inotropic and cardioprotecting effect of cardioplegia. The data of literature sources regarding the effect of gender on efficacy of IPost are limited. PMID- 27935875 TI - [Modified circulating low-density lipoproteins: pathogenetic significance in angiology]. AB - Low-density lipoproteins (LDLs) having various modifications are known to be atherogenic, i. e., possessing ability of inducing atherosclerosis. Circulating modified LDLs (cmLDLs) were found in blood of patients diagnosed with atherosclerosis confirmed angiographically. They appear to contain 2-3-fold less sialic acid as compared to LDLs in blood of apparently healthy people; cmLDLs differ by their physical properties: having higher density, smaller diameter, and greater electronegativity; by chemical properties: the amount of neutral sugars (N-acetyl-galactosamine, N-acetyl-glucosamine, galactose and glucose) in cmLSLs of patients with atherosclerosis is 1,5-2 times lower than in native lipoproteins, the levels of free and etherified cholesterol and triglycerides, monoglycerides and free fatty acids are higher, cmLDLs are oxidized and contain altered apolipoprotein B. It is also known that cmLDLs enhance proliferation of subendothelial smooth-muscle cells of the vascular intima, activating synthesis of protein by cells and components of the connective-tissue matrix, determining early clinical manifestations of atherosclerosis. The presented review summarizes the results of many-year studies of cmLDLs, carried out at the Scientific Research Institute for Atherosclerosis and the Laboratory of Angiopathology of the Scientific Research Institute of General Pathology and Pathophysiology both headed by A.N. Orekhov, and dedicated to various aspects of the effect of modified LDLs on the inner vascular wall. PMID- 27935876 TI - [Concentration of matrix metalloproteinases and magnesium ions in patients with varicose veins of lower limbs]. AB - The study was aimed at investigating alterations in the concentration of matrix metalloproteinases (MMP-1, MMP-9) and the tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as the level of magnesium ions (Mg2+) as an indicator of connective tissue dysplasia (CTD) in patients presenting with lower limb varicose veins. The study included a total of 110 people. Of these, the Study Group comprised 90 patients with lower limb varicose veins of clinical class C2-C6 (according to the CEAP classification) and the Control Group was composed of 20 apparently healthy volunteers. Samples of peripheral blood were examined. The content of MMP-9, MMP-1 and TIMP-1 in blood serum was determined by means of the quantitative solid-phase immunoenzymatic assay. The concentration of Mg2+ was determined by the colorimetric method. We revealed a statistically significant interrelationship between the concentrations of matrix metalloproteinases and severity of varicose transformation of lower-limb veins, with the highest level of matrix metalloproteinases being observed in patients with cutaneous alterations and trophic ulcers. Determination of the level of matrix metalloproteinases and magnesium ions, characterizing connective tissue dysplasia, makes it possible to predict the development of lower limb chronic venous insufficiency and to evaluate the degree of its severity. PMID- 27935877 TI - [Assessing the influence of predictors of the development of chronic obliterating diseases of lower-limb arteries]. AB - The authors assessed the probability and terms of the development of chronic obliterating diseases of lower-limb arteries under the influence of the predictors studied. Using the Statistica 6.0 programme we carried out the analysis of the function of survival on a sample of 7,959 people. Based on the Kaplan-Mayer method and Cox regression model we determined the most significant predictors influencing the development of subclinical lesions of lower-extremity arteries. Also determined was the duration of the influence of each predictor prior to clinical manifestation and contribution of each predictor to the development of the examined outcomes. PMID- 27935878 TI - [Five-year results of treating patients with chronic lower limb ischaemia by means of gene engineering]. AB - The authors share their experience in comprehensive conservative treatment of patients presenting with chronic lower limb ischaemia (CLLI) associated with atherosclerosis of peripheral arteries by means of the first Russian registered gene therapeutic agent "Neovasculgen" (plasmid with the vegf165 gene), analysing the long-term outcomes of treating a total of 45 patients with stage II and III CLLI according to the classification of Pokrovsky-Fontain. The patients were followed up for 5 years. Efficacy of treatment was assessed by registering the dynamics of the pain-free walking distance (PFWD), linear blood velocity (LBV), ankle-brachial index (ABI), as well as the limb salvage rate and survival of patients. All patients showed good tolerance of treatment, with neither side effects nor complications noted. Clinical improvement in stage IIB CLLI was observed in 91% of patients with complete stabilization of the clinical course during 5 years. The limb salvage rate in this group amounted to 95%, with the survival rate equalling 82%. In patients with stage III CLLI, improvement was noted in 78% of cases, manifesting itself by a decrease of its degree to stage IIB (44.4%) and to stage IIA (33.3%). Progression of CLLI followed by amputation was registered in 22% of cases, with the survival rate of 78%. Hence, the use of a single course of combined treatment including the gene therapeutic agent "Neovasculgen" in patients with stage II and III CLLI resulted in a persistent positive effect in a considerable majority of patients in the remote period of not less than 5 years. PMID- 27935879 TI - [Comprehensive physical antiedematous therapy in treatment of patients with lymphedema]. AB - Presented in the article is retrospective analysis of the results of treatment of patients with lymphedema. We treated a total of 33 patients with primary (n=6) and secondary (n=27) lymphedema. Stage II lymphedema was diagnosed in 18 (54.5%) patients, stage III lymphedema in 15 (45.5%) patients. The 33 patients had a total of 44 affected limbs (9 hands and 35 legs). All patients were subjected to comprehensive physical antiedematous therapy including: manual lymph drainage massage, formation of compression bandage, selection of individual class 3 plain stitch compression knitwear, special complex of therapeutic exercises, care of the skin of the affected limb. A positive effect was achieved in all cases. In patients with upper limb lesions the volume of the extremity decreased averagely by 1'235.0+/-283.7 cm3 (22.6% of the baseline volume, p<0.005), in patients with lower limb lesions it decreased by 2'712.0+/-350.3 cm3 (22.1% of the initial volume, p<0.005). The carried out therapeutic course resulted in improvement of quality of life at the expense of decrease of the deformity and improvement of the function of the limb, increase of the scope of movements in the joints, regression of trophic alterations, widening of possibilities of wearing footgear and clothes. A conclusion was made that comprehensive antiedematous physical therapy is an effective method of treatment of patients with limb lymphedema, making it possible to attain regression of trophic disorders and to improve patients' quality of life. PMID- 27935880 TI - [Efficacy of intramuscular administration of stem/progenitor cells in experiment on the model of lower limb ischaemia]. AB - An experimental model of lower limb ischaemia induced by ligation of the femoral artery in CBA-line mail rats was used to study efficacy and effect of intramuscular administration of autologous bone-marrow stem/progenitor cells on the process of angiogenesis. Based on the findings of laser Doppler flowmetry it was shown that administration of autologous stem/progenitor cells promotes acceleration of the processes of neoangiogenesis, which was confirmed by the results of histological study. PMID- 27935881 TI - [Contrast-free MR phlebography as a method of screening of phlebothromboses and extravasal compression of the inferior vena cava and its basin]. AB - The study was aimed at assessing possibilities and determining diagnostic significance of the method of contrast-free magnetic resonance phlebography (MR phlebography) in diagnosis of diseases of the inferior vena cava (IVC) and its basin. Presented herein is experience with examining a total of 74 patients at two therapeutic-diagnostic facilities: the National Medical Surgical Centre named after N.I. Pirogov and the Medical Diagnostic Centre "Ramsey Diagnostics". The studies were carried out on magnetic resonance tomographs "Philips Intera Nova" and "GE Optima MR360", using a special protocol of contrast-free MR-phlebography in consequences at free breathing, followed by 3D reconstruction and processing of the obtained images as MIP and 3D. According to the obtained results our method makes it possible to visualize the anatomical passage of the vessels of the IVC basin, interrelationship with adjoining structures and osseous elements, to determine localization of the thrombus, its length, diameter of the vessel and degree of its narrowing at the level of the lesion, as well as to assess the collateral outflow without contrast enhancement. The sensitivity of the method in thromboses of the IVC basin veins amounted to 92%, with the specificity amounting to 90%. Hence, contrast-free MR phlebography is the most optimal screening method requiring no contrast medium, short in time and absolutely safe procedure in diagnosing the causes of extra- and intravasal pathology of the IVC and its basin as compared with ultrasonographic examination, contrast-enhanced phlebography, computed tomography (CT) and contrast-enhanced magnetic resonance tomography. PMID- 27935882 TI - [Puncture treatment of pseudoaneurysms of femoral arteries with the use of human thrombin]. AB - The authors analysed both immediate and remote results of puncture treatment with the use of human thrombin under ultrasound control in patients with iatrogenic false aneurysms of femoral arteries. The study included a total of 32 patients presenting with post-puncture pseudoaneurysms of femoral arteries after previous endovascular manipulations. The clinical diagnosis was verified by means of ultrasound duplex scanning. Puncture treatment was carried out using lyophilisate of human thrombin at a concentration of 500 IU according to the patented technique. The obtained outcomes were assessed at various terms (up to 12 months). The predominant ultrasound characteristics of a false aneurysm were as follows: an arterial defect sized 2.1-3 mm with prevailing localization in the superficial femoral artery (singe-chamber pseudoaneurysm with the volume of its cavity amounting to 31-60 cm3). The average dose of thrombin sufficient for obliteration of the cavity amounted to 320.8+/-104.6 IU. The puncture treatment proved to be effective in 30 (93.7%) patients. In the remaining 2 (6.3%) cases the outcomes of puncture treatment turned out unsatisfactory, thus requiring an operative intervention. No relapsed were observed in the remote period. A conclusion was drawn that puncture treatment is a highly effective method in relation to false aneurysms of femoral arteries and is neither accompanied by relapses nor followed by allergic, thrombotic, infectious complication at various terms of follow up. Efficacy of treatment with human thrombin does not depend on taking antithrombotic agents by the patients. PMID- 27935883 TI - [Roentgen endovascular treatment of common carotid artery dissection after eversion carotid endarterectomy]. AB - The article deals with the use of self-expanding stents for endovascular treatment in patients presenting with dissection of the common carotid artery, exemplified by two clinical case reports. In both cases, dissection of the common carotid artery developed after eversion carotid endarterectomy. Intimal detachment was eliminated in both cases by implanting self-expanding stents. These cases demonstrated possibilities of roentgen endovascular methods of treatment making it possible to successfully replace a repeat, technically difficult surgical intervention for iatrogenic dissection of the common carotid artery. PMID- 27935884 TI - [Use of the "Multitask" device while performing endarterectomy from iliac arteries]. AB - AIM: The study was aimed at assessing efficacy of using the "MultiTASK" device manufactured by the Le Maitre Company while performing extended endarterectomy from iliac arteries in patients presenting with multilevel atherosclerotic lesions of the arterial bed and chronic ischaemia of lower extremities. PATIENTS AND METHODS: We analysed the outcomes of surgical management of a total of 37 patients presenting with multilevel atherosclerotic lesions of the common and external iliac arteries and arteries below the inguinal ligament over the period from 2012 to 2015 at the Department of Emergency Vascular Surgery of the Scientific Research Institute of Emergency Ambulance Care named after N.V. Sklifosovsky. Twenty one (56.8%) patients presented with haemodynamically significant stenoses of the iliac artery. Eleven (29.7%) patients had occlusion of the external iliac artery and five (13.5%) patients presented with occlusion of the common iliac artery in the distal portion. In all cases there was a second block, i. e. occlusion of the superficial femoral artery. RESULTS: The primary patency rate of the external iliac artery after endarterectomy amounted to 100%. Immediate complications directly associated with endarterectomy from the external iliac artery were encountered in one (2.7%) case - during back traction of the loop there occurred perforation of the wall of the external iliac artery by a calcified plaque, thus requiring external-iliac-common-femoral prosthetic repair. Amputation was performed in two (5.4%) patients (in both cases due to thrombosis and the development of ischaemic gangrene owing to poor condition of the distal arterial bed). One (2.7%) patient died of acute myocardial infarction. CONCLUSION: Extended endarterectomy by means of the "MultiTASC" device turned out efficient, yielding good immediate outcomes in atherosclerotic lesions of femoral arteries both as an independent operation and when combined with reconstruction of arteries beneath the inguinal ligament. PMID- 27935886 TI - [Adjuvant phlebotrophic therapy and its effect on anti-inflammatory response after sclerotherapy]. AB - The study was aimed at evaluating the degree of the systemic and local inflammatory reaction after sclerotherapy, as well as the effect of micronized purified flavonoid fraction (Detralex) thereupon. The study comprised a total of 60 female patients presenting with reticular veins and telangiectasias (clinical class C1 according to the CEAP classification). The patients were subdivided into two groups, each comprising 30 women. The Study Group patients two weeks prior to the forthcoming sclerotherapy had been taking Detralex prescribed at a daily dose of 1,000 mg whose administration was prolonged by not less than 2 months after the procedure. The Control Group patients received no drug. We determined the systemic and local levels of inflammatory markers, anti-inflammatory cytokines and growth factors: C-reactive protein in a highly sensitive range, histamine, interleukin-1, tumour necrosis factor alpha and vascular endothelial growth factor. Patients in the Study and Control Groups on day 10 after sclerotherapy demonstrated a considerable increase in the levels of anti-inflammatory cytokines and inflammatory markers. At the same time, excess of the baseline levels of the parameters in patients taking Detralex was statistically significantly lower as compared with the Control Group patients: C-reactive protein - 6.0+/-0.9 mg/l vs 8.3+/-1.0 mg/l; histamine - 87.0+/-9.8 ug/l vs 156.9+/-33.9 ug/l; interleukin-1 - 5.9+/-0.4 pg/ml vs7.6+/-0.6 pg/ml; tumour necrosis factor alpha - 5.9+/-0.9 pg/ml vs 7.5+/-0.4 pg/ml; vascular endothelial growth factor - 252.3+/-26.0 pg/ml vs 325.1+/-47.7 pg/ml. A conclusion was made that microsclerotherapy with the use of low-concentration detergent drugs was accompanied by a local vein-specific inflammatory reaction whose degree may be diminished by means of prescribing micronized purified flavonoid fraction (Detralex) two weeks prior to and during the whole subsequent period of phlebosclerosing treatment in a standard daily dose of 1,000 mg. PMID- 27935885 TI - [Use of an iliac branched endoprostheis in endovascular treatment for an abdominal aortic aneurysm combined with aneurysms of both common iliac arteries]. AB - An abdominal aortic aneurysm appears to be combined with aneurysmatic lesions of the common iliac arteries in 30-40% of cases. Like abdominal aortic aneurysms, aneurysms of the common iliac arteries rarely manifest themselves clinically. The lethality rate in case of rupture is comparable to that for rupture of an abdominal aortic aneurysm. During endoprosthetic repair of abdominal aortic aneurysms combined with aneurysms of the common iliac arteries, in order to prevent endoleaks and to improve the distal zone of fixation of endografts surgeons often resort to embolization of internal iliac arteries, which may lead to ischaemic postoperative complications. One of the methods of preserving pelvic blood flow is the use of an iliac branched endograft. A series of studies evaluating long-term outcomes demonstrated that this method proved to be both safe and effective, and with the suitable anatomy is a method of choice in high surgical risk patients. The present article deals with a clinical case report concerning bilateral endoprosthetic repair of the common iliac arteries, combined with endoprosthetic repair of an abdominal aortic aneurysm, with the description of technical peculiarities of implanting an iliac branched graft. PMID- 27935887 TI - [Efficacy of using rivaroxaban for treatment of heat-induced thrombosis after endovenous laser ablation]. AB - AIM: The study was aimed at assessing efficacy of using rivaroxaban for treatment of endothermal heat-induced thrombosis (EHIT) after endovenous laser ablation (EVLA) of saphenous veins. MATERIAL AND METHODS: Our prospective study included a total of 1,326 patients subjected to 1,514 EVLAs. In 1,091 (72.1%) cases the great saphenous vein (GSV) was ablated, in 124 (8.2%) cases the anterior accessory vein (AAV) was treated and in 299 (19.7%) cases the small saphenous vein (SSV) was treated. Heat-induced thrombosis developed in 21 (1.4%) cases: in 19 cases in the basin of the great saphenous vein and in 2 cases in the anterior accessory saphenous vein. No heat-induced thromboses in the basin of the small saphenous vein were observed. In 9 (0.6%) cases there was class 1 EHIT (according to the Kabnick classification), class 2 EHIT was noted in 10 (0.7%) cases and class 3 EHIT was observed in 2 (0.1%) cases. All patients with EHIT were given rivaroxaban: patients with class 1 EHIT received it at a single daily dose of 20 mg, patients with class 2 and 3 EHIT - at a dose of 15 mg twice daily. In one (4.8%) case the drug had to be discontinued on day two due to the development of dyspeptic events. All patients were found to have complete regression of the heat induced thrombus within 6-25 days. No cases of clinical manifestations of pulmonary artery thromboembolism were observed. A conclusion was drawn that in clinical practice EHIT is an important and insufficiently studied problem. Rivaroxaban may be used as an oral agent for treatment of heat-induced thromboses after EVLA. Further studies are required to examine its efficacy and safety profile. PMID- 27935888 TI - [Effect of angioprotective therapy with bioflavonoids on endothelial dysfunction in patients with acute venous thromboses]. AB - The study was aimed at evaluating a possibility of correcting endothelial dysfunction by means of angioprotective therapy with natural-origin bioflavonoids in patients presenting with acute venous thromboses. Ours was an open comparative prospective study including a total of thirty 34-to-60-year-old patients suffering from lower limb deep vein thrombosis. The patients were subdivided into two groups. The Study Group was composed of 15 patients receiving on the background of anticoagulant therapy with direct thrombin inhibitors (dabigatran etexilate at a daily dose of 300 mg) natural-origin angioprotectors (red grape leaf extract). The Control Group also consisted of 15 patients undergoing anticoagulant therapy with direct thrombin inhibitors alone. Blood sampling for laboratory monitoring [the quantitative level of von Willebrand factor (vWF) in blood plasma, integral assessment of the links of blood coagulation and fibrinolysis by means of thromboelastography] and ultrasonographic angioscanning of lower extremities were carried out in both Group twice: at the beginning of the study and 3 months after the beginning of therapy. The absolute majority of patients demonstrated a quantitative increase in vWF (the median in the Study Group amounted to 208.3%, being 190.0% in the Control Group, with the cut-off level equaling 140.8%). Assessing dynamics of the vWF level after 3 months on the background of using natural-origin flavonoids (the Study Group) showed a more pronounced decrease in the vWF level in the Study Group patients as compared with the Control Group patients (98.4%). Comparing the dynamic composite indices of the thromboelastogram revealed that with similar parameters in patients from the Study and Control Groups at admission, in dynamics there was observed greater growth of the level of indices of the process of dissolution of the fibrin clot (lysis) in the Study Group as compared to the Control Group. Also noted was more pronounced recanalization of the venous bed in patients taking the natural-origin bioflavonoid. A conclusion was drawn that including angioprotectors (red vine leaf extract) into the comprehensive therapy in order to correct endothelial dysfunction may improve the immediate results and terms of treatment of patients with acute venous thrombosis. PMID- 27935889 TI - [Current aspects of endothelial protection in treatment of patients with chronic venous insufficiency at the stage of trophic disorders]. AB - The authors analysed the results of comprehensive examination and treatment of a total of 40 patients presenting with lower limb chronic venous insufficiency at the stage of trophic disorders (class C6), including 28 (70%) patients with varicose disease of lower extremities and 12 (30%) patients with post-thrombotic disease. Studying the microcirculatory blood flow by means of laser Doppler flowmetry showed a statistically significant (p<0.05) baseline decrease in the index of microcirculation in patients (12.2+/-2.4 perf. units for varicose disease and 10.8+/-1.8 perf. units for post-thrombotic disease) as compared with the control group of apparently healthy volunteers (20.4+/-1.5 perf. units). All stages of treatment included the program of stimulation of reparative processes and normalization of microcirculation by means of sulodexide. Conservative measures were independent therapeutic procedures in 31 patients. Of these, trophic ulcers completely epithelialized in 9 patients and decreased by half of its initial surface in 22 patients. The study of the microcirculatory blood flow in dynamics suggested improvement of microcirculation during treatment. Hence, comprehensive therapy using sulodexide in patients with venous trophic ulcers is accompanied by an endothelium-protecting effect and leads to improvement of the indices of microcirculation of the skin of the crus. PMID- 27935890 TI - [Surgical prevention of ischaemic strokes by means of an extraintracranial microanastomosis (EICMA) in the carotid basin]. AB - BACKGROUND: Not less than 50% of all ischaemic strokes appear to occur resulting from pathology of extracranial arteries. Occlusions and stenoses are more commonly encountered in carotid arteries, with the incidence of occlusion of the internal carotid artery (ICA) ranging from 5 to 10% within the structure of all lesions of brachiocephalic arteries (BCA). AIM: The study was aimed at assessing the results of a surgical procedure of extra-intracranial microanastomosis (EICMA) performed in patients presenting with occlusive and stenotic lesions of BCA at the Neurosurgical Department. PATIENTS AND METHODS: During the period between January 1st 2009 to September 30th 2015, specialists of the Neurosurgery Department of the Research Institute of Emergency Medical Care named after N.V. Sklifosovsky treated a total of 1,101 patients presenting with atherosclerotic lesions of BCA, with a total of 1,038 surgical interventions performed. Of these, there were 837 operations of carotid endarterectomy and 180 operations of EICMA in the carotid basin. The indications for performing EICMA in patients from the group with occlusive-stenosing lesions of the major arteries of the head and neck were as follows: the presence of occlusion of the internal carotid artery or M1 segment of the middle cerebral artery, verified by the findings of angiographic examinations; previously endured ischaemic-type cerebral circulation impairment in the basin on the side of occlusion; a decrease in the perfusion reserve of the brain on the side of occlusion by the findings of positron emission tomography (PET), single-photon emission computed tomography (SPECT) or CT-perfusion with loading tests. RESULTS: After performing EICMA, the neurological status in patients averagely improved by 1.2 points according to the NIH Stroke Scale; by 0.5 point according to the Rankin scale, and by 3.5 points according to the Rivermead Mobility Index (Table 1). The dynamics of functional outcomes of EICMA turned out to depend on the terms of the operation (R=2143, p<0.05) and the degree of neurological deficit prior to surgery (R=3422, p<0.05): the deeper the neurological deficiency was and the sooner after acute cerebral ischaemia (ACI) the operation was performed, the more significant restoration of the functions was at the moment of discharge from hospital. Major complications of EICMA in patients operated on at various terms of ischaemic stroke were as follows: recurrent cerebral circulatory impairments - in 6 (3.3%) patients, subdural and intracranial haemorrhage - in 2 (1.1%), temporal deepening of the neurological deficit on the background of reperfusion, confirmed by the findings of SPECT - in 2 (1.1%), pneumonia with a lethal outcome - in 1 (0.6%), fatal ischaemic stroke of the opposite hemisphere - in 1 (0.6%) subject. The lethality rate amounted to 1.1% (2 cases). The risk for the development of complications was higher in elderly and aged patients (75 years and over), in patients with pronounced neurological deficit and significant somatic disorders. CONCLUSION: The indications for surgical prevention of recurrent ischaemic stroke by means of EICMA should be based on the following factors: the presence of confirmed occlusion of the ICA, a history of endured acute cerebral ischaemia, and decreased cerebrovascular reserve. Performing a surgical intervention is not appropriate for patients presenting with pronounced neurological deficit and significant somatic pathology. Careful selection of patients, the use of modern methods of neuroimaging, and intraoperative control make it possible to achieve favourable functional outcomes and to decrease the postoperative complications rate. PMID- 27935891 TI - [Rate of in-hospital cardiovascular complications in patients with postoperative renal dysfunction after surgical myocardial revascularization]. AB - The study was aimed at revealing the factors associated with renal dysfunction having developed after coronary artery bypass grafting (CABG) and assessing the in-hospital cardiovascular complications rate amongst patients with postoperative renal dysfunction. The study included a total of 99 patients presenting with stable angina pectoris and having indications for CABG. The mean age of the patients amounted to 57+/-7 years, with the average duration of coronary artery disease (CAD) of 6+/-5.7 years. A multi-vessel lesion of coronary arteries was revealed in 69.7% of patients, >= 50% stenosis of the trunk of the left coronary artery was diagnosed in a further 15.1%. CABG was performed in conditions of assisted circulation (AC) in 88.9% of patients and on the functioning heart in 11.1%. We implanted from 1 to 4 grafts to each patient. At admission, and then on the first and second postoperative days after CABG we determined blood serum creatinine and calculated the creatinine clearance (CrCl) according to the Cockcroft-Gault equation. A decrease in the CrCl < 60 ml/min was regarded as renal dysfunction. Assessing the cardiovascular complications rate we took into consideration cases of cardiac death, perioperative myocardial infarctions (POMI), severe acute cardiac insufficiency having required placement of a counterpulsator, and as well as the proportion of patients with paroxysmal atrial fibrillation. We also evaluated the frequency of repeat sternotomy. The incidence rate of transitory renal dysfunction following CABG amounted to 18.2%. The factors associated with a decrease in the CrCl < 60 ml/min after CABG were found to be as follows: age above - Me 62.5 (range 59-68) years, increased duration of AC above - Me 103 (range 88-133) min and prolonged time of aortic occlusion (AO) above - Me 53 (range 44-60) min, severe postoperative acute cardiac insufficiency, and re-sternotomy. The cumulative rate of in-hospital cardiovascular complications turned out to be significantly higher (55.6 versus 18.5%, p=0.001) amongst patients with postoperative renal dysfunction. We also revealed a substantially higher incidence rate of re-sternotomies in the cohort of patients with a CrCl < 60 ml/min after CABG (11.1 vs.1.2%, p=0.027). Hence, moderate transitory renal dysfunction appears to develop nearly in every fifth patient in the early period after CABG. The risk factors for the development of postoperative renal dysfunction include: age, increased duration of the period of artificial circulation (AC) and time of aortic occlusion (AO), severe acute postoperative cardiac insufficiency, and re-sternotomy. Even moderately pronounced transitory renal dysfunction after CABG is associated with an unfavourable prognosis of in-hospital cardiovascular complications. PMID- 27935892 TI - [Two-year results of infrainguinal reconstructions using autovenous shunts and xenografts]. AB - The authors analysed two-year results of inftrainguinal distal arterial reconstructions using xenograft ("kemAngioprosthesis") as compared with an autovein. Ours was a retrospective study including a total of 110 patients who endured 57 femoropopliteal (distal) and 54 femorotibial bypasses by means of both an autovein and a xenograft used as a shunt. The indications for reconstructive operation in the majority of cases was critical ischaemia induced by an atherosclerotic lesion of the femoropoplitealtibial segment corresponding to type D according to the TASC II classification. A xenograft was used only in case when the patient had neither great nor small saphenous vein suitable for use. Xenografts were used in 38 operations. In femoropopliteal (distal) bypasses the primary two-year patency of the xenograft virtually did not differ from that of autovenous shunts (70.1 and 76.5%, respectively). The two-year limb salvage rate for xenografts and autoveins used as shunts amounted to 87.1 and 88.7%, respectively. In For femorotibial bypass grafting, primary 2-year patency of xenografts was considerably worse and amounted to 35.8 versus 73.7% for autovenous shunts. The two-year limb salvage rate did not depend upon the type of the shunt, amounting in both cases to 80.2%. A characteristic complication for using xenografts was aneurysmatic degeneration of the shunts, which was observed in 21% of cases averagely 2 years after surgery. A conclusion was made that using xenografts for infrainguinal bypass operations may be considered as an adequate alternative in case of no autovenous material available. PMID- 27935893 TI - [Results of using various methods of autovenous femoropopliteal bypass grafting below the knee-joint fissure]. AB - The objective of the study was to improve therapeutic outcomes in patients presenting with lower limb critical ischaemia by means of optimizing the technique of femoropopliteal bypass grafting. The authors analysed the results of comprehensive examination and treatment of a total of 90 patients presenting with critical lower limb ischaemia on the background of atherosclerotic lesions of arteries of the femoropopliteal and crural segments. Depending on the technology of performing femoropopliteal bypass grafting, the patients were subdivided into three groups each consisting of 30 subjects. The groups were comparable by gender, age, concomitant diseases, degree of damage to arteries of the femoro popliteal-crural segment, and the state of the distal vascular channel. Group One patients underwent conventional autovenous bypass grafting with a reversed great saphenous vein. Group Two patients endured surgery according to the "in situ" technique. Group Three patients were subjected to an original technology of bypass grafting using a free autovenous graft with destroyed valves without reversion of the vein. It was demonstrated that the use of a free autovenous transplant with destroyed valves increased the volumetric blood flow through the shunt in the remote postoperative period 2.4-fold as compared with the reversed vein and 1.7-fold as compared with the "in situ" autovein. The proposed technique of femoropopliteal bypass grafting made it possible in the immediate postoperative period to decrease the rate of early postoperative complications by 23.4% as compared with the option of using the reversed vein and by 13.3% as compared with the "in situ" technique, as well as to lower the incidence rate of late shunt thromboses by 40 and 13.3%, respectively, and the number of limb amputations by 30 and 6.7%, respectively. The use of a free autovenous graft with destroyed valves is pathogenetically justified and makes it possible to optimize the results of treatment of patients. PMID- 27935894 TI - [Outcomes of surgical management of patients with nonspecific aortoarteritis with isolated lesion of brachiocephalic arteries]. AB - The authors analysed herein the results of examination and surgical treatment of patients presenting with Takayasu aortoarteritis with an isolated lesion of the aortic arch branches. Discrepancy between the degree of ischaemia, dissemination, and localization of lesions, as well as ambiguity of neurological manifestations suggests large compensatory possibilities of the cerebral circulation in this disease. The revealed peculiarities of lesions of the brachiocephalic arteries characteristic the pathology concerned were as follows: high incidence of lesions of subclavian arteries (mainly in the second and third segments), utterly rare involvement of the brachiocephalic trunk, a stenosisng pattern of lesion of carotid arteries with predominant localization in the common carotid artery, not involving it into the process of bifurcation. The outcomes of surgical treatment of patients suggest high efficacy of reconstructive operations in the overwhelming majority of the operated patients, also demonstrating considerable advantage of extrathoracic operations as compared with transthoracic ones. PMID- 27935895 TI - [Structural alterations of a biological prosthesis]. AB - The authors studied dilatation of a biological prosthesis (a specially treated xenograft made of bovine arteries) used as a femoropopliteal bypass in patients presenting with diseases of peripheral arteries. Structural alterations (ectasia) were examined in a total of 15 patients within the terms varying from 1 year to 7 years after the operation, resulting in working out a methodology of calculating structural changes of the conduit with characteristics of the composite index of dilatation of the conduit. The presence of aneurysmatically dilated portions whose dimension exceeded the initial size of the xenograft 3-4-fold did not influence the long-term patency of the shunt with preserved blood flow approximated to the major one. This made it possible to avoid a repeat surgical intervention. PMID- 27935896 TI - [Endoprosthetic repair of an abdominal aortic aneurysm, complicated by ischaemic necrosis of the sigmoid colon]. AB - Presented herein is a clinical case report regarding treatment of a patient after endovascular prosthetic repair of an abdominal aortic aneurysm, complicated by ischaemic necrosis of the sigmoid colon. This is followed by analysing the causes of the development of the complication, as well as by a brief review of the literature concerning this problem. PMID- 27935898 TI - [Conservative treatment of patients with peripheral artery diseases: possibilities and existing problems]. AB - With due regard to the requirements of evidence-based medicine, the article contains a review of present-day positions concerning conservative therapy in patients with peripheral artery diseases and chronic arterial ischaemia, represented in the latest Russian and foreign consensus documents, showing importance of bringing the basic provisions of the consensus documents to the notice of practical health-care providers with the aim of working out more effective therapeutic regimens. Some sections of the guidelines regarding the duration of treatment, among the number, require definite specification with the wording of more clear-cut practical conclusions. PMID- 27935897 TI - [Thrombosis of the portal, upper mesenteric, and splenic veins in a patient with thrombophilia (a clinical case report)]. AB - Currently there are several dozens of hereditarily associated thrombophilias and acquired states known to condition the development of a thrombus. Thrombosis of visceral veins appears to be a considerably less often encountered event than thrombosis in the system of visceral arteries. Presented herein in the article is a clinical case report concerning subacute thrombosis of the portal, upper mesenteric and splenic veins, having developed on the background of mutations of 7 genes of the system of haemostasis in a young adult patient. Timely comprehensive examination with determining polymorphism of the haemostasis system genes made it possible to verify the aetiology of the disease in the patient, while multispiral computed tomography contributed favourably to specifying the extension of thrombosis. Due to the developed segmental necrosis of the small intestine the patient was subjected to resection of the necrotised portion of the small intestine followed by establishing an entero-enteric anastomosis. In the postoperative period adequate anticoagulant therapy was adjusted in order to prevent relapse of thrombogenesis. PMID- 27935899 TI - [Algorithm for selection of individual therapy with clopidogrel in vascular surgical practice]. AB - For treatment of patients with diseases of lower limb arteries and prevention of cardiovascular complications in high-risk patients (those with diabetes mellitus, arterial hypertension, dyslipidemia, obesity) permanent antiplatelet therapy is indicated. A problem is variable individual sensitivity to therapeutic agents. For antiplatelet therapy in patients with atherosclerosis of lower limb arteries there has been obtained an evidence-supported base concerning efficacy of long term administration of clopidogrel preparations, unlike patients with acute coronary syndrome, for whom there has been accumulated an evidence-confirmed base of administering clopidogrel preparations, as well as ticagrelor and prasugrel in various clinical situations. Clopidogrel is currently the best known representative from the group of thienopyridines. It is a pro-drug and has complicated metabolism: two-stage oxidation under the effect of isoforms of cytochrome 2C19. Its active form irreversibly inhibits binding of ADP with P2Y12 receptors of thrombocytes. This is followed by inhibition of binding of fibrinogen with the glycoprotein IIb/IIIa receptor and a decrease of aggregation. Determining blood platelet aggregation with ADP, collagen and arachidonic acid forms the basis of clinical assessment of the functional state of thrombocytic activity and may be a marker of efficacy of treatment with antiaggregants. A complicated mechanism of action of clopidogrel implies individual policy of the attending physician in making a decision concerning the duration of therapy and selection of the dose. These prerequisites resulted in working out a recommended algorithm of individual dosing of clopidogrel (based on the analysis of case histories of patients with atherosclerosis of lower limb arteries by the level of platelet aggregation to a series of inducers) and correction of the dose of the drug based on the results of molecular-genetic testing of the cytochrome CYPC19 gene. The algorithm makes it possible to achieve a maximum level of efficacy and safety of treatment with antiaggregants. PMID- 27935900 TI - [Thromboangiitis obliterans (Buerger's disease): state of the art]. AB - Thromboangiitis obliterans (Buerger's disease) is systemic vasculitis with predominant development of thrombotic occlusions of small-to-medium diameter arteries of distal portions of both upper and lower limbs. A distinctive feature of Buerger's disease from other vasculitides is the involvement of the venous bed into the pathological process in the form of migrating thrombophlebitis. The disease is encountered more often in young adult males, predominantly tobacco smokers. The clinical pattern is presented by symptoms of increasing insufficiency of blood supply of tissues of extremities. The diagnosis is made by means of ruling out other vascular diseases (atherosclerosis, diabetes mellitus, systemic diseases of connective tissue, hypercoagulation conditions) based on clinical and laboratory findings, as well as modern methods of visualization, including multislice spiral computed tomographic angiography. Of special importance is a pathomorphological examination aimed at detecting the signs specific for Buerger's disease: arteries showing intimal hyperplasia (from stenosis to complete obliteration according to the capillary angiomatosis type, vascular "recalibration", obliteration of lumens by thrombi, lack of calcification of the tunica media; venous alterations are presented by panphlebitis with intimal hyperplasia, and occlusion with thrombi. Treatment is aimed at eliminating the aetiological stimulus (i. e, smoking), improving blood circulation by means of regular, dosed physical exercises, and administration of anti-ischaemic agents (analogues of prostaglandins, calcium channel antagonists, antiaggregants and anticoagulants). Failure of conservative treatment failed should be followed by making a decision to perform revascularization (endovascular interventions, bypass reconstructive operations, arterialization of the venous blood flow of the foot, resection of the posterior tibial veins, transplantation of the greater omentum onto the crus). PMID- 27935901 TI - Sodium supply influences plasma sodium concentration and the risks of hyper- and hyponatremia in extremely preterm infants. AB - BACKGROUND: Hyper- and hyponatremia occur frequently in extremely preterm infants. Our purpose was to investigate plasma sodium (P-Na) concentrations, the incidence of hyper- and hyponatremia, and the impact of possible predisposing factors in extremely preterm infants. METHODS: In this observational study, we analyzed data from the EXtremely PREterm (< 27 wk.) infants in Sweden Study (EXPRESS, n = 707). Detailed nutritional, laboratory, and weight data were collected retrospectively from patient records. RESULTS: Mean +/- SD P-Na increased from 135.5 +/- 3.0 at birth to 144.3 +/- 6.1 mmol/l at a postnatal age of 3 d and decreased thereafter. Fifty percent of infants had hypernatremia (P-Na > 145 mmol/l) during the first week of life while 79% displayed hyponatremia (P Na < 135 mmol/l) during week 2. Initially, the main sodium sources were blood products and saline injections/infusions, gradually shifting to parenteral and enteral nutrition towards the end of the first week. The major determinant of P Na and the risks of hyper- and hyponatremia was sodium supply. Fluid volume provision was associated with postnatal weight change but not with P-Na. CONCLUSION: The supply of sodium, rather than fluid volume, is the major factor determining P-Na concentrations and the risks of hyper- and hyponatremia. PMID- 27935902 TI - Objectively measured physical activity and sedentary time in young adults born preterm-The ESTER study. AB - BACKGROUND: Young adults born preterm have higher levels of cardio metabolic risk factors and they report less physical activity than their peers born at term. Physical activity provides important cardio metabolic health benefits. We hypothesized that objectively measured physical activity levels are lower and time spent sedentary is higher among preterm-born individuals compared with controls. METHODS: We studied unimpaired participants of the ESTER birth cohort study at age 23.3 y (SD: 1.2): 60 born early preterm (<34 wk), 108 late preterm (34-36 wk), and 178 at term (controls). Physical activity and sedentary time were measured by hip-worn accelerometer (ActiGraph). RESULTS: As compared with controls' (mean physical activity, 303 counts per minute (cpm; SD 129)), physical activity was similar among adults born early preterm (mean difference = 21 cpm, 95% CI -61, 19) or late preterm (5 cpm, -27, 38). Time spent sedentary was also similar. Adjustments for early life confounders or current mediating characteristics did not change the results. CONCLUSION: In contrast to our hypothesis, we found no difference in objectively measured physical activity or time spent sedentary between adults born preterm and at term. The previously reported differences may be limited to physical activity captured by self-report. PMID- 27935904 TI - Determinants of Postgraduate Students' Choices of Speciality. AB - INTRODUCTION: Postgraduate specialization is perceived as essential for success with high competition for enrolment. The reasons how medical students choose their postgraduate specialty are complex. Understanding the factors that influence career choice helps in workforce planning. So, we tried to identify the specialty preferred by postgraduate students and the factors that influenced these choices in a post graduate institution. METHODS: A cross-sectional observational study was conducted in National Academy of Medical Sciences. All the postgraduate students of batch 2011 AD were enrolled for the study. The responses were rated on a five point Likert scale. RESULTS: Significant gender preference was observed in specialties. General Surgery, Internal Medicine and Orthopedics were chosen by male students (P-Values, respectively, 0.001, 0.033 and 0.000) while Obstetrics and Gynecology and Ophthalmology being chosen by female students (P-Values, respectively, 0.000 and 0.006). Significant difference was observed between male and female student responses to the factor - scope in future (P - value 0.042), between married and unmarried students to the factor - workload flexibility (P - value 0.011), students who tried to go abroad versus who didn't, for the factor - Illness of self/family/friend (P - value 0.016), and between those who worked in rural area versus those who didn't, to the factor - Influence of friends/ seniors (P - value 0.038). CONCLUSIONS: Various factors affect the choices for preferred specialty. Policy makers should look at the needs of the nation, and ensure that specialty postgraduate education programs reflect those needs. PMID- 27935903 TI - Prevalence of primary ciliary dyskinesia in consecutive referrals of suspect cases and the transmission electron microscopy detection rate: a systematic review and meta-analysis. AB - Diagnostic testing for primary ciliary dyskinesia (PCD) usually includes transmission electron microscopy (TEM), nasal nitric oxide, high-speed video microscopy, and genetics. Diagnostic performance of each test should be assessed toward the development of PCD diagnostic algorithms. We systematically reviewed the literature and quantified PCD prevalence among referrals and TEM detection rate in confirmed PCD patients. Major electronic databases were searched until December 2015 using appropriate terms. Included studies described cohorts of consecutive PCD referrals in which PCD was confirmed by at least TEM and one additional test, in order to compare the index test performance with other test(s). Meta-analyses of pooled PCD prevalence and TEM detection rate across studies were performed. PCD prevalence among referrals was 32% (95% CI: 25-39%, I2 = 92%). TEM detection rate among PCD patients was 83% (95% CI: 75-90%, I2 = 90%). Exclusion of studies reporting isolated inner dynein arm defects as PCD, reduced TEM detection rate and explained an important fraction of observed heterogeneity (74%, 95% CI: 66-83%, I2 = 66%). Approximately, one third of referrals, are diagnosed with PCD. Among PCD patients, a significant percentage, at least as high as 26%, is missed by TEM, a limitation that should be accounted toward the development of an efficacious PCD diagnostic algorithm. PMID- 27935905 TI - Socio-demographic, Epidemiological and Environmental Determinants of Acute Gastroenteritis in Western India. AB - INTRODUCTION: An outbreak of acute gastroenteritis had occurred in Rajpara village of Bhavnagar district. The objective of this study was to find out the socio-demographic, epidemiological and environmental determinants of this outbreak. METHODS: A case-control study was conducted in Rajpara village among 238 cases of acute gastroenteritis and an equal number of controls in January 2015. Multiple logistic regression was used for identifying the variables independently predicting acute gastroenteritis. RESULTS: Upper socio-economic status, occupation requiring travel outside village, source of drinking water from well of 'new' Rajpara village, change in taste of water, use of chlorine tablets, travel outside village in last week, another family member affected with acute gastroenteritis, using common utensil for hand washing, hand washing before eating, ate food from outside in last week, having sanitary latrine at house, waste disposal in a common dump (instead of at house), waste accumulation around house and flies inside house were significantly associated with occurrence of acute gastroenteritis. On multiple logistic regression, change in taste of water (P<0.001), waste disposal in a common dump (P=0.012), another family member been affected (P<0.001), waste accumulation around house (P<0.001), higher socio economic status (P=0.002) and eating outside food (P=0.011) made a significant contribution to prediction. CONCLUSIONS: Socio-demographic factors (higher socio economic status), epidemiological correlates (change in taste of water, another family member been affected with acute gastroenteritis and eating outside food) and environmental determinants (waste disposal in a common dump and waste accumulation around house) significantly determines the occurrence of cases of acute gastroenteritis. PMID- 27935906 TI - Cognitive Dysfunctions in Patients with Alcohol Dependence Syndrome in a Tertiary Hospital in Kathmandu. AB - INTRODUCTION: Alcohol dependence is a chronic disorder, accompanied by neuropsychological deficits. Patients with alcohol dependence were evaluated to identify the cognitive dysfunctions. METHODS: The study followed descriptive design and recruited participants (N=62) from inpatient services of the Department of Psychiatry and Mental Health by convenient sampling. Participants were evaluated with the Severity of Alcohol Dependence Questionnaire, Frontal Assessment Battery and PGI Memory Scale for the severity of alcohol dependence, executive impairments and memory dysfunctions respectively once they had completed alcohol detoxification. RESULTS: Total duration of alcohol consumption was 13.93 +/- 8.74 years, period of dependence was 2.97 +/- 2.23 years and 56.5% had moderate level of dependence. 33.9% of the participants had executive impairments particularly in conceptualization, programming and mental flexibility. 38% of variance in executive dysfunction was explained by illness variables, where period of alcohol dependence and education were significant predictors. 54.8% had significant memory dysfunction particularly in visual retention, remote memory, verbal retention of dissimilar pairs and delayed recall. Memory dysfunction differed significantly among the age groups (F=10.22, p<0.01) and age was a significant predictor (beta=.542, p<0.001). 19% variance in memory dysfunction was explained by illness variables, where duration of alcohol consumption was a significant predictor (beta = .485, p<0.01). CONCLUSION: Findings indicate that cognitive dysfunctions are prevalent among patients with alcohol dependence. Hence, routine neuropsychological assessment is of particular importance for early detection and remediation of underlying deficits, which completes the treatment of alcohol dependence. PMID- 27935907 TI - Eclampsia: Feto-Maternal Outcomes in A Tertiary Care Centre in Eastern Nepal. AB - INTRODUCTION: Eclampsia is a preventable and treatable cause of maternal morbidity and mortality with poor feto-maternal outcome in developing countries. Despite development in the level of health education expertise in human resources and institutional obstetric care in our country, the delay in early recognition of the problem, transportation to proper health facility and getting proper expert care are major hurdles to reduce complications. Therefore, we decided to study feto-maternal outcomes in our setting. METHODS: A retrospective cross sectional hospital based study carried out in Nobel Medical College,Biratnagar, from 17th June 2014 to 16th June 2015. Details and data obtained from Medical Record Section were analysed. All patients with eclampsia were included and fetomaternal outcomes measured in terms of complications. Simple descriptive statistical method was applied for analysis. RESULTS: Among 8,066 deliveries, 112 had eclampsia with incidence of 13.8/1000 deliveries. Majority (41%) were of <19 years of age. Above 90% were unbooked. Aoubt 63.4% were primiparas and 83% had antepartum eclampsia. Eclamptic fits were more common (41.6%) in 37-40 weeks period of gestation. Fits to delivery interval was more than six hours in 89.1% women and 69.3% women underwent caesarean delivery. About 18.9% women developed eclampsia related complications.Common causes of maternal deaths (5.36%) were pulmonary edema, aspiration pneumonia,cerebrovascular accidents and HELLP syndrome. Perinatal death was nine percent. CONCLUSIONS: Although the obstetric care facilities are improving with time, the feto-maternal outcomes are still poor in our country. Therefore early recognition and proper management are vital to tackle this challenge. PMID- 27935908 TI - Intestinal Worm Infestation and Anaemia in Pregnant Women. AB - INTRODUCTION: Severe Anaemia during pregnancy is an important contributor to maternal mortality, as well as to the low birth weight which is in turn an important risk factor for infant mortality. We aim to determine the prevalence of anaemia in the region amongst pregnant women and identify their problems and to easily provide them with the clinical services. METHODS: A community based cross sectional study done in PHCRC Chapagaun, Lalitpur from July 17,2011 to September 17,2011. Date from pregnant women presenting at PHCRC, , were filled and analysed using standard guidelines from WHO and Indian council of Medical research. RESULTS: Out of 192 pregnant women, the average age of pregnancy was 21-25 years (46.55), mean haemoglobin (Hb) in pregnancy was 11g/dl. Majority pregnant women are Newar (35.4%) ethnicity,67.7% of them housewives and 31.5% have primary level education. Only 24% was found to have their haemoglobin level in anaemic range. Among the pregnant women (n) =192; 48 (25%) had worm infestation, 119 (62%) had negative stool report and 25 (13%) had other than worms were found. Only about one third of the sample has actually taken albendazole. CONCLUSIONS: Aanaemia is prevalent in pregnant women of PHCRC, chapagaun and there was a significant correlation between anaemia and worm infestation. However, the relation among the haemoglobin level, iron, folic acid and albendazole was not significant. PMID- 27935909 TI - Exploring the Diagnosis and Management of Bouveret's Syndrome. AB - Bouveret's syndrome is an unusual cause of gastric outlet obstruction secondary to gallstone impaction. It is so rare that it is commonly missed in clinical practice if it is not considered in differential diagnoses of intestinal obstruction more specifically in man who does not report the history of gall stone. Furthermore, there are no definitive guidelines on approach and management of this condition. We present a seventy eight year old man who developed acute abdominal symptoms due to impaction of a gallstone in the duodenum. He did not have history of gall stone. The diagnosis was supported via CT abdomen and Endoscopy. The patient was successfully managed by exploratory laparotomy followed by anterior pylorotomy to remove the stone without cholecystectomy and fistula repair. PMID- 27935910 TI - Ascites and Adnexal Mass with Raised CA125: How Arduous can be the Path of Diagnosis. AB - Ascites, adnexal mass and elevated CA125 levels almost always suggest advanced ovarian carcinoma. We present a case of a 37 years old multiparous lady who presented with such a classical picture. Radiological picture was suggestive of ovarian carcinoma with peritoneal metastasis. However, ascitic fluid cytology was negative for malignant cells. A differential diagnosis of tubercular mass was made. Ascitic fluid was sent for adenosine deaminase test that was negative. Fine needle aspiration cytology failed to reveal any sufficient sample for evaluation. Open laparotomy and biopsy was done that showed granulomas suggestive of tuberculosis. Category one anti tubercular treatment was started and symptoms resolved within one month. PMID- 27935911 TI - Giant Left Atrium - A Rare Case of Acute Upper Gastrointestinal Bleeding. AB - Acute upper GI bleeding is a common medical emergency with a hospital mortality of approximately 10%. Non variceal UGI bleeding is the most common cause followed by oesophageal varices. Various rare causes have been described in the literature but there are very few cases of giant left atrium leading to oesophageal erosion and causing upper GI bleeding. We are presenting a case of rheumatic valvular heart disease with giant left atrium who presented in our department with acute upper GI bleeding. PMID- 27935912 TI - Epidermoid Cyst of Tongue. AB - Epidermoid cyst occurring within the tongue is rare. A 5 year old male child was brought to OPD with a tongue mass which was gradually increasing in size. There was associated difficulty in speech and mastication as the swelling increased in size. Intraoral examination revealed moderately tender,fluctuant and enlarged tongue. A diagnosis of dermoid cyst was made and the patient was booked for surgery. Excision of the cyst was done under general anaesthesia. Post-operative histopathology was done. The histopathological findings confirm the diagnosis of an epidermoid cyst, characterized by the presence of: (I) a cyst cavity lined by stratified squamous epithelium with keratinization on the surface; and (II) connective tissue with a mild inflammation. The proposed treatment was considered successful as the case was solved and there was no recurrence. PMID- 27935913 TI - Forensic Odontology: A Boon to Community in Medico-legal Affairs. AB - Forensic odontology is a sub-discipline of dental science which involves the relationship between dentistry and the law. The specialty of forensic odontology is applied in radiographic investigation, human bite marks analysis, anthropologic examination and during mass disasters. Besides the fact that radiographs require pretentious laboratory, it is still claimed to be a facile, rapid, non-invasive method of age identification in the deceased. The budding DNA technology has conquered the traditional procedures and currently being contemplated as chief investigating tool in revealing the hidden mysteries of victims and suspects, especially in hopeless circumstances. Forensic odontology has played a chief role in solving cold cases and proved to be strong evidence in the court of law. Systematic collection of dental records and preservation of the same would marshal the legal officials in identification of the deceased. To serve the forensic operation and legal authorities, dental professionals need to be familiar with the basics of forensic odontology, which would create a consciousness to preserve the dental data. The aim of this paper is to emphasize the vital applications of forensic odontology in medico-legal issues. Conjointly the recent advancements applied in forensic human identification have been updated. PMID- 27935914 TI - Road Traffic Accident and its Characteristics in Kathmandu Valley. AB - INTRODUCTION: Road traffic accident is alarming in Nepal. The objective of this research is to find out the characteristics of RTA in central part of Nepal. METHODS: A prospective descriptive study was taken from 1 August 2014 to 31 July 2015. Data were collected from postmortem department and nine hospitals in Kathmandu Valley. Inventory sheets with targeted variables for secondary sources were created. RESULTS: A total of 3461 morbidity cases from hospitals and 265 mortality cases from postmortem department were included in this study. The ratio of male victim to female was 2.3:1. Around 75% of victims were between 15-49 years old. Pedestrians were the most vulnerable (33%) followed by riders of motorized 2-3 wheelers. Two wheeler motorized vehicles were most frequently (67.2%)involved in RTAs. More RTA occurred on daytime, Saturdays, July and November. Around half of the victims did not arrive in hospitals in one hour. The most common injury type was soft tissue injury (37.6%), followed by open wound (20.9%), fracture (18%) and traumatic brain injuries (12.7%). CONCLUSIONS: According to the characteristic of RTA found in this study, following preventive measures are recommended Helmet was necessary for two wheeled backseat riders. Road safety education towards age group of 15-49 was compulsory. Precaution should neither be omitted regarding road safety on weekends, holidays, nor in rainy and festival season. Future studies could be focused on estimation of burden of disease caused by RTA and its determinants in Nepal. PMID- 27935915 TI - Medication Practice of Patients with Dermatophytosis. AB - INTRODUCTION: Dermatophytosis is one of the commonest dermatoses observed in Dermatology OPD. It is caused by Fungus Dermatophyte. Its pattern and prevalence varies from region to region. As self medication practice is very common, we aim to find the prevalence of various clinical pattern of dermatophytosis and to find out the medication commonly used by the patients for this condition. METHODS: This was cross sectional observational study. The case collection was done from outpatient department of Dermatology and Venereology of a Teaching Hospital from 15th March, 2013 to 14 March, 2014. Demographic, Clinical and other relevant details were recorded in Proforma after history and examination. RESULTS: The total number of cases were 594. Crural area was the most commonly involved. Tinea corporis was most common dermatophytosis followed by Tinea incognito. Risk of recurrence was highest in buttocks [odds ratio-2.404 (1.510, 3.827) and crural area [odds ratio- 2.298 (1.637,3.266). Topical steroid and topical steroid with antifungal was used by 225 (30.1%) and 226 (30.2%) respectively. Patients who consulted dermatologist were more likely to use antifungal, odds ratio-12.060 (4.907, 29.643). CONCLUSIONS: Tinea corporis was the commonest dermatophytosis. Due to practice of topical steroid misuse T. incognito was second common. It is essential to educate the general public, pharmacist and paramedics regarding the proper use of topical steroid. PMID- 27935916 TI - Self-prescription of Paracetamol by Undergraduate Students in BP Koirala Institution of Health Sciences. AB - INTRODUCTION: Self-prescription of medicines are common especially in low income countries.Paracetamol is a common medicine that is self-prescribed also among university students. Incorrect use of paracetamol can lead to ill effects on health including liver failure. There is scarce evidence of the use of paracetamol by self-medication in Nepal. The objective of this study is to evaluate the paracetamol use by self-prescription among the undergraduate students of BPKIHS. METHODS: A cross-sectional study was conducted among 570 undergraduate students of BPKIHS from February 2016 till July 2016. Pretested semi-structured, self-administered questionnaire was used to collect information regarding socio-demographic characteristics, paracetamol use and perception regarding paracetamol use. Systematic random sampling was done from a list of all medical dental and nursing students to select the study sample. RESULTS: Most (86%) students are in the category of 20-24 years. Female students are slightly more than male. Majority of the students are from Nepal. More than half of the students are from medical stream. Self-prescription of paracetamol is seen among 90.1% of the students in our study. Correct dose of paracetamol was mentioned by less than half (49.3%) of the students. Self-prescription of paracetamol is considered beneficial by all participants of this study. CONCLUSIONS: Self prescription of paracetamol by health sciences students of B P Koirala Institute of Health Sciences is high, while the knowledge of correct dose of paracetamol for adults is low. There is a need to further explore this gap and possibly conduct further studies for other medicines as well. PMID- 27935917 TI - Safety and Efficacy of Azathioprine as a Second Line Therapy for Primary Immune Thrombocytopenic Purpura. AB - INTRODUCTION: Immune thrombocytopenic purpura remains common blood disease in Nepal. Azathioprine is an oral immunosupressive medicine which has been used widely in various autoimmune disease and solid organ transplant patients. It is inexpensive, easily available and well tolerated medicine. This study was carried out to evaluate efficacy and safety of azathioprine as a second line medicine for primary ITP patients who were refractory to steroid therapy. METHODS: The observational, pre-post study was conducted at Government of Nepal Civil Service Hospital, Kathmandu from January to October 2014. Twenty four primary ITP patients who were steroid refractory were treated with Azathioprine. Patients were termed steroid refractory if platelet counts were less than 30,000/ul on day 21st of steroid therapy. From day 22 onwards oral azathioprine 2mg/kg was started and steroids were tapered 10mg/week and stopped. Platelet counts of more than 30000/ul after one month of stopping steroid, while still on azathioprine, were termed response to azathioprine. Platelet count of more than 100,000/ul was termed complete response. The associations among age, gender, duration and platelets counts were analyzed by chi square test and Fisher's exact test (when individual cell frequency was less than 5). The comparison of platelets counts among the start and day 90 of Azathioprine therapy was performed by the paired t test. RESULTS: The study showed that there was not significant association among age and gender of the patients and their platelets count on the start of Azathioprine therapy (p value 0.354 and 0.725 respectively) and on day 90 of Azathioprine therapy (p value 0.082 and 0.762 respectively). The duration-wise comparisons of platelets count on both the start and day 90 of Azathioprine therapy were significant (p values 0.029 and 0.008 respectively). The paired comparison among platelets count on the start and day 90 of Azathioprine therapy was highly significant (p value 0.000). CONCLUSIONS: The study showed the therapeutic implication of azathioprine in ITP patients. It also showed that efficacy of azathioprine was comparable with other modes of treatment. In low income countries like Nepal azathioprine can be considered as second line treatment for steroid refractory ITP patients. PMID- 27935918 TI - Study of Infertile Couples Attending a Teaching Hospital in Eastern Nepal. AB - INTRODUCTION: Infertility is a global health issue and a socially destabilizing condition for couples with several stigmas including medical, social, psychological burdens and a marital disharmony. The aim was to study the incidence of infertility in couples attending outdoor of Nobel Medical College and to know the contributing factors among the infertile couples. METHODS: A prospective cross-sectional study was carried out in the outpatient department of a teaching hospital July 2015-June 2016, where the incidence of infertility and the contributing factors for the same were evaluated. RESULTS: The incidence of infertility in this study was 5.45% and it was dominated by secondary infertility. The most important cause was male factor in 37.39%. Majority of male factor abnormality was due to exposure to heat as these male work abroad in Arabian Countries. CONCLUSIONS: The study shows a dominance of secondary infertility and male factor being a major contributor. The most common semen abnormality was oligospermia. PMID- 27935919 TI - Hysteroscopy in Abnormal Uterine Bleeding vs Ultrasonography and Histopathology Report in Perimenopausal and Postmenopausal Women. AB - INTRODUCTION: Abnormal uterine bleeding is one of the most common morbidity landing women to attend medical attention in gynecology outpatient department. This study aims to evaluate the hysteroscopy finding in diagnosis of AUB and its correlation with ultrasonography finding and histopathological reports. METHODS: This was a prospective comparative study in which ultrasonography was performed in fifty patients with abnormal uterine bleeding attending OPD then hysteroscopy was performed.After removing hysteroscopy dilation and curettage was done and sample sent for histopathology.At the end reports of hysteroscopy finding were compared with sonograhic and pathological results. RESULTS: In the study women aged from 45 to 64 years with the symptoms duration of 15 days to 6 months. Post menopausal women seek medical attention more early then the menstruating women.Common symptoms are menorrhagia, metrorrhagia and postmenopausal bleeding. Most common abnormality was menorrhagia (32%) followed by post menopausal bleeding 28 %. Ultrasonography showed 46% of abnormal finding in which 17 (47%) menstruating women and 6 (43%) women were postmenopausal women. Among 50 women 17 (34%) had negative finding and 43 (66%) had abnormal finding in which most common finding of hyperplastic endometrium. Hysteroscopy correctly diagnose atrophic endometrium, polyp and endometrial Ca which is also confirmed by histopathology finding. CONCLUSIONS: Hysteroscopy is reliable method for evaluating cases of AUB and it can be used as first line diagnostic method for benign lesions. Hysteroscopy guided biopsy has most accurate in diagnosing pathology. PMID- 27935920 TI - It's Even Here! Two Rare Cases of Pyriformis Myocysticercus. AB - Cysticercus, the larval form of Taenia Solium, a tapeworm, can infest various tissues in the human body. Though central nervous system involvement is the most dramatic form of infestation, several other uncommon sites of has been reported in the literature. One such involvement is that of the musculature. The most easily recalled manifestation of myocysticercus is that in the orbit where the patients present with painful proptosis. However, other less common muscular sites of involvement are documented in case reports. To the best of our knowledge, there are no documented cases of pyriformis muscle infestation with cysticercus. We came across two interesting cases, where imaging established the diagnosis of isolated pyriformis cysticercosis. Follow up after one month of antihelminthic treatment imaging revealed disappearance of the lesions. PMID- 27935921 TI - Isolated PTH Renal Resistance Pseudohypoparathyroidism 1b: A Rare Cause of Hypocalcemia. AB - A case of Pseudohypoparathyroidism 1b is reported, who presented with signs and symptoms of hypocalcemia. Causes, diagnosis and management with new insight into genetic novel mutations in PHP are discussed. The objectives are to provide information regarding problems of Calcium balance, causes and making diagnosis of pseudohypoparathyroidism, learn complexities of PTH cellular interactions and calcium homeostasis and learn the genetic novel mutations of various types of PHP. PMID- 27935923 TI - Strategy of Making Hand Washing a Routine Habit: Principles of 5Es and 3Rs. AB - Regular hand washing habit has potential to reduce morbidity and mortality due to diseases and improves child development and reduces absenteeism of children, teachers and workforce. Improving hand washing behavior is more cost effective than improving clean water and sanitation infrastructure. There are numbers of initiatives and interventions in place, which have gained momentum with key messages of a call to action with increasing investment in schools, engaging policy makers and demonstration them with evidence. However, change in behavior as a routine habit has not reached to an optimum level and requires institutionalizing hand washing practices in schools, from schools and by schools and develop it as a curriculum. Therefore, we are purposing principles of 5Es and 3Rs - a strategy to make hand washing a routine habit. These 5E principles are: i) Embedding in a system, ii) Enabling Environment, iii) Eliminating Friction, iv) Encouraging all, and v) Establishing intervention and 3Rs are practicing them Religiously, Routinely and Repeatedly. Numbers of interventions have well demonstrated that hand hygiene educational interventions can help maintaining good practices. Finally, if schools and community start doing today, we can observe behavioral change practices for hand washing as a routine habit by at least 10 years after. PMID- 27935922 TI - Maxillary Calcifying Epithelial Odontogenic Tumour. AB - The calcifying epithelial odontogenic tumor is a benign, locally invasive, slow growing neoplasm occurring as intraosseous (94%) and extraosseous (6%) variants and with a frequency of 1-2%. Extraosseous variant is diagnosed slightly earlier than the intraosseous type. The intraosseous CEOT shows a maxilla:mandible site ratio of 1:2 and are mainly located in the premolar/molar region. Histologically, the CEOT is characterized by the occurrence of sheets, nests and masses of polyhedral, eosinophilic epithelial cells which may show cellular abnormalities including giant cell formation and nuclear pleomorphism. Some cells increase in size and produce a homogeneous, eosinophilic, 'amyloid-like' substance which may become calcified and which may be liberated as the cells break down. Enucleation with a margin of macroscopically normal tissue is the recommended treatment for CEOT involving the mandible. Maxillary CEOT are treated more aggressively, as they tend to grow more rapidly and do not usually remain well confined. PMID- 27935924 TI - Smoking Cessation and Attitudes, Belief, Observation, and Education of Medical Students, in Turkey. AB - INTRODUCTION: Tobacco use is an important public health problem around the world.Aim of this study is to assess attitudes,belief and observation of the students on smoking cessation and medical education. METHODS: This study is part of a multi-country study called "Global Health Profession Student Survey". The study population consisted of third year medical students in Turkey. The sample consisted of a total of 1834 medical students from randomly selected 12 medical schools. RESULTS: Of the students, 1209 (92.1%)thought that health professionals should get specific training on cessation techniques, and that health professionals should serve as "role models" for their patients and the public. The percentage of the students who answered "Health professionals should routinely advise their patients who smoke to quit smoking" was 1211 (93.3%). Of the students, 1204 (60.8%) responded that health professionals who use other tobacco products were less likely to advise patients to stop smoking. The percentage of the students who had received a formal training on smoking cessation approaches was 48.2% (1196). Of the students, 91.5% (1203) had heard of nicotine replacement therapies in tobacco cessation programs. More than half of smokers tried to quit smoking last year, and majority of them did not take professional help or advice. CONCLUSIONS: Majority of students are aware of health professionals' role on smoking cessation. Most of the students are willingness to take specific formal training on tobacco. Student's behaviours and attitudes were different by gender and smoking status.Improvement of tobacco cessation issues in medical curricula will be beneficial. PMID- 27935925 TI - Clinical Evaluation of Fused/Ankylosed Hip with Severe Flexion Deformity after Conversion to Total Hip Arthroplasty. AB - INTRODUCTION: Fused or Ankylosed hip is late complication of chronic inflammatory disorder with progressive changes in and around articular as well as periarticular structures with alteration in bio-force line of body which later lead to severe flexion deformity of joint. This not only results decreased movements of hip, it's also increase pain around the hip, back and contralateral hip. METHODS: Retrospectively, all patients aged 18 years or older undergoing THA between June 2006 to June 2012 were reviewed with selection criteria. The five ankylosed hips (three left and two right) with severe flexion deformities which ankylosed spontaneously were successfully converted to THA at time period of 2006 to June 2012. Range of motion, Harris Hip Score and flexion deformity angle at preoperative, postoperative and follow-up periods were used as evaluation. RESULTS: Mean follow up is 42 months. Mean HHS increased from 21.6+/-4.97 to 81.8+/-4.02 points with one excellent, two good and two fair cases. The FDA is corrected to mean 8 degrees +/-10.95 postoperatively and 4 degrees +/-5.47 at final follow up from 81.6 degrees +/-4.39 with two hips of 10 degrees residual deformity. Hip ROM is improved as flexion 70 degrees to 100 degrees , adduction 10 degrees to 20 degrees , abduction 10 degrees to 30 degrees , internal rotation 5 degrees to 10 degrees and external rotation 2 degrees to 50 degrees from 0 degrees activity. As complications, one hip had loose prosthesis, two had early postoperative dislocations, one had Deep Vein Thrombosis and one had femoral nerve palsy with quadriceps weakness. CONCLUSIONS: THA is an effective treatment for ankylosed hip with severe flexion deformity although complications are noted more than routine hip arthroplasties. PMID- 27935927 TI - Molecular Identification of Extended-Spectrum beta-lactamase and Integron Genes in Klebsiella Pneumonia. AB - INTRODUCTION: Infections caused by Gram negative bacteria, producing extended spectrum beta-lactamase, including Klebsiella pneumoniae are increasing all over the world with high morbidity and mortality. The aim of the present study was determined antimicrobial profile susceptibility and the prevalence of antibiotic resistance genes by multiplex PCR. METHODS: In the present study, we obtained one hundred isolates of K. pneumoniae from different clinical samples. The antibiotic susceptibility testing was done in thirteen antibiotic and, therefore, M-PCRs were conducted using the DNA amplification for detection of ESBLs (blaTEM, blaCTX M, blaSHV) and int (I, II, III) genes. RESULTS: The results of resistance to amoxicillin/clavulanate, ciprofloxacin, amikacin, trimethoprim-sulfamethoxazole, cefotaxime, ampicillin, aztreonam, imipenem, gentamicin, ceftazidime, Cefepime, ceftriaxone and levofloxacin were obtained 37%, 37%, 93%, 84%, 52%, 87%, 59%, 8%, 24%, 67%, 52%, 43% and 26%, respectively. The frequency of the extended-spectrum beta-lactamase K. pneumoniae was obtained 37%. The prevalence of resistance genes of ESBLs in the M-PCR method showed that the blaTEM, blaCTX and blaSHV were 38%, 24% and 19%, respectively, however, only 8 (8%) out of 100 isolates were found to have positive outcomes for the existence of class 1 integrons and there were no detected class 2 or class 3 integrons. CONCLUSIONS: Our results recommend the likely co-carriage of some ESBLs genes and antibiotic resistance integrons on the same plasmids harboring the MDR genes. PMID- 27935926 TI - Hyponatremia in Patients with Community Acquired Pneumonia. AB - INTRODUCTION: Community acquired pneumonia is one the frequent cause of hospital admissions. Whereas, hyponatremia is a common electrolyte abnormality in hospitalized patients and has been shown to be associated with considerable morbidity and mortality. We aim to studyt the association of hyponatremia with community acquired pneumonia in terms of morbidity and mortality. METHODS: A prospective observational hospital based study was conducted in a hospital for a year. All patients with a diagnosis of community acquired pneumonia and admitted in medicine ward, were included. Patients with diarrhea, known Chronic Kidney Disease, Heart Failure, Cirrhosis of Liver, Malignancy, taking diuretics, chemical pneumonitis, interstitial pneumonias and other debilitating disease were excluded. RESULTS: Among the 72 cases of CAP, 61% were females and 39% were males. The mean age of patients was 51.3 years, 22 (30.55%) patients had severe CAP. A total of 7 cases expired with an overall mortality of 13.7%. The mortality risk increased with increasing CURB-65 score; CURB-65 score 0, 0%; CURB-65 score 1, 0%; CURB-65 score 2, 0%; CURB-65 score 3, 10%; CURB-65 score 4, 33%; CURB-65 score 5, 100%. i.e higher the CURB-65 score, higher the death rate of CAP patients (p<0.05). Hyponatremia was a common occurrence at hospital admission with an incidence of 36.11%. Hyponatremia at hospital admission was also associated with a longer length of hospital stay in cured CAP patients. The mean length of hospital stay was 4.3 days. CONCLUSIONS: High CURB-65 scores and lower values of serum sodium at admission in patients of CAP are associated with adverse outcomes both in terms of mortality and longer length of hospital stay. CURB-65 score should be incorporated into assessment of CAP and sodium of the patients during admission. PMID- 27935928 TI - Myomectomy Revisited: Experiences in a Teaching Hospital. AB - INTRODUCTION: Uterine myomas are the most common benign tumors of the female reproductive tract with myomectomy being one of the major modalities of the treatment in our set up. The aim of this study was to share the experiences of open myomectomy from a Teaching Hospital. METHODS: A observational study was conducted from a records of myomectomy cases in the department of Obstetrics and Gynaecology at Nobel Medical College teaching Hospital from June 2014- May 2016. RESULTS: Total 38 cases of myomectomy were performed during the study period in the women most commong age group being 35-39 years, followed by 30-34. The most common presenting symptoms was abnormal uterine bleeding in 15 (39.47%) followed by mass per abdomen in 10 (26.31%). The most common location of the myoma was intramural followed by subserosal, submucus. Degeneration was also noted in majority of the cases. All the myomectomies were done with Inj Vasopressin injected paracervically except in one case where tourniquet was used. None of the patients had significant post-operative morbidity except fever in the first 24 hours. CONCLUSIONS: Abdominal myomectomy is a safe and effective procedure for uterine myomas for infertile women in the past but it should be offered to those desiring for uterine preservation irrespective of age and reproductive status. PMID- 27935929 TI - Muscular Hamartoma of Intestine Causing Intestinal Obstruction. AB - Hamartomatous causes of small bowel obstructionare uncommon and of them, most are attributed to inflammatory bowel diseases and also certain medications such as NSAIDs. We describe a case of muscular hamartoma in a patient without prior chronic medical condition with brief review of literature. PMID- 27935931 TI - Caesarian Scar Pregnancy- a Diagnostic Dilemma. AB - Caesarean scar pregnancy is one of the rarest forms of ectopic pregnancy. Transvaginal ultrasound and color flow Doppler provides a high diagnostic accuracy. A delay in diagnosis and treatment can lead to uterine rupture, major hemorrhage, hysterectomy and serious maternal morbidity and mortality. Early diagnosis can offer treatment options of avoiding uterine rupture and hemorrhage, thus preserving the uterus and future fertility. Primary health care provider should know about this rare entity, because if diagnosed timely, and referral to specialized centre is done without delay will definitely save maternal morbidity and mortality. Management plan should be individualized. Termination of pregnancy is the treatment of choice in the first trimester. Expectant treatment has a poor prognosis because of risk of rupture. In this case report we aim to discuss the associated diagnostic dilemma, most appropriate methods of diagnosis and management, with their implications in clinical practice. PMID- 27935930 TI - Acute Ischemic Stroke and Acute on Chronic Kidney Disease. AB - Ischemic stroke is due to either local thrombus formation or emboli that occlude a cerebral artery, together with chronic kidney disease represent major mortality and morbidity.Here we present a case of 53 years old Malay man, admitted to a hospital in Malaysia complaining of sudden on set of weakness on right sided upper and lower limb associated with slurred speech. Patient was also suffering from uncontrolled hypertension, hyperlipidemia, chronic kidney disease stage 4, and diabetes mellitus (uncontrolled). He was diagnosed with acute ischemic stroke with cranial nerve 7 palsy (with right hemiparesis), acute on chronic kidney disease precipitated by dehydration and ACE inhibitor, and hyperkalemia. Patients with ischemic disease and chronic kidney disaese require constant monitering and careful selected pharmacotherapy. Patient was placed under observation and was prescribed multiple pharamacotherpay to stabalise detoriating condition. PMID- 27935932 TI - Early Recognition of Fibrodysplasia Ossificans Progressiva-Important For the Clinician. AB - Fibrodysplasia ossificans progressiva is a rare disorder of heterotopic ossification. Procedures like biopsy and surgery are known to be aggravating factors in promoting heterotopic ossification Clues to clinical diagnosis may therefore be a great advantage to treating orthopedician. Valgus deformity of great toe is an important diagnostic clue for treating physicians and thus aids in preventing the clinicians from subjecting the patients to unnecessary invasive and traumatic procedures. Hence clinical clues to early diagnosis are important in establishing the correct diagnosis and directing future management. PMID- 27935933 TI - Comprehensive Diabetes and Non-Communicable Disease Educator in the Low-Resource Settings. AB - The role of self-management education in diabetes and other major non communicable diseases is clearly evident. To take care of and educate people with diabetes and other major NCD under the supervision of medical professionals and for education of other health care professionals, Comprehensive Diabetes and NCD Educators are needed in the routine service in peripheral health clinics and hospitals. The areas of training of CDNCD educator should match with the cost effective interventions for diabetes and other major NCD that are feasible and planned for implementation in primary care in the low resource settings. Most of such interventions are part of diabetes education as required for Diabetes Self Management Education programmes and traditional Diabetes Educator. The addition of use of inhaled steroids and bronchodilator in chronic respiratory disease and identification of presenting features of cancer, also required for many people with diabetes with various such common co-morbidities, will complete the areas of training of traditional Diabetes Educator as that of CDNCD Educator. Staff nurse and health assistants, who are as such already providing routine clinical service to all patients including with diabetes and major NCD in peripheral health clinics and hospitals, are most appropriate for CDNCD Educator training. The training of CDNCD Educator, like that of traditional Diabetes Educator, requires fulfilment of sufficient hours of practical work experience under supervision and achievement of the essential competencies entailing at least 6 month or more of intensive training schedules to be eligible to appear in its final certifying examination. PMID- 27935934 TI - Beyond the Hypercube: Evolutionary Accessibility of Fitness Landscapes with Realistic Mutational Networks. AB - Evolutionary pathways describe trajectories of biological evolution in the space of different variants of organisms (genotypes). The probability of existence and the number of evolutionary pathways that lead from a given genotype to a better adapted genotype are important measures of accessibility of local fitness optima and the reproducibility of evolution. Both quantities have been studied in simple mathematical models where genotypes are represented as binary sequences of two types of basic units, and the network of permitted mutations between the genotypes is a hypercube graph. However, it is unclear how these results translate to the biologically relevant case in which genotypes are represented by sequences of more than two units, for example four nucleotides (DNA) or 20 amino acids (proteins), and the mutational graph is not the hypercube. Here we investigate accessibility of the best-adapted genotype in the general case of K > 2 units. Using computer generated and experimental fitness landscapes we show that accessibility of the global fitness maximum increases with K and can be much higher than for binary sequences. The increase in accessibility comes from the increase in the number of indirect trajectories exploited by evolution for higher K. As one of the consequences, the fraction of genotypes that are accessible increases by three orders of magnitude when the number of units K increases from 2 to 16 for landscapes of size N ~ 106 genotypes. This suggests that evolution can follow many different trajectories on such landscapes and the reconstruction of evolutionary pathways from experimental data might be an extremely difficult task. PMID- 27935936 TI - Understanding Peripheral Bat Populations Using Maximum-Entropy Suitability Modeling. AB - Individuals along the periphery of a species distribution regularly encounter more challenging environmental and climatic conditions than conspecifics near the center of the distribution. Due to these potential constraints, individuals in peripheral margins are expected to change their habitat and behavioral characteristics. Managers typically rely on species distribution maps when developing adequate management practices. However, these range maps are often too simplistic and do not provide adequate information as to what fine-scale biotic and abiotic factors are driving a species occurrence. In the last decade, habitat suitability modelling has become widely used as a substitute for simplistic distribution mapping which allows regional managers the ability to fine-tune management resources. The objectives of this study were to use maximum-entropy modeling to produce habitat suitability models for seven species that have a peripheral margin intersecting the state of North Dakota, according to current IUCN distributions, and determine the vegetative and climatic characteristics driving these models. Mistnetting resulted in the documentation of five species outside the IUCN distribution in North Dakota, indicating that current range maps for North Dakota, and potentially the northern Great Plains, are in need of update. Maximum-entropy modeling showed that temperature and not precipitation were the variables most important for model production. This fine-scale result highlights the importance of habitat suitability modelling as this information cannot be extracted from distribution maps. Our results provide baseline information needed for future research about how and why individuals residing in the peripheral margins of a species' distribution may show marked differences in habitat use as a result of urban expansion, habitat loss, and climate change compared to more centralized populations. PMID- 27935935 TI - Stimulus-Driven Population Activity Patterns in Macaque Primary Visual Cortex. AB - Dimensionality reduction has been applied in various brain areas to study the activity of populations of neurons. To interpret the outputs of dimensionality reduction, it is important to first understand its outputs for brain areas for which the relationship between the stimulus and neural response is well characterized. Here, we applied principal component analysis (PCA) to trial averaged neural responses in macaque primary visual cortex (V1) to study two fundamental, population-level questions. First, we characterized how neural complexity relates to stimulus complexity, where complexity is measured using relative comparisons of dimensionality. Second, we assessed the extent to which responses to different stimuli occupy similar dimensions of the population activity space using a novel statistical method. For comparison, we performed the same dimensionality reduction analyses on the activity of a recently-proposed V1 receptive field model and a deep convolutional neural network. Our results show that the dimensionality of the population response changes systematically with alterations in the properties and complexity of the visual stimulus. PMID- 27935937 TI - Let's Not Waste Time: Using Temporal Information in Clustered Activity Estimation with Spatial Adjacency Restrictions (CAESAR) for Parcellating FMRI Data. AB - We have proposed a Bayesian approach for functional parcellation of whole-brain FMRI measurements which we call Clustered Activity Estimation with Spatial Adjacency Restrictions (CAESAR). We use distance-dependent Chinese restaurant processes (dd-CRPs) to define a flexible prior which partitions the voxel measurements into clusters whose number and shapes are unknown a priori. With dd CRPs we can conveniently implement spatial constraints to ensure that our parcellations remain spatially contiguous and thereby physiologically meaningful. In the present work, we extend CAESAR by using Gaussian process (GP) priors to model the temporally smooth haemodynamic signals that give rise to the measured FMRI data. A challenge for GP inference in our setting is the cubic scaling with respect to the number of time points, which can become computationally prohibitive with FMRI measurements, potentially consisting of long time series. As a solution we describe an efficient implementation that is practically as fast as the corresponding time-independent non-GP model with typically-sized FMRI data sets. We also employ a population Monte-Carlo algorithm that can significantly speed up convergence compared to traditional single-chain methods. First we illustrate the benefits of CAESAR and the GP priors with simulated experiments. Next, we demonstrate our approach by parcellating resting state FMRI data measured from twenty participants as taken from the Human Connectome Project data repository. Results show that CAESAR affords highly robust and scalable whole brain clustering of FMRI timecourses. PMID- 27935938 TI - Retinal Capillary Rarefaction in Patients with Type 2 Diabetes Mellitus. AB - PURPOSE: In diabetes mellitus type 2, capillary rarefaction plays a pivotal role in the pathogenesis of end-organ damage. We investigated retinal capillary density in patients with early disease. METHODS: This cross-sectional study compares retinal capillary rarefaction determined by intercapillary distance (ICD) and capillary area (CapA), measured non-invasively and in vivo by scanning laser Doppler flowmetry, in 73 patients with type 2 diabetes, 55 healthy controls and 134 individuals with hypertension stage 1 or 2. RESULTS: In diabetic patients, ICD was greater (23.2+/-5.5 vs 20.2+/-4.2, p = 0.013) and CapA smaller (1592+/-595 vs 1821+/-652, p = 0.019) than in healthy controls after adjustment for differences in cardiovascular risk factors between the groups. Compared to hypertensive patients, diabetic individuals showed no difference in ICD (23.1+/ 5.8, p = 0.781) and CapA (1556+/-649, p = 0.768). CONCLUSION: In the early stage of diabetes type 2, patients showed capillary rarefaction compared to healthy individuals. PMID- 27935940 TI - Molecular Characterization of Resistance to Soybean Rust (Phakopsora pachyrhizi Syd. & Syd.) in Soybean Cultivar DT 2000 (PI 635999). AB - Resistance to soybean rust (SBR), caused by Phakopsora pachyrhizi Syd. & Syd., has been identified in many soybean germplasm accessions and is conferred by either dominant or recessive genes that have been mapped to six independent loci (Rpp1 -Rpp6), but No U.S. cultivars are resistant to SBR. The cultivar DT 2000 (PI 635999) has resistance to P. pachyrhizi isolates and field populations from the United States as well as Vietnam. A F6:7 recombinant inbred line (RIL) population derived from Williams 82 * DT 2000 was used to identify genomic regions associated with resistance to SBR in the field in Ha Noi, Vietnam, and in Quincy, Florida, in 2008. Bulked segregant analysis (BSA) was conducted using the soybean single nucleotide polymorphism (SNP) USLP 1.0 panel along with simple sequence repeat (SSR) markers to detect regions of the genome associated with resistance. BSA identified four BARC_SNP markers near the Rpp3 locus on chromosome (Chr.) 6. Genetic analysis identified an additional genomic region around the Rpp4 locus on Chr. 18 that was significantly associated with variation in the area under disease progress curve (AUDPC) values and sporulation in Vietnam. Molecular markers tightly linked to the DT 2000 resistance alleles on Chrs. 6 and 18 will be useful for marker-assisted selection and backcrossing in order to pyramid these genes with other available SBR resistance genes to develop new varieties with enhanced and durable resistance to SBR. PMID- 27935939 TI - Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase. AB - The allosteric inhibitors of integrase (termed ALLINIs) interfere with HIV replication by binding to the viral-encoded integrase (IN) protein. Surprisingly, ALLINIs interfere not with DNA integration but with viral particle assembly late during HIV replication. To investigate the ALLINI inhibitory mechanism, we crystallized full-length HIV-1 IN bound to the ALLINI GSK1264 and determined the structure of the complex at 4.4 A resolution. The structure shows GSK1264 buried between the IN C-terminal domain (CTD) and the catalytic core domain. In the crystal lattice, the interacting domains are contributed by two different dimers so that IN forms an open polymer mediated by inhibitor-bridged contacts; the N terminal domains do not participate and are structurally disordered. Engineered amino acid substitutions at the inhibitor interface blocked ALLINI-induced multimerization. HIV escape mutants with reduced sensitivity to ALLINIs commonly altered amino acids at or near the inhibitor-bound interface, and these substitutions also diminished IN multimerization. We propose that ALLINIs inhibit particle assembly by stimulating inappropriate polymerization of IN via interactions between the catalytic core domain and the CTD and that understanding the interface involved offers new routes to inhibitor optimization. PMID- 27935941 TI - Objectives and Design of BLEEDS: A Cohort Study to Identify New Risk Factors and Predictors for Major Bleeding during Treatment with Vitamin K Antagonists. AB - BACKGROUND: Risk scores for patients who are at high risk for major bleeding complications during treatment with vitamin K antagonists (VKAs) do not perform that well. BLEEDS was initiated to search for new biomarkers that predict bleeding in these patients. OBJECTIVES: To describe the outline and objectives of BLEEDS and to examine whether the study population is generalizable to other VKA treated populations. METHODS: A cohort was created consisting of all patients starting VKA treatment at three Dutch anticoagulation clinics between January 2012 and July-2014. We stored leftover plasma and DNA following analysis of the INR. RESULTS: Of 16,706 eligible patients, 16,570 (99%) were included in BLEEDS and plasma was stored from 13,779 patients (83%). Patients had a mean age of 70 years (SD 14), 8713 were male (53%). The most common VKA indications were atrial fibrillation (10,876 patients, 66%) and venous thrombosis (3920 patients, 24%). 326 Major bleeds occurred during 17,613 years of follow-up (incidence rate 1.85/100 person years, 95%CI 1.66-2.06). The risk for major bleeding was highest in the initial three months of VKA treatment and increased when the international normalized ratio increased. These results and characteristics are in concordance with results from other VKA treated populations. CONCLUSION: BLEEDS is generalizable to other VKA treated populations and will permit innovative and unbiased research of biomarkers that may predict major bleeding during VKA treatment. PMID- 27935942 TI - Inhibition of BDNF-AS Provides Neuroprotection for Retinal Ganglion Cells against Ischemic Injury. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) protects retinal ganglion cells against ischemia in ocular degenerative diseases. We aimed to determine the effect of BDNF-AS on the ischemic injury of retinal ganglion cells. METHODS: The levels of BDNF and BDNF-AS were measured in retinal ganglion cells subjected to oxygen and glucose deprivation. The lentiviral vectors were constructed to either overexpress or knock out BDNF-AS. The luciferase reporter gene assay was used to determine whether BDNF-AS could target its seed sequence on BDNF mRNA. The methyl thiazolyl tetrazolium assay was used to determine cell viability, and TUNEL staining was used for cell apoptosis. RESULTS: The levels of BDNF-AS were negatively correlated with BDNF in ischemic retinal ganglion cells. BDNF-AS directly targeted its complementary sequences on BDNF mRNA. BDNF-AS regulated the expression of BDNF and its related genes in retinal ganglion cells. Down regulation of BDNF-AS increased cell viability and decreased the number of TUNEL positive retinal ganglion cells under oxygen and glucose deprivation conditions. CONCLUSION: Inhibition of BDNF-AS protected retinal ganglion cells against ischemia by increasing the levels of BDNF. PMID- 27935945 TI - Correction: Improved Metabolic Models for E. coli and Mycoplasma genitalium from GlobalFit, an Algorithm That Simultaneously Matches Growth and Non-Growth Data Sets. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005036.]. PMID- 27935943 TI - Confined Mobility of TonB and FepA in Escherichia coli Membranes. AB - The important process of nutrient uptake in Escherichia coli, in many cases, involves transit of the nutrient through a class of beta-barrel proteins in the outer membrane known as TonB-dependent transporters (TBDTs) and requires interaction with the inner membrane protein TonB. Here we have imaged the mobility of the ferric enterobactin transporter FepA and TonB by tracking them in the membranes of live E. coli with single-molecule resolution at time-scales ranging from milliseconds to seconds. We employed simple simulations to model/analyze the lateral diffusion in the membranes of E.coli, to take into account both the highly curved geometry of the cell and artifactual effects expected due to finite exposure time imaging. We find that both molecules perform confined lateral diffusion in their respective membranes in the absence of ligand with FepA confined to a region [Formula: see text] MUm in radius in the outer membrane and TonB confined to a region [Formula: see text] MUm in radius in the inner membrane. The diffusion coefficient of these molecules on millisecond time scales was estimated to be [Formula: see text] MUm2/s and [Formula: see text] MUm2/s for FepA and TonB, respectively, implying that each molecule is free to diffuse within its domain. Disruption of the inner membrane potential, deletion of ExbB/D from the inner membrane, presence of ligand or antibody to FepA and disruption of the MreB cytoskeleton was all found to further restrict the mobility of both molecules. Results are analyzed in terms of changes in confinement size and interactions between the two proteins. PMID- 27935944 TI - Novel and Lost Forests in the Upper Midwestern United States, from New Estimates of Settlement-Era Composition, Stem Density, and Biomass. AB - BACKGROUND: EuroAmerican land-use and its legacies have transformed forest structure and composition across the United States (US). More accurate reconstructions of historical states are critical to understanding the processes governing past, current, and future forest dynamics. Here we present new gridded (8x8km) reconstructions of pre-settlement (1800s) forest composition and structure from the upper Midwestern US (Minnesota, Wisconsin, and most of Michigan), using 19th Century Public Land Survey System (PLSS), with estimates of relative composition, above-ground biomass, stem density, and basal area for 28 tree types. This mapping is more robust than past efforts, using spatially varying correction factors to accommodate sampling design, azimuthal censoring, and biases in tree selection. CHANGES IN FOREST STRUCTURE: We compare pre settlement to modern forests using US Forest Service Forest Inventory and Analysis (FIA) data to show the prevalence of lost forests (pre-settlement forests with no current analog), and novel forests (modern forests with no past analogs). Differences between pre-settlement and modern forests are spatially structured owing to differences in land-use impacts and accompanying ecological responses. Modern forests are more homogeneous, and ecotonal gradients are more diffuse today than in the past. Novel forest assemblages represent 28% of all FIA cells, and 28% of pre-settlement forests no longer exist in a modern context. Lost forests include tamarack forests in northeastern Minnesota, hemlock and cedar dominated forests in north-central Wisconsin and along the Upper Peninsula of Michigan, and elm, oak, basswood and ironwood forests along the forest-prairie boundary in south central Minnesota and eastern Wisconsin. Novel FIA forest assemblages are distributed evenly across the region, but novelty shows a strong relationship to spatial distance from remnant forests in the upper Midwest, with novelty predicted at between 20 to 60km from remnants, depending on historical forest type. The spatial relationships between remnant and novel forests, shifts in ecotone structure and the loss of historic forest types point to significant challenges for land managers if landscape restoration is a priority. The spatial signals of novelty and ecological change also point to potential challenges in using modern spatial distributions of species and communities and their relationship to underlying geophysical and climatic attributes in understanding potential responses to changing climate. The signal of human settlement on modern forests is broad, spatially varying and acts to homogenize modern forests relative to their historic counterparts, with significant implications for future management. PMID- 27935946 TI - The Economics of a Successful Raccoon Rabies Elimination Program on Long Island, New York. AB - Raccoon rabies is endemic in the eastern U.S.; however, an epizootic had not been confirmed on Long Island, New York until 2004. An oral rabies vaccination (ORV) program was initiated soon after the first rabies-positive raccoon was discovered, and continued until raccoon rabies was eliminated from the vaccination zone. The cost-effectiveness and economic impact of this rabies control program were unknown. A public health surveillance data set was evaluated following the ORV program on Long Island, and is used here as a case study in the health economics of rabies prevention and control efforts. A benefit-cost analysis was performed to determine the cost-effectiveness of the program, and a regional economic model was used to estimate the macroeconomic impacts of raccoon rabies elimination to New York State. The cost of the program, approximately $2.6 million, was recovered within eight years by reducing costs associated with post exposure prophylaxis (PEP) and veterinary diagnostic testing of rabies suspect animals. By 2019, the State of New York is projected to benefit from the ORV program by almost $27 million. The benefit-cost ratio will reach 1.71 in 2019, meaning that for every dollar spent on the program $1.71 will be saved. Regional economic modeling estimated employment growth of over 100 jobs and a Gross Domestic Product (GDP) increase of $9.2 million through 2019. This analysis suggests that baiting to eliminate rabies in a geographically constrained area can provide positive economic returns. PMID- 27935947 TI - A Stochastic Model of the Yeast Cell Cycle Reveals Roles for Feedback Regulation in Limiting Cellular Variability. AB - The cell division cycle of eukaryotes is governed by a complex network of cyclin dependent protein kinases (CDKs) and auxiliary proteins that govern CDK activities. The control system must function reliably in the context of molecular noise that is inevitable in tiny yeast cells, because mistakes in sequencing cell cycle events are detrimental or fatal to the cell or its progeny. To assess the effects of noise on cell cycle progression requires not only extensive, quantitative, experimental measurements of cellular heterogeneity but also comprehensive, accurate, mathematical models of stochastic fluctuations in the CDK control system. In this paper we provide a stochastic model of the budding yeast cell cycle that accurately accounts for the variable phenotypes of wild type cells and more than 20 mutant yeast strains simulated in different growth conditions. We specifically tested the role of feedback regulations mediated by G1- and SG2M-phase cyclins to minimize the noise in cell cycle progression. Details of the model are informed and tested by quantitative measurements (by fluorescence in situ hybridization) of the joint distributions of mRNA populations in yeast cells. We use the model to predict the phenotypes of ~30 mutant yeast strains that have not yet been characterized experimentally. PMID- 27935948 TI - Alternative Splicing within and between Drosophila Species, Sexes, Tissues, and Developmental Stages. AB - Alternative pre-mRNA splicing ("AS") greatly expands proteome diversity, but little is known about the evolutionary landscape of AS in Drosophila and how it differs between embryonic and adult stages or males and females. Here we study the transcriptomes from several tissues and developmental stages in males and females from four species across the Drosophila genus. We find that 20-37% of multi-exon genes are alternatively spliced. While males generally express a larger number of genes, AS is more prevalent in females, suggesting that the sexes adopt different expression strategies for their specialized function. While the number of total genes expressed increases during early embryonic development, the proportion of expressed genes that are alternatively spliced is highest in the very early embryo, before the onset of zygotic transcription. This indicates that females deposit a diversity of isoforms into the egg, consistent with abundant AS found in ovary. Cluster analysis by gene expression ("GE") levels shows mostly stage-specific clustering in embryonic samples, and tissue-specific clustering in adult tissues. Clustering embryonic stages and adult tissues based on AS profiles results in stronger species-specific clustering, suggesting that diversification of splicing contributes to lineage-specific evolution in Drosophila. Most sex-biased AS found in flies is due to AS in gonads, with little sex-specific splicing in somatic tissues. PMID- 27935949 TI - Alpha Helices Are More Robust to Mutations than Beta Strands. AB - The rapidly increasing amount of data on human genetic variation has resulted in a growing demand to identify pathogenic mutations computationally, as their experimental validation is currently beyond reach. Here we show that alpha helices and beta strands differ significantly in their ability to tolerate mutations: helices can accumulate more mutations than strands without change, due to the higher numbers of inter-residue contacts in helices. This results in two patterns: a) the same number of mutations causes less structural change in helices than in strands; b) helices diverge more rapidly in sequence than strands within the same domains. Additionally, both helices and strands are significantly more robust than coils. Based on this observation we show that human missense mutations that change secondary structure are more likely to be pathogenic than those that do not. Moreover, inclusion of predicted secondary structure changes shows significant utility for improving upon state-of-the-art pathogenicity predictions. PMID- 27935951 TI - Correction: Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to SF3B4 Mutations in Rodriguez Acrofacial Dysostosis. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006307.]. PMID- 27935950 TI - Utility and Limitations of Using Gene Expression Data to Identify Functional Associations. AB - Gene co-expression has been widely used to hypothesize gene function through guilt-by association. However, it is not clear to what degree co-expression is informative, whether it can be applied to genes involved in different biological processes, and how the type of dataset impacts inferences about gene functions. Here our goal is to assess the utility and limitations of using co-expression as a criterion to recover functional associations between genes. By determining the percentage of gene pairs in a metabolic pathway with significant expression correlation, we found that many genes in the same pathway do not have similar transcript profiles and the choice of dataset, annotation quality, gene function, expression similarity measure, and clustering approach significantly impacts the ability to recover functional associations between genes using Arabidopsis thaliana as an example. Some datasets are more informative in capturing coordinated expression profiles and larger data sets are not always better. In addition, to recover the maximum number of known pathways and identify candidate genes with similar functions, it is important to explore rather exhaustively multiple dataset combinations, similarity measures, clustering algorithms and parameters. Finally, we validated the biological relevance of co-expression cluster memberships with an independent phenomics dataset and found that genes that consistently cluster with leucine degradation genes tend to have similar leucine levels in mutants. This study provides a framework for obtaining gene functional associations by maximizing the information that can be obtained from gene expression datasets. PMID- 27935952 TI - Neoadjuvant Gemcitabine Chemotherapy followed by Concurrent IMRT Simultaneous Boost Achieves High R0 Resection in Borderline Resectable Pancreatic Cancer Patients. AB - BACKGROUND: To study the feasibility of down stage the borderline resectable pancreatic cancer (BRPC) to resectable disease, we reported our institutional results using an intensity-modulated radiation therapy (IMRT) simultaneous integrated boost (SIB) dose escalation approach to improve R0 resectability. METHODS: We reviewed our past 7 years of experience of using neoadjuvant induction chemotherapy with Gemcitabine followed by concurrent chemoradiaiton for BRPC. During the concurrent, chemo was 5-FU and radiation were IMRT with SIB technique to target the key areas with dose escalation to 5600 in 28 fractions. The key areas were defined by PET positive area. This was followed by restaging imaging to rule out distant metastases before resection. RESULTS: 25 finished dose escalation protocol. 2 of the 25 cases developed distant metastases, 23 (92%) patients without distant metastases underwent pancreatectomy. Among the those received pancreatectomy, 22 (95%) achieved negative margin (R0). The gastrointestinal toxicity > grade 2 was 8% and there was no grade 4 toxicity. CONCLUSION: Neoadjuvant Gemcitabine-based induction chemotherapy followed by 5-FU based IMRT-SIB is a feasible option in improving the likelihood of R0 resection rate in BRPC without compromising the organs at risk for toxicity. PMID- 27935953 TI - Factors Predicting HBsAg Seroclearance and Alanine Transaminase Elevation in HBeAg-Negative Hepatitis B Virus-Infected Patients with Persistently Normal Liver Function. AB - BACKGROUND: A certain proportion of hepatitis B virus (HBV)-infected patients with persistently normal alanine transaminase (ALT) levels have significant fibrosis. Using liver stiffness measurements (Fibroscan(r)) and laboratory data, including serum ALT, quantitative HBsAg (qHBsAg), and HBV DNA, we attempted to predict the natural histories of these patients. METHODS: Non-cirrhotic HBeAg negative chronic hepatitis B patients with persistently normal ALT were followed up prospectively with the end points of HBsAg seroclearance and ALT elevation above the upper limit of normal. The factors that were predictive of the end points were identified. RESULTS: A total of 235 patients with an average age of 48.1 +/- 10.7 years were followed up for 7 years. Eight patients (3.4%) lost HBsAg, and 15 patients (6.4%) experienced ALT elevation. The overall cumulative HBsAg seroclearances were 0.4%, 1.3% and 2.3% at years 1, 3 and 5, respectively. Regarding HBsAg seroclearance, the qHBsAg (< 30 IU/ml) cutoff resulted in a hazard ratio (HR) of 19.6 with a 95% confidence interval (CI) of 2.2-166.7 (P = 0.008). The baseline ALT level (odd ratio (OR) 1.075, 95% CI 1.020-1.132, P = 0.006) and a qHBsAg above 1000 IU/ml (3.7, 1.1-12.4, P = 0.032) were associated with ALT elevation. Limited to men, the baseline liver stiffness (1.6, 1.0-2.5, P = 0.031) and a qHBsAg above 1000 IU/ml (10.4, 2.1-52.4, P = 0.004) were factors that were independently associated with ALT elevation. CONCLUSION: A low qHBsAg level predicted HBsAg clearance. Baseline ALT and a qHBsAg above 1000 IU/ml were independent predictive factors for ALT elevation. Among the men, the independent predictive factors for ALT elevation were qHBsAg and liver stiffness. PMID- 27935955 TI - Online 3D Ear Recognition by Combining Global and Local Features. AB - The three-dimensional shape of the ear has been proven to be a stable candidate for biometric authentication because of its desirable properties such as universality, uniqueness, and permanence. In this paper, a special laser scanner designed for online three-dimensional ear acquisition was described. Based on the dataset collected by our scanner, two novel feature classes were defined from a three-dimensional ear image: the global feature class (empty centers and angles) and local feature class (points, lines, and areas). These features are extracted and combined in an optimal way for three-dimensional ear recognition. Using a large dataset consisting of 2,000 samples, the experimental results illustrate the effectiveness of fusing global and local features, obtaining an equal error rate of 2.2%. PMID- 27935954 TI - Normal Wound Healing and Tumor Angiogenesis as a Game of Competitive Inhibition. AB - Both normal wound healing and tumor angiogenesis are mitigated by the sequential, carefully orchestrated release of growth stimulators and inhibitors. These regulators are released from platelet clots formed at the sites of activated endothelium in a temporally and spatially controlled manner, and the order of their release depends on their affinity to glycosaminoglycans (GAG) such as heparan sulfate (HS) within the extracellular matrix, and platelet open canallicular system. The formation of vessel sprouts, triggered by angiogenesis regulating factors with lowest affinities for heparan sulfate (e.g. VEGF), is followed by vessel-stabilizing PDGF-B or bFGF with medium affinity for HS, and by inhibitors such as PF-4 and TSP-1 with the highest affinities for HS. The invasive wound-like edge of growing tumors has an overabundance of angiogenesis stimulators, and we propose that their abundance out-competes angiogenesis inhibitors, effectively preventing inhibition of angiogenesis and vessel maturation. We evaluate this hypothesis using an experimentally motivated agent based model, and propose a general theoretical framework for understanding mechanistic similarities and differences between the processes of normal wound healing and pathological angiogenesis from the point of view of competitive inhibition. PMID- 27935956 TI - Correction: Chromosomal-Level Assembly of the Asian Seabass Genome Using Long Sequence Reads and Multi-layered Scaffolding. AB - [This corrects the article DOI: 10.1371/journal.pgen.1005954.]. PMID- 27935957 TI - Intracellular Zn(II) Intoxication Leads to Dysregulation of the PerR Regulon Resulting in Heme Toxicity in Bacillus subtilis. AB - Transition metal ions (Zn(II), Cu(II)/(I), Fe(III)/(II), Mn(II)) are essential for life and participate in a wide range of biological functions. Cellular Zn(II) levels must be high enough to ensure that it can perform its essential roles. Yet, since Zn(II) binds to ligands with high avidity, excess Zn(II) can lead to protein mismetallation. The major targets of mismetallation, and the underlying causes of Zn(II) intoxication, are not well understood. Here, we use a forward genetic selection to identify targets of Zn(II) toxicity. In wild-type cells, in which Zn(II) efflux prevents intoxication of the cytoplasm, extracellular Zn(II) inhibits the electron transport chain due to the inactivation of the major aerobic cytochrome oxidase. This toxicity can be ameliorated by depression of an alternate oxidase or by mutations that restrict access of Zn(II) to the cell surface. Conversely, efflux deficient cells are sensitive to low levels of Zn(II) that do not inhibit the respiratory chain. Under these conditions, intracellular Zn(II) accumulates and leads to heme toxicity. Heme accumulation results from dysregulation of the regulon controlled by PerR, a metal-dependent repressor of peroxide stress genes. When metallated with Fe(II) or Mn(II), PerR represses both heme biosynthesis (hemAXCDBL operon) and the abundant heme protein catalase (katA). Metallation of PerR with Zn(II) disrupts this coordination, resulting in depression of heme biosynthesis but continued repression of catalase. Our results support a model in which excess heme partitions to the membrane and undergoes redox cycling catalyzed by reduced menaquinone thereby resulting in oxidative stress. PMID- 27935958 TI - Synchronization and Random Triggering of Lymphatic Vessel Contractions. AB - The lymphatic system is responsible for transporting interstitial fluid back to the bloodstream, but unlike the cardiovascular system, lacks a centralized pump the heart-to drive flow. Instead, each collecting lymphatic vessel can individually contract and dilate producing unidirectional flow enforced by intraluminal check valves. Due to the large number and spatial distribution of such pumps, high-level coordination would be unwieldy. This leads to the question of how each segment of lymphatic vessel responds to local signals that can contribute to the coordination of pumping on a network basis. Beginning with elementary fluid mechanics and known cellular behaviors, we show that two complementary oscillators emerge from i) mechanical stretch with calcium ion transport and ii) fluid shear stress induced nitric oxide production (NO). Using numerical simulation and linear stability analysis we show that the newly identified shear-NO oscillator shares similarities with the well-known Van der Pol oscillator, but has unique characteristics. Depending on the operating conditions, the shear-NO process may i) be inherently stable, ii) oscillate spontaneously in response to random disturbances or iii) synchronize with weak periodic stimuli. When the complementary shear-driven and stretch-driven oscillators interact, either may dominate, producing a rich family of behaviors similar to those observed in vivo. PMID- 27935959 TI - Crystal Structure of Schistosoma mansoni Adenosine Phosphorylase/5' Methylthioadenosine Phosphorylase and Its Importance on Adenosine Salvage Pathway. AB - Schistosoma mansoni do not have de novo purine pathways and rely on purine salvage for their purine supply. It has been demonstrated that, unlike humans, the S. mansoni is able to produce adenine directly from adenosine, although the enzyme responsible for this activity was unknown. In the present work we show that S. mansoni 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP, E.C. 2.4.2.28) is capable of use adenosine as a substrate to the production of adenine. Through kinetics assays, we show that the Schistosoma mansoni MTAP (SmMTAP), unlike the mammalian MTAP, uses adenosine substrate with the same efficiency as MTA phosphorolysis, which suggests that this enzyme is part of the purine pathway salvage in S. mansoni and could be a promising target for anti schistosoma therapies. Here, we present 13 SmMTAP structures from the wild type (WT), including three single and one double mutant, and generate a solid structural framework for structure description. These crystal structures of SmMTAP reveal that the active site contains three substitutions within and near the active site when compared to it mammalian counterpart, thus opening up the possibility of developing specific inhibitors to the parasite MTAP. The structural and kinetic data for 5 substrates reveal the structural basis for this interaction, providing substract for inteligent design of new compounds for block this enzyme activity. PMID- 27935960 TI - Hydrological Regime and Water Shortage as Drivers of the Seasonal Incidence of Diarrheal Diseases in a Tropical Montane Environment. AB - BACKGROUND: The global burden of diarrhea is a leading cause of morbidity and mortality worldwide. In montane areas of South-East Asia such as northern Laos, recent changes in land use have induced increased runoff, soil erosion and in stream suspended sediment loads, and potential pathogen dissemination. To our knowledge, few studies have related diarrhea incidences to catchment scale hydrological factors such as river discharge, and loads of suspended sediment and of Fecal Indicator Bacteria (FIB) such as Escherichia coli, together with sociological factors such as hygiene practices. We hypothesized that climate factors combined with human behavior control diarrhea incidence, either because higher rainfall, leading to higher stream discharges, suspended sediment loads and FIB counts, are associated with higher numbers of reported diarrhea cases during the rainy season, or because water shortage leads to the use of less safe water sources during the dry season. Using E. coli as a FIB, the objectives of this study were thus (1) to characterize the epidemiological dynamics of diarrhea in Northern Laos, and (2) to identify which hydro-meteorological and sociological risk factors were associated with diarrhea epidemics. METHODS: Considering two unconnected river catchments of 22 and 7,448 km2, respectively, we conducted a retrospective time series analysis of meteorological variables (rainfall, air temperature), hydrological variables (discharge, suspended sediments, FIB counts, water temperature), and the number of diarrheal disease cases reported at 6 health centers located in the 5 southern districts of the Luang Prabang Province, Lao PDR. We also examined the socio-demographic factors potentially affecting vulnerability to the effect of the climate factors, such as drinking water sources, hygiene habits, and recreational water exposure. RESULTS: Using thus a mixed methods approach, we found E. coli to be present all year long (100-1,000 Most Probable Number or MPN 100 mL-1) indicating that fecal contamination is ubiquitous and constant. We found that populations switch their water supply from wells to surface water during drought periods, the latter of which appear to be at higher risk of bacterial contamination than municipal water fountains. We thus found that water shortage in the Luang Prabang area triggers diarrhea peaks during the dry and hot season and that rainfall and aquifer refill ends the epidemic during the wet season. The temporal trends of reported daily diarrhea cases were generally bimodal with hospital admissions peaking in February-March and later in May-July. Annual incidence rates were higher in more densely populated areas and mostly concerned the 0-4 age group and male patients. CONCLUSIONS: We found that anthropogenic drivers, such as hygiene practices, were at least as important as environmental drivers in determining the seasonal pattern of a diarrhea epidemic. For diarrheal disease risk monitoring, discharge or groundwater level can be considered as relevant proxies. These variables should be monitored in the framework of an early warning system provided that a tradeoff is found between the size of the monitored catchment and the frequency of the measurement. PMID- 27935961 TI - Emerging Infectious Disease Implications of Invasive Mammalian Species: The Greater White-Toothed Shrew (Crocidura russula) Is Associated With a Novel Serovar of Pathogenic Leptospira in Ireland. AB - The greater white-toothed shrew (Crocidura russula) is an invasive mammalian species that was first recorded in Ireland in 2007. It currently occupies an area of approximately 7,600 km2 on the island. C. russula is normally distributed in Northern Africa and Western Europe, and was previously absent from the British Isles. Whilst invasive species can have dramatic and rapid impacts on faunal and floral communities, they may also be carriers of pathogens facilitating disease transmission in potentially naive populations. Pathogenic leptospires are endemic in Ireland and a significant cause of human and animal disease. From 18 trapped C. russula, 3 isolates of Leptospira were cultured. However, typing of these isolates by standard serological reference methods was negative, and suggested an, as yet, unidentified serovar. Sequence analysis of 16S ribosomal RNA and secY indicated that these novel isolates belong to Leptospira alstonii, a unique pathogenic species of which only 7 isolates have been described to date. Earlier isolations were limited geographically to China, Japan and Malaysia, and this leptospiral species had not previously been cultured from mammals. Restriction enzyme analysis (REA) further confirms the novelty of these strains since no similar patterns were observed with a reference database of leptospires. As with other pathogenic Leptospira species, these isolates contain lipL32 and do not grow in the presence of 8-azagunaine; however no evidence of disease was apparent after experimental infection of hamsters. These isolates are genetically related to L. alstonii but have a novel REA pattern; they represent a new serovar which we designate as serovar Room22. This study demonstrates that invasive mammalian species act as bridge vectors of novel zoonotic pathogens such as Leptospira. PMID- 27935963 TI - Modeling and Simulating Passenger Behavior for a Station Closure in a Rail Transit Network. AB - A station closure is an abnormal operational situation in which the entrances or exits of a rail transit station have to be closed for some time due to an unexpected incident. A novel approach is developed to estimate the impacts of the alternative station closure scenarios on both passenger behavioral choices at the individual level and passenger demand at the disaggregate level in a rail transit network. Therefore, the contributions of this study are two-fold: (1) A basic passenger behavior optimization model is mathematically constructed based on 0-1 integer programming to describe passengers' responses to alternative origin station closure scenarios and destination station closure scenarios; this model also considers the availability of multi-mode transportation and the uncertain duration of the station closure; (2) An integrated solution algorithm based on the passenger simulation is developed to solve the proposed model and to estimate the effects of a station closure on passenger demand in a rail transit network. Furthermore, 13 groups of numerical experiments based on the Beijing rail transit network are performed as case studies with 2,074,267 records of smart card data. The comparisons of the model outputs and the manual survey show that the accuracy of our proposed behavior optimization model is approximately 80%. The results also show that our model can be used to capture the passenger behavior and to quantitatively estimate the effects of alternative closure scenarios on passenger flow demand for the rail transit network. Moreover, the closure duration and its overestimation greatly influence the individual behavioral choices of the affected passengers and the passenger demand. Furthermore, if the rail transit operator can more accurately estimate the closure duration (namely, as g approaches 1), the impact of the closure can be somewhat mitigated. PMID- 27935962 TI - MAP3K19 Is Overexpressed in COPD and Is a Central Mediator of Cigarette Smoke Induced Pulmonary Inflammation and Lower Airway Destruction. AB - Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and lung inflammation resulting in a progressive decline in lung function whose principle cause is cigarette smoke. MAP3K19 is a novel kinase expressed predominantly by alveolar and interstitial macrophages and bronchial epithelial cells in the lung. We found that MAP3K19 mRNA was overexpressed in a limited sampling of lung tissue from COPD patients, and a closer examination found it to be overexpressed in bronchoalveolar macrophages from COPD patients, as well as the bronchial epithelium and inflammatory cells in the lamina propria. We further found MAP3K19 to be induced in various cell lines upon environmental stress, such as cigarette smoke, oxidative and osmotic stress. Exogenous expression of MAP3K19 in cells caused an upregulation of transcriptionally active NF-kappaB, and secretion of the chemokines CXCL-8, CCL-20 and CCL-7. Inhibition of MAP3K19 activity by siRNA or small molecular weight inhibitors caused a decrease in cigarette smoke-induced inflammation in various murine models, which included a decrease in pulmonary neutrophilia and KC levels. In a chronic cigarette smoke model, inhibition of MAP3K19 significantly attenuated emphysematous changes in airway parenchyma. Finally, in a viral exacerbation model, mice exposed to cigarette smoke and influenza A virus showed a decrease in pulmonary neutrophilia, pro-inflammatory cytokines and viral load upon inhibition of MAP3K19. Collectively, these results suggest that inhibition of MAP3K19 may represent a novel strategy to target COPD that promises to have a potential therapeutic benefit for patients. PMID- 27935964 TI - GW182-Free microRNA Silencing Complex Controls Post-transcriptional Gene Expression during Caenorhabditis elegans Embryogenesis. AB - MicroRNAs and Argonaute form the microRNA induced silencing complex or miRISC that recruits GW182, causing mRNA degradation and/or translational repression. Despite the clear conservation and molecular significance, it is unknown if miRISC-GW182 interaction is essential for gene silencing during animal development. Using Caenorhabditis elegans to explore this question, we examined the relationship and effect on gene silencing between the GW182 orthologs, AIN-1 and AIN-2, and the microRNA-specific Argonaute, ALG-1. Homology modeling based on human Argonaute structures indicated that ALG-1 possesses conserved Tryptophan binding Pockets required for GW182 binding. We show in vitro and in vivo that their mutations severely altered the association with AIN-1 and AIN-2. ALG-1 tryptophan-binding pockets mutant animals retained microRNA-binding and processing ability, but were deficient in reporter silencing activity. Interestingly, the ALG-1 tryptophan-binding pockets mutant phenocopied the loss of alg-1 in worms during larval stages, yet was sufficient to rescue embryonic lethality, indicating the dispensability of AINs association with the miRISC at this developmental stage. The dispensability of AINs in miRNA regulation is further demonstrated by the capacity of ALG-1 tryptophan-binding pockets mutant to regulate a target of the embryonic mir-35 microRNA family. Thus, our results demonstrate that the microRNA pathway can act independently of GW182 proteins during C. elegans embryogenesis. PMID- 27935965 TI - Bypass of Candida albicans Filamentation/Biofilm Regulators through Diminished Expression of Protein Kinase Cak1. AB - Biofilm formation on implanted medical devices is a major source of lethal invasive infection by Candida albicans. Filamentous growth of this fungus is tied to biofilm formation because many filamentation-associated genes are required for surface adherence. Cell cycle or cell growth defects can induce filamentation, but we have limited information about the coupling between filamentation and filamentation-associated gene expression after cell cycle/cell growth inhibition. Here we identified the CDK activating protein kinase Cak1 as a determinant of filamentation and filamentation-associated gene expression through a screen of mutations that diminish expression of protein kinase-related genes implicated in cell cycle/cell growth control. A cak1 diminished expression (DX) strain displays filamentous growth and expresses filamentation-associated genes in the absence of typical inducing signals. In a wild-type background, expression of filamentation associated genes depends upon the transcription factors Bcr1, Brg1, Efg1, Tec1, and Ume6. In the cak1 DX background, the dependence of filamentation-associated gene expression on each transcription factor is substantially relieved. The unexpected bypass of filamentation-associated gene expression activators has the functional consequence of enabling biofilm formation in the absence of Bcr1, Brg1, Tec1, Ume6, or in the absence of both Brg1 and Ume6. It also enables filamentous cell morphogenesis, though not biofilm formation, in the absence of Efg1. Because these transcription factors are known to have shared target genes, we suggest that cell cycle/cell growth limitation leads to activation of several transcription factors, thus relieving dependence on any one. PMID- 27935967 TI - Large-Scale Analysis of Gene Expression Data Reveals a Novel Gene Expression Signature Associated with Colorectal Cancer Distant Recurrence. AB - Colorectal cancer (CRC) is the fourth-ranked cause of cancer-related deaths worldwide. Despite recent advances in CRC management, distant recurrence (DR) remains the major cause of mortality in patients with preoperative chemotherapy and radiotherapy, underscoring a need to precisely identify novel gene signatures for predicting the risk of systemic relapse. Herein, we integrated two independent CRC gene expression datasets: the GSE71222 dataset, including 26 patients who developed DR and 126 patients who did not develop DR, and the GSE21510 dataset, including 23 patients who developed DR and 76 patients who did not develop DR. Our data revealed 37 common upregulated genes (fold change (FC) >= 1.5, P < 0.05) and three common downregulated genes (FC <= 1.5, P < 0.05) between DR and non-recurrent patients from the two datasets. We subsequently validated the upregulated gene panel in the Cancer Genome Atlas CRC datasets (379 patients), which identified a five-gene signature (S100A2, VIP, HOXC6, DACT1, KIF26B) associated with poor overall survival (OS, log-rank test P-value: 1.19 * 10-4) and poor disease-free survival (DFS, log-rank test P-value: 0.002). In a Cox proportional hazards multiple regression model, the five-gene signature and tumor stage retained their significance as independent prognostic factors for CRC DFS and OS. Therefore, our data identified a novel DR gene expression signature associated with worse prognosis in CRC. PMID- 27935966 TI - The Transcription Factor Nfatc2 Regulates beta-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets. AB - Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of the candidate T2D-associated genes within these loci is regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show that the expression of ~40% of the T2D-associated genes is linked to a broad region on mouse chromosome (Chr) 2. As all but 9 of these genes are not physically located on Chr 2, linkage to Chr 2 suggests a genomic factor(s) located on Chr 2 regulates their expression in trans. The transcription factor Nfatc2 is physically located on Chr 2 and its expression demonstrates cis linkage; i.e., its expression maps to itself. When conditioned on the expression of Nfatc2, linkage for the T2D-associated genes was greatly diminished, supporting Nfatc2 as a driver of their expression. Plasma insulin also showed linkage to the same broad region on Chr 2. Overexpression of a constitutively active (ca) form of Nfatc2 induced beta-cell proliferation in mouse and human islets, and transcriptionally regulated more than half of the T2D associated genes. Overexpression of either ca-Nfatc2 or ca-Nfatc1 in mouse islets enhanced insulin secretion, whereas only ca-Nfatc2 was able to promote beta-cell proliferation, suggesting distinct molecular pathways mediating insulin secretion vs. beta-cell proliferation are regulated by NFAT. Our results suggest that many of the T2D-associated genes are downstream transcriptional targets of NFAT, and may act coordinately in a pathway through which NFAT regulates beta-cell proliferation in both mouse and human islets. PMID- 27935968 TI - Localization of Low Copy Number Plasmid pRC4 in Replicating Rod and Non Replicating Cocci Cells of Rhodococcus erythropolis PR4. AB - Rhodococcus are gram-positive bacteria, which can exist in two different shapes rod and cocci. A number of studies have been done in the past on replication and stability of small plasmids in this bacterium; however, there are no reports on spatial localization and segregation of these plasmids. In the present study, a low copy number plasmid pDS3 containing pRC4 replicon was visualized in growing cells of Rhodococcus erythropolis PR4 (NBRC100887) using P1 parS-ParB-GFP system. Cells were initially cocci and then became rod shaped in exponential phase. Cocci cells were found to be non-replicating as evident by the presence of single fluorescence focus corresponding to the plasmid and diffuse fluorescence of DnaB GFP. Rod shaped cells contained plasmid either present as one fluorescent focus observed at the cell center or two foci localized at quarter positions. The results suggest that the plasmid is replicated at the cell center and then it goes to quarter position. In order to observe the localization of plasmid with respect to nucleoid, plasmid segregation was also studied in filaments where it was found to be replicated at the cell center in a nucleoid free region. To the best of our knowledge, this is the first report on segregation of small plasmids in R. erythropolis. PMID- 27935969 TI - Effects of Heavy Metals from Soil and Dust Source on DNA Damage of the Leymus chinensis Leaves in Coal-Mining Area in Northwest China. AB - Air and soil pollution from mining activities has been considered as a critical issue to the health of living organisms. However, few efforts have been made in distinguishing the main pathway of organism genetic damage by heavy metals related to mining activities. Therefore, we investigated the genetic damage of Leymus chinensis leaf cells, the air particulate matter (PM) contents, and concentrations of the main heavy metals (Pb, Cd, Cr, Hg) in soil and foliar dust samples collected from seven experiment points at the core mining area and one control point 20 kilometers away from the core mining area in Inner Mongolia in 2013. Comet assay was used to test the genetic damage of the Leymus chinensis leaf cells; the Tail DNA% and Tail Moment were used to characterize the genetic damage degree of the plant cells. The comet assay results showed that the cell genetic damage ratio was up to 77.0% in experiment points but was only 35.0% in control point. The control point also had the slight Tail DNA% and Tail Moment values than other experiment groups. The cell damage degree of the control group was 0.935 and experiment groups were 1.299-1.815. The geo-accumulation index and comperehensive pollution index(CPI) were used to characterize heavy metal pollution in foliar dust samples, and single factor pollution index and CPI were used to characterize the heavy metal pollution in soil samples. The CPIfoliar dust of control group was 0.36 and experiment groups were 1.45-2.57; the CPIsoil of control group was 0.04 and experiment groups were 0.07-0.12. The results of correlation analyze showed that Air Quality Index (AQI) -CPIfoliar dust(r = 0.955**)>Damage degree-CPIfoliar dust(r = 0.923**)>Damage degree-AQI(r = 0.908**)>Damage degree-CPIsoil (r = 0.824*). The present research proved that mining activity had a high level of positive correlation with organism genetic damage caused by heavy metals through comparing with the control point; soil and atmosphere were both the important action pathway for heavy metal induced genetic damage in mining area. Furthermore, heavy metal contents in foliar dust showed a higher positive correlation with genetic damage than when compared with soil. This means the heavy metal contents that L.chinensis absorbed through respiration from the atmosphere could make more serious genetic damage than when absorbed by root systems from soil in the mining area. This study can provide theoretical support for research on plant genetic damage mechanisms and exposure pathways induced by environmental pollution. PMID- 27935970 TI - Sanshool on The Fingertip Interferes with Vibration Detection in a Rapidly Adapting (RA) Tactile Channel. AB - An Asian spice, Szechuan pepper (sanshool), is well known for the tingling sensation it induces on the mouth and on the lips. Electrophysiological studies have revealed that its active ingredient can induce firing of mechanoreceptor fibres that typically respond to mechanical vibration. Moreover, a human behavioral study has reported that the perceived frequency of sanshool-induced tingling matches with the preferred frequency range of the tactile rapidly adapting (RA) channel, suggesting the contribution of sanshool-induced RA channel firing to its unique perceptual experience. However, since the RA channel may not be the only channel activated by sanshool, there could be a possibility that the sanshool tingling percept may be caused in whole or in part by other sensory channels. Here, by using a perceptual interference paradigm, we show that the sanshool-induced RA input indeed contributes to the human tactile processing. The absolute detection thresholds for vibrotactile input were measured with and without sanshool application on the fingertip. Sanshool significantly impaired detection of vibrations at 30 Hz (RA channel dominant frequency), but did not impair detection of higher frequency vibrations at 240 Hz (Pacinian-corpuscle (PC) channel dominant frequency) or lower frequency vibrations at 1 Hz (slowly adapting 1 (SA1) channel dominant frequency). These results show that the sanshool induces a peripheral RA channel activation that is relevant for tactile perception. This anomalous activation of RA channels may contribute to the unique tingling experience of sanshool. PMID- 27935971 TI - Costs of Care of HIV-Infected Children Initiating Lopinavir/Ritonavir-Based Antiretroviral Therapy before the Age of Two in Cote d'Ivoire. AB - OBJECTIVES: To access the costs of care for Ivoirian children before and after initiating LPV/r-based antiretroviral therapy (ART) before the age of two. METHODS: We assessed the direct costs of care for all HIV-infected children over the first 12 months on LPV/r-based ART initiated <2 years of age in Abidjan. We recorded all drug prescriptions, ART and cotrimoxazole prophylaxis delivery, medical analyses/examinations and hospital admissions. We compared these costs to those accrued in the month prior to ART initiation. Costs and 95% confidence intervals (95%CI) were estimated per child-month, according to severe morbidity. RESULTS: Of the 114 children screened, 99 initiated LPV/r-based ART at a median age of 13.5 months (IQR: 6.8-18.6); 45% had reached World Health Organization stage 3 or 4. During the first 12 months on ART, 5% died and 3% were lost to follow-up. In the month before ART initiation, the mean cost of care per child month reached $123.39 (95%CI:$121.02-$125.74). After ART initiation, it was $42.53 (95%CI:$42.15-$42.91); 50% were ART costs. The remaining costs were non antiretroviral drugs (18%) and medical analyses/examinations (14%). Mean costs were significantly higher within the first three months on ART ($48.76, 95%CI:$47.95-$49.56) and in children experiencing severe morbidity ($49.76, 95%CI:$48.61-50.90). CONCLUSION: ART reduces the overall monthly cost of care of HIV-infected children < 2 years. Because children were treated at an advanced HIV disease stage, the additional costs of treating severe morbidity on ART remain substantial. Strategies for treating HIV-infected children as early as possible must remain a priority in Cote d'Ivoire. PMID- 27935973 TI - The Effects of Compensatory Scanning Training on Mobility in Patients with Homonymous Visual Field Defects: Further Support, Predictive Variables and Follow Up. AB - INTRODUCTION: People with homonymous visual field defects (HVFD) often report difficulty detecting obstacles in the periphery on their blind side in time when moving around. Recently, a randomized controlled trial showed that the InSight Hemianopia Compensatory Scanning Training (IH-CST) specifically improved detection of peripheral stimuli and avoiding obstacles when moving around, especially in dual task situations. METHOD: The within-group training effects of the previously reported IH-CST are examined in an extended patient group. Performance of patients with HVFD on a pre-assessment, post-assessment and follow up assessment and performance of a healthy control group are compared. Furthermore, it is examined whether training effects can be predicted by demographic characteristics, variables related to the visual disorder, and neuropsychological test results. RESULTS: Performance on both subjective and objective measures of mobility-related scanning was improved after training, while no evidence was found for improvement in visual functions (including visual fields), reading, visual search and dot counting. Self-reported improvement did not correlate with improvement in objective mobility performance. According to the participants, the positive effects were still present six to ten months after training. No demographic characteristics, variables related to the visual disorder, and neuropsychological test results were found to predict the size of training effect, although some inconclusive evidence was found for more improvement in patients with left-sided HVFD than in patients with right-sided HFVD. CONCLUSION: Further support was found for a positive effect of IH-CST on detection of visual stimuli during mobility-related activities specifically. Based on the reports given by patients, these effects appear to be long-term effects. However, no conclusions can be drawn on the objective long-term training effects. PMID- 27935972 TI - Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes. AB - Tobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking-associated methylation changes in whole blood and leukocyte subtypes, we used Illumina 450K arrays and Reduced Representation Bisulfite Sequencing (RRBS) to assess genome-wide DNA methylation. Differential methylation analysis in whole blood DNA from 172 smokers and 81 nonsmokers revealed 738 CpGs, including 616 previously unreported CpGs, genome wide significantly associated with current smoking (p <1.2x10-7, Bonferroni correction). Several CpGs (MTSS1, NKX6-2, BTG2) were associated with smoking duration among heavy smokers (>22 cigarettes/day, n = 86) which might relate to long-term heavy-smoking pathology. In purified leukocyte subtypes from an independent group of 20 smokers and 14 nonsmokers we further examined methylation and gene expression for selected genes among CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, and CD2+ T cells. In 10 smokers and 10 nonsmokers we used RRBS to fine map differential methylation in CD4+ T cells, CD8+ T cells, CD14+, CD15+, CD19+, and CD56+ natural killer cells. Distinct cell-type differences in smoking associated methylation and gene expression were identified. AHRR (cg05575921), ALPPL2 (cg21566642), GFI1 (cg09935388), IER3 (cg06126421) and F2RL3 (cg03636183) showed a distinct pattern of significant smoking-associated methylation differences across cell types: granulocytes> monocytes>> B cells. In contrast GPR15 (cg19859270) was highly significant in T and B cells and ITGAL (cg09099830) significant only in T cells. Numerous other CpGs displayed distinctive cell-type responses to tobacco smoke exposure that were not apparent in whole blood DNA. Assessing the overlap between these CpG sites and differential methylated regions (DMRs) with RRBS in 6 cell types, we confirmed cell-type specificity in the context of DMRs. We identified new CpGs associated with current smoking, pack years, duration, and revealed unique profiles of smoking-associated DNA methylation and gene expression among immune cell types, providing potential clues to hematopoietic lineage-specific effects in disease etiology. PMID- 27935975 TI - Baseline Body Mass Index and the Efficacy of Hypoglycemic Treatment in Type 2 Diabetes: A Meta-Analysis. AB - AIM: The aim of this study is to compare the effects of hypoglycemic treatments in groups of patients categorized according to the mean baseline body mass indexes (BMIs). METHODS: Studies were identified by a literature search and all the studies were double blind, placebo-controlled randomized trials in type 2 diabetes patients; study length of >=12 weeks with the efficacy evaluated by changes in HbA1c from baseline in groups. The electronic search was first conducted in January 2015 and repeated in June 2015. RESULTS: 227 studies were included. Treatment with sulfonylureas was compared with placebo in overweight patients and resulted in a significantly greater change in the HbA1c levels (weighted mean difference (WMD), -1.39%) compared to obese patients (WMD, 0.77%)(p<0.05). Treatment with metformin in overweight patients resulted in a comparable change in the HbA1c levels (WMD, -0.99%) compared to obese patients (WMD, -1.06%)(p>0.05). Treatment with alpha glucosidase inhibitors in normal weight patients was associated with a HbA1c change (WMD, -0.94%) that was comparable that in overweight (WMD, -0.72%) and obese patients (WMD, 0.56%)(p>0.05). Treatment with thiazolidinediones in normal weight patients was associated with a HbA1c change (WMD, -1.04%) that was comparable with that in overweight (WMD, -1.02%) and obese patients (WMD, -0.88%)(p>0.05). Treatment with DPP-4 inhibitors in normal weight patients was associated with a HbA1c change (WMD, -0.93%) that was comparable with that in overweight (WMD, -0.66%) and obese patients (WMD, -0.61%)(p>0.05). In total, of the seven hypoglycemic agents, regression analysis indicated that the mean baseline BMI was not associated with the mean HbA1c changes from baseline. CONCLUSION: In each kind of hypoglycemic therapy in type 2 diabetes, the baseline BMI was not associated with the efficacy of HbA1c changes from baseline. PMID- 27935976 TI - Flexible and Stretchable Microneedle Patches with Integrated Rigid Stainless Steel Microneedles for Transdermal Biointerfacing. AB - This paper demonstrates flexible and stretchable microneedle patches that combine soft and flexible base substrates with hard and sharp stainless steel microneedles. An elastomeric polymer base enables conformal contact between the microneedle patch and the complex topography and texture of the underlying skin, while robust and sharp stainless steel microneedles reliably pierce the outer layers of the skin. The flexible microneedle patches have been realized by magnetically assembling short stainless steel microneedles into a flexible polymer supporting base. In our experimental investigation, the microneedle patches were applied to human skin and an excellent adaptation of the patch to the wrinkles and deformations of the skin was verified, while at the same time the microneedles reliably penetrate the surface of the skin. The unobtrusive flexible and stretchable microneedle patches have great potential for transdermal biointerfacing in a variety of emerging applications such as transdermal drug delivery, bioelectric treatments and wearable bio-electronics for health and fitness monitoring. PMID- 27935974 TI - Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis. AB - Osteopontin (OPN) promotes hepatic fibrosis, and developing therapies targeting OPN expression in settings of hepatic injury holds promise. The polyphenol epigallocatechin-3-gallate (EGCG), found in high concentrations in green tea, downregulates OPN expression through OPN mRNA degradation, but the mechanism is unknown. Previous work has shown that microRNAs can decrease OPN mRNA levels, and other studies have shown that EGCG modulates the expression of multiple microRNAs. In our study, we first demonstrated that OPN induces hepatic stellate cells to transform into an activated state. We then identified three microRNAs which target OPN mRNA: miR-181a, miR-10b, and miR-221. In vitro results show that EGCG upregulates all three microRNAs, and all three microRNAs are capable of down regulating OPN mRNA when administered alone. Interestingly, only miR-221 is necessary for EGCG-mediated OPN mRNA degradation and miR-221 inhibition reduces the effects of EGCG on cell function. In vivo experiments show that thioacetamide (TAA)-induced cell cytotoxicity upregulates OPN expression; treatment with EGCG blocks the effects of TAA. Furthermore, chronic treatment of EGCG in vivo upregulates all three microRNAs equally, suggesting that in more chronic treatment all three microRNAs are involved in modulating OPN expression. We conclude that in in vitro and in vivo models of TAA-induced hepatic fibrosis, EGCG inhibits OPN-dependent injury and fibrosis. EGCG works primarily by upregulating miR-221 to accelerate OPN degradation. EGCG may therefore have utility as a protective agent in settings of liver injury. PMID- 27935977 TI - The Effects of a Community-Based Sodium Reduction Program in Rural China - A Cluster-Randomized Trial. AB - BACKGROUND: Average sodium intake and stroke mortality in northern China are both among the highest in the world. An effective, low-cost strategy to reduce sodium intake in this population is urgently needed. OBJECTIVE: We sought to determine the effects of a community-based sodium reduction program on salt consumption in rural northern China. DESIGN: This study was a cluster-randomized trial done over 18 months in 120 townships (one village from each township) from five provinces. Sixty control villages were compared to 60 intervention villages that were given access to a reduced-sodium, added-potassium salt substitute in conjunction with a community-based health education program focusing on sodium reduction. The primary outcome was the difference in 24-hour urinary sodium excretion between randomized groups. RESULTS: Among 1,903 people with valid 24-hour urine collections, mean urinary sodium excretion in intervention compared with control villages was reduced by 5.5% (-14mmol/day, 95% confidence interval -26 to -1; p = 0.03), potassium excretion was increased by 16% (+7mmol/day, +4 to +10; p<0.001), and sodium to potassium ratio declined by 15% (-0.9, -1.2 to -0.5; p<0.001). Mean blood pressure differences were -1.1 mm Hg systolic (-3.3 to +1.1; p = 0.33) and 0.7 mm Hg diastolic (-2.2 to +0.8, p = 0.35) and the difference in the proportion with hypertension was -1.3% (-5.1 to 2.5, p = 0.56). CONCLUSION: There were clear differences in population sodium and potassium intake between villages that were most likely a consequence of increased use of salt substitute. The absence of effects on blood pressure reflects the moderate changes in sodium and potassium intake achieved. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01259700. PMID- 27935978 TI - Genome Wide Identification, Phylogeny, and Expression of Aquaporin Genes in Common Carp (Cyprinus carpio). AB - BACKGROUND: Aquaporins (Aqps) are integral membrane proteins that facilitate the transport of water and small solutes across cell membranes. Among vertebrate species, Aqps are highly conserved in both gene structure and amino acid sequence. These proteins are vital for maintaining water homeostasis in living organisms, especially for aquatic animals such as teleost fish. Studies on teleost Aqps are mainly limited to several model species with diploid genomes. Common carp, which has a tetraploidized genome, is one of the most common aquaculture species being adapted to a wide range of aquatic environments. The complete common carp genome has recently been released, providing us the possibility for gene evolution of aqp gene family after whole genome duplication. RESULTS: In this study, we identified a total of 37 aqp genes from common carp genome. Phylogenetic analysis revealed that most of aqps are highly conserved. Comparative analysis was performed across five typical vertebrate genomes. We found that almost all of the aqp genes in common carp were duplicated in the evolution of the gene family. We postulated that the expansion of the aqp gene family in common carp was the result of an additional whole genome duplication event and that the aqp gene family in other teleosts has been lost in their evolution history with the reason that the functions of genes are redundant and conservation. Expression patterns were assessed in various tissues, including brain, heart, spleen, liver, intestine, gill, muscle, and skin, which demonstrated the comprehensive expression profiles of aqp genes in the tetraploidized genome. Significant gene expression divergences have been observed, revealing substantial expression divergences or functional divergences in those duplicated aqp genes post the latest WGD event. CONCLUSIONS: To some extent, the gene families are also considered as a unique source for evolutionary studies. Moreover, the whole set of common carp aqp gene family provides an essential genomic resource for future biochemical, toxicological, physiological, and evolutionary studies in common carp. PMID- 27935979 TI - Uncovering Urban Temporal Patterns from Geo-Tagged Photography. AB - We live in a world where digital trails of different forms of human activities compose big urban data, allowing us to detect many aspects of how people experience the city in which they live or come to visit. In this study we propose to enhance urban planning by taking into a consideration individual preferences using information from an unconventional big data source: dataset of geo-tagged photographs that people take in cities which we then use as a measure of urban attractiveness. We discover and compare a temporal behavior of residents and visitors in ten most photographed cities in the world. Looking at the periodicity in urban attractiveness, the results show that the strongest periodic patterns for visitors are usually weekly or monthly. Moreover, by dividing cities into two groups based on which continent they belong to (i.e., North America or Europe), it can be concluded that unlike European cities, behavior of visitors in the US cities in general is similar to the behavior of their residents. Finally, we apply two indices, called "dilatation attractiveness index" and "dilatation index", to our dataset which tell us the spatial and temporal attractiveness pulsations in the city. The proposed methodology is not only important for urban planning, but also does support various business and public stakeholder decision processes, concentrated for example around the question how to attract more visitors to the city or estimate the impact of special events organized there. PMID- 27935980 TI - Changes in Prevalence of HIV or Syphilis among Male Sex Workers and Non Commercial Men Who Have Sex with Men in Shenzhen, China: Results of a Second Survey. AB - BACKGROUND: A previous time-location sampling survey (TLS) was performed in 2008 to evaluate the HIV or syphilis infection rate among male sex workers (MSWs) and non-commercial men who have sex with men (ncMSM) in Shenzhen, China. This is a second TLS performed in 2014. This article describes the findings and changes in the prevalence of HIV and syphilis. METHODS: TLS was used to collect information as a second cross-sectional survey to an earlier TLS assessment. Data on behavior (e.g., sexual history and sexual behavior) were analyzed. Blood specimens were drawn for HIV and syphilis testing. To determine the changes in the prevalence of HIV and syphilis, we analyzed these results and compared them to the results of our first survey. RESULTS: A total of 965 participants were recruited, including 489 MSWs and 476 ncMSM. Overall, the prevalence of HIV was 9.7%: 2.9% for MSWs and 16.8% for ncMSM (P<0.001). 10.9% of the 965 participants tested positive for syphilis: 4.5% among MSWs and 17.4% among ncMSM (P<0.001). The HIV prevalence in MSWs decreased from 4.5% in 2008 to 2.9% in 2014 (P = 0.143) but increased in ncMSM (7.0% in 2008 vs 16.8% in 2014, P<0.001). Decreased syphilis rates were observed in both MSWs (12.9% in 2008 vs 4.5% in 2014, P<0.001) and ncMSM (20.2% in 2008 vs 17.4% in 2014, P = 0.221). CONCLUSIONS: Overall, there was a decline in the prevalence of HIV and syphilis in MSWs but not in ncMSM. The study indicated the need for continued efforts to improve public health, particularly to counter the rising rate of HIV in ncMSM. PMID- 27935981 TI - Sympathetic Hyperactivity, Increased Tyrosine Hydroxylase and Exaggerated Corpus Cavernosum Relaxations Associated with Oxidative Stress Plays a Major Role in the Penis Dysfunction in Townes Sickle Cell Mouse. AB - BACKGROUND: Sickle cell disease patients display priapism that may progress to erectile dysfunction. However, little is known about the pathophysiological alterations of corpus cavernosum in sickle cell disease. OBJECTIVE: Thus, this study aimed to evaluate the functional and molecular alterations of sympathetic machinery and nitric oxide-cyclic guanosine monophosphate signaling pathway in Townes transgenic sickle cell disease mice. METHODS: Concentration-response curves to contractile (phenylephrine) and relaxant agents (acetylcholine and sodium nitroprusside) were obtained in corpus cavernosum strips from sickle and C57BL/6 (control) mice. Neurogenic contractions and nitrergic relaxations were obtained using electrical-field stimulation. Measurements of endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), phosphodiesterase-5 (PDE5) and alpha1A-, alpha1B- and alpha1D-adrenoceptor mRNA expressions and reactive-oxygen species were performed. Tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expressions in cavernosal tissues were also measured. RESULTS: The neurogenic contractions were higher in the sickle cell disease group, in association with elevated tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expression, as well as increased tyrosine hydroxylase mRNA expression. Likewise, phenylephrine induced contractions were greater in the sickle mice, whereas alpha1A-, alpha1B- and alpha1D-adrenoceptor mRNA expression remained unchanged. Cavernosal relaxations to acetylcholine, sodium nitroprusside and EFS were higher in sickle mice, accompanied by decreased eNOS and nNOS, along with lower PDE5 mRNA expression. An increase of about 40% in reactive-oxygen species generation in corpus cavernosum from sickle mice was also detected. CONCLUSION: Our study shows that decreased nitric oxide bioavailability in erectile tissue due to increased oxidative stress leads to both sympathetic hyperactivity and dysregulation of nitric oxide signaling in corpus cavernosum from Townes sickle mice. PMID- 27935982 TI - A Cost-Effective Method to Assemble Biomimetic 3D Cell Culture Platforms. AB - METHODS: We utilized the hAM to provide the biological and the three dimensional (3D) topographic components of the prototype. The 3D nano-roughness of the hAM was characterized using surface electron microscopy and surface image analysis (ImageJ and SurfaceJ). We developed additional macro-scale and micro-scale versions of the platform which provided additional shear stress factors to simulate the fluid dynamics of the in vivo extracellular fluids. RESULTS: Three models of varying complexities of the prototype were assembled. A well-defined 3D surface modulation of the hAM in comparable to commercial 3D biomaterial culture substrates was achieved without complex fabrication and with significantly lower cost. Performance of the prototype was demonstrated through culture of primary human umbilical cord mononuclear blood cells (MNCs), human bone marrow mesenchymal stem cell line (hBMSC), and human breast cancer tissue. CONCLUSION: This study presents methods of assembling an integrated, flexible and low cost biomimetic cell culture platform for diverse cell culture applications. PMID- 27935983 TI - Involvement of Pancreatic Stellate Cells in Regeneration of Remnant Pancreas after Partial Pancreatectomy. AB - BACKGROUND AND OBJECTIVES: Mechanism of regeneration of remnant pancreas after partial pancreatectomy (PX) is still unknown. In this study, effect of siRNA against the collagen specific chaperone, HSP47, which inhibits collagen secretion from activated pancreas stellate cells (aPSCs), and induces their apoptosis, on regeneration of remnant pancreas was determined. METHODS: Pancreatectomy was performed according to established methods. Proliferation of cells was assessed by BrdU incorporation. Immunostaining of HSP47 was employed to identify PSCs. Progenitor cells were identified by SOX9 staining. Acinar cells were immunostained for amylase. Co-culture of acinar cells with aPSCs were carried out in a double chamber with a cell culture insert. siRNA HSP47 encapsulated in vitamin A-coupled liposome (VA-lip siRNA HSP47) was delivered to aPSCs by iv injection. RESULTS: In remnant pancreas of 90% PX rat, new areas of foci were located separately from duodenal areas with normal pancreatic features. After PX, BrdU uptake of acinar cells and islet cells significantly increased, but was suppressed by treatment with VA-lip siRNA HSP47. BrdU uptake by acinar cells was augmented by co-culturing with aPSCs and the augmentation was nullified by siRNA HSP47. BrdU uptake by progenitor cells in foci area was slightly enhanced by the same treatment. New area which exhibited intermediate features between those of duodenal and area of foci, emerged after the treatment. CONCLUSION: aPSCs play a crucial role in regeneration of remnant pancreas, proliferation of acinar and islet cells after PX through the activity of secreted collagen. Characterization of new area emerged by siRNA HSP47 treatment as to its origin is a future task. PMID- 27935984 TI - A Biodegradable Polyethylenimine-Based Vector Modified by Trifunctional Peptide R18 for Enhancing Gene Transfection Efficiency In Vivo. AB - Lack of capacity to cross the nucleus membrane seems to be one of the main reasons for the lower transfection efficiency of gene vectors observed in vivo study than in vitro. To solve this problem, a new non-viral gene vector was designed. First, a degradable polyethylenimine (PEI) derivate was synthesized by crosslinking low-molecular-weight (LMW) PEI with N-octyl-N-quaternary chitosan (OTMCS), and then adopting a designed trifunctional peptide (RGDC-TAT-NLS) with good tumor targeting, cell uptake and nucleus transport capabilities to modify OTMCS-PEI. The new gene vector was termed as OTMCS-PEI-R18 and characterized in terms of its chemical structure and biophysical parameters. Gene transfection efficiency and nucleus transport mechanism of this vector were also evaluated. The polymer showed controlled degradation and remarkable buffer capabilities with the particle size around 100-300 nm and the zeta potential ranged from 5 mV to 40 mV. Agraose gel electrophoresis showed that OTMCS-PEI-R18 could effectively condensed plasmid DNA at a ratio of 1.0. Besides, the polymer was stable in the presence of sodium heparin and could resist digestion by DNase I at a concentration of 63U DNase I/DNA. OTMCS-PEI-R18 also showed much lower cytotoxicity and better transfection rates compared to polymers OTMCS-PEI-R13, OTMCS-PEI and PEI 25 KDa in vitro and in vivo. Furthermore, OTMCS-PEI-R18/DNA complexes could accumulate in the nucleus well soon and not rely on mitosis absolutely due to the newly incorporated ligand peptide NLS with the specific nuclear delivery pathway indicating that the gene delivery system OTMCS-PEI-R18 could reinforce gene transfection efficiency in vivo. PMID- 27935986 TI - Quantifying Adaptive and Innate Immune Responses in HIV-Infected Participants Using a Novel High Throughput Assay. AB - OBJECTIVES: HIV infection is characterised by persistent immune dysfunction of both the adaptive and innate immune responses. The aim of this study was to evaluate these responses using a novel high throughput assay in healthy controls and HIV-infected individuals prior to and following anti-retroviral treatment (ART). DESIGN: Cross-sectional study. METHODS: Whole blood was assessed using the QuantiFERON Monitor(r) (QFM) assay containing adaptive and innate immunostimulants. Interferon (IFN)-gamma levels (IU/mL) were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: We recruited HIV-infected participants (n = 20 off ART and viremic; n = 59 on suppressive ART) and HIV uninfected controls (n = 229). Median IFN-gamma production was significantly higher in HIV-infected participants compared to controls (IFN-gamma 512 vs 223 IU/ml, p<0.0001), but within the HIV-infected participants there was no difference between those on or off ART (median IFN-gamma 512 vs 593 IU/ml p = 0.94). Amongst the HIV-infected participants, IFN-gamma production was higher in individuals with CD4 count>350 compared to <350 cells/MUL (IFN-gamma IU/ml 561 vs 259 p = 0.02) and in males compared to females (IFN-gamma 542 vs 77 IU/ml p = 0.04). There were no associations between IFN-gamma production and age, plasma HIV RNA, nadir CD4 count or duration of HIV infection. Using a multivariable analysis, neither CD4 nor sex were independently predictive of IFN-gamma production. CONCLUSION: Using a high throughput assay which assesses both adaptive and innate immune function, we showed elevated IFN-gamma production in HIV-infected patients both on and off ART. Further research is warranted to determine if changes in QuantiFERON Monitor(r) are associated with clinical outcomes. PMID- 27935985 TI - miR-125b Enhances IL-8 Production in Early-Onset Severe Preeclampsia by Targeting Sphingosine-1-Phosphate Lyase 1. AB - Preeclampsia (PE) is one of the leading causes of maternal and perinatal mortality and morbidity. One of the main hallmarks observed in PE is impaired inflammation state. In the current study, we found that miR-125b was deregulated in placental tissues and plasma derived from PE patients, which suggest a potential association between this miRNA and the pathogenesis of PE. Overexpression of miR-125b significantly reduced SGPL1 expression, and luciferase assays confirmed that SGPL1 is a direct target of miR-125b. We also found that miR-125b enhanced IL-8 production by directly targeting sphingosine-1-phosphate lyase 1 (SGPL1), and this effect could be reversed by SGPL1 overexpression. In placentas derived from PE patients, a negative correlation of miR-125b and SGPL1 was observed, and IL-8 was validated to be increased in the circulation of PE patients. Our data demonstrated a critical role of miR-125b in IL-8 production and the development of PE. PMID- 27935987 TI - Patient-Reported Treatment Satisfaction with Rivaroxaban for Stroke Prevention in Atrial Fibrillation. A French Observational Study, the SAFARI Study. AB - BACKGROUND: For antithrombotic treatments, Patient Reported Outcomes (PRO) and patient satisfaction with treatment are essential data for physicians because of the strong relationship between patient satisfaction and adherence to treatment. The impact of rivaroxaban on patient satisfaction and quality of life was not sufficiently documented in phase III studies. There is a need for further data in this field especially in real life conditions. METHODS: The SAFARI study is composed of patients with non-valvular atrial fibrillation (AF), previously treated with vitamin K antagonist (VKA) and switched to rivaroxaban. Patient satisfaction with anticoagulant therapy was measured by the Anti-Clot Treatment Scale (ACTS), a validated 15-item patient-reported scale including a 12-item ACTS Burdens scale and a 3-item ACTS Benefits scale. Satisfaction of medication was compared between baseline and 1, 3 and 6 months. RESULTS: Study population was composed of 405 patients. Mean age was 74.8 (standard deviation = 9.0) years and 63.0% were male. Mean CHA2DS2-VASc score was 3.4 (1.5) and mean HAS-BLED score was 2.9 (1.0). After 3 months of treatment with rivaroxaban, patient satisfaction improved compared with VKA: mean ACTS burdens scores significantly increased by 8.3 (8.9) points (p<0.0001) and ACTS benefits scale by 0.4 (2.9) (p<0.001). Compared with baseline, the improvement in ACTS burdens and benefits became apparent at 1 month (46.5 vs. 53.6 p<0.001 and 10.4 vs. 10.7, p<0.05 respectively) and persisted at 6 months (46.5 vs. 54.76 p<0.001 and 10.4 vs. 10.8 p = 0.02 respectively). Rivaroxaban persistence was 88.7% at 6 months. CONCLUSIONS: SAFARI data support a good risk-benefit balance for rivaroxaban, with a good safety profile and encourage PRO design studies. The switch from VKA to rivaroxaban improved patient satisfaction at 1, 3 and 6 months after rivaroxaban initiation among patients with AF, particularly in reducing patient reported anticoagulation burden. PMID- 27935988 TI - Effects of a Community-Based Healthy Lifestyle Intervention Program (Co-HELP) among Adults with Prediabetes in a Developing Country: A Quasi-Experimental Study. AB - BACKGROUND: The prevalence of type 2 diabetes among Malaysian adults has increased by more than two folds over the past two decades. Strategies to collaborate with the existing community partners may become a promising channel for wide-scale dissemination of diabetes prevention in the country. The objectives of this study were to determine the effects of community-based lifestyle interventions delivered to adults with prediabetes and their health related quality of life as compared to the usual care group. METHODS: This was a quasi-experimental study conducted in two sub-urban communities in Seremban, Malaysia. A total of 268 participants with prediabetes aged between 18 to 65 years old were assigned to either the community-based lifestyle intervention (Co HELP) (n = 122) or the usual care (n = 146) groups. The Co-HELP program was delivered in partnership with the existing community volunteers to incorporate diet, physical activity, and behaviour modification strategies. Participants in the Co-HELP group received twelve group-based sessions and two individual counselling to reinforce behavioural change. Participants in the usual care group received standard health education from primary health providers in the clinic setting. Primary outcomes were fasting blood glucose, 2-hour plasma glucose, and HbA1C. Secondary outcomes included weight, BMI, waist circumference, total cholesterol, triglyceride, LDL cholesterol, HDL cholesterol, systolic and diastolic blood pressure, physical activity, diet, and health-related quality of life (HRQOL). RESULTS: An intention-to-treat analysis of between-groups at 12 month (mean difference, 95% CI) revealed that the Co-HELP participants' mean fasting plasma glucose reduced by -0.40 mmol/l (-0.51 to -0.28, p<0.001), 2-hour post glucose by -0.58 mmol/l (-0.91 to -0.24, p<0.001), HbA1C by -0.24% (-0.34 to -0.15, p<0.001), diastolic blood pressure by -2.63 mmHg (-3.79 to -1.48, p<0.01), and waist circumference by -2.44 cm (-4.75 to -0.12, p<0.05) whereas HDL cholesterol increased by 0.12 mmol/l (0.05 to 0.13, p<0.01), compared to the usual care group. Significant improvements were also found in HRQOL for both physical component (PCS) by 6.51 points (5.21 to 7.80, p<0.001) and mental component (MCS) by 7.79 points (6.44 to 9.14, p<0.001). Greater proportion of participants from the Co-HELP group met the clinical recommended target of 5% or more weight loss from the initial weight (24.6% vs 3.4%, p<0.001) and physical activity of >600 METS/min/wk (60.7% vs 32.2%, p<0.001) compared to the usual care group. CONCLUSIONS: This study provides evidence that a culturally adapted diabetes prevention program can be implemented in the community setting, with reduction of several diabetes risk factors and improvement of HRQOL. Collaboration with existing community partners demonstrated a promising channel for the wide-scale dissemination of diabetes prevention at the community level. Further studies are required to determine whether similar outcomes could be achieved in communities with different socioeconomic backgrounds and geographical areas. TRIAL REGISTRATION: IRCT201104106163N1. PMID- 27935989 TI - BRCAness and Prognosis in Triple-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy. AB - BRCAness is defined as the set of traits in which BRCA1 dysfunction, arising from gene mutation, methylation or deletion, results in DNA repair deficiency. In the present study, we addressed BRCAness, therapeutic efficacy, recurrence, and survival in patients with triple negative breast cancer (TNBC) who were treated with neoadjuvant chemotherapy at Kitasato University Hospital, Japan, between April 2006 and October 2012. BRCAness was determined by preoperative core needle biopsy (CNB) specimens and surgical specimens. Assay was performed using Multiplex Ligation-dependent Probe Amplification (MLPA) with P376-B2 BRCA1ness probemix (MRC-Holland, Amsterdam, The Netherlands). The relative copy number ratio of each sample was compared to Human Genomic DNA (Promega, Madison, WI, USA) as reference samples was calculated with Coffalyser.NET default settings. The BRCAness score was calculated with the relative copy number ratio of various DNA sequences. Values of 0.5 or more were determined as the BRCA1-like Type (BRCAness) and those of less than 0.5 as the Sporadic Type to analyze pathological complete response (pCR) rate, recurrence, and survival. pCR (ypT0/Tis/N0) was observed in 15 patients (pCR rate: 37.5%). These patients had no recurrence. Twelve patients recurred, 8 died from breast cancer. The BRCA1 like Type were 22 and Sporadic Type were 18 in CNB specimens. No major differences were observed between the BRCA1-like Type and Sporadic Type with pCR rate, recurrence rate and survival. Twenty four surgical specimens of non-pCR patients were available and 9 were BRCA1-like Type, who had more recurrences (7/9 vs. 5/15), and their relapse-free survival was also lower (p<0.05) than that of Sporadic Type. Seven BRCA1-like Type patients remained BRCA1-like Type in surgical specimens, were worse in recurrence (p<0.01) and survival (p<0.05) compared with 6 patients whose BRCA status in surgical specimens turned to Sporadic Type. New clinical trials assessing the true recurrence (TR) rate of BRCA-type patients are expected since neither platinum-containing drugs nor poly (ADP-ribose) polymerase (PARP) inhibitors are effective against tumors with nonfunctional BRCA genes. PMID- 27935990 TI - Hyperalgesia and Persistent Pain after Breast Cancer Surgery: A Prospective Randomized Controlled Trial with Perioperative COX-2 Inhibition. AB - BACKGROUND: Persistent pain is a challenging clinical problem after breast cancer treatment. After surgery, inflammatory pain and nociceptive input from nerve injury induce central sensitization which may play a role in the genesis of persistent pain. Using quantitative sensory testing, we tested the hypothesis that adding COX-2 inhibition to standard treatment reduces hyperalgesia after breast cancer surgery. A secondary hypothesis was that patients developing persistent pain would exhibit more postoperative hyperalgesia. METHODS: 138 women scheduled for lumpectomy/mastectomy under general anesthesia with paravertebral block were randomized to COX-2 inhibition (2x40mg parecoxib on day of surgery, thereafter 2x200mg celecoxib/day until day five) or placebo. Preoperatively and 1, 5, 15 days and 1, 3, 6, 12 months postoperatively, we determined electric and pressure pain tolerance thresholds in dermatomes C6/T4/L1 and a 100mm VAS score for pain. We calculated the sum of pain tolerance thresholds and analyzed change in these versus preoperatively using mixed models analysis with factor medication. To assess hyperalgesia in persistent pain patients we performed an additional analysis on patients reporting VAS>30 at 12 months. RESULTS: 48 COX-2 inhibition and 46 placebo patients were analyzed in a modified intention to treat analysis. Contrary to our primary hypothesis, change in the sum of tolerance thresholds in the COX-2 inhibition group was not different versus placebo. COX-2 inhibition had an effect on pain on movement at postoperative day 5 (p<0.01). Consistent with our secondary hypothesis, change in sum of pressure pain tolerance thresholds in 11 patients that developed persistent pain was negative versus patients without pain (p<0.01) from day 5 to 1 year postoperatively. CONCLUSIONS: Perioperative COX-2 inhibition has limited value in preventing sensitization and persistent pain after breast cancer surgery. Central sensitization may play a role in the genesis of persistent postsurgical pain. PMID- 27935991 TI - A Competency Model for Clinical Physicians in China: A Cross-Sectional Survey. AB - BACKGROUND: Around the world, regulatory bodies have taken the lead in determining the competencies required to become a physician. As a first step in addressing this project, it was decided to develop a set of core competencies that were unique to China and that might serve as a basis for medical education. The purpose of this paper was to construct a competency model for clinical physicians in China. METHODS: Data was collected using a cross-sectional survey of 6247 clinicians from seven administrative regions (31 provinces, autonomous regions and municipalities directly under the central government) in China. The total sample was randomly divided into two sub-samples, an initial sample (Sample 1) and a replication sample (Sample 2). Independent exploratory factor analysis was conducted in each sample and the results were compared to determine the stability. After that the confirmatory factor analysis was used to ascertain the competency model for physicians. The reliability, convergent and discriminant validity of competency-based instrument were also examined. RESULTS: 76 items with 8 dimensions were identified, accounting for 68.41% of the construct's total variance in the initial sample and 67.47% in the replication sample. For the two samples, the overall scale reliability (Cronbach's alpha) was both 0.985 with dimensions from 0.905 to 0.954 for the initial sample and from 0.902 to 0.955 for the replication sample after deleting the items. In confirmatory factor analysis, the result showed that all items had acceptable goodness of fit index. RMSEA and SRMR were less than 0.08 (RMSEA = 0.046, SRMR = 0.040), while GFI, NFI, IFI, and CFI were higher than 0.9 (GFI = 0.905, NFI = 0.903, IFI = 0.909, CFI = 0.909), leading to acceptable construct validity. All construct reliability values of the factors were higher than 0.70, and all average variance extracted values exceeded 0.50. Thus, we considered the reliability and validity of the 8 dimensions were acceptable. CONCLUSIONS: The instrument was shown to be both valid and reliable for measuring clinical physicians' competency in China. The results of the competency-based instrument can be used by ministry of health and administrators of hospitals to assess physicians' competencies, encourage and guide them to modify their behaviors according to the evaluation criteria, and also cultivate physicians with strong clinical practice, innovation and independent scientific research ability. Through these measurements and understandings, the overall level of clinical physicians will be increased in China. PMID- 27935992 TI - Intense Exercise and Aerobic Conditioning Associated with Chromium or L-Carnitine Supplementation Modified the Fecal Microbiota of Fillies. AB - Recent studies performed in humans and rats have reported that exercise can alter the intestinal microbiota. Athletic horses perform intense exercise regularly, but studies characterizing horse microbiome during aerobic conditioning programs are still limited. Evidence has indicated that this microbial community is involved in the metabolic homeostasis of the host. Research on ergogenic substances using new sequencing technologies have been limited to the intestinal microbiota and there is a considerable demand for scientific studies that verify the effectiveness of these supplements in horses. L-carnitine and chromium are potentially ergogenic substances for athletic humans and horses since they are possibly able to modify the metabolism of carbohydrates and lipids. This study aimed to assess the impact of acute exercise and aerobic conditioning, associated either with L-carnitine or chromium supplementation, on the intestinal microbiota of fillies. Twelve "Mangalarga Marchador" fillies in the incipient fitness stage were distributed into four groups: control (no exercise), exercise, L-carnitine (10g/day) and chelated chromium (10mg/day). In order to investigate the impact of acute exercise or aerobic conditioning on fecal microbiota all fillies undergoing the conditioning program were analyzed as a separate treatment. The fillies underwent two incremental exercise tests before and after training on a treadmill for 42 days at 70-80% of the lactate threshold intensity. Fecal samples were obtained before and 48 h after acute exercise (incremental exercise test). Bacterial populations were characterized by sequencing the V4 region of the 16S rRNA gene using the MiSeq Illumina platform, and 5,224,389 sequences were obtained from 48 samples. The results showed that, overall, the two most abundant phyla were Firmicutes (50.22%) followed by Verrucomicrobia (15.13%). The taxa with the highest relative abundances were unclassified Clostridiales (17.06%) and "5 genus incertae sedis" from the phylum Verrucomicrobia (12.98%). There was a decrease in the phylum Chlamydiae and in the genus Mycobacterium after the second incremental exercise test. Intense exercise changed the community's structure and aerobic conditioning was associated with changes in the composition and structure of the intestinal bacterial population of fillies. The intra-group comparison showed that chromium or L-carnitine induced moderate changes in the fecal microbiota of fillies, but the microbiota did not differ from the control group, which was exercised with no supplementation. Fecal pH correlated positively with Simpson's index, while plasma pH correlated negatively. Our results show that exercise and aerobic conditioning can change in the microbiota and provide a basis for further studies enrolling a larger number of horses at different fitness levels to better understand the effects of exercise and training on the intestinal microbiota of horses. PMID- 27935993 TI - Development of a Search Strategy for an Evidence Based Retrieval Service. AB - BACKGROUND: Physicians are often encouraged to locate answers for their clinical queries via an evidence-based literature search approach. The methods used are often not clearly specified. Inappropriate search strategies, time constraint and contradictory information complicate evidence retrieval. AIMS: Our study aimed to develop a search strategy to answer clinical queries among physicians in a primary care setting. METHODS: Six clinical questions of different medical conditions seen in primary care were formulated. A series of experimental searches to answer each question was conducted on 3 commonly advocated medical databases. We compared search results from a PICO (patients, intervention, comparison, outcome) framework for questions using different combinations of PICO elements. We also compared outcomes from doing searches using text words, Medical Subject Headings (MeSH), or a combination of both. All searches were documented using screenshots and saved search strategies. RESULTS: Answers to all 6 questions using the PICO framework were found. A higher number of systematic reviews were obtained using a 2 PICO element search compared to a 4 element search. A more optimal choice of search is a combination of both text words and MeSH terms. Despite searching using the Systematic Review filter, many non systematic reviews or narrative reviews were found in PubMed. There was poor overlap between outcomes of searches using different databases. The duration of search and screening for the 6 questions ranged from 1 to 4 hours. CONCLUSION: This strategy has been shown to be feasible and can provide evidence to doctors' clinical questions. It has the potential to be incorporated into an interventional study to determine the impact of an online evidence retrieval system. PMID- 27935994 TI - Comparison of Polyethylene Wear before and after Hip Revision with Liner Exchange Fixed with the Original Locking Mechanism. AB - OBJECTIVE: To compare the wear of conventional ultra-high molecular weight polyethylene (CUHMWPE) and highly cross-linked polyethylene (HCLPE) in hip revision with liner exchange fixed with original locking mechanism using analysis of history medical data. METHODS: From Jan. 1, 2000, to Dec. 31, 2007, 26 patients (with 29 involved hips) underwent liner exchange revision fixed with the original locking mechanism due to wear of CUHMWPE and/or osteolysis. The mean age was 53 +/- 9 years at the time of the primary total hip arthroplasty (THA) and 64 +/- 9 years at the revision. The exchanged liners (Marathon, Depuy) were made of HCLPE. Annual X-rays were used to measure linear wear and osteolysis. The annual linear penetration was measured using PolyWare(r) software (Draftware Inc.). Annual Harris Hip Scores(HSS) were recorded. RESULTS: The mean follow-up time between the primary and revision THAs was 11 +/- 2 years and 8 +/- 2 years after revision. The mean Harris Hip Score(HHS) before primary THA, 1 year after primary THA, before revision and 1 year after revision was 43+/-5, 85+/-5, 71+/-6, 83+/-7 individually. The mean penetration of the CUHMWPE and HCLPE liners occurring in the first year were 0.44 +/- 0.28 mm and 0.38 +/- 0.14 mm, respectively (p = 0.211). The mean annual linear penetration of CUHMWPE and HCLPE from the second year onward were 0.29+/-0.09 mm and 0.08 +/- 0.03 mm respectively (p <0.01). All THAs with CUHMWPE showed osteolysis on acetabular and/or femoral side before revision. No HCLPE liner showed osteolysis at the last follow-up. Conclusion: The CUHMWPE liner had a significantly higher wear rate than did the HCLPE liner. The HCLPE liner showed a satisfactory liner penetration rate after revision with isolated liner exchange fixed with the original locking mechanism. PMID- 27935996 TI - Magnetoelectric Response in Multiferroic SrFe12O19 Ceramics. AB - We report here realization of ferroelectricity, ferromagnetism and magnetocapacitance effect in singleSrFe12O19ceramic at room temperature. The ceramics demonstrate a saturated polarization hysteresis loop, two nonlinear I-V peaks and large anomaly of dielectric constant near Curie temperature, which confirm the intrinsic ferroelectricity of SrFe12O19 ceramicswith subsequent heat treatment in O2atmosphere. The remnant polarization of the SrFe12O19 ceramic is estimated to be 103MUC/cm2. The ceramic also exhibits strong ferromagnetic characterization, the coercive field and remnant magnetic moment are 6192Oe and 35.8emu/g, respectively. Subsequent annealing SrFe12O19 ceramics in O2 plays a key role on revealing its intrinsic ferroelectricity and improving the ferromagnetism through transforming Fe2+ into Fe3+. By applying a magnetic field, the capacitance demonstrates remarkable change along with B field, the maximum rate of change in epsilon (Deltaepsilon(B)/epsilon(0)) is 1174%, which reflects a giant magnetocapacitance effect in SrFe12O19. XPS and molecular magnetic moment measurements confirmed the transformation of Fe2+ into Fe3+ and removal of oxygen vacancies upon O2 heat treatment. These combined functional responses in SrFe12O19 ceramics opens substantial possibilities for applications in novel electric devices. PMID- 27935995 TI - Into the Bowels of Depression: Unravelling Medical Symptoms Associated with Depression by Applying Machine-Learning Techniques to a Community Based Population Sample. AB - BACKGROUND: Depression is commonly comorbid with many other somatic diseases and symptoms. Identification of individuals in clusters with comorbid symptoms may reveal new pathophysiological mechanisms and treatment targets. The aim of this research was to combine machine-learning (ML) algorithms with traditional regression techniques by utilising self-reported medical symptoms to identify and describe clusters of individuals with increased rates of depression from a large cross-sectional community based population epidemiological study. METHODS: A multi-staged methodology utilising ML and traditional statistical techniques was performed using the community based population National Health and Nutrition Examination Study (2009-2010) (N = 3,922). A Self-organised Mapping (SOM) ML algorithm, combined with hierarchical clustering, was performed to create participant clusters based on 68 medical symptoms. Binary logistic regression, controlling for sociodemographic confounders, was used to then identify the key clusters of participants with higher levels of depression (PHQ-9>=10, n = 377). Finally, a Multiple Additive Regression Tree boosted ML algorithm was run to identify the important medical symptoms for each key cluster within 17 broad categories: heart, liver, thyroid, respiratory, diabetes, arthritis, fractures and osteoporosis, skeletal pain, blood pressure, blood transfusion, cholesterol, vision, hearing, psoriasis, weight, bowels and urinary. RESULTS: Five clusters of participants, based on medical symptoms, were identified to have significantly increased rates of depression compared to the cluster with the lowest rate: odds ratios ranged from 2.24 (95% CI 1.56, 3.24) to 6.33 (95% CI 1.67, 24.02). The ML boosted regression algorithm identified three key medical condition categories as being significantly more common in these clusters: bowel, pain and urinary symptoms. Bowel-related symptoms was found to dominate the relative importance of symptoms within the five key clusters. CONCLUSION: This methodology shows promise for the identification of conditions in general populations and supports the current focus on the potential importance of bowel symptoms and the gut in mental health research. PMID- 27935998 TI - Pro-Resolving Effects of Resolvin D2 in LTD4 and TNF-alpha Pre-Treated Human Bronchi. AB - Inflammation is a major burden in respiratory diseases, resulting in airway hyperresponsiveness. Our hypothesis is that resolution of inflammation may represent a long-term solution in preventing human bronchial dysfunctions. The aim of the present study was to assess the anti-inflammatory effects of RvD2, a member of the D-series resolving family, with concomitant effects on ASM mechanical reactivity. The role and mode of action of RvD2 were assessed in an in vitro model of human bronchi under pro-inflammatory conditions, induced either by 1 MUM LTD4 or 10 ng/ml TNF-alpha pre-treatment for 48h. TNF-alpha and LTD4 both induced hyperreactivity in response to pharmacological stimuli. Enhanced 5 Lipoxygenase (5-LOX) and cysteinyl leukotriene receptor 1 (CysLTR1) detection was documented in LTD4 or TNF-alpha pre-treated human bronchi when compared to control (untreated) human bronchi. In contrast, RvD2 treatments reversed 5 LOX/beta-actin and CysLTR1/beta-actin ratios and decreased the phosphorylation levels of AP-1 subunits (c-Fos, c-Jun) and p38-MAP kinase, while increasing the detection of the ALX/FPR2 receptor. Moreover, various pharmacological agents revealed the blunting effects of RvD2 on LTD4 or TNF-alpha induced hyper responsiveness. Combined treatment with 300 nM RvD2 and 1 MUM WRW4 (an ALX/FPR2 receptor inhibitor) blunted the pro-resolving and broncho-modulatory effects of RvD2. The present data provide new evidence regarding the role of RvD2 in a human model of airway inflammation and hyperrresponsiveness. PMID- 27935999 TI - Evaluating Conservation Breeding Success for an Extinct-in-the-Wild Antelope. AB - With the number of threatened species increasing globally, conservation breeding is vitally important now more than ever. However, no previous peer-reviewed study has attempted to determine how the varying conditions across zoos have influenced breeding by an extinct-in-the-wild species. We therefore use questionnaires and studbook data to evaluate the influence of husbandry practices and enclosure design on scimitar-horned oryx (Oryx dammah) breeding success, at the herd level. Regression models were used to identify the variables that best predicted breeding success among 29 zoos across a five-year period. Calf survival decreased with herd age and the use of soft substrates in hardstand areas (yard area usually adjacent to the indoor housing), explaining 30.7% of overall variation. Calf survival also decreased where herds were small and where food provisions were not raised (and hence likely incited competition), although these were less influential. Likewise, birth rate decreased with soft substrates in hardstand areas and unraised food provisions, although these were less influential than for calf survival. Birth rate increased with year-round male presence, yet this decreased calf survival. Compared to previous studies, the number of enclosure/husbandry influences on breeding were relatively few. Nevertheless, these few enclosure/husbandry influences explained over one third of the variation in calf survival. Our data therefore suggest some potential improvements and hence that extinct-in-the-wild species stand a greater chance of survival with empirical design of zoo enclosures and husbandry methods. PMID- 27935997 TI - Endoplasmic Reticulum-Targeted Subunit Toxins Provide a New Approach to Rescue Misfolded Mutant Proteins and Revert Cell Models of Genetic Diseases. AB - Many germ line diseases stem from a relatively minor disturbance in mutant protein endoplasmic reticulum (ER) 3D assembly. Chaperones are recruited which, on failure to correct folding, sort the mutant for retrotranslocation and cytosolic proteasomal degradation (ER-associated degradation-ERAD), to initiate/exacerbate deficiency-disease symptoms. Several bacterial (and plant) subunit toxins, retrograde transport to the ER after initial cell surface receptor binding/internalization. The A subunit has evolved to mimic a misfolded protein and hijack the ERAD membrane translocon (dislocon), to effect cytosolic access and cytopathology. We show such toxins compete for ERAD to rescue endogenous misfolded proteins. Cholera toxin or verotoxin (Shiga toxin) containing genetically inactivated (+/- an N-terminal polyleucine tail) A subunit can, within 2-4 hrs, temporarily increase F508delCFTR protein, the major cystic fibrosis (CF) mutant (5-10x), F508delCFTR Golgi maturation (<10x), cell surface expression (20x) and chloride transport (2x) in F508del CFTR transfected cells and patient-derived F508delCFTR bronchiolar epithelia, without apparent cytopathology. These toxoids also increase glucocerobrosidase (GCC) in N370SGCC Gaucher Disease fibroblasts (3x), another ERAD-exacerbated misfiling disease. We identify a new, potentially benign approach to the treatment of certain genetic protein misfolding diseases. PMID- 27936000 TI - Association of Prenatal Ibuprofen Exposure with Birth Weight and Gestational Age: A Population-Based Sibling Study. AB - OBJECTIVES: Three studies so far have investigated the effect of prenatal non steroidal anti-inflammatory drug (NSAID) exposure on birth weight and gestational age. The aim in this study was to evaluate the association of prenatal ibuprofen with birth weight and gestational age at birth, using a sibling design in an attempt to adjust for the possibility of familial confounding. DESIGN: Using data from the Norwegian Mother and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway (MBRN), we identified 28 597 siblings, of whom 1080 were prenatally exposed to ibuprofen and 26 824 were not exposed to any NSAID. Random and fixed effects models with propensity score adjustment were used to evaluate the effects of ibuprofen exposure on birth weight and gestational age. RESULTS: Ibuprofen exposure during the first trimester was associated with a decrease in birth weight of 79 grams (95% confidence interval -133 to -25 grams). In contrast, second and/or third trimester exposure, and duration of exposure had no impact on the effect estimates. We found no association between ibuprofen exposure and gestational age at birth. CONCLUSIONS: Our results suggest that prenatal exposure to ibuprofen during the first trimester is associated with a slight decrease in birth weight. The association does not seem to be attributable to shared genetics and family environment, and could be explained by either exposure to ibuprofen, or to non-shared confounding between pregnancies. PMID- 27936002 TI - The Significance of Prolonged and Saddleback Fever in Hospitalised Adult Dengue. AB - Dengue fever is gaining importance in Singapore with an increase in the number of cases and mortality in recent years. Although prolonged and saddleback fever have been reported in dengue fever, there are no specific studies on their significance in dengue. This study aims to examine the prevalence of prolonged and saddleback fever in dengue as well as their associations with dengue severity. A total of 2843 polymerase-chain reaction (PCR) confirmed dengue patients admitted to Tan Tock Seng Hospital from 2004 to 2008 were included in the study. Sixty-nine percent of them were male with a median age of 34 years. Prolonged fever (fever > 7 days duration) was present in 572 (20.1%) of patients. Dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS) and severe dengue (SD) were significantly more likely to occur in patients with prolonged fever. Mucosal bleeding, anorexia, diarrhea, abdominal pain, nausea or vomiting, lethargy, rash, clinical fluid accumulation, hepatomegaly, nosocomial infection, leukopenia, higher neutrophil count, higher hematocrit, higher alanine transaminase (ALT) and aspartate transaminase (AST), higher creatinine, lower protein and prolonged activated partial thromboplastin time (APTT) were significantly associated with prolonged fever but not platelet count or prothrombin time (PT). Saddleback fever was present in 165 (5.8%). Although DHF and SD were more likely to occur in patients in those with saddleback fever, DSS was not. Compared with prolonged fever, saddleback fever did not show many significant associations except for diarrhea, abdominal pain, clinical fluid accumulation, hematocrit and platelet change, and lower systolic blood pressure. This study demonstrates that prolonged fever may be associated with various warning signs and more severe forms of dengue (SD, DSS, DHF), while saddleback fever showed associations with DHF and SD but not DSS. The presence of prolonged or saddleback fever in dengue patients should therefore prompt detailed evaluation for complications of dengue, as well as early investigation to evaluate for development of nosocomial infection. PMID- 27936001 TI - Computerized Analysis of Verbal Fluency: Normative Data and the Effects of Repeated Testing, Simulated Malingering, and Traumatic Brain Injury. AB - In verbal fluency (VF) tests, subjects articulate words in a specified category during a short test period (typically 60 s). Verbal fluency tests are widely used to study language development and to evaluate memory retrieval in neuropsychiatric disorders. Performance is usually measured as the total number of correct words retrieved. Here, we describe the properties of a computerized VF (C-VF) test that tallies correct words and repetitions while providing additional lexical measures of word frequency, syllable count, and typicality. In addition, the C-VF permits (1) the analysis of the rate of responding over time, and (2) the analysis of the semantic relationships between words using a new method, Explicit Semantic Analysis (ESA), as well as the established semantic clustering and switching measures developed by Troyer et al. (1997). In Experiment 1, we gathered normative data from 180 subjects ranging in age from 18 to 82 years in semantic ("animals") and phonemic (letter "F") conditions. The number of words retrieved in 90 s correlated with education and daily hours of computer-use. The rate of word production declined sharply over time during both tests. In semantic conditions, correct-word scores correlated strongly with the number of ESA and Troyer-defined semantic switches as well as with an ESA-defined semantic organization index (SOI). In phonemic conditions, ESA revealed significant semantic influences in the sequence of words retrieved. In Experiment 2, we examined the test-retest reliability of different measures across three weekly tests in 40 young subjects. Different categories were used for each semantic ("animals", "parts of the body", and "foods") and phonemic (letters "F", "A", and "S") condition. After regressing out the influences of education and computer use, we found that correct-word z-scores in the first session did not differ from those of the subjects in Experiment 1. Word production was uniformly greater in semantic than phonemic conditions. Intraclass correlation coefficients (ICCs) of correct-word z-scores were higher for phonemic (0.91) than semantic (0.77) tests. In semantic conditions, good reliability was also seen for the SOI (ICC = 0.68) and ESA-defined switches in semantic categories (ICC = 0.62). In Experiment 3, we examined the performance of subjects from Experiment 2 when instructed to malinger: 38% showed abnormal (p< 0.05) performance in semantic conditions. Simulated malingerers with abnormal scores could be distinguished with 80% sensitivity and 89% specificity from subjects with abnormal scores in Experiment 1 using lexical, temporal, and semantic measures. In Experiment 4, we tested patients with mild and severe traumatic brain injury (mTBI and sTBI). Patients with mTBI performed within the normal range, while patients with sTBI showed significant impairments in correct-word z-scores and category shifts. The lexical, temporal, and semantic measures of the C-VF provide an automated and comprehensive description of verbal fluency performance. PMID- 27936004 TI - Effects of Drought-Stress on Fusarium Crown Rot Development in Barley. AB - Fusarium crown rot (FCR), caused by various Fusarium species, is a chronic disease of cereals in many semi-arid regions worldwide. To clarify what effects drought-stress may have on FCR development, visual assessment, histological analysis and quantitative PCR were used to analyse the infection process of F. pseudograminearum in barley. This study observed for the first time that the severity of FCR symptom reflects the quantity of pathogens in infected tissues of barley under both drought-stressed and well-watered conditions. Drought-stress prolongs the initial infection phase but enhances the proliferation and spread of Fusarium pathogens after the initial infection phase. Under drought-stressed conditions, the invading hyphae were frequently observed to re-emerge from stomata and invade again the surrounding epidermis cells. Under the well-watered conditions, however, very few hyphae re-emerged from stomata and most infection was caused by hyphae intracellularly grown. It was also observed that drought stress increased the length and density of trichomes dramatically especially in the susceptible genotypes, and that the length and density of trichomes were positively related to fungal biomass of F. pseudograminearum in plants. PMID- 27936003 TI - Growth of Murine Splenic Tissue Is Suppressed by Lymphotoxin beta-Receptor Signaling (LTbetaR) Originating from Splenic and Non-Splenic Tissues. AB - Development and maintenance of secondary lymphoid organs such as lymph nodes and spleen essentially depend on lymphotoxin beta-receptor (LTbetaR) signaling. It is unclear, however, by which molecular mechanism their size is limited. Here, we investigate whether the LTbetaR pathway is also growth suppressing. By using splenic tissue transplantation it is possible to analyze a potential contribution of LTbetaR signaling inside and outside of the implanted tissue. We show that LTbetaR signaling within the endogenous spleen and within non-splenic tissues both significantly suppressed the regeneration of implanted splenic tissue. The suppressive activity positively correlated with the total number of LTbetaR expressing cells in the animal (regenerate weights of 115 +/- 8 mg in LTbetaR deficient recipients and of 12 +/- 9 mg in wild-type recipients), affected also developed splenic tissue, and was induced but not executed via LTbetaR signaling. Two-dimensional differential gel electrophoresis and subsequent mass spectrometry of stromal splenic tissue was applied to screen for potential factors mediating the LTbetaR dependent suppressive activity. Thus, LTbetaR dependent growth suppression is involved in regulating the size of secondary lymphoid organs, and might be therapeutically used to eradicate tertiary lymphoid tissues during autoimmune diseases. PMID- 27936005 TI - Rare Variants in NOD1 Associated with Carotid Bifurcation Intima-Media Thickness in Dominican Republic Families. AB - Cardiovascular disorders including ischemic stroke (IS) and myocardial infarction (MI) are heritable; however, few replicated loci have been identified. One strategy to identify loci influencing these complex disorders is to study subclinical phenotypes, such as carotid bifurcation intima-media thickness (bIMT). We have previously shown bIMT to be heritable and found evidence for linkage and association with common variants on chromosome 7p for bIMT. In this study, we aimed to characterize contributions of rare variants (RVs) in 7p to bIMT. To achieve this aim, we sequenced the 1 LOD unit down region on 7p in nine extended families from the Dominican Republic (DR) with strong evidence for linkage to bIMT. We then performed the family-based sequence kernel association test (famSKAT) on genes within the 7p region. Analyses were restricted to single nucleotide variants (SNVs) with population based minor allele frequency (MAF) <5%. We first analyzed all exonic RVs and then the subset of only non-synonymous RVs. There were 68 genes in our analyses. Nucleotide-binding oligomerization domain (NOD1) was the most significantly associated gene when analyzing exonic RVs (famSKAT p = 9.2x10-4; number of SNVs = 14). We achieved suggestive replication of NOD1 in an independent sample of twelve extended families from the DR (p = 0.055). Our study provides suggestive statistical evidence for a role of rare variants in NOD1 in bIMT. Studies in mice have shown Nod1 to play a role in heart function and atherosclerosis, providing biologic plausibility for a role in bIMT thus making NOD1 an excellent bIMT candidate. PMID- 27936006 TI - Prognostic Value of Red Blood Cell Distribution Width in Non-Cardiovascular Critically or Acutely Patients: A Systematic Review. AB - BACKGROUND: RDW (red cell distribution width) has been reported to been associated with the prognosis of patients with cardiovascular diseases. However, RDW is often overlooked by clinicians in treating patients with non cardiovascular diseases, especially in an emergency. The objective of this systematic review is to explore the prognostic value of RDW in non-cardiovascular emergencies. METHODS: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically searched from their inception to December 31, 2015. We included studies examining the relationship between RDW and mortality rate by adjusting important covariables in non-cardiovascular emergencies. All included studies were divided into three groups. Group A: general critically ill patients; Group B: patients with infectious disease; Group C: other conditions. We extracted each study' characteristics, outcomes, covariables, and other items independently. RESULTS: A total of 32 studies were eligible for inclusion in our meta-analysis. Six studies belonged to Group A, 9 studies belonged to Group B and 17 studies belonged to Group C. Among these included studies, RDW was assessed as a continuous variable (per 1% increase) in 16 studies, as a binary variable in 8 studies, and as a categorical variable in 8 studies. In addition, AUCs (area under the receiver operating characteristic curve) of RDW for predicting mortality were reported in 25 studies. All studies were published between 2011-2015. The qualities of included 32 studies were moderate or high. CONCLUSION: The present systematic review indicates that the increased RDW is significantly associated with a higher mortality rate in an non cardiovascular emergency. The low cost and readily accessible of this laboratory variable may strengthen its usefulness in daily practice in the future. PMID- 27936008 TI - Cultivar-Based Introgression Mapping Reveals Wild Species-Derived Pm-0, the Major Powdery Mildew Resistance Locus in Squash. AB - Powdery mildew is a major fungal disease on squash and pumpkin (Cucurbita spp.) in the US and throughout the world. Genetic resistance to the disease is not known to occur naturally within Cucurbita pepo and only infrequently in Cucurbita moschata, but has been achieved in both species through the introgression of a major resistance gene from the wild species Cucurbita okeechobeensis subsp. martinezii. At present, this gene, Pm-0, is used extensively in breeding, and is found in nearly all powdery mildew-resistant C. pepo and C. moschata commercial cultivars. In this study, we mapped C. okeechobeensis subsp. martinezii-derived single nucleotide polymorphism (SNP) alleles in a set of taxonomically and morphologically diverse and resistant C. pepo and C. moschata cultivars bred at Cornell University that, by common possession of Pm-0, form a shared-trait introgression panel. High marker density was achieved using genotyping-by sequencing, which yielded over 50,000 de novo SNP markers in each of the three Cucurbita species genotyped. A single 516.4 kb wild-derived introgression was present in all of the resistant cultivars and absent in a diverse set of heirlooms that predated the Pm-0 introgression. The contribution of this interval to powdery mildew resistance was confirmed by association mapping in a C. pepo cultivar panel that included the Cornell lines, heirlooms, and 68 additional C. pepo cultivars and with an independent F2 population derived from C. okeechobeensis subsp. martinezii x C. moschata. The interval was refined to a final candidate interval of 76.4 kb and CAPS markers were developed inside this interval to facilitate marker-assisted selection. PMID- 27936007 TI - A 99mTc-Labelled Tetrazine for Bioorthogonal Chemistry. Synthesis and Biodistribution Studies with Small Molecule trans-Cyclooctene Derivatives. AB - A convenient strategy to radiolabel a hydrazinonicotonic acid (HYNIC)-derived tetrazine with 99mTc was developed, and its utility for creating probes to image bone metabolism and bacterial infection using both active and pretargeting strategies was demonstrated. The 99mTc-labelled HYNIC-tetrazine was synthesized in 75% yield and exhibited high stability in vitro and in vivo. A trans cyclooctene (TCO)-labelled bisphosphonate (TCO-BP) that binds to regions of active calcium metabolism was used to evaluate the utility of the labelled tetrazine for bioorthogonal chemistry. The pretargeting approach, with 99mTc HYNIC-tetrazine administered to mice one hour after TCO-BP, showed significant uptake of radioactivity in regions of active bone metabolism (knees and shoulders) at 6 hours post-injection. For comparison, TCO-BP was reacted with 99mTc-HYNIC-tetrazine before injection and this active targeting also showed high specific uptake in the knees and shoulders, whereas control 99mTc-HYNIC-tetrazine alone did not. A TCO-vancomycin derivative was similarly employed for targeting Staphylococcus aureus infection in vitro and in vivo. Pretargeting and active targeting strategies showed 2.5- and 3-fold uptake, respectively, at the sites of a calf-muscle infection in a murine model, compared to the contralateral control muscle. These results demonstrate the utility of the 99mTc-HYNIC-tetrazine for preparing new technetium radiopharmaceuticals, including those based on small molecule targeting constructs containing TCO, using either active or pretargeting strategies. PMID- 27936009 TI - Predicting Virtual World User Population Fluctuations with Deep Learning. AB - This paper proposes a system for predicting increases in virtual world user actions. The virtual world user population is a very important aspect of these worlds; however, methods for predicting fluctuations in these populations have not been well documented. Therefore, we attempt to predict changes in virtual world user populations with deep learning, using easily accessible online data, including formal datasets from Google Trends, Wikipedia, and online communities, as well as informal datasets collected from online forums. We use the proposed system to analyze the user population of EVE Online, one of the largest virtual worlds. PMID- 27936010 TI - New Insights on the Composition and the Structure of the Acellular Extrinsic Fiber Cementum by Raman Analysis. AB - Acellular extrinsic fiber cementum is a mineralized tissue that covers the cervical half of the tooth root surface. It contains mainly extrinsic or Sharpey's fibers that run perpendicular to the root surface to anchor the tooth via the periodontal ligament. Acellular cementum is continuously and slowly produced throughout life and exhibits an alternating bright and dark pattern under light microscopy. However, although a better understanding of the structural background of acellular cementum is relevant to many fields, such as cementochronology, periodontology and tissue engineering, acellular cementum remains rarely studied and poorly understood. In this work, we studied the acellular cementum at the incremental line scale of five human mandibular canines using polarized Raman spectroscopy. We provided Raman imaging analysis and polarized acquisitions as a function of the angular orientation of the sample. The results showed that mineral crystals were always parallel to collagen fibrils, and at a larger scale, we proposed an organizational model in which we found radial collagen fibers, "orthogonal" to the cementum surface, and "non orthogonal" fibers, which consist of branching and bending radial fibers. Concerning the alternating pattern, we observed that the dark lines corresponded to smaller, more mineralized and probably more organized bands, which is consistent with the zoological assumption that incremental lines are produced during a winter rest period of acellular cementum growth. PMID- 27936011 TI - Overload Control for Signaling Congestion of Machine Type Communications in 3GPP Networks. AB - Because of the limited resources on radio access channels of third generation partnership projection (3GPP) network, one of the most challenging tasks posted by 3GPP cellular-based machine type communications (MTC) is congestion due to massive requests for connection to radio access network (RAN). In this paper, an overload control algorithm in 3GPP RAN is proposed, which proactively disperses the simultaneous access attempts in evenly distributed time window. Through periodic reservation strategy, massive access requests of MTC devices are dispersed in time, which reduces the probability of confliction of signaling. By the compensation and prediction mechanism, each device can communicate with MTC server with dynamic load of air interface. Numerical results prove that proposed method makes MTC applications friendly to 3GPP cellular network. PMID- 27936013 TI - beta-Asarone Rescues Pb-Induced Impairments of Spatial Memory and Synaptogenesis in Rats. AB - Chronic lead (Pb) exposure causes cognitive deficits. This study aimed to explore the neuroprotective effect and mechanism of beta-asarone, an active component from Chinese Herbs Acorus tatarinowii Schott, to alleviate impairments of spatial memory and synaptogenesis in Pb-exposed rats. Both Sprague-Dawley developmental rat pups and adult rats were used in the study. Developmental rat pups were exposed to Pb throughout the lactation period and beta-asarone (10, 40mg kg-1, respectively) was given intraperitoneally from postnatal day 14 to 21. Also, the adult rats were exposed to Pb from embryo stage to 11 weeks old and beta-asarone (2.5, 10, 40mg kg-1, respectively) was given from 9 to 11 weeks old. The level of beta-asarone in brain tissue was measured by High Performance Liquid Chromatography. The Morris water maze test and Golgi-Cox staining method were used to assess spatial memory ability and synaptogenesis. The protein expression of NR2B subunit of NMDA receptor, Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and Wnt family member 7A (Wnt7a) in hippocampus, as well as mRNA expression of Arc/Arg3.1 and Wnt7a, was also explored. We found that beta asarone could pass through the blood brain barrier quickly. And beta-asarone effectively attenuated Pb-induced reduction of spine density in hippocampal CA1 and dentate gyrus areas in a dose-dependent manner both in developmental and adult rats, meanwhile the Pb-induced impairments of learning and memory were partially rescued. In addition, beta-asarone effectively up-regulated the protein expression of NR2B, Arc and Wnt7a, as well as the mRNA levels of Arc/Arg3.1 and Wnt7a, which had been suppressed by Pb exposure. The results suggest the neuroprotective properties of beta-asarone against Pb-induced memory impairments, and the effect is possibly through the regulation of synaptogenesis, which is mediated via Arc/Arg3.1 and Wnt pathway. PMID- 27936012 TI - Sugarcane transcriptome analysis in response to infection caused by Acidovorax avenae subsp. avenae. AB - Sugarcane is an important tropical crop mainly cultivated to produce ethanol and sugar. Crop productivity is negatively affected by Acidovorax avenae subsp avenae (Aaa), which causes the red stripe disease. Little is known about the molecular mechanisms triggered in response to the infection. We have investigated the molecular mechanism activated in sugarcane using a RNA-seq approach. We have produced a de novo transcriptome assembly (TR7) from sugarcane RNA-seq libraries submitted to drought and infection with Aaa. Together, these libraries present 247 million of raw reads and resulted in 168,767 reference transcripts. Mapping in TR7 of reads obtained from infected libraries, revealed 798 differentially expressed transcripts, of which 723 were annotated, corresponding to 467 genes. GO and KEGG enrichment analysis showed that several metabolic pathways, such as code for proteins response to stress, metabolism of carbohydrates, processes of transcription and translation of proteins, amino acid metabolism and biosynthesis of secondary metabolites were significantly regulated in sugarcane. Differential analysis revealed that genes in the biosynthetic pathways of ET and JA PRRs, oxidative burst genes, NBS-LRR genes, cell wall fortification genes, SAR induced genes and pathogenesis-related genes (PR) were upregulated. In addition, 20 genes were validated by RT-qPCR. Together, these data contribute to a better understanding of the molecular mechanisms triggered by the Aaa in sugarcane and opens the opportunity for the development of molecular markers associated with disease tolerance in breeding programs. PMID- 27936015 TI - Towards Assessing the Human Trajectory Planning Horizon. AB - Mobile robots are envisioned to cooperate closely with humans and to integrate seamlessly into a shared environment. For locomotion, these environments resemble traversable areas which are shared between multiple agents like humans and robots. The seamless integration of mobile robots into these environments requires accurate predictions of human locomotion. This work considers optimal control and model predictive control approaches for accurate trajectory prediction and proposes to integrate aspects of human behavior to improve their performance. Recently developed models are not able to reproduce accurately trajectories that result from sudden avoidance maneuvers. Particularly, the human locomotion behavior when handling disturbances from other agents poses a problem. The goal of this work is to investigate whether humans alter their trajectory planning horizon, in order to resolve abruptly emerging collision situations. By modeling humans as model predictive controllers, the influence of the planning horizon is investigated in simulations. Based on these results, an experiment is designed to identify, whether humans initiate a change in their locomotion planning behavior while moving in a complex environment. The results support the hypothesis, that humans employ a shorter planning horizon to avoid collisions that are triggered by unexpected disturbances. Observations presented in this work are expected to further improve the generalizability and accuracy of prediction methods based on dynamic models. PMID- 27936014 TI - Inhibition of Interleukin-6 Receptor in a Murine Model of Myocardial Ischemia Reperfusion. AB - BACKGROUND: Interleukin-6 (IL-6) levels are upregulated in myocardial infarction. Recent data suggest a causal role of the IL-6 receptor (IL-6R) in coronary heart disease. We evaluated if IL-6R blockade by a monoclonal antibody (MR16-1) prevents the heart from adverse left ventricular remodeling in a mouse model of ischemia-reperfusion (I/R). METHODS: CJ57/BL6 mice underwent I/R injury (left coronary artery ligation for 45 minutes) or sham surgery, and thereafter received MR16-1 (2mg/mouse) 5 minutes before reperfusion and 0.5mg/mouse weekly during four weeks, or control IgG treatment. Cardiac Magnetic Resonance Imaging (CMR) and hemodynamic measurements were performed to determine cardiac function after four weeks. RESULTS: I/R caused left ventricular dilatation and a decrease in left ventricular ejection fraction (LVEF). However, LVEF was significantly lower in the MR16-1 treatment group compared to the IgG group (28+/-4% vs. 35+/-6%, p = 0.02; sham 45+/-6% vs. 43+/-4%, respectively; p = NS). Cardiac relaxation (assessed by dP/dT) was not significantly different between the MR16-1 and IgG groups. Also, no differences were observed in histological myocardial fibrosis, infarct size and myocyte hypertrophy between the groups. CONCLUSION: Blockade of the IL-6R receptor by the monoclonal MR16-1 antibody for four weeks started directly after I/R injury did not prevent the process of cardiac remodeling in mice, but rather associated with a deterioration in the process of adverse cardiac remodeling. PMID- 27936016 TI - A Tool for Investigating Asthma and COPD Exacerbations: A Newly Manufactured and Well Characterised GMP Wild-Type Human Rhinovirus for Use in the Human Viral Challenge Model. AB - BACKGROUND: Human Rhinovirus infection is an important precursor to asthma and chronic obstructive pulmonary disease exacerbations and the Human Viral Challenge model may provide a powerful tool in studying these and other chronic respiratory diseases. In this study we have reported the production and human characterisation of a new Wild-Type HRV-16 challenge virus produced specifically for this purpose. METHODS AND STOCK DEVELOPMENT: A HRV-16 isolate from an 18 year old experimentally infected healthy female volunteer (University of Virginia Children's Hospital, USA) was obtained with appropriate medical history and consent. We manufactured a new HRV-16 stock by minimal passage in a WI-38 cell line under Good Manufacturing Practice conditions. Having first subjected the stock to rigorous adventitious agent testing and determining the virus suitability for human use, we conducted an initial safety and pathogenicity clinical study in adult volunteers in our dedicated clinical quarantine facility in London. HUMAN CHALLENGE AND CONCLUSIONS: In this study we have demonstrated the new Wild-Type HRV-16 Challenge Virus to be both safe and pathogenic, causing an appropriate level of disease in experimentally inoculated healthy adult volunteers. Furthermore, by inoculating volunteers with a range of different inoculum titres, we have established the minimum inoculum titre required to achieve reproducible disease. We have demonstrated that although inoculation titres as low as 1 TCID50 can produce relatively high infection rates, the optimal titre for progression with future HRV challenge model development with this virus stock was 10 TCID50. Studies currently underway are evaluating the use of this virus as a challenge agent in asthmatics. TRIAL REGISTRATION: ClinicalTrials.gov NCT02522832. PMID- 27936017 TI - Cellular Prion Protein Combined with Galectin-3 and -6 Affects the Infectivity Titer of an Endogenous Retrovirus Assayed in Hippocampal Neuronal Cells. AB - Prion diseases are infectious and fatal neurodegenerative diseases which require the cellular prion protein, PrPC, for development of diseases. The current study shows that the PrPC augments infectivity and plaque formation of a mouse endogenous retrovirus, MuLV. We have established four neuronal cell lines expressing mouse PrPC, PrP+/+; two express wild type PrPC (MoPrPwild) and the other two express mutant PrPC (MoPrPmut). Infection of neuronal cells from various PrP+/+ and PrP-/- (MoPrPKO) lines with MuLV yielded at least three times as many plaques in PrP+/+ than in PrP-/-. Furthermore, among the four PrP+/+ lines, one mutant line, P101L, had at least 2.5 times as many plaques as the other three PrP+/+ lines. Plaques in P101L were four times larger than those in other PrP+/+ lines. Colocalization of PrP and CAgag was seen in MuLV-infected PrP+/+ cells. In the PrP-MuLV interaction, the involvement of galectin-3 and -6 was observed by immunoprecipitation with antibody to PrPC. These results suggest that PrPC combined with galectin-3 and -6 can act as a receptor for MuLV. P101L, the disease form of mutant PrPC results suggest the genetic mutant form of PrPC may be more susceptible to viral infection. PMID- 27936018 TI - Stillbirths at Term: Case Control Study of Risk Factors, Growth Status and Placental Histology. AB - OBJECTIVE: To investigate the proportion of stillbirths at term associated with abnormal growth using customized birth weight percentiles and to compare histological placental findings both in underweight stillborn fetuses and in live births. METHODS: A retrospective case-control study of 150 singleton term stillbirths. The livebirth control groups included 586 cases of low-risk pregnancies and 153 late fetal growth restriction fetuses. Stillbirths and livebirths from low-risk pregnancies were classified using customized standards for fetal weight at birth, as adequate for gestational age (AGA; 10-90th percentile), small (SGA; <10th percentile) or large for gestational age (LGA; >90th percentile). Placental characteristics in stillbirth were compared with those from livebirths using four categories: inflammation, disruptive, obstructive and adaptive lesions. RESULTS: There was a higher rate of SGA (26% vs 6%, p<0.001) and LGA fetuses (10.6% vs 5.6%, p<0.05) in the stillbirth group. Among stillbirth fetuses, almost half of the SGA were very low birthweight (<=3 degrees percentile) (12% vs 0.3%, p<0.001). The disruptive (7.3% vs 0.17%;p<0.001), obstructive (54.6% vs 7.5%;p<0.001) and adaptive (46.6% vs 35.8%;p<0.001) findings were significantly more common in than in livebirth-low risk. Placental characteristics of AGA and SGA stillbirth were compared with those of AGA and FGR livebirth. In stillbirths-SGA we found a higher number of disruptive (12.8% vs 0%; p<0.001), obstructive (58.9% vs 23.5%;p<0.001) and adaptive lesions (56.4% vs 49%; p 0.47) than in livebirth-FGR. CONCLUSION: The assessment of fetal weight with customized curves can identify fetuses which have not reached their genetically determined growth potential and are therefore at risk for adverse outcomes. Placental evaluation in stillbirths can reveal chronic histological signs that might be useful to clinical assessment, especially in underweight fetuses. PMID- 27936019 TI - Ultrasensitive Detection of Porcine Epidemic Diarrhea Virus from Fecal Samples Using Functionalized Nanoparticles. AB - Porcine epidemic diarrhea virus (PEDV) is the main causative agent of porcine diarrhea, which has resulted in devastating damage to swine industry and become a perplexed global problem. PEDV infection causes lesions and clinical symptoms, and infected pigs often succumb to severe dehydration. If there is not a timely and effective method to control its infection, PEDV will spread rapidly across the whole swine farm. Therefore, preclinical identification of PEDV is of great significance for preventing the outbreak and spread of this disease. In this study, a functionalized nanoparticles-based PCR method (UNDP-PCR) specific for PEDV was developed through systematic optimization of functionalized magnetic beads and gold nanoparticles which were further used to specifically enrich viral RNA from the lysate of PEDV stool samples, forming a MMPs-RNA-AuNPs complex. Then, oligonucleotides specific for PEDV coated on AuNPs were eluted from the complex and were further amplified and characterized by PCR. The detection limitation of the established UNDP-PCR method for PEDV was 25 copies in per gram PEDV stool samples, which is 400-fold more sensitive than conventional RT-PCR for stool samples. The UNDP-PCR for PEDV exhibited reliable reproducibility and high specificity, no cross-reaction was observed with other porcine viruses. In 153 preclinical fecal samples, the positive detection rate of UNDP-PCR specific for PEDV (30.72%) was much higher than that of conventional RT-PCR (5.88%) and SYBR Green real-time RT-PCR. In a word, this study provided a RNA extraction and transcription free, rapid and economical method for preclinical PEDV infection, which showed higher sensitivity, specificity and reproducibility, and exhibited application potency for evaluating viral loads of preclinical samples. PMID- 27936020 TI - Y Shape Osteotomy in Ankylosing Spondylitis, a Prospective Case Series with Minimum 2 Year Follow-Up. AB - The aim of the study is to evaluate the efficacy of a spinal osteotomy technique, Y shape osteotomy, for correcting kyphosis in AS patients planned preoperatively with computer software-assistance. 36 consecutive AS patients with thoracolumbar kyphosis were treated with one-stage posterior Y shape osteotomy and preoperative surgical planning was done with the aid of the Surgimap Spine. Radiological parameters of simulation and immediate postoperation were documented. Clinical and radiological results were evaluated in the preoperative, the early postoperative periods and during the last follow-up. The lumbar lordosis was found as 40.7 +/- 4.1 degrees in the surgical planning and 49.7 +/- 3.9 degrees postoperatively (p<0.01). PI-LL was 3.8+/- 0.9 degrees in the simulation procedure and 6.6+/- 1.5 degrees postoperatively (p<0.01). At the final follow up, Global sagittal balance was restored and Both Oswestry Disability Index and Scoliosis Research Society scores improved largely. In conclusion, Y shape osteotomy is a safe and effective treatment option for AS patients with kyphosis deformity. PMID- 27936021 TI - Metabolic Syndrome and Associated Factors in Adults of the Amazon Region. AB - Metabolic syndrome (MS) plays a key role in the origin of cardiovascular diseases. Studies on the MS in Brazil are recent, and its epidemiology in more isolated regions such as the Amazon is still unknown. The study aimed to estimate the prevalence of MS and associated factors in adults of the Brazilian Amazon. This study was conducted in 2012-2013. It is a cross-sectional population-based study, involving 787 adults randomly selected from the urban area of four cities in the state of Para, in the Brazilian Eastern Amazon. The participants underwent anthropometric measurements, laboratory examination, and were questioned about their lifestyle. MS was defined by the Joint Interim Statement criteria, using the multiple logistic regression to investigate the potential association of risk factors with the presence of MS. The overall prevalence of MS was 34.1% (95% CI = 30.8-37.4), increasing linearly with the increasing body mass index and age. From 40-49 years of age, MS was observed in about half of the women (46.0%), while men only experienced a high prevalence in the fifth decade of life (43.3%). The low HDL-c (64.4%) and abdominal obesity (58.9%) were higher in women (p < 0.001), while for men, high blood pressure was significantly higher (p < 0.001). Individuals aged 40-59 years old (odds ratio [OR] = 3.35 [95% CI = 2.30-4.90]), >= 60 years old (OR = 5.80 [3.63-9.27]), overweight (OR = 4.17 [2.77-6.29]), and obese (OR = 8.82 [5.56-13.98]) were more likely to have MS. The study population experienced high cardiometabolic risk, requiring government efforts to control MS and related risk factors, especially obesity. PMID- 27936022 TI - Cognitive Costs of Reappraisal Depend on Both Emotional Stimulus Intensity and Individual Differences in Habitual Reappraisal. AB - Recent models of emotion regulation suggest that the cognitive costs of reappraisal depend on stimulus intensity and habitual reappraisal. In the current experiment, we tested these hypotheses by manipulating the intensity of unpleasant and pleasant images, which participants reappraised, viewed, or suppressed their emotions to. To assess cognitive costs, we measured participants' performance on a concurrent simple reaction time task. Participants also reported on their everyday use of reappraisal and suppression. Higher intensity stimuli were associated with greater cognitive costs of reappraisal, for unpleasant, but not pleasant pictures. Also, greater habitual reappraisal predicted lower cognitive costs of reappraisal and greater reductions in subjective feelings. Results support the role of stimulus intensity and habitual use of reappraisal in predicting the cognitive costs of reappraisal. PMID- 27936023 TI - A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila. AB - Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling-the serotonin transporter-in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior. PMID- 27936024 TI - Estimation of Physical Activity Energy Expenditure during Free-Living from Wrist Accelerometry in UK Adults. AB - BACKGROUND: Wrist-worn accelerometers are emerging as the most common instrument for measuring physical activity in large-scale epidemiological studies, though little is known about the relationship between wrist acceleration and physical activity energy expenditure (PAEE). METHODS: 1695 UK adults wore two devices simultaneously for six days; a combined sensor and a wrist accelerometer. The combined sensor measured heart rate and trunk acceleration, which was combined with a treadmill test to yield a signal of individually-calibrated PAEE. Multi level regression models were used to characterise the relationship between the two time-series, and their estimations were evaluated in an independent holdout sample. Finally, the relationship between PAEE and BMI was described separately for each source of PAEE estimate (wrist acceleration models and combined sensing). RESULTS: Wrist acceleration explained 44-47% between-individual variance in PAEE, with RMSE between 34-39 J*min-1*kg-1. Estimations agreed well with PAEE in cross-validation (mean bias [95% limits of agreement]: 0.07 [ 70.6:70.7]) but overestimated in women by 3% and underestimated in men by 4%. Estimation error was inversely related to age (-2.3 J*min-1*kg-1 per 10y) and BMI (-0.3 J*min-1*kg-1 per kg/m2). Associations with BMI were similar for all PAEE estimates (approximately -0.08 kg/m2 per J*min-1*kg-1). CONCLUSIONS: A strong relationship exists between wrist acceleration and PAEE in free-living adults, such that irrespective of the objective method of PAEE assessment, a strong inverse association between PAEE and BMI was observed. PMID- 27936025 TI - Inactivation of Lipase and Lipoxygenase of Wheat Germ with Temperature-Controlled Short Wave Infrared Radiation and Its Effect on Storage Stability and Quality of Wheat Germ Oil. AB - Wheat germ (WG) is quite susceptible to deterioration due to the presence of lipase (LA) and lipoxygenase (LOX). Therefore it is indispensable to adopt a stabilization step to decrease the activity of LA and LOX while retaining a maximum level of nutrients. But over-drying can make foodstuffs more susceptible to autoxidation. So a stabilization protocol for inactivating LA and LOX of WG with a temperature- controlled short wave infrared (SIR) radiation system was adopted to retard its rancidity and retain a maximum level of fat-soluble nutrients. Meanwhile, the critical storage water activity (Aw) of WG for inhibiting both hydrolytic and oxidative rancidity was appraised. Results indicate that WG irradiated at 90 degrees C for 20 min acquired the optimal stabilization effect, and its residual LA and LOX activity were 18.02% and 19.21%, respectively. At this condition, the free fatty acids (FFA) content and peroxide value (PV) increment of WG oil at 40 degrees C remained below 5% and 2.24 meq O2/kg for 60 days, respectively. The residual Aw of this WG sample was 0.13, and it is near the Aw corresponding to its monolayer. No significant decrease of fatty acids was observed during SIR processing, while about 96.42% of its original tocopherols still retained in WG treated at 90 degrees C for 20 min. PMID- 27936027 TI - Two-Photon Microscopy Analysis of Gold Nanoparticle Uptake in 3D Cell Spheroids. AB - Nanomaterials can be synthesized from a wide range of material systems in numerous morphologies, creating an extremely diverse portfolio. As result of this tunability, these materials are emerging as a new class of nanotherapeutics and imaging agents. One particularly interesting nanomaterial is the gold nanoparticle. Due to its inherent biocompatibility and tunable photothermal behavior, it has made a rapid transition from the lab setting to in vivo testing. In most nanotherapeutic applications, the efficacy of the agent is directly related to the target of interest. However, the optimization of the AuNP size and shape for efficacy in vitro, prior to testing in in vivo models of a disease, has been largely limited to two dimensional monolayers of cells. Two dimensional cell cultures are unable to reproduce conditions experienced by AuNP in the body. In this article, we systematically investigate the effect of different properties of AuNP on the penetration depth into 3D cell spheroids using two-photon microscopy. The 3D spheroids are formed from the HCT116 cell line, a colorectal carcinoma cell line. In addition to studying different sizes and shapes of AuNPs, we also study the effect of an oligo surface chemistry. There is a significant difference between AuNP uptake profiles in the 2D monolayers of cells as compared to the 3D cell spheroids. Additionally, the range of sizes and shapes studied here also exhibit marked differences in uptake penetration depth and efficacy. Finally, our results demonstrate that two-photon microscopy enables quantitative AuNP localization and concentration data to be obtained at the single spheroid level without fluorescent labeling of the AuNP, thus, providing a viable technique for large scale screening of AuNP properties in 3D cell spheroids as compared to tedious and time consuming techniques like electron microscopy. PMID- 27936026 TI - A Comparison and Integration of MiSeq and MinION Platforms for Sequencing Single Source and Mixed Mitochondrial Genomes. AB - Single source and multiple donor (mixed) samples of human mitochondrial DNA were analyzed and compared using the MinION and the MiSeq platforms. A generalized variant detection strategy was employed to provide a cursory framework for evaluating the reliability and accuracy of mitochondrial sequences produced by the MinION. The feasibility of long-read phasing was investigated to establish its efficacy in quantitatively distinguishing and deconvolving individuals in a mixture. Finally, a proof-of-concept was demonstrated by integrating both platforms in a hybrid assembly that leverages solely mixture data to accurately reconstruct full mitochondrial genomes. PMID- 27936028 TI - Cost Effectiveness of Screening Colonoscopy Depends on Adequate Bowel Preparation Rates - A Modeling Study. AB - BACKGROUND: Inadequate bowel preparation during screening colonoscopy necessitates repeating colonoscopy. Studies suggest inadequate bowel preparation rates of 20-60%. This increases the cost of colonoscopy for our society. AIM: The aim of this study is to determine the impact of inadequate bowel preparation rate on the cost effectiveness of colonoscopy compared to other screening strategies for colorectal cancer (CRC). METHODS: A microsimulation model of CRC screening strategies for the general population at average risk for CRC. The strategies include fecal immunochemistry test (FIT) every year, colonoscopy every ten years, sigmoidoscopy every five years, or stool DNA test every 3 years. The screening could be performed at private practice offices, outpatient hospitals, and ambulatory surgical centers. RESULTS: At the current assumed inadequate bowel preparation rate of 25%, the cost of colonoscopy as a screening strategy is above society's willingness to pay (<$50,000/QALY). Threshold analysis demonstrated that an inadequate bowel preparation rate of 13% or less is necessary before colonoscopy is considered more cost effective than FIT. At inadequate bowel preparation rates of 25%, colonoscopy is still more cost effective compared to sigmoidoscopy and stool DNA test. Sensitivity analysis of all inputs adjusted by +/-10% showed incremental cost effectiveness ratio values were influenced most by the specificity, adherence, and sensitivity of FIT and colonoscopy. CONCLUSIONS: Screening colonoscopy is not a cost effective strategy when compared with fecal immunochemical test, as long as the inadequate bowel preparation rate is greater than 13%. PMID- 27936029 TI - Growth Hormone Mediates Its Protective Effect in Hepatic Apoptosis through Hnf6. AB - BACKGROUND AND AIMS: Growth hormone (GH) not only supports hepatic metabolism but also protects against hepatocyte cell death. Hnf6 (or Oc1) belonging to the Onecut family of hepatocyte transcription factors known to regulate differentiated hepatic function, is a GH-responsive gene. We evaluate if GH mediates Hnf6 activity to attenuate hepatic apoptotic injury. METHODS: We used an animal model of hepatic apoptosis by bile duct ligation (BDL) with Hnf6 -/- (KO) mice in which hepatic Hnf6 was conditionally inactivated. GH was administered to adult wild type WT and KO mice for the 7 days of BDL to enhance Hnf6 expression. In vitro, primary hepatocytes derived from KO and WT liver were treated with LPS and hepatocyte apoptosis was assessed with and without GH treatment. RESULTS: In WT mice, GH treatment enhanced Hnf6 expression during BDL, inhibited Caspase -3, 8 and -9 responses and diminished hepatic apoptotic and fibrotic injury. GH mediated upregulation of Hnf6 expression and parallel suppression of apoptosis and fibrosis in WT BDL liver were abrogated in KO mice. LPS activated apoptosis and suppressed Hnf6 expression in primary hepatocytes. GH/LPS co-treatment enhanced Hnf6 expression with corresponding attenuation of apoptosis in WT derived hepatocytes, but not in KO hepatocytes. ChiP-on-ChiP and electromobility shift assays of KO and WT liver nuclear extracts identified Ciap1 (or Birc2) as an Hnf6-bound target gene. Ciap1 expression patterns closely follow Hnf6 expression in the liver and in hepatocytes. CONCLUSION: GH broad protective actions on hepatocytes during liver injury are effected through Hnf6, with Hnf6 transcriptional activation of Ciap1 as an underlying molecular mediator. PMID- 27936030 TI - Novel Methods to Generate Active Ingredients-Enriched Ashwagandha Leaves and Extracts. AB - Ashwagandha (Withania somnifera) is an Ayurvedic herb commonly used in world renowned traditional Indian home medicine system. Roots of Ashwagandha have been traditionally known to possess a variety of therapeutic and health promoting potentials that have not been sufficiently supported by laboratory studies. Nevertheless, most, if not all, of the preventive and therapeutic potentials have been assigned to its bioactive components, steroidal alkaloids and lactones. In contrast to the traditional use of roots, we have been exploring bioactivities in leaves of Ashwagandha. Here, we report that the leaves possess higher content of active Withanolides, Withaferin-A (Wi-A) and Withanone (Wi-N), as compared to the roots. We also established, for the first time, hydroponic cultivation of Ashwagandha and investigated the effect of various cultivation conditions on the content of Wi-A and Wi-N by chemical analysis and bioassays. We report that the Withanone/Withaferin A-rich leaves could be obtained by manipulating light condition during hydroponic cultivation. Furthermore, we recruited cyclodextrins to prepare extracts with desired ratio of Wi-N and Wi-A. Hydroponically grown Ashwagandha and its extracts with high ratio of withanolides are valuable for cancer treatment. PMID- 27936031 TI - Schistosoma mansoni Infections, Undernutrition and Anaemia among Primary Schoolchildren in Two Onshore Villages in Rorya District, North-Western Tanzania. AB - BACKGROUND: Undernutrition and anaemia remains to be a major public health problem in many developing countries, where they mostly affect children. Intestinal parasitic infections are known to affect both growth and haemoglobin levels. Much has been reported on the impact of geohelminths on anaemia and undernutrition, leaving that of Schistosoma mansoni not well studied. Therefore this study intended to determine the association between S.mansoni infections, anaemia and undernutrition among schoolchildren in Rorya district, Northwestern Tanzania. METHODOLOGY: A cross-sectional study was carried among schoolchildren in two onshore villages namely Busanga and Kibuyi in Rorya district. Single stool specimens were collected from 513 randomly selected schoolchildren and processed for microscopic examination using the Kato-Katz method. Nutritional status was determined by anthropometry. Blood samples were also collected and examined for malaria parasites and haemoglobin levels using the Giemsa stain and HaemoCue methods, respectively. A pretested questionnaire was used to collect socio demographic data and associated factors. RESULTS: The prevalence of S. mansoni infection and malaria was 84.02% and 9.16%, respectively. Other parasites found were Ascaris lumbricoides (1.36%) and Hookworm (1.36%). The prevalence of stunting and wasting was 38.21% and 14.42%, respectively. The prevalence of anaemia was 29.43%, whereby 0.58% had severe anaemia. S. mansoni infection was not found to be associated with undernutrition or anaemia (p>0.05). The risk of stunting and wasting increased with increasing age (p<0.001). Anaemia was associated with age, sex and village of residence (p<0.05). CONCLUSIONS: S.mansoni, undernutrition and anaemia are highly prevalent in the study area. The observed rates of undernutrition and anaemia were seen not to be associated with S.mansoni infection suggesting possibly being a result of poor dietary nutrients. This study suggests that policy makers should consider Rorya district for inclusion into national schistosomiasis control and school feeding programmes. PMID- 27936032 TI - The RFC1 80G>A, among Common One-Carbon Polymorphisms, Relates to Survival Rate According to DNA Global Methylation in Primary Liver Cancers. AB - Polymorphisms within one-carbon metabolism genes have been largely studied in relation to cancer risk for the function of this pathway in nucleotide synthesis and DNA methylation. Aims of this study were to explore the possible link among several common functional gene polymorphisms within one-carbon metabolism and survival rate in primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma, and to assess the additional effect of global DNA methylation on survival rate and mortality risk. Forty-seven primary liver cancer patients were genotyped for ten polymorphisms: DHFR 19bp ins/del, TS 2rpt-3rpt, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, BHMT 716 A>G, TC II 776C>G. Methylation was determined in peripheral blood mononuclear cells (PBMCs) DNA as methylcytosine (mCyt) content using LC/MS/MS. Among the polymorphisms analysed, the RFC1 80G>A (rs1051266) influenced the survival rate in primary liver cancers. The RFC1 80AA was associated to a significantly reduced survival rate (22.2%) as compared to both GG and GA genotypes (61.5% and 76% respectively, p = 0.005). When the cancer patients were stratified according to the mCyt median value as high (>5.34%) or low (<=5.34%), the concomitant presence of AA genotype and low mCyt level led to a significantly worse survival rate as compared to the G allele carriership (p<0.0001) with a higher Hazard Ratio (HR = 6.62, p = 0.001). The subjects carrying the AA genotype in association with high mCyt did not show a significant difference in survival rate as compared with the G allele carriers (p = 0.919). The RFC1 80G>A polymorphism influenced the survival rate, and the presence of RFC1 80AA genotype with low global methylation in PBMCs DNA was associated with poorer prognosis and higher mortality risk, therefore highlighting novel molecular signatures potentially helpful to define prognostic markers for primary liver cancers. PMID- 27936033 TI - Automated Detection of Cancer Associated Genes Using a Combined Fuzzy-Rough-Set Based F-Information and Water Swirl Algorithm of Human Gene Expression Data. AB - This study describes a novel approach to reducing the challenges of highly nonlinear multiclass gene expression values for cancer diagnosis. To build a fruitful system for cancer diagnosis, in this study, we introduced two levels of gene selection such as filtering and embedding for selection of potential genes and the most relevant genes associated with cancer, respectively. The filter procedure was implemented by developing a fuzzy rough set (FR)-based method for redefining the criterion function of f-information (FI) to identify the potential genes without discretizing the continuous gene expression values. The embedded procedure is implemented by means of a water swirl algorithm (WSA), which attempts to optimize the rule set and membership function required to classify samples using a fuzzy-rule-based multiclassification system (FRBMS). Two novel update equations are proposed in WSA, which have better exploration and exploitation abilities while designing a self-learning FRBMS. The efficiency of our new approach was evaluated on 13 multicategory and 9 binary datasets of cancer gene expression. Additionally, the performance of the proposed FRFI-WSA method in designing an FRBMS was compared with existing methods for gene selection and optimization such as genetic algorithm (GA), particle swarm optimization (PSO), and artificial bee colony algorithm (ABC) on all the datasets. In the global cancer map with repeated measurements (GCM_RM) dataset, the FRFI-WSA showed the smallest number of 16 most relevant genes associated with cancer using a minimal number of 26 compact rules with the highest classification accuracy (96.45%). In addition, the statistical validation used in this study revealed that the biological relevance of the most relevant genes associated with cancer and their linguistics detected by the proposed FRFI-WSA approach are better than those in the other methods. The simple interpretable rules with most relevant genes and effectively classified samples suggest that the proposed FRFI WSA approach is reliable for classification of an individual's cancer gene expression data with high precision and therefore it could be helpful for clinicians as a clinical decision support system. PMID- 27936034 TI - Flow Cytometry as a Tool for Quality Control of Fluorescent Conjugates Used in Immunoassays. AB - The use of antibodies in immunodiagnostic kits generally implies the conjugation of these proteins with other molecules such as chromophores or fluorochromes. The development of more sensitive quality control procedures than spectrophotometry is essential to assure the use of better fluorescent conjugates since the fluorescent conjugates are critical reagents for a variety of immunodiagnostic kits. In this article, we demonstrate a new flow cytometric protocol to evaluate conjugates by molecules of equivalent soluble fluorochromes (MESF) and by traditional flow cytometric analysis. We have coupled microspheres with anti-IgG PE and anti-HBSAg-PE conjugates from distinct manufactures and/or different lots and evaluated by flow cytometry. Their fluorescence intensities were followed for a period of 18 months. Our results showed that there was a great difference in the fluorescence intensities between the conjugates studied. The differences were observed between manufactures and lots from both anti-IgG-PE and anti-HBSAg-PE conjugates. Coefficients of variation (CVs) showed that this parameter can be used to determine better coupling conditions, such as homogenous coupling. The MESF analysis, as well as geometric mean evaluation by traditional flow cytometry, showed a decrease in the values for all conjugates during the study and were indispensable tools to validate the results of stability tests. Our data demonstrated the feasibility of the flow cytometric method as a standard quality control of immunoassay kits. PMID- 27936035 TI - Natural Endogenous Human Matriptase and Prostasin Undergo Zymogen Activation via Independent Mechanisms in an Uncoupled Manner. AB - The membrane-associated serine proteases matriptase and prostasin are believed to function in close partnership. Their zymogen activation has been reported to be tightly coupled, either as a matriptase-initiated proteolytic cascade or through a mutually dependent mechanism involving the formation of a reciprocal zymogen activation complex. Here we show that this putative relationship may not apply in the context of human matriptase and prostasin. First, the tightly coupled proteolytic cascade between matriptase and prostasin might not occur when modest matriptase activation is induced by sphingosine 1-phospahte in human mammary epithelial cells. Second, prostasin is not required and/or involved in matriptase autoactivation because matriptase can undergo zymogen activation in cells that do not endogenously express prostasin. Third, matriptase is not required for and/or involved in prostasin activation, since activated prostasin can be detected in cells expressing no endogenous matriptase. Finally, matriptase and prostasin both undergo zymogen activation through an apparently un-coupled mechanism in cells endogenously expressing both proteases, such as in Caco-2 cells. In these human enterocytes, matriptase is detected primarily in the zymogen form and prostasin predominantly as the activated form, either in complexes with protease inhibitors or as the free active form. The negligible levels of prostasin zymogen with high levels of matriptase zymogen suggests that the reciprocal zymogen activation complex is likely not the mechanism for matriptase zymogen activation. Furthermore, high level prostasin activation still occurs in Caco-2 variants with reduced or absent matriptase expression, indicating that matriptase is not required and/or involved in prostasin zymogen activation. Collectively, these data suggest that any functional relationship between natural endogenous human matriptase and prostasin does not occur at the level of zymogen activation. PMID- 27936036 TI - The rs3957357C>T SNP in GSTA1 Is Associated with a Higher Risk of Occurrence of Hepatocellular Carcinoma in European Individuals. AB - Glutathione S-transferases (GSTs) detoxify toxic molecules by conjugation with reduced glutathione and regulate cell signaling. Single nucleotide polymorphisms (SNPs) of GST genes have been suggested to affect GST functions and thus to increase the risk of human hepatocellular carcinoma (HCC). As GSTA1 is expressed in hepatocytes and the rs3957357C>T (TT) SNP is known to downregulate GSTA1 mRNA expression, the aims of this study were: (i) to explore the relationship between the TT SNP in GSTA1 and the occurrence of HCC; (ii) to measure GSTA1 mRNA expression in HCCs. For that purpose, we genotyped non-tumor-tissue-derived DNA from 48 HCC patients and white-blood-cell-derived DNA from 37 healthy individuals by restriction fragment length polymorphism (RFLP). In addition, expression of GSTA1 mRNA was assessed by real-time PCR in 18 matching pairs of HCCs and non tumor livers. Survival analysis was performed on an annotated microarray dataset containing 247 HCC patients (GSE14520). The GSTA1 TT genotype was more frequent in HCC than in non-HCC patients (27% versus 5%, respectively), suggesting that individuals carrying this genotype could be associated with 2-fold higher risk of developing HCCs (odds ratio = 2.1; p = 0.02). Also, we found that GSTA1 mRNA expression was lower in HCCs than in non-tumor livers. HCCs expressing the highest GSTA1 mRNA levels were the smallest in size (R = -0.67; p = 0.007), expressed the highest levels of liver-enriched genes such as ALB (albumin, R = 0.67; p = 0.007) and COL18A1 (procollagen type XVIII, R = -0.50; p = 0.03) and showed the most favorable disease-free (OR = 0.54; p<0.001) and overall (OR = 0.56; p = 0.006) outcomes. Moreover, GSTA1 was found within a 263-gene network involved in well-differentiated hepatocyte functions. In conclusion, HCCs are characterized by two GSTA1 features: the TT SNP and reduced GSTA1 gene expression in a context of hepatocyte de-differentiation. PMID- 27936039 TI - Multivariate Multi-Objective Allocation in Stratified Random Sampling: A Game Theoretic Approach. AB - We consider the problem of multivariate multi-objective allocation where no or limited information is available within the stratum variance. Results show that a game theoretic approach (based on weighted goal programming) can be applied to sample size allocation problems. We use simulation technique to determine payoff matrix and to solve a minimax game. PMID- 27936037 TI - The Antioxidative Fraction of White Mulberry Induces Apoptosis through Regulation of p53 and NFkappaB in EAC Cells. AB - In this study, the antioxidative fraction of white mulberry (Morus alba) was found to have an apotogenic effect on Ehrlich's ascites carcinoma cell-induced mice (EAC mice) that correlate with upregulated p53 and downregulated NFkappaB signaling. The antioxidant activities and polyphenolic contents of various mulberry fractions were evaluated by spectrophotometry and the ethyl acetate fraction (EAF) was selected for further analysis. Strikingly, the EAF caused 70.20% tumor growth inhibition with S-phase cell cycle arrest, normalized blood parameters including red/white blood cell counts and suppressed the tumor weight of EAC mice compared with untreated controls. Fluorescence microscopy analysis of EAF-treated EAC cells revealed DNA fragmentation, cell shrinkage, and plasma membrane blebbing. These characteristic morphological features of apoptosis influenced us to further investigate pro- and anti-apoptotic signals in EAF treated EAC mice. Interestingly, apoptosis correlated with the upregulation of p53 and its target genes PARP-1 and Bax, and also with the down-regulation of NFkappaB and its target genes Bcl-2 and Bcl-xL. Our results suggest that the tumor- suppressive effect of the antioxidative fraction of white mulberry is likely due to apoptosis mediated by p53 and NFkappaB signaling. PMID- 27936038 TI - Abuse and Diversion of Immediate Release Opioid Analgesics as Compared to Extended Release Formulations in the United States. AB - BACKGROUND: Therapeutic use and abuse of prescription opioids in the United States increased substantially between 1990 and 2010. The Centers for Disease Control estimated deaths related to pharmaceutical opioids reached nearly 19,000 in 2014. Of prescription opioids sold, 10% are extended release (ER) and 90% immediate release (IR). However, most regulations and interventions have focused on decreasing ER abuse. Our objective was to compare rates of abuse and diversion of ER and IR opioid analgesics over time using multiple surveillance programs. METHODS: Rates of abuse and diversion of ER and IR opioid formulations were compared using data from four surveillance programs in the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS(r)) System. Data were evaluated from 2009 through 2015, and Poisson regression used to compare IR and ER opioid cases over time. RESULTS: From 2009 to 2015, IR opioids were prescribed at a rate 12 to 16 times higher than ER. In the Poison Center Program, population adjusted rates of Intentional Abuse for IR were 4.6 fold higher than ER opioids (p<0.001). In the Drug Diversion Program, population-adjusted rates of diversion were 6.1 fold higher for IR than ER opioids (p<0.001). In the Opioid Treatment Program, population-adjusted rates of endorsements for abuse were 1.6 fold higher for IR opioids than ER (p = 0.002). In the Survey of Key Informants' Patients Program, population-adjusted rates of endorsements for abuse were 1.5 fold higher for IR opioids than ER (p<0.001). CONCLUSIONS: Between 2009 and 2015, IR opioids were prescribed at a much higher rate than ER opioids. Results from four surveillance programs show population-adjusted rates of prescription opioid abuse were markedly higher for IR than ER medications. For the greatest public health benefit, future interventions to decrease prescription opioid abuse should focus on both IR and ER formulations. PMID- 27936040 TI - A High-Throughput Strategy for Dissecting Mammalian Genetic Interactions. AB - Comprehensive delineation of complex cellular networks requires high-throughput interrogation of genetic interactions. To address this challenge, we describe the development of a multiplex combinatorial strategy to assess pairwise genetic interactions using CRISPR-Cas9 genome editing and next-generation sequencing. We characterize the performance of combinatorial genome editing and analysis using different promoter and gRNA designs and identified regions of the chimeric RNA that are compatible with next-generation sequencing preparation and quantification. This approach is an important step towards elucidating genetic networks relevant to human diseases and the development of more efficient Cas9 based therapeutics. PMID- 27936041 TI - Recreating Stable Brachypodium hybridum Allotetraploids by Uniting the Divergent Genomes of B. distachyon and B. stacei. AB - Brachypodium hybridum (2n = 30) is a natural allopolyploid with highly divergent sub-genomes derived from two extant diploid species, B. distachyon (2n = 10) and B. stacei (2n = 20) that differ in chromosome evolution and number. We created synthetic B. hybridum allotetraploids by hybridizing various lines of B. distachyon and B. stacei. The initial amphihaploid F1 interspecific hybrids were obtained at low frequencies when B. distachyon was used as the maternal parent (0.15% or 0.245% depending on the line used) and were sterile. No hybrids were obtained from reciprocal crosses or when autotetraploids of the parental species were crossed. Colchicine treatment was used to double the genome of the F1 amphihaploid lines leading to allotetraploids. The genome-doubled F1 plants produced a few S1 (first selfed generation) seeds after self-pollination. S1 plants from one parental combination (Bd3-1*Bsta5) were fertile and gave rise to further generations whereas those of another parental combination (Bd21*ABR114) were sterile, illustrating the importance of the parental lineages crossed. The synthetic allotetraploids were stable and resembled the natural B. hybridum at the phenotypic, cytogenetic and genomic levels. The successful creation of synthetic B. hybridum offers the possibility to study changes in genome structure and regulation at the earliest stages of allopolyploid formation in comparison with the parental species and natural B. hybridum. PMID- 27936044 TI - Comparison of Reef Fish Survey Data Gathered by Open and Closed Circuit SCUBA Divers Reveals Differences in Areas With Higher Fishing Pressure. AB - Visual survey by divers using open-circuit (OC) SCUBA is the most widely used approach to survey coral reef fishes. Therefore, it is important to quantify sources of bias in OC surveys, such as the possibility that avoidance of OC divers by fishes can lead to undercounting in areas where targeted species have come to associate divers with a risk of being speared. One potential way to reduce diver avoidance is to utilize closed circuit rebreathers (CCRs), which do not produce the noise and bubbles that are a major source of disturbance associated with OC diving. For this study, we conducted 66 paired OC and CCR fish surveys in the Main Hawaiian Islands at locations with relatively high, moderate, and light fishing pressure. We found no significant differences in biomass estimates between OC and CCR surveys when data were pooled across all sites, however there were differences at the most heavily fished location, Oahu. There, biomass estimates from OC divers were significantly lower for several targeted fish groups, including surgeonfishes, targeted wrasses, and snappers, as well as for all targeted fishes combined, with mean OC biomass between 32 and 68% of mean CCR biomass. There were no clear differences between OC and CCR biomass estimates for these groups at sites with moderate or low fishing pressure, or at any location for other targeted fish groups, including groupers, parrotfishes, and goatfishes. Bias associated with avoidance of OC divers at heavily fished locations could be substantially reduced, or at least calibrated for, by utilization of CCR. In addition to being affected by fishing pressure, the extent to which avoidance of OC divers is problematic for visual surveys varies greatly among taxa, and is likely to be highly influenced by the survey methodology and dimensions used. PMID- 27936042 TI - Influence of Biodentine(r) - A Dentine Substitute - On Collagen Type I Synthesis in Pulp Fibroblasts In Vitro. AB - Preserving a patient's own teeth-even in a difficult situation-is nowadays preferable to surgical intervention and therefore promotes development of suitable dental repair materials. Biodentine(r), a mineral trioxide aggregate substitute, has been used to replace dentine in a bioactive and biocompatible manner in both the dental crown and the root. The aim of our study was to evaluate the influence of Biodentine(r) on pulp fibroblasts in vitro. For this study, one to five Biodentine(r) discs with a diameter of 5.1mm were incubated in DMEM. To obtain Biodentine(r) suspensions the media were collected and replaced with fresh medium every 24h for 4 days. Primary pulp cells were isolated from freshly extracted wisdom teeth of 20-23 year old patients and incubated with the Biodentine(r) suspensions. Proliferation, cell morphology, cell integrity and cell viability were monitored. To evaluate the effect of Biodentine(r) on collagen type I synthesis, the secretion of the N-terminal domain of pro-collagen type I (P1NP) and the release of transforming growth factor-beta1 (TGF-beta1) were quantified. None of the Biodentine(r) suspensions tested influenced cell morphology, proliferation or cell integrity. The cell viability varied slightly depending on the suspension used. However, the concentrations of P1NP of all pulp fibroblast cultures treated for 24h with the moderate to high Biodentine(r) concentration containing suspensions of day 1 were reduced to 5% of the control. Furthermore, a significant TGF-beta1 reduction was observed after treatment with these suspensions. It could be shown that Biodentine(r) is biocompatible. However, dissolved particles of the moderate to high concentrated Biodentine(r) suspensions 24h after mixing induce a significant reduction of TGF-beta1 release and reduce the secretion of collagen type I of primary pulp fibroblasts. PMID- 27936043 TI - Reproducibility for Heart Rate Variability Analysis during 6-Min Walk Test in Patients with Heart Failure and Agreement between Devices. AB - Heart rate variability (HRV) analysis is a useful method to assess abnormal functioning in the autonomic nervous system and to predict cardiac events in patients with heart failure (HF). HRV measurements with heart rate monitors have been validated with an electrocardiograph in healthy subjects but not in patients with HF. We explored the reproducibility of HRV in two consecutive six-minute walk tests (6MW), 60-minute apart, using a heart rate monitor (PolarS810i) and a portable electrocardiograph (called Holter) in 50 HF patients (mean age 59 years, NYHA II, left ventricular ejection fraction ~35%). The reproducibility for each device was analysed using a paired t-test or the Wilcoxon signed-rank test. Additionally, we assessed the agreement between the two devices based on the HRV indices at rest, during the 6MW and during recovery using concordance correlation coefficients (CCC), 95% confidence intervals and Bland-Altman plots. The test retest for the HRV analyses was reproducible using Holter and PolarS810i at rest but not during recovery. In the second 6MW, patients showed significant increases in rMSSD and walking distance. The PolarS810i measurements had remarkably high concordance correlation [0.861 cm). RESULTS: There were no significant differences in the gender, age, multifocality, Hashimoto's thyroiditis, TNM stage, PEDF protein expression, rate of recurrence, or mean follow-up duration between patients with PTMC or LPTC. The prevalence of extrathyroidal invasion (EI), lymph node metastasis (LNM), and BRAF mutation in patients with PTMC was significantly lower than in patients with LPTC. In addition, in PTMC patients with EI and/or LNM and/or positive BRAF (high-risk PTMC patients), the prevalence of extrathyroidal invasion, Hashimoto's disease, lymph node metastasis, tumor TNM stage, PEDF positive protein expression, the rate of recurrent disease, and the mRNA expression of anti-angiogenic factors was almost as high as in patients with larger PTC, but with no significant difference. CONCLUSIONS: Extrathyroid invasion, lymph node metastases, and BRAFV600E mutation were the high risk factors of PTMC. PTMC should be considered for the same treatment strategy as LPTC when any of these factors is found. Particularly, PTMC with BRAFV600E gene mutations needed earlier surgical treatment. In addition, the high cell subtype of PTMC with BRAFV600E gene mutation is recommended for total thyroidectomy in primary surgery to reduce the risk of recurrence. PMID- 27936050 TI - Gene-Targeted Mice with the Human Troponin T R141W Mutation Develop Dilated Cardiomyopathy with Calcium Desensitization. AB - Most studies of the mechanisms leading to hereditary dilated cardiomyopathy (DCM) have been performed in reconstituted in vitro systems. Genetically engineered murine models offer the opportunity to dissect these mechanisms in vivo. We generated a gene-targeted knock-in murine model of the autosomal dominant Arg141Trp (R141W) mutation in Tnnt2, which was first described in a human family with DCM. Mice heterozygous for the mutation (Tnnt2R141W/+) recapitulated the human phenotype, developing left ventricular dilation and reduced contractility. There was a gene dosage effect, so that the phenotype in Tnnt2R141W/+mice was attenuated by transgenic overexpression of wildtype Tnnt2 mRNA transcript. Male mice exhibited poorer survival than females. Biomechanical studies on skinned fibers from Tnnt2R141W/+ hearts showed a significant decrease in pCa50 ( log[Ca2+] required for generation of 50% of maximal force) relative to wildtype hearts, indicating Ca2+ desensitization. Optical mapping studies of Langendorff perfused Tnnt2R141W/+ hearts showed marked increases in diastolic and peak systolic intracellular Ca2+ ([Ca2+]i), and prolonged systolic rise and diastolic fall of [Ca2+]i. Perfused Tnnt2R141W/+ hearts had slower intrinsic rates in sinus rhythm and reduced peak heart rates in response to isoproterenol. Tnnt2R141W/+ hearts exhibited a reduction in phosphorylated phospholamban relative to wildtype mice. However, crossing Tnnt2R141W/+ mice with phospholamban knockout (Pln-/-) mice, which exhibit increased Ca2+ transients and contractility, had no effect on the DCM phenotype. We conclude that the Tnnt2 R141W mutation causes a Ca2+ desensitization and mice adapt by increasing Ca2+-transient amplitudes, which impairs Ca2+ handling dynamics, metabolism and responses to beta-adrenergic activation. PMID- 27936051 TI - Forsythia suspensa Suppresses House Dust Mite Extract-Induced Atopic Dermatitis in NC/Nga Mice. AB - Forsythia suspensa (F. suspensa) is a traditional medicine for treatment of inflammation. In this study, we evaluated the therapeutic effects of an ethanol extract from F. suspensa fruits on atopic dermatitis both in vivo and in vitro. We investigated the inhibitory effects of F. suspensa extract on the development of atopic dermatitis-like skin lesions in an NC/Nga mouse model exposed to Dermatophagoides farinae crude extract. Topical application of F. suspensa extract to the mice attenuated the atopic dermatitis symptoms, including increased dermatitis severity score, ear thickness, infiltration of inflammatory cells in the skin lesions, serum levels of IgE, TNF-alpha, and histamine, and expression of chemokines, cytokines, and adhesion molecules in ear tissue. In addition, F. suspensa extract inhibited the production of chemokines in TNF alpha/IFN-gamma-activated human keratinocytes. High-performance liquid chromatography analysis of FSE revealed the presence of four chemical constituents (forsythiaside, phillyrin, pinoresinol, and phylligenin). These compounds inhibited the production of chemokines in TNF-alpha/IFN-gamma-activated human keratinocytes. These results suggest that the F. suspensa might be a useful candidate for treating allergic skin inflammatory disorders. PMID- 27936052 TI - MicroRNA-182 Suppresses HGF/SF-Induced Increases in Retinal Pigment Epithelial Cell Proliferation and Migration through Targeting c-Met. AB - As increases in hepatocyte growth factor/scatter factor (HGF/SF) induce retinal pigment epithelial (RPE) migration and proliferation into the vitreous cavity and contribute to proliferative vitreoretinopathy (PVR) development, we determined if changes in miR-182 expression affect such behavioral changes. We found that miR 182 expression was less in PVR clinical samples than in primary RPE cells whereas c-Met was upregulated. Ectopic miR-182 inhibited RPE cell proliferation, cell cycle, and migration. Bioinformatic analysis identified c-Met as a miR-182 target, which was confirmed with the luciferase reporter assay. Transfection of miR-182 into RPE cells induced c-Met downregulation, which led to reduced cell proliferation and migration through declines in p-Akt formation. MiR-182 downregulation along with c-Met upregulation in PVR tissues suggest that these two opposing effects play important roles in PVR development. As ectopic miR-182 expression suppressed RPE cell proliferation and migration, strategies to selectively upregulate miR-182 expression in a clinical setting may provide a novel option to treat this disease. PMID- 27936053 TI - Predicting 30-Day Readmissions in an Asian Population: Building a Predictive Model by Incorporating Markers of Hospitalization Severity. AB - BACKGROUND: To reduce readmissions, it may be cost-effective to consider risk stratification, with targeting intervention programs to patients at high risk of readmissions. In this study, we aimed to derive and validate a prediction model including several novel markers of hospitalization severity, and compare the model with the LACE index (Length of stay, Acuity of admission, Charlson comorbidity index, Emergency department visits in past 6 months), an established risk stratification tool. METHOD: This was a retrospective cohort study of all patients >= 21 years of age, who were admitted to a tertiary hospital in Singapore from January 1, 2013 through May 31, 2015. Data were extracted from the hospital's electronic health records. The outcome was defined as unplanned readmissions within 30 days of discharge from the index hospitalization. Candidate predictive variables were broadly grouped into five categories: Patient demographics, social determinants of health, past healthcare utilization, medical comorbidities, and markers of hospitalization severity. Multivariable logistic regression was used to predict the outcome, and receiver operating characteristic analysis was performed to compare our model with the LACE index. RESULTS: 74,102 cases were enrolled for analysis. Of these, 11,492 patient cases (15.5%) were readmitted within 30 days of discharge. A total of fifteen predictive variables were strongly associated with the risk of 30-day readmissions, including number of emergency department visits in the past 6 months, Charlson Comorbidity Index, markers of hospitalization severity such as 'requiring inpatient dialysis during index admission, and 'treatment with intravenous furosemide 40 milligrams or more' during index admission. Our predictive model outperformed the LACE index by achieving larger area under the curve values: 0.78 (95% confidence interval [CI]: 0.77-0.79) versus 0.70 (95% CI: 0.69-0.71). CONCLUSION: Several factors are important for the risk of 30-day readmissions, including proxy markers of hospitalization severity. PMID- 27936054 TI - High Prevalence of Faecal Carriage of ESBL-Producing Enterobacteriaceae among Children in Dar es Salaam, Tanzania. AB - BACKGROUND: Faecal carriage of ESBL-producing bacteria is a potential risk for transmission and infection. Little is known about faecal carriage of antibiotic resistance in Tanzania. This study aimed to investigate the prevalence of faecal carriage of ESBL-producing Enterobacteriaceae and to identify risk factors for carriage among young children in Tanzania. METHODOLOGY/PRINCIPAL FINDINGS: From August 2010 to July 2011, children below 2 years of age were recruited in Dar es Salaam, including healthy community children (n = 250) and children hospitalized due to diarrhoea (n = 250) or other diseases (n = 103). ChromID ESBL agar and ChromID CARBA SMART agar were used for screening. Antimicrobial susceptibility testing was performed by the disk diffusion method. ESBL genotypes were identified by Real-Time PCR and sequencing. The overall prevalence of ESBL carriage was 34.3% (207/ 603). The prevalence of ESBL carriage was significantly higher among hospitalized children (50.4%), compared to community children (11.6%; P < 0.001; OR = 7.75; 95% CI: 4.99-12.03). We found high prevalence of Multidrug-resistance (94%) among Escherichia coli and Klebsiella pneumoniae isolates. No resistance to carbapenems was detected. For the majority of isolates (94.7%) we detected a blaCTX-M-15-like gene. In addition, the plasmid mediated AmpC beta-lactamase CMY-2 was detected for the first time in Tanzania. ESBL prevalence was significantly higher among HIV positive (89.7%) than HIV negative (16.9%) children (P = 0.001; OR = 9.99; 95% CI: 2.52-39.57). Use of antibiotics during the past 14 days and age below 1 year was also associated with ESBL carriage. CONCLUSIONS/SIGNIFICANCE: We report a high rate of faecal carriage of ESBL-producing Enterobacteriaceae among children below 2 years of age in Tanzania, particularly those with HIV-infection. Resistance to a majority of the available antimicrobials commonly used for children in Tanzania leaves few treatment options for infections when caused by these bacteria. PMID- 27936056 TI - Spatial-Temporal Analysis of Environmental Data of North Beijing District Using Hilbert-Huang Transform. AB - Temperature, solar radiation and water are major important variables in ecosystem models which are measurable via wireless sensor networks (WSN). Effective data analysis is necessary to extract significant spatial and temporal information. In this work, information regarding the long term variation of seasonal field environment conditions is explored using Hilbert-Huang transform (HHT) based analysis on the wireless sensor network data collection. The data collection network, consisting of 36 wireless nodes, covers an area of 100 square kilometres in Yanqing, the northwest of Beijing CBD, in China and data collection involves environmental parameter observations taken over a period of three months in 2011. The analysis used the empirical mode decomposition (EMD/EEMD) to break a time sequence of data down to a finite set of intrinsic mode functions (IMFs). Both spatial and temporal properties of data explored by HHT analysis are demonstrated. Our research shows potential for better understanding the spatial temporal relationships among environmental parameters using WSN and HHT. PMID- 27936057 TI - Correction: The BD FACSPresto Point of Care CD4 Test accurately enumerates CD4+ T cell counts. AB - [This corrects the article DOI: 10.1371/journal.pone.0145586.]. PMID- 27936055 TI - Microbial Diversity of Source and Point-of-Use Water in Rural Haiti - A Pyrosequencing-Based Metagenomic Survey. AB - Haiti endures the poorest water and sanitation infrastructure in the Western Hemisphere, where waterborne diseases cause significant morbidity and mortality. Most of these diseases are reported to be caused by waterborne pathogens. In this study, we examined the overall bacterial diversity of selected source and point of-use water from rural areas in Central Plateau, Haiti using pyrosequencing of 16s rRNA genes. Taxonomic composition of water samples revealed an abundance of Firmicutes phyla, followed by Proteobacteria and Bacteroidetes. A total of 38 bacterial families and 60 genera were identified. The presence of several Klebsiella spp. (tentatively, K. pneumoniae, K. variicola and other Klebsiella spp.) was detected in most water samples. Several other human pathogens such as Aeromonas, Bacillus, Clostridium, and Yersinia constituted significantly higher proportion of bacterial communities in the point-of-use water samples compared to source water. Bacterial genera traditionally associated with biofilm formation, such as Chryseobacterium, Fusobacterium, Prevotella, Pseudomonas were found in the point-of-use waters obtained from water filters or domestic water storage containers. Although the pyrosequencing method utilized in this study did not reveal the viability status of these pathogens, the abundance of genetic footprints of the pathogens in water samples indicate the probable risk of bacterial transmission to humans. Therefore, the importance of appropriate handling, purification, and treatment of the source water needed to be clearly communicated to the communities in rural Haiti to ensure the water is safe for their daily use and intake. PMID- 27936058 TI - Modeling the Role of Lanthionine Synthetase C-Like 2 (LANCL2) in the Modulation of Immune Responses to Helicobacter pylori Infection. AB - Immune responses to Helicobacter pylori are orchestrated through complex balances of host-bacterial interactions, including inflammatory and regulatory immune responses across scales that can lead to the development of the gastric disease or the promotion of beneficial systemic effects. While inflammation in response to the bacterium has been reasonably characterized, the regulatory pathways that contribute to preventing inflammatory events during H. pylori infection are incompletely understood. To aid in this effort, we have generated a computational model incorporating recent developments in the understanding of H. pylori-host interactions. Sensitivity analysis of this model reveals that a regulatory macrophage population is critical in maintaining high H. pylori colonization without the generation of an inflammatory response. To address how this myeloid cell subset arises, we developed a second model describing an intracellular signaling network for the differentiation of macrophages. Modeling studies predicted that LANCL2 is a central regulator of inflammatory and effector pathways and its activation promotes regulatory responses characterized by IL-10 production while suppressing effector responses. The predicted impairment of regulatory macrophage differentiation by the loss of LANCL2 was simulated based on multiscale linkages between the tissue-level gastric mucosa and the intracellular models. The simulated deletion of LANCL2 resulted in a greater clearance of H. pylori, but also greater IFNgamma responses and damage to the epithelium. The model predictions were validated within a mouse model of H. pylori colonization in wild-type (WT), LANCL2 whole body KO and myeloid-specific LANCL2-/- (LANCL2Myeloid) mice, which displayed similar decreases in H. pylori burden, CX3CR1+ IL-10-producing macrophages, and type 1 regulatory (Tr1) T cells. This study shows the importance of LANCL2 in the induction of regulatory responses in macrophages and T cells during H. pylori infection. PMID- 27936059 TI - Baroreflex Sensitivity Predicts Short-Term Outcome of Postural Tachycardia Syndrome in Children. AB - OBJECTIVE: The study was designed to examine if baroreflex sensitivity (BRS) could predict the short-term outcome of postural tachycardia syndrome (POTS) in children. METHODS: Seventy-seven children subjects were included in the study. Among them, 45 children were in the POTS group and another 32 healthy children were in the control group. A ninety-day clinical follow-up was conducted and the symptom score before and after the follow-up was calculated for POTS patients by using POTS score system. Hemodynamics and continuous BRS monitoring were recorded by Finapres Medical System-FMS (FinometerPRO, FMS Company, Netherlands). According to the symptom score change during follow-up period, POTS patients were further divided into subgroup A (n = 24) with symptom score decreased by at least two points and subgroup B (n = 21) with symptom score decreased by less than two points. The predictive value of BRS in the short-term outcome of POTS in children was analyzed using receiver-operating characteristic (ROC) curve. RESULTS: BRS of POTS children was significantly higher than that of the healthy children (18.76+/ 9.96 ms/mmHg vs 10+/-5.42 ms/mmHg, P<0.01). It was higher in subgroup B than that of subgroup A (24.7+/-9.9 ms/mmHg vs 13.5+/-6.6 ms/mmHg, P <0.01). BRS was positively correlated with HR change in POTS Group (r = 0.304, P <0.05). Area under curve (AUC) was 0.855 (95% of confidence interval 0.735-0.975), and BRS of 17.01 ms/mmHg as a cut-off value yielded the predictive sensitivity of 85.7% and specificity of 87.5%. CONCLUSIONS: BRS is a useful index to predict the short term outcome of POTS in children. PMID- 27936061 TI - In Vivo Measurements of T2 Relaxation Time of Mouse Lungs during Inspiration and Expiration. AB - PURPOSE: The interest in measurements of magnetic resonance imaging relaxation times, T1, T2, T2*, with intention to characterize healthy and diseased lungs has increased recently. Animal studies play an important role in this context providing models for understanding and linking the measured relaxation time changes to the underlying physiology or disease. The aim of this work was to study how the measured transversal relaxation time (T2) in healthy lungs is affected by normal respiration in mouse. METHOD: T2 of lung was measured in anaesthetized freely breathing mice. Image acquisition was performed on a 4.7 T, Bruker BioSpec with a multi spin-echo sequence (Car-Purcell-Meiboom-Gill) in both end-expiration and end-inspiration. The echo trains consisted of ten echoes of inter echo time 3.5 ms or 4.0 ms. The proton density, T2 and noise floor were fitted to the measured signals of the lung parenchyma with a Levenberg-Marquardt least-squares three-parameter fit. RESULTS: T2 in the lungs was longer (p<0.01) at end-expiration (9.7+/-0.7 ms) than at end-inspiration (9.0+/-0.8 ms) measured with inter-echo time 3.5 ms. The corresponding relative proton density (lung/muscle tissue) was higher (p<0.001) during end-expiration, (0.61+/-0.06) than during end-inspiration (0.48+/-0.05). The ratio of relative proton density at end-inspiration to that at end-expiration was 0.78+/-0.09. Similar results were found for inter-echo time 4.0 ms and there was no significant difference between the T2 values or proton densities acquired with different interecho times. The T2 value increased linearly (p< 0.001) with proton density. CONCLUSION: The measured T2 in-vivo is affected by diffusion across internal magnetic susceptibility gradients. In the lungs these gradients are modulated by respiration, as verified by calculations. In conclusion the measured T2 was found to be dependent on the size of the alveoli. PMID- 27936060 TI - A Non Linear Scoring Approach for Evaluating Balance: Classification of Elderly as Fallers and Non-Fallers. AB - Almost one third of population 65 years-old and older faces at least one fall per year. An accurate evaluation of the risk of fall through simple and easy-to-use measurements is an important issue in current clinic. A common way to evaluate balance in posturography is through the recording of the centre-of-pressure (CoP) displacement (statokinesigram) with force platforms. A variety of indices have been proposed to differentiate fallers from non fallers. However, no agreement has been reached whether these analyses alone can explain sufficiently the complex synergies of postural control. In this work, we study the statokinesigrams of 84 elderly subjects (80.3+- 6.4 years old), which had no impairment related to balance control. Each subject was recorded 25 seconds with eyes open and 25 seconds with eyes closed and information pertaining to the presence of problems of balance, such as fall, in the last six months, was collected. Five descriptors of the statokinesigrams were computed for each record, and a Ranking Forest algorithm was used to combine those features in order to evaluate each subject's balance with a score. A classical train-test split approach was used to evaluate the performance of the method through ROC analysis. ROC analysis showed that the performance of each descriptor separately was close to a random classifier (AUC between 0.49 and 0.54). On the other hand, the score obtained by our method reached an AUC of 0.75 on the test set, consistent over multiple train-test split. This non linear multi-dimensional approach seems appropriate in evaluating complex postural control. PMID- 27936064 TI - GWRM: An R Package for Identifying Sources of Variation in Overdispersed Count Data. AB - Understanding why a random variable is actually random has been in the core of Statistics from its beginnings. The generalized Waring regression model for count data explains that inherent variability is given by three possible sources: randomness, liability and proneness. The model extends the negative binomial regression model and it is not included in the family of generalized linear models. In order to avoid that shortcoming, we developed the GWRM R package for fitting, describing and validating the model. The version we introduce in this communication provides a new design of the modelling function as well as new methods operating on the associated fitted model objects, so that the new software integrates easily into the computational toolbox for modelling count data in R. The release of a plug-in in order to use the package from the interface R Commander tries to contribute to the spreading of the model among non advanced users. We illustrate the usage and the possibilities of the software with two examples from the fields of health and sport. PMID- 27936062 TI - On the Antecedents of an Electrophysiological Signature of Retrieval Mode. AB - It has been proposed that people employ a common set of sustained operations (retrieval mode) when preparing to remember different kinds of episodic information. In two experiments, however, there was no evidence for the pattern of brain activity commonly assumed to index these operations. In both experiments event-related potentials (ERPs) were recorded time-locked to alternating preparatory cues signalling that participants should prepare for different retrieval tasks. One cue signalled episodic retrieval: remember the location where the object was presented in a prior study phase. The other signalled semantic retrieval: identify the location where the object is most commonly found (Experiment 1) or identify the typical size of the object (Experiment 2). In both experiments, only two trials of the same task were completed in succession. This enabled ERP contrasts between 'repeat' trials (the cue on the preceding trial signalled the same retrieval task), and 'switch' trials (the cue differed from the preceding trial). There were differences between the ERPs elicited by the preparatory task cues in Experiment 1 only: these were evident only on switch trials and comprised more positive-going activity over right-frontal scalp for the semantic than for the episodic task. These findings diverge from previous outcomes where the activity differentiating cues signalling preparation for episodic or semantic retrieval has been restricted to right-frontal scalp sites, comprising more positive-going activity for the episodic than for the semantic task. While these findings are consistent with the view that there is not a common set of operations engaged when people prepare to remember different kinds of episodic information, an alternative account is offered here, which is that these outcomes are a consequence of structural and temporal components of the experiment designs. PMID- 27936063 TI - Hydrophobins in the Life Cycle of the Ectomycorrhizal Basidiomycete Tricholoma vaccinum. AB - Hydrophobins-secreted small cysteine-rich, amphipathic proteins-foster interactions of fungal hyphae with hydrophobic surfaces, and are involved in the formation of aerial hyphae. Phylogenetic analyses of Tricholoma vaccinum hydrophobins showed a grouping with hydrophobins of other ectomycorrhizal fungi, which might be a result of co-evolution. Further analyses indicate angiosperms as likely host trees for the last common ancestor of the genus Tricholoma. The nine hydrophobin genes in the T. vaccinum genome were investigated to infer their individual roles in different stages of the life cycle, host interaction, asexual and sexual development, and with respect to different stresses. In aerial mycelium, hyd8 was up-regulated. In silico analysis predicted three packing arrangements, i.e., ring-like, plus-like and sheet-like structure for Hyd8; the first two may assemble to rodlets of hydrophobin covering aerial hyphae, whereas the third is expected to be involved in forming a two-dimensional network of hydrophobins. Metal stress induced hydrophobin gene hyd5. In early steps of mycorrhization, induction of hyd4 and hyd5 by plant root exudates and root volatiles could be shown, followed by hyd5 up-regulation during formation of mantle, Hartig' net, and rhizomorphs with concomitant repression of hyd8 and hyd9. During fruiting body formation, mainly hyd3, but also hyd8 were induced. Host preference between the compatible host Picea abies and the low compatibility host Pinus sylvestris could be linked to a stronger induction of hyd4 and hyd5 by the preferred host and a stronger repression of hyd8, whereas the repression of hyd9 was comparable between the two hosts. PMID- 27936065 TI - Kinase Screening in Pichia pastoris Identified Promising Targets Involved in Cell Growth and Alcohol Oxidase 1 Promoter (PAOX1) Regulation. AB - As one of the most commonly used eukaryotic recombinant protein expression systems, P. pastoris relies heavily on the AOX1 promoter (PAOX1), which is strongly induced by methanol but strictly repressed by glycerol and glucose. However, the complicated signaling pathways involved in PAOX1 regulation when supplemented with different carbon sources are poorly understood. Here we constructed a kinase deletion library in P. pastoris and identified 27 mutants which showed peculiar phenotypes in cell growth or PAOX1 regulation. We analyzed both annotations and possible functions of these 27 targets, and then focused on the MAP kinase Hog1. In order to locate its potential downstream components, we performed the phosphoproteome analysis on glycerol cultured WT and Deltahog1 strains and identified 157 differentially phosphorylated proteins. Our results identified important kinases involved in P. pastoris cell growth and PAOX1 regulation, which could serve as valuable targets for further mechanistic studies. PMID- 27936066 TI - The Influence of Articular Cartilage Thickness Reduction on Meniscus Biomechanics. AB - OBJECTIVE: Evaluation of the biomechanical interaction between meniscus and cartilage in medial compartment knee osteoarthritis. METHODS: The finite element method was used to simulate knee joint contact mechanics. Three knee models were created on the basis of knee geometry from the Open Knee project. We reduced the thickness of medial cartilages in the intact knee model by approximately 50% to obtain a medial knee osteoarthritis (OA) model. Two variants of medial knee OA model with congruent and incongruent contact surfaces were analysed to investigate the influence of congruency. A nonlinear static analysis for one compressive load case was performed. The focus of the study was the influence of cartilage degeneration on meniscal extrusion and the values of the contact forces and contact areas. RESULTS: In the model with incongruent contact surfaces, we observed maximal compressive stress on the tibial plateau. In this model, the value of medial meniscus external shift was 95.3% greater, while the contact area between the tibial cartilage and medial meniscus was 50% lower than in the congruent contact surfaces model. After the non-uniform reduction of cartilage thickness, the medial meniscus carried only 48.4% of load in the medial compartment in comparison to 71.2% in the healthy knee model. CONCLUSIONS: We have shown that the change in articular cartilage geometry may significantly reduce the role of meniscus in load transmission and the contact area between the meniscus and cartilage. Additionally, medial knee OA may increase the risk of meniscal extrusion in the medial compartment of the knee joint. PMID- 27936068 TI - Correction: An Empirical Biomarker-Based Calculator for Cystic Index in a Model of Autosomal Recessive Polycystic Kidney Disease-The Nieto-Narayan Formula. AB - [This corrects the article DOI: 10.1371/journal.pone.0163063.]. PMID- 27936067 TI - Deletion at the GCNT2 Locus Causes Autosomal Recessive Congenital Cataracts. AB - PURPOSE: The aim of this study is to identify the molecular basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous pedigree. METHODS: All participating individuals underwent a detailed ophthalmic examination. Each patient's medical history, particularly of cataracts and other ocular abnormalities, was compiled from available medical records and interviews with family elders. Blood samples were donated by all participating family members and used to extract genomic DNA. Genetic analysis was performed to rule out linkage to known arCC loci and genes. Whole-exome sequencing libraries were prepared and paired-end sequenced. A large deletion was found that segregated with arCC in the family, and chromosome walking was conducted to estimate the proximal and distal boundaries of the deletion mutation. RESULTS: Exclusion and linkage analysis suggested linkage to a region of chromosome 6p24 harboring GCNT2 (glucosaminyl (N-acetyl) transferase 2) with a two-point logarithm of odds score of 5.78. PCR amplifications of the coding exons of GCNT2 failed in individuals with arCC, and whole-exome data analysis revealed a large deletion on chromosome 6p in the region harboring GCNT2. Chromosomal walking using multiple primer pairs delineated the extent of the deletion to approximately 190 kb. Interestingly, a failure to amplify a junctional fragment of the deletion break strongly suggests an insertion in addition to the large deletion. CONCLUSION: Here, we report a novel insertion/deletion mutation at the GCNT2 locus that is responsible for congenital cataracts in a large consanguineous family. PMID- 27936069 TI - Multimodal Imaging of Photoreceptor Structure in Choroideremia. AB - PURPOSE: Choroideremia is a progressive X-linked recessive dystrophy, characterized by degeneration of the retinal pigment epithelium (RPE), choroid, choriocapillaris, and photoreceptors. We examined photoreceptor structure in a series of subjects with choroideremia with particular attention to areas bordering atrophic lesions. METHODS: Twelve males with clinically-diagnosed choroideremia and confirmed hemizygous mutations in the CHM gene were examined. High-resolution images of the retina were obtained using spectral domain optical coherence tomography (SD-OCT) and both confocal and non-confocal split-detector adaptive optics scanning light ophthalmoscope (AOSLO) techniques. RESULTS: Eleven CHM gene mutations (3 novel) were identified; three subjects had the same mutation and one subject had two mutations. SD-OCT findings included interdigitation zone (IZ) attenuation or loss in 10/12 subjects, often in areas with intact ellipsoid zones; RPE thinning in all subjects; interlaminar bridges in the imaged areas of 10/12 subjects; and outer retinal tubulations (ORTs) in 10/12 subjects. Only split-detector AOSLO could reliably resolve cones near lesion borders, and such cones were abnormally heterogeneous in morphology, diameter and density. On split-detector imaging, the cone mosaic terminated sharply at lesion borders in 5/5 cases examined. Split-detector imaging detected remnant cone inner segments within ORTs, which were generally contiguous with a central patch of preserved retina. CONCLUSIONS: Early IZ dropout and RPE thinning on SD-OCT are consistent with previously published results. Evidence of remnant cone inner segments within ORTs and the continuity of the ORTs with preserved retina suggests that these may represent an intermediate state of retinal degeneration prior to complete atrophy. Taken together, these results supports a model of choroideremia in which the RPE degenerates before photoreceptors. PMID- 27936070 TI - Attraction, Oviposition and Larval Survival of the Fungus Gnat, Lycoriella ingenua, on Fungal Species Isolated from Adults, Larvae, and Mushroom Compost. AB - We previously showed that the females of the mushroom sciarid, Lycoriella ingenua (Dufour, 1839) (Diptera: Sciaridae), one of the most severe pests of the cultivated white button mushroom, Agaricus bisporus (J.E. Lange) Emil J. Imbach (Agaricales: Agaricaceae), are attracted to the mushroom compost that mushrooms are grown on and not to the mushrooms themselves. We also showed that females are attracted to the parasitic green mold, Trichoderma aggressivum. In an attempt to identify what is in the mushroom compost that attracts female L. ingenua, we isolated several species of fungi from adult males and females, third instar larvae, and mushroom compost itself. We then analyzed the attraction of females to these substrates using a static-flow two choice olfactometer, as well as their oviposition tendencies in another type of assay under choice and no-choice conditions. We also assessed the survival of larvae to adulthood when first instar larvae were placed on each of the isolated fungal species. We found that female flies were attracted most to the mycoparasitic green mold, T. aggressivum, to Penicilium citrinum isolated from adult female bodies, and to Scatylidium thermophilium isolated from the mushroom compost. Gravid female flies laid the most eggs on T. aggressivum, Aspergillus flavus isolated from third instar larval frass, Aspergillus fumigatus isolated from adult male bodies, and on P. citrinum. This egg-laying trend remained consistent under no-choice conditions as females aged. First instar larvae developed to adulthood only on S. thermophilium and Chaetomium sp. isolated from mushroom compost, and on P. citrinum. Our results indicate that the volatiles from a suite of different fungal species act in tandem in the natural setting of mushroom compost, with some first attracting gravid female flies and then others causing them to oviposit. The ecological context of these findings is important for creating an optimal strategy for using possible semiochemicals isolated from these fungal species to better monitor and control this pestiferous mushroom fly species. PMID- 27936071 TI - Foot Conditions among Homeless Persons: A Systematic Review. AB - INTRODUCTION: Foot problems are common among homeless persons, but are often overlooked. The objectives of this systematic review are to summarize what is known about foot conditions and associated interventions among homeless persons. METHODS: A literature search was conducted on MEDLINE (1966-2016), EMBASE (1947 2016), and CINAHL (1982-2016) and complemented by manual searches of reference lists. Articles that described foot conditions in homeless persons or associated interventions were included. Data were independently extracted on: general study characteristics; participants; foot assessment methods; foot conditions and associated interventions; study findings; quality score assessed using the Downs and Black checklist. RESULTS: Of 333 articles screened, 17 articles met criteria and were included in the study. Prevalence of any foot problem ranged from 9% to 65% across study populations. Common foot-related concerns were corns and calluses, nail pathologies, and infections. Foot pathologies related to chronic diseases such as diabetes were identified. Compared to housed individuals across studies, homeless individuals were more likely to have foot problems including tinea pedis, foot pain, functional limitations with walking, and improperly fitting shoes. DISCUSSION: Foot conditions were highly prevalent among homeless individuals with up to two thirds reporting a foot health concern, approximately one quarter of individuals visiting a health professional, and one fifth of individuals requiring further follow-up due to the severity of their condition. Homeless individuals often had inadequate foot hygiene practices and improperly fitting shoes. These findings have service provision and public health implications, highlighting the need for evidence-based interventions to improve foot health in this population. An effective interventional approach could include optimization of foot hygiene and footwear, provision of comprehensive medical treatment, and addressing social factors that lead to increased risk of foot problems. Targeted efforts to screen for and treat foot problems could result in improved health and social outcomes for homeless individuals. PMID- 27936072 TI - Delonix regia Leaf Extract (DRLE): A Potential Therapeutic Agent for Cardioprotection. AB - Delonix regia (Boj. Ex. Hook) is a flowering plant in the pea family found in tropical areas and its leaves are used informally to treat diseases in folk medicine. However, the cardioprotective effects in this plant are still unclear. In this study, we found that the Delonix regia leaf extract (DRLE) (400 mg/kg/d) can reduce the mortality rate in an isoproterenol (ISO)-induced heart injury and hypertrophy mouse model. Decreased serum levels of creatine phosphokinase, LDH, GOT, TNF-alpha and increased nitric oxide levels were found in DRLE-treated ISO injured mice. In the in vitro study, the porcine coronary artery exhibited vasodilation effect induced by DRLE in a dose-dependent manner. In the DRLE toxic test, overdose of DRLE showed the high safety in normal mice and may have the ability to remove the metabolic wastes in blood. In conclusion, we demonstrated for the first time that DRLE has the cardioprotective effects by activating the vasodilation through NO pathway and preventing the myocyte injury via inhibition of TNF-alpha pathway. We suggest that DRLE may act as a promising novel herbal medicine for cardioprotection. PMID- 27936073 TI - Socio-Demographic, Social-Cognitive, Health-Related and Physical Environmental Variables Associated with Context-Specific Sitting Time in Belgian Adolescents: A One-Year Follow-Up Study. AB - INTRODUCTION: More knowledge is warranted about multilevel ecological variables associated with context-specific sitting time among adolescents. The present study explored cross-sectional and longitudinal associations of ecological domains of sedentary behaviour, including socio-demographic, social-cognitive, health-related and physical-environmental variables with sitting during TV viewing, computer use, electronic gaming and motorized transport among adolescents. METHODS: For this longitudinal study, a sample of Belgian adolescents completed questionnaires at school on context-specific sitting time and associated ecological variables. At baseline, complete data were gathered from 513 adolescents (15.0+/-1.7 years). At one-year follow-up, complete data of 340 participants were available (retention rate: 66.3%). Multilevel linear regression analyses were conducted to explore cross-sectional correlates (baseline variables) and longitudinal predictors (change scores variables) of context-specific sitting time. RESULTS: Social-cognitive correlates/predictors were most frequently associated with context-specific sitting time. Longitudinal analyses revealed that increases over time in considering it pleasant to watch TV (p < .001), in perceiving TV watching as a way to relax (p < .05), in TV time of parents/care givers (p < .01) and in TV time of siblings (p < .001) were associated with more sitting during TV viewing at follow-up. Increases over time in considering it pleasant to use a computer in leisure time (p < .01) and in the computer time of siblings (p < .001) were associated with more sitting during computer use at follow-up. None of the changes in potential predictors were significantly related to changes in sitting during motorized transport or during electronic gaming. CONCLUSIONS: Future intervention studies aiming to decrease TV viewing and computer use should acknowledge the importance of the behaviour of siblings and the pleasure adolescents experience during these screen-related behaviours. In addition, more time parents or care givers spent sitting may lead to more sitting during TV viewing of the adolescents, so that a family-based approach may be preferable for interventions. Experimental study designs are warranted to confirm the present findings. PMID- 27936074 TI - Association between Metabolic Syndrome and Cognitive Impairment after Acute Ischemic Stroke: A Cross-Sectional Study in a Chinese Population. AB - BACKGROUND AND OBJECTIVES: Metabolic syndrome (MetS), a risk factor for many vascular conditions, is associated with vascular cognitive disorders. The objective of the present study was to explore the associations of MetS and its individual components with the risks of cognitive impairment and neurological dysfunction in patients after acute stroke. METHODS: This cross-sectional study enrolled 840 patients ranging in age from 53 to 89 years from the Tianjin area of North China. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination. Neuropsychiatric behavior was assessed using the Neuropsychiatric Inventory Questionnaire. Emotional state was examined according to the Hamilton Depression Rating Scale, and neuromotor function was evaluated using the National Institutes of Health Stroke Scale, Barthel index, and the Activity of Daily Living test. After overnight fasting, blood samples were obtained to measure biochemistry indicators. RESULTS: MetS and its individual components were closely correlated with MoCA score. MetS patients had high levels of inflammation and a 3.542-fold increased odds ratio (OR) for cognitive impairment [95% confidence interval (CI): 1.972-6.361]. Of the individual MetS components, central obesity (OR 3.039; 95% CI: 1.839-5.023), high fasting plasma glucose (OR 1.915; 95% CI: 1.016-3.607), and type 2 diabetes (OR 2.241; 95% CI: 1.630-3.081) were associated with an increased incidence of cognitive impairment. Consistent and significant worsening in different neurological domains was observed with greater numbers of MetS components. CONCLUSIONS: MetS was associated with worse cognitive function, neuromotor dysfunction, and neuropsychological symptoms among Chinese acute stroke patients. PMID- 27936075 TI - Ophiobolin A Induces Autophagy and Activates the Mitochondrial Pathway of Apoptosis in Human Melanoma Cells. AB - Ophiobolin A, a fungal toxin from Bipolaris species known to affect different cellular processes in plants, has recently been shown to have anti-cancer activity in mammalian cells. In the present study, we investigated the anti proliferative effect of Ophiobolin A on human melanoma A375 and CHL-1 cell lines. This cellular model was chosen because of the incidence of melanoma malignant tumor on human population and its resistance to chemical treatments. Ophyobolin A strongly reduced cell viability of melanoma cells by affecting mitochondrial functionality. The toxin induced depolarization of mitochondrial membrane potential, reactive oxygen species production and mitochondrial network fragmentation, leading to autophagy induction and ultimately resulting in cell death by activation of the mitochondrial pathway of apoptosis. Finally, a comparative proteomic investigation on A375 cells allowed to identify several Ophiobolin A down-regulated proteins, which are involved in fundamental processes for cell homeostasis and viability. PMID- 27936077 TI - Routine Vaccination Coverage in Northern Nigeria: Results from 40 District-Level Cluster Surveys, 2014-2015. AB - BACKGROUND: Despite recent success towards controlling poliovirus transmission, Nigeria has struggled to achieve uniformly high routine vaccination coverage. A lack of reliable vaccination coverage data at the operational level makes it challenging to target program improvement. To reliably estimate vaccination coverage, we conducted district-level vaccine coverage surveys using a pre existing infrastructure of polio technical staff in northern Nigeria. METHODS: Household-level cluster surveys were conducted in 40 polio high risk districts of Nigeria during 2014-2015. Global positioning system technology and intensive supervision by a pool of qualified technical staff were used to ensure high survey quality. Vaccination status of children aged 12-23 months was documented based on vaccination card or caretaker's recall. District-level coverage estimates were calculated using survey methods. RESULTS: Data from 7,815 children across 40 districts were analyzed. District-level coverage with the third dose of diphtheria-pertussis-tetanus vaccine (DPT3) ranged widely from 1-63%, with all districts having DPT3 coverage below the target of 80%. Median coverage across all districts for each of eight vaccine doses (1 Bacille Calmette-Guerin dose, 3 DPT doses, 3 oral poliovirus vaccine doses, and 1 measles vaccine dose) was <50%. DPT3 coverage by survey was substantially lower (range: 28%-139%) than the 2013 administrative coverage reported among children aged <12 months. Common reported reasons for non-vaccination included lack of knowledge about vaccines and vaccination services (50%) and factors related to access to routine immunization services (15%). CONCLUSIONS: Survey results highlighted vaccine coverage gaps that were systematically underestimated by administrative reporting across 40 polio high risk districts in northern Nigeria. Given the limitations of administrative coverage data, our approach to conducting quality district-level coverage surveys and providing data to assess and remediate issues contributing to poor vaccination coverage could serve as an example in countries with sub optimal vaccination coverage, similar to Nigeria. PMID- 27936076 TI - Angiogenic Capacity of Periodontal Ligament Stem Cells Pretreated with Deferoxamine and/or Fibroblast Growth Factor-2. AB - Periodontal ligament stem cells (PDLSCs) represent a good source of multipotent cells for cell-based therapies in regenerative medicine. The success rate of these treatments is severely dependent on the establishment of adequate vasculature in order to provide oxygen and nutrients to the transplanted cells. Pharmacological preconditioning of stem cells has been proposed as a promising method to augment their therapeutic efficacy. In this study, the aim was to improve the intrinsic angiogenic properties of PDLSCs by in vitro pretreatment with deferoxamine (DFX; 100MUM), fibroblast growth factor-2 (FGF-2; 10ng/mL) or both substances combined. An antibody array revealed the differential expression of several proteins, including vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). ELISA data confirmed a 1.5 to 1.8-fold increase in VEGF for all tested conditions. Moreover, 48 hours after the removal of DFX, VEGF levels remained elevated (1.8-fold) compared to control conditions. FGF-2 and combination treatment resulted in a 5.4 to 13.1-fold increase in PlGF secretion, whereas DFX treatment had no effect. Furthermore, both PDLSCs as pretreated PDLSCs induced endothelial migration. Despite the significant elevated VEGF levels of pretreated PDLSCs, the induced endothelial migration was not higher by pretreated PDLSCs. We find that the observed induced endothelial cell motility was not dependent on VEGF, since blocking the VEGFR1-3 with Axitinib (0.5nM) did not inhibit endothelial motility towards PDLSCs. Taken together, this study provides evidence that preconditioning with DFX and/or FGF-2 significantly improves the angiogenic secretome of PDLSCs, in particular VEGF and PlGF secretion. However, our data suggest that VEGF is not the only player when it comes to influencing endothelial behavior by the PDLSCs. PMID- 27936078 TI - Associations between Childhood Parental Mental Health Difficulties and Depressive Symptoms in Late Adulthood: The Influence of Life-Course Socioeconomic, Health and Lifestyle Factors. AB - BACKGROUND: Depression among older adults (i.e., the 50+) is a major health concern. The objective of this study is to investigate whether growing up with a parent suffering from mental health problems is associated with depressive symptoms in late-adulthood and how this association is influenced by life-course socio-economic, health and lifestyle factors in childhood and late adulthood. METHODS: We used life-history data from the SHARE survey, consisting of 21,127 participants living in 13 European countries. Symptoms of depression were assessed using the EURO-D scale. Parental mental health was assessed by asking respondents to report whether any of their parents had mental health problems during the respondents' childhood. Logistic regression models were used to assess the association between parental mental health status and depression. Variables on childhood and late-life socio-economic, health and lifestyle factors were sequentially added to the model to assess the extent to which this association is influenced by life-course circumstances. RESULTS: Individuals who were exposed during childhood to a parent with mental health problems suffered from depressive symptoms more often in late adulthood than those who were not (OR 1.76, 95% CI: 1.43-2.17). Adjustment for life-course socio-economic, health and lifestyle factors in childhood and late adulthood diminished this association to an OR of 1.54 (95% CI: 1.24-1.90) and OR of 1.45 (95% CI: 1.16-1.82), respectively. CONCLUSION: Our results indicate a substantial association between parental mental health problems in childhood and depression in late adulthood and that this association is partly explained by childhood as well as late adulthood socio economic, health and lifestyle factors. PMID- 27936079 TI - High-Temperature-Induced Defects in Tomato (Solanum lycopersicum) Anther and Pollen Development Are Associated with Reduced Expression of B-Class Floral Patterning Genes. AB - Sexual reproduction is a critical process in the life-cycle of plants and very sensitive to environmental perturbations. To better understand the effect of high temperature on plant reproduction, we cultivated tomato (Solanum lycopersicum) plants in continuous mild heat. Under this condition we observed a simultaneous reduction in pollen viability and appearance of anthers with pistil-like structures, while in a more thermotolerant genotype, both traits were improved. Ectopic expression of two pistil-specific genes, TRANSMITTING TISSUE SPECIFIC and TOMATO AGAMOUS LIKE11, in the anthers confirmed that the anthers had gained partial pistil identity. Concomitantly, expression of the B-class genes TOMATO APETALA3, TOMATO MADS BOX GENE6 (TM6) and LePISTILLATA was reduced in anthers under continuous mild heat. Plants in which TM6 was partially silenced reacted hypersensitively to temperature elevation with regard to the frequency of pistilloid anthers, pollen viability and pollen quantity. Taken together, these results suggest that high-temperature-induced down-regulation of tomato B-class genes contributes to anther deformations and reduced male fertility. Improving our understanding of how temperature perturbs the molecular mechanisms of anther and pollen development will be important in the view of maintaining agricultural output under current climate changes. PMID- 27936080 TI - Effects of Pyrogallol on Growth and Cytotoxicity of Wild-Type and katG Mutant Strains of Vibrio vulnificus. AB - Vibrio vulnificus is a causative agent of fatal septicemia and necrotic wound infection and the pathogen infection became an important public health problem in many counties. Vibrio vulnificus causes RtxA1 toxin-induced acute cell death. We tried to identify natural products that inhibit the acute cytotoxicity of V. vulnificus using a lactate hydrogenase assay. A polyphenol pyrogallol protected HeLa cells from V. vulnificus-induced cytotoxicity. Pyrogallol also decreased the growth of V. vulnificus; this inhibitory effect was more significant during log phase than stationary phase. To further elucidate the inhibitory mechanism, pyrogallol-induced toxicity was compared between a V. vulnificus catalase peroxidase mutant (katG-) and the isogenic wild-type MO6-24/O strains. No growth was observed for the katG- mutant in the presence of pyrogallol (50 MUg/mL) even after 24 h, whereas the wild-type strain demonstrated growth recovery following a prolonged lag phase. Pyrogallol-mediated growth inhibition of the katG- mutant strain was partially rescued by exogenous catalase treatment. These results indicate that the mechanism by which pyrogallol inhibits the growth and cytotoxicity of V. vulnificus likely involves polyphenol-induced prooxidant damage. Taken together, these results suggest that pyrogallol has potential for development as a new paradigm drug to treat infectious diseases. PMID- 27936081 TI - Comparative Analysis of Fruit Metabolites and Pungency Candidate Genes Expression between Bhut Jolokia and Other Capsicum Species. AB - Bhut jolokia, commonly known as Ghost chili, a native Capsicum species found in North East India was recorded as the naturally occurring hottest chili in the world by the Guinness Book of World Records in 2006. Although few studies have reported variation in pungency content of this particular species, no study till date has reported detailed expression analysis of candidate genes involved in capsaicinoids (pungency) biosynthesis pathway and other fruit metabolites. Therefore, the present study was designed to evaluate the diversity of fruit morphology, fruiting habit, capsaicinoids and other metabolite contents in 136 different genotypes mainly collected from North East India. Significant intra and inter-specific variations for fruit morphological traits, fruiting habits and 65 fruit metabolites were observed in the collected Capsicum germplasm belonging to three Capsicum species i.e., Capsicum chinense (Bhut jolokia, 63 accessions), C. frutescens (17 accessions) and C. annuum (56 accessions). The pungency level, measured in Scoville Heat Unit (SHU) and antioxidant activity measured by 2, 2 diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay showed maximum levels in C. chinense accessions followed by C. frutescens accessions, while C. annuum accessions showed the lowest value for both the traits. The number of different fruit metabolites detected did not vary significantly among the different species but the metabolite such as benzoic acid hydroxyl esters identified in large percentage in majority of C. annuum genotypes was totally absent in the C. chinense genotypes and sparingly present in few genotypes of C. frutescens. Significant correlations were observed between fruit metabolites capsaicin, dihydrocapsaicin, hexadecanoic acid, cyclopentane, alpha-tocopherol and antioxidant activity. Furthermore, comparative expression analysis (through qRT-PCR) of candidate genes involved in capsaicinoid biosynthesis pathway revealed many fold higher expression of majority of the genes in C. chinense compared to C. frutescens and C. annuum suggesting that the possible reason for extremely high pungency might be due to the higher level of candidate gene(s) expression although nucleotide variation in pungency related genes may also be involved in imparting variations in level of pungency. PMID- 27936082 TI - Three Molecular Markers Show No Evidence of Population Genetic Structure in the Gouldian Finch (Erythrura gouldiae). AB - Assessment of genetic diversity and connectivity between regions can inform conservation managers about risk of inbreeding, potential for adaptation and where population boundaries lie. The Gouldian finch (Erythrura gouldiae) is a threatened species in northern Australia, occupying the savannah woodlands of the biogeographically complex monsoon tropics. We present the most comprehensive population genetic analysis of diversity and structure the Gouldian finch using 16 microsatellite markers, mitochondrial control region and 3,389 SNPs from genotyping-by-sequencing. Mitochondrial diversity is compared across three related, co-distributed finches with different conservation threat-statuses. There was no evidence of genetic differentiation across the western part of the range in any of the molecular markers, and haplotype diversity but not richness was lower than a common co-distributed species. Individuals within the panmictic population in the west may be highly dispersive within this wide area, and we urge caution when interpreting anecdotal observations of changes to the distribution and/or flock sizes of Gouldian finch populations as evidence of overall changes to the population size of this species. PMID- 27936083 TI - Effectiveness and Cost-Effectiveness of a Cluster-Randomized Prenatal Lifestyle Counseling Trial: A Seven-Year Follow-Up. AB - There is a link between the pregnancy and its long-term influence on health and susceptibility to future chronic disease both in mother and offspring. The objective was to determine whether individual counseling on physical activity and diet and weight gain at five antenatal visits can prevent type 2 diabetes mellitus (T2DM) and overweight or improve glycemic parameters, among all at-risk mothers and their children. Another objective was to evaluate whether gestational lifestyle intervention was cost-effective as measured with mother's sickness absence and quality-adjusted life years (QALY). This study was a seven-year follow-up study for women, who were enrolled to the antenatal cluster-randomized controlled trial (RCT). Analysis of the outcome included all women whose outcome was available, in addition with subgroup analysis including women adherent to all lifestyle aims. A total of 173 women with their children participated to the study, representing 43% (173/399) of the women who finished the original RCT. Main outcome measures were: T2DM based on medication use or fasting blood glucose or oral glucose tolerance test (OGTT), body mass index (BMI), glycosylated hemoglobin (HbA1c). None of the women were diagnosed to have T2DM. HbA1c or fasting blood glucose differences were not found among mothers or children. Differences in BMI were non-significant among mothers (Intervention 27.3, Usual care 28.1 kg/m2, p = 0.33) and children (I 21.3 vs U 22.5 kg/m2, p = 0.07). Children's BMI was significantly lower among adherent group (I 20.5 vs U 22.5, p = 0.04). The mean total cost per person was 30.6% lower in the intervention group than in the usual care group (I ?2,944 vs. U ?4,243; p = 0.74). Intervention was cost-effective in terms of sickness absence but not in QALY gained i.e. if society is willing to pay additional ?100 per one avoided sickness absence day; there is a 90% probability of the intervention arm to be cost-effective. Long term effectiveness of antenatal lifestyle counseling was not shown, in spite of possible effect on children's BMI. Cost-effectiveness of the intervention in terms of sickness absence may have larger societal impact. PMID- 27936084 TI - Inter-Individual Variability in the Adaptive Responses to Endurance and Sprint Interval Training: A Randomized Crossover Study. AB - The current study examined the adaptive response to both endurance (END) and sprint interval training (SIT) in a group of twenty-one recreationally active adults. All participants completed three weeks (four days/ week) of both END (30 minutes at ~65% VO2peak work rate (WR) and SIT (eight, 20-second intervals at ~170% VO2peak WR separated by 10 seconds of active rest) following a randomized crossover study design with a three-month washout period between training interventions. While a main effect of training was observed for VO2peak, lactate threshold, and submaximal heart rate (HR), considerable variability was observed in the individual responses to both END and SIT. No significant positive relationships were observed between END and SIT for individual changes in any variable. Non-responses were determined using two times the typical error (TE) of measurement for VO2peak (0.107 L/min), lactate threshold (15.7 W), and submaximal HR (10.7bpm). Non-responders in VO2peak, lactate threshold, and submaximal HR were observed following both END and SIT, however, the individual patterns of response differed following END and SIT. Interestingly, all individuals responded in at least one variable when exposed to both END and SIT. These results suggest that the individual response to exercise training is highly variable following different training protocols and that the incidence of non-response to exercise training may be reduced by changing the training stimulus for non-responders to three weeks of END or SIT. PMID- 27936085 TI - Development of Embryonic Market Squid, Doryteuthis opalescens, under Chronic Exposure to Low Environmental pH and [O2]. AB - The market squid, Doryteuthis opalescens, is an important forage species for the inshore ecosystems of the California Current System. Due to increased upwelling and expansion of the oxygen minimum zone in the California Current Ecosystem, the inshore environment is expected to experience lower pH and [O2] conditions in the future, potentially impacting the development of seafloor-attached encapsulated embryos. To understand the consequences of this co-occurring environmental pH and [O2] stress for D. opalescens encapsulated embryos, we performed two laboratory experiments. In Experiment 1, embryo capsules were chronically exposed to a treatment of higher (normal) pH (7.93) and [O2] (242 MUM) or a treatment of low pH (7.57) and [O2] (80 MUM), characteristic of upwelling events and/or La Nina conditions. The low pH and low [O2] treatment extended embryo development duration by 5-7 days; embryos remained at less developed stages more often and had 54.7% smaller statolith area at a given embryo size. Importantly, the embryos that did develop to mature embryonic stages grew to sizes that were similar (non distinct) to those exposed to the high pH and high [O2] treatment. In Experiment 2, we exposed encapsulated embryos to a single stressor, low pH (7.56) or low [O2] (85 MUM), to understand the importance of environmental pH and [O2] rising and falling together for squid embryogenesis. Embryos in the low pH only treatment had smaller yolk reserves and bigger statoliths compared to those in low [O2] only treatment. These results suggest that D. opalescens developmental duration and statolith size are impacted by exposure to environmental [O2] and pH (pCO2) and provide insight into embryo resilience to these effects. PMID- 27936086 TI - Geographical Heterogeneity of Multiple Sclerosis Prevalence in France. AB - INTRODUCTION: Geographical variation in the prevalence of multiple sclerosis (MS) is controversial. Heterogeneity is important to acknowledge to adapt the provision of care within the healthcare system. We aimed to investigate differences in prevalence of MS in departments in the French territory. METHODS: We estimated MS prevalence on October 31, 2004 in 21 administrative departments in France (22% of the metropolitan departments) by using multiple data sources: the main French health insurance systems, neurologist networks devoted to MS and the Technical Information Agency of Hospitalization. We used a spatial Bayesian approach based on estimating the number of MS cases from 2005 and 2008 capture recapture studies to analyze differences in prevalence. RESULTS: The age- and sex standardized prevalence of MS per 100,000 inhabitants ranged from 68.1 (95% credible interval 54.6, 84.4) in Hautes-Pyrenees (southwest France) to 296.5 (258.8, 338.9) in Moselle (northeast France). The greatest prevalence was in the northeast departments, and the other departments showed great variability. DISCUSSION: By combining multiple data sources into a spatial Bayesian model, we found heterogeneity in MS prevalence among the 21 departments of France, some with higher prevalence than anticipated from previous publications. No clear explanation related to health insurance coverage and hospital facilities can be advanced. Population migration, socioeconomic status of the population studied and environmental effects are suspected. PMID- 27936088 TI - A Single-Granule-Level Approach Reveals Ecological Heterogeneity in an Upflow Anaerobic Sludge Blanket Reactor. AB - Upflow anaerobic sludge blanket (UASB) reactor has served as an effective process to treat industrial wastewater such as purified terephthalic acid (PTA) wastewater. For optimal UASB performance, balanced ecological interactions between syntrophs, methanogens, and fermenters are critical. However, much of the interactions remain unclear because UASB have been studied at a "macro"-level perspective of the reactor ecosystem. In reality, such reactors are composed of a suite of granules, each forming individual micro-ecosystems treating wastewater. Thus, typical approaches may be oversimplifying the complexity of the microbial ecology and granular development. To identify critical microbial interactions at both macro- and micro- level ecosystem ecology, we perform community and network analyses on 300 PTA-degrading granules from a lab-scale UASB reactor and two full scale reactors. Based on MiSeq-based 16S rRNA gene sequencing of individual granules, different granule-types co-exist in both full-scale reactors regardless of granule size and reactor sampling depth, suggesting that distinct microbial interactions occur in different granules throughout the reactor. In addition, we identify novel networks of syntrophic metabolic interactions in different granules, perhaps caused by distinct thermodynamic conditions. Moreover, unseen methanogenic relationships (e.g. "Candidatus Aminicenantes" and Methanosaeta) are observed in UASB reactors. In total, we discover unexpected microbial interactions in granular micro-ecosystems supporting UASB ecology and treatment through a unique single-granule level approach. PMID- 27936087 TI - Detection of Placental Proteomes at Different Uterine Positions in Large White and Meishan Gilts on Gestational Day 90. AB - Within-litter uniformity in pigs is a major factor affecting piglet survival and growth performance. We know that Meishan (MS) gilts have higher piglet survival rate than Large White (LW) gilts because their foetal weight is less varied. To understand the molecular basis for placental nutritional transport during the late stages of gestation in LW and MS, we employed the isobaric tags for relative and absolute quantification (iTRAQ) method to investigate alterations in the placental proteomes of LW and MS gilts on gestational day 90. Investigation of foetal weight at different uterine positions revealed that the foetal and placental weights as well as the foetal concentration of glucose were significantly higher in LW gilts positioned towards the utero-tubal junction than in those positioned toward the cervix; however, no such differences were observed in MS gilts, and MS gilts had a greater uniformity in foetal weight on day 90 of gestation. Comparisons of the proteomes between placentas positioned toward the cervix and those positioned toward the utero-tubal junction identified 38 differentially expressed proteins in the two breeds. These proteins play a central role in nutrient transport and metabolism, as well as in transcriptional and translational regulation. Of particular interest is the finding that the placentas of LW gilts showed 14 differential expression of proteins mainly related to lipid transport and energy metabolism (including solute carrier family 27, mitochondrial trifunctional protein, and NADH dehydrogenase [ubiquinone] flavoprotein 2), but only 2 proteins in MS gilts. In contrast, the differentially expressed proteins in MS gilts were primarily involved in transcriptional and translational regulation (such as ribosome-sec61 and 40S ribosomal protein S23), with a few related to glucose and coenzyme transport and metabolism (including glucose transport protein and ferrochelatase). Our results revealed that placental lipid and energy metabolism might play a crucial role in the regulation of foetal weight, based on uterine position in two distinct pig breeds. These findings provide a deeper understanding of placental efficiency that can be utilized to provide a new method to enhance the efficiency of livestock production. PMID- 27936089 TI - Interaction Potency of Single-Walled Carbon Nanotubes with DNAs: A Novel Assay for Assessment of Hazard Risk. AB - Increasing use of single-walled carbon nanotubes (SWCNTs) necessitates a novel method for hazard risk assessment. In this work, we investigated the interaction of several types of commercial SWCNTs with single-stranded (ss) and double stranded (ds) DNA oligonucleotides (20-mer and 20 bp). Based on the results achieved, we proposed a novel assay that employed the DNA interaction potency to assess the hazard risk of SWCNTs. It was found that SWCNTs in different sizes or different batches of the same product number of SWCNTs showed dramatically different potency of interaction with DNAs. In addition, the same SWCNTs also exerted strikingly different interaction potency with ss- versus ds- DNAs. The interaction rates of SWCNTs with DNAs were investigated, which could be utilized as the indicator of potential hazard for acute exposure. Compared to solid SWCNTs, the SWCNTs dispersed in liquid medium (2% sodium cholate solution) exhibited dramatically different interaction potency with DNAs. This indicates that the exposure medium may greatly influence the subsequent toxicity and hazard risk produced by SWCNTs. Based on the findings of dose-dependences and time dependences from the interactions between SWCNTs and DNAs, a new chemistry based assay for hazard risk assessment of nanomaterials including SWCNTs has been presented. PMID- 27936090 TI - Manure Preferences and Postemergence Learning of Two Filth Fly Parasitoids, Spalangia cameroni and Muscidifurax raptor (Hymenoptera: Pteromalidae). AB - The efficiency of host-seeking behavior is crucial to the reproductive performance of female parasitoids. Initially, parasitoids may use chemical information garnered from the microhabitat in which they emerge to locate hosts. Spalangia cameroni and Muscidifurax raptor are commercially available parasitoids of filth flies. Postemergence exposure to a specific manure may provide a way to increase parasitism in specific microhabitats found at livestock facilities upon release. In this study, female parasitoids of both species were exposed to equine manure, bovine manure, or clean pupae. Females from each emergence exposure were tested in a two-choice arena (house fly hosts in bovine manure versus clean pupae, equine manure versus clean pupae, and equine manure versus bovine manure) for progeny production. There was a detectable but small effect of postemergence exposure on S. cameroni, but it was not sufficient to reverse innate preferences. Females consistently produced more progeny in hosts found in any manure over clean pupae, and in equine manure over bovine manure. The effect of postemergence exposure on M. raptor was also detectable but small. Females produced equal numbers of progeny in bovine manure versus clean pupae, as opposed to preferring to oviposit in clean pupae as with all other treatments. Preferences by M. raptor were overall less marked than for S. cameroni; indeed most of the variability observed for this species did not result from the treatment design. Residual host mortality was also detectably altered by exposure in both species, but the effect was small. Thus, postemergence exposure did not consistently and effectively manipulate these parasitoids to producing progeny in different exposure manures, suggesting that microhabitat preferences are largely determined by other factors. PMID- 27936091 TI - Development of Serum Marker Models to Increase Diagnostic Accuracy of Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: The New LINKI Algorithm Compared with Established Algorithms. AB - BACKGROUND AND AIM: Detection of advanced fibrosis (F3-F4) in nonalcoholic fatty liver disease (NAFLD) is important for ascertaining prognosis. Serum markers have been proposed as alternatives to biopsy. We attempted to develop a novel algorithm for detection of advanced fibrosis based on a more efficient combination of serological markers and to compare this with established algorithms. METHODS: We included 158 patients with biopsy-proven NAFLD. Of these, 38 had advanced fibrosis. The following fibrosis algorithms were calculated: NAFLD fibrosis score, BARD, NIKEI, NASH-CRN regression score, APRI, FIB-4, King's score, GUCI, Lok index, Forns score, and ELF. Study population was randomly divided in a training and a validation group. A multiple logistic regression analysis using bootstrapping methods was applied to the training group. Among many variables analyzed age, fasting glucose, hyaluronic acid and AST were included, and a model (LINKI-1) for predicting advanced fibrosis was created. Moreover, these variables were combined with platelet count in a mathematical way exaggerating the opposing effects, and alternative models (LINKI-2) were also created. Models were compared using area under the receiver operator characteristic curves (AUROC). RESULTS: Of established algorithms FIB-4 and King's score had the best diagnostic accuracy with AUROCs 0.84 and 0.83, respectively. Higher accuracy was achieved with the novel LINKI algorithms. AUROCs in the total cohort for LINKI-1 was 0.91 and for LINKI-2 models 0.89. CONCLUSION: The LINKI algorithms for detection of advanced fibrosis in NAFLD showed better accuracy than established algorithms and should be validated in further studies including larger cohorts. PMID- 27936092 TI - The Association between Sexually Transmitted Infections, Length of Service and Other Demographic Factors in the U.S. Military. AB - BACKGROUND: Numerous studies have found higher rates of sexually transmitted infections (STIs) among military personnel than the general population, but the cumulative risk of acquiring STIs throughout an individual's military career has not been described. METHODS: Using ICD-9 diagnosis codes, we analyzed the medical records of 100,005 individuals from all service branches, divided in equal cohorts (n = 6,667) between 1997 and 2011. As women receive frequent STI screening compared to men, these groups were analyzed separately. Incidence rates were calculated for pathogen-specific STIs along with syndromic diagnoses. Descriptive statistics were used to characterize the individuals within each accession year cohort; repeat infections were censored. RESULTS: The total sample included 29,010 females and 70,995 males. The STI incidence rates (per 100 person years) for women and men, respectively, were as follows: chlamydia (3.5 and 0.7), gonorrhea (1.1 and 0.4), HIV (0.04 and 0.07) and syphilis (0.14 and 0.15). During the study period, 22% of women and 3.3% of men received a pathogen-specific STI diagnosis; inclusion of syndromic diagnoses increased STI prevalence to 41% and 5.5%, respectively. In multivariate analyses, factors associated with etiologic and syndromic STIs among women included African American race, younger age and fewer years of education. In the overall sample, increasing number of years of service was associated with an increased likelihood of an STI diagnosis (p<0.001 for trend). CONCLUSION: In this survey of military personnel, we found very high rates of STI acquisition throughout military service, especially among women, demonstrating that STI-related risk is significant and ongoing throughout military service. Lower STI incidence rates among men may represent under diagnosis and demonstrate a need for enhancing male-directed screening and diagnostic interventions. PMID- 27936093 TI - Olfactory Assessment of Competitors to the Nest Site: An Experiment on a Passerine Species. AB - Since most avian species have been considered anosmic or microsmatic, olfaction and associated behavioural patterns have hardly been investigated. Most importantly, empirical data on avian olfaction is not equally distributed among species. Initial investigations focused on species with relatively big olfactory bulbs because they were thought to have better olfactory capabilities. Hence, in this study we tested the ability of house sparrows (Passer domesticus) to use chemical cues as parameters to estimate nest features. House sparrows are a commonly used model species, but their olfactory capabilities have not been studied so far. We offered two different odours to males and females, namely the scent of mouse urine (Mus musculus domesticus), representing a possible competitor and a threat to eggs and hatchlings, and the odour of hay, representing a familiar and innocuous odour. The experiment was performed at the sunset to simulate a first inspection to new possible roosting or nesting sites. Interestingly, males but not females preferred to spend significantly more time in front of the hay odour, than in front of the scent of mouse urine. Our results strengthen the hypothesis that oscines can not only perceive odours but also use olfaction to assess the environment and estimate nest site quality. PMID- 27936094 TI - Lutein Attenuates Both Apoptosis and Autophagy upon Cobalt (II) Chloride-Induced Hypoxia in Rat Muller Cells. AB - Retinal ischemia/reperfusion injury is a common feature of various retinal diseases such as glaucoma and diabetic retinopathy. Lutein, a potent anti oxidant, is used to improve visual function in patients with age-related macular degeneration (AMD). Lutein attenuates apoptosis, oxidative stress and inflammation in animal models of acute retinal ischemia/hypoxia. Here, we further show that lutein improved Muller cell viability and enhanced cell survival upon hypoxia-induced cell death through regulation of intrinsic apoptotic pathway. Moreover, autophagy was activated upon treatment of cobalt (II) chloride, indicating that hypoxic injury not only triggered apoptosis but also autophagy in our in vitro model. Most importantly, we report for the first time that lutein treatment suppressed autophagosome formation after hypoxic insult and lutein administration could inhibit autophagic event after activation of autophagy by a pharmacological approach (rapamycin). Taken together, lutein may have a beneficial role in enhancing glial cell survival after hypoxic injury through regulating both apoptosis and autophagy. PMID- 27936095 TI - Dual Specificity Phosphatase 5 Is Essential for T Cell Survival. AB - The mitogen-activated protein kinase (MAPK) pathway regulates many key cellular processes such as differentiation, apoptosis, and survival. The final proteins in this pathway, ERK1/2, are regulated by dual specificity phosphatase 5 (DUSP5). DUSP5 is a nuclear, inducible phosphatase with high affinity and fidelity for ERK1/2. By regulating the final step in the MAPK signaling cascade, DUSP5 exerts strong regulatory control over a central cellular pathway. Like other DUSPs, DUSP5 plays an important role in immune function. In this study, we have utilized new knockout mouse reagents to explore its function further. We demonstrate that global loss of DUSP5 does not result in any gross phenotypic changes. However, loss of DUSP5 affects memory/effector CD8+ T cell populations in response to acute viral infection. Specifically, Dusp5-/- mice have decreased proportions of short-lived effector cells (SLECs) and increased proportions of memory precursor effector cells (MPECs) in response to infection. Further, we show that this phenotype is T cell intrinsic; a bone marrow chimera model restricting loss of DUSP5 to the CD8+ T cell compartment displays a similar phenotype. Dusp5-/- T cells also display increased proliferation, increased apoptosis, and altered metabolic profiles, suggesting that DUSP5 is a pro-survival protein in T cells. PMID- 27936096 TI - Factors Associated with Disability in Rural Bangladesh: Bangladesh Population Based Diabetes and Eye Study (BPDES). AB - BACKGROUND: To assess factors associated with disability in a rural district of Bangladesh. METHODS: Using a population-based systematic sampling technique, data were collected from 3104 adults aged >= 30 years from the Banshgram union of Narail district. Data collected included an interviewer administered questionnaire to report physical disabilities including impairment that prevents engagement with paid work, visual, hearing, and mobility as well as mental disabilities. Socio-demographic and anthropometric factors including educational attainment and body mass index, as well as clinical factors such as blood pressure, and fasting blood glucose were also collected. Binary and multinomial logistic regression techniques were used to explore the association of various socio-demographic and clinical factors with disability. RESULTS: The mean (SD), minimum and maximum ages of the participants were 51 (12), 30 and 89 years. Of total participants, 65% were female. The prevalence of disability varied from 29.1% for visual impairment (highest) to 16.5% for hearing, 14.7% for movement difficulties and 1.6% (lowest) for any other disability that prevented engagement with paid work. Overall, the prevalence of a single disability was 28.6% and that of two or more disabilities was 14.7%. Older age, gender (female), lower socio economic status (SES), and hypertension were associated with a higher prevalence of most of the disability components. The prevalence of hearing problems (24.5% vs. 13.3%, p<0.001) and movement difficulties (24.9% vs. 13.0%, p<0.001) was significantly higher among lower-income participants than their higher-income counterparts after controlling for age. Prevalence of visual impairment (54.6% vs. 9.2%, p<0.001), hearing (32.2% vs. 6.7%, p<0.001) and movement difficulties (29.2% vs. 5.5%, p<0.001) were significantly higher in people of aged 60 years or older than those aged 30-34 years. After multivariate adjustment, the prevalence of single disability (prevalence risk ratio [PRR] 1.25, 95% CI: 1.09-1.42, p<0.001), and multiple disabilities (PRR 1.41, 95% CI 1.14-1.73, p<0.001) was higher among females than males. The prevalence of single disability and multiple disabilities was respectively 21% (PRR 1.21, 95% CI: 1.02-1.42, p<0.001) and 88% (PRR 1.88, 95% CI: 1.38-2.54, p<0.001) higher among participants with low educational attainment (primary level or less) than those with at least a secondary level of education. CONCLUSIONS: In rural Bangladesh, the prevalence of disability is high. Public health programs should target those of low SES, older age, and female participants and aim to provide necessary supports in order to bridge disability-related inequities. PMID- 27936097 TI - PeTMbase: A Database of Plant Endogenous Target Mimics (eTMs). AB - MicroRNAs (miRNA) are small endogenous RNA molecules, which regulate target gene expression at post-transcriptional level. Besides, miRNA activity can be controlled by a newly discovered regulatory mechanism called endogenous target mimicry (eTM). In target mimicry, eTMs bind to the corresponding miRNAs to block the binding of specific transcript leading to increase mRNA expression. Thus, miRNA-eTM-target-mRNA regulation modules involving a wide range of biological processes; an increasing need for a comprehensive eTM database arose. Except miRSponge with limited number of Arabidopsis eTM data no available database and/or repository was developed and released for plant eTMs yet. Here, we present an online plant eTM database, called PeTMbase (http://petmbase.org), with a highly efficient search tool. To establish the repository a number of identified eTMs was obtained utilizing from high-throughput RNA-sequencing data of 11 plant species. Each transcriptome libraries is first mapped to corresponding plant genome, then long non-coding RNA (lncRNA) transcripts are characterized. Furthermore, additional lncRNAs retrieved from GREENC and PNRD were incorporated into the lncRNA catalog. Then, utilizing the lncRNA and miRNA sources a total of 2,728 eTMs were successfully predicted. Our regularly updated database, PeTMbase, provides high quality information regarding miRNA:eTM modules and will aid functional genomics studies particularly, on miRNA regulatory networks. PMID- 27936098 TI - Analysis of HIV Diversity in HIV-Infected Black Men Who Have Sex with Men (HPTN 061). AB - BACKGROUND: HIV populations often diversify in response to selective pressures, such as the immune response and antiretroviral drug use. We analyzed HIV diversity in Black men who have sex with men who were enrolled in the HIV Prevention Trials Network 061 study. METHODS: A high resolution melting (HRM) diversity assay was used to measure diversity in six regions of the HIV genome: two in gag, one in pol, and three in env. HIV diversity was analyzed for 146 men who were HIV infected at study enrollment, including three with acute infection and 13 with recent infection (identified using a multi-assay algorithm), and for 21 men who seroconverted during the study. HIV diversification was analyzed in a paired analysis for 62 HIV-infected men using plasma samples from the enrollment and 12-month (end of study) visits. RESULTS: Men with acute or recent infection at enrollment and seroconverters had lower median HRM scores (lower HIV diversity) than men with non-recent infection in all six regions analyzed. In univariate analyses, younger age, higher CD4 cell count, and HIV drug resistance were associated with lower median HRM scores in multiple regions; ARV drug detection was marginally associated with lower diversity in the pol region. In multivariate analysis, acute or recent infection (all six regions) and HIV drug resistance (both gag regions) were associated with lower median HRM scores. Diversification in the pol region over 12 months was greater for men with acute or recent infection, higher CD4 cell count, and lower HIV viral load at study enrollment. CONCLUSIONS: HIV diversity was significantly associated with duration of HIV infection, and lower gag diversity was observed in men who had HIV drug resistance. HIV pol diversification was more pronounced in men with acute or recent infection, higher CD4 cell count, and lower HIV viral load. PMID- 27936099 TI - Characterization of Arginase Expression in Glioma-Associated Microglia and Macrophages. AB - Microglia (MG) and macrophages (MPs) represent a significant component of the inflammatory response to gliomas. When activated, MG/MP release a variety of pro inflammatory cytokines, however, they also secrete anti-inflammatory factors that limit their cytotoxic function. The balance between pro and anti-inflammatory functions dictates their antitumor activity. To evaluate potential variations in MG and MP function in gliomas, we isolated these cells (and other Gr1+ cells) from intracranial GL261 murine gliomas by FACS and evaluated their gene expression profiles by microarray analysis. As expected, arginase 1 (Arg1, M2 marker) was highly expressed by tumor-associated Gr1+, MG and MP. However, in contrast to MP and Gr1+ cells that expressed Arg1 shortly after tumor trafficking, Arg1 expression in MG was delayed and occurred in larger tumors. Interestingly, depletion of MPs in tumors did not prevent MG polarization, suggesting direct influence of tumor-specific factors on MG Arg1 upregulation. Finally, Arg1 expression was confirmed in human GBM samples, but most Arg1+ cells were neutrophils and not MPs. These findings confirm variations in tumor MG and MP polarization states and its dependency on tumor microenvironmental factors. PMID- 27936100 TI - A High-Resolution Crystal Structure of a Psychrohalophilic alpha-Carbonic Anhydrase from Photobacterium profundum Reveals a Unique Dimer Interface. AB - Bacterial alpha-carbonic anhydrases (alpha-CA) are zinc containing metalloenzymes that catalyze the rapid interconversion of CO2 to bicarbonate and a proton. We report the first crystal structure of a pyschrohalophilic alpha-CA from a deep sea bacterium, Photobacterium profundum. Size exclusion chromatography of the purified P. profundum alpha-CA (PprCA) reveals that the protein is a heterogeneous mix of monomers and dimers. Furthermore, an "in-gel" carbonic anhydrase activity assay, also known as protonography, revealed two distinct bands corresponding to monomeric and dimeric forms of PprCA that are catalytically active. The crystal structure of PprCA was determined in its native form and reveals a highly conserved "knot-topology" that is characteristic of alpha-CA's. Similar to other bacterial alpha-CA's, PprCA also crystallized as a dimer. Furthermore, dimer interface analysis revealed the presence of a chloride ion (Cl-) in the interface which is unique to PprCA and has not been observed in any other alpha-CA's characterized so far. Molecular dynamics simulation and chloride ion occupancy analysis shows 100% occupancy for the Cl- ion in the dimer interface. Zinc coordinating triple histidine residues, substrate binding hydrophobic patch residues, and the hydrophilic proton wire residues are highly conserved in PprCA and are identical to other well-studied alpha-CA's. PMID- 27936101 TI - Susceptibility to Aminoglycosides and Distribution of aph and aac(3)-XI Genes among Corynebacterium striatum Clinical Isolates. AB - Corynebacterium striatum is an opportunistic pathogen, often multidrug-resistant, which has been associated with serious infections in humans. Aminoglycosides are second-line or complementary antibiotics used for the treatment of Corynebacterium infections. We investigated the susceptibility to six aminoglycosides and the molecular mechanisms involved in aminoglycoside resistance in a collection of 64 Corynebacterium striatum isolated in our laboratory during the period 2005-2009. Antimicrobial susceptibility was determined using E-test. The mechanisms of aminoglycoside resistance were investigated by PCR and sequencing. The 64 C. striatum were assessed for the possibility of clonal spreading by Pulsed-field Gel Electrophoresis (PFGE). Netilmicin and amikacin were active against the 64 C. striatum isolates (MICs90 = 0.38 and 0.5 mg/L, respectively). Twenty-seven of the 64 C. striatum strains showed a MIC90 for kanamycin > 256 mg/L, and 26 out the 27 were positive for the aph(3')-Ic gene. Thirty-six out of our 64 C. striatum were streptomycin resistant, and 23 out of the 36 carried both the aph(3")-Ib and aph(6)-Id genes. The gene aac(3)-XI encoding a new aminoglycoside 3-N acetyl transferase from C. striatum was present in 44 out of the 64 isolates, all of them showing MICs of gentamicin and tobramycin > 1 mg/L. CS4933, a C. striatum showing very low susceptibility to kanamycin and streptomycin, contains an aminoglycoside resistance region that includes the aph(3')-Ic gene, and the tandem of genes aph(3")-Ib and aph(6)-Id. Forty-six major PFGE types were identified among the 64 C. striatum isolates, indicating that they were mainly not clonal. Our results showed that the 64 clinical C. striatum were highly resistant to aminoglycosides and mostly unrelated. PMID- 27936102 TI - AM251 Suppresses Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells. AB - Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells is one of the causative mechanisms of kidney fibrosis. In our study, we screened lipophilic compounds using a lipid library including approximately 200 lipids to identify those that suppressed EMT induced by a transforming growth factor (TGF) beta1 stimulus. Initial screening was performed with the immortalized HK-2 renal tubule epithelial cell line. The most promising compounds were further tested in RPTEC primary renal tubule epithelial cells. We found that the synthetic lipid AM251 suppressed two hallmark events associated with EMT, the upregulation of collagen 1A1 (COL1A1) and downregulation of E-cadherin. Though AM251 is known to act as an antagonist for the cannabinoid receptor type 1 (CB1) and an agonist for the G protein-coupled receptor 55 (GRP55), the suppression of EMT by AM251 was not mediated through either receptor. Microarray analyses revealed that AM251 inhibited induction of several EMT transcription factors such as SNAIL1, which is the key inducer of EMT, and the AP-1 transcription factors FOSB and JUNB. Activation of SMAD2/3 and p38 mitogen-activated protein kinase (MAPK) was inhibited by AM251, with greater inhibition of the latter, indicating that AM251 acted upstream of SMAD/p38 MAPK in the TGF-beta signaling pathway. Our findings regarding the effects of AM251 on the TGF-beta signaling pathway may inform development of a novel therapeutic agent suppressing EMT, thus preventing kidney fibrosis. PMID- 27936103 TI - Washback Effect of University Entrance exams in Applied Mathematics to Social Sciences. AB - Curricular issues of subject Applied Mathematics to Social Sciences are studied in relation to university entrance exams performed in several Spanish regions between 2009-2014. By using quantitative and qualitative analyses, it has been studied how these exams align with curriculum and how they produce a washback on curriculum and teachers' work. Additionally, one questionnaire about teachers' practices has been performed, in order to find out how the exams are influencing teaching methodology development. Main results obtained show that evaluation is producing a bias on the official curriculum, substantially simplifying the specific orientation that should guide applied mathematics. Furthermore, teachers' practices are influenced by the exams, and they usually approach their teaching methodology to the frequent types of exams. Also, slight differences among the teachers lead to distinguish two behavioral subgroups. Results can also be useful in an international context, because of the importance of standardized exit exams in OECD countries. PMID- 27936104 TI - Mechanical Loading Attenuates Radiation-Induced Bone Loss in Bone Marrow Transplanted Mice. AB - Exposure of bone to ionizing radiation, as occurs during radiotherapy for some localized malignancies and blood or bone marrow cancers, as well as during space travel, incites dose-dependent bone morbidity and increased fracture risk. Rapid trabecular and endosteal bone loss reflects acutely increased osteoclastic resorption as well as decreased bone formation due to depletion of osteoprogenitors. Because of this dysregulation of bone turnover, bone's capacity to respond to a mechanical loading stimulus in the aftermath of irradiation is unknown. We employed a mouse model of total body irradiation and bone marrow transplantation simulating treatment of hematologic cancers, hypothesizing that compression loading would attenuate bone loss. Furthermore, we hypothesized that loading would upregulate donor cell presence in loaded tibias due to increased engraftment and proliferation. We lethally irradiated 16 female C57Bl/6J mice at age 16 wks with 10.75 Gy, then IV-injected 20 million GFP(+) total bone marrow cells. That same day, we initiated 3 wks compression loading (1200 cycles 5x/wk, 10 N) in the right tibia of 10 of these mice while 6 mice were irradiated, non mechanically-loaded controls. As anticipated, before-and-after microCT scans demonstrated loss of trabecular bone (-48.2% Tb.BV/TV) and cortical thickness ( 8.3%) at 3 wks following irradiation. However, loaded bones lost 31% less Tb.BV/TV and 8% less cortical thickness (both p<0.001). Loaded bones also had significant increases in trabecular thickness and tissue mineral densities from baseline. Mechanical loading did not affect donor cell engraftment. Importantly, these results demonstrate that both cortical and trabecular bone exposed to high dose therapeutic radiation remain capable of an anabolic response to mechanical loading. These findings inform our management of bone health in cases of radiation exposure. PMID- 27936105 TI - Serogroup and Clonal Characterization of Czech Invasive Neisseria meningitidis Strains Isolated from 1971 to 2015. AB - BACKGROUND: This study presents antigenic and genetic characteristics of Neisseria meningitidis strains recovered from invasive meningococcal disease (IMD) in the Czech Republic in 1971-2015. MATERIAL AND METHODS: A total of 1970 isolates from IMD, referred to the National Reference Laboratory for Meningococcal Infections in 1971-2015, were studied. All isolates were identified and characterized by conventional biochemical and serological tests. Most isolates (82.5%) were characterized by multilocus sequence typing method. RESULTS: In the study period 1971-2015, the leading serogroup was B (52.4%), most often assigned to clonal complexes cc32, cc41/44, cc18, and cc269. A significant percentage of strains were of serogroup C (41.4%), with high clonal homogeneity due to hyperinvasive complex cc11, which played an important role in IMD in the Czech Republic in the mid-1990s. Serogroup Y isolates, mostly assigned to cc23, and isolates of clonally homogeneous serogroup W have also been recovered more often over the last years. CONCLUSION: The incidence of IMD and distribution of serogroups and clonal complexes of N. meningitidis in the Czech Republic varied over time, as can be seen from the long-term monitoring, including molecular surveillance data. Data from the conventional and molecular IMD surveillance are helpful in refining the antimeningococcal vaccination strategy in the Czech Republic. PMID- 27936106 TI - Feasibility of 10-Minute Delayed Hepatocyte Phase Imaging Using a 30 degrees Flip Angle in Gd-EOB-DTPA-Enhanced Liver MRI for the Detection of Hepatocellular Carcinoma in Patients with Chronic Hepatitis or Cirrhosis. AB - OBJECTIVES: To compare 10-minute (min) delayed hepatocyte phase imaging (HPI) using a 30 degrees flip angle (FA) (10m-FA30) and 20-min delayed HPI using a 10 degrees FA (20m-FA10) or 30 degrees FA (20m-FA30) in Gd-EOB-DTPA-enhanced MRI in patients with chronic hepatitis or cirrhosis, in terms of lesion-to-liver contrast-to-noise ratio (CNR) for hepatocellular carcinoma (HCC) and detection sensitivity for focal hepatic lesions (FHLs). MATERIALS AND METHODS: One hundred and four patients with 168 HCCs and 55 benign FHLs who underwent Gd-EOB-DTPA enhanced MRI with 10m-FA30, 20m-FA10, and 20m-FA30 were enrolled. Patients were divided into two groups according to the Child-Pugh classification: group A with chronic hepatitis or Child-Pugh A cirrhosis and group B with Child-Pugh B or C cirrhosis. Lesion-to-liver CNR for HCCs was compared between 10m-FA30 and 20m FA10 or 20m-FA30 for each group. The presence of FHLs was evaluated using a four point scale by two independent reviewers, and the detection sensitivity was analyzed. RESULTS: In group A, the CNR for HCCs (n = 86) on 10m-FA30 (165.8 +/- 99.7) was significantly higher than that on 20m-FA10 (113.4 +/- 71.4) and lower than that of 20m-FA30 (210.2 +/- 129.3). However, there was no significant difference in the sensitivity of FHL detection between 10m-FA30 (mean 95.0% for two reviewers) and 20m-FA10 (94.7%) or 20m-FA30 (94.7%). In group B, the CNR (54.0 +/- 36.4) for HCCs (n = 57) and the sensitivity (94.2%) of FHL detection for 10m-FA30 were significantly higher than those for 20m-FA10 (41.8 +/- 36.4 and 80.8%, respectively) and were not different from those for 20m-FA30 (62.7 +/- 44.4 and 93.3%, respectively). CONCLUSION: The diagnostic performance of 10m-FA30 was similar to or higher than 20m-FA10 or 20m-FA30 in both groups A and B. This finding indicates that 10m-FA30 could replace 20-min delayed HPI regardless of patient liver function and reduce the delay time by 10 minutes. PMID- 27936108 TI - Aligning Metabolic Pathways Exploiting Binary Relation of Reactions. AB - Metabolic pathway alignment has been widely used to find one-to-one and/or one-to many reaction mappings to identify the alternative pathways that have similar functions through different sets of reactions, which has important applications in reconstructing phylogeny and understanding metabolic functions. The existing alignment methods exhaustively search reaction sets, which may become infeasible for large pathways. To address this problem, we present an effective alignment method for accurately extracting reaction mappings between two metabolic pathways. We show that connected relation between reactions can be formalized as binary relation of reactions in metabolic pathways, and the multiplications of zero-one matrices for binary relations of reactions can be accomplished in finite steps. By utilizing the multiplications of zero-one matrices for binary relation of reactions, we efficiently obtain reaction sets in a small number of steps without exhaustive search, and accurately uncover biologically relevant reaction mappings. Furthermore, we introduce a measure of topological similarity of nodes (reactions) by comparing the structural similarity of the k-neighborhood subgraphs of the nodes in aligning metabolic pathways. We employ this similarity metric to improve the accuracy of the alignments. The experimental results on the KEGG database show that when compared with other state-of-the-art methods, in most cases, our method obtains better performance in the node correctness and edge correctness, and the number of the edges of the largest common connected subgraph for one-to-one reaction mappings, and the number of correct one-to-many reaction mappings. Our method is scalable in finding more reaction mappings with better biological relevance in large metabolic pathways. PMID- 27936107 TI - Structural Analysis of Thymidylate Synthase from Kaposi's Sarcoma-Associated Herpesvirus with the Anticancer Drug Raltitrexed. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is a highly infectious human herpesvirus that causes Kaposi's sarcoma. KSHV encodes functional thymidylate synthase, which is a target for anticancer drugs such as raltitrexed or 5 fluorouracil. Thymidylate synthase catalyzes the conversion of 2'-deoxyuridine-5' monophosphate (dUMP) to thymidine-5'-monophosphate (dTMP) using 5,10 methylenetetrahydrofolate (mTHF) as a co-substrate. The crystal structures of thymidylate synthase from KSHV (apo), complexes with dUMP (binary), and complexes with both dUMP and raltitrexed (ternary) were determined at 1.7 A, 2.0 A, and 2.4 A, respectively. While the ternary complex structures of human thymidylate synthase and E. coli thymidylate synthase had a closed conformation, the ternary complex structure of KSHV thymidylate synthase was observed in an open conformation, similar to that of rat thymidylate synthase. The complex structures of KSHV thymidylate synthase did not have a covalent bond between the sulfhydryl group of Cys219 and C6 atom of dUMP, unlike the human thymidylate synthase. The catalytic Cys residue demonstrated a dual conformation in the apo structure, and its sulfhydryl group was oriented toward the C6 atom of dUMP with no covalent bond upon ligand binding in the complex structures. These structural data provide the potential use of antifolates such as raltitrexed as a viral induced anticancer drug and structural basis to design drugs for targeting the thymidylate synthase of KSHV. PMID- 27936109 TI - Predictive Role of the Number of 18F-FDG-Positive Lymph Nodes Detected by PET/CT for Pre-Treatment Evaluation of Locally Advanced Gastric Cancer. AB - OBJECTIVES: The aim of this study was to investigate the predictive value of the numbers of metabolically positive lymph nodes (MPLN) detected by 18F fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in patients with locally advanced gastric cancer (LAGC). METHODS: We retrospectively analyzed the records of 50 patients with LAGC (stage T2-T4) who had undergone pre-operative PET/CT examination and laparotomy (total gastrectomy, n = 11; subtotal gastrectomy, n = 13; distal gastrectomy, n = 22; and bypass with gastrojejunstomy, n = 4). The numbers of MPLN were determined by combining visual observations with semi-quantitative measurements of the maximized standardized uptake value (SUVmax). Performance was investigated in terms of predicting post-surgical overall survival (OS). RESULTS: The median post surgical OS was 32.57 months (range 3.0-94 months). The numbers of MPLN were moderately correlated with the numbers of histological positive LN (r = 0.694, p = 0.001). In univariate analyses, the numbers of MPLN (<= 2 vs. >=3), PET/CT LN (positivity vs. negativity), SUVmax of LN (< 2.8 vs. >= 2.8), TNM stage (I, II vs. III, IV), and surgery type (R0 vs. non-R0) were significantly associated with OS. In multivariate analysis, surgery type (R0 vs. non-R0) and numbers of MPLN (<= 2 vs. >= 3) were both independent factors for poor OS. CONCLUSIONS: This explored study indicates that the number of MPLN could provide additional information for LAGC prognosis. Patients with MPLNs >= 3 may be at the risk of the more bad outcomes, and the further clinical trials are needed. PMID- 27936111 TI - Sediment Properties as Important Predictors of Carbon Storage in Zostera marina Meadows: A Comparison of Four European Areas. AB - Seagrass ecosystems are important natural carbon sinks but their efficiency varies greatly depending on species composition and environmental conditions. What causes this variation is not fully known and could have important implications for management and protection of the seagrass habitat to continue to act as a natural carbon sink. Here, we assessed sedimentary organic carbon in Zostera marina meadows (and adjacent unvegetated sediment) in four distinct areas of Europe (Gullmar Fjord on the Swedish Skagerrak coast, Asko in the Baltic Sea, Sozopol in the Black Sea and Ria Formosa in southern Portugal) down to ~35 cm depth. We also tested how sedimentary organic carbon in Z. marina meadows relates to different sediment characteristics, a range of seagrass-associated variables and water depth. The seagrass carbon storage varied greatly among areas, with an average organic carbon content ranging from 2.79 +/- 0.50% in the Gullmar Fjord to 0.17 +/- 0.02% in the area of Sozopol. We found that a high proportion of fine grain size, high porosity and low density of the sediment is strongly related to high carbon content in Z. marina sediment. We suggest that sediment properties should be included as an important factor when evaluating high priority areas in management of Z. marina generated carbon sinks. PMID- 27936110 TI - Women's Perceived Reasons for Their Excessive Postpartum Weight Retention: A Qualitative Interview Study. AB - INTRODUCTION: Obesity in Sweden has doubled to 14% over the last 20 years. New strategies for treatment and prevention are needed. Excessive gestational weight gain has been found to contribute substantially to obesity, and there is a consistent association between postpartum weight retention and obesity later in life. We aimed to explore what factors women perceive as reasons for having substantial postpartum weight retention, to identify areas for new and improved interventions. METHODS: Qualitative interview study (semi-structured) using an emergent design. Fifteen women, with a postpartum weight retention >= 10 kg, were interviewed by a trained cognitive therapist. Eight women had pre-pregnancy BMI below 30 kg/m2. Interviews were transcribed verbatim and data analysed using inductive manifest content analysis. Salient text passages were extracted, shortened, coded and clustered into categories. RESULTS: Participants reported no knowledge of current gestational weight gain recommendations or of risks for adverse pregnancy outcomes with excessive weight gain or postpartum weight retention. Excessive eating emerged as a common strategy to provide relief of psychological, emotional and physical discomfort, such as depression and morning sickness. Women perceived medical staff as being unconcerned about weight, and postpartum weight loss support was scarce or absent. Some women reported eating more due to a belief that breastfeeding would automatically lead to weight loss. CONCLUSION: There is a need to raise awareness about risks with unhealthy gestational weight development and postpartum weight retention in women of childbearing age. The common strategy to cope with psychological, emotional or physical discomfort by eating is an important factor to target with intervention. The postpartum year is a neglected period where additional follow-up on weight and weight loss support is strongly indicated. PMID- 27936112 TI - Genome-Wide Association of Heroin Dependence in Han Chinese. AB - Drug addiction is a costly and recurring healthcare problem, necessitating a need to understand risk factors and mechanisms of addiction, and to identify new biomarkers. To date, genome-wide association studies (GWAS) for heroin addiction have been limited; moreover they have been restricted to examining samples of European and African-American origin due to difficulty of recruiting samples from other populations. This is the first study to test a Han Chinese population; we performed a GWAS on a homogeneous sample of 370 Han Chinese subjects diagnosed with heroin dependence using the DSM-IV criteria and 134 ethnically matched controls. Analysis using the diagnostic criteria of heroin dependence yielded suggestive evidence for association between variants in the genes CCDC42 (coiled coil domain 42; p = 2.8x10-7) and BRSK2 (BR serine/threonine 2; p = 4.110-6). In addition, we found evidence for risk variants within the ARHGEF10 (Rho guanine nucleotide exchange factor 10) gene on chromosome 8 and variants in a region on chromosome 20q13, which is gene-poor but has a concentration of mRNAs and predicted miRNAs. Gene-based association analysis identified genome-wide significant association between variants in CCDC42 and heroin addiction. Additionally, when we investigated shared risk variants between heroin addiction and risk of other addiction-related and psychiatric phenotypes using polygenic risk scores, we found a suggestive relationship with variants predicting tobacco addiction, and a significant relationship with variants predicting schizophrenia. Our genome wide association study of heroin dependence provides data in a novel sample, with functionally plausible results and evidence of genetic data of value to the field. PMID- 27936113 TI - Preoperative CSF Melatonin Concentrations and the Occurrence of Delirium in Older Hip Fracture Patients: A Preliminary Study. AB - BACKGROUND: Delirium is characterized by disturbances in circadian rhythm. Melatonin regulates our circadian rhythm. Our aim was to compare preoperative cerebrospinal fluid (CSF) melatonin levels in patients with and without postoperative delirium. METHODS: Prospective cohort study with hip fracture patients >= 65 years who were acutely admitted to the hospital for surgical treatment and received spinal anaesthesia. CSF was collected after cannulation, before administering anaesthetics. Melatonin was measured by radioimmunoassay (RIA). Data on delirium was obtained from medical and nursing records. Nurses screened every shift for delirium using the Delirium Observation Screening Scale (DOSS). If the DOSS was >=3, a psychiatrist was consulted to diagnose possible delirium using the DSM-IV criteria. At admission, demographic data, medical history, and information on functional and cognitive status was obtained. RESULTS: Seventy-six patients met the inclusion criteria. Sixty patients were included in the analysis. Main reasons for exclusion were technical difficulties, insufficient CSF or exogenous melatonin use. Thirteen patients (21.7%) experienced delirium during hospitalisation. Baseline characteristics did not differ between patients with and without postoperative delirium. In patients with and without postoperative delirium melatonin levels were 12.88 pg/ml (SD 6.3) and 11.72 pg/ml (SD 4.5) respectively, p-value 0.47. No differences between patients with and without delirium were found in mean melatonin levels in analyses stratified for cognitive impairment or age. CONCLUSION: Preoperative CSF melatonin levels did not differ between patients with and without postoperative delirium. This suggests that, if disturbances in melatonin secretion occur, these might occur after surgery due to postoperative inflammation. PMID- 27936115 TI - Long-Term Changes in Refractive Error and Clinical Evaluation in Partially Accommodative Esotropia after Surgery. AB - We investigate the changes in refractive error and clinical evaluation in partially accommodative esotropia(PAET) after surgery. A total of 68 patients PAET who received at least 2 years of follow-up after surgery were enrolled in this study. We performed a retrospective study in patients who underwent unilateral or bilateral medial rectus recession for a non-accommodative component of PAET between January 2005 and March 2013. Patients were divided into groups according to the presence of dominancy (dominant, non-dominant, alternative eye), and presence of amblyopia (amblyopic, fellow, normal eye). Changes and changing pattern in SE refractive error were analyzed in all patients and compared between groups. Patients were divided into two groups, those weaned off of hyperopic glasses and those who continued using them, then factors that significantly influenced the continued use of glasses were analyzed. The changes and changing pattern in SE refractive error according to time after operation and presence of amblyopia or dominancy. The mean length of follow-up was 4.89+/-1.74 years after surgery and the mean change in SE refractive error rate per year was -0.284+/ 0.411 diopters (D). The pattern of changes in the mean SE refractive error for those with dominant, non-dominant, and alternative eyes was not significantly different (p = 0.292). The pattern of changes in the mean SE refractive error for those with amblyopic, fellow, and normal eyes was significantly different (p = 0.0002). Patients were successfully weaned off of hyperopic glasses at an average age of 9.41+/-2.74 years. The average SE refractive error in the group weaned off of hyperopic glasses was significantly lower than that in the group maintained on hyperopic glasses (p = 0.0002). The change of SE refractive error in amblyopic eyes decreased less than that in fellow or normal eyes, which may be correlated with the presence of amblyopia. Patients with a smaller esodeviated angle without hyperopic correction, a lower degree of hyperopia, and who were older at the time of disease onset were discontinued from hyperopic glasses sooner after surgery. PMID- 27936114 TI - Long-Circulating Curcumin-Loaded Liposome Formulations with High Incorporation Efficiency, Stability and Anticancer Activity towards Pancreatic Adenocarcinoma Cell Lines In Vitro. AB - The incorporation of hydrophobic drugs into liposomes improve their bioavailability and leads to increased stability and anticancer activity, along with decreased drug toxicity. Curcumin (Cur) is a natural polyphenol compound with a potent anticancer activity in pancreatic adenocarcinoma (PA). In the present study, different types of Cur-loaded liposomal formulations were prepared and characterized in terms of size, shape, zeta potential, optimal drug-to-lipid ratio and stability at 4 degrees C, 37 degrees C; and in human plasma in vitro. The best formulation in terms of these parameters was PEGylated, cholesterol-free formulation based upon hydrogenated soya PC (HSPC:DSPE-PEG2000:Cur, termed H5), which had a 0.05/10 molar ratio of drug-to-lipid, was found to be stable and had a 96% Cur incorporation efficiency. All Cur-loaded liposomal formulations had potent anticancer activity on the PA cancer cell lines AsPC-1 and BxPC-3, and were less toxic to a normal cell line (NHDF). Furthermore, apoptosis-induction induced by Cur in PA cells was associated with morphological changes including cell shrinkage, cytoplasmic blebbing, irregularity in shape and the externalization of cell membrane phosphatidylserine, which was preceded by an increase in intracellular reactive oxygen species (ROS) generation and caspase 3/7 activation. Because the liposomal formulations tested here, especially the H5 variant which exhibited slow release of the Cur in the human plasma test, the formulation may be stable enough to facilitate the accumulation of pharmacologically active amounts of Cur in target cancer tissue by EPR. Therefore, our formulations could serve as a promising therapeutic approach for pancreatic cancer and other cancers. PMID- 27936116 TI - Using the Amino Acid Network to Modulate the Hydrolytic Activity of beta Glycosidases. AB - The active site residues in GH1 beta-glycosidases are compartmentalized into 3 functional regions, involved in catalysis or binding of glycone and aglycone motifs from substrate. However, it still remains unclear how residues outside the active site modulate the enzymatic activity. To tackle this question, we solved the crystal structure of the GH1 beta-glycosidase from Spodoptera frugiperda (Sfbetagly) to systematically map its residue contact network and correlate effects of mutations within and outside the active site. External mutations neighbouring the functional residues involved in catalysis and glycone-binding are deleterious, whereas mutations neighbouring the aglycone-binding site are less detrimental or even beneficial. The large dataset of new and previously characterized Sfbetagly mutants supports that external perturbations are coherently transmitted to active site residues possibly through contacts and specifically disturb functional regions they interact to, reproducing the effects observed for direct mutations of functional residues. This allowed us to suggest that positions related to the aglycone-binding site are preferential targets for introduction of mutations aiming to further improve the hydrolytic activity of beta-glycosidases. PMID- 27936117 TI - No Modulation of Visual Cortex Excitability by Transcranial Direct Current Stimulation. AB - Measuring phosphene thresholds (PTs) is often used to investigate changes in the excitability of the human visual cortex through different brain stimulation methods like repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS). In several studies, PT increase or decrease has been shown after rTMS or tDCS application. Recently, using PT measurements we showed that the state of the neurons in the visual cortex after rTMS might have an influence on the modulatory effects of stimulation. In the present study we aimed to investigate whether visual cortex activity following stimulation influences the modulatory effects of tDCS as well. In a between-group design, anodal or cathodal tDCS was applied to the visual cortex twice per subject, with either high or low visual demand following stimulation. We observed no modulation of PT neither directly following both anodal and cathodal tDCS nor following the visual demand periods. We rather found high inter-individual variability in the response to tDCS, and intra-individual reliability in the direction of modulation was observed for cathodal tDCS only. Thus, our results do not confirm the modulatory effects of tDCS on visual cortex excitability published previously. Moreover, they support the confirmation that tDCS effects have little reliability on varied TMS outcome measurements. PMID- 27936118 TI - Challenges in Evaluating the Severity of Fibropapillomatosis: A Proposal for Objective Index and Score System for Green Sea Turtles (Chelonia mydas) in Brazil. AB - Fibropapillomatosis (FP) is a neoplastic disease that affects marine turtles worldwide, especially green sea turtles (Chelonia mydas). FP tumors can develop on the body surface of marine turtles and also internally in the oral cavity and viscera. Depending on their quantity, size and anatomical distribution, these tumors can interfere with hydrodynamics and the ability to feed, hence scoring systems have been proposed in an attempt to quantify the clinical manifestation of FP. In order to establish a new scoring system adapted to geographic regions, we examined 214 juvenile green sea turtles with FP caught or rescued at Brazilian feeding areas, counted their 7466 tumors and classified them in relation to their size and anatomical distribution. The patterns in quantity, size and distribution of tumors revealed interesting aspects in the clinical manifestation of FP in specimens studied in Brazil, and that FP scoring systems developed for other areas might not perform adequately when applied to sea turtles on the Southwest Atlantic Ocean. We therefore propose a novel method to evaluate the clinical manifestation of FP: fibropapillomatosis index (FPI) that provides the Southwest Atlantic fibropapillomatosis score (FPSSWA). In combination, these indexing and scoring systems allow for a more objective, rapid and detailed evaluation of the severity of FP in green sea turtles. While primarily designed for the clinical manifestation of FP currently witnessed in our dataset, this index and the score system can be adapted for other areas and compare the characteristics of the disease across regions. In conclusion, scoring systems to classify the severity of FP can assist our understanding on the environmental factors that modulate its development and its impacts on the individual and population health of green sea turtles. PMID- 27936119 TI - Anti-TNF-alpha Drugs Differently Affect the TNFalpha-sTNFR System and Monocyte Subsets in Patients with Psoriasis. AB - TNF-alpha has a central role in the development and maintenance of psoriatic plaques, and its serum levels correlate with disease activity. Anti-TNF-alpha drugs are, however, ineffective in a relevant percentage of patients for reasons that are currently unknown. To understand whether the response to anti-TNF-alpha drugs is influenced by the production of anti-drug antibodies or by the modulation of the TNFalpha-TNFalpha receptor system, and to identify changes in monocyte phenotype and activity, we analysed 119 psoriatic patients who either responded or did not respond to different anti-TNF-alpha therapies (adalimumab, etanercept or infliximab), and measured plasma levels of TNF-alpha, TNF-alpha soluble receptors, drug and anti-drug antibodies. Moreover, we analyzed the production of TNF-alpha and TNF-alpha soluble receptors by peripheral blood mononuclear cells (PBMCs), and characterized different monocyte populations. We found that: i) the drug levels varied between responders and non-responders; ii) anti-infliximab antibodies were present in 15% of infliximab-treated patients, while anti-etanercept or anti-adalimumab antibodies were never detected; iii) plasma TNF-alpha levels were higher in patients treated with etanercept compared to patients treated with adalimumab or infliximab; iv) PBMCs from patients responding to adalimumab and etanercept produced more TNF-alpha and sTNFRII in vitro than patients responding to infliximab; v) PBMCs from patients not responding to infliximab produce higher levels of TNF-alpha and sTNFRII than patients responding to infliximab; vi) anti- TNF-alpha drugs significantly altered monocyte subsets. A complex remodelling of the TNFalpha-TNFalpha receptor system thus takes place in patients treated with anti-TNF-alpha drugs, that involves either the production of anti-drug antibodies or the modulation of monocyte phenotype or inflammatory activity. PMID- 27936120 TI - Sweat Facilitated Amino Acid Losses in Male Athletes during Exercise at 32-34 degrees C. AB - Sweat contains amino acids and electrolytes derived from plasma and athletes can lose 1-2L of sweat per hour during exercise. Sweat may also contain contributions of amino acids as well as urea, sodium and potassium from the natural moisturizing factors (NMF) produced in the stratum corneum. In preliminary experiments, one participant was tested on three separate occasions to compare sweat composition with surface water washings from the same area of skin to assess contributions from NMF. Two participants performed a 40 minute self-paced cycle session with sweat collected from cleansed skin at regular intervals to assess the contributions to the sweat load from NMF over the period of exercise. The main study investigated sweat amino acid composition collected from nineteen male athletes following standardised endurance exercise regimes at 32-34 degrees C and 20-30% RH. Plasma was also collected from ten of the athletes to compare sweat and plasma composition of amino acids. The amino acid profiles of the skin washings were similar to the sweat, suggesting that the NMF could contribute certain amino acids into sweat. Since the sweat collected from athletes contained some amino acid contributions from the skin, this fluid was subsequently referred to as "faux" sweat. Samples taken over 40 minutes of exercise showed that these contributions diminished over time and were minimal at 35 minutes. In the main study, the faux sweat samples collected from the athletes with minimal NMF contributions, were characterised by relatively high levels of serine, histidine, ornithine, glycine and alanine compared with the corresponding levels measured in the plasma. Aspartic acid was detected in faux sweat but not in the plasma. Glutamine and proline were lower in the faux sweat than plasma in all the athletes. Three phenotypic groups of athletes were defined based on faux sweat volumes and composition profiles of amino acids with varying relative abundances of histidine, serine, glycine and ornithine. It was concluded that for some individuals, faux sweat resulting from exercise at 32-34 degrees C and 20-30% RH posed a potentially significant source of amino acid loss. PMID- 27936121 TI - Impact of Reclassification on Thyroid Nodules with Architectural Atypia: From Non Invasive Encapsulated Follicular Variant Papillary Thyroid Carcinomas to Non Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features. AB - BACKGROUND: The follicular variant of papillary thyroid cancer (FVPTC), especially the encapsulated non-invasive subtype, is a controversial entity. Recent study suggested using 'non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)' for these indolent carcinomas. We evaluated the impact of reclassification from non-invasive encapsulated FVPTCs (EFVPTCs) to NIFTPs in the diagnosis of thyroid nodules with architectural atypia. METHODS: We reviewed 1301 thyroid nodules with architectural atypia in core needle biopsy (CNB) specimens obtained from March 2012 to February 2013. Nodules were classified into atypia of undetermined significance with architectural atypia (AUS-A, 984, 76%) or follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN, 317, 24%). Among them, diagnostic surgery was performed in 384 nodules (30%). RESULTS: In total, 160 nodules (42%) presented final malignant diagnoses including 39 non-invasive encapsulated FVPTCs (10%). The malignancy rate was estimated to be 7-35% in AUS-A nodules and 28-49% in FN/SFN nodules. After reclassification, the malignancy rate was much decreased and estimated to be 5-24% in AUS-A nodules, and 23-39% in FN/SFN nodules. Thyroid nodules with final malignant diagnoses were significantly more likely to have a FN/SFN CNB diagnosis, malignant US features and concomitant nuclear atypia in CNB specimens. However, these factors could not differentiate NIFTPs from other malignancies. CONCLUSIONS: After reclassification of non-invasive EFVPTCs to NIFTPs, the malignancy rate of thyroid nodules with architectural atypia in CNB specimens was decreased. However, there were no preoperative factors differentiating other malignancies from NIFTPs. The presence of malignant US features or concomitant nuclear atypia might help clinicians deciding diagnostic surgery but, these features also might indicate NIFTPs. PMID- 27936123 TI - Correction: Myosin Light Chain Kinase (MLCK) Gene Influences Exercise Induced Muscle Damage during a Competitive Marathon. AB - [This corrects the article DOI: 10.1371/journal.pone.0160053.]. PMID- 27936122 TI - Association of Odor Thresholds and Responses in Cerebral Blood Flow of the Prefrontal Area during Olfactory Stimulation in Patients with Multiple Chemical Sensitivity. AB - Multiple chemical sensitivity (MCS) is a disorder characterized by nonspecific and recurrent symptoms from various organ systems associated with exposure to low levels of chemicals. Patients with MCS process odors differently than controls do. Previously, we suggested that this odor processing was associated with increased regional cerebral blood flow (rCBF) in the prefrontal area during olfactory stimulation using near-infrared spectroscopic (NIRS) imaging. The aim of this study was to investigate the association of odor thresholds and changes in rCBF during olfactory stimulation at odor threshold levels in patients with MCS. We investigated changes in the prefrontal area using NIRS imaging and a T&T olfactometer during olfactory stimulation with two different odorants (sweet and fecal) at three concentrations (zero, odor recognition threshold, and normal perceived odor level) in 10 patients with MCS and six controls. The T&T olfactometer threshold test and subjective assessment of irritating and hedonic odors were also performed. The results indicated that the scores for both unpleasant and pungent odors were significantly higher for those for sweet odors at the normal perceived level in patients with MCS than in controls. The brain responses at the recognition threshold (fecal odor) and normal perceived levels (sweet and fecal odors) were stronger in patients with MCS than in controls. However, significant differences in the odor detection and recognition thresholds and odor intensity score between the two groups were not observed. These brain responses may involve cognitive and memory processing systems during past exposure to chemicals. Further research regarding the cognitive features of sensory perception and memory due to past exposure to chemicals and their associations with MCS symptoms is needed. PMID- 27936124 TI - Low Serum Levels of Vitamins A, D, and E Are Associated with Recurrent Respiratory Tract Infections in Children Living in Northern China: A Case Control Study. AB - BACKGROUND: This study aimed to investigate the association of serum concentrations of vitamin A, D, and E with recurrent respiratory tract infections (RRTIs). METHODS: A total of 1200 children aged at 0.5-14 years were selected via a face-to-face survey in Harbin, China. Among the participants, 600 children with RRTIs comprised the symptomatic group (RRTI group), whereas 600 healthy children were used as controls (control group). Blood samples were collected to measure serum levels of vitamins A and E by HPLC; the serum level of 25 hydroxycholecalciferol (25(OH)D), was measured by HPLC-MS/MS. RESULTS: Serum levels of vitamins A and E, as well as 25(OH)D, were significantly lower in the RRTI group than the control group. The conditional logistic regression model and the receiver-operating characteristic curve showed that the insufficiency or deficiency of vitamins A, D, and E was positively correlated with RRTI occurrence (p < 0.05). CONCLUSIONS: Low serum concentrations of vitamins A, D, and E were associated with RRTIs in children from northern China. PMID- 27936125 TI - Automatic Coronary Artery Calcium Scoring on Radiotherapy Planning CT Scans of Breast Cancer Patients: Reproducibility and Association with Traditional Cardiovascular Risk Factors. AB - OBJECTIVES: Coronary artery calcium (CAC) is a strong and independent predictor of cardiovascular disease (CVD) risk. This study assesses reproducibility of automatic CAC scoring on radiotherapy planning computed tomography (CT) scans of breast cancer patients, and examines its association with traditional cardiovascular risk factors. METHODS: This study included 561 breast cancer patients undergoing radiotherapy between 2013 and 2015. CAC was automatically scored with an algorithm using supervised pattern recognition, expressed as Agatston scores and categorized into five categories (0, 1-10, 11-100, 101-400, >400). Reproducibility between automatic and manual expert scoring was assessed in 79 patients with automatically determined CAC above zero and 84 randomly selected patients without automatically determined CAC. Interscan reproducibility of automatic scoring was assessed in 294 patients having received two scans (82% on the same day). Association between CAC and CVD risk factors was assessed in 36 patients with CAC scores >100, 72 randomly selected patients with scores 1-100, and 72 randomly selected patients without CAC. Reliability was assessed with linearly weighted kappa and agreement with proportional agreement. RESULTS: 134 out of 561 (24%) patients had a CAC score above zero. Reliability of CVD risk categorization between automatic and manual scoring was 0.80 (95% Confidence Interval (CI): 0.74-0.87), and slightly higher for scans with breath-hold. Agreement was 0.79 (95% CI: 0.72-0.85). Interscan reliability was 0.61 (95% CI: 0.50-0.72) with an agreement of 0.84 (95% CI: 0.80-0.89). Ten out of 36 (27.8%) patients with CAC scores above 100 did not have other cardiovascular risk factors. CONCLUSIONS: Automatic CAC scoring on radiotherapy planning CT scans is a reliable method to assess CVD risk based on Agatston scores. One in four breast cancer patients planned for radiotherapy have elevated CAC score. One in three patients with high CAC scores don't have other CVD risk factors and wouldn't have been identified as high risk. PMID- 27936126 TI - The NS4A Cofactor Dependent Enhancement of HCV NS3 Protease Activity Correlates with a 4D Geometrical Measure of the Catalytic Triad Region. AB - We are developing a 4D computational methodology, based on 3D structure modeling and molecular dynamics simulation, to analyze the active site of HCV NS3 proteases, in relation to their catalytic activity. In our previous work, the 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) yielded divergent, gradual and genotype-dependent, 4D conformational instability measures, which strongly correlate with the known disparate catalytic activities among genotypes. Here, the correlation of our 4D geometrical measure is extended to intra-genotypic alterations in NS3 protease activity, due to sequence variations in the NS4A activating cofactor. The correlation between the 4D measure and the enzymatic activity is qualitatively evident, which further validates our methodology, leading to the development of an accurate quantitative metric to predict protease activity in silico. The results suggest plausible "communication" pathways for conformational propagation from the activation subunit (the NS4A cofactor binding site) to the catalytic subunit (the catalytic triad). The results also strongly suggest that the well-sampled (via convergence quantification) structural dynamics are more connected to the divergent catalytic activity observed in HCV NS3 proteases than to rigid structures. The method could also be applicable to predict patients' responses to interferon therapy and better understand the innate interferon activation pathway. PMID- 27936127 TI - Interactions between Thermal Acclimation, Growth Rate, and Phylogeny Influence Prochlorococcus Elemental Stoichiometry. AB - Variability in plankton elemental requirements can be important for global ocean biogeochemistry but we currently have a limited understanding of how ocean temperature influences the plankton C/N/P ratio. Multiple studies have put forward a 'translation-compensation' hypothesis to describe the positive relationship between temperature and plankton N/P or C/P as cells should have lower demand for P-rich ribosomes and associated depressed QP when growing at higher temperature. However, temperature affects many cellular processes beyond translation with unknown outcomes on cellular elemental composition. In addition, the impact of temperature on growth and elemental composition of phytoplankton is likely modulated by the life history and growth rate of the organism. To test the direct and indirect (via growth rate changes) effect of temperature, we here analyzed the elemental composition and ratios in six strains affiliated with the globally abundant marine Cyanobacteria Prochlorococcus. We found that temperature had a significant positive effect on the carbon and nitrogen cell quota, whereas no clear trend was observed for the phosphorus cell quota. The effect on N/P and C/P were marginally significantly positive across Prochlorococcus. The elemental composition and ratios of individual strains were also affected but we found complex interactions between the strain identity, temperature, and growth rate in controlling the individual elemental ratios in Prochlorococcus and no common trends emerged. Thus, the observations presented here does not support the 'translation-compensation' theory and instead suggest unique cellular elemental effects as a result of rising temperature among closely related phytoplankton lineages. Thus, the biodiversity context should be considered when predicting future elemental ratios and how cycles of carbon, nitrogen, and phosphorus may change in a future ocean. PMID- 27936130 TI - Angiogenic proteins, placental weight and perinatal outcomes among pregnant women in Tanzania. AB - INTRODUCTION: Placental vascular development, and ultimately placental weight, is essential to healthy fetal development. Here, we examined placental weight in a cohort of Tanzanian women in association with angiogenic proteins known to regulate placental vascular development and perinatal outcomes. METHODS: A total of n = 6579 women with recorded placental weight were included in this study. The relative risk of adverse perinatal outcomes (Apgar score, death, asphyxia, respiratory distress, seizures, pneumonia and sepsis) was compared between placental weight in the bottom and top 10th percentiles. We quantified angiogenic mediators (Ang-1, Ang-2, VEGF, PGF and sFlt-1) in plasma samples (n = 901) collected between 12 to 27 weeks of pregnancy using ELISA and assessed the relative risk of placental weight in the bottom and top 10th percentiles by protein levels in quartiles. RESULTS: Women with Ang-2 levels in the highest quartile had an increased relative risk of placental weight in the bottom 10th percentile (RR = 1.45 (1.10, 1.91), p = 0.01). Women with VEGF-A (RR = 0.73 (0.56, 0.96), p = 0.05) and PGF (RR = 0.58 (0.44, 0.72), p = 0.002) in the highest quartile had a reduced relative risk of placental weight in the bottom 10th percentile. Low placental weight (in bottom 10th percentile) was associated with an increased relative risk of Apgar score of <7 at 1 minute (RR = 2.31 (1.70, 3.13), p = 0.001), at 5 minutes (RR = 3.53 (2.34, 5.33), p = 0.001), neonatal death (RR = 5.02 (3.61, 7.00), p = 0.001), respiratory distress (RR = 4.80(1.71, 13.45), p = 0.001), and seizures (RR = 4.18 (1.16, 15.02), p = 0.03). DISCUSSION: The association between low placental weight and risk of adverse perinatal outcomes in this cohort suggests that placental weight could serve as a useful indicator, providing additional insight into high-risk pregnancies and identifying neonates that may require additional monitoring and follow-up. PMID- 27936128 TI - Crystal Structure of the Streptomyces coelicolor Sortase E1 Transpeptidase Provides Insight into the Binding Mode of the Novel Class E Sorting Signal. AB - Many species of Gram-positive bacteria use sortase transpeptidases to covalently affix proteins to their cell wall or to assemble pili. Sortase-displayed proteins perform critical and diverse functions for cell survival, including cell adhesion, nutrient acquisition, and morphological development, among others. Based on their amino acid sequences, there are at least six types of sortases (class A to F enzymes); however, class E enzymes have not been extensively studied. Class E sortases are used by soil and freshwater-dwelling Actinobacteria to display proteins that contain a non-canonical LAXTG sorting signal, which differs from 90% of known sorting signals by substitution of alanine for proline. Here we report the first crystal structure of a class E sortase, the 1.93 A resolution structure of the SrtE1 enzyme from Streptomyces coelicolor. The active site is bound to a tripeptide, providing insight into the mechanism of substrate binding. SrtE1 possesses beta3/beta4 and beta6/beta7 active site loops that contact the LAXTG substrate and are structurally distinct from other classes. We propose that SrtE1 and other class E sortases employ a conserved tyrosine residue within their beta3/beta4 loop to recognize the amide nitrogen of alanine at position P3 of the sorting signal through a hydrogen bond, as seen here. Incapability of hydrogen-bonding with canonical proline-containing sorting signals likely contributes to class E substrate specificity. Furthermore, we demonstrate that surface anchoring of proteins involved in aerial hyphae formation requires an N-terminal segment in SrtE1 that is presumably positioned within the cytoplasm. Combined, our results reveal unique features within class E enzymes that enable them to recognize distinct sorting signals, and could facilitate the development of substrate-based inhibitors of this important enzyme family. PMID- 27936129 TI - Characteristics of Differently Located Colorectal Cancers Support Proximal and Distal Classification: A Population-Based Study of 57,847 Patients. AB - BACKGROUND: It has been suggested that colorectal cancer be regarded as several subgroups defined according to tumor location rather than as a single entity. The current study aimed to identify the most useful method for grouping colorectal cancer by tumor location according to both baseline and survival characteristics. METHODS: Cases of pathologically confirmed colorectal adenocarcinoma diagnosed from 2000 to 2012 were identified from the Surveillance, Epidemiology, and End Results database and categorized into three groups: right colon cancer (RCC), left colon cancer (LCC), and rectal cancer (ReC). Adjusted hazard ratios for known predictors of disease-specific survival (DSS) in colorectal cancer were obtained using a Cox proportional hazards regression model. RESULTS: The study included 57847 patients: 43.5% with RCC, 37.7% with LCC, and 18.8% with ReC. Compared with LCC and ReC, RCC was more likely to affect old patients and women, and to be at advanced stage, poorly differentiated or un-differentiated, and mucinous. Patients with LCC or ReC had better DSS than those with RCC in subgroups including stage III or IV disease, age <=70 years and non-mucinous adenocarcinoma. Conversely, patients with LCC or ReC had worse DSS than those with RCC in subgroups including age ?70 years and mucinous adenocarcinoma. CONCLUSIONS: RCC differed from both LCC and ReC in several clinicopathologic characteristics and in DSS. It seems reasonable to group colorectal cancer into right-sided (i.e., proximal) and left-sided (i.e., distal) ones. PMID- 27936132 TI - Neighbourhood Poverty, Work Commitment and Unemployment in Early Adulthood: A Longitudinal Study into the Moderating Effect of Personality. AB - We studied how personality moderates the effect of neighbourhood disadvantage on work commitment and unemployment in early adulthood. Using a personality typology of resilients, overcontrollers, and undercontrollers, we hypothesised that the association between neighbourhood poverty and both work commitment and unemployment would be stronger for overcontrollers and undercontrollers than for resilients. We used longitudinal data (N = 249) to test whether the length of exposure to neighbourhood poverty between age 16 and 21 predicts work commitment and unemployment at age 25. In line with our hypothesis, the findings showed that longer exposure was related to weaker work commitment among undercontrollers and overcontrollers and to higher unemployment among undercontrollers. Resilients' work commitment and unemployment were not predicted by neighbourhood poverty. PMID- 27936131 TI - Immunolocalization of a Histidine-Rich Epidermal Differentiation Protein in the Chicken Supports the Hypothesis of an Evolutionary Developmental Link between the Embryonic Subperiderm and Feather Barbs and Barbules. AB - The morphogenesis of feathers is a complex process that depends on a tight spatiotemporal regulation of gene expression and assembly of the protein components of mature feathers. Recent comparative genomics and gene transcription studies have indicated that genes within the epidermal differentiation complex (EDC) encode numerous structural proteins of cornifying skin cells in amniotes including birds. Here, we determined the localization of one of these proteins, termed EDMTFH (Epidermal Differentiation Protein starting with a MTF motif and rich in Histidine), which belongs to a group of EDC-encoded proteins rich in aromatic amino acid residues. We raised an antibody against an EDMTFH-specific epitope and performed immunohistochemical investigations by light microscopy and immunogold labeling by electron microscopy of chicken embryos at days 14-18 of development. EDMTFH was specifically present in the subperiderm, a transient layer of the embryonic epidermis, and in barbs and barbules of feathers. In the latter, it partially localized to bundles of so-called feather beta-keratins (corneous beta-proteins, CBPs). Cells of the embryonic periderm, the epidermis proper, and the feather sheath were immunonegative for EDMTFH. The results of this study indicate that EDMTFH may contribute to the unique mechanical properties of feathers and define EDMTFH as a common marker of the subperiderm and the feather barbules. This expression pattern of EDMTFH resembles that of epidermal differentiation cysteine-rich protein (EDCRP) and feather CBPs and is in accordance with the hypothesis that a major part of the cyclically regenerating feather follicle is topologically, developmentally and evolutionarily related to the embryonic subperiderm. PMID- 27936134 TI - Correction: Early Fluid Resuscitation by Lactated Ringer's Solution Alleviate the Cardiac Apoptosis in Rats with Trauma-Hemorrhagic Shock. AB - [This corrects the article DOI: 10.1371/journal.pone.0165406.]. PMID- 27936133 TI - Polyglycine Acts as a Rejection Signal for Protein Transport at the Chloroplast Envelope. AB - PolyGly is present in many proteins in various organisms. One example is found in a transmembrane beta-barrel protein, translocon at the outer-envelope-membrane of chloroplasts 75 (Toc75). Toc75 requires its N-terminal extension (t75) for proper localization. t75 comprises signals for chloroplast import (n75) and envelope sorting (c75) in tandem. n75 and c75 are removed by stromal processing peptidase and plastidic type I signal peptidase 1, respectively. PolyGly is present within c75 and its deletion or substitution causes mistargeting of Toc75 to the stroma. Here we have examined the properties of polyGly-dependent protein targeting using two soluble passenger proteins, the mature portion of the small subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase (mSS) and enhanced green fluorescent protein (EGFP). Both t75-mSS and t75-EGFP were imported into isolated chloroplasts and their n75 removed. Resultant c75-mSS was associated with the envelope at the intermembrane space, whereas c75-EGFP was partially exposed outside the envelope. Deletion of polyGly or substitution of tri-Ala for the critical tri-Gly segment within polyGly caused each passenger to be targeted to the stroma. Transient expression of t75-EGFP in Nicotiana benthamiana resulted in accumulation of c75-EGFP exposed at the surface of the chloroplast, but the majority of the EGFP passenger was found free in the cytosol with most of its c75 attachment removed. Results of circular dichroism analyses suggest that polyGly within c75 may form an extended conformation, which is disrupted by tri-Ala substitution. These data suggest that polyGly is distinct from a canonical stop transfer sequence and acts as a rejection signal at the chloroplast inner envelope. PMID- 27936135 TI - Identifying Major Transitions in the Evolution of Lithic Cutting Edge Production Rates. AB - The notion that the evolution of core reduction strategies involved increasing efficiency in cutting edge production is prevalent in narratives of hominin technological evolution. Yet a number of studies comparing two different knapping technologies have found no significant differences in edge production. Using digital analysis methods we present an investigation of raw material efficiency in eight core technologies broadly representative of the long-term evolution of lithic technology. These are bipolar, multiplatform, discoidal, biface, Levallois, prismatic blade, punch blade and pressure blade production. Raw material efficiency is assessed by the ratio of cutting edge length to original core mass. We also examine which flake attributes contribute to maximising raw material efficiency, as well as compare the difference between expert and intermediate knappers in terms of cutting edge produced per gram of core. We identify a gradual increase in raw material efficiency over the broad sweep of lithic technological evolution. The results indicate that the most significant transition in efficiency likely took place with the introduction of small foliate biface, Levallois and prismatic blade knapping, all introduced in the Middle Stone Age / Middle Palaeolithic among early Homo sapiens and Neanderthals. This suggests that no difference in raw material efficiency existed between these species. With prismatic blade technology securely dated to the Middle Palaeolithic, by including the more recent punch and pressure blade technology our results dispel the notion that the transition to the Upper Palaeolithic was accompanied by an increase in efficiency. However, further increases in cutting edge efficiency are evident, with pressure blades possessing the highest efficiency in this study, indicating that late/epi-Palaeolithic and Neolithic blade technologies further increased efficiency. PMID- 27936136 TI - Improving the Non-Hydrostatic Numerical Dust Model by Integrating Soil Moisture and Greenness Vegetation Fraction Data with Different Spatiotemporal Resolutions. AB - Dust storms are devastating natural disasters that cost billions of dollars and many human lives every year. Using the Non-Hydrostatic Mesoscale Dust Model (NMM dust), this research studies how different spatiotemporal resolutions of two input parameters (soil moisture and greenness vegetation fraction) impact the sensitivity and accuracy of a dust model. Experiments are conducted by simulating dust concentration during July 1-7, 2014, for the target area covering part of Arizona and California (31, 37, -118, -112), with a resolution of ~ 3 km. Using ground-based and satellite observations, this research validates the temporal evolution and spatial distribution of dust storm output from the NMM-dust, and quantifies model error using measurements of four evaluation metrics (mean bias error, root mean square error, correlation coefficient and fractional gross error). Results showed that the default configuration of NMM-dust (with a low spatiotemporal resolution of both input parameters) generates an overestimation of Aerosol Optical Depth (AOD). Although it is able to qualitatively reproduce the temporal trend of the dust event, the default configuration of NMM-dust cannot fully capture its actual spatial distribution. Adjusting the spatiotemporal resolution of soil moisture and vegetation cover datasets showed that the model is sensitive to both parameters. Increasing the spatiotemporal resolution of soil moisture effectively reduces model's overestimation of AOD, while increasing the spatiotemporal resolution of vegetation cover changes the spatial distribution of reproduced dust storm. The adjustment of both parameters enables NMM-dust to capture the spatial distribution of dust storms, as well as reproducing more accurate dust concentration. PMID- 27936137 TI - Patchiness of Ciliate Communities Sampled at Varying Spatial Scales along the New England Shelf. AB - Although protists (microbial eukaryotes) provide an important link between bacteria and Metazoa in food webs, we do not yet have a clear understanding of the spatial scales on which protist diversity varies. Here, we use a combination of DNA fingerprinting (denaturant gradient gel electrophoresis or DGGE) and high throughput sequencing (HTS) to assess the ciliate community in the class Spirotrichea at varying scales of 1-3 km sampled in three locations separated by at least 25 km-offshore, midshelf and inshore-along the New England shelf. Analyses of both abundant community (DGGE) and the total community (HTS) members reveal that: 1) ciliate communities are patchily distributed inshore (i.e. the middle station of a transect is distinct from its two neighboring stations), whereas communities are more homogeneous among samples within the midshelf and offshore stations; 2) a ciliate closely related to Pelagostrobilidium paraepacrum 'blooms' inshore and; 3) environmental factors may differentially impact the distributions of individual ciliates (i.e. OTUs) rather than the community as a whole as OTUs tend to show distinct biogeographies (e.g. some OTUs are restricted to the offshore locations, some to the surface, etc.). Together, these data show the complexity underlying the spatial distributions of marine protists, and suggest that biogeography may be a property of ciliate species rather than communities. PMID- 27936138 TI - Diffusion-Based Design of Multi-Layered Ophthalmic Lenses for Controlled Drug Release. AB - The study of ocular drug delivery systems has been one of the most covered topics in drug delivery research. One potential drug carrier solution is the use of materials that are already commercially available in ophthalmic lenses for the correction of refractive errors. In this study, we present a diffusion-based mathematical model in which the parameters can be adjusted based on experimental results obtained under controlled conditions. The model allows for the design of multi-layered therapeutic ophthalmic lenses for controlled drug delivery. We show that the proper combination of materials with adequate drug diffusion coefficients, thicknesses and interfacial transport characteristics allows for the control of the delivery of drugs from multi-layered ophthalmic lenses, such that drug bursts can be minimized, and the release time can be maximized. As far as we know, this combination of a mathematical modelling approach with experimental validation of non-constant activity source lamellar structures, made of layers of different materials, accounting for the interface resistance to the drug diffusion, is a novel approach to the design of drug loaded multi-layered contact lenses. PMID- 27936139 TI - Epidemiological and Virological Characteristics of Influenza in Chongqing, China, 2011-2015. AB - BACKGROUND: Chongqing is the largest municipality and located in Southwestern of China, with over 30 million registered inhabitants. There are few reports regarding the epidemiology of influenza in Chongqing. The objective of the paper is to explore the epidemiology of influenza in Chongqing, in order to provide scientific basis for prevention and control of influenza. METHODOLOGY /PRINCIPAL FINDINGS: From 2011 to 2015, we collected information on influenza-like illness (ILI) patients fulfilling the case definition, and took nasalpharyngeal or throat swabs specimens from ILI cases per week at the 7 sentinel hospitals. Specimens were tested by reverse transcription-polymerase chain reaction(RT-PCR) for influenza. Descriptive epidemiology was applied to analyze the epidemiology and etiology of influenza. A total of 9,696,212 cases were enrolled, of which 111,589 were ILI. Of those 24,868 samples from ILI cases, 13.3% (3,314/24,868) tested positive for influenza virus (65.7% influenza A, 34.1% influenza B, and 0.2% influenza A and B co-infection). Among the influenza A viruses, 71.3% were seasonal influenza A(H3N2) and 28.7% were influenza A(H1N1)pdm09. No cases of seasonal A(H1N1) were detected. The isolation rate was highest in children aged 5 14 years old. Influenza activity consistently peaked during January-March in 2011 2015, and June-July in 2012, 2014 and 2015. CONCLUSIONS: Influenza is an important public health problem among ILI patients in Chongqing, especially among school-aged children. It might be beneficial to prioritize influenza vaccination for school-aged children and implement the school-based intervention to prevent and mitigating influenza outbreaks in Chongqing, particularly during the seasonal peaks. PMID- 27936143 TI - Correction: ALK Positive Lung Cancer: Clinical Profile, Practice and Outcomes in a Developing Country. AB - [This corrects the article DOI: 10.1371/journal.pone.0160752.]. PMID- 27936140 TI - Time-Dependent Regulation of IL-2R alpha-Chain (CD25) Expression by TCR Signal Strength and IL-2-Induced STAT5 Signaling in Activated Human Blood T Lymphocytes. AB - The expression of the IL-2R alpha-chain (IL-2Ralpha) is regulated at the transcriptional level via TCR- and IL-2R-signaling. The question is how to precede in time the activation signals to induce the IL-2Ralpha expression in native primary T cells. By comparing the effects of selective drugs on the dynamics of CD25 expression during the mitogen stimulation of human peripheral blood lymphocytes, we identified distinct Src- and JAK-dependent stages of IL 2Ralpha upregulation. PP2, a selective inhibitor of TCR-associated Src kinase, prevents CD25 expression at initial stages of T cell activation, prior to the cell growth. This early IL-2Ralpha upregulation underlies the T cell competence and the IL-2 responsiveness. We found that the activated with "weak" mitogen, the population of blood lymphocytes has some pool of competent CD25+ cells bearing a high affinity IL-2R. A distinct pattern of IL-2R signaling in resting and competent T lymphocytes has been shown. Based on the inhibitory effect of WHI P131, a selective drug of JAK3 kinase activity, we concluded that in quiescent primary T lymphocytes, the constitutive STAT3 and the IL-2-induced prolonged STAT5 activity (assayed by tyrosine phosphorylation) is mostly JAK3-independent. In competent T cells, in the presence of IL-2 JAK3/STAT5 pathway is switched to maintain the higher and sustained IL-2Ralpha expression as well as cell growth and proliferation. We believe that understanding the temporal coordination of antigen- and cytokine-evoked signals in primary T cells may be useful for improving immunotherapeutic strategies. PMID- 27936141 TI - HbS Binding to GP1balpha Activates Platelets in Sickle Cell Disease. AB - Intravascular hemolysis increases the risk of thrombosis in hemolytic disorders. Our previous study showed that the binding of adult hemoglobin (HbA) to glycoprotein (GP) 1balpha induced the activation of platelets. The elevated plasma Hb or platelet surface bound Hb positively correlated with platelet activation in patients with paroxysmal nocturnal hemoglobinuria (PNH). Furthermore, this study shows that the sickle Hb [HbS, occurs due to single nucleotide polymorphism at A>T of beta-globin gene of Hb and causes sickle cell disease (SCD)] also bound to GP1balpha and activated platelets in a concentration dependent manner. The HbS bound to glycocalicin (extramembranous part of GP1balpha) with KD ~ 10.46 +/- 3 MUM. HbS induced phosphorylation of signaling adapter proteins, such as Lyn, PI3K, Akt and ERK in platelets, and also increased the surface expression of platelet activation markers such as P-selectin (10.7 fold) and PAC1 binding (10.4 fold) in platelet surface in a concentration dependent manner. HbS also increased the platelet microparticle-generation (4.7 fold) and thrombus-formation (4.3 fold) in a concentration-dependent manner. An elevated level of extracellular Hb in plasma correlated directly with platelet activation markers such as P-selectin (r = 0.7947), PAC1 binding (r = 0.5914) on platelet surface and plasma levels of platelet-derived microparticles (r = 0.7834) in patients with SCD. Our study therefore suggests that the HbS-induced platelet activation may play a crucial role in intravascular clot formation observed in SCD patients characterized by high propensity to vascular occlusion and hypercoagulable states. PMID- 27936142 TI - Gene Co-Expression Network Analysis Unraveling Transcriptional Regulation of High Altitude Adaptation of Tibetan Pig. AB - Tibetan pigs have survived at high altitude for millennia and they have a suite of adaptive features to tolerate the hypoxic environment. However, the molecular mechanisms underlying the regulation of hypoxia-adaptive phenotypes have not been completely elucidated. In this study, we analyzed differentially expressed genes (DEGs), biological pathways and constructed co-expression regulation networks using whole-transcriptome microarrays from lung tissues of Tibetan and Duroc pigs both at high and low altitude. A total of 3,066 DEGs were identified and this list was over-represented for the ontology terms including metabolic process, catalytic activity, and KEGG pathway including metabolic pathway and PI3K-Akt signaling pathway. The regulatory (RIF) and phenotypic (PIF) impact factor analysis identified several known and several potentially novel regulators of hypoxia adaption, including: IKBKG, KLF6 and RBPJ (RIF1), SF3B1, EFEMP1, HOXB6 and ATF6 (RIF2). These findings provide new details of the regulatory architecture of hypoxia-adaptive genes and also insight into which genes may undergo epigenetic modification for further study in the high-altitude adaptation. PMID- 27936144 TI - Correction: LudusScope: Accessible Interactive Smartphone Microscopy for Life Science Education. AB - [This corrects the article DOI: 10.1371/journal.pone.0162602.]. PMID- 27936145 TI - Diurnal Patterns of Physical Activity in Relation to Activity Induced Energy Expenditure in 52 to 83 Years-Old Adults. AB - BACKGROUND: Ageing is associated with a declining physical activity level (PAL) and changes in the diurnal activity pattern. Changes in the activity pattern might help explaining the age-associated reduction of physical activity. OBJECTIVE: The aims were to investigate diurnal activity patterns within groups of older adults classified by PAL, to investigate diurnal activity patterns within age-groups and to investigate the association between the drop in activity and aerobic fitness. METHODS: Thirty-one healthy subjects aged between 52 and 83y were recruited for the study. Subjects were divided in sedentary (PAL<1.75), moderately active (1.75=66 years old with lower aerobic fitness. PMID- 27936146 TI - Performance of Clinical Screening Algorithms for Tuberculosis Intensified Case Finding among People Living with HIV in Western Kenya. AB - OBJECTIVE: To assess the performance of symptom-based screening for tuberculosis (TB), alone and with chest radiography among people living with HIV (PLHIV), including pregnant women, in Western Kenya. DESIGN: Prospective cohort study. METHODS: PLHIV from 15 randomly-selected HIV clinics were screened with three clinical algorithms [World Health Organization (WHO), Ministry of Health (MOH), and "Improving Diagnosis of TB in HIV-infected persons" (ID-TB/HIV) study], underwent chest radiography (unless pregnant), and provided two or more sputum specimens for smear microscopy, liquid culture, and Xpert MTB/RIF. Performance of clinical screening was compared to laboratory results, controlling for the complex design of the survey. RESULTS: Overall, 738 (85.6%) of 862 PLHIV enrolled were included in the analysis. Estimated TB prevalence was 11.2% (95% CI, 9.9 12.7). Sensitivity of the three screening algorithms was similar [WHO, 74.1% (95% CI, 64.1-82.2); MOH, 77.5% (95% CI, 68.6-84.5); and ID-TB/HIV, 72.5% (95% CI, 60.9-81.7)]. Sensitivity of the WHO algorithm was significantly lower among HIV infected pregnant women [28.2% (95% CI, 14.9-46.7)] compared to non-pregnant women [78.3% (95% CI, 67.3-86.4)] and men [77.2% (95% CI, 68.3-84.2)]. Chest radiography increased WHO algorithm sensitivity and negative predictive value to 90.9% (95% CI, 86.4-93.9) and 96.1% (95% CI, 94.4-97.3), respectively, among asymptomatic men and non-pregnant women. CONCLUSIONS: Clinical screening missed approximately 25% of laboratory-confirmed TB cases among all PLHIV and more than 70% among HIV-infected pregnant women. National HIV programs should evaluate the feasibility of laboratory-based screening for TB, such as a single Xpert MTB/RIF test for all PLHIV, especially pregnant women, at enrollment in HIV services. PMID- 27936147 TI - Absence of Association between Behavior Problems in Childhood and Hypertension in Midlife. AB - BACKGROUND: It is known that behavior in childhood is associated with certain physical and mental health problems in midlife. However, there is limited evidence on the role of childhood behavior problems in the development of hypertension in adulthood. The present study aimed to examine whether behavior problems in childhood influenced the risk of hypertension in midlife in the United Kingdom 1958 birth cohort. METHODS: The 1958 British birth cohort comprised 17,638 individuals born in the first week of March 1958 in the United Kingdom. Behavior problems were assessed at 7, 11, and 16 years of age by parents and teachers. At age 45, blood pressure was measured and hypertension was recorded if blood pressure was >=140/90 mm Hg or if the participants were informed by their health professionals that they had high blood pressure. Behavioral information was reported according to the Rutter Children's Behaviour Questionnaire (RCBQ) and the Bristol Social Adjustment Guide (BSAG). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine behavior problems in childhood in relation to hypertension at 45 years of age according to logistic regression analysis, with adjustment for sex, social class in childhood and adulthood, childhood cognition, birth weight, gestational age at birth, body mass index (BMI), smoking, alcohol consumption, and physical activity. RESULTS: Behavior problems reported by parents at 7, 11, and 16 years were not associated with hypertension in midlife (OR, 0.93; 95% CI, 0.81, 1.07; OR, 0.95; 95% CI, 0.81, 1.11; OR, 0.98; 95% CI, 0.85, 1.12, respectively). Similarly, teacher reported behavior problems at 7, 11, and 16 years were not associated with hypertension in midlife (OR, 0.92; 95% CI, 0.72, 1.18; OR, 0.92; 95% CI, 0.84, 1.02; OR, 1.03; 95% CI, 0.92, 1.15, respectively). Further separate analyses showed similar results for males and females. CONCLUSION: There is no association between behavior problems in childhood and hypertension in midlife. PMID- 27936148 TI - Screening for Dyslexia Using Eye Tracking during Reading. AB - Dyslexia is a neurodevelopmental reading disability estimated to affect 5-10% of the population. While there is yet no full understanding of the cause of dyslexia, or agreement on its precise definition, it is certain that many individuals suffer persistent problems in learning to read for no apparent reason. Although it is generally agreed that early intervention is the best form of support for children with dyslexia, there is still a lack of efficient and objective means to help identify those at risk during the early years of school. Here we show that it is possible to identify 9-10 year old individuals at risk of persistent reading difficulties by using eye tracking during reading to probe the processes that underlie reading ability. In contrast to current screening methods, which rely on oral or written tests, eye tracking does not depend on the subject to produce some overt verbal response and thus provides a natural means to objectively assess the reading process as it unfolds in real-time. Our study is based on a sample of 97 high-risk subjects with early identified word decoding difficulties and a control group of 88 low-risk subjects. These subjects were selected from a larger population of 2165 school children attending second grade. Using predictive modeling and statistical resampling techniques, we develop classification models from eye tracking records less than one minute in duration and show that the models are able to differentiate high-risk subjects from low risk subjects with high accuracy. Although dyslexia is fundamentally a language based learning disability, our results suggest that eye movements in reading can be highly predictive of individual reading ability and that eye tracking can be an efficient means to identify children at risk of long-term reading difficulties. PMID- 27936149 TI - Increased Bone Mass in Female Mice Lacking Mast Cell Chymase. AB - Here we addressed the potential impact of chymase, a mast-cell restricted protease, on mouse bone phenotype. We show that female mice lacking the chymase Mcpt4 acquired a persistent expansion of diaphyseal bone in comparison with wild type controls, reaching a 15% larger diaphyseal cross sectional area at 12 months of age. Mcpt4-/- mice also showed increased levels of a bone anabolic serum marker and higher periosteal bone formation rate. However, they were not protected from experimental osteoporosis, suggesting that chymase regulates normal bone homeostasis rather than the course of osteoporosis. Further, the absence of Mcpt4 resulted in age-dependent upregulation of numerous genes important for bone formation but no effects on osteoclast activity. In spite of the latter, Mcpt4-/- bones had increased cortical porosity and reduced endocortical mineralization. Mast cells were found periosteally and, notably, bone-proximal mast cells in Mcpt4-/- mice were degranulated to a larger extent than in wild type mice. Hence, chymase regulates degranulation of bone mast cells, which could affect the release of mast cell-derived factors influencing bone remodelling. Together, these findings reveal a functional impact of mast cell chymase on bone. Further studies exploring the possibility of using chymase inhibitors as a strategy to increase bone volume may be warranted. PMID- 27936151 TI - Osmoregulated Chloride Currents in Hemocytes from Mytilus galloprovincialis. AB - We investigated the biophysical properties of the transport mediated by ion channels in hemocytes from the hemolymph of the bivalve Mytilus galloprovincialis. Besides other transporters, mytilus hemocytes possess a specialized channel sensitive to the osmotic pressure with functional properties similar to those of other transport proteins present in vertebrates. As chloride fluxes may play an important role in the regulation of cell volume in case of modifications of the ionic composition of the external medium, we focused our attention on an inwardly-rectifying voltage-dependent, chloride-selective channel activated by negative membrane potentials and potentiated by the low osmolality of the external solution. The chloride channel was slightly inhibited by micromolar concentrations of zinc chloride in the bath solution, while the antifouling agent zinc pyrithione did not affect the channel conductance at all. This is the first direct electrophysiological characterization of a functional ion channel in ancestral immunocytes of mytilus, which may bring a contribution to the understanding of the response of bivalves to salt and contaminant stresses. PMID- 27936150 TI - Oxidative Stress Induces Mouse Follicular Granulosa Cells Apoptosis via JNK/FoxO1 Pathway. AB - The c-Jun N-terminal protein kinase (JNK) plays an important role in the regulation of cell apoptosis. Forkhead box O (FoxO) transcription factors are involved in diverse biological processes, including cellular metabolism, cell apoptosis, and cell cycle. However, the JNK/FoxO1 pathway involved in the process of apoptosis induced by oxidative stress remains to be elucidated. Here, we demonstrated that the JNK activity significantly increased in response to oxidative stress in mouse follicular granulosa cells (MGCs). SP600125, a selective JNK inhibitor, attenuated the oxidative stress-induced MGCs apoptosis. Oxidative stress enhanced the FoxO1 nuclear translocation by activating the JNK activity. Moreover, JNK mediated the dissociation of FoxO1 from 14-3-3 proteins in MGCs after the treatment with H2O2. Finally, oxidative stress up-regulated the expression of FoxO1 via JNK mediation of FoxO1 self-regulation in MGCs. Taken together, our findings suggest that JNK/FoxO1 is involved in the regulation of oxidative stress-induced cell apoptosis in MGCs. PMID- 27936152 TI - Variety of Antimicrobial Resistances and Virulence Factors in Staphylococcus aureus Isolates from Meat Products Legally and Illegally Introduced to Germany. AB - Food products of animal origin can serve as a vehicle for Staphylococcus (S.) aureus, a facultative pathogen involved in a variety of diseases. As a result, international trade and illegal transportation of foodstuffs can facilitate the distribution of S. aureus over long distances. In this study, we investigated S. aureus isolates recovered from meat products confiscated from passengers returning from non-EU countries at two German airports and from samples of legally imported meats from non-EU countries. The aim was to characterize isolates in regard to their genetic relatedness as well as their antimicrobial resistance profiles and major virulence factors in order to assess potential risks associated with these products. The isolates were characterized by spa typing, MLST, macrorestriction analysis, microarray analysis and antimicrobial susceptibility testing. MRSA isolates were further characterized by dru typing. The characteristics of the majority of the isolates indicated a human origin, rather than an association with livestock. The results further revealed a considerable heterogeneity among the MRSA isolates, despite their common origin. Overall, a plenitude of major virulence factors and antimicrobial resistances was detected among the isolates, highlighting the potential risks associated with contaminated meat products and the transportation of such products among different countries. PMID- 27936153 TI - Impact of Transient and Persistent Acute Kidney Injury on Chronic Kidney Disease Progression and Mortality after Gastric Surgery for Gastric Cancer. AB - Acute kidney injury (AKI) is common after gastric surgery for gastric cancer and associated with adverse outcomes. However, the impact of transient or persistent AKI on clinical outcomes after gastric surgery for gastric cancer has not been described. We performed a retrospective study of 4,886 patients with normal renal function who underwent partial or total gastrectomy for gastric cancer between June 2002 and December 2012. AKI patients were classified as transient and persistent AKI based on the return of serum creatinine to the level indicating no AKI within 7 days. Our outcomes included occurrence of new-onset chronic kidney disease (CKD) and mortality 1 year after gastric surgery. AKI occurred in 638 (13.1%) after gastric surgery. Transient AKI was documented in 574 (90%). Use of diuretics and contrast agents was a common risk factor for persistent and transient AKI. Length of intensive care unit (ICU) and hospital stay, and ICU admission rate were higher in patients with transient AKI than in those without AKI. Although patients with persistent AKI had a higher new-onset CKD 1 year after gastric surgery after adjusting for multiple covariates, transient AKI was not associated with new-onset CKD. The 1-year mortality rates were significantly higher in patients with transient and persistent AKI. Not only persistent AKI but transient AKI is associated with increased risk of hospital complications and a significantly higher risk of long-term mortality than patients without AKI after gastric surgery. Moreover, persistent AKI, but not transient AKI, is associated with CKD progression at 1 year. PMID- 27936154 TI - Retinal Morphology and Sensitivity Are Primarily Impaired in Eyes with Neuromyelitis Optica Spectrum Disorder (NMOSD). AB - BACKGROUND: Previous studies of neuromyelitis optica spectrum disorder (NMOSD) using spectral domain optical coherence tomography (SD-OCT) showed that the outer nuclear layer (ONL) in eyes without a history of optic neuritis (ON) was thinner than that of healthy controls. It remains unclear whether the ONL thinning is caused by a direct attack on the retina by an autoantibody or a retrograde degeneration. OBJECTIVE: To determine the mechanisms involved in the retinal damage in eyes with NMOSD without ON. METHODS: SD-OCT was used to determine the thicknesses of the different retinal layers of 21 eyes of 12 NMOSD patients without prior ON and 19 eyes of 10 healthy controls. Eyes with peripapillary retinal nerve fiber layer (RNFL) thinning were excluded to eliminate the confounding effects of retrograde degeneration. Microperimetry was used to determine the central retinal sensitivity. The data of the two groups were compared using generalized estimated equation models to account for inter-eye dependencies. RESULTS: The ganglion cell plus inner plexiform layer and the inner nuclear layer plus outer plexiform layer thicknesses of the NMOSD eyes were not significantly different from that of the control eyes (P = 0.28, P = 0.78). However, the ONL and average macular thickness (AMT) in the NMOSD eyes were significantly thinner than that of the control eyes (P = 0.022, P = 0.036). The retinal sensitivity in the central 10 degrees , 10 degrees to 2 degrees , and 2 degrees sectors were significantly lower in the NMOSD eyes than in the control eyes (P = 0.013, P = 0.022, P = 0.002). CONCLUSIONS: The ONL thinning, AMT thinning, and reduced retinal sensitivity in eyes with NMOSD without significant peripapillary RNFL thinning are most likely due to direct retinal pathology. PMID- 27936155 TI - Variation in Plant Response to Herbivory Underscored by Functional Traits. AB - The effects of herbivory can shape plant communities and evolution. However, the many forms of herbivory costs and the wide variation in herbivory pressure, including across latitudinal gradients, can make predicting the effects of herbivory on different plant species difficult. Functional trait approaches may aid in contextualizing and standardizing the assessment of herbivory impacts. Here we assessed the response of 26 old-field plant species to simulated defoliation in a greenhouse setting by measuring whole plant and leaf level traits in control and treated individuals. Simulated defoliation had no significant effects on any plant traits measured. However, the baseline leaf level traits of healthy plants consistently predicted the log response ratio for these species whole plant response to defoliation. The latitudinal mid-point of species' distributions was also significantly correlated with aboveground biomass and total leaf area responses, with plants with a more northern distribution being more negatively impacted by treatment. These results indicate that even in the absence of significant overall impacts, functional traits may aid in predicting variability in plant responses to defoliation and in identifying the underlying limitations driving those responses. PMID- 27936157 TI - Correction: The Hog Cycle of Law Professors: An Econometric Time Series Analysis of the Entry-Level Job Market in Legal Academia. AB - [This corrects the article DOI: 10.1371/journal.pone.0159815.]. PMID- 27936156 TI - Primary Postnatal Dorsal Root Ganglion Culture from Conventionally Slaughtered Calves. AB - Neurological disorders in ruminants have an important impact on veterinary health, but very few host-specific in vitro models have been established to study diseases affecting the nervous system. Here we describe a primary neuronal dorsal root ganglia (DRG) culture derived from calves after being conventionally slaughtered for food consumption. The study focuses on the in vitro characterization of bovine DRG cell populations by immunofluorescence analysis. The effects of various growth factors on neuron viability, neurite outgrowth and arborisation were evaluated by morphological analysis. Bovine DRG neurons are able to survive for more than 4 weeks in culture. GF supplementation is not required for neuronal survival and neurite outgrowth. However, exogenously added growth factors promote neurite outgrowth. DRG cultures from regularly slaughtered calves represent a promising and sustainable host specific model for the investigation of pain and neurological diseases in bovines. PMID- 27936159 TI - The Effect of Altered Soil Moisture on Hybridization Rate in a Crop-Wild System (Raphanus spp.). AB - Since plant mating choices are flexible and responsive to the environment, rates of spontaneous hybridization may vary across ecological clines. Developing a robust and predictive framework for rates of plant gene flow requires assessing the role of environmental sensitivity on plant reproductive traits, relative abundance, and pollen vectors. Therefore, across a soil moisture gradient, we quantified pollinator movement, life-history trait variation, and unidirectional hybridization rates from crop (Raphanus sativus) to wild (Raphanus raphanistrum) radish populations. Both radish species were grown together in relatively dry (no rain), relatively wet (double rain), or control soil moisture conditions in Ohio, USA. We measured wild and crop radish life-history, phenology and pollinator visitation patterns. To quantify hybridization rates from crop-to-wild species, we used a simply inherited morphological marker to detect F1 hybrid progeny. Although crop-to-wild hybridization did not respond to watering treatments, the abundance of hybrid offspring was higher in fruits produced late in the period of phenological overlap, when both species had roughly equal numbers of open flowers. Therefore, the timing of fruit production and its relationship to flowering overlap may be more important to hybrid zone formation in Raphanus spp. than soil moisture or pollen vector movements. PMID- 27936158 TI - Modulation of Re-initiation of Measles Virus Transcription at Intergenic Regions by PXD to NTAIL Binding Strength. AB - Measles virus (MeV) and all Paramyxoviridae members rely on a complex polymerase machinery to ensure viral transcription and replication. Their polymerase associates the phosphoprotein (P) and the L protein that is endowed with all necessary enzymatic activities. To be processive, the polymerase uses as template a nucleocapsid made of genomic RNA entirely wrapped into a continuous oligomer of the nucleoprotein (N). The polymerase enters the nucleocapsid at the 3'end of the genome where are located the promoters for transcription and replication. Transcription of the six genes occurs sequentially. This implies ending and re initiating mRNA synthesis at each intergenic region (IGR). We explored here to which extent the binding of the X domain of P (XD) to the C-terminal region of the N protein (NTAIL) is involved in maintaining the P/L complex anchored to the nucleocapsid template during the sequential transcription. Amino acid substitutions introduced in the XD-binding site on NTAIL resulted in a wide range of binding affinities as determined by combining protein complementation assays in E. coli and human cells and isothermal titration calorimetry. Molecular dynamics simulations revealed that XD binding to NTAIL involves a complex network of hydrogen bonds, the disruption of which by two individual amino acid substitutions markedly reduced the binding affinity. Using a newly designed, highly sensitive dual-luciferase reporter minigenome assay, the efficiency of re initiation through the five measles virus IGRs was found to correlate with NTAIL/XD KD. Correlatively, P transcript accumulation rate and F/N transcript ratios from recombinant viruses expressing N variants were also found to correlate with the NTAIL to XD binding strength. Altogether, our data support a key role for XD binding to NTAIL in maintaining proper anchor of the P/L complex thereby ensuring transcription re-initiation at each intergenic region. PMID- 27936161 TI - Correction: Use of the 'Accountability for Reasonableness' Approach to Improve Fairness in Accessing Dialysis in a Middle-Income Country. AB - [This corrects the article DOI: 10.1371/journal.pone.0164201.]. PMID- 27936160 TI - A CBL-Interacting Protein Kinase TaCIPK2 Confers Drought Tolerance in Transgenic Tobacco Plants through Regulating the Stomatal Movement. AB - In plants, the CBL-CIPK signaling pathways play key roles in the response to abiotic stresses. However, functional studies of CIPKs in the important staple crop wheat are very rare. In this study, we identified a CIPK gene from wheat, designated TaCIPK2. Expression analysis results showed that TaCIPK2 could be up regulated in wheat leaves by polyethylene glycol, abscisic acid and H2O2 treatments. Subcellular localization analyses revealed that TaCIPK2 was present in whole wheat epidermal cells. A yeast two-hybrid assay indicated that TaCIPK2 interacted with TaCBL1, 2, 3 and 4 in vitro. Transgenic tobacco plants over expressing TaCIPK2 exhibited increased drought tolerance, indicated by a larger proportion of green cotyledons and higher survival rates under the osmotic and drought stress conditions compared with control plants. Additionally, physiological index analyses revealed that the transgenic tobacco plants had lower water loss rates and ion leakage, accumulated less malondialdehyde and H2O2, and had higher catalase and superoxide dismutase activities than the control plants. The transgenic plants also exhibited faster stomatal closure following exposure to osmotic stress conditions. The seed germination rates and stomatal aperture of TaCIPK2-overexpressing tobacco plants decreased after exogenous abscisic acid treatment was applied, implying that the transgenic tobacco plants were more sensitive to exogenous abscisic acid than the control plants. Our results indicate that TaCIPK2 plays a positive regulatory role in drought stress responses in transgenic tobacco plants. PMID- 27936162 TI - Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling. AB - FOXO factors are tumour suppressor proteins commonly inactivated in human tumours by posttranslational modifications. Furthermore, genetic variation within the FOXO3a gene is consistently associated with human longevity. Therefore, the pharmacological activation of FOXO proteins is considered as an attractive therapeutic approach to treat cancer and age-related diseases. In order to identify agents capable of activating FOXOs, we tested a collection of small chemical compounds using image-based high content screening technology. Here, we report the discovery of LOM612 (compound 1a), a newly synthesized isothiazolonaphthoquinone as a potent FOXO relocator. Compound 1a induces nuclear translocation of a FOXO3a reporter protein as well as endogenous FOXO3a and FOXO1 in U2OS cells in a dose-dependent manner. This activity does not affect the subcellular localization of other cellular proteins including NFkB or inhibit CRM1-mediated nuclear export. Furthermore, compound 1a shows a potent antiproliferative effect in human cancer cell lines. PMID- 27936163 TI - Origin and Evolution of Allopolyploid Wheatgrass Elymus fibrosus (Schrenk) Tzvelev (Poaceae: Triticeae) Reveals the Effect of Its Origination on Genetic Diversity. AB - Origin and evolution of tetraploid Elymus fibrosus (Schrenk) Tzvelev were characterized using low-copy nuclear gene Rpb2 (the second largest subunit of RNA polymerase II), and chloroplast region trnL-trnF (spacer between the tRNA Leu (UAA) gene and the tRNA-Phe (GAA) gene). Ten accessions of E. fibrosus along with 19 Elymus species with StH genomic constitution and diploid species in the tribe Triticeae were analyzed. Chloroplast trnL-trnF sequence data suggested that Pseudoroegneria (St genome) was the maternal donor of E. fibrosus. Rpb2 data confirmed the presence of StH genomes in E. fibrosus, and suggested that St and H genomes in E. fibrosus each is more likely originated from single gene pool. Single origin of E. fibrosus might be one of the reasons causing genetic diversity in E. fibrosus lower than those in E. caninus and E. trachycaulus, which have similar ecological preferences and breeding systems with E. fibrosus, and each was originated from multiple sources. Convergent evolution of St and H copy Rpb2 sequences in some accessions of E. fibrosus might have occurred during the evolutionary history of this allotetraploid. PMID- 27936164 TI - Transcriptome and Metabolome Analyses in Exogenous FABP4- and FABP5-Treated Adipose-Derived Stem Cells. AB - Adipose-derived stem cells (ADSC), which exist near adipocytes in adipose tissue, have been used as a potential tool of regenerative medicine. Lipid chaperones, fatty acid-binding protein 4 (FABP4) and 5 (FABP5), are abundantly expressed in adipocytes. FABP4 has recently been shown to be secreted from adipocytes during lipolysis in a non-classical pathway and may act as an adipokine. Here, we investigated the role of exogenous FABP4 and FABP5 in transcriptional and metabolic regulation in ADSC. FABP4 and FABP5 were little expressed in ADSC. However, both FABP4 and FABP5 were significantly induced after adipocyte differentiation of ADSC and were secreted from the differentiated adipocytes. Analysis of microarray data, including gene ontology enrichment analysis and cascade analysis of the protein-protein interaction network using a transcription factor binding site search, demonstrated that treatment of ADSC with FABP4 or FABP5 affected several kinds of genes related to inflammatory and metabolic responses and the process of cell differentiation. Notably, myogenic factors, including myocyte enhancer factors, myogenic differentiation 1 and myogenin, were modulated by treatment of ADSC with FABP4, indicating that exogenous FABP4 treatment is partially associated with myogenesis in ADSC. Metabolome analysis showed that treatment of ADSC with FABP4 and with FABP5 similarly, but differently in extent, promoted hydrolysis and/or uptake of lipids, consequentially together with enhancement of beta oxidation, inhibition of downstream of the glycolysis pathway, accumulation of amino acids, reduction of nucleic acid components and increase in the ratio of reduced and oxidized nicotinamide adenine dinucleotide phosphates (NADPH/NADP+), an indicator of reducing power, and the ratio of adenosine triphosphate and adenosine monophosphate (ATP/AMP), an indicator of the energy state, in ADSC. In conclusion, secreted FABP4 and FABP5 from adipocytes as adipokines differentially affect transcriptional and metabolic regulation in ADSC near adipocytes. The adiposity condition in the host of regenerative medicine may affect characteristics of ADSC by exposure of the balance of FABP4 and FABP5. PMID- 27936165 TI - Enzymatically Modified Starch Favorably Modulated Intestinal Transit Time and Hindgut Fermentation in Growing Pigs. AB - Aside from being used as stabilizing agents in many processed foods, chemically modified starches may act as functional dietary ingredients. Therefore, development of chemically modified starches that are less digestible in the upper intestinal segments and promote fermentation in the hindgut receives considerable attention. This study aimed to investigate the impact of an enzymatically modified starch (EMS) on nutrient flow, passage rate, and bacterial activity at ileal and post-ileal level. Eight ileal-cannulated growing pigs were fed 2 diets containing 72% purified starch (EMS or waxy cornstarch as control) in a cross over design for 10 d, followed by a 4-d collection of feces and 2-d collection of ileal digesta. On d 17, solid and liquid phase markers were added to the diet to determine ileal digesta flow for 8 h after feeding. Reduced small intestinal digestion after the consumption of the EMS diet was indicated by a 10%-increase in ileal flow and fecal excretion of dry matter and energy compared to the control diet (P<0.05). Moreover, EMS feeding reduced ileal transit time of both liquid and solid fractions compared to the control diet (P<0.05). The greater substrate flow to the large intestine with the EMS diet increased the concentrations of total and individual short-chain fatty acids (SCFA) in feces (P<0.05). Total bacterial 16S rRNA gene abundance was not affected by diet, whereas the relative abundance of the Lactobacillus group decreased (P<0.01) by 50% and of Enterobacteriaceae tended (P<0.1) to increase by 20% in ileal digesta with the EMS diet compared to the control diet. In conclusion, EMS appears to resemble a slowly digestible starch by reducing intestinal transit and increasing SCFA in the distal large intestine. PMID- 27936166 TI - Increased Age, but Not Parity Predisposes to Higher Bacteriuria Burdens Due to Streptococcus Urinary Tract Infection and Influences Bladder Cytokine Responses, Which Develop Independent of Tissue Bacterial Loads. AB - Streptococcus agalactiae causes urinary tract infection (UTI) in pregnant adults, non-pregnant adults, immune-compromised individuals and the elderly. The pathogenesis of S. agalactiae UTI in distinct patient populations is poorly understood. In this study, we used murine models of UTI incorporating young mice, aged and dam mice to show that uropathogenic S. agalactiae causes bacteriuria at significantly higher levels in aged mice compared to young mice and this occurs coincident with equivalent levels of bladder tissue colonisation at 24 h post infection (p.i.). In addition, aged mice exhibited significantly higher bacteriuria burdens at 48 h compared to young mice, confirming a divergent pattern of bacterial colonization in the urinary tract of aged and young mice. Multiparous mice, in contrast, exhibited significantly lower urinary titres of S. agalactiae compared to age-matched nulliparous mice suggesting that parity enhances the ability of the host to control S. agalactiae bacteriuria. Additionally, we show that both age and parity alter the expression levels of several key regulatory and pro-inflammatory cytokines, which are known to be important the immune response to UTI, including Interleukin (IL)-1beta, IL 12(p40), and Monocyte Chemoattractant Protein-1 (MCP-1). Finally, we demonstrate that other cytokines, including IL-17 are induced significantly in the S. agalactiae-infected bladder regardless of age and parity status. Collectively, these findings show that the host environment plays an important role in influencing the severity of S. agalactiae UTI; infection dynamics, particularly in the context of bacteriuria, depend on age and parity, which also affect the nature of innate immune responses to infection. PMID- 27936168 TI - Transcriptome Analysis of Ceriops tagal in Saline Environments Using RNA Sequencing. AB - Identification of genes involved in mangrove species' adaptation to salt stress can provide valuable information for developing salt-tolerant crops and understanding the molecular evolution of salt tolerance in halophiles. Ceriops tagal is a salt-tolerant mangrove tree growing in mudflats and marshes in tropical and subtropical areas, without any prior genome information. In this study, we assessed the biochemical and transcriptional responses of C. tagal to high salt treatment (500 mmol/L NaCl) by hydroponic experiments and RNA-seq. In C. tagal root tissues under salt stress, proline accumulated strongly from 3 to 12 h of treatment; meanwhile, malondialdehyde content progressively increased from 0 to 9 h, then dropped to lower than control levels by 24 h. These implied that C. tagal plants could survive salt stress through biochemical modification. Using the Illumina sequencing platform, approximately 27.39 million RNA-seq reads were obtained from three salt-treated and control (untreated) root samples. These reads were assembled into 47,111 transcripts with an average length of 514 bp and an N50 of 632 bp. Approximately 78% of the transcripts were annotated, and a total of 437 genes were putative transcription factors. Digital gene expression analysis was conducted by comparing transcripts from the untreated control to the three salt treated samples, and 7,330 differentially expressed transcripts were identified. Using k-means clustering, these transcripts were divided into six clusters that differed in their expression patterns across four treatment time points. The genes identified as being up- or downregulated are involved in salt stress responses, signal transduction, and DNA repair. Our study shows the main adaptive pathway of C. tagal in saline environments, under short-term and long term treatments of salt stress. This provides vital clues as to which genes may be candidates for breeding salt-tolerant crops and clarifying molecular mechanisms of salt tolerance in C. tagal. The expression levels of 20 candidate genes measured by RNA-Seq were validated via qRT-PCR. Eighteen genes showed consistent expression patterns in RNA-Seq and qRT-PCR results, suggesting that the RNA-seq dataset was dependable for gene expression pattern analysis. PMID- 27936170 TI - Correction: Phylogenetic Analysis Reveals a Cryptic Species Blastomyces gilchristii, sp. nov. within the Human Pathogenic Fungus Blastomyces dermatitidis. AB - [This corrects the article DOI: 10.1371/journal.pone.0059237.]. PMID- 27936167 TI - The Slavic NBN Founder Mutation: A Role for Reproductive Fitness? AB - The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2. PMID- 27936169 TI - Effects of Supplementation of the Synbiotic Ecologic(r) 825/FOS P6 on Intestinal Barrier Function in Healthy Humans: A Randomized Controlled Trial. AB - BACKGROUND AND AIMS: Probiotics, prebiotics and synbiotics have been suggested as dietary strategies to improve intestinal barrier function. This study aimed to assess the effect of two weeks synbiotic supplementation on intestinal permeability under basal and stressed conditions. Secondary aims were the assessment of two weeks synbiotic supplementation on systemic immune function and gastrointestinal symptoms including defecation pattern. DESIGN: Twenty healthy adults completed a double-blind, controlled, randomized, parallel design study. INTERVENTION: Groups either received synbiotic (1.5 * 1010 CFU Ecologic(r) 825 + 10 g fructo-oligosaccharides (FOS P6) per day) or control supplements for two weeks. OUTCOMES: Intestinal segment specific permeability was assessed non invasively by oral administration of multiple sugar probes and, subsequently, assessing the excretion of these probes in urine. This test was conducted at baseline and at the end of intervention, in the absence and in the presence of an indomethacin challenge. Indomethacin was applied to induce a compromised gut state. Plasma zonulin, cytokines and chemokines were measured at baseline and at the end of intervention. Gastrointestinal symptoms and stool frequency were recorded at baseline and daily during intervention. RESULTS: Significantly more male subjects were in the synbiotic group compared to the control group (P = 0.025). Indomethacin significantly increased urinary lactulose/rhamnose ratio versus without indomethacin, both in the control group (P = 0.005) and in the synbiotic group (P = 0.017). Urinary sugar recoveries and ratios, plasma levels of zonulin, cytokines and chemokines, and gastrointestinal symptom scores were not significantly different after control or synbiotic intervention. Stool frequency within the synbiotic group was significantly increased during synbiotic intervention compared to baseline (P = 0.039) and higher compared to control intervention (P = 0.045). CONCLUSION: Two weeks Ecologic(r) 825/FOS P6 supplementation increased stool frequency, but did not affect intestinal permeability neither under basal nor under indomethacin-induced stressed conditions, immune function or gastrointestinal symptoms in healthy adults. PMID- 27936171 TI - Development of High Tryptophan Maize Near Isogenic Lines Adapted to Temperate Regions through Marker Assisted Selection - Impediments and Benefits. AB - Breeding program aimed at converting standard maize inbred lines to their quality protein maize (QPM) counterparts for growing in temperate climate is being conducted at Maize Research Institute (MRI). The objective of the research presented herein was to develop QPM versions of two commercial ZP inbreds through marker assisted selection (MAS) with opaque2 specific molecular markers, while maintaining their good agronomic performances and combining abilities. Donor line was a tropical QPM line CML 144. After two backcross and three selfing generations, six near isogenic lines (NILs) with 93% recovery of the recurrent parent genome were created from one cross. Average increments of 30% in tryptophan content and 36% in quality index were obtained, as well as kernels with less than 25% opaque endosperm. Grain yield was increased by 11-31% and combining abilities of the improved lines were on a par with the original line. Correlations between biochemical and agronomic parameters revealed that selection for plant height, ear length and kernel row number together with tryptophan content could be recommended for development of QPM with this material. However, several impediments emerged during selection. Major drawbacks in NIL development were small number of opaque2 recessive homozygotes (4.5% and 7.6% in BC2F2 of two crosses) and poor seed set throughout selection, which led to the loss of one cross. Moreover, in the other cross many plants in different generations had to be omitted from further selection due to the insufficient number of kernels. This phenomenon could be explained by incompatibility between pollen and style, possibly due to the exotic donor germplasm. Overall, it could be expected that the use of NILs, which are adapted to temperate climate and have high percentage of domestic germplasm, would outbalance the noted impediments and increase MAS efficiency in different breeding programs. PMID- 27936174 TI - Comparing Dislodgeable 2,4-D Residues across Athletic Field Turfgrass Species and Time. AB - 2,4-dimethylamine salt (2,4-D) is an herbicide commonly applied on athletic fields for broadleaf weed control that can dislodge from treated turfgrass. Dislodge potential is affected by numerous factors, including turfgrass canopy conditions. Building on previous research confirming herbicide-turfgrass dynamics can vary widely between species, field research was initiated in 2014 and 2015 in Raleigh, NC, USA to quantify dislodgeable 2,4-D residues from dormant hybrid bermudagrass (Cynodon dactylon L. x C. transvaalensis) and hybrid bermudagrass overseeded with perennial ryegrass (Lolium perenne L.), which are common athletic field playing surfaces in subtropical climates. Additionally, dislodgeable 2,4-D was compared at AM (7:00 eastern standard time) and PM (14:00) sample timings within a day. Samples collected from perennial ryegrass consistently resulted in greater 2,4-D dislodgment immediately after application (9.4 to 9.9% of applied) compared to dormant hybrid bermudagrass (2.3 to 2.9%), as well as at all AM compared to PM timings from 1 to 3 d after treatment (DAT; 0.4 to 6.3% compared to 0.1 to 0.8%). Dislodgeable 2,4-D did not differ across turfgrass species at PM sample collections, with <= 0.1% of the 2,4-D applied dislodged from 1 to 6 DAT, and 2,4-D detection did not occur at 12 and 24 DAT. In conclusion, dislodgeable 2,4-D from treated turfgrass can vary between species and over short time-scales within a day. This information should be taken into account in human exposure risk assessments, as well as by turfgrass managers and athletic field event coordinators to minimize 2,4-D exposure. PMID- 27936172 TI - Tamoxifen Isomers and Metabolites Exhibit Distinct Affinity and Activity at Cannabinoid Receptors: Potential Scaffold for Drug Development. AB - Tamoxifen (Tam) is a selective estrogen receptor (ER) modulator (SERM) that is an essential drug to treat ER-positive breast cancer. Aside from known actions at ERs, recent studies have suggested that some SERMs like Tam also exhibit novel activity at cannabinoid subtype 1 and 2 receptors (CB1R and CB2Rs). Interestingly, cis- (E-Tam) and trans- (Z-Tam) isomers of Tam exhibit over a 100 fold difference in affinity for ERs. Therefore, the current study assessed individual isomers of Tam and subsequent cytochrome P450 metabolic products, 4 hydroxytamoxifen (4OHT) and 4-hydroxy-N-desmethyl tamoxifen (End) for affinity and activity at CBRs. Results showed that Z-4OHT, but not Z-Tam or Z-End, exhibits higher affinity for both CB1 and CB2Rs relative to the E-isomer. Furthermore, Z- and E-isomers of Tam and 4OHT show slightly higher affinity for CB2Rs, while both End isomers are relatively CB1R-selective. When functional activity was assessed by G-protein activation and regulation of the downstream effector adenylyl cyclase, all isomers examined act as full CB1 and CB2R inverse agonists. Interestingly, Z-Tam appears to be more efficacious than the full inverse agonist AM630 at CB2Rs, while both Z-Tam and Z-End exhibit characteristics of insurmountable antagonism at CB1 and CB2Rs, respectively. Collectively, these results suggest that the SERMs Tam, 4OHT and End elicit ER independent actions via CBRs in an isomer-specific manner. As such, this novel structural scaffold might be used to develop therapeutically useful drugs for treatment of a variety of diseases mediated via CBRs. PMID- 27936173 TI - Insights into Basal Signaling Regulation, Oligomerization, and Structural Organization of the Human G-Protein Coupled Receptor 83. AB - The murine G-protein coupled receptor 83 (mGPR83) is expressed in the hypothalamus and was previously suggested to be involved in the regulation of metabolism. The neuropeptide PEN has been recently identified as a potent GPR83 ligand. Moreover, GPR83 constitutes functionally relevant hetero-oligomers with other G-protein coupled receptors (GPCR) such as the ghrelin receptor (GHSR) or GPR171. Previous deletion studies also revealed that the long N-terminal extracellular receptor domain (eNDo) of mGPR83 may act as an intra-molecular ligand, which participates in the regulation of basal signaling activity, which is a key feature of GPCR function. Here, we investigated particular amino acids at the eNDo of human GPR83 (hGPR83) by side-directed mutagenesis to identify determinants of the internal ligand. These studies were accompanied by structure homology modeling to combine functional insights with structural information. The capacity for hetero-oligomer formation of hGPR83 with diverse family A GPCRs such as the melanocortin-4 receptor (MC4R) was also investigated, with a specific emphasis on the impact of the eNDo on oligomerization and basal signaling properties. Finally, we demonstrate that hGPR83 exhibits an unusual basal signaling for different effectors, which also supports signaling promiscuity. hGPR83 interacts with a variety of hypothalamic GPCRs such as the MC4R or GHSR. These interactions are not dependent on the ectodomain and most likely occur at interfaces constituted in the transmembrane regions. Moreover, several amino acids at the transition between the eNDo and transmembrane helix 1 were identified, where mutations lead also to biased basal signaling modulation. PMID- 27936176 TI - Correction: Role of MicroRNA 1207-5P and Its Host Gene, the Long Non-Coding RNA Pvt1, as Mediators of Extracellular Matrix Accumulation in the Kidney: Implications for Diabetic Nephropathy. AB - [This corrects the article DOI: 10.1371/journal.pone.0077468.]. PMID- 27936175 TI - Effects of Neonatal Dexamethasone Exposure on Adult Neuropsychiatric Traits in Rats. AB - The effects of early life stress in utero or in neonates has long-term consequences on hypothalamic-pituitary-adrenal (HPA) stress axis function and neurodevelopment. These effects extend into adulthood and may underpin a variety of mental illnesses and be related to various developmental and cognitive changes. We examined the potential role of neonatal HPA axis activation on adult psychopathology and dopamine sensitivity in the mature rat using neonatal exposure to the synthetic glucocorticoid receptor agonist and stress hormone, dexamethasone. We utilized a comprehensive battery of assessments for behaviour, brain function and gene expression to determine if elevated early life HPA activation is associated with adult-onset neuropsychiatric traits. Dexamethasone exposure increased startle reactivity under all conditions tested, but decreased sensitivity of sensorimotor gating to dopaminergic disruption-contrasting with what is observed in several neuropsychiatric diseases. Under certain conditions there also appeared to be mild long-term changes in stress and anxiety-related behaviours with neonatal dexamethasone exposure. Electrophysiology revealed that there were no consistent neuropsychiatric abnormalities in auditory processing or resting state brain function with dexamethasone exposure. However, neonatal dexamethasone altered auditory cortex glucocorticoid activation, and auditory cortex synchronization. Our results indicate that neonatal HPA axis activation by dexamethasone alters several aspects of adult brain function and behaviour and may induce long-term changes in emotional stress-reactivity. However, neonatal dexamethasone exposure is not specifically related to any particular neuropsychiatric disease. PMID- 27936177 TI - Rapid Karyotype Evolution in Lasiopodomys Involved at Least Two Autosome - Sex Chromosome Translocations. AB - The generic status of Lasiopodomys and its division into subgenera Lasiopodomys (L. mandarinus, L. brandtii) and Stenocranius (L. gregalis, L. raddei) are not generally accepted because of contradictions between the morphological and molecular data. To obtain cytogenetic evidence for the Lasiopodomys genus and its subgenera and to test the autosome to sex chromosome translocation hypothesis of sex chromosome complex origin in L. mandarinus proposed previously, we hybridized chromosome painting probes from the field vole (Microtus agrestis, MAG) and the Arctic lemming (Dicrostonyx torquatus, DTO) onto the metaphases of a female Mandarin vole (L. mandarinus, 2n = 47) and a male Brandt's vole (L. brandtii, 2n = 34). In addition, we hybridized Arctic lemming painting probes onto chromosomes of a female narrow-headed vole (L. gregalis, 2n = 36). Cross-species painting revealed three cytogenetic signatures (MAG12/18, 17a/19, and 22/24) that could validate the genus Lasiopodomys and indicate the evolutionary affinity of L. gregalis to the genus. Moreover, all three species retained the associations MAG1bc/17b and 2/8a detected previously in karyotypes of all arvicolins studied. The associations MAG2a/8a/19b, 8b/21, 9b/23, 11/13b, 12b/18, 17a/19a, and 5 fissions of ancestral segments appear to be characteristic for the subgenus Lasiopodomys. We also validated the autosome to sex chromosome translocation hypothesis on the origin of complex sex chromosomes in L. mandarinus. Two translocations of autosomes onto the ancestral X chromosome in L. mandarinus led to a complex of neo-X1, neo-X2, and neo-X3 elements. Our results demonstrate that genus Lasiopodomys represents a striking example of rapid chromosome evolution involving both autosomes and sex chromosomes. Multiple reshuffling events including Robertsonian fusions, chromosomal fissions, inversions and heterochromatin expansion have led to the formation of modern species karyotypes in a very short time, about 2.4 MY. PMID- 27936178 TI - Ex Vivo Lung Perfusion in the Rat: Detailed Procedure and Videos. AB - Ex vivo lung perfusion (EVLP) is a promising procedure for evaluation, reconditioning, and treatment of marginal lungs before transplantation. Small animal models can contribute to improve clinical development of this technique and represent a substantial platform for bio-molecular investigations. However, to accomplish this purpose, EVLP models must sustain a prolonged reperfusion without pharmacological interventions. Currently available protocols only partly satisfy this need. The aim of the present research was accomplishment and optimization of a reproducible model for a protracted rat EVLP in the absence of anti-inflammatory treatment. A 180 min, uninjured and untreated perfusion was achieved through a stepwise implementation of the protocol. Flow rate, temperature, and tidal volume were gradually increased during the initial reperfusion phase to reduce hemodynamic and oxidative stress. Low flow rate combined with open atrium and protective ventilation strategy were applied to prevent lung damage. The videos enclosed show management of the most critical technical steps. The stability and reproducibility of the present procedure were confirmed by lung function evaluation and edema assessment. The meticulous description of the protocol provided in this paper can enable other laboratories to reproduce it effortlessly, supporting research in the EVLP field. PMID- 27936179 TI - CO2-Induced ATP-Dependent Release of Acetylcholine on the Ventral Surface of the Medulla Oblongata. AB - Complex mechanisms that detect changes in brainstem parenchymal PCO2/[H+] and trigger adaptive changes in lung ventilation are responsible for central respiratory CO2 chemosensitivity. Previous studies of chemosensory signalling pathways suggest that at the level of the ventral surface of the medulla oblongata (VMS), CO2-induced changes in ventilation are (at least in part) mediated by the release and actions of ATP and/or acetylcholine (ACh). Here we performed simultaneous real-time biosensor recordings of CO2-induced ATP and ACh release from the VMS in vivo and in vitro, to test the hypothesis that central respiratory CO2 chemosensory transduction involves simultaneous recruitment of purinergic and cholinergic signalling pathways. In anaesthetised and artificially ventilated rats, an increase in inspired CO2 triggered ACh release on the VMS with a peak amplitude of ~5 MUM. Release of ACh was only detected after the onset of CO2-induced activation of the respiratory activity and was markedly reduced (by ~70%) by ATP receptor blockade. In horizontal slices of the VMS, CO2-induced release of ATP was reliably detected, whereas CO2 or bath application of ATP (100 MUM) failed to trigger release of ACh. These results suggest that during hypercapnia locally produced ATP induces or potentiates the release of ACh (likely from the medullary projections of distal groups of cholinergic neurones), which may also contribute to the development and/or maintenance of the ventilatory response to CO2. PMID- 27936180 TI - Genetic Diversity and Symbiotic Efficiency of Nodulating Rhizobia Isolated from Root Nodules of Faba Bean in One Field. AB - Thirty-one nodulating rhizobium strains were collected from root nodules of spring and winter type faba bean cultivars grown in micro ecoarea, i.e. the same field in Chengdu plain, China. The symbiotic efficiency and phylogeny of these strains were studied. Effectively nitrogen fixing strains were isolated from both winter type and spring type cultivars. Based on phylogenetic analysis of 16S rRNA gene and concatenated sequence of atpD, glnII and recA genes, the isolates were assigned as Rhizobium anhuiense and a potential new Rhizobium species. The isolates were diverse on symbiosis related gene level, carrying five, four and three variants of nifH, nodC and nodD, respectively. Strains carrying similar gene combinations were trapped by both winter and spring cultivars, disagreeing with the specificity of symbiotic genotypes to reported earlier faba bean ecotypes. PMID- 27936181 TI - In Vivo Modelling of ATP1A3 G316S-Induced Ataxia in C. elegans Using CRISPR/Cas9 Mediated Homologous Recombination Reveals Dominant Loss of Function Defects. AB - The NIH Undiagnosed Diseases Program admitted a male patient with unclassifiable late-onset ataxia-like symptoms. Exome sequencing revealed a heterozygous de novo mutation converting glycine 316 to serine in ATP1A3, which might cause disease. ATP1A3 encodes the Na+/K+ ATPase pump alpha3-subunit. Using CRISPR/Cas9-mediated homologous recombination for genome editing, we modelled this putative disease causing allele in Caenorhabditis elegans, recreating the patient amino acid change in eat-6, the orthologue of ATP1A3. The impact of the mutation on eat-6 function at the neuromuscular junction was examined using two behavioural assays: rate of pharyngeal pumping and sensitivity to aldicarb, a drug that causes paralysis over time via the inhibition of acetylcholinesterase. The patient allele decreased pumping rates and caused hypersensitivity to aldicarb. Animals heterozygous for the allele exhibited similar defects, whereas loss of function mutations in eat-6 were recessive. These results indicate that the mutation is dominant and impairs the neuromuscular function. Thus, we conclude that the de novo G316S mutation in ATP1A3 likely causes or contributes to patient symptoms. More broadly, we conclude that, for conserved genes, it is possible to rapidly and easily model human diseases in C. elegans using CRIPSR/Cas9 genome editing. PMID- 27936182 TI - Structural Changes in Molluscan Community over a 15-Year Period before and after the 2011 Great East Japan Earthquake and Subsequent Tsunami around Matsushima Bay, Miyagi Prefecture, Northeastern Japan. AB - We examined structural changes in the molluscan community for ten years (2001 2010) before and five years (2011-2015) after the 2011 Great East Japan Earthquake and subsequent tsunami around Matsushima Bay, Miyagi Prefecture, northeastern Japan. Before the earthquake and tsunami, Ruditapes philippinarum, Macoma incongrua, Pillucina pisidium, and Batillaria cumingii were dominant, and an alien predator Laguncula pulchella appeared in 2002 and increased in number. After the tsunami, R. philippinarum and M. incongrua populations quickly recovered in 2012, but P. pisidium and B. cumingii populations did not recover until 2015. By contrast, Musculista senhousia, Mya arenaria, Retusa sp., and Solen strictus were found in low densities before the tsunami, but they rapidly increased in abundance/number over five years after the tsunami. These results suggest that the molluscan community on the Tona Coast was drastically changed by the earthquake and tsunami, and some species mainly inhabiting the intertidal subtidal zone may have increased in number because of land subsidence. We also emphasize that the seawall delayed recovery of the intertidal community after the earthquake and tsunami. PMID- 27936183 TI - Molecular Evolution of PTEN Pseudogenes in Mammals. AB - Phosphatase and tensin homolog (PTEN) is a tumor-suppressor gene. PTEN pseudogene (PTENp) acts as an endogenous RNA, which regulates its parental gene by competitively binding to the 3' UTR of PTEN gene in the human. Despite the importance of this pseudogene, little is known about the molecular evolution of PTENp in mammals. In this study, we identified 37 pseudogenes from 65 mammalian genomes. Among them, 32 were from rodents or primates. Phylogenetic analyse showed a complex evolutionary history of this gene family. Some PTENps were shared both in primates and rodents. However, some PTENps were shown to be species-specific, such as the tasmanian devil PTENp1, nine banded armadillo PTENp1 and gibbon PTENp1. Most interestingly, the naked mole rat (NMR), an anticancer model organism, possessed 17 copies of PTENps, which were classified into four clades based on the phylogenetic analyses. Furthermore, we found that all the 3'UTR of PTEN and PTENps shared common microRNA (MicroRNA) binding sites in NMR, based on our prediction of specific MicroRNA binding sites. Our findings suggested that multiple gene duplications have occurred in the formation of PTEN/PTENp gene family during the evolution of mammals. Some PTENps were relatively ancient and were shared by primates and rodents; others were newly originated through species- specific gene duplications. PTENps in NMR may function as competitive endogenous RNAs (ceRNAs) to regulate their counterpart genes by competing for common MicroRNAs, which may be one of the interpretations for the cancer resistance in NMR. PMID- 27936184 TI - Freshwater Detention by Oyster Reefs: Quantifying a Keystone Ecosystem Service. AB - Oyster reefs provide myriad ecosystem services, including water quality improvement, fisheries and other faunal support, shoreline protection from erosion and storm surge, and economic productivity. However, their role in directing flow during non-storm conditions has been largely neglected. In regions where oyster reefs form near the mouth of estuarine rivers, they likely alter ocean-estuary exchange by acting as fresh water "dams". We hypothesize that these reefs have the potential to detain fresh water and influence salinity over extensive areas, thus providing a "keystone" ecosystem service by supporting estuarine functions that rely on the maintenance of estuarine (i.e., brackish) conditions in the near-shore environment. In this work, we investigated the effects of shore-parallel reefs on estuarine salinity using field data and hydrodynamic modeling in a degraded reef complex in the northeastern Gulf of Mexico. Results suggested that freshwater detention by long linear chains of oyster reefs plays an important role in modulating salinities, not only in the oysters' local environment, but over extensive estuarine areas (tens of square kilometers). Field data confirmed the presence of salinity differences between landward and seaward sides of the reef, with long-term mean salinity differences of >30% between sides. Modeled results expanded experimental findings by illustrating how oyster reefs affect the lateral and offshore extent of freshwater influence. In general, the effects of simulated reefs were most pronounced when they were highest in elevation, without gaps, and when riverine discharge was low. Taken together, these results describe a poorly documented ecosystem service provided by oyster reefs; provide an estimate of the magnitude and spatial extent of this service; and offer quantitative information to help guide future oyster reef restoration. PMID- 27936186 TI - Maternal Separation Impairs Cocaine-Induced Behavioural Sensitization in Adolescent Mice. AB - Adverse early-life conditions induce persistent disturbances that give rise to negative emotional states. Therefore, early life stress confers increased vulnerability to substance use disorders, mainly during adolescence as the brain is still developing. In this study, we investigated the consequences of maternal separation, a model of maternal neglect, on the psychotropic effects of cocaine and the neuroplasticity of the dopaminergic system. Our results show that mice exposed to maternal separation displayed attenuated behavioural sensitization, while no changes were found in the rewarding effects of cocaine in the conditioned place preference paradigm and in the reinforcing effects of cocaine in the self-administration paradigm. The evaluation of neuroplasticity in the striatal dopaminergic pathways revealed that mice exposed to maternal separation exhibited decreased protein expression levels of D2 receptors and increased levels of the transcriptional factor Nurr1. Furthermore, animals exposed to maternal separation and treated with cocaine exhibited increased DA turnover and protein expression levels of DAT and D2R, while decreased Nurr1 and Pitx3 protein expression levels were observed when compared with saline-treated mice. Taken together, our data demonstrate that maternal separation caused an impairment of cocaine-induced behavioural sensitization possibly due to a dysfunction of the dopaminergic system, a dysfunction that has been proposed as a factor of vulnerability for developing substance use disorders. PMID- 27936185 TI - Hedgehog Signaling Overcomes an EZH2-Dependent Epigenetic Barrier to Promote Cholangiocyte Expansion. AB - BACKGROUND & AIMS: Developmental morphogens play an important role in coordinating the ductular reaction and portal fibrosis occurring in the setting of cholangiopathies. However, little is known about how membrane signaling events in ductular reactive cells (DRCs) are transduced into nuclear transcriptional changes to drive cholangiocyte maturation and matrix deposition. Therefore, the aim of this study was to investigate potential mechanistic links between cell signaling events and epigenetic regulators in DRCs. METHODS: Using directed differentiation of induced pluripotent stem cells (iPSC), isolated DRCs, and in vivo models, we examine the mechanisms whereby sonic hedgehog (Shh) overcomes an epigenetic barrier in biliary precursors and promotes both cholangiocyte maturation and deposition of fibronectin (FN). RESULTS: We demonstrate, for the first time, that Gli1 influences the differentiation state and fibrogenic capacity of iPSC-derived hepatic progenitors and isolated DRCs. We outline a novel pathway wherein Shh-mediated Gli1 binding in key cholangiocyte gene promoters overcomes an epigenetic barrier conferred by the polycomb protein, enhancer of zeste homolog 2 (EZH2) and initiates the transcriptional program of cholangiocyte maturation. We also define previously unknown functional Gli1 binding sites in the promoters of cytokeratin (CK)7, CK19, and FN. Our in vivo results show that EZH2 KO mice fed the choline-deficient, ethanolamine supplemented (CDE) diet have an exaggerated cholangiocyte expansion associated with more robust ductular reaction and increased peri-portal fibrosis. CONCLUSION: We conclude that Shh/Gli1 signaling plays an integral role in cholangiocyte maturation in vitro by overcoming an EZH2-dependent epigenetic barrier and this mechanism also promotes biliary expansion in vivo. PMID- 27936187 TI - Stroke as the First Manifestation of Atrial Fibrillation. AB - Atrial fibrillation may remain undiagnosed until an ischemic stroke occurs. In this retrospective cohort study we assessed the prevalence of ischemic stroke or transient ischemic attack as the first manifestation of atrial fibrillation in 3,623 patients treated for their first ever stroke or transient ischemic attack during 2003-2012. Two groups were formed: patients with a history of atrial fibrillation and patients with new atrial fibrillation diagnosed during hospitalization for stroke or transient ischemic attack. A control group of 781 patients with intracranial hemorrhage was compiled similarly to explore causality between new atrial fibrillation and stroke. The median age of the patients was 78.3 [13.0] years and 2,009 (55.5%) were women. New atrial fibrillation was diagnosed in 753 (20.8%) patients with stroke or transient ischemic attack, compared to 15 (1.9%) with intracranial hemorrhage. Younger age and no history of coronary artery disease or other vascular diseases, heart failure, or hypertension were the independent predictors of new atrial fibrillation detected concomitantly with an ischemic event. Thus, ischemic stroke was the first clinical manifestation of atrial fibrillation in 37% of younger (<75 years) patients with no history of cardiovascular diseases. In conclusion, atrial fibrillation is too often diagnosed only after an ischemic stroke has occurred, especially in middle-aged healthy individuals. New atrial fibrillation seems to be predominantly the cause of the ischemic stroke and not triggered by the acute cerebrovascular event. PMID- 27936188 TI - Risk Factors for Complications after Reduction Mammoplasty: A Meta-Analysis. AB - BACKGROUND: Reduction mammoplasty (RM) is a proven method of treating macromastia, but the risk factors for postoperative complications have not been clearly identified. Through this meta-analysis, the authors aimed to identify the risk factors of RM complications. METHODS: An extensive search of the literature describing complications after RM was performed using the PubMed Central, Embase, and Cochrane databases. The following risk factors were extracted: age, body mass index (BMI), tissue resection weight per breast (TRW), smoking and radiation therapy. Odds ratios (OR) were pooled with 95% confidence intervals (CI) to evaluate the relationship between these risk factors and complications after RM. RESULTS: A total of 16 unique studies including 10 593 patients were included in the final analysis. It showed that there was a significant difference in complications in BMI >=30 kg/m2 (OR 0.73; 95% CI: 0.61-0.89, p = 0.001) and smoking (OR 1.56; 95% CI: 0.98-2.49, p = 0.06). Infection in those with BMI >=30 kg/m2 showed a significant difference (OR 0.68; 95% CI: 0.52-0.89, p = 0.004), as well as wound dehiscence in smokers (OR 2.73; 95% CI: 1.60-4.67, p = 0.0002) and infection in irradiated breasts (OR 20.38; 95% CI: 3.42-121.35, p = 0.0009). However, there was no significant difference in age >=50 years (OR 0.96; 95% CI: 0.71-1.29, p = 0.78), combined TRW >=1000 g (OR 1.04; 95% CI: 0.43-2.50, p = 0.93). CONCLUSIONS: BMI >=30 kg/m2 and smoking increase the risk of complications. Persons who are obese or irradiated are more likely to develop infections, and smokers experienced a higher incidence of wound dehiscence than did nonsmokers. However, patients aged >=50 years and TRW >=1000 g are not associated with complications from RM. PMID- 27936189 TI - Impact of Attending Physicians' Comments on Residents' Workloads in the Emergency Department: Results from Two J(^o^)PAN Randomized Controlled Trials. AB - OBJECTIVE: To examine whether peppy comments from attending physicians increased the workload of residents working in the emergency department (ED). METHODS: We conducted two parallel-group, assessor-blinded, randomized trials at the ED in a tertiary care hospital in western Japan. Twenty-five residents who examined either ambulatory (J(^o^)PAN-1 Trial) or transferred patients (J(^o^)PAN-2 Trial) in the ED on weekdays. Participants were randomly assigned to groups that either received a peppy message such as "Hope you have a quiet day!" (intervention group) or did not (control group) from the attending physicians. Both trials were conducted from June 2014 through March 2015. For each trial, residents rated the number of patients examined during and the busyness and difficulty of their shifts on a 5-point Likert scale. RESULTS: A total of 169 randomizations (intervention group, 81; control group, 88) were performed for the J(^o^)PAN-1 Trial, and 178 (intervention group, 85; control group, 93) for the J(^o^)PAN-2 Trial. In the J(^o^)PAN-1 trial, no differences were observed in the number of ambulatory patients examined during their shifts (5.5 and 5.7, respectively, p = 0.48), the busyness of their shifts (2.8 vs 2.8; p = 0.58), or the difficulty of their shifts (3.1 vs 3.1, p = 0.94). However, in the J(^o^)PAN-2 trial, although busyness (2.8 vs 2.7; p = 0.40) and difficulty (3.1 vs 3.2; p = 0.75) were similar between groups, the intervention group examined more transferred patients than the control group (4.4 vs 3.9; p = 0.01). CONCLUSIONS: Peppy comments from attending physicians had a minimal jinxing effect on the workload of residents working in the ED. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), UMIN000017193 and UMIN000017194. PMID- 27936191 TI - A Scalable Data Access Layer to Manage Structured Heterogeneous Biomedical Data. AB - This work presents a scalable data access layer, called PyEHR, designed to support the implementation of data management systems for secondary use of structured heterogeneous biomedical and clinical data. PyEHR adopts the openEHR's formalisms to guarantee the decoupling of data descriptions from implementation details and exploits structure indexing to accelerate searches. Data persistence is guaranteed by a driver layer with a common driver interface. Interfaces for two NoSQL Database Management Systems are already implemented: MongoDB and Elasticsearch. We evaluated the scalability of PyEHR experimentally through two types of tests, called "Constant Load" and "Constant Number of Records", with queries of increasing complexity on synthetic datasets of ten million records each, containing very complex openEHR archetype structures, distributed on up to ten computing nodes. PMID- 27936190 TI - Two Isoforms of Yersinia pestis Plasminogen Activator Pla: Intraspecies Distribution, Intrinsic Disorder Propensity, and Contribution to Virulence. AB - It has been shown previously that several endemic Y. pestis isolates with limited virulence contained the I259 isoform of the outer membrane protease Pla, while the epidemic highly virulent strains possessed only the T259 Pla isoform. Our sequence analysis of the pla gene from 118 Y. pestis subsp. microtus strains revealed that the I259 isoform was present exclusively in the endemic strains providing a convictive evidence of more ancestral origin of this isoform. Analysis of the effects of the I259T polymorphism on the intrinsic disorder propensity of Pla revealed that the I259T mutation slightly increases the intrinsic disorder propensity of the C-terminal tail of Pla and makes this protein slightly more prone for disorder-based protein-protein interactions, suggesting that the T259 Pla could be functionally more active than the I259 Pla. This assumption was proven experimentally by assessing the coagulase and fibrinolytic activities of the two Pla isoforms in human plasma, as well as in a direct fluorometric assay with the Pla peptide substrate. The virulence testing of Pla-negative or expressing the I259 and T259 Pla isoforms Y. pestis subsp. microtus and subsp. pestis strains did not reveal any significant difference in LD50 values and dose-dependent survival assays between them by using a subcutaneous route of challenge of mice and guinea pigs or intradermal challenge of mice. However, a significant decrease in time-to-death was observed in animals infected with the epidemic T259 Pla-producing strains as compared to the parent Pla-negative variants. Survival curves of the endemic I259 Pla+ strains fit between them, but significant difference in mean time to death post infection between the Pla-strains and their I259 Pla+ variants could be seen only in the isogenic set of subsp. pestis strains. These findings suggest an essential role for the outer membrane protease Pla evolution in Y. pestis bubonic infection exacerbation that is necessary for intensification of epidemic process from endemic natural focality with sporadic cases in men to rapidly expanding epizootics followed by human epidemic outbreaks, local epidemics or even pandemics. PMID- 27936192 TI - Insecticidal Activity of Melaleuca alternifolia Essential Oil and RNA-Seq Analysis of Sitophilus zeamais Transcriptome in Response to Oil Fumigation. AB - BACKGROUND: The cereal weevil, Sitophilus zeamais is one of the most destructive pests of stored cereals worldwide. Frequent use of fumigants for managing stored product insects has led to the development of resistance in insects. Essential oils from aromatic plants including the tea oil plant, Melaleuca alternifolia may provide environmentally friendly alternatives to currently used pest control agents. However, little is known about molecular events involved in stored product insects in response to plant essential oil fumigation. RESULTS: M. alternifolia essential oil was shown to possess the fumigant toxicity against S. zeamais. The constituent, terpinen-4-ol was the most effective compound for fumigant toxicity. M. alternifolia essential oil significantly inhibited the activity of three enzymes in S. zeamais, including two detoxifying enzymes, glutathione S-transferase (GST), and carboxylesterase (CarE), as well as a nerve conduction enzyme, acetylcholinesterase (AChE). Comparative transcriptome analysis of S. zeamais through RNA-Seq identified a total of 3,562 differentially expressed genes (DEGs), of which 2,836 and 726 were up-regulated and down regulated in response to M. alternifolia essential oil fumigation, respectively. Based on gene ontology (GO) analysis, the majority of DEGs were involved in insecticide detoxification and mitochondrial function. Furthermore, an abundance of DEGs mapped into the metabolism pathway in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database were associated with respiration and metabolism of xenobiotics, including cytochrome P450s, CarEs, GSTs, and ATP-binding cassette transporters (ABC transporters). Some DEGs mapped into the proteasome and phagosome pathway were found to be significantly enriched. These results led us to propose a model of insecticide action that M. alternifolia essential oil likely directly affects the hydrogen carrier to block the electron flow and interfere energy synthesis in mitochondrial respiratory chain. CONCLUSION: This is the first study to perform a comparative transcriptome analysis of S. zeamais in response to M. alternifolia essential oil fumigation. Our results provide new insights into the insecticidal mechanism of M. alternifolia essential oil fumigation against S. zeamais and eventually contribute to the management of this important agricultural pest. PMID- 27936193 TI - Occurrence of Asymptomatic Acute Neuromyelitis Optica Spectrum Disorder-Typical Brain Lesions during an Attack of Optic Neuritis or Myelitis. AB - We aimed to investigate the frequency of asymptomatic acute brain MRI abnormalities accompanying optic neuritis (ON) or myelitis in neuromyelitis optica spectrum disorder (NMOSD) patients with aquaporin-4 antibodies (AQP4-Ab). We reviewed 324 brain MRI scans that were obtained during acute attacks of ON or myelitis, in 165 NMOSD patients with AQP4-Ab. We observed that acute asymptomatic NMOSD-typical brain lesions accompanied 27 (8%) acute attacks of ON or myelitis in 24 (15%) patients. The most common asymptomatic brain abnormalities included edematous corpus callosum lesions (n = 17), followed by lesions on the internal capsule and/or cerebral peduncle lesions (n = 9), periependymal surfaces of the fourth ventricle (n = 5), large deep white matter lesions (n = 4), periependymal cerebral lesions surrounding the lateral ventricles (n = 3), and hypothalamic lesions (n = 1). If asymptomatic NMOSD-typical brain abnormalities were considered as evidence for DIS, while also assuming that the AQP4-IgG status was unknown, the median time to diagnosis using the 2015 diagnosis criteria for NMOSD was shortened from 28 months to 6 months (p = 0.008). Asymptomatic acute NMOSD typical brain lesions can be accompanied by an acute attack of ON or myelitis. Identifying these asymptomatic brain lesions may help facilitate earlier diagnosis of NMOSD. PMID- 27936194 TI - Change in 18F-Fluoromisonidazole PET Is an Early Predictor of the Prognosis in the Patients with Recurrent High-Grade Glioma Receiving Bevacizumab Treatment. AB - BACKGROUND: Bevacizumab (BEV), a humanized monoclonal antibody, become a currently important chemotherapeutic option for the patients with recurrent glioma. The aim of this retrospective study is to investigate whether 18F Fluoromisonidazole (FMISO) PET have the potential to detect BEV-resistant gliomas in the early-stage. METHODS: We reviewed the FMISO PET and MRI appearances before and 3 to 4 courses after BEV treatment on 18 recurrent glioma patients. FMISO accumulation was assessed by visual inspection and semi-quantitative values which were tumor-to-normal (T/N) ratio and hypoxic volume. MRI responses were evaluated based on RANO (Response Assessment in Neuro-Oncology) criteria. The prognostic analysis was performed in relation to the response assessment by FMISO PET and MRI using overall survival (OS) after BEV application. RESULTS: After BEV application, MRI revealed partial response in 14 of 18 patients (78%), of which 9 patients also demonstrated decreased FMISO accumulation. These 9 patients (50%) were classified as "MRI-FMISO double responder". As for the other 5 patients (28%), FMISO accumulation volumes increased or remained stable after BEV treatment although partial responses were achieved on MRI. Therefore, these cases were classified as "MRI-only responder". The remaining 4 patients (22%) did not show treatment response on FMISO PET or MRI ("non-responder"). MRI-FMISO double responders showed significantly longer OS than that in other groups (median 12.4 vs 5.7 months; P < 0.001), whereas there were no overall survival difference between MRI-only responders and non-responders (median OS, 5.7 and 4.8 months; P = 0.58). Among the pre-treatment clinical factors, high FMISO T/N ratio was a significant prognostic factor of overall survival in these patients under the assessment of Cox proportional hazard model. CONCLUSIONS: Recurrent gliomas with decreasing FMISO accumulation after short-term BEV application could derive a survival benefit from BEV treatment. Change in FMISO PET appearance can identify BEV-resistant gliomas in early-stage regardless of MRI findings in a comprehensible way. PMID- 27936195 TI - Plaque Characteristics in Coronary Artery Disease Patients with Impaired Glucose Tolerance. AB - BACKGROUND: Impaired glucose tolerance (IGT) patients are known to have a high risk of cardiovascular events and their prognosis has been reported to be poor. The present study aimed to compare coronary plaque characteristics among coronary artery disease (CAD) patients with normal glucose tolerance (NGT), those with IGT, and those with diabetes mellitus (DM) by using optical coherence tomography (OCT). METHODS: The present study included 101 coronary artery disease patients (mean age, 67.9 +/- 10.4 years; 82.4% male). OCT was performed for target and non target vessels during percutaneous coronary intervention. The patients were divided into the following 3 groups: the NGT, IGT, and DM groups. RESULTS: A total of 136 non-target residual plaques were found in 101 patients (27, 30, and 44 in the NGT, IGT, and DM groups, respectively). The size of the lipid core expressed as the mean angle of the lipid arc was significantly greater in the IGT and DM groups than in the NGT group (163.0 +/- 58.7 degrees , 170.1 +/- 59.3 degrees , and 130.9 +/- 37.7 degrees , respectively, P < 0.05). The fibrous cap covering the lipid core was significantly thinner in the IGT group than in the NGT group (77.0 +/- 23.4 MUm vs. 105.6 +/- 47.0 MUm, P = 0.040). CONCLUSION: The coronary plaques in CAD patients are more vulnerable when having IGT compared to those with NGT, and similar to those with DM. This finding may explain the high risk of cardiovascular events in CAD patients with IGT. PMID- 27936196 TI - Resilience and Associated Factors among Mainland Chinese Women Newly Diagnosed with Breast Cancer. AB - PURPOSE: Resilience is the individual's ability to bounce back from trauma. It has been studied for some time in the U.S., but few studies in China have addressed this important construct. In mainland China, relatively little is known about the resilience of patients in clinical settings, especially among patients with breast cancer. In this study, we aimed to evaluate the level of resilience and identify predictors of resilience among mainland Chinese women newly diagnosed with breast cancer. METHODS: A cross-sectional descriptive study was conducted with 213 mainland Chinese women newly diagnosed with breast cancer between November 2014 and June 2015. Participants were assessed with the Connor Davidson Resilience Scale (CD-RISC), Social Support Rating Scale (SSRS), Medical Coping Modes Questionnaire (MCMQ, including 3 subscales: confrontation, avoidance, and acceptance-resignation), Herth Hope Index (HHI), and demographic and disease-related information. Descriptive statistics, bivariate analyses and multiple stepwise regression were conducted to explore predictors for resilience. RESULTS: The average score for CD-RISC was 60.97, ranging from 37 to 69. Resilience was positively associated with educational level, family income, time span after diagnosis, social support, confrontation, avoidance, and hope. However, resilience was negatively associated with age, body mass index (BMI), and acceptance-resignation. Multiple stepwise regression analysis indicated that hope (beta = 0.343, P<0.001), educational level of junior college or above (beta = 0.272, P<0.001), educational level of high school (beta = 0.235, P<0.001), avoidance (beta = 0.220, P<0.001), confrontation (beta = 0.187, P = 0.001), and age (beta = -0.108, P = 0.037) significantly affected resilience and explained 50.1% of the total variance in resilience. CONCLUSIONS: Women with newly diagnosed breast cancer from mainland China demonstrated particularly low resilience level, which was predicted by hope educational level, avoidance, confrontation, and age. PMID- 27936197 TI - Vascular Tone Regulation Induced by C-Type Natriuretic Peptide: Differences in Endothelium-Dependent and -Independent Mechanisms Involved in Normotensive and Spontaneously Hypertensive Rats. AB - Given that the role of C-type natriuretic peptide (CNP) in the regulation of vascular tone in hypertensive states is unclear, we hypothesized that impaired response of the nitric oxide system to CNP in spontaneously hypertensive rats (SHR) could affect vascular relaxation induced by the peptide in this model of hypertension, and that other endothelial systems or potassium channels opening could also be involved. We examined the effect of CNP on isolated SHR aortas, and the hindlimb vascular resistance (HVR) in response to CNP administration compared to normotensive rats. Aortas were mounted in an isometric organ bath and contracted with phenylephrine. CNP relaxed arteries in a concentration-dependent manner but was less potent in inducing relaxation in SHR. The action of CNP was diminished by removal of the endothelium, inhibition of nitric oxide synthase by Nomega-nitro-L-arginine methyl ester, and inhibition of soluble guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one in both groups. In contrast, blockade of cyclooxygenase or subtype 2 bradykinin receptor increased CNP potency only in SHR. In both Wistar and SHR, CNP relaxation was blunted by tetraethylammonium and partially inhibited by BaCl2 and iberiotoxin, indicating that it was due to opening of the Kir and BKCa channels. However, SHR seem to be more sensitive to Kir channel blockade and less sensitive to BKCa channel blockade than normotensive rats. In addition, CNP decreases HVR in Wistar and SHR, but the effect of CNP increasing blood flow was more marked in SHR. We conclude that CNP induces aorta relaxation by activation of the nitric oxide system and opening of potassium channels, but the response to the peptide is impaired in conductance vessel of hypertensive rats. PMID- 27936198 TI - Tree Diversity Enhances Stand Carbon Storage but Not Leaf Area in a Subtropical Forest. AB - Research about biodiversity-productivity relationships has focused on herbaceous ecosystems, with results from tree field studies only recently beginning to emerge. Also, the latter are concentrated largely in the temperate zone. Tree species diversity generally is much higher in subtropical and tropical than in temperate or boreal forests, with reasons not fully understood. Niche overlap and thus complementarity in the use of resources that support productivity may be lower in forests than in herbaceous ecosystems, suggesting weaker productivity responses to diversity change in forests. We studied stand basal area, vertical structure, leaf area, and their relationship with tree species richness in a subtropical forest in south-east China. Permanent forest plots of 30 x 30 m were selected to span largely independent gradients in tree species richness and secondary successional age. Plots with higher tree species richness had a higher stand basal area. Also, stand basal area increases over a 4-year census interval were larger at high than at low diversity. These effects translated into increased carbon stocks in aboveground phytomass (estimated using allometric equations). A higher variability in tree height in more diverse plots suggested that these effects were facilitated by denser canopy packing due to architectural complementarity between species. In contrast, leaf area was not or even negatively affected by tree diversity, indicating a decoupling of carbon accumulation from leaf area. Alternatively, the same community leaf area might have assimilated more C per time interval in more than in less diverse plots because of differences in leaf turnover and productivity or because of differences in the display of leaves in vertical and horizontal space. Overall, our study suggests that in species-rich forests niche-based processes support a positive diversity-productivity relationship and that this translates into increased carbon storage in long-lived woody structures. Given the high growth rates of these forests during secondary succession, our results further indicate that a forest management promoting tree diversity after disturbance may accelerate CO2 sequestration from the atmosphere and thus be relevant in a climate-change context. PMID- 27936200 TI - Correction: Assessment of Telomere Length in Archived Formalin-Fixed, Paraffinized Human Tissue Is Confounded by Chronological Age and Storage Duration. AB - [This corrects the article DOI: 10.1371/journal.pone.0161720.]. PMID- 27936199 TI - Circulating Microvesicles Are Elevated Acutely following Major Burns Injury and Associated with Clinical Severity. AB - Microvesicles are cell-derived signaling particles emerging as important mediators and biomarkers of systemic inflammation, but their production in severe burn injury patients has not been described. In this pilot investigation, we measured circulating microvesicle levels following severe burns, with severe sepsis patients as a comparator group. We hypothesized that levels of circulating vascular cell-derived microvesicles are elevated acutely following burns injury, mirroring clinical severity due to the early onset and prevalence of systemic inflammatory response syndrome (SIRS) in these patients. Blood samples were obtained from patients with moderate to severe thermal injury burns, with severe sepsis, and from healthy volunteers. Circulating microvesicles derived from total leukocytes, granulocytes, monocytes, and endothelial cells were quantified in plasma by flow cytometry. All circulating microvesicle subpopulations were elevated in burns patients on day of admission (day 0) compared to healthy volunteers (leukocyte-microvesicles: 3.5-fold, p = 0.005; granulocyte microvesicles: 12.8-fold, p<0.0001; monocyte-microvesicles: 20.4-fold, p<0.0001; endothelial- microvesicles: 9.6-fold, p = 0.01), but decreased significantly by day 2. Microvesicle levels were increased with severe sepsis, but less consistently between patients. Leukocyte- and granulocyte-derived microvesicles on day 0 correlated with clinical assessment scores and were higher in burns ICU non-survivors compared to survivors (leukocyte MVs 4.6 fold, p = 0.002; granulocyte MVs 4.8 fold, p = 0.003). Mortality prediction analysis of area under receiver operating characteristic curve was 0.92 (p = 0.01) for total leukocyte microvesicles and 0.85 (p = 0.04) for granulocyte microvesicles. These findings demonstrate, for the first time, acute increases in circulating microvesicles following burns injury in patients and point to their potential role in propagation of sterile SIRS-related pathophysiology. PMID- 27936201 TI - Sterol O-Acyltransferase 2 Contributes to the Yolk Cholesterol Trafficking during Zebrafish Embryogenesis. AB - To elucidate whether Sterol O-acyltransferase (Soat) mediates the absorption and transportation of yolk lipids to the developing embryo, zebrafish soat1 and soat2 were cloned and studied. In the adult zebrafish, soat1 was detected ubiquitously while soat2 mRNA was detected specifically in the liver, intestine, brain and testis. Whole mount in situ hybridization demonstrated that both soat1 and soat2 expressed in the yolk syncytial layer, hatching gland and developing cardiovascular as well as digestive systems, suggesting that Soats may play important roles in the lipid trafficking and utilization during embryonic development. The enzymatic activity of zebrafish Soat2 was confirmed by Oil Red O staining in the HEK293 cells overexpressing this gene, and could be quenched by Soat2 inhibitor Pyripyropene A (PPPA). The zebrafish embryos injected with PPPA or morpholino oligo against soat2 in the yolk showed significantly larger yolk when compared with wild-type embryos, especially at 72 hpf, indicating a slower rate of yolk consumption. Our result indicated that zebrafish Soat2 is catalytically active in synthesizing cholesteryl esters and contributes to the yolk cholesterol trafficking during zebrafish embryogenesis. PMID- 27936202 TI - New Altered Non-Fibrillar Collagens in Human Dilated Cardiomyopathy: Role in the Remodeling Process. AB - BACKGROUND: In dilated cardiomyopathy (DCM), cardiac failure is accompanied by profound alterations of extracellular matrix associated with the progression of cardiac dilation and left ventricular (LV) dysfunction. Recently, we reported alterations of non-fibrillar collagen expression in ischemic cardiomyopathy linked to fibrosis and cardiac remodeling. We suspect that expression changes in genes coding for non-fibrillar collagens may have a potential role in DCM development. OBJECTIVES: This study sought to analyze changes in the expression profile of non-fibrillar collagen genes in patients with DCM and to examine relationships between cardiac remodeling parameters and the expression levels of these genes. METHODS AND RESULTS: Twenty-three human left ventricle tissue samples were obtained from DCM patients (n = 13) undergoing heart transplantation and control donors (n = 10) for RNA sequencing analysis. We found increased mRNA levels of six non-fibrillar collagen genes, such as COL4A5, COL9A1, COL21A1, and COL23A1 (P < 0.05 for all), not previously described in DCM. Protein levels of COL8A1 and COL16A1 (P < 0.05 for both), were correspondingly increased. We also identified TGF-beta1 significantly upregulated and related to both COL8A1 and COL16A1. Interestingly, we found a significant relationship between LV mass index and the gene expression level of COL8A1 (r = 0.653, P < 0.05). CONCLUSIONS: In our research, we identified new non-fibrillar collagens with altered expression in DCM, being COL8A1 overexpression directly related to LV mass index, suggesting that they may be involved in the progression of cardiac dilation and remodeling. PMID- 27936203 TI - Early Respiratory Infections and Dental Caries in the First 27 Years of Life: A Population-Based Cohort Study. AB - Early-life respiratory tract infections (RTIs) and dental caries are among the most common infectious diseases worldwide. The relations between early RTIs and development of caries in permanent teeth have not been studied earlier. We assessed childhood RTIs as potential predictors of caries in young adulthood in a 20-year prospective population-based cohort study (The Espoo Cohort Study). Information on lower respiratory tract infections (LRTIs) that had required hospitalization was retrieved from the National Hospital Discharge Registry (n = 1623). Additional information on LRTIs and upper RTIs (URTIs) was assessed based on the questionnaire reports that covered the preceding 12 months. Caries was measured as the number of teeth with fillings (i.e. filled teeth, FT) reported in the 20-year follow-up questionnaire. The absolute and relative excess numbers of FT were estimated applying negative binomial regression. The mean number of FT in young adulthood was 1.4 greater among subjects who had experienced LRTIs requiring hospitalization before the age of 2 years (SD 4.8) compared to those without any such infections (SD 3.4), and the adjusted relative excess number of FT was 1.5 (95% CI 1.0-2.2). LRTIs up to 7 years were associated with an absolute increase of 0.9 in the mean FT number, the adjusted relative excess being 1.3 (1.0-1.8). Also the questionnaire-based LRTIs (adjusted relative excess 1.3; 95% CI 0.9-1.8) and URTIs (adjusted relative excess 1.4, 1.0-1.8) before the age of 2 years predicted higher occurrence of FT. Findings suggest that early RTIs have a role in the development of dental caries in permanent teeth. PMID- 27936205 TI - Hyperhomocysteinemia in ApoE-/- Mice Leads to Overexpression of Enhancer of Zeste Homolog 2 via miR-92a Regulation. AB - Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases, such as atherosclerosis. HHcy promotes atherogenesis by modifying the histone methylation patterns and miRNA regulation. In this study, we investigated the effects of homocysteine (Hcy) on the expression of enhancer of zeste homolog 2 (EZH2), and tested our hypothesis that Hcy-induced atherosclerosis is mediated by increased EZH2 expression, which is regulated by miR-92a. The levels of EZH2 and H3K27me3 were increased in the aorta of ApoE-/- mice fed a high-methionine diet for 16 weeks, whereas miR-92a expression was decreased. Over-expression of EZH2 increased H3K27me3 level and the accumulation of total cholesterol and triglycerides in the foam cells. Furthermore, upregulation of miR-92a reduced EZH2 expression in the foam cells. These data suggested that EZH2 plays a key role in Hcy-mediated lipid metabolism disorders, and that miR-92a may be a novel therapeutic target in Hcy-related atherosclerosis. PMID- 27936204 TI - Serotypes and Antimicrobial Resistance in Salmonella enterica Recovered from Clinical Samples from Cattle and Swine in Minnesota, 2006 to 2015. AB - Salmonellosis remains one of the leading causes of foodborne disease worldwide despite preventive efforts at various stages of the food production chain. The emergence of multi-drug resistant (MDR) non-typhoidal Salmonella enterica represents an additional challenge for public health authorities. Food animals are considered a major reservoir and potential source of foodborne salmonellosis; thus, monitoring of Salmonella strains in livestock may help to detect emergence of new serotypes/MDR phenotypes and to gain a better understanding of Salmonella epidemiology. For this reason, we analyzed trends over a nine-year period in serotypes, and antimicrobial resistance, of Salmonella isolates recovered at the Minnesota Veterinary Diagnostic Laboratory (MVDL) from swine (n = 2,537) and cattle (n = 1,028) samples. Prevalence of predominant serotypes changed over time; in swine, S. Typhimurium and S. Derby decreased and S. Agona and S. 4,5,12:i:- increased throughout the study period. In cattle, S. Dublin, S. Montevideo and S. Cerro increased and S. Muenster became less frequent. Median minimum inhibitory concentration (MIC) values and proportion of antibiotic resistant isolates were higher for those recovered from swine compared with cattle, and were particularly high for certain antibiotic-serotype combinations. The proportion of resistant swine isolates was also higher than observed in the NARMS data, probably due to the different cohort of animals represented in each dataset. Results provide insight into the dynamics of antimicrobial resistant Salmonella in livestock in Minnesota, and can help to monitor emerging trends in antimicrobial resistance. PMID- 27936206 TI - Abdominal Adiposity, Not Cardiorespiratory Fitness, Mediates the Exercise-Induced Change in Insulin Sensitivity in Older Adults. AB - Abdominal obesity and low cardiorespiratory fitness (CRF) are associated with insulin resistance in older adults. Exercise is associated with improvement in insulin sensitivity. Whether this association is mediated by change in CRF and/or abdominal obesity is unclear. The current study is a secondary analysis of data from a randomized controlled trial in Kingston, Ontario. Sedentary older adults (60-80 years) (N = 80) who completed the exercise (N = 59) or control (N = 21) conditions for 6 months were included. CRF was measured using a treadmill test, adipose tissue (AT) by magnetic resonance imaging, and insulin sensitivity by hyperinsulinemic-euglycemic clamp. Waist circumference (WC) was measured at the iliac crest. Mediation analyses were used to assess whether abdominal AT and/or CRF mediated the exercise-induced change in insulin sensitivity. By comparison to controls, reduction (mean +/- SD) was observed for visceral (-0.4 +/- 0.4 kg) and abdominal subcutaneous (-0.4 +/- 0.4) AT depots, WC (-4.1 +/- 3.2 cm) and BMI ( 0.9 +/- 0.8 kg/m2) (p < 0.05). Insulin sensitivity (4.2 +/- 5.2 M/I) and CRF (0.2 +/- 0.3 L/min) improved in the exercise group (p < 0.05). All AT variables, BMI and WC were mediators of the change in insulin sensitivity (p < 0.05). After adjustment for change in total AT, abdominal AT remained a mediator with an effect ratio of 0.79 (p < 0.05), whereas total AT was not significant when adjusted for abdominal AT (p > 0.05). The effect ratio for change in WC and BMI combined (0.63, p<0.05) was greater than either alone. In conclusion, CRF did not mediate the exercise-induced change in insulin sensitivity in older adults. Abdominal adiposity was a strong mediator independent of change in total adiposity. PMID- 27936207 TI - Correction: Investigation of a Measles Outbreak in China to Identify Gaps in Vaccination Coverage, Routes of Transmission, and Interventions. AB - [This corrects the article DOI: 10.1371/journal.pone.0133983.]. PMID- 27936209 TI - Occurrence and Spread of the Invasive Asian Bush Mosquito Aedes japonicus japonicus (Diptera: Culicidae) in West and North Germany since Detection in 2012 and 2013, Respectively. AB - The invasive Asian bush mosquito Aedes japonicus japonicus was first recognised as established in Germany in 2008. In addition to the first known and quickly expanding population in the southwestern part of the country, three separate populations were discovered in West, North and southeastern Germany in 2012, 2013 and 2015, respectively, by means of the 'Mueckenatlas', a German instrument of passive mosquito surveillance. Since the first findings of mosquito specimens in West and North Germany, these regions were checked annually for continuing colonisation and spread of the species. Both affected areas were covered by a virtual 10x10km2 grid pattern in the cells of which cemeteries were screened for immature stages of the mosquito. The cells were considered populated as soon as larvae or pupae were detected, whereas they were classified as negative when no mosquito stages were found in the cemeteries of at least three different towns or villages. Presence was also recorded when Ae. j. japonicus adults were submitted to the 'Mueckenatlas' from the respective cell or when there was evidence of local occurrence in localities other than cemeteries. Based on this approach, a significant expansion of the populated area was documented in West Germany since the first detection of Ae. j. japonicus in 2012 (increase in positive grid cells by more than 400%), while the North German population appears not to be expanding so far (reduction of positive grid cells by ca. 30% since 2013). As Ae. j. japonicus finds suitable climatic and ecological conditions in Germany, the differential expansion of the two populations might be attributed to the West German population being older and thus more firmly established than the closely related but younger North German population that might still be in its founder phase. However, geographic spread of all German populations in the future is anticipated. Continuous surveillance is recommended, as Ae. j. japonicus is a competent vector of several pathogens in the laboratory. PMID- 27936208 TI - Developmental Stage, Muscle and Genetic Type Modify Muscle Transcriptome in Pigs: Effects on Gene Expression and Regulatory Factors Involved in Growth and Metabolism. AB - Iberian pig production includes purebred (IB) and Duroc-crossbred (IBxDU) pigs, which show important differences in growth, fattening and tissue composition. This experiment was conducted to investigate the effects of genetic type and muscle (Longissimus dorsi (LD) vs Biceps femoris (BF)) on gene expression and transcriptional regulation at two developmental stages. Nine IB and 10 IBxDU piglets were slaughtered at birth, and seven IB and 10 IBxDU at four months of age (growing period). Carcass traits and LD intramuscular fat (IMF) content were measured. Muscle transcriptome was analyzed on LD samples with RNA-Seq technology. Carcasses were smaller in IB than in IBxDU neonates (p < 0.001), while growing IB pigs showed greater IMF content (p < 0.05). Gene expression was affected (p < 0.01 and Fold change > 1.5) by the developmental stage (5,812 genes), muscle type (135 genes), and genetic type (261 genes at birth and 113 at growth). Newborns transcriptome reflected a highly proliferative developmental stage, while older pigs showed upregulation of catabolic and muscle functioning processes. Regarding the genetic type effect, IBxDU newborns showed enrichment of gene pathways involved in muscle growth, in agreement with the higher prenatal growth observed in these pigs. However, IB growing pigs showed enrichment of pathways involved in protein deposition and cellular growth, supporting the compensatory gain experienced by IB pigs during this period. Moreover, newborn and growing IB pigs showed more active glucose and lipid metabolism than IBxDU pigs. Moreover, LD muscle seems to have more active muscular and cell growth, while BF points towards lipid metabolism and fat deposition. Several regulators controlling transcriptome changes in both genotypes were identified across muscles and ages (SIM1, PVALB, MEFs, TCF7L2 or FOXO1), being strong candidate genes to drive expression and thus, phenotypic differences between IB and IBxDU pigs. Many of the identified regulators were known to be involved in muscle and adipose tissues development, but others not previously associated with pig muscle growth were also identified, as PVALB, KLF1 or IRF2. The present study discloses potential molecular mechanisms underlying phenotypic differences observed between IB and IBxDU pigs and highlights candidate genes implicated in these molecular mechanisms. PMID- 27936210 TI - Genetic Analysis and QTL Mapping of Fruit Peduncle Length in Cucumber (Cucumis sativus L.). AB - Mechanized harvesting of cucumbers offers significant advantages compared to manual labor as both shortages and costs of labor increase. However the efficient use of machines depends on breeding plants with longer peduncles, but the genetic and molecular basis of fruit peduncle development in cucumber is not well understood. In this study, F2 populations were developed from a cross between two inbred lines, 1101 with a long peduncle and 1694 with a short peduncle. These were grown at two field sites, Hainan, with a tropical marine climate, in December 2014, and Beijing, with a warm temperate climate, in May 2015. Electron microscope examination of the pith cells in the peduncles of the two parental lines showed that line 1101 had significantly greater numbers of smaller cells compared to line 1694. The inheritance of cucumber fruit peduncle length (FPL) was investigated by the mixed major gene and polygene inheritance model. Genetic analysis indicated that FPL in cucumber is quantitatively inherited and controlled by one additive major gene and additive-dominant polygenes (D-2 model). A total of 1460 pairs of SSR (simple sequence repeat) primers were analyzed to identify quantitative trait loci (QTLs). Two similar genetic maps with 78 SSR markers which covered 720.6 cM in seven linkage groups were constructed based on two F2 populations. QTL analysis from the data collected at the two field sites showed that there are two minor QTLs on chromosome 1, named qfpl1.1 and qfpl1.2, and one major QTL on chromosome 6, named qfpl6.1. The marker UW021226, which was the closest one to qfpl6.1, had an accuracy rate of 79.0% when tested against plants selected from populations of the two parents. The results from this study provide insights into the inheritance and molecular mechanism of the variation of FPL in cucumber, and further research will be carried out to fine map qfpl6.1 to develop more accurate markers for MAS breeding. PMID- 27936211 TI - Reliability of Diagnosis and Clinical Efficacy of Cranial Osteopathy: A Systematic Review. AB - CONTEXT: In 2010, the World Health Organization released benchmarks for training in osteopathy in which they considered cranial osteopathy as an important osteopathic skill. However, the evidence supporting the reliability of diagnosis and the efficacy of treatment in this field appears scientifically weak and inconsistent. OBJECTIVES: To identify and critically evaluate the scientific literature dealing with the reliability of diagnosis and the clinical efficacy of techniques and therapeutic strategies used in cranial osteopathy. METHODS: Relevant keywords were used to search the electronic databases MEDLINE, PEDro, OSTMED.DR, Cochrane Library, and in Google Scholar, Journal of American Osteopathy Association and International Journal of Osteopathic Medicine websites. Searches were conducted up to end June 2016 with no date restriction as to when the studies were completed. As a complementary approach we explored the bibliography of included articles and consulted available previous reviews dealing with this topic. STUDY SELECTION: Regarding diagnostic processes in cranial osteopathy, we analyzed studies that compared the results obtained by at least two examiners or by the same examiner on at least two occasions. For efficacy studies, only randomized-controlled-trials or crossover-studies were eligible. We excluded articles that were not in English or French, and for which the full-text version was not openly available. We also excluded studies with unsuitable study design, in which there was no clear indication of the use of techniques or therapeutic strategies concerning the cranial field, looked at combined treatments, used a non-human examiner and subjects or used healthy subjects for efficacy studies. There was no restriction regarding the type of disease. SEARCH RESULTS: In our electronic search we found 1280 references concerning reliability of diagnosis studies plus four references via our complementary strategy. Based on the title 18 articles were selected for analysis. Nine were retained after applying our exclusion criteria. Regarding efficacy, we extracted 556 references from the databases plus 14 references through our complementary strategy. Based on the title 46 articles were selected. Thirty two articles were not retained on the grounds of our exclusion criteria. DATA EXTRACTION AND ANALYSIS: Risk of bias in reliability studies was assessed using a modified version of the quality appraisal tool for studies of diagnostic reliability. The methodological quality of the efficacy studies was assessed using the Cochrane risk of bias tool. Two screeners conducted these analyses. RESULTS: For reliability studies, our analysis leads us to conclude that the diagnostic procedures used in cranial osteopathy are unreliable in many ways. For efficacy studies, the Cochrane risk of bias tool we used shows that 2 studies had a high risk of bias, 9 were rated as having major doubt regarding risk of bias and 3 had a low risk of bias. In the 3 studies with a low risk of bias alternative interpretations of the results, such as a non-specific effect of treatment, were not considered. CONCLUSION: Our results demonstrate, consistently with those of previous reviews, that methodologically strong evidence on the reliability of diagnostic procedures and the efficacy of techniques and therapeutic strategies in cranial osteopathy is almost non-existent. PMID- 27936212 TI - Effect of Simultaneous Bilingualism on Speech Intelligibility across Different Masker Types, Modalities, and Signal-to-Noise Ratios in School-Age Children. AB - Recognizing speech in adverse listening conditions is a significant cognitive, perceptual, and linguistic challenge, especially for children. Prior studies have yielded mixed results on the impact of bilingualism on speech perception in noise. Methodological variations across studies make it difficult to converge on a conclusion regarding the effect of bilingualism on speech-in-noise performance. Moreover, there is a dearth of speech-in-noise evidence for bilingual children who learn two languages simultaneously. The aim of the present study was to examine the extent to which various adverse listening conditions modulate differences in speech-in-noise performance between monolingual and simultaneous bilingual children. To that end, sentence recognition was assessed in twenty-four school-aged children (12 monolinguals; 12 simultaneous bilinguals, age of English acquisition <= 3 yrs.). We implemented a comprehensive speech-in-noise battery to examine recognition of English sentences across different modalities (audio-only, audiovisual), masker types (steady-state pink noise, two-talker babble), and a range of signal-to-noise ratios (SNRs; 0 to -16 dB). Results revealed no difference in performance between monolingual and simultaneous bilingual children across each combination of modality, masker, and SNR. Our findings suggest that when English age of acquisition and socioeconomic status is similar between groups, monolingual and bilingual children exhibit comparable speech-in-noise performance across a range of conditions analogous to everyday listening environments. PMID- 27936215 TI - Correction: PlexinD1 Is a Novel Transcriptional Target and Effector of Notch Signaling in Cancer Cells. AB - [This corrects the article DOI: 10.1371/journal.pone.0164660.]. PMID- 27936214 TI - Deep Neuromuscular Block Improves Surgical Conditions during Bariatric Surgery and Reduces Postoperative Pain: A Randomized Double Blind Controlled Trial. AB - BACKGROUND: It remains unknown whether the administration of a deep neuromuscular block (NMB) during bariatric surgery improves surgical conditions and patient outcome. The authors studied the effect of deep versus moderate NMB in laparoscopic bariatric surgery on surgical conditions and postoperative pain. METHODS AND RESULTS: One hundred patients scheduled to undergo elective bariatric surgery were randomized to a deep NMB (post-tetanic-count 2-3) or a moderate NMB (train-of-four 1-2). The quality of the surgical field was scored using the Leiden-Surgical Rating Scale (L-SRS), a 5-point scale ranging from 1 (extremely poor conditions) to 5 (optimal conditions). Three surgeons scored the L-SRS at 10 min intervals during surgery; postoperative pain scores were obtained in the postanesthesia-care-unit (PACU) and on the ward. Mean (95% confidence interval) L SRS scores in moderate NMB 4.2 (4.0-4.4) versus 4.8 (4.7-4.9) in deep NMB (p < 0.001). Moderate NMB resulted in 17% of scores at L-SRS scores of 1-3, while deep NMB resulted in 100% scores at the high end of the L-SRS (4-5). Deep NMB led to improved pain scores in the PACU (4.6 (4.2-4.9) versus 3.9 (3.6-4.4), p = 0.03) and reduced shoulder pain on the ward (1.8 (1.5-2.1) versus 1.3 (1.1-1.5), p = 0.03). A composite score of pain and opioid use in the PACU favoured deep NMB (p = 0.001). CONCLUSIONS: In bariatric surgery, deep relaxation has advantages for surgeon and patient. Compared to moderate NMB, deep NMB produced stable and improved surgical conditions with less postoperative pain. PMID- 27936213 TI - Radiologic-Histopathologic Correlation of Cerebral Microbleeds Using Pre-Mortem and Post-Mortem MRI. AB - INTRODUCTION: Cerebral microbleeds (CMB), also known as cerebral microhemorrhages, are small areas of susceptibility on brain magnetic resonance imaging (MRI), that are increasingly detected due to the higher availability of high-field MRI systems and dedicated pulse sequences. The prevalence of CMBs increases in cases with cognitive decline. The current investigation assessed the poorly investigated radiologic-histopathologic correlation of CMBs on MRI. METHODS: The local ethical committee approved the current investigation. We retrospectively assessed a consecutive series of 1303 autopsy cases hospitalized in Geneva University Hospitals between 2000-2014. Of 112 cases with pre-mortem T2* sequences, we included 25 cases (mean age 77.3 +/- 9.6, 9 females) with at least one CMB. We compared pre-mortem CMBs with targeted histopathology and post mortem MRI. RESULTS: 25 cases had 31 CMB lesions detected by pre-mortem MRI. 25 additional CMB were detected on histopathology. 4 CMBs on pre-mortem MRI were false positives, resulting in a total of 52 CMBs. 27 CMBs on pre-mortem MRI were confirmed on histopathology, corresponding to a sensitivity or true positive rate of 51.9% (95% CI 37.6-66.0%). The false negative rate of pre-mortem MRI was 48.1% (95% CI 34.0-62.4%). Post-mortem MRI showed only 3 cases with additional CMBs. Overall, pre-mortem MRI significantly underestimated CMBs (p = 0.0001). CONCLUSIONS: Routine clinical brain MRI underestimates the prevalence of CMBs by approximately 50%, and 12% of radiologic pre-mortem MRI CMBs were false positives. Post-mortem MRI confirmed that this discordance is not explained by microbleeds occurring after the pre-mortem MRI. PMID- 27936216 TI - Genetic Association Analysis of Common Variants in FOXO3 Related to Longevity in a Chinese Population. AB - Recent studies suggested that forkhead box class O3 (FOXO3) functions as a key regulator for the insulin/insulin-like growth factor-1signaling pathway that influence aging and longevity. This study aimed to comprehensively elucidate the association of common genetic variants in FOXO3 with human longevity in a Chinese population. Eighteen single-nucleotide polymorphisms (SNPs) in FOXO3 were successfully genotyped in 616 unrelated long-lived individuals and 846 younger controls. No nominally significant effects were found. However, when stratifying by gender, four SNPs (rs10499051, rs7762395, rs4946933 and rs3800230) previously reported to be associated with longevity and one novel SNP (rs4945815) showed significant association with male longevity (P-values: 0.007-0.032), but all SNPs were not associated with female longevity. Correspondingly, males carrying the G G-T-G haplotype of rs10499051, rs7762395, rs4945815 and rs3800230 tended to have longer lifespan than those carrying the most common haplotype A-G-C-T (odds ratio = 2.36, 95% confidence interval = 1.20-4.63, P = 0.013). However, none of the associated SNPs and haplotype remained significant after Bonferroni correction. In conclusion, our findings revealed that the FOXO3 variants we tested in our population of Chinese men and women were associated with longevity in men only. None of these associations passed Bonferroni correction. Bonferroni correction is very stringent for association studies. We therefore believe the effects of these nominally significant variants on human longevity will be confirmed by future studies. PMID- 27936217 TI - Quantum Decision Theory in Simple Risky Choices. AB - Quantum decision theory (QDT) is a recently developed theory of decision making based on the mathematics of Hilbert spaces, a framework known in physics for its application to quantum mechanics. This framework formalizes the concept of uncertainty and other effects that are particularly manifest in cognitive processes, which makes it well suited for the study of decision making. QDT describes a decision maker's choice as a stochastic event occurring with a probability that is the sum of an objective utility factor and a subjective attraction factor. QDT offers a prediction for the average effect of subjectivity on decision makers, the quarter law. We examine individual and aggregated (group) data, and find that the results are in good agreement with the quarter law at the level of groups. At the individual level, it appears that the quarter law could be refined in order to reflect individual characteristics. This article revisits the formalism of QDT along a concrete example and offers a practical guide to researchers who are interested in applying QDT to a dataset of binary lotteries in the domain of gains. PMID- 27936218 TI - A Key Role for Inhibins in Dendritic Cell Maturation and Function. AB - Inhibins are members of the TGFbeta superfamily, which regulate many cellular processes including differentiation, proliferation, survival and apoptosis. Although initially described as hormones regulating the hypothalamus-pituitary gonadal axis, based on their ability to antagonize Activins, our group has recently reported that they play a role in thymocyte differentiation and survival, as well as in thymic stromal cell maturation and nTreg generation. Here, we used Inhibin knock out mice (Inhalpha-/-) to investigate the role of Inhibins in peripheral dendritic cell maturation and function. We first demonstrated that LPS treated Inhalpha+/+ bone marrow derived dendritic cells (BMDC) were capable to produce significant levels of Inhibin A. Interestingly, Inhalpha-/- BMDC showed reduced MHCII and CD86 upregulation and increased PD-L1 expression in response to LPS compared to Inhalpha+/+, which correlated with reduced ability to induce proliferation of allogeneic T cells. The "semi-mature" phenotype displayed by Inhalpha-/- mBMDC correlated with increased levels of IL 10 and slightly decreased IL-6 production after LPS stimulation. In addition, Inhalpha-/- mBMDC showed impaired migration towards CCL19 and CCL21, assessed by in vitro chemotaxis and in vivo competitive homing experiments, despite their normal CCR7 expression. Furthermore, in vivo LPS-induced DC maturation was also diminished in Inhalpha-/- mice, specially within the LC (CD207+ CD11b+ CD103-) subpopulation. Finally, analysis of delayed type hypersensitivity responses in Inhalpha-/- mice, showed reduced ear swelling as a result of reduced cellular infiltration in the skin, correlating with impaired homing of CD207+ DCs to the draining lymph nodes. In summary, our data demonstrate for the first time that Inhibins play a key role in peripheral DC maturation and function, regulating the balance between immunity and tolerance. PMID- 27936219 TI - Combined EMD-sLORETA Analysis of EEG Data Collected during a Contour Integration Task. AB - Lately, Ensemble Empirical Mode Decomposition (EEMD) techniques receive growing interest in biomedical data analysis. Event-Related Modes (ERMs) represent features extracted by an EEMD from electroencephalographic (EEG) recordings. We present a new approach for source localization of EEG data based on combining ERMs with inverse models. As the first step, 64 channel EEG recordings are pooled according to six brain areas and decomposed, by applying an EEMD, into their underlying ERMs. Then, based upon the problem at hand, the most closely related ERM, in terms of frequency and amplitude, is combined with inverse modeling techniques for source localization. More specifically, the standardized low resolution brain electromagnetic tomography (sLORETA) procedure is employed in this work. Accuracy and robustness of the results indicate that this approach deems highly promising in source localization techniques for EEG data. PMID- 27936220 TI - Effects of Ion Irradiation on Seedlings Growth Monitored by Ultraweak Delayed Luminescence. AB - The optical technique based on the measurement of delayed luminescence emitted from the biological samples has demonstrated its ability to provide valid and predictive information on the functional status of various biological systems. We want to extend this technique to study the effect of ionizing radiation on biological systems. In particular we are interested in the action of ion beams, used for therapeutic purposes or to increase the biological diversity. In general, the assessment of the damage that radiation produces both in the target objects and in the surrounding tissues, requires considerable time because is based on biochemical analysis or on the examination of the evolution of the irradiated systems. The delayed luminescence technique could help to simplify this investigation. We have so started our studies performing irradiations of some relatively simple vegetable models. In this paper we report results obtained from mung bean (Vigna radiata) seeds submitted to a 12C ion beam at the energy of 62 MeV/nucleon. The dry seeds were irradiated at doses from 50 to 7000 Gy. The photoinduced delayed luminescence of each seed before and after ion irradiation was measured. The growth of seedlings after irradiation was compared with that of untreated seeds. A growth reduction on increasing the dose was registered. The results show strong correlations between the ion irradiation dose, seeds growth and delayed luminescence intensity. In particular, the delayed luminescence intensity is correlated by a logistic function to the seedlings elongation and, after performing a suitable measurement campaign based on blind tests, it could become a tool able to predict the growth of seeds after ion irradiation. Moreover these results demonstrate that measurements of delayed luminescence could be used as a fast and non-invasive technique to check the effects of ion beams on relatively simple biological systems. PMID- 27936221 TI - Fish Distribution and Habitat Complexity on Banks of the Strait of Sicily (Central Mediterranean Sea) from Remotely-Operated Vehicle (ROV) Explorations. AB - The Strait of Sicily was recognized internationally as an "Ecologically or Biologically Significant Area" by the Contracting Parties of the Convention on Biological Diversity in 2014. However, basic aspects of its fish diversity are still unknown and most of the information comes from traditional trawl surveys. This paper provides the first detailed description, using a Remotely Operated Vehicle (ROV), of the composition and depth distribution of the demersal fish assemblages found on banks of the Strait of Sicily and the related habitat complexity from 35 to 240 m depth. A total of 24 families and 52 fish species were recorded and depth was consistently associated with a significant proportion of the variation of the fish assemblage. The highest species richness was observed at the shallowest depth layer (0-50 m) and significantly decreased, remaining almost constant, in deeper layers. Similarly the highest abundance was recorded at 0-50 m, where C. julis represented the most abundant species, and decreased progressively throughout the whole depth gradient. Although the factor habitat complexity explained only a small proportion of the fish assemblage variation, significant differences among different degrees of habitat complexity were observed, together with a general positive trend for species richness and abundance with increasing habitat complexity. The ROV also allowed us to observe some rare or poorly known fish species such as Scorpaenodes arenai, Hyporthodus haifensis, Myliobatis aquila, Gadella maraldi, Epinephelus caninus and Lappanella fasciata. These findings show that banks serve as reservoirs for fish abundance and biodiversity and that immediate environmental conservation and management actions represent a priority not only for Italy but also for other countries which share the same area. PMID- 27936222 TI - Combined Oral and Intravenous Immunization Stimulates Strong IgA Responses in Both Systemic and Mucosal Compartments. AB - To investigate the influence of immunization routes onIgG, IgA and IgM production in systemic and mucosal compartments, we immunized mice with keyhole limpet hemocyanin (KLH) via oral, intranasal (i.n.) or subcutaneous (s.c.) routes alone or combined with the intravenous (i.v.) route. We found that administering antigen intravenously could affect antibody production and formation of antibody secreting cells (ASCs) depending on the immunization route previously used. Combined oral/i.v. immunization but not s.c./i.v. immunization caused a great increase of IgA ASCs in the spleen and enhanced IgA production in the small intestine and serum. Combined i.n./i.v. immunization could also increase IgA ASCs in the spleen and enhance IgA production in serum but had no effect on IgA production in the small intestine. Oral/i.v. immunization caused increase of IgG ASCs in both the spleen and bone marrow. In comparison, combined i.n./i.v. and s.c./i.v. immunization could increase IgG ASCs in the spleen but not in bone marrow. Intravenous administration of KLH in mice that had been immunized via oral, i.n. or s.c. routes caused some increase of IgM ASCs in the spleen but not in bone marrow. In conclusion, combined oral and i.v. administration of an antigen can induce fast and strong immune responses, especially for IgA, in both systemic and mucosal compartments. PMID- 27936223 TI - Central Obesity and H. pylori Infection Influence Risk of Barrett's Esophagus in an Asian Population. AB - BACKGROUND AND AIM: The prevalence rates of Barrett's esophagus (BE) in western countries are higher than Asian ones, but little is known about their difference among risk factors of BE. The aim of this study is to investigate the associations of various risk factors including central obesity, body mass index (BMI), metabolic syndrome and H. pylori infection, with BE. METHODS: A total of 161 subjects with BE were enrolled and compared to age- and gender-matched controls randomly sampled (1:4) from check-up center in same hospital. Central obesity was defined by waist circumference (female>80cm; male>90cm), metabolic syndrome by the modified National Cholesterol Education Program Adult Treatment Panel III criteria in Taiwan. Independent risk factors for BE were identified by multiple logistic regression analyses. RESULTS: The mean age for BE was 53.8+/ 13.7 years and 75.8% was male. H. pylori infection status was detected by the rapid urease test with the prevalence of 28.4% and 44.4% in the BE patients and controls, respectively. The univariate logistic regression analyses showed the risk was associated with higher waist circumference (odds ratio [OR], 2.53; 95% confidence interval [CI], 1.78-3.60), metabolic syndrome (OR, 2.02; 95% CI, 1.38 2.96) and negative H. pylori infection (OR, 0.50; 95% CI, 0.34-0.74). However, multivariate logistic regression analyses revealed that BE associated with higher waist circumference (adjusted OR, 2.79; 95% CI, 1.89-4.12) and negative H. pylori infection (adjusted OR, 0.46; 95% CI, 0.30-0.70). CONCLUSIONS: Central obesity is associated with a higher risk of BE whereas H. pylori infection with a lower risk in an ethnic Chinese population. PMID- 27936224 TI - Change in Serum Bilirubin Level as a Predictor of Incident Metabolic Syndrome. AB - AIM: Serum bilirubin level was negatively associated with the prevalence of metabolic syndrome (MetS) in previous cross-sectional studies. However, bilirubin variance preceding the development of MetS has yet to be investigated. We aimed to determine the effect of change in bilirubin concentration on the risk of incident MetS in healthy Korean adults. METHODS: We conducted a retrospective longitudinal study of subjects who had undergone at least four yearly health check-ups between 2006 and 2012. Of 24,185 total individuals who received annual check-ups, 11,613 non-MetS participants with a baseline bilirubin level not exceeding 34.2 MUmol/l were enrolled. We evaluated the association between percent change in bilirubin and risk of incident MetS. RESULTS: During 55,407 person-years of follow-up, 2,439 cases of incident MetS developed (21.0%). Baseline serum bilirubin level clearly showed no association with the development of MetS in men but an independent significant inverse association in women which attenuated (hence may be mediated) by elevated homeostatic model assessment index 2 for insulin resistance (HOMA2-IR). However, increased risk for incident MetS was observed in higher percent change in bilirubin quartiles, with hazard ratios of 2.415 (95% CI 2.094-2.785) in men and 2.156 (95% CI 1.738-2.675) in women in the fourth quartile, compared to the lowest quartile, after adjusting for age, smoking status, medication history, alanine aminotransferase, uric acid, estimated glomerular filtration rate, fasting glucose, baseline diabetes mellitus prevalence, systolic blood pressure, waist circumference, and body mass index. The hazard ratios per one standard deviation increase in percent change in bilirubin as a continuous variable were 1.277 (95% CI 1.229-1.326) in men and 1.366 (95% CI 1.288-1.447) in women. CONCLUSIONS: Increases in serum bilirubin concentration were positively associated with a higher risk of incident MetS. Serum bilirubin increment might be a sensitive marker for the development of MetS. PMID- 27936226 TI - Correction: Serum Reactive Oxygen Metabolite Levels Predict Severe Exacerbations of Asthma. AB - [This corrects the article DOI: 10.1371/journal.pone.0164948.]. PMID- 27936228 TI - Correction: Identifying Maternal Constraints on Fetal Growth and Subsequent Perinatal Outcomes Using a Multiple Embryo Implantation Model. AB - [This corrects the article DOI: 10.1371/journal.pone.0166222.]. PMID- 27936225 TI - Evaluation of Antigens for Development of a Serological Test for Human African Trypanosomiasis. AB - BACKGROUND: Control and elimination of human African trypanosomiasis (HAT) can be accelerated through the use of diagnostic tests that are more accurate and easier to deploy. The goal of this work was to evaluate the immuno-reactivity of antigens and identify candidates to be considered for development of a simple serological test for the detection of Trypanosoma brucei gambiense or T. b. rhodesiense infections, ideally both. METHODOLOGY/PRINCIPAL FINDINGS: The reactivity of 35 antigens was independently evaluated by slot blot and ELISA against sera from both T. b. gambiense and T. b. rhodesiense infected patients and controls. The antigens that were most reactive by both tests to T. b. gambiense sera were the membrane proteins VSG LiTat 1.3, VSG LiTat 1.5 and ISG64. Reactivity to T. b. rhodesiense sera was highest with VSG LiTat 1.3, VSG LiTat 1.5 and SRA, although much lower than with T. b. gambiense samples. The reactivity of all possible combinations of antigens was also calculated. When the slot blot results of 2 antigens were paired, a VSG LiTat 1.3- ISG75 combination performed best on T. b. gambiense sera, while a VSG LiTat 1.3-VSG LiTat 1.5 combination was the most reactive using ELISA. A combination of SRA and either VSG LiTat 1.3 or VSG LiTat 1.5 had the highest reactivity on T. b. rhodesiense sera according to slot blot, while in ELISA, pairing SRA with either GM6 or VSG LiTat 1.3 yielded the best results. CONCLUSIONS: This study identified antigens that were highly reactive to T. b. gambiense sera, which could be considered for developing a serological test for gambiense HAT, either individually or in combination. Antigens with potential for inclusion in a test for T. b. rhodesiense HAT were also identified, but because their reactivity was comparatively lower, a search for additional antigens would be required before developing a test for this form of the disease. PMID- 27936227 TI - Epidemiology of Trichomoniasis in South Korea and Increasing Trend in Incidence, Health Insurance Review and Assessment 2009-2014. AB - Trichomoniasis, which is caused by Trichomonas vaginalis, is one of the most common non-viral sexually transmitted infections; however, limited population based data are available that describe patterns and trends of the disease. We summarized insurance claims of trichomoniasis cases reported during 2009-2014 to South Korea Health Insurance Review and Assessment Service. The average annual incidence in South Korea was 276.8 persons per 100,000 population, and a substantial sex-associated variation was observed. The incidence rate among female subjects trended upward over 6 years, that is, it increased from 501 in 2009 to 625.8 in 2014 per 100,000 female population, which indicates a 25% overall increase. This trend was sharpest in the >=60 years group of female population. However, a 66% decrease in incidence rates was observed among male subjects (23.7 in 2009 to 15.7 in 2014 per 100,000 male population). Further, substantial decrease was observed in the >=40 years groups of male population. The incidence of trichomoniasis varied across regions and was the highest in Jeju province of South Korea. Overall, as the incidence of trichomoniasis appears to have increased in South Korea during 2009-2014, the disease burden is increasing; hence, there is a need to better understand the disease transmission. PMID- 27936229 TI - Endothelial-Mesenchymal Transition in Vascular Calcification of Ins2Akita/+ Mice. AB - Endothelial-mesenchymal transition (EndMT) drives endothelium to contribute to normal development and disease processes. Here, we report that EndMTs occur in the diabetic endothelium of Ins2Akita/wt mouse, and show that induction of sex determining region Y-box 2 (Sox2) is a mediator of excess BMP signaling that results in activation of EndMTs and increased vascular calcification. We also find an induction of a complex of serine proteases in the diabetic endothelium, required for the up-regulation of Sox2. Our results suggest that EndMTs contribute to vascular calcification in diabetic arteries. PMID- 27936231 TI - Correction: Riyadh Mother and Baby Multicenter Cohort Study: The Cohort Profile. AB - [This corrects the article DOI: 10.1371/journal.pone.0150297.]. PMID- 27936230 TI - The Circulating CTRP13 in Type 2 Diabetes and Non-Alcoholic Fatty Liver Patients. AB - Numerous studies have shown that C1q/TNF-related proteins (CTRPs) are involved in the pathophysiology of metabolic disorders, such as Non-alcoholic fatty liver disease (NAFLD) and Type 2 Diabetes (T2DM). There is a little information concerning CTRP13 in the context of NAFLD and T2DM. We evaluated the plasma levels of CTRP13 in healthy control and patients with NAFLD, T2DM and NAFLD+T2DM, and also correlations between CTRP13 plasma levels and clinical and subclinical features. Circulating CTRP13 was examined in 88 male (20 healthy control, 22 T2DM patients, 22 NAFLD patients and 22 NAFLD+T2DM patients). CTRP13 and adiponectin plasma levels were measured by ELISA method. CTRP13 serum levels were higher in the control group than the other groups (all p <0.001). CTRP13 had significant negative correlation with unfavorable anthropometric and metabolic factors including BMI, visceral fat, Insulin, HOMA-IR, TG, AST, ALT and gamma-GT and have a positive correlation with plasma concentration of adiponectin. CTRP13 had a significant inverse correlation with cIMT (r = -0.345) and liver stiffness (LS) (r = -0.372) (both, p <0.001). Also, the multiple stepwise linear regression has shown that visceral fat is a significant predictor of CTRP13 serum levels (p <0.001). Multiple stepwise linear regression with LS as the dependent variable showed that ALT (p < 0.001) and SBP (p = 0.010) were two predictor factors for LS. Strikingly, multiple stepwise linear regression showed that CTRP13 (p = 0.006) and SBP (p = 0.007) were two independent predictors for cIMT. Lower CTRP13 in patients with T2DM, NAFLD and NAFLD + T2DM was associated with increased risk of the diseases. CTRP13 have negative associations with unfavorable metabolic factors and also is a negative predictor of cIMT. Our results suggested that CTRP13 could be an associated factor with NAFLD in patients with and without T2DM. PMID- 27936232 TI - Correction: Thermodynamic Driving Force of Hydrogen on Rumen Microbial Metabolism: A Theoretical Investigation. AB - [This corrects the article DOI: 10.1371/journal.pone.0161362.]. PMID- 27936235 TI - Correction: CATALISE: A Multinational and Multidisciplinary Delphi Consensus Study. Identifying Language Impairments in Children. AB - [This corrects the article DOI: 10.1371/journal.pone.0158753.]. PMID- 27936234 TI - Cell Density-Dependent Increase in Tyrosine-Monophosphorylated ERK2 in MDCK Cells Expressing Active Ras or Raf. AB - The extracellular signal-regulated kinase (ERK) is one of the principal hub proteins that transmit growth signals from upstream oncogene products including Ras and BRaf to downstream effector proteins. However, there are both reports supporting and refuting the increase in ERK activity in cancer tissues expressing the active Ras and BRaf proteins. We considered that the cell density might account for this discrepancy. To examine this possibility, we prepared Madin Darby canine kidney (MDCK) cells that expressed an active HRas, NRas, KRas, or BRaf and an ERK biosensor based on the principle of Forster resonance energy transfer (FRET). As we anticipated, expression of the active Ras or BRaf increased ERK activity at low cell densities. However, the ERK activity was markedly suppressed at high cell densities irrespective of the expression of the active Ras or BRaf. Western blotting analysis with Phos-tag gel revealed the decrease of tyrosine and threonine-diphosphorylated active ERK and the increase of tyrosine-monophosphorylated inactive ERK at high cell density. In addition, we found that calyculin A, an inhibitor for PPP-subfamily protein serine/threonine phosphatases, decreased the tyrosine-monophosphorylated ERK. Our study suggests that PPP-subfamily phosphatases may be responsible for cell density-dependent ERK dephosphorylation in cancer cells expressing active Ras or BRaf protein. PMID- 27936233 TI - Malaria in HIV-Infected Children Receiving HIV Protease-Inhibitor- Compared with Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy, IMPAACT P1068s, Substudy to P1060. AB - BACKGROUND: HIV and malaria geographically overlap. HIV protease inhibitors kill malaria parasites in vitro and in vivo, but further evaluation in clinical studies is needed. METHODS: Thirty-one children from Malawi aged 4-62 months were followed every 3 months and at intercurrent illness visits for <=47 months (September 2009-December 2011). We compared malaria parasite carriage by blood smear microscopy (BS) and confirmed clinical malaria incidence (CCM, or positive BS with malaria symptoms) in children initiated on HIV antiretroviral therapy (ART) with zidovudine, lamivudine, and either nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, or lopinavir-ritonavir (LPV-rtv), a protease inhibitor. RESULTS: We found an association between increased time to recurrent positive BS, but not CCM, when anti-malarial treatment and LPV-rtv based ART were used concurrently and when accounting for a LPV-rtv and antimalarial treatment interaction (adjusted HR 0.39; 95% CI (0.17,0.89); p = 0.03). CONCLUSIONS: LPV rtv in combination with malaria treatment was associated with lower risk of recurrent positive BS, but not CCM, in HIV-infected children. Larger, randomized studies are needed to confirm these findings which may permit ART optimization for malaria-endemic settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT00719602. PMID- 27936236 TI - An Evaluation of Selected Populations for HIV-1 Vaccine Cohort Development in Nigeria. AB - Development of a globally effective HIV-1 vaccine will need to encompass Nigeria, one of the hardest hit areas, with an estimated 3.2 million people living with HIV. This cross-sectional Institutional Review Board (IRB) approved study was conducted in 2009-12 at four market sites and two highway settlements sites in Nigeria to identify and characterize populations at high risk for HIV; engage support of local stakeholders; and assess the level of interest in future vaccine studies. Demographic, HIV risk data were collected by structured interviewer administered questionnaires. Blood samples were tested on site by HIV rapid diagnostic tests, followed by rigorous confirmatory testing, subtype evaluation and testing for HBV and HCV markers in a clinical reference laboratory. Of 3229 study participants, 326 were HIV infected as confirmed by Western Blot or RNA, with a HIV prevalence of 15.4%-23.9% at highway settlements and 3.1%-9.1% at market sites. There was no observable correlation of prevalence of HIV-1 (10.1%) with HBV (10.9%) or HCV (2.9%). Major HIV-1 subtypes included CRF02_AG (37.5%); G (27.5%); G/CRF02_AG (25.9%); and non-typeable (8.9%), with 0.3% HIV-2. Univariate analysis found age, gender, marital status, level of education, and sex under substance influence as significant risk factors for HIV (p<0.001). Educating and winning the trust of local community leadership ensured high level of participation (53.3-77.9%) and willingness to participate in future studies (95%). The high HIV prevalence and high risk of HIV infection at highway settlement and mammy markets make them well suited for targeting future vaccine trials in Nigeria. PMID- 27936237 TI - The Immunomodulatory Small Molecule Imiquimod Induces Apoptosis in Devil Facial Tumour Cell Lines. AB - The survival of the Tasmanian devil (Sarcophilus harrisii) is threatened by devil facial tumour disease (DFTD). This transmissible cancer is usually fatal, and no successful treatments have been developed. In human studies, the small immunomodulatory molecule imiquimod is a successful immunotherapy, activating anti-tumour immunity via stimulation of toll-like receptor-7 (TLR7) signaling pathways. In addition, imiquimod is a potent inducer of apoptosis in human tumour cell lines via TLR7 independent mechanisms. Here we investigate the potential of imiquimod as a DFTD therapy through analysis of treated DFTD cell lines and Tasmanian devil fibroblasts. WST-8 proliferation assays and annexin V apoptosis assays were performed to monitor apoptosis, and changes to the expression of pro- and anti-apoptotic genes were analysed using qRT-PCR. Our results show that DFTD cell lines, but not Tasmanian devil fibroblasts, are sensitive to imiquimod induced apoptosis in a time and concentration dependent manner. Induction of apoptosis was accompanied by down-regulation of the anti-apoptotic BCL2 and BCLXL genes, and up-regulation of the pro-apoptotic BIM gene. Continuous imiquimod treatment was required for these effects to occur. These results demonstrate that imiquimod can deregulate DFTD cell growth and survival in direct and targeted manner. In vivo, this may increase DFTD vulnerability to imiquimod-induced TLR7 mediated immune responses. Our findings have improved the current knowledge of imiquimod action in tumour cells for application to both DFTD and human cancer therapy. PMID- 27936238 TI - Trehalose-6-Phosphate-Mediated Toxicity Determines Essentiality of OtsB2 in Mycobacterium tuberculosis In Vitro and in Mice. AB - Trehalose biosynthesis is considered an attractive target for the development of antimicrobials against fungal, helminthic and bacterial pathogens including Mycobacterium tuberculosis. The most common biosynthetic route involves trehalose 6-phosphate (T6P) synthase OtsA and T6P phosphatase OtsB that generate trehalose from ADP/UDP-glucose and glucose-6-phosphate. In order to assess the drug target potential of T6P phosphatase, we generated a conditional mutant of M. tuberculosis allowing the regulated gene silencing of the T6P phosphatase gene otsB2. We found that otsB2 is essential for growth of M. tuberculosis in vitro as well as for the acute infection phase in mice following aerosol infection. By contrast, otsB2 is not essential for the chronic infection phase in mice, highlighting the substantial remodelling of trehalose metabolism during infection by M. tuberculosis. Blocking OtsB2 resulted in the accumulation of its substrate T6P, which appears to be toxic, leading to the self-poisoning of cells. Accordingly, blocking T6P production in a DeltaotsA mutant abrogated otsB2 essentiality. T6P accumulation elicited a global upregulation of more than 800 genes, which might result from an increase in RNA stability implied by the enhanced neutralization of toxins exhibiting ribonuclease activity. Surprisingly, overlap with the stress response caused by the accumulation of another toxic sugar phosphate molecule, maltose-1-phosphate, was minimal. A genome-wide screen for synthetic lethal interactions with otsA identified numerous genes, revealing additional potential drug targets synergistic with OtsB2 suitable for combination therapies that would minimize the emergence of resistance to OtsB2 inhibitors. PMID- 27936241 TI - Correction: Intrasession and Between-Visit Variability of Sector Peripapillary Angioflow Vessel Density Values Measured with the Angiovue Optical Coherence Tomograph in Different Retinal Layers in Ocular Hypertension and Glaucoma. AB - [This corrects the article DOI: 10.1371/journal.pone.0161631.]. PMID- 27936239 TI - A Broad-Spectrum Chemokine-Binding Protein of Bovine Papular Stomatitis Virus Inhibits Neutrophil and Monocyte Infiltration in Inflammatory and Wound Models of Mouse Skin. AB - Bovine papular stomatitis virus (BPSV) is a Parapoxvirus that induces acute pustular skin lesions in cattle and is transmissible to humans. Previous studies have shown that BPSV encodes a distinctive chemokine-binding protein (CBP). Chemokines are critically involved in the trafficking of immune cells to sites of inflammation and infected tissue, suggesting that the CBP plays a role in immune evasion by preventing immune cells reaching sites of infection. We hypothesised that the BPSV-CBP binds a wide range of inflammatory chemokines particularly those involved in BPSV skin infection, and inhibits the recruitment of immune cells from the blood into inflamed skin. Molecular analysis of the purified protein revealed that the BPSV-CBP is a homodimeric polypeptide with a MW of 82.4 kDa whilst a comprehensive screen of inflammatory chemokines by surface plasmon resonance showed high-affinity binding to a range of chemokines within the CXC, CC and XC subfamilies. Structural analysis of BPSV-CBP, based on the crystal structure of orf virus CBP, provided a probable explanation for these chemokine specificities at a molecular level. Functional analysis of the BPSV-CBP using transwell migration assays demonstrated that it potently inhibited chemotaxis of murine neutrophils and monocytes in response to CXCL1, CXCL2 as well as CCL2, CCL3 and CCL5 chemokines. In order to examine the effects of CBP in vivo, we used murine skin models to determine its impact on inflammatory cell recruitment such as that observed during BPSV infection. Intradermal injection of BPSV-CBP blocked the influx of neutrophils and monocytes in murine skin in which inflammation was induced with lipopolysaccharide. Furthermore, intradermal injection of BPSV-CBP into injured skin, which more closely mimics BPSV lesions, delayed the influx of neutrophils and reduced the recruitment of MHC-II+ immune cells to the wound bed. Our findings suggest that the CBP could be important in pathogenesis of BPSV infections. PMID- 27936240 TI - Composting-Like Conditions Are More Efficient for Enrichment and Diversity of Organisms Containing Cellulase-Encoding Genes than Submerged Cultures. AB - Cost-effective biofuel production from lignocellulosic biomass depends on efficient degradation of the plant cell wall. One of the major obstacles for the development of a cost-efficient process is the lack of resistance of currently used fungal enzymes to harsh conditions such as high temperature. Adapted, thermophilic microbial communities provide a huge reservoir of potentially interesting lignocellulose-degrading enzymes for improvement of the cellulose hydrolysis step. In order to identify such enzymes, a leaf and wood chip compost was enriched on a mixture of thermo-chemically pretreated wheat straw, poplar and Miscanthus under thermophile conditions, but in two different set-ups. Unexpectedly, metagenome sequencing revealed that incubation of the lignocellulosic substrate with compost as inoculum in a suspension culture resulted in an impoverishment of putative cellulase- and hemicellulase-encoding genes. However, mimicking composting conditions without liquid phase yielded a high number and diversity of glycoside hydrolase genes and an enrichment of genes encoding cellulose binding domains. These identified genes were most closely related to species from Actinobacteria, which seem to constitute important players of lignocellulose degradation under the applied conditions. The study highlights that subtle changes in an enrichment set-up can have an important impact on composition and functions of the microcosm. Composting-like conditions were found to be the most successful method for enrichment in species with high biomass degrading capacity. PMID- 27936242 TI - Performance in Object-Choice Aesop's Fable Tasks Are Influenced by Object Biases in New Caledonian Crows but not in Human Children. AB - The ability to reason about causality underlies key aspects of human cognition, but the extent to which non-humans understand causality is still largely unknown. The Aesop's Fable paradigm, where objects are inserted into water-filled tubes to obtain out-of-reach rewards, has been used to test casual reasoning in birds and children. However, success on these tasks may be influenced by other factors, specifically, object preferences present prior to testing or arising during pre test stone-dropping training. Here, we assessed this 'object-bias' hypothesis by giving New Caledonian crows and 5-10 year old children two object-choice Aesop's Fable experiments: sinking vs. floating objects, and solid vs. hollow objects. Before each test, we assessed subjects' object preferences and/or trained them to prefer the alternative object. Both crows and children showed pre-test object preferences, suggesting that birds in previous Aesop's Fable studies may also have had initial preferences for objects that proved to be functional on test. After training to prefer the non-functional object, crows, but not children, performed more poorly on these two object-choice Aesop's Fable tasks than subjects in previous studies. Crows dropped the non-functional objects into the tube on their first trials, indicating that, unlike many children, they do not appear to have an a priori understanding of water displacement. Alternatively, issues with inhibition could explain their performance. The crows did, however, learn to solve the tasks over time. We tested crows further to determine whether their eventual success was based on learning about the functional properties of the objects, or associating dropping the functional object with reward. Crows inserted significantly more rewarded, non-functional objects than non-rewarded, functional objects. These findings suggest that the ability of New Caledonian crows to produce performances rivaling those of young children on object-choice Aesop's Fable tasks is partly due to pre-existing object preferences. PMID- 27936243 TI - Can Wound Exudate from Venous Leg Ulcers Measure Wound Pain Status?: A Pilot Study. AB - We investigated the associations between the self-evaluated pain status and two pain biomarker candidates, nerve growth factor and S100A8/A9, in exudate from venous leg ulcer to finally develop an objective pain evaluation method. Patients with venous leg ulcer participated in this cross-sectional observational study conducted between April and October 2014 at two medical facilities. During routine wound care, each participant self-evaluated their pain status at each examination using the 10-point numerical rating scale (present pain intensity) and the short-form McGill Pain Questionnaire 2 (continuous pain, intermittent pain, neuropathic pain, affective descriptors, and total score). Venous leg ulcer exudate sample was collected after wound cleansing. The nerve growth factor and S100A8/A9 concentrations in the venous leg ulcer exudate were measured by enzyme linked immunosorbent assay and standardized according to the wound area. The association between each pain status and the two standardized protein concentrations was evaluated using Spearman's correlation coefficient. In 30 sample collected from 13 participants, the standardized nerve growth factor concentration was negatively correlated with continuous pain (rho = -0.47, P = 0.01), intermittent pain (rho = -0.48, P = 0.01), neuropathic pain (rho = -0.51, P = 0.01), and total score (rho = -0.46, P = 0.01). The standardized S100A8/A9 concentration was positively correlated with present pain intensity (rho = 0.46, P = 0.03) and continuous pain (rho = 0.48, P = 0.03). Thus, these two proteins may be useful for objective evaluation of wound pain in venous leg ulcer patients. PMID- 27936244 TI - Gene Expression and Silencing Studies in Phytophthora infestans Reveal Infection Specific Nutrient Transporters and a Role for the Nitrate Reductase Pathway in Plant Pathogenesis. AB - To help learn how phytopathogens feed from their hosts, genes for nutrient transporters from the hemibiotrophic potato and tomato pest Phytophthora infestans were annotated. This identified 453 genes from 19 families. Comparisons with a necrotrophic oomycete, Pythium ultimum var. ultimum, and a hemibiotrophic fungus, Magnaporthe oryzae, revealed diversity in the size of some families although a similar fraction of genes encoded transporters. RNA-seq of infected potato tubers, tomato leaves, and several artificial media revealed that 56 and 207 transporters from P. infestans were significantly up- or down-regulated, respectively, during early infection timepoints of leaves or tubers versus media. About 17 were up-regulated >4-fold in both leaves and tubers compared to media and expressed primarily in the biotrophic stage. The transcription pattern of many genes was host-organ specific. For example, the mRNA level of a nitrate transporter (NRT) was about 100-fold higher during mid-infection in leaves, which are nitrate-rich, than in tubers and three types of artificial media, which are nitrate-poor. The NRT gene is physically linked with genes encoding nitrate reductase (NR) and nitrite reductase (NiR), which mobilize nitrate into ammonium and amino acids. All three genes were coregulated. For example, the three genes were expressed primarily at mid-stage infection timepoints in both potato and tomato leaves, but showed little expression in potato tubers. Transformants down regulated for all three genes were generated by DNA-directed RNAi, with silencing spreading from the NR target to the flanking NRT and NiR genes. The silenced strains were nonpathogenic on leaves but colonized tubers. We propose that the nitrate assimilation genes play roles both in obtaining nitrogen for amino acid biosynthesis and protecting P. infestans from natural or fertilization-induced nitrate and nitrite toxicity. PMID- 27936245 TI - In Vitro Selective Growth-Inhibitory Effect of 8-Hydroxyquinoline on Clostridium perfringens versus Bifidobacteria in a Medium Containing Chicken Ileal Digesta. AB - Clostridium perfringens-induced necrotic enteritis is generally controlled by antibiotics. However, because of increasing antibiotic resistance, other antibacterial agents are required, preferably ones that do not affect the beneficial intestinal microbiota of the host. This study evaluated the in vitro selective growth-inhibitory effect of 8-hydroxyquinoline (8HQ) on C. perfringens vs. bifidobacteria in a medium containing chicken ileal digesta. Prior to the experiments, the minimum inhibitory concentrations of 8HQ and penicillin G were determined by broth microdilution assay. The minimum inhibitory concentration values of 8HQ for C. perfringens were 16-32 times lower than the values for bifidobacteria. Treatment of autoclaved and non-autoclaved chicken ileal digesta with 8HQ showed a selective anticlostridial effect. After incubation of C. perfringens with autoclaved ileal digesta for 3 h, all 8HQ concentrations tested (32-2048 MUg/mL) significantly reduced C. perfringens bacterial count. In contrast, the same treatment had no or only a slight effect on bifidobacteria counts. Unlike 8HQ, penicillin G did not exhibit any selectivity. Similar results were obtained after incubation for 24 h. In non-autoclaved ileal digesta, all 8HQ concentrations tested significantly reduced C. perfringens bacterial counts after incubation for 30 min and 3 h, while no effect was observed on bifidobacteria. These results suggest that 8HQ may serve as a prospective veterinary compound for use against necrotic enteritis in poultry. PMID- 27936246 TI - Diagnostic Accuracy of Clinical Examination and Imaging Findings for Identifying Subacromial Pain. AB - BACKGROUND: The diagnosis of subacromial pathology is limited by the poor accuracy of clinical tests for specific pathologies. The aim of this study was to estimate the diagnostic accuracy of clinical examination and imaging features for identifying subacromial pain (SAP) defined by a positive response to diagnostic injection, and to evaluate the influence of imaging findings on the clinical diagnosis of SAP. METHODS AND FINDINGS: In a prospective, diagnostic accuracy design, 208 consecutive patients presenting to their primary healthcare practitioner for the first time with a new episode of shoulder pain were recruited. All participants underwent a standardized clinical examination, shoulder x-ray series and diagnostic ultrasound scan. Results were compared with the response to a diagnostic block of xylocaineTM injected into the SAB under ultrasound guidance using >=80% post-injection reduction in pain intensity as the positive anaesthetic response (PAR) criterion. Diagnostic accuracy statistics were calculated for combinations of clinical and imaging variables demonstrating the highest likelihood of a PAR. A PAR was reported by 34% of participants. In participants with no loss of passive external rotation, combinations of three clinical variables (anterior shoulder pain, strain injury, absence of symptoms at end-range external rotation (in abduction)) demonstrated 100% specificity for a PAR when all three were positive (LR+ infinity; 95%CI 2.9, infinity). A full thickness supraspinatus tear on ultrasound increased the likelihood of a PAR irrespective of age (specificity 98% (95%CI 94, 100); LR+ 6.2; 95% CI 1.5, 25.7)). Imaging did not improve the ability to rule-out a PAR. CONCLUSION: Combinations of clinical examination findings and a full-thickness supraspinatus tear on ultrasound scan can help confirm, but not exclude, the presence of subacromial pain. Other imaging findings were of limited value for diagnosing SAP. PMID- 27936247 TI - Land-Use and Socioeconomic Change, Medicinal Plant Selection and Biodiversity Resilience in Far Western Nepal. AB - Indigenous plant use-systems have evolved under, and constantly adapted to human and non-human impacts. In the last decades however, increasing socioeconomic and cultural transformations, including land-use change, outmigration, globalized markets, the introduction of new species, and climate change have led to a decreasing availability of indigenous resources, and are ultimately leading to a reduction of local use-knowledge. Participant observations, discussions, walks-in the-woods, semi-structured interviews and informal meetings were carried out in 12 villages of far western Nepal between 2011 and 2015 to assess how sociocultural changes have affected the sustenance of indigenous systems and local biodiversity, when compared to studies carried out in the previous decades. Our findings show that there were no statistically significant differences in subject variable means, but differences were relatively important to plant parts use and plant growth-forms (p = 0.183 and 0.088 respectively). Cissampelos pareira, Acorus calamus, Calotropis gigantea were found to have the greatest relative importance, whereas Ageratina adenophora, Melia azedarach, Carum carvi were most important based on use values. Among them, C. pareira and A. adenophora were introduced. The spatial distribution of species collected for medicine showed that all habitats were important for collection however, habitats close to villages were more favored. The use of non-indigenous and easily available species and more accessible habitats is becoming more prevalent as primary forests become increasingly overexploited, indigenous species become limited, and sociocultural cause of land use change expand. The utilization of indigenous and non-indigenous species and nearby habitats, although possibly affecting the quality of medicinal species, nonetheless reveals the dynamism of indigenous medicines as an adaptive asset mitigating human and non-human environmental changes. PMID- 27936248 TI - Light Mediated Generation of Silver Nanoparticles by Spinach Thylakoids/Chloroplasts. AB - The unique potential of chloroplasts/thylakoids to harness light energy to transport electrons from H2O to various entities was exploited for reduction of Ag+ to generate nanoparticles (NPs). Spinach thylakoids/chloroplasts turned AgNO3 solutions brown in light, but not in dark. Besides showing Ag-NPs specific surface plasmon resonance band, these brown solutions showed presence of 5-30 nm crystalline NPs composed of Ag. Powder X-ray diffraction (PXRD) analysis revealed that Ag-NPs were biphasic composed of face-centered cubic Ag0 and cubic Ag2O. X ray photoelectron spectroscopy (XPS) data further corroborated the presence of Ag2O in Ag-NPs. Limited formation of Ag-NPs in dark and increased generation of Ag0/Ag2O-NPs with increase in light intensity (photon flux density) by thylakoids/chloroplasts, established the role of light-harvesting photosynthetic machinery in generation of Ag0/Ag2O-NPs. Potential of thylakoids/chloroplasts to generate Ag-NPs from Ag+ on exposure to red and blue wavelength regions of visible light of electromagnetic spectrum, further confirmed the involvement of photosynthetic electron transport in reduction of Ag+ and generation of Ag-NPs. While light energy mediated photosynthetic electron transport donates energized electrons extracted from H2O to Ag+ to form Ag0-NPs, O2 released as a by-product during photolysis of H2O oxidizes Ag0 to form Ag2O-NPs. Our findings furnish a novel, simple, economic and green method that can be exploited for commercial production of Ag0/Ag2O-NPs. PMID- 27936250 TI - ? PMID- 27936249 TI - The Impact of Exercise on Statin-Associated Skeletal Muscle Myopathy. AB - HMG-CoA reductase inhibitors (statins) are the most effective pharmacological means of reducing cardiovascular disease risk. The most common side effect of statin use is skeletal muscle myopathy, which may be exacerbated by exercise. Hypercholesterolemia and training status are factors that are rarely considered in the progression of myopathy. The purpose of this study was to determine the extent to which acute and chronic exercise can influence statin-induced myopathy in hypercholesterolemic (ApoE-/-) mice. Mice either received daily injections of saline or simvastatin (20 mg/kg) while: 1) remaining sedentary (Sed), 2) engaging in daily exercise for two weeks (novel, Nov), or 3) engaging in daily exercise for two weeks after a brief period of training (accustomed, Acct) (2x3 design, n = 60). Cholesterol, activity, strength, and indices of myofiber damage and atrophy were assessed. Running wheel activity declined in both exercise groups receiving statins (statin x time interaction, p<0.05). Cholesterol, grip strength, and maximal isometric force were significantly lower in all groups following statin treatment (statin main effect, p<0.05). Mitochondrial content and myofiber size were increased and 4-HNE was decreased by exercise (statin x exercise interaction, p<0.05), and these beneficial effects were abrogated by statin treatment. Exercise (Acct and Nov) increased atrogin-1 mRNA in combination with statin treatment, yet enhanced fiber damage or atrophy was not observed. The results from this study suggest that exercise (Nov, Acct) does not exacerbate statin-induced myopathy in ApoE-/- mice, yet statin treatment reduces activity in a manner that prevents muscle from mounting a beneficial adaptive response to training. PMID- 27936252 TI - [The Historical Collection of the Institut universitaire en sante mentale de Montreal: from the Quill to the Electronic Record, 140 Years of Mental Health Records]. AB - Few institutions have kept the vast majority of their records. It is the enviable position of l'IUSMM. The article describes the collection, the challenges of preserving and sharing with limited budget within a legal context protecting confidentiality. PMID- 27936251 TI - [Searching for the Lost Psychiatric Archive. History of the Alfred Binet's Archives Collections]. AB - This paper examines the history of Alfred Binet's Archives. It precises the formation of its different collections. It shows and studies the dispersal which often qualifies psychiatric archives and enlightens the difficulties of the historical work relative to this kind of source. PMID- 27936253 TI - [Lack of Collaboration, Lack of Staff or Disappearance of the Data: the Difficult Access to the Psychiatric Archives]. AB - This paper presents the way we try to track the history of mental health services offered to residents of official language minority communities throughout Northern and Eastern Ontario. The study also holds an interest in the post deinstitutionalization paths of patients suffering from mental health conditions. Our research strand concerns Northern Ontario, its patient associations, its services, its specialists and its institutions and the access to hospitals archives. PMID- 27936255 TI - [Nursing Progress Notes in Psychiatry: Mental Health Archival Data]. AB - Introduction Nurses' notes are used primarily as a communication tool between nurses, doctors and member of the professional team to ensure continuity of patient care. They contain life-history of individuals with mental health disorders. This nurses' communication tool describes the patient care during hospitalization in acute psychiatric ward. In fact, these observations contained in the progress notes represent more than a simple picture of mental illness. They always tell a story constructed by socio-cultural norms.Objectives The purpose of this article is to demonstrate the value of these narratives data as a comprehensive source of information to understand the experience of mental health following the deinstitutionalization project.Results The use of nursing progress notes of the Psychiatric Department allows, among other things, a better understanding of the life course of some hospitalized patients. The narrative data in those documents enhance the intersection between personal experiences and social, institutional and professional structures. These primary sources offer a multitude of possibilities in mental health research and can be examined from different angles of analysis. They deserve to be exploited in future research project to increase our understanding of mental illness. PMID- 27936254 TI - [The Iconographic Archive: what does the Visual Culture of the Origins of French Psychiatry in the Early Nineteenth Century reveal to us?] AB - This article constructs a new history of the birth of psychiatry that of its visual culture, through the study of heretofore unpublished and neglected archives.The analysis of artworks commissioned by the first French psychiatrists at the beginning of the nineteenth century highlights, in an exceptional way, the recognition of subjectivation and autonomy of the mentally sick person, which is the inherent hope of psychiatry's initial project.The artists who fulfilled the first psychiatrists' commissions expressed this ideal, which was conveyed both by the humanist philanthropy of early psychiatry and by the artistic vocabulary of the nineteenth century. These works thus display both a search for subjective expression and for objectivity. Some artists recognized this subjectivity in the sick persons: either in their portrayals of the ill as autonomous individuals; in portraits of psychiatrists, which infer the presence of the sick persons under the scrutiny of the doctor; and in the asylum architecture that addressed itself to the sick individual's sensibility and cognition. PMID- 27936256 TI - [The Psychiatric Archives: An Opportunity to Grasp the Patient's Experience (in Belgium during the inter-war years)]. AB - This paper presents an exploratory reflection on the question of individual experience by patients in psychiatric institutions, in its historical dimension. Are such experiences comprehensible through an analysis of the archives originating in the hospital? This reflection forms part of a study concerning the circumstances in which women were placed in psychiatric institutions, in Belgium during interwar period (1918-1940); its ultimate objective is to come to an understanding of the social, individual and familial situations that lead to a decision to intern a woman in a closed psychiatric institution. Here, the concept of experience is used to ascertain whether a different understanding of psychiatry is viable, that is to say, to understand it as a personal life-story and as a social fact. Could we, by dint of the psychiatric archives produced by medical institutions, go beyond institutional and medical issues, so as to understand how those placed in a psychiatric institution lived through their mental illness? The objective of this article is also to prepare several methodological markers with respect to issues of interpretation, of individual experience and of emotion. This article is not so much a summing-up of the results of research conducted in psychiatric archives, but rather a deliberation on the historian's approach and appropriate course of action on the question of first-hand experience in psychiatry. PMID- 27936257 TI - [Institutions without History. An Investigation into the Archives of a Private Psychiatric Hospital (France 1930-1950)]. AB - Objectives Discovered by following the story of a Parisian patient, l'Hopital psychiatrique de Saint-Remy opened in 1937 in the east of France. It is a special institution that was created for profit and in an emergency context during the 1930s.Methods Due to the absence of administrative records, the history of this institution can be written only by using the archives of the Parisian administration and patient records. The story of this special institution allows several issues in the historiography of psychiatry: the funding of mental health, the patient transfers, the revival of the criticism against the psychiatric hospital.Results The creation of this institution in the 1930s corresponds to a specific context of demographic and economic crisis and represents a new mode of management of chronic mental illness. L'Hopital psychiatrique de Saint-Remy is a new place of banishment for some populations at the end of the thirties as well as a source of profit for entrepreneurs bound to the most influential political and economic networks of time.Conclusions The history and the archives of the Hopital psychiatrique de Saint-Remy inform us about the evolution of the psychiatric assistance but also about the treatment of madness during a difficult time of the history. PMID- 27936258 TI - [The Gang of Six Demands more Freedom. Juvenile Offenders Interned in Saint-Jean de-Dieu, Mid-20th Century]. AB - In recent years, we have worked with many psychiatric records kept by the Archive Services of the Institut universitaire en sante mentale de Montreal (IUSMM). The proposed article is focused on the February 12th 1959 document Assemblee des medecins located within the records of six illegitimate children admitted to the Hopital Saint-Jean-de-Dieu in the late 1950s. Our study, inspired by the work of historian Roy Porter and his approach from below, contributes to the historical discourse seeking to incorporate patient's voices, in this case, a gang of young offenders identified by a life course shaped by repeated institutional experience. PMID- 27936260 TI - [Psychiatric Archives: Archive for which History? The Writings and Drawings of Rene L.] AB - The archives of the psychiatric institutions are often mobilized to investigate the history of the treatment of mental disorders and its modalities in our societies. From a patient's record, interned in the Hopital du Bon Sauveur in the department of Manche in France in 1963, this article shows how these archives are part of writing a different story that of decolonization and particularly the independence of Algeria and the end of French colonization. In particular, studied the drawings by this patient and the way it reflects the collective history. PMID- 27936259 TI - [Reconstructing a Scholarly Network from the Bonneval Hospital Collections: Relationships and Misconceptions Derived from Historical Archives]. AB - The French psychiatric hospital Henri Ey in Bonneval (Eure-et-Loir, Central France) is known in the history of psychiatry for a series of conferences, which brought together several key figures in the mental health field in the 1940s. The conference sessions have been published in two major volumes: Le Probleme de la psychogenese des nevroses et des psychoses (The Problem of the Psychogenesis of Neuroses and Psychoses, 1950), and L'Inconscient (The Unconscious, 1966). The proceedings consist of theoretical essays and minutes of the intellectual discussions between French psychiatrists, neurologists, psychologists, psychoanalysts and philosophers. We will analyze this network through an investigation into the archives of the journal L'Evolution psychiatrique (The Evolution of Psychiatry) in order to reconstruct the history of the intellectual life of French psychiatrists in postwar society, in the course of successive reforms in medical education (Debre and Faure Reforms, 1958-1968). PMID- 27936261 TI - [Socio-cultural Representations of Suicide in Mid-20th Century Quebec: A Case Study]. AB - By comparing the narratives in a 1958 Montreal newspaper article with the data compiled in the Coroner inquest report, this case study seeks to assess the value of journalistic sources in historicizing the shifts in the modes of representation and emotion surrounding suicide in the province of Quebec in the middle of the twentieth century. PMID- 27936262 TI - [A mental health hygiene experiment: the case of Les Pinceaux d'Or]. AB - Many research, notably that of Gene Cohen (2007), have shown positive impact of artistic activities for seniors. In 2006 in Quebec City, three professional painters have created a none lucrative organization called Les Pinceaux d'Or (The Golden Brushes). Its mission is to create a positive experience of painting learning in elderly needing persons. The organization operates in long-term health-care facilities or in low-income housings and day centers. It offers free painting courses to elderly persons referred by local community health centers or community organizations as seniors with psychosocial needs. The only condition for participation is to be a person able to hold a brush. The person often uses his memories to personalize the subject, positive emotional exchange with others, not to mention pleasant moments, sharing, discovering that we still can learn, even in the presence of Alzheimer's or stroke sequel. Participants averaged 81 years old, and four of them are over hundred (one person was 110 years old). We expect to present the humanistic approach of the organization and, in summary, the results of a qualitative study of the perceived effects of those courses on participants. Finally, we want to illustrate that we face there an evolutionary artistic process and that artistic activity is a form of hygiene, especially when someone is getting older. Second, we suggest that the process of healthy aging involves an adjustment of personal development that should never stop. Through these courses, the seniors develop a personal growth congruent to the recovery ideology: a life project (mostly leave a mark to family members); empowerment; social inclusion; and finally citizenship. PMID- 27936263 TI - [Highlighting the Lived Experience of Families: Family Peer Support Services Initiative]. AB - To support personal recovery, any person with a mental illness should have access to a range of practices recommended by scientific evidence. The peer support are some of the services recommended by the Mental Health Commission of Canada for the reduction of the economic and social burden of mental illness. If peer support from families is poorly documented, peer support and mutual aid from users have been the subject of several studies. Based on two studies in which she participated, addressing the needs of families, and its experience as a non profit support organization for families, the Quebec Society of Schizophrenia (QSS) has reflected on the family support problem upon entry in the health system as well as the involvement of families as peer support. This article presents the implementation pilot project of Family Peer Support services initiative, fruit of collaboration between QSS and University Institute of Mental Health in Montreal and the issues and recommendations of the first year of implementation. PMID- 27936264 TI - 4D Graph-Based Segmentation for Reproducible and Sensitive Choroid Quantification From Longitudinal OCT Scans. AB - Purpose: Longitudinal imaging is becoming more commonplace for studies of disease progression, response to treatment, and healthy maturation. Accurate and reproducible quantification methods are desirable to fully mine the wealth of data in such datasets. However, most current retinal OCT segmentation methods are cross-sectional and fail to leverage the inherent context present in longitudinal sequences of images. Methods: We propose a novel graph-based method for segmentation of multiple three-dimensional (3D) scans over time (termed 3D + time or 4D). The usefulness of this approach in retinal imaging is illustrated in the segmentation of the choroidal surfaces from longitudinal optical coherence tomography (OCT) scans. A total of 3219 synthetic (3070) and patient (149) OCT images were segmented for validation of our approach. Results: The results show that the proposed 4D segmentation method is significantly more reproducible (P < 0.001) than the 3D approach and is significantly more sensitive to temporal changes (P < 0.0001) achieved by the substantial increase of measurement robustness. Conclusions: This is the first automated 4D method for jointly quantifying choroidal thickness in longitudinal OCT studies. Our method is robust to image noise and produces more reproducible choroidal thickness measurements than a sequence of independent 3D segmentations, without sacrificing sensitivity to temporal changes. PMID- 27936266 TI - Quantitative optical coherence microscopy for the in situ investigation of the biofilm. AB - This paper explores the potential of optical coherence microscopy (OCM) for the C and 388A>G polymorphisms are commonly occurring variants in ethnically diverse populations and numerous in vitro and clinical studies have evaluated the consequences of these variants to interindividual differences in drug disposition and response. OATP1B1 is particularly important for the disposition of HMG-CoA reductase inhibitors, or statins, as it is known to efficiently transport most statins to their site of action within hepatocytes. Many studies have focused on the consequences of OATP1B1 variants to statin disposition in vitro and in vivo and would suggest that genetic variability in SLCO1B1 has important implications for statin pharmacokinetics, risk for statin induced myopathy, and modulation of statin treatment response. This review describes what is currently known regarding SLCO1B1 genotype, OATP1B1 protein expression and interindividual and interethnic consequences to drug disposition, with particular focus on statin pharmacokinetics and implications for drug response and toxicity. PMID- 27936283 TI - Purity, adulteration and price of drugs bought on-line versus off-line in the Netherlands. AB - BACKGROUND AND AIMS: On-line drug markets flourish and consumers have high expectations of on-line quality and drug value. The aim of this study was to (i) describe on-line drug purchases and (ii) compare on-line with off-line purchased drugs regarding purity, adulteration and price. DESIGN: Comparison of laboratory analyses of 32 663 drug consumer samples (stimulants and hallucinogens) purchased between January 2013 and January 2016, 928 of which were bought on-line. SETTING: The Netherlands. MEASUREMENTS: Primary outcome measures were (i) the percentage of samples purchased on-line and (ii) the chemical purity of powders (or dosage per tablet); adulteration; and the price per gram, blotter or tablet of drugs bought on-line compared with drugs bought off-line. FINDINGS: The proportion of drug samples purchased on-line increased from 1.4% in 2013 to 4.1% in 2015. The frequency varied widely, from a maximum of 6% for controlled, traditional substances [ecstasy tablets, 3,4-methylenedioxy-methamphetamine (MDMA) powder, amphetamine powder, cocaine powder, 4-bromo-2,5-dimethoxyphenethylamine (2C-B) and lysergic acid diethylamide (LSD)] to more than a third for new psychoactive substances (NPS) [4-fluoroamphetamine (4-FA), 5/6-(2-aminopropyl)benzofuran (5/6 APB) and methoxetamine (MXE)]. There were no large differences in drug purity, yet small but statistically significant differences were found for 4-FA (on-line 59% versus off-line 52% purity for 4-FA on average, P = 0.001), MDMA powders (45 versus 61% purity for MDMA, P = 0.02), 2C-B tablets (21 versus 10 mg 2C-B/tablet dosage, P = 0.49) and ecstasy tablets (131 versus 121 mg MDMA/tablet dosage, P = 0.05). The proportion of adulterated samples purchased on-line and off-line did not differ, except for 4-FA powder, being less adulterated on-line (chi2 = 8.3; P < 0.02). Drug prices were mainly higher on-line, ranging for various drugs from 10 to 23% higher than that of drugs purchased off-line (six of 10 substances: P < 0.05). CONCLUSIONS: Dutch drug users increasingly purchase drugs on-line: new psychoactive substances in particular. Purity and adulteration do not vary considerably between drugs purchased on-line and off-line for most substances, while on-line prices are mostly higher than off-line prices. PMID- 27936285 TI - What Do Reactive Fragments Actually Do in Cells? AB - Covalently binding molecules are frequently regarded as being generally promiscuous. In a recent study, binding selectivities and cellular target proteins of a wide variety of reactive fragments are examined in a proteome-wide context. PMID- 27936286 TI - Ultrafast Digital Printing toward 4D Shape Changing Materials. AB - Ultrafast 4D printing (<30 s) of responsive polymers is reported. Visible-light triggered polymerization of commercial monomers defines digitally stress distribution in a 2D polymer film. Releasing the stress after the printing converts the structure into 3D. An additional dimension can be incorporated by choosing the printing precursors. The process overcomes the speed limiting steps of typical 3D (4D) printing. PMID- 27936287 TI - Combining item response theory with multiple imputation to equate health assessment questionnaires. AB - The assessment of patients' functional status across the continuum of care requires a common patient assessment tool. However, assessment tools that are used in various health care settings differ and cannot be easily contrasted. For example, the Functional Independence Measure (FIM) is used to evaluate the functional status of patients who stay in inpatient rehabilitation facilities, the Minimum Data Set (MDS) is collected for all patients who stay in skilled nursing facilities, and the Outcome and Assessment Information Set (OASIS) is collected if they choose home health care provided by home health agencies. All three instruments or questionnaires include functional status items, but the specific items, rating scales, and instructions for scoring different activities vary between the different settings. We consider equating different health assessment questionnaires as a missing data problem, and propose a variant of predictive mean matching method that relies on Item Response Theory (IRT) models to impute unmeasured item responses. Using real data sets, we simulated missing measurements and compared our proposed approach to existing methods for missing data imputation. We show that, for all of the estimands considered, and in most of the experimental conditions that were examined, the proposed approach provides valid inferences, and generally has better coverages, relatively smaller biases, and shorter interval estimates. The proposed method is further illustrated using a real data set. PMID- 27936288 TI - Staple crops biofortified with increased vitamins and minerals: considerations for a public health strategy. AB - Biofortification of staple crops has been proposed as a strategy to address micronutrient malnutrition, particularly with respect to insufficient intake of vitamin A, iron, zinc, and folate. The World Health Organization, in collaboration with the Food and Agriculture Organization of the United Nations and the Sackler Institute for Nutrition Science at the New York Academy of Sciences, convened a technical consultation entitled "Staple Crops Biofortified with Vitamins and Minerals: Considerations for a Public Health Strategy" in April 2016. Participants of the consultation reviewed the definition of biofortification of staple crops, patterns of crops production, processing, consumption, seed varieties, and micronutrient stability and bioavailability, as well as farmers' adoption and acceptability of the modified crops. Also discussed were economic, environmental, safety, and equity aspects of biofortified crops, as well as legal, policy, regulatory, and ethical issues for the implementation of biofortification strategies in agriculture and nutrition. Consultation working groups identified important and emerging technical issues, lessons learned, and research priorities to better support the evidence of improved nutrition and unintended adverse effects of biofortification. This paper provides the background and rationale of the technical consultation, synopsizes the presentations, and provides a summary of the main considerations proposed by the working groups. PMID- 27936284 TI - Utility of preclinical drug versus food choice procedures to evaluate candidate medications for methamphetamine use disorder. AB - Substance use disorders are diagnosed as a manifestation of inappropriate behavioral allocation toward abused drugs and away from other behaviors maintained by more adaptive nondrug reinforcers (e.g., money and social relationships). Substance use disorder treatment goals include not only decreasing drug-maintained behavior but also promoting behavioral reallocation toward these socially adaptive alternative reinforcers. Preclinical drug self administration procedures that offer concurrent access to both drug and nondrug reinforcers provide a translationally relevant dependent measure of behavioral allocation that may be useful for candidate medication evaluation. In contrast to other abused drugs, such as heroin or cocaine, preclinical methamphetamine versus food choice procedures have been a more recent development. We hypothesize that preclinical to clinical translatability would be improved by the evaluation of repeated pharmacological treatment effects on methamphetamine self-administration under a methamphetamine versus food choice procedure. In support of this hypothesis, a literature review suggests strong concordance between preclinical pharmacological treatment effects on methamphetamine versus food choice in nonhuman primates and clinical medication treatment effects on methamphetamine self-administration in human laboratory studies or methamphetamine abuse metrics in clinical trials. In conclusion, this literature suggests preclinical methamphetamine versus food choice procedures may be useful in developing innovative pharmacotherapies for methamphetamine use disorder. PMID- 27936289 TI - Anisotropic Change in the Magnetic Susceptibility of a Dynamic Single Crystal of a Cobalt(II) Complex. AB - Atypically anisotropic and large changes in magnetic susceptibility, along with a change in crystalline shape, were observed in a CoII complex at near room temperature. This was achieved by combining oxalate molecules, acting as rotor, and a CoII ion with unquenched orbital angular momentum. A thermally controlled 90 degrees rotation of the oxalate counter anion triggered a symmetry-breaking ferroelastic phase transition, accompanied by contraction-expansion behavior (ca. 4.5 %) along the long axis of a rod-like single crystal. The molecular rotation induced a minute variation in the coordination geometry around the CoII ion, resulting in an abrupt decrease and a remarkable increase in magnetic susceptibility along the direction perpendicular and parallel to the long axis of the crystal, respectively. Theoretical calculations suggested that such an unusual anisotropic change in magnetic susceptibility was due to a substantial reorientation of magnetic anisotropy induced by slight disruption in the ideal D3 coordination environment of the complex cation. PMID- 27936290 TI - Nanoscale Control of Homoepitaxial Growth on a Two-Dimensional Zeolite. AB - Nanoscale crystal growth control is crucial for tailoring two-dimensional (2D) zeolites (crystallites with thickness less than two unit cells) and thicker zeolite nanosheets for applications in separation membranes and as hierarchical catalysts. However, methods to control zeolite crystal growth with nanometer precision are still in their infancy. Herein, we report solution-based growth conditions leading to anisotropic epitaxial growth of 2D zeolites with rates as low as few nanometers per day. Contributions from misoriented surface nucleation and rotational intergrowths are eliminated. Growth monitoring at the single-unit cell level reveals novel nanoscale crystal-growth phenomena associated with the lateral size and surface curvature of 2D zeolites. PMID- 27936292 TI - Domain Wall Architecture in Tetragonal Ferroelectric Thin Films. AB - Non-Ising-like 180 degrees ferroelectric domain wall architecture and domain distribution in tetragonal PbZrx Ti1-x O3 thin films are probed using a combination of optical second harmonic generation and scanning transmission electron microscopy. In the remnant state, a specific nonlinear optical signature of tilted 180 degrees domain walls corresponding to a mixed Ising-Neel-type rotation of polarization across the wall is shown. PMID- 27936294 TI - Disulfide-Catalyzed Visible-Light-Mediated Oxidative Cleavage of C=C Bonds and Evidence of an Olefin-Disulfide Charge-Transfer Complex. AB - A photocatalytic method for the aerobic oxidative cleavage of C=C bonds has been developed. Electron-rich aromatic disulfides were employed as photocatalyst. Upon visible-light irradiation, typical mono- and multi-substituted aromatic olefins could be converted into ketones and aldehydes at ambient temperature. Experimental and computational studies suggest that a disulfide-olefin charge transfer complex is possibly responsible for the unconventional dissociation of S S bond under visible light. PMID- 27936293 TI - Effects of incentives for naltrexone adherence on opiate abstinence in heroin dependent adults. AB - AIM: To test whether an incentive-based intervention that increased adherence to naltrexone also increased opiate abstinence. DESIGN: Post-hoc combined analysis of three earlier randomized controlled trials that showed individually that incentives for adherence to oral and to extended-release injection naltrexone dosing schedules increased naltrexone adherence, but not opiate abstinence. SETTING: Out-patient therapeutic work-place in Baltimore, MD, USA. PARTICIPANTS: One hundred and forty unemployed heroin-dependent adults participating from 2006 to 2010. INTERVENTIONS: Participants were hired in a model work-place for 26 weeks and randomized to a contingency (n = 72) or prescription (n = 68) group. Both groups were offered naltrexone. Contingency participants were required to take scheduled doses of naltrexone in order to work and earn wages. Prescription participants could earn wages independent of naltrexone adherence. MEASURES: Thrice-weekly and monthly urine samples tested for opiates and cocaine and measures of naltrexone adherence (percentage of monthly urine samples positive for naltrexone or percentage of scheduled injections received). All analyses included pre-randomization attendance, opiate use and cocaine use as covariates. Additional analyses controlled for cocaine use and naltrexone adherence during the intervention. FINDINGS: Contingency participants had more opiate abstinence than prescription participants (68.1 versus 52.9% opiate-negative thrice-weekly urine samples, respectively; and 71.9 versus 61.7% opiate-negative monthly urine samples, respectively) based on initial analyses [thrice-weekly samples, odds ratio (OR) = 3.3, 95% confidence interval (CI) = 1.7-6.5, P < 0.01; monthly samples, OR = 2.6, 95% CI = 1.0-7.1, P = 0.06] and on analyses that controlled for cocaine use (thrice-weekly samples, OR = 3.9, 95% CI = 3.3-4.5, P < 0.01; monthly samples, OR = 3.4, 95% CI = 1.1-11.1, P = 0.04), which was high and associated with opiate use. The difference in opiate abstinence rates between contingency and prescription participants was reduced when controlling for naltrexone adherence (monthly samples, OR = 1.1, 95% CI = 0.7-1.7, P = 0.84). CONCLUSIONS: Incentives for naltrexone adherence increase opiate abstinence in heroin-dependent adults, an effect that appears to be due to increased naltrexone adherence produced by the incentives. PMID- 27936295 TI - Variability of Pinus halepensis Mill. Essential Oils and Their Antioxidant Activities Depending on the Stage of Growth During Vegetative Cycle. AB - The impact of growth stages during vegetative cycle (B0 - B5 ) on chemical composition and antioxidant activities of Pinus halepensis Mill. needles essential oils was investigated for the first time. GC and GC/MS analyses pointed to a quantitative variability of components; terpene hydrocarbons derivatives, represented by alpha-pinene (8.5 - 12.9%), myrcene (17.5 - 21.6%), p-cymene (7.9 11.9%) and (Z)-beta-caryophyllene (17.3 - 21.2%) as major components, decreased from 88.9% at B0 growth stage to 66.9% at B5 growth stage, whereas oxygenated derivatives, represented by caryophyllene oxide (5.4 - 12.6%) and terpinen-4-ol (0.4 - 3.3%) as major components, increased from 7% at B0 growth stage to 28.4% at B5 growth stage. Furthermore, our findings showed that essential oil of P. halepensis needles collected at B5 growth stage possess higher antioxidant activities by four different testing systems than those collected at B0 - B4 growth stages. This highlighted variability led to conclude that we should select essential oils to be investigated carefully depending on growth stage, in order to have the highest effectiveness of essential oil in terms of biological activities for human health purposes. PMID- 27936296 TI - Antiangiogenic and Toxic Effects of Genistein, Usnic Acid, and Their Copper Complexes in Zebrafish Embryos at Different Developmental Stages. AB - Angiogenesis plays a major role in the normal embryonic development and in diseases such as cancer. Drugs that control angiogenesis are an alternative way to tackle this disease. The polyphenols usnic acid (3), genistein (5), and daidzein (6) were tested for antiangiogenic and unwanted effects in zebrafish embryos whose blood vessel system resembles that of mammals. The established tyrosine kinase inhibitors axitinib (1) and tyrphostin AG490 (2) were included for comparison. All compounds except 6 caused distinct antiangiogenic effects such as a concentration-dependent reduction of intersegmental vessels, dorsal longitudinal anastomotic vessels, subintestinal veins and secondary sprouts. As side effects, pericardial oedema and the impairment of blood flow were observed. Usnic acid (3), genistein (5) and Cu(II)-genisteinate (7) gave rise to a curvature of the spine. Compounds 5 and 7 also induced cell death in the head of the embryos at higher doses. All effects were more pronounced when the compounds had been applied at an early stage (24 hpf) rather than at 48 hpf. The copper complexes 4 and 7 showed a stronger antiangiogenic effect than the free ligands 3 and 5. The genistein complex 7 was antiangiogenic at doses so low that side effects were tolerable, and thus it may be a potential anticancer drug candidate. PMID- 27936298 TI - Alessandro Volta Medal: C. Amatore / Centenary Award: P. Cramer / RUSNANOPRIZE: C. A. Mirkin / Frontiers in Chemical Energy Science Award: W. B. Tolman. PMID- 27936291 TI - Pleiotropy, constraint, and modularity in the evolution of life histories: insights from genomic analyses. AB - Multicellular organisms display an enormous range of life history (LH) strategies and present an evolutionary conundrum; despite strong natural selection, LH traits are characterized by high levels of genetic variation. To understand the evolution of life histories and maintenance of this variation, the specific phenotypic effects of segregating alleles and the genetic networks in which they act need to be elucidated. In particular, the extent to which LH evolution is constrained by the pleiotropy of alleles contributing to LH variation is generally unknown. Here, we review recent empirical results that shed light on this question, with an emphasis on studies employing genomic analyses. While genome-scale analyses are increasingly practical and affordable, they face limitations of genetic resolution and statistical power. We describe new research approaches that we believe can produce new insights and evaluate their promise and applicability to different kinds of organisms. Two approaches seem particularly promising: experiments that manipulate selection in multiple dimensions and measure phenotypic and genomic response and analytical approaches that take into account genome-wide associations between markers and phenotypes, rather than applying a traditional marker-by-marker approach. PMID- 27936297 TI - AIEgen with Fluorescence-Phosphorescence Dual Mechanoluminescence at Room Temperature. AB - We report the first example of an AIEgen (DPP-BO) with fluorescence phosphorescence dual emission under mechanical stimulation. By carefully analyzing the crystal structure of DPP-BO, the efficient intermolecular and intramolecular interactions should account for its unique mechanoluminescence (ML) properties, especially the abnormal phosphorescence, as further confirmed by controlled experiments and theoretical calculations for the presence of ISC transitions. These results provide important information for understanding the complex ML process, possibly opening up a new way to study the inherent mechanism of ML by broadening the application of AIEgens. PMID- 27936299 TI - Dehydrogenation of the NH-NH Bond Triggered by Potassium tert-Butoxide in Liquid Ammonia. AB - A novel strategy for the dehydrogenation of the NH-NH bond is disclosed using potassium tert-butoxide (tBuOK) in liquid ammonia (NH3 ) under air at room temperature. Its synthetic value is well demonstrated by the highly efficient synthesis of aromatic azo compounds (up to 100 % yield, 3 min), heterocyclic azo compounds, and dehydrazination of phenylhydrazine. The broad application of this strategy and its benefit to chemical biology is proved by a novel, convenient, one-pot synthesis of aliphatic diazirines, which are important photoreactive agents for photoaffinity labeling. PMID- 27936300 TI - Efficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench-Stable Precursor (Me4 N)SCF3. AB - Reported herein is the one-pot synthesis of trifluoromethylated amines at room temperature using the bench-stable (Me4 N)SCF3 reagent and AgF. The method is rapid, operationally simple and highly selective. It proceeds via a formal umpolung reaction of the SCF3 with the amine, giving quantitative formation of thiocarbamoyl fluoride intermediates within minutes that can readily be transformed to N-CF3 . The mildness and high functional group tolerance render the method highly attractive for the late-stage introduction of trifluoromethyl groups on amines, as demonstrated herein for a range of pharmaceutically relevant drug molecules. PMID- 27936302 TI - Highly Site Selective Formal [5+2] and [4+2] Annulations of Isoxazoles with Heterosubstituted Alkynes by Platinum Catalysis: Rapid Access to Functionalized 1,3-Oxazepines and 2,5-Dihydropyridines. AB - Platinum-catalyzed formal [5+2] and [4+2] annulations of isoxazoles with heterosubstituted alkynes enabled the atom-economical synthesis of valuable 1,3 oxazepines and 2,5-dihydropyridines, respectively. Importantly, this Pt catalysis not only led to unique reactivity dramatically divergent from that observed under Au catalysis, but also proceeded via unprecedented alpha-imino platinum carbene intermediates. PMID- 27936303 TI - Using multiple group modeling to test moderators in meta-analysis. AB - Meta-analysis is a popular and flexible analysis that can be fit in many modeling frameworks. Two methods of fitting meta-analyses that are growing in popularity are structural equation modeling (SEM) and multilevel modeling (MLM). By using SEM or MLM to fit a meta-analysis researchers have access to powerful techniques associated with SEM and MLM. This paper details how to use one such technique, multiple group analysis, to test categorical moderators in meta-analysis. In a multiple group meta-analysis a model is fit to each level of the moderator simultaneously. By constraining parameters across groups any model parameter can be tested for equality. Using multiple groups to test for moderators is especially relevant in random-effects meta-analysis where both the mean and the between studies variance of the effect size may be compared across groups. A simulation study and the analysis of a real data set are used to illustrate multiple group modeling with both SEM and MLM. Issues related to multiple group meta-analysis and future directions for research are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27936301 TI - New Furanone Derivatives and Alkaloids from the Co-Culture of Marine-Derived Fungi Aspergillus sclerotiorum and Penicillium citrinum. AB - Six new compounds including two furanone derivatives sclerotiorumins A and B (1 and 2), one novel oxadiazin derivative sclerotiorumin C (3), one pyrrole derivative 1-(4-benzyl-1H-pyrrol-3-yl)ethanone (4), and two complexes of neoaspergillic acid aluminiumneohydroxyaspergillin (5) and ferrineohydroxyaspergillin (6) were isolated from the co-culture of marine derived fungi Aspergillus sclerotiorum and Penicillium citrinum. Compound 3 was the first natural 1,2,4-oxadiazin-6-one. Compound 5 showed significant and selective cytotoxicity against human histiocytic lymphoma U937 cell line (IC50 = 4.2 MUm) and strong toxicity towards brine shrimp (LC50 = 6.1 MUm), and oppositely increased the growth and biofilm formation of Staphylococcus aureus. PMID- 27936304 TI - Continuous Flow Synthesis and Purification of Aryldiazomethanes through Hydrazone Fragmentation. AB - Electron-rich diazo compounds, such as aryldiazomethanes, are powerful reagents for the synthesis of complex structures, but the risks associated with their toxicity and instability often limit their use. Flow chemistry techniques make these issues avoidable, as the hazardous intermediate can be used as it is produced, avoiding accumulation and handling. Unfortunately, the produced stream is often contaminated with other reagents and by-products, making it incompatible with many applications, especially in catalysis. Herein is reported a metal-free continuous flow method for the production of aryldiazomethane solutions in a non coordinating solvent from easily prepared, bench-stable sulfonylhydrazones. All by-products are removed by an in-line aqueous wash, leaving a clean, base-free diazo stream. Three successful sensitive metal-catalyzed transformations demonstrated the value of the method. PMID- 27936305 TI - Confinement Alters the Structure and Function of Calmodulin. AB - Many cellular reactions involving proteins, including their biosynthesis, misfolding, and transport, occur in confined compartments. Despite its importance, a structural basis of understanding of how confined environments alter protein function is still lacking. Herein, we explore structure-function correlations of calmodulin (CaM), a multidomain protein involved in many calcium mediated signaling pathways, in reverse micelles. Confinement dramatically alters CaM structure and function. The protein forms an extended structure in bulk water, but becomes compacted in reverse micelles. In addition, confinement changes the function of CaM. Specifically, the protein binds the MLCK, AcN19, and somatostatin peptides in dilute buffer, but binds only the MLCK and AcN19 peptides in reverse micelles. In summary, we determined a new CaM structure in reverse micelles and demonstrate that confinement can modulate both protein structure and function. PMID- 27936306 TI - Hybrid Polymer/Garnet Electrolyte with a Small Interfacial Resistance for Lithium Ion Batteries. AB - Li7 La3 Zr2 O12 -based Li-rich garnets react with water and carbon dioxide in air to form a Li-ion insulating Li2 CO3 layer on the surface of the garnet particles, which results in a large interfacial resistance for Li-ion transfer. Here, we introduce LiF to garnet Li6.5 La3 Zr1.5 Ta0.5 O12 (LLZT) to increase the stability of the garnet electrolyte against moist air; the garnet LLZT-2 wt % LiF (LLZT-2LiF) has less Li2 CO3 on the surface and shows a small interfacial resistance with Li metal, a solid polymer electrolyte, and organic-liquid electrolytes. An all-solid-state Li/polymer/LLZT-2LiF/LiFePO4 battery has a high Coulombic efficiency and long cycle life; a Li-S cell with the LLZT-2LiF electrolyte as a separator, which blocks the polysulfide transport towards the Li metal, also has high Coulombic efficiency and kept 93 % of its capacity after 100 cycles. PMID- 27936307 TI - Synthesis of Functionalized [3], [4], [5] and [6]Dendralenes through Palladium Catalyzed Cross-Couplings of Substituted Allenoates. AB - A mild method for the synthesis of highly functionalized [3]-[6]dendralenes is reported, representing a general strategy to diversely substituted higher homologues of the dendralenes. The methodology utilizes allenoates bearing various substitution patterns, along with a wide range of boron and alkenyl nucleophiles that couple under palladium catalysis leading to sp-, sp2 -, and sp3 -substituted arrays. Regioselective transformations of the newly formed unsymmetrical dendralene derivatives are demonstrated. The use of micellar catalysis, where water is the global reaction medium, and room temperature reaction conditions, highlights the green nature of this technology. PMID- 27936308 TI - Amidinyl Radical Formation through Anodic N-H Bond Cleavage and Its Application in Aromatic C-H Bond Functionalization. AB - We report herein an atom-economical and sustainable approach to access amidinyl radical intermediates through the anodic cleavage of N-H bonds. The resulting nitrogen-centered radicals undergo cyclizations with (hetero)arenes, followed by rearomatization, to afford functionalized tetracyclic benzimidazoles in a highly straightforward and efficient manner. This metal- and reagent-free C-H/N-H cross coupling reaction exhibits a broad substrate scope and proceeds with high chemoselectivity. PMID- 27936309 TI - Synthesis of meta-Functionalized Pyridines by Selective Dehydrogenative Heterocondensation of beta- and gamma-Amino Alcohols. AB - New reactions that convert alcohols into important classes of compounds are becoming increasingly important as their development contributes to the conservation of our fossil carbon feedstock and the reduction of CO2 emissions. Two key catalytic alcohol conversion concepts are borrowing hydrogen or hydrogen autotransfer and acceptorless dehydrogenative condensation. Herein, we combined both concepts to synthesize meta-functionalized pyridines. First, diols and amines were linked to beta-amino alcohols, which can then undergo a selective dehydrogenative heterocondensation with gamma-amino alcohols. Iridium catalysts stabilized by PN5 P pincer ligands that were developed in our laboratory mediate the reactions most efficiently. All of the 3-aminopyridines that we describe in this paper have been synthesized for the first time, emphasizing the degree of innovation of this method and the problems associated with the synthesis of such meta-functionalized pyridines. PMID- 27936310 TI - Schistosomicidal Effects of the Essential Oils of Citrus limonia and Citrus reticulata Against Schistosoma mansoni. AB - We report the in vitro schistosomicidal effects of the essential oil obtained from Citrus limonia leaves (CL-EO) and C. reticulata fruit peels (CR-EO), cultivated in Brazil, against Schistosoma mansoni worms. Limonene (29.9%), beta pinene (12.0%), sabinene (9.0%), citronellal (9.0%), and citronellol (5.8%) are the major constituents of CL-EO; limonene (26.5%), gamma-terpinene (17.2%), linalool (11.1%), octanal (8.0%), myrcene (6.2%), and capraldehyde (3.9%) predominate in CR-EO. CL-EO displayed moderate lethal concentration 50% (LC50 ) of 81.7 and 38.9 MUg/ml against male and female worms at 24 and 72 h, respectively. At concentrations of 25 and 100 MUg/ml, CL-EO separated between 50 and 75% of the coupled worm pairs during the evaluated period. CR-EO presented moderate LC50 of 81.7 MUg/ml against male and female worms at 24 and 72 h. However, this oil separated coupled worm pairs more effectively than CL-EO and displayed lower cytotoxicity to GM07492-A cells (IC50 = 987.7 +/- 88.9 MUg/ml) as compared to CL-EO (IC50 = 187.8 +/- 2.9 MUg/ml). The enantiomers (+)-(R)-limonene and (-)-(S)-limonene did not affect S. mansoni adult worm pairs significantly. Taken together, these data indicate that CL-EO and CR-EO exhibit moderate in vitro schistosomicidal activity against adult S. mansoni worms. PMID- 27936311 TI - Glucose-Responsive Sequential Generation of Hydrogen Peroxide and Nitric Oxide for Synergistic Cancer Starving-Like/Gas Therapy. AB - Glucose is a key energy supplier and nutrient for tumor growth. Herein, inspired by the glucose oxidase (GOx)-assisted conversion of glucose into gluconic acid and toxic H2 O2 , a novel treatment paradigm of starving-like therapy is developed for significant tumor-killing effects, more effective than conventional starving therapy by only cutting off the energy supply. Furthermore, the generated acidic H2 O2 can oxidize l-Arginine (l-Arg) into NO for enhanced gas therapy. By using hollow mesoporous organosilica nanoparticle (HMON) as a biocompatible/biodegradable nanocarrier for the co-delivery of GOx and l-Arg, a novel glucose-responsive nanomedicine (l-Arg-HMON-GOx) has been for the first time constructed for synergistic cancer starving-like/gas therapy without the need of external excitation, which yields a remarkable H2 O2 -NO cooperative anticancer effect with minimal adverse effect. PMID- 27936312 TI - Synthesis, Characterization, and Computational Analysis of the Dialanate Dianion, [H3 Al-AlH3 ]2- : A Valence Isoelectronic Analogue of Ethane. AB - The first example of a well-defined binary, low-oxidation-state aluminum hydride species that is stable at ambient temperature, namely the dianion in [{(Dep Nacnac)Mg}2 (MU-H)]2 [H3 Al-AlH3 ] (Dep Nacnac=[(DepNCMe)2 CH]- , Dep=2,6 diethylphenyl), has been prepared via a magnesium(I) reduction of the alanate complex, (Dep Nacnac)Mg(MU-H)3 AlH(NEt3 ). An X-ray crystallographic analysis has shown the compound to be a contact ion complex, which computational studies have revealed to be the source of the stability of the aluminum(II) dianion. PMID- 27936313 TI - Knight Shift in 13 C NMR Resonances Confirms the Coordination of N-Heterocyclic Carbene Ligands to Water-Soluble Palladium Nanoparticles. AB - The coordination of N-heterocyclic carbene (NHC) ligands to the surface of 3.7 nm palladium nanoparticles (PdNPs) can be unambiguously established by observation of Knight shift (KS) in the 13 C resonance of the carbenic carbon. In order to validate this coordination, PdNPs with sizes ranging from 1.3 to 4.8 nm were prepared by thermal decomposition or reduction with CO of a dimethyl NHC PdII complex. NMR studies after 13 CO adsorption established that the KS shifts the 13 C resonances of the chemisorbed molecules several hundreds of ppm to high frequencies only when the particle exceeds a critical size of around 2 nm. Finally, the resonance of a carbenic carbon is reported to be Knight-shifted to 600 ppm for 13 C-labelled NHCs bound to PdNPs of 3.7 nm. The observation of these very broad KS resonances was facilitated by using Car-Purcell-Meiboom-Gill (CPMG) echo train acquisition NMR experiments. PMID- 27936314 TI - A Composite Polymeric Carbon Nitride with In Situ Formed Isotype Heterojunctions for Highly Improved Photocatalysis under Visible Light. AB - Introducing heterojunction is an effective way for improving the intrinsic photocatalytic activity of a graphitic carbon nitride (GCN) semiconductor. These heterostructures are mostly introduced by interfacing GCN with foreign materials that normally have entirely different physicochemical properties and show unfavorable compatibility, thus resulting in a limited improvement of the photocatalytic performance of the resultant materials. Herein, a composite polymeric carbon nitride (CPCN) that contains both melon-based GCN and triazine based crystalline carbon nitride (CCN) is prepared by a simple thermal reaction between lithium chloride and GCN. Thanks to the intimate contact and good compatibility between GCN and CCN, an in situ formed heterojunction acts as a driving force for separating the photogenerated charge carriers in CPCN. As a result, CPCN exhibits a significantly improved photocatalytic performance under visible light irradiation, which is, respectively, 10.6 and 5.3 times as high as those of the GCN and CCN alone. This well designed isotype heterojunction by a coupling of CCN presents an effective avenue for developing efficient GCN photocatalysts. PMID- 27936315 TI - Chemical Variability of Ivoirian Xylopia rubescens Leaf Oil. AB - Forty-two essential oil samples were isolated from leaves of Xylopia rubescens harvested in three forests of Southern Ivory Coast. All the samples have been submitted to GC-FID and the retention indices (RIs) of individual components have been measured on two capillary columns of different polarity. In addition, 20 oil samples, selected on the basis of their chromatographic profile, were also analyzed by 13 C-NMR and 24 components (78.0 - 92.4% of the whole compositions) have been identified. The content of the main components varied drastically from sample to sample: furanoguaia-1,4-diene (5.7 - 54.1%), furanoguaia-1,3-diene (1.1 - 10.5%), (8Z,11Z,14Z)-heptadeca-8,11,14-trien-2-one (4.3 - 16.0%), and (E)-beta caryophyllene (1.7 - 17.3%). Hierarchical cluster and principal components analysis of the 42 oil compositions allowed the distinction of two well differentiated groups of unequal importance within the oil samples. Oil samples of the main group (Group II) contained mainly furanoguaia-1,4-diene (mean [M] = 43.1%; standard deviation [SD] = 3.2%) while furanoguaia-1,3-diene (M = 8.4%; SD = 0.9%) and (8Z,11Z,14Z)-heptadeca-8,11,14-trien-2-one (M = 7.1%; SD = 1.5%) were present at appreciable contents. The composition of Group I was dominated by furanoguaia-1,4-diene (M = 17.0%; SD = 8.5%), (8Z,11Z,14Z)-heptadeca-8,11,14 trien-2-one (M = 10.2%; SD = 2.4%) and (E)-beta-caryophyllene (M = 9.5%; SD = 5.3%). PMID- 27936316 TI - Bioprospecting of Turbinaria Macroalgae as a Potential Source of Health Protective Compounds. AB - The present study aims to focus on the bioprospecting of marine macroalgae of Turbinaria species, plenteous biomass of the world ocean. Three types of solvents, i.e., H2 O, MeOH/H2 O (80:20, v/v) and hexane/i-PrOH (50:50, v/v), were used for extraction. Both the biological activity and the pattern of present chemicals were characterized. For the cell proliferation assay, the human embryonic kidney 293 cells, cervix/breast/pancreatic adenocarcinoma, and osteosarcoma cells were used. For the antioxidant activity determination, both intracellular assay with human embryonic kidney and cervix adenocarcinoma cells, as well as the biochemical DPPH test, were employed. To complete the information about macroalgae composition, organic compounds were characterized by the liquid chromatography coupled with high resolution tandem mass spectrometry. Attention was concentrated mainly on the lipidomic profile characterization. In spite the fact that any significant antiproliferative effect was not observed for cancer cells, both the Turbinaria species were shown to be good protectors against the oxidative stress of the non-cancer cells. Most of the antioxidants were determined in the hexane/i-PrOH extract. As regards the lipids identified, most of them belonged to the triacylglycerols followed by sphingomyelins, diacylglycerols, and polar (lyso)phospholipids. Additionally to fatty acids with 14, 16 and 18 carbons, also those with odd carbon numbers were frequently present. PMID- 27936317 TI - Au108 S24 (PPh3 )16 : A Highly Symmetric Nanoscale Gold Cluster Confirms the General Concept of Metalloid Clusters. AB - The reduction of (Ph3 P)AuCl with NaBH4 in the presence of HSC(SiMe3 )3 , leads to one of the largest metalloid gold clusters: Au108 S24 (PPh3 )16 (1). Within 1 an octahedral Au44 core of gold atoms arranged as in Au metal is surrounded by 48 oxidized Au atoms of an Au48 S24 shell, a novel building block in gold chemistry. The protecting Au48 S24 shell is completed by additional 16 Au(PPh3 ) units, leading to a complete protection of the gold core. Within 1 the Au-Au distances get more molecular on going from the center to the ligand shell. Cluster 1 represents novel structural motives in the field of metalloid gold clusters which also are partly typical for metal atoms in metalloid clusters: Mn Rm (n>m). PMID- 27936318 TI - Copper(II)-Thymine Coordination Polymer Nanoribbons as Potential Oligonucleotide Nanocarriers. AB - The direct reaction between copper nitrate, thymine-1-acetic acid, and 4,4' bipyridine in water leads to the formation of a blue colloid comprising uniform crystalline nanoribbons (length >1 MUm; width ca. 150-185 nm; diameter ca. 15-60 nm) of a coordination polymer. The polymer displays a thymine-based structure freely available for supramolecular interactions. These nanostructures show significant selective interaction with single-stranded oligonucleotides based on adenine. Remarkably, they present low cell toxicity in three cell lines-despite the copper(II) content-and can be used as nanocarriers of oligonucleotides. These results suggest the potential of these types of nanostructures in several biological applications. PMID- 27936319 TI - A Unique Blend of 2-Fluorenyl-2-anthracene and 2-Anthryl-2-anthracence Showing White Emission and High Charge Mobility. AB - White-light-emitting materials with high mobility are necessary for organic white light-emitting transistors, which can be used for self-driven OLED displays or OLED lighting. In this study, we combined two materials with similar structures-2 fluorenyl-2-anthracene (FlAnt) with blue emission and 2-anthryl-2-anthracence (2A) with greenish-yellow emission-to fabricate OLED devices, which showed unusual solid-state white-light emission with the CIE coordinates (0.33, 0.34) at 10 V. The similar crystal structures ensured that the OTFTs based on mixed FlAnt and 2A showed high mobility of 1.56 cm2 V-1 s-1 . This simple method provides new insight into the design of high-performance white-emitting transistor materials and structures. PMID- 27936320 TI - Income-Based Greenhouse Gas Emissions of Nations. AB - Accounting for greenhouse gas (GHG) emissions of nations is essential to understanding their importance to global climate change and help inform the policymaking on global GHG mitigation. Previous studies have made efforts to evaluate direct GHG emissions of nations (a.k.a. production-based accounting method) and GHG emissions caused by the final consumption of nations (a.k.a. consumption-based accounting method), but overlooked downstream GHG emissions enabled by primary inputs of individual nations and sectors (a.k.a. income-based accounting method). Here we show that the income-based accounting method reveals new GHG emission profiles for nations and sectors. The rapid development of mining industries drives income-based GHG emissions of resource-exporting nations (e.g., Australia, Canada, and Russia) during 1995-2009. Moreover, the rapid development of sectors producing basic materials and providing financial intermediation services drives income-based GHG emissions of developing nations (e.g., China, Indonesia, India, and Brazil) during this period. The income-based accounting can support supply side policy decisions and provide additional information for determining GHG emission quotas based on cumulative emissions of nations and designing policies for shared responsibilities. PMID- 27936321 TI - Stability of a Transient Protein Complex in a Charged Aqueous Droplet with Variable pH. AB - Electrospray ionization mass spectrometry (ESI-MS) has the potential to become a high-throughput robust experimental method for the detection of protein-protein equilibrium constants. Poorly understood processes that affect the stability of weak noncovalent protein complexes in the intervening droplet environment are a significant factor that precludes the advancement of the method. We use molecular dynamics to study the stability of a ubiquitin and ubiquitin-associated domain complex (RCSB PDB code 2MRO ) in an aqueous droplet with changing size and charge concentration. We present evidence that a weak protein complex changes conformation and may dissociate in shrinking droplets. Then, the droplets containing these dissociated proteins divide. Our findings suggest that in some cases ESI-MS does not measure the correct association constants. The study intends to stimulate research for systematic development of experimental protocols that stabilize weakly bound protein interfaces in droplets. PMID- 27936322 TI - Control of Activation Mode To Achieve Diastereodivergence in Asymmetric Syntheses of Chiral Spiropiperidinone Derivatives. AB - An efficient organocatalytic cascade reaction has been developed involving a Michael-hemiaminalization relay for the asymmetric synthesis of spiropiperidinone derivatives bearing adjacent quaternary and tertiary chiral centers via LUMO or HOMO activation. Importantly, this methodology demonstrates that applying distinct activation modes to different substrates in the same reaction can diverge diastereoselectivity. To our knowledge, this is also one of the few published cases of primary amine catalytic [3 + 3] cycloaddition reactions involving alpha-branched beta-ketoamides. PMID- 27936323 TI - Decyltrimethylammonium Bromide Micelles in Acidic Solutions: Counterion Binding, Water Structuring, and Micelle Shape. AB - Wide-angle neutron scattering experiments combined with empirical potential structural refinement modeling have been used to study the detailed structure of decyltrimethylammonium bromide micelles in the presence of acid solutions of HCl or HBr. These experiments demonstrate considerable variation in micelle structure and water structuring between micelles in the two acid solutions and in comparison with the same micelles in pure water. In the presence of the acids, the micelles are smaller; however, in the presence of HCl the micelles are more loosely structured and disordered while in the presence of HBr the micelles are more compact and closer to spherical. Bromide ions bind strongly to the micelle surface in the HBr solution, while in HCl solutions, ion binding to the micelle is similar to that found in pure water. The hydration numbers of the anions and extent of counterion binding follow the predictions of the Hofmeister series for these species. PMID- 27936324 TI - Influence of Thermal Treatments on the Evolution of Conductive Paths in Carbon Nanotube-Al2O3 Hybrid Reinforced Epoxy Composites. AB - The conductive path formed by carbon nanotubes (CNTs) in a polymer matrix is one of the most attractive topics for developing multifunctional nanocomposites. In this article, we studied the evolution of conductive paths and interactions in the interfacial regions in epoxy-based composites reinforced by an urchinlike hybrid of CNTs and alumina microparticles (MUAl2O3). A homogeneous dispersion of CNTs in the epoxy matrix was achieved thanks to the core-shell structures of CNTs MUAl2O3 hybrids, resulting in the interpenetrated epoxy's cross-linking network that strongly bonds with CNTs. Furthermore, thermal treatments at different temperatures around the glass-transition temperature (Tg) were conducted under vacuum on composites near the percolation threshold. It was found that the dielectric behavior and the Tg were shifted in spite of the constant CNT mass fraction used. This was mainly due to the fact that thermal treatment generated the adjustment of the cross-linking network of epoxy, and the distances between adjacent CNTs were reduced gradually. This study can provide insight into the evolution of conductive paths in the interfacial regions from a more straightforward perspective. PMID- 27936325 TI - Effect of Heteroatom Substitution on Transport in Alkanedithiol-Based Molecular Tunnel Junctions: Evidence for Universal Behavior. AB - The transport properties of molecular junctions based on alkanedithiols with three different methylene chain lengths were compared with junctions based on similar chains wherein every third -CH2- was replaced with O or S, that is, following the general formula HS(CH2CH2X)nCH2CH2SH, where X = CH2, O, or S and n = 1, 2, or 3. Conducting probe atomic force microscopy revealed that the low bias resistance of the chains increased upon substitution in the order CH2 < O < S. This change in resistance is ascribed to the observed identical trend in contact resistance, Rc, whereas the exponential prefactor beta (length sensitivity) was essentially the same for all chains. Using an established, analytical single level model, we computed the effective energy offset epsilonh (i.e., Fermi level relative to the effective HOMO level) and the electronic coupling strength Gamma from the current-voltage (I-V) data. The epsilonh values were only weakly affected by heteroatom substitution, whereas the interface coupling strength Gamma varied by over an order of magnitude. Consequently, we ascribe the strong variation in Rc to the systematic change in Gamma. Quantum chemical calculations reveal that the HOMO density shifts from the terminal SH groups for the alkanedithiols to the heteroatoms in the substituted chains, which provides a plausible explanation for the marked decrease in Gamma for the dithiols with electron-rich heteroatoms. The results indicate that the electronic coupling and thus the resistance of alkanedithiols can be tuned by substitution of even a single atom in the middle of the molecule. Importantly, when appropriately normalized, the experimental I-V curves were accurately simulated over the full bias range (+/-1.5 V) using the single-level model with no adjustable parameters. The data could be collapsed to a single universal curve predicted by the model, providing clear evidence that the essential physics is captured by this analytical approach and supporting its utility for molecular electronics. PMID- 27936326 TI - Piezoelectric and Triboelectric Dual Effects in Mechanical-Energy Harvesting Using BaTiO3/Polydimethylsiloxane Composite Film. AB - Piezoelectric and triboelectric nanogenerators have been developed as rising energy-harvesting devices in the past few years to effectively convert mechanical energy into electricity. Here, a novel hybrid piezo/triboelectric nanogenerator based on BaTiO3 NP/PDMS composite film was developed in a simple and low-cost way. The effects of the BTO content and polarization degree on the output performance were systematically studied. The device with 20 wt % BTO in PDMS and a 100-MUm-thick film showed the highest output power. We also designed three measurement modes to record hybrid, triboelectric, and piezoelectric outputs separately with a simple structure that has only two electrodes. The hybrid output performance is higher than the tribo- and piezoelectric performances. This work will provide not only a new way to enhance the output power of nanogenerators, but also new opportunities for developing built-in power sources in self-powered electronics. PMID- 27936327 TI - Preparation of the TiO2/Graphic Carbon Nitride Core-Shell Array as a Photoanode for Efficient Photoelectrochemical Water Splitting. AB - The photoelectrochemical (PEC) oxygen evolution reaction over a photoanode is a promising process for renewable energy. The fascinating properties of graphic carbon nitride (g-CN) in water splitting make the photoelectrode engineering of it for PEC use quite meaningful. In this work, we report the fabrication of the core-shell-structured TiO2/g-CN composite film by hydrothermal growth for TiO2 nanorod arrays and solvothermal growth for the g-CN layer. Herein, TiO2 is used as an effective electron-transfer layer, and g-CN is used as a visible light absorption layer. Different reaction conditions were investigated in order to obtain the uniform TiO2/g-CN nanorod core-shell structure. Outstanding photoelectrochemical performances of the optimized composites were obtained compared to that of pristine TiO2 or g-CN because the high-quality heterojunction between g-CN and TiO2 turned out to effectively reduce the recombination of charge carriers and improve the photoelectric conversion ability. Thus, the photocurrent density under visible light of TiO2/g-CN reached 80.9 MUA cm-2, which is 21 times that of g-CN under 0.6 V (vs SCE). Finally, a systematic photoelectrocatalytic mechanism of charge carrier migration and the recombination path in the TiO2/g-CN nanorod core-shell heterojunction was proposed, which can be considered to be a probable explanation of efficient PEC performance. PMID- 27936328 TI - Segmental Deuteration of alpha-Synuclein for Neutron Reflectometry on Tethered Bilayers. AB - Neutron reflectometry (NR) is uniquely suited for studying protein interaction with phospholipid bilayers along the bilayer normal on an angstrom scale. However, NR on its own cannot discern specific membrane-bound regions due to a lack of scattering contrast within a protein. Here we report the successful coupling of native chemical ligation (NCL) and NR to study alpha-synuclein (alpha syn), a membrane-binding neuronal protein central in Parkinson's disease. Two alpha-syn variants were generated where either the first 86 or last 54 residues are deuterated, allowing for region-specific contrast within the protein and the identification of membrane interacting residues by NR. Residues 1-86 are positioned at the hydrocarbon/headgroup interface of the outer leaflet, whereas the density distribution of the 54 C-terminal residues ranges from the hydrocarbon region to the aqueous environment. Coupling of NCL and NR should have broad utility in studies of membrane protein folding. PMID- 27936330 TI - Addiction and Mental Health Across the Lifespan: An Overview of Some Contemporary Issues. PMID- 27936331 TI - Parenting Emerging Adults Who Game Excessively: Parents' Lived Experiences. AB - Excessive gaming among emerging adults is a growing concern, especially in cases where it interferes with key developmental milestones such as gaining an education or establishing a career. Although researchers have begun to understand the effects of excessive gaming on young people themselves, we know remarkably little about how emerging adults' gaming may affect family relationships. Utilizing phenomenological interviewing of parents of emerging adult sons who game excessively, this study presents a rich description of the experience of parenting a young adult who games excessively. In-depth interviews were conducted with two fathers and two mothers. Findings suggested that parents felt their sons were missing out on aspects of their life due to their gaming and were not meeting their full potential. They also felt their sons were different from other people their age and found it difficult to talk to them about their gaming. Finally, they believed their sons were addicted to gaming. PMID- 27936329 TI - Chemomechanical Coupling in Hexameric Protein-Protein Interfaces Harnesses Energy within V-Type ATPases. AB - ATP synthase is the most prominent bioenergetic macromolecular motor in all life forms, utilizing the proton gradient across the cell membrane to fuel the synthesis of ATP. Notwithstanding the wealth of available biochemical and structural information inferred from years of experiments, the precise molecular mechanism whereby vacuolar (V-type) ATP synthase fulfills its biological function remains largely fragmentary. Recently, crystallographers provided the first high resolution view of ATP activity in Enterococcus hirae V1-ATPase. Employing a combination of transition-path sampling and high-performance free-energy methods, the sequence of conformational transitions involved in a functional cycle accompanying ATP hydrolysis has been investigated in unprecedented detail over an aggregate simulation time of 65 MUs. Our simulated pathways reveal that the chemical energy produced by ATP hydrolysis is harnessed via the concerted motion of the protein-protein interfaces in the V1-ring, and is nearly entirely consumed in the rotation of the central stalk. Surprisingly, in an ATPase devoid of a central stalk, the interfaces of this ring are perfectly designed for inducing ATP hydrolysis. However, in a complete V1-ATPase, the mechanical property of the central stalk is a key determinant of the rate of ATP turnover. The simulations further unveil a sequence of events, whereby unbinding of the hydrolysis product (ADP + Pi) is followed by ATP uptake, which, in turn, leads to the torque generation step and rotation of the center stalk. Molecular trajectories also bring to light multiple intermediates, two of which have been isolated in independent crystallography experiments. PMID- 27936332 TI - An association of serum ALT with elevated blood pressure in senior adults: a case control study. AB - Hypertension is a major risk factor for cardiovascular diseases in China; hence, identifying good serum markers might provide cost benefits in terms of reducing morbidity rates. In this population-based case-control study, participants were recruited from five districts in Hunan province, and 416 cases were matched with an equal number of controls. Markers related to elevated blood pressure were assessed: Body Mass Index, total cholesterol, triglycerides, fasting blood glucose, and creatinine. Three potential serum markers homocysteine (HCY), C reactive protein (CRP), and alanine aminotransferase (ALT) were dichotomized as normal or high level. Binary logistic regression was used to determine odds ratios (ORs) and 95% confidence intervals (CIs). The findings showed that ALT is a powerful serum marker for predicting high risk of high blood pressure with OR = 2.94, 95% CI (1.44-6.02), while there were no significant differences between cases and controls for HCY and CRP. Additionally, it seems likely that high concentrations of HCY conferred a protective effect against elevated blood pressure. When adjusted for sex, ORs for hypertensive females were nearly five times higher than for hypertensive males (OR = 4.34, 95% CI = 1.17-16.04). The study strongly supports findings showing ALT is a potential indicator for patients with hypertension. PMID- 27936333 TI - Alcohol Use Disorder in Older Adults: Challenges in Assessment and Treatment. AB - Alcohol use disorder (AUD) is a common, under-recognized, and under-treated health concern in older adults. Its prevalence is expected to reach unprecedented levels as the U.S. population ages; consequently, it is poised to place a significant burden on the healthcare system. Given the growing body of evidence regarding the patterns of use in this age group and the serious consequences of its misuse, it is critical that nurses and other healthcare providers assess for AUD in order to identify older adults in need of treatment. Yet, differences in symptom presentation, problems in isolating the symptoms of AUD from other healthcare complaints associated with aging, as well as the denial and fear of stigma that is especially pervasive in this age group, are major barriers to its identification and subsequent treatment. Furthermore, the lack of consistent use of evidence-based, age-specific screening instruments to identify those at risk is another significant obstacle to successful treatment. Healthcare providers in primary care are especially well-positioned to perform a systematic assessment utilizing appropriate instruments to identify AUD and initiate age-specific interventions, including the use of alcohol screening and brief interventions (ASBIs). The use of ASBIs, along with other targeted interventions such as mutual help groups (MHGs), such as Alcoholics Anonymous, can be key in encouraging insight, dismantling denial, and supporting treatment success, lifelong recovery, and overall quality of life in this vulnerable group. PMID- 27936334 TI - Overview of Substance Use and Mental Health Among the "Baby Boomers" Generation. AB - As the population ages, risk factors commonly shared by chronic degenerative disease can be exacerbated by behaviours and lifestyle choices. There is increasing evidence that those affected by chronic disease (and associated symptoms such as pain), depression and adverse behavioural and lifestyle patterns are at risk of substance misuse. This paper overviews substance use in Baby Boomers, which are defined as people aged between 52-70 years old, and the implications this may have on their mental health and well-being. We provide an overview of the characteristics of the Baby Boomer generation, their health status and what is currently known about their substance use and misuse. A strengthening of older adult mental health outpatient services is recommended to prevent and address substance use among older adults. Further research examining factors that influence substance use among this group could better inform health promotion programs targeting Baby Boomers. PMID- 27936336 TI - Experiences of Health Professionals Caring for People Presenting to the Emergency Department After Taking Crystal Methamphetamine ("ICE"). AB - Globally, addiction to "ICE" (crystal methamphetamine) is increasing and presents emergency health care services personnel with a number of challenges. This paper reports the first of two major themes arising from a qualitative study investigating health professionals' experiences' managing people presenting to the Emergency Department (ED) after taking "ICE." The theme "Caring for people who use 'ICE' when presenting to EDs" comprises five subthemes. These are: (a) expecting the unexpected: "they're just off their heads"; (b) complexity of care: "underlying trauma and emotional dysregulation"; PMID- 27936335 TI - RAC2-P38 MAPK-dependent NADPH oxidase activity is associated with the resistance of quiescent cells to ionizing radiation. AB - Our recent study showed that quiescent G0 cells are more resistant to ionizing radiation than G1 cells; however, the underlying mechanism for this increased radioresistance is unknown. Based on the relatively lower DNA damage induced in G0 cells, we hypothesize that these cells are exposed to less oxidative stress during exposure. As a catalytic subunit of NADPH oxidase, Ras-related C3 botulinum toxin substrate 2 (RAC2) may be involved in the cellular response to ionizing radiation. Here, we show that RAC2 was expressed at low levels in G0 cells but increased substantially in G1 cells. Relative to G1 cells, the total antioxidant capacity in G0 phase cells increased upon exposure to X-ray radiation, whereas the intracellular concentration of ROS and malondialdehyde increased only slightly. The induction of DNA single- and double-stranded breaks in G1 cells by X-ray radiation was inhibited by knockdown of RAC2. P38 MAPK interaction with RAC2 resulted in a decrease of functional RAC2. Increased phosphorylation of P38 MAPK in G0 cells also increased cellular radioresistance; however, excessive production of ROS caused P38 MAPK dephosphorylation. P38 MAPK, phosphorylated P38 MAPK, and RAC2 regulated in mutual feedback and negative feedback regulatory pathways, resulting in the radioresistance of G0 cells. PMID- 27936337 TI - Alcohol Use in an Older Adult Referred to a Consultation-Liaison Psychiatry Service: A Case Report. AB - Alcohol use disorder in older adults is associated with a number of substantial medical complications, including cognitive decline. Due to limited success and application of screening approaches in this cohort, older adults are more likely to present to general hospital settings with undiagnosed problematic alcohol use. Consultation-liaison psychiatry services operating in general hospital settings are likely to be referred older adults with alcohol use disorders for assessment and management. A 77-year-old female presented to a metropolitan hospital with symptoms including frequent falls, slurred speech, difficulty judging distance, hypersomnia, poor reasoning, and odd behaviours. She also presented with severe anxiety and bruxism. Several diagnostic tests were inconclusive, and a consultation-liaison psychiatry assessment revealed a prominent heavy drinking pattern and concurrent abuse of oxycodone and benzodiazepines. This report adds further support to the case for uniform screening of all older adults for alcohol and other drug (AOD) use. A number of weeks had passed before the patient's drinking pattern was established, with no withdrawal management in place. A multifaceted treatment approach, including antidepressant therapy, anticraving medication, benzodiazepine as well as opiate rationalisation, and AOD counselling support was commenced prior to discharge from the general hospital. PMID- 27936338 TI - beta-Raf activation of the myocardial Na+/H+ exchanger. PMID- 27936339 TI - Evaluation of a short home blood pressure measurement in an outpatient population of hypertensives. AB - Current guidelines suggest the use of home blood pressure monitoring (HBPM) as a method complementary to ambulatory blood pressure monitoring (ABPM) for the identification of arterial hypertension. A cross-sectional study was conducted to evaluate the accuracy of a short HBPM schedule compared with ABPM, and to evaluate to what extent HBPM can replace ABPM. A total of 310 patients who performed ABPM in our hypertension clinic were enrolled between November 2011 and June 2015. They performed a 4-day HBPM schedule, with two readings in the morning and two readings at night. Results showed a moderate correlation between HBPM and ABPM (r = 0.59 for systolic blood pressure (SBP) and r = 0.72 for diastolic blood pressure (DBP)) and moderate diagnostic agreement (area under curve: 0.791 for SBP and 0.857 for DBP). No significant difference was found between first-day average and those of days 2-4. Diagnostic agreement between the two techniques was moderate, supporting the notion that HBPM cannot replace ABPM in the general population. However, we identified two HBPM thresholds, 123/75 and 144/87 mm Hg, through which subjects who may not require further ABPM can be identified. PMID- 27936340 TI - High morning blood pressure surge is associated with oxidative stress and paraoxonase 1 activity in newly diagnosed hypertensive patients. AB - BACKGROUND: Both oxidative stress and morning surge (MS) of blood pressure (BP) were found to be closely related with cardiovascular and cerebrovascular diseases. We investigated the association between MS of BP and oxidative stress in newly diagnosed hypertensive patients. METHODS: We prospectively included 237 newly diagnosed hypertensive patients in the present study (mean age: 51.6 +/- 11.7 years). The patients were classified according to the extent of the sleep through surge as follows: the top decile of sleep-through surge (>47.2 mmHg, n = 27; EMShigh group), versus all others (n = 210, EMSlow group). Total antioxidant capacity (TAC) and total oxidant status (TOS) levels were determined by using an automated measurement method. The oxidative stress index (OSI) was calculated as the ratio of TOS to TAC. Serum paraoxonase 1 (PON-1) activity was measured spectrophotometrically. RESULTS: Patients in EMShigh group were found to have higher hs-CRP, TOS, and OSI values and lower TAC and PON-1 values (p < 0.01, for all). MS of BP was associated with hs-CRP, PON-1, TOS, TAC, and OSI levels in bivariate analysis. Multivariate linear regression analysis showed that MS of BP was significantly associated with PON-1(beta = -0.206, p < 0.001), OSI (beta = 0.602, p < 0.001) and hs-CRP (beta = 0.210, p < 0.001). CONCLUSION: Present study shows that OSI is increased and antioxidant PON-1 activity is decreased in patients with enhanced MS of BP. There is a close association between high MS of BP and oxidative stress markers in newly diagnosed hypertensive patients. PMID- 27936342 TI - BBMRI-ERIC Directory: 515 Biobanks with Over 60 Million Biological Samples. PMID- 27936341 TI - Single nucleotide polymorphism of adiponectin +276 G/T is associated with the susceptibility to essential hypertension in a Turkish population. AB - BACKGROUND: It is well known that arterial stiffness is associated with hypertension. Recent studies have shown that adiponectin +276 G/T, ACE I/D, AGTR1 A1166C, and eNOS E298D polymorphisms are likely to be risk factors for arterial stiffness. In this study, we aimed to investigate possible associations between these single-nucleotide polymorphisms (SNPs) and essential hypertension in a Turkish population. METHODS: The study population consisted of 170 patients who were diagnosed with essential hypertension and 170 sex- and age-matched controls. Genotyping of adiponectin +276 G/T, ACE I/D, AGTR1 A1166C, and eNOS E298D SNPs were performed using real-time polymerase chain reaction and commercially produced kits. RESULTS: The percentage of the adiponectin +276 T allele carriers was significantly higher in the patients with hypertension (33%) than in the controls (25%, p < 0.011). Through multiple logistic regression analysis, the adiponectin +276 T allele carrier was found to be associated with an increased risk of hypertension (TT vs. GG and TG: odds ratio = 3.318, p = 0.014, 95% confidence interval: 1.269-8.678). The genotype distributions or allelic frequencies of ACE I/D, AGTR1 A1166C, and eNOS E298D SNPs did not significantly differ between the patients with hypertension and the controls. CONCLUSION: The present study demonstrated that the adiponectin +276 G/T SNP is likely to be a risk factor for essential hypertension in a Turkish population. PMID- 27936343 TI - Assessing bioequivalence and drug interchangeability. AB - As indicated by the US Food and Drug Administration (FDA), approved generic drug products can be used as substitutes for their respective innovative drug products. The FDA, however, does not indicate that two generic copies of the same innovative drug can be used interchangeably, even though they have been shown to be bioequivalent to the same innovative drug product. As more and more generic drug products become available in the market place, it is a concern whether these approved generic drug products have the same quality and safety/efficacy and hence can be used interchangeably. To address the issue of drug interchangeability, several criteria such as individual bioequivalence criterion, a criterion based on the variability due to subject-by-drug interaction, and a scaled criterion for drug interchangeability (SCDI) have been proposed in the literature. In this article, the performances of these criteria, including a newly proposed reversed average bioequivalence criterion, are studied under a 2x4 replicated crossover design in terms of the percentage of passing at the best and worst possible scenarios of similarity. The goal of this paper is to investigate the interchangeability in terms of switchability between a generic (test) drug product and an originator (reference) drug product. PMID- 27936344 TI - Safety and immunogenicity of a Herpes Zoster subunit vaccine in Japanese population aged >=50 years when administered subcutaneously vs. intramuscularly. AB - The impact of alternate routes of vaccine administration, subcutaneous (SC) or intramuscular (IM), on the safety and immunogenicity of herpes zoster subunit candidate vaccine (HZ/su) was assessed in Japanese adults aged >= 50 y. During this phase III open-label study, 60 subjects were randomized (1:1) to receive HZ/su through SC or IM routes in a 0, 2 month schedule. Vaccine response rates (VRRs) and geometric mean concentrations (GMCs) of varicella zoster virus glycoprotein E (gE)-specific antibodies were determined by ELISA. Solicited and unsolicited symptoms were recorded for 7 and 30 d after each vaccination and graded 1-3 in severity. Serious adverse events (SAEs) were recorded throughout the study. At one month post-dose 2, VRRs were 100% (95% Confidence Interval (CI): 88.1-100) in both groups; anti-gE antibody GMCs were 44126.1 mIU/ml (95% CI: 36326.1-53601.0) and 45521.5 mIU/ml (95% CI; 37549.5-55185.9) in the SC and IM groups, respectively. Injection site reactions (pain, swelling and redness) were common, and observed more frequently following SC administration. Grade 3 redness and swelling were more frequently observed after SC administration. Fatigue and headache were the most frequently reported general symptoms for both routes of administration. Ten and 7 unsolicited AEs were reported in the SC and IM group, respectively. Two unsolicited AEs (1 in SC; 1 in IM) were considered related to vaccination by the investigator. Three non-fatal SAEs considered unrelated to vaccination were reported during the study. Administration of the HZ/su vaccine candidate resulted in a substantial immune response that was comparable between SC and IM subjects, but local reactogenicity may be greater for SC. PMID- 27936345 TI - Targeting integrin-linked kinase to suppress oncogenic KRAS signaling in pancreatic cancer. AB - Although oncogenic KRAS represents a therapeutically relevant target in pancreatic cancer, it is deemed "non-druggable" because of the intrinsic difficulty in designing direct inhibitors of KRAS. Our recent work demonstrated a KRAS-integrin-linked kinase (ILK) regulatory feedback loop that allows pancreatic cancer cells to regulate KRAS expression and to interact with the tumor microenvironment to promote aggressive phenotype. KRAS induces E2F1-mediated transcriptional activation of ILK expression, and ILK, in turn, controls KRAS expression via hnRNPA1, which binds and destabilizes the G-quadruplex in the KRAS promoter. Moreover, ILK inhibition blocked KRAS-driven EMT and growth factor stimulated KRAS expression. This regulatory loop, however, was not noted in KRAS mutant colorectal and lung cancer cells examined as knockdown of KRAS or ILK did not affect each other's expression, suggesting that this KRAS-ILK feedback regulation is specific for pancreatic cancer. In sum, this regulatory loop provides a strong mechanistic rationale for suppressing oncogenic KRAS signaling through targeting ILK, and this creating a potential new therapeutic strategy for pancreatic cancer. PMID- 27936346 TI - Antibodies to Staphylococcus aureus capsular polysaccharides 5 and 8 perform similarly in vitro but are functionally distinct in vivo. AB - The capsular polysaccharide (CP) produced by Staphylococcus aureus is a virulence factor that allows the organism to evade uptake and killing by host neutrophils. Polyclonal antibodies to the serotype 5 (CP5) and type 8 (CP8) capsular polysaccharides are opsonic and protect mice against experimental bacteremia provoked by encapsulated staphylococci. Thus, passive immunotherapy using CP antibodies has been considered for the prevention or treatment of invasive antibiotic-resistant S. aureus infections. In this report, we generated monoclonal antibodies (mAbs) against S. aureus CP5 or CP8. Backbone specific mAbs reacted with native and O-deacetylated CPs, whereas O-acetyl specific mAbs reacted only with native CPs. Reference strains of S. aureus and a selection of clinical isolates reacted by colony immunoblot with the CP5 and CP8 mAbs in a serotype-specific manner. The mAbs mediated in vitro CP type-specific opsonophagocytic killing of S. aureus strains, and mice passively immunized with CP5 mAbs were protected against S. aureus bacteremia. Neither CP8-specific mAbs or polyclonal antibodies protected mice against bacteremia provoked by serotype 8 S. aureus clinical isolates, although these same antibodies did protect against a serotype 5 S. aureus strain genetically engineered to produce CP8. We detected soluble CP8 in culture supernatants of serotype 8 clinical isolates and in the plasma of infected animals. Serotype 5 S. aureus released significantly less soluble CP5 in vitro and in vivo. The release of soluble CP8 by S. aureus may contribute to the inability of CP8 vaccines or antibodies to protect against serotype 8 staphylococcal infections. PMID- 27936347 TI - The infectious intracellular lifestyle of Salmonella enterica relies on the adaptation to nutritional conditions within the Salmonella-containing vacuole. AB - Salmonella enterica serovar Typhimurium (S. Typhimurium) is a Gram-negative pathogen that causes various host-specific diseases. During their life cycle, Salmonellae survive frequent exposures to a variety of environmental stresses, e.g. carbon-source starvation. The virulence of this pathogen relies on its ability to establish a replicative niche, named Salmonella-containing vacuole, inside host cells. However, the microenvironment of the SCV and the bacterial metabolic pathways required during infection are largely undefined. In this work we developed different biological probes whose expression is modulated by the environment and the physiological state of the bacterium. We constructed transcriptional reporters by fusing promoter regions to the gfpmut3a gene to monitor the expression profile of genes involved in glucose utilization and lipid catabolism. The induction of these probes by a specific metabolic change was first tested in vitro, and then during different conditions of infection in macrophages. We were able to determine that Entner-Doudoroff is the main metabolic pathway utilized by Salmonella during infection in mouse macrophages. Furthermore, we found sub-populations of bacteria expressing genes involved in pathways for the utilization of different sources of carbon. These populations are modified in presence of different metabolizable substrates, suggesting the coexistence of Salmonella with diverse metabolic states during the infection. PMID- 27936350 TI - Adaptation of Reactive Saccades is Influenced by Unconscious Priming of the Attention Focus. AB - The authors investigated whether the size of the attention focus can influence saccadic adaptation, and whether this influence changes in older age. Using the scrambled sentence task, young and older participants were either primed for a wide attention focus, or primed of a narrow attention focus, or were not primed for any specific attention focus. Subsequently, all participants underwent a double-step saccadic adaptation paradigm aimed at changing the direction of reflexive saccades. The authors found that compared to the nonprimed control group, priming for a wide attention focus enhanced saccadic adaptation in both age groups by a similar amount; the benefit persisted throughout the adaptation phase, but was absent during the deadaptation phase. In contrast, the authors found no effects of priming with a narrow attention focus on saccadic adaptation. From this the authors conclude that a wide attention focus is beneficial for workaround strategies but not for adaptive recalibration, and that those benefits are similar in young and older persons. PMID- 27936349 TI - Shedding of porcine circovirus type 1 DNA and rotavirus RNA by infants vaccinated with Rotarix(r). AB - Thirty-three infants aged ~2 months had serial stool samples collected after receipt of Rotarix(r) vaccine dose 1, and were assessed for shedding of porcine circovirus type 1 DNA and Rotavirus group A RNA by molecular methods. We did not find strong evidence that porcine circovirus type 1 replication occurred. Porcine circovirus type 1 genome with the same sequence as that in Rotarix(r) was detected in a few infants as late as day >= 13; while this timing could suggest there may have been replication and not just transient passage through the gastrointestinal tract, the lack of increase in copy number in any infant supports transient passage and there are inherent limitations to the results. We found that 21% of infants did not shed Rotarix(r) RVA RNA beyond the day 3 sample, which may suggest lack of vaccine virus replication. Of the infants in whom Rotarix RVA RNA shedding continued, peak copy numbers were reached on days 3 5 for ~40%, and after day 5 in ~60%, and shedding can be prolonged (>= 45 days). PMID- 27936348 TI - Current prospects and future challenges for nasal vaccine delivery. AB - Nasal delivery offers many benefits over traditional approaches to vaccine administration. These include ease of administration without needles that reduces issues associated with needlestick injuries and disposal. Additionally, this route offers easy access to a key part of the immune system that can stimulate other mucosal sites throughout the body. Increased acceptance of nasal vaccine products in both adults and children has led to a burgeoning pipeline of nasal delivery technology. Key challenges and opportunities for the future will include translating in vivo data to clinical outcomes. Particular focus should be brought to designing delivery strategies that take into account the broad range of diseases, populations and healthcare delivery settings that stand to benefit from this unique mucosal route. PMID- 27936352 TI - Prescott tests of equality in binary data under a three-treatment three-period crossover design. AB - Three test procedures accounting for patients with tied responses based on Prescott's ideas are developed for comparing three treatments under a three period crossover trial in binary data. Monte Carlo simulation is employed to evaluate the performance of these test procedures in a variety of situations. The test procedures proposed here are noted to have power larger than those procedures, which utilize only those patients with un-tied responses. The data taken from a three-period crossover trial comparing two different doses of an analgesic with placebo for the relief of primary dysmenorrhea are used to illustrate the use of the test procedures developed here. PMID- 27936351 TI - Metal Exposures at three U.S. electronic scrap recycling facilities. AB - Many metals found in electronic scrap are known to cause serious health effects, including but not limited to cancer and respiratory, neurologic, renal, and reproductive damage. The National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention performed three health hazard evaluations at electronic scrap recycling facilities in the U.S. to characterize employee exposure to metals and recommend control strategies to reduce these exposures. We performed air, surface, and biological monitoring for metals. We found one overexposure to lead and two overexposures to cadmium. We found metals on non-production surfaces, and the skin and clothing of workers before they left work in all of the facilities. We also found some elevated blood lead levels (above 10 micrograms per deciliter), however no employees at any facility had detectable mercury in their urine or exceeded 34% of the OELs for blood or urine cadmium. This article focuses on sampling results for lead, cadmium, mercury, and indium. We provided recommendations for improving local exhaust ventilation, reducing the recirculation of potentially contaminated air, using respirators until exposures are controlled, and reducing the migration of contaminants from production to non-production areas. We also recommended ways for employees to prevent taking home metal dust by using work uniforms laundered on-site, storing personal and work items in separate lockers, and using washing facilities equipped with lead-removing cleaning products. PMID- 27936353 TI - Evaluation of a therapeutic education program for French family caregivers of elderly people suffering from major neurocognitive disorders: Preliminary study. AB - The pertinence of a therapeutic program of education has been studied with regard to carers of patients suffering from major neurocognitive disorders. The program, adapted to the needs expressed by the carers, consisted of three workshops with a view to supplying general information about the pathologies, specific information on behavioral disorders, and specific aids to identify and manage their emotional reactions. The results of this preliminary study show a moderate significant benefit to the level of anxiety in the participants, taking into account the specific expectations of the carers and bringing to light further needs. PMID- 27936354 TI - Comparison of tests of contingency tables. AB - We explore the use of bootstrap for testing independence of two categorical variables. We develop a theoretical justification for bootstrapping a contingency table and provide more accurate inference for small sample sizes. We also study the effect of equalized marginals on tests of independence. The small sample properties of the proposed and existing tests of independence are examined using Monte Carlo simulations. It is shown that the Fisher exact test and the Chi squared test with continuity correction are very conservative and cannot be recommended to test independence with small sample sizes. PMID- 27936355 TI - Sample size determination for a three-arm equivalence trial of Poisson and negative binomial responses. AB - Assessing equivalence or similarity has drawn much attention recently as many drug products have lost or will lose their patents in the next few years, especially certain best-selling biologics. To claim equivalence between the test treatment and the reference treatment when assay sensitivity is well established from historical data, one has to demonstrate both superiority of the test treatment over placebo and equivalence between the test treatment and the reference treatment. Thus, there is urgency for practitioners to derive a practical way to calculate sample size for a three-arm equivalence trial. The primary endpoints of a clinical trial may not always be continuous, but may be discrete. In this paper, the authors derive power function and discuss sample size requirement for a three-arm equivalence trial with Poisson and negative binomial clinical endpoints. In addition, the authors examine the effect of the dispersion parameter on the power and the sample size by varying its coefficient from small to large. In extensive numerical studies, the authors demonstrate that required sample size heavily depends on the dispersion parameter. Therefore, misusing a Poisson model for negative binomial data may easily lose power up to 20%, depending on the value of the dispersion parameter. PMID- 27936356 TI - Bayesian quantile regression for nonlinear mixed-effects joint models for longitudinal data in the presence of mismeasured covariate errors. AB - Quantile regression (QR) models have recently received increasing attention in longitudinal studies where measurements of the same individuals are taken repeatedly over time. When continuous (longitudinal) responses follow a distribution that is quite different from a normal distribution, usual mean regression (MR)-based linear models may fail to produce efficient estimators, whereas QR-based linear models may perform satisfactorily. To the best of our knowledge, there have been very few studies on QR-based nonlinear models for longitudinal data in comparison to MR-based nonlinear models. In this article, we study QR-based nonlinear mixed-effects (NLME) joint models for longitudinal data with non-central location and outliers and/or heavy tails in response, and non normality and measurement errors in covariate under Bayesian framework. The proposed QR-based modeling method is compared with an MR-based one by an AIDS clinical dataset and through simulation studies. The proposed QR joint modeling approach can be not only applied to AIDS clinical studies, but also may have general applications in other fields as long as relevant technical specifications are met. PMID- 27936358 TI - Moving Beyond Simple Answers to Complex Questions: How Does Context Affect Alcohol's Role in Sexual Assault Perpetration? A Commentary on Testa and Cleveland (2017). PMID- 27936357 TI - Does Alcohol Contribute to College Men's Sexual Assault Perpetration? Between- and Within-Person Effects Over Five Semesters. AB - OBJECTIVE: The current longitudinal study was designed to consider the time varying effects of men's heavy episodic drinking (HED) and drinking setting attendance on college sexual assault perpetration. METHOD: Freshman men (N = 992) were recruited in their first semester and completed online measures at the end of their first five semesters. Using multilevel models, we examined whether men with higher frequency HED (or party or bar attendance) were more likely to perpetrate sexual assault (between-person, Level 2 effect) and whether sexual assault perpetration was more likely in semesters in which HED (or party or bar attendance) was higher than each individual's average (within-person, Level 1 effect). RESULTS: The between-person effect of HED on sexual assault was not significant after accounting for the between-person effects of antisocial behavior, impersonal sex orientation, and low self-control. The within-person effect of HED on sexual assault perpetration was not significant. However, models substituting frequency of party attendance or bar attendance revealed both between- and within-person effects. The odds of sexual assault were increased for men with higher bar and party attendance than the sample as a whole, and in semesters in which party or bar attendance was higher than their own average. Supplemental analyses suggested that these drinking setting effects were explained by hookups, with sexual assault perpetration more likely in semesters in which the number of hookups exceeded one's own average. CONCLUSIONS: Findings point toward the importance of drinking contexts, rather than drinking per se, as predictors of college men's sexual assault perpetration. PMID- 27936360 TI - It Depends on How You Look at It: The Role of Alcohol in Men's Sexual Aggression Perpetration. PMID- 27936359 TI - Does Alcohol Really Contribute to College Men's Sexual Assault Perpetration? A Commentary on Testa and Cleveland (2017). PMID- 27936361 TI - The Relationship Between Drinking Pattern, Social Capital, and Area-Deprivation: Findings From the Health Survey for England. AB - OBJECTIVE: The purpose of this study was to establish the relationships between heavy episodic and drinking frequency with area-deprivation and social capital in England. METHOD: Using the Health Survey for England 2002-2006, a nationally representative crosssectional survey (N = 54,422), multilevel logistic regression models with individuals nested within primary sampling units were carried out, stratified by sex, on (a) drinkers versus nondrinkers, (b) heavy episodic drinking versus drinking less (on the heaviest drinking day), and (c) fewer than 2 drink-free days versus at least 2 drink-free days. Key exposures were individual social capital variables (social trust, active civic participation, social support, neighborhood perception). Models adjusted for age, area deprivation, economic activity, education, ethnicity, longstanding illness, marital status, and children in the household. RESULTS: Lack of social support (men: OR = 0.69, 95% CI [0.60, 0.79]; women: OR = 0.77, 95% CI [0.69, 0.86]) and no civic participation (men: OR = 0.75, 95% CI [0.67, 0.83]; women: OR = 0.73, 95% CI [0.68, 0.78]) decreased the odds of being a drinker versus a nondrinker. Among men, low social trust increased (OR = 1.16, 95% CI [1.04, 1.30]) and no civic participation decreased (OR = 0.81, 95% CI [0.74, 0.89]) the odds of heavy episodic drinking; among women, good overall neighborhood perception decreased the odds (OR = 0.91, 95% CI [0.86, 0.97]). Lack of social support (men: OR = 1.25, 95% CI [1.14, 1.36]; women: OR = 1.20, 95% CI [1.02, 1.40]) and no civic participation (men: OR = 1.25, 95% CI [1.14, 1.36]; women: OR = 1.37, 95% CI [1.25, 1.51]) increased the odds of having fewer than 2 drink-free days. Men and women living in the most deprived areas were less likely to drink, more likely to engage in heavy episodic drinking, and more likely to have at least 2 alcohol free days, after social capital variables were adjusted for. CONCLUSIONS: Social capital is associated with drinking alcohol, and low forms is associated with heavy episodic and frequent drinking. Interventions to reduce heavy episodic consumption should be targeted at those with low social capital and those living in deprived areas where heavy drinking is normalized. Drink-free days recommended in guidelines could be further targeted at those lacking social support. PMID- 27936362 TI - Prevalence of Self-Reported Prescription Drug Use in a National Sample of U.S. Drivers. AB - OBJECTIVE: Drug-involved driving has become an increasing concern. Although the focus has been on illegal drugs, there is evidence that prescribed medications can impair driving ability. The purpose of this study was to determine the self reported prevalence of prescription drug use, including medical and nonmedical use, among a nationally representative sample of drivers and to report related driver characteristics. METHOD: As part of the 2013-2014 National Roadside Survey, drivers from 60 sites were randomly recruited and asked to complete a survey on prescription drug use. RESULTS: Almost 20% of drivers reported using a prescription drug within the past 2 days, with the most common drug class being sedatives (8.0%), followed by antidepressants (7.7%), narcotics (7.5%), and stimulants (3.9%). Drivers who reported prescription drug use were significantly more likely to be female, older, non-Hispanic White, and report disability. Three of four drivers who reported medication use (78.2%) said the drug was prescribed for their use; the odds of using without a prescription were significantly higher for males, Black/African American, and Hispanic drivers, and lower for older drivers. Among those with a prescription, taking more than prescribed was most common for narcotics (6.8%), followed by sedatives (4.8%), stimulants (3.8%), and antidepressants (1.5%). CONCLUSIONS: These findings help to identify drivers using potentially impairing prescription drugs, both medically and nonmedically, and may inform the targeting of interventions to reduce impaired driving related to medications. PMID- 27936364 TI - Parent-Offspring Resemblance for Drinking Behaviors in a Longitudinal Twin Sample. AB - OBJECTIVE: The purpose of the current study was to evaluate parent-offspring resemblance for alcohol consumption and dependence symptoms, including sex specific effects, and how these patterns change across adolescence and early adulthood. METHOD: Three cohorts of twins were assessed longitudinally at five time points between ages 14 and 29 years, with parents directly assessed at intake, using structured interviews. Twin offspring and parents from the population-based Minnesota Twin Family Study were included for a total sample size of 3,762 offspring (52% female) and their parents. Alcohol use was measured using an index based on drinking quantity, frequency, maximum drinks, and number of intoxications. Alcohol dependence symptom counts were also used. RESULTS: Parent-offspring correlations for alcohol consumption increased from age 14 (r = .12) to age 17 (r = .25), remained stable from ages 17 through 24, and then decreased slightly by age 29 (r = .19). Familial resemblance for symptoms of alcohol dependence peaked at age 17 (r = .18) then decreased through age 29 (r = .11). Parent-offspring correlations of both measures did not vary significantly by sex of offspring or sex of parent. CONCLUSIONS: Overall, parent-offspring resemblance for alcohol use and problems is relatively stable after early adulthood, with resemblance for alcohol use at higher magnitudes across offspring development. Evidence for differential resemblance based on sex of offspring or parents was lacking. PMID- 27936363 TI - Predictors of Patterns of Alcohol-Related Blackouts Over Time in Youth From the Collaborative Study of the Genetics of Alcoholism: The Roles of Genetics and Cannabis. AB - OBJECTIVE: Alcohol-related blackouts (ARBs) are anterograde amnesias related to heavy alcohol intake seen in about 50% of drinkers. Although a major determinant of ARBs relates to blood alcohol concentrations, additional contributions come from genetic vulnerabilities and possible impacts of cannabis use disorders (CUDs). We evaluated relationships of genetics and cannabis use to latent class trajectories of ARBs in 829 subjects from the Collaborative Study of the Genetics of Alcoholism (COGA). METHOD: The number of ARBs experienced every 2 years from subjects with average ages of 18 to 25 were entered into a latent class growth analysis in Mplus, and resulting class membership was evaluated in light of baseline characteristics, including CUDs. Correlations of number of ARBs across assessments were also compared for sibling pairs versus unrelated subjects. RESULTS: Latent class growth analysis identified ARB-based Classes 1 (consistent low = 42.5%), 2 (moderate low = 28.3%), 3 (moderate high = 22.9%), and 4 (consistent high = 6.3%). A multinomial logistic regression analysis within latent class growth analysis revealed that baseline CUDs related most closely to Classes 3 and 4. The number of ARBs across time correlated .23 for sibling pairs and -.10 for unrelated subjects. CONCLUSIONS: Baseline CUDs related to the most severe latent ARB course over time, even when considered along with other trajectory predictors, including baseline alcohol use disorders and maximum number of drinks. Data indicated significant roles for genetic factors for alcohol use disorder patterns over time. Future research is needed to improve understanding of how cannabis adds to the ARB risk and to find genes that contribute to risks for ARBs among drinkers. PMID- 27936366 TI - The Association Between Secondhand Harms From Alcohol and Mental Health Outcomes Among Postsecondary Students. AB - OBJECTIVE: There is a paucity of research on the prevalence and consequences of secondhand harms from alcohol. The current study (a) investigated whether secondhand harms can be clustered into latent factors that reflect distinct but related types of harms and (b) examined the associations between experiencing secondhand harms and mental health outcomes, including anxiety, depression, and subjective mental well-being, among first-year Canadian postsecondary students. The moderating effect of living arrangement (i.e., living on campus or not) on the associations was also tested. METHOD: The sample included 1,885 first-year undergraduate students (49.8% female; mean age = 18.31 years) from three Canadian universities. Exploratory and confirmatory factor analyses were used to determine the factor structure of the harms measure. Path analysis was used to assess the association between harms and mental health outcomes. Models accounted for age, sex, and frequency of heavy drinking. RESULTS: Seventy-one percent of the sample reported experiencing at least one type of secondhand harm. The harms examined clustered into two distinct but related factors: strains (e.g., interrupted sleep) and threats (e.g., being harassed or insulted). Both threats and strains were associated with higher levels of anxiety and depression and poorer subjective well-being. Associations were stronger for threats and did not differ by living arrangement. CONCLUSIONS: Experiencing secondhand harms from alcohol, particularly threats, may have negative implications for student mental health over and above students' own drinking. Programs and policies on university campuses targeting both alcohol use and mental health should consider how to reduce both the prevalence and impact of secondhand harms from alcohol on students. PMID- 27936367 TI - Alcohol Warning Label Perceptions: Do Warning Sizes and Plain Packaging Matter? AB - OBJECTIVE: There is a dearth of research on the effectiveness of stringent alcohol warning labels. Our experiment tested whether increasing the size of an alcohol health warning lowers product-based ratings. We examined whether plain packaging lowers ratings of alcohol products and the consumers who use them, increases ratings of bottle "boringness," and enhances warning recognition compared with branded packaging. METHOD: A total of 440 adults (51.7% female) viewed one of three warning sizes (50%, 75%, or 90% of label surface) on either a plain or branded bottle of distilled spirits, wine, and beer. Participants also rated alcohol bottles on product-based (assessing the product itself), consumer based (assessing perceptions of consumers of the product), and bottle boringness ratings, and then attempted to recognize the correct warning out of four choices. RESULTS: As expected, the size of warning labels lowered product-based ratings. Similarly, plain packaging lowered product-based and consumer-based ratings and increased bottle boringness but only for wine bottles. Further, plain packaging increased the odds of warning recognition on bottles of distilled spirits. CONCLUSIONS: This study shows that plain packaging and warning size (similar to the graphic warnings on cigarette packages) affect perceptions about alcohol bottles. It also shows that plain packaging increases the likelihood for correct health warning recognition, which builds the case for alcohol warning and packaging research and policy. PMID- 27936365 TI - How Much Is Too Much? Patterns of Drinking During Alcohol Treatment and Associations With Post-Treatment Outcomes Across Three Alcohol Clinical Trials. AB - OBJECTIVE: This secondary data analysis examined patterns of drinking during alcohol treatment and associated drinking outcomes during the first year following treatment. The goal was to provide clinicians with guidance on which patients may be most at risk for negative long-term outcomes based on drinking patterns during treatment. METHOD: This study was an analysis of existing data (N = 3,851) from three randomized clinical trials for alcohol use disorder: the COMBINE Study (n = 1,383), Project MATCH (n = 1,726), and the United Kingdom Alcohol Treatment Trial (n = 742). Indicators of abstinence, non-heavy drinking, and heavy drinking (defined as 4/5 or more drinks per day for women/men) were examined during each week of treatment using repeated-measures latent class analysis. Associations between drinking patterns during treatment and drinking intensity, drinking consequences, and physical and mental health 12 months following intake were examined. RESULTS: Seven drinking patterns were identified. Patients who engaged in persistent heavy drinking throughout treatment and those who returned to persistent heavy drinking during treatment had the worst long term outcomes. Patients who engaged in some heavy drinking during treatment had better long-term outcomes than persistent heavy drinkers. Patients who reported low-risk drinking or abstinence had the best long-term outcomes. There were no differences in outcomes between low-risk drinkers and abstainers. CONCLUSIONS: Abstinence, low-risk drinking, or even some heavy drinking during treatment are associated with the best long-term outcomes. Patients who are engaging in persistent heavy drinking are likely to have the worst outcomes and may require a higher level of care. PMID- 27936368 TI - Utility of Brief Versions of the Alcohol Use Disorders Identification Test (AUDIT) to Identify Excessive Drinking Among Patients in HIV Care in South Africa. AB - OBJECTIVE: In sub-Saharan Africa, large proportions of patients who are on antiretroviral therapy (ART) engage in excessive alcohol use, which may lead to adverse health consequences and may go undetected. Consequently, health care workers need brief screening tools to be able to routinely identify and manage excessive alcohol use among their patients. Various brief versions of the valid and reliable 10-item Alcohol Use Disorders Identification Test (AUDIT) (i.e., the AUDIT-C, AUDIT-3, AUDIT-QF, AUDIT-PC, AUDIT-4, and m-FAST) may potentially replace the full AUDIT in busy HIV care settings. This study aims to assess the utility of these six brief versions of the AUDIT relative to the full AUDIT for identifying excessive alcohol use among patients in HIV care settings in South Africa. METHOD: Participants were 188 (95 women) patients from three ART clinics within district hospitals in the City of Tshwane Metropolitan Municipality who reported past-12-month alcohol use. Performance of each brief AUDIT measure for identifying excessive alcohol use was evaluated against that of the full AUDIT (with a cutoff score of >=6 for women and >=8 for men) as the gold standard. We used receiver-operating characteristic (ROC) analysis. RESULTS: Most brief AUDIT measures had an area under the receiver operating curve (AUROC) above .90 when compared with the full AUDIT (five of six for women and three of six for men). The AUDIT-PC, AUDIT-4, and m-FAST had the highest AUROCs, whereas the three brief measures comprising only consumption items had low specificities at the most optimal cutoff levels. CONCLUSIONS: Various brief versions of the AUDIT may be appropriate substitutes for the full AUDIT for screening for excessive alcohol use in HIV clinics in sub-Saharan Africa. PMID- 27936369 TI - The Association Between Body Image and Behavioral Misperception (BIBM) and Alcohol Use Among High School Girls: Results From the 2013 Youth Risk Behavioral Survey. AB - OBJECTIVE: The need to be thin is pervasive in adolescent culture and is associated with increased risk outcomes among adolescent girls. Body image and behavioral misperception (BIBM) exists when there is a disconnect between body weight perception and actions taken related to perceived weight status. To understand this further, we examined the relationship between BIBM and alcohol use among high school girls in the United States. METHOD: Using 2013 Youth Risk Behavior Survey data, we ran survey-weighted multivariable logistic regression analyses to examine BIBM and (a) lifetime alcohol use, (b) current alcohol use, and (c) current heavy episodic drinking (>=5 drinks in a few hours) among female high school students (N = 6,579). RESULTS: A total of 37.5% of high school females screened positive for BIBM, and 67.7%, 32.9%, and 17.8% reported lifetime alcohol use, current alcohol use, and heavy episodic drinking, respectively. In the final model, controlling for demographics, reporting a BIBM was associated with a 1.29 (95% CI [1.10, 1.51], p = .002) greater odds of lifetime alcohol use compared with those who did not; however, reporting BIBM was not significantly associated with current alcohol use. BIBM was also associated with a 1.22 (95% CI [1.02, 1.47], p = .03) greater odds of heavy episodic drinking compared with those without BIBM. CONCLUSIONS: The phenomenon of BIBM was associated with lifetime and heavy episodic drinking, but not current alcohol use, indicating that timing of alcohol use and onset of BIBM may be related. Potential explanations include shared underlying risk factors and using alcohol excessively as a coping mechanism, weight-gain strategy, or weight-loss strategy. PMID- 27936370 TI - Episodic Future Thinking Involving the Nonsmoking Self Can Induce Lower Discounting and Cigarette Consumption. AB - OBJECTIVE: Building on recent advances showing that the engagement in episodic future thinking (EFT) rather than semantic future thinking (SFT) can induce individuals to delay gratification and that activation of the ideal self may promote goal attainment, we tested whether imagining life events after smoking cessation led to lower discounting and reduced smoking. METHOD: Ninety smokers (21 women, 69 men) with intentions to quit or reduce smoking were randomly assigned to one of the three experimental conditions: EFT, SFT, and control. The dependent measures were discounting rate and number of cigarettes smoked during an ostensible survey. The number of cigarettes smoked in the following week was also recorded. RESULTS: Participants who engaged in EFT that involved imagining positive life experiences after smoking cessation discounted the future less (M = 0.43, SD = 0.25) in a monetary choice task than did participants who engaged in SFT (M = 0.56, SD = 0.20) and control participants (M = 0.58, SD = 0.22). Participants under the EFT condition were less likely to smoke (50.0%) at a subsequent survey than were participants under the SFT condition (73.3%) and controls (80.0%). During the post-experimental week, the EFT group also smoked less (M = 88.90 cigarettes, SD = 30.12) than did the SFT group (M = 108.67 cigarettes, SD = 32.56) and the control group (M = 112.97 cigarettes, SD = 36.24). CONCLUSIONS: Our findings indicate that smokers who engage in EFT involving the self after smoking cessation show reduced smoking, and this suggests that EFT involving the ideal self (e.g., the nonsmoking self for smokers intending to quit or reduce smoking) may constitute a new approach to controlling impulsive or addictive behaviors. PMID- 27936372 TI - Strategic Self-Presentation or Authentic Communication? Predicting Adolescents' Alcohol References on Social Media. AB - OBJECTIVE: The current study is one of the first to examine how self-reported alcohol consumption, friends' perceived alcohol consumption, and the perceived number of friends sharing alcohol references on social networking sites (SNS) is associated with adolescents' sharing of alcohol references on SNS. METHOD: A cross-sectional paper-and-pencil survey was administered among 3,172 adolescents (n = 3,133 used for analyses, mean age = 17.16 years, SD = 0.93; 50.7% male). Structural equation modeling was used to test the hypotheses. RESULTS: First, the results indicated that both self-reported drinking behavior and the perceived number of friends sharing alcohol references were related to sharing alcohol references on SNS, but the perceived number of friends sharing alcohol references was a stronger predictor than self-reported drinking behavior. Friends' perceived drinking behavior was not a significant predictor. In the second place, self reported drinking behavior was a stronger predictor for girls than for boys, whereas the perceived number of friends sharing alcohol references was a stronger predictor for boys than for girls. CONCLUSIONS: Adolescents' alcohol-related self representation is in line with their alcohol consumption and is also strongly related to what their friends are sharing. Thus, adolescents appear to communicate authentically about their drinking experiences, but the decision to do so is heavily influenced by the prevailing social norm regarding alcohol related communication. PMID- 27936373 TI - Is 4/20 an Event-Specific Marijuana Holiday? A Daily Diary Investigation of Marijuana Use and Consequences Among College Students. AB - OBJECTIVE: Given the popular association between April 20 ("4/20") and marijuana, the present study examined marijuana use and consequences on 4/20 compared with other days in order to test whether 4/20 is a high-risk, event-specific marijuana use holiday among college student marijuana users. METHOD: Fifty-nine college student marijuana users from three different, large U.S. universities located in Virginia, New Mexico, and Colorado completed daily brief surveys (<10 minutes) over a 12-day (April 15-April 26) period assessing prior-day marijuana use (i.e., percentage of users who consumed marijuana, number of unique marijuana use sessions, subjective high/intoxication while under the influence of marijuana, and number of grams of marijuana consumed) and marijuana-related consequences. RESULTS: Using oneway repeated-measures analyses of variance, we found that (a) 50% of students reported using marijuana on 4/20, which was significantly more than weekdays (28%) and weekend days (37%); (b) students reported a significantly higher number of unique marijuana use sessions on 4/20 (M = 1.47) compared with weekdays (M = 0.91); and (c) students reported a significantly higher number of grams consumed on 4/20 (M = 0.79) compared with weekdays (M = 0.35) and weekend days (M = 0.47). CONCLUSIONS: Our study provides preliminary support that 4/20 is a day associated with increased marijuana use but provides little evidence for an association with more problematic use. PMID- 27936371 TI - Testing Cross-Sectional and Prospective Mediators of Internalized Heterosexism on Heavy Drinking, Alcohol Problems, and Psychological Distress Among Heavy Drinking Men Who Have Sex With Men. AB - OBJECTIVE: Minority stress theory is one of the primary theories used to understand substance use among lesbian, gay, and bisexual populations. This study tested whether drinking to cope with stress (DTC), loneliness, and gay community participation (GCP) mediated the relationship between one type of minority stress (i.e., internalized heterosexism) and behavioral health outcomes. METHOD: Using secondary data analysis and the PROCESS procedure, relationships between internalized heterosexism, the mediators (DTC, loneliness, and GCP), and outcomes (heavy drinking, alcohol problems, and psychological distress) were explored, both cross-sectionally and in a lagged manner, among both treatment-seeking and non-treatment-seeking problem drinking men who have sex with men. Problem drinkers (N = 187) were assessed, provided brief normative feedback about their drinking, given the choice to receive brief alcohol use disorder treatment or change on their own, and then followed for 9 months. RESULTS: Cross-sectional findings revealed that internalized heterosexism was significantly associated with heavy drinking, alcohol problems, and psychological distress. DTC emerged as a significant mediator of internalized heterosexism for all the health outcomes. Loneliness and GCP were significant mediators of internalized heterosexism for alcohol problems and psychological distress. Multiple mediation models reveal that all three mediators significantly contribute to internalized heterosexism's effect on health outcomes. Lagged analyses did not yield any significant indirect effects. CONCLUSIONS: DTC, loneliness, and GCP all play an integral, mediational role in the relationship between internalized heterosexism and alcohol problems and psychological distress. Findings underscore the necessity of addressing internalized heterosexism in psychosocial interventions along with coping skills training, emphasizing culturally relevant social support and loneliness. PMID- 27936374 TI - Testing a Matching Hypothesis for Emerging Adults in Project MATCH: During Treatment and One-Year Outcomes. AB - OBJECTIVE: Compared with older adults, emerging adults (18-29 years old) entering treatment typically have less severe alcohol use consequences. Also, their unique clinical presentations (e.g., modest initial abstinence motivation) and developmental contexts (e.g., drinking-rich social networks) may make a straightforward implementation of treatments developed for adults less effective. Yet, this has seldom been examined empirically. This study was a secondary analysis of Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity) data examining (a) overall differences between emerging adults and older adults (>=30 years old) on outcomes during treatment and at 1-year follow up, and (b) whether emerging adults had poorer outcomes on any of the three Project MATCH treatments in particular. METHOD: Participants were 267 emerging adults and 1,459 older adults randomly assigned to individually delivered cognitive-behavioral therapy (CBT), motivational enhancement therapy (MET), or 12 step facilitation (TSF). Multilevel growth curve models tested differences on percentage of days abstinent (PDA) and drinks per drinking day (DDD) by age group and treatment assignment. RESULTS: During treatment, compared with older adults, emerging adults reported more DDD but similar PDA. Further, emerging adults assigned to TSF had less PDA and more DDD than emerging adults and older adults assigned to CBT or MET during treatment (i.e., emerging adults in TSF has poorer outcomes initially), but this matching effect was not evident at 1-year follow up. CONCLUSIONS: This study is among the first to test age group differences across three psychosocial interventions shown to be efficacious treatments for alcohol use disorder. Although emerging adults generally did as well as their older counterparts, they may require a more developmentally sensitive approach to bolster TSF effects during treatment. PMID- 27936375 TI - Putting Adolescents at Risk: Riding With Drinking Drivers Who Are Adults in the Home. AB - OBJECTIVE: Alcohol-related car crashes are a leading cause of adolescent death, and one in five U.S. adolescents reports recent riding in a car with a drinking driver. How often the driver is an adult in the home (e.g., parent) is unknown. Pediatric visits offer an opportunity to counsel families to reduce this risk. Our study aim was to determine the prevalence of recent riding with a drinking driver (RWDD) who was an adult in the home among adolescent primary care patients and to identify the demographic and environmental (substance use among family members) profiles of those at increased risk. METHOD: We recruited 12- to 18-year olds arriving for routine medical care between 11/2005 and 10/2008 from nine practices in New England. Computer self-administered questionnaires assessed demographics, past-3-month RWDD, driver characteristics, and parent/sibling substance use. We computed adjusted relative risk ratios using multiple logistic regression modeling. RESULTS: Among 2,096 adolescents (86% participation rate; mean age = 15.8 years, SD = 2.0; 58% girls; 65% White non-Hispanic), 8.2% reported past-3-month RWDD who was an adult in the home (36.6% of those reporting any past-3-month RWDD). Risk was higher for girls, younger adolescents (<17 year olds), White non-Hispanic and Hispanic versus Black youth, those with non-college graduate parents, and those with substance-involved parents. CONCLUSIONS: For a substantial proportion of adolescent primary care patients RWDD, the driver is a parent or other household adult, suggesting an important target for screening and counseling. PMID- 27936376 TI - Peer Network Counseling as Brief Treatment for Urban Adolescent Heavy Cannabis Users. AB - OBJECTIVE: A small body of evidence supports targeting adolescents who are heavy users of cannabis with brief interventions, yet more research is needed to confirm the effectiveness of these studies. We conducted a secondary analysis of our Peer Network Counseling (PNC) study (Mason et al., 2015), focusing on 46 adolescents of the sample of 119 who reported heavy cannabis use at baseline. METHOD: Urban adolescents (91% African American) presenting for primary health care were randomized to intervention or control conditions and followed for 6 months. We selected cases (n = 46) to analyze based on heavy cannabis use reported at baseline (>=10 times in past month). The ordinal response data (cannabis use) were modeled using a mixed-effects proportional odds model, including fixed effects for treatment, time, and their interaction, and a subject level random effect. RESULTS: In the subsample of adolescents with heavy cannabis use, those assigned to PNC had a 35.9% probability of being abstinent at 6 months, compared with a 13.2% probability in the control condition. Adolescents in the PNC condition had a 16.6% probability of using cannabis 10 or more times per month, compared with a 38.1% probability in the control condition. This differs from results of the full sample (N = 119), where no significant effects on cannabis use were found. CONCLUSIONS: PNC increased the probability of abstinence and reduced heavy cannabis use. These results provide initial support for PNC as a model for brief treatment with non-treatment seeking adolescents who are heavy users of cannabis. PMID- 27936377 TI - Broad Thinking: An Interview With Harold Kalant. AB - In this interview, Harold Kalant, M.D., Ph.D., professor emeritus at the University of Toronto, talks about his career in addiction science; his professional associations with E. M. Jellinek, Griffith Edwards, and other luminaries; the growth of the addiction field; and the issue of cannabis legalization in Canada, among other topics. PMID- 27936378 TI - Genome-wide identification of neuronal activity-regulated genes in Drosophila. AB - Activity-regulated genes (ARGs) are important for neuronal functions like long term memory and are well-characterized in mammals but poorly studied in other model organisms like Drosophila. Here we stimulated fly neurons with different paradigms and identified ARGs using high-throughput sequencing from brains as well as from sorted neurons: they included a narrow set of circadian neurons as well as dopaminergic neurons. Surprisingly, many ARGs are specific to the stimulation paradigm and very specific to neuron type. In addition and unlike mammalian immediate early genes (IEGs), fly ARGs do not have short gene lengths and are less enriched for transcription factor function. Chromatin assays using ATAC-sequencing show that the transcription start sites (TSS) of ARGs do not change with neural firing but are already accessible prior to stimulation. Lastly based on binding site enrichment in ARGs, we identified transcription factor mediators of firing and created neuronal activity reporters. PMID- 27936379 TI - Clinical and epidemiological characteristics associated with unfavorable tuberculosis treatment outcomes in TB-HIV co-infected patients in Brazil: a hierarchical polytomous analysis. AB - BACKGROUND: TB patients co-infected with HIV have worse treatment outcomes than non-coinfected patients. How clinical characteristics of TB and socioeconomic characteristics influence these outcomes is poorly understood. Here, we use polytomous regression analysis to identify clinical and epidemiological characteristics associated with unfavorable treatment outcomes among TB-HIV co infected patients in Brazil. METHODS: TB-HIV cases reported in the Brazilian information system (SINAN) between January 1, 2001 and December 31, 2011 were identified and categorized by TB treatment outcome (cure, default, death, and development of MDR TB). We modeled treatment outcome as a function of clinical characteristics of TB and patient socioeconomic characteristics by polytomous regression analysis. For each treatment outcome, we used cure as the reference outcome. RESULTS: Between 2001 and 2011, 990,017 cases of TB were reported in SINAN, of which 93,147 (9.4%) were HIV co-infected. Patients aged 15-19 (OR=2.86; 95% CI: 2.09-3.91) and 20-39 years old (OR=2.30; 95% CI: 1.81-2.92) were more likely to default on TB treatment than those aged 0-14 years old. In contrast, patients aged >=60 years were more likely to die from TB (OR=2.22; 95% CI: 1.43 3.44) or other causes (OR=2.86; 95% CI: 2.14-3.83). Black patients were more likely to default on TB treatment (OR=1.33; 95% CI: 1.22-1.44) and die from TB (OR=1.50; 95% CI: 1.29-1.74). Finally, alcoholism was associated with all unfavorable outcomes: default (OR=1.94; 95% CI: 1.73-2.17), death due to TB (OR=1.46; 95% CI: 1.25-1.71), death due to other causes (OR=1.38; 95% CI: 1.21 1.57) and MDR-TB (OR=2.29; 95% CI: 1.46-3.58). CONCLUSIONS: Socio-economic vulnerability has a significant effect on treatment outcomes among TB-HIV co infected patients in Brazil. Enhancing social support, incorporation of alcohol abuse screening and counseling into current TB surveillance programs and targeting interventions to specific age groups are interventions that could improve treatment outcomes. PMID- 27936380 TI - Extrahepatic manifestations of chronic hepatitis C infection: a consecutive study in Brazilian patients. PMID- 27936381 TI - A proteomic approach for rapid identification of Weissella species isolated from Korean fermented foods on MALDI-TOF MS supplemented with an in-house database. AB - Weissella are obligate heterofermentative lactic acid bacteria belonging to the Leuconostocaceae family. Some Weissella can be found in salted and fermented foods, such as kimchi and jeotgal, and plays an important role in the fermentation process. In the present study, for the first time, a rapid and accurate identification method for Weissella species from kimchi and jeotgal was developed based on MALDI-TOF MS, supplemented with an in-house database. Of the 135 Weissella spectra aligned with the MALDI bioTyper database, 56 isolates (41.5%) yielded no reliable identification results with low log scores (<1.7). After registering the spectra of six Weissella reference strains, all of the isolates were correctly identified, of which 113 (83.7%) and 22 (16.3%) were identified at the species and genus level, respectively. Moreover, a dendrogram generated by protein profiles of the different Weissella species clearly presented distinctive clusters, and PCA analysis separated the spectra of Weissella species into four clusters. In comparing food origins, different Weissella species were identified from two fermented foods. W. soli and W. cibaria were isolated from kimchi, while W. thailandensis and W. halotolerans were isolated from jeotgal. The results of our proteomic approach confirm that the MALDI bioTyper database, with our in-house Weissella database, is sufficient for Weissella identification. The MALDI-TOF MS method provides fast and reliable discrimination between different species in the genus Weissella and, therefore, will be useful for safety control in fish farms or in the production of fermented foods. This method can also be applied to the control of opportunistic pathogenic Weissella in human clinical infections. PMID- 27936383 TI - Reply by Authors. PMID- 27936384 TI - Editorial Comment. PMID- 27936382 TI - Editorial Comment. PMID- 27936386 TI - Editorial Comment. PMID- 27936385 TI - Interrater Reliability in Pediatric Urodynamic Tracings: A Pilot Study. AB - PURPOSE: Urodynamic studies are crucial to neuropathic bladder management and they often determine surgical intervention. However, current evidence indicates that interpretations show poor agreement across physicians. We sought to determine the interrater reliability of urodynamic interpretation in our practice. We hypothesized that there would be strong correlation among pediatric urologists of similar training in a single academic practice. MATERIALS AND METHODS: We retrospectively identified patients with neuropathic bladder who underwent urodynamics at our institution between 2014 and 2015. An anonymous electronic survey (phase I) was developed with 20 clinical scenarios, each containing a brief history, a single urodynamic tracing and an accompanying fluoroscopic image. Faculty members assessed each tracing by an online instrument developed using urodynamic reports and published literature. The primary outcome was statistical correlation across raters as measured by the Spearman correlation coefficient. In a followup study (phase II) we investigated the sources of variability in urodynamic interpretations. RESULTS: Six faculty members completed the study with a response rate of 100%. In comparing urodynamic interpretation across raters, the faculty demonstrated a weak to strong correlation (rs 0.39 0.61, p <0.001). A strong correlation was found for fluoroscopic and clinical decision making variables, while electromyography synergy and detrusor overactivity demonstrated weaker correlation across physicians. CONCLUSIONS: Faculty interpretations of urodynamic tracings showed only moderate agreement despite a close working relationship and similar training at a single institution. Variability in interpretation can strongly impact patient treatment. Therefore, further work is needed to standardize the reporting and interpretation of urodynamic studies to optimize patient care. PMID- 27936387 TI - Editorial Comment. PMID- 27936388 TI - Nanoliposome encapsulated anesthetics for local anesthesia application. AB - The systemic administration of opioids leads to potentially severe and undesirable and side effects like sedation and drowsiness, vomiting and nausea, allergies, respiratory depression, and neutrophil dysfunction. The application of nanotechnology in medical field has drawn a great attention in recent times. Several treatments available are tedious and expensive. Application of nanotechnology brings about faster cure and cost effectiveness. Nanoliposomes are one of the widely used names for nanoparticles used in medicine. Recently, nanoliposomes are used as a crucial novel drug delivery systems. The use of nanoliposomal formulation brings about a good results to pain control, rapid patient recovery, increased patient comfort, treatment costs reduction, and shortens length of hospitalization. This review presents a brief description about the achievements in the field of nanoscience and nanotechnology related to the application of nanoliposomes in anesthesia. PMID- 27936389 TI - Ethanolic extract of Dalbergia sissoo promotes rapid regeneration of cortical bone in drill-hole defect model of rat. AB - Leaves of Dalbergia sissoo is known to have protective actions against postmenopausal bone loss in rat. In this study, we have evaluated the fracture healing properties of ethanolic extract (EE) of Dalbergia sissoo leaves. To observe the fracture healing property in the drill-hole injury model, we randomly divided total 32 adult female Sprague Dawley rats (180+/-200g) into 4 groups: (i) Control operated group; (ii) EE (250mg/kg/day); (iii) EE (500mg/kg/day) and (iv) EE (1000mg/kg/day). The right femora were fractured at the mid-diaphysis region and each group of rats received their respective treatment for 15days. Ethanol extract dose dependently induced bone regeneration at the fracture site assessed by fluorochrome labeling. All of three doses, 250mg/kg/day dose significantly increased bone volume fraction, trabecular thickness, trabecular number, and connectivity density and decreased trabecular separation in bone. Furthermore, the extract induced the expression of osteogenic genes including BMP-2, BMP-4, RunX-2 and COL-1 compared to the control group. The EE improved fracture healing much earlier (day 15) than the normal healing process, as assessed by the increased callus volumes and mineralized nodule formation. This extract is found beneficial in fracture healing of rat. PMID- 27936390 TI - IRAP inhibition using HFI419 prevents moderate to severe acetylcholine mediated vasoconstriction in a rabbit model. AB - Coronary artery vasospasm (constriction) caused by reduced nitric oxide bioavailability leads to myocardial infarction. Reduced endothelial release of nitric oxide by the neurotransmitter acetylcholine, leads to paradoxical vasoconstriction as it binds to smooth muscle cell M3 receptors. Thus, inhibition of coronary artery vasospasm will improve clinical outcomes. Inhibition of insulin regulated aminopeptidase has been shown to improve vessel function, thus we tested the hypothesis that HFI419, an inhibitor of insulin regulated aminopeptidase, could reduce blood vessel constriction to acetylcholine. The abdominal aorta was excised from New Zealand white rabbits (n=15) and incubated with 3mM Hcy to induce vascular dysfunction in vitro for 1h. HFI419 was added 5min prior to assessment of vascular function by cumulative doses of acetylcholine. In some rings, vasoconstriction to acetylcholine was observed in aortic rings after pre-incubation with 3mM homocysteine. Incubation with HFI419 inhibited the vasoconstrictive response to acetylcholine, thus improving, but not normalizing, vascular function (11.5+/-8.9% relaxation vs 79.2+/-37% constriction, p<0.05). Similarly, in another group with mild vasoconstriction, HFI419 inhibited this effect (34.9+/-4.6% relaxation vs 11.1+/-5.2%, constriction, p<0.05). HFI419 had no effect on control aorta or aorta with mild aortic dysfunction. The present study shows that HFI419 prevents acetylcholine mediated vasoconstriction in dysfunctional blood vessels. HFI419 had no effect on normal vasodilation. Our results indicate a therapeutic potential of HFI419 in reducing coronary artery vasospasm. PMID- 27936391 TI - Contrary influence of clinically applied sorafenib concentrations among hepatocellular carcinoma patients. AB - The treatment responses of sorafenib in hepatocellular carcinoma are modest which may be due to different characteristics of cancer cells or insufficient therapeutic concentrations. This study was to clarify this issue. The anti proliferative effects and differential expressions of 8 genes related to sorafenib anti-cancer mechanisms (tyrosine kinase receptor genes: KDR, PDGFRB; RAF cascade: RAF1, BRAF, MAP2K1, MAP2K2, MAPK1, MAPK3) were investigated in primary cultured hepatocellular carcinoma cells collected from 8 patients using clinically applied sorafenib concentrations (5, 10MUg/mL). The anti-proliferative effects of sorafenib at either 5 or 10MUg/mL, which were related to down regulations of KDR, PDGFRB and/or genes in the RAF cascade, were achieved only in one patient (HCC38/KMUH). However, either 5 or 10MUg/mL sorafenib promoted proliferation in 4 patients (HCC29/KMUH, HCC62/KMUH, HCC87/KMUH, HCC98/KMUH). Among them, the RAF cascade, PDGFRB and/or KDR were up-regulated in 3 patients but no gene was differentially expressed in the remaining one patient (HCC87/KMUH). Increase the sorafenib concentration to 10MUg/mL paradoxically up regulated and/or obliterated the previously down-regulated genes in the RAF cascade and/or KDR in 4 patients (HCC29/KMUH, HCC76/KMUH, HCC87/KMUH, HCC98/KMUH). Significant down-regulations of the RAF cascade and PDGFRB by sorafenib but without anti-proliferative effects were detected in one patient (HCC54/KMUH). In conclusion, influence of sorafenib on proliferation is not simply through the RAF cascade. The responses of KDR, PDGFRB and the RAF cascade to sorafenib among patients are diverse or even contrary. Increase the sorafenib concentration has potential to up-regulate genes favored angiogenesis and proliferation. PMID- 27936392 TI - Rutin protects endothelial dysfunction by disturbing Nox4 and ROS-sensitive NLRP3 inflammasome. AB - High glucose induced endothelial dysfunction is blamed for initiation of vascular complication in Type 2 diabetes mellitus. Rutin has been described in possessing comprehensive pharmacological activities, but the mechanism involved in endothelial protection through regulating oxidative stress and damage is still ambiguous. In the present study, rutin was evaluated in high glucose stimulated human umbilical vein endothelial cells (HUVECs) and high glucose diet-treated SD rats were applied to explored the molecular mechanism in rutin counteracting oxidative stress and damage. Firstly, 30 and 100MUM rutin effectively increased HUVECs viability in high glucose challenge. Then we found that rutin could dose dependently reduced high glucose mediated mRNA and protein expressions of Nox4. With Nox4 and Nox2 inhibitors, we further confirm that Nox4, but not Nox2, was responsible for reactive oxygen species (ROS) production in high glucose environment. Moreover, rutin and Nox4 inhibitor significantly ameliorated ROS generation and TXNIP, NLRP3, caspase-1 and IL-1beta proteins expression in vivo. Furthermore, rutin substantially recovered nitric oxide production in HUVECs under high glucose condition. However, rutin could not inhibited inflammasome protein expressions and improved nitric oxide production in Nox4-overexpressed HUVECs under high glucose challenges. Finally, we found that rutin restored phenylephrine-mediated contractions and acetylcholine induced relaxations in aortic tissue of high glucose diet treated rats. In vitro, expressions of TXNIP, NLRP3, and caspase-1 in aortic tissue of high glucose diet treated rats were decreased under rutin administration. In summary, rutin may protect endothelial dysfunction through inhibiting Nox4 responsive oxidative stress and ROS-sensitive NLRP3 signaling pathway under high glucose stress both in vivo and vitro. PMID- 27936393 TI - Suppression of protein tyrosine phosphatase PTPN22 gene induces apoptosis in T cell leukemia cell line (Jurkat) through the AKT and ERK pathways. AB - The aim of this study was to investigate the effect of specific PTPN22 small interfering RNAs (siRNAs) on the viability and induction of apoptosis in Jurkat cells and to evaluate apoptosis signaling pathways. In this study, Jurkat cells were transfected with specific PTPN22 siRNA. Relative PTPN22 mRNA expression was measured by Quantitative Real-time PCR. Western blotting was performed to determine the protein levels of PTPN22, AKT, P-AKT, ERK, and P-ERK. The cytotoxic effects of PTPN22 siRNA were determined using the MTT assay. Apoptosis was quantified using TUNEL assay and flow cytometry. Results showed that in Jurkat cells after transfection with PTPN22 siRNA, the expression of PTPN22 in both mRNA and protein levels was effectively reduced. Moreover, siRNA transfection induced apoptosis on the viability of T-cell acute leukemia cells. More importantly, PTPN22 positively regulated the anti-apoptotic AKT kinase, which provides a powerful survival signal to T-ALL cells as well as the suppression of PTPN22 down regulated ERK activity. Our results suggest that the PTPN22 specific siRNA effectively decreases the viability of T-cell acute leukemia cells, induces apoptosis in this cell line, and therefore could be considered as a potent adjuvant in T-ALL therapy. PMID- 27936394 TI - Increased intracellular Ca2+ decreases cisplatin resistance by regulating iNOS expression in human ovarian cancer cells. AB - Previous studies have reported that intracellular Ca2+ signals and inducible nitric oxide synthase (iNOS) are involved in cell apoptosis. However, the role of iNOS in cisplatin resistance in ovarian cancer remains unclear. Here, we demonstrate that SKOV3/DDP ovarian cancer cells were more resistant to cisplatin than were SKOV3 ovarian cancer cells. The expression of intracellular Ca2+ and iNOS was more strongly induced by cisplatin in SKOV3 cells than in SKOV3/DDP cells. TAT-conjugated IP3R-derived peptide (TAT-IDPS) increased cisplatin-induced iNOS expression and apoptosis in SKOV3/DDP cells. 2-Aminoethoxydiphenyl borate (2 APB) decreased cisplatin-induced iNOS expression and apoptosis in SKOV3 cells. Thus, iNOS induction may be a valuable strategy for improving the anti-tumor efficacy of cisplatin in ovarian cancer. PMID- 27936395 TI - Population based report on health related quality of life in adolescents born very preterm. AB - BACKGROUND: As the survival rate of preterm infants constantly improves, knowledge on the impact of prematurity on long-term health-related quality of life (HRQoL) is important for clinical and parental guidance. We aimed to assess HRQoL in a national cohort of young adolescents born very preterm, and to identify predictors for poorer HRQoL. PATIENTS AND METHODS: All surviving Swiss live-born children below 30weeks of gestation during the year 2000 (290 subjects) were contacted at age 12years, together with their parents (262 families). HRQoL of the study children was assessed using both the Kidscreen-27 (KS-27) self- and parent forms. Neonatal data of the cohort were prospectively collected. RESULTS: Among the contacted families, 176 returned the complete set of questionnaires for 194 adolescents (67%): 100 (51%) females, mean (range) gestational age was 27.8 (24.1-29.9) weeks, birth weight 1025 (420-1730) grams, mean age at assessment 12.0 (11.0-13.0) years. Included children had similar neonatal and socio demographic characteristics as non-responders. Average self- and parent-reported HRQoL of former preterms was similar to Swiss KS-27 norms. According to the multivariable models (r2=0.2), surgical closure of patent ductus arteriosus, attention deficit/hyperactivity disorder, severe neurodevelopment impairment were negatively associated with both self- and parent-reported HRQoL. CONCLUSIONS: HRQoL in this population-based cohort of adolescents born very preterm is good. Surgical closure of patent ductus arteriosus, attention deficit/hyperactivity disorder, severe neurodevelopment impairment were identified as predictors of poorer HRQoL using multivariable models, explaining however only a low proportion of variance in HRQoL. PMID- 27936397 TI - Design of a new comprehensive continuous monitoring system for environmental radioactive aerosol. AB - In order to comprehensive monitoring the radioactive isotopes from nuclear facilities, we developed a dual channel spectral monitoring instrument, and realized synchronous measurement for alpha, beta and gamma radionuclides. This article focuses on how to ensure its accuracy, stability and efficiency. First is the accuracy. In order to lower the interference of environmental and detector performance variation, the zero phase shift filter was designed to ensure the accuracy of characteristic peak position. Lorenz fitting algorithm was designed to reduce the effect of spectral low-energy tailing. Multi thread processing was introduced to ensure that there was sufficient time to complete our complex algorithms. Second is the stability. The complicated measuring process was decomposed into several sub-states. A state monitoring method was set up to timely dispose the abnormal operation. Third is the efficiency. Sampling process and measurement process were designed in synchronous to save monitoring time, which is especially useful for environmental low level radioactive monitoring. Continuous test for seven days shows that the detection limit is less than 0.0003Bq/m3 for U, 239Pu, and less than 0.048Bq/m3 for beta and 137Cs. PMID- 27936396 TI - GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes. AB - BACKGROUND: GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes. METHODS: We defined markedly increased iron stores as serum ferritin >2247pmol/L (>1000MUg/L) and either hepatic iron >236MUmol/g dry weight or iron >10g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin <674.1pmol/L (<300MUg/L) or either age>=40y with iron <=2.5g iron by induction phlebotomy or age>=50y with <=3.0g iron by induction phlebotomy (men only). We compared participant subgroups using univariate methods. Using multivariable logistic regression, we evaluated associations of markedly increased iron stores with these variables: age; iron supplement use (dichotomous); whole blood units donated; erythrocyte units received as transfusion; daily alcohol consumption, g; and p.D519G positivity (heterozygosity or homozygosity). RESULTS: The mean age of 56 participants (94.6% men) was 55+/-10 (SD) y; 41 had markedly increased iron stores. Prevalences of swollen/tender 2nd/3rd metacarpophalangeal joints and elevated aspartate or alanine aminotransferase were significantly greater in participants with markedly increased iron stores. Only participants with markedly increased iron stores had cirrhosis. In multivariable analyses, p.D519G positivity was the only exposure variable significantly associated with markedly increased iron stores (odds ratio 9.9, 95% CI [1.6, 60.3], p=0.0126). CONCLUSIONS: GNPAT p.D519G is strongly associated with markedly increased iron stores in p.C282Y homozygotes after correction for age, iron-related variables, and alcohol consumption. PMID- 27936398 TI - MicroRNA138 regulates keratin 17 protein expression to affect HaCaT cell proliferation and apoptosis by targeting hTERT in psoriasis vulgaris. AB - The purpose of this study is to explore the how microRNA-138 (miR-138) affects the expression of keratin 17 (K17) and psoriasis development. Twenty-eight skin lesions from patients with psoriasis vulgaris and twenty-four normal skin tissues from healthy controls were collected. The HaCaT cells were assigned into blank, negative control (NC), miR-138 mimic, miR-138 inhibitor, hTERT siRNA and miR-138 inhibitor+hTERT siRNA groups. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the miR-138 expression. The hTERT and K17 protein expression were testified by Western Blotting. MTT assay, flow cytometry with PI single staining and Annexin V/PI double staining were performed to detect the cell proliferation activity, cell cycle and apoptosis, respectively. Compared with the healthy skin, the expression of miR-138 decreased in the psoriatic skin, but hTERT and K17 protein expressions increased. The miR-138 mimic and hTERT siRNA groups showed significantly decreased hTERT and K17 protein expressions, inhibited cell proliferation, increased number of cells at G1 phase and elevated apoptosis rate in comparison to the rest three groups. The hTERT and K17 protein expressions in the miR-138 inhibitor group were up-regulated with promoted cell proliferation and reduced apoptosis rate as compared with the other four groups. In the miR-138 inhibitor+hTERT siRNA group, the hTERT and K17 protein expressions, cell proliferation and apoptosis were intermediate between the miR 138 inhibitor and hTERT siRNA groups. These findings indicated that the expression of miR-138 was lower in the psoriatic skin, which was negatively correlated to K17 expression. MiR-138 may regulate K17 protein expression to affect HaCaT cell proliferation and apoptosis by targeting hTERT gene. PMID- 27936400 TI - Wicking of light hydrophobic liquid phase from water by pulverized rubber: Theoretical and experimental analyses. AB - Pulverized rubber (PR) can be utilized for capturing floating oils to prevent spreading and volatilization of hydrocarbons. Experiments were conducted using PR with four different particle sizes (ranging from 0.075 to 0.600mm) and South Louisiana crude oil. The oil capture performance of the PR particles was compared with that of powdered activated carbon (AC). Oil-particle interactions were analyzed using capillary theories for lateral aggregation and wicking processes, as well as sorption capacity in relation to particle size. The sorption capacity (as oil to sorbent ratio) for PR with particle size 0.115mm (4.41g/g) was comparable to that of AC with particle size 0.187mm (5.00g/g). Sorption efficiency (oil:powder ratio, g/g) of the PR increased with decreasing particle size. Sorption of oil by PR occurred rapidly (in less than 10min) which indicated strong capillary action. No additional sorption occurred after 30min. For the PR sample with larger particle size (0.600-0.400mm), lateral aggregation was clearly noticeable. The PR-oil aggregates could be easily removed from the water surface without breaking. The cost, availability and recycling potential of PR make it a feasible alternative material for oil spill response and industrial applications which require removal of floating oils. PMID- 27936399 TI - Gastrodia elata attenuates inflammatory response by inhibiting the NF-kappaB pathway in rheumatoid arthritis fibroblast-like synoviocytes. AB - Gastrodia elata (GE), which belongs to the Orchidaceae family, was found to possess anti-inflammatory activity. However, the effect of GE on inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) remains largely unknown. Thus, the aim of this study was to investigate the effects of GE on tumor necrosis factor-alpha (TNF-alpha)-induced inflammatory response in RA FLS and the underlying molecular mechanism was also explored. Our results demonstrated that GE significantly attenuated TNF-alpha-induced IL-6 and IL-8 production in RA-FLS. GE also inhibited TNF-alpha-induced MMP-3 and MMP-13 expression in RA-FLS. Furthermore, pretreatment with GE significantly attenuated TNF-alpha-induced the expression of p-p65 and IkappaBalpha degradation in RA-FLS. In conclusion, this study demonstrated for the first time that GE attenuated inflammatory response by inhibiting the NF-kappaB pathway signaling in RA-FLS. Thus, GE might have a therapeutic potential towards the treatment of RA. PMID- 27936401 TI - Adsorptive removal and separation of chemicals with metal-organic frameworks: Contribution of pi-complexation. AB - Efficient removal and separation of chemicals from the environment has become a vital issue from a biological and environmental point of view. Currently, adsorptive removal/separation is one of the most promising approaches for cleaning purposes. Selective adsorption/removal of various sulfur- and nitrogen containing compounds, olefins, and pi-electron-rich gases via pi-complex formation between an adsorbent and adsorbate molecules is very competitive. Porous metal-organic framework (MOF) materials are very promising in the adsorption/separation of various liquids and gases owing to their distinct characteristics. This review summarizes the literature on the adsorptive removal/separation of various pi-electron-rich compounds mainly from fuel and gases using MOF materials containing metal ions that are active for pi complexation. Details of the pi-complexation, including mechanism, pros/cons, applications, and efficient ways to form the complex, are discussed systematically. For in-depth understanding, molecular orbital calculations regarding charge transfer between the pi-complexing species are also explained in a separate section. From this review, readers will gain an understanding of pi complexation for adsorption and separation, especially with MOFs, to develop new insight for future research. PMID- 27936402 TI - Influence of triethyl phosphate on phosphatase activity in shooting range soil: Isolation of a zinc-resistant bacterium with an acid phosphatase. AB - Phosphatase-mediated hydrolysis of organic phosphate may be a viable means of stabilizing heavy metals via precipitation as a metal phosphate in bioremediation applications. We investigated the effect of triethyl phosphate (TEP) on soil microbial-phosphatase activity in a heavy-metal contaminated soil. Gaseous TEP has been used at subsurface sites for bioremediation of organic contaminants but not applied in heavy-metal contaminated areas. Little is known about how TEP affects microbial activity in soils and it is postulated that TEP can serve as a phosphate source in nutrient-poor groundwater and soil/sediments. Over a 3-week period, TEP amendment to microcosms containing heavy-metal contaminated soil resulted in increased activity of soil acid-phosphatase and repression of alkaline phosphatase, indicating a stimulatory effect on the microbial population. A soil-free enrichment of microorganisms adapted to heavy-metal and acidic conditions was derived from the TEP-amended soil microcosms using TEP as the sole phosphate source and the selected microbial consortium maintained a high acid-phosphatase activity with repression of alkaline phosphatase. Addition of 5mM zinc to soil-free microcosms had little effect on acid phosphatase but inhibited alkaline phosphatase. One bacterial member from the consortium, identified as Burkholderia cepacia sp., expressed an acid-phosphatase activity uninhibited by high concentrations of zinc and produced a soluble, indigo pigment under phosphate limitation. The pigment was produced in a phosphate-free medium and was not produced in the presence of TEP or phosphate ion, indicative of purple acid-phosphatase types that are pressed by bioavailable phosphate. These results demonstrate that TEP amendment was bioavailable and increased overall phosphatase activity in both soil and soil-free microcosms supporting the possibility of positive outcomes in bioremediation applications. PMID- 27936404 TI - Dexmedetomidine vs propofol sedation reduces delirium in patients after cardiac surgery: A meta-analysis with trial sequential analysis of randomized controlled trials. AB - PURPOSE: It is uncertain whether dexmedetomidine is better than propofol for sedation in postcardiac surgery patients. The purpose of this meta-analysis was to compare the effects of dexmedetomidine and propofol sedation on outcomes in adult patients after cardiac surgery. METHODS: Randomized controlled trials comparing outcomes in cardiac surgery patients sedated with dexmedetomidine or propofol were retrieved from PubMed, Embase, Web of Science, the Cochrane Library, and Clinicaltrials.Gov until May 23, 2016. RESULTS: A total of 969 patients in 8 studies met the selection criteria. The results revealed that dexmedetomidine was associated with a lower risk of delirium (risk ratio, 0.40;95% confidence interval [CI], 0.24-0.64; P=.0002), a shorter length of intubation (hours; mean difference, -0.95; 95% CI, -1.26 to -0.64; P<.00001), but a higher incidence of bradycardia (risk ratio 3.17; 95% CI, 1.41-7.10; P=.005) as compared to propofol. There were no statistical differences in the incidence of hypotension or atrial fibrillation, or the length of intensive care unit stay between dexmedetomidine and propofol sedation regimens. CONCLUSIONS: Dexmedetomidine sedation could reduce postoperative delirium and was associated with shorter length of intubation, but might increase bradycardia in patients after cardiac surgery compared with propofol. PMID- 27936403 TI - Arsenic accumulation and speciation in rice grown in arsanilic acid-elevated paddy soil. AB - P-arsanilic acid (AsA) is a emerging but less concerned contaminant used in animal feeding operations, for it can be degraded to more toxic metabolites after being excreted by animals. Rice is the staple food in many parts of the world, and also more efficient in accumulating arsenic (As) compared to other cereals. However, the uptake and transformation of AsA by rice is unclear. This study aimed to evaluate the potential risk of using AsA as a feed additive and using the AsA contaminated animal manure as a fertilizer. Five rice cultivars were grown in soil containing 100mg AsA/kg soil, after harvest, As species and their concentrations in different tissues were determined. Total As concentration of the hybrid rice cultivar was more than conventional rice cultivars for whole rice plant. For rice organs, the highest As concentration was found in roots. AsA could be absorbed by rice, partly degraded and converted to arsenite, monomethylarsonic acid, dimethylarsinic acid, arsenate. The number of As species and their concentrations in each cultivar were related to their genotypes. The soil containing 100mg AsA/kg or more is unsuitable for growing rice. The use of AsA and the disposal of animal manure requires detailed attention. PMID- 27936405 TI - Identification of lipopolysaccharide-interacting plasma membrane-type proteins in Arabidopsis thaliana. AB - Lipopolysaccharide (LPS) is an amphiphatic bacterial glycoconjugate found on the external membrane of Gram-negative bacteria. This endotoxin is considered as a microbe-associated molecular pattern (MAMP) molecule and has been shown to elicit defense responses in plants. Here, LPS-interacting proteins from Arabidopsis thaliana plasma membrane (PM)-type fractions were captured and identified in order to investigate those involved in LPS perception and linked to triggering of innate immune responses. A novel proteomics-based affinity-capture strategy coupled to liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed for the enrichment and identification of LPS-interacting proteins. As such, LPS isolated from Burkholderia cepacia (LPSB.cep.) was immobilized on three independent and distinct affinity-based matrices to serve as bait for interacting proteins from A. thaliana leaf and callus tissue. These were resolved by 1D electrophoresis and identified by mass spectrometry. Proteins specifically bound to LPSB.cep. have been implicated in membrane structure (e.g. COBRA-like and tubulin proteins), membrane trafficking and/or transport (e.g. soluble NSF attachment protein receptor (SNARE) proteins, patellin, aquaporin, PM instrinsic proteins (PIP) and H+-ATPase), signal transduction (receptor-like kinases and calcium-dependent protein kinases) as well as defense/stress responses (e.g. hypersensitive-induced response (HIR) proteins, jacalin-like lectin domain containing protein and myrosinase-binding proteins). The novel affinity-capture strategy for the enrichment of LPS-interacting proteins proved to be effective, especially in the binding of proteins involved in plant defense responses, and can thus be used to elucidate LPS-mediated molecular recognition and disease mechanism(s). PMID- 27936406 TI - Mobile demersal megafauna at common offshore wind turbine foundations in the German Bight (North Sea) two years after deployment - increased production rate of Cancer pagurus. AB - Within the next decades the construction of thousands of different types of large wind turbine foundations in the North Sea will substantially increase the amount of habitat available to reef fauna. To gain first insights which effect these substantial changes in habitat structure and diversity might have on faunal stocks settling on hard substrata, we compared the mobile demersal megafauna associated with the common types of wind turbine foundations ('jacket', 'tripod' and 'monopile with scour protections of natural rock') in the southern German Bight, North Sea. Monopiles with scour protection were mostly colonized by typical reef fauna. They were inhabited by an average of about 5000 edible crabs Cancer pagurus (per foundation), which is more than twice as much as found at the foundation types without scour protection. Strong evidence was found that all three foundation types not only function as aggregation sites, but also as nursery grounds for C. pagurus. Assuming equal shares of the three foundation types in future wind farms, we project that about 27% of the local stock of C. pagurus might be produced on site. When, for example, comparing the existing fauna at 1000 ship wrecks and on the autochthonous soft substrate with those which probably will establish at the foundations of 5000 hypothetically realized wind turbines, it becomes clear that the German Bight in the future will provide new artificial reef habitats for another 320% crabs (C. pagurus) and 50% wrasse (Ctenolabrus rupestris) representing substrata-limited mobile demersal hard bottom species. Further research is urgently required in order to evaluate this overspill as it would be an important ecological effect of the recent offshore wind power development. PMID- 27936407 TI - Sentence context influences the subjective perception of foreign accents. AB - We examined whether sentence context (the predictability of the final word) influences listeners' ratings of foreign-accented words. Previous work has demonstrated that accent manipulations affect listeners' processing of spoken language. We examined the converse of this relationship; whether context manipulations affect listeners' perceptions of accents. If there is a bidirectional relationship, listeners should be more likely to rate an accent as strong when the accented word is not predicted by the sentence. In Experiment 1, the results revealed that participants were significantly more likely to rate words spoken by foreign-accented speakers as "Strong Accent" in the unpredictable sentences when compared to the predictable sentences. Moreover, in Experiment 2, this effect was replicated and extended to a native speaker. These results support the idea that there is a bidirectional relationship between language processing and perceptions of accents. We discuss the practical implications for foreign-accented speakers. PMID- 27936408 TI - Biased mu-opioid receptor ligands: a promising new generation of pain therapeutics. AB - Opioid chemistry and biology occupy a pivotal place in the history of pharmacology and medicine. Morphine offers unmatched efficacy in alleviating acute pain, but is also associated with a host of adverse side effects. The advent of biased agonism at G protein-coupled receptors has expanded our understanding of intracellular signaling and highlighted the concept that certain ligands are able to differentially modulate downstream pathways. The ability to target one pathway over another has allowed for the development of biased ligands with robust clinical efficacy and fewer adverse events. In this review we summarize these concepts with an emphasis on biased mu opioid receptor pharmacology and highlight how far opioid pharmacology has evolved. PMID- 27936409 TI - Is body shame a significant mediator of the relationship between mindfulness skills and the quality of life of treatment-seeking children and adolescents with overweight and obesity? AB - This study aimed to examine (a) whether mindfulness skills were associated with higher quality of life through lower body shame for treatment-seeking children/adolescents with overweight and obesity and (b) whether this indirect effect was moderated by children/adolescents' age and gender. The sample included 153 children/adolescents with overweight/obesity followed in individual nutrition consultations. Participants completed self-report measures of mindfulness, body shame, and quality of life. Moderated mediation analyses showed that higher levels of mindfulness were associated with better perceived quality of life through lower body shame, but only among girls. For boys, higher levels of body shame did not translate into a poorer perception of quality of life, and the indirect effect of mindfulness on quality of life via lower body shame was not significant. These results suggest that body shame is an important mechanism to explain why mindfulness may help girls with overweight/obesity perceive a better quality of life. PMID- 27936410 TI - Body image and emotional distress in newly diagnosed cancer patients: The mediating role of dysfunctional attitudes and rumination. AB - Body image concerns (BIC) has been reported to be associated with emotional distress for cancers across various sites. This study sought to examine two cognitive vulnerability mechanisms: dysfunctional attitudes and rumination, and their combined effects on the relationship between BIC and emotional distress in newly diagnosed Asian cancer patients. Participants were 221 newly diagnosed adult cancer patients who were assessed on BIC, rumination, dysfunctional attitudes, and emotional distress. Path analysis was used to examine the hypothesized mediation model. The hypothesized mediation model controlling for age, sex, marital status, education level, cancer type, cancer stage, and treatment modality revealed that both dysfunctional attitudes and rumination mediated the relationship between BIC and emotional distress. The present study provides evidence for a mediating role of dysfunctional attitudes and rumination between BIC and emotional distress. Psychological treatment should target dysfunctional attitudes and rumination in cancer patients experiencing BIC. PMID- 27936411 TI - A network analysis of DSM-5 posttraumatic stress disorder symptoms and correlates in U.S. military veterans. AB - OBJECTIVE: Recent developments in psychometrics enable the application of network models to analyze psychological disorders, such as PTSD. Instead of understanding symptoms as indicators of an underlying common cause, this approach suggests symptoms co-occur in syndromes due to causal interactions. The current study has two goals: (1) examine the network structure among the 20 DSM-5 PTSD symptoms, and (2) incorporate clinically relevant variables to the network to investigate whether PTSD symptoms exhibit differential relationships with suicidal ideation, depression, anxiety, physical functioning/quality of life (QoL), mental functioning/QoL, age, and sex. METHOD: We utilized a nationally representative U.S. military veteran's sample; and analyzed the data from a subsample of 221 veterans who reported clinically significant DSM-5 PTSD symptoms. Networks were estimated using state-of-the-art regularized partial correlation models. Data and code are published along with the paper. RESULTS: The 20-item DSM-5 PTSD network revealed that symptoms were positively connected within the network. Especially strong connections emerged between nightmares and flashbacks; blame of self or others and negative trauma-related emotions, detachment and restricted affect; and hypervigilance and exaggerated startle response. The most central symptoms were negative trauma-related emotions, flashbacks, detachment, and physiological cue reactivity. Incorporation of clinically relevant covariates into the network revealed paths between self-destructive behavior and suicidal ideation; concentration difficulties and anxiety, depression, and mental QoL; and depression and restricted affect. CONCLUSION: These results demonstrate the utility of a network approach in modeling the structure of DSM-5 PTSD symptoms, and suggest differential associations between specific DSM-5 PTSD symptoms and clinical outcomes in trauma survivors. Implications of these results for informing the assessment and treatment of this disorder, are discussed. PMID- 27936412 TI - Contribution of cellular autolysis to tissular functions during plant development. AB - Plant development requires specific cells to be eliminated in a predictable and genetically regulated manner referred to as programmed cell death (PCD). However, the target cells do not merely die but they also undergo autolysis to degrade their cellular corpses. Recent progress in understanding developmental cell elimination suggests that distinct proteins execute PCD sensu stricto and autolysis. In addition, cell death alone and cell dismantlement can fulfill different functions. Hence, it appears biologically meaningful to distinguish between the modules of PCD and autolysis during plant development. PMID- 27936413 TI - Interactive registration between supine and prone scans in computed tomography colonography using band-height images. AB - In computed tomographic colonography (CTC), a patient is commonly scanned twice including supine and prone scans to improve the sensitivity of polyp detection. Typically, a radiologist must manually match the corresponding areas in the supine and prone CT scans, which is a difficult and time-consuming task, even for experienced scan readers. In this paper, we propose a method of supine-prone registration utilizing band-height images, which are directly constructed from the CT scans using a ray-casting algorithm containing neighboring shape information. In our method, we first identify anatomical feature points and establish initial correspondences using local extreme points on centerlines. We then correct correspondences using band-height images that contain neighboring shape information. We use geometrical and image-based information to match positions between the supine and prone centerlines. Finally, our algorithm searches the correspondence of user input points using the matched anatomical feature point pairs as key points and band-height images. The proposed method achieved accurate matching and relatively faster processing time than other previously proposed methods. The mean error of the matching between the supine and prone points for uniformly sampled positions was 18.41+/-22.07mm in 20 CTC datasets. The average pre-processing time was 62.9+/-8.6s, and the interactive matching was performed in nearly real-time. Our supine-prone registration method is expected to be helpful for the accurate and fast diagnosis of polyps. PMID- 27936414 TI - "Am I too emotional for this job?" An exploration of student midwives' experiences of coping with traumatic events in the labour ward. AB - BACKGROUND: midwifery is emotionally challenging work, and learning to be a midwife brings its own particular challenges. For the student midwife, clinical placement in a hospital labour ward is especially demanding. In the context of organisational tensions and pressures the experience of supporting women through the unpredictable intensity of the labour process can be a significant source of stress for student midwives. Although increasing attention is now being paid to midwives' traumatic experiences and wellbeing few researchers have examined the traumatic experiences of student midwives. Such research is necessary to support the women in their care as well as to protect and retain future midwives. AIM: this paper develops themes from a research study by Davies and Coldridge (2015) which explored student midwives' sense of what was traumatic for them during their undergraduate midwifery education and how they were supported with such events. It examines the psychological tensions and anxieties that students face from a psychotherapeutic perspective. DESIGN: a qualitative descriptive study using semi-structured interviews. SETTING: a midwifery undergraduate programme in one university in the North West of England. PARTICIPANTS: 11second and third year students. ANALYSIS: interviews were analysed using interpretative phenomenological analysis. FINDINGS: the study found five themes related to what the students found traumatic. The first theme Wearing the Blues referred to their enculturation within the profession and experiences within practice environments. A second theme No Man's Land explored students' role in the existential space between the woman and the qualified midwives. Three further themes described the experiences of engaging with emergency or unforeseen events in practice and how they coped with them ("Get the Red Box!", The Aftermath and Learning to Cope).This paper re-examines aspects of the themes from a psychotherapeutic perspective. KEY CONCLUSIONS: researchers have suggested that midwives' empathic relationships with women may leave them particularly vulnerable to secondary traumatic stress. For student midwives in the study the close relationships they formed with women, coupled with their diminished control as learners may have amplified their personal vulnerability. The profession as a whole is seen by them as struggling to help them to safely and creatively articulate the emotional freight of the role. IMPLICATIONS FOR PRACTICE: for midwifery educators, a focus on the psychological complexities in the midwifery role could assist in giving voice to and normalising the inevitable anxieties and difficulties inherent in the role. Further research could explore whether assisting students to have a psychological language with which to reflect upon this emotionally challenging work may promote safety, resilience and self-care. PMID- 27936415 TI - Hydraulic fracturing in cells and tissues: fracking meets cell biology. AB - The animal body is largely made of water. A small fraction of body water is freely flowing in blood and lymph, but most of it is trapped in hydrogels such as the extracellular matrix (ECM), the cytoskeleton, and chromatin. Besides providing a medium for biological molecules to diffuse, water trapped in hydrogels plays a fundamental mechanical role. This role is well captured by the theory of poroelasticity, which explains how any deformation applied to a hydrogel causes pressure gradients and water flows, much like compressing a sponge squeezes water out of it. Here we review recent evidence that poroelastic pressures and flows can fracture essential biological barriers such as the nuclear envelope, the cellular cortex, and epithelial layers. This type of fracture is known in engineering literature as hydraulic fracturing or 'fracking'. PMID- 27936416 TI - Antigen recognition-triggered drug delivery mediated by nanocapsule functionalized cytotoxic T-cells. AB - Cytotoxic T-Lymphocytes (CTLs) kill pathogen-infected or transformed cells following interaction of their T-cell receptors (TCRs) with foreign (e.g. virus derived) peptides bound to MHC-I molecules on the target cell. TCR binding triggers CTLs to secrete perforin, which forms pores in the target cell membrane, promoting target death. Here, we show that by conjugating drug-loaded lipid nanoparticles to the surface of CTLs, their lytic machinery can be co-opted to lyse the cell-bound drug carrier, providing triggered release of drug cargo upon target cell recognition. Protein encapsulated in T-cell-bound nanoparticles was released following culture of CTLs with target cells in an antigen dose- and perforin-dependent manner and coincided with target cell lysis. Using this approach, we demonstrate the capacity of HIV-specific CTLs to deliver an immunotherapeutic agent to an anatomical site of viral replication. This strategy provides a novel means to couple drug delivery to the action of therapeutic cells in vivo. PMID- 27936417 TI - Mesoporous silica-based versatile theranostic nanoplatform constructed by layer by-layer assembly for excellent photodynamic/chemo therapy. AB - Supramolecular photosensitizers (supraPSs) have emerged as effective photodynamic therapy (PDT) agents. Here, we propose the assembling capacity of supraPSs as a new strategy to construct theranostic nanoplatform with versatile functions aming at high-performance tumor therapy. By coating tirapazamine (TPZ)-loaded mesoporous silica nanoparticles (MSNs) with layer-by-layer (LbL) assembled multilayer, the versatile nanoplatform (TPZ@MCMSN-Gd3+) was obtained with the formation of supraPSs via host-guest interaction and the chelation with paramagnetic Gd3+. The TPZ@MCMSN-Gd3+ could be specifically uptaken by CD44 receptor overexpressed tumor cells and respond to hyaluronidase (HAase) to trigger the release of therapeutics. As confirmed by in vivo studies, TPZ@MCMSN Gd3+ showed preferential accumulation in tumor site and significantly inhibited the tumor progression by the collaboration of PDT and bioreductive chemotherapy under NIR fluorescence/MR imaging guidance. Taken together, this supraPSs based strategy paves a new paradigm of the way for the construction of theranostic nanoplatform. PMID- 27936418 TI - The impact of monomer sequence and stereochemistry on the swelling and erosion of biodegradable poly(lactic-co-glycolic acid) matrices. AB - Monomer sequence is demonstrated to be a primary factor in determining the hydrolytic degradation profile of poly(lactic-co-glycolic acid)s (PLGAs). Although many approaches have been used to tune the degradation of PLGAs, little effort has been expended in exploring the sequence-control strategy exploited by nature in biopolymers. Cylindrical matrices and films prepared from a series of sequenced and random PLGAs were subjected to hydrolysis in a pH 7.4 buffer at 37 degrees C. Swelling ranged from 107% for the random racemic PLGA with a 50:50 ratio of lactic (L) to glycolic (G) units to 6% for the sequenced alternating copolymer poly LG. Erosion followed an inverse trend with the random 50:50 PLGA showing an erosion half-life of 3-4 weeks while poly LG required ca. >10 weeks. Stereosequence was found to play a large role in determining swelling and erosion; stereopure analogs swelled less and were slower to lose mass. Molecular weight loss followed similar trends and increases in dispersity correlated with the onset of significant swelling. The relative proportion of rapidly cleavable G G linkages relative to G-L/L-G (moderate) and L-L (slow) correlates strongly with the degree of swelling observed and the rate of erosion. The dramatic sequence dependent variation in swelling, in the absence of a parallel hydrophilicity trend, suggest that osmotic pressure, driven by the differential accumulation of degradation products, plays an important role. PMID- 27936419 TI - Unexplained gastrointestinal bleed due to arteriobiliary fistula after percutaneous liver biopsy. AB - We represent a case of a 54-year-old male who presented to the emergency department with right upper quadrant abdominal pain and melena three weeks after percutaneous liver biopsy. He was found to have anemia secondary to an upper gastrointestinal hemorrhage, unresponsive to multiple blood transfusions. Angiography later revealed an arteriobiliary fistula with contrast extravasation entering the duodenum. The fistula was successfully embolized and the patient was discharged without complication. This report demonstrates the importance in considering a vascular intrahepatic fistula in patients with right upper quadrant abdominal pain after remote liver biopsy. PMID- 27936420 TI - Myofibroblastoma of the male breast: a rare entity with radiologic-pathologic correlation. AB - A 73-year old man with a history of multiple genitourinary malignancies was found to have a left retroareolar soft tissue mass on CT assessment of disease, and dedicated breast imaging was recommended. Diagnostic mammography and ultrasonography confirmed a solid mass, for which biopsy was recommended. Pathologic analysis demonstrated a spindle cell neoplasm with an immunoreactivity pattern consistent with myofibroblastoma. While this entity is benign, nonspecific imaging features necessitate tissue sampling for pathologic diagnosis, and, given pathologic rarity, open communication between the radiologist and pathologist is important to establish the correct diagnosis and to recommend appropriate management. PMID- 27936422 TI - Social network types among older Korean adults: Associations with subjective health. AB - With population aging now a global phenomenon, the health of older adults is becoming an increasingly important issue. Because the Korean population is aging at an unprecedented rate, preparing for public health problems associated with old age is particularly salient in this country. As the physical and mental health of older adults is related to their social relationships, investigating the social networks of older adults and their relationship to health status is important for establishing public health policies. The aims of this study were to identify social network types among older adults in South Korea and to examine the relationship of these social network types with self-rated health and depression. Data from the Korean Social Life, Health, and Aging Project were analyzed. Model-based clustering using finite normal mixture modeling was conducted to identify the social network types based on ten criterion variables of social relationships and activities: marital status, number of children, number of close relatives, number of friends, frequency of attendance at religious services, attendance at organized group meetings, in-degree centrality, out-degree centrality, closeness centrality, and betweenness centrality. Multivariate regression analysis was conducted to examine associations between the identified social network types and self-rated health and depression. The model-based clustering analysis revealed that social networks clustered into five types: diverse, family, congregant, congregant-restricted, and restricted. Diverse or family social network types were significantly associated with more favorable subjective mental health, whereas the restricted network type was significantly associated with poorer ratings of mental and physical health. In addition, our analysis identified unique social network types related to religious activities. In summary, we developed a comprehensive social network typology for older Korean adults. PMID- 27936421 TI - Catheter-directed endovascular application of thrombin: Report of 3 cases and review of the literature. AB - PURPOSE: To report 3 new cases of catheter-directed endovascular application of thrombin and explore trends by analysis of published case series. MATERIALS AND METHODS: Institutional Review Board approved this retrospective study. All cases of non-tumoral arterial embolization performed from January 2003 to January 2015 at our institution were retrospectively reviewed. Thrombin was used in 7 of 589 cases. In 3 cases intra arterial thrombin was injected via catheter to treat active hemorrhage. Four cases were excluded due to percutaneous injection into visceral pseudoaneurysms (n=3) and making ex vivo autologous clot to be injected via catheter (n=1). Fisher's exact and the Wilcoxon rank sum tests were used to assess for association with acute nontarget thrombosis. RESULTS: Catheter directed thrombin was used in 3/589 (0.5%) cases at our institution. All three cases were technically successful with no further bleeding (100%). Nontarget thrombosis of proximal branches occurred in 2 patients (67%) with no significant clinical consequences. Including our 3 cases, a total of 28 cases were reviewed. Of the variables examined-location (p=0.99), size (p=0.66) and etiology of vascular lesion (p=0.92), pseudoaneurysm neck anatomy (p=0.14), thrombin units (p=0.47), volume (p=0.76) or technique of use of small doses (p=0.99), use of other embolic material (p=0.67) and use of adjunct techniques (p=0.99)-none were found to be significantly associated with acute nontarget thrombosis. Technical success was 96% with no reports of reperfusion after treatment. CONCLUSIONS: Catheter-directed endovascular thrombin can be an additional tool to treat pseudoaneurysms not amenable to conventional embolization. Further studies are required to optimize technique and outcomes. PMID- 27936424 TI - Boar taint, meat quality and fail rate in entire male pigs and male pigs immunized against gonadotrophin releasing factor as related to body weight and feeding regime. AB - The objective of this experiment was to compare the pork quality of entire male pigs and pigs immunized against GnRF (IC males) at both light (64.8kg) and heavy (106kg) liveweights and two feeding regimes (restricted at 2.5 times maintenance and ad libitum). There was no difference in objective measurements (P>0.05) or eating pork quality (P>0.1) between entire male and IC males. Fail rates were reduced by 9.1% and 12% for pork from IC males for quality grade (P=0.007) and re purchase intention (P=0.001), respectively, compared to pork from entire males. Skatole (P=0.001) and androstenone (P<0.001) levels in belly fat were higher in entire male than IC male pigs. In addition, 37.5% of the light entire male pigs fed ad libitum showed skatole levels that exceeded the sensory threshold of 0.2MUg/g. This work confirms that immunization against GnRF is effective in eliminating boar taint and reducing pork quality fail rates by approximately 10% compared to pork from entire males. PMID- 27936423 TI - Optimising the community-based approach to healthcare improvement: Comparative case studies of the clinical community model in practice. AB - Community-based approaches to healthcare improvement are receiving increasing attention. Such approaches could offer an infrastructure for efficient knowledge sharing and a potent means of influencing behaviours, but their potential is yet to be optimised. After briefly reviewing challenges to community-based approaches, we describe in detail the clinical community model. Through exploring clinical communities in practice, we seek to identify practical lessons for optimising this community-based approach to healthcare improvement. Through comparative case studies based on secondary analysis, we examine two contrasting examples of clinical communities in practice - the USA-based Michigan Keystone ICU programme, and the UK-based Improving Lung Cancer Outcomes Project. We focus on three main issues. First, both cases were successful in mobilising diverse communities: favourable starting conditions, core teams with personal credibility, reputable institutional backing and embeddedness in wider networks were important. Second, top-down input to organise regular meetings, minimise conflict and empower those at risk of marginalisation helped establish a strong sense of community and reciprocal ties, while intervention components and measures common to the whole community strengthened peer-norming effects. Third, to drive implementation, technical expertise and responsiveness from the core team were important, but so too were 'hard tactics' (e.g. strict limits on local customisation); these were more easily deployed where the intervention was standardised across the community and a strong evidence-base existed. Contrary to the idea of self-organising communities, our cases make clear that vertical and horizontal forces depend on each other synergistically for their effectiveness. We offer practical lessons for establishing an effective balance of horizontal and vertical influences, and for identifying the types of quality problems most amenable to community-based improvement. PMID- 27936425 TI - Did a "lucky shot" sink the submarine H.L. Hunley? AB - The H.L. Hunley was the first submarine to be successful in combat, sinking the Union vessel Housatonic outside Charleston Harbor in 1864 during the Civil War. However, despite marking a milestone in military history, little is known about this vessel or why it sank. One popular theory is the "lucky shot" theory: the hypothesis that small arms fire from the crew of the Housatonic may have sufficiently damaged the submarine to sink it. However, ballistic experiments with cast iron samples, analysis of historical experiments firing Civil War-era projectiles at cast iron samples, and calculation of the tidal currents and sinking trajectory of the submarine indicate that this theory is not likely. Based on our results, the "lucky shot" theory does not explain the sinking of the world's first successful combat submarine. PMID- 27936426 TI - Statistical comparison of mass spectra for identification of amphetamine-type stimulants. AB - A method for the statistical comparison of mass spectral data is demonstrated for applications in controlled substance analysis. The method uses an unequal variance t-test at each mass-to-charge ratio in the scan range to determine if two spectra are statistically associated or discriminated. If the two spectra are associated, a random-match probability is calculated to estimate the likelihood that the mass spectral fragmentation pattern in question occurs by random chance alone. If the two spectra are discriminated, the fragment ions responsible for the discrimination are determined. In this work, mass spectral data from case samples containing amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), phentermine, and psilocin were investigated. All spectra were collected in an accredited forensic laboratory using routine methods for controlled substance analysis. Using the statistical method, spectra of case samples were statistically associated to the corresponding reference standard at the 99.9% confidence level. In these instances, random-match probabilities ranged from 10-39 to 10-29, indicating the probability that the characteristic fragmentation pattern occurred by random chance is extremely small. Further, spectra of case samples were discriminated from other reference standards at the 99.9% or 99.0% confidence level, with 1-26 ions responsible for discrimination in each comparison. PMID- 27936427 TI - An observed rise in gamma-hydroxybutyrate-associated deaths in London: Evidence to suggest a possible link with concomitant rise in chemsex. AB - BACKGROUND: Gamma-hydroxybutyrate (GHB) is the drug most linked to acute harm out of those used in chemsex, the incidence of which is reported to be increasing. However, there have been few systematic studies of the harms associated with GHB use. We investigated GHB-associated deaths from London coroners' jurisdictions between 2011 and 2015. METHODS: Blood and urine samples were collected by pathologists and submitted for toxicological analysis at the request of coroners. Data from the Toxicology Unit, Imperial College London was retrospectively analysed. This comprised of 6633 cases from seven out of eight coroners' jurisdictions in London that underwent toxicological analysis between January 2011 and December 2015. RESULTS: A total of 61 GHB-associated deaths (0.92% of total cases), 184 cocaine-associated deaths (2.8% of total cases) and 83 MDMA associated deaths (1.3% of total cases) were identified. There was a 119% increase in the proportion of GHB-associated deaths detected in 2015 compared to 2014. Over the same time period there was a 25% increase in cocaine-associated deaths and a 10% decrease in MDMA-associated deaths. CONCLUSIONS: Our data suggest that GHB-associated deaths are increasing in London, and that this is likely at least in part due to increasing use of GHB for chemsex. Further studies on the use of GHB are urgently required to understand the extent of its use, whether this is as prevalent in other major urban areas in the UK, and the full extent of the harms it causes. PMID- 27936428 TI - Dental Age Estimation-Root Pulp Visibility (RPV) patterns: A reliable Mandibular Maturity Marker at the 18 year threshold. AB - : The purpose of this paper was to explore the potential application of Root Pulp Visibility (RPV) to determine whether or not a subject of unknown date of birth is under or over the 18year threshold. PATIENTS, MATERIALS AND METHODS: Two thousand Dental Panoramic Radiographs comprising equal numbers of females and males evenly distributed between the ages of 16 and 26 years were examined. All third molars were scored using the Anglo-Canadian 8 Stage Tooth Development system [1]. The Lower Left Third Molar was censored to avoid redundant data being included in the data array for the Age at Attainment of Stage H, the final stage of tooth development (Roberts et al., 2015 [2]). A filter cascade was applied to the data to select the data array for 1. Teeth in the final stage of development, 2. Female or male gender, 3. The definitive stage of RPV: RPV-A, RPV-B, RPV-C, or RPV-D. RESULTS: The summary data for each of these stages was derived and the minimum value for each was used to determine the relationship of the minimum value of A, B, C or D to the 18 Year threshold. It was found that for both females and males the minimum value for RPV-A and RPV-B indicated that subjects displaying this could be under 18 years old. For RPV-C and RPV-D, the minimum values show unequivocally that for both females and males the subject was over 18 years old. CONCLUSION: RPV has an important role in unambiguously determining whether a subject is below or above the 18year threshold. PMID- 27936429 TI - Investigation of biomechanical response of Hoffa's fat pad and comparative characterization. AB - The infrapatellar adipose body (Hoffa's fat pad, IFP) is situated between the patellar tendon, the femoral condyle and the tibial plateau. The IFP consists of lobules of white adipose tissue delimited by thin connective septa. The actual structural functionality of the IFP is debated and should pertain to a cushioning role in the knee joint, providing to distribute and to damp mechanical stresses during articular activity. The present study is aimed to analyze the correlation between histological configuration and mechanical properties of the IFP, compared to other adipose tissues, partially differentiated by composition and conformation. Histological and ultrastructural methods were exploited to analyze the microscopic anatomies of IFP, knee (KSF) and abdominal (ASF) subcutaneous fat tissues. Numerical micro-models of the different tissues were developed by using histo-morphometric data, as the size of adipose lobules, the thickness of the septa and their composition. Numerical analyses made it possible to evaluate the mechanical functionality of the different fat tissues considering the characteristic loading conditions, as compressive and shear actions. The results pointed out the actual mechanical relevance of IFP and KSF, while ASF exhibited different mechanical properties. Furthermore, the contribution of connective septa and adipose lobules to compressive and shear mechanical behavior was elucidated. This preliminary investigation represents the basis for biomechanical interpretation and the definition of more refined model to be developed on the acquisition of additional histological and morphometric data. PMID- 27936430 TI - Collagen tissue treated with chitosan solution in H2O/CO2 mixtures: Influence of clathrates hydrates on the structure and mechanical properties. AB - A mixture of water/carbon dioxide is a "green" perspective solvent from the viewpoint of biomedical applications. Clathrate hydrates are formed this solvent under certain conditions and a very interesting question is the impact of clathrates hydrates on the structure and properties of bovine pericardium, which is used in biomedicine, in particular as a main part of biological heart valve prostheses. The aim of the present work is to investigate the influence of clathrates on the structure and mechanical properties of the collagen tissue treated with chitosan in H2O/CO2 mixtures under pressure 3.0-3.5MPa and temperatures 2-4 degrees C. It was first found that the clathrate hydrates in this media due to the strong fluctuations "bomb" collagen tissue of bovine pericardium, which is manifested in the appearance of numerous small gaps (pores) with mean size of 225+/-25nm and large pores with size of 1-3MU on the surface and within collagen matrices. High porosity leads to averaging characteristics of the organization structure in tissues with different orientation of the collagen fibers. As a result, the mechanical properties of the collagen tissue with a different orientation of the collagen fibrils become similar, which is quite different from their original properties. The structural changes caused by the influence of the environment clathrate hydrates led to a significant decrease of the tensile strength (30-47% in total, p<0.05) and initial elastic moduli (74 83%, p<0.05). However, the final elastic moduli and the maximum tensile virtually unchanged compared to the control. Nevertheless, it was found that the direct deposition of chitosan from the H2O/CO2 mixtures with clathrate improve the mechanical-strength properties of the porous matrices. We believe that these improved mechanical properties are achieved due to particularly deep and uniform impregnation of the collagen matrix with chitosan from its pressurized solutions in H2O/CO2 mixtures. PMID- 27936431 TI - Description of the anterior cerebral artery and its cortical branches: Variation in presence, origin, and size. AB - OBJECTIVE: Certain aspects of the anterior cerebral artery (ACA) cortical branches tend to vary, including absent or additional arteries, variation in origin, and changes to diameter and length. Knowledge of these factors can be crucial in aneurysm and arteriovenous malformation surgery. Few studies report on these aspects and a South African study have not been completed. Therefore, the aim of this study is to report absent or additional arteries, the origin, diameter and length of ACA cortical branches in a Western Cape population. METHODS: A coloured silicone was injected into the ACA of 121 hemispheres (60 right, 61 left), consisting of 83 males and 38 females. Specimens were divided in groups younger than 34 (n=36), between 35 and 48 (n=35), older than 49 (n=40), and unknown (n=10). There were three population groups; coloured (n=72), black (n=37), white (n=10), and unknown (n=2). Any absent or additional arteries were noted, as well as the origins. External diameter and lengths were measured using a digital micrometre, string and a ruler. RESULTS: The diameter and lengths indicated significant differences between right and left, sex, age and population groups. Most commonly absent (callosomarginal artery) and additional (paracentral lobule artery) arteries were noted. Origins were similar to the literature; however, previously unreported origins and common trunks were also observed. CONCLUSION: The aspects reported have been neglected in previous work and neurosurgeons should be aware of these variations and anomalies to avoid complications. Studies should continue to assess the cerebral vasculature since undocumented variations are still being reported. PMID- 27936432 TI - The role of the water tankers market in water stressed semi-arid urban areas:Implications on water quality and economic burden. AB - Population growth and development are associated with increased water demand that often exceeds the capacity of existing resources, resulting in water shortages, particularly in urban areas, where more than 60% of the world's population resides. In many developing communities, shortages often force households to depend on water tankers amongst other potential sources for the delivery of water for domestic and/or potable use. While water tankers have become an integral part of the water supply system in many countries, the sector is often unregulated and operates with little governmental supervision. Users are invariably unaware of the origin or the quality of purchased water. In an effort to better assess this sector, a field survey of water vending wells and tankers coupled with a water quality sampling and analysis program was implemented in a pilot semi-arid urban area (Beirut, Lebanon) to shed light on the environmental and socio-economic impacts of the water tanker sector. Total dissolved solids (TDS), chloride (Cl-), and microbial loads exceeded drinking water quality standards. While TDS and Cl- levels were mostly due to saltwater intrusion in coastal wells, tankers were found to be a significant source of total coliforms. Delivered water costs varied depending on the tanker size, the quality of the distributed water, and pre treatment used, with a markup of nearly 8-24 folds of the public water supply and an equivalent economic burden of 16% of the average household income excluding environmental externalities of water quality. The study concludes with a management framework towards consumer protection under integrated supply and demand side measures. PMID- 27936433 TI - Carbon starvation induces lipid degradation via autophagy in the model alga Micrasterias. AB - Autophagy is regarded as crucial intracellular process in plant development but also in intracellular stress response. It is known to be controlled by the energy level of the cell and consequently can be triggered by energy deprivation. In this study carbon starvation evoked in different ways was investigated in the freshwater algae model system Micrasterias denticulata (Streptophyta) which is closely related to higher plants. Cells exposed to the photosynthesis inhibiting herbicide DCMU, to the glycolysis inhibitor 2-Deoxy-d-glucose and to complete darkness over up to 9 weeks for preventing metabolism downstream of glucose supply, were investigated by means of Nile red staining and analyses in CLSM, and TEM after cryo-preparation. Our results show that lipid bodies containing both neutral and polar lipids are evenly distributed inside the chloroplast in control cells. During carbon starvation they are displaced into the cytoplasm and are either degraded via autophagy and/or excreted from the cell. Upon discharge from the chloroplast lipid bodies become engulfed by double membranes probably deriving from the ER, thus forming autophagosomes which later fuse with vacuoles. Coincidently indications for autophagy of other organelles and cytoplasmic portions were found during starvation and particularly in DCMU treated cells the number of starch grains decreased and pyrenoids disintegrated. Additionally our molecular data provide first evidence for the existence of a single ATG8 isoform in Micrasterias. ATG8 is known as main regulator of both bulk and selective autophagy in eucaryotes. Our study indicates that lipid degradation during carbon starvation is achieved via "classical" autophagy in the alga Micrasterias. This process has so far only been very rarely observed in plant cells and seems to allow recruitment of lipids for energy supply on the one hand and elimination of unusable or toxicated lipids on the other hand. PMID- 27936434 TI - Mineralocorticoid receptor haplotype, estradiol, progesterone and emotional information processing. AB - BACKGROUND: Carriers of MR-haplotype 1 and 3 (GA/CG; rs5522 and rs2070951) are more sensitive to the influence of oral contraceptives (OC) and menstrual cycle phase on emotional information processing than MR-haplotype 2 (CA) carriers. We investigated whether this effect is associated with estradiol (E2) and/or progesterone (P4) levels. METHOD: Healthy MR-genotyped premenopausal women were tested twice in a counterbalanced design. Naturally cycling (NC) women were tested in the early-follicular and mid-luteal phase and OC-users during OC-intake and in the pill-free week. At both sessions E2 and P4 were assessed in saliva. Tests included implicit and explicit positive and negative affect, attentional blink accuracy, emotional memory, emotion recognition, and risky decision-making (gambling). RESULTS: MR-haplotype 2 homozygotes had higher implicit happiness scores than MR-haplotype 2 heterozygotes (p=0.031) and MR-haplotype 1/3 carriers (p<0.001). MR-haplotype 2 homozygotes also had longer reaction times to happy faces in an emotion recognition test than MR-haplotype 1/3 (p=0.001). Practice effects were observed for most measures. The pattern of correlations between information processing and P4 or E2 differed between sessions, as well as the moderating effects of the MR genotype. In the first session the MR-genotype moderated the influence of P4 on implicit anxiety (sr=-0.30; p=0.005): higher P4 was associated with reduction in implicit anxiety, but only in MR-haplotype 2 homozygotes (sr=-0.61; p=0.012). In the second session the MR-genotype moderated the influence of E2 on the recognition of facial expressions of happiness (sr= 0.21; p=0.035): only in MR-haplotype 1/3 higher E2 was correlated with happiness recognition (sr=0.29; p=0.005). In the second session higher E2 and P4 were negatively correlated with accuracy in lag2 trials of the attentional blink task (p<0.001). Thus NC women, compared to OC-users, performed worse on lag 2 trials (p=0.041). CONCLUSION: The higher implicit happiness scores of MR-haplotype 2 homozygotes are in line with previous reports. Performance in the attentional blink task may be influenced by OC-use. The MR-genotype moderates the influence of E2 and P4 on emotional information processing. This moderating effect may depend on the novelty of the situation. PMID- 27936435 TI - Bilobalide abates inflammation, insulin resistance and secretion of angiogenic factors induced by hypoxia in 3T3-L1 adipocytes by controlling NF-kappaB and JNK activation. AB - Obesity leads to inflammation and insulin resistance in adipose tissue. Hypoxia, observed in obese adipose tissue is suggested as a major cause of inflammation and insulin resistance in obesity. However, the role of hypoxia in adipose tissue during obesity and insulin resistance was not well established. Here we mainly explored the crosstalk between hypoxia induced inflammation, and insulin resistance and also secretion of angiogenic factors in 3T3-L1 adipocytes and possible reversal with bilobalide. Hypoxia for 24h significantly (P<=0.05) increased the secretion of MCP-1 (4.59 fold), leptin (2.96 fold) and reduced adiponectin secretion (2.93 fold). In addition, the mRNA level of resistin (6.8 fold) and TLR4 receptors (8.8 fold) was upregulated in hypoxic adipocytes. The release of inflammatory cytokines and expression of TLR4 receptors led to activation of JNK and NF-kappaB signalling. We further investigated the effects of JNK and NF-kappaB activation on insulin signalling receptors. The present study showed increased (P<=0.05) serine 307 phosphorylation of IRS-1 (1.9 fold) and decreased expression of IRS-2 (0.53 fold) in hypoxic group showing hypoxia induced impairment in insulin signalling. Hypoxia significantly (P<=0.05) increased basal glucose uptake (3.3 fold) as well as GLUT-1 expression in adipocytes indicating GLUT-1 mediated glucose uptake. Hypoxia for 24h significantly increased (P<=0.05) the expression of angiogenic factors. Bilobalide protected adipocytes from hypoxia induced inflammation and insulin resistance mainly by reducing inflammatory adipokine secretion, improving adiponectin secretion, reducing NF-kappaB/JNK activation, and inhibiting serine phosphorylation of IRS-1 receptors of insulin signalling pathway. PMID- 27936436 TI - Spectroscopic, single crystal X-ray, Hirshfeld, in vitro and in silico biological evaluation of a new series of potent thiazole nucleus integrated with pyrazoline scaffolds. AB - In the present study, the spectroscopic characterization of a new series of substituted thiazole linked pyrazoline scaffolds 4a-l was performed. The formation of 4a-l from the intermediate 3-(4-chlorophenyl)-5-[4-(propan-2 yl)phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide 2 and substituted 2-bromo-1 phenylethanone 3a-l was evidenced through the changes in FTIR, 1H NMR, 13C NMR, LCMS data. The X-ray diffraction studies revealed that compound 2 and 4g crystallized in monoclinic crystal system with P21/n space group. Compound 4j crystallized in triclinic system, P1 space group with Z=4. The percentage of intermolecular contacts and distribution of electrostatic potential of molecular crystal structures was resolved by Hirshfeld surface analysis with 2D finger plots and electrostatic potential map. The newly synthesized derivatives were screened for their in vitro antioxidant and antimicrobial activity. The single crystal studies revealed that, for compounds 2, 4g and 4j the isopropyl phenyl ring is positioned at near right angle with the other rings. Due to the lack of planarity of bulkier group substituted to phenyl ring (ring B), all the synthesized molecules showed weak to moderate radical scavenging capacity owing to the destabilization of the radical formed during oxidation. Also, on performing molecular docking studies to explore the interactions of ligand with the target pyrimidine nucleoside hydrolase YbeK with bound ribose complex (PNH, PDB ID-3GHW), disclosed that active compounds emerged for in vitro studies also bound to PNH more efficiently. The compounds with polar group substitution interacted through hydrogen bonding while other molecules with non-covalent interactions. PMID- 27936437 TI - Clinical trial methodology to assess the efficacy/effectiveness of long-acting antipsychotics: Randomized controlled trials vs naturalistic studies. AB - Schizophrenia presents unique difficulties in clinical trial design associated with the condition's variable presentation and clinical course, and multiple features influencing affect, cognition, volition and perception. Randomized controlled trials (RCTs) are explanatory studies using a carefully selected patient population, predefined assessment intervals and, generally, symptom focused endpoints. Naturalistic studies are pragmatic, with no active intervention, and outcomes that are generally those used in clinical practice (e.g. hospitalization, relapse rate). Both naturalistic studies and RCTs have pros and cons, making it difficult for physicians in clinical practice to apply research findings to their own treatment decisions. The choice of clinical trial design can have a significant impact on the comparative effectiveness or efficacy of drugs. This is particularly true for studies comparing long-acting injectable (LAI) antipsychotics with oral antipsychotics in schizophrenia, in which RCTs generally show no benefit for LAIs over oral drugs, whereas observational studies do. The more pragmatic the study design, the more likely it is to show a benefit for LAIs versus oral therapy. This article reviews the pros and cons of different study types, using published examples. Criteria are outlined to help physicians design appropriate prospective studies in schizophrenia including the relevant pragmatic and/or explanatory features, as required. PMID- 27936438 TI - Stressful life transitions and wellbeing: A comparison of the stress buffering hypothesis and the social identity model of identity change. AB - The relationship between stressful life transitions and wellbeing is well established, however, the protective role of social connectedness has received mixed support. We test two theoretical models, the Stress Buffering Hypothesis and the Social Identity Model of Identity Change, to determine which best explains the relationship between social connectedness, stress, and wellbeing. Study 1 (N=165) was an experiment in which participants considered the impact of moving cities versus receiving a serious health diagnosis. Study 2 (N=79) was a longitudinal study that examined the adjustment of international students to university over the course of their first semester. Both studies found limited evidence for the buffering role of social support as predicted by the Stress Buffering Hypothesis; instead people who experienced a loss of social identities as a result of a stressor had a subsequent decline in wellbeing, consistent with the Social Identity Model of Identity Change. We conclude that stressful life events are best conceptualised as identity transitions. Such events are more likely to be perceived as stressful and compromise wellbeing when they entail identity loss. PMID- 27936439 TI - Symptoms of prolonged grief, post-traumatic stress, and depression after loss in a Dutch community sample: A latent class analysis. AB - Mental health problems following loss can manifest as heterogeneous symptomatology that may include symptoms of Prolonged Grief Disorder (PGD), Post Traumatic Stress Disorder (PTSD), and Major Depressive Disorder (MDD). However, the co-occurrence of symptoms of these three disorders is still only partially explored. The aims of this study were to identify subgroups (i.e., classes) in a Dutch sample of bereaved individuals, based on severity and/or co-occurrence of symptoms and to identify predictors for these subgroups, taking into account all three disorders. Using data from 496 participants who filled in questionnaires assessing PGD, PTSD and MDD, we conducted latent class analyses to identify different symptom classes. Predictors of these classes were identified using one way ANOVA, Chi Square tests and multinomial regression analysis. We found three different classes: a resilient class, a PGD class and a combined PGD/PTSD class. Violent cause of death, loss of a child, and loss of a partner were associated with membership of the combined PGD/PTSD class. This study increases our understanding of the predictability of symptomology outcome following bereavement. This is a first step towards designing assessment and intervention methods, specifically directed towards subgroups of individuals sharing characteristic symptomatology. PMID- 27936441 TI - Intra and intersession repeatability and reliability of the S-Plate(r) pressure platform. AB - AIM: The aim of this study was to assess the repeatability and reliability of the S-Plate(r) pressure platform in a group of healthy subjects. MATERIAL AND METHODS: Forty subjects, free from physical conditions that would affect normal gait, walked along a five-meter corridor while data were recorded from the pressure platform. A total of 10 steps (five each side) were obtained as well as five static trials; the same measurements were repeated one week later. Peak and mean plantar pressures and contact area were recorded for both dynamic and static trials. Additionally, weight supported on each limb was documented during static trials. To assess intrasession and intersession repeatability and reliability, the intraclass correlation coefficients (ICCs) and coefficient of variation (CoV) were calculated. RESULTS: Taking the ICC values into account, every static and dynamic variable analysed showed moderate to excellent reliability and the CoV values were all below 12%. CONCLUSION: Measurements of either static or dynamic plantar pressure variables with the S-Plate(r) pressure platform show good repeatability and reliability, and so it is useful for comparing steps within and between sessions. PMID- 27936440 TI - Stride variability measures derived from wrist- and hip-worn accelerometers. AB - Many epidemiological and clinical studies use accelerometry to objectively measure physical activity using the activity counts, vector magnitude, or number of steps. These measures use just a fraction of the information in the raw accelerometry data as they are typically summarized at the minute level. To address this problem, we define and estimate two measures of temporal stride-to stride gait variability based on raw accelerometry data: Amplitude Deviation (AD) and Phase Deviation (PD). We explore the sensitivity of our approach to on-body placement of the accelerometer by comparing hip, left and right wrist placements. We illustrate the approach by estimating AD and PD in 46 elderly participants in the Developmental Epidemiologic Cohort Study (DECOS) who worn accelerometers during a 400m walk test. We also show that AD and PD have a statistically significant association with the gait speed and sit-to-stand test performance. PMID- 27936442 TI - Label-free colorimetric detection of cancer related gene based on two-step amplification of molecular machine. AB - Highly sensitive detection of K-ras gene is of great significance in biomedical research and clinical diagnosis. Here, we developed a colorimetric biosensing system for the detection of proto-oncogene K-ras based on enhanced amplification effect of DNA molecular machine, where dual isothermal circular strand displacement amplification (D-SDA) occurs on two arms in one-to-one correspondence. Specifically, we designed a primer-locked hairpin probe (HP) and a primer-contained linear polymerization template (PPT). In the presence of target gene, HP can hybridize with PPT, forming a DNA molecular machine with dual functional arms (called DFA-machine). Each of the two probes in this machine is able to be extended by polymerase on its counterpart species. Moreover, with the help of nicking endonuclease, the dual isothermal polymerization is converted into dual circular strand-displacement amplification, generating a large amount of anti-hemin aptamer-contained products. After binding to hemins, the aptamer/hemin duplex, horseradish peroxidase (HRP)-mimicking DNAzyme, was formed and catalyzed the oxidation of colorless ABTS by H2O2, producing a visible green color. The proposed colorimetric assay exhibits a wide linear range from 0.01 to 150nM with a low detection limit of 10pM. More interestingly, the mutations existing in target gene are easily observed by the naked eye. It should be noted that this colorimetric system was proved by the analysis of K-ras gene of SW620 cell lines. The simple and powerful DFA-machine is expected to provide promising potential in the sensitive detection of biomarkers for cancer diagnosis, prognosis and therapy. PMID- 27936443 TI - Antifungal potential of marine natural products. AB - Fungal diseases represent an increasing threat to human health worldwide which in some cases might be associated with substantial morbidity and mortality. However, only few antifungal drugs are currently available for the treatment of life threatening fungal infections. Furthermore, plant diseases caused by fungal pathogens represent a worldwide economic problem for the agriculture industry. The marine environment continues to provide structurally diverse and biologically active secondary metabolites, several of which have inspired the development of new classes of therapeutic agents. Among these secondary metabolites, several compounds with noteworthy antifungal activities have been isolated from marine microorganisms, invertebrates, and algae. During the last fifteen years, around 65% of marine natural products possessing antifungal activities have been isolated from sponges and bacteria. This review gives an overview of natural products from diverse marine organisms that have shown in vitro and/or in vivo potential as antifungal agents, with their mechanism of action whenever applicable. The natural products literature is covered from January 2000 until June 2015, and we are reporting the chemical structures together with their biological activities, as well as the isolation source. PMID- 27936444 TI - Amino derivatives of platanic acid act as selective and potent inhibitors of butyrylcholinesterase. AB - A set of thirtyfive 30-norlupan derivatives (2-36) was prepared from the natural triterpenoid platanic acid (PA), and the hydroxyl group at C-3, the carboxyl group at C-17 and the carbonyl group at C-20 were modified. These derivatives were tested for their inhibitory activity for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) using Ellman's assay. Extra enzyme kinetic studies were performed. The most active compound was (3beta, 20R)-3-acetyloxy-20-amino-30-norlupan-28-oate (32) showing a Ki value of 0.01 +/- 0.003 MUM for BChE. This compound proved to be a selective (FB = 851), mixed-type inhibitor for BChE. PMID- 27936445 TI - Synthesis and antifungal activity of novel indole-replaced streptochlorin analogues. AB - Based on examples of the successful applications in drug discovery of bioisosterism, a series of streptochlorin analogues in which indole has been replaced by other heterocycles has been designed and synthesized, as a continuation of our studies aimed at the discovery of novel streptochlorin analogues with improved antifungal activity. Biological testing showed that most of the indole-replaced streptochlorin analogues were inactive, though compound 6f had a broad spectrum of antifungal activity with significant activity against Alternaria solani. The SAR study demonstrated that indole ring is an essential moiety for the antifungal activity of streptochlorin analogues, promoting the idea of indole ring as a framework that might be exploited in the future. PMID- 27936446 TI - Design, synthesis and evaluation of 4-aminoquinoline-purine hybrids as potential antiplasmodial agents. AB - A novel series of 4-aminoquinoline-purine hybrids were synthesized and assessed for their antiplasmodial activity against CQ-sensitive and CQ-resistant strains of P. falciparum. It was envisaged that linking of the 4-aminoquinoline pharmacophore (targeting heme-detoxification pathway of malarial parasite) with the purine functionality (targeting plasmodial HG(X)PRT enzyme) will produce a hybrid antiplasmodial agent with increased potency. The synthesized hybrids displayed good antiplasmodial activities against both the sensitive and resistant strains of P. falciparum with up to six-fold better activity (compound 10i, IC50: 0.08 MUM) compared to the reference drug CQ (IC50: 0.5 MUM) against the resistant strain. The synthesized compounds were also checked for their cytotoxicity towards mammalian cells and with the exception of two compounds out of the twenty synthesized hybrids, all others were non-cytotoxic up to 11.86 MUM concentration. Mechanistic heme-binding studies were performed to identify the mechanism of action of the synthesized molecules and good binding interactions were observed. Computational docking studies showed that the most active hybrids dock well within the binding site of HGPRT protein. In silico ADME predictions of the most active hybrids showed that these compounds possess good pharmacokinetic behavior. PMID- 27936447 TI - Single-incision laparoscopic excision of a chylous mesenteric cyst: A case report. AB - INTRODUCTION: Chylous mesenteric cysts are rare intra-abdominal lesions located in the mesentery of the gastrointestinal tract and may extend from the base of the mesentery into the retroperitoneum. The treatment is the complete removal of the cyst PRESENTATION OF CASE: A 49-year-old female presented with abdominal pain. Abdominal computed tomography showed a 5.0-cm-diameter intraabdominal, homogenous cystic lesion located on the mesentery of the small intestine. Single incision laparoscopic surgery was performed for complete resection. DISCUSSION: Only a handful of cases of laparoscopic surgery for a mesenteric cyst have been reported, and no reports have been published regarding single-incision laparoscopic surgery for a mesenteric cyst. CONCLUSION: We report the first known case of a chylous mesenteric cyst that was successfully treated by single incision laparoscopic surgery. PMID- 27936449 TI - Methotrexate-treated ectopic pregnancy: beta human chorionic gonadotropin serum changes as a success predictor using a mathematical model validation. AB - BACKGROUND: Surgical rescue of methotrexate-treated ectopic pregnancy is necessary when tubal rupture or medical therapy failure is detected during post therapeutic monitoring. It is known that an increased beta human chorionic gonadotropin (beta-hCG) concentration is the most important factor associated with treatment failure. Therefore, we suggested that relative changes in serum beta-hCG could predict a successful result of medical treatment, leading to facilitation of the decision to forgo the prospect of possible surgical rescue. METHODS: A retrospective observational study of 115 patients with an ectopic pregnancy who were treated with a single dosage protocol of 50mg/m2 of methotrexate injected intramuscularly was performed at Puerta de Hierro University Hospital and Gregorio Maranon University General Hospital. Standard statistical tests were applied in order to evaluate the relative changes in beta hCG concentration between the 1st and the 4th days following methotrexate injection. RESULTS: Methotrexate treatment has a 95% probability to be successful if the relative change of beta-hCG from the 1st to the 4th day of monitoring is within the following interval: [-1.02; 0.15]. Moreover, if the values of beta-hCG relative change from 1st to 4th day of monitoring are within [0.54; 1.2], it assures a negative result of treatment with 95% probability. Therefore, the value 0.15 (15%) of beta-hCG relative change can be considered a cut-off value for a positive result to treatment. CONCLUSIONS: Our data support that negative beta hCG relative changes on the 4th day of treatment likely predict a successful result of methotrexate therapy, with a cut-off point of 0.15. Expectant management should be carried out in these cases if no clinical indications of surgery are presented. PMID- 27936448 TI - Flavivirus transmission focusing on Zika. AB - Flaviviruses are among the most diverse viruses with over 85 species recognized. Taxonomically, this genus is one of the 4 recognized genera within the family Flaviviridae. Most flaviviruses of human public health significance, for example, dengue, yellow fever and Zika viruses, are arthropod-borne (arboviruses) and have two evolutionarily and ecologically distinct transmission cycles: a sylvatic transmission cycle, where the virus circulates between zoonotic vertebrate reservoir and amplification hosts and arboreal mosquitoes; and an urban transmission cycle, where the virus circulates between humans and peridomestic Aedes spp. mosquitoes. Zika virus (ZIKV), a flavivirus closely related to West Nile, dengue, Spondweni, Japanese encephalitis and yellow fever viruses, remained in obscurity since its discovery in 1947, but has recently emerged to cause a series of epidemics in the South Pacific, and most recently reaching nearly pandemic levels with its introduction in the Americas. Available epidemiologic and experimental evidence points to Aedes aegypti as the principal urban vector, possibly supplemented by Aedes albopictus in some locations. Unfortunately, the former is one of the most difficult mosquitoes to control owing to its highly anthropophilic behavior. PMID- 27936450 TI - Clinical outcome following medical treatment of cavernous malformation related epilepsy. AB - PURPOSE: The study was conducted to assess the long-term outcome of antiepileptic drug (AED) treatment in drug-naive patients with cavernous malformation (CM) related epilepsy (CRE). METHOD: This is a retrospective, single-center, long-term observational study of 34 patients with previously untreated seizures related to CM. All patients were followed-up for at least two years. Drug resistant epilepsy (DRE) was defined as two or more seizures per year after trial of two appropriate AEDs. Patients who had only one seizure during the previous one year were assigned as "epilepsy with rare seizures (ERSs)". RESULTS: Terminal 1-year seizure remission (1-YTR) was achieved in 22 (64.7%) patients, nine (26.5%) patients were diagnosed as DRE, and three (8.8%) patients were as ERSs. 1-YTR was achieved in 18 (52.9%) patients by the first drug regimen and in additional four (11.8%) patients by the second drug regimen. None of nine patients who failed to first two drug regimens did achieve 1-YTR. The location of CM in the temporal lobe was the only prognostic factor predicting a poor seizure outcome (p=0.012). CONCLUSION: The outcome of AEDs therapy in patients who were presented with new onset of CRE was quite comparable with that of patients with newly diagnosed epilepsy. Failure to achieve seizure-free after adequate trials of two AEDs seems appropriate as the criteria for their referral to surgical treatment. For patients with temporal lobe CRE, earlier presurgical evaluation may be considered justifiable once they failed to an adequate trial of the first drug. PMID- 27936451 TI - Onset polarity in bipolar disorder: A strong association between first depressive episode and suicide attempts. AB - BACKGROUND: The role of onset polarity (OP) in patients with bipolar disorder (BD) has been increasingly investigated over the last few years, for its clinical, prognostic, and therapeutic implications. The present study sought to assess whether OP was associated with specific correlates, in particular with a differential suicidal risk in BD patients. METHODS: A sample of 362 recovered BD patients was dichotomized by OP: depressed (DO) or elevated onset (EO: hypomanic/manic/mixed). Socio-demographic and clinical variables were compared between the subgroups. Additionally, binary logistic regression was performed to assess features associated with OP. RESULTS: DO compared with EO patients had older current age and were more often female, but less often single and unemployed. Clinically, DO versus EO had a more than doubled rate of suicide attempts, as well as significantly higher rates of BD II diagnosis, lifetime stressful events, current psychotropics and antidepressants use, longer duration of the most recent episode (more often depressive), but lower rates of psychosis and involuntary commitments. LIMITATIONS: Retrospective design limiting the accurate assessment of total number of prior episodes of each polarity. CONCLUSIONS: Our results support the influence of OP on BD course and outcome. Moreover, in light of the relationship between DO and a higher rate of suicide attempts, further investigation may help clinicians in identifying patients at higher risk of suicide attempts. PMID- 27936452 TI - Exercise is an effective treatment for positive valence symptoms in major depression. AB - INTRODUCTION: Measurement of symptoms domains and their response to treatment in relative isolation from diagnosed mental disorders has gained new urgency, as reflected by the National Institute of Mental Health's introduction of the Research Domain Criteria (RDoC). The Snaith Hamilton Pleasure Scale (SHAPS) and the Motivation and Energy Inventory (MEI) are two scales measuring positive valence symptoms. We evaluated the effect of exercise on positive valence symptoms of Major Depressive Disorder (MDD). METHODS: Subjects in the Treatment with Exercise Augmentation for Depression (TREAD) study completed self-reported SHAPS and MEI during 12 weeks of exercise augmentation for depression. We evaluated the effect of exercise on SHAPS and MEI scores, and whether the changes were related to overall MDD severity measured with the Quick Inventory of Depression Symptomatology (QIDS). RESULTS: SHAPS and MEI scores significantly improved with exercise. MEI score change had larger effect size and greater correlation with change in QIDS score. MEI also showed significant moderator and mediator effects of exercise in MDD. LIMITATIONS: Generalizability to other treatments is limited. This study lacked other bio-behavioral markers that would enhance understanding of the relationship of RDoC and the measures used. CONCLUSIONS: Positive valence symptoms improve with exercise treatment for depression, and this change correlates well with overall outcome. Motivation and energy may be more clinically relevant to outcome of exercise treatment than anhedonia. PMID- 27936453 TI - Biological mechanisms of depression following treatment with interferon for chronic hepatitis C: A critical systematic review. AB - BACKGROUND: A significant subset of patients infected by the hepatitis C virus (HCV) develops a major depressive episode (MDE) during Interferon-alpha (IFN alpha) based immunotherapy. We performed a systematic review of studies which examined biological mechanisms contributing to the onset of a MDE during IFN alpha-based immunotherapy for HCV. METHODS: Major electronic databases were searched from inception up until 15th February 2016 for peer-reviewed prospective studies that had enrolled HCV infected patients who received IFN-alpha treatment. A diagnosis of MDE had to be established by means of a standardized diagnostic interview at baseline and endpoint. RESULTS: Eight unique references met inclusion criteria. A total of 826 participants with HCV (37.3% females, mean age 46.7 years) were included in this systematic review. The overall MDE incidence rate was 34.8%, with follow-up ranging between 4 and 48 weeks. The methodological quality varied across selected studies. It was observed that Interleukin-6, salivary cortisol, arachidonic acid / eicosapentaenoicacid plus docosahexaenoic acid ratio, and genetic polymorphisms may present variations which are linked to a predisposition to INF-alpha-induced depression. LIMITATIONS: A meta-analysis could not be performed due to the diverse biological mechanisms investigated and the lack of replicated evidence. CONCLUSIONS: This systematic review indicates that several potential mechanisms may be implicated in the onset of a MDE following IFN-alpha-based immunotherapy for chronic HCV. However, replicated evidence is lacking and therefore the mechanisms involved in IFN-alpha-induced depression in humans remain unclear. PMID- 27936454 TI - White matter volumes in youth offspring of bipolar parents. AB - BACKGROUND: Studying youth at high risk of developing bipolar disorder may clarify neurobiological factors associated with vulnerability to this illness. We present here a baseline characterization of brain structure in youth at-risk for bipolar disorder. METHODS: Magnetic resonance images were obtained from 115 child and adolescent offspring of bipolar disorder type I subjects and 57 healthy child and adolescent offspring of healthy parents (healthy control offspring). Offspring of parents with bipolar disorder were divided into healthy bipolar offspring (n=47) or symptomatic bipolar offspring (n=68), according to presence or absence of childhood-onset psychopathology. All bipolar offspring were free of major mood and psychotic disorders. Gray (GM) and white matter (WM) volumes were compared between groups using voxel-based morphometry. RESULTS: No differences in GM volumes were found across groups. Healthy bipolar offspring presented with decreased WM volumes in areas of the right frontal, temporal and parietal lobes, and in the left temporal and parietal lobes compared to healthy control offspring. Symptomatic bipolar offspring did not present with any differences in WM volumes compared to either healthy bipolar offspring or healthy control offspring. LIMITATIONS: Cross-sectional design and heterogeneous sample of symptomatic bipolar offspring. CONCLUSIONS: WM volume decreases in areas of the frontal, occipital, and parietal lobes are present in bipolar offspring prior to the development of any psychiatric symptoms, and may be a correlate of familial risk to bipolar disorder. In this large cohort, we have not found evidence for regional GM volume abnormalities as an endophenotype for bipolar disorder. PMID- 27936455 TI - Non-suicidal self-injury and frequency of suicide attempts: The role of pain persistence. AB - BACKGROUND: Non-suicidal self-injury (NSSI) and suicidal behavior exhibit a robust association with one another. Research on the contexts within which this relationship is stronger or weaker, however, is limited. The interpersonal theory of suicidal behavior (ITS) posits that NSSI influences suicidal behavior through a habituation to physical pain and, as such, pain tolerance has been theorized to play an important role. We tested whether pain persistence, the difference between pain threshold and pain tolerance, would moderate the relationship between frequency of NSSI and suicidal behavior in both an undergraduate and community sample. METHOD: Study 1 assessed healthy undergraduates, whereas Study 2 was comprised of community members recruited largely based upon a history of suicidal behavior. Across both samples, participants completed self-report measures of NSSI and a structured interview on suicidal behavior. In both studies, pain was measured using a pressure algometer and, in Study 2, persistence was also assessed using the Enhanced Distress Tolerance Test (DTT-E). RESULTS: Consistent with the notion that suicidal behavior requires persistence amidst pain and distress, results indicated that the willingness to remain engaged with pain and distress may significantly influence the degree to which NSSI is related to suicidal behavior. LIMITATIONS: Both studies were limited by a cross-sectional design, which precluded assessments of causality and directionally of effects. CONCLUSIONS: These results call attention to the potential importance of persistence through pain and/or distress in the association between NSSI and suicidal behavior. PMID- 27936458 TI - Predictors of functional disability with focus on activities of daily living: A community based follow-up study in older adults in India. AB - BACKGROUND: Disability in activities of daily living is a growing concern among older populations all over the world. India has one of the rapidly ageing populations and predicted burden of functional disability is higher for Indian older adults as compared to other ageing Asian countries. METHODS: Total 1140 aged 60 years and over participated in a baseline study. 560 of them participated in the prospective cohort study conducted in the city of Pune, India. An interview and functional assessment using a questionnaire and Pune-FAAT tool was carried out in 2013-14. Binary logistic regression was used to obtain the factors that increased the odds of having ADL disability at follow-up. RESULTS: The mean age of the study population was 69.73+/-5.48years. Squatting, walking and climbing functions were affected significantly. Total 376 participants (67.1%) reported difficulties and/or disability in performing activities of daily living (ADL) at follow-up. Hospitalization (OR=3.6; 95% CI: 1.9-6.7), being female (OR=2.3; 95% CI: 1.5-3.5), presence of two or more chronic diseases (OR=1.7; 95% CI: 1.1-2.7), experience of memory loss (OR=1.9; 95% CI: 1.2-3.0) and feeling of loneliness (OR=2.3; 95% CI: 1.0-5.3) increased the odds of being in the "With disability" group at follow-up. Apart from this, self-rated health and self reported depression were associated with limitations in ADL. CONCLUSION: Hospitalization and being female appeared to be the most significant risk factors for disability in urban older adults in India. Rehabilitation services after hospitalization, physical exercise, effective control on chronic illness, and social participation to reduce loneliness is recommended. PMID- 27936456 TI - 1alpha,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase. AB - Both increased de novo fatty acid synthesis and higher neutral lipid accumulation are a common phenotype observed in aggressive breast cancer cells, making lipid metabolism a promising target for breast cancer prevention. In the present studies, we demonstrate a novel effect of the active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D (1,25(OH)2D) on lipid metabolism in malignant breast epithelial cells. Treatment of MCF10CA1a breast epithelial cells with 1,25(OH)2D (10 nM) for 5 and 7 days decreased the level of triacylglycerol, the most abundant form of neutral lipids, by 20%(+/-3.9) and 50%(+/-5.9), respectively. In addition, 1,25(OH)2D treatment for 5 days decreased palmitate synthesis from glucose, the major fatty acid synthesized de novo (48%+/-5.5 relative to vehicle). We have further identified the anaplerotic enzyme pyruvate carboxylase (PC) as a target of 1,25(OH)2D-mediated regulation and hypothesized that 1,25(OH)2D regulates breast cancer cell lipid metabolism through inhibition of PC. PC mRNA expression was down-regulated with 1,25(OH)2D treatment at 2 (73%+/-6 relative to vehicle) and 5 (56%+/-8 relative to vehicle) days. Decrease in mRNA abundance corresponded with a decrease in PC protein expression at 5 days of treatment (54%+/-12 relative to vehicle). Constitutive overexpression of PC in MCF10CA1a cells using a pCMV6-PC plasmid inhibited the effect of 1,25(OH)2D on both TAG accumulation and de novo palmitate synthesis from glucose. Together, these studies demonstrate a novel mechanism through which 1,25(OH)2D regulates lipid metabolism in malignant breast epithelial cells. PMID- 27936457 TI - Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis. AB - BACKGROUND AND AIMS: In hereditary hemochromatosis, iron deposition in the liver parenchyma may lead to fibrosis, cirrhosis and hepatocellular carcinoma. Most cases are ascribed to a common mutation in the HFE gene, but the extent of clinical expression is greatly influenced by the combined action of yet unidentified genetic and/or environmental modifying factors. In mice, transcription factor NRF2 is a critical determinant of hepatocyte viability during exposure to acute dietary iron overload. We evaluated if the genetic disruption of Nrf2 would prompt the development of liver damage in Hfe-/- mice (an established model of human HFE-hemochromatosis). METHODS: Wild-type, Nrf2-/-, Hfe-/- and double knockout (Hfe/Nrf2-/-) female mice on C57BL/6 genetic background were sacrificed at the age of 6 (young), 12-18 (middle-aged) or 24 months (old) for evaluation of liver pathology. RESULTS: Despite the parenchymal iron accumulation, Hfe-/- mice presented no liver injury. The combination of iron overload (Hfe-/-) and defective antioxidant defences (Nrf2-/-) increased the number of iron-related necroinflammatory lesions (sideronecrosis), possibly due to the accumulation of toxic oxidation products such as 4-hydroxy-2-nonenal protein adducts. The engulfment of dead hepatocytes led to a gradual accumulation of iron within macrophages, featuring large aggregates. Myofibroblasts recruited towards the injury areas produced substantial amounts of collagen fibers involving the liver parenchyma of double-knockout animals with increased hepatic fibrosis in an age-dependent manner. CONCLUSIONS: The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis) to liver injury in Hfe /- mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron. PMID- 27936459 TI - MiR-23a inhibited IL-17-mediated proinflammatory mediators expression via targeting IKKalpha in articular chondrocytes. AB - The inflammatory cytokine interleukin 17 (IL-17) is an important contributor of rheumatoid arthritis (RA) chronicity. Although several microRNAs (miRNAs) have been shown to regulate RA pathogenesis, the function of miRNAs in articular chondrocytes during rheumatoid arthritis pathogenesis is unclear. Here we showed that miR-23a was downregulated in articular cartilage tissues from rheumatoid arthritis patients. MiR-23a suppressed IL-17 inflammatory cytokine-induced NF kappaB activation and several proinflammatory mediators expression, such as cytokine IL-6, chemokine MCP-1, and matrix metalloproteinase MMP-3 in articular chondrocytes. Furthermore, we found that the miR-23a expression was inversely correlated with IKKalpha expression in articular cartilage tissues from rheumatoid arthritis patients. We identified that IKKalpha was the direct target of miR-23a and miR-23a inhibited IL-17-mediated proinflammatory mediators expression via targeting the IKKalpha in primary articular chondrocytes. Together, our study provides the first evidence of a role for miR-23a regulated IL-17-mediated proinflammatory mediators expression in rheumatoid arthritis by directly targeting IKKalpha. Our findings provide novel evidence that may be useful for future studies exploring therapeutic approaches for rheumatoid arthritis by targeting miR-23a. Thus, miR-23a may be a common therapeutic target for rheumatoid arthritis. PMID- 27936460 TI - B cells present skewed profile and lose the function of supporting T cell inflammation after Roux-en-Y gastric bypass. AB - Bariatric surgeries, including Roux-en-Y gastric bypass (RYGB) are currently the best treatment for obesity and obesity-related comorbidities, such as type 2 diabetes. However, the underlying mechanism of bariatric surgeries is not entirely understood. Further investigations are needed to improve the success rate and achieve sustained health benefits. Given that B cell dysregulation is a critical component of etiology in inflammatory diseases, whereas obesity and type 2 diabetes represent two major inflammatory disorders, we investigated the effect of RYGB on B cell inflammation. We found that B cells after RYGB presented significantly elevated frequency of interleukin (IL)-10-producing cells and reduced frequency of IL-6-producing cells compared to those before RYGB. When grouping B cell subsets into regulatory (secreting IL-10 and transforming growth factor beta [TGF-beta]) and effector (secreting IL-2, IL-4, IL-6, IL-12, interferon gamma [IFN-gamma] and tumor necrosis factor alpha [TNF-alpha]) types, we found that after RYGB, the regulatory to effector B cell ratio was significantly increased. Function analyses showed that B cells before RYGB supported IL-17 secretion from T cells whereas these cells after RYGB lost such capacity. B cells after RYGB also gained the capacity to suppress T cell IFN gamma production through TGF-beta-mediated effects, a feature not present in B cells before RYGB. Interestingly, the regulatory to effector B cell ratio was directly associated with the reductions in obesity markers following RYGB, such as BMI and fat mass percentage. Together, these results demonstrated a potential mechanism through which RYGB promoted amelioration of obesity and type 2 diabetes. PMID- 27936461 TI - Pterostilbene protects against myocardial ischemia/reperfusion injury via suppressing oxidative/nitrative stress and inflammatory response. AB - Recent studies have shown that pterostilbene (Pte) confers protection against myocardial ischemia/reperfusion injury. The oxidative/nitrative stress and inflammation induce injury after myocardial ischemia/reperfusion. The present study was designed to evaluate whether treatment with Pte attenuates oxidative/nitrative stress and inflammation in myocardial ischemia/reperfusion (MI/R). Rats were subjected to 30min of myocardial ischemia and 3h of reperfusion, and the rats were administered with vehicle or Pte. The results showed that Pte (10mg/kg) dramatically improved cardiac function and reduced myocardial infarction and myocardial apoptosis following MI/R. As an indicator of oxidative/nitrative stress, myocardial ONOO- content was markedly reduced after Pte treatment. And, Pte led to a dramatic decrease in superoxide generation and malondialdehyde (MDA) content and a dramatic increase in superoxide dismutase (SOD) activity. In addition, Pte treatment significantly reduced p38 MAPK activation and the expression of iNOS and gp91phox and increased phosphorylated eNOS expression. Pte treatment dramatically decreased myocardial TNF-alpha, and IL-1beta levels and myeloperoxidase (MPO) activity. Furthermore, ONOO- suppression by either Pte or uric acid (UA), an ONOO- scavenger, reduced myocardial injury. In conclusion, Pte exerts a protective effect against MI/R injury by suppressing oxidative/nitrative stress. These results provide evidence that Pte might be a therapeutic approach for the treatment of MI/R injury. PMID- 27936462 TI - Sinu virus, a novel and divergent orthomyxovirus related to members of the genus Thogotovirus isolated from mosquitoes in Colombia. AB - The genome and structural organization of a novel insect-specific orthomyxovirus, designated Sinu virus, is described. Sinu virus (SINUV) was isolated in cultures of C6/36 cells from a pool of mosquitoes collected in northwestern Colombia. The virus has six negative-sense ssRNA segments. Genetic analysis of each segment demonstrated the presence of six distinct ORFs encoding the following genes: PB2 (Segment 1), PB1, (Segment 2), PA protein (Segment 3), envelope GP gene (Segment 4), the NP (Segment 5), and M-like gene (Segment 6). Phylogenetically, SINUV appears to be most closed related to viruses in the genus Thogotovirus. PMID- 27936463 TI - Virus-like particles displaying H5, H7, H9 hemagglutinins and N1 neuraminidase elicit protective immunity to heterologous avian influenza viruses in chickens. AB - Avian influenza (AI) viruses circulating in wild birds pose a serious threat to public health. Human and veterinary vaccines against AI subtypes are needed. Here we prepared triple-subtype VLPs that co-localized H5, H7 and H9 antigens derived from H5N1, H7N3 and H9N2 viruses. VLPs also contained influenza N1 neuraminidase and retroviral gag protein. The H5/H7/H9/N1/gag VLPs were prepared using baculovirus expression. Biochemical, functional and antigenic characteristics were determined including hemagglutination and neuraminidase enzyme activities. VLPs were further evaluated in a chicken AI challenge model for safety, immunogenicity and protective efficacy against heterologous AI viruses including H5N2, H7N3 and H9N2 subtypes. All vaccinated birds survived challenges with H5N2 and H7N3 highly pathogenic AI (HPAI) viruses, while all controls died. Immune response was also detectable after challenge with low pathogenicity AI (LPAI) H9N2 virus suggesting that H5/H7/H9/N1/gag VLPs represent a promising approach for the development of broadly protective AI vaccine. PMID- 27936464 TI - Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine. AB - Testicular germ cell tumors (TGCTs) are the most common cancers of young males. A substantial portion of TGCT patients are refractory to cisplatin. There are no effective therapies for these patients, many of whom die from progressive disease. Embryonal carcinoma (EC) are the stem cells of TGCTs. In prior in vitro studies we found that EC cells were highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). Here, as an initial step in bringing demethylation therapy to the clinic for TGCT patients, we evaluated the effects of the clinically optimized, second generation demethylating agent guadecitabine (SGI-110) on EC cells in an animal model of cisplatin refractory testicular cancer. EC cells were exquisitely sensitive to guadecitabine and the hypersensitivity was dependent on high levels of DNA methyltransferase 3B. Guadecitabine mediated transcriptional reprogramming of EC cells included induction of p53 targets and repression of pluripotency genes. As a single agent, guadecitabine completely abolished progression and induced complete regression of cisplatin resistant EC xenografts even at doses well below those required to impact somatic solid tumors. Low dose guadecitabine also sensitized refractory EC cells to cisplatin in vivo. Genome-wide analysis indicated that in vivo antitumor activity was associated with activation of p53 and immune-related pathways and the antitumor effects of guadecitabine were dependent on p53, a gene rarely mutated in TGCTs. These preclinical findings suggest that guadecitabine alone or in combination with cisplatin is a promising strategy to treat refractory TGCT patients. PMID- 27936465 TI - Meta-analysis of transcatheter arterial chemoembolization plus radiofrequency ablation versus transcatheter arterial chemoembolization alone for hepatocellular carcinoma. AB - This meta-analysis was conducted to compare transcatheter arterial chemoembolization (TACE) plus radiofrequency ablation (RFA) with TACE alone for hepatocellular carcinoma. We searched MEDLINE, EMBASE and CENTRAL for all relative randomized controlled trials (RCTs) and retrospective studies until October 31 2016. Tumor response, recurrence-free survival, overall survival and postoperative complications were the major evaluation indices. Review Manager (version 5.3) was used to analyze the data. Dichotomous data was calculated by odds ratio (OR) with 95% confidence intervals (CI). There were 1 RCT and 10 retrospective studies with 928 patients in this meta-analysis: 412 patients with TACE plus RFA and 516 patients with TACE alone. Compared with TACE alone group, TACE plus RFA group attained higher tumor response rates (OR = 6.08, 95% CI = 4.00 to 9.26, P < 0.00001), achieved longer recurrence-free survival rates (ORRFS = 3.78, 95% CI: 2.38 to 6.02, P < 0.00001) and overall survival rates (OR1-year = 3.92, 95% CI = 2.41-6.39, P < 0.00001; OR3-year = 2.56; 95% CI = 1.81-3.60; P < 0.00001; OR5-year = 2.78; 95% CI = 1.77-4.38; P < 0.0001). Serious postoperative complications were not observed, although complications were higher in TACE plus RFA group than that in TACE alone group (OR = 2.74, 95% CI = 1.07 to 7.07, P = 0.04). In conclusion, the use of TACE plus RFA for intermediate stage hepatocellular carcinoma can attain higher tumor response rates and improve survival rates than TACE alone. PMID- 27936466 TI - DPP4/CD26 overexpression in urothelial carcinoma confers an independent prognostic impact and correlates with intrinsic biological aggressiveness. AB - Urothelial carcinoma (UC) is common cancer worldwide. The molecular aberrations regarding tumor progression remain unclear. Pericellular proteolysis is crucial in tumorigenesis, but its significance is unexplored in UC. By data mining the datasets in Gene Expression Omnibus, specifically focus on the proteolysis pathway, and followed by a preliminary validation in a pilot batch of tumor samples, we identified that the upregulation of dipeptidyl peptidase 4 (DPP4) was most significantly associated with clinical aggressiveness of UCs. Quantitative RT-PCR confirmed upregulation of DPP4 mRNA in advanced stage UCs. The clinical significance of DPP4 expression was validated in our large cohort consists of 635 UCs from upper urinary tract and urinary bladder. Univariate and multivariate analyses show that DPP4 is an independent prognosticatory biomarker for disease specific survival and metastasis-free survival. Comparing the DPP4 expression level of three urothelial cell lines with normal urothelial cells, J82 and RTCC-1 showed a significantly increased in transcript and protein expression. DPP4 knockdown as conducted by using short-hairpin RNA resulted in a significantly decreased cell viability, proliferation, migration, and invasion in J82 and RTCC 1 cells. These findings implicate that DPP4 plays a role in the aggressiveness of UCs, and can serve as a novel prognostic marker and therapeutic target. PMID- 27936467 TI - Clinical relevance of cell-free DNA in gastrointestinal tract malignancy. AB - BACKGROUND: Cell-free DNA (cfDNA) extracted from blood has become a clinically feasible biomarker in various types of cancer. However, the clinical significance of cfDNA in gastrointestinal (GI) tract cancer among Asian populations requires further investigation. RESULTS: The median cfDNA copy number was highest in esophageal cancer, followed by colorectal cancer and gastric cancer, which were all significantly higher than those of healthy individuals. The cfDNA levels were higher in GI tract cancer, followed by those in carcinoma in situ and then healthy individuals (P = 0.019). During the postoperative surveillance, the cfDNA level tended to be more sensitive than the carcinoembryonic antigen level in predicting recurrence. For recurrent gastric cancer, a persistently high cfDNA level and an increasing trend was observed after surgery. For stage IV colorectal cancer, dynamic changes in the cfDNA level were correlated with the responses to chemotherapy and surgery. MATERIALS AND METHODS: Blood samples were collected from 95 healthy individuals and from 855 patients diagnosed with GI tract malignancy, including 98 with esophageal cancer, 428 with stomach cancer, 329 with colorectal cancer and 30 with carcinoma in situ. The copy numbers of extracted cfDNA were analyzed and compared among the different types of GI cancers. CONCLUSIONS: The cfDNA level can serve as a feasible biomarker for detecting tumors in GI tract cancer. The cfDNA level may play a role in predicting tumor responses to chemotherapy and surgery in colorectal cancer; tumor recurrence should be considered in gastric cancer with a persistently high cfDNA level after surgery. PMID- 27936468 TI - Rosiglitazone reduces breast cancer risk in Taiwanese female patients with type 2 diabetes mellitus. AB - This study investigated whether rosiglitazone may affect breast cancer risk in female patients with type 2 diabetes mellitus in Taiwan. The reimbursement database of all female patients with type 2 diabetes mellitus under oral antidiabetic agents or insulin from 1996 to 2009 was retrieved from the National Health Insurance. An entry date was set on 1 January 2006 and a total of 431447 patients were followed up for breast cancer incidence till the end of 2009. Incidences for ever users, never users and subgroups of rosiglitazone dose response parameters (tertile cutoffs of cumulative duration and cumulative dose) were calculated and hazard ratios estimated by Cox regression. There were 53029 ever users and 378418 never users, respective numbers of incident breast cancer 410 (0.77%) and 3292 (0.87%), and respective incidence 217.53 and 249.12 per 100000 person-years. The overall hazard ratio was 0.889 (95% confidence interval: 0.797-0.992) in the fully adjusted model. Significantly lower risk was observed for the third tertiles of cumulative duration (> 14 months) and cumulative dose (> 1792 mg) while compared to never users, with respective adjusted hazard ratio of 0.815 (95% confidence interval: 0.682-0.973) and 0.815 (95% confidence interval: 0.682-0.974). Additionally, a significant interaction between metformin and rosiglitazone was observed. The lowest risk was seen in patients who used both drugs (hazard ratio 0.812, 95% confidence interval: 0.705-0.934). In conclusion, rosiglitazone reduces breast cancer risk in female patients with type 2 diabetes mellitus, which shows a significant interaction with metformin. PMID- 27936469 TI - Diabetic Retinopathy: Battling the Global Epidemic. PMID- 27936470 TI - Ocular Delivery of PACAP1-27 Protects the Retina From Ischemic Damage in Rodents. AB - Purpose: Pituitary adenylate cyclase activating polypeptide (PACAP) is neuroprotective in neuronal injuries. Bilateral common carotid artery occlusion (BCCAO) causes chronic hypoperfusion-induced degeneration in the rat retina, where we proved the retinoprotective effect of intravitreal PACAP. Although this route of administration is a common clinical practice in several diseases, easier routes are clinically important. Our aim was to investigate the potential retinoprotective effects of PACAP eye drops in BCCAO-induced ischemic retinopathy. Methods: After performing BCCAO in rats, the right eyes were treated with PACAP1-27 eye drops (1 MUg/drop, 2 * 1 drops/day for 5 days), containing different vehicles: saline, water for injections, thiomersal or benzalkonium solution for ophthalmic use (SOCB). Histology and immunohistochemistry were performed 2 weeks after surgery, while molecular analysis was performed 24 hours after BCCAO. Passage of PACAP1-27 through the ocular layers was tested with radioactive PACAP-SOCB in mice. Results: Bilateral common carotid artery occlusion led to a severe degeneration of all retinal layers. Solution for ophthalmic use was the most effective vehicle for delivering PACAP (PACAP-SOCB), significantly ameliorating BCCAO-induced damage. The massive upregulation of GFAP was not observed in retinas treated with PACAP-SOCB eye drops. PACAP-SOCB treatment also increased activation of the protective Akt and ERK1/2 in hypoperfused retinas. The cytokine profile showing upregulation in different cytokines was attenuated by PACAP-SOCB. Radioactive PACAP reached the retina when delivered in SOCB-containing eye drops. Conclusions: PACAP1-27, delivered in the SOCB vehicle as eye drops, was retinoprotective in ischemic retinopathy, providing the basis for future therapeutic administration. PMID- 27936471 TI - Prevalence of Lens Opacities in Adult Chinese Americans: The Chinese American Eye Study (CHES). AB - Purpose: We determined the age- and sex-specific prevalence of posterior subcapsular (PSC), nuclear, cortical, and mixed lens opacities in a population based sample of Chinese-American adults. Methods: A population-based sample of Chinese-Americans 50 years and older, from 10 census tracts in Monterey Park, CA, USA, underwent a detailed interview and a comprehensive clinical examination that included assessment of different types of lens opacities by the slit-lamp-based Lens Opacities Classification System II (LOCS II). All lens changes (including pseudophakia/aphakia), PSC, nuclear, and/or cortical opacities, were evaluated and graded. Results: Of the 5782 eligible subjects, 4582 (79.2%) Chinese Americans aged 50 years and older completed a comprehensive eye examination. Of the participants with LOCS II grading (n = 4234/4582, 92%), 3.0% had PSC opacities, 38.1% had nuclear opacities, and 23.4% had cortical opacities. The prevalence of all lens changes was 48.0% for all age groups and was higher by 10 year increasing age groups (P < 0.0001). The prevalence of visual impairment in the better-seeing eye with cortical only, nuclear only, PSC only, and mixed opacities was 3.9%, 5.0%, 14.3%, and 9.4%, respectively. A total of 454 (9.9%) individuals had undergone cataract extraction in at least one eye. Conclusions: Chinese Americans have a high prevalence of visual impairment associated with lens opacities, and a high prevalence of nuclear opacities. Public health policies and programs designed to improve cataract detection and treatment could help reduce the burden of visual impairment in Chinese Americans. PMID- 27936472 TI - Relaxant Effect of Sodium Tanshinone IIA Sulphonate on Mouse Tracheal Smooth Muscle. AB - Sodium tanshinone IIA sulphonate, a water-soluble derivative of tanshinone IIA, has been proven to possess versatile biological properties, but its pharmacological effect on tracheal smooth muscle remains elusive. This paper presents a study on the relaxant effect and underlying mechanisms of sodium tanshinone IIA sulphonate on mouse tracheal smooth muscle. The relaxant effect of sodium tanshinone IIA sulphonate was evaluated in mouse tracheal rings using a mechanical recording system. Intracellular Ca2+ concentration was measured in primary cultured tracheal smooth muscle cells using confocal imaging system. The results showed that sodium tanshinone IIA sulphonate induced dose-dependent relaxation of mouse tracheal rings in a beta-adrenoceptor- and epithelium independent manner. Pretreatment with the ATP-sensitive K+ channel blocker glibenclamide partly attenuated the relaxation response. Administration of sodium tanshinone IIA sulphonate notably inhibited the extracellular Ca2+-induced contraction. High KCl or carbachol-evoked elevation in the intracellular Ca2+ concentration was also abrogated by sodium tanshinone IIA sulphonate in tracheal smooth muscle cells. In conclusion, the tracheal relaxant effect of sodium tanshinone IIA sulphonate was independent of beta-adrenoceptor and airway epithelium, mediated primarily by inhibition of extracellular Ca2+ influx via L type voltage-dependent Ca2+ channels and partially by activation of the ATP sensitive K+ channel. These results indicate the potential therapeutic value of sodium tanshinone IIA sulphonate for asthma treatment. PMID- 27936473 TI - Outcome of a Severe Blunt Trauma after SMILE (Small Incision Lenticule Extraction). PMID- 27936474 TI - [Three Years Follow-up Study after Refractive Small Incision Lenticule Extraction (SMILE) Using 500 kHz Femtosecond Laser in "Fast Mode"]. AB - Background The aim of this clinical trial was to check the results of laser built-in settings 3 years after ReLEx SMILE for moderate and high myopia in unselected "real life" patients. Patients and Methods 50 myopic eyes of 27 patients were called in for examination after 3 years. 25 of these eyes with a preoperative myopia under - 6D comprised the "moderate myopia subgroup". All surgeries were performed with the 500 kHz VisuMax(r) femtosecond laser (Carl Zeiss Meditec AG, Jena) in the "fast mode" setting. Results The spherical equivalent (SE) of the entire group changed from - 6.18 D (+/- 1.91) prior to surgery to - 0.18 D (+/- 0.39) 3 years later. The preoperative SE in the moderate myopia subgroup changed from - 4.71 D (+/- 0.94) to - 0.04 D (+/- 0.23). 14 % of 50 eyes gained one line and 22 % lost one line of CDVA. The regression between month 3 and 36 was 0.07D for the entire group and 0.06 D for the moderate myopia subgroup. There were no late side effects. Primary undercorrection was predominantly seen in eyes over - 6 D. Conclusion ReLEx SMILE shows remarkable stability over the entire range of myopias after 3 years, however primary undercorrection occurs predominantly in eyes of - 6.0 D, which necessitates nomogram adjustment. PMID- 27936475 TI - [Jewish Participants and Contributions to the Conferences of the German Ophthalmological Society during National Socialism]. PMID- 27936476 TI - Necrotizing Enterocolitis and Growth in Preterm Infants Fed Predominantly Maternal Milk, Pasteurized Donor Milk, or Preterm Formula: A Retrospective Study. AB - Objective To evaluate the association between necrotizing enterocolitis (NEC), growth, and feeding. Methods This is a retrospective study of 551 infants (birth weight <= 1,500 g, <=32 weeks' gestation). NEC, Bell's stage >= 2, was confirmed by independent review of sentinel radiographs. Feeding type was defined as >= 50% maternal milk (MM), pasteurized donor human milk (PDHM), or preterm formula (PF). Demographic and clinical characteristics including growth were compared between the three groups. Multivariable regression analysis was performed to control variables that differed in bivariate analysis. Results PDHM and PF mothers were more likely to be African-American, be enrolled in Medicaid, and have chorioamnionitis. PF mothers received antenatal steroids less frequently. NEC rates were different by feeding group (MM: 5.3%; PHDM: 4.3%; PF: 11.4%; p = 0.04). Adjusting for group differences, lower gestational age (adjusted odds ratio [aOR]: 0.85; 95% confidence interval [CI]: 0.74-0.97; p = 0.02], and PF (aOR: 2.53; 95% CI: 1.15-5.53; p = 0.02] were associated with NEC. There were no differences in other health outcomes or growth at hospital discharge. Conclusion MM and PDHM feedings, given until 34 weeks postmenstrual age, were associated with lower rates of NEC in very low birth weight infants without interfering with growth. PMID- 27936477 TI - [Hepatology 2017: from basics to clinics - future perspectives]. PMID- 27936478 TI - Future Organization of Clinical Research in Germany: The Road to the "German Centre for Digestive Health" (GCDH). PMID- 27936479 TI - The GALAD scoring algorithm based on AFP, AFP-L3, and DCP significantly improves detection of BCLC early stage hepatocellular carcinoma. AB - Background: Hepatocellular carcinoma (HCC) is one of the leading causes of death in cirrhotic patients worldwide. The detection rate for early stage HCC remains low despite screening programs. Thus, the majority of HCC cases are detected at advanced tumor stages with limited treatment options. To facilitate earlier diagnosis, this study aims to validate the added benefit of the combination of AFP, the novel biomarkers AFP-L3, DCP, and an associated novel diagnostic algorithm called GALAD. Material and methods: Between 2007 and 2008 and from 2010 to 2012, 285 patients newly diagnosed with HCC and 402 control patients suffering from chronic liver disease were enrolled. AFP, AFP-L3, and DCP were measured using the uTASWako i30 automated immunoanalyzer. The diagnostic performance of biomarkers was measured as single parameters and in a logistic regression model. Furthermore, a diagnostic algorithm (GALAD) based on gender, age, and the biomarkers mentioned above was validated. Results: AFP, AFP-L3, and DCP showed comparable sensitivities and specifities for HCC detection. The combination of all biomarkers had the highest sensitivity with decreased specificity. In contrast, utilization of the biomarker-based GALAD score resulted in a superior specificity of 93.3 % and sensitivity of 85.6 %. In the scenario of BCLC 0/A stage HCC, the GALAD algorithm provided the highest overall AUROC with 0.9242, which was superior to any other marker combination. Conclusions: We could demonstrate in our cohort the superior detection of early stage HCC with the combined use of the respective biomarkers and in particular GALAD even in AFP negative tumors. PMID- 27936480 TI - Treatment of fulminant acute Hepatitis B with nucles(t)id analogues is safe and does not lead to secondary chronification of Hepatitis B. AB - Background: Acute hepatitis B virus (HBV) infection is still a major cause of acute liver failure (ALF), necessitating a high rate of emergency liver transplantation (LTx). Acute infection is followed by high viral replication rates leading to hepatocyte death and, ultimately, ALF. The objective of treating HBV-induced ALF thus is to eliminate, or significantly suppress, HBV replication and therefore reduce cell death and support regeneration. Objective: In this retrospective study, we want to evaluate the timing, the safety, and the long term virological outcome of this approach. Methods/results: In this study, we included 32 patients (16 female and 16 males; median age 39.5 years) with ALF due to hepatitis B, who were transferred to the university hospital Essen, Germany between January 2009 and December 2013. Before treatment, transaminases were highly elevated, bilirubin was increased, and elevated international normalized ratio (INR) revealed impaired liver function. HBV-DNA and HBsAg were positive. All 32 patients received oral antiviral treatment (3 lamivudine, 21 entecavir, and 8 tenofovir) between 1 day and 4 months after diagnosis of acute hepatitis B. One patient died, 2 were transplanted, one died shortly after LTx the other patient survived after LTx. These 3 patients received treatment in a state of advanced liver failure, and 1 patient 4 months after initial diagnosis of hepatitis B. Twenty-nine patients survived without LTx. Five patients were discharged without further follow-up. All 24 remaining patients became HBV-DNA negative in median of 100 days. Twenty-two patients were followed further, and all patients lost their HBsAg in median of 108 days. Sixteen of the 22 patients experienced a seroconversion to anti-HBs in median of 137 days. Four patients who were followed for 1 more year after HBsAg did not develop anti-HBs. None of the patients developed chronic hepatitis B. Conclusion: Immediate treatment of HBV induced ALF with nucleos(t)id-analogues (NUCs) appears save and prevents LTx and death, and there is no indication for increased chronicity. PMID- 27936481 TI - Patients with ultrasound diagnosis of hepatic steatosis are at high metabolic risk. AB - Background and aims: Hepatic steatosis is the basis of non-alcoholic fatty liver disease (NALFD). Mere fat accumulation within hepatocytes is considered the mild form of NAFLD, but can progress in some patients to advanced steatohepatitis (NASH), which may lead to fibrosis, cirrhosis or hepatocellular carcinoma. However, even hepatic steatosis alone may be a risk factor for cardiovascular disease (CVD). Patients and methods: In the present real life study 106 patients from the outpatient clinic of the Department for Gastroenterology and Hepatology with either NAFLD (n = 60) or other typical diagnoses (n = 46) were included. Ultrasound examination identified 77 patients with hepatic steatosis. Liver enzymes, lipid profile, surrogate cell death markers, and adiponectin were determined. Transient elastography (Fibroscan(r)) and bioelectrical impedance analysis (BIA) were performed. Results: Mean patient age was 46 years (23 - 62) for non-NAFLD and 53 years (18 - 71) for the NAFLD group. ALT and AST did not differ significantly between the two groups. Adiponectin and HDL were significantly lower in NAFLD (p < 0.05) and BIA profiles showed higher fat and fat free mass. Non-NAFLD patients with steatosis also exhibited an adverse metabolic profile. Overall steatosis was associated with factors of metabolic syndrome (MS) and CVD. Prevalence of CVD and factors of MS hint to steatosis as an early event for these conditions. Conclusion: Patients with steatosis are at higher cardiovascular and metabolic risk without differences in transaminases levels compared to those without steatosis. Steatosis diagnosed by ultrasound needs to rise attention for further metabolic alterations including CVD. PMID- 27936483 TI - Perspectives of immunotherapy in hepatocellular carcinoma (HCC). AB - Immunotherapy is considered a new treatment option for many tumor entities, as decades of research into cancer immunotherapy have recently yielded promising results. Indeed, impressive clinical results of checkpoint blockade inhibitors in malignant melanoma and non-small cell lung cancer indicate the therapeutic potential of tumor-specific immune restoration. Over the years, different immunotherapeutic approaches have been evaluated for the treatment of hepatocellular carcinoma (HCC) with some respectable results. In this review article, we will summarize the key studies of the past 30 years and will elucidate in which direction the dynamic field of HCC immunotherapy is currently moving. PMID- 27936482 TI - Intrahepatic cholestasis of pregnancy (ICP): case report and review of the literature. AB - Intrahepatic cholestasis of pregnancy (ICP) represents the most common pregnancy related liver disease in women. Women frequently present in the third trimester with pruritus and elevated serum bile acid and/or alanine transaminase levels. Clinical symptoms quickly resolve after delivery; however, recurrence in subsequent pregnancies has to be expected. Intrahepatic cholestasis of pregnancy is associated with increased perinatal complications, such as premature delivery, meconium staining of the amniotic fluid, respiratory distress, low Apgar scores, and even stillbirth. The risk for the fetus is significantly increased with maternal serum bile acid levels above 40 umol/L, which characterize severe ICP. An important factor for ICP development is a rise of gestational hormones leading to cholestasis in genetically predisposed women. Variants in the bile salt export pump (BSEP) and the multidrug resistance protein 3 (MDR3) are most often identified in ICP. Here, we give an overview of the current literature on ICP and present the case of a woman with recurrent severe ICP. A common BSEP polymorphism as well as a rare MDR3 mutation may underlie the development of ICP in our patient. She had a premature delivery with meconium staining of the amniotic fluid. The neonate showed signs of respiratory distress with a low Apgar score. This case emphasizes that women with severe ICP have an increased risk for perinatal complications. Furthermore, severe ICP was associated with a MDR3 mutation, which has already been described in adult patients with liver cirrhosis. Thus, ICP may unmask an underlying MDR3 defect, which may predispose to development of hepatobiliary diseases such as gallstone disease, liver fibrosis/cirrhosis, as well as hepatobiliary malignancies. Therefore, genetic testing should be considered in women with severe as well as early onset ICP. Furthermore, regular follow-up should be discussed for women with genetic variants. PMID- 27936484 TI - Gartland Type II Supracondylar Humerus Fractures, Their Operative Treatment and Lateral Pinning Are Increasing: A Population-Based Epidemiologic Study of Extension-Type Supracondylar Humerus Fractures in Children. AB - Background Supracondylar humerus fractures are usual in children but their recent trends are unclear. Material and Methods A population-based study was performed to determine the epidemiology of childhood supracondylar humerus fractures during the decade, 2000 to 2009, in a geographic area of Oulu, Finland. Altogether, 565 extension-type supracondylar humerus fractures were included. The fractures and their treatment were analyzed according to the Gartland classification. Results Fracture incidence increased by 28%, from 50.9 to 65.2 per 100,000 during 2000 to 2009 (beta = 1.03, p < 0.001). The increase was from 41.3 to 57.6 per 100,000 in girls (beta = 1.9, p < 0.001). Trampoline-related fractures in particular increased in girls. Type II fractures increased twofold from 7.1 to 16.3 per 100,000 (beta = 1.1, p < 0.001), whereas type I fractures decreased from 22.4 to 20.9 per 100,000 (beta = -0.3, p = 0.026).Surgical treatment increased during the 10 years study period from 32.6 to 51.8% (p = 0.022); it was in particular due to increase of operative care of type II fractures (from 5.9% in 2000-2001 to 37.1% in 2008-2009; p = 0.011). Lateral pin fixation increased from nil to six (10.7%) (p < 0.001). Conclusion The incidence and surgical stabilization of type II fractures in particular are increasing. There is a trend toward lateral pin fixation. PMID- 27936485 TI - X-ray crystal structure of cytochrome P450 monooxygenase CYP101J2 from Sphingobium yanoikuyae strain B2. AB - The cytochrome P450 monooxygenases (P450s) catalyze a vast array of oxygenation reactions that can be useful in biocatalytic applications. CYP101J2 from Sphingobium yanoikuyae is a P450 that catalyzes the hydroxylation of 1,8-cineole. Here we report the crystallization and X-ray structure elucidation of recombinant CYP101J2 to 1.8 A resolution. The CYP101J2 structure shows the canonical P450 fold and has an open conformation in the absence of substrate. Analysis of the structure revealed that CYP101J2, in the absence of substrate, forms a well ordered substrate-binding channel that suggests a unique form of substrate guidance in comparison to other bacterial 1,8-cineole-hydroxylating P450 enzymes. Proteins 2017; 85:945-950. (c) 2016 Wiley Periodicals, Inc. PMID- 27936486 TI - MicroRNA-4656 is a prognostic factor and tumor suppressor in human pancreatic cancer through a downstream target of TrkA. AB - BACKGROUND: In the present study, we investigated the expression profile and functional mechanism of microRNA-4656 in human pancreatic cancer (PC). METHODS: MiR-4656 expression in PC tumors was examined using a quantitative reverse transcriptase-polymerase chain reaction in 134 patients. Associations between tumorous miR-4656 expression and clinicopathological parameters of patients, as well as overall survival, were analyzed. MiR-4656 expression was also examined in PC in vitro cell lines. In Capan-1 and AsPC-1 PC cells, lentivirus-induced miR 4656 overexpression or downregulation was applied to investigate its functional regulations on PC in vitro proliferation and invasion, as well as in vivo transplant growth. The association of miR-4656 and its downstream target, the tropomyosin receptor kinase A (TrkA) gene, was investigated in both cell line and clinical pancreatic tumors. In miR-4656-overerxpressed PC cells, TrkA was overexpressed with the aim of investigating its role in miR-4656-induced functional regulation in PC. RESULTS: MiR-4656 was downregulated in PC. Low tumorous miR-4656 expression was associated with a poor prognosis and overall survival of patients. MiR-4656 was also found to be downregulated in PC cell lines. MiR-4656 overexpression in Capan-1 and AsPC-1 cells significantly inhibited cancer proliferation and invasion in vitro, as well as explant growth in vivo, whereas miR-4656 downregulation had no effect on cancer development. The TrkA gene was directly bound by miR-4656, and reversely expressed in PC tumors as miR-4656. TrkA overexpression reversed the inhibitory effect of miR-4656 overexpression on PC proliferation and invasion. CONCLUSIONS: MiR-4656 is expressed to a low extent and is a potential biomarker in PC. Overexpressing miR 4656 has tumor suppressive effects on PC development both in vitro and in vivo, likely through its downstream target of the TrkA gene. PMID- 27936488 TI - Ro52/TRIM21-deficient expression and function in different subsets of peripheral blood mononuclear cells is associated with a proinflammatory cytokine response in patients with idiopathic inflammatory myopathies. AB - The presence of anti-Ro52/tripartite motif 21 (Trim21) autoantibodies has been associated with a distinctive clinical profile and has gained value as a prognostic marker in idiopathic inflammatory myopathies (IIM). The aim of the present work was to analyse Ro52/Trim21 expression in different subsets of peripheral blood mononuclear cells (PBMCs) of patients with IIM, as well as the ubiquitination profile and its association with proinflammatory cytokine production. We included 18 patients with recent-onset IIM and 18 age- and gender matched healthy donors. PBMCs were isolated and different subsets (CD4+ , CD8+ , CD14+ ) were purified by magnetic selection. The expression of Ro52/Trim21 in different PBMC subsets of patients with IIM and healthy donors was analysed by Western blot. We assessed the presence of myositis-specific and associated autoantibodies by enzyme-linked immunosorbent assay (ELISA). Cytokine levels were measured by cytometric bead array. Patients with IIM showed decreased protein expression of Ro52/Trim21 in comparison to healthy controls in PBMC (0.97 +/- 0.60 versus 1.84 +/- 0.92, P = 0.016), CD4+ lymphocytes (0.79 +/- 0.54 versus 2.41 +/- 0.78, P = 0.017), and monocytes (0.87 +/- 0.35 versus 1.89 +/- 0.20, P < 0.001). There were no significant differences among IIM groups. Also, a lower K48 mediated ubiquitination profile was found, predominantly in CD4+ lymphocytes. Furthermore, after mitogenic stimulation, there was a higher synthesis of proinflammatory cytokines by T cells [interleukin (IL)-17A and tumour necrosis factor (TNF)-alpha] and monocytes [IL-6 and interferon (IFN)-alpha] from IIM patients compared with healthy controls. Our data suggest that patients with IIM, mainly DM, are characterized by a deficient expression of Ro52/TRIM21 in different PBMC subsets (CD4+ lymphocytes and monocytes), along with lower K48 mediated ubiquitination, which is associated with a proinflammatory cytokine response. PMID- 27936489 TI - Follow-Up of Alcohol Consumption After Liver Transplantation: Interest of an Addiction Team? AB - BACKGROUND: Alcohol relapses after liver transplantation (LT) constitute a critical issue. Because there is no widely accepted definition of LT, its prevalence varies from 7 to 95% across studies. Only a severe relapse, the frequency of which is estimated to be 11 to 26%, decreases life expectancy after 5 years of LT and requires specific care. To improve the early identification of alcohol consumption among transplanted patients, liver transplant teams may be helped by input from an addiction team. Nevertheless, added benefit of involvement by addiction specialists in treating posttransplant patients has not been demonstrated. Thus, the aim of this study was to compare the evaluation of the alcohol consumption after LT performed routinely during the transplant consultation or obtained from a specific addiction consultation. METHODS: This was a prospective single-site study. Patients were seen consecutively by their hepatologist and by an addiction specialist, and they completed the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C). Thus, the patient's alcohol status was assessed using 3 different sources of information: the hepatologist's interview, the AUDIT-C score, and the addiction specialist visit. RESULTS: One hundred forty-one patients were consecutively evaluated. Alcohol consumption was identified by the hepatologist in 31 patients (21.9%), in 52 (36.8%) using the AUDIT-C questionnaire, and in 58 (41.1%) by the addiction specialist. The 31 patients concerned reported an average of 6.5 alcohol units/wk to the transplant physician, a number which was significantly greater (p = 0.001) by 8.6 units/wk when they were interviewed by the addiction specialist. CONCLUSIONS: This study highlights the clinical utility of a systematic addiction consultation among liver transplant patients, irrespective of the reason for transplantation. PMID- 27936490 TI - Combining ancestral sequence reconstruction with protein design to identify an interface hotspot in a key metabolic enzyme complex. AB - It is important to identify hotspot residues that determine protein-protein interactions in interfaces of macromolecular complexes. We have applied a combination of ancestral sequence reconstruction and protein design to identify hotspots within imidazole glycerol phosphate synthase (ImGPS). ImGPS is a key metabolic enzyme complex, which links histidine and de novo purine biosynthesis and consists of the cyclase subunit HisF and the glutaminase subunit HisH. Initial fluorescence titration experiments showed that HisH from Zymomonas mobilis (zmHisH) binds with high affinity to the reconstructed HisF from the last universal common ancestor (LUCA-HisF) but not to HisF from Pyrobaculum arsenaticum (paHisF), which differ by 103 residues. Subsequent titration experiments with a reconstructed evolutionary intermediate linking LUCA-HisF and paHisF and inspection of the subunit interface of a contemporary ImGPS allowed us to narrow down the differences crucial for zmHisH binding to nine amino acids of HisF. Homology modeling and in silico mutagenesis studies suggested that at most two of these nine HisF residues are crucial for zmHisH binding. These computational results were verified by experimental site-directed mutagenesis, which finally enabled us to pinpoint a single amino acid residue in HisF that is decisive for high-affinity binding of zmHisH. Our work shows that the identification of protein interface hotspots can be very efficient when reconstructed proteins with different binding properties are included in the analysis. Proteins 2017; 85:312-321. (c) 2016 Wiley Periodicals, Inc. PMID- 27936487 TI - The evolution of function within the Nudix homology clan. AB - The Nudix homology clan encompasses over 80,000 protein domains from all three domains of life, defined by homology to each other. Proteins with a domain from this clan fall into four general functional classes: pyrophosphohydrolases, isopentenyl diphosphate isomerases (IDIs), adenine/guanine mismatch-specific adenine glycosylases (A/G-specific adenine glycosylases), and nonenzymatic activities such as protein/protein interaction and transcriptional regulation. The largest group, pyrophosphohydrolases, encompasses more than 100 distinct hydrolase specificities. To understand the evolution of this vast number of activities, we assembled and analyzed experimental and structural data for 205 Nudix proteins collected from the literature. We corrected erroneous functions or provided more appropriate descriptions for 53 annotations described in the Gene Ontology Annotation database in this family, and propose 275 new experimentally based annotations. We manually constructed a structure-guided sequence alignment of 78 Nudix proteins. Using the structural alignment as a seed, we then made an alignment of 347 "select" Nudix homology domains, curated from structurally determined, functionally characterized, or phylogenetically important Nudix domains. Based on our review of Nudix pyrophosphohydrolase structures and specificities, we further analyzed a loop region downstream of the Nudix hydrolase motif previously shown to contact the substrate molecule and possess known functional motifs. This loop region provides a potential structural basis for the functional radiation and evolution of substrate specificity within the hydrolase family. Finally, phylogenetic analyses of the 347 select protein domains and of the complete Nudix homology clan revealed general monophyly with regard to function and a few instances of probable homoplasy. Proteins 2017; 85:775-811. (c) 2016 Wiley Periodicals, Inc. PMID- 27936492 TI - Long non-coding RNA: a versatile regulator of the nuclear factor-kappaB signalling circuit. AB - The nuclear factor-kappaB (NF-kappaB) family of transcription factors play an essential role for the regulation of inflammatory responses, immune function and malignant transformation. Aberrant activity of this signalling pathway may lead to inflammation, autoimmune diseases and oncogenesis. Over the last two decades great progress has been made in the understanding of NF-kappaB activation and how the response is counteracted for maintaining tissue homeostasis. Therapeutic targeting of this pathway has largely remained ineffective due to the widespread role of this vital pathway and the lack of specificity of the therapies currently available. Besides regulatory proteins and microRNAs, long non-coding RNA (lncRNA) is emerging as another critical layer of the intricate modulatory architecture for the control of the NF-kappaB signalling circuit. In this paper we focus on recent progress concerning lncRNA-mediated modulation of the NF kappaB pathway, and evaluate the potential therapeutic uses and challenges of using lncRNAs that regulate NF-kappaB activity. PMID- 27936494 TI - Five New C19 -Diterpenoid Alkaloids from Delphinium tianshanicum W.T.Wang. AB - Five new diterpenoid alkaloids, tianshanitines A-E (1 - 5), along with ten known compounds (6 - 15), were isolated from the EtOH extracts of the whole plant of Delphinium tianshanicum W.T.Wang. Their structures were determined based on extensive spectroscopic analyses, including 1D- and 2D-NMR, HR-ESI-MS, and the structure of tianshanitine C (3) was confirmed by X-ray diffraction analysis. Tianshanitine A (1) is the first example of natural diterpenoid alkaloid containing a benzoyl group at C(1) position. Tianshanitine B (2) is a rare natural diterpenoid alkaloid bearing a OH group at C(16) position. Compounds 1 - 5, 6, 8, 10, 12 and 14 were evaluated for cytotoxicity against HCT116, MCF-7 and HepG2 human cancer cell lines. PMID- 27936491 TI - Intrinsic alpha helix propensities compact hydrodynamic radii in intrinsically disordered proteins. AB - Proteins that lack tertiary stability under normal conditions, known as intrinsically disordered, exhibit a wide range of biological activities. Molecular descriptions for the biology of intrinsically disordered proteins (IDPs) consequently rely on disordered structural models, which in turn require experiments that assess the origins to structural features observed. For example, while hydrodynamic size is mostly insensitive to sequence composition in chemically denatured proteins, IDPs show strong sequence-specific effects in the hydrodynamic radius (Rh ) when measured under normal conditions. To investigate sequence-modulation of IDP Rh , disordered ensembles generated by a hard sphere collision model modified with a structure-based parameterization of the solution energetics were used to parse the contributions of net charge, main chain dihedral angle bias, and excluded volume on hydrodynamic size. Ensembles for polypeptides 10-35 residues in length were then used to establish power-law scaling relationships for comparison to experimental Rh from 26 IDPs. Results showed the expected outcomes of increased hydrodynamic size from increases in excluded volume and net charge, and compaction from chain-solvent interactions. Chain bias representing intrinsic preferences for alpha helix and polyproline II (PPII ), however, modulated Rh with intricate dependence on the simulated propensities. PPII propensities at levels expected in IDPs correlated with heightened Rh sensitivity to even weak alpha helix propensities, indicating bias for common (phi, psi) are important determinants of hydrodynamic size. Moreover, data show that IDP Rh can be predicted from sequence with good accuracy from a small set of physicochemical properties, namely intrinsic conformational propensities and net charge. Proteins 2017; 85:296-311. (c) 2016 Wiley Periodicals, Inc. PMID- 27936493 TI - New additions to the ClusPro server motivated by CAPRI. AB - The heavily used protein-protein docking server ClusPro performs three computational steps as follows: (1) rigid body docking, (2) RMSD based clustering of the 1000 lowest energy structures, and (3) the removal of steric clashes by energy minimization. In response to challenges encountered in recent CAPRI targets, we added three new options to ClusPro. These are (1) accounting for small angle X-ray scattering data in docking; (2) considering pairwise interaction data as restraints; and (3) enabling discrimination between biological and crystallographic dimers. In addition, we have developed an extremely fast docking algorithm based on 5D rotational manifold FFT, and an algorithm for docking flexible peptides that include known sequence motifs. We feel that these developments will further improve the utility of ClusPro. However, CAPRI emphasized several shortcomings of the current server, including the problem of selecting the right energy parameters among the five options provided, and the problem of selecting the best models among the 10 generated for each parameter set. In addition, results convinced us that further development is needed for docking homology models. Finally, we discuss the difficulties we have encountered when attempting to develop a refinement algorithm that would be computationally efficient enough for inclusion in a heavily used server. Proteins 2017; 85:435-444. (c) 2016 Wiley Periodicals, Inc. PMID- 27936495 TI - T-bet over-expression regulates aryl hydrocarbon receptor-mediated T helper type 17 differentiation through an interferon (IFN)gamma-independent pathway. AB - Various transcription factors are also known to enhance or suppress T helper type 17 (Th17) differentiation. We have shown previously that the development of collagen-induced arthritis was suppressed in T-bet transgenic (T-bet Tg) mice, and T-bet seemed to suppress Th17 differentiation through an interferon (IFN) gamma-independent pathway, although the precise mechanism remains to be clarified. The present study was designed to investigate further the mechanisms involved in the regulation of Th17 differentiation by T-bet over-expression, and we found the new relationship between T-bet and aryl hydrocarbon receptor (AHR). Both T-bet Tg mice and IFN-gamma-/- -over-expressing T-bet (T-bet Tg/IFN-gamma-/- ) mice showed inhibition of retinoic acid-related orphan receptor (ROR)gammat expression and IL-17 production by CD4+ T cells cultured under conditions that promote Th-17 differentiation, and decreased IL-6 receptor (IL-6R) expression and signal transducer and activator of transcription-3 (STAT-3) phosphorylation in CD4+ T cells. The mRNA expression of ahr and rorc were suppressed in CD4+ T cells cultured under Th-17 conditions from T-bet Tg mice and T-bet Tg/IFN-gamma-/- mice. CD4+ T cells of wild-type (WT) and IFN-gamma-/- mice transduced with T-bet expressing retrovirus also showed inhibition of IL-17 production, whereas T-bet transduction had no effect on IL-6R expression and STAT-3 phosphorylation. Interestingly, the mRNA expression of ahr and rorc were suppressed in CD4+ T cells with T-bet transduction cultured under Th17 conditions. The enhancement of interleukin (IL)-17 production from CD4+ T cells by the addition of AHR ligand with Th17 conditions was cancelled by T-bet over-expression. Our findings suggest that T-bet over-expression-induced suppression of Th17 differentiation is mediated through IFN-gamma-independent AHR suppression. PMID- 27936496 TI - Simultaneous stimulation of sedoheptulose 1,7-bisphosphatase, fructose 1,6 bisphophate aldolase and the photorespiratory glycine decarboxylase-H protein increases CO2 assimilation, vegetative biomass and seed yield in Arabidopsis. AB - In this article, we have altered the levels of three different enzymes involved in the Calvin-Benson cycle and photorespiratory pathway. We have generated transgenic Arabidopsis plants with altered combinations of sedoheptulose 1,7 bisphosphatase (SBPase), fructose 1,6-bisphophate aldolase (FBPA) and the glycine decarboxylase-H protein (GDC-H) gene identified as targets to improve photosynthesis based on previous studies. Here, we show that increasing the levels of the three corresponding proteins, either independently or in combination, significantly increases the quantum efficiency of PSII. Furthermore, photosynthetic measurements demonstrated an increase in the maximum efficiency of CO2 fixation in lines over-expressing SBPase and FBPA. Moreover, the co expression of GDC-H with SBPase and FBPA resulted in a cumulative positive impact on leaf area and biomass. Finally, further analysis of transgenic lines revealed a cumulative increase of seed yield in SFH lines grown in high light. These results demonstrate the potential of multigene stacking for improving the productivity of food and energy crops. PMID- 27936499 TI - The anatomy of mammalian sweet taste receptors. AB - All sweet-tasting compounds are detected by a single G-protein coupled receptor (GPCR), the heterodimer T1R2-T1R3, for which no experimental structure is available. The sweet taste receptor is a class C GPCR, and the recently published crystallographic structures of metabotropic glutamate receptor (mGluR) 1 and 5 provide a significant step forward for understanding structure-function relationships within this family. In this article, we recapitulate more than 600 single point site-directed mutations and available structural data to obtain a critical alignment of the sweet taste receptor sequences with respect to other class C GPCRs. Using this alignment, a homology 3D-model of the human sweet taste receptor is built and analyzed to dissect out the role of key residues involved in ligand binding and those responsible for receptor activation. Proteins 2017; 85:332-341. (c) 2016 Wiley Periodicals, Inc. PMID- 27936498 TI - Invasive exotic shrub modifies a classic animal-habitat relationship and alters patterns of vertebrate seed predation. AB - Recent evidence suggests that invasive exotic plants can provide novel habitats that alter animal behavior. However, it remains unclear whether classic animal habitat associations that influence the spatial distribution of plant-animal interactions, such as small mammal use of downed woody debris, persist in invaded habitats. We removed an invasive exotic shrub (buckthorn, Rhamnus cathartica) from 7 of 15 plots in Wisconsin. In each plot, we deployed 200 tagged Quercus rubra seeds in November 2014. After five months, tags were recovered to track spatial patterns of small mammal seed predation. Most recovered tags were associated with consumed seeds (95%); live-trapping, ancillary camera-trapping, and previous behavioral studies suggest that white-footed mice (Peromyscus leucopus) were responsible for most seed predation. In habitats without R. cathartica, most seed predation occurred near woody debris. In habitats with R. cathartica, small mammals rarely consumed seeds near woody debris, and seed predation occurred farther from the plot center and was less spatially clustered. Our results illustrate that invasive exotic shrubs can disrupt an otherwise common animal-habitat relationship. Failing to account for changes in habitat use may diminish our ability to predict animal distributions and outcomes of species interactions in novel habitats created by invasive exotic plants. PMID- 27936497 TI - Proinflammatory cytokine interferon-gamma and microbiome-derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease. AB - Coeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (Treg ) are CD4+ CD25++ forkhead box protein 3 (FoxP3+ ) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 Delta2, cannot properly down-regulate the Th17-driven immune response. As the active state of CD has been associated with impairments in Treg cell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 Delta2 isoform over FL, while both isoforms were expressed similarly in non-coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate-producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)-gamma and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial-derived metabolites. PMID- 27936500 TI - Sodium co-limits and catalyzes macronutrients in a prairie food web. AB - Nitrogen and phosphorus frequently limit terrestrial plant production, but have a mixed record in regulating the abundance of terrestrial invertebrates. We contrasted four ways that Na could interact with an NP fertilizer to shape the plants and invertebrates of an inland prairie. We applied NP and Na to m2 plots in a factorial design. Aboveground invertebrate abundance was independently co limited by NaCl and NP, but with +NP plots supporting more individuals. We suggest the disparity arises because NP enhanced plant height by 35% (1 SD) over controls, providing both food and habitat, whereas NaCl provides only food. Belowground invertebrates showed evidence of serial co-limitation, where NaCl additions alone were ineffectual, but catalyzed access to NP. This suggests the increased belowground food availability in NP plots increased Na demand. Na and NP supply rates vary with climate, land use, and with inputs like urine. The co limitation and catalysis of N and P by Na thus has the potential for predicting patterns of abundance and diversity across spatial scales. PMID- 27936502 TI - Commentary on Morgenstern et al. (2017): Party-themed advertisements and initiation of alcohol consumption. PMID- 27936503 TI - Commentary on Niemela et al. (2017): Maternal smoking during pregnancy-an independent risk factor of postnatal health disorders. PMID- 27936504 TI - Prolonged mental health effects of ethylphenidate beyond cessation of use. PMID- 27936505 TI - Commentary on Bora & Zorlu (2017): Social cognition deficits in addiction-an attachment problem? PMID- 27936508 TI - Commentary on Vrolijk et al. (2017): The paradox of the quality control problem. PMID- 27936507 TI - The need for a comprehensive framework. PMID- 27936509 TI - Corrigendum. PMID- 27936510 TI - Systematic evaluation of CS-Rosetta for membrane protein structure prediction with sparse NOE restraints. AB - We critically test and validate the CS-Rosetta methodology for de novo structure prediction of alpha-helical membrane proteins (MPs) from NMR data, such as chemical shifts and NOE distance restraints. By systematically reducing the number and types of NOE restraints, we focus on determining the regime in which MP structures can be reliably predicted and pinpoint the boundaries of the approach. Five MPs of known structure were used as test systems, phototaxis sensory rhodopsin II (pSRII), a subdomain of pSRII, disulfide binding protein B (DsbB), microsomal prostaglandin E2 synthase-1 (mPGES-1), and translocator protein (TSPO). For pSRII and DsbB, where NMR and X-ray structures are available, resolution-adapted structural recombination (RASREC) CS-Rosetta yields structures that are as close to the X-ray structure as the published NMR structures if all available NMR data are used to guide structure prediction. For mPGES-1 and Bacillus cereus TSPO, where only X-ray crystal structures are available, highly accurate structures are obtained using simulated NMR data. One main advantage of RASREC CS-Rosetta is its robustness with respect to even a drastic reduction of the number of NOEs. Close-to-native structures were obtained with one randomly picked long-range NOEs for every 14, 31, 38, and 8 residues for full-length pSRII, the pSRII subdomain, TSPO, and DsbB, respectively, in addition to using chemical shifts. For mPGES-1, atomically accurate structures could be predicted even from chemical shifts alone. Our results show that atomic level accuracy for helical membrane proteins is achievable with CS-Rosetta using very sparse NOE restraint sets to guide structure prediction. Proteins 2017; 85:812-826. (c) 2016 Wiley Periodicals, Inc. PMID- 27936512 TI - Genome editing of the disease susceptibility gene CsLOB1 in citrus confers resistance to citrus canker. AB - Citrus is a highly valued tree crop worldwide, while, at the same time, citrus production faces many biotic challenges, including bacterial canker and Huanglongbing (HLB). Breeding for disease-resistant varieties is the most efficient and sustainable approach to control plant diseases. Traditional breeding of citrus varieties is challenging due to multiple limitations, including polyploidy, polyembryony, extended juvenility and long crossing cycles. Targeted genome editing technology has the potential to shorten varietal development for some traits, including disease resistance. Here, we used CRISPR/Cas9/sgRNA technology to modify the canker susceptibility gene CsLOB1 in Duncan grapefruit. Six independent lines, DLOB 2, DLOB 3, DLOB 9, DLOB 10, DLOB 11 and DLOB 12, were generated. Targeted next-generation sequencing of the six lines showed the mutation rate was 31.58%, 23.80%, 89.36%, 88.79%, 46.91% and 51.12% for DLOB 2, DLOB 3, DLOB 9, DLOB 10, DLOB 11 and DLOB 12, respectively, of the cells in each line. DLOB 2 and DLOB 3 showed canker symptoms similar to wild type grapefruit, when inoculated with the pathogen Xanthomonas citri subsp. citri (Xcc). No canker symptoms were observed on DLOB 9, DLOB 10, DLOB 11 and DLOB 12 at 4 days postinoculation (DPI) with Xcc. Pustules caused by Xcc were observed on DLOB 9, DLOB 10, DLOB 11 and DLOB 12 in later stages, which were much reduced compared to that on wild-type grapefruit. The pustules on DLOB 9 and DLOB 10 did not develop into typical canker symptoms. No side effects and off-target mutations were detected in the mutated plants. This study indicates that genome editing using CRISPR technology will provide a promising pathway to generate disease-resistant citrus varieties. PMID- 27936511 TI - ZNF208 polymorphisms associated with ischemic stroke in a southern Chinese Han population. AB - BACKGROUND: Ischemic stroke is one of the most common diseases with a high burden of neurological deficits, disability and death. Zinc finger protein 208 (ZNF208) was found to be involved in coronary heart disease, although little information is available about its association with ischemic stroke. We performed the present case-control study to clarify the association between single-nucleotide polymorphisms (SNPs) within ZNF208 and the risk of ischemic stroke in a southern Chinese Han population. METHODS: A total of 799 subjects (400 cases and 399 healthy controls) were enrolled in the present study. Five SNPs within ZNF208 gene were selected and genotyped using Sequenom MassARRY technology (Sequenom, Inc., San Diego, CA, USA). Data management and statistical analyses were conducted using Sequenom Typer, version 4.0, and a chi-squared test, as well as unconditional logistic regression. RESULTS: Statistical results showed that three variants were associated with the risk of ischemic stroke under allele models (rs2188971, rs2188972, rs8103163 and rs7248488). The variant rs2188972 was also associated with the risk of ischemic stroke in a recessive model after adjustment for age and sex. Haplotype analysis suggested that a significant difference existed between the Ars2188972 Trs2188971 Ars8103163 Ars7248488 haplotype and the risk of ischemic stroke, although this disappeared after adjustment for sex and age. CONCLUSIONS: The results obtained in the present study indicate a potential association between ZNF208 variants and the risk of ischemic risk in a southern Chinese Han population. PMID- 27936513 TI - Probing the structural dynamics of the CRISPR-Cas9 RNA-guided DNA-cleavage system by coarse-grained modeling. AB - In the adaptive immune systems of many bacteria and archaea, the Cas9 endonuclease forms a complex with specific guide/scaffold RNA to identify and cleave complementary target sequences in foreign DNA. This DNA targeting machinery has been exploited in numerous applications of genome editing and transcription control. However, the molecular mechanism of the Cas9 system is still obscure. Recently, high-resolution structures have been solved for Cas9 in different structural forms (e.g., unbound forms, RNA-bound binary complexes, and RNA-DNA-bound tertiary complexes, corresponding to an inactive state, a pre target-bound state, and a cleavage-competent or product state), which offered key structural insights to the Cas9 mechanism. To further probe the structural dynamics of Cas9 interacting with RNA and DNA at the amino-acid level of details, we have performed systematic coarse-grained modeling using an elastic network model and related analyses. Our normal mode analysis predicted a few key modes of collective motions that capture the observed conformational changes featuring large domain motions triggered by binding of RNA and DNA. Our flexibility analysis identified specific regions with high or low flexibility that coincide with key functional sites (such as DNA/RNA-binding sites, nuclease cleavage sites, and key hinges). We also identified a small set of hotspot residues that control the energetics of functional motions, which overlap with known functional sites and offer promising targets for future mutagenesis efforts to improve the specificity of Cas9. Finally, we modeled the conformational transitions of Cas9 from the unbound form to the binary complex and then the tertiary complex, and predicted a distinct sequence of domain motions. In sum, our findings have offered rich structural and dynamic details relevant to the Cas9 machinery, and will guide future investigation and engineering of the Cas9 systems. Proteins 2017; 85:342-353. (c) 2016 Wiley Periodicals, Inc. PMID- 27936514 TI - Comparing acquired angioedema with hereditary angioedema (types I/II): findings from the Icatibant Outcome Survey. AB - Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1-INH-HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor deficiency (C1-INH-AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1-INH-AAE and compare disease characteristics with those with C1-INH-HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6-month intervals during patient follow up visits. In the icatibant-treated population, 16 patients with C1-INH-AAE had 287 attacks and 415 patients with C1-INH-HAE types I/II had 2245 attacks. Patients with C1-INH-AAE versus C1-INH-HAE types I/II were more often male (69 versus 42%; P = 0.035) and had a significantly later mean (95% confidence interval) age of symptom onset [57.9 (51.33-64.53) versus 14.0 (12.70-15.26) years]. Time from symptom onset to diagnosis was significantly shorter in patients with C1-INH-AAE versus C1-INH-HAE types I/II (mean 12.3 months versus 118.1 months; P = 0.006). Patients with C1-INH-AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P = 0.064). Overall, angioedema attacks were more severe in patients with C1-INH-HAE types I/II versus C1-INH-AAE (61 versus 40% of attacks were classified as severe to very severe; P < 0.001). Median total attack duration was 5.0 h and 9.0 h for patients with C1-INH-AAE versus C1-INH-HAE types I/II, respectively. PMID- 27936515 TI - Designer chemistry. PMID- 27936516 TI - Neuroprotection of hypoxic postconditioning against global cerebral ischemia through influencing posttranslational regulations of heat shock protein 27 in adult rats. AB - We previously reported that hypoxic postconditioning (HPC) ameliorated hippocampal neuronal death induced by transient global cerebral ischemia (tGCI) in adult rats. However, the mechanism of HPC-induced neuroprotection is still elusive. Notably, heat shock protein 27 (Hsp27) has recently emerged as a potent neuroprotectant in cerebral ischemia. Although its robust protective effect on stroke has been recognized, the mechanism of Hsp27-mediated neuroprotection is largely unknown. Here, we investigated the potential molecular mechanism by which HPC modulates the posttranslational regulations of Hsp27 after tGCI. We found that HPC increased expression of Hsp27 in CA1 subregion after tGCI. Inhibition of Hsp27 expression with lentivirus-mediated short hairpin RNA (shRNA) abolished the neuroprotection induced by HPC in vivo. Furthermore, pretreatment with cycloheximide, a protein synthesis inhibitor, resulted in a significant decrease in the degradation rate of Hsp27 protein in postconditioned rats, suggesting that the increase in the expression of Hsp27 after HPC might result from its decreased degradation. Next, pretreatment with leupeptin, a lysosomal inhibitor, resulted in an accumulation of Hsp27 after tGCI, indicating that autophagic pathway may be responsible for the degradation of Hsp27. We further showed that the formation of LC3-II and autophagosomes increased after tGCI. Meanwhile, the degradation of Hsp27 was suppressed and neuronal damage was reduced when blocking autophagy with 3-Methyladenine, whereas activating autophagy with rapamycin showed an opposite tendency. Lastly, we confirmed that HPC increased the expression of phosphorylated MAPKAP kinase 2 (MK2) and Hsp27 after tGCI. Also, administration of SB203580, a p38 mitogen-activated protein kinase inhibitor, decreased the expressions of phosphorylated MK2 and Hsp27. Our results suggested that inhibition of Hsp27 degradation mediated by down-regulation of autophagy may induce ischemic tolerance after HPC. Additionally, phosphorylation of Hsp27 induced by MK2 might be associated with the neuroprotection of HPC. PMID- 27936518 TI - Computational investigation of proton transfer, pKa shifts and pH-optimum of protein-DNA and protein-RNA complexes. AB - Protein-nucleic acid interactions play a crucial role in many biological processes. This work investigates the changes of pKa values and protonation states of ionizable groups (including nucleic acid bases) that may occur at protein-nucleic acid binding. Taking advantage of the recently developed pKa calculation tool DelphiPka, we utilize the large protein-nucleic acid interaction database (NPIDB database) to model pKa shifts caused by binding. It has been found that the protein's interfacial basic residues experience favorable electrostatic interactions while the protein acidic residues undergo proton uptake to reduce the energy cost upon the binding. This is in contrast with observations made for protein-protein complexes. In terms of DNA/RNA, both base groups and phosphate groups of nucleotides are found to participate in binding. Some DNA/RNA bases undergo pKa shifts at complex formation, with the binding process tending to suppress charged states of nucleic acid bases. In addition, a weak correlation is found between the pH-optimum of protein-DNA/RNA binding free energy and the pH-optimum of protein folding free energy. Overall, the pH dependence of protein-nucleic acid binding is not predicted to be as significant as that of protein-protein association. Proteins 2017; 85:282-295. (c) 2016 Wiley Periodicals, Inc. PMID- 27936517 TI - Novel biomarkers for the assessment of paediatric systemic lupus erythematosus nephritis. AB - The discovery of serum biomarkers specific for paediatric lupus nephritis (pLN) will facilitate the non-invasive diagnosis, follow-up and more appropriate use of treatment. The aim of this study was to explore the role of serum high-mobility group box 1 (HMGB1) protein, antibodies against nucleosomes (anti-NCS), complement factor C1q (anti-C1q) and glomerular basement membrane (anti-GBM) in pLN. Serum samples of 42 patients with paediatric systemic lupus erythematosus (pSLE) (22 with pLN and 20 without renal involvement), 15 patients with other autoimmune nephritis (AN) and 26 healthy controls (HCs) were examined using enzyme-linked immunosorbent assay (ELISA). The activity of both pSLE and pLN was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) tool. The levels of all four biomarkers were significantly higher in pLN compared to AN and to HCs. The anti-NCS, anti-GBM and HMGB1 serum levels were significantly higher in pLN than in pSLE without renal involvement. The anti-C1q and the HMGB1 serum levels were correlated positively with pSLE activity. The HMGB1 serum levels were also correlated positively with pLN activity. These findings suggest that serum anti-NCS, anti-GBM and HMGB1 may serve as biomarkers specific for the presence of nephritis in pSLE. HMGB1 emerged as a useful biomarker for the assessment of pLN and pSLE activity, whereas anti-C1q only of pSLE activity. PMID- 27936519 TI - A computational approach for studying antibody-antigen interactions without prior structural information: the anti-testosterone binding antibody as a case study. AB - Given the increasing exploitation of antibodies in different contexts such as molecular diagnostics and therapeutics, it would be beneficial to unravel the atomistic level properties of antibody-antigen complexes with the help of computational modeling. Thus, here we have studied the feasibility of computational tools to gather atomic scale information regarding the antibody antigen complexes solely starting from an amino acid sequence. First, we constructed a homology model for the anti-testosterone binding antibody based on the knowledge based classification of complementary determining regions (CDRs) and implicit solvent molecular dynamics simulations. To further examine whether the generated homology model is suitable for studying antibody-antigen interactions, docking calculations were carried out followed by binding free energy simulations. Our results indicate that with the antibody modeling approach presented here it is possible to construct accurate homology models for antibodies which correctly describes the antibody-antigen interactions, and produces absolute binding free-energies that are comparable with experimental values. In addition, our simulations suggest that the conformations of complementary determining regions (CDRs) may considerably change from the X-ray configuration upon solvation. In conclusion, here we have introduced an antibody modeling workflow that can be used in studying the interactions between antibody and antigen solely based on an amino acid sequence, which in turn provides novel opportunities to tune the properties of antibodies in different applications. Proteins 2017; 85:322-331. (c) 2016 Wiley Periodicals, Inc. PMID- 27936520 TI - Factors effective on peritoneal phosphorus transport and clearance in peritoneal dialysis patients?. AB - AIMS: Transport characteristics of phosphorus are different from other small solutes that are evaluated in routine peritoneal equilibration test (PET) in peritoneal dialysis (PD) patients. We aimed to evaluate peritoneal phosphorus clearance and permeability, and their relationship with peritoneal membrane transport type and creatinine clearance as well as factors affecting peritoneal phosphorus clearance. METHODS: 70 adult patients on a PD program were included in our study. Phosphorus transport status was classified according to dialysate/plasma (D/P) phosphorus at the 4th hour of PET as slow transporter (< 0.47), slow-average transporter (0.47 - 0.56), fast-average transporter (0.57 - 0.67), and fast transporter (> 0.67). We evaluated the relationship of peritoneal phosphorus clearance and transport type with PD regime, phosphorus level, and presence of residual renal function in addition to investigating factors that are effective on peritoneal phosphorus clearance. RESULTS: D/P phosphorus and peritoneal phosphorus clearance were positively correlated with D/P creatinine and peritoneal creatinine clearance, respectively. Automated PD and continuous ambulatory PD patients were similar regarding phosphorus and creatinine clearances and transport status based on D/P phosphorus. The major determinant of peritoneal phosphorus clearance was anuria status. Anuric patients had higher dialysate volume (11.6 +/- 3.0 L vs. 8.4 +/- 2.1 L, p < 0.001) and therefore higher peritoneal phosphorus clearance (61.7 +/- 15.1 L/week/1.73 m2 vs. 48.4 +/- 14.0 L/week/1.73 m2, p = 0.001). Hyperphosphatemia was present in 40% and 11% of anuric patients and those with residual renal function, respectively (p = 0.005). CONCLUSIONS: Peritoneal phosphorus transport characteristics are similar to that of creatinine. Although increased dialysis dose may increase peritoneal phosphorus clearance, it may be insufficient to prevent hyperphosphatemia in anuric patients.?. PMID- 27936521 TI - Perioperative and long-term outcomes in octogenarians after kidney transplantation: the US perspective?. AB - BACKGROUND: We aimed to study outcomes on octogenarian patients undergoing kidney transplantation in the US. METHODS: We queried the UNOS dataset from 1988 through 2013 and found 471 octogenarians transplanted during the study period. RESULTS: 86 (18.3%) were female and 385 (81.7%) were male with a mean age of 81.58 years. The octogenarians had a significantly higher incidence of diabetes, at 17.2% compared to 13.7% in the non-octogenarian group (p < 0.001). The mean donor age was 50.32 years in the octogenarian group vs. 38.02 years in the younger group (p < 0.001). The cold ischemic time of the octogenarian group was 16.72 hours vs. 14.29 hours in non-octogenarians (p < 0.001). Length of stay (LOS) was increased by 1 day in the octogenarians. We demonstrated that patients with age >= 80 have a 2.2-fold increased risk of perioperative death. The Cox analysis demonstrated that octogenarians have a 3.2-fold and 84% increased risk of graft failure and decreased survival, respectively. CONCLUSION: Octogenarians have significantly increased LOS, perioperative mortality, and rates of graft loss. Age older than 80 was an independent risk factor associated with decreased patient survival. Future studies should address differences in outcomes and quality of life of octogenarians on dialysis compared to those after kidney transplantation.?. PMID- 27936522 TI - A study comparing the safety and efficacy of febuxostat, allopurinol, and benzbromarone in Chinese gout patients: a retrospective cohort study?. AB - OBJECTIVE: To evaluate and compare the safety and efficacy of three urate lowering agents: febuxostat, allopurinol, and benzbromarone, when used to treat Chinese gout patients. METHODS: A total of 120 patients treated in our department from November 2011 to December 2014 were randomly selected and divided into four groups: febuxostat (40 mg per day), febuxostat (80 mg per day), allopurinol (100 mg, 3 * per day) or benzbromarone (50 mg per day), (n = 30 patients/group). The serum uric acid (UA) concentrations of the patients in each group were recorded and compared from week 2 through week 24 after the treatments, and all adverse events were evaluated to determine the safety of the various treatment regimens. RESULTS: Treatment with febuxostat (40 mg) significantly reduced serum UA levels to those achieved with allopurinol or benzbromarone treatment. The treatment with febuxostat (80 mg) produced the best therapeutic effect and achieved the targeted UA level as early as week 2. However, the total number of patients experiencing adverse events was significantly higher in the febuxostat 80-mg group. The incidences of abnormal liver function, hyperlipidemia, and gout flare were higher in both febuxostat treatment groups. The allopurinol group had a higher incidence of hypersensitivity, and the benzbromarone group had a higher incidence of renal dysfunction. CONCLUSION: Chinese patients treated with the 40-mg dose of febuxostat experienced a treatment effect and total rate of adverse events similar to those produced by allopurinol or benzbromarone. To achieve a better therapeutic effect, the dose of febuxostat can be elevated to 80 mg per day; however, patients receiving the higher dose must be closely monitored for signs of liver dysfunction. Febuxostat is an alternative treatment for Chinese gout patients who are at a much higher risk for severe cutaneous adverse reactions as well as for patients with a history of kidney stones.?. PMID- 27936523 TI - Single- and multiple-dose pharmacokinetics and tolerability of a paroxetine controlled-release tablet in healthy Chinese subjects?. AB - OBJECTIVES: To evaluate the pharmacokinetics of paroxetine controlled-release (CR) tablets after single and multiple oral administrations and to evaluate its safety profile in healthy Chinese subjects. METHODS: This was a phase 1, open label, single- and multiple-dose combined study. All 12 healthy subjects received a single oral dose of 25-mg paroxetine CR, followed by a washout period of 5 days. Then, the subjects received multiple oral doses of 25-mg paroxetine CR for 14 consecutive days. Serial venous blood samples were collected 96 hours after single dosing and 24 hours after the last dose in multiple-dosing. Blood samples were analyzed using LC-MS/MS. Pharmacokinetic parameters of paroxetine were calculated via noncompartmental analysis using the WinNonlin software (Pharsight Corp., Mountain View, CA, USA). RESULTS: For both single- and multiple-dose regimens, a lag time of ~ 4 hours was observed before the absorption of paroxetine CR tablet with a tmax of ~ 7 - 9 hours. From single- to multiple-dose regimens, the mean Cmax increased from 7.08 to 36.95 ng/mL, the mean AUC0-24h increased from 100.91 to 706.75 h*ng/mL, and the mean t1/2 increased from 12.3 to 83.6 hours (all p < 0.05). The point estimate and 90% confidence intervals of the Ctrough ratio indicated that the concentration of paroxetine reached steady state after 14 days of repeated dosing. The point estimate of the accumulation factor indicated that the extent of drug exposure at steady state was ~ 9 times that of single dosing. All reported adverse events were considered to be mild. CONCLUSIONS: Paroxetine CR tablet is absorbed with a delay of ~ 4 hours after oral administration, and the accumulation factor is ~ 9 at steady state. Paroxetine CR tablet is well tolerated by healthy Chinese subjects.?. PMID- 27936524 TI - Comparative pharmacodynamic effects of two clopidogrel formulations under steady state conditions in healthy Thai volunteers?. AB - OBJECTIVE: Clopidogrel is a commonly used antiplatelet aggregation agent. Compared with the reference clopidogrel product, most commercially available generic clopidogrel products contain different crystalline forms of clopidogrel. This study was aimed to compare the pharmacodynamics of a commonly used generic clopidogrel product in Thailand with the reference clopidogrel product under steady state conditions. METHODS: A multiple-dose, randomized 2-way crossover study was conducted in 32 healthy male Thai volunteers. The subjects were assigned to receive 75 mg once daily of the test or the reference product for 7 days with a 2-week wash out period. Blood samples were collected on days 1, 5, 6, and 7 prior to drug administration and at 1, 2, 3, 4, 8, 12, and 24 hours after the last dose administered. The antiplatelet aggregation effects of clopidogrel were determined by using two different ex-vivo platelet aggregation tests including the whole blood impedance assay (WBA) and the VerifyNow(r) P2Y12 assay. Both pharmacodynamic parameters, the maximal antiplatelet effect (Emax) and the areas under the antiplatelet effect-time curve (AUEC0-24h), were calculated. RESULTS: Neither the mean values of Emax (90.70 +/- 15.15 vs. 89.50 +/- 10.71% inhibition) nor of AUEC0-24h (1,892.84 +/- 657.22 vs. 1,853.58 +/- 673.95% inhibition * h) under steady-state conditions obtained using the WBA method of these two clopidogrel products were significantly different. The results obtained using the VerifyNow(r) P2Y12 assay were consistent with those of the WBA assay. CONCLUSION: This study clearly demonstrated that ex-vivo antiplatelet aggregation effect under steady-state conditions of the test product was not significantly different from the reference product.?. PMID- 27936525 TI - A case of multiple vertebral compression fractures due to glucocorticoid-induced osteoporosis in a pediatric patient with nephrotic syndrome?. AB - INTRODUCTION: Glucocorticoid therapy has a number of adverse effects, among which osteoporosis and bone fracture can be major complications. Immunosuppressive therapy for nephrotic syndrome is effective and can help to reduce the cumulative dose of glucocorticoids. Therefore, for this reason, the number of patients with nephrotic syndrome who develop glucocorticoid-related osteoporotic compression fracture is decreasing. Here we describe a pediatric case of multiple vertebral compression fractures due to glucocorticoid-induced osteoporosis during treatment for nephrotic syndrome. CASE PRESENTATION: A 12-year-old boy with nephrotic syndrome was treated with the standard corticosteroid regimen stipulated by the International Study of Kidney Disease in Children (ISKDC). Although he achieved complete remission, he suffered two episodes of relapse, and after the second such episode, the disease became resistant to the steroid therapy. Therefore, the patient received steroid pulse therapy followed by steroid tapering concomitant with cyclosporine administration. However, ~ 9 months after the start of steroid therapy, the patient developed multiple vertebral compression fractures with severe back pain. CONCLUSION: It is necessary to evaluate the state of bone at an early stage of treatment for nephrotic syndrome in children, even if the cumulative dose of glucocorticoid is not particularly high.?. PMID- 27936526 TI - Diclofenac systemic bioavailability of a topical 1% diclofenac + 3% menthol combination gel vs. an oral diclofenac tablet in healthy volunteers: a randomized, open-label, crossover study?. AB - OBJECTIVE: Evaluate systemic exposure with repeated topical application of a fixed-combination topical gel product containing 1% diclofenac sodium and 3% menthol in either of 2 formulation packages relative to oral administration. METHODS: In this phase 1, single-center, 4-way crossover study, healthy volunteers aged 18 - 50 years underwent consecutive 3-day treatment regimens in a randomly assigned sequence with each of 4 treatment groups: 4 g of topical 1% diclofenac + 3% menthol gel administered via an aluminum tube or roll-on device applied 4 times daily; 4 g of topical 1% diclofenac sodium gel (Voltaren Gel) applied 4 times daily; and oral diclofenac sodium tablets 50 mg 3 times daily. Treatment regimens were separated by 2-day washout periods. RESULTS: A total of 18 subjects enrolled and completed the study. Relative to oral administration, area under the concentration time curve from 48 to 72 hours (AUC48-72) with topical administration of 1% diclofenac + 3% menthol gel from a tube or roll on device was 16.1% (90% CI: 12.2 - 21.1%) and 14.4% (90% CI: 11.0 - 19.0%), respectively. The diclofenac/menthol combination delivered significantly higher exposures of diclofenac compared with Voltaren Gel. A higher number of adverse events (AEs) occurred with the topical diclofenac/menthol combination (61%) vs. Voltaren Gel (22%) or oral diclofenac (6%); most were local skin reactions. No difference in systemic AEs was observed among the groups. CONCLUSION: As expected, systemic exposure was significantly lower with the topical diclofenac/menthol treatment regimens compared with oral diclofenac. Local skin AEs were increased with the topical combination product, but the risk of systemic AEs was low.?. PMID- 27936527 TI - Individualized dosing of enoxaparin in a morbidly obese patient by monitoring the anti-factor Xa. PMID- 27936528 TI - Infratentorial ganglioglioma mimicking pilocytic astrocytoma. AB - Majority of tumors arising in posterior fossa in children are pilocytic astrocytoma. However, a small subset of these have a neuronal component that may either be admixed throughout with the glial component or may be segregated to one or two regions within the glial element. Interestingly, the radiological features of this subgroup are also distinctive, showing midline location, frequent cyst formation, hemorrhage, and circumscribed nature. Taken together, both radiological and pathological features can fairly predict the subgroup categorization within infratentorial gangliogliomas (GG), as has been recently elucidated. Moreover, these are characterized by distinct molecular abnormalities that are therapeutically targetable, making their recognition critical. We describe an example of infratentorial tumor with its radiology and morphological features distinct enough to place it under the category of GG, group II or pilocytic astrocytoma with gangliocytic differentiation.?. PMID- 27936529 TI - Endocrinology Update: Foreword. PMID- 27936530 TI - Endocrinology Update: Thyroid Disorders. AB - Thyroid disease affects nearly every organ system in the body. Hypothyroidism is a state of thyroid hormone insufficiency that results in decreased metabolism and secondary effects including fatigue and weight gain. Primary hypothyroidism typically is a result of autoimmune thyroiditis or iodine deficiency and is assessed by measurement of the thyroid-stimulating hormone (TSH) level. This level usually is elevated in patients with hypothyroidism and low in patients with hyperthyroidism. Levothyroxine is the treatment of choice for hypothyroidism. Hyperthyroidism is a state of thyroid hormone excess, which increases the metabolic rate and causes symptoms including anxiety and tremor. Graves disease is the most common etiology in developed countries. Patients with hyperthyroidism are evaluated with measurement of TSH and free thyroxine levels. Management options include antithyroid drugs, radioactive iodine, and surgery. Thyroid nodules are detected commonly in family medicine, and may or may not be associated with thyroid hormone abnormalities. Patients with thyroid nodules should be evaluated with TSH level measurement and thyroid ultrasonography to guide further testing. PMID- 27936531 TI - Endocrinology Update: Hirsutism. AB - Hirsutism is defined as excessive terminal hair growth, such as coarse sexual or secondary hair, that typically appears in a male growth pattern in androgen dependent areas of the female body. It can occur in men and women. Common etiologies include polycystic ovary syndrome, idiopathic hyperandrogenemia, idiopathic hirsutism, adrenal hyperplasia due to 21-hydroxylase deficiency, androgen-secreting tumors, iatrogenic hirsutism, acromegaly, Cushing syndrome, hyperprolactinemia, and hypo- or hyperthyroidism. Diagnostic guidelines are predominantly aimed at premenopausal women but an appropriate evaluation for underlying endocrinopathies in postmenopausal women and men may be required. Management is aimed at eliminating drugs that cause hirsutism when possible, evaluation of underlying hypothalamic-pituitary-gonadal axis dysregulation, and detection of androgen-secreting tumors. Pharmacotherapy options include combination estrogens-progestins, antiandrogens, 5-alpha reductase inhibitors, biguanides, gonadotropin-releasing hormone agonists, and topical ornithine decarboxylase inhibitors. Surgical excision may be needed for pituitary, adrenal, or ovarian adenomas. PMID- 27936532 TI - Endocrinology Update: Hypopituitarism. AB - Hypopituitarism is defined as a deficiency of one or more pituitary hormones due to a decline in function of the pituitary gland and/or hypothalamus, which can result in higher risks of morbidity and mortality and decreased quality of life. Although hypopituitarism is a rare condition, it commonly develops after traumatic brain injury and in the setting of functioning and nonfunctioning pituitary adenomas. The diagnosis is based on detailed investigation of symptoms of target endocrine gland function relative to the corresponding pituitary hormone deficiency. The clinical manifestations of hypopituitarism result from the degree of the specific hormone deficiency. A thorough and longitudinal history and physical examination, including visual field testing, are paramount. Management consists of prompt pharmacotherapy, surgery, and/or radiotherapy to restore normal endocrine function and quality of life. In most patients with anterior and posterior pituitary hormone deficiency, corresponding hormone replacement is the mainstay of therapy. The prognosis for patients with hypopituitarism depends on the manner of and age at presentation, degree and severity of hormonal impairment, and response to medical and surgical therapies. Patients with hypopituitarism require lifelong monitoring of serum hormone levels and symptoms of hormone deficiency or excess. PMID- 27936533 TI - Endocrinology Update: Testicular Hypogonadism. AB - Testicular hypogonadism, or androgen deficiency, is defined as a clinical condition resulting from failure of the testes to produce physiologic levels of testosterone and a normal number of spermatozoa because of disruption of the hypothalamic-pituitary-gonadal axis. Testosterone deficiency (TD) is defined as a serum level less than 300 ng/dL on a morning total testosterone test. It is estimated that more than one-third of men 45 years and older have testosterone deficiency. Associated symptoms include decreased libido, erectile dysfunction, decreased physical stamina and strength, depressed mood, fatigue, increased visceral adiposity, sleep disturbance, and/or poor concentration and memory. These conditions have a direct relationship with cardiometabolic parameters, including insulin resistance, hypertension, hyperlipidemia, and endothelial dysfunction in aging men. No single sign or symptom defines TD. Controversy exists relative to the benefits versus risks of testosterone replacement therapy in men with testicular hypogonadism. Benefits include improvements in the symptoms related to deficiency as well as cardiometabolic parameters, yet recent retrospective and observational trials have suggested an increased risk of cardiovascular mortality without a proven direct cause-and-effect relationship. PMID- 27936534 TI - Novel Platform of Cardiomyocyte Culture and Coculture via Fibroblast-Derived Matrix-Coupled Aligned Electrospun Nanofiber. AB - For cardiac tissue engineering, much attention has been given to the artificial cardiac microenvironment in which anisotropic design of scaffold and extracellular matrix (ECM) are the major cues. Here we propose poly(l-lactide-co caprolactone) and fibroblast-derived ECM (PLCL/FDM), a hybrid scaffold that combines aligned electrospun PLCL fibers and FDM. Fibroblasts were grown on the PLCL fibers for 5-7 days and subsequently decellularized to produce PLCL/FDM. Various analyses confirmed aligned, FDM-deposited PLCL fibers. Compared to fibronectin (FN)-coated electrospun PLCL fibers (control), H9c2 cardiomyoblast differentiation was significantly effective, and neonatal rat cardiomyocyte (CM) phenotype and maturation was improved on PLCL/FDM. Moreover, a coculture platform was created using multilayer PLCL/FDM in which two different cells make indirect or direct cell-cell contacts. Such coculture platforms demonstrate their feasibility in terms of higher cell viability, efficiency of target cell harvest (>95% in noncontact; 85% in contact mode), and molecular diffusion through the PLCL/FDM layer. Coculture of primary CMs and fibroblasts exhibited much better CM phenotype and improvement of CM maturity upon either direct or indirect interactions, compared to the conventional coculture systems (transwell insert and tissue culture plate (TCP)). Taken together, our platform should be very useful and have significant contributions in investigating some scientific or practical issues of crosstalks between multiple cell types. PMID- 27936535 TI - Toward Switchable Photovoltaic Effect via Tailoring Mobile Oxygen Vacancies in Perovskite Oxide Films. AB - The defect chemistry of perovskite oxides involves the cause to most of their abundant functional properties, including interface magnetism, charge transport, ionic exchange, and catalytic activity. The possibility to achieve dynamic control over oxygen anion vacancies offers a unique opportunity for the development of appealing switchable devices, which at present are commonly based on ferroelectric materials. Herein, we report the discovery of a switchable photovoltaic effect, that the sign of the open voltage and the short circuit current can be reversed by inverting the polarity of the applied field, upon electrically tailoring the distribution of oxygen vacancies in perovskite oxide films. This phenomenon is demonstrated in lateral photovoltaic devices based on both ferroelectric BiFeO3 and paraelectric SrTiO3 films, under a reversed applied field whose magnitude is much smaller than the coercivity value of BiFeO3. The migration of oxygen vacancies was directly observed by employing an advanced annular bright-field scanning transmission electron microscopy technique with in situ biasing equipment. We conclude that the band bending induced by the motion of oxygen vacancies is the driving force for the reversible switching between two photovoltaic states. The present work can provide an active path for the design of novel switchable photovoltaic devices with a wide range of transition metal oxides in terms of the ionic degrees of freedom. PMID- 27936536 TI - Photoswitchable Emission Color Change in Nanodots Containing Conjugated Polymer and Photochrome. AB - A simple approach for the preparation of conjugated polymer (CP)-based fluorescent nanodots containing photochrome (dithienylethene, DTE) is reported. The CP in the nanodots was designed to exhibit dual emissions of blue and green. The photochromic, fluorescent, composite nanodots (PNDs) were able to tune the emission color from green to blue using selective energy transfer from the CP to DTE under ultraviolet (UV) irradiation. The UV-irradiation-induced ring closure of the DTE within the PNDs provided a spectral overlap between the green emission of the CP and the absorption of DTE, leading to quenching of the green emission and, concomitantly, maintaining of the blue emission. The photoswitchable fluorescent PNDs with high on-off green fluorescence contrast were successfully applied in a living zebrafish imaging. Our design strategy provided a versatile tool for constructing a special photomodulated color-changeable nanostructure in bioimaging. PMID- 27936537 TI - Chemical Strategies for Enhancing Activity and Charge Transfer in Ultrathin Pt Nanowires Immobilized onto Nanotube Supports for the Oxygen Reduction Reaction. AB - Multiwalled carbon nanotubes (MWNTs) represent a promising support medium for electrocatalysts, especially Pt nanoparticles (NPs). The advantages of using MWNTs include their large surface area, high conductivity, as well as long-term stability. Surface functionalization of MWNTs with various terminal groups, such as -COOH, -SH, and -NH2, allows for rational electronic tuning of catalyst support interactions. However, several issues still need to be addressed for such systems. First, over the course of an electrochemical run, catalyst durability can decrease, due in part to metal NP dissolution, a process facilitated by the inherently high surface defect concentration within the support. Second, the covalent functionalization treatment of MWNTs adopted by most groups tends to lead to a loss of structural integrity of the nanotubes (NTs). To mitigate for all of these issues, we have utilized two different attachment approaches (i.e., covalent versus noncovalent) to functionalize the outer walls of pristine MWNTs and compared the catalytic performance of as-deposited ultrathin (<2 nm) 1D Pt nanowires with that of conventional Pt NPs toward the oxygen reduction reaction (ORR). Our results demonstrated that the electrochemical activity of Pt nanostructures immobilized onto functionalized carbon nanotube (CNT) supports could be dramatically improved by using ultrathin Pt nanowires (instead of NPs) with noncovalently (as opposed to covalently) functionalized CNT supports. Spectroscopic evidence corroborated the definitive presence of charge transfer between the metal catalysts and the underlying NT support, whose direction and magnitude are a direct function of (i) the terminal chemistry as well as (ii) the attachment methodology, both of which simultaneously impact upon the observed electrocatalytic performance. Specifically, the use of a noncovalent pi-pi stacking method coupled with a -COOH terminal moiety yielded the highest performance results, reported to date, for any similar system consisting of Pt (commercial NPs or otherwise) deposited onto carbon-based supports, a finding of broader interest toward the fabrication of high-performing electrocatalysts in general. PMID- 27936538 TI - Single Stage Simultaneous Electrochemical Exfoliation and Functionalization of Graphene. AB - Development of applications for graphene are currently hampered by its poor dispersion in common, low boiling point solvents. Covalent functionalization is considered as one method for addressing this challenge. To date, approaches have tended to focus upon producing the graphene and functionalizing subsequently. Herein, we describe simultaneous electrochemical exfoliation and functionalization of graphite using diazonium salts at a single applied potential for the first time. Such an approach is advantageous, compared to postfunctionalization of premade graphene, as both functionalization and exfoliation occur at the same time, meaning that monolayer or few-layer graphene can be functionalized and stabilized in situ before they aggregate. Furthermore, the N2 generated during in situ diazonium reduction is found to aid the separation of functionalized graphene sheets. The degree of graphene functionalization was controlled by varying the concentration of the diazonium species in the exfoliation solution. The formation of functionalized graphene was confirmed using Raman spectroscopy, scanning electron microscopy, transmission electron microscopy, atomic force microscopy, and X-ray photoelectron spectroscopy. The functionalized graphene was soluble in aqueous systems, and its solubility was 2 orders of magnitude higher than the nonfunctionalized electrochemically exfoliated graphene sheets. Moreover, the functionalization enhanced the charge storage capacity when used as an electrode in supercapacitor devices with the specific capacitance being highly dependent on the degree of graphene functionalization. This simple method of in situ simultaneous exfoliation and functionaliztion may aid the processing of graphene for various applications. PMID- 27936539 TI - Oriented Clay Nanotube Membrane Assembled on Microporous Polymeric Substrates. AB - Organized arrays of halloysite clay nanotubes have great potential in molecular separation, absorption, and biomedical applications. A highly oriented layer of halloysite on polyacrylonitrile porous membrane was prepared via a facile evaporation-induced method. Scanning electronic microscopy, surface attenuated total reflection Fourier transform infrared spectroscopy, and energy dispersive X ray spectroscopy mapping indicated formation of the nanoarchitecture-controlled membrane. The well-ordered nanotube coating allowed for the excellent dye rejection (97.7% for reactive black 5) with high salt permeation (86.5% for aqueous NaCl), and thus these membranes were suitable for dye purification or concentration. These well-aligned nanotubes' composite membranes also showed very good fouling resistance against dye accumulation and bovine serum albumin adsorption as compared to the pristine polyacrylonitrile or membrane coated with disordered halloysite layer. PMID- 27936540 TI - Electrostatic-Induced Assembly of Graphene-Encapsulated Carbon@Nickel-Aluminum Layered Double Hydroxide Core-Shell Spheres Hybrid Structure for High-Energy and High-Power-Density Asymmetric Supercapacitor. AB - Achieving high energy density while retaining high power density is difficult in electrical double-layer capacitors and in pseudocapacitors considering the origin of different charge storage mechanisms. Rational structural design became an appealing strategy in circumventing these trade-offs between energy and power densities. A hybrid structure consists of chemically converted graphene encapsulated carbon@nickel-aluminum layered double hydroxide core-shell spheres as spacers among graphene layers (G-CLS) used as an advanced electrode to achieve high energy density while retaining high power density for high-performance supercapacitors. The merits of the proposed architecture are as follows: (1) CLS act as spacers to avoid the close restacking of graphene; (2) highly conductive carbon sphere and graphene preserve the mechanical integrity and improve the electrical conductivity of LDHs hybrid. Thus, the proposed hybrid structure can simultaneously achieve high electrical double-layer capacitance and pseudocapacitance resulting in the overall highly active electrode. The G-CLS electrode exhibited high specific capacitance (1710.5 F g-1 at 1 A g-1) under three-electrode tests. An ASC fabricated using the G-CLS as positive electrode and reduced graphite oxide as negative electrode demonstrated remarkable electrochemical performance. The ASC device operated at 1.4 V and delivered a high energy density of 35.5 Wh kg-1 at a 670.7 W kg-1 power density at 1 A g-1 with an excellent rate capability as well as a robust long-term cycling stability of up to 10 000 cycles. PMID- 27936541 TI - Cadmium Removal from Aqueous Solution by a Deionization Supercapacitor with a Birnessite Electrode. AB - Birnessite is widely used as an excellent adsorbent for heavy metal ions and as active electrode materials for supercapacitors. The occurrence of redox reactions of manganese oxides is usually accompanied by the intercalation-deintercalation of cations during the charge-discharge processes of supercapacitors. In this study, based on the charge-discharge principle of the supercapacitor and excellent adsorption properties of birnessite, a birnessite-based electrode was used to remove Cd2+ from aqueous solutions. The Cd2+ removal mechanism and the influences of birnessite loading and pH on the removal performance were investigated. The results showed that Cd2+ was adsorbed on the surfaces and interlayers of birnessite, and the maximum electrosorption capacity of birnessite for Cd2+ was about 900.7 mg g-1 (8.01 mmol g-1), which was significantly higher than the adsorption isotherm capacity of birnessite (125.8 mg g-1). The electrosorption specific capacity of birnessite for Cd2+ increased with an increase in initial Cd2+ concentration and decreased with an increase in the loading of active birnessite. In the pH range of 3.0-6.0, the electrosorption capacity increased at first with an increase in pH and then reached equilibrium above pH 4.0. This work provides a new method for the highly efficient adsorption of Cd2+ from polluted wastewater. PMID- 27936542 TI - Contact Electrification of Individual Dielectric Microparticles Measured by Optical Tweezers in Air. AB - We measure charging of single dielectric microparticles after interaction with a glass substrate using optical tweezers to control the particle, measure its charge with a sensitivity of a few electrons, and precisely contact the particle with the substrate. Polystyrene (PS) microparticles adhered to the substrate can be selected based on size, shape, or optical properties and repeatedly loaded into the optical trap using a piezoelectric (PZT) transducer. Separation from the substrate leads to charge transfer through contact electrification. The charge on the trapped microparticles is measured from the response of the particle motion to a step excitation of a uniform electric field. The particle is then placed onto a target location of the substrate in a controlled manner. Thus, the triboelectric charging profile of the selected PS microparticle can be measured and controlled through repeated cycles of trap loading followed by charge measurement. Reversible optical trap loading and manipulation of the selected particle leads to new capabilities to study and control successive and small changes in surface interactions. PMID- 27936543 TI - Direct Electrospinning of Ultrafine Fibers with Interconnected Macropores Enabled by in Situ Mixing Microfluidics. AB - Porous ultrafine fibers are of great importance to various applications. Herein, we report a method to directly fabricate macro-porous ultrafine fibers by an in situ mixing microfluidics which allows for the simultaneous electrospinning of solution immediately after mixing. The formation mechanism of macro-pores should be attributed to the incomplete mixing coupled with nonsolvent-induced phase separation, which was elucidated by systematical investigation of various solvent systems and mixing solvents. The diameter of the macro-porous fibers can be tuned from 1.80 +/- 0.40 to 6.75 +/- 0.48 MUm by adjusting the solution concentration and the feeding rate of mixing solvent. The results indicated that macro-porous fibers exhibited higher specific surface area (48.66 +/- 8.30 m2 g-1), larger pore size (116.73 nm) and pore volume (0.169 +/- 0.007 cm3 g-1) than conventional electrospun porous fibers, enabling the high oil absorption capacities of 95.68, 57.98, and 34.82 g g-1 for silicon oil, motor oil, and peanut oil, respectively. Our method has greatly expanded the solution scope for electrospinning from stable solution systems to unstable or substable solution systems, thus providing intriguing opportunities for the investigation and fabrication of heterogeneous fibers by in situ mixing of various immiscible solvents/solutions. Our findings can serve as guidelines for the electrospinning of ultrafine fibers with interconnected macro-pores (>50 nm). PMID- 27936544 TI - Surface Surgery of the Nickel-Rich Cathode Material LiNi0.815Co0.15Al0.035O2: Toward a Complete and Ordered Surface Layered Structure and Better Electrochemical Properties. AB - A complete and ordered layered structure on the surface of LiNi0.815Co0.15Al0.035O2 (NCA) has been achieved via a facile surface-oxidation method with Na2S2O8. The field-emission transmission electron microscopy images clearly show that preoxidation of the hydroxide precursor can eliminate the crystal defects and convert Ni(OH)2 into layered beta-NiOOH, which leads to a highly ordered crystalline NCA, with its (006) planes perpendicular to the surface in the sintering process. X-ray photoelectron spectroscopy and Raman shift results demonstrate that the contents of Ni2+ and Co2+ ions are reduced with preoxidization on the surface of the hydroxide precursor. The level of Li+/Ni2+ disordering in the modified NCA determined by the peak intensity ratio I(003)/I(104) in X-ray diffraction patterns decreases. Thanks to the complete and ordered layered structure on the surface of secondary particles, lithium ions can easily intercalate/extract in the discharging-charging process, leading to greatly improved electrochemical properties. PMID- 27936545 TI - Broad Band Light Absorption and High Photocurrent of (In,Ga)N Nanowire Photoanodes Resulting from a Radial Stark Effect. AB - The photoelectrochemical properties of (In,Ga)N nanowire photoanodes are investigated using H2O2 as a hole scavenger to prevent photocorrosion. Under simulated solar illumination, In0.16Ga0.84N nanowires grown by plasma-assisted molecular beam epitaxy show a high photocurrent of 2.7 mA/cm2 at 1.2 V vs reversible hydrogen electrode. This value is almost the theoretical maximum expected from the corresponding band gap (2.8 eV) for homogeneous bulk material without taking into account surface effects. These nanowires exhibit a higher incident photon-to-current conversion efficiency over a broader wavelength range and a higher photocurrent than a compact layer with higher In content of 28%. These results are explained by the combination of built-in electric fields at the nanowire sidewall surfaces and compositional fluctuations in (In,Ga)N, which gives rise to a radial Stark effect. This effect enables spatially indirect transitions at energies much lower than the band gap. The resulting broad band light absorption leads to high photocurrents. This benefit of the radial Stark effect in (In,Ga)N nanowires for solar harvesting applications opens up the perspective to break the theoretical limit for photocurrents. PMID- 27936546 TI - Long-Term Stable Adhesion for Conducting Polymers in Biomedical Applications: IrOx and Nanostructured Platinum Solve the Chronic Challenge. AB - Conducting polymers (CPs) have frequently been described as outstanding coating materials for neural microelectrodes, providing significantly reduced impedance or higher charge injection compared to pure metals. Usability has until now, however, been limited by poor adhesion of polymers like poly(3,4 ethylenedioxythiophene) (PEDOT) to metallic substrates, ultimately precluding long-term applications. The aim of this study was to overcome this weakness of CPs by introducing two novel adhesion improvement strategies that can easily be integrated with standard microelectrode fabrication processes. Iridium Oxide (IrOx) demonstrated exceptional stability for PEDOT coatings, resulting in polymer survival over 10 000 redox cycles and 110 days under accelerated aging conditions at 60 degrees C. Nanostructured Pt was furthermore introduced as a purely mechanical adhesion promoter providing 10-fold adhesion improvement compared to smooth Pt substrates by simply altering the morphology of Pt. This layer can be realized in a very simple process that is compatible with any electrode design, turning nanostructured Pt into a universal adhesion layer for CP coatings. By the introduction of these adhesion-promoting strategies, the weakness of CP-based neural probes can ultimately be eliminated and true long term stable use of PEDOT on neural probes will be possible in future electrode generations. PMID- 27936547 TI - Ultrahigh-Performance Cu2ZnSnS4 Thin Film and Its Application in Microscale Thin Film Lithium-Ion Battery: Comparison with SnO2. AB - To develop a high-performance anode for thin-film lithium-ion batteries (TFBs, with a total thickness on the scale of micrometers), a Cu2ZnSnS4 (CZTS) thin film is fabricated by magnetron sputtering and exhibits an ultrahigh performance of 950 mAh g-1 even after 500 cycles, which is the highest among the reported CZTS for lithium storage so far. The characterization and electrochemical tests reveal that the thin-film structure and additional reactions both contribute to the excellent properties. Furthermore, the microscale TFBs with effective footprints of 0.52 mm2 utilizing the CZTS thin film as anode are manufactured by microfabrication techniques, showing superior capability than the analogous TFBs with the SnO2 thin film as anode. This work demonstrates the advantages of exploiting thin-film electrodes and novel materials into micropower sources by electronic manufacture methods. PMID- 27936548 TI - Enhanced Giant Piezoresistance Performance of Sandwiched ZnS/Si/SiO2 Radial Heterostructure Nanotubes for Nonvolatile Stress Memory with Repeatable Writing and Erasing. AB - It is a challenge to realize nonvolatile stress-writing memory. Herein, we propose a strategy to construct rewritable stress information storage devices, consisting of deliberately designing individual sandwiched ZnS/Si/SiO2 radial heterostructure nanotubes synthesized by one-step thermal evaporation method. A bulk trap-related Poole-Frenkel hopping mechanism is proposed. Carriers are localized in a narrow bandgap Si intermediate layer; moreover, incorporated impurities and heterointerface defects can serve as charge trap centers or storage mediators. Compressive strain can induce trap barrier height to decrease at relatively low operation bias voltage, whereas tensile strain can induce it to increase, resulting in a giant piezoresistance effect. After both loading compressive and tensile strains at low bias voltage, additionally, the emptying of trap states results in a high resistance state. However, the emptied trap states can be filled by applying a relatively high bias voltage without strains and, correspondingly, the memories return to low resistance state. The emptying and filling of trap states, respectively applied by strains and high electric field, result in a repeatable writing/erasing nonvolatile memory effect. The results indicate that the creation and modification of trap states in multiscale nanostructures can give an avenue to the development of novel nanodevices for rewritable nonvolatile stress sensor and memory. PMID- 27936549 TI - Mechanisms of Sodium Insertion/Extraction on the Surface of Defective Graphenes. AB - Two chemically synthesized defective graphene materials with distinctly contrasting extended structures and surface chemistry are used to prepare sodium ion battery electrodes. The difference in electrode performance between the chemically prepared graphene materials is qualified based on correlations with intrinsic structural and chemical dissimilarities. The overall effects of the materials' physical and chemical discrepancies are quantified by measuring the electrode capacities after repeated charge/discharge cycles. Solvothermal synthesized graphene (STSG) electrodes produce capacities of 92 mAh/g in sodium ion batteries after 50 cycles at 10 mA/g, while thermally exfoliated graphite oxide (TEGO) electrodes produce capacities of 248 mAh/g after 50 cycles at 100 mA/g. Solid-state 23Na nuclear magnetic resonance spectroscopy is employed to locally probe distinct sodium environments on and between the surface of the graphene layers after charge/discharge cycles that are responsible for the variations in electrode capacities. Multiple distinct sodium environments of which at least 3 are mobile during the charge-discharge cycle are found in both cases, but the majority of Na is predominantly located in an immobile site, assigned to the solid electrolyte interface (SEI) layer. Mechanisms of sodium insertion and extraction on and between the defective graphene surfaces are proposed and discussed in relation to electrode performance. This work provides a direct account of the chemical and structural environments on the surface of graphene that govern the feasibility of graphene materials for use as sodium-ion battery electrodes. PMID- 27936550 TI - NiSe2 Nanooctahedra as an Anode Material for High-Rate and Long-Life Sodium-Ion Battery. AB - In this article, we report NiSe2 nanooctahedra as a promising anode material for sodium-ion batteries (SIBs). They exhibit outstanding long-term cyclic stability (313 mAh/g after 4000 cycles at 5 A/g) and excellent high-rate capability (175 mAh/g at 20 A/g). Besides, the initial Coulombic efficiency of NiSe2 is also very impressive (over 90%). Such remarkable performances are attributed to good conductivity, structural stability, and the pseudocapacitive behavior of the NiSe2. Furthermore, the sodium ion storage mechanism of NiSe2 is first investigated by in situ XRD and ex situ XRD. These highlights give NiSe2 a competitive strength for rechargeable SIBs. PMID- 27936551 TI - High Efficiency CdS/CdSe Quantum Dot Sensitized Solar Cells with Two ZnSe Layers. AB - CdS/CdSe quantum dot sensitized solar cells (QDSCs) have been intensively investigated; however, most of the reported power conversion efficiency (PCE) is still lower than 7% due to serious charge recombination and a low loading amount of QDs. Therefore, suppressing charge recombination and enhancing light absorption are required to improve the performance of QDSCs. The present study demonstrated successful design and fabrication of QDSCs with a high efficiency of 7.24% based on CdS/CdSe QDs with two ZnSe layers inserted at the interfaces between QDs and TiO2 and electrolyte. The effects of two ZnSe layers on the performance of the QDSCs were systematically investigated. The results indicated that the inner ZnSe buffer layer located between QDs and TiO2 serves as a seed layer to enhance the subsequent deposition of CdS/CdSe QDs, which leads to higher loading amount and covering ratio of QDs on the TiO2 photoanode. The outer ZnSe layer located between QDs and electrolyte behaves as an effective passivation layer, which not only reduces the surface charge recombination, but also enhances the light harvesting. PMID- 27936552 TI - Highly Selective Xylene Sensor Based on NiO/NiMoO4 Nanocomposite Hierarchical Spheres for Indoor Air Monitoring. AB - Xylene is a hazardous volatile organic compound, which should be measured precisely for monitoring of indoor air quality. The selective detection of ppm level xylene using oxide semiconductor chemiresistors, however, remains a challenging issue. In this study, NiO/NiMoO4 nanocomposite hierarchical spheres assembled from nanosheets were prepared by hydrothermal reaction, and the potential of sensors composed of these nanocomposites to selectively detect xylene gas was investigated. The sensors based on the NiO/NiMoO4 nanocomposite hierarchical spheres exhibited high responses (maximum resistance ratio =101.5) to 5 ppm p-xylene with low cross-responses (resistance ratios <30) to 5 ppm toluene, benzene, C2H5OH, CH3COCH3, HCHO, CO, trimethylamine, and NH3. In contrast, a sensor based on pure NiO hierarchical spheres exhibited negligibly low responses to all 9 analyte gases. The gas-sensing mechanism underlying the high selectivity and response to xylene in the NiO/NiMoO4 nanocomposite hierarchical spheres is discussed in relation to the catalytic promotion of the xylene-sensing reaction by synergistic combination between NiO and NiMoO4, gas accessible hierarchical morphology, and electronic sensitization by Mo addition. Highly selective detection of xylene can pave the road toward a new solution for precise monitoring of indoor air pollution. PMID- 27936553 TI - A Thiophene-Containing Conductive Metallopolymer Using an Fe(II) Bis(terpyridine) Core for Electrochromic Materials. AB - Three Fe(II) bis(terpyridine)-based complexes with thiophene (Fe(L1)2), bithiophene (Fe(L2)2), and 3,4-ethylenedioxythiophene (Fe(L3)2) side chains were designed and synthesized for the purpose of providing two terminal active sites for electrochemical polymerization. The corresponding metallopolymers (poly Fe(Ln)2, n = 2 or 3) were synthesized on indium tin oxide (ITO)-coated glass substrates via oxidative electropolymerization of the thiophene-substituted monomers and characterized using electrochemistry, X-ray photoelectron spectroscopy, UV-vis spectroscopy, and atomic force microscopy. The film poly Fe(L2)2 was further studied for electrochromic (EC) color-switching properties and fabricated into a solid-state EC device. Poly-Fe(L2)2 films exhibit an intense MLCT absorption band at 596 nm (epsilon = 4.7 * 104 M-1 cm-1) in the UV vis spectra without any applied voltage. Upon application of low potentials (between 1.1 and 0.4 V vs Fc+/Fc), the obtained electropolymerized film exhibited great contrast with a change of transmittance percentage (DeltaT%) of 40% and a high coloration efficiency of 3823 cm2 C-1 with a switching time of 1 s. The film demonstrates commonplace stability and reversibility with a 10% loss in peak current intensity after 200 cyclic voltammetry cycles and almost no loss in change of transmittance (DeltaT%) after 900 potential switches between 1.1 and 0.4 V (vs Fc+/Fc) with a time interval of 0.75 s. The electropolymerization of Fe(L2)2 provides convenient and controllable film fabrication. Electrochromic behavior was also achieved in a solid-state device composed of a poly-Fe(L2)2 film and a polymer-supported electrolyte sandwiched between two ITO-coated glass electrodes. PMID- 27936554 TI - An Asymmetric Supercapacitor with Both Ultra-High Gravimetric and Volumetric Energy Density Based on 3D Ni(OH)2/MnO2@Carbon Nanotube and Activated Polyaniline Derived Carbon. AB - Development of a supercapacitor device with both high gravimetric and volumetric energy density is one of the most important requirements for their practical application in energy storage/conversion systems. Currently, improvement of the gravimetric/volumetric energy density of a supercapacitor is restricted by the insufficient utilization of positive materials at high loading density and the inferior capacitive behavior of negative electrodes. To solve these problems, we elaborately designed and prepared a 3D core-shell structured Ni(OH)2/MnO2@carbon nanotube (CNT) composite via a facile solvothermal process by using the thermal chemical vapor deposition grown-CNTs as support. Owing to the superiorities of core-shell architecture in improving the service efficiency of pseudocapacitive materials at high loading density, the prepared Ni(OH)2/MnO2@CNT electrode demonstrated a high capacitance value of 2648 F g-1 (1 A g-1) at a high loading density of 6.52 mg cm-2. Coupled with high-performance activated polyaniline derived carbon (APDC, 400 F g-1 at 1 A g-1), the assembled Ni(OH)2/MnO2@CNT//APDC asymmetric device delivered both high gravimetric and volumetric energy density (126.4 Wh kg-1 and 10.9 mWh cm-3, respectively), together with superb rate performance and cycling lifetime. Moreover, we demonstrate an effective approach for building a high-performance supercapacitor with high gravimetric/volumetric energy density. PMID- 27936555 TI - Low-Temperature All-Solution-Processed Transparent Silver Nanowire-Polymer/AZO Nanoparticles Composite Electrodes for Efficient ITO-Free Polymer Solar Cells. AB - We present a kind of all-solution-processed transparent conductive film comprising of silver nanowire (AgNW), polyvinyl butyral (PVB), and Al-doped ZnO nanoparticles (AZO NPs) composite (APA) by layer-by-layer blade-coating on glass substrate at low temperature. This kind of transparent APA film exhibits high transmittance at a wide range of 400-700 nm. The sheet resistance of the APA film can be as low as 21 Omega sq-1 with transmittance over 94% at 550 nm. The introduction of PVB significantly improves the APA composite adhesion to glass substrate. The overlaid coating of AZO NPs not only reduces the sheet resistance but also improves the ambient and thermal stability of the APA film. This highly conductive and transparent APA film on glass substrate is employed as the bottom electrode to fabricate high-efficiency polymer solar cells (PSCs). A power conversion efficiency of 8.98% is achieved for the PBDTTT-EFT:PC71BM PSCs employing the APA composite as transparent bottom electrode, close to 9.54% of the control device fabricated on the commercial indium tin oxide substrate. As it can be easily prepared with all-solution-processed blade-coating method at low temperature, this kind of AgNW-based composite film is promising to integrate with roll-to-roll manufacturing of flexible PSCs. PMID- 27936556 TI - Nanodiamond-Gold Nanocomposites with the Peroxidase-Like Oxidative Catalytic Activity. AB - Novel nanodiamond-gold nanocomposites (NDAus) are prepared, and their oxidative catalytic activity is examined. Gold nanoparticles are deposited on carboxylated nanodiamonds (NDs) by in situ chemical reduction of gold precursor ions to produce NDAus, which exhibit catalytic activity for the oxidation of o phenylenediamine in the presence of hydrogen peroxide similarly to a peroxidase. This remarkable catalytic activity is exhibited only by the gold nanoparticle decorated NDs and is not observed for either Au nanoparticles or NDs separately. Kinetic oxidative catalysis studies show that NDAus exhibit a ping-pong mechanism with an activation energy of 93.3 kJ mol-1, with the oxidation reaction rate being proportional to the substrate concentration. NDAus retain considerable activity even after several instances of reuse and are compatible with a natural enzyme, allowing the detection of xanthine using cascade catalysis. Association with gold nanoparticles makes NDs a good carbonic catalyst due to charge transfer at the metal-carbon interface and facilitated substrate adsorption. The results of this study suggest that diverse carbonic catalysts can be obtained by interfacial incorporation of various metal/inorganic substances. PMID- 27936557 TI - Molecular Insights into the Complex Relationship between Capacitance and Pore Morphology in Nanoporous Carbon-based Supercapacitors. AB - Electrochemical double layer capacitors, or supercapacitors, are high-power energy storage devices that consist of large surface area electrodes (filled with electrolyte) to accommodate ion packing in accordance with classical electric double layer (EDL) theory. Nanoporous carbons (NPCs) have recently emerged as a class of electrode materials with the potential to dramatically improve the capacitance of these devices by leveraging ion confinement. However, the molecular mechanisms underlying such enhancements are a clear departure from EDL theory and remain an open question. In this paper, we present the concept of ion reorganization kinetics during charge/discharge cycles, especially within highly confining subnanometer pores, which necessarily dictates the capacitance. Our molecular dynamics voltammetric simulations of ionic liquid immersed in NPC electrodes (of varying pore size distributions) demonstrate that the most efficient ion migration, and thereby largest capacitance, is facilitated by nonuniformity of shape (e.g., from cylindrical to slitlike) along nanopore channels. On the basis of this understanding, we propose that a new structural descriptor, coined as the pore shape factor, can provide a new avenue for materials optimization. These findings also present a framework to understand and evaluate ion migration kinetics within charged nanoporous materials. PMID- 27936558 TI - Interfacial Control of Ferromagnetism in Ultrathin La0.67Ca0.33MnO3 Sandwiched between CaRu1-xTixO3 (x = 0-0.8) Epilayers. AB - Controlling functionalities in oxide heterostructures remains challenging for the rather complex interfacial interactions. Here, by modifying the interface properties with chemical doping, we achieve a nontrivial control over the ferromagnetism in ultrathin La0.67Ca0.33MnO3 (LCMO) layer sandwiched between CaRu1-xTixO3 [CRTO(x)] epilayers. The Ti doping suppresses the interfacial electron transfer from CRTO(x) to LCMO side; as a result, a steadily decreased Curie temperature with increasing x, from 262 K at x = 0 to 186 K at x = 0.8, is observed for the structures with LCMO fixed at 3.2 nm. Moreover, for more insulating CRTO(x >= 0.5), the electron confinement induces an interfacial Mn eg(x2-y2) orbital order in LCMO which further attenuates the ferromagnetism. Also, in order to characterize the heterointerfaces, for the first time the doping- and thickness-dependent metal-insulator transitions in CRTO(x) films are examined. Our results demonstrate that the LCMO/CRTO(x) heterostructure could be a model system for investigating the interfacial multiple interactions in correlated oxides. PMID- 27936559 TI - Optically Active AuNR@Ag Core-Shell Nanoparticles and Hierarchical Assembly via DNA-Mediated Surface Chemistry. AB - To manipulate the chiroptical activity of plasmonic metal nanoparticles (MNPs) and control their hierarchical self-assembly are of great fundamental and technological significance; however, they remain a big challenge. Here, we in situ fabricated anisotropic bimetallic AuNR@Ag core-shell nanoparticles (AuNR@Ag NPs) capped with designed DNA molecules and systematically studied the plasmonic chiroptical properties of the individual AuNR@Ag NPs and their assemblies. The AuNR@Ag NPs were facilely prepared by employing DNA-capped Au nanorods (AuNRs) as seeds to grow Ag shells, and it was found that the as-prepared AuNR@Ag NP surfaces were encoded by the original DNA molecules through an in situ DNA "desorption and re-adsorption" dynamic process during shell overgrowth. This observation is distinctly different from the previous results that DNA molecules were embedded in the Ag shell. Interestingly, with this in situ DNA-mediated surface chemistry, plasmonic chiroptical activities were observed from individual AuNR@Ag NPs, and the chiroptical responses were conveniently manipulated over a broad optical window by simply modifying the shape anisotropy of the building blocks. Furthermore, the DNA molecules capped on the AuNR@Ag NP surface facilitate the hierarchical assembly of homogeneous and heterogeneous nanostructures with distinct chiral optical responses. PMID- 27936560 TI - Tellurophene-Based N-type Copolymers for Photovoltaic Applications. AB - Novel tellurophene-based n-type copolymers are synthesized and characterized with thermal analysis, electrochemistry, optical spectroscopy, and DFT calculations. The copolymers demonstrate reversible interactions with bromine. Through tuning of the building blocks and alkyl chains together with device engineering, the maximum power conversion efficiency of all-polymer solar cells improves from 2.8 to 4.3%, which is supported by photoluminescence, atomic force microscopy, transmission electron microscopy, the space charge limit current method, and exciton dynamic studies. These results suggest that tellurophene-based n-type copolymers are promising electron acceptors for organic solar cells and potential sensor materials for bromine detection. PMID- 27936561 TI - Stem-Cell-Membrane Camouflaging on Near-Infrared Photoactivated Upconversion Nanoarchitectures for in Vivo Remote-Controlled Photodynamic Therapy. AB - The upconversion nanoparticle (UCNP)-based photodynamic therapy (PDT) agents are promising for deep-tissue cancer treatment because they may overcome current limitations due to the shallow penetration depth of visible light. However, limited blood circulation time and poor tumor-targeting capability challenge the therapeutic efficacy of UCNP-based PDT in vivo. Here, we demonstrate intravenous injectable stem-cell-membrane-camouflaged upconversion nanoarchitectures as a biomimetic tumor PDT platform. The biomimetic PDT system is constructed by fusing mesoporous-silica-encapsulated beta-NaYF4:Yb3+,Er3+ UCNPs with stem-cell membranes. Translocation of the stem-cell membranes to the UCNPs led to the translation of multiple membrane components, bringing the membranes' long circulation and tumor-targeting capability to the resulting platform. Multiphotosensitizers were encapsulated and simultaneously activated by a 980 nm single laser because of the multicolor emission capability of the UCNP cores. In vitro and in vivo experiments demonstrate that this novel platform inherits the tumor-targeting properties of stem cells and exhibits remarkable accumulation at the tumor site. In vivo tumor PDT results show higher tumor inhibition efficacy by tail intravenous administration of this new photosensitizer-loaded system. This stem-cell-membrane-camouflaged upconversion nanoarchitecture provides artificial UCNPs with natural cell membranes and holds considerable promise for deep-tissue PDT cancer treatment by systemic administration. PMID- 27936562 TI - pH-Switchable Stratification of Colloidal Coatings: Surfaces "On Demand". AB - Stratified coatings are used to provide properties at a surface, such as hardness or refractive index, which are different from underlying layers. Although time savings are offered by self-assembly approaches, there have been no methods yet reported to offer stratification on demand. Here, we demonstrate a strategy to create self-assembled stratified coatings, which can be switched to homogeneous structures when required. We use blends of large and small colloidal polymer particle dispersions in water that self-assemble during drying because of an osmotic pressure gradient that leads to a downward velocity of larger particles. Our confocal fluorescent microscopy images reveal a distinct surface layer created by the small particles. When the pH of the initial dispersion is raised, the hydrophilic shells of the small particles swell substantially, and the stratification is switched off. Brownian dynamics simulations explain the suppression of stratification when the small particles are swollen as a result of reduced particle mobility, a drop in the pressure gradient, and less time available before particle jamming. Our strategy paves the way for applications in antireflection films and protective coatings in which the required surface composition can be achieved on demand, simply by adjusting the pH prior to deposition. PMID- 27936563 TI - Ultrahigh Thermal Rectification in Pillared Graphene Structure with Carbon Nanotube-Graphene Intramolecular Junctions. AB - In this letter, graded pillared graphene structures with carbon nanotube-graphene intramolecular junctions are demonstrated to exhibit ultrahigh thermal rectification. The designed graded two-stage pillared graphene structures are shown to have rectification values of 790.8 and 1173.0% at average temperatures 300 and 200 K, respectively. The ultrahigh thermal rectification is found to be a result of the obvious phonon spectra mismatch before and after reversing the applied thermal bias. This outcome is attributed to both the device shape asymmetry and the size asymmetric boundary thermal contacts. We also find that the significant and stable standing waves that exist in graded two-stage pillared graphene structures play an important role in this kind of thermal rectifier, and are responsible for the ultrahigh thermal rectification of the two-stage ones as well. Our work demonstrates that pillared graphene structure with SWCNT-graphene intramolecular junctions is an excellent and promising phononic device. PMID- 27936564 TI - Application of the Metal-Organic Framework [Eu(BTC)] as a Luminescent Marker for Gunshot Residues: A Synthesis, Characterization, and Toxicity Study. AB - The 3D metal-organic framework (MOF) [Eu(BTC)] (where BTC = trimesic acid) was synthesized in 20 min by a microwave-assisted hydrothermal method with a yield of 89%. A structural and spectroscopic study, performed by X-ray diffraction, thermogravimetry, and photoluminescence spectroscopy, showed that this framework has high crystallinity, thermal stability, and luminescence. This MOF had a red orange luminescence when excited with ultraviolet (UV) radiation (lambda = 254 nm) and a high potential for use as a luminescent marker for gunshot residues (GSR). When added to 9 mm nontoxic ammunition, it greatly improved quality of the crime scene investigation, allowing for direct visualization of the luminescent GSR on the shooter's hand and firearm and at the firing range using only a portable UV lamp. The marked luminescent GSR was easily collected and characterized by nondestructive techniques, including with a Video Spectral Comparator and scanning electron microscopy/energy-dispersive spectroscopy, wherein the presence of Eu3+ ions was confirmed. Furthermore, the oral acute toxicity of this MOF was assessed in adult female Wistar rats using the Organisation for Economic Cooperation and Development 423 guidelines. This study classified the MOF [Eu(BTC)] in a less toxic Globally Harmonized System category (category 5), with a LD50 (lethal dose) of 5000 mg/kg, ensuring a wide security range for its application. PMID- 27936565 TI - Heparin-Promoted Cellular Uptake of the Cell-Penetrating Glycosaminoglycan Binding Peptide, GBPECP, Depends on a Single Tryptophan. AB - A 10-residue, glycosaminoglycan-binding peptide, GBPECP, derived from human eosinophil cationic protein has been recently designated as a potent cell penetrating peptide. A model system containing peptide, glycan, and lipid was monitored by nuclear magnetic resonance (NMR) spectroscopy to determine the cell penetrating mechanism. Heparin octasaccharide with dodecylphosphocholine (DPC) lipid micelle was titrated into the GBPECP solution. Our data revealed substantial roles for the charged residues Arg5 and Lys7 in recognizing heparin, whereas Arg3 had less effect. The aromatic residue Trp4 acted as an irreplaceable moiety for membrane insertion, as the replacement of Trp4 with Arg4 abolished cell penetration, although it significantly improved the heparin-binding ability. GBPECP bound either heparin or lipid in the presence or absence of the other ligand indicating that the peptide has two alternative binding sites: Trp4 is responsible for lipid insertion, and Arg5 and Lys7 are for GAG binding. We developed a molecular model showing that the two effects synergistically promote the penetration. The loss of either effect would abolish the penetration. GBPECP has been proven to enter cells through macropinocytosis. The GBPECP treatment inhibited A549 lung cancer cell migration and invasion, implying that the cellular microenvironment would be modulated by GBPECP internalization. The intracellular penetration of GBPECP leading to inhibition of epithelial cell migration and invasion depends on the presence of the tryptophan residue in its sequence compared with similar derivative peptides. Therefore, GBPECP shows substantial potential as a novel delivery therapeutic through rapid and effective internalization and interference with cell mobility. PMID- 27936567 TI - Magnesium-Assisted Continuous Growth of Strongly Iron-Enriched Incisors. AB - Teeth are an excellent example where optimally designed nanoarchitectures with precisely constructed components consist of simple compounds. Typically, these simple constituent phases with insignificant properties show mechanical property amplifications when formed into composite architectures. Material properties of functional composites are generally regulated on the nanoscale, which makes their characterization particularly demanding. Using advanced analytical and imaging transmission electron microscopy techniques, we identified innovative microstructural adjustments combined with astonishing compositional adaptations in incisors of coypu. Unique constituents, recognized as an additional amorphous Fe-rich surface layer followed by a transition zone covering pigmented enamel, provide the required structural stability to withstand repeated mechanical load. The chemically diverse Fe-rich surface layer, including ferrihydrite and iron calcium phosphates, gives the typical orange-brown coloration to the incisors. Within the spaces between elongated hydroxyapatite crystals in the pigmented enamel, only ferrihydrite was found, implying that enamel pigmentation is a very strictly controlled process. Most significantly, an unprecedentedly high amount of Mg was measured in the amorphous flake-like material within the dentinal tubules of the incisors, suggesting the presence of a (Mg,Ca) phosphate phase. This unusually high influx of Mg into the dentin of incisors, but not molars, suggests a substantial functionality of Mg in the initial formation stages and constant growth of incisors. The present results emphasize the strong mutual correlation among the microstructure, chemical composition, and mechanical properties of mineralized dental tissues. PMID- 27936568 TI - Small Structures, Big Droplets: The Role of Nanoscience in Fog Harvesting. AB - Designing materials for water harvesting has gained much attention in recent years as water scarcity continues to be one of the biggest problems facing mankind. In this issue of ACS Nano, Xu et al. propose a new device for harvesting water from fog. They use conically shaped copper wires with periodic roughness to enhance condensation and transport of water drops. While the periodic roughness enhances drop coalescence and motion, the conical shape of the wires guides the drops in a specific direction. Together, a self-sustained water-harvesting system is described which does not require additional external stimulus but makes use of a smart design and economic production. PMID- 27936566 TI - A Chemical Biology Solution to Problems with Studying Biologically Important but Unstable 9-O-Acetyl Sialic Acids. AB - 9-O-Acetylation is a common natural modification on sialic acids (Sias) that terminate many vertebrate glycan chains. This ester group has striking effects on many biological phenomena, including microbe-host interactions, complement action, regulation of immune responses, sialidase action, cellular apoptosis, and tumor immunology. Despite such findings, 9-O-acetyl sialoglycoconjugates have remained largely understudied, primarily because of marked lability of the 9-O acetyl group to even small pH variations and/or the action of mammalian or microbial esterases. Our current studies involving 9-O-acetylated sialoglycans on glycan microarrays revealed that even the most careful precautions cannot ensure complete stability of the 9-O-acetyl group. We now demonstrate a simple chemical biology solution to many of these problems by substituting the oxygen atom in the ester with a nitrogen atom, resulting in sialic acids with a chemically and biologically stable 9-N-acetyl group. We present an efficient one-pot multienzyme method to synthesize a sialoglycan containing 9-acetamido-9-deoxy-N acetylneuraminic acid (Neu5Ac9NAc) and compare it to the one with naturally occurring 9-O-acetyl-N-acetylneuraminic acid (Neu5,9Ac2). Conformational resemblance of the two molecules was confirmed by computational molecular dynamics simulations. Microarray studies showed that the Neu5Ac9NAc-sialoglycan is a ligand for viruses naturally recognizing Neu5,9Ac2, with a similar affinity but with much improved stability in handling and study. Feeding of Neu5Ac9NAc or Neu5,9Ac2 to mammalian cells resulted in comparable incorporation and surface expression as well as binding to 9-O-acetyl-Sia-specific viruses. However, cells fed with Neu5Ac9NAc remained resistant to viral esterases and showed a slower turnover. This simple approach opens numerous research opportunities that have heretofore proved intractable. PMID- 27936569 TI - Probing the Binding Interfaces of Histone-Aptamer by Photo Cross-Linking Mass Spectrometry. AB - Histone proteins, which could interact with DNA, play important roles in the regulation of chromatin structures, transcription, and other DNA-based biological processes. Here, we developed a novel aptamer-based probe for the analysis of histone H4-aptamer interfaces. This probe contains a DNA sequence for specific recognition of histone H4, a biotin tag for affinity enrichment, an aryl azide photoactive group for cross-linking and a cleavable disulfide group to dissociate aptamer from labeled histones. We successfully achieved specific enrichment of histone H4 and further developed a new analysis strategy for histone-aptamer interaction by photo cross-linking mass spectrometry. The binding area of histone H4 to aptamer was investigated and discussed for the first time. This strategy exhibits great potential and might further contribute to the understanding of histone-DNA interaction patterns. PMID- 27936570 TI - Magnetic Gold Confined in Ordered Mesoporous Titania Thin Films: A Noble Approach for Magnetic Devices. AB - In the past decade, the surprising magnetic behavior of gold nanoparticles has been reported. This unexpected property is mainly attributed both to size and surface effects. Mesoporous thin films are ideal matrices for metallic nanoparticles inclusion, because of their highly accessible and tailorable pore systems that lead to completely tunable chemical environments. Exploiting these features, we synthesized Au nanoparticles within mesoporous titania thin films (film thickness of ~150 nm and pore diameter of ~5 nm), and we studied their magnetic properties under confinement. Here, we present the results of the magnetization as a function of temperature and magnetic field for this system, which are consistent with the previously reported for free (unconfined) thiol capped gold nanoparticles. The successful inclusion of stable magnetic Au nanoparticles within transparent mesoporous thin films opens the gates for the application of these nanocomposites in two-dimensional (2D) microdevices technology and magneto-optical devices. PMID- 27936571 TI - Exfoliation of Layered Topological Insulators Bi2Se3 and Bi2Te3 via Electrochemistry. AB - Among layered materials, topological insulators such as Bi2Se3 and Bi2Te3 are lately attracting much attention due to particular electronic properties and, especially with Bi2Te3, excellent thermoelectric properties. Methods of preparation of few-layered nanosheets of Bi2Se3 and Bi2Te3 range from the bottom up chemical vapor deposition or hydrothermal synthesis from oxide precursors to the top-down mechanical exfoliation and liquid-based exfoliation supported by sonication from the natural bulk crystals. Here, we propose a simple and rapid electrochemical approach to exfoliate natural Bi2Se3 and Bi2Te3 crystals in aqueous media to single/few-layer sheets. The exfoliated materials have been characterized by scanning transmission electron microscopy, X-ray photoelectron spectroscopy, X-ray powder diffraction, high-resolution transmission electron microscopy, and Raman spectroscopy in addition to evaluation of their electrochemical properties. This electrochemical procedure represents a simple, reagent-free, and scalable method for the fabrication of single/few-layer sheets of these materials. PMID- 27936572 TI - Simultaneous Ionic Current and Potential Detection of Nanoparticles by a Multifunctional Nanopipette. AB - Nanopore sensing-based technologies have made significant progress for single molecule and single nanoparticle detection and analysis. In recent years, multimode sensing by multifunctional nanopores shows the potential to greatly improve the sensitivity and selectivity of traditional resistive-pulse sensing methods. In this paper, we showed that two label-free electric sensing modes could work cooperatively to detect the motion of 40 nm diameter spherical gold nanoparticles (GNPs) in solution by a multifunctional nanopipette. The multifunctional nanopipettes containing both nanopore and nanoelectrode (pyrolytic carbon) at the tip were fabricated quickly and cheaply. We demonstrated that the ionic current and local electrical potential changes could be detected simultaneously during the translocation of individual GNPs. We also showed that the nanopore/CNE tip geometry enabled the CNE not only to detect the translocation of single GNP but also to collectively detect several GNPs outside the nanopore entrance. The dynamic accumulation of GNPs near the nanopore entrance resulted in no detectable current changes, but was detected by the potential changes at the CNE. We revealed the motions of GNPs both outside and inside the nanopore, individually and collectively, with the combination of ionic current and potential measurements. PMID- 27936573 TI - Impurity Compensation Effect Induced by Tin Valence Change in alpha-Ga1.4Sn0.6O3 Thin Films. AB - Corundum-structured alpha-phase Ga1.4Sn0.6O3 thin films have been deposited on m plane Al2O3(300) substrates using laser molecular beam epitaxy technology. With increasing of the oxygen partial pressure, the crystal lattice of Ga1.4Sn0.6O3 films expands due to tin ions valence changes from Sn4+ to Sn2+. The resistivity of the film deposited under 3 * 10-5 Pa is 3.54 * 104 Omega.cm, which decreases by about 2 orders of magnitude than that fabricated under 3 * 10-1 Pa. The mixture valence of Sn2+ and Sn4+ ions leads to the impurity altitude compensation effect. The deep ultraviolet photodetector based on alpha-phase Ga1.4Sn0.6O3 thin films was fabricated. With the oxygen partial pressure reducing gradually, the dark current and the photocurrent increase, and the relaxation time constants diminish, respectively. PMID- 27936575 TI - Surface Imprints: Advantageous Application of Ready2use Materials for Bacterial Quartz-Crystal Microbalance Sensors. AB - Four different materials (two ab initio synthesized polyurethanes; ready-to-use: Epon1002F and poly(vinyl alcohol)/N-methyl-4(4'-formylstyryl)pyridinium methosulfate acetal) for the generation of Escherichia coli surface imprints are compared in this work. The use of commercially available, ready-to-use materials instead of self-synthesized polymers represents an innovative and convenient way of molecular imprint fabrication. This was herein investigated for large, biological templates. Fully synthesized imprint materials (polyurethanes) were developed and optimized regarding their OH excess and the use of catalyst in the polymerization reaction. No to low OH excess (0-10%) and a noncatalyzed synthesis were determined to be superior for the imprinting of the Gram-negative bacteria. Imprints were characterized using atomic force microscopy, with Epon1002F yielding the most distinguished imprints, along with a smooth surface. The imprints were afterward tested as plastic antibody coatings in a mass-sensitive quartz-crystal microbalance measurement. Dilutions of E. coli suspensions, down to a limit of detection of 1.4 * 107 CFU/mL, were successfully measured. Best results were obtained with Epon1002F and self-synthesized, stoichiometric polyurethane. Since ready-to-use Epon1002F was superior in terms of signal intensities and sensitivity, it can advantageously replace self-synthesized polymers for the generation of imprinted sensor surfaces. Easy day-to-day reproducibility and further shortening of imprint fabrication time are other advantages of employing the ready-to-use material instead of conventionally synthesized polymers. PMID- 27936574 TI - Photoluminescence Imaging of Polyfluorene Surface Structures on Semiconducting Carbon Nanotubes: Implications for Thin Film Exciton Transport. AB - Single-walled carbon nanotubes (SWCNTs) have potential to act as light-harvesting elements in thin film photovoltaic devices, but performance is in part limited by the efficiency of exciton diffusion processes within the films. Factors contributing to exciton transport can include film morphology encompassing nanotube orientation, connectivity, and interaction geometry. Such factors are often defined by nanotube surface structures that are not yet well understood. Here, we present the results of a combined pump-probe and photoluminescence imaging study of polyfluorene (PFO)-wrapped (6,5) and (7,5) SWCNTs that provide additional insight into the role played by polymer structures in defining exciton transport. Pump-probe measurements suggest exciton transport occurs over larger length scales in films composed of PFO-wrapped (7,5) SWCNTs, compared to those prepared from PFO-bpy-wrapped (6,5) SWCNTs. To explore the role the difference in polymer structure may play as a possible origin of differing transport behaviors, we performed a photoluminescence imaging study of individual polymer-wrapped (6,5) and (7,5) SWCNTs. The PFO-bpy-wrapped (6,5) SWCNTs showed more uniform intensity distributions along their lengths, in contrast to the PFO-wrapped (7,5) SWCNTs, which showed irregular, discontinuous intensity distributions. These differences likely originate from differences in surface coverage and suggest the PFO wrapping on (7,5) nanotubes produces a more open surface structure than is available with the PFO-bpy wrapping of (6,5) nanotubes. The open structure likely leads to improved intertube coupling that enhances exciton transport within the (7,5) films, consistent with the results of our pump-probe measurements. PMID- 27936576 TI - Diffusion and Directionality of Charged Nanoparticles on Lipid Bilayer Membrane. AB - Diffusion dynamics of charged nanoparticles on the lipid membrane is of essential importance to cellular functioning. Yet a fundamental insight into electrostatics mediated diffusion dynamics of charged nanoparticles on the membrane is lacking and remains to be an urgent issue. Here we present the computational investigation to uncover the pivotal role of electrostatics in the diffusion dynamics of charged nanoparticles on the lipid membrane. Our results demonstrate diffusive behaviors and directional transport of a charged nanoparticle, significantly depending on the sign and spatial distribution of charges on its surface. In contrast to the Fickian diffusion of neutral nanoparticles, randomly charged nanoparticles undergo superdiffusive transport with directionality. However, the dynamics of uniformly charged nanoparticles favors Fickian diffusion that is significantly enhanced. Such observations can be explained in term of electrostatics-induced surface reconstruction and fluctuation of lipid membrane. We finally present an analytical model connecting surface reconstruction and local deformation of the membrane. Our findings bear wide implications for the understanding and control of the transport of charged nanoparticles on the cell membrane. PMID- 27936577 TI - Precise Coating of a Wide Range of DNA Templates by a Protein Polymer with a DNA Binding Domain. AB - Emerging DNA-based nanotechnologies would benefit from the ability to modulate the properties (e.g., solubility, melting temperature, chemical stability) of diverse DNA templates (single molecules or origami nanostructures) through controlled, self-assembling coatings. We here introduce a DNA coating agent, called C8-BSso7d, which binds to and coats with high specificity and affinity, individual DNA molecules as well as folded origami nanostructures. C8-BSso7d coats and protects without condensing, collapsing or destroying the spatial structure of the underlying DNA template. C8-BSso7d combines the specific nonelectrostatic DNA binding affinity of an archeal-derived DNA binding domain (Sso7d, 7 kDa) with a long hydrophilic random coil polypeptide (C8, 73 kDa), which provides colloidal stability (solubility) through formation of polymer brushes around the DNA templates. C8-BSso7d is produced recombinantly in yeast and has a precise (but engineerable) amino acid sequence of precise length. Using electrophoresis, AFM, and fluorescence microscopy we demonstrate protein coat formation with stiffening of one-dimensional templates (linear dsDNA, supercoiled dsDNA and circular ssDNA), as well as coat formation without any structural distortion or disruption of two-dimensional DNA origami template. Combining the programmability of DNA with the nonperturbing precise coating capability of the engineered protein C8-BSso7d holds promise for future applications such as the creation of DNA-protein hybrid networks, or the efficient transfection of individual DNA nanostructures into cells. PMID- 27936578 TI - Colloidal Cluster Assembly into Ordered Superstructures via Engineered Directional Binding. AB - Recent experimental studies have demonstrated a facile route for fabricating large numbers of geometrically uniform colloidal clusters out of submicron DNA functionalized spheres. These clusters are ideally suited for use as anisotropic building blocks for hierarchical assembly of superstructures with symmetries that are otherwise inaccessible with simple spherical particles. We study computationally the self-assembly of cubic, tetrahedral, and octahedral clusters mediated by "bond spheres" that dock with the clusters at specific preferential sites, providing robust and well-defined directional bonding. We analyze the assembly process with a combination of direct molecular dynamics simulations of superstructure growth and state-of-the-art umbrella sampling techniques to compute nucleation free energy profiles. The simulations confirm the versatility and robustness of hierarchical cluster assembly but also reveal potential obstacles in the form of energetically accessible defect states. We find and study solutions for bypassing these defects that rely on appropriate selection of particle size and interparticle interaction as a function of building block shape and, therefore, provide operational guidelines for future experimental demonstrations. PMID- 27936580 TI - Matchmaking in Catalyst-Transfer Polycondensation: Optimizing Catalysts based on Mechanistic Insight. AB - Catalyst-transfer polycondensation (CTP) has emerged as a useful living, chain growth polymerization method for synthesizing conjugated (hetero)arene-based polymers with targetable molecular weights, narrow dispersities, and controllable copolymer sequences-all properties that significantly influence their performance in devices. Over the past decade, several phosphine- and carbene-ligated Ni- and Pd-based precatalysts have been shown to be effective in CTP. One current limitation is that these traditional CTP catalysts lead to nonliving, non-chain growth behavior when complex monomer scaffolds are utilized. Because these monomers are often found in the highest-performing materials, there is a significant need to identify alternative CTP catalysts. Recent mechanistic insight into CTP has laid the foundation for designing new catalysts to expand the CTP monomer scope. Building off this insight, we have designed and implemented model systems to identify effective catalysts by understanding their underlying mechanistic behaviors and systematically modifying catalyst structures to improve their chain-growth behavior. In this Account, we describe how each catalyst parameter-the ancillary ligand(s), reactive ligand(s), and transition metal-influences CTP. As an example, ancillary ligands often dictate the turnover limiting step of the catalytic cycle, and perhaps more importantly, they can be used to promote the formation of the key intermediate (a metal-arene associative complex) and its subsequent reactivity. The fidelity of this intermediate is central to the mechanism for the living, chain-growth polymerization. Reactive ligands, on the other hand, can be used to improve catalyst solubility and accelerate initiation. Additional advantages of the reactive ligand include providing access points for postpolymerization modification and synthesizing polymers directly off surfaces. While the most frequently used CTP catalysts contain nickel, palladium-based catalysts exhibit a higher functional group tolerance and broader substrate scope (e.g., monomers with boron, magnesium, tin, and gold transmetalating agents). Overall, we anticipate that applying the tools and lessons detailed in this Account to other monomers should facilitate a better "matchmaking" process that will lead to new catalyst-transfer polycondensations. PMID- 27936579 TI - Reinforcing Doses of Intravenous Cocaine Produce Only Modest Dopamine Uptake Inhibition. AB - The reinforcing efficacy of cocaine is thought to stem from inhibition of the dopamine transporter (DAT) and subsequent increases in extracellular dopamine concentrations in the brain. In humans, this hypothesis has generally been supported by positron emission tomography imaging studies where the percent of DATs occupied by cocaine is used as a measure of cocaine activity in the brain. Interpretation of these studies, however, often relies on the assumption that measures of DAT occupancy directly correspond with functional DAT blockade. In the current studies, we used in vivo and in vitro fast scan cyclic voltammetry in mice to measure dopamine uptake inhibition following varying doses of cocaine as well as two high affinity DAT inhibitors. We then compared dopamine clearance rates following these drug treatments to dopamine clearance obtained from DAT knockout mice as a proxy for complete DAT blockade. We found that administration of abused doses of cocaine resulted in approximately 2% of maximal DAT blockade. Overall, our data indicate that abused doses of cocaine produce a relatively modest degree of DA uptake inhibition, and suggest that the relationship between DAT occupancy and functional blockade of the DAT is more complex than originally posited. PMID- 27936581 TI - Comparison of the Atomic Layer Deposition of Tantalum Oxide Thin Films Using Ta(NtBu)(NEt2)3, Ta(NtBu)(NEt2)2Cp, and H2O. AB - The growth characteristics of Ta2O5 thin films by atomic layer deposition (ALD) were examined using Ta(NtBu)(NEt2)3 (TBTDET) and Ta(NtBu)(NEt2)2Cp (TBDETCp) as Ta-precursors, where tBu, Et, and Cp represent tert-butyl, ethyl, and cyclopentadienyl groups, respectively, along with water vapor as oxygen source. The grown Ta2O5 films were amorphous with very smooth surface morphology for both the Ta-precursors. The saturated ALD growth rates of Ta2O5 films were 0.77 A cycle-1 at 250 degrees C and 0.67 A cycle-1 at 300 degrees C using TBTDET and TBDETCp precursors, respectively. The thermal decomposition of the amido ligand (NEt2) limited the ALD process temperature below 275 degrees C for TBTDET precursor. However, the ALD temperature window could be extended up to 325 degrees C due to a strong Ta-Cp bond for the TBDETCp precursor. Because of the improved thermal stability of TBDETCp precursor, excellent nonuniformity of ~2% in 200 mm wafer could be achieved with a step coverage of ~90% in a deep hole structure (aspect ratio 5:1) which is promising for 3-dimensional architecture to form high density memories. Nonetheless, a rather high concentration (~7 at. %) of carbon impurities was incorporated into the Ta2O5 film using TBDETCp, which was possibly due to readsorption of dissociated ligands as small organic molecules in the growth of Ta2O5 film by ALD. Despite the presence of high carbon concentration which might be an origin of large leakage current under electric fields, the Ta2O5 film using TBDETCp showed a promising resistive switching performance with an endurance cycle as high as ~17 500 for resistance switching random access memory application. The optical refractive index of the deposited Ta2O5 films was 2.1-2.2 at 632.8 nm using both the Ta-precursors, and indirect optical band gap was estimated to be ~4.1 eV for both the cases. PMID- 27936582 TI - Solution-Based Photo-Patterned Gold Film Formation on Silicon Nitride. AB - Silicon nitride fabricated by low-pressure chemical vapor deposition (LPCVD) to be silicon-rich (SiNx), is a ubiquitous insulating thin film in the microelectronics industry, and an exceptional structural material for nanofabrication. Free-standing <100 nm thick SiNx membranes are especially compelling, particularly when used to deliver forefront molecular sensing capabilities in nanofluidic devices. We developed an accessible, gentle, and solution-based photodirected surface metallization approach well-suited to forming patterned metal films as integral structural and functional features in thin-membrane-based SiNx devices-for use as electrodes or surface chemical functionalization platforms, for example-augmenting existing device capabilities and properties for a wide range of applications. PMID- 27936583 TI - Strong Influence of Humidity on Low-Temperature Thin-Film Fabrication via Metal Aqua Complex for High Performance Oxide Semiconductor Thin-Film Transistors. AB - Oxide semiconductors thin film transistors (OS TFTs) with good transparency and electrical performance have great potential for future display technology. In particular, solution-processed OS TFTs have been attracted much attention due to many advantages such as continuous, large scale, and low cost processability. Recently, OS TFTs fabricated with a metal aqua complex have been focused because they have low temperature processability for deposition on flexible substrate as well as high field-effect mobility for application of advanced display. However, despite some remarkable results, important factors to optimize their electrical performance with reproducibility and uniformity have not yet been achieved. Here, we newly introduce the strong effects of humidity to enhance the electrical performance of OS TFTs fabricated with the metal aqua complex. Through humidity control during the spin-coating process and annealing process, we successfully demonstrate solution-processed InOx/SiO2 TFTs with a good electrical uniformity of ~5% standard deviation, showing high average field-effect mobility of 2.76 cm2V-1s-1 and 15.28 cm2V-1s-1 fabricated at 200 and 250 degrees C, respectively. Also, on the basis of the systematic analyses, we demonstrate the mechanism for the change in electrical properties of InOx TFTs depending on the humidity control. Finally, on the basis of the mechanism, we extended the humidity control to the fabrication of the AlOx insulator. Subsequently, we successfully achieved humidity-controlled InOx/AlOx TFTs fabricated at 200 degrees C showing high average field-effect mobility of 9.5 cm2V-1s-1. PMID- 27936584 TI - Highly Stable and Effective Doping of Graphene by Selective Atomic Layer Deposition of Ruthenium. AB - The sheet resistance of graphene synthesized by chemical vapor deposition is found to be significantly reduced by the selective atomic layer deposition (ALD) of Ru onto defect sites such as wrinkles and grain boundaries. With 200 ALD cycles, the sheet resistance is reduced from ~500 to <50 Omega/sq, and the p-type carrier density is drastically increased from 1013 to 1015 cm-2. At the same time, the carrier mobility is reduced from ~670 to less than 100 cm2 V-1 s-1. This doping of graphene proved to be very stable, with the electrical properties remaining unchanged over eight weeks of measurement. Selective deposition of Ru on defect sites also makes it possible to obtain a graphene film that is both highly transparent and electrically conductive (e.g., a sheet resistance of 125 Omega/sq with 92% optical transmittance at 550 nm). Highly doped graphene layers achieved by Ru ALD are therefore expected to provide a viable basis for transparent conducting electrodes. PMID- 27936585 TI - The Effects of Extensive Glomerular Filtration of Thin Graphene Oxide Sheets on Kidney Physiology. AB - Understanding how two-dimensional (2D) nanomaterials interact with the biological milieu is fundamental for their development toward biomedical applications. When thin, individualized graphene oxide (GO) sheets were administered intravenously in mice, extensive urinary excretion was observed, indicating rapid transit across the glomerular filtration barrier (GFB). A detailed analysis of kidney function, histopathology, and ultrastructure was performed, along with the in vitro responses of two highly specialized GFB cells (glomerular endothelial cells and podocytes) following exposure to GO. We investigated whether these cells preserved their unique barrier function at doses 100 times greater than the dose expected to reach the GFB in vivo. Both serum and urine analyses revealed that there was no impairment of kidney function up to 1 month after injection of GO at escalating doses. Histological examination suggested no damage to the glomerular and tubular regions of the kidneys. Ultrastructural analysis by transmission electron microscopy showed absence of damage, with no change in the size of podocyte slits, endothelial cell fenestra, or the glomerular basement membrane width. The endothelial and podocyte cell cultures regained their full barrier function after >48 h of GO exposure, and cellular uptake was significant in both cell types after 24 h. This study provided a previously unreported understanding of the interaction between thin GO sheets with different components of the GFB in vitro and in vivo to highlight that the glomerular excretion of significant amounts of GO did not induce any signs of acute nephrotoxicity or glomerular barrier dysfunction. PMID- 27936586 TI - Inspired by Stenocara Beetles: From Water Collection to High-Efficiency Water-in Oil Emulsion Separation. AB - Inspired by the water-collecting mechanism of the Stenocara beetle's back structure, we prepared a superhydrophilic bumps-superhydrophobic/superoleophilic stainless steel mesh (SBS-SSM) filter via a facile and environmentally friendly method. Specifically, hydrophilic silica microparticles are assembled on the as cleaned stainless steel mesh surface, followed by further spin-coating with a fluoropolymer/SiO2 nanoparticle solution. On the special surface of SBS-SSM, attributed to the steep surface energy gradient, the superhydrophilic bumps (hydrophilic silica microparticles) are able to capture emulsified water droplets and collect water from the emulsion even when their size is smaller than the pore size of the stainless steel mesh. The oil portion of the water-in-oil emulsion therefore permeates through pores of the superhydrophobic/superoleophilic mesh coating freely and gets purified. We demonstrated an oil recovery purity up to 99.95 wt % for surfactant-stabilized water-in-oil emulsions on the biomimetic SBS SSM filter, which is superior to that of the traditional superhydrophobic/superoleophilic stainless steel mesh (S-SSM) filter lacking the superhydrophilic bump structure. Together with a facile and environmentally friendly coating strategy, this tool shows great application potential for water in-oil emulsion separation and oil purification. PMID- 27936587 TI - Auger Up-Conversion of Low-Intensity Infrared Light in Engineered Quantum Dots. AB - One source of efficiency losses in photovoltaic cells is their transparency toward solar photons with energies below the band gap of the absorbing layer. This loss can be reduced using a process of up-conversion whereby two or more sub band-gap photons generate a single above-gap exciton. Traditional approaches to up-conversion, such as nonlinear two-photon absorption (2PA) or triplet fusion, suffer from low efficiency at solar light intensities, a narrow absorption bandwidth, nonoptimal absorption energies, and difficulties for implementing in practical devices. Here we show that these deficiencies can be alleviated using the effect of Auger up-conversion in thick-shell PbSe/CdSe quantum dots. This process relies on Auger recombination whereby two low-energy, core-based excitons are converted into a single higher-energy, shell-based exciton. Compared to their monocomponent counterparts, the tailored PbSe/CdSe heterostructures feature enhanced absorption cross-sections, a higher efficiency of the "productive" Auger pathway involving re-excitation of a hole, and longer lifetimes of both core- and shell-localized excitons. These features lead to effective up-conversion cross sections that are more than 6 orders of magnitude higher than for standard nonlinear 2PA, which allows for efficient up-conversion of continuous wave infrared light at intensities as low as a few watts per square centimeter. PMID- 27936588 TI - Identification of the Ferric-Acinetobactin Outer Membrane Receptor in Aeromonas salmonicida subsp. salmonicida and Structure-Activity Relationships of Synthetic Acinetobactin Analogues. AB - Aeromonas salmonicida subsp. salmonicida, the causative agent of furunculosis in several fish species, produces acinetobactin and amonabactin as siderophores. In a previous study, we chemically characterized these siderophores and proposed a biosynthetic pathway based on genetic analysis. However, the internalization mechanisms of ferric-acinetobactin and ferric-amonabactin remain largely unknown. In the present study, we demonstrate that the outer membrane protein FstB is the ferric-acinetobactin receptor in A. salmonicida since an fstB defective mutant is unable to grow under iron limitation and does not use acinetobactin as an iron source. In order to study the effect that structural changes in acinetobactin have on its siderophore activity, a collection of acinetobactin-based analogues was synthesized, including its enantiomer and four demethylated derivatives. The biological activity of these analogues on an fstB(+) strain compared to an fstB( ) strain allowed structure-activity relationships to be elucidated. We found a lack of enantiomer preference on the siderophore activity of acinetobactin over A. salmonicida or on the molecular recognition by FstB protein receptor. In addition, it was observed that A. salmonicida could not use acinetobactin analogues when imidazole or a similar heterocyclic ring was absent from the structure. Surprisingly, removal of the methyl group at the isoxazolidinone ring induced a higher biological activity, thus suggesting alternative route(s) of entry into the cell that must be further investigated. It is proposed that some of the synthetic acinetobactin analogues described here could be used as starting points in the development of novel drugs against A. salmonicida and probably against other acinetobactin producers like the human pathogen Acinetobacter baumannii. PMID- 27936589 TI - Molecular Understanding of Abeta-hIAPP Cross-Seeding Assemblies on Lipid Membranes. AB - Amyloid-beta (Abeta) and human islet polypeptide (hIAPP) are the causative agents responsible for Alzheimer's disease (AD) and type II diabetes (T2D), respectively. While numerous studies have reported the cross-seeding behavior of Abeta and hIAPP in solution, little effort has been made to examine the cross seeding of Abeta and hIAPP in the presence of cell membranes, which is more biologically relevant to the pathological link between AD and T2D. In this work, we computationally study the cross-seeding and adsorption behaviors of Abeta and hIAPP on zwitterionic POPC and anionic 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol (POPG) mixed bilayers using all-atom molecular dynamics (MD) simulations, particularly aiming to the effects of the initial orientation of the Abeta-hIAPP assembly and the lipid composition of cell membranes on mutual structural and interaction changes in both Abeta-hIAPP assembly and lipid bilayers at the atomic level. Abeta-hIAPP cross-seeding assembly always preferred to adopt a specific orientation and interface to associate with both lipid bilayers strongly via the N-terminal strands of Abeta. Such membrane-bound orientation explains experimental observation that hybrid Abeta-hIAPP fibrils on cell membranes showed similar morphologies to pure hIAPP fibrils. Moreover, Abeta-hIAPP assembly, regardless of its initial orientations, interacted more strongly with POPC/POPG bilayer than POPC bilayer, indicating that electrostatic interactions are the major forces governing peptide-lipid interactions. Strong electrostatic interactions were also attributed to the formation of Ca2+ bridges connecting both negatively charged Glu of Abeta and PO4 head groups of lipids, which facilitate the association of Abeta-hIAPP with the POPC/POPG bilayer. It was also found that the strong peptide-lipid binding reduced lipid fluidity. Both facts imply that Abeta-hIAPP assembly may induce cell damage by altering calcium homeostasis and cell membrane phase. This work provides a better fundamental understanding of cross-seeding of Abeta and hIAPP on cell membranes and a potential pathological link between AD and T2D. PMID- 27936590 TI - Brominated Graphene as Mimetic Peroxidase for Sulfide Ion Recognition. AB - Brominated graphene (GBR) with ~3% bromine content has shown novel peroxidase mimetic activity toward 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H2O2. Optimum activity has been observed at pH 4.48 and after a minimum ~30 min of equilibration time. Among the different analytes studied using the sensor combining TMB, H2O2, and GBR in phosphate buffer of pH 4.48, the S2- ion has effectively shown a short duration of sensing (~2 min) within the detection range of 0.04-1 mM. A calibration curve for S2- ion estimation has been constructed with the experimental linearity in 0.04-0.4 mM range and having the limit of detection (LOD) value of 25.3 MUM. A standard addition experiment has validated the method. A paper strip sensor has been fabricated for successful detection of S2- ion. PMID- 27936592 TI - Multicore Magnetic Nanoparticles Coated with Oligomeric Micelles: Characterization and Potential for the Extraction of Contaminants over a Wide Polarity Range. AB - Oligomeric micelles from sodium undecylenate (oSUD) were chemisorbed to magnetic iron oxide nanoparticles (MNPs) through a single-step synthetic route involving the simultaneous nanoparticle formation and functionalization in an aqueous medium. The resulting spherical nanoparticles (MNPs-oSUD) consisted of a concatenation of iron oxide cores, with an average size of 7.7 nm, bound by oSUD micelles (particle average diameter of ca. 200 nm). Micellar coverage was ~50% of the MNP-oSUD (by weight) and offered multiple retention mechanisms (e.g., dispersion, hydrogen bonding, polar, and ionic) for solute solubilization while keeping it intact during analyte elution. The high density of micelles and variety of interactions provided by this sorbent rendered it highly efficient for the extraction of aromatic amines in a wide polarity range (log Kow values from 0.80 to 4.05) from textiles, urine, and wastewater. Extraction took 5 min, no cleanup or evaporation of the extracts was needed and the method, based on LC MS/MS quantitation, proved matrix-independent. Recoveries for 17 aromatic amines in samples were in the range of 93%-123% while those with negative log Kow values were in the range of 69%-87%. Detection limits for aromatic amines in textiles (0.007-2 mg kg-1) were well below the limits legislated by the European Union (EU) (30 mg kg-1) and those in urine and wastewater (0.004-1.5 MUg L-1) were at the level usually found in real-world applications. All the analyzed samples were positive in aromatic amines. The easy synthesis and excellent extraction properties of MNPs-oSUD anticipate their high potential not only for multiresidue analysis but also in other fields such as water remediation. PMID- 27936593 TI - Efficient Determination of Specific Surface Area of Shale Samples Using a Tracer Based Headspace Gas Chromatographic Technique. AB - This paper reports on a novel method for determining the specific surface area (SSA) of shale via headspace gas chromatography (HS-GC). The method is based on the water adsorption on the surface of shale sample after achieving phase equilibrium at an elevated temperature (i.e., heating at 125 degrees C for 48 h). A mathematical model shows that the SSA can be determined from the signal of the vapor water released during HS-GC analysis. The results obtained by this method correlated well (R2 = 0.992) with data obtained by the reference BET method. Because the phase equilibrium step for multiple samples can be conducted simultaneously, and because the phase re-equilibrium step is much faster in the HS-GC measurement, the present method is more efficient for batch sample testing. PMID- 27936591 TI - Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer's Disease. AB - A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer's disease (AD). First-in-class dual inhibitors bearing a sildenafil core have been very recently reported, and the lead molecule 7 has proven this strategy in AD animal models. Because scaffolds may play a critical role in primary activities and ADME Tox profiling as well as on intellectual property, we have explored alternative scaffolds (vardenafil- and tadalafil-based cores) and evaluated their impact on critical parameters such as primary activities, permeability, toxicity, and in vivo (pharmacokinetics and functional response in hippocampus) to identify a potential alternative lead molecule bearing a different chemotype for in vivo testing. PMID- 27936594 TI - ICL-Based OF-CEAS: A Sensitive Tool for Analytical Chemistry. AB - Optical-feedback cavity-enhanced absorption spectroscopy (OF-CEAS) using mid infrared interband cascade lasers (ICLs) is a sensitive technique for trace gas sensing. The setup of a V-shaped optical cavity operating with a 3.29 MUm cw ICL is detailed, and a quantitative characterization of the injection efficiency, locking stability, mode matching, and detection sensitivity is presented. The experimental data are supported by a model to show how optical feedback affects the laser frequency as it is scanned across several longitudinal modes of the optical cavity. The model predicts that feedback enhancement effects under strongly absorbing conditions can cause underestimations in the measured absorption, and these predictions are verified experimentally. The technique is then used in application to the detection of nitrous oxide as an exemplar of the utility of this technique for analytical gas phase spectroscopy. The analytical performance of the spectrometer, expressed as noise equivalent absorption coefficient, was estimated as 4.9 * 10-9 cm -1 Hz-1/2, which compares well with recently reported values. PMID- 27936596 TI - Challenges Determining the Correct Deposition Order of Different Intersecting Black Inks by Time-of-Flight Secondary Ion Mass Spectrometry. AB - The distinction of different inks and determination of their deposition order are important forensic tasks when evaluating questioned documents. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) has received attention for these tasks due to the technique's nondestructive nature, rich mass spectral information, ability to provide chemical images, and excellent surface sensitivity. Prior literature results demonstrate the ability of ToF-SIMS to differentiate between many varieties of blue ballpoint pens and to determine the correct deposition order for selected ink intersections. The current work therefore sought to further study the intersections of different black inks. Three black pens were initially tested and were successfully distinguished. However, interesting phenomena were observed where certain inks dominated over others, causing distinctly incorrect conclusions to be made regarding ink deposition order. To explore whether these incorrect results could be corrected, different primary ions (Bi3+, Bi3+2, and Ar1000+) were used and positive and negative secondary ions were evaluated. In data analysis, restriction of the mass range was considered and different multivariate analysis techniques, principal component analysis (PCA) and multivariate curve resolution (MCR), were performed on the secondary ion images and spectra from selected regions of interest. Issues regarding incorrect apparent order of deposition persisted through the variation of all these parameters. In addition to ink differentiation, and deposition order, evidence of ink aging was also observed. These results raise several questions to be answered regarding the widespread use of ToF-SIMS for forensic ink analysis. PMID- 27936597 TI - Quantitating PrP Polymorphisms Present in Prions from Heterozygous Scrapie Infected Sheep. AB - Scrapie is a prion (PrPSc) disease of sheep. The incubation period of sheep scrapie is strongly influenced by polymorphisms at positions 136, 154, and 171 of a sheep's normal cellular prion protein (PrPC). Chymotrypsin was used to digest sheep recombinant PrP to identify a set of characteristic peptides [M132LGSXMSRPL141 (X = A or V), Y153XENMY158 (X,= H or R), and Y166RPVDXY172 (X = H, K, Q, or R)] that could be used to detect and quantitate polymorphisms at positions 136, 154, and 171 of sheep PrPC or PrPSc. These peptides were used to develop a multiple reaction monitoring method (MRM) to detect the amounts of a particular polymorphism in a sample of PrPSc isolated from sheep heterozygous for their PrPC proteins. The limit of detection for these peptides was less than 50 attomole. Spinal cord tissue from heterozygous (ARQ/VRQ or ARH/ARQ) scrapie infected Rasa Aragonesa sheep was analyzed using this MRM method. Both sets of heterozygotes show the presence of both polymorphisms in PrPSc. This was true for samples containing both proteinase K (PK)-sensitive and PK-resistant PrPSc and samples containing only the PK-resistant PrPSc. These results show that heterozygous animals contain PrPSc that is composed of significant amounts of both PrP polymorphisms. PMID- 27936595 TI - Physiological Mg2+ Conditions Significantly Alter the Inhibition of HIV-1 and HIV 2 Reverse Transcriptases by Nucleoside and Non-Nucleoside Inhibitors in Vitro. AB - Reverse transcriptases (RTs) are typically assayed in vitro with 5-10 mM Mg2+, whereas the free Mg2+ concentration in cells is much lower. Artificially high Mg2+ concentrations used in vitro can misrepresent different properties of human immunodeficiency virus (HIV) RT, including fidelity, catalysis, pausing, and RNase H activity. Here, we analyzed nucleoside (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) in primer extension assays at different concentrations of free Mg2+. At low concentrations of Mg2+, NRTIs and dideoxynucleotides (AZTTP, ddCTP, ddGTP, and 3TCTP) inhibited HIV-1 and HIV-2 RT synthesis less efficiently than they did with large amounts of Mg2+, whereas inhibition by the "translocation-defective RT inhibitor" EFdA (4'-ethynyl-2-fluoro-2' deoxyadenosine) was unaffected by Mg2+ concentrations. Steady-state kinetic analyses revealed that the reduced level of inhibition at low Mg2+ concentrations resulted from a 3-9-fold (depending on the particular nucleotide and inhibitor) less efficient incorporation (based on kcat/Km) of these NRTIs under this condition compared to incorporation of natural dNTPs. In contrast, EFdATP was incorporated with an efficiency similar to that of its analogue dATP at low Mg2+ concentrations. Unlike NRTIs, NNRTIs (nevirapine, efavirenz, and rilviripine), were approximately 4-fold (based on IC50 values) more effective at low than at high Mg2+ concentrations. Drug-resistant HIV-1 RT mutants also displayed the Mg2+ dependent difference in susceptibility to NRTIs and NNRTIs. In summary, analyzing the efficiency of inhibitors under more physiologically relevant low-Mg2+ conditions yielded results dramatically different from those from measurements using commonly employed high-Mg2+ in vitro conditions. These results also emphasize differences in Mg2+ sensitivity between the translocation inhibitor EFdATP and other NRTIs. PMID- 27936598 TI - Effect of N-Terminal Myristoylation on the Active Conformation of Galphai1-GTP. AB - G proteins are part of the G-protein-coupled receptor (GPCR) signal transduction cascade in which they transfer a signal from the membrane-embedded GPCR to other proteins in the cell. In the case of the inhibitory G-protein heterotrimer, permanent N-terminal myristoylation can transiently localize the Galphai subunit at the membrane as well as crucially influence Galphai's function in the GTP bound conformation. The attachment of lipids to proteins is known to be essential for membrane trafficking; however, our results suggest that lipidation is also important for protein-protein interactions during signal transduction. Here we investigate the effect of myristoylation on the structure and dynamics of soluble Galphai1 and its possible implication for signal transduction. A 2 MUs classical molecular dynamics simulation of a myristoylated Galphai1-GTP complex suggests that the myristoyl-induced conformational changes of the switch II and alpha helical domains create new possibilities for protein-protein interactions and emphasize the importance of permanent lipid attachment for the conformation and functional tunability of signaling proteins. PMID- 27936600 TI - Design and Synthesis of an Easily Obtainable Maleimide Reagent N-[2-(4 [18F]fluoro-N-methylbenzenesulfonamido)ethyl]maleimide ([18F]FBSEM) to Radiolabel Thiols in Proteins. AB - An easily obtainable thiol-selective labeling reagent [18F]FBSEM (N-[2-(4 [18F]fluoro-N-methylbenzenesulfonamido)ethyl]maleimide) was developed. The advantage of the design is that the precursor and [18F]FBSEM have the same backbone and backbone construction is not required; in contrast, known thiol specific labeling reagents do require backbone construction, and this is thought to be the cause of their complicated synthesis. [18F]FBSEM was successfully obtained in higher yield (25%) and in a simpler way (two fluorination and deprotection steps in 65 min) than the widely used [18F]FBEM (N-[2-(4 [18F]fluorobenzamide)ethyl]maleimide). The labeling efficacy of [18F]FBSEM was confirmed by conjugation with glutathione. [18F]FBSEM is a promising labeling agent for proteins. PMID- 27936599 TI - Computational and Experimental Characterization of Patient Derived Mutations Reveal an Unusual Mode of Regulatory Spine Assembly and Drug Sensitivity in EGFR Kinase. AB - The catalytic activation of protein kinases requires precise positioning of key conserved catalytic and regulatory motifs in the kinase core. The Regulatory Spine (RS) is one such structural motif that is dynamically assembled upon kinase activation. The RS is also a mutational hotspot in cancers; however, the mechanisms by which cancer mutations impact RS assembly and kinase activity are not fully understood. In this study, through mutational analysis of patient derived mutations in the RS of EGFR kinase, we identify an activating mutation, M766T, at the RS3 position. RS3 is located in the regulatory alphaC-helix, and a series of mutations at the RS3 position suggest a strong correlation between the amino acid type present at the RS3 position and ligand (EGF) independent EGFR activation. Small polar amino acids increase ligand independent activity, while large aromatic amino acids decrease kinase activity. M766T relies on the canonical asymmetric dimer for full activation. Molecular modeling and molecular dynamics simulations of WT and mutant EGFR suggest a model in which M766T activates the kinase domain by disrupting conserved autoinhibitory interactions between M766 and hydrophobic residues in the activation segment. In addition, a water mediated hydrogen bond network between T766, the conserved K745-E762 salt bridge, and the backbone amide of the DFG motif is identified as a key determinant of M766T-mediated activation. M766T is resistant to FDA approved EGFR inhibitors such as gefitinib and erlotinib, and computational estimation of ligand binding free energy identifies key residues associated with drug sensitivity. In sum, our studies suggest an unusual mode of RS assembly and oncogenic EGFR activation, and provide new clues for the design of allosteric protein kinase inhibitors. PMID- 27936602 TI - Direct Determination of Oxidation States of Uranium in Mixed-Valent Uranium Oxides Using Total Reflection X-ray Fluorescence X-ray Absorption Near-Edge Spectroscopy. AB - Total reflection X-ray fluorescence (TXRF)-based X-ray absorption near-edge spectroscopy has been used to determine the oxidation state of uranium in mixed valent U3O8 and U3O7 uranium oxides. The TXRF spectra of the compounds were measured using variable X-ray energies in the vicinity of the U L3 edge in the TXRF excitation mode at the microfocus beamline of the Indus-2 synchrotron facility. The TXRF-based X-ray absorption near-edge spectroscopy (TXRF-XANES) spectra were deduced from the emission spectra measured using the energies below and above the U L3 edge in the XANES region. The data processing using TXRF-XANES spectra of U(IV), U(V), and U(VI) standard compounds revealed that U present in U3O8 is a mixture of U(V) and U(VI), whereas U in U3O7 is mixture of U(IV) and U(VI). The results obtained in this study are similar to that reported in literature using the U M edge. The present study has demonstrated the possibility of application of TXRF for the oxidation state determination and elemental speciation of radioactive substances in a nondestructive manner with very small amount of sample requirement. PMID- 27936601 TI - Regioregular Alternating Polyampholytes Have Enhanced Biomimetic Ice Recrystallization Activity Compared to Random Copolymers and the Role of Side Chain versus Main Chain Hydrophobicity. AB - Antifreeze proteins from polar fish species are potent ice recrystallization inhibitors (IRIs) effectively stopping all ice growth. Additives that have IRI activity have been shown to enhance cellular cryopreservation with potential to improve the distribution of donor cells and tissue. Polyampholytes, polymers with both anionic and cationic side chains, are a rapidly emerging class of polymer cryoprotectants, but their mode of action and the structural features essential for activity are not clear. Here regioregular polyampholytes are synthesized from maleic anhydride copolymers to enable stoichiometric installation of the charged groups, ensuring regioregularity, which is not possible using conventional random copolymerization. A modular synthetic strategy is employed to enable the backbone and side chain hydrophobicity to be varied, with side chain hydrophobicity found to have a profound effect on the IRI activity. The activity of the regioregular polymers was found to be superior to those derived from a standard random copolymerization with statistical incorporation of monomers, demonstrating that sequence composition is crucial to the activity of IRI active polyampholytes. PMID- 27936603 TI - Quantitative Trait Loci (QTL)-Guided Metabolic Engineering of a Complex Trait. AB - Engineering complex phenotypes for industrial and synthetic biology applications is difficult and often confounds rational design. Bioethanol production from lignocellulosic feedstocks is a complex trait that requires multiple host systems to utilize, detoxify, and metabolize a mixture of sugars and inhibitors present in plant hydrolysates. Here, we demonstrate an integrated approach to discovering and optimizing host factors that impact fitness of Saccharomyces cerevisiae during fermentation of a Miscanthus x giganteus plant hydrolysate. We first used high-resolution Quantitative Trait Loci (QTL) mapping and systematic bulk Reciprocal Hemizygosity Analysis (bRHA) to discover 17 loci that differentiate hydrolysate tolerance between an industrially related (JAY291) and a laboratory (S288C) strain. We then used this data to identify a subset of favorable allelic loci that were most amenable for strain engineering. Guided by this "genetic blueprint", and using a dual-guide Cas9-based method to efficiently perform multikilobase locus replacements, we engineered an S288C-derived strain with superior hydrolysate tolerance than JAY291. Our methods should be generalizable to engineering any complex trait in S. cerevisiae, as well as other organisms. PMID- 27936605 TI - Hydrodynamic Analysis Resolves the Pharmaceutically-Relevant Absolute Molar Mass and Solution Properties of Synthetic Poly(ethylene glycol)s Created by Varying Initiation Sites. AB - The solution behavior originating from molecular characteristics of synthetic macromolecules plays a pivotal role in many areas, in particular the life sciences. This situation necessitates the use of complementary hydrodynamic analytical methods as the only means for a complete structural understanding of any macromolecule in solution. To this end, we present a combined hydrodynamic approach for studying in-house prepared, low dispersity poly(ethylene glycols)s (PEGs), also known as poly(ethylene oxide)s (PEOs) depending on the classification used, synthesized from varying initiation sites by the living anionic ring opening polymerization. The series of linear PEGs in the molar mass range of only a few thousand to 50 000 g mol-1 have been studied in detail via viscometry and sedimentation-diffusion analysis by analytical ultracentrifugation. The obtained estimations for intrinsic viscosity, diffusion coefficients, and sedimentation coefficients of the macromolecules in the solution-based analysis clearly showed self-consistency of the followed hydrodynamic approach. This self-consistency is underpinned by appropriate and physically sound values of hydrodynamic invariants, indicating adequate values of derived absolute molar masses. The classical scaling relations of Kuhn-Mark Houwink-Sakurada of all molar-mass dependent hydrodynamic estimates show linear trends, allowing for interrelation of all parametric macromolecular characteristics. Differences among these are ascribed to the observation of alpha end and chain-length dependent solvation of the macromolecules, identified from viscometric studies. This important information allows for analytical tracing of variations of scaling relationships and a physically sound estimation of hydrodynamic characteristics. The demonstrated self-sufficient methodology paves an important way for a complete structural understanding and potential replacement of pharmaceutically relevant PEGs by alternative macromolecules offering a suite of similar or tractably distinct physicochemical properties. PMID- 27936606 TI - Polymeric Self-Assemblies with Boron-Containing Near-Infrared Dye Dimers for Photoacoustic Imaging Probes. AB - Polymers containing pyrrolopyrrole aza-BODIPY (PPAB) and thiophene-bridged BODIPY dimers (TBD) having poly(ethylene glycol) (PEG) or PEGylated hyaluronic acid (HA) were prepared by facile conjugation approaches. Self-assemblies consisting of TBD conjugated polymers more efficiently generated photoacoustic (PA) signals than PPAB-PEG conjugate upon irradiation with near-infrared pulsed laser light. Among dye-conjugated polymers examined, TBD-HA-PEG conjugates efficiently generated photoacoustic signals, 1.49-1.83 times stronger than that of commercially available indocyanine green (ICG). We found that the following two factors are essential to enhance PA signals from self-assemblies: (1) the formation of strongly interacting TBD aggregates and (2) enhancement of the elastic modulus of self-assemblies by conjugating TBDs with HA. TBD-conjugated HA derivatives circulated in blood vessels for a longer time (15.6 +/- 4.9% injected dose (ID) in blood 24 h after injection) and more specifically accumulated in tumor tissues (17.8 +/- 3.5% ID/g in tumor 24 h after injection) than ICG-conjugated HA derivatives, visualizing a tumor site more clearly. The cell uptake experiment of dye-HA conjugates indicates that ICG-conjugated polymers internalized into cells or merged with cell walls to emit strong fluorescence, while TBD-conjugated polymers were not internalized into cells. Because the disassembly of the TBD conjugated HA derivatives is suppressed, aggregated TBDs emit weak fluorescence but efficiently generate strong PA signals in tumor tissues. PMID- 27936604 TI - Microscale Measurements of Michaelis-Menten Constants of Neuraminidase with Nanogel Capillary Electrophoresis for the Determination of the Sialic Acid Linkage. AB - Phospholipid nanogels enhance the stability and performance of the exoglycosidase enzyme neuraminidase and are used to create a fixed zone of enzyme within a capillary. With nanogels, there is no need to covalently immobilize the enzyme, as it is physically constrained. This enables rapid quantification of Michaelis Menten constants (KM) for different substrates and ultimately provides a means to quantify the linkage (i.e., 2-3 versus 2-6) of sialic acids. The fixed zone of enzyme is inexpensive and easily positioned in the capillary to support electrophoresis mediated microanalysis using neuraminidase to analyze sialic acid linkages. To circumvent the limitations of diffusion during static incubation, the incubation period is reproducibly achieved by varying the number of forward and reverse passes the substrate makes through the stationary fixed zone using in capillary electrophoretic mixing. A KM value of 3.3 +/- 0.8 mM (Vmax, 2100 +/- 200 MUM/min) was obtained for 3'-sialyllactose labeled with 2-aminobenzoic acid using neuraminidase from Clostridium perfringens that cleaves sialic acid monomers with an alpha2-3,6,8,9 linkage, which is similar to values reported in the literature that required benchtop analyses. The enzyme cleaves the 2-3 linkage faster than the 2-6, and a KM of 2 +/- 1 mM (Vmax, 400 +/- 100 MUM/min) was obtained for the 6'-sialyllactose substrate. An alternative neuraminidase selective for 2-3 sialic acid linkages generated a KM value of 3 +/- 2 mM (Vmax, 900 +/- 300 MUM/min) for 3'-sialyllactose. With a knowledge of Vmax, the method was applied to a mixture of 2-3 and 2-6 sialyllactose as well as 2-3 and 2-6 sialylated triantennary glycan. Nanogel electrophoresis is an inexpensive, rapid, and simple alternative to current technologies used to distinguish the composition of 3' and 6' sialic acid linkages. PMID- 27936608 TI - Mass Spectrometry and Ion Mobility Characterization of Bioactive Peptide Synthetic Polymer Conjugates. AB - The bioconjugate BMP2-(PEO-HA)2, composed of a dendron with two monodisperse poly(ethylene oxide) (PEO) branches terminated by a hydroxyapatite binding peptide (HA), and a focal point substituted with a bone growth stimulating peptide (BMP2), has been comprehensively characterized by mass spectrometry (MS) methods, encompassing matrix-assisted laser desorption ionization (MALDI), electrospray ionization (ESI), tandem mass spectrometry (MS2), and ion mobility mass spectrometry (IM-MS). MS2 experiments using different ion activation techniques validated the sequences of the synthetic, bioactive peptides HA and BMP2, which contained highly basic amino acid residues either at the N-terminus (BMP2) or C-terminus (HA). Application of MALDI-MS, ESI-MS, and IM-MS to the polymer-peptide biomaterial confirmed its composition. Collision cross-section measurements and molecular modeling indicated that BMP2-(PEO-HA)2 exists in several folded and extended conformations, depending on the degree of protonation. Protonation of all basic sites of the hybrid material nearly doubles its conformational space and accessible surface area. PMID- 27936609 TI - Direct Pb Isotopic Analysis of a Nuclear Fallout Debris Particle from the Trinity Nuclear Test. AB - The Pb isotope composition of a nuclear fallout debris particle has been directly measured in post-detonation materials produced during the Trinity nuclear test by a secondary ion mass spectrometry (SIMS) scanning ion image technique (SII). This technique permits the visual assessment of the spatial distribution of Pb and can be used to obtain full Pb isotope compositions in user-defined regions in a 70 MUm * 70 MUm analytical window. In conjunction with backscattered electron (BSE) and energy-dispersive spectroscopy (EDS) mapping of the same particle, the Pb measured in this fallout particle cannot be from a major phase in the precursor arkosic sand. Similarly, the Pb isotope composition of the particle is resolvable from the surrounding glass at the 2sigma uncertainty level (where sigma represents the standard deviation). The Pb isotope composition measured in the particle here is in excellent agreement with that inferred from measurements of green and red trinitite, suggesting that these types of particles are responsible for the Pb isotope compositions measured in both trinitite glasses. PMID- 27936610 TI - Dynamics of Aromatic Side Chains in the Active Site of FKBP12. AB - FKBP12, a small human enzyme, aids protein folding by catalyzing cis-trans isomerization of peptidyl-prolyl bonds, and is involved in cell signaling pathways, calcium regulation, and the immune response. The underlying molecular mechanisms are not fully understood, but it is well-known that aromatic residues in the active site and neighboring loops are important for substrate binding and catalysis. Here we report micro- to millisecond exchange dynamics of aromatic side chains in the active site region of ligand-free FKBP12, involving a minor state population of 0.5% and an exchange rate of 3600 s-1, similar to previous results for the backbone and methyl-bearing side chains. The exchange process involves tautomerization of H87. In the major state H87 is highly flexible and occupies the common HNepsilon2 tautomer, while in the minor state it occupies the rare HNdelta1 tautomer, which typically requires stabilization by specific interactions, such as hydrogen bonds. This finding suggests that the exchange process is coupled to a rearrangement of the hydrogen bond network around H87. Upon addition of the active-site inhibitor FK506 the exchange of all aromatic residues is quenched, with exception of H87. The H87 resonances are broadened beyond detection, suggesting that interconversion between tautomers prevail in the FK506-bound state. While key active-site residues undergo conformational exchange in the apo state, the exchange rate is considerably faster than the catalytic turnover, as determined herein by Michaelis-Menten type analysis of NMR line shapes and chemical shifts. We discuss alternative interpretations of this observation in terms of FKBP12 function. PMID- 27936607 TI - pH-Sensitive O6-Benzylguanosine Polymer Modified Magnetic Nanoparticles for Treatment of Glioblastomas. AB - Nanoparticle-mediated delivery of chemotherapeutics has demonstrated potential in improving anticancer efficacy by increasing serum half-life and providing tissue specificity and controlled drug release to improve biodistribution of hydrophobic chemotherapeutics. However, suboptimal drug loading, particularly for solid core nanoparticles (NPs), remains a challenge that limits their clinical application. In this study we formulated a NP coated with a pH-sensitive polymer of O6 methylguanine-DNA methyltransferase (MGMT) inhibitor analog, dialdehyde modified O6-benzylguanosine (DABGS) to achieve high drug loading, and polyethylene glycol (PEG) to ameliorate water solubility and maintain NP stability. The base nanovector consists of an iron oxide core (9 nm) coated with hydrazide functionalized PEG (IOPH). DABGS and PEG-dihydrazide were polymerized on the iron oxide nanoparticle surface (IOPH-pBGS) through acid-labile hydrazone bonds utilizing a rapid, freeze-thaw catalysis approach. DABGS polymerization was confirmed by FTIR and quantitated by UV-vis spectroscopy. IOPH-pBGS demonstrated excellent drug loading of 33.4 +/- 5.1% by weight while maintaining small size (36.5 +/- 1.8 nm). Drug release was monitored at biologically relevant pHs and demonstrated pH dependent release with maximum release at pH 5.5 (intracellular conditions), and minimal release at physiological pH (7.4). IOPH-pBGS significantly suppressed activity of MGMT and potentiated Temozolomide (TMZ) toxicity in vitro, demonstrating potential as a new treatment option for glioblastomas (GBMs). PMID- 27936611 TI - Electrically Transduced Sensors Based on Nanomaterials (2012-2016). PMID- 27936612 TI - Paper-Based Microfluidic Devices: Emerging Themes and Applications. PMID- 27936613 TI - Development and Application of the Diffusive Gradients in Thin Films Technique for the Measurement of Nitrate in Soils. AB - Nitrate (NO3-N), the main plant/microbial nitrogen source, has a fast turnover in soil driven by species transformation (nitrification/denitrification) and phyto/microbiota assimilation. The technique of diffusive gradients in thin films (DGT) is capable of a robust, low disturbance measurement of NO3-N but has not been implemented due to the absence of a binding layer suitable for deployment in soils. In this study, a new styrene divinylbenzene-based absorbent with amine functional groups (SIR-100-HP) was cast into an agarose gel support. The NO3-N ion selectivity of the SIR-100-HP/agarose binding layer was retained in the presence of high multivalent ion concentrations and was used successfully to acquire in situ NO3-N measurements in bulk soil. The kinetics of binding and the maximum binding capacity were determined. The total capacity of the DGT containing the SIR-100-HP/agarose binding phase was 667 MUg of NO3-N. The performance of DGT was not affected by varying pH (3-8) or ionic strength (0 0.018 mol L-1), while anion competition effects at concentrations reflecting those in common agricultural soils were found to be negligible. Complete elution (100% efficiency) of NO3-N from the binding phase was achieved using a solution of 5% NaCl. This technique was validated in three contrasting soils. CDGT measurements were in excellent agreement with pore water NO3-N values. Two dimensional NO3-N mapping of a profile of flooded rice paddy soil demonstrated the potential of this novel methodology for improved characterization of in situ N speciation for further understanding of bioavailability and biogeochemical processes of NO3-N in soils. PMID- 27936615 TI - Nonhierarchical Flux Regulation Exposes the Fitness Burden Associated with Lactate Production in Synechocystis sp. PCC6803. AB - Cyanobacteria are mostly engineered to be sustainable cell-factories by genetic manipulations alone. Here, by modulating the concentration of allosteric effectors, we focus on increasing product formation without further burdening the cells with increased expression of enzymes. Resorting to a novel 96-well microplate cultivation system for cyanobacteria, and using lactate-producing strains of Synechocystis PCC6803 expressing different l-lactate dehydrogenases (LDH), we titrated the effect of 2,5-anhydro-mannitol supplementation. The latter acts in cells as a nonmetabolizable analogue of fructose 1,6-bisphosphate, a known allosteric regulator of one of the tested LDHs. In this strain (SAA023), we achieved over 2-fold increase of lactate productivity. Furthermore, we observed that as carbon is increasingly deviated during growth toward product formation, there is an increased fixation rate in the population of spontaneous mutants harboring an impaired production pathway. This is a challenge in the development of green cell factories, which may be countered by the incorporation in biotechnological processes of strategies such as the one pioneered here. PMID- 27936616 TI - A Novel Synthetic Pathway Enables Microbial Production of Polyphenols Independent from the Endogenous Aromatic Amino Acid Metabolism. AB - Numerous plant polyphenols have potential applications as pharmaceuticals or nutraceuticals. Stilbenes and flavonoids as most abundant polyphenols are synthesized from phenylpropanoids, which are exclusively derived from aromatic amino acids in nature. Several microorganisms were engineered for the synthesis of biotechnologically interesting plant polyphenols; however, low activity of heterologous ammonia lyases, linking endogenous microbial aromatic amino acid biosynthesis to phenylpropanoid synthesis, turned out to be the limiting step during microbial synthesis. We here developed an alternative strategy for polyphenol production from cheap benzoic acids by reversal of a beta-oxidative phenylpropanoid degradation pathway avoiding any ammonia lyase activity. The synthetic pathway running in the non-natural direction is feasible with respect to thermodynamics and involved reaction mechanisms. Instantly, product titers of 5 mg/L resveratrol could be achieved in recombinant Corynebacterium glutamicum strains indicating that phenylpropanoid synthesis from 4-hydroxybenzoic acid can in principle be implemented independently from aromatic amino acids and ammonia lyase activity. PMID- 27936614 TI - Structural Basis for the Strict Substrate Selectivity of the Mycobacterial Hydrolase LipW. AB - The complex life cycle of Mycobacterium tuberculosis requires diverse energy mobilization and utilization strategies facilitated by a battery of lipid metabolism enzymes. Among lipid metabolism enzymes, the Lip family of mycobacterial serine hydrolases is essential to lipid scavenging, metabolic cycles, and reactivation from dormancy. On the basis of the homologous rescue strategy for mycobacterial drug targets, we have characterized the three dimensional structure of full length LipW from Mycobacterium marinum, the first structure of a catalytically active Lip family member. LipW contains a deep, expansive substrate-binding pocket with only a narrow, restrictive active site, suggesting tight substrate selectivity for short, unbranched esters. Structural alignment reinforced this strict substrate selectivity of LipW, as the binding pocket of LipW aligned most closely with the bacterial acyl esterase superfamily. Detailed kinetic analysis of two different LipW homologues confirmed this strict substrate selectivity, as each homologue selected for unbranched propionyl ester substrates, irrespective of the alcohol portion of the ester. Using comprehensive substitutional analysis across the binding pocket, the strict substrate selectivity of LipW for propionyl esters was assigned to a narrow funnel in the acyl-binding pocket capped by a key hydrophobic valine residue. The polar, negatively charged alcohol-binding pocket also contributed to substrate orientation and stabilization of rotameric states in the catalytic serine. Together, the structural, enzymatic, and substitutional analyses of LipW provide a connection between the structure and metabolic properties of a Lip family hydrolase that refines its biological function in active and dormant tuberculosis infection. PMID- 27936617 TI - Assessment of N-Oxide Formation during Wastewater Ozonation. AB - Worldwide, ozonation of secondary wastewater effluents is increasingly considered in order to decrease the load of organic contaminants before environmental discharge. However, despite the constantly growing knowledge of ozonation over the past few years, the characterization of transformation products (TPs) is still a major concern, particularly because such TPs might remain biologically active. It has been shown for selected tertiary amine pharmaceuticals that they react with ozone and form the corresponding N-oxides. This study therefore applies liquid chromatography-high resolution mass spectrometry (LC-HRMS) to assess the overall N-oxide formation during the pilot-scale ozonation of a secondary wastewater effluent from a major city in Germany. Sample analysis by LC HRMS revealed the occurrence of 1,229 compounds, among which 853 were precursors attenuated by ozone and 165 were TPs. Further examination of precursors and TPs using Kendrick mass and Kendrick mass defect analysis revealed 34 pairs of precursors and products corresponding to a mono-oxygenation. Among these, 27 pairs (16% of all TPs) were consistent with N-oxides since the TP had a higher retention time than the precursor, a characteristic of these compounds. Using high resolution tandem mass spectrometry, 10 of these N-oxides could be identified and were shown to be stable during a subsequent filtration step. PMID- 27936618 TI - Continuous Separation of DNA Molecules by Size Using Insulator-Based Dielectrophoresis. AB - Separation of nucleic acids has long served as a central goal of analytical research. Innovations in this field may soon enable the development of rapid, on site sequencing devices that significantly improve both the availability and accuracy of detailed bioinformatics. However, achieving efficient continuous-flow operation and size-based fractionation of DNA still presents considerable challenges. Current methods have not yet satisfied the need for rapid fractionation of size-heterogeneous nucleic acid samples into specific and narrow size distributions. Dielectrophoretic (DEP) mechanisms integrated in microfluidic devices offer unique advantages for such applications, including short processing times, microscale reaction volumes, and the potential for low cost and portability. To facilitate such developments, we have adapted a microfluidic constriction sorter device to separate a wide range of nucleic acid analytes into distinct microchannel outlets. This work demonstrates selective and tunable deflection of DNA using alternating current (AC) insulator-based dielectrophoresis. We report conditions for size-based DEP sorting of 1.0, 10.2, 19.5, and 48.5 kbp dsDNA analytes, including both plasmid and genomic DNA. Applied potentials range from 200 to 2400 Vpp with frequencies ranging from 50 Hz to 20 kHz. These conditions result in sorting efficiencies up to 92% with a strong dependence on applied potentials and frequencies. In low-frequency AC fields, long DNA molecules form macro-ion clusters. This behavior is associated with an apparent shift from positive to negative DEP sorting behavior. Using a finite element model, we characterize the dynamics of sorting in the microdevice and link differential sorting to differences in dielectrophoretic mobility. We propose the use of a continuous-flow sorting strategy to facilitate future coupling to next generation sequencing approaches. PMID- 27936619 TI - Ring-Opening Copolymerization of Epoxides and Cyclic Anhydrides with Discrete Metal Complexes: Structure-Property Relationships. AB - Polyesters synthesized through the alternating copolymerization of epoxides and cyclic anhydrides compose a growing class of polymers that exhibit an impressive array of chemical and physical properties. Because they are synthesized through the chain-growth polymerization of two variable monomers, their syntheses can be controlled by discrete metal complexes, and the resulting materials vary widely in their functionality and physical properties. This polymer-focused review gives a perspective on the current state of the field of epoxide/anhydride copolymerization mediated by discrete catalysts and the relationships between the structures and properties of these polyesters. PMID- 27936620 TI - Integrated Evaluation Concept to Assess the Efficacy of Advanced Wastewater Treatment Processes for the Elimination of Micropollutants and Pathogens. AB - A multidisciplinary concept has been developed to compare advanced wastewater treatment processes for their efficacy of eliminating micropollutants and pathogens. The concept is based on (i) the removal/formation of selected indicator substances and their transformation products (TPs), (ii) the assessment of ecotoxicity via in vitro tests, and (iii) the removal of pathogens and antibiotic resistant bacteria. It includes substances passing biological wastewater treatment plants regulated or proposed to be regulated in the European Water Framework Directive, TPs formed in biological processes or during ozonation, agonistic/antagonistic endocrine activities, mutagenic/genotoxic activities, cytotoxic activities, further activities like neurotoxicity as well as antibiotics resistance genes, and taxonomic gene markers for pathogens. At a pilot plant, ozonation of conventionally treated wastewater resulted in the removal of micropollutants and pathogens and the reduction of estrogenic effects, whereas the in vitro mutagenicity increased. Subsequent post-treatment of the ozonated water by granular activated carbon (GAC) significantly reduced the mutagenic effects as well as the concentrations of remaining micropollutants, whereas this was not the case for biofiltration. The results demonstrate the suitability of the evaluation concept to assess processes of advanced wastewater treatment including ozonation and GAC by considering chemical, ecotoxicological, and microbiological parameters. PMID- 27936621 TI - Are Optical Gas Imaging Technologies Effective For Methane Leak Detection? AB - Concerns over mitigating methane leakage from the natural gas system have become ever more prominent in recent years. Recently, the U.S. Environmental Protection Agency proposed regulations requiring use of optical gas imaging (OGI) technologies to identify and repair leaks. In this work, we develop an open source predictive model to accurately simulate the most common OGI technology, passive infrared (IR) imaging. The model accurately reproduces IR images of controlled methane release field experiments as well as reported minimum detection limits. We show that imaging distance is the most important parameter affecting IR detection effectiveness. In a simulated well-site, over 80% of emissions can be detected from an imaging distance of 10 m. Also, the presence of "superemitters" greatly enhance the effectiveness of IR leak detection. The minimum detectable limits of this technology can be used to selectively target "superemitters", thereby providing a method for approximate leak-rate quantification. In addition, model results show that imaging backdrop controls IR imaging effectiveness: land-based detection against sky or low-emissivity backgrounds have higher detection efficiency compared to aerial measurements. Finally, we show that minimum IR detection thresholds can be significantly lower for gas compositions that include a significant fraction nonmethane hydrocarbons. PMID- 27936623 TI - Automated Strong Cation-Exchange Cleanup To Remove Macromolecular Crowding Agents for Protein Hydrogen Exchange Mass Spectrometry. AB - Measuring amide hydrogen exchange (HX) of intrinsically disordered proteins (IDPs) in solutions containing high concentrations of macromolecular crowding agents would give new insights into the structure and dynamics of these proteins under crowded conditions. High concentrations of artificial crowders, required to simulate cellular crowding, introduce overwhelming interferences to mass spectrometry (MS) analysis. We have developed a fully automated, dual-stage online cleanup that uses strong cation-exchange (SCX) followed by reversed-phase desalting to remove Ficoll, a synthetic polymer, for HX-MS analysis of proteins under crowded conditions. We tested the efficiency of our method by measuring the HX-MS signal intensities of myoglobin peptides from crowded samples containing 300 g L-1 Ficoll and from uncrowded samples. Although there was loss of abundance relative to uncrowded myoglobin analyzed using conventional HX-MS, 97% coverage of the myoglobin sequence was still obtained. Control HX-MS experiments using unstructured peptides labeled at pD 4.0 under crowded and uncrowded conditions confirmed that Ficoll does not alter chemical exchange and that the same extent of HX is achieved in uncrowded solutions as in solutions containing 300 g L-1 of predeuterated Ficoll. We validated our method by measuring HX of CBP, the intrinsically disordered nuclear coactivator binding domain of CREB binding protein (UniProt CBP_MOUSE P45481 ), residues 2059-2117, at pD 6.5 under crowded and uncrowded conditions. Ficoll induced both protection and deprotection from HX in different regions of CBP, with the greatest deprotection occurring at the edges of helices. These results are consistent with previous observation of IDPs under the influence of synthetic polymers. PMID- 27936624 TI - Microporous Hexanuclear Ln(III) Cluster-Based Metal-Organic Frameworks: Color Tunability for Barcode Application and Selective Removal of Methylene Blue. AB - Two hexanuclear Ln(III) cluster-based metal-organic frameworks (MOFs) (Ln = Tb or Eu) and a series of isomorphic bimetallic Ln(III)-MOFs have been synthesized by changing the ratio of Tb(III) and Eu(III) under solvothermal conditions. The excellent linear color tunability (from green to red) makes them suitable for barcode application. In addition, the anionic Ln(III)-MOFs exhibit superior uptake capacity toward methylene blue (MB+) by an ion-exchange process, and its reversible adsorption performance makes 1 suitable for removal of organic dye MB+. The as-prepared anionic hexanuclear Ln(III) cluster-based MOFs can serve as a multifunctional material for an optical and environmental area. PMID- 27936622 TI - DNA Adducts from Anticancer Drugs as Candidate Predictive Markers for Precision Medicine. AB - Biomarker-driven drug selection plays a central role in cancer drug discovery and development, and in diagnostic strategies to improve the use of traditional chemotherapeutic drugs. DNA-modifying anticancer drugs are still used as first line medication, but drawbacks such as resistance and side effects remain an issue. Monitoring the formation and level of DNA modifications induced by anticancer drugs is a potential strategy for stratifying patients and predicting drug efficacy. In this perspective, preclinical and clinical data concerning the relationship between drug-induced DNA adducts and biological response for platinum drugs and combination therapies, nitrogen mustards and half-mustards, hypoxia-activated drugs, reductase-activated drugs, and minor groove binding agents are presented and discussed. Aspects including measurement strategies, identification of adducts, and biological factors that influence the predictive relationship between DNA modification and biological response are addressed. A positive correlation between DNA adduct levels and response was observed for the majority of the studies, demonstrating the high potential of using DNA adducts from anticancer drugs as mechanism-based biomarkers of susceptibility, especially as bioanalysis approaches with higher sensitivity and throughput emerge. PMID- 27936625 TI - Self-Assembly of an alpha-Helical Peptide into a Crystalline Two-Dimensional Nanoporous Framework. AB - Sequence-specific peptides have been demonstrated to self-assemble into structurally defined nanoscale objects including nanofibers, nanotubes, and nanosheets. The latter structures display significant promise for the construction of hybrid materials for functional devices due to their extended planar geometry. Realization of this objective necessitates the ability to control the structural features of the resultant assemblies through the peptide sequence. The design of a amphiphilic peptide, 3FD-IL, is described that comprises two repeats of a canonical 18 amino acid sequence associated with straight alpha-helical structures. Peptide 3FD-IL displays 3-fold screw symmetry in a helical conformation and self-assembles into nanosheets based on hexagonal packing of helices. Biophysical evidence from TEM, cryo-TEM, SAXS, AFM, and STEM measurements on the 3FD-IL nanosheets support a structural model based on a honeycomb lattice, in which the length of the peptide determines the thickness of the nanosheet and the packing of helices defines the presence of nanoscale channels that permeate the sheet. The honeycomb structure can be rationalized on the basis of geometrical packing frustration in which the channels occupy defect sites that define a periodic superlattice. The resultant 2D materials may have potential as materials for nanoscale transport and controlled release applications. PMID- 27936629 TI - Coordination Polymerization of 5,5'-Dinitro-2H,2H'-3,3'-bi-1,2,4-triazole Leads to a Dense Explosive with High Thermal Stability. AB - High-energy coordination polymers (CPs) based on nitrogen-rich ligands are an emerging class of explosives. However, modulation of the energetic properties of high-energy CPs and the establishment of their structure-function relationship remain in their infancy. In the present study, the utility of coordination polymerization as a technique to modulate the application of critical energetic properties, such as density and thermal stability, of a secondary explosive, 5,5' dinitro-2H,2H'-3,3'-bi-1,2,4-triazole (DNBT), is presented. Ni-DNBT is a discrete octahedral complex with density lower than that of DNBT. Cu-DNBT also contains octahedral metal coordination, similar to that in Ni-DNBT, as the building unit; however, the partial reduction of CuII to CuI ions during the reaction and their unique geometrical preferences lead to linking of the octahedral CuII complexes by tetrahedral CuI ions and render the resultant material a one-dimensional polymer with high density. In fact, Cu-DNBT has the highest density among all of the DNBT-based energetics. Furthermore, Cu-DNBT exhibits thermal stability superior to that of both Ni-DNBT and DNBT. Cu-DNBT is one of the two DNBT-based energetic materials and one of the few energetics that are stable at temperatures higher than 300 degrees C. PMID- 27936628 TI - Light Lanthanide Complexes with Crown Ether and Its Aza Derivative Which Show Slow Magnetic Relaxation Behaviors. AB - Two sets of isostructural Ln(III) mononuclear complexes, [Ln(NO3)3(18-crown-6)] (Ln = Ce (1), Pr (2), and Nd (3)) and [Ln(NO3)3(1,10-diaza-18-crown-6)] (Ln = Ce (4), Pr (5), and Nd (6)), were synthesized, and their slow magnetic relaxation behavior was investigated. Since Ln(III) ions are located in an axially stressed ligand field in both sets of complexes, they can exhibit single-molecule magnet (SMM) behavior owing to the oblate-type electronic distributions of the ground sublevels found in Ce(III), Pr(III), and Nd(III). Field-induced slow magnetic relaxation was observed for Ce(III) and Nd(III) complexes 1, 3, 4, and 6 under an applied bias dc field of 1000 Oe, whereas no slow relaxation was observed for Pr(III) complexes 2 and 5. The slow magnetic relaxation behavior of 1, 3, 4, and 6 was correlated with the even-numbered Jz sublevels of Ce(III) and Nd(III) ions, known as the Kramers system. PMID- 27936627 TI - Profiling the Serum Albumin Cys34 Adductome of Solid Fuel Users in Xuanwei and Fuyuan, China. AB - Xuanwei and Fuyuan counties in China have the highest lung cancer rates in the world due to household air pollution from combustion of smoky coal for cooking and heating. To discover potential biomarkers of indoor combustion products, we profiled adducts at the Cys34 locus of human serum albumin (HSA) in 29 nonsmoking Xuanwei and Fuyuan females who used smoky coal, smokeless coal, or wood and 10 local controls who used electricity or gas fuel. Our untargeted "adductomics" method detected 50 tryptic peptides of HSA, containing Cys34 and prominent post translational modifications. Putative adducts included Cys34 oxidation products, mixed disulfides, rearrangements, and truncations. The most significant differences in adduct levels across fuel types were observed for S-glutathione (S GSH) and S-gamma-glutamylcysteine (S-gamma-GluCys), both of which were present at lower levels in subjects exposed to combustion products than in controls. After adjustment for age and personal measurements of airborne benzo(a)pyrene, the largest reductions in levels of S-GSH and S-gamma-GluCys relative to controls were observed for users of smoky coal, compared to users of smokeless coal and wood. These results point to possible depletion of GSH, an essential antioxidant, and its precursor gamma-GluCys in nonsmoking females exposed to indoor-combustion products in Xuanwei and Fuyuan, China. PMID- 27936630 TI - Material Flow Analysis as a Tool to improve Waste Management Systems: The Case of Austria. AB - This paper demonstrates the power of material flow analysis (MFA) for designing waste management (WM) systems and for supporting decisions with regards to given environmental and resource goals. Based on a comprehensive case study of a nationwide WM-system, advantages and drawbacks of a mass balance approach are discussed. Using the software STAN, a material flow system comprising all relevant inputs, stocks and outputs of wastes, products, residues, and emissions is established and quantified. Material balances on the level of goods and selected substances (C, Cd, Cr, Cu, Fe, Hg, N, Ni, P, Pb, Zn) are developed to characterize this WM-system. The MFA results serve well as a base for further assessments. Based on given goals, stakeholders engaged in this study selected the following seven criteria for evaluating their WM-system: (i) waste input into the system, (ii) export of waste (iii) gaseous emissions from waste treatment plants, (iv) long-term gaseous and liquid emissions from landfills, (v) waste being recycled, (vi) waste for energy recovery, (vii) total waste landfilled. By scenario analysis, strengths and weaknesses of different measures were identified. The results reveal the benefits of a mass balance approach due to redundancy, data consistency, and transparency for optimization, design, and decision making in WM. PMID- 27936631 TI - Organocatalytic Asymmetric Synthesis of Chiral Dioxazinanes and Dioxazepanes with in Situ Generated Nitrones via a Tandem Reaction Pathway Using a Cooperative Cation Binding Catalyst. AB - Heterocyclic skeletons play major roles in pharmaceuticals and biological processes. Cycloaddition reactions are most suitable synthetic tools to efficiently construct chemically diverse sets of heterocycles with great structural complexity owing to the simultaneous or sequential formation of two or more bonds, often with a high degree of selectivity. Herein, we report an unprecedented formal cycloaddition of N-Boc-N-hydroxy amido sulfones as the nitrone precursors with terminal-hydroxy alpha,beta-unsaturated carbonyls in the presence of Song's chiral oligoethylene glycol as a cation-binding catalyst and KF as a base to afford a wide range of highly enantio- and diastereo-enriched six membered dioxazinane and seven-membered dioxazepane heterocycles. In this process, nitrones as well as terminal-hydroxy alpha,beta-unsaturated carbonyls serve as "amphiphilic" building units, and the reaction proceeds through a tandem pathway sequence of oxa-Mannich reaction/oxa-Michael reaction/tautomerization/protonation. The cation-binding catalysis in a densely confined chiral space in situ formed by the incorporation of potassium salt is the key to this successful catalysis. This strategy opens a new pathway for the asymmetric synthesis of diverse heterocyclic skeletons of great complexity. PMID- 27936632 TI - Light-Driven Liquid Crystalline Materials: From Photo-Induced Phase Transitions and Property Modulations to Applications. AB - Light-driven phenomena both in living systems and nonliving materials have enabled truly fascinating and incredible dynamic architectures with terrific forms and functions. Recently, liquid crystalline materials endowed with photoresponsive capability have emerged as enticing systems. In this Review, we focus on the developments of light-driven liquid crystalline materials containing photochromic components over the past decade. Design and synthesis of photochromic liquid crystals (LCs), photoinduced phase transitions in LC, and photoalignment and photoorientation of LCs have been covered. Photomodulation of pitch, polarization, lattice constant and handedness inversion of chiral LCs is discussed. Light-driven phenomena and properties of liquid crystalline polymers, elastomers, and networks have also been analyzed. The applications of photoinduced phase transitions, photoalignment, photomodulation of chiral LCs, and photomobile polymers have been highlighted wherever appropriate. The combination of photochromism, liquid crystallinity, and fabrication techniques has enabled some fascinating functional materials which can be driven by ultraviolet, visible, and infrared light irradiation. Nanoscale particles have been incorporated to widen and diversify the scope of the light-driven liquid crystalline materials. The developed materials possess huge potential for applications in optics, photonics, adaptive materials, nanotechnology, etc. The challenges and opportunities in this area are discussed at the end of the Review. PMID- 27936633 TI - Atmospheric Chemistry of (CF3)2CF-C=N: A Replacement Compound for the Most Potent Industrial Greenhouse Gas, SF6. AB - FTIR/smog chamber experiments and ab initio quantum calculations were performed to investigate the atmospheric chemistry of (CF3)2CFCN, a proposed replacement compound for the industrially important sulfur hexafluoride, SF6. The present study determined k(Cl + (CF3)2CFCN) = (2.33 +/- 0.87) * 10-17, k(OH + (CF3)2CFCN) = (1.45 +/- 0.25) * 10-15, and k(O3 + (CF3)2CFCN) <= 6 * 10-24 cm3 molecule-1 s 1, respectively, in 700 Torr of N2 or air diluent at 296 +/- 2 K. The main atmospheric sink for (CF3)2CFCN was determined to be reaction with OH radicals. Quantum chemistry calculations, supported by experimental evidence, shows that the (CF3)2CFCN + OH reaction proceeds via OH addition to -C(=N), followed by O2 addition to -C(OH)?N., internal H-shift, and OH regeneration. The sole atmospheric degradation products of (CF3)2CFCN appear to be NO, COF2, and CF3C(O)F. The atmospheric lifetime of (CF3)2CFCN is approximately 22 years. The integrated cross section (650-1500 cm-1) for (CF3)2CFCN is (2.22 +/- 0.11) * 10 16 cm2 molecule-1 cm-1 which results in a radiative efficiency of 0.217 W m-2 ppb 1. The 100-year Global Warming Potential (GWP) for (CF3)2CFCN was calculated as 1490, a factor of 15 less than that of SF6. PMID- 27936634 TI - Influence of Polyoxometalate Protecting Ligands on Catalytic Aerobic Oxidation at the Surfaces of Gold Nanoparticles in Water. AB - Metal oxide cluster-anion (polyoxometalate, or POM) protecting ligands, [alpha PW11O39]7- (1), modify the rates at which 14 nm gold nanoparticles (Au NPs) catalyze an important model reaction, the aerobic (O2) oxidation of CO to CO2 in water. At 20 degrees C and pH 6.2, the following stoichiometry was observed: CO + O2 + H2O = CO2 + H2O2. After control experiments verified that the H2O2 product was sufficiently stable and did not react with 1 under turnover conditions, quantitative analysis of H2O2 was used to monitor the rates of CO oxidation, which increased linearly with the percent coverage of the Au NPs by 1 (0-64% coverage, with the latter value corresponding to 211 +/- 19 surface-bound molecules of 1). X-ray photoelectron spectroscopy of Au NPs protected by a series of POM ligands (K+ salts): 1, the Wells-Dawson ion [alpha-P2W18O62]6- (2) and the monodefect Keggin anion [alpha-SiW11O39]8- (3) revealed that binding energies of electrons in the Au 4f7/2 and 4f5/2 atomic orbitals decreased as a linear function of the POM charge and percent coverage of Au NPs, providing a direct correlation between the electronic effects of the POMs bound to the surfaces of the Au NPs and the rates of CO oxidation by O2. Additional data show that this effect is not limited to POMs but occurs, albeit to a lesser extent, when common anions capable of binding to Au-NP surfaces, such as citrate or phosphate, are present. PMID- 27936635 TI - Carbon, Hydrogen and Chlorine Stable Isotope Fingerprinting for Forensic Investigations of Hexachlorocyclohexanes. AB - Multielemental stable isotope analysis of persistent organic pollutants (POPs) has the potential to characterize sources, sinks, and degradation processes in the environment. To verify the applicability of this approach for source identification of hexachlorocyclohexane (HCHs), we provide a data set of carbon, hydrogen, and chlorine stable isotope ratios (delta13C, delta2H, delta37Cl) of its main stereoisomers (alpha-, beta-, delta- and gamma-HCHs) from a sample collection based on worldwide manufacturing. This sample collection comprises production stocks, agricultural and pharmaceutical products, chemical waste dumps, and analytical-grade material, covering the production time period from the late 1960s until now. Stable isotope ratios of HCHs cover the ranges from 2330/00 to +10/00, from -35.90/00 to -22.70/00, and from -6.690/00 to +0.540/00 for delta2H, delta13C, and delta37Cl values, respectively. Four groups of samples with distinct multielemental stable isotope fingerprints were differentiated, most probably as a result of purification and isolation processes. No clear temporal trend in the isotope compositions of HCHs was found at the global scale. The multielemental stable isotope fingerprints facilitate the source identification of HCHs at the regional scale and can be used to assess transformation processes. The data set and methodology reported herein provide basic information for the assessment of environmental field sites contaminated with HCHs. PMID- 27936636 TI - Pt-Mg, Pt-Ca, and Pt-Zn Lantern Complexes and Metal-Only Donor-Acceptor Interactions. AB - Pt-based heterobimetallic lantern complexes of the form [PtM(SOCR)4(L)] have been shown previously to form intermolecular metallophilic interactions and engage in antiferromagnetic coupling between lanterns having M atoms with open shell configurations. In order to understand better the influence of the carboxylate bridge and terminal ligand on the electronic structure, as well as the metal metal interactions within each lantern unit, a series of diamagnetic lantern complexes, [PtMg(SAc)4(OH2)] (1), [PtMg(tba)4(OH2)] (2), [PtCa(tba)4(OH2)] (3), [PtZn(tba)4(OH2)] (4), and a mononuclear control (Ph4P)2[Pt(SAc)4] (5) have been synthesized. Crystallographic data show close Pt-M contacts enforced by the lantern structure in each dinuclear case. 195Pt-NMR spectroscopy of 1-4, (Ph4P)2[Pt(SAc)4] (5), and several previously reported lanterns revealed a strong chemical shift dependence on the identity of the second metal (M), mild influence by the thiocarboxylate ligand (SOCR; R = CH3 (thioacetate, SAc), C6H5 (thiobenzoate, tba)), and modest influence from the terminal ligand (L). Fluorescence spectroscopy has provided evidence for a Pt...Zn metallophilic interaction in [PtZn(SAc)4(OH2)], and computational studies demonstrate significant dative character. In all of 1-4, the short Pt-M distances suggest that metal-only Lewis donor (Pt)-Lewis acceptor (M) interactions could be present. DFT and NBO calculations, however, show that only the Zn examples have appreciable covalent character, whereas the Mg and Ca complexes are much more ionic. PMID- 27936638 TI - The Hexachlorocerate(III) Anion: A Potent, Benchtop Stable, and Readily Available Ultraviolet A Photosensitizer for Aryl Chlorides. AB - The hexachlorocerate(III) anion, [CeIIICl6]3-, was found to be a potent photoreductant in acetonitrile solution with an estimated excited-state reduction potential of -3.45 V versus Cp2Fe0/+. Despite a short lifetime of 22.1(1) ns, the anion exhibited a photoluminescence quantum yield of 0.61(4) and fast quenching kinetics toward organohalogens allowing for its application in the photocatalytic reduction of aryl chloride substrates. PMID- 27936639 TI - Synthesis, Structure, and Photoluminescence of Color-Tunable and White-Light Emitting Lanthanide Metal-Organic Open Frameworks Composed of AlMo6(OH)6O183- Polyanion and Nicotinate. AB - A series of isostructural compounds Na(HL)(CH3COO)Ln(Al(OH)6Mo6O18)(H2O)6.10H2O [L = nicotinate; Ln = Eu (1), Tb (2)] and Na(HL)(CH3COO)EumTbnLa1-m n(AlMo6(OH)6O18)(H2O)6.10H2O (3-8, L = nicotinate), wherein Anderson-type polyanions AlMo6(OH)6O183- as basic inorganic building blocks are connected by Eu(CH3COO)(HL)(H2O)3]24+ and [Na2(H2O)8]2+ cations, resulting in formation of three-dimensional lanthanide metal-organic open frameworks, were synthesized successfully with AlCl3.6H2O, Na2MoO4.2H2O, nicotinic acid, and lanthanide nitrates as starting materials. The compounds were characterized by UV-vis, IR, elemental analysis, powder XRD, and TG-DTA measurements. The single-crystal structures of compounds 1 and 2 show that the two compounds display three dimensional open frameworks with 1D channels along the b and c axes. Investigation of the energy transfer mechanism indicated that the organic nicotinate ligand can transfer energy efficiently to Tb3+ rather than Eu3+. The influence of the POM moiety on the fluorescence of the compounds is also studied. Compounds 1-8 exhibit tunable luminescence color, and emitting of white light was realized through adjusting the molar ratio of Eu:Tb:La within the compounds. PMID- 27936640 TI - Stoichiometric Responses to an Agricultural Pesticide Are Modified by Predator Cues. AB - Current ecological risk assessment of pesticides fails to protect aquatic ecosystem health. To get better insight in how pesticides may affect aquatic ecosystems, we tested how sublethal pesticide concentrations modify body stoichiometry. Moreover, as interactions with natural stressors may cause underestimates of the impact of pesticides, we also tested whether this pathway depended on the presence of predator cues. Therefore, we exposed damselfly larvae to chlorpyrifos and cues from predatory dragonflies and focused on body stoichiometry and associated explanatory variables (growth rate, RNA:DNA, and energy storage molecules). The way the predator cues modulated the pesticide effects strongly differed between endpoints. Exposure to chlorpyrifos affected the key body stoichiometric ratios: chlorpyrifos consistently increased N:P, while its effects on C:N (decrease with predator cues) and C:P (increase without predator cues) strongly depended upon the presence of the natural stressor. These stoichiometric responses could be explained by associated changes in growth, RNA:DNA, and in C-rich fat and sugars and N-rich proteins. The observed changes in body stoichiometry may affect the damselflies' food quality and have the potential to cascade through the food web and shape nutrient cycling. PMID- 27936637 TI - Transition-Metal-Catalyzed C-H Bond Addition to Carbonyls, Imines, and Related Polarized pi Bonds. AB - The transition-metal-catalyzed addition of C-H bonds to carbonyls, imines, and related polarized pi bonds has emerged as a particularly efficient and powerful approach for the construction of an incredibly diverse array of heteroatom substituted products. Readily available and stable inputs are typically employed, and reactions often proceed with very high functional group compatibility and without the production of waste byproducts. Additionally, many transition-metal catalyzed C-H bond additions to polarized pi bonds occur within cascade reaction sequences to provide rapid access to a diverse array of different heterocyclic as well as carbocyclic products. This review highlights the diversity of transformations that have been achieved, catalysts that have been used, and types of products that have been prepared through the transition-metal-catalyzed addition of C-H bonds to carbonyls, imines, and related polarized pi bonds. PMID- 27936641 TI - Anodic Oxidation of 18 Halogenated and/or Methylated Derivatives of CB11H12. AB - Anodic oxidation of [CB11H12]- and 18 of its halogenated and/or methylated derivatives was examined. Reversible oxidation was found for four of the anions in liquid SO2 and for four more in 1,1,1,3,3,3-hexafluoroisopropyl alcohol. The oxidation occurred at ~1 V (for [CB11Me12]-) up to more than 4 V (for [1-H-(2-6) F5-(7-12)-(CF3)6-CB11]-) relative to ferrocene/ferricinium. The anodic peak potentials are reproduced by a set of additive position-sensitive substituent increments. PMID- 27936642 TI - Microplastics Affect the Ecological Functioning of an Important Biogenic Habitat. AB - Biological effects of microplastics on the health of bivalves have been demonstrated elsewhere, but ecological impacts on the biodiversity and ecosystem functioning of bivalve-dominated habitats are unknown. Thus, we exposed intact sediment cores containing European flat oysters (Ostrea edulis) or blue mussels (Mytilus edulis) in seawater to two different densities (2.5 or 25 MUg L-1) of biodegradable or conventional microplastics in outdoor mesocosms. We hypothesized that filtration rates of the bivalves, inorganic nitrogen cycling, primary productivity of sediment dwelling microphytobenthos, and the structure of invertebrate benthic assemblages would be influenced by microplastics. After 50 days, filtration by M. edulis was significantly less when exposed to 25 MUg L-1 of either type of microplastics, but there were no effects on ecosystem functioning or the associated invertebrate assemblages. Contrastingly, filtration by O. edulis significantly increased when exposed to 2.5 or 25 MUg L-1 of microplastics, and porewater ammonium and biomass of benthic cyanobacteria decreased. Additionally the associated infaunal invertebrate assemblages differed, with significantly less polychaetes and more oligochaetes in treatments exposed to microplastics. These findings highlight the potential of microplastics to impact the functioning and structure of sedimentary habitats and show that such effects may depend on the dominant bivalve present. PMID- 27936643 TI - Hypoelectronicity and Chirality in Dimetallaboranes of Group 9 Metals. AB - The structures and energetics of the dimetallaboranes Cp2M2Bn-2Hn-2 (n = 8, 9, 10, 11, 12; M = Co, Rh, Ir; Cp = eta5-C5H5) were studied using density functional theory. The lowest energy Cp2M2B6H6 and Cp2M2B7H7 structures are chiral C2 structures based on the corresponding closo deltahedra, namely the bisdisphenoid and the tricapped trigonal prism. The permethylated iridaboranes Cp*2Ir2B6H6 and Cp*2Ir2B7H7 (Cp* = eta5-Me5C5) were synthesized by Ghosh and co-workers. However, they were found by X-ray crystallography to have nondeltahedral structures containing a quadrilateral face, namely a bicapped trigonal prism and a capped square antiprism for the 8- and 9-vertex systems, respectively. These structures correspond to a mean of the two opposite enantiomers and can also represent the "square" intermediate in the interconversion of the two enantiomers. The lowest energy structures for the 10-vertex Cp2M2B8H8 systems are two isocloso deltahedra with one metal atom at a degree 6 vertex and the other metal atom at a degree 5 vertex. Both isomers have been realized experimentally for Cp2Ir2B8H8. The lowest energy structures for the 11-vertex Cp2M2B9H9 systems have central closo/isocloso deltahedra with one metal atom at a degree 6 vertex and the other metal atom at a nonadjacent degree 5 vertex. This structure type has been found experimentally in both the rhodaboranes and iridaboranes Cp*2M2B9H9 (M = Rh, Ir). The lowest energy structures for the 12-vertex systems Cp2M2B10H10 (M = Co, Rh, Ir) are deltahedra with two adjacent degree 6 vertices for the metal atoms. This type of structure is found experimentally in the rhodium complexes Cp*2Rh2B10H10-n(OH)n (n = 1, 2). PMID- 27936644 TI - Palladium-Catalyzed Asymmetric alpha-Arylation of Alkylnitriles. AB - Asymmetric arylation of alkylnitriles forms quaternary stereocenters in good enantiocontrol for the first time. A lithium heterodimer consisting of an alkylnitrile anion and a disilylamide ion is the actual species responsible for the stereodetermining transmetalation in the catalytic cycle. PMID- 27936645 TI - Direct Superassemblies of Freestanding Metal-Carbon Frameworks Featuring Reversible Crystalline-Phase Transformation for Electrochemical Sodium Storage. AB - High-power sodium-ion batteries (SIBs) with long-term cycling attract increasing attention for large-scale energy storage. However, traditional SIBs toward practical applications still suffer from low rate capability and poor cycle induced by pulverization and amorphorization of anodes at high rate (over 5 C) during the fast ion insertion/extraction process. The present work demonstrates a robust strategy for a variety of (Sb-C, Bi-C, Sn-C, Ge-C, Sb-Bi-C) freestanding metal-carbon framework thin films via a space-confined superassembly (SCSA) strategy. The sodium-ion battery employing the Sb-C framework exhibits an unprecedented performance with a high specific capacity of 246 mAh g-1, long life cycle (5000 cycles), and superb capacity retention (almost 100%) at a high rate of 7.5 C (3.51A g-1). Further investigation indicates that the unique framework structure enables unusual reversible crystalline-phase transformation, guaranteeing the fast and long-cyclability sodium storage. This study may open an avenue to developing long-cycle-life and high-power SIBs for practical energy applications. PMID- 27936646 TI - Formation of Haloacetonitriles, Haloacetamides, and Nitrogenous Heterocyclic Byproducts by Chloramination of Phenolic Compounds. AB - The potential formation of nitrogenous disinfection byproducts (N-DBPs) was investigated from the chloramination of nitrogenous and non-nitrogenous aromatic compounds. All molecules led to the formation of known N-DBPs (e.g., dichloroacetonitrile, dichloroacetamide) with various production yields. Resorcinol, a major precursor of chloroform, also formed di/trichloroacetonitrile, di/trichloroacetamide, and haloacetic acids, indicating that it is a precursor of both N-DBPs and carbonaceous DBPs (C-DBPs) upon chloramination. More detailed experiments were conducted on resorcinol to understand N-DBPs formation mechanisms and to identify reaction intermediates. Based on the accurate mass from high resolution Quadrupole Time-of-Flight GC-MS (GC-QTOF) and fragmentation patterns from electronic impact and positive chemical ionization modes, several products were tentatively identified as nitrogenous heterocyclic compounds (e.g., 3-chloro-5-hydroxy-1H-pyrrole-2-one with dichloromethyl group, 3-chloro-2,5-pyrroledione). These products were structurally similar to the heterocyclic compounds formed during chlorination, such as the highly mutagenic MX (3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H) furanone) or halogenated pyrroles. To our knowledge, this is the first time that the formation of halogenated nitrogenous heterocyclic compounds is reported from chloramination process. The formation of these nitrogenous byproducts during chloramination might be of concern considering their potential toxicity. PMID- 27936626 TI - Oxidative Cyclization in Natural Product Biosynthesis. AB - Oxidative cyclizations are important transformations that occur widely during natural product biosynthesis. The transformations from acyclic precursors to cyclized products can afford morphed scaffolds, structural rigidity, and biological activities. Some of the most dramatic structural alterations in natural product biosynthesis occur through oxidative cyclization. In this Review, we examine the different strategies used by nature to create new intra(inter)molecular bonds via redox chemistry. This Review will cover both oxidation- and reduction-enabled cyclization mechanisms, with an emphasis on the former. Radical cyclizations catalyzed by P450, nonheme iron, alpha-KG-dependent oxygenases, and radical SAM enzymes are discussed to illustrate the use of molecular oxygen and S-adenosylmethionine to forge new bonds at unactivated sites via one-electron manifolds. Nonradical cyclizations catalyzed by flavin-dependent monooxygenases and NAD(P)H-dependent reductases are covered to show the use of two-electron manifolds in initiating cyclization reactions. The oxidative installations of epoxides and halogens into acyclic scaffolds to drive subsequent cyclizations are separately discussed as examples of "disappearing" reactive handles. Last, oxidative rearrangement of rings systems, including contractions and expansions, will be covered. PMID- 27936647 TI - Selective Formation of Chromogen I from N-Acetyl-d-glucosamine upon Lanthanide Coordination. AB - We report two nonanuclear lanthanide complexes, [Ln9(MU4-O)(MU3 OH)8(LH)4(OAc)4(H2O)12].5ClO4.24H2O (Ln = Gd, 1; Dy, 2), where LH2- is the doubly deprotonated chiral ligand Chromogen I (2-acetamido-2,3-dideoxy-D-erythro-hex-2 enofuranose), one of the many products from the dehydration of N-acetyl-D glucosamine (GlcNAc). Mass spectroscopic studies established the solution stability of these clusters. Through hydrogen bonding, the cluster complex self organizes into a nanostructured 54-metal cagelike assembly featuring six of its units occupying the vertices of an octahedron. Free Chromogen I can be obtained in pure form and high yield by a straightforward workup of the cluster complex. This is the first report of dehydrating GlcNAc without the need of a catalyst or forcing conditions. PMID- 27936648 TI - Microplastics in Sewage Sludge: Effects of Treatment. AB - Waste water treatment plants (WWTPs) are receptors for the cumulative loading of microplastics (MPs) derived from industry, landfill, domestic wastewater and stormwater. The partitioning of MPs through the settlement processes of wastewater treatment results in the majority becoming entrained in the sewage sludge. This study characterized MPs in sludge samples from seven WWTPs in Ireland which use anaerobic digestion (AD), thermal drying (TD), or lime stabilization (LS) treatment processes. Abundances ranged from 4196 to 15 385 particles kg-1 (dry weight). Results of a general linear mixed model (GLMM) showed significantly higher abundances of MPs in smaller size classes in the LS samples, suggesting that the treatment process of LS shears MP particles. In contrast, lower abundances of MPs found in the AD samples suggests that this process may reduce MP abundances. Surface morphologies examined using scanning electron microscopy (SEM) showed characteristics of melting and blistering of TD MPs and shredding and flaking of LS MPs. This study highlights the potential for sewage sludge treatment processes to affect the risk of MP pollution prior to land spreading and may have implications for legislation governing the application of biosolids to agricultural land. PMID- 27936649 TI - Prediction of Adsorption Equilibrium of VOCs onto Hyper-Cross-Linked Polymeric Resin at Environmentally Relevant Temperatures and Concentrations Using Inverse Gas Chromatography. AB - Hyper-cross-linked polymeric resin (HPR) represents a class of predominantly microporous adsorbents and has good adsorption performance toward VOCs. However, adsorption equilibrium of VOCs onto HPR are limited. In this research, a novel method for predicting adsorption capacities of VOCs on HPR at environmentally relevant temperatures and concentrations using inverse gas chromatography data was proposed. Adsorption equilibrium of six VOCs (n-pentane, n-hexane, dichloromethane, acetone, benzene, 1, 2-dichloroethane) onto HPR in the temperature range of 403-443 K were measured by inverse gas chromatography (IGC). Adsorption capacities at environmentally relevant temperatures (293-328 K) and concentrations (P/Ps = 0.1-0.7) were predicted using Dubinin-Radushkevich (DR) equation based on Polany's theory. Taking consideration of the swelling properties of HPR, the volume swelling ratio (r) was introduced and r.Vmicro was used instead of Vmicro determined by N2 adsorption data at 77 K as the parameter q0 (limiting micropore volume) of the DR equation. The results showed that the adsorption capacities of VOCs at environmentally relevant temperatures and concentrations can be predicted effectively using IGC data, the root-mean-square errors between the predicted and experimental data was below 9.63%. The results are meaningful because they allow accurate prediction of adsorption capacities of adsorbents more quickly and conveniently using IGC data. PMID- 27936651 TI - Silver(I)-Mediated Modification, Dimerization, and Polymerization of an Open-Cage Fullerene. AB - The reactions of the open-cage fullerene, MMK-9, with an open 12-membered ring on its surface and silver(I) salts have been examined. The structure of MMK-9 itself has been determined by single-crystal X-ray diffraction. MMK-9 reacts with silver trifluoroacetate in air to form the dimer, {MMK-9(OCH3)5Ag(AgO2CCF3)}2. Remarkably, five MeO groups have added to the surface of the open cage in a pattern that surrounds a pentagon immediately adjacent to the opening in the cage. Dioxygen has been implicated as the oxidant in this unusual addition of five groups to the open cage. Two silver ions connected to each other by a short argentophillic interaction reside at the core of the centrosymmetric dimer. The reaction of silver nitrate with MMK-9 yields the crystalline polymer, [{MMK 9(OCH3)5Ag(AgOCH3)}2.H2O]n. This polymer consists of dimeric {MMK-9(OCH3)5Ag}2 units that are connected into strands through silver ions, which are chelated by the amine functions of one open cage and bound in eta2-fashion to a pair of carbon atoms on an adjacent open cage. PMID- 27936650 TI - Relaxation Dynamics of Identical Trigonal Bipyramidal Cobalt Molecules with Different Local Symmetries and Packing Arrangements: Magnetostructural Correlations and ab inito Calculations. AB - A family of isostructural, mononuclear CoII complexes with distorted trigonal bipyramidal coordination environments is reported. The degree of distortion as well as the overall symmetry of the molecules varies among the members of the series. Different experimental procedures resulted in the isolation of solvomorphs (pseudopolymorphs with different solvent content) for some of the family members. Importantly, their disparate packing arrangements lead to very different dynamic magnetic behavior. The results of magnetostructural correlations and ab initio calculations reveal that the deciding factor for SMM behavior is not the degree of distortion which, a priori, would be expected to be the case, but rather the interactions between neighboring molecules in the solid state. PMID- 27936652 TI - Non-Adiabatic Effects on Excited States of Vinylidene Observed with Slow Photoelectron Velocity-Map Imaging. AB - High-resolution slow photoelectron velocity-map imaging spectra of cryogenically cooled X2B2 H2CC- and D2CC- in the region of the vinylidene triplet excited states are reported. Three electronic bands are observed and, with the assistance of electronic structure calculations and quantum dynamics on ab initio-based near equilibrium potential energy surfaces, are assigned as detachment to the [Formula: see text] 3B2 (T1), b 3A2 (T2), and A 1A2 (S1) excited states of neutral vinylidene. This work provides the first experimental observation of the A singlet excited state of H2CC. While regular vibrational structure is observed for the a and A electronic bands, a number of irregular features are resolved in the vicinity of the b band vibrational origin. High-level ab initio calculations suggest that this anomalous structure arises from a conical intersection between the a and b triplet states near the b state minimum, which strongly perturbs the vibrational levels in the two electronic states through nonadiabatic coupling. Using the adiabatic electron affinity of H2CC previously measured to be 0.490(6) eV by Ervin and co-workers [J. Chem. Phys. 1989, 91, 5974], term energies for the excited neutral states of H2CC are found to be T0(a 3B2) = 2.064(6), T0(b 3A2) = 2.738(6), and T0(A 1A2) = 2.991(6) eV. PMID- 27936653 TI - Identifying Glyceraldehyde 3-Phosphate Dehydrogenase as a Cyclic Adenosine Diphosphoribose Binding Protein by Photoaffinity Protein-Ligand Labeling Approach. AB - Cyclic adenosine diphosphoribose (cADPR), an endogenous nucleotide derived from nicotinamide adenine dinucleotide (NAD+), mobilizes Ca2+ release from endoplasmic reticulum (ER) via ryanodine receptors (RyRs), yet the bridging protein(s) between cADPR and RyRs remain(s) unknown. Here we synthesized a novel photoaffinity labeling (PAL) cADPR agonist, PAL-cIDPRE, and subsequently applied it to purify its binding proteins in human Jurkat T cells. We identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as one of the cADPR binding protein(s), characterized the binding affinity between cADPR and GAPDH in vitro by surface plasmon resonance (SPR) assay, and mapped cADPR's binding sites in GAPDH. We further demonstrated that cADPR induces the transient interaction between GAPDH and RyRs in vivo and that GAPDH knockdown abolished cADPR-induced Ca2+ release. However, GAPDH did not catalyze cADPR into any other known or novel compound(s). In summary, our data clearly indicate that GAPDH is the long-sought after cADPR binding protein and is required for cADPR-mediated Ca2+ mobilization from ER via RyRs. PMID- 27936654 TI - Light-Induced Conversion of Chemical Permeability to Enhance Electron and Molecular Transfer in Nanoscale Assemblies. AB - In this paper, we demonstrate how photochemically enhancing the permeability of metal-organic assemblies results in a significant enhancement of the electrochemical activity of metal complexes located within the assembly. The molecular assemblies consist of different layers of redox-active metal complexes ([M(mbpy-py)3][PF6]2; M = Ru or Os) that are separated by redox-inactive spacers consisting of 1,4-bis[2-(4-pyridyl)ethenyl]benzene (BPEB) and PdCl2 of variable thicknesses (0-13.4 nm). UV-irradiation (lambda = 254 nm) of our assemblies induces a photochemical reaction in the redox-inactive spacer increasing the permeability of the assembly. The observed increase was evident by trapping organic (nBu4NBF4) and inorganic (NiCl2) salts inside the assemblies, and by evaluating the electrochemical response of quinones absorbed inside the molecular assemblies before and after UV irradiation. The increase in permeability is reflected by higher currents and a change in the directionality of electron transfer, i.e., from mono- to bidirectional, between the redox-active metal complexes and the electrode surface. The supramolecular structure of the assemblies dominates the overall electron transfer properties and overrules possible electron transfer mediated by the extensive pi-conjugation of its individual organic components. PMID- 27936655 TI - Mechanism of Molybdenum-Mediated Carbon Monoxide Deoxygenation and Coupling: Mono and Dicarbyne Complexes Precede C-O Bond Cleavage and C-C Bond Formation. AB - Deoxygenative coupling of CO to value-added C>=2 products is challenging and mechanistically poorly understood. Herein, we report a mechanistic investigation into the reductive coupling of CO, which provides new fundamental insights into a multielectron bond-breaking and bond-making transformation. In our studies, the formation of a bis(siloxycarbyne) complex precedes C-O bond cleavage. At -78 degrees C, over days, C-C coupling occurs without C-O cleavage. However, upon warming to 0 degrees C, C-O cleavage is observed from this bis(siloxycarbyne) complex. A siloxycarbyne/CO species undergoes C-O bond cleavage at lower temperatures, indicating that monosilylation, and a more electron-rich Mo center, favors deoxygenative pathways. From the bis(siloxycarbyne), isotopic labeling experiments and kinetics are consistent with a mechanism involving unimolecular silyl loss or C-O cleavage as rate-determining steps toward carbide formation. Reduction of Mo(IV) CO adducts of carbide and silylcarbyne species allowed for the spectroscopic detection of reduced silylcarbyne/CO and mixed silylcarbyne/siloxycarbyne complexes, respectively. Upon warming, both of these silylcarbynes undergo C-C bond formation, releasing silylated C2O1 fragments and demonstrating that the multiple bonded terminal Mo=C moiety is an intermediate on the path to deoxygenated, C-C coupled products. The electronic structures of Mo carbide and carbyne species were investigated quantum mechanically. Overall, the present studies establish the elementary reactions steps by which CO is cleaved and coupled at a single metal site. PMID- 27936656 TI - Multiple Converged Conduction Bands in K2Bi8Se13: A Promising Thermoelectric Material with Extremely Low Thermal Conductivity. AB - We report that K2Bi8Se13 exhibits multiple conduction bands that lie close in energy and can be activated through doping, leading to a highly enhanced Seebeck coefficient and a high power factor with elevated temperature. Meanwhile, the large unit cell, complex low symmetry crystal structure, and nondirectional bonding lead to the very low lattice thermal conductivity of K2Bi8Se13, ranging between 0.42 and 0.20 W m-1 K-1 in the temperature interval 300-873 K. Experimentally, we further support the low thermal conductivity of K2Bi8Se13 using phonon velocity measurements; the results show a low average phonon velocity (1605 ms-1), small Young's modulus (37.1 GPa), large Gruneisen parameter (1.71), and low Debye temperature (154 K). A detailed investigation of the microstructure and defects was carried out using electron diffraction and transmission microscopy which reveal the presence of a K2.5Bi8.5Se14 minor phase intergrown along the side of the K2Bi8Se13 phase. The combination of enhanced power factor and low thermal conductivity results in a high ZT value of ~1.3 at 873 K in electron doped K2Bi8Se13 material. PMID- 27936657 TI - Constructing Three-Dimensional Mesoporous Bouquet-Posy-like TiO2 Superstructures with Radially Oriented Mesochannels and Single-Crystal Walls. AB - Constructing three-dimensional (3-D) hierarchical mesostructures with unique morphology, pore orientation, single-crystal nature, and functionality remains a great challenge in materials science. Here, we report a confined microemulsion self-assembly approach to synthesize an unprecedented type of 3-D highly ordered mesoporous TiO2 superstructure (Level-1), which consists of 1 spherical core and 12 symmetric satellite hemispheres epitaxially growing out of the core vertices. A more complex and asymmetric TiO2 superstructure (Level-2) with 13 spherical cores and up to 44 symmetric satellite hemispheres can also be well manipulated by increasing the size or content of impregnated TiO2 precursor emulsion droplets. The obtained 3-D mesoporous TiO2 superstructures have well-defined bouquet-posy-like topologies, oriented hexagonal mesochannels, high accessible surface area (134-148 m2/g), large pore volume (0.48-0.51 cm3/g), and well single crystalline anatase walls with dominant (001) active facets. More interestingly, all cylindrical mesopore channels are highly interconnected and radially distributed within the whole superstructures, and all TiO2 nanocrystal building blocks are oriented grown into a single-crystal anatase wall, making them ideal candidates for various applications ranging from catalysis to optoelectronics. As expected, the bouquet-posy-like mesoporous TiO2 superstructure supported catalysts show excellent catalytic activity (>=99.7%) and selectivity (>=96%) in cis-semihydrogenation of various alkynes, exceeding that of commercial TiO2 (P25) supported catalyst by a factor of 10. No decay in the activity was observed for 25 cycles, revealing a high stability of the mesoporous TiO2 superstructure supported catalyst. PMID- 27936658 TI - Mechanism Studies of Ir-Catalyzed Asymmetric Hydrogenation of Unsaturated Carboxylic Acids. AB - The Ir-catalyzed asymmetric hydrogenation of olefins is widely used for production of value-added bulk and fine chemicals. The iridium catalysts with chiral spiro phosphine-oxazoline ligands developed in our group show high activity and high enantioselectivity in the hydrogenation of olefins bearing a coordinative carboxyl group, such as alpha,beta-unsaturated carboxylic acids, beta,gamma-unsaturated carboxylic acids, and gamma,delta-unsaturated carboxylic acids. Here we conducted detailed mechanistic studies on these Ir-catalyzed asymmetric hydrogenation reactions by using (E)-2-methyl-3-phenylacrylic acid as a model substrate. We isolated and characterized several key intermediates having Ir-H bonds under the real hydrogenation conditions. Particularly, an Ir(III) migratory insertion intermediate was first isolated in an asymmetric hydrogenation reaction promoted by chiral Ir catalysts. That this intermediate cannot undergo reductive elimination in the absence of hydrogen strongly supports the involvement of an Ir(III)/Ir(V) cycle in the hydrogenation. On the basis of the structure of the Ir(III) intermediate, variable-temperature NMR spectroscopy, and density functional theory calculations, we elucidated the mechanistic details of the Ir-catalyzed hydrogenation of unsaturated carboxylic acids and explained the enantioselectivity of the reactions. These findings experimentally and computationally elucidate the mechanism of Ir-catalyzed asymmetric hydrogenation of olefins with a strong coordinative carboxyl group and will likely inspire further catalyst design. PMID- 27936659 TI - Hexaaminobenzene as a building block for a Family of 2D Coordination Polymers. AB - A family of 2D coordination polymers were successfully synthesized through "bottom-up" techniques using Ni2+, Cu2+, Co2+, and hexaaminobenzene. Liquid liquid and air-liquid interfacial reactions were used to realize thick (~1-2 MUm) and thin (<10 nm) stacked layers of nanosheet, respectively. Atomic-force microscopy and scanning electron microscopy both revealed the smooth and flat nature of the nanosheets. Selected area diffraction was used to elucidate the hexagonal crystal structure of the framework. Electronic devices were fabricated on thin samples of the Ni analogue and they were found to be mildly conducting and also showed back gate dependent conductance. PMID- 27936660 TI - Room Temperature Magnetic Switchability Assisted by Hysteretic Valence Tautomerism in a Layered Two-Dimensional Manganese-Radical Coordination Framework. AB - The manganese-nitronyl-nitroxide two-dimensional coordination polymer {[Mn2(NITIm)3]ClO4}n (1) (NITImH = 2-(2-imidazolyl)-4,4,5,5-tetramethyl-4,5 dihydro-1H-3-oxide-1-oxyl) undergoes an unusual hysteretic thermo-induced valence tautomeric transition near room temperature, during which the manganese(II) ions are oxidized to manganese(III) and two of the three deprotonated radicals (NITIm ) are reduced to their diamagnetic aminoxyl form (denoted NITRed2-). Upon cooling, the high-temperature species {[MnII2(NITIm)3]ClO4}n (1HT) turns into the low-temperature species {[MnIII2(NITRed)2(NITIm)]ClO4}n (1LT) around 274 K, while on heating the process is reversed at about 287 K. This valence tautomeric phenomenon is supported by temperature-dependent magnetic susceptibility measurements, differential scanning calorimetry (DSC), crystal structure determination, UV-vis absorption, X-ray absorption (XAS), and emission (XES) and electron paramagnetic resonance (EPR) spectroscopies in the solid state. PMID- 27936661 TI - Differentiating Left- and Right-Handed Carbon Nanotubes by DNA. AB - New structural characteristics emerge when solid-state crystals are constructed in lower dimensions. This is exemplified by single-wall carbon nanotubes, which exhibit a degree of freedom in handedness and a multitude of helicities that give rise to three distinct types of electronic structures: metals, quasi-metals, and semiconductors. Here we report the use of intrinsically chiral single-stranded DNA to achieve simultaneous handedness and helicity control for all three types of nanotubes. We apply polymer aqueous two-phase systems to select special DNA wrapped carbon nanotubes, each of which we argue must have an ordered DNA structure that binds to a nanotube of defined handedness and helicity and resembles a well-folded biomacromolecule with innate stereoselectivity. We have screened over 300 short single-stranded DNA sequences with palindrome symmetry, leading to the selection of more than 20 distinct carbon nanotube structures that have defined helicity and handedness and cover the entire chiral angle range and all three electronic types. The mechanism of handedness selection is illustrated by a DNA sequence that adopts two distinct folds on a pair of (6,5) nanotube enantiomers, rendering them large differences in fluorescence intensity and chemical reactivity. This result establishes a first example of functionally distinguishable left- and right-handed carbon nanotubes. Taken together, our work demonstrates highly efficient enantiomer differentiation by DNA and offers a first comprehensive solution to achieve simultaneous handedness and helicity control for all three electronic types of carbon nanotubes. PMID- 27936662 TI - Does Each Atom Count in the Reactivity of Vanadia Nanoclusters? AB - Vanadium oxide cluster anions (V2O5)nVxOy- (n = 1-31; x = 0, 1; and x + y <= 5) with different oxygen deficiencies (Delta = 2y-1-5x = 0, +/- 1, and +/-2) have been prepared by laser ablation and reacted to abstract hydrogen atoms from alkane molecules (n-butane) in a fast flow reactor. When the cluster size n is less than 25, the Delta = 1 series [(V2O5)nO- clusters] that can contain atomic oxygen radical anions (O*-) generally have much higher reactivity than the other four cluster series (Delta = -2, -1, 0, and 2), indicating that each atom counts in the hydrogen-atom abstraction (HAA) reactivity. Unexpectedly, all of the five cluster series have similar HAA reactivity when the cluster size is greater than 25. The critical dimension of vanadia particles separating the cluster behavior (each atom counts) from the bulk behavior (each atom contributes a little part) is thus about 1.6 nm (~V50O125). The strong electron-phonon coupling of the vanadia particles has been proposed to create the O*- radicals (V5+ = O2-+ heat > V4+-O*-) for the n > 25 clusters with Delta = -2, -1, 0, and 2. Such a mechanism is supported by a comparative study with the scandium system [(Sc2O3)nScxOy- (n = 1-29; x = 0, 1; and x + y <= 4)] for which the Delta = 1 series [(Sc2O3)nO- clusters] always have much higher HAA reactivity than the other cluster series. PMID- 27936664 TI - Guest-Induced Two-Way Structural Transformation in a Layered Metal-Organic Framework Thin Film. AB - Fabrication of thin films made of metal-organic frameworks (MOFs) has been intensively pursued for practical applications that use the structural response of MOFs. However, to date, only physisorption-induced structural response has been studied in these films. Chemisorption can be expected to provide a remarkable structural response because of the formation of bonds between guest molecules and reactive metal sites in host MOFs. Here, we report that chemisorption-induced two-way structural transformation in a nanometer-sized MOF thin film. We prepared a two-dimensional layered-type MOF Fe[Pt(CN)4] thin film using a step-by-step approach. Although the as-synthesized film showed poor crystallinity, the dehydrated form of this thin film had a highly oriented crystalline nature (Film-D) as confirmed by synchrotron X-ray diffraction (XRD). Surprisingly, under water and pyridine vapors, Film-D showed chemisorption induced dynamic structural transformations to Fe(L)2[Pt(CN)4] thin films [L = H2O (Film-H), pyridine (Film-P)], where water and pyridine coordinated to the open Fe2+ site. Dynamic structural transformations were also confirmed by in situ XRD, sorption measurement, and infrared reflection absorption spectroscopy. This is the first report of chemisorption-induced dynamic structural response in a MOF thin film, and it provides useful insights, which would lead to future practical applications of MOFs utilizing chemisorption-induced structural responses. PMID- 27936665 TI - Observation of Multipeak Collision Behavior during the Electro-Oxidation of Single Ag Nanoparticles. AB - The dynamic collision behavior of the electro-oxidation of single Ag nanoparticles is observed at Au microelectrodes using stochastic single nanoparticle collision amperometry. Results show that an Ag nanoparticle collision/oxidation event typically consists of a series of 1 to ~10 discrete "sub-events" over an ~20 ms interval. Results also show that the Ag nanoparticles typically undergo only partial oxidation prior to diffusing away from the Au electrode into the bulk solution. Both behaviors are characterized and shown to exist under a variety of experimental conditions. These previously unreported behaviors suggest that nanoparticle collision and electro-dissolution is a highly dynamic process driven by fast particle-electrode interactions and nanoparticle diffusion. PMID- 27936663 TI - Structure-Based Mechanism for Oxidative Decarboxylation Reactions Mediated by Amino Acids and Heme Propionates in Coproheme Decarboxylase (HemQ). AB - Coproheme decarboxylase catalyzes two sequential oxidative decarboxylations with H2O2 as the oxidant, coproheme III as substrate and cofactor, and heme b as the product. Each reaction breaks a C-C bond and results in net loss of hydride, via steps that are not clear. Solution and solid-state structural characterization of the protein in complex with a substrate analog revealed a highly unconventional H2O2-activating distal environment with the reactive propionic acids (2 and 4) on the opposite side of the porphyrin plane. This suggested that, in contrast to direct C-H bond cleavage catalyzed by a high-valent iron intermediate, the coproheme oxidations must occur through mediating amino acid residues. A tyrosine that hydrogen bonds to propionate 2 in a position analogous to the substrate in ascorbate peroxidase is essential for both decarboxylations, while a lysine that salt bridges to propionate 4 is required solely for the second. A mechanism is proposed in which propionate 2 relays an oxidizing equivalent from a coproheme compound I intermediate to the reactive deprotonated tyrosine, forming Tyr*. This residue then abstracts a net hydrogen atom (H*) from propionate 2, followed by migration of the unpaired propionyl electron to the coproheme iron to yield the ferric harderoheme and CO2 products. A similar pathway is proposed for decarboxylation of propionate 4, but with a lysine residue as an essential proton shuttle. The proposed reaction suggests an extended relay of heme-mediated e-/H+ transfers and a novel route for the conversion of carboxylic acids to alkenes. PMID- 27936666 TI - Spin Crossover in Anionic Cobalt-Bridged Fullerene (Bu4N+){Co(Ph3P)}2(MU2-Cl )(MU2-eta2,eta2-C60)2 Dimers. AB - A spin crossover phenomena is observed in an anionic (Bu4N+){Co(Ph3P)}2(MU2-Cl )(MU2-eta2,eta2-C60)2.2C6H14 (1) complex in which two cobalt atoms bridge two fullerene molecules to form a dimer. The dimer has a triplet ground state with two weakly coupling Co0 atoms (S = 1/2). The spin transition realized above 150 K is accompanied by a cobalt-to-fullerene charge transfer that forms a quintet excited state with a high spin CoI (S = 1) and C60*- (S = 1/2). PMID- 27936667 TI - Magnetically Retrievable Nanocomposite Based on Thiosemicarbazide-Formaldehyde Resin as a Versatile Nucleophilic Scavenger. AB - A magnetically retrievable nanocomposite was prepared by in situ polycondensation and entrapment of iron oxide nanoparticles. This material was found to be efficient in trapping excess electrophilic reagents such as carbonyl compounds, acid chlorides and isothiocyanates. Advantages of the new scavenger include facile preparation, high loading capacity, low cost, satisfactory swelling properties in polar solvents, and convenient magnetic recovery. PMID- 27936668 TI - Synthesis and Evaluation of a Library of Trifunctional Scaffold-Derived Compounds as Modulators of the Insulin Receptor. AB - We designed a combinatorial library of trifunctional scaffold-derived compounds, which were derivatized with 30 different in-house-made azides. The compounds were proposed to mimic insulin receptor (IR)-binding epitopes in the insulin molecule and bind to and activate this receptor. This work has enabled us to test our synthetic and biological methodology and to prove its robustness and reliability for the solid-phase synthesis and testing of combinatorial libraries of the trifunctional scaffold-derived compounds. Our effort resulted in the discovery of two compounds, which were able to weakly induce the autophosphorylation of IR and weakly bind to this receptor at a 0.1 mM concentration. Despite these modest biological results, which well document the well-known difficulty in modulating protein-protein interactions, this study represents a unique example of targeting the IR with a set of nonpeptide compounds that were specifically designed and synthesized for this purpose. We believe that this work can open new perspectives for the development of next-generation insulin mimetics based on the scaffold structure. PMID- 27936669 TI - Rigid, Conjugated Macrocycles for High Performance Organic Photodetectors. AB - Organic photodetectors (OPDs) are attractive for their high optical absorption coefficient, broad wavelength tunability, and compatibility with lightweight and flexible devices. Here we describe a new molecular design that enables high performance organic photodetectors. We use a rigid, conjugated macrocycle as the electron acceptor in devices to obtain high photocurrent and low dark current. We make a direct comparison between the devices made with the macrocyclic acceptor and an acyclic control molecule; we find that the superior performance of the macrocycle originates from its rigid, conjugated, and cyclic structure. The macrocycle's rigid structure reduces the number of charged defects originating from deformed sp2 carbons and covalent defects from photo/thermoactivation. With this molecular design, we are able to suppress dark current density while retaining high responsivity in an ultrasensitive nonfullerene OPD. Importantly, we achieve a detectivity of ~1014 Jones at near zero bias voltage. This is without the need for extra carrier blocking layers commonly employed in fullerene based devices. Our devices are comparable to the best fullerene-based photodetectors, and the sensitivity at low working voltages (<0.1 V) is a record for nonfullerene OPDs. PMID- 27936670 TI - Simulation-Based Algorithm for Two-Dimensional Chemical Structure Diagram Generation of Complex Molecules and Ligand-Protein Interactions. AB - Computer programs for structure diagram generation (SDG) are indispensable cheminformatic tools that translate one- or three-dimensional (1D or 3D) chemical structure data stored in electronic formats to human-readable 2D depictions. Although many such programs are known, only a moderate part of chemical space can be handled by existing algorithms. For many classes of natural and synthetic compounds the results obtained with current SDG methods are illegible. A new algorithm based solely on a physical simulation of a molecule has been developed. The method allows for a general and global approach to avoid overlapping atoms and substituents. While the algorithm shows no advantage for trivial molecules, it shows superior performance over existing methods in depicting the most challenging compounds. The algorithm can generate chemically correct and legible 2D structure diagrams of many classes of natural and synthetic compounds that are intractable with existing SDG algorithms. The use of the method for generating schematic ligand-receptor interaction diagrams is also discussed. PMID- 27936671 TI - Fabrication of Concentrated Fish Oil Emulsions Using Dual-Channel Microfluidization: Impact of Droplet Concentration on Physical Properties and Lipid Oxidation. AB - Chemically unstable lipophilic bioactives, such as polyunsaturated lipids, often have to be encapsulated in emulsion-based delivery systems before they can be incorporated into foods, supplements, and pharmaceuticals. The objective of this study was to develop highly concentrated emulsion-based fish oil delivery systems using natural emulsifiers. Fish oil-in-water emulsions were fabricated using a highly efficient dual-channel high-pressure microfluidizer. The impact of oil concentration on the formation, physical properties, and oxidative stability of fish oil emulsions prepared using two natural emulsifiers (quillaja saponins and rhamnolipids) and one synthetic emulsifier (Tween-80) was examined. The mean droplet size, polydispersity, and apparent viscosity of the fish oil emulsions increased with increasing oil content. However, physically stable emulsions with high fish oil levels (30 or 40 wt %) could be produced using all three emulsifiers, with rhamnolipids giving the smallest droplet size (d < 160 nm). The stability of the emulsions to lipid oxidation increased as the oil content increased. The oxidative stability of the emulsions also depended on the nature of the emulsifier coating the lipid droplets, with the oxidative stability decreasing in the following order: rhamnolipids > saponins ~ Tween-80. These results suggest that rhamnolipids may be particularly effective at producing emulsions containing high concentrations of omega-3 polyunsaturated fatty acids rich fish oil. PMID- 27936672 TI - Zeolite CAN and AFI-Type Zeolitic Imidazolate Frameworks with Large 12-Membered Ring Pore Openings Synthesized Using Bulky Amides as Structure-Directing Agents. AB - Using bulky amides as the structure-directing agents (SDAs) is an alternative synthetic strategy for the exploration of crystalline large pore (>=12-membered ring) zeolitic imidazolate frameworks (ZIFs). Specifically, by using the bulky amides, dibutylformamide (DBF) and dipropylformamide (DPF) as solvent and imidazole (Im) as a ligand, two ZIFs mimicking the CAN and AlPO-5 (AFI) zeotypes with 12-membered ring (MR) pore openings were synthesized, and denoted as CAN [Zn(Im)2] and AFI-[Zn(Im)2], respectively. These two materials are the first known examples of Zn(Im)2 polymorphs with 12-MR pores and AFI-[Zn(Im)2] has the largest pore apertures reported to date for ZIF materials. The concept that the bulky amides used were not simply acting as the solvent, but were in fact acting as SDAs or templates during the synthesis of the large pore ZIFs, was suggested by the closeness of the geometrical fit between the guest DBF and the can cages (composite building units) of the CAN-[Zn(Im)2]. PMID- 27936673 TI - Structural Descriptors of Zeolitic-Imidazolate Frameworks Are Keys to the Activity of Fe-N-C Catalysts. AB - Active and inexpensive catalysts for oxygen reduction are crucially needed for the widespread development of polymer electrolyte fuel cells and metal-air batteries. While iron-nitrogen-carbon materials pyrolytically prepared from ZIF 8, a specific zeolitic imidazolate framework (ZIF) with sodalite topology, have shown enhanced activities toward oxygen reduction in acidic electrolyte, the rational design of sacrificial metal-organic frameworks toward this application has hitherto remained elusive. Here, we report for the first time that the oxygen reduction activity of Fe-N-C catalysts positively correlates with the cavity size and mass-specific pore volume in pristine ZIFs. The high activity of Fe-N-C materials prepared from ZIF-8 could be rationalized, and another ZIF structure leading to even higher activity was identified. In contrast, the ORR activity is mostly unaffected by the ligand chemistry in pristine ZIFs. These structure property relationships will help identifying novel sacrificial ZIF or porous metal-organic frameworks leading to even more active Fe-N-C catalysts. The findings are of great interest for a broader application of the class of inexpensive metal-nitrogen-carbon catalysts that have shown promising activity also for the hydrogen evolution (Co-N-C) and carbon dioxide reduction (Fe-N-C and Mn-N-C). PMID- 27936674 TI - NMR Spectroscopic Characterization of Charge Assisted Strong Hydrogen Bonds in Bronsted Acid Catalysis. AB - Hydrogen bonding plays a crucial role in Bronsted acid catalysis. However, the hydrogen bond properties responsible for the activation of the substrate are still under debate. Here, we report an in depth study of the properties and geometries of the hydrogen bonds in (R)-TRIP imine complexes (TRIP: 3,3' Bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diylhydrogen phosphate). From NMR spectroscopic investigations 1H and 15N chemical shifts, a Steiner-Limbach correlation, a deuterium isotope effect as well as quantitative values of 1JNH,2hJPH and 3hJPN were used to determine atomic distances (rOH, rNH, rNO) and geometry information. Calculations at SCS-MP2/CBS//TPSS-D3/def2-SVP-level of theory provided potential surfaces, atomic distances and angles. In addition, scalar coupling constants were computed at TPSS-D3/IGLO-III. The combined experimental and theoretical data reveal mainly ion pair complexes providing strong hydrogen bonds with an asymmetric single well potential. The geometries of the hydrogen bonds are not affected by varying the steric or electronic properties of the aromatic imines. Hence, the strong hydrogen bond reduces the degree of freedom of the substrate and acts as a structural anchor in the (R) TRIP imine complex. PMID- 27936676 TI - Multiscale Structural Changes of Wheat and Yam Starches during Cooking and Their Effect on in Vitro Enzymatic Digestibility. AB - In the present study, the multiscale structures and in vitro digestibility of wheat and yam starches with different water contents after heating at 100 degrees C were investigated. After heating for the same time, the degree of gelatinization of both starches increased with increasing water content, followed by the gradual disruption of multiscale structures of starch granules. At a water content of 37% for wheat and 46% for yam starch, both starches were almost completely gelatinized after heating for 5 min at 100 degrees C. Heat treatment increased greatly in vitro enzymatic digestibility of both starches, especially at a water content of >28%. It is interesting to note that extending heat treatment did not further disrupt the multiscale structures nor increase the in vitro enzymatic digestibility of both starches with the same water content. In contrast to wheat starch, yam starch showed a higher resistance to heat treatment. From this study, we can conclude that water content plays a more important role in determining the gelatinization behavior and in vitro enzymatic digestibility of starch than the duration of heating. PMID- 27936675 TI - Stacking Geometries of Early Protoporphyrin IX Aggregates Revealed by Gas-Phase Infrared Spectroscopy. AB - Amphiphilic porphyrins are of great interest in the field of supramolecular chemistry because they can be fabricated into highly ordered architectures that are stabilized by pi-pi stacking of porphine rings as well as by non-covalent interactions between their hydrophilic substituents. Protoporphyrin IX (PPIX) has two flexible propionic acid tails and is one of the most common amphiphilic porphyrins. However, unlike other PPIX analogues, PPIX does not form stable extended nanostructures, and the reason for this is still not understood. Here, we employ ion mobility mass spectrometry in combination with infrared multiple photon dissociation spectroscopy to investigate early aggregates of PPIX. The ion mobility results show that growth occurs via single-stranded face-to-face stacking of PPIX. From the infrared spectroscopy on well-defined aggregates, it can be concluded that pairing of the carboxylic acid groups of the tails is a stabilizing element and that such a pairing occurs across a third residue from residue n to residue n+2. The tetramer appears to be especially stable, because all of its propionic acid tails are optimally paired and no free tails to promote further growth are present, which possibly prevents PPIX from forming larger, well-ordered assemblies. PMID- 27936677 TI - Visualizing the Cu/Cu2(O) Interface Transition in Nanoparticles with Environmental Scanning Transmission Electron Microscopy. AB - Understanding the oxidation and reduction mechanisms of catalytically active transition metal nanoparticles is important to improve their application in a variety of chemical processes. In nanocatalysis the nanoparticles can undergo oxidation or reduction in situ, and thus the redox species are not what are observed before and after reactions. We have used the novel environmental scanning transmission electron microscope (ESTEM) with 0.1 nm resolution in systematic studies of complex dynamic oxidation and reduction mechanisms of copper nanoparticles. The oxidation of copper has previously been reported to be dependent on its crystallography and its interaction with the substrate. By following the dynamic oxidation process in situ in real time with high-angle annular dark-field imaging in the ESTEM, we use conditions ideal to track the oxidation front as it progresses across a copper nanoparticle by following the changes in the atomic number (Z) contrast with time. The oxidation occurs via the nucleation of the oxide phase (Cu2O) from one area of the nanoparticle which then progresses unidirectionally across the particle, with the Cu-to-Cu2O interface having a relationship of Cu{111}//Cu2O{111}. The oxidation kinetics are related to the temperature and oxygen pressure. When the process is reversed in hydrogen, the reduction process is observed to be similar to the oxidation, with the same crystallographic relationship between the two phases. The dynamic observations provide unique insights into redox mechanisms which are important to understanding and controlling the oxidation and reduction of copper-based nanoparticles. PMID- 27936678 TI - Copper(II) Activation of Nitrite: Nitrosation of Nucleophiles and Generation of NO by Thiols. AB - Nitrite (NO2-) and nitroso compounds (E-NO, E = RS, RO, and R2N) in mammalian plasma and cells serve important roles in nitric oxide (NO) dependent as well as NO independent signaling. Employing an electron deficient beta-diketiminato copper(II) nitrito complex [Cl2NNF6]Cu(kappa2-O2N).THF, thiols mediate reduction of nitrite to NO. In contrast to NO generation upon reaction of thiols at iron nitrite species, at copper this conversion proceeds through nucleophilic attack of thiol RSH on the bound nitrite in [CuII](kappa2-O2N) that leads to S nitrosation to give the S-nitrosothiol RSNO and copper(II) hydroxide [CuII]-OH. This nitrosation pathway is general and results in the nitrosation of the amine Ph2NH and alcohol tBuOH to give Ph2NNO and tBuONO, respectively. NO formation from thiols occurs from the reaction of RSNO and a copper(II) thiolate [CuII]-SR intermediate formed upon reaction of an additional equiv thiol with [CuII]-OH. PMID- 27936679 TI - The Reaction Mechanism with Free Energy Barriers at Constant Potentials for the Oxygen Evolution Reaction at the IrO(2) (110) Surface. AB - How to efficiently oxidize H2O to O2 (oxygen evolution reaction, OER) in photoelectrochemical cells (PEC) is a great challenge due to its complex charge transfer process, high overpotential, and corrosion. So far no OER mechanism has been fully explained atomistically with both thermodynamic and kinetics. IrO2 is the only known OER catalyst with both high catalytic activity and stability in acidic conditions. This is important because PEC experiments often operate at extreme pH conditions. In this work, we performed first-principles calculations integrated with implicit solvation at constant potentials to examine the detailed atomistic reaction mechanism of OER at the IrO2 (110) surface. We determined the surface phase diagram, explored the possible reaction pathways including kinetic barriers, and computed reaction rates based on the microkinetic models. This allowed us to resolve several long-standing puzzles about the atomistic OER mechanism. PMID- 27936680 TI - Novel Barley (1->3,1->4)-beta-Glucan Endohydrolase Alleles Confer Increased Enzyme Thermostability. AB - Barley (1->3,1->4)-beta-glucan endohydrolases (beta-glucanases; EI and EII) are primarily responsible for hydrolyzing high molecular weight (1->3,1->4)-beta glucans (beta-glucan) during germination. Incomplete endosperm modification during malting results in residual beta-glucan that can contribute to increased wort viscosity and beer chill haze. Four newly identified forms of EI and EII and the reference enzymes EI-a and EII-a were expressed in Escherichia coli, and the recombinant proteins were characterized for enzyme kinetics and thermostability. EI and EII variants that exhibited higher residual beta-glucanase activity than EI-a and EII-a after heat treatment also exhibited increased substrate affinity and decreased turnover rates. The novel EII-l form exhibited significantly increased thermostability compared with the reference EII-a when activity was measured at elevated temperature. EII-l exhibited a T50 value, which indicates the temperature at which 50% of beta-glucanase activity remains, 1.3 degrees C higher than that of EII-a. The irreversible thermal inactivation difference between EII-a and EII-l after 5 min of heat treatment at 56 degrees C was 11.9%. The functional significance of the three amino acid differences between EII-a and EII-l was examined by making combinatorial mutations in EII-a using site-directed mutagenesis. The S20G and D284E amino acid substitutions were shown to be responsible for the increase in EII-1 thermostability. PMID- 27936682 TI - Catalytic Kinetic Resolution of Saturated N-Heterocycles by Enantioselective Amidation with Chiral Hydroxamic Acids. AB - The preparation of enantioenriched chiral compounds by kinetic resolution dates back to the laboratories of Louis Pasteur in the middle of the 19th century. Unlike asymmetric synthesis, this process can always deliver enantiopure material (ee > 99%) if the reactions are allowed to proceed to sufficient conversion and the selectivity of the process is not unity (s > 1). One of the most appealing and practical variants is acylative kinetic resolution, which affords easily separable reaction products, and several highly efficient enzymatic and small molecule catalysts are available. Unfortunately, this method is applicable to limited substrate classes such as alcohols and primary benzylamines. This Account focuses on our work in catalytic acylative kinetic resolution of saturated N heterocycles, a class of molecules that has been notoriously difficult to access via asymmetric synthesis. We document the development of hydroxamic acids as suitable catalysts for enantioselective acylation of amines through relay catalysis. Alongside catalyst optimization and reaction development, we present mechanistic studies and theoretical calculation accounting for the origins of selectivity and revealing the concerted nature of many amide-bond forming reactions. Immobilization of the hydroxamic acid to form a polymer supported reagent allows simplification of the experimental setup, improvement in product purification, and extension of the substrate scope. The kinetic resolutions are operationally straight forward: reactions proceed at room temperature and open to air conditions, without generation of difficult-to-remove side products. This was utilized to achieve decagram scale resolution of antimalarial drug mefloquine to prepare more than 50 g of (+)-erythro-meflqouine (er > 99:1) from the racemate. The immobilized quasienantiomeric acyl hydroxamic acid reagents were also exploited for a rare practical implementation of parallel kinetic resolution that affords both enantiomers of the amine products in high enantiopurity. The success of this process relied on identification of two cleavable acyl groups alongside implementation of flow-chemistry techniques to ensure reusability of the resolving agents. The work discussed in this Account has laid foundations for new catalyst design as well as development of desymmetrization and dynamic kinetic resolution processes. In the meantime, as all the requisite reagents are commercially available, we hope that hydroxamic acid promoted acylative kinetic resolution will become a method of choice for preparation of saturated N heterocycles in enantiopure form. PMID- 27936681 TI - Khellin and Visnagin, Furanochromones from Ammi visnaga (L.) Lam., as Potential Bioherbicides. AB - Plants constitute a source of novel phytotoxic compounds to be explored in searching for effective and environmentally safe herbicides. From a previous screening of plant extracts for their phytotoxicity, a dichloromethane extract of Ammi visnaga (L.) Lam. was selected for further study. Phytotoxicity-guided fractionation of this extract yielded two furanochromones, khellin and visnagin, for which herbicidal activity had not been described before. Khellin and visnagin were phytotoxic to model species lettuce (Lactuca sativa) and duckweed (Lemna paucicostata), with IC50 values ranging from 110 to 175 MUM. These compounds also inhibited the growth and germination of a diverse group of weeds at 0.5 and 1 mM. These weeds included five grasses [ryegrass (Lolium multiflorum), barnyardgrass (Echinocloa crus-galli), crabgrass (Digitaria sanguinalis), foxtail (Setaria italica), and millet (Panicum sp.)] and two broadleaf species [morningglory (Ipomea sp.) and velvetleaf (Abutilon theophrasti)]. During greenhouse studies visnagin was the most active and showed significant contact postemergence herbicidal activity on velvetleaf and crabgrass at 2 kg active ingredient (ai) ha 1. Moreover, its effect at 4 kg ai ha-1 was comparable to the bioherbicide pelargonic acid at the same rate. The mode of action of khellin and visnagin was not a light-dependent process. Both compounds caused membrane destabilization, photosynthetic efficiency reduction, inhibition of cell division, and cell death. These results support the potential of visnagin and, possibly, khellin as bioherbicides or lead molecules for the development of new herbicides. PMID- 27936683 TI - Development and Scope of the Arene-Fused Domino Michael/Mannich Reaction: Application to the Total Syntheses of Aspidosperma Alkaloids (-) Aspidospermidine, (-)-Tabersonine, and (-)-Vincadifformine. AB - The development and application of the arene-fused domino Michael/Mannich route to the tetrahydrocarbazole (ABE) core of Aspidosperma alkaloids is described. The scope of this novel transformation was studied in terms of the nucleophilic component (i.e., N-sulfinyl metallodienamine) and the electrophilic component (i.e., Michael acceptor). The successful application of this methodology toward the concise total syntheses of classical indole alkaloids (-)-aspidospermidine, ( )-tabersonine, and (-)-vincadifformine in 10-11 steps, respectively, is also discussed. PMID- 27936685 TI - NMR Spectroscopic Profiling of Arabinan and Galactan Structural Elements. AB - Pectic arabinans and galactans presumably affect the physiological and technological properties of plant cell walls and dietary fiber. Their complex structures are usually analyzed by time-consuming methods, which are based on chemical cleavage to monomers. To gain more detailed insights into the arabinan and galactan structures, a time-efficient approach based on enzymatic cleavage and two-dimensional NMR spectroscopy was developed. Heteronuclear single quantum coherence spectroscopy (HSQC) marker signals were evaluated for various structural elements, and relative response factors were determined, allowing a semiquantitative estimation of the structural composition. The method was applied to analyze different insoluble plant materials and soluble polysaccharides. It was demonstrated that the developed approach yielded comparable information about various structural elements that can also be detected by using the conventional methylation analysis. However, by using the NMR method, additional structural information, such as the anomeric configuration of the monomers, is obtained, demonstrating the value of this novel approach. PMID- 27936684 TI - Purification and Characterization of a Black Walnut (Juglans nigra) Allergen, Jug n 4. AB - Tree nuts as a group cause a significant number of fatal anaphylactic reactions to foods. Walnuts (Juglans spp.) are one of the leading causes of allergic reactions to tree nuts in the U.S. and Japan. The purpose of this study was to purify and characterize potential food allergens from black walnut. Here, we report the isolation of the black walnuts allergen Jug n 4 (an 11S globulin) by ammonium sulfate precipitation, hydrophobic interaction, and size exclusion chromatography. Reducing SDS-PAGE analysis indicated that purified Jug n 4 consists of three major bands. N-Terminal sequencing data of these bands indicated that they were the results of a post-transcriptional protease cleavage of the mature protein at a site that consists of a known conserved protease recognition motif, NGXEET. Western blot experiments revealed that 32% of the sera from 25 patients with double-blind, placebo-controlled clinical walnut allergy contained IgE antibodies that recognized Jug n 4, indicating that it is a walnut allergen. Identifying this and additional allergens may facilitate the understanding of the allergenicity of seed storage proteins in tree nuts and their cross-reactivity. PMID- 27936686 TI - Two-Coordinate Co(II) Imido Complexes as Outstanding Single-Molecule Magnets. AB - The pursuit of single-molecule magnets (SMMs) with better performance urges new molecular design that can endow SMMs larger magnetic anisotropy. Here we report that two-coordinate cobalt imido complexes featuring highly covalent Co?N cores exhibit slow relaxation of magnetization under zero direct-current field with a high effective relaxation barrier up to 413 cm-1, a new record for transition metal based SMMs. Two theoretical models were carried out to investigate the anisotropy of these complexes: single-ion model and Co-N coupling model. The former indicates that the pseudo linear ligand field helps to preserve the first order orbital momentum, while the latter suggests that the strong ferromagnetic interaction between Co and N makes the [CoN]+ fragment a pseudo single paramagnetic ion, and that the excellent performance of these cobalt imido SMMs is attributed to the inherent large magnetic anisotropy of the [CoN]+ core with |MJ = +/- 7/2? ground Kramers doublet. PMID- 27936687 TI - Discovery and LC-MS Characterization of New Crocins in Gardeniae Fructus and Their Neuroprotective Potential. AB - Ten new crocins, neocrocins B-J (1-9) and 13-cis-crocetin-8'-O-beta-d gentiobioside (14), along with 10 known crocins, were isolated from the fruits of Gardenia jasminoides Ellis (Gardeniae Fructus). The structures of these compounds were elucidated by analyzing HRESIMS, UV/vis, and 1D and 2D NMR spectra, and their neuroprotective effects against hydrogen peroxide- and l-glutamic acid induced SH-SY5Y cell injury were evaluated. The UPLC-Q/TOF-MS chromatogram of a crocin-rich fraction derived from gardenia fruit extracts was established using the obtained crocin compounds as references. Most of the peaks were identified (the total integral area of the identified peaks accounted for 95% of total peak areas), and bioactive crocins were a large portion of this fraction (the areas of peaks from the neuroprotective compounds accounted for 70% of the total). PMID- 27936688 TI - P(NMe2)3-Mediated Aziridination of Imines with alpha-Ketoesters for Synthesis of Aziridine-2-carboxylates. AB - Aziridination of N-sulfonyl imines with alpha-ketoesters in the presence of P(NMe2)3 is reported. Adducts derived from trivalent phosphorus reagents and alpha-ketoesters are effectively intercepted by imines, affording a range of aziridine-2-carboxylates. The diastereoselectivity of the reaction depends on steric hindrance from substituents on the substrates. PMID- 27936690 TI - Mixture of Clustered Bayesian Neural Networks for Modeling Friction Processes at the Nanoscale. AB - Friction and wear are the source of every mechanical device failure, and lubricants are essential for the operation of the devices. These physical phenomena have a complex nature so that no model capable of accurately predicting the behavior of lubricants exists. Thus, lubricants cannot be designed from scratch but have to be screened through expensive trial-error tests. In this study we propose a machine learning (ML) method that infers the relationship between chemical composition of lubricants and their performance from a database. Because no such database of desirable size and completeness is publicly available, we compiled one from molecular dynamics (MD) simulations of toy-model fluids nanoconfined between shearing surfaces. The fluid-friction relation is modeled by a Bayesian neural network (BNN), trained to reproduce the results for a training set of fluids. Due to the inhomogeneous data distribution it was necessary to carefully pick fluids for training and validation from the database with advanced clustering algorithms, rather than using the standard random selection. Different BNNs were then trained on the data clusters and their predictions combined into a mixture of experts. The model provides a prediction of lubricants performance as well as an error bar, at a fraction of the cost of MD. Because most values agree with the actual MD simulations within the estimated error sigma, we conclude that the model is satisfactory. This method addresses the challenges brought by noisy, badly distributed, high-dimensional data that are likely to appear in reality as well, and it can be extended to real fluids, if a database could be provided. PMID- 27936689 TI - Triazole- and Tetrazole-Bridged Nucleic Acids: Synthesis, Duplex Stability, Nuclease Resistance, and in Vitro and in Vivo Antisense Potency. AB - Antisense oligonucleotides are attractive therapeutic agents for several types of disease. One of the most promising modifications of antisense oligonucleotides is the introduction of bridged nucleic acids. As we report here, we designed novel bridged nucleic acids, triazole-bridged nucleic acid (TrNA), and tetrazole bridged nucleic acid (TeNA), whose sugar conformations are restricted to N-type by heteroaromatic ring-bridged structures. We then successfully synthesized TrNA and TeNA and introduced these monomers into oligonucleotides. In UV-melting experiments, TrNA-modified oligonucleotides exhibited increased binding affinity toward complementary RNA and decreased binding affinity toward complementary DNA, although TeNA-modified oligonucleotides were decomposed under the annealing conditions. Enzymatic degradation experiments demonstrated that introduction of TrNA at the 3'-terminus rendered oligonucleotides resistant to nuclease digestion. Furthermore, we tested the silencing potencies of TrNA-modified antisense oligonucleotides using in vitro and in vivo assays. These experiments revealed that TrNA-modified antisense oligonucleotides induced potent downregulation of gene expression in liver. In addition, TrNA-modified antisense oligonucleotides showed a tendency for increased liver biodistribution. Taken together, our findings indicate that TrNA is a good candidate for practical application in antisense methodology. PMID- 27936691 TI - Synthesis of C-4-Substituted Steviol Derivatives and Their Inhibitory Effects against Hepatitis B Virus. AB - ent-13-Hydroxykaur-16-ene-19-N-butylureide (6) was one of 33 synthesized C-4 substituted steviol derivatives that were evaluated for their effects on hepatitis B virus (HBV) surface antigen (HBsAg) secretion. The IC50 (16.9 MUM) and SI (57.7) values for inhibiting HBV DNA replication of compound 6 were greater than those of the reference compound, lamivudine (3-TC; IC50: 107.5 MUM; SI: 22.0). Thus, the anti-HBV mechanism of 6 was investigated, and it specifically inhibited viral gene expression and reduced viral DNA levels, as well as potently attenuated all of the viral promoter activity of HBV-expressing Huh7 cells. Examination of cellular signaling pathways found that 6 inhibited the activities of the nuclear factor (NF)-kappaB- and activator protein (AP)-1 element-containing promoters, but had no effects on AP-2 or interferon-stimulated response element (ISRE)-containing promoters in HBV-expressing cells. Meanwhile, it significantly eliminated NF-kappaB and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling-related protein levels and inhibited their phosphorylation in HBV-transfected Huh7 cells. The inhibitory potency of 6 against HBV DNA replication was reversed by cotransfecting the NF kappaB p65 expression plasmid. Using the MAPK-specific activator anisomycin also reversed the inhibitory effect of 6 on viral DNA replication. The present findings suggest that the anti-HBV mechanism of 6 is partly mediated through the NF-kappaB and MAPK signaling pathways. PMID- 27936692 TI - Rhodium-Catalyzed Synthesis of Unsymmetric Di(heteroaryl) Sulfides Using Heteroaryl Ethers and S-Heteroaryl Thioesters via Heteroarylthio Exchange. AB - Unsymmetric di(heteroaryl) sulfides were synthesized by a rhodium-catalyzed heteroarylthio exchange reaction of heteroaryl aryl ethers and S-(heteroaryl) thioesters. The reaction has broad applicability, giving diverse unsymmetric di(heteroaryl) sulfides containing five- and six-membered heteroarenes. No base is required in this reaction, which has been developed by the judicious design of organic substrates. PMID- 27936693 TI - Copper-Catalyzed Decarboxylative Difluoroalkylation and Perfluoroalkylation of alpha,beta-Unsaturated Carboxylic Acids. AB - Copper-catalyzed decarboxylative difluoroalkylation and perfluoroalkylation of alpha,beta-unsaturated carboxylic acids is described. Promoted by dialkyl phosphite, this novel reaction affords fluoroalkylated motifs with excellent stereoselectivity and broad substrate scope under mild reaction conditions from readily available fluoroalkyl iodides and bromides. Preliminary mechanism study suggests that radical pathway was involved in the catalytic cycle and dialkyl phosphite had played an indispensable role in this reaction. PMID- 27936694 TI - Chiral N,N'-Dioxide Organocatalyzed Asymmetric Electrophilic alpha-Cyanation of beta-Keto Esters and beta-Keto Amides. AB - An enantioselective electrophilic alpha-cyanation of 1-indanone-derived beta-keto esters and beta-keto amides using a hypervalent iodine as the cyanide-transfer reagent was realized. A chiral N,N'-dioxide was used as the efficient bifunctional organocatalyst in the presence of inorganic base, which gave the corresponding alpha-cyano dicarbonyl compounds in yields of 50-99% with good enantioselectivities (87-97% ee). PMID- 27936696 TI - Acid/Phosphide-Induced Radical Route to Alkyl and Alkenyl Sulfides and Phosphonothioates from Sodium Arylsulfinates in Water. AB - A newly developed aqueous system with acid and phosphide was introduced in which odorless and stable sodium arylsulfinates can in situ generate arylsulfenyl radicals. These radicals have high reactivity to react with alkynes, alkenes, and H-phosphine oxides for the synthesis of alkyl and alkenyl sulfides and phosphonothioates. The control experiments and quantum calculations are also performed to gain insights into the generation mechanism of arylsulfenyl radicals. Notably, the chemistry is free of thiol odors, organic solvents, and metals. PMID- 27936695 TI - Substrate-Controlled Transformation of Azobenzenes to Indazoles and Indoles via Rh(III)-Catalysis. AB - Rh(III)-catalyzed substrate-controlled transformation of azobenzenes to indazoles and 2-acyl (NH) indoles is achieved via C-H functionalization. Generally, good functional groups tolerance, satisfying yields, and excellent regio-selectivity are achieved in this reaction. Mechanistically, the reaction with acrylates undergoes beta-hydride elimination, while the reaction with vinyl ketones or acrylamides undergoes nucleophilic addition. Copper acetate was supposed to play different roles in the beta-hydride elimination to furnish indazoles and nucleophilic addition of C-Rh bond to deliver 2-acyl (NH) indoles. PMID- 27936697 TI - The Effect of Liposomes on the Kinetics and Mechanism of the Photocatalytic Reduction of 5,5'-Dithiobis(2-Nitrobenzoic Acid) by Triethanolamine. AB - Recently, the addition of negatively charged liposomes was shown to increase the quantum yield of the photocatalytic reduction of 5,5'-dithio(2-nitrobenzoic acid) (H2DTNB) to 2-nitro-5-thiobenzoic acid (H2NTB) by triethanolamine using meso tetra(4-(N-methylpyridinium)porphyrinato zinc chloride as photosensitizer. In this work, we investigate in detail the kinetics of this photocatalytic reaction both in homogeneous solution and at the surface of negatively charged liposomes, to unravel the effects of liposomes on the mechanism of the photoreaction. In homogeneous solution, the reaction is initiated by oxidative quenching. Both static (singlet) and dynamic (triplet) quenching of the photosensitizer contribute to the formation of the photoproduct. In these conditions, the reaction is limited by the low efficiency of reductive regeneration of the photosensitizer, compared to charge recombination. Upon adsorption of the positively charged photosensitizer to the negative surface of the liposomes, however, both static and dynamic oxidative quenching become ineffective due to electrostatic repulsion of the dianionic DTNB2- from the negatively charged membrane. In such conditions, photoreduction occurs via reductive quenching, showing that the addition of liposomes can truly modify the mechanism of photocatalyzed redox reactions. PMID- 27936698 TI - Correction to Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline 1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors. PMID- 27936699 TI - Protein Concentrate Production from Thin Stillage. AB - Two-stage fermentation (TSF) of saccharified wheat with a consortium of endemic lactobacilli produced CO2 and induced colloid separation of fermented solution to produce a protein concentrate (PC). Protein-rich slurry (50%, db) was obtained by decanting solution or skimming floating material during or after TSF. Washing and drying processes were explored to improve protein content, extend storage life of slurry, and yield converted stillage for compound recovery. Centrifuging and washing slurry afforded a PC and clarified solution. PC protein content increased to 60% (w/w, db). The PC was dried in a spray dryer or drum dryer or tray dryer. Dried PC water activity ranged 0.23-0.30. The dried PC lysine content was low, but lysine availability (95%) was excellent. Liquid from TSF and washing was readily microfiltered. Mass recovery of protein, glycerol, 1,3-propanediol, lactic acid, acetic acid, and glycerylphosphorylcholine from combined TSF, washing, and filtration were 66, 76, 72, 77, 74, and 84%, respectively. PMID- 27936700 TI - Polyhedral Oligomeric Silsesquioxane Polymer-Caged Silver Nanoparticle as a Smart Colorimetric Probe for the Detection of Hydrogen Sulfide. AB - The rapid and accurate detection of hydrogen sulfide is of great concern due to its unique role on environmental pollution and signal transmission in physiological systems. Herein, we report a smart colorimetric probe for the selective detection of H2S. The probe is prepared via a surfactant-free route with cross-linked polyhedral oligomeric silsesquioxane (POSS) polymer cage as capping ligand and reducing agent under microwave irradiation, called poly-POSS formaldehyde polymer (PPF) cage-AgNPs or PPF-AgNPs for short. The caged silver nanoparticles are well-dispersed with narrow size distribution within 6.0-8.4 nm. Chloride ions and aldehyde groups in PPF make the nucleation and growth of Ag nanoparticles accomplished within a very short time of 1 min. The positively charged PPF-AgNPs exhibit excellent selectivity to H2S against other anionic species and thiols due to the specific Ag-H2S interaction, where the favorable protection effect of PPF polymer cage from the nanoparticle aggregation is demonstrated. The colorimetric probe presents a quick response to H2S (<3 min) and favorable sensitivity within a linear range of 0.7-10 MUM along with a detection limit of 0.2 MUM. The probe is well demonstrated by analysis of H2S in various water and biological samples. PMID- 27936701 TI - Total Synthesis of the Bis-silyl Ether of (+)-15-epi-Aetheramide A. AB - Synthesis of the macrolactone depsipeptide aetheramide A was attempted by three different approaches. The first approach to form the macrolactone involving macrolactonization to form the C1-C21 bond and the second approach using a ring closing metathesis (RCM) strategy to form the C10-C11 olefinic bond failed. The third approach starting from R-mandelic acid, involving the RCM reaction to install the C18-C19 ring junction, was successful in assembling the macrolactone. PMID- 27936702 TI - Controlled Cross-Linking with Glucose Oxidase for the Enhancement of Gelling Potential of Pork Myofibrillar Protein. AB - Differential oxidative modifications of myofibrillar protein (MP) by hydroxyl radicals generated in an enzymatic system with glucose oxidase (GluOx) in the presence of glucose/FeSO4 versus a Fenton system (H2O2/FeSO4) were investigated. Pork MP was modified at 4 degrees C and pH 6.25 with hydroxyl radicals produced from 1 mg/mL glucose in the presence of 80, 160, or 320 MUg/mL GluOx and 10 MUM FeSO4. Total sulfhydryl content, solubility, cross-linking pattern, and gelation properties of MP were measured. H2O2 production proceeded linearly with the concentration of GluOx and increased with reaction time. GluOx- and H2O2-dose dependent protein polymerization, evidenced by faded myosin heavy chain and actin in SDS-PAGE as well as significant decreases in sulfhydryls, coincided with protein solubility loss. Firmer and more elastic MP gels were produced by GluOx than by the Fenton system at comparable H2O2 levels due to an altered radical reaction pathway. PMID- 27936703 TI - Understanding Atomic-Scale Behavior of Liquid Crystals at Aqueous Interfaces. AB - The ordered environment presented by liquid crystals at interfaces enables a range of novel functionalities that is only now beginning to be exploited in applications ranging from light focusing devices to biosensors. One key feature of liquid crystals is that molecular events occurring at an interface propagate over large distances through the bulk. In spite of their importance, our fundamental understanding of liquid crystal-water and liquid crystal-air interfaces remains limited. In this work, we present results from large-scale atomistic molecular dynamics simulations on the organization of the nematic and isotropic phases of the nitrile-containing mesogenic molecule 4-cyano-4' pentylbiphenyl (5CB) in the vicinity of vacuum and aqueous interfaces. Hybrid boundary conditions are imposed by confining 5CB films between vacuum and an aqueous medium to examine how those two types of interfaces influence the specific structural arrangement and ordering of 5CB. Consistent with experiments, our results indicate that 5CB exhibits homeotropic anchoring at the vacuum interface, and planar alignment at aqueous interfaces. Two-dimensional molecular dynamics potential of mean force calculations and average polarization densities show that the polar nitrile group of 5CB remains hydrated near the aqueous interface, where it modulates the orientation of water molecules. Estimates of the anchoring strength reveal an oscillatory decay and a semilinear decay with distance from the interface in vacuum and water, respectively. PMID- 27936704 TI - In Situ Mass Spectrometric Monitoring of the Dynamic Electrochemical Process at the Electrode-Electrolyte Interface: a SIMS Approach. AB - The in situ molecular characterization of reaction intermediates and products at electrode-electrolyte interfaces is central to mechanistic studies of complex electrochemical processes, yet a great challenge. The coupling of electrochemistry (EC) and mass spectrometry (MS) has seen rapid development and found broad applicability in tackling challenges in analytical and bioanalytical chemistry. However, few truly in situ and real-time EC-MS studies have been reported at electrode-electrolyte interfaces. An innovative EC-MS coupling method named in situ liquid secondary ion mass spectrometry (SIMS) was recently developed by combining SIMS with a vacuum compatible microfluidic electrochemical device. Using this novel capability, we report the first in situ elucidation of the electro-oxidation mechanism of a biologically significant organic compound, ascorbic acid (AA), at the electrode-electrolyte interface. The short-lived radical intermediate was successfully captured, which had not been detected directly before. Moreover, we demonstrated the power of this new technique in real-time monitoring of the formation and dynamic evolution of electrical double layers at the electrode-electrolyte interface. This work suggests further promising applications of in situ liquid SIMS in studying more complex chemical and biological events at the electrode-electrolyte interface. PMID- 27936705 TI - Theoretical Identification of Three C66 Fullerene Isomers and Related Chlorinated Derivatives by X-ray Photoelectron Spectroscopy and Near-edge X-ray Absorption Fine Structure Spectroscopy. AB - C 1s X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine structure (NEXAFS) spectra for three C66 fullerene isomers and related chlorinated species have been calculated by density functional theory (DFT) method. The XPS spectra show isomer dependence for the three pristine C66 isomers but not for the chlorinated species. The NEXAFS spectra exhibit strong dependence on the structures of all the investigated molecules and thus can be well employed to identify the three C66 fullerene isomers and related chlorinated species. Both XPS and NEXAFS spectra of the chlorinated species present significant variations compared with the pristine fullerenes. The spectral components for carbon atoms of different local environments have been explored as well. The spectra for the carbon atoms connecting to chlorine atoms exhibit a significant blue shift compared to the others. PMID- 27936706 TI - Computational Chemistry Data Management Platform Based on the Semantic Web. AB - This paper presents a formal data publishing platform for computational chemistry using semantic web technologies. This platform encapsulates computational chemistry data from a variety of packages in an Extensible Markup Language (XML) file called CSX (Common Standard for eXchange). On the basis of a Gainesville Core (GC) ontology for computational chemistry, a CSX XML file is converted into the JavaScript Object Notation for Linked Data (JSON-LD) format using an XML Stylesheet Language Transformation (XSLT) file. Ultimately the JSON-LD file is converted to subject-predicate-object triples in a Turtle (TTL) file and published on the web portal. By leveraging semantic web technologies, we are able to place computational chemistry data onto web portals as a component of a Giant Global Graph (GGG) such that computer agents, as well as individual chemists, can access the data. PMID- 27936707 TI - Study on Mobility, Distribution and Rapid Ion Mobility Spectrometry Detection of Seven Pesticide Residues in Cucumber, Apple, and Cherry Tomato. AB - This research explores the mobility and distribution rules of simazine, acetamiprid, hexazinone, paclobutrazol, amitraz, clofentezine, and boscalid in the pulp and peel of apple, cucumber, and cherry tomato. A laboratory test was carried out by treating the matrices with standard solution for different periods of time. The percentage sorption of pesticides ranged from 0.02 to 89.3% for the three matrices. The pesticides' distribution was also determined, and all pesticides showed ratio values (Q) between pulp and peel concentrations in the three matrices of <0.8, which proved that the highest pesticides' content was found in the peel. In addition, a rapid and simple process combining a surface swab capture method and pulse glow discharge-ion mobility spectrometry (PGD-IMS) detection was established for the detection of pesticides on matrix surfaces. In the swab method, the whole matrix surface was swabbed manually by swab sticks, and swab sticks were agitated in acetonitrile to release the pesticides. The releasing factors of pesticides in the three matrices were calculated. The linearity, LOD, LOQ, and matrix effect were investigated to assess the applicability of the swab-IMS process in practical analysis. The swab-IMS method is rapid, sensitive, and quantitative and can be achieved in the field. PMID- 27936708 TI - Geometry and Electronic Structure of Titanabenzene and Its Valence Isomers. AB - Potentially aromatic metallocycles are of interest due to their possible use as experimental catalytic materials and to their assistance in developing theoretical understanding of metal-carbon bonds. Ab initio analysis of titanabenzene and its valence isomers reveals the lack of aromatic stability for the planar, heterosubstituted benzene molecule. The planar molecule is in fact a transition state on the potential energy surface. Due to a pseudo-Jahn-Teller effect, the planar titanabenzene molecule is predicted to be less stable than the Dewar-titanabenzene molecule by 25.9 kcal/mol. However, the most stable structural isomer of HTiC5H5 is found to be the open-sandwich (eta5 cyclopentadienyl)titanium(II) hydride structure that is a ground-state triplet and 50.3 kcal/mol lower in energy than Dewar-titanabenzene. Electronic structures and bonding within these valence isomers are presented from analysis of the population bond order density matrices based on the novel oriented valence quasi atomic molecular orbitals (QUAOs) obtained from TCSCF wave functions. PMID- 27936710 TI - Diastereoselective Synthesis of Rauhut-Currier-Type Adducts via an Unexpected alpha-Addition of alpha,beta-Unsaturated gamma-Butyrolactams to Coumarin Derivatives. AB - A novel, base-catalyzed and highly diastereoselective direct Michael addition isomerization sequence is presented for the efficient synthesis of Rauhut-Currier type adducts. An unexpected alpha-addition of gamma-butyrolactam onto the 3-acyl coumarin derivatives was observed rather than the gamma-addition, which is more common. The adducts could further undergo hydrolysis/decarboxylation to generate the products which are equivalent to those obtained by alpha-addition of gamma butyrolactam onto the corresponding chalcones. PMID- 27936711 TI - New Parameters for Higher Accuracy in the Computation of Binding Free Energy Differences upon Alanine Scanning Mutagenesis on Protein-Protein Interfaces. AB - Knowing how proteins make stable complexes enables the development of inhibitors to preclude protein-protein (P:P) binding. The identification of the specific interfacial residues that mostly contribute to protein binding, denominated as hot spots, is thus critical. Here, we refine an in silico alanine scanning mutagenesis protocol, based on a residue-dependent dielectric constant version of the Molecular Mechanics/Poisson-Boltzmann Surface Area method. We have used a large data set of structurally diverse P:P complexes to redefine the residue dependent dielectric constants used in the determination of binding free energies. The accuracy of the method was validated through comparison with experimental data, considering the per-residue P:P binding free energy (DeltaDeltaGbinding) differences upon alanine mutation. Different protocols were tested, i.e., a geometry optimization protocol and three molecular dynamics (MD) protocols: (1) one using explicit water molecules, (2) another with an implicit solvation model, and (3) a third where we have carried out an accelerated MD with explicit water molecules. Using a set of protein dielectric constants (within the range from 1 to 20) we showed that the dielectric constants of 7 for nonpolar and polar residues and 11 for charged residues (and histidine) provide optimal DeltaDeltaGbinding predictions. An overall mean unsigned error (MUE) of 1.4 kcal mol-1 relative to the experiment was achieved in 210 mutations only with geometry optimization, which was further reduced with MD simulations (MUE of 1.1 kcal mol 1 for the MD employing explicit solvent). This recalibrated method allows for a better computational identification of hot spots, avoiding expensive and time consuming experiments or thermodynamic integration/ free energy perturbation/ uBAR calculations, and will hopefully help new drug discovery campaigns in their quest of searching spots of interest for binding small drug-like molecules at P:P interfaces. PMID- 27936712 TI - Effects of Solvation and Hydrogen Bond Formation on Singlet and Triplet Alkyl or Aryl Carbenes. AB - Formation of hydrogen-bonded complexes involving singlet and triplet alkyl or aryl carbenes and the impacts of solvation and hydrogen bonding upon the carbene singlet-triplet gaps have been investigated using computational methods. Single point CCSD(T)-F12 and MRCI+Q methodologies have been employed with aug-cc-pVDZ and aug-cc-pVTZ basis sets to determine accurate singlet-triplet gaps of carbenes and hydrogen-bonded complexes involving carbenes, with geometries and vibrational frequencies obtained at the B3LYP-D3/aug-cc-pVTZ level. Using the PCM continuum solvent method and density functional theory (B3LYP/aug-cc-pVTZ), the singlet triplet gaps of the carbenes are found to exhibit significant solvent effects; due its higher polarity, the singlet carbene is stabilized to a greater degree than the corresponding triplet carbene, impacting the singlet-triplet gap by as much as 4.4 kcal/mol. In addition, water and methanol, acting as hydrogen bond donors, form hydrogen bonds with all the singlet and triplet carbenes studied in this work. Singlet carbenes form relatively strong hydrogen bonds with binding energies in the range 3-9 kcal/mol; triplet carbenes form weaker hydrogen bonds with binding energies in the range 1-4 kcal/mol. NBO analysis demonstrates that the singlet carbene hydrogen bonds are stabilized in typical fashion, through donation of electron density from the lone pair orbital on carbon into the O-H antibonding orbital. This stabilizing interaction also is present in triplet carbene hydrogen bonds; however, a back-donation from the O-H bonding orbital into the carbon lone pair orbitals also is observed, which leads to reduced charge transfer in the triplet carbene hydrogen-bonded complexes. With the exception of methylene, hydrogen bond formation is strong enough to reverse the ordering of the singlet and triplet states for the carbenes possessing triplet ground states. PMID- 27936709 TI - A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models. AB - Here we describe a new approach for tumor targeting in which augmented concentrations of Fe(II) in cancer cells and/or the tumor microenvironment triggers drug release from an Fe(II)-reactive prodrug conjugate. The 1,2,4 trioxolane scaffold developed to enable this approach can in principle be applied to a broad range of cancer therapeutics and is illustrated here with Fe(II) targeted forms of a microtubule toxin and a duocarmycin-class DNA-alkylating agent. We show that the intrinsic reactivity/toxicity of the duocarmycin analog is masked in the conjugated form and this greatly reduced toxicity in mice. This in turn permitted elevated dosing levels, leading to higher systemic exposure and a significantly improved response in tumor xenograft models. Overall our results suggest that Fe(II)-dependent drug delivery via trioxolane conjugates could have significant utility in expanding the therapeutic index of a range of clinical and preclinical stage cancer chemotherapeutics. PMID- 27936713 TI - Photon Counting Data Analysis: Application of the Maximum Likelihood and Related Methods for the Determination of Lifetimes in Mixtures of Rose Bengal and Rhodamine B. AB - It is often convenient to know the minimum amount of data needed to obtain a result of desired accuracy and precision. It is a necessity in the case of subdiffraction-limited microscopies, such as stimulated emission depletion (STED) microscopy, owing to the limited sample volumes and the extreme sensitivity of the samples to photobleaching and photodamage. We present a detailed comparison of probability-based techniques (the maximum likelihood method and methods based on the binomial and the Poisson distributions) with residual minimization-based techniques for retrieving the fluorescence decay parameters for various two fluorophore mixtures, as a function of the total number of photon counts, in time correlated, single-photon counting experiments. The probability-based techniques proved to be the most robust (insensitive to initial values) in retrieving the target parameters and, in fact, performed equivalently to 2-3 significant figures. This is to be expected, as we demonstrate that the three methods are fundamentally related. Furthermore, methods based on the Poisson and binomial distributions have the desirable feature of providing a bin-by-bin analysis of a single fluorescence decay trace, which thus permits statistics to be acquired using only the one trace not only for the mean and median values of the fluorescence decay parameters but also for the associated standard deviations. These probability-based methods lend themselves well to the analysis of the sparse data sets that are encountered in subdiffraction-limited microscopies. PMID- 27936714 TI - Thermal and Structural Properties of Silk Biomaterials Plasticized by Glycerol. AB - The molecular interactions of silk materials plasticized using glycerol were studied, as these materials provide options for biodegradable and flexible protein-based systems. Plasticizer interactions with silk were analyzed by thermal, spectroscopic, and solid-state NMR analyses. Spectroscopic analysis implied that glycerol was hydrogen bonded to the peptide matrix, but may be displaced with polar solvents. Solid-state NMR indicated that glycerol induced beta-sheet formation in the dried silk materials, but not to the extent of methanol treatment. Fast scanning calorimetry suggested that beta-sheet crystal formation in silk-glycerol films appeared to be less organized than in the methanol treated silk films. We propose that glycerol may be simultaneously inducing and interfering with beta-sheet formation in silk materials, causing some improper folding that results in less-organized silk II structures even after the glycerol is removed. This difference, along with trace residual glycerol, allows glycerol extracted silk materials to retain more flexibility than methanol processed versions. PMID- 27936715 TI - A Closer Look at the Impact of Molecular Imprinting on Adsorption Capacity and Selectivity for Protein Templates. AB - Molecularly imprinted polymers (MIPs) are often investigated as lower cost, more environmentally robust alternatives to natural recognitive biomolecules, such as antibodies. When synthesized on the surface of nanomaterial supports, MIPs are capable of quick and effective binding of macromolecular templates when compared to traditional bulk-imprinted polymers. We have developed a method for imprinting proteins on biodegradable nanoparticle supports and have used these materials to investigate the impact of molecular imprinting on adsorption capacity and selectivity for lysozyme, the template protein. The imprinting process increased the adsorption capacity of the polymer for the template, lysozyme, with the MIPs being able to bind up to 83.5% of their dry weight as compared to 55.7% for nonimprinted polymers (NIPs). In noncompetitive binding experiments, where proteins were independently incubated with MIPs, the difference between adsorption capacity for lysozyme and proteins with much lower isoelectric points (pI < 8.0) was statistically significant. However, there was no statistical difference between adsorption capacity for lysozyme and other high-isoelectric point proteins, suggesting that MIPs are semiselective for this class of proteins. In competitive binding experiments, both MIPs and NIPs preferentially bound lysozyme over other high-isoelectric point proteins. This result demonstrated that imprinting alone could not account for the observed selectivity for lysozyme. Analysis of the solvent accessible surface area of lysozyme and its high-isoelectric point competitors revealed why lysozyme is an exceptional binder to the polymer system used in this work, with or without imprinting. PMID- 27936716 TI - Binary Complex Based on Zein and Propylene Glycol Alginate for Delivery of Quercetagetin. AB - Propylene glycol alginate (PGA) was found to be able to dissolve in aqueous ethanol solution and applied to interact with zein to form a noncovalent binary complex by the antisolvent coprecipitation method at pH 4.0. Quercetagetin (Q) was employed to explore the Q-delivery potential of Zein-PGA binary complex. A fruit tree-like microstructure was observed for Zein-PGA binary complex as its "branches" were closely adsorbed by zein particles. A solid sponge-like entity was formed after lyophilization of Zein-PGA binary complex colloidal dispersion. A synergistic effect was found between zein and PGA on improving the entrapment efficiency and loading capacity of Q. The incorporation of Q at a high concentration induced a significant effect on the tertiary structure of zein. Electrostatic attraction, hydrogen bond, and hydrophobic effects were mainly involved in the interactions between zein and PGA. Schematics with four possible structures were proposed to explain the formation mechanism of composites. PMID- 27936717 TI - Preparation and Antibacterial Mechanism Insight of Polypeptide-Based Micelles with Excellent Antibacterial Activities. AB - Traditional antibiotics usually sterilize in chemical ways, which may lead to serious drug resistance. By contrast, peptide-based antibacterial materials are less susceptible to drug resistance. Herein we report the preparation of an antibacterial peptide-based copolymer micelle and the investigation of its membrane-penetration antibacterial mechanism by transmission electron microscopy (TEM). The copolymer is poly(l-lactide)-block-poly(phenylalanine-stat-lysine) [PLLA31-b-poly(Phe24-stat-Lys36)], which is synthesized by ring-opening polymerization. The PLLA chains form the core, whereas the polypeptide chains form the coronas of the micelle in aqueous solution. This micelle boasts excellent antibacterial efficacy against both Gram-positive and Gram-negative bacteria. Furthermore, TEM studies clearly reveal that the micelles pierce and then destroy the cell membrane of the bacteria. We also compared the advantages and disadvantages of two general methods for measuring the Minimal Inhibitory Concentration (MIC) values of antibacterial micelles. Overall, this study provides us with direct evidence for the antibacterial mechanism of polypeptide based micelles and a strategy for synthesizing biodegradable antibacterial nanomaterials without antibiotic resistance. PMID- 27936718 TI - Heparin-Like Chitosan Hydrogels with Tunable Swelling Behavior, Prolonged Clotting Times, and Prevented Contact Activation and Complement Activation. AB - The aim of this study was to create heparin-like chitosan hydrogels (HLCHs) for blood purification. Herein, we prepared two heparin-like chitosans (HLCSs) with various carboxymethyl and sulfate groups, followed by a cross-linking reaction with glutaraldehyde. The synthetic chitosan derivatives were characterized by X ray photoelectron spectroscopy, gel permeation chromatography, FTIR and NMR. The average sulfonation degrees of two HLCSs were 0.69 and 0.94 per sugar unit, respectively. The swelling ratio of the HLCH could reach up to 4800%, and the HLCHs remained a well-defined shape and stable below 170 degrees C. Moreover, the activated partial thromboplastin time and thrombin time results indicated that both of the HLCSs and their hydrogels exhibited excellent thrombus inhibition property. Furthermore, the contact activation and complement activation results also proved that the hydrogels possessed good blood compatibility and had the potential to be used as blood-contacting materials. PMID- 27936719 TI - Stable Aqueous Foams from Cellulose Nanocrystals and Methyl Cellulose. AB - The addition of cellulose nanocrystals (CNC) greatly enhanced the properties of methylcellulose (MC) stabilized aqueous foams. CNC addition decreased air bubble size, initial foam densities and drainage rates. Mixtures of 2 wt % CNC + 0.5 wt % MC gave the lowest density foams. This composition sits near the onset of nematic phase formation and also near the overlap concentration of methylcellulose. More than 94% of the added CNC particles remained in the foam phase, not leaving with the draining water. We propose that the nanoscale CNC particles bind to the larger MC coils both in solution and with MC at the air/water interface, forming weak gels that stabilize air bubbles. Wet CNC-MC foams were sufficiently robust to withstand high temperature (70 degrees C for 6 h) polymerization of water-soluble monomers giving macroporous CNC composite hydrogels based on acrylamide (AM), 2-hydroxyethyl methacrylate (HEMA), or polyethylene glycol diacrylate (PEGDA). At high temperatures, the MC was present as a fibrillar gel phase reinforced by CNC particles, explaining the very high foam stability. Finally, our CNC-MC foams are based on commercially available forms of CNC and MC, already approved for many applications. This is a "shovel ready" technology. PMID- 27936720 TI - Nonwoven Carboxylated Agarose-Based Fiber Meshes with Antimicrobial Properties. AB - Hydrogel forming polysaccharides, such as the seaweed derived agarose, are well suited for wound dressing applications as they have excellent cell and soft tissue compatibility. For wound dressings, fibrous structure is desirable as the high surface area can favor adsorption of wound exudate and promote drug delivery. Although electrospinning offers a straightforward means to produce nonwoven fibrous polymeric structures, processing agarose and its derivatives into fibers through electrospinning is challenging as it has limited solubility in solvents other than water. In this study we describe the processing of carboxylated agarose (CA) fibers with antibacterial properties by electrospinning from a solution of the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride ([Bmim]+Cl-) possessing antimicrobial properties. The extent of carboxylation was found to impact fiber diameter, mesh elastic modulus, fiber swelling, and the loading and release of IL. IL-bearing CA fibers inhibited the growth of Staphylococcus aureus and Pseudomonas aeruginosa, bacteria commonly found in wound exudate. In sum, nonwoven CA fibers processed from IL are promising as biomaterials for wound dressing applications. PMID- 27936721 TI - Synthesis and Characterization of Injectable Sulfonate-Containing Hydrogels. AB - Sulfonate-containing hydrogels are of particular interest because of their tunable mechanical and swelling properties, as well as their biological effects. Polysulfonate copolymers were synthesized by reacting 2-acrylamido-2 methylpropanesulfonic acid (AMPS), acrylamide (AM), and acrylic acid (AA). We found that the incorporation rate of sulfonate-containing monomer and the molecular weight of the copolymer were significantly enhanced by increasing the ionic strength of the solution. We introduced thiol groups by modifying the pendant carboxylates or copolymerizing along with a disulfide-containing monomer. The thiol-containing copolymers were reacted with a 4-arm acrylamide-terminated poly(ethylene glycol) via a thiol-ene click reaction, which was mediated by a photoinitiator, a redox initiator, or a base-catalyzed Michael-Addition. We were able to tailor the storage modulus (33-1800 Pa) and swelling capacity (1-91 wt %) of the hydrogel by varying the concentration of the copolymers. We determined that the injectable sulfonate-containing hydrogels were biocompatible up to 20 mg/mL, as observed by an electric cell-substrate impedance sensing (ECIS) technique, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using three different cell lines: human retinal pigment epithelial cells (ARPE-19), fibroblasts (NIH 3T3), and Chinese hamster ovary cells (CHO). PMID- 27936723 TI - Tumor Microenvironment-Responsive Nanoparticle Delivery of Chemotherapy for Enhanced Selective Cellular Uptake and Transportation within Tumor. AB - A novel drug delivery strategy featured with enhanced uptake of nanoparticles (NPs) by targeted tumor cells and subsequent intratumoral cellular hitchhiking of chemotherapy to deep tumor regions was described. The NP delivery system was obtained from assembly of poly(lactic acid-co-glycolic acid)-grafted hyaluronic acid (HA-g-PLGA) together with an anticancer drug, SN38, in aqueous phase, followed by implementing the NP surface with a layer of methoxypoly(ethylene glycol)-b-poly(histamine methacrylamide) (mPEG-b-PHMA) via hydrophobic association to improve the colloidal stability both in vitro and in vivo. Upon arrival of these PEGylated NPs at the acidic tumor site through the EPR effect, mPEG-b-PHMA became detached from the NP surface by the charge transition of the PHMA blocks from neutral (hydrophobic) to positively charged (hydrophilic) state via acid-induced protonation of their imidazole groups in tumor microenvironment. The exposure of HA shell on the naked NP thus resulted in enhanced uptake of NPs by CD44-expressed tumor cells, including cancer cells and tumor-associated macrophages (TAMs). Along with the TAMs being further chemotactically recruited by hypoxia cells, the engulfed nanotherapeutics was thus transported into the avascular area in which the anticancer action of chemotherapy occurred by virtue of the drug release alongside PLGA degradation, similar to those arising in other tumor nonhypoxia regions. PMID- 27936722 TI - Modular and Adaptable Tumor Niche Prepared from Visible Light Initiated Thiol Norbornene Photopolymerization. AB - Photopolymerized biomimetic hydrogels with adaptable properties have been widely used for cell and tissue engineering applications. As a widely adopted gel cross linking method, photopolymerization provides experimenters on-demand and spatial temporal controls in gelation kinetics. Long wavelength ultraviolet (UV) light initiated photopolymerization is among the most popular methods in the fabrication of cell-laden hydrogels owing to its rapid and relatively mild gelation conditions. The use of UV light, however, still causes concerns regarding its potential negative impacts on cells. Alternatively, visible light based photopolymerization can be used to cross-link cell-laden hydrogels. The majority of visible light based gelation schemes involve photoinitiator, co initiator, and comonomer. This multicomponent initiation system creates added challenges for optimizing hydrogel formulations. Here, we report a co initiator/comonomer-free visible light initiated thiol-norbornene photopolymerization scheme to prepare modular biomimetic hydrogels suitable for in situ cell encapsulation. Eosin-Y was used as the sole initiator to initiate modular gelation between synthetic macromers (e.g., thiolated poly(vinyl alcohol) or poly(ethylene glycol)) and functionalized extracellular matrices (ECMs) including norbornene-functionalized gelatin (GelNB) or thiolated hyaluronic acid (THA). These components are modularly cross-linked to afford bioinert (i.e., purely synthetic), bioactive (i.e., using gelatin), and biomimetic (i.e., using gelatin and hyaluronic acid) hydrogels. The stiffness of the hydrogels can be easily tuned without affecting the contents of the bioactive components. Furthermore, the use of naturally derived biomacromolecules (e.g., gelatin and HA) renders these hydrogels susceptible to enzyme-mediated degradation. In addition to demonstrating efficient and tunable visible light mediated gelation, we also utilized this biomimetic modular gelation system to formulate artificial tumor niche and to study the effects of cell density and gel modulus on the formation of pancreatic ductal adenocarcinoma (PDAC) spheroids. PMID- 27936724 TI - Molecular Design: Network Architecture and Its Impact on the Organization and Mechanics of Peptide-Polyurea Hybrids. AB - Nature has achieved controlled and tunable mechanics via hierarchical organization driven by physical and covalent interactions. Polymer-peptide hybrids have been designed to mimic natural materials utilizing these architectural strategies, obtaining diverse mechanical properties, stimuli responsiveness, and bioactivity. Here, utilizing a molecular design pathway, peptide-polyurea hybrid networks were synthesized to investigate the role of architecture and structural interplay on peptide hydrogen bonding, assembly, and mechanics. Networks formed from poly(beta-benzyl-l-aspartate) poly(dimethylsiloxane) copolymers covalently cross-linked with a triisocyanate yielded polyurea films with a globular-like morphology and parallel beta-sheet secondary structures. The geometrical constraints imposed by the network led to an increase in peptide loading and ~7x increase in Young's modulus while maintaining extensibility (~160%). Thus, the interplay of physical and chemical bonds allowed for the modulation of resulting mechanical properties. This investigation provides a framework for the utilization of structural interplay and mechanical tuning in polymer-peptide hybrids, which offers a pathway for the design of future hybrid biomaterial systems. PMID- 27936725 TI - Triple Block Nanocarrier Platform for Synergistic Cancer Therapy of Antagonistic Drugs. AB - A unique biodegradable triple block nanocarrier (TBN) is designed and developed for synergistic combination therapy of antagonistic drugs for cancer treatment. The TBN was built with hydrophilic polyethylene glycol (PEG) outer shell; a middle hydrophobic and biodegradable polycaprolactone (PCL) block for encapsulating anthracycline anticancer drug like doxorubicin (DOX), and an inner carboxylic-functionalized polycaprolactone (CPCL) core for cisplatin (CP) drug conjugation. TBN-cisplatin drug conjugate self-assembled as stable nanoparticles in saline (also in PBS) wherein the hydrophobic PCL block functions as a shield for Pt-drug stability against GSH detoxification. Enzymatic-biodegradation of TBN exclusively occurred at the intracellular environment to deliver both cisplatin (CP) and doxorubicin (DOX) simultaneously to the nucleus. As a result, the TBN cisplatin conjugate and its DOX-loaded nanoparticles accomplished 100% cell growth inhibition in GSH overexpressed breast cancer cells. Combination therapy revealed that free drugs were antagonistic to each other, whereas the dual drug loaded TBN exhibited excellent synergistic cell killing at much lower drug concentrations in breast cancer cells. Confocal microscopic analysis confirmed the localization of drugs in the cytoplasm and at peri-nuclear site. Flow cytometry analysis revealed that the drugs were taken up 4-fold better while delivering them from TBN platform compared to free form. The TBNs approach is a perfect platform to overcome the GSH detoxification in Pt-drugs and enable the codelivery of antagonistic drugs like cisplatin and DOX from single polymer dose to accomplish synergistic killing in breast cancer cells. PMID- 27936726 TI - Enzymatic Synthesis of a Bio-Based Copolyester from Poly(butylene succinate) and Poly((R)-3-hydroxybutyrate): Study of Reaction Parameters on the Transesterification Rate. AB - The enzyme-catalyzed synthesis of fully biobased poly(3-hydroxybutyrate-co butylene succinate) (poly(HB-co-BS)) copolyesters is reported for the first time. Different Candida antarctica lipase B (CALB)-catalyzed copolyesters were produced in solution, via a one-step or a two-step process from 1,4-butanediol, diethyl succinate, and synthesized telechelic hydroxylated poly(3-hydroxybutyrate) oligomers (PHB-diol). The influence of the ester/hydroxyl functionality ratio, catalyst amount, PHB-diol oligomer chain length, hydroxybutyrate (HB) and butylene succinate (BS) contents, and the nature of the solvent were investigated. The two-step process allowed the synthesis of copolyesters of high molar masses (Mn up to 18 000 g/mol), compared to the one-step process (Mn ~ 8000 g/mol), without thermal degradation. The highest molar masses were obtained with diphenyl ether as solvent, compared with dibenzyl ether or anisole. During the two-step process, the transesterification rate between the HB and BS segments (i) increased with increasing amount of catalyst and decreasing molar mass of the PHB diol oligomer, (ii) decreased when anisole was used as the solvent, and (iii) was not influenced by the HB/BS ratio. Tendencies toward block or random macromolecular architectures were observed as a function of the reaction time, the PHB-diol oligomer chain length, and the chosen solvent. Immobilized CALB catalyzed copolyesters were thermally stable up to 200 degrees C. The crystalline structure of the poly(HB-co-BS) copolyesters depended on the HB/BS ratio and the average sequence length of the segments. The crystalline content, Tm and Tc decreased with increasing HB content and the randomness of the copolymer structure. PMID- 27936727 TI - Targeting Heparin to Collagen within Extracellular Matrix Significantly Reduces Thrombogenicity and Improves Endothelialization of Decellularized Tissues. AB - Thrombosis within small-diameter vascular grafts limits the development of bioartificial, engineered vascular conduits, especially those derived from extracellular matrix (ECM). Here we describe an easy-to-implement strategy to chemically modify vascular ECM by covalently linking a collagen binding peptide (CBP) to heparin to form a heparin derivative (CBP-heparin) that selectively binds a subset of collagens. Modification of ECM with CBP-heparin leads to increased deposition of functional heparin (by ~7.2-fold measured by glycosaminoglycan composition) and a corresponding reduction in platelet binding (>70%) and whole blood clotting (>80%) onto the ECM. Furthermore, addition of CBP heparin to the ECM stabilizes long-term endothelial cell attachment to the lumen of ECM-derived vascular conduits, potentially through recruitment of heparin binding growth factors that ultimately improve the durability of endothelialization in vitro. Overall, our findings provide a simple yet effective method to increase deposition of functional heparin on the surface of ECM-based vascular grafts and thereby minimize thrombogenicity of decellularized tissue, overcoming a significant challenge in tissue engineering of bioartificial vessels and vascularized organs. PMID- 27936728 TI - Conjugation of Polyphosphoester and Antimicrobial Peptide for Enhanced Bactericidal Activity and Biocompatibility. AB - Enhancing the bactericidal activity and moderating the toxicity are two important challenges in the design of upcoming antimicrobial compounds. Herein, antimicrobial macromolecules were developed by conjugating CysHHC10 peptide and polyphosphoester for the modulation of microbiocidal activity and biocompatibility. The conjugation was carried out via thiol-yne "click" chemistry between the cysteine terminal of the peptide and the pendant propargyl moieties of the polyphosphoester. The bactericidal efficacy of the polyphosphoester peptide conjugates were investigated by microbial growth inhibition toward the Gram-positive and Gram-negative bacteria. On the basis of peptide mass fraction, the polyphosphoester-peptide conjugates exhibited lower values of minimum inhibitory concentration than that of the free peptide. The polyphosphoester peptide conjugates also exhibited ultralow hemolytic characteristic at a concentration of 4000 MUg/mL, indicating significant improvement of erythrocytes compatibility as compared to the free peptide that readily caused lysis of 50% of red blood cells at 1000 MUg/mL. Cytotoxicity of the polyphosphoester-peptide conjugates toward 3T3 fibroblast cells was also reduced in comparison to that of the free peptide. Conjugation of the polyphosphoester thus improves the bactericidal efficacy and biocompatibility of the antimicrobial peptide. PMID- 27936729 TI - Octreotide Functionalized Nano-Contrast Agent for Targeted Magnetic Resonance Imaging. AB - Reversible addition-fragmentation chain transfer (RAFT) polymerization has been employed to synthesize branched block copolymer nanoparticles possessing 1,4,7,10 tetraazacyclododecane-N,N,'N,"N,'''-tetraacetic acid (DO3A) macrocycles within their cores and octreotide (somatostatin mimic) cyclic peptides at their periphery. These polymeric nanoparticles have been chelated with Gd3+ and applied as magnetic resonance imaging (MRI) nanocontrast agents. This nanoparticle system has an r1 relaxivity of 8.3 mM-1 s-1, which is 3 times the r1 of commercial gadolinium-based contrast agents (GBCAs). The in vitro targeted binding efficiency of these nanoparticles shows 5 times greater affinity to somatostatin receptor type 2 (SSTR2) with Ki = 77 pM (compared to somatostatin with Ki = 0.385 nM). We have also evaluated the tumor targeting molecular imaging ability of these branched copolymer nanoparticle in vivo using nude/NCr mice bearing AR42J rat pancreatic tumor (SSTR2 positive) and A549 human lung carcinoma tumor (SSTR2 negative) xenografts. PMID- 27936731 TI - Gas Phase Oxidation of Campholenic Aldehyde and Solution Phase Reactivity of its Epoxide Derivative. AB - The rate constant for the OH reaction with campholenic aldehyde (CA) was measured using the flow tube-chemical ionization mass spectrometry method with a relative rate kinetics technique and was found to be (6.54 +/- 0.52) * 10-11 cm3 molecule 1 s-1 at 100 Torr pressure and 298 K. A mechanism for the formation of the observed products was developed for both NO-free and NO-present conditions. On the basis of measurements of the pressure dependent yields of the products, between 5 and 20% of the CA oxidation at atmospheric pressure is predicted to lead to campholenic aldehyde epoxide (CAE). The aqueous solution reaction rate constants for CAE were determined via NMR spectroscopy and were found to be (2.241 +/- 0.036) * 10-5 s-1 for neutral conditions and 0.0989 +/- 0.0053 M-1 s-1 for acid-catalyzed conditions at 298 K. The products of the CAE aqueous solution reaction were identified as an isomer of CAE and the aldehyde group hydrated form of this isomer. Unlike the isoprene-derived epoxide, IEPOX, a nucleophilic addition mechanism was not observed. On the basis of the rate constants determined for CA and CAE, it is likely that these species are reactive on atmospherically relevant time scales in the gas and aerosol phases, respectively. The results of the present study largely support a previous supposition that alpha-pinene-derived secondary organic aerosol may be influenced by the multiphase processing of various intermediate species, including those with epoxide functionality. PMID- 27936730 TI - Profluorescent PPV-Based Micellar System as a Versatile Probe for Bioimaging and Drug Delivery. AB - Although micelles are commonly used for drug delivery purposes, their long-term fate is often unknown due to photobleaching of the fluorescent labels or the use of toxic materials. Here, we present a metal-free, nontoxic, nonbleaching, fluorescent micelle that can address these shortcomings. A simple, yet versatile, profluorescent micellar system, built from amphiphilic poly(p-phenylenevinylene) (PPV) block copolymers, for use in drug delivery applications is introduced. Polymer micelles made from PPV show excellent stability for up to 1 year and are successfully loaded with anticancer drugs (curcumin or doxorubicin) without requiring introduction of physical or chemical cross-links. The micelles are taken up efficiently by the cells, which triggers disassembly, releasing the encapsulated material. Disassembly of the micelles and drug release is conveniently monitored as fluorescence of the single polymer chains appear, which enables not only to monitor the release of the payload, but in principle also the fate of the polymer over longer periods of time. PMID- 27936732 TI - Entropy-Driven Segregation and Its Competition with Crystal Nucleation in the Binary Blends of Stretched and Free Guest Polymers. AB - Enhancing the dynamic asymmetry between liquid-like and solid-like components leads to spontaneous segregation. As a typical example, the binary blends of stretched and free guest polymers were investigated by our dynamic Monte Carlo simulations. The results evidenced an entropic driving force for the strain induced segregation between two components, similar to that for Onsager's lyotropic liquid crystals. In addition, with the decrease of strain rates, its competition with strain-induced crystal nucleation results in variable compositions in crystal precursors. The scenario helps to settle down the controversial arguments on the flow-induced precursors of shish-kebab crystallites in the melt. PMID- 27936733 TI - Synthesis of Quinolines through Three-Component Cascade Annulation of Aryl Diazonium Salts, Nitriles, and Alkynes. AB - An efficient and rapid synthesis of multiply substituted quinolines is described. This method is enabled by a three-component cascade annulation of readily available aryl diazonium salts, nitriles, and alkynes. This reaction is catalyst- and additive-free. Various aryl diazonium salts, nitriles, and alkynes can participate in this transformation, and the yields are up to 83%. PMID- 27936735 TI - Site-Specific Electron-Relaxation Caused by Si:2p Core-Level Photoionization: Comparison between F3SiCH2CH2Si(CH3)3 and Cl3SiCH2CH2Si(CH3)3 Vapors by Means of Photoelectron Auger Electron Coincidence Spectroscopy. AB - Site-specific electron relaxations caused by Si:2p core-level photoionizations in F3SiCH2CH2Si(CH3)3 and Cl3SiCH2CH2Si(CH3)3 vapors have been studied by means of the photoelectron Auger electron coincidence spectroscopy. F3SiCH2CH2Si(CH3)3 shows almost 100% site-specificity in fragmentation caused by the Si:2p ionization. However, substitution of Cl for F of F3SiCH2CH2Si(CH3)3 considerably reduces the site-specificity at the Si atom bonded to three halogen atoms, with the site-specificity at the Si site bonded to three methyl groups remaining largely unchanged. The site-specificity reduction in Cl3SiCH2CH2Si(CH3)3 is considered to take place during the transient period between Si:L23VV Auger electron emission and the subsequent fragmentation. The reason for the reduction can be explained in terms of some differences between these two molecules in the L23VV Auger decay at the Si site bonded to the three halogen atoms. PMID- 27936736 TI - Thermodynamic Study of Molecular Interactions in Eutectic Mixtures Containing Camphene. AB - Terpenes are an abundant and diverse class of chemicals having numerous applications in different areas of chemistry. Therefore, a detailed knowledge of physical and thermodynamic properties of terpenes and their mixtures with other compounds is highly desired. This paper reports both a thermodynamic study on solid-liquid equilibrium (SLE) phase diagrams in binary systems formed by (+/-) camphene (a representative terpene) and one of the following solvents: n-decane, n-dodecane, 1-decanol, 1-dodecanol, phenylmethanol, 2-phenylethanol, 2 cyclohexylethanol. The observed trends in the measured SLE data are discussed in terms of structure (alkyl chain length, aromacity) of the solvent and molecular interactions. Modeling of the considered SLE phase diagrams with three well established thermodynamic models, namely, modified UNIFAC (Dortmund), perturbed chain statistical associating fluid theory (PC-SAFT) and conductor-like screening model for real solvents (COSMO-RS), is presented. A comparative analysis of their performance is given in terms of average absolute deviations between predicted and experimental SLE temperature. PMID- 27936734 TI - CHARMM-GUI MDFF/xMDFF Utilizer for Molecular Dynamics Flexible Fitting Simulations in Various Environments. AB - X-ray crystallography and cryo-electron microscopy are two popular methods for the structure determination of biological molecules. Atomic structures are derived through the fitting and refinement of an initial model into electron density maps constructed by both experiments. Two computational approaches, MDFF and xMDFF, have been developed to facilitate this process by integrating the experimental data with molecular dynamics simulation. However, the setup of an MDFF/xMDFF simulation requires knowledge of both experimental and computational methods, which is not straightforward for nonexpert users. In addition, sometimes it is desirable to include realistic environments, such as explicit solvent and lipid bilayers during the simulation, which poses another challenge even for expert users. To alleviate these difficulties, we have developed MDFF/xMDFF Utilizer in CHARMM-GUI that helps users to set up an MDFF/xMDFF simulation. The capability of MDFF/xMDFF Utilizer is greatly enhanced by integration with other CHARMM-GUI modules, including protein structure manipulation, a diverse set of lipid types, and all-atom CHARMM and coarse-grained PACE force fields. With this integration, various simulation environments are available for MDFF Utilizer (vacuum, implicit/explicit solvent, and bilayers) and xMDFF Utilizer (vacuum and solution). In this work, three examples are shown to demonstrate the usage of MDFF/xMDFF Utilizer. PMID- 27936737 TI - Field Continuous Measurement of Dissolved Gases with a CF-MIMS: Applications to the Physics and Biogeochemistry of Groundwater Flow. AB - In the perspective of a temporal and spatial exploration of aquatic environments (surface and groundwater), we developed a technique for field continuous measurements of dissolved gases with a precision better than 1% for N2, O2, CO2, He, Ar, 2% for Kr, 8% for Xe, and 3% for CH4, N2O and Ne. With a large resolution (from 1 * 10-9 to 1 * 10-2 ccSTP/g) and a capability of high frequency analysis (1 measure every 2 s), the CF-MIMS (Continuous Flow Membrane Inlet Mass Spectrometer) is an innovative tool allowing the investigation of a large panel of hydrological and biogeochemical processes in aquatic systems. Based on the available MIMS technology, this study introduces the development of the CF-MIMS (conception for field experiments, membrane choices, ionization) and an original calibration procedure allowing the quantification of mass spectral overlaps and temperature effects on membrane permeability. This study also presents two field applications of the CF-MIMS involving the well-logging of dissolved gases and the implementation of groundwater tracer tests with dissolved 4He. The results demonstrate the analytical capabilities of the CF-MIMS in the field. Therefore, the CF-MIMS is a valuable tool for the field characterization of biogeochemical reactivity, aquifer transport properties, groundwater recharge, groundwater residence time and aquifer-river exchanges from few hours to several weeks experiments. PMID- 27936738 TI - Calibrating Reaction Enthalpies: Use of Density Functional Theory and the Correlation Consistent Composite Approach in the Design of Photochromic Materials. AB - Acquisition of highly accurate energetic data for chromium-containing molecules and various chromium carbonyl complexes is a major step toward calibrating bond energies and thermal isomerization energies from mechanisms for Cr-centered photochromic materials being developed in our laboratories. The performance of six density functionals in conjunction with seven basis sets, utilizing Gaussian type orbitals, has been evaluated for the calculation of gas-phase enthalpies of formation and enthalpies of reaction at 298.15 K on various chromium-containing systems. Nineteen molecules were examined: Cr(CO)6, Cr(CO)5, Cr(CO)5(C2H4), Cr(CO)5(C2ClH3), Cr(CO)5(cis-(C2Cl2H2)), Cr(CO)5(gem-(C2Cl2H2)), Cr(CO)5(trans (C2Cl2H2)), Cr(CO)5(C2Cl3H), Cr(CO)5(C2Cl4), CrO2, CrF2, CrCl2, CrCl4, CrBr2, CrBr4, CrOCl2, CrO2Cl2, CrOF2, and CrO2F2. The performance of 69 density functionals in conjunction with a single basis set utilizing Slater-type orbitals (STO) and a zeroth-order relativistic approximation was also evaluated for the same test set. Values derived from density functional theory were compared to experimental values where available, or values derived from the correlation consistent composite approach (ccCA). When all reactions were considered, the functionals that exhibited the smallest mean absolute deviations (MADs, in kcal mol-1) from ccCA-derived values were B97-1 (6.9), VS98 (9.0), and KCIS (9.4) in conjunction with quadruple-zeta STO basis sets and B97-1 (9.3) in conjunction with cc-pVTZ basis sets. When considering only the set of gas-phase reaction enthalpies (DeltarH degrees gas), the functional that exhibited the smallest MADs from ccCA-derived values were B97-1 in conjunction with cc-pVTZ basis sets (9.1) and PBEPBE in conjunction with polarized valence triple-zeta basis set/effective core potential combination for Cr and augmented and multiple polarized triple zeta Pople style basis sets (9.5). Also of interest, certainly because of known cancellation of errors, PBEPBE with the least-computationally expensive basis set combination considered in the present study (valence double-zeta basis set/effective core potential combination for Cr and singly-polarized double-zeta Pople style basis sets) also provided reasonable accuracy (11.1). An increase in basis set size was found to have an improvement in accuracy for the best performing functional (B97-1). PMID- 27936739 TI - Phase Transformation, Exceptional Quenching Efficiency, and Discriminative Recognition of Nitroaromatic Analytes in Hydrophobic, Nonporous Zn(II) Coordination Frameworks. AB - Five-fold interpenetrated Zn(II) frameworks (1 and 2) have been prepared, and an irreversible phase transformation from 1 to 2 is found to occur through a dissolution-recrystallization process. Compound 1 exhibits the highest quenching efficiency (>96%) for nitrobenzene at 7 ppm among luminescent coordination polymers. Selective discrimination of nitroaromatic molecules including o nitrophenol (o-NP), p-nitrophenol (p-NP), 2,4-dinitrophenol (DNP), and 2,4,6 trinitrophenol (TNP) is realized in 1 and 2 as a result of the fact that the framework-analyte interaction affords characteristic emission signals. This observation is the first case of a nonporous coordination framework for such discriminative detection. Notably, significant hydrophobicity is evident in the framework 1 because of its surface roughness, which accounts for the enhanced quenching ability. PMID- 27936740 TI - Atomistic Molecular Dynamics Simulations of Carbon Dioxide Diffusivity in n Hexane, n-Decane, n-Hexadecane, Cyclohexane, and Squalane. AB - Atomistic molecular dynamics simulations were carried out to obtain the diffusion coefficients of CO2 in n-hexane, n-decane, n-hexadecane, cyclohexane, and squalane at temperatures up to 423.15 K and pressures up to 65 MPa. Three popular models were used for the representation of hydrocarbons: the united atom TraPPE (TraPPE-UA), the all-atom OPLS, and an optimized version of OPLS, namely, L-OPLS. All models qualitatively reproduce the pressure dependence of the diffusion coefficient of CO2 in hydrocarbons measured recently, and L-OPLS was found to be the most accurate. Specifically for n-alkanes, L-OPLS also reproduced the measured viscosities and densities much more accurately than the original OPLS and TraPPE-UA models, indicating that the optimization of the torsional potential is crucial for the accurate description of transport properties of long chain molecules. The three force fields predict different microscopic properties such as the mean square radius of gyration for the n-alkane molecules and pair correlation functions for the CO2-n-alkane interactions. CO2 diffusion coefficients in all hydrocarbons studied are shown to deviate significantly from the Stokes-Einstein behavior. PMID- 27936741 TI - Interaction of a Cationic Porphyrin and Its Metal Derivatives with G-Quadruplex DNA. AB - G-quadruplex (GQ) structures formed from guanine-rich sequences are found throughout the genome and are overrepresented in the promoter regions of some oncogenes, at the telomeric ends of eukaryotic chromosomes, and at the 5' untranslated regions of mRNA. Interaction of small molecule ligands with GQ DNA is an area of great research interest to develop novel anticancer therapeutics and GQ sensors. In this paper we examine the interactions of TMPyP4, its isomer TMPyP2 (containing N-methyl-2-pyridyl substituents, N-Me-2Py) as well as two metal derivatives ZnTMPyP4 and CuTMPyP4 with GQs formed by dT4G4 and dT4G4T in 100 mM K+ or Na+ conditions. The DNA sequences were chosen to elucidate the effect of the 3'-T on the stabilization effect of porphyrins, binding modes, affinities, and stoichiometries determined via circular dichroism melting studies, UV-vis titrations, continuous variation analysis, and fluorescence studies. Our findings demonstrate that the stabilizing abilities of porphyrins are stronger toward (dT4G4)4 as compared to (dT4G4T)4 (DeltaTm is 4.4 vs -6.4 for TMPyP4; 12.7 vs 5.7 for TMPyP2; 16.4 vs 12.1 for ZnTMPyP4; and 1.9 vs -8.4 degrees C for CuTMPyP4) suggesting that the 3'G-tetrad presents at least one of the binding sites. The binding affinity was determined to be moderate (Ka ~ 106 107 MUM-1) with a typical binding stoichiometry of 1:1 or 2:1 porphyrin-to-GQ. In all studies, ZnTMPyP4 emerged as a ligand superior to TMPyP4. Overall, our work contributes to clearer understanding of interactions between porphyrins and GQ DNA. PMID- 27936742 TI - Quantum Dot/Siloxane Composite Film Exceptionally Stable against Oxidation under Heat and Moisture. AB - We report on the fabrication of a siloxane-encapsulated quantum dot (QD) film (QD silox film), which exhibits stable emission intensity for over 1 month even at elevated temperature and humidity. QD-silox films are solidified via free radical addition reaction between oligosiloxane resin and ligand molecules on QDs. We prepare the QD-oligosiloxane resin by sol-gel condensation reaction of silane precursors with QDs blended in the precursor solution, forgoing ligand-exchange of QDs. The resulting QD-oligosiloxane resin remains optically clear after 40 days of storage, in contrast to other QD-containing resins which turn turbid and ultimately form sediments. QDs also disperse uniformly in the QD-silox film, whose photoluminescence (PL) quantum yield (QY) remains nearly unaltered under harsh conditions; for example, 85 degrees C/5% relative humidity (RH), 85 degrees C/85% RH, strongly acidic, and strongly basic environments for 40 days. The QD-silox film appears to remain equally emissive even after being immersed into boiling water (100 degrees C). Interestingly, the PL QY of the QD-silox film noticeably increases when the film is exposed to a moist environment, which opens a new, facile avenue to curing dimmed QD-containing films. Given its excellent stability, we envision that the QD-silox film is best suited in display applications, particularly as a PL-type down-conversion layer. PMID- 27936743 TI - Validity of the Electrodiffusion Model for Calculating Conductance of Simple Ion Channels. AB - We examine the validity and utility of the electrodiffusion (ED) equation, i.e., the generalized Nernst-Planck equation, to characterize, in combination with molecular dynamics, the electrophysiological behavior of simple ion channels. As models, we consider three systems-two naturally occurring channels formed by alpha-helical bundles of peptaibols, trichotoxin, and alamethicin, and a synthetic, hexameric channel, formed by a peptide that contains only leucine and serine. All these channels mediate transport of potassium and chloride ions. Starting with equilibrium properties, such as the potential of mean force experienced by an ion traversing the channel and diffusivity, obtained from molecular dynamics simulations, the ED equation can be used to determine the full current-voltage dependence with modest or no additional effort. The potential of mean force can be obtained not only from equilibrium simulations, but also, with comparable accuracy, from nonequilibrium simulations at a single voltage. The main assumptions underlying the ED equation appear to hold well for the channels and voltages studied here. To expand the utility of the ED equation, we examine what are the necessary and sufficient conditions for Ohmic and nonrectifying behavior and relate deviations from this behavior to the shape of the ionic potential of mean force. PMID- 27936744 TI - Propeller Chirality of Boron Heptaaryldipyrromethene: Unprecedented Supramolecular Dimerization and Chiroptical Properties. AB - Chiral boron dipyrromethenes (BPs) enjoy high fluorescence efficiency at visible to near-IR wavelength regions with a reasonable range of dissymmetry factors. Here, we demonstrate that the (quasi)propeller chirality, similarly to hexagonal propeller in hexaarylbenzene, can be effectively induced in heptaarylated BP. In addition, supramolecular dimer was formed at low temperatures in nonpolar solvent, which exhibits strong bisignate Cotton effects at BP transitions (the couplet amplitude A = 193 M-1 cm-1) in the circular dichroism (CD). Due to the bulky substituents on the propeller blades, but with void space around boron atoms, BP chromophores in the dimer are aligned in a head-to-tail manner with a small torsion (phi ~ 15 degrees ), to avoid fluorescence quenching usually observed in H-type dimer of BPs, exhibiting strong circularly polarized luminescence (CPL) signals (glum = 2.0 * 10-3, Philum = 0.45). Such supramolecular dimer formation would be viewed as an alternative approach for designing and developing novel chiroptical materials. PMID- 27936746 TI - Highly Efficient All-Inorganic Planar Heterojunction Perovskite Solar Cells Produced by Thermal Coevaporation of CsI and PbI2. AB - We report here all inorganic CsPbI3 planar junction perovskite solar cells fabricated by thermal coevaporation of CsI and PbI2 precursors. The best devices delivered power conversion efficiency (PCE) of 9.3 to 10.5%, thus coming close to the reference MAPbI3-based devices (PCE ~ 12%). These results emphasize that all inorganic lead halide perovskites can successfully compete in terms of photovoltaic performance with the most widely used hybrid materials such as MAPbI3. PMID- 27936745 TI - Quantum Mechanical Calculations of Vibrational Sum-Frequency-Generation (SFG) Spectra of Cellulose: Dependence of the CH and OH Peak Intensity on the Polarity of Cellulose Chains within the SFG Coherence Domain. AB - Vibrational sum-frequency-generation (SFG) spectroscopy is capable of selectively detecting crystalline biopolymers interspersed in amorphous polymer matrices. However, the spectral interpretation is difficult due to the lack of knowledge on how spatial arrangements of crystalline segments influence SFG spectra features. Here we report time-dependent density functional theory (TD-DFT) calculations of cellulose crystallites in intimate contact with two different polarities: parallel versus antiparallel. TD-DFT calculations reveal that the CH/OH intensity ratio is very sensitive to the polarity of the crystallite packing. Theoretical calculations of hyperpolarizability tensors (betaabc) clearly show the dependence of SFG intensities on the polarity of crystallite packing within the SFG coherence length, which provides the basis for interpretation of the empirically observed SFG features of native cellulose in biological systems. PMID- 27936747 TI - Kinetic Analysis of the Methyl-beta-cyclodextrin-Mediated Intervesicular Transfer of Pyrene-Labeled Phospholipids. AB - Methyl-beta-cyclodextrin (MbetaCD) can transfer phospholipids between vesicles, and its transfer ability has been utilized for the preparation of asymmetric vesicle and lipid incorporation into culture cells. Nevertheless, a detailed kinetic analysis of the MbetaCD-mediated phospholipid transfer has not yet been carried out. We performed real-time monitoring of intervesicular lipid transfer by means of the fluorescence of pyrene-labeled phospholipids. Intermolecular excimer formation of the pyrene-labeled lipids in a membrane strongly depends on the local concentration of the fluorophore and decreases when the pyrene-labeled lipids are transferred from donor (fluorophore-containing) vesicles to acceptor (fluorophore-free) vesicles. We monitored the fluorescence intensity of the pyrene monomer and excimer simultaneously and found that the excimer/monomer ratio decreased in the presence of MbetaCD, pointing to MbetaCD-mediated lipid transfer. The transfer rate depended on the MbetaCD concentration but not on the lipid concentration, suggesting that dissociation from the membrane via extraction by MbetaCD is the rate-limiting step of the lipid transfer. Calibration of the excimer/monomer ratio to the molar fraction of the pyrene labeled lipids enabled us to evaluate the dissociation rate constant correctly. From the temperature dependence of the transfer, we obtained the thermodynamic activation parameters, which revealed that the extraction of phosphatidylcholine by MbetaCD from membranes is less enthalpically unfavorable than that of phosphatidylglycerol and phosphatidylinositol. PMID- 27936748 TI - A Base-Resistant Metalloporphyrin Metal-Organic Framework for C-H Bond Halogenation. AB - A base-resistant porphyrin metal-organic framework (MOF), namely PCN-602 has been constructed with 12-connected [Ni8(OH)4(H2O)2Pz12] (Pz = pyrazolate) cluster and a newly designed pyrazolate-based porphyrin ligand, 5,10,15,20-tetrakis(4 (pyrazolate-4-yl)phenyl)porphyrin under the guidance of the reticular synthesis strategy. Besides its robustness in hydroxide solution, PCN-602 also shows excellent stability in aqueous solutions of F-, CO32-, and PO43- ions. Interestingly, the Mn3+-porphyrinic PCN-602, as a recyclable MOF catalyst, presents high catalytic activity for the C-H bond halogenation reaction in a basic system, significantly outperforming its homogeneous counterpart. For the first time, a porphyrinic MOF was thus used as an efficient catalyst in a basic solution with coordinating anions, to the best of our knowledge. PMID- 27936749 TI - Au-Catalyzed Biaryl Coupling To Generate 5- to 9-Membered Rings: Turnover Limiting Reductive Elimination versus pi-Complexation. AB - The intramolecular gold-catalyzed arylation of arenes by aryl-trimethylsilanes has been investigated from both mechanistic and preparative aspects. The reaction generates 5- to 9-membered rings, and of the 44 examples studied, 10 include a heteroatom (N, O). Tethering of the arene to the arylsilane provides not only a tool to probe the impact of the conformational flexibility of Ar-Au-Ar intermediates, via systematic modulation of the length of aryl-aryl linkage, but also the ability to arylate neutral and electron-poor arenes-substrates that do not react at all in the intermolecular process. Rendering the arylation intramolecular also results in phenomenologically simpler reaction kinetics, and overall these features have facilitated a detailed study of linear free energy relationships, kinetic isotope effects, and the first quantitative experimental data on the effects of aryl electron demand and conformational freedom on the rate of reductive elimination from diaryl-gold(III) species. The turnover limiting step for the formation of a series of fluorene derivatives is sensitive to the reactivity of the arene and changes from reductive elimination to pi complexation for arenes bearing strongly electron-withdrawing substituents (sigma > 0.43). Reductive elimination is accelerated by electron-donating substituents (rho = -2.0) on one or both rings, with the individual sigma-values being additive in nature. Longer and more flexible tethers between the two aryl rings result in faster reductive elimination from Ar-Au(X)-Ar and lead to the pi complexation of the arene by Ar-AuX2 becoming the turnover-limiting step. PMID- 27936750 TI - Extension of Pd-Mediated One-Pot Ketone Synthesis to Macrocyclization: Application to a New Convergent Synthesis of Eribulin. AB - Recently reported Pd-mediated one-pot ketone synthesis from an unactivated alkyl bromide and a thioester has been extended to a macrocyclic ketone synthesis. In situ generation of alkylzinc halide via single electron transfer (SET), using NbCpCl4 and CrCl3, was the key for the success of macrocyclization. A new convergent synthesis of eribulin has been achieved, using (1) catalytic asymmetric Ni/Cr-mediated coupling to form the C19-C20 bond, (2) base-induced cyclization to form the methylenetetrahydrofuran ring, and (3) Pd-mediated one pot ketone synthesis to form the macrocyclic ketone. PMID- 27936751 TI - Effective Retinal Penetration of Lipophilic and Lipid-Conjugated Hydrophilic Agents Delivered by Engineered Liposomes. AB - Efficient delivery of drugs to the retina is critical but difficult to achieve with current methods. There have been a number of attempts to use intravitreal injection of liposomes, artificial vesicles composed of a phospholipid bilayer, to overcome the limitations of conventional intravitreal injection (short retention time, toxicity, poor penetration, etc.). Here, we report an optimal liposomal formulation that can diffuse through the vitreous humor, deliver the incorporated agents to all retinal layers effectively, and maintain them for a relatively long time. We first delivered lipophilic compounds and phospholipid conjugated hydrophilic agents to the inner limiting membrane using engineered liposomes. Subsequently, the agents penetrated the retina deeply, presumably via extracellular vesicles, nanoscale vesicles secreted from retinal-associated cells. These results suggest that this engineered liposomal formulation can leverage the biological transport system for effective retinal penetration of lipophilic and lipid-conjugated agents. PMID- 27936752 TI - High Aerobic Capacity Mitigates Changes in the Plasma Metabolomic Profile Associated with Aging. AB - Advancing age is associated with declines in maximal oxygen consumption. Declines in aerobic capacity not only contribute to the aging process but also are an independent risk factor for morbidity, cardiovascular disease, and all-cause mortality. Although statistically convincing, the relationships between aerobic capacity, aging, and disease risk remain largely unresolved. To this end, we employed sensitive, system-based metabolomics approach to determine whether enhanced aerobic capacity could mitigate some of the changes seen in the plasma metabolomic profile associated with aging. Metabolomic profiles of plasma samples obtained from young (13 month) and old (26 month) rats bred for low (LCR) or high (HCR) running capacity using proton nuclear magnetic resonance spectroscopy (1H NMR) were examined. Results demonstrated strong profile separation in old and low aerobic capacity rats, whereas young and high aerobic capacity rat models were less predictive. Significantly differential metabolites between the groups include taurine, acetone, valine, and trimethylamine-N-oxide among other metabolites, specifically citrate, succinate, isovalerate, and proline, were differentially increased in older HCR animals compared with their younger counterparts. When interactions between age and aerobic capacity were examined, results demonstrated that enhanced aerobic capacity could mitigate some but not all age-associated alterations in the metabolomic profile. PMID- 27936754 TI - Polarization-Directed Surface Plasmon Polariton Launching. AB - The relative intensities of propagating surface plasmons (PSPs) simultaneously launched from opposing edges of a symmetric trench structure etched into a silver thin film may be controllably varied by tuning the linear polarization of the driving field. This is demonstrated through transient multiphoton photoemission electron microscopy measurements performed using a pair of spatially separated phase-locked femtosecond pulses. Our measurements are rationalized using finite difference time domain simulations, which reveal that the coupling efficiency into the PSP modes is inversely proportional to the magnitude of the localized surface plasmon fields excited at the trench edges. Our combined experimental and computational results allude to the interplay between localized and propagating surface plasmon modes in the trench; strong coupling to the localized modes at the edges correlates to weak coupling to the PSP modes. Polarization-directed PSP launching measurements reveal an optimal PSP contrast ratio of 4.2 using a 500 nm wide trench. PMID- 27936755 TI - Spontaneous Vesiculation and pH-Induced Disassembly of a Lysosomotropic Detergent: Impacts on Lysosomotropism and Lysosomal Delivery. AB - Lysosomotropic detergents (LDs) selectively rupture lysosomal membranes through mechanisms that have yet to be characterized. A consensus view, currently, holds that LDs, which are weakly basic, diffuse across cellular membranes as monomers in an uncharged state, and via protonation in the acidic lysosomal compartment, they become trapped, accumulate, and subsequently solubilize the membrane and induce lysosomal membrane permeabilization. Here we demonstrate that the lysosomotropic detergent O-methyl-serine dodecylamide hydrochloride (MSDH) spontaneously assembles into vesicles at, and above, cytosolic pH, and that the vesicles disassemble as the pH reaches 6.4 or lower. The aggregation commences at concentrations below the range of those used in cell studies. Assembly and disassembly of the vesicles was studied via dynamic light scattering, zeta potential measurements, cryo-TEM, and fluorescence correlation spectroscopy and was found to be reversible via control of the pH. Aggregation of MSDH into closed vesicles under cytosolic conditions is at variance with the commonly held view of LD behavior, and we propose that endocytotic pathways should be considered as possible routes of LD entry into lysosomes. We further demonstrate that MSDH vesicles can be loaded with fluorophores via a solution transition from low to high pH, for subsequent release when the pH is lowered again. The ability to encapsulate molecular cargo into MSDH vesicles together with its ability to disaggregate at low pH and to permeabilize the lysosomal membrane presents an intriguing possibility to use MSDH as a delivery system. PMID- 27936756 TI - Development of a Rainbow Lateral Flow Immunoassay for the Simultaneous Detection of Four Mycotoxins. AB - A multiplex lateral flow immunoassay (LFIA) for the determination of the mycotoxins deoxynivalenol, zearalenone, and T2/HT2-toxin in barley was developed with luminescent quantum dots (QDs) as label. The synthesized QDs were hydrophilized by two strategies, that is, coating with an amphiphilic polymer or silica. The water-soluble QDs were compared with regard to their bioconjugation with monoclonal antibody (mAb) and were tested on a LFIA. Silica-coated QDs that contained epoxy groups were most promising. Therefore, green, orange, and red epoxy-functionalized silica-coated QDs were conjugated with anti-ZEN, anti-DON, and anti-T2 mAb, respectively. The LFIA was developed in accordance with the European Commission legal limits with cutoff limits of 1000, 80, and 80 MUg/kg for deoxynivalenol, zearalenone, and T2/HT2-toxin, respectively. The LFIA gave a fast result (15 min) with a low false-negative rate (<5%), and the results were easy to interpret without any sophisticated equipment. PMID- 27936753 TI - Identification and Characterization of Human Proteoforms by Top-Down LC-21 Tesla FT-ICR Mass Spectrometry. AB - Successful high-throughput characterization of intact proteins from complex biological samples by mass spectrometry requires instrumentation capable of high mass resolving power, mass accuracy, sensitivity, and spectral acquisition rate. These limitations often necessitate the performance of hundreds of LC-MS/MS experiments to obtain reasonable coverage of the targeted proteome, which is still typically limited to molecular weights below 30 kDa. The National High Magnetic Field Laboratory (NHMFL) recently installed a 21 T FT-ICR mass spectrometer, which is part of the NHMFL FT-ICR User Facility and available to all qualified users. Here we demonstrate top-down LC-21 T FT-ICR MS/MS of intact proteins derived from human colorectal cancer cell lysate. We identified a combined total of 684 unique protein entries observed as 3238 unique proteoforms at a 1% false discovery rate, based on rapid, data-dependent acquisition of collision-induced and electron-transfer dissociation tandem mass spectra from just 40 LC-MS/MS experiments. Our identifications included 372 proteoforms with molecular weights over 30 kDa detected at isotopic resolution, which substantially extends the accessible mass range for high-throughput top-down LC MS/MS. PMID- 27936757 TI - Polyclonal Immunoglobulin G N-Glycosylation in the Pathogenesis of Plasma Cell Disorders. AB - The pathological progression from benign monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma (SMM) and finally to active myeloma (MM) is poorly understood. Abnormal immunoglobulin G (IgG) glycosylation in myeloma has been reported. Using a glycomic platform composed of hydrophilic interaction UPLC, exoglycosidase digestions, weak anion-exchange chromatography, and mass spectrometry, polyclonal IgG N-glycosylation profiles from 35 patients [MGUS (n = 8), SMM (n = 5), MM (n = 8), complete-response (CR) post-treatment (n = 5), relapse (n = 4), healthy age-matched control (n = 5)] were characterized to map glycan structures in distinct disease phases of multiple myeloma. N-Glycan profiles from MGUS resembled normal control. The abundance of neutral glycans containing terminal galactose was highest in SMM, while agalactosylated glycans and fucosylated glycans were lowest in MM. Three afucosyl-biantennary digalactosylated-sialylated species (A2G2S1, A2BG2S1, and A2BG2S2) decreased 2.38 , 2.4-, and 4.25-fold, respectively, from benign to active myeloma. Increased light chain sialylation was observed in a longitudinal case of transformation from MGUS to MM. Bisecting N-acetylglucosamine was lowest in the CR group, while highest in relapsed disease. Gene expression levels of FUT 8, ST6GAL1, B4GALT1, RECK, and BACH2 identified from publicly available GEP data supported the glycomic changes seen in MM compared to control. The observed differential glycosylation underlined the heterogeneity of the myeloma spectrum. This study demonstrates the feasibility of mapping glycan modifications on the IgG molecule and provides proof of principle that differential IgG glycosylation patterns can be successfully identified in plasma cell disorders. PMID- 27936758 TI - Introducing Time Resolution to Detect Ce3+ Catalytically Active Sites at the Pt/CeO2 Interface through Ambient Pressure X-ray Photoelectron Spectroscopy. AB - X-ray photoelectron spectroscopy has been employed for the qualitative and quantitative characterization of both model and real catalytic surfaces. Recent progress in the detection of photoelectrons has enabled the acquisition of spectra at pressures up to a few tens of millibars. Although reducing the pressure gap represents a remarkable advantage for catalysis, active sites may be short-lived or hidden in the majority of spectator species. Time-resolved experiments, conducted under transient conditions, are a suitable strategy for discriminating between active sites and spectators. In the present work, we characterized the surface of a Pt/CeO2 powder catalyst at 1.0 mbar of a reacting mixture of carbon monoxide and oxygen and, by means of time resolution, identified short-lived active species. We replaced oxygen with nitrogen in the reaction mixture while fast-detecting the core level peaks of cerium. The results indicate that active Ce3+ sites form transiently at the surface when the oxygen is switched off. Analysis of the depth profile shows that Ce3+ ions are located at the ceria surface. The same experiment, performed on platinum-free ceria, reveals negligible reduction, indicating that platinum boosts the formation of Ce3+ active sites at the interface. PMID- 27936759 TI - Use of the rVV10 Nonlocal Correlation Functional in the B97M-V Density Functional: Defining B97M-rV and Related Functionals. AB - The VV10 and rVV10 nonlocal correlation functionals are consistently implemented and assessed, with the goal of determining if the rVV10 nonlocal correlation functional can replace the VV10 nonlocal correlation functional in the recently developed B97M-V density functional, to give the B97M-rV density functional. Along the way, four density functionals are simultaneously tested: VV10, rVV10, B97M-V, and B97M-rV. An initial assessment is carried out across the S22 data set, and the short-range damping variable, b, is varied for all four density functionals in order to determine the sensitivity of the functionals to the empirical parameter. The results of this test indicate that a value of b = 6 (fortuitously the same as that in B97M-V) is suitable for B97M-rV. The functionals are then compared across an extensive database of interaction energies, and it is demonstrated that B97M-rV either matches or outperforms B97M V for all of the tests considered. Finally, the optimization of b across the S22 data set is extended to two range-separated hybrid density functionals, omegaB97X V and omegaB97M-V, and a value of b = 6.2 is recommended for both omegaB97X-rV and omegaB97M-rV. PMID- 27936761 TI - Solution-Synthesized Chevron Graphene Nanoribbons Exfoliated onto H:Si(100). AB - There has been tremendous progress in designing and synthesizing graphene nanoribbons (GNRs). The ability to control the width, edge structure, and dopant level with atomic precision has created a large class of accessible electronic landscapes for use in logic applications. One of the major limitations preventing the realization of GNR devices is the difficulty of transferring GNRs onto nonmetallic substrates. In this work, we developed a new approach for clean deposition of solution-synthesized atomically precise chevron GNRs onto H:Si(100) under ultrahigh vacuum. A clean transfer allowed ultrahigh-vacuum scanning tunneling microscopy (STM) to provide high-resolution imaging and spectroscopy and reveal details of the electronic structure of chevron nanoribbons that have not been previously reported. We also demonstrate STM nanomanipulation of GNRs, characterization of multilayer GNR cross-junctions, and STM nanolithography for local depassivation of H:Si(100), which allowed us to probe GNR-Si interactions and revealed a semiconducting-to-metallic transition. The results of STM measurements were shown to be in good agreement with first-principles computational modeling. PMID- 27936760 TI - System-Wide Quantitative Proteomics of the Metabolic Syndrome in Mice: Genotypic and Dietary Effects. AB - Advances in mass spectrometry have made the quantitative measurement of proteins across multiple samples a reality, allowing for the study of complex biological systems such as the metabolic syndrome. Although the deregulation of lipid metabolism and increased hepatic storage of triacylglycerides are known to play a part in the onset of the metabolic syndrome, its molecular basis and dependency on dietary and genotypic factors are poorly characterized. Here, we used an experimental design with two different mouse strains and dietary and metabolic perturbations to generate a compendium of quantitative proteome data using three mass spectrometric techniques. The data reproduce known properties of the metabolic system and indicate differential molecular adaptation of the two mouse strains to perturbations, contributing to a better understanding of the metabolic syndrome. We show that high-quality, high-throughput proteomic data sets provide an unbiased broad overview of the behavior of complex systems after perturbation. PMID- 27936762 TI - Visible-Light-Driven, Radical-Triggered Tandem Cyclization of o-Hydroxyaryl Enaminones: Facile Access to 3-CF2 /CF3-Containing Chromones. AB - A practical and straightforward synthetic route to construct a variety of 3 CF2/CF3-containing chromones via photoredox catalysis was developed. This novel protocol features a visible-light-induced radical-triggered tandem cyclization. PMID- 27936763 TI - Nanocavity Integrated van der Waals Heterostructure Light-Emitting Tunneling Diode. AB - Developing a nanoscale, integrable, and electrically pumped single mode light source is an essential step toward on-chip optical information technologies and sensors. Here, we demonstrate nanocavity enhanced electroluminescence in van der Waals heterostructures (vdWhs) at room temperature. The vertically assembled light-emitting device uses graphene/boron nitride as top and bottom tunneling contacts and monolayer WSe2 as an active light emitter. By integrating a photonic crystal cavity on top of the vdWh, we observe the electroluminescence is locally enhanced (>4 times) by the nanocavity. The emission at the cavity resonance is single mode and highly linearly polarized (84%) along the cavity mode. By applying voltage pulses, we demonstrate direct modulation of this single mode electroluminescence at a speed of ~1 MHz, which is faster than most of the planar optoelectronics based on transition metal chalcogenides (TMDCs). Our work shows that cavity integrated vdWhs present a promising nanoscale optoelectronic platform. PMID- 27936764 TI - Visible and Near-Infrared Plasmon-Mediated Molecular Release from Cucurbit[6]uril Mesoporous Gated Systems. AB - Several hybrid mesoporous materials were synthesized in order to obtain a drug/cargo delivery system in which it is possible to control both the start and rate of the cargo release via surface plasmon (SPR) excitation. The successful incorporation of a thermoresponsive gate based on a cucurbit[6]uril-hexamethylene diamine (CB6-Hex) host-guest complex conferred the system with the desired "zero" premature release. This feature combined with the incorporation of gold nanorods (AuNR) and gold nanoparticles (AuNP) capable of acting as a heat source upon SPR excitation enabled a controlled cargo release system active to green and NIR irradiation. The results obtained prove that it is possible to disassemble the CB6-Hex gate complex in a few minutes using either green or NIR irradiation in order to activate the system and start the release process (that can take hours), as well as to further control the diffusion of Naproxen as a model drug. PMID- 27936765 TI - Microfluidic Platform for the Continuous Production and Characterization of Multilamellar Vesicles: A Synchrotron Small-Angle X-ray Scattering (SAXS) Study. AB - A microfluidic platform combined with synchrotron small-angle X-ray scattering (SAXS) was used for monitoring the continuous production of multilamellar vesicles (MLVs). Their production was fast and started to evolve within less than 0.43 s of contact between the lipids and the aqueous phase. To obtain nanoparticles with a narrow size distribution, it was important to use a modified hydrodynamic flow focusing (HFF) microfluidic device with narrower microchannels than those normally used for SAXS experiments. Monodispersed MLVs as small as 160 nm in size, with a polydispersity index (PDI) of approximately 0.15 were achieved. The nanoparticles produced were smaller and had a narrower size distribution than those obtained via conventional bulk mixing methods. This microfluidic platform therefore has a great potential for the continuous production of monodispersed NPs. PMID- 27936767 TI - Shear-Induced Breakup of Cellulose Nanocrystal Aggregates. AB - The flow properties of two kinds of cellulose nanocrystal (CNC) rods with different aspect ratios and similar zeta potentials in aqueous suspensions have been investigated. The aqueous CNC suspensions undergo a direct transition from dilute solution to colloidal glass instead of phase separation with the increasing CNC concentration. The viscosity profile shows a single shear-thinning behavior over the whole range of shear rates investigated. The shear-thinning behavior becomes stronger with the increasing CNC concentration. The viscosity is much higher for the unsonicated suspension when compared with the sonicated suspensions. The CNC rods appear arrested without alignment with an increasing shear rate from the small-angle light scattering patterns. The arrested glass state results from electric double layers surrounding the CNC rods, which give rise to long-ranged repulsive interactions. For the first time, we demonstrate that, within a narrow range of CNC concentrations, a shear-induced breakup process of the CNC aggregates exists when the shear rate is over a critical value and that the process is reversible in the sense that the aggregates can be reformed. We discuss the competition between the shear-induced breakup and the concentration-driven aggregation based on the experimental observations. The generated aggregate structure during the breakup process is characterized by a fractal dimension of 2.41. Furthermore, we determine two important variables-the breakup rate and the characteristic aggregate size-and derive analytical expressions for their evolution during the breakup process. The model predictions are in quantitative agreement with the experimental results. PMID- 27936766 TI - Discovery of Mycobacterium tuberculosis InhA Inhibitors by Binding Sites Comparison and Ligands Prediction. AB - Drug discovery is usually focused on a single protein target; in this process, existing compounds that bind to related proteins are often ignored. We describe ProBiS plugin, extension of our earlier ProBiS-ligands approach, which for a given protein structure allows prediction of its binding sites and, for each binding site, the ligands from similar binding sites in the Protein Data Bank. We developed a new database of precalculated binding site comparisons of about 290000 proteins to allow fast prediction of binding sites in existing proteins. The plugin enables advanced viewing of predicted binding sites, ligands' poses, and their interactions in three-dimensional graphics. Using the InhA query protein, an enoyl reductase enzyme in the Mycobacterium tuberculosis fatty acid biosynthesis pathway, we predicted its possible ligands and assessed their inhibitory activity experimentally. This resulted in three previously unrecognized inhibitors with novel scaffolds, demonstrating the plugin's utility in the early drug discovery process. PMID- 27936768 TI - Oligomerization Study of Human Organic Anion Transporting Polypeptide 1B1. AB - Organic anion-transporting polypeptides play important roles in the uptake of various endogenous and exogenous compounds. It has been proposed that OATP family members, as membrane proteins, may form oligomers. However, oligomerization status of OATPs is still largely unclear. In the present study, HEK293 cells stably expressing OATP1B1 were generated to investigate the oligomerization status of the transporter. Chemical cross-linking and coimmunoprecipitation experiments revealed that OATP1B1 may form homo-oligomers, possibly through disulfide bonds. When wild-type OATP1B1 was coexpressed with a loss-of-function mutant W258A, cells showed reduced uptake of prototypic substrate estrone-3 sulfate (ES). Interestingly, such a coexpression did not affect OATP1B1 transport activity of high concentrations ES, implicating that oligomerization status may affect only the high affinity component of ES. OATP1B1 possesses three GXXXG motifs that have been associated with protein dimerization in other membrane proteins. When glycine residues were replaced with alanine, G219A and G393A showed drastically reduced uptake function. Further studies revealed that G219A has a similar association capability to that of the wild-type, while mutation at Gly393 may affect oligomerization status of the transporter. Kinetic analysis showed that both G219A and G393A have a dramatically reduced Vmax for ES uptake. Km of G219A was increased while that of G393A exhibited a decreased value for high affinity component of ES binding. Our studies demonstrated that OATP1B1 may function as oligomers in the high affinity site of ES while acting as monomers for the low affinity binding component of the substrate. PMID- 27936769 TI - Wetting of Inkjet Polymer Droplets on Porous Alumina Substrates. AB - The resolution of inkjet printing technology is determined by wetting and evaporation processes after the jet drop contacts the substrate. Here, the wetting of different picoliter solubilized polymer droplets jetting onto one-end closed porous alumina was investigated. The selected polymers are commonly used in inkjet ink. The synergistic effects of the hierarchical structure and substrate surface modification were used to control the behavior of polymer-based ink drops. A model that invokes the effect of surface tension was applied to calculate the amount of polymer solution penetrating into the pores. The calculation corroborates experimental observations and shows that the volume of polymer solution in the pores increases with an increase in pore radius and depth, resulting in less solution remaining on the substrate surface. The structure of the porous substrate coupled with intrinsic polymer properties and surface modifications all contribute to the resolution that can be achieved via inkjet printing. PMID- 27936770 TI - Nickel-Catalyzed Aerobic Oxidative Isocyanide Insertion: Access to Benzimidazoquinazoline Derivatives via a Sequential Double Annulation Cascade (SDAC) Strategy. AB - An efficient protocol for the synthesis of quinazoline derivatives through nickel catalyzed ligand-/base-free oxidative isocyanide insertion under aerobic conditions with intramolecular bis-amine nucleophiles has been developed. A one pot sequential double annulation cascade (SDAC) strategy involving an opening of isatoic anhydride and annulation to benzimidazole and further nickel-catalyzed intramolecular isocyanide insertion has also been demonstrated. The method is operationally simple to implement with a wide variety of substrates and represents a new approach for multiple C-N bond formations. The methodology has been successfully applied to the syntheses of hitherto unreported imidazo-fused benzimidazoquinazolines via a deprotection-GBB reaction sequence. Further, a florescence study reveals the potential of the present strategy for the discovery of highly fluorescent probes. PMID- 27936771 TI - S...O and S...N Sulfur Bonding Interactions in Protein-Ligand Complexes: Empirical Considerations and Scoring Function. AB - Sulfur bonding interactions between organosulfur compounds and proteins were examined using crystal structures deposited to-date in the PDB. The data was analyzed as a function of sulfur-sigma-hole-bonding (i.e., sulfur bonds) to main chain Lewis bases, viz. oxygen and nitrogen atoms of the backbone amide linkages. The analyses also included an examination of sulfur bonding to side chain Lewis bases (O, N, and S) and to the "non-classical" Lewis bases present in electron rich aromatic amino acids as-well-as to donor-acceptor bond angle distributions. The interactions analyzed included those restricted to the sum of van der Waals radii of the respective atoms or to a distance of 4 A. The surveyed data revealed that sulfur bonding tendencies (C-S-C bond angles) were impacted not only by steric effects but perhaps also by enthalpic features present in both the donor and acceptor participants. This knowledge is not only of fundamental interest but is also important in terms of materials and drug-design involving moieties incorporating the sulfur atom. Additionally, a new empirical scoring function was developed to address the anisotropy of sulfur in protein-ligand interactions. This newly developed scoring function is incorporated into AutoDock Vina molecular docking program and is valuable for modeling and drug design. PMID- 27936772 TI - Liquid-Liquid Phase Equilibria and Interactions between Droplets in Water-in-Oil Microemulsions. AB - The liquid-liquid phase equilibria of [water/sodium bis(2 ethylhexyl)sulfosuccinate (AOT)/n-decane] with the molar ratio w0 of water to AOT being 37.9 and [water/AOT/ethoxylated-2,5,8,11-tetramethyl-6-dodecyne-5,8 diol(Dynol-604)/n-decane] with w0 = 37.9 and the mole fraction alpha of Dynol-604 in the total surfactants being 0.158 were measured in this study. From the data collected in the critical region, the critical exponent beta corresponding to the width of the coexistence curve was determined, which showed good agreement with the 3D-Ising value. A thermodynamic approach based on the Carnahan-Starling-van der Waals type equation was proposed to describe the coexistence curves and to deduce the interaction properties between droplets in the microemulsions. The interaction enthalpies were found to be positive for the studied systems, which evidenced that the entropy effect dominated the phase separations as the temperature increased. The addition of Dynol-604 into the (water/AOT/n-decane) microemulsion resulted in the decrease in the critical temperature and the interaction enthalpy. Combining the liquid-liquid equilibrium data for (water/AOT/n-decane) microemulsions with various w0 values determined previously, it was shown that the interaction enthalpy decreased with w0 and tended to change its sign at low w0, which coincided with the results from the isothermal titration calorimetry investigation. All of these behaviors were interpreted by the effects of entropy and enthalpy and their competition, which resulted from the release of solvent molecules entrapped in the interface of microemulsion droplets and were dependent on the rigidity of the surfactant layers and the size of the droplet. PMID- 27936773 TI - "Core-Shell" Nanostructured Supported Size-Selective Catalysts with High Catalytic Activity. AB - We report the synthesis of a highly active, supported nanostructured metal nanoparticle catalyst with an ultrathin porous shell and gaps between the metal nanoparticles and the shell for size-selective reactions. The size-selectivity of the catalysts could be realized through the porous shell. The gaps were able to reduce catalytic activity loss due to the contact areas between the shell and the catalytic sites. Evaluations of the activity and selectivity of the catalysts were made by catalytic hydrogenation of n-hexene versus cis-cyclooctene. Further verification of the high catalytic activity of the nanostructured catalysts was by oxidation of carbon monoxide. PMID- 27936775 TI - Inducing Optimal Antitumor Immune Response through Coadministering iRGD with Pirarubicin Loaded Nanostructured Lipid Carriers for Breast Cancer Therapy. AB - Chemotherapeutic agents trigger antitumor immune response through inducing immunogenic tumor cell death. However, severe toxicity to immune system and insufficient immunogenic cell death hinder chemotherapy from arousing efficient antitumor immunity in vivo. In this study, the cytotoxic drug, pirarubicin (THP), was entrapped into nanostructured lipid carriers (NLC); THP-NLC significantly reduced the toxicity of THP to immune system and improved immune status of breast cancer bearing mice. When THP-NLC was coinjected with iRGD (a tumor-penetrating peptide), drug accumulation in tumors was greatly elevated, which led to significant control of tumor growth and increase of immunogenic tumor cell death. Subsequently, the cytotoxic T lymphocytes (CD3+ and CD8+ cells) infiltration and cytokine (IFN-gamma and INF-alpha) secretion in tumors were heavily increased. The efficient T-cell dependent control of tumors in the late stage and the lower side effects contributed to the longest whole survival of THP-NLC + iRGD treated mice. Therefore, the coadministration of THP-NLC with iRGD resulted in increased tumor cell direct-killing death and enhanced antitumor immune response. Our results illustrated that THP could serve as an immunogenic cell death inducer and the proposed drug delivery strategy might impact cancer immunotherapy by arousing increased immunogenic tumor cell death. PMID- 27936776 TI - Unraveling the Proteome Composition and Immuno-profiling of Western India Russell's Viper Venom for In-Depth Understanding of Its Pharmacological Properties, Clinical Manifestations, and Effective Antivenom Treatment. AB - The proteome composition of western India (WI) Russell's viper venom (RVV) was correlated with pharmacological properties and pathological manifestations of RV envenomation. Proteins in the 5-19 and 100-110 kDa mass ranges were the most predominate (~35.1%) and least abundant (~3.4%) components, respectively, of WI RVV. Non-reduced SDS-PAGE indicated the occurrence of multiple subunits, non covalent oligomers, self-aggregation, and/or interactions among the RVV proteins. A total of 55 proteins belonging to 13 distinct snake venom families were unambiguously identified by ESI-LC-MS/MS analysis. Phospholipase A2 (32.5%) and Kunitz-type serine protease inhibitors (12.5%) represented the most abundant enzymatic and non-enzymatic proteins, respectively. However, ATPase, ADPase, and hyaluronidase, detected by enzyme assays, were not identified by proteomic analysis owing to limitations in protein database deposition. Several biochemical and pharmacological properties of WI RVV were also investigated. Neurological symptoms exhibited by some RV-bite patients in WI may be correlated to the presence of neurotoxic phospholipase A2 enzymes and Kunitz-type serine protease inhibitor complex in this venom. Monovalent antivenom was found to be better than polyvalent antivenom in immuno-recognition and neutralization of the tested pharmacological properties and enzyme activities of WI RVV; nevertheless, both antivenoms demonstrated poor cross-reactivity and neutralization of pharmacological activities shown by low-molecular-mass proteins (<18 kDa) of this venom. PMID- 27936777 TI - Peptizing Mechanism at the Molecular Level of Laponite Nanoclay Gels. AB - In the presence of additives such as etidronic acid (1-hydroxyethane-1,1 diphosphonic acid, HEDP), a process of peptizing of Laponite clay gels takes place. The peptizing process at the molecular level was directly revealed by 31P and 1H high-resolution magic-angle sample spinning (HRMAS) NMR spectroscopy. Two NMR spectral components were detected and assigned to free etidronic acid and bound to the Laponite disk edges. Furthermore, with increase of temperature the ratio of bound-to-free etidronic acid increases. This thermal activation process could be explained by the increase in electrical polarization of the hydroxyl group at the edges and by the exfoliation of the tactoids that leads to more access to the additive molecules to the electrical charges of platelet edges. 31P HRNMR spectroscopy on sodium fluorohectorite with an aspect ratio of ~750 shows a reduction of the bound etidronic acid molecules. Transmission electron microscopy (TEM), field-emission scanning microscopy (FESEM), UV-vis spectrophotometry, dynamic light scattering (DLS), and zeta potential results support the proposed peptizing mechanisms. PMID- 27936778 TI - Computational Models of the Gastrointestinal Environment. 2. Phase Behavior and Drug Solubilization Capacity of a Type I Lipid-Based Drug Formulation after Digestion. AB - Lipid-based drug formulations can greatly enhance the bioavailability of poorly water-soluble drugs. Following the oral administration of formulations containing tri- or diglycerides, the digestive processes occurring within the gastrointestinal (GI) tract hydrolyze the glycerides to mixtures of free fatty acids and monoglycerides that are, in turn, solubilized by bile. The behavior of drugs within the resulting colloidal mixtures is currently not well characterized. This work presents matched in vitro experimental and molecular dynamics (MD) theoretical models of the GI microenvironment containing a digested triglyceride-based (Type I) drug formulation. Both the experimental and theoretical models consist of molecular species representing bile (glycodeoxycholic acid), digested triglyceride (1:2 glyceryl-1-monooleate and oleic acid), and water. We have characterized the phase behavior of the physical system using nephelometry, dynamic light scattering, and polarizing light microscopy and compared these measurements to phase behavior observed in multiple MD simulations. Using this model microenvironment, we have investigated the dissolution of the poorly water-soluble drug danazol experimentally using LC-MS and theoretically by MD simulation. The results show how the formulation lipids alter the environment of the GI tract and improve the solubility of danazol. The MD simulations successfully reproduce the experimental results showing the utility of MD in modeling the fate of drugs after digestion of lipid-based formulations within the intestinal lumen. PMID- 27936779 TI - Iron-Catalyzed C-H Alkylation of Heterocyclic C-H Bonds. AB - An efficient, iron-catalyzed C-H alkylation of benzothiazoles by using alkyl diacyl peroxides and alkyl tert-butyl peresters which are readily accessible from carboxylic acids to synthesize 2-alkylbenzothiazoles is developed. This reaction is environmentally benign and compatible with a broad range of functional groups. Various primary, secondary, and tertiary alkyl groups can be efficiently incorporated into diverse benzothiazoles. The effectiveness of this method is illustrated by late-stage functionalization of biologically active heterocycles. PMID- 27936780 TI - Conformal, Nanoscale ZnO Surface Modification of Garnet-Based Solid-State Electrolyte for Lithium Metal Anodes. AB - Solid-state electrolytes are known for nonflammability, dendrite blocking, and stability over large potential windows. Garnet-based solid-state electrolytes have attracted much attention for their high ionic conductivities and stability with lithium metal anodes. However, high-interface resistance with lithium anodes hinders their application to lithium metal batteries. Here, we demonstrate an ultrathin, conformal ZnO surface coating by atomic layer deposition for improved wettability of garnet solid-state electrolytes to molten lithium that significantly decreases the interface resistance to as low as ~20 Omega.cm2. The ZnO coating demonstrates a high reactivity with lithium metal, which is systematically characterized. As a proof-of-concept, we successfully infiltrated lithium metal into porous garnet electrolyte, which can potentially serve as a self-supported lithium metal composite anode having both high ionic and electrical conductivity for solid-state lithium metal batteries. The facile surface treatment method offers a simple strategy to solve the interface problem in solid-state lithium metal batteries with garnet solid electrolytes. PMID- 27936781 TI - Synthesis of 12,12'-azo-13,13'-diepi-Ritterazine N. AB - A synthesis of the 12,12'-azo-analogue of ritterazine N from hecogenin is reported. Ring contraction of two 6/5 bicyclic ring systems, one trans-fused and another spiro, to 5/5 spiro ring systems is accomplished with excellent stereochemical control. Key transformations include an abnormal Baeyer-Villiger oxidation, a Norrish type I cleavage, an intramolecular dipolar [3 + 2] cycloaddition, and an intramolecular oxymecuration. Failing to uncover the beta OH ketone from the isoxazoline ring, we end up with a synthesis of a cyclic analogue of ritterazine N. PMID- 27936782 TI - Tailoring the Interfacial Chemical Interaction for High-Efficiency Perovskite Solar Cells. AB - The ionic nature of perovskite photovoltaic materials makes it easy to form various chemical interactions with different functional groups. Here, we demonstrate that interfacial chemical interactions are a critical factor in determining the optoelectronic properties of perovskite solar cells. By depositing different self-assembled monolayers (SAMs), we introduce different functional groups onto the SnO2 surface to form various chemical interactions with the perovskite layer. It is observed that the perovskite solar cell device performance shows an opposite trend to that of the energy level alignment theory, which shows that chemical interactions are the predominant factor governing the interfacial optoelectronic properties. Further analysis verifies that proper interfacial interactions can significantly reduce trap state density and facilitate the interfacial charge transfer. Through use of the 4 pyridinecarboxylic acid SAM, the resulting perovskite solar cell exhibits striking improvements to the reach the highest efficiency of 18.8%, which constitutes an ~10% enhancement compared to those without SAMs. Our work highlights the importance of chemical interactions at perovskite/electrode interfaces and paves the way for further optimizing performances of perovskite solar cells. PMID- 27936783 TI - A Robust Hybrid Zn-Battery with Ultralong Cycle Life. AB - Advanced batteries with long cycle life and capable of harnessing more energies from multiple electrochemical reactions are both fundamentally interesting and practically attractive. Herein, we report a robust hybrid zinc-battery that makes use of transition-metal-based redox reaction (M-O-OH -> M-O, M = Ni and Co) and oxygen reduction reaction (ORR) to deliver more electrochemical energies of comparably higher voltage with much longer cycle life. The hybrid battery was constructed using an integrated electrode of NiCo2O4 nanowire arrays grown on carbon-coated nickel foam, coupled with a zinc plate anode in alkaline electrolyte. Benefitted from the M-O/M-O-OH redox reactions and rich ORR active sites in NiCo2O4, the battery has concurrently exhibited high working voltage (by M-O-OH -> M-O) and high energy density (by ORR). The good oxygen evolution reaction (OER) activity of the electrode and the reversible M-O <-> M-O-OH reactions also enabled smooth recharging of the batteries, leading to excellent cycling stabilities. Impressively, the hybrid batteries maintained highly stable charge-discharge voltage profile under various testing conditions, for example, almost no change was observed over 5000 cycles at a current density of 5 mA cm-2 after some initial stabilization. With merits of higher working voltage, high energy density, and ultralong cycle life, such hybrid batteries promise high potential for practical applications. PMID- 27936784 TI - Dynamic Reflection Phase and Polarization Control in Metasurfaces. AB - Optical metasurfaces are two-dimensional optical elements composed of dense arrays of subwavelength optical antennas and afford on-demand manipulation of the basic properties of light waves. Following the pioneering works on active metasurfaces capable of modulating wave amplitude, there is now a growing interest to dynamically control other fundamental properties of light. Here, we present metasurfaces that facilitate electrical tuning of the reflection phase and polarization properties. To realize these devices, we leverage the properties of actively controlled plasmonic antennas and fundamental insights provided by coupled mode theory. Indium-tin-oxide is embedded into gap-plasmon resonator antennas as it offers electrically tunable optical properties. By judiciously controlling the resonant properties of the antennas from under- to overcoupling regimes, we experimentally demonstrate tuning of the reflection phase over 180 degrees . This work opens up new design strategies for active metasurfaces for displacement measurements and tunable waveplates. PMID- 27936785 TI - Synthesis of Mono-O-alkylated Homooxacalix[3]arene and a Protection-Deprotection Strategy for Homooxacalix[3]arene. AB - The regioselective synthesis of mono-O-alkylated homooxacalix[3]arene is accomplished for the first time. The synthetic route relies on two key steps: (i) a facile protection of two OH groups at the lower rim of the homooxacalix[3]arene and (ii) the deprotection of 9-anthrylmethyl groups via the Pd/C-catalyzed hydrogenation under atmospheric hydrogen. An efficient protection-deprotection strategy for the functionalization of homooxacalix[3]arene is presented. PMID- 27936788 TI - Synthesis of 6-Substituted 6H-Indolo[2,3-b]quinolines from Isoindigos. AB - A facile approach to 6-aryl/alkyl substituted 6H-indolo[2,3-b]quinolines from mono-N-substituted isoindigo derivatives in the presence of SnCl2.2H2O in acid media is described. Pyrrole and pyridine rings are synchronously constructed in one pot for these tetracyclic molecules. A plausible reduction/hydrolysis/decarboxylation/cyclization/aromatization domino reaction mechanism is proposed. Bis-N-substituted isoindigo only gives the corresponding reduction product, 3,3'-bioxindole. PMID- 27936787 TI - Formation of Cyclopenta[c]pyridine Derivatives from 2,5-Disubstituted Pyrroles and 1,4-Dibromo-1,3-butadienes via Pyrrole-Ring One-Carbon Expansion. AB - Reactions between 1,4-dibromo-1,3-butadienes and 2,5-disubstituted pyrroles afforded cyclopenta[c]pyridine derivatives in high yield, catalyzed by palladium and a cyclopentadiene-phosphine ligand (L1). Insertion of one terminal carbon of the butadienyl skeleton into one C?C double bond in the pyrrole ring resulted in ring expansion, along with a 1,2-shift of an alkyl or an aryl substituent on the butadienes. PMID- 27936786 TI - Additive-Free Pd-Catalyzed alpha-Allylation of Imine-Containing Heterocycles. AB - An additive-free Pd-catalyzed alpha-allylation of different imino-group-ontaining heterocycles is reported. The activation of alpha-CH pronucleophiles (pKa (DMSO) > 25) occurs without the addition of strong bases or Lewis acids using only the Pd/Xantphos catalyst system. The reaction scope has been studied for various 5- and 6-membered nitrogen-containing heterocycles (yields up to 96%). Mechanistic investigations suggest an initial allylation of the imine-N followed by a Pd catalyzed formal aza-Claisen rearrangement. PMID- 27936789 TI - Study of the Alpha-l-Fucosidase Langmuir Monolayer at the Air-Water Interface. AB - Alpha-l-fucosidase is a known biomarker for hepatocellular carcinoma that has shown great potential in diagnostics. Most of the focus for this enzyme has been on the free form found in serum; however, little is known of the properties of the minor portion of membrane-bound alpha-l-fucosidase. To better understand the properties of membrane-bound alpha-l-fucosidase, this enzyme was surveyed at the air-water interface. Alpha-l-fucosidase is able to form a stable Langmuir monolayer, which was confirmed through surface-pressure and surface-potential area isotherms, as well as infrared reflection-absorption spectroscopy (IRRAS). Furthermore, an interaction between the alpha-l-fucosidase Langmuir monolayer and a specific antibody for this enzyme, FUCA2, was observed. PMID- 27936790 TI - Conformational Change in Molecular Assembly of Nickel(II) Tetra(n propyl)porphycene Triggered by Potential Manipulation. AB - Metal-coordinated porphyrin and related compounds are important for developing molecular architectures that mimic enzymes. Porphycene, a structural isomer of porphyrin, has shown unique properties in semiartificial myoglobin. To explore its potential as a molecular building block, we studied the molecular assembly of nickel(II) tetra(n-propyl)porphycene (NiTPrPc), a metalloporphycene with introduced tetra n-propyl moieties, on the Au(111) electrode surface using in situ scanning tunneling microscopy. Because of the low molecular symmetry of NiTPrPc, the molecular assembly undergoes unique phase transitions due to conformational change of the n-propyl moieties. The phase transitions can be precisely controlled by the electrode potential, demonstrating that the latter can play an important role in the porphycene molecular assembly on Au surface. This new discovery indicates possible uses of this porphycene framework in molecular engineering. PMID- 27936791 TI - Plant Isoquinoline Alkaloid Berberine Exhibits Chromatin Remodeling by Modulation of Histone Deacetylase To Induce Growth Arrest and Apoptosis in the A549 Cell Line. AB - Histone deacetylases (HDACs) are a group of epigenetic enzymes that control gene expression through their repressive influence on histone deacetylation transcription. HDACs are probable therapeutic targets for cancer treatment, spurring the progress of different types of HDAC inhibitors. Further, natural source-based derived bioactive compounds possess HDAC inhibitor property. In this way, we hypothesized that plant isoquinoline alkaloid berberine (BBR) could be a HDAC inhibitor in the human lung cancer A549 cell line. BBR represses total HDAC and also class I, II, and IV HDAC activity through hyperacetylation of histones. Furthermore, BBR triggers positive regulation of the sub-G0/G1 cell cycle progression phase in A549 cells. Moreover, BBR-induced A549 cell growth arrest and morphological changes were confirmed using different fluorescence-dye-based microscope techniques. Additionally, BBR downregulates oncogenes (TNF-alpha, COX 2, MMP-2, and MMP-9) and upregulates tumor suppressor genes (p21 and p53) mRNA and protein expressions. Besides, BBR actively regulates Bcl-2/Bax family proteins and also triggered the caspase cascade apoptotic pathway in A549 cells. Our finding suggests that BBR mediates epigenetic reprogramming by HDAC inhibition, which may be the key mechanism for its antineoplastic activity. PMID- 27936792 TI - Selective Chemical Vapor Deposition Growth of Cubic FeGe Nanowires That Support Stabilized Magnetic Skyrmions. AB - Magnetic skyrmions are topologically stable vortex-like spin structures that are promising for next generation information storage applications. Materials that host magnetic skyrmions, such as MnSi and FeGe with the noncentrosymmetric cubic B20 crystal structure, have been shown to stabilize skyrmions upon nanostructuring. Here, we report a chemical vapor deposition method to selectively grow nanowires (NWs) of cubic FeGe out of three possible FeGe polymorphs for the first time using finely ground particles of cubic FeGe as seeds. X-ray diffraction and transmission electron microscopy (TEM) confirm that these micron-length NWs with ~100 nm to 1 MUm diameters have the cubic B20 crystal structure. Although Fe13Ge8 NWs are also formed, the two types of NWs can be readily differentiated by their faceting. Lorentz TEM imaging of the cubic FeGe NWs reveals a skyrmion lattice phase under small applied magnetic fields (~0.1 T) at 233 K, a skyrmion chain state at lower temperatures (95 K) and under high magnetic fields (~0.4 T), and a larger skyrmion stability window than bulk FeGe. This synthetic approach to cubic FeGe NWs that support stabilized skyrmions opens a route toward the exploration of new skyrmion physics and devices based on similar nanostructures. PMID- 27936793 TI - Biomimetic Total Synthesis of the Pentacyclic Amaryllidaceae Alkaloid Derivative Gracilamine. AB - The illustrated azomethine ylide, produced through a Schiff base condensation of the corresponding aldehyde-containing C3a-arylhexahydroindole with ethyl l leucinate, engages in a stereoselective intramolecular cycloaddition reaction to give adduct 23 that has been elaborated, over eight steps, into the racemic modification of the alkaloid derivative gracilamine (1). The formation of this ylide and its conversion into isomer 23 mimics the proposed biogenesis of the pentacyclic framework of compound 1. PMID- 27936795 TI - Behavior of Deep Eutectic Solvents under External Electric Fields: A Molecular Dynamics Approach. AB - The properties of selected deep eutectic solvents (DESs) comprising choline chloride as a hydrogen bond acceptor and several types of hydrogen bond donors under static and dynamic external electric fields (EEFs) have been studied in this work using classical molecular dynamics simulations. The effects of field intensities under static conditions and of field frequencies under dynamic conditions were simulated. The response of the fluids to the external fields was analyzed from the changes in dipolar arrangements, intermolecular interaction energies, nanoscopic arrangements, and molecular diffusion. These results show for the very first time the nonequilibrium behavior of DESs under EEFs. PMID- 27936794 TI - Gate-Variable Mid-Infrared Optical Transitions in a (Bi1-xSbx)2Te3 Topological Insulator. AB - We report mid-infrared spectroscopy measurements of ultrathin, electrostatically gated (Bi1-xSbx)2Te3 topological insulator films in which we observe several percent modulation of transmittance and reflectance as gating shifts the Fermi level. Infrared transmittance measurements of gated films were enabled by use of an epitaxial lift-off method for large-area transfer of topological insulator films from infrared-absorbing SrTiO3 growth substrates to thermal oxidized silicon substrates. We combine these optical experiments with transport measurements and angle-resolved photoemission spectroscopy to identify the observed spectral modulation as a gate-driven transfer of spectral weight between both bulk and 2D topological surface channels and interband and intraband channels. We develop a model for the complex permittivity of gated (Bi1-xSbx)2Te3 and find a good match to our experimental data. These results open the path for layered topological insulator materials as a new candidate for tunable, ultrathin infrared optics and highlight the possibility of switching topological optoelectronic phenomena between bulk and spin-polarized surface regimes. PMID- 27936796 TI - Entropy-Driven Pt3Co Nanocube Assembles and Thermally Mediated Electrical Conductivity with Anisotropic Variation of the Rhombohedral Superlattice. AB - Understanding the shape-dependent superlattices and resultant anisotropies of both structure and property allows for rational design of materials processing and engineering to fabricate transformative materials with useful properties for applications. This work shows the structural evolution from square lattice of two dimensional (2D) thin film to rhombic lattice of large three-dimensional (3D) assembles of Pt3Co nanocubes (NCs). Synchrotron-based X-ray supercrystallography determines the superlattice of large 3D supercrystal into an obtuse rhombohedral (Rh) symmetry, which holds a long-range coherence of both NC translation and atomic crystallographic orientation. The Rh superlattice has a trigonal cell angle of 104 degrees , and the constitute NCs orient their atomic Pt3Co(111) planes to the superlattice Rh[111] direction. The temperature-dependent in situ small and wide-angle X-ray scattering (SAXS/WAXS) measurements reveal a thermally induced superlattice contraction of supercrystal, which maintains translational ordering but slightly develops orientational disordering. The observed increases of both the packing density and the rotation magnitude of NCs indicate a rational compromise between configurational and rotational entropies of NCs. The resultant minimization of the total free energy is responsible for the formation and stability of the obtuse Rh superlattice. The temperature-dependent in situ measurements of SAXS and electrical resistance reveal that, in conjunction with the thermally induced sharp contraction of superlattice at 160 degrees C, the supercrystal becomes measurable of electrical resistance, which was followed by a temperature-dependent linear increase. Upon rapid annealing from 250 degrees C, the supercrystal remains almost constant in both structure and electrical resistance. The heating-enabled electrical conductivity of the supercrystal at high temperature implies the formation of a NC-interconnected architecture. The experiments and overall analysis provide solid evidence and essential information for the use of shape-dependent structural anisotropies of supercrystal to create nanobased novel architecture with desired properties. PMID- 27936797 TI - Visible-Light-Mediated Achmatowicz Rearrangement. AB - Visible-light-mediated photoredox catalysis is a viable method to access highly reactive intermediates from cheap, readily available, and shelf-stable reagents to perform clean chemical transformations. Here, we report the first photoredox catalyzed Achmatowicz reaction of furfuryl alcohol derivatives to produce functionalized dihydropyranones while only forming easily separable NaHSO4 as a byproduct. The water solubility of the byproduct facilitates direct Boc protection of the resulting hemiacetal without the need for column purification. The reaction is very robust and permits the use of various aqueous solutions and light sources including sunlight. PMID- 27936798 TI - Local Electron Attachment Energy and Its Use for Predicting Nucleophilic Reactions and Halogen Bonding. AB - A new local property, the local electron attachment energy [E(r)], is introduced and is demonstrated to be a useful guide to predict intermolecular interactions and chemical reactivity. The E(r) is analogous to the average local ionization energy but indicates susceptibility toward interactions with nucleophiles rather than electrophiles. The functional form E(r) is motivated based on Janak's theorem and the piecewise linear energy dependence of electron addition to atomic and molecular systems. Within the generalized Kohn-Sham method (GKS-DFT), only the virtual orbitals with negative eigenvalues contribute to E(r). In the present study, E(r) has been computed from orbitals obtained from GKS-DFT computations with a hybrid exchange-correlation functional. It is shown that E(r) computed on a molecular isodensity surface, ES(r), reflects the regioselectivity and relative reactivity for nucleophilic aromatic substitution, nucleophilic addition to activated double bonds, and formation of halogen bonds. Good to excellent correlations between experimental or theoretical measures of interaction strengths and minima in ES(r) (ES,min) are demonstrated. PMID- 27936799 TI - Borane-Catalyzed Selective Hydrosilylation of Internal Ynamides Leading to beta Silyl (Z)-Enamides. AB - We have developed a borane-catalyzed regio- and stereoselective hydrosilylation of internal ynamides for the first time. The scope of ynamide substrates and silane reactants was broad under mild reaction conditions, affording synthetically versatile beta-silyl (Z)-enamide products. The observed stereoselectivity was reasoned to be due to the beta-silicon effect on a postulated ketene iminium intermediate. PMID- 27936800 TI - Symmetry, Dynamics, and Defects in Methylammonium Lead Halide Perovskites. AB - In order to better understand the structure and dynamics of methylammonium lead halide perovskites, we performed NMR, NQR, and DFT studies of CH3NH3PbI3 in the tetragonal and cubic phase. Our results indicate that the space group of the tetragonal phase is the nonpolar I4/mcm. The highly dynamic methylammonium moiety shows no indication of the occurrence of additional orientations of the C-N bond close to the c-axis at temperatures approaching the cubic phase. Crystal quality effects are shown to influence the 14N NMR and 127I NQR spectra, and the effects of high-temperature annealing on defects can be observed. A strong increase in T2 relaxation time of the 207Pb NMR signal on cooling is found, and is an indication of slow motions in the PbI6 octahedra at room temperature. These results aid in the understanding of the structure of methylammonium lead halides and enable further studies of defects in these materials. PMID- 27936801 TI - Insulating Material Requirements for Low-Power-Consumption Electrowetting-Based Liquid Lenses. AB - Insulating materials from the parylene family were investigated for use in low power-consumption electrowetting-based liquid lenses. It was shown that for DC driven operations, parylene C leads to hysteresis, regardless of the presence of a hydrophobic top coat. This hysteresis was attributed to the non-negligible time needed to reach a stable contact angle, due to charge injection and finite conductivity of the material. It was further demonstrated that by using materials with better insulating properties, such as parylene HT and VT4, satisfactory results can be obtained under DC voltages, reaching a low contact angle hysteresis of below 0.2 degrees . We propose a simplified model that takes into account the injection of charges from both sides of the insulating material (the liquid side and the electrode side), showing that electrowetting response can be both increased and decreased. PMID- 27936803 TI - Self-Assembly and External Modulation of a Flexible Porphyrin Derivative on Highly Oriented Pyrolytic Graphite. AB - With the aid of scanning tunneling microscopy, we have examined the two dimensional hydrogen-bonded networks of carboxyl-functionalized porphyrin derivative H2TCPp molecules at the heptanoic acid/HOPG interface. Moreover, we have successfully modulated the self-assembly structure of H2TCPp by introducing 1,2-di(4-pyridyl)ethylene molecules into the assembled system. By performing density functional theory calculations, we also revealed the formation mechanisms of the different assemblies and the modulation process. Comparing the self assembly structures at the liquid/solid interface with those in bulk crystals, we have obtained deep insight into the differences in H2TCPp assemblies between 2D and 3D networks. Furthermore, this research is expected to deepen our understanding of on-surface phenomena and to provide a feasible process toward 2D assembly regulation. PMID- 27936804 TI - Nanopolygons of Monolayer MS2: Best Morphology and Size for HER Catalysis. AB - With first-principles calculations, we find a new strategy for developing high performance catalysts for hydrogen evolution reaction (HER) via controlling the morphology and size of nanopolygons of monolayer transition-metal dichalcogenides (npm-MS2, with M = Mo, W, or V). Particularly, through devising a quantitative method to measure HER-active sites per unit mass and using such HER site density to comparatively gauge npm-MS2 performance, we identify three keys in making npm MS2 with optimal HER performance: (a) npm-MS2 should be triangular with each edge being M-terminated and each edge-M atom passivated by one S atom; (b) each edge of npm-MoS2 and WS2 should have 5-6 metal atoms as HER site density drops below/above these sizes optimal both for HER and practical npm growth; and (c) npm-VS2 is immune to this overly fastidious size dependence. Known experimental data on npm-MoS2 indeed support the plausibility of practicing these design rules. We expect that raising the nucleation density and controlling the growth time to favor the production of our proposed ultrasmall npm-MS2 are critical but practical. Research on npm-VS2 would bear the highest impact because of its size forgiving HER performance and relatively high abundance and low cost. PMID- 27936802 TI - Biocompatible Polymer Nanoformulation To Improve the Release and Safety of a Drug Mimic Molecule Detectable via ICP-MS. AB - Fluorescent poly(epsilon-caprolactone)-based nanoparticles (NPs) have been synthesized and successfully loaded with a titanium organometallic compound as a mimic of a water-insoluble drug. The nature of this nanovector enabled us to combine the quantification of the metal in tissues after systemic administration in healthy immunocompetent mice by inductively coupled plasma mass spectroscopy (ICP-MS) followed by the visualization of NPs in organ sections by confocal microscopy. This innovative method of nanodrug screening has enabled us to elucidate the crucial parameters of their kinetics. The organometallic compound is a good mimic of most anticancer drugs, and this approach is an interesting starting point to design the relevance of a broad range of nanoformulations in terms of safety and targeted delivery of the cargoes. PMID- 27936805 TI - Tip-Enhanced Raman Voltammetry: Coverage Dependence and Quantitative Modeling. AB - Electrochemical atomic force microscopy tip-enhanced Raman spectroscopy (EC-AFM TERS) was employed for the first time to observe nanoscale spatial variations in the formal potential, E0', of a surface-bound redox couple. TERS cyclic voltammograms (TERS CVs) of single Nile Blue (NB) molecules were acquired at different locations spaced 5-10 nm apart on an indium tin oxide (ITO) electrode. Analysis of TERS CVs at different coverages was used to verify the observation of single-molecule electrochemistry. The resulting TERS CVs were fit to the Laviron model for surface-bound electroactive species to quantitatively extract the formal potential E0' at each spatial location. Histograms of single-molecule E0' at each coverage indicate that the electrochemical behavior of the cationic oxidized species is less sensitive to local environment than the neutral reduced species. This information is not accessible using purely electrochemical methods or ensemble spectroelectrochemical measurements. We anticipate that quantitative modeling and measurement of site-specific electrochemistry with EC-AFM-TERS will have a profound impact on our understanding of the role of nanoscale electrode heterogeneity in applications such as electrocatalysis, biological electron transfer, and energy production and storage. PMID- 27936806 TI - Total Synthesis and Determination of the Absolute Configuration of Naturally Occurring Mangromicin A, with Potent Antitrypanosomal Activity. AB - An enantioselective total synthesis of (+)-mangromicin A has been accomplished. The tetrahydrofuran ring of mangromicin A, possessing a tetrasubstituted carbon center, was constructed by Mukaiyama-type vinylogous alkylation via a cyclic oxocarbenium intermediate derived from a gamma-hydroxy ketone with ideal stereoselectivity, and the 4-hydroxydihydropyrone scaffold was generated via Dieckmann cyclization at a late stage of the total synthesis. The reliable asymmetric synthesis of (+)-mangromicin A has revealed the absolute configuration of naturally occurring mangromicin A. PMID- 27936807 TI - tRNA-Derived RNA Fragments Associate with Human Multisynthetase Complex (MSC) and Modulate Ribosomal Protein Translation. AB - The functionality of small RNAs from abundant species of "housekeeping" noncoding RNAs (e.g., rRNA, tRNA, snRNA, snoRNA, etc.) remains a highly studied topic. The current state of research on short RNAs derived from transfer RNA (tRNA), called tRNA-derived fragments (tRFs), has been restricted largely to expression studies and limited functional studies. 5' tRFs are known translational inhibitors in mammalian cells, yet little is known about their functionality. Here we report on the first experimental evidence of the tRF protein interactome, identifying the mammalian multisynthetase complex as the primary interactor of the 5' tRF Gln19. We also present proteome-wide SILAC evidence that 5' tRFs increase ribosomal and poly(A)-binding protein translation. PMID- 27936808 TI - Iridium-Catalyzed Asymmetric Hydrogenation of Racemic beta-Keto Lactams via Dynamic Kinetic Resolution. AB - A highly efficient Ir-catalyzed asymmetric hydrogenation of racemic beta-keto lactams via dynamic kinetic resolution (DKR) for the synthesis of optically active beta-hydroxyl lactams has been described. With the Ir-SpiroSAP catalyst, a series of racemic beta-keto lactams including beta-keto gamma-, delta-, and epsilon-lactams were hydrogenated to chiral beta-hydroxy lactams in high yields (87-99%) with excellent enantio- and diastereoselectivity (83-99.9% ee, syn/anti: 97:3->99:1) at low catalyst loading under mild reaction conditions. This efficient method has been successfully applied in the synthesis of the chiral intermediate of fluoroquinolone antibiotic premafloxacine. PMID- 27936809 TI - Provenance information as a tool for addressing engineered nanoparticle reproducibility challenges. AB - Nanoparticles of various types are of increasing research and technological importance in biological and other applications. Difficulties in the production and delivery of nanoparticles with consistent and well defined properties appear in many forms and have a variety of causes. Among several issues are those associated with incomplete information about the history of particles involved in research studies, including the synthesis method, sample history after synthesis, including time and nature of storage, and the detailed nature of any sample processing or modification. In addition, the tendency of particles to change with time or environmental condition suggests that the time between analysis and application is important and some type of consistency or verification process can be important. The essential history of a set of particles can be identified as provenance information and tells the origin or source of a batch of nano-objects along with information related to handling and any changes that may have taken place since it was originated. A record of sample provenance information for a set of particles can play a useful role in identifying some of the sources and decreasing the extent of particle variability and the lack of reproducibility observed by many researchers. PMID- 27936812 TI - Inferences about competing measures based on patterns of binary significance tests are questionable. AB - An important step in demonstrating the validity of a new measure is to show that it is a better predictor of outcomes than existing measures-often called incremental validity. Investigators can use regression methods to argue for the incremental validity of new measures, while adjusting for competing or existing measures. The argument is often based on patterns of binary significance tests (BST): (a) both measures are significantly related to the outcome, (b) when adjusted for the new measure the competing measure is no longer significantly related to the outcome, but (c) when adjusted for the competing measure the new measure is still significantly related to the outcome. We show that the BST argument can lead to false conclusions up to 30% of the time when the validity study has modest statistical power. We review alternate methods for making strong inferences about validity and illustrate these with data on construal level in the context of relationships. Researchers often present results in black and white terms using statistical significance tests; the conclusions from such results can be misleading. We focus on a special case of this style of reporting whereby a new measure is said to be as good as, or better than, another measure because it is significantly related to an outcome whereas the other measure is not significant when both measures are tested jointly. In our tutorial on inference in regression, we show that arguments based on binary (black and white) patterns can lead to incorrect conclusions more than a third of the time, and we explain why this result is obtained. We further distinguish 3 situations where 2 measures are compared and show better ways of making arguments: (a) when 2 measures are thought to be literally equivalent, (b) when the new measure is thought to be better than the other, and (c) when the new measure adds information to the other, even if it is not equivalent or superior. We illustrate the statistical arguments with data on a new measure of construal level (specific vs. general thinking) in the context of relationships. (PsycINFO Database Record PMID- 27936813 TI - The social regulation of emotion and updating negative contents of working memory. AB - The social regulation of emotion reduces negative affect and may also help remove negative contents from working memory. The present studies investigated whether the social regulation of emotion (in the form of handholding) altered the ability to update negative contents from working memory and whether a person's level of desired emotional closeness moderated this effect. In each of 2 studies, an unselected sample of undergraduate students completed an emotional working memory task that measured the ability to remove irrelevant information from working memory and a self-report questionnaire measuring their level of desired emotional closeness. In Study 1 (N = 109), the task consisted only of negative images, and each participant performed half of the task while holding someone's hand and the other half while not holding someone's hand. Study 2 (N = 195) included a few changes (e.g., using both negative and neutral images, altering the control condition to consist of holding a stress ball, using a between-participants design, measuring comfort with handholding) to address a few potential alternative explanations. Overall, there appeared to be a better ability to update negative contents of working memory in the handholding condition of each study than the control condition among people with high desired emotional closeness but not among people with low desired emotional closeness. The present findings provide evidence that the social regulation of emotion can facilitate the removal of irrelevant negative contents of working memory. This process may be one way in which supportive relationships protect against psychological distress. (PsycINFO Database Record PMID- 27936814 TI - Neural substrates and social consequences of interpersonal gratitude: Intention matters. AB - Voluntary help during a time of need fosters interpersonal gratitude, which has positive social and personal consequences such as improved social relationships, increased reciprocity, and decreased distress. In a behavioral and a functional magnetic resonance imaging (fMRI) experiment, participants played a multiround interactive game where they received pain stimulation. An anonymous partner interacted with the participants and either intentionally or unintentionally (i.e., determined by a computer program) bore part of the participants' pain. In each round, participants either evaluated their perceived pain intensity (behavioral experiment) or transferred an amount of money to the partner (fMRI experiment). Intentional (relative to unintentional) help led to lower experience of pain, higher reciprocity (money allocation), and increased interpersonal closeness toward the partner. fMRI revealed that for the most grateful condition (i.e., intentional help), value-related structures such as the ventromedial prefrontal cortex (vmPFC) showed the highest activation in response to the partner's decision, whereas the primary sensory area and the anterior insula exhibited the lowest activation at the pain delivery stage. Moreover, the vmPFC activation was predictive of the individual differences in reciprocal behavior, and the posterior cingulate cortex (PCC) activation was predictive of self reported gratitude. Furthermore, using multivariate pattern analysis (MVPA), we showed that the neural activation pattern in the septum/hypothalamus, an area associated with affiliative affect and social bonding, and value-related structures specifically and sensitively dissociated intentional help from unintentional help conditions. These findings contribute to our understanding of the psychological and neural substrates of the experience of interpersonal gratitude and the social consequences of this emotion. (PsycINFO Database Record PMID- 27936811 TI - Parental influence on driver licensure in adolescence: A randomized controlled trial. AB - OBJECTIVE: Newly licensed adolescent drivers have skill deficits that increase risk for motor vehicle crashes. Development of programs targeted to prelicensed adolescents has been hindered by concerns about encouraging overconfidence and early licensure. The study had 2 primary objectives: (a) determine whether an Internet-based intervention designed to improve parent-supervised practice (TeenDrivingPlan [TDP]) influenced adolescents' time to licensure and parents' perceptions of adolescents' driving skill, expertise, and safety and (b) evaluate the association of these perceptions and practice diversity (number of different environments where practiced occurred) with time to licensure. METHOD: A randomized controlled trial was used to compare TDP with a control condition. Participants (N = 295 parent-adolescent dyads) completed periodic surveys over 24 weeks and were subsequently followed for up to a year to determine adolescents' licensure status. RESULTS: TDP did not influence time to licensure and did not affect parents' perceptions of skill, expertise, and safety. Practice diversity was associated with faster licensure. A more favorable perception of adolescents' skill in comparison to peers was associated with faster licensure. CONCLUSIONS: Targeting parents' beliefs about adolescents' safety in relation to other road users may not be conducive to altering licensing trajectories, whereas sensitizing parents to their adolescents' emerging skills might be more effective in promoting safe entry into licensure. (PsycINFO Database Record PMID- 27936815 TI - The effect of the social regulation of emotion on emotional long-term memory. AB - Memories for emotional events tend to be stronger than for neutral events, and weakening negative memories can be helpful to promote well-being. The present study examined whether the social regulation of emotion (in the form of handholding) altered the strength of emotional long-term memory. A sample of 219 undergraduate students viewed sets of negative, neutral, and positive images. Each participant held a stress ball while viewing half of the images and held someone's hand while viewing the other half. Participants returned 1 week later to complete a recognition task. Performance on the recognition task demonstrated that participants had lower memory accuracy for negative but not for positive pictures that were shown while they were holding someone's hand compared with when they were holding a stress ball. Although handholding altered the strength of negative emotional long-term memory, it did not down-regulate negative affective response as measured by self-report or facial expressivity. The present findings provide evidence that the social regulation of emotion can help weaken memory for negative information. Given the role of strong negative memories in different forms of psychopathology (e.g., depression, posttraumatic stress disorder), these findings may help better understand how close relationships protect against psychopathology. (PsycINFO Database Record PMID- 27936817 TI - Development and validation of the Gambling Pathways Questionnaire (GPQ). AB - The Pathways Model (Blaszczynski & Nower, 2002) is a theoretical framework that proposes three pathways for identifying etiological subtypes of problem gamblers. The model has been used to assist clinicians in developing individualized treatments that target not only the gambling behavior but also associated risk factors that may undermine recovery and precipitate relapse. The current study sought to develop and validate a new screening instrument, based on the Pathways Model for treatment-seeking gamblers. Participants were gamblers age 18 and over who scored 1+ symptoms on the Problem Gambling Severity Index of the Canadian Problem Gambling Index and presented to one of 22 participating treatment centers in Canada, the United States, and Australia (N = 1,176). Data were collected on 127 items, consisting of 62 core items that reflected variables in the Pathways Model and 65 experimental items derived from recent scholarly literature in gambling etiology. Exploratory and confirmatory factor analyses identified the following six factors: Antisocial Impulsive Risk-Taking, Stress-Coping, Mood Pre Problem-Gambling Onset, Mood Post-Problem-Gambling Onset, Child Maltreatment, and Meaning Motivation. The Gambling Pathways Questionnaire showed excellent internal consistency (alpha = .937), with good to high reliability found for each of the six factors, ranging from .851 to .945. Cluster analysis results demonstrated that the three-factor model produced good model fit to the data: Cluster 1 (Behaviorally Conditioned Subtype), Cluster 2 (Emotionally Vulnerable Subtype) and Cluster 3 (Antisocial, Impulsive Risk-Taking Subtype). The present study is the first to present an empirical measure for assigning problem gamblers to etiological subtypes for use as a screening tool in treatment settings. (PsycINFO Database Record PMID- 27936816 TI - Altered subjective reward valuation among female heavy marijuana users. AB - Maladaptive decision-making is a cardinal feature of drug use, contributing to ongoing use, and reflecting alterations in how drug users assess uncertain reward value. Accumulating evidence indicates the consequences of heavy marijuana use are worse for female versus male animals and humans, but research assessing sex differences in reward-related decision-making among marijuana users remains scarce. We examined sex differences in the subjective valuation of certain and uncertain rewards among heavy marijuana users (52; 26 male and 26 female) and controls (52; 26 male and 26 female). We offered male and female heavy marijuana users and controls monetary rewards of certain and uncertain (probabilistic) values. We measured how preferences for uncertain rewards varied by the objective value of those rewards, moderators of reward uncertainty, Marijuana Group and Sex. Men were more sensitive to changes in the objective value of uncertain rewards than women. However, this effect of Sex differed by Marijuana Group. Female heavy marijuana users were more sensitive to changes in uncertain reward value, particularly when the "stakes" were high (i.e., greater difference between potential uncertain rewards), than female controls. Female heavy marijuana users' sensitivity to changes in the value of high stakes uncertain rewards was comparable to male marijuana users and controls. In contrast, male marijuana users' sensitivity to changes in the value of high stakes uncertain rewards did not differ from male controls. These results suggest sex differences in sensitivity to high risk rewards may be one pathway contributing to severer consequences of heavy marijuana use among women. (PsycINFO Database Record PMID- 27936819 TI - Assessment of the Depression, Anxiety, and Stress Scale (DASS-21) in untreated obstructive sleep apnea (OSA). AB - The assessment of depression in obstructive sleep apnea (OSA) is confounded by symptom overlap. The Depression, Anxiety, and Stress Scale-short form (DASS-21) is a commonly used measure of negative affect, but it not known whether the DASS 21 is suitable for use in an OSA sample. This study compared the fit of Lovibond and Lovibond's (1995) correlated 3-factor structure of the DASS-21 and measurement invariance between a non-OSA and an OSA sample using confirmatory factor analysis. As measurement invariance was not found, to determine the source of non-invariance differential item functioning (DIF) was examined using dMACS. The correlated 3-factor structure (with correlated errors) of the DASS-21 was a better fit in the non-OSA sample. dMACS indicated that there was a degree of DIF for each of the subscales, especially for the Anxiety subscale, in which 2 symptoms (that are also physiological symptoms of OSA) produced lower severity scores in the OSA sample compared with the non-OSA sample. However, the degree of DIF for each of the subscales is not sufficient to cause concern when using the DASS-21; therefore, the total DASS-21 is suitable for use in an OSA sample. Interestingly, the impact of symptom overlap in anxiety symptoms may be reducing anxiety scores because of DIF, which contrasts with the proposed effect of symptom overlap in depression, where it leads to the inflation of depression scores in OSA. This deserves greater consideration in relation to OSA and other clinical disorders or chronic illness conditions with different patterns of overlapping symptoms. (PsycINFO Database Record PMID- 27936820 TI - Measuring regulation in the here and now: The development and validation of the State Emotion Regulation Inventory (SERI). AB - The relationship between context and emotion regulation is currently at the center of a burgeoning area of research. Commonly used emotion regulation questionnaires, however, are predominantly trait-based, and insensitive to situational choice of regulatory strategy. The current work describes the development and validation of the State Emotion Regulation Inventory (SERI), a brief measure of situational use of distraction, reappraisal, brooding and acceptance. In Study 1, an initial item pool was constructed, based on commonly used trait-based emotion regulation surveys. Then, the psychometric properties of the items were examined with a group of 181 participants who recalled a saddening autobiographical event, identified a distressing thought it triggered, and then waited for 3 minutes without instruction, as an opportunity to allow for spontaneous emotion regulation. Participants then completed the initial item pool, and other relevant trait-based scales. Exploratory factor analysis suggested a 4-factor solution, corresponding to the 4 regulatory strategies measured in the SERI. The 4 items to exclusively load highest on each factor were selected for the final measure. Assembled subscales correlated with relevant trait-based subscales in the expected directions. In Study 2, another sample of 155 participants completed the same procedure and the new SERI, and confirmatory factor analysis supported the 4-factor structure of this instrument. As a brief, validated instrument, the SERI may be a useful measure for studies of state emotion regulation, in protocols that use repeated measures in a single session, over the course of multiple sessions, or via ecological momentary assessments. (PsycINFO Database Record PMID- 27936821 TI - Chrysippus's pigeon: Exclusion-based responding in an avian model. AB - Inference by exclusion can be exhibited by deductively responding to new stimuli that are presented in the context of familiar stimuli. We investigated exclusion based responding in pigeons using a 2-alternative forced-choice discrimination task. In Phase 1, pigeons learned to associate 2 stimuli (A and B) with Response 1 and 2 stimuli (C and D) with Response 2. Following successful acquisition of these stimulus-response pairings, pigeons advanced to Phase 2, in which stimuli A and B were now reassigned to Response 2. Based on their Phase 1 training, pigeons should initially choose Response 1 when presented with A and B in Phase 2 (this response is now incorrect, but the birds would not yet have had the opportunity to learn the new stimulus-response associations). Also, in Phase 2, stimuli E and F-new stimuli replacing stimuli C and D-were concurrently presented and assigned to Response 1. Without prior training, pigeons' initial responding to E and F in Phase 2 should be at chance. However, if the pigeons were to apply an exclusion rule (stimuli E and F stand in opposition to stimuli A and B), then they might initially choose Response 2 for new stimuli E and F because they are concurrently choosing Response 1 for stimuli A and B. If that is the case, then choice accuracy for stimuli E and F should also be below chance. Indeed, our pigeons responded at reliably below chance levels to stimuli E and F, consistent with their exhibiting an exclusion rule-based strategy, which could actually arise from a more mechanical underlying process such as acquired equivalence formation. (PsycINFO Database Record PMID- 27936818 TI - Do brief motivational interventions reduce drinking game frequency in mandated students? An analysis of data from two randomized controlled trials. AB - College students frequently engage in drinking games (DGs) and experience a variety of consequences as a result. It is currently unknown whether brief motivational interventions (BMIs) that provide feedback on DG participation can reduce this high risk behavior. This study examined outcome data from 2 randomized clinical trials to examine whether BMIs facilitate change in DG frequency and how these changes may occur. Mandated college students (Trial 1, N = 198, 46% female; Trial 2, N = 412; 32% female) were randomized to BMI or comparison control conditions. Hierarchical linear modeling (HLM) was used to compare the BMI and comparison groups to determine whether the BMI reduced DG participation over time. Percent change talk (PCT) during the discussion of DG during the session was examined as a predictor of change in DG frequency, and gender was examined as a moderator of treatment effects. Controlling for regular drinking frequency, participants who received a BMI did not significantly reduce their DG frequency relative to the comparison group in either sample, and the BMI was equally ineffective at reducing DG behavior for men and women. DG-related PCT during the BMI was associated with lower DG frequency at the second follow-up in both trials. In Trial 1, PCT during the BMI was associated with less steep increases in DG frequency across the course of all follow-ups. Effects of PCT on DG behavior were not moderated by gender. Findings did not support hypothesized reductions in DG participation following a BMI. Future research should explore whether targeted DG-specific interventions could reduce DG participation and the role of in-session client language in facilitating such change. (PsycINFO Database Record PMID- 27936823 TI - Child neglect and maternal cross-relational social cognitive and neurocognitive disturbances. AB - A social information processing (SIP) theory of parenting risk posits that social cognitive and neurocognitive incapacities characterize at-risk parents, and that these cognitive difficulties operate across relational domains. This study focused on highly disadvantaged mothers of preschoolers and compared mothers with histories of perpetrating child neglect (n = 69) to demographically similar mothers without such histories (n = 76). Participants completed measures of unrealistic expectations for children and other adults, social problem-solving in parenting and nonparenting situations, executive functioning (EF), and attributions for children and other adults. As predicted, associations among these measures were found within and across relational domains. Exploratory factor analysis revealed two distinct clusters that distinguished the two groups. The first included measures of expectations and attributions (for both children and other adults) and the second included problem-solving difficulties and EF. When group differences were examined on individual variables, mothers with histories of perpetrating neglect exhibited more unrealistic expectations of children and other adults, more hostile attributions toward children and other adults, and poorer performance on tests of EF than comparisons. Only interpersonal problem-solving (in both parenting and nonparenting situations) failed to differentiate the neglect group from comparisons. In regression analyses, both parenting and nonparenting social cognition and EF contributed significantly to child neglect. These findings provide some support for this cognitive model of parenting risk and suggest widespread disturbances in parenting and nonparenting social cognition and neurocognition, may play a role in child neglect. (PsycINFO Database Record PMID- 27936822 TI - Neighborhood and school ethnic structuring and cultural adaptations among Mexican origin adolescents. AB - The ethnic and racial structuring of U.S. neighborhoods may have important implications for developmental competencies during adolescence, including the development of heritage and mainstream cultural orientations. In particular, living in highly concentrated Latino neighborhoods during early adolescence-which channels adolescents into related school environments-may promote retention of the ethnic or heritage culture, but it also may constrain adaptation to the mainstream U.S. culture. We tested these hypotheses longitudinally in a sample of 246 Mexican origin adolescents (50.8% girls) and their parents. Data were collected 4 times over 8 years, with adolescents averaging 12.5 (SD = .58) to 19.6 (SD = .66) years of age across the period of the study. Latino ethnic concentration in early adolescents' neighborhoods promoted the retention of Mexican cultural orientations; Latino ethnic concentration in middle schools undermined the development of mainstream U.S cultural orientations. Findings are discussed in terms of integrating cultural-developmental theory with mainstream neighborhood theory to improve understandings of neighborhood and school ethnic concentration effects on adolescent development. (PsycINFO Database Record PMID- 27936824 TI - Relations between mothers' daily work, home, and relationship stress with characteristics of mother-child conflict interactions. AB - This study examined whether daily variations in levels of mothers' work, home, and relationship stress were related to collaborative and oppositional qualities of mother-child conflict interactions across 1 week. Mothers reported on 1 specific conflict interaction with their 5- to 8-year-old child and their work, home, and relationship stress through online surveys each day for 7 consecutive days. Diary data from 142 mothers were analyzed in 6 multilevel models, each including within- and between-family levels of a stressor predicting collaborative or oppositional conflict qualities. Results suggested that families in the sample differed from each other, and also varied during the week, in collaborative and oppositional conflict qualities as well as stress in all 3 domains. Mothers reported a greater degree of oppositional conflict qualities on days characterized by higher perceptions of home chaos. Additionally, mothers who reported higher average levels of negativity in romantic relationships endorsed oppositional conflict qualities to a greater extent than mothers with lower relationship negativity. Two multilevel models including all 3 stressors in relation to collaborative and oppositional conflict revealed that for mothers managing multiple roles, average romantic relationship stress was the most important unique contributor to mother-child conflict qualities and daily relationship stress was particularly influential among mothers with sons compared to those with daughters. Results support the spillover hypothesis of stress within the family system and are discussed in terms of mothers' coping mechanisms and emotional engagement. (PsycINFO Database Record PMID- 27936825 TI - Police reports of mock suspect interrogations: A test of accuracy and perception. AB - A 2-phased experiment assessed the accuracy and completeness of police reports on mock interrogations and their effects on people's perceptions. In Phase 1, 16 experienced officers investigated a mock crime scene, interrogated 2 innocent suspects-1 described by the experimenter as more suspicious than the other-and filed an incident report. All 32 sessions were covertly recorded; the recordings were later used to assess the reports. In Phase 2, 96 lay participants were presented with a brief summary of the case and then either read 1 police report, read 1 verbatim interrogation transcript, or listened to an audiotape of a session. Results showed that (a) Police and suspects diverged in their perceptions of the interrogations; (b) Police committed frequent errors of omission in their reports, understating their use of confrontation, maximization, leniency, and false evidence; and (c) Phase 2 participants who read a police report, compared to those who read a verbatim transcript, perceived the process as less pressure-filled and were more likely to misjudge suspects as guilty. These findings are limited by the brevity and low-stakes nature of the task and by the fact that no significant effects were obtained for our suspicion manipulation, suggesting a need for more research. Limitations notwithstanding, this study adds to a growing empirical literature indicating the need for a requirement that all suspect interrogations be electronically recorded. To provide a more objective and accurate account of what transpired, this study also suggests the benefit of producing verbatim transcripts. (PsycINFO Database Record PMID- 27936826 TI - PCL-R field validity in prison and hospital settings. AB - Recent field studies have questioned the interrater reliability (IRR) and predictive validity regarding (violent) recidivism of the Psychopathy Checklist Revised (PCL-R). Using a forensic psychiatric sample, the current study investigated discrepancies in scoring between hospital and prison settings, as well as differences in predictive validity across these two settings. PCL-R information was collected from prison and hospital files, resulting in 224 PCL-R total scores and 74 double scores. When examining repeated measurements, large individual differences were found together with an intraclass correlation coefficient (ICCA,1) of .42 for the total score. Discrepant results were found for Factor 2, with repeated scores within the same setting having an ICCA,1 of .28 versus an ICCA,1 of .57 for repeated scores between settings. However, areas under the curve (AUCs) from receiver operating characteristic (ROC) analyses for total, factor and facet scores did not differ between settings. For the whole sample, Factor 2 scores marginally predicted violent and general recidivism after 2 years (AUC = .62 and .63), whereas Factor 1 did not predict (violent) recidivism. Consistent with recent studies from other countries, these results suggest inadequate field reliability and validity in prison and hospital settings in Flanders (Belgium). (PsycINFO Database Record PMID- 27936827 TI - The cultural dimension of uncertainty avoidance impacts police-civilian interaction. AB - This research examines how the cultural dimension of uncertainty avoidance-a person's (in)tolerance for uncertain or unknown situations-impacts communication alignment in crisis negotiations. We hypothesized that perpetrators high on uncertainty avoidance would respond better to negotiators who use formal language and legitimize their position with reference to law, procedures, and moral codes. Data were transcriptions of 53 negotiations from a Dutch-German police training initiative, where police negotiators interacted with a high (German) and low (Dutch) uncertainty-avoidant mock perpetrator. Consistent with accounts of cross cultural interaction, negotiators tended to achieve more alignment in within culture interactions compared to cross-cultural interactions. Moreover, German negotiators, who scored higher on uncertainty avoidance than the Dutch negotiators, were found to use more legitimizing messages and more formal language than their Dutch counterparts. Critically, irrespective of the negotiators cultural background, the use of these behaviors was a significant moderator of the degree to which negotiator and perpetrator aligned their communicative frames: Using legitimizing and formal language helped with German perpetrators but had no effect on Dutch perpetrators. Our findings show the effects of cultural background on communication alignment and demonstrate the benefits of using more formal language and messages that emphasize law and regulations when interacting with perpetrators high on uncertainty avoidance. (PsycINFO Database Record PMID- 27936828 TI - Defeating abusive supervision: Training supervisors to support subordinates. AB - Although much is known about the antecedents and consequences of abusive supervision, scant attention has been paid to investigating procedures to reduce its frequency. We conducted a quasiexperiment to examine the effects of supervisor support training on subordinate perceptions of abusive supervision and supervisor support. Supervisors (n = 23) in 4 restaurants were trained in 4 supportive supervision strategies (benevolence, sincerity, fairness, and experiential processing) during 4 2-hr sessions over a period of 2 months. We compared perceived supervisor support and abusive supervision before and 9 months after training for 208 employees whose supervisors received support training and 241 employees in 4 similar control restaurants. Compared to employees in the control restaurants, employees whose supervisors received the support training reported higher levels of perceived supervisor support and less abusive supervision. These findings suggest that a relatively brief training program can help managers become more supportive and less abusive. Theoretical and practical implications for effectively managing abusive supervision are discussed. (PsycINFO Database Record PMID- 27936829 TI - Bullying at work: Cognitive appraisal of negative acts, coping, wellbeing, and performance. AB - The negative outcomes of experiencing workplace bullying are well documented, but a strong theoretical explanation for this has been relatively neglected. We draw on cognitive appraisal theory to suggest that individuals' appraisals of and responses to negative acts at work will moderate the impact of said acts on wellbeing and performance outcomes. In a large study (N = 3,217) in Southeast Asia, we examine moderators in the form of (a) the extent to which individuals identify themselves as being bullied and (b) the coping strategies that individuals use to deal with negative acts. We find that these factors do moderate the impact of experiencing negative acts, in particular work-related negative acts. When individuals are subject to work-related negative acts but do not see themselves as being bullied they report higher levels of performance than those who do identify themselves as being bullied. Problem-focused coping was found to be effective for those sometimes targeted, but for persistent targets was detrimental to wellbeing. The present research has important implications for bullying research in examining factors that contribute to outcomes of bullying. (PsycINFO Database Record PMID- 27936830 TI - Promoting personal resources and reducing exhaustion through positive work reflection among caregivers. AB - The aim of this study was to test the effects of a daily positive work reflection intervention on fostering personal resources (i.e., hope and optimism) and decreasing exhaustion (i.e., emotional exhaustion and fatigue) among caregivers for the elderly and caregivers who provide services at patients' homes. Using an intervention/waitlist control group design, 46 caregivers in an intervention group were compared with 44 caregivers in a control group at 3 points of measurement: pre-intervention, post-intervention, and at a 2-week follow-up. The results show that emotional exhaustion and fatigue were reduced for the intervention group. Primarily, caregivers with a high need for recovery at baseline benefited from the intervention. The results reveal no intervention effects for personal resources; however, they reveal a trend that the intervention led to an increase in hope and optimism among caregivers with a high need for recovery. Overall, the findings show that caregivers benefit from a daily positive work reflection intervention, particularly when their baseline levels of resources and well-being are low. (PsycINFO Database Record PMID- 27936831 TI - "How readers understand causal and correlational expressions used in news headlines": Correction to Adams et al. (2016). AB - Reports an error in "How Readers Understand Causal and Correlational Expressions Used in News Headlines" by Rachel C. Adams, Petroc Sumner, Solveiga Vivian Griffiths, Amy Barrington, Andrew Williams, Jacky Boivin, Christopher D. Chambers and Lewis Bott (Journal of Experimental Psychology: Applied, Advanced Online Publication, Nov 3, 2016, np). In the article, the fourth author was inadvertently omitted from the advance online version. Also, the second paragraph of the author note should have included the following: "Amy Barrington contributed to the design and data collection for Experiments 2 and 3. We thank the following undergraduate students for contributions to Experiment 1 and pilot work leading up to the project: Laura Benjamin, Cecily Donnelly, Cameron Dunlop, Rebecca Emerson, Rose Fisher, Laura Jones, Olivia Manship, Hannah McCarthy, Naomi Scott, Eliza Walwyn-Jones, Leanne Whelan, and Joe Wilton." All versions of this article have been corrected. (The following abstract of the original article appeared in record 2016-52933-001.) Science-related news stories can have a profound impact on how the public make decisions. The current study presents 4 experiments that examine how participants understand scientific expressions used in news headlines. The expressions concerned causal and correlational relationships between variables (e.g., "being breast fed makes children behave better"). Participants rated or ranked headlines according to the extent that one variable caused the other. Our results suggest that participants differentiate between 3 distinct categories of relationship: direct cause statements (e.g., "makes," "increases"), which were interpreted as the most causal; can cause statements (e.g., "can make," "can increase"); and moderate cause statements (e.g., "might cause," "linked," "associated with"), but do not consistently distinguish within the last group despite the logical distinction between cause and association. On the basis of this evidence, we make recommendations for appropriately communicating cause and effect in news headlines. (PsycINFO Database Record PMID- 27936832 TI - Improving approximate number sense abilities in preschoolers: PLUS games. AB - Previous studies in both typically and atypically developing children have shown that approximate number system (ANS) abilities predict formal mathematical knowledge later on in life. The current study investigated whether playing specially designed training games that targets the ANS system using nonsymbolic stimuli only would improve preschool children's ANS abilities. Thirty-eight preschool children were randomly allocated to either the training or control group. For 5 weeks, 20 preschoolers (9 girls) in the training group played daily games for 10 min that included guessing and comparing numerosities, whereas 18 control children (6 girls) were involved in interactive picture book reading sessions. Children's ANS abilities were assessed using a computerized task before and after the training program. An analysis of covariance with posttraining ANS scores as dependent variable and pretraining scores as a covariate showed that the children in the training group had higher ANS abilities after the training, in contrast to children in the control group (p = .012, etap2 = .171). This study provides evidence that ANS abilities can be improved in preschool children through a daily training program that targets the ANS specifically. These findings provide support for further training programs for preschool children who show mathematical difficulties early on in life. (PsycINFO Database Record PMID- 27936833 TI - Understanding the cognitive and motivational underpinnings of sexual passion from a dualistic model. AB - Sexual passion has always been conceptualized as a one-dimensional phenomenon that emerges from interactions with partners. Drawing from the literature on passionate activities, sexual passion was defined in terms of its intrapersonal motivational and cognitive components and examined from a dualistic perspective. More specifically, in 5 studies, we investigated how 2 types of sexual passion, harmonious and obsessive, can lead to clearly distinct subjective, relational, and cognitive outcomes. Study 1 validated a scale measuring harmonious and obsessive sexual passion, and showed that each type of sexual passion leads to common, but also distinct, subjective consequences during sexual activity engagement for both singles and romantically engaged individuals. Studies 2 and 3 differentiated the constructs of harmonious and obsessive sexual passion from competing constructs existing in the literature and provided evidence for its predictive validity regarding various relational outcomes, including relationship sustainability over time. Finally, Studies 4 and 5 investigated the cognitive consequences of each type of sexual passion by showing how they reflect distinct levels of integration of sexual and relational representations, and how they can lead to biased processing of sexual information (Study 4) and conflict with ongoing sex-unrelated goals (Studies 5a and 5b). Overall, the present series of studies provides a new look at sexual passion from a motivational and cognitive intrapersonal perspective that is not restricted to interpersonal ramifications with partners. (PsycINFO Database Record PMID- 27936834 TI - Artful paltering: The risks and rewards of using truthful statements to mislead others. AB - Paltering is the active use of truthful statements to convey a misleading impression. Across 2 pilot studies and 6 experiments, we identify paltering as a distinct form of deception. Paltering differs from lying by omission (the passive omission of relevant information) and lying by commission (the active use of false statements). Our findings reveal that paltering is common in negotiations and that many negotiators prefer to palter than to lie by commission. Paltering, however, may promote conflict fueled by self-serving interpretations; palterers focus on the veracity of their statements ("I told the truth"), whereas targets focus on the misleading impression palters convey ("I was misled"). We also find that targets perceive palters to be especially unethical when palters are used in response to direct questions as opposed to when they are unprompted. Taken together, we show that paltering is a common, but risky, negotiation tactic. Compared with negotiators who tell the truth, negotiators who palter are likely to claim additional value, but increase the likelihood of impasse and harm to their reputations. (PsycINFO Database Record PMID- 27936835 TI - The effect of mood on judgments of subjective well-being: Nine tests of the judgment model. AB - Life satisfaction judgments are thought to represent an overall evaluation of the quality of a person's life as a whole. Thus, they should reflect relatively important and stable characteristics of that person's life. Previous highly cited research has suggested that transient factors, such as the mood that a person experiences at the time that well-being judgments are made, can influence these judgments. However, most existing studies used small sample sizes, and few replications have been attempted. Nine direct and conceptual replications of past studies testing the effects of mood on life satisfaction judgments were conducted using sample sizes that were considerably larger than previous studies (Ns = 202, 200, 269, 118, 320, 401, 285, 129, 122). Most of the 9 studies resulted in nonsignificant effects on life satisfaction and happiness judgments, and those that were significant were substantially smaller than effects found in previous research. (PsycINFO Database Record PMID- 27936836 TI - Conflicting effects of context in change detection and visual search: A dual process account. AB - Congruent contexts often facilitate performance in visual search and categorisation tasks using natural scenes. A congruent context is thought to contain predictive information about the types of objects likely to be encountered, as well as their location. However, in change detection tasks, changes embedded in congruent contexts often produce impaired performance relative to incongruent contexts. Using a stimulus set controlled for object perceptual salience, we compare performance across change detection and visual search tasks, as well as a hybrid of these 2 tasks. The results support a dual process account with opposing influences of context congruency on change detection and object identification processes, which contribute differentially to performance in visual search and change detection tasks. (PsycINFO Database Record PMID- 27936837 TI - Using the locus-of-slack logic to determine whether inhibition of return in a cue target paradigm is delaying early or late stages of processing. AB - Inhibition of return (IOR) is a phenomenon characterized by slower responses to targets at cued locations relative to those at uncued locations. Based on the results of previous research, it has been suggested that IOR affects a process at the input end of the processing continuum when it is generated while the reflexive oculomotor system is suppressed (cf. Satel, Hilchey, Wang, Story, & Klein, 2013). To test this theory, we employed a modified psychological refractory period paradigm designed to elicit input IOR with visual stimuli, allowing us to use the locus-of-slack logic to determine whether an early or late stage of processing was inhibited by IOR. On each trial a visual cue was presented, followed by an auditory target (T1) and visual target (T2) separated by a target-target onset asynchrony (TTOA) of varying lengths (200 ms, 400 ms, or 800 ms). Participants (31 young adults) were instructed to ignore the cue and respond to the targets as quickly and accurately as possible. Eye tracking was used to ensure that participants actively suppressed eye movements during trials. As predicted, the inhibitory effect of the cue was observed at the longest TTOA but not when TTOAs were short, supporting our hypothesis that, when generated while the reflexive oculomotor system is suppressed, IOR affects processing before response selection. (PsycINFO Database Record PMID- 27936838 TI - Anticipatory and consummatory pleasure and displeasure in major depressive disorder: An experience sampling study. AB - Pleasure and displeasure can be parsed into anticipatory and consummatory phases. However, research on pleasure and displeasure in major depressive disorder (MDD), a disorder characterized by anhedonia, has largely focused on deficits in the consummatory phase. Moreover, most studies in this area have been laboratory based, raising the question of how component processes of pleasure and displeasure are experienced in the daily lives of depressed individuals. Using experience sampling, we compared anticipatory and consummatory pleasure and displeasure for daily activities reported by adults with MDD (n = 41) and healthy controls (n = 39). Participants carried electronic devices for one week and were randomly prompted eight times a day to answer questions about activities to which they most and least looked forward. Compared to healthy controls, MDD participants reported blunted levels of both anticipatory and consummatory pleasure and elevated levels of both anticipatory and consummatory displeasure for daily activities. Independent of MDD status, participants accurately predicted pleasure but overestimated displeasure. These results are the first to provide evidence that, across both anticipatory and consummatory phases, individuals with MDD experience blunted pleasure and elevated displeasure for daily activities. Our findings clarify the disturbances in pleasure and displeasure that characterize MDD and may inform treatment for this debilitating disorder. (PsycINFO Database Record PMID- 27936839 TI - Potential effects of severe bilateral amygdala damage on psychopathic personality features: A case report. AB - The fearlessness model posits that psychopathy is underpinned by a deficiency in the capacity to experience fear, predisposing to other features of the condition, such as superficial charm, guiltlessness, callousness, narcissism, and dishonesty. Nevertheless, it is unclear whether fearlessness is irrelevant, necessary, sufficient, or merely contributory to psychopathy. In the present case study, we sought to examine the fearlessness model by studying an extensively investigated female patient-S. M.-who experienced early emerging bilateral calcifications of the amygdala, resulting in a virtual absence of fear. We aimed to replicate findings regarding S. M.'s deficient experience of self-reported fear and examine her levels of triarchic psychopathy dimensions (boldness, meanness, disinhibition). We also examined S. M.'s history of heroic behaviors given conjectures that fearlessness contributes to both heroism and psychopathy. Compared with population-based norms, S. M. reported deficient levels of self reported fear and self-control, as well as elevated levels of heroism. She did not, however, exhibit elevated levels of the core affective deficits of psychopathy, as reflected in measures of coldheartedness and meanness. These findings suggest that severe fear deficits may be insufficient to yield the full clinical picture of psychopathy, although they do not preclude the possibility that these deficits are necessary. (PsycINFO Database Record PMID- 27936841 TI - A career of harnessing group variability. AB - Neuroscience research, particularly in brain-injured patients, is often hampered by the problems of variability of performance among the individuals included in what seems like a well-defined supposedly homogeneous group. This review presents examples from the author's research in traumatic brain injury (TBI) and the effects of frontal lobe focal pathology to illustrate how variability was explored and "harnessed" to advance the understanding of specific brain-behaviour relations and the role of the frontal lobes in human behaviour. A final section summarizes how this approach informed the establishment of an administrative structure that integrates different types of information (genetic to behavioural) and basic and clinical science to improve diagnoses and care. (PsycINFO Database Record PMID- 27936840 TI - Social disadvantage and borderline personality disorder: A study of social networks. AB - Examining differences in social integration, social support, and relationship characteristics in social networks may be critical for understanding the character and costs of the social difficulties experienced of borderline personality disorder (BPD). We conducted an ego-based (self-reported, individual) social network analysis of 142 participants recruited from clinical and community sources. Each participant listed the 30 most significant people (called alters) in their social network, then rated each alter in terms of amount of contact, social support, attachment strength and negative interactions. In addition, measures of social integration were determined using participant's report of the connection between people in their networks. BPD was associated with poorer social support, more frequent negative interactions, and less social integration. Examination of alter-by-BPD interactions indicated that whereas participants with low BPD symptoms had close relationships with people with high centrality within their networks, participants with high BPD symptoms had their closest relationships with people less central to their networks. The results suggest that individuals with BPD are at a social disadvantage: Those with whom they are most closely linked (including romantic partners) are less socially connected (i.e., less central) within their social network. (PsycINFO Database Record PMID- 27936842 TI - Comprendre le stade compensatoire de la maladie d'Alzheimer et agir pour promouvoir la cognition et la plasticite cerebrale. AB - Alzheimer's disease begins with a phase of mild cognitive impairment (MCI), characterized by the presence of minor symptoms that have little or no impact on functional independence. The study of patients with MCI has led to spectacular advances in understanding the prodrome of the disease. It has also produced a typical cognitive profile: an impairment of episodic memory, especially delayed recall and associative memory, deficit in executive functions or working memory and certain semantic problems. Recent studies have also examined compensatory processes that take place during the early phase of the disease. Functional magnetic resonance imagery indicates that the brain is more active in persons with MCI than in normal people. Some researchers have interpreted this hyperactivity as playing a compensatory role. Intervention studies have relied on cognitive training programs to promote adaptation and compensatory plasticity processes. These studies have shown that the memory and well-being of people with MCI could be improved by such programs. They have also revealed changes in the level of cerebral activation among persons with MCI who received this type of intervention. In Summary, studies in neuropsychology and in cognitive neuroscience have greatly contributed to characterizing this critical phase of Alzheimer's disease and offer avenues for intervention that could increase adaptation and improve the quality of life of people suffering from the disease. (PsycINFO Database Record PMID- 27936843 TI - Abstracts of the 2016 CSBBCS Annual Meeting: Resumes du congres annuel 2016 de la SCCCSC. AB - Provides a collection of abstracts from the 2016 CSBBCS Annual Meeting. (PsycINFO Database Record PMID- 27936844 TI - Self-paced preparation for a task switch eliminates attentional inertia but not the performance switch cost. AB - The performance overhead associated with changing tasks (the "switch cost") usually diminishes when the task is specified in advance but is rarely eliminated by preparation. A popular account of the "residual" (asymptotic) switch cost is that it reflects "task-set inertia": carry-over of task-set parameters from the preceding trial(s). New evidence for a component of "task-set inertia" comes from eye-tracking, where the location associated with the previously (but no longer) relevant task is fixated preferentially over other irrelevant locations, even when preparation intervals are generous. Might such limits in overcoming task-set inertia in general, and "attentional inertia" in particular, result from suboptimal scheduling of preparation when the time available is outside one's control? In the present study, the stimulus comprised 3 digits located at the points of an invisible triangle, preceded by a central verbal cue specifying which of 3 classification tasks to perform, each consistently applied to just 1 digit location. The digits were presented only when fixation moved away from the cue, thus giving the participant control over preparation time. In contrast to our previous research with experimenter-determined preparation intervals, we found no sign of attentional inertia for the long preparation intervals. Self paced preparation reduced but did not eliminate the performance switch cost leaving a clear residual component in both reaction time and error rates. That the scheduling of preparation accounts for some, but not all, components of the residual switch cost, challenges existing accounts of the switch cost, even those which distinguish between preparatory and poststimulus reconfiguration processes. (PsycINFO Database Record PMID- 27936845 TI - Dealing with prospective memory demands while performing an ongoing task: Shared processing, increased on-task focus, or both? AB - Prospective memory (PM) is the cognitive ability to remember to fulfill intended action plans at the appropriate future moment. Current theories assume that PM fulfillment draws on attentional processes. Accordingly, pending PM intentions interfere with other ongoing tasks to the extent to which both tasks rely on the same processes. How do people manage the competition between PM and ongoing-task demands? Based on research relating mind wandering and attentional control (Kane & McVay, 2012), we argue that people may not only change the way they process ongoing-task stimuli when given a PM intention, but they may also engage in less off-task thinking than they otherwise would. That is, people focus more strongly on the tasks at hand and dedicate considerable conscious thought to the PM goal. We tested this hypothesis by asking subjects to periodically report on their thoughts during prototypical PM (and control) tasks. Task-unrelated thought rates dropped when participants performed an ongoing task while holding a PM intention versus performing the ongoing task alone (Experiment 1), even when PM demands were minimized (Experiment 2) and more so when PM execution was especially rewarded (Experiment 3). Our findings suggest that PM demands not only elicit a cost to ongoing-task processing, but they also induce a stronger on-task focus and promote conscious thoughts about the PM intention. (PsycINFO Database Record PMID- 27936846 TI - The memorability of people: Intrinsic memorability across transformations of a person's face. AB - When encountering new people for a brief instant, some seem to last in our memories while others are quickly forgotten. Memorability-whether a stimulus is likely to be later remembered-is highly consistent across different group of observers; people tend to remember and forget the same face images. However, is memorability intrinsic to just the picture of a face, or to a person's identity, generalizable across views and emotions? Thousands of participants completed an online experiment testing face identity recognition over five different emotional and viewpoint transformations (neutral, happy, angry, 3/4 view, and profile view). Memorability was found to be highly consistent within each image, as well as across transformations-if a face was remembered in one image, it was also likely to be remembered in another. Most other face attributes, including what participants thought would be memorable, did not show consistency within an identity. Overall, these results support the existence of memorability as a uniquely intrinsic, core attribute to a person, stable across images. (PsycINFO Database Record PMID- 27936847 TI - Reading aloud: On the determinants of the joint effects of stimulus quality and word frequency. AB - There are multiple reports, in the context of the time taken to read aloud, that the joint effects of stimulus quality and word frequency (a) interact when only words appear in the list but (b) are additive when nonwords are intermixed with words (O'Malley & Besner, 2008). This triple interaction has been explained in terms of the idea that different processing modes are in play in these different contexts. Processing is cascaded when only words appear in the list, allowing the effect of stimulus quality to influence the downstream process(es) affected by word frequency. In contrast, when nonwords appear in the list an early process affected by stimulus quality, but not word frequency, is staged (thresholded) so as to reduce the probability of lexicalizations (reading a nonword as a word) when stimulus quality is low. The present experiment addresses the issue of whether such thresholding in the presence of nonwords is driven by the orthography or phonology of the nonwords included in the stimulus set. Participants read words aloud that varied in word frequency and were randomly intermixed with nonwords that all sounded identical to words (e.g., BRANE for BRAIN). Stimulus quality and word frequency had additive effects on the time to read aloud in this context, consistent with the view that it is the orthography of the nonwords that matters. Other aspects of the results suggest that between level feed-back is in play when this particular kind of nonword is used. (PsycINFO Database Record PMID- 27936848 TI - Memory inhibition as a critical factor preventing creative problem solving. AB - The hypothesis that reduced accessibility to relevant information can negatively affect problem solving in a remote associate test (RAT) was tested by using, immediately before the RAT, a retrieval practice procedure to hinder access to target solutions. The results of 2 experiments clearly showed that, relative to baseline, target words that had been competitors during selective retrieval were much less likely to be provided as solutions in the RAT, demonstrating that performance in the problem-solving task was strongly influenced by the predetermined accessibility status of the solutions in memory. Importantly, this was so even when participants were unaware of the relationship between the memory and the problem-solving procedures in the experiments. This finding is consistent with an inhibitory account of retrieval-induced forgetting effects and, more generally, constitutes support for the idea that the activation status of mental representations originating in a given task (e.g., episodic memory) can unwittingly have significant consequences for a different, unrelated task (e.g., problem solving). (PsycINFO Database Record PMID- 27936849 TI - Occupational functioning and employment services use among VA primary care patients with posttraumatic stress disorder. AB - OBJECTIVE: Veterans with posttraumatic stress disorder (PTSD) exhibit high levels of unemployment. The Department of Veterans Affairs' Veterans Health Administration (VHA) offers a variety of employment services; however, few veterans with PTSD use these services. Because many veterans with mental health conditions are seen in primary care clinics, employment service needs may be best addressed in this setting. The current study was designed to assess employment status and support needs in VHA primary care patients who screen positive for PTSD. METHOD: In the study, 287 working-age VHA patients with recent primary care use completed web-based surveys that assessed employment status, PTSD symptoms, employment support preferences, and barriers to service usage. RESULTS: Individuals who screened positive for PTSD were less likely to be employed than were those without PTSD (55% vs. 69%; p = .03). After adjusting for sociodemographic characteristics, individuals with PTSD had higher barriers to employment (beta = 3.52, p < .001) and higher barriers to employment service use (beta = 0.57, p = .02). Only 14% of those with PTSD had used VHA employment services, but 86% said they would use those services. CONCLUSIONS: Although the single site included in the study may not be representative of all VHA primary care clinics, our results suggest that there is high need for and substantial interest in VHA employment services among VHA patients with PTSD. Future work should focus on implementing employment support services for individuals with PTSD in primary care settings. (PsycINFO Database Record PMID- 27936850 TI - Spiritual struggles and suicide in veterans seeking PTSD treatment. AB - OBJECTIVE: Research indicates that trauma can precipitate a loss of faith and struggles in the spiritual domain, leading to increased suicide risk. However, little is known about the specific types of spiritual struggles that may confer risk. This brief report examines the utility of a newly developed measure, the Religious and Spiritual Struggles Scale in gauging suicide risk in veterans. METHOD: As part of their initial assessment, 52 veterans presenting to an outpatient posttraumatic stress disorder and substance use clinic were administered self-report symptom measures. RESULTS: Multiple regression analyses revealed that divine struggles and struggles with the ultimate meaning were significantly and positively associated with increased suicide risk, even after controlling for relevant demographic (e.g., being male and Caucasian) and psychological variables (e.g., posttraumatic stress disorder symptoms as well as alcohol and substance use symptoms). CONCLUSIONS: Results provide preliminary support for use of the Religious and Spiritual Struggles Scale with veterans and highlight the potential utility in assessing for spiritual struggles when assessing suicide risk. (PsycINFO Database Record PMID- 27936851 TI - Relationship between negative social reactions to sexual assault disclosure and mental health outcomes of Black and White female survivors. AB - OBJECTIVE: This study investigates the effect of race on the relationship between negative reactions to sexual assault disclosure and the psychological sequelae such as posttraumatic stress disorder (PTSD), depression, and problem drinking in female sexual assault survivors. METHOD: Using hierarchical regression in an ethnically diverse community sample of 622 female adult sexual assault victims, we assessed for sexual assault; negative reactions to sexual assault disclosure; and symptom severity for PTSD, depression, and problem drinking. RESULTS: Negative social reactions to sexual assault disclosures were significantly associated with negative mental health outcomes across race. Race moderated the influence of negative disclosure reactions on psychological symptoms; however, the moderation was not similar across racial groups and psychological outcome measures. Although Black and White survivors evidenced distress through depression, PTSD, and substance use, Black women who received low to moderate negative reactions to their disclosures of assault were more likely to show increases in PTSD and depression whereas high negative reactions to disclosure were related to higher PTSD and depression similarly for both Black and White women. In addition, Black and White women who experienced more negative social reactions had greater substance abuse, with no difference by race. CONCLUSION: The results provide further support for detrimental effects of negative reactions on Black and White survivors and highlight the importance of educating people in the community about sexual assault and how to respond in more supportive ways. (PsycINFO Database Record PMID- 27936852 TI - Racial/ethnic disparities in the risk of posttraumatic stress disorder symptoms among mothers of children diagnosed with cancer and Type-1 diabetes mellitus. AB - OBJECTIVE: Research findings have indicated that mothers of children diagnosed with life-threatening illnesses can be at risk for posttraumatic stress disorder (PTSD) symptoms (PTSS), with African American mothers being especially vulnerable because of evidence suggesting higher rates of PTSD among both African Americans and women. Race/ethnicity, past trauma exposure and the interaction of these variables were evaluated as risk factors for PTSS, depression, and state and trait anxiety among African American and Caucasian mothers of chronically ill children. METHOD: Mothers of children (N = 91) diagnosed with a life-threatening illness (i.e., cancer or Type-I diabetes mellitus [T1DM]) completed standardized measures and provided a salivary cortisol sample while attending medical appointments for their ill children. RESULTS: A MANCOVA revealed that mothers of children diagnosed with T1DM had higher cortisol levels than mothers of children with cancer. There was no racial or ethnic disparity in the risk of PTSS among the mothers. CONCLUSION: These findings suggest that mothers of children with T1DM may be vulnerable to stress reactions, as reflected by cortisol, a biological marker. Clinicians and researchers might consider illness-specific features when evaluating the risk of stress reactions among mothers of children with life-threatening illnesses. (PsycINFO Database Record PMID- 27936853 TI - Improving metacomprehension accuracy in an undergraduate course context. AB - Students tend to have poor metacomprehension when learning from text, meaning they are not able to distinguish between what they have understood well and what they have not. Although there are a good number of studies that have explored comprehension monitoring accuracy in laboratory experiments, fewer studies have explored this in authentic course contexts. This study investigated the effect of an instructional condition that encouraged comprehension-test-expectancy and self explanation during study on metacomprehension accuracy in the context of an undergraduate course in research methods. Results indicated that when students received this instructional condition, relative metacomprehension accuracy was better than in a comparison condition. In addition, differences were also seen in absolute metacomprehension accuracy measures, strategic study behaviors, and learning outcomes. The results of the current study demonstrate that a condition that has improved relative metacomprehension accuracy in laboratory contexts may have value in real classroom contexts as well. (PsycINFO Database Record PMID- 27936854 TI - Interword and interletter spacing effects during reading revisited: Interactions with word and font characteristics. AB - Despite the large number of eye movement studies conducted over the past 30+ years, relatively few have examined the influence that font characteristics have on reading. However, there has been renewed interest in 1 particular font characteristic, letter spacing, which has both theoretical (visual word recognition) and applied (font design) importance. Recently published results that letter spacing has a bigger impact on the reading performance of dyslexic children have perhaps garnered the most attention (Zorzi et al., 2012). Unfortunately, the effects of increased interletter spacing have been mixed with some authors reporting facilitation and others reporting inhibition (van den Boer & Hakvoort, 2015). The authors present findings from 3 experiments designed to resolve the seemingly inconsistent letter-spacing effects and provide clarity to researchers and font designers and researchers. The results indicate that the direction of spacing effects depend on the size of the default spacing chosen by font developers. Experiment 3 found that interletter spacing interacts with interword spacing, as the required space between words depends on the amount of space used between letters. Interword spacing also interacted with word type as the inhibition seen with smaller interword spacing was evident with nouns and verbs but not with function words. (PsycINFO Database Record PMID- 27936855 TI - Evaluating probe techniques and a situated theory of situation awareness. AB - Probe techniques for measuring situation awareness (SA) vary in whether scenarios are paused and displays visible while questions are presented. We examined which technique is least intrusive on workload and performance in air traffic control, and which is most sensitive at capturing differences in SA when automation varies. We also tested predictions from the situated SA theory, which holds that operators offload specific and low-priority information onto displays to limit internal processing. To accomplish these goals, Experiments 1 and 2 manipulated whether radar displays were visible and scenarios paused during queries. Experiment 2 also manipulated the amount of automation by varying the percentage of aircraft equipped with NextGen tools. We found all probe techniques were equally sensitive at capturing SA differences for different levels of equipage, but those that paused scenarios were least intrusive. Moreover, consistent with situated SA, blanking displays impaired ability to answer questions about specific but not general information. Experiment 3 recorded eye gaze frequency and duration during queries when scenarios were visible and not paused and, as predicted by situated SA, found participants were more likely to look at radar displays while answering specific and low-priority questions than general and high-priority questions. (PsycINFO Database Record PMID- 27936856 TI - Contextual information and perceptual-cognitive expertise in a dynamic, temporally-constrained task. AB - Skilled performers extract and process postural information from an opponent during anticipation more effectively than their less-skilled counterparts. In contrast, the role and importance of contextual information in anticipation has received only minimal attention. We evaluate the importance of contextual information in anticipation and examine the underlying perceptual-cognitive processes. We present skilled and less-skilled tennis players with normal video or animated footage of the same rallies. In the animated condition, sequences were created using player movement and ball trajectory data, and postural information from the players was removed, constraining participants to anticipate based on contextual information alone. Participants judged ball bounce location of the opponent's final occluded shot. The 2 groups were more accurate than chance in both display conditions with skilled being more accurate than less skilled (Exp. 1) participants. When anticipating based on contextual information alone, skilled participants employed different gaze behaviors to less-skilled counterparts and provided verbal reports of thoughts which were indicative of more thorough evaluation of contextual information (Exp. 2). Findings highlight the importance of both postural and contextual information in anticipation and indicate that perceptual-cognitive expertise is underpinned by processes that facilitate more effective processing of contextual information, in the absence of postural information. (PsycINFO Database Record PMID- 27936857 TI - In the same group but moving in different directions: Coordination effects in tasks with simultaneous intellective and judgmental performance criteria. AB - Cooperative work can seldom be meaningfully reduced to a single performance criterion. However, there is little theory regarding how groups address tasks with multiple success criteria. Generalizing from the theory of task demonstrability we offer a foundation for understanding group performance on multifaceted tasks that includes a focus on subtask performance, overall performance, and the subjective experience of group members. We predict and find that the composition of groups with respect to member priorities (i.e., having a single member that is oriented toward an intellective criterion or multiple members oriented toward a judgmental criterion) outperform groups that do not meet these composition thresholds. Groups simultaneously meeting both thresholds outperform all comparisons, however their members report a poor shared understanding of the task, less cooperation, and less desire to work in that same group in the future. This research extends the traditional group performance literature into the more complex and ecologically valid area of multicriteria performance and addresses both theoretical and practical implications. (PsycINFO Database Record PMID- 27936858 TI - You must be lying because I don't understand you: Language proficiency and lie detection. AB - We examined the impact of interviewees' language proficiencies on observers' lie detection performance. Observers (N = 132) were randomly assigned to make deception judgments about interviewees (N = 56) from Four proficiency groups (i.e., native, advanced, intermediate, and beginner English speakers). Discrimination between lie- and truth-tellers was poorest when observers judged beginner English speakers compared to interviewees from any other proficiency group. Observers were also less likely to exhibit a truth-bias toward nonnative than native English speakers. These results suggest that interviewing individuals in their nonnative languages can create inequalities in the justice system. (PsycINFO Database Record PMID- 27936859 TI - Extracting critical information from group members' partial knowledge using the Searching Concealed Information Test. AB - The Concealed Information Test (CIT) is a psychophysiological method designed to detect information that an individual cannot or does not wish to reveal. The present study used a version of the CIT, the Searching Concealed Information Test (SCIT), to extract information from partial information that participants possessed on a planned jailbreak. In the first experiment, 52 undergraduate students were randomly, but not equally, allocated into 15 different clusters of partial knowledge. In each, participants possessed knowledge about 2 of 6 critical items. Using a lenient decision rule, and a combined measure defined as the mean of 3 individual measures (skin conductance response amplitude, finger pulse, and respiration line length) 5 of the 6 critical items were identified. Experiment 2 extended the first experiment to unequal proportions of critical knowledge. Forty-six undergraduate students were randomly allocated into 25 clusters of partial knowledge in which 0, 1, 2, 3, or 6 pieces of information were known. Using the same lenient decision rule and the combined measure, all 6 items were identified. It was suggested that the Group SCIT is capable of assembling a comprehensive picture out of partial information possessed by informed innocent participants. (PsycINFO Database Record PMID- 27936860 TI - Detection of acrA, acrB, aac(6')-Ib-cr, and qepA genes among clinical isolates of Escherichia coli and Klebsiella pneumoniae. AB - BACKGROUND: The distribution of drug resistance among clinical isolates of Escherichia coli and Klebsiella pneumoniae has limited the therapeutic options. The aim of this study was to report the prevalence of quinolone resistance genes among E. coli and K. pneumoniae clinical strains isolated from three educational hospitals of Tehran, Iran. MATERIALS AND METHODS: A total of 100 strains of E. coli from Labbafinejad and Taleghani Hospitals and 100 strains of K. pneumoniae from Mofid Children and Taleghani Hospitals were collected between January 2013 and May 2014. Antimicrobial susceptibility tests were done by disk diffusion method based on Clinical and Laboratory Standards Institute guidelines. Detection of qepA, aac(6')-Ib-cr, acrA, and acrB genes was done by polymerase chain reaction (PCR). RESULTS: In this study, fosfomycin and imipenem against E. coli and fosfomycin and tigecycline against K. pneumoniae had the best effect in antimicrobial susceptibility tests. PCR assay using specific primers demonstrated that the prevalence of qepA, aac(6')-Ib-cr, acrA, and acrB genes among the 100 E. coli isolates was 0 (0%), 87 (87%), 92 (92%), and 84 (84%), respectively. The prevalence of qepA, aac(6')-Ib-cr, acrA, and acrB genes among the 100 K. pneumoniae isolates was 4 (4%), 85 (85%), 94 (94%), and 87 (87%), respectively. CONCLUSION: The distribution of qepA, aac(6')-Ib-cr, acrA, and acrB resistance determinants in E. coli and K. pneumoniae is a great concern. Therefore, infection control and prevention of spread of drug-resistant bacteria need careful management of medication and identification of resistant isolates. PMID- 27936862 TI - Emotional experience in patients with advanced Alzheimer's disease from the perspective of families, professional caregivers, physicians, and scientists. AB - OBJECTIVES: The objective of this qualitative study was to gain insight into families' and professionals' understanding of the emotional experience in patients with advanced Alzheimer's disease. METHOD: A total of ten focus group interviews were carried out with 63 participants (relatives n = 20; caregivers n = 17; physicians n = 12; scientists n = 14) recruited using purposive sampling strategies. Each focus group was audiotaped, transcribed and analysed using the method of structured qualitative content analysis. RESULTS: Study findings show that for all groups with the exception of relatives, emotionality is one of the most important characteristics retained despite the illness. Indicators are patient's continued ability to produce emotional signals, be responsive to others, and retain emotional information despite memory loss. In the spectrum of emotions, professional caregivers emphasize positive emotional states more strongly than physicians or scientists. In contrast, relatives emphasize the loss of emotional experience. Critical indicators denying subjective emotional experience are impairment of (autobiographical) memory (especially the non recognition of relatives), the reduction of means of verbal expression with simultaneous uncertainty in interpreting nonverbal expression as well as the perceived discrepancy between present emotional experience and behaviour and that of the premorbid personality. CONCLUSION: When relatives anchor on the premorbid personality, the perceived discontinuity of emotional reactions to stimuli triggering an emotional response in contrast to their own expectations gives rise to an extremely ambiguous situation. Training programmes should be developed for families to help them comprehend and respond to nonverbal emotional expression. PMID- 27936861 TI - Effects of hemin, CO2, and pH on the branching of Candida albicans filamentous forms. AB - Morphological transitions of wild-type and oxidative stress-tolerant Candida albicans strains were followed in the RPMI-FBS culture medium at pH values and CO2 levels characteristic for the anatomical niches inhabited by this opportunistic human pathogen fungus, including the oral cavity as well as the intestinal and vaginal lumens. Selected cultures were also supplemented with hemin modeling bleedings. Germination as well as elongation and branching of hyphae were monitored in the cultures using time-lapse video microscopy. Unexpectedly, branching time, which is defined as the time taken until the first branch of hypha emerges for the first time after germination, correlated well with alterations in the environmental conditions meanwhile no such correlations were found for germination time (time lasted until the appearance of the germination tube). Based on these observations, hypotheses were set up to estimate the significance of branching time in the pathogenesis of both superficial and systemic candidiases. PMID- 27936863 TI - Missed Opportunities for Repeat HIV Testing in Pregnancy: Implications for Elimination of Mother-to-Child Transmission in the United States. AB - HIV testing is an effective intervention that is used for reducing perinatal HIV transmission. Centers for Disease Control and Prevention recommends a second HIV test during the third trimester of pregnancy for women in settings with an elevated HIV incidence (>=17 cases per 100,000 person-years). We conducted a retrospective cohort study at a single hospital in Baltimore, Maryland, to determine whether a second HIV test was done and to compare HIV retesting with mandated syphilis retesting. Of women who delivered at this hospital, 98.8% received prenatal care. Descriptive, bivariate, and multivariable analyses were performed. Among 1632 women, mean age was 27.6 years (standard deviation: 6.3), 59.6% were black, and 55.5% were single. HIV retesting was done in 28.4% of women, which was significantly less often compared with the state-mandated syphilis retesting (78.7%, p < 0.001). The odds of having an HIV retest were 15 times higher among women who received prenatal care at a teaching clinic [adjusted odds ratio (aOR): 15.58; 95% confidence interval (CI): 11.12-21.81], and they were lower among women with private insurance (aOR: 0.54, 95% CI: 0.34 0.86). The odds of having a syphilis retest were twice as high among women who received prenatal care at a faculty practice (aOR: 2.17; 95% CI: 1.53-3.09), and they were lower among women with private insurance (aOR: 0.61, 95% CI: 0.43 0.88). Emphasizing an "opt-out" HIV retesting approach through state laws may minimize risk perception, and this is one strategy that can be considered in areas of high HIV incidence to reach the goal of eliminating perinatal HIV transmission in the United States. PMID- 27936864 TI - Phytoremediation-biorefinery tandem for effective clean-up of metal contaminated soil and biomass valorisation. AB - During the last few decades, phytoremediation process has attracted much attention because of the growing concerns about the deteriorating quality of soil caused by anthropogenic activities. Here, a tandem phytoremediation/biorefinery process was proposed as a way to turn phytoremediation into a viable commercial method by producing valuable chemicals in addition to cleaned soil. Two agricultural plants (Sinapis alba and Helianthus annuus) were grown in moderately contaminated soil with ca. 100 ppm of Ni and further degraded by a fungal lignin degrader-Phanerochaete chrysosporium. Several parameters have been studied, including the viability of plants, biomass yield, and their accumulating and remediating potentials. Further, downstream processing showed that up to 80% of Ni can be easily extracted from contaminated biomass by aqueous extraction at mild conditions. Finally, it was demonstrated that the growth of plants on the contaminated soil could be degraded by P. chrysosporium, and the effect of nickel and biomass pretreatment on the solid-state fermentation was studied. The proposed and studied methodology in this work could pave the way for successful commercialization of the phytoremediation process in the near future. PMID- 27936865 TI - Alleviation of heavy metals toxicity by the application of plant growth promoting rhizobacteria and effects on wheat grown in saline sodic field. AB - The aim of the study was to determine tolerance of plant growth promoting rhizobacteria (PGPR) in different concentrations of Cu, Cr, Co, Cd, Ni, Mn, and Pb and to evaluate the PGPR-modulated bioavailability of different heavy metals in the rhizosphere soil and wheat tissues, grown in saline sodic soil. Bacillus cereus and Pseudomonas moraviensis were isolated from Cenchrus ciliaris L. growing in the Khewra salt range. Seven-day-old cultures of PGPR were applied on wheat as single inoculum, co-inoculation and carrier-based biofertilizer (using maize straw and sugarcane husk as carrier). At 100 ppm of Cr and Cu, the survival rates of rhizobacteria were decreased by 40%. Single inoculation of PGPR decreased 50% of Co, Ni, Cr and Mn concentrations in the rhizosphere soil. Co inoculation of PGPR and biofertilizer treatment further augmented the decreases by 15% in Co, Ni, Cr and Mn over single inoculation except Pb and Co where decreases were 40% and 77%, respectively. The maximum decrease in biological concentration factor (BCF) was observed for Cd, Co, Cr, and Mn. P. moraviensis inoculation decreases the biological accumulation coefficient (BAC) as well as translocation factor (TF) for Cd, Cr, Cu Mn, and Ni. The PGPR inoculation minimized the deleterious effects of heavy metals, and the addition of carriers further assisted the PGPR. PMID- 27936866 TI - Phytoremediation of metals using lemongrass (Cymbopogon citratus (D.C.) Stapf.) grown under different levels of red mud in soil amended with biowastes. AB - Due to hostile condition of red mud (RM), its utilization for vegetation is restricted. Therefore, RM with biowastes as soil amendment may offer suitable combination to support plant growth with reduced risk of metal toxicity. To evaluate the effects of RM on soil properties, plant growth performance, and metal accumulation in lemongrass, a study was conducted using different RM concentrations (0, 5, 10, and 15% w/w) in soil amended with biowastes [cow dung manure (CD) or sewage-sludge (SS)]. Application of RM in soil with biowastes improved organic matter and nutrient contents and caused reduction in phytoavailable metal contents. Total plant biomass was increased under all treatments, maximally at 5% RM in soil with SS (91.4%) and CD (51.7%) compared to that in control (no RM and biowastes). Lemongrass acted as a potential metal tolerant plant as its metal tolerance index is >100%. Based on translocation and bioconcentration factors, lemongrass acted as a potential phytostabilizer of Fe, Mn, and Cu in roots and was found efficient in translocation of Al, Zn, Cd, Pb, Cr, As, and Ni from roots to shoot. The study suggests that 5% RM with biowastes preferably SS may be used to enhance phytoremediation potential of lemongrass. PMID- 27936867 TI - Opportunities for probiotics and polyunsaturated fatty acids to improve metabolic health of overweight pregnant women. AB - Overweight during pregnancy predisposes both the mother and foetus to health complications. Maternal complications include gestational diabetes, obstetric problems and type 2 diabetes later in life. Complications for the offspring are not only restricted to the foetal period or birth, such as prematurity and foetal macrosomia, but may also have long-term metabolic health implications through the mechanism of early nutrition programming. One of the key metabolic components characterising overweight in the non-pregnant state is low-grade inflammation manifested by elevated levels of circulatory pro-inflammatory cytokines. In pregnancy, in addition to adipose tissue and placenta, inflammatory response may originate from the gut. The extent to which overweight induces metabolic maladaptation during pregnancy and further compromises maternal and child health is currently poorly understood. In this review, we evaluate recent scientific literature and describe the suggested links between overweight, gut and low-grade inflammation associated metabolic disorders. We focus on overweight pregnant women and gestational diabetes, and discuss how specific dietary factors, probiotics and long-chain polyunsaturated fatty acids (fish oil), might confer health benefits in combatting against metabolic risk factors. PMID- 27936868 TI - Decontamination of coal mine effluent generated at the Rajrappa coal mine using phytoremediation technology. AB - Toxicity of the effluent generated at the Rajrappa coal mine complex under the Central Coalfields Limited (CCL, a subsidiary of Coal India Limited) in Jharkhand, India was investigated. The concentrations (mg L-1) of all the toxic metals (Fe, Mn, Ni, Zn, Cu, Pb, Cr, and Cd) in the coal mine effluent were above the safe limit suggested by the Environmental Protection Agency (EPA 2003). Among these, Fe showed the highest concentration (18.21 +/- 3.865), while Cr had the lowest effluent concentration (0.15 +/- 0.014). Efforts were also made to detoxify the effluent using two species of aquatic macrophytes namely "'Salvinia molesta and Pistia stratiotes." After 10 days of phytoremediation, S. molesta removed Pb (96.96%) > Ni (97.01%) > Cu (96.77%) > Zn (96.38%) > Mn (96.22%) > Fe (94.12%) > Cr (92.85%) > Cd (80.99%), and P. stratiotes removed Pb (96.21%) > Fe (94.34%) > Ni (92.53%) > Mn (85.24%) > Zn (79.51%) > Cr (78.57%) > Cu (74.19%) > Cd (72.72%). The impact of coal mine exposure on chlorophyll content showed a significant decrease of 42.49% and 24.54% from control values in S. molesta and P. stratiotes, respectively, perhaps due to the damage inflicted by the toxic metals, leading to the decay of plant tissues. PMID- 27936869 TI - Cadmium phytoextraction from loam soil in tropical southern China by Sorghum bicolor. AB - The cadmium (Cd) uptake characteristics by Sorghum bicolor cv. Nengsi 2# and Cowley from the acidic sandy loam soil (pH = 6.1) during the entire growth period (100 days) were investigated in pot outdoors in a tropical district of southern China, Hainan Island. The Cd-spiked levels in soil were set as 3 and 15 mg/kg. Correspondingly, the available Cd levels in soil extracted by Mehlich III solution were 2.71 and 9.41 mg/kg, respectively. Basically, two varieties in a full growth period (100 days) did not show a significant difference in their growth and Cd uptake. Under high Cd stress, the plant growth was inhibited and its biomass weight and height decreased by 38.7-51.5% and 27.6-28.5%, respectively. However, S. bicolor showed higher bioaccumulation capability of Cd from soil to plant [bioconcentration factor (BCF)>4], and higher transfer capability of Cd from roots to shoots [translocation factor (TF)>1] under high Cd stress; Cd contents in the roots, stems, and leaves of S. bicolor reached 43.79 46.07, 63.28-70.60, and 63.10-66.06 mg/kg, respectively. S. bicolor exhibited the potential phytoextraction capability for low or moderate Cd-contamination in acidic sandy loam soil. PMID- 27936870 TI - Emerging biomarkers for PD-1 pathway cancer therapy. AB - The field of immuno-oncology has witnessed unprecedented success in recent years, with several PD=1 and PD-L1 inhibitors obtaining US FDA registration and breakthrough drug therapy designation in multiple tumor types. Despite its clear efficacy in certain cancers, treatment with these agents carries a risk of immune related toxicities and substantial financial burden. It is, therefore, critical to identify patients likely to benefit from such immunotherapies and develop strategies to differentiate responders from nonresponders early during treatment. Here we discuss the development of predictive and treatment response biomarkers for immune checkpoint inhibitors. We first examine the role of PD-L1 expression, the most extensively studied predictive biomarker of response, and further discuss emerging putative predictive biomarkers. We also detail challenges faced in the development of response assessments for immunotherapeutics and propose other biomarkers that may be useful as surrogate intermediate end points of response. PMID- 27936871 TI - Trends in Biobanking Business Planning: Initial Results of a Survey of Biobankers. PMID- 27936872 TI - Full-length VP2 gene analysis of canine parvovirus reveals emergence of newer variants in India. AB - The canine parvovirus (CPV) infection is a highly contagious and serious enteric disease of dogs with high fatality rate. The present study was taken up to characterize the full-length viral polypeptide 2 (VP2) gene of CPV of Indian origin along with the commercially available vaccines. The faecal samples from parvovirus suspected dogs were collected from various states of India for screening by PCR assay and 66.29% of samples were found positive. Six CPV-2a, three CPV-2b, and one CPV-2c types were identified by sequence analysis. Several unique and existing mutations have been noticed in CPV types analyzed indicating emergence of newer variants of CPV in India. The phylogenetic analysis revealed that all the field CPV types were grouped in different subclades within two main clades, but away from the commercial vaccine strains. CPV-2b and CPV-2c types with unique mutations were found to be establishing in India apart from the prevailing CPV-2a type. Mutations and the positive selection of the mutants were found to be the major mechanism of emergence and evolution of parvovirus. Therefore, the incorporation of local strain in the vaccine formulation may be considered for effective control of CPV infections in India. PMID- 27936873 TI - Composition of endophytic fungal community associated with leaves of maize cultivated in south Brazilian field. AB - The objective of this study was to conduct a survey about fungi associated with leaves from two different maize plant lineages and to analyze their microbiota diversity. Isolated fungi were identified by morphological analysis and molecular taxonomy was performed using ITS1-5.8S-ITS2 rDNA. About 27 fungi morphotypes were obtained, 15 of them were from the first maize lineage. About 86.7% of the individuals belonged to the Dothideomycetes class (Phoma sorghina, Epicocum nigrum, Cladosporium sp., Bipolaris zeicola, and Alternaria alternata complex) and 13.3% to the Sordariomycetes class (Diaporthe/Phomopsis sp. and Nigrospora sp.). This ratio was opposite in the other maize lineage with 25.0% of Dothideomycetes (E. nigrum and Pleosporales) and 75.0% of Sordariomycetes (Gibberella fujikuroi complex, Fusarium graminearum complex, Diaporthe/Phomopsis sp., and Nigrospora sp.). By concerning the analyses of morphological characteristics and molecular phylogeny, this study intended to identify the groups of saprophytic, phytopathogenic, and mycotoxin fungi, which differently co inhabit leaf tissue of maize plants in both tested lineages. PMID- 27936875 TI - A step-by-step translation of evidence into a psychosocial intervention for everyday activities in dementia: a focus group study. AB - OBJECTIVE: In order to increase the efficacy of psychosocial interventions in dementia, a step-by-step process translating evidence and public engagement should be adhered to. This paper describes such a process by involving a two stage focus group with people with dementia (PwD), informal carers, and staff. METHODS: Based on previous evidence, general aspects of effective interventions were drawn out. These were tested in the first stage of focus groups, one with informal carers and PwD and one with staff. Findings from this stage helped shape the intervention further specifying its content. In the second stage, participants were consulted about the detailed components. FINDINGS: The extant evidence base and focus groups helped to identify six practical and situation specific elements worthy of consideration in planning such an intervention, including underlying theory and personal motivations for participation. Carers, PwD, and staff highlighted the importance of rapport between practitioners and PwD prior to commencing the intervention. It was also considered important that the intervention would be personalised to each individual. CONCLUSIONS: This paper shows how valuable public involvement can be to intervention development, and outlines a process of public involvement for future intervention development. The next step would be to formally test the intervention. PMID- 27936874 TI - Effects of Physician-targeted Pay for Performance on Use of Spontaneous Breathing Trials in Mechanically Ventilated Patients. AB - RATIONALE: Pay for performance is an increasingly common quality improvement strategy despite the absence of robust supporting evidence. OBJECTIVES: To determine the impact of a financial incentive program rewarding physicians for the completion of daily spontaneous breathing trials (SBTs) in three academic hospitals. METHODS: We compared data from mechanically ventilated patients from 6 months before to 2 years after introduction of a financial incentive program that provided annual payments to critical care physicians contingent on unit-level SBT completion rates. We used Poisson regression to compare the frequency of days on which SBTs were completed among eligible patients and days on which patients were excluded from SBT eligibility among all mechanically ventilated patients. We used multivariate regression to compare risk-adjusted duration of mechanical ventilation and in-hospital mortality. MEASUREMENTS AND MAIN RESULTS: The cohort included 7,291 mechanically ventilated patients with 75,621 ventilator days. Baseline daily SBT rates were 96.8% (hospital A), 16.4% (hospital B), and 74.7% (hospital C). In hospital A, with the best baseline performance, there was no change in SBT rates, exclusion rates, or duration of mechanical ventilation across time periods. In hospitals B and C, with lower SBT completion rates at baseline, there was an increase in daily SBT completion rates and a concomitant increase in exclusions from eligibility. Duration of mechanical ventilation decreased in hospital C but not in hospital B. Mortality was unchanged for all hospitals. CONCLUSIONS: In hospitals with low baseline SBT completion, physician targeted financial incentives were associated with increased SBT rates driven in part by increased exclusion rates, without consistent improvements in outcome. PMID- 27936876 TI - ICT-based applications to improve social health and social participation in older adults with dementia. A systematic literature review. AB - OBJECTIVES: Information and communication technologies (ICT) developers, together with dementia experts have created several technological solutions to improve and facilitate social health and social participation and quality of life of older adults living with dementia. However, there is a need to carry out a systematic literature review that focuses on the validity and efficacy of these new technologies assessing their utility to promote 'social health' and 'active ageing' in people with dementia. METHOD: Searches in electronic databases identified 3824 articles of which 6 met the inclusion criteria and were coded according to their methodological approach, sample sizes, type of outcomes and results. RESULTS: Six papers were identified reporting the use of 10 different interventions with people with dementia. Qualitative studies (four) showed a benefit of the use of technologies to foster social participation in people with dementia. At the same time, barriers to a widespread use of these technologies in this population were identified. A quantitative study and a mixed-method study with quantitative outcomes showed that ICT-based interventions promote more social behaviours than non-technology-based interventions. CONCLUSIONS: In the last years, several technological devices for living independently and fostering social health and social participation in people with dementia have been developed. However, specific outcome measures to assess social health and social participation are needed. Even though the analysed studies provided some evidence base for the use of technology in this field, there is an urge to develop high quality studies and specific outcome measures. PMID- 27936877 TI - [A rare ECG manifestation of left sided pneumothorax: inferior STEMI with precordial Brugada pattern]. AB - Recognition and identification of the cause of non-coronary ST elevation is important in daily practice, mainly for avoiding unnecessary diagnostic and therapeutic procedures. In this case, a rare cause, spontaneous, left sided tension pneumothorax was in the background of the suddenly appearing, complex ECG changes - ST elevation mimicking inferior wall myocardial infarction associated with type 1 Brugada pattern ("coved" ST-segment elevation >= 2 mm) in the precordial leads. The clinical picture and course, the differential diagnostic problems related to the case and the possible causes of the ECG changes will be presented. Orv. Hetil., 2016, 157(50), 2007-2010. PMID- 27936878 TI - [Characterisctics of ragweed allergy in Hungary]. AB - INTRODUCTION: Although the prevalence of ragweed allergy in Europe is still low, it is increasing according to recent statistics. In contrast, in Hungary ragweed is the most common allergen with very high sensitisation in the general Hungarian population. AIM: We investigated the number and clinical characteristics of ragweed allergy in the Hungarian population, as the first comprehensive study to evaluate ragweed allergy in Hungary. METHOD: One thousand Hungarian adult subjects were screened with a questionnaire for ragweed allergy. People with ragweed allergy answered further specific questions about their disease history, symptoms and medication use. RESULTS: 305 subjects reported allergy from which 218 patients had symptoms during ragweed pollination suggesting ragweed allergy. 40% of these had symptoms for more than 5 years. Asthma was reported in 18.3%. Around 24% of these patients were undiagnosed; they did not take any medications or visited professionals because of their symptoms. Compared to the non-ragweed allergic patients, subjects with ragweed allergy were older and better educated, but the dominance of female gender was less prominent than in the non-ragweed group (all p<0.05). CONCLUSIONS: Around 22% of the Hungarian population suffers from ragweed allergy. Studies should focus on eradication strategy and improvement of patient care. Orv. Hetil., 2016, 157(50), 1989-1993. PMID- 27936879 TI - [Cryosclerosis. The forgotten endovenous cryoablation of the great saphenous vein. Mid-term results of a prospective comparative trial]. AB - INTRODUCTION: Cryosclerosis was introduced by Milleret and Le Pivert in the 1980s. METHOD: A prospective non-randomized comparative study has been performed on initial 96 patients. 48 patients were treated by cryosclerosis and the others received conventional stripping. 52 cases were analyzed for 2-years. The primary end-point of the study was to determine the occlusion rate of cryosclerosis. The clinical failure, the improvement in the Clinical Etiologic Anatomic Pathophysiologic classification and Venous Clinical Severity Scores were analyzed as secondary outcome. RESULTS: Total recanalization of the great saphenous vein causing clinical failure was observed in one case (4%). The reopening of the great saphenous vein was observed in 4 limbs (15%) that did not cause the incompetence of the trunk. The occlusion rate was 81%. Recurrent varicosity was observed by 35% and 42% of the patients in the cryosclerosis and stripping groups respectively. There was no significant difference between the groups (log rank test, p = 0.391). There was significant improvement in both the Clinical Etiologic Anatomic Pathophysiologic classification and Venous Clinical Severity Scores in each group without remarkable differences observed between the groups either at baseline or on the mid-term. CONCLUSIONS: Cryosclerosis seems to be effective in the remodeling of the great saphenous vein. The method has no remarkable mid-term clinical advantages over classical stripping so far. Orv. Hetil., 2016, 157(50), 1994-2001. PMID- 27936880 TI - [Everyday suspicion: our life is delusional]. AB - Suspicious thinking in given situations can be useful and helps the adaptation as events occurring in the world also corroborate this. Factors participating in the development of paranoia can be listed as psychodynamic (projection), salience attributional, neurobiological (dopamine), impaired perceptual (hearing loss), sociocultural (minority, pseudocommunity), self-esteem (worrying, depression, mania), and cognitive (jump-to-conclusion) mechanisms. Along the spectrum of thinking, from the mild to the severe, enhanced worrying, salience attribution, overvalued concepts, suspicion/mistrust, paranoid ideations, and crystallized delusions may occur with different contents. In recent years intensive research has been started to reveal the presence of subclinical paranoid thoughts in the general population. Applying various screening methods developed for this purpose (delusions inventories, psychometric tests, virtual reality laboratory) it has been found that suspicious/mistrustful ideations are fairly common in nonclinical samples and some of these are comparable to that seen in patient population. From the larger occurrence of milder forms to the smaller frequency of more severe delusional thoughts the whole hierarchical phenomenon can be described as a 'paranoia pyramid'. Based on this everyday paranoid thinking style lurking in people, it may well be that 'our life is delusional'. Orv. Hetil., 2016, 157(50), 1979-1988. PMID- 27936881 TI - [The practical measurement of health literacy in Hungary and in international comparison]. AB - INTRODUCTION: The study presents results of an innovative measurement of practical health literacy in international context. AIM: To show the level of practical health literacy in the Hungarian society and in international comparison. METHOD: We measured practical health literacy with Newest Vital Sign test on a Hungarian national representative sample, asked from 1008 persons, between May and June, 2015 from population 16 years or older, using methodological standards of Eurobarometer. The sample is representative to the above mentioned population by gender, age, region and settlement-size. RESULTS: Based on Newest Vital Sign test, members of the Hungarian society have good practical health literacy. The accomplishment is inconsistent with self-reported health literacy, since it shows weak results. CONCLUSIONS: As low level of self reported health literacy implies that respondents don't have daily routine in practicing their skills, we could draw people's attention to food-information, that are important and show, how to utilize them. Orv. Hetil., 2016, 157(50), 2002-2006. PMID- 27936882 TI - [Poems of Bocatius on medicine]. PMID- 27936884 TI - Exophytic Lesion of the Tongue in a Patient with Undetectable HIV-RNA in the Past 3 Years. PMID- 27936885 TI - Assessment of Ziziphus mauritiana grown on fly ash dumps: Prospects for phytoremediation but concerns with the use of edible fruit. AB - A field study was carried out on fly ash dumps of Panki Thermal Power Station to assess the phytoaccumulation of elements in various plant parts of edible fruit tree Ziziphus mauritiana. Out of the twelve analysed elements, the highest concentration was found for Fe followed by Mn > Se > Zn > Mo > Cu > Cr > Pb > Cd >Ni > As > Co in rhizospheric substrate of Z. mauritiana grown on fly ash dumps. Metal accumulation, bioconcentration factor and translocation factor for each metal was calculated in various parts of the edible fruit tree. Significant variations of metal accumulations were observed amongst various plant parts. Accumulation of toxic elements was higher in roots and it gradually declined towards the aerial parts of the plant corresponding to its distance from the ground. The concentration of some elements in fruit tree was found to be above prescribed limits in edible parts. Therefore, the present study suggested that additional care should be undertaken, if edible fruit trees are considered for phytoremediation or afforestation programs of FA dumps. PMID- 27936887 TI - Imaging appearance of topical haemostatic agents: pictorial review. AB - Topical haemostatic agents have become an essential tool to assist with the control of bleeding during surgery as well as to facilitate wound closure. The imaging appearance of these agents can overlap that of abscess or tumour. Knowledge of the appearance of these various agents on ultrasound and CT is crucial to avoid misdiagnosing pathology, potentially resulting in unnecessary interventional procedures. PMID- 27936888 TI - The B3 conundrum-the radiologists' perspective. AB - The management of B3 lesions is both controversial and complicated. There have been recent publications regarding how best to manage this heterogeneous group particularly in light of the Marmot Review and with the advent of vacuum-assisted biopsy technique. It is recognized that B3 lesions on core biopsy can be upgraded to malignancy in up to one-third of cases, but this is predominantly to ductal carcinoma in situ or low-grade invasive tumours. The upgrade rate is mainly associated with B3 lesions with epithelial atypia. This review summarizes the current management and focuses on the proposed future management of these B3 lesions. PMID- 27936886 TI - Quantitative radiomics studies for tissue characterization: a review of technology and methodological procedures. AB - Quantitative analysis of tumour characteristics based on medical imaging is an emerging field of research. In recent years, quantitative imaging features derived from CT, positron emission tomography and MR scans were shown to be of added value in the prediction of outcome parameters in oncology, in what is called the radiomics field. However, results might be difficult to compare owing to a lack of standardized methodologies to conduct quantitative image analyses. In this review, we aim to present an overview of the current challenges, technical routines and protocols that are involved in quantitative imaging studies. The first issue that should be overcome is the dependency of several features on the scan acquisition and image reconstruction parameters. Adopting consistent methods in the subsequent target segmentation step is evenly crucial. To further establish robust quantitative image analyses, standardization or at least calibration of imaging features based on different feature extraction settings is required, especially for texture- and filter-based features. Several open-source and commercial software packages to perform feature extraction are currently available, all with slightly different functionalities, which makes benchmarking quite challenging. The number of imaging features calculated is typically larger than the number of patients studied, which emphasizes the importance of proper feature selection and prediction model-building routines to prevent overfitting. Even though many of these challenges still need to be addressed before quantitative imaging can be brought into daily clinical practice, radiomics is expected to be a critical component for the integration of image-derived information to personalize treatment in the future. PMID- 27936890 TI - Incidental findings in the skeletal musculature on computed tomography. AB - OBJECTIVE: The purpose of this study was to analyze intramuscular incidental findings identified on CT in a large patient cohort. METHODS: In the time period from 2010 to 2015, a total of 44,794 patients with several diagnoses were investigated by CT. Only those patients who underwent body CT including the neck, thorax, abdomen and pelvic regions after the i.v. application of a contrast medium were involved in the study. There were 4085 patients. On further analysis, only patients with intramuscular findings (IFs) incidentally detected on CT were included. Osseous or soft-tissue lesions with invasion into the musculature were excluded from the study. Patients with known or clinically suspicious muscle disorders were also excluded. Overall, 639 (15.64% of the 4085 analyzed cases) patients, 253 females and 386 males, with mean age 72.43 +/- 12.02 years, were identified. Collected data were evaluated by means of descriptive statistics. RESULTS: In the 639 patients, 917 IFs were identified. More often, several benign disorders were diagnosed (n = 803, 87.6%). There were hernias (33.5%), atrophy of different muscles (22%), lipomas (21%), intramuscular calcifications (8.7%), bursitis (1.2%) and intramuscular bleeding (1.1%). Malignant IFs (n = 114, 12.4%) included intramuscular metastases (11.9%) and lymphomas (0.6%). Most frequently, the identified IFs were localized in the abdominal wall musculature, paravertebral and gluteal muscles. In 657 cases (71.6% of all IFs), the identified muscle findings were not diagnosed by the radiologist who initially assessed the investigation. CONCLUSION: CT can detect different incidental disorders within the skeletal musculature. Most of them were benign. However, malignant lesions can also occur. Therefore, skeletal muscles should be carefully evaluated on CT performed for other reasons. Advances in knowledge: IFs occur in 15.6% of CT investigations. Benign findings represent 87.6% and malignant lesions can be identified in 12.4%. PMID- 27936889 TI - Hamartomas from head to toe: an imaging overview. AB - Hamartomas are tumours composed of mesenchymal tissues such as cartilage, fat, connective tissue and smooth muscle and can be found in virtually any organ system. These masses commonly develop sporadically, but are also seen in certain syndromes such as tuberous sclerosis or Carney triad. While their imaging appearance varies depending on the organ they arise from, findings are usually unique and a diagnosis can be confidently made. Radiologists must be aware of the clinical and imaging presentations of these lesions with the particular goal of avoiding unnecessary studies or invasive procedures. Furthermore, knowledge of common syndromic entities is crucial, as the radiologist may be the first to suggest the diagnosis. PMID- 27936892 TI - The Control of Electromagnetic Fields at Work Regulations 2016 and medical MRI. AB - This short commentary provides the MRI community in the UK with practical advice on the impact of the Control of Electromagnetic Fields at Work Regulations 2016 in clinical and research settings. The regulations are the UK implementation of the European Union Physical Agents (Electromagnetic Fields) Directive, which has been the subject of much discussion and concern over the past 13 years. However, thanks to concessions achieved through negotiation, and sensible and proportionate transposition into UK law by the Health and Safety Executive, the negative consequences that were foreseen have been averted. MRI activities are exempt from the occupational exposure limits contained in the regulations, subject to meeting certain conditions. The commentary gives advice on compliance with these conditions and on how to satisfy the other requirements of the regulations, all of which are either already required under existing legislation or represent good MR safety practice. PMID- 27936891 TI - Comparison of different contouring definitions of the rectum as organ at risk (OAR) and dose-volume parameters predicting rectal inflammation in radiotherapy of prostate cancer: which definition to use? AB - OBJECTIVE: The objective of this retrospective planning study was to find a contouring definition for the rectum as an organ at risk (OAR) in curative three dimensional external beam radiotherapy (EBRT) for prostate cancer (PCa) with a predictive correlation between the dose-volume histogram (DVH) and rectal toxicity. METHODS: In a pre-study, the planning CT scans of 23 patients with PCa receiving definitive EBRT were analyzed. The rectum was contoured according to 13 different definitions, and the dose distribution was correlated with the respective rectal volumes by generating DVH curves. Three definitions were identified to represent the most distinct differences in the shapes of the DVH curves: one anatomical definition recommended by the Radiation Therapy Oncology Group (RTOG) and two functional definitions based on the target volume. In the main study, the correlation between different relative DVH parameters derived from these three contouring definitions and the occurrence of rectal toxicity during and after EBRT was studied in two consecutive collectives. The first cohort consisted of 97 patients receiving primary curative EBRT and the second cohort consisted of 66 patients treated for biochemical recurrence after prostatectomy. Rectal toxicity was investigated by clinical investigation and scored according to the Common Terminology Criteria for Adverse Events. Candidate parameters were the volume of the rectum, mean dose, maximal dose, volume receiving at least 60 Gy (V60), area under the DVH curve up to 25 Gy and area under the DVH curve up to 75 Gy in dependence of each chosen rectum definition. Multivariable logistic regression considered other clinical factors such as pelvine lymphatics vs local target volume, diabetes, prior rectal surgery, anticoagulation or haemorrhoids too. RESULTS: In Cohort 1 (primary EBRT), the mean rectal volumes for definitions "RTOG", planning target volume "(PTV)-based" and "PTV-linked" were 100 cm3 [standard deviation (SD) 43 cm3], 60 cm3 (SD 26 cm3) and 74 cm3 (SD 31 cm3), respectively (p < 0.01; analysis of variance). The mean rectal doses according to these definitions were 35 Gy (SD 8 Gy), 48 Gy (SD 4 Gy) and 44 Gy (SD 5 Gy) (p < 0.01). In Cohort 2 (salvage EBRT), the mean rectal volumes were 114 cm3 (SD 47 cm3), 64 cm3 (SD 26 cm3) and 81 cm3 (SD 30 cm3) (p < 0.01) and the mean doses received by the rectum were 36 Gy (SD 8 Gy), 49 Gy (SD 5 Gy) and 44 Gy (SD 5 Gy) (p < 0.01). Acute or subacute rectal inflammation occurred in 69 (71.9%) patients in Cohort 1 and in 43 (70.5%) in Cohort 2. We did not find a correlation between all investigated DVH parameters and rectal toxicity, irrespective of the investigated definition. By adding additional variables in multivariate analysis, the predictive ability was substantially improved. Still, there was essentially no difference in the probability of predicting rectal inflammation occurrence between the tested contouring definitions. CONCLUSION: The RTOG anatomy-based recommendations are questionable in comparison with functional definitions, as they result in higher variances in several relative DVH parameters. Moreover, the anatomy-based definition is no better and no worse in the predictive value concerning clinical end points. Advances in knowledge: Functional definitions for the rectum as OAR are easier to apply, faster to contour, have smaller variances and do not offer less information than the anatomy-based RTOG definition. PMID- 27936893 TI - Clinical respiratory motion correction software (reconstruct, register and averaged-RRA), for 18F-FDG-PET-CT: phantom validation, practical implications and patient evaluation. AB - OBJECTIVE: On fluorine-18 fludeoxyglucose (18F-FDG) positron emission tomography (PET) CT of pulmonary or hepatic lesions, standard uptake value (SUV) is often underestimated due to patient breathing. The aim of this study is to validate, on phantom and patient data, a motion correction algorithm [reconstruct, register and averaged (RRA)] implemented on a PET-CT system. METHODS: Three phantoms containing five spheres filled with 18F-FDG and suspended in a water or Styrofoam(r)18F-FDG-filled tank to create different contrasts and attenuation environment were acquired on a Discovery GE710. The spheres were animated with a 2-cm longitudinal respiratory-based movement. Respiratory-gated (RRA) and ungated PET images were compared with static reference images (without movement). The optimal acquisition time, number of phases and the best phase within the respiratory cycle were investigated. The impact of irregular motion was also investigated. Quantification impact was computed on each sphere. Quantification improvement on 28 lung lesions was also investigated. RESULTS: Phantoms: 4 min was required to obtain a stable quantification with the RRA method. The reference phase and the number of phases used for RRA did not affect the quantification which was similar on static acquisitions but different on ungated images. The results showed that the maximum standard uptake value (SUVmax) restoration is majored for the smallest spheres (<=2.1 ml). PATIENTS: SUVmax on RRA and ungated acquisitions were statistically different to the SUVmax on whole-body images (p = 0.05) but not different from each other (mean SUVmax: 7.0 +/- 7.8 vs 6.9 +/- 7.8, p = 0.23 on RRA and ungated images, respectively). We observed a statistically significant correlation between SUV restoration and lesion displacement, with a real SUV quantitation improvement for lesion with movement >1.2 mm. CONCLUSION: According to the results obtained using phantoms, RRA method is promising, showing a real impact on the lesion quantification on phantom data. With regard to the patient study, our results showed a trend towards an increase in the SUVs and a decrease in the volume between the ungated and RRA data. We also noticed a statistically significant correlation between the quantitative restoration obtained with RRA compared with ungated data and lesion displacement, indicating that the RRA approach should be reserved to patients with small lesions or nodes moving with a displacement larger than 1.2 cm. Advances in knowledge: This article investigates the performances of motion correction software recently introduced in PET. The conclusion revealed that such respiratory motion correction approach shows a real impact on the lesion quantification but must be reserved to the patient for whom lesion displacement was confirmed and high enough to clearly impact lesion evaluation. PMID- 27936895 TI - Portulaca grandiflora as green roof vegetation: Plant growth and phytoremediation experiments. AB - Finding appropriate rooftop vegetation may improve the quality of runoff from green roofs. Portulaca grandiflora was examined as possible vegetation for green roofs. Green roof substrate was found to have low bulk density (360.7 kg/m3) and high water-holding capacity (49.4%), air-filled porosity (21.1%), and hydraulic conductivity (5270 mm/hour). The optimal substrate also supported the growth of P. grandiflora with biomass multiplication of 450.3% and relative growth rate of 0.038. Phytoextraction potential of P. grandiflora was evaluated using metal spiked green roof substrate as a function of time and spiked substrate metal concentration. It was identified that P. grandiflora accumulated all metals (Al, Cd, Cr, Cu, Fe, Ni, Pb, and Zn) from metal-spiked green roof substrate. At the end of 40 days, P. grandiflora accumulated 811 +/- 26.7, 87.2 +/- 3.59, 416 +/- 15.8, 459 +/- 15.6, 746 +/- 20.9, 357 +/- 18.5, 565 +/- 6.8, and 596 +/- 24.4 mg/kg of Al, Cd, Cr, Cu, Fe, Ni, Pb and Zn, respectively. Results also indicated that spiked substrate metal concentration strongly influenced metal accumulation property of P. grandiflora with metal uptake increased and accumulation factor decreased with increase in substrate metal concentration. P. grandiflora also showed potential to translocate all the examined metals with translocation factor greater than 1 for Al, Cu, Fe, and Zn, indicating hyperaccumulation property. PMID- 27936894 TI - Fractionated stereotactic radiation therapy for brain metastases: a systematic review with tumour control probability modelling. AB - OBJECTIVE: Fractionated stereotactic radiotherapy (FSRT) is a relatively new option for the treatment of brain metastases. We performed a quantitative systematic review to determine if local control (LC) following is affected by FSRT dosing regimen. METHODS: We reviewed articles describing LC following FSRT for brain metastases. LC data from each study were extracted from actuarial survival curves and aggregated to form a single data set. LC curves were generated using the Kaplan-Meier method. Log-rank testing and Cox proportional hazards modelling were utilized to test for associations between the biologically effective dose (BED) and LC. Tumour control probability modelling was performed to illustrate the relationship between the BED and the likelihood of LC after FSRT. RESULTS: 10 studies (720 metastases) met inclusion criteria. Prescription doses ranged from 18 to 42 Gy, delivered in 3-12 fractions (BED range: 29-100 Gy10). 1- and 2-year actuarial LC rates were 80% and 69%, respectively. Increasing BED was associated with improved LC (HR = 0.77 per increase of 10 Gy10, p = 0.009). Tumour control probability models demonstrated that the BEDs of 40, 50 and 60 Gy10 yield predicted 1-year LC rates of 73%, 78% and 84%, respectively. The BEDs of 40, 50 and 60 Gy10 yield 2-year LC rates of 62%, 69% and 81%, respectively. CONCLUSION: FSRT provides high rates of LC for patients with brain metastases. We found evidence for a dose-response relationship that should be explored in prospective trials. Advances in knowledge: This review identified a dose-response relationship for LC in patients treated with FSRT for brain metastases. PMID- 27936896 TI - Biosorption of Food Green 3 by a novel green generation composite biosorbent from aqueous environment. AB - A green type composite biosorbent composed of pine, oak, hornbeam, and fir sawdust biomasses modified with cetyltrimethylammonium bromide (CTAB) was first used for biosorption of an unsafe synthetic food dye, Food Green 3 from liquid medium in this study. Batch studies were carried by observing the effects of pH, dye concentration, biosorbent amount, and contact time. The equilibrium data were analyzed using Freundlich, Langmuir, and Dubinin-Radushkevich equations. Freundlich model gave a better conformity than other equations. The maximum dye removal potential of biosorbent was found to be 36.6 mg/g based on Langmuir isotherm. The pseudo-first-order, pseudo-second-order, Elovich, and intra particle diffusion models were applied to clarify the process kinetics of biosorption. The mechanism studies suggested the biosorption process obeying Elovich kinetics and involving pore diffusion. The estimated values of biosorption free energy from Dubinin-Radushkevich isotherm (E value <8 kJ/mol) and thermodynamic studies (0 < DeltaG degrees < -20 kJ/mol) implied a spontaneous, feasible, and physical process. Hence, this investigation suggested that the CTAB modified mix sawdust biomass could be a promising biosorbent for biosorption of such problematic dyes from impacted media. PMID- 27936897 TI - Expression profiles and associations of adiponectin and adiponectin receptors with intramuscular fat in Tibetan chicken. AB - 1. Adiponectin and its receptors (ADIPOR1 and ADIPOR2) are novel endocrine systems that act at various levels to modulate glucose and lipid metabolism. This study was designed to investigate the spatial expression of adiponectin, ADIPOR1 and ADIPOR2 genes in various tissues in Tibetan chicken. The temporal expression of adiponectin and its receptor mRNAs were also studied in adipose tissue, breast muscle and thigh muscle and the correlations of the levels of adiponectin, ADIPOR1 and ADIPOR2 mRNA with the contents of intramuscular fat in breast muscle and thigh muscle of Tibetan chicken were determined. 2. Quantitative real-time PCR detected chicken adiponectin, ADIPOR1 and ADIPOR2 mRNA transcripts in heart, liver, spleen, lung, kidney, skeletal muscle and adipose tissue. 3. Adipose tissue contained the highest amount of adiponectin mRNA followed by the kidney and liver. The expression levels of ADIPOR1 mRNA were significantly higher in adipose tissue, lung and spleen, and adipose tissue exhibited significantly higher levels of ADIPOR2 mRNA followed by the spleen and lung compared with other tissues. 4. Temporal expression profiles of adiponectin, ADIPOR1 and ADIPOR2 mRNA showed gender differences in adipose tissue and skeletal muscle at certain ages. In adipose tissue, adiponectin mRNA was higher in 154-d-old females and ADIPOR1 mRNA was higher in 154-d-old males: Adiponectin and ADIPOR2 mRNA were higher, and ADIPOR1 mRNA was lower, in thigh muscle in female compared with male chickens. 5. The correlation data showed that, except for adiponectin mRNA, the levels of ADIPOR1 and ADIPOR2 mRNA in thigh muscle of males were significantly positively correlated with IMF (r = 0.206 for the ADIPOR1 gene and r = 0.676 for the ADIPOR2 gene). 6. Taken together, it was concluded that adiponectin and the ADIPOR1 and ADIPOR2 genes are ubiquitously expressed in various tissues of Tibetan chicken and the expression of the adiponectin system is gender-dependant at certain ages in adipose tissue and skeletal muscle. PMID- 27936899 TI - Mentalizing techniques used by psychodynamic therapists working with children and early adolescents. AB - The aim of this study was to identify, categorize, and develop a conceptual frame of mentalization-based interventions used by experienced child and adolescent psychodynamic therapists. Two experienced therapists selected 14 sessions that represented their work during the first year of treatment. Sessions were transcribed and segmented to identify interactional units for coding. QDA Miner software was used to facilitate data analysis. A systematic qualitative, inductive/deductive approach was followed starting from categories identified in the literature, but also including newly emerging categories and interventions. Seven sessions were double coded to stabilize the coding tree and a "member check" was completed where therapists rated their own transcripts. A total of 24 mentalization-based techniques were identified, including 17 additional techniques. A conceptual framework organizing all observed mentalization-based interventions is proposed. The findings of this study provide a framework for studying techniques that may enhance the capacity to mentalize, and that could be features of therapeutic practice across a range of modalities of psychotherapy. PMID- 27936898 TI - Pharmacokinetics of a Novel Amphetamine Extended-Release Orally Disintegrating Tablet in Children with Attention-Deficit/Hyperactivity Disorder. AB - BACKGROUND: A novel formulation for treating attention-deficit/hyperactivity disorder (ADHD) has recently been developed-amphetamine extended-release orally disintegrating tablets (AMP XR-ODTs). In this study, we assessed the rate of absorption and exposure of AMP XR-ODT under fasted conditions in children with ADHD. METHODS: Children (6-12 years) with ADHD were enrolled in a single-dose, open-label, single-period pharmacokinetic (PK) study. Patients were stratified by age (6-7, 8-9, and 10-12 year olds) and were dosed with 18.8-mg AMP XR-ODT under fasted conditions. Plasma samples were analyzed for d-and l-amphetamine. Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the concentration-time curve from time zero-infinity (AUCinf), weight normalized clearance (CL/F), and weight-normalized volume of distribution (Vz/F) were assessed. The geometric mean and 95% confidence intervals (CIs) were calculated for weight-normalized CL/F and Vz/F in each age group to determine if the 95% CIs were within the target range of 60%-140%. RESULTS: A total of 28 children completed the study. The 95% CIs for the geometric mean CL/F/kg and Vz/F/kg for both d- and l-amphetamine fell within the target range of 60%-140% for each age group, thus meeting the primary end point. Four participants experienced treatment-related adverse events, including vomiting (n = 3), abdominal pain (n = 2), dry mouth (n = 1), and insomnia (n = 1). CONCLUSIONS: AMP XR-ODT, a novel formulation that does not require swallowing an intact tablet or capsule, was well tolerated and demonstrated a PK profile consistent with once daily dosing in children with ADHD. PMID- 27936900 TI - Real time functional MRI training to decrease motion in imaging studies: Lack of significant improvement. AB - Functional magnetic resonance imaging (fMRI) is widely used to study brain circuitry in healthy controls and in psychiatry. A major problem of fMRI studies is motion, which affects the quality of images, is a major source of noise, and can confound data if, for example, the experimental groups move differently. Despite continual reminders to experimental subjects about keeping still, however, movement in the scanner remains a problem. The authors hypothesized that showing head movement during a scanning session may help subjects learn how to keep their head still. The authors scanned subjects and displayed in real time a plot of head movement that had three regions. The authors found, in a limited sample, that the improvements were marginal and inconsistent. Thus, they concluded that this strategy, even if likely to work for some people, is probably not sufficiently successful to be implemented at this time. PMID- 27936901 TI - Psychosomatic patients in integrated care: Which treatment mediators do we have to focus on? AB - The field of psychosomatics has gained increasing significance; it has been struggling to establish its position as either an independent discipline or a subdomain of specific areas such as internal medicine or psychiatry. However, the rise of psychosomatic syndromes and disease patterns as well as an increase of specific integrated psychosomatic wards is a clear indication for the growing importance of interdisciplinary approaches to psychosomatic disorders. The study presents data from an 8-week inpatient treatment at a psychosomatic facility and investigates whether patients improved in their subjective symptom experience. A complex treatment approach, ranging from pharmacological treatment and group and individual psychotherapy to physiotherapy and ergotherapy was integrated into this intervention. In essence, containment of intrapsychic aggression derivatives played a central role in the treatment of psychosomatic symptoms. A significant factor contributing to a successful treatment is the doctor-patient relationship. All these factors were investigated in the present study. PMID- 27936902 TI - Psychiatrists' emotional reactions: Useful for precise diagnosis in adolescence? AB - Therapist response (countertransference) can be defined as the range of emotions a clinician experiences when interacting with a patient. Previous research has shown that this reaction plays an important role in the establishment of the therapeutic relationship, and that certain psychiatric disorders are systematically related to strong countertransference reactions in clinicians. For this study, 30 videotaped sessions were retrospectively analyzed by one observer using the Therapist Response Questionnaire (TRQ). The authors aimed to investigate the differences in therapist response between an adolescent case group consisting of 19 patients diagnosed with a cluster B personality disorder (PD), and a control group composed of 11 adolescents diagnosed with anorexia nervosa. The PD group scored significantly higher on the hostile/mistreated, helpless/inadequate, disengaged and overwhelmed/disorganized factors. This study adds evidence to the preexisting empirical literature on therapist response in regard to personality disorders and emphasizes the continuing need for recognition of countertransference across all psychotherapy orientations. PMID- 27936905 TI - Commentary: Adverse experiences in psychiatric hospitals might be the cause of some postdischarge suicides. AB - In this article, the authors comment on "Postdischarge Suicide: A Psychodynamic Understanding of Subjective Experience and Its Importance in Suicide Prevention," by Schechter, Goldblatt, Ronningstam, Herbstman, and Maltsberger (Bulletin of the Menninger Clinic, 2016, volume 80, pp. 80-96). Suicide after discharge from psychiatric hospitals is an enduring and serious problem. Consideration needs to be given to the possibility that adverse experiences associated with hospitalization, experiences such as trauma, stigma, and loss of social support, might precipitate some suicides after discharge. PMID- 27936903 TI - Paradoxical increase in synthetic cannabinoid emergency-related presentations after a citywide ban: Lessons from Houston, Texas. AB - Synthetic cannabinoids (SCs) have become a major drug of abuse associated with severe hospital presentations. There have been a variety of legislative efforts to regulate these drugs: The authors focus on trends in SC-related hospitalizations at Ben Taub General Hospital before and after a ban enacted by the city of Houston. Data from all consults seen by Ben Taub's Licensed Chemical Dependency Counselor were examined for changes in SC-related presentations before and after the ban. The findings were compared alongside other reports of current SC use. A significant increase was found in the prevalence of SC-related presentations at Ben Taub Hospital following Houston's citywide ban. These findings are consistent with other state and national data. Houston's ordinance was expected to decrease harmful effects of SC in the community; however, the data suggest an increase in presentations since the legislation was passed. While further study is needed, it initially appears that the threat of SCs is still considerable despite policy efforts. These results suggest the need for further monitoring of SC use and continued collaboration toward effective public health measures. PMID- 27936906 TI - Metabolic Consequences of Obstructive Sleep Apnea in Adolescents with Obesity: A Systematic Literature Review and Meta-Analysis. AB - BACKGROUND: Adolescents who are obese are at high risk of developing obstructive sleep apnea (OSA). Although there is clear evidence associating OSA with metabolic dysfunction in adults, the evidence is less clear cut with adolescents. The purpose of this review was determine the association of sleep apnea with dyslipidemia, insulin resistance, cardiovascular disease risk, nonalcoholic fatty liver disease, and difficulty with weight loss in adolescents. METHODS: A systematic literature review using PubMed, Scopus, CINAHL, Google Scholar, and PsycINFO was performed and articles were screened and reviewed with an a priori protocol. RESULTS: Sixteen articles were included in qualitative synthesis and 10 were included in meta-analysis. Results from the meta-analysis indicate that OSA in adolescents is associated with greater risk of dyslipidemia, insulin resistance, and hypertension. CONCLUSIONS: Although obesity leads to increased metabolic risk, OSA appears to independently increase metabolic impairment. Adolescents with obesity should be frequently screened for OSA to determine need for treatment and reduce this metabolic burden. PMID- 27936907 TI - Adverse effects of carbamazepine monotherapy among patients in Nigeria: a pilot study and implications. AB - AIM: Antiepileptic drugs do cause adverse effects, affecting patients' quality of life, adherence and seizures. Consequently, there is a need to study this among Nigerian patients. METHODS: Descriptive cross-sectional study assessing the extent of adverse effects with carbamazepine monotherapy and potential factors. RESULTS: 54 patients (64.3%) reported no adverse effects, while 30 did. The most common adverse effects were memory problems followed by headaches, restlessness, tiredness and depression. Adverse effects were significantly higher in females, with females with low educational levels having significantly higher rates. Dose, co-medications, seizure control and comorbid conditions did not significantly affect adverse effects. CONCLUSION: Perception of adverse effects was common in patients on carbamazepine monotherapy, more common in women than men. Educational status was important in women. PMID- 27936908 TI - The FBXO7 homologue nutcracker and binding partner PI31 in Drosophila melanogaster models of Parkinson's disease. AB - Parkinsonian-pyramidal syndrome (PPS) is an early onset form of Parkinson's disease (PD) that shows degeneration of the extrapyramidal region of the brain to result in a severe form of PD. The toxic protein build-up has been implicated in the onset of PPS. Protein removal is mediated by an intracellular proteasome complex: an E3 ubiquitin ligase, the targeting component, is essential for function. FBXO7 encodes the F-box component of the SCF E3 ubiquitin ligase linked to familial forms of PPS. The Drosophila melanogaster homologue nutcracker (ntc) and a binding partner, PI31, have been shown to be active in proteasome function. We show that altered expression of either ntc or PI31 in dopaminergic neurons leads to a decrease in longevity and locomotor ability, phenotypes both associated with models of PD. Furthermore, expression of ntc-RNAi in an established alpha-synuclein-dependent model of PD rescues the phenotypes of diminished longevity and locomotor control. PMID- 27936910 TI - Corrigendum. PMID- 27936909 TI - Variation in the Use of Open Pyeloplasty, Minimally Invasive Pyeloplasty, and Endopyelotomy for the Treatment of Ureteropelvic Junction Obstruction in Adults. AB - BACKGROUND AND PURPOSE: Ureteropelvic junction obstruction is a common condition that can be treated with open pyeloplasty, minimally invasive pyeloplasty, and endopyelotomy. While all these treatments are effective, the extent to which they are used is unclear. We sought to examine the dissemination of these treatments. PATIENTS AND METHODS: Using the MarketScan(r) database, we identified adults 18 to 64 years old who underwent treatment for ureteropelvic junction obstruction between 2002 and 2010. Our primary outcome was ureteropelvic junction obstruction treatment (i.e., open pyeloplasty, minimally invasive pyeloplasty, endopyelotomy). We fit a multilevel multinomial logistic regression model accounting for patients nested within providers to examine several factors associated with treatment. RESULTS: Rates of minimally invasive pyeloplasty increased 10-fold, while rates of open pyeloplasty decreased by over 40%, and rates of endopyelotomy were relatively stable. Factors associated with receiving an open vs a minimally invasive pyeloplasty were largely similar. Compared with endopyelotomy, patients receiving minimally invasive pyeloplasty were less likely to be older (odds ratio [OR] 0.96; 95% confidence interval [CI], 0.95, 0.97) and live in the south (OR 0.52; 95% CI, 0.33, 0.81) and west regions (OR 0.57; 95% CI 0.33, 0.98) compared with the northeast and were more likely to live in metropolitan statistical areas (OR 1.52; 95% CI 1.08, 2.13). CONCLUSIONS: Over this 9-year period, the landscape of ureteropelvic junction obstruction treatment has changed dramatically. Further research is needed to understand why geographic factors were associated with receiving a minimally invasive pyeloplasty or an endopyelotomy. PMID- 27936912 TI - A parametric model of child body shape in seated postures. AB - OBJECTIVE: The shape of the current physical and computational surrogates of children used for restraint system assessments is based largely on standard anthropometric dimensions. These scalar dimensions provide valuable information on the overall size of the individual but do not provide good guidance on shape or posture. This study introduced the development of a parametric model that statistically predicts individual child body shapes in seated postures with a few given parameters. METHODS: Surface geometry data from a laser scanner of children ages 3 to 11 (n = 135) were standardized by a 2-level fitting method using intermediate templates. The standardized data were analyzed by principal component analysis (PCA) to efficiently describe the body shape variance. Parameters such as stature, body mass index, erect sitting height, and 2 posture variables related to torso recline and lumbar spine flexion were associated with the PCA model using regression. RESULTS: When the original scan data were compared with the predictions of the model using the given subject dimensions, the average root mean square error for the torso was 9.5 mm, and the 95th percentile error was 17.35 mm. CONCLUSIONS: For the first time, a statistical model of child body shapes in seated postures is available. This parametric model allows the generation of an infinite number of virtual children spanning a wide range of body sizes and postures. The results have broad applicability in product design and safety analysis. Future work is needed to improve the representation of hands and feet and to extend the age range of the model. The model presented in this article is publicly available online through HumanShape.org. PMID- 27936913 TI - Anti-inflammatory effect of selenium nanoparticles on the inflammation induced in irradiated rats. AB - Selenium (Se) has been reported to possess anti-inflammatory properties, but its bioavailability and toxicity are considerable limiting factors. The present study aimed to investigate the possible anti-inflammatory and analgesic effects of selenium nanoparticles (Nano-Se) on inflammation induced in irradiated rats. Paw volume and nociceptive threshold were measured in carrageenan-induced paw edema and hyperalgesia model. Leukocytic count, tumor necrosis factor-alpha (TNF alpha), prostaglandin E2 (PGE2), thiobarbituric acid reactive substances (TBAR), and total nitrate/nitrite (NOx) were estimated in the exudate collected from 6 day old air pouch model. Irradiated rats were exposed to 6 Gy gamma (gamma) irradiation. Nano-Se were administered orally in a dose of 2.55 mg/kg once before carrageenan injection in the first model and twice in the second model. The paw volume but not the nociceptive response produced by carrageenan in irradiated rats was higher than that induced in non-irradiated rats. Nano-Se were effective in reducing the paw volume in non-irradiated and irradiated rats but it did not alter the nociceptive threshold. The inflammation induced in irradiated rats increased all the estimated parameters in the exudate whereas; Nano-Se decreased their elevation in non-irradiated and irradiated rats. Nano-Se possess a potential anti-inflammatory activity on inflammation induced in irradiated rats. PMID- 27936914 TI - Characteristic features of the odontogenic myxoma on cone beam computed tomography. AB - OBJECTIVES: To illustrate the characteristic features of odontogenic myxoma (OM) on CBCT. METHODS: From 52 subjects with histopathologically diagnosed OMs, 18 subjects who underwent a CBCT examination were retrieved between May 2009 and April 2016. Features on CBCT images and clinical records were carefully observed and analyzed. RESULTS: Characteristic features include: (1) fine and straight septa that were recognized to separate the tumour into triangular, square or rectangular spaces, which appeared as "tennis racket" or "honeycomb" patterns; (2) septa that frequently scattered to the borders of lesions and appeared perpendicular to the margins; (3) tooth displacement and resorption that were seen in most of the OM lesions; (4) OMs that were noted to have a tendency to involve the alveolar process, scallop between the roots and affect the integrity of the alveolar ridge; (5) the cortex of OMs that appeared normally perforated and the edge of the cortex expanded into the soft tissue. CONCLUSIONS: CBCT is highly effective in demonstrating the comprehensive internal structures of the lesions precisely and providing detailed information for the diagnosis of OM. PMID- 27936911 TI - Bacterial and cytokine mixtures predict the length of gestation and are associated with miRNA expression in the cervix. AB - AIM: Bacterial vaginosis may lead to preterm birth through epigenetic programming of the inflammatory response, specifically via miRNA expression. METHODS: We quantified bacterial 16S rRNA, cytokine mRNA and 800 miRNA from cervical swabs obtained from 80 women at 16-19 weeks' gestation. We generated bacterial and cytokine indices using weighted quantile sum regression and examined associations with miRNA and gestational age at delivery. RESULTS & DISCUSSION: Each decile of the bacterial and cytokine indices was associated with shorter gestations (p < 0.005). The bacterial index was associated with miR-494, 371a, 4286, 185, 320e, 888 and 23a (p < 0.05). miR-494 remained significant after false discovery rate correction (q < 0.1). The cytokine index was associated with 27 miRNAs (p < 0.05; q < 0.01). CONCLUSION: Future investigation into the role of bacterial vaginosis- and inflammation-associated miRNA and preterm birth is warranted. PMID- 27936915 TI - Promethazine improves antibiotic efficacy and disrupts biofilms of Burkholderia pseudomallei. AB - Efflux pumps are important defense mechanisms against antimicrobial drugs and maintenance of Burkholderia pseudomallei biofilms. This study evaluated the effect of the efflux pump inhibitor promethazine on the structure and antimicrobial susceptibility of B. pseudomallei biofilms. Susceptibility of planktonic cells and biofilms to promethazine alone and combined with antimicrobials was assessed by the broth microdilution test and biofilm metabolic activity was determined with resazurin. The effect of promethazine on 48 h-grown biofilms was also evaluated through confocal and electronic microscopy. The minimum inhibitory concentration (MIC) of promethazine was 780 mg l-1, while the minimum biofilm elimination concentration (MBEC) was 780-3,120 mg l-1. Promethazine reduced the MIC values for erythromycin, trimethoprim/sulfamethoxazole, gentamicin and ciprofloxacin and reduced the MBEC values for all tested drugs (p<0.05). Microscopic analyses demonstrated that promethazine altered the biofilm structure of B. pseudomallei, even at subinhibitory concentrations, possibly facilitating antibiotic penetration. Promethazine improves antibiotics efficacy against B. pseudomallei biofilms, by disrupting biofilm structure. PMID- 27936916 TI - Identical twins doubly exchanged at birth: a case report of genetic and environmental influences on the adult epigenome. AB - AIM: Epigenetic comparisons within monozygotic twin pairs have enhanced our understanding of nongenetic mechanisms underlying disease etiology. We present epigenetic findings for a unique case of doubly exchanged Colombian male monozygotic twins raised in extremely different environments. RESULTS: Using genome-wide DNA methylation data from cheek swabs from which blood-specific differentially methylated probes had been removed, the individuals grouped by shared genetics rather than shared environment, except for one twin who presented as an outlier. Closer inspection of DNA methylation differences within both reared-apart twin pairs revealed several genes and genetic pathways likely to be influenced by the rearing environment. CONCLUSION: Together with our previous findings, we suggest that genetics, pre- and postnatal environments contribute to the epigenetic profile, although additional studies are needed to quantify these effects. PMID- 27936917 TI - Imaging findings of childhood B-cell lymphoblastic lymphoma in the mental region: a case report. AB - Lymphoblastic lymphoma (LBL) is an uncommon neoplasm that accounts for about 5% of all non-Hodgkin's lymphomas. Approximately 90% of LBLs are of immature T-cell lineage, with B-cell lymphoblastic lymphoma (B-LBL) accounting for only about 10%. Owing to infrequency, the clinicopathological features and the imaging findings of B-LBL are not well defined. LBLs frequently affect extranodal sites. The most common site is the skin, followed by the bone, and the head and neck region is rarely involved. We report herein a case of childhood B-LBL occurring in the mental region, with emphasis on the findings of several imaging studies, including contrast-enhanced CT, MRI and fluorodeoxyglucose-positron emission tomography/CT. PMID- 27936918 TI - Post-processing open-source software for the CBCT monitoring of periapical lesions healing following endodontic treatment: technical report of two cases. AB - OBJECTIVES: To describe the use of open-source software for the post-processing of CBCT imaging for the assessment of periapical lesions development after endodontic treatment. METHODS: CBCT scans were retrieved from endodontic records of two patients. Three-dimensional virtual models, voxel counting, volumetric measurement (mm3) and mean intensity of the periapical lesion were performed with ITK-SNAP v. 3.0 software. Three-dimensional models of the lesions were aligned and overlapped through the MeshLab software, which performed an automatic recording of the anatomical structures, based on the best fit. Qualitative and quantitative analyses of the changes in lesions size after treatment were performed with the 3DMeshMetric software. RESULTS: The ITK-SNAP v. 3.0 showed the smaller value corresponding to the voxel count and the volume of the lesion segmented in yellow, indicating reduction in volume of the lesion after the treatment. A higher value of the mean intensity of the segmented image in yellow was also observed, which suggested new bone formation. Colour mapping and "point value" tool allowed the visualization of the reduction of periapical lesions in several regions. CONCLUSIONS: Researchers and clinicians in the monitoring of endodontic periapical lesions have the opportunity to use open-source software. PMID- 27936919 TI - T2 relaxation mapping MRI of healthy and inflamed gingival tissue. AB - OBJECTIVES: To investigate the use and reproducibility of MRI transverse relaxation time (T2) mapping in healthy and inflamed gingivae. METHODS: 21 subjects were recruited into 2 groups: those without evidence of gingivitis ("healthy"; n = 11, age 24.0 +/- 3.66 years) by visual assessment and those with moderate to severe gingivitis ("gingivitis"; n = 10, age 28.9 +/- 6.03 years) exhibited across the second mandibular premolar and first mandibular molar buccal gingivae. Subjects were imaged by MRI twice in a single day. Three T2 weighted turbo spin-echo volumes with 0.25 * 0.25 * 0.8-mm3 resolution were acquired at echo times of 16, 32 and 48 ms for T2 decay fitting. Image analysis was fully blinded; the two imaging sessions were not identifiable as coming from the same subject. Each imaging session had independent regions of interest drawn on the first echo image and applied to the calculated T2 decay maps. RESULTS: The coefficient of variation was low and similar in healthy and gingivitis populations: 6.10 and 5.25% populations, respectively, with 5.65% populations across both groups. Bland-Altman analysis revealed no bias (mean -2.93%; 95% confidence intervals -22.20 to 16.34%) between sessions. The intersession agreement was good (r = 0.744, rho = 0.568, intraclass correlation coefficient = 0.68). T2 mapping did not differentiate healthy from gingivitis groups. The mean T2 value in the healthy group (63.7 ms) was similar to that of the gingivitis group (65.23 ms) (p = 0.30). CONCLUSIONS: Mapping of the T2 decay in the gingivae was a repeatable process; however, T2 value alone did not differentiate those with clinical examination-determined gingivitis from those without signs of gingivitis. PMID- 27936920 TI - Management of children with congenital heart defect: state of the art and future prospects. AB - The treatment of children with congenital heart defects has evolved in the last 60 years from conservative care to a highly specialized management where advances in imaging, surgical, interventional and support techniques meet together to ensure satisfactory development and good quality of life to the child and to the upcoming grown up. Management of congenital heart defects best begins before birth with the aim, whenever possible, to maintain or establish biventricular physiology or, if this is excluded, to optimize the conditions for univentricular physiology. Current research in the field of genetics, device bioengineering and miniaturization, stem cell therapy, and fusion imaging technology is expected to help to improve further patient outcome. In this review, current management strategies and future prospects are discussed. PMID- 27936921 TI - Chemometric profile & antimicrobial activities of leaf extract of Calotropis procera and Calotropis gigantea. AB - Calotropis procera and Calotropis gigantea are medicinal plant having therapeutic value. The leaf extracts of C. procera have been investigated, its pharmacological actions in detail and leaf extracts of C. gigantea were not studied till date. The objective of present work was to find the bioactive constituents present in the ethanolic leaf extract of C. procera and C. gigantea to evaluate their antibacterial and anifungal activities. The major phytochemical groups in C. procera ethanolic leaf extracts were fatty acid ethyl ester (21.36%), palmitic acid ester (10.24%), linoleic acid (7.43%) and amino acid (8.10%) respectively, whereas ethanolic leaf extracts of C. gigantea contain palmitic acid (46.01%), diterpene (26.53%), triterpene (17.39%), linoleic acid (5.13%) as the major phytochemical groups. Ethanol extract of C. procera leaves showed the highest inhibition (11 mm) against Escherichia coli, while ethanolic extract of C. gigantea leaves inhibited Klebsiella (20 mm). These findings will use in new directions in pharmacological investigations. PMID- 27936922 TI - Dissimilar evolutionary histories of two resistance gene families in the genus Solanum. AB - Genomic analyses have shown that most genes in eukaryotic lineages belong to families. Gene families vary in terms of number of members, nucleotide similarity, gene integrity, expression, and function. Often, the members of gene families are arranged in clusters, which contribute to maintaining similarity among gene copies and also to generate duplicates through replication errors. Gene families offer us an opportunity to examine the forces involved in the evolution of the genomes and to study recombination events and genomic rearrangements. In this work, we focused on the evolution of two plant resistance gene families, Sw5 and Mi-1, and analyzed the completely sequenced nuclear genomes of potato and tomato. We first noticed that the potato genome carries larger resistance gene families than tomato, but all gene copies are pseudogenes. Second, phylogenetic analyses indicated that Sw5 and Mi-1 gene families had dissimilar evolutionary histories. In contrast to Sw5, Mi-1 homologues suffered repeated gene conversion events among the gene copies, particularly in the tomato genome. PMID- 27936923 TI - Evaluation of the automated Becton Dickinson MAX real-time PCR platform for detection of Pneumocystis jirovecii. AB - AIM: We evaluated the performance of the automated quantitative BD MAX (Becton Dickinson) real-time PCR platform for detecting Pneumocystis jirovecii. MATERIALS & METHODS: A total of 34 retrospective and 137 prospective samples were included. RESULTS: Retrospectively, all (100%) positive samples were correctly detected by this platform compared with a nested PCR. Among prospective samples, the overall sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 92.6%, 94.5%, 17.0 and 0.1, respectively. All bronchoalveolar lavage fluid (BALF)/bronchial washing samples were correctly identified by this platform. Samples from patients with colonization had significantly higher median amplification cycle threshold values than patients with P. jirovecii pneumonia. CONCLUSION: The quantitative BD MAX real-time PCR is a rapid and highly sensitive modality for detecting P. jirovecii, especially in samples from bronchoalveolar lavage fluid/bronchial washing fluid. PMID- 27936924 TI - Three new cyclotetrapeptides isolated from Streptomyces sp. 447. AB - Three new cyclotetrapeptides, named cyclo-(L-Leu-L-Glu-L-Leu-L-Glu) (1) cyclo-(L Ile-L-Glu-L-Ile-L-Glu) (2) and cyclo-(L-Val-L-Glu-L-Val-L-Glu) (3), were isolated from Streptomyces sp. 447 obtained from endophytic actinobacteria. The producer strain was characterized as Streptomyces sp. by 16s rDNA sequencing. The structures of the three peptides were successfully assigned on the basis of 1D and 2D NMR spectroscopic and mass spectrometry analysis, while the absolute configuration of the amino acid residues was established by amino acid hydrolysis followed by derivatization and GC-MS experiments. Antimicrobial activities of the new compounds were studied. PMID- 27936925 TI - Comparing an Atomic Model or Structure to a Corresponding Cryo-electron Microscopy Image at the Central Axis of a Helix. AB - Three-dimensional density maps of biological specimens from cryo-electron microscopy (cryo-EM) can be interpreted in the form of atomic models that are modeled into the density, or they can be compared to known atomic structures. When the central axis of a helix is detectable in a cryo-EM density map, it is possible to quantify the agreement between this central axis and a central axis calculated from the atomic model or structure. We propose a novel arc-length association method to compare the two axes reliably. This method was applied to 79 helices in simulated density maps and six case studies using cryo-EM maps at 6.4-7.7 A resolution. The arc-length association method is then compared to three existing measures that evaluate the separation of two helical axes: a two-way distance between point sets, the length difference between two axes, and the individual amino acid detection accuracy. The results show that our proposed method sensitively distinguishes lateral and longitudinal discrepancies between the two axes, which makes the method particularly suitable for the systematic investigation of cryo-EM map-model pairs. PMID- 27936926 TI - The application of genome-wide 5-hydroxymethylcytosine studies in cancer research. AB - Early detection and characterization of molecular events associated with tumorgenesis remain high priorities. Genome-wide epigenetic assays are promising diagnostic tools, as aberrant epigenetic events are frequent and often cancer specific. The deposition and analysis of multiple patient-derived cancer epigenomic profiles contributes to our appreciation of the underlying biology; aiding the detection of novel identifiers for cancer subtypes. Modifying enzymes and co-factors regulating these epigenetic marks are frequently mutated in cancers, and as epigenetic modifications themselves are reversible, this makes their study very attractive with respect to pharmaceutical intervention. Here we focus on the novel modified base, 5-hydoxymethylcytosine, and discuss how genome wide 5-hydoxymethylcytosine profiling expedites our molecular understanding of cancer, serves as a lineage tracer, classifies the mode of action of potentially carcinogenic agents and clarifies the roles of potential novel cancer drug targets; thus assisting the development of new diagnostic/prognostic tools. PMID- 27936927 TI - Evaluating semantic metamemory: Retrospective confidence judgements on the information subtest. AB - The current research explored the potential value of adding a supplementary measure of metamemory to the Information subtest of the Wechsler Adult Intelligence Scale - Third Edition (WAIS-III in Study 1) or Fourth Edition (WAIS IV in Study 2) in order to assess its relationship to other neuropsychological measures and to brain injury. After completing the Information subtest, neuropsychological examinees were asked to make retrospective confidence judgements (RCJ) by rating their answer certainty in the original order of item administration. In Study 1 (N = 52) and study 2 (N = 30), correct answers were rated with significantly more certainty than wrong answers (termed a "confidence gap"), and in both studies, higher confidence for wrong answers was significantly correlated with poorer performance on the Wisconsin Card Sorting Test (for categories completed r = -.58 in Study 1, and r = -.47 in Study 2; for perseverative errors r = .44 in Study 1, and r = .45 in Study 2). In both studies, a number of examinees with positive CT findings had a very small or reversed confidence gap. These findings suggest that semantic metamemory is sensitive to executive functioning and brain injury and should be assessed in the neuropsychological examination. PMID- 27936928 TI - Use of Main Renal Artery Clamping Predominates Over Minimal Clamping Techniques During Robotic Partial Nephrectomy for Complex Tumors. AB - INTRODUCTION: Hilar clamping is often performed to facilitate robotic partial nephrectomy (RPN). Minimal clamping techniques may reduce renal ischemia, including early unclamping, selective clamping, and off-clamp RPN. We assess the utilization of clamping techniques in a large international consortium of surgeons performing RPN for complex tumors. METHODS: We retrospectively evaluated 721 patients with complex tumors, who underwent RPN at 11 centers worldwide between 2008 and 2014. Complex tumors were defined as renal masses with a nephrometry score >6. Total clamping was defined as complete clamping of the main renal artery. Minimal clamping techniques included early unclamping, selective clamping, and off-clamp RPN. Clamping techniques were additionally assessed in patients with estimated glomerular filtration rate (eGFR) <60 and in patients with a solitary kidney. Two-tailed t-tests (p < 0.05) were used to statistically analyze differences in mean warm ischemia time (WIT). RESULTS: Most patients underwent complete clamping (75.1%). Minimal clamping (24.9%) included early unclamping (10.8%), selective clamping (8.7%), and off-clamp (5.4%). Mean WIT of total clamping, selective clamping, and early unclamping was 22.2, 21.2, and 17.3 minutes, respectively. Of patients with an eGFR <60 (n = 90), 26.6% underwent minimal clamping, including 15.5% early unclamping, 4.4% selective clamping, and 6.7% off-clamp. Of patients with solitary kidneys (n = 12), 10 (83%) were performed with total clamping with mean WIT of 14.9 minutes. CONCLUSIONS: In this large international series of RPN for complex tumors, most patients underwent total clamping of the main renal artery. Minimal clamping techniques, including early unclamping, selective clamping, and off-clamp techniques, were used in a minority of cases. There was no significant increase in use of minimal clamping, even in patients with chronic kidney disease or solitary kidneys. However, mean WIT was low (<23 minutes) in all patient groups. PMID- 27936929 TI - Daptomycin use: where is the truth? PMID- 27936931 TI - Characterization of Urolithiasis in Patients Following Lower Urinary Tract Reconstruction with Intestinal Segments. AB - PURPOSE: Urinary diversion and augmentation cystoplasty are associated with long term complications, including metabolic derangements, infectious complications, and urolithiasis. The aim of this series was to characterize upper and lower urinary tract (LUT) calculi in this population. METHODS: A retrospective chart review was performed on all patients with a history of urinary diversion or augmentation cystoplasty who subsequently underwent treatment for urolithiasis between January 1998 and May 2015. Data collected included demographics, perioperative characteristics, type of reconstructive procedure, urine culture, stone analysis, and metabolic evaluation. A statistical analysis was performed. RESULTS: Ninety-nine patients were identified with a history of urolithiasis and incontinent urinary diversion (28), neobladder (21), continent cutaneous diversion (12), and augmentation cystoplasty (38). LUT stones were more common than upper tract stones in all except for incontinent diversions, which only had one lower tract stone (p = 0.0001). Twenty-three percent of stones were metabolic. Several metabolic derangements were noted, including hypocitraturia (100%), elevated urine pH (100%), low urine volume (70%), and hyperoxaluria (35%). There was a 44% rate of recurrent urolithiasis. CONCLUSIONS: Given the high rate of stone recurrence among patients with a history of urinary diversion and augmentation cystoplasty, all measures should be taken to prevent recurrent stones. In addition to actions aimed to prevent infectious stones such as bladder and pouch irrigation, we recommend these patients undergo a full metabolic workup with targeted dietary changes and medical therapies. PMID- 27936930 TI - Different Contributions of CDKAL1, KIF21B, and LRRK2/MUC19 Polymorphisms to SAPHO Syndrome, Rheumatoid Arthritis, Ankylosing Spondylitis, and Seronegative Spondyloarthropathy. AB - OBJECTIVES: Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, rheumatoid arthritis (RA), ankylosing spondylitis (AS), and seronegative spondyloarthropathy (SPA) are autoimmune diseases of unknown etiology, which share some clinical manifestations in common. Previous family based investigations support genetic contributions to the susceptibility of these diseases. The current study evaluated whether three previously reported AS associated single-nucleotide polymorphisms (SNPs), rs6908425 T>C in CDKAL1, rs11584383 T>C near KIF21B, and rs11175593 C>T near LRRK2/MUC19, have any genetic overlap across multiple autoimmune diseases including SAPHO syndrome, RA, AS, and SPA. MATERIALS AND METHODS: Genomic DNA was obtained from 71 SAPHO, 125 RA, 67 AS, and 35 SPA Han Chinese patients, as well as 104 healthy controls. SNPs were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Genotype and allele frequencies were analyzed using chi-square test. RESULTS: rs6908425 T>C in CDKAL1 was significantly different between SAPHO cases and healthy controls (odds ratios = 2.056, 95% confidence intervals: 1.211 3.490; p = 0.007), but no SNPs were associated with the risk of developing RA, AS, or SPA (p > 0.05). Analysis of genotype distributions showed similar results. A significant difference was only found in the genotype frequency of rs6908425 in SAPHO cases (p = 0.004); no significant differences were detected among patients with RA, AS, and SPA (p > 0.05). CONCLUSIONS: Our results suggest that rs6908425 in CDKAL1 is associated with the risk of developing SAPHO in Han Chinese populations. People who carry the risk allele T of rs6908425 might be more prone to developing SAPHO syndrome. PMID- 27936932 TI - Disruption of the 3D cancer genome blueprint. AB - Recent advances in chromosome conformation capture technologies are improving the current appreciation of how 3D genome architecture affects its function in different cell types and disease. Long-range chromatin interactions are organized into topologically associated domains, which are known to play a role in constraining gene expression patterns. However, in cancer cells there are alterations in the 3D genome structure, which impacts on gene regulation. Disruption of topologically associated domains architecture can result in alterations in chromatin interactions that bring new regulatory elements and genes together, leading to altered expression of oncogenes and tumor suppressor genes. Here, we discuss the impact of genetic and epigenetic changes in cancer and how this affects the spatial organization of chromatin. Understanding how disruptions to the 3D architecture contribute to the cancer genome will provide novel insights into the principles of epigenetic gene regulation in cancer and mechanisms responsible for cancer associated mutations and rearrangements. PMID- 27936933 TI - Review of genetic diversification of bats in the Caribbean and biogeographic relationships to Neotropical species based on DNA barcodes. AB - DNA barcoding is helping in discovering high levels of cryptic species and an underestimation of biodiversity in many groups of organisms. Although mammals are arguably the most studied and one of the least speciose taxonomic classes, the rate of species discovery is increasing and biased for small mammals on islands. An earlier study found bats in the Caribbean as a taxonomic and geographic deficiency in the International Barcode of Life initiative to establish a genetic reference database to enable specimen identification to species. Recent surveys in Dominican Republic, Jamaica, and Martinique have documented and barcoded half of the 58 bat species known from the Caribbean. I analyze all available barcode data of Caribbean bats to investigate biogeography and cryptic species in the Neotropical region. Analysis of the mitochondrial DNA gene cytochrome c oxidase subunit 1 results in a phylogenetic tree with all but one species as well supported and reciprocally monophyletic. With a broader sampling across the Neotropics, there are also divergent lineages that exhibit biogeographic structuring: (i) a phylogenetic split between northern and southern Dominican Republic in three species, (ii) two taxa with cryptic species associated with higher degree of island endemism, (iii) populations of two widely distributed species with deep divergence between the Caribbean and North and Central America, and (iv) one species in the Caribbean with affinities to taxa in South America. PMID- 27936934 TI - pathTiMEx: Joint Inference of Mutually Exclusive Cancer Pathways and Their Progression Dynamics. AB - High-throughput sequencing technologies have facilitated the generation of an unprecedented amount of genomic cancer data, opening the way to a more profound understanding of tumorigenesis. In this endeavor, two fundamental questions have emerged, namely (1) which alterations drive tumor progression and (2) in which order do they occur? Answering these questions is crucial for therapeutic decisions involving targeted agents. Because of interpatient heterogeneity, progression at the level of pathways is more reproducible than progression at the level of single genes. In this study, we introduce pathTiMEx, a generative probabilistic graphical model that describes tumor progression as a partially ordered set of mutually exclusive driver pathways. pathTiMEx employs a stochastic optimization procedure to jointly optimize the assignment of genes to pathways and the evolutionary order constraints among pathways. On real cancer data, pathTiMEx recapitulates previous knowledge on tumorigenesis, such as the temporal order among pathways which include APC, KRAS, and TP53 in colorectal cancer, while also proposing new biological hypotheses, such as the existence of a single early causal event consisting of the amplification of CDK4 and the deletion of CDKN2A in glioblastoma. pathTiMEx is available as an R package. PMID- 27936935 TI - Positive Parenting and Callous-Unemotional Traits: Their Association With School Behavior Problems in Young Children. AB - The current study tested the associations of both positive (i.e., warm and responsive) and negative (i.e., harsh and inconsistent) aspects of parenting with callous-unemotional (CU) traits and conduct problems. Caregivers and teachers of 92 ethnically diverse (33% African American) kindergarten students (61% female) were recruited to complete a series of survey measures. Students' average age was 6.2 (SD = 0.42) years. Parent report of positive parenting practices, but not negative parenting practices, was associated with teacher report of conduct problems. Further, positive parenting interacted with CU traits in their association with conduct problems. Parental use of positive reinforcement was more strongly negatively related to conduct problems for youth with high levels of CU traits, whereas parent-child cooperation was positively related to conduct problems only for youth with low levels of CU traits. Finally, only parental warmth was negatively correlated with CU traits after controlling for level of conduct problems. Results were generally not moderated by the child's gender or ethnicity. These findings highlight the importance of positive parenting practices for understanding CU traits and as potential targets in clinical interventions to treat children who show elevated levels of these traits. PMID- 27936936 TI - Additional Evidence Supports Association of Common Variants in COL11A1 with Increased Risk of Hip Osteoarthritis Susceptibility. AB - OBJECTIVE: In a recent study single nucleotide polymorphisms (SNPs) in the COL11A1 gene were found to be associated with hip osteoarthritis (OA) among European populations. In this study, our aim was to identify common genetic variants in COL11A1 predisposing to primary hip OA in Han Chinese individuals. METHODS: We designed a case-control study that included 313 hip OA patients and 911 unrelated healthy controls. Fourteen tagging single-nucleotide polymorphisms (SNPs) were genotyped, and single SNP and haplotypic association analyses were performed. RESULTS: Two SNPs (rs1241164 and rs4907986) were found to be significantly associated with hip OA risk (adjusted p = 0.000731 and 0.000477). An increased risk of OA was associated with possession of the C allele of rs1241164 (adjusted odds ratio [OR] = 1.73, 95% confidence interval [CI] = 1.27 2.36) and the T allele of rs4907986 (adjusted OR = 1.72, 95% CI = 1.24-2.35). Similar results were confirmed via genotypic association analyses. Moreover, two different haplotype blocks, including rs1241164 and rs4907986, respectively, were found to be strongly associated with hip OA risk as well. CONCLUSION: Variants in the COL11A1 gene modify individual susceptibility to hip OA in the Han Chinese population. PMID- 27936937 TI - Driving in mild cognitive impairment: The role of depressive symptoms. AB - OBJECTIVES: Previous studies indicate a negative association between depression and driving fitness in the general population. Our goal was to cover a gap in the literature and to explore the link between depressive symptoms and driving behavior in individuals with mild cognitive impairment (MCI) through the use of a driving simulator experiment. METHODS: Twenty-four individuals with MCI (mean age = 67.42, SD = 7.13) and 23 cognitively healthy individuals (mean age = 65.13, SD = 7.21) were introduced in the study. A valid driving license and regular car use served as main inclusion criteria. Data collection included a neurological/neuropsychological assessment and a driving simulator evaluation. Depressive symptomatology was assessed with the Patient Health Questionnaire (PHQ 9). RESULTS: Significant interaction effects indicating a greater negative impact of depressive symptoms in drivers with MCI than in cognitively healthy drivers were observed in the case of various driving indexes, namely, average speed, accident risk, side bar hits, headway distance, headway distance variation, and lateral position variation. The associations between depressive symptoms and driving behavior remained significant after controlling for daytime sleepiness and cognition. CONCLUSIONS: Depressive symptoms could be a factor explaining why certain patients with MCI present altered driving skills. Therefore, interventions for treating the depressive symptoms of individuals with MCI could prove to be beneficial regarding their driving performance. PMID- 27936938 TI - A qualitative study of the emotional coping and support needs of children living with a parent with a brain injury. AB - PRIMARY OBJECTIVE: To examine emotional coping and support needs in children of persons with acquired brain injury, with a view to understanding what interventions would be helpful for these children. DESIGN: The study was qualitative, using a thematic analysis approach. METHODS AND PROCEDURE: Six children between 9-18 years of age, six parents (three with ABI) and three support workers were interviewed either at home or at a support centre, using a semi-structured interview guide. RESULTS: Children reported using a variety of adaptive and maladaptive emotional coping strategies, but were consistent in expressing a need for credible validation, i.e. sharing experiences with peers. The results are presented under four overarching themes: difficulties faced; emotions experienced; coping strategies; and reported support needs. CONCLUSIONS: The results reveal an interaction between the child's experiences of complex loss that is difficult to acknowledge, emotional distancing between parent and child and the children's need for credible validation. All children expressed a desire for talking to peers in a similar situation to themselves, but had not had this opportunity. Interventions should set up such peer interaction to create credible validation for the specific distress suffered by this population. PMID- 27936939 TI - A study of the internal construct and predictive validity of the SMART assessment for emergence from vegetative state. AB - OBJECTIVE: The Sensory Modality Assessment and Rehabilitation Technique (SMART) was developed to assess the levels of awareness, functional, sensory and communicative abilities of adults in vegetative (VS) or minimally-conscious states following severe brain injury. The current study seeks to ascertain if a total score can be derived from the individual assessments contained within SMART and to test the internal construct and predictive validity of that total score. SUBJECTS: Persons in VS were recruited over a 3-year period and current status was determined after a 17-year follow-up. DESIGN: Data were evaluated by fit to the Rasch model. Predictive validity for emergence from VS was ascertained through an Area-Under-the-Curve [AUC] analysis. RESULTS: Sixty people in VS were assessed on several occasions. Average age on admission was 38.8 years; 30 had anoxic brain damage; 21 traumatic injury. The Rasch analysis indicated the raw score was a sufficient statistic for awareness. Over half [55%] failed to emerge from VS. For those with anoxic brain injury, a SMART cut point of 85 gave an AUC of 0.966 (95% CI = 0.910-1.00) for emergence, as did a cut point of 68 for those with traumatic brain injury. DISCUSSION: The current analysis suggests that SMART may have important predictive attributes for emergence (or lack thereof). No change in status of those discharged in VS has been reported to this present day. PMID- 27936940 TI - Acute massive cerebellar infarction associated with craniocervical junction complex malformation: a case report and literature review. AB - We report a case of acute massive cerebellar infarction associated with craniocervical junction (CVJ) complex malformation in a 21-year-old male. Timely surgical intervention prevented the deterioration of his neurological status. PMID- 27936942 TI - Implantable cardioverter defibrillator treatment in long QT syndrome patients: a national study on adherence to international guidelines. AB - OBJECTIVES: Implantable cardioverter defibrillator (ICD) treatment is effective among long QT syndrome (LQTS) patients at a high risk of sudden cardiac death. Previous studies show that the international guidelines are not always followed, and that risk stratification may be based on genotype rather than individual risk profile. We analysed data from the Swedish ICD & Pacemaker Registry and medical records to examine how international guidelines were followed with regards to phenotype and genotype. METHODS AND RESULTS: ICD treatment was used in 150 Swedish LQTS patients from 1989-2013. The annual number of implantations increased over the study period. A total of 109 patients were included in the analysis. Most patients (91%) were symptomatic before the implantation. Seventy percent of patients who received ICD treatment met the 2006 Class I or Class IIa recommendations for LQTS treatment. Thirty-one percent of the LQT3 patients received ICD treatment despite being asymptomatic. Among LQT1 patients, 45% received ICD treatment after syncope despite beta-blockers. CONCLUSIONS: Thirty percent of Swedish LQTS patients with ICD received the treatment without a strong indication based on international guidelines. LQT3 patients were over-represented among asymptomatic patients. Many LQT1 patients received ICD despite the known effect of beta-blockers in this group. PMID- 27936944 TI - Adolescents' and Best Friend's Depressive Symptoms and Conflict Management: Intraindividual and Interpersonal Processes Over Time. AB - This 6-year longitudinal study examined the relation between 3 conflict management styles (i.e., problem solving, conflict engagement, and compliance) and depressive symptoms in adolescent-best friend relationships. Participants were 479 Dutch adolescents and their best friend who reported annually on depressive symptoms and conflict management styles toward each other. Bidirectional effects between conflict management styles and depressive symptoms were studied both within adolescents (intraindividual) and between adolescent best friends (interpersonal). A positive interpersonal effect of depressive symptoms of one dyad member on depressive symptoms of the other member was found. Similarly, higher positive problem solving and conflict engagement of one dyad member predicted respectively higher problem solving and conflict engagement of the other dyad member. Adolescents who reported more depressive symptoms reported more conflict engagement and compliance over time. In addition, for boys, higher levels of depressive symptoms of one dyad member were related to more problem solving by the other member over time. The current study contributed to the literature by showing that depressive symptoms and conflict management are related constructs in adolescents and that both intrapersonal and interpersonal processes contribute to this relation. PMID- 27936943 TI - Association of sleep habits with blood pressure in elderly people. AB - We investigated the impact of sleep habits on blood pressure (BP) in cross sectional analyses of 1533 participants aged >= 70 without cardiovascular disease or treatment for hypertension, diabetes mellitus, and dyslipidemia. We assessed sleep habits [time in bed (TIB), bed time, and taking sleeping pills], using the Pittsburgh Sleep Quality Index. For groups where TIB was >8 h and <6 h, systolic BP was significantly higher than the group where TIB ranged 6-8 h (134.2 +/- 17.5, 134.8 +/- 19.6 vs. 130.1 +/- 17.7, p < 0.05, p < 0.001, respectively). Systolic BP was significantly higher in the group whose bed time was before 21:00 than that whose bed time was 21:00 or later (136.6 +/- 18.6 vs. 132.0 +/- 18.4, p < 0.01). Both systolic and diastolic BPs were lower in the group taking sleeping pills (133.2 +/- 18.6 vs. 128.1 +/- 17.3, p < 0.0001; 75.3 +/- 11.5 vs. 73.3 +/- 10.7, p < 0.05). Multiple regression analyses revealed that after adjusting for age, gender, body mass index, smoking, and alcohol intake, taking sleeping pills and short or long TIB were significantly associated with systolic BP, whereas bed time was not. These results suggested that inappropriate TIB and sleeping pills were associated with BP in elderly people. PMID- 27936941 TI - Comparison of direct renin inhibitor and angiotensin II receptor blocker on clinic and ambulatory blood pressure profiles in hypertension with chronic kidney disease. AB - We compared the therapeutic effects of aliskiren (direct renin inhibitor (DRI) group) with angiotensin II (Ang II) type 1 receptor blockers (ARBs) (ARB group) on clinic blood pressure (BP) and ambulatory BP in 36 hypertensive chronic kidney disease (CKD) patients. The baseline clinic BP levels and the after treatment/baseline (A/B) ratios of clinic BP levels, estimated after 24-week treatment period, were similar in DRI group (n = 18) and ARB group (n = 18). With respect to the effects on ambulatory BP, the A/B ratios of the daytime and nighttime systolic BP in DRI group were significantly higher than those in ARB group. The A/B ratio of ankle-brachial pressure index after the study was higher in the DRI group compared with the ARB group. The results of the present study suggest that DRI therapy is not superior to ARB therapy in lowering ambulatory BP in hypertensive CKD patients, in spite of comparable clinic BP-lowering effects. PMID- 27936945 TI - Zero-link polymerized hemoglobin (OxyVita(r)Hb) stabilizes the heme environment: potential for lowering vascular oxidative stress. AB - A study was conducted to compare the resistance to heme exposure between myoglobin, bovine hemoglobin, and OxyVita(r)Hb (zero-link-hemoglobin-polymer). The rate of release of heme-iron is related to the tissue oxidative stress that can elicit deleterious effects in clinical uses of blood substitutes. Experimental work has focused on the unfolding of hemoglobin molecules, resulting in heme loss, by using urea as a denaturant and analyzing the Soret spectral region. These unfolding studies provide evidence for both the structural integrity and redox stability of OxyVita(r)Hb and demonstrate that OxyVita(r)Hb does not readily unfold and its heme exposure/release is greatly reduced. PMID- 27936946 TI - Study of the effects of polymerized porcine hemoglobin (pPolyHb) in an acute anemia rat model. AB - The objective of this study was to investigate the recovery ability of polymerized porcine hemoglobin (pPolyHb) in a rat model of acute anemia caused by normovolemic hemodilution (ANH). After the ANH procedure, rats were infused with either pPolyHb or red blood cells. The results showed pPolyHb could carry a sufficient amount of oxygen to the tissues to maintain normal aerobic metabolism and hemodynamic stability, without any significant toxic effects on renal and liver function according to pathological, and biochemical analysis. The data suggest pPolyHb may be a good candidate for the treatment of acute anemia in future clinical trials. PMID- 27936947 TI - Blood pressure and autonomic responses following isolated and combined aerobic and resistance exercise in hypertensive older women. AB - PURPOSE: This study aimed to compare blood pressure (BP) after isolated and combined sessions of aerobic and resistance exercises in hypertensive older women. Heart rate (HR) and heart rate variability (HRV) were included as additional variables. METHODS: Twenty-one older women (63+/-1.9 years; 69.9+/-2.7 kg; 158.8+/-2.1 cm) with controlled hypertension (resting BP = 132.2 +/- 3.1/74.1 +/- 4.0 mmHg) performed four random sessions on different days: 1) aerobic exercise (AE: treadmill walking/running; 40 min; 50-60% HRreserve); 2) resistance exercise (RE: 8 exercises; 3 sets; 15 reps; 40% 1RM)); 3) aerobic exercise followed by resistance exercise (A+R); 4); control (CON). BP, HR and HRV were measured at rest and during 180 min after the sessions. RESULTS: The AE and A+R sessions demonstrated significant decreases in SBP and DBP (30, 60, 120, and 180 min; P < 0.05) and increases in HR (30 and 60 min; P < 0.05) compared to the CON. The RE session demonstrated significant reductions compared to the CON only for DBP (120 and 180 min; P < 0.05). No significant differences were observed in HRV between resting and all sessions. CONCLUSION: All sessions that involved aerobic exercise (AE and A+R) caused postexercise hypotension in comparison to the CON, with no differences in HRV. PMID- 27936948 TI - High-intensity focused ultrasonic ablation of sacral chordoma is feasible: a series of four cases and details of a national clinical trial. AB - High-intensity focused ultrasound describes the use of high-intensity focused ultrasound (HIFU) to ablate tumours without requiring an incision or other invasive procedure. This technique has been trialled on a range of tumours including uterine fibroids, prostate, liver and renal cancer. We describe our experience of using HIFU to ablate sacral chordoma in four patients with advanced tumours. Patients were treated under general anaesthetic or sedation using an ultrasound-guided HIFU device. HIFU therapy was associated with a reduction in tumour volume over time in three patients for whom follow up scans were available. Tumour necrosis was reliably demonstrated in two of the three patients. We have established a national trial to assess if HIFU may improve long term outcome from sacral chordoma, details are given. PMID- 27936949 TI - Comparison of valsartan and amlodipine on ambulatory blood pressure variability in hypertensive patients. AB - We tested the hypothesis that calcium channel blockers (CCBs: amlodipine group, n = 38)) are superior to angiotensin receptor blockers (ARBs: valsartan group, n = 38) against ambulatory blood pressure variability (BPV) in untreated Japanese hypertensive patients. Both drugs significantly reduced ambulatory systolic and diastolic BP values. With regard to BPV, standard deviation (SD) in SBP did not change with the administration of either drug, but the ARB significantly increased SD in awake DBP (12 +/- 4-14 +/- 4 mmHg). The ARB also significantly increased the coefficients of variation (CVs)in awake and 24-h SBP/DBP (all P < 0.05), but amlodipine did not change the CV. CCB significantly reduced the maximum values of awake SBP (193 +/- 24-182 +/- 27 mmHg, P = 0.02), sleep SBP (156 +/- 18-139 +/- 14 mmHg, P < 0 .001), and awake and sleep DBP (P < 0.01 in both cases), but the ARB did not change the maximum BP values. In conclusion, a once-daily morning dose of CCB amlodipine was more effective at controlling ambulatory BPV than ARB valsartan, especially in reducing maximum BP levels. PMID- 27936950 TI - Cardiometabolic diseases of civilization: history and maturation of an evolving global threat. An update and call to action. AB - Despite striking extensions of lifespan, leading causes of death in most countries now constitute chronic, degenerative diseases which outpace the capacity of health systems. Cardiovascular disease is the most common cause of death in both developed and undeveloped countries. In America, nearly half of the adult population has at least one chronic disease, and polypharmacy is commonplace. Prevalence of ideal cardiovascular health has not meaningfully improved over the past two decades. The fall in cardiovascular deaths in Western countries, half due to a fall in risk factors and half due to improved treatments, have plateaued, and this reversal is due to the dual epidemics of obesity and diabetes type 2. High burdens of cardiovascular risk factors are also evident globally. Undeveloped nations bear the burdens of both infectious diseases and high childhood death rates. Unacceptable rates of morbidity and mortality arise from insufficient resources to improve sanitation, pure water, and hygiene, ultimately linked to poverty and disparities. Simultaneously, about 80% of cardiovascular deaths now occur in low- and middle-income nations. For these reasons, risk factors for noncommunicable diseases, including poverty, health illiteracy, and lack of adherence, must be targeted with unprecedented vigor worldwide. Key messages In developed and relatively wealthy countries, chronic "degenerative" diseases have attained crisis proportions that threaten to reverse health gains made within the past decades. Although poverty, disparities, and poor sanitation still cause unnecessary death and despair in developing nations, they are now also burdened with increasing cardiovascular mortality. Poor adherence and low levels of health literacy contribute to the high background levels of cardiovascular risk. PMID- 27936951 TI - Factors affecting treatment compliance in new hypertensive patients in Korea. AB - This study aims to analyze continuity of care according to complications and examine the relationship between the continuity of care and health outcomes (hospitalization, emergency department visits, and complications) using data of new hypertensive patients from Korea's National Health Insurance Claims database. There were a total of 715,053 new hypertensive patients followed up for three years until 2011. Indices of continuity of care were Continuity of Care Index (COC), Modified, Modified Continuity Index (MMCI), and Most Frequent Provider Continuity (MFPC). The mean values of COC, MMCI, and MFPC were 0.79, 0.77, and 0.87, respectively, in new hypertensive patients with complications, and 0.80, 0.79, and 0.87, respectively, in those without complications. The factors affecting the continuity of care were sex, ambulatory care visits, number of providers, main medical institution, and Charlson's comorbidity score. Following analysis of the correlation between the treatment compliance and health outcomes, the low COC group had a higher association with hospitalization, the emergency department visit, and complications as compared with the high COC group. COC and medication adherence were associated with a reduction of hospitalization, emergency department visits, and complications. This indicates it would be mandatory to manage the patients' continuity of care. PMID- 27936952 TI - Reliability of the NINDS common data elements cranial tomography (CT) rating variables for traumatic brain injury (TBI). AB - BACKGROUND: Non-contrast head computer tomography (CT) is widely used to evaluate eligibility of patients after acute traumatic brain injury (TBI) for clinical trials. The NINDS Common Data Elements (CDEs) TBI were developed to standardize collection of CT variables. The objectives of this study were to train research assistants (RAs) to rate CDEs and then to evaluate their performance. The aim was to assess inter-rater reliability (IRR) of CDEs between trained RAs and a neurologist and to evaluate applicability of CDEs in acute and sub-acute TBI to test the feasibility of using CDE CT ratings in future trials and ultimately in clinical practice. The second aim was to confirm that the ratings of CDEs reflect pathophysiological events after TBI. METHODS AND RESULTS: First, a manual was developed for application of the CDEs, which was used to rate brain CTs (n = 100). An excellent agreement was found in combined kappas between RAs on admission and on 24-hour follow-up CTs (Iota = 0.803 and 0.787, respectively). Good IRR (kappa > 0.61) was shown for six CDEs on admissions and for seven CDEs on follow-up CTs. Low IRR (kappa < 0.4) was determined for five CDEs on admission and for four CDEs on follow-up CT. Combined IRR of each assistant with the neurologist were good on admission (Iota = 0.613 and 0.787) and excellent on follow-up CT (Iota = 0.906 and 0.977). Second, Principal Component Analysis (PCA) was applied to cluster the rated CDEs (n = 255) and five major components were found that explain 53% of the variance. CONCLUSIONS: CT CDEs are useful in clinical studies of TBI. Trained RAs can reliably collect variables. PCA identifies CDE clusters with clinical and biologic plausibility. ABBREVIATIONS: RA, research assistant; CT, Cranial Tomography; TBI, Traumatic Brain Injury; CDE, Common Data Elements; IRR, inter-rater reliability; PCA, Principal Component Analysis; GCS, Glasgow Coma Scale; R, rater; CI, confidence interval; CCC, Concordance correlation coefficient; IVH, Intraventricular haemorrhage; DCA, Discriminant Component analysis; SAH, Subarachnoid Haemorrhage. PMID- 27936953 TI - The feasibility and impact of a yoga pilot programme on the quality-of-life of adults with acquired brain injury. AB - OBJECTIVE: This pilot study measured the feasibility and impact of an 8-week yoga programme on the quality-of-life of adults with acquired brain injury (ABI). METHODS: Thirty-one adults with ABI were allocated to yoga (n = 16) or control (n = 15) groups. Participants completed the Quality of Life After Brain Injury (QOLIBRI) measure pre- and post-intervention; individuals in the yoga group also rated programme satisfaction. Mann-Whitney/Wilcoxon and the Wilcoxon Signed Rank tests were used to evaluate between- and within-group differences for the total and sub-scale QOLIBRI scores, respectively. RESULTS: No significant differences emerged between groups on the QOLIBRI pre- or post-intervention. However, there were significant improvements on overall quality-of-life and on Emotions and Feeling sub-scales for the intervention group only. The overall QOLIBRI score improved from 1.93 (SD = 0.27) to 2.15 (SD = 0.34, p = 0.01). The mean Emotions sub-scale increased from 1.69 (SD = 0.40) to 2.01 (SD = 0.52, p = 0.01), and the mean Feeling sub-scale from 2.1 (SD = 0.34) to 2.42 (SD = 0.39, p = 0.01). CONCLUSION: Adults with ABI experienced improvements in overall quality-of-life following an 8-week yoga programme. Specific improvements in self-perception and negative emotions also emerged. High attendance and satisfaction ratings support the feasibility of this type of intervention for people with brain injury. PMID- 27936954 TI - The influence of scale structure and sex on parental reports of children's social (pragmatic) communication symptoms. AB - The addition of social (pragmatic) communication disorder [S(P)CD] to the DSM-5 taxonomy has left clinicians and researchers searching for appropriate diagnostic measures. Factor analysis procedures examined the extent to which S(P)CD symptoms presented within the Children's Communication Checklist-Second Edition (CCC-2) represented a unique construct and whether these factors were influenced by children's sex. Parents of 208 children (males = 125 and females = 83) from a community-based sample completed the CCC-2. Two pragmatic scores from the CCC-2 were analysed as follows: the social interaction difference index (SIDI) and a pragmatic composite from the original CCC (PC-5). Factor analysis failed to find a unique factor structure for either pragmatic composite. Analyses uncovered different factor structures for the CCC-2 SIDI and PC-5 composites and for boys and girls. S(P)CD represents a complex combination of symptoms that are poorly differentiated from other language and socioemotional behavioural difficulties. PMID- 27936956 TI - Relationship among multifaceted factors including blood pressure at discharge and long-term clinical outcome in patients with cardiovascular diseases. AB - The relationship among blood pressure (BP) levels at discharge, other multifaceted factors assessed in cardiac rehabilitation programs, and prognosis for up to 2 years was examined in 154 consecutive cases (132 patients; 69 males; 79 +/- 12 years, mean +/- SD). A total of 72 composite events occurred (58 rehospitalizations from cardiovascular causes and 14 all-cause death events). The relationship between the systolic BP (SBP) at discharge and the long-term prognosis formed a J-shaped curve, with the event rate being lowest in patients with SBP of 115-125 mmHg. This relationship was still significant after adjustment of multifaceted factors assessed in cardiac rehabilitation programs. PMID- 27936955 TI - Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study. AB - A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting RP-PCR data. Our objective was to determine the properties of these sequence variations with regard to prevalence, the range of variation, and effect on disease prognosis. We screened a multi-national cohort (n = 6981) for the HREM and samples with deviant RP-PCR curves were identified. The deviant samples were subsequently sequenced to determine sequence alteration. Our results show that in the USA and European cohorts (n = 6508) 10.7% carried the HREM and 3% had a sequence variant, while no HREM or sequence variants were observed in the Japanese cohort (n = 473). Sequence variations were more common on HREM alleles; however, certain population specific variants were associated with a non-expanded allele.In conclusion, we identified 38 different sequence variants, most located within the first 50 bp downstream of the HREM region. Furthermore, the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival, while sequence variation did not have any correlation with these parameters. PMID- 27936957 TI - Implications of World Health Organization classification for body mass index on the correlations between common electrocardiographic indexes for left ventricular hypertrophy and left ventricular mass. AB - BACKGROUND: Some electrocardiographic indexes such as Cornell index, Cornell product index, or Sokolow-Lyon index remain to be used in the clinical setting. We assessed the effects of body mass index (BMI) on the correlations between these ECG indexes and left ventricular mass (LVM). METHODS: One hundred ninety six outpatients who underwent both ECG and echocardiography on the same day were included in this study. In accordance with the World Health Organization (WHO) classification of BMI, the patients were classified into the four groups: underweight (<18.5 kg/m2, n = 30), normal weight (18.5-24.9 kg/m2, n = 83), overweight (25-29.9 kg/m2, n = 43), and obese (>=30 kg/m2, n = 40). RESULTS: With increasing WHO classification of BMI, Cornell index (RaVL+SV3), Cornell product index [(RaVL+SV3)RQRS duration], and LVM increased. On the other hand, Sokolow Lyon index (SV1+RV5) decreased. Cornell index correlated with LVM in normal weight group (r = 0.27, p = 0.015), but did not in the other groups. Cornell product index also correlated with LVM in normal weight group (r = 0.30, p = 0.006), but did not in the other groups. Sokolow-Lyon index correlated with LVM well in normal weight group (r = 0.32, p = 0.004) and better in underweight group (r = 0.61, p = 0.0004). However, no correlations were found in overweight and obese groups. CONCLUSIONS: Our results suggest that BMI influences the correlations between these ECG indexes and LVM, and should be taken into consideration when assessing LVH. PMID- 27936958 TI - Kidney resistive index relates to variations of home blood pressure in chronic kidney diseases. AB - BACKGROUND: Kidney resistive index (RI) correlates with tubulointerstitial changes and predicts renal prognosis. Most patients with chronic kidney diseases (CKDs) manifest high blood pressure and atherosclerotic cardiovascular diseases. In addition, various atherosclerotic indexes relate to variations in blood pressure. METHODS: Subjects were 70 CKD patients, who visited our office and agreed to measure home blood pressure and receive renal ultrasonography. Cross sectional analyses were performed. RESULTS: Patient age was averaged 61 +/- 15 (SD) y/o and 60% were male. Mean serum creatinine and proteinuria were 1.2 +/- 0.5 mg/dl and 0.2 +/- 0.5 g/gCr, respectively. Office blood pressure and kidney RI were 128 +/- 17/75 +/- 11 mmHg and 0.66 +/- 0.08, respectively. Multivariate regression analysis revealed that age and office blood pressure independently correlated to kidney RI (p < 0.05 for each). Home blood pressure was averaged 122 +/- 7/70 +/- 6 mmHg. Both standard deviation and the maximal-minimal difference in home systolic blood pressure related to kidney RI (p < 0.05). CONCLUSIONS: The present results indicate that office blood pressure correlates to kidney RI, which predicts renal prognosis. In addition, our data implicate that kidney RI relates to variations in home systolic blood pressure, and suggest that kidney RI may be a good index for atherosclerosis in CKD patients. PMID- 27936959 TI - Significance of perioperative goal-directed hemodynamic approach in preventing postoperative complications in patients after cardiac surgery: a meta-analysis and systematic review. AB - PURPOSE: Goal-directed hemodynamic therapy (GDT) is used to prevent hypoperfusion resulting from surgery. The objective of this study was to analyze the efficacy and importance of perioperative GDT. METHODS: PUBMED, MEDLINE, CENTRAL, and Google Scholar databases were searched until 17 June 2016 using the search terms: cardiac output, cardiac surgical procedures, hemodynamics, goal-directed therapy, and intraoperative. Randomized-controlled trials with pre-emptive hemodynamic intervention for cardiac surgical population versus standard hemodynamic therapy were included. RESULTS: Nine studies were included with a total of 1148 patients. The overall analysis revealed no significant difference in the all-cause mortality (pooled peto OR =0.58, 95%CI =0.27-1.525, p = 0.164), duration of mechanical ventilation (pooled difference in mean= -1.48, 95%CI= -3.24 to 0.28, p = 0.099), or length of intensive care unit (ICU) stay (pooled difference in mean= -9.10, 95%CI= -20.14 to 1.93, p = 0.106) between patients in the GDT and control groups. Patients in the GDP group were associated with shorter hospital stay than those in the control group (pooled difference in mean= -1.52, 95%CI= -2.31 to 0.73, p < 0.001). CONCLUSION: GDT reduces the length of hospital stay compared with the standard of care. Further studies are necessary to continually assess the benefit of GDT following major surgery. Key Messages The results of this analysis revealed no significant difference between cardiac surgery patients receiving goal-directed hemodynamic therapy (GDT) or conventional fluid therapy in terms of the all-cause mortality, duration of mechanical intervention, and length of ICU-stay. The length of hospital stay was significantly reduced in patients treated with GDT compare to conventional fluid therapy. GDT may have limited benefit in reducing mortality; however, the association to shorter length of hospital stay may suggest that better hemodynamic balance can facilitate postoperative recovery. PMID- 27936960 TI - The effects of mild traumatic brain injury on postural control. AB - PRIMARY OBJECTIVE: The purpose of this study was to investigate the effects of mild traumatic brain injury (mTBI) on multiple postural indices that characterize body sway behaviour. METHODS AND PROCEDURES: The body's centre of pressure (COP) displacement was recorded from 11 individuals with a history of mTBI (29.4 +/- 6.7 years old) and 11 healthy controls (26.8 +/- 3.7 years old) performing bipedal stance on a force platform for 120 seconds. Spatio-temporal (area, amplitude and mean velocity of the COP displacement) and frequency characteristics (frequency containing 80% of the power spectral density) of the body oscillation, as well as its dynamic characteristics (sample entropy estimate of the COP displacement) were extracted from COP signals. MAIN OUTCOMES AND RESULTS: All postural indices studied were significantly affected by mTBI (p < 0.010). Participants with a history of mTBI presented a larger, slower, and more random body oscillation compared to controls. CONCLUSION: The results suggest that (a) balance deficits can be recognized as an effect of mTBI; (b) balance deficits induced by mTBI are multi-dimensional, affecting all three domains included in this study; and PMID- 27936961 TI - Exaggerated exercise blood pressure response in middle-aged men as a predictor of future blood pressure: a 10-year follow-up. AB - OBJECTIVE: The prognostic value of an exaggerated exercise systolic blood pressure response (EESBPR) remains controversial. This study was designed to assess whether an EESBPR is associated with the predictor of future blood pressure. METHODS: From an initial population of 1,534 male-subjects with normal BP or no medication who underwent ergometric exercise, 733 subjects (mean age: 41 years old) at baseline to follow-up BP after an average of 10 years were selected. A 12-min exercise tolerance test with three phases of estimated load from predictive maximum oxygen intake was performed at baseline, and exercise BP was measured. RESULTS: Exercise BP response was classified by three group: Low group (G) (exercise SBP < 180 mmHg), Middle G (exercise BP:180-199 mmHg), High G (exercise BP:200 mmHg ?). BP after 10 years in Low G was 123 +/- 12/79 +/- 7 mmHg, in Middle G:127 +/- 13/81 +/- 8 mmHg, in High G :134 +/- 15/84 +/- 10 mmHg. Compared with in Low G, BP after 10 years in High G significantly increased (p < 0.05). Multiple regression analysis was carried out to clarify the relationship of exercise SBP at baseline to BP after 10 years. In multivariate-adjusted models, the relationship of SBP at follow-up was stronger to exercise SBP (beta = 0.271, P < 0.001) than to resting SBP (beta = 0.148, P < 0.001). Maximum oxygen intake (beta = -0.193, P = 0.003) and resting SBP correlated with SBP after 10 years. CONCLUSIONS: In middle-aged men, exercise SBP would be a stronger predictor of future SBP, DBP rather than BP at rest. In optimal of classification of BP (SBP < 120 mmHg), exercise BP response was clearly associated with BP after 10 years. PMID- 27936962 TI - Using high-content screening technology for studying drug-induced hepatotoxicity in preclinical studies. AB - INTRODUCTION: The need for alternatives to animal experimentation and traditional testing methods has been widely discussed in recent years. This has led scientists and regulatory authorities to investigate alternative methods for toxicity testing. High-content screening (HCS) has emerged as a powerful tool in predictive toxicology since it permits molecular, cellular and tissue-based toxicity assessments. HCS allows automated image acquisition and analysis, and provides information on multiple properties of individual cells loaded simultaneously with fluorescent dyes, which is used for drug safety evaluations. Areas covered: Herein, the authors review the principles of HCS technology and some of the most widely used HCS assays for studying drug-induced hepatotoxicity in preclinical studies in general and in the pharmaceutical industry in particular. Expert opinion: The widespread acceptation of HCS by pharmaceutical companies and academic researchers highlights the potential usefulness of this technology as a prioritization tool in drug development. The improvement of different key points such as fluorescent probes or bioinformatics tools will consolidate HCS in drug discovery. PMID- 27936963 TI - Stuttering in relation to the morphophonemics of Kannada. AB - The present study investigated the effect of certain unique morphophonemic features of Kannada words on the rate of stutters in a group of 22 adolescent and adult persons who stuttered in an oral reading task. A linear regression analysis showed that word length ranging from 1 to 8 syllables was a potent variable in the occurrence of stutters accounting for 25.3% of stutters. A composite index of morphophonemic complexity with points assigned for sandhi, geminates, consonant clusters, and number of morphemes accounted for a small 7.5% variability in observed stutter rates. Sandhi words and the hybrid content-function words were no more effective than other words in determining stutter rates. Results are discussed in relation to past findings for other languages and current neurolinguistic models of speech production. PMID- 27936964 TI - Preoperative serum thyroglobulin and changes in serum thyroglobulin during TSH suppression independently predict follicular thyroid carcinoma in thyroid nodules with a cytological diagnosis of follicular lesion. AB - BACKGROUND: Fine-needle aspiration biopsy (FNAB) cannot distinguish a follicular thyroid carcinoma (FTC) from a follicular adenoma in follicular lesions. We designed this study to determine whether the preoperative thyroglobulin (Tg) and change in serum Tg during thyroid-stimulating hormone (TSH) suppression can predict FTC in thyroid nodules with a cytological diagnosis of follicular lesion. METHODS: Among 854 patients who underwent thyroid surgery, the 198 patients who presented with thyroid nodules with a cytological diagnosis of follicular lesion were analyzed. Predictive factors for malignancy were evaluated using multivariate logistic regression models. Subgroup analyses of patients with TSH suppression therapy by levothyroxine were also conducted. RESULTS: Thirty-two patients (16%) had FTC, and 166 patients had confirmed benign nodules. The median preoperative serum Tg levels were significantly higher in patients with FTC compared to those with benign pathology (449 vs. 34 ng/mL, p < 0.001). The serum Tg (odds ratios (OR) 10.311, p < 0.001) and tumor volume (OR 4.500, p = 0.035) were found to be independent predictors for FTC in all patients with a cytological diagnosis of follicular lesion. Forty-eight patients received TSH suppression therapy. When we performed subgroup analyses on the patients with TSH suppression therapy, decrease less than 15% in serum Tg during TSH suppression was found to be an independent predictor of FTC (OR 13.918, p = 0.018). CONCLUSION: Preoperative serum Tg and changes in serum Tg during TSH suppression independently predict FTC in thyroid nodules with a cytological diagnosis of follicular lesion. PMID- 27936965 TI - AVP-786 for the treatment of agitation in dementia of the Alzheimer's type. AB - INTRODUCTION: Agitation is common and distressing in patients with Alzheimer-type dementia, but safe, effective treatments remain elusive. Psychological treatments are first-line options, but they have limited efficacy. Off-label psychotropic medications are frequently used, but they also have limited effectiveness, and their use may have harmful side effects, including death. Areas covered: This review discusses the history leading to the conception of AVP-786 (deuterated (d6)-dextromethorphan/quinidine), its pharmacokinetic and pharmacodynamic profiles and safety issues, together with an overview of recent clinical trials. Data were found in the medical literature, in US and EU clinical trial registries and in information provided by the manufacturer. Expert opinion: AVP-786 is one of six investigational compounds in recent phase III clinical development for agitation in Alzheimer disease (AD). Quinidine and deuteration appear to prolong dextromethorphan's plasma half-life and facilitate brain penetration. The FDA granted fast-track designation to AVP-786 and allowed use of data generated on dextromethorphan-quinidine (AVP-923, Nuedexta(r)) for regulatory filings. AVP-923 reduced agitation in AD and was well tolerated in a phase II RCT that included more than 200 patients. A phase III clinical development program of AVP-786 for AD agitation was recently initiated. This program is expected to start generating results in July 2018. PMID- 27936966 TI - Liraglutide for weight management: benefits and risks. PMID- 27936967 TI - Potential roles of myeloperoxidase and hypochlorous acid in metabolism and toxicity of alkene hydrocarbons and drug molecules containing olefinic moieties. AB - INTRODUCTION: Adverse drug reactions (ADRs) pose a significant health problem and are generally attributed to reactive metabolites. Olefinic moieties in drugs can undergo cytochrome P450-mediated bioactivation to produce reactive metabolites but myeloperoxidase (MPO)-mediated bioactivation of these moieties has not been reported. Thus, small molecules of alkene hydrocarbons are used as model compounds to characterize the MPO-mediated metabolism. Areas covered: The authors focus on MPO-mediated metabolism of alkene hydrocarbons to form chlorohydrins and the potential role of chlorohydrins in alkene toxicity and carcinogenicity. A case study is presented, in which a carcinogenic alkene, 1,3-butadiene, is demonstrated to form 1-chloro-2-hydroxy-3-butene (CHB) through the MPO-mediated pathway. Further bioactivation of CHB yields a cross-linking metabolite, 1-chloro 3-buten-2-one (CBO), which is highly reactive toward glutathione, proteins, nucleosides, and DNA. Toxicity and mutagenicity of CHB and CBO are also presented. Expert opinion: Alkene hydrocarbons readily undergo MPO-mediated bioactivation to form chlorohydrins, which can further be biotransformed into proteins/DNA-modifying reactive metabolites. Therefore, chlorohydrin formation may play an important role in alkene toxicity and carcinogenicity. Olefinic moieties in drugs are expected to undergo similar bioactivation, which may contribute to ADRs. Studies to investigate the roles of MPO and chlorohydrin formation in ADRs are thus warranted. PMID- 27936968 TI - Workplace accommodations for persons with physical disabilities: evidence synthesis of the peer-reviewed literature. AB - PURPOSE: To identify and synthesize research evidence on workplace accommodations used by employers to recruit, hire, retain, and promote persons with physical disabilities. METHOD: A structured search of six electronic journal databases was undertaken to identify peer-reviewed literature on the topic published from January 1990 to March 2016. Articles describing or evaluating workplace disability accommodation policies and practices were given a full-text review. Topic experts were contacted to identify additional studies. RESULTS: Details on specific accommodations described in 117 articles were synthesized and organized into three groups comprised of a total of 12 categories. The majority of studies did not rigorously evaluate effectiveness or cost-effectiveness of the accommodations under study. CONCLUSIONS: This evidence synthesis provides an overview of the peer-reviewed literature of value to occupational rehabilitation professionals and employers seeking guidance on workplace accommodation policies and practices for persons with physical disabilities. A wide range of accommodation options is available for addressing physical, social, and attitudinal barriers to successful employment. Besides physical/technological modifications, accommodations to enhance workplace flexibility and worker autonomy and strategies to promote workplace inclusion and integration are important. More comprehensive reporting and evaluations of the effectiveness of accommodations in research literature are needed to develop best practices for accommodating persons with disabilities. Implications for rehabilitation There is a substantial peer-reviewed literature that provides insights into the barriers for persons with physical disabilities and the workplace accommodation practices to address them, though rigorous evaluations of effectiveness and cost effectiveness are uncommon. Attitudinal and social barriers stemming from stereotypes, ignorance and lack of knowledge are as important as physical barriers to employment for persons with physical disabilities. In addition to physical/technological modifications, accommodations to enhance workplace flexibility and autonomy of a worker, as well as strategies to promote workplace inclusion and integration may facilitate successful employment of persons with physical disabilities. PMID- 27936969 TI - The impact of stroke on female sexuality. AB - PURPOSE: The purpose of this study was to explore the impact of stroke on female sexuality from the perspective of women who have had a stroke. METHOD: A descriptive qualitative study. Nine female stroke survivors living in metropolitan and surrounding districts of Sydney, Australia took part in semi structured conversational interviews. The mean length of time from stroke onset to interview was around 6 years and 2 months (range 1 year, 2 months to 15 years, 9 months). The interviews were digitally recorded and transcribed. The transcripts were systematically analysed using inductive thematic analysis. RESULTS: The women experienced many and varied bodily alterations as a consequence of stroke which impacted negatively on their sexuality. These bodily alterations impacted on female sexuality in two ways: one was as an assault on the female sense of self and the other was by limiting possibilities for enacting female sexuality. CONCLUSION: Stroke impacts on female sexuality through bodily alterations and their consequences and because sexuality is important to female stroke survivors, it should be addressed as part of person-centred rehabilitation. Implications for Rehabilitation Sexuality is about much more than just "having sex" and is important to female stroke survivors. Stroke impacts on female sexuality through bodily alterations and their consequences. Understanding the impact of stroke on female sexuality is a step towards more person-centred rehabilitation. PMID- 27936970 TI - Corrigendum. PMID- 27936971 TI - Drug reaction with eosinophilia and systemic symptoms (DRESS): incidence, pathogenesis and management. AB - INTRODUCTION: Drug-induced hypersensitivity syndrome(DiHS), often referred to as drug reaction with eosinophilia and systemic symptoms (DRESS), is a life threatening multi-organ system reaction induced by drugs and associated with sequential reactivations of herpesviruses. This syndrome has several unique features, creating uncertainty over whether it represents true drug eruption. Areas covered: A literature review of all the cases was made by a Pub Med search. The delayed onset, paradoxical worsening of clinical symptoms after withdrawal of the causative drug and unexplained cross-reactivity to multiple drugs are unique features of this syndrome, which could prompt infection to be an initial consideration. Regulatory T cells (Tregs) are expanded at the acute stage but, upon clinical resolution, their function become gradually defective. Because such a gradual loss of Treg function occurring after resolution of DiHS/DRESS could increase the risk of developing autoimmune sequelae, systemic corticosteroids administered during the acute stage may serve to prevent not only tissue damage but also the gradual loss of Treg function by restoring the impaired Treg activity. Expert opinion: Systemic corticosteroids give promising results in terms of not only alleviating a variety of clinical symptoms at the acute stage but also of preventing the generation of autoimmune responses occurring at the resolution stage. PMID- 27936972 TI - Fixed combination calcipotriol plus betamethasone dipropionate aerosol foam in the treatment of psoriasis vulgaris: rationale for development and clinical profile. AB - INTRODUCTION: Psoriasis is a chronic, immune-mediated inflammatory disorder with a significant negative impact on quality of life. Most patients with mild-to moderate psoriasis manage their disease with topical therapies; the most commonly used formulations contain corticosteroids and/or vitamin D3 analogues. However, adherence to topical treatment remains a significant issue as the daily treatment regimen can be cumbersome and time consuming and many patients do not obtain complete/almost complete clearance. Areas covered: Published pre-clinical and clinical data evaluating calcipotriol 50 ug/g (Cal) and betamethasone 0.5 mg/g as dipropionate (BD) aerosol foam in patients with psoriasis. Expert opinion: Cal/BD aerosol foam, a once-daily, alcohol-free, paraffin-based vehicle with emollient properties, was developed to increase the therapeutic options available to patients. Cal/BD aerosol foam is rapidly effective for treating psoriasis and the greater efficacy compared with the ointment and gel formulations is consistent and clinically relevant. This enhanced efficacy is due to improved skin penetration of the active ingredients following the formation of a stable supersaturated solution on the skin. Studies have shown increasing patient satisfaction with Cal/BD aerosol foam. It is hoped that this optimized formulation of Cal/BD will improve adherence and help to address the unmet medical needs of patients with mild-to-moderate psoriasis. PMID- 27936973 TI - Premature chromatid separation and altered proliferation of human leukocytes treated with vanadium (III) oxide. AB - Vanadium is a widely distributed metal in the Earth's surface and is released into the environment by either natural or anthropogenic causes. Vanadium (III) oxide (V2O3) is present in the environment, and many organisms are exposed to this compound; however, its effects at the cellular and genetic levels are still unknown. Therefore, in this study, the ability of V2O3 to induce chromosomal damage and impair cell proliferation was tested on human leukocytes in vitro. The cultures cells were treated for 48 h with different concentrations 2, 4, 8 or 16 MUg/mL of V2O3, and we use the sister chromatid exchange's (SCE) test and the viability assay to evaluate the effects. In the results, no change was observed in either the viability or the frequency of SCE; however, a significant increase was observed in the incidence of premature chromatid separation (PCS), and a decrease was observed in both the mitotic index (MI) and the replication index (RI). Therefore, it can be suggested that V2O3 induces a genotoxic effect at the centromere level, indicating that it is a cause of aneuploidy that is capable of altering cell cycle progression. PMID- 27936974 TI - The practical management of chronic hepatitis C infection in Japan - dual therapy of daclatasvir + asunaprevir. AB - INTRODUCTION: Without treatment, many of the 200 million people worldwide with chronic hepatitis C virus (HCV) infection will develop cirrhosis or liver cancer. Japan was the first nation to approve an interferon-free therapy for HCV, and sustained viral response (SVR) rates >90% have been achieved with asunaprevir, a protease inhibitor, plus daclatasvir, an inhibitor of the non-structural 5A (NS5A) protein. Areas covered: This review provides an overview of the results from both clinical trials and real world experience with asunaprevir and daclatasvir therapy focused primarily on Japan. A literature search using the keywords 'asunaprevir,' 'daclatasvir,' 'interferon-free therapy,' and 'direct acting antiviral drugs' was initially used to select relevant literature for inclusion in the review. Expert commentary: While not approved in the United States, dual therapy with asunaprevir plus daclatasvir has already been successfully used in Japan and throughout East Asia to treat many thousands of patients. Pre-existing or treatment-emergent NS5A-Y93 or -L31 resistance associated variants (RAVs) may lead to viral breakthrough, and alternative therapies should be considered for these patients, but patients who harbor NS5A RAVs only at low frequency are likely to achieve SVR. The therapy has also been shown to be safe and effective with renal dysfunction or liver cirrhosis. PMID- 27936975 TI - Asthma phenotypes in children and stratified pharmacological treatment regimens. AB - INTRODUCTION: Asthma is the most common inflammatory disease in childhood. The interaction of genetic, environmental and host factors may contribute to the development of childhood asthma and defines its progress, including persistence and severity. Until now, various classifications of childhood asthma phenotypes have been suggested based on patient's age during onset of symptoms, type of inflammatory cells, response to treatment and disease severity. Many efforts have been carried out to identify childhood asthma phenotypes and to clarify which are the risk factors that define asthma prediction and the response to therapy. The identification of asthma phenotypes has not only prognostic but also therapeutic role. However, the classification of asthma phenotypes is complex due to the heterogeneity of the disease. Areas covered: The current childhood asthma phenotypes and the new therapeutic strategies for each phenotype are reviewed. Expert commentary: There are multiple phenotypes in childhood asthma and it is crucial to define them before the initiation of personalized treatment. Both the therapeutic strategy and monitoring should follow the recent guidelines. PMID- 27936976 TI - Exon skipping: a first in class strategy for Duchenne muscular dystrophy. AB - INTRODUCTION: Exon skipping is a therapeutic approach for Duchenne muscular dystrophy (DMD) that has been in development for close to two decades. This approach uses antisense oligonucleotides (AONs) to modulate pre-mRNA splicing of dystrophin transcripts to restore the disrupted DMD reading frame. The approach has moved from in vitro proof of concept studies to the clinical trial phase and marketing authorization applications with regulators. The first AON (eteplirsen) has recently received accelerated approval by the Food and Drug Administration in the US. Areas covered: In this review the authors explain the antisense-mediated exon skipping approach, outline how it needs be tailored for different DMD mutation types and describe the challenges and opportunities for each mutation type. The authors summarize the clinical development of antisense-mediated exon 51 skipping, and discuss methods to improve efficiency. Finally, the authors provide their opinion on current developments and identify topics for future prioritization. Expert opinion: Exon skipping development has been a learning experience for all those involved. Aside from an approved therapy, its development has yielded side benefits including the development of tools for clinical trials and has increased collaboration between academics, patients, industry and regulators. PMID- 27936977 TI - Tanezumab in the treatment of chronic musculoskeletal conditions. AB - INTRODUCTION: The management of pain associated with chronic musculoskeletal conditions represents a significant challenge for the clinician. There remains a need for novel medications that have a significant analgesic benefit and are also safe and well tolerated. Both pre-clinical and clinical data have provided evidence of the role of nerve growth factor (NGF) in a multitude of pain eliciting conditions. Therefore, the development of monoclonal antibodies to NGF for chronic painful musculoskeletal conditions has generated interest. Areas covered: This manuscript is a review that examines both the pharmacological properties and clinical studies of tanezumab, the most widely studied antibody to NGF, for management of osteoarthritis (OA) and low back pain. In addition, the safety and tolerability profile and development history of tanezumab are also discussed. Expert opinion: Most studies provide strong support for the ability of tanezumab to provide clinically meaningful pain relief in individuals with these conditions, with longer-term studies suggesting durability of effect. The adverse event profile appears favorable, assuming the risk mitigation strategies are effective at reducing the incidence of joint-related side effects. Further data are being collected to define the optimal dose and dosing strategy in both OA and chronic low back pain. PMID- 27936979 TI - Thrombocytopenia and infections. AB - INTRODUCTION: Acquired thrombocytopenia recognizes a myriad of causes. Among these, infectious diseases play a relevant role since a low platelet count is commonplace along with other abnormal laboratory data. Areas covered: This narrative review, after a brief presentation of the possible pathogenic mechanisms, is focused on the most prevalent infections associated with thrombocytopenia, namely those attributable to hepatitis C virus (HCV), human immunodeficiency virus (HIV) and Helicobacter pylori. Expert commentary: An underlying HCV or HIV infection should always be suspected in patients at risk who present with isolated thrombocytopenia. The eradication of Helicobacter pylori is advisable in infected patients with secondary immune thrombocytopenia, because this will increase the platelet count in a substantial number of cases, thus avoiding more aggressive and prolonged treatments. PMID- 27936978 TI - Mature aggressive B-cell lymphoma across age groups - molecular advances and therapeutic implications. AB - INTRODUCTION: Mature B-cell lymphoma represents the most common type of Non Hodgkin lymphoma, and different subtypes prevail at different patient ages. Areas covered: We review recent data on differences and commonalities in mature B-cell lymphoma occurring in adult and pediatric patients, with a special emphasis on molecular advances and therapeutic implications. To this end, we will discuss knowledge on diffuse large B-cell lymphoma and Burkitt lymphoma/leukemia, which are the most frequent subtypes in adult and pediatric patients, respectively, and on primary mediastinal B-cell lymphoma, which is a subtype of mature B-cell lymphoma occurring mainly in adolescents and young adults with a female predominance. Expert commentary: Molecular profiling has revealed molecular alterations that can be used to further classify the subtypes of mature B-cell lymphoma. These new subgroups frequently respond differentially to targeted therapeutic strategies. Future clinical trials utilizing new drugs will address this issue by combining clinical data and response assessment with a molecular workup of the corresponding lymphomas. PMID- 27936980 TI - Chronic lymphocytic leukemia and small lymphocytic lymphoma: two faces of the same disease. AB - INTRODUCTION: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are considered indolent lymphocytic malignancies, more often requiring active surveillance rather than intervention. Despite the indolent nature of CLL/SLL, treatment is likely indicated in a patients' lifetime. Recent changes in the therapeutic landscape have created more options to the clinician. Areas covered: The authors provide a broad assessment of the current state of disease, including the work-up, prognostic features, and mutational aspects of the disease that should be acknowledged when developing a rational treatment plan. Key studies, guideline recommendations, and expert analysis are used to create this update on CLL/SLL. Expert commentary: The recent pace of treatment additions in CLL/SLL is a welcome addition. Moving forward, it is anticipated that treatment modalities will continue to evolve, leading to additional management options that truly would define CLL/SLL as a chronic disease. PMID- 27936981 TI - The impact of price-cap regulations on market entry by generic pharmaceutical firms. AB - BACKGROUND: In 1998, the province of Ontario, Canada implemented price-cap '70/90' regulations: the first generic must be priced at <=70% of the associated brand-name price and subsequent generics must be priced at <=90% of the first generics' price. The price-cap was further lowered to 50% in 2006 and 25% in 2010 for all generic drugs regardless of the first or subsequent generic entrants. This study assessed the impact of such price-cap regulations on market entry by generic firms using the formulary database from 9 provinces (January 2004-March 2013). METHODS: A logistic regression was estimated to compare the probability of entry during the three policy periods in Ontario ('70/90', '25', versus '50'). Since different price-caps were subsequently introduced in other provinces, Alberta, British Columbia, New Brunswick and Saskatchewan, difference-in differences was used to compare market entry. RESULTS: In Ontario, compared with the period '50', generic firms were 76% and 63% less likely to enter markets in the periods '25' and '70/90', respectively. The difference-in-differences showed that the entry probability decreased the most in Ontario during the '25' period from the '50' period. CONCLUSION: Lowering the price-cap level to 25% leads to a significantly lower probability of market entry by generic firms. PMID- 27936983 TI - Molecular diagnosis of invasive mycoses of the central nervous system. AB - INTRODUCTION: In September 2012, the Centers for Disease Control and Prevention (CDC) began investigating an outbreak of fungal meningitis among patients who had received contaminated preservative-free methyl prednisolone acetate injections from the New England Compounding Center in Framingham, Massachusetts. Thousands of patients were potentially exposed to tainted corticosteroids, but establishing the diagnosis of fungal meningitis during the nationwide outbreak was difficult because little was known about the natural history of the disease. Areas covered: The challenges associated with this outbreak highlighted the need for rapid and reliable methodologies to assist in the diagnosis of invasive mycoses of the central nervous system (IMCNS), which may be devastating and difficult to treat. In this paper, we review the causative agents of these potentially-lethal infections, which include cryptococcal meningitis, cerebral aspergillosis, and hematogenous Candida meningoencephalitis. Expert commentary: While microscopy, culture, and histopathologic identification of fungal pathogens remain the gold standard for diagnosis, new platforms and species-specific assays have recently emerged, including lateral flow immunoassays (LFA), matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), and multiplex PCR in conjunction with magnetic resonance (MR) to potentially aid in the diagnosis of IMCNS. PMID- 27936984 TI - Development of oligonucleotides and multiplex probes for quick and accurate identification of wheat and Thinopyrum bessarabicum chromosomes. AB - In comparison with general FISH for preparing probes in terms of time and cost, synthesized oligonucleotide (oligo hereafter) probes for FISH have many advantages such as ease of design, synthesis, and labeling. Low cost and high sensitivity and resolution of oligo probes greatly simplify the FISH procedure as a simple, fast, and efficient method of chromosome identification. In this study, we developed new oligo and oligo multiplex probes to accurately and efficiently distinguish wheat (Triticum aestivum, 2n = 6x, AABBDD) and Thinopyrum bessarabicum (2n = 2x = 14, JJ) chromosomes. The oligo probes contained more nucleotides or more repeat units that produced stronger signals for more efficient chromosome painting. Four Th. bessarabicum-specific oligo probes were developed based on genomic DNA sequences of Th. bessarabicum chromosome arm 4JL, and one of them (oligo DP4J27982) was pooled with the oligo multiplex #1 to simultaneously detect wheat and Th. bessarabicum chromosomes for quick and accurate identification of Chinese Spring (CS) - Th. bessarabicum alien chromosome introgression lines. Oligo multiplex #4 revealed chromosome variations among CS and eight wheat cultivars by a single round of FISH analysis. This research demonstrated the high efficiency of using oligos and oligo multiplexes in chromosome identification and manipulation. PMID- 27936982 TI - MERS-CoV spike protein: a key target for antivirals. AB - INTRODUCTION: The continual Middle East respiratory syndrome (MERS) threat highlights the importance of developing effective antiviral therapeutics to prevent and treat MERS coronavirus (MERS-CoV) infection. A surface spike (S) protein guides MERS-CoV entry into host cells by binding to cellular receptor dipeptidyl peptidase-4 (DPP4), followed by fusion between virus and host cell membranes. MERS-CoV S protein represents a key target for developing therapeutics to block viral entry and inhibit membrane fusion. Areas covered: This review illustrates MERS-CoV S protein's structure and function, particularly S1 receptor binding domain (RBD) and S2 heptad repeat 1 (HR1) as therapeutic targets, and summarizes current advancement on developing anti-MERS-CoV therapeutics, focusing on neutralizing monoclonal antibodies (mAbs) and antiviral peptides. Expert opinion: No anti-MERS-CoV therapeutic is approved for human use. Several S targeting neutralizing mAbs and peptides have demonstrated efficacy against MERS CoV infection, providing feasibility for development. Generally, human neutralizing mAbs targeting RBD are more potent than those targeting other regions of S protein. However, emergence of escape mutant viruses and mAb's limitations make it necessary for combining neutralizing mAbs recognizing different neutralizing epitopes and engineering them with improved efficacy and reduced cost. Optimization of the peptide sequences is expected to produce next generation anti-MERS-CoV peptides with improved potency. PMID- 27936985 TI - T lymphocytes to predict radiation-induced late effects in normal tissues. AB - INTRODUCTION: Radiotherapy is one of the main treatments for solid tumors. The total dose that can be delivered to the tumor is limited by the radiation amount received by the surrounding normal tissues, which are at risk of developing acute and late radiation-induced effects. Areas covered: Severe late radiation-induced toxicity occurs in 5% to 10% of patients following radiotherapy. However, the current radiotherapy and radiation protection protocols do not take into account the variations in radiosensitivity among individuals. This review will focus on late radiotherapy-induced side effects and on the different cellular assays (gamma-H2AX/53BP1 focus formation, G2 metaphase, G0 micronucleus formation and radio-induced apoptosis in CD8+ T-lymphocytes: level I evidence) that have been developed to predict their occurrence in patients. Expert commentary: The routine prediction of late radiation-induced toxicity in normal tissues in the clinic will allow personalized radiotherapy with better outcome and less side effects. Patients at low risk of late toxicity could receive a higher total dose to the tumor. Conversely, patients at high risk of late toxicity should receive lower radiation doses per fraction, using state-of-the-art treatment techniques, or alternative therapies to avoid radiation-induced side effects. PMID- 27936986 TI - The use of modified-release methylphenidate in the treatment of attention deficit/hyperactivity disorder. AB - INTRODUCTION: Since Ritalin(r) (Methylphenidate-Immediate release or MPH-IR) was introduced for the treatment of attention-deficit/hyperactivity disorder, multiple formulations of MPH have been developed. The specific formulation determines the pharmacokinetic (PK) profile and the onset and duration of action for the compound. Areas covered: Aptensio XR(r) is a multilayer-release MPH (MPH MLR) consisting of an MPH-IR layer (40%) and an extended-release (ER) portion of 60% of MPH. It has an initial maximum MPH concentration at about two hours (h) and a second concentration peak at approximately 8 h. This formulation allows for a rapid onset of effect by 1 h and a duration of action through 12 h after dosing. The chemistry, PK, efficacy and adverse event profile of MPH-MLR will be reviewed. Expert commentary: Although the PK profile may prove beneficial to patients in the late afternoon and early evening, it is not clear if this is a significant advantage compared with other MPH-ER formulations. PMID- 27936987 TI - Residents' View of Quality in Ordinary Housing with Housing Support for People with Psychiatric Disabilities. AB - The aim of the present study was to investigate the quality of housing support provided in housing services for people with psychiatric disabilities living in ordinary housing with housing support from the residents' perspective, by using the QPC-H instrument. A sample of 174 residents in ordinary housing, receiving housing support from 22 housing support services in nine Swedish municipalities, participated in this study. The results show that the quality of psychiatric care in housing services was mainly rated highly as measured with the QPC-H instrument. The dimensions Encounter and Secluded Environment were the aspects that were rated as the two with the highest quality of housing service. The dimensions Participation and Secure Environment were rated as those with the lowest quality. There were more residents who totally disagreed with the statements in the dimensions Participation and Housing Specific than in the other dimensions. The perceived lower quality in Encounter, Participation, Support and the Housing Specific dimensions was associated with a low frequency of psychiatric outpatient clinic contacts. A conclusion is that the support staff could be more observant regarding the residents' need for support and also talk more with them about what could be done to assist them. It also seems important that the support staff discuss with the residents regarding how they can help them to feel more secure in their accommodation. PMID- 27936988 TI - Effect of fetal gender on induction of labor failure rates. AB - PURPOSE: To evaluate gender effect on induction of labor (IoL) failure rates stratified by indication to delivery. METHODS: Retrospective cohort analysis of singleton pregnancies 34-42 weeks undergoing cervical ripening using controlled release PGE2 vaginal insert. IoL Indications were divided into: (1) maternal; (2) hypertensive disorders; (3) premature rupture of membrane or (4) fetal (growth abnormalities, oligohydramnios, postdate, etc,). IoL failure was defined as: (1) Bishop-score <=7 after 24 hours of PGE2; (2) cesarean delivery due to failed induction; (3) fetal distress followed by PGE2 removal and emergent cesarean. IoL failure rates were stratified by neonatal gender and indication to induction. Logistic regression analysis was utilized to control outcomes to potential confounders. RESULTS: Overall, 1062 pregnancies were included - 521 (49%) had male fetuses. IoL indications did not differ by gender. IoL failure rate was 20.1% (213/1062) - 76% for unfavorable Bishop-score after PGE2 removal; 5.2% for failed induction and 18.8% for fetal-distress while on PGE2. Overall, 14.3% delivered by cesarean section. There were no differences in IoL failure as a group or by indications to induction stratified by fetal gender (21.7% vs. 18.5%, male vs. females, p < 0.05). CONCLUSIONS: IoL failure rate is not affected by fetal gender regardless of indication to induction. PMID- 27936989 TI - The regulatory mechanism of fungal elicitor-induced secondary metabolite biosynthesis in medical plants. AB - A wide range of external stress stimuli trigger plant cells to undergo complex network of reactions that ultimately lead to the synthesis and accumulation of secondary metabolites. Accumulation of such metabolites often occurs in plants subjected to stresses including various elicitors or signal molecules. Throughout evolution, endophytic fungi, an important constituent in the environment of medicinal plants, have known to form long-term stable and mutually beneficial symbiosis with medicinal plants. The endophytic fungal elicitor can rapidly and specifically induce the expression of specific genes in medicinal plants which can result in the activation of a series of specific secondary metabolic pathways resulting in the significant accumulation of active ingredients. Here we summarize the progress made on the mechanisms of fungal elicitor including elicitor signal recognition, signal transduction, gene expression and activation of the key enzymes and its application. This review provides guidance on studies which may be conducted to promote the efficient synthesis and accumulation of active ingredients by the endogenous fungal elicitor in medicinal plant cells, and provides new ideas and methods of studying the regulation of secondary metabolism in medicinal plants. PMID- 27936991 TI - Evaluation of interprofessional relational coordination and patients' perception of care in outpatient oncology teams. AB - This pilot study was designed to measure teamwork and the relationship of teamwork to patient perceptions of care among 63 members of 12 oncology teams at a Cancer Centre in the Midwest. Lack of teamwork in cancer care can result in serious clinical errors, fragmentation of care, and poor quality of care. Many oncology team members, highly skilled in clinical care, are not trained to work effectively as members of a care team. The research team administered the Relational Coordination survey to core oncology team members-medical oncologists, nurse coordinators, and clinical secretaries-to measure seven dimensions of team skills (four relating to communication [frequency, timeliness, accuracy, and problem solving] and three relating to relationship [shared goals, shared knowledge, and mutual respect]) averaged to create a Relational Coordination Index. The results indicated that among the team member roles, nurse coordinator relational coordination indices were the strongest and most positively correlated with patient perception of care. Statistically significant correlations were intra-nurse coordinator relational coordination indices and two patient perception of care factors (information and education and patient's preferences). All other nurse coordinator intra-role as well as inter-role correlations were also positively correlated, although not statistically significant. PMID- 27936990 TI - Improving postpartum glucose monitoring in women with gestational diabetes. AB - OBJECTIVE: To improve 6-week postpartum visit attendance, glucose test ordering and test completion among postpartum patients with a history of gestational diabetes (GDM). METHODS: Pre- and post-intervention GDM women at Mount Sinai Hospital were studied via chart review. Interventions included advanced order sets for glucose monitoring at the 35-week pregnancy visit, educational modules, and nutritionist phone calls reminding patients to attend postpartum visits fasting. RESULTS: One hundred and seven pre-intervention and 42 post-intervention women were studied. Percentages of orders placed for postpartum testing was higher post-intervention vs. pre-intervention (57% vs. 42%, p = 0.03). There were higher test completion rates post-intervention vs. pre-intervention (36% vs. 17%, p = 0.01). Postpartum visit attendance rates did not vary between the groups (73% vs. 69% p = 0.60). Six percent of patients pre-intervention fasted for postpartum visits vs. 60% post-intervention. CONCLUSION: There was no observed increase in women attending their 6-week postpartum visits, yet rates of completed orders for postpartum testing, women attending visits fasting, and postpartum test completions were higher post-intervention. More research may identify the barriers to attendance at 6-week postpartum visits. PMID- 27936992 TI - The value of acute phase reactants in predicting preterm delivery. AB - OBJECTIVE: We aimed to determine the potential value of maternal serum levels of acute phase reactants in the prediction of preterm delivery in women with threatened preterm labor (TPL). METHODS: Ninety-one pregnant women diagnosed with TPL and 83 healthy pregnant women as a control group were included in this prospective controlled study. All the pregnant women were followed until delivery and obstetric data and the serum levels of acute phase reactants were recorded for each participant. The study group was further divided into two groups according to the gestational age at delivery, which include women delivering prematurely and the ones who gave birth at term. RESULTS: Serum albumin levels were significantly lower and mean serum ferritin levels were significantly higher in the study groups when compared the control group. CONCLUSION: Although an association between decreased serum albumin level and TPL, also between increased serum ferritin levels and preterm birth and low birth weight were demonstrated, more extensive studies are needed to clarify the potential use of the acute phase reactants in the prediction of preterm birth. PMID- 27936993 TI - Validation of the prediction model for success of vaginal birth after cesarean delivery at the university hospital in Barcelona. AB - OBJECTIVE: To validate the prediction model for successful vaginal birth after cesarean delivery (VBAC) based on variables easily obtainable at the first antenatal visit, in a Spanish population. METHODS: Retrospective observational study. Women with a single live fetus in cephalic presentation with one previous low-transverse CD who underwent trial of labor after cesarean delivery (TOLAC) at >=37 gestational weeks between January 2011 and December 2015 were identified in the hospital's information system. Their antenatal medical records and delivery summary reports were reviewed and individual probabilities of successful VBAC were calculated, according to a previously published model. These probabilities were categorized into deciles. For calibration, each decile of predicted probabilities was compared to the observed rates. To assess the accuracy of the prediction model, receiver operating characteristic curve was constructed and the area under the curve (AUC) was calculated. RESULTS: In total, 630 women who underwent TOLAC had all required information and were included in the study. Among them, 450 (71.4%) women had successful VBAC. The AUC was 0.70 (95% confidence interval 0.66-0.74). CONCLUSION: Prediction ability of the validated model was in agreement with the original study. PMID- 27936994 TI - Blood-based biomarkers of adverse perinatal outcomes in maternal obesity. AB - OBJECTIVE: Increasing maternal weight has been shown to predict adverse perinatal outcome, including increases in the relative risk of fetal death, stillbirth, neonatal death, perinatal death and infant death. In order to better understand the pathophysiological factors associated with obesity during pregnancy, the role of biomarkers associated with adverse outcomes in obese pregnant women is under investigation. The purpose of this review study was to examine potential biomarkers that could serve as effective screening strategies in obese pregnant women to reduce fetal and neonatal morbidity, as well as maternal morbidity. METHODS: Electronic databases (Pubmed, Embase) were searched for previously published research studies that investigated biomarkers associated with perinatal outcomes in obese pregnant women and the putative mechanisms underlying biomarker effects on pregnancy outcomes. RESULTS: It is evident that while several biomarkers predict perinatal complications in obese pregnant women, none fulfilled the criteria to be considered clinically useful. CONCLUSION: There is a critical need for reliable blood-based biomarkers associated with an increased risk of adverse perinatal outcomes in obese pregnant women. PMID- 27936995 TI - Societal implications of medical insurance coverage for imatinib as first-line treatment of chronic myeloid leukemia in China: a cost-effectiveness analysis. AB - OBJECTIVES: Imatinib (Glivec) and nilotinib (Tasigna) have been covered by critical disease insurance in Jiangsu province of China since 2013, which changed local treatment patterns and outcomes of patients with chronic myeloid leukemia (CML). This study evaluated the long-term cost-effectiveness of insurance coverage with imatinib as the first-line treatment for patients with CML in China from a societal perspective. METHODS: A decision-analytic model based on previously published and real-world evidence was applied to simulate and evaluate the lifetime clinical and economic outcomes associated with CML treatments before and after imatinib was covered by medical insurance. Incremental cost effectiveness ratio (ICER) was calculated with both costs and quality-adjusted life years (QALYs) discounted at 3% annually. Different assumptions of treatment benefits and costs were taken to address uncertainties and were tested with sensitivity analyses. RESULTS: In base case analysis, both cost and effectiveness of CML treatments increased after imatinib was covered by the medical insurance; on average, the incremental QALY and cost were 5.5 and Y277,030 per patient in lifetime, respectively. The ICER of insurance coverage with imatinib was Y50,641, which is less than the GDP per capita of China. Monte Carlo simulation resulted in the estimate of 100% probability that the insurance coverage of imatinib is cost-effective. Total cost was substantially saved at 5 years after patients initiated imatinib treatment with insurance coverage compared to no insurance coverage, the saved cost at 5 years was Y99,565, which included the cost savings from both direct (e.g. cost of bone marrow or stem cell transplant) and indirect costs (e.g. productivity loss of patients and care-givers). CONCLUSIONS: The insurance coverage of imatinib is very cost-effective in China, according to the local cost and clinical data in Jiangsu province. More importantly, the insurance coverage of imatinib and nilotinib have changed the treatment patterns of CML patients, thus dramatically increasing life expectancy and quality-of-life (QoL) saving on productivity losses for both CML patients and their caregivers. PMID- 27936996 TI - A review of benefits of cord milking over delayed cord clamping in the preterm infant and future directions of research. AB - PURPOSE OF REVIEW: The recommended method of handling the umbilical cord has undergone a complete 360 degrees turn over the years and current knowledge and research has led the direction to delayed clamping and cord milking. This practice has also been supported by American College of Obstetrics and Gynecology (ACOG) in 2012. This review is a summary of current evidence on delayed cord clamping (DCC), umbilical cord milking (UCM), and comparison between the two and future directions. RECENT FINDINGS: Multiple studies have been published establishing the safety of umbilical cord milking. Data comparing UCM to DCC favor milking specifically in terms of improved systemic perfusion and higher hemoglobin concentrations. SUMMARY: UCM is emerging as a safe, quick alternative to DCC and more advantageous especially among premature infants and those delivered via cesarean section. PMID- 27936997 TI - Smoking and placenta previa: a meta-analysis. AB - OBJECTIVE: Previous studies found a positive association between placenta previa and smoking during pregnancy. However, the results of these studies are inconsistent. The aim was to perform meta-analysis of the association between smoking during pregnancy and placenta previa. METHODS: Major electronic databases, including PubMed, Web of Science, and Scopus were searched until June 2015. The heterogeneity across studies was explored by Q-test and I2 statistic. The possibility of publication bias was assessed using Begg's and Egger's tests. The results were reported using odds ratio (OR) estimate with its 95% confidence intervals using a random-effects model. RESULTS: The literature search yielded 991 publications until October 2015 with 9,094,443 participants. Based on the random effect model, compared to nonsmoker women, the estimated OR and RR of placenta previa was 1.42 (95% CI: 1.30, 1.54) and 1.27 (95% CI: 1.18, 1.35), respectively. CONCLUSIONS: There is sufficient documents based on the observational studies that smoking during pregnancy is significantly associated with an increased risk of placenta previa. Therefore, smoking during pregnancy can be considered as a predictor of placenta previa. PMID- 27936998 TI - A comparison of maternal and perinatal outcome between in vitro fertilization and spontaneous dichorionic-diamniotic twin pregnancies. AB - OBJECTIVE: To compare the maternal and neonatal outcome of dichorionic diamniotic in vitro fertilization (IVF) twin and spontaneous twin pregnancies. MATERIAL AND METHODS: Maternal and fetal data of all consecutive dichorionic-diamniotic twin pregnancies delivered in our institution between January 2009 and May 2015 were abstracted from medical records and pregnancy outcome of IVF twin was compared to spontaneous twin. RESULTS: Overall 708 twin pregnancies (449 IVF and 259 spontaneous) were included. Women in the IVF group were 2 years older and more frequently nulliparous. The rate of pregnancy induced hypertension and preeclampsia (PIH/PET) was three times higher in the IVF group than in the spontaneous group. The rate of preterm births, before 37 weeks of gestation and the rate of cesarean section were higher in the IVF group. These results were confirmed by multivariate analysis. The neonatal outcome was similar in both the groups except for a lower mean newborn birthweight in the IVF group. CONCLUSION: Women with IVF twins are at a significantly higher risk of having preterm births, PIH/PET and cesarean section but there was no significant adverse effect on neonatal outcome except for a lower mean newborn birth weight. PMID- 27937000 TI - Do Studies Evaluating QT/QTc Interval Prolongation with Dietary Supplements Meet FDA Standards: A Systematic Review. AB - PURPOSE: Dietary supplement use is continuously increasing, but the safety evaluation of these products remains partial. While dietary supplements have no mandate for assessing cardiovascular safety, all new drug entities (NDE) are required to undergo a thorough QT/corrected QT (QTc) assessment to determine their propensity to impact cardiac repolarization. Independent investigators and manufacturers of dietary supplements voluntarily initiate safety studies; however, the quality of these studies is controversial. We sought to compare studies evaluating the QT/QTc effects of dietary supplements based on the International Conference of Harmonization (ICH)-E14 recommendations for NDE. CASE SUMMARY: Twenty-six published dietary supplement studies assessed QT/QTc interval prolongation. Sample sizes ranged from nine subjects to 206 among the 15 crossover studies, six parallel design studies, and five observational studies. A plan to account for electrocardiogram (ECG) morphological abnormalities was included in 10 studies, and two studies reported cardiovascular adverse events. Eight studies found a significant change in QT/QTc intervals. CONCLUSIONS: The majority of studies included in this review contained many of the critical elements recommended by the ICH E14, which includes the U.S. Food and Drug Administration guidance document for QT/QTc interval assessment. Compared with the thorough QT (TQT) standards, studies are typically well performed but can be bolstered by some study design changes. More than 30% of the included studies showed some degree of ECG changes, suggesting the need for continued cardiovascular safety assessment of dietary supplements. PMID- 27936999 TI - Effect of single-pill irbesartan/amlodipine combination-based therapy on clinic and home blood pressure profiles in hypertension with chronic kidney diseases. AB - We examined the efficacy of single-pill irbesartan/amlodipine combination-based therapy for 12 weeks in 20 hypertensive chronic kidney disease (CKD) patients, by evaluating self-measured home blood pressure (BP) profile. The single-pill irbesartan/amlodipine combination-based therapy decreased clinic BP and home BP (morning, evening, and nighttime BPs), and improved within-visit clinic BP variability, day-by-day home BP variability (morning and evening), and nighttime home BP variability. Furthermore, the single-pill combination-based therapy reduced albuminuria and exerted improved parameters of vascular function. These results indicate that this single-pill combination-based therapy may exert beneficial effects on clinic and home BP profiles as well as on renal and vascular damages, in hypertension with CKD. PMID- 27937001 TI - Preventive Strategies and Processes to Counteract Bullying in Health Care Settings: Focus Group Discussions. AB - The aim of the present study was to explore preventive strategies and processes to counteract bullying in workplaces. Data were collected by individual interviews and focus group discussions at one hospital and two nursing home wards for elderly, a total of 29 participants. In the analysis of the interviews we were inspired by constructivist grounded theory. Persistent work with a humanistic value system by supervisor and coworkers, raising awareness about the bullying problem, strong group collaboration, and conflict management, along with an open atmosphere at the workplace, appears to be imperative for accomplishing a policy of zero tolerance for bullying. PMID- 27937002 TI - Comment on "the interaction of personality profile and lactation differs between mothers of late preterm and term neonates". PMID- 27937003 TI - Troponins, heat shock proteins and glycogen phosphorylase BB in umbilical cord blood of complicated pregnancies. AB - PURPOSE OF THE STUDY: Heat shock proteins (Hsp) are evolutionary conserved molecules with a chaperone role in cell survival. We hypothesized that cord blood concentrations of molecules reflecting fetal cardiac muscle insult, including Hsp, troponins cTnI and cTnT, and glycol-phosphorylase BB (GP-BB) would be elevated in pregnancies complicated by gestational diabetes (GDM) or preeclampsia (PIH) compared to healthy controls. MATERIALS AND METHODS: Pregnant women admitted for delivery at >28 weeks were divided into four groups: healthy patients delivered vaginally (VAG), healthy patients delivered by c-section (CS), patients with PIH, and patients with GDM. Demographics, clinical characteristics, and cord blood concentrations of Hsp, troponins cTnI and cTnT, and GP-BB were compared between groups. Statistical analyses included t-test, Chi square, and Wilcoxon rank sum as appropriate. RESULTS: cTnI concentrations were significantly higher in the PIH group compared to the GDM and VAG groups and they were higher in the CS group compared to the VAG group. Concentrations of Hsp70 were higher in the GDM group compared to the VAG and CS groups. Concentration of GP-BB was higher in the PIH group compared to the VAG group. CONCLUSIONS: GP-BB and cTNI are the most sensitive markers for PIH-related fetal myocyte injury as is Hsp70 in pregnancies complicated by GDM. PMID- 27937004 TI - Detecting signatures of selection within the Tibetan sheep mitochondrial genome. AB - Tibetan sheep, a Chinese indigenous breed, are mainly distributed in plateau and mountain-valley areas at a terrestrial elevation between 2260 and 4100 m. The herd is genetically distinct from the other domestic sheep and undergoes acclimatization to adapt to the hypoxic environment. To date, whether the mitochondrial DNA modification of Tibetan sheep shares the same feature as the other domestic breed remains unknown. In this study, we compared the whole mitogenome sequences from 32 Tibetan sheep, 22 domestic sheep and 24 commercial sheep to identify the selection signatures of hypoxic-tolerant in Tibetan sheep. Nucleotide diversity analysis using the sliding window method showed that the highest level of nucleotide diversity was observed in the control region with a peak value of pi = 0.05215, while the lowest pi value was detected in the tRNAs region. qPCR results showed that the relative mtDNA copy number in Tibetan sheep was significantly lower than that in Suffolk sheep. None of the mutations in 12S rRNA were fixed in Tibetan sheep, which indicated that there has been less artificial selection in this herd than the other domestic and commercial breeds. Although one site (1277G) might undergo the purifying selection, it was not identified as the breed-specific allele in Tibetan sheep. We proposed that nature selection was the main drive during the domestication of Tibetan sheep and single mutation (or locus) could not reveal the signature of selection as for the high diversity in the mitogenome of Tibetan sheep. PMID- 27937005 TI - Sorbus alnifolia protects dopaminergic neurodegeneration in Caenorhabditis elegans. AB - CONTEXT: The twigs of Sorbus alnifolia (Sieb. et Zucc.) K. Koch (Rosaceae) have been used to treat neurological disorders as a traditional medicine in Korea. However, there are limited data describing the efficacy of S. alnifolia in Parkinson's disease (PD). OBJECTIVE: This study was conducted to identify the protective effects of the methanol extracts of S. alnifolia (MESA) on the dopaminergic (DA) neurodegeneration in Caenorhabditis elegans. MATERIALS AND METHODS: To test the neuroprotective action of MESA, viability assay was performed after 48 h exposure to 1-methyl-4-phenylpyridine (MMP+) in PC12 cells and C. elegans (400 MUM and 2 mM of MMP+, respectively). Fluorescence intensity was quantified using transgenic mutants such as BZ555 (Pdat-1::GFP) and and UA57 (Pdat-1::GFP and Pdat-1::CAT-2) to determine MESA's effects on DA neurodegeneration in C. elegans. Aggregation of alpha-synuclein was observed using NL5901 strain (unc-54p::alpha-synuclein::YFP). MESA's protective effects on the DA neuronal functions were examined by food-sensing assay. Lifespan assay was conducted to test the effects of MESA on the longevity. RESULTS: MESA restored MPP+-induced loss of viability in both PC12 cells and C. elegans (85.8% and 54.9%, respectively). In C. elegans, MESA provided protection against chemically and genetically-induced DA neurodegeneration, respectively. Moreover, food sensing functions were increased 58.4% by MESA in the DA neuron degraded worms. MESA also prolonged the average lifespan by 25.6%. However, MESA failed to alter alpha-synuclein aggregation. DISCUSSION AND CONCLUSIONS: These results revealed that MESA protects DA neurodegeneration and recovers diminished DA neuronal functions, thereby can be a valuable candidate for the treatment of PD. PMID- 27937007 TI - Hemoglobin amino acids by the numbers. PMID- 27937006 TI - Combination of real-time PCR and sequencing to detect multiple clinically relevant genetic variations in the lactase gene. AB - BACKGROUND: Lactase persistence is an autosomal dominant trait commonly distributed in Europe as well as some parts of east Africa and the Arabian Peninsula. Using real-time PCR to detect the -13910C > T variant common in the European population is a reliable analysis although other variants in the probe binding site may cause errors in analysis. The aim of this study was to determine the prevalence of the variants in a Danish cohort examined for lactose intolerance as well as to improve the real-time PCR analysis for detection of the different variants. METHODS: We genotyped 3395 routine samples using real-time PCR for the -13910C > T-variant. All consecutive samples identified as -13910CC were sequenced using Sanger Sequencing. Using the SDS software we examined various quality value settings to improve on the genetic analysis. RESULTS: Using real-time PCR resulted in 100% successful genotyping of the -13910C > T variant. By using a quality value of 99% and sequencing the undetermined samples we improved the ability of the assay to identify variants other than -13910C > T. This resulted in a reduction of the diagnostic error rate by a factor of 2.4 while increasing the expenses only 3%. CONCLUSIONS: We conclude that using a quality value of 99% in the SDS software significantly improves the diagnostic efficiency of the real-time PCR assay for detecting variants associated to lactase persistence. PMID- 27937008 TI - Abnormal leukocyte scattergrams and immature platelet fraction on Sysmex XN-9000 analyzer: a new diagnostic tool for altered megakaryopoiesis? PMID- 27937010 TI - High occurrence of length heteroplasmy in domestic Bactrian camel (Camelus bactrianus). AB - Heteroplasmy is the presence of more than one mitochondrial DNA (mtDNA) variant within a cell, tissue, or individual. In this study, sequence variation was investigated in the control region (CR) of mitochondrial DNA (mtDNA) from 135 individuals belonging to five primary domestic Bactrian camel breeds in China and Mongolia. Due to variation of the repeat unit G(T/C)(AC)n, length heteroplasmy was detected within each camel by direct sequencing and fragment analysis. A high occurrence of mtDNA heteroplasmy, up to 100 percentages was observed in five camel populations. Our study provides the first evidence of extensive length heteroplasmy in Bactrian camels. PMID- 27937009 TI - The anti-arthritic activity of total glycosides from Pterocephalus hookeri, a traditional Tibetan herbal medicine. AB - CONTEXT: Pterocephalus hookeri (C. B. Clarke) Hock., a traditional Tibetan herbal medicine rich in glycosides, has been used to treat several diseases including rheumatoid arthritis. OBJECTIVE: To evaluate the anti-arthritic activity of total glycosides from P. hookeri, and its possible mechanisms of action. MATERIALS AND METHODS: Anti-arthritic activity of total glycosides from P. hookeri (oral administration for 30 days at 14-56 mg/kg) was evaluated using paw swelling, arthritis scores and histopathological measurement in adjuvant-induced arthritis (AA) Sprague-Dawley rats. The NF-kappaB p65 expression in synovial tissues, and serum superoxide dismutase (SOD) activity, malondialdehyde (MDA) and nitric oxide (NO) levels was measured in AA rats, respectively. Further assessment of anti inflammatory and analgesic activities of these glycosides were carried out using inflammation and hyperalgesia models induced by xylene, carrageenan, agar and acetic acid, respectively. RESULTS: Total glycosides (56 mg/kg) decreased the paw swelling (38.0%, p < 0.01), arthritis scores (25.3%, p < 0.01) and synovial inflammation in AA rats. The glycosides significantly (p < 0.05-0.01) attenuated the inflammation induced by xylene, carrageenan, acetic acid and agar, increased the pain threshold in acetic acid-induced writhing in mice and mechanical stimuli induced hyperalgia in AA rats. The glycosides (14, 28, 56 mg/kg) also suppressed the NF-kappaB p65 expression (33.1-78.2%, p < 0.05-0.01), reduced MDA (21.3 35.9%, p < 0.01) and NO (20.3-32.4%, p < 0.05-0.01) levels, respectively, enhanced the SOD activity (7.8%, p < 0.05) at 56 mg/kg in AA rats. DISCUSSION AND CONCLUSION: Our findings confirmed the anti-arthritic property of the total glycosides from P. hookeri, which may be attributed to its inhibition on NF kappaB signalling and oxidative stress. PMID- 27937012 TI - Planning for the unexpected: Ebola virus, Zika virus, what's next? AB - Since 2000 we have witnessed global pandemics and public health emergencies of international concern. This review details which viruses are likely to caused further outbreaks and looks at the strategies and tools available to UK medical professionals to mitigate the threat posed. PMID- 27937011 TI - Effects and mechanisms of pirfenidone, prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models. AB - CONTEXT: Previous studies have reported that caveolin-1 (Cav-1) is associated with lung fibrosis. However, the role of Cav-1 expression in pirfenidone-treated idiopathic pulmonary fibrosis (IPF) is unknown. OBJECTIVE: This study investigated Cav-1 expression in pirfenidone-treated IPF, and compared the effects of pirfenidone with acetylcysteine and prednisone on IPF. MATERIALS AND METHODS: Rat IPF model was established by endotracheal injection of 5 mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone (P, 100 mg/kg once daily), prednisone (H, 5 mg/kg once daily) and acetylcysteine (N, 4 mg/kg 3 times per day) were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without IPF were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real time quantitative PCR and Western blot; the expression of tumour necrosis factor alpha (TNF-alpha), transforming growth factor-beta1 (TGF-beta1) and platelet derived growth factor (PDGF) was determined by enzyme-linked immunosorbent assay. RESULTS: After 15, 30 and 45 days of drug treatment, comparison of the three drug treated groups with the model group showed significantly lower (p < 0.05) significance of airsacculitis and fibrosis scores of lung tissues, as well as expression of TGF-beta1, TNF-alpha and PDGF, but the expression of Cav-1 was higher (p < 0.05). Compared with the N group, the fibrosis score was significantly lower and the protein expression of Cav-1 was significantly higher in the P group (p < 0.05). Additionally, the expression of Cav-1 was negatively correlated with the airsacculitis and fibrosis scores (r = -0.506, p < 0.01; r = 0.676, p < 0.01) as well as expression of TGF-beta1, TNF-alpha and PDGF (r = 0.590, p < 0.01; r = -0.530, p < 0.01; r = -0.553, p < 0.01). DISCUSSION AND CONCLUSION: Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and pulmonary fibrosis in rat IPF models, which may be related with enhanced caveolin-1, reduced TNF-alpha, TGF-beta1, PDGF. PMID- 27937014 TI - A role for mycobacterial blood culture and molecular analysis of lymph node tissue. PMID- 27937015 TI - A ward round proforma improves documentation and communication. AB - This article present the results of an audit cycle which evaluated the quality of inpatient ward round documentation in a busy district general hospital before and after the implementation of a standardized proforma which was specifically designed for trauma and orthopaedic patients. In each cycle, 20 case notes were examined and the data analysed to examine three main areas: Diagnosis, management and/or discharge plan Objective assessments including neurovascular status, weight-bearing status, surgical wound review, observations, results of investigations and decision from the daily trauma meeting Logistics of the documentation such as legibility, date and time, name and grade of the doctor and contact number. This audit demonstrated that using a ward round proforma can significantly enhance the quality of documentation and improve communication between multidisciplinary team members. PMID- 27937016 TI - M*A*S*H and malaria: the career resonance of a BJHM elective in 1993. PMID- 27937017 TI - Maternity triage: a guide for trainees. PMID- 27937018 TI - Biofilms: prevention and treatment. AB - Biofilms are a major aetiological factor in many infections. Bacteria growing within a biofilm are extremely resilient to standard antimicrobials; biofilm associated infections are thus challenging to treat. Understanding how and why biofilms form can improve prevention and management of biofilm infections. PMID- 27937021 TI - Incidental non-functional ectopic thyroid in a returning traveller. PMID- 27937019 TI - Upper gastrointestinal bleeding caused by fistula of the stomach and splenic artery pseudoaneurysm. PMID- 27937022 TI - Causes and management of facial nerve palsy. AB - Facial nerve palsy causes disfigurement with cosmetic, functional and psychological repercussions. The facial nerve can be affected anywhere along its course. A comprehensive assessment considering all differential diagnoses is critical to optimal management, as prompt, appropriate therapy leads to better outcomes. PMID- 27937023 TI - Internal carotid artery dissection. AB - Internal carotid artery dissection is an important cause of ischaemic stroke in those aged under 50 years. Awareness of the clinical features is crucial as they may offer the opportunity to intervene to reduce strokes occurring or recurring. PMID- 27937024 TI - A rare case of congenital heart disease with first presentation in adulthood. PMID- 27937025 TI - Sir William Gull: distinguished physician. PMID- 27937026 TI - Palliative care in the emergency department: avoidable or appropriate? PMID- 27937027 TI - Prevention and management of venous thromboembolism in pregnancy. PMID- 27937028 TI - A patient-centred approach to diversity. PMID- 27937030 TI - Cochlear implantation: a review of current clinical practice. AB - Cochlear implants treat severe hearing loss by providing direct electrical stimulation to auditory nerve endings. This article reviews the clinical assessment, surgical procedure and outcomes, and looks at newer developments such as preservation of residual hearing and bilateral implantation. PMID- 27937029 TI - Clinical examination and management of the dizzy patient. AB - Dizziness is the commonest reason for a GP appointment over the age of 75 years and many dizzy patients will end up in hospital. This article introduces the range of vestibular disorders commonly seen in hospital practice with a symptom based approach and discusses the range of treatments that might be considered. PMID- 27937031 TI - Pre-pregnancy care for women with diabetes mellitus. PMID- 27937033 TI - Epidemiology of Uveitis in a Tertiary-care Referral Institute in North India. AB - PURPOSE: To report epidemiology of uveitis in a tertiary-care referral institute in North India. METHODS: Hospital records of patients with uveitis between June 2011 and September 2014 were retrospectively analyzed. RESULTS: Of the 1912 patients, 56.64% were males. Anterior uveitis (43.04%) was the most common manifestation followed by posterior uveitis (24.58%), panuveitis (16.21%), and intermediate uveitis (10.66%). Specific etiologies could be ascertained in 60.56%. Tuberculosis (22.9%) was the most common infectious and HLA-B27 associated uveitis (9.46%) among non-infectious causes. CONCLUSIONS: There is a trend towards a decrease in idiopathic etiologies of uveitis. Tuberculosis remains the most common infectious etiology in North India. PMID- 27937032 TI - Effects of naringin on physical fatigue and serum MMP-9 concentration in female rats. AB - CONTEXT: Oxidative stress has a critical role in the development of physical fatigue and activation of matrix metalloproteinases-9 (MMP-9). Naringin (Nar) is a bioflavonoid that has antioxidant activity and suppresses MMP-9 expression. OBJECTIVE: The present study evaluates the anti-fatigue activity of Nar on physical fatigue and serum MMP-9 concentration in rats. MATERIALS AND METHODS: Fifty female Wistar rats were randomly divided into five groups (n = 10); a control group, vehicle group and three Nar treatment groups. The Nar treated groups received different doses of Nar (40, 80 and 160 mg/kg/day) for 30 days. On the 30th day, rats were sacrificed immediately after exhaustive swimming test. Serum MMP-9 concentration and several biochemical parameters related to fatigue were measured. RESULTS: Exhaustive swimming time in the Nar-80 group significantly increased 1.78-, 1.53-, 1.5- and 1.3-fold compared with the control, vehicle, Nar-40 and Nar-160 groups, respectively. In addition, exhaustive swimming time in the Nar-160 group significantly increased 1.36-fold compared with the control group. Nar-80 significantly decreased LDH activity by 60.45% and 57.47% compared with the vehicle and control groups, respectively. Furthermore, Nar-80 and Nar-160 increased blood glucose levels by 19.56% and 18.38% compared with the control group, respectively. Nar-80 and Nar-160 significantly decreased serum MMP-9 concentration by 61.57% and 83.39% compared with the control group, respectively. CONCLUSION: Based on our data, Nar has anti fatigue effects which may be attributed to its property in modulating energy metabolism and reducing serum MMP-9 concentration. Thus, Nar may be a promising agent for the treatment of physical fatigue. PMID- 27937034 TI - Phytochemical analysis and antioxidant activity of Lycium barbarum (Goji) cultivated in Greece. AB - CONTEXT: The fruit of Lycium barbarum L. (Solanaceae), known as goji berry, has been exploited for a long time in traditional Chinese medicine. In recent decades, it has received much attention as one of the trendiest functional foods with a wide array of pharmacological activities in Western diets. OBJECTIVE: In this study the phenolic profile and potential antioxidant capacity of Lycium barbarum cultivated in Crete (Greece) were investigated. MATERIALS AND METHODS: The berries were defatted with hexane and then extracted with dichloromethane and methanol using a Soxhlet apparatus. Furthermore, the methanol extract was fractionated with ethyl acetate and butanol. All fractions/extracts were tested for their antioxidant activity (DPPH, FRAP, chemiluminescence). Folin-Ciocalteu and LC-DAD-MS analyses were utilized for the identification of the phenolic compounds. RESULTS: The total phenolic content ranged from 14.13 +/- 0.40 (water fraction) to 109.72 +/- 4.09 (ethyl acetate fraction) mg gallic acid equivalent/g dry extract. Ethyl acetate extract exhibited the highest scavenging activities determined as EC50 (4.73 +/- 0.20 mg/mL) and IC50 (0.47 +/- 0.001 mg/mL) using DPPH and chemiluminescence assays. Seventeen phenolic compounds, including cinnamoylquinic acids and derivatives, hydrocinnamic acids and flavonoid derivatives, were tentatively identified. To the best of our knowledge, quercetin 3-O-hexose coumaric ester and quercetin 3-O-hexose-O-hexose-O-rhamnose are reported for the first time in goji berry fruits. DISCUSSION AND CONCLUSION: The results of this study suggest that consumption of goji berry fruits could serve as a potential source of natural antioxidant compounds and that goji berry phenolic extracts could be exploited for nutritional pharmaceutical purposes. PMID- 27937035 TI - Synthesis and neuroprotective effects of the complex nanoparticles of iron and sapogenin isolated from the defatted seeds of Camellia oleifera. AB - CONTEXT: The defatted seeds of Camellia oleifera var. monosperma Hung T. Chang (Theaceae) are currently discarded without effective utilization. However, sapogenin has been isolated and shows antioxidative, anti-inflammatory and analgesic activities suggestive of its neuroprotective function. OBJECTIVE: In order to improve the activities of sapogenin, the nanoparticles of iron-sapogenin have been synthesized, and the neuroprotective effects are evaluated. MATERIALS AND METHODS: Structural characters of the nanoparticles were analyzed, and the antioxidant effect was assessed by DPPH method, and the neuroprotective effect was evaluated by rotenone-induced neurodegeneration in Kunming mice injected subcutaneously into the back of neck with rotenone (50 mg/kg/day) for 6 weeks and then treated by tail intravenous injection with the iron-sapogenin at the dose of 25, 50 and 100 mg/kg for 7 days. Mice behaviour and neurotransmitters were tested. RESULTS: The product had an average size of 162 nm with spherical shape, and scavenged more than 90% DPPH radicals at 0.8 mg/mL concentration. It decreased behavioural disorder and malondialdehyde content in mice brain, and increased superoxide dismutase activity, tyrosine hydroxylase expression, dopamine and acetylcholine levels in brain in dose dependence, and their maximum changes were respectively up to 60.83%, 25.17%, 22.13%, 105.26%, 42.17% and 22.89% as compared to vehicle group. Iron-sapogenin nanoparticle shows significantly better effects than the sapogenin. DISCUSSION AND CONCLUSION: Iron sapogenin alleviates neurodegeneration of mice injured by neurotoxicity of rotenone, it is a superior candidate of drugs for neuroprotection. PMID- 27937038 TI - Boston-keratoprosthesis for Idiopathic Limbal Stem Cell Deficiency. PMID- 27937036 TI - Gastroprotective activity of the resin from Virola oleifera. AB - CONTEXT: The resin from the trunk wood of Virola oleifera (Schott) A. C. Smith (Myristicaceae) is used in folk medicine to hasten wound repair and to treat pain and inflammatory conditions, and our previous report indicated the anti-oxidative properties in other oxidative stress model. OBJECTIVE: To investigate the protective effects of resin from V. oleifera in two experimental models of gastric ulcer oxidative-stress dependent. MATERIALS AND METHODS: Plant material was collected and the resin was subjected to partitioning with organic solvents. The buthanol fraction was subjected to chromatographic and spectrometric methods for isolation and structural elucidation. The resin was quantified for polyphenols and flavonoids by colorimetric methods. Furthermore, the antioxidant activity of resin was determined by three different methods. The ulcers were induced acutely in Swiss male mice with ethanol/HCl and indomethacin using single doses of 10 and 100 mg/kg. The gastroprotection of the experimental groups was comparable to reference control lansoprazole (3 mg/kg). RESULTS: The high content of polyphenols (~82%) and the presence of epicatechin and eriodictyol were determined. The LD50 was estimated at 2500 mg/kg. At minimum (10 mg/kg) and maximum (100 mg/kg) dosage of resin, both in ethanol/HCl as indomethacin ulcer induction models demonstrate reduction of lesions (minimum: ~97% and ~66%; maximum: ~95% and ~59%). DISCUSSION: The gastroprotection might be related to tannins, phenolic acids and flavonoids present in the resin by antioxidant properties. CONCLUSIONS: The results indicate that this resin has gastroprotective activity probably associated with the presence of phenolic antioxidant substances. PMID- 27937037 TI - GC-MS analysis and hepatoprotective activity of the n-hexane extract of Acrocarpus fraxinifolius leaves against paracetamol-induced hepatotoxicity in male albino rats. AB - CONTEXT: In Egypt, the burden of liver diseases is exceptionally high. OBJECTIVE: To investigate the components of the n-hexane extract of Acrocarpus fraxinifolius Arn. (Leguminosae) and its hepatoprotective activity against paracetamol (APAP) induced hepatotoxicity in rats. MATERIAL AND METHODS: TRACE GC ultra gas chromatogaphic spectrometry was used for extract analysis. Thirty albino rats were divided into six groups (five rats in each). Group 1 was the healthy control; Groups 2 and 3 were healthy treated groups (250 and 500 mg/kg b.w. of the extract, respectively) for seven days. Group 4 was hepatotoxicity control (APAP intoxicated group). Groups 5 and 6 received APAP + extract 250 and APAP + extract 500, respectively. RESULTS: Chromatographic analysis revealed the presence of 36 components. Major compounds were alpha-tocopherol (18.23%), labda 8 (20)-13-dien-15-oic acid (13.15%), lupeol (11.93%), phytol (10.95%) and squalene (7.19%). In the acute oral toxicity study, the mortality rates and behavioural signs of toxicity were zero in all groups (doses from 0 to 5 g/kg b.w. of A. fraxinifolius). LD50 was found to be greater than 5 g/kg of the extract. Only the high dose (500 mg/kg b.w.) of extract significantly alleviated the liver relative weight (4.01 +/- 0.06) and biomarkers, as serum aspartate aminotransferase (62.87 +/- 1.41), alanine aminotransferase (46.74 +/- 1.45), alkaline phosphatase (65.96 +/- 0.74), lipid profiles (180.39 +/- 3.51), bilirubin profiles (2.30 +/- 0.06) and hepatic lipid peroxidation (114.20 +/- 2.06), and increased body weight (11.58 +/- 0.20), serum protein profile (11.09 +/- 0.46) and hepatic total antioxidant capacity (23.78 +/- 0.66) in APAP-induced hepatotoxicity in rats. CONCLUSION: Our study proves the antihepatotoxic/antioxidant efficacies of A. fraxinifolius hexane extract. PMID- 27937039 TI - Effects of butanol fraction of Ziziphus mucronata root ethanol extract on glucose homeostasis, serum insulin and other diabetes-related parameters in a murine model for type 2 diabetes. AB - CONTEXT: Ziziphus mucronata Willd (Rhamnaceae) is currently used in Nigerian traditional treatment of diabetes mellitus. However, detailed information on the antidiabetic potential of the plant parts is presently unknown. OBJECTIVES: The present study investigated the antidiabetic effects of the butanol fraction of Z. mucronata root (ZMBF) in a type 2 diabetes (T2D) model of rats. MATERIALS AND METHODS: T2D was induced in rats by feeding a 10% fructose solution ad libitum for two weeks followed by an intraperitoneal injection of streptozotocin (40 mg/kg bw) and the animals were orally treated with ZMBF 150 or 300 mg/kg bw for five days a week for four weeks. Food and fluid intake, body weight changes and blood glucose levels were monitored during the experiment while other blood and organ specific diabetes-associated parameters were measured at the end of the experiment. RESULTS: After four-week treatment, significantly (p < 0.05) lower blood glucose (19.24 vs 28.96 mmol/L), improved glucose tolerance ability (21.26 vs 28.56 mmol/L), higher serum insulin (131.37 vs 64.20 pmol/L) and liver glycogen (2.40 vs 1.54 mg/g tissue) were observed in the 300 mg/kg ZMBF ingested group compared with the diabetic control group. However, food and fluid intake, body weight gain, HOMA-beta, HOMA-IR, serum fructosamine level, hepatic and renal function tests were not significantly (p > 0.05) affected by the treatment of ZMBF. CONCLUSION: Results of this study suggest that ZMBF treatment, at 300 mg/kg bw, possess antidiabetic activity, but could not ameliorate some diabetes-related parameters in type 2 diabetic rats. PMID- 27937040 TI - Multiparametric or practical quantitative liver MRI: towards millisecond, fat fraction, kilopascal and function era. AB - INTRODUCTION: New advances in liver magnetic resonance imaging (MRI) may enable diagnosis of unseen pathologies by conventional techniques. Normal T1 (550-620 ms for 1.5 T and 700-850 ms for 3 T), T2, T2* (>20 ms), T1rho (40-50 ms) mapping, proton density fat fraction (PDFF) (<=5%) and stiffness (2-3kPa) values can enable differentiation of a normal liver from chronic liver and diffuse diseases. Gd-EOB-DTPA can enable assessment of liver function by using postcontrast hepatobiliary phase or T1 reduction rate (normally above 60%). T1 mapping can be important for the assessment of fibrosis, amyloidosis and copper overload. T1rho mapping is promising for the assessment of liver collagen deposition. PDFF can allow objective treatment assessment in NAFLD and NASH patients. T2 and T2* are used for iron overload determination. MR fingerprinting may enable single slice acquisition and easy implementation of multiparametric MRI and follow-up of patients. Areas covered: T1, T2, T2*, PDFF and stiffness, diffusion weighted imaging, intravoxel incoherent motion imaging (ADC, D, D* and f values) and function analysis are reviewed. Expert commentary: Multiparametric MRI can enable biopsyless diagnosis and more objective staging of diffuse liver disease, cirrhosis and predisposing diseases. A comprehensive approach is needed to understand and overcome the effects of iron, fat, fibrosis, edema, inflammation and copper on MR relaxometry values in diffuse liver disease. PMID- 27937041 TI - New developments in the early diagnosis of pancreatic cancer. AB - INTRODUCTION: Pancreatic cancer is an aggressive carcinoma of the digestive system and radical resection, which is available to very few patients, is the only possibility for cure. Since therapeutic choices are limited at the advanced stage, screening and early diagnostic tools are indispensable for a better prognosis. Areas covered: This review illustrates serologic and imaging examinations, and carbohydrate antigens, microRNAs, methylation biomarkers, molecules in exosomes, ultrasound, computed tomography, magnetic resonance imaging, positron emission tomography and endoscopic retrograde cholangiopancreatography, among other topics. No matter which approach is used, the accuracy of early diagnosis is extremely low. Combining different methods greatly improves the accuracy of early diagnosis. This review was conducted utilizing PubMed with key search words pancreatic cancer, early diagnosis, biomarkers and imaging. Expert commentary: Appropriate combination of biomarkers and imaging technologies will become standard practice in the future. Because the incidence of and mortality from pancreatic cancer is rising, further study of new approaches for the early detection of pancreatic tumors is essential. PMID- 27937043 TI - Mapping Trachoma in the Solomon Islands: Results of Three Baseline Population Based Prevalence Surveys Conducted with the Global Trachoma Mapping Project. AB - PURPOSE: We sought to complete the baseline trachoma map of the Solomon Islands by establishing prevalences of active trachoma and trichiasis in the provinces of Choiseul, Western, Rennell-Bellona, and Temotu. METHODS: Using the standardized methodology developed for the Global Trachoma Mapping Project, we conducted cross sectional community-based surveys from September to November 2013. Choiseul and Western provinces were each mapped as separate evaluation units (EUs); Rennell Bellona and Temotu were combined to form a third EU. RESULTS: A total of 9819 individuals were sampled for inclusion, with 9224 (93.3%) consenting to examination, of whom 4587 (46.3%) were female. Survey teams visited 82 villages, and surveyed 2448 households. Two EUs had prevalences of trachomatous inflammation - follicular (TF) in 1-9-year-olds over the 10% threshold at which WHO recommends mass distribution of azithromycin for at least 3 years (Western 20.4%, 95% confidence interval, CI 15.6-26.3%; Rennell-Bellona/Temotu 22.0%, 95% CI 18.5-26.0%). Choiseul had a TF prevalence of 6.1% (95% CI 4.1-8.6%), and met the criterion for a single round of mass antibiotic distribution before re survey. The adjusted prevalences of trichiasis in those aged 15+ years were 0.0% (95% CI 0.0-0.2%) in Choiseul, 0.16% (95% CI 0.0-0.5%) in Western, and 0.10% (95% CI 0-0.3%) in Rennell-Bellona/Temotu provinces. All three EUs require implementation of the facial cleanliness and environmental improvement components of the trachoma elimination strategy. CONCLUSION: Active trachoma is prevalent in the Solomon Islands. However, there is little evidence of the blinding complications of trachoma being a public health problem there. Further research into the explanation for this phenomenon is warranted. PMID- 27937042 TI - Prevention of hypertension-induced vascular dementia by Lactobacillus paracasei subsp. paracasei NTU 101-fermented products. AB - CONTEXT: Numerous etiological studies have established positive clinical association between hypertension and vascular dementia (VaD). Lactobacillus paracasei subsp. paracasei NTU 101-fermented products have been shown to decrease vascular risk factors such as hypertension, atherosclerosis, hyperlipidemia and obesity. OBJECTIVE: This study investigated the effect of ethanol extract of Lactobacillus paracasei subsp. paracasei NTU 101-fermented products (NTU101F) in hypertension-induced VaD in rats. MATERIALS AND METHODS: Hypertension was promoted by subcutaneous injection of deoxycorticosterone acetate (DOCA, 25 mg/kg body weight/day, twice a week) and substitution of drinking water with 1.0% NaCl and 0.2% KCl. The NTU101F groups (0.5, 1.0, and 5.0) administered NTU101F at the concentrations 11, 22, and 110 mg/kg body weight/day, respectively, starting from day 51 day of DOCA-salt treatment. Morris water maze (MWM) was used for testing learning and memory. Different biochemical estimations were used to assess oxidative stress and inflammatory response in hippocampus. RESULTS: Oral administration of NTU101F in DOCA-salt hypertension-induced VaD rats resulted in a significant decrease in blood pressure by 18.3-23.2% (p < 0.001), which was regulated by increasing eNOS density (about 3-fold) in the aorta, promoting NO production, and decreasing of matrix metallopeptidase 9 activity (about 2-fold) in the hippocampus, in addition to improve the kidney function and structure, decrease escape latency and increase the times spent in the target quadrant by 23.5-27.8% (p < 0.05). CONCLUSION: Overall, our findings suggest that NTU101F could exert neuroprotection in the brain and attenuate hypertension-induced VaD. PMID- 27937045 TI - Sempervivum davisii: phytochemical composition, antioxidant and lipase-inhibitory activities. AB - CONTEXT: Sempervivum davisii Muirhead (Crassulaceae) is a traditional medicinal herb from Eastern Anatolia. To date the composition of phytochemicals and physiological properties of this herb were not subjected to any research. OBJECTIVE: This study identifies compounds in S. davisii hydrophilic extracts and evaluates their potential biological properties. MATERIALS AND METHODS: Ethanol based lyophilized extracts were obtained from aerial parts of plant (10 g of ground dry plant material in 200 mL of acidified aqueous ethanol, shaken for 2 h at 22 degrees C with supernatant collected and freeze-dried under vacuum). Phytochemical composition was investigated by liquid chromatography mass spectrometry (LC-MS/MS, phenolics) and gas chromatography mass spectrometry (GC MS, volatiles). Phenolic compounds were quantified by high-performance liquid chromatography (HPLC) and the Folin-Ciocalteu assay. Subsequently, antioxidant capacity [ferric reducing antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC) assays] and enzyme inhibitory properties (isolated porcine pancreatic lipase) of the extracts were determined. RESULTS: Polyphenolic compounds were the main constituents of lyophilized extracts, among which kaempferol glycosides and quercetin hexoside dominated. The extracts exhibited potent antioxidant (FRAP values of 1925.2-5973.3 MUM Fe2+/g DW; ORAC values of 1858.5-4208.7 MUM Trolox Eq./g DW) and moderate lipase inhibitory (IC50: 11.6 2.96 mg/mL) activities. Volatile compounds (nonanal, dehydroxylinalool oxide isomers, 2-decenal, 2-undecenal, 2,6-di-tetr-butylphenol) were also found. CONCLUSIONS: Phenolic compounds with the dominating kaempferol and quercetin derivatives are the sources of potent antioxidant properties of S. davisii hydrophilic extracts. The extracts exhibit moderate inhibitory properties towards isolated pancreatic lipase. PMID- 27937044 TI - 3-Hydroxy-4,7-megastigmadien-9-one, isolated from Ulva pertusa, attenuates TLR9 mediated inflammatory response by down-regulating mitogen-activated protein kinase and NF-kappaB pathways. AB - CONTEXT: Seaweeds are rich in bioactive compounds in the form of vitamins, phycobilins, polyphenols, carotenoids, phycocyanins and polysaccharides; many of these are known to have advantageous applications in human health. 3-Hydroxy-4,7 megastigmadien-9-one (comp) was isolated from Ulva pertusa (U. pertusa) Kjellman (Ulvaceae), which is a familiar edible green seaweed. OBJECTIVE: This study evaluates the anti-inflammatory activity of comp in CpG DNA-stimulated bone marrow-derived dendritic cells (BMDCs). MATERIALS AND METHODS: For evaluating the effect of comp on cytokines production, BMDCs were treated with doses of comp (0, 0.5, 1, 2, 5, 10, 25 and 50 MUM) for 1 h before stimulation with CpG DNA (1 MUM). Cytokine production was measured by ELISA. Western blotting was conducted for evaluating effect of comp (50 MUM) on MAPKs and NF-kappaB pathways. Luciferase reporter gene assay was conducted for effect of comp (0, 5, 10 and 25 MUM) on transcriptional activity of AP-1 and NF-kappaB. RESULTS: Comp exhibited strong inhibition of interleukin (IL)-12 p40, IL-6 and TNF-alpha cytokine production with IC50 values of 6.02 +/- 0.35, 27.14 +/- 0.73, and 7.56 +/- 0.21 MUM, respectively. It blocked MAPKs and NF-kappaB pathways by inhibiting the phosphorylation of ERK1/2, JNK1/2, p38 and IkappaBalpha. In addition, it strongly inhibited the transcriptional activity of AP-1 and NF-kappaB with IC50 values of 8.74 +/- 0.31 and 12.08 +/- 0.24 MUM, respectively. DISCUSSION AND CONCLUSION: Taken together, these data suggest that comp has a significant anti-inflammatory property and warrants further studies concerning the potential of comp for medicinal use. PMID- 27937046 TI - Contribution of Dry Needling to Individualized Physical Therapy Treatment of Shoulder Pain: A Randomized Clinical Trial. AB - Study Design Multicenter, parallel randomized clinical trial. Background Myofascial trigger points (MTrPs) are implicated in shoulder pain and functional limitations. An intervention intended to treat MTrPs is dry needling. Objectives To investigate the effectiveness of dry needling in addition to evidence-based personalized physical therapy treatment in the treatment of shoulder pain. Methods One hundred twenty patients with nonspecific shoulder pain were randomly allocated into 2 parallel groups: (1) personalized, evidencebased physical therapy treatment; and (2) trigger point dry needling in addition to personalized, evidence-based physical therapy treatment. Patients were assessed at baseline, posttreatment, and 3-month follow-up. The primary outcome measure was pain assessed by a visual analog scale at 3 months, and secondary variables were joint range-of-motion limitations, Constant-Murley score for pain and function, and number of active MTrPs. Clinical efficacy was assessed using intention-to-treat analysis. Results Of the 120 enrolled patients, 63 were randomly assigned to the control group and 57 to the intervention group. There were no significant differences in outcome between the 2 treatment groups. Both groups showed improvement over time. Conclusion Dry needling did not offer benefits in addition to personalized, evidencebased physical therapy treatment for patients with nonspecific shoulder pain. Level of Evidence Therapy, level 1b. Registered February 11, 2009 at www.isrctn.com (ISRCTN30907460). J Orthop Sports Phys Ther 2017;47(1):11-20. Epub 9 Dec 2016. doi:10.2519/jospt.2017.6698. PMID- 27937048 TI - Effects of cytochrome P450 3A4 and non-genetic factors on initial voriconazole serum trough concentrations in hematological patients with different cytochrome P450 2C19 genotypes. AB - 1. Polymorphisms of cytochrome P450 2C19 (CYP2C19) is an important factor contributing to variability of voriconazole pharmacokinetics. Polymorphisms of CYP3A4, CYP3A5, CYP2C9 and non-genetic factors such as age, gender, body mass index (BMI), transaminase levels, concomitant medications might also affect voriconazole initial steady serum trough concentration (VICmin) in haematological patients, but the effects were not clear. 2. Eighteen single-nucleotide polymorphisms in CYP2C19, CYP3A4, CYP3A5, CYP2C9 were genotyped. Patients were stratified into two groups according to CYP2C19 genotype. Group 1 were patients with CYP2C19*2 or CYP2C19*3, and Group 2 were homozygous extensive metabolizers. The effects were studied in different groups. VICmin was adjusted on daily dose (VICmin/D) for overcoming effect of dose. 3. A total of 106 blood samples from 86 patients were included. In final optimal scaling regression models, polymorphisms of rs4646437 (CYP3A4), age, BMI was identified to be factors of VICmin/D in Group 1 (R2 = .255, p < .001). Only age was confirmed as a factor of VICmin/D in Group 2 (R2 = 0.144, p = .021). 4. Besides polymorphisms of CYP2C19, in individualized medication of voriconazole in haematological patients, polymorphisms of CYP3A4, and non-genetic factors as BMI, age should also be taken into account, especially for individuals with CYP2C19*2 or CYP2C19*3. PMID- 27937049 TI - Agglomeration of celecoxib by quasi-emulsion solvent diffusion method without stabilizer: effect of good solvent. AB - AIM: The aim of the present research is to investigate the feasibility of agglomeration of crystals by the quasi-emulsion solvent diffusion method without using a stabilizer. METHOD: Two solvent systems comprising a solvent and an antisolvent (water) were used to prepare celecoxib agglomerates. To this end, seven solvents including propanol, methyl acetate, methyl ethyl ketone, butanol, ethyl acetate, isopropyl acetate, and pentanol were examined. The agglomerates were evaluated by micromeritic properties (e.g., size, density, flowability), yield, drug physical state, friability, and dissolution behavior. RESULTS: In the present study the clear trend was observed experimentally in the agglomerate properties as a function of physical properties of the solvent such as miscibility with water. Solvents with high water miscibility (25% v/v) resulted in sticky and hollow particles, while solvents with low water miscibility (3%v/v) led to the formation of agglomerates with low strength. However, the agglomerates made from the solvents with intermediate water miscibility (10% v/v), may reflect a greater integrity of the agglomerates regarding yield and strength. CONCLUSION: Results of this study offer a useful starting point for a conceptual framework to guide the selection of solvent systems for the quasi-emulsion solvent diffusion method without using a stabilizer. PMID- 27937050 TI - Emerging uricosurics for gout. PMID- 27937047 TI - Effects of garlic extract on TNF-alpha expression and oxidative stress status in the kidneys of rats with STZ + nicotinamide-induced diabetes. AB - CONTEXT: Allium sativum L. (Liliaceae) (garlic) is a medicinal plant that is widely used in herbal medicine. Nephropathy is a complication of diabetes that is induced by long-term hyperglycaemia. OBJECTIVE: The effects of aqueous extract of garlic (AGE) on the expression of tumour necrosis factor-alpha (TNF-alpha) and oxidative stress status were studied in the kidneys of rats with streptozotocin (STZ) + nicotinamide-induced diabetes. MATERIALS AND METHODS: Twenty-four Wistar rats were divided into four groups: control rats, rats with STZ + nicotinamide induced diabetes that received a single dose of STZ (65 mg/kg) and nicotinamide (110 mg/kg) intraperitoneally, diabetic rats that were treated with garlic (2 g/kg/d, gavage), and normal rats that received garlic (2 g/kg/d, gavage). The glucose level was determined in the start of study, 7 d after induction of diabetes and 33 d after treatment with garlic. At the end of the treatment period, urea, uric acid and creatinine levels were estimated in sera. Malondialdehyde (MDA), total oxidant status (TOS), nitric oxide (NO) levels and TNF-alpha gene and protein expression were measured in the renal tissues of the rats. RESULTS: The glucose, uric acid, and urea levels increased in the serum of diabetic rats compared with control rats, and decreased in garlic-treated diabetic rats compared with diabetic rats (p < 0.05). MDA, TOS and NO increased (p < 0.001) in diabetic rats compared with the control group, and decreased in garlic-treated diabetic rats compared with diabetic rats (p < 0.01). The level of TNF-alpha mRNA did not differ between groups but the TNF-alpha protein level in diabetic rats was higher than in the control rats (p < 0.01), whereas after treatment with garlic, it was close to the normal level (p < 0.01). DISCUSSION AND CONCLUSION: These results indicate that garlic extract has hypoglycaemic, antioxidant and anti-inflammatory properties; therefore, it can be useful for the alleviation of diabetic complications. PMID- 27937051 TI - Wnt10b and Dkk-1 gene therapy differentially influenced trabecular bone architecture, soft tissue integrity, and osteophytosis in a skeletally mature rat model of osteoarthritis. AB - AIMS: Our goals in the current experiments were to determine if (a) upregulation of Wnt signaling would induce osteoarthritis changes in stable stifle joints and (b) if downregulation of Wnt signaling in destabilized joints would influence the progression of OA. METHODS: At 37 weeks of age, rats were injected in the stifle joint with a recombinant adeno-associated viral vector containing the Wnt inhibitor Dkk-1 or a Wnt10b transgene. At 40 weeks of age, rats underwent surgical destabilization of the joint. At 50 weeks of age, stifle joints were submitted for micro-computed tomography and histopathological analysis. RESULTS: Injection of either Wnt10b or Dkk-1 transgenes in stable joints improved bone architectural parameters, but worsened soft tissue integrity. Osteophytosis was decreased by Dkk-1, but unchanged by Wnt10b. Destabilization negatively influenced bone architecture, increased osteophytosis, and decreased soft tissue integrity. Dkk-1 exacerbated the negative effects of destabilization, whereas Wnt10b had little effect on these parameters. Osteophytosis was improved, whereas soft tissue integrity was worsened by both transgenes in destabilized joints. CONCLUSIONS: The Wnt-inhibitor Dkk-1 does not appear to completely inhibit the effects of Wnt signaling on bone remodeling. In vivo upregulation of Wnt10b and its inhibitor, Dkk-1, can produce both parallel or contrasting phenotypic responses depending on the specific parameter measured and the fidelity of the examined joint. These observations elucidate different roles for Wnt signaling in stable versus destabilized joints and may help to explain the conflicting results previously reported for the role of Dkk-1 in joint disease. PMID- 27937052 TI - To Those in Enterprise: 10 Years Later. PMID- 27937053 TI - Association of PEAR1 rs12041331 polymorphism and pharmacodynamics of ticagrelor in healthy Chinese volunteers. AB - 1. Genetic polymorphisms in platelet endothelial aggregation receptor 1 (PEAR1) were associated with responsiveness to aspirin and P2Y12 receptor antagonists. This study aimed to investigate whether PEAR1 polymorphism is associated with ticagrelor pharmacodynamics in healthy Chinese subjects. 2. The in vitro inhibition of platelet aggregation (IPA) was evaluated before and after ticagrelor incubated with platelet-rich plasma from 196 healthy Chinese male subjects. Eight polymorphisms at PEAR1 locus were genotyped. Eighteen volunteers (six in each rs12041331 genotype group) were randomly selected. After a single oral 180 mg dose of ticagrelor, plasma levels of ticagrelor and the active metabolite AR-C124910XX were measured and pharmacodynamics parameters including IPA and VASP-platelet reactivity index (PRI) were assessed. 3. No significant difference in ticagrelor pharmacokinetics among rs12041331 genotype was observed. As compared with rs12041331 G allele carriers, AA homozygotes exhibited increased IPA after 15 MUM ticagrelor incubation (p < 0.01), increased area under the time effect curve of IPA and lower PRI at 2 h after ticagrelor administration (p < 0.05, respectively). Rs4661012 GG homozygotes showed increased IPA after 50 MUM ticagrelor incubation as compared to T allele carriers (p < 0.01). 4. PEAR1 polymorphism may influence ticagrelor pharmacodynamics in healthy Chinese subjects. PMID- 27937054 TI - Efficacy of aspirin (325 mg) + omeprazole (40 mg) in treating coronary artery disease. AB - INTRODUCTION: Aspirin is indicated for primary and secondary prevention of cardiovascular diseases (CVD) by major guidelines. However, its use may be associated with gastrointestinal (GI) toxicities, including, but not limited to, GI bleeding. This may lead to increased morbidity and mortality, as well as diminished compliance, which again leads to increased risk of major cardiovascular events. Modified formulations of aspirin often have comparable risks of GI toxicity despite their dose or formulation and have had limited success to prevent GI toxicities. Simultaneous treatment with Proton pump inhibitors (PPIs) has been used successfully to prevent GI toxicities from aspirin. However, addition of an extra medication may lead to lower compliance and hence ineffective or less than optimal treatment. Areas covered: After a selective literature search, a brief review of the available evidence regarding GI toxicity of aspirin and the protective effects of PPIs was conducted. The concept of combination tablets, and the available data about Aralez Pharmaceuticals' YOSPRALA (aspirin (81 mg or 325 mg) and omeprazole (40 mg) fixed dose combination tablet being evaluated for secondary prevention of cardiovascular and cerebrovascular events in patients at risk for GI complications of aspirin therapy) is also presented. Expert opinion: The available evidence suggests that PPIs are the best option to prevent aspirin related GI toxicities, but compliance is low in people who are prescribed both aspirin and PPI. Combination tablets containing both aspirin and a PPI may be a good option for providing protection against GI toxicities in people who require aspirin for secondary prevention of cardiovascular diseases. PMID- 27937056 TI - Scintigraphy for detecting tumour necrosis factor-alpha on the skin of patients with psoriatic arthritis. AB - OBJECTIVE: This study assessed the use of scintigraphy and magnetic resonance imaging (MRI) in identifying the presence and amount of tumour necrosis factor alpha (TNF-alpha) in the joint or skin of patients with psoriatic arthritis, to guide the course of treatment more efficiently. METHOD: We compared the results of scintigraphy and MRI in two patients with psoriatic arthritis who underwent technetium-99m (99mTc)-anti-TNF-alpha scintigraphy, and MRI 5 days later. RESULTS: Greater uptake of 99mTc-anti-TNF-alpha was observed in the left wrist and right second metacarpal in patient 1, and in the left ulnocarpal joint and distal interphalangeal joint of the left first metacarpal in patient 2. These results correlated with the MRI findings. CONCLUSIONS: 99mTc-anti-TNF-alpha scintigraphy may recognize the molecule involved in the inflammatory process. This may provide crucial information to help physicians make decisions about which drugs to use based on biological evidence, and which are cost-effective and appropriate for the treatment of choice. To the best of our knowledge, this is the first time that TNF-alpha has been shown in the skin of a patient using diagnostic imaging methods. PMID- 27937058 TI - Myxoid leiomyosarcoma of the cervix: A case report. PMID- 27937057 TI - Radical cystectomy: do we need standardization? AB - INTRODUCTION: The first series of radical cystectomy with a definition of surgical landmarks was published in 1949 and was characterized by a high perioperative mortality and a 5-year survival rate around 50%. Decades later, nevertheless many surgical progresses were made and the perioperative mortality dropped to 2,5%, this had not lead to an improvement of long term survival rates, also because a standardization of the procedure is still missing. Areas covered: Radical cystectomy is performed with different surgical techniques obmitting a standardization. The comparability of many studies is therefore difficult or havely compromised. A paragon with other diciplines was made emphazing that there high surgical quality is defined, measured and controlled. A systematic literature search was made selecting finally 76 article adressing this issue. Expert commentary: Surgical guidelines in uro-oncology are vague and a definition of surgical quality is missing. A view outside of the box could be very helpful. This is a plea for a change. PMID- 27937059 TI - Statistical evaluation of the scaled criterion for drug interchangeability. AB - As more and more generic drug products become available in the marketplace, it is a concern whether these generic drug products can be used interchangeably in terms of their quality, safety, and efficacy. The United States Food and Drug Administration (FDA) indicates that an approved generic drug product can serve as a substitute for the innovative drug product. The FDA, however, does not indicate that approved generic drug products can be used interchangeably even if they are bioequivalent to the same innovative drug product. In the past decade, several criteria for assessing interchangeability were proposed in regulatory guidances and/or literature. Chow, Xu, and Endrenyi proposed a scaled criterion for drug interchangeability (SCDI), which takes both intra-subject variability and subject by-drug variability into consideration. In this paper, the performance of this criterion is statistically evaluated by deriving the upper confidence limit of the test statistic and extrapolating expression of the power to facilitate sample size calculation. The performance of SCDI is also compared with that of the criterion for assessment of individual bioequivalence (IBE) for addressing drug switchability recommended by the FDA, which also takes into account the subject by-drug variability, under various parameter specifications. PMID- 27937055 TI - Curcumin-loaded nanoliposomes linked to homing peptides for integrin targeting and neuropilin-1-mediated internalization. AB - CONTEXT: Curcumin, a naturally occurring polyphenol, has been extensively studied for its broad-spectrum anticancer effects. The potential benefits are, however, limited due to its poor water solubility and rapid degradation which result in low bioavailability on administration. OBJECTIVES: This study encapsulates curcumin in nanoliposomes including an integrin-homing peptide combined with a C end R neuropilin-1 targeting motif for targeted delivery and receptor-mediated internalization, respectively. MATERIALS AND METHODS: The linear GHHNGR (Glycine Histidine-Histidine-Asparagine-Glycine-Arginine) was synthesized through F-moc chemistry on 2-chlorotrityl chloride resin and conjugated to oleic acid. The lipoyl-peptide units were then co-assembled with lecithin and 0-75 mole % Tween 80 into liposomes. Curcumin was passively entrapped using a film hydration technique and its degradation profile was examined within seven consecutive days. The cytotoxic effects of the curcumin-loaded liposomes were studied on MCF-7 and MDA-MB-468, during 24 h exposure in MTT assay. RESULTS: The maximum curcumin entrapment (15.5% W/W) and minimum degradation (< 23%) were obtained in a pH switch loading method from 5.7 to 8, in nanoliposomes (< 50 nm) containing oleyl peptide, lecithin and Tween-80 (1:1:0.75 mole ratio). The oleyl-peptide did not prove any haemolytic activity (< 1.5%) up to 10-fold of its experimental concentration. The curcumin-loaded liposomes displayed significant reduction in the viabilities of MCF-7 (IC50 3.8 MUM) and MDA-MB-468 (IC50 5.4 MUM). DISCUSSION AND CONCLUSION: This study indicated potential advantages of the peptide conjugated liposomes in drug transport to the cancer cells. This feature might be an outcome of probable interactions between the targeted nanoliposomes with the integrin and neuropilin-1 receptors. PMID- 27937060 TI - Update on therapeutic options for Middle East Respiratory Syndrome Coronavirus (MERS-CoV). AB - INTRODUCTION: The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an important emerging respiratory pathogen. MERS-CoV resulted in multiple hospital outbreaks within and outside the Arabian Peninsula. The disease has a high case fatality rate, with the need for a therapeutic option. Areas covered: In this review, we provide an overview of the progress in the development of therapeutic strategies for MERS. We searched PubMed, Embase, Cochrane, Scopus, and Google Scholar, using the following terms: 'MERS', 'MERS-CoV', 'Middle East respiratory syndrome' in combination with 'treatment' or 'therapy'. Expert commentary: There are multiple agents tried in vitro and in vivo. None of these agents were used in large clinical studies. Available clinical studies are limited to the use of the combination of interferon and other agents. These clinical studies are based solely on case reports and case series. There are no prospective or randomized trials. There is a need to have prospective and randomized clinical trials for the therapy of MERS-CoV. However, this strategy might be hampered by the sporadic cases outside the large hospital outbreaks. PMID- 27937061 TI - Herd effects of child vaccination with pneumococcal conjugate vaccine against pneumococcal non-invasive community-acquired pneumonia: What is the evidence? AB - Quantification of pneumococcal conjugate vaccines (PCVs) herd effects are mainly performed on invasive pneumococcal disease (IPD) but there is conflicting evidence regarding herd effects of PCVs on non-IPD pneumococcal community acquired pneumonia. This review summarizes the available literature on herd effects of PCVs on non-IPD pneumococcal community-acquired pneumonia. PMID- 27937062 TI - Cognitive Flexibility in Juvenile Anorexia Nervosain Relation to Comorbid Symptoms of Depression, Obsessive Compulsive Symptoms and Duration of Illness. AB - OBJECTIVE: Whereas the evidence in adolescents is inconsistent, anorexia nervosa (AN) in adults is characterized by weak cognitive flexibility. This study investigates cognitive flexibility in adolescents with AN and its potential associations with symptoms of depression, obsessive compulsive disorder (OCD), and duration of illness. METHODS: 69 patients and 63 age-matched healthy controls (HC) from 9 till 19 years of age were assessed using the Trail-Making Test (TMT) and self-report questionnaires. RESULTS: In hierarchical regression analyses, set shifting ability did not differ between AN and HC, whereas AN patients reported significantly higher rates of depression symptoms and OCD symptoms. Age significantly predicted set-shifting in the total sample. Only among AN patients aged 14 years and older did set-shifting decline with increasing age. DISCUSSION: The presence of AN with depression or OCD symptoms or the duration of illness do not influence cognitive flexibility in children and adolescents. Early interventions may be helpful to prevent a decline in cognitive flexibility in adolescent AN with increasing age. PMID- 27937063 TI - Recent advances in proteomic applications for schistosomiasis research: potential clinical impact. AB - INTRODUCTION: Schistosomiasis is a neglected tropical disease affecting hundreds of millions of people worldwide. Recent advances in the field of proteomics and the development of new and highly sensitive mass spectrometers and quantitative techniques have provided new tools for advancing the molecular biology, cell biology, diagnosis and vaccine development for public health threats such as schistosomiasis. Areas covered: In this review we describe the latest advances in research that utilizes proteomics-based tools to address some of the key challenges to developing effective interventions against schistosomiasis. We also provide information about the potential of extracellular vesicles to advance the fight against this devastating disease. Expert commentary: Different proteins are already being tested as vaccines against schistosomiasis with promising results. The re-analysis of the Schistosoma spp. proteomes using new and more sensitive mass spectrometers as well as better separation approaches will help identify more vaccine targets in a rational and informed manner. In addition, the recent development of new proteome microarrays will facilitate characterisation of novel markers of infection as well as new vaccine and diagnostic candidate antigens. PMID- 27937064 TI - Safety, efficacy, and dose response of fluticasone propionate delivered via the novel MDPI in patients with severe asthma: A randomized, controlled, dose-ranging study. AB - OBJECTIVE: Evaluate fluticasone propionate (Fp) using a novel, inhalation-driven, multidose dry powder inhaler (MDPI) in patients with severe persistent asthma, versus placebo MDPI and Fp dry powder inhaler (DPI). METHODS: Patients with persistent asthma despite use of high-dose inhaled corticosteroids were randomized to Fp MDPI 50, 100, 200, or 400 mcg; Fp DPI 250 mcg; or placebo MDPI twice daily for 12 weeks. The primary outcome measure was change from baseline in trough forced expiratory volume in 1 second (FEV1) over the 12-week period, compared with placebo; secondary measures included change from baseline in peak expiratory flow (PEF), rescue inhaler use, and time to withdrawal due to meeting stopping criteria. Safety included adverse events and laboratory evaluations. RESULTS: Six hundred forty patients were randomized; 459 (72%) completed the study. Numerical dose-related improvements in FEV1 were observed in all Fp MDPI groups over 12 weeks but were not significantly greater versus placebo. Increases in morning PEF (baseline to week 12) were substantially greater than placebo in all Fp MDPI groups. The Fp MDPI and Fp DPI groups had substantial reductions in rescue inhaler use from baseline to end point versus placebo (p <= 0.05). Efficacy was comparable between Fp MDPI and Fp DPI. No new safety signals were detected; the safety profile of Fp MDPI was similar to that of Fp DPI. CONCLUSIONS: Clinical benefit observed with Fp MDPI in patients with persistent asthma was comparable to Fp DPI. Safety was reassuring with no unexpected findings. These results support further evaluation of Fp MDPI in asthma. (ClinicalTrials.gov identifier NCT01576718; EudraCT number 2010-023601-35). PMID- 27937065 TI - An evaluation of the suitability of COI and COII gene variation for reconstructing the phylogeny of, and identifying cryptic species in, anopheline mosquitoes (Diptera Culicidae). AB - We assessed the practicality and effectiveness of using variation in the mitochondrial COI and COII genes to discriminate species and reconstruct the phylogeny of anophelene mosquitoes. Phylogenetic relationships among the subfamily Anophelinae were inferred from portions of the mitochondrial COI (92 species) and COII genes (108 species). Phylogenetic trees were reconstructed on the basis of parsimony, maximum likelihood and Bayesian methods. The suitability of COI and COII gene variation for identifying cryptic species was compared by comparing the sequence divergence within species groups and complexes. The results show that the COI gene was more useful for identifying sibling and cryptic species, but that phylogenetic relationships reconstructed using the COII gene were more similar to those based on morphological data. We conclude that: (1) there is a significant molecular divergence among An. sinensis; (2) the COI and COII are valid genetic markers for resolving taxonomic relationships among anopheline mosquitoes and the resultant phylogeny raises some questions about the taxonomic status of anopheline species groups and complexes; (3) the genus Anopheles is not demonstrably monophyletic with regard to the genus Bironella; (4) the subgenera Kerteszia and Nyssorhynchus are monophyletic; (5) below the group-level, COI data support the existence of monophyletic taxa within the Anopheles funestus, Anopheles maculipennis and Anopheles strode and Anopheles barbirostris subgroups, and within the Anopheles nuneztovari complex, whereas COII data support the monophyletic taxa within the Anopheles minimus and Anopheles oswaldoi subgroups, and Anopheles hyrcanus group. The monophyletic taxa within the Anopheles gambiae and Anopheles albitarsis complexes are supported by both COI and COII data. PMID- 27937067 TI - Time-to-event endpoints in operable non-small-cell lung cancer randomized clinical trials. AB - INTRODUCTION: No guideline for time-to-event endpoints (TTEE) definitions in lung cancer trials exists. Areas covered: The aim of the study was to evaluate the reporting of TTEE in operable non-small-cell lung cancer randomized clinical trials. Expert commentary: Sixty-two TTEE were recorded. In the Methods section, using four key points to define TTEE we observed that the 'starting point', 'events', 'information on censoring', 'assessment of events' were clearly defined for 43 (69.4%), 34 (54.8%), 6 (9.7%), 33 (53.2%) endpoints respectively. In the results section, using five key points, we observed that the 'Kaplan-Meier estimation', 'estimation of effect size', 'precision (confidence interval)', 'number of events', 'number of patients at risk', 'multivariate analysis' were clearly identified for 46 (74.2%), 31 (50%), 30 (48.4%), 37 (59.7%), 28 (45.2%), and 17 (27.4%) endpoints, respectively. A majority of articles failed to provide a complete reporting of TTEE. Guidelines for TTEE is warranted. PMID- 27937070 TI - Summing Up the Highlights of 2016. PMID- 27937066 TI - Purification of common light chain IgG-like bispecific antibodies using highly linear pH gradients. AB - Monovalent bispecific antibodies (BsAbs) are projected to have broad clinical applications due to their ability to bind two different targets simultaneously. Although they can be produced using recombinant technologies, the correct pairing of heavy and light chains is a significant manufacturing problem. Various approaches exploit mutations or linkers to favor the formation of the desired BsAb, but a format using a single common light chain has the advantage that no other modification to the antibody is required. This strategy reduces the number of formed molecules to three (the BsAb and the two parent mAbs), but the separation of the BsAb from the two monovalent parent molecules still poses a potentially difficult purification challenge. Current methods employ ion exchange chromatography and linear salt gradients, but are only successful if the difference in the observed isoelectric points (pIs) of two parent molecules is relatively large. Here, we describe the use of highly linear pH gradients for the facile purification of common light chain BsAbs. The method is effective at separating molecules with differences in pI as little as 0.10, and differing in their sequence by only a single charged amino acid. We also demonstrate that purification resins validated for manufacturing are compatible with this approach. PMID- 27937069 TI - Capitalising on Engagement: An Underutilised and Undervalued Resource in Healthcare. PMID- 27937071 TI - Resolving the phylogenetic status and taxonomic relationships of the Hangul (Cervus elaphus hanglu) in the family Cervidae. AB - The Hangul (Cervus elaphus hanglu) is a "Least Concern" deer species, and it is the only survivor of the Red Deer group in the Indian subcontinent. The phylogenetic status of the Hangul relative to the other members of the family Cervidae is not known because sequence data are not available in public databases. Therefore, this study was carried out to determine the phylogenetic status and delineate the genetic boundaries of the Hangul with respect to the other Red Deer subspecies on the basis of cytochrome b gene sequence data (ca 421 bp). There are three major monophyletic groups of the Red Deer in the phylogenetic tree, which are referred to as the western (Hap-01 to Hap-10), eastern (Hap-11 to Hap-20) and tarim (Hap-21 to Hap-25) groups. The overall haplotype diversity and per-site nucleotide diversity were 0.9771 (+/-0.0523) and 0.0388 (+/-0.00261), respectively. In the phylogenetic tree, the Hangul clustered with the tarim group (Yarkand and Bactrian Red Deer) with a strong bootstrap support (92%) and was found to be genetically closer to the Bactrian Red Deer than to the Yarkand Red Deer. Our molecular analysis supported the idea that the Hangul diverged from the Bactrian Red Deer and migrated to India from Tajikistan approximately 1.2 MYA. PMID- 27937073 TI - Social perception in synaesthesia for colour. AB - Synaesthesia is a rare phenomenon in which stimulation in one modality (e.g., audition) evokes a secondary percept not associated with the first (e.g., colour). Prior work has suggested links between synaesthesia and other neurodevelopmental conditions that are linked to altered social perception abilities. With this in mind, here we sought to examine social perception abilities in grapheme-colour synaesthesia (where achromatic graphemes evoke colour experiences) by examining facial identity and facial emotion perception in synaesthetes and controls. Our results indicate that individuals who experience grapheme-colour synaesthesia outperformed controls on tasks involving fine visual discrimination of facial identity and emotion, but not on tasks involving holistic face processing. These findings are discussed in the context of broader perceptual and cognitive traits previously associated with synaesthesia for colour, with the suggestion that performance benefits shown by grapheme-colour synaesthetes may be related to domain-general visual discrimination biases observed in this group. PMID- 27937072 TI - Altered expression of G1/S phase cell cycle regulators in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise. AB - Herein, we evaluated whether Placental Mesenchymal Stromal Cells (PDMSCs) derived from normal and Preeclamptic (PE) placentae presented differences in the expression of G1/S-phase regulators p16INK4A, p18INK4C, CDK4 and CDK6. Finally, we investigated normal and PE-PDMSCs paracrine effects on JunB, Cyclin D1, p16INK4A, p18INK4C, CDK4 and CDK6 expressions in physiological term villous explants. PDMSCs were isolated from physiological (n = 20) and PE (n = 24) placentae. Passage three normal and PE-PDMSC and conditioned media (CM) were collected after 48h. Physiological villous explants (n = 60) were treated for 72h with normal or PE-PDMSCs CM. Explants viability was assessed by Lactate Dehydrogenase Cytotoxicity assay. Cyclin D1 localization was evaluated by Immuofluorescence (IF) while JunB, Cyclin-D1 p16INK4A, p18INK4C, CDK4 and CDK6 levels were assessed by Real Time PCR and Western Blot assay. We reported significantly increased p16INK4A and p18INK4C expression in PE- relative to normal PDMSCs while no differences in CDK4 and CDK6 levels were detected. Explants viability was not affected by normal or PE-PDMSCs CM. Normal PDMSCs CM increased JunB, p16INK4 and p18INK4C and decreased Cyclin-D1 in placental tissues. In contrast, PE-PDMSCs CM induced JunB downregulation and Cyclin D1 increase in placental explants. Cyclin D1 IF staining showed that CM treatment targeted mainly the syncytiotrophoblast. We showed Cyclin D1-p16INK4A/p18INK4C altered pathway in PE-PDMSCs demonstrating an aberrant G1/S phase transition in these pathological cells. The abnormal Cyclin D1-p16INK4A/p18INK4C expression in explants conditioned by PE-PDMSCs media suggest a key contribution of mesenchymal cells to the altered trophoblast cell cycle regulation typical of PE pregnancies with fetal-placental compromise. PMID- 27937074 TI - Negative perceptions of hepatitis B vaccination among attendees of an urban free testing center for sexually transmitted infections in France. AB - BACKGROUND: Official French health care policy recommends vaccinations against hepatitis B for all infants and at-risk adults. Attendees at our free testing center for sexually transmitted infections (FTC-STI) routinely express hepatitis B vaccine hesitancy. We aimed in this exposed population to explore the extent of knowledge concerning HBV infection, to quantify HBV vaccine refusal, and to identify the reasons for this refusal. METHODS: During a 3-month period in 2013, all attendees at the Grenoble FTC-STI were given an anonymous questionnaire exploring their knowledge of hepatitis B, perception of the hepatitis B vaccine, acceptance of free same-day hepatitis B vaccination, and reasons for refusing this offer (where applicable). RESULTS: The questionnaire was completed by 735 attendees (64.7% of those attending during the study period)(59.9% men; age 27.9 +/- 9.2). Most respondents identified hepatitis B as a potentially severe, potentially lifelong illness existing in France. Concerning the hepatitis B vaccine, less than 50% totally or mostly agreed that it is safe; when asked whether the vaccine is dangerous, 44.2% answered "I don't know" and 14.0% agreed; when asked whether the vaccine is "not well characterized," 45.0%, answered "I don't know" and 26.5% agreed. When asked whether they mistrust the hepatitis B vaccine or all vaccines in general, 39.0% and 28.9% of those unvaccinated agreed, respectively. Two thirds refused to get vaccinated on the same day. When asked whether they were afraid of the adverse effects of this vaccine, only 18.7% disagreed. CONCLUSION: Negative perceptions of the hepatitis B vaccine are widespread in this at-risk population. Consequently, a successful communication strategy must reassure this at-risk population of the vaccine's innocuous nature. PMID- 27937075 TI - Evaluation of different Mediterranean essential oils as prophylactic agents in anisakidosis. AB - CONTEXT: Anisakis Dujardin 1845 (Anisakidae) nematodes can cause gastrointestinal and allergic diseases when humans eat raw or undercooked seafood containing larvae. There is currently no drug available in the market against this parasitic disease, and the study of plant-derived molecules could be useful in the discovery of effective compounds. OBJECTIVE: This research assesses the biocidal activity of a range of essential oils (EOs) from some Mediterranean plants against larvae found in the musculature of fresh fish. MATERIALS AND METHODS: EOs composition was analyzed by gas chromatography-mass spectroscopy. All the EOs were diluted at 5% v/v in olive oil to cover the fish with the solutions for 24 h. The larvae that abandoned the muscle and the larvae obtained from the artificial digestion of the fish were collected. Controls were carried out in parallel. Furthermore, Wistar rats were infected with the live larvae collected from the in vitro trials in order to find any larvae that may have penetrated the gastrointestinal wall. RESULTS: Between 60.8% and 87.6% of parasites treated with EOs abandoned the fish muscle, and the highest in vitro mortality rate was achieved with oregano EO (53.9%). Rats previously treated with oregano, cumin and Spanish lavender EOs showed no detectable lesions in the digestive tract due to the infection with larvae. CONCLUSIONS: Oregano (Origanum vulgare L. Lamiaceae), cumin (Cuminum cyminum L. Apiaceae) and Spanish lavender (Lavender stoechas L. Lamiaceae) EOs could be used as promising ingredients in the development of products for the control of anisakiasis. PMID- 27937076 TI - Uveitic Glaucoma: Long-term Clinical Outcome and Risk Factors for Progression. AB - PURPOSE: To study the long-term clinical outcomes of uveitic glaucoma and to identify risk factors for progression. METHODS: Retrospective study of uveitic glaucoma patients in two tertiary medical centers in 2003-2015. Patient- and disease-related data was retrieved. Clinical parameters and visual fields measured at predetermined time points were recorded. Outcome measures included maintaining intraocular pressure <=21 mmHg and preserving visual fields. RESULTS: Included were 34 patients (53 eyes), with a mean follow-up of 7 years. Idiopathic anterior uveitis and open-angle glaucoma were most common. In total, 62% of eyes were steroid responders. Higher IOP was associated with posterior synechiae, peripheral-anterior synechiae, steroidal, and immunomodulatory therapy (p<0.05). Glaucomatous field defects developed in 49%, with most showing no progression, despite elevation of cup-to-disc ratio (p<0.05). CONCLUSIONS: Chronic severe uveitis, expressed by structural complications and immunomodulatory therapy, was associated with high IOP and the need for more IOP lowering medications, but was unrelated to glaucomatous damage. PMID- 27937078 TI - Introduction of Guest Editor of Special Issue on Addiction and Mental Health Across the Lifespan. PMID- 27937077 TI - Hypocholesterolemic efficacy of royal jelly in healthy mild hypercholesterolemic adults. AB - CONTEXT: Royal jelly (RJ) has been reported for its health promoting factors such as antioxidant, anti-inflammatory and lipid lowering activities. OBJECTIVE: The present randomized, placebo-controlled study examines the hypolipidemic beneficial effect of RJ through evaluating anthropometric measurements, lipid profile and various hormone levels in mildly hypercholesterolemic participants. MATERIALS AND METHODS: Forty subjects with mild hypercholesterolemia (180-200 mg/dL) were randomly selected and divided into two groups as experimental or placebo, who requested to intake nine capsules (350 mg/capsule) of RJ or placebo/day, respectively, for three months with one month of follow-up without any supplementation. RESULTS: No significant changes were noted in any of the anthropometric parameters like body weight, waist and body fat. The serum total cholesterol (TC; 207.05-183.15 mg/dL) and low-density lipoprotein cholesterol (LDL-c; 126.44-120.31 mg/dL) levels were reduced significantly (p < 0.05) after administration of RJ. However, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-c) levels were not considerably altered. Moreover, three months of RJ consumption significantly ameliorated (p < 0.05) the concentration of sex hormones like dehydroepiandrosterone sulphate (DHEA-S; 1788.09-1992.31 ng/mL). Also, intake of RJ did not elicit any hepatic or renal damage. DISCUSSION AND CONCLUSION: Intervention with RJ for three months considerably lowered the TC and LDL-c levels through improving the levels of DHEA-S and thus alleviates the risk of cardiovascular disease (CVD). PMID- 27937079 TI - Long-term Follow-up of Patients with Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome. AB - PURPOSE: To evaluate the response to treatment in patients with tubulointerstitial nephritis and uveitis (TINU) syndrome over a long-term follow up period. METHODS: Nine patients with TINU syndrome were retrospectively reviewed. The mean follow-up was 54.8 months (range: 24-133 months). RESULTS: The mean number of recurrences per year declined from 1.7 in the 1st year to 0.66 in the 2nd year of treatment. The ocular inflammation responded to local corticosteroids in two patients, systemic corticosteroids in two patients, immunosuppressive therapy in four patients, and anti-TNF-alpha blocking agent in one patient. The therapy could be discontinued in six (67%) patients after a mean treatment period of 29.5 months. In five patients, remission with the recurrence free period of 12.8 months was achieved. CONCLUSIONS: TINU syndrome was characterized by limited responsiveness to corticosteroid therapy and less by severe complications. A long-term course of immunosuppressants or biologics was necessary to control the uveitis and led to induction of remission. PMID- 27937080 TI - Photoprotective effects of cranberry juice and its various fractions against blue light-induced impairment in human retinal pigment epithelial cells. AB - CONTEXT: Cranberry has numerous biological activities, including antioxidation, anticancer, cardioprotection, as well as treatment of urinary tract infection (UTI), attributed to abundant phenolic contents. OBJECTIVE: The current study focused on the effect of cranberry juice (CJ) on blue light exposed human retinal pigment epithelial (ARPE-19) cells which mimic age-related macular degeneration (AMD). MATERIALS AND METHODS: Preliminary phytochemical and HPLC analysis, as well as total antioxidant capacity and scavenging activity of cranberry ethyl acetate extract and different CJ fractions (condensed tannins containing fraction), were evaluated. In cell line model, ARPE-19 were irradiated with blue light at 450 nm wavelength for 10 h (mimic AMD) and treated with different fractions of CJ extract at different doses (5-50 MUg/mL) by assessing the cell viability or proliferation rate using MTT assay (repairing efficacy). RESULTS: Phytochemical and HPLC analysis reveals the presence of several phenolic compounds (flavonoids, proanthocyanidin, quercetin) in ethyl acetate extract and different fractions of CJ. However, the condensed tannin containing fraction of ethyl acetate extract of CJ displayed the greater (p < 0.05) scavenging activity especially at the dose of 1 mg/mL. Similarly, the condensed tannin containing fraction at 50 MUg/mL presented better (p < 0.05) repairing ability (increased cell viability). Furthermore, the oligomeric condensed tannin containing fraction display the best (p < 0.05) repairing efficiency at 50 MUg/mL. DISCUSSION AND CONCLUSION: In conclusion, this study distinctly proved that condensed tannin containing fraction of CJ probably exhibits better free radicals scavenging activity and thereby effectively protected the ARPE-19 cells and thus, hampers the progress of AMD. PMID- 27937082 TI - The correlation between mothers' participation in infant care in the NICU and their anxiety and problem-solving skill levels in caregiving. AB - OBJECTIVE: To examine the correlation between mothers' participation in infant care in the Neonatal Intensive Care Unit (NICU) and their anxiety and problem solving skill levels in caregiving. METHODS: The cross-sectional study was conducted with 340 mothers whose babies were in the NICU. Data were collected with a questionnaire, a Participation in Caregiving Observation Form, the State and Trait Anxiety Inventory and the Problem-solving Skills Evaluation Form. Descriptive statistics and correlation analysis were used in the evaluation of the data. RESULTS: The mothers were with their babies an average of 6.28 +/- 2.43 (range: 1-20) times a day, participating in many basic procedures of care. A negative correlation was found between the mothers' scores on the Participation in Caregiving Observation Form and their State and Trait Anxiety Inventory scores (respectively, r = -0.48, p < 0.001 and r = -0.12, p < 0.05), but a positive correlation was observed between the Problem-solving Process (r = 0.41, p < 0.001) and the Baby Care Skills (r = 0.24, p < 0.001) Subscale scores. CONCLUSIONS: The study revealed that mothers participated in many basic caregiving procedures in the NICU and this participation resulted in reduced state and trait anxiety levels and an improvement in the mothers' problem-solving skills with respect to baby care and related problems. PMID- 27937083 TI - Medical education in difficult circumstances: A global responsibility to contribute. AB - Medical and health professions' education is becoming increasingly standardized across the world in terms of core standards and competencies. Yet, the context in which education and training occurs is far from even. Many educators face challenges in providing health professions' education, ranging from individual challenges and organizational struggles, to working in countries experiencing major conflict or environmental disaster. This commentary sets the scene for an international discussion on might constitute "difficult circumstances" and invites educators from around the world to contribute to the discussion by sharing their stories and suggesting strategies and solutions in a themed issue of MedEdPublish, AMEE's (the Association for Medical Education in Europe) innovative online journal. PMID- 27937081 TI - Effects of type 2 diabetes mellitus on the pharmacokinetics of berberine in rats. AB - CONTEXT: Berberine is an active alkaloid isolated from Rhizoma coptidis [Coptis chinensis Franch. (Ranunculaceae)] that is widely used for the treatment of diabetes, hyperlipidemia and hypertension. However, the pharmacokinetics of berberine in normal rats and type 2 diabetes mellitus (T2DM) model rats are not clear. OBJECTIVE: This study compares the pharmacokinetics of berberine between normal and T2DM model rats. MATERIALS AND METHODS: The T2DM model rats were fed with high fat diet for 4 weeks, induced by low-dose (30 mg/kg) streptozotocin for 72 h and validated by determining the peripheral blood glucose level. Rats were orally treated with berberine at a dose of 20 mg/kg and then berberine concentration in rat plasma was determined by employing a sensitive and rapid LC MS/MS method. RESULTS: The significantly different pharmacokinetic behaviour of berberine was observed between normal and T2DM model rats. When compared with the normal group, Cmax, t1/2 and AUC(0-t) of berberine were significantly increased in the model group (17.35 +/- 3.24 vs 34.41 +/- 4.25 MUg/L; 3.95 +/- 1.27 vs 9.29 +/- 2.75 h; 151.21 +/- 23.96 vs 283.81 +/- 53.92 MUg/h/L, respectively). In addition, oral clearance of berberine was significantly decreased in the model group (134.73 +/- 32.15 vs 62.55 +/- 16.34 L/h/kg). DISCUSSION AND CONCLUSION: In T2DM model rats, the pharmacokinetic behaviour of berberine was significantly altered, which indicated that berberine dosage should be modified in T2DM patients. PMID- 27937084 TI - Randomized Comparison Between Rebamipide Ophthalmic Suspension and Diquafosol Ophthalmic Solution for Dry Eye After Penetrating Keratoplasty. AB - PURPOSE: To compare the ocular surfaces of patients treated with rebamipide (REB) ophthalmic suspension or diquafosol (DQS) ophthalmic solution for dry eye syndrome after penetrating keratoplasty (PK). METHODS: A total of 40 eyes of 40 patients who had dry eyes after undergoing PK were enrolled and randomly divided into an REB group and a DQS group. Both REB and DQS groups used each eye drop four times. The tear breakup time (TBUT), corneal fluorescein staining scores, and dry eye-related quality-of-life score (DEQS) were evaluated before treatment, 2 weeks after start of treatment and 4 weeks after start of treatment. RESULTS: We found a significant improvement in TBUT (P < 0.001, Dunnett's test) and fluorescein scores (P < 0.001) 4 weeks after treatment in the REB group. Similar results were obtained in the DQS group (P < 0.001 and P = 0.01, respectively). No significant improvements in DEQS were found 4 weeks after treatment in each group (P = 0.15 and P = 0.63, analysis of variance, respectively). No significant differences were seen in these variables and in the changes between the groups after treatment. CONCLUSIONS: REB and DQS may be effective for the management of dry eye syndrome after PK in terms of ocular surface findings. In our study, effects of REB appear to be equivalent to those of DQS in the patients. PMID- 27937086 TI - Exposure control practices for administering nitrous oxide: A survey of dentists, dental hygienists, and dental assistants. AB - Engineering, administrative, and work practice controls have been recommended for many years to minimize exposure to nitrous oxide during dental procedures. To better understand the extent to which these exposure controls are used, the NIOSH Health and Safety Practices Survey of Healthcare Workers was conducted among members of professional practice organizations representing dentists, dental hygienists and dental assistants. The anonymous, modular, web-based survey was completed by 284 dental professionals in private practice who administered nitrous oxide to adult and/or pediatric patients in the seven days prior to the survey. Use of primary engineering controls (i.e., nasal scavenging mask and/or local exhaust ventilation (LEV) near the patient's mouth) was nearly universal, reported by 93% and 96% of respondents who administered to adult (A) and pediatric (P) patients, respectively. However, adherence to other recommended precautionary practices were lacking to varying degrees, and were essentially no different among those administering nitrous oxide to adult or pediatric patients. Examples of work practices which increase exposure risk, expressed as percent of respondents, included: not checking nitrous oxide equipment for leaks (41% A; 48% P); starting nitrous oxide gas flow before delivery mask or airway mask was applied to patient (13% A; 12% P); and not turning off nitrous oxide gas flow before turning off oxygen flow to the patient (8% A; 7% P). Absence of standard procedures to minimize worker exposure to nitrous oxide (13% of all respondents) and not being trained on safe handling and administration of nitrous oxide (3%) were examples of breaches of administrative controls which may also increase exposure risk. Successful management of nitrous oxide emissions should include properly fitted nasal scavenging masks, supplemental LEV (when nitrous oxide levels cannot be adequately controlled using nasal masks alone), adequate general ventilation, regular inspection of nitrous oxide delivery and scavenging equipment for leaks, availability of standard procedures to minimize exposure, periodic training, ambient air and exposure monitoring, and medical surveillance. PMID- 27937088 TI - Reply to J.B. Aragon-Ching and D. Dalela et al. PMID- 27937085 TI - An in vitro demonstration of overcoming drug resistance in SKOV3 TR and MCF7 ADR with targeted delivery of polymer pro-drug conjugates. AB - Drug resistance is a common phenomenon that occurs in cancer chemotherapy. Delivery of chemotherapeutic agents as polymer pro-drug conjugates (PPDCs) pretargeted with bispecific antibodies could circumvent drug resistance in cancer cells. To demonstrate this approach to overcome drug resistance, Paclitaxel (Ptxl)-resistant SKOV3 TR human ovarian- and doxorubicin (Dox)-resistant MCF7 ADR human mammary-carcinoma cell lines were used. Pre-targeting over-expressed biotin or HER2/neu receptors on cancer cells was conducted by biotinylated anti-DTPA or anti-HER2/neu affibody - anti-DTPA Fab bispecific antibody complexes. The targeting PPDCs are either D-Dox-PGA or D-Ptxl-PGA. Cytotoxicity studies demonstrate that the pretargeted approach increases cytotoxicity of Ptxl or Dox in SKOV3 TR or MCF7 ADR resistant cell lines by 5.4 and 27 times, respectively. Epifluorescent microscopy - used to track internalization of D-Dox-PGA and Dox in MCF7 ADR cells - shows that the pretargeted delivery of D-Dox-PGA resulted in a 2 to 4-fold increase in intracellular Dox concentration relative to treatment with free Dox. The mechanism of internalization of PPDCs is consistent with endocytosis. Enhanced drug delivery and intracellular retention following pretargeted delivery of PPDCs resulted in greater tumor cell toxicity in the current in vitro studies. PMID- 27937087 TI - Tailored Therapy for Stage I Non-Small-Cell Lung Cancer. PMID- 27937089 TI - Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. AB - Purpose To provide current recommendations on the use of sentinel node biopsy (SNB) for patients with early-stage breast cancer. Methods PubMed and the Cochrane Library were searched for randomized controlled trials, systematic reviews, meta-analyses, and clinical practice guidelines from 2012 through July 2016. An Update Panel reviewed the identified abstracts. Results Of the eight publications identified and reviewed, none prompted a change in the 2014 recommendations, which are reaffirmed by the updated literature review. Conclusion Women without sentinel lymph node (SLN) metastases should not receive axillary lymph node dissection (ALND). Women with one to two metastatic SLNs who are planning to undergo breast-conserving surgery with whole-breast radiotherapy should not undergo ALND (in most cases). Women with SLN metastases who will undergo mastectomy should be offered ALND. These three recommendations are based on randomized controlled trials. Women with operable breast cancer and multicentric tumors, with ductal carcinoma in situ, who will undergo mastectomy, who previously underwent breast and/or axillary surgery, or who received preoperative/neoadjuvant systemic therapy may be offered SNB. Women who have large or locally advanced invasive breast cancer (tumor size T3/T4), inflammatory breast cancer, or ductal carcinoma in situ (when breast-conserving surgery is planned) or are pregnant should not undergo SNB. PMID- 27937090 TI - Reply to J.B. Aragon-Ching and D. Dalela et al. PMID- 27937093 TI - Promises and Pitfalls of Primary Local Treatment in Metastatic Prostate Cancer. PMID- 27937091 TI - Personal Genomic Testing for Cancer Risk: Results From the Impact of Personal Genomics Study. AB - Purpose Significant concerns exist regarding the potential for unwarranted behavior changes and the overuse of health care resources in response to direct to-consumer personal genomic testing (PGT). However, little is known about customers' behaviors after PGT. Methods Longitudinal surveys were given to new customers of 23andMe (Mountain View, CA) and Pathway Genomics (San Diego, CA). Survey data were linked to individual-level PGT results through a secure data transfer process. Results Of the 1,042 customers who completed baseline and 6 month surveys (response rate, 71.2%), 762 had complete cancer-related data and were analyzed. Most customers reported that learning about their genetic risk of cancers was a motivation for testing (colorectal, 88%; prostate, 95%; breast, 94%). No customers tested positive for pathogenic mutations in highly penetrant cancer susceptibility genes. A minority of individuals received elevated single nucleotide polymorphism-based PGT cancer risk estimates (colorectal, 24%; prostate, 24%; breast, 12%). At 6 months, customers who received elevated PGT cancer risk estimates were not significantly more likely to change their diet, exercise, or advanced planning behaviors or engage in cancer screening, compared with individuals at average or reduced risk. Men who received elevated PGT prostate cancer risk estimates changed their vitamin and supplement use more than those at average or reduced risk (22% v 7.6%, respectively; adjusted odds ratio, 3.41; 95% CI, 1.44 to 8.18). Predictors of 6-month behavior include baseline behavior (exercise, vitamin or supplement use, and screening), worse health status (diet and vitamin or supplement use), and older age (advanced planning, screening). Conclusion Most adults receiving elevated direct-to-consumer PGT single nucleotide polymorphism-based cancer risk estimates did not significantly change their diet, exercise, advanced care planning, or cancer screening behaviors. PMID- 27937094 TI - Improved Survival With Local Treatment of Prostate Cancer in Men With Metastatic Disease: Look Before You Leap. PMID- 27937092 TI - Cetuximab Plus Chemoradiotherapy for HIV-Associated Anal Carcinoma: A Phase II AIDS Malignancy Consortium Trial. AB - Purpose Squamous cell carcinoma of the anal canal (SCCAC) is characterized by high locoregional failure (LRF) rates after definitive chemoradiation (CRT), associated with anogenital human papilloma virus, and often appears in HIV infection. Because cetuximab enhances the effect of radiation therapy in human papilloma virus-associated oropharyngeal SCC, we hypothesized that adding cetuximab to CRT would reduce LRF in SCCAC. Methods Forty-five patients with stage I to III SCCAC and HIV infection received CRT: 45 to 54 Gy radiation therapy to the primary tumor and regional lymph nodes plus eight once-weekly doses of concurrent cetuximab and two cycles of cisplatin and fluorouracil. The study was designed to detect at least a 50% reduction in 3-year LRF rate (one sided alpha, 0.10; power, 90%), assuming a 35% LRF rate from historical data. Results The 3-year LRF rate was 42% (95% CI, 28% to 56%; one-sided P = .9) by binomial proportional estimate using the prespecified end point (LRF or alive without LRF and followed < 3 years), and 20% (95% CI, 10% to 37%) by Kaplan-Meier estimate in post hoc analysis using definitions and methods consistent with historical data. Three-year rates by Kaplan-Meier estimate were 72% (95% CI, 56% to 84%) for progression-free survival and 79% (95% CI, 63% to 89%) for overall survival. Grade 4 toxicity occurred in 26%, and 4% had treatment-associated deaths. Conclusion HIV-associated SCCAC is potentially curable with definitive CRT. Although addition of cetuximab may result in less LRF, the 20% recurrence and 26% grade 4 toxicity rates indicate the continued need for more-effective and less-toxic therapies. PMID- 27937096 TI - Results From the Phase III Randomized Trial of Onartuzumab Plus Erlotinib Versus Erlotinib in Previously Treated Stage IIIB or IV Non-Small-Cell Lung Cancer: METLung. AB - Purpose The phase III OAM4971g study (METLung) examined the efficacy and safety of onartuzumab plus erlotinib in patients with locally advanced or metastatic non small-cell lung cancer selected by MET immunohistochemistry whose disease had progressed after treatment with a platinum-based chemotherapy regimen. Patients and Methods Patients were randomly assigned at a one-to-one ratio to receive onartuzumab (15 mg/kg intravenously on day 1 of each 21-day cycle) plus daily oral erlotinib 150 mg or intravenous placebo plus daily oral erlotinib 150 mg. The primary end point was overall survival (OS) in the intent-to-treat population. Secondary end points included median progression-free survival, overall response rate, biomarker analysis, and safety. Results A total of 499 patients were enrolled (onartuzumab, n = 250; placebo, n = 249). Median OS was 6.8 versus 9.1 months for onartuzumab versus placebo (stratified hazard ratio [HR], 1.27; 95% CI, 0.98 to 1.65; P = .067), with a greater number of deaths in the onartuzumab arm (130 [52%] v 114 [46%]). Median progression-free survival was 2.7 versus 2.6 months (stratified HR, 0.99; 95% CI, 0.81 to 1.20; P = .92), and overall response rate was 8.4% and 9.6% for onartuzumab versus placebo, respectively. Exploratory analyses using MET fluorescence in situ hybridization status and gene expression showed no benefit for onartuzumab; patients with EGFR mutations showed a trend toward shorter OS with onartuzumab treatment (HR, 4.68; 95% CI, 0.97 to 22.63). Grade 3 to 5 adverse events were reported by 56.0% and 51.2% of patients, with serious AEs in 33.9% and 30.7%, for experimental versus control arms, respectively. Conclusion Onartuzumab plus erlotinib did not improve clinical outcomes, with shorter OS in the onartuzumab arm, compared with erlotinib in patients with MET-positive non-small-cell lung cancer. PMID- 27937098 TI - Staphylococcus aureus Induced Endogenous Endophthalmitis with Pink Hypopyon. PMID- 27937095 TI - Group-Wide, Prospective Study of Ototoxicity Assessment in Children Receiving Cisplatin Chemotherapy (ACCL05C1): A Report From the Children's Oncology Group. AB - Purpose Optimal assessment methods and criteria for reporting hearing outcomes in children who receive treatment with cisplatin are uncertain. The objectives of our study were to compare different ototoxicity classification systems, to evaluate the feasibility of including otoacoustic emissions and extended high frequency audiometry, and to evaluate a central review mechanism for audiologic results for cisplatin-treated children in the cooperative group setting. Patients and Methods Eligible participants were 1 to 30 years, with planned cisplatin containing treatment. Hearing evaluations were conducted at baseline, before each cisplatin cycle, and at the end of therapy. Audiologic results were assessed and graded by the testing audiologist and by two central review audiologists using the American Speech-Language-Hearing Association Ototoxicity Criteria (ASHA), Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE), and Brock Ototoxicity Grades (Brock). One central reviewer also used the Society for Industrial and Organizational Psychology Ototoxicity Scale (SIOP). Results At the end of treatment, the prevalence of any degree of ototoxicity ranged from 40% to 56%, and severe ototoxicity ranged from 7% to 22%. Compared with CTCAE, SIOP detected significantly more ototoxicity ( P = .004), whereas Brock criteria detected significantly fewer patients with any or severe ototoxicity ( P < .001 for both). SIOP detected ototoxicity earlier than did the other scales. Agreement between the central reviewers and the institutional audiologist was almost perfect for ASHA and Brock, whereas the poorest agreement occurred with CTCAE. Conclusion The SIOP scale may be superior to ASHA, Brock, and CTCAE scales for classifying ototoxicity in pediatric patients who were treated with cisplatin. Future studies should evaluate inter-rater reliability of the SIOP scale. PMID- 27937097 TI - Treatment of Helicobacter pylori infected mice with Bryophyllum pinnatum, a medicinal plant with antioxidant and antimicrobial properties, reduces bacterial load. AB - CONTEXT: Bryophyllum pinnatum (Lam.) Kurz (Crassulaceae) is a plant known for its antiulcer properties. OBJECTIVE: This study evaluates the anti-Helicobacter pylori activity of Bryophyllum pinnutum methanol extract with a mouse model and its antioxidant properties. MATERIALS AND METHODS: Dried leaves of Bryophyllum pinnutum were extracted with methanol and ethyl acetate. Broth microdilution method was used to evaluate the anti-Helicobacter activity of extract samples in vitro. Swiss mice were inoculated with a suspension of Helicobacter pylori and divided into control group and four others that received 125, 250, 500 mg/kg of methanol extract or ciprofloxacin (500 mg/kg), respectively, for 7 days. Helicobacter pylori colonization and bacterial load of mouse stomach was assessed on day 1 and 7 post-treatment. The antioxidant activity of Bryophyllum pinnutum was evaluated through DPPH radical, hydroxyl radical and reducing power assay. RESULTS: Methanol extract showed a significant anti-Helicobacter activity with MIC and MBC values of 32 and 256 MUg/mL, respectively. Bryophyllum pinnatum and ciprofloxacin reduced H. pylori colonization of gastric tissue from 100% to 17%. Bryophyllum pinnatum extract (85.91 +/- 52.91 CFU) and standard (25.74 +/- 16.15 CFU) also reduced significantly (p < 0.05) bacterial load of gastric mucosa as compared to untreated infected mice (11883 +/- 1831 CFU). DPPH radical, hydroxyl radical and reducing power assays showed IC50 values of 25.31 +/- 0.34, 55.94 +/- 0.68 and 11.18 +/- 0.74 MUg/mL, respectively. DISCUSSION AND CONCLUSION: The data suggest that the methanol extract of Bryophyllum pinnatum could inhibit Helicobacter pylori growth, and may also acts as an antioxidant to protect gastric mucosa against reactive oxygen species. PMID- 27937100 TI - Should iodine be reconsidered in wound management? AB - A report of a consensus meeting on the use of iodine in wound care. PMID- 27937099 TI - Pressure area care and estimating the cost of pressure sores: Critique 3. AB - The 'silver' book, Pressure Area Care for the City and Hackney Health Authority, produced in 1988, probably takes second place in the development of pressure area care in the UK only to the 'blue book', An Investigation of Geriatric Nursing Problems in Hospital, published in 1962. Although Hibbs's work was intended only as a local service manual, it rapidly generated a much wider demand, with revision and updating in 1992. Hibbs herself says it is now out of date, but it is worth examining the precepts which formed the basis of modern pressure sore prevention. PMID- 27937101 TI - Pressure area care and estimating the cost of pressure sores: Critique 2. AB - This study was an important landmark in pressure area management, and in bringing attention to previously largely neglected economic factors. The study states that 'the first aim of pressure area care must be the prevention of pressure sores'. PMID- 27937102 TI - Pressure area care and estimating the cost of pressure sores. AB - Three reviewers critique the article cited below and assess its influence on the management of pressure sores, both in hospital and in community care. PMID- 27937105 TI - Readers' Questions. AB - APPROPRIATE WOUND DRESSINGS SHARP DEBRIDEMENT. PMID- 27937103 TI - Editorial. AB - Consensus statements Journal of Wound Care Awards. PMID- 27937106 TI - Letters. AB - SURGICAL DEBRIDEMENT CORRECTION. PMID- 27937107 TI - From the Journals. AB - MEASURING TEMPERATURE IN WOUND HEALING WATER VAPOUR TRANSMISSION RATES DYNAMIC PULSATION THERAPY. PMID- 27937108 TI - From the Journals. AB - STIMULATION OF ANGIOGENESIS BY GROWTH FACTORS CHRONIC VENOUS DISEASE OF THE LEG. PMID- 27937109 TI - Readers' Questions. AB - THE SELECTION AND USE OF COMPRESSION BANDAGES. PMID- 27937110 TI - Paediatric wound care. AB - The vast majority of wounds in children heal quickly with few or no problems. However, for those with a chronic illness, such as Crohn's disease, renal failure or neurological conditions, wound healing may be problematic because of the illness. Healing is often delayed by a poor nutritiona state, complications of surgery, infection or chemotherapy. PMID- 27937113 TI - Pressure sore treatment: Clinical guidelines. AB - Clinical guidelines, like any intervention, can and should be appraised systematically. Evaluation is essential since an intervention that appears as if it will improve care may not do so in practice. Furthermore, guidelines rely on a change in behaviour on the part of practitioners and failure to achieve this may undermine potential health gains. The key areas considered here are evaluation of guidelines themselves and assessment of their impact on care. PMID- 27937114 TI - Case Report Challenge. AB - We present three prize-winners from the journal of Wound Care Challenge in the January 1997 issue. PMID- 27937112 TI - Antifungal and antiproliferative activities of endophytic fungi isolated from the leaves of Markhamia tomentosa. AB - CONTEXT: Plants harbor endophytes with potential bioactivity. Markhamia tomentosa (Benth) K. Schum ex. Engl. (Bignoniaceae) is reported to possess antioxidant, anti-inflammatory and anticancer activities. OBJECTIVE: The antifungal and antiproliferative properties of endophytic fungi extracts and fractions from M. tomentosa were evaluated. MATERIAL AND METHODS: Endophytic fungi were isolated from the leaves of M. tomentosa and identified by ITS-rDNA sequence analysis. The antagonistic effect of the fungal strains was investigated against pathogenic fungi viz, Fusarium oxysporum, Sclerotinia sclerotiorium, Rhizoctonia solani, and Botrytis cinerea using the dual culture assay for 5-7 days. Antiproliferative effect of the fungal extracts and fractions (3.91-250 MUg/mL) on HeLa cancer cell line was tested and IC50 was calculated. Poisoning food assay and antifeedant activity against the pathogenic fungi and Spodoptera litura larvae, for 7 days and 2 h, respectively, was also tested at concentrations of 250, 500 and 1000 MUg/mL. RESULTS: Fungal endophytes Trichoderma longibrachiatum and Syncephalastrum racemosum were isolated from the leaves of M. tomentosa. Isolated endophytic fungal strains and solvent extracts showed MIC value of 1000 MUg/mL against tested pathogenic fungi in the dual culture and poisoning food assays. Methanol fraction of S. racemosum isolate showed the most effective antiproliferative activity with IC50 of 43.56 MUg/mL. Minimal feeding deterrent activity against S. litura larvae was also observed. DISCUSSION AND CONCLUSION: These findings showed that the leaves of Markhamia tomentosa harbor strains of endophytic fungi with promising health benefits, and suggest their antifungal and antiproliferative effects against pathogenic fungi and HeLa cancer cell line. PMID- 27937115 TI - Managing pressure sores: a master class. AB - The masterclass reports in this issue (page 398) raise serious questions about our understanding and practice of the management of pressure sores. PMID- 27937117 TI - Pressure sore treatment: Evidence of effectiveness. AB - The treatment of established pressure sores in the UK has markedly changed since David et al1 reviewed this area of nursing practice in 1983. For example, the use of novel wound-management products and pressure-redistributing support surfaces has been quickly established throughout the NHS. PMID- 27937116 TI - Letters. AB - MEDIEVAL ULCER MANAGEMENT SCIENTIFIC PAPERS SPECIAL EQUIPMENT IN NURSING HOMES TWO BANDAGING SYSTEMS SELECTION OF DRESSINGS FOR DIABETIC FOOT ULCERS. PMID- 27937119 TI - From the Journals. AB - THERAPEUTIC TOUCH COMPARING ELASTOMERIC PROPERTIES OF BANDAGES PRESSURE SORE PREVENTION. PMID- 27937120 TI - Pressure sore treatment. AB - The following three papers were presented at a recent master class held in association with Smith and Nephew. The first presents a guide to the appraisal of published data focusing on risk assessment tools and grading systems. The second highlights the need for randomised controlled clinical trials to provide high quality evidence for the use of pressure-redistributing support surfaces, while the third paper discusses the need for the development and implementation of pressure sore guidelines that have been based on high-quality evidence. PMID- 27937121 TI - Statistical inference for response adaptive randomization procedures with adjusted optimal allocation proportions. AB - Seamless phase II/III clinical trials have attracted increasing attention recently. They mainly use Bayesian response adaptive randomization (RAR) designs. There has been little research into seamless clinical trials using frequentist RAR designs because of the difficulty in performing valid statistical inference following this procedure. The well-designed frequentist RAR designs can target theoretically optimal allocation proportions, and they have explicit asymptotic results. In this paper, we study the asymptotic properties of frequentist RAR designs with adjusted target allocation proportions, and investigate statistical inference for this procedure. The properties of the proposed design provide an important theoretical foundation for advanced seamless clinical trials. Our numerical studies demonstrate that the design is ethical and efficient. PMID- 27937122 TI - Rational screening of peroxisome proliferator-activated receptor-gamma agonists from natural products: potential therapeutics for heart failure. AB - CONTEXT: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Activation of PPARgamma pathway has been shown to enhance fatty acid oxidation, improve endothelial cell function, and decrease myocardial fibrosis in heart failure. Thus, the protein has been raised as an attractive target for heart failure therapy. OBJECTIVE: This work attempted to discover new and potent PPARgamma agonists from natural products using a synthetic strategy of computer virtual screening and transactivation reporter assay. MATERIALS AND METHODS: A large library of structurally diverse, drug-like natural products was compiled, from which those with unsatisfactory pharmacokinetic profile and/or structurally redundant compounds were excluded. The binding mode of remaining candidates to PPARgamma ligand-binding domain (LBD) was computationally modelled using molecular docking and their relative binding potency was ranked by an empirical scoring scheme. Consequently, eight commercially available hits with top scores were selected and their biological activity was determined using a cell-based reporter-gene assay. RESULTS: Four natural product compounds, namely ZINC13408172, ZINC4292805, ZINC44179 and ZINC901461, were identified to have high or moderate agonistic potency against human PPARgamma with EC50 values of 0.084, 2.1, 0.35 and 5.6 MUM, respectively, which are comparable to or even better than that of the approved PPARgamma full agonists pioglitazone (EC50 = 0.16 MUM) and rosiglitazone (EC50 = 0.034 MUM). Hydrophobic interactions and van der Waals contacts are the primary chemical forces to stabilize the complex architecture of PPARgamma LBD domain with these agonist ligands, while few hydrogen bonds, salt bridges and/or pi-pi stacking at the complex interfaces confer selectivity and specificity for the domain-agonist recognition. DISCUSSION AND CONCLUSION: The integrated in vitro-in silico screening strategy can be successfully applied to rational discovery of biologically active compounds. The newly identified natural products with PPARgamma agonistic potency are considered as promising lead scaffolds to develop novel chemical therapeutics for heart failure. PMID- 27937123 TI - Metabolic engineering of Saccharomyces cerevisiae for improvement in stresses tolerance. AB - Lignocellulosic biomass is an attractive low-cost feedstock for bioethanol production. During bioethanol production, Saccharomyces cerevisiae, the common used starter, faces several environmental stresses such as aldehydes, glucose, ethanol, high temperature, acid, alkaline and osmotic pressure. The aim of this study was to construct a genetic recombinant S. cerevisiae starter with high tolerance against various environmental stresses. Trehalose-6-phosphate synthase gene (tps1) and aldehyde reductase gene (ari1) were co-overexpressed in nth1 (coded for neutral trehalase gene, trehalose degrading enzyme) deleted S. cerevisiae. The engineered strain exhibited ethanol tolerance up to 14% of ethanol, while the growth of wild strain was inhibited by 6% of ethanol. Compared with the wild strain, the engineered strain showed greater ethanol yield under high stress condition induced by combining 30% glucose, 30 mM furfural and 30 mM 5-hydroxymethylfurfural (HMF). PMID- 27937126 TI - A pressure measurement tool for plantar wound management. AB - This case report describes a new initiative that was designed for the long-term management of ulcer recurrence in a patient with a diabetic foot wound. PMID- 27937130 TI - Managing chronic wounds. AB - The update article published in this month's issue (page 479) provides a welcome overview of current thinking on the classification and management of chronic wounds. Over recent years, the author of this paper has played a pivotal role in promoting greater understanding of the complexities of wound healing and his published work offers clinicians an invaluable guide through the claims of dressings manufacturers, which all too often can lead the unsuspecting practitioner away from evidence-based practice. PMID- 27937131 TI - From the Journals. AB - INNOVATIVE TREATMENT FOR DIABETIC FOOT ULCERATION A MULTIDISCIPLINARY WOUND ASSESSMENT TOOL LOW-DOSE CYCLOSPORIN IN THE TREATMENT OF PYODERMA GANGRENOSUM INTERPRETING REPORTS OF COMMERCIAL DRUG TRIALS. PMID- 27937124 TI - Antioxidant, anti-inflammatory and anti-septic potential of phenolic acids and flavonoid fractions isolated from Lolium multiflorum. AB - CONTEXT: Interest has recently renewed in using Lolium multiflorum Lam. (Poaceae) (called Italian ryegrass; IRG) silage as an antioxidant and anti-inflammatory diet. OBJECTIVE: This study investigated the antioxidant, anti-inflammatory and anti-septic potential of IRG silage and identified the primary components in IRG active fractions. MATERIALS AND METHODS: Total 16 fractions were separated from the chloroform-soluble extract of IRG aerial part using Sephadex LH-20 column before HPLC analysis. Antioxidant and anti-inflammatory activities of the fractions at doses of 0-100 MUg/mL were investigated using various cell-free and cell-mediated assay systems. To explore anti-septic effect of IRG fractions, female ICR and BALB/c mice orally received 40 mg/kg of phenolic acid and flavonoid-rich active fractions F7 and F8 every other day for 10 days, respectively, followed by LPS challenge. RESULTS: The active fractions showed greater antioxidant and anti-inflammatory potential compared with other fractions. IC50 values of F7 and F8 to reduce LPS-stimulated NO and TNF-alpha production were around 15 and 30 MUg/mL, respectively. Comparison of retention times with authentic compounds through HPLC analysis revealed the presence of caffeic acid, ferulic acid, myricetin and kaempferol in the fractions as primary components. These fractions inhibited LPS-stimulated MAPK and NF-kappaB activation. Supplementation with F7 or F8 improved the survival rates of mice to 70 and 60%, respectively, in LPS-injected mice and reduced near completely serum TNF-alpha and IL-6 levels. DISCUSSION AND CONCLUSION: This study highlights antioxidant, anti-inflammatory and anti-septic activities of IRG active fractions, eventually suggesting their usefulness in preventing oxidative damage and inflammatory disorders. PMID- 27937134 TI - Letters. AB - SPINAL INJURY AND PRESSURE SORE PREVENTION TREATMENT FOR OVERGRANULATION. PMID- 27937136 TI - Economic appraisal in pressure sore management. AB - This article describes the nature and relevance of economic appraisal in the evaluation of pressure sore management. PMID- 27937137 TI - Reviews. AB - WOUND MANAGEMENT. PMID- 27937138 TI - Computerized cognitive training during physical inactivity improves executive functioning in older adults. AB - The hippocampus is closely tied to spatial navigation, a central component in cognitive functioning, and critically involved in age-associated cognitive decline and dementia. This study evaluated a novel, cognitive computerized spatial navigation training (CSNT) program targeting the hippocampus, with expectation of mitigating possible cognitive decline with bed rest (BR). During a 14-day BR study with 16 healthy, older men (mean age = 60 +/- 3, range = 55-65 years), half received CSNT for 12 days in 50-min sessions and half were controls (watching documentaries). This design uniquely controlled diet, sleep, and other personal and environmental activities. Although there were no cognitive declines in controls post-BR, CSNT participants demonstrated significant increases in executive/attention ability and processing speed, and continued spatial navigation testing showed improvement to 400 days post-BR. This intervention may prove useful to mitigate cognitive declines known to occur in long periods of immobilization and could have broader implications in protecting against age related cognitive decline. PMID- 27937140 TI - Evaluation of Whole-Brain Resting-State Functional Connectivity in Spinal Cord Injury: A Large-Scale Network Analysis Using Network-Based Statistic. AB - Large-scale network analysis characterizes the brain as a complex network of nodes and edges to evaluate functional connectivity patterns. The utility of graph-based techniques has been demonstrated in an increasing number of resting state functional MRI (rs-fMRI) studies in the normal and diseased brain. However, to our knowledge, graph theory has not been used to study the reorganization pattern of resting-state brain networks in patients with traumatic complete spinal cord injury (SCI). In the present analysis, we applied a graph-theoretical approach to explore changes to global brain network architecture as a result of SCI. Fifteen subjects with chronic (> 2 years) complete (American Spinal Injury Association [ASIA] A) cervical SCI and 15 neurologically intact controls were scanned using rs-fMRI. The data were preprocessed followed by parcellation of the brain into 116 regions of interest (ROI) or nodes. The average time series was extracted at each node, and correlation analysis was performed between every pair of nodes. A functional connectivity matrix for each subject was then generated. Subsequently, the matrices were averaged across groups, and network changes were evaluated between groups using the network-based statistic (NBS) method. Our results showed decreased connectivity in a subnetwork of the whole brain in SCI compared with control subjects. Upon further examination, increased connectivity was observed in a subnetwork of the sensorimotor cortex and cerebellum network in SCI. In conclusion, our findings emphasize the applicability of NBS to study functional connectivity architecture in diseased brain states. Further, we show reorganization of large-scale resting-state brain networks in traumatic SCI, with potential prognostic and therapeutic implications. PMID- 27937139 TI - Effects of Aicardi-Goutieres syndrome mutations predicted from ADAR-RNA structures. AB - Adenosine (A) to inosine (I) RNA editing is important for life in metazoan organisms. Dysregulation or mutations that compromise the efficacy of A to I editing results in neurological disorders and a shorten life span. These reactions are catalyzed by adenosine deaminases acting on RNA (ADARs), which hydrolytically deaminate adenosines in regions of duplex RNA. Because inosine mimics guanosine in hydrogen bonding, this prolific RNA editing alters the sequence and structural information in the RNA landscape. Aicardi-Goutieres syndrome (AGS) is a severe childhood autoimmune disease that is one of a broader set of inherited disorders characterized by constitutive upregulation of type I interferon (IFN) referred to as type I interferonopathies. AGS is caused by mutations in multiple genes whose protein products, including ADAR1, are all involved in nucleic acid metabolism or sensing. The recent crystal structures of human ADAR2 deaminase domain complexed with duplex RNA substrates enabled modeling of how AGS causing mutations may influence RNA binding and catalysis. The mutations can be broadly characterized into three groups; mutations on RNA binding loops that directly affect RNA binding, "second-layer" mutations that can alter the disposition of RNA-binding loops, and mutations that can alter the position of an alpha-helix bearing an essential catalytic residue. PMID- 27937141 TI - The impact of medical insurance coverage and molecular monitoring frequency on outcomes in chronic myeloid leukemia: real-world evidence in China. AB - OBJECTIVES: Imatinib (Glivec) has been covered by critical disease insurance for treatment of chronic myeloid leukemia (CML) in Jiangsu province of China since 2013. Further, free molecular monitoring has been provided to patients at top clinical centers as part of a pilot study that has changed the local treatment pattern and outcomes of patients with CML. This study evaluates the impact of medical insurance coverage and the molecular monitoring frequency on outcomes of patients with CML treated at a central hospital in Jiangsu, China, according to patient-level data. METHODS: The study investigated 335 CML patients receiving medical treatment in a central hospital between January 1, 2011 and December 31, 2014. Demographic and clinical characteristics were extracted from the patients' clinical records. Univariate and multivariate analyses using the logistic regression model were performed to identify the differences in outcomes of major molecular response (MMR) or complete cytogenetic response (CCyR) between patients who were insured vs uninsured, or between patients with frequency of PCR monitoring <=2 times vs >=3 times per year. RESULTS: Both the achievement of MMR (BCR-ABLIS <=0.1%) (50.4% vs 37.5%) and CCyR (80.7% vs 62.8%) at 12 months have shown significant differences that favored patients with insurance coverage of imatinib, while there was no significant difference in the outcome of BCR-ABLIS <=1% between insured and non-insured groups (56.0% vs 51.3%) at 6 months. The long-term results at 24 months demonstrated that there was a statistically significant difference in MMR rates between the group with 3 or more PCR monitoring tests per year and the group of patients with 2 or less PCR tests per year (76.9% vs 52.2%). CONCLUSIONS: The study findings suggest that CML patients benefit from insurance coverage of imatinib and higher frequency (>=3) of regularly scheduled molecular monitoring PCR in China. PMID- 27937143 TI - Discriminating cognitive screening and cognitive testing from neuropsychological assessment: implications for professional practice. AB - OBJECTIVE: To provide clarification on the distinction between cognitive screening, cognitive testing, and neuropsychological assessment and highlight practical implications. METHOD: Non-systematic brief clinical review. RESULTS: There is a present lack of explicit distinction between the various levels of measurement of cognitive functioning with regard to goals, indications for use, levels of complexity, and outcome. There is also a lack of guidance regarding the identification of who should be responsible for the administration and interpretation at each level. CONCLUSIONS: There is a growing awareness of the importance of cognitive health and disability, and of the importance of measurement of cognitive functions across the lifespan. For example, cognitive screening has been mandated by the Patient Protection and Affordable Care Act of 2010, and language contained within new psychiatric diagnostic criteria and healthcare regulatory changes reflect increased consideration of the importance of measurement of cognition. Changes such as these necessitate greater clarity on this important issue as it bears implications for professional practice, which ranges from education and training competencies, practice standards, and the way that neuropsychologists clarify and advocate for the value of specialty referrals for comprehensive assessment in a competitive and ever-changing healthcare market. PMID- 27937142 TI - Risky decision-making in children with and without ADHD: A prospective study. AB - Learning from past decisions can enhance successful decision-making. It is unclear whether difficulties in learning from experience may contribute to risky decision-making, which may be altered among individuals with attention deficit/hyperactivity disorder (ADHD). This study follows 192 children with and without ADHD aged 5 to 10 years for approximately 2.5 years and examines their risky decision-making using the Balloon Emotional Learning Task (BELT), a computerized assessment of sequential risky decision-making in which participants pump up a series of virtual balloons for points. The BELT contains three task conditions: one with a variable explosion point, one with a stable and early explosion point, and one with a stable and late explosion point. These conditions may be learned via experience on the task. Contrary to expectations, ADHD status was not found to be related to greater risk-taking on the BELT, and among younger children ADHD status is in fact associated with reduced risk-taking. In addition, the typically-developing children without ADHD showed significant learning related gains on both stable task conditions. However, the children with ADHD demonstrated learning on the condition with a stable and early explosion point, but not on the condition with the stable and late explosion point, in which more pumps are required before learning when the balloon will explode. Learning during decision-making may be more difficult for children with ADHD. Because adapting to changing environmental demands requires the use of feedback to guide future behavior, negative outcomes associated with childhood ADHD may partially reflect difficulties in learning from experience. PMID- 27937174 TI - Providing Optimal Palliative Care for Persons Living with Dementia: A Comparison of Physician Perceptions in the Netherlands and the United Kingdom. AB - BACKGROUND: The European Association for Palliative Care (EAPC) recently issued a framework that defines optimal palliative care in dementia. However, implementation of the guidelines may pose challenges for physicians working with dementia patients in practice. OBJECTIVE: To measure and compare the perceptions of physicians in two European regions regarding the importance and challenges of implementing recommendations for optimal palliative care in dementia patients. DESIGN: Cross-sectional observational study. SETTING: The Netherlands and the United Kingdom. SUBJECTS: Physicians (n = 317) providing palliative care to patients with dementia. MEASUREMENTS: Postal survey. RESULTS: Physicians in the Netherlands and Northern Ireland (NI), United Kingdom, prioritized the same domains of optimal palliative care for dementia and these match the priorities in the EAPC-endorsed guidelines. Respondents in both countries rated lack of education of professional teams and lack of awareness of the general public among the most important barriers to providing palliative care in dementia. NI respondents also identified access to specialist support as a barrier. The results indicate that there is a strong consensus among experts, elderly care physicians, and general practitioners across a variety of settings in Europe that person-centered care involving optimal communication and shared decision making is the top priority for delivering optimal palliative care in dementia. CONCLUSIONS: The current findings both support and enhance the new recommendations ratified by the EAPC. To take forward the implementation of EAPC guidelines for palliative care for dementia, it will be necessary to assess the challenges more thoroughly at a country-specific level and to design and test interventions that may include systemic changes to help physicians overcome such challenges. PMID- 27937175 TI - The Glycosylphosphatidylinositol Anchor Biosynthesis Genes GPI12, GAA1, and GPI8 Are Essential for Cell-Wall Integrity and Pathogenicity of the Maize Anthracnose Fungus Colletotrichum graminicola. AB - Glycosylphosphatidylinositol (GPI) anchoring of proteins is one of the most common posttranslational modifications of proteins in eukaryotic cells and is important for associating proteins with the cell surface. In fungi, GPI-anchored proteins play essential roles in cross-linking of beta-glucan cell-wall polymers and cell-wall rigidity. GPI-anchor synthesis is successively performed at the cytoplasmic and the luminal face of the ER membrane and involves approximately 25 proteins. While mutagenesis of auxiliary genes of this pathway suggested roles of GPI-anchored proteins in hyphal growth and virulence, essential genes of this pathway have not been characterized. Taking advantage of RNA interference (RNAi) we analyzed the function of the three essential genes GPI12, GAA1 and GPI8, encoding a cytoplasmic N-acetylglucosaminylphosphatidylinositol deacetylase, a metallo-peptide-synthetase and a cystein protease, the latter two representing catalytic components of the GPI transamidase complex. RNAi strains showed drastic cell-wall defects, resulting in exploding infection cells on the plant surface and severe distortion of in planta-differentiated infection hyphae, including formation of intrahyphal hyphae. Reduction of transcript abundance of the genes analyzed resulted in nonpathogenicity. We show here for the first time that the GPI synthesis genes GPI12, GAA1, and GPI8 are indispensable for vegetative development and pathogenicity of the causal agent of maize anthracnose, Colletotrichum graminicola. PMID- 27937337 TI - A jaundiced bodybuilder Cholestatic hepatitis as side effect of injectable anabolic-androgenic steroids. AB - The use of anabolic steroids is prevalent in recreational athletes. This case report describes a young amateur bodybuilder who was referred to our outpatient clinic with jaundice and loss of appetite due to cholestatic hepatitis. Additional tests including a liver biopsy made it likely that the hepatitis was caused by the injectable anabolic steroid trenbolone enanthate. Cholestatic hepatitis may not be limited to the use of oral anabolic-androgenic steroids, as is widely assumed. Therefore, and because of other side effects, the recreational use of all forms of anabolic steroids should be discouraged. PMID- 27937389 TI - Perceptual and acoustic differences between authentic and acted nonverbal emotional vocalizations. AB - Most research on nonverbal emotional vocalizations is based on actor portrayals, but how similar are they to the vocalizations produced spontaneously in everyday life? Perceptual and acoustic differences have been discovered between spontaneous and volitional laughs, but little is known about other emotions. We compared 362 acted vocalizations from seven corpora with 427 authentic vocalizations using acoustic analysis, and 278 vocalizations (139 authentic and 139 acted) were also tested in a forced-choice authenticity detection task ( N = 154 listeners). Target emotions were: achievement, amusement, anger, disgust, fear, pain, pleasure, and sadness. Listeners distinguished between authentic and acted vocalizations with accuracy levels above chance across all emotions (overall accuracy 65%). Accuracy was highest for vocalizations of achievement, anger, fear, and pleasure, which also displayed the largest differences in acoustic characteristics. In contrast, both perceptual and acoustic differences between authentic and acted vocalizations of amusement, disgust, and sadness were relatively small. Acoustic predictors of authenticity included higher and more variable pitch, lower harmonicity, and less regular temporal structure. The existence of perceptual and acoustic differences between authentic and acted vocalizations for all analysed emotions suggests that it may be useful to include spontaneous expressions in datasets for psychological research and affective computing. PMID- 27937437 TI - New frontiers in couple-based interventions in cancer care: refining the prescription for spousal communication. AB - BACKGROUND: The diagnosis and treatment of cancer is a life-altering experience that signals profound changes in a person's life. However, most people do not experience cancer in isolation or cope alone. Despite the fact that partners (i.e. spouses, significant others) provide emotional support and play a critical role in caregiving, cancer exacts a heavy toll on them and challenges their relationship with the patient by altering established communication patterns and roles. In recognition of this, a burgeoning literature involving couple-based interventions to improve patient and partner quality of life and adaptation has emerged. However, questions remain regarding how we can improve these interventions to exact greater impact on patient and partner outcomes. MATERIAL AND METHODS: A narrative review of the literature on couples' communication processes in cancer was conducted in order to describe knowledge gaps and directions for future research. RESULTS: Most couple-based interventions have included a communication skills training component because communication is an important process through which couples make sense of cancer, engage in social support, negotiate role changes and coordinate coping responses. However, scholars still know very little about what they should instruct couples to talk about, how often they should talk and when talking (or not talking) is beneficial (and for whom - the patient, partner, or both). CONCLUSION: In order push this field forward, we need to develop a more nuanced view of couples' communication that acknowledges that there are multiple ways to talk, different aspects of the cancer experience to talk about, and preexisting communication patterns and preferences for different couples that may influence the utility of talk. Interventions that replace the unilateral and generic prescription to talk openly about cancer with targeted questions that prompt reflection on couples' unique strengths, preexisting communication patterns and support resources may thus help bolster the impact of couple-based interventions on patient and partner quality of life. PMID- 27937534 TI - Patterns of HIV Risks and Related Factors among People Who Inject Drugs in Kermanshah, Iran: A Latent Class Analysis. AB - The objective of this study was to explore patterns of drug use and sexual risk behaviors among people who inject drugs (PWID) in Iran. We surveyed 500 PWID in Kermanshah concerning demographic characteristics, sexual risk behaviors, and drug-related risk behaviors in the month prior to study. We used latent class analysis (LCA) to establish a baseline model of risk profiles and to identify the optimal number of latent classes, and we used ordinal regression to identify factors associated with class membership. Three classes of multiple HIV risk were identified. The probability of membership in the high-risk class was 0.33, compared to 0.26 and 0.40 for the low- and moderate-risk classes, respectively. Compared to members in the lowest-risk class (reference group), the highest-risk class members had higher odds of being homeless (OR = 4.5, CI: 1.44-8.22; p = 0.001) in the past 12 months. Members of the high-risk class had lower odds of regularly visiting a needle and syringe exchange program as compared to the lowest-risk class members (AOR = 0.42, CI: 0.2-0.81; p = 0.01). Findings show the sexual and drug-related HIV risk clusters among PWID in Iran, and emphasize the importance of developing targeted prevention and harm reduction programs for all domains of risk behaviors, both sexual and drug use related. PMID- 27937671 TI - Is there really an eccentric action of the hamstrings during the swing phase of high-speed running? part I: A critical review of the literature. AB - It is widely assumed that there is an eccentric hamstring muscle fibre action during the swing phase of high-speed running. However, animal and modelling studies in humans show that the increasing distance between musculotendinous attachment points during forward swing is primarily due to passive lengthening associated with the take-up of muscle slack. Later in the swing phase, the contractile element (CE) maintains a near isometric action while the series elastic (tendinous) element first stretches as the knee extends, and then recoils causing the swing leg to forcefully retract prior to ground contact. Although modelling studies showed some active lengthening of the contractile (muscular) element during the mid-swing phase of high-speed running, we argue that the increasing distance between the attachment points should not be interpreted as an eccentric action of the CE due to the effects of muscle slack. Therefore, there may actually be no significant eccentric, but rather predominantly an isometric action of the hamstrings CE during the swing phase of high-speed running when the attachment points of the hamstrings are moving apart. Based on this, we propose that isometric rather than eccentric exercises are a more specific way of conditioning the hamstrings for high-speed running. PMID- 27937672 TI - From the Journals. AB - THE USE OF TAP WATER FOR CLEANSING TRAUMATIC WOUNDS TISSUE ADHESIVES IN THE MANAGEMENT OF LACERATIONS EVALUATING COMPRESSION THERAPY FOR LEG ULCERS THE EFFECTS OF DRESSINGS ON THE HEALING OF VENOUS LEG ULCERS. PMID- 27937673 TI - The aetiology and management of plantar callus formation. AB - This update reviews the assessment and management of patients with callus. PMID- 27937674 TI - Wound Care Awards 1997. AB - The Journal of Wound Care, five years after its launch, now has 7300 subscribers. A recent reader survey tells us that an average of three people read each copy - about 21 000 people every month. Back in 1992 few could have predicted this level of interest. The success of this year's Wound Care Awards, with over 50 entries from all over the world, representing many different disciplines, reveals that wound management is now firmly on the clinical agenda. PMID- 27937535 TI - The emerging biology of RNA post-transcriptional modifications. AB - RNA modifications have long been known to be central in the proper function of tRNA and rRNA. While chemical modifications in mRNA were discovered decades ago, their function has remained largely mysterious until recently. Using enrichment strategies coupled to next generation sequencing, multiple modifications have now been mapped on a transcriptome-wide scale in a variety of contexts. We now know that RNA modifications influence cell biology by many different mechanisms - by influencing RNA structure, by tuning interactions within the ribosome, and by recruiting specific binding proteins that intersect with other signaling pathways. They are also dynamic, changing in distribution or level in response to stresses such as heat shock and nutrient deprivation. Here, we provide an overview of recent themes that have emerged from the substantial progress that has been made in our understanding of chemical modifications across many major RNA classes in eukaryotes. PMID- 27937670 TI - Griflola frondosa (GF) produces significant antidepressant effects involving AMPA receptor activation in mice. AB - CONTEXT: Griflola frondosa (Fr) S.F. Gray (Meripilaceae) (GF) is a medical mushroom, and its regulation of the immune system is of interest for the treatment of mood disorders. alpha-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors are the central mediator for the treatment of depression. OBJECTIVE: This study examines the antidepressant effects of GF and the role of AMPA in these antidepressant effects. MATERIALS AND METHODS: The CD-1 mice were fed with GF- or Pleurotus ostreatus [(Jacq.: Fr) Kumm (Pleurotaceae)] (PO) containing food for 1 day or 5 days. The antidepressant effects was determined in the tail suspension test (TST), forced swim test (FST), and open field test (OFT). The involvement of AMPA receptors was determined by the application of the AMPA-specific blocker GYKI 52466. RESULTS: Treatments with 20%, 33% or 50% of GF containing food significantly decreased the immobility time (63.6, 56.9, and 52.0% in TST; and 50.8, 43.2, and 38.2% in FST) after 1 day and (62.3, 51.8, and 52.8% in TST; and 49.5, 45.1, and 40.3% in FST) after 5 days. GF-containing food did not cause hyperactive effects in the OFT. The antidepressant effects of the 33% of GF-containing food (down-to 51.3% in 1-day TST and 46.8% in 5-day FST) were significantly stronger than that of the 33% of PO-containing food (down-to 85.5% in 1-day TST and 82.0% in 5-day FST). AMPA-specific blocker GYKI 52466 was able to block the antidepressant effects of the GF-containing food. CONCLUSION: GF demonstrated the potential as a safe medical food supplement for the patient with depression. PMID- 27937675 TI - Reviews. AB - CHRONIC WOUND CARE: A CLINICAL SOURCE BOOK FOR HEALTHCARE PROFESSIONALS (2nd edition). PMID- 27937677 TI - Absorbent dressings: Critique II. AB - Two critiques review the classic paper cited below and discuss its influence on the development of surgical dressings. PMID- 27937676 TI - Physiological characteristics, dry matter, and active component accumulation patterns of Changium smyrnioides in response to a light intensity gradient. AB - CONTEXT: Changium smyrnioides Wolff (Apiaceae) is an endangered medicinal plant with numerous pharmacological uses. OBJECTIVE: To investigate the effect of light intensity levels on the growth and accumulation of secondary metabolites of C. smyrnioides, cultivated seedlings were subjected to different relative light intensities via sun-shading. MATERIALS AND METHODS: Changium smyrnioides seedlings were subjected to five irradiance treatments (100, 60.54, 44.84, 31.39, and 10.56% sunlight) in glasshouse for 9 months. Enzymatic and non-enzymatic antioxidants with spectrophotometric method, photosynthetic parameters with Li 6400XT, dry matter accumulation and active component contents in the root with spectrophotometric and HPLC method were analyzed. RESULTS: With an increase in relative light intensity levels, activities of enzymatic and non-enzymatic antioxidants, and malondialdehyde (MDA) contents were increased overall, while net photosynthetic rate (Pn) and dry matter accumulation patter first increased and then declined. The highest net photosynthetic rate (30.68 MUmol/m2.s) and dry root weight (5.07 g) were achieved under 60.54% sunlight. Lower relative light intensity levels stimulated the accumulation levels of bioactive compounds in the roots so that the highest contents of mannitol (1.35%) and choline (405.58 MUg/g) were recorded under 31.39% sunlight, and the highest polysaccharide content (10.80%) were achieved under 44.84% sunlight. With a decrease in the relative light intensity levels, the water-soluble component content increased first and then decreased. DISCUSSION AND CONCLUSION: The results revealed that 31.39-60.54% sunlight serve as appropriate relative light intensity conditions for cultivated C. smyrnioides. PMID- 27937679 TI - Readers' Questions. AB - HYPERTROPHIC BURN SCARS. PMID- 27937678 TI - From the Journals. AB - THE USE OF SYSTEMIC ANTIBIOTICS IN THE TREATMENT OF CHRONIC WOUNDS NEW DEVELOPMENTS IN ANTIMICROBIAL THERAPY AND THEIR IMPLICATIONS FOR WOUND CARE. PMID- 27937680 TI - Tissue viability education. AB - In recent years there has been a considerable increase in the number of nurses in the UK who have adopted the title 'tissue viability nurse'. Who are they, and what do they do? PMID- 27937682 TI - The Role of Internal Health Locus of Control in Relation to Self-Rated Health in Older Adults. AB - The present study examined how internal health locus of control is associated with older adults' self-rated health. Multivariate analyses with older participants (aged >= 60) in the MIDUS II (n = 1,533) showed that internal health locus of control was not only directly associated with positive ratings of health but also interacted with gender and race. The positive impact of internal health locus of control on self-rated health was particularly greater in females and Whites than their counterparts. Findings highlight the important role of internal health locus of control in the psychological mechanism of health and call attention to group-specific strategies for health promotion. PMID- 27937683 TI - Hydroxyapatite-based sorbents: elaboration, characterization and application for the removal of catechol from the aqueous phase. AB - Hydroxyapatite (HAP) is highly considered as good sorbent for the removal of metals from the aqueous phase. However, soluble metals co-exist with organic pollutants in wastewaters. But little work has been devoted to investigate the reactivity of HAP for the removal of organic compounds. The main objective of this work is to study the reactivity of HAP-based sorbents for the removal of catechol as a model organic pollutant from an aqueous solution. Thus, HAP sorbents were firstly synthesized using calcium carbonate and potassium dihydrogen phosphate under moderate conditions (25-80 degrees C, atmospheric pressure). A zinc-doped HAP was also used as sorbent, which was obtained from the contact of HAP with an aqueous solution of zinc nitrate. All the sorbents were characterized by different standard physico-chemical techniques. The sorption of catechol was carried out in a batch reactor under stirring at room temperature and pressure. Zinc-doped HAP sorbent was found to be more reactive than non-doped HAP sorbents for the fixation of catechol. The highest sorption capacity was of 15 mg of C per gram of zinc-doped HAP sorbent. The results obtained suggest the reaction scheme of HAP sorbents with metals and organic pollutants when HAP sorbents were used for the treatment of complex wastewaters. PMID- 27937685 TI - Encouraging Community in a Continuing Care Retirement Community. PMID- 27937684 TI - Yinzhihuang oral liquid in the treatment of neonatal jaundice: a meta-analysis. AB - CONTEXT: Yinzhihuang oral liquid, a well-known Chinese herbal formula, is a clinical drug for the treatment of neonatal jaundice, and a number of clinical trials have been published addressing this issue, but there is no comprehensive analysis that evaluates its efficacy for the treatment of newborn with hyperbilirubinaemia. OBJECTIVE: A meta-analysis was conducted to evaluate the efficacy of Yinzhihuang oral liquid on neonatal jaundice. METHODS: Search was performed throughout PubMed, Cochrane Library, EMBASE, Ovid, Wanfang, VIP Medicine Information System (VMIS) and China National Knowledge Infrastructure (CNKI) databases up to December 2015. The search terms were (Yinzhihuang oral liquid or Yinzhihuang oral solution), (neonatal jaundice or neonatal hyperbilirubinaemia), and (efficacy). Review Manager 5.2 software was used for analyzing the data. Data were pooled by using the random-effects models and expressed as relative ratio (RR), standardized mean difference (SMD) or mean difference (MD) with a 95% confidence interval (CI). The Cochrane tool was applied to assess the risk of bias of the trials. RESULTS: Yinzhihuang oral liquid in conjunction with other therapy increased effective rate of neonatal jaundice therapy (RR =1.14, 95%CI: 1.08-1.20). Yinzhihuang oral liquid significantly eliminated overproduced bilirubin which was measured by TSB or TCB at the third day and fifth day during the treatment {[third day, SMD = -1.63, 95%CI: -2.20 to (-1.06)], [fifth day, SMD = -5.00, 95%CI: -7.88 to (-2.12)]}; Yinzhihuang oral liquid significantly shortened jaundice subsiding time [MD = 3.20, 95%CI: -6.01to (-0.39)]. CONCLUSION: Yinzhihuang oral liquid can be considered as an effective treatment option for neonatal jaundice. PMID- 27937736 TI - Characteristics of flocs formed by polymer-only coagulation in water treatment and their impacts on the performance of downstream membrane separation. AB - Two different quaternary amine polymers were examined as primary coagulants for the removal of natural organic matter (NOM) and concurrent production of flocs favorable for downstream membrane separation. The primary issue explored was the relationship between various coagulation conditions on the floc characteristics and the subsequent performance of microfiltration when filtering coagulated NOM. The size distribution and morphological properties of flocs formed through the coagulation of NOM were characterized and the effects of polymer type and dose on these characteristics were also examined. Coagulation of NOM using polydiallyldimethyl-ammonium chloride (pDADMAC) produced looser and less settleable flocs compared to dosing the equivalent amount of epichlorohydrin/dimethylamine (epi/DMA). This was associated with the formation of a relatively denser cake layer on the top of the membrane for the filtration of NOM coagulated with epi/DMA. The charge neutralization coagulation condition with the polymers removed almost all of the fouling tendency that had occurred when filtering raw NOM. The median diameter and the fractal dimension of the flocs produced increased as the zeta potential approached zero, which resulted in the formation of a cake layer that was easily removed from the surface of the membrane. PMID- 27937738 TI - Cellulose dressings: Critique II. AB - Wood reported, possibly for the first time, that gauze applied directly to a wound surface left behind fibres that could become incorporated into granulation tissue and interfere with normal healing. Unfortunately, his paper contains several inaccuracies and unsubstantiated statements and he also appears to have been confused about the structure and composition of the products to which he refers. PMID- 27937735 TI - Deazaguanine derivatives, examples of crosstalk between RNA and DNA modification pathways. AB - Seven-deazapurine modifications were thought to be highly specific of tRNAs, but have now been discovered in DNA of phages and of phylogenetically diverse bacteria, illustrating the plasticity of these modification pathways. The intermediate 7-cyano-7-deazaguanine (preQ0) is a shared precursor in the pathways leading to the insetion of 7-deazapurine derivatives in both tRNA and DNA. It is also used as an intermediate in the synthesis of secondary metabolites such as toyocamacin. The presence of 7-deazapurine in DNA is proposed to be a protection mechanism against endonucleases. This makes preQ0 a metabolite of underappreaciated but central importance. PMID- 27937740 TI - From the Journals. AB - MEASURING WOUND VOLUME: ACCURACY OF ALGINATE MOULDS HYALURONIC ACID IN HEALING CHRONIC WOUNDS. PMID- 27937741 TI - Case Report Challenge. AB - We present two prizewinners from the Journal of Wound Care Challenge in the June 1996 issue. PMID- 27937737 TI - Multilevel analysis exploring the links between stress, depression, and sleep problems among two-year college students. AB - OBJECTIVE: This study explored the association of stress and depression with a multidimensional sleep problems construct in a sample of 2-year college students. PARTICIPANTS: The sample consisted of 440 students enrolled in 2-year study from Fall 2011 to Fall 2013. METHODS: Participants in an obesity prevention study completed surveys assessing sleep, stress, and depression at baseline, 4, 12, and 24 months. Multilevel models predicting sleep problems were conducted to distinguish episodic from chronic reports of stress and depression. RESULTS: Participants were primarily women (68%), white (73%), young adults (M age = 22.8), with an average of 8.4 hours of sleep per night. Neither stress nor depression was predictive of sleep quantity; however, they were predictive of sleep quality. CONCLUSIONS: Results show that sleep quality rather than sleep quantity may be the greater health concern for young adults, suggesting that intervention programs targeting depression, stress management, and healthy sleep patterns are warranted. PMID- 27937742 TI - Delivering excellence. AB - Joining the Journal of Wound Care team has given me a unique opportunity to contribute towards dissemination of information in the field to complement my current activities in research and education. As a lecturer and researcher, I knew my role but moving on to unfamiliar territory it is important for me to have a vision for the journal in advancing wound management, research and education. Practitioners, researchers and educators share the goal of delivering excellence in wound care and the journal aims to ensure its articles are relevant and interesting to all concerned professionals. PMID- 27937743 TI - Cellulose dressings. AB - Two critiques review the classic paper cited below and discuss its influence on the development of surgical dressings. PMID- 27937744 TI - Crab collagenase in wound debridement. AB - A comparative study was performed of the caseinolytic, necrolytic and fibrinolytic activities of a crab collagenase product prepared from the hepatopancreas of the king crab (Paralithodes camtschatica) and four enzyme preparations (trypsin/chymotrypsin and protease complexes isolated from Aspergillus terricola, Carica papaya and pseudomonodaceae). This paper reports an in vitro investigation, an in vivo study with rats and a clinical evaluation. It was found that crab collagenase has the highest proteolytic activity measured with respect to fibrin clot and necrotic eschar in vitro although its caseinolytic activity is the lowest. A clinical trial involving 21 patients with leg ulcers confirmed the clinical efficiency of crab collagenase compared with trypsin/chymotrypsin. The results suggest that crab collagenase is useful in wound debridement. PMID- 27937745 TI - Ionizing Radiation Alters Human Embryonic Stem Cell Properties and Differentiation Capacity by Diminishing the Expression of Activin Receptors. AB - Exposure of the embryo to ionizing radiation (IR) is detrimental as it can cause genotoxic stress leading to immediate and latent consequences such as functional defects, malformations, or cancer. Human embryonic stem (hES) cells can mimic the preimplantation embryo and help to assess the biological effects of IR during early development. In this study, we describe the alterations H9 hES cells exhibit after X-ray irradiation in respect to cell cycle progression, apoptosis, genomic stability, stem cell signaling, and their capacity to differentiate into definitive endoderm. Early postirradiation, hES cells responded with an arrest in G2/M phase, elevated apoptosis, and increased chromosomal aberrations. Significant downregulation of stem cell signaling markers of the TGF beta-, Wnt-, and Hedgehog pathways was observed. Most prominent were alterations in the expression of activin receptors. However, hES cells responded differently depending on the culture conditions chosen for maintenance. Enzymatically passaged cells were less sensitive to IR than mechanically passaged ones showing fewer apoptotic cells and fewer changes in the stem cell signaling 24 h after irradiation, but displayed higher levels of chromosomal aberrations. Even though many of the observed changes were transient, surviving hES cells, which were differentiated 4 days postirradiation, showed a lower efficiency to form definitive endoderm than their mock-irradiated counterparts. This was demonstrated by lower expression levels of SOX17 and microRNA miR-375. In conclusion, hES cells are a suitable tool for the IR risk assessment during early human development. However, careful choice of the culture methods and a vigorous monitoring of the stem cell quality are mandatory for the use of these cells. Exposure to IR influences the stem cell properties of hES cells even when immediate radiation effects are overcome. This warrants consideration in the risk assessment of radiation effects during the earliest stages of human development. PMID- 27937747 TI - From the Journals. AB - TOXICITY OF ANTISEPTIC WOUND CLEANSERS PSEUDOMONAS FOLLICULITIS ENZYME DEBRIDEMENT. PMID- 27937746 TI - Teriflunomide in multiple sclerosis: an update. AB - Teriflunomide, a once-daily, oral disease-modifying therapy, has demonstrated efficacy in patients with relapsing forms of multiple sclerosis (MS) and patients with a first clinical episode suggestive of MS. As the only disease-modifying therapy with positive disability results in two Phase III trials, teriflunomide significantly slowed disability in patients with relapsing forms of MS. We highlight data from the Phase II study and the TEMSO, TOWER, TOPIC and TENERE teriflunomide studies. TEMSO MRI outcomes have been supported with Structural Image Evaluation Using Normalization of Atrophy analyses. We present data from long-term extensions of the Phase II study, TEMSO and TOWER, as well as results from patients who switched from other disease-modifying therapies to teriflunomide, patient-reported outcomes and supplementary measures of response. PMID- 27937748 TI - Readers' Questions. AB - TOPICAL ANALGESICS IN LEG ULCER PATIENTS. PMID- 27937749 TI - Letters. AB - PRESSURE SORE PROTOCOL TEA TREE BURN GELS. PMID- 27937751 TI - Failure to Integrate Quantitative Measurement Methods of Ocular Inflammation Hampers Clinical Practice and Trials on New Therapies for Posterior Uveitis. AB - Uveitis is one of the fields in ophthalmology where a tremendous evolution took place in the past 25 years. Not only did we gain access to more efficient, more targeted, and better tolerated therapies, but also in parallel precise and quantitative measurement methods developed allowing the clinician to evaluate these therapies and adjust therapeutic intervention with a high degree of precision. Objective and quantitative measurement of the global level of intraocular inflammation became possible for most inflammatory diseases with direct or spill-over anterior chamber inflammation, thanks to laser flare photometry. The amount of retinal inflammation could be quantified by using fluorescein angiography to score retinal angiographic signs. Indocyanine green angiography gave imaging insight into the hitherto inaccessible choroidal compartment, rendering possible the quantification of choroiditis by scoring indocyanine green angiographic signs. Optical coherence tomography has enabled measurement and objective monitoring of retinal and choroidal thickness. This multimodal quantitative appraisal of intraocular inflammation represents an exquisite security in monitoring uveitis. What is enigmatic, however, is the slow pace with which these improvements are integrated in some areas. What is even more difficult to understand is the fact that clinical trials to assess new therapeutic agents still mostly rely on subjective parameters such as clinical evaluation of vitreous haze as a main endpoint; whereas a whole array of precise, quantitative, and objective modalities are available for the design of clinical studies. The scope of this work was to review the quantitative investigations that improved the management of uveitis in the past 2-3 decades. PMID- 27937752 TI - Identification of Root-Secreted Compounds Involved in the Communication Between Cucumber, the Beneficial Bacillus amyloliquefaciens, and the Soil-Borne Pathogen Fusarium oxysporum. AB - Colonization of plant growth-promoting rhizobacteria (PGPR) is critical for exerting their beneficial effects on the plant. Root exudation is a major factor influencing the colonization of both PGPR and soil-borne pathogens within the root system. However, the tripartite interaction of PGPR, plant roots, and soil borne pathogens is poorly understood. We screened root exudates for signals that mediate tripartite interactions in the rhizosphere. In a split-root system, we found that root colonization of PGPR strain Bacillus amyloliquefaciens SQR9 on cucumber root was significantly enhanced by preinoculation with SQR9 or the soil borne pathogen Fusarium oxysporum f. sp. cucumerinum, whereas root colonization of F. oxysporum f. sp. cucumerinum was reduced upon preinoculation with SQR9 or F. oxysporum f. sp. cucumerinum. Root exudates from cucumbers preinoculated with SQR9 or F. oxysporum f. sp. cucumerinum were analyzed and 109 compounds were identified. Correlation analysis highlighted eight compounds that significantly correlated with root colonization of SQR9 or F. oxysporum f. sp. cucumerinum. After performing colonization experiments with these chemicals, raffinose and tryptophan were shown to positively affect the root colonization of F. oxysporum f. sp. cucumerinum and SQR9, respectively. These results indicate that cucumber roots colonized by F. oxysporum f. sp. cucumerinum or SQR9 increase root secretion of tryptophan to strengthen further colonization of SQR9. In contrast, these colonized cucumber roots reduce raffinose secretion to inhibit root colonization of F. oxysporum f. sp. cucumerinum. PMID- 27937753 TI - Isolation and Characterization of Multipotent Mesenchymal Stem Cells Adhering to Adipocytes in Canine Bone Marrow. AB - The ceiling culture method has been used to isolate mature adipocytes from adipose tissue that can be dedifferentiated into fibroblastic cells, also known as dedifferentiated fat (DFAT) cells that self-renew and are multipotent, with much higher homogeneity and colony-forming efficiency than those of adipose tissue-derived mesenchymal stem cells. We cultured adipocytes from canine bone marrow using this technique, with the expectation of obtaining DFAT cells. However, contrary to our expectations, continuous monitoring of ceiling cultures by time-lapse microscopy revealed many small cells adhering to adipocytes that proliferated rapidly into cells with a fibroblastic morphology and without any dedifferentiation from adipocytes. We named these cells bone marrow peri adipocyte cells (BM-PACs) and demonstrated the multipotent properties of BM-PACs compared to that of conventionally cultured canine bone marrow mesenchymal stem cells (BMMSCs). BM-PACs showed significantly greater clonogenicity and proliferation ability than BMMSCs. An in vitro trilineage differentiation assay revealed that BM-PACs possess adipogenic, osteogenic, and chondrogenic capacities superior to those of BMMSCs. Flow cytometric analysis revealed that the expression of CD73, which plays an important role in cell growth and differentiation, was significantly higher in BM-PACs than in BMMSCs. These results indicate that canine BM-PACs have stem cell characteristics that are superior to those of BMMSCs, and that these mesenchymal stem cells (MSCs) appear to be a feasible source for cell-based therapies in dogs. PMID- 27937806 TI - Association Between Hyperuricemia and Major Adverse Cardiac Events in Patients with Acute Myocardial Infarction. AB - BACKGROUND: To investigate the association between hyperuricemia and major adverse cardiac events (MACE) in patients with acute myocardial infarction (AMI). METHODS: Consecutive patients admitted with AMI to the Coronary Care Unit at R. K. Khan Hospital (Durban, South Africa) between the years 2006 and 2014 were included. Demographic data, including clinical and biochemical information stored in an electronic database, were obtained from all patients. RESULTS: A total of 2683 patients were studied, of whom 65% were males. The mean age of the participants was 57.1 +/- 11.5 years, with 79% presenting with ST elevation myocardial infarction. Sixty-one percent were smokers, 59% had diabetes mellitus, 52% had hypertension, and 58% presented with a family history of premature coronary artery disease. Twenty-six percent (n = 690) had hyperuricemia, were older (59 +/- 12.1 vs. 56.5 +/- 11.2 years) and more likely to present with hypertension (P < 0.001), lower ejection fraction (P < 0.001), and higher median creatinine levels (P < 0.001). A significantly greater proportion of patients with hyperuricemia experienced MACE (45% vs. 30%, P < 0.001). In both sexes, considerable heterogeneity for risk factors and clinical events was noted in individuals with hyperuricemia. Multivariable analyses for risk factors associated with mortality suggest that hyperuricemia conferred a significantly increased risk of mortality after adjustment [odds ratio (OR) 1.7 (95% confidence interval 1.0-2.8); P = 0.042]. A significant increasing risk trend for MACE was observed for increasing tertiles of serum uric acid concentrations above normal (P < 0.001), particularly for cardiac failure (P < 0.001) and death (P = 0.006). CONCLUSIONS: Hyperuricemia is significantly associated with hypertension, renal dysfunction, MACE, and independently confers a higher risk of mortality in patients with AMI. Significant heterogeneity was found by gender for risk factors and clinical events in individuals with hyperuricemia. A graded increase was demonstrated in the risk of MACE, particularly for cardiac failure and death, by increasing tertiles of hyperuricemia. PMID- 27937807 TI - Age and sex influences on running mechanics and coordination variability. AB - The purpose of this study was to examine the impact of age on running mechanics separately for male and female runners and to quantify sex differences in running mechanics and coordination variability for older runners. Kinematics and kinetics were captured for 20 younger (10 male) and 20 older (10 male) adults running overground at 3.5 m . s-1. A modified vector coding technique was used to calculate segment coordination variability. Lower extremity joint angles, moments and segment coordination variability were compared between age and sex groups. Significant sex-age interaction effects were found for heel-strike hip flexion and ankle in/eversion angles and peak ankle dorsiflexion angle. In older adults, mid-stance knee flexion angle, ankle inversion and abduction moments and hip abduction and external rotation moments differed by sex. Older compared with younger females had reduced coordination variability in the thigh-shank transverse plane couple but greater coordination variability for the shank rotation-foot eversion couple in early stance. These results suggest there may be a non-equivalent aging process in the movement mechanics for males and females. The age and sex differences in running mechanics and coordination variability highlight the need for sex-based analyses for future studies examining injury risk with age. PMID- 27937808 TI - Complainer Profile Identification (CPI): properties of a new questionnaire on subjective cognitive complaints. AB - Subjective cognitive complaints (SCC) and their role as a possible indicator for subsequent dementia became of growing interest in recent research. In contrast to studies that focused primarily on memory complaints, we aimed to (a) evaluate a questionnaire to register SCC in multiple cognitive domains (Complainer Profile Identification, CPI), (b) assess the association between SCC and psychosocial variables, and (c) assess whether complainer types can be differentiated. Confirmatory factor analysis to evaluate construct validity was computed based on a sample of 734 healthy participants (mean [M] = 43.15 years). On a subsample of 644 participants, the relationship between the total level of SCC with age, depression, social integration, and aging stereotypes was assessed utilizing multiple regression analysis. Differences in complainer types were assessed by multivariate analysis of variance. The results indicate sound psychometric properties of the CPI. The overall level of SCC is largely influenced by depressiveness, whereas executive complainers show the highest level of depressive affect, being overall younger and less socially integrated. PMID- 27937967 TI - Tensiomyographical responses to accelerometer loads in female collegiate basketball players. AB - The purpose of the present study was to characterise the relationship between relative versus absolute internal and external loads in collegiate basketball players throughout the course of a season. Five Division I basketball players wore triaxial accelerometers throughout the 2015-2016 season and were tensiomyographically assessed weekly. One-way repeated-measure analysis of variance (RM ANOVA) with least-significant-difference (LSD) pairwise comparisons was used to determine which absolute weekly loads were different across the season. Cohen's d was used to supplement the determination of meaningful relative load changes. Overall RM ANOVA models suggest absolute external load differences occurred (PlayerLoadTM F = 17.63; IMATM F = 31.63). Two-way RM ANOVA models revealed main effect differences were revealed between muscle groups for Tc (F = 9.11) and Dm (F = 3.25). Meaningful relative load changes between weeks were observed for both external and internal. The present study observed that tensiomyography utilised as a tool to monitor internal load may be more suitable for detecting fatigue from relative external load changes versus absolute load attained. Limiting weekly training volume changes to <=10% may maintain appropriate adaptation. Mediolateral plane IMATM and adductor longus muscle group may be pertinent metrics when monitoring female collegiate basketball athletes. PMID- 27937809 TI - Independent suppression of ribosomal +1 frameshifts by different tRNA anticodon loop modifications. AB - Recently, a role for the anticodon wobble uridine modification 5 methoxycarbonylmethyl-2-thiouridine (mcm5s2U) has been revealed in the suppression of translational +1 frameshifts in Saccharomyces cerevisiae. Loss of either the mcm5U or s2U parts of the modification elevated +1 frameshift rates and results obtained with reporters involving a tRNALysUUU dependent frameshift site suggested these effects are caused by reduced ribosomal A-site binding of the hypomodified tRNA. Combined loss of mcm5U and s2U leads to increased ribosome pausing at tRNALysUUU dependent codons and synergistic growth defects but effects on +1 frameshift rates remained undefined to this end. We show in here that simultaneous removal of mcm5U and s2U results in synergistically increased +1 frameshift rates that are suppressible by extra copies of tRNALysUUU. Thus, two distinct chemical modifications of the same wobble base independently contribute to reading frame maintenance, loss of which may cause or contribute to observed growth defects. Since the thiolation pathway is sensitive to moderately elevated temperatures in yeast, we observe a heat-induced increase of +1 frameshift rates in wild type cells that depends on the sulfur transfer protein Urm1. Furthermore, we find that temperature-induced frameshifting is kept in check by the dehydration of N6-threonylcarbamoyladenosine (t6A) to its cyclic derivative (ct6A) at the anticodon adjacent position 37. Since loss of ct6A in elp3 or urm1 mutant cells is detrimental for temperature stress resistance we assume that conversion of t6A to ct6A serves to limit deleterious effects on translational fidelity caused by hypomodified states of wobble uridine bases. PMID- 27937968 TI - Exploration of Choice for Older People with Daily Care Needs: Scottish Professionals' Perspectives on Self-Directed Support. AB - This article explores The Social Care (Self-Directed Support [SDS]) (Scotland) Act 2013 developments, influence's on individuals informed choices for care decisions and implications for direct practice situations. The article discusses perspectives from 18 professionals and front-line care workers interviewed in Scotland on SDS policy changes. Barriers included attitudes on dependence, power and control, shortage of direct client contact time, clients becoming "employers," and reductions in the number of qualified social workers. Some recommendations included allowing social workers freedom of creativity, sharing and application of practice experience. Findings revealed an outcome-focused, person-centered approach was utilized to support an independent living environment. PMID- 27937969 TI - Future orientation and suicide risk in Hungarian college students: Burdensomeness and belongingness as mediators. AB - We tested a model consistent with the notion that perceived burdensomeness and thwarted belongingness mediate the association between future orientation and suicide risk (viz., depressive symptoms and suicide ideation) in college students. The sample was comprised of 195 Hungarian college students. Results indicated that the negative associations found between future orientation and suicide risk outcomes were accounted for by both perceived burdensomeness and thwarted belongingness. The present findings highlight the importance of studying positive future cognitions in suicide risk and provide support for perceived burdensomeness and thwarted belongingness as potential proximal mechanisms associated with heighted suicide risk in adults. PMID- 27938024 TI - Conflicting Family Narrative Regarding an AIDS-Related Death. PMID- 27937970 TI - Effects of oncoming target velocities on rapid force production and accuracy of force production intensity and timing. AB - The present study aimed to clarify the effects of oncoming target velocities on the ability of rapid force production and accuracy and variability of simultaneous control of both force production intensity and timing. Twenty male participants (age: 21.0 +/- 1.4 years) performed rapid gripping with a handgrip dynamometer to coincide with the arrival of an oncoming target by using a horizontal electronic trackway. The oncoming target velocities were 4, 8, and 12 m . s-1, which were randomly produced. The grip force required was 30% of the maximal voluntary contraction. Although the peak force (Pf) and rate of force development (RFD) increased with increasing target velocity, the value of the RFD to Pf ratio was constant across the 3 target velocities. The accuracy of both force production intensity and timing decreased at higher target velocities. Moreover, the intrapersonal variability in temporal parameters was lower in the fast target velocity condition, but constant variability in 3 target velocities was observed in force intensity parameters. These results suggest that oncoming target velocity does not intrinsically affect the ability for rapid force production. However, the oncoming target velocity affects accuracy and variability of force production intensity and timing during rapid force production. PMID- 27938025 TI - Advancing Hospice and Palliative Care Social Work Leadership in Interprofessional Education and Practice. AB - The importance of interprofessional collaboration in achieving high quality outcomes, improving patient quality of life, and decreasing costs has been growing significantly in health care. Palliative care has been viewed as an exemplary model of interprofessional care delivery, yet best practices in both interprofessional education (IPE) and interprofessional practice (IPP) in the field are still developing. So, too, is the leadership of hospice and palliative care social workers within IPE and IPP. Generating evidence regarding best practices that can prepare social work professionals for collaborative practice is essential. Lessons learned from practice experiences of social workers working in hospice and palliative care can inform educational efforts of all professionals. The emergence of interprofessional education and competencies is a development that is relevant to social work practice in this field. Opportunities for hospice and palliative social workers to demonstrate leadership in IPE and IPP are presented in this article. PMID- 27938027 TI - The Stigma Experienced by Terminally Ill Patients: Evidence From a Portuguese Ethnographic Study. AB - The aim of this study was to offer an understanding of the ways in which terminally ill patients may face discrimination due to their visibly altered body. An ethnographic approach was adopted and fieldwork was conducted over 10 months in 2 inpatient hospice units in Portugal. Participant observation was complemented by 50 in-depth interviews with terminally ill patients, family members, and hospice staff. The stigma experienced by terminally ill patients derived mostly from the behavior of peers, extended family members, and friends toward their visibly altered body. There was no evidence that these patients were discredited by their immediate family when they became visibly unwell; unlike what has been reported in previous studies. This finding could be related to the strong familial culture of Portuguese society. PMID- 27938026 TI - Caregiving Youth Knowledge and Perceptions of Parental End-of-Life Wishes in Huntington's Disease. AB - Knowledge of patient end-of-life (EOL) wishes and discussions are vital for family caregivers, including children and youth who may be in caregiving roles ("young carers" or "caregiving youth"). However, little is known about caregiving youth awareness and perceptions of EOL issues. This study sought to explore caregiving youth knowledge of EOL wishes and their willingness for EOL discussions. Face-to-face interviews with 40 caregiving youth ages 10-20, who have a parent with Huntington's disease (HD), provided information about their knowledge of the presence of their ill parent's living will (LW) and durable power of attorney for health care (DPAHC), and willingness to talk with the parent about EOL choices and possibility of death. Less than one-half of the participants were aware of the parent's LW or DPAHC. Content analysis revealed themes in reasons to want or not want EOL discussion with the parent: respect for the parent's wishes, caregiving youths' opinion not valued, and avoidance of EOL issues. Themes also included reasons to not want discussion with the parent about possibility of death: protecting the parent, parent in denial, parent not ready, and realization of the terminal outcome. Findings suggest HD patients and their caregiving youth need support for open EOL discussions, and could benefit from educational programs and support groups around EOL issues. PMID- 27938029 TI - Editor's Introduction. PMID- 27938028 TI - My Nana's Hands. PMID- 27938031 TI - Letters. AB - A NEW CLASSIFICATION OF LEG ULCERS CYTOCOMPATIBILITY OF HYDROCOLLOID DRESSINGS CORRECTION. PMID- 27938030 TI - A Humble Letter to a Very Sick Friend (A Suggestive Missive). PMID- 27938032 TI - Reviews. AB - PRESSURE SORES. PMID- 27938033 TI - Long-term Leucine Supplementation Improves Metabolic But Not Molecular Responses in the Skeletal Muscle of Trained Rats Submitted to Exhaustive Exercise. AB - AIM: Although there is some evidence of an ergogenic effect of leucine supplementation on acute response to exercise, there is a paucity of information on whether long-term leucine supplementation influences the adaptive response to chronic endurance training and performance. The main aim of our study was to assess the role of long-term leucine supplementation on molecular and metabolic response in skeletal muscle of trained rats after an exhaustion test. METHODS: Twenty-four male Wistar rats were randomly allocated into 4 groups. Two of them (control and trained groups) received a balanced control diet (18% protein) and the other 2 (control leucine and trained leucine groups) received a leucine-rich diet (15% protein with 3% leucine) for 6 weeks. The trained groups were submitted to 1 hour of swimming exercise, 5 d/wk for 6 weeks. Three days after the exercise training period, trained groups were submitted to swimming exercise until exhaustion and muscle metabolic and molecular parameters were assessed. RESULTS: Endurance training increased citrate synthase activity significantly, whereas exercise until exhaustion increased cytokine levels and led to a lack of activation of phosphorylation of the signaling intermediates assessed. Long-term leucine supplementation enhanced muscle glycogen level in trained rats and citrate synthase activity in sedentary ones. However, it failed to enhance endurance performance of trained rats submitted to an exhaustion test and did not prevent exercise-induced reduction in Akt and mTOR activation. CONCLUSION: Long term leucine supplementation can enhance citrate synthase activity by itself in sedentary individuals and glycogen content when combined with exercise; however, it does not improve endurance performance or prevent Akt and mTOR exercise induced inhibition. PMID- 27938087 TI - Bioactivity-guided isolation of anti-proliferative compounds from endemic Centaurea kilaea. AB - CONTEXT: The genus Centaurea L. (Asteraceae) is one of the largest genera in Turkey. Compounds and extracts obtained from different Centaurea species have significant anti-cancer activity against various cancer cell lines. OBJECTIVE: To determine the anti-proliferative activity of isolates from the chloroform extract of C. kilaea Boiss. MATERIALS AND METHODS: Eleven compounds were isolated using column chromatography and preparative TLC from the chloroform extract of aerial parts of endemic C. kilaea. The structures of the isolated compounds were elucidated by various spectroscopic methods, including UV, lH-NMR and 13C-NMR. Anti-proliferative activity of compounds (0.5-50 MUg/mL) were measured against one normal cell line (L-929, mouse fibroblast) and three human cancer cell lines (Hela, cervix carcinoma; MCF-7, breast carcinoma; PC-3, prostate carcinoma) using MTT assay. Results were expressed as IC50 values. RESULTS: None of the 11 compounds displayed activity against L-929 and HeLa. Two of these compounds, cnicin and cirsimaritin, showed fairly strong activity against MCF-7 and PC-3 with IC50 values of 3.25 and 4.3 MUg/mL, respectively. DISCUSSION AND CONCLUSION: This is the first report on cirsimaritin. Cirsimaritin and cnicin could serve as potential anti-cancer drug candidates against breast and prostate cancer, respectively. PMID- 27938192 TI - Hyperreligiosity in malignant brain tumors: a case report and accompanying bibliographic review. AB - Religion is a complex cognitive process with biopsychosocial and cultural dimensions, product of the activation of different circuits of the neocortex. In some cases, religiosity can appear as a pathological correlate in patients with brain lesions in the areas involved. We present the clinical case of a patient with an astrocytoma in the right prefrontal region, with apparent inflammatory involvement of the right temporal lobe. This tumor debuted almost exclusively as an alteration of personality consisting of hyperreligiosity, logorrhea, and mystical experiences. A review of the literature has been conducted and possible pathophysiological mechanisms are proposed. PMID- 27938241 TI - Potato virus Y Transmission Efficiency from Potato Infected with Single or Multiple Virus Strains. AB - There has been a recent shift in the prevalence of Potato virus Y (PVY) strains affecting potato with the ordinary strain PVYO declining and the recombinant strains PVYNTN and PVYN:O emerging in the United States. Multiple PVY strains are commonly found in potato fields and even in individual plants. Factors contributing to the emergence of the recombinant strains are not well defined but differential aphid transmission of strains from single and mixed infections may play a role. We found that the transmission efficiencies by Myzus persicae, the green peach aphid, of PVYNTN, PVYN:O, and PVYO varied depending on the potato cultivar serving as the virus source. Overall transmission efficiency was highest from sources infected with three virus strains, whereas transmission from sources infected with one or two virus strains was not significantly different. Two strains were concomitantly transmitted by individual aphids from many of the mixed-source combinations, especially if PVYO was present. Triple-strain infections were not transmitted by any single aphid. PVYO was transmitted most efficiently from mixed-strain infection sources. The data do not support the hypothesis that differential transmission of PVY strains by M. persicae is a major contributing factor in the emergence of recombinant PVY strains in the U.S. potato crop. PMID- 27938242 TI - A Synoptic Analysis of the Temporal and Spatial Aspects of Grapevine Leafroll Disease in a Historic Napa Vineyard and Experimental Vine Blocks. AB - Five Grapevine leafroll-associated virus 3 (GLRaV-3) epidemics were analyzed utilizing a standardized approach to robustly characterize the temporal and spatial parameters. Published data included in the analysis are from Spain, New Zealand, and Napa Valley, CA together with new data from a historic vineyard in Napa Valley, CA. Linear regression analyses of logit-transformed incidence data indicated a maximum average increase of 11% per year in disease incidence, with considerable variation among locations. Spatial analyses, including distribution fitting, examination of the effective sample size, and evaluation of the parameters of the binary power law fitted to variance data for disease incidence, indicated a high degree of consistency among the data sets. In all cases, except at very low disease incidence, a high degree of spatial aggregation was noted, with evidence that the degree of aggregation varied as a function of mean disease incidence. The polyetic dynamics of disease follow a logistic-like pattern over multiple seasons, consistent with limitation by inoculum availability (infected vines) at low incidence and limitation by disease-free vines at high incidence. PMID- 27938243 TI - The DinJ/RelE Toxin-Antitoxin System Suppresses Bacterial Proliferation and Virulence of Xylella fastidiosa in Grapevine. AB - Xylella fastidiosa, the causal agent of Pierce's disease of grapes, is a slow growing, xylem-limited, bacterial pathogen. Disease progression is characterized by systemic spread of the bacterium through xylem vessel networks, causing leaf scorching symptoms, senescence, and vine decline. It appears to be advantageous to this pathogen to avoid excessive blockage of xylem vessels, because living bacterial cells are generally found in plant tissue with low bacterial cell density and minimal scorching symptoms. The DinJ/RelE toxin-antitoxin system is characterized here for a role in controlling bacterial proliferation and population size during plant colonization. The DinJ/RelE locus is transcribed from two separate promoters, allowing for coexpression of antitoxin DinJ with endoribonuclease toxin RelE, in addition to independent expression of RelE. The ratio of antitoxin/toxin expressed is dependent on bacterial growth conditions, with lower amounts of antitoxin present under conditions designed to mimic grapevine xylem sap. A knockout mutant of DinJ/RelE exhibits a hypervirulent phenotype, with higher bacterial populations and increased symptom development and plant decline. It is likely that DinJ/RelE acts to prevent excessive population growth, contributing to the ability of the pathogen to spread systemically without completely blocking the xylem vessels and increasing probability of acquisition by the insect vector. PMID- 27938244 TI - Races of the Celery Pathogen Fusarium oxysporum f. sp. apii Are Polyphyletic. AB - Fusarium oxysporum species complex (FOSC) isolates were obtained from celery with symptoms of Fusarium yellows between 1993 and 2013 primarily in California. Virulence tests and a two-gene dataset from 174 isolates indicated that virulent isolates collected before 2013 were a highly clonal population of F. oxysporum f. sp. apii race 2. In 2013, new highly virulent clonal isolates, designated race 4, were discovered in production fields in Camarillo, California. Long-read Illumina data were used to analyze 16 isolates: six race 2, one of each from races 1, 3, and 4, and seven genetically diverse FOSC that were isolated from symptomatic celery but are nonpathogenic on this host. Analyses of a 10-gene dataset comprising 38 kb indicated that F. oxysporum f. sp. apii is polyphyletic; race 2 is nested within clade 3, whereas the evolutionary origins of races 1, 3, and 4 are within clade 2. Based on 6,898 single nucleotide polymorphisms from the core FOSC genome, race 3 and the new highly virulent race 4 are highly similar with Nei's Da = 0.0019, suggesting that F. oxysporum f. sp. apii race 4 evolved from race 3. Next generation sequences were used to develop PCR primers that allow rapid diagnosis of races 2 and 4 in planta. PMID- 27938246 TI - Inconsistency of decision-making, the Achilles heel of referees. AB - This study assessed whether decisions made by six qualified referees were consistent when watching the live 2016 televised Champions League Final. Referees were paired off into three separate rooms. Two referees watched the game with no supporters present. Two watched the game surrounded by Real Madrid supporters, and the remaining two watched the game surrounded by Athletic Madrid supporters. Referees were asked to decide whether each decision made by the on-field referee was either correct or incorrect. Results identified two types of refereeing inconsistency. The first type was a systematic tendency of the supporting crowds (both rooms) to influence the adjudicating referees to make fewer incorrect (disagree with the on-field referee) decisions (8 and 5) than referees in the "no supporters" room (19) (chi2 = 11.22 [df = 2], P = 0.004). The second type of inconsistency was the home advantage "bias", where the surrounding crowd influenced the adjudicating referees to favour their team, by disagreeing with the decision made by the on-field referee (chi2 = 6.0 [df = 2], P = 0.0498). One explanation for these inconsistencies is that referees adopt a coping strategy of "avoidance", i.e., when faced with difficult decisions, referees simply avoid making unpopular decisions by waving "play on". PMID- 27938245 TI - Post Surgical Pyoderma Gangrenosum in flap surgery: diagnostic clues and treatment recommendations. AB - BACKGROUND: Post Surgical Pyoderma Gangrenosum (PSPG) is a neutrophilic dermatosis causing aseptic necrotic ulcerations within surgical sites. It is often misdiagnosed as infection or ischemia and worsened by the inappropriate treatment. Therefore diagnostic clues must be identified and awareness for PSPG raised. METHODS: We present two cases of PSPG after flap surgery and a review of the literature. RESULTS: Seventeen cases of PSPG after flap surgery were found. Fever, pain and redness are the most common initial symptoms. In 63%, lesions were on the flap and the adjacent skin. In 63%, the donor site is also involved. Time to diagnosis was nine days to four years. Frequent debridement (89%) and administration of antibiotics (74%) illustrate the misdiagnosis of infection or ischemia. PSPG in flap surgery seems to be less associated with underlying diseases, than other forms of Pyoderma Gangrenosum. Corticoids are the most commonly used treatment. Of the 19 cases, 10 experienced partial or total flap loss. CONCLUSION: PSPG must be included in the differential diagnosis of postoperative wound problems. Recognizing the diagnostic clues can lead to early diagnosis and treatment with systemic immunotherapy. Associated diseases should be investigated and additional surgery can only be successful when associated with immunotherapy. PMID- 27938247 TI - Estimating diesel fuel exposure for a plumber repairing an underground pipe. AB - We estimated the diesel fuel exposure of a plumber repairing an underground water line leak at a truck stop. The repair work was performed over three days during which the plumber spent most of his time in a pit filled with a mixture of water and diesel fuel. Thus, the plumber was exposed via both the inhalation and dermal routes. While previously asymptomatic, he was diagnosed with acute renal failure 35 days after working at this site. No measurements were available for estimating either inhalation or dermal exposures or the cumulative dose and, therefore, two different approaches were used that were based on simple models of the exposure scenario. The first approach used the ideal gas law with the vapor pressure of the diesel fuel mixture to estimate a saturation vapor concentration, while the second one used a mass balance of the petroleum hydrocarbon component of diesel fuel in conjunction with the Henry's Law constant for this mixture. These inhalation exposure estimates were then adjusted to account for the limited ventilation in a confined space. The inhalation exposure concentrations predicted when handling the water layer alone is much lower than that expected from the organic layer. This case study illustrates the large differences in inhalation exposure associated with volatile organic layers and aqueous solution containing these chemicals. The estimate of dermal exposure was negligible compared to the inhalation exposure because the skin presents a much smaller surface area of exposure to the contaminant compared to the lungs. The methodology presented here is useful for situations where little information is available for more formal mathematical exposure modeling, but where adjustments to the worst-case exposures, estimated simply, can provide reasonable exposure estimates. PMID- 27938248 TI - "Working with COW": Social Work Supporting Older Women Living in the Community. AB - Australia, like all developed Western countries, is experiencing a demographic shift resulting in an increasing proportion of the population being over the age of 65 years. Contrary to stereotypes, the vast majority of older people live independently in communities. This article explores the potential of social work practice informed by community development principles to enable socially disadvantaged older women to live in vibrant and supportive communities, in which they feel safe and are able to access the support services they need. It argues that participation in social action not only builds older women's well-being but also enables them to become (or continue to be) agents for social change in local communities. Adopting a community-based research methodology, this article draws on a decade of community development practice with the Concerned Older Women's (COW) Group. This data suggests that community development practice based on participation, empowerment, and social action founded on respectful relationships may accrue significant benefits to individuals and the broader community. This social work practice creates the social conditions to facilitate older women's capacity to work collectively to achieve social change, challenging ageist stereotypes. PMID- 27938307 TI - Readers' Questions. AB - ALLERGIES IN LEG ULCER PATIENTS. PMID- 27938308 TI - Chronic ulceration of the leg. AB - Two reviewers critique the article cited below and assess its influence on the management of leg ulcers. PMID- 27938309 TI - Reviews. AB - PRESSURE SORE PREVENTION RESEARCH MINDEDNESS FOR PRACTICE: AN INTERACTIVE APPROACH FOR NURSING AND HEALTH CARE. PMID- 27938310 TI - Chronic ulceration of the leg: Critique 2. AB - The aim of the study was to identify those providing care within the Lothian and Forth Valley health districts and all patients receiving treatment for chronic leg ulceration. Questionnaires were sent to all community and hospital services. Respondents were asked to identify all patients who were then undergoing treatment for active chronic leg ulceration or who had received treatment in the previous three months. A postal survey is cheaper than using clinical examination but the results are dependent on response rates and the validity of the questionnaire. To ensure maximum response rates follow-up letters were sent out and telephone calls made to non-responders. PMID- 27938305 TI - Choosing to Live or Die: Online Narratives of Recovering from Methamphetamine Abuse. AB - The goal of this study is to explore motivating factors for recovering from methamphetamine abuse. The source of data was 202 anonymous letters and stories submitted to an online support platform for methamphetamine users. Qualitative data were analyzed in Dedoose software using grounded theory methodology. Ten primary motivating factors for recovering from methamphetamine abuse were identified and mapped onto four constructs from the Health Belief Model: (1) perceived susceptibility (learning from others and learning from self); (2) perceived severity (fear of death and declining health); (3) perceived benefits (reconnecting with family, reconnecting with society, and recovering self esteem); and (4) cues to action (hitting rock bottom, finding God, and becoming pregnant). By using data from an online support group and categorizing emerging themes within a theoretical framework, findings from this study provide a comprehensive understanding of factors involved in recovery from methamphetamine abuse and offer further insights in developing theoretically informed interventions for methamphetamine users. This study suggests the utility of online platforms for obtaining anonymous but unique experiences about drug abuse and recovery. Findings may benefit healthcare professionals, counselors, and researchers by helping to develop theoretically informed interventions for methamphetamine abuse. PMID- 27938311 TI - From the Journals. AB - LOCAL COMPRESSION AND BLOOD FLOW UNDERNUTRITION OF HOSPITAL PATIENTS. PMID- 27938312 TI - Prescribing in the community. AB - A White Paper issued in December 1996 (Primary Care: Delivering the future), stated that 'the current arrangements for the prescribing, supply and administration of medicines would be subject to review'. In mid-February, the Minister of Health, Gerald Malone, gave details of the team, chaired by Dr June Crown, to carry out this review over the next 12 months. The objectives will be to determine the circumstances in which health professionals may undertake new roles in the prescribing, administration and supply of medicines and the legal and training implications of these changes. PMID- 27938313 TI - Age-related differences in effectiveness of item restudy choices: the role of value. AB - We examined the effect of value on effectiveness of restudy choices in younger and older adults by using an honor or dishonor procedure. In the honor condition, participants restudied the half of the items that they selected for restudy. In the dishonor condition, participants restudied the half of the items that they did not select for restudy. The results showed that younger adults restudied more low-value (1-point) items that they had rated as least-well learned, while older adults restudied more high-value (5-point) items. For younger adults, 1-point value item performance in the honor condition was reliably higher than it was in the dishonor condition. For older adults, 5-point-value items performance in the honor condition was reliably higher than it was in the dishonor condition. These results suggest that older adults can exert effective restudy choices like younger adults when item value is manipulated. PMID- 27938314 TI - Sequential Onset of Varicella-Zoster Virus Encephalomeningitis and Progressive Multifocal Leukoencephalopathy in an Allogeneic Hematopoietic Stem Cell Transplant Recipient. AB - Here, we describe a case of sequential varicella-zoster virus encephalomeningitis and progressive multifocal leukoencephalopathy following an allogeneic hematopoietic stem cell transplant procedure. A 37-year-old male patient presented with fever, incomplete paralysis of bilateral legs, and bullous eruptions 8 months after allogeneic transplant. Polymerase chain reaction assays of cerebrospinal fluid samples for varicella-zoster virus were positive. Bullous eruptions and incomplete paralysis of bilateral legs improved after administration of acyclovir. However, higher brain dysfunction was present and getting worse. We detected no herpes simplex virus, varicella-zoster virus, Cytomegalovirus, human herpes virus 6, Epstein-Barr virus, or JC virus in cerebrospinal fluid samples with polymerase chain reaction assays. Pathologic findings and polymerase chain reaction assays with brain biopsy samples revealed that the patient had progressive multifocal leukoencephalopathy. This is the first report of a case showing dual central nervous system infections due to varicella-zoster virus and JC virus after allogeneic stem cell transplant. PMID- 27938315 TI - Epilepsy After Heart Transplant: A Single Center Experience. AB - OBJECTIVES: Cardiac transplant is the best treatment for patients with end-stage heart failure. Neurologic complications occur at a rate of 30% to 80% in patients undergoing cardiac transplant. Seizures occur at a rate of 2% to 20%. The main causative factors include immunosuppressant drug toxicity, infections, brain lesions, and metabolic disorders. Here, our aim was to determine seizure types and associated conditions in patients undergoing cardiac transplant and to report our treatment experience at our institution. MATERIALS AND METHODS: We retrospectively evaluated the medical records of 109 patients who underwent cardiac transplant between 2004 and 2016. We recorded demographic data, immunosuppressive treatment, seizure type, cause, recurrence rate, and treatment. RESULTS: Of 109 patients, 13 had seizures after cardiac transplant. Our study involved 69 adult and 40 pediatric patients. The pediatric patients had an age range of 1 to 17 years, with a mean age of 9.6 years (22 female and 18 male patients). Five pediatric patients had seizures (4 female and 1 male patient). The seizure causes included 2 postarrest hypoxic encephalopathies and 3 posterior reversible encephalopathies. Adult patients ranged from 18 to 63 years old, with a mean age of 42.3 years (54 male and 15 female patients). Eight patients in the adult patient group had seizures (5 female and 3 male patients). Seizure causes were ischemic cerebrovascular events in 2 patients, metabolic disorders in 2, posterior reversible encephalopathies in 3, and postarrest hypoxic brain in 1. CONCLUSIONS: Seizure is an important complication after cardiac transplant. At our institution, the most common cause of seizure was posterior reversible encephalopathy, with immunosuppressant drugs being responsible. PMID- 27938316 TI - Two Decades of Tacrolimus in Renal Transplant: Basic Science and Clinical Evidences. AB - Tacrolimus, a calcineurin inhibitor, has been the cornerstone of immunosuppressive regimens in renal transplant over 2 decades. This has significantly improved the outcomes of renal transplant, including reduction of acute rejection episodes, improvement of renal function and graft survival, and reduction of some of the adverse effects associated with cyclosporine. However, use of tacrolimus is associated with a number of undesirable effects, such as nephrotoxicity, posttransplant diabetes mellitus, neurotoxicity, and cosmetic and electrolyte disturbances. To alleviate these effects, several strategies have been adopted to minimize or eliminate tacrolimus from maintenance regimens of immunosuppression, with some success. This review focuses on advancements in the understanding of the basic science related to tacrolimus and the clinical evidences that have examined the efficacy and safety of tacrolimus in renal transplant over the past 2 decades and highlights the future directions. PMID- 27938317 TI - Cell Viability of Human Embryonic Stem Cells Stored for a Period of 9 Years. AB - OBJECTIVES: Human embryonic stem cells are pluripotent cell lines usually derived from human blastocysts. Their potential critically depends on long-term proliferative capacity, developmental potential after prolonged culture, and karyotypic stability. Cell viability is an important parameter for assessing cell sample quality. Here, we elaborate the stored human embryonic stem cell lines' viability in a ready to use form for a period of 9 years (from 2007 to 2015). MATERIALS AND METHODS: Spare pre implantation stage in vitro fertilized ovum derived cell lines were cultured in suitable media. Thereafter, they were centrifuged at 1000 revolutions/min over 5 minutes, and pellets were suspended in normal saline. Next, they were tested for viability from storage at -20 degrees C. After being allowed to thaw slowly, the cells were stained with propidium iodide and analyzed using flow cytometry. Images of cells were taken at *40 and *100 magnification. RESULTS: At *100 magnification, cell population size ranged from 0.2 to 2 MUm. The percentage of live cells was more than 95% throughout the 9 years. Cells frozen in 2015 showed cell viability of 96.8%. CONCLUSIONS: We observed high cell viability in our cell lines for 9 years. Human embryonic stem cell lines in a ready-to-use form can be preserved for long-term purposes. Thus, they could be made available globally. PMID- 27938318 TI - Incisional Infections after Renal Transplant: Outcome Data From 238 Consecutive Recipients. AB - OBJECTIVES: Surgical incision infections, along with urinary tract infections, are among the most common infective complications after kidney transplant. The aim of this retrospective study is to evaluate the incidence and predisposing factors of surgical incision infection development in renal transplant recipients. MATERIALS AND METHODS: Between 1 January 2012 and 31 December 2015, there were 238 consecutive kidney transplant procedures performed in our unit. Of these, 146 patients received deceased donor kidney allografts and 92 had transplants from living related donors. Deceased donor data, data about surgical procedures, and recipient data were collected. RESULTS: This study demonstrated a surgical incision infection rate of 7.56%. Predisposing factors were found to be kidneys from deceased donors, antithymocyte globulin as antirejection therapy, body mass index > 30 kg/m2, cold ischemia time > 16.3 hours, delayed graft function, postoperative serum glucose > 280 mg/dL, second kidney transplant, and BK virus infection. CONCLUSIONS: Surgical incision infection is a common postoperative infection after kidney transplant. The findings of this study elucidated the potential role of specific risk factors in surgical incision infection development (increased cold ischemia time, delayed graft function, antithymocyte globulin administration). Further evaluation of these findings in a prospective study is needed to avoid potential bias. PMID- 27938319 TI - LARGER, SHARPER & DEEPER. AB - Microscopy continues to expand our knowledge of brain structure and function. Sarah Webb looks at some of the latest tools and techniques leading the charge. PMID- 27938320 TI - [Letter to the Editor] Many commercial hot-start polymerases demonstrate activity prior to thermal activation. AB - Address correspondence to Martin A. Kennedy, Department of Pathology & Carney Centre for Pharmacogenomics, University of Otago, Christchurch, PO Box 4345, Christchurch, New Zealand. E-mail: martin.kennedy@otago.ac.nz. PMID- 27938321 TI - High-yield recombinant expression and purification of marginally soluble, short elastin-like polypeptides. AB - The protocol described here is designed as an extension of existing techniques for creating elastin-like polypeptides. It allows for the expression and purification of elastin-like polypeptide (ELP) constructs that are poorly expressed or have very low transition temperatures. DNA concatemerization has been modified to reduce issues caused by methylation sensitivity and inefficient cloning. Linearization of the modified expression vector has been altered to greatly increase cleavage efficiency. The purification regimen is based upon using denaturing metal affinity chromatography to fully solubilize and, if necessary, pre-concentrate the target peptide before purification by inverse temperature cycling (ITC). This protocol has been used to express multiple leucine-containing elastin-like polypeptides, with final yields of 250-660 mg per liter of cells, depending on the specific construct. This was considerably greater than previously reported yields for similar ELPs. Due to the relative hydrophobicity of the tested constructs, even compared with commonly employed ELPs, conventional methods would not have been able to be purify these peptides. PMID- 27938322 TI - Protein consensus-based surface engineering (ProCoS): a computer-assisted method for directed protein evolution. AB - Protein consensus-based surface engineering (ProCoS) is a simple and efficient method for directed protein evolution combining computational analysis and molecular biology tools to engineer protein surfaces. ProCoS is based on the hypothesis that conserved residues originated from a common ancestor and that these residues are crucial for the function of a protein, whereas highly variable regions (situated on the surface of a protein) can be targeted for surface engineering to maximize performance. ProCoS comprises four main steps: (i) identification of conserved and highly variable regions; (ii) protein sequence design by substituting residues in the highly variable regions, and gene synthesis; (iii) in vitro DNA recombination of synthetic genes; and (iv) screening for active variants. ProCoS is a simple method for surface mutagenesis in which multiple sequence alignment is used for selection of surface residues based on a structural model. To demonstrate the technique's utility for directed evolution, the surface of a phytase enzyme from Yersinia mollaretii (Ymphytase) was subjected to ProCoS. Screening just 1050 clones from ProCoS engineering guided mutant libraries yielded an enzyme with 34 amino acid substitutions. The surface-engineered Ymphytase exhibited 3.8-fold higher pH stability (at pH 2.8 for 3 h) and retained 40% of the enzyme's specific activity (400 U/mg) compared with the wild-type Ymphytase. The pH stability might be attributed to a significantly increased (20 percentage points; from 9% to 29%) number of negatively charged amino acids on the surface of the engineered phytase. PMID- 27938324 TI - Analysis and quantification of in vitro myoblast fusion using the LADD Multiple Stain. AB - Myoblast fusion, which is essential for muscle development, regeneration, and repair, can be assessed in vitro via the calculation of a fusion index. Traditionally, this requires use of either immunocytochemistry or fluorescently labeled cytoskeletal staining, followed by microscopy and laborious analysis. The expense and time-consuming nature of the optimization and application of antibody based techniques such as immunocytochemistry, as well as the need for specialized analytical equipment such as fluorescence microscopes, presents a barrier to the routine analysis of this crucial step during terminal differentiation. Here, we describe (i) a novel use of the commonly available LADD Multiple Stain for visualization of myoblast fusion in vitro; (ii) the optimization of a simple image analysis method to generate quick, quantifiable data representative of a fusion index; and (iii) the use of a protocol combining these two procedures to investigate in vitro myoblast fusion in a simple and efficient manner as proof-of concept. PMID- 27938323 TI - Targeted capture and sequencing of gene-sized DNA molecules. AB - Targeted capture provides an efficient and sensitive means for sequencing specific genomic regions in a high-throughput manner. To date, this method has mostly been used to capture exons from the genome (the exome) using short insert libraries and short-read sequencing technology, enabling the identification of genetic variants or new members of large gene families. Sequencing larger molecules results in the capture of whole genes, including intronic and intergenic sequences that are typically more polymorphic and allow the resolution of the gene structure of homologous genes, which are often clustered together on the chromosome. Here, we describe an improved method for the capture and single molecule sequencing of DNA molecules as large as 7 kb by means of size selection and optimized PCR conditions. Our approach can be used to capture, sequence, and distinguish between similar members of the NB-LRR gene family-key genes in plant immune systems. PMID- 27938325 TI - Enhanced candicidal compound production by a new soil isolate Penicillium verruculosum MKH7 under submerged fermentation. AB - BACKGROUND: Microorganisms are a rich source of structurally diverse secondary metabolites that exert a major impact on the control of infectious diseases and other medical conditions. The biosynthesis of these metabolites can be improved by manipulating the nutritional or environmental factors. This work evaluates the effects of fermentation parameters on the production of a lactone compound effective against Candida albicans by Penicillium verruculosum MKH7 under submerged fermentation. Design-Expert version8.0 software was used for construction of the experimental design and statistical analysis of the experimental data. RESULTS: The important factors influencing antibiotic production selected in accordance with the Plackett-Burman design were found to be initial pH, temperature, peptone, MgSO4.7H2O. Orthogonal central composite design and response surface methodology were adopted to further investigate the mutual interaction between the variables and identify the optimum values that catalyse maximum metabolite production. The determination coefficient (R2) of the fitted second order model was 0.9852. The validation experiments using optimized conditions of initial pH 7.4, temperature 27 degrees C, peptone 9.2 g/l and MgSO4.7H2O 0.39 g/l resulted in a significant increase (almost 7 fold from 30 to 205.5 mg/l) in the metabolite production which was in agreement with the prediction (211.24 mg/l). Stability of the compound was also assessed on the basis of its response to physical and chemical stresses. CONCLUSIONS: So far as our knowledge goes, till date there are no reports available on the production of antibiotics by Penicillium verruculosum through media optimization using RSM. Optimization not only led to a 7 fold increase in metabolite yield but the same was achieved at much lesser time (8-10 days compared to the earlier 12-15 days). The enhanced yield of the antibiotic strongly suggests that the fungus P. verruculosum MKH7 can be efficiently used for antibiotic production on a large scale. PMID- 27938327 TI - Commentary on the 6th International Symposium of Animal Functional Genomics. PMID- 27938326 TI - Whole genome sequencing and comparative genomics of closely related Fusarium Head Blight fungi: Fusarium graminearum, F. meridionale and F. asiaticum. AB - BACKGROUND: The Fusarium graminearum species complex is composed of many distinct fungal species that cause several diseases in economically important crops, including Fusarium Head Blight of wheat. Despite being closely related, these species and individuals within species have distinct phenotypic differences in toxin production and pathogenicity, with some isolates reported as non-pathogenic on certain hosts. In this report, we compare genomes and gene content of six new isolates from the species complex, including the first available genomes of F. asiaticum and F. meridionale, with four other genomes reported in previous studies. RESULTS: A comparison of genome structure and gene content revealed a 93 99% overlap across all ten genomes. We identified more than 700 k base pairs (kb) of single nucleotide polymorphisms (SNPs), insertions, and deletions (indels) within common regions of the genome, which validated the species and genetic populations reported within species. We constructed a non-redundant pan gene list containing 15,297 genes from the ten genomes and among them 1827 genes or 12% were absent in at least one genome. These genes were co-localized in telomeric regions and select regions within chromosomes with a corresponding increase in SNPs and indels. Many are also predicted to encode for proteins involved in secondary metabolism and other functions associated with disease. Genes that were common between isolates contained high levels of nucleotide variation and may be pseudogenes, allelic, or under diversifying selection. CONCLUSIONS: The genomic resources we have contributed will be useful for the identification of genes that contribute to the phenotypic variation and niche specialization that have been reported among members of the F. graminearum species complex. PMID- 27938329 TI - Erratum to: Development and validation of the FRAGIRE tool for assessment an older person's risk for frailty. PMID- 27938328 TI - Combining independent de novo assemblies optimizes the coding transcriptome for nonconventional model eukaryotic organisms. AB - BACKGROUND: Next-generation sequencing (NGS) technologies are arguably the most revolutionary technical development to join the list of tools available to molecular biologists since PCR. For researchers working with nonconventional model organisms one major problem with the currently dominant NGS platform (Illumina) stems from the obligatory fragmentation of nucleic acid material that occurs prior to sequencing during library preparation. This step creates a significant bioinformatic challenge for accurate de novo assembly of novel transcriptome data. This challenge becomes apparent when a variety of modern assembly tools (of which there is no shortage) are applied to the same raw NGS dataset. With the same assembly parameters these tools can generate markedly different assembly outputs. RESULTS: In this study we present an approach that generates an optimized consensus de novo assembly of eukaryotic coding transcriptomes. This approach does not represent a new assembler, rather it combines the outputs of a variety of established assembly packages, and removes redundancy via a series of clustering steps. We test and validate our approach using Illumina datasets from six phylogenetically diverse eukaryotes (three metazoans, two plants and a yeast) and two simulated datasets derived from metazoan reference genome annotations. All of these datasets were assembled using three currently popular assembly packages (CLC, Trinity and IDBA-tran). In addition, we experimentally demonstrate that transcripts unique to one particular assembly package are likely to be bioinformatic artefacts. For all eight datasets our pipeline generates more concise transcriptomes that in fact possess more unique annotatable protein domains than any of the three individual assemblers we employed. Another measure of assembly completeness (using the purpose built BUSCO databases) also confirmed that our approach yields more information. CONCLUSIONS: Our approach yields coding transcriptome assemblies that are more likely to be closer to biological reality than any of the three individual assembly packages we investigated. This approach (freely available as a simple perl script) will be of use to researchers working with species for which there is little or no reference data against which the assembly of a transcriptome can be performed. PMID- 27938330 TI - Novel insight into the composition of human single-stranded DNA-binding protein 1 (hSSB1)-containing protein complexes. AB - BACKGROUND: Single-stranded DNA-binding proteins are essential cellular components required for the protection, metabolism and processing of single stranded DNA. Human single-stranded DNA-binding protein 1 (hSSB1) is one such protein, with described roles in genome stability maintenance and transcriptional regulation. As yet, however, the mechanisms through which hSSB1 functions and the binding partners with which it interacts remain poorly understood. RESULTS: In this work, hSSB1 was immunoprecipitated from cell lysate samples that had been enriched for non-soluble nuclear proteins and those associating with hSSB1 identified by mass spectrometry. In doing so, 334 potential hSSB1-associating proteins were identified, with known roles in a range of distinct biological processes. Unexpectedly, whilst hSSB1 has largely been studied in a genome stability context, few other DNA repair or replication proteins were detected. By contrast, a large number of proteins were identified with roles in mRNA metabolism, reflecting a currently emerging area of hSSB1 study. In addition, numerous proteins were detected that comprise various chromatin-remodelling complexes. CONCLUSIONS: These findings provide new insight into the binding partners of hSSB1 and will likely function as a platform for future research. PMID- 27938331 TI - Robust multi-group gene set analysis with few replicates. AB - BACKGROUND: Competitive gene set analysis is a standard exploratory tool for gene expression data. Permutation-based competitive gene set analysis methods are preferable to parametric ones because the latter make strong statistical assumptions which are not always met. For permutation-based methods, we permute samples, as opposed to genes, as doing so preserves the inter-gene correlation structure. Unfortunately, up until now, sample permutation-based methods have required a minimum of six replicates per sample group. RESULTS: We propose a new permutation-based competitive gene set analysis method for multi-group gene expression data with as few as three replicates per group. The method is based on advanced sample permutation technique that utilizes all groups within a data set for pairwise comparisons. We present a comprehensive evaluation of different permutation techniques, using multiple data sets and contrast the performance of our method, mGSZm, with other state of the art methods. We show that mGSZm is robust, and that, despite only using less than six replicates, we are able to consistently identify a high proportion of the top ranked gene sets from the analysis of a substantially larger data set. Further, we highlight other methods where performance is highly variable and appears dependent on the underlying data set being analyzed. CONCLUSIONS: Our results demonstrate that robust gene set analysis of multi-group gene expression data is permissible with as few as three replicates. In doing so, we have extended the applicability of such approaches to resource constrained experiments where additional data generation is prohibitively difficult or expensive. An R package implementing the proposed method and supplementary materials are available from the website http://ekhidna.biocenter.helsinki.fi/downloads/pashupati/mGSZm.html . PMID- 27938332 TI - A single nucleotide polymorphism in the UMOD promoter is associated with end stage renal disease. AB - BACKGROUND: Several genome-wide association studies revealed that several variants of UMOD gene were related to the estimated glomerular filtration rate (eGFR), CKD or hypertension. In this study, we investigated the association between a common variant rs13333226 in the promoter region of UMOD gene and end stage renal disease (ESRD). METHODS: Variant rs13333226 of UMOD gene was genotyped by using the ABI Real time TaqMan allelic discrimination assay in a case-control study including 638 unrelated patients with ESRD and 366 controls. RESULTS: The frequency of UMOD SNP rs13333226 GG/GA genotype was significantly higher (36.83% vs. 20.22%, P = 4.02 * 10-8) and the frequency of G allele was much higher (19.04% vs. 11.20%, P = 4.00 * 10-6) in the patients with ESRD than in the controls. The G allele was associated with an increased risk of ESRD (odds ratio 2.30, 95% confidence interval 1.70-3.11, P = 6.10 * 10-8). And G allele (odds ratio 2.33, 95% confidence interval 1.32-4.13, P = 3.65 * 10-3) was associated independently with ESRD. CONCLUSIONS: A common variation rs13333226 in the promoter region of UMOD gene was independently associated with ESRD in Han Chinese. PMID- 27938333 TI - Pseudomyxoma peritonei of a mature ovarian teratoma caused by mismatch repair deficiency in a patient with Lynch syndrome: a case report. AB - BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare disease with an estimated incidence of 1-2 cases per million individuals per year. PMP is characterized by the accumulation of abundant mucinous or gelatinous fluid derived from disseminated tumorous cells. Most of the tumorous cells are originated from rupture of appendiceal neoplasms, but some are from the metastasis of cancer of the colon, ovary, fallopian tube, urachus, colorectum, gallbladder, stomach, pancreas, lung and breast. Although frequent mutations in KRAS and/or GNAS genes have been reported, precise molecular mechanism underlying PMP remains to be elucidated. It is of note that mucinous tumour is one of the frequent histological features of colorectal cancer (CRC) in Lynch syndrome (LS), an autosomal dominantly inherited disease caused by a germline mutation of the DNA mismatch repair (MMR) genes including human mutL homolog 1 (MLH1), human mutS homolog 2 (MSH2), human mutS homolog 6 (MSH6), and postmeiotic segregation increased 2 (PMS2). Therefore, typical LS-associated tumours show mismatch repair instability. Although LS patients are most strongly predisposed to CRC, PMPs from mucinous CRC have not been reported in LS patients. CASE PRESENTATION: In this report, we report a case of PMP originating from an ovarian teratoma in a LS patient. The patient had surgical treatment of PMP arising from an ovarian teratoma at the age of 38 years, and later developed a transverse colon cancer at the age of 40. The patient's family history fulfilled the Amsterdam criteria, and genetic analysis of the peripheral leukocytes identified a germ line mutation in the MLH1 gene (MLH1 c.1546dupC p.Q516PfsX3). Interestingly, immunohistochemical staining showed that the expression of MLH1 was lost in the colon cancer as well as the ovarian teratoma. Consistent with the loss of MLH1 expression, both tumours showed high microsatellite instability (MSI-H). CONCLUSION: This case suggested that LS patients may develop various types of tumours including ovarian PMP, and that mismatch repair deficiency may play a role in the development of PMP derived from, at least, a part of ovarian teratomas. PMID- 27938334 TI - Prevalent peripheral arterial disease and inflammatory burden. AB - BACKGROUND: Strong evidence implicates inflammation in the development of atherosclerotic heart disease but less is known about peripheral arterial disease (PAD). Our objective was to test the hypothesis that a composite index of inflammatory burden is associated with PAD. METHODS: Cross-sectional analysis of a randomly-selected group of 903 community-dwelling men in the MrOS cohort recruited between 2000 and 2002. Using blood samples, we measured seven cytokines and related these levels to prevalent PAD (ankle-brachial index (ABI) <0.9) both individually and as part of an "inflammatory burden score" (a composite sum of the number of pro-inflammatory cytokines in the highest quartile). RESULTS: Overall, 6.75% of men had ABI <0.9. The odds of prevalent PAD were higher in men with the highest quartile (Q4) levels of interleukin-6 multivariable (MV) adjusted (odds ratio (OR) =3.95 (95% CI, 1.4-11.3), tumor necrosis factor alpha OR = 4.44 (95% confidence interval (CI), 1.5-12.8), and C-reactive protein OR = 3.63 (95% CI, 1.4-9.4) compared to men in Q1. The magnitude of the association of these cytokines with PAD was similar to the effect of being 10 years older, OR = 2.41 (95% CI, 1.16-3.7). These significant effects persisted after additional MV adjustment for smoking except for CRP. Men with the highest inflammatory burden score (>=3) had 3.6 (95% CI, 1.5-8.7) increased odds of PAD, p trend = 0.03. After smoking adjustment the linear trend was borderline statistically significant (p trend = 0.10). CONCLUSION: Inflammatory burden is associated with prevalent PAD, an association similar to aging 10 years. The inflammatory effects of smoking contributes to the underlying association between inflammation and PAD. PMID- 27938335 TI - Genome sequence, population history, and pelage genetics of the endangered African wild dog (Lycaon pictus). AB - BACKGROUND: The African wild dog (Lycaon pictus) is an endangered African canid threatened by severe habitat fragmentation, human-wildlife conflict, and infectious disease. A highly specialized carnivore, it is distinguished by its social structure, dental morphology, absence of dewclaws, and colorful pelage. RESULTS: We sequenced the genomes of two individuals from populations representing two distinct ecological histories (Laikipia County, Kenya and KwaZulu-Natal Province, South Africa). We reconstructed population demographic histories for the two individuals and scanned the genomes for evidence of selection. CONCLUSIONS: We show that the African wild dog has undergone at least two effective population size reductions in the last 1,000,000 years. We found evidence of Lycaon individual-specific regions of low diversity, suggestive of inbreeding or population-specific selection. Further research is needed to clarify whether these population reductions and low diversity regions are characteristic of the species as a whole. We documented positive selection on the Lycaon mitochondrial genome. Finally, we identified several candidate genes (ASIP, MITF, MLPH, PMEL) that may play a role in the characteristic Lycaon pelage. PMID- 27938336 TI - Regional variation in antibiotic prescribing among medicare part D enrollees, 2013. AB - BACKGROUND: Antibiotics are among the most widely prescribed medications. The geographic variation in antibiotic prescribing patterns and associated costs among Medicare Part D recipients have not been described. The purpose of this study was to assess the regional variation in antibiotic prescriptions and costs among Medicare Part D enrollees in 2013. METHODS: Retrospective cohort review of all Medicare Part D enrollees in 2013, using the Medicare Provider Utilization and Payment Data: Part D Prescriber Public Use File. All original or refill prescription claims for antibiotics as listed in the Part D Prescriber Public Use File were included. Our primary outcomes were total antibiotic claims and antibiotic cost per Medicare Part D Enrollee. Data were analyzed descriptively by state and by geographic region as defined by the United States Census Bureau. Antibiotic claims were described overall and by antibiotic class. RESULTS: Over 54 million outpatient antibiotic claims were filed for Part D enrollees in 2013, representing more than $1.5 billion in total antibiotic expenditures. Antibiotic use was highest in the South (1,623 claims/1,000 enrollees), followed by the Midwest (1,401 claims/1,000 enrollees), Northeast (1,366 claims/1,000 enrollees), and West (1,292 claims/1,000 enrollees). Average antibiotic costs per enrollee in each region were as follows: South $46.58, Northeast $43.70, Midwest $40.54, and West $36.42. Fluoroquinolones were the most commonly prescribed class overall (12.2 million claims). CONCLUSIONS: Antibiotic use among elderly Medicare enrollees in the United States was highest in the South region. Fluoroquinolones were the most common antibiotics used in all regions. These patterns could be utilized in the development of targeted antimicrobial stewardship efforts. PMID- 27938337 TI - Performance of Syphilis Sentinel Surveillance in the context of endemic Treponematoses: experience from Ghana. AB - BACKGROUND: Use of treponemal tests to screen for syphilis (caused by Treponema pallidum pallidum) poses challenges with infection status classification, especially in settings where other treponemal infections are endemic. This study aimed to determine the validity of the syphilis surveillance testing strategy implemented since 2004 using two treponemal tests, and estimate the seroprevalence of active syphilis infection in Ghana where yaws (caused by Treponema pallidum pertenue) is endemic. METHODS: We retested sera from the 2007 HIV sentinel survey (HSS) using a traditional algorithm, quantitative rapid plasma reagin test followed by qualitative Treponema pallidum haemagglutination assay. The adjusted seroprevalence of active syphilis was calculated by applying the proportions of active syphilis within identified categories of HSS samples during the retesting, to the entire population of HSS samples. The 95% confidence intervals (CIs) were calculated for each proportion, and the t-test was used to assess differences in proportions. RESULTS: Of 2,214 samples that were retested, 203 (9.2%) had active syphilis infection, 21 (0.9%) were biological false reactions, 640 (28.9%) were past or treated syphilis infections, and 1,350 (61%) were uninfected. The current syphilis testing strategy overestimated the seroprevalence of active syphilis infection by a third (HSS versus traditional algorithm: 6.0% (95% CI: 5.6-6.3) vs. 4.5% (95% CI: 4.2-4.8); p < 0.001), and had low positive predictive value (16.8%) for detecting active syphilis infection. More than half (51.9%) of HSS syphilis positive cases were actually past/treated treponemal infections, possibly previous exposure to yaws. CONCLUSION: There is an urgent need to review the current syphilis sentinel surveillance testing strategy in Ghana in the context of concurrent endemic treponematoses, to better inform policy. PMID- 27938338 TI - Salmonella enterica subspecies arizonae infection of adult patients in Southern Taiwan: a case series in a non-endemic area and literature review. AB - BACKGROUND: The majority of Salmonella arizonae human infections have been reported in southwestern United States, where rattlesnake-based products are commonly used to treat illness; however, little is known in non-endemic areas. We reviewed and analyzed the clinical manifestations and treatment outcomes in adult patients with S. arizonae infection at our institution. METHOD: A retrospective study was conducted at a regional teaching hospital in southern Taiwan from July 2007 to June 2014. All adult patients diagnosed with S. arizonae infections and treated for at least three days at Chia-Yi Christian Hospital were included. Patients were followed till discharge. RESULTS: A total of 18 patients with S. arizonae infections (median age: 63.5 years) were enrolled for analysis, of whom two thirds were male. The three leading underlying diseases were diabetes mellitus, peptic ulcer disease and malignancy. Ten patients had bacteraemia and the most common infection focus was the lower respiratory tract. Most of the patients (72.2%) received third-generation cephalosporins as definitive therapy. In contrast, ampicillin-based regimens (accounting for 45.2%) were the major treatment modalities in previous reports. The crude in-hospital mortality was 5.6%, which was much lower than what was previously reported (22.7%). CONCLUSIONS: Though uncommon, there were cases of S. arizonae infections in Taiwan. Patients receiving third-generation cephalosporins treatment had better prognosis compared with those treated with ampicillin-based regimen. PMID- 27938339 TI - Bayesian reversible-jump for epistasis analysis in genomic studies. AB - BACKGROUND: The large amount of data used in genomic analysis has allowed geneticists to achieve some understanding of the genetic architecture of complex traits. Although the information gathered by molecular markers has permitted gains in predictive accuracy and gene discovery, epistatic effects have been ignored based on exhaustive searches requesting estimates of its effects on the whole genome. In this work, we propose the reversible-jump technique to estimate epistasis in the genome without drastically altering the model dimension. To this end, we used a real maize dataset based on 256 F2:3 progenies plus a simulation data set based on 300 F2 individuals. In the simulation scenario, six QTL presenting main effects (additive and dominance) were combined with seven other epistatic effects totaling 13 QTL controlling the trait. RESULTS: Our model explored 18,624 candidate epistases, but even in this vast space, only one spurious interaction was found. The three epistases selected by our model, named here as 18x26, 56x68 and 59x93, were very close to simulated ones (19x25, 54x72, 59x91 and 59x94). In the real dataset, we estimate 33,024 epistatic effects, and several minor epistatic combinations were found to explain a significant proportion of the genetic variance. The broad participation of epistasis in the real dataset may indicate the presence of pervasive epistasis acting on maize grain yield. CONCLUSIONS: The power of selecting true epistasis in thousands of possible combinations suggests the attractiveness of our model to handle genomic data. PMID- 27938340 TI - Stillbirth - a challenge for the 21st century. PMID- 27938341 TI - Fetal membrane imaging and the prediction of preterm birth: a systematic review, current issues, and future directions. AB - BACKGROUND: Preterm premature rupture of membranes (PPROM) is the largest identifiable cause of preterm birth. There is currently no good screening test for PPROM in low-risk asymptomatic patients. Our goal was to identify how imaging methods can be utilized for examining the risks for PPROM in asymptomatic patients. METHODS: This paper is a systematic review of the literature on fetal membrane thickness and its use for the prediction of PPROM. Four key studies are identified and reviewed; two in vitro studies and two in vivo ultrasound studies each using differing methodologies. Additionally reviewed is a study using Optical Coherence Tomography, an emerging technique using near-infrared technology to produce high-resolution images. RESULTS: There is currently insufficient data to determine the association between fetal membrane thickness and PPROM by ultrasound. CONCLUSIONS: Fetal membrane thickness could have relevant clinical ramifications for the prediction of PPROM. Suggested improvements in study methodology and design will lead to progress in this area of research, as well as the use of newer technologies. Larger sample sizes, histological comparison, uniform methodologies for data collection, longitudinal study design and expanding data analysis beyond fetal membrane thickness to other properties would expand our knowledge in this field. In addition, transvaginal ultrasound should be utilized to improve resolution, as well as emerging methodologies such as MRI fusion imaging using ultrasound and Shear Wave Elastography. PMID- 27938342 TI - Comparative analysis of solar pasteurization versus solar disinfection for the treatment of harvested rainwater. AB - BACKGROUND: Numerous pathogens and opportunistic pathogens have been detected in harvested rainwater. Developing countries, in particular, require time- and cost effective treatment strategies to improve the quality of this water source. The primary aim of the current study was thus to compare solar pasteurization (SOPAS; 70 to 79 degrees C; 80 to 89 degrees C; and >=90 degrees C) to solar disinfection (SODIS; 6 and 8 hrs) for their efficiency in reducing the level of microbial contamination in harvested rainwater. The chemical quality (anions and cations) of the SOPAS and SODIS treated and untreated rainwater samples were also monitored. RESULTS: While the anion concentrations in all the samples were within drinking water guidelines, the concentrations of lead (Pb) and nickel (Ni) exceeded the guidelines in all the SOPAS samples. Additionally, the iron (Fe) concentrations in both the SODIS 6 and 8 hr samples were above the drinking water guidelines. A >99% reduction in Escherichia coli and heterotrophic bacteria counts was then obtained in the SOPAS and SODIS samples. Ethidium monoazide bromide quantitative polymerase chain reaction (EMA-qPCR) analysis revealed a 94.70% reduction in viable Legionella copy numbers in the SOPAS samples, while SODIS after 6 and 8 hrs yielded a 50.60% and 75.22% decrease, respectively. Similarly, a 99.61% reduction in viable Pseudomonas copy numbers was observed after SOPAS treatment, while SODIS after 6 and 8 hrs yielded a 47.27% and 58.31% decrease, respectively. CONCLUSION: While both the SOPAS and SODIS systems reduced the indicator counts to below the detection limit, EMA-qPCR analysis indicated that SOPAS treatment yielded a 2- and 3-log reduction in viable Legionella and Pseudomonas copy numbers, respectively. Additionally, SODIS after 8 hrs yielded a 2-log and 1-log reduction in Legionella and Pseudomonas copy numbers, respectively and could be considered as an alternative, cost-effective treatment method for harvested rainwater. PMID- 27938343 TI - Thromboembolic events, bleeding, and drug discontinuation in patients with atrial fibrillation on anticoagulation: a prospective hospital-based registry. AB - BACKGROUND: The clinical practice of stroke prevention in atrial fibrillation (AF) with direct oral anticoagulants (DOACS) differs from anticoagulation in randomized trial patients. We investigated the risk of thromboembolism, bleeding, and drug discontinuation in a hospital-based real-world setting. METHODS: All comer patients with non-valvular AF were recruited into a registry at an academic tertiary care center. After informed consent, patients underwent a personal structured interview including medical history, past and current anticoagulation, and returned for follow-up after 6-12 months. RESULTS: The registry comprised 282 patients (42% women, median age 71 years) with a median CHA2DS2-Vasc-Score of 4 (25. to 75. percentile 2.5-5), who were prospectively followed 285 days in median. At inclusion, 118 patients took vitamin-K-antagonists, 33 dabigatran, 87 rivaroxaban, 30 apixaban, 5 low-molecular-weight heparin, and 9 were on no anticoagulant. Occurrence of stroke (rate 2.8/100 patient-years), was associated with prior stroke (hazard ratio [HR] 18.5, 95% confidence interval 2.16-159), increased HbA1c (HR per 1% increase 1.71, 1.20-2.45) and borderline significantly associated with vascular disease (HR 8.33, 0.97-71.3). Further we observed a high rate of major bleeding (2.8/100 patient-years), clinically relevant non-major bleeding (4.1/100 patient-years), and venous thromboembolism (2.8/100 patient years). Anticoagulation was discontinued by 80 patients (36.9/100 patient-years), and diabetes (HR 2.31, 1.32-4.02), history of bleeding (HR 2.51, 1.44-4.37) and elevated leucocyte count (HR per 1G/l increase 1.02, 1.00-1.05) were associated with increased risk of discontinuation. CONCLUSIONS: In this hospital-based registry, patients with atrial fibrillation had an increased risk of thromboembolic events despite anticoagulation. The low drug persistence may be attributable to distinct comorbid conditions and bleeding complications. PMID- 27938344 TI - Colonization of patients, healthcare workers, and the environment with healthcare associated Staphylococcus epidermidis genotypes in an intensive care unit: a prospective observational cohort study. AB - BACKGROUND: During the last decades, healthcare-associated genotypes of methicillin-resistant Staphylococcus epidermidis (HA-MRSE) have been established as important opportunistic pathogens. However, data on potential reservoirs on HA MRSE is limited. The aim of the present study was to investigate the dynamics and to which extent HA-MRSE genotypes colonize patients, healthcare workers (HCWs) and the environment in an intensive care unit (ICU). METHODS: Over 12 months in 2006-2007, swab samples were obtained from patients admitted directly from the community to the ICU and patients transferred from a referral hospital, as well as from HCWs, and the ICU environment. Patients were sampled every third day during hospitalization. Antibiotic susceptibility testing was performed according to EUCAST guidelines. Pulsed-field gel electrophoresis and multilocus sequence typing were used to determine the genetic relatedness of a subset of MRSE isolates. RESULTS: We identified 620 MRSE isolates from 570 cultures obtained from 37 HCWs, 14 patients, and 14 environmental surfaces in the ICU. HA-MRSE genotypes were identified at admission in only one of the nine patients admitted directly from the community, of which the majority subsequently were colonized by HA-MRSE genotypes within 3 days during hospitalization. Almost all (89%) of HCWs were nasal carriers of HA-MRSE genotypes. Similarly, a significant proportion of patients transferred from the referral hospital and fomites in the ICU were widely colonized with HA-MRSE genotypes. CONCLUSIONS: Patients transferred from a referral hospital, HCWs, and the hospital environment serve as important reservoirs for HA-MRSE. These observations highlight the need for implementation of effective infection prevention and control measures aiming at reducing HA-MRSE transmission in the healthcare setting. PMID- 27938346 TI - Evaluation of the Home Environment Assessment for the Visually Impaired (HEAVI): an instrument designed to quantify fall-related hazards in the visually impaired. AB - BACKGROUND: To (1) develop and refine the Home Environment Assessment for the Visually Impaired (HEAVI), and (2) determine the interrater reliability of this instrument, which was designed to quantify the number of fall-related hazards in the homes of individuals with visual impairment. METHODS: Twenty homes of community-dwelling adults were included in this study. Each home was graded by an occupational therapist (OT) and two non-expert (NE) graders. Seventy-three HEAVI items were evaluated in eight rooms, for a total of 185 potential hazards per home (some items were assessed in multiple rooms). Pairwise and three-way agreement between graders was evaluated at the item, room, and home level using Krippendorff's alpha and intraclass correlation coefficients (ICC). Additionally, the most hazardous home locations and items were determined by comparing the mean and standard deviation of the number of hazards by room and grader. RESULTS: Of the 73 items, 45 (62%) demonstrated at least moderate agreement overall and for each OT/NE pair (Krippendorff's alpha >0.4), and remained in the final instrument (a total of 119 potential hazards per home as some items were assessed in multiple rooms). Of these 119 potential hazards, an average of 35.7, 33.2, and 33.3 hazards per home were identified by the OT and NE graders, respectively. Moderate to almost perfect agreement on the number of hazards per home and number of hazards per room, except the dining room, was found (ICCs of 0.58 to 0.93). Bathroom items were most often classified as hazards (>40% of items for all graders). The item classes most commonly graded as hazardous were handrails and lighting (>30% of items). CONCLUSION: Our results indicate that NE graders can accurately administer the HEAVI tool to identify fall-related hazards. Items in the bathroom and those related to handrails and lighting were most often identified as hazards, making these areas and items important targets for interventions when addressing falls. PMID- 27938345 TI - Assessment of platelet function in patients with stroke using multiple electrode platelet aggregometry: a prospective observational study. AB - BACKGROUND: There is a link between high on-treatment platelet reactivity (HPR) and adverse vascular events in stroke. This study aimed to compare multiple electrode platelet aggregometry (MEA), in healthy subjects and ischaemic stroke patients, and between patients naive to antiplatelet drugs (AP) and those on regular low dose AP. We also aimed to determine prevalence of HPR at baseline and at 3-5 days after loading doses of aspirin. METHODS: Patients with first ever ischaemic stroke were age and sex-matched to a healthy control group. Three venous blood samples were collected: on admission before any treatment given (baseline); at 24 h and 3-5 days after standard treatment. MEA was determined using a Mutliplate(r) analyser and agonists tested were arachidonic acid (ASPI), adenosine diphosphate (ADP) and collagen (COL). RESULTS: Seventy patients (mean age 73 years [SD 13]; 42 men, 28 women) were age and sex-matched to 72 healthy subjects. Thirty-three patients were on antiplatelet drugs (AP) prior to stroke onset and 37 were AP-naive. MEA results for all agonists were significantly increased in AP-naive patients compared to healthy subjects: ADP 98 +/- 31 vs 81 +/- 24, p < 0.005; ASPI 117 +/- 31 vs 98 +/- 27, p < 0.005; COL 100 +/- 25 vs 82 +/- 20, p < 0.005. For patients on long term AP, 33% (10/30) of patients were considered aspirin-resistant. At 3-5 days following loading doses of aspirin, only 11.1% were aspirin resistant based on an ASPI cut-off value of 40 AU*min. CONCLUSIONS: Many patients receiving low dose aspirin met the criteria of aspirin resistance but this was much lower at 3-5 days following loading doses of aspirin. Future studies are needed to establish the causes of HPR and potential benefits of individualizing AP treatment based on platelet function testing. PMID- 27938348 TI - Early antiretroviral treatment (eART) limits viral diversity over time in a long term HIV viral suppressed perinatally infected child. AB - BACKGROUND: HIV genetic diversity implicates major challenges for the control of viral infection by the immune system and for the identification of an effective immunotherapeutic strategy. With the present case report we underline as HIV evolution could be effectively halted by early antiretroviral treatment (eART). Few cases supported this evidence due to the difficulty of performing amplification and sequencing analysis in long-term viral suppressed patients. Here, we reported the case of limited HIV-1 viral evolution over time in a successful early treated child. CASE PRESENTATION: A perinatally HIV-1 infected infant was treated within 7 weeks of age with zidovudine, lamivudine, nevirapine and lopinavir/ritonavir. At antiretroviral treatment (ART) initiation HIV-1 viral load (VL) and CD4 percentage were >500,000 copies/ml and 35%, respectively. Plasma genotypic resistance test showed a wild-type virus. The child reached VL undetectability after 33 weeks of combination antiretroviral therapy (cART) since he maintained a stable VL <40copies/ml. After 116 weeks on ART we were able to perform amplification and sequencing assay on the plasma virus. At this time VL was <40 copies/ml and CD4 percentage was 40%. Again the genotypic resistance test revealed a wild-type virus. The phylogenetic analysis performed on the HIV-1 pol sequences of the mother and the child revealed that sequences clustered with C subtype reference strains and formed a monophyletic cluster distinct from the other C sequences included in the analysis (bootstrap value >90%). Any major evolutionary divergence was detected. CONCLUSIONS: eART limits the viral evolution avoiding the emergence of new viral variants. This result may have important implications in host immune control and may sustain the challenge search of new personalized immunotherapeutic approaches to achieve a prolonged viral remission. PMID- 27938350 TI - Central retinal artery occlusion and cerebral infarction associated with Mycoplasma pneumonia infection in children. AB - BACKGROUND: Central retinal artery occlusion (CRAO) is an arterial ischemic stroke, rarely occurred in children accompanied with asymptomatic cerebral infarction and almost never involved in severe pneumonia related to Mycoplasma pneumonia infection. CASE PRESENTATION: An 8-year-old boy with severe pneumonia related to Mycoplasma pneumonia infection that developed loss of vision in the left eye on the 14th day. No light perception and no pupillary reaction to light were found in the left eye. The fundus examination revealed a cherry red spot with severe retinal edema at the macular and peripapillary area, and the optic disc was pale in the left eye but normal in the right eye, suggesting CRAO in the left eye. No obvious neurological symptoms and signs were observed on presentation. Magnetic resonance imaging of the brain showed an abnormal signal of the left lentiform nucleus, caudate nucleus and within the temporal lobe, suggesting an acute cerebral infarction. The analysis of cerebrospinal fluid showed an increasing leukocyte count, but no any pathogenic microorganisms were found. His respiratory symptoms disappeared promptly after therapy, and the patient was discharged after 11 days later, but there was no light in the left eye 2 months after discharge. CONCLUSION: M. pneumoniae infection could be developed the risk for cerebral ischemic stroke, including CRAO in children with severe pneumonia. CRAO is a devastating ophthalmologic event leading to a severe impairment of vision. Patients treated within about 6 h of vision loss had a better visual outcome after the onset of vision loss. PMID- 27938347 TI - Globally distributed root endophyte Phialocephala subalpina links pathogenic and saprophytic lifestyles. AB - BACKGROUND: Whereas an increasing number of pathogenic and mutualistic ascomycetous species were sequenced in the past decade, species showing a seemingly neutral association such as root endophytes received less attention. In the present study, the genome of Phialocephala subalpina, the most frequent species of the Phialocephala fortinii s.l. - Acephala applanata species complex, was sequenced for insight in the genome structure and gene inventory of these wide-spread root endophytes. RESULTS: The genome of P. subalpina was sequenced using Roche/454 GS FLX technology and a whole genome shotgun strategy. The assembly resulted in 205 scaffolds and a genome size of 69.7 Mb. The expanded genome size in P. subalpina was not due to the proliferation of transposable elements or other repeats, as is the case with other ascomycetous genomes. Instead, P. subalpina revealed an expanded gene inventory that includes 20,173 gene models. Comparative genome analysis of P. subalpina with 13 ascomycetes shows that P. subalpina uses a versatile gene inventory including genes specific for pathogens and saprophytes. Moreover, the gene inventory for carbohydrate active enzymes (CAZymes) was expanded including genes involved in degradation of biopolymers, such as pectin, hemicellulose, cellulose and lignin. CONCLUSIONS: The analysis of a globally distributed root endophyte allowed detailed insights in the gene inventory and genome organization of a yet largely neglected group of organisms. We showed that the ubiquitous root endophyte P. subalpina has a broad gene inventory that links pathogenic and saprophytic lifestyles. PMID- 27938349 TI - Clinical usefulness of capnographic monitoring when inserting a feeding tube in critically ill patients: retrospective cohort study. AB - BACKGROUND: It is not rare for a small-bore feeding tube to be inserted incorrectly into the respiratory system in critically ill patients. Thus, monitoring is necessary to prevent respiratory malplacement of the tube. We investigated the utility of capnographic monitoring to prevent respiratory complications due to feeding tube mispositioning in critically ill patients. METHODS: This study was a pre and post-interventional study, including 445 feeding tube placements events studied retrospectively in the medical and surgical intensive care units of the Samsung Medical Center. We compared outcomes between time periods before and after capnographic monitoring and documented any respiratory complications. RESULTS: Feeding tubes were inserted in 275 cases without capnographic monitoring. Capnographic monitoring was performed in 170 cases. Sixteen patients (4%) had respiratory complications of all tube placements. Feeding tube was inserted into the trachea in 11 (2%) patients and for a pneumothorax in five (1%) patients. Fourteen cases of respiratory complications were detected in the control group (14/275, 5%, 10 tracheal insertions and four pneumothoraxes). Two respiratory complications were detected in the capnographic monitoring group (2/170, 1%, one tracheal insertion and one pneumothorax). Respiratory complications were detected less frequently in the capnographic monitoring group than that in the control group (P = 0.035). CONCLUSIONS: Capnographic monitoring is simple, easy to learn, and may be useful to prevent respiratory complications when placing a feeding tube in a critically ill patient. PMID- 27938351 TI - Modular assembly of synthetic proteins that span the plasma membrane in mammalian cells. AB - BACKGROUND: To achieve synthetic control over how a cell responds to other cells or the extracellular environment, it is important to reliably engineer proteins that can traffic and span the plasma membrane. Using a modular approach to assemble proteins, we identified the minimum necessary components required to engineer such membrane-spanning proteins with predictable orientation in mammalian cells. RESULTS: While a transmembrane domain (TM) fused to the N terminus of a protein is sufficient to traffic it to the endoplasmic reticulum (ER), an additional signal peptidase cleavage site downstream of this TM enhanced sorting out of the ER. Next, a second TM in the synthetic protein helped anchor and accumulate the membrane-spanning protein on the plasma membrane. The orientation of the components of the synthetic protein were determined through measuring intracellular Ca2+ signaling using the R-GECO biosensor and through measuring extracellular quenching of yellow fluorescent protein variants by saturating acidic and salt conditions. CONCLUSIONS: This work forms the basis of engineering novel proteins that span the plasma membrane to potentially control intracellular responses to extracellular conditions. PMID- 27938352 TI - Prediction of cancer progression in a group of 73 gastric cancer patients by circulating cell-free DNA. AB - BACKGROUND: Circulating cell-free DNA (ccf-DNA) in plasma may contain both specific and non-specific of tumor markers. The concentration and integrity of ccf-DNA may be clinical useful for detecting and predicting cancer progression. METHODS: Plasma samples from 40 healthy controls and 73 patients with gastric cancers (two stage 0, 17 stage I, 11 stage II, 33 stage III, and 10 stage IV according to American Joint Committee on Cancer stage) were assessed respectively. qPCR targeting the Alu repeats was performed using two different sets of primers amplifying the long and short segments. DNA integrity was calculated as a ratio of the long to the short fragments of Alu repeats. RESULTS: Plasma DNA concentration was significantly higher in patients with stage III and IV gastric cancers than in healthy controls (p = 0.028 and 0.029 respectively). The receiver operating characteristic (ROC) curve for discriminating patients with stage III and IV gastric cancers from healthy controls had an area under the curve (AUC) of 0.744 (95% CI, 0.64 to 0.85). Circulating cell-free DNA concentration increased within 21 days following surgery and dropped by 3 months after surgery. CONCLUSIONS: Concentration of ccf-DNA is a promising molecular marker for assessing gastric cancer progression. TRIAL REGISTRATION: Current Controlled Trials ChiCTR-DDT-12002848 , 8 October 2012. PMID- 27938353 TI - The quality of reporting of randomized controlled trials of electroacupuncture for stroke. AB - BACKGROUND: Electroacupuncture (EA), as an extension technique of acupuncture based on traditional acupuncture combined with modern electrotherapy, is commonly used for stroke in clinical treatment and researches. However, there is still a lack of enough evidence to recommend the routine use of EA for stroke. This study is aimed at evaluating the quality of reporting of randomized controlled trials (RCTs) on EA for stroke. METHODS: RCTs on EA for stroke were evaluated by using CONSORT guidelines and STRICTA guidelines. Microsoft Excel 2010 and the R software were used for descriptive statistics analyses. RESULTS: Seventy studies involving 5468 stroke patients were identified. The CONSORT scores ranged from 16.2 to 67.6% and STRICTA scores from 29.4 to 82.4%. The central items in CONSORT as eligibility criterion, sample size calculation, primary outcome, method of randomization sequence generation, allocation concealment, implementation of randomization, description of blinding, and detailed statistical methods were reported in 100, 6, 68, 37, 14, 10, 16, and 97% of trials, respectively. The reporting of items in STRICTA as acupuncture rationale was 1a (91%), 1b (86%) and 1c 0%; needling details 2a (33%), 2b (97%), 2c (29%), 2d (64%), 2e (100%), 2f (55%) and 2 g (66%); treatment regimen 3a (69%) and 3b (100%); other components of treatment 4a (86%) and 4b (13%); practitioner background item 5 (16%); control intervention(s) 6a (93%) and 6b (10%). CONCLUSIONS: The quality of reporting of RCTs on EA for stroke was generally moderate. The reporting quality needs further improvement. PMID- 27938354 TI - Seroepidemiology and associated risk factors of Toxoplasma gondii in sheep and goats in Southwestern Ethiopia. AB - BACKGROUND: T.gondii is a global zoonotic disease and is considered as the most neglected tropical disease in sub-Saharan countries. The exact seroepidemiological distribution and risk factors for the infection of food animals and humans in Ethiopia was less studied although, such studies are important. The objective of the current study was to determine the seroprevalence and potential risk factors of T. gondii infection in sheep and goats in Southwestern Ethiopia. METHODS: Cross sectional study was conducted from November 2014 to March 2015 in South west Ethiopia in four selected districts of Jimma zone (n = 368). Slide agglutination test (Toxo-latex) was used to detect anti T.gondii antibodies. Logistic regression was used to determine potential risk factors. RESULTS: An overall seroprevalence of 57.60% (212/368; 95% CI: 52.55 62.6) was detected. 58.18% (148/252; 95% CI: 52.75-64.88) and 55.18% (64/116; 95% CI: 46.13-64.23) sero prevalence was found in sheep and goats respectively. Multivariable logistic regression analysis showed that the risk of T. gondii infection was significantly higher in adult sheep and goats [(sheep: Odds Ratio (OR) = 2.5, confidence interval (CI): 1.19-5.23; p = 0.015), (goats: OR = 3.9, confidence interval (CI):1.64-9.41: p = 0.002)] than in young sheep and goats, in female [(sheep: OR = 1.93, CI: 1.11-3.36, p = 0.018, (goats: OR = 2.9, CI: 121 6.93, p = 0.002)] than in males sheep and goats, in Highland [(sheep: OR = 4.57, CI: 1.75-12.66, P = 0.000, (goats: OR = 4.4, CI: 1.75-13.66, p = 0.004)] than sheep and goats from lowland. CONCLUSION: This study indicates that seroprevalence of latent toxoplasmosis in small ruminants is high, therefore, it is decidedly indispensable to minimize risk factors exposing to the infection like consumption of raw meat as source of infection for humans. PMID- 27938355 TI - Metalloproteinases and their inhibitors are influenced by inhalative glucocorticoid therapy in combination with environmental dust reduction in equine recurrent airway obstruction. AB - BACKGROUND: Overexpression of matrix-metalloproteinases (MMPs) has been shown to lead to tissue damage in equine recurrent airway obstruction (RAO), as a misbalance with their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), occurs. This favors irreversible pulmonary fibrosis formation. Increased levels of MMPs, TIMPs or altered ratios between them can be used as biomarkers of respiratory disease. We hypothesized that levels of MMPs, TIMPs and their ratios correlate with improvement in clinical findings and bronchoalveolar lavage fluid (BALF) cytology after 10 days of inhalative glucocorticoid therapy and environmental dust reduction (EDR) and may be used to monitor treatment success. Ten horses with a history of RAO participated in a prospective clinical study. Clinical and cytological scoring was performed before and after inhalative therapy using budesonide (1500 MUg BID over 10 days) and EDR (bedding of wood shavings and wet hay as roughage). Gelatin zymography was performed for qualitative and semi-quantitative evaluation of MMP-2 and MMP-9 in BALF supernatant, while fluorimetry was used to evaluate MMP-8 activity. Additionally, specific equine ELISA assays were used for quantitative assessment of MMP-2, MMP-9, TIMP-1 and TIMP-2. RESULTS: A significant reduction in the total and several single parameters of the clinical score were found after 10 days of inhalative therapy and EDR. The concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 (ELISA) as well as their activities (MMP-2 and MMP-9 zymography and MMP-8 fluorimetry) were significantly decreased after therapy. Significant improvements in MMP-8/TIMP-1 and MMP-8/TIMP-2 ratios were also found, differences between other ratios before and after therapy were insignificant. CONCLUSIONS: Metalloproteinases and their inhibitors, in particular MMP-9 and TIMP-2, are valuable markers for clinical improvement in RAO. PMID- 27938357 TI - Erratum to: Neonatal Hyperbilirubinemia in infants with G6PD c.563C > T Variant. PMID- 27938358 TI - High strength extrafine pMDI beclometasone/formoterol (200/6 MUg) is effective in asthma patients not adequately controlled on medium-high dose of inhaled corticosteroids. AB - BACKGROUND: A high strength of beclomethasone/formoterol fumarate (BDP/FF) in a pressurised metered dose inhaler (pMDI), which contains extrafine BDP (200 MUg/actuation) and FF (6 MUg/actuation) has been developed to treat those asthmatics who are not adequately controlled on previous treatments. METHODS: A 12-week, randomized, double-blind, parallel group study was performed to compare the efficacy and safety of pMDI BDP/FF 200/6 (two actuations bid) with BDP 100 MUg (four actuation bid) in a population of 376 randomized adult asthmatics not adequately controlled with high dose of inhaled corticosteroids (ICS) or medium dose of ICS plus long acting beta2agonists (LABA). RESULTS: The primary endpoint [change from baseline over the entire treatment period in average pre-dose morning peak expiratory flow (PEF)] demonstrated the superiority of BDP/FF over BDP monotherapy, with an adjusted mean difference of 19 L/min, which is above the minimal important clinical difference reported for this parameter. Overall, BDP/FF and BDP showed a similar improvement of symptom-based parameters and of the use of rescue medication after 3-month treatment. The safety profile of the two drugs was comparable, although BDP monotherapy, but not BDP/FF, slightly reduced the levels of serum cortisol. CONCLUSIONS: The study proved that pMDI BDP/FF 200/6 MUg was superior to BDP alone in improving lung function with comparable safety profiles. Therefore it may be considered as an effective treatment for adults with asthma not adequately controlled with high dose of ICS monotherapy or medium dose of ICS/LABA combinations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01577082 , date 06/04/2012. PMID- 27938356 TI - Plasmodium falciparum genotype and gametocyte prevalence in children with uncomplicated malaria in coastal Ghana. AB - BACKGROUND: Plasmodium falciparum gametocytes are vital to sustaining malaria transmission. Parasite densities, multiplicity of infection as well as asexual genotype are features that have been found to influence gametocyte production. Measurements of the prevalence of Plasmodium sp. gametocytes may serve as a tool to monitor the success of malaria eradication efforts. METHODS: Whole blood was collected from 112 children aged between 6 months and 13 years with uncomplicated P. falciparum malaria attending three health facilities in southern Ghana from June to August, 2014 before (day 0) and 4 days after completion of anti-malaria drug treatment (day 7). Malaria parasites were observed by microscopy and polymerase chain reaction (PCR); submicroscopic gametocyte carriage was measured by a Pfs25 (PF3D7_1031000) mRNA real time reverse transcriptase polymerase chain reaction (RT-PCR). Parasite genotyping was performed on gDNA extracted from dried filter paper blood blots by amplification of the polymorphic regions of msp1 (PF3D7_0930300) and msp2 (PF3D7_0206800) using PCR. RESULTS: Microscopy estimated 3.1% (3/96) of the total population to carry gametocytes on day 0, which decreased to 2.1% (2/96) on day 7. In contrast, reverse transcriptase-real time PCR (RT-PCR) analysis of a subset of 35 samples estimated submicroscopic gametocyte carriage to be as high as 77% (27/35) using primers specific for Pfs25 (CT < 35) on day 0 and by day 7 this only declined to 60% (21/35). Genotyping the msp2 gene identified higher levels of MOI than the msp1 gene. CONCLUSIONS: Although below detection by microscopy, gametocyte prevalence at submicroscopic levels are high in this region and emphasize the need for more effective elimination approaches like the development of transmission-blocking vaccines and safer gametocytocidal drugs. PMID- 27938359 TI - Comparison of contrast-enhanced multidetector computed tomography angiography and splenoportography for the evaluation of portosystemic-shunt occlusion after cellophane banding in dogs. AB - BACKGROUND: Many patients with a congenital extrahepatic portosystemic shunt (PSS) do not tolerate an immediate shunt closure. Therefore, slow progressive techniques were developed. To evaluate the success of shunt closure diagnostic imaging is essential to identify possible residual blood flow through the shunt vessel. There is a lack of information about the reliability of computed tomography angiography (CTA) for evaluating residual flow through a PSS after treatment. The purpose of this prospective study was to compare the results of CTA with splenoportography. Three months after cellophane banding CTA and splenoportography were performed in 20 dogs and reviewed by three independent examiners, respectively. In both imaging modalities the presences of a residual shunt was judged as present or absent and the extent of visibility of portal vasculature was recorded. RESULTS: Based on the evaluation of the splenoportography residual flow through shunt was present in 6 dogs. The classification of residual shunt present or absent showed a substantial to perfect agreement (kappa = 0.65-1.00) between the observers in splenoportography and a slight to moderate agreement (kappa = 0.11-0.51) for CTA. Sensitivity and specificity varied between 0.50 and 1.00 and 0.57-0.85, respectively. Significant correlation between CTA and splenoportography for the classification of residual shunt was present only in one observer but not in the other two. CONCLUSION: More studies were classified as residual shunt positive with CTA compared to splenoportography. It remains unclear which methods do reflect reality better and thus which method is superior. The greater inter-rater agreement for splenoportography suggests a greater reliability of this technique. PMID- 27938360 TI - Overweight and obesity epidemic in Ghana-a systematic review and meta-analysis. AB - BACKGROUND: In many low and middle income countries (LMICs), the distribution of adulthood nutritional imbalance is shifting from a predominance of undernutrition to overnutrition. This complex problem poses a huge challenge to governments, non state actors, and individuals desirous of addressing the problem of malnutrition in LMICs. The objective of this study was to systematically review the literature towards providing an estimate of the prevalence of overweight and obesity among adult Ghanaians. METHODS: This study followed the recommendations outlined in the PRISMA statement. Searches were performed in PubMed, Science Direct, google scholar, Africa Journals Online (AJOL) and the WHO African Index Medicus database. This retrieved studies (published up to 31st March 2016) that reported overweight and obesity prevalence among Ghanaians. All online searches were supplemented by reference screening of retrieved papers to identify additional studies. RESULTS: Forty-three (43) studies involving a total population of 48,966 sampled across all the ten (10) regions of Ghana were selected for the review. Our analysis indicates that nearly 43% of Ghanaian adults are either overweight or obese. The national prevalence of overweight and obesity were estimated as 25.4% (95% CI 22.2-28.7%) and 17.1% (95% CI = 14.7-19.5%), respectively. Higher prevalence of overweight (27.2% vs 16.7%) and obesity (20.6% vs 8.0%) were estimated for urban than rural dwellers. Prevalence of overweight (27.8% vs 21.8%) and obesity (21.9% vs 6.0%) were also significantly higher in women than men. About 45.6% of adult diabetes patients in Ghana are either overweight or obese. At the regional level, about 43.4%, 36.9%, 32.4% and 55.2% of residents in Ashanti, Central, Northern and Greater Accra region, respectively are overweight or obese. These patterns generally mimic the levels of urbanization. Per studies' publication years, consistent increases in overweight and obesity prevalence were observed in Ghana in the period 1998-2016. CONCLUSIONS: There is a high and rising prevalence of overweight and obesity among Ghanaian adults. The possible implications on current and future population health, burden of chronic diseases, health care spending and broader economy could be enormous for a country still battling many infectious and parasitic diseases. Public health preventive measures that are appropriate for the Ghanaian context, culturally sensitive, cost-effective and sustainable are urgently needed to tackle this epidemic. PMID- 27938361 TI - Evaluation of the efficacy of a short-course, personalized self-management and intensive spa therapy intervention as active prevention of musculoskeletal disorders of the upper extremities (Muska): a research protocol for a randomized controlled trial. AB - BACKGROUND: Musculoskeletal disorders (MSDs) constitute a major occupational health problem in the working population, substantially impacting the quality of life of employees. They also cause considerable economic cost to the healthcare system, with, notably, the reimbursement of treatments and compensation for lost income. MSDs manifest as localized pain or functional difficulty in one or more anatomical areas, such as the cervical spine, shoulder, elbow, hand, and wrist. Although prevalence varies depending on the region considered and the method of assessment, a prevalence of 30% is found in different epidemiological studies. The disease needs to be prevented, not only for medical and economic reasons, but also for legal reasons, owing to the requirement of assessing occupational risks. The strategy envisaged may thus revolve around active, multimodal prevention that has employees fully involved at the heart of their care. Although physical exercise is widely recommended, few studies with a good level of evidence have enabled us to base a complete, well-constructed intervention on exercise that can be offered as secondary prevention in these disorders. METHODS: A prospective, multicenter, comparative (intervention arm vs. control arm), randomized (immediate vs. later treatment) study using Zelen's design. This study falls under active prevention of MSDs of the upper extremities (UE-MSDs). Participants are workers aged between 18 and 65 years with latent or symptomatic MSDS, with any type of job or workstation, with or without an history of sick leave. The primary aim is to show the superiority at 3 months of a combination of spa therapy, exercise, and self-management workshops for 6 days over usual care in the management of MSDs in terms of employee functional capacity in personal and professional daily life. Secondary aims are to assess the benefit of the intervention in terms of pain, quality of life, and accumulated duration of sick leave. DISCUSSION: This randomized controlled trial is the first that will aim to evaluate multidisciplinary management of UE-MSDs using nonpharmacological treatment combining exercise, self-management, and spa therapy. The originality of this intervention lies, in its short, intensive format, which is compatible with remaining in work; and in its multidisciplinary approach. This trial has the potential to demonstrate, with a good level of evidence, the benefits of a short course of spa therapy combined with a personalized self-management program on the functional capacity, pain, and quality of life of employees in their daily life. TRIAL REGISTRATION: Clinical trial.gov NCT02702466 retrospectively registered. PROTOCOL: Version 4 of 9/10/2015. PMID- 27938362 TI - Impact of ao-dake-humi, Japanese traditional bamboo foot stimulator, on lower urinary tract symptoms, constipation and hypersensitivity to cold: a single-arm prospective pilot study. AB - BACKGROUND: Ao-dake-humi is a traditional Japanese bamboo foot stimulator consisting of a half-pipe-shaped step made of bamboo used to stimulate the foot by stepping on it, and is commonly used to promote general health among the elderly in Japan. However, its efficacy has not been reported in the scientific literature. This study was performed to investigate the role of ao-dake-humi focusing on lower urinary tract symptoms (LUTS), constipation, and hypersensitivity to cold (HC). METHODS: Participants with LUTS, constipation, or HC were enrolled in this study. Ao-dake-humi was used twice a day for 28 days. Before and 28 days after starting ao-dake-humi use, international prostate symptom score (IPSS), quality-of-life (QoL) score, and overactive bladder symptom score (OABSS) were measured to evaluate the efficacy of ao-dake-humi on LUTS. To evaluate the objective efficacy of ao-dake-humi on LUTS, a frequency-volume chart (FVC) was plotted in LUTS patients for 3 days. A visual analogue scale (VAS) was used to evaluate the efficacy of ao-dake-humi on constipation (VAS-constipation) and HC (VAS-HC) in the participants with constipation or HC. RESULTS: A total of 24 participants were enrolled in this study. Twenty-one participants had LUTS, 11 had constipation, and 17 participants had HC. IPSS, especially storage-subscore, QoL score and OABSS, decreased significantly after use of ao-dake-humi. The use of ao-dake-humi increased maximal bladder capacity, resulting in a significant decrease in urinary frequency as determined from the FVC. In accordance with the results of VAS-constipation and VAS-HC, both constipation and HC were significantly relieved after ao-dake-humi use. CONCLUSION: The results of this prospective pilot study indicated that ao-dake-humi is safe and has therapeutic efficacy in cases of LUTS, constipation and HC. The possibility of using ao-dake humi as physical neuromodulation therapy was shown in the management of LUTS, constipation and HC. TRIAL REGISTRATION: UMIN000019333 (UMIN-CTR, Registered October-15-2015) retrospectively registered. PMID- 27938363 TI - Reasons for defaulting from childhood immunization program: a qualitative study from Hadiya zone, Southern Ethiopia. AB - BACKGROUND: Reduction of mortality and morbidity from vaccine-preventable diseases in developing countries involves successfully implementing strategies that ensure high coverage and minimize drop-outs and missed opportunities. Achieving maximum coverage, however, has been a challenge due to many reasons, including high rates of defaulters from the program. The objective of this study was to explore the reasons behind defaulting from the immunization program. METHODS: A qualitative study was conducted in two districts of Hadiya zone, Southern Ethiopia between November 2014 and April 2015. A total of twenty-six in depth interviews were held with mothers of defaulted children aged 6-11months old and key informants from the communities, health centers, and health offices. Observations and review of relevant documents were also conducted. Thematic analysis was used to analyze the data. RESULTS: In this study, the main reason for defaulting from the immunization was inadequate counseling of mothers that led to a lack of information about vaccination schedules and service arrangements, including in unusual circumstances such as after missed appointment, loss of vaccination card and when the health workers failed to make home visits. Provider-client relationships are poor with mothers reporting fear of mistreatment and lack of cooperation from service providers. Contrary to what health workers and managers believe, mothers were knowledgeable about the benefits of vaccination. The high workload on mothers compounded by the lack of support from male partners was also found to contribute to the problem. Health system factors that contributed to the problem were poorly arranged and coordinated immunization services, vaccine and supplies stock outs, and lack of viable defaulter tracking systems in the health facilities. CONCLUSIONS: The main reasons for defaulting from the immunization program are poor counseling of mothers, unsupportive provider-client relationships, poor immunization service arrangements, and lack of systems for tracking defaulters. Efforts to reduce defaulter rates from the immunization program need to focus on improving counseling of mothers and strengthening the health systems, especially with regards to service arrangements and tracking of defaulters. PMID- 27938364 TI - Procalcitonin as a biomarker in equine chronic pneumopathies. AB - BACKGROUND: Procalcitonin (PCT), a precursor protein of the hormone calcitonin, is a sensitive inflammatory marker in human medicine, which is primarily used for diagnosis of bacterial sepsis, but is also useful in diagnosis of exacerbation of asthma and COPD. In this study, PCT was evaluated as a potential biomarker for different chronic pneumopathies in the horse using an equine specific ELISA in comparison to established clinical markers and different interleukins. Sixty-four horses were classified as free of respiratory disease, recurrent airway obstruction (RAO), inflammatory airway disease (IAD) or chronic interstitial pneumopathy (CIP) using a scoring system. PCT concentrations were measured in plasma (n = 17) and in the cell-free supernatant of bronchoalveolar lavage (n = 64). PCT concentrations were correlated to interleukins IL-1beta and IL-6 in BALF, clinical findings and BALF cytology. RESULTS: The median PCT concentrations in plasma were increased in respiratory disease (174.46 ng/ml, n = 7) compared to controls (13.94 ng/ml, n = 10, P = 0.05) and correlated to PCT in BALF supernatant (rs = 0.48). Compared to controls (5.49 ng/ml, n = 15), median PCT concentrations in BALF supernatant correlated to the overall clinical score (rs = 0.32, P = 0.007) and were significantly increased in RAO (13.40 ng/ml, n = 21) and IAD (16.89 ng/ml, n = 16), while no differences were found for CIP (12.02 ng/ml, n = 12). No significant increases were found for IL-1 and IL-6 between controls and respiratory disease in general as well as different disease groups. CONCLUSIONS: Although some correlations were found between PCT in plasma, BALF supernatant and clinical scores, PCT in BALF does not seem to be a superior marker compared to established clinical markers. PCT in plasma seems to be more promising and a greater number of samples should be evaluated in further studies. PMID- 27938365 TI - Comparing the effects of different dynamic sitting strategies in wheelchair seating on lumbar-pelvic angle. AB - BACKGROUND: Prolonged static sitting in a wheelchair is associated with an increased risk of lower back pain. The wheelchair seating system is a key factor of this risk because it affects spinal loading in the sitting position. In this study, 7 dynamic sitting strategies (DSSs) are examined: lumbar prominent dynamic sitting (LPDS), back reclined dynamic sitting (BRDS), femur upward dynamic sitting (FUDS), lumbar prominent with back reclined dynamic sitting (LBDS), lumbar prominent with femur upward dynamic sitting (LFDS), back reclined with femur upward dynamic sitting (BFDS), and lumbar prominent with back reclined with femur upward dynamic sitting (LBFDS). The objective of this study was to analyze the biomechanical effects of these sitting strategies on lumbar-pelvic angles. METHODS: Twenty able-bodied participants were recruited for the study. All participants performed LPDS, BRDS, FUDS, LBDS, LFDS, BFDS, and LBFDS in a random order. All lumbar-pelvic angle parameters, including the static lumbar angle, static pelvic angle, lumbar range of motion, and pelvic range of motion were measured and compared. RESULTS: Results show that LBDS and LBFDS enabled the most beneficial lumbar movements, although the difference between the 2 strategies was nonsignificant. BRDS and BFDS enabled the most beneficial pelvic movements, although the difference between the 2 strategies was nonsignificant. Among all the upright DSSs, LPDS and LFDS enabled the most beneficial lumbar and pelvic movements, although no significant difference was observed between these 2 strategies. CONCLUSIONS: We identified the effects and differences among 7 DSSs on lumbar-pelvic angles. Wheelchair users can choose the most suitable DSS that meets their needs. These findings may serve as a reference for practicing physicians or wheelchair users to choose an appropriate dynamic wheelchair seating system. TRIAL REGISTRATION: ISRCTN12389808 , 18th November 2016, retrospectively registered. PMID- 27938366 TI - Motives for self-referral to the emergency department: a systematic review of the literature. AB - BACKGROUND: In several western countries patients' use of Emergency Departments (EDs) is increasing. A substantial number of patients is self-referred, but does not need emergency care. In order to have more influence on unnecessary self referral, it is essential to know why patients visit the ED without referral. The goal of this systematic review therefore is to explore what motivates self referred patients in those countries to visit the ED. METHODS: Recommendations from the PRISMA were used to search and analyze the literature. The following databases; PUBMED, MEDLINE, EMBASE, CINAHL and Cochrane Library, were systematically searched from inception up to the first of February 2015. The reference lists of the included articles were screened for additional relevant articles. All studies that reported on the motives of self-referred patients to visit an ED were selected. The reasons for self-referral were categorized into seven main themes: health concerns, expected investigations; convenience of the ED; lesser accessibility of primary care; no confidence in general practitioner/primary care; advice from others and financial considerations. A random-effects meta-analysis was performed. RESULTS: Thirty publications were identified from the literature studied. The most reported themes for self referral were 'health concerns' and 'expected investigations': 36% (95% Confidence Interval 23-50%) and 35% (95% CI 20-51%) respectively. Financial considerations most often played a role in the United States with a reported percentage of 33% versus 4% in other countries (p < 0.001). CONCLUSIONS: Worldwide, the most important reasons to self-refer to an ED are health concerns and expected investigations. Financial considerations mainly play a role in the United States. PMID- 27938367 TI - Anatomical success rate of pars plana vitrectomy for treatment of complex rhegmatogenous retinal detachment. AB - BACKGROUND: Pars plana vitrectomy (PPV) is preferred surgical procedure for the management of complex rhegmatogenous retinal detachment (RRD). The purpose of this study was to evaluate the anatomical results of primary PPV for the treatment of primary complex RRD and to determine the influence of lens status, tamponading agent, preoperative proliferative vitreoretinopathy (PVR) and axial length (AL) of the eye upon the anatomical outcome. METHODS: A retrospective consecutive chart analysis was performed on 117 eyes from 117 patients with complex RRD managed with PPV. Fifty-nine eyes were phakic and 58 pseudophakic eyes. All patients had a minimum follow-up period of 12 months. Eyes were classified into groups using independent variables (first classification based upon lens status and tamponade used, second classification based upon lens and PVR status and third classification based upon AL of the eye). The groups were compared for anatomical outcomes (dependent variables) using nonparametric- or, in case of normally distributed data, parametric- statistical tests. RESULTS: Retinal reattachment rate in phakic eyes was 94.9% compared to 93.1% in pseudophakic, with no statistically significant difference between the two. The overall retinal reattachment rate with single surgery was 94.0%. Final reattachment rate was 97.4%. In case of established PVR >= C1, the reattachment rate was not statistically different (92.6%) from eyes with no PVR (91.1%) irrespective of lens status. A statistically significant difference was found between redetachment rates only between phakic eyes with gas tamponade compared to silicon oil (SO) (p = 0.001). Reattachment rate proved to be similar in both AL groups (<=24 mm and > 24 mm). CONCLUSIONS: High anatomical success rate of primary vitrectomy for complex RRD with either gas or SO tamponade was achieved in phakic as well as pseudophakic eyes irrespective of AL of the eye. PMID- 27938368 TI - Psychiatrists' experiences of suicide assessment. AB - BACKGROUND: Clinical guidelines for suicide prevention often stress the identification of risk and protective factors as well as the evaluation of suicidal intent. However, we know very little about what psychiatrists actually do when they make these assessments. The aim was to investigate psychiatrists' own accounts of suicide assessment consultations, with a focus on their behaviors, attitudes and emotions. METHOD: Semi-structured in depth interviews were carried out with a purposive selection of 15 psychiatrists. RESULTS: Thematic analysis revealed three main themes: understanding the patient in a precarious situation, understanding one's own reactions, and understanding how the doctor-patient relationship impacted on risk assessment and management decisions. Emotional contact and credibility issues were common subthemes that arose when the respondents talked about trying to understand the patient. The psychiatrists stressed the semi-intuitive nature of their assessments. Problems related to the use of risk factor assessments and rating scales were apparent. Assessment consultations could evoke physical and emotional symptoms of anxiety, and concerns about responsibility could lead to repressive management decisions. In situations of mutual trust, however, the assessment consultation could kick start a therapeutic process. CONCLUSION: This study highlights psychiatrists' experiences in clinical suicide assessment situations. Findings have implications for professional development as well as for service delivery. PMID- 27938370 TI - Menstrual pattern among adolescent girls of Pokhara Valley: a cross sectional study. AB - BACKGROUND: Menstruation is a normal physiological process occurring every month throughout the reproductive age of the females. However, significant variation in menstrual pattern is observed among adolescents. The objective of this study was to determine menstrual pattern among adolescent girls of Pokhara Valley. METHOD: A cross sectional study was conducted in seven schools of Pokhara Valley. A total of 260 adolescent girls were included in the study. Girls were requested to complete questionnaire containing 19 items. Selected girls voluntarily agreed to answer questionnaire under the supervision of the researcher and then the data was analyzed. RESULTS: Mean age of the girls was 14.0 +/- 1.3 years. Mean age at menarche was 12.2 +/- 0.9 years. The mean cycle length of the subjects was 34.8 +/- 11.8 days. It was observed that as many as 167(64.2%) girls had irregular menstrual cycle and significant association was found between regularity of menstruation and ethnicity. Seven (2.7%) girls had a menstrual cycle length shorter than 21 days, 60(23.1%) had cycle longer than 35 days and 193(74.2%) had a normal cycle length between 21 and 35 days. Majority 231(88.8%) had normal duration of menstruation. Dysmenorrhoea was reported by more than half of the girls and significant association was found between severity of dysmenorrhoea with school absenteeism and treatment needed. CONCLUSION: Dysmenorrhoea was the most common menstrual problem among adolescent girls. Girls' school attendance was affected due to menstrual pain. Girls with severe dysmenorrhea needed medical treatment. Irregular menstruation was reported by more than half of the girls and significant association was found with the ethnicity. PMID- 27938369 TI - Achieving development goals for HIV, tuberculosis and malaria in sub-Saharan Africa through integrated antenatal care: barriers and challenges. AB - BACKGROUND: The global health community is currently transitioning from the Millennium Development Goals (MDGs) to the Sustainable Development Goals (SDGs). Unfortunately, progress towards maternal, newborn and infant health MDGs has lagged significantly behind other key health goals, demanding a renewed global effort in this key health area. The World Health Organization and other institutions heralded integrated antenatal care (ANC) as the best way to address the inter-related health issues of HIV, tuberculosis (TB) and malaria in the high risk groups of pregnant women and infants; integrated ANC services also offer a mechanism to address slow progress towards improved maternal health. DISCUSSION: There is remarkably limited evidence on best practice approaches of program implementation, acceptability and effectiveness for integrated ANC models targeting multiple diseases. Here, we discuss current integrated ANC global guidelines and the limited literature describing integrated ANC implementation and evidence for their role in addressing HIV, malaria and TB during pregnancy in sub-Saharan Africa. We highlight the paucity of data on the effectiveness of integrated ANC models and identify significant structural barriers in the health system (funding, infrastructure, distribution, human resources), the adoption system (limited buy-in from implementers, leadership, governance) and, in the broader context, patient-centred barriers (fear, stigma, personal burdens) and barriers in funding structures. We highlight recommendations for action and discuss avenues for the global health community to develop systems to integrate multiple disease programs into ANC models of care that better address these three priority infectious diseases. With the current transition to the SDGs and concerns regarding the failure to meet maternal health MDGs, the global health community, researchers, implementers and funding bodies must work together to ensure the establishment of quality operational and implementation research to inform integrated ANC models. It is imperative that the global health community engages in a timely discussion about such implementation innovations and instigates appropriate actions to ensure advances in maternal health are sufficient to meet applicable SDGs. PMID- 27938371 TI - The role of osmolality in saline fluid nebulization after tracheostomy: time for changing? AB - BACKGROUND: Saline fluid nebulization is highly recommend to combat the complications following tracheostomy, yet the understandings on the role of osmolality in saline solution for nebulization remain unclear. OBJECTIVES: To investigate the biological changes in the early stage after tracheostomy, to verify the efficacy of saline fluid nebulization and explore the potential role of osmolality of saline nebulization after tracheostomy. METHODS: Sprague-Dawley rats undergone tracheostomy were taken for study model, the sputum viscosity was detected by rotational viscometer, the expressions of TNF-alpha, AQP4 in bronchoalveolar lavage fluid were assessed by western blot analysis, and the histological changes in endothelium were evaluated by HE staining and scanning electron microscopy (SEM). RESULTS: Study results revealed that tracheostomy gave rise to the increase of sputum viscosity, TNF-alpha and AQP4 expression, mucosa and cilia damage, yet the saline fluid nebulization could significantly decrease the changes of those indicators, besides, the hypertonic, isotonic and hypertonic saline nebulization produced different efficacy. CONCLUSIONS: Osmolality plays an important role in the saline fluid nebulization after tracheostomy, and 3% saline fluid nebulization seems to be more beneficial, further studies on the role of osmolality in saline fluid nebulization are warranted. PMID- 27938372 TI - Mapping the decision pathways of acute infection management in secondary care among UK medical physicians: a qualitative study. AB - BACKGROUND: The inappropriate use of antimicrobials drives antimicrobial resistance. We conducted a study to map physician decision-making processes for acute infection management in secondary care to identify potential targets for quality improvement interventions. METHODS: Physicians newly qualified to consultant level participated in semi-structured interviews. Interviews were audio recorded and transcribed verbatim for analysis using NVIVO11.0 software. Grounded theory methodology was applied. Analytical categories were created using constant comparison approach to the data and participants were recruited to the study until thematic saturation was reached. RESULTS: Twenty physicians were interviewed. The decision pathway for the management of acute infections follows a Bayesian-like step-wise approach, with information processed and systematically added to prior assumptions to guide management. The main emerging themes identified as determinants of the decision-making of individual physicians were (1) perceptions of providing 'optimal' care for the patient with infection by providing rapid and often intravenous therapy; (2) perceptions that stopping/de escalating therapy was a senior doctor decision with junior trainees not expected to contribute; and (3) expectation of interactions with local guidelines and microbiology service advice. Feedback on review of junior doctor prescribing decisions was often lacking, causing frustration and confusion on appropriate practice within this cohort. CONCLUSION: Interventions to improve infection management must incorporate mechanisms to promote distribution of responsibility for decisions made. The disparity between expectations of prescribers to start but not review/stop therapy must be urgently addressed with mechanisms to improve communication and feedback to junior prescribers to facilitate their continued development as prudent antimicrobial prescribers. PMID- 27938373 TI - Pre-hospital transfusion of plasma in hemorrhaging trauma patients independently improves hemostatic competence and acidosis. AB - BACKGROUND: The early use of blood products has been associated with improved patient outcomes following severe hemorrhage or traumatic injury. We aimed to investigate the influence of pre-hospital blood products (i.e. plasma and/or RBCs) on admission hemostatic properties and patient outcomes. We hypothesized that pre-hospital plasma would improve hemostatic function as evaluated by rapid thrombelastography (rTEG). METHODS: We conducted a prospective observational study recruiting 257 trauma patients admitted to a Level I trauma center having received either blood products pre-hospital or in-hospital within 6 hours of admission. Clinical data on patient demographics, blood biochemistry, injury severity score and mortality were collected. Admission rTEG was conducted to characterize the coagulation profile and hemostatic function. RESULTS: 75 patients received pre-hospital plasma and/or RBCs (PH group; nearly half received both RBCs and plasma) whereas 182 patients only received in-hospital blood products (RBCs, Plasma and Platelets) within 6 hours of admission (IH group). PH patients had lower Glasgow coma scale (GCS) scores, more penetrating injuries, lower systolic blood pressures, lower hemoglobin levels, lower platelet counts and greater acidosis upon ED admission than the IH group (all p < 0.05). Despite differences in type of injury and admission vitals indicating that the PH group had more signs of bleeding than the IH group, there were no significant differences in in-hospital mortality (PH 26.7% vs. IH 20.9% p = 0.31). When comparing rTEG variables between PH patients transfused with 0, 1 or 2 units of plasma, more pre-hospital plasma transfusion was tendency towards improved rTEG variables. When adjusting for pre-hospital RBC, pre-hospital plasma was associated with significantly higher rTEG MA (p = 0.012) at hospital admission. DISCUSSION: After adjusting for pre-hospital RBCs, pre-hospital plasma transfusion was independently associated with increased rTEG MA, as well as arrival indices of shock and hemodynamic instability. Besides more severe injury and worse clinical presentation, the group that received pre-hospital transfusion had early and late mortality similar to patients not transfused pre-hospital. CONCLUSIONS: These data suggest that early administration of plasma can provide significant hemostatic and potential survival benefit to severely hemorrhaging trauma patients. PMID- 27938374 TI - Research on health equity in the SDG era: the urgent need for greater focus on implementation. AB - BACKGROUND: The tremendous increase in knowledge on inequities in health and their drivers in recent decades has not been matched by improvements in health inequities themselves, or by systematic evidence of what works to reduce health inequities. Within health equity research there is a skew towards diagnostic studies in comparison to intervention studies showing evidence of how interventions can reduce disparities. MAIN TEXT: The lack of sufficient specific evidence on how to implement specific policies and interventions in specific contexts to reduce health inequities creates policy confusion and partly explains the lack of progress on health inequities. In the field of research on equity in health, the time has come to stop focusing so much energy on prevalence and pathways, and instead shift to proposing and testing solutions. Four promising approaches to do so are implementation research, natural experimental policy studies, research on buy-in by policy-makers to action on health inequities, and geospatial analysis. CONCLUSION: The case for action on social determinants and health inequities has well and truly been made. The community of researchers on health equity now need to turn their attention to supporting implementation efforts towards achievements of the Sustainable Development Goals and substantive reductions in health inequities. PMID- 27938376 TI - Results of a participatory needs assessment demonstrate an opportunity to involve people who use alcohol in drug user activism and harm reduction. AB - BACKGROUND: Drug users' organizations have made progress in recent years in advocating for the health and human rights of people who use illicit drugs but have historically not emphasized the needs of people who drink alcohol. METHODS: This paper reports on a qualitative participatory needs assessment with people who use illicit substances in British Columbia, Canada. We held workshops in 17 communities; these were facilitated by people who use illicit drugs, recorded with ethnographic fieldnotes, and analyzed using critical theory. RESULTS: Although the workshops were targeted to people who use illicit drugs, people who primarily consume alcohol also attended. An unexpected finding was the potential for drug users' organizations and other harm reduction programs to involve "illicit drinkers": people who drink non-beverage alcohol (e.g. mouthwash, rubbing alcohol) and those who drink beverage alcohol in criminalized ways (e.g., homeless drinkers). Potential points of alliance between these groups are common priorities (specifically, improving treatment by health professionals and the police, expanding housing options, and implementing harm reduction services), common values (reducing surveillance and improving accountability of services), and polysubstance use. CONCLUSIONS: Despite these potential points of alliance, there has historically been limited involvement of illicit drinkers in drug users' activism. Possible barriers to involvement of illicit drinkers in drug users' organizations include racism (as discourses around alcohol use are highly racialized), horizontal violence, the extreme marginalization of illicit drinkers, and knowledge gaps around harm reduction for alcohol. Understanding the commonalities between people who use drugs and people who use alcohol, as well as the potential barriers to alliance between them, may facilitate the greater involvement of illicit drinkers in drug users' organizations and harm reduction services. PMID- 27938377 TI - Rapid and sensitive point-of-care detection of Orthopoxviruses by ABICAP immunofiltration. AB - BACKGROUND: The rapid and reliable detection of infectious agents is one of the most challenging tasks in scenarios lacking well-equipped laboratory infrastructure, like diagnostics in rural areas of developing countries. Commercially available point-of-care diagnostic tests for emerging and rare diseases are particularly scarce. RESULTS: In this work we present a point-of care test for the detection of Orthopoxviruses (OPV). The OPV ABICAP assay detects down to 1 * 104 plaque forming units/mL of OPV particles within 45 min. It can be applied to clinical material like skin crusts and detects all zoonotic OPV infecting humans, including Vaccinia, Cowpox, Monkeypox, and most importantly Variola virus. CONCLUSIONS: Given the high sensitivity and the ease of handling, the novel assay could be highly useful for on-site diagnostics of suspected Monkeypox virus infections in areas lacking proper laboratory infrastructure as well as rapid on-site testing of suspected bioterrorism samples. PMID- 27938375 TI - Effectiveness of a girls' empowerment programme on early childbearing, marriage and school dropout among adolescent girls in rural Zambia: study protocol for a cluster randomized trial. AB - BACKGROUND: Adolescent pregnancies pose a risk to the young mothers and their babies. In Zambia, 35% of young girls in rural areas have given birth by the age of 18 years. Pregnancy rates are particularly high among out-of-school girls. Poverty, low enrolment in secondary school, myths and community norms all contribute to early childbearing. This protocol describes a trial aiming to measure the effect on early childbearing rates in a rural Zambian context of (1) economic support to girls and their families, and (2) combining economic support with a community intervention to enhance knowledge about sexual and reproductive health and supportive community norms. METHODS/DESIGN: This cluster randomized controlled trial (CRCT) will have three arms. The clusters are rural schools with surrounding communities. Approximately 4900 girls in grade 7 in 2016 will be recruited from 157 schools in 12 districts. In one intervention arm, participating girls and their guardians will be offered cash transfers and payment of school fees. In the second intervention arm, there will be both economic support and a community intervention. The interventions will be implemented for approximately 2 years. The final survey will be 4.5 years after recruitment. The primary outcomes will be "incidence of births within 8 months of the end of the intervention period", "incidence of births before girls' 18th birthday" and "proportion of girls who sit for the grade 9 exam". Final survey interviewers will be unaware of the intervention status of respondents. Analysis will be by intention-to-treat and adjusted for cluster design and confounders. Qualitative process evaluation will be conducted. DISCUSSION: This is the first CRCT to measure the effect of combining economic support with a community intervention to prevent adolescent childbearing in a low- or middle-income country. We have designed a programme that will be sustainable and feasible to scale up. The findings will be relevant for programmes for adolescent reproductive health in Zambia and similar contexts. TRIAL REGISTRATION: ISRCTN registry: ISRCTN12727868 , (4 March 2016). PMID- 27938378 TI - Ten years of the Genomics of Common Diseases: "The end of the beginning". AB - The 10th anniversary 'Genomics of Common Diseases' meeting was held in Baltimore, September 25-28, 2016. Professor Chris Haley reports from the meeting on progress and challenges in the field. PMID- 27938379 TI - STAT3 signaling drives EZH2 transcriptional activation and mediates poor prognosis in gastric cancer. AB - BACKGROUND: STAT3 signaling plays the pivotal role in tumorigenesis through EZH2 epigenetic modification, which enhanced STAT3 activity by increased tyrosine phosphorylation of STAT3. Here, another possible feedback mechanism and clinical significance of EZH2 and STAT3 were investigated in gastric cancer (GC). METHODS: STAT3, p-STAT3 (Tyr 705) and EZH2 expression were examined in 63 GC specimens with matched normal tissues by IHC staining. EZH2 and STAT3 were also identified in five GC cell lines using RT-PCR and western blot analyses. p-STAT3 protein was detected by western blotting. In order to investigate whether EZH2 expression was directly regulated by STAT3, EZH2 expression was further detected using siRNA for STAT3 or IL-6 stimulation, with dual luciferase reporter analyses, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. The clinical significance of STAT3, p-STAT3 and EZH2 expression was evaluated by multi-factor COX regression and Kaplan-Meier analyses. RESULTS: Hyper-activation of STAT3, p-STAT3 and EZH2 expression were observed in GC cells and tissues. STAT3 signaling was correlated with EZH2 expression in GC (R = 0.373, P = 0.003), which was consistent with our data showing that STAT3 as the transcriptional factor enhanced EZH2 transcriptional activity by binding the relative promoter region (-214 ~ -206). STAT3 was an independent signature for poor survival (P = 0.002). Patients with STAT3+/EZH2+ or p-STAT3+/EZH2+ had a worse outcome than others (P < 0.001); Besides, high levels of STAT3 and EZH2 was associated with advanced TNM staging (P = 0.017). Moreover, treatment with a combination of siSTAT3 and EZH2-specific inhibitor, 3-deazaneplanocin A (DZNEP), increased the apoptotic ratio of cells. It is benefit for targeting STAT3-EZH2 interplay in GC treatment. CONCLUSIONS: Our results indicate that STAT3 status mediated EZH2 upregulation, associated with advanced TNM stage and poor prognosis, suggesting that combination with knockdown of STAT3 and EZH2 inhibitor might be a novel therapy in GC treatment. Collectively, STAT3, p-STAT3 and EZH2 expression were provided for the precision medicine in GC patients. PMID- 27938380 TI - Effect of the saliva from different triatomine species on the biology and immunity of TLR-4 ligand and Trypanosoma cruzi-stimulated dendritic cells. AB - BACKGROUND: Triatomines are blood-sucking vectors of Trypanosoma cruzi, the causative agent of Chagas disease. During feeding, triatomines surpass the skin host response through biomolecules present in their saliva. Dendritic cells (DCs) play a crucial role in the induction of the protection to aggressive agents, including blood-sucking arthropods. Here, we evaluated if salivary components of triatomines from different genera evade the host immunity by modulating the biology and the function of LPS- or T. cruzi-stimulated DCs. METHODS: Saliva of Panstrongylus lignarius, Meccus pallidipennis, Triatoma lecticularia and Rhodnius prolixus were obtained by dissection of salivary glands and the DCs were obtained from the differentiation of mouse bone marrow precursors. RESULTS: The differentiation of DCs was inhibited by saliva of all species tested. Saliva differentially inhibited the expression of MHC-II, CD40, CD80 and CD86 in LPS matured DCs. Except for the saliva of R. prolixus, which induced IL-6 cytokine production, TNF-alpha, IL-12 and IL-6 were inhibited by the saliva of the other three tested species and IL-10 was increased in all of them. Saliva per se, also induced the production of IL-12, IL-6 and IL-10. Only the saliva of R. prolixus induced DCs apoptosis. The presence of PGE2 was not detected in the saliva of the four triatomines studied. Finally, T. cruzi invasion on DCs is enhanced by the presence of the triatomine saliva. CONCLUSIONS: These results demonstrate that saliva from different triatomine species exhibit immunomodulatory effects on LPS and T. cruzi-stimulated DCs. These effects could be related to hematophagy and transmission of T. cruzi during feeding. PMID- 27938381 TI - Assessment of antibiotic resistance in Klebsiella pneumoniae exposed to sequential in vitro antibiotic treatments. AB - BACKGROUND: Bacteria treated with different classes of antibiotics exhibit changes in susceptibility to successive antibiotic treatments. This study was designed to evaluate the influence of sequential antibiotic treatments on the development of antibiotic resistance in Klebsiella pneumoniae associated with beta-lactamase and efflux pump activities. METHODS: The antibiotic susceptibility, beta-lactamase activity, and efflux activity were determined in K. pneumoniae grown at 37 degrees C by adding initial (0 h) and second antibiotics (8 or 12 h). Treatments include control (CON; no first and second antibiotic addition), no initial antibiotic addition followed by 1 MIC ciprofloxacin addition (CON-CIP), no initial antibiotic addition followed by 1 MIC meropenem addition (CON-MER), initial 1/4 MIC ciprofloxacin addition followed by no antibiotic addition (1/4CIP-CON), initial 1/4 MIC ciprofloxacin addition followed by 1 MIC ciprofloxacin addition (1/4CIP-CIP), and initial 1/4 MIC ciprofloxacin addition followed by 1 MIC meropenem addition (1/4CIP-MER). RESULTS: Compared to the CON, the initial addition of 1/4 MIC ciprofloxacin inhibited the growth of K. pneumoniae throughout the incubation period. The ciprofloxacin treatments (CON-CIP and 1/4CIP-CIP) showed significant reduction in the number of K. pneumoniae cells compared to meropenem (CON-MER and 1/4CIP-MER). The 1/4CIP-CIP achieved a further 1 log reduction of K. pneumoniae, when compared to the 1/4CIP-CON and 1/CIP-MER. The increase in sensitivity of K. pneumoniae to cefotaxime, kanamycin, levofloxacin, nalidixic acid was observed for CON-CIP. Noticeable cross-resistance pattern was observed at the 1/4CIP-CIP, showing the increased resistance of K. pneumoniae to chloramphenicol, ciprofloxacin, kanamycin, levofloxacin, nalidixic acid norfloxacin, sulphamethoxazole/trimethoprim, and tetracycline. The levels of beta-lactamase activities were estimated to be 8.4 MUmol/min/ml for CON, 7.7 MUmol/min/ml for 1/4CIP-CON and as low as 2.9 MUmol/min/ml for CON-CIP. Compared to the absence of phenylalanine-arginine-beta-naphthylamide (PAbetaN), the fluorescence intensity of EtBr was increased in K. pneumoniae cells treated at the CON, CON-CIP, and CON MER in the presence of PAbetaN. However, the efflux pump activity remained in K. pneumoniae cells treated at the 1/CIP, 1/CIP-CIP, and 1/CIP-MER in the presence of PAbetaN. CONCLUSION: The results suggest that the pre-exposed antibiotic history, treatment order, and concentrations influenced the development of multiple antibiotic resistant associated with beta-lactamase and efflux pump activities. This study highlights the importance of antibiotic treatment conditions, which would be taken into consideration when new antibiotic strategy is designed to prevent antibiotic resistance. PMID- 27938382 TI - Emerging therapeutic agents for lung cancer. AB - Lung cancer continues to be the most common cause of cancer-related mortality worldwide. Recent advances in molecular diagnostics and immunotherapeutics have propelled the rapid development of novel treatment agents across all cancer subtypes, including lung cancer. Additionally, more pharmaceutical therapies for lung cancer have been approved by the US Food and Drug Administration in the last 5 years than in previous two decades. These drugs have ushered in a new era of lung cancer managements that have promising efficacy and safety and also provide treatment opportunities to patients who otherwise would have no conventional chemotherapy available. In this review, we summarize recent advances in lung cancer therapeutics with a specific focus on first in-human or early-phase I/II clinical trials. These drugs either offer better alternatives to drugs in their class or are a completely new class of drugs with novel mechanisms of action. We have divided our discussion into targeted agents, immunotherapies, and antibody drug conjugates for small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). We briefly review the emerging agents and ongoing clinical studies. We have attempted to provide the most current review on emerging therapeutic agents on horizon for lung cancer. PMID- 27938383 TI - Drug-related celebrity deaths: A cross-sectional study. AB - BACKGROUND: Celebrities are at risk for premature mortality as well as drug related death. Despite being a vulnerable patient group, celebrities influence people's health behaviours through biological, psychological and social processes. Therefore, celebrity endorsement of the topic could be one way to challenge the current "opioid endemic". Our aim was to better understand the factors surrounding drug-related celebrity deaths by investigating the incidence as well as substances used between 1970 and 2015 using a cross-sectional study design. METHOD: We searched public databases for drug-related celebrity deaths between 1970 and 2015. They were categorized for sex, profession, age at death, year of death and substances involved. The main outcome measures are descriptive values including number of drug deaths per year and substances involved. Secondary outcome measures are analytical questions to examine whether and which factors influence age at death and year of death (e.g. type of substance use disorder). RESULTS: We identified 220 celebrities who died a drug-related death with a clear indication of involved substances between 1970 and 2015. The average age at death was 38.6 years; 75% were male. Most celebrities died between the age of 25 and 40. The number of drug-related deaths increased in the 21st century, with a significant increase in the use of prescription opioids. Deaths involving prescription opioids and heroin were associated with a significantly lower mean age at death compared to deaths where these substances were not involved. CONCLUSIONS: Compared to the 20th century, the total number of celebrities who died from a drug-related death in the 21st century increased, possibly due to an increased involvement of prescription opioids. Negative effects on individual health decisions of celebrity's followers could be the result. PMID- 27938384 TI - Macrophage activation syndrome triggered by coeliac disease: a unique case report. AB - BACKGROUND: Macrophage activation syndrome is described as a "clinical syndrome of hyperinflammation resulting in an uncontrolled and ineffective immune response" in the context of an autoinflammatory or rheumatic disease. Current associations of macrophage activation syndrome with autoimmune disease most notably include a host of rheumatological conditions and inflammatory bowel disease. Epidemiological studies have shown that macrophage activation syndrome is precipitated by autoimmune disease more commonly than previously thought. Diagnosing the precipitating factor is essential for effective treatment and prognosis. CASE PRESENTATION: We report a case of a six year old girl with coeliac disease diagnosed after two episodes of secondary haemophagocytic lymphohistiocytosis. Her condition only responded to treatment once the patient was placed on a gluten free diet. Further immunological testing confirmed anti transglutaminase and anti-endomysial antibodies, however histological biopsy was deemed inappropriate due to the severity of her condition. She has remained stable with no further episodes of macrophage activation syndrome since commencing a gluten free diet. CONCLUSION: This case report is the first literature that links macrophage activation syndrome to coeliac disease and highlights the challenge of diagnosing coeliac disease with unusual features such as associated prolonged fever. Clinicians should have a low threshold for screening children with other autoimmune diseases for coeliac disease. PMID- 27938386 TI - Erratum to: Quantification of the cellular dose and characterization of nanoparticle transport during in vitro testing. PMID- 27938385 TI - Comparison of the effect of a combination of eight micronutrients versus a standard mono preparation on sperm parameters. AB - BACKGROUND: There are reports showing that l-carnitine alone or in combination with other micronutrients improve sperm parameters. However, comparative studies are still lacking. This study was carried out to compare the short term effects of a combination of eight micronutrients including l-carnitine vs. a mono substance (l-carnitine alone) on sperm parameters. METHODS: This was a prospective, open-labelled, nonrandomized study that included male subjects (20 to 60 years) with at least 1 year of subfertility and at least one pathological semen analysis who received 3 months treatment with a mono-substance (500 mg l carnitine/twice a day, n = 156) or a combined compound (440 mg l-carnitine + 250 mg l-arginine + 40 mg zinc + 120 mg vitamin E + 80 mg glutathione + 60 MUg selenium + 15 mg coenzyme Q10 + 800 MUg folic acid/once a day, n = 143) for the same time period. Sperm parameters were analyzed before and after treatment and groups comparisons performed. RESULTS: Baseline characteristics were similar among studied groups (age and body mass indices). Semen parameters (volume, density, overall progressive motility [including slow and fast motility]) and percentage of sperm with normal morphology improved after 3 months in both groups as compared to baseline. However, relative change (expressed as % increase of absolute values) for sperm density and overall progressive motility (including fast motility) was found to be higher for the combined micronutrient treatment group as compared to the mono-treatment using l-carnitine alone. CONCLUSION: Both analyzed groups displayed a positive short term effect on all sperm parameters; however effect on density and motility was significantly better for the combined formulation. There is need for more research in this matter that includes long term outcome data. TRIAL REGISTRATION: Retrospectively registered at ISRCTN (7th October 2016). Study ID: ISRCTN48594239. PMID- 27938387 TI - Impact of Cushing's sign in the prehospital setting on predicting the need for immediate neurosurgical intervention in trauma patients: a nationwide retrospective observational study. AB - BACKGROUND: Cushing's reflex usually results from intracranial hypertension. Although Cushing's sign can implicate severe traumatic brain injury (TBI) in injured patients, no major investigations have been made. The purpose of this study was to assess the predictability of life-threatening brain injury requiring immediate neurosurgical intervention (LT-BI) among trauma patients with Cushing's sign in the prehospital setting. METHODS: This was a retrospective study using data from the Japan Trauma Data Bank from the period of 2010 to 2014. Patients 16 years old or older with blunt mechanisms of injury who were transported directly from the scene and Glasgow Coma Scale for eye opening of one in the prehospital setting were included. LT-BI was defined as patients requiring burr hole evacuation or craniotomy within 24 h of hospital arrival and patients who were non-survivors due to isolated severe TBI. Prehospital systolic blood pressure (pSBP) and heart rate (pHR) were assessed using area under the receiver operating characteristic curve (AUROC) and multiple logistic regression analysis to predict LT-BI. RESULTS: Of 6332 eligible patients, 1859 (29%) exhibited LT-BI. AUROC of LT-BI using pSBP and pHR was 0.666 (95% confidence interval (CI); 0.652-0.681, P < 0.001), and 0.578 (95% CI; 0.563-0.594, P < 0.001), respectively. AUROC of pSBP was the highest among the 60 <= pHR <= 99 subgroup, of which AUROC was 0.680 (95% CI; 0.662-0.699, P < 0.001). Multiple logistic regression analysis showed that the higher the pSBP and the lower the pHR, the more likely that the patients had LT-BI. In a group with pSBP >= 180 mmHg and pHR <= 59 beats/min, the odds ratio and 95% CI of LT-BI after adjusting for age, sex, and severity of injuries to other body regions was 4.77 (2.85-7.97), P < 0.001 was compared with the reference group, which was defined as patients with normal vital signs. DISCUSSION: Our study has found that the combination of hypertension and bradycardia, which are the components of Cushing's sign without eye opening in the prehospital setting was a weak but a significant predictor of LT-BI, or death due to possible isolated severe TBI. CONCLUSIONS: Prehospital Cushing's sign with disturbed level of consciousness in trauma patients was a weak but significant predictor of the need for immediate neurosurgical intervention. PMID- 27938388 TI - Berberine increases adipose triglyceride lipase in 3T3-L1 adipocytes through the AMPK pathway. AB - BACKGROUND: Obesity is closely related to the metabolism of triacylglycerol (TG) in adipocytes. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are rate-limiting enzymes that control the hydrolysis of TG. Effects on ATGL and HSL to increase lipolysis may counteract obesity. Berberine (BBR) is a compound derived from the Chinese medicine plant Coptis chinensis. In the present study we show the effects of BBR on ATGL and HSL and explore the potential underlying mechanisms of these effects. METHODS: The TG content in cells was measured using a colorimetric assay. The expressions of HSL, ATGL and GPAT3 were evaluated by Western-blotting. The expression of ATGL was also evaluated by real time PCR and radioimmunoassay. Compound C, an inhibitor of AMP-activated protein kinase (AMPK), was used to explore the possible pathway that involved in the effect of BBR on ATGL. RESULTS: TG content of differentiated 3T3-L1 cells was significantly decreased by more than 10% after treated with BBR. In differentiated 3T3-L1 adipocytes, BBR increased the expression of p-HSL and ATGL, and these effects were time-depended (p <0.01). The effect of BBR on ATGL expression could be abolished by Compound C which suggested that AMPK pathway was involved in the effects of BBR on p-HSL and ATGL. CONCLUSIONS: BBR could increase the expression of ATGL and therefore stimulate basal lipolysis in mature adipocytes through the associated mechanisms related to the AMPK pathway. PMID- 27938389 TI - Hot topics, urgent priorities, and ensuring success for racial/ethnic minority young investigators in academic pediatrics. AB - BACKGROUND: The number of racial/ethnic minority children will exceed the number of white children in the USA by 2018. Although 38% of Americans are minorities, only 12% of pediatricians, 5% of medical-school faculty, and 3% of medical-school professors are minorities. Furthermore, only 5% of all R01 applications for National Institutes of Health grants are from African-American, Latino, and American Indian investigators. Prompted by the persistent lack of diversity in the pediatric and biomedical research workforces, the Academic Pediatric Association Research in Academic Pediatrics Initiative on Diversity (RAPID) was initiated in 2012. RAPID targets applicants who are members of an underrepresented minority group (URM), disabled, or from a socially, culturally, economically, or educationally disadvantaged background. The program, which consists of both a research project and career and leadership development activities, includes an annual career-development and leadership conference which is open to any resident, fellow, or junior faculty member from an URM, disabled, or disadvantaged background who is interested in a career in academic general pediatrics. METHODS: As part of the annual RAPID conference, a Hot Topic Session is held in which the young investigators spend several hours developing a list of hot topics on the most useful faculty and career-development issues. These hot topics are then posed in the form of six "burning questions" to the RAPID National Advisory Committee (comprised of accomplished, nationally recognized senior investigators who are seasoned mentors), the RAPID Director and Co Director, and the keynote speaker. RESULTS/CONCLUSIONS: The six compelling questions posed by the 10 young investigators-along with the responses of the senior conference leadership-provide a unique resource and "survival guide" for ensuring the academic success and optimal career development of young investigators in academic pediatrics from diverse backgrounds. A rich conversation ensued on the topics addressed, consisting of negotiating for protected research time, career trajectories as academic institutions move away from an emphasis on tenure-track positions, how "non-academic" products fit into career development, racism and discrimination in academic medicine and how to address them, coping with isolation as a minority faculty member, and how best to mentor the next generation of academic physicians. PMID- 27938391 TI - False data, positive results in neurobiology: moving beyond the epigenetics of blood and saliva samples in mental disorders. AB - Many psychiatric diseases are influenced by a set of several genetic and environmental factors that genetics alone cannot explain. Specifically, in schizophrenia and bipolar disorder the absence of consistently replicated genetic effects together with evidence for lasting changes in gene expression after environmental exposures suggest a role of epigenetic mechanisms in its pathophysiological mechanisms. In this field, the presence of positive results could potentially uncover molecular mechanisms of deregulated gene expression in these complex disorders. In this commentary we have reviewed the positive data obtained over the last 5 years from the scientific literature published in PubMed and we have shown that these results are based on peripheral samples (blood, saliva and other fluids) that do not allow us to obtain reliable and/or valid results, under any circumstances. Finally, we highlight the need to employ human brain samples in the epigenetic study of mental disorders. PMID- 27938390 TI - The moderating effect of psychosocial factors in the relation between neighborhood walkability and children's physical activity. AB - BACKGROUND: The study aimed to investigate if psychosocial factors moderate the association between objective walkability and different domains of children's physical activity (PA). A second aim of the study was to investigate the direct associations between psychosocial factors and children's PA. Based on previous literature, it was hypothesized that walkability would be more strongly related to PA among children with negative psychosocial profiles. METHODS: Data were collected between December 2011 and May 2013 as part of the Belgian Environmental Physical Activity Study in children (BEPAS-child). In total, data from 494 children and one of their parents were included in the study. Children wore an accelerometer for 7 consecutive days and together with one of their parents, they completed the Flemish Physical Activity Questionnaire. Parents filled out a questionnaire concerning their child's psychosocial factors toward PA (i.e. parental attitude toward their child's PA, parental social norm toward their child's PA, parental support, friend support, children's self-efficacy, and perceived benefits and barriers toward sports and PA). Neighborhood walkability was calculated using geographical information systems (GIS). Multilevel cross classified analyses were conducted. RESULTS: Of the 42 investigated interactions between neighborhood walkability and psychosocial factors in relation to PA among children, only 7 significant interactions were found of which 3 were only significant among children from low-income neighborhoods. Parental support and self-efficacy were positive correlates of children's PA in high- and low-income neighborhoods independent of the level of walkability, but effect sizes were small. CONCLUSIONS: The hypothesis that walkability would be more strongly related to PA among children with negative psychosocial profiles could not be confirmed and in general, psychosocial factors and objective walkability did not interact in relation to children's PA. Focusing on parental support and self efficacy towards PA can possibly cause small effects on children's PA in both high- and low-walkable neighborhoods, as well as in high- and low-income neighborhoods. PMID- 27938393 TI - Drug use and health behaviour among German men who have sex with men: Results of a qualitative, multi-centre study. AB - BACKGROUND: Men who have sex with men (MSM) are a risk group for new HIV infections. Drug use among men who have sex with men is often accompanied by risky sexual behaviours. Local AIDS help centres and gay advice centres are recording an increase in drug use among MSM clients in Germany. This study examines reasons for drug use and drug use contexts for MSM, including syndemic factors and experiences of social support. METHODS: The study is based on a qualitative research approach. We conducted 14 structured, in-depth interviews with substance-using MSM in three German cities. An interview guidance document was used that was developed on the basis of the syndemic approach. Data analysis was based on structured analysis of content. RESULTS: The MSM interviewed had extensive experience of drug use, in particular amyl nitrate, amphetamines, methamphetamine, ketamine, cocaine and cannabis. The drugs were used both at parties and in connection with sexual experiences (chemsex). Twelve men said that they had an existing HIV infection at the time of the interview. The men also reported experiences of violence and discrimination because of their sexual orientation. The social networks of the MSM and dating apps are highly relevant for experiencing chemsex. Certain places in the MSM community also have an impact on drug purchase, drug consumption and chemsex sessions. CONCLUSIONS: MSM are a group that is vulnerable to psychological problems, in particular problematic drug use. This group requires specific help from drug services and AIDS support services that are orientated towards the life situation and substance use contexts of the clients. Both support systems should work together more closely and network. Furthermore, specific prevention strategies, aimed at both mental and physical well-being, should be developed for substance-using MSM. PMID- 27938392 TI - ULK1-mediated phosphorylation of ATG14 promotes autophagy and is impaired in Huntington's disease models. AB - BACKGROUND: Autophagy is a bulk degradation pathway for long-lived proteins, protein aggregates, and damaged organelles. ULK1 protein kinase and Vps34 lipid kinase are two key autophagy regulators that are critical for autophagosome biogenesis. However, it isn't fully understood how ULK1 regulates Vps34, especially in the context of disease. Polyglutamine expansion in huntingtin (Htt) causes aberrant accumulation of the aggregated protein and disrupts various cellular pathways including autophagy, a lysosomal degradation pathway, underlying the pathogenesis of Huntington's disease (HD). Although autophagic clearance of Htt aggregates is under investigation as therapeutic strategy for HD, the precise mechanism of autophagy impairment remains poorly understood. Moreover, in-vivo assays of autophagy have been particularly challenging due to lack of reliable and robust molecular biomarkers. METHOD: We generated anti phosphorylated ATG14 antibody to determine ATG14-mediated autophagy regulation; we employed Huntington's disease (HD) genetic cell models and animal models as well as autophagy reporter animal model to understand autophagy signaling and regulation in vivo. We applied biochemical analysis and molecular biology approaches to dissect the alteration of autophagy kinase activity and regulation. RESULTS: Here, we demonstrate that ULK1 phosphorylates ATG14 at serine 29 in an mTOR-dependent manner. This phosphorylation critically regulates ATG14-Vps34 lipid kinase activity to control autophagy level. We also show that ATG14 associated Vps34 activity and ULK1-mediated phosphorylation of ATG14 and Beclin 1 are compromised in the Q175 mouse model of Huntington's disease. Finally, we show that ATG14 phosphorylation is decreased during general proteotoxic stress caused by proteasomal inhibition. This reduction of the specific phosphorylation of ATG14 and Beclin 1 is mediated, in part, by p62-induced sequestration of ULK1 to an insoluble cellular fraction. We show that increased ULK1 levels and phosphor mimetic mutant ATG14 facilitate the clearance of polyQ mutant in cells. CONCLUSION: Our study identifies a new regulatory mechanism for ATG14-Vps34 kinase activity by ULK1, which can be used as valuable molecular markers for in vivo autophagic activity as well as potential therapeutic target for the clearance of polyglutamine disease protein. PMID- 27938394 TI - Complications after surgical management of distal lower leg fractures. AB - BACKGROUND: Osseous healing of distal lower leg fractures can be prolonged and is often associated with wound healing problems because of the marginal soft - tissue and vascular supply in this area. Postoperative complications are frequent, and according to the literature, open reduction and plate fixation is thought to be associated with higher complication rates. The objective of this study was to evaluate the most common postoperative complications following intramedullary nailing or plate osteosynthesis of distal lower leg injuries with a focus on combined tibio-fibular fractures. The outcomes of patients with and without complications associated the two surgical techniques were compared. METHODS: During a 5-year period, all surgically treated distal tibiofibular fractures were retrospectively collected from the clinical database and were evaluated for the presence of postoperative complications which included compartment syndrome, wound infection, delayed union and non-union, synostosis and rotational malalignment. Postoperative complications were reviewed and correlated with patient risk factors. RESULTS: A total of 199 patients were included in the study, and 75 complications were reported. The majority of complications were associated with closed fracture types treated with intramedullary nailing, delayed union being the most frequent. For open fractures, surgical treatment with plate fixation had a complication rate of 12% compared with 25% after intramedullary nailing. DISCUSSION: In general, distal lower leg fractures are associated with a high risk of postoperative complications. Distal diaphyseal tibial fractures that have been treated with intramedullary nailing devices have a higher risk of delayed union or non - union. CONCLUSION: Plate fixation in distal metaphyseal fractures has a higher risk of problems related to wound healing and postoperative wound infections. PMID- 27938395 TI - Assessment of afoxolaner efficacy against Otodectes cynotis infestations of dogs. AB - BACKGROUND: The efficacy of a single 2.5 mg/kg dose of afoxolaner (NexGard(r), Merial) against induced Otodectes cynotis infestations was assessed in eight afoxolaner-treated dogs, compared to eight untreated dogs. METHODS: After O. cynotis infestations were established and confirmed by otoscopic assessments in 16 dogs, all of the dogs were included in the study and allocated to two separate treatment groups. The first group of eight ear mite-infested dogs remained untreated, while afoxolaner was administered orally to the second group of dogs at the minimum recommended dose once on Day 0. Otoscopic assessments performed on all dogs (Days -7, -2, 14 and 28) confirmed the presence or absence of live mites throughout the study. No serious adverse events were recorded throughout the study, and no adverse events were likely related to the administration of NexGard. RESULTS: By Day 28, seven out of eight untreated dogs were still infested with ear mites, while only two out of eight afoxolaner-treated dogs were infested, with one and four ear mites, respectively. On Day 28, the reductions of mite counts in the afoxolaner-treated group versus those of the control dogs were 98.5% based on geometric means, and 99.4% based on arithmetic means. Significantly fewer (P < 0.05) live mites were present in the afoxolaner-treated group than the untreated group on Day 28. CONCLUSION: The results of this study demonstrated that a single oral administration of afoxolaner at the minimum recommended dose is highly effective (>98%) in treating dogs with induced O. cynotis infestations. PMID- 27938396 TI - Genetic polymorphisms of patients on stable warfarin maintenance therapy in a Ghanaian population. AB - BACKGROUND: Warfarin is a widely prescribed anticoagulant with narrow therapeutic window for thromboembolic events. Warfarin displays large individual variability in dose requirements. The purpose of this study is to assess the contribution of patient-specific and genetic risk factors to dose requirements of patients on either high or low warfarin maintenance dose in Ghana. Blood samples were collected from 141 (62 males, 79 females) Ghanaian patients on stable warfarin dose to determine their INR. Influence of patient specific factors and gene variations within VKORC1, CYP2C9 and CYP4F2 were determined in patients on either high or low warfarin maintenance dose. RESULTS: One hundred and forty-one patients took part in the study with 79 (56%) participants being Female. The median age of the study participants was 48 years [IQR: 34-58]. The median duration for patients to be on warfarin therapy was 24 months [IQR: 10-72]. Majority of the study participants (80.9%, n = 114) did not have any side effects to warfarin. CYP2C9*2 and CYP2C9*3 variant alleles were not detected. VKORC1 variant allele was observed at 6% and CYP4F2 variant allele was observed at 41%. Duration of patients on warfarin therapy was marginally associated with high warfarin dose (adjusted OR = 1.01 [95% CI 1.00-1.02], p = 0.033) while the odds of heterozygous individuals (G/A) for VKORC1 gene to have high warfarin dose compared to persons with homozygous (G/G) (adjusted OR = 0.06 [95% CI 0.01-0.63], p = 0.019). Age, gender, diagnosis, presence of side effects and other medications were not associated with warfarin dose (p = 0.05). CONCLUSION: This study provides data on VKORC1 and CYP4F2 variants among an indigenous African population. Duration of patients on warfarin therapy was marginally associated with high warfarin dose. CYP2C9*2 and *3 variants were not detected and may not be the most important genetic factor for warfarin maintenance dose among Ghanaians. PMID- 27938397 TI - Risk factors of peripheral arterial disease: a case control study in Sri Lanka. AB - BACKGROUND: Peripheral artery disease (PAD) is an important global health problem and contributes to notable proportion of morbidity and mortality. This particular manifestation of systemic atherosclerosis is largely under diagnosed and undertreated. For sustainable preventive strategies in a country, it is mandatory to identify country-specific risk factors. We intended to assess the risk factors of PAD among adults aged 40-74 years. METHODS: This case control study was conducted in 2012-2013 in Sri Lanka. Seventy-nine cases and 158 controls in the age group of 40-74 years were selected for the study in order to have case to control ratio 1:2. The criterion for selecting cases and control was based on Ankle brachial pressure index (ABPI). Cases were selected from those who had ABPI 0.85 or less (ABPI <=0.85) in either lower limb. Controls were selected from those ABPI score between 1.18 and 1.28 in both lower limbs. Only newly identified individuals with PAD were selected as cases. Controls were selected from the same geographical location and within the 5 year age group as cases. RESULTS: The history of diabetes mellitus more than 10 years (OR 5.8, 95% CI 2.2-14.2), history of dyslipidemia for more than 10 years (OR 4.9, 95% CI 2.1-16.2), history of hypertension for more than 10 years (OR 3.8, 95% CI 1.8-12.7) and smoking (OR 2.9, 95% CI 1.2-6.9), elevated HsCRP (OR 3.7, 95% CI 1.2-12.0) and hyperhomocysteinemia (OR 3.0, 95% CI 1.1-8.1) were revealed as country specific significant risk factor of PAD. CONCLUSIONS: Diabetes mellitus, hypertension, dyslipidemia, smoking as well as elevated homocysteine and HsCRP found as risk factors of PAD. Longer the duration or higher level exposure to these risk factors has increased the risk of PAD. These findings emphasis the need for routine screening of PAD among patients with the identified risk factors. PMID- 27938398 TI - High glucose suppresses embryonic stem cell differentiation into cardiomyocytes : High glucose inhibits ES cell cardiogenesis. AB - BACKGROUND: Babies born to mothers with pregestational diabetes have a high risk for congenital heart defects (CHD). Embryonic stem cells (ESCs) are excellent in vitro models for studying the effect of high glucose on cardiac lineage specification because ESCs can be differentiated into cardiomyocytes. ESC maintenance and differentiation are currently performed under high glucose conditions, whose adverse effects have never been clarified. METHOD: We investigated the effect of high glucose on cardiomyocyte differentiation from a well-characterized ESC line, E14, derived from mouse blastocysts. E14 cells maintained under high glucose (25 mM) failed to generate any beating cardiomyocytes using the hanging-drop embryonic body method. We created a glucose responsive E14 cell line (GR-E14) through a graduated low glucose adaptation. The expression of stem cell markers was similar in the parent E14 cells and the GR E14 cells. RESULTS: Glucose transporter 2 gene was increased in GR-E14 cells. When GR-E14 cells were differentiated into cardiomyocytes under low (5 mM) or high (25 mM) glucose conditions, high glucose significantly delayed the appearance and reduced the number of TNNT2 (Troponin T Type 2)-positive contracting cardiomyocytes. High glucose suppressed the expression of precardiac mesoderm markers, cardiac transcription factors, mature cardiomyocyte markers, and potassium channel proteins. High glucose impaired the functionality of ESC derived cardiomyocytes by suppressing the frequencies of Ca2+ wave and contraction. CONCLUSIONS: Our findings suggest that high glucose inhibits ESC cardiogenesis by suppressing key developmental genes essential for the cardiac program. PMID- 27938400 TI - Developing the ethics of implementation research in health. AB - Implementation research (IR) is growing in recognition as an important generator of practical knowledge that can be translated into health policy. With its aim to answer questions about how to improve access to interventions that have been shown to work but have not reached many of the people who could benefit from them, IR involves a range of particular ethical considerations that have not yet been comprehensively covered in international guidelines on health research ethics. The fundamental ethical principles governing clinical research apply equally in IR, but the application of these principles may differ depending on the IR question, context, and the nature of the proposed intervention. IR questions cover a broad range of topics that focus on improving health system functioning and improving equitable and just access to effective health care interventions. As such, IR designs are flexible and often innovative, and ethical principles cannot simply be extrapolated from their applications in clinical research. Meaningful engagement with all stakeholders including communities and research participants is a fundamental ethical requirement that cuts across all study phases of IR and links most ethical concerns. Careful modification of the informed consent process may be required in IR to permit study of a needed intervention. The risks associated with IR may be difficult to anticipate and may be very context-specific. The benefits of IR may not accrue to the same groups who participate in the research, therefore justifying the risks versus benefits of IR may be ethically challenging. The expectation that knowledge generated through IR should be rapidly translated into health policy and practice necessitates up-front commitments from decision-makers to sustainability and scalability of effective interventions. Greater awareness of the particular ethical implications of the features of IR is urgently needed to facilitate optimal ethical conduct of IR and uniform ethical review. PMID- 27938401 TI - Testing modes of computerized sepsis alert notification delivery systems. AB - BACKGROUND: The number of electronic health record (EHR)-based notifications continues to rise. One common method to deliver urgent and emergent notifications (alerts) is paging. Despite of wide presence of smartphones, the use of these devices for secure alerting remains a relatively new phenomenon. METHODS: We compared three methods of alert delivery (pagers, EHR-based notifications, and smartphones) to determine the best method of urgent alerting in the intensive care unit (ICU) setting. ICU clinicians received randomized automated sepsis alerts: pager, EHR-based notification, or a personal smartphone/tablet device. Time to notification acknowledgement, fatigue measurement, and user preferences (structured survey) were studied. RESULTS: Twenty three clinicians participated over the course of 3 months. A total of 48 randomized sepsis alerts were generated for 46 unique patients. Although all alerts were acknowledged, the primary outcome was confounded by technical failure of alert delivery in the smartphone/tablet arm. Median time to acknowledgment of urgent alerts was shorter by pager (102 mins) than EHR (169 mins). Secondary outcomes of fatigue measurement and user preference did not demonstrate significant differences between these notification delivery study arms. CONCLUSIONS: Technical failure of secure smartphone/tablet alert delivery presents a barrier to testing the optimal method of urgent alert delivery in the ICU setting. Results from fatigue evaluation and user preferences for alert delivery methods were similar in all arms. Further investigation is thus necessary to understand human and technical barriers to implementation of commonplace modern technology in the hospital setting. PMID- 27938399 TI - Adiposity markers and lung function in smokers: a cross-sectional study in a Mediterranean population. AB - BACKGROUND: The aim of this study was to assess the association of key adiposity markers with lung function in smokers without respiratory disease in a Mediterranean population. METHODS: We performed a cross-sectional study with baseline data from a representative sample of the ESPITAP study in Spain. Participants were 738 smokers (52.3% men) without respiratory disease, aged 35 to 70, selected from 12 primary health care centres. We assessed weight, height, body mass index (BMI), waist circumference (WC) and waist-to-height ratio (WHtR). The pulmonary functional parameters were forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC ratio. RESULTS: In this cohort of smokers, 22.2% of individuals had central obesity. FVC% was inversely associated with all anthropometric measures (BMI, WC and WHtR) in the overall population and in men; in women, only BMI was associated with FVC%. FEV1% was inversely associated to BMI and WC in the overall population, and to all anthropometric measures in men. Furthermore, both BMI and obesity were positively associated with FEV1/FVC ratio overall and when stratified by sex; this suggests a restrictive pattern explained by the altered ventilator mechanics experienced by people with obesity. CONCLUSION: In a Mediterranean population of smokers without respiratory symptoms, abdominal obesity, evaluated not only by BMI and WC but also WHtR, is inversely associated with lung function. Fat distribution appears more strongly related to pulmonary function parameters in men than in women. In smokers with high values for WC, WHtR and BMI, assessment of lung function is recommended. TRIAL REGISTRATION: Current Controlled Trials NCT01194596 . Registered 2 September 2010. PMID- 27938402 TI - A quantitative study on factors influencing enrolment of dairy farmers in a community health insurance scheme. AB - BACKGROUND: Access to affordable and effective health care is a challenge in low- and middle- income countries. Out-of-pocket expenditure for health care is a major cause of impoverishment. One way to facilitate access and overcome catastrophic expenditure is through a health insurance mechanism, whereby risks are shared and financial inputs pooled by way of contributions. This study examined factors that influenced the enrolment status of dairy farmers in Western Kenya to a community health insurance (CHI) scheme. METHODS: Quantitative, cross sectional research was used to describe factors influencing the enrolment in the CHI scheme. Quota and convenience sampling was used, recruiting a sample of 135 farmers who supply milk to a dairy cooperation. Data were collected using a structured interview schedule and analysed using Stata SE, Data Analysis and Statistical Software, Version 12. RESULTS: Factors influencing non-enrolment were identified as affordability (40%; n = 47), unfamiliarity with the management of the scheme (37%; n = 44) and a lack of understanding about the scheme (41%; n = 48). An exploratory factor analysis was used to reduce the variables to two factors: information provision and understanding community health insurance (CHI). Logistic regression identified factors associated with enrolment in the Tanykina Community Healthcare Plan (TCHP). Supplies of less than six litres of milk per day (OR: 0.22; 95% CI: 0.06-0.84) and information provision (OR: 8.77; 95% CI: 2.25-34.16) were significantly associated with enrolment in the TCHP. Nearly 30% (29.6%; n = 40) of the respondents remarked that TCHP is expensive and 17% (n = 23) asked for more education on CHI and TCHP in an open-ended question. CONCLUSION: Recommendations related to marketing strategies, financial approach, information provision and further research were outlined to be made to the management of the TCHP as well as to those involved in public health. PMID- 27938403 TI - Obtaining consumer perspectives using a citizens' jury: does the current country of origin labelling in Australia allow for informed food choices? AB - BACKGROUND: Contemporary food systems are vast and complex, creating greater distance between consumers and their food. Consequently, consumers are required to put faith in a system of which they have limited knowledge or control. Country of origin labelling (CoOL) is one mechanism that theoretically enables consumer knowledge of provenance of food products. However, this labelling system has recently come under Australian Government review and recommendations for improvements have been proposed. Consumer engagement in this process has been limited. Therefore this study sought to obtain further consumer opinion on the issue of CoOL and to identify the extent to which Australian consumers agree with Australian Government recommendations for improvements. METHODS: A citizens' jury was conducted with a sample of 14 South Australian consumers to explore their perceptions on whether the CoOL system allows them to make informed food choices, as well as what changes (if any) need to be made to enable informed food choices (recommendations). RESULTS: Overall, jurors' perception of usefulness of CoOL, including its ability to enable consumers to make informed food choices, fluctuated throughout the Citizens' Jury. Initially, the majority of the jurors indicated that the labels allowed informed food choice, however by the end of the session the majority disagreed with this statement. Inconsistencies within jurors' opinions were observed, particularly following delivery of information from expert witnesses and jury deliberation. Jurors provided recommendations for changes to be made to CoOL, which were similar to those provided in the Australian Government inquiry. CONCLUSIONS: Consumers in this study engaged with the topical issue of CoOL and provided their opinions. Overall, consumers do not think that the current CoOL system in Australia enables consumers to make informed choices. Recommendations for changes, including increasing the size of the label and the label's font, and standardising its position, were made. PMID- 27938404 TI - BMI and waist circumference cut-offs for corresponding levels of insulin sensitivity in a Middle Eastern immigrant versus a native Swedish population - the MEDIM population based study. AB - BACKGROUND: The aim of this study was to identify corresponding body mass index (BMI) and waist circumference cut-offs for equivalent levels of insulin sensitivity in a Middle Eastern immigrant population compared with native Swedes. METHODS: Citizens of Malmo, Sweden aged 30 to 75 years, who were born in Iraq or Sweden, were in 2010-2012 invited to participate in a health examination including anthropometrics, oral glucose tolerance test, fasting samples and interviews concerning sociodemographic factors and lifestyle behaviours. RESULTS: In total, 1176 individuals born in Iraq and 688 born in Sweden, without previously diagnosed type 2 diabetes, participated in the study. In normal weight participants (BMI < 25 kg/m2), 21.2% of Iraqis vs 9.3% of Swedes were insulin resistant. Corresponding figures in participants without abdominal obesity (waist circumference, men < 94 cm, women < 80 cm) were 28.2% of Iraqis vs 9.4% of Swedes. The age-adjusted insulin sensitivity index (ISI) for obese Swedes (BMI 30 kg/m2) corresponded in Iraqi men with BMI of 28.5 kg/m2, and in Iraqi women with BMI of 27.5 kg/m2. The ISI level in abdominally obese Swedes corresponded with waist circumference cut-offs of 84.0 cm and 71.0 cm in Iraqi men and women, respectively. In men only, larger waist circumference (P interaction = 0.026) presented a stronger association with impaired ISI in Iraqis as compared to Swedes. CONCLUSIONS: Our data shows that the impact of BMI and waist circumference on ISI is ethnic- and gender-specific, indicating a disturbed fat metabolism in Iraqi males in particular. Our data suggests that 10 cm lower cut off values for abdominal obesity, than is currently recommended by major organisations, should be considered when estimating diabetes risk in Middle Eastern populations. PMID- 27938405 TI - Effect of a web-based audit and feedback intervention with outreach visits on the clinical performance of multidisciplinary teams: a cluster-randomized trial in cardiac rehabilitation. AB - BACKGROUND: The objective of this study was to assess the effect of a web-based audit and feedback (A&F) intervention with outreach visits to support decision making by multidisciplinary teams. METHODS: We performed a multicentre cluster randomized trial within the field of comprehensive cardiac rehabilitation (CR) in the Netherlands. Our participants were multidisciplinary teams in Dutch CR centres who were enrolled in the study between July 2012 and December 2013 and received the intervention for at least 1 year. The intervention included web based A&F with feedback on clinical performance, facilities for goal setting and action planning, and educational outreach visits. Teams were randomized either to receive feedback that was limited to psychosocial rehabilitation (study group A) or to physical rehabilitation (study group B). The main outcome measure was the difference in performance between study groups in 11 care processes and six patient outcomes, measured at patient level. Secondary outcomes included effects on guideline concordance for the four main CR therapies. RESULTS: Data from 18 centres (14,847 patients) were analysed, of which 12 centres (9353 patients) were assigned to group A and six (5494 patients) to group B. During the intervention, a total of 233 quality improvement goals was identified by participating teams, of which 49 (21%) were achieved during the study period. Except for a modest improvement in data completeness (4.5% improvement per year; 95% CI 0.65 to 8.36), we found no effect of our intervention on any of our primary or secondary outcome measures. CONCLUSIONS: Within a multidisciplinary setting, our web-based A&F intervention engaged teams to define local performance improvement goals but failed to support them in actually completing the improvement actions that were needed to achieve those goals. Future research should focus on improving the actionability of feedback on clinical performance and on addressing the socio technical perspective of the implementation process. TRIAL REGISTRATION: NTR3251. PMID- 27938407 TI - Psychometric properties of the Satisfaction with Life Scale (SWLS): secondary analysis of the Mexican Health and Aging Study. AB - BACKGROUND: The Satisfaction with Life Scale (SWLS) has been widely used and has proven to be a valid and reliable instrument for assessing satisfaction with life in diverse population groups, however, research on satisfaction with life and validation of different measuring instruments in Mexican adults is still lacking. The objective was to evaluate the psychometric properties of the Satisfaction with Life Scale (SWLS) in a representative sample of Mexican adults. METHODS: This is a methodological study to evaluate a satisfaction with life scale in a sample of 13,220 Mexican adults 50 years of age or older from the 2012 Mexican Health and Aging Study. The scale's reliability (internal consistency) was analysed using Cronbach's alpha and inter-item correlations. An exploratory factor analysis was also performed. Known-groups validity was evaluated comparing good-health and bad-health participants. Comorbidity, perceived financial situation, self-reported general health, depression symptoms, and social support were included to evaluate the validity between these measures and the total score of the scale using Spearman's correlations. RESULTS: The analysis of the scale's reliability showed good internal consistency (alpha = 0.74). The exploratory factor analysis confirmed the existence of a unique factor structure that explained 54% of the variance. SWLS was related to depression, perceived health, financial situation, and social support, and these relations were all statistically significant (P < .01). There was significant difference in life satisfaction between the good- and bad-health groups. CONCLUSIONS: Results show good internal consistency and construct validity of the SWLS. These results are comparable with results from previous studies. Meeting the study's objective to validate the scale, the results show that the Spanish version of the SWLS is a reliable and valid measure of satisfaction with life in the Mexican context. PMID- 27938408 TI - Mammary inflammatory gene expression was associated with reproductive stage and regulated by docosahexenoic acid: in vitro and in vivo studies. AB - BACKGROUND: Periparturient mastitis is the most prevalent disease affecting lactating animals. However, it has long been relied on antibiotics to deal with mastitis, leading to a potential threat to food safety. This study was aimed to investigate the expression of pro-inflammatory cytokines in mammary glands of sows around parturition when mastitis and oxidative stress usually occur, and evaluate the anti-inflammatory effect of docosahexenoic acid (DHA) in porcine mammary epithelial cells (PMEC) challenged by lipopolysaccharide (LPS). METHODS: Mammary tissues and blood samples were collected from seven pregnant sows at different reproductive stages. Primarily cultured PMEC at passage 4 were assigned to four treatments: basal medium (control), basal medium with LPS (10 MUg/mL) (LPS treatment), basal medium with LPS (10 MUg/mL) and DHA (100 or 200 MUM) (LPS + DHA treatments), and cell samples were harvested after 24 h incubation. The measurements included oxidative stress markers in blood samples and gene expression in mammary tissues and PMEC samples. RESULTS: Serum alpha-tocopherol concentration was lower at parturition than at day 90 of gestation and day 28 post parturition, while serum malondialdehyde concentration was higher at day 28 post parturition than at day 90 of gestation. Higher interleukin (IL)-1beta mRNA abundance while lower LPS binding protein mRNA abundance in mammary tissues were observed at day 90 of gestation compared with that at parturition and at day 28 and 35 post parturition. Mammary tumor necrosis factor (TNF)-alpha mRNA abundance were lower at parturition than at day 90 of gestation and day 28 and 35 post parturition, whereas mammary IL-8 mRNA abundance were lower at parturition than at day 35 post parturition. In the PMEC experiment, compared with the control, increased mRNA abundances of Toll-like receptor (TLR)-4 downstream target, myeloid differentiation factor 88 (MyD88), IL-6 and IL-8 were observed in LPS treatment, whereas DHA appeared to decrease mRNA abundances of MyD88, IL-6 and IL 8 induced by LPS. CONCLUSIONS: The down-regulated expression of pro-inflammatory cytokines in mammary tissues and aggravated systemic oxidative stress at parturition suggest that sows are in a vulnerable status during periparturient period. DHA appears to attenuate inflammatory responses in LPS-challenged PMEC through modulation of TLR4 signalling pathway. PMID- 27938409 TI - The effectiveness of evidence summaries on health policymakers and health system managers use of evidence from systematic reviews: a systematic review. AB - BACKGROUND: Systematic reviews are important for decision makers. They offer many potential benefits but are often written in technical language, are too long, and do not contain contextual details which make them hard to use for decision making. There are many organizations that develop and disseminate derivative products, such as evidence summaries, from systematic reviews for different populations or subsets of decision makers. This systematic review aimed to (1) assess the effectiveness of evidence summaries on policymakers' use of the evidence and (2) identify the most effective summary components for increasing policymakers' use of the evidence. We present an overview of the available evidence on systematic review derivative products. METHODS: We included studies of policymakers at all levels as well as health system managers. We included studies examining any type of "evidence summary," "policy brief," or other products derived from systematic reviews that presented evidence in a summarized form. The primary outcomes were the (1) use of systematic review summaries in decision-making (e.g., self-reported use of the evidence in policymaking and decision-making) and (2) policymakers' understanding, knowledge, and/or beliefs (e.g., changes in knowledge scores about the topic included in the summary). We also assessed perceived relevance, credibility, usefulness, understandability, and desirability (e.g., format) of the summaries. RESULTS: Our database search combined with our gray literature search yielded 10,113 references after removal of duplicates. From these, 54 were reviewed in full text, and we included six studies (reported in seven papers) as well as protocols from two ongoing studies. Two studies assessed the use of evidence summaries in decision-making and found little to no difference in effect. There was also little to no difference in effect for knowledge, understanding or beliefs (four studies), and perceived usefulness or usability (three studies). Summary of findings tables and graded entry summaries were perceived as slightly easier to understand compared to complete systematic reviews. Two studies assessed formatting changes and found that for summary of findings tables, certain elements, such as reporting study event rates and absolute differences, were preferred as well as avoiding the use of footnotes. CONCLUSIONS: Evidence summaries are likely easier to understand than complete systematic reviews. However, their ability to increase the use of systematic review evidence in policymaking is unclear. TRIAL REGISTRATION: The protocol was published in the journal Systematic Reviews (2015;4:122). PMID- 27938406 TI - NOTCH receptors in gastric and other gastrointestinal cancers: oncogenes or tumor suppressors? AB - Gastric cancer (GC) ranks the most common cancer types and is one of the leading causes of cancer-related death. Due to delayed diagnosis and high metastatic frequency, 5-year survival rate of GC is rather low. It is a complex disease resulting from the interaction between environmental factors and host genetic alterations that deregulate multiple signaling pathways. The Notch signaling pathway, a highly conserved system in the regulation of the fate in several cell types, plays a pivotal role in cell differentiation, survival and proliferation. Notch is also one of the most commonly activated signaling pathways in tumors and its aberrant activation plays a key role in cancer advancement. Whether Notch cascade exerts oncogenic or tumor suppressive function in different cancer types depends on the cellular context. Mammals have four NOTCH receptors that modulate Notch pathway activity. In this review, we provide a comprehensive summary on the functional role of NOTCH receptors in gastric and other gastrointestinal cancers. Increasing knowledge of NOTCH receptors in gastrointestinal cancers will help us recognize the underlying mechanisms of Notch signaling and develop novel therapeutic strategies for GC. PMID- 27938410 TI - 3D culture models of Alzheimer's disease: a road map to a "cure-in-a-dish". AB - Alzheimer's disease (AD) transgenic mice have been used as a standard AD model for basic mechanistic studies and drug discovery. These mouse models showed symbolic AD pathologies including beta-amyloid (Abeta) plaques, gliosis and memory deficits but failed to fully recapitulate AD pathogenic cascades including robust phospho tau (p-tau) accumulation, clear neurofibrillary tangles (NFTs) and neurodegeneration, solely driven by familial AD (FAD) mutation(s). Recent advances in human stem cell and three-dimensional (3D) culture technologies made it possible to generate novel 3D neural cell culture models that recapitulate AD pathologies including robust Abeta deposition and Abeta-driven NFT-like tau pathology. These new 3D human cell culture models of AD hold a promise for a novel platform that can be used for mechanism studies in human brain-like environment and high-throughput drug screening (HTS). In this review, we will summarize the current progress in recapitulating AD pathogenic cascades in human neural cell culture models using AD patient-derived induced pluripotent stem cells (iPSCs) or genetically modified human stem cell lines. We will also explain how new 3D culture technologies were applied to accelerate Abeta and p-tau pathologies in human neural cell cultures, as compared the standard two dimensional (2D) culture conditions. Finally, we will discuss a potential impact of the human 3D human neural cell culture models on the AD drug-development process. These revolutionary 3D culture models of AD will contribute to accelerate the discovery of novel AD drugs. PMID- 27938411 TI - Butyrate attenuates lipolysis in adipocytes co-cultured with macrophages through non-prostaglandin E2-mediated and prostaglandin E2-mediated pathways. AB - BACKGROUND: Interactions between adipocytes and macrophages are associated with metabolic disorders. Production of pro-inflammatory mediators and the release of free fatty acids (FFAs) increase when these cells are co-cultured; butyrate significantly diminishes these effects by suppressing both the macrophage inflammatory and adipocyte lipolysis pathways. Butyrate is known to up-regulate the expression of prostaglandin E2 (PGE2). Therefore, we hypothesized that PGE2 is associated with the suppression of lipolysis by butyrate in co-culture. METHODS: Using contact or transwell co-culture methods with differentiated 3T3-L1 adipocytes and RAW264.7 macrophages, we investigated the effects of butyrate on the release of PGE2 into the medium and on lipolysis in adipocytes. To elucidate the underlying mechanism, we examined the effects of butyrate on cyclooxygenase-2 (COX2) and phospholipase A2 (PLA2) in co-cultured cells, and cyclic adenine monophosphate (cAMP) and protein kinase A type 1-alpha regulatory subunit (PRKAR1A) in co-cultured adipocytes. Silent interfering (si)RNA targeting of G protein-coupled receptor (GPR)41 and 109A was employed to examine the effect on lipolysis in TNF-alpha-stimulated adipocytes. RESULTS: Co-culture increased PGE2 release into the medium, compared with cells cultured separately. Butyrate significantly increased PGE2 production. Co-culture elevated COX2 expression in macrophages and adipocytes, and butyrate further enhanced this effect. Co-culture enhanced cytosolic PLA2 activity in macrophages, which was further enhanced by butyrate. As for lipolysis, co-culture increased the release of FFAs and free glycerol into the medium, whereas butyrate (and to a lesser extent, PGE2) suppressed FFAs and free glycerol release. An inhibition study using a prostaglandin E receptor 3-selective antagonist suggested that approximately 40% of the suppressive effect of butyrate depends on the PGE2-mediated pathway, whereas 60% depends on a non-PGE2-mediated pathway. Co-culture increased cAMP and PRKAR1A levels in adipocytes, whereas butyrate restored the levels to those of the control. Similarly, in TNF-alpha-stimulated adipocytes, butyrate reduced FFAs and free glycerol release. siRNA inhibition of GPR41 and GPR109A suggested that the GPR109A-mediated pathway predominates, but the GPR41-mediated pathway also regulates the effect of butyrate on lipolysis in TNF-alpha-stimulated 3T3-L1 cells. CONCLUSIONS: Butyrate attenuates lipolysis in adipocytes co-cultured with macrophages via non-PGE2-mediated and PGE2-mediated pathways. PMID- 27938412 TI - A systematic review of randomised controlled trials examining the therapeutic effects of adult bone marrow-derived stem cells for non-ischaemic dilated cardiomyopathy. AB - BACKGROUND: Certain early-phase clinical trials have suggested that bone marrow derived stem cell transplantation might improve left ventricular function in patients with non-ischaemic dilated cardiomyopathy (NIDCM), whereas others trials have revealed no benefit from this approach. We sought to evaluate the therapeutic effects of bone marrow-derived stem cell therapy on NIDCM. METHODS: We searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases (through February 2016) for randomised controlled clinical trials that reported on bone marrow-derived stem cell transplantation for patients with NIDCM with a follow-up period >=12 months. The co-primary endpoints were changes in mortality rate and left ventricular ejection fraction (LVEF); the secondary endpoints were changes in the 6-minute-walk test (6MWT) and left ventricular chamber size. Seven trials involving bone marrow-derived stem cell therapy that included 482 patients satisfied the inclusion and exclusion criteria. RESULTS: Subjects who received bone marrow-derived stem cell therapy exhibited a significant reduction in mortality rate (19.7% in the cell group vs. 27.1% in the control group; 95% confidence interval (CI) -0.16 to -0.00, I 2 = 52%, p = 0.04). Bone marrow-derived stem cell therapy tended to produce LVEF improvement within 6 months (1.83% increase; 95% CI -0.27 to 3.94, I 2 = 74%, p = 0.09) and significantly improved LVEF after mid-term (6-12 months) follow-up (3.53% increase; 95% CI 0.76 to 6.29, I 2 = 88%, p = 0.01). However, this therapy produced no significant benefit in the 6MWT (p = 0.18). Finally, the transplantation of increased numbers of stem cells resulted in no observable additional benefit with respect to LVEF. CONCLUSIONS: Bone marrow-derived stem cell therapy might have improved prognoses and appeared to provide moderate benefits in cardiac systolic function at mid-term follow-up. However, this therapy produced no observed improvement in exercise tolerance. PMID- 27938413 TI - Retraction Note to: A new inducible transgenic mouse model for C9orf72-associated GGGGCC repeat expansion supports a gain-of-function mechanism in C9orf72 associated ALS and FTD. PMID- 27938414 TI - The effects of the novel A53E alpha-synuclein mutation on its oligomerization and aggregation. AB - alpha-synuclein (aSyn) is associated with both sporadic and familial forms of Parkinson's disease (PD), the second most common neurodegenerative disorder after Alzheimer's disease. In particular, multiplications and point mutations in the gene encoding for aSyn cause familial forms of PD. Moreover, the accumulation of aSyn in Lewy Bodies and Lewy neurites in disorders such as PD, dementia with Lewy bodies, or multiple system atrophy, suggests aSyn misfolding and aggregation plays an important role in these disorders, collectively known as synucleinopathies. The exact function of aSyn remains unclear, but it is known to be associated with vesicles and membranes, and to have an impact on important cellular functions such as intracellular trafficking and protein degradation systems, leading to cellular pathologies that can be readily studied in cell based models. Thus, understanding the molecular effects of aSyn point mutations may provide important insight into the molecular mechanisms underlying disease onset.We investigated the effect of the recently identified A53E aSyn mutation. Combining in vitro studies with studies in cell models, we found that this mutation reduces aSyn aggregation and increases proteasome activity, altering normal proteostasis.We observed that, in our experimental paradigms, the A53E mutation affects specific steps of the aggregation process of aSyn and different cellular processes, providing novel ideas about the molecular mechanisms involved in synucleinopathies. PMID- 27938415 TI - Triatomine bugs, their microbiota and Trypanosoma cruzi: asymmetric responses of bacteria to an infected blood meal. AB - BACKGROUND: Triatomine bugs (Hemiptera: Reduviidae) are vectors of the flagellate Trypanosoma cruzi, the causative agent of Chagas disease. The study of triatomine gut microbiota has gained relevance in the last years due to its possible role in vector competence and prospective use in control strategies. The objective of this study is to examine changes in the gut microbiota composition of triatomines in response to a T. cruzi-infected blood meal and identifying key factors determining those changes. RESULTS: We sampled colony-reared individuals from six triatomine vectors (Panstrongylus megistus, Rhodnius prolixus, Triatoma brasiliensis, T. infestans, T. juazeirensis and T. sherlocki) comparing experimentally T. cruzi strain 0354-challenged and non-challenged insects. The microbiota of gut and gonad tissues was characterized using high throughput sequencing of region V3-V4 of bacterial 16S rRNA gene. The triatomine microbiota had a low intra-individual diversity, and a high inter-individual variation within the same host species. Arsenophonous appeared as the dominant triatomine bacterial symbiont in our study (59% of the total 16S coverage), but there were significant differences in the distribution of bacterial genera among vectors. In Rhodnius prolixus the dominant symbiont was Pectobacterium. CONCLUSIONS: Trypanosoma cruzi-challenge significantly affects microbiota composition, with challenged vectors harbouring a significantly more diverse bacterial community, both in the gut and the gonads. Our results show that blood-feeding with T. cruzi epimastigotes strongly affects microbiota composition in a species-specific manner. We suggest that triatomine-adapted enterobacteria such as Arsenophonus could be used as stable vectors for genetic transformation of triatomine bugs and control of Chagas disease. PMID- 27938416 TI - Active animal health surveillance in European Union Member States: gaps and opportunities. AB - Animal health surveillance enables the detection and control of animal diseases including zoonoses. Under the EU-FP7 project RISKSUR, a survey was conducted in 11 EU Member States and Switzerland to describe active surveillance components in 2011 managed by the public or private sector and identify gaps and opportunities. Information was collected about hazard, target population, geographical focus, legal obligation, management, surveillance design, risk-based sampling, and multi hazard surveillance. Two countries were excluded due to incompleteness of data. Most of the 664 components targeted cattle (26.7%), pigs (17.5%) or poultry (16.0%). The most common surveillance objectives were demonstrating freedom from disease (43.8%) and case detection (26.8%). Over half of components applied risk based sampling (57.1%), but mainly focused on a single population stratum (targeted risk-based) rather than differentiating between risk levels of different strata (stratified risk-based). About a third of components were multi hazard (37.3%). Both risk-based sampling and multi-hazard surveillance were used more frequently in privately funded components. The study identified several gaps (e.g. lack of systematic documentation, inconsistent application of terminology) and opportunities (e.g. stratified risk-based sampling). The greater flexibility provided by the new EU Animal Health Law means that systematic evaluation of surveillance alternatives will be required to optimize cost-effectiveness. PMID- 27938418 TI - GROWING UP IN PORTUGAL: CAPE VERDEAN ANCESTRY CHILDREN EXHIBIT LOW OVERWEIGHT AND OBESITY COMPARED WITH PORTUGUESE IN URBAN LISBON. AB - Portugal has one of the highest rates of childhood overweight and obesity in Europe. However, little is known about the health of ethnic minorities living in its capital city, Lisbon. The Cape Verdean community in Lisbon tend to have low educational levels, material deprivation and struggle with discrimination and racism, factors that would probably be associated with a higher prevalence of overweight and obesity. Data for the Cape Verdean population were collected in three different time periods by three different research teams in 1993, 2009 and 2013 and included children aged 6-12 years living in the Cova da Moura neighbourhood of the Greater Lisbon Metro Area. The Portuguese national survey was conducted between 2009 and 2010 at public and private schools in mainland Portugal and included height, weight, skinfolds and arm and waist circumferences. From these survey data body mass index (BMI) and prevalence of stunting (chronic malnutrition - low height-for-age) and underweight (low weight-for-age) were calculated according to reference values proposed by Frisancho (2008). Overweight and obesity prevalence values were defined based on the references established by the International Obesity Task Force. The results show significant differences in height between Cape Verdean and Portuguese boys and girls. Generally, Cape Verdeans' growth falls within the healthy range of international growth references across all of the survey data collected. Cape Verdean rates for combined overnutrition (overweight and obesity) in 2013 (9.8% for boys and 16.7% for girls) were lower than those of the Portuguese (33% for boys and 31.7% for girls). Logistic regression models showed that Cape Verdean children had a lower risk of being overweight or obese when accounting for breast-feeding, birth weight, maternal education and occupation. Despite living in a deprived neighbourhood these Cape Verdean children seemed to have grown more healthily than Portuguese ancestry children. The challenge for policymakers will be to support improvement of the poverty-related living conditions of this community without creating a risky environment for increasing prevalence of overweight and obesity. PMID- 27938417 TI - Prevalence, hematological findings and genetic diversity of Bartonella spp. in domestic cats from Valdivia, Southern Chile. AB - The present study determined the prevalence, hematological findings and genetic diversity of Bartonella spp. in domestic cats from Valdivia, Southern Chile. A complete blood count and nuoG gene real-time quantitative PCR (qPCR) for Bartonella spp. were performed in 370 blood samples from cats in Valdivia, Southern Chile. nuoG qPCR-positive samples were submitted to conventional PCR for the gltA gene and sequencing for species differentiation and phylogenetic analysis. Alignment of gltA gene was used to calculate the nucleotide diversity, polymorphic level, number of variable sites and average number of nucleotide differences. Bartonella DNA prevalence in cats was 18.1% (67/370). Twenty-nine samples were sequenced with 62.0% (18/29) identified as Bartonella henselae, 34.4% (10/29) as Bartonella clarridgeiae, and 3.4% (1/29) as Bartonella koehlerae. Bartonella-positive cats had low DNA bacterial loads and their hematological parameters varied minimally. Each Bartonella species from Chile clustered together and with other Bartonella spp. described in cats worldwide. Bartonella henselae and B. clarridgeiae showed a low number of variable sites, haplotypes and nucleotide diversity. Bartonella clarridgeiae and B. koehlerae are reported for the first time in cats from Chile and South America, respectively. PMID- 27938419 TI - Increased GABAA receptor binding in amygdala after prenatal administration of valproic acid to rats. AB - OBJECTIVE: Prenatal exposure to valproic acid (VPA) enhances the risk for later development of autism spectrum disorders (ASD). An altered gamma-aminobutyric acid (GABA) system may be a key factor in ASD. Here we investigated possible changes in the GABA system in rats exposed to a low dose of prenatal VPA. METHOD: We performed autoradiography with [3H]muscimol, (a GABAA receptor agonist), and [11C]Ro15-4513 (a partial agonist of the GABAA alpha1+5 receptor subtypes), in brain sections containing amygdala, thalamus and hippocampus of rats treated prenatally with 20 mg/kg VPA or saline from the 12th day of gestation. Result Prenatal VPA significantly increased [11C]Ro15-4513 binding in the left amygdala compared with controls (p<0.05). This difference was not observed in the hippocampus, thalamus or right amygdala. No differences were observed in [3H]muscimol binding. CONCLUSION: We observed an asymmetric increase in GABAA receptor binding. Disturbances in the GABAA receptor system have also been detected in human autism with [11C]Ro15-4513. PMID- 27938420 TI - The high resolution melting analysis (HRM) as a molecular tool for monitoring parasites of the wildlife. AB - In an interconnected world, the international pet trade on wild animals is becoming increasingly important. As a consequence, non-native parasite species are introduced, which affect the health of wildlife and contribute to the loss of biodiversity. Because the investigation of parasite diversity within vulnerable host species implies the molecular identification of large samples of parasite eggs, the sequencing of DNA barcodes is time-consuming and costly. Thereby, the objectives of our study were to apply the high resolution melting (HRM) approach for species determination from pools of parasite eggs. Molecular assays were validated on flatworm parasites (polystomes) infecting the Mediterranean pond turtle Mauremys leprosa and the invasive red-eared slider Trachemys scripta elegans in French natural environments. HRM analysis results indicated that double or multiple parasitic infections could be detected from wild animal populations. They also showed that the cycle of parasite eggs production was not regular over time and may depend on several factors, among which the ecological niche and the target species. Thereby, monitoring parasites from wild endangered animals implies periodic parasitological surveys to avoid false negative diagnostics, based solely on eggs production. PMID- 27938421 TI - High prevalence of fosfomycin resistance gene fosA3 in bla CTX-M-harbouring Escherichia coli from urine in a Chinese tertiary hospital during 2010-2014. AB - Fosfomycin has become a therapeutic option in urinary tract infections. We identified 57 fosfomycin-resistant Escherichia coli from 465 urine-derived extended-spectrum beta-lactamase (ESBL)-producing isolates from a Chinese hospital during 2010-2014. Of the 57 fosfomycin-resistant isolates, 51 (89.5%) carried fosA3, and one carried fosA1. Divergent pulsed-field gel electrophoresis profiles and multi-locus sequence typing results revealed high clonal diversity in the fosA3-positive isolates. Conjugation experiments showed that the fosA3 genes from 50 isolates were transferable, with IncFII or IncI1 being the most prevalent types of plasmids. The high prevalence of fosA3 was closely associated with that of bla CTX-M. Horizontal transfer, rather than clonal expansion, might play a central role in dissemination. Such strains may constitute an important reservoir of fosA3 and bla CTX-M, which may well be readily disseminated to other potential human pathogens. Since most ESBL-producing E. coli have acquired resistance to fluoroquinolones worldwide, further spread of fosA3 in such E. coli isolates should be monitored closely. PMID- 27938422 TI - Detection and molecular identification of Hepatozoon canis and Babesia vogeli from domestic dogs in Palestine. AB - Dogs serve as hosts for a great number of parasites, which may affect their health and wellbeing. This study aimed to observe tick borne pathogens in dogs from Palestine including Hepatozoon canis and Babesia species. The prevalence of both H. canis and Babesia species infections in apparently healthy dogs, from ten districts of the West Bank was surveyed. DNA was extracted from blood samples obtained from dogs (n = 362) and ticks (n = 213) collected from dogs (n = 77). A primer set that amplifies a partial sequence of the Babesia and Hepatozoon 18S rRNA gene was used for PCR and the DNA sequences of the PCR products of all samples were determined. Twenty-nine (8.0%) of the dogs were found infected including 20 with H. canis (5.5%), seven with Babesia vogeli (1.9%) and two with undefined Babesia spp. (0.6%). Twelve Rhipicephalus sanguineus s.l ticks were pathogen-positive, including ten with H. canis (4.7%), one with B. vogeli (0.5%), and one with Hepatozoon felis (0.5%). The results indicated that a wide range of tick borne pathogens is circulating in the canine population in the surveyed region. This study is the first report on the prevalence of H. canis, B. vogeli and Babesia spp. in dogs in Palestine and its results will assist in the management of diseases associated with these blood parasites. PMID- 27938424 TI - Folate intakes from diet and supplements may place certain Canadians at risk for folic acid toxicity - CORRIGENDUM. PMID- 27938423 TI - Hypogyrification in obsessive-compulsive disorder. AB - BACKGROUND: Previous studies hypothesized that neurodevelopmental risk factors may play a role in the pathogenesis of obsessive-compulsive disorder (OCD). Cortical folding has been shown to be a reliable indicator for normal and altered neurodevelopment, but in OCD it has barely been investigated up to now. The present study investigates whether alterations in gyrification are detectable in OCD and, if so, how these are associated with clinical characteristics. METHOD: We compared the local Gyrification Index (lGI) between 75 OCD patients and 75 matched healthy subjects across the whole brain. In addition, for those regions exhibiting an altered lGI in patients we explored a potential relationship to symptom severity, age of onset, and influence of medication. RESULTS: OCD patients had a significantly decreased lGI in right parietal, precentral but also insula, temporal, pars triangularis and rostral middle frontal regions compared to healthy subjects. A positive association with age of onset was found but no association with symptom severity. There was no effect of co-morbidity or medication. CONCLUSIONS: The reduced gyrification found in OCD confirms previous findings in other psychiatric disorders and suggests that alterations may already occur during early stages of brain development. Our findings support the idea that altered cortical folding might represent a trait characteristic of the disorder although longitudinal studies are needed to clarify the trajectory of this morphological measure in OCD. PMID- 27938426 TI - Genetic polymorphism and population structure of Echinococcus ortleppi. AB - The zoonotic cestode Echinococcus ortleppi (Lopez-Neyra and Soler Planas, 1943) is mainly transmitted between dogs and cattle. It occurs worldwide but is only found sporadically in most regions, with the notable exception of parts of southern Africa and South America. Its epidemiology is little understood and the extent of intraspecific variability is unknown. We have analysed in the present study the genetic diversity among 178 E. ortleppi isolates from sub-Saharan Africa, Europe and South America using the complete mitochondrial cox1 (1608 bp) and nad1 (894 bp) DNA sequences. Genetic polymorphism within the loci revealed 15 cox1 and six nad1 haplotypes, respectively, and 20 haplotypes of the concatenated genes. Presence of most haplotypes was correlated to geographical regions, and only one haplotype had a wider spread in both eastern and southern Africa. Intraspecific microvariance was low in comparison with Echinococcus granulosus sensu stricto, despite the wide geographic range of examined isolates. In addition, the various sub-populations showed only subtle deviation from neutrality and were mostly genetically differentiated. This is the first insight into the population genetics of the enigmatic cattle adapted Echinococcus ortleppi. It, therefore, provides baseline data for biogeographical comparison among E. ortleppi endemic regions and for tracing its translocation paths. PMID- 27938425 TI - New mobile methods for dietary assessment: review of image-assisted and image based dietary assessment methods. AB - For nutrition practitioners and researchers, assessing dietary intake of children and adults with a high level of accuracy continues to be a challenge. Developments in mobile technologies have created a role for images in the assessment of dietary intake. The objective of this review was to examine peer reviewed published papers covering development, evaluation and/or validation of image-assisted or image-based dietary assessment methods from December 2013 to January 2016. Images taken with handheld devices or wearable cameras have been used to assist traditional dietary assessment methods for portion size estimations made by dietitians (image-assisted methods). Image-assisted approaches can supplement either dietary records or 24-h dietary recalls. In recent years, image-based approaches integrating application technology for mobile devices have been developed (image-based methods). Image-based approaches aim at capturing all eating occasions by images as the primary record of dietary intake, and therefore follow the methodology of food records. The present paper reviews several image-assisted and image-based methods, their benefits and challenges; followed by details on an image-based mobile food record. Mobile technology offers a wide range of feasible options for dietary assessment, which are easier to incorporate into daily routines. The presented studies illustrate that image-assisted methods can improve the accuracy of conventional dietary assessment methods by adding eating occasion detail via pictures captured by an individual (dynamic images). All of the studies reduced underreporting with the help of images compared with results with traditional assessment methods. Studies with larger sample sizes are needed to better delineate attributes with regards to age of user, degree of error and cost. PMID- 27938428 TI - Plasmodium knowlesi: a relevant, versatile experimental malaria model. AB - The primate malaria Plasmodium knowlesi has a long-standing history as an experimental malaria model. Studies using this model parasite in combination with its various natural and experimental non-human primate hosts have led to important advances in vaccine development and in our understanding of malaria invasion, immunology and parasite-host interactions. The adaptation to long-term in vitro continuous blood stage culture in rhesus monkey, Macaca fascicularis and human red blood cells, as well as the development of various transfection methodologies has resulted in a highly versatile experimental malaria model, further increasing the potential of what was already a very powerful model. The growing evidence that P. knowlesi is an important human zoonosis in South-East Asia has added relevance to former and future studies of this parasite species. PMID- 27938427 TI - A stochastic model for MRSA transmission within a hospital ward incorporating environmental contamination. AB - Methicillin-resistant Staphylococcus aureus (MRSA) transmission in hospital wards is associated with adverse outcomes for patients and increased costs for hospitals. The transmission process is inherently stochastic and the randomness emphasized by the small population sizes involved. As such, a stochastic model was proposed to describe the MRSA transmission process, taking into account the related contribution and modelling of the associated microbiological environmental contamination. The model was used to evaluate the performance of five common interventions and their combinations on six potential outcome measures of interest under two hypothetical disease burden settings. The model showed that the optimal intervention combination varied depending on the outcome measure and burden setting. In particular, it was found that certain outcomes only required a small subset of targeted interventions to control the outcome measure, while other outcomes still reported reduction in the outcome distribution with up to all five interventions included. This study describes a new stochastic model for MRSA transmission within a ward and highlights the use of the generalized Mann-Whitney statistic to compare the distribution of the outcome measures under different intervention combinations to assist in planning future interventions in hospital wards under different potential outcome measures and disease burden. PMID- 27938429 TI - Metabolic dysregulation and late-life depression: a prospective study. AB - BACKGROUND: Depression is associated with the metabolic syndrome (MS). We examined whether metabolic dysregulation predicted the 2-year course of clinical depression. METHOD: A total of 285 older persons (?60 years) suffering from depressive disorder according to DSM-IV-TR criteria was followed up for 2 years. Severity of depression was assessed with the Inventory of Depressive Symptomatology (IDS) at 6-month intervals. Metabolic syndrome was defined according the National Cholesterol Education Programme (NCEP-ATP III). We applied logistic regression and linear mixed models adjusted for age, sex, years of education, smoking, alcohol use, physical activity, somatic co-morbidity, cognitive functioning and drug use (antidepressants, anti-inflammatory drugs) and severity of depression at baseline. RESULTS: MS predicted non-remission at 2 years (odds ratioper component = 1.26, 95% confidence interval 1.00-1.58), p = 0.047), which was driven by the waist circumference and HDL cholesterol. MS was not associated with IDS sum score. Subsequent analyses on its subscales, however, identified an association with the somatic symptom subscale score over time (interaction time * somatic subscale, p = 0.005), driven by higher waist circumference and elevated fasting glucose level. CONCLUSIONS: Metabolic dysregulation predicts a poor course of late-life depression. This finding supports the concept of 'metabolic depression', recently proposed on population based findings of a protracted course of depressive symptoms in the presence of metabolic dysregulation. Our findings seem to be driven by abdominal obesity (as indicated by the waist circumference) and HDL cholesterol dysregulation. PMID- 27938430 TI - Cognition as a treatment target in depression. AB - Cognitive dysfunction in depression is associated with poorer clinical outcomes and impaired psychosocial functioning. However, most treatments for depression do not specifically target cognition. Neurocognitive deficits such as memory and concentration problems tend to persist after mood symptoms recover. Improving cognition in depression requires a better understanding of brain systems implicated in depression. A comprehensive approach is warranted for refined methods of assessing and treating cognitive dysfunction in depression. PMID- 27938431 TI - High rates of infection by blood parasites during the nestling phase in UK Columbids with notes on ecological associations. AB - Studies of blood parasite infection in nestling birds rarely find a high prevalence of infection. This is likely due to a combination of short nestling periods (limiting the age at which nestlings can be sampled) and long parasite prepatent periods before gametocytes can be detected in peripheral blood. Here we examine rates of blood parasite infection in nestlings from three Columbid species in the UK. We use this system to address two key hypotheses in the epidemiology of avian haemoparasites: first, that nestlings in open nests have a higher prevalence of infection; and second, that nestlings sampled at 14 days old have a higher apparent infection rate than those sampled at 7 days old. Open nesting individuals had a 54% infection rate compared with 25% for box-nesters, probably due to an increased exposure of open-nesting species to dipteran vectors. Nestlings sampled at 14 days had a 68% infection rate compared with 32% in nestlings sampled at 7 days, suggesting that rates of infection in the nest are high. Further work should examine nestlings post-fledging to identify rates of successful parasite infection (as opposed to abortive development within a dead-end host) as well as impacts on host post-fledging survival and behaviour. PMID- 27938432 TI - Comprehensive biometric, biochemical and histopathological assessment of nutrient deficiencies in gilthead sea bream fed semi-purified diets - CORRIGENDUM. PMID- 27938433 TI - Deep microbleeds and periventricular white matter disintegrity are independent predictors of attention/executive dysfunction in non-dementia patients with small vessel disease. AB - BACKGROUND: Cerebral small vessel disease (SVD) is the common cause of cognitive decline in the old population. MRI can be used to clarify its mechanisms. However, the surrogate markers of MRI for early cognitive impairment in SVD remain uncertain to date. We investigated the cognitive impacts of cerebral microbleeds (CMBs), diffusion tensor imaging (DTI), and brain volumetric measurements in a cohort of post-stroke non-dementia SVD patients. METHODS: Fifty five non-dementia SVD patients were consecutively recruited and categorized into two groups as no cognitive impairment (NCI) (n = 23) or vascular mild cognitive impairment (VaMCI) (n = 32). Detailed neuropsychological assessment and multimodal MRI were completed. RESULTS: The two groups differed significantly on Z scores of all cognitive domains (all p < 0.01) except for the language. There were more patients with hypertension (p = 0.038) or depression (p = 0.019) in the VaMCI than those in the NCI group. Multiple regression analysis of cognition showed periventricular mean diffusivity (MD) (beta = -0.457, p < 0.01) and deep CMBs numbers (beta = -0.352, p < 0.01) as the predictors of attention/executive function, which explained 45.2% of the total variance. Periventricular MD was the independent predictor for either memory (beta = -0.314, p < 0.05) or visuo spatial function (beta = -0.375, p < 0.01); however, only small proportion of variance could be accounted for (9.8% and 12.4%, respectively). Language was not found to be correlated with any of the MRI parameters. No correlation was found between brain atrophic indices and any of the cognitive measures. CONCLUSION: Arteriosclerotic CMBs and periventricular white matter disintegrity seem to be independent MRI surrogated markers in the early stage of cognitive impairment in SVD. PMID- 27938434 TI - Early detection of West Nile virus in France: quantitative assessment of syndromic surveillance system using nervous signs in horses. AB - West Nile virus (WNV) is a growing public health concern in Europe and there is a need to develop more efficient early detection systems. Nervous signs in horses are considered to be an early indicator of WNV and, using them in a syndromic surveillance system, might be relevant. In our study, we assessed whether or not data collected by the passive French surveillance system for the surveillance of equine diseases can be used routinely for the detection of WNV. We tested several pre-processing methods and detection algorithms based on regression. We evaluated system performances using simulated and authentic data and compared them to those of the surveillance system currently in place. Our results show that the current detection algorithm provided similar performances to those tested using simulated and real data. However, regression models can be easily and better adapted to surveillance objectives. The detection performances obtained were compatible with the early detection of WNV outbreaks in France (i.e. sensitivity 98%, specificity >94%, timeliness 2.5 weeks and around four false alarms per year) but further work is needed to determine the most suitable alarm threshold for WNV surveillance in France using cost-efficiency analysis. PMID- 27938435 TI - Alcohol use, depression, and life satisfaction among older persons in Jamaica. AB - BACKGROUND: We aimed to determine the prevalence of alcohol use among older Jamaicans as well as to explore among this population the relationships between alcohol use and: age, sex, depressive symptoms, and life satisfaction. Although the nature of these relationships among the proposed study population were uncertain, in other settings alcohol use has tended to decline with increasing age, occur more commonly among men than women, and show non-linear relationships with depressive symptoms and life satisfaction. METHODS: Data gathered by two stage cluster sampling for a nationally representative health and lifestyle survey of 2,943 community-dwelling older Jamaicans, aged 60 to 103 years, were subjected to secondary analysis using the Student's t-test and chi 2 test as appropriate. RESULTS: Current alcohol use was reported by 21.4% of the participants. It steadily declined with age and was six times more prevalent among men (37.6%) than women (6.2%). These findings were statistically significant as were associations of current alcohol use with comparatively lower levels of depressive symptoms. Current alcohol use was also more prevalent among persons who were either highly satisfied or highly dissatisfied with their lives, compared to others who had levels of life satisfaction between these two extremes. CONCLUSIONS: Current alcohol use among older Jamaicans occurs primarily among men, declines with increasing age, and is associated with a relatively low likelihood of depression. It is also associated with very high and very low levels of life satisfaction. PMID- 27938436 TI - Molecular cloning, characterization and antigenicity of Babesia sp. BQ1 (Lintan) (Babesia cf. motasi) apical membrane antigen-1 (AMA-1). AB - Apical membrane antigen-1 (AMA-1) has been described as a potential vaccine candidate in apicomplexan parasites. Here we characterize the ama-1 gene. The full-length ama-1 gene of Babesia sp. BQ1 (Lintan) (BLTAMA-1) is 1785 bp, which contains an open reading frame (ORF) encoding a 65-kDa protein of 594 amino acid residues; by definition, the 5' UTR precedes the first methionine of the ORF. Phylogenetic analysis based on AMA-1 amino acid sequences clearly separated Piroplasmida from other Apicomplexa parasites. The Babesia sp. BQ1 (Lintan) AMA-1 sequence is most closely associated with that of B. ovata and B. bigemina, with high bootstrap value. A recombinant protein encoding a conserved region and containing ectodomains I and II of BLTAMA-1 was constructed. BLTrAMA-1-DI/DII proteins were tested for reactivity with sera from sheep infected by Babesia sp. BQ1 (Lintan). In Western-blot analysis, native Babesia sp. BQ1 (Lintan) AMA-1 proteins were recognized by antibodies raised in rabbits against BLTrAMA-1 in vitro. The results of this study are discussed in terms of gene characterization, taxonomy and antigenicity. PMID- 27938437 TI - Haemosporida prevalence and diversity are similar in endangered wild whooping cranes (Grus americana) and sympatric sandhill cranes (Grus canadensis). AB - The population growth of endangered whooping cranes (Grus americana) is not consistent with species recovery goals, and the impact of parasite infection on whooping crane populations is largely unknown. Disease ecology and epidemiology research of endangered species is often hindered by limited ability to conduct invasive sampling on the target taxa. Accordingly, we hypothesized that sandhill cranes (Grus canadensis) would be a useful surrogate species to investigate the health impacts of Haemosporida infection in whooping cranes. Our goal was to compare the prevalence and diversity of Haemosporida infection between whooping cranes and sandhill cranes. We detected an overall infection prevalence of 83.6% (n = 61) in whooping cranes and 59.6% (n = 47) and 63.6 (n = 22) in two sympatric sandhill crane populations captured in Texas. Prevalence was significantly lower in allopatric sandhill cranes captured in New Mexico (12.1%, n = 33). Haemoproteus antigonis was the most abundant haemoparasite in cranes, present in 57.4% of whooping cranes and 39.2% of sandhill cranes; Plasmodium and Leucocytozoon were present at significantly lower levels. The high prevalence of Haemosporida in whooping cranes and sympatric sandhill cranes, with shared parasite lineages between the two species, supports sandhill cranes as a surrogate species for understanding health threats to endangered whooping cranes. PMID- 27938438 TI - The effects of seasonality on host-bat fly ecological networks in a temperate mountain cave. AB - Changes in the specialization of parasite-host interactions will be influenced by variations in host species composition. We evaluated this hypothesis by comparing the composition of bats and bat flies within a roost cave over one annual. Five bat and five bat fly species occupied the cave over the course of the study. Bat species composition was 40% different in the rainy season compared with the dry cold and dry-warm seasons. Despite the incorporation of three new bat species into the cave during the rainy season, bat fly species composition was not affected by seasonality, since the bats that arrived in the rainy season only contributed one new bat fly species at a low prevalence. Bat-bat fly ecological networks were less specialized in the rainy season compared with the dry-cold and dry-warm seasons because of the increase of host overlap among bat fly species during this season. This study suggests that seasonality promote: (1) differences in host species composition, and (2) a reduction in the specialization of host parasite ecological networks. PMID- 27938440 TI - A multimodality approach to sinonasal undifferentiated carcinoma: a single institute experience. AB - BACKGROUND: Sinonasal undifferentiated carcinoma is a rare aggressive tumour arising from the Schneiderian epithelium lining the sinonasal tract. Although considered the cornerstone of therapy, surgical resection can only be performed in a limited number of patients. This report describes the experience of treating sinonasal undifferentiated carcinoma with a multimodality approach. METHOD: The treatment charts of sinonasal undifferentiated carcinoma patients treated at a tertiary care centre from 2004 to 2012 were retrospectively reviewed. RESULTS: A total of 16 sinonasal undifferentiated carcinoma patients with a median age at diagnosis of 47.5 years (range 8-65 years) were included: 19 per cent had neck nodal metastasis at presentation. Four patients (25 per cent) underwent surgery: of these, two had post-operative radiotherapy, one had pre-operative radiotherapy and one had adjuvant chemotherapy alone. Six patients (38 per cent) received definitive radiotherapy: five had received neoadjuvant chemotherapy to reduce tumour size and help in radiotherapy planning, while four (25 per cent) received palliative radiotherapy. The median follow up was 10.4 months (range 1-42.5 months). The estimated median progression-free survival time was 29.3 months. One and three-year progression-free survival rates were 77 per cent and 41 per cent, respectively. CONCLUSION: Surgery is the best treatment option for sinonasal undifferentiated carcinoma, although most patients require post-operative radiotherapy for advanced disease and close tumour margins. Definitive radiotherapy with or without chemotherapy may be suitable for patients with inoperable locally advanced disease. Elective nodal irradiation to address the high nodal involvement rates should be considered to improve the survival rate. PMID- 27938439 TI - The antileishmanial activity of xanthohumol is mediated by mitochondrial inhibition. AB - Xanthohumol (Xan) is a natural constituent of human nutrition. Little is known about its actions on leishmanial parasites and their mitochondria as putative target. Therefore, we determined the antileishmanial activity of Xan and resveratrol (Res, as alternative compound with antileishmanial activity) with respect to mitochondria in Leishmania amazonensis promastigotes/amastigotes (LaP/LaA) in comparison with their activity in peritoneal macrophages from mouse (PMM) and macrophage cell line J774A.1 (J774). Mechanistic studies were conducted in Leishmania tarentolae promastigotes (LtP) and mitochondrial fractions isolated from LtP. Xan and Res demonstrated antileishmanial activity in LaA [half inhibitory concentration (IC50): Xan 7 u m, Res 14 u m]; while they had less influence on the viability of PMM (IC50: Xan 70 u m, Res >438 u m). In contrast to Res, Xan strongly inhibited oxygen consumption in Leishmania (LtP) but not in J774 cells. This was based on the inhibition of the mitochondrial electron transfer complex II/III by Xan, which was less pronounced with Res. Neither Xan nor Res increased mitochondrial superoxide release in LtP, while both decreased the mitochondrial membrane potential in LtP. Bioenergetic studies showed that LtP mitochondria have no spare respiratory capacity in contrast to mitochondria in J774 cells and can therefore much less adapt to stress by mitochondrial inhibitors, such as Xan. These data show that Xan may have antileishmanial activity, which is mediated by mitochondrial inhibition. PMID- 27938441 TI - A dual inhibitor of FAAH and TRPV1 channels shows dose-dependent effect on depression-like behaviour in rats. AB - OBJECTIVE: The cannabinoid receptor 1 (CB1) and transient receptor potential cation channel subfamily V member 1 (TRPV1) are proposed to mediate opposite behavioural responses. Their common denominator is the endocannabinoid ligand anandamide (AEA), which is believed to mediate antidepressant-like effect via CB1 R stimulation and depressive-like effect via TRPV1 activation. This is supposed to explain the bell-shaped dose-response curve for anandamide in preclinical models. METHODS: We investigated this assumption by administering the dual inhibitor of AEA hydrolysis and TRPV1 activation N-arachidonoyl-serotonin (AA 5HT) into the medial prefrontal cortex of rats. AA-5HT was given in three different doses (0.125, 0.250, 0.500 nmol/0.4 ul/side) and rat behaviour was assessed in the forced swim test. RESULTS: Our results show significant antidepressant-like effect of AA-5HT (0.250 nmol) but no effects of low or high doses. The effect of 0.250 nmol AA-5HT was partially attenuated when coadministering the inverse CB1-agonist rimonabant (1.6 ug). CONCLUSION: A 0.250 nmol of AA-5HT administration into the medial prefrontal cortex induced a significant antidepressant-like effect that was partially attenuated by locally blocking CB1-receptor. PMID- 27938442 TI - An outbreak of oriental theileriosis in dairy cattle imported to Vietnam from Australia. AB - This study reports an outbreak of oriental theileriosis in dairy cattle imported to Vietnam from Australia. Following clinical and pathological diagnoses, a total of 112 cattle blood samples were divided into three groups and tested using multiplexed tandem PCR. Group 1 were from aborted heifers in Vietnam; group 2 were from cattle before shipment from group 1 cattle and group 3 were from the same batch of cattle but transported to Taiwan. Theileria orientalis DNA was detected in 72.3% cattle. The prevalences of T. orientalis in groups 1, 2 and 3 were 77.6, 86.9 and 57.5%, respectively, and the difference in prevalence was significant between groups 1 and 3 (P < 0.0001). The infection intensities of genotypes chitose and ikeda of T. orientalis were higher in groups 1 (57 721 and 33 709, respectively) and 3 (5897 and 61 766, respectively) than those in group 2 (2071 and 6331, respectively). Phylogenetic analyses of the major piroplasm surface protein sequences revealed that genotypes chitose and ikeda determined herein were closely related to those previously reported from Australia. This first report of an outbreak of oriental theileriosis in imported cattle emphasizes improved measures for the export and import of cattle infected with T. orientalis. PMID- 27938443 TI - Hepatozoon silvestris sp. nov.: morphological and molecular characterization of a new species of Hepatozoon (Adeleorina: Hepatozoidae) from the European wild cat (Felis silvestris silvestris). AB - Based on morphological and genetic characteristics, we describe a new species of Hepatozoon in the European wild cat (Felis silvestris silvestris), herein named Hepatozoon silvestris sp. nov. The study also provides the first data on the occurrence of H. felis in this wild felid. Hepatozoon meronts were observed in multiple cross-sections of different organs of four (44%) cats. Additionally, extracellular forms, resembling mature gamonts of Hepatozoon, were found in the spleen and myocardium of two cats. Furthermore, tissues of six animals (67%) were positive by PCR. Hepatozoon felis was identified infecting one cat (11%), whereas the 18S rRNA sequences of the remaining five cats (56%) were identical, but distinct from the sequences of H. felis. Phylogenetic analyses revealed that those sequences form a highly supported clade distant from other Hepatozoon spp. Future studies should include domestic cats from the areas where the wild cats positive for H. silvestris sp. nov. were found, in order to investigate their potential role to serve as intermediate hosts of this newly described species. Identification of its definitive host(s) and experimental transmission studies are required for elucidating the full life cycle of this parasite and the possible alternative routes of its transmission. PMID- 27938444 TI - Changes in body fatness affect cardiovascular outcomes more than changes in physical activity. AB - OBJECTIVE: The aim of this study was to analyse whether changes in physical activity and body fatness are related to modifications in cardiovascular risk factors among adolescents. Material and methods A sample of 89 healthy adolescents was recruited for this study. We assessed habitual physical activity, body fat percentage, arterial thickness, blood sample, and biological maturation. Multivariate models were used to analyse the relationships between independent and dependent variables. RESULTS: Physical activity (mean difference: 429.4 steps [95% confidence interval=-427 to 1286]) and body fatness (mean difference: -0.7% [95% confidence interval=-1.6-0.2]) remained stable during the study period. Independent of changes in physical activity, for each percentage increase in body fatness, femoral intima-media thickness increased by 0.007 mm (beta=0.007 [95% confidence interval=0.001-0.013]). Longitudinal relationships were found for high density lipoprotein-cholesterol (beta=-0.477 mg/dl [95% confidence interval= 0.805 to -0.149]) and triacylglycerol (beta=2.329 mg/dl [95% confidence interval=0.275-4.384]). CONCLUSION: Changes in body fatness are more important than the amount of physical activity on cardiovascular and metabolic risks. PMID- 27938445 TI - Sleep disturbance: an emerging opportunity for Alzheimer's disease prevention? AB - As the older segment of our population grows, cognitive decline and dementia will increase in prevalence, with Alzheimer's disease (AD) as the cause in most cases. Until a cure exists, prevention through the identification and manipulation of modifiable risk factors for dementia, in general, or AD, in particular, will be our only means of reducing dementia prevalence or delaying its onset. Furthermore, it is likely that eventual treatments for AD, when available, will depend on the ability to identify individuals at greatest risk for developing AD. Sleep disturbances are common in later life - roughly half of older adults experience regular insomnia (Ohayon, 2002) and about as many have some degree of sleep-disordered breathing (SDB) (Ancoli-Israel et al., 1991) - and accumulating evidence suggests they may contribute to cognitive decline, at least in part, by promoting the development of AD pathology (Spira et al., 2014). Because they are treatable, sleep disturbances are an important potential target for ongoing study in AD prevention. Moreover, understanding the mechanisms underlying an effect of sleep on subsequent cognitive decline and AD would allow for better identification of opportunities and optimal timing for treatment of sleep disorders, and ultimately perhaps, AD prevention. PMID- 27938446 TI - Assessment of a left circumflex coronary artery-left ventricle fistula by multimodality imaging in a child. AB - Multimodality imaging revealed a left circumflex coronary artery-left ventricle fistula in a 4-year-old boy. MRI tissue tracking revealed a slight abnormality in the left ventricular myocardial strain. Early surgery was suggested to avoid serious complications. PMID- 27938447 TI - The campylobacteriosis conundrum - examining the incidence of infection with Campylobacter sp. in Australia, 1998-2013. AB - Campylobacter sp. are a globally significant cause of gastroenteritis. Although rates of infection in Australia are among the highest in the industrialized world, studies describing campylobacteriosis incidence in Australia are lacking. Using national disease notification data between 1998 and 2013 we examined Campylobacter infections by gender, age group, season and state and territory. Negative binomial regression was used to estimate incidence rate ratios (IRRs), including trends by age group over time, with post-estimation commands used to obtain adjusted incidence rates. The incidence rate for males was significantly higher than for females [IRR 1.20, 95% confidence interval (CI) 1.18-1.21], while a distinct seasonality was demonstrated with higher rates in both spring (IRR 1.18, 95% CI 1.16-1.20) and summer (IRR 1.17, 95% CI 1.16-1.19). Examination of trends in age-specific incidence over time showed declines in incidence in those aged <40 years combined with contemporaneous increases in older age groups, notably those aged 70-79 years (IRR 1998-2013: 1.75, 95% CI 1.63-1.88). While crude rates continue to be highest in children, our findings suggest the age structure for campylobacteriosis in Australia is changing, carrying significant public health implications for older Australians. PMID- 27938448 TI - Bicuspid aortic valve outcomes. AB - BACKGROUND: Bicuspid aortic valve is the most common CHD. Its association with early valvular dysfunction, endocarditis, thoracic aorta dilatation, and aortic dissection is well established. OBJECTIVE: The aim of this study was to assess the incidence and predictors of cardiac events in adults with bicuspid aortic valve. METHODS: We carried out a retrospective analysis of cardiac outcomes in ambulatory adults with bicuspid aortic valve followed-up in a tertiary hospital centre. Outcomes were defined as follows: interventional - intervention on the aortic valve or thoracic aorta; medical - death, aortic dissection, aortic valve endocarditis, congestive heart failure, arrhythmias, or ischaemic heart disease requiring hospital admission; and a composite end point of both. Kaplan-Meier curves were generated to determine event rates, and predictors of cardiac events were determined by multivariate analysis. RESULTS: A total of 227 patients were followed-up over 13+/-9 years; 29% of patients developed severe aortic valve dysfunction and 12.3% reached ascending thoracic aorta dimensions above 45 mm. At least one cardiac outcome occurred in 38.8% of patients, with an incidence rate at 20 years of follow-up of 47+/-4%; 33% of patients were submitted to an aortic valve or thoracic aorta intervention. Survival 20 years after diagnosis was 94+/ 2%. Independent predictors of the composite end point were baseline moderate severe aortic valve dysfunction (hazard ratio, 3.19; 95% confidence interval, 1.35-7.54; p<0.01) and aortic valve leaflets calcification (hazard ratio, 4.72; 95% confidence interval, 1.91-11.64; p<0.005). CONCLUSIONS: In this study of bicuspid aortic valve, the long-term survival was excellent but with occurrence of frequent cardiovascular events. Baseline aortic valve calcification and dysfunction were the only independent predictors of events. PMID- 27938449 TI - EMS Systems in Lower-Middle Income Countries: A Literature Review. AB - : Introduction Prehospital care is one of the many issues that require addressing by lower-middle income countries (LMICs) where approximately 90% of global injuries occur. This may arise from more traffic in LMICs, poor road conditions, lack of public awareness of the importance of road safety, and the lack of ability to provide first aid to the victims. However, prehospital care in LMICs remains underdeveloped. Problem There is insufficient evidence regarding the development of prehospital care among LMICs. Thus, the objective of this study was to investigate the status of Emergency Medical Services (EMS) systems in these countries. METHODS: A review of medical-related electronic databases was designed to identify the development of EMS systems in LMICs. A search of the literature was undertaken using three electronic databases, CINAHL, Ovid Medline, and EMBASE via Ovid, from their commencement date until the end of July 2015. The grey literature was searched using Google Scholar. Articles were included if they reported on the establishment and current status of an EMS system and were excluded if they were letters to the editor, articles focusing on disaster management, a combination of more than one country if the other country was not a LMIC, written in a language other than English or Bahasa Indonesia, and/or focusing only on in-hospital care. RESULTS: There were 337 articles identified in CINAHL, 731 in Ovid Medline, 891 in EMBASE via Ovid, and 41 in Google Scholar. Based on the title and abstract, 31 articles from CINAHL, 40 from Ovid Medline, 43 from EMBASE, and 11 from Google Scholar were retrieved for further review. There were 92 articles that met the inclusion criteria with 35 articles removed, as they were duplicated, leaving 57 articles to be reviewed. From those 48 countries categorized as LMICs, there were 16 (33.3%) countries that had information about an EMS system, including injury types, patient demographic, prehospital transport, and the obstacles in implementing the prehospital care system. CONCLUSION: The implementation and development of an EMS system is varied among LMICs. Many LMICs lack an organized EMS system with most ambulances used purely for transport and not as an emergency care vehicle. Financial issues are the most common problems faced by LMICs with support from developed countries a necessity. Suryanto , Plummer V , Boyle M . EMS systems in lower-middle income countries: a literature review. Prehosp Disaster Med. 2017;32(1):64-70. PMID- 27938450 TI - Estimation of the Demand for Hospital Care After a Possible High-Magnitude Earthquake in the City of Lima, Peru. AB - : Introduction A model prepared by National Civil Defense (INDECI; Lima, Peru) estimated that an earthquake with an intensity of 8.0 Mw in front of the central coast of Peru would result in 51,019 deaths and 686,105 injured in districts of Metropolitan Lima and Callao. Using this information as a base, a study was designed to determine the characteristics of the demand for treatment in public hospitals and to estimate gaps in care in the hours immediately after such an event. METHODS: A probabilistic model was designed that included the following variables: demand for hospital care; time of arrival at the hospitals; type of medical treatment; reason for hospital admission; and the need for specialized care like hemodialysis, blood transfusions, and surgical procedures. The values for these variables were obtained through a literature search of the databases of the MEDLINE medical bibliography, the Cochrane and SciELO libraries, and Google Scholar for information on earthquakes over the last 30 years of over magnitude 6.0 on the moment magnitude scale. RESULTS: If a high-magnitude earthquake were to occur in Lima, it was estimated that between 23,328 and 178,387 injured would go to hospitals, of which between 4,666 and 121,303 would require inpatient care, while between 18,662 and 57,084 could be treated as outpatients. It was estimated that there would be an average of 8,768 cases of crush syndrome and 54,217 cases of other health problems. Enough blood would be required for 8,761 wounded in the first 24 hours. Furthermore, it was expected that there would be a deficit of hospital beds and operating theaters due to the high demand. CONCLUSION: Sudden and violent disasters, such as earthquakes, represent significant challenges for health systems and services. This study shows the deficit of preparation and capacity to respond to a possible high-magnitude earthquake. The study also showed there are not enough resources to face mega-disasters, especially in large cities. Bambaren C , Uyen A , Rodriguez M . Estimation of the demand for hospital care after a possible high-magnitude earthquake in the City of Lima, Peru. Prehosp Disaster Med. 2017;32(1):106-111. PMID- 27938451 TI - Imaging of Dental Hard Tissue Surfaces Prepared by an Ultrashort Pulsed Laser System (USPL). AB - The aim of this study was to compare surface structures of laser-irradiated dental hard tissues using confocal (CFM), atomic force (AFM), and scanning electron microscopy (SEM). The general potential of the AFM in analyzing laser irradiated surfaces was determined in this context. Specimens of human enamel and dentin were irradiated using an 8.6 W Nd:YVO4 laser with a pulse duration of 8 ps, lambda Center=1,064 nm, and a pulse repetition rate of 500 kHz. Surface topology of irradiated areas (1 mm2) was investigated using AFM, CFM, and SEM. Surface roughness R z was measured only with the AFM and the CFM. For non irradiated enamel and dentin surfaces, roughnesses for CFM and AFM are in the nanometer range. However, major differences in roughness were determined for laser-prepared surfaces. For enamel, R z (CFM)=2.33 MUm is much higher compared with R z (AFM)=0.09 MUm; in the case of dentin, R z (CFM)=5.35 MUm is also much higher compared with R z (AFM)=0.093 MUm. Information regarding structural properties of surfaces needs real dimensions, particularly for use in dentistry. In this respect, AFM technology provides no additional results that lead to a significant improvement. PMID- 27938452 TI - Transcatheter closure or surgical repair of right pulmonary artery-left atrial fistula. AB - Right pulmonary artery-left atrial fistula is a rare congenitalcardiac anomaly, and only a few articles published so far have reported the diagnosis and treatment of right pulmonary artery-left atrial fistula. In this study, we report three cases of successful transcatheter closure or surgical repair of right pulmonary artery-left atrial fistula. PMID- 27938453 TI - Role of low kilovoltage electrocardiographic-gated multidetector CT in electrophysiological procedures in the paediatric age group. AB - Treatment of arrhythmias by catheter ablation targeting the anatomical foci of arrhythmias by radiofrequency has evolved dramatically in recent years. A road map for the relevant heart structures is an important asset for the success of the procedure and should be obtained before the intervention. This can be achieved by intra-cardiac echocardiography, conventional angiographic methods, multidetector CT, or MRI. The electrophysiological technique comprises a diagnostic procedure and an interventional - therapeutic - procedure. Electrocardiographic-gated multidetector CT is important in the diagnostic session to evaluate the anatomical details in combination with electric activity mapping. This combined protocol provides a unique view of the propagation of electrical activity, either normal or abnormal, over cardiac structures and allows a precise functional and anatomical evaluation to be obtained. In this review, we evaluate the role of electrocardiographic-gated multidetector CT in roadmapping arrhythmias in the paediatric age group, focussing on its strengths; we also evaluated some additional aspects that need further improvement in the future. PMID- 27938454 TI - Cardiac manifestations of congenital LMNA-related muscular dystrophy in children: three case reports and recommendations for care. AB - Skeletal and cardiac muscle laminopathies, caused by mutations in the lamin A/C gene, have a clinical spectrum from congenital LMNA-related muscular dystrophy to later-onset Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, and dilated cardiomyopathy. Although cardiac involvement is observed at all ages, it has only been well described in adults. We present the evolution of cardiac disease in three children with congenital muscular dystrophy presentation of LMNA related muscular dystrophy. In this series, atrial arrhythmia was the presenting cardiac finding in all three patients. Heart failure developed up to 5 years later. Symptoms of right heart failure, including diarrhoea and peripheral oedema, preceded a rapid decline in left ventricular ejection fraction. Recommendations for cardiac surveillance and management in these patients are made. PMID- 27938455 TI - Late-term development of an atrial defect and thrombus formation after device fracture following successful transcatheter closure of an atrial septal defect with a STARFlex device. AB - Development of a new defect following transcatheter closure of an atrial septal defect has yet to be reported. In this study, we present an acutely successful atrial septal defect closure with a STARFlex device, resulting in surgical explantation after discovery of device fracture, thrombus formation, and a second atrial defect 5 years after catheterisation. This case highlights the need for ongoing device surveillance, even in late follow-up. PMID- 27938456 TI - Inhibition and Switching in Healthy Aging: A Longitudinal Study. AB - OBJECTIVES: Discrepant findings of age-related effects between cross-sectional and longitudinal studies on executive function (EF) have been described across different studies. The aim of the present study was to examine longitudinal age effects on inhibition and switching, two key subfunctions of EF, calculated from results on the Color Word Interference Test (CWIT). METHODS: One hundred twenty three healthy aging individuals (average age 61.4 years; 67% women) performed the CWIT up to three times, over a period of more than 6 years. Measures of inhibition, switching, and combined inhibition and switching were analyzed. A longitudinal linear mixed effects models analysis was run including basic CWIT conditions, and measures of processing speed, retest effect, gender, education, and age as predictors. RESULTS: After taking all predictors into account, age added significantly to the predictive value of the longitudinal models of (i) inhibition, (ii) switching, and (iii) combined inhibition and switching. The basic CWIT conditions and the processing speed measure added to the predictive value of the models, while retest effect, gender, and education did not. CONCLUSIONS: The present study on middle-aged to older individuals showed age related decline in inhibition and switching abilities. This decline was retained even when basic CWIT conditions, processing speed, attrition, gender, and education were controlled. (JINS, 2017, 23, 90-97). PMID- 27938457 TI - Hybrid stenting for left ventricular outflow tract obstruction in congenitally corrected transposition of the great arteries. AB - Congenitally corrected transposition of the great arteries is commonly associated with left ventricular outflow tract obstruction. We describe a case of congenitally corrected transposition of the great arteries and previous surgical ventricular septal defect repair with recurrent left ventricular outflow tract obstruction. The patient underwent a hybrid procedure to stent the left ventricular outflow tract, which was successful with no re-intervention through 3 years of follow-up. PMID- 27938458 TI - Unexpected complication of uncovered aortic end in ductal stenting. AB - A newborn with tricuspid atresia and pulmonary atresia underwent ductal stenting. The aortic end of the ductus was not completely covered and was wide open; the baby was discharged on dual antiplatelets. The baby presented after a month with desaturation, and an angiogram showed extensive thrombus in the stent and the right pulmonary artery. The angle formed by the stent with the uncovered aortic end is likely to have precipitated the thrombus. PMID- 27938459 TI - Recent advances in the understanding of the mechanisms underlying postural tachycardia syndrome in children: practical implications for treatment. AB - Postural tachycardia syndrome is defined by a heart rate increment of 40 beats/minute (bpm) (or a heart rate that exceeds 125 bpm) within 10 minutes of change from the supine position to an upright position in the absence of obvious orthostatic hypotension. There are multiple pathophysiological mechanisms that underlie postural tachycardia syndrome, including peripheral denervation, beta receptor supersensitivity, hypovolaemia, and impaired muscle pump. Some children afflicted with postural orthostatic tachycardia syndrome and hypovolaemic dysregulation have been found to have perturbed renin-angiotensin-aldosterone profile, disturbed vascular endothelial function, and abnormal vasodilation. The hyperadrenergic state in some postural tachycardia syndrome patients is likely a driver for orthostatic tachycardia. Other mechanisms include the presence of treatable autonomic neuropathies. An understanding of these pathophysiological mechanisms might be helpful for the effective treatment of postural tachycardia syndrome. PMID- 27938460 TI - Health Service Impact from Mass Gatherings: A Systematic Literature Review. AB - BACKGROUND: During a mass gathering, some participants may receive health care for injuries or illnesses that occur during the event. In-event first responders provide initial assessment and management at the event. However, when further definitive care is required, municipal ambulance services provide additional assessment, treatment, and transport of participants to acute care settings, such as hospitals. The impact on both ambulance services and hospitals from mass gathering events is the focus of this literature review. Aim This literature review aimed to develop an understanding of the impact of mass gatherings on local health services, specifically pertaining to in-event and external health services. METHOD: This research used a systematic literature review methodology. Electronic databases were searched to find articles related to the aim of the review. Articles focused on mass-gathering health, provision of in-event health services, ambulance service transportation, and hospital utilization. RESULTS: Twenty-four studies were identified for inclusion in this review. These studies were all case-study-based and retrospective in design. The majority of studies (n=23) provided details of in-event first responder services. There was variation noted in reporting of the number and type of in-event health professional services at mass gatherings. All articles reported that patients were transported to hospital by the ambulance service. Only nine articles reported on patients presenting to hospital. However, details pertaining to the impact on ambulance and hospital services were not reported. CONCLUSIONS: There is minimal research focusing on the impact of mass gatherings on in-event and external health services, such as ambulance services and hospitals. A recommendation for future mass-gathering research and evaluation is to link patient-level data from in event mass gatherings to external health services. This type of study design would provide information regarding the impact on health services from a mass gathering to more accurately inform future health planning for mass gatherings across the health care continuum. Ranse J , Hutton A , Keene T , Lenson S , Luther M , Bost N , Johnston ANB , Crilly J , Cannon M , Jones N , Hayes C , Burke B . Health service impact from mass gatherings: a systematic literature review. Prehosp Disaster Med. 2017;32(1):71-77. PMID- 27938462 TI - Comparison of distortion product otoacoustic emissions and pure tone audiometry in occupational screening for auditory deficit due to noise exposure. PMID- 27938461 TI - Effect of fortified milk on growth and nutritional status in young children: a systematic review and meta-analysis. AB - OBJECTIVE: Adequate nutrition is critical for optimal growth and development. However, young children may be at risk of nutrient deficiencies when transitioning to weaning foods for a variety of reasons. Supplementation with fortified milk may provide potentially lacking essential nutrients, but effects on growth and nutritional status are yet to be established. DESIGN: Five databases were searched for randomised controlled trials using fortified milk against control milk in young children. Outcomes were growth, body composition and/or biochemical markers. Pooled differences in means were calculated for continuous outcomes and odds ratios for binary outcomes. SETTING: Randomised controlled trials set in any country. SUBJECTS: Otherwise healthy children aged 6 47 months. RESULTS: Fifteen articles met the eligibility criteria. Fortification varied from Fe, Zn, vitamins, essential fatty acids, to pre- and/or probiotics. Frequently reported outcomes were weight, height and Fe status. Studies varied in geographical location, sample size and duration. Fortified milk had minimal effects on weight gain (mean difference=0.17 kg; 95 % CI 0.02, 0.31 kg) compared with control milk. The risk of anaemia was reduced in fortified milk groups (OR=0.32; 95 % CI 0.15, 0.66) compared with control groups. There were no significant effects on height gain, changes in body composition or Hb concentration. CONCLUSIONS: Fortified milk is an effective source of complementary nutrition to supplement children in need when consumed in appropriate amounts in addition to a normal diet. Due to compositional differences, further research on fortified milk is warranted before making global recommendations on benefits for growth and nutritional outcomes in young children. PMID- 27938463 TI - Effectiveness of endoscopic cricopharyngeal myotomy in adults with neurological disease: systematic review. AB - OBJECTIVE: To determine the effectiveness of endoscopic cricopharyngeal myotomy on upper oesophageal sphincter dysfunction in adults with upper oesophageal sphincter dysfunction and neurological disease. DATA SOURCES: Published and unpublished studies with a quasi-experimental design investigating endoscopic cricopharyngeal myotomy effects on upper oesophageal sphincter dysfunction in humans were considered eligible. Electronic databases, grey literature and reference lists of included studies were systematically searched. REVIEW METHODS: Data were extracted by two independent reviewers. Methodological quality was assessed independently using the PEDro scale and MINORS tool. RESULTS: Of 2938 records identified, 2 studies were eligible. Risk of bias assessment indicated areas of methodological concern in the literature. Statistical analysis was not possible because of the limited number of eligible studies. CONCLUSION: No determinations could be made regarding endoscopic cricopharyngeal myotomy effectiveness in the cohort of interest. Reliable and valid evidence on the following is required to support increasing clinical usage of endoscopic cricopharyngeal myotomy: optimal candidacy selection; standardised post-operative management protocol; complications; and endoscopic cricopharyngeal myotomy effects on aspiration of food and laryngeal penetration, mean upper oesophageal sphincter resting pressure and quality of life. PMID- 27938464 TI - One hundred years ago: the physician magician Blakesley presented his ethmoid forceps. AB - BACKGROUND: The Blakesley fenestrated ethmoid forceps, eponymously named after Theodore Seward Blakesley, belong today in every set of endonasal surgical instruments. This study aimed to go back to Blakesley's original description, and to follow its introduction, variations and acceptation by rhinosurgeons. METHOD: Historical review of literature. RESULTS: In 1915, Blakesley described two nasal instruments: a submucous septum resection instrument and an ethmoid instrument. The history of the ethmoid instrument is in close relationship to another quite similar one described by Moriz Weil. The difference between the Weil and the Blakesley ethmoid forceps lies essentially in the base of the cutting jaws, which are narrower in Weil's instrument. CONCLUSION: Blakesley's eponym must only be used for the instrument without the narrower base of the cutting jaws. PMID- 27938465 TI - Surgical treatment of head and neck cancers in the ancient world. PMID- 27938466 TI - Otological symptoms and audiometric findings in patients with temporomandibular disorders: Costen's syndrome revisited. AB - OBJECTIVE: Otological symptoms (otalgia, subjective hearing loss, blocked ear sensation, tinnitus and vertigo) associated with temporomandibular disorders are documented features of Costen's syndrome. However, the origin of these symptoms and the causes of hearing loss are unknown. This study aimed to characterise hearing loss in a large number of patients with temporomandibular disorders. The causes of these symptoms were explored in patients with otological symptoms and normal audiometric findings. METHODS: A prospective case study and literature review were performed. The audiometric features of 104 temporomandibular disorder patients were compared with those of 110 control participants. RESULTS: A large proportion of temporomandibular disorder patients had several otological symptoms. Twenty-five per cent of unilateral or bilateral temporomandibular disorder patients had either unilateral (ipsilateral) or bilateral hearing loss; respectively, which was usually mild (p = 0.001). Hearing loss was predominantly sensorineural. CONCLUSION: The main cause of otological symptoms (apart from otalgia) and of audiometric findings in temporomandibular disorder patients is postulated to be an altered middle-ear to inner-ear pressure equilibrium. PMID- 27938467 TI - Platelet-rich plasma in otolaryngology. AB - BACKGROUND: Platelet-rich plasma is a novel material that is being used more frequently in many surgical specialties. METHODS: A literature review on the current and potential uses of platelet-rich plasma in otolaryngology was performed. RESULTS: There is limited evidence on the use of platelet-rich plasma in otolaryngology compared with other specialties: only 11 studies on various subspecialties (otology, rhinology and laryngology) were included in the final review. CONCLUSION: Based on the limited number of studies, we cannot draw safe conclusions about the value of platelet-rich plasma in otolaryngology. Nevertheless, the available literature suggests that platelet-rich plasma holds promise for future research and may have a number of clinical applications. PMID- 27938468 TI - Adenoid cystic carcinoma, dynamic Eustachian tube imaging and a touch of magic. PMID- 27938469 TI - The Birth and Growth of the National Ambulance Service in Ghana. AB - : Introduction This study aimed to document the growth and challenges encountered in the decade since inception of the National Ambulance Service (NAS) in Ghana, West Africa. By doing so, potentially instructive examples for other low- and middle-income countries (LMICs) planning a formal prehospital care system or attempting to identify ways to improve existing emergency services could be identified. METHODS: Data routinely collected by the Ghana NAS from 2004-2014 were described, including: patient demographics, reason for the call, response location, target destination, and ti1mes of service. Additionally, the organizational structure and challenges encountered during the development and maturation of the NAS were reported. RESULTS: In 2004, the NAS piloted operations with 69 newly trained emergency medical technicians (EMTs), nine ambulances, and seven stations. The NAS expanded service delivery with 199 ambulances at 128 stations operated by 1,651 EMTs and 47 administrative and maintenance staff in 2014. In 2004, nine percent of the country was covered by NAS services; in 2014, 81% of Ghana was covered. Health care transfers and roadside responses comprised the majority of services (43%-80% and 10%-57% by year, respectively). Increased mean response time, stable case holding time, and shorter vehicle engaged time reflect greater response ranges due to increased service uptake and improved efficiency of ambulance usage. Specific internal and external challenges with regard to NAS operations also were described. CONCLUSION: The steady growth of the NAS is evidence of the need for Emergency Medical Services and the effects of sound planning and timely responses to changes in program indicators. The way forward includes further capacity building to increase the number of scene responses, strengthening ties with local health facilities to ensure timely emergency medical care and appropriateness of transfers, assuring a more stable funding stream, and improving public awareness of NAS services. Zakariah A , Stewart BT , Boateng E , Achena C , Tansley G , Mock C . The birth and growth of the National Ambulance Service in Ghana. Prehosp Disaster Med. 2017;32(1):83-93. PMID- 27938471 TI - Human Recombinant Antithrombin (ATryn(r)) Administration Improves Survival and Prevents Intravascular Coagulation After Intraportal Islet Transplantation in a Piglet Model. AB - Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1DM). However, pancreatic islet inflammation after transplantation induced by innate immune responses is likely to hinder graft function. This is mediated by incompatibility between islets and the blood interface, known as instant blood-mediated inflammatory reaction (IBMIR). Herein we hypothesized that portal venous administration of islet cells with human recombinant antithrombin (ATryn(r)), a serine protease inhibitor (serpin), which plays a central role in the physiological regulation of coagulation and exerts indirect anti-inflammatory activities, may offset coagulation abnormalities such as disseminated intravascular coagulation (DIC) and IBMIR. The current prospective, randomized experiment was conducted using an established preclinical pig model. Three groups were constituted for digested pancreatic tissue transplantation (0.15 ml/kg): control, NaCl 0.9% (n = 7); gold standard, heparin (25 UI/kg) (n = 7); and human recombinant ATryn(r) (500 UI/kg) (n = 7). Blood samples were collected over time (T0 to 24 h), and biochemical, coagulation, and inflammatory parameters were evaluated. In both the control and heparin groups, one animal died after a portal thrombosis, while no deaths occurred in the ATryn(r)-treated group. As expected, islet transplantation was associated with an increase in plasma IL-6 or TNF-alpha levels in all three groups. However, DIC was only observed in the control group, an effect that was suppressed after ATryn(r) administration. ATryn(r) administration increased antithrombin activity by 800%, which remained at 200% for the remaining period of the study, without any hemorrhagic complications. These studies suggest that coadministration of ATryn(r) and pancreatic islets via intraportal transplantation may be a valuable therapeutic approach for DIC without risk for islets and subjects. PMID- 27938473 TI - Are Adipose-Derived Stem Cells From Liver Falciform Ligaments Another Possible Source of Mesenchymal Stem Cells? AB - Falciform ligaments in the liver are surrounded by adipose tissue. We investigated the capability of adipose-derived stem cells from human liver falciform ligaments (hLF-ADSCs) to differentiate into hepatic-type cells and confirmed the functional capacity of the cells. Mesenchymal stem cells (MSCs) were isolated from the liver falciform ligament and abdominal subcutaneous adipose tissue in patients undergoing partial hepatectomy for liver disease. Cells were cultivated in MSC culture medium. Properties of MSCs were confirmed by flow cytometry, RT-PCR analysis, immunocytochemistry assays, and multilineage differentiation. Hepatic induction was performed using a three-step differentiation protocol with various growth factors. Morphology, capacity for expansion, and characteristics were similar between hLF-ADSCs and adipose-derived stem cells from human abdominal subcutaneous adipose tissue (hAS-ADSCs). However, hematopoietic- and mesenchymal-epithelial transition (MET)-related surface markers (CD133, CD34, CD45, and E-cadherin) had a higher expression in hLF-ADSCs. The hepatic induction marker genes had a higher expression in hLF-ADSCs on days 7 and 10 after the hepatic induction. Albumin secretion was similar between hLF ADSCs and hAS-ADSCs at 20 days after the hepatic induction. The hLF-ADSCs had a different pattern of surface marker expression relative to hAS-ADSCs. However, proliferation, multilineage capacity, and hepatic induction were similar between the cell types. Accordingly, it may be a useful source of MSCs for patients with liver disease. PMID- 27938474 TI - Muse Cells, Nontumorigenic Pluripotent-Like Stem Cells, Have Liver Regeneration Capacity Through Specific Homing and Cell Replacement in a Mouse Model of Liver Fibrosis. AB - Muse cells, a novel type of nontumorigenic pluripotent-like stem cells, reside in the bone marrow, skin, and adipose tissue and are collectable as cells positive for pluripotent surface marker SSEA-3. They are able to differentiate into cells representative of all three germ layers. The capacity of intravenously injected human bone marrow-derived Muse cells to repair an immunodeficient mouse model of liver fibrosis was evaluated in this study. The cells exhibited the ability to spontaneously differentiate into hepatoblast/hepatocyte lineage cells in vitro. They demonstrated a high migration capacity toward the serum and liver section of carbon tetrachloride-treated mice in vitro. In vivo, they specifically accumulated in the liver, but not in other organs except, to a lesser extent, in the lungs at 2 weeks after intravenous injection in the liver fibrosis model. After homing, Muse cells spontaneously differentiated in vivo into HepPar-1 (71.1 +/- 15.2%), human albumin (54.3 +/- 8.2%), and anti-trypsin (47.9 +/- 4.6%) positive cells without fusing with host hepatocytes, and expressed mature functional markers such as human CYP1A2 and human Glc-6-Pase at 8 weeks after injection. Recovery in serum, total bilirubin, and albumin and significant attenuation of fibrosis were recognized with statistical differences between the Muse cell-transplanted group and the control groups, which received the vehicle or the same number of a non-Muse cell population of MSCs (MSCs in which Muse cells were eliminated). Thus, unlike ESCs and iPSCs, Muse cells are unique in their efficient migration and integration into the damaged liver after intravenous injection, nontumorigenicity, and spontaneous differentiation into hepatocytes, rendering induction into hepatocytes prior to transplantation unnecessary. They may repair liver fibrosis by two simple steps: expansion after collection from the bone marrow and intravenous injection. A therapeutic strategy such as this is feasible and may provide significant advancements toward liver regeneration in patients with liver disease. PMID- 27938475 TI - Imbalanced Production of Reactive Oxygen Species and Mitochondrial Antioxidant SOD2 in Fabry Disease-Specific Human Induced Pluripotent Stem Cell-Differentiated Vascular Endothelial Cells. AB - Fabry disease (FD) is an X-linked inherited lysosomal storage disease caused by alpha-galactosidase A (GLA) deficiency. Progressive intracellular accumulation of globotriaosylceramide (Gb3) is considered to be pathogenically responsible for the phenotype variability of FD that causes cardiovascular dysfunction; however, molecular mechanisms underlying the impairment of FD-associated cardiovascular tissues remain unclear. In this study, we reprogrammed human induced pluripotent stem cells (hiPSCs) from peripheral blood cells of patients with FD (FD-iPSCs); subsequently differentiated them into vascular endothelial-like cells (FD-ECs) expressing CD31, VE-cadherin, and vWF; and investigated their ability to form vascular tube-like structures. FD-ECs recapitulated the FD pathophysiological phenotype exhibiting intracellular Gb3 accumulation under a transmission electron microscope. Moreover, compared with healthy control iPSC-derived endothelial cells (NC-ECs), reactive oxygen species (ROS) production considerably increased in FD-ECs. Microarray analysis was performed to explore the possible mechanism underlying Gb3 accumulation-induced ROS production in FD-ECs. Our results revealed that superoxide dismutase 2 (SOD2), a mitochondrial antioxidant, was significantly downregulated in FD-ECs. Compared with NC-ECs, AMPK activity was significantly enhanced in FD-ECs. Furthermore, to investigate the role of Gb3 in these effects, human umbilical vein endothelial cells (HUVECs) were treated with Gb3. After Gb3 treatment, we observed that SOD2 expression was suppressed and AMPK activity was enhanced in a dose-dependent manner. Collectively, our results indicate that excess accumulation of Gb3 suppressed SOD2 expression, increased ROS production, enhanced AMPK activation, and finally caused vascular endothelial dysfunction. Our findings suggest that dysregulated mitochondrial ROS may be a potential target for treating FD. PMID- 27938478 TI - A Novel CXCR4 Antagonist CX549 Induces Neuroprotection in Stroke Brain. AB - C-X-C chemokine receptor type 4 (CXCR4) is a receptor for a pleiotropic chemokine CXCL12. Previous studies have shown that the acute administration of the CXCR4 antagonist AMD3100 reduced neuroinflammation in stroke brain and mobilized bone marrow hematopoietic stem cells (HSCs). The purpose of this study was to characterize the neuroprotective and neurotrophic effect of a novel CXCR4 antagonist CX549. We demonstrated that CX549 had a higher affinity for CXCR4 and was more potent than AMD3100 to inhibit CXCL12-mediated chemotaxis in culture. CX549 effectively reduced the activation of microglia and improved neuronal survival after injury in neuron/microglia cocultures. Early poststroke treatment with CX549 significantly improved behavioral function, reduced brain infarction, and suppressed the expression of inflammatory markers. Compared to AMD3100, CX549 has a higher affinity for CXCR4, is more efficient to mobilize HSCs for transplantation, and induces behavioral improvement. Our data support that CX549 is a potent anti-inflammatory agent, is neuroprotective against ischemic brain injury, and may have clinical implications for the treatment of stroke. PMID- 27938479 TI - Human Bone Progenitor Cells for Clinical Application: What Kind of Immune Reaction Does Fetal Xenograft Tissue Trigger in Immunocompetent Rats? AB - The potential of human fetal bone cells for successful bone regeneration has been shown in vivo. In particular, it has been demonstrated that the seeding of these cells in porous poly-(l-lactic acid)/beta-tricalcium phosphate scaffolds improved the bone formation compared to cell-free scaffolds in skulls of rats. However, even if the outcome is an improvement of bone formation, a thorough analysis concerning any immune responses, due to the implantation of a xenograft tissue, is not known. As the immune response and skeletal system relationship may contribute to either the success or failure of an implant, we were interested in evaluating the presence of any immune cells and specific reactions of human fetal cells (also called human bone progenitor cells) once implanted in femoral condyles of rats. For this purpose, (1) cell-free scaffolds, (2) human bone progenitor cells, or (3) osteogenic human bone progenitor cells within scaffolds were implanted over 3, 7, 14 days, and 12 weeks. The key finding is that human bone progenitor cells and osteogenic human bone progenitor cells do not trigger any particular specific immune reactions in immunocompetent rats but are noted to delay some bone formation. PMID- 27938480 TI - Human Amnion Epithelial Cells Protect Against White Matter Brain Injury After Repeated Endotoxin Exposure in the Preterm Ovine Fetus. AB - Intrauterine inflammation is a significant cause of injury to the developing fetal brain. Using a preterm fetal sheep model of in utero infection, we asked whether human amnion epithelial cells (hAECs) were able to reduce inflammation induced fetal brain injury. Surgery was undertaken on pregnant sheep at ~105 days gestation (term is 147 days) for implantation of vascular catheters. Lipopolysaccharide (LPS; 150 ng/kg bolus) or saline was administered IV at 109, 110, and 111 days. Sixty million fluorescent-labeled hAECs were administered at 110, 111, and 112 days gestation via the brachial artery catheter. Brains were collected at 114 days for histological assessment. hAECs were observed within the cortex, white matter, and hippocampus. Compared to control lambs, LPS administration was associated with significant and widespread fetal brain inflammation and injury as evidenced by increased number of activated microglia in the periventricular white matter (p = 0.02), increased pyknosis, cell degeneration (p = 0.01), and a nonsignificant trend of fewer oligodendrocytes in the subcortical and periventricular white matter. Administration of hAECs to LPS treated animals was associated with a significant mitigation in both inflammation and injury as evidenced by fewer activated microglia (p = 0.03) and pyknotic cells (p = 0.03), significantly more oligodendrocytes in the subcortical and periventricular white matter (p = 0.01 and 0.02, respectively), and more myelin basic protein-positive cells within the periventricular white matter (p = 0.02). hAEC administration to fetal sheep exposed to multiple doses of LPS dampens the resultant fetal inflammatory response and mitigates associated brain injury. PMID- 27938481 TI - miR-133b Inhibits Cell Growth, Migration, and Invasion by Targeting MMP9 in Non Small Cell Lung Cancer. AB - Although increasing evidence indicates that the deregulation of microRNAs (miRNAs) contributes to tumorigenesis and invasion, little is known about the role of miR-133b in human non-small cell lung cancer (NSCLC). In the present study, we revealed that the introduction of miR-133b dramatically suppressed NSCLC cell growth, migration, and invasion in vitro. On the contrary, miR-133b inhibitors promoted cell growth, migration, and invasion in vitro. Further studies revealed that matrix metallopeptidase 9 (MMP9) is a direct target gene of miR-133b. Silencing MMP9 inhibited cell growth, migration, and invasion of NSCLC cells, which was consistent with the effect of miR-133b overexpression. In clinical specimens, reduced miR-133b was an unfavorable factor and negatively correlated with MMP9 expression. Our studies demonstrate that miR-133b inhibits cell growth, migration, and invasion by targeting MMP9 in NSCLC. PMID- 27938482 TI - Repetitive and Prolonged Omega-3 Fatty Acid Treatment After Traumatic Brain Injury Enhances Long-Term Tissue Restoration and Cognitive Recovery. AB - Traumatic brain injury (TBI) is one of the most disabling clinical conditions that could lead to neurocognitive disorders in survivors. Our group and others previously reported that prophylactic enrichment of dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) markedly ameliorate cognitive deficits after TBI. However, it remains unclear whether a clinically relevant therapeutic regimen with n-3 PUFAs administered after TBI would still offer significant improvement of long-term cognitive recovery. In the present study, we employed the decline of spatial cognitive function as a main outcome after TBI to investigate the therapeutic efficacy of post-TBI n-3 PUFA treatment and the underlying mechanisms. Mice were subjected to sham operation or controlled cortical impact, followed by random assignment to receive the following four treatments: (1) vehicle control; (2) daily intraperitoneal injections of n-3 PUFAs for 2 weeks, beginning 2 h after TBI; (3) fish oil dietary supplementation throughout the study, beginning 1 day after TBI; or (4) combination of treatments (2) and (3). Spatial cognitive deficits and chronic brain tissue loss, as well as endogenous brain repair processes such as neurogenesis, angiogenesis, and oligodendrogenesis, were evaluated up to 35 days after TBI. The results revealed prominent spatial cognitive deficits and massive tissue loss caused by TBI. Among all mice receiving post-TBI n-3 PUFA treatments, the combined treatment of fish oil dietary supplement and n-3 PUFA injections demonstrated a reproducible beneficial effect in attenuating cognitive deficits although without reducing gross tissue loss. Mechanistically, the combined treatment promoted post-TBI restorative processes in the brain, including generation of immature neurons, microvessels, and oligodendrocytes, each of which was significantly correlated with the improved cognitive recovery. These results indicated that repetitive and prolonged n-3 PUFA treatments after TBI are capable of enhancing brain remodeling and could be developed as a potential therapy to treat TBI victims in the clinic. PMID- 27938483 TI - Transplantation of Mesenchymal Stromal Cells in Patients With Amyotrophic Lateral Sclerosis: Results of Phase I/IIa Clinical Trial. AB - Amyotrophic lateral sclerosis (ALS) is a progressive untreatable neurodegenerative disorder, leading to the death of the cortical and spinal motoneurons (MNs). Bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) may represent a new approach to slowing down the progression of ALS by providing neurotrophic support to host MNs and by having an anti-inflammatory effect. We have designed a prospective, nonrandomized, open-label clinical trial (phase I/IIa, EudraCT No. 2011-000362-35) to assess the safety and efficacy of autologous multipotent BM-MSCs in ALS treatment. Autologous BM-MSCs were isolated and expanded under GMP conditions. Patients received 15 +/- 4.5 * 106 of BM-MSCs via lumbar puncture into the cerebrospinal fluid. Patients were monitored for 6 months before treatment and then for an 18-month follow-up period. Potential adverse reactions were assessed, and the clinical outcome was evaluated by the ALS functional rating scale (ALSFRS), forced vital capacity (FVC), and weakness scales (WSs) to assess muscle strength on the lower and upper extremities. In total, 26 patients were enrolled in the study and were assessed for safety; 23 patients were suitable for efficacy evaluation. After intrathecal BM-MSC application, about 30% of the patients experienced a mild to moderate headache, resembling the headaches after a standard lumbar puncture. No suspected serious adverse reactions (SUSAR) were observed. We found a reduction in ALSFRS decline at 3 months after application (p < 0.02) that, in some cases, persisted for 6 months ( p < 0.05). In about 80% of the patients, FVC values remained stable or above 70% for a time period of 9 months. Values of WS were stable in 75% of patients at 3 months after application. Our results demonstrate that the intrathecal application of BM-MSCs in ALS patients is a safe procedure and that it can slow down progression of the disease. PMID- 27938484 TI - Mesenchymal Stem Cells: The Magic Cure for Intraventricular Hemorrhage? AB - Severe intraventricular hemorrhage (IVH) remains a major cause of mortality and long-term neurologic morbidities in premature infants, despite recent advances in neonatal intensive care medicine. Several preclinical studies have demonstrated the beneficial effects of mesenchymal stem cell (MSC) transplantation in attenuating brain injuries resulting from severe IVH. Because there currently exists no effective intervention for severe IVH, the therapeutic potential of MSC transplantation in this intractable and devastating disease is creating excitement in this field. This review summarizes recent progress in stem cell research for treating neonatal brain injury due to severe IVH, with a particular focus on preclinical data concerning important issues, such as mechanism of protective action and determining optimal source, route, timing, and dose of MSC transplantation, and on the translation of these preclinical study results to a clinical trial. PMID- 27938485 TI - Neuroprotection of Granulocyte Colony-Stimulating Factor for Early Stage Parkinson's Disease. AB - Parkinson's disease (PD) is a slowly progressive neurodegenerative disease. Both medical and surgical choices provide symptomatic treatment. Granulocyte colony stimulating factor (G-CSF), a conventional treatment for hematological diseases, has demonstrated its effectiveness in acute and chronic neurological diseases through its anti-inflammatory and antiapoptosis mechanisms. Based on previous in vitro and in vivo studies, we administered a lower dose (3.3 MUg/kg) G-CSF injection for 5 days and six courses for 1 year in early-stage PD patients as a phase I trial. The four PD patient's mean unified PD rating scale motor scores in medication off status remained stable from 23 before the first G-CSF injection to 22 during the 2-year follow-up. 3,4-Dihydroxy-6-18F-fluoro-l-phenylalanine (18F DOPA) positron emission tomography (PET) studies also revealed an annual 3.5% decrease in radiotracer uptake over the caudate nucleus and 7% in the putamen, both slower than those of previous reports of PD. Adverse effects included transient muscular-skeletal pain, nausea, vomiting, and elevated liver enzymes. Based on this preliminary report, G-CSF seems to alleviate disease deterioration for early stage PD patients. The effectiveness of G-CSF was possibly due to its amelioration of progressive dopaminergic neuron degeneration. PMID- 27938486 TI - A Comparison of Exogenous Labels for the Histological Identification of Transplanted Neural Stem Cells. AB - The interpretation of cell transplantation experiments is often dependent on the presence of an exogenous label for the identification of implanted cells. The exogenous labels Hoechst 33342, 5-bromo-2'-deoxyuridine (BrdU), PKH26, and Qtracker were compared for their labeling efficiency, cellular effects, and reliability to identify a human neural stem cell (hNSC) line implanted intracerebrally into the rat brain. Hoechst 33342 (2 mg/ml) exhibited a delayed cytotoxicity that killed all cells within 7 days. This label was hence not progressed to in vivo studies. PKH26 (5 MUM), Qtracker (15 nM), and BrdU (0.2 MUM) labeled 100% of the cell population at day 1, although BrdU labeling declined by day 7. BrdU and Qtracker exerted effects on proliferation and differentiation. PKH26 reduced viability and proliferation at day 1, but this normalized by day 7. In an in vitro coculture assay, all labels transferred to unlabeled cells. After transplantation, the reliability of exogenous labels was assessed against the gold standard of a human-specific nuclear antigen (HNA) antibody. BrdU, PKH26, and Qtracker resulted in a very small proportion (<2%) of false positives, but a significant amount of false negatives (~30%), with little change between 1 and 7 days. Exogenous labels can therefore be reliable to identify transplanted cells without exerting major cellular effects, but validation is required. The interpretation of cell transplantation experiments should be presented in the context of the label's limitations. PMID- 27938487 TI - Conceptual Design and Procedure for an Autonomous Intramyocardial Injection Catheter. AB - This article discusses existing catheter systems and proposes a conceptual design and procedure for an autonomous cell injection catheter for the purpose of transferring committed myogenic or undifferentiated stem cells into the infarct boundary zones of the left ventricle. Operation of existing catheters used for cell delivery is far from optimal. Commercial injection catheters available are handheld devices operated manually by means of tip deflection and torque capabilities. Interventionists require a hefty learning curve and often encounter difficulties in catheter stabilization and infarct detection, resulting in lengthy operation times and nonprecise injections. We examined current technologies and proposed a design incorporating robotic positional control, feedback signals, and an adaptable operational sequence to overcome these problems. The design provides the basis for robotic catheter construction that is able to autonomously assist the physician in transferring myogenic cells to the left ventricle infarct boundary zones. PMID- 27938488 TI - A Subpopulation of Dopaminergic Neurons Coexpresses Serotonin in Ventral Mesencephalic Cultures But Not After Intrastriatal Transplantation in a Rat Model of Parkinson's Disease. AB - Cell replacement therapy is a promising avenue into the investigation and treatment of Parkinson's disease (PD), and in some cases, significant long-term motor improvements have been demonstrated. The main source of donor tissue is the human fetal ventral mesencephalon (FVM), which consists of a mixed neuronal population, and its heterogeneity likely contributes to the inconsistent outcome observed in clinical trials. Therefore, detailed knowledge about the neuronal subpopulations in the VM seems essential for successful cell transplantation. Interestingly, it has been reported that some tyrosine hydroxylase-positive (TH+) neurons in the VM of adult rats and in cultured midbrain-derived neuroblasts coexpress additional neurotransmitters. Thus, the present study investigated, by means of colocalization analyses, the possible expression of GABA or serotonin in TH+ neurons. For that purpose, both fetal rat and human dissociated, organotypic and neurosphere FVM cultures as well as an animal model of PD were investigated. In dissociated rat FVM cultures, approximately 30% of the TH+ neurons coexpressed serotonin, while no colocalization with GABA was observed. Interestingly, coexpression of TH and serotonin was found to be dependent on the time in culture, the plating density, and the exposure to neurotrophic factors, that is, higher cell densities and treatment with brain-derived neurotrophic factor resulted in a significantly reduced coexpression rate. Notably, even though approximately 30% of the dopaminergic neurons in the donor tissue coexpressed serotonin, no colocalization could be detected in grafts 1 month after intrastriatal transplantation into hemiparkinsonian rats. In conclusion, a significant and susceptible subpopulation of dopaminergic neurons in FVM tissues coexpresses serotonin. This might have potential implications for the future selection and handling of cells prior to transplantation in PD. PMID- 27938489 TI - A Comparative Study of Three Different Types of Stem Cells for Treatment of Rat Spinal Cord Injury. AB - Three different sources of human stem cells-bone marrow-derived mesenchymal stem cells (BM-MSCs), neural progenitors (NPs) derived from immortalized spinal fetal cell line (SPC-01), and induced pluripotent stem cells (iPSCs)-were compared in the treatment of a balloon-induced spinal cord compression lesion in rats. One week after lesioning, the rats received either BM-MSCs (intrathecally) or NPs (SPC-01 cells or iPSC-NPs, both intraspinally), or saline. The rats were assessed for their locomotor skills (BBB, flat beam test, and rotarod). Morphometric analyses of spared white and gray matter, axonal sprouting, and glial scar formation, as well as qPCR and Luminex assay, were conducted to detect endogenous gene expression, while inflammatory cytokine levels were performed to evaluate the host tissue response to stem cell therapy. The highest locomotor recovery was observed in iPSC-NP-grafted animals, which also displayed the highest amount of preserved white and gray matter. Grafted iPSC-NPs and SPC-01 cells significantly increased the number of growth-associated protein 43 (GAP43+) axons, reduced astrogliosis, downregulated Casp3 expression, and increased IL-6 and IL-12 levels. hMSCs transiently decreased levels of inflammatory IL-2 and TNF-alpha. These findings correlate with the short survival of hMSCs, while NPs survived for 2 months and matured slowly into glia- and tissue-specific neuronal precursors. SPC-01 cells differentiated more in astroglial phenotypes with a dense structure of the implant, whereas iPSC-NPs displayed a more neuronal phenotype with a loose structure of the graft. We concluded that the BBB scores of iPSC-NP- and hMSC injected rats were superior to the SPC-01-treated group. The iPSC-NP treatment of spinal cord injury (SCI) provided the highest recovery of locomotor function due to robust graft survival and its effect on tissue sparing, reduction of glial scarring, and increased axonal sprouting. PMID- 27938490 TI - Transgenic Expression of Glucagon-Like Peptide-1 (GLP-1) and Activated Muscarinic Receptor (M3R) Significantly Improves Pig Islet Secretory Function. AB - Porcine islets show notoriously low insulin secretion levels in response to glucose stimulation. While this is somehow expected in the case of immature islets isolated from fetal and neonatal pigs, disappointingly low secretory responses are frequently reported in studies using in vitro-maturated fetal and neonatal islets and even fully differentiated adult islets. Herein we show that beta-cell-specific expression of a modified glucagon-like peptide-1 (GLP-1) and of a constitutively activated type 3 muscarinic receptor (M3R) efficiently amplifies glucose-stimulated insulin secretion (GSIS). Both adult and neonatal isolated pig islets were treated with adenoviral expression vectors carrying sequences encoding for GLP-1 and/or M3R. GSIS from transduced and control islets was evaluated during static incubation and dynamic perifusion assays. While expression of GLP-1 did not affect basal or stimulated insulin secretion, activated M3R produced a twofold increase in both first and second phases of GSIS. Coexpression of GLP-1 and M3R caused an even greater increase in the secretory response, which was amplified fourfold compared to controls. In conclusion, our work highlights pig islet insulin secretion deficiencies and proposes concomitant activation of cAMP-dependent and cholinergic pathways as a solution to ameliorate GSIS from pig islets used for transplantation. PMID- 27938492 TI - Histone Acetyltransferase 1 Promotes Cell Proliferation and Induces Cisplatin Resistance in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant diseases in the world. Mutations, overexpression, and improper recruitment of HATs can lead to tumorigenesis. HAT1 is the first histone acetyltransferase identified and is related with developing HCC, but the mechanism is still unclear. Interestingly, we found that HAT1 was upregulated in HCC patient specimens and showed that its upregulation facilitates HCC cell growth in vitro and in vivo. Moreover, we demonstrated that HAT1 promoted glycolysis in HCC cells and knockdown of HAT1 sensitized HCC cells to apoptotic death induced by cisplatin. Our results suggest that HAT1 might act as an oncogenic protein promoting cell proliferation and inducing cisplatin resistance in HCC, and targeting HAT1 represents a viable strategy for effective treatment of advanced HCC. PMID- 27938491 TI - Regulator of Cell Cycle (RGCC) Expression During the Progression of Alzheimer's Disease. AB - Unscheduled cell cycle reentry of postmitotic neurons has been described in cases of mild cognitive impairment (MCI) and Alzheimer's disease (AD) and may form a basis for selective neuronal vulnerability during disease progression. In this regard, the multifunctional protein regulator of cell cycle (RGCC) has been implicated in driving G1/S and G2/M phase transitions through its interactions with cdc/cyclin-dependent kinase 1 (cdk1) and is induced by p53, which mediates apoptosis in neurons. We tested whether RGCC levels were dysregulated in frontal cortex samples obtained postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), MCI, or AD. RGCC mRNA and protein levels were upregulated by ~50%-60% in MCI and AD compared to NCI, and RGCC protein levels were associated with poorer antemortem global cognitive performance in the subjects examined. To test whether RGCC might regulate neuronal cell cycle reentry and apoptosis, we differentiated neuronotypic PC12 cultures with nerve growth factor (NGF) followed by NGF withdrawal to induce abortive cell cycle activation and cell death. Experimental reduction of RGCC levels increased cell survival and reduced levels of the cdk1 target cyclin B1. RGCC may be a candidate cell cycle target for neuroprotection during the onset of AD. PMID- 27938493 TI - Thrombospondin-1-Derived Peptide RFYVVMWK Improves the Adhesive Phenotype of CD34+ Cells From Atherosclerotic Patients With Type 2 Diabetes. AB - CD34+ progenitor cells are growing in use for vascular repair. However, in diabetic individuals with cardiovascular diseases, these cells have dysfunctional engraftment capabilities, which compromise their use for autologous cell therapy. The thrombospondin-1-derived peptide RFYVVMWK has previously been reported to stimulate cell adhesiveness through CD47 and integrin activation pathways. Our aim was to test whether RFYVVMWK preconditioning could modulate CD34+ cell phenotype and enhance its proadhesive properties in diabetic patients. Peripheral blood mononuclear CD34+ cells isolated from 40 atherosclerotic patients with type 2 diabetes (T2D; n = 20) or without (non-T2D; n = 20) were preconditioned with 30 MUM RFYVVMWK or truncated peptide RFYVVM. CD34+ cell adhesion was assessed on a vitronectin-collagen matrix and on TNF-alpha or IL-1beta-stimulated HUVEC monolayers. Adhesion receptors, platelet/CD34+ cell conjugates, and cell viability were analyzed by flow cytometry and confocal microscopy. RFYVVMWK increased the adhesion of T2D CD34+ cells by eightfold to the vitronectin collagen matrix (p < 0.001) corresponding to a threefold increase compared to unstimulated non-T2D CD34+ cells. The peptide induced the formation of platelet/CD34+ conjugates and increased the expression of TSP-1, CD29, CD51/CD61, and CD62P in both T2D and non-T2D cells. However, RFYVVMWK treatment did not affect the viability/apoptosis of CD34+ progenitor cells. In conclusion, priming CD34+ cells with RFYVVMWK may enhance their vascular engraftment during autologous proangiogenic cell therapy. PMID- 27938494 TI - CD34 Antigen and the MPL Receptor Expression Defines a Novel Class of Human Cord Blood-Derived Primitive Hematopoietic Stem Cells. AB - In the murine hematopoietic stem cell (HSC) compartment, thrombopoietin (THPO)/MPL (THPO receptor) signaling plays an important role in the maintenance of adult quiescent HSCs. However, the role of THPO/MPL signaling in the human primitive HSC compartment has not yet been elucidated. We have identified very primitive human cord blood (CB)-derived CD34- severe combined immunodeficiency (SCID)-repopulating cells (SRCs) using the intra-bone marrow injection method. In this study, we investigated the roles of the MPL expression in the human primitive HSC compartment. The SRC activities of the highly purified CB-derived 18Lin-CD34+/-MPL+/- cells were analyzed using NOG mice. In the primary recipient mice, nearly all mice that received CD34+/-MPL+/- cells were repopulated with human CD45+ cells. Nearly all of these mice that received CD34+MPL+/- and CD34 MPL- cells showed a secondary repopulation. Interestingly, the secondary recipient mice that received CD34+/-MPL- cells showed a distinct tertiary repopulation. These results clearly indicate that the CD34+/- SRCs not expressing MPL sustain a long-term (LT) (>1 year) human cell repopulation in NOG mice. Moreover, CD34- SRCs generate CD34+CD38-CD90+ SRCs in vitro and in vivo. These findings provide a new concept that CD34-MPL- SRCs reside at the apex of the human HSC hierarchy. PMID- 27938495 TI - Efficacy of Two Delivery Routes for Transplanting Human Neural Progenitor Cells (NPCs) Into the Spastic Han-Wistar Rat, a Model of Ataxia. AB - An emerging avenue for recalcitrant neurodegenerative disease treatment is neural progenitor cell (NPC) transplantation. In this study, we investigated the effectiveness of two different delivery routes of human-derived NPC inoculation: injection into the common carotid artery or unilateral stereotactic implantation into the degenerating cerebellum and hippocampus of spastic Han-Wistar (sHW) rats, a model of ataxia. At 30 days of age, sHW mutants were implanted with osmotic pumps preloaded with cyclosporine. Ten days after pump implantation, the animals were given either 3,000,000 live human-derived NPCs (hNPCs; n = 12) or 3,000,000 dead NPCs (dNPCs; n = 12) injected into the common carotid artery, or were given two unilateral implantations of 500,000 hNPCs into the cerebellum and 500,000 hNPCs into the hippocampus of each sHW rat (n = 12) or 500,000 dNPCs by unilateral implantation into the cerebellum and hippocampus (n = 12). We also compared treated sHW rats to untreated sHW rats: normal rats (n = 12) and sibling sHW rats (n = 12). Motor activity and animal weights were monitored every 5 days to ascertain effectiveness of the two types of delivery methods compared to the untreated mutant and normal animals. Mutant rats with hNPC implantations, but not dNPC or carotid artery injections, showed significant deceleration of motor deterioration (p < 0.05). These mutants with hNPC implantations also retained weight longer than dNPC mutants did (p < 0.05). At the end of the experiment, animals were sacrificed for histological evaluation. Using fluorescent markers (Qtracker) incorporated into the hNPC prior to implantation and human nuclear immunostaining, we observed few hNPCs in the brains of carotid artery-injected mutants. However, significant numbers of surviving hNPCs were seen using these techniques in mutant cerebellums and hippocampi implanted with hNPC. Our results show that direct implantation of hNPCs reduced ataxic symptoms in the sHW rat, demonstrating that stereotactic route of stem cell delivery correlates to improved clinical outcomes. PMID- 27938497 TI - Silencing of LIM and SH3 Protein 1 (LASP-1) Inhibits Thyroid Cancer Cell Proliferation and Invasion. AB - LIM and SH3 protein 1 (LASP-1) is a specific focal adhesion protein that was first identified in breast cancer and then reported to be involved in cell proliferation and migration. Many studies have demonstrated the essential role of LASP-1 in cancer progression. However, there have been no studies on the association of LASP-1 with thyroid cancer. In this study, we investigated the expression pattern and biological function of LASP-1 in thyroid cancer. We found that LASP-1 was highly expressed in thyroid cancer tissues and cell lines. LASP-1 silencing had antiproliferative and anti-invasive effects on thyroid cancer cells. Moreover, tumor xenograft experiments showed that LASP-1 silencing suppressed thyroid cancer cell growth in vivo. We also demonstrated that LASP-1 silencing decreased the protein expression of p-PI3K and p-Akt. In conclusion, these findings suggest LASP-1 to be an oncogene and a potential therapeutic target in thyroid cancer. PMID- 27938498 TI - Adiponectin Potentially Contributes to the Antidepressive Effects of Baduanjin Qigong Exercise in Women With Chronic Fatigue Syndrome-Like Illness. AB - Our recent study demonstrates that adiponectin signaling plays a significant role in mediating physical exercise-exerted effects on hippocampal neurogenesis and antidepression in mice. Whether the findings can be translated to humans remains unknown. This study aimed to investigate the effects of Baduanjin Qigong exercise on adiponectin and to evaluate whether adiponectin is involved in the antidepressive effects of Qigong exercise on chronic fatigue syndrome (CFS)-like illness. This is a randomized, waitlist-controlled trial. One hundred eight female participants were randomly assigned to either Qigong exercise or waitlist groups. Sixteen 1.5-h Qigong lessons were conducted. Outcome measures were taken at three time points. Baseline adiponectin levels were negatively associated with body weight, body mass index, waist circumference, hip circumference, and waist/hip ratio in women with CFS-like illness. Compared with the waitlist control, Qigong exercise significantly reduced anxiety and depression symptoms and significantly raised plasma adiponectin levels (median = 0.8 vs. -0.1, p < 0.05). More interestingly, increases in adiponectin levels following Qigong exercise were associated with decreases in depression scores for the Qigong group (r = -0.38, p = 0.04). Moreover, adjusted linear regression analysis further identified Qigong exercise and change in adiponectin levels as the significant factors accounting for reduction of depression symptoms. Baduanjin Qigong significantly increased adiponectin levels in females with CFS-like illness. Decreases in depression symptoms were associated with increases in adiponectin levels following Qigong exercise, indicating that the potential contribution of adiponectin to Qigong exercise elicited antidepressive effects in human subjects. PMID- 27938499 TI - Knockdown of Long Noncoding RNA CCAT2 Inhibits Cellular Proliferation, Invasion, and Epithelial-Mesenchymal Transition in Glioma Cells. AB - Long noncoding RNA (lncRNA) colon cancer-associated transcript 2 (CCAT2) has been demonstrated to play an important role in diverse tumorigenesis. However, the biological function of lncRNAs in glioma is still unknown. In this study, we found that lncRNA CCAT2 was overexpressed in glioma tissues and cell lines and associated with tumor grade and size. Furthermore, patients with high levels of lncRNA CCAT2 had poorer survival than those with lower levels of lncRNA CCAT2. Knocking down lncRNA CCAT2 expression significantly suppressed the glioma cell growth, migration, and invasion, as well as induced early apoptosis of glioma cells in vitro. Moreover, lncRNA CCAT2 regulated epithelial-mesenchymal transition (EMT)-associated gene expression. In conclusion, lncRNA CCAT2 plays an important role in glioma tumorigenesis and progression and may act as a potential biomarker for therapeutic strategy and prognostic prediction. PMID- 27938500 TI - Is Immune Modulation the Mechanism Underlying the Beneficial Effects of Amniotic Cells and Their Derivatives in Regenerative Medicine? AB - Regenerative medicine aims to repair and regenerate damaged cells, tissues, and organs in order to restore function. Regeneration can be obtained either by cell replacement or by stimulating the body's own repair mechanisms. Importantly, a favorable environment is required before any regenerative signal can stimulate resident stem/stromal cells, and regeneration is possible only after the resolution of injury-induced inflammation. An exacerbated immune response is often present in cases of degenerative, inflammatory-based diseases. Here we discuss how amniotic membrane cells, and their derivatives, can contribute to the resolution of many diseases with altered immune response by acting on different inflammatory mediators. PMID- 27938501 TI - miR-107 Promotes Proliferation and Inhibits Apoptosis of Colon Cancer Cells by Targeting Prostate Apoptosis Response-4 (Par4). AB - Colorectal cancer (CRC) is one of the most common malignancies in the world, with a high incidence and a high mortality. However, the pathogenesis of CRC carcinogenesis is still unexplored. In this study, we investigated the role of miR-107 in the regulation of CRC cell proliferation and apoptosis. First, the expression of miR-107 was observed to be aberrantly increased in human CRC tumor tissues and cell lines when compared to the colonic control tissues and colon epithelial cells. Further study showed that the proliferative and apoptotic capacities of human CRC SW480 and LoVo cells were aberrantly regulated by miR 107. The proliferation of SW480 and LoVo cells was remarkably enhanced by the miR 107 mimic but suppressed by the miR-107 inhibitor when compared to the negative control. On the contrary, the apoptotic rate of both SW480 and LoVo cells was significantly inhibited by miR-107 overexpression but increased by miR-107 inhibition. In addition, we identified prostate apoptosis response-4 (Par4) as a direct target of miR-107 with a potential binding site on the 3'-UTR of mRNA, as evaluated by bioinformatics prediction and luciferase reporter assay. Par4 expression levels were significantly inhibited by the miR-107 mimic but upregulated by the miR-107 inhibitor in both SW480 and LoVo cells. Compared to the control, the increase in Par4 expression significantly inhibited the induction role of miR-107 in the proliferation of SW480 and LoVo cells, and the apoptotic rate of cells repressed by the miR-107 mimic was also reversed by Par4 overexpression. In summary, our results demonstrated that miR-107 exerts a positive role in the survival of CRC cells by directly targeting Par4. This might reveal a novel understanding about human CRC pathogenesis. PMID- 27938502 TI - Novel Advances in Understanding of Molecular Pathogenesis of Hepatoblastoma: A Wnt/beta-Catenin Perspective. AB - Hepatoblastoma is the most common pediatric liver malignancy, typically striking children within the first 3 years of their young lives. While advances in chemotherapy and newer surgical techniques have improved survival in patients with localized disease, unfortunately, for the 25% of patients with metastasis, the overall survival remains poor. These tumors, which are thought to arise from hepatic progenitors or hepatoblasts, hence the name hepatoblastoma, can be categorized by histological subtyping based on their level of cell differentiation. Genomic and histological analysis of human tumor samples has shown exon-3 deletions or missense mutations in gene coding for beta-catenin, a downstream effector of the Wnt signaling pathway, in up to 90% of hepatoblastoma cases. The current article will review key aberrations in molecular pathways that are implicated in various subtypes of hepatoblastoma with an emphasis on Wnt signaling. It will also discuss cooperation among components of pathways such as beta-catenin and Yes-associated protein in cancer development. Understanding the complex network of molecular signaling in oncogenesis will undoubtedly aid in the discovery of new therapeutics to help combat hepatoblastoma. PMID- 27938503 TI - MicroRNA-181b Inhibits Cellular Proliferation and Invasion of Glioma Cells via Targeting Sal-Like Protein 4. AB - MicroRNAs (miRs), a class of noncoding RNAs that are 18-25 nucleotides in length, are able to suppress gene expression by targeting complementary regions of mRNAs and inhibiting protein translation. Recently, miR-181b was found to play a suppressive role in glioma, but the regulatory mechanism of miR-181b in the malignant phenotypes of glioma cells remains largely unclear. In this study, we found that miR-181b was significantly downregulated in glioma tissues when compared with normal brain tissues, and decreased miR-181b levels were significantly associated with high-grade pathology and a poor prognosis for patients with glioma. Moreover, miR-181b was downregulated in glioma cell lines (U87, SHG44, U373, and U251) compared to normal astrocytes. Overexpression of miR 181b significantly decreased the proliferation, migration, and invasion of glioma U251 cells. Sal-like protein 4 (SALL4) was identified as a novel target gene of miR-181b in U251 cells. The expression of SALL4 was significantly upregulated in glioma tissues and cell lines, and an inverse correlation was observed between the miR-181b and SALL4 expression levels in glioma. Further investigation showed that the protein expression of SALL4 was negatively regulated by miR-181b in U251 cells. Knockdown of SALL4 significantly inhibited the proliferation, migration, and invasion of U251 cells, while overexpression of SALL4 effectively reversed the suppressive effects of miR-181b on these malignant phenotypes of U251 cells. In conclusion, our study demonstrates that miR-181b has a suppressive effect on the malignant phenotypes of glioma cells, at least partly, by directly targeting SALL4. Therefore, the miR-181b/SALL4 axis may become a potential therapeutic target for glioma. PMID- 27938504 TI - Knockdown of miR-23, miR-27, and miR-24 Alters Fetal Liver Development and Blocks Fibrosis in Mice. AB - MicroRNAs (miRNAs) regulate cell fate selection and cellular differentiation. miRNAs of the miR23b polycistron (miR-23b, miR-27b, and miR-24) target components of the TGF-beta signaling pathway and affect murine bile ductular and hepatocyte cell fate selection in vitro. Here we show that miR-23b polycistron miRNAs directly target murine Smad4, which is required for TGF-beta signaling. Injection of antagomirs against these miRNAs directly into E16.5 murine fetuses caused increased cytokeratin expression in sinusoids and primitive ductular elements throughout the parenchyma of newborn mice. Similar antagomir injection in newborn mice increased bile ductular differentiation in the liver periphery and reduced hepatocyte proliferation. Antagomir injection in newborn Alb/TGF-beta1 transgenic mice that develop fibrosis inhibited the development of fibrosis, and injection of older mice caused the resolution of existing fibrosis. Furthermore, murine stellate cell activation, including ColA1 and ACTA2 expression, is regulated by miR-23b cluster miRNAs. In summary, knockdown of miR-23b cluster miRNAs in fetal and newborn liver promotes bile duct differentiation and can block or revert TGF beta-induced liver fibrosis that is dependent on stellate cell activation. These data may find practical application in the highly needed development of therapies for the treatment of fibrosis. PMID- 27938505 TI - Upregulated miR-9-3p Promotes Cell Growth and Inhibits Apoptosis in Medullary Thyroid Carcinoma by Targeting BLCAP. AB - Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer derived from parafollicular C cells in the thyroid gland. It has great interest as a research focus because of its unusual genetic, clinical, and prognostic characteristics. However, the pathogenesis in MTC is not completely clear. We investigated the role of miR-9-3p and bladder cancer-associated protein (BLCAP) in MTC TT cells. First, miR-9-3p expression was upregulated in human MTC tissues and TT cells and compared to the control by RT-PCR. Flow cytometric analysis indicated that the cell cycle progression in TT cells was significantly inhibited by the miR-9-3p inhibitor but was increased by the miR-9-3p mimic. On the contrary, the apoptosis of TT cells was significantly increased by the miR-9-3p inhibitor and suppressed by the miR-9-3p mimic. A similar change pattern was observed in the expression of apoptosis-regulated protein caspase 3 induced by the miR-9-3p mimic or inhibitor in TT cells. We then identified that BLCAP is a target of miR-9-3p by bioinformatic prediction and luciferase reporter assay. The expression of BLCAP was also significantly downregulated by the miR-9-3p mimic while being upregulated by the miR-9-3p inhibitor in TT cells. Furthermore, we confirmed that the inhibited apoptosis of TT cells induced by the miR-9-3p mimic was enhanced by BLCAP overexpression. The levels of apoptosis were strongly decreased by BLCAP silencing in TT cells, which were not further influenced by the miR-9-3p inhibitor. In summary, upregulated miR-9-3p has a positive role in human MTC progression by regulating the growth and apoptosis of cancer cells via targeting BLCAP. This might represent a possible diagnosis or therapeutic target for MTC. PMID- 27938506 TI - MicroRNA-98 Plays a Suppressive Role in Non-Small Cell Lung Cancer Through Inhibition of SALL4 Protein Expression. AB - MicroRNAs (miRs) have been demonstrated to be significantly associated with the development and progression of non-small cell lung cancer (NSCLC). However, the underlying mechanism of miR-98 in mediating the malignant phenotypes of NSCLC cells remains obscure. In this study, we found that miR-98 was significantly downregulated in NSCLC tissues compared to nontumor lung tissues. Downregulation of miR-98 was significantly associated with poor differentiation and advanced clinical stage. Restoration of miR-98 expression significantly decreased the proliferation, migration, and invasion of NSCLC A549 and H1229 cells. SALL4 was identified as a target gene of miR-98, and the protein expression of SALL4 was negatively regulated by miR-98 in NSCLC A549 and H1229 cells. Overexpression of SALL4 promoted A549 and H1229 cell proliferation, migration, and invasion and reversed the suppressive effects of miR-98 on the malignant phenotypes of A549 and H1229 cells. Moreover, SALL4 was found to be significantly upregulated in NSCLC tissues compared to the nontumor lung tissues. We then observed an inverse correlation between the miR-98 and SALL4 levels in NSCLC tissues. In vivo study revealed that miR-98 overexpression suppressed NSCLC growth. In summary, we demonstrate that miR-98 acts as a tumor suppressor in NSCLC cells by inhibiting the protein expression of its target gene SALL4. Therefore, our study highlights the importance of the miR-98/SALL4 axis in NSCLC. PMID- 27938507 TI - Overexpression of Forkhead Box L1 (FOXL1) Inhibits the Proliferation and Invasion of Breast Cancer Cells. AB - Forkhead box L1 (FOXL1) is a member of the Forkhead box (FOX) superfamily and was reported to be dysregulated in various types of cancers. However, its expression pattern and underlying cellular function in breast cancer remain largely unexplored. Thus, the aim of this study was to detect FOXL1 expression in breast cancer and to analyze its role in the progression of breast cancer. Our results demonstrated that FOXL1 expression at both the mRNA and protein levels was downregulated in breast cancer tissues and cell lines. Ectopic FOXL1 suppressed breast cancer cell proliferation, migration, and invasion in vitro. Furthermore, overexpression of FOXL1 significantly attenuated tumor growth in breast xenograft models in vivo. Finally, overexpression of FOXL1 significantly downregulated the protein expression levels of beta-catenin, c-Myc, and cyclin D1 in MDA-MB-231 cells. Taken together, the present study demonstrated that FOXL1 inhibited the proliferation, invasion, and migration of breast cancer in vitro and breast tumor growth in vivo through deactivating the Wnt/beta-catenin signaling pathway. Thus, these findings suggest that FOXL1 may be a potential novel target for breast cancer therapy. PMID- 27938508 TI - Regorafenib Plus FOLFIRI With Irinotecan Dose Escalated According to Uridine Diphosphate Glucuronosyltransferase 1A1 Genotyping in Patients With Metastatic Colorectal Cancer. AB - We analyzed the results of previously treated patients with metastatic colorectal cancer (mCRC) who received regorafenib plus FOLFIRI with the irinotecan dose escalation on the basis of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping. Thirteen patients with previously treated mCRC were subjected to UGT1A1 genotyping between October 2013 and June 2015 and were administered regorafenib plus FOLFIRI with irinotecan dose escalation. Patients with UGT1A1*1/*1 and *1/*28 genotypes were administered 180 mg/m2 of irinotecan, whereas those with the UGT1A1*28/*28 genotype were administered 120 mg/m2 of irinotecan. For all patients, the irinotecan dose was increased by 30 mg/m2 every two cycles until grade >=3 adverse events or severe adverse events developed, following which the dose was reverted to and maintained at the previously tolerated level. The oral regorafenib dose was adjusted to 120 mg/day daily. The median follow-up period was 10.0 months (1.0-21.0 months). The disease control rate was 69.2%, whereas the median progression-free survival and overall survival were 9.5 and 13.0 months, respectively. Our findings indicate that regorafenib plus FOLFIRI with irinotecan dose escalation based on UGT1A1 genotyping in previously treated patients with mCRC and with UGT1A1*1/*1 and UGT1A1*1/*28 genotypes is clinically effective and yields improved oncological outcomes. PMID- 27938509 TI - Sorafenib and 2-Deoxyglucose Synergistically Inhibit Proliferation of Both Sorafenib-Sensitive and -Resistant HCC Cells by Inhibiting ATP Production. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. Sorafenib is the only first-line systemic drug for advanced HCC, but it has very limited survival benefits because patients treated with sorafenib either suffer from side effects or show disease progression after initial response. Thus, there is an urgent need to develop novel strategies for first line and second-line therapies. The association between sorafenib resistance and glycolysis prompted us to screen several drugs with known antiglycolytic activity to identify those that will sensitize cells to sorafenib. We demonstrate that the combination of glycolytic inhibitor 2-deoxyglucose (2DG) and sorafenib drastically inhibits viability of sorafenib-sensitive and -resistant cells. However, the combination of other antiglycolytic drugs like lonidamine, gossypol, 3-bromopyruvate, and imatinib with sorafenib does not show synergistic effect. Cell cycle analysis revealed that the combination of 2DG and sorafenib induced cell cycle arrest at G0/G1. Mechanistic investigation suggests that the cell cycle arrest is due to depletion of cellular ATP that activates AMP-activated protein kinase (AMPK), which, in turn, inhibits mammalian target of rapamycin (mTOR) to induce cell cycle arrest. This study provides strong evidence for the therapeutic potential of the combination of sorafenib and 2DG for HCC. PMID- 27938510 TI - Bile Duct Ligation Induces ATZ Globule Clearance in a Mouse Model of alpha-1 Antitrypsin Deficiency. AB - alpha-1 Antitrypsin deficiency (A1ATD) can progress to cirrhosis and hepatocellular carcinoma; however, not all patients are susceptible to severe liver disease. In A1ATD, a toxic gain-of-function mutation generates insoluble ATZ "globules" in hepatocytes, overwhelming protein clearance mechanisms. The relationship between bile acids and hepatocytic autophagy is less clear but may involve altered gene expression pathways. Based on previous findings that bile duct ligation (BDL) induces autophagy, we hypothesized that retained bile acids may have hepatoprotective effects in PiZZ transgenic mice, which model A1ATD. We performed BDL and partial BDL (pBDL) in PiZZ mice, followed by analysis of liver tissues. PiZZ liver subjected to BDL showed up to 50% clearance of ATZ globules, with increased expression of autophagy proteins. Analysis of transcription factors revealed significant changes. Surprisingly nuclear TFEB, a master regulator of autophagy, remained unchanged. pBDL confirmed that ATZ globule clearance was induced by localized stimuli rather than diet or systemic effects. Several genes involved in bile metabolism were overexpressed in globule-devoid hepatocytes, compared to globule-containing cells. Retained bile acids led to a dramatic reduction of ATZ globules, with enhanced hepatocyte regeneration and autophagy. These findings support investigation of synthetic bile acids as potential autophagy-enhancing agents. PMID- 27938511 TI - Hiding in clear sight: Complications of immunosuppressive therapies. PMID- 27938512 TI - Thrombolysis in submassive pulmonary embolism: Finding the balance. PMID- 27938513 TI - When should an indwelling pleural catheter be considered for malignant pleural effusion? PMID- 27938514 TI - What stool testing is appropriate when diarrhea develops in a hospitalized patient? PMID- 27938515 TI - Do patients with submassive pulmonary embolism benefit from thrombolytic therapy? AB - Despite growing interest in thrombolytic agents to treat submassive pulmonary embolism, their role in this scenario remains controversial. Needed is a way to identify patients with this condition who are at risk of clinical deterioration and who would benefit from thrombolytic therapy. Here, we review the use of thrombolytic agents in submassive pulmonary embolism to help distinguish the risk and benefits of this therapy. PMID- 27938516 TI - Radiation-induced heart disease: A practical guide to diagnosis and management. AB - Radiation-induced heart disease (RIHD) is a recognized late sequela of chest radiotherapy for conditions such as breast cancer and lymphoma and can involve any cardiac structure. Consensus guidelines from the European Association of Cardiovascular Imaging and the American Society of Echocardiography stress the importance of regular screening for the cardiac effects of radiotherapy. However, a gulf remains between these guidelines and clinical practice. PMID- 27938517 TI - Women's health 2016: An update for internists. AB - Internists are called upon on a daily basis to address a range of women's health issues. Staying up to date with the evidence in this wide field can be challenging. This article reviews important studies published in 2015 and early 2016 pertinent to urinary tract infection, osteoporosis, ovarian cancer screening, and contraception. PMID- 27938518 TI - Taurine, energy drinks, and neuroendocrine effects. AB - Taurine is an amino acid found abundantly in brain, retina, heart, and reproductive organ cells, as well as in meat and seafood. But it is also a major ingredient in popular "energy drinks," which thus constitute a major source of taurine supplementation. Unfortunately, little is known about taurine's neuroendocrine effects. The authors review the sparse data and provide a basic background on the structure, synthesis, distribution, metabolism, mechanisms, effects, safety, and currently proposed therapeutic targets of taurine. PMID- 27938519 TI - Minocycline-induced hyperpigmentation. PMID- 27938520 TI - Phlegmasia cerulea dolens from radiation-induced venous stenosis. PMID- 27938521 TI - Abdominal pain under immunosuppressive conditions. PMID- 27938522 TI - Human Tick-Borne Encephalitis, the Netherlands. PMID- 27938523 TI - Fishing Quotas, Induced Allee Effect, and Fluctuation-Driven Extinction. AB - We explore the potential of modifications to standard fishery models (for example Gordon-Schafer-Munro) to help understand events such as the collapse of the North Atlantic cod fishery. In particular we find that quota-driven and similar harvesting strategies induce an effective strong Allee effect (collapse if the population falls below a critical level). In the presence of environmental noise, fish population dynamics is similar to a random walk with (non-linear) drift. The expected survival time (first passage time to collapse) is shown to depend sensitively upon the amount of environmental noise and size of the 'safe zone' between the deterministic steady state population and the critical population level at which the system collapses; more precisely it is exponential in the cube of the size of the safe zone divided by the variance of the noise process. Similar scaling can be expected for more survival in more general systems with multiple steady states. Our calculations imply an amplification effect under which small increases in harvest yield large decreases in expected survival time, and one should be cautious in changes in harvesting, especially in fisheries with poor or limited data and fisheries affected by climate change. PMID- 27938524 TI - How to Modify Psychopathological States? Hypotheses Based on Complex Systems Theory. AB - In mathematical analysis based on the assumptions of complexity science, the emergence of a pattern is the result of a competition of modes, which each have a parameter value attached. In the context of visual pattern recognition, a specific connectionist system (the synergetic computer SC) was developed, which was derived from the assumptions of synergetics, a theory of complex systems. We adapted the processes of visual pattern recognition performed by the SC to a different context, psychopathology and therapeutic interventions, assuming these scenarios are analogous. The problem then becomes, under which conditions will a previously established psychopathological pattern not be restituted? We discuss several cases by using the equations of the SC. Translated to the psychopathological context, we interpret the mathematical findings and proofs in such a way that successful corrective interventions, e.g. by psychotherapy, should focus on one alternative pattern only. This alternative cognition-behavior experience pattern is to be constructed individually by a therapist and a patient in the therapeutic alliance. The alternative pattern must be provided with higher valence (i.e. affective and motivational intensity) than possessed by the psychopathological pattern. Our findings do not support a linear symptom-oriented therapy approach based on specific intervention techniques, but rather a holistic approach. This is consistent with empirical results of psychotherapy research, especially the theory of common factors. PMID- 27938525 TI - Honing Theory: A Complex Systems Framework for Creativity. AB - This paper proposes a theory of creativity, referred to as honing theory, which posits that creativity fuels the process by which culture evolves through communal exchange amongst minds that are self-organizing, self-maintaining, and self-reproducing. According to honing theory, minds, like other self-organizing systems, modify their contents and adapt to their environments to minimize entropy. Creativity begins with detection of high psychological entropy material, which provokes uncertainty and is arousal-inducing. The creative process involves recursively considering this material from new contexts until it is sufficiently restructured that arousal dissipates. Restructuring involves neural synchrony and dynamic binding, and may be facilitated by temporarily shifting to a more associative mode of thought. A creative work may similarly induce restructuring in others, and thereby contribute to the cultural evolution of more nuanced worldviews. Since lines of cultural descent connecting creative outputs may exhibit little continuity, it is proposed that cultural evolution occurs at the level of self-organizing minds; outputs reflect their evolutionary state. Honing theory addresses challenges not addressed by other theories of creativity, such as the factors that guide restructuring, and in what sense creative works evolve. Evidence comes from empirical studies, an agent-based computational model of cultural evolution, and a model of concept combination. PMID- 27938526 TI - A Cusp Catastrophe Model of Tax Behavior. AB - The paper addresses the timeless failure of the tax system in Greece despite its constant reform, highlighting the study of tax evasion phenomenon with a different approach. This study aims to assess tax behavior with a model of cusp catastrophe, where fear and peer pressure are control parameters. The survey involved 320 taxpayers from the entire Greek territory. Mathematical study using linear analysis and catastrophe modelling showed that a non-linear system is dramatically better in representing tax behavior than is any linear model. Specifically, the Cusp catastrophe model is much more accurate (R2 = .911) bettering the corresponding linear model (R2 = .003). These results strongly infer the conclusion that tax behavior in Greece might involve systemic uncertainty. PMID- 27938527 TI - Cover Images: Flow Visualization. AB - Flow visualization is most often the 'first tool' used by investigators in their quest for understanding turbulent and other unsteady flow phenomena. The authors explain photography with the smoke-wire technique that has become an art form. PMID- 27938529 TI - Adhesions small bowel obstruction in emergency setting: conservative or operative treatment? AB - Adhesions small bowel obstructions (aSBO) are among the leading causes of emergency operative intervention. About the 80% of aSBO cases resolve without a surgical treatment. It's important to identify which patients could undergo a conservative treatment to prevent an useless surgery The aim of this study is to determine findings that can indicate whether patients with aSBO should undergo a conservative or a surgical treatment. 313 patients with diagnosis of submission of aSBO were restudied. Patients were divided into two groups based on the different type of treatment received, 225 patients who underwent surgical treatment within 24 hours after admission, 88 patients which underwent conservative treatment successfully. For each patient, clinical, hematochemical and radiological findings have been analysed. The treatment of aSBO should be, at the beginning, conservative except that cases that presents clinical and/or CT scan findings predictive for a surgical treatment (free peritoneal fluid, mesenterial edema, transitional point) or a peritonitis (pneumatosis intestinalis, pneumoperitoneum). PMID- 27938530 TI - Surgical management of gynecomastia: experience of a general surgery center. AB - AIM: Gynecomastia is a common finding in male population of all ages. The aim of our study was to present our experience and goals in surgical treatment of gynecomastia. PATIENTS AND METHODS: Clinical records of patients affected by gynecomastia referred to our Department of Surgery between September 2008 and January 2015 were analyzed. 50 patients were included in this study. RESULTS: Gynecomastia was monolateral in 12 patients (24%) and bilateral in 38 (76%); idiopathic in 41 patients (82%) and secondary in 9 (18%). 39 patients (78%) underwent surgical operation under general anaesthesia, 11 (22%) under local anaesthesia. 3 patients (6%) presented recurrent disease. Webster technique was performed in 28 patients (56%), Davidson technique in 16 patients (32%); in 2 patients (4%) Pitanguy technique was performed and in 4 patients (8%) a mixed surgical technique was performed. Mean surgical time was 80.72+/-35.14 minutes, median postoperative stay was 1.46+/-0.88 days. 2 patients (4%) operated using Davidson technique developed a hematoma, 1 patient (2%) operated with the same technique developed hypertrophic scar. CONCLUSIONS: Several surgical techniques are described for surgical correction of gynecomastia. If performed by skilled general surgeons surgical treatment of gynecomastia is safe and permits to reach satisfactory aesthetic results. PMID- 27938531 TI - Pancreas divisum: correlation between anatomical abnormalities and bile precipitation in the gallbladder in seven patients. AB - Pancreas divisum is a genetic defect associated with recurrent acute pancreatitis due to insufficient drainage of the accessory pancreatic duct. Seven young patients diagnosed with pancreatic divisum and thickening of the gallbladder bile as shown on magnetic resonance cholangio-pancreatography without pancreatic ductal changes underwent laparoscopic cholecystectomy. During the mean follow-up of 32 months no episode of pancreatitis was reported. There is an association between PD and higher concentration of bile in the gallbladder. Cholecystectomy can be considered curative in patients with PD in the absence of indications for major surgery. PMID- 27938532 TI - A rare case of perforation of the subhepatic appendix by a toothpick in a patient with intestinal malrotation: laparoscopic approach. AB - Foreign body ingestion is not an uncommon problem in clinical practice. While most ingested foreign bodies pass uneventfully through the gastrointestinal tract, sharp foreign bodies such as toothpicks should cause intestinal perforation. We reported the case of a perforation of the appendix caused by a toothpick, which also pierced the liver without hepatic damages, in a male with an intestinal malrotation and subhepatic appendix. The patient was admitted to our hospital for abdominal pain in the right upper quadrant. An abdominal computed tomography scan revealed the anomalous position of the first portion of the large intestine with inflamed appendix. A laparoscopic appendicectomy and the exploration of the abdominal cavity was performed using minimally invasive technique. PMID- 27938533 TI - Laparoscopic treatment of a large pedunculated hemangioma of the liver: a case report. AB - Hepatic hemangiomas are the most common benign tumors of the liver, often asymptomatic and discovered incidentally. A 62-year-old woman was referred to our Institution under the suspicion of having an 8 cm-sized GIST. Due to the atypical features of the lesion on TC scan, a biopsy was performed. We report the case of pedunculated hepatic hemangioma with the aim to discuss the diagnostic approach, the possible causes of misdiagnosis and the opportunity of the laparoscopic approach. PMID- 27938534 TI - Chyloperitoneum associated with idiopathic pancreatitis: case report and review of the literature. AB - Acute chylous peritonitis is defined as the onset of acute abdomen findings due to abrupt chylous fluid accumulation in the peritoneal space. A correct diagnosis of this condition is seldom made preoperatively. The optimal management of true chylous pancreatitis depends upon the underlying etiology. Thorough lavage of the abdomen and adequate drainage has proven to be an excellent treatment modality for acute chylous peritonitis, since resolution of chylous ascites usually occurs within the next few days. However, conservative treatment may be appropriate in selected cases. We present a case report and a brief review of the literature. PMID- 27938535 TI - Coexisting incarcerated femoral and obturator hernia: a case report. AB - BACKGROUND: Obturator hernia is a rare condition associated with a high morbidity and mortality. It is an uncommon cause of bowel obstruction most commonly described in elderly females with comorbidity. Surgical intervention is often delayed as a result of subtle presenting signs. Coexisting ipsilateral femoral hernia is an even rarer condition represented by non-exhaustive series in the literature. CASE PRESENTATION: We report a case of a healthy 36 years old lady, nulliparous, with abdominal pain and swelling in the right groin. Preoperative CT showed only a right groin hernia, that was found to be femoral at operative intervention. She recovered and was discharged from hospital but represented with further symptoms of obstruction 9 days later. Diagnostic laparoscopy demonstrated a ipsilateral obturator hernia with associated bowel infarct. The bowel was resected and the defect was repaired. DISCUSSION AND CONCLUSIONS: Obturator hernia presents subtly with medial thigh pain and no lump. They are notorious for difficulty to diagnosis. We describe the first case of coexisting ipsilateral femoral and obturator hernias in a young nulliparous woman with bowel obstruction. Appropriate intraoperative exploration should always be considered. PMID- 27938536 TI - Acute appendicitis: should the laparoscopic approach be proposed as the gold standard? Six-year experience in an Emergency Surgery Unit. AB - Acute appendicitis is common in an Emergency Surgery Unit. Although the laparoscopic approach is a method accepted for its treatment, no strong data are available for determining how many procedures must an experienced surgeon carry out for obtaining all the advantages of this technique and if this approach can become the gold standard in the activity of a general emergency unit with senior surgeons variously skilled on the basic laparoscopy. 142 patients that underwent appendectomy (90 laparoscopic, 52 conventional) for acute appendicitis were enrolled in this institutional retrospective cohort study. The surgeons were classified with a descriptor-based grading and divided in two groups regarding the skill. The only relevant result of our study was the significant reduction of conversion rate in case of laparoscopic approach. No strong differences were found concerning the duration of the procedure and the hospital stay between the two groups. The rate of complications were very low in both groups. In conclusion, the experienced surgeons can easily perform a laparoscopic approach independently from the specific skill in this approach. PMID- 27938537 TI - Uncommon localizations of hydatid cyst. Review of the literature. AB - INTRODUCTION: Hydatid disease is an endemic anthropozoonosis with usual localization in liver and lungs. Rarely it localizes in uncommon sites as spleen, skeleton, kidney, brain, cardiac muscle, peritoneum, sub cutis. Complications of uncommon localizations are the same that for usual ones. MATERIAL AND METHODS: Review of the literature on rare and atypical localization of hydatid cysts in soft tissues. Key-words used on Pub-Med [(echinococ OR hydatid) AND (soft tissue OR subcutaneous OR cutaneous)] without time limit. There were found 282 articles; 242 were excluded because of muscular or bone localizations. 40 were coherent. RESULTS: Different variables are taken into account: age, sex, geographic area, anatomic localization of the cyst, dimension, symptoms, signs, mobility, blood exams and specific serological tests, imaging techniques for diagnosis, existing of septa in the structure, treatment, anaesthesia, spillage, neo-adjuvant and adjuvant treatment, follow-up period, recurrent lesions. CONCLUSION: It would be useful create an homogeneous and standardized collection of data of these rare and potentially life-threatening conditions in order to create guide-line of diagnostic and therapeutic process and create (or adopt) unique classification of the lesions. PMID- 27938539 TI - [Make well the degree medicine of obstructive sleep apnea-hypopnea syndrome in China]. PMID- 27938538 TI - Una lettera di Lister. PMID- 27938540 TI - [Protective effect of hydrogen on the lung of sanitation workers exposed to haze]. AB - Objective: To study the protective effect of hydrogen inhalation on the lungs of sanitation workers exposed to haze. Methods: In this randomized, double-blind, placebo controlled clinical trial, 96 sanitation workers living in Shijiazhuang urban area were recruited during January to February, 2016. All enrolled participants were randomized to 2 groups; the treatment group inhaled H2?O2 mixture (66.67%?33.33%) 1 hour per day for 30 days, while the control group inhaled N2?O2 mixture (66.67%?33.33%) 1 hour per day for 30 days. Respiratory symptoms were evaluated and fractional exhaled nitric oxide(FeNO), biochemical indexes, lung function were measured at baseline(the 0th day) and during treatment (the 8th day, 15th day, and 30th day). Results: (1)The FeNO levels of the treatment group (16+/-5)*109 were lower than those of the control group(21+/ 14)*109 on 8th day of treatment, with significant difference(F=6.94, P<0.05). (2)The levels of FEV1 were significantly higher in participants from the treatment group as compared to the control group on both 8th [(96+/-13)% vs(94+/ 14)%(F=3.96, P<0.05)] and 30th day [(97+/-14)% vs (95+/-12)%(F=8.5, P<0.05)] of treatment, while PEF was also increased on 15th day [(73+/-15)% vs(67+/ 18)%(F=8.68, P<0.05)]. (3)The sputum levels of MMP-12 and SOD3 were consistently lower in the treatment group as compared to the control group at each time point, and the levels of IL-10 were higher in the treatment group as compared to the control group on the 15th and 30th day. MDA and IL-2 levels were lower in the treatment group than in the control group on the 30th day(P<0.05). The sputum levels of CRP and TGF-beta1 at each time point were not different between the 2 groups (P>0.05). (4)The serum levels of IL-2 and SOD3 were lower in the treatment group as compared to the control group while IL-10 was higher than in the control group at each time point, and MMP-12 was lower in the treatment group than that in the control group on the 30th day(P<0.05). The relative ratios of CRP, TGF beta1 and MDA in serum at each time point between the 2 groups were not significantly different (P>0.05). (5)Hydrogen inhalation improved respiratory symptoms such as cough. Conclusions: Inhalation of hydrogen gas could alleviate airway inflammation and oxidative stress of sanitation workers exposed to air pollution. There was even a significant inhibitory effect on the level of systemic inflammatory response. Importantly, inhalation of hydrogen could improve respiratory symptoms such as cough. PMID- 27938541 TI - [A study of population pharmacokinetics of linezolid in Chinese]. AB - Objective: To study the population pharmacokinetic (PPK) profiles of linezolid in Chinese healthy volunteers and infected patients. Methods: Linezolid 600 mg was administered to 31 Chinese healthy volunteers with a single dose and to 57 infected patients every 12 h for at least 5 doses. High performance liquid chromatography was applied to determine the plasma concentration of linezolid. Nonlinear mixed-effects modeling method was applied to analyze the PPK profiles. Results: For healthy volunteers with single dose of linezolid, 2-compartment with linear elimination model was the most appropriate structural pharmacokinetic model. The population typical value of apparent volume of central compartment was 26.99 L, volume of peripheral compartment was 22.22 L, apparent clearance of central compartment was 7.99 L/h, and clearance of peripheral compartment was 101.28 L/h. For each 1 kg deviation of weight from the mean value, 0.62 L of volume of peripheral compartment was correlated. For Chinese infected patients with multiple doses of linezolid, 1-compartment with linear elimination model was the most appropriate structural pharmacokinetic model. The population typical value of apparent volume was 38.85 L, and apparent clearance was 4.70 L/h. For each 1 kg deviation of weight from the mean value, 0.79 L of volume, as well as 0.04 L/h of clearance were correlated. For each 1 year deviation of age from the mean value, -0.045 L/h of clearance was correlated. Conclusions: The pharmacokinetic profiles of linezolid in Chinese simulate a 2-compartment with linear elimination model when single dose is administrated, and the weight is linearly positive-correlated to volume. While a 1-compartment with linear elimination model is appropriate when multiple doses are administrated, and the weight is linearly positive-correlated to volume and clearance, but the age is linearly negative-correlated to clearance. PMID- 27938542 TI - [The diagnostic performance of galactomannan detection for invasive pulmonary aspergillosis in non-neutropenic hosts]. AB - Objective: To evaluate the diagnostic performance of galactomannan(GM)detection in serum and BALF for invasive pulmonary aspergillosis (IPA) in non-neutropenic hosts. Methods: A pospective study was performed for 1 356 non-neutropenic hosts admitted to the Department of Pulmonary and Critical Care Medicine of the First Affiliated Hospital of Wenzhou Medical University from September 2014 to October 2015. Serum GM test was performed for all, and BALF GM test for a proportion of the patients. The patients were divided into an IPA group and a non-IPA group. SPSS 20.0 was adopted for statistical analysis. Results: A total of 1 361 cases were enrolled, aging 18-96 years, with an average age of (64+/-15) years. There were 879 male and 477 female patients. Thirty-nine cases were diagnosed as IPA, accounting for 2.9%. For serum GM test, the sensitivity, specificity, PPV and NPV were 43.6%(17/39), 94.1%(1 239/1 317), 17.9%(17/95)and 98.3%(1 239/1 261)respectively. Ninety-six cases received serum and BALF GM tests at the same time. If the cut-off value of BALF GM test was 0.8, the sensitivity, specificity, PPV and NPV were 86.7%(13/15), 60.5%(49/81), 28.9%(13/45), 96.1%(49/51)respectively, but if the value was 1.0, the sensitivity, specificity, PPV and NPV were 86.7%(13/15), 74.1%(60/81), 38.2%(13/34), 96.8%(60/62)respectively. The ROC curve area of BALF GM, serum GM and the combined serum and BALF GM was 0.87, 0.75 and 0.90, respectively. Conclusions: The sensitivity of serum GM test in non-neutropenic hosts was low, but it had a high negative predictive value.The best BALF GM cut-off value was 1.0. The combined serum and BALF GM tests improved the diagnostic performance. PMID- 27938543 TI - [The clinical significance of increased neutrophils in bronchoalveolar lavage fluid in sarcoidosis]. AB - Objective: To investigate the clinical implications of increased neutrophils in bronchoalveolar lavage fluid (BALF) in sarcoidosis. Methods: A retrospective analysis was performed for 72 cases of histologically diagnosed, treatment-naive sarcoidosis admitted to Peking University Third Hospital from January 2000 to October 2014. The patients included 18 men and 54 women, 26 to 75 years of age [(50+/-10) years], with the disease course 0.5 month to 12 years (median disease course, 3 months). Results of cell count and differentials of BALF were analyzed and the patients were grouped based on the percentage of neutrophils: those with increased neutrophils (>3%) and those without (<=3%). Clinical manifestations, pulmonary function tests, radiological features, bronchoscopic findings, and other laboratory data were compared between the 2 groups. Finally 67 patients were followed for 6 to 240 months (median 36 months). The subsequent changes of radiological manifestations and relapses after therapy were recorded and compared. Results: There were 72 patients in the study, including 16 with increased BALF neutrophils(stage I/II/III, 4/10/2) and 56 without(stage I/II/III, 9/45/2). Compared with patients without increased neutrophils, those with increased neutrophils had more reticular changes in the lungs(6/16, 8/56), more common diffusion dysfunction (7/13, 11/46) with lower DLCO% [(70+/-19)% vs (89+/ 23)%], higher percentage of CD8+ lymphocytes [(19+/-4)% vs (11+/-4)%, P<0.05] in BALF. Sixteen (stage I/II/III, 4/10/2) and 51 (stage I/II/III, 9/41/1) patients with and without increased neutrophils were followed respectively. Compared with patients without increased neutrophils, those with increased neutrophils tended to deteriorate and relapse despite corticosteroid therapy. Conclusions: Sarcoidosis patients with BALF neutrophilia had more severe pulmonary fibrosis and diffusion dysfunction, poorer response to corticosteroid therapy and higher relapse rate. These patients, therefore, should be monitored more closely during therapy or follow-up. PMID- 27938544 TI - [The alterations and clinical significance of serum thyroid hormone levels in patients with acute exacerbation of chronic obstructive pulmonary disease]. AB - Objective: To observe the alterations of serum thyroid hormone levels in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients without thyroid disease and therefore to investigate the association between serum thyroid hormone levels and the severity and prognosis of AECOPD. Methods: Serum thyroid hormone levels including TT4, TT3, TSH, FT4 and FT3 were measured by chemiluminescence immunoassay in 84 hospitalized patients with AECOPD [male 52, female 32, aged 50-93 years, average (78+/-10) years] and in 35 healthy subjects [male 20, female 15, aged 51-87 years, average (73+/-11) years] from 2013 to 2014. Results: The serum TT4, TT3 and FT3 levels in AECOPD patients before therapy were significantly lower than those after therapy(P<0.05). The serum TT4, TT3 and FT3 levels in AECOPD post-therapy were significantly lower than those in the healthy control group(TT4: 80+/-18, 89+/-18, 113+/-21; TT3: 0.84+/-0.25, 1.37+/-0.31, 1.60+/-0.35; FT3: 2.57+/-0.73, 3.49+/-0.64, 4.21+/-0.75, P<0.05). The serum FT4 level in AECOPD pre-therapy was significantly lower than that in AECOPD post-therapy and the control group(15.0+/-2.8, 16.3+/-2.5, 16.7+/-2.4, P<0.05). The difference of serum FT4 level between AECOPD post-therapy group and the control group was not statistically significant(P>0.05). The Serum TT4, TT3, FT4 and FT3 levels in type I respiratory failure subgroup and type II respiratory failure subgroup were both significantly lower than those in the non-respiratory failure subgroup(TT4: 78+/-14, 70+/-16, 92+/-17; TT3: 0.73+/-0.16, 0.73+/-0.23, 1.04+/-0.21; FT4: 14.4+/-2.4, 14.1+/-2.4, 16.3+/-2.9; FT3: 2.27+/-0.65, 2.32+/ 0.66, 3.05+/-0.62, P<0.05). The differences of serum TT4, TT3, FT4 and FT3 levels between type I respiratory failure subgroup and type II respiratory failure subgroup were not statistically significant(P>0.05). The serum TT3 and FT3 levels in the survival subgroup were significantly higher than those in the fatal subgroup(TT3: 0.90+/-0.25, 0.68+/-0.18; FT3: 2.76+/-0.67, 2.07+/-0.68, P<0.05). The differences of serum TT4(82+/-18, 75+/-17), FT4(15.2+/-2.8, 14.2+/-2.7) and TSH(1.1+/-1.1, 1.5+/-1.5) levels between the 2 subgroups were not statistically significant(P>0.05). Conclusion: Serum thyroid hormone levels are related to the condition of AECOPD. They are reduced in patients with AECOPD and can recover to different degrees as the primary disease improves. Hypoxia and carbon dioxide retention can result in decreased levels of serum thyroid hormones. Serum thyroid hormone levels are significantly associated with the severity and prognosis of patients with AECOPD. PMID- 27938545 TI - [Latent tuberculosis infection and associated risk factors among the tuberculosis contacts in one of district in Shanghai]. AB - Objective: To investigate the prevalence of latent tuberculosis infection(LTBI) and associated risk factors among the tuberculosis(TB) contacts in Minhang District of Shanghai. Methods: A self-designed questionnaire was used to acquire socio-demographic information and to assess the degree of exposure to index cases. LTBI screening was performed by T-SPOT.TB assay. Pearson chi-square test and Logistic regression analyses were used to identify the risk factors associated with LTBI among the TB contacts. Results: A total of 137 contacts from 59 mycobacterial (culture) positive pulmonary TB patients were enrolled in this study. In these contacts, there were 54 men and 83 women, with the average age of 42. LTBI was identified in 20% (27/137) of these contacts. Several risk factors were found by logistic analyses in this study. The worse the ventilation in the exposure location was, the more likely to develop LTBI. Contacts aged more than 60 (42.1%) were 3.9 times more likely to develop LTBI than those aged less than 60 (16.1%). Individuals in contact with TB patients for more than 40 h/week(25.8%) had a 4.2 times risk of LTBI as compared to those for less than 40 h/week(6.8%). Conclusion: The prevalence of LTBI was 20% among the TB contacts in this study, highlighting the need of TB screening and intervention among TB contacts. PMID- 27938546 TI - [Soft-tissue angiosarcoma with pulmonary metastases: case report and literature review]. AB - Objective: To investigate the differential diagnosis between pulmonary metastases from soft-tissue angiosarcoma and primary pulmonary angiosarcoma. Methods: A case of soft-tissue angiosarcoma with pulmonary metastases was reported and related literatures were reviewed. Results: A 39 year-old man complaining of hemoptysis, cough, and sputum for 10 months was admitted to our hospital in September 2013. He was initially diagnosed as having primary pulmonary angiosarcoma after wedge resection biopsy of the lung. After 22 months since onset, he felt discomfort in his leg, which led to the confirmative diagnosis of soft-tissue angiosarcoma of the leg with multiple pulmonary metastases by a full-body PET/CT scan and core needle biopsy of the leg. Twenty-three articles concerning primary pulmonary angiosarcoma with complete records of history, treatment and follow-up of patients were included in the literature review. A total of 26 patients were reported in these articles, including 18 males, 8 females, age 19-85 years, average (52+/-18) years. Primary pulmonary angiosarcoma was mainly manifested as single or multiple pulmonary nodules or masses, with or without ground glass opacity. In our case, chest CT showed multiple thin-wall cysts and ground glass opacities, and recurrent spontaneous pneumothorax, which had never been reported in literatures on primary pulmonary angiosarcoma. Conclusions: Pulmonary metastases from soft-tissue angiosarcoma differed from primary pulmonary lesions in terms of chest imaging, with the former usually showing thin-wall cysts and pneumothorax. A full-body PET-CT was essential for differential diagnosis between primary and metastatic pulmonary angiosarcoma. PMID- 27938547 TI - [Effect of self-expanding bare metal stents of different diameters on the trachea of dogs]. AB - Objective: To study the effect of self-expanding bare metal stents on the trachea of dogs, and therefore to provide useful information for choice of airway stents by interventional physicians. Methods: In this experiment, 8 beagles were randomly divided into 4 groups. Four self-expanding metal stents of different diameters (16, 18, 20 and 22 mm, respectively) were placed in the trachea of these beagles for 3 months and their impacts on normal trachea were observed. Results: In the 16 mm stent group (stent-to-airway diameter ratio 103%), good epithelialization was observed and the tracheal structure had no significant damage. In the 18 mm stent group (stent-to-airway diameter ratio 116%), slight granulation tissues were observed, but the cartilage and outer membrane were normal. In the 20 mm stent group (stent-to-airway diameter ratio 129%), severe granulation tissues were observed. Cartilage was damaged but outer membrane was normal. In the 22 mm stent group (stent-to-airway diameter ratio 142%), no obvious granulation tissues were found. Cartilage was normal, but outer membrane was ruptured. Conclusion: In a certain range, tracheal granulation tissues increased as the stent diameter increased. However, if the stent diameter continued to increase, a decreasing trend of tracheal granulation was observed, but severe tracheal injury by stent expansion force would occur. PMID- 27938549 TI - [Advance in pathogenesis and treatment of idiopathic pulmonary alveolar proteinosis]. PMID- 27938548 TI - [Effect of oxidative stress-associated damage to the lung tissue caused by different body mass index in the rat models]. AB - Objective: To investigate the influence of different diets on serum protein expression levels of 4-hydroxynonenal (4-HNE), thioredoxin (Trx), thioredoxin reductase (TrxR) and the activities of Trx and TrxR, and to explore the effect of damage to the lung tissue and the underlying mechanisms of different body mass index caused by different diets in the rat models . Method: Healthy clean male SD rats were randomly divided into normal group, emaciation group and fat group, which were raised by different diets for 6 months.Then the rats were sacrificed and the serum and lung tissue were prepared. The levels of 4-HNE, Trx and TrxR in peripheral blood were quantitatively analyzed by enzyme-linked immunosorbent assay(ELISA), and the activities of Trx and TrxR were measured by chemical methods. Results: Compared with the normal group, the lung tissue had more apparent emphysema in the emaciation and the fat groups under light microscope, and more inflammatory cell infiltration in alveolar septum was observed in the fat group.The levels of 4-HNE in the fat group[(24.7+/-8.7)mg/L]was significantly higher than that in the normal group[(15.4+/-4.7)mg/L, P<0.05)], but there was no significant difference(P>0.05)in the levels of 4-HNE between the emaciation and the normal groups. The levels of TrxR in the emaciation group[(7.7+/ 1.4)MUg/ml]was significantly higher than that in the normal and the fat groups[(6.2+/-1.1), (4.9+/-1.4)MUg/ml, all P<0.05)]. The level of TrxR in the fat group was significantly lower than that in the normal group(P<0.05); The differences in the levels of Trx among the 3 groups were not significant(P>0.05). The activity of Trx in the emaciation group[(32.4+/-8.5)*10-3A.min-1.mg-1]was significantly higher than that in the normal group[(19.6+/-3.3)*10-3A.min-1.mg 1]and the fat group[(11.3+/-7.5)*10-3A.min-1.mg-1, all P<0.01]. The activity of Trx in the fat group was significantly lower than that in the normal group(P<0.05). The activity of TrxR in the emaciation group[(17.6+/-4.6)*10 3A.min-1.mg-1]was significantly higher than that in the fat group[(7.8+/-2.3)*10 3A.min-1.mg-1, P<0.01], but the TrxR activity of the 2 groups showed no significant difference as compared with the normal group(P>0.05). Conclusion: Both high BMI and low BMI can affect the oxidative stress of the body, resulting in increased oxidants and decreased antioxidants, and can cause damage to the lung tissue in the rat models. PMID- 27938550 TI - [TRPV1 pathway related theapeutic drugs for chronic cough hypersensitivity syndrome]. PMID- 27938551 TI - [Research progress of biomarkers in acute respiratory distress syndrome]. PMID- 27938552 TI - [Research progress on the frequent exacerbator phenotype of chronic obstructive pulmonary disease]. PMID- 27938553 TI - [Research advances on animal models of tuberous sclerosis and lymphangioleiomyomatosis]. PMID- 27938554 TI - [Current status of treatment of refractory ascites in patients with liver cirrhosis]. AB - Ascites is a common clinical manifestation of cirrhotic portal hypertension, and about 60%-80% of cirrhotic patients develop the symptom of ascites within 10 years. Once ascites occurs, the 5-year survival rate is reduced from 80% to 50%. With the progression of liver diseases, approximately 5%-10% of patients with ascites develop refractory ascites, and the median survival time is only 6-12 months. This article reviews the definition and diagnosis of refractory ascites, evaluation of prognostic factors, and treatment regimens, including large-volume paracentesis combined with protein supplementation, transjugular intrahepatic portosystemic shunt, and liver transplantation. PMID- 27938555 TI - [Clinical features and significance of cirrhosis-associated immune dysfunction]. AB - Cirrhosis-associated immune dysfunction (CAID) refers to immunodeficiency and systemic inflammation in cirrhotic patients and is the characteristic pathophysiological change of liver cirrhosis of various causes. The phenotype of CAID changes dynamically with the progression of liver cirrhosis. In patients with stable cirrhotic ascites, CAID is manifested as "pro-inflammatory" state, and in patients with severe decompensated liver cirrhosis complicated by extrahepatic organ failure, it is manifested as "immunodeficiency". CAID affects the clinical manifestations and prognosis of liver cirrhosis, aggravates the condition of cirrhotic patients, and increases the risk of infection. This article briefly introduces the mechanism, features, and clinical significance of CAID. PMID- 27938556 TI - [Hereditary polycystic kidney disease: a neglected etiology of liver cirrhosis]. AB - There are two common types of hereditary polycystic kidney diseases, autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease. Congenital hepatic fibrosis is an autosomal recessive disorder and can occur in hereditary polycystic kidney disease. Therefore, hereditary polycystic kidney disease is one of the causes of unexplained liver fibrosis and liver cirrhosis. PMID- 27938557 TI - [Clinical effect of low-molecular-weight heparin in prevention and treatment of liver cirrhosis and portal vein thrombosis after splenectomy: a systematic review and meta-analysis]. AB - Objective: To investigate the clinical effect of low-molecular-weight heparin (LMWH) in the treatment of liver cirrhosis and portal vein thrombosis and the value of early application of LMWH in the prevention of portal vein thrombosis after splenectomy. Methods: The databases of PubMed, Google Scholar, CNKI, Wanfang Data, and VIP were searched, and manual searching and internet searching were used to retrieve grey literature. The articles which met the inclusion criteria were included, and a systematic review and meta-analysis was performed. Results: A total of 12 randomized controlled trials were included, with 1397 patients enrolled, among whom 723 were enrolled in the LMWH group and 674 were enrolled in the control group. A meta-analysis was performed for the trials above, and the results showed that the patients with early application of LMWH had a lower rate of thrombosis compared with those in the control group (OR = 0.37, 95% CI 0.28-0.48, P < 0.001). The results of three randomized trials with the application of LMWH in the treatment of portal vein embolism showed that the patients treated with LMWH had a higher rate of recanalization of thrombus than those in the control group (OR = 5.08, 95% CI 1.74-14.84, P < 0.001). Conclusion: Early application of LMWH can reduce the rate of portal vein thrombosis after splenectomy, and LMWH for the treatment of portal vein embolism can increase the rate of recanalization of thrombus. PMID- 27938558 TI - [A retrospective study on HBsAg clearance rate after antiviral therapy in children with HBeAg-positive chronic hepatitis B aged 1-7 years]. AB - Objective: To investigate the HBsAg clearance rate after antiviral therapy in children with HBeAg-positive chronic hepatitis B (CHB) aged 1-7 years. Methods: A retrospective analysis was performed for the HBsAg clearance rate in 293 children who were hospitalized in 302 Hospital of PLA from June 2006 to December 2013, met the inclusion criteria, received antiviral therapy, and were followed up for at least 6 months after the withdrawal of antiviral therapy. The t-test or the rank sum test was applied according to the distribution of continuous data, and the chi-square test was used for comparison of categorical data. Results: The HBsAg positive rate of children's mothers was 91.1%. In the age groups of >1-<=2 years, >2-<=3 years, >3-<=4 years, >4-<=5 years, >5-<=6 years, and >6-<=7 years, the HBsAg clearance rates were 66.1%, 65.5%, 45.7%, 41.3%, 20.6%, and 27.6%, respectively. There were significant differences in HBsAg clearance rate between the age groups of >1-<=3 years and >3-<=5 years, >1-<=3 years and >5-<=7 years, and >3-<=5 years and >5-<=7 years (P = 0.001, 0.000, and 0.008). Of all children, 64.8% were boys, among whom 41.1% achieved HBsAg clearance, and 35.2% were girls, among whom 61.2% achieved HBsAg clearance; there was a significant difference in HBsAg clearance rate between boys and girls (P = 0.001). The children with pretreatment alanine aminotransferase (ALT) levels of <=80 IU/L, > 80 IU/L, <=200 IU/L, and > 200 IU/L had HBsAg clearance rates of 40.7%, 51.2%, 47.6%, and 49.4%, respectively; there were no significant differences in HBsAg clearance rate between the ALT <=80 IU/L and ALT > 80 IU/L groups and the ALT <=200 IU/L and ALT > 200 IU/L groups (P = 0.101 and 0.778). There was no significant difference in HBsAg clearance rate between the pretreatment HBV DNA load < 1*107 IU/ml and >=1*107 IU/ml groups (54.9% vs 46.7%, P = 0.286). Of all children, 14.2% had genotype B and an HBsAg clearance rate of 57.1%, and 85% had genotype C and an HBsAg clearance rate of 39.5%; there was no significant difference in HBsAg clearance rate between the genotype B group and the genotype C group (P = 0.051). Of all children, 90.4% underwent liver biopsy, among whom 10.9% had severe liver fibrosis (F>=3) and liver cirrhosis, as well as an HBsAg clearance rate of 31%; the non-severe liver fibrosis/liver cirrhosis group had an HBsAg clearance rate of 49.2%, and there was no significant difference in HBsAg clearance rate between these two groups (P = 0.065). There was no significant difference in HBsAg clearance rate between the liver inflammation grade (G) < 2 group and the G >= 2 group (39.5% vs 50.9%, P = 0.084). Of all children, 58.7% received interferon antiviral therapy alone and had an HBsAg clearance rate of 48.8%, and 41.3% received interferon alone for 6 months followed by lamivudine antiviral therapy and had an HBsAg clearance rate of 47.1%; there was no significant difference between these two groups (P = 0.770). Conclusion: In children with HBeAg-positive CHB aged 1-7 years who receive antiviral therapy, HBsAg clearance rate is correlated with age and sex, and the children aged < 5 years can achieve a higher HBsAg clearance rate. PMID- 27938559 TI - [Serum CXCL-10 level in chronic hepatitis C patients with cryoglobulinemia and its influence on antiviral therapy]. AB - Objective: To investigate the serum CXCL-10 level in chronic hepatitis C (CHC) patients with cryoglobulinemia and its influence on the effect of antiviral therapy. Methods: A total of 50 CHC patients were enrolled in the study. Cryoprecipitation was used to determine the nature of cryoglobulins in serum before treatment, and ELISA was used to measure the serum CXCL-10 level. The hepatitis C virus (HCV) genotype was detected, and serum HCV RNA level was measured at baseline, 4, 12, and 24 weeks of treatment, the end of treatment, and 24 weeks after treatment.. Results: Compared with the cryoglobulin-negative patients, the cryoglobulin-positive patients had significantly higher baseline levels of HCV RNA [(6.28+/-0.79) log10 copies/ml vs (5.48+/-1.20) log10 copies/ml, P = 0.009] and CXCL-10 (541.67+/-224.07 pg/ml vs 394.39+/-179.71 pg/ml, P = 0.015). After the treatment with pegylated interferon-alpha-2a and ribavirin, the cryoglobulin-positive patients had a significantly lower proportion of individuals who achieved rapid virological response compared with the cryoglobulin-negative patients (33.3% vs 82.6%, P < 0.001). The cryoglobulin positive patients had a significantly lower rate of sustained virologic response than the cryoglobulin-negative patients (33.3% vs 78.3%, P = 0.001). Conclusion: The patients with cryoglobulinemia have higher serum levels of HCV RNA and CXCL 10 and poor outcomes compared with those without cryoglobulinemia. PMID- 27938560 TI - [Effect of targeted inhibition of hypoxia-inducible factor-1alpha by 3-(5' hydroxymethyl-2'-furyl)-1-benzylindazole on the progression of non-alcoholic fatty liver disease in rats]. AB - Objective: To investigate the effect of targeted inhibition of hypoxia-inducible factor-1alpha (HIF-1alpha) by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC 1) on the progression of non-alcoholic fat liver diseases (NAFLD) in rats. Methods: A total of 72 male Sprague-Dawley rats were randomly divided into normal group, model group, and intervention group, and the rats were given high-fat feed to establish the rat model of fatty liver disease. After the establishment of the model, the rats in the intervention group were given intraperitoneally injected YC-1 (at a dose of 2 mg/kg) every two weeks and were observed at 4, 8, 12, and 16 weeks. Blood samples and liver tissues were collected after the end of intervention, and blood lipid, biochemical markers for liver function, fasting blood glucose, and insulin were measured. Histopathological examinations were performed, and insulin resistance index was calculated. Real-time PCR was used to measure the mRNA transcriptional levels of HIF-1alpha, peroxisome proliferator activated receptor alpha, and nuclear factor-kappa B (NF-kappaB), and Western blot was used to measure their protein expression levels. An analysis of variance with group design and the Kruskal-Wallis H test were used for comparison of continuous data between multiple groups, and the least significant difference method was used for comparison between any two groups. P <0.05 was considered statistically significant. Results: Compared with the model group, the intervention group had significant reductions in the serum levels of alanine aminotransferase, aspartate aminotransferase, triglyceride, and total cholesterol after 12 weeks of continuous administration (P < 0.05); after 8 weeks of continuous injection of YC-1, the intervention group had significant alleviation in hepatic steatosis and significant improvement in inflammation degree (P < 0.05), and after 12 weeks of continuous injection of YC-1, the intervention group had a significant reduction in liver fibrosis degree (P < 0.05); after 12 and 16 weeks of continuous administration, the intervention group had a significant increase in the mRNA expression of peroxisome proliferator-activated receptor alpha and a significant reduction in the mRNA expression of NF-kappaB. The protein expression of HIF-1alpha, peroxisome proliferator-activated receptor alpha, and NF-kappaB in fatty liver tissues at different time points showed similar results as the mRNA expression. There were no significant differences in insulin resistance index at each time point between the model group and the intervention group. Conclusion: Targeted inhibition of YC-1 can effectively delay the progression of experimental fatty liver disease and improve lipid metabolism, but it has no significant effect on insulin resistance. PMID- 27938561 TI - [Value of albumin in diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency]. AB - Objective: To investigate the clinical value of albumin (Alb) in the diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Methods: A retrospective analysis was performed for the clinical data of 90 children with NICCD who visited Children's Hospital of Fudan University from January 2007 to December 2014, and according to the content of Alb, these children were divided into Alb < 30 g/L (LA) group with 20 children and Alb >=30 g/L (NA) group with 70 children. The clinical manifestations, results of laboratory examination, results of blood tandem mass spectrometry and urine gas chromatography-mass spectrometry, and gene detection results were compared between the two groups. The t-test and the chi-square test were used for statistical analysis.. Results: There were significant differences between the LA group and the NA group in splenomegaly degree (3.28+/-1.95 cm vs 1.92+/-1.06 cm, P = 0.030), aspartate aminotransferase/alanine aminotransferase ratio [3.15 (0.38-5.93) vs 2.14 (0.26 6.67), P = 0.010], activated partial thromboplastin time (53.27+/-11.68 s vs 45.06+/-9.79 s, P = 0.003), and international normalized ratio (1.92+/-1.35 vs 1.29+/-0.33, P = 0.001). The SLC25A13 mutation I 851_854del4 was associated with Alb (chi2 = 4.76, P = 0.025). Conclusion: As for the children with Alb < 30g/L who are highly suspected of having NICCD, SLC25A13 gene detection and blood/urine mass spectrometry should be performed as early as possible, in order to initiate intervention treatment as soon as possible, prevent and treat complications, and improve prognosis. PMID- 27938562 TI - [Augmenter of liver regeneration promotes the proliferation of HL-7702 cells in carbon tetrachloride-induced acute liver injury via increasing autophagy]. AB - Objective: To investigate the protective effect of augmenter of liver regeneration (ALR) against acute liver injury and related mechanisms. Methods: HL 7702 cells were divided into normal control group, carbon tetrachloride (CCl4) induced acute liver injury group, ALR+CCl4 intervention group, 3-methyladenine (3 MA)+CCl4 intervention group, and ALR+3-MA+CCl4 intervention group. The ALR+CCl4 and ALR+3-MA+CCl4 intervention groups were transfected with ALR plasmids at 8 hours before CCl4 treatment. All groups except the normal control group were treated with CCl4, and 30 minutes later, the 3-MA+CCl4 and ALR+3-MA+CCl4 intervention groups were treated with 3-MA. The cells were collected at 24 hours after CCl4 treatment. The HL-7702 cells and supernatant were collected to measure the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (IU/L). Western blot was used to measure the levels of ALR, cyclin D, cyclin E, proliferating cell nuclear antigen (PCNA), autophagy-related gene 7 (Atg7), and autophagy genes LC3, p62, and Beclin-1. Quantitative real-time PCR was used to measure the mRNA expression of ALR. A one-way analysis of variance was used for comparison of means between any two groups. Results: The ALR+CCl4 intervention group had significant increases in the protein and mRNA expression of ALR compared with the acute liver injury group (both P < 0.05). The CCl4-induced acute liver injury group had significant increases in the protein and mRNA expression of ALR compared with the normal control group (both P < 0.05). Compared with the CCl4-induced acute liver injury group, the ALR+CCl4 intervention group had significant reductions in ALT (0.73+/-0.17 IU/L vs 1.43+/ 0.38 IU/L, P < 0.05) and AST (19.85+/-1.83 IU/L vs 56.73+/-6.25 IU/L, P < 0.05) in supernatant, significantly increased expression of cyclin D, cyclin E, PCNA, LC3, Atg7, and Beclin-1 in hepatocytes, and significantly reduced expression of p62, which suggested that ALR protected the liver against acute liver injury, promoted the regeneration of hepatocytes, and enhanced the autophagy of hepatocytes. The ALR+3-MA+CCl4 intervention group had a significant reduction in the expression of regeneration-associated proteins compared with the ALR+CCl4 intervention group, while there was no significant difference between the ALR+3 MA+CCl4 intervention group and 3-MA+CCl4 intervention group, which suggested that after the inhibition of autophagy, there were significant reductions in the regeneration of hepatocytes and liver regeneration promoted by ALR. Conclusion: ALR can promote the regeneration of hepatocytes in liver parenchyma, which is achieved by the regulation of autophagy. PMID- 27938563 TI - [Effect of nicotinic acetylcholine receptor alpha7 subunit gene on liver inflammatory reaction in mice with nonalcoholic steatohepatitis and related mechanisms]. AB - Objective: To investigate the effect of nicotinic acetylcholine receptor alpha7 (alpha7nAChR) subunit gene on liver inflammation in mice with nonalcoholic steatohepatitis (NASH) and related mechanisms. Methods: C57BL/6J mice and alpha7nAChR gene knockout mice were fed for 24 weeks to establish the NASH model, and the mice were sacrificed to isolate and culture the primary liver macrophages. After the treatment with nicotine and endotoxin, ELISA was used to measure the levels of the inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in supernatant; indirect immunofluorescence assay and Western blot were used to observe the effect on the NF-kappaB signaling pathway, and quantitative PCR was used to measure the mRNA expression of Toll like receptor-4 (TLR-4) in macrophages. An analysis of variance was used for comparison of means between multiple groups. Results: The results of ELISA showed that compared with the endotoxin+nicotine group of C57 NASH mice, the endotoxin+nicotine group of gene knockout NASH mice had significantly higher levels of IL-6 and TNF-alpha in supernatant (IL-6: 1 599+/-65 pg/ml vs 1 465+/-45 pg/ml, P < 0.05; TNF-alpha: 1 567+/-66 pg/ml vs 1 433+/-50 pg/ml, P < 0.05). The results of Western blot showed that compared with the endotoxin+nicotine group of C57 NASH mice, the endotoxin+nicotine group of gene knockout NASH mice had significantly higher relative protein expression of phosphorylated NF-kappaB and TLR-4 (NF-kappaB: 69 425+/-600 vs 51 133+/-200, P < 0.05; TLR-4: 93 387+/-684 vs 64 198+/-630, P < 0.05). The results of indirect immunofluorescence assay showed that the endotoxin+nicotine group of gene knockout NASH mice had a significantly higher fluorescence intensity of NF-kappaB than the endotoxin+nicotine group of C57 NASH mice. The results of PCR showed that the endotoxin+nicotine group of gene knockout NASH mice had significantly higher relative mRNA expression of TLR 4 than the endotoxin+nicotine group of C57 NASH mice (4.13+/-0.13 vs 2.93+/-0.14, P < 0.05). Conclusion: The alpha7nAChR gene knockout can aggravate the degree of inflammatory reaction in NASH, and its mechanism may be related to the fact that the NF-kappaB signaling pathway cannot be inhibited, which aggravates inflammatory reaction. PMID- 27938564 TI - [Protective effect of astragaloside IV against acute liver failure in experimental mice]. AB - Objective: To investigate the clinical effect of astragaloside IV in the early treatment of mice with acute liver failure and possible mechanisms. Methods: A mouse model of acute liver failure induced by D-galactosamine/lipopolysaccharide (D-GalN/LPS) was established, and the mice were given astragaloside IV at different doses. The survival rate of mice, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver histopathological changes, apoptosis of hepatocytes, and the expression of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured in each group. The least significant difference test was used for data with homogeneity of variances, the Dunnett's T3 test was used for data with heterogeneity of variance, and the Kaplan-Meier method was used for survival analysis. Results: Compared with the model group, the high-dose astragaloside IV group had a significant increase in the 48-hour survival rate [60% (9/15) vs 13.3% (2/15), P < 0.05], significant reductions in the serum ALT and AST levels (P < 0.01), and significant reductions in liver histopathological indices and the degree of apoptosis of hepatocytes (P < 0.01), as well as a significant reduction in the content of MDA in liver homogenate (P < 0.01) and a significant increase in the activity of SOD (P < 0.05). Conclusion: High-dose astragaloside IV has a significant protective effect against D-GalN/LPS induced acute liver injury in mice, and its mechanisms may be associated with its effects against cell apoptosis and oxidative damage. PMID- 27938565 TI - [A study on artificial liver system combined with 131I in treatment of hyperthyroidism complicated by liver failure]. PMID- 27938566 TI - [Application of HBsAg-positive liver donor in liver transplantation for HBV related liver disease]. PMID- 27938567 TI - [Clinical effect of endoscopic tissue adhesive injection versus its combination with modified lauromacrogol sandwich injection in treatment of gastric varices]. PMID- 27938568 TI - [Association between apolipoprotein E gene polymorphisms and status of chronic hepatitis B virus infection]. PMID- 27938569 TI - [Correlation between angiotensin II level and severity of liver cirrhosis]. PMID- 27938570 TI - [Advances in diagnosis and treatment of acute kidney injury in patients with liver cirrhosis]. AB - Since the 21st century, nephrology and emergency and critical care medicine have proposed the concept of acute kidney injury (AKI), and its core lies in early diagnosis and early treatment to improve prognosis. The concept of AKI has also been used in the diagnosis and treatment of kidney injury in patients with liver cirrhosis. AKI is one of the common complications in patients with decompensated liver cirrhosis, and AKI has unique features in patients with liver cirrhosis. AKI greatly affects the prognosis of patients with liver cirrhosis and increases hospitalization rate and medical burden. This article reviews the advances in the diagnosis and treatment of AKI and hepatorenal syndrome-type AKI in patients with cirrhotic ascites. PMID- 27938571 TI - [Surgical treatment of pancreatic carcinoma: problems and recent advances]. AB - Nowadays surgical technologies develop fast under the guidance of minimally invasive medicine, evidence-based medicine, multi-disciplinary team and other ideas. However, the long-term outcome of pancreatic cancer remains dismal. In addition to the improvement of surgical resection rate, more attention should be paid to improve the overall survival rate of the patients with pancreatic cancer after surgery. Clinical studies of neoadjuvant therapies for the treatment of borderline resectable pancreatic cancer are advocated. Various types of pancreaticojejunostmy should be applied individually to improve the anastomosis quality and to reduce the postoperative complications. In the system of precision medicine, standardized surgical treatment pattern remains important. PMID- 27938572 TI - [Give attention to both minimally invasive surgery and precision medicine to promote the scientificality on individualized clinical practice of rectal cancer]. AB - Based on the research results of COLORII, COREAN, ACOSOG and ALacaRT trials, NCCN rectal cancer clinical practice guidelines (Version 1.2016) made an important update, that rectal cancer can be considered to be performed by laparoscopic method in some patients with surgical indication. The eighth edition of the TNM staging system of the AJCC will be available in 2017, in which increasing molecular biomarkers and establishing a prognostic evaluation system should be emphasized. The launch of the"cancer precision medicine"program will promote the progress on comprehensive diagnosis and treatment of rectal cancer. Seeking minimal invasiveness of surgical procedures, according to the precision of diagnosis and promoting the scientificality of individualized treatment, will be the future direction of clinical practice and research of rectal cancer. PMID- 27938573 TI - [Investigate the radical extent of lymphadenectomy of right colon cancer]. AB - Considering radical surgeries of right colon cancer, the reasonable extent of lymphadenectomy has always been argued. The concept of complete mesocolic excision (CME) has recently been established and optimized, which follows similar oncological principles as total mesorectal excision (TME) does for rectal cancer and is recommended by more and more surgeons. Studies published so far in the literature have been comprehensively reviewed, they do not, however, provide convincing evidence that demonstrate the standardized operation indications. Moreover, the existence of potential surgical risk and discernible oncological benefit has not been determined. Thus future studies are needed to further investigate the safety and efficacy of CME surgery, as has been demonstrated with TME such that it should become the procedure of choice in surgical practice. PMID- 27938574 TI - [Effects of neoadjuvant chemoradiotherapy on the rates of sphincter preserving surgery in lower rectal cancer and analysis of their prognostic factors]. AB - Objectives: To identify independent factors of sphincter preserving surgery, and to evaluated whether preoperative chemoradiotherapy (CRT) improves the sphincter preservation rate for lower rectal cancers. Methods: A total of 541 consecutive patients who underwent curative surgery for locally advanced rectal cancer (cT3 4Nx or cTxN+ ) within 6 cm of the anal verge with or without neoadjuvant CRT in Department of Colorectal Surgery, Union Hospital, Fujian Medical University between September 2000 and September 2013 were reviewed. Of these, 333 patients underwent surgery alone (Non-CRT group) and 208 patients also received preoperative chemoradiotherapy (CRT group). Clinical data were retrospectively reviewed to determine the factors influencing sphincter preservation, and to evaluate sphincter preservation rate according to tumor height over 1-cm intervals. The categorical variables were compared using chi2 test and Fisher exact test. Continuous variables were compared using t test. Logistic regression was used to identify factors influencing sphincter preservation. A receiver operating characteristic (ROC) curve was constructed, and Youden's index was calculated to evaluate the predictive abilities of factors. Results: Multivariate analysis indicated that the independent factors influencing sphincter preservation were tumor height (OR=5.867, 95% CI: 4.155 to 8.285, P=0.000), pathological T stage (OR=0.688, 95% CI: 0.462 to 1.025, P=0.066), CRT (OR=2.088, 95% CI: 0.971 to 4.492, P=0.060) and histopathological type (OR=0.288, 95% CI: 0.136 to 0.611, P=0.001). The results of ROC analysis showed that the cut-off points for factors affecting sphincter preservation were as follows: (1) tumor height prior to CRT higher than 4.5 cm, (2) not mucinous or signet ring adenocarcinoma, (3) pathological T stage higher than T3, (4) had received preoperative CRT. In an analysis according to tumor height, the sphincter preservation rate was higher in CRT group only when tumor was located in 3.0 to 3.9 cm and 4.0 to 4.9 cm from the annal verge (3.0 to 3.9 cm, 59.4% vs. 2.8%, chi2=26.138, P=0.000; 4.0 to 4.9 cm, 76.9% vs. 37.9%, chi2=10.563, P=0.001). Conclusions: There is a large increased rate of sphincter preservation when patients meet the following conditions: (1) tumor height prior to CRT higher than 4.5 cm, (2) not mucinous or signet ring adenocarcinoma, (3)pathological T stage higher than T3, (4) had received preoperative CRT. Only when tumors are between 3 and 5 cm from the anal verge, CRT could increase the rate of anal sphincter preservation. PMID- 27938575 TI - [Prognostic factors of postoperative incisional surgical site infections for colorectal cancer]. AB - Objective: To explore the prognostic factors of postoperative incisional surgical site infections (I-SSI) for colorectal cancer. Methods: Clinical data of 2 385 colorectal cancer patients undergoing resection by the same surgical team in Department of Colon and Rectum Surgery, Fujian Medical University Union Hospital from January 2000 to February 2014 was analyzed retrospectively. There were 1 421 male and 964 female patients, with a mean age of (59+/-13) years. Univariate analysis and multivariate Logistic regression analysis were performed for independent prognostic factors of I-SSI. Results: The I-SSI occurred in 77 patients (3.23%). The results of univariate analysis showed that there were statistical differences in body mass index (t=-3.356), operation time (t=-3.609), length of incision (t=-5.492), radical operation (chi2=8.963), laparoscopic surgery (chi2=25.884), combined evisceration (chi2=6.349) and intraoperative blood infusion (chi2=4.176) between two groups (all P<0.05) . The results of multivariate Logistic regression analysis showed that independent prognostic factors of I-SSI were identified to be body mass index (OR=1.087, 95%CI: 1.023 to 1.155, P=0.007), operation time (OR=1.007, 95%CI: 1.002 to 1.012, P=0.006), preoperative chemoradiotherapy (OR=2.434, 95%CI: 1.099 to 5.393, P=0.028) and combined evisceration (OR=2.596, 95%CI: 1.060 to 6.357, P=0.037). The independent protective prognostic factor of I-SSI was identified to be the laparoscopic surgery (OR=0.386, 95%CI: 0.170 to 0.877, P=0.023). Conclusions: Body mass index, operation time, preoperative chemoradiotherapy and combined evisceration are identified to be independent prognostic factors for I-SSI. High-risk patients should receive individualized perioperative intervention. Nevertheless, the laparoscopic surgery can decrease the incidence of I-SSI. PMID- 27938576 TI - [Preliminary clinical experience of single incision laparoscopic colorectal surgery]. AB - Objective: To discuss the preliminary experience of single incision laparoscopic colorectal surgery. Methods: The clinical data and surgical outcomes of 104 selected patients who underwent single incision laparoscopic colorectal surgery in the 2nd Department of General Surgery, Shengjing Hospital of China Medical University from January 2010 to September 2015 were retrospectively analyzed. There were 62 male and 42 female patients, aging from 21 to 87 years with a mean of (61+/-12) years. Eighty-five patients were diagnosed with malignancy while the rest 19 cases were benign diseases. All the procedures were performed by the same surgeon using the rigid laparoscopic instruments. Surgical and oncological outcomes were analyzed in 4 kinds of procedures which are over 5 cases respectively, including low anterior resection, abdominoperineal resection, radical right colon resection and radical sigmoidectomy. Results: Single incision laparoscopic colorectal surgery was performed in 104 selected patients and was successfully managed in 99 cases with a total conversion rate of 4.8%. Radical procedures for malignancy in cases with the number of patients more than 5 were performed for 74 cases. For low anterior resection, 35 cases with an average surgical time of (191+/-57) minutes, average estimated blood loss of (117+/-72) ml and average number of harvested lymph nodes of 14.6+/-1.1. For abdominoperineal resection, 9 cases with an average surgical time of (226+/-54) minutes, average estimated blood loss of (194+/-95) ml and average number of harvested lymph nodes of 14.1+/-1.5. For radical right colon resection, 16 cases with an average surgical time of (222+/-62) minutes, average estimated blood loss of (142+/-68) ml and average number of harvested lymph nodes of 15.4+/-2.4. For radical sigmoidectomy, 14 cases with an average surgical time of (159+/-32) minutes, average estimated blood loss of (94+/-33) ml and average number of harvested lymph nodes of 13.9+/-1.5. The overall intraoperative complication rate was 2.7% (2 cases) and postoperative complication rate was 8.1% (6 cases) in these 74 cases. Conclusion: Single incision laparoscopic colorectal surgery is safe and feasible with acceptable surgical outcomes and cosmetic benefits in the hands of skilled laparoscopic surgeon in well-selected patients. PMID- 27938577 TI - [Analysis of prognostic factors of portal hypertension treated with devascularization]. AB - Objective: To explore the prognostic factors of portal hypertension treated with devascularization. Methods: A total of 397 patients with portal hypertension underwent devascularization in Nanjing Drum Tower Hospital from February 1993 to April 2014, among which there were 242 male and 155 female patients with median age of 48 years. The perioperative data were retrospectively collected. Logistic regression was used to find the risk factors which affect the operative complications. Follow-up evaluation was in progress regularly. Kaplan-Meier survival curve, Log-rank test and Cox regression model were used to find out factors which affect the long-term results. Results: All together 397 patients underwent devascularization, in whom 8 patients died perioperative, 389 patients discharged successfully. Logistic regression showed that age (>=48 years) (chi2=4.559, OR=2.048, P=0.033), red color sign before surgery (chi2=4.959, OR=2.129, P=0.026) and without portosystemic collateral vessels reserved (chi2=13.348, OR=5.122, P=0.000) were risk factors of perioperative complications. The follow-up time was (5.7+/-4.6) years. Totally 27 patients were lost from follow-up, 103 patients died for the disease during follow-up. The survival rate at 1-, 3-, 5-, 10-, 15- and 20-years was 93.6%, 86.9%, 80.1%, 59.3%, 54.1% and 38.5% respectively.Univariate analysis showed that gender (male), age (>=48 years), hemorrhage before surgery (>=500 ml per time), hepatitis virus and without portosystemic collateral vessels reserved were risk factors of the long-term survival (P<0.05). Cox regression analysis showed that age (>=48 years) (chi2=9.850, RR=1.904, P=0.002), hemorrhage before surgery (>=500 ml per time) (chi2=34.402, RR=3.273, P=0.000), hepatitis virus (chi2=7.573, RR=2.525, P=0.006) and without portosystemic collateral vessels reserved (chi2=5.905, RR=1.889, P=0.015) were independent risk factors that affect the long-term survival. Conclusion: Devascularization with portosystemic collateral vessels reserved has favorable perioperative and long-term outcome, and it definitely is a very safe and effective technique for portal hypertension. PMID- 27938578 TI - [Analysis of prognostic factors of patients with hepatocellular carcinoma after radical resection]. AB - Objective: To explore the prognostic factors of patients with hepatocellular carcinoma(HCC) after radical resection. Methods: From June 2006 to November 2009, preoperative peripheral blood and the clinicopathological data of 208 patients with HCC after curative resection treated in Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, were collected and analyzed, including 173 male and 35 female patients with mean age of 53 years. Univariate analyses were applied by the Kaplan-Meier method, and then, significant clinical factors were used for further multivariate analyses by Cox proportional hazard regression model.The patients were divided into low- lymphocyte-monocyte ratio(MLR) group(MLR<=1.2) and high-MLR group(MLR>1.2) according to preoperative MLR. Results: The enrolled 208 patients with median overall survival time for 38 months(1.5-82.2 months), median recurrence-free survival time for 36 months(1.0-82.0 months). Univariate analyses revealed alanine aminotransferase, serum albumin, tumor differentiation, tumor size, TNM stage and clinical stages and MLR might affect the prognosis significantly(all P<0.05), and multiple analyses showed that TNM stage and MLR could influence patients with HCC after radical resection of overall survival time and recurrence free survival time(all P<0.05). The overall survival time(42.1 months) and recurrence-free survival time(38.1 months) of low-MLR group were longer than high MLR group(32.7 months and 25.3 months)(both P<0.01). Conclusions: MLR might be associated with prognosis of patients with HCC after curative resection was significantly negative correlation.TNM stage and MLR might be used as an independent prognostic factors for the prognosis of patients with HCC after curative resection. PMID- 27938579 TI - [Application of indocyanine green-fluorescent imaging technique in planning resection line and real-time surgical navigation in small hepatocellular carcinoma]. AB - Objective: To explore the value of near-infrared technology guided by indolecyanine green(ICG) in planning resection line and real-time surgical navigation in small liver cancer. Methods: From March to September 2015, 11 patients with hepatic tumors received hepatectomy were treated in First Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University.There were 5 male and 6 female patients with average age of (55+/ 10)years (range 39-70 years). Among whom, there were 9 cases with hepatocellular carcinoma and 2 cases with colorectal cancer. A near-infrared light camera system was used to detect the liver surfaces before resection, and to plan resection line and surgical specimens. A student's t test was used to compare continuous parametric variables. Results: The ICG-fluorescent imaging and histological examination had been used in the 15 lesions of the 11 patients. Among the 15 lesions, 7 lesions were detected by visual inspections, palpation and ICG fluorescent imaging, 6 lesions were identified only by ICG-fluorescent imaging, 2 lesions were detected only by ICG-fluorescent imaging after resection.Results of pathologic examination indicated that the total fluorescent type include 5 well differentiated hepatocellular carcinoma and 2 cirrhotic nodule; the partial fluorescent type include 3 moderately differentiated hepatocellular carcinomas and 1 well differentiated hepatocellular carcinomas; the rim fluorescent type included 2 liver metastatic carcinoma and 2 poorly differentiated hepatocellular carcinomas. The average diameter of the tumor size measured by CT was (1.7+/ 0.2)cm, while the average diameter measured by ICG-fluorescent imaging was (1.7+/ 0.3)cm(t=-0.188, P>0.05). Conclusion: Near-infrared technology guided by ICG has important value in planning resection line and real-time surgical navigation in small liver cancer. PMID- 27938580 TI - [Posterior debridement combined with atlantoaxial fusion to upper cervical tuberculosis]. AB - Objective: To explore clinical results of posterior debridement combined with atlantoaxial fusion for upper cervical Tuberculosis. Methods: From March 2007 to April 2012, 8 patients with upper cervical Tuberculosis underwent posterior debridement combined with atlantoaxial fusion in our hospital were selected for retrospective analysis. 3 cases were males and 5 females, aged 29-65 (43.5+/ 13.2) years. According to the pedicle destruction, using different screws (pedicle screw or laminar screw) fixation.In the preoperative and final follow up, Japanese Orthopaedic Association score (JOA) and neck disability index (NDI) were used to evaluate neurological function and calculate improvement rate JOA score. At final follow-up, clinical efficacy was evaluated by Odom's grade. situation of internal fixation, fusion of upper cervical were assessed by imaging examination. During follow-up, complications were documented and analyzed. Results: Postoperatively 12 months, all bony fusion were achieved. Tuberculosis were reached clinical cure in 12-18 months. The JOA score increased from 10.5+/ 2.0 preoperatively to 15.6 +/-1.1 in final follow-up(P<0.05), and the NDI decreased from 29.9 +/- 6.2 preoperatively to 8.6+/-1.6 (P<0.05). At last follow up, according to Odom's standard, excellent were obtained in 6 cases (75.0%), good 1 cases (12.5%) and ordinary 1 case (12.5%). No severe complications was documented during follow-up. Conclusions: The treatment of posterior debridement combine with atlantoaxial fusion, and structure grafting and local anti Tuberculosis drug using intraoperative, not only could obtain reliable clinical efficacy, completely removal of lesions, but also obtain strong stability, which plays an important role in the treatment of cervical tuberculosis. PMID- 27938581 TI - [Correlative study between X-ray type after healing of congenital pseudarthrosis of the tibia in children and postoperative refracture]. AB - Objective: To investigate the relationship between postoperative X-ray type in 2 years after healing of congenital pseudarthrosis of the tibia(CPT) and refracture of CPT in children. Methods: A retrospective study was performed on 67 children patients with Crawford type IV CPT who were treated with combined surgeries from December 2007 to August 2012.There were 46 male and 21 female patients with 37 cases with left CPT and 30 cases with right CPT. There were 12 cases with proximal tibia dysplasia, 56 cases with neurofibromatosis type 1. The median age when operation was 2.8 years(from 0.6 to 11.2 years). The patients were divided into three groups, CPT with hypertrophic group, CPT with mediate group and CPT with atrophic group, on the basis of ratio of healing cross-sectional area and transition zone in pseudarthrosis.The incidence of refracture in the three groups were investigated. Results: The refracture rates of three groups were 13%(5/38), 14%(3/21), 5/8, respectively.The refracture rate difference between CPT with hypertrophic group and CPT with mediate group was not statistically significant(P=0.590). The refracture rate of CPT with atrophic group was statistically significant lower than that of CPT with hypertrophic group and CPT with mediate group(P=0.007, 0.019). In addition, the refracture-free cumulative survival rate of CPT with hypertrophic group or CPT with mediate group was higher than that of CPT with atrophic group with the statistically significant difference(both P<0.05). And the refracture-free cumulative survival rate in CPT with hypertrophic group was lower than that in CPT with mediate group, the difference was not significant(P>0.05). Conclusion: After the union of CPT, patients with hypertrophic, mediate type X ray characteristic showed lower incidence of refracture than those with atrophic type. PMID- 27938582 TI - [Short-term outcomes of minimally invasive Sweet esophagectomy for Siewert type II esophagogastric junction adenocarcinoma]. AB - Objective: To describe the technique for minimally invasive Sweet esophagectomy and to evaluate the feasibility, safety and the short-term clinical outcomes of this approach in the treatment of Siewert type II esophagogastric junction adenocarcinoma. Methods: The clinical data of 122 patients with Siewert type II esophagogastric junction adenocarcinoma who received Sweet esophagectomy between October 2013 and June 2015 in Department of Thoracic Surgery, Anhui Provincial Hospital Affiliated with Anhui Medical University was analyzed retrospectively. The study group consisted of 87 men and 35 women, and the ages ranged from 48 to 78 years (median: 67 years). Of those 122 patients, 47 underwent minimally invasive approach and 75 underwent open left transthoracic sweet esophagectomy. This study included 16 stage Ia patients, 35 stage Ib patients, 32 stage IIa patients, 28 stage IIb patients, and 11 stage IIIa patients. The clinicopathologic factors, operational factors and postoperative complications of the two groups were compared by t test and chi2 test. Results: The two groups were similar in terms of gender, age, American Society of Anesthesiologists grade, preoperative staging and incidence of comorbidities (P>0.05). The minimally invasive approach was associated with significant increase in the number of total lymph nodes dissected or the stations of the total lymph nodes dissected (18.1+/-2.7 vs. 15.0+/-2.5, t= 6.612, P=0.001; 8.9+/-1.1 vs. 6.7+/-1.2, t=9.960, P=0.003), significant decrease in surgical blood loss ((88+/-32) ml vs. (120+/-34) ml, t=5.052, P=0.001), chest tube duration ((8+/-4) d vs. (10+/-4) d, t=3.110, P=0.002) and postoperative stay ((9+/-5) d vs. (12+/-4) d, t=3.167, P=0.002) relative to the open approach. The postoperative in-hospital mortality and total morbidity did not differ between the two groups (P>0.05). The minimally invasive approach was associated with significantly fewer respiratory complications than the open approach (8.5% vs. 22.7%, chi2=4.063, P=0.044). Conclusion: Minimally invasive technique for Siewert type II esophagogastric junction adenocarcinoma can be safely and effectively performed for intrathoracic anastomosis with favorable early outcomes. PMID- 27938583 TI - [Meta-analysis: somatostatin for prophylaxis against post endoscopic retrograde cholangiopancreatography pancreatitis]. AB - Objective: To evaluate the efficacy of somatostatin in preventing pancreatitis after endoscopic retrograde cholangiopancreatography(ERCP). Methods: A standardized comprehensive literature search was performed by Cochrane library, PubMed, OVID, Springer Linker, Science Direct, EBSCO. Randomized controlled studies on the prevention of pancreatitis after ERCP before Octorber 2015 were enrolled in the study and were analyzed by 2 independent reviewers. Random effects model(REM) or fixed-effects model (FEM) was applied to calculate pooled estimates of drug efficacy depending on the outcomes. The bias risk of the included studies was evaluated by Cochrane Handbook 5.1. All data were analyzed by the RevMan 5.3 software. Results: Twelve studies, including 3 268 participants, met the inclusion criteria. The results of subgroup analysis showed that high-dose somatostatin infused over 12 h could significantly decrease the incidence of pancreatitis after ERCP(11.3% vs. 4.9%, OR=0.34, 95% CI: 0.20-0.58, P=0.000), however, low-dose or bolus injection proved ineffective in reducing rate of pancreatitis after ERCP (8.5% vs. 6.4%, OR=1.37, 95% CI: 0.89-2.12, P=0.150; 4.9% vs. 9.3%, OR=0.39, 95% CI: 0.14-1.04, P=0.060). Results of intention-to-treat analysis showed that high-dose somatostatin infused over 12 h could significantly decrease the incidence of pancreatitis after ERCP (OR=0.45, 0.49; 95% CI: 0.25-0.81, 0.27-0.91; P=0.008, 0.020). Conclusions: High-dose somatostatin could prevent post-ERCP pancreatitis. Low-dose nor bolus injection somatostatin produced no significant effect in reducing pancreatic injury. PMID- 27938584 TI - [Review of numerical simulation study of Stanford type B thoracic aortic dissection]. AB - According to the previous studies, some key indicators such as the hemodynamic parameters (pressure, flow rate, shear stress, etc.) as well as the geometry and the location of tear are closely related to the development of aortic dissection but are hard to measure in vivo. With the help of computational fluid dynamic method, a promising way is just shown to investigate the mechanisms and treatment of aortic dissection from the perspective of hemodynamics by constructing a three dimensional model to simulate blood flow. This paper presents a systematic review of the development of aortic dissection research and the major research progress of computational fluid dynamics applied to the analysis of aortic dissection. PMID- 27938585 TI - [Improve the ability of pediatricians at the basic level to guide the infant feeding]. PMID- 27938586 TI - [Infant and young child feeding guideline (0 - 3 years): information for primary health workers]. PMID- 27938587 TI - [Interpretation for the global consensus recommendations on prevention and management of nutritional rickets]. PMID- 27938588 TI - [Interpretation of the 4th Triennial Yale/Harvard Workshop on probiotic recommendations]. PMID- 27938589 TI - [Effect of family integrate care on the development of preterm infants at 18 months of age]. AB - Objective: To study the effect of family integrated care (FIC) in neonatal intensive care unit (NICU) to the development of preterm infants at 18 months of age. Method: This is a prospective parallel case-control study. Infants in FIC group were preterm infants enrolled in previous FIC study with gestational age (GA) 28-35 weeks. Study period was from July 2015 to July 2016. Subjects were all enrolled from Department of Child Healthcare in the Third Xiangya Hospital of Central South University. Infants in control group were gender, birth weight (BW), BW percentile and days of life (DOL) at follow-up matched (1?1 ratio) preterm infants who did not enter FIC in NICU. The age at follow-up was 18 months. Study parameters were maternal education year, socioeconomic status (SES) by Graffar method, home observation for measurement of the environment (HOME), mental development index (MDI) and psychomotor development index (PDI) by mental and psychomotor Bayley scales of infant development (BSID). SPSS 20.0 of chi2 test, t test, Pearson coefficient test and Spearman coefficient test were used for the statistical analysis. Result: Totally 67 infants were enrolled in each of FIC group and control group, with percentage of male gender 52% (35 infants) and 51% (34 infants), representatively. GA of FIC group and control group was (32.4+/ 1.7) and (32.2+/-1.6) weeks, BW was (1 690+/-415) and (1 719+/-412) g. Weight at 18 months follow-up was (10+/-1) and (10+/-1) kg, maternal education year was (15+/-2) and (15+/-2) years, SES was (42+/-6) and (41+/-6) score, HOME was (31+/ 5) and (32+/-5) score, representatively. There was no significant difference between FIC group and control group in the above parameters, making these 2 groups comparable. The MDI and PDI of FIC group were significantly higher than those of control group ((95+/-9) vs. (86+/-9), (87+/-9) vs. (80+/-8) score, t=5.506, 4.502, both P=0.000). The MDI and PDI of all groups were positively correlated to GA (r=0.398 and 0.272, P=0.000 and 0.001), but the difference of MDI or PDI between FIC group and control group was not related to GA (r=0.679 and -0.393, P=0.094 and 0.383). Conclusion: FIC in NICU is beneficial to the development of preterm infants at 18 months of age. It is worthwhile to promote FIC in NICU in China. Trial registration: Chinese Clinical Trial Registry, ChiCTR TRC-14004736. PMID- 27938590 TI - [Effects of infant feeding practice on eczema during early childhood in Shanghai, Hohhot, and Fuzhou]. AB - Objective: To estimate the prevalence of eczema in early childhood and effect of infant feeding practice on eczema by different regions of China with diverse climate and dietary patterns. Method: A questionnaire survey was conducted from June 2012 to October 2012 in Shanghai, Hohhot, and Fuzhou. The parent or guardian of the children aged between 2.5 to 3.5 years attending routine health visit in the chosen communities were invited to complete a modified questionnaire of the International Study of Asthma and Allergy in Childhood (ISAAC). Logistic regression model was used to analyze of the family history of allergy, duration of breastfeeding, timing of introduction of complementary foods and other potential confounders. Result: A total of 2 242 children were interviewed, 750 from Shanghai, 716 from Hohhot, and 776 from Fuzhou. The prevalence of eczema in early childhood was significantly different among Shanghai (16.9%, 95%CI 16.87 16.93), Hohhot (34.5%, 95%CI 34.46-34.54)and Fuzhou (44.3%, 95%CI 44.26-44.34). The difference was statistically significant between 3 groups (chi2=72.05, P<0.05). Introducing complementary food after the age of 6 months was associated with a decreased risk for eczema when compared to introduction between 4 to 6 months(odds ratio (OR) 0.58, 95%CI 0.41-0.81) in Fuzhou, while there was no significant association between timing of introduction of complementary foods and eczema in Shanghai and Hohhot. Conclusion: The prevalence of eczema during early childhood is various among three cities. The relationship between timing of introduction of complementary foods and eczema in Fuzhou is different from that in Shanghai and Hohhot. The role of climate and dietary patterns on prevalence of eczema needs further studies. PMID- 27938591 TI - [Electroencephalogram power development of cognitive function at age 7 to 12 years: a comparative study between attention deficit hyperactivity disorder and healthy children]. AB - Objective: To compare brain electrical cognitive tasks and brain development between study about 7 to 12 years old attention deficit hyperactivity disorder (ADHD) and normal children. Method: Prospectic case-control study was used. A total of 110 children with ADHD (63 boys and 47 girls) and 116 normal children (66 boys and 50 girls), were enrolled in this study. The electroencephalogram (EEG) was recorded when attention tasks were conducted, the EEG power was extracted from the original data and comparatively analyzed the absolute power (theta, alpha, beta spectrum) and relative power (theta/total, alpha/total, theta/alpha, theta/beta). Result: (1) Absolute power: ADHD children theta absolute power was higher than that of normal children in Pz lead ((52+/-28)vs. (40+/-30)MUV2, t=3.906, P<0.05), with statistical significance. (2) Relative power: theta/total, theta/alpha, theta/beta in ADHD are higher than normal children(0.23+/-0.07 vs. 0.20+/-0.05, 1.35+/-0.76 vs. 1.00+/-0.56, 4.75+/-2.49 vs. 3.56+/-2.08, t=2.900 and 3.954 and 3.901, P=0.004 and 0.000 and 0.000), alpha/total in ADHD is lower (0.21+/-0.09 vs. 0.24+/-0.10, t=-2.517, P=0.013). (3) The comparative study of the development of EEG power theta/beta between ADHD and normal children showed age-related correlation in both groups (r=-0.378 and 0.398, P=0.000 for both). Conclusion: ADHD children's EEG power on slow spectrum was higher than that of the normal children, it was more significant in the parietal region than in frontal region. With the increase of age, the theta relative power in ADHD and normal children gradually declined, in the normal children it linearly related, but in ADHD there was no significant regularity. theta/beta can be used as a sensitive index to assess ADHD children's cognitive function. PMID- 27938592 TI - [Clinical analysis of 51 cases with rare childhood soft tissue sarcomas]. AB - Objective: To analyze the clinical characteristics and prognosis of rare soft tissue sarcomas. Method: Clinical data of 51 patients with rare soft tissue sarcomas including fibrosarcoma, synovial sarcoma, extrarenal rhabdoid tumor, alveolar soft part sarcoma, desmoplastic small round cell tumor and undifferentiated sarcoma in children and adolescents, diagnosed at Shanghai Children's Medical Center from June 1998 to December 2013, were retrospectively analyzed. All types were treated with the same strategy and chemotherapy regimens. Their clinical features, treatment and prognosis were discussed. Result: Seventeen patients with fibrosarcoma, 10 with synovial sarcoma, 9 with extrarenal rhabdoid tumor, 6 with alveolar soft part sarcoma, 3 with desmoplastic small round cell tumor and 6 with undifferentiated sarcoma were included. The mean age at initial diagnosis was 5 years(range from 1 month to 13.5 years). The most common primary site of tumors was limbs, followed by the thoracic and abdominal cavity, accounting for 41% and 24% respectively. Twelve cases presented distant tissue or organ involvement in which bone metastases occupied the first place. Seven cases(accounting for 14%)were at stage I, 13 cases were at stage II(accounting for 25%), 19 cases were at stage III(accounting for 37%) and 12 cases were at stage IV(accounting for 24%). The median follow-up period was 36 months(range from 1 month to 123 months). Forty-four patients achieved complete remission and 3 patients achieved partial remission after initial treatment, the overall response rate was 92%. Subsequent follow-up showed 29 patients remained relapse-free while 13 patients had relapsed disease. Overall survival and event free survival at 2 years were 88% and 57%.Postoperative surgical staging was the main prognostic factors. Patients with stage III+ IV had poorer results than those with I+ II (chi2=4.909, P=0.027). Conclusion: These 6 types of soft tissue sarcomas are rare in children and adolescents. The tumor can occur anywhere in the body but commonly presents in the extremities. Complete resection of tumor remains the most important modality of treatment and is directly related to prognosis. Neoadjuvant chemotherapy helps improve the resection rate of some unresectable tumors at diagnosis. Radiation therapy is primarily adopted for focal tumor control. PMID- 27938593 TI - [Analysis of individualized primary prophylactic treatment of 19 cases of children with severe hemophilia A]. AB - Objective: To study the current situation of primary prophylaxis in severe hemophilia A children and to explore rational regimen in order to provide evidence for the development of primary prophylaxis in China. Method: A retrospective clinical data collection and analysis was conducted for 19 severe hemophilia A children who received primary prophylaxis in Beijing Children's Hospital outpatient clinic between February 2011 and September 2015 and evaluated the regimen and efficacy. Result: (1) Primary prophylaxis regimen: the median beginning age 1.8 (range 0.5-2.9) years, the median FVIII preparation using dosage 16.7 (8.0-23.5) U/(kg.time), the median using frequency was 1.0 (1.0-3.0) time/week. Eight cases among the patients received escalation of treatment intensity because of the poor bleeding control. (2) Efficacy: the median annual bleeding rate (ABR) was 1.9 (0-6.0) times/year, the median annual joint bleeding rate (AJBR) was 0 (0-3.3) times/year, without life threatening bleeding. All of them kept in 4th scale of Beijing Children Hospital daily activity level. The median annual factor consumption was 1 844 (840-5 040) U/kg. Conclusion: Low-dose primary prophylaxis regimen which were in low-dose /low frequencies and adjusted by bleeding frequency could decrease bleeding and joint bleeding frequency significantly, maintained the normal daily activity capacity and saved the factor consumption compared to standard regimen in severe hemophilia A children. PMID- 27938594 TI - [Clinical, biochemical and gene mutation characteristics of short chain acyl coenzyme A dehydrogenase deficiency by neonatal screening]. AB - Objective: To investigate the incidence, clinical, biochemical and gene mutation characteristics of short chain acyl-coenzyme A dehydrogenase deficiency (SCADD). Method: From January, 2009 to October, 2015, a retrospective analysis of the urine organic acids and acyl-coenzyme A dehydrogenase (ACADS) gene mutation characteristics of patients diagnosed as SCADD by newborn screening using tandem mass spectrometry in Department of Genetics and Metabolism (Newborn screening Center of Zhejiang Province), Children's Hospital, Zhejiang University School of Medicine. Dietary guidance, life management and supplementation of L-carnitine were conducted, and growth and intelligence development were observed during follow-up among the SCADD patients. Result: A total of 1 430 024 neonates, seventeen cases were diagnosed with SCADD with an incidence of 1/84 117. All patients had no clinical symptoms, and intelligence and physical development were normal. Blood butylacyl-carnitine (C4) levels and the ratios increased, C4 0.713.14 MUmol/L(reference value 0.03-0.48 MUmol/L), C4/C2 0.07-0.23(reference value 0.01-0.04), C4/C3 0.65-2.04(reference value 0.05-0.39). Thirteen with increased urinary ethyl malonic acid (9.30-90.99 mg/g creatinine (reference value 0-6.20 mg/g creatinine )), one patient was accompanied by increased methyl succinic acid (12.33 mg/g creatinine(reference value 0-6.40 mg/g creatinine)), one subject with increased acetylglycine (3.52 mg/g creatinine(reference value 0 0.70 mg/g creatinine)). A total of 13 known mutations were detected in the ACADS gene, 1 homozygous mutation (c.1031A>G), the others are compound heterozygous mutations. One frameshift mutation (c.508_509delGC) and 12 missense mutations were detected. Common mutation were c. 1031A>G(35.3%), c. 164C>T(20.6%) and c. 991G>A(11.8%). SCADD in newborn screening program had no clinical symptoms and normal growth development after 8-42 months follow-up. Conclusion: Cases with SCADD had no clinical symptoms with an incidence of 1/84117. The c. 164C>T and c. 1031A>G may be the common mutations. PMID- 27938595 TI - [Two cases with generalized intracranial calcification due to hereditary folate malabsorption and literature review]. AB - Objective: This study aimed to investigate the clinical, biochemical and genetic features of two Chinese children with hereditary folate malabsorption. Method: Clinical features, laboratory examinations, treatment and SLC46A1 gene of two cases were studied. Reports on hereditary folate malabsorption utill September of 2016 were searched and the clinical and genetic characteristics of reported cases were summarized. Result: The two patients presented with megaloblastic anemia from their infant period and seizures, psychomotor retardation and regression. In case1, mean corpuscular volume (MCV) was 100 fl. Serum folate was 9.96 nmol/L. Folate and 5-methylenetetrahydrofolate in cerebrospinal fluid were 0 and 0.01 separately. In case 2, MCV was 93.9 fl. Serum folate was 4.49 nmol/L. The concentration of folate and 5-methylenetetrahydrofolate in cerebrospinal fluid were both zero. On their brain CT, progressive bilateral symmetrical calcification was observed. On their SLC46A1 gene, four mutations were identified. Case 1 had one novel mutation, c. 1238T>C (L413P) and c. 194-195insG (p.Cys66LeufsX99). From Case 2, two reported mutations, c. 1A>T (M1L) and c. 194 195insG (p.Cys66LeufsX99) were identified. The administration of folinic acid (60 to 120 mg per day) was initiated after diagnosis. Clinical improvement and normalized hematologic markers were observed after treatment. Totally 37 cases were reported in reviewed English literature, including 30 cases with mutations on SLC46A1 gene (only one Chinese patient). All the cases had the onset in infancy. The ratio of boys to girls was 1 to 1.5. Main manifestations were characterized by megaloblastic anemia (77%), failure to thrive (50%), diarrhea (27%), psychomotor retardation (63.6%), epilepsy (27%), and infection of respiratory system (45.5%). The concentration of folate in both serum and cerebrospinal fluid was decreased (72.7% and 63.6% respectively). Hypoimmunoglobulinemia accounted for 27.3%. Most of mutations in HFM were distributed between p. 65 and p. 68 (c.194-c.204), mainly due to insertion- or deletion-related frame shifts or generation of stop codons. Oral and parenteral folinic acid treatment was effective. Conclusion: Hereditary folate malabsorption often presented with megaloblastic anemia, abnormalities of digestive and nervous system, and hypoimmunoglobulinemia with recurrent infections. Low level of serum and CSF folate and screening SLC46A1 gene are keys to the etiologic study of the patients. Early supplement with folinic acid is beneficial to the prognosis. PMID- 27938596 TI - [Focal segmental glomerulosclerosis after renal transplantation in a child with ANCA-associated glomerulonephritis: case report and literature review]. AB - Objective: To study the clinical features and treatment of focal segmental glomerulosclerosis (FSGS) after renal transplantation in a child with ANCA associated glomerulonephritis. Method: The clinical and pathological data of the patient treated in the Department of Pediatrics as well as in the Department of Organ Transplantation in November 2015 in the First Affiliated Hospital of Sun Yat-sen University, who was diagnosed with de novo FSGS after renal transplantation with a primary disease ANCA-associated glomerulonephritis, was analyzed retrospectively. Reports on "ANCA-associated glomerulonephritis" "(renal OR kidney) transplantation" "focal segmental glomerular sclerosis" were searched and reviewed. Result: A ten years old female was definitely diagnosed with ANCA associated glomerulonephritis on the 81st day after the onset of primary ANCA associated glomerulonephritis. Because of progressive decline of renal function, a hemodialysis period for 7 months was administered following the pulsed methylprednisolone as well as cyclophosphamide treatment. The renal transplantation was then carried out 18 months later, the renal function recovered 7 days later while proteinuria reappeared 28 days after renal transplantation. Based on the anti-rejection treatment, 3 times pulsed methylprednisolone administration did not make difference on reducing the proteinuria and then a renal biopsy was conducted and the transplanted kidney proved to be a newly developed FSGS. Consequently, plasma exchange therapy was administrated. When the plasma exchange course finished, the proteinuria decreased significantly (from 3.270 g/24 h to 0.370 g/24 h). No reports were retrieved either in Chinese databases or at PubMed as well as Medline databases. Conclusion: FSGS appears in transplanted kidney in patient with a primary renal disease as ANCA associated glomerulonephritis with early proteinuria after transplantation as well as negative P-ANCA and MPO. Pathology of renal biopsy revealed FSGS while the pathology of other recipient was not FSGS. The patient had no response to pulsed methylprednisolone therapy. Instead, plasma exchange therapy was an alternative also effective treatment for de novo FSGS in transplanted kidney. PMID- 27938597 TI - [Diagnosis of a case with Williams-Beuren syndrome with nephrocalcinosis using chromosome microarray analysis]. AB - Objective: To explore the clinical phenotypes and the genetic cause for a boy with unexplained growth retardation, nephrocalcinosis, auditory anomalies and multi-organ/system developmental disorders. Method: Routine G-banding and chromosome microarray analysis were applied to a child with unexplained growth retardation, nephrocalcinosis, auditory anomalies and multi-organ/system developmental disorders treated in the Department of Pediatrics of Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology in September 2015 and his parents to conduct the chromosomal karyotype analysis and the whole genome scanning. Deleted genes were searched in the Decipher and NCBI databases, and their relationships with the clinical phenotypes were analyzed. Result: A six-month-old boy was refered to us because of unexplained growth retardation and feeding intolerance.The affected child presented with abnormal manifestation such as special face, umbilical hernia, growth retardation, hypothyroidism, congenital heart disease, right ear sensorineural deafness, hypercalcemia and nephrocalcinosis. The child's karyotype was 46, XY, 16qh+ , and his parents' karyotypes were normal. Chromosome microarray analysis revealed a 1 436 kb deletion on the 7q11.23(72701098_74136633) region of the child. This region included 23 protein coding genes, which were reported to be corresponding to Williams-Beuren syndrome and its certain clinical phenotypes. His parents' results of chromosome microarray analysis were normal. Conclusion: A boy with characteristic manifestation of Williams-Beuren syndrome and rare nephrocalcinosis was diagnosed using chromosome microarray analysis. The deletion on the 7q11.23 might be related to the clinical phenotypes of Williams-Beuren syndrome, yet further studies are needed. PMID- 27938599 TI - [A case report of protein-C deficency related neonatal purpura fulminans]. PMID- 27938598 TI - [Infantile systemic hyalinosis: a case report and literature review]. AB - Objective: To investigate the clinical, pathological and gene mutation features of infantile systemic hyalinosis(ISH). Method: Data of a child with ISH seen in Haikou Hospital were retrospectively analyzed for the diagnosis and differential diagnosis of infantile systemic hyalinosis and the relevant reports in literature were reviewed. Result: A 1 year and 1 month old boy showed limbs joint stiffness, limited mobility and double knee flexion at his first month of life. At third month, red rashes appeared on the body and gradually became purple, most of them were seen on the back and they were higher than the skin surface, uneven and did not fade when pressed. Undergoing X-ray the boy showed double knee varus deformity. Histopathological examination of the neck skin lesions proved hyalinosis. The gene examination revealed ANTXR2 exon 13, c. 1073 delC/c.1074 delT mutations, which were hot spots mutation of ISH, then the diagnosis of ISH was confirmed. Using "Infantile systemic hyalinosis" as a keyword, literature in Wanfang network, PubMed and China National Knowledge Infrastructure from 1978 to 2015 was searched, we found 48 foreign cases, one Chinese Taiwan case. All the cases had joint contractures. Short stature and skin lesions with hyperpigmentation in 40 cases, gingival hyperplasia in 36 cases, perianal nodules in 32 cases, skin thickening in 31 cases, osteoporosis in 30 cases, recurrent diarrhea in 30 cases, repeated infections in 25 cases; 49 cases were reported as autosomal recessive genetic disease, of whom 18 cases underwent genetic testing, the pathogenic gene was located in the fourth chromosome q21 position, the gene was encoded as capillary morphogenesis Protein 2 (CMG2), also known as anthrax toxin receptor 2 (ANTXR2), but there were various mutation spots in the gene. Among the 18 cases, 9 were of frameshift, 8 of missense and 1 of splice defect . Onset ages were mainly within 4 months after birth. Without special treatment most patients died at about 2 years of age due to repeated infections. Conclusion: ISH is a rare disease, which occurs at early age. ISH has special clinical features: joint contracture and limited mobility, special skin rash and pigmentation, skin hyaline degeneration of pathological examination. ISH is an autosomal recessive genetic disease with mutation gene located in the fourth chromosome q21 position. Currently there is no effective treatment for ISH, with which patients are prone to die of recurrent infections. PMID- 27938600 TI - [Neonatal lupus complicated by stroke: case report]. PMID- 27938601 TI - [Understanding the effects of allergic diseases on children with attention deficit hyperactivity disorder]. PMID- 27938602 TI - [Gastrointestinal difficulties in children with autism spectrum disorder]. PMID- 27938603 TI - [The research progress of Kawasaki disease shock syndrome]. PMID- 27938604 TI - [Evaluation of the clinical characteristics of patients with positional obstructive sleep apnea hypopnea syndrome]. AB - Objective: To evaluate the clinical characteristics of patients with positional obstructive sleep apnea hypopnea syndrome (P-OSAHS). Methods: The study retrospectively analyzed 171 men diagnosed as having OSAHS in Beijing Tongren Hospital, Capital Medical University, during July 2012 to June 2014. That the apnea hypopnea index (AHI) during supine position of >= 2 times by the AHI during lateral position was employed as the standard for P-OSAHS. Subjective symptoms, physical examinations, polysomnography (PSG), and three-dimensional computer tomography (3-D CT) were compared between P-OSAHS group and control group with non-positional OSAHS. Results: Of 171 patients with OSAHS, 47(27.5%) had P-OSAHS and 124 (72.5%) presented with non-positional OSAHS. There were significant differences between two groups in BMI, neck circumference, AHI, the lowest oxygen saturation, the percentage of time with oxygen saturation below 90% (CT90), and the minimal anterior-posterior airway dimension of the glossopharynx (P<0.05). The AHI was the only predictive parameter for P-OSAHS (P<0.01). There were significant differences in the incidence of P-OSAHS between patient with mild or moderate disease (AHI<30), severe disease (AHI>=30 but<60), and extremely severe disease (AHI>=60) (81.8% (18/22) vs 45.3% (24/53) vs 5.2% (5/96), P<0.05). Conclusion: The severity of OSAHS closely related to the incidence of P-OSAHS, with significant differentce in the incidence of P-OSAHS between the patients with different severity of OSAHS. PMID- 27938605 TI - [Evaluation of polysomnographic diagnostic criteria for obstructive sleep apnea syndrome in children]. AB - Objective: To determine the appropriate criteria of obstructive sleep apnea syndrome (OSAS) in children. Method: Children with snoring and healthy children were recruited from October 2014 to September 2015. Subjects were divided into four groups based on polysomnography(PSG). Group 1: children with obstructive apnea hypopnea index(OAHI)>=1 (the OSAS criteria of the International Classification of Sleep Disorders, ICSD) but their AHI<=5 or OAI <=1 (under the OSAS criteria of AHI>5 or OAI>1 by the American Thoracic Society, ATS); Group 2: children with OAHI<1 (the primary snoring criteria of the ICSD); Group 3: children with AHI>5 or OAI>1; and Group 4: normal children as controls. Sleep disorder scales and polysomnography parameters were compared among the four groups. Results: A total of 1 115 children were included.There were 143, 345, 529 and 98 children in each group. After adjust for age, gender and body mass index(BMI), children in group 1 had higher total sleep disorder scale score (P<0.01), as well as sub-scores for severe snoring (P<0.01), daytime behavior problem (P<0.01) and sleep related nighttime abnormality (P<0.05) compared with normal controls, and they had longer mean and longest duration of obstructive apnea and hypopnea and lower minimum oxygen saturation compared with children with obstructive AHI<1 (all P<0.05 or <0.01). Conclusion: OAHI>1 should be defined as the criteria of OSAS in children. PMID- 27938606 TI - [The validity and reliability of simplified Chinese version of the pediatric sleep questionnaire for screening children with obstructive sleep apnea syndrome in Beijing]. AB - Objective: To evaluate the validity and reliability of the simplified Chinese version of pediatric sleep questionnaire (PSQ) used in screening obstructive sleep apnea syndrome (OSAS) of children in Beijing. Methods: Children with snoring who presented to the Sleep Center of Beijing Children's Hospital between August 2014 and July 2015 and healthy children were included in the study. All children underwent PSG and then were divided into OSAS group and control group based on the PSG and their guardians were asked to complete the simplified Chinese version of PSQ that was formed by both translation from PSQ and retroversion to PSQ. Structure validity evaluation included confirmatory factor analysis which used Amos structural equation model and exploratory factor analysis which used principal component analysis. Predictive validity were measured with Logistic regression model. Internal reliability and test-retest reliability were evaluated by Cronbach 's alpha coefficient and intra-class correlation coefficient (ICC), respectively. The screening efficiency was evaluated by the receiver operating characteristic curve (ROC). Results: The study included 235 children aged 3-16 years old, 145 children of them with the age of (5.8+/-2.1) in OSAS group and 90 children with the age of (7.7+/-3.3) in control group. Confirmatory factor analysis indicated most items belonging to individual factors with load coefficient >= 0.5. Predictive validity analysis revealed 13 items positively related to the diagnosis of OSAS (all OR>1, all P<0.05). Cronbach's alpha coefficients were respectively 0.703 (overall reliability), 0.767 (breathing factor), 0.849 (sleepiness factor) and 0.689 (behavior factor). The test-retest ICC reliability was 0.986 (PSQ), 0.991 (breathing factor), 0.727 (sleepiness factor), and 0.870 (behavior factor) with P<0.05. In receiver operating characteristic curve, the area under curve of simplified Chinese version PSQ score was 0.922 with P<0.05 and the cutoff value of PSQ score was 7 in 22 items with the sensitivity of 0.776, specificity of 0.867, positive predictive value of 0.868 and negative prediction value of 0.774. Conclusions: The simplified Chinese version of PSQ is suitable to the screen of OSAS for the children in Beijing area with good reliability and validity. It also has acceptable sensitivity and specificity for screening children with OSAS when the cutoff score is 7 points. PMID- 27938607 TI - [Prevalence of hearing disorders in China: a population-based survey in four provinces of China]. AB - Objective: To investigate the prevalence, severity of hearing disorders and demographics of people with hearing disorders based on the whole population in Jilin, Guangdong, Shannxi and Gansu provinces in China. Methods: According to " WHO Ear and Hearing Disorders Survey Protocol" , 144 clusters were chosen with probability proportional sampling(PPS) method from the four provinces covering 194, 688, 061 residents. Audiological test, otological examination and questionnaire surveying were conducted for all samples from August, 2014 to September, 2015. The hearing disorders were classified according to WHO criteria and classification. Results: Among 47 511 targeted residents, 45, 052 individuals (94.82% response rate) participated in the survey. The standardized prevalence rates of hearing disorders and disabling hearing disorders were 15.84 % and 5.17 % respectively. Almost 50% of people with hearing disorders had no awareness of it or its starting time. There was significant difference in the prevalence among people of different ages, genders, occupations, provinces, marital status and education levels. The prevalence of hearing disorders increased significantly as age grew. People above 60 years old occupied 55.31% of the total hearing disorders. The prevalence of hearing disorders among male, people of low education and those who lost husband or wife, as well as workers and farmers was relatively higher. Conclusions: The prevalence of hearing disorders is high, and hearing disorders are " invisible" . Demographics and socioeconomic factors significantly influence the prevalence of hearing disorders. PMID- 27938608 TI - [Detection of the electric brain stem auditory response before cochlear implantation and its significance]. AB - Objective: Analysis of the outcome of the electric brain stem auditory response (EABR) before cochlear implantation (CI) and the mapping parameters after CI in 187 cases, to explore the significance of EABR before CI. Methods: From February, 2008 to December, 2014, EABR were performed in 187 patients with normal cochlear structures before CI with Nucleus 24R multi-channel cochlear. Including 105 cases of male, 82 cases of female; 152 cases of no residual hearing, 35 cases of residual hearing. Self-design electrical stimulator and US Bio-logic auditory evoked potential were taken, EABR were performed under general anesthesia before CI, recording EABR waveforms, measuring the latency of II, III, IV, V wave and the III-V interval, V-wave amplitude, V-wave threshold and I/O curve slope. Data were analysis by SPSS19.0. Results: EABR waveforms were recorded in all 187 patients. The II, III, IV, V waves are similar with the acoustic evoked ABR, the waveforms differentiation were different in ages, but no significant difference in gender. At 50 MUs pulse electrical stimulation, the average threshold of V wave was (156.37+/-21.44)CL, the average dynamic range was (36.33+/-8.63)CL. 20 CL above the threshold, average latency of wave II, III, V was (1.54+/-0.12)ms, (2.06+/-0.23)ms and (4.14+/-0.25)ms, the III-V interval was (2.08+/-0.24)ms, the average amplitude of V-wave was (0.35+/-0.07)MUV. One month later, the 187 patients achieved different degrees of hearing, the average C value of mapping was (163.55+/-27.43)CL, significantly correlated with EABR threshold(r=0.915, P=0.013). The EABR threshold in 35 cases of no residual hearing value was (163.82+/-16.21)CL and V-wave I/O curve slope was 0.035 227+/-0.013 918, and the threshold was (148.41+/-15.38)CL , the slope was 0.041 364+/-0.013 623 in paired group of 35 residual hearing patients, there was a statistically significant difference between two groups(t=15.838 and 4.328, P<0.05). Conclusions: The EABR detection method is reliable, extraction rate is high. EABR can be used to evaluate the auditory pathway before inserting electrode, which could provide the help for the screening operative indications of CI. PMID- 27938609 TI - [SOX10 mutation is relevant to inner ear malformation in patients with Waardenburg syndrome]. AB - Objective: To determine the relevance between the SOX10 mutation and Waardenburg syndrome (WS) accompanied with inner ear abnormality by analyzing the inner ear imaging results and molecular and genetic results of the WS patients with the SOX10 mutation. Methods: This study included 36 WS in patients during 2001 and 2015 in the department of otorhinolaryngology head and neck surgery, Chinese Peoples's Liberation Army General Hospital. The condition of the inner ear of each patient was assessed by analyzing HRCT scans of the temporal bone and MRI scans of the brain and internal auditory canal. Meanwhile, the possible pathogenic genes of WS, including SOX10, MITF, and PAX3, were also screened. Patients were divided into two groups according to SOX10 mutation.The Fisher accuracy test was used to determine statistical difference of inner ear deformation incidence between the two groups. Results: Among all 36 patients, 12 were found to have inner ear abnormality. Most abnormalities were posterior semicircular canal deformations, some accompanied with cochlear deformation and an enlarged vestibule. Among all patients, 9 patients were SOX10 heterozygous mutation carriers, among which six showed bilateral inner ear abnormality. Fisher accuracy test results suggested a significant correlation between the SOX10 mutation and inner ear abnormality in WS patients (P=0.036). Conclusion: This study found that WS patients with the SOX10 mutation are more likely to have deformed inner ears when compared to WS patients without the SOX10 mutation. PMID- 27938612 TI - [Repeated carotid blowout's rescue experience of a postoperative patient with hypopharyngeal carcinoma]. PMID- 27938610 TI - [Characteristics of postviral olfactory disorder]. AB - Objective: To explore the clinical characteristics of patients with olfactory dysfunction after upper respiratory tract infection. Methods: Through clinical specialist examination and imaging examination, 95 cases of patients with olfactory dysfunction after upper respiratory tract infection were confirmed, 58 cases in anosmia group and 37 cases in hyposmia group. All were performed by a subjective olfactometry (Sniffin'Sticks test) and a subjective taste function tests. The results were statistically analyzed by SPSS 17.0 software. Results: In 58 cases of anosmia group, 21 cases of male, 37 cases of female; Twenty-six cases of youth, 23 cases of middle age, 9 cases of old age; Twenty-seven cases occurs in spring, 11 cases in summer, 12 in autumn and 8 in winter. Among 37 cases of hyposmia group, 12 cases of male, 25 cases of female; Eighteen cases of youth, 16 cases of middle age, 3 cases of old age; Fourteen cases occurs in spring, 8 cases in summer, 7 in autumn and 8 in winter. There was no statistically significant difference in gender, age and the onset season between the two groups(chi2=0.142, P>0.05; chi2=1.124, P>0.05; chi2=1.335, P>0.05). In anosmia group, with 4 cases of ageusia, 22 cases of hypogeusia, 32 cases of normal taste; in hyposmia group, with 0 cases of ageusia, 10 cases of hypogeusia, 27 cases of normal taste. There were significant differences between the two groups with different types of taste disorder(Pearson correlation coefficient r=0.210, P<0.05), it was positive correlation. Conclusions: It is suggested that after the upper respiratory tract infection, the olfactory dysfunction is often accompanied by the sense of taste dysfunction, the more severe the damage of olfactory function, the degree of damage to the taste function is also increased. Olfactory impairment degree exhibited no relationship with gender, age or onset seasons. PMID- 27938611 TI - [The clinical significance of Delphian lymph node metastasis in papillary thyroid cancer]. AB - Objective: To evaluate the clinical significance of Delphian lymph node (DLN) metastasis in papillary thyroid cancer (PTC). Method: A total of 505 cases with PTC confirmed pathologically in our hospital between January 2015 and December 2015 were retrospectively reviewed. 208 patients with DLN assessed separately by histopathologic examination who underwent primary surgery for PTC were included for the following analysis. Results: In 208 patients, the detection rate of DLN was 63.0% and the metastasis rate of DLN was 21.4%. DLN metastasis was correlated with PTC multifocality (P=0.038), tumor size over 1cm (P=0.001), BRAFV600E mutation (P=0.017) and central neck node metastasis (P<0.001). Tumor size over 1cm (95%CI 1.308-9.909, OR=3.600, P=0.013) and the number of node with central neck metastasis (95%CI 1.313-2.163, OR=1.685, P<0.001) were independent risk factors for DLN metastasis. The presence of DLN metastasis was associated with an 8.8-fold higher frequency of central neck node metastasis compared to cases without DLN metastasis. Among patients with DLN metastases, central lymph node metastasis was more common in the cases with lateral neck node metastases compared to those without lateral neck node metastases (6.5+/-3.0 vs 1.5+/-0.7, P=0.009), and 5 of the 6 patients also presented with PTC multifocality and BRAFV600E mutation. Conclusion: DLN metastasis implies a higher possibility of central neck lymph node metastasis. DLN should be assessed during operation to provide information for neck dissection, post-operative administration and follow up strategy. PMID- 27938613 TI - [Extracranial meningiomas from inferior turbinate: a case report]. PMID- 27938614 TI - [Malignant peripheral nerve sheath tumor of the nasal cavity and nasopharynx in child: a case report]. PMID- 27938615 TI - [Choanal polyp originated from the supra-ethmoidal bulla recess: a case report]. PMID- 27938616 TI - [Sphenoid sinus inverted papilloma: a case report]. PMID- 27938617 TI - [One case report of incomplete Kawasaki disease presented as retropharyngeal inflammation]. PMID- 27938618 TI - [Summary of the 2016 National Conference of Otology]. PMID- 27938619 TI - [Sidelights of European Academy of Allergy and Clinical Immunology Congress 2016]. PMID- 27938620 TI - [Application of narrow-band imaging endoscope in diagnosis and treatment of recurrent respirator papillomatosis]. PMID- 27938621 TI - [Chronic subjective dizziness]. AB - Chronic subjective dizziness(CSD) was defined as persistent nonvertiginous dizziness or subjective unsteadiness. Patients are hypersensitivity to motion stimuli, such as head movement and motion of objects in the visual surrounding, and have difficulty with precise visual tasks. The concept of CSD was first proposed by Staab and Ruckenstein, which indicates relationships between chronic dizziness and acute vestibular or psychiatric disorders, including neuro-otologic type, psychiatric type or interactive type. Treatment includes vestibular rehabilitation therapy, pharmacologic interventions and psycho-behavioral interventions(cognitive behavioral therapy). PMID- 27938622 TI - [RET pro-oncogene and medullary thyroid carcinoma]. AB - Medullary thyroid carcinoma (MTC) originats from the parafollicular C cells of the thyroid, which is one of the most aggressive forms of thyroid malignancy with the poor prognosis. Hereditary MTC has multiple endocrine neoplasia types 1, 2A and 2B. The mutation of RET proto-oncogene has been identified as the main cause of MTC, and all mutations locate among the exons 5, 8, 10, 11, 13, 14, 15, and 16. Mutation analysis of the RET may provide a theoretical basis for the prevention, diagnosis and treatment of MTC. PMID- 27938623 TI - [Personalized combined modality therapy based on pathophysiology of obstructive sleep apnea hypopnea syndrome]. PMID- 27938624 TI - Do rates of depression vary by level of alcohol misuse in Australian general practice? AB - Limited data exist regarding co-occurring alcohol misuse and depression among general practice patients. This study examined the prevalence of depression by level of alcohol misuse, and the sociodemographic factors associated with depression and increased alcohol misuse severity. A cross-sectional survey was administered to 3559 Australian general practice patients. Patients completed their demographic details, the Patient Health Questionnaire (9-item) and the Alcohol Use Disorder Identification Test (Consumption items). The prevalence of alcohol misuse and depression was 6.7%, and depression prevalence varied significantly according to level of alcohol misuse (P<0.001). Age, gender, Aboriginality and number of chronic diseases were associated with depression and higher levels of alcohol misuse. These findings may assist General Practitioners in identifying those at risk of experiencing co-morbid depression and alcohol use, and aid in effective treatment and referral. PMID- 27938625 TI - Presence of vascular endothelial growth factor during the first half of IVM improves the meiotic and developmental competence of porcine oocytes from small follicles. AB - The aim of the present study was to investigate the effect of vascular endothelial growth factor (VEGF) on the meiotic and developmental competence of porcine oocytes from small follicles (SF; 0.5-3mm diameter). When cumulus-oocyte complexes (COCs) from medium-sized follicles (MF; 3-6mm diameter) and SF were cultured for IVM, the maturation rates were significantly higher for oocytes from MF than SF. Concentrations of VEGF in the medium were significantly higher for COCs cultured from MF than SF. When COCs from SF were exposed to 200ngmL-1 VEGF during the first 20h of IVM, the maturation rate improved significantly and was similar to that of oocytes derived from MF. The fertilisability of oocytes was also significantly higher than that of VEGF-free SF controls. Following parthenogenetic activation, the blastocyst formation rate improved significantly when SF COC culture was supplemented with 200ngmL-1 VEGF, with the rate similar to that of oocytes from MF. The results of the present study indicate that VEGF markedly improves the meiotic and developmental competence of oocytes derived from SF, especially at a concentration of 200ngmL-1 during the first 20h of IVM. PMID- 27938626 TI - Prepartum maternal diets supplemented with oilseeds alter the fatty acid profile in bovine neonatal plasma possibly through reduced placental expression of fatty acid transporter protein 4 and fatty acid translocase. AB - In the present study, we determined the effects of maternal dietary fat and the type of fat on plasma fatty acids and the expression of placental fatty acid transporter genes. In Experiment 1, Holstein cows in the last 35 days of gestation received diets containing sunflower seed (n=8; high in linoleic acid (LA)), canola seed (n=7; high in oleic acid (OLA)) or no oilseed (n=7; control). Fatty acids were quantified in dam and neonate plasma at calving. In Experiment 2, placental cotyledons were collected (LA: n=4; OLA: n=4; control: n=5) to quantify gene expression. Maternal long-chain polyunsaturated fatty acids, neonatal total n-3 fatty acids and eicosapentaenoic acid (EPA) declined, whereas docosahexaenoic acid (DHA) and total fat tended to decline following fat supplementation prepartum. Feeding of LA versus OLA prepartum tended to increase peroxisome proliferator-activated receptor alpha (PPARA) expression, whereas peroxisome proliferator-activated receptor delta (PPARD) and peroxisome proliferator-activated receptor gamma (PPARG) expression tended to be higher in OLA- than LA-fed cows. Expression of fatty acid transporter protein 4 (FATP4) and fatty acid translocase (FAT/CD36) expression was lower in placental tissue of cows fed fat compared with control cows. Reduced total n-3 fatty acids, EPA and DHA in neonates born of dams fed fat prepartum is likely due to changes in PPARs and reduced expression of placental FATP4 and FAT/CD36. PMID- 27938627 TI - Modulation of adiponectin system expression in the porcine uterus during early pregnancy by prostaglandin E2 and F2alpha. AB - Studies have demonstrated that adiponectin could be a link between reproductive functions and energy metabolism in animals. The aim of the present study was to investigate the effects of prostaglandin (PG) E2 and PGF2alpha (10, 50, 100, 250 and 500ngmL-1) on the expression and secretion of adiponectin and its receptor genes and proteins by cultured in vitro porcine endometrial and myometrial tissues on Days 10-28 of pregnancy and Days 10-11 of the oestrous cycle. The gene expression was analysed using the real-time PCR method. Adiponectin protein secretion was determined by ELISA, whereas the receptors proteins content was defined using Western Blot analysis. Both PGE2 and PGF2alpha modulated the expression of adiponectin system genes and proteins in the uterus during early pregnancy. PGE2 and PGF2alpha had similar effects on the adiponectin system, which differed between the stages of gestation and between pregnancy and the oestrous cycle. On Days 10-11 of gestation, PGE2 and PGF2alpha generally increased adiponectin secretion by endometrial and myometrial tissues. Both PGs decreased levels of endometrial adiponectin receptor type 1 (AdipoR1), whereas only PGF2alpha decreased myometrial levels of AdipoR1. Both PGs increased myometrial adiponectin receptor type 2 (AdipoR2) levels. On Days 12-13 of gestation, PGE2 decreased AdipoR1 concentrations in both tissues and AdipoR2 levels in the endometrium. PGF2alpha decreased myometrial concentrations of both receptors. On Days 15-16 of gestation, both PGE2 and PGF2alpha increased concentrations of AdipoR1 and AdipoR2 in the endometrium and myometrium. PGE2 stimulated the secretion of adiponectin in the endometrium, but not in the myometrium. On Days 27-28 of pregnancy, both PGE2 and PGF2alpha inhibited the expression of AdipoR1 and AdipoR2 in endometrial and myometrial tissues and decreased the secretion of endometrial adiponectin. Both PGE2 and PGF2alpha had tissue-specific and dose-dependent effects on the adiponectin system. PMID- 27938628 TI - Anthropogenic antibiotic resistance genes mobilization to the polar regions. AB - Anthropogenic influences in the southern polar region have been rare, but lately microorganisms associated with humans have reached Antarctica, possibly from military bases, fishing boats, scientific expeditions, and/or ship-borne tourism. Studies of seawater in areas of human intervention and proximal to fresh penguin feces revealed the presence of Escherichia coli strains least resistant to antibiotics in penguins, whereas E. coli from seawater elsewhere showed resistance to one or more of the following antibiotics: ampicillin, tetracycline, streptomycin, and trim-sulfa. In seawater samples, bacteria were found carrying extended-spectrum beta-lactamase (ESBL)-type CTX-M genes in which multilocus sequencing typing (MLST) showed different sequence types (STs), previously reported in humans. In the Arctic, on the contrary, people have been present for a long time, and the presence of antibiotic resistance genes (ARGs) appears to be much more wide-spread than was previously reported. Studies of E coli from Arctic birds (Bering Strait) revealed reduced susceptibility to antibiotics, but one globally spreading clone of E. coli genotype O25b-ST131, carrying genes of ESBL type CTX-M, was identified. In the few years between sample collections in the same area, differences in resistance pattern were observed, with E. coli from birds showing resistance to a maximum of five different antibiotics. Presence of resistance-type ESBLs (TEM, SHV, and CTX-M) in E. coli and Klebsiella pneumoniae was also confirmed by specified PCR methods. MLST revealed that those bacteria carried STs that connect them to previously described strains in humans. In conclusion, bacteria previously related to humans could be found in relatively pristine environments, and presently human-associated, antibiotic-resistant bacteria have reached a high global level of distribution that they are now found even in the polar regions. PMID- 27938629 TI - "Struggle to obtain redress": Women's experiences of living with symptoms attributed to dental restorative materials and/or electromagnetic fields. AB - The aim of this study was to explore the experiences of illness and the encounters with health care professionals among women who attributed their symptoms and illness to either dental restorative materials and/or electromagnetic fields, despite the fact that research on health effects from dental fillings or electricity has failed to substantiate the reported symptoms. Thirteen women (aged 37-63 years) were invited to the study and a qualitative approach was chosen as the study design, and data were collected using semi structured interviews. The analysis was conducted with a constant comparative method, according to Grounded Theory. The analysis of the results can be described with the core category, "Struggle to obtain redress," the two categories, "Stricken with illness" and "A blot in the protocol," and five subcategories. The core category represents the women's fight for approval and arose in the conflict between their experience of developing a severe illness and the doctors' or dentists' rejection of the symptoms as a disease, which made the women feel like malingerers. The informants experienced better support and confirmation from alternative medicine practitioners. However, sick-leave certificates from alternative medicine practitioners were not approved and this led to a continuous cycle of visits in the health care system. To avoid conflicting encounters, it is important for caregivers to listen to the patient's explanatory models and experience of illness, even if a medical answer cannot be given. PMID- 27938630 TI - Health system reform in peri-urban communities: an exploratory study of policy strategies towards healthcare worker reform in Epworth, Zimbabwe. AB - BACKGROUND: Human resources for health (HRH) remains a critical challenge, according to the Kampala Declaration and Agenda for Global Action of 2008 and the 2030 Sustainable Development Agenda. Available literature on health system reforms does not provide a detailed narrative on strategies that have been used to reform HRH challenges in peri-urban communities. This study explores such strategies implemented in Epworth, Zimbabwe, during 2009-2014, and the implications these strategies might have on other peri-urban areas. DESIGN: Qualitative and quantitative methods were used in an exploratory and cross sectional design. Purposive sampling was used to select key informants, a sample of healthcare workers that participated in in-depth interviews and community members who took part in focus group discussions. Secondary data were collected through a documentary search. Qualitative data were analysed through thematic analysis. Quantitative secondary data were examined using descriptive statistics and then compared with qualitative data to reinforce analysis. RESULTS: The HRH reform policy strategies that were identified included ministerial intervention; policy review; and revival of the human resource for health planning, financial planning, multi-sector collaboration, and community engagement. These had some positive effects; however, desired outcomes were undermined by financial, material, human resource, and social constraints. CONCLUSIONS: Despite constraints, the strategies helped revive the health delivery system in Epworth. In turn, this had a favourable outlook on post-2008 efforts by the Global Health Alliance towards healthcare worker reform and the 2030 Sustainable Development Agenda in peri-urban communities. PMID- 27938631 TI - An evaluation of the competencies of primary health care clinic nursing managers in two South African provinces. AB - BACKGROUND: Managerial competencies to enhance individual and organisational performance have gained currency in global efforts to strengthen health systems. Competent managers are essential in the implementation of primary health care (PHC) reforms that aim to achieve universal health coverage. OBJECTIVE: To evaluate the competencies of PHC clinic nursing managers in two South African provinces. DESIGN: A cross-sectional study was conducted in two South African provinces. Using stratified random sampling, 111 PHC clinic nursing managers were selected. All supervisors (n=104) and subordinate nurses (n=383) were invited to participate in the survey on the day of data collection. Following informed consent, the nursing managers, their supervisors, and subordinate nurses completed a 40-item, 360-degree competency assessment questionnaire, with six domains: communication, leadership and management, staff management, financial management, planning and priority setting, and problem-solving. Standard deviations, medians, and inter-quartile ranges (IQRs) were computed separately for PHC nursing managers, supervisors, and subordinate nurses for competencies in the six domains. The Tinsley and Weiss index was used to assess agreement between each of the three possible pairs of raters. RESULTS: A 95.4% response rate was obtained, with 105 nursing managers in Gauteng and Free State completing the questionnaires. There was a lack of agreement about nursing managers' competencies among the three groups of raters. Overall, clinic nursing managers rated themselves high on the five domains of communication (8.6), leadership and management (8.67), staff management (8.75), planning and priority setting (8.6), and problem-solving (8.83). The exception was financial management with a median score of 7.94 (IQR 6.33-9.11). Compared to the PHC clinic managers, the supervisors and subordinate nurses gave PHC nursing managers lower ratings on all six competency domains, with the lowest rating for financial management (supervisor median rating 6.56; subordinate median rating 7.31). CONCLUSION: The financial management competencies of PHC clinic nursing managers need to be prioritised in continuing professional development programmes. PMID- 27938632 TI - Association between individual-level and community-level socio-economic status and blood pressure among Inuit in Greenland. AB - BACKGROUND: Despite abundant evidence that socio-economic status (SES) is a fundamental determinant of health, there is a dearth of research examining association between SES, measured at the individual and community levels, and cardiovascular risk factors and morbidity among indigenous populations. OBJECTIVES: To examine the influence of individual-level and community-level SES on systolic and diastolic blood pressure among Greenlandic Inuit. METHODS: Multilevel analysis of cross-sectional data from the Inuit Health in Transition - Greenland Survey, to which 3,108 Greenlandic Inuit aged 18 years and older participated. Blood pressure is measured using an automatic device, according to standardized protocol. Individual SES is measured by education. Community socio economic conditions are measured using combined information on average disposable household income and settlement type. RESULTS: Education was not significantly associated with blood pressure. There was an inverse U-shape association between community socio-economic conditions and blood pressure with significantly lower SBP and DBP among participants living in remote traditional villages characterized by lower average disposable household income and in affluent more urbanized towns. Sex-stratified analyses demonstrate the salience of community conditions for men. CONCLUSIONS: The association observed between blood pressure and community-level socio-economic conditions suggests that public health and social policies, programmes and interventions aiming to improve living conditions might improve cardiovascular health in Greenland. Studies are required to further examine social gradients in cardiovascular risk factors and morbidity among indigenous populations using different measures of SES. PMID- 27938633 TI - Children in Greenland: disease patterns and contacts to the health care system. AB - BACKGROUND: Previous studies of Greenlandic children's disease pattern and contacts to the health care system are sparse and have focused on the primary health care sector. OBJECTIVE: We aimed to identify the disease pattern and use of health care facilities of children aged 0-10 in two Greenlandic cohorts. METHODS AND DESIGN: In a retrospective, descriptive follow-up of the Ivaaq (The Greenland Child Cohort) and the CLEAR (climate changes, environmental contaminants and reproductive health) birth cohorts (total n=1,000), we reviewed medical records of children aged 6-10 in 2012 with residence in Nuuk or Ilulissat (n=332). Data on diseases and health care system contacts were extracted. Diagnoses were validated retrospectively. Primary health care contacts were reviewed for a random sample of 1:6. RESULTS: In 311 children with valid social security number, the total number of health care system contacts was 12,471 equalling 4.6 contacts per child per year. The annual incidence rate of hospital admissions was 1:10 children (total n=266, 1,220 days, 4.6 days/admission), outpatient contacts 2:10 children and primary care 3.6 per child. Contacts were overall more frequent in boys compared with girls, 39.5 versus 34.6 during the study period, p=0.02. The highest annual contact rates for diseases were: hospitalisations/acute respiratory diseases 13.9:1,000; outpatient contacts/otitis media 5.1:1,000; primary care/conjunctivitis or nasopharyngitis 410:1,000 children. Outpatient screening for respiratory tuberculosis accounted 6.2:1,000, primary care non-disease (Z-diagnosis) 2,081:1,000 annually. Complete adherence to the child vaccination programme was seen in 40%, while 5% did not receive any vaccinations. CONCLUSIONS: In this first study of its kind, the health care contact pattern in Greenlandic children showed a relatively high hospitalisation rate and duration per admission, and a low primary health care contact rate. The overall contact rate and disease pattern resembled those in Denmark, except for tuberculosis screening. Adherence to the vaccination programme was low. These findings may be helpful for the organisation and dimensioning of the Greenlandic health care system for children. PMID- 27938634 TI - Spirometry in Greenland: a cross-sectional study on patients treated with medication targeting obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is globally increasing in frequency and is expected to be the third largest cause of death by 2020. Smoking is the main risk factor of developing COPD. In Greenland, more than half of the adult population are daily smokers, and COPD may be common. International guidelines recommend the usage of spirometry as a golden standard for diagnosing COPD. The current number of spirometries performed among patients treated with medication targeting obstructive pulmonary disease in Greenland remains unexplored. OBJECTIVE: To estimate the prevalence of patients aged 50 years or above treated with medication targeting obstructive pulmonary disease and the extent to which spirometry was performed among them within 2 years. DESIGN: An observational, cross-sectional study based on the review of data obtained from electronic medical records in Greenland was performed. The inclusion criterion was that patients must have been permanent residents aged 50 years or above who had medication targeting obstructive pulmonary disease prescribed within a period of 15 months prior to data extraction. A full review of electronic patient records was done on each of the identified users of medication targeting obstructive pulmonary disease. Information on age, gender, town and spirometry was registered for each patient within the period from October 2013 to October 2015. RESULTS: The prevalence of patients treated with medication targeting obstructive pulmonary disease aged 50 years or above was 7.9%. Of those, 34.8% had spirometry performed within 2 years and 50% had a forced expiratory volume (1 sec)/ forced vital capacity (FEV1/FVC) under 70% indicating obstructive pulmonary disease. CONCLUSION: The use of medication targeting obstructive pulmonary disease among patients over 50 years old is common in Greenland. About one third of the patients had a spirometry performed within 2 years. To further increase spirometry performance, it is recommended to explore possible barriers in health care professionals' usage of spirometry in different health care settings in Greenland. PMID- 27938635 TI - Youth perspectives on sexually transmitted infections and sexual health in Northern Canada and implications for public health practice. AB - OBJECTIVE: High rates of sexually transmitted infections in the Arctic have been a focus of recent research, and youth are believed to be at greatest risk of infection. Little research has focused on understanding youth perspectives on sexual health. The goal of this study was to collect the perspectives of youth in Nunavut on sexual health and relationships with the intent of informing public health practice. METHOD: This qualitative research study was conducted within an Indigenous knowledge framework with a focus on Inuit ways of knowing. Data were collected through face-to-face interviews in three Nunavut communities with 17 youth between the ages of 14 and 19 years. Participants were asked open-ended questions about their experiences talking about sexual health and relationships with their family, peers, teachers or others in the community. RESULTS: There are four key findings, which are important for public health: (a) Parents/caregivers are the preferred source of knowledge about sexual health and relationships among youth respondents; (b) youth did not report using the Internet for sexual health information; (c) youth related sexual decision-making to the broader community context and determinants of health, such as poverty; and (d) youth discussed sexual health in terms of desire and love, which is an aspect of sexual health often omitted from the discourse. IMPLICATIONS AND CONTRIBUTION: The youth in this study articulated perspectives on sexual health, which are largely neglected in current public health practice in the North. The findings from this study underscore the important role of community-led participatory research in contributing to our understanding of the public health challenges in our communities today, and provide direction for future interventions and research. PMID- 27938636 TI - Performance indicators for maternity care in a circumpolar context: a scoping review. AB - BACKGROUND: In circumpolar regions, harsh climates and scattered populations have prompted the centralization of care and reduction of local maternity services. The resulting practice of routine evacuation for birth from smaller towns to larger urban centres points to a potential conflict between the necessity to ensure patient safety and the importance of delivering services that are responsive to the health needs and values of populations served. OBJECTIVE: To identify recommended performance/quality indicators for use in circumpolar maternity care systems. METHODS: We searched Scopus, Ebscohost databases (including Academic Search Complete and CINAHL), the Global Health Database, High North Research Documents, and online grey literature. Articles were included if they focused on maternal health indicators in the population of interest (Indigenous women, women receiving care in circumpolar or remote regions). Articles were excluded if they were not related to pregnancy, birth or the immediate post-partum or neonatal periods. Two reviewers independently reviewed articles for inclusion and extracted relevant data. RESULTS: Twenty-six documents were included. Twelve were government documents, seven were review articles or indicator compilations, four were indicator sets recommended by academics or non governmental organizations and three were research papers. We extracted and categorized 81 unique health indicators. The majority of indicators reflected health systems processes and outcomes during the antenatal and intra-partum periods. Only two governmental indicator sets explicitly considered the needs of Indigenous peoples. CONCLUSIONS: This review demonstrates that, although most circumpolar health systems engage in performance reporting for maternity care, efforts to capture local priorities and values are limited in most regions. Future work in this area should involve northern stakeholders in the process of indicator selection and development. PMID- 27938637 TI - Conducting rigorous research with subgroups of at-risk youth: lessons learned from a teen pregnancy prevention project in Alaska. AB - In 2010, Alaska Department of Health and Social Services (DHSS) received federal funding to test an evidence-based teen pregnancy prevention program. The grant required a major modification to an existing program and a randomized control trial (RCT) to test its effectiveness. As the major modifications, Alaska used peer educators instead of adults to deliver the program to youth aged 14-19 instead of the original curriculum intended age range of 12-14. Cultural and approach adaptations were included as well. After 4 years of implementation and data collection, the sample was too small to provide statistically significant results. The lack of findings gave no information about the modification, nor any explanation of how the curriculum was received, or reasons for the small sample. This paper reports on a case study follow-up to the RCT to better understand outcome and implementation results. For this study, researchers reviewed project documents and interviewed peer educators, state and local staff, and evaluators. Three themes emerged from the data: (a) the professional growth of peer educators and development of peer education, (b) difficulties resulting from curriculum content, especially for subpopulations of sexually active youth, youth identified as lesbian, gay, bisexual, transgender, queer, intersex and/or asexual, pregnant, and parenting youth and (c) the appropriateness of an RCT with subpopulations of at-risk youth. Three recommendations emerged from the case study. First, including as many stakeholders as possible in the program and evaluation design phases is essential, and must be supported by appropriate funding streams and training. Second, there must be recognition of the multiple small subpopulations found in Alaska when adapting programs designed for a larger and more homogeneous population. Third, RCTs may not be appropriate for all population subgroups. PMID- 27938638 TI - Teen pregnancy in Inuit communities - gaps still needed to be filled. AB - Teen pregnancy is depicted around the world as an important cause of health disparities both for the child and the mother. Accordingly, much effort has been invested in its prevention and led to its decline in the northern hemisphere since the mid-1990s. Despite that, high rates are still observed in the circumpolar regions. As Inuit communities have granted better understanding of teenage pregnancy a priority for the coming years, this article comprehensively reviews this multidimensional issue. By depicting current prevalence, likely determinants and possible impacts documented among Inuit of Canada, Alaska and Greenland, and contrasting them to common knowledge that has emerged from other populations over the years, great gaps surface. In some regions, the number of pregnancies per number of Inuit women aged between 15 and 19 years has increased since the turn of the millennium, while statistics from others are either absent or difficult to compare. Only few likely determinants of teenage pregnancy such as low education and some household factors have actually been recognized among Inuit populations. Documented impacts of early pregnancy on Inuit women and their children are also limited compared to those from other populations. As a way to better address early pregnancy in the circumpolar context, the defence for additional scientific efforts and the provision of culturally adapted sexual health prevention programmes appear critical. PMID- 27938639 TI - Staying healthy "under the sheets": Inuit youth experiences of access to sexual and reproductive health and rights in Arviat, Nunavut, Canada. AB - BACKGROUND: Inuit youth are reported to experience considerably worse sexual and reproductive health and rights (SRHR) outcomes than Canadian youth in general, as evidenced through public health data on sexually transmitted infections, unintended young pregnancies and rates of sexual violence in Nunavut compared to national averages. Existing literature on Inuit SRHR has identified the impact of westernization and colonialism on health outcomes, though gaps remain in addressing youth- and community-specific experiences of SRHR. OBJECTIVE: This study aims to generate youth-focused evidence on experiences of SRHR relating to access to care in Arviat in order to better inform locally authored interventions geared towards improving youth SRHR. DESIGN: The Piliriqatigiinniq Partnership Community Health Research Model (PRM) developed by the Qaujigiartiit Health Research Centre was followed to generate data on youth experiences of SRHR support access in Arviat. In-depth interviews were conducted with 9 male youth (ages 17-22 years), 10 female youth (ages 16-22 years) and 6 community leaders (aged 25+). Snowball sampling was used to engage informants, and data analysis followed an approach similar to conventional content analysis, where emphasis was placed on "immersion and crystallization" of data, corresponding to the Inuit concept of Iqqaumaqatigiinniq in the PRM. Findings were continuously checked with community members in Arviat during the analysis phase, and their feedback was incorporated into the report. RESULTS: Youth in Arviat were found to face significant barriers to SRHR care and support. Three major themes emerged as important factors conditioning youth access to SRHR resources in the community: trust of support workers in the community; stigma/taboos surrounding SRHR topics; and feelings of powerlessness impeding female and lesbian/gay/bisexual/transgender/queer youth in particular from accessing care. CONCLUSIONS: The locally specific ways these themes emerged revealed important structural factors at play in the community, which seem to persistently work against youths' abilities to achieve good SRHR outcomes. To address poor micro level health outcomes in Arviat, it thus appears that locally authored programming must take into account broader structural factors at the root of SRHR access barriers. PMID- 27938640 TI - Inuit women's stories of strength: informing Inuit community-based HIV and STI prevention and sexual health promotion programming. AB - BACKGROUND: There is a dearth of literature to guide the development of community based HIV and sexually transmitted infection (STI) prevention and sexual health promotion programs within Inuit communities. OBJECTIVE: The aim of this study was to create a dialogue with Inuit women to address the lack of information available to inform programming to improve the sexual health of Inuit women, their families, and their communities in the Canadian Arctic. DESIGN: This study used Indigenous methodologies and methods by drawing from Inuit Qaujimajatuqangit and postcolonial research theory in a framework of Two-Eyed Seeing, and using storytelling sessions to gather data. Community-based participatory research principles informed the design of the study, ensuring participants were involved in all stages of the project. Nine storytelling sessions took place with 21 Inuit women aged 18-61 years. Storytelling sessions were audio recorded and transcribed verbatim, and Atlas.ti aided in the organization of the data for collaborative thematic analysis within three participatory analysis sessions with 13 of the participating women. RESULTS: From the storytelling and analysis sessions, five major themes emerged: (a) the way it used to be, (b) change, (c) family, (d) intimate relationships and (e) holistic strategies. Participating women emphasized that HIV and STI prevention and sexual health promotion programming needs to take a holistic, community-wide, family-focused and youth-centred approach within their communities. CONCLUSION: Participants identified several important determinants of sexual health and shared ideas for innovative approaches they believe will work as prevention efforts within their communities. This article specifically focuses on key characteristics of programming aimed at STI and HIV prevention and sexual health promotion that were identified throughout participants' stories. This study has provided a narrative to complement the epidemiological data that highlight the urgent need for prevention programming. PMID- 27938641 TI - Kivalliq Inuit Centre boarding home and the provision of prenatal education. AB - The Kivalliq Inuit Centre (KIC), a boarding home in Winnipeg, Manitoba, is unique in its provision of a pilot prenatal education class and public health nursing services for Nunavummiut who are beneficiaries of the Nunavut Land Claim Agreement. Through a critical review of literature, policies and interviews related to evacuation for birth, we argue that the pilot at the KIC has the potential to play an important role in improving maternal child health for residents of Nunavut. PMID- 27938643 TI - Adapting a model of response to child abuse to the conditions in the circumpolar north. PMID- 27938642 TI - An evaluation of the interaction of place and community-based participatory research as a research methodology in the implementation of a sexually transmitted infection intervention for Greenlandic youth. AB - Newly emerging research suggests that the actual physical location of a study and the geographic context in which a study is implemented influences the types of research methods most appropriate to use in a study as well as the study's research outcomes. This article presents a reflection on the extent to which place influenced the use of community-based participatory research (CBPR) as a research methodology in the implementation of an intervention to address sexually transmitted infections in Greenland. An evaluation of the interaction between place and CBPR suggests that the physicality of place influenced the intervention's successes and challenges. Future research that uses CBPR as a research methodology in sexual and reproductive health research in the Arctic warrants situating the research design, implementation and outcomes within the context of place. PMID- 27938644 TI - Creating exclusive breastfeeding knowledge translation tools with First Nations mothers in Northwest Territories, Canada. AB - BACKGROUND: Breastfeeding is an ideal method of infant feeding affecting lifelong health, and yet the uptake of breastfeeding in some Indigenous communities in Canada's north is low. OBJECTIVE: The aims of this project were to determine the rate and determinants of exclusive breastfeeding in a remote community in the Northwest Territories and to create knowledge translation tools to enhance breastfeeding locally. METHODS: The study methodology followed three steps. Firstly, a series of retrospective chart audits were conducted from hospital birth records of Tlicho women (n=198) who gave birth during the period of 1 January 2010 to 31 December 2012. A second follow-up chart audit determined the rate of exclusive breastfeeding and was conducted in the local Community Health Centre. Chart audit data included the following factors related to breastfeeding: age of mother, parity, birthweight and Apgar scores. Secondly, semi-structured interviews with a purposive sample of Tlicho mothers (n=8) and one Elder were conducted to identify breastfeeding practices, beliefs and the most appropriate medium to use to deliver health messages in Tlicho. Third, based on the information obtained in Step 2, two knowledge translation tools were developed in collaboration with a local community Advisory Committee. RESULTS: The rate of exclusive breastfeeding initiation in the Tlicho region is less than 30%. Physiological and demographic factors related to breastfeeding were identified. Thematic analysis revealed two overarching themes from the data, namely, "the pull to formula" (lifestyle preferences, drug and alcohol use, supplementation practices and limited role models) and "the pull to breast feeding" (traditional feeding method, spiritual practice and increased bonding with infant). CONCLUSION: There are a myriad of influences on breastfeeding for women living in remote locations. Ultimately, society informs the choice of infant feeding for the new mother, since mothers' feeding choices are based on contextual realities and circumstances in their lives that are out of their control. As health care providers, it is imperative that we recognize the realities of women's lives and the overlapping social determinants of health that may limit a mother's ability or choice to breastfeed. Further health promotion efforts, grounded in community based research and a social determinants framework, are needed to improve prenatal and postnatal care of Indigenous women and children in Canada. PMID- 27938645 TI - What is missing? Addressing the complex issues surrounding sexual and reproductive health in the circumpolar north. PMID- 27938647 TI - Assessing evidence of inequalities in access to medication for diabetic populations in low- and middle-income countries: a systematic review. AB - BACKGROUND: Inequalities in access to medications among people diagnosed with diabetes inlow- and middle-income countries (LMICs) is a public health concern since untreated diabetes can lead to severe complications and premature death. OBJECTIVE: To assess evidence of inequalities in access to medication for diabetes in adult populations of people with diagnosed diabetes in LMICs. DESIGN: We conducted a systematic review of the literature using the PRISMA-Equity guidelines. A search of five databases - PubMed, Cochrane, CINAHL, PsycINFO, and EMBASE - was conducted from inception to November 2015. Using deductive content analysis, information extracted from the selected articles was analysed according to the PRISMA-Equity guidelines, based on exposure variables (place of residence, race/ethnicity, occupation, gender, religion, education, socio-economic status, social capital, and others). RESULTS: Fifteen articles (seven quantitative and eight qualitative studies) are included in this review. There were inconsistent findings between studies conducted in different countries and regions although financial and geographic barriers generally contributed to inequalities in access to diabetes medications. The poor, those with relatively low education, and people living in remote areas had less access to diabetes medications. Furthermore, we found that the level of government political commitment through primary health care and in the provision of essential medicines was an important factor in promoting access to medications. CONCLUSIONS: The review indicates that inequalities exist in accessing medication among diabetic populations, although this was not evident in all LMICs. Further research is needed to assess the social determinants of health and medication access for people with diabetes in LMICs. PMID- 27938646 TI - Increased frequencies of CD8+CD57+ T cells are associated with antibody neutralization breadth against HIV in viraemic controllers. AB - INTRODUCTION: An effective prophylactic vaccine against HIV will need to elicit antibody responses capable of recognizing and neutralizing rapidly evolving antigenic regions. The immunologic milieu associated with development of neutralizing antibody breadth remains to be fully defined. In this study, we sought to identify immunological signatures associated with neutralization breadth in HIV controllers. We applied an immune monitoring approach to analyze markers of T cell and myeloid cell activation by flow cytometry, comparing broad neutralizers with low- and non-neutralizers using multivariate and univariate analyses. METHODS: Antibody neutralization breadth was determined, and cryopreserved peripheral blood mononuclear cells were stained for T cell and myeloid cell activation markers. Subjects were grouped according to neutralization breadth, and T cell and myeloid cell activation was analyzed by partial least squares discriminant analysis to determine immune signatures associated with high neutralization breadth. RESULTS: We show that neutralization breadth in HIV viraemic controllers (VC) was strongly associated with increased frequencies of CD8+CD57+ T cells and that this association was independent of viral load, CD4 count and time since HIV diagnosis. CONCLUSIONS: Our data show elevated frequencies of CD8+CD57+ T cells in VC who develop neutralization breadth against HIV. This immune signature could serve as a potential biomarker of neutralization breadth and should be further investigated in other HIV positive cohorts and in HIV vaccine trials. PMID- 27938649 TI - Hepatitis and HIV in Northern Ireland prisons: a cross-sectional study. AB - A study was undertaken in Northern Ireland (NI) prisons to (i) determine prevalence of bloodborne viruses among inmates, (ii) estimate the extent of self reported risk behaviours. All three prisons in NI were included in the study. Outcome measures included (i) antibodies to hepatitis C (HCV), hepatitis B (HBV) core antigen, HIV, (ii) self-reported risk behaviour. Five prisoners (0.75%) tested positive for HBV, seven (1.1%) for HCV and none for HIV. Eleven per cent reported ever having injected drugs. Of these, 20% had started injecting while in prison, and 12% shared injecting equipment in prison. Two per cent had completed HBV immunisation. Injecting drugs was associated with HCV (adjusted prevalence ratio=5.2; 95% CI 0.9-16) and HBV infection (adjusted prevalence ratio=4.1; 95% CI 0.7-23). The low prevalence of bloodborne viruses within NI prisons is not consistent with findings of studies in other countries, possibly reflecting the unique sociopolitical situation in NI. In spite of knowledge of the risks of transmission of bloodborne viruses in prison, high-risk practices are occurring. Preventing risk behaviours and transmission of infection in prisons now poses a challenge for health services in the United Kingdom. PMID- 27938648 TI - Menstrual hygiene management among adolescent schoolgirls in low- and middle income countries: research priorities. AB - BACKGROUND: A lack of adequate guidance on menstrual management; water, disposal, and private changing facilities; and sanitary hygiene materials in low- and middle-income countries leaves schoolgirls with limited options for healthy personal hygiene during monthly menses. While a plethora of observational studies have described how menstrual hygiene management (MHM) barriers in school impact girls' dignity, well-being, and engagement in school activities, studies have yet to confirm if inadequate information and facilities for MHM significantly affects quantifiable school and health outcomes influencing girls' life chances. Evidence on these hard outcomes will take time to accrue; however, a current lack of standardized methods, tools, and research funding is hampering progress and must be addressed. OBJECTIVES: Compile research priorities for MHM and types of research methods that can be used. RESULTS: In this article, we highlight the current knowledge gaps in school-aged girls' MHM research, and identify opportunities for addressing the dearth of hard evidence limiting the ability of governments, donors, and other agencies to appropriately target resources. We outline a series of research priorities and methodologies that were drawn from an expert panel to address global priorities for MHM in schools for the next 10 years. CONCLUSIONS: A strong evidence base for different settings, standardized definitions regarding MHM outcomes, improved study designs and methodologies, and the creation of an MHM research consortia to focus attention on this neglected global issue. PMID- 27938650 TI - [The search for balance in the therapeutic decision-making process: the example of Class II malocclusion treatments in children and adolescents]. AB - INTRODUCTION: Therapeutic decision-making is essentially the key to our clinical practice, and its most medical feature. The history of orthodontics is studded with multiple intellectual debates and stand-offs between conflicting treatment philosophies, the authors of which all aspire to a balance guaranteeing optimal treatment for their patients. Among the wealth of published data, which items should we select to ensure balanced treatment decisions in our daily practice and how can we remain serene in the face of the uncertainty and loneliness engendered by therapeutic decision-making process? MATERIALS AND METHODS: Evidence-based orthodontics is an aid to clinical decisionmaking. Its main features are illustrated by four clinical cases describing the treatment of class II malocclusions in children and adolescents. RESULTS: A search for the best pre evaluated data on two-step treatments shows that : (1) a significant reduction in the prevalence of incisive trauma is observed in children when an increased overjet is corrected by an initial treatment phase, compared to single-stage treatments conducted in early adolescence; (2) the long-term impact of the first treatment phase on the amount of mandibular growth is at best weak and clinically insignificant. DISCUSSION: The evidence-based approach, particularly when performed in user mode, enables us to reach more balanced clinical decisions. However, the article points out the key role of the clinician and the double risk of reducing the evidence-based approach to a mere standard of care - which it is not - and the subordination of treatment management to the strict clinical application of data in the literature. PMID- 27938651 TI - ? PMID- 27938652 TI - [Orthodontic correction of malpositioned teeth before restorative treatment: efficiency improvement using Temporary Anchorage Devices (TADs)]. AB - INTRODUCTION: Orthodontic treatment is a fundamental tool when approaching in a multidisciplinary manner a prosthetic rehabilitation, thanks to the possibility to place in an ideal position the involved teeth and to improve or even correct any periodontal defects. Several orthodontic tricks and version have been developed to limit as much as possible orthodontic appliances extension and treatment duration. However, it is not always easy to control teeth movements and manage anchorage when only few teeth are involved. Furthermore, treatment duration can increase due to the need to apply light forces and to correct adverse dental movements that eventually could appear. MATERIAL AND METHODS: Different clinical cases are presented. RESULTS: These exemples illustrate how, with the addition of the TADs in clinical practice, the biomechanics of the multidisciplinary treatment can be simplified, the result becomes highly predictable and the treatment time can often be reduced. PMID- 27938653 TI - [3D imaging benefits in clinical pratice of orthodontics]. AB - INTRODUCTION: 3D imaging possibilities raised up in the last few years in the orthodontic field. In 2016, it can be used for diagnosis improvement and treatment planning by using digital set up combined to CBCT. It is relevant for orthodontic mechanic updating by creating visible or invisible customised appliances. It forms the basis of numerous scientific researches. MATERIALS AND METHODS: The author explains the progress 3D imaging brings to diagnosis and clinics but also highlights the requirements it creates. DISCUSSION: The daily use of these processes in orthodontic clinical practices needs to be regulated regarding the benefit/risk ratio and the patient satisfaction. RESULTS: The command of the digital work flow created by these technics requires habits modifications from the orthodontist and his staff. PMID- 27938654 TI - [Orthognathic surgery: the incisor decompensation and its effect on articulation]. AB - INTRODUCTION: The surgical protocols are based on arches preparation before or immediately after the surgical phase. Incisor guides normalization is achieved by incisor decompensation in three dimensions. Place and extend of surgical movements depend on the incisor position obtained at the end of orthodontic preparation. Extraction versus non extraction depends on incisor position planning. Orthognathic surgery induces muscular and temporo-mandibular joint stress which can cause temporo mandibular dysfunction (TMD). OBJECTIVES: This article studies relations between incisor decompensation amplitude, orthognathic surgical procedures and risk to create or to increase TMD. CONCLUSIONS: Sagittal, vertical and transversal incisor decompensation impact to place and amplitude of surgical movements. Incisor decompensation does not seem to induce TMD during orthodontic preparation even if occlusal guide controls are lost. Temporo mandibular dysfunction degrees define surgical movements area, moderate specially mandibular surgical movements and incisor decompensation objectives. PMID- 27938655 TI - [A perspective on the use of bone anchorage as opposed to other types of anchorage techniques]. AB - INTRODUCTION: To convert our objectives into the desired treatment results, we need to control our mechanics and thus the anchorage used by avoiding any unwanted movements. It now seems unthinkable, at the dawn of the 21st century, to ignore the useful contribution of orthodontic screw-borne anchorage. Nevertheless, we are entitled to raise a number of legitimate questions. Do these forms of anchorage offer an alternative to all types of mechanics? Will they permit us to manage clinical situations which are beyond the scope of a more classical approach? Can they enhance the quality of our treatments? MATERIALS AND METHODS: Each of the authors describes clinical situations using screw-borne anchorage and compares with a conventional approach in order to make a non exhaustive analysis of the mechanics applied, in their own office, and then highlights the most effective technique. RESULTS: With 15 years experience in the use of miniscrews, orthodontists have now adopted them with their many advantages as an integral item in their therapeutic armamentarium. However, treatment plans must be coherent. Our mechanics must be well thought-out and represent a cogent entity under the control of the practitioner. Creating screw-borne anchorage demands total control over anchorage stability. PMID- 27938656 TI - [Embedded micro-screws, the universal bone anchorage]. AB - INTRODUCTION: This article revises how embedded micro-screws are used for orthodontic anchorage and points out advantages. MATERIALS AND METHODS: The use of surgical screws, their placement and connections are described in detail. The clinical methodology is explained step by step with illustrations and clinical cases. RESULTS: Using micro-screw has no doubt many advantages, at the material, anatomic, surgical and mechanical level, as well as the comfort and reliability it provides. It represents a real universal bone anchorage. PMID- 27938657 TI - [Retaining corrected skeletal open bites. How can we increase the stability of our results?] AB - INTRODUCTION: Retaining corrected skeletal anterior open bites is challenging. If it is possible to identify the aetiological factors causing an open bite, an appropriate choice of treatment and retention may reduce relapse. Extruding anterior teeth to close anterior open bites is known to be unstable, so treatment is typically aimed at controlling the vertical position of maxillary molars, in addition to removing causative factors, such as breaking habits and improving tongue posture. Relapse rates are high, with relapse estimated at about 20-30%, with slightly more stability for a surgical approach. MATERIALS AND METHODS: Various approaches with retainers are described that aim to restrict the eruption of posterior teeth, and improve the position of the tongue. RESULTS: These retainers often require excellent patient compliance and there is a lack of high quality evidence to support their use. Further research is required to confirm the effectiveness of these approaches. PMID- 27938658 TI - [Etiology and treatment options of anterior open bite in growing patients: a narrative review]. AB - INTRODUCTION: Anterior open bite represents a malocclusion that is still under study because of the still lacking evidence about etiology and best treatment options in growing subjects according to success rate and stability. Etiology involves the interaction of environmental factors such as prolonged sucking habits, mouth breathing, tongue or lip thrusting, tongue dimension, eruption disturbances with a genetically determined vertical facial growth pattern. The treatment options for the early treatment of anterior open bite are still controversial. OBJECTIVES: The aim of this study was to evaluate the actual available evidence on treatments of anterior open bite in the mixed dentition in order to assess the effectiveness of the early treatment in reducing open bite, the most efficacious treatment strategy and the stability of the results. PMID- 27938659 TI - [The long face syndrome]. AB - INTRODUCTION: Since the beginning of cephalometric analysis, a significant number of approaches to vertical facial proportions have been proposed. In our view, diagnosing a vertical problem has nothing to do with numbers or measurements. It's all about perceptions and - rather subjective - impressions. An "impression" of long face may be provoked by the following causes isolated or combined: vertical maxillary hyperplasia, open bite, anterior vertical mandibular hyperplasia, narrow face, lack of chin-neck definition. METHOD: Clinical planning in these cases is followed by 3D simulation and CAD/CAM generation of surgical splints. CONCLUSION: Surgical management of the Long Face Syndrome may include the following strategies isolated or combined : maxillary impaction, vertical chin reduction, counterclockwise rotation of the occlusal plane. PMID- 27938660 TI - Regulation of signaling directionality revealed by 3D snapshots of a kinase:regulator complex in action. AB - Two-component systems (TCS) are protein machineries that enable cells to respond to input signals. Histidine kinases (HK) are the sensory component, transferring information toward downstream response regulators (RR). HKs transfer phosphoryl groups to their specific RRs, but also dephosphorylate them, overall ensuring proper signaling. The mechanisms by which HKs discriminate between such disparate directions, are yet unknown. We now disclose crystal structures of the HK:RR complex DesK:DesR from Bacillus subtilis, comprising snapshots of the phosphotransfer and the dephosphorylation reactions. The HK dictates the reactional outcome through conformational rearrangements that include the reactive histidine. The phosphotransfer center is asymmetric, poised for dissociative nucleophilic substitution. The structural bases of HK phosphatase/phosphotransferase control are uncovered, and the unexpected discovery of a dissociative reactional center, sheds light on the evolution of TCS phosphotransfer reversibility. Our findings should be applicable to a broad range of signaling systems and instrumental in synthetic TCS rewiring. PMID- 27938661 TI - Akt1-Inhibitor of DNA binding2 is essential for growth cone formation and axon growth and promotes central nervous system axon regeneration. AB - Mechanistic studies of axon growth during development are beneficial to the search for neuron-intrinsic regulators of axon regeneration. Here, we discovered that, in the developing neuron from rat, Akt signaling regulates axon growth and growth cone formation through phosphorylation of serine 14 (S14) on Inhibitor of DNA binding 2 (Id2). This enhances Id2 protein stability by means of escape from proteasomal degradation, and steers its localization to the growth cone, where Id2 interacts with radixin that is critical for growth cone formation. Knockdown of Id2, or abrogation of Id2 phosphorylation at S14, greatly impairs axon growth and the architecture of growth cone. Intriguingly, reinstatement of Akt/Id2 signaling after injury in mouse hippocampal slices redeemed growth promoting ability, leading to obvious axon regeneration. Our results suggest that Akt/Id2 signaling is a key module for growth cone formation and axon growth, and its augmentation plays a potential role in CNS axonal regeneration. PMID- 27938662 TI - Transient protein-protein interactions perturb E. coli metabolome and cause gene dosage toxicity. AB - Gene dosage toxicity (GDT) is an important factor that determines optimal levels of protein abundances, yet its molecular underpinnings remain unknown. Here, we demonstrate that overexpression of DHFR in E. coli causes a toxic metabolic imbalance triggered by interactions with several functionally related enzymes. Though deleterious in the overexpression regime, surprisingly, these interactions are beneficial at physiological concentrations, implying their functional significance in vivo. Moreover, we found that overexpression of orthologous DHFR proteins had minimal effect on all levels of cellular organization - molecular, systems, and phenotypic, in sharp contrast to E. coli DHFR. Dramatic difference of GDT between 'E. coli's self' and 'foreign' proteins suggests the crucial role of evolutionary selection in shaping protein-protein interaction (PPI) networks at the whole proteome level. This study shows how protein overexpression perturbs a dynamic metabolon of weak yet potentially functional PPI, with consequences for the metabolic state of cells and their fitness. PMID- 27938663 TI - RNase H enables efficient repair of R-loop induced DNA damage. AB - R-loops, three-stranded structures that form when transcripts hybridize to chromosomal DNA, are potent agents of genome instability. This instability has been explained by the ability of R-loops to induce DNA damage. Here, we show that persistent R-loops also compromise DNA repair. Depleting endogenous RNase H activity impairs R-loop removal in Saccharomyces cerevisiae, causing DNA damage that occurs preferentially in the repetitive ribosomal DNA locus (rDNA). We analyzed the repair kinetics of this damage and identified mutants that modulate repair. We present a model that the persistence of R-loops at sites of DNA damage induces repair by break-induced replication (BIR). This R-loop induced BIR is particularly susceptible to the formation of lethal repair intermediates at the rDNA because of a barrier imposed by RNA polymerase I. PMID- 27938664 TI - Distinct memory engrams in the infralimbic cortex of rats control opposing environmental actions on a learned behavior. AB - Conflicting evidence exists regarding the role of infralimbic cortex (IL) in the environmental control of appetitive behavior. Inhibition of IL, irrespective of its intrinsic neural activity, attenuates not only the ability of environmental cues predictive of reward availability to promote reward seeking, but also the ability of environmental cues predictive of reward omission to suppress this behavior. Here we report that such bidirectional behavioral modulation in rats is mediated by functionally distinct units of neurons (neural ensembles) that are concurrently localized within the same IL brain area but selectively reactive to different environmental cues. Ensemble-specific neural activity is thought to function as a memory engram representing a learned association between environment and behavior. Our findings establish the causal evidence for the concurrent existence of two distinct engrams within a single brain site, each mediating opposing environmental actions on a learned behavior. PMID- 27938666 TI - How ants send signals in saliva. AB - Adult ants use saliva to transfer juvenile hormone and other chemical signals to their larvae. PMID- 27938665 TI - Experimental reconstitution of chronic ER stress in the liver reveals feedback suppression of BiP mRNA expression. AB - Endoplasmic reticulum (ER) stress is implicated in many chronic diseases, but very little is known about how the unfolded protein response (UPR) responds to persistent ER stress in vivo. Here, we experimentally reconstituted chronic ER stress in the mouse liver, using repeated injection of a low dose of the ER stressor tunicamycin. Paradoxically, this treatment led to feedback-mediated suppression of a select group of mRNAs, including those encoding the ER chaperones BiP and GRP94. This suppression was due to both silencing of the ATF6alpha pathway of UPR-dependent transcription and enhancement of mRNA degradation, possibly via regulated IRE1-dependent decay (RIDD). The suppression of mRNA encoding BiP was phenocopied by ectopic overexpression of BiP protein, and was also observed in obese mice. Our findings suggest that persistent cycles of UPR activation and deactivation create an altered, quasi-stable setpoint for UPR-dependent transcriptional regulation-an outcome that could be relevant to conditions such as metabolic syndrome. PMID- 27938667 TI - Biogenesis of phased siRNAs on membrane-bound polysomes in Arabidopsis. AB - Small RNAs are central players in RNA silencing, yet their cytoplasmic compartmentalization and the effects it may have on their activities have not been studied at the genomic scale. Here we report that Arabidopsis microRNAs (miRNAs) and small interfering RNAs (siRNAs) are distinctly partitioned between the endoplasmic reticulum (ER) and cytosol. All miRNAs are associated with membrane-bound polysomes (MBPs) as opposed to polysomes in general. The MBP association is functionally linked to a deeply conserved and tightly regulated activity of miRNAs - production of phased siRNAs (phasiRNAs) from select target RNAs. The phasiRNA precursor RNAs, thought to be noncoding, are on MBPs and are occupied by ribosomes in a manner that supports miRNA-triggered phasiRNA production, suggesting that ribosomes on the rough ER impact siRNA biogenesis. This study reveals global patterns of cytoplasmic partitioning of small RNAs and expands the known functions of ribosomes and ER. PMID- 27938669 TI - HIV and Aging. PMID- 27938668 TI - Cellular encoding of Cy dyes for single-molecule imaging. AB - A general method is described for the site-specific genetic encoding of cyanine dyes as non-canonical amino acids (Cy-ncAAs) into proteins. The approach relies on an improved technique for nonsense suppression with in vitro misacylated orthogonal tRNA. The data show that Cy-ncAAs (based on Cy3 and Cy5) are tolerated by the eukaryotic ribosome in cell-free and whole-cell environments and can be incorporated into soluble and membrane proteins. In the context of the Xenopus laevis oocyte expression system, this technique yields ion channels with encoded Cy-ncAAs that are trafficked to the plasma membrane where they display robust function and distinct fluorescent signals as detected by TIRF microscopy. This is the first demonstration of an encoded cyanine dye as a ncAA in a eukaryotic expression system and opens the door for the analysis of proteins with single molecule resolution in a cellular environment. PMID- 27938670 TI - Antimicrobial resistance surveillance in Escherichia coli by using normalized resistance interpretation. AB - OBJECTIVES: To improve antimicrobial surveillance accuracy for results obtained by disk diffusion for porcine Escherichia coli, by comparing traditional clinical breakpoint interpretation with the Normalized Resistance Interpretation (NRI) method. METHODS: The susceptibilities of 921 E. coli isolates from clinically healthy pigs at slaughter age was determined for 15 antimicrobials by the Kirby Bauer disk diffusion technique. NRI with previously established optimal controlled parameters for E. coli ATCC25922 was used to reconstruct the fully susceptible population of the tested E. coli isolates. Based on a lower limit for susceptibility, set at 2.5 standard deviations below the mean of the reconstructed susceptible population, the non-wild type percentage isolates was compared with the clinical resistance percentage. RESULTS: The NRI method was applicable for 11 out of the 15 antimicrobials tested. Antimicrobials for which no normal distribution of inhibition zones for the population of susceptible isolates was seen, could not be used to reconstruct the susceptible population. Clinical breakpoints much lower than the epidemiological cut-off values resulted into presumptively identifying isolates as clinically susceptible, but likely carrying acquired resistance determinants. Otherwise, clinical breakpoints did cut through the WT population for several antibiotics tested, categorizing isolates from the WT population as not susceptible. CONCLUSIONS: NRI was shown to be a valid method to define the WT population for disk diffusion outcomes, provided a normal distribution of the susceptible bacterial species population is present. Until international harmonization of breakpoints is achieved, it might give rise to a wide application in monitoring antimicrobial resistance in veterinary medicine. PMID- 27938671 TI - Clinical and immunological assessment of therapeutic immunization with a subunit vaccine for recurrent ocular canine herpesvirus-1 infection in dogs. AB - Latent canine herpesvirus-1 (CHV-1) infections are common in domestic dogs and reactivation of latent virus may be associated with recurrent ocular disease. The objectives of the present study were to evaluate the ability of a subunit CHV-1 vaccine to stimulate peripheral CHV-1 specific immunity and prevent recurrent CHV 1 ocular disease and viral shedding. Mature dogs with experimentally-induced latent CHV-1 infection received a 2-dose CHV-1 vaccine series. Recurrent ocular CHV-1 infection was induced by corticosteroid administration in the prevaccinal, short-term postvaccinal (2 weeks post-vaccination), and long-term postvacccinal (34 weeks post-vaccination) periods. Immunological, virological, and clinical parameters were evaluated during each study period. Quantitative assessment of peripheral immunity included lymphocyte immunophenotyping, proliferation response, and interferon-gamma production; and CHV-1 virus neutralizing antibody production. In the present study, vaccination did not prevent development of ocular disease and viral shedding; however, there was a significant decrease in clinical ocular disease scores in the short-term postvaccinal period. Significant alterations in peripheral immunity detected in the dogs during the short-term and long-term postvaccinal periods included increased T and B lymphocyte subpopulation percentage distributions, increased lymphocyte expression of major histocompatibility complex class I and II, increased CHV-1 virus neutralizing antibody titers, decreased lymphocyte proliferation, and decreased interferon gamma production. Vaccination of latently infected mature dogs with the selected subunit CHV-1 vaccine was not effective in preventing recurrent ocular CHV-1 infection and viral shedding induced by corticosteroid administration. The vaccine did induce long-term CHV-1 specific immunity and may decrease the severity of clinical ocular disease in the immediate postvaccinal period. PMID- 27938672 TI - The interaction of Rotavirus A pig/China/NMTL/2008/G9P[23] VP6 with cellular beta actin is required for optimal RV replication and infectivity. AB - VP6 forms the intermediate layer of the rotavirus (RV) capsid, and it plays important roles after RV penetration and uncoating. These functions rely on its ability to interact with host cell proteins. To gain further insights into the role of VP6 in porcine RV (PoRV) infection, a glutathione S-transferase pull-down assay was utilized to find unknown cellular factors that interact with VP6. In this study, beta-actin, tropomyosin 1, and 40S ribosomal protein S16 were identified as interaction partners of VP6 by mass spectrometry and co immunoprecipitation. The interaction with beta-actin was further studied. By immunoelectron microscopy, we observed VP6 proteins that labeled with colloidal gold localized on the actin microfilaments at the early stage of PoRV infection, we also found VP6 distributed in the ribosome, mitochondria, endoplasmic reticulum and nucleus in the infected cells. Actin binding protein spin-down assays verified PoRV double-layered particles (DLPs) bound to F-actin in vitro, but didn't have actin polymerization enhancement activity. After a small interfering RNA (siACTB) was used to knock down beta-actin expression, PoRV VP6 expression and the infection rates of newly synthesized virions releasing into culture supernatants decreased dramatically. Our results confirm and extend previous reports indicating that the interaction between PoRV VP6 and beta-actin plays vital roles in the PoRV lifecycle. PMID- 27938673 TI - A canine-specific probiotic product in treating acute or intermittent diarrhea in dogs: A double-blind placebo-controlled efficacy study. AB - A double-blind placebo-controlled intervention study on 60 dogs recruited from a pool of canine patients visiting a veterinary practice and diagnosed with acute diarrhea was conducted. The dogs received in randomized manner either a sour-milk product containing three canine-derived Lactobacillus sp. probiotics in combination of Lactobacillus fermentum VET 9A, L. rhamnosus VET 16A, and L. plantarum VET 14A (2*109cfu/ml), or placebo. Stool consistency, general well being, and the numbers of specific pathogens in stool samples were analyzed. Our results demonstrated that the treatment with the study sour-milk product had a normalizing effect on canine stool consistency. The treatment also enhanced the well-being of the pet by maintaining appetite and may reduce vomiting. In addition, the concentrations of Clostridium perfringens and Enterococcus faecium, which typically increase during diarrhea episodes in dogs, were decreased in probiotic group feces when compared with the placebo group. Taken together, the sour-milk with the specific probiotic combination had a normalizing effect on acute diarrhea in dogs which was associated with decreased numbers of potential pathogens in the feces of probiotic-treated dogs. PMID- 27938674 TI - Mannheimia haemolytica biofilm formation on bovine respiratory epithelial cells. AB - Mannheimia haemolytica is the most important bacterial agent associated with the bovine respiratory disease complex (BRDC), which causes worldwide economic losses to the cattle industry. M. haemolytica cells initially colonize the tonsillar crypts in the upper respiratory tract of cattle, from where they can subsequently descend into the lungs to cause disease. Many bacteria exist as biofilms inside their hosts. We hypothesize that M. haemolytica colonization of cattle during its commensal state may include biofilm formation. To begin to assess this possibility, we developed an in vitro system to study biofilm formation directly on bovine respiratory epithelial cells. Using fixed primary bovine bronchial epithelial cells, we observed M. haemolytica biofilm formation after a 48h incubation period at 37 degrees C. Addition of mucin, the main component of mucus present in the upper respiratory tract, decreased M. haemolytica biofilm formation on bovine epithelial cells. We investigated the effects of prior viral infection of the epithelial cells on subsequent biofilm formation by M. haemolytica and found negligible effects. Utilization of this model system will provide new insights into the potential role of biofilm formation by M. haemolytica in the pathogenesis of BRDC. PMID- 27938675 TI - Re-emergence of Peste des Petits Ruminants virus in 2015 in Morocco: Molecular characterization and experimental infection in Alpine goats. AB - Peste des Petits Ruminants (PPR) is a transboundary viral disease of small ruminants that causes huge economic losses in Africa, The Middle East and Asia. In Morocco, the first PPR outbreak was notified in 2008. Since then no cases were reported for seven years, probably due to three successive vaccination campaigns during 2008-2011 and close surveillance at the border areas. In June 2015, the disease re-emerged in Morocco, raising questions about the origin of the virus. The PPR virus was confirmed by qRT-PCR and virus was isolated from clinical samples on VeroNectin-4 cells. The disease was experimentally reproduced in Alpine goats using both sheep and goat derived outbreak isolates. Molecular characterization of the 2015 Moroccan PPR isolate confirmed the identity of the virus as lineage IV, closely related to the 2012 Algerian (KP793696) and 2012 Tunisian (KM068121) isolates and significantly distinct from the previous PPRV Morocco 2008 strain (HQ131927). Therefore this study confirms a new incursion of PPR virus in Morocco during 2015 and highlights the urgency of implementation of a common control strategy to combat PPR in Maghreb region in North Africa. PMID- 27938676 TI - Control of African swine fever epidemics in industrialized swine populations. AB - African swine fever (ASF) is a notifiable infectious disease with a high impact on swine health. The disease is endemic in certain regions in the Baltic countries and has spread to Poland constituting a risk of ASF spread toward Western Europe. Therefore, as part of contingency planning, it is important to explore strategies that can effectively control an epidemic of ASF. In this study, the epidemiological and economic effects of strategies to control the spread of ASF between domestic swine herds were examined using a published model (DTU-DADS-ASF). The control strategies were the basic EU and national strategy (Basic), the basic strategy plus pre-emptive depopulation of neighboring swine herds, and intensive surveillance of herds in the control zones, including testing live or dead animals. Virus spread via wild boar was not modelled. Under the basic control strategy, the median epidemic duration was predicted to be 21days (5th and 95th percentiles; 1-55days), the median number of infected herds was predicted to be 3 herds (1-8), and the total costs were predicted to be ?326 million (?256-?442 million). Adding pre-emptive depopulation or intensive surveillance by testing live animals resulted in marginal improvements to the control of the epidemics. However, adding testing of dead animals in the protection and surveillance zones was predicted to be the optimal control scenario for an ASF epidemic in industrialized swine populations without contact to wild boar. This optimal scenario reduced the epidemic duration to 9days (1-38) and the total costs to ?294 million (?257-?392 million). Export losses were the driving force of the total costs of the epidemics. PMID- 27938677 TI - First evaluation of an influenza viral vector based Brucella abortus vaccine in sheep and goats: Assessment of safety, immunogenicity and protective efficacy against Brucella melitensis infection. AB - Previously we developed and evaluated a candidate influenza viral vector based Brucella abortus vaccine (Flu-BA) administered with a potent adjuvant Montanide Gel01 in cattle, which was found safe and highly effective. This study was aimed to establish a proof-of-concept of the efficacy of Flu-BA vaccine formulation in sheep and goats. We vaccinated sheep and goats with Flu-BA vaccine and as a positive control vaccinated a group of animals with a commercial B. melitensis Rev.1 vaccine. Clinically, both Flu-BA and Rev.1 vaccines were found safe. Serological analysis showed the animals received Flu-BA vaccine did not induce antibody response against Brucella Omp16 and L7/L12 proteins during the period of our study (56days post-initial vaccination, PIV). But observed significant antigen-specific T cell response indicated by increased lymphocyte stimulation index and enhanced secretion of IFN-gamma at day 56 PIV in Flu-BA group. The Flu BA vaccinated animals completely protected 57.1% of sheep and 42.9% of goats against B. melitensis 16M challenge. The severity of brucellosis in terms of infection index and colonization of Brucella in tissues was significantly lower in the Flu-BA group compared to negative control animals group. Nevertheless, positive control commercial Rev.1 vaccine provided strong antigen-specific T cell immunity and protection against B. melitensis 16M infection. We conclude that the Flu-BA vaccine induces a significant antigen-specific T-cell response and provides complete protection in approximately 50% of sheep and goats against B. melitensis 16M infection. Further investigations are needed to improve the efficacy of Flu-BA and explore its practical application in small ruminants. PMID- 27938678 TI - Inter-laboratory study to characterize the detection of serum antibodies against porcine epidemic diarrhoea virus. AB - Porcine epidemic diarrhea virus (PEDV) has caused extensive economic losses to pig producers in many countries. It was recently introduced, for the first time, into North America and outbreaks have occurred again in multiple countries within Europe as well. To assess the properties of various diagnostic assays for the detection of PEDV infection, multiple panels of porcine sera have been shared and tested for the presence of antibodies against PEDV in an inter-laboratory ring trial. Different laboratories have used a variety of "in house" ELISAs and also one commercial assay. The sensitivity and specificity of each assay has been estimated using a Bayesian analysis applied to the ring trial results obtained with the different assays in the absence of a gold standard. Although different characteristics were found, it can be concluded that each of the assays used can detect infection of pigs at a herd level by either the early European strains of PEDV or the recently circulating strains (INDEL and non-INDEL). However, not all the assays seem suitable for demonstrating freedom from disease in a country. The results from individual animals, especially when the infection has occurred within an experimental situation, show more variation. PMID- 27938679 TI - Single N-glycosylation site of bovine leukemia virus SU is involved in conformation and viral escape. AB - The bovine leukaemia virus (BLV) envelope protein (Env) is synthesized as a polyprotein precursor (gp72) proteolytically cleaved into the mature surface (SU) and transmembrane (TM) glycoproteins. The amino-terminal region of SU contains conformational epitopes F, G and H, which require a glycosylated SU to be recognized by monoclonal antibodies (MAbs) and antibodies from BLV-infected cattle. The SU contains eight asparagine (N) residues that are putative N glycosylation sites. The N129, N203, N230 and N251 appear involved in carbohydrate binding, play an essential role in the in vitro infection. To determine which sites were actually glycosylated, we generated mutated SU forms, where each N-glycosylation site was changed to alanine (A). Subsequently, these N to A mutations were inserted into the env gene to generate Env mutants. The increase of electrophoretic mobility of EnvA256 and EnvA271 derived SU showed that the asparagine residues N256 and N271 were also glycosylated. ELISA revealed that only the N129 oligosaccharide determined the antigenic conformation of SU. The syncytium formation induced by EnvA129 showed that fusogenic capacity was independent of amino-terminal SU glycan conformational structure. Finally, anti BLV serum inhibited syncytia formation even with the EnvA129 mutant. The latter inhibition was higher than Env, suggesting that the oligosaccharides could be also involved in the glycan shield for viral escape. PMID- 27938680 TI - Full genome analysis of Australian infectious bronchitis viruses suggests frequent recombination events between vaccine strains and multiple phylogenetically distant avian coronaviruses of unknown origin. AB - Australian strains of infectious bronchitis virus (IBV) have been evolving independently for many years, with control achieved by vaccination with local attenuated strains. Previous studies have documented the emergence of recombinants over the last 20 years, with the most recent one, Ck/Aus/N1/08, detected in 2008. These recombinants did not appear to be controlled by the vaccines currently in use. In this study we sequenced the complete genomes of three emergent Australian strains of IBV (IBV/Ck/Aus/N1/88, IBV/Ck/Aus/N1/03 and IBV/Ck/Aus/N1/08) and a previously incompletely characterised vaccine strain, IBV/Ck/Aus/Armidale, and compared them to the genome of the vaccine strain VicS. We detected multiple recombination events throughout the genome between wild type viruses and the vaccine strains in all three emergent isolates. Moreover, we found that strain N1/88 was not entirely exogenous, as was previously hypothesised. Rather, it originated from a recombination event involving the VicS vaccine strain. The S glycoprotein genes of N1/88 and N1/03 were known to be genetically distinct from previously characterised circulating strains and from each other, and the original donors of these genes remains unknown. The S1 glycoprotein gene of N1/88, a subgroup 2 strain, shares a high nucleotide identity with the sequence of the S1 gene of the recent isolate N1/08. As the subgroup 2 strains have not been isolated for at least 20 years, it appears likely that an unknown avian coronavirus that was the donor of the S1 glycoprotein sequence of N1/88 in the 1980s is still recombining with IBV strains in the field. PMID- 27938681 TI - Characterization of the role in adherence of Mycoplasma hyorhinis variable lipoproteins containing different repeat unit copy numbers. AB - Mycoplasma hyorhinis (M. hyorhinis) is an important pathogen of pigs. In previous studies, the variable lipoprotein (Vlp) family has been shown to play a role in mediating M. hyorhinis cytoadhesion. Herein, we performed several experiments to study the function of each Vlp family member in detail, especially examining the cytoadhesion functional domain and how the repeat unit copy number impacts on function. Recombinant proteins rVlpII, composed of region II from all seven Vlp members; rVlpIII, composed of repeat peptides from region III of all of Vlp members; as well as a series of recombinant rVlp proteins for each member containing different repeat unit copy numbers were constructed. All of the proteins were expressed in Escherichia coli and purified by affinity chromatography. The recombinant proteins, as well as seven keyhole limpet hemocyanin-conjugated Vlp peptides containing two copies of the repeat unit, were analyzed for their adherence to swine tracheal epithelial cells using a microtiter plate adherence assay. Both rVlpII and rVlpIII proteins were able to bind to cell membrane proteins. Among the repeat unit peptides, only PepVlpB and PepVlpG were able to bind to cell membrane proteins. All of the Vlp members had cytoadhesion capability. The adhesion abilities of the proteins containing 0 or 3 copies of the repeat unit were stronger than those of the proteins containing 12 copies. For rVlpA, rVlpB, rVlpD, rVlpF and rVlpG, the proteins containing no copies bound stronger than the proteins containing 3 copies. In contrast, the adherence of rVlpC3 was stronger than that of rVlpC0. There was no significant difference between the adherence of rVlpE3 and that of rVlpE0. Our results suggest that the major cytoadhesion sites of Vlps are mainly contained in region II, the function of which would be blocked by region III when region III is longer. PMID- 27938682 TI - Comparison of potential protection conferred by three immunization strategies (protein/protein, DNA/DNA, and DNA/protein) against Brucella infection using Omp2b in BALB/c Mice. AB - In the present study, immunogenicity and protective efficacy of the Brucella outer membrane protein 2b (Omp2b) was evaluated in BALB/c mice using Protein/Protein, DNA/DNA and DNA/Protein vaccine strategies. Immunization of mice with three vaccine regimens elicited a strong specific IgG response (higher IgG2a titers over IgG1 titers) and provided Th1-oriented immune response. Vaccination of BALB/c mice with the DNA/Pro regimen induced higher levels of IFN-gamma/IL-2 and conferred more protection levels against B. melitenisis and B. abortus challenge than did the protein or DNA alone. In conclusion, Omp2b is able to stimulate specific immune responses and to confer cross protection against B. melitensis and B. abortus infection. Therefore, it could be introduced as a new potential candidate for the development of a subunit vaccine against Brucella infection. PMID- 27938683 TI - The adherent abilities of Clostridium perfringens strains are critical for the pathogenesis of avian necrotic enteritis. AB - Necrotic enteritis of poultry is an emerging disease of substantial economic importance, but aspects of the pathogenesis of this multi-factorial disease are still unclear. We recently demonstrated that the ability of avian strains of the causative bacterium, Clostridium perfringens, to bind to specific collagen types correlated strongly with their virulence and we postulated that binding of the pathogen to collagen types IV and V and gelatin may involve the putative adhesin encoding gene cnaA, which is found in the VR-10B locus. In this study we have used site-directed mutagenesis to demonstrate that disruption of the cnaA gene leads to a reduction in the expression of the three genes immediately downstream of cnaA and reduced adherence to collagen types IV and V and gelatin. In addition, a cnaA mutant of strain EHE-NE18 was no longer capable of causing necrotic enteritis in a chicken disease induction model and had a significantly reduced ability to colonise the chicken intestinal mucosa. These results were confirmed by generating and analysing a similar mutant in an independent necrotic enteritis causing C. perfringens strain. This study expands our understanding of the mechanisms involved in necrotic enteritis pathogenesis by demonstrating the importance of C. perfringens adherence to extracellular matrix proteins. PMID- 27938684 TI - Characterization of fowl adenoviruses isolated between 2007 and 2014 in China. AB - Forty-three fowl adenovirus (FAdV) strains were isolated in China from 2007 to 2014 from poultry and ostriches with inclusion body hepatitis (IBH) and hydropericardium syndrome (HPS). Phylogenetic analysis showed that 28/43 strains clustered into Fowl aviadenovirus D (FAdV-D) and 9/43 strains clustered into FAdV E. FAdV-C included three isolates of ostrich origin, one of goose origin and two of chicken origin. Based on hexon loop 1 gene sequencing analysis, these viruses were genetically related to FAdV-4, FAdV-8a, FAdV-8b and FAdV-11, of which FAdV 11 was dominant. The isolation in 2014 of three FAdV strains belonging to serotype 4 from ostrich flocks is to our knowledge the first finding of FAdV-4 infection and HPS cases in ostriches. Epidemiological analysis showed that FAdV has been circulating in northern and eastern China, where more than 50% of layers and broilers are raised. The hosts of this pathogen included broilers, layers, geese and ostriches. IBH and HPS cases had a sporadic or cluster distribution from 2007 to 2013; however, since 2014 the number of cases has increased sharply. To control FAdV, strict biosecurity protection measures are necessary and a multivalent vaccine may be needed. PMID- 27938685 TI - Up-regulation of IL-10 upon PRRSV vaccination impacts on the immune response against CSFV. AB - Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) infection negatively impacts the efficacy of classical swine fever virus (CSFV) vaccine. This paper investigates whether the PRRSV vaccine also impacts the CSFV vaccine and if the impact is time-related. Forty-eight piglets born from four sows were divided into five groups (G1-G5). The piglets in G1 to G4 were given PRRSV vaccine at 14, 21, 28 and 35days of age. The G5 group was not vaccinated with the PRRSV. All pigs were given the CSFV vaccine at 35days of age. Immune responses to the CSFV vaccine were evaluated by testing CSFV-specific sera antibodies, lymphocyte proliferation and cytokine secretion. The results demonstrate that the PRRSV vaccine significantly reduces the immune responses of the CSFV vaccination when immunised both vaccines at the same time or with only a one week interval. The PRRSV vaccination induced higher levels of IL-10 expression in the first week and this may be why the CSFV vaccination is immunosuppressed. The findings indicate that a time interval of more than one week is necessary for vaccinated CSF after the PRRSV immunisation. PMID- 27938686 TI - PCV2d-2 is the predominant type of PCV2 DNA in pig samples collected in the U.S. during 2014-2016. AB - Porcine circovirus type 2 (PCV2) vaccination was introduced in the US in 2006 and since has been adopted by most pig producers. While porcine circovirus associated disease (PCVAD) outbreaks are now relatively uncommon in the US, PCV2 remains a concern which is emphasized by increasing numbers of PCR and sequencing requests for PCV2. In the present study, randomly selected lung tissues from 586 pigs submitted in 2015 were tested for presence of PCV2 DNA. Positive samples were further characterized by sequencing and combined with available PCV2 open-reading frame (ORF) 2 sequences from the client data base of the Iowa State University Veterinary Diagnostic Laboratory. The prevalence of PCV2 in the randomly selected lung tissues was 23% (135/586) with 11.3% PCV2a, 29% PCV2b and 71.8% for PCV2d subgroup PCV2d-2. A total of 455 ORF2 sequences obtained from 2014 through 2016 were analyzed and PCV2d accounted for 66.7% of the 2014 sequences, 71.8% of the 2015 sequences, and 72% of the 2016 sequences. Interestingly, only 1.9% (9/455) of the sequences belonged to the recently identified PCV2e genotype. The present data indicates that despite an almost 100% PCV2 vaccine coverage in the US, PCV2 DNA can still be detected in almost 1 of 4 randomly selected pig tissues. PCV2d-2 is now the predominant genotype in the USA suggesting that PCV2d-2 may have some advantage over PCV2a and PCV2b in its ability to replicate in pigs under vaccination pressure. PMID- 27938687 TI - Sheep carrying pathogenic Yersinia enterocolitica bioserotypes 2/O:9 and 5/O:3 in the feces at slaughter. AB - Yersinia enterocolitica is a heterogeneous species including non-pathogenic strains belonging to biotype 1A and pathogenic strains belonging to biotypes 1B and 2-5. Pathogenic strains of biotypes 2-4 carrying the ail virulence gene have frequently been isolated from domestic pigs at slaughter. In sheep, mostly non pathogenic biotype 1A strains have been reported. In our study, the prevalence of ail-positive Y. enterocolitica was studied by PCR and culturing in 406 young sheep (<1year of age) and 139 older sheep at slaughter in Finland. When using PCR, the detection rate was 11% (45/406) in young sheep originating from 11 (18%) farms. Surprisingly, Y. enterocolitica belonging to bioserotypes 2/O:9 and 5/O:3, carrying both chromosomal and plasmid-borne virulence genes, were isolated from the fecal samples of 10 (2%) and 23 (4%) sheep, respectively. All isolates of bioserotypes 2/O:9 (19 isolates) and 5/O:3 (53 isolates) carried the chromosomal virulence genes ail, inv, ystA, and myfA, and almost all isolates (71/72) also carried the virulence genes virF and yadA located on the virulence plasmid. The isolates showed high susceptibility to tested antimicrobials and low genetic diversity by PFGE. Y. enterocolitica bioserotype 5/O:3 is a very rare bioserotype, and has earlier only sporadically been reported in European wildlife and in sheep in Australia and New Zealand. Bioserotype 2/O:9 is a common bioserotype found in humans with yersiniosis, and has sporadically been isolated in wild and domestic animals. PMID- 27938688 TI - Protective efficacy of four recombinant fimbrial proteins of virulent Aeromonas hydrophila strain ML09-119 in channel catfish. AB - Aeromonas hydrophila is a reemerging pathogen of channel catfish (Ictalurus punctatus); recent outbreaks from 2009 to 2014 have caused the loss of more than 12 million pounds of market size catfish in Alabama and Mississippi. Genome sequencing revealed a clonal group of A. hydrophila isolates with unique genetic and phenotypic features that is highly pathogenic in channel catfish. Comparison of the genome sequence of a representative catfish isolate (ML09-119) from this virulent clonal group with lower virulence A. hydrophila isolates revealed four fimbrial proteins unique to strain ML09-119. In this work, we expressed and purified four A. hydrophila fimbrial proteins (FimA, Fim, MrfG, and FimOM) and assessed their ability to protect and stimulate protective immunity in channel catfish fingerlings against A. hydrophila ML09-119 infection for vaccine development. Our results showed catfish immunized with FimA, Fim, FimMrfG, and FimOM exhibited 59.83%, 95.41%, 85.72%, and 75.01% relative percent survival, respectively, after challenge with A. hydrophila strain ML09-119. Bacterial concentrations in liver, spleen, and anterior kidney were significantly (p<0.05) lower in vaccinated fish compared to the non-vaccinated sham groups at 48h post infection. However, only the Fim immunized group showed a significantly higher antibody titer in comparison to the non-vaccinated treatment group (p<0.05) at 21days post-vaccination. Altogether, Fim and FimMrfG recombinant proteins have potential for vaccine development against virulent A. hydrophila infection. PMID- 27938689 TI - Quantifying the effect of lactogenic antibody on porcine epidemic diarrhea virus infection in neonatal piglets. AB - The contribution of lactogenic antibody to the protection of piglets against porcine epidemic diarrhea virus (PEDV) was evaluated. Pregnant multiparous sows and their litters were allocated to one of 3 treatment groups: Group 1-6 serum antibody-negative sows and a subset (n=11) of their piglets. Group 2-8 serum antibody-positive sows and their 91 piglets. Piglets were orally inoculated with PEDV at 4 (Group 1) or 2 (Group 2) days of age. Group 3-2 PEDV serum antibody negative sows and 22 piglets, provided a baseline for piglet survivability and growth rate. Piglets were monitored daily for clinical signs, body weight, and body temperature through day post-inoculation (DPI) 12 (Groups 2 and 3) or 14 (Group 1). Serum and mammary secretions were tested for PEDV IgG, IgA, and virus neutralizing antibody. Feces were tested by PEDV real-time, reverse transcriptase PCR (rRT-PCR). Piglets on sows without (Group 1) or with (Group 2) anti-PEDV antibody showed significantly different responses to PEDV infection in virus shedding (p<0.05), thermoregulation (p<0.05), growth rate (p<0.05), and survivability (p<0.0001). Specifically, Group 1 piglets shed more virus on DPIs 1 to 5, were hypothermic at all sampling points except DPIs 9, 11, and 12, gained weight more slowly, and exhibited lower survivability than Group 2 piglets. Within Group 2 litters, significant differences were found in virus shedding (p<0.05), and body temperature (p<0.05), but not in piglet survival rate. The number of sows and litters in Group 2 was insufficient to derive the relationship between specific levels of lactogenic antibody (FFN, IgA, and IgG) and the amelioration of clinical effects. However, when combined with previous PEDV literature, it can be concluded that the optimal protection to piglets will be provided by dams able to deliver sufficient lactogenic immunity, both humoral and cellular, to their offspring. PMID- 27938692 TI - Special issue: Polylactide (PLA) Based Biopolymers. PMID- 27938691 TI - Should we administrate anticoagulants to critically ill patients with new onset supraventricular arrhythmias? PMID- 27938690 TI - Pathogenicity and antigenicity of a novel NADC30-like strain of porcine reproductive and respiratory syndrome virus emerged in China. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) has spread globally and caused huge economic loss. In recent years, a new kind of highly pathogenic NADC30-like strain has emerged in China. However, the pathogenicity and antigenicity of the virus are not well understood. In this study, PRRSV strain FJ1402 was isolated from piglets with clinical signs in Fujian Province in China in 2014. The complete genomic sequence analysis showed that it arose from recombination of North America NADC30 strain and highly pathogenic PRRSV (HP PRRSV) in China. Experiment in piglets showed that FJ1402 had similar virulence to HP-PRRSV strain BB0907. The commercial PRRSV modified live vaccines TJM-F92 and R98 could partly provide protective efficacy against FJ1402 challenge in piglets. This should be helpful for preventing and controlling this disease in the future. PMID- 27938693 TI - Evidence of dietary calcium and vitamin D inadequacies in a population of dental patients. AB - OBJECTIVES: To determine the dietary calcium and vitamin D intake of a cohort of dental patients identified as being at risk of inadequacy based on a 24-hour food recall. METHODS: A retrospective chart analysis was carried out on 5-day food record and nutrient analyses of 670 dental patients aged 18 to 82 years obtained over a 10-year period. All patients had scored poorly on a 24-hour food recall survey during their initial examination. RESULTS: The overall mean and median calcium and vitamin D intakes of the patients were significantly lower than the current estimated needs for the general population. Although calcium intake did not change over the 10-year period, vitamin D consumption decreased. The greatest dietary intake inadequacies for both calcium and vitamin D were seen in both male and female patients over age 50 years. CONCLUSIONS: A 24-Hour Food Recall Questionnaire may be an effective means for the oral health professional to screen patients for calcium and vitamin D and other nutrient inadequacies. CLINICAL SIGNIFICANCE: Screening for potential dietary inadequacies of calcium and vitamin D may identify patients potentially at risk for poor bone health. Our results indicate that the dental health professional can obtain evidence necessary to change patient dietary behavior and thus contribute to successful treatment outcomes. PMID- 27938694 TI - Confidence in outcome estimates from systematic reviews used in informed consent. AB - OBJECTIVES: Evidence-based dentistry now guides informed consent in which clinicians are obliged to provide patients with the most current, best evidence, or best estimates of outcomes, of regimens, therapies, treatments, procedures, materials, and equipment or devices when developing personal oral health care, treatment plans. Yet, clinicians require that the estimates provided from systematic reviews be verified to their validity, reliability, and contextualized as to performance competency so that clinicians may have confidence in explaining outcomes to patients in clinical practice. ANALYSIS WITH RESULTS: The purpose of this paper was to describe types of informed estimates from which clinicians may have confidence in their capacity to assist patients in competent decision making, one of the most important concepts of informed consent. METHODS: Using systematic review methodology, researchers provide clinicians with valid best estimates of outcomes regarding a subject of interest from best evidence. Best evidence is verified through critical appraisals using acceptable sampling methodology either by scoring instruments (Timmer analysis) or checklist (grade), a Cochrane Collaboration standard that allows transparency in open reviews. These valid best estimates are then tested for reliability using large databases. Finally, valid and reliable best estimates are assessed for meaning using quantification of margins and uncertainties. ANALYSIS: Through manufacturer and researcher specifications, quantification of margins and uncertainties develops a performance competency continuum by which valid, reliable best estimates may be contextualized for their performance competency: at a lowest margin performance competency (structural failure), high margin performance competency (estimated true value of success), or clinically determined critical values (clinical failure). CONCLUSIONS: Informed consent may be achieved when clinicians are confident of their ability to provide useful and accurate best estimates of outcomes regarding regimens, therapies, treatments, and equipment or devices to patients in their clinical practices and when developing personal, oral health care, treatment plans. PMID- 27938695 TI - Feasibility assessment for using telehealth technology to improve access to dental care for rural and underserved populations. AB - OBJECTIVE: South Carolina Dental Association members were surveyed on telehealth knowledge, need, and interest in using it for access to care improvements. METHODS: Dependent variables were Medicaid patient population size (less than or greater than 10%), career stage (early to middle and advanced), and National Health Service Corps participation (yes or no). Practice and provider characteristics were screener questions. Data were collected electronically and analyzed with SAS. Descriptive and bivariate analyses were conducted. RESULTS: Most (69.3%) reported some or no teledentistry knowledge. Distribution of needing consults was: endodontics (40.2%), oral-maxillofacial surgery (37.9%), orthodontia (30.7%), periodontics (28.4%), and pediatrics (12.5%). Consultations for diagnosis (72.9%), emergencies (56.7%), and continuing education (53.3%) were most frequently identified telehealth uses. Medicaid patient population size was the only dependent measure with statistical significance. Compared to <10% Medicaid, >10% was more likely to (1) frequently need consults for orthodontics (25.5% vs 43.4%, P = .0043) and pediatrics (5.9% vs 29.0%, P < .0001); (2) use telehealth for children with special health care needs (44.1% vs 65.8%, P = .0017), complex health conditions (54.3% vs 78.1%, P = .0004), conditions exacerbated by unmet dental needs (44.6% vs 65.8%, P = .0022); and (3) use telehealth for extending practice to underserved populations (14.6% vs 33.8%, P = .0004). CONCLUSIONS: Despite need for telehealth knowledge improvement, sufficient interest exists. Further study will determine if demand for teledentistry is in balance with consultant availability. It has been suggested that access to care improvements require capacity expansions in private practices. States will need to engage dental communities determine if teledentistry is an effective solution. PMID- 27938696 TI - Weak Evidence Hinders the Understanding of the Benefits of Periodontal Therapy on Glycemic Control in Patients With Diabetes and Periodontitis. AB - ARTICLE TITLE AND BIBLIOGRAPHICAL INFORMATION: Treatment of periodontal disease for glycaemic control in people with diabetes mellitus. Simpson TC, Weldon JC, Worthington HV, Needleman I, Wild SH, Moles DR, Stevenson B, Furness S, Iheozor Ejiofor Z. Cochrane Database Syst Rev 2015;11:CD004714. SOURCE OF FUNDING: This project was supported by the NIHR, via Cochrane Infrastructure funding to the Cochrane Oral Health Group, School of Dentistry, University of Manchester (UK), Manchester Academic Health Sciences Centre (UK), and the National Institute for Health Research (UK) TYPE OF STUDY/DESIGN: Systematic review with meta-analysis. PMID- 27938697 TI - Noninvasive Caries Risk-based Management in Private Practice Settings May Lead to Reduced Caries Experience Over Time. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: The Caries Management System: are preventive effects sustained postclinical trial? Evans RW, Clark P, Jia N. Community Dent Oral Epidemiol 2016;44(2):188-97. SOURCES OF FUNDING: Foundation: Oral Health Foundation, University of Sydney; and the Australian Dental Research Foundation; government: National Health and Medical Research Council; other: Dental Board of New South Wales TYPE OF STUDY/DESIGN: The original 3-year study was a multicenter cluster randomized controlled clinical trial. PMID- 27938698 TI - Treatment of Select Intrabony Defects by Periodontal Regeneration Could Be Cost effective Long Term in Compliant Patients. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Periodontal regeneration compared with access flap surgery in human intrabony defects: 20-year follow-up of a randomized clinical trial: tooth regeneration, periodontitis recurrence and costs. Cortellini P, Buti J, Prato GP, Tonetti MS.J Clin Periodontolhttp://dx.doi.org/10.1111/jcpe.12638 [Pre pub/accepted manuscript] SOURCE OF FUNDING: Nonprofit, foundations: European Research Group on Periodontology, Genova, Italy; other: Accademia Toscana di Ricerca Odontostomatologica, Florence, Italy TYPE OF STUDY/DESIGN: Randomized controlled trial. PMID- 27938699 TI - Semiannual Fluoride Applications in Low-Risk Toddlers May Not Be More Effective Than Toothbrushing Instruction and Dietary Counseling in Controlling Dental Caries. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Effectiveness of early preventive intervention with semiannual fluoride varnish application in toddlers living in high-risk areas: A stratified cluster-randomized controlled trial. Anderson M, Dahlof G, Twetman S, Jansson L, Bergenlid AC, Grindefjord M. Caries Res 2016;50(1):17-23. SOURCE OF FUNDING: The study was commissioned and supported by Stockholm County Council and Karolinska Institutet. TYPE OF STUDY/DESIGN: Non blinded, cluster-randomized controlled field trial with two parallel arms. PMID- 27938700 TI - Limited Evidence Suggested That Unfinished Root Canal Treatments May Increase the Risk of Cardiovascular Disease. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Unfinished root canal treatments and the risk of cardiovascular disease. Lin PY, Chien KL, Chang HJ, Chi LY. J Endod 2015;41(12):1991-6. SOURCE OF FUNDING: The National Science Council in Taiwan (Government) TYPE OF STUDY/DESIGN: Retrospective cohort study. PMID- 27938701 TI - Low-grade Systemic Inflammation May Increase the Risk of Periodontitis. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Longitudinal effects of systemic inflammation markers on periodontitis. Pink C, Kocher T, Meisel P, Dorr M, Markus MRP, Jablonowski L, Grotevendt A, Nauck M, Holtfreter B. J Clin Periodontol 2015;42(11):988-97. SOURCE OF FUNDING: The parent study was supported by the German Federal Ministry of Education and Research (BMBF) (grant 01ZZ96030, 01ZZ0701), the Ministry of Education, Research and Cultural Affairs, and the Ministry of Social Affairs of the Federal State of Mecklenburg-West Pomerania. GABA, Switzerland, provided an unlimited educational grant to support B.H. and C.P. This publication was made possible in part by grant number T32-GM081740 from NIH-NIGMS. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIGMS or NIH. CONFLICT OF INTEREST: The authors have no actual or potential conflicts of interest. TYPE OF STUDY/DESIGN: Prospective cohort study. PMID- 27938702 TI - Erythrocyte copper chaperone for superoxide dismutase and superoxide dismutase as biomarkers for hepatic copper concentrations in Labrador retrievers. AB - Hereditary hepatic copper accumulation in Labrador retrievers leads to hepatitis with fibrosis and eventually cirrhosis. The development of a non-invasive blood based biomarker for copper status in dogs could be helpful in identifying dogs at risk and to monitor copper concentrations during treatment. In this study, two cellular copper metabolism proteins, Cu/Zn superoxide dismutase (SOD1) and its chaperone (copper chaperone for SOD1, CCS) were measured in erythrocytes and tested for association with hepatic copper concentrations in 15 Labrador retrievers with normal or increased hepatic copper concentrations. Antibodies against CCS and SOD1 were applicable for use in canine specimens. This was demonstrated by the loss of immune-reactive bands for CCS and SOD1 in siRNA treated canine bile duct epithelial cells. Erythrocyte CCS and CCS/SOD1 ratios were decreased 2.37 (P <0.001) and 3.29 (P <0.001) fold in the high copper group compared to the normal copper group. Erythrocyte CCS and CCS/SOD1 ratio are potential new biomarkers for hepatic copper concentrations in Labrador retrievers and could facilitate early diagnosis and treatment monitoring for copper associated hepatitis in dogs. PMID- 27938703 TI - Detection and prevalence of boid inclusion body disease in collections of boas and pythons using immunological assays. AB - Inclusion body disease (IBD) of boas and pythons is characterized by the intracytoplasmic accumulation of an antigenic 68 kDa viral protein IBDP, more recently known as the nucleoprotein (NP) of the reptarenaviruses. Blood samples of 131 captive boas and pythons (53 boa constrictors, Boa constrictor; 35 rainbow boas, Epicrates cenchria; 22 ball pythons, Python regius; 5 carpet pythons, Morelia spilota; 6 Burmese pythons, Python bivittatus; 4 Jamaican boas, Epicrates subflavus; 5 anacondas, Eunectes spp.; and 1 green tree python, Morelia viridis) were obtained from 28 collections in the USA. Diagnosis of IBD was initially made by the identification of eosinophilic intracytoplasmic inclusion bodies in hematoxylin and eosin (HE) stained blood films and isolated peripheral white blood cells (PWBC). The overall prevalence of IBD in study snakes was 25/131 or 19% (95% CI = 12.4%, 25.8%) with boa constrictors being more commonly infected (22/53 or 41.5%; 95% CI = 28.2%, 54.8%) than other species in this study. Of the 22 IBD positive boa constrictors, 87% were clinically healthy, 13% had various signs of chronic illness, and none showed signs of central nervous system disease. Using a validated monoclonal anti-NP antibody, NP was confirmed within the isolated PWBC by immunohistochemical staining and Western blots. The presence of reptarenaviruses within blood samples of 27 boa constrictors and three rainbow boas was also assessed by PCR. Among boa constrictors, very good agreements were shown between the observation of inclusion bodies (by HE stain) and the presence of NP (by immunohistochemistry, kappa = 0.92; and Western blots, kappa = 0.89), or the presence of reptarenaviruses (by PCR; kappa = 0.92). PMID- 27938704 TI - Evaluation of ompA and pgtE genes in determining pathogenicity in Salmonella enterica serovar Enteritidis. AB - Salmonella enterica subsp. enterica serovar Enteritidis (S. Enteritidis) is a major causative agent of gastroenteritis in humans. This important food-borne pathogen also colonises the intestinal tracts of poultry and can spread systemically, especially in chickens. To identify the S. Enteritidis virulence genes involved in infection and colonisation of chickens, chromosomal deletion mutants of the ompA and pgtE genes, which encode essential components of omptins, were constructed. There were no significant differences between the wild-type and ompA and pgtE mutants in a series of in vitro assays, including an intracellular survival assay, survival in specific-pathogen-free (SPF) chicken serum, and in vitro competition assays. In contrast, in vivo competition assays revealed that ompA and pgtE mutants underwent attenuated growth in liver, cardiac blood, spleen, lung, and kidney compared to a wild-type strain (CVCC3378). When tested in SPF chickens, ompA or pgtE gene inactivation substantially reduced organ colonisation and delayed systemic infection compared with the wild-type strain. Colonisation was restored in S. Enteritidis mutants by reintroduction of the whole ompA or pgtE gene with the native promoters. The results of this study demonstrate that ompA and pgtE play an important role in the pathogenesis of S. Enteritidis and its ability to infect chickens. PMID- 27938706 TI - Diagnostic significance of anatomical distribution patterns of nervous systemic lymphoma. PMID- 27938705 TI - Antibody profiling of canine IgG responses to the OspC protein of the Lyme disease spirochetes supports a multivalent approach in vaccine and diagnostic assay development. AB - OspC performs essential functions during the enzootic cycle of the Lyme disease (LD) spirochetes. In this study, the specificity of antibody (Ab) responses to OspC was profiled to define the antigenic determinants during infection and after vaccination. Several OspC variants or 'types' were screened with serum from SNAP4Dx C6 positive dogs and with serum from rabbits hyperimmunized with OspC proteins. The OspC type-specific nature of the Ab response revealed that variable domains of OspC are immunodominant during infection and upon vaccination. To assess the potential of OspC to elicit Ab in the context of a bacterin vaccine, OspC production in strains cultivated in vitro was assessed. Immunoblot and indirect immunofluorescent antibody analyses demonstrated that production is low and that only a subset of cells actively produces OspC in vitro, raising questions about the potential of bacterin vaccines to stimulate significant anti OspC Ab responses. The specificity of the OspC Ab response in experimentally infected mice over time was assessed to determine if domains shielded in the OspC homodimer become accessible and stimulate Ab production as infection progresses. The results demonstrate that the OspC Ab response remains focused on surface exposed variable regions of the protein throughout infection. In contrast to some earlier studies, it is concluded that conserved domains of OspC, including the C7 or C10 domain, do not elicit significant Ab responses during infection or upon vaccination. Collectively, the results indicate that OspC diversity must be considered in vaccine design and in the interpretation of diagnostic assays that employ OspC as a diagnostic antigen. PMID- 27938707 TI - Shortened egg reappearance after ivermectin or moxidectin use in horses in the UK. AB - This study reports ivermectin and moxidectin egg reappearance periods (ERP) from UK horses with persistently positive faecal egg counts (FEC), defined as positive FEC within the ERP of an anthelmintic post-treatment, or with FECs that remained positive after the normal ERP post-anthelmintic treatment. A selected population of UK pleasure horses deemed at high risk of strongyle infection was studied. The earliest ERP recorded after ivermectin or moxidectin, using first positive FEC, was 5 weeks. From 16 premises where moxidectin was used, five had ERP >=12 weeks using two further metrics. For premises where moxidectin was administered to only one animal (present or tested), and evaluated as one group (n = 61), ERP was >=10 weeks. For premises where ivermectin was used, the ERP was >=5 weeks. Premises with only one horse (present or tested), dosed with ivermectin (n = 31), analysed as one group, demonstrated egg reappearance >=6 weeks. These field data suggest shortened ERPs following macrocyclic lactone treatment compared to previously published values (8-10 and >13 weeks respectively) when these drugs were first marketed. PMID- 27938708 TI - Challenges and opportunities for monoclonal antibody therapy in veterinary oncology. AB - Monoclonal antibodies (mAbs) have come to dominate the biologics market in human cancer therapy. Nevertheless, in veterinary medicine, very few clinical trials have been initiated using this form of therapy. Some of the advantages of mAb therapeutics over conventional drugs are high specificity, precise mode of action and long half-life, which favour infrequent dosing of the antibody. Further advancement in the field of biomedical sciences has led to the production of different forms of antibodies, such as single chain antibody fragment, Fab, bi specific antibodies and drug conjugates for use in diagnostic and therapeutic purposes. This review describes the potential for mAbs in veterinary oncology in supporting both diagnosis and therapy of cancer. The technical and financial hurdles to facilitate clinical acceptance of mAbs are explored and insights into novel technologies and targets that could support more rapid clinical development are offered. PMID- 27938709 TI - Effects of etoposide alone and in combination with piroxicam on canine osteosarcoma cell lines. AB - Osteosarcoma (OSA) is the most common primary bone tumour in dogs. The poor survival rate in dogs with OSA highlights the need for new therapeutic approaches. This study evaluated the cytotoxic effects of etoposide, alone and in combination with piroxicam, on canine OSA cell cultures. Etoposide alone significantly suppressed cell growth and viability, whereas etoposide in combination with piroxicam exhibited concentration dependent cytotoxicity. The anti-proliferative effect was a result of inactivity of the Cdc2-cyclin B1 complex, which correlated with an increase in the G2/M fraction. This subsequently activated the apoptosis cascade, as indicated by elevated apoptosis levels and up-regulation of poly (ADP-ribose) polymerase proteolytic cleavage. Down-regulation of survivin expression induced by the combination treatment may have contributed to the enhanced cytotoxicity. The results of this study suggest that further investigation of etoposide and piroxicam as a therapeutic combination for canine OSA is warranted. PMID- 27938710 TI - Comparison of standardised versus non-standardised methods for testing the in vitro potency of oxytetracycline against Mannheimia haemolytica and Pasteurella multocida. AB - The in vitro pharmacodynamics of oxytetracycline was established for six isolates of each of the calf pneumonia pathogens Mannheimia haemolytica and Pasteurella multocida. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and bacterial time-kill curves were determined in two matrices, Mueller Hinton broth (MHB) and calf serum. Geometric mean MIC ratios, serum:MHB, were 25.2:1 (M. haemolytica) and 27.4:1 (P. multocida). The degree of binding of oxytetracycline to serum protein was 52.4%. Differences between serum and broth MICs could not be accounted for by oxytetracycline binding to serum protein. In vitro time-kill data suggested a co-dependent killing action of oxytetracycline. The in vitro data indicate inhibition of the killing action of oxytetracycline by serum factor(s). The nature of the inhibition requires further study. The outcome of treatment with oxytetracycline of respiratory tract infections in calves caused by M. haemolytica and P. multocida may not be related solely to a direct killing action. PMID- 27938711 TI - Activity of florfenicol for Actinobacillus pleuropneumoniae and Pasteurella multocida using standardised versus non-standardised methodology. AB - Four indices of antimicrobial potency were determined for florfenicol and the pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), mutant prevention concentration (MPC) and time-kill curves were determined in two matrices, broth and pig serum. Five overlapping sets of two-fold dilutions were used to increase accuracy of the measurements. MIC and MBC serum:broth ratios for A. pleuropneumoniae were 0.96:1 and 1.07:1, respectively, and corresponding values for P. multocida were 0.72:1 and 0.50:1. The percentage binding of florfenicol to serum protein was 65.4%, and fraction unbound (fu) serum MICs were significantly lower, by 2.71-fold and 3.82-fold, respectively, than predicted for free serum concentrations for A. pleuropneumoniae and P. multocida. Similar culture medium differences were obtained for MBC and MPC. MICs in serum and broth were increased significantly and progressively for high, medium and low initial inoculum counts. Serum MPC:MIC ratios for A. pleuropneumoniae and P. multocida were 12.5:1 and 13.6:1, respectively; ratios for broth were similar. The killing action of florfenicol had the characteristics of concentration dependency for both species in both growth media. These data indicate the value of using a biological medium, when determining microbiological potency indices, to predict dosage for clinical use. PMID- 27938712 TI - The stability and microbial contamination of bupivacaine, lidocaine and mepivacaine used for lameness diagnostics in horses. AB - Local anaesthetics (LAs) are frequently used for diagnostic procedures in equine veterinary practice. The objective of this study was to investigate the physico chemical stability and bacterial contamination of bupivacaine, lidocaine and mepivacaine used for lameness examinations in horses. The LAs were stored in 12 different groups at different temperatures (-18 degrees C to 70 degrees C), light intensities and in common veterinary field conditions for up to 16 months. The pH, presence of bacterial contamination and concentrations of LAs and methylparaben (a preservative present in lidocaine) were determined serially in both new and repeatedly punctured (RP) vials. Mepivacaine remained chemically stable. A 1.9% increase in bupivacaine concentration was evident in one group, whereas a 1.9-3.7% decrease was noted in six groups. Risk factors associated with a change in concentration were light and RP vials. Lidocaine concentration decreased 6.3% in one group and increased 5.3-7.2% in two groups. Risk factors for degradation were heat and RP vials whereas storage in practice vehicles was a risk factor for increased concentrations. Methylparaben decreased 8.3-75.0% in seven groups, and RP vials, heat and storage in practice vehicles were risk factors for degradation. No contamination was present in any of the LAs and pH remained stable. Commercially available solutions of lidocaine, mepivacaine and bupivacaine stored under common veterinary field conditions are extremely stable and sterile for extended periods. The minor changes in concentration documented in this study are unlikely to affect anaesthetic efficacy during equine lameness examinations. When using products containing methylparaben, degradation of the preservative over time is to be expected. PMID- 27938713 TI - Cellular response markers and cytokine gene expression in the central nervous system of cattle naturally infected with bovine herpesvirus 5. AB - The present study reports an investigation on the phenotype of inflammatory and immune cells, cytokine and viral gene expression in the brains of cattle naturally infected with bovine herpesvirus 5 (BHV5). Brain sections of 38 affected animals were analysed for the nature and extent of perivascular cuffs in the Virchow-Robin space and parenchyma. Histopathological changes were severe in the olfactory bulbs (Obs), hippocampus, piriform, frontal, temporal and parietal cortices/lobes and were characterized by inflammatory infiltrates in Virchow Robin spaces. The histopathological changes correlated positively with the distribution of BHV5 antigens (r = 0.947; P < 0.005). Cells of CD3+ phenotype were predominant in areas with severe perivascular cuffs. Viral antigens and genomic viral DNA were detected in the Obs and piriform lobe, simultaneously (r = 0.987; P < 0.005). Similarly, pro-inflammatory cytokine genes INFG, IL2, TNF and LTBR were expressed in the same brain areas (P < 0.005). These results provide important information on the inflammatory and immunological events accompanying BHV5 neurological infections. Our findings provide the first evidence for increased immune activation followed by inflammatory cytokine expression, positively correlated with viral replication in the cranial areas of the brain. Taken together, these results suggest that the host immune response and inflammation play a crucial role in the pathogenesis of acute encephalitis by BHV5 in cattle. PMID- 27938714 TI - The welfare risks and impacts of heat stress on sheep shipped from Australia to the Middle East. AB - This review considers the welfare issues confronting sheep due to heat stress on board ships undertaking long distance voyages. Sheep engage in behavioural and physiologic mechanisms to attempt to mitigate heat stress, but the evidence from Australian shipments from 2005 to 2014 is that mortality approximately doubles when sheep are transported from Australia in winter to the Middle East in summer. Much of this increase has been attributed to salmonellosis and inanition, but this may have been mistaken for, or exacerbated by, heat stress. The Australian government's estimate of the heat stress threshold of sheep is substantially higher than that observed under simulated live export conditions, which leads to an underestimate of the importance of heat stress in sheep on voyages where mortality is high. Improved temperature monitoring on ships and the creation of both a robust model of the impact of increased temperatures on sheep morbidity and mortality, and a heat stress scale for sheep would assist in understanding and addressing this welfare concern. The high risk to sheep exported from Australia during summer in the Middle East is sufficient to warrant consideration of restriction of trade during this period. PMID- 27938715 TI - [How to improve health care: The importance of implementation]. PMID- 27938716 TI - Guest Editorial. PMID- 27938717 TI - How we load our data sets with theories and why we do so purposefully. AB - In this paper, I compare theory-laden perceptions with imputed data sets. The similarities between the two allow me to show how the phenomenon of theory ladenness can manifest itself in statistical analyses. More importantly, elucidating the differences between them will allow me to broaden the focus of the existing literature on theory-ladenness and to introduce some much-needed nuances. The topic of statistical imputation has received no attention in philosophy of science. Yet, imputed data sets are very similar to theory-laden perceptions, and they are now an integral part of many scientific inferences. Unlike the existence of theory-laden perceptions, that of imputed data sets cannot be challenged or reduced to a manageable source of error. In fact, imputed data sets are created purposefully in order to improve the quality of our inferences. They do not undermine the possibility of scientific knowledge; on the contrary, they are epistemically desirable. PMID- 27938718 TI - Repertoires: A post-Kuhnian perspective on scientific change and collaborative research. AB - We propose a framework to describe, analyze, and explain the conditions under which scientific communities organize themselves to do research, particularly within large-scale, multidisciplinary projects. The framework centers on the notion of a research repertoire, which encompasses well-aligned assemblages of the skills, behaviors, and material, social, and epistemic components that a group may use to practice certain kinds of science, and whose enactment affects the methods and results of research. This account provides an alternative to the idea of Kuhnian paradigms for understanding scientific change in the following ways: (1) it does not frame change as primarily generated and shaped by theoretical developments, but rather takes account of administrative, material, technological, and institutional innovations that contribute to change and explicitly questions whether and how such innovations accompany, underpin, and/or undercut theoretical shifts; (2) it thus allows for tracking of the organization, continuity, and coherence in research practices which Kuhn characterized as 'normal science' without relying on the occurrence of paradigmatic shifts and revolutions to be able to identify relevant components; and (3) it requires particular attention be paid to the performative aspects of science, whose study Kuhn pioneered but which he did not extensively conceptualize. We provide a detailed characterization of repertoires and discuss their relationship with communities, disciplines, and other forms of collaborative activities within science, building on an analysis of historical episodes and contemporary developments in the life sciences, as well as cases drawn from social and historical studies of physics, psychology, and medicine. PMID- 27938719 TI - Forms of presentism in the history of science. Rethinking the project of historical epistemology. AB - Since the late 1980s, presentism has seen a resurgence among some historians of science. Most of them draw a line between a good form of presentism and typical anachronism, but where the line should be drawn remains an open question. The present article aims at resolving this problem. In the first part I define the four main distinct forms of presentism at work in the history of science and the different purposes they serve. Based on this typology, the second part reconsiders what counts as anachronism, Whiggism and positivist history. This clarification is used as a basis to rethink the research program of historical epistemology in the third section. Throughout this article, I examine the conceptual core of historical epistemology more than its actual history, from Bachelard to Foucault or others. Its project should be defined - as Canguilhem suggested - as an attempt to account for both the contingency and the rationality of science. As such, historical epistemology is based on a complex fifth form of presentism, which I call critical presentism. The critical relation at stake not only works from the present to the past, because of the acknowledged rationality of science, but also from the past to the present because of the contingency and historicity of scientific knowledge. PMID- 27938720 TI - Did Samuel Clarke really disavow action at a distance in his correspondence with Leibniz?: Newton, Clarke, and Bentley on gravitation and action at a distance. AB - In this paper I ague against John Henry's claim that Newton embraced unmediated action at a distance as an explanation of gravity (Henry, 1994, 1999, 2011, 2014). In particular, I take issue with his apparent suggestion that the fact, as he sees it, that two of Newton's prominent followers, namely, Richard Bentley and Samuel Clarke, embraced unmediated action at a distance as an explanation of gravity provides significant supporting evidence that Newton did as well (see Henry, 1994 and 1999). Instead, I argue that while Bentley did ultimately defend the notion of unmediated action at a distance as an explanation of gravity, Newton himself accepted that notion neither in his correspondence with Bentley, as Henry has maintained, nor in any of his later works. I also provide evidence that suggests that Newton did, in fact, accept both the principle of local causation and the passivity of matter. Finally, I argue that whatever the case may be with respect to Newton on the matter, it is clear from his correspondence with Leibniz, as well as from his Boyle lectures, that contrary to what Henry has maintained, Clarke was a stalwart opponent of unmediated action at a distance due to his strong commitment to both the principle of local causation and the passivity of matter. PMID- 27938721 TI - Whewell on the classification of the sciences. AB - Despite deserving a place amongst the historic milestones of the philosophy of disciplines, the system of the sciences put forward by Whewell has so far received little interest. Yet his ideas had a significant impact on the researches subsequently carried out on the topic, exerting in particular a decisive influence on Peirce and Spencer. The present paper aims to display the innovatory nature of the philosophical foundations of the Whewellian classification of the sciences. In this respect, we will argue that the most striking feature of his disciplinary system lies in a heuristic categorization of the sciences according to their "methods of discovery". This represents a double departure from both the Aristotelian and the Baconian disciplinary paradigms, which are instead underpinned by ontological and epistemological criteria, respectively. Next, we will explore the pivotal role of Whewell's classification of the sciences for his overall project of a philosophy of scientific discovery. PMID- 27938722 TI - Can the behavioral sciences self-correct? A social epistemic study. AB - Advocates of the self-corrective thesis argue that scientific method will refute false theories and find closer approximations to the truth in the long run. I discuss a contemporary interpretation of this thesis in terms of frequentist statistics in the context of the behavioral sciences. First, I identify experimental replications and systematic aggregation of evidence (meta-analysis) as the self-corrective mechanism. Then, I present a computer simulation study of scientific communities that implement this mechanism to argue that frequentist statistics may converge upon a correct estimate or not depending on the social structure of the community that uses it. Based on this study, I argue that methodological explanations of the "replicability crisis" in psychology are limited and propose an alternative explanation in terms of biases. Finally, I conclude suggesting that scientific self-correction should be understood as an interaction effect between inference methods and social structures. PMID- 27938723 TI - From secondary causes to artificial instruments: Pierre-Sylvain Regis's rethinking of scholastic accounts of causation. AB - Although several of Descartes's disciples established occasionalism as the natural outcome of Cartesianism, Pierre-Sylvain Regis forcefully resisted this conclusion by developing an account of secondary causes in which God does not immediately intervene in the natural world. In order to understand this view, it has been argued that Regis melds Aquinas's concurrentism with the new, mechanist natural philosophy defended in Cartesian physics. In this paper, I contend that such a reading of Regis's position is misleading for our understanding of both his account of secondary causality and the relationship between medieval debates and seventeenth century natural philosophy. I show that Regis's account of secondary causality denies two fundamental features at the core of the account proposed by Aquinas, namely that God acts immediately in nature and that secondary causes are per se causes. I contend that Regis's view more closely resembles a specific account of artificial instrumental causality developed by Duns Scotus. The comparison with Scotus shows that Regis is still dealing with conceptual tools that can be traced back to the scholastic tradition. Yet, Regis implements these tools to establish an account of causation that is fundamentally irreconcilable with scholastic natural philosophy. PMID- 27938724 TI - Locke on measurement. AB - Like many virtuosi in his day, the English philosopher John Locke maintained an active interest in metrology. Yet for Locke, this was no mere hobby: questions concerning measurement were also implicated in his ongoing philosophical project to develop an account of human understanding. This paper follows Locke's treatment of four problems of measurement from the early Drafts A and B of the Essay concerning Human Understanding to the publication of this famous book and its aftermath. It traces Locke's attempt to develop a natural or universal standard for the measure of length, his attempts to grapple with the measurement of duration, as well as the problems of determining comparative measures for secondary qualities, and the problem of discriminating small differences in the conventional measures of his day. It is argued that the salient context for Locke's treatment of these problems is the new experimental philosophy and its method of experimental natural history. PMID- 27938725 TI - [How do authors of systematic reviews restrict their literature searches when only studies from Germany should be included?] AB - INTRODUCTION: The use of search filters (e. g. for study types) facilitates the process of literature searching. Regional limits might be helpful depending on the research question. Regional search filters are already available for some regions, but not for Germany. Our aim is to give an overview of applied search strategies in systematic reviews (SRs) focusing on Germany. METHODS: We searched Medline (via Pubmed) applying a focused search strategy to identify SRs focusing on Germany in January 2016. Study selection and data extraction were performed by two reviewers independently. The search strategies with a focus on Germany were analyzed in terms of reasonableness and completeness relying on the Peer Review of Electronic Search Strategies (PRESS) criteria. A narrative evidence synthesis was performed. RESULTS: In total, 36 SRs (13 written in English) were included. 78% were published in 2012 or later. The majority (89%) of SRs utilized at least two different sources for their search with databases and checking references being the most common. 17 SRs did not use any truncations, ten SRs did not restrict their search to Germany, six SRs reported to have searched for German OR Germany. Only ten articles searched for the term Germany (occasionally jointly with the term Deutschland) without any use of an adjective such as German. DISCUSSION: There is a high interest in regionally focused SRs. The identified search strategies revealed a need for improvement. It would be helpful to develop a regional search filter for Germany that is able to identify studies performed in Germany. PMID- 27938726 TI - [The remains of the day: A working day in a university children's hospital]. AB - BACKGROUND: Limited time available for direct patient contact and a lot of time required for administrative duties have been reported by physicians working in adult medicine. OBJECTIVE: To characterize the typical daily work routine in a major pediatric university hospital. MATERIALS AND METHODS: A self-administered questionnaire was completed by physicians in the University Children's Hospital, Munich. The questionnaire captured the time spent on direct patient contact and on administrative tasks as well as the physicians' clinical experience and the location where the respective work was actually carried out (inpatient ward, outpatient emergency department, specialized outpatient clinic or department for developmental medicine). RESULTS: Most physicians (91.7 %) reported daily working hours beyond the regular schedule of 8.5hours. The proportion of time dedicated to direct patient contact was 31.2 % (95 % confidence interval: 25.2-37.1). Considering the number of patients in the work units, the average amount of time available for each individual patient varied between 14 minutes in the pediatric ward and 52 minutes in the department for developmental medicine. The reported times spent on patient contact did not significantly differ between physicians with > 5 years and those with <= 5 years of clinical experience. CONCLUSION: Although physicians in a university pediatric hospital work long daily hours, only restricted time is available for direct patient contact defined as physical examination of the child and face-to-face communication with patients and families. PMID- 27938727 TI - [Evaluation of the population-based 'Integrated Health Care System Gesundes Kinzigtal' (IHGK). Findings on health care quality based on administrative data]. AB - BACKGROUND AND OBJECTIVES: The management company "Gesundes Kinzigtal GmbH" signed an agreement on integrated healthcare with the statutory health insurer AOK Baden-Wurttemberg, effective as of November 1, 2005. The aim of the evaluation was to check whether the extent of overuse and underuse of healthcare services in the area of intervention declined or increased compared with usual care. METHODS: Longitudinal study with non-randomised control group based on health insurers' claims data from the years 2004-2011. Intervention group: residents of the Kinzigtal region insured by AOK. CONTROL GROUP: persons insured with the AOK in other regions of Baden-Wurttemberg. Healthcare quality indicators were derived from other studies and guidelines. Fifteen out of the 18 indicators related to overuse or underuse; three related to an outcome, namely avoidable hospital stays, the appearance of fractures in patients with osteoporosis, and mortality. Trend and outcome analyses rely on Poisson and Cox regressions adjusted for age, sex, the Charlson Index, and multimorbidity. RESULTS: Two out of 5 indicators for overuse and 2 out of 10 for underuse showed significant improvement for the intervention population relative to the control group. The risk of a fracture in patients with osteoporosis (HR: 0.809; 95 % CI: 0.740 to 0.885; p<0.0001) and mortality (HR: 0.944; 95% CI; 0.899-0.991; p=0.0194) were significantly lower in the Kinzigtal population. No negative trends were found. CONCLUSIONS: Compared with the control group, which represents the secular trend, significant improvements of healthcare quality in the intervention group (6 out of 18 indicators) are considerably more frequent than significant changes for the worse (0 out of 18 indicators). To date, the effects are not very strong, as all insured persons from the Kinzigtal form the basis of the analysis irrespective of their participation in the integrated care program. Claims data are appIicable to indicator based evaluation, but it would be necessary to consider additional years to see whether observed positive trends could be enhanced. PMID- 27938728 TI - [Continuity of hospital identifiers in hospital discharge data - Analysis of the nationwide German DRG Statistics from 2005 to 2013]. AB - BACKGROUND: In Germany, nationwide hospital discharge data (DRG statistics provided by the research data centers of the Federal Statistical Office and the Statistical Offices of the 'Lander') are increasingly used as data source for health services research. Within this data hospitals can be separated via their hospital identifier ([Institutionskennzeichen] IK). However, this hospital identifier primarily designates the invoicing unit and is not necessarily equivalent to one hospital location. Aiming to investigate direction and extent of possible bias in hospital-level analyses this study examines the continuity of the hospital identifier within a cross-sectional and longitudinal approach and compares the results to official hospital census statistics. METHODS: Within the DRG statistics from 2005 to 2013 the annual number of hospitals as classified by hospital identifiers was counted for each year of observation. The annual number of hospitals derived from DRG statistics was compared to the number of hospitals in the official census statistics 'Grunddaten der Krankenhauser'. Subsequently, the temporal continuity of hospital identifiers in the DRG statistics was analyzed within cohorts of hospitals. RESULTS: Until 2013, the annual number of hospital identifiers in the DRG statistics fell by 175 (from 1,725 to 1,550). This decline affected only providers with small or medium case volume. The number of hospitals identified in the DRG statistics was lower than the number given in the census statistics (e.g., in 2013 1,550 IK vs. 1,668 hospitals in the census statistics). The longitudinal analyses revealed that the majority of hospital identifiers persisted in the years of observation, while one fifth of hospital identifiers changed. CONCLUSION: In cross-sectional studies of German hospital discharge data the separation of hospitals via the hospital identifier might lead to underestimating the number of hospitals and consequential overestimation of caseload per hospital. Discontinuities of hospital identifiers over time might impair the follow-up of hospital cohorts. These limitations must be taken into account in analyses of German hospital discharge data focusing on the hospital level. PMID- 27938729 TI - [How do general practitioners evaluate collaborative care of elderly depressed patients? Results of a qualitative study]. AB - BACKGROUND: Depression is a very common disease among the elderly. Various studies demonstrated the need to improve the care for elderly depressed patients. Within the GermanIMPACT trial specifically trained care managers were engaged to cooperate with general practitioners (GPs). This study investigates how GPs evaluate this cooperation and their attitude towards collaborative care. METHODS: To explore the perspective of GPs a qualitative study design with semi-structured interviews was chosen. The guideline-based interviews were conducted with GPs from the intervention group, the control group and with GPs who had decided not to participate in the trial. The interviews were audio-taped, fully transcribed and analysed. RESULTS: Eighteen GPs were interviewed. Almost all GPs from the intervention group appreciated the support by care managers. Advantages they mentioned included their own relief by the committed conversation between patient and care manager, the continuous monitoring of the patients as well as the regular feedback via protocols. GPs who refused to take part in the study expressed different attitudes towards collaborative care. CONCLUSION: Due to the general overall positive valuation of care managers as well as their positive attitude towards collaborative care a continuation of the IMPACT program in Germany should be considered. More investigation needs to be done to answer the question how care managers can be integrated in everyday primary care. PMID- 27938730 TI - ? PMID- 27938731 TI - [Consultation skills training as an element of general practice training in Germany - a qualitative survey]. AB - INTRODUCTION: The consultation is at the heart of general practice. It is the central setting through which primary care is delivered. The competency requirements are laid down internationally by competency-based curricula for undergraduate and postgraduate education. So far, there is no competency-based vocational training to develop consultation skills in general practice in Germany. The study describes experiences with consultation skills training as an element of general practice training as reported by trainees and trainers in Germany. METHODS: A qualitative and exploring approach was chosen because there is little experience with the German situation. We conducted structured focus group interviews with trainees and trainers, respectively. We recruited all participants by e-mail via the mail distributor "Junge Allgemeinmedizin Deutschland" (JADE, a trainee and junior GP organization) and the academic teachers of the Friedrich-Alexander University Erlangen-Nurnberg. Altogether, four focus group interviews with three to five participants were conducted, varying in length from 25 to 65minutes. All interviews were recorded digitally and transcribed verbatim. Then a qualitative content analysis was performed. RESULTS: The statements of the ten trainees and five trainers mapped a system of four main categories: (a) association with the term consultation, (b) parts of a consultation, (c) competencies required for professional practice, (d) consultation skills training as an element of vocational training. Overall, all participants regarded the consultation as the most important element in general practice. Important content of consultations is to build a relationship with the patient, gather information, conduct physical examinations and achieve informed consent on further proceedings. All participants agreed that physicians need different sets of competencies: medical expertise, communication skills, examination skills and professionalism. Finally, there was a broad consensus that a competency-based general practice training to support the development of consultation skills is lacking in Germany. The majority acknowledged the need for change. CONCLUSION: So far, the consultation skills development within the general practice training in Germany is regarded as deficient. Both trainees and trainers have stressed the importance of change in vocational training. With the new competency-based curriculum for general practice in Germany and the associated development of supporting tools important prerequisites have been provided. PMID- 27938733 TI - ? PMID- 27938732 TI - [Five-year experience with Train-the-Trainer courses for general practice trainers - a qualitative and quantitative analysis]. AB - BACKGROUND: A Train-The-Trainer course (TTT course) for general practice trainers was developed as part of the program Verbundweiterbildungplus Baden-Wurttemberg. The course included aspects of training such as organizational and legal knowledge as well as didactic skills for trainers in 9.5 teaching units (45minutes each). The present article analyzes the evaluation of the course and considers possible future developments for TTT courses in Germany. METHODS: An evaluation tool was used covering aspects such as information, relevance for daily work, opportunities for participant engagement in the seminars and working environment as well as didactic competencies among teachers. Within five years, 256 trainers participated in a TTT course and received an evaluation sheet. Data were analyzed descriptively. RESULTS: 249 evaluation sheets were included (response rate 97 %). Overall, the participants were (very) satisfied with the course in general, its organization, the exchange with colleagues and the teaching units. The participants used the free text mode to give positive feedback; in particular, teaching units in organizational and legal regulations as well as practical feedback training to strengthen professionalism were evaluated positively. Suggestions for improvements included follow-up courses or a deepening of understanding of course contents. CONCLUSION: The participants gave a very positive overall rating and claimed to have benefited from the course contents. Future projects should address further qualifications of general practice trainers and facilitate the exchange with colleagues on an ongoing basis. PMID- 27938734 TI - [Principles for the evaluation of telemedicine applications: Results of a systematic review and consensus process]. AB - BACKGROUND: The limited number of telemedicine applications being transferred to standard medical care in Germany may to some extent be explained by deficits in the current evaluation practice. Effectiveness and cost effectiveness can only be demonstrated to decision makers and potential users with methodologically sound and fully published evaluations. There is a lack of well-founded and mandatory standards for adequate, comparable evaluations of telemedicine applications. METHODS: As part of the project CCS Telehealth Eastern Saxony (CCS THOS), a systematic review on evaluation concepts for telemedicine applications (search period until September 2014, databases Medline, Embase, HTA-Database, DARE, NHS EED) as well as an additional selective literature search were conducted. Suggestions for evaluation fundamentals were derived from the results. These suggestions were subjected to a formal consensus process (nominal group process) with relevant stakeholder groups (healthcare payers, healthcare providers, health policy representatives, researchers). RESULTS: 19 papers were included in the systematic review. In accordance with the predefined inclusion criteria, each presented an evaluation concept for telemedicine applications that was based upon a systematic review and/or a consensus process. Via a formal consensus process, the suggestions for evaluation principles derived from the review and the selective literature search (23 papers) resulted in ten agreed evaluation principles. Eight of them were unanimously agreed upon, two were arrived at with one abstention each. The principles enclose criteria for the planning, conduct and reporting of telemedicine evaluations. Adherence to them is obligatory for users of the telemedical infrastructure provided by CCS THOS. Furthermore, right from the beginning the intention was very much for these principles to be seized upon by other projects and initiatives. CONCLUSIONS: The agreed evaluation principles for telemedicine applications are the first in Germany to be based both upon evidence and consensus. Due to the methodology of development, they have a strong scientific and health policy legitimation. Therefore, and because of their general applicability, adherence to these principles beyond the context of the telemedicine platform developed within CCS THOS is recommended, namely throughout the German telemedicine scene. PMID- 27938735 TI - Preface. PMID- 27938736 TI - FDA Encourages Reporting of Tobacco Product Adverse Experiences. PMID- 27938737 TI - Endobronchial Ultrasonography: A Sublime Procedure and a Guide to the Proper Valuation of Health Care. PMID- 27938738 TI - The High Road, the Low Road, or Both: Effects of Positive Airway Pressure Route of Administration on Treatment Efficacy for OSA. PMID- 27938739 TI - Nontuberculous Mycobacterial Disease Therapy: Take It to the Limit One More Time. PMID- 27938740 TI - Cost-effectiveness of Fluid Resuscitation of Critically Ill Adults: New Insights From Uncharted Territory. PMID- 27938741 TI - Direct Comparison of Dabigatran, Rivaroxaban, and Apixaban for Effectiveness and Safety in Nonvalvular Atrial Fibrillation. AB - BACKGROUND: The introduction of non-vitamin K antagonist oral anticoagulants (NOACs) has been a major advance for stroke prevention in atrial fibrillation (AF). Patients and clinicians now have a choice between different NOACs, but there is no direct comparative effectiveness evidence to guide decision-making. We aimed to compare the effectiveness and safety of dabigatran, rivaroxaban, and apixaban in clinical practice. METHODS: Using a large US administrative claims database, we created three one-to-one propensity-score-matched cohorts of patients with nonvalvular AF who were users of dabigatran, rivaroxaban, or apixaban between October 1, 2010 and February 28, 2015 (rivaroxaban vs dabigatran, n = 31,574; apixaban vs dabigatran, n = 13,084; and apixaban vs rivaroxaban, n = 13,130). The primary outcomes were stroke and systemic embolism (effectiveness) and major bleeding (safety) that occurred during treatment. Cox proportional hazards models were used to compare outcomes in propensity-score matched cohorts. RESULTS: We found no differences between the three NOACs in the risk of stroke or systemic embolism (hazard ratio [HR], 1.00; 95% CI, 0.75-1.32 for rivaroxaban vs dabigatran; HR, 0.82; 95% CI, 0.51-1.31 for apixaban vs dabigatran; and HR, 1.05; 95% CI, 0.64-1.72 for apixaban vs rivaroxaban). Apixaban was associated with a lower risk of major bleeding (HR, 0.50; 95% CI, 0.36-0.70; P < .001 vs dabigatran and HR, 0.39; 95% CI, 0.28-0.54; P < .001 vs rivaroxaban). Rivaroxaban was associated with an increased risk of major bleeding (HR, 1.30; 95% CI, 1.10-1.53; P < .01) and intracranial bleeding (HR, 1.79; 95% CI, 1.12-2.86; P < .05) compared with dabigatran. CONCLUSIONS: Dabigatran, rivaroxaban, and apixaban appear to have similar effectiveness, although apixaban may be associated with a lower bleeding risk and rivaroxaban may be associated with an elevated bleeding risk. PMID- 27938746 TI - Response. PMID- 27938747 TI - Potential Effects of Hypoxia Preconditioning in Obesity Hypoventilation Syndrome? PMID- 27938748 TI - Does Nocturnal Hypoventilation Have a Protective Effect on Cardiovascular Comorbidity in Obesity Hypoventilation Syndrome? PMID- 27938749 TI - Response. PMID- 27938750 TI - Introducing High-Sensitivity Cardiac Troponin T as a Biomarker of OSA-Related Cardiovascular Morbidity in Obesity Hypoventilation Syndrome. PMID- 27938751 TI - Response. PMID- 27938752 TI - Cardiovascular Protection From Severe OSA: The Pickwickian Paradox: Is Bigger Really Better? PMID- 27938753 TI - Response. PMID- 27938754 TI - Cancer and OSA: Beyond Hypoxia. PMID- 27938755 TI - Response. PMID- 27938756 TI - Clinimetric Properties of the Lung Clearance Index in Adults and Children With Cystic Fibrosis. PMID- 27938757 TI - Response. PMID- 27938759 TI - A Low-Cost Training Phantom for Lung Ultrasonography. PMID- 27938758 TI - Diversity in the Pulmonary Embolism Response Team Model: An Organizational Survey of the National PERT Consortium Members. PMID- 27938761 TI - Reducing Procedural Hemorrhage Risk. PMID- 27938760 TI - Pleural Infections in Intensive Care. PMID- 27938762 TI - Response. PMID- 27938763 TI - Occupational Causation of Sarcoidosis. PMID- 27938764 TI - Response. PMID- 27938765 TI - Pleurodesis. PMID- 27938766 TI - Response. PMID- 27938767 TI - Deconstructing the Code of Medical Ethics and Practice in End-of-Life Care Disputes: Infringing on Well-Grounded Cultural Values in Pluralistic Societies. PMID- 27938768 TI - Response. PMID- 27938769 TI - Successful Late Removal of Endobronchial Coils. AB - Although endobronchial coils for the treatment of severe emphysema are associated with an acceptable safety profile, adverse events such as pneumothorax and thoracic pain may occur. The coils are indicated as a permanent implant and are deemed very difficult to remove. We describe the first successful removal of two coils 10 months after placement in a patient who experienced persistent thoracic pain. This case report highlights that very distal (subpleural) coil placement may induce pneumothorax and subsequent thoracic pain and that nonsurgical removal of coils up to 10 months after implantation is feasible. PMID- 27938770 TI - Successful Healing of Tracheal Radionecrosis: Role of Hyperbaric Oxygen Therapy. AB - Hyperbaric oxygen therapy, the administration of 100% oxygen at pressures > 1 atm, is believed to promote wound healing by increasing angiogenesis and collagen synthesis. To our knowledge, this treatment modality has never been described in patients with tracheal radionecrosis. Here, we report the case of a 55-year-old man diagnosed with stage IIIB lung adenocarcinoma who was treated with chemotherapy and concomitant external intensity-modulated radiotherapy involving the left lung and mediastinum. Nine months later, he presented with neck pain, cough with mucopurulent sputum, and fever. A PET-CT scan revealed a fissure in the posterior wall of the left upper trachea. Flexible bronchoscopy showed a tracheal ulceration with a small left posterior wall fissure that extended into the mediastinum. To our knowledge, this is the first report in the literature that suggests that treatment with hyperbaric oxygen therapy, local debridement, and antibiotics is a feasible and successful management option for patients with complicated tracheal radionecrosis. PMID- 27938771 TI - A 78-Year-Old Man With Diffuse Lymphadenopathy, a Pleural Effusion, and Shortness of Breath. PMID- 27938773 TI - A 40-Year-Old Woman With Back Pain. AB - A 40-year-old woman consulted our ED for a 7-month history of left dorsal back pain and dyspnea. The pain was initially dull and mechanical. Her general practitioner started nonsteroidal antiinflammatory drugs and physiotherapy, which provided partial relief. One week before consulting, the intensity of the pain increased, and she started to feel shortness of breath when performing her daily activities. She had lost 5 kg during the previous month. The patient was a healthy woman who lived in an urban area of Barcelona, Spain. She did not smoke or take drugs of abuse, and she worked as a butcher. During the initial evaluation, her blood pressure was 131/76 mm Hg, heart rate was 120 beats/min, temperature was 36.2 degrees C, and ambient air pulse oximetry was 98%. PMID- 27938772 TI - A 67-Year-Old Man With Severe Posttraumatic ARDS in Extracorporeal Membrane Oxygenation Presents Sudden Desaturation. PMID- 27938774 TI - A 48-Year-Old Man With Leukopenia, Jaundice, and Skin Rash After Lung Transplantation. AB - A 48-year-old African-American male subject presented with progressive fatigue, jaundice, and new-onset leukopenia 12 weeks after undergoing bilateral lung transplantation for advanced pulmonary sarcoidosis. His transplant surgery and immediate posttransplantation course were uneventful. Induction immunosuppression included methylprednisolone 500 mg intraoperatively and basiliximab (anti-IL-2 monoclonal antibody) on days 0 and 4 after transplantation. His maintenance immunosuppression posttransplantation was prednisone 20 mg daily, tacrolimus with target tacrolimus levels 10 to 15 ng/mL, and mycophenolate mofetil 750 mg twice daily. Both the donor and recipient were seropositive for cytomegalovirus and Epstein-Barr virus. Infectious disease prophylaxis consisted of valganciclovir, trimethoprim/sulfamethoxazole, and voriconazole. Results of the surveillance bronchoscopy conducted after the lung transplant were negative for acute cellular rejection or infection at 4 and 12 weeks' posttransplantation. Findings on spirometry had continuously improved since transplantation. PMID- 27938775 TI - A Woman in Her 60s With Fever and Altered Mental Status in a Psychiatric Hospital. AB - A woman in her 60s with a history of hepatitis C with cirrhosis and major depressive disorder with psychotic features was admitted to the inpatient psychiatric unit for suicidal ideation. She was initially treated with a combination of sertraline and paliperidone. The paliperidone was subsequently changed to risperidone and ultimately to olanzapine. She developed worsening mental status and was then treated for catatonia with benzodiazepines. Over 2 days, her mental status continued to worsen and she developed fever and tachycardia. She was transferred to the ICU and endotracheally intubated for inability to protect her airway. She was started on lactulose via orogastric tube but showed no improvement in her mental status after 2 days despite having two or three bowel movements per day. PMID- 27938776 TI - A Man in His 20s With Diffuse Lung Opacities and Acute Respiratory Failure After Hookah Smoking. AB - A man in his 20s with no medical history presented with 2 days of progressively worsening shortness of breath accompanied by subjective fevers, chills, body aches, decreased appetite, night sweats, and cough producing nonbloody sputum. He denied childhood lung diseases, allergies, or a family history of lung disease. He did not smoke cigarettes but had smoked hookah in Saudi Arabia before moving to the United States 1 month before presentation and had restarted 2 days before the start of symptoms. He denied travel outside of the northeastern United States. He did not take medications, use illicit drugs, or engage in high-risk behavior. PMID- 27938778 TI - Foreword. PMID- 27938777 TI - Contingent Vs. Non-Contingent Rewards: Time-Based Intervention Response Patterns Among Stimulant-Using Men Who Have Sex With Men. AB - Stimulant use rates are higher among men who have sex with men (MSM) than the general population. Contingency management (CM) may be an effective intervention for reducing stimulant use in this population. To specify both the mechanism and temporal effects of contingent reward on behavior change, logistic growth trajectory modeling (LGTM) was used to contrast a non-contingent matched rewards condition (i.e., non-contingent yoked controls; NCYC) to a voucher-based CM intervention (maximum=$430) to reduce stimulant use among MSM. Stimulant-using MSM were randomized to either a CM intervention (n=70) or a NCYC condition (n=70). Results from a LGTM (analytical sample n=119; nCM=61; nNCYC=58) indicated four distinct intervention response patterns: responders (i.e., predicted >90% stimulant metabolite-free urinalyses; 64.7% of sample); worsening intervention response (14.3%); non-responders (12.6%); and, single-positive (8.4%); all estimated trajectory coefficients were significant at p<0.03 (2-tailed). Participants receiving CM were significantly overrepresented in the responder (64%) and single-positive (80%) categories (chi2(3)=29.04; p<0.001); all non responders and 76.5% of the worsening intervention response category were in the NCYC condition. Results demonstrate the utility of trajectory modeling and further support the contingent application of reward as the operative mechanism associated with patterns of stimulant abstinence with CM applied to a sample of stimulant-using MSM outside the context of formal drug treatment. PMID- 27938779 TI - Surveillance for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) appears mainly in patients with underlying liver disease and it is recognized as one of the most important causes of death in this population. Early detection by surveillance has been suggested as an effective tool for reducing cancer-specific mortality and the most accepted strategy is semiannual abdominal ultrasound in those patients at risk of HCC development. The benefit of HCC surveillance is proven by a randomized-controlled study, several prospective or retrospective analyses, and multiple modeling studies and according to the current scientific evidence, surveillance of HCC should be recommended and widely implemented. Major efforts should be done for improving the diagnostic accuracy of the screening tools and for better identifying those patients at risk of HCC development in whom a surveillance program would be cost effective. PMID- 27938780 TI - Cancer surveillance in gastroenterology practice. PMID- 27938781 TI - Organization of surveillance in GI practice. AB - BACKGROUND: Several reports documented an inefficient utilisation of available resources, as well as a suboptimal compliance with surveillance recommendations. Although, evidence suggests that organisational issues can influence the quality of care delivered, surveillance protocols are usually based on non-organized approaches. METHODS: We conducted a literature search (publication date: 01/2000 06/2016) on PubMed and Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Cochrane Central Register of Controlled Trials for guidelines, or consensus statements, for surveys of practice, reporting information about patients, or providers attitudes and behaviours, for intervention studies to enhance compliance with guidelines. Related articles were also scrutinised. Based on the clinical relevance and burden on endoscopy services this review was focused on surveillance for Barrett's oesophagus, IBD and post-polypectomy surveillance of colonic adenomas. RESULTS: Existing guidelines are generally recognising structure and process requirements influencing delivery of surveillance interventions, while less attention had been devoted to transitions and interfaces in the care process. Available evidence from practice surveys is suggesting the need to design organizational strategies aimed to enable patients to attend and providers to deliver timely and appropriate care. Well designed studies assessing the effectiveness of specific interventions in this setting are however lacking. Indirect evidence from screening settings would suggest that the implementation of automated standardized recall systems, utilisation of clinical registries, removing financial barriers, could improve appropriateness of use and compliance with recommendations. CONCLUSIONS: Lack of sound evidence regarding utility and methodology of surveillance can contribute to explain the observed variability in providers and patients attitudes and in compliance with the recommended surveillance. PMID- 27938782 TI - Methodological considerations for surveillance in GI practice. AB - Surveillance is recommended for various GI cancers, and substantial resources are invested. However, little is known about the effect of surveillance, neither for good, nor for bad. Most evidence stems from observational studies, but observational studies of surveillance can be subject to various biases that may severely influence the results. In this chapter we discuss challenges related to various research questions, study designs, choice of endpoints, and how to deal with different forms of bias. We hope this chapter will be helpful for researchers when performing high-quality studies of surveillance, and to enable physicians and policy-makers to understand the possibilities and limitations of current evidence. PMID- 27938783 TI - Cost effectiveness of surveillance for GI cancers. AB - Gastrointestinal (GI) diseases are among the leading causes of death in the world. To reduce the burden of GI diseases, surveillance is recommended for some diseases, including for patients with inflammatory bowel diseases, Barrett's oesophagus, precancerous gastric lesions, colorectal adenoma, and pancreatic neoplasms. This review aims to provide an overview of the evidence on cost effectiveness of surveillance of individuals with GI conditions predisposing them to cancer, specifically focussing on the aforementioned conditions. We searched the literature and reviewed 21 studies. Despite heterogeneity of studies in terms of settings, study populations, surveillance strategies and outcomes, most reviewed studies suggested at least some surveillance of patients with these GI conditions to be cost-effective. For some high-risk conditions frequent surveillance with 3-month intervals was warranted, while for other conditions, surveillance may only be cost-effective every 10 years. Further studies based on more robust effectiveness evidence are needed to inform and optimise surveillance programmes for GI cancers. PMID- 27938784 TI - Surveillance of patients at high-risk of squamous cell esophageal cancer. AB - Currently curative treatment for esophageal squamous cell cancer (ESCC) is possible only in patients with early-stage, usually asymptomatic disease. In Western countries, where the incidence of ESCC is relatively low, a screening of asymptomatic, average-risk population is untenable. In order to detect early stage ESCC or its precursor lesions it is important to identify high-risk patients and consider endoscopic surveillance in these groups. These high-risk groups include patients after curative treatment for head and neck cancer, previous endoscopic resection of ESCC, caustic injury, and patients with tylosis or achalasia. This paper discuss the evidence and proposed method of endoscopy surveillance of these high-risk patients. PMID- 27938785 TI - Review: Surveillance of patients with Barrett oesophagus. AB - There has been a rapid increase in the incidence of oesophageal adenocarcinoma in most Western countries over the past thirty years. Barrett's oesophagus (BE) is a common premalignant lesion of oesophageal adenocarcinoma, although the risk of developing cancer in BE remains low. Therefore, screening is not recommended in the general population. Surveillance of BE is recommended to detect high grade dysplasia or carcinoma in an early stage, although there is no clear evidence that surveillance leads to a reduced mortality. This review discusses the several screening and surveillance techniques, including chromoendoscopy, narrow band imaging, autofluorescence imaging and confocal laser endomicroscopy, pointing out the areas that are well established as well as the new techniques that require more research. PMID- 27938786 TI - Surveillance of patients with gastric precancerous conditions. AB - Intestinal-type gastric adenocarcinoma arises from a multistep process starting with Helicobacter pylori infection followed by gastric atrophy, gastric intestinal metaplasia and dysplasia. Indeed, patients with gastric precancerous conditions or lesions (GPC) are at increased risk to develop gastric cancer even in regions with low incidence. Thus, the identification and surveillance of a high risk subgroup could lead to the diagnosis of cancer at early stage and improve survival. However, both endoscopic and histological accuracy and interobserver agreement in the diagnosis of GPC are still far from optimal. Also, there are conceptual differences between the West and the East in the diagnosis and surveillance of patients. In the former, multiple gastric biopsies are still recommended but Eastern gastroenterologists select patients to surveillance according to the results of endoscopy or serology. In this literature review we describe the cascade of GPC and we highlight the differences between eastern and western clinical practice. PMID- 27938787 TI - Surveillance of patients with hereditary gastrointestinal cancer syndromes. AB - Gastrointestinal cancers are among the most frequent tumors. Although most cases are sporadic, up to 5-6% develops in the context of gastrointestinal hereditary syndromes. These entities have specific characteristics and often a germline mutation identified, thus allowing performing genetic counseling. This review summarizes the most common gastrointestinal hereditary syndromes, focusing on the surveillance recommendations. PMID- 27938788 TI - Surveillance after colorectal polyp removal. AB - Surveillance colonoscopy is aimed to reduce CRC incidence and mortality by removing adenomas and detecting CRC in early stage. However, colonoscopy is an invasive and expensive procedure and surveillance colonoscopy should be targeted at those who are most likely to benefit at the minimum frequency required to protect for cancer. Surveillance recommendations are based on guidelines, but the recommendations in those guidelines are based on moderate to low quality evidence and adherence to these guidelines is poor. As surveillance colonoscopy is one of the main indications for colonoscopy and surveillance colonoscopies are filling colonoscopy lists, the current surveillance practice results in spending lots of money and capacity in a suboptimal way. Randomized controlled trials to compare surveillance intervals are not available. However, current evidence based on several case-control and cohort studies suggests there is no need for surveillance in patients with low-risk adenomas, i.e. 1-2 adenomas smaller than 10 mm. Patients with 3 or more adenomas or any adenoma larger than 10 mm seem to be the ones at real risk for metachronous adenomas or cancer. In those patients, surveillance colonoscopy is indicated at 3 years after baseline until ongoing studies will confirm the safety of enlarging this interval. Randomized controlled trials and experimental research are important in order to provide the necessary scientific evidence for the optimization of follow-up strategies for patients with adenomas and serrated polyps. PMID- 27938789 TI - Surveillance of patients with inflammatory bowel disease. AB - Patients with inflammatory bowel disease involving the colon are at increased risk for developing colorectal cancer. Colonoscopy surveillance is important to identify and treat IBD associated dysplasia. The SCENIC consensus provides evidence-based recommendations for optimal surveillance and management of dysplasia in IBD. Chromoendoscopy, with the surface application of dyes to enhance mucosal visualization, is the superior endoscopic surveillance strategy to detect dysplasia. Most dysplasia is visible, and can be endoscopically resected. Future studies should determine the effect of new surveillance strategies on the incidence of CRC and mortality in patients with IBD. PMID- 27938790 TI - Surveillance after endoscopic and surgical resection of colorectal cancer. AB - With the increase in colorectal cancer burden, surveillance following endoscopic and surgical resection is an essential issue. The aim of surveillance programs is improvement of patient survival by early detection of residual tumor tissue or local recurrence, metachronous colorectal tumors, and metastases. Appropriate surveillance should be determined according to this risk of factors. In current guidelines, only surveillance colonoscopy is recommended after endoscopic resection of polyps with high-grade dysplasia, whereas intensive, multimodality surveillance using colonoscopy, radiological imaging and tumor marker measurements is recommended following surgical resection of invasive colorectal cancer. Detailed recommendations, including the timing of surveillance, are described based on high-quality evidence. However, there are still many unresolved issues for which more high-quality evidence is required. PMID- 27938792 TI - Surveillance in cholangiocellular carcinoma. AB - Cholangiocellular carcinoma is the most frequent malignant neoplasm originating from the epithelium of intra- or extrahepatic bile ducts. In the past decades, the incidence of cholangiocarcinoma has been shown to increase while overall mortality has remained high with an approximate 5-year overall survival below 20%. Surgery remains the only curative option while systemic treatment is limited to palliative chemotherapy. Therefore, surveillance strategies for patients at risk of developing cholangiocarcinoma are urgently needed, particularly in patients with primary sclerosing cholangitis and patients infected with liver flukes. Here we summarize the currently available data on surveillance of risk populations and methods for the detection of cholangiocarcinoma. PMID- 27938793 TI - Taking Action on Maternal Mortality. PMID- 27938794 TI - Commentary on a Cochrane Review of Routine Ultrasound in Late Pregnancy. AB - Diagnostic ultrasound can be used in late pregnancy to assess a fetus's condition, especially when there are complications. However, it remains controversial to carry out scans in late pregnancy on all pregnant women. Reasons for performing these scans include detecting clinical conditions that place a fetus or woman at high risk that would not necessarily have been detected by other means (such as clinical examination) and for which subsequent management would improve perinatal outcomes. PMID- 27938791 TI - Surveillance for neoplasia in the pancreas. AB - Despite its low incidence in the general population, pancreatic cancer is one of the leading causes of cancer-related mortality. Survival greatly depends on operability, but most patients present with unresectable disease. Therefore, there is great interest in the early detection of pancreatic cancer and its precursor lesions by surveillance. Worldwide, several programs have been initiated for individuals at high risk for pancreatic cancer. Their first results suggest that surveillance in high-risk individuals is feasible, but their effectiveness in decreasing mortality remains to be proven. This review will discuss which individuals are eligible for surveillance, which lesions are aimed to be detected, and which surveillance modalities are being used in current clinical practice. Furthermore, it addresses the management of abnormalities found during surveillance and topics for future research. PMID- 27938795 TI - A Practice Improvement Project to Reduce Cesarean Surgical Site Infection Rates. AB - We implemented an evidence-based practice improvement project at a health care facility in the Midwestern United States to address the increasing rate of cesarean surgical site infections. Women who experienced cesarean birth were cared for using a standardized evidence-based protocol including preoperative and postoperative care and education. In addition, a team-created educational video was used by both women and their families during the postoperative period and at home after discharge. This new protocol resulted in a decrease in the rate of cesarean surgical site infections from 1.35% in 2013 to 0.7% in 2014 and 0.36% in 2015. Our interdisciplinary approach to integrate best-practice strategies resulted in decreased infection rates and improved patient satisfaction scores. PMID- 27938796 TI - Improving Postpartum Education About Warning Signs Of Maternal Morbidity and Mortality. AB - Maternal morbidity and mortality rates remain high in the United States compared with other developed countries. Of particular concern is the rise in postpartum deaths, because many of the risk factors for complications associated with maternal morbidity and mortality may not be clearly identified before a woman's discharge after birth. Although nurses provide some form of postpartum discharge education to all women who give birth, the information women receive on common potential complications is not always consistent or evidence based. By improving postpartum education, nurses may be better poised to teach women how to recognize and respond to warning signs. This article describes a project intended to increase women's access to predischarge education about the risks for postbirth complications. PMID- 27938797 TI - Effect of Nurse-Led Review Plus Simulation on Obstetric/Perinatal Nurses' Self Assessed Knowledge and Confidence. AB - Simulation may help both novice and experienced clinicians maintain competence in managing high-risk, low-frequency obstetric and perinatal complications and emergencies. Therefore, we designed a pre-/posttest study to determine whether a day of nurse-led lecture plus low-fidelity simulation would increase registered nurses' self-assessed knowledge and confidence in managing five high-risk obstetric/perinatal situations. The Nursing Management of OB/Perinatal Complications & Emergencies (NursOB) scale was distributed to 67 labor/birth and postpartum nurses before and after a simulation training day. Preliminary findings supported validity and reliability of the NursOB scale, but nurses' knowledge and confidence did not improve after the simulation (p < .05). Anecdotally, nurses' interest in competence reviews was reinvigorated, and we gained practical knowledge in simulation delivery. Future simulations could enhance outcome measures, improve drills, and establish criterion-related validity of the NursOB scale. More research is warranted. PMID- 27938799 TI - Partnering With Women for Postpartum Pain Management. AB - Our obstetric nursing unit was faced with low patient satisfaction scores in the area of pain management. We wondered if enabling women to control their own over the-counter medication administration would help with the scores. Working together with interdisciplinary teams, members of this nursing unit implemented practice changes and, in the process, realized improved patient satisfaction scores. PMID- 27938798 TI - A Systematic Literature Review of the Childbearing Cycle as Experienced by Survivors of Sexual Abuse. AB - For women who have experienced sexual abuse, the physical changes associated with pregnancy and the lack of control during birth can be catalysts for trauma from past abuse to resurface. This systematic review offers women's health care providers a thorough evaluation of the state of the science on survivors' childbearing experiences. The literature shows that lack of control, dissociation, and flashbacks are common themes. Re-experiencing of the trauma occurred during various stages of childbirth and was traumatizing to women. Nurses and other clinicians providing care to childbearing women can provide control to survivors during health care encounters and can form therapeutic relationships to help them have more positive childbirth experiences. PMID- 27938800 TI - Barriers to and Facilitators of Perinatal Depression Screening. AB - Depression is a significant health issue for women of reproductive age. A number of professional organizations have issued guidance regarding perinatal depression screening. However, some health care providers are reluctant to screen women. This column takes a second look at two recent research studies in which investigators examined the barriers to and facilitators of perinatal depression screening. PMID- 27938802 TI - Immediate and Sustained Skin-to-Skin Contact for the Healthy Term Newborn After Birth: AWHONN Practice Brief Number 5. PMID- 27938801 TI - Skin Care for Women. AB - Women are inundated with advertisements for products promising younger-looking, healthier skin. The truth is that many of these products can be expensive and produce results that do not live up to the claims. Health care providers can educate women about proven best practices and how to evaluate products' claims of benefits. The best advice is that a well-balanced diet, adequate hydration, use of a topical moisturizer, protection from the sun, and avoiding smoking and tobacco are the most effective measures to not only healthy skin but a healthful life. PMID- 27938803 TI - Dear New Mom. PMID- 27938804 TI - Editorial of Special Issue: Bio-electronics and prosthetics for neurological diseases. PMID- 27938805 TI - Acrally distributed dermatoses. PMID- 27938806 TI - Pressure and disenchantment in physicians-Part II: Lessons for physicians from the Tao Te Ching. AB - Physicians are faced with many stressors today that place them at risk of disenchantment, depression, and "burnout." Although this is costly to the individual physician, it is equally costly to society because physician stress can lead to exercise of poor judgment and medical errors. It also threatens to exacerbate physician shortages, as more physicians opt to retire or, in some cases, change careers altogether. In this essay, suggestions are made as to how to deal with these stressors that, if used, can ameliorate them at least to some degree. A Chinese spiritual text, the Tao Te Ching, will be explored in depth as yet another tool that physicians can use as a guide for living with less stress. (c) 2016 Elsevier Inc. All rights reserved. PMID- 27938807 TI - Categorization of and comments on isomorphic and isotopic skin reactions. AB - Locus minoris resistentiae (lmr) can be defined as a site of the body that offers lesser resistance than the rest of the body to the onset of disease. The well known Kobner phenomenon is itself a clear example of lmr in dermatology. The new term locus maioris resistentiae (LMR), a site of the body that offers greater resistance than the rest of the body to the onset of disease, defines the opposite condition. Renbok phenomenon (reverse Kobner's isomorphic response) typically represents an example of LMR. PMID- 27938809 TI - Acral manifestations of fungal infections. AB - Fungal infections, which are named according to the body site involved, can affect any skin area, the fingernails, or the toenails. Numerous fungal agents are responsible for both superficial and deep fungal diseases. Dermatophytes and Candida spp are the most common causative organisms on the surface of the hands, feet, and nails of patients with superficial fungal diseases; however, although deep fungal infections of the skin are less common compared with superficial fungal diseases, their incidence is increasing worldwide due to cross-border travel. Most superficial fungal diseases are diagnosed clinically, but sometimes direct microscopic examination with potassium hydroxide and fungal culture may be necessary for diagnosis, especially in patients suspected of having tinea incognito. In cases of superficial fungal infections except for onychomycosis and tinea incognito, topical treatments are usually sufficient and effective, but systemic treatments may be required in recalcitrant cases. Deep fungal diseases may resemble each other clinically; therefore, the organism must be identified with laboratory methods and should be treated for a long period. We review the most important clinical, diagnostic, and therapeutic aspects of fungal diseases. This paper covers fungal problems encountered both in hospitals and in general practice. PMID- 27938808 TI - Palmoplantar psoriasis. AB - Palmoplantar psoriasis refers to a localized psoriasis variant. The disease can be associated with many clinical forms, including predominantly pustular lesions to thick scaly, hyperkeratotic plaques, or an overlapping of both of them. Palmoplantar psoriasis accounts for 3-4% of all psoriasis cases in most studies. Although it is localized only on the palms and the soles, the fissures, the hardening of the tissue, and hyperkeratosis affect daily routine activities. Taking the body surface area as a measure of severity can sometimes be misleading. In clinical practice, the level of functional impairment should be taken into account rather than relying on traditional instruments to evaluate the severity. Palmoplantar psoriasis is usually managed with topical therapy as a first step. Systemic therapy is needed when the topicals fail or when the disease becomes more severe. Sometimes, biologic agents are required for adequate maintenance of clinical response. PMID- 27938810 TI - Occupational acral dermatitis and where the twain shall meet. AB - This contribution, which is somewhat of a departure from the usual format, will focus on dermatologic conditions that are consequences of the patients' choices of employment, hobby, or even other forms of recreation. Most of the cutaneous changes involve the hands and feet, and each is labeled according to the anatomic location. PMID- 27938811 TI - Acral manifestations of viral infections. AB - Viruses are considered intracellular obligates with a nucleic acid RNA or DNA. They have the ability to encode proteins involved in viral replication and production of the protective coat within the host cells but require host cell ribosomes and mitochondria for translation. The members of the families Herpesviridae, Poxviridae, Papovaviridae, and Picornaviridae are the most commonly known agents for cutaneous viral diseases, but other virus families, such as Adenoviridae, Togaviridae, Parvoviridae, Paramyxoviridae, Flaviviridae, and Hepadnaviridae, can also infect the skin. Herpetic whitlow should be considered under the title of special viral infections of the acral region, where surgical incision is not recommended; along with verruca plantaris with its resistance to treatment and the search for a new group of treatments, including human papillomavirus vaccines; HIV with maculopapular eruptions and palmoplantar desquamation; orf and milker's nodule with its nodular lesions; papular-purpuric gloves and socks syndrome with its typical clinical presentation; necrolytic acral erythema with its relationship with zinc; and hand, foot, and mouth disease with its characteristics of causing infection with its strains, with high risk for complication. PMID- 27938812 TI - Acral manifestations of paraneoplastic and collagen vascular diseases. AB - The skin often signals a number of systemic disease, making skin findings of paramount significance. Paraneoplastic diseases and collagen vascular diseases are vitally important illnesses. Paraneoplastic diseases and collagen vascular diseases may also occur with many different acral skin findings. Paraneoplastic skin diseases, associated with some cancers, are by definition nonmalignant skin disorders. These diseases can occur before, simultaneously, or after the diagnosis of cancer. Acral paraneoplastic diseases include acanthosis nigricans maligna, acquired pachydermatoglyphia, acrokeratosis paraneoplastica, palmoplantar keratoderma, and paraneoplastic nail disorders. Collagen vascular diseases include the acral skin findings of lupus erythematosus, scleroderma, dermatomyositis, and rheumatoid arthritis. Any acral skin finding may be encountered as the first finding of an undiagnosed malignancy or collagen vascular diseases. The role of the dermatologist is significant for often being the first physician to suspect a malignancy or collagen vascular disease. PMID- 27938813 TI - Acral manifestations of systemic diseases: Drug-induced and infectious diseases. AB - Drug reactions and systemic diseases often involve the skin. In particular, most drug-induced reactions and many infectious diseases present with dermatologic manifestations localized acrally, that is on distal portions of limbs (hand, foot) and head (ears, nose). A detailed review of all acral dermatologic signs of drug reactions and systemic diseases is beyond the scope of this paper, although some of these disorders will be discussed specifically here. PMID- 27938814 TI - Acrodermatitis caused by nutritional deficiency and metabolic disorders. AB - Both the metabolism and dietary intake of vitamins and minerals are essential to homeostatic function in the body. Dietary excess or deficiency, as well as genetic and acquired disorders in metabolism, can present dermatologically and systemically. More specifically, disorders in metabolism of zinc, biotin, essential fatty acids, and vitamin B, can appear with acrally distributed dermatoses. Recognition of the dermatologic manifestations associated with nutritional disorders is important for early diagnosis and management. PMID- 27938815 TI - Acrally distributed dermatoses: Vascular dermatoses (purpura and vasculitis). AB - Purpuric lesions appear in acral distribution in a variety of conditions and often provide clues to the clinical diagnosis. Purpuric means "hemorrhagic"-that is, the lesions do not blanch from pressure. This review focuses on dermatoses that produce hemorrhagic lesions in acral distribution from the large groups of the vasculitic diseases and their mimics. Cutaneous small vessel vasculitis is confined to the skin, involves mainly postcapillary venules, and has the hallmark manifestation of palpable purpura. Henoch-Schonlein purpura is an immune complex mediated systemic vasculitis of the small vessels with manifestations from the skin, joints, kidneys, and gastrointestinal system. Only cases where the immune complexes contain immunoglobulin A type are classified as Henoch-Schonlein purpura. Cryoglobulinemic vasculitis is induced by the deposition of cold precipitated immune complexes in the small vessels. Urticarial vasculitis comprises a spectrum of conditions with the characteristic course of chronic urticaria, with wheals that persist longer than 24 hours, leave hyperpigmentation, and have leukocytoclastic vasculitis on histologic examination. Polyarteritis nodosa is a rare multisystem, segmental necrotizing vasculitis of mainly the medium-sized vessels. Pigmented purpuric dermatoses are chronic benign dermatoses characterized by petechiae, purpura, and increased skin pigmentation. The hallmark of pigmented purpuric dermatoses is their orange brown, speckled, cayenne pepper-like discoloration. PMID- 27938816 TI - Acral manifestations of Sweet syndrome (neutrophilic dermatosis of the hands). AB - Neutrophilic dermatosis of the hand (NDH) is a rare localized variant of the syndrome, originally described two decades ago by Strutton et al. The lesions of NDH and Sweet syndrome are similar, as indicated in the first report of NDH. Both diagnoses are characterized by an acute onset of fever, leukocytosis, and tender, erythematous infiltrated plaques. There are also bullae and ulceration in NDH, in contrast to Sweet syndrome, in which bullae are quite uncommon, especially at the early stages. Similar to Sweet syndrome, the majority of NDH patients are women (69%). Patients with NDH present with fever, peripheral neutrophilia, leukocytosis, and/or an elevated erythrocyte sedimentation rate or C-reactive protein level, but at a significantly lower rate than those in Sweet syndrome (33%). Similar to Sweet syndrome, NDH has been associated with the following conditions: Malignancies (particularly hematological [21%], most common of which is acute myelogenous leukemia, but many other malignancies as well), inflammatory bowel disease (19%), medication and vaccination-related eruptions, bacterial and viral infections, rheumatologic diseases, and others. The clues to the diagnosis of NDH are the same as for Sweet syndrome. Awareness of this diagnosis is important not only to avoid unnecessary medical and surgical therapy and to expediently initiate the administration of steroids for this highly responsive dermatosis, but also to conduct an appropriate workup to exclude associated diseases, especially malignancies. PMID- 27938817 TI - Acral manifestations of soft tissue tumors. AB - This group of biologically diverse entities is united by topographic localization to the hands and feet. Categorizing tumors by body site narrows the differential into a short list of possibilities that can facilitate accurate and rapid diagnosis. The goal of this review is to provide a practical approach to soft tissue tumors of acral locations for clinicians, pathologists, and researchers alike. What ensues in the following text is that tight coupling of the clinical picture and histopathologic findings should produce the correct diagnosis, or at least an abbreviated differential. The salient clinicopathologic, immunohistochemical, and molecular features are presented alongside current treatment recommendations for each entity. PMID- 27938818 TI - Acral manifestations of contact dermatitis. AB - Contact dermatitis is a broad term that encompasses both nonimmunologic irritant contact dermatitis (ICD) and immunologically mediated allergic contact dermatitis (ACD). Both ICD and ACD can negatively affect a patient's quality of life and are a source of exorbitant medical and societal costs. Avoidance of inciting irritants and/or allergens and liberal use of emollients or humectants are the cornerstone of therapy. When an allergic cause is suspected, patch testing is highly encouraged. In this contribution, we highlight both the commonalities and differences of acral contact dermatitis as it relates to specific regions of the body. In addition, a review of the predisposing conditions, risk factors, and treatment options in the literature is presented to help with the care of these challenging patients. PMID- 27938819 TI - The Funding for the NCD: The Optimistic View. PMID- 27938820 TI - A Chronology of Global Assistance Funding for NCD. AB - Funding from the global community for noncommunicable disease (NCD) prevention and control in developing countries is miniscule-dwarfed by donor support for communicable diseases, maternal and child health, and other traditional health concerns in low-income countries. Yet, NCD now constitute the bulk of illness and deaths in low-income countries with, to date, only a small uptick in donor funding evident as a response. This paper describes recent magnitude and trends in the development of assistance for NCD; identifies the main sources among the 3 groupings of multilateral, bilateral, and private philanthropic funders; and discusses issues in tracking NCD donor funding, and challenges to mobilizing donor funding for NCD. Finally, it concludes with a more (slightly) optimistic outlook. PMID- 27938821 TI - Cardiovascular Diseases on the Global Agenda: The United Nations High Level Meeting, Sustainable Development Goals, and the Way Forward. AB - In 2011, the United Nations (UN) organized the first ever meeting for heads of state to discuss the problem of noncommunicable diseases (NCD), including cardiovascular disease (CVD), cancer, chronic respiratory disease, and diabetes mellitus. Recognizing that these had emerged as leading causes of morbidity and mortality in the world, including in many low- and middle-income countries, advocates from government and civil society had called for increased attention and a UN response. Earlier, NCD including CVD were absent from the global health agenda in part because of their omission from the Millennium Development Goals. The UN meeting and the global advocacy response offered a game-changing opportunity to redress this omission. The World Heart Federation (WHF) played an instrumental role in the UN meeting and follow up, including inclusion of CVD in the Sustainable Development Goals. The next phase of the global CVD movement is expected through national action, including CVD roadmaps and partnering with the World Health Organization. The WHF is heavily committed to these goals and the other nongovernmental organizations invested in the mission must help take this historical mandate forward. Instrumental to this will be the engagement of people affected by or at risk of developing CVD, to draw more attention and resources to NCD and to ensure that successes to date in global policy translate into action at the national level. PMID- 27938822 TI - And Why So Great a "No?": The Donor and Academic Communities' Failure to Confront Global Chronic Disease. AB - Chronic diseases are the dominant issues for global public health in terms of mortality, morbidity, and cost, and they have been identified as such for >40 years. Despite their predominance, however, these diseases-cardiovascular disease (CVD), diabetes, cancer, pulmonary disease, mental health, and dementia-attract little attention in the public health curriculum and even less from the funding community. We explore the rationales that have perpetuated this inability or unwillingness to match need with effort. We examine 3 concepts that impede changing this relationship: 1) the traditional contextual view of public health that emerged, to be sure with great success, in the post-World War II era; 2) the failure of public health to transition to economic development as the goal of health assistance; and 3) the unwillingness of public health to confront social, political, and economic policies as the foci of upstream drivers of the public's health. We conclude with a discussion of the need for public health to expand its horizon and tear down the walls of the silos that inhibit the emergence of relevant global public health. PMID- 27938823 TI - Why Did North Karelia-Finland Work?: Is it Transferrable? AB - Successful prevention of cardiovascular diseases in the North Karelia Project and Finland has drawn international attention, particularly as cardiovascular diseases and more generally noncommunicable diseases have become the leading cause of premature mortality in the world. The questions have often been asked about what were the main reasons for success and whether or not the experience could be transferred elsewhere. The main lesson is that the possibilities and potential of cardiovascular prevention are great. The principles of population based prevention are universal and are expressed in the strategies of World Health Organization. But, the practical implementation of the preventive work must be tailored to local cultural, social, and administrative (political) situations. This paper discusses many elements of the work in North Karelia and Finland that were likely important for success. PMID- 27938824 TI - The Global Burden of Disease Study and the Preventable Burden of NCD. AB - Noncommunicable diseases (NCD) now account for more than one-half of the global burden of disease. Cardiovascular diseases account for about one-half of NCD deaths, and the majority of cardiovascular disease deaths occur in low- and middle-income countries. The GBD (Global Burden of Disease) study measures and benchmarks health loss from death or disability from more than 300 diseases in over 100 countries. According to GBD analyses, the rise of NCD is in part due to increased life expectancy due to reduced premature mortality from communicable, child, and maternal illnesses, but preventable risk factors also contribute and present targets for NCD control efforts. In addition to traditional NCD risk factors, like tobacco smoking, high blood pressure, and unhealthful diet, nontraditional risk factors like air pollution and unhealthful alcohol consumption also play a role. The GBD study continues to grow by gathering more data from country partners than ever before, and by measuring health at the national and subnational levels and in smaller time increments. The GBD study will continue to provide the data to set priorities for and measure progress in the global effort to control the rising burden of NCD. PMID- 27938825 TI - How Can Progress on Global Tobacco Control Inform Progress on NCD? AB - Dr. Gro Harlem Brundtland's appointment as Director General of the World Health Organization (WHO) in 1998 led to a stronger global focus on tobacco control, and eventually, all noncommunicable diseases (NCD) and mental health. Since the adoption of the Framework Convention on Tobacco Control (FCTC) in 2003, global health has turned toward addressing all NCD. I pose 2 questions. 1) What lessons can we apply from the WHO FCTC development and implementation processes to broader aspects of NCD prevention and control? 2) In retrospect, what could we have done better? I also propose 3 lessons: 1) it takes a broad-based alliance to make progress; 2) visible and courageous leadership matters, and is aided by financial support; and 3) in developing the FCTC, WHO focused on a few messages: demonize industry, tax, and regulate tobacco. We now need to broaden public and private players required for progress, use insights on levering market forces for NCD control, and build approaches that demonstrate empathy for millions struggling with NCD risks. PMID- 27938827 TI - Confronting Global Chronic Disease: The Role for Schools of Public Health. PMID- 27938828 TI - Combating Chronic Diseases: The Role of the World Health Organization. PMID- 27938826 TI - Can the Success of HIV Scale-Up Advance the Global Chronic NCD Agenda? AB - Noncommunicable diseases (NCD) are the leading causes of death and disability worldwide but have received suboptimal attention and funding from the global health community. Although the first United Nations General Assembly Special Session (UNGASS) for NCD in 2011 aimed to stimulate donor funding and political action, only 1.3% of official development assistance for health was allocated to NCD in 2015, even less than in 2011. In stark contrast, the UNGASS on human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) in 2001 sparked billions of dollars in funding for HIV and enabled millions of HIV infected individuals to access antiretroviral treatment. Using an existing analytic framework, we compare the global responses to the HIV and NCD epidemics and distill lessons from the HIV response that might be utilized to enhance the global NCD response. These include: 1) further educating and empowering communities and patients to increase demand for NCD services and to hold national governments accountable for establishing and achieving NCD targets; and 2) evidence to support the feasibility and effectiveness of large-scale NCD screening and treatment programs in low-resource settings. We conclude with a case study from Swaziland, a country that is making progress in confronting both HIV and NCD. PMID- 27938829 TI - Chronic Disease in India: An Impending Economic Crisis and Evolving Resolve. PMID- 27938830 TI - A Platform to Accelerate Global Reductions in Chronic Diseases: Toward Action. PMID- 27938831 TI - USAID: Standing By on NCD. PMID- 27938832 TI - Global Chronic Disease: The Role of the American College of Cardiology. PMID- 27938833 TI - Has There Been Adequate Progress in Addressing the NCD Epidemic in LMIC? PMID- 27938834 TI - Chronic Disease Challenges in the Caribbean. PMID- 27938836 TI - China's Multisectoral Approach to Chronic Disease. PMID- 27938835 TI - The Need for Brazil to Focus on CVD. PMID- 27938837 TI - Mexico's Commitment to Global Health. PMID- 27938838 TI - The Fight Against CVD in a Region of the Russian Federation. PMID- 27938839 TI - Tackling Chronic Disease in the Gulf Region: Swings and Roundabouts. PMID- 27938840 TI - The Role of the Private Sector in Tilting Health Systems Toward Chronic Disease Prevention. PMID- 27938842 TI - Leveraging Digital Health for Global Chronic Diseases. PMID- 27938841 TI - Community Health Workers: An Underappreciated Asset to Tackle NCD. PMID- 27938843 TI - A Global Social Network to Catalyze Solutions for Chronic NCD: A Case Study on the Young Professionals Chronic Disease Network. PMID- 27938844 TI - Little Beacons of Change: Targeting Preschool Children to Drive a Culture of Health. PMID- 27938845 TI - Polypill: Can its Potential Enhancement of Efficacy Trigger New Interest? PMID- 27938846 TI - New Partnerships to Advance Global Health Research for NCD. PMID- 27938848 TI - ? PMID- 27938847 TI - NCD Research in the Post-2015 Global Health Agenda: Perspectives from the NHLBI Strategic Vision. PMID- 27938849 TI - Preface. PMID- 27938850 TI - Exploring the unanticipated effects of multi-sectoral partnerships in chronic disease prevention. AB - Multi-sectoral partnerships are important parts of many public health efforts to address chronic diseases, such as cancer, diabetes, and cardiovascular disease. Despite the potential value of multi-sectoral approaches, uncertainty exists regarding their effects on individuals, organizations, communities and populations. This article reports on a study that examined the unanticipated effects (both positive and negative) of the Public Health Agency of Canada's (the Agency) Multi-sectoral Partnerships initiative, which supports more than 30 multi sectoral partnership projects across Canada. Thirteen semi-structured interviews were conducted with staff from organizations participating in 3 diverse partnership projects as part of the Agency's multi-sectoral partnerships initiative. Multiple unanticipated effects were identified and organized into 4 themes: (1) insights about the flexibility and responsiveness of government; (2) access to new and valuable resources (people, skills, expertise); (3) opportunity to build new capacities; and (4) understanding realistic timelines for partnership activities and outcomes. While these effects were unanticipated for study participants, they resonate with insights from the literature on multi sectoral partnerships. These results raise a number of questions for consideration as partnership initiatives continue to evolve, including the types of training that partners might need; the individual and organizational capacities required for partnership approaches; and the evaluation techniques that might be most useful to capture the non-linear effects of partnership approaches. PMID- 27938851 TI - From the Editor. PMID- 27938852 TI - Electrocardiographic measures of left ventricular hypertrophy in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. AB - Left ventricular hypertrophy (LVH) predicts cardiovascular risk in hypertensive patients. We analyzed baseline/follow-up electrocardiographies in 26,376 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial participants randomized to amlodipine (A), lisinopril (L), or chlorthalidone (C). Prevalent/incident LVH was examined using continuous and categorical classifications of Cornell voltage. At 2 and 4 years, prevalence of LVH in the C group (5.57%; 6.14%) was not statistically different from A group (2 years: 5.47%; P = .806, 4 years: 6.54%; P = .857) or L group (2 years: 5.64%; P = .857, 4 years: 6.50%; P = .430). Incident LVH followed similarly, with no difference at 2 years for C (2.99%) compared to A (2.57%; P = .173) or L (3.16%; P = .605) and at 4 years (C = 3.52%, A = 3.29%, L = 3.71%; P = .521 C vs. A, P = .618 C vs. L). Mean Cornell voltage decreased comparably across treatment groups (Delta baseline, 2 years = +3 to -27 MUV, analysis of variance P = .8612; 4 years = +10 to -17 MUV, analysis of variance P = .9692). We conclude that risk reductions associated with C treatment in secondary end points of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial cannot be attributed to differential improvements in electrocardiography LVH. PMID- 27938853 TI - Opposing effects of sodium intake on uric acid and blood pressure and their causal implication. AB - Reducing uric acid is hypothesized to lower blood pressure, although evidence is inconsistent. In this ancillary of the DASH-Sodium trial, we examined whether sodium-induced changes in serum uric acid (SUA) were associated with changes in blood pressure. One hundred and three adults with prestage or stage 1 hypertension were randomly assigned to receive either the DASH diet or a control diet (typical of the average American diet) and were fed each of the three sodium levels (low, medium, and high) for 30 days in random order. Body weight was kept constant. SUA was measured at baseline and following each feeding period. Participants were 55% women and 75% black. Mean age was 52 (SD, 10) years, and mean SUA at baseline was 5.0 (SD, 1.3) mg/dL. Increasing sodium intake from low to high reduced SUA (-0.4 mg/dL; P < .001) but increased systolic (4.3 mm Hg; P < .001) and diastolic blood pressure (2.3 mm Hg; P < .001). Furthermore, changes in SUA were independent of changes in systolic (P = .15) and diastolic (P = .63) blood pressure, regardless of baseline blood pressure, baseline SUA, and randomized diet, as well as sodium sensitivity. Although both SUA and blood pressure were influenced by sodium, a common environmental factor, their effects were in opposite directions and were unrelated to each other. These findings do not support a consistent causal relationship between SUA and BP. PMID- 27938854 TI - The influence of time point of blood pressure measurement on the outcome in hemodialysis patients. AB - The blood pressure (BP) behaviors of hemodialysis (HD) population presented a unique pattern much different from that of the general population. This pattern is composed of chronic BP burden over interdialytic period and acute BP fluctuation during dialysis sessions. Peridialysis, interdialysis, and intradialysis are three routinely used time points to capture this complex BP behavior. However, BP at each time point was measured in various forms and conveyed different prognostic information. The measurement and interpretation of the tide-like BP behavior in HD population posed great challenge. In this review, we focused on the prognostic information of the BP behavior at each time point in HD patients and further discussed the optimal measurement of this unique BP behavior to best capture the BP-outcome association. PMID- 27938855 TI - Management of severe asymptomatic hypertension in the hospitalized patient. AB - Hypertension is common in the hospital setting. While the epidemiology, management, and outcomes of chronic hypertension are well defined, data and clinical guidance on the management of severe blood pressure elevations in the hospitalized patient are lacking. This article aims to review the literature related to the risks and benefits of managing severe asymptomatic hypertension in the hospitalized patient, summarize the concerns regarding managing severe asymptomatic hypertension with as-needed antihypertensive medication, and suggest alternative management strategies. PMID- 27938856 TI - Endothelial-mesenchymal transition in human atrial fibrillation. AB - BACKGROUND: Atrial fibrosis is a hallmark of atrial structural remodeling leading to the persistence of atrial fibrillation. Although fibroblasts play a major role in atrial fibrosis, their source in the adult atrium is unclear. We tested the hypothesis that endothelial cells contribute to fibroblast accumulation through an endothelial-mesenchymal transition in the atrium of patients with atrial fibrillation. METHODS AND RESULTS: The study group consisted of patients with atrial fibrillation and valvular disease or atrial septal defect who underwent left atrial appendectomy during cardiac surgery (n=38). The amount of fibrotic depositions in the left atrium positively correlated with left atrial dimension. Furthermore, snail and S100A4, indicative of endothelial-mesenchymal transition, were quantified in the left atrium using western blot analysis, which showed statistically significant correlations with left atrial dimension. Immunofluorescence assay of the left atrial tissue identified snail and S100A4 being expressed within the endocardium which is composed of CD31+ cells. The snail-positive endocardium also showed the expression of membrane type 1-matrix metalloproteinase. Immunofluorescence multi-labeling experiments identified that heat shock protein 47, prolyl-4-hydroxylase, and procollagen type 1 co-localized with snail and S100A4 within the endothelial cells of the left atrium, indicating the mesenchymal phenotype to produce collagen. CONCLUSIONS: In this study, we showed that the endothelial-mesenchymal transition occurs in the atrium of patients with atrial fibrillation. This observation should help in constructing a novel therapeutic approach for preventing atrial structural remodeling. PMID- 27938857 TI - Aneurinifactin, a new lipopeptide biosurfactant produced by a marine Aneurinibacillus aneurinilyticus SBP-11 isolated from Gulf of Mannar: Purification, characterization and its biological evaluation. AB - Biosurfactants are microbial-derived amphiphilic molecules having hydrophobic and hydrophilic moieties produced by bacteria, fungi, yeasts and algae and are extracellular or cell wall-associated compounds. In an ongoing survey for bioactive microbial metabolites from microbes isolated from diverse ecological niches, a new lipopeptide biosurfactant was identified from a marine bacterium; Aneurinibacillus aneurinilyticus strain SBP-11, which was isolated from a marine diversity hotspot, Gulf of Mannar, India. A new lipopeptide biosurfactant was purified and characterized based on TLC, FT-IR, NMR, GC-MS, HPLC, MALDI-TOF-MS and tandem MS analysis as Stearic acid-Thr-Tyr-Val-Ser-Tyr-Thr (named as Aneurinifactin). The critical micelle concentration of Aneurinifactin was 26mgL-1 at a surface tension of 26mNm-1. Further, the biosurfactant showed stable emulsification at a wide range of pH (2-9) and temperature up to 80 degrees C. Aneurinifactin showed promising antimicrobial activity and concentration dependent efficient oil recovery. This is the first report on Aneurinifactin, a lipopeptide biosurfactant produced by a marine A. aneurinilyticus SBP-11, which could be explored as a promising candidate for use in various biomedical and industrial applications. PMID- 27938858 TI - Rhizospheric soil and root endogenous fungal diversity and composition in response to continuous Panax notoginseng cropping practices. AB - Rhizosphere and endophytic fungal communities are considered critically important for plant health and soil fertility. In response to continuous cropping, Panax notoginseng becomes vulnerable to attack by fungal pathogens. In the present study, culture-independent Illumina MiSeq was used to investigate the rhizospheric and root endophytic fungi in response to continuous Panax notoginseng cropping practices. The results demonstrated that fungal diversity is increased inside the roots and in rhizospheric. Ascomycota, Zygomycota, Basidiomycota and Chytridiomycota were the dominant phyla detected during the continuous cropping of Panax notoginseng. The fungal diversity in the rhizospheric soil and roots of root-rot P. notoginseng plants are less than that of healthy plants in the same cultivating year, thus showing that root-rot disease also affects the community structure and diversity of rhizospheric and root endophytic fungi. Similarities in the major fungal components show that endophytic fungal communities are similar to rhizospheric soil fungal community based on a specialized subset of organisms. Canonical correspondence analysis on the fungal communities in root-rot rhizospheric from both healthy plants and rotation soils reveals that the soil pH and organic matter have the greatest impact upon the microbial community composition during continuous cropping, whereas soil nutrition status does not significantly affect the fungal community composition in response to continuous cropping practices. In addition, the results suggest that the unclassified genera Leotiomycetes, Cylindrocarpon, Fusarium and Mycocentrospora are shown as the potential pathogens which are responsible for the obstacles in continuous cropping of P. notoginseng. Further exploration of these potential pathogens might be useful for the biological control of continuous cropping of P. notoginseng. PMID- 27938859 TI - Cyanogenic Pseudomonas spp. strains are concentrated in the rhizosphere of alpine pioneer plants. AB - HCN producing bacteria have previously been isolated from alpine mineral soil and their ecophysiology was presumed to be associated with mineral weathering. Nevertheless, the high ecological patchiness of the alpine environment calls for an extensive and detailed analysis of the spatial distribution of HCN producing bacterial populations and their associated weathering traits. Our results of such an analysis showed that primarily the rhizosphere of pioneer plants was rich in HPPs, harbouring the most potent HCN producers. HCN production incidence and intensity were dependent on the plant-associated microhabitat and type of bedrock/mineral soil, however the HCN+ phenotype was not associated with one of the particular genotypes which we determined by BOX-PCR. In HPP isolates, HCN production most commonly co-occurred with the production of hydroxamate-type siderophores, but was less often associated with inorganic phosphate solubilization activity and the production of catechol-type siderophores. These observations indicate that a plant's physiotype, not species, provide physicochemical conditions that determine selective pressure, which enables the growth of Pseudomonas spp. with a random genotype, but phenotypically predetermined to increase mineral weathering via a particular combination of phosphate solubilization and iron complexation with siderophores and HCN. PMID- 27938860 TI - Delta9 desaturase from Trypanosoma cruzi: Key enzyme in the parasite metabolism. Cloning and overexpression. AB - Desaturases, key enzymes in the metabolism of fatty acids, regulate the physical and biochemical properties of membranes. They adjust the composition of saturated and unsaturated fatty acids in response to changes in the environmental. We demonstrated the existence of Delta9 desaturase activity in epimastigotes of the Trypanosoma cruzi Tulahuen strain. In the present study, showed that this enzyme has an approximate molecular mass of 50kDa and a pI value of approximately 9. In order to characterize the Delta9 desaturase of Trypanosoma cruzi, (TcDelta9DES) we have cloned, sequenced and expressed in Escherichia coli. The gene consists of 1300bp and encodes a peptide of 433 amino acids with a molecular weight of 50kDa. Analysis of the amino acid sequence revealed three clusters of histidine and two hydrophobic regions, characteristic of membrane-bound desaturases. Gene expression studies showed that TcDelta9DES was overexpressed as an active protein. Fatty acid analysis showed that the expressed protein was confirmed to be functional with Delta9 desaturase activity. This enzyme changed the fatty acid profile of TcDelta9DES-expressing E. coli, decreasing the levels of palmitic (16:0) and stearic (18:0) acids and enhancing palmitoleic (16:1Delta9) and monounsaturated 18 carbons fatty acids. When [1-14C]palmitic or [1-14C]stearic acid was used as substrate, TcDelta9DES-expressing E. coli exhibited high desaturase activity associated with increased levels of monounsaturated fatty acids, suggesting that the TcDelta9DES enzyme was actively expressed in E. coli. To check the commitment of TcDelta9DES against sterol biosynthesis inhibitors we tested the activity under ketoconazole effect. Native TcDelta9DES, showed a significant activity inhibition. Since TcDelta9DES has shown active participation under different environmental factors, among them, ketoconazole, we consider that it plays a critical role in the metabolism of the parasite. PMID- 27938861 TI - Increased production of outer membrane vesicles by cultured freshwater bacteria in response to ultraviolet radiation. AB - Secretion of membrane vesicles is an important biological process of both eukaryotic and prokaryotic cells. This process has been characterized in pathogenic bacteria, but is less clear in non-pathogenic bacteria from aquatic ecosystems. Here, we investigated, for the first time, the process of formation of outer membranes vesicles (OMVs), nanoscale vesicles extruded from the outer membrane (OM) of gram-negative bacteria, in cultures of freshwater bacteria after exposure or not to ultraviolet radiation (UVR) as an environmental stressor. Non axenic cultures of freshwater bacteria isolated from a Brazilian aquatic ecosystem (Funil reservoir) were exposed or not to UVR (UVA+UVB) over a 3h period, during which cell density, viability and ultrastructure were analyzed. First, we showed that UVR induce bacterial death. UVR triggered significant negative effect on cell density after 3h of UVR treatment. This decrease was directly associated with cell death as revealed by a cell viability fluorescent probe that enables the distinction of live/dead bacteria. Transmission electron microscopy (TEM) revealed changes indicative of cell death after 3h of UVR exposure, with significant increase of damaged cells compared to the control group. Second, we demonstrated that gram-negative bacteria release OMVs during normal growth and after UVR exposure. OMVs were clearly identified as round, membrane-bound vesicles budding off from the bacterial OM as isolated or clustered vesicles or free in the extracellular medium. Remarkably, quantitative TEM analyses showed that bacteria respond to UVR with increased formation of OMVs. Moreover, while OMVs numbers per intact or damaged cell did not differ in the untreated group, UVR led to a higher vesiculation by bacteria in process of death. This means that degenerating bacteria release OMVs before lysis and that this secretion might be an adaptive/protective response to rapid changes in environmental conditions such as UV radiation. PMID- 27938862 TI - The aldehyde dehydrogenase, AldA, is essential for L-1,2-propanediol utilization in laboratory-evolved Escherichia coli. AB - Most Escherichia coli strains are naturally unable to grow on 1,2-propanediol (PDO) as a sole carbon source. Recently, however, a K-12 descendent E. coli strain was evolved to grow on 1,2-PDO, and it was hypothesized that this evolved ability was dependent on the aldehyde dehydrogenase, AldA, which is highly conserved among members of the family Enterobacteriacea. To test this hypothesis, we first performed computational model simulation, which confirmed the essentiality of the aldA gene for 1,2-PDO utilization by the evolved PDO degrading E. coli. Next, we deleted the aldA gene from the evolved strain, and this deletion was sufficient to abolish the evolved phenotype. On re-introducing the gene on a plasmid, the evolved phenotype was restored. These findings provide experimental evidence for the computationally predicted role of AldA in 1,2-PDO utilization, and represent a good example of E. coli robustness, demonstrated by the bacterial deployment of a generalist enzyme (here AldA) in multiple pathways to survive carbon starvation and to grow on a non-native substrate when no native carbon source is available. PMID- 27938863 TI - Embryos with morphokinetic abnormalities may develop into euploid blastocysts. AB - Irregular cleavage divisions are expected to produce chromosomally deviant embryos. We investigated whether embryos from irregular cleavages could develop into euploid blastocysts, and, if so, whether any evidence existed of a self correction mechanism of the embryo. We also investigated the role of different dynamic aspects of morula compaction in this process. A total of 791 embryos from 141 patients undergoing pre-implantation genetic screening were retrospectively analysed using a time-lapse imaging system, and multiple cell divisions were evaluated. A total of 276 embryos developed into blastocysts suitable for biopsy and chromosome screening through array-comparative genomic hybridization. As well as testing trophectoderm biopsy specimens for aneuploidy, excluded cells of 18 blastocysts, which developed from partially compacted morulas, were also analysed. Unique data on the developmental fate of embryos with cleavage abnormalities are presented, and a potential mechanism of 'aneuploidy rescue' is postulated through which mosaic embryos may form partially compacted morulas to exclude aneuploid cells. In addition, this process seems to be less efficient in older women. The data obtained also provide further evidence that excluded cells should not be used to infer the cytogenetic status of the embryo. PMID- 27938864 TI - Editorial. PMID- 27938865 TI - Female Genital Mutilation and challenges in disseminating high quality healthcare guidelines. PMID- 27938866 TI - Equitable abortion care - A challenge for health care providers. Experiences from abortion care encounters with immigrant women in Stockholm, Sweden. AB - OBJECTIVE: To explore health care providers' experiences of providing care to immigrant women seeking abortion care. METHODS: A qualitative study including interviews with ten midwives and three medical doctors at four abortion clinics in the Stockholm area. Interviews were analysed using thematic analysis. RESULTS: Initially, health care providers were reluctant to make statements concerning the specific needs among immigrant women. Yet, the health care providers sometimes found it challenging to deal with the specific needs among immigrant, mostly non European, women. Three themes were identified: (1) Reluctance to acknowledge specific needs among immigrant women; (2) Striving to provide contraceptive counselling to immigrant women; (3) Organizational barriers hindering patient centred abortion care to immigrant women CONCLUSIONS: Health care providers' experiences of the specific needs among non-European, immigrant women are not openly discussed, although they are acknowledged. To achieve equitable access to sexual and reproductive health (SRH), health care providers need to be better equipped when encountering immigrant women in abortion care, especially regarding contraceptive counselling. The potential impact of patients' knowledge, norms and values is not adequately dealt with in the clinical encounter. Moreover, to provide patient-centred care, it is crucial to understand how to develop and implement SRH care that ensures equal access to high-quality care. PMID- 27938867 TI - Has perinatal outcome improved after introduction of a guideline in favour of routine induction and increased surveillance prior to 42 weeks of gestation?: A cross-sectional population-based registry study. AB - OBJECTIVE: To investigate whether new national guidelines of routine induction of labour and increased surveillance in low risk pregnancies at 41+2-5 weeks of gestation as an alternative to expectant management until 42+0 weeks of gestation has improved perinatal outcome. METHODS: A questionnaire-based study regarding local induction practices among all Danish delivery units and a cross-sectional population-based registry study based on data from the Danish Medical Birth Registry (DMBR) in the years 2009-2012. OUTCOME MEASURES: Primary outcomes were frequencies of induced labour and perinatal mortality; secondary outcomes were indicators of perinatal morbidity and instrumental delivery rates. RESULTS: The questionnaire data showed that 22 of the 24 Danish delivery units complied with the new guidelines in 2012. The study population retrieved from the DMBR included 36,845 low-risk pregnancies at or beyond 41+2 weeks of gestation. The number of labour inductions within the study population had doubled after implementation of the new guideline. The increased proportion of induced labour did not appear to influence perinatal morbidity or instrumental delivery rates. Perinatal mortality remained steady in the years 2009, 2010 and 2011 whereas a reduction of 60 % was seen in 2012. However, this change was not statistically significant (P = 0.10). CONCLUSION: This population-based study with a high reported adherence to the new national guideline found no changes in instrumental deliveries or perinatal outcomes after implementation of earlier routine induction of labour and increased surveillance in low risk pregnancies. PMID- 27938868 TI - Antenatal and postnatal risk factors of postpartum depression symptoms in Thai women: A case-control study. AB - OBJECTIVE: To examine the effects of different predictors on the incidence and severity of postpartum depression (PPD) symptoms in a Thai population. METHODS: In this case control study we delineate the clinical, demographic and socio economic risk factors associated with PPD symptoms. We used the Edinburgh Postnatal Depression Scale (EPDS) 4-6 weeks postpartum to divide parturients into those with (n = 53) and without (n = 260) PPD using a cutoff score of 11. RESULTS: This study confirms previous risk factors for PPD (i.e. a history of lifetime major depression and PPD, a history of depression during pregnancy, multi-parity, unwanted pregnancy, childcare stress, premenstrual syndrome, pain symptoms in the early puerperium), and describes new risk factors (i.e. use of caffeine during pregnancy and baby feeding problems). There are significant associations between (a) a lifetime history of major depression and depression during pregnancy, a history of postpartum depression and lifetime mania; and (b) a history of lifetime mania and a history of depression during pregnancy and a history of postpartum depression. CONCLUSIONS: A history of lifetime major depression and depression during pregnancy are the most important risk factors for postnatal depression, suggesting that sensitization processes increase risk towards postpartum depression. Postpartum depression may be a subtype of unipolar depression or bipolar disorder. PMID- 27938869 TI - Effect of female genital mutilation/cutting on sexual functions. AB - BACKGROUND: Female Genital Mutilation/Cutting (FGM/C) or female circumcision is the procedure of eliminating some or all parts of the external female genitalia. FGM/C is carried out by traditional circumcisers. They usually use cutting tools like a blade or straight-razor. Although FGM/C is well described in the African continent and some Arabic countries, data from Iran are scarce. OBJECTIVES: The major objective of this current study was to investigate the effects of FGM/C on the female sexual function of married women compared to the non-circumcised women in the Kurdistan province of Iran. METHODS: A case-control study was conducted in a sample of 280 married women (140 circumcised-women and 140 non-circumcised women) who referred to the healthcare centers for vaccination, midwifery, or family planning services. Participants were requested to complete the Persian translated version of the Female Sexual Function Index. MAIN OUTCOME MEASURES: The total score of the FSFI and its individual domains. RESULTS: Of the circumcised women, 51.4% reported circumcision procedures before the age of 3 years. Religion motivation (53.6%) was mentioned as the most important factor for the family leading to FGM/C. Almost all operations were performed by traditional circumcisers. Non-circumcised women had significantly higher Persian-FSFI total score (25.3 +/- 4.34) compared to the circumcised women (17.9 +/- 5.39). CONCLUSION: Sexual function in women with FGM/C is adversely altered. In Kurdistan province women, FGM/C is associated with reduction of scores of Persian FSFI on all domain scores. Education in general and informing the people that FGM/C is not a religious Hadith certainly would have a great impact on the suffering of the women from FGM/C as well as the level of "desire, arousal, lubrication, orgasm, satisfaction, and pain in the sexual function of women". PMID- 27938870 TI - Antenatal education in small classes may increase childbirth self-efficacy: Results from a Danish randomised trial. AB - Antenatal education in small classes may increase childbirth self-efficacy. In this randomised trial we assessed the effect of a structured antenatal programme versus auditorium-based lectures on childbirth self-efficacy measured by three single items. We found that women in the intervention group reported statistically significant higher levels of confidence in their ability to cope at home during labour compared to the control group. Likewise, the intervention had a positive effect on the women's confidence in own ability to handle the birth process. PMID- 27938871 TI - Client and provider knowledge and views on safer conception for people living with HIV (PLHIV). AB - OBJECTIVE(S): The childbearing needs of people living with HIV (PLHIV) and the experiences of healthcare providers serving them are explored. We examine provider and client knowledge and views on safer conception methods. METHODS: The study uses exploratory qualitative research to understand provider and client perspectives on childbearing and safer conception. Interviews were conducted at 3 sites (1 rural, 2 urban) in eThekwini District, KwaZulu-Natal, South Africa between May 2011 and August 2012, including in-depth interviews with 43 PLHIV, 2 focus group discussions and 12 in-depth interviews with providers. RESULTS: Clients had little knowledge and providers had limited knowledge of safer conception methods. While clients were eager to receive counseling on safer conception, providers had some hesitations but were eager to receive training in delivering safer conception services. Clients and providers noted that biological parentage is a major concern of PLHIV. Clients were willing to use any of the described methods to have biological children but some expressed concerns about potential risks associated with timed unprotected intercourse. Male clients required access to reproductive health information. CONCLUSIONS: Providers need to routinely initiate discussions with clients about childbearing intentions. Providers need to be enabled with approved guidelines and training to support client access to safer conception methods. PMID- 27938872 TI - Experiential avoidance, self-compassion, self-judgment and coping styles in infertility. AB - OBJECTIVES: This study sought out to explore the existence of differences regarding emotion regulation processes (psychological inflexibility/experiential avoidance, self-judgment and self-compassion) and coping styles (emotional/detached, avoidant and rational) in three different groups of couples: 120 fertile couples (FG), 147 couples with an infertility diagnosis who were pursuing medical treatment for their fertility problem(s) (IG), and 59 couples with infertility applying for adoption (AG). STUDY DESIGN: Cross-sectional survey, using the couple as unit of analysis. MAIN OUTCOME MEASURES: Participants filled in paper-pencil questionnaires assessing coping styles, psychological inflexibility/experiential avoidance, self-judgment and self-compassion. RESULTS: IG couples, and particularly women, tend to use more experiential avoidance and self-judgment mechanisms and less emotional/detached coping style. When compared to FG couples, IG and AG couples tend to apply more avoidant coping strategies. AG couples showed higher self-compassion. CONCLUSIONS: Findings suggest that emotion regulation processes may be an important target in psychological interventions for patients dealing with infertility and with the demands of medical treatment. PMID- 27938873 TI - Shaping the midwifery profession in Nepal - Uncovering actors' connections using a Complex Adaptive Systems framework. AB - OBJECTIVES: To explore how actors connect in a system aiming at promoting the establishment of a midwifery profession in Nepal. METHODS: A qualitative explorative study based on the framework of Complex Adaptive Systems. Semi structured interviews were conducted with 17 key people representing eight different organisations (actors) promoting the development of the midwifery profession. RESULTS: The actors' connections can be described with a complex set of facilitators for and barriers to promoting the establishment of a midwifery profession. The identified facilitators for this establishment in Nepal are (1) a common goal and (2) a desire to collaborate, whilst the barriers are (1) different political interests and priorities, (2) competing interests of the nursing profession and societal views, (3) divergent academic opinions on a midwifery profession, and (4) insufficient communication. The results also showed that Nepalese society cannot distinguish between nursing and midwifery and that the public support for a midwifery profession was hence minimal. CONCLUSION: The move of midwifery from an occupation to a profession in Nepal is an on-going, challenging process. The study indicates the importance of understanding the motivations of, and barriers perceived by, actors that can promote or obstruct the establishment of the midwifery profession. It also points to the importance of informing the wider public about the role and responsibility of an autonomous midwifery profession. PMID- 27938874 TI - Rationale, study protocol and the cluster randomization process in a controlled trial including 40,000 women investigating the effects of mindfetalness. AB - BACKGROUND: Shortening pre-hospital delay may decrease stillbirth rates and rates of babies born with a compromised health. Stillbirth may be preceded by a decrease in fetal movements. Mindfetalness has been developed as a response to the shortcomings of kick-counting for the monitoring of fetal movements by the pregnant woman. We do not know if practicing Mindfetalness may diminish pre hospital delay. Nor do we know if practicing Mindfetalness may increase or decrease the percentage of women seeking health care for unfounded, from a medical perspective, worry for her fetus' well-being. METHODS: This article describes the rationale, study protocol and the randomization process for a planned study randomly allocating 40,000 pregnant women to receive, or not receive, proactive information about practicing Mindfetalness. The unit of randomization is 63 antenatal clinics in the Stockholm area. Midwives in the antenatal clinics randomized to Mindfetalness will verbally inform about practicing Mindfetalness, hand out brochures (printed in seven languages) and inform about a website giving information about Mindfetalness. Routine care will continue in the control clinics. All information for the analyses, including the main endpoint of an Apgar score below 7 (e.g., 0-6 with stillbirth giving a score of 0), measured five minutes after birth, will be retrieved from population-based registers. RESULTS: We have randomized 33 antenatal clinics to Mindfetalness and 30 to routine care. In two clinics a pilot study has been performed. One of the clinics randomly allocated to inform about Mindfetalness will not do so (but will be included in the intention-to-treat analysis). In October 2016 we started to recruit women for the main study. CONCLUSION: The work up to now follows the outlined time schedule. We expect to present the first results concerning the effects of Mindfetalness during 2018. PMID- 27938875 TI - Situating stigma in stratified reproduction: Abortion stigma and miscarriage stigma as barriers to reproductive healthcare. AB - OBJECTIVES: To examine whether race and reported history of abortion are associated with abortion stigma and miscarriage stigma, both independently and comparatively. STUDY DESIGN: Self-administered surveys with 306 new mothers in Boston and Cincinnati, United States. MAIN OUTCOME MEASURES: Abortion stigma perception (ASP); miscarriage stigma perception (MSP); and comparative stigma perception (CSP: abortion stigma perception net of miscarriage stigma perception). RESULTS: Regardless of whether or not they reported having an abortion, white women perceived abortion (ASP) to be more stigmatizing than Black and Latina women. Perceptions of miscarriage stigma (MSP), on the other hand, were dependent on reporting an abortion. Among those who reported an abortion, Black women perceived more stigma from miscarriage than white women, but these responses were flipped for women who did not report abortion. Reporting abortion also influenced our comparative measure (CSP). Among those who did report an abortion, white women perceived more stigma from abortion than miscarriage, while Black and Latina women perceived more stigma from miscarriage than abortion. CONCLUSIONS: By measuring abortion stigma in comparison to miscarriage stigma, we can reach a more nuanced understanding of how perceptions of reproductive stigmas are stratified by race and reported reproductive history. Clinicians should be aware that reproductive stigmas do not similarly affect all groups. Stigma from specific reproductive outcomes is more or less salient dependent upon a woman's social position and lived experience. PMID- 27938876 TI - Accessing sexual and reproductive health care and information: Perspectives and recommendations from young Asian American women. AB - OBJECTIVES: Understanding the influence of culture on how sexual and reproductive health is perceived and addressed in Asian American communities is important for the effective provision of care and health information. This study aimed to explore how and when sexual and reproductive health information is shared within Asian American families and communities, barriers and facilitators to accessing sexual and reproductive health care and information for young Asian American women, and their recommendations to improve access. METHODS: Qualitative data were collected through six focus groups conducted with a total of 33 young Asian American women. RESULTS: The majority of participants reported that stigma created a barrier to discussing these topics within their families and communities, and discussed ways in which they confidentially seek out care and information. Responses varied with respect to participants' preferred means of increasing access to care and information; some recommended strategies that would increase communication about these issues in their families and communities, while others expressed a desire to maintain confidentiality. CONCLUSIONS: These findings suggest that diversified strategies are needed to connect Asian American women with sexual and reproductive health care and information in order to meet their varied preferences, including strategies that are community-driven and culturally appropriate. PMID- 27938877 TI - Coagulopathy and transfusion requirements in war related penetrating traumatic brain injury. A single centre study in a French role 3 medical treatment facility in Afghanistan. AB - INTRODUCTION: Traumatic brain injury associated coagulopathy is frequent, either in isolated traumatic brain injury in civilian practice and in combat traumatic brain injury. In war zone, it is a matter of concern because head and neck are the second most frequent site of wartime casualty burden. Data focusing on transfusion requirements in patients with war related TBI coagulopathy are limited. MATERIALS AND METHODS: A descriptive analysis was conducted of 77 penetrating traumatic brain injuries referred to a French role 3 medical treatment facility in Kabul, Afghanistan, deployed on the Kabul International Airport (KaIA), over a 30 months period. RESULTS: On 77 patients, 23 died during the prehospital phase and were not included in the study. Severe traumatic brain injury represented 50% of patients. Explosions were the most common injury mechanism. Extracranial injuries were present in 72% of patients. Traumatic brain injury coagulopathy was diagnosed in 67% of patients at role 3 admission. Red blood cell units (RBCu) were transfused in 39 (72%) patients, French lyophilized plasma (FLYP) in 41 (76%), and fresh whole blood (FWB) in 17 (31%). CONCLUSION: The results of this study support previous observations of coagulopathy as a frequent complication of traumatic brain injury. The majority of patients with war related penetrating traumatic brain injury presented with extracranial lesions. Most of them required a high level of transfusion capacity. PMID- 27938878 TI - Paving the Way for New Clinical Trials for Alzheimer's Disease. PMID- 27938879 TI - Profiling Regulatory Variation in the Brain: Methods for Exploring the Neuronal Epigenome. PMID- 27938881 TI - [On the fifty-eighth National Surgical Week]. PMID- 27938880 TI - Checking the Brain's Immune Privilege: Evolving Theories of Brain-Immune Interactions. PMID- 27938882 TI - [A fallacious document]. PMID- 27938883 TI - Predictors of Donor Heart Utilization for Transplantation in United States. AB - BACKGROUND: Optimum use of donor organs can increase the reach of the transplantation therapy to more patients on waiting list. The heart transplantation (HTx) has remained stagnant in United States over the past decade at approximately 2,500 HTx annually. With the use of the United Network of Organ Sharing (UNOS) deceased donor database (DCD) we aimed to evaluate donor factors predicting donor heart utilization. METHODS: UNOS DCD was queried from 2005 to 2014 to identify total number of donors who had at least one of their organs donated. We then generated a multivariate logistic regression model using various demographic and clinical donor factors to predict donor heart use for HTx. Donor hearts not recovered due to consent or family issues or recovered for nontransplantation reasons were excluded from the analysis. RESULTS: During the study period there were 80,782 donors of which 23,606 (29%) were used for HTx, and 38,877 transplants (48%) were not used after obtaining consent because of poor organ function (37%), donor medical history (13%), and organ refused by all programs (5%). Of all, 22,791 donors with complete data were used for logistic regression (13,389 HTx, 9,402 no-HTx) which showed significant predictors of donor heart use for HTx. From this model we assigned probability of donor heart use and identified 3,070 donors with HTx-eligible unused hearts for reasons of poor organ function (28%), organ refused by all programs (15%), and recipient not located (9%). CONCLUSIONS: An objective system based on donor factors can predict donor heart use for HTx and may help increase availability of hearts for transplantation from existing donor pool. PMID- 27938884 TI - Outcomes of Dialysis-Dependent Patients After Cardiac Operations in a Single Center Experience of 483 Patients. AB - BACKGROUND: The aim of this study was to determine the preoperative predictors of in-hospital and medium-term mortality in patients with dialysis-dependent chronic renal failure (DD CRF) undergoing cardiac operations. METHODS: Between January 1996 and June 2014, 483 consecutive patients with DD CRF underwent cardiac surgical procedures. The mean age was 65 +/- 11 years, and 32. 3% were women. Isolated coronary artery bypass grafting (CABG) or isolated valve operations were performed in 39.8% and 32.3%, of patients, respectively. Combined surgical procedures (CABG with valve operations) were necessary in 20.3% of patients. Endocarditis was an indication for surgical intervention in 11% of patients. Urgent or emergent operations were performed in 49.3% of patients. RESULTS: The in-hospital mortality was 15.3%. Postoperative respiratory failure, gastrointestinal complications, low cardiac output, stroke, and sepsis occurred in 25.7%, 12.4%, 11.8%, 5.6%, and 5.2% of patients, respectively. The independent predictors of in-hospital mortality were combined mitral and aortic valve pathologic conditions (odds ratio [OR], 3.7, 95% CI, 1. 5-9; p = 0.003), chronic obstructive pulmonary disease (OR, 2.6; 95% CI, 1.1-5.9; p = 0. 03), peripheral vascular disease (OR, 2.3; 95% CI, 1.04-4; p = 0.003), left ventricular ejection fraction (LVEF) <30% (OR, 2.9; 95% CI, 1.3-6. 4; p = 0.008), and active endocarditis (OR, 2.2; 95% CI, 1.04-4.6; p = 0.04). The estimated 2-, 4-, and 6 year survival was 50.1% +/- 2%, 34.3% +/- 2%, and 20.3% +/- 2%, respectively. Previous cerebrovascular accident, active endocarditis, previous cardiac operations, and combined aortic/mitral valve pathologic conditions were independent predictors of medium-term mortality. CONCLUSIONS: Patients with DD CRF undergoing cardiac operations have high perioperative and medium-term mortality, particularly in the presence of combined aortic and mitral valve pathologic conditions, active endocarditis, and poor left ventricular function. PMID- 27938886 TI - The Society of Thoracic Surgeons Mitral Valve Repair/Replacement Plus Coronary Artery Bypass Grafting Composite Score: A Report of The Society of Thoracic Surgeons Quality Measurement Task Force. AB - BACKGROUND: The Society of Thoracic Surgeons (STS) Quality Measurement Task Force has developed a composite performance measure for mitral repair/replacement (MVRR) with concomitant coronary artery bypass grafting (CABG). METHODS: Data were acquired from the STS Adult Cardiac Surgery Database for 26,463 patients undergoing MVRR + CABG operations between July 1, 2011, and June 30, 2014. Established STS risk models were applied, along with modifications enabling the inclusion of patients with concomitant closures of atrial septal defects and patent foramen ovale, surgical ablation for atrial fibrillation, and tricuspid valve repair (TVR). Participants with fewer than 10 eligible cases over 3 years were excluded. The MVRR + CABG composite consisted of two domains: risk-adjusted mortality and the any-or-none occurrence of major morbidity (prolonged ventilation, deep sternal infection, permanent stroke, renal failure, and reoperation). Composite performance scores were calculated with the use of hierarchic regression models, and high-performing and low-performing outliers were determined with the use of 95% Bayesian credible intervals. RESULTS: There were 24,740 patients at 703 participant sites after exclusions. Two percent (14/703) of programs were classified as 1-star (lower than expected performance), 95% (666/703) were classified as 2-star (as-expected performance), and 3% (23/703) were classified as 3-star (higher than expected performance). The average unadjusted operative mortality was 6.2% (1,532/24,740), and a monotonic decline in both mortality and morbidity was observed as star rating scores increased. CONCLUSIONS: An STS composite performance measure was developed for MVRR + CABG operations. This measure may be useful for outcome assessment, quality improvement, patient counseling, clinical research, and public reporting. PMID- 27938885 TI - Valve Repair Is Superior to Replacement in Most Patients With Coexisting Degenerative Mitral Valve and Coronary Artery Diseases. AB - BACKGROUND: For mitral regurgitation (MR) from degenerative mitral disease in patients with coexisting coronary artery disease, the appropriate surgical strategy remains controversial. METHODS: From 1985 to 2011, 1,071 adults (age 70 +/- 9.3 years, 77% men) underwent combined coronary artery bypass grafting and either mitral valve repair (n = 872, 81%) or replacement (n=199, 19%) for degenerative MR. Propensity matching (177 patient pairs, 89% of possible matches) was used to compare early outcomes and time-related recurrence of MR after mitral valve repair, mitral valve reoperation, and mortality. Risk factors for death were identified with multivariable, multiphase hazard-function analysis. RESULTS: Patients undergoing valve replacement were older, with more valve calcification and a higher prevalence of preoperative atrial fibrillation and heart failure (all p < .0001). Among matched pairs, mitral replacement versus repair was associated with higher hospital mortality (5.0% vs 1.0%, p = .0001) and more postoperative renal failure (7.0% vs 3.2%, p = .01), reexplorations for bleeding (6.0% vs 3.1%, p = .05), and respiratory failure (14% vs 4.7%, p < .0001). Of matched patients undergoing repair, 18% had MR above 3+ by 5 years. Mitral valve durability was similar between matched groups, but survival at 15 years was 18% after replacement versus 52% after repair. Nomograms from the multivariable equation revealed that in 94% of cases, 10-year survival was calculated to be higher after repair than after replacement. CONCLUSIONS: In patients with coexisting degenerative mitral valve and coronary artery diseases, mitral valve repair is expected to confer a long-term survival advantage over replacement despite some recurrence of MR. When feasible, it is the procedure of choice for these patients. PMID- 27938887 TI - Years of Life Lost After Complications of Coronary Artery Bypass Operations. AB - BACKGROUND: We currently have an incomplete understanding of which postoperative complications after coronary artery bypass grafting (CABG) are associated with long-term death. The purpose of this study was to find the associations between complications and attributable death. METHODS: Prospectively collected data on patient characteristics, risk factors, and complications of patients undergoing isolated CABG with 20-year follow-up were analyzed with a Cox regression model to calculate the overall hazard of dying associated with each postoperative complication. An individual's age and hazard of dying from each complication were then used to calculate years of life lost to each complication. RESULTS: The postoperative mortality rate was 0.79% (69 of 8,773) at 30 days, 2.85% (250 of 8,773) at 180 days, and 6.38% (560 of 8,773) at 2 years. At a median follow-up of 9.8 years, 1,891 patients (21.6%) had died. Postoperative complications occurred in 3,438 patients (39.2%). Cardiac arrest (hazard ratio, 2.153), reoperation (hazard ratio, 1.679), and new dialysis (hazard ratio, 1.64) were the complications with the greatest hazard of death. After adjusting for complication incidence and patient age, cardiac arrest (703 years), reoperation (544 years), atrial fibrillation (470 years), and prolonged mechanical ventilation (371 years) were associated with the greatest number of years of life lost. CONCLUSIONS: Acute cardiac arrest, reoperation for other cardiac reasons, new dialysis, atrial fibrillation, and prolonged mechanical ventilation are associated with the largest increase in attributable deaths. Prevention and treatment of these complications may improve mortality rates after cardiac operations. PMID- 27938888 TI - Open Repair of Thoracoabdominal Aortic Aneurysm in Patients 50 Years Old and Younger. AB - BACKGROUND: Evolving endovascular approaches to thoracoabdominal aortic aneurysm (TAAA) repair are attractive alternatives to the "gold standard" of conventional open TAAA repair. However, open repair may be more suitable for younger patients. We compared the outcomes of open TAAA repair in younger (<=50 years) and older (>50 years) patients to evaluate operative risk in younger patients. METHODS: We analyzed retrospective and prospective data from 3,346 cases of open TAAA repair performed between 1986 and 2015. Of those patients, 445 (13.3%) were 50 years old or younger and 2,901 (86.7%) were older than 50 years at the time of repair. In the younger cohort, 237 patients (53.3%) had connective tissue disorder, and many (n = 359, 80.7%) had aortic dissection. Younger patients tended to be in good health, and rupture was uncommon (n = 11, 2.5%). The outcomes examined included adverse event, a composite endpoint that comprised operative death or persistent stroke, paraplegia, paraparesis, or renal failure requiring dialysis. RESULTS: Comparisons between the two age groups showed that younger patients underwent more extent II repairs, urgent/emergent repairs, and visceral artery bypass procedures and had longer aortic clamp times. Nevertheless, younger patients had better early outcomes than did older patients, including lower rates of operative death (3.2% vs 8.2%, p = 0.002) and adverse events (5.2% vs 15.9%, p < 0.001). Multivariable analyses determined age 50 years old or younger to be an independent predictor of reduced adverse events (relative risk ratio = 0.29, p < 0.001). CONCLUSIONS: Early outcomes of open TAAA repair were excellent for patients 50 years old or younger, despite the fact that these patients typically required extensive repairs. PMID- 27938889 TI - The Oncologic Outcome of Esophageal Squamous Cell Carcinoma Patients After Robot Assisted Thoracoscopic Esophagectomy With Total Mediastinal Lymphadenectomy. AB - BACKGROUND: The oncologic outcome of esophageal squamous cell carcinoma (ESCC) patients after robot-assisted thoracoscopic esophagectomy (RATE) with total mediastinal lymphadenectomy (ML) has not been reported. This study was performed to determine the oncologic outcome of RATE and the effectiveness of total ML for ESCC. METHODS: The 115 patients who underwent RATE without neoadjuvant therapy from 2006 to 2014 were reviewed. The efficacy index (EI) was calculated by multiplying the incidence of metastasis by the 3-year survival rate of the patients for each node station. RESULTS: The majority of patients were male (92.2%), and the mean age was 63.2 +/- 0.8 years. Tumor location was the upper esophagus in 12 patients (10.4%), the middle esophagus in 59 patients (51.3%), and the lower esophagus in 44 patients (38.3%). R0 resection was achieved in 110 (95.7%) patients; the mean number of dissected nodes was 49.0 +/- 1.9. Operative mortalities were 4 (3.5%) cases; in the remaining 111 patients, the mean follow up time was 32.4 +/- 2.2 months. Overall survival (OS) and recurrence-free interval (RFI) at 3 years were 85.0% and 79.4%, respectively. The 3-year OS and RFI were 94.4% and 96.2% in patients with stage I disease, 86.2% and 80.1% in stage II disease, and 77.8% and 79.5% in stage IIIA disease, respectively. High EI values were determined in the bilateral recurrent laryngeal nerve (RLN) nodes in upper and middle ESCC, and in the left gastric and paracardial nodes in lower ESCC. CONCLUSIONS: The oncologic outcome of RATE was acceptable. Total ML, including dissection of the RLN nodes, is recommended especially in upper or middle ESCC. PMID- 27938890 TI - Hybrid Nuss Procedure for Pectus Excavatum With Severe Retrosternal Adhesions After Sternotomy. AB - BACKGROUND: The most striking feature of pectus excavatum (PE) after previous congenital heart disease (CHD) surgery through a median sternotomy is the postsurgical adhesions between the sternum and heart. For patients with severe adhesions, passing the introducer can be difficult and hazardous when performing a Nuss repair. We describe a hybrid Nuss procedure using a small subxiphoid incision for blunt and sharp anterior mediastinal dissection and using a thoracoscope to ensure the whole process of dissection is under direct visualization. METHODS: A retrospective case review was conducted of PE patients (previous CHD operation) who had undergone the hybrid Nuss procedure between January 2012 and June 2015. Demographic, treatment, and outcome variables were recorded. RESULTS: Eleven patients were included. The mean age was 4.7 +/- 1.7 years (range, 3.2 to 8.9). The mean Haller index based on computed tomography was 4.15 +/- 0.78 (range, 3.2 to 5.8). All cases were the symmetric type. Mean operating time was 95.5 +/- 8.4 minutes (range, 80 to 110); mean blood loss was 15 +/- 2.3 mL; and mean length of hospitalization was 6.0 +/- 1.4 days (range, 4 to 8). There was no pneumothorax, cardiac injury, wound infection, discomfort requiring removal, or bar rotation at the average 27-month (range, 9 to 50) follow-up. Two patients had the bars removed. No reoperations were performed owing to recurrence. CONCLUSIONS: The hybrid Nuss procedure is a safe, simple modification of the Nuss repair for patients with severe retrosternal adhesions. This procedure achieves dissection with direct visualization. Hence, the risk of death due to cardiac perforation can be prevented. PMID- 27938891 TI - Reference Standards for Cardiorespiratory Fitness Measured With Cardiopulmonary Exercise Testing Using Cycle Ergometry: Data From the Fitness Registry and the Importance of Exercise National Database (FRIEND) Registry. AB - The importance of cardiorespiratory fitness (CRF) is well established. This report provides newly developed standards for CRF reference values derived from cardiopulmonary exercise testing (CPX) using cycle ergometry in the United States. Ten laboratories in the United States experienced in CPX administration with established quality control procedures contributed to the "Fitness Registry and the Importance of Exercise: A National Database" (FRIEND) Registry from April 2014 through May 2016. Data from 4494 maximal (respiratory exchange ratio, >=1.1) cycle ergometer tests from men and women (20-79 years) from 27 states, without cardiovascular disease, were used to develop these references values. Percentiles of maximum oxygen consumption (VO2max) for men and women were determined for each decade from age 20 years through age 79 years. Comparisons of VO2max were made to reference data established with CPX data from treadmill data in the FRIEND Registry and previously published reports. As expected, there were significant differences between sex and age groups for VO2max (P<.01). For cycle tests within the FRIEND Registry, the 50th percentile VO2max of men and women aged 20 to 29 years declined from 41.9 and 31.0 mLO2/kg/min to 19.5 and 14.8 mLO2/kg/min for ages 70 to 79 years, respectively. The rate of decline in this cohort was approximately 10% per decade. The FRIEND Registry reference data will be useful in providing more accurate interpretations for the US population of CPX-measured VO2max from exercise tests using cycle ergometry compared with previous approaches based on estimations of standard differences from treadmill testing reference values. PMID- 27938892 TI - High-Throughput Fabrication of Nanocomplexes Using 3D-Printed Micromixers. AB - 3D printing allows a rapid and inexpensive manufacturing of custom made and prototype devices. Micromixers are used for rapid and controlled production of nanoparticles intended for therapeutic delivery. In this study, we demonstrate the fabrication of micromixers using computational design and 3D printing, which enable a continuous and industrial scale production of nanocomplexes formed by electrostatic complexation, using the polymers poly(diallyldimethylammonium chloride) and poly(sodium 4-styrenesulfonate). Several parameters including polymer concentration, flow rate, and flow ratio were systematically varied and their effect on the properties of nanocomplexes was studied and compared with nanocomplexes prepared by bulk mixing. Particles fabricated using this cost effective device were equally small and homogenous but more consistent and controllable in size compared with those prepared manually via bulk mixing. Moreover, each micromixer could process more than 2 liters per hour with unaffected performance and the setup could easily be scaled-up by aligning several micromixers in parallel. This demonstrates that 3D printing can be used to prepare disposable high-throughput micromixers for production of therapeutic nanoparticles. PMID- 27938893 TI - Isolation, Solubility, and Characterization of D-Mannitol Esters of 4 Methoxybenzeneboronic Acid. AB - The purpose of this study was to determine the aqueous solubility of a model phenyl boronic acid, 4-methoxybenzeneboronic acid, as a function of pH both in the absence and in the presence of varying D-mannitol concentration. Solid isolated D-mannitol esters were characterized by differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction, and single crystal X-ray studies, and the boronic acid-to-D-mannitol ratio was quantified by HPLC. Hydrolysis of the monoester was studied using UV spectral differences between the monoester and the parent boronic acid. Two D-mannitol esters of 4 methoxybenzeneboronic acid were isolated. The triboronate ester was very insoluble whereas a symmetrical monoboronate monohydrate was also less soluble than the parent. Both esters were crystalline. The monoboronate monohydrate was, however, more soluble than the parent at alkaline pH values due to its lower pKa value (6.53) compared to the parent acid (9.41). Hydrolysis of the monoboronate was extremely fast when even small amount of water was added to dry acetonitrile solutions of the ester. The hydrolysis was buffer concentration dependent and apparent pH sensitive with hydrolysis accelerated by acid. Implications affecting the formulation of future boronic acid drugs are discussed. PMID- 27938894 TI - Full Out-of-Die Compressibility and Compactibility Profiles From Two Tablets. AB - In this study, a method is presented that can be used to generate full out-of-die compressibility and compactibility profiles using the data from only 2 tablets. For each material, one tablet was compacted at the maximum pressure of interest and a second tablet at a relatively low pressure. The in-die data collected during compaction to the maximum pressure of interest and the solid fraction change after ejection for both tablets were used to generate a profile equivalent to a complete out-of-die compressibility profile. After measuring the tensile strengths of each tablet, a compactibility profile was produced by fitting the out-of-die porosity and tensile strength data to the Ryshkewitch-Duckworth equation. This method generated accurate out-of-die compressibility and compactibility profiles for each of the materials studied. Not only is this technique computationally simple, but in cases where only small amounts of raw material are available, this method allows a detailed understanding of a material's mechanical behavior to be assessed. PMID- 27938895 TI - Dispersive Raman Spectroscopy for Quantifying Amorphous Drug Content in Intact Tablets. AB - Process-induced inadvertent phase change of an active pharmaceutical ingredient in a drug product could impact chemical stability, physical stability, shelf life, and bioperformance. In this study, dispersive Raman spectroscopy is presented as an alternative method for the nondestructive, high-throughput, at line quantification of amorphous conversion. A quantitative Raman method was developed using a multivariate partial least squares (PLS) regression calibration technique with solid-state nuclear magnetic resonance (ssNMR) spectroscopy as the reference method. Compositionally identical calibration tablets containing 20% w/w total MK-A drug in varying weight proportions (0%-50% w/w based on total MK A) of amorphous and crystalline MK-A were compressed at 10-45 kN force. PLS predictions of amorphous content of tablets using Raman spectroscopy correlated well with ssNMR quantification. The predictive accuracy of this model led to a strong correlation (R2 = 0.987) with a root mean-squared error of prediction of 1.5% w/w amorphous MK-A in tablets up to 50% w/w amorphous conversion in compressive stress range of 60-320 MPa. Overall, these results suggest that dispersive Raman spectroscopy offers fast, sensitive, and high-throughput (<5 min/tablet) method for quantitating amorphous conversion. PMID- 27938896 TI - A Feasibility Trial of Home Administration of Intranasal Vaccine by Parents to Eligible Children. AB - PURPOSE: Intranasal vaccines are being developed for protection against many different infectious agents. The currently available intranasal live attenuated influenza vaccine (LAIV) is only approved for administration by medical personnel. We conducted a pilot study to investigate the feasibility of training parents to give LAIV to their own children. METHODS: Subjects were recruited from several sources: a university-based outpatient clinic, university employee e-mail announcement, and direct referrals from study subjects. After confirming eligibility to receive LAIV, consented parents were trained by viewing a video with the study staff. LAIV was provided in a cooler with instructions to vaccinate within 24 hours. Telephone follow-up was conducted to confirm proper administration and to assess parental attitudes about home administration. At season's end, immunization registry and hospital records were reviewed to confirm no additional doses were given. FINDINGS: Twenty-seven families with 41 children were enrolled. All participants successfully administered LAIV to their children, and all preferred or strongly preferred home administration to an office visit for getting vaccinated. Two families stated that without this option they would not have otherwise vaccinated their children. Adverse events were minor. All patients had their state vaccine registries accurately updated and none received duplicate doses. Upon review, no reimbursement was received for vaccination. IMPLICATIONS: Home administration of intranasal LAIV was successful and well received. This option could be used in the future for LAIV or other intranasal vaccines as a way to increase vaccination rates and convenience for parents. ClinicalTrials.gov identifier: NCT01938170. PMID- 27938897 TI - Translating Clinical Findings into the Patient's Perspective: Post-hoc Pooled Analysis of Bowel Movement Changes as a Predictor of Improvement in Patients' Opioid-induced Constipation Symptoms and Outcomes. AB - PURPOSE: Opioid-induced constipation (OIC) is a bothersome side effect of opioid use for the management of noncancer pain, affecting patients' health-related quality of life and chronic-pain management. The objective of this study was to examine the relationship between changes in the frequency of spontaneous bowel movements (SBMs) and changes in patient-reported outcomes (PROs) among patients with OIC treated with naloxegol. METHODS: Post hoc analyses were conducted using pooled data from two Phase III 12-week, placebo-controlled trials of naloxegol for the treatment of OIC (NCT01309841 and NCT01323790). Patients completed the Patient Assessment of Constipation-Quality of Life (PAC-QOL) and PAC-Symptoms (PAC-SYM) at each study visit, and the Straining Scale and Bristol Stool Scale (BSS) with each bowel movement for the study duration. Four subgroups were created based on improvements from baseline in mean frequency of SBMs per week: 0 or worse (no change), +1 SBM, +2 SBMs, and +>=3 SBMs. Spearman correlations assessed the association between mean SBM changes from baseline and mean changes from baseline in PROs; analysis of covariance was used to compare changes from baseline. FINDINGS: A total of 1337 patients with mean (SD) age of 52.2 (11.0) years were included in this analysis. The patient population was predominantly white (79.0%) and female (62.4%). At baseline, mean SBM frequency was 1.4 (1.0) per week. At study end, all 4 SBM-change subgroups experienced improvements in PAC-QOL, PAC-SYM, Straining Scale, and BSS scores, and these changes were significantly correlated with mean changes from baseline in SBMs per week. The subgroup of patients with an increase in SBMs of >=3 per week experienced the greatest improvements in PROs. IMPLICATIONS: In these patients with OIC, an improvement in the frequency of SBMs by >=3 per week was associated with consistent improvements in PROs, providing support for the use of improvements in SBMs as a clinical outcome surrogate for managing patients with OIC. Further research is needed to determine a threshold for change in SBMs that is clinically meaningful in both research and clinical settings. A key limitation was the post hoc nature of the study, which was not powered prospectively to examine these relationships. PMID- 27938898 TI - The impact of a multidisciplinary blood conservation protocol on patient outcomes and cost after cardiac surgery. AB - OBJECTIVE: Although associations between transfusion and inferior outcomes have been documented, there is a lack of blood transfusion standardization in cardiac surgery. At the Inova Heart and Vascular Institute, a multidisciplinary, criterion-driven algorithm for transfusion management was implemented. We examined the effect of our blood conservation protocol on transfusion rates and outcomes after cardiac surgery and on stability of transfusion over time. METHODS: Patients undergoing first-time cardiac surgery from 2006 (full year before protocol) were compared with those in 2009 (after protocol) and propensity score matched to improve balance. Data were prospectively collected. Stability of transfusion incidence also was compared (2005-2006 vs 2008-2014). RESULTS: After matching, 890 patients from each year were included. Use of blood products decreased from 54% in 2006 to 25% in 2009 (P < .001). Patients in 2009 had a lower incidence of postoperative renal failure (2.6% vs 4%, P = .04), reoperations for bleeding (2% vs 4%, P = .004), and readmissions at less than 30 days (6% vs 12%, P < .001). No differences were found for operative mortality, deep sternal wound infection, or permanent strokes. Patients in 2009 had greater improvement in physical (P = .001) and mental (P = .02) quality of life than patients in 2006. Reduction of blood products led to significant cost savings for packed erythrocytes (P < .001) and platelets (P < .001). After protocol implementation, transfusion incidence remained 30% or less, with less than 28% in most years. CONCLUSIONS: A multidisciplinary blood conservation program can significantly control blood transfusion rates, improve outcomes, and be sustained over time. Efforts are needed to implement evidence-based protocols to standardize and decrease blood use in cardiac surgery to improve outcomes and reduce cost. PMID- 27938899 TI - A stentless strategy for the small annulus. PMID- 27938901 TI - Zipping up after a median sternotomy: Are we at the end of the wire? PMID- 27938902 TI - Preoperative labs: Less is more. PMID- 27938903 TI - Impact of cardiac arrest resuscitated donors on heart transplant recipients' outcome. AB - OBJECTIVE: To evaluate the influence of cardiac arrest-resuscitated donors (CARDs) on the outcome of heart recipients. METHODS: Patients transplanted between July 2004 and December 2012 were divided into 2 groups according to the history of cardiac arrest in donors and their clinical records were retrospectively reviewed. RESULTS: A total of 584 heart transplantations were performed during the study period, and 117 recipients received an organ from a CARD. There were no differences between the 2 groups with regards to recipient age, sex, cardiomyopathy, preoperative extracorporeal membrane oxygenation, national high emergency waiting list, and redo surgery. Donors who sustained a cardiac arrest were significantly younger (44 [32-51] vs 49 [41-56] years; P < .001), their main cause of death was anoxia (57% vs 1%; P < .001), and they had significantly greater troponin T peak levels (0.51 [0.128-3.108] vs 0.11 [0.04 0.43] ng/mL; P < .001). Median cardiac arrest duration was 15 minutes (5-25). No difference was noted in donors with regards to left ventricular ejection fraction at time of organ procurement (62% +/- 8% vs 63% +/- 8%; P = .2). There were no differences between the 2 groups with regards to ischemic time (179 +/- 60 vs 183 +/- 59 minutes; P = .43), need for postoperative extracorporeal membrane oxygenation for primary graft failure (31% vs 30%; P = .993) and 30-days mortality. Recipients receiving an organ from a CARD had a significantly better 10 year survival (69.4% vs 50.4%; P = .017). CONCLUSIONS: History of cardiac arrest in donors with a preserved left ventricular ejection fraction at time of organ procurement doesn't affect outcome of heart recipients. PMID- 27938900 TI - Preclinical study of patient-specific cell-free nanofiber tissue-engineered vascular grafts using 3-dimensional printing in a sheep model. AB - BACKGROUND: Tissue-engineered vascular grafts (TEVGs) offer potential to overcome limitations of current approaches for reconstruction in congenital heart disease by providing biodegradable scaffolds on which autologous cells proliferate and provide physiologic functionality. However, current TEVGs do not address the diverse anatomic requirements of individual patients. This study explores the feasibility of creating patient-specific TEVGs by combining 3-dimensional (3D) printing and electrospinning technology. METHODS: An electrospinning mandrel was 3D-printed after computer-aided design based on preoperative imaging of the ovine thoracic inferior vena cava (IVC). TEVG scaffolds were then electrospun around the 3D-printed mandrel. Six patient-specific TEVGs were implanted as cell-free IVC interposition conduits in a sheep model and explanted after 6 months for histologic, biochemical, and biomechanical evaluation. RESULTS: All sheep survived without complications, and all grafts were patent without aneurysm formation or ectopic calcification. Serial angiography revealed significant decreases in TEVG pressure gradients between 3 and 6 months as the grafts remodeled. At explant, the nanofiber scaffold was nearly completely resorbed and the TEVG showed similar mechanical properties to that of native IVC. Histological analysis demonstrated an organized smooth muscle cell layer, extracellular matrix deposition, and endothelialization. No significant difference in elastin and collagen content between the TEVG and native IVC was identified. There was a significant positive correlation between wall thickness and CD68+ macrophage infiltration into the TEVG. CONCLUSIONS: Creation of patient-specific nanofiber TEVGs by combining electrospinning and 3D printing is a feasible technology as future clinical option. Further preclinical studies involving more complex anatomical shapes are warranted. PMID- 27938904 TI - Myocardial rescue with autologous mitochondrial transplantation in a porcine model of ischemia/reperfusion. AB - OBJECTIVE: To demonstrate the clinical efficacy of autologous mitochondrial transplantation in preparation for translation to human application using an in vivo swine model. METHODS: A left mini-thoracotomy was performed on Yorkshire pigs. The pectoralis major was dissected, and skeletal muscle tissue was removed and used for the isolation of autologous mitochondria. The heart was subjected to regional ischemia (RI) by temporarily snaring the circumflex artery. After 24 minutes of RI, hearts received 8 * 0.1 mL injections of vehicle (vehicle-only group; n = 6) or vehicle containing mitochondria (mitochondria group; n = 6) into the area at risk (AAR), and the snare was released. The thoracotomy was closed, and the pigs were allowed to recover for 4 weeks. RESULTS: Levels of creatine kinase-MB isoenzyme and cardiac troponin I were significantly increased (P = .006) in the vehicle-only group compared with the mitochondria group. Immune, inflammatory, and cytokine activation markers showed no significant difference between groups. There was no significant between-group difference in the AAR (P = .48), but infarct size was significantly greater in the vehicle group (P = .004). Echocardiography showed no significant differences in global function. Histochemistry and transmission electron microscopy revealed damaged heart tissue in the vehicle group that was not apparent in the mitochondria group. T2-weighted magnetic resonance imaging and histology demonstrated that the injected mitochondria were present for 4 weeks. CONCLUSIONS: Autologous mitochondrial transplantation provides a novel technique to significantly enhance myocardial cell viability following ischemia and reperfusion in the clinically relevant swine model. PMID- 27938906 TI - Discussion. PMID- 27938905 TI - The effects of postoperative hematocrit on shunt occlusion for neonates undergoing single ventricle palliation. AB - OBJECTIVES: Our primary objective was to test the effects of first postoperative hematocrit on early shunt occlusion for children undergoing systemic to pulmonary artery shunt placement. Because any intervention to reduce shunt occlusion is only beneficial if it reduces mortality or is, at least, mortality neutral, we also tested the effects of first postoperative hematocrit on in-hospital mortality. METHODS: We conducted a retrospective study on all neonates who underwent primary systemic to pulmonary artery shunt placement, with or without a Norwood/Damus-Kaye-Stansel procedure, at Columbia University Medical Center between January 2010 and July 2015. Univariable regression was used to test the effects of first postoperative hematocrit on early shunt occlusion and 30-day mortality, clustering standard errors by surgeon. In secondary analyses, we also tested associations between red blood cell transfusion volumes in the first 24 postoperative hours and first postoperative hematocrit, shunt occlusion, and mortality. RESULTS: Eighty infants met inclusion criteria. Median initial postoperative hematocrit was 41.7% (interquartile range, 37.9-46.0). Six infants (7.5%) died. Four infants (5.0%) died within the first 30 days. Five infants (6.3%) experienced early shunt occlusion. No children with early shunt occlusion died. In univariable models, for every 5 additional percentage points of hematocrit, an infant's odds of early shunt occlusion more than doubled (odds ratio, 2.70; P = .009). The odds of all-cause 30-day mortality remained unchanged. CONCLUSIONS: Higher postoperative hematocrit levels are associated with early shunt occlusions in infants undergoing primary systemic to pulmonary artery shunt placement. Multicenter investigations are warranted to validate these findings and to determine ideal postoperative hematocrit targets for this population. PMID- 27938907 TI - Nutritional risk assessment and cultural validation of the modified NUTRIC score in critically ill patients-A multicenter prospective cohort study. PMID- 27938908 TI - Establishing a Dedicated General Thoracic Surgery Subspecialty Program Improves Lung Cancer Outcomes. AB - BACKGROUND: Various factors may influence outcomes after lobectomy for lung cancer. Postgraduate subspecialty training in general thoracic surgery with a focus on minimally invasive surgery (MIS) and thoracic oncology was completed by an established cardiothoracic surgeon on the hospital staff in July 2007, and principles emphasized in that training were incorporated into practice through formation of a subspecialty program. We hypothesized that establishing a dedicated general thoracic surgeon-lead subspecialty program, with focus on MIS and thoracic oncology, would improve short-term and long-term outcomes. METHODS: Patients entered into the hospital cancer registry have survival status updated annually through correspondence with patients, physicians, and searches of the Social Security Death Index and obituaries. The registry was queried for all patients undergoing lobectomy for lung cancer, 2002 to 2013, and divided into two groups for comparison, before and after, based on operation date relative to January 2008. Patients (n = 279) who had lobectomy for lung cancer were identified in the registry. Data included surgical approach (percent of video assisted thoracoscopy [VATS]), pathologic stage, number of lymph nodes and stations sampled, hospital length of stay (LOS), and survival. chi2 statistics were used for proportions, t tests for continuous variables, and a nonparametric test for LOS. A Cox proportional hazard model was created, and survival curves were constructed using time between operation and death or last follow-up. RESULTS: Patients having lobectomy in the after group had substantially more VATS procedures (53.9% versus 9.5%), decreased LOS (median 3.5 versus 7.0 days), greater mean total lymph nodes (9.0 versus 6.3), and nodal stations (4.2 versus 2.8) sampled per patient. Thirty-day, 90-day, and 1-year survival were similar in both groups. Overall survival was better in the after group (hazard ratio [HR] 0.41, 95% confidence interval: 0.25 to 0.68), and this survival benefit remained statistically significant when comparing groups stratified by lung cancer stage (stage I: HR 0.46, stage II: HR 0.32, combined stage III to IV: HR 0.19). CONCLUSIONS: Establishing a dedicated general thoracic surgeon-lead subspecialty program, with focus on MIS and thoracic oncology, can substantially improve short term outcomes with increased VATS utilization, decreased LOS, and increased lymph node sampling. Long-term survival was also significantly improved. PMID- 27938909 TI - Racial disparities in sleep: the role of neighborhood disadvantage. AB - OBJECTIVE: Disparities in sleep duration and efficiency between Black/African American (AA) and White/European American (EA) adults are well-documented. The objective of this study was to examine neighborhood disadvantage as an explanation for race differences in objectively measured sleep. METHODS: Data were from 133 AA and 293 EA adults who participated in the sleep assessment protocol of the Midlife in the United States (MIDUS) study (57% female; Mean Age = 56.8 years, SD = 11.4). Sleep minutes, onset latency, and waking after sleep onset (WASO) were assessed over seven nights using wrist actigraphy. Neighborhood characteristics were assessed by linking home addresses to tract-level socioeconomic data from the 2000 US Census. Multilevel models estimated associations between neighborhood disadvantage and sleep, and the degree to which neighborhood disadvantage mediated race differences in sleep controlling for family socioeconomic position and demographic variables. RESULTS: AAs had shorter sleep duration, greater onset latency, and higher WASO than EAs (ps < 0.001). Neighborhood disadvantage was significantly associated with WASO (B = 3.54, p = 0.028), but not sleep minutes (B = -2.21, p = 0.60) or latency (B = 1.55, p = 0.38). Furthermore, race was indirectly associated with WASO via neighborhood disadvantage (B = 4.63, p = 0.035), which explained 24% of the race difference. When measures of depression, health behaviors, and obesity were added to the model, the association between neighborhood disadvantage and WASO was attenuated by 11% but remained significant. CONCLUSION: Findings suggest that neighborhood disadvantage mediates a portion of race differences in WASO, an important indicator of sleep efficiency. PMID- 27938910 TI - Predictors of long-term effectiveness to mandibular repositioning device treatment in obstructive sleep apnea patients after 1000 days. AB - OBJECTIVE/BACKGROUND: In obstructive sleep apnea (OSA), long-term adherence to treatment is crucial. This prospective single-center study investigated factors associated with long-term adherence to mandibular repositioning device (MRD) therapy. PATIENTS/METHODS: All OSA patients who had MRD treatment initiated in the previous year were prospectively contacted to evaluate long-term effectiveness and compliance. Long-term adherence was based on continuation of treatment (yes/no). Predictors of long-term adherence were analyzed using an adjusted multivariate analysis. RESULTS: Median follow-up was 1002 days (interquartile range: 668-1345) in 279 patients (age 58 [50-64] years); 63% of patients were continuing MRD treatment with a good efficacy, tolerability and compliance over time. In some patients, relapse of nocturia was observed while efficacy was maintained for snoring and somnolence. In adjusted multivariate analysis, significant predictors of continuing MRD treatment were early >=50% reduction in AHI (odds ratio [OR] 2.73, 95% confidence interval [CI] 1.466-5.10; p = 0.0002) and complete symptom resolution (OR 3.83, 95% CI 1.74-8.48; p = 0.0014). In the 37% of patients who stopped MRD treatment, median treatment duration was 351 (174-752) days. The main reasons for late stopping of treatment were inefficacy (26.2%), discomfort (25.2%) and side effects (21.4%). CONCLUSIONS: After three years, MRD was effective for the two-thirds of OSA patients who continued treatment. Relapse of nocturia might be an early signal of MRD wear that may explain long-term cessation of treatment in some patients. Short-term control of OSA by MAD was predictive of long-term efficiency. The major criteria were a >=50% reduction in AHI and complete symptom resolution at short-term evaluation. PMID- 27938911 TI - Propofol sedation in children: sleep trumps amnesia. AB - OBJECTIVE: Detailed assessments of the effects of propofol on memory in children are lacking. We assessed the feasibility of measuring memory during propofol infusion, as commonly performed in sedation for MRI scanning. In addition, we determined the onset of memory loss in relation to the onset of sedation measured by verbal responsiveness. MATERIALS AND METHODS: Children scheduled for sedation for MRI received a 10-min infusion of propofol (3 mg/kg) as they viewed and named 100 simple line drawings, one shown every five seconds, until they were no longer responsive (encoding). A control group receiving no sedation for MRI underwent similar tasks. Sedation was measured as any verbal response, regardless of correctness. After recovery from sedation, recognition memory was tested, with correct yes/no recognitions matched to sedation responses during encoding (subsequent memory paradigm). RESULTS: Of the 48 children who received propofol, 30 could complete all study tasks (6.2 +/- 1.6 years, 16 males). Individual responses could be modeled in all 30 children. On average, there was a 50% probability of no verbal response 3.1 min after the start of infusion, with 50% memory loss at 2.7 min. Children receiving propofol recognized 65 +/- 16% of the pictures seen, whereas the control group recognized 93 +/- 5%. CONCLUSION: Measurement of memory and sedation is possible in verbal children receiving propofol by infusion in a clinical setting. Despite propofol being an amnestic agent, there was little or no amnestic effect of propofol while the child was verbally responsive. It is important for sedation providers to realize that propofol sedation does not always produce amnesia while the child is responsive. CLINICALTRIALS. GOV NUMBER: NCT02278003. PMID- 27938912 TI - Improvements of central respiratory events, Cheyne-Stokes respiration and oxygenation in patients hospitalized for acute decompensated heart failure. AB - BACKGROUND: Sleep-disordered breathing (SDB), and Cheyne-Stokes respiration (CSR) in particular, are associated with reduced survival in patients with acute decompensated heart failure (ADHF). CSR cycle length (CL) has been shown to mirror heart failure severity and therefore may be a predictor of outcome. However, studies characterizing CSR in ADHF are rare and no study has investigated changes in CSR from admission to discharge in ADHF patients. METHODS: Consecutive patients admitted to our Academic Medical Center with ADHF were eligible. Study patients underwent two multichannel cardiorespiratory polygraphy (PG) recordings, one on admission and another during recompensation. RESULTS: 105 patients (age 71.5 +/- 12.1 years, 66.7% male, NYHA class 3.2 +/- 0.6, left ventricular ejection fraction 38.5 +/- 13.3%, brain natriuretic peptide 1299 +/- 1290 pg/ml); 77 had two fully analyzable PG recordings. CSA prevalence on the first PG was 77%. Based on the apnea-hypopnea index (AHI), CSA was mild, moderate or severe in 21%, 39% and 40% of patients, respectively. During ADHF treatment, AHI decreased non-significantly from 54 +/- 17/h to 48 +/- 9/h (p = 0.06), central hypopnea index from 20.9 +/- 14/h to 17.1 +/- 6.2/h (p < 0.01), and time spent in CSR from 65.5 +/- 28.4 to 63.7 +/- 17.8 min (p < 0.01); oxygenation improved from 91.4 +/- 2.6% to 92.0 +/- 1.5% (p < 0.05). There was no significant change in CL. CONCLUSIONS: Patients with ADHF have a high prevalence of central respiratory events, which decreased during cardiac recompensation. Cardiac recompensation also non-significantly improved the AHI and time spent in CSR and oxygenation, but had no clear impact on CSR CL, which leaves clinical account open to further investigation. PMID- 27938914 TI - Early effects of continuous positive airway pressure in a rodent model of allergic rhinitis. AB - BACKGROUND: Continuous positive airway pressure (CPAP) is the most commonly used treatment in obstructive sleep apnea. In a previous rat model study, we demonstrated that nasal CPAP induces early rhinitis expressed by nasal neutrophil extravasation. Here we hypothesized that nasal CPAP would worsen nasal inflammation on a previously inflamed mucosa. The objective of this study was to evaluate the early nasal CPAP effects of allergic rhinitis (AR) in a rodent model. METHODS: Twenty Sprague-Dawley rats were sensitized with intraperitoneal ovalbumin (OVA). Nasal inflammation was induced by the administration of intranasal OVA during consecutive days. The same procedure was performed in 20 control rats treated with saline solution. The allergic (AR) and non-allergic (NAR) rats were then randomized to nasal CPAP at 10 cm H2O for five hours or to sham CPAP. The degree of nasal inflammation was assessed by evaluating the percentage of neutrophils, eosinophils, basophils, and lymphocytes in the nasal mucosa. An unpaired Mann-Whitney test was used to analyze differences between groups. RESULTS: The greatest inflammation was observed in the group of AR without CPAP (1.24% +/- 0.94%), followed by NAR with CPAP (0.64% +/- 0.30%), AR with CPAP (0.64% +/- 0.40%), and NAR without CPAP (0.21% +/- 0.29%). CONCLUSIONS: Administration of nasal CPAP or allergy sensitization can produce, individually, neutrophil extravasation on the nasal mucosa of a rat model. The application of both stimuli is not responsible for increased inflammation. Therefore, this study suggests that rhinitis is not a major limitation for CPAP administration. PMID- 27938913 TI - Changes in ischemic stroke occurrence following daylight saving time transitions. AB - BACKGROUND: Circadian rhythm disruption has been associated with increased risk of ischemic stroke (IS). Daylight saving time (DST) transitions disrupt circadian rhythms and shifts the pattern of diurnal variation in stroke onset, but effects on the incidence of IS are unknown. METHODS: Effects of 2004-2013 DST transitions on IS hospitalizations and in-hospital mortality were studied nationwide in Finland. Hospitalizations during the week following DST transition (study group, n = 3033) were compared to expected hospitalizations (control group, n = 11,801), calculated as the mean occurrence during two weeks prior to and two weeks after the index week. RESULTS: Hospitalizations for IS increased during the first two days (Relative Risk 1.08; CI 1.01-1.15, P = 0.020) after transition, but difference was diluted when observing the whole week (RR 1.03; 0.99-1.06; P = 0.069). Weekday-specific increase was observed on the second day (Monday; RR 1.09; CI 1.00-1.90; P = 0.023) and fifth day (Thursday; RR 1.11; CI 1.01-1.21; P = 0.016) after transition. Women were more susceptible than men to temporal changes during the week after DST transitions. Advanced age (>65 years) (RR 1.20; CI 1.04-1.38; P = 0.020) was associated with increased risk during the first two days, and malignancy (RR 1.25; CI 1.00-1.56; P = 0.047) during the week after DST transition. CONCLUSIONS: DST transitions appear to be associated with an increase in IS hospitalizations during the first two days after transitions but not during the entire following week. Susceptibility to effects of DST transitions on occurrence of ischemic stroke may be modulated by gender, age and malignant comorbidities. PMID- 27938915 TI - Six-month-old infant long sleepers prefer a human face. AB - BACKGROUND: Sleep is known to influence socio-emotional regulation among children and preschoolers, whereas little is known about the association between sleep and social preference during infancy. METHODS: In the current study, habitual sleep of 49 infants aged around six months old were surveyed by questionnaire, and their social preference was revealed by their preferential gaze in three conditions: (1) a human face paired with an object (ie, a cup), (2) a human face paired with an animal face (ie, a dog), and (3) a dog face paired with a cup. RESULTS: In general, images with richer social information (ie, a human face and dog) attracted infants' gaze significantly more than nonsocial images (ie, cup). Infants with shorter sleep duration (ie, <13 h a day) show a significant reduction in their preference toward a human face when paired with a dog than infants with longer sleep duration. CONCLUSIONS: Our findings suggest an early positive link between sleep duration and preference towards socially rich stimuli (eg, a human face) during infancy. PMID- 27938916 TI - The effect of sleep apnea on all-cause mortality in nondialyzed chronic kidney disease patients. AB - BACKGROUND: The prevalence of sleep-disordered breathing (SDB) in people with chronic kidney disease (CKD) is high. Studies on the effects of sleep apnea (SA) on treatment outcomes have been mostly focused on dialyzed CKD or renal transplant patients. Studies on the effects of SA on all-cause mortality in nondialyzed CKD patients are scarce. METHODS: We enrolled and followed up all adults who were referred for diagnostic testing for sleep apnea between March 2007 and July 2014, had undergone polysomnography, and whose records of serum creatinine levels were available. The outcomes were all-cause mortality and renal outcome. RESULTS: A total of 1454 participants were included in the study. Of these, 103 patients (7.08%) had CKD and 38 patients (2.61%) died. CKD was associated with central sleep apnea (CSA) (odds ratio [OR] = 5.158 [95% confidence interval {CI} = 1.992-13.355], p = 0.001) and severe SDB (OR = 1.737 [1.119-2.695], p = 0.014). CSA was a risk factor for all-cause mortality in nondialyzed subjects (adjusted hazard ratio [HR]= <4.250 [CI = 1.560-11.573], p = 0.005), whereas CSA was found to be a stronger risk factor for all-cause mortality in subjects with CKD (adjusted HR = 40.728 [CI = 4.765-348.117], p = 0.001). Mixed sleep apnea was related to rapid decline of renal function in nondialyzed subjects (adjusted HR = 1.932 [CI = 1.183-3.155], p = 0.009), whereas, OSA was (adjusted HR = 3.315 [CI = 1.188-9.248], p = 0.022) in CKD subjects. CONCLUSION: In nondialyzed patients, CKD was each associated with central sleep apnea (CSA) and severe SDB. CSA was an independent risk factor for all-cause mortality, and was a more evident mortality risk in CKD patients than in non-CKD participants. Rapid decline of renal function may play a role in the mortality of CKD patients associated with SA. PMID- 27938917 TI - Sleep duration and total cancer mortality: a meta-analysis of prospective studies. AB - OBJECTIVE: Epidemiological evidence suggests a possible association between sleep duration and cancer-related mortality, but the reported findings are inconsistent. We conducted a meta-analysis of prospective studies to evaluate the relationships between sleep duration and cancer mortality. METHODS: Potentially relevant studies were identified by searching PubMed and Embase databases in addition to manual searches of references of retrieved full publications. The summary relative risks (RRs) with 95% confidence intervals (CIs) were computed using a random-effect model. The meta-regression analyses were performed to explore any potential effect modifier. RESULTS: A total of 17 reports from 11 independent prospective studies were included in this meta-analysis. When comparing with reasonable sleep duration (mostly defined as 7 or 7-8 h), the summary RR for long sleep duration (mostly defined as >=9 or >=10 h) and short sleep duration (mostly defined as <=6 or <=5 h) was 1.11 (95% CI = 1.05-1.18) and 1.05 (95% CI = 0.99-1.11), respectively, with little evidence of heterogeneity. There was evidence of publication bias for the association of long sleep duration with cancer mortality, and the summary RR was slightly attenuated to be 1.10 (95% CI = 1.02-1.18) after using a statistical method to correct for the bias. CONCLUSION: This meta-analysis of prospective studies suggests that long, not short sleep duration is associated with significantly increased risk of total cancer mortality. PMID- 27938918 TI - Findings of the Maintenance of Wakefulness Test and its relationship with response to modafinil therapy for residual excessive daytime sleepiness in obstructive sleep apnea patients adequately treated with nasal continuous positive airway pressure. AB - OBJECTIVE: We aimed to examine the relationship between subjective and objective sleepiness in obstructive sleep apnea syndrome (OSAS) patients with residual sleepiness, and to determine whether baseline objective sleepiness severity predicts the response to modafinil therapy. METHODS: Data were obtained from a randomized, placebo-controlled modafinil (200 mg/day) study in Japanese OSAS patients with residual sleepiness receiving nasal continuous positive pressure (n CPAP) treatment. We analyzed 50 participants whose subjective (Epworth Sleepiness Scale [ESS] total score) and objective (Maintenance of Wakefulness Test [MWT] sleep latency) sleepiness were evaluated before and after treatment. Subjects were dichotomized into two subgroups according to the mean baseline MWT sleep latency. ESS total score and MWT sleep latency changes after treatment were compared between the placebo and modafinil groups in both subgroups. RESULTS: The mean baseline ESS total score and MWT sleep latency were 14.1 +/- 2.8 and 14.2 +/ 4.9 min, respectively; there was no significant correlation between these two variables. Patient characteristics were similar between the two subgroups (MWT sleep latency: <14 min, n = 23; >=14 min, n = 27). In the <14-min subgroup, changes in ESS total score and MWT sleep latency after treatment were significantly greater in the modafinil group than in the placebo group (p = 0.005). In the >=14-min subgroup, changes in these parameters did not differ between the treatment groups. CONCLUSION: In OSAS patients with residual sleepiness, the objective sleepiness level was not as high as expected, despite increased subjective sleepiness. Improvements in subjective and objective sleepiness seemed difficult to achieve with modafinil treatment among subjects with less objective sleepiness. PMID- 27938919 TI - Normative values of polysomnographic parameters in Chinese children and adolescents: a cross-sectional study. AB - OBJECTIVE: The objectives of this study were to characterise age-specific normal polysomnography values in healthy children and to establish reference values for paediatric sleep studies. METHODS: Healthy children and adolescents aged 3-14 years were recruited from families of hospital employees. The subjects were divided into young (three to five years old) and old (6-14 years old) groups. Each child was subjected to overnight polysomnography. The polysomnographic parameters of sleep architecture, respiratory events and oxygen saturations of the two groups were compared. RESULTS: Ninety-nine subjects, including 33 3-5 year olds and 66 6-14 years olds, were recruited. The old group yielded a higher per cent of N2 sleep and lower per cent of R sleep than the young group. Sleep efficiency and latency were similar between the two groups. The average of the total apnoea/hypopnoea index (AHI) was different between the two groups (1.02 +/- 0.99 vs 0.51 +/- 0.57, p = 0.007). The average central apnoea index (CAI) in the young group was higher than that of the old group (0.7 +/- 0.82 vs 0.28 +/- 0.42, p = 0.001), with 97.5 percentile of 3.8 and 1.4, respectively. The obstructive apnoea index (OAI) and obstructive apnoea hypopnoea index(OAHI) were similar in the two groups (OAI: 0.08 +/- 0.12 and 0.07 +/- 0.14, and OAHI: 0.18 +/- 0.21 and 0.19 +/- 0.26, respectively). The mean lowest SaO2 in the young group was significantly lower than that of the old group because of central apnoea events. CONCLUSIONS: The findings were consistent with previously published data regarding sleep architecture, oxygen saturations, and relative rarity of respiratory events in normal children. The occurrence of central apnoea varied with age. Therefore, it is suggested that different normal cut-off values be used for children in different age groups. PMID- 27938921 TI - Night-waking trajectories and associated factors in French preschoolers from the EDEN birth-cohort. AB - Night waking in preschoolers has been associated with adverse health outcomes in cross-sectional studies, but has rarely been analyzed in a longitudinal setting. Therefore, little is known about the evolution of night waking in early childhood. The objectives of the present study were: to identify night-waking trajectories in preschoolers, and to examine the risk factors associated with those trajectories. Analyses were based on the French birth-cohort study EDEN, which recruited 2002 pregnant women between 2003 and 2006. Data on a child's night waking at the ages of two, three, and five, six years, and potential confounders, were collected through parental self-reported questionnaires. Night waking trajectories were computerized using group-based trajectory modeling on 1346 children. Two distinct developmental patterns were identified: the "2-5 rare night-waking" (77% of the children) and the "2-5 common night-waking" pattern. Logistic regressions were performed to identify the factors associated with the trajectories. Risk factors for belonging to the "2-5 common night-waking" trajectory were: exposure to passive smoking at home, daycare in a collective setting, watching television for extended periods, bottle feeding at night, high emotionality, and low shyness. This approach allowed identification of risk factors associated with night waking during a critical age window, and laid the groundwork for identifying children at higher risk of deleterious sleep patterns. Those risk factors were mainly living habits, which indicated that prevention and intervention programs could be highly beneficial in this population. PMID- 27938920 TI - Impact of different hypopnea definitions on obstructive sleep apnea severity and cardiovascular mortality risk in women and elderly individuals. AB - OBJECTIVE: To assess the impact of three hypopnea definitions on the severity classification of obstructive sleep apnea (OSA) and its association with cardiovascular mortality risk in women and elderly individuals. METHODS: We analyzed two Spanish clinical cohorts (1116 women and 939 elderly individuals) who were studied for suspicion of OSA between 1998 and 2007. A calibration model was used to apply different definitions of hypopnea to our two cohorts. Hypopnea was defined as a 30-90% reduction in oronasal flow for >=10 s followed by (1) >=4% fall in oxyhemoglobin saturation-AHI4%; (2) >=3% fall in oxyhemoglobin saturation-AHI3%; or (3) >=3% fall in oxyhemoglobin saturation or an event related arousal-AHI3%a. RESULTS: In both cohorts, the prevalence of an AHI >=30 events/h increased by 14% with AHI3%a, compared to AHI4% criteria. The percentage of women with an AHI <5 events/h decreased from 13.9% with AHI4% to 1.1% with the AHI3%a definition. In fully adjusted multivariable analyses, AHI >=30 events/h was associated with increased cardiovascular mortality risk in women, regardless of the hypopnea definition, and in elderly individuals diagnosed using the AHI4% and AHI3% but not the AHI3%a definition. CONCLUSIONS: Our findings suggest that hypopnea definitions substantially influence OSA prevalence and severity classification, and also affect the association with cardiovascular outcomes. With the currently recommended criterion (AHI3%a), a threshold of 30 events/h is appropriate to identify women, but not elderly individuals with increased risk of cardiovascular death. PMID- 27938922 TI - Predicting obstructive sleep apnea using the STOP-Bang questionnaire in the general population. AB - OBJECTIVE: The STOP-Bang questionnaire was developed as a quick and simple screening tool for obstructive sleep apnea (OSA) in preoperative clinics. We aimed to evaluate the validity of the STOP-Bang questionnaire to predict moderate to-severe and severe OSA in the general population. METHODS: A sample of 242 subjects selected from a population-based cohort in Singapore completed home based sleep testing with a type 3 monitor. Subjects were asked to complete the STOP questionnaire while body mass index (BMI), age, neck circumference, and sex were recorded. A score of >=3 on the questionnaire indicated high risk of OSA. RESULTS: A total of 68 subjects (28.1%) and 26 subjects (10.7%) had an apnea hypopnea index (AHI) of >=15 and >=30 events per hour, respectively. Of the subjects, 89 (36.8%) were classified as high risk based on the questionnaire. The sensitivity of a STOP-Bang score of >=3 was 66.2% to detect AHI >=15 and 69.2% to detect AHI >=30. The specificities were 74.7% and 67.1%, respectively. The negative predictive values were 85% for moderate-to-severe OSA and 94.8% for severe OSA. The corresponding positive predictive values were 50.6% and 20.2%, respectively. Using BMI cutoffs of 30 and 27.5 for Asians compared to the original cutoff of 35 did not improve the questionnaire performance significantly. CONCLUSION: The STOP-Bang questionnaire can be used as a screening tool in the general population in view of its moderate sensitivity and high negative predictive value for subjects with moderate-to-severe and severe OSA. The cutoff of BMI >35 can be used in Asians, as lower BMI cutoffs did not improve questionnaire performance. PMID- 27938924 TI - Effect of carbamazepine on the sleep microstructure of temporal lobe epilepsy patients: a cyclic alternating pattern-based study. AB - BACKGROUND: Studies looking at the effect of anti-epileptic drugs on the sleep microstructure of patients with epilepsy are scarce. The aim of this study was to compare the sleep microstructural characteristics of drug-naive temporal lobe epilepsy (TLE) patients and those on carbamazepine (CBZ) monotherapy. METHODS: Three age-matched (p = 0.286) and sex-matched (p = 0.398) groups were studied: drug-naive TLE (n = 20); TLE on CBZ (n = 20); and healthy controls (n = 40). All groups underwent overnight polysomnography. Scoring and analysis of arousals and cyclic alternating pattern (CAP) parameters were performed. Comparison of arousal parameters and CAP parameters was performed using either one-way analysis of variance or the Kruskal-Wallis test, followed by pairwise comparisons (p <= 0.05). RESULTS: Rapid eye movement (REM) arousal indices and overall CAP rates were higher in patients with TLE (group 1, p < 0.001; group 2, p < 0.001) compared to controls. Furthermore, the overall CAP rate was higher in patients on CBZ. The CAP cycle/sequences indices (group 1, p < 0.001; group 2, p < 0.001) were higher, and conversely, the average duration of CAP cycles/sequences (group 1, p = 0.018; group 2, p = 0.003) was lower in patients with TLE. Finally, an increase in A2 percentage was noted in patients with TLE (group 1, p = 0.011; group 2, p = 0.011). CONCLUSION: We found significant alterations in REM arousal indices and CAP parameters in patients with TLE as compared to controls. Moreover, many of these CAP alterations were greater in patients on CBZ. These findings suggest that anti-epileptic drugs such as CBZ may augment arousal instability in patients with TLE, and hence worsen sleep quality and continuity. PMID- 27938925 TI - Oximetry in obese children with sleep-disordered breathing. AB - BACKGROUND: Obesity is an important risk factor for obstructive sleep apnea syndrome (OSAS), and obese children with OSAS have frequently shown oxygen desaturations when compared with normal-weight children. The aim of our study was to investigate the oximetry characteristics in children with obesity and sleep disordered breathing (SDB). METHODS: Children referred for suspected OSAS were enrolled in the study. All children underwent sleep clinical record (SCR), pulse oximetry, and polysomnography (PSG). RESULTS: A total of 248 children with SDB were recruited (128 obese and 120 normal-weight children). Obese children showed higher oxygen desaturation index (ODI) and lower nadir oxygen saturation (nadir SaO2) compared to non-obese children (p < 0.05). ODI and nadir SaO2 correlated with obesity (p < 0.05). The SCR evaluation showed that deep bite and overjet were more common among obese children (p < 0.05), whereas habitual nasal obstruction and arched palate were more common among non-obese children (p < 0.05). Furthermore, skeletal malocclusion and tonsillar hypertrophy were significant risk factors in obese children associated with severe desaturation (p < 0.05). CONCLUSION: Obese children with SDB have a more significant oxygen desaturation; adeno-tonsillar hypertrophy is not the only important risk factor for its development but also the presence of malocclusions. PMID- 27938923 TI - Associations between actigraphy-assessed sleep, inflammatory markers, and insulin resistance in the Midlife Development in the United States (MIDUS) study. AB - BACKGROUND: Disturbed sleep has been associated with increased insulin resistance and elevated inflammation. Although there is growing body of evidence that activation of inflammatory pathways plays a crucial role in the development of insulin resistance, the mediational model whereby sleep disturbances influence inflammation that drives insulin resistance has not been fully assessed in general population studies with objectively measured sleep. This study aimed to examine associations between objectively measured sleep, inflammatory markers, and insulin resistance simultaneously and in a mediational analysis, thereby offering insights into the possible causal model. METHODS: Cross-sectional data collected from 2004 to 2009 during the Midlife Development in the United States II biomarker project were used. The study population included 374 community-based participants (138 men and 236 women) who completed seven nights of wrist actigraphy. Multiple regressions controlling for age and statistically significant variables in univariate regressions were performed to evaluate the associations between actigraphy-assessed sleep measures, inflammatory cytokines, and insulin resistance. RESULTS: The regression models showed that in women, higher sleep onset latency (SOL) was associated with higher insulin resistance after controlling for age, smoking, obesity, diabetes, depression, and inflammatory cytokines. Higher SOL was also associated with higher interleukin (IL)-6 and C-reactive protein (CRP) levels in women, but no association was found in men. Using mediation models in women, the association between SOL and insulin resistance was partially explained by the indirect effect of inflammatory cytokines. CONCLUSION: A combination of inflammation and other unidentified pathways may contribute to the relationship between disturbed sleep and glucose homeostasis. PMID- 27938926 TI - Sleep quality and health service utilization in Chinese general population: a cross-sectional study in Dongguan, China. AB - OBJECTIVES: The aims of this study were to explore the Pittsburgh Sleep Quality Index (PSQI) and health service utilization in Chinese general population, to investigate the association between PSQI and health service utilization and to identify the independent contributions of social demographic variables, health related factors and PSQI to health service utilization. METHODS: In a cross sectional community-based health survey using a multi-instrument questionnaire, 4067 subjects (>=15 years old) were studied. The Chinese version of the PSQI was used to assess sleep quality. Health service utilization was measured by recent two-week physician visit and annual hospitalization rates. RESULTS: Higher PSQI scores were associated with more frequent health service utilization. Higher scores in subjective sleep quality were associated with higher rate of recent two week physician visit (adjusted OR = 1.24 per SD increase, P = 0.015). Higher scores in habitual sleep efficiency (adjusted OR = 1.24 per SD increase, P = 0.038) and sleep disturbances (adjusted OR = 2.09 per SD increase, P < 0.001) were associated with more frequent annual hospitalization. The independent influence of PSQI on the risk of recent two-week physician visit was 0.7%, and that of annual hospitalization 31.4%. CONCLUSIONS: Poorer sleep quality predicted more frequent health service utilization. The independent contribution of PSQI on health service utilization was smaller than social demographic variables. PMID- 27938927 TI - Association between sleep duration and the prevalence of hypertension in an elderly rural population of China. AB - BACKGROUND: Previous studies have examined an association between sleep duration and hypertension, but the conclusions remain inconsistent. METHODS: We conducted a cross-sectional study in a community-based rural elderly population of Beijing, China. A total of 2397 participants (967 male and 1430 female) completed the survey. Sleep duration was assessed in a face-to-face interview and was self reported. Hypertension was defined as systolic blood pressure (BP) >= 140 mm Hg and/or diastolic BP >= 90 mm Hg and/or receiving treatment for hypertension. Multiple logistic regression was used to estimate the association between gender specific sleep duration and hypertension prevalence. RESULTS: Overall, no significant differences were observed among female participants and the total participants, and the differences were statistically significant only in men. After adjusting for potential confounding variables, the odds ratio (OR) and 95% confidential interval (CI) of having hypertension was 1.33 (1.00, 1.77) in men who slept for >=9 h compared with those slept for six to eight hours per 24-h period. Furthermore, a one hour nap was associated with less likelihood of hypertension in men compared with those who did not nap, with an adjusted OR (95% CI) of 0.61 (0.41, 0.90). CONCLUSION: In a community-based rural elderly population of China, we found that sleep duration of six to eight hours per 24-h period and a one hour nap were significantly associated with lower risk of hypertension only among male participants after adjustment for potential confounders. Further studies are still needed to determine the relationships between 24-h, nighttime, and daytime sleep duration separately with hypertension, and to explore the biological mechanisms underlying the gender-related association. PMID- 27938928 TI - Prevalence and predictors of obstructive sleep apnoea in young children with Down syndrome. AB - BACKGROUND: Children with Down syndrome (DS) are vulnerable to obstructive sleep apnoea (OSA) because of their unique craniofacial anatomy and hypotonia. Understanding the predictors of OSA in DS may enable targeted screening. METHODS: Children with DS (n = 202) aged from six months to below six years (110 boys) were recruited from three UK children's hospitals. The clinical assessment included height, weight and tonsillar size. The parents either set up cardiorespiratory polygraphy at home or chose laboratory studies. Studies with less than four hours of interpretable data were repeated where possible. American Academy of Sleep Medicine (AASM) 2012 scoring criteria were used to derive an obstructive apnoea/hypopnoea index (OAHI). Predictors of moderate to severe OSA were examined. RESULTS: In total, 188/202 (93%) participants were successfully studied. Of these, 169 studies were completed at home and 19 in a sleep laboratory. Moderate to severe OSA, defined by an OAHI of >5/h, was found in 14% and mild to moderate OSA (1/h>=OAHI <5/h) was found in 59% of the children. Male gender and habitual snoring predicted OSA but did not have independent predictive power in the presence of the other factors. Age in months, body mass index (BMI) centile and tonsillar size did not predict OSA. CONCLUSIONS: Moderate to severe OSA is common in very young children with DS. Examination of tonsillar size did not predict OSA severity. Population-based screening for OSA is recommended in these children, and domiciliary cardiorespiratory polygraphy is an acceptable screening approach. Further research is required to understand the natural history, associated morbidity, optimal screening methodology and treatment modality for OSA in these children. PMID- 27938929 TI - Surgical management of psoas abscess in the Human Immunodeficiency Virus era. AB - OBJECTIVES: Thai aims of this study were to provide an epidemiological and microbiological analysis of psoas abscess in the human immunodeficiency virus (HIV)-infected population, and to describe the optimal investigative and management approach of this condition. METHODS: A retrospective chart analysis of 20 patients with a diagnosis of psoas abscess admitted to a regional academic hospital from January 2012 to December 2014 was performed. RESULTS: Twenty patients with psoas abscess were identified, of which 14 were HIV positive (70%) and five HIV negative (25%). One patient remained untested (5%). The mean CD4 count was 402 cells/mL (range 150-796 cells/mL, median 367 cells/mL). Acid fast bacilli were positive in psoas abscess aspirates in 13 cases (65%). Staphylococcus aureus and Escherichia coli were identified in 15% of cases. The radioisotope bone scan showed increased vertebral uptake in 10 patients (62.5%), with the lumbar spine (L1-L4) being most commonly involved (31%). There was a statistically significant increase in radioisotope uptake in the lumbar vertebrae in tuberculous psoas abscess than in pyogenic psoas abscess (p=0.003). Ultrasound guided percutaneous drainage was used in 16 patients (80%) with a success rate of 87.5%; only two cases required repeat drainage (12.5%). Open drainage was used in four patients (30%) with a 100% success rate. There were no mortalities at 30-day follow-up. CONCLUSION: Tuberculous psoas abscess from underlying vertebral osteomyelitis is more common than pyogenic psoas abscess. Ultrasound has high diagnostic accuracy and guides percutaneous drainage with excellent success rates. Ultrasound-guided percutaneous drainage should be regarded as the first line therapeutic modality. PMID- 27938931 TI - Alopecia, Follicular Papules, and Short Stature. PMID- 27938930 TI - Clinical Characteristics and Outcomes in a Population With Disseminated Herpes Zoster: A Retrospective Cohort Study. AB - INTRODUCTION: Shingles is the cutaneous expression of the reactivation of latent varicella zoster virus infection in sensory ganglia. It presents as vesicles in the corresponding dermatome. The condition is called disseminated herpes zoster (DHZ) when more than 2 contiguous dermatomes are affected, more than 20 vesicles are observed outside the initial dermatome, or involvement is systemic. DHZ is rare and most frequently occurs in immunocompromised patients. OBJECTIVES: To describe the epidemiology, predisposing factors, clinical presentation, laboratory findings, and clinical course of patients with DHZ, and to compare the findings in immunocompromised and immunocompetent patients. METHODOLOGY: We analyzed a retrospective case series of adults hospitalized between February 2010 and October 2015. RESULTS: Forty-one patients with virologically confirmed manifestations of DHZ were included. Stress as a trigger factor was detected in 39% and immunodepression in 58.5%. Immunocompromised patients were younger than the immunocompetent patients (mean ages, 60.5 vs 82 years, P<.01). The 8 immunocompetent patients with no detectable trigger factors were older (mean age, 85 years). In 95% of cases, DHZ was initially limited to a single dermatome and then spread to other dermatomes or became disseminated. Thrombocytopenia was detected in 56% of cases. Complication rates were similar in immunocompromised and immunocompetent patients (54% vs 59%, P>.01). Six patients died; there was no difference in mortality between the 2 groups. CONCLUSION: This study provides evidence on the relationship between DHZ, the presence of underlying immunodepression, and complications. Immunosenescence may play an important role in the onset of this disease in older immunocompetent patients. PMID- 27938932 TI - Objective Structured Clinical Examination as an Assessment Tool for Clinical Skills in Dermatology. AB - BACKGROUND: Objective Structured Clinical Evaluation (OSCE) is an excellent method to evaluate student's abilities, but there are no previous reports implementing it in dermatology. OBJECTIVES: To determine the feasibility of implementation of a dermatology OSCE in the medical school. METHODS: Five stations with standardized patients and image-based assessment were designed. A specific checklist was elaborated in each station with different items which evaluated one competency and were classified into five groups (medical history, physical examination, technical skills, case management and prevention). RESULTS: A total of 28 students were tested. Twenty-five of them (83.3%) passed the exam globally. Concerning each group of items tested: medical interrogation had a mean score of 71.0; physical examination had a mean score of 63.0; management had a mean score of 58.0; and prevention had a mean score of 58.0 points. The highest results were obtained in interpersonal skills items with 91.8 points. LIMITATIONS: Testing a small sample of voluntary students may hinder generalization of our study. CONCLUSIONS: OSCE is an useful tool for assessing clinical skills in dermatology and it is possible to carry it out. Our experience enhances that medical school curriculum needs to establish OSCE as an assessment tool in dermatology. PMID- 27938933 TI - Dissecting cellulitis of the scalp. PMID- 27938934 TI - Medial approach of ultrasound-guided costoclavicular plexus block and its effects on regional perfussion. AB - INTRODUCTION: Ultrasound-guided infraclavicular block in the costoclavicular space located between the clavicle and the first rib, reaches the secondary trunks when they are clustered together and lateral to the axillary artery. This block is most often performed through a lateral approach, the difficulty being finding the coracoid process an obstacle and guiding the needle towards the vessels and pleura. A medial approach, meaning from inside to outside, will avoid these structures. Traditionally the assessment of a successful block is through motor or sensitive responses but a sympathetic fibre block can also be evaluated measuring the changes in humeral artery blood flow, skin temperature and/or perfusion index. OBJECTIVE: To describe the medial approach of the ultrasound guided costoclavicular block evaluating its development by motor and sensitive response and measurement of sympathetic changes. MATERIALS AND METHODS: Description of the technique and administration of 20ml of contrast in a fresh cadaver model, evaluating the distribution with CT-scan and sagittal sections of the anatomic piece. Subsequently in a clinical phase, including 11 patients, we evaluated the establishment of motor, sensitive and sympathetic blocks. We evaluated the sympathetic changes reflected by humeral artery blood flow, skin temperature and distal perfusion index. RESULTS: In the anatomical model the block was conducted without difficulties, showing an adequate periclavicular distribution of the contrast in the CT-scan and in sagittal sections, reaching the interscalenic space as far as the secondary trunks. Successful blocks were observed in 91% of patients after 25minutes. All the parameters reflecting sympathetic block increased significantly. The humeral artery blood flow showed an increase from 108 +/- 86 to 188+/-141ml/min (P=.05), skin temperature from 32.1+/-2 to 32.8+/-9 degrees C (P=.03) and perfusion index from 4+/-3 to 9+/-5 (P=.003). CONCLUSIONS: The medial approach of the ultrasound-guided costoclavicular block is anatomically feasible, with high clinical effectiveness using 20ml of 1.5% mepivacaine. The sympathetic block can be evaluated with all three parameters studied. PMID- 27938936 TI - Perioperative medicine and the role of hemodynamic monitoring. PMID- 27938935 TI - Anaesthetic management in thoracoscopic distal tracheal resection. AB - Surgical resection of tracheal tumours, especially distal tracheal tumours, is a challenge for the anaesthesiologists involved, mainly due to difficulties in ensuring adequate control of the airway and ventilation. We report the case of a patient undergoing tracheal resection and anastomosis by VATS, emphasizing the anaesthetic management. PMID- 27938937 TI - Amylin and Leptin: Co-Regulators of Energy Homeostasis and Neuronal Development. AB - While the regulation of energy homeostasis by amylin is already well characterized, emerging data suggest that amylin is also crucial for the development of neural pathways in the hypothalamus and caudal hindbrain (area postrema, AP; nucleus tractus solitarius, NTS). Exciting new findings demonstrate crucial amylin-leptin interactions in altering the activity of specific hypothalamic and AP neurons, and a role for amylin as a novel class of 'leptin sensitizers' which enhance leptin signaling in both leptin-sensitive and resistant individuals, in part by stimulating IL-6 production by hypothalamic microglia. This review summarizes these findings and provides a hypothetical framework for future studies to elucidate the mechanisms by which amylin and leptin act individually and as co-conspirators to alter energy homeostasis and neuronal development. PMID- 27938938 TI - Overexpression of HIF-1alpha in mesenchymal stem cells contributes to repairing hypoxic-ischemic brain damage in rats. AB - Preclinical researches on mesenchymal stem cells (MSCs) transplantation, which is used to treat hypoxic-ischemic (HI) brain damage, have received inspiring achievements. However, the insufficient migration of active cells to damaged tissues has limited their potential therapeutic effects. There are some evidences that hypoxia inducible factor-1 alpha (HIF-1alpha) promotes the viability and migration of the cells. Here, we aim to investigate whether overexpression of HIF 1alpha in MSCs could improve the viability and migration capacity of cells, and its therapeutic efficiency on HI brain damage. In the study, MSCs with HIF-1alpha overexpression was achieved by recombinant lentiviral vector and transplanted to the rats subsequent to HI. Our data indicated that overexpression of HIF-1alpha promoted the viability and migration of MSCs, HIF-1alpha overexpressed MSCs also had a stronger therapeutic efficiency on HI brain damaged treatment by mitigating the injury on behavioral and histological changes evoked by HI insults, accompanied with more MSCs migrating to cerebral damaged area. This study demonstrated that HIF-1alpha overexpression could increase the MSCs' therapeutic efficiency in HI and the promotion of the cells' directional migration to cerebral HI area by overexpression may be responsible for it, which showed that transplantation of MSCs with HIF-1alpha overexpression is an attractive therapeutic option to treat HI-induced brain injury in the future. PMID- 27938939 TI - Expression of the Galanthus nivalis agglutinin (GNA) gene in transgenic potato plants confers resistance to aphids. AB - Aphids, the largest group of sap-sucking pests, cause significant yield losses in agricultural crops worldwide every year. The massive use of pesticides to combat this pest causes severe damage to the environment, putting in risk the human health. In this study, transgenic potato plants expressing Galanthus nivalis agglutinin (GNA) gene were developed using CaMV 35S and ST-LS1 promoters generating six transgenic lines (35S1-35S3 and ST1-ST3 corresponding to the first and second promoter, respectively). Quantitative real-time polymerase chain reaction (qRT-PCR) analysis indicated that the GNA gene was expressed in leaves, stems and roots of transgenic plants under the control of the CaMV 35S promoter, while it was only expressed in leaves and stems under the control of the ST-LS1 promoter. The levels of aphid mortality after 5 days of the inoculation in the assessed transgenic lines ranged from 20 to 53.3%. The range of the aphid population in transgenic plants 15 days after inoculation was between 17.0+/-1.43 (ST2) and 36.6+/-0.99 (35S3) aphids per plant, which corresponds to 24.9-53.5% of the aphid population in non-transformed plants. The results of our study suggest that GNA expressed in transgenic potato plants confers a potential tolerance to aphid attack, which appears to be an alternative against the use of pesticides in the future. PMID- 27938941 TI - Changing of the guard. PMID- 27938942 TI - Accuracy of segmentation of tooth structures using 3 different CBCT machines. AB - OBJECTIVE: The aim of this study was to evaluate the volumetric accuracy and reliability of cone beam computed tomography (CBCT)-based tooth segmentation using 4 different CBCT exposure protocols. METHODS: Two dry, intact adult human mandibles of unknown gender were scanned using 4 different CBCT exposure protocols (3 CBCT systems). The available mandibular premolars (3 per mandible) were segmented, resulting in a total of 24 segmented teeth. To assess the accuracy of the segmented teeth, volumetric and morphologic differences between the real anatomic teeth and the reconstructed images were evaluated both physically and using a high-resolution micro-computed tomography system. RESULTS: Results revealed a high accuracy of CBCT reconstructed images when comparing volumetric measures of CBCT-based segmented premolars to physical measurements of corresponding physical teeth. Volumetric differences were below 2%. Morphologic differences using the segmented model and the corresponding micro-computed tomography scans of the physical teeth indicated that when inaccuracies occurred, they were at the apical and coronal parts of the tooth. CONCLUSION: Based on these results, CBCT can be used as a tool for segmentation and pretherapeutic planning procedures. PMID- 27938940 TI - Beverage Intake and Metabolic Syndrome Risk Over 14 Years: The Study of Women's Health Across the Nation. AB - BACKGROUND: Alcohol and energy-dense beverages consumption have been implicated in cardiometabolic disease, albeit inconsistently. OBJECTIVE: This study tested prospective associations between intakes of alcohol, energy-dense beverages, and low-calorie beverages and cardiometabolic risk in midlife women. DESIGN: The Study of Women's Health Across the Nation is a 14-year, multisite prospective cohort study (1996-2011). Beverage intake and cardiometabolic risk factors that define the metabolic syndrome (hypertension, abdominal obesity, impaired fasting glucose, low high-density lipoprotein cholesterol level, and hypertriglyceridemia) were assessed throughout follow-up. PARTICIPANTS/SETTING: Participants (N=1,448) were African American, Chinese, Japanese, and non-Hispanic white midlife women from six US cities. MAIN OUTCOME MEASURES: The primary outcomes were incident metabolic syndrome and the individual metabolic syndrome components. STATISTICAL ANALYSES PERFORMED: Generalized linear mixed models tested associations between intakes within each beverage category and odds of meeting criteria for metabolic syndrome and each of the metabolic syndrome components. RESULTS: Energy-dense beverage consumption was highest among African American women and lowest among women with college degrees. Non-Hispanic white women consumed the largest quantities of alcohol. Independent of energy intake and potential confounders, each additional 355 mL energy-dense beverages consumed per day was associated with higher odds of developing metabolic syndrome in each successive year of follow-up (odds ratio [OR] 1.05, 95% CI 1.02 to 1.08). Greater energy-dense beverage intake was associated with more rapidly increasing odds of developing hypertension (OR 1.06, 95% CI 1.02 to 1.11) and abdominal obesity (OR 1.10, 95% CI 1.03 to 1.16) over time, but not with the other metabolic syndrome components. Intakes of alcohol and low-calorie coffees, teas, and diet cola were not associated with metabolic syndrome risk. CONCLUSIONS: Over 14 years of follow up, energy-dense nonalcoholic beverage consumption was associated with incident metabolic syndrome in midlife women. The observed differences in intakes by ethnicity/race and education suggest that consumption of these beverages may contribute to disparities in risk factors for diabetes and cardiovascular disease. PMID- 27938943 TI - Correlation of upper airway radiographic measurements with risk status for obstructive sleep apnea syndrome in young dental patients. AB - OBJECTIVE: The aim of the present study is to compare radiographic measurements of the upper airway (UA) in young adult patients with different levels of risk status for obstructive sleep apnea syndrome. STUDY DESIGN: The study included 50 patients between 18 and 30 years of age who were referred for dental examination and evaluation of impacted third molars. Case record forms, including habit history, along with the Berlin Questionnaire and the Epworth Sleepiness Scale, were completed by the patients and their relatives. According to the answers, 25 low-risk patients and 25 high-risk patients were selected. Cephalometric radiographs and cone beam computed radiography images were obtained for radiographic analysis when the patients were admitted into the study. RESULTS: There were significant differences in body mass index, neck circumference measurements, Epworth score, and smoking status between risk groups. There were significant differences for UA measurements on radiographic evaluation. Body mass index (BMI) was found to be correlated positively with neck circumference and Epworth scores and negatively with UA measurements for all patients. Velopharyngeal measurements showed the highest correlation with Epworth scores, BMI, and neck circumference. CONCLUSIONS: The radiographic findings correlated with the survey results. Our data suggest that radiographic measurements of UA may be used as a predictor of risk for obstructive sleep apnea syndrome in a young population. PMID- 27938944 TI - Diagnostic approach to intramasseteric nodules. AB - Intramuscular nodules can be the clinical presentation of several groups of lesions, such as reactive disorders and benign and malignant tumors. Here, we present three cases with similar clinical features and image aspects on Doppler ultrasonography. Two of the lesions were diagnosed as intramasseteric hemangioma and the third as intramasseteric metastasis from high-grade pleomorphic sarcoma of the thigh. The diagnosis of intramasseteric nodules is challenging, and various differential diagnoses must be considered. Clinical features, evolution time, and information from complementary examinations, such as Doppler ultrasonography and fine-needle aspiration cytology, are useful in making a precise diagnosis and providing appropriate treatment. PMID- 27938945 TI - Complications after fine-needle aspiration cytology: a retrospective study of 7449 consecutive thyroid nodules. AB - Although fine-needle aspiration (FNA) cytology of thyroid nodules is invasive, it is simple, reliable, safe, and well-accepted by patients. Local pain and minor haematomas are the most common complications, and serious ones are rare. We report the complications associated with ultrasound-guided FNA of 7449 thyroid nodules in a series of 6323 patients (5121 women and 1202 men) treated between January 2007 and March 2016 at our institution. We reviewed their medical and imaging records, and recorded the number and type of complications, time of detection, time to recovery, management, and permanent consequences. Ten patients (0.15%) had complications, which included a focal carotid intramural haematoma that spread along the carotid wall for 7cm in a young patient, and one case of tumour seeding. No complications caused permanent problems. This series shows that ultrasound-guided FNA of thyroid lesions is safe and has few complications. However, physicians should always consider the risks and benefits for each patient before the procedure. PMID- 27938947 TI - Shaping the future of ophthalmology in Canada. PMID- 27938946 TI - NOX2-ROS-HIF-1alpha signaling is critical for the inhibitory effect of oleanolic acid on rectal cancer cell proliferation. AB - Rectal cancer is the second leading cause of cancer mortality in the western countries and accounts for 10% incidence and mortality of cancer in the whole world. Drug resistance and severe toxicity severely limited the efficiency of chemotherapy of rectal cancer. Oleanolic acid (OA) is a natural triterpenoid and an aglycone of many saponins. In the present study, we aimed to investigate the effect of OA on rectal cancer cell proliferation and its possible mechanism. We showed that OA concentration-dependently inhibited cell proliferation in HCT-15, HT-29, HCT-8 and Colo 205 human rectal cancer cell lines. OA significantly increased reactive oxygen species (ROS) generation and NADPH oxidase 2 (NOX2) expression in a concentration-dependent manner. In HCT-15 and HT-29 cells, siNOX2 notably suppressed OA-induced ROS generation, inhibition of cell proliferation, increase of S phase cell population and decrease of cyclin D1 and CDK2 expression. OA markedly decreased hypoxia-inducible factor 1alpha (HIF-1alpha) expression in HCT-15 and HT-29 cells in a concentration-dependent manner. Overexpression of HIF-1alpha significantly suppressed OA-induced inhibition of cell proliferation, increase of S phase cell population and decrease of cyclin D1 and CDK2 expression. Inhibition of NOX2 by siRNA notably blocked OA-induced suppression of HIF-1alpha expression. Our findings provide novel insights into OA induced inhibition of rectal cancer cell proliferation and highlight NOX2/ROS/HIF 1alpha axis as a novel therapeutic target for the treatment of rectal cancer. PMID- 27938948 TI - Effect of transverse conjunctival advancement flap surgery for primary pterygium. AB - OBJECTIVE: To introduce a new surgical technique, transverse conjunctival advancement flap, and to evaluate the efficacy and safety of the technique in primary pterygium surgery. DESIGN: Retrospective, noncomparative, interventional case-series analysis. PARTICIPANTS: Sixty-three eyes of 63 patients. METHODS: The patients with primary pterygium were treated with transverse conjunctival advancement flap technique. After excision of the pterygium head and the perilimbal part of the pterygium body (within 2 mm from the limbus), the bare sclera was covered with the transverse conjunctival advancement flap using the conjunctiva of the remaining posterior part of the pterygium body. The patients were followed up for more than 6 months. RESULTS: The mean age of patients was 64.9 +/- 8.7 years (range 43-85 years), and the mean follow-up period was 9.8 +/- 3.9 months (range 6-18 months). In all cases, surgery did not exceed 20 minutes. During the follow-up period, recurrence of the pterygium occurred in 1 (1.5%) of the 63 cases, with recurrence only in the conjunctiva. There was no occurrence of serious complications. CONCLUSIONS: The transverse conjunctival advancement flap technique may be considered a safe and effective method, with a low rate of pterygium recurrence, after primary pterygium excision. PMID- 27938949 TI - Dual-purpose corneal tissue for anterior lamellar keratoplasty and Descemet's membrane endothelial keratoplasty. AB - OBJECTIVE: To assess the intraoperative issues and surgical outcomes of preparing a single-donor corneal tissue for same-day use in both deep anterior lamellar keratoplasty (DALK) and Descemet's membrane endothelial keratoplasty (DMEK). DESIGN: Consecutive retrospective case series. PARTICIPANTS: Ten eyes of 10 patients who underwent DALK (5 patients) or DMEK (5 patients) surgery using dual purpose corneal tissue. METHODS: Five dual-purpose corneoscleral rims were used to prepare tissue for 5 DMEK and 5 DALK procedures. The submerged cornea using backgrounds away technique was first used to harvest the 5 DMEK grafts, and the remaining tissue was used for the 5 DALK grafts. Tissue preparation and operative use occurred on the same day. Tissue preparation challenges, intraoperative complications, and visual recovery were assessed. RESULTS: There were no difficulties in preparing the 5 dual-purpose tissues, and all 10 lamellar transplants were completed successfully. At the 6-month follow-up, the mean best corrected distance visual acuity improved from 20/250 to 20/80 in the DALK patients, and from 20/300 to 20/25 in the DMEK patients. Postoperative complications after DALK included retained viscoelastic agent at the interface in 1 patient and a double anterior chamber managed with rebubbling in another. After DMEK, a peripheral partial graft detachment occurred in 1 patient and was managed successfully with rebubbling. All corneas demonstrated clarity on slit-lamp examination. CONCLUSIONS: Single-donor corneal tissue can be effectively used for both DALK and DMEK, and may represent a more efficient use of corneal tissue. Complications with the preparation of dual-purpose tissue were not encountered. PMID- 27938950 TI - Pterygium excision with conjunctival autograft and subconjunctival amniotic membrane as antirecurrence agents. AB - OBJECTIVE: To determine the outcome of pterygium excision with a conjunctival autograft when the adjunctive use of a subconjunctival graft of amniotic membrane is employed to reduce fibrosis and recurrence after surgery. DESIGN: This is a retrospective, noncomparative study of postoperative outcomes. PARTICIPANTS: Eighty-four patients totalling 101 eyes with clinically significant pterygia that warranted surgical excision. METHODS: Surgeries were performed at South Orange County Outpatient Surgery Center (San Clemente, Calif.) between June 6, 2006, and October 23, 2013, by a single surgeon (J.A.H.). Patients were included in the study according to the need for pterygium surgery and the type of surgery performed. Exclusion criteria included patients with recurrent pterygium, those with pseudopterygium, and those whose treatment plan included prophylactic mitomycin during or after surgery. Initial pterygia measurements and postoperative findings were taken through standard slit-lamp examinations. RESULTS: Pterygium recurrence was defined as growth greater than 1 mm onto the corneal limbus at or after 6 months. There was 1 case of pterygium recurrence for a recurrence rate of 0.99% +/- 1.93% (n = 101, p = 0.05). The mean extent of preoperative horizontal encroachment of pterygium on the cornea was 2.4 +/- 0.87 mm. CONCLUSIONS: Pterygium excision with a conjunctival autograft and prophylactic placement of a subconjunctival amniotic membrane graft has a low recurrence rate with minimal added surgical time and minimal added risk to the patient and has merit as a surgical technique. PMID- 27938951 TI - Outcomes of photorefractive keratectomy following laser in situ keratomileusis: a cohort study. AB - OBJECTIVE: To analyze the outcomes of photorefractive keratectomy (PRK) on residual myopia and hyperopia post-laser in situ keratomileusis (LASIK) and to compare these results with PRK on eyes without previous laser refractive surgery. DESIGN: Retrospective comparative cohort study. PARTICIPANTS: Patients undergoing PRK between 2006 and 2010 were reviewed. METHODS: Patients were divided into 4 groups, myopic or hyperopic PRK post-LASIK (mPRK-PL and hPRK-PL, respectively) and myopic or hyperopic PRK on corneas without previous laser refractive surgery (mPRK and hPRK, respectively). Uncorrected and corrected distance visual acuity, mean refractive spherical equivalent (MRSE), and mean keratometry and aberrations (total, higher order [HOA], coma, trefoil, and spherical aberration) were recorded at months 3 and 6 postoperatively, as were complications and attempted versus achieved MRSE. RESULTS: Thirty-three eyes of 25 patients who underwent PRK post-LASIK (21 eyes of 14 patients for hPRK-PL and 12 eyes of 11 patients for mPRK-PL) and 35 eyes of 21 patients who underwent PRK on virgin eyes (11 eyes of 8 patients for hPRK and 24 eyes of 13 patients for mPRK) were included in the study. The only significant differences in outcomes were found to be HOA at 3 months for hPRK-PL as compared with both hPRK and mPRK. Achieved MRSE was significantly different from expected MRSE for hPRK-PL at 3 months postoperatively. No haze- or flap-related complications were observed. CONCLUSION: Outcomes of PRK were not different in myopic and hyperopic corrections post-LASIK by 6 months or when compared with PRK in virgin eyes. HOA may render hPRK-PL results less predictable early in the postoperative period. PMID- 27938952 TI - In toto extraction of spontaneous conjunctival cysts without incision under slit lamp microscopic view. AB - OBJECTIVE: We describe a technique for the in toto extraction of spontaneous conjunctival cysts without incision under slit-lamp microscopic view. DESIGN: Interventional case series. PARTICIPANTS: Eleven eyes of 11 patients. METHODS: This was a multicentre study. Selection criterion was symptomatic conjunctival spontaneous cysts. Topical anaesthesia was applied, and the conjunctival cyst was extracted with a 26-gauge * 0.5-inch needle attached to a 1-mL disposable syringe. The bevel of the needle was oriented toward the surgeon, and it was inserted into the conjunctival cyst. The surgeon then pulled the plunger to produce negative pressure and sucked the fluid from the cyst. After the fluid was drained, the negative pressure also sucked the inner walls of the cysts into the needle tip. The surgeon slowly pulled the needle tip from the subconjunctival space. In most cases, a stump of the cyst remained at the entry site; it was grasped with forceps and totally extracted. RESULTS: This technique was used on 11 eyes that were followed for 23.2 months. The conjunctival cysts were extracted in toto from all eyes, and a recurrence was observed in 1 eye during the follow up period. In the 1 eye, a small residual cyst recurred, and it was extracted by the same technique. CONCLUSIONS: This method of extracting conjunctival cysts is indicated for spontaneous conjunctival cysts that are considered to be free from adhesion to the surrounding tissue. It is an easy and minimally invasive method of extraction under a slit-lamp microscope without incision. PMID- 27938953 TI - Frequency of unplanned interventions in patients attending for a presumed routine glaucoma follow-up appointment. AB - OBJECTIVE: To determine the frequency of patient visits in which an unplanned treatment modification was required in chronic patients attending a glaucoma clinic for routine follow-up and to identify the treatment interventions most commonly employed. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: A total of 630 previously stable patients attending a glaucoma clinic for routine follow-up. METHODS: This was a single-centre survey of all eligible patients returning to an academic glaucoma clinic. Data regarding whether patients' visit remained routine or required intervention, which clinical parameter had changed, and any alterations in treatment regimens were studied. RESULTS: The percentage of patients found to require a change in management was 20.79% (131 of 630 patients); 16.9% were found to have a cause for change because of glaucoma, and the remaining 4% required intervention because of a nonglaucomatous condition. The most common parameter that changed treatment was intraocular pressure (43.87%), followed by visual fields (21.29%). The frequency of abnormal parameters varied within each subtype of glaucoma. The frequency of treatment changes among those with primary open-angle glaucoma was 22.58% compared with 16.5% of glaucoma suspects, 14% of ocular hypertensives, 32% of pseudoexfoliative glaucoma, and 50% of normal tension glaucoma patients. The most common intervention (32.84%) was a change in antiglaucoma medications. The next most frequent interventions were laser procedures (21.90%) and surgery (16.06%). CONCLUSIONS: This study suggests that a significant minority of patients attending a glaucoma clinic for a routine appointment require treatment modification. PMID- 27938954 TI - Prospective observation of filtration blebs in high-risk eyes with limbal-based conjunctival flap. AB - OBJECTIVE: To evaluate time-dependent changes in filtering bleb parameters using 3-dimensional anterior segment optical coherence tomography (3-D AS-OCT) in high risk eyes after a limbal-based trabeculectomy procedure. DESIGN: Prospective, observational study. PARTICIPANTS: Twenty-three patients who underwent uncombined limbal-based trabeculectomy surgery and who also had a history of prior intraocular surgery. METHODS: Of 23 eyes, 15 eyes were followed for 1 year without additional glaucoma surgeries, and their bleb parameters were measured 0.5, 3, 6, and 12 months after the trabeculectomy using 3-dimensional anterior segment optical coherence tomography. The correlations of these parameters to other clinical data were investigated. RESULTS: Statistical analysis showed significant changes in the bleb wall thickness (0.7 +/- 0.4 mm vs 0.4 +/- 0.2 mm; p = 0.007) and fluid cavity height (0.3 +/- 0.2 mm vs 0.7 +/- 0.4 mm; p = 0.005) between 0.5 and 3 months only. The width of the filtration openings at 0.5 months after trabeculectomy (2.1 +/- 1.0 mm) was significantly associated with the intraocular pressure at 12 months (15.1 +/- 5.7 mm Hg; R2 = 0.37, t = -2.65, and p = 0.021). CONCLUSIONS: The width of the filtration opening in the early stage may be a prognostic factor for long-term intraocular pressure control. PMID- 27938955 TI - Limbus-insertion distance of superior rectus in primary angle closure glaucoma: an anterior segment OCT study. AB - OBJECTIVE: To compare the distance from the corneoscleral limbus to the insertion site of the superior rectus of primary angle-closure glaucoma (PACG) patients with normal controls and to identify potential characteristics associated with limbus-insertion distance. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 92 subjects (eyes) were enrolled in the study: 35 were nonglaucoma controls and 57 were PACG patients. METHODS: The limbus-insertion distance of the superior rectus was measured by anterior segment optical coherence tomography (AS-OCT) and intraoperative surgical caliper. The anterior chamber parameters were also measured using AS-OCT to identify potential characteristics associated with limbus-insertion distance. RESULTS: The limbus-insertion distance of the superior rectus was 0.40 +/- 0.08 mm shorter in the PACG group than in the normal control group (p < 0.001). Anterior segment parameter values, including anterior chamber depth (ACD), anterior chamber width (ACW), anterior chamber area (ACA), and anterior chamber volume (ACV), were smaller in the PACG group than in the normal control group, but the lens vault was larger (all p < 0.001). A shorter limbus insertion distance of the superior rectus was significantly associated with shorter axial length and "crowded" angle (smaller ACD, ACW, ACA, and ACV) (all p < 0.05). CONCLUSIONS: This is the first study to demonstrate that the limbus insertion distance of the superior rectus was shorter in PACG eyes than in normal eyes. The shorter limbus-insertion distance may be another anatomic characteristic of PACG eyes. PMID- 27938956 TI - Improvement of the visual field index in clinical glaucoma care. AB - OBJECTIVE: This article investigates the prevalence and attributes of patients with open-angle glaucoma who exhibit improvement of visual field loss in a clinical setting. DESIGN: We conducted a retrospective chart review of patients in a clinical glaucoma practice. PARTICIPANTS: We identified 719 glaucoma patients with at least 5 SITA strategy visual field tests and a minimum continuous follow-up period of 5 years. METHODS: The change in the slope of the visual field index (VFI) over time was illustrated using histogram analysis for the study eye with the worst VFI at baseline. Multiple variables were analyzed to determine their impact on rates of visual field progression, including sex, age, disease staging, intraocular pressure (IOP), and incisional surgeries. Eyes with severe nonophthalmic and ophthalmic comorbidities were excluded. RESULTS: Considering 582 eligible eyes, 232 (39.9%) showed significantly positive slopes of the VFI as a function of time, 76 (13.1%) showed nonsignificant slopes, and 276 (47.4%) showed significantly negative slopes. In all, 10 eyes (1.7%) demonstrated VFI slope improvement of >=2% per year, whereas 21 (3.6%) demonstrated VFI slope reduction >=2% per year. More advanced disease stage was significantly associated with a negative VFI slope (p < 0.0001). Trabeculectomy and poor compliance were not associated with a negative VFI slope, whereas cataract surgery correlated with higher odds of a negative VFI slope (p = 0.048). CONCLUSIONS: In a clinical setting, a significant VFI improvement over time was observed over an interval of greater than 5 years. PMID- 27938957 TI - Socioeconomic status and utilization of amblyopia services at a tertiary pediatric hospital in Canada. AB - OBJECTIVE: To evaluate whether socioeconomic status is associated with equal utilization of amblyopia services at The Hospital for Sick Children (SickKids), a pediatric tertiary hospital in Canada. DESIGN: This is a retrospective, cross sectional study. PARTICIPANTS: The medical records of children aged under 7 years diagnosed with amblyopia at SickKids from 2007 to 2009 were reviewed. METHODS: Socioeconomic status was derived from patients' residential postal codes through linking with income data in the 2006 Canadian census report. Patients were divided into 5 income quintiles to compare with amblyopia service utilization. The main outcome measure was the observed distribution of amblyopia patients by socioeconomic status versus the expected distribution of 20% for each quintile. RESULTS: The analyses included 336 patients. Children with amblyopia at SickKids were more likely to come from the richest neighbourhood (32.5%), whereas children from each of the 3 lowest quintiles (14.6%-15.5%) were less likely to present at SickKids. These results differed significantly from the expected 20% for each quintile (p < 0.0001). All types of amblyopia were significantly under represented for children from the lower socioeconomic groups. When analyses were stratified by travel distance to the hospital, a significant inequality between the lower and higher income quintiles remained for nonmetropolitan Toronto patients, but not for metropolitan Toronto patients. CONCLUSION: Despite a publicly funded health-care system in Canada, children from lower socioeconomic neighbourhoods in distant areas utilize the amblyopia services in a tertiary pediatric centre less often than those from higher socioeconomic status. PMID- 27938958 TI - Anterior ischemic optic neuropathy and hematologic malignancy: a systematic review of case reports and case series. AB - OBJECTIVE: Demographic and clinical characteristics associated with nonarteritic anterior ischemic optic neuropathy (NAION) are well described. Patients with hematologic neoplasms may share some of these characteristics, and it may be useful clinically to better understand this set of patients. Our objective is to review systematically the characteristics of patients with both hematologic malignancies and NAION. DESIGN: Systematic review. PARTICIPANTS: Patients with NAION diagnosis related in time to a hematologic neoplasm. METHODS: Data sources for the study included MEDLINE, Web of Science, LILACS, SciELO, and OpenGrey. The study eligibility criteria included case reports and case series. RESULTS: We found 261 records, with 15 studies included plus our case report. A total of 19 patients (8 female) with mean age of 54.6 years (range, 12-87) were analyzed: 37% (7) non-Hodgkin lymphoma; 26% (5) myeloproliferative neoplasms; 21% (4) myelodysplasia; 16% (3) leukemias. The limitations included verification bias, inability to test statistical association between NAION and hematologic neoplasms, the small number of cases, and confounding factors related to medical history and specific interventions in each case limited the robustness of our conclusions. CONCLUSIONS: Our results identified the characteristics of patients with NAION and hematologic neoplasms related in time. Additional observational studies may enlighten the importance of looking for evidence of an occult neoplastic disorder in patients presenting with NAION. A prompt diagnosis would be of invaluable significance for the best management, in terms of follow-up and therapeutics. PMID- 27938959 TI - Six-year prevalence and incidence of diabetic retinopathy and cost-effectiveness of tele-ophthalmology in Manitoba. AB - OBJECTIVE: The purpose of this study was to evaluate the diabetic retinopathy (DR) tele-ophthalmology screening program in Manitoba to determine prevalence and incidence of DR, as well as to estimate the program's cost-effectiveness. DESIGN: Retrospective chart review. PARTICIPANTS: A total of 4676 patients with type 2 diabetes examined 9334 times from 2007 to 2013. METHODS: Focused ophthalmic histories were recorded and examinations were performed by trained nurses, including visual acuities, intraocular pressure, and mydriatic 7 standard field stereoscopic fundus photography. Images were evaluated by retinal specialists according to the Early Treatment of Diabetic Retinopathy Study criteria. DR prevalence and incidence were then calculated during the study period. Cost effectiveness was estimated by comparing the cost of running the tele ophthalmology program compared with the cost of screening the same volume of patients in-office. RESULTS: The average prevalence of any DR in each year was 25.1%. The cumulative incidence of DR across 6 years was 17.1% (95% CI, 15.4% 18.7%). The average savings per tele-ophthalmology examination was $1007. CONCLUSIONS: DR is highly prevalent among the studied population. Tele ophthalmology provides a cost-effective means of monitoring patients as well as identifying new or treatable disease. PMID- 27938960 TI - Assessing a narrated white board animation as part of the consent process for intravenous fluorescein angiography: a randomized educational study. AB - OBJECTIVE: To determine if a narrated white board animation (nWBA) video as part of the consent process for intravenous fluorescein angiography (IVFA) improves patient comprehension compared with a standard consent process. DESIGN: Prospective, randomized study. PARTICIPANTS: Patients undergoing an initial IVFA investigation. METHODS: Three groups of 26 patients (N = 78) naive to the IVFA procedure were included. Groups 1 and 2 consisted of patients undergoing IVFA for diagnostic purposes. Group 1 received the IVFA information via standard physician patient interaction to obtain standard consent. Group 2 received IVFA information by watching an nWBA explaining the purpose, method, and risks of the diagnostic test to obtain informed consent. Group 3 comprised patients who were not scheduled to undergo IVFA. This group was exposed to both the standard and nWBA consent. All groups completed a 6-question knowledge quiz to assess retained information and a survey to reflect on the consent experience. RESULTS: Participants receiving information via standard physician-patient interaction to obtain informed consent had a lower mean knowledge score (4.38 out of 6; 73%) than participants receiving the information to obtain consent via nWBA (5.04 out of 6, 84%; P = 0.023). Of participants receiving both forms of information (group 3) to obtain informed consent, 73% preferred the nWBA to the standard consent process. CONCLUSIONS: Participants receiving consent information for an IVFA diagnostic test via nWBA have better knowledge retention regarding the IVFA procedure and preferred this medium compared with participants receiving the standard physician-patient interaction for obtaining consent. Incorporation of multimedia into the informed consent process should be explored for other diagnostic tests. PMID- 27938961 TI - Clinical predictors of positive temporal artery biopsy. AB - OBJECTIVE: We investigated the ability of known clinical signs and symptoms, as well as common laboratory tests, to correctly predict a positive temporal artery biopsy. DESIGN: A prospective cohort study. PARTICIPANTS: Consecutive patients in a tertiary referral centre undergoing temporal artery biopsy. METHODS: Clinical information was collected using a predesigned questionnaire. Pathology results and laboratory information were collected from digital patient records. MAIN OUTCOME MEASURE: The predictive value of clinical signs, symptoms, and laboratory values of a positive temporal artery biopsy. RESULTS: Over a 3-year period, 259 patients were enrolled and 251 patients were analyzed. Sixty-one patients had a positive biopsy. Clinical features most predictive of a positive biopsy were jaw claudication (positive likelihood ratio [LR+] 2.31) and abnormal temporal artery pulse (LR+ 2.62). Receiver operating characteristic curves generated for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelets values showed an area under curve (AUC) value of 0.71, 0.75, and 0.76, respectively. The initiation of steroids decreased the diagnostic utility of the ESR, CRP, and platelets values (AUC = 0.58, 0.61, and 0.63, respectively). CONCLUSIONS: A variety of clinical signs and symptoms were observed in patients referred for a temporal artery biopsy. Clinical signs and symptoms were less accurate in predicting a positive biopsy than laboratory tests. No combination of clinical signs and symptoms tested was able to predict giant cell arteritis with the certainty necessary to justify or withhold long-term steroid therapy. PMID- 27938962 TI - Histopathological changes in involutional lower eyelid entropion: the tarsus is thickened! AB - OBJECTIVE: Evaluation of histopathological changes in lower eyelid involutional entropion. DESIGN: Case-control, comparative study at a single institution. PARTICIPANTS: A total of 20 consecutive patients with previously untreated involutional lower eyelid entropion and 20 matching patients with lateral lower eyelid basal cell carcinoma (BCC). METHODS: Patients with involutional entropion were operated using our modified surgical method, and patients with BCC underwent full-thickness pentagonal excision with 3-mm surgical margins. Histopathological analysis of the full-thickness eyelid specimens of both groups included measurements of tarsal thickness and height, thickness of the pretarsal orbicularis oculi muscle, diameter of muscle fibres, and qualitative changes in lower eyelid retractor attachment. RESULTS: The tarsus was significantly thicker in the entropion group (p = 0.006). The mean tarsal thickness was 1.40 +/- 0.32 mm, whereas in the BCC group it was 1.16 +/- 0.19 mm. There was no statistically significant difference in the tarsal height and the thickness of the pretarsal orbicularis oculi muscle between the 2 groups. In the entropion group, 60% of the lids had total and 35% partial dehiscence of the retractor, whereas in the BCC group, dehiscence was found in only 45% of the lids. The difference was statistically significant (p = 0.002). CONCLUSIONS: To the best of our knowledge, this is the first histopathological study documenting thickening of the tarsus in involutional lower eyelid entropion. Moreover, dehiscence of the lower eyelid retractor was proven histopathologically in 95% of the entropic lids. With this in mind, correction of vertical instability should be mandatory in involutional lower eyelid entropion repair. PMID- 27938963 TI - Successful treatment of methicillin-resistant Staphylococcus aureus infection associated with Jones tube using vancomycin eye drops and rifampicin. AB - OBJECTIVE: Complications associated with the lacrimal Lester Jones tube have been reported. The infections associated with the tube and proper treatment are not well known. The authors have introduced a successful treatment regimen for persistent methicillin-resistant Staphylococcus aureus (MRSA) periocular infection associated with the lacrimal Lester Jones tube without tube removal. DESIGN: Retrospective case series. PARTICIPANTS: Six patients with MRSA infection associated with the Lester Jones tube without tube removal. METHODS: Four patients had improper tube position with total regurgitation and 2 patients had relative normal tube position with a partial to normal passage, but the tube tip irritated the nasal mucosa wound persistently. In all 6 cases, development of a biofilm on the tube was observed. All cultures were positive for MRSA. RESULTS: All patients were prescribed a combination therapy of topical ocular vancomycin and oral rifampicin before or after the dislocated tube reposition. Periocular symptoms resolved within 1 week, and the biofilm on the tube was gradually reduced during combination therapy. Signs of recurrence of infection were not noted during the follow-up visits. CONCLUSION: Patients showing infection signs associated with the Jones tube need to be examined before complete removal of the infected tube. Medical treatment with vancomycin eye drops combined with oral rifampicin for persistent MRSA infection associated with the Lester Jones tube produced a successful result. Removal of the biofilm on the tube at follow-up visits is important to prevent micro-organisms from dispersing around the tissue. If the Jones tube is dislocated, repositioning is highly recommended to prevent periocular MRSA infection recurrence. PMID- 27938965 TI - Circadian rhythm affects intraocular pressure level after penetrating keratoplasty and Descemet's stripping. PMID- 27938964 TI - Preservative content in generic and brand name glaucoma eye drops. PMID- 27938966 TI - More debate on underemployment of ophthalmologists needed. PMID- 27938967 TI - Re: State-of-the-art: low vision rehabilitation, S. Markowitz, Vol. 51, No. 2, April 2016. PMID- 27938968 TI - Re: State-of-the-art: low vision rehabilitation. PMID- 27938969 TI - Aplastic anemia presenting with bilateral, symmetric preretinal macular hemorrhages. PMID- 27938970 TI - A christmas tree cataract. PMID- 27938971 TI - In-the-bag intraocular lens exchange 13 years after refractive lens extraction. PMID- 27938972 TI - Recurrent hyphema following iStent surgery managed by surgical removal. PMID- 27938973 TI - A case of delayed-onset recurrent hyphema after iStent surgery. PMID- 27938974 TI - Inadvertent implantation of an iStent in the supraciliary space identified by ultrasound biomicroscopy. PMID- 27938975 TI - Adult-onset asthma and periocular xanthogranuloma: A rare case report. PMID- 27938976 TI - Acute visual loss secondary to ruptured sinus mucoceles. PMID- 27938977 TI - Staged endonasal-external resection of esthesioneuroblastoma involving the nasolacrimal duct and lacrimal sac. PMID- 27938978 TI - Comprehensive imaging studies of nasolacrimal duct obstruction secondary to maxillary sinus surgery. PMID- 27938979 TI - Treatment of grade IV diffuse lamellar keratitis with oral doxycycline and topical 10% sodium citrate. PMID- 27938980 TI - Respiratory (choristomatous) cyst of the conjunctiva. PMID- 27938981 TI - Infiltration of hydrogel implant into the sclera with calcification: a case report with histologic findings. PMID- 27938982 TI - Retrobulbar hemorrhage and prasugrel. PMID- 27938983 TI - Acute severe multiorgan dysfunction syndrome with oral acetamiprid poisoning. PMID- 27938984 TI - 1H NMR-based metabolomics analysis of adult zebrafish (Danio rerio) after exposure to diniconazole as well as its bioaccumulation behavior. AB - As a systemic triazole fungicide, limited information is known about diniconazole. In this study, toxicological effects and bioaccumulation behavior of diniconazole in zebrafish were both evaluated to perform an overall assessment of its environmental risk towards aquatic organisms. The 1H NMR-based metabolomics analysis revealed that 70 MUg L-1 diniconazole exposure increased valine, leucine, isoleucine, alanine, lactate and choline, accompanied by decreased glucose, creatine and taurine, in comparison to the control. In the exposure group of 300 MUg L-1 diniconazole, only down-regulated glucose and creatine were observed. The above results indicated that diniconazole disturbed energy metabolism, amino acid metabolism and lipid metabolism. Histological examination showed that the swell and vacuolization in the liver, as well as the reduction of spermatids in the diniconazole exposure groups. No enantioselectivity was observed in the bioaccumulation process of both 70 and 300 MUg L-1 diniconazole exposure groups. The above results play a vital role for a comprehensive environmental assessment of diniconazole. PMID- 27938985 TI - Effects of Perfluorooctane sulfonate on immobilization, heartbeat, reproductive and biochemical performance of Daphnia magna. AB - In recent years, Perfluorooctane sulfonate (PFOS) was widely detected in Yellow Bohai Sea and other areas, causing a series of adverse effects in aquatic organisms. However, present studies of its chronic and acute toxicity on aquatic organisms were far more inadequate. Therefore, in the present study, Daphnia magna was used to investigate PFOS toxicity on their immobilization, heartbeat, reproductive and biochemical performance in acute, subchronic and chronic exposure. The results showed that the 48h-EC50 value for immobilization was 79.35 mg L-1 and the toxicity was classified as intermediate. Heartbeat was significantly stimulated and reproductive parameters were significantly suppressed by PFOS, which can be used to reflect the toxicological effects on individuals. On the other hand, intrinsic rate of natural increase was more sensitive than reproductive parameters, which indicated negative responses on population dynamics of Daphnia magna. In addition, there were different degrees of inhibition on GST, CAT and ChE activity, which indicated three types of enzyme could become biomarkers to chronic PFOS exposure. Most of selected and evaluated endpoints have significant sensitivity to PFOS at the concentration of 8 mg L-1 during subchronic and chronic exposure. PMID- 27938986 TI - Reduction in hospital-associated methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus with daily chlorhexidine gluconate bathing for medical inpatients. AB - BACKGROUND: Daily bathing with chlorhexidine gluconate (CHG) is increasingly used in intensive care units to prevent hospital-associated infections, but limited evidence exists for noncritical care settings. METHODS: A prospective crossover study was conducted on 4 medical inpatient units in an urban, academic Canadian hospital from May 1, 2014-August 10, 2015. Intervention units used CHG over a 7 month period, including a 1-month wash-in phase, while control units used nonmedicated soap and water bathing. Rates of hospital-associated methicillin resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) colonization or infection were the primary end point. Hospital-associated S. aureus were investigated for CHG resistance with a qacA/B and smr polymerase chain reaction (PCR) and agar dilution. RESULTS: Compliance with daily CHG bathing was 58%. Hospital-associated MRSA and VRE was decreased by 55% (5.1 vs 11.4 cases per 10,000 inpatient days, P = .04) and 36% (23.2 vs 36.0 cases per 10,000 inpatient days, P = .03), respectively, compared with control cohorts. There was no significant difference in rates of hospital-associated Clostridium difficile. Chlorhexidine resistance testing identified 1 isolate with an elevated minimum inhibitory concentration (8 ug/mL), but it was PCR negative. CONCLUSIONS: This prospective pragmatic study to assess daily bathing for CHG on inpatient medical units was effective in reducing hospital-associated MRSA and VRE. A critical component of CHG bathing on medical units is sustained and appropriate application, which can be a challenge to accurately assess and needs to be considered before systematic implementation. PMID- 27938987 TI - Social cohesion: The missing factor required for a successful hand hygiene program. AB - BACKGROUND: There are limited explorations into hospital staff reactions to automated hand hygiene surveillance or hand hygiene interventions. METHODS: An automated surveillance system with daily feedback and a behavioral intervention component was trialed in 2 wards in an Australian tertiary teaching hospital. After 9 months, 12 clinicians from each ward were interviewed prior to the completion of the trial to explore satisfaction with the system and behavioral component of nudging each other with a reminder to comply. Only on completion of the trial were transcripts analyzed for themes. RESULTS: Staff from the ward with improved compliance described a socially cohesive team with a well-liked nurse unit manager who accessed daily compliance rates and worked with staff to set goals. This contrasted with the ward without improvement in compliance, whose staff described their great reluctance and discomfort to nudge each other to comply and distrust of the authenticity of the rates established from the automated system. CONCLUSIONS: Interventions for improving compliance are more likely to be successful in a ward with a social cohesive team. Patient safety interventions, in the first instance, may benefit from purposeful selection of wards with cohesive teams and skilled leaders who can transform clinicians into early adopters of the program. PMID- 27938989 TI - Geoff Burnstock standing down from Editor-in Chief position. PMID- 27938988 TI - Incidence and risk factors for surgical site infection post-hysterectomy in a tertiary care center. AB - BACKGROUND: Preoperative antibiotic prophylaxis and surgical technological advances have greatly reduced, but not totally eliminated surgical site infection (SSI) posthysterectomy. We aimed to identify risk factors for SSI posthysterectomy among women with a high prevalence of gynecologic malignancies, in a tertiary care setting where compliance with the Joint Commission's Surgical Care Improvement Project core measures is excellent. METHODS: The study was a matched case-control, 2 controls per case, matched on date of surgery. Study time was January 2, 2012-December 31, 2015. Procedures included abdominal and vaginal hysterectomies (open, laparoscopic, and robotic). SSI (superficial incisional or deep/organ/space) was defined as within 30 days postoperatively, per Centers for Disease Control and Prevention criteria. Statistical analysis included bivariate analysis and conditional logistic regression controlling for demographic and clinical variables, both patient-related and surgery-related, including detailed prophylactic antibiotic exposure. RESULTS: Of the total 1,531 hysterectomies performed, we identified 52 SSIs (3%), with 60% being deep incisional or organ/space infections. All case patients received appropriate preoperative antibiotics (timing, choice, and weight-based dosing). Bivariate analysis showed that higher median weight, higher median Charlson comorbidity index, immune suppressed state, American Society of Anesthesiologists score >= 3, prior surgery within 60 days, clindamycin/gentamicin prophylaxis, surgery involving the omentum or gastrointestinal tract, longer surgery duration, >=4 surgeons present in the operating room, higher median blood loss, >=7 catheters or invasive devices in the operating room, and higher median length of hospital stay increased SSI risk (P < .05 for all). Cefazolin preoperative prophylaxis, robot-assisted surgery, and laparoscopic surgery were protective (P < .05 for all). Duration of surgery was the only independent risk factor for SSI identified on multivariate analysis (odds ratio, 3.45; 95% confidence interval, 1.21-9.76; P = .02). CONCLUSIONS: In our population of women with multimorbidity and hysterectomies largely due to underlying gynecologic malignancies, duration of surgery, presumed a marker of surgical complexity, is a significant SSI risk factor. The choice of preoperative antibiotic did not alter SSI risk in our study. PMID- 27938990 TI - Effect of Low-Energy Linear Shockwave Therapy on Erectile Dysfunction-A Double Blinded, Sham-Controlled, Randomized Clinical Trial. AB - INTRODUCTION: Previous studies have shown that focal low-energy extracorporeal shockwave therapy (Li-ESWT) can have a positive effect in men with erectile dysfunction (ED). Linear Li-ESWT (LLi-ESWT) for ED has not been previously assessed in a randomized trial. AIM: To evaluate the treatment outcome of LLi ESWT for ED. METHODS: Men with ED (n = 126) and a score lower than 25 points on the International Index of Erectile Function erectile function domain (IIEF-EF) were included. Subjects were allocated to receive LLi-ESWT once a week for 5 weeks or sham treatment once a week for 5 weeks. After a 4-week break, the two groups received active treatment once a week for 5 weeks. Subjects completed the IIEF, Erection Hardness Scale (EHS), Sexual Quality of Life-Men, and the Erectile Dysfunction Inventory of Treatment Satisfaction at baseline, after 9 weeks, and after 18 weeks. MAIN OUTCOME MEASURES: The primary outcome measurement was an increase of at least five points on the IIEF-EF score. The secondary outcome measurement was an increased EHS score to at least 3 in men with a score no higher than 2 at baseline. Data were analyzed by linear and logistic regression. RESULTS: Mean IIEF-EF scores were 11.5 at baseline (95% CI = 9.8-13.2), 13.0 after five sessions (95% CI = 11.0-15.0), and 12.6 after 10 sessions (95% CI = 11.0-14.2) in the sham group and correspondingly 10.9 (95% CI = 9.1-12.7), 13.1 (95% CI = 9.3-13.4), and 11.8 (95% CI = 10.1-13.4) in the ESWT group. Success rates based on IIEF-EF score were 38.3% in the sham group and 37.9% in the ESWT group (odds ratio = 0.95, 95% CI = 0.45-2.02, P = .902). Success rates based on EHS score were 6.7% in the sham group and 3.5% in the ESWT group (odds ratio = 0.44, 95% CI = 0.08-2.61, P = .369). A limitation of this study is that device settings (number of shockwaves and penetration depth) were estimated based on an existing trial on focused ESWT. CONCLUSION: No clinically relevant effect of LLi ESWT on ED was found. PMID- 27938991 TI - Successful Placement of Penile Prostheses in Men With Severe Corporal Fibrosis Following Vacuum Therapy Protocol. AB - INTRODUCTION: Penile prosthesis (PP) implantation in men with severe corporal fibrosis presents a significant surgical challenge. For the past 7 years, we have used a novel, preoperative protocol of daily vacuum therapy (VT) using a vacuum erection device for at least 3 months before PP placement for men with severe corporal fibrosis from PP infection or ischemic priapism. AIM: To evaluate this standardized preoperative regimen. METHODS: We retrospectively reviewed all patients who underwent three-piece PP placement at our institution from 2008 through 2015. Of these, 13 men had severe corporal fibrosis from prior PP infection (11 of 13) or prolonged ischemic priapism (2 of 13). Our protocol included VT for 10 to 15 minutes at least two times daily in all patients for at least 3 months (mean = 3.5 months). MAIN OUTCOME MEASURES: We report on our surgical experience and post-VT stretched flaccid penile length (SFPL) compared with baseline SFPL. RESULTS: All 13 men underwent successful three-piece PP placement with standard-size cylinders without additional surgical maneuvers. There was one infection and one erosion requiring revision. Daily average use of VT was 32.5 minutes. SFPL increased 0.92 cm (range = 0-2 cm, SD = 0.76 cm) after VT and three-piece PP placement compared with preoperative SFPL. These men also noted improved quality of life and sexuality as measured by postoperative office interviews. CONCLUSION: The use of VT before surgery appears to result in softening of corporal fibrosis and facilitates placement of a PP regardless of the period from developing corporal fibrosis to starting VT. We strongly recommend preoperative corporal tissue rehabilitation with VT to improve surgical outcomes and to decrease difficulty during PP implantation in men with severe corporal fibrosis. PMID- 27938992 TI - Sexual Sensation Seeking, Sexual Compulsivity, and Gender Identity and Its Relationship With Sexual Functioning in a Population Sample of Men and Women. AB - INTRODUCTION: Despite awareness of the importance of psycho-affective factors in the development of sexual problems, there is a lack of studies exploring the relation of sexual sensation seeking (SSS) and sexual compulsivity (SC) to sexual functioning. Because sex differences in SSS and SC have been reported, gender identity (GI; an individual's own experience of his or her gender that is unrelated to the actual biological sex) might act as a moderator in this relation. AIM: To understand the role of SSS and SC for men and women's sexual functioning and to explore whether these potential associations are moderated by GI. METHODS: A population-based cross-sectional online survey targeted 279 individuals (69.2% women, 30.8% men; mean age = 32 years). Validated questionnaires, including the Sexual Sensation Seeking Scale, the Sexual Compulsivity Scale, the Female Sexual Function Index, the Premature Ejaculation Diagnostic Tool, and the International Index of Erectile Function, were applied. MAIN OUTCOME MEASURES: Variations in SSS and SC and their association with sexual functioning were investigated using Spearman rank correlation. Moderation analyses were conducted using regression models in which the interaction terms between SSS and GI and between SCS and GI as predictors of sexual functioning were included. RESULTS: A statistically significant correlation between SSS and SC could be detected in men and women (r = 0.41 and 0.33, respectively; P < .001 for the two comparisons). In women, higher levels of SSS were associated with higher levels of desire, arousal, lubrication, and orgasm and less sexual pain (P < .05 for all comparisons). No moderating effect of GI could be detected. In men, GI was a significant moderator in the relation between SC and erectile function (beta = 0.47; P < .001) and between SSS and erectile and ejaculatory function (beta = -0.41 and 0.30; P < .001 for the two comparisons). CONCLUSION: The present study is the first to show a link between SSS and SC and sexual functioning. The results might have important clinical implications and can provide useful information for programs aimed at sexual health enhancement. PMID- 27938993 TI - Meta-analysis of 701 published cases of sinonasal neuroendocrine carcinoma: The importance of differentiation grade in determining treatment strategy. AB - The aim of this meta-analysis was to provide treatment guidelines for sinonasal neuroendocrine carcinoma (SNC) by combining all available data in the literature. A literature search for all studies concerning SNC was performed against the MEDLINE and EMBASE databases. Available clinical data was normalized, pooled, and statistically analyzed. A total of 701 cases of SNC were available for analysis, comprising 127 well or moderately differentiated sinonasal neuroendocrine carcinomas (SNEC), 459 sinonasal undifferentiated carcinoma (SNUC) and 115 sinonasal small cell carcinoma (SmCC). Tumor type was the most important predictor of survival, with a 5-year disease-specific survival (DSS) of 70.2% for SNEC, 35.9% for SNUC and 46.1% for SmCC. Tumor stage on presentation was of limited value in predicting survival or response to treatment. Overall, the application of surgery yielded significantly better results (5-year DSS 52.2% versus 30.1%, p<0.001). In SNUC, radiotherapy was a beneficial supplement to surgery (5-year DSS 54.7% versus 15.7%, p=0.027), while radiotherapy as monotherapy performed poorly (5-year DSS 17.9%). Chemotherapy did not appear to contribute to survival. Based on these findings, we can conclude that the most important predictors of survival in SNC are differentiation grade and the associated choice of treatment modality. In contrast to other head and neck cancers, tumor staging appears of limited value in predicting survival or deciding on a treatment strategy. Surgery should be the cornerstone of treatment, supplemented by radiotherapy in poorly differentiated subtypes (SNUC, SmCC). Chemotherapy does not appear to contribute to survival. PMID- 27938994 TI - Expectations and preferences for palliative chemotherapy in head and neck cancers patients. AB - BACKGROUND: Head and neck cancer patients undergoing palliative chemotherapy have a limited overall survival. Expectations and preferences of such patients towards palliative chemotherapy after explanation of disease prognosis and treatment options are unknown. METHODS: This was a single arm, prospective, observational study where newly diagnosed head and neck cancer patients warranting palliative chemotherapy underwent protocol defined counselling. Following counselling, they were administered chemotherapy expectation and preference proforma (CEP). The primary objective of this study was to estimate the percentage of patients opting for an increase in survival as the primary expectation from chemotherapy. RESULTS: We recruited two hundred patients all patients except one answered the CEP. Prolongation of life as the primary expectation from palliative chemotherapy was seen only in 82 patients (41.0%; 95% CI 34.4-47.9%). Symptom relief was the primary expectation or an equally important expectation amongst the remaining 117 patients (58.5%; 95% CI 51.6-65.1%). There was a statistically significant difference between the preferences of patients having a primary expectation of prolongation of life as opposed to symptom relief regarding the minimum expected number of patients need to treat to get prolongation of life (p value -0.00). The minimum expected increment in life expectancy for taking palliative chemotherapy was ">1year" in 190 patients (94.5%; 95% CI 91.5-97.7%). CONCLUSION: The primary expectation from palliative chemotherapy in head and neck cancer patients is not necessarily living longer in all patients. The magnitude of benefit preferred by the patients from chemotherapy far exceeded the current standards for drug approval. PMID- 27938995 TI - CT-based volumetric tumor growth velocity: A novel imaging prognostic indicator in oropharyngeal cancer patients receiving radiotherapy. AB - OBJECTIVES: Volumetric tumor growth velocity (TGV) reflects in vitro tumor aggressiveness, but its prognostic value has not been investigated in vivo. We examined the prognostic impact of TGV on oncologic outcomes in patients with oropharyngeal squamous cell cancer (OSCC). MATERIALS AND METHODS: 101 OSCC patients with two pretreatment CTs with time gap of 2 or more weeks treated at a single institution between 2004 and 2008 were identified. Primary tumor and nodal targets were segmented in scans. Linear growth rates were calculated. Recursive partitioning analysis (RPA) identified cut point associated with outcomes. RESULTS: Median follow-up was 59months (range 7-118). Median primary TGV was 0.65% increase per day (range 0-9.37%). RPA identified TGV cut point associated with local control (LC) of 1% per day. Patients with higher TGV had decreased 5 year LC (73% vs. 98%, p=0.0004), distant control (DC, 62% vs. 91%, p=0.0007), and overall survival (OS, 38% versus 93%, p<0.0001). In multivariate analysis including demographics, tumor stage, subsite, and treatment factors, TGV?1% per day independently predicted worsened LC (p = 0.02), DC (p = 0.003), and OS (p < 0.0001). However, this TGV cutoff was not significantly predictive of LC, DC, or OS for a subset of presumed HPV-positive patients. CONCLUSION: OSCC TGV?1% per day is a substantive negative prognostic indicator for disease control and overall survival, particularly in HPV non-associated tumors. This novel CT-based volumetric assessment of TGV suggests a simple methodology for risk stratification of patients. PMID- 27938996 TI - HPV knowledge gaps and information seeking by oral cancer patients. AB - OBJECTIVES: The incidence of human papillomavirus (HPV) positive oral squamous cell carcinoma (OSCC) continues to increase over time, challenging healthcare providers to address their patients' HPV-related concerns. MATERIALS AND METHODS: This prospective study assessed health literacy, HPV knowledge, utilization and trust in information sources among patients with incident HPV-positive or HPV negative OSCC diagnosed at the Ohio State University from 2011 to 2015. Health literacy was assessed with a standardized scale. Additional questions evaluated HPV knowledge (including transmission, prevalence, health consequences and treatment), the frequency and type of information sources sought, and trust in those sources. RESULTS: Surveys were collected from 372 OSCC cases (HPV-positive, n=188; HPV-negative, n=184). Despite high mean health literacy scores, only 45.2% of HPV-related knowledge questions were answered correctly. HPV was known to be a sexually transmitted infection and a cause of cervical and anal cancer by 66.0%, 56.5% and 15.2%, respectively. In all domains, cases with HPV-positive OSCC were significantly more informed than HPV-negative cases (for all, p<0.01). Only 52.7% and 56.2% of patients with HPV-positive OSCC felt they knew enough to be comfortable discussing HPV with their doctor or sexual partner, respectively. The most frequently used information source was the internet (80.9%), which ranked 8th in trust of 15 possible sources. Although most (95.5%) patients trusted information from their doctors, only 37.9% used doctors as an information source. CONCLUSIONS: Doctors are a highly trusted, but infrequent utilized, information source and should facilitate patient access to high-quality HPV information sources. PMID- 27938997 TI - Circulating miRNAs from blood, plasma or serum as promising clinical biomarkers in oral squamous cell carcinoma: A systematic review of current findings. AB - The purpose of this systematic review was to summarize current findings on the use of circulating miRNAs from blood, serum and plasma as cancer biomarkers in patients with oral squamous cell carcinoma. Studies were gathered after searching four different electronic databases: PUBMED, SCOPUS, Cochrane Library and Web of Science. Additional search was carried out through cross check on bibliography of selected articles. After the selection process made by two of the authors, 16 articles met the inclusion criteria and were included in the review. Results showed that circulating miRNAs from blood, serum or plasma represent promising candidates as cancer biomarkers in patients suffering from oral cancer. The possibility to predict recurrences and metastases through follow-up quantification of candidate miRNAs represents another potential feature to be addressed in future studies. However, methodological standardization and uniform sampling is needed to increase the power and accuracy of results. PMID- 27938998 TI - Epidermal growth factor receptor (EGFR) pathway polymorphisms as predictive markers of cetuximab toxicity in locally advanced head and neck squamous cell carcinoma (HNSCC) in a Spanish population. AB - OBJECTIVES: To examine the relationship between polymorphisms of the epidermal growth factor receptor (EGFR) pathway and toxicity in head and neck squamous cell carcinoma (HNSCC) patients treated with cetuximab. MATERIAL AND METHODS: Multicenter, retrospective, observational pilot study which included 110 patients with histologically-confirmed human papillomavirus (HPV) negative HNSCC in locally advanced stages (III-IVA-B) and who were treated with chemotherapy and radiotherapy plus cetuximab between 2003 and 2013. Genetic analyses for single nucleotide polymorphisms (SNP) in genes EGFR, CCDN1, FCGR2A, FCGR3A and KRAS-LCS6 were performed though available allelic discrimination assay and/or polymerase chain reaction-restriction fragment length polymorphism methods. RESULTS: Acneiform rash was observed in 55.5% of patients, dry skin in 45.5% and pruritus in 20.9%. A significant association with dry skin and global cetuximab-related toxicity was observed for the KRAS-LCS6 (rs61764370) variant (p<0.05); carriers of the G allele (genotypes TG+GG) in the dominant model were observed to have a decreased susceptibility of developing dry skin (OR=0.287 [95%CI=0.119-0.695]). Carriers of the A (GA+AA) allele for EGFR (rs2227983) showed a decreased risk of suffering from pruritus (OR=0.345 [0.124-0.958]). Similarly, KRAS (rs1801274) was related with lower global cetuximab-related toxicity (OR=0.266 [0.114-0.622]). CONCLUSION: This pilot study provides preliminary evidence supporting genetic variation of EGFR (rs2227983), KRAS (rs61764370) and FCGR2A (rs180127) as useful biomarkers for predicting reduced skin toxicity in HNSCC patients treated with a cetuximab-based therapy. Alternative therapeutic options should be explored for these patients. PMID- 27938999 TI - Overcoming radioresistance in head and neck squamous cell carcinoma. AB - Radiation therapy plays an essential role in the treatment of head and neck squamous cell carcinoma (HNSCC), yet therapeutic efficacy is hindered by treatment-associated toxicity and tumor recurrence. In comparison to other cancers, innovation has proved challenging, with the epidermal growth factor receptor (EGFR) antibody cetuximab being the only new radiosensitizing agent approved by the FDA in over half a century. This review examines the physiological mechanisms that contribute to radioresistance in HNSCC as well as preclinical and clinical data regarding novel radiosensitizing agents, with an emphasis on those with highest translational promise. PMID- 27939000 TI - A comparison of mandible preservation method and mandibulotomy approach in oral and oropharyngeal cancer: A meta-analysis. AB - OBJECTIVE: This study aims to compare the prognoses outcomes of mandibular preservation method (MPM) and the mandibulotomy approach (MLA) in oral and oropharyngeal cancer (OOPC) patients. METHOD: We searched PubMed, Web of Science, EMBASE, Chinese BioMedical Literature Database (CBM), Cochrane Library, and clinicaltrials.gov up to September 2016 to identify the studies that compared the prognoses of the MPM versus the MLA in OOPC patients. Two authors individually extracted the data and performed quality assessment. The surgical margins, overall survival rate, total and local recurrence rates, fistula formation, and other functional outcomes were evaluated. RESULT: Six studies with 309 patients were included in our analysis. No significant difference was found regarding the surgical margins, overall survival rate, total and local recurrence rates, and speech and tongue movement between the MPM and MLA groups. However, the MPM group showed a significantly lower fistula formation rate than the MLA group after the operation. CONCLUSION: These findings suggest that the MPM may provide a similar clinical outcome to the MLA, but that the MPM has a lower complication rate in the treatment of OOPC patients. PMID- 27939001 TI - The association between human papillomavirus and oropharyngeal squamous cell Carcinoma: Reviewed according to the Bradford Hill criteria for causality. AB - There is emerging evidence of the association between human papillomavirus and a subset of head and neck cancers. However, the role of human papillomavirus as a causal factor is still debated. This review addresses the association between human papillomavirus and oropharyngeal squamous cell carcinoma using the Bradford Hill criteria. The strength of the association is supported by, detection of human papillomavirus infection and antibodies prior to oropharyngeal squamous cell carcinoma. This is furthermore reinforced by the absence of human papillomavirus DNA in healthy tonsils. The association is geographically consistent throughout the economically developed world. The presence and integration of high-risk human papillomavirus genome in tonsillar tumours, and expression of viral oncogenes, are specific and plausible. Analogous to human papillomavirus in cervical cancer, the rising incidence in human papillomavirus positive oropharyngeal squamous cell carcinoma is associated with sexual behaviour. These associations have been repeatedly observed and are in accordance with our current knowledge. The time relation between cause and effect remains the main challenge, due to the lack of well-defined premalignant lesions. However, a causal relationship between human papillomavirus infection and oropharyngeal squamous cell carcinoma seems evident. PMID- 27939003 TI - Erratum. PMID- 27939004 TI - Access to Health Care. PMID- 27939002 TI - Individualized risk prediction of outcomes for oral cavity cancer patients. AB - BACKGROUND: Optimal management of oral cancer relies upon accurate and individualized risk prediction of relevant clinical outcomes. Individualized prognostic calculators have been developed to guide patient-physician communication and treatment-related decision-making. However it is critical to scrutinize their accuracy prior to integrating into clinical care. AIM: To compare and evaluate oral cavity cancer prognostic calculators using an independent dataset. METHODS: Five prognostic calculators incorporating patient and tumor characteristics were identified that evaluated five-year overall survival. A total of 505 patients with previously untreated oral cancer diagnosed between 2003 and 2014 were analyzed. Calculators were applied to each patient to generate individual predicted survival probabilities. Predictions were compared among prognostic tools and with observed outcomes using Kaplan-Meier plots, ROC curves and calibration plots. RESULTS: Correlation between the five calculators varied from 0.59 to 0.86. There were considerable differences between individual predictions from pairs of calculators, with as many as 64% of patients having predictions that differed by more than 10%. Four of five calculators were well calibrated. For all calculators the predictions were associated with survival outcomes. The area under the ROC curve ranged from 0.65 to 0.71, with C-indices ranging from 0.63 to 0.67. An average of the 5 predictions had slightly better performance than any individual calculator. CONCLUSION: Five prognostic calculators designed to predict individual outcomes of oral cancer differed significantly in their assessments of risk. Most were well calibrated and had modest discriminatory ability. Given the increasing importance of individualized risk prediction, more robust models are needed. PMID- 27939005 TI - Oxidative stress signaling: Too much of a good thing. PMID- 27939006 TI - Colorectal cancer: Quality of surgical care in Michigan. AB - OBJECTIVE: Surgery remains the cornerstone therapy for colorectal cancer (CRC). This study assesses CRC quality measures for surgical cases in Michigan. METHODS: In this retrospective cohort study, processes of care and outcomes for CRC resection cases were abstracted in 30 hospitals in the Michigan Surgical Quality Collaborative (2014-2015). Measures were case-mix and reliability adjusted, using logistic regression models. RESULTS: For 871 cases (640 colon cancer, 231 rectal cancer), adjusted morbidity (27.4%) and mortality rates (1.5%) were low. Adjusted process measures showed gaps in quality of care. Mesorectal excision was documented in 59.4% of rectal cancer (RC) cases, 65% of RC cases had sphincter preserving surgery, 18.7% of cases had < 12 lymph nodes examined, 7.9% had a positive margin, 52.1% of stage II/III RC cases had neoadjuvant therapy, and 36% of ostomy cases had site marking. CONCLUSION: This study finds gaps in quality of care measures for CRC, suggesting opportunity for regional quality improvement. PMID- 27939007 TI - A novel Minute Feedback System for medical students. AB - BACKGROUND: Medical students often report a lack of timely, useful feedback during clerkship rotations. The purpose of this study was to develop a novel Minute Feedback System and determine whether it would generate frequent, high quality, documented feedback for students during the third year surgery clerkship. METHODS: The Minute Feedback System was created using the Qualtrics(c) survey software platform and piloted with surgery clerkship students. These students were surveyed about the frequency and quality of feedback and their overall rating of the surgery clerkship and compared to students who did not use the feedback system. RESULTS: The initial pilot of the Minute Feedback System involved 6/34 M3 surgery clerkship students and generated a total of 70 unique comments from faculty and residents over 3 weeks. When the 6 pilot students were compared to the 28 students without access to the Minute Feedback System, they respectively rated the frequency of feedback 4.50 vs 2.83 (p < 0.01); the quality of feedback 4.70 vs 3.33 (p < 0.01) and the overall rating of the surgery clerkship 4.67 vs 4.05 (p < 0.01) higher. The system was then made available to all students on the M3 surgery clerkship (n = 31) over the subsequent 2 month rotation. 354 unique feedback comments were generated from 399 student requests (89% response rate). Students using the Minute Feedback System (n = 31) compared to students in the previous academic year without (n = 170) rated the quality of feedback (3.76 vs 3.4, p < 0.01), that feedback was provided during clerkship (100% vs 90%, p < 0.01) and the overall quality of the clerkship (3.94 vs 3.87, p = 0.2) higher. CONCLUSION: The novel Minute Feedback System allows for frequent, timely, useful and documented feedback to medical students. PMID- 27939008 TI - Is routine use of adjuvant chemotherapy for rectal cancer with complete pathological response justified? AB - BACKGROUND: Patients with locally advanced rectal cancer (LARC) receiving neoadjuvant chemoradiation (nCRT) can have a complete pathologic response (pCR), and are given postoperative adjuvant chemotherapy (ACT). METHODS: A prospectively maintained outcomes database was queried for patients who had pCR to nCRT for LARC from 2000 to 2012. Local recurrence and survival were analyzed according to whether patients received ACT. RESULTS: We identified 139 patients and excluded 9 due to lack of follow-up. Mean age was 58.9 +/- 11.8 years. 83 patients (63.8%) did not receive ACT (Group A) and 47 (36.2%) did (Group B). Mean follow-up was 5.7 +/- 3 and 5.6 +/- 3.5 years for Groups A and B respectively (p = 0.51). Groups were comparable in age, gender, tumor differentiation, and clinical staging. There were no differences in oncological outcomes. CONCLUSION: Avoiding routine use of ACT in patients with a pCR may be considered. Further justification of this approach warrants prospective randomized studies. PMID- 27939009 TI - [Care pathways before diagnosis in children and adolescents with malignancies]. AB - OBJECTIVE: to describe medical care pathways between first symptoms and first oncologic consultation in children and adolescents with solid cancers in order to analyze a possible relationship between delayed diagnosis and its potential consequences. METHODS: Retrospective study on patients aged less than 25 years at first consultation in the oncology department of pediatric, adolescent and young adult in Institut Curie during one year. Were collected data on cancer characteristics, components of care pathways, and sociodemographic parents' characteristics. RESULTS: Hundred and six patients were selected, with median age of 6 years. Most represented tumor was low-grade cerebral tumor (17.0%). Pain was the most frequent type of disorder observed as first sign (34.3% of patients). First signs were unspecific in only 27.6% of cases. Most patients were first seen by a general practitioner (29.3%). Median total time to diagnosis was one month [ranges: 0-64]. Median number of consultations before referral to oncology expert was 2 [0-7]. Retrospective analysis found a possible delayed diagnosis in 44.3% of patients, with potential vital and functional risks estimated respectively at 14.1 and 20.7% of overall population. Time to diagnosis was shorter if father was of foreign nationality vs. French (34 days vs. 72 days, P<0.05), and longer if parents were separated (74.5 days vs. 42.5 days, P<0.03). CONCLUSIONS: Overall time to diagnosis is quite fast, even if first signs of pediatric cancers are very polymorphic. Some medical and sociodemographic factors could influence characteristics of care pathways. PMID- 27939010 TI - Addition of Video-Assisted Thoracoscopic Surgery to the Treatment of Flail Chest. AB - BACKGROUND: Video-assisted thoracoscopic surgery (VATS) is increasingly used in chest trauma for diagnostic and therapeutic purposes. In this report we describe our single-institutional experience with VATS in the surgical treatment of patients with flail chest after high-energy trauma. METHODS: From January 2013 to July 2014, 15 patients with flail chest after high-energy trauma were treated in our hospital. The Injury Severity Score (ISS) ranged from 16 to 44. Rib fixation was performed with precontoured plates or intramedullary splints. In all, patients we additionally used VATS to explore the thoracic cavity and evacuate any hemothorax. RESULTS: In 10 patients a prominent hemothorax was present, which needed evacuation. The median operative time was 120 minutes (range, 60 to 180 minutes), with a median blood loss of 150 mL (range, <100 to 400 mL). The mean stay in the intensive care unit was 5.27 days (SD 6.79). Ten patients were extubated directly after operation in the operating room. The other 5 patients were extubated after 1 to 13 days. The mean duration of mechanical ventilation was 2 days (SD 4.17). No patient required a tracheostomy. Three patients had minor postoperative adverse events. All patients were discharged after 6 to 44 days (mean, 11.9 hospitalization days) (SD 9.57). CONCLUSIONS: We believe VATS is effective and safe and can be of additional value by providing the possibility to adjust the planned incision for rib fixation and decrease the area of muscle destruction. Additional pulmonary or mediastinal pathologic conditions can be identified and complete evacuation of hemothorax can be achieved simultaneously. PMID- 27939011 TI - Surgery and Surgical Consult Rates for Early Stage Lung Cancer in Ontario: A Population-Based Study. AB - BACKGROUND: Surgery offers the best chance for survival for early (stage I and II) non-small cell lung cancer (NSCLC), but worldwide resection rates range from 49% to 77%. We investigated factors that may play a role in resection rates. METHODS: Using administrative data, new diagnoses of NSCLC from 2010 through 2012 were captured. The rate of surgical consultation and resection overall and by age group were determined, as well as rates of pulmonary function testing and radiation therapy. RESULTS: Of 4,309 persons diagnosed with stage I or II NSCLC between 2010 and 2012, 3,487 (80.9%) received surgical consultations, but only 58.9% (2,539) received surgery. Rates of consultation and surgery decreased with increasing patient age: only 60.3% of patients older than 80 received consultations and 29.9% had resections. Of the 1,770 patients who did not receive surgery, 948 (53.6%) received a surgical consultation, and in this group, 688 (72.5%) were treated with radiation. Of the 822 patients who did not see a surgeon, only 476 (57.9%) were treated with radiation. Pulmonary function testing was performed in 799 (84.3%) of patients who had surgical consults but in only 569 (69.2%) of those who did not see a surgeon. CONCLUSIONS: Resection rates for early lung cancer appear low, which may be partly due to low rates of surgical consultation. Interestingly, patients who are seen by surgeons but who do not receive surgery are more likely to receive radiation than patients who are not referred for surgery. Further research is required to identify factors influencing resection rates. PMID- 27939012 TI - Immunofocusing using conformationally constrained V3 peptide immunogens improves HIV-1 neutralization. AB - V3-directed antibodies are present in practically all HIV-1 infected patients and in individuals vaccinated with gp120. The levels of maternal V3-directed antibodies were recently shown to correlate with reduced mother to child transmission, and V3 IgGs were found to be a negative correlate of risk in the RV 144 human trial. mAb directed to the tip of the V3 are capable of broad neutralization of Tier-1 and some Tier-2 viruses. Here we report an immunofocusing approach using conformationally constrained V3 peptides of different lengths. Immunofocusing with short constrained V3 peptides following immunizations with long constrained V3 peptides resulted in sera with improved neutralization of Tier-1B viruses in comparison with immunizations with the long constrained peptide alone. Immunizations only with the short constrained peptide were ineffective. Our results demonstrate that immunofocusing with constrained V3 peptides of different lengths could improve the induction of HIV-1 neutralizing antibodies. PMID- 27939013 TI - Do antibody responses to the influenza vaccine persist year-round in the elderly? A systematic review and meta-analysis. AB - INTRODUCTION: The influenza vaccine is less immunogenic in older than younger adults, and the duration of protection is unclear. Determining if protection persists beyond a typical seasonal epidemic is important for climates where influenza virus activity is year-round. METHODS: A systematic review protocol was developed and registered with PROSPERO [CRD42015023847]. Electronic databases were searched systematically for studies reporting haemagglutination-inhibition (HI) titres 180-360days following vaccination with inactivated trivalent seasonal influenza vaccine, in adults aged ?65years. Geometric mean titre (GMT) and seroprotection (HI titre ?1:40) at each time point was extracted. A Bayesian model was developed of titre trajectories from pre-vaccination to Day 360. In the meta-analysis, studies were aggregated using a random-effects model to compare pre-vaccination with post-vaccination HI titres at Day 21-42 ('seroconversion'), Day 180 and Day 360. Potential sources of bias were systematically assessed, and heterogeneity explored. RESULTS: 2864 articles were identified in the literature search, of which nineteen met study inclusion/exclusion criteria. Sixteen studies contained analysable data from 2565 subjects. In the Bayesian model, the proportion of subjects seroprotected increased from 41-51% pre-vaccination to 75 78% at seroconversion. Seroprotection subsequently fell below 60% for all serotypes by Day 360: A/H1 42% (95% CI 38-46), A/H3 59% (54-63), B 47% (42-52). The Bayesian model of GMT trajectories revealed a similar pattern. By Day 360, titres were similar to pre-vaccination levels. In the meta-analysis, no significant difference in proportion of subjects seroprotected, 0 (-0.11, 0.11) or in log2GMT 0.30 (-0.02, 0.63) was identified by Day 360 compared with pre vaccination. The quality of this evidence was limited to moderate on account of significant participant dropout. CONCLUSIONS: The review found consistent evidence that HI antibody responses following influenza vaccination do not reliably persist year-round in older adults. Alternative vaccination strategies could provide clinical benefits in regions where year-round protection is important. PMID- 27939014 TI - Immunogenicity and protective efficacy induced by self-amplifying mRNA vaccines encoding bacterial antigens. AB - Nucleic acid vaccines represent an attractive approach to vaccination, combining the positive attributes of both viral vectors and live-attenuated vaccines, without the inherent limitations of each technology. We have developed a novel technology, the Self-Amplifying mRNA (SAM) platform, which is based on the synthesis of self-amplifying mRNA formulated and delivered as a vaccine. SAM vaccines have been shown to stimulate robust innate and adaptive immune responses in small animals and non-human primates against a variety of viral antigens, thus representing a safe and versatile tool against viral infections. To assess whether the SAM technology could be used for a broader range of targets, we investigated the immunogenicity and efficacy of SAM vaccines expressing antigens from Group A (GAS) and Group B (GBS) Streptococci, as models of bacterial pathogens. Two prototype bacterial antigens (the double-mutated GAS Streptolysin O (SLOdm) and the GBS pilus 2a backbone protein (BP-2a)) were successfully expressed by SAM vectors. Mice immunized with both vaccines produced significant amounts of fully functional serum antibodies. The antibody responses generated by SAM vaccines were capable of conferring consistent protection in murine models of GAS and GBS infections. Inclusion of a eukaryotic secretion signal or boosting with the recombinant protein resulted in higher specific-antibody levels and protection. Our results support the concept of using SAM vaccines as potential solution for a wide range of both viral and bacterial pathogens, due to the versatility of the manufacturing processes and the broad spectrum of elicited protective immune response. PMID- 27939015 TI - The importance of the patient voice in vaccination and vaccine safety-are we listening? AB - Much has been written about the patient-physician relationship over the years. This relationship is essential in maintaining trust in the complex arena of modern diagnostic techniques, treatment and prevention, including vaccines and vaccine safety. However, a great deal of this material was written from the viewpoint of clinicians and academics. The patient voice may be positive or negative, fragmented or complex. Information sources are weighed and treated differently, according to the value system and risk perceptions of the individual. In post-trust societies, when people have less confidence in health authorities, communication needs to be more than a paternalistic top-down process. Notions of empowerment and individual patient choice are becoming crucial in medical care. The 'voice of the patient', which includes healthy individuals receiving vaccines, needs to be heard, considered and addressed. With respect to childhood immunizations, this will be the voice of the parent or caregiver. The key to addressing any concerns could be to listen more and to develop a communication style that is trust-based and science-informed. Regulatory agencies are encouraging clinical and patient-reported outcomes research under the umbrella of personalized medicine, and this is an important step forward. This paper attempts to reflect the paradigm shift towards increasing attention to the patient voice in vaccination and vaccine safety. PMID- 27939016 TI - Diagnosing pulmonary embolisms: the clinician's point of view. AB - Pulmonary thromboembolism is common and potentially severe. To ensure the correct approach to the diagnostic workup of pulmonary thromboembolism, it is essential to know the basic concepts governing the use of the different tests available. The diagnostic approach to pulmonary thromboembolism is an example of the application of the conditional probabilities of Bayes' theorem in daily practice. To interpret the available diagnostic tests correctly, it is necessary to analyze different concepts that are fundamental for decision making. Thus, it is necessary to know what the likelihood ratios, 95% confidence intervals, and decision thresholds mean. Whether to determine the D-dimer concentration or to do CT angiography or other imaging tests depends on their capacity to modify the pretest probability of having the disease to a posttest probability that is higher or lower than the thresholds for action. This review aims to clarify the diagnostic sequence of thromboembolic pulmonary disease, analyzing the main diagnostic tools (clinical examination, laboratory tests, and imaging tests), placing special emphasis on the principles that govern evidence-based medicine. PMID- 27939017 TI - Regional analgesia in postsurgical critically ill patients. AB - Regional analgesia intrinsically, based on its physiological effects, is routinely used for the perioperative treatment of pain associated with surgical procedures. However, in other areas such as the non-surgical treatment of acute pain for patients in a critical condition, it has not been subjected to specific prospective studies. If we confine ourselves to the physiological effects of the nerve block, in a situation of stress, the indications for regional anaesthesia in this group of patients extend to the management of a wide variety of medical as well as postsurgical conditions, of trauma patients and of other painful procedures performed in the patient's bed. The critical patient certainly must be analyzed individually as their own primary conditions is of vital importance, as well as any associated conditions they have developed that can potentially increase the risk of systemic toxicity or morbidity, such as, coagulopathies, infection, immunosuppressive states, sedation and problems associated with mechanical ventilation. This review aims to assess the role of regional analgesia in critically ill patients, placing it within the algorithm decision tree of the professional responsible for patients in critical care units, all based on the evidence of potential benefits according to the published literature. PMID- 27939018 TI - Exposure to ambient PM10 and NO2 and the incidence of attention-deficit hyperactivity disorder in childhood. AB - BACKGROUND: Epidemiological studies have implicated air pollution in the causation of neurodevelopmental disorders, including attention-deficit hyperactivity disorder (ADHD), but definitive evidence of this linkage is lacking. OBJECTIVES: We examined the association between cumulative exposure to air pollutants from birth to diagnosis, particularly particulate matter of <10MUm (PM10) and nitric dioxide (NO2), and childhood ADHD. METHODS: We used the National Health Insurance Service-National Sample Cohort (2002-2012), a population-wide health insurance claims dataset. A total of 8936 infants (age 0) born between January 2002 and December 2002 were followed-up for a 10-year period (2003-2012). ADHD was defined as per ICD-10 code F90.0. Exposure levels of PM10 and NO2 were extrapolated using geographic information systems and collated with the subjects' administrative district code, and individual exposure levels assigned. Hazard ratios (HRs) were calculated for the development of ADHD, after adjusting for gender, metropolitan area, income, and history of diseases. RESULTS: During the study period, ADHD occurred in 314 subjects (3.5%). With the increase in 1MUg/m3 of air pollutants, the HRs of childhood ADHD were 1.18 (95% CI: 1.15-1.21) in case of PM10 and 1.03 (95% CI: 1.02-1.04) in case of NO2. Compared with infants with the lowest tertile of PM10 or NO2 exposure, those with the highest tertile of PM10 (HR=3.88; 95% CI: 2.87-5.23) or NO2 (HR=2.10; 95% CI, 1.54-2.85) exposure had a 2 to 3 fold increased risk for ADHD. CONCLUSION: Exposure to PM10 and NO2 was associated with the incidence of ADHD in childhood. PMID- 27939019 TI - Pilot Study to Evaluate Postsurgical Dehiscence After Continuous Suture by Tissue Planes. PMID- 27939020 TI - Nodules on the Hands and Musculoskeletal Abnormalities. PMID- 27939021 TI - Fabrication and evaluation of magnetic activated carbon as adsorbent for ultrasonic assisted magnetic solid phase dispersive extraction of bisphenol A from milk prior to high performance liquid chromatographic analysis with ultraviolet detection. AB - In the present study, the impregnation of a micro - meso porous activated carbon with magnetite (Fe3O4) was successfully achieved by sonication and the magnetic activated carbon prepared (Bmi) was evaluated as a new adsorbent for ultrasonic assisted magnetic solid phase dispersive extraction of Bisphenol A (BPA) from cow milk and human breast milk samples, prior to the determination by HPLC with UV detection. The prepared Bmi was characterized by X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). The effect of pH on adsorption, initial concentration, contact time and desorption were studied. The main experimental parameters influencing extraction efficiency of BPA, such as type and amount of the adsorbent, sample amount, type of desorption solvent, time of adsorption and desorption, type of precipitation solvent, were investigated and optimized. Under the optimal extraction conditions the absolute recovery of BPA was 81% and 95% in cow milk and human breast milk samples, respectively. Good linearity was observed in the investigated concentration range of 2.5MUgkg-1-5000MUgkg-1 (R2=0.9997). Limit of detection (LOD) was 0.75MUgL-1, which is in accordance with the specific migration limit (SML) established by the European Union, and limit of quantification (LOQ) was 2.5MUgL-1. Within-day and between-day recoveries ranged from 91.4% to 98.6% and 89.1% to 99.4% respectively and the RSDs were less than 3.7%. Due to the excellent magnetic behavior of Bmi the proposed method was shown to be simple and rapid. Besides these, this method is sensitive, low cost, efficient and environmentally friendly. PMID- 27939022 TI - Trauma surgeon utilization of computerized tomography scanning: Room for improvement? AB - BACKGROUND: We aimed to evaluate computerized tomography (CT) utilization and yield rates for trauma team activations (TTA). METHODS: A retrospective review of all TTAs was conducted over nine months. TTAs consisted of two levels--trauma alert (TAL) and trauma response (TR). Yields of CT for significant findings (SF) for four CT types (brain, cervical, chest, abdomen/pelvis) were recorded. RESULTS: 647 patients were included. There was no difference in the utilization rates of CTs except for brain CTs (TAL, 98% vs TR, 94%, p = 0.008). There was no difference in the yield rates except for cervical spine CTs (TAL, 8% vs TR, 4%, p = 0.03). Over 80% received a pan scan regardless of TTA level; 63% who had any CT had no SF. The median ratio of scans with SF to the total number of scans per patient was 0. CONCLUSIONS: Regardless of activation level, CT seems to be over utilized. More selective use of CT should be evaluated. PMID- 27939023 TI - Ultrasound based focused neck exploration for primary hyperparathyroidism. AB - OBJECTIVE: We review our experience with focused neck exploration (FNE) based on ultrasound (USN) alone, in patients with primary hyperparathyroidism (PHP) and negative sestamibi scans (SES). METHODS: 124 patients with PHP were evaluated for FNE and studied with SES and USN. 53 patients (43%) had a negative SES. 49 of those patients (92%) were selected for FNE based on USN criteria of a single abnormal gland, .5 cm or greater, as determined by an experienced surgeon sonographer. RESULTS: 40 of 49 patients (82%) selected on USN criteria alone underwent successful FNE. Of the 9 patients who required neck exploration 6 (12%) were incorrectly localized, 2 (4%) were found to have hyperplasia, and 1 (2%) was correctly localized but not found on the initial exploration. US had a 97.5% sensitivity and a 25% specificity as a diagnostic test for single adenomas, both within the 95% confidence interval. Of those glands successfully imaged by USN, image size correlated well with the measured size of the adenoma at path, on average within 0.40 cm (Standard deviation 0.30 cm). CONCLUSION: We feel our data show that USN provides reliable information in patient selection for FNE. The literature supports SES as a more reliable study when positive for parathyroid adenoma, but false negative rates of 30-40% have been reported. Routine use of preoperative US by experienced surgeon-sonographers would result in more patients selected for FNE vs. routine neck exploration with expected benefits. PMID- 27939024 TI - Partial versus complete removal of the infected mesh after abdominal wall hernia repair. AB - BACKGROUND: To compare the results with complete mesh removal (CMR) versus partial mesh removal (PMR) in the treatment of mesh infection after abdominal wall hernia repair (AWHR). METHODS: Retrospective review of all patients who underwent surgery for mesh infection between January 2004 and May 2014 at a tertiary center. RESULTS: Of 3470 cases of AWHR, we reported 66 cases (1.9%) of mesh infection, and 48 repairs (72.7%) required mesh explantation. CMR was achieved on 38 occasions, while PMR was undertaken ten times. We observed more postoperative complications in CMR than PMR group (p = 0.04). Three patients with intestinal fistula were reoperated in postoperative period after a difficult mesh removal; one of them died due to multiple organ failure. The overall recurrence rate after explantation was 47.9%: recurrence was more frequent in CMR group (p = 0.001), although persistent or new mesh infection was observed more frequently with PMR (p = 0.001). CONCLUSIONS: Although PMR has less postoperative morbidity, shorter duration of hospitalization and lower rate of recurrence than CMR, prosthetic infection persists in up to 50% of cases. PMID- 27939025 TI - Metabolic syndrome and atypical antipsychotics: Possibility of prediction and control. AB - INTRODUCTION: Schizophrenia and other psychotic disorders are associated with high morbidity and mortality, due to inherent health factors, genetic factors, and factors related to psychopharmacological treatment. Antipsychotics, like other drugs, have side-effects that can substantially affect the physical health of patients, with substantive differences in the side-effect profile and in the patients in which these side-effects occur. To understand and identify these risk groups could help to prevent the occurrence of the undesired effects. MATERIAL AND METHOD: A prospective study, with 24 months follow-up, was conducted in order to analyse the physical health of severe mental patients under maintenance treatment with atypical antipsychotics, as well as to determine any predictive parameters at anthropometric and/or analytical level for good/bad outcome of metabolic syndrome in these patients. RESULTS: There were no significant changes in the physical and biochemical parameters individually analysed throughout the different visits. The baseline abdominal circumference (lambda Wilks P=.013) and baseline HDL-cholesterol levels (lambda Wilks P=.000) were the parameters that seem to be more relevant above the rest of the metabolic syndrome constituents diagnosis criteria as predictors in the long-term. CONCLUSIONS: In the search for predictive factors of metabolic syndrome, HDL-cholesterol and abdominal circumference at the time of inclusion were selected, as such that the worst the baseline results were, the higher probability of long-term improvement. PMID- 27939027 TI - Prevalence of obesity according to Edmonton staging in the Internal Medicine consultations. Results of the OBEMI study. AB - OBJECTIVES: To estimate the prevalence of obesity in patients treated by departments of Internal Medicine and to classify the patients according to the Edmonton Obesity Staging System (EOSS). MATERIAL AND METHODS: An observational, descriptive cross-sectional study included outpatients older than 18 years, with a body mass index (BMI)>30, from 38 hospitals between the 1st and 14th of February, 2016. We classified the patients according to the EOSS and analysed their clinical, laboratory and demographic variables. A value of P<.05 was considered statistically significant. RESULTS: Of the 1,262 patients treated in consultations, we recruited 298 and analysed 265. The prevalence of obesity was 23.6%, the mean age was 62.47+/-15.27 years, and the mean BMI was 36.1+/ 5.3kg/m2. According to EOSS stage (0, 1, 2, 3 and 4), the prevalence was 4.9, 14.7, 62.3, 15.5 and 2.64%, respectively. Those patients with EOSS>2 were significantly older and had significantly more comorbidities. The multivariate analysis related age (OR 1.06; P<.0003), blood glucose (OR 1.04; P<.0006), total cholesterol (OR 0.98; P<.02) and uric acid (OR 1.32; P<.02) levels with an EOSS>2. An analysis of correspondence grouped, with an explanatory percentage of 78.2%, the patients according to their EOSS, comorbidity, education level, employment status and functional capacity. CONCLUSIONS: The prevalence of obesity in the patients treated by Internal Medicine departments is similar to that of the general population, although the patients are older and have a higher BMI. EOSS is useful for implementing a comprehensive approach for patients with obesity, regardless of the BMI, which can help achieve better health and quality of-life results. PMID- 27939026 TI - Depression and associated variables in people over 50 years in Spain. AB - INTRODUCTION: Depression is a common and disabling psychiatric disorder in adulthood and is associated with higher mortality and functional disability. OBJECTIVES: To determine the association between clinical and sociodemographic variables with depression in a sample of people over 50 years old living in Spain, and compare the prevalence of depression with the other Survey of Health, Ageing and Retirement (SHARE) countries. MATERIAL AND METHODS: There were 5,830 participants in the Spanish sample of the Wave 5, 2013, of SHARE. Tools used: EURO-D (Depression) and CASP-12 (Quality of Life). STATISTICAL ANALYSIS: Bivariate, and binary logistic. RESULTS: The variables associated with depression in the binary logistic regression (EURO-D >=4) were poor self-perceived physical health (OR=13.34; 95% CI: 9.74-18.27), having more than 2 difficulties in Activities of Daily Living (ADL) (OR=4.46; 95% CI: 3.13-6.34) and female gender (OR=2.16; 95% CI: 1.83-2.56). Depression was more common among participants with Alzheimer (76.4%), emotional disorders (73.9%), Parkinson (57.4%), hip fracture (55.4%), and rheumatism (50.9%). Compared with other European countries, Spain had a percentage of people with depression (29.3%) that was higher than the European average (27.9%). CONCLUSIONS: The most important variables associated with depression were poor perceived physical health, presence of difficulties in ADL, and female gender. PMID- 27939028 TI - The role of nursing staff in the activities of daily living of nursing home residents. AB - The aim of this cross-sectional study was to explore the role of nursing staff in residents' activities. Nursing home residents (n = 723) were observed in their wards, randomly five times for one minute between 7 a.m. and 11 p.m. Resident's (in)activity and the role of nursing staff or others in this activity were recorded. Roles were defined as 'taking over the activity', 'giving support', or 'supervision'. Nurse observers were interviewed to obtain insight into their observation-experiences. Residents were observed in activities of daily living in 31% of all 3282 observations, and inactive in 57%. Nursing staff provided support in 51% of the observations and took over activities in 45%; supervision was rarely observed (4%). Nurse observers who knew the residents reported that a large part of activities were taken over unnecessarily. Based on these results, nursing staff are recommended to provide more supervision and support to optimize residents' activities and independence. PMID- 27939029 TI - Corrigendum to "Septic pulmonary and cerebral embolism caused by community associated methicillin-resistant Staphylococcus aureus in a healthy child" [J Microbiol Immunol Infect 49(5) (2016) 826-827]. PMID- 27939030 TI - Clinical nomograms: Is a picture worth a thousand words? PMID- 27939032 TI - Discussion. PMID- 27939033 TI - Walking away from thoracoabdominal aortic aneurysm repair: Advancing intervention to make it more common. PMID- 27939031 TI - Early hemodynamics and clinical outcomes of isolated aortic valve replacement with stentless or transcatheter valve in intermediate-risk patients. AB - OBJECTIVE: Stentless aortic valves have been developed to overcome obstructive limitations associated with stented bioprostheses. The aim of the current multi institutional study was to compare hemodynamics of transcatheter (TAVR) and the Freedom SOLO Stentless (FS) valve in an intermediate risk population undergoing surgical aortic valve replacement. METHODS: From 2010 to 2014, 420 consecutive patients underwent isolated surgical aortic valve replacement with FS and 375 patients underwent TAVR. Only patients with intermediate operative risk (Society of Thoracic Surgeons score 4-10) and small aortic annulus (<=23 mm) were included. After a propensity matched analysis 142 patients in each group were selected. Thirty-day postoperative clinical and echocardiographic parameters were evaluated. RESULTS: Mean prosthesis diameter was 22.2 +/- 0.9 mm for FS and 22.4 +/- 1.0 mm for TAVR. In-hospital mortality was 2.1% for FS and 6.3% for TAVR (P = .02). Postoperative FS peak gradients were 19.1 +/- 9.6 mm Hg (mean 10.8 +/- 5.9 mm Hg); TAVR peak gradients were 20.2 +/- 9.5 mm Hg (mean 10.7 +/- 6.9 mm Hg) P = .57 (P = .88). Postoperative effective orifice area was 1.93 +/- 0.52 cm2 for FS and 1.83 +/- 0.3 cm2 for TAVR (P = .65). There was no prostheses-patient mismatch in either group. Postoperative grade 2-3 paravalvular leak was present in 3.5% for TAVR and 0.7% for FS. Postoperative permanent pacemaker implant rate was 12% for TAVR and only 1 case (0.7%) in the FS group (P < .001). CONCLUSIONS: In patients with small aortic annulus and intermediate risk, both FS and TAVR demonstrated similar excellent hemodynamic performance. TAVR demonstrated greater mortality and rates of pacemaker insertion. Further studies are warranted to validate TAVR indications in this subset of patients. PMID- 27939034 TI - Motion of a liquid bridge between nonparallel surfaces. AB - Bulk motion of a liquid bridge between two nonparallel identical solid surfaces undergoing multiple loading cycles (compressing and stretching) was investigated numerically and experimentally. The effects of the following governing parameters were studied: the dihedral angle between the two surfaces (psi), the amount of compressing and stretching (Deltah), and wettability parameters i.e. the advancing contact angle (thetaa) and Contact Angle Hysteresis (CAH). Experiments were done using various combinations of psi, Deltah and on surfaces with different wettabilities to understand the effect of each parameter individually. Additionally, a numerical model using Surface Evolver software was developed to augment the experimental data and extract information about the shape of the bridge. An empirical function was proposed and validated to calculate the minimum amount of Deltah needed to initiate the bulk motion (i.e. to overcome the initial lag of the motion in response to the compressing of the bridge), at a given dihedral angle psi. The effect of governing parameters on magnitude and precision of the motion was investigated. The magnitude of the motion was found to be increased by increasing psi and Deltah, and/or by decreasing thetaa and CAH. We demonstrated the possibility of modulating the precision of the motion with thetaa. Additionally, it was shown that the magnitude of the motion (in one loading cycle) increases after each loading cycle, if the contact lines depin only on the narrower side of the bridge during compressing and only on the wider side during stretching (asymmetric depinning). Whereas, depinning on both sides of the bridge (symmetric depinning) reduced the magnitude of bridge motion in each cycle under cyclic loading. A larger psi was found to convert symmetric depinning into asymmetric depinning. These findings not only enhance the understanding of bridge motion between nonparallel surfaces, but also are beneficial in controlling magnitude, precision, and lag of the motion in practical applications. PMID- 27939036 TI - Another step towards prevention of food allergy. PMID- 27939035 TI - Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Evidence is accumulating that early consumption is more beneficial than is delayed introduction as a strategy for primary prevention of food allergy. However, allergic reactions caused by early introduction of such solid foods have been a problematic issue. We investigated whether or not early stepwise introduction of eggs to infants with eczema combined with optimal eczema treatment would prevent egg allergy at 1 year of age. METHODS: In this randomised, double-blind, placebo-controlled trial, we enrolled infants 4-5 months of age with eczema from two centres in Japan. Exclusion criteria were being born before 37 weeks of gestational age, experience of ingestion of hen's eggs or egg products, history of immediate allergic reaction to hen's eggs, history of non-immediate allergic reaction to a particular type of food, and complications of any severe disease. Infants were randomly assigned (block size of four; stratified by institution and sex) to early introduction of egg or placebo (1:1). Participants in the egg group consumed orally 50 mg of heated egg powder per day from 6 months to 9 months of age and 250 mg per day thereafter until 12 months of age. We aggressively treated participants' eczema at entry and maintained control without exacerbations throughout the intervention period. Participants and physicians were masked to assignment, and allocation was concealed. The primary outcome was the proportion of participants with hen's egg allergy confirmed by open oral food challenges at 12 months of age, assessed blindly by standardised methods, in all randomly allocated participants who received the intervention. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000008673. FINDINGS: Between Sept 18, 2012, and Feb 13, 2015, we randomly allocated 147 participants (73 [50%] to the egg group and 74 [50%] to the placebo group). This trial was terminated on the basis of the results of the scheduled interim analysis of 100 participants, which showed a significant difference between the two groups (four [9%] of 47 participants had an egg allergy in the egg group vs 18 [38%] of 47 in the placebo group; risk ratio 0.222 [95% CI 0.081-0.607]; p=0.0012). In the primary analysis population, five (8%) of 60 participants had an egg allergy in the egg group compared with 23 (38%) of 61 in the placebo group (risk ratio 0.221 [0.090-0.543]; p=0.0001). The only difference in adverse events between groups was admissions to hospital (six [10%] of 60 in the egg group vs none in the placebo group; p=0.022). 19 acute events occurred in nine (15%) participants in the egg group versus 14 events in 11 (18%) participants in the placebo group after intake of the trial powder. INTERPRETATION: Introduction of heated egg in a stepwise manner along with aggressive eczema treatment is a safe and efficacious way to prevent hen's egg allergy in high-risk infants. In this study, we developed a practical approach to overcome the second wave of the allergic epidemic caused by food allergy. FUNDING: Ministry of Health, Labour and Welfare, and National Centre for Child Health and Development, Japan. PMID- 27939037 TI - Craniofacial structure variations in patients with palatal anomalies and velopharyngeal dysfunction. AB - PURPOSE: Cephalometric evaluation of craniofacial and craniopharyngeal morphology is important for understanding the factors affecting velopharyngeal dysfunction (VPD) in patients with palatal anomalies. MATERIALS AND METHODS: In this study, 366 patients with VPD were retrospectively stratified into cleft lip and palate (CLP), cleft palate (CP), submucous cleft palate (SMCP), occult submucous cleft palate (OSMCP), and non-CP groups. Lateral cephalometrics were used to assess craniofacial, craniopharyngeal, and velopharyngeal anatomy. RESULTS: The average craniofacial morphology in patients with VPD differed significantly according to the type of palatal anomaly. The non-CP and OSMCP groups differed from the CLP, CP, and SMCP groups in nasopharyngeal size and shape as depicted by a larger ANS Ptm-Ve angle, a smaller S-N-Ba and NBa-PP angles, and a shorter linear value of S Ar in the non-CP group. The CLP and CP groups had shorter ANS-Ptm, shorter Ptm-P, and smaller SNA and SNB angles. CONCLUSION: VPD patients with overt clefts have different skeletal and nasopharyngeal shapes compared to non-CP and OSMCP. Velopharyngeal function assessment should include the size and shape of the nasopharyngeal space in addition to the size and the activity of the velum and posterior and lateral walls of the nasopharynx. This should enable a more precise understanding of VPD pathology, and lead to improvements in the posterior pharyngeal flap technique in order to obtain better postoperative speech outcomes after surgical management of velopharyngeal dysfunction. PMID- 27939038 TI - Novel technique for harvesting the sternoclavicular graft. AB - PURPOSE: Originally introduced for mandibular reconstruction more than 40 years ago, the sternoclavicular graft (SCG) has gained widespread popularity for the reconstruction of the ramus-condyle unit (RCU) owing to its anatomic and histological likeness to the normal mandibular condyle. Conventional longitudinal osteotomy design for its harvest has been fraught with considerable complications at the donor site including fracture clavicle and major neurovascular injury. In an attempt to alleviate these ill effects, a new technique for procuring the sternoclavicular graft is presented. MATERIAL AND METHODS: A split-thickness cortico-cancellous graft was harvested form the sternal end of the clavicle along with the articular disk with the osteotomy cut oriented parallel to the coronal plane, with limited soft tissue dissection. Donor site complications were assessed in terms of incidence of clavicle fracture, neurovascular injury, pleural tear and radiographic healing as seen in the six-month postoperative chest radiograph. RESULTS: 17 patients suffering from unilateral temporomandibular joint ankylosis underwent SCG harvesting for RCU reconstruction following osteoarthrectomy. No adverse events were seen in the intra- and post operative period in any patient and satisfactory radiographic osseous healing was observed after six months. CONCLUSION: The proposed harvest technique for SCG results in reduced donor site morbidity and favourable healing and greater patient comfort. PMID- 27939039 TI - Velopharyngeal insufficiency treated with levator muscle repositioning and unilateral myomucosal buccinator flap. AB - PURPOSE: Velopharyngeal insufficiency (VPI) is common (20-30%) after cleft palate closure. The myomucosal buccinator flap has become an important treatment option for velopharyngeal insufficiency; however, published studies all use bilateral buccinator flaps. This study assesses outcomes with a unilateral myomucosal buccinator flap that might result in less operating time and might prevent the need of a bite block and an extra procedure for division of the flap pedicle at a later stage. MATERIALS AND METHODS: Forty-two consecutive patients who underwent a unilateral myomucosal buccinator flap procedure were retrospectively reviewed. Overall clinical judgment of speech, speech analysis, and velopharyngeal closure were evaluated by a multidisciplinary cleft palate team. RESULTS: Median follow up was 1.2 years. In 83% of patients, overall clinical judgment of optimal speech was obtained and thus no further velopharyngeal surgery was necessary. In 7 patients, further surgery was necessary, of whom 57% (4/7) had bilateral cleft lip-palate. Mean level of intelligibility improved significantly as evaluated by speech pathologists (2.5 +/- 0.9 vs 3.5 +/- 0.9; P < 0.0001) and by parents (2.1 +/- 0.9 vs 3.2 +/- 0.7; P < 0.0001). Mean level of resonance improved significantly (0.7 +/- 0.9 vs 2.0 +/- 1.0; P < 0.0001), and velopharyngeal closure improved in 83% postoperatively. CONCLUSION: The unilateral myomucosal buccinator flap seems to be an effective and safe procedure and should become part of the armamentarium of cleft surgeons. PMID- 27939040 TI - Facial thirds-based evaluation of facial asymmetry using stereophotogrammetric devices: Application to facial palsy subjects. AB - Many conditions can compromise facial symmetry, resulting in an impairment of the affected person from both esthetic and functional points of view. For these reasons, a detailed, focused, and objective evaluation of facial asymmetry is needed, both for surgical planning and for treatment evaluation. In this study, we present a new quantitative method to assess symmetry in different facial thirds, objectively defined on the territories of distribution of trigeminal branches. A total of 70 subjects (40 healthy controls and 30 patients with unilateral facial palsy) participated. A stereophotogrammetric system and the level of asymmetry of the subjects' hemi-facial thirds was evaluated, comparing the root mean square of the distances (RMSD) between their original and mirrored facial surfaces. Results show a high average reproducibility of area selection (98.8%) and significant differences in RMSD values between controls and patients (p = 0.000) for all of the facial thirds. No significant differences were found on different thirds among controls (p > 0.05), whereas significant differences were found for the upper, middle, and lower thirds of patients (p = 0.000). The presented method provides an accurate, reproducible, and local facial symmetry analysis that can be used for different conditions, especially when only part of the face is asymmetric. PMID- 27939041 TI - Buccal bone thickness at dental implants in the aesthetic zone: A 1-year follow up cone beam computed tomography study. AB - Sufficient buccal bone thickness (BBT) is important for an optimal aesthetic outcome of implant treatment in the aesthetic zone. The aim of the study was to assess BBT at dental implants placed in the aesthetic zone (incisor, canine or first premolar in the maxilla) (immediate or delayed, with or without immediate provisionalization) with cone beam computed tomography (CBCT) as a function of time. Eighty patients were divided into 4 groups according to size of the buccal bony defect (<5 or >=5 mm) after removal of the tooth, and timing of implant placement and provisionalization. CBCTs were made 1 month and 1 year after placement of the implant crown. BBT varied from 0.79 mm to 2.12 mm at 1 month and from 0.71 mm to 2.04 mm at 1 year. Change of BBT between 1 month and 1 year was negligible. This study concluded that BBT at dental implants in the aesthetic zone appears to be stable for immediate and delayed placed implants after placement of the definitive crown, independent of the size of buccal bone defect prior to implant insertion and timing of provisionalization. PMID- 27939042 TI - Facial palsy after dental procedures - Is viral reactivation responsible? AB - OBJECTIVES: Herpes labialis viral reactivation has been reported following dental procedures, but the incidence, characteristics and outcomes of delayed peripheral facial nerve palsy following dental work is poorly understood. Herein we describe the unique features of delayed facial paresis following dental procedures. MATERIALS AND METHODS: An institutional retrospective review was performed to identify patients diagnosed with delayed facial nerve palsy within 30 days of dental manipulation. Demographics, prodromal signs and symptoms, initial medical treatment and outcomes were assessed. RESULTS: Of 2471 patients with facial palsy, 16 (0.7%) had delayed facial paresis following ipsilateral dental procedures. Average age at presentation was 44 yrs and 56% (9/16) were female. Clinical evaluation was consistent with Bell's palsy in 14 (88%) and Ramsay-Hunt syndrome in 2 patients (12%). Patients developed facial paresis an average of 3.9 days after the dental procedure, with all individuals developing a flaccid paralysis (House Brackmann (HB) grade VI) during the acute stage. 50% of patients developed persistent facial palsy in the form of non-flaccid facial paralysis (HBIII-IV). CONCLUSION: Facial palsy, like herpes labialis, can occur in the days following dental procedures and may also be related to viral reactivation. In this small cohort, long-term facial outcomes appear worse than for spontaneous Bell's palsy. PMID- 27939043 TI - Periostin: The bone and beyond. AB - In recent years the relationship between bone, metabolism and many pathophysiologic mechanisms involving other organs and the immune system, was increasingly apparent. This observation concerns vitamin D, osteopontin and periostin (PO). PO is expressed in the periosteum of long bones but also in many other tissues and organs, including heart, kidney, skin and lungs, being enhanced by mechanical stress or injury. PO has a relevant physiological function in promoting injury repair in a large number of tissues. However, its overexpression was observed in different diseases characterized by inflammation, fibrosis and tumorigenesis. Here we review the current knowledge on the role of PO in physiologic and pathologic pathways of different diseases. A specific focus regards the correlation between the level of PO and lung diseases and the identification of PO also as an inflammatory key effector in asthma, strongly associated with airways eosinophilia. In fact PO seems to be a useful biomarker of "Th2-high" asthma compared to "Th2-low" asthma phenotype and a predictor of response to therapeutic agents. Currently, a growing number of studies suggests a possible role of PO as a new diagnostic marker and/or therapeutic target for different diseases and its usefulness in clinical practice should be supported and confirmed by further and larger studies. PMID- 27939044 TI - [Health technology assessments by the Haute Autorite de Sante (HAS)]. PMID- 27939046 TI - Including non-public data and studies in systematic reviews and systematic maps. AB - Systematic reviews and maps should be based on the best available evidence, and reviewers should make all reasonable efforts to source and include potentially relevant studies. However, reviewers may not be able to consider all existing evidence, since some data and studies may not be publicly available. Including non-public studies in reviews provides a valuable opportunity to increase systematic review/map comprehensiveness, potentially mitigating negative impacts of publication bias. Studies may be non-public for many reasons: some may still be in the process of being published (publication can take a long time); some may not be published due to author/publisher restrictions; publication bias may make it difficult to publish non-significant or negative results. Here, we consider what forms these non-public studies may take and the implications of including them in systematic reviews and maps. Reviewers should carefully consider the advantages and disadvantages of including non-public studies, weighing risks of bias against benefits of increased comprehensiveness. As with all systematic reviews and maps, reviewers must be transparent about methods used to obtain data and avoid risks of bias in their synthesis. We make tentative suggestions for reviewers in situations where non-public data may be present in an evidence base. PMID- 27939047 TI - Erratum. PMID- 27939045 TI - Air pollution and cardiovascular mortality with over 25years follow-up: A combined analysis of two British cohorts. AB - BACKGROUND: Adverse effects of air pollution on cardiovascular disease (CVD) mortality are well established. There are comparatively fewer studies in Europe, and in the UK particularly, than in North America. We examined associations in two British cohorts with >25years of follow-up. METHODS: Annual average NO2, SO2 and black smoke (BS) air pollution exposure estimates for 1991 were obtained from land use regression models using contemporaneous monitoring data. From the European Study of Cohorts and Air Pollution (ESCAPE), air pollution estimates in 2010-11 were obtained for NO2, NOx, PM10, PMcoarse and PM2.5. The exposure estimates were assigned to place of residence 1989 for participants in a national birth cohort born in 1946, the MRC National Study of Health and Development (NSHD), and an adult multi-ethnic London cohort, Southall and Brent Revisited (SABRE) recruited 1988-91. The combined median follow-up was 26years. Single pollutant competing risk models were employed, adjusting for individual risk factors. RESULTS: Elevated non-significant hazard ratios for CVD mortality were seen with 1991 BS and SO2 and with ESCAPE PM10 and PM2.5 in fully adjusted linear models. Per 10MUg/m3 increase HRs were 1.11 [95% CI: 0.76-1.61] for BS, 1.05 [95% CI: 0.91-1.22] for SO2, 1.16 [95% CI: 0.70-1.92] for PM10 and 1.30 [95% CI: 0.39 4.34] for PM2.5, with largest effects seen in the fourth quartile of BS and PM2.5 compared to the first with HR 1.24 [95% CI: 0.91-1.61] and 1.21 [95% CI: 0.88 1.66] respectively. There were no consistent associations with other ESCAPE pollutants, or with 1991 NO2. Modelling using Cox regression led to similar results. CONCLUSION: Our results support a detrimental long-term effect for air pollutants on cardiovascular mortality. PMID- 27939048 TI - Stroke and myocardial infarction following bronchial artery embolization in a cystic fibrosis patient. PMID- 27939049 TI - Impact of Methodologic Differences in Three-Dimensional Echocardiographic Measurements of the Aortic Annulus Compared with Computed Tomographic Angiography Before Transcatheter Aortic Valve Replacement. AB - BACKGROUND: Three-dimensional (3D) echocardiographic (3DE) imaging is an alternative to multi-detector row computed tomography (MDCT) for aortic annular measurement before transcatheter aortic valve replacement (TAVR). A commonly used direct planimetry from a reconstructed short-axis view has not been compared with semiautomated 3DE methods. Typically accepted optimal cutoffs for percent prosthesis-area oversizing of the balloon-expandable SAPIEN or SAPIEN XT valve to native annular size are approximately 5% to 15%. The aim of this study was to compare semiautomated and direct planimetric 3DE methods for aortic annular sizing with a gold standard of MDCT to determine predictive value for paravalvular regurgitation (PVR) and balloon postdilatation. METHODS: In this retrospective analysis, aortic annular cross-sectional area was measured from pre TAVR imaging using (1) MDCT (CT_Area), (2) a 3D transesophageal echocardiographic (TEE) semiautomated method (3DE_Area_SA), and (3) a 3D TEE direct planimetric method (3DE_Area_Direct). Annular area percent oversizing was calculated. PVR after TAVR was assessed from intraoperative TEE imaging. Need for balloon postdilatation was recorded. RESULTS: One hundred patients who underwent TAVR with either the SAPIEN or SAPIEN XT balloon-expandable prosthesis were analyzed. Twenty-three patients had mild or greater PVR after TAVR. CT_Area was 442 +/- 79 mm2, 3DE_Area_SA was 435 +/- 81 mm2, and 3DE_Area_Direct was 429 +/- 82 mm2. Both 3DE_Area_SA and 3DE_Area_Direct underestimated MDCT (P < .05). All methods were highly correlative (R = 0.88-0.93, P < .0001). Percent oversizing obtained by the three methods significantly predicted mild or greater PVR and need for balloon postdilatation by receiver operating characteristic analysis, with optimal cutoffs for CT_Area (9%-10%) and 3DE_Area_SA (14%) within the recommended ranges for the studied transcatheter valves and for 3DE_Area_Direct higher than the recommended range (18%-19%). Inter- and intraobserver reproducibility were lowest for 3DE_Area_Direct. CONCLUSIONS: Caution must be used when using 3D TEE direct planimetry of the aortic annulus, as optimal percent oversizing ranges approach the level associated with root injury, and measurements are less reproducible. Therefore, semiautomated 3DE planimetry is preferred to 3DE direct planimetry for aortic annulus sizing. PMID- 27939050 TI - Impaired Left Atrial Function in Fabry Disease: A Longitudinal Speckle-Tracking Echocardiography Study. AB - BACKGROUND: Fabry disease (FD) is characterized by the accumulation of sphingolipids in multiple organs, including the left atrium. It is uncertain if the left atrial (LA) reservoir, conduit, and contractile functions evaluated by speckle-tracking echocardiography are affected in Fabry cardiomyopathy and whether enzyme replacement therapy can improve LA function. METHODS: In this retrospective cohort study, LA strain, strain rates, and phasic LA volumes were studied in 50 patients with FD and compared with values in 50 healthy control subjects. RESULTS: All three LA phasic functions were altered. Peak positive strain (reservoir function) was 38.9 +/- 14.9% versus 46.5 +/- 10.9% (P = .004), and late diastolic strain (contractile function) was 12.6 +/- 5.9% versus 15.6 +/ 5.3% (P = .010). In 15 patients who started enzyme replacement therapy during the study, most of the LA parameters improved at 1-year follow-up (peak positive strain from 32.0 +/- 13.5% to 38.0 +/- 13.5%, P = .006), whereas there was a trend toward deterioration in 15 patients who never received treatment (peak positive strain from 47.3 +/- 10.8% to 41.3 +/- 9.3%, P = .058). Nine patients with FD (21%) experienced new-onset atrial fibrillation or stroke during 4-year follow-up. By univariate analysis, peak positive strain and early diastolic strain demonstrated significant associations with clinical events, surpassing conventional echocardiographic parameters and clinical characteristics. CONCLUSIONS: LA reservoir, conduit, and contractile functions by speckle-tracking echocardiography were all affected in FD. Enzyme replacement therapy improved LA function. LA strain parameters were associated with atrial fibrillation and stroke. PMID- 27939051 TI - Right-Dominant Unbalanced Atrioventricular Septal Defect: Echocardiography in Surgical Decision Making. AB - BACKGROUND: Management of right-dominant atrioventricular septal defect (AVSD) remains a challenge given the spectrum of ventricular hypoplasia. The purpose of this study was to assess whether reported echocardiographic indices and additional measurements were associated with operative strategy in right-dominant AVSD. METHODS: A blinded observer retrospectively reviewed preoperative echocardiograms of patients who underwent surgery for right-dominant AVSD (January 2000 to July 2013). Ventricular dimensions, atrioventricular valve index (AVVI; left valve area/right valve area), and right ventricular (RV)/left ventricular (RV/LV) inflow angle were measured. A second observer measured a subset of studies to assess agreement. Pearson correlation analysis was performed to examine the relationship between ventricular septal defect size (indexed to body surface area) and RV/LV inflow angle in systole. A separate validation cohort was identified using the same methodology (August 2013 to July 2016). RESULTS: Of 46 patients with right-dominant AVSD (median age, 1 day; range, 0-11 months), overall survival was 76% at 7 years. Twenty-eight patients (61%) underwent single-ventricle palliation and had smaller LV dimensions and volumes, AVVIs (P = .005), and RV/LV inflow angles in systole (P = .007) compared with those who underwent biventricular operations. Three patients undergoing biventricular operations underwent transplantation or died and had lower indexed LV end-diastolic volumes compared with the remaining patients (P = .005). Interobserver agreement for the measured echocardiographic indices was good (intraclass correlation coefficient = 0.70-0.95). Ventricular septal defect size and RV/LV inflow angle in systole had a strong negative correlation (r = -0.7, P < .001). In the validation cohort (n = 12), RV/LV inflow angle in systole <= 114 degrees yielded sensitivity of 100% and AVVI <= 0.70 yielded sensitivity of 88% for single-ventricle palliation. CONCLUSIONS: Mortality remains high among patients with right-dominant AVSD. RV/LV inflow angle in systole and AVVI are reproducible measurements that may be used in conjunction with several echocardiographic parameters to support suitability for a biventricular operation in right-dominant AVSD. PMID- 27939052 TI - Acoustic Behavior of a Reactivated, Commercially Available Ultrasound Contrast Agent. AB - BACKGROUND: Commercially available microbubbles such as Definity contain octafluoropropane encapsulated in a lipid shell. This perfluorocarbon can be compressed into liquid nanodroplets at room temperatures and activated with transthoracic diagnostic ultrasound. The aim of this study was to determine the size range and acoustic characteristics of Definity nanodroplets (DNDs) compared with Definity microbubbles (DMBs). METHODS: An in vitro flow system was used with a diagnostic ultrasound transducer (S5-1, iE33). DMBs were prepared using package insert instructions. DNDs were prepared by cooling DMBs in a -10 degrees C to -15 degrees C isopropyl alcohol bath before hand-pressurizing the solution. The formed DNDs were sized, diluted to 1% solutions, and infused continuously into a phosphate-buffered saline solution running within Silastic tubing. Acoustic intensity (AI) was compared with equivalent dilutions of DMBs at different mechanical indices (MIs) ranging from 0.2 to 1.4 (n = 6 comparisons at each MI) using real-time 56-Hz and triggered 2-Hz frame rates (FRs). A 3-cm-thick tissue mimicking phantom was used to simulate transthoracic attenuation. In vivo transthoracic studies were performed in four normal pigs infused with 10% intravenous infusions of DMBs or DNDs at real-time and triggered end-systolic FRs to compare differences in myocardial and left ventricular cavity AI. RESULTS: DNDs were smaller than DMBs and ranged in size from 50 to 1,000 nm. In vitro studies revealed that at an MI of 0.2 and an FR of 56 Hz, DMBs had high AI (37 +/ 2 dB), but AI dropped to 25 +/- 2 dB at an MI of 1.0 (P < .001, analysis of variance). In comparison, DNDs had virtually no AI at MIs of 0.2 to 0.6 at both triggered and 56-Hz FRs (1 +/- 0 dB), but AI increased to 34 +/- 2 dB at an MI of 1.4 using an FR of 56 Hz (P < .001 vs MI of 0.2). AI also persisted longer at 56 Hz with DNDs when using higher MIs. In vivo studies demonstrated higher myocardial AI for DNDs at higher MIs when using real-time FR, most likely from microvascular nanodroplet activation. CONCLUSION: These data indicate significant differences in acoustic responses of the commercially available DMBs when administered as an equivalent number of DNDs. The DND formulation may render them more useful for high-MI real-time imaging and other targeted transthoracic diagnostic applications. PMID- 27939053 TI - Experimental variation of social stress in virtual reality - Feasibility and first results in patients with psychotic disorders. AB - BACKGROUND AND OBJECTIVES: Social interaction might lead to increased stress levels in patients with psychotic disorders. Impaired social stress tolerance is critical for social functioning and closely linked with symptom relapse and hospitalization. We present an interactive office built-up in virtual reality (VR). METHODS: Patients with psychotic disorders (PP, N = 26 including N = 5 dropouts) and matched healthy controls (HC, N = 20) were examined with a VR simulating an open-plan office. In a randomized, controlled cross-over design, participants were introduced to virtual co-workers (avatars) and requested to ask them for task assistance. Social feedback in each of the two sessions was either cooperative or rejective in randomized order. RESULTS: The office environment was tolerable for most PP and all HC, five PP and none of the HC dropped out for any reason. Drop-outs reported simulator sickness, influence on thoughts and symptom exacerbations. Statistical trends indicated heightened paranoid ideations for PP after social rejection. State measures of paranoid ideations showed high convergent validity with conventional measures of delusions. Of note, measures of presence were higher for PP than for HC. LIMITATIONS: The exploratory design limits the robustness of the findings. Only statistical trends on paranoid ideation were found. CONCLUSION: The use of VR to assess the effects of social rejection is feasible and tolerable for most PP (87%). However, its implementation for PP is challenged by increased simulator sickness and an additional stress load for some patients. Further studies continuing on these first results that point towards an increased paranoid ideation evoked by negative social feedback and generally higher subjective presence are needed. PMID- 27939055 TI - Juxtarenal aortoiliac occlusive disease in a patient with left sided inferior vena cava. PMID- 27939054 TI - Concomitant administration of a fully liquid, ready-to-use DTaP-IPV-HB-PRP-T hexavalent vaccine with a meningococcal serogroup C conjugate vaccine in infants. AB - DTaP-IPV-HB-PRP-T or hexavalent vaccines are indicated for primary and booster vaccination of infants and toddlers against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasive diseases caused by Haemophilus influenzae type b (Hib). The present study evaluates the safety and immunogenicity of a ready-to-use hexavalent vaccine when co-administered with a meningococcal serogroup C conjugate (MenC) vaccine in infants. This was a phase III, open label, randomised, multicentre study conducted in Finland. Healthy infants, aged 46-74days (n=350), were randomised in a ratio of 1:1 to receive DTaP-IPV-HB-PRP-T vaccine at two, three and four months, either with a MenC vaccine co-administered at two and four months (Group 1; n=175) or without MenC vaccine (Group 2; n=175). All infants also received routine rotavirus and 13-valent pneumococcal conjugate vaccines. The proportion of participants with an anti-HBs concentration ?10mIU/mL assessed one month after the third dose of DTaP-IPV-HB-PRP-T vaccine was 97.5% [95%CI: 93.1-99.3] in the coadministration group and 96.1% [95%CI: 91.8-98.6] in the group without MenC vaccine. The proportion of participants with an anti-MenC SBA titre ?8 assessed one month after the second dose of MenC vaccine was 100% in the coadministration group. Both primary objectives were achieved. Secondary immunogenicity and safety analyses showed that co-administration of DTaP-IPV-HB PRP-T and MenC vaccines did not impact the immune response to the antigens of each of the two vaccines. All vaccines were well tolerated and the safety profile of DTaP-IPV-HB-PRP-T vaccine was similar in both groups. ClinicalTrials.gov identifier: NCT01839175; EudraCT number: 2012-005547-24. PMID- 27939056 TI - Laparoscopic myotomy after transjugular intrahepatic portosystemic shunt placement and embolization of gastroesophageal varices in patients with achalasia and cirrhosis. PMID- 27939057 TI - Advances in the treatment of advanced oestrogen-receptor-positive breast cancer. AB - Oestrogen-receptor-positive breast cancer is the most common subtype of breast cancer. Endocrine therapies that target the dependence of this subtype on the oestrogen receptor have substantial activity, yet the development of resistance to therapy is inevitable in advanced cancer. Major progress has been made in identifying the drivers of oestrogen-receptor-positive breast cancer and the mechanisms of resistance to endocrine therapy. This progress has translated into major advances in the treatment of advanced breast cancer, with several targeted therapies that enhance the efficacy of endocrine therapy; inhibitors of mTOR and inhibitors of the cyclin-dependent kinases CDK4 and CDK6 substantially improve progression-free survival. A new wave of targeted therapies is being developed, including inhibitors of PI3K, AKT, and HER2, and a new generation of oestrogen receptor degraders. Considerable challenges remain in patient selection, deciding on the most appropriate order in which to administer therapies, and establishing whether cross-resistance occurs between therapies. PMID- 27939058 TI - A cleaner burning biomass-fuelled cookstove intervention to prevent pneumonia in children under 5 years old in rural Malawi (the Cooking and Pneumonia Study): a cluster randomised controlled trial. AB - BACKGROUND: WHO estimates exposure to air pollution from cooking with solid fuels is associated with over 4 million premature deaths worldwide every year including half a million children under the age of 5 years from pneumonia. We hypothesised that replacing open fires with cleaner burning biomass-fuelled cookstoves would reduce pneumonia incidence in young children. METHODS: We did a community-level open cluster randomised controlled trial to compare the effects of a cleaner burning biomass-fuelled cookstove intervention to continuation of open fire cooking on pneumonia in children living in two rural districts, Chikhwawa and Karonga, of Malawi. Clusters were randomly allocated to intervention and control groups using a computer-generated randomisation schedule with stratification by site, distance from health centre, and size of cluster. Within clusters, households with a child under the age of 4.5 years were eligible. Intervention households received two biomass-fuelled cookstoves and a solar panel. The primary outcome was WHO Integrated Management of Childhood Illness (IMCI)-defined pneumonia episodes in children under 5 years of age. Efficacy and safety analyses were by intention to treat. The trial is registered with ISRCTN, number ISRCTN59448623. FINDINGS: We enrolled 10 750 children from 8626 households across 150 clusters between Dec 9, 2013, and Feb 28, 2016. 10 543 children from 8470 households contributed 15 991 child-years of follow-up data to the intention-to treat analysis. The IMCI pneumonia incidence rate in the intervention group was 15.76 (95% CI 14.89-16.63) per 100 child-years and in the control group 15.58 (95% CI 14.72-16.45) per 100 child-years, with an intervention versus control incidence rate ratio (IRR) of 1.01 (95% CI 0.91-1.13; p=0.80). Cooking-related serious adverse events (burns) were seen in 19 children; nine in the intervention and ten (one death) in the control group (IRR 0.91 [95% CI 0.37-2.23]; p=0.83). INTERPRETATION: We found no evidence that an intervention comprising cleaner burning biomass-fuelled cookstoves reduced the risk of pneumonia in young children in rural Malawi. Effective strategies to reduce the adverse health effects of household air pollution are needed. FUNDING: Medical Research Council, UK Department for International Development, and Wellcome Trust. PMID- 27939059 TI - Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. AB - BACKGROUND: Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. METHODS: This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656. FINDINGS: 20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0.0001), improvements in CHOP-INTEND motor function scores (p=0.0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0.0103) and peroneal nerve (p<0.0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0.0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord. INTERPRETATION: Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy. FUNDING: Ionis Pharmaceuticals, Inc and Biogen. PMID- 27939060 TI - Household energy and health: where next for research and practice? PMID- 27939061 TI - Department of Error. PMID- 27939062 TI - Dawn of a new therapeutic era for spinal muscular atrophy. PMID- 27939063 TI - Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. AB - Triple-negative breast cancer is a heterogeneous disease and specific therapies have not been available for a long time. Therefore, conventional chemotherapy is still considered the clinical state of the art. Different subgroups of triple negative breast cancer have been identified on the basis of protein expression, mRNA signatures, and genomic alterations. Important elements of triple-negative breast cancer biology include high proliferative activity, an increased immunological infiltrate, a basal-like and a mesenchymal phenotype, and deficiency in homologous recombination, which is in part associated with loss of BRCA1 or BRCA2 function. A minority of triple-negative tumours express luminal markers, such as androgen receptors, and have a lower proliferative activity. These biological subgroups are overlapping and currently cannot be combined into a unified model of triple-negative breast cancer biology. Nevertheless, the molecular analysis of this disease has identified potential options for targeted therapeutic intervention. This has led to promising clinical strategies, including modified chemotherapy approaches targeting the DNA damage response, angiogenesis inhibitors, immune checkpoint inhibitors, or even anti-androgens, all of which are being evaluated in phase 1-3 clinical studies. This Series paper focuses on the most relevant clinical questions, summarises the results of recent clinical trials, and gives an overview of ongoing studies and trial concepts that will lead to a more refined therapy for this tumour type. PMID- 27939064 TI - HER2-positive breast cancer. AB - Anti-HER2 treatment for HER2-positive breast cancer has changed the natural biology of this disease. This Series article reviews the main achievements so far in the treatment of both metastatic and early HER2-positive breast cancer. The success of neoadjuvant therapy in HER2-positive early breast cancer is especially acknowledged, as pertuzumab has been approved on the basis of a higher proportion of patients achieving a pathological complete response with pertuzumab and trastuzumab than with trastuzumab alone in a neoadjuvant study. Event-free survival after the confirmatory adjuvant trial completed recruitment was numerically better with pertuzumab plus trastuzumab than with trastuzumab alone. With survival rates of almost 5 years in women with metastatic HER2-positive breast cancer and 75% of patients achieving a pathological complete response, new treatments in the past decade have clearly improved the prognosis of HER2 positive breast cancer. Despite these achievements, however, the persisting high toll of deaths resulting from HER2-positive breast cancer calls for continued, intensive clinical research of newer therapies and combinations. PMID- 27939065 TI - Efficiency control of dietary pesticide intake reduction by human biomonitoring. AB - In spite of food safety controls for pesticide residues, a conventional diet still leads to a noticeable exposure of the general population to several pesticides. In a pilot study the response of exposure reduction by organic diet intervention on the urinary levels of pesticide metabolites was investigated. In the study two adult individuals were kept on a conventional diet for 11days and morning urine voids were collected at the last four days of the period. Afterwards, the participants switched to exclusively organic food intake for 18days and likewise morning urine samples were collected at the last four days of this period. In the urine samples six pyrethroid metabolites, six dialkylphosphates, four phenolic parameter for organophosphate pesticides and carbamates, 6-chloronicotinic acid (ClNA) as parameter for neonicotinoid insecticides, seven phenoxy herbicides, glyphosate and its metabolite AMPA were quantified using gas chromatographic mass spectrometric methods. Generally, the comparative analyses revealed greater shares as well as higher levels of the parameters in the samples taken during the common diet period compared to the organic diet period. Considerable decrease of the levels was found for almost all pyrethroid metabolites, dialkyphosphates and phenoxy herbicids, as well as for the phenolic metabolites 4-nitrophenol and 3,5,6-trichloropyridinol. In contrast, higher values were found for the organic diet period for ClNA and the metabolite of coumaphos in one of the volunteers. The present study confirms the results of former studies which indicated that an organic diet intervention results in considerable lower exposure to organophosphate pesticides and pyrethroids. It also verifies the former experience that monitoring of urinary parameters for non persistent pesticides permits a reliable efficiency control of short-time effects by dietary interventions. Additionally to former studies, the results of the present study highlight the need of an extension of the parameter spectrum to all prominent pesticide groups. PMID- 27939066 TI - Dissipativity and stability analysis of fractional-order complex-valued neural networks with time delay. AB - As we know, the notion of dissipativity is an important dynamical property of neural networks. Thus, the analysis of dissipativity of neural networks with time delay is becoming more and more important in the research field. In this paper, the authors establish a class of fractional-order complex-valued neural networks (FCVNNs) with time delay, and intensively study the problem of dissipativity, as well as global asymptotic stability of the considered FCVNNs with time delay. Based on the fractional Halanay inequality and suitable Lyapunov functions, some new sufficient conditions are obtained that guarantee the dissipativity of FCVNNs with time delay. Moreover, some sufficient conditions are derived in order to ensure the global asymptotic stability of the addressed FCVNNs with time delay. Finally, two numerical simulations are posed to ensure that the attention of our main results are valuable. PMID- 27939067 TI - Decreased Synovial Inflammation in Atraumatic Hip Microinstability Compared With Femoroacetabular Impingement. AB - PURPOSE: To compare the inflammatory profile of hip synovial tissue in those with atraumatic microinstability to patients with femoroacetabular impingement (FAI). METHODS: Patients with cam and mixed-type FAI (FAI group) and patients with hip instability underwent sampling of the anterolateral synovium. Demographic data, intraoperative measurements, and functional outcome scores (International Hip Outcomes Tool and Short Form-12) were recorded. Cryosections were stained and examined under light microscopy as well as confocal fluorescent microscopy for anti-CD45 (common leukocyte antigen), anti-CD31 (endothelial), and anti-CD68 (macrophage) cell surface markers. A grading system was used to quantify synovitis under light microscopy whereas digital image analysis was used to quantify immunofluorescence staining area. Comparison were made with Student t test, Mann-Whitney U, chi2, and regression analysis. RESULTS: There were 12 patients in the FAI group and 5 in the instability group. Mean age was not significantly different (P > .05), but there was a significantly greater proportion of females in the instability group versus the FAI group (P < .001). There was a significant correlation (r = 0.653; P = .005) between number of turns needed for 10 mm of distraction and increased synovitis. Synovitis scores also were increased significantly in patients with cam morphology and articular cartilage damage (P = .024) versus those without. Immunohistochemistry did not reveal differences (P > .082) between the instability and FAI groups, but CD68 staining was significantly greater in those with cam morphology and cartilage damage (P < .045). CD45+/CD68- cells were noted in the perivascular area while CD45+/CD68+ cells were noted within the synovial lining in both groups. CONCLUSIONS: Increased synovial inflammation was associated with an increased number of turns to achieve joint distraction. Both instability and FAI groups demonstrated baseline levels of synovial inflammation. Synovitis scores also were increased in patients with cartilage damage. CLINICAL RELEVANCE: An understanding of the molecular and cellular mechanisms behind both hip instability and FAI may lead to novel therapeutic anti-inflammatory therapy, which may serve as an adjunct to treatment of mechanical abnormalities in this conditions. PMID- 27939068 TI - Subscapularis Tendon Slip Number and Coracoid Overlap Are More Related Parameters for Subcoracoid Impingement in Subscapularis Tears: A Magnetic Resonance Imaging Comparison Study. AB - PURPOSE: To investigate the effects of the subscapularis tendon slip number (STSN) and coracoid morphology by magnetic resonance imaging in patients with and without subscapularis tears. METHODS: Patients who underwent shoulder arthroscopy between February 2004 and June 2015 were re-evaluated. Those with a subscapularis tear (study group) and those with other pathologies (control group) were compared with each other. Magnetic resonance imaging scans and surgery videos of the patients were reassessed. Transverse and sagittal coracohumeral distance (CHD), coracoid overlap (CO), coraco-coracoid base angle (CBA), coracoglenoid distance (CGD), and STSN were measured. RESULTS: The study and control groups comprised 141 and 78 patients, respectively. The mean age was 57.01 +/- 10.95 (similar in both the groups). The mean transverse CHD and sagittal CHD were not different between the groups and also between female and male patients. For the study and control groups, the mean CBA and CGD values were also similar. The mean CO was 24.01 +/- 4.9 and 21.29 +/- 4.58 for the study and control groups, respectively (P < .001). With the receiver operating characteristic curve of the CO, the sensitivity was 62% and the specificity was 64% at the cutoff value of 22.85 mm. The STSN was in the range between 1 and 6; the STSN was 3 or less in 61.5% of the study group and in 38.5% of the control group (P = .005). CONCLUSIONS: The CO was the most valuable parameter predicting any potential subcoracoid impingement, and the STSN was inversely correlated with subscapularis tears. However, in predicting a potential subcoracoid impingement, the CHD measurements were not significant, as well the CGD and CBA. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 27939069 TI - Reverse Anterior Cruciate Ligament Reconstruction Fixation: A Biomechanical Comparison Study of Tibial Cross-Pin and Femoral Interference Screw Fixation. AB - PURPOSE: To evaluate the biomechanical performance of tibial cross-pin (TCP) fixation relative to femoral cross-pin (FCP), femoral interference screw (FIS), and tibial interference screw (TIS) fixation. METHODS: We randomized 40 porcine specimens (20 tibias and 20 femurs) to TIS fixation (group 1, n = 10), FIS fixation (group 2, n = 10), TCP fixation (group 3, n = 10), or FCP fixation (group 4, n = 10) and performed biomechanical testing to compare ultimate load, stiffness, yield load, cyclic displacement, and load at 5-mm displacement. We performed cross-pin fixation of the looped end and interference screw fixation of the free ends of 9-mm-diameter bovine extensor digitorum communis tendon grafts. Graft fixation constructs were cyclically loaded and then loaded to failure in line with the tunnels. RESULTS: Regarding yield load, FIS was superior to TIS (704 +/- 125 N vs 504 +/- 118 N, P = .002), TCP was superior to TIS (1,449 +/- 265 N vs 504 +/- 118 N, P < .001), and TCP was superior to FCP (1,449 +/- 265 N vs 792 +/- 397 N, P < .001). Cyclic displacement for FCP was superior to TCP. Cyclic displacement for TIS versus FIS showed no statistically significant difference (2.5 +/- 1.0 mm vs 2.2 +/- 0.6 mm, P = .298). Interference screw fixation consistently failed by graft slippage, whereas TCP fixation failed by tibial bone failure. FCP fixation failed by either femoral bone failure or failure elsewhere in the testing apparatus. CONCLUSIONS: Regarding yield load, TCP fixation performed biomechanically superior to the clinically proven FCP at time zero. Because TIS fixation shows the lowest yield strength, it represents the weak link, and combined TCP-FIS fixation theoretically would be biomechanically superior relative to combined FCP-TIS fixation with regard to yield load. Cyclic displacement showed a small difference in favor of FCP over TCP fixation and no difference between TIS and FIS. CLINICAL RELEVANCE: Time-zero biomechanics of TCP fixation paired with FIS fixation show that this method of fixation can be considered a potential alternative to current practice and may pose clinical benefits in different clinical scenarios of anterior cruciate ligament reconstruction. PMID- 27939070 TI - Femoroacetabular Impingement and Pelvic Incidence: Radiographic Comparison to an Asymptomatic Control. AB - PURPOSE: To investigate whether pelvic incidence (PI) in patients with symptomatic femoroacetabular impingement was different from that in a normal population. METHODS: Retrospective analysis of 30 consecutive female and 30 consecutive male patients with computed tomography scans who underwent hip arthroscopy for FAI. PI was measured using scout lateral radiographs. The center edge angle (CEA), acetabular version, and alpha angle were also measured. Each patient was subcategorized as having a cam-type deformity (alpha angle >55 degrees ), a deep socket deformity (CEA >39 degrees ), and/or a retroverted acetabulum (acetabular anteversion <15 degrees ). Our group and subgroups were compared with a historical control group from a previously published study of 300 volunteers. Each group was compared using a Student t test. RESULTS: Our mean PI was 49.31 degrees +/- 12.34 degrees (range, 28.4 degrees -79.5 degrees ), less than the asymptomatic historical control (n = 300) with a mean PI of 55.0 degrees +/- 10.6 degrees (range, 33 degrees -82 degrees ) (P < .001). The subgroups for cam deformity, deep socket deformity, and acetabular retroversion have a mean PI of 48.89 degrees +/- 11.81 degrees , 38.30 degrees +/- 7.56 degrees , and 44.93 degrees +/- 11.32 degrees , respectively. All had a significantly lower PI than the historical control (P < .001, P < .001, P < .001, respectively). CONCLUSIONS: We conclude that patients presenting with FAI may have a lower PI than the general population. The clinical significance of a 5.7 degrees difference in PI remains unknown. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 27939071 TI - Agomelatine-induced thrombocytopenic purpura, a possible new adverse effect. PMID- 27939072 TI - Improvements in Sexual Activity After Total Knee Arthroplasty. AB - BACKGROUND: Sexual limitations in the setting of total knee arthroplasty (TKA) are poorly understood. METHODS: Surveys were designed to assess preoperative and postoperative sexual function, and limitations were retrospectively administered to 91 sexually active TKA patients at an average of 2.1 years (range, 0.5-4.0) after surgery. Preoperative and postoperative responses were compared using 1 tailed and 2-proportion z tests, with P < .05 as the threshold for significance. RESULTS: Before TKA, sexual quality and/or frequency was limited in 45% of patients because of their knee. Patients experienced an average 17.1 months (range, 0-60) of sexual limitations before surgery, resulting largely from pain (87%) and diminished range of motion or flexibility (44%). Fifty-five percent of patients reported the need to change their sexual positions to accommodate their knee, with 97% of these patients indicating the need to avoid kneeling during sex. Postoperatively, fewer patients had to adjust their sexual positions to accommodate their knee (55% vs 28%, P = .0005), and avoid bearing weight on the afflicted knee during sex (97% vs 79%, P = .0213). Patients resumed sexual activity after an average of 2.4 months (range, 0-18). Despite these general improvements, 25% of individuals had less sex in the first year after surgery. After 1 year of recovery, however, 60% indicated that they more easily engaged in sexual activity than in the previous year, with 84% of these patients experiencing less pain, and 30% experiencing greater mobility or range of motion. CONCLUSION: TKA does not eliminate sexual limitations, but it significantly decreases kneeling dysfunction and gives patients more liberty in selecting their sexual positions. PMID- 27939073 TI - Validation of a Contemporary Five-tiered Gleason Grade Grouping Using Population based Data. AB - : This population-based study assesses whether a proposed five-tiered Gleason grade grouping (GGG) system predicts prostate cancer-specific mortality (PCSM). Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 331320 prostate cancer patients who had primary and secondary Gleason patterns diagnosed between January 2006 and December 2012. We used the Fine and Gray proportional hazards model for subdistributions and the corresponding cumulative incidence to quantify the risk of PCSM. We found that the risk of PCSM approximately doubled with each GGG increase. Among men who underwent radical prostatectomy and using GGG1 (Gleason score <=6) as the reference group, the adjusted hazard ratio for PCSM was 1.13 (95% confidence interval [CI] 0.83-1.54) for GGG2, 1.87 (95% CI 1.33-2.65) for GGG3, 5.03 (95% CI 3.59-7.06) for GGG4, and 10.92 (CI 8.03-14.84) for GGG5. Similar patterns were observed regardless of the type of primary cancer treatment received or clinical stage. In summary, our study, with large, racially diverse populations that reflect real world experiences, demonstrates that the new five-tiered GGG system predicts PCSM well regardless of treatment received or clinical stage at diagnosis. PATIENT SUMMARY: In this report we examined prostate cancer mortality using the new five-tiered cancer grading system using data for a large US population. We found that the new five-tiered cancer grading system can predict prostate cancer-specific mortality well, regardless of the type of primary cancer treatment and clinical stage. We conclude that this new five-tiered cancer grading system is useful in guiding treatment decisions. PMID- 27939074 TI - Reply to Harry Herr's Letter to the Editor re: Marko Babjuk, Andreas Bohle, Maximilian Burger, et al. EAU Guidelines on Non-muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol 2017;71:447-61. PMID- 27939077 TI - Great expectations for simtuzumab in IPF fall short. PMID- 27939076 TI - Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial. AB - BACKGROUND: Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the efficacy and safety of simtuzumab, a monoclonal antibody against LOXL2, in patients with IPF. METHODS: In this randomised, double blind, phase 2 trial, we recruited patients aged 45-85 years with definite IPF diagnosed prior to 3 years of screening from 183 hospitals and respiratory clinics in 14 countries. Eligible patients, stratified by baseline forced vital capacity (FVC), serum LOXL2 (sLOXL2) concentrations, and pirfenidone and nintedanib use, were randomly assigned (1:1) to inject 125 mg/mL simtuzumab or placebo subcutaneously once a week. The primary endpoints were progression-free survival, defined as time to all-cause death or a categorical decrease from baseline in FVC % predicted, in the intention-to-treat population, in patients with sLOXL2 concentrations in the 50th percentile or higher, and in patients with sLOXL2 concentrations in the 75th percentile or higher. Treatment duration was event-driven, and interim analyses were planned and conducted after approximately 120 and 200 progression-free survival events, respectively, occurred. We compared treatment groups with the stratified log-rank test. This study is registered with ClinicalTrials.gov, number NCT01769196. FINDINGS: Patients with IPF were recruited between Jan 31, 2013, and June 1, 2015. The intention-to-treat population included 544 randomly assigned patients (272 patients in both groups), and the safety population included 543 randomly assigned patients who received at least one dose of study medication. The study was terminated when the second interim analysis met the prespecified futility stopping criteria in the intention to-treat population. We noted no difference in progression-free survival between simtuzumab and placebo in the intention-to-treat population (median progression free survival times of 12.6 months and 15.4 months for simtuzumab and placebo, respectively; stratified HR 1.13, 95% CI 0.88-1.45; p=0.329) and in patients with baseline sLOXL2 in the 50th percentile or higher (median progression-free survival 11.7 months and 14.3 months for simtuzumab and placebo, respectively; stratified HR 1.03, 95% CI 0.74-1.43; p=0.851), or in the 75th percentile or higher (median progression-free survival 11.6 months and 16.9 months for simtuzumab and placebo, respectively; stratified HR 1.20, 95% CI 0.72-2.00; p=0.475). The incidence of adverse events and serious adverse events was similar between treatment groups. The most common adverse events in both the simtuzumab and placebo groups were dyspnoea, cough, upper respiratory tract infection, and worsening of IPF; and the most common grade 3 or 4 adverse events were worsening of IPF, dyspnoea, and pneumonia. INTERPRETATION: Simtuzumab did not improve progression-free survival in a well-defined population of patients with IPF. Our data do not support the use of simtuzumab for patients with IPF. FUNDING: Gilead Sciences Inc. PMID- 27939078 TI - Seasonal contributions to size-resolved n-alkanes (C8-C40) in the Shanghai atmosphere from regional anthropogenic activities and terrestrial plant waxes. AB - Size-resolved aerosol samples from the Shanghai atmosphere were analyzed for normal alkanes (n-alkanes, C8-C40) by comprehensive two-dimensional gas chromatography-flame ionization detection and gas chromatography-triple quadruple mass spectroscopy to study their size distribution and contributions from potential regional sources based on a one-year (2012-2013) sampling campaign. The n-alkane concentrations ranged from 62.3 to 398.5ngm-3, with an annual average of 227.6ngm-3. Particle-associated n-alkanes exhibited a bimodal distribution with one peak in the accumulation-mode size range and the other in the coarse-mode size range. As the carbon number increased, the peak in the accumulation mode intensified and the peak in the coarse mode weakened, in accordance with variation of their corresponding volatilities. Source indices (carbon preference index, average chain length, odd-even carbon number preference, unresolved to resolved n-alkanes ratio, and plant wax n-alkanes ratio) indicated that the n alkane source profile shifted from an anthropogenic-dominated pattern in winter and spring to a terrestrial plant wax-influenced pattern in summer and autumn. Further trajectory cluster analysis and potential source contribution function modeling showed that anthropogenic activities were mainly in the North China Plain and East China and that terrestrial plant waxes originated in Anhui, Zhejiang, and Jiangxi Provinces. The results of our study provide useful information for evaluating the influence of anthropogenic and biogenic activities on the atmospheric transport of important secondary organic aerosol precursors to megacities in East Asia. PMID- 27939075 TI - A Systematic Review and Meta-analysis Comparing the Effectiveness and Adverse Effects of Different Systemic Treatments for Non-clear Cell Renal Cell Carcinoma. AB - CONTEXT: While vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibition are effective strategies in treating clear cell renal cell carcinoma (ccRCC), the most effective therapeutic approach for patients with non-clear cell RCC (non-ccRCC) is unknown. OBJECTIVE: To systematically review relevant literature comparing the oncological outcomes and adverse events of different systemic therapies for patients with metastatic non ccRCC. EVIDENCE ACQUISITION: Relevant databases including MEDLINE, Embase, and the Cochrane Library were searched up to March 24, 2016. Only comparative studies were included. Risk of bias and confounding assessments were performed. A meta analysis was planned for and only performed if methodologically appropriate; otherwise, a narrative synthesis was undertaken. EVIDENCE SYNTHESIS: The literature search identified 812 potential titles and abstracts. Five randomized controlled trials, recruiting a total of 365 patients, were included. Three studies compared sunitinib against everolimus, one of which reported the results for non-ccRCC as a subgroup rather than as an entire randomized cohort. Individually, the studies showed a trend towards favoring sunitinib in terms of overall survival and progression-free survival (PFS; Everolimus versus Sunitinib in Patients with Metastatic Non-clear Cell Renal Cell Carcinoma hazard ratio [HR]: 1.41, 80% confidence interval [CI] 1.03-1.92 and 1.41, 95% CI: 0.88-2.27, Evaluation in Metastatic Non-clear Cell Renal Cell Carcinoma HR: 1.16, 95% CI: 0.67-2.01, Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First line and Second-line Treatment of Patients with Metastatic Renal Cell Carcinoma HR: 1.5, 95% CI: 0.9-2.8), but this trend did not reach statistical significance in any study. Meta-analysis was performed on two studies which solely recruited patients with non-ccRCC reporting on PFS, the results of which were inconclusive (HR: 1.30, 95% CI: 0.91-1.86). Sunitinib was associated with more Grade 3-4 adverse events than everolimus, although this was not statistically significant. CONCLUSIONS: This systematic review and meta-analysis represent a robust summary of the evidence base for systemic treatment of metastatic non-ccRCC. The results show a trend towards favoring vascular endothelial growth factor-targeted therapy for PFS and overall survival compared with mammalian target of rapamycin inhibitors, although statistical significance was not reached. The relative benefits and harms of these treatments remain uncertain. Further research, either in the form of an individual patient data meta-analysis involving all relevant trials, or a randomized controlled trial with sufficient power to detect potential differences between treatments, is needed. PATIENT SUMMARY: We examined the literature to determine the most effective treatments for advanced kidney cancer patients whose tumors are not of the clear cell subtype. The results suggest that a drug called sunitinib might be more effective than everolimus, but the statistics supporting this statement are not yet entirely reliable. Further research is required to clarify this unmet medical need. PMID- 27939079 TI - Radon and thoron inhalation doses in dwellings with earthen architecture: Comparison of measurement methods. AB - The radioactive noble gas radon (222Rn) and its decay products have been considered a health risk in the indoor environment for many years because of their contribution to the radiation dose of the lungs. The radioisotope thoron (220Rn) and its decay products came into focus of being a health risk only recently. The reason for this is its short half-life, so only building material can become a significant source for indoor thoron. In this study, dwellings with earthen architecture were investigated with different independent measurement techniques in order to determine appropriate methods for reliable dose assessment of the dwellers. While for radon dose assessment, radon gas measurement and the assumption of a common indoor equilibrium factor often are sufficient, thoron gas has proven to be an unreliable surrogate for a direct measurement of thoron decay products. Active/time-resolved but also passive/integrating measurements of the total concentration of thoron decay products demonstrated being precise and efficient methods for determining the exposure and inhalation dose from thoron and its decay products. Exhalation rate measurements are a useful method for a rough dose estimate only if the exhalation rate is homogeneous throughout the house. Before the construction of a building in-vitro exhalation rate measurements on the building material can yield information about the exposure that is to be expected. Determining the unattached fraction of radon decay products and even more of thoron decay products leads to only a slightly better precision; this confirms the relative unimportance of the unattached thoron decay products due to their low concentration. The results of this study thereby give advice on the proper measurement method in similar exposure situations. PMID- 27939080 TI - Air quality in the Olona Valley and in vitro human health effects. AB - Air quality is a major point in current health policies in force globally to protect human health and ecosystems. Cardiovascular and lung diseases are the pathologies most commonly associated with air pollution and it has been estimated that exposure to particulate matters and ground-level ozone and nitric oxides caused >500.000 premature deaths in Europe. Although air quality was generally improved in the recent years, further efforts are required to reduce the impact of air pollution on humans. The present study applied a multidisciplinary approach to estimate the adverse effects on the health of the inhabitants of the Olona Valley in the north of Italy. Chemical analyses quantified the air levels of metals, dioxins, PCBs, PAHs and some macropollutants, including total, fine and coarse airborne particles. These results were used as input for the health risk assessment and in vitro bioassays were used to evaluate possible adverse effects on the respiratory tract due to the organic pollutants adsorbed on the airborne particulate matter. Critical alerts were identified from the air characterization and from the chemical-based risk assessment in view of the levels of arsenic, nickel, benzene, fine and coarse particulate matters found in the investigated zone, which can induce severe adverse effects on human health. These findings were confirmed by bioassays with A549 and BEAS-2B cells. We also used the cell transformation assay with BALB/c 3T3 cells to assess the carcinogenicity of the organic extracts of collected particles as an innovative tool to establish the possible chronic effects of inhaled pollutants. No significant changes in morphological transformation were found suggesting that, although the extracts contain compounds with proven carcinogenic potential, in our experimental conditions the levels of these pollutants were too low to induce carcinogenesis as resulted also by the chemical-based risk assessment. PMID- 27939081 TI - Environmental signatures and effects of an oil and gas wastewater spill in the Williston Basin, North Dakota. AB - Wastewaters from oil and gas development pose largely unknown risks to environmental resources. In January 2015, 11.4ML (million liters) of wastewater (300g/L TDS) from oil production in the Williston Basin was reported to have leaked from a pipeline, spilling into Blacktail Creek, North Dakota. Geochemical and biological samples were collected in February and June 2015 to identify geochemical signatures of spilled wastewaters as well as biological responses along a 44-km river reach. February water samples had elevated chloride (1030mg/L) and bromide (7.8mg/L) downstream from the spill, compared to upstream levels (11mg/L and <0.4mg/L, respectively). Lithium (0.25mg/L), boron (1.75mg/L) and strontium (7.1mg/L) were present downstream at 5-10 times upstream concentrations. Light hydrocarbon measurements indicated a persistent thermogenic source of methane in the stream. Semi-volatile hydrocarbons indicative of oil were not detected in filtered samples but low levels, including tetramethylbenzenes and di-methylnaphthalenes, were detected in unfiltered water samples downstream from the spill. Labile sediment-bound barium and strontium concentrations (June 2015) were higher downstream from the Spill Site. Radium activities in sediment downstream from the Spill Site were up to 15 times the upstream activities and, combined with Sr isotope ratios, suggest contributions from the pipeline fluid and support the conclusion that elevated concentrations in Blacktail Creek water are from the leaking pipeline. Results from June 2015 demonstrate the persistence of wastewater effects in Blacktail Creek several months after remediation efforts started. Aquatic health effects were observed in June 2015; fish bioassays showed only 2.5% survival at 7.1km downstream from the spill compared to 89% at the upstream reference site. Additional potential biological impacts were indicated by estrogenic inhibition in downstream waters. Our findings demonstrate that environmental signatures from wastewater spills are persistent and create the potential for long-term environmental health effects. PMID- 27939082 TI - Bioconcentration of polybrominated diphenyl ethers and organochlorine pesticides in algae is an important contaminant route to higher trophic levels. AB - Persistent organic pollutants (POPs) present in water may be bioconcentrated in phytoplankton and further transferred into higher trophic levels. In the present study, seawater, sediment, phytoplankton and macroalgae (Ulva lactuca L.) samples were collected from two estuarine bays in South China and analyzed for 24 polybrominated diphenyl ethers (PBDEs) and 22 organochlorine pesticides (OCPs). The concentrations of PBDE congeners except BDE-209 were low in both phytoplankton and Ulva. BDE-209 was the predominant congener in phytoplankton and Ulva, accounting for 89.5% and 86.6% of the total average concentrations of PBDEs (48.5 and 4.1ngg-1dw), respectively. The average concentrations of DDTs, HCHs and 1-chloro-2,2-bis(4-chlorophenyl)ethane (p,p'-DDMU) in phytoplankton were 398, 241 and 11.3ngg-1dw, respectively, while those of DDTs and HCHs in Ulva were 8.4 and 33.1ngg-1dw. The levels of both PBDEs and OCPs were an order of magnitude higher in phytoplankton than in Ulva, indicating that phytoplankton with larger surface areas have higher uptake efficiency for POPs than Ulva. Bioconcentration factors (BCFs) of DDT and PBDE in phytoplankton from the two bays were in the range of 105-106, suggesting that bioconcentration may be one of the key sources of POPs and algae can be an important route for POPs to move toward higher trophic levels. PMID- 27939083 TI - Long-term diffuse phosphorus pollution dynamics under the combined influence of land use and soil property variations. AB - Analyses of the spatial-temporal distribution of diffuse pollution in agricultural regions are essential to the sustained management of water resources. Although nutrients, such as phosphorus fertilizers, can promote crop growth while improving soil fertility, excessive nutrient inputs can produce diffuse pollution, which may results in water quality degradation. The objective of this paper is to employ the SWAT (Soil and Water Assessment Tool) to estimate diffuse P effects on temporal and spatial distributions for a typical agricultural watershed and to identify the conjunct and independent influences of long-term land use and soil properties variation on diffuse P. With the validated model, the four-period simulation results (from 1979 to 2009) indicate that land use changes from agricultural development increased diffuse P yields. However, regarding updated soil properties, no significant differences of P yield were found between 1979 and 2009, demonstrating that impact of the cropland expansion were naturalized with soil property variations. An F-test was employed to assess the essentiality of all of the variables examined during the simulation period, and the test results indicated that diffuse P loading was more sensitive to soil properties than to land use. Before the P pollution control project about the land use optimization planning, it is more effective to distinguish the impacts of land use and soil properties. PMID- 27939084 TI - Hazard screening of photo-transformation products from pharmaceuticals: Application to selective beta1-blockers atenolol and metoprolol. AB - The identification of toxic components in cocktail mixtures of pollutants, their metabolites and transformation products (TPs) generated from environmental and treatment processes remains an arduous task. This study expanded in this area by applying a combination of chemical analytics, a battery of in vitro bioassays and an in silico "testing battery" to UV photolysis mixtures of active pharmaceutical ingredients. The objectives were to understand the toxic nature of the mixtures and to prioritize photo-TPs for risk analysis. The selective beta1-blockers Atenolol (ATL) and Metoprolol (MTL) that are ubiquitous in the aquatic environment were used as an example. The photolysis mixtures were cytotoxic to Vibrio fischeri and mammalian cells but not mutagenic in the Ames test or genotoxic in the in vitro micronucleus and umu tests. Potentially hazardous TPs were proposed by relating the observed effects to the kinetics of TP occurrence and applying in silico toxicity predictions for individual photo-TPs. This model study was done to identify principal mechanisms rather than accurately simulating environmental transformation processes. Several photo-TPs were proposed to present a greater hazard than the selected beta-blockers and therefore fate and toxicity assessments may be required to determine their environmental relevance. PMID- 27939086 TI - Cerebral circulatory arrest detected by insonation of extracranial arteries. PMID- 27939087 TI - [Precancerous lesions of the buccal epithelium]. AB - Squamous cell carcinomas of the oral cavity and lips consistently have a high incidence (they constitute the fifth most common form of cancer in France) and carry a heavy prognosis, particularly if diagnosed late. According to different studies, between 10 and 80% of such carcinomas occur in a pre-existing or precancerous lesion. The World Health Organisation (WHO) recommends the use of two terms for such lesions: precursor lesions, i.e. histological lesions associated with intraepithelial neoplasia (IEN) and verrucous hyperplasia (VH), frequently resulting clinically in leukoplakia or erythroplakia; "at risk" lesions, which include lichen planus, submucosal oral fibrosis and certain forms of genodermatosis. PMID- 27939085 TI - A SEER Database Analysis of the Survival Advantage of Transarterial Chemoembolization for Hepatocellular Carcinoma: An Underutilized Therapy. AB - PURPOSE: To measure transarterial chemoembolization utilization and survival benefit among patients with hepatocellular carcinoma (HCC) in the Surveillance, Epidemiology, and End Results (SEER) patient population. MATERIALS AND METHODS: A retrospective study identified 37,832 patients with HCC diagnosed between 1991 and 2011. Survival was estimated by Kaplan-Meier method and compared by log-rank test. Propensity-score matching was used to address an imbalance of covariates. RESULTS: More than 75% of patients with HCC did not receive any HCC-directed treatment. Transarterial chemoembolization was the most common initial therapy (15.9%). Factors associated with the use of chemoembolization included younger age, more HCC risk factors, more comorbidities, higher socioeconomic status, intrahepatic tumor, unifocal tumor, vascular invasion, and smaller tumor size (all P < .001). Median survival was improved in patients treated with chemoembolization compared with those not treated with chemoembolization (20.1 vs 4.3 mo; P < .0001). Similar findings were demonstrated in propensity-scoring analysis (14.5 vs 4.2 mo; P < .0001) and immortal time bias sensitivity analysis (9.5 vs 3.6 mo; P < .0001). There was a significantly improved survival hazard ratio (HR) in patients treated with chemoembolization (HR, 0.42; 95% confidence interval, 0.39-0.45). CONCLUSIONS: Patients with HCC treated with transarterial chemoembolization experienced a significant survival advantage compared with those not treated with transarterial chemoembolization. More than 75% of SEER/Medicare patients diagnosed with HCC received no identifiable oncologic treatment. There is a significant public health need to increase awareness of efficacious HCC treatments such as transarterial chemoembolization. PMID- 27939088 TI - Aging: Somatic Mutations, Epigenetic Drift and Gene Dosage Imbalance. AB - Aging involves a progressive decline of metabolic function and an increased incidence of late-onset degenerative disorders and cancer. To a large extent, these processes are influenced by alterations affecting the integrity of genome architecture and, ultimately, its phenotypic expression. Despite the progress made towards establishing causal links between genomic and epigenomic changes and aging, mechanisms underlying metabolic dysregulation and age-related phenotypes remain obscure. Here, we present a model linking genome-wide changes and their age-related phenotypic consequences via the alteration of macromolecular complexes and cellular networks. This approach may provide a better understanding of the dynamically changing genome-phenome map with age, but also deeper insights to developing more targeted therapies to prevent and/or manage late-onset degenerative disorders as well as decelerate aging. PMID- 27939089 TI - The RESOLVE Trial for people with chronic low back pain: protocol for a randomised clinical trial. AB - INTRODUCTION: Low back pain is the leading worldwide cause of disability, and results in significant personal hardship. Most available treatments, when tested in high-quality randomised, controlled trials, achieve only modest improvements in pain, at best. Recently, treatments that target central nervous system function have been developed and tested in small studies. Combining treatments that target central nervous system function with traditional treatments directed towards functioning of the back is a promising approach that has yet to be tested in adequately powered, prospectively registered, clinical trials. The RESOLVE trial will be the first high-quality assessment of two treatment programs that combine central nervous system-directed and traditional interventions in order to improve chronic low back pain. AIM: To compare the effectiveness of two treatment programs that combine central nervous system-directed and traditional interventions at reducing pain intensity at 18 weeks post randomisation in a randomised clinical trial of people with chronic low back pain. DESIGN: Two group, randomised, clinical trial with blinding of participants and assessors. PARTICIPANTS AND SETTING: Two hundred and seventy-five participants with chronic low back pain that has persisted longer than 3 months and no specific spinal pathology will be recruited from the community and primary care in Sydney, Australia. INTERVENTIONS: Both of the interventions contain treatments that target central nervous system function combined with treatments directed towards functioning of the back. Adherence to the intervention will be monitored using an individual treatment diary and adverse events recorded through passive capture. Participants are informed prior to providing informed consent that some of the treatments are not active. Blinding is maintained by not disclosing any further information. Complete disclosure of the contents of the intervention has been made with the UNSW HREC (HC15357) and an embargoed project registration has been made on the Open Science Framework to meet the Declaration of Helsinki requirement for transparent reporting of trial methods a priori. INTERVENTION A: Participants randomised to Intervention A will receive a 12-session treatment program delivered as 60-minute sessions, scheduled approximately weekly, over a period of 12 to 18 weeks. All treatment sessions are one-on-one. The program includes a home treatment component of 30minutes, five times per week. The intervention comprises discussion of the participant's low back pain experience, graded sensory training, graded motor imagery training and graded, precision focused and feedback-enriched, functional movement training. Treatment progression is determined by participant proficiency, with mandatory advancement at set time points with respect to a standard protocol. INTERVENTION B: Participants randomised to Intervention B will receive a 12-session treatment program of the same duration and structure as Intervention A. The intervention comprises discussion of the participant's low back pain experience, transcranial direct current stimulation to the motor and pre-frontal cortices, cranial electrical stimulation, and low-intensity laser therapy and pulsed electromagnetic energy to the area of greatest pain. Treatment is delivered according to published recommendations and progressed with respect to a standard protocol. MEASUREMENTS: The primary outcome is pain intensity at 18 weeks post randomisation. Secondary outcomes will include disability, depression, pain catastrophising, kinesiophobia, beliefs about back pain, pain self-efficacy, quality of life, healthcare resource use, and treatment credibility. Assessment will occur at baseline and at 18, 26 and 52 weeks after randomisation. Treatment credibility will be assessed at baseline and 2 weeks after randomisation only. ANALYSIS: A statistician blinded to group status will analyse the data by intention-to-treat using linear mixed models with random intercepts. Linear contrasts will be constructed to compare the adjusted mean change (continuous variables) in outcome from baseline to each time point between intervention A and intervention B. This will provide effect estimates and 95% confidence intervals for any difference between the interventions. SIGNIFICANCE: Preliminary data suggest that combining treatments that target central nervous system function with traditional interventions is a promising approach to chronic low back pain treatment. In the context of modest effects on pain intensity from most available treatments, this approach may lead to improved clinical outcomes for people with chronic low back pain. The trial will determine which, if either, of two treatment programs that combine central nervous system-directed and traditional interventions is more effective at reducing pain intensity in a chronic low back pain cohort. Central nervous system-directed interventions constitute a completely new treatment paradigm for chronic low back pain management. The results have the potential to be far reaching and change current physiotherapy management of chronic low back pain in Australia and internationally. PMID- 27939090 TI - Why screen for type 2 diabetes? PMID- 27939091 TI - Understanding the acute inflammatory response to Pseudomonas aeruginosa infection: differences between susceptible and multidrug-resistant strains in a mouse peritonitis model. AB - The increasing emergence of multidrug-resistant (MDR) Pseudomonas aeruginosa strains is associated with the spread of a few international epidemic clones called high-risk clones. The existence of a fitness cost associated with multidrug resistance remains unclear, and little is known about the host inflammatory response in acute P. aeruginosa infections. This study aimed to investigate how the inflammatory response occurs in the most relevant high-risk clones and to compare the process with that recorded in clinical susceptible isolates. Nine P. aeruginosa strains were studied, including the most relevant MDR high-risk clones (ST111, ST175 and ST235) circulating worldwide. The inflammatory response in terms of the release of interleukins in serum was investigated in a mouse peritonitis-sepsis model at three time points (4, 8 and 12 h). TNFalpha and interleukin-10 (IL-10) levels were significantly higher at all time points in mice inoculated with clinical susceptible strains compared with those inoculated with MDR strains. IL-6 levels were significantly higher in the clinical susceptible strain group at 8 h and 12 h (P = 0.036 and P = 0.007, respectively). Bacterial counts (log CFU/mL) in peritoneal fluid were higher in the clinical susceptible strain group compared with the MDR strain group at 8 h [6.00 (4.30-6.90) vs. 4.46 (3.30-5.34); P = 0.005] and 12 h [7.75 (4.00-7.97) vs. 4.04 (2.58-4.94); P = 0.003]. MDR P. aeruginosa strains elicited a weaker inflammatory response than susceptible strains in an experimental mouse model, suggesting the existence of a fitness cost associated with multidrug resistance. PMID- 27939092 TI - Prosthetic joints: shining lights on challenging blind spots. PMID- 27939094 TI - Biogeochemistry of trace elements in the environment - Editorial to the special issue. PMID- 27939093 TI - Susceptibility to cephalosporin combinations and aztreonam/avibactam among third generation cephalosporin-resistant Enterobacteriaceae recovered on hospital admission. AB - As part of the multicentre Antibiotic Therapy Optimisation Study (ATHOS), minimum inhibitory concentrations (MICs) were determined for cephalosporins alone and in combination with the beta-lactamase inhibitors tazobactam, clavulanic acid and avibactam against third-generation cephalosporin-resistant Escherichia coli, Klebsiella spp. and Enterobacter spp. isolates collected in German hospitals. MIC50/90 values were 0.25-4 mg/L for cefepime/tazobactam, 0.25-2 mg/L for ceftazidime/avibactam, 0.125-0.5 mg/L for ceftaroline/avibactam, 0.5-4 mg/L for cefpodoxime/clavulanic acid and 0.25-1 mg/L for aztreonam/avibactam, depending on the underlying resistance mechanism and organism. Based on in vitro testing, beta lactam antibiotics play an important role in the treatment of infections due to beta-lactamase-producing organisms. PMID- 27939096 TI - Focal Adhesion Kinase: A promising therapeutic target in pancreatic adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) remains a deadly cancer, characterized by a uniquely immunosuppressive and fibrotic microenvironment responsible for its high chemoresistance. Jiang et al. identify FAK (focal adhesion kinase) activity as an interesting therapeutic target, the inhibition of which drastically reduces PDAC microenvironment deleterious features. In combination with gemcitabine and immune-checkpoint therapy, FAK inhibitor promotes long-term tumor stasis with extended survival in PDAC mouse models. In conclusion, Jiang et al. provide proof of concept that FAK inhibitors combined with chemotherapy will highly profit PDAC patients. PMID- 27939095 TI - A multiscale Bayesian data integration approach for mapping air dose rates around the Fukushima Daiichi Nuclear Power Plant. AB - This paper presents a multiscale data integration method to estimate the spatial distribution of air dose rates in the regional scale around the Fukushima Daiichi Nuclear Power Plant. We integrate various types of datasets, such as ground-based walk and car surveys, and airborne surveys, all of which have different scales, resolutions, spatial coverage, and accuracy. This method is based on geostatistics to represent spatial heterogeneous structures, and also on Bayesian hierarchical models to integrate multiscale, multi-type datasets in a consistent manner. The Bayesian method allows us to quantify the uncertainty in the estimates, and to provide the confidence intervals that are critical for robust decision-making. Although this approach is primarily data-driven, it has great flexibility to include mechanistic models for representing radiation transport or other complex correlations. We demonstrate our approach using three types of datasets collected at the same time over Fukushima City in Japan: (1) coarse resolution airborne surveys covering the entire area, (2) car surveys along major roads, and (3) walk surveys in multiple neighborhoods. Results show that the method can successfully integrate three types of datasets and create an integrated map (including the confidence intervals) of air dose rates over the domain in high resolution. Moreover, this study provides us with various insights into the characteristics of each dataset, as well as radiocaesium distribution. In particular, the urban areas show high heterogeneity in the contaminant distribution due to human activities as well as large discrepancy among different surveys due to such heterogeneity. PMID- 27939097 TI - Primary hepatic pregnancy. PMID- 27939098 TI - Biomechanical properties of human T cells in the process of activation based on diametric compression by micromanipulation. AB - A crucial step in enabling adoptive T cell therapy is the isolation of antigen (Ag)-specific CD8+ T lymphocytes. Mechanical changes that accompany CD8+ T lymphocyte activation and migration from circulating blood across endothelial cells into target tissue, may be used as parameters for microfluidic sorting of activated CD8+ T cells. CD8+ T cells were activated in vitro using anti-CD3 for a total of 4 days, and samples of cells were mechanically tested on day 0 prior to activation and on day 2 and 4 post-activation using a micromanipulation technique. The diameter of activated CD8+ T cells was significantly larger than resting cells suggesting that activation was accompanied by an increase in cell volume. While the Young's modulus value as determined by the force versus displacement data up to a nominal deformation of 10% decreased after activation, this may be due to the activation causing a weakening of the cell membrane and cytoskeleton. However, nominal rupture tension determined by compressing single cells to large deformations until rupture, decreased from day 0 to day 2, and then recovered on day 4 post-activation. This may be related to the mechanical properties of the cell nucleus. These novel data show unique biomechanical changes of activated CD8+ T cells which may be further exploited for the development of new microfluidic cell separation systems. PMID- 27939099 TI - Effect of various factors on pull out strength of pedicle screw in normal and osteoporotic cancellous bone models. AB - Pedicle screws are widely used for the treatment of spinal instability by spine fusion. Screw loosening is a major problem of spine fusion, contributing to delayed patient recovery. The present study aimed to understand the factor and interaction effects of density, insertion depth and insertion angle on pedicle screw pull out strength and insertion torque. A pull out study was carried out on rigid polyurethane foam blocks representing osteoporotic to normal bone densities according to the ASTM-1839 standard. It was found that density contributes most to pullout strength and insertion torque. The interaction effect is significant (p < 0.05) and contributes 8% to pull out strength. Axial pullout strength was 34% lower than angled pull out strength in the osteoporotic bone model. Insertion angle had no significant effect (p > 0.05) on insertion torque. Pullout strength and insertion torque had no significant correlation (p > 0.05) in the case of the extremely osteoporotic bone model. PMID- 27939101 TI - Review: Bio-compartmentalization of microRNAs in exosomes during gestational diabetes mellitus. AB - Analysis of the human genome revealed that only 1.2% encoded for proteins, which raised questions regarding the biological significance of the remaining genome. We now know that approximately 80% of the genome serves at least one biochemical function within the cell. A portion of this 80% consists of a family of non coding regulatory RNAs, one important member being microRNAs (miRNAs). miRNAs can be detected in tissues and biofluids, where miRNAs in the latter can be bound to proteins or encapsulated within lipid vesicles such as exosomes. Gestational diabetes mellitus (GDM) is a complication of pregnancy, which has harmful health impacts on both the fetus as well as the mother. The incidence of GDM worldwide varies, but reached 18% in the HAPO cohort using the new International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Not only has GDM been associated with increased risks of further complications during pregnancy, but also poses long-term risks for both the mother and the baby. Thus, understanding the pathophysiology of GDM is important from a public health perspective. Literature has demonstrated that GDM is associated with elevated levels of circulating exosomes in maternal circulation. However, there is a paucity of data defining the expression, role, and diagnostic utility of miRNAs in GDM. This review briefly summarizes recent advances in the function and quantification of intracellular and extracellular miRNAs in GDM. PMID- 27939100 TI - Single pulse electrical stimulation to probe functional and pathological connectivity in epilepsy. AB - In the last decade, single pulse electrical stimulation (SPES) has been used as an investigational tool in the field of epilepsy surgery. Direct cortical stimulation applied at a frequency of ~1Hz can probe cortico-cortical connections by averaging electrocorticogram time-lock to the stimuli (2*20-30 trials). These evoked potentials that emanate from adjacent and remote cortices have been termed cortico-cortical evoked potentials (CCEPs). Although limited to patients undergoing invasive presurgical evaluations with intracranial electrodes, CCEP provides a novel way to explore inter-areal connectivity in vivo in the living human brain to probe functional brain networks such as language and cognitive motor networks. In addition to its impact on systems neuroscience, this method, in combination with 50Hz electrical cortical stimulation, could contribute clinically to map the functional brain systems by tracking the cortico-cortical connections among the functional cortical regions in each individual patient. This approach may help identify the normal cortico-cortical network within pathology as well as reveal connections that might arise from neural plasticity. Because of its high practicality, it has been recently applied for intraoperative monitoring of the functional brain networks for patients with brain tumor. With regard to epilepsy, SPES has been used for the two major purposes, one to probe cortical excitability of the focus, namely, epileptogenicity, and the other to probe seizure networks. Both early (i.e., CCEP) and delayed responses, and probably their high frequency oscillation counterparts, are regarded as a surrogate marker of epileptogenicity. With regards to its impact on the human brain connectivity map, worldwide collaboration is warranted to establish the standardized CCEP connectivity map as a solid reference for non-invasive connectome researches. PMID- 27939102 TI - Review: The blood-brain barrier; protecting the developing fetal brain. AB - While placental function is fundamental to normal fetal development, the blood brain barrier provides a second checkpoint critical to protecting the fetal brain and ensuring healthy brain development. The placenta is considered the key barrier between the mother and fetus, regulating delivery of essential nutrients, removing waste as well as protecting the fetus from potentially noxious substances. However, disturbances to the maternal environment and subsequent adaptations to placental function may render the placenta ineffective for providing a suitable environment for the developing fetus and to providing sufficient protection from harmful substances. The developing brain is particularly vulnerable to changes in the maternal/fetal environment. Development of the blood-brain barrier and maturation of barrier transporter systems work to protect the fetal brain from exposure to drugs, excluding them from the fetal CNS. This review will focus on the role of the 'other' key barrier during gestation - the blood-brain barrier - which has been shown to be functional as early as 8 weeks' gestation. PMID- 27939103 TI - Lifelong Persistence of Toxoplasma Cysts: A Questionable Dogma? AB - It is believed that infection by Toxoplasma gondii triggers a lifelong protective immunity due to the persistence of parasitic cysts which induce immunoprotection against reinfection. A review of the scientific literature since the 1950s did not yield any definitive data regarding the duration of cysts in the host or the presence of lifelong protective immunity, which led us to question this dogma. We put forward the hypothesis that sustained immunity to T. gondii requires repeated antigenic stimulations. The decline of seroprevalence recently observed in many countries might contribute to explain the loss of immunity. We address the potential consequences of this phenomenon, should it persist and worsen. PMID- 27939105 TI - The role of sleep problems in the relationship between peer victimization and antisocial behavior: A five-year longitudinal study. AB - RATIONALE: Peer victimization in children and adolescents is a serious public health concern. Growing evidence exists for negative consequences of peer victimization, but research has mostly been short term and little is known about the mechanisms that moderate and mediate the impacts of peer victimization on subsequent antisocial behavior. OBJECTIVE: The current study intended to examine the longitudinal relationship between peer victimization in adolescence and antisocial behavior in young adulthood and to determine whether sleep problems influence this relationship. METHODS: In total, 2006 adolescents participated in a prospective study from 2009 to 2013. The moderating role of sleep problems was examined by testing the significance of the interaction between peer victimization and sleep problems. The mediating role of sleep problems was tested by using bootstrapping mediational analyses. All analyses were conducted using SAS 9.3 software. RESULTS: We found that peer victimization during adolescence was positively and significantly associated with antisocial behavior in young adulthood (beta = 0.10, p < 0.0001). This association was mediated, but not moderated by sleep problems. Specifically, peer victimization first increased levels of sleep problems, which in turn elevated the risk of antisocial behavior (indirect effect: 0.01, 95% bootstrap confidence interval: 0.004, 0.021). CONCLUSION: These findings imply that sleep problems may operate as a potential mechanism through which peer victimization during adolescence leads to increases in antisocial behavior in young adulthood. Prevention and intervention programs that target sleep problems may yield benefits for decreasing antisocial behavior in adolescents who have been victimized by peers. PMID- 27939104 TI - The complement system in age-related macular degeneration: A review of rare genetic variants and implications for personalized treatment. AB - Age-related macular degeneration (AMD) is a progressive retinal disease and the major cause of irreversible vision loss in the elderly. Numerous studies have found both common and rare genetic variants in the complement pathway to play a role in the pathogenesis of AMD. In this review we provide an overview of rare variants identified in AMD patients, and summarize the functional consequences of rare genetic variation in complement genes on the complement system. Finally, we discuss the relevance of this work in light of ongoing clinical trials that study the effectiveness of complement inhibitors against AMD. PMID- 27939106 TI - Clinical Features and Outcome of Ebola Virus Disease in Pediatric Patients: A Retrospective Case Series. AB - Clinical and outcome data on pediatric Ebola virus disease are limited. We report a case-series of 33 pediatric patients with Ebola virus disease in a single Ebola Treatment Center in 2014-2015. The case-fatality rate was 42%, with the majority of deaths occurring within 10 days of admission. PMID- 27939107 TI - The Effect of Skin Pigmentation on the Accuracy of Pulse Oximetry in Infants with Hypoxemia. AB - To compare pulse oximetry measurement bias between infants with hypoxemia with either dark skin or light skin with Masimo Radical 7 and Nellcor Oximax. There was no significant difference in systematic bias based on skin pigment for either oximeter. PMID- 27939108 TI - A Randomized Controlled Trial of End-Tidal Carbon Dioxide Detection of Preterm Infants in the Delivery Room. AB - OBJECTIVE: To compare the ability of qualitative versus quantitative methods of end-tidal carbon dioxide (EtCO2) detection to maintain normocarbia during face mask ventilation (FMV) of preterm infants (<32 weeks) in the delivery room. STUDY DESIGN: Preterm infants <32 weeks were randomly assigned to the use of a disposable PediCap EtCO2 detector (Covidien, Dublin, Ireland) (qualitative) or a Microstream side stream capnography device (Covidien) (quantitative) for FMV in the delivery room, via a NeoPuff T-piece resuscitator (Fisher and Paykel, Auckland, New Zealand). The primary outcome was the presence of normocarbia, based on partial pressure of CO2 (PaCO2) readings obtained in the neonatal intensive care unit within an hour of birth. Normocarbia was defined as a PaCO2 measure between 37.5 and 60 mm Hg (5-8 kPa). RESULTS: Of the 59 infants included, 59% (35/59) were within the PaCO2 target range within an hour of birth. There was no difference in the primary outcome; 64% (21/33) of infants in the quantitative group were within the PaCO2 range compared with 54% (14/26) in the qualitative group (P = .594); and 93% of participants <28 weeks' gestation were within the PaCO2 normocarbic range (90% [9/10] in quantitative group and 100% [5/5] in the qualitative group [P = 1]). There was no difference in the intubation rate, days of ventilation, or bronchopulmonary dysplasia rates between the 2 groups. CONCLUSIONS: Quantitative or qualitative EtCO2 detection methods are both feasible for FMV in the delivery room. Although there was no difference in the incidence of normocarbia, the use of either form of EtCO2 monitoring should be considered during newborn stabilization, especially in infants less than 28 weeks' gestation. TRIAL REGISTRATION: ISRCTN: ISRCTN10934870. PMID- 27939109 TI - Provision of mental health support and Caesarean birth for women with fear of childbirth: a national survey. PMID- 27939111 TI - Update on the pathophysiology and management of syringomyelia unrelated to Chiari malformation. AB - INTRODUCTION: Much has been published on syringomyelia related to Chiari malformation. In contrast, little is known about the condition when it is not associated with this malformation, but this presentation of syringomyelia constitutes a different entity and therefore requires specific management. We conducted a literature review to summarise the most accepted and widespread ideas about the pathophysiology, management and other aspects of syringomyelia unrelated to Chiari malformation. DEVELOPMENT: We reviewed the most relevant literature on this condition, focusing on the pathophysiology, clinical presentation, diagnosis, and treatment. CONCLUSIONS: Syringomyelia unrelated to Chiari malformation is a distinct entity that must be well understood to guarantee correct diagnosis, monitoring, and management. When the disease is suspected, a thorough study should be conducted to identify its aetiology. Treatment must aim to eliminate the cause of the disease; symptomatic treatment should remain a second-line option. PMID- 27939112 TI - Validity and reliability of the Spanish-language version of the self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) pain scale. AB - INTRODUCTION: The self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) scale is a tool designed to identify patients with pain with neuropathic features. OBJECTIVE: To assess the validity and reliability of the Spanish-language version of the S-LANSS scale. METHODS: Our study included a total of 182 patients with chronic pain to assess the convergent and discriminant validity of the S-LANSS; the sample was increased to 321 patients to evaluate construct validity and reliability. The validated Spanish-language version of the ID-Pain questionnaire was used as the criterion variable. All participants completed the ID-Pain, the S-LANSS, and the Numerical Rating Scale for pain. Discriminant validity was evaluated by analysing sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC). Construct validity was assessed with factor analysis and by comparing the odds ratio of each S-LANSS item to the total score. Convergent validity and reliability were evaluated with Pearson's r and Cronbach's alpha, respectively. RESULTS: The optimal cut-off point for S-LANSS was >=12 points (AUC=.89; sensitivity=88.7; specificity=76.6). Factor analysis yielded one factor; furthermore, all items contributed significantly to the positive total score on the S-LANSS (P<.05). The S-LANSS showed a significant correlation with ID-Pain (r=.734, alpha=.71). CONCLUSION: The Spanish-language version of the S-LANSS is valid and reliable for identifying patients with chronic pain with neuropathic features. PMID- 27939110 TI - Familial clustering of nasopharyngeal carcinoma in non-endemic area. Report of three families. AB - Nasopharyngeal carcinoma is the predominant tumour type arising in the nasopharynx. Its aetiology is multifactorial; racial and geographical distribution, EBV infection and environmental exposure to specific substances are considered risk factors. This condition is endemic in some Asian areas, where a genetic predisposition in its oncogenesis has been established. There is a strong susceptibility between nasopharyngeal carcinoma and HLA, where related specific haplotypes have been found. In areas where the incidence is low, there are few reported cases of families affected. We report 3 cases of families with nasopharyngeal carcinoma among siblings, in the non-Asian population, probably related to EBV infection. PMID- 27939113 TI - Effects of auditory cues on gait initiation and turning in patients with Parkinson's disease. AB - OBJECTIVE: To review the available scientific evidence about the effectiveness of auditory cues during gait initiation and turning in patients with Parkinson's disease. METHODS: We conducted a literature search in the following databases: Brain, PubMed, Medline, CINAHL, Scopus, Science Direct, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Library Plus, CENTRAL, Trip Database, PEDro, DARE, OTseeker, and Google Scholar. We included all studies published between 2007 and 2016 and evaluating the influence of auditory cues on independent gait initiation and turning in patients with Parkinson's disease. The methodological quality of the studies was assessed with the Jadad scale. RESULTS: We included 13 studies, all of which had a low methodological quality (Jadad scale score<=2). In these studies, high-intensity, high-frequency auditory cues had a positive impact on gait initiation and turning. More specifically, they 1) improved spatiotemporal and kinematic parameters; 2) decreased freezing, turning duration, and falls; and 3) increased gait initiation speed, muscle activation, and gait speed and cadence in patients with Parkinson's disease. CONCLUSIONS: We need studies of better methodological quality to establish the Parkinson's disease stage in which auditory cues are most beneficial, as well as to determine the most effective type and frequency of the auditory cue during gait initiation and turning in patients with Parkinson's disease. PMID- 27939114 TI - Chromosome 17p13.3 microdeletion syndrome with unaltered PAFAH1B1 gene. PMID- 27939115 TI - Subarachnoid haemorrhage following supra-aortic bypass: A rare form of presentation of cerebral hypoperfusion syndrome. PMID- 27939116 TI - Prevalence of cognitive impairment in Spain: The Gomez de Caso study in health sentinel networks. AB - INTRODUCTION: Cognitive impairment, a clinical entity causing complete or partial intellectual dysfunction, is a major public health concern that poses a challenge for health and social services. The purpose of this study is to estimate the prevalence of this disorder in people aged 65 and older visiting the primary care physician in 5 health sentinel networks. METHOD: A sample of patients visiting their primary care doctor on 4 randomly selected days completed the Mini-Cog screening test. Diagnosis of cognitive impairment was confirmed with the Mini Mental State Examination and the Alzheimer's Questionnaire. We estimated raw and adjusted rates using demographic and social variables. RESULTS: We included 4,624 patients from 5 autonomous communities and representing a population of 1,723,216 inhabitants. The adjusted prevalence rate was 18.5% (95% CI 17.3-19.7], with differences between sentinel networks. Women showed higher adjusted rates than men: 18.5 vs. 14.3%. The highest prevalence rate was observed in people aged 85 and older (45.3%); prevalence rates vary depending on education level and marital status. CONCLUSIONS: Cognitive impairment is a frequent reason for consultations in primary care. Its prevalence is higher in women and increases exponentially with age. A number of sensitive, validated tools have been proven useful in screening for and confirming cognitive impairment. Using these tools in primary care settings enables early treatment of these patients. PMID- 27939117 TI - Diagnostic and therapeutic approach for neurocutaneous melanosis in a young adult. PMID- 27939118 TI - Treatment of idiopathic intracranial hypertension with bariatric surgery. PMID- 27939120 TI - Aerobic Exercise as a Warm-up for Singing: Acoustic Impacts. AB - OBJECTIVES: In a previous work, it was found that a 30-minute aerobic workout significantly increased singers' sound pressure level and airflow during voicing, suggesting a shift to flow phonation. This companion study was designed to assess the impact of the same workout on pitch accuracy, vibrato rate, extent and regularity, and the singing power ratio. STUDY DESIGN: This study is a cohort experimental study. METHODS: Twenty-two students in an academic vocal performance program participated. They performed an aerobic workout for 30 minutes. Before and after the workout, they sang the first seven notes of the "Star-Spangled Banner" on /pa/, producing seven /pa/s on the last note. The students then sang an ascending and descending scale to the ninth on "ah." The following measures were obtained from the "Star-Spangled Banner": pitch accuracy calculated on the seventh note ("by"); and vibrato rate, regularity, and extent, calculated on the most sustained sixth note ("see"). For the scale, the following measures were calculated from each note: pitch accuracy; vibrato rate, regularity, and extent; and the singing power ratio. RESULTS: There were no significant differences from pre- to postworkout across any measures. CONCLUSIONS: It appears that an aerobic workout positively impacts the respiratory driving force for voice production but does little for phonation. Critical for performance is the fine tuning and balancing across the respiratory, laryngeal, and resonance systems. It appears that this can only be achieved with vocalization exercises, facilitating coordination within and across the physiological systems involved in the complex art of bel canto. PMID- 27939119 TI - Acoustic Measures of Voice and Physiologic Measures of Autonomic Arousal during Speech as a Function of Cognitive Load. AB - OBJECTIVES/HYPOTHESIS: This study aimed to determine the relationship among cognitive load condition and measures of autonomic arousal and voice production in healthy adults. STUDY DESIGN: A prospective study design was conducted. METHODS: Sixteen healthy young adults (eight men, eight women) produced a sentence containing an embedded Stroop task in each of two cognitive load conditions: congruent and incongruent. In both conditions, participants said the font color of the color words instead of the word text. In the incongruent condition, font color differed from the word text, creating an increase in cognitive load relative to the congruent condition in which font color and word text matched. Three physiologic measures of autonomic arousal (pulse volume amplitude, pulse period, and skin conductance response amplitude) and four acoustic measures of voice (sound pressure level, fundamental frequency, cepstral peak prominence, and low-to-high spectral energy ratio) were analyzed for eight sentence productions in each cognitive load condition per participant. RESULTS: A logistic regression model was constructed to predict the cognitive load condition (congruent or incongruent) using subject as a categorical predictor and the three autonomic measures and four acoustic measures as continuous predictors. It revealed that skin conductance response amplitude, cepstral peak prominence, and low-to-high spectral energy ratio were significantly associated with cognitive load condition. CONCLUSIONS: During speech produced under increased cognitive load, healthy young adults show changes in physiologic markers of heightened autonomic arousal and acoustic measures of voice quality. Future work is necessary to examine these measures in older adults and individuals with voice disorders. PMID- 27939121 TI - The Anastomoses of the Recurrent Laryngeal Nerve in the Larynx: A Meta-Analysis and Systematic Review. AB - OBJECTIVES: The recurrent laryngeal nerve and its branches form a great variety of anastomoses. These nerve communications can alter the innervation patterns of the laryngeal muscles and can affect both the diagnosis and treatment of paralyzed vocal cords. The aim of this study was to assess the prevalence and anatomical characteristics of the laryngeal nerve connections, and to review their function and clinical significance. STUDY DESIGN: Meta-analysis and systematic review. METHODS: The major electronic databases were thoroughly searched to identify all studies reporting data on the anastomoses of the laryngeal nerves. Data on the prevalence of each type of anastomosis were extracted and pooled into a meta-analysis using MetaXL version 3.0 (EpiGear International Pty. Ltd., Wilston, Queensland, Australia). RESULTS: Twenty-two cadaveric studies (n = 1404 hemilarynges) were included in the meta-analysis. The two most common communications were Galen's anastamosis and the arytenoid plexus. The pooled prevalence estimate for Galen's anastamosis was 76.7% (95% confidence interval [CI]: 59.0-90.0), of which the single trunk type was most common (92.3%). The arytenoid plexus had a pooled prevalence estimate of 79.7% (95% CI: 41.1-100). CONCLUSIONS: Owing to the high prevalences and variability of nerve connections in the larynx, detailed anatomical knowledge of these anastomoses can be crucial for the accurate interpretation of laryngoscopy results, reducing iatrogenic injury during surgical procedures, and facilitating the development of novel strategies for treating laryngeal paralyses. PMID- 27939122 TI - Sleep Patterns and Mental Health Correlates in US Adolescents. AB - OBJECTIVE: To investigate systematically the associations of sleep patterns with a range of mental disorders and other outcomes among a nationally representative sample of US adolescents. STUDY DESIGN: Using the National Comorbidity Survey Adolescent Supplement, a nationally representative cross-sectional survey of 10 123 US adolescents 13-18 years of age, we assessed associations between adolescent-reported sleep patterns (tertiles of weeknight bedtime, weeknight sleep duration, weekend bedtime delay, and weekend oversleep) and past-year mental disorders based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, smoking, injury, suicidality, and perceived mental and physical health, assessed via direct diagnostic interview. RESULTS: The average weeknight bedtime was at 22:37 and sleep duration was 7.72 hours. Average weekend bedtime delay was 1.81 hours and average weekend oversleep was 1.17 hours. Later weeknight bedtime, shorter weeknight sleep duration, greater weekend bedtime delay, and both short and long periods of weekend oversleep were associated with increased odds of mood, anxiety, substance use, and behavioral disorders, as well as suicidality, tobacco smoking, and poor perceived mental and physical health. ORs ranged from 1.27 to 2.15. The only outcomes not associated with any sleep patterns were past-year injury and eating disorder. CONCLUSIONS: Suboptimal sleep patterns were associated with an array of mental disorders and other health related outcomes among adolescents. Abnormal sleep patterns may serve as markers of prodromal or untreated mental disorders among adolescents, and may provide opportunities for prevention and intervention in mental disorders. PMID- 27939123 TI - Feeding Methods at Discharge Predict Long-Term Feeding and Neurodevelopmental Outcomes in Preterm Infants Referred for Gastrostomy Evaluation. AB - OBJECTIVE: To test the hypothesis that oral feeding at first neonatal intensive care unit discharge is associated with less neurodevelopmental impairment and better feeding milestones compared with discharge with a gastrostomy tube (G tube). STUDY DESIGN: We studied outcomes for a retrospective cohort of 194 neonates <37 weeks' gestation referred for evaluation and management of feeding difficulties between July 2006 and July 2012. Discharge milestones, length of hospitalization, and Bayley Scales of Infant Development-Third Edition scores at 18-24 months were examined. chi2, Mann-Whitney U, or t tests and multivariable logistic regression models were used. RESULTS: A total of 60% (n = 117) of infants were discharged on oral feedings; of these, 96% remained oral-fed at 1 year. The remaining 40% (n = 77) were discharged on G-tube feedings; of these, 31 (40%) remained G-tube dependent, 17 (22%) became oral-fed, and 29 (38%) were on oral and G-tube feedings at 1 year. Infants discharged on a G-tube had lower cognitive (P <.01), communication (P = .03), and motor (P <.01) composite scores. The presence of a G-tube, younger gestation, bronchopulmonary dysplasia, or intraventricular hemorrhage was associated significantly with neurodevelopmental delay. CONCLUSIONS: For infants referred for feeding concerns, G-tube evaluations, and feeding management, the majority did not require a G-tube. Full oral feeding at first neonatal intensive care unit discharge was associated with superior feeding milestones and less long-term neurodevelopmental impairment, relative to full or partial G-tube feeding. Evaluation and feeding management before and after G-tube placement may improve long-term feeding and neurodevelopmental outcomes. PMID- 27939124 TI - Household Consumption of Thiamin-Fortified Fish Sauce Increases Erythrocyte Thiamin Concentrations among Rural Cambodian Women and Their Children Younger Than 5 Years of Age: A Randomized Controlled Efficacy Trial. AB - OBJECTIVES: To assess whether ad libitum consumption of thiamin-fortified fish sauce over 6 months yields higher erythrocyte thiamin diphosphate concentrations (eTDP) among women of childbearing age and their children aged 12-59 months compared with control sauce containing no thiamin. STUDY DESIGN: In this double blind, randomized controlled efficacy trial, 276 nonpregnant, nonlactating women (18-45 years of age) and their families in Prey Veng, Cambodia, were randomized to receive 1 of 3 fish sauce formulations: low thiamin concentration (low, 2 g/L), high thiamin concentration (high, 8 g/L), or a control (no thiamin) fish sauce. Baseline (t = 0) and endline (t = 6 months) eTDP were measured with the use of high-performance liquid chromatography with a fluorescence detector. RESULTS: Fish sauce consumption did not differ between treatment groups (P = .19). In intent-to-treat analysis, women's baseline-adjusted endline eTDP (mean; 95% CI) was higher among women in the low (259; 245-274 nmol/L) and high (257; 237-276 nmol/L) groups compared with control (184; 169-198 nmol/L; P < .001); low and high groups did not differ (P = .83). Similarly, children's baseline-adjusted eTDP was higher in the low (259; 246-271 nmol/L) and high (257; 243-270 nmol/L) groups compared with control (213; 202-224 nmol/L; P < .001). CONCLUSION: Fortified fish sauce appears to be an efficacious means of improving biochemical thiamin status in nonpregnant, nonlactating women and their children (1-5 years of age) living in rural Cambodia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02221063. PMID- 27939125 TI - Radiologic Response Assessment in Pediatric Soft Tissue Sarcoma: Computed Assisted Volume Evaluation. AB - OBJECTIVES: To compare 3 methods of dimensional assessment, with particular attention to a new software assisted method of volume calculation, in soft tissue sarcoma, and to investigate the interobserver agreement and the intermethod agreement in chemotherapy response classification and resultant clinical repercussions. STUDY DESIGN: We studied 34 pediatric patients with nonmetastatic soft tissue sarcoma who had undergone only diagnostic biopsy. Tumor size was measured both at diagnosis and after induction chemotherapy by 3 observers and using 3 measurement methods: maximum axis (1 diameter), estimated volume (3 diameters), and computed volume (software-assisted volume calculation). We used overall concordance correlation coefficient and Bland-Altman statistical methods to assess interobserver agreement and overall concordance correlation coefficient and the kappa Cohen coefficient to assess intermethod agreement. RESULTS: According to overall concordance correlation coefficient, the interobserver agreement was very high for each method, with a slight superiority of the software assisted method; this agreement was not confirmed in Bland-Altman plots for maximum axis and estimated volume methods. According to kappa coefficients, the intermethod agreement in chemotherapy response evaluation was poor. CONCLUSIONS: Computed volume was the most accurate method in soft tissue sarcoma tumor size assessment. One- and 3-dimensional methods are not concordant in chemotherapy response classification. In particular, the maximum axis method underestimates chemotherapy response and can lead to switching the chemotherapy regimen erroneously. PMID- 27939126 TI - Pulmonary arterial hypertension after ibuprofen treatment in the first week of life? PMID- 27939127 TI - Cocontribution of Rotavirus and Pneumococcal Conjugate Vaccines to the Reduction of Pediatric Hospital Visits in Young Children. AB - OBJECTIVE: To assess rotavirus vaccine and pneumococcal conjugate vaccines (PCVs) cumulative impact on the pediatric emergency department visits and hospitalization rates in children <2 years of age in southern Israel between April 2006 and March 2014. STUDY DESIGN: This prospective, population-based observational study calculated the rates of rotavirus gastroenteritis (RVGE), non RVGE, community-acquired alveolar pneumonia (CAAP), nonalveolar lower respiratory tract infection, and all-cause hospital visits. PCV7, PCV13, and rotavirus vaccination programs were implemented in Israel in July 2009, November 2010, and January 2011, respectively. RESULTS: From 2006-2009 to 2013-2014, the rates of hospitilizations for RVGE, non-RVGE, CAAP, and nonalveolar lower respiratory tract infection decreased by 78%, 21%, 46%, and 7%, respectively. In outpatients, the respective decreases were 80%, 16%, 67%, and 14%. All-cause outpatient pediatric emergency department visits and hospitalization rates were reduced by 12% and 11%, respectively. During the peak season (October through March), RVGE, non-RVGE, CAAP, and nonalveolar lower respiratory tract infection hospitalization rates decreased significantly by 86%, 44.6%, 23.3%, and 10.5%, respectively. In outpatients, the respective decreases were 81.7%, 73.5%, 13.8%, and 10.7%. The proportion of RVGE and CAAP (grouped) of all-cause hospitalizations and outpatient pediatric ED visits decreased from 19.9% to 12.3% and from 6.9% to 1.8%, respectively. CONCLUSIONS: Rotavirus vaccine and PCV introduction cocontributed to a rapid, considerable reduction in hospital burden in children <2 years of age. Because seasonalities of both diseases overlap, this reduction is particularly helpful in relieving burdens of disease and care during the most cumbersome morbidity season. PMID- 27939128 TI - Variations in Utilization of Inpatient Rehabilitation Services among Pediatric Trauma Patients. AB - OBJECTIVE: To assess clinical and nonclinical characteristics associated with the use of pediatric inpatient rehabilitation services among children with traumatic injuries. We hypothesized there would be no nonclinical variations in the use of pediatric inpatient rehabilitation services. STUDY DESIGN: Retrospective analysis of 1139 patients who were injured seriously (0-18 years of age) from our institutional trauma registry (2004-2014). Patients' nonclinical and clinical characteristics were analyzed. We used a full matching technique to compare characteristics between those admitted to rehabilitation (cases) to those discharged home (controls). We matched patients by age category, sex, maximum Abbreviated Injury Scale, and body region of maximum Abbreviated Injury Scale. We used survey-based multivariate logistic regression to identify characteristics associated with inpatient rehabilitation services, controlling for multiple injuries, distance from home to rehabilitation center, year of service, hospital length of stay, and clinically relevant interactions. RESULTS: Ninety-eight patients (8.6%) were admitted to inpatient rehabilitation and 968 (85.0%) were discharged home. Black and other minority patients had increased odds of receiving inpatient rehabilitation compared with white patients (OR, 7.6 [P< .001] and OR, 1.6 [P= .03], respectively). Patients with private compared with public insurance had increased odds of receiving inpatient rehabilitation (OR, 2.4; P< .001). CONCLUSIONS: Pediatric inpatient rehabilitation beds are a scarce resource that should be available to those with the greatest clinical need. The mechanism creating differences in the use of inpatient rehabilitation based on nonclinical characteristics such as race/ethnicity or insurance status must be understood to prevent disparities in access to inpatient rehabilitation services. PMID- 27939129 TI - Guillain Barre Syndrome is induced in Non-Obese Diabetic (NOD) mice following Campylobacter jejuni infection and is exacerbated by antibiotics. AB - Campylobacter jejuni is a leading cause of bacterial gastroenteritis linked to several serious autoimmune sequelae such as the peripheral neuropathies Guillain Barre syndrome (GBS) and Miller Fisher syndrome (MFS). We hypothesized that GBS and MFS can result in NOD wild type (WT) mice or their congenic interleukin (IL) 10 or B7-2 knockouts secondary to C. jejuni infection. Mice were gavaged orally with C. jejuni strains HB93-13 and 260.94 from patients with GBS or CF93-6 from a patient with MFS and assessed for clinical neurological signs and phenotypes, anti-ganglioside antibodies, and cellular infiltrates and lesions in gut and peripheral nerve tissues. Significant increases in autoantibodies against single gangliosides (GM1, GQ1b, GD1a) occurred in infected NOD mice of all genotypes, although the isotypes varied (NOD WT had IgG1, IgG3; NOD B7-2-/- had IgG3; NOD IL 10-/- had IgG1, IgG3, IgG2a). Infected NOD WT and NOD IL-10-/- mice also produced anti-ganglioside antibodies of the IgG1 isotype directed against a mixture of GM1/GQ1b gangliosides. Phenotypic tests showed significant differences between treatment groups of all mouse genotypes. Peripheral nerve lesions with macrophage infiltrates were significantly increased in infected mice of NOD WT and IL-10-/- genotypes compared to sham-inoculated controls, while lesions with T cell infiltrates were significantly increased in infected mice of the NOD B7-2-/- genotype compared to sham-inoculated controls. In both infected and sham inoculated NOD IL-10-/- mice, antibiotic treatment exacerbated neurological signs, lesions and the amount and number of different isotypes of antiganglioside autoantibodies produced. Thus, inducible mouse models of post-C. jejuni GBS are feasible and can be characterized based on evaluation of three factors-onset of GBS clinical signs/phenotypes, anti-ganglioside autoantibodies and nerve lesions. Based on these factors we characterized 1) NOD B-7-/- mice as an acute inflammatory demyelinating polyneuropathy (AIDP)-like model, 2) NOD IL-10-/- mice as an acute motor axonal neuropathy (AMAN)-like model best employed over a limited time frame, and 3) NOD WT mice as an AMAN model with mild clinical signs and lesions. Taken together these data demonstrate that C. jejuni strain genotype, host genotype and antibiotic treatment affect GBS disease outcomes in mice and that many disease phenotypes are possible. PMID- 27939130 TI - The Natural History of Pneumonic Tularemia in Female Fischer 344 Rats after Inhalational Exposure to Aerosolized Francisella tularensis Subspecies tularensis Strain SCHU S4. AB - The inbred Fischer 344 rat is being evaluated for testing novel vaccines and therapeutics against pneumonic tularemia. Although primary pneumonic tularemia in humans typically occurs by inhalation of aerosolized bacteria, the rat model has relied on intratracheal inoculation of organisms because of safety and equipment issues. We now report the natural history of pneumonic tularemia in female Fischer 344 rats after nose-only inhalational exposure to lethal doses of aerosolized Francisella tularensis subspecies tularensis, strain SCHU S4. Our results are consistent with initial uptake of aerosolized SCHU S4 from the nasal cavity, lungs, and possibly the gastrointestinal tract. Bacteremia with hematogenous dissemination was first detected 2 days after exposure. Shortly thereafter, the infected rats exhibited fever, tachypnea, and hypertension that persisted for 24 to 36 hours and then rapidly decreased as animals succumbed to infection between days 5 and 8 after exposure. Tachycardia was observed briefly, but only after the core body temperature and blood pressure began to decrease as the animals were near death. Initial neutrophilic and histiocytic inflammation in affected tissues became progressively more fibrinous and necrotizing over time. At death, as many as 1010 colony-forming units were found in the lungs, spleen, and liver. Death was attributed to sepsis and disseminated intravascular coagulation. Overall, the pathogenesis of pneumonic tularemia in the female F344 rat model appears to replicate the disease in humans. PMID- 27939131 TI - A Role for cAMP and Protein Kinase A in Experimental Necrotizing Enterocolitis. AB - Necrotizing enterocolitis (NEC) is a devastating intestinal disease that has been associated with Cronobacter sakazakii and typically affects premature infants. Although NEC has been actively investigated, little is known about the mechanisms underlying the pathophysiology of epithelial injury and intestinal barrier damage. Cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) are important mediators and regulators of apoptosis. To test the hypothesis that C. sakazakii increases cAMP and PKA activation in experimental NEC resulting in increased epithelial apoptosis, we investigated the effects of C. sakazakii on cAMP and PKA in vitro and in vivo. Specifically, rat intestinal epithelial cells and a human intestinal epithelial cell line were infected with C. sakazakii, and cAMP levels and phosphorylation of PKA were measured. An increase in cAMP was demonstrated after infection, as well as an increase in phosphorylated PKA. Similarly, increased intestinal cAMP and PKA phosphorylation were demonstrated in a rat pup model of NEC. These increases were correlated with increased intestinal epithelial apoptosis. The additional of a PKA inhibitor (KT5720) significantly ameliorated these effects and decreased the severity of experimental NEC. Findings were compared with results from human tissue samples. Collectively, these observations indicate that cAMP and PKA phosphorylation are associated with increased apoptosis in NEC and that inhibition of PKA activation protects against apoptosis and experimental NEC. PMID- 27939132 TI - Neuronal Protein 3.1 Deficiency Leads to Reduced Cutaneous Scar Collagen Deposition and Tensile Strength due to Impaired Transforming Growth Factor-beta1 to -beta3 Translation. AB - Neuronal protein 3.1 (P311), a conserved RNA-binding protein, represents the first documented protein known to stimulate transforming growth factor (TGF) beta1 to -beta3 translation in vitro and in vivo. Because TGF-betas play critical roles in fibrogenesis, we initiated efforts to define the role of P311 in skin scar formation. Here, we show that P311 is up-regulated in skin wounds and in normal and hypertrophic scars. Genetic ablation of p311 resulted in a significant decrease in skin scar collagen deposition. Lentiviral transfer of P311 corrected the deficits, whereas down-regulation of P311 levels by lentiviral RNA interference reproduced the deficits seen in P311-/- mice. The decrease in collagen deposition resulted in scars with reduced stiffness but also reduced scar tensile strength. In vitro studies using murine and human dermal fibroblasts showed that P311 stimulated TGF-beta1 to -beta3 translation, a process that involved eukaryotic translation initiation factor 3 subunit b as a P311 binding partner. This resulted in increased TGF-beta levels/activity and increased collagen production. In addition, P311 induced dermal fibroblast activation and proliferation. Finally, exogenous TGF-beta1 to -beta3, each restituted the normal scar phenotype. These studies demonstrate that P311 is required for the production of normal cutaneous scars and place P311 immediately up-stream of TGF betas in the process of fibrogenesis. Conditions that decrease P311 levels could result in less tensile scars, which could potentially lead to higher incidence of dehiscence after surgery. PMID- 27939133 TI - Progressive Structural Defects in Canine Centronuclear Myopathy Indicate a Role for HACD1 in Maintaining Skeletal Muscle Membrane Systems. AB - Mutations in HACD1/PTPLA cause recessive congenital myopathies in humans and dogs. Hydroxyacyl-coA dehydratases are required for elongation of very long chain fatty acids, and HACD1 has a role in early myogenesis, but the functions of this striated muscle-specific enzyme in more differentiated skeletal muscle remain unknown. Canine HACD1 deficiency is histopathologically classified as a centronuclear myopathy (CNM). We investigated the hypothesis that muscle from HACD1-deficient dogs has membrane abnormalities in common with CNMs with different genetic causes. We found progressive changes in tubuloreticular and sarcolemmal membranes and mislocalized triads and mitochondria in skeletal muscle from animals deficient in HACD1. Furthermore, comparable membranous abnormalities in cultured HACD1-deficient myotubes provide additional evidence that these defects are a primary consequence of altered HACD1 expression. Our novel findings, including T-tubule dilatation and disorganization, associated with defects in this additional CNM-associated gene provide a definitive pathophysiologic link with these disorders, confirm that dogs deficient in HACD1 are relevant models, and strengthen the evidence for a unifying pathogenesis in CNMs via defective membrane trafficking and excitation-contraction coupling in muscle. These results build on previous work by determining further functional roles of HACD1 in muscle and provide new insight into the pathology and pathogenetic mechanisms of HACD1 CNM. Consequently, alterations in membrane properties associated with HACD1 mutations should be investigated in humans with related phenotypes. PMID- 27939134 TI - Persistence of Vascular Calcification after Reversal of Uremia. AB - The extent to which vascular calcification is reversible and the possible mechanisms are unclear. To address this, calcified aortas from uremic mice were transplanted orthotopically into normal mice, and the calcium content, histology, and minerals of the allografts were compared with the nontransplanted donor aorta. Calcium content decreased immediately after transplantation but remained constant thereafter, with 68% +/- 12% remaining after 34 weeks. X-ray diffraction showed the presence of apatite in both donor aortas and allografts. Osteoclasts were absent in the allografts and there was no expression of the macrophage marker CD11b, the osteoclast marker tartrate-resistant acid phosphatase, or carbonic anhydrase II. The initial loss of calcium was less in heavily calcified aortas and was associated with an increase in the Ca/P ratio from 1.49 to 1.63, consistent with a loss of nonapatitic calcium. The results indicate that vascular calcification persists after reversal of uremia, because of a lack of active resorption of apatite. This failure to resorb established calcifications may contribute to the severity of vascular calcification and suggests that therapy should be aimed at prevention. PMID- 27939135 TI - Chronic lurasidone treatment normalizes GABAergic marker alterations in the dorsal hippocampus of mice exposed to prenatal immune activation. AB - Prenatal maternal infection represents a risk factor for the development of psychopathologic conditions later in life. Clinical evidence is also supported by animal models in which the vulnerability to develop a schizophrenic-like phenotype likely originates from inflammatory processes as early as in the womb. Prenatal immune challenge, for example, induces a variety of long-term behavioral alterations in mice, such as deficits in recognition and spatial working memory, perseverative behaviors and social impairments, which are relevant to different symptom clusters of schizophrenia. Here, we investigated the modulation of GABAergic markers in the dorsal and ventral hippocampus of adult mice exposed to late prenatal immune challenge with the viral mimetic Poly(I:C) (polyriboinosinic polyribocytidilic-acid) at gestational day 17, and we evaluated the ability of chronic treatment with the multi-receptor antipsychotic lurasidone to modulate the alterations produced by maternal infection. Poly(I:C) mice show a significant reduction of key GABAergic markers, such as GAD67 and parvalbumin, specifically in the dorsal hippocampus, which were normalized by chronic lurasidone administration. Moreover, chronic drug administration increases the expression of the pool of brain derived neurotrophic factor (BDNF) transcripts with the long 3' UTR as well as the levels of mature BDNF protein in the synaptosomal compartment, selectively in dorsal hippocampus. All in all, our findings demonstrate that lurasidone is effective in ameliorating molecular abnormalities observed in Poly(I:C) mice, providing further support to the neuroplastic properties of this multi-receptor antipsychotic drug. PMID- 27939136 TI - Electromagnetic hypersensitivity (EHS) in occupational and primary health care: A nation-wide survey among general practitioners, occupational physicians and hygienists in the Netherlands. AB - Subjects who attribute health complaints to every day levels of non-ionizing electromagnetic fields (EMF) have been referred to as electrohypersensitive (EHS). Previous surveys in Europe showed that 68-75% of general practitioners had ever been consulted on EHS. Given the lack of data on EHS in the Netherlands in the general population and on EHS in occupational settings, we performed a national survey among three professional groups that are likely in the first line of being consulted by EHS individuals. Results show that about one third of occupational hygienists, occupational physicians and general practitioners had ever been consulted by one or more EHS subjects. Many of these professionals considered a causal relationship between EMF and health complaints to some degree plausible, and their approach often included exposure reduction advice. Given the lack of scientific evidence for EHS and how low level EMF exposure could cause reported health complaints and given the finding that the majority of these professionals felt insufficiently informed about EMF and health, targeted information campaigns might assist them in their evidence based dealing with subjects who attribute symptoms to EMF. PMID- 27939137 TI - Temporal variability of blood lead, mercury, and cadmium levels in elderly panel study (2008-2014). AB - BACKGROUND: Biological measurements have been employed as useful biomarkers for exposure. Because of its property of reflecting toxicokinetic differences, however, within-subject variability leads to biased results in epidemiologic studies. METHOD: We examined the variability of lead (Pb), mercury (Hg), and cadmium (Cd) levels in blood samples from 1429 participants among 1677 elderly individuals aged over 60 years who lived in an urban area from August 2008 to April 2015. RESULTS: The geometric means of blood Pb, Hg, Cd were 1.92MUg/dL, 2.48MUg/L, and 1.33MUg/L, and the intra-class correlations (ICCs) were 0.81, 0.71, and 0.83, respectively. The mean values of Pb and Hg levels in this study were lower than the results from single spot samples in other national biomonitoring surveys in Korea, with the exception of Cd was higher than those in other studies. Moreover, the predicted exceedances over the guidance levels for Pb, Hg, and Cd were 1.9%, 4.2%, and 0.3%, respectively. CONCLUSION: Korean elderly were exposed to high levels of Pb, Hg and Cd. Especially, those who had high levels of Cd were continuously exposed to Cd during study period with the 6 collection intervals. Therefore, factors affecting environmental Cd exposure should be further studied in the future. PMID- 27939138 TI - Investigation of the relationship between electroglottogram waveform, fundamental frequency, and sound pressure level using clustering. AB - Although it has been shown in previous research (Orlikoff, 1991; Henrich et al, 2005; Kuang et al, 2014; Awan, 2015) that there exists a relationship between the electroglottogram (EGG) waveform and the acoustic signal, this relationship is still not fully understood. To investigate this relationship, the EGG and acoustic signals were measured for four male amateur choir singers who each produced eight consecutive tones of increasing and decreasing vocal intensity. The EGG signals were processed cycle-synchronously to obtain the discrete Fourier transform, and the data were used as an input to a clustering algorithm. The acoustic signal was analyzed in terms of sound pressure level (dB SPL) and fundamental frequency (fo) of vibration, and the results of both EGG and acoustic analysis were depicted on a two-dimensional plane with fo on the x-axis and SPL on the y-axis. All the subjects were seen to have a weak, near-sinusoidal EGG waveform in their lowest SPL range, whereas increase in SPL coincided with progressive enrichment in harmonic content of the EGG waveforms. The results of the clustering were additionally used to classify waveforms across subjects to enable inter-subject comparisons and assessment of individual strategies of exploring the fo-SPL dimensions. In these male subjects, the EGG waveform shape appeared to vary with SPL and to remain essentially constant with fo over one octave. PMID- 27939139 TI - Influence of yeast and lactic acid bacterium on the constituent profile of soy sauce during fermentation. AB - Soy sauce is a Japanese traditional seasoning composed of various constituents that are produced by various microbes during a long-term fermentation process. Due to the complexity of the process, the investigation of the constituent profile during fermentation is difficult. Metabolomics, the comprehensive study of low molecular weight compounds in biological samples, is thought to be a promising strategy for deep understanding of the constituent contribution to food flavor characteristics. Therefore, metabolomics is suitable for the analysis of soy sauce fermentation. Unfortunately, only few and unrefined studies of soy sauce fermentation using metabolomics approach have been reported. Therefore, we investigated changes in low molecular weight hydrophilic and volatile compounds of soy sauce using gas chromatography/mass spectrometry (GC/MS)-based non targeted metabolic profiling. The data were analyzed by statistical analysis to evaluate influences of yeast and lactic acid bacterium on the constituent profile. Consequently, our results suggested a novel finding that lactic acid bacterium affected the production of several constituents such as cyclotene, furfural, furfuryl alcohol and methional in the soy sauce fermentation process. PMID- 27939140 TI - Prognostic value of non-high-density lipoprotein cholesterol for mortality in patients with coronary heart disease: A systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Recent studies have indicated the predictive value of non high-density lipoprotein cholesterol (non-HDL-C) for mortality in patients without coronary heart disease (CHD). However, its independent prognostic value on patients with CHD has yet been explored. The purpose of this study was to investigate whether non-HDL-C could predict long-term mortality in patients with CHD. METHODS: A comprehensive search for literature was performed in several database, including Medline, the Cochrane library, Embase and 3 Chinese databases. Studies were included if they reported risk estimation of mortality on CHD patients. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated to assess the association. We performed sensitivity analyses to explore the potential sources of heterogeneity. Statistical analyses were carried out by Stata 12.0. RESULTS: After screening 533 studies, 6 trials (follow up range from 18 to 148months) enrolling 11,057 CHD patients were included. CHD patients with high non-HDL-C level at baseline was associated with higher risk of mortality (RR: 1.24, 95%CI: 1.05-1.46, p: 0.011). Results from continuous analyze showed that each 10mg/dl increase in non-HDL-C was associated with an increased risk of mortality in CHD patients (RR: 1.13, 95%CI: 1.06-1.21, p<0.001). CONCLUSION: The increased levels of non-HDL-C were significantly associated with an increased risk of mortality on CHD patients. Baseline non-HDL-C levels might be a practical predictor of long-term death in patients with CHD. PMID- 27939141 TI - Clinical Profile and Changes of Serum Lipid Levels in Epileptic Patients after Cerebral Infarction. AB - BACKGROUND: Antiepileptic drugs (AEDs) may increase development of dyslipidemia and cerebrovascular disease (CVD). We examined the clinical profile and changes of serum lipid levels after AED monotherapy in patients with poststroke epilepsy (PSE) after cerebral infarction (CI). SUBJECTS AND METHODS: Medical records were reviewed in consecutive 2144 CI patients. Monotherapy of valproate, carbamazepine (CBZ), phenytoin (PHT), zonisamide, levetiracetam, or lamotrigine was performed in PSE patients. Serum lipid levels were measured before and at 3 months after AED treatment. RESULTS: The prevalence of PSE was 7.0% in CI patients. The TOAST etiology disclosed large-artery atherosclerosis in 68 patients (45%), cardioembolism in 63 patients (42%), and undetermined cause in 19 patients (13%). CVD risk profile showed obesity of 18 patients (12%), current smoker of 30 patients (20%), hypertension of 75 patients (50%), diabetes mellitus of 32 patients (21%), dyslipidemia of 15 patients (10%), and atrial fibrillation of 63 patients (42%). CBZ or PHT administration increased serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels significantly compared to baseline and AED-untreated controls. Those levels were not increased significantly in other AED and control groups. Serum high-density lipoprotein cholesterol and triglyceride levels did not differ statistically in all groups. CONCLUSIONS: The prevalence of post-CI epilepsy was 7.0%. The pathogenesis contributed to atherothrombosis and cardioembolism. CBZ or PHT administration increased serum TC and LDL-C significantly. Thus, we should pay more attention to serum lipid levels in patients receiving cytochrome P450 (CYP)-induced AEDs, and might considerer switching to non-CYP-induced AEDs in patients with unfavorable serum lipid changes. PMID- 27939142 TI - Venous Infarcts Mimicking Large Vessel Arterial Disease: Watershed Lesions in Deep Cerebral Venous Thrombosis. PMID- 27939143 TI - Synthetic, organic compound vepoloxamer (P-188) potentiates tissue plasminogen activator. AB - OBJECTIVE: Poloxamer-188 is a synthetic, organic compound that acts by binding hydrophobic pockets on damaged lipid bilayers in the circulation. P-188 reduces blood viscosity and confers anti-inflammatory and cytoprotective effects. Vepoloxamer (Mast Therapeutics, San Diego, Calif) is a purified version of this compound that has limited side effects. The aim of this study was to investigate drug interactions between vepoloxamer and heparin and tissue plasminogen activator (tPA). METHODS: An experimental rat tail transection model was used to study vepoloxamer's interaction with heparin. Sprague-Dawley rats were divided into saline (1 mL/kg; group 1) or vepoloxamer (25 mg/kg; group 2) treatment groups. The rats were then subjected to saline (n = 6), low-dose heparin (125 MUg/kg; n = 6), or high-dose heparin (250 MUg/kg; n = 6). After 5 minutes, the distal 2 mm of the tail was transected, and time to clot formation was measured as bleeding time. A rat internal jugular vein thrombosis model was used to assess vepoloxamer's interaction with tPA. Sprague-Dawley rats were divided into saline (1 mL/kg; group 1) or vepoloxamer (25 mg/kg; group 2) treatment groups. After internal jugular vein thrombosis, rats were treated with saline (n = 6), systemic low-dose tPA (0.5 mg/kg; n = 6), or systemic high-dose tPA (1.0 mg/kg; n = 6). Clot lysis was assessed using an ultrasound Doppler probe to detect blood flow. No flow up to 15 minutes was recorded as no lysis. RESULTS: Interaction with heparin: Vepoloxamer by itself, without any heparin, increased tail bleeding time (10.3 vs 7.1 minutes; P = .001). Effects of heparin on tail bleeding time were enhanced by vepoloxamer at low dose (14.2 vs 6.2 minutes; P < .001). At high-dose heparin, vepoloxamer did not prolong bleeding time (17.8 vs 17.0 minutes). Interaction with tPA: No rat exhibited spontaneous clot lysis with either saline or vepoloxamer. The effect of tPA was facilitated by vepoloxamer at low dose, as more rats showed clot lysis (4/6 [66%]) compared with tPA alone, which showed no clot lysis (0/6), although statistical significance was not reached (P = .06). At high-dose tPA, vepoloxamer had no additional effects on clot lysis (5/6 [83% ] vs 4/6 [66%]). CONCLUSIONS: Vepoloxamer alone modestly increased bleeding time. Vepoloxamer also increased bleeding time in rats treated with low-dose heparin but not with high-dose heparin. Vepoloxamer potentiated clot lysis in the setting of low-dose tPA. PMID- 27939144 TI - Computational Methods in Systems Biology. PMID- 27939145 TI - Whole genome SNP analysis of bovine B. anthracis strains from Switzerland reflects strict regional separation of Simmental and Swiss Brown breeds in the past. AB - Bacillus anthracis is an evolutionarily young species that presents an extremely low genetic diversity due to its slow mode of propagation, determined by short replication phases and long sporulation periods. In our ongoing efforts to elucidate phylogenetic relationships between European B. anthracis isolates, the genomes of five strains from Switzerland belonging to lineages B.Br.CNEVA and A.Br.Aust94 were sequenced. Comparative analysis with additional, available genomes from both lineages, were used to reconstruct the substructure of these populations. Genome-wide single-nucleotide polymorphism analysis revealed two phylogeographical different groups among the Swiss B.Br.CNEVA strains (central and eastern Switzerland), that define the oldest most recent common ancestor of the B.Br.CNEVA lineage currently known. Age-old practices of livestock selection, breeding and preservation of unique traits of local breeds in Alpine valleys have likely favored differentiation of regional B. anthracis populations over centuries and the emergence of genetically distinct strains in an otherwise similar environment. PMID- 27939146 TI - Recombinant NDV expressing cytokines or fliC confers a quick immune response against NDV challenge and resistance to maternal antibody. AB - Currently, there are two major bottleneck problems which seriously affect prevention of the Newcastle disease (ND): interference of maternal antibody on NDV vaccination and slow production of neutralization antibody. To overcome these problems, in present study, four rNDV vaccine strains expressing bio-adjuvants chIL2, chIL15, chGM-CSF or fliC gene were constructed and rescued using reverse genetics approach. The HI antibody titers of SPF birds immunized with rNDV reached to 5.5log2, 4.7log2, 6.5log2 and 5.8log2, respectively at the 8th day post immunization, while the antibody titers of the parental virus and control were 3.3log2 and 1log2, respectively. The immunized chickens were challenged by 104ELD50 dose of the virulent NDV BJ strains at the 7th day post immunization. The protection rate of the four rNDVs bio-adjuvant groups was 100%, while the protection rate of the parental group was 80%. We also examined the anti-maternal antibody activity of these adjuvant vaccines by detection HI titer after vaccination of chickens with high (8.4log2) or low (5log2) maternal antibody levels. In chicken flock with higher maternal antibody, parental strain could not resist the influence of the maternal antibody and induce any notable change of HI antibody kinetics. However, both rClon30-chGM-CSF and rClon30-flic were able to resist the influence of the maternal antibody and maintained the HI antibody above the protection level during the 14day's experiment. In chicken flock with lower maternal antibody, the parental rclone30 strain could not induce HI titer to the protection level until the 14th day, but both rClon30-GM-CSF and clone30 fliC raised the HI antibody to above the protection level at the 7th day post vaccination. PMID- 27939147 TI - Genetic characterization of Australian Mycoplasma bovis isolates through whole genome sequencing analysis. AB - Mycoplasma bovis is a major pathogen in cattle causing mastitis, arthritis and pneumonia. First isolated in Australian cattle in 1970, M. bovis has persisted causing serious disease in infected herds. To date, genetic analysis of Australian M. bovis isolates has not been performed. With whole genome sequencing (WGS) becoming a common tool for genetic characterization, this method was utilized to determine the degree of genetic diversity among Australian M. bovis isolates collected over a nine year period (2006-2015) from various geographical locations, anatomical sites, and from clinically affected and non-clinical carrier animals. Eighty-two M. bovis isolates underwent WGS from which single nucleotide polymorphism (SNP) analysis, comparative genomics and analysis of virulence genes was completed. SNP analysis identified a single M. bovis strain circulating throughout Australia with marked genomic similarity. Comparative genomics suggested minimal variation in gene content between isolates from clinical and carrier animals, and between isolates recovered from different anatomical sites. A total of 50 virulence genes from the virulence factors database (VFDB) were identified as highly similar in the Australian isolates, while the presence of variable surface lipoprotein (vsp) genes was greatly reduced compared to reference strain M. bovis PG45. These results highlight that, while the introduction of multiple M. bovis strains has been prevented, elimination of the current strain has not been successful. The persistence of this strain may be due to the significant role that carrier animals play in harboring the pathogen. The similarity of clinical and non-clinical isolates suggests host and environmental factors play a significant role in determining host pathogen outcomes. PMID- 27939148 TI - Detection of the biofilm component polysaccharide intercellular adhesin in Staphylococcus aureus infected cow udders. AB - Biofilms are communities of microorganisms embedded in a self-produced extracellular matrix made up of polymeric substances. They reduce the effects of antibiotics and allow the microorganisms to evade the innate immune system. This can lead to persistent or recurrent infections. In dairy cow herds, mastitis is a serious problem. The present study aimed to investigate the occurrence of biofilms in the udders of dairy cows infected with Staphylococcus (S.) aureus, because biofilms may affect the response to treatment of bovine mastitis. Immunofluorescence staining of polysaccharide intercellular adhesin (PIA), a component of S. aureus biofilms, was carried out based on swabs taken from different areas of S. aureus infected udders. We were able to demonstrate the presence of PIA in S. aureus infected bovine udders. However, the applied method is invasive and therefore only really suitable for scientific research and not for clinical diagnosis. PMID- 27939149 TI - Kinetics of maternally derived antibodies upon intramuscular vaccination against classical swine fever with Suvaxyn(r) CSF Marker (CP7_E2alf). AB - Classical swine fever (CSF) remains one of the most important viral diseases that impact on sustainable pig production world wide. To control the disease in either endemic situations or in case of large, high-impact contingencies, safe and highly efficacious live attenuated vaccines exist since decades. However, until recently, the available live vaccines did not allow a serological marker concept that would be important to circumvent long-term trade restrictions. Recently, a new live attenuated marker vaccine, Suvaxyn(r) CSF Marker (Zoetis), was licensed by the European Medicines Agency (EMA). To supplement the data that are necessary for the design of appropriate vaccination strategies, a trial was carried out with single "emergency-type" vaccination of two pregnant sows. Focus was laid on the kinetics of maternally derived antibodies (MDA) in the screening assays of their offspring that would be used in case of a CSF outbreaks, i.e. CSFV E2 and Erns antibody ELISA. Neutralization peroxidase linked antibody assays were carried out to allow a rough estimate of protection. Upon vaccination with Suvaxyn(r) CSF Marker 21days before farrowing, MDAs were measurable in all piglets born to the vaccinated sows. The E2 ELISA reactivities showed an almost linear decrease over 10 weeks after which all piglets were tested negative in the ELISA again. No problems were observed in DIVA assays (Erns antibodies) when heat inactivated sera were used. The protective effect of MDA needs further investigations as the titers were found to be lower than reported for C-strain vaccines. PMID- 27939151 TI - Effective interference between Simbu serogroup orthobunyaviruses in mammalian cells. AB - The Simbu serogroup of orthobunyaviruses comprises a wide range of viruses with different medical and veterinary relevance. These viruses are known to reassort, and coinfection of the same cell is one of the prerequisites for reassortment. Here, a mammalian cell line was infected with various members of this virus group, inoculated after several time points with a second Simbu serogroup virus, and analyzed by strain or species specific immunofluorescence staining. Different virus species or different strains of the same virus species were able to co infect mammalian cells, but only for a limited time frame. After a few hours, the replication of the first virus led to a gradual inhibition of a second virus until a complete resistance to superinfection after 24h regardless whether it is another strain of the same virus species or a distinct member of the serogroup. PMID- 27939150 TI - Haemophilus parasuis modulates cellular invasion via TGF-beta1 signaling. AB - TGF-beta1 plays an important role during the invasion of some bacteria into cells by regulating the expression of integrins, fibronectin, and other extracellular matrix proteins. We postulated that TGF-beta1 levels could affect the invasion of Haemophilus parasuis into PK-15 cells. After infection by H. parasuis, PK-15 cells had elevated levels of TGF-beta1 expression. Treatment of PK-15 cells with TGF-beta1 prior to infection significantly decreased invasion by H. parasuis. Both TGF-beta1 treatment and H. parasuis infection resulted in significant induction of fibronectin (Fn) and alpha5 integrin. Although pretreatment of PK-15 cells with siRNA fragments targeting Fn and alpha5 integrin resulted in enhanced H. parasuis invasion, H. parasuis attachment was elevated only on cells treated with the alpha5 integrin siRNA, there was no corresponding increase in attachment to cells treated with Fn siRNA. Our results firstly demonstrated that expression of TGF-beta1, Fn and alpha5 integrin inhibited invasion of H. parasuis in PK-15 cells. PMID- 27939152 TI - Whole-genome characterization of a Peruvian alpaca rotavirus isolate expressing a novel VP4 genotype. AB - The SA44 isolate of Rotavirus A (RVA) was identified from a neonatal Peruvian alpaca presenting with diarrhea, and the full-length genome sequence of the isolate (designated RVA/Alpaca-tc/PER/SA44/2014/G3P[40]) was determined. Phylogenetic analyses showed that the isolate possessed the genotype constellation G3-P[40]-I8-R3-C3-M3-A9-N3-T3-E3-H6, which differs considerably from those of RVA strains isolated from other species of the order Artiodactyla. Overall, the genetic constellation of the SA44 strain was quite similar to those of RVA strains isolated from a bat in Asia (MSLH14 and MYAS33). Nonetheless, phylogenetic analyses of each genome segment identified a distinct combination of genes. Several sequences were closely related to corresponding gene sequences in RVA strains from other species, including human (VP1, VP2, NSP1, and NSP2), simian (VP3 and NSP5), bat (VP6 and NSP4), and equine (NSP3). The VP7 gene sequence was closely related to RVA strains from a Peruvian alpaca (K'ayra/3368 10; 99.0% nucleotide and 99.7% amino acid identity) and from humans (RCH272; 95% nucleotide and 99.0% amino acid identity). The nucleotide sequence of the VP4 gene was distantly related to other VP4 sequences and was designated as the reference strain for the new P[40] genotype. This unique genetic makeup suggests that the SA44 strain emerged from multiple reassortment events between bat-, equine-, and human-like RVA strains. PMID- 27939153 TI - Whole-genome comparative analysis of the pathogen Piscirickettsia salmonis. AB - The intracellular pathogen Piscirickettsia salmonis is the etiological agent of piscirickettsiosis, the most important bacterial disease that affects the Chilean salmon industry. Despite its importance, little is known regarding the biology of the pathogen. In this study, recently published sequencing data was used in order to characterize the genome of P. salmonis, defining groups of genes associated with bacterial processes such as, invasion and intracellular survival. Moreover, one Chilean P. salmonis isolate, which is known to be virulent at in vitro and in vivo assays, was sequenced, assembled, annotated and functionally characterized. Whole-genome comparisons between public P. salmonis isolates confirmed the existence of two different genogroups associated with the LF-89 and EM-90 strains, and the bacterial pan and core genome were defined. Additionally, differences were observed at the genomic level between the P. salmonis reference strain and a Norwegian isolate, which is known to produce milder piscirickettsiosis outbreaks. Finally, candidate genes for invasion and intracellular survival were chosen from phylogenetically related bacteria, and annotated in P. salmonis using comparative genomics. These results showed the presence of several genes that might be related to bacterial pathogenesis, for example those of the type III, IV and VI secretion systems, in which some amino acidic differences within both genogroups and the Norwegian isolate were established. Altogether, these results will be relevant for understanding the host-pathogen interaction and further studies, aimed at generating new disease control strategies, should be devised using this information. PMID- 27939154 TI - High and low-virulent bovine Pasteurella multocida capsular type A isolates exhibit different virulence gene expression patterns in vitro and in vivo. AB - Pasteurella multocida capsular type A causes respiratory disease in cattle. P. multocida virulence gene expression patterns, especially among different virulent isolates, during in vitro and in vivo growth are poorly understood. Here we show that the highly virulent bovine P. multocida capsular type A isolate PmCQ2 exhibits a significantly higher growth rate in mice, as compared with a strain of lower virulence, P. multocida capsular type A isolate PmCQ6. Among the six known and potential virulence genes (ompA, ompH, pfhB2, hasR, pm0979, and pm0442) investigated, most genes were expressed more highly in both isolates when grown in vivo as compared with in vitro, with ompH and pm0442 having the highest magnitude of expression. Virulence gene expression was higher in PmCQ6 than in PmCQ2 during in vitro growth. However, in mice, most virulence genes were expressed more highly in PmCQ2 as compared with PmCQ6. Virulence gene expression was highest in the liver and lowest in the lung, but was uncorrelated to bacterial loads. This study indicates that individual pathogenic capacity of P. multocida isolates is associated with the virulence gene expression patterns in vivo growth but not in vitro, and the investigation of virulence gene expression in pathogen should be performed in vivo. PMID- 27939156 TI - WITHDRAWN: Evaluating the association between body weight and the intestinal microbiota of weaned piglets via 16S rRNA sequencing. AB - This article has been removed: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).The publisher regrets that an error occurred due to a technical issue which led to the premature publication of this paper. This error bears no reflection on the article or its authors. The publisher apologizes to the authors and the readers for this unfortunate error. PMID- 27939155 TI - Efficacy of the marker vaccine rAdV-SFV-E2 against classical swine fever in the presence of maternally derived antibodies to rAdV-SFV-E2 or C-strain. AB - Classical swine fever (CSF) is an economically important disease caused by Classical swine fever virus (CSFV). In order to eradicate CSF, many marker vaccines that allow differentiation of infected from vaccinated animals (DIVA) have been developed. In our previous studies, a DIVA CSF vaccine rAdV-SFV-E2 has been demonstrated to completely protect pigs against lethal CSFV challenge. In the context of risk assessments for an emergency vaccination scenario, the question has been raised whether preexisting maternally derived antibodies (MDAs) interfere with the efficacy of the vaccine. In this study, six groups of piglets (n=5), with or without anti-C-strain or anti-rAdV-SFV-E2 MDAs, were immunized twice with 106 TCID50 rAdV-SFV-E2 and challenged with the CSFV Shimen strain. Clinical signs, CSFV-specific antibodies, viremia and pathological and histopathological changes were monitored. The results showed that the vaccinated piglets, either with or without MDAs directed against C-strain (about 67% blocking rate) or rAdV-SFV-E2 (about 50% blocking rate) were completely protected; however, the mock-vaccinated piglets displayed severe CSF-typical clinical symptoms, viremia, pathological/histopathological changes and deaths (5/5). These findings demonstrate that the MDAs to either rAdV-SFV-E2 or C-strain do not interfere with the efficacy of rAdV-SFV-E2, which highlights the great potential of the vaccine for control and eradication of CSF. PMID- 27939157 TI - A dominant lineage of Mycoplasma bovis is associated with an increased number of severe mastitis cases in cattle. AB - Mycoplasma bovis is the most frequent etiologic agent of bovine mycoplasmosis. It causes various diseases in bovines and considerable economic loss due to the lack of effective treatment or preventive measures such as vaccination. In contrast to the US, where M. bovis-mastitis has been reported for a long time, M. bovis infections in Switzerland and Austria were predominantly associated with pneumonia and subclinical mastitis. However, since 2007 the situation has changed with the emergence of severe M. bovis-associated mastitis cases in both countries. In order to evaluate the molecular epidemiology of the bacteria isolated from these infections, recent and old Swiss, along with recent Austrian M. bovis isolates were analyzed by a typing method displaying intermediate resolution of evolutionary relationships among isolates called Multi-Locus Sequence Typing (MLST). The analysis of Swiss and Austrian M. bovis isolates revealed two major lineages. Isolates collected since 2007 in both countries cluster in the lineage I including ST5, ST33, ST34, 36, and ST38-40 (clonal complex 1), while all Swiss isolates recovered before 2007 cluster in the lineage II comprising ST17 and ST35 (clonal complex 5). Further investigations are necessary to understand if lineage I has a higher predilection or virulence toward mammary gland cells than the old lineage or if other factors are involved in the increased number of severe mastitis cases. PMID- 27939158 TI - The arcA gene contributes to the serum resistance and virulence of Haemophilus parasuis serovar 13 clinical strain EP3. AB - As a global transcriptional factor, ArcA regulates the expression of hundreds of genes involved in aerobic and anaerobic metabolism. Here we deleted arcA gene and investigated the biological characteristics of arcA deletion mutant (DeltaarcA) in Haemophilus parasuis (H. parasuis) serovar 13 clinical strain EP3. Results indicated that deletion of arcA impaired growth of EP3 strain under anaerobic condition, and reduced virulence of EP3 strain in mice. Additionally, the DeltaarcA strain showed greater sensitivity in porcine serum and produced less biofilm mass than the EP3 strain. Taken together, these findings suggested that the arcA gene may be involved in pathogenesis in Haemophilus parasuis. PMID- 27939159 TI - Lambs are an important source of atypical enteropathogenic Escherichia coli in southern Brazil. AB - Food-producing animals can harbor Escherichia coli strains with potential to cause diseases in humans. In this study, the presence of enteropathogenic E. coli (EPEC) was investigated in fecal samples from 130 healthy sheep (92 lambs and 38 adults) raised for meat in southern Brazil. EPEC was detected in 19.2% of the sheep examined, but only lambs were found to be positive. A total of 25 isolates was characterized and designated atypical EPEC (aEPEC) as tested negative for bfpA gene and BFP production. The presence of virulence markers linked to human disease as ehxA, paa, and lpfAO113 was observed in 60%, 24%, and 88% of the isolates, respectively. Of the 11 serotypes identified, eight were described among human pathogenic strains, while three (O1:H8, O11:H21 and O125:H19) were not previously detected in aEPEC. Associations between intimin subtypes and phylogroups were observed, including eae-theta2/A, eae-beta1/B1, eae-alpha2/B2 and eae-gamma1/D. Although PFGE typing of 16 aEPEC isolates resulted in 14 unique pulsetypes suggesting a genetic diversity, specific clones were found to be distributed in some flocks. In conclusion, potentially pathogenic aEPEC strains are present in sheep raised for meat, particularly in lambs, which can better contribute to dissemination of these bacteria than adult animals. PMID- 27939160 TI - Chlamydial infections in wildlife-conservation threats and/or reservoirs of 'spill-over' infections? AB - Members of the order Chlamydiales are biphasic intracellular pathogens known to cause disease in both humans and animals. As we learn more about the genetic diversity of this group of pathogens, evidence is growing that these bacteria infect a broader range of animal hosts than previously thought. Over 400 host species are now documented globally with the majority of these being wild animals. Given the impact of chlamydial infections on humans and domesticated animals, the identification of members of the order Chlamydiales in wildlife raises significant questions over a) their impact on animal health and b) the relationships to those strains also found in humans and domestic animals. In some species such as the iconic marsupial, the koala, the conservation impact is known with chlamydial infections associated with debilitating disease, however, in general, little is known about the pathogenic potential of Chlamydiae infecting most wildlife hosts. Accumulating evidence suggests contact with wild animals is a risk factor for infections in domestic animals and/or humans. Beyond the well recognised zoonotic pathogen, Chlamydia psittaci, a range of studies have now reported traditional pathogens in the family Chlamydiaceae such as Chlamydia pecorum, Chlamydia suis, Chlamydia pneumoniae and Chlamydia abortus in wild animals. The spectre of cross-host transmission 'spill-over' and 'spill-back' in the epidemiology of infections is of potential concern, however, comprehensive epidemiological studies are lacking for most of these. Accurate evaluation of the significance of chlamydial infections in wildlife is otherwise hampered by i) the cross-sectional nature of most impact studies, ii) a lack of standardised diagnostic approaches, iii) limited study sizes, and iv) biases associated with opportunistic sampling. PMID- 27939161 TI - Epidemiologic analysis of a sarcoid outbreak involving 12 of 111 donkeys in Northern Italy. AB - Equine sarcoids develop upon bovine papillomavirus type 1 or 2 (BPV1, BPV2) infection in conjunction with trauma and represent the most common tumour disease in horses and other equids, including donkeys. In face of a sarcoid outbreak involving 12 of 111 donkeys and mules at the 'Rifugio degli Asinelli', a subsidiary charity organization of The Donkey Sanctuary, non-invasively collected sample material including crusts, dandruff, swabs and hair roots was collected from sarcoid-affected and 26 healthy donkeys, as well as dandruff from a grooming kit and tabanids caught from or in the vicinity of sarcoid patients. In addition five previously collected sarcoids stored in formalin were provided. DNA isolated from collected material was tested for the presence of the BPV1/2 E5 oncogene using PCR. Positive samples were further analysed by E2/E4 and LCR PCR and amplicon sequencing to determine a possible common source of infection via comparative alignment of intralesional BPV1/2 gene variants. IC/PCR was used to assess sample aliquots for the presence of BPV1/2 virions, and IHC to analyse five tumours for BPV1 E5 and L1 protein expression. All sarcoid-affected donkeys, two of 55 tabanids and dandruff from a curry comb tested positive for BPV1/2 E5, yet negative by IC/PCR. Healthy animals were BPV1/2-free. IHC revealed different levels of intralesional E5 and L1 expression. A series of BPV1 E5, E2, and LCR variants and BPV2 E5 were detected from donkeys, indicating that they had accidently developed sarcoids at about the same time rather than having acquired disease from each other. PMID- 27939162 TI - Impact of a potential glycosylation site at neuraminidase amino acid 264 of influenza A/H9N2 virus. AB - To determine the role of the potential glycosylation site NA264N, which has been shown to be prevalent in recent Chinese H9N2 isolates, four reverse genetic viruses, rgWS1-NA264N, rgWS1-NA264H, rgBJ-NA264H and rgBJ-NA264N, were rescued. Growth kinetics showed that viruses with NA264H grew faster than viruses with NA264N. Mouse studies revealed that rgBJ-NA264H replicated to a significantly higher titer than rgBJ-NA264N at 3dpi. Notably, in contact chickens, rgBJ-NA264H and rgWS1-NA264H shed significantly more virus than rgBJ-NA264N at 6dpi from the larynx and rgWS1-NA264N at 4dpi from the cloaca, respectively. The present study demonstrates that NA264N affects viral replication of H9N2. PMID- 27939163 TI - Evidence of Brucella strain ST27 in bottlenose dolphin (Tursiops truncatus) in Europe. AB - Marine mammal brucellosis has been known for more than 20 years, but recent work suggests it is more widespread than originally thought. Brucella (B.) pinnipedialis has been isolated from pinnipeds, while B. ceti strains have been associated with cetaceans. Here we report a Brucella strain isolated from multiple lymph nodes of one bottlenose dolphin (Tursiops truncatus) during routine examination of dolphin carcasses found in the Croatian part of the northern Adriatic Sea during the summer of 2015. Classical bacteriological biotyping, PCR-based techniques (single, multiplex, PCR-RFLP) and 16S rRNA DNA sequencing were used to identify Brucella spp. Multiple-locus variable number tandem repeat analysis of 16 loci and multilocus sequence typing of 9 loci were used for genotyping and species determination. The combination of bacteriological, molecular and genotyping techniques identified our strain as ST27, previously identified as a human pathogen. This report provides, to our knowledge, the first evidence of ST27 in the Adriatic Sea in particular and in European waters in general. The zoonotic nature of the strain and its presence in the Adriatic, which is inhabited by bottlenose dolphins, suggest that the strain may pose a significant threat to human health. PMID- 27939164 TI - Isolation, genomic characterization, and pathogenicity of a Chinese porcine deltacoronavirus strain CHN-HN-2014. AB - Porcine deltacoronavirus (PDCoV) is an emerging swine coronavirus that causes diarrhea in piglets. Since the first outbreak of PDCoV in the United States in 2014, this novel porcine coronavirus has been detected in South Korea, Canada, Mexico, Thailand, and China. In this study, a Chinese PDCoV strain, designated CHN-HN-2014, was isolated from piglets with severe diarrhea on a pig farm in Henan Province, China, and examined with a specific immunofluorescence assay and electron microscopy. Genomic analysis showed that CHN-HN-2014 shares 91.6%-99.4% nucleotide identity with other known PDCoV strains. The pathogenicity of CHN-HN 2014 was further investigated in 5-day-old and 21-day-old piglets. Both kinds of piglets developed clear clinical symptoms, including vomiting, anorexia, lethargy, and severe diarrhea, by 2days postinoculation (DPI), and diarrhea persisted for about 5-6 days. Viral shedding was detected in rectal swabs until 14 DPI in challenged 5-day-old pigs and until 18 DPI in challenged 21-day-old pigs. At necropsy at 4 DPI, macroscopic and microscopic lesions were observed and viral antigen was detected in the small intestines with immunohistochemical staining. These data demonstrate that Chinese PDCoV strain CHN-HN-2014 shares high nucleotide identity with previously reported PDCoV strains and is pathogenic in 5-day-old and 21-day-old piglets. PMID- 27939166 TI - Letter on the article "A rare tumour of the neck in a child". PMID- 27939165 TI - Using residential segregation to predict colorectal cancer stage at diagnosis: two different approaches. AB - PURPOSE: Studies have found a variety of evidence regarding the association between residential segregation measures and health outcomes in the United States. Some have focused on any individuals living in residentially segregated places, whereas others have examined whether persons of specific races or ethnicities living in places with high segregation of their own race or ethnicity have differential outcomes. This article compares and contrasts these two approaches in the study of predictors of late-stage colorectal cancer (CRC) diagnoses in a cross-national study. We argue that it is very important when interpreting results from studies like this to carefully consider the geographic scope of the analysis, which can significantly change the context and meaning of the results. METHODS: We use US Cancer Statistics Registry data from 40 states to identify late-stage diagnoses among over 500,000 CRC cases diagnosed during 2004 2009. We pool data over the states and estimate a multilevel model with person, county, and state levels and a random intercepts specification to ensure robust effect estimates. The isolation index of residential segregation is defined for racial and ethnic groups at the county level using Census 2000 data. The association between isolation indices and late-stage CRC diagnosis was measured by (1) anyone living in minority-segregated areas (place-centered approach) and by (2) individuals living in areas segregated by one's own racial or ethnic peers (person-centered approach). RESULTS: Findings from the place-centered approach suggest that living in a highly segregated African American community is associated with lower likelihood of late-stage CRC diagnosis, whereas the opposite is true for people living in highly segregated Asian communities, and living in highly segregated Hispanic communities has no significant association. Using the person-centered approach, we find that living in places segregated by one's racial or ethnic peers is associated with lower likelihood of late-stage CRC diagnosis. CONCLUSIONS: In a model that covers a large geographic area across the nation, the place-centered approach is most likely picking up geographic disparities that may be deepened by targeted interventions in minority communities. By contrast, the person-centered approach provides a national average estimate suggesting that residential isolation may confer community cohesion or support that is associated with better CRC prevention. PMID- 27939167 TI - Iron mediated toxicity and programmed cell death: A review and a re-examination of existing paradigms. AB - Iron is an essential micronutrient that is problematic for biological systems since it is toxic as it generates free radicals by interconverting between ferrous (Fe2+) and ferric (Fe3+) forms. Additionally, even though iron is abundant, it is largely insoluble so cells must treat biologically available iron as a valuable commodity. Thus elaborate mechanisms have evolved to absorb, re cycle and store iron while minimizing toxicity. Focusing on rarely encountered situations, most of the existing literature suggests that iron toxicity is common. A more nuanced examination clearly demonstrates that existing regulatory processes are more than adequate to limit the toxicity of iron even in response to iron overload. Only under pathological or artificially harsh situations of exposure to excess iron does it become problematic. Here we review iron metabolism and its toxicity as well as the literature demonstrating that intracellular iron is not toxic but a stress responsive programmed cell death inducing second messenger. PMID- 27939168 TI - PKC mediated phosphorylation of TIMAP regulates PP1c activity and endothelial barrier function. AB - TGF-beta inhibited membrane-associated protein (TIMAP) is greatly expressed in endothelial cell lines and serves as a protein phosphatase 1 (PP1) regulatory subunit. Phosphorylation state of TIMAP, through affecting PP1 activity, has a remarkable effect on endothelial barrier function. Here we present evidence for a previously unidentified PKC phosphorylation site in TIMAP. Protein-protein interaction was detected in pulmonary endothelial cells between endogenous TIMAP and activated PKCalpha. PKCalpha phosphorylated the full length recombinant TIMAP in in vitro kinase assay and Ser331 of TIMAP was shown to be phosphorylated by PKC. Phosphorylation of TIMAP upon PKC activation in endothelial cells results in enrichment of TIMAP in the membrane, but no such change can be observed in PKC depleted cells. However, the previously identified PKA/GSK-3beta induced enrichment of TIMAP at the plasma membrane was not affected in the absence of PKC. Interaction between TIMAP and the TIMAP-PP1 substrate phospho-ERM was described earlier, but now we show that binding of PKC phosphorylated TIMAP to ERM is severely reduced. This suggests an inhibitory effect of phospho-Ser331 on TIMAP-PP1 activity toward phospho-ERM. Accordingly, phospho-ERM level in the membrane fraction of the phospho-mimic S331D TIMAP mutant transfected cells was increased, but the S331A mutant overexpressing endothelial cells had a lower phospho-ERM level. Consistent with the phospho-ERM level, electric resistance measurements showed that the S331A mutation of TIMAP resulted in faster recovery from the PMA treatment. Taken together, phosphorylation of TIMAP on Ser331 by PKC represents a new mechanism of endothelial barrier regulation, through the inhibition of phospho-ERM dephosphorylation. PMID- 27939169 TI - Overcoming barriers to diabetic polyneuropathy management in primary care. AB - Diabetic polyneuropathy is a highly prevalent and costly complication of diabetes that is frequently underdiagnosed and undertreated in primary care settings. In this article, we discuss challenges in the management of diabetic polyneuropathy symptoms, including diagnostic complexity, the limited efficacy and high side effect rates associated with available treatments and the time constrained primary care visit. We call for the development of novel patient-centric, system level strategies that engage patients between physician visits in order to facilitate timely communication of symptoms and treatment response and to promote patient-centered care. PMID- 27939170 TI - Advancing medical device innovation through collaboration and coordination of structured data capture pilots: Report from the Medical Device Epidemiology Network (MDEpiNet) Specific, Measurable, Achievable, Results-Oriented, Time Bound (SMART) Think Tank. AB - The Medical Device Epidemiology Network (MDEpiNet) is a public private partnership (PPP) that provides a platform for collaboration on medical device evaluation and depth of expertise for supporting pilots to capture, exchange and use device information for improving device safety and protecting public health. The MDEpiNet SMART Think Tank, held in February, 2013, sought to engage expert stakeholders who were committed to improving the capture of device data, including Unique Device Identification (UDI), in key electronic health information. Prior to the Think Tank there was limited collaboration among stakeholders beyond a few single health care organizations engaged in electronic capture and exchange of device data. The Think Tank resulted in what has become two sustainable multi-stakeholder device data capture initiatives, BUILD and VANGUARD. These initiatives continue to mature within the MDEpiNet PPP structure and are well aligned with the goals outlined in recent FDA-initiated National Medical Device Planning Board and Medical Device Registry Task Force white papers as well as the vision for the National Evaluation System for health Technology.%. PMID- 27939171 TI - Improving the electronic nexus between generalists and specialists: A public health imperative? AB - Recent changes in healthcare delivery and payment policy have precipitated interest among healthcare providers across the U.S. seeking innovative strategies to achieve higher quality, lower cost care through improved resource-utilization. One dimension of healthcare delivery with distinctive potential for improvement is care coordination between primary care and specialist providers. Optimizing the nexus between PCPs and specialists through innovations including eConsultation platforms portends reductions in unnecessary referrals and testing, and may help align incentives to promote high-value care. Opportunities and challenges surrounding effective and versatile operationalization of such technologies are assessed, focusing on specific public health needs of access and utilization. PMID- 27939172 TI - Stable bipedal walking with a swing-leg protraction strategy. AB - In bipedal locomotion, swing-leg protraction and retraction refer to the forward and backward motion, respectively, of the swing-leg before touchdown. Past studies have shown that swing-leg retraction strategy can lead to stable walking. We show that swing-leg protraction can also lead to stable walking. We use a simple 2D model of passive dynamic walking but with the addition of an actuator between the legs. We use the actuator to do full correction of the disturbance in a single step (a one-step dead-beat control). Specifically, for a given limit cycle we perturb the velocity at mid-stance. Then, we determine the foot placement strategy that allows the walker to return to the limit cycle in a single step. For a given limit cycle, we find that there is swing-leg protraction at shallow slopes and swing-leg retraction at steep slopes. As the limit cycle speed increases, the swing-leg protraction region increases. On close examination, we observe that the choice of swing-leg strategy is based on two opposing effects that determine the time from mid-stance to touchdown: the walker speed at mid-stance and the adjustment in the step length for one-step dead-beat control. When the walker speed dominates, the swing-leg retracts but when the step length dominates, the swing-leg protracts. This result suggests that swing leg strategy for stable walking depends on the model parameters, the terrain, and the stability measure used for control. This novel finding has a clear implication in the development of controllers for robots, exoskeletons, and prosthetics and to understand stability in human gaits. PMID- 27939173 TI - Proposing a new index to quantify instantaneous symmetry during manual wheelchair propulsion. AB - Propelling a manual wheelchair (MWC) is a strenuous task that causes upper limb musculoskeletal disorders (MSD) in a large proportion of MWC users. Although most studies on MWC propulsion biomechanics assume that MWC propulsion is a relatively symmetric task, recent literature suggests that this is the case only when the assessed outcome measures are averaged over long periods of time, and not over short periods (i.e., instantaneously). No method is currently available to assess instantaneous symmetry. In this work, we present the Instantaneous Symmetry Index (ISI), a new method that quantifies how a variable has been instantaneously asymmetric during a selected time period. Thirteen experienced MWC users propelled on different cross slopes of 0%, 2%, 4%, 6% and 8%. As the cross slope is increased, the upper hand produced less propulsive moments and the lower hand produced more propulsive movements. This has been reflected in the ISI, which increased from 0.20 (0% slope) to 0.84 (8% slope) with a Spearman's coefficient of 0.90. The ISI has great potential to evaluate the ability of a user to propel symmetrically and synchronously, and will be a relevant measure to include in future studies on the impact of MWC propulsion asymmetry on MSD risk. PMID- 27939174 TI - Challenges in the development of an M4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs. AB - This letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration). PMID- 27939175 TI - Synthesis, characterization, and in vitro SAR evaluation of N,N'-bis(arylmethyl) C2-alkyl substituted imidazolium salts. AB - A series of C2-alkyl substituted N,N'-bis(arylmethyl)imidazolium salts were synthesized, characterized, and tested for their in vitro anti-cancer activity against multiple non-small cell lung cancer cell lines by our group and the National Cancer Institute's-60 human tumor cell line screen to establish a structure-activity relationship. Compounds are related to previously published N,N'-bis(arylmethyl)imidazolium salts but utilize the historical quinoline motif and anion effects to increase the aqueous solubility. Multiple derivatives displayed high anti-cancer activity with IC50 values in the nanomolar to low micromolar range against a panel of non-small cell lung cancer cell lines. Several of these derivatives have high aqueous solubilities with potent anti proliferative properties and are ideal candidates for future in vivo xenograft studies and have high potential to progress into clinic use. PMID- 27939176 TI - Lack of impact of umbilical cord blood unit processing techniques on clinical outcomes in adult double cord blood transplant recipients. AB - BACKGROUND AIMS: Despite widespread use of umbilical cord blood (UCB) transplantation and distinct practice preferences displayed by individual UCB banks and transplant centers, little information exists on how processing variations affect patient outcomes. METHODS: We reviewed 133 adult double UCB transplants performed at a single center: 98 after reduced-intensity and 35 after myeloablative conditioning. Processing associated with contributing UCB banks and units was surveyed to identify differences in practice. We analyzed effect of selected variables on clinical outcomes of engraftment, dominance, transplant related mortality, and survival. RESULTS: Eighty-eight percent of banks queried currently practice red blood cell (RBC) depletion before cryopreservation. This reflects a shift in practice because previously 65% of banks employed RBC-replete processing methods (i.e., cryopreservation or plasma/volume reduction). Neither neutrophil nor platelet engraftment was affected by processing conditions analyzed. RBC depletion was not associated with clinical outcomes, except in 17 recipients of 2 RBC-replete units, where survival was better than that observed in 116 recipients of >=1 RBC-depleted units (hazard ratio 3.26, P = 0.004). When analyzed by attributes of the dominant unit, RBC depletion, time in storage, bank years in existence, and inventory size did not affect clinical outcomes. Postthaw viability and CD34 dose were factors impacting engraftment. Notably, all RBC replete units in this cohort were washed in dextran-human serum albumin before infusion. DISCUSSION: These findings support continued utilization of the entire existing pool of cord blood units, despite recent trends in processing, and have important implications for banking resources and UCB selection practices. PMID- 27939177 TI - The ER-mitochondria encounter structure contributes to hyphal growth, mitochondrial morphology and virulence of the pathogenic mold Aspergillus fumigatus. AB - Aspergillus fumigatus is an opportunistic fungal pathogen and the primary causative species of invasive aspergillosis, a systemic disease associated with high mortality rates. Treatment of invasive fungal infection relies on a very limited number of antifungal drug classes. In order to extend the spectrum of antifungal drugs novel target structures have to be identified. The ER mitochondria encounter structure (ERMES), a recently discovered tether that links mitochondria and endoplasmic reticulum, is a potential drug target based on its absence in Metazoa. Very recently, it was shown that ERMES is important for the fitness and immune evasion of the pathogenic yeast Candida albicans. We studied the role of the four ERMES core components Mdm10, Mdm12, Mdm34 and Mmm1 in the pathogenic mold A. fumigatus. By construction and characterizing conditional mutants of all four core components and deletion mutants of mdm10 and mdm12, we show that each component is of significant importance for growth of the fungal pathogen. While markedness of the individual mutant phenotypes differed slightly, all components are important for maintenance of the mitochondrial morphology and the intra-organellar distribution of nucleoids. Characterization of the Mmm1 ERMES mutant in a Galleria mellonella infection model indicates that ERMES contributes to virulence of A. fumigatus. Our results demonstrate that pharmacologic inhibition of ERMES could exert antifungal activity against this important pathogen. PMID- 27939178 TI - Establishing a standard protocol for the voiding cystourethrography. AB - The voiding cystourethrogram (VCUG) is a frequently performed test to diagnose a variety of urologic conditions, such as vesicoureteral reflux (VUR). The test results determine whether continued observation or an interventional procedure is indicated. VCUGs are ordered by many specialists and primary care providers, including pediatricians, family practitioners, nephrologists, hospitalists, emergency room physicians, and urologists. Current protocols for performing and interpreting a VCUG are based on the International Reflux Study in 1985. However, more recent information provided by many national and international institutions suggests a need to refine those recommendations. The lead author of the 1985 study, R.L. Lebowitz, agreed to and participated in the current protocol. In addition, a recent survey directed to the chairpersons of pediatric radiology of 65 children's hospitals throughout the United States and Canada showed that VCUG protocols vary substantially. Recent guidelines from the American Academy of Pediatrics (AAP) recommend a VCUG for children between 2 and 24 months of age with urinary tract infections but did not specify how this test should be performed. To improve patient safety and to standardize the data obtained when a VCUG is performed, the AAP Section on Radiology and the AAP Section on Urology initiated the current VCUG protocol to create a consensus on how to perform this test. PMID- 27939179 TI - Importance of neuropsychiatric evaluation in children with primary monosymptomatic enuresis. AB - BACKGROUND: Nocturnal enuresis (NE) is an involuntary voiding during sleep. It is a very common disorder in school-age children. Comorbid psychopathologies are common in patients affected by enuresis. According to the ICCS, the rate of behavioral and emotional disorders in children with enuresis is doubled compared with healthy control (HC) children. OBJECTIVE: The aim of the present study was to investigate the prevalence of neuropsychiatric comorbidities in children affected by NE. STUDY DESIGN: Two hundred children with a diagnosis of enuresis were recruited from the Neuropsychiatric Unit of Catania University and 200 age matched neurologically intact HC children were recruited from local schools. The inclusion criteria were a normal IQ and the absence of other pathological clinical conditions such as diabetes or kidney malformation. The exclusion criteria were failure to complete the initial evaluation or clinical/diagnostic procedures, inability (because of young age) to complete study questionnaires, and severe neurological or physical impairment. RESULTS: Age and gender proportions were not significantly different between the groups. In the NE group, 138 subjects (69%) had a familial history of NE, compared with 24 subjects (12%) in the HC group (p < 0.01). The NE group demonstrated significantly higher scores in the Child Behavior Check List, Conners' Multidimensional Anxiety Scale for Children, and the Child Depression Inventory compared than the HC group as well as the Yale Global Tic Severity Score and Child-Yale-Brown Obsessive Compulsive Scale scores (p < 0.01). Quality of life scores were significantly lower in the NE group than in the HCs group; specifically, between-group differences were significant in the relationship and self domains (p > 0.01 for both comparisons) (Figure). DISCUSSION: The present case-control study evaluates the prevalence of different neuropsychiatric comorbidities in children with NE as diagnosed according to the new ICCS criteria. An important finding was that neuropsychiatric conditions were more prevalent in NE patients than in age matched HC subjects. To the best of our knowledge, this is the first study to report associations between enuresis and obsessive compulsive disorder as well as tic disorder, and is the first to describe the comparative psychopathological profiles of 200 children with enuresis and 200 matched HC children. CONCLUSION: The results suggest that clinicians should not underestimate the effects of enuresis on psychosocial development. Childhood NE should be managed carefully and comprehensively in order to prevent the development of more serious behavioral problems in the future. PMID- 27939180 TI - Long-term morbidity after staging laparotomy for Hodgkin lymphoma. AB - BACKGROUND: A large cohort of Hodgkin lymphoma (HL) survivors exist. With patients transitioning from pediatric to adult care, practitioners should be aware of potential complications. The aim of this study was to describe the long term complications of patients who had staging laparotomy for the treatment of HL. METHODS: After institutional review board approval, a retrospective review of hospital records at our institution was performed. Data extracted included demographics, treatment course and long-term postoperative complications. RESULTS: 24 patients with HL underwent staging laparotomy from 1971 to 1994 with median follow-up of 27.9years. Six (33%) had intraabdominal disease. Three patients (17%) required four repeat laparotomies for bowel obstruction. Of these, one had radiation to the inguinal region for local control, one had mantle radiation. Five patients developed a second malignancy. There were no documented cases of postsplenectomy sepsis. Other late effects that were unlikely related to surgery included pulmonary fibrosis (4), heart failure (2), hypothyroidism (4), and dysphagia (3). One patient died of metastatic adenocarcinoma. CONCLUSIONS: Long-term follow-up of patients who underwent staging laparotomy for HL revealed an increased incidence of repeat laparotomy and secondary malignancy. This underscores the importance of a high index of suspicion and screening in this population. LEVEL OF EVIDENCE: Level III. PMID- 27939181 TI - Chronic ankle instability: Arthroscopic anatomical repair. AB - INTRODUCTION: Ankle sprains are one of the most common injuries. Despite appropriate conservative treatment, approximately 20-40% of patients continue to have chronic ankle instability and pain. In 75-80% of cases there is an isolated rupture of the anterior talofibular ligament. MATERIAL AND METHOD: A retrospective observational study was conducted on 21 patients surgically treated for chronic ankle instability by means of an arthroscopic anatomical repair, between May 2012 and January 2013. There were 15 men and 6 women, with a mean age of 30.43 years (range 18-48). The mean follow-up was 29 months (range 25-33). All patients were treated by arthroscopic anatomical repair of anterior talofibular ligament. Four (19%) patients were found to have varus hindfoot deformity. Associated injuries were present in 13 (62%) patients. There were 6 cases of osteochondral lesions, 3 cases of posterior ankle impingement syndrome, and 6 cases of peroneal pathology. All these injuries were surgically treated in the same surgical time. RESULTS: A clinical-functional study was performed using the American Orthopaedic Foot and Ankle Society (AOFAS) score. The mean score before surgery was 66.12 (range 60-71), and after surgery it increased up to a mean of 96.95 (range 90-100). All patients were able to return to their previous sport activity within a mean of 21.5 weeks (range 17-28). Complications were found in 3 (14%) patients. CONCLUSIONS: Arthroscopic anatomical ligament repair technique has excellent clinical-functional results with a low percentage of complications, and enables patients to return to their previous sport activity within a short period of time. PMID- 27939182 TI - Implementing Precision Medicine: The Ethical Challenges. AB - Precision medicine aims to individualize care by understanding differences in genetics, lifestyle, and environment. Pharmacogenomics and cancer genetics represent two promising areas for this approach. Pharmacogenomic tests have the potential to direct drug prescribing to increase safety and effectiveness because individuals vary on a genetic basis in their response to many drugs. Similarly, tests to identify people with an inherited cancer risk can guide prevention. For both, a few tests have entered clinical practice and more are under development. Implementation challenges include the limited evidence base available to guide clinical use and the lack of data from diverse populations. Accordingly, ongoing research should prioritize procedures that enhance the trustworthiness of clinical practice guidelines and create decision support for clinicians and patients that address their needs and accommodate flexibility. Each step involves choices with ethical implications. PMID- 27939183 TI - Emergence of polymyxin resistance in Gram-negative bacteria. PMID- 27939184 TI - Reply by the Authors. PMID- 27939185 TI - Ovulation, fertilization and preimplantation embryonic development in raccoon dogs (Nyctereutes procyonoides). AB - A study involving 32 sexual mature females was conducted to characterize ovulation, fertilization and early embryonic development in vivo in raccoon dogs. Oocytes and embryos were collected from the oviducts and uteri, evaluated by stereomicroscopy. Ovulation occurred 25-32h after a female first accepted mounting, regardless of copulation, when the females were paired with a male in the same cage. Ovulated oocytes were at the primary stage. The number of ovulated eggs in females with or without mating was 9.96+/-2.65 and 9.00+/-1.92, respectively. Embryos at 2-4 cell, 8-16 cell, morula, blastocyst, and hatched blastocyst stage were observed at 29-73, 48-100, 98-126, 169-198 and 217-268h after first mating, respectively. Embryos were located in the oviduct prior to 4 cell stage and moved into the uterus after 16-cell stage. Embryos at different stages were often obtained from the same female. During the zygote underwent a series of cleavage divisions, the diameter of the embryo cell mass continuously increased through the 2-cell and 4-cell stage, then started to decrease and was the minimum size at the morula stage. At the blastocyst stage, embryos increased in volume, and finally developed into a hatching blastocyst with a thinner zona pellucida. This is the first full report of preimplantation embryonic development in the raccoon dog, which will facilitate the application of advanced assisted reproductive technology in canine species. PMID- 27939186 TI - Structure, thermodynamic and kinetic signatures of a synthetic polyelectrolyte coacervating system. AB - While many studies on coacervation have targeted biomacromolecules, we review in this article the key structure, thermodynamic and kinetic features of a fully synthetic coacervating system based on polyacrylic acid (PAA) and poly(diallyldimethylammonium chloride) (PDADMAC) oppositely charged polyelectrolytes at pH10, where PAA chains are fully deprotonated. Among the main points of interest, we can highlight (i) the presence of polyelectrolyte complex (PEC) nanoparticles that, unexpectedly, coexist with a certain amount of coacervate droplets in a large range of compositions, even far from stoichiometry; (ii) the fact that these PEC nanoparticles are likely precursors of the coacervation occurring at stoichiometry; (iii) the formation of soluble PECs only in a certain range of physicochemical conditions; (iv) the equilibrium properties of the system; (v) and last but not least a distinctive kinetic signature at stoichiometry evidenced by a peak in light scattering at very short times (~100ms). Some of these results can be rationalized on the basis of weak interaction unfolding between oppositely charged PAA and PDADMAC chains as revealed by microcalorimetry measurements. PMID- 27939187 TI - Statistical learning of an auditory sequence and reorganization of acquired knowledge: A time course of word segmentation and ordering. AB - Previous neural studies have supported the hypothesis that statistical learning mechanisms are used broadly across different domains such as language and music. However, these studies have only investigated a single aspect of statistical learning at a time, such as recognizing word boundaries or learning word order patterns. In this study, we neutrally investigated how the two levels of statistical learning for recognizing word boundaries and word ordering could be reflected in neuromagnetic responses and how acquired statistical knowledge is reorganised when the syntactic rules are revised. Neuromagnetic responses to the Japanese-vowel sequence (a, e, i, o, and u), presented every .45s, were recorded from 14 right-handed Japanese participants. The vowel order was constrained by a Markov stochastic model such that five nonsense words (aue, eao, iea, oiu, and uoi) were chained with an either-or rule: the probability of the forthcoming word was statistically defined (80% for one word; 20% for the other word) by the most recent two words. All of the word transition probabilities (80% and 20%) were switched in the middle of the sequence. In the first and second quarters of the sequence, the neuromagnetic responses to the words that appeared with higher transitional probability were significantly reduced compared with those that appeared with a lower transitional probability. After switching the word transition probabilities, the response reduction was replicated in the last quarter of the sequence. The responses to the final vowels in the words were significantly reduced compared with those to the initial vowels in the last quarter of the sequence. The results suggest that both within-word and between word statistical learning are reflected in neural responses. The present study supports the hypothesis that listeners learn larger structures such as phrases first, and they subsequently extract smaller structures, such as words, from the learned phrases. The present study provides the first neurophysiological evidence that the correction of statistical knowledge requires more time than the acquisition of new statistical knowledge. PMID- 27939188 TI - Effects of working memory training on neural correlates of Go/Nogo response control in adults with ADHD: A randomized controlled trial. AB - Working memory and response control are conceptualized as functions that are part of a closely connected and integrated executive function system mediated by the prefrontal cortex and other related brain structures. In the present paper, we asked whether effects of intensive and adaptive computerized working memory training (CWMT) would generalize to enhancements in response control at behavioral and neural levels. A total of 135 postsecondary students with Attention-Deficit/Hyperactivity Disorder (ADHD), a condition associated with executive function impairments, were randomized into a Standard-length CWMT (45 min /session, 25 sessions), Shortened-length CWMT (15min/session, 25 sessions), and a waitlist group. Both training groups received CWMT for 5 days a week for 5 weeks long. All participants completed a Go-Nogo task while neural activity was measured using Electroencephalography (EEG), before and after CWMT. Behavioral results showed trend level evidence (p=0.061) for benefits of CWMT on response control (i.e., improved accuracy of Go responses). Among several neural measures results showed statistically significant changes after CWMT only for the Go trial ERP N2 and P3 in frontal electrodes (p=0.039 and 0.001, respectively). However, given the lack of relationship between behavioral and neural changes and especially the clear lack of predicted does effects (i.e., standard length > short length > control), we conclude that there is no convincing evidence that the working memory training per se changes neural activation patterns in untrained executive functions. The positive finding of general training related changes in this study should have no clinical implications, but may contribute to the literature in better understanding the relationship between neural plasticity and transfer. PMID- 27939189 TI - Linking language to the visual world: Neural correlates of comprehending verbal reference to objects through pointing and visual cues. AB - In everyday communication speakers often refer in speech and/or gesture to objects in their immediate environment, thereby shifting their addressee's attention to an intended referent. The neurobiological infrastructure involved in the comprehension of such basic multimodal communicative acts remains unclear. In an event-related fMRI study, we presented participants with pictures of a speaker and two objects while they concurrently listened to her speech. In each picture, one of the objects was singled out, either through the speaker's index-finger pointing gesture or through a visual cue that made the object perceptually more salient in the absence of gesture. A mismatch (compared to a match) between speech and the object singled out by the speaker's pointing gesture led to enhanced activation in left IFG and bilateral pMTG, showing the importance of these areas in conceptual matching between speech and referent. Moreover, a match (compared to a mismatch) between speech and the object made salient through a visual cue led to enhanced activation in the mentalizing system, arguably reflecting an attempt to converge on a jointly attended referent in the absence of pointing. These findings shed new light on the neurobiological underpinnings of the core communicative process of comprehending a speaker's multimodal referential act and stress the power of pointing as an important natural device to link speech to objects. PMID- 27939190 TI - Effects of acoustic periodicity and intelligibility on the neural oscillations in response to speech. AB - Although several studies have investigated neural oscillations in response to acoustically degraded speech, it is still a matter of debate which neural frequencies reflect speech intelligibility. Part of the problem is that effects of acoustics and intelligibility have so far not been considered independently. In the current electroencephalography (EEG) study the amount of acoustic periodicity (i.e. the amount of time the stimulus sentences were voiced) was manipulated, while using the listeners' spoken responses to control for differences in intelligibility. Firstly, the total EEG power changes in response to completely aperiodic (noise-vocoded) speech and speech with a natural mix of periodicity and aperiodicity were almost identical, while an increase in theta power (5-6.3Hz) and a trend for less beta power (11-18Hz) were observed in response to completely periodic speech. These two effects are taken to indicate an information processing conflict caused by the unnatural acoustic properties of the stimuli, and that the subjects may have internally rehearsed the sentences as a result of this. Secondly, we separately investigated effects of intelligibility by sorting the trials in the periodic condition according to the listeners' spoken responses. The comparison of intelligible and largely unintelligible trials revealed that the total EEG power in the delta band (1.7-2.7Hz) was markedly increased during the second half of the intelligible trials, which suggests that delta oscillations are an indicator of successful speech understanding. PMID- 27939191 TI - An elevated pro-inflammatory cytokines profile in Behcet's disease: A multiplex analysis. AB - The serum levels of sixteen cytokines related to innate immunity, Th1, Th2 and Th17 cells in the sera of 44 patients with Behcet's Disease (BD) and 44 healthy controls have been investigated using the cytokine array technique. Among the cytokines related to innate immunity, the levels of IL-1alpha, IL-1 beta, IL-6, IL-12, IL-15 and TNF-alpha were statistically higher in BD patients than healthy controls. In the case of Th1- and Th17-related cytokines, IL-2, IFN-gamma, IL-17 and IL-23 were significantly higher in patients. From Th2-related cytokines, only IL-13 showed statistically higher levels in patients than controls. Among different evaluated cytokines, the differences in IL-1 alpha, IL-1 beta, IL-6 and ?innate-related cytokines were more prominent between cases and controls. In addition, the results showed that ?innate- and ?Th17-related cytokines are better indicators of cytokines imbalances in BD than each one of the innate- and Th17 related cytokines. Moreover, disease activity score and clinical activity index can also be affected by the levels of pro-inflammatory (IL-6) and anti inflammatory (IL-4) cytokines. In conclusion, the results revealed that imbalances in the expression of innate immunity- as well as Th1- and Th17-related cytokines may play not only a pivotal role in BD pathogenesis but also can be important in disease severity. PMID- 27939193 TI - Three-Dimensional Echocardiographic Assessment of a Paravalvular Leak. PMID- 27939192 TI - Ultrasound-Guided Serratus Anterior Plane Block Versus Thoracic Epidural Analgesia for Thoracotomy Pain. AB - OBJECTIVE: Thoracotomy is one of the most painful surgical procedures. The aim of this study was to assess the efficacy and safety of ultrasound-guided serratus anterior plane block (SAPB) compared with thoracic epidural analgesia (TEA) for controlling acute thoracotomy pain. DESIGN: A prospective, randomized, observer blinded, controlled study. SETTING: The study was performed as a single institution study in the National Cancer Institute, Cairo University, Egypt. PARTICIPANTS: All participants were cancer patients scheduled for thoracotomy. INTERVENTIONS: This study was conducted from February to December 2015. Forty patients scheduled for thoracotomy under general anesthesia were allocated randomly into 1 of 2 groups with 20 patients each. SAPB was performed before extubation with an injection of 30 mL of 0.25% levobupivacaine followed by 5 mL/hour of 0.125% levobupivacaine. In the TEA group, thoracic epidural catheters were inserted preoperatively to be activated before extubation using a lower dose regimen to the SAPB group. Heart rate, mean arterial pressure, and the visual analog pain score (VAS) measurements were recorded for 24 hours. Rescue analgesia using intravenous morphine, 0.1 mL/kg, was administered if the VAS was >3. MEASUREMENTS AND MAIN RESULTS: Compared with preoperative values, the mean arterial pressure in the SAPB group did not change significantly (p = 0.181), whereas it decreased significantly (p = 0.006) in the TEA group. VAS scores and the total dose of morphine consumed were comparable in the 2 groups. CONCLUSIONS: SAPB appeared to be a safe and effective alternative for postoperative analgesia after thoracotomy. PMID- 27939194 TI - An analysis of aerosol liquid water content and related impact factors in Pearl River Delta. AB - Aerosol liquid water content (ALWC) has an important effect on atmospheric visibility as well as heterogeneous chemical reactions. In this paper, we used the data size-resolved particle hygroscopic growth factor, and particle number size distribution (PNSD) obtained from H-TDMA and SMPS to compute ALWC at the Guangzhou Panyu site from the winter of 2014 and the spring of 2015. The corresponding results were relatively consistent with the trend for ALWCISO calculated from the ISORROPIA II thermodynamic equilibrium model based on the measurement of aerosol water-soluble ionic compositions obtained from MARGA, with a linear fit yielding an R2 value of 0.76. The fact that ALWCHTDMA was somewhat higher than ALWCISO at low RH values was at least partially attributable to the fact that effects resulting from organic matter hygroscopicity were not taken into account when computing ALWCISO. In sensitivity testing, ambient relative humidity, PNSD and particle hygroscopicity were all found to affect ALWC, in that order. Particles of different modes made different contributions to ALWC with the contributions of nuclear, Aitken, accumulation and coarse modes assessed at <1%, 3%, 85% and 12%, respectively, indicating that the contribution of accumulation mode particles to ALWC dominated among all the aerosol particle modes. During clean processes, decreases in relative humidity and PM2.5 both resulted in a decrease in ALWC. During the pollution processes, calm winds caused local particle accumulation, with ALWC increasing as RH increased. Intraday trends in ALWC and relative humidity were consistent, with minimum mean values observed in the afternoon due to low ambient relative humidity inhibiting an increase in ALWC. However, diurnal variation of aerosol hygroscopicity and ALWC tended to be somewhat anti-correlated, indicating that diurnal changes in aerosol hygroscopicity are not a primary factor resulting in ambient AWLC changes. PMID- 27939195 TI - Characterization of transformations of maize residues into soil organic matter. AB - An awareness of the transformation of plant residues returned to cultivated soils is vital for a better understanding of carbon cycles, the maintenance of soil fertility and the practice of a sustainable agriculture. The transformation of maize (Zea mays L) straw residues into soil organic matter (SOM) in a one year incubation experiment was studied in a soil that had been under long term cultivation with wheat (Triticum aestivum L) for >30years. A novel sequential exhaustive extraction and fractionation procedure isolated a series of fractions of SOM. The samples were characterized by elemental and delta13C analyses, by amino acids and neutral sugars analyses, by Fourier transformed infrared (FTIR) spectrometry, and by solid state 13C nuclear magnetic resonance (NMR) spectroscopy and with chemical shift anisotropy (CSA) -filter and dipolar dephasing (DD) spectral editing NMR techniques. The delta13C data indicated that 59% and 38% of the newly transformed organic carbon was in the humic and fulvic acid fractions, respectively, and in general a greater proportion of the transformed carbon was in the fractions isolated at the higher pH values. Results for SOM fractions from the amended soil indicate dominant contributions from carbohydrate and lignin-like material, and that can be clearly identified by FTIR, CP/TOSS, and spectral editing of CSA-filter and DD. The compositions of the fractions from the amended and non-amended soils fractions can be clearly differentiated using principal component analysis (PCA) for the data collected. The sequential extraction procedure showed that the hydrophilicity of humic fractions increased as the result of the maize amendment, and the aromaticity of the fraction decreased. The data may give some indications of transformations that take place during humification processes. PMID- 27939196 TI - Progesterone potentially degrades to potent androgens in surface waters. AB - Progesterone is a natural hormone, excreted in higher concentrations than estrogens, and has been detected in the aqueous environment. As with other compounds, it is transformed during wastewater treatment processes and in the environment. However, minor modifications to the structure may result in transformation products which still exhibit biological activity, so understanding what transformation products are formed is of importance. The current study was undertaken to identify putative transformation products resulting from spiking river water with progesterone in a laboratory-based degradation study and hence to follow the metabolic breakdown pathways. On the basis of literature reports and predictions from the EAWAG Biocatalysis/biodegradation database, target putative transformation products were initially monitored under unit resolution mass spectrometry. The identity of these transformation products was confirmed by using accurate-mass quadrupole time-of-flight. The study results highlight that transformation of progesterone can potentially create other classes of steroids, some of which may still be potent, and possess other types of biological activity. PMID- 27939197 TI - Experimental considerations in metal mobilization from soil by chelating ligands: The influence of soil-solution ratio and pre-equilibration - A case study on Fe acquisition by phytosiderophores. AB - The efficiency of chelating ligands in mobilizing metals from soils and sediments is generally examined under conditions remote from those under which they are exuded or applied in the field. This may lead to incorrect estimations of the mobilizing efficiency. The aim of this study was to establish the influence of the soil solution ratio (SSR) and pre-equilibration with electrolyte solution on metal mobilization and metal displacement. For this purpose a series of interaction experiments with a calcareous clay soil and a biogenic chelating agent, the phytosiderophore 2'-deoxymugineic acid (DMA) were carried out. For a fixed ligand concentration, the SSR had a strong influence on metal mobilization and displacement. Metal complexation was faster at higher SSR. Reactive pools of metals that were predominantly mobilized at SSR 6 (in this case Cu), became depleted at SSR 0.1, whereas metals that were marginally mobilized at SSR 6, were dominantly mobilized at SSR 0.1 (in this case Fe), because of large soil reactive pools. For a fixed "amount of ligand"-to-"amount of soil"-ratio, metal complexation scaled linearly with the SSR. The efficiency of ligands in mobilizing metals under field conditions can be predicted with batch experiments, as long as the ligand-to-soil-ratio is matched. In most previously reported studies this criterion was not met. Equivalent metal-complex concentrations under field conditions can be back-calculated using adsorption isotherms for the respective metal-complexes. Drying and dry storage created labile pools of Fe, Cu and Zn, which were rapidly mobilized upon addition of DMA solution to dry soil. Pre-equilibration decreased these labile pools, leading to smaller concentrations of these metals during initial mobilization, but did not reduce the lag time between ligand addition and onset of microbial degradation of the metal complexes. Hence SSR and pre-equilibration should be carefully considered when testing the metal mobilizing efficiency of chelating ligands. PMID- 27939198 TI - Indicators of improved water access in the context of schistosomiasis transmission in rural Eastern Region, Ghana. AB - Populations with poor access to water, sanitation and hygiene (WASH) infrastructure are disproportionately affected by the neglected tropical diseases (NTDs). As a result, WASH has gained increasing prominence in integrated control and elimination of NTDs, including schistosomiasis. In order to identify underserved populations, relevant measures of access to WASH infrastructure at sub-national or local levels are needed. We conducted a field survey of all public water sources in 74 rural communities in the Eastern Region of Ghana and computed indicators of water access using two methods: one based on the design capacity and another on the spatial distribution of water sources. The spatial method was applied to improved and surface water sources. According to the spatial method, improved water sources in the study area were well-distributed within communities with 95% (CI95%: 91, 98) of the population having access within 500m when all, and 87% (CI95%: 81, 93) when only functional water sources were considered. According to the design capacity-based method, indicator values were lower: 63% (CI95%: 57, 69) for all and 49% (CI95%: 43, 55) for only functional sources. Surface water access was substantial with 62% (CI95%: 54, 71) of the population located within 500m of a perennial surface water source. A negative relationship was observed between functional improved water access and surface water access within 300m. In this context, perceived water quality of the improved sources was also important, with a 17% increase in surface water access in towns with one reported water quality problem as compared to towns with no problems. Our study offers a potential methodology to use water point mapping data to identify communities in need of improved water access to achieve schistosomiasis risk reduction. PMID- 27939199 TI - Damage assessment for soybean cultivated in soil with either CeO2 or ZnO manufactured nanomaterials. AB - With increasing use, manufactured nanomaterials (MNMs) may enter soils and impact agriculture. Herein, soybean (Glycine max) was grown in soil amended with either nano-CeO2 (0.1, 0.5, or 1.0gkg-1 soil) or nano-ZnO (0.05, 0.1, or 0.5gkg-1 soil). Leaf chlorosis, necrosis, and photosystem II (PSII) quantum efficiency were monitored during plant growth. Seed protein and protein carbonyl, plus leaf chlorophyll, reactive oxygen species (ROS), lipid peroxidation, and genotoxicity were measured for plants at harvest. Neither PSII quantum efficiency, seed protein, nor protein carbonyl indicated negative MNM effects. However, increased ROS, lipid peroxidation, and visible damage, along with decreased total chlorophyll concentrations, were observed for soybean leaves in the nano-CeO2 treatments. These effects correlated to aboveground leaf, pod, and stem production, and to root nodule N2 fixation potential. Soybeans grown in soil amended with nano-ZnO maintained growth, yield, and N2 fixation potential similarly to the controls, without increased leaf ROS or lipid peroxidation. Leaf damage was observed for the nano-ZnO treatments, and genotoxicity appeared for the highest nano-ZnO treatment, but only for one plant. Total chlorophyll concentrations decreased with increasing leaf Zn concentration, which was attributable to zinc complexes-not nano-ZnO-in the leaves. Overall, nano-ZnO and nano-CeO2 amended to soils differentially triggered aboveground soybean leaf stress and damage. However, the consequences of leaf stress and damage to N2 fixation, plant growth, and yield were only observed for nano-CeO2. PMID- 27939200 TI - Newly graduated nurses' intention to leave in their first year of practice in Shanghai: A longitudinal study. AB - BACKGROUND: During the transition, newly graduated nurses undergo complex challenges, which exacerbate their intention to leave. PURPOSE: To examine the longitudinal change of intention to leave and identify the potential factors of intention to leave in the first year. METHODS: A total of 343 newly graduated nurses were included in this longitudinal study. Nurses were surveyed to explore their intention to leave, occupational stress, coping style, professional identity, and locus of control. Data were analyzed using descriptive statistics and logistic regression analysis. DISCUSSION: The high prevalence rate of intention to leave in the first year of practice of newly graduated nurses is alarming. This study reveals that occupational stress and professional identity consistently predict intention to leave. CONCLUSION: In planning retention strategies, nurse managers should provide support to neophyte nurses to reduce their stress and enhance their professional identity. PMID- 27939201 TI - Cardiac atlas development and validation for automatic segmentation of cardiac substructures. AB - PURPOSE: To develop and validate a set of atlases for auto-contouring cardiac substructures. METHODS: Eight radiation oncologists manually and independently delineated 15 cardiac substructures from noncontrast CT images of 6 patients by referring to their respective fused contrast CT images. Individual contours were fused together for each structure, edited by 2 physicians, and became atlases to delineate other 6 patients. The auto-delineated contours of the 6 additional patients became templates for manual contouring. These 12 patients with well defined contours composed the final atlases for multi-atlas segmentation. RESULTS: The average time for manually contouring the 15 cardiac substructures was about 40min. Inter-observer variability was small for the heart, the chambers, and the aorta compared with that for other structures that were not clearly distinguishable in CT images. The mean dice similarity coefficient and mean surface distance of auto-segmented contours were within one standard deviation of expert contouring variability. Good agreement between auto-segmented and manual contours was observed for the heart, the chambers, and the great vessels. Independent validation on other 19 patients showed reasonable agreement for the heart chambers. CONCLUSIONS: A set of cardiac atlases was created for auto-contouring from noncontrast CT images. The accuracy of auto-contouring for the heart, chambers, and great vessels was validated for potential clinical use. PMID- 27939202 TI - G2-checkpoint targeting and radiosensitization of HPV/p16-positive HNSCC cells through the inhibition of Chk1 and Wee1. AB - BACKGROUND AND PURPOSE: HPV-positive HNSCC cells are characterized by radiosensitivity, inefficient DNA double-strand break repair and a profound and prolonged arrest in G2. Here we explored the effect of clinically relevant inhibitors of Chk1 and Wee1 to inhibit the radiation-induced G2-arrest in order to achieve further radiosensitization. MATERIAL AND METHODS: Assessment of Chk1 activity by Western blot; assessment of cell cycle distribution by propidium iodide staining and flow cytometry; assessment of cell survival by colony formation assay. HPV+ HNSCC cell lines: UD-SCC-2, UM-SCC-47 and UPCI-SCC-154; Chk1 inhibitors: LY2603618, MK8776; Wee1 inhibitor: AZD1775. RESULTS: Specific Chk1 inhibitors efficiently abrogated the radiation-induced G2-arrest and caused radiosensitization. Wee-inhibition by AZD1775 resulted in the activation of Chk1. This feedback mechanism is likely to counteract some of the effects of Wee1 inhibition but could be antagonized through the combined inhibition of both kinases. Combined inhibition was effective using profoundly reduced concentrations of both inhibitors and resulted in more efficient radiosensitization of the HPV-positive cell lines compared to p53 proficient normal human fibroblasts. CONCLUSIONS: Specific Chk1 inhibitors as well as the combined inhibition of Chk1 and Wee1 radiosensitize HPV-positive HNSCC cells. PMID- 27939203 TI - Improvement of mesh recolonization in abdominal wall reconstruction with adipose vs. bone marrow mesenchymal stem cells in a rodent model. AB - BACKGROUND: Reconstruction of muscle defects remains a challenge. Our work assessed the potential of an engineered construct made of a human acellular collagen matrix (HACM) seeded with porcine mesenchymal stem cells (MSCs) to reconstruct abdominal wall muscle defects in a rodent model. METHODS: This study compared 2 sources of MSCs (bone-marrow, BMSCs, and adipose, ASCs) in vitro and in vivo for parietal defect reconstruction. Cellular viability and growth factor release (VEGF, FGF-Beta, HGF, IGF-1, TGF-Beta) were investigated under normoxic/hypoxic culture conditions. Processed and recellularized HACMs were mechanically assessed. The construct was tested in vivo in full thickness abdominal wall defect treated with HACM alone vs. HACM+ASCs or BMSCs (n=14). Tissue remodeling was studied at day 30 for neo-angiogenesis and muscular reconstruction. RESULTS: A significantly lower secretion of IGF was observed with ASCs vs. BMSCs under hypoxic conditions (-97.6%, p<0.005) whereas significantly higher VEGF/FGF secretions were found with ASCs (+92%, p<0.001 and +72%, p<0.05, respectively). Processing and recellularization did not impair the mechanical properties of the HACM. In vivo, angiogenesis and muscle healing were significantly improved by the HACM+ASCs in comparison to BMSCs (p<0.05) at day 30. CONCLUSION: A composite graft made of an HACM seeded with ASCs can improve muscle repair by specific growth factor release in hypoxic conditions and by in vivo remodeling (neo-angiogenesis/graft integration) while maintaining mechanical properties. PMID- 27939204 TI - Role of glycopyrrolate in healing of anastomotic dehiscence after primary repair of esophageal atresia in a low resource setting-A randomized controlled study. AB - AIMS: To investigate the role of glycopyrrolate in decreasing oral secretions in patients of esophageal atresia (EA) with anastomotic leak and evaluate its effect on healing of anastomotic dehiscence. METHODS: The study comprised consecutive neonates of esophageal atresia, who had undergone primary surgery and developed anastomotic leak. The patients were randomized into two groups with the observer blinded to the group. The patients in the treatment group were administered glycopyrrolate in the dose of 8 MUg/kg 8 hourly, whereas placebo group patients were injected normal saline only. Neonates, in both the groups, were managed conservatively based on the clinical and radiological parameters. The end points of the study were either resolution or progression of the leak. The study was approved by the institute ethics committee. RESULTS: There were 21 patients each in two groups with comparable preoperative characteristics. All the cases had anastomotic leaks clinically detectable in the chest tube. Saliva alone constituted the leak material in 18 cases in the treatment group and 10 in the placebo group. Cumulative total of mean chest tube output per patient for all patients in the treatment group was 124.15ml as compared to 370.27ml in the placebo group (p=0.001). Anastomotic leak stopped in 16 cases (76%) in the treatment group, as compared to 6 cases (29%) in the placebo group (p=0.004). The postoperative ventilation was required in 8 cases (8/21, 38%) in the treatment group and 17 cases (17/21, 81%) in the placebo group (p=0.010). In the treatment group, the diversion procedures were carried out in 2 out of 21 cases (10%), whereas in the placebo group, 52% of the patients (11/21) required such an intervention (p=0.003). At the time of discharge, the oral feeds could be started in 15 cases (15/21, 71%) in the treatment group, as compared to 3 (3/21, 14%) in the placebo group (p=0.0004). CONCLUSIONS: Administration of glycopyrrolate in patients of anastomotic leak after primary repair of esophageal atresia resulted in reduced oral secretions, which helped in healing of the anastomotic dehiscence in a significant number of patients. PMID- 27939205 TI - Characterization of the upper pouch tracheo-oesophageal fistula in oesophageal atresia. AB - AIM: A small proportion of infants with oesophageal atresia (OA) are thought to have a proximal tracheoesophageal fistula (TOF). Failure to recognize these can hamper mobilization of the upper pouch and lead to life-threatening episodes of aspiration once oral feeding starts. We reviewed our experience of upper pouch fistulae to identify characteristic features of proximal TOF. METHODS: A retrospective review of TOF/OA patient notes and bronchoscopy photographs and videos, identified from our database from 01/01/2006 to 12/31/2015, was performed. RESULTS: Eight (6.1%) infants were identified (M:F 5:3) from a total population of 131 newly diagnosed TOF/OA infants during the period. Their median gestational age was 33 (range 28-39) weeks, and median birth weight was 1647g (range 1100-3400g). Five were initially diagnosed with pure OA and 3 with a distal TOF. All patients underwent rigid bronchoscopy at the initial surgery but only one proximal fistula was identified. The 7 missed proximal fistulae were subsequently found either during on-table oesophagograms for gap assessment (n=2), at the time of thoracotomy when mobilizing the upper pouch (n=3), or during subsequent bronchoscopy for symptoms post OA repair (n=2). Two patients needed a further operation to divide the fistula. Review of the bronchoscopy videos identified four characteristic differences between upper and lower pouch fistulae. Proximal fistulae are found just distal to the vocal cords, are very small, often no more than a pit, do not open and close with ventilation, and are best identified by insufflation of the esophagus. CONCLUSION: Upper pouch fistulae are relatively easy to miss because of different characteristics compared with H-type or distal fistulae that have not previously been mentioned in the literature. LEVEL OF EVIDENCE: level IV. PMID- 27939206 TI - Quartz in ash, and air in a high lung cancer incidence area in China. AB - Exposure to crystalline silica (quartz) has been implicated as a potential cause of the high lung cancer rates in the neighbouring counties of Xuanwei and Fuyuan, China, where the domestic combustion of locally sourced "smoky" coal (a bituminous coal) is responsible for some of the highest lung cancer rates in the nation, irrespective of gender or smoking status. Previous studies have shown that smoky coal contains approximately twice as much quartz when compared to alternative fuels in the area, although it is unclear how the quartz in coal relates to household air pollution. Samples of ash and fine particulate matter (PM2.5) were collected from 163 households and analysed for quartz content by Fourier transformed infrared spectroscopy (FT-IR). Additionally, air samples from 12 further households, were analysed by scanning electron microscopy (SEM) to evaluate particle structure and silica content. The majority (89%) of household air samples had undetectable quartz levels (<0.2 MUg/m3) with no clear differences by fuel-type. SEM analyses indicated that there were higher amounts of silica in the smoke of smoky coal than smokeless coal (0.27 MUg/m3 vs. 0.03 MUg/m3). We also identified fibre-like particles in a higher concentration within the smoke of smoky coal than smokeless coal (5800 fibres/m3 vs. 550 fibres/m3). Ash analysis suggested that the bulk of the quartz in smoky coal went on to form part of the ash. These findings indicate that the quartz within smoky coal does not become adequately airborne during the combustion process to cause significant lung cancer risk, instead going on to form part of the ash. The identification of fibre-like particles in air samples is an interesting finding, although the clinical relevance of this finding remains unclear. PMID- 27939207 TI - Source apportionment and heavy metal health risk (HMHR) quantification from sources in a southern city in China, using an ME2-HMHR model. AB - Heavy metals (Cr, Co, Ni, As, Cd, and Pb) can be bound to PM adversely affecting human health. Quantifying the source impacts on heavy metals can provide source specific estimates of the heavy metal health risk (HMHR) to guide effective development of strategies to reduce such risks from exposure to heavy metals in PM2.5 (particulate matter (PM) with aerodynamic diameter less than or equal to 2.5 MUm). In this study, a method combining Multilinear Engine 2 (ME2) and a risk assessment model is developed to more effectively quantify source contributions to HMHR, including heavy metal non-cancer risk (non-HMCR) and cancer risk (HMCR). The combined model (called ME2-HMHR) has two steps: step1, source contributions to heavy metals are estimated by employing the ME2 model; step2, the source contributions in step 1 are introduced into the risk assessment model to calculate the source contributions to HMHR. The approach was applied to Huzou, China and five significant sources were identified. Soil dust is the largest source of non-HMCR. For HMCR, the source contributions of soil dust, coal combustion, cement dust, vehicle, and secondary sources are 1.0 * 10-4, 3.7 * 10 5, 2.7 * 10-6, 1.6 * 10-6 and 1.9 * 10-9, respectively. The soil dust is the largest contributor to HMCR, being driven by the high impact of soil dust on PM2.5 and the abundance of heavy metals in soil dust. PMID- 27939209 TI - Methylmercury production and accumulation in urban stormwater ponds and habitat wetlands. AB - Stormwater management ponds and created habitat wetlands effectively manage erosion, flooding, and pollutant loadings while providing biodiversity and aesthetic benefits, but these structures are also potential sources of methylmercury (MeHg), a bioaccumulative neurotoxin. While MeHg accumulation has been confirmed in habitat wetlands, the extent of MeHg production and accumulation in stormwater ponds is unknown. Additionally, the fine-scale spatial variation in MeHg in these wetlands has never been explored despite the possibility that cycles of wetting and drying, and the presence of aquatic plants may stimulate methylation at their margins. To address these knowledge gaps, we compared MeHg and inorganic mercury concentrations, the percent of total mercury present as MeHg (%MeHg), and potential mercury methylation rate constants (Kmeth) in the sediments of terrestrial-aquatic transects through several stormwater and habitat wetlands. We present novel evidence confirming the in situ production of MeHg in both stormwater ponds and habitat wetlands, but observe no systematic differences across the terrestrial-aquatic gradient, suggesting that routine variations in water level do not alter MeHg production and accumulation. Stormwater ponds effectively trap mercury while converting relatively little to MeHg, as evidenced by lower MeHg concentrations, %-MeHg, and Kmeth values than habitat wetlands, but often greater inorganic Hg concentrations. The relationship of aquatic vegetation to MeHg accumulation is weak and ambiguous, suggesting plants are not strong drivers of MeHg biogeochemistry in these systems. Although the MeHg hazard associated with individual artificial wetlands is low, they may be important sources of MeHg at the landscape level. PMID- 27939208 TI - Evergreen or deciduous trees for capturing PAHs from ambient air? A case study. AB - Tree canopies play a key role in the cycling of polycyclic aromatic hydrocarbons (PAHs) in terrestrial ecosystems, as leaves can capture PAHs from the air. In this study, accumulation of PAHs was compared in an evergreen species, P. pinaster, and in a deciduous species, Q. robur, in relation to some physio morphological characteristics. For this purpose, pine needles and oak leaves collected from different sites across Galicia (NW Spain) were analysed to determine PAH contents, specific leaf area, stomatal density and conductance. Leaves and needles contained similar total amounts of PAHs. The major contribution of particle-bound PAHs in oak (the concentrations of 4- and 5-ring PAHs were two times higher, and those of 6-ring PAHs five times higher in oak than in pine) may be related to the higher specific leaf area (13 and 4 cm2 g-1 dry mass in respectively oak and pine). However, the major contribution of vapor phase PAHs in pines may be affected by the stomatal conductance (two times higher in pine than in oak). Moreover, an increase in the diameter at breast height of trees led to an increase in accumulation of PAHs, with pine capturing higher amounts of low and medium molecular weight PAHs. The study findings underline the potential role of trees in improving air quality, taking into account the canopy biomass and life cycle. PMID- 27939210 TI - Studies of innate immune systems against human cells. AB - BACKGROUND: Pigs are frequently used as animal models for experiments in the surgical field, including allo- and xeno-transplantation. Regeneration studies, including studies dealing with human- and monkey-induced pluripotent stem cells (iPSC), have gradually progressed, with pigs sometimes being used as the scaffold. However, the immunological response of pigs against humans, especially innate immunities, remain unclear. This study reports on a comprehensive study of pig innate immunity against humans. METHODS: Hemolytic complement activity of pig serum was measured using a microtitration technique. The pig natural anti-human antibody (Ab) was examined using human peripheral blood mononuclear cells (PBMC). The reaction of pig natural killer (NK) cells and monocytes/macrophages against human cells was also assessed. RESULTS: Most of the pig complement titers were measured based on methods used in human complement assays. The alternative pathway for pig complement reacts with human cells, indicating that pig complement can react with human cells. Pig serum contains relatively high levels of natural antibodies, IgM and IgG, to human PBMC. Furthermore, the killing of NK cells- and monocyte/macrophage-mediated human cells was clearly confirmed. CONCLUSION: The collective findings indicate that the pig innate immunological systems, not only serum but also cellular factors, are able to recognize and injure human cells. PMID- 27939211 TI - Author Reply. PMID- 27939212 TI - Editorial Comment. PMID- 27939213 TI - Author Reply. PMID- 27939214 TI - Editorial Comment. PMID- 27939215 TI - The functional activities of complement factor H are impaired in patients with ANCA-positive vasculitis. AB - Increasing evidences have demonstrated that the activation of the alternative complement pathway is crucial for the pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Our recent study found that circulating levels of complement factor H (FH), a key regulator of the alternative pathway, were associated with disease activity. In the current study, functional activities of FH were assessed to further explore the potential role of FH in the pathogenesis of AAV. We found that the two patients with ANCA negative pauci-immune necrotizing crescentic glomerulonephritis exhibited relatively normal functional activities of FH. However, patients with ANCA positive vasculitis exhibited deficient functional activities of FH, in terms of interaction with and the regulation of C3b, binding to mCRP and endothelial cells, and the protection of host cells against complement attack. Our findings indicate that functional activities of FH are deficient in patients with ANCA positive vasculitis, potentially contributing to the disease development. PMID- 27939216 TI - The value of health and weight loss among primary care patients with moderate to severe obesity: Do quality of life factors have a larger influence than comorbidities? PMID- 27939217 TI - PHB Associates with the HIRA Complex to Control an Epigenetic-Metabolic Circuit in Human ESCs. AB - The chromatin landscape and cellular metabolism both contribute to cell fate determination, but their interplay remains poorly understood. Using genome-wide siRNA screening, we have identified prohibitin (PHB) as an essential factor in self-renewal of human embryonic stem cells (hESCs). Mechanistically, PHB forms protein complexes with HIRA, a histone H3.3 chaperone, and stabilizes the protein levels of HIRA complex components. Like PHB, HIRA is required for hESC self renewal. PHB and HIRA act together to control global deposition of histone H3.3 and gene expression in hESCs. Of particular note, PHB and HIRA regulate the chromatin architecture at the promoters of isocitrate dehydrogenase genes to promote transcription and, thus, production of alpha-ketoglutarate, a key metabolite in the regulation of ESC fate. Our study shows that PHB has an unexpected nuclear role in hESCs that is required for self-renewal and that it acts with HIRA in chromatin organization to link epigenetic organization to a metabolic circuit. PMID- 27939220 TI - A Practitioners Guide to Diseases and Conditions Leading to Neurologic Dysfunction in the Ruminant. PMID- 27939219 TI - Induced Quiescence of Lgr5+ Stem Cells in Intestinal Organoids Enables Differentiation of Hormone-Producing Enteroendocrine Cells. AB - Lgr5+ adult intestinal stem cells are highly proliferative throughout life. Single Lgr5+ stem cells can be cultured into three-dimensional organoids containing all intestinal epithelial cell types at near-normal ratios. Conditions to generate the main cell types (enterocyte, goblet cells, Paneth cells, and M cells) are well established, but signals to induce the spectrum of hormone producing enteroendocrine cells (EECs) have remained elusive. Here, we induce Lgr5+ stem cell quiescence in vitro by blocking epidermal growth factor receptor (EGFR) or mitogen-associated protein kinase (MAPK) signaling pathways in organoids and show that their quiescent state is readily reverted. Quiescent Lgr5+ stem cells acquire a distinct molecular signature biased toward EEC differentiation. Indeed, combined inhibition of Wnt, Notch, and MAPK pathways efficiently generates a diversity of EEC hormone-expressing subtypes in vitro. Our observations uncouple Wnt-dependent stem cell maintenance from EGF-dependent proliferation and provide an approach for the study of the elusive EECs in a defined environment. PMID- 27939221 TI - Cerebral Disorders of Calves. AB - Neurologic diseases of the cerebrum are relatively common in cattle. In calves, the primary cerebral disorders are polioencephalomalacia, meningitis, and sodium toxicity. Because diagnostic testing is not always readily available, the practitioner must often decide on a course of treatment based on knowledge of the likely disease, as well as his or her own clinical experience. This is particularly true with neurologic diseases in which the prognosis is often poor and euthanasia may be the most humane outcome. This article reviews the most common diseases affecting the cerebrum of calves with a focus on pathophysiology, diagnosis, and treatment. PMID- 27939218 TI - A Multi-step Transcriptional and Chromatin State Cascade Underlies Motor Neuron Programming from Embryonic Stem Cells. AB - Direct cell programming via overexpression of transcription factors (TFs) aims to control cell fate with the degree of precision needed for clinical applications. However, the regulatory steps involved in successful terminal cell fate programming remain obscure. We have investigated the underlying mechanisms by looking at gene expression, chromatin states, and TF binding during the uniquely efficient Ngn2, Isl1, and Lhx3 motor neuron programming pathway. Our analysis reveals a highly dynamic process in which Ngn2 and the Isl1/Lhx3 pair initially engage distinct regulatory regions. Subsequently, Isl1/Lhx3 binding shifts from one set of targets to another, controlling regulatory region activity and gene expression as cell differentiation progresses. Binding of Isl1/Lhx3 to later motor neuron enhancers depends on the Ebf and Onecut TFs, which are induced by Ngn2 during the programming process. Thus, motor neuron programming is the product of two initially independent transcriptional modules that converge with a feedforward transcriptional logic. PMID- 27939222 TI - Augmented nonlinear differentiator design and application to nonlinear uncertain systems. AB - In this paper, an augmented nonlinear differentiator (AND) based on sigmoid function is developed to calculate the noise-less time derivative under noisy measurement condition. The essential philosophy of proposed AND in achieving high attenuation of noise effect is established by expanding the signal dynamics with extra state variable representing the integrated noisy measurement, then with the integral of measurement as input, the augmented differentiator is formulated to improve the estimation quality. The prominent advantages of the present differentiation technique are: (i) better noise suppression ability can be achieved without appreciable delay; (ii) the improved methodology can be readily extended to construct augmented high-order differentiator to obtain multiple derivatives. In addition, the convergence property and robustness performance against noises are investigated via singular perturbation theory and describing function method, respectively. Also, comparison with several classical differentiators is given to illustrate the superiority of AND in noise suppression. Finally, the robust control problems of nonlinear uncertain systems, including a numerical example and a mass spring system, are addressed to demonstrate the effectiveness of AND in precisely estimating the disturbance and providing the unavailable differential estimate to implement output feedback based controller. PMID- 27939223 TI - Dominant pole placement with fractional order PID controllers: D-decomposition approach. AB - Dominant pole placement is a useful technique designed to deal with the problem of controlling a high order or time-delay systems with low order controller such as the PID controller. This paper tries to solve this problem by using D decomposition method. Straightforward analytic procedure makes this method extremely powerful and easy to apply. This technique is applicable to a wide range of transfer functions: with or without time-delay, rational and non rational ones, and those describing distributed parameter systems. In order to control as many different processes as possible, a fractional order PID controller is introduced, as a generalization of classical PID controller. As a consequence, it provides additional parameters for better adjusting system performances. The design method presented in this paper tunes the parameters of PID and fractional PID controller in order to obtain good load disturbance response with a constraint on the maximum sensitivity and sensitivity to noise measurement. Good set point response is also one of the design goals of this technique. Numerous examples taken from the process industry are given, and D decomposition approach is compared with other PID optimization methods to show its effectiveness. PMID- 27939224 TI - Effect of a Reminder Statement on Echocardiography Reports on Referrals for Implantable Cardioverter-Defibrillators for Primary Prevention. AB - Numerous trials show the benefit of implantable cardioverter-defibrillators (ICDs) for primary prevention in patients with low ejection fraction (EF), a class I indication. However, underutilization is well documented. We retrospectively reviewed charts to see whether placing a reminder statement into echocardiogram reports for appropriate patients increased adherence to guidelines. From January through June 2013, a brief reminder of the ICD guidelines was automatically inserted into echocardiogram reports with EF <= 35% (reminder period). Charts were reviewed to determine if these patients (1) were referred to Electrophysiology (EP) within 6 months of the index echo and (2) received an ICD within 6 months of EP referral. Chart review of all patients who had an echocardiogram performed between March and August 2012 with an EF <= 35% provided a control period. More patients were referred to EP in the reminder period compared with control period, 68% (54 of 80) versus 51% (53 of 104), p = 0.03. There was also a higher rate of discussions in the reminder period between patients and physicians about ICD therapy (71% vs 54%, p = 0.02). Among patients appropriate for ICD, 52% of patients during the reminder period received an ICD versus 38% of patients during the control period (p = 0.11). A simple reminder statement on echocardiography reports led to a significant improvement in appropriate EP referrals and a trend toward increased ICD implantation in appropriate patients. PMID- 27939225 TI - Identification of Factors Associated With Improved Survival After Renal Artery Stenting. AB - Atherosclerotic renal artery stenosis (RAS) is associated with high mortality rates, but large randomized trials have not shown improvement in survival with renal artery stenting. These results suggest that factors other than ongoing renal hypoperfusion are important in determining survival in patients with RAS. Using logistic regression models, we performed a single-center, case-control study that included 188 patients with >=70% RAS with an average age of 67 +/- 10 years, 54% women, 20% black, and 70% smokers; 118 patients (63%) underwent renal artery stenting. A total of 89 patients (47%) died during an average follow-up of 5.1 years. Previous myocardial infarction (MI) (odds ratio 2.6 95% confidence interval [1.4 to 4.7]), left ventricular ejection fraction (LVEF) <=35% (odds ratio 4.1 95% confidence interval [1.6 to 10.6]), and renal insufficiency were predictors of mortality in this study. The risk associated with LVEF <=35% and previous MI were additive with mortality of 40%, 54%, and 85%, respectively, with 0, 1, or both these factors. Renal artery stenting was associated with a 43% reduction in mortality in patients with 0 or 1 mortality risk factors (defined as LVEF <=35%, previous MI, and glomerular filtration rate <=45 ml/min/1.73 m2) but had no effect on mortality in patients with 2 or 3 mortality risk factors. Systolic blood pressure, diastolic blood pressure, or severity of RAS did not correlate with survival. In conclusion, this retrospective analysis suggests that clinical, in addition to anatomic and physiological, factors should be considered in future studies examining effects of renal artery stenting on survival. PMID- 27939226 TI - Effectiveness of a Prehospital Wireless 12-Lead Electrocardiogram and Cardiac Catheterization Laboratory Activation for ST-Elevation Myocardial Infarction. AB - The aim of the study was to determine the prevalence of false-positive and inappropriate cardiac catheterization laboratory (CCL) activation in patients suspected with ST-elevation myocardial infarction (STEMI) diverted to a percutaneous coronary intervention (PCI) facility after paramedics wireless 12 lead electrocardiogram transmission to an emergency physician at an online medical control center. This retrospective study collected data from medical records of patients with suspected STEMI from 2006 to 2014. It included demographics, coronaropathic risk factors, cardiac biomarkers, time from the first medical contact to treatment, and final diagnosis. Primary outcome was the rate of false-positive and inappropriate CCL activation. As secondary outcomes, we compared patient characteristics between cases of appropriate and inappropriate CCL activation, and we assessed the presence of cardiac biomarkers, time from first medical contact to start of PCI, and final diagnosis. Overall, 673 patients with suspected STEMI were included in the analysis. A total of 640 patients (95%) had coronarography, of which 10% (62 of 640) did not have a culprit coronary artery (false positive). Angiography was canceled for 5% (33 of 673) of patients. The total false-positive and inappropriate CCL activation rate was 14% (95 of 673). Average time from the first medical contact to the start of PCI was 47 +/- 18.1 minutes. Unwanted CCL activations were more likely to involve men aged >65 years and patients with a history of coronary artery disease. In conclusion, our system of transmitted prehospital electrocardiography and STEMI interpretation by emergency physicians at an online medical control center showed a total false-positive and inappropriate CCL activation rate of 14% over the 8 year study period. PMID- 27939228 TI - Long-Term Risk of Atrial Fibrillation and Stroke in Patients With Atrial Septal Defect Diagnosed in Childhood. AB - The aim of this study was to evaluate the long-term risk of atrial fibrillation (AF) and stroke in patients with atrial septal defect (ASD) diagnosed before the age of 18 years. Patients diagnosed with ASD from 1963 to 2011 were identified through national Danish registers, of which 1,111 fulfilled the inclusion criteria. Each patient was matched with 10 control subjects on age and gender. Risk of AF and stroke was assessed using Cox proportional hazards regression. Cumulative incidences were calculated using Fine and Gray competing risk regression. Median follow-up time was 24 years (range 1 to 49 years). Patients with ASD had a significantly increased risk of AF; both with closure (adjusted hazard ratio [HR] 18.5, 95% confidence interval [CI] 7.8 to 44.1, p <0.0001) and without closure (HR 16.4, 95% CI 6.8 to 39.8, p <0.0001) were compared with control subjects. A comparison of surgical closure with transcatheter closure showed no difference in risk of AF (HR 1.1, 95% CI 0.3 to 4.8, p = 0.864). Risk of stroke was increased in patients with ASD closure (adjusted HR 5.0, 95% CI 2.3 to 11.1, p <0.0001) compared to the control subjects. The use of anticoagulants was increased in patients with ASD regardless of closure (adjusted HR 7.7, 95% CI 4.9 to 12.1, p <0.0001 with closure and HR 4.0, 95% CI 1.9 to 8.7, p <0.0001 without closure). Usage of antiarrhythmic drugs was significantly increased in patients with ASD with closure (adjusted HR 14.8, 95% CI 7.2 to 30.2, p <0.0001). In conclusion, patients diagnosed with an ASD before the age of 18 years had an increased risk of AF in adulthood compared to controls. The risk of AF and stroke was increased despite closure in childhood, and method of closure did not affect the risk of developing AF later in life. PMID- 27939227 TI - Usefulness of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) in Women to Lower Triglyceride Levels (Results from the MARINE and ANCHOR Trials). AB - There are limited data on the efficacy and safety of triglyceride (TG)-lowering agents in women. We conducted subgroup analyses of the effects of icosapent ethyl (a high-purity prescription form of the ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid) on TG levels (primary efficacy variable) and other atherogenic and inflammatory parameters in a total of 215 women with a broad range of TG levels (200-2000 mg/dl) enrolled in two 12-week placebo-controlled trials: MARINE (n = 18; placebo, n = 18) and ANCHOR (n = 91; placebo, n = 88). Icosapent ethyl 4 g/day significantly reduced TG levels from baseline to week 12 versus placebo in both MARINE (-22.7%; p = 0.0327) and ANCHOR (-21.5%; p <0.0001) without increasing low-density lipoprotein cholesterol levels. Significant improvements were also observed in non-high-density lipoprotein cholesterol levels in MARINE (-15.7%; p = 0.0082) and ANCHOR (-14.2%; p <0.0001) and total cholesterol levels in MARINE (-14.9%; p = 0.0023) and ANCHOR (-12.1%; p <0.0001), along with significant increases of >500% in eicosapentaenoic acid levels in plasma and red blood cells (all p <0.001). Icosapent ethyl was well tolerated, with adverse-event profiles comparable with findings in the overall studies. In conclusion, icosapent ethyl 4 g/day significantly reduced TG levels and other atherogenic parameters in women without increasing low-density lipoprotein cholesterol levels compared with placebo; the clinical implications of these findings are being evaluated in the REDUCtion of Cardiovascular Events With Eicosapentaenoic Acid [EPA]-Intervention Trial (REDUCE-IT) cardiovascular outcomes study. PMID- 27939229 TI - Adjunctive Use of Noninvasive Ventilation During Exercise in Patients With Decompensated Heart Failure. AB - Noninvasive ventilation (NIV) as an adjunct strategy for increasing exercise tolerance has been widely investigated in patients with pulmonary diseases. To our knowledge, there are no studies that have used NIV during exercise in patients with decompensated heart failure (HF). The aim of this study was to evaluate the effects of NIV on exercise tolerance in hospitalized patients with decompensated HF. Thirteen patients (77 +/- 15 years) with a mean left ventricular ejection fraction of 35 +/- 15% were included. Patients underwent 2 submaximal exercise tests with constant load for lower limbs using a portable cycle ergometer. Tests were performed on the same day with a 60-minute interval between each one, using a randomized crossover design: sham ventilation (continuous positive airway pressure mode, 4 cm H2O) and intervention situation (NIV in bilevel mode). Primary outcome was the endurance time performed during exercise tests with constant load. Submaximal exercise with NIV in bilevel mode improved endurance time (7.2 +/- 2.7 minutes) compared to the tests performed with continuous positive airway pressure (5.1 +/- 1.5 minutes; p = 0.008). Increase in endurance time (Delta time) with bilevel test showed a significant correlation with reduction in the slope of dyspnea (Delta Borg) over time (r = 0.73; p = 0.004). There was a significant correlation between endurance time in bilevel tests and maximum inspiratory pressure % predicted (r = 0.68; p = 0.02). In conclusion, NIV was effective in increasing exercise tolerance in hospitalized patients with decompensated HF. (ClinicalTrials.gov registration NCT02122848). PMID- 27939230 TI - Relation of Variability of Low-Density Lipoprotein Cholesterol and Blood Pressure to Events in Patients With Previous Myocardial Infarction from the IDEAL Trial. AB - In patients with previous myocardial infarction (MI), aggressive hypertension control and low-density lipoprotein cholesterol (LDL-C) reduction are important secondary prevention measures. However, residual risk remains despite aggressive treatment. Whether variability in blood pressure (BP) and LDL-C can explain this residual risk is not known. Patients enrolled in the Incremental Decrease in End Points Through Aggressive Lipid-Lowering trial with at least 1 post-baseline measurement of LDL-C and blood pressure (BP) were included. Visit-to-visit LDL-C and BP variabilities were evaluated using various measures of variability. Primary outcome was any coronary event with the secondary outcomes of any cardiovascular event (CV), MI, stroke, death, and CV death. Among the 8,658 patients included, each 1-SD (10.8 mg/dl) increase in LDL-C variability increased the risk of any coronary event (adjusted HR [HRadj] 1.07; 95% CI 1.04 to 1.11; p <0.0001), any CV event, MI, and death (HRadj 1.19; 95% CI 1.14 to 1.25; p <0.0001). Similarly, each 1-SD (7.2 mm Hg) increase in systolic BP variability increased the risk of any coronary event (HRadj 1.15; 95% CI 1.10 to 1.20; p <0.0001), any CV event, MI, stroke, death (HRadj 1.28; 95% CI 1.18 to 1.38; p <0.0001), and CV death. Compared with the group with low variability for both LDL C and systolic BP, the group with high variability for both had a significant increase in any coronary event (HRadj 1.48; 95% CI 1.30 to 1.70), any CV event (HRadj 1.43; 95% CI 1.27 to 1.61), and MI (HRadj 1.87; 95% CI 1.46 to 2.41). In conclusions, in patients with a history of MI, variabilities in LDL-C and BP are powerful and independent predictors of CV events including death. PMID- 27939231 TI - Effect of Pretransplant Continuous-Flow Left Ventricular Assist Devices on Cellular and Antibody-Mediated Rejection and Subsequent Allograft Outcomes. AB - The aim of this study was to evaluate the impact of continuous-flow left ventricular assist devices (CF-LVAD) on subsequent rejection after heart transplantation (HT) by using cellular rejection score and antibody-mediated rejection score (AMRS) and correlating with subsequent allograft outcomes. We retrospectively analyzed 108 consecutive patients who underwent HT without (n = 67) or with (n = 41) previous CF-LVAD in 2008 to 2014. The 24 months cumulative effect of rejection was calculated by using cellular rejection scores and AMRS, based on the total number of rejections divided by valid biopsy samples. Vasculopathy was assessed both by routine coronary angiogram and intravascular ultrasound. Patients who underwent pretransplant CF-LVAD demonstrated a significant increase in the number of cellular rejection episodes as compared with the nonbridged patients, for 1 and 2 years of follow-up (p = 0.026 and p = 0.016), respectively. There were no differences in AMRS (p >0.05) and allograft outcomes, such as vasculopathy and overall survival (p >0.05) over the period of follow-up. Implantation of a CF-LVAD before HT impacts cellular rejection during the post-transplant period. Despite these findings, CF-LVAD does not translate to differences in allograft outcomes after transplant, such as vasculopathy and overall survival over the period of the study. In conclusion, whether this affects longer term outcomes than studied remains to be determined. PMID- 27939232 TI - Age-related changes of metallothionein 1/2 and metallothionein 3 expression in rat brain. AB - Neurodegeneration is one of the main physiological consequences of aging on brain. Metallothioneins (MTs), low molecular weight, cysteine-rich proteins that bind heavy-metal ions and oxygen-free radicals, are commonly expressed in various tissues of mammals. MTs are involved in the regulation of cell proliferation and protection, and may be engaged in aging. Expression of the ubiquitous MTs (1 and 2) and the brain specific MT3 have been studied in many neurodegenerative disorders. The research results indicate that MTs may play important, although not yet fully known, roles in brain diseases; in addition, data lack the ability to identify the MT isoforms functionally involved. The aim of this study was to analyse the level of gene expression of selected MT isoforms during brain aging. By using real-time PCR analysis, we determined the MT1/2 and MT3 expression profiles in cerebral cortex and hippocampus of adolescent (2months), adult (4 and 8months), and middle-aged (16months) rats. We show that the relative abundance of all types of MT transcripts changes during aging in both hippocampus and cortex; the first effect is a generalized decrease in the content of MTs transcripts from 2- to 8-months-old rats. After passing middle age, at 16months, we observe a huge increase in MT3 transcripts in both cortical and hippocampal areas, while the MT1/2 mRNA content increases slightly, returning to the levels measured in adolescent rats. These findings demonstrate an age-related expression of the MT3 gene. A possible link between the increasing amount of MT3 in brain aging and its different metal-binding behaviour is discussed. PMID- 27939233 TI - Balancing Equity and Advancement: The Role of Health Technology Assessment in Radiotherapy Resource Allocation. AB - Radiotherapy is an essential modality for effective cancer control, yet enormous inequalities in access in low- and middle-income countries (LMICs) have created one of the largest global technology gaps in medicine today. The Global Task Force on Radiotherapy for Cancer Control quantified this gap and showed that over half of patients worldwide do not have access to treatment. Governments, policy makers and the global health community have ignored this crisis due to the complexity of radiotherapy technology and its seemingly high upfront costs. However, understanding the cost of treatment in the context of a dramatic clinical benefit could help to demonstrate the feasibility of radiotherapy in diverse income settings. When there are scarce resources, such analysis is essential in order to set priorities and provide high-value interventions to large populations. Here we explore the current status of economic evaluation tools in LMICs and some of the barriers to their use. We describe how the concepts of health technology assessment, value-based care and investment frameworks can be applied to the global crisis of radiotherapy availability to guide appropriate capacity building and resource utilisation. The development of local expertise in these health economic tools can be a powerful level to improve cancer care in LMICs and to build universal global access to radiotherapy. PMID- 27939234 TI - Evaluation of Granulated Lactose as a Carrier for Dry Powder Inhaler Formulations 2: Effect of Drugs and Drug Loading. AB - Previously, granulated lactose carriers were shown to improve uniformity and aerosolization of a low-dose model drug. In the present study, the blending uniformity and aerosol dispersion performance were assessed for 2 model drugs salbutamol sulfate (SS) and rifampicin (RIF), blended at high loadings (10% or 30% drug) with granulated lactose carriers. The model drug powders differed in particle size distribution, morphology, density, and surface energies. Content uniformity of RIF blends was better than that of SS. Aerosolization studies showed that all blend formulations had acceptable emitted fractions (>70%). The SS blends showed low induction-port deposition (6%-10%) compared to RIF (5%-30%). This difference was greater at high flow rates. At 90 L/min, the low induction port deposition of SS blends allowed high fine particle fraction (FPF) of 73% 81%, whereas the FPF of the RIF blends was around 43%-45% with higher induction port deposition. However, SS blends exhibited strong flow rate-dependent performance. Increasing the flow rate from 30 L/min to 90 L/min increased SS FPF from approximately 20% to 80%. Conversely, RIF blends were flow rate and drug loading independent. It was concluded that the aerosolization of high drug-loaded dry powder inhaler formulations using granulated lactose, particularly flow rate dependency, varies with active pharmaceutical ingredient properties. PMID- 27939235 TI - Ongoing Implementation Challenges to the Patient Protection and Affordable Care Act's Contraceptive Mandate. PMID- 27939236 TI - Smoking Habits and Body Weight Over the Adult Lifespan in Postmenopausal Women. AB - INTRODUCTION: The inter-relationships between smoking habits and weight gain are complex. However, few studies have examined the association of smoking habits with weight gain over the life course. METHODS: Major smoking parameters and weight gain over time were examined in a large cohort of postmenopausal women aged 50-79 years at enrollment between 1993 and 1998 (N=161,808) and followed through 2014 (analyses conducted in 2016). Cross-sectional analyses were used to assess the association of smoking and body weight at baseline. Retrospective data were used to correlate smoking status with body weight over a 45-year period prior to enrollment. In addition, the association of smoking with weight gain over 6 years of follow-up was examined. RESULTS: At baseline, women who had quit smoking prior to enrollment weighed 4.7 kg more than current smokers and 2.6 kg more than never smokers. Former, never, and current smokers all gained weight over the 45-year period from age 18 years to time of enrollment (average age, 63 years): 16.8, 16.4, and 14.6 kg, respectively. In prospective analyses, women who were current smokers at baseline but who quit smoking during follow-up gained more than 5 kg by Year 6 compared with current smokers at baseline who continued to smoke. Among long-term quitters, greater intensity of smoking and more recent quitting were associated with greater weight gain. CONCLUSIONS: These results suggest that excess weight gain associated with smoking cessation occurs soon after quitting and is modest relative to weight gain in never smokers over the adult lifespan. PMID- 27939238 TI - Brief Counseling and Exercise Referral Scheme: A Pragmatic Trial in Mexico. AB - INTRODUCTION: The effectiveness of clinical-community linkages for promotion of physical activity (PA) has not been explored in low- and middle-income countries. This study assessed the effectiveness of a primary care-based, 16-week intervention rooted in behavioral theory approaches to increase compliance with aerobic PA recommendations. STUDY DESIGN: Pragmatic cluster randomized trial. SETTING/PARTICIPANTS: Patients had diagnosed (<5 years) hypertension, were aged 35-70 years, self-reported as physically inactive, had a stated intention to engage in PA, and attended Primary Healthcare Centers in the Social Security health system in Cuernavaca, Mexico. Of 23 Primary Healthcare Centers, four were selected based on proximity (5 km radius) to a center. INTERVENTION: Each center was randomized to a brief PA counseling (BC, n=2) or an exercise referral (ER, n=2) intervention. The study was conducted between 2011 and 2012. MAIN OUTCOME MEASURES: Change in objectively measured PA levels (ActiGraph GT3X accelerometers) at baseline, 16, and 24 weeks. Intention-to-treat analyses were used to assess the effectiveness of the intervention overall and according to ER intervention attendance. Longitudinal multilevel mixed-effects analyses considering the interaction (time by intervention) were conducted. Each model was also adjusted by baseline value of the outcome measure, demographic and health variables, social support, PA self-efficacy, and barriers. RESULTS: Minutes/week of objectively measured moderate to vigorous PA increased by 40 and 53 minutes in the ER and BC groups, respectively (p=0.59). Participants attending >50% of ER program sessions increased their moderate to vigorous PA by 104 minutes/week and compliance with aerobic PA recommendations by 23.8%, versus the BC group (both p<0.05). CONCLUSIONS: Both BC and ER led to modest improvements in PA levels, with no significant differences between groups. Adequate adherence with the ER program sessions led to significant improvements in compliance with aerobic PA recommendations versus BC. These results can help guide development and implementation of programs integrating standardized PA assessment, counseling, and referrals via clinical-community linkages in Mexico and other low- and middle income countries in the region. PMID- 27939237 TI - Weight-Gain Reduction Among 2-Year College Students: The CHOICES RCT. AB - INTRODUCTION: The young adult years have been recognized as an influential period for excess weight gain. Non-traditional students and those attending 2-year community colleges are at particularly high risk for a range of adverse weight related outcomes. DESIGN: Choosing Healthy Options in College Environments and Settings was an RCT with students randomly assigned into a control or intervention condition after baseline assessment. The study was designed to evaluate if a 24-month weight-gain prevention intervention reduces the expected increase in BMI and overweight prevalence in young adults attending 2-year colleges. Two cohorts were recruited, corresponding to the fall and spring semesters. Data collection occurred at four time points for each cohort, with baseline occurring in fall 2011 for Cohort 1 and spring 2012 for Cohort 2. The 24 month follow-up occurred in fall 2013 for Cohort 1 and spring 2014 for Cohort 2. Data analysis occurred in 2015-2016. SETTING/PARTICIPANTS: This research was conducted with 441 students from three community colleges in Minnesota. INTERVENTION: The 24-month intervention began with a 1-credit college course on healthy weight behaviors. A social networking and social support website was introduced as part of the course and participation encouraged for the duration of the trial. MAIN OUTCOME MEASURES: Changes in BMI, weight, body fat percentage, waist circumference, and weight status were assessed. RESULTS: Retention of the cohorts at 24 months was 83.4%. There was not a statistically significant difference in BMI between conditions at the end of the trial. However, there was a statically significant difference in the prevalence of overweight/obesity between treatment conditions at 24 months. Also, participants randomized to the intervention who were overweight or obese at baseline were more than three times as likely to transition to a healthy weight by the end of the trial as compared with control students. CONCLUSIONS: The intervention was not successful in achieving BMI differences between treatment groups. However, an 8% reduction in the prevalence of overweight and obesity over time may have population-level significance. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT01134783. PMID- 27939240 TI - Challenging the Dual-Hinge Approach to Intervening on Sedentary Behavior. PMID- 27939239 TI - Reduced Cardiovascular Disease Incidence With a National Lifestyle Change Program. AB - INTRODUCTION: Lifestyle change programs implemented within healthcare systems could reach many Americans, but their impact on cardiovascular disease (CVD) remains unclear. The MOVE! program is the largest lifestyle change program implemented in a healthcare setting in the U.S. This study aimed to determine whether MOVE! participation was associated with reduced CVD incidence. METHODS: This retrospective cohort study, analyzed in 2013-2015, used national Veterans Health Administration databases to identify MOVE! participants and eligible non participants for comparison (2005-2012). Patients eligible for MOVE!-obese or overweight with a weight-related health condition, and no baseline CVD-were examined (N=1,463,003). Of these, 169,248 (12%) were MOVE! PARTICIPANTS: Patients were 92% male, 76% white, with mean age 52 years and BMI of 32. The main outcome was incidence of CVD (ICD-9 and procedure codes for coronary artery disease, cerebrovascular disease, peripheral vascular disease, and heart failure). RESULTS: Adjusting for age, race, sex, BMI, statin use, and baseline comorbidities, over a mean 4.9 years of follow-up, MOVE! participation was associated with lower incidence of total CVD (hazard ratio [HR]=0.83, 95% CI=0.80, 0.86); coronary artery disease (HR=0.81, 95% CI=0.77, 0.86); cerebrovascular disease (HR=0.87, 95% CI=0.82, 0.92); peripheral vascular disease (HR=0.89, 95% CI=0.83, 0.94); and heart failure (HR=0.78, 95% CI=0.74, 0.83). The association between MOVE! participation and CVD incidence remained significant when examined across categories of race/ethnicity, BMI, diabetes, hypertension, smoking status, and statin use. CONCLUSIONS: Although participation was limited, MOVE! was associated with reduced CVD incidence in a nationwide healthcare setting. PMID- 27939241 TI - The anti-ALS drug riluzole attenuates pericyte loss in the diabetic retinopathy of streptozotocin-treated mice. AB - Loss of pericytes, considered an early hallmark of diabetic retinopathy, is thought to involve abnormal activation of protein kinase C (PKC). We previously showed that the anti-amyotrophic lateral sclerosis (ALS) drug riluzole functions as a PKC inhibitor. Here, we examined the effects of riluzole on pathological changes in diabetic retinopathy. Pathological endpoints examined in vivo included the number of pericytes and integrity of retinal vessels in streptozotocin (STZ) induced diabetic mice. In addition, PKC activation and the induction of monocyte chemotactic protein (MCP1) were assessed in diabetic mice and in human retinal pericytes exposed to advanced glycation end product (AGE) or modified low-density lipoprotein (mLDL). The diameter of retinal vessels and the number of pericytes were severely reduced, and the levels of MCP1 and PKC were increased in STZ induced diabetic mice. Administration of riluzole reversed all of these changes. Furthermore, the increased expression of MCP1 in AGE- or mLDL-treated cultured retinal pericytes was inhibited by treatment with riluzole or the PKC inhibitor GF109203X. In silico modeling showed that riluzole fits well within the catalytic pocket of PKC. Taken together, our results demonstrate that riluzole attenuates both MCP1 induction and pericyte loss in diabetic retinopathy, likely through its direct inhibitory effect on PKC. PMID- 27939242 TI - EX4 stabilizes and activates Nrf2 via PKCdelta, contributing to the prevention of oxidative stress-induced pancreatic beta cell damage. AB - Oxidative stress in pancreatic beta cells can inhibit insulin secretion and promote apoptotic cell death. Exendin-4 (EX4), a glucagon-like peptide-1 receptor agonist, can suppress beta cell apoptosis, improve beta cell function and protect against oxidative damage. In this study, we investigated the molecular mechanisms for antioxidative effects of EX4 in pancreatic beta cells. INS-1 cells, a rat insulinoma cell line, were pretreated with EX4 and exposed to palmitate or H2O2. Reactive oxygen species (ROS) production, and glutathione and insulin secretion were measured. The mRNA and protein expression levels of antioxidant genes were examined. The level of nuclear factor erythroid 2-related factor 2 (Nrf2), its binding to antioxidant response element (ARE), and its ubiquination in the presence of EX4 were determined. The Nrf2 signaling pathway was determined using rottlerin (protein kinase [PK]Cdelta inhibitor), H89 (PKA inhibitor) and LY294002 (phosphatidylinositide 3-kinase [PI3K] inhibitor). EX4 treatment decreased ROS production, recovered cellular glutathione levels and insulin secretion in the presence of oxidative stress in INS-1 cells. The expression levels of glutamate cysteine ligase catalytic subunit and heme oxygenase-1 were increased by EX4 treatment. EX4 promoted Nrf2 translocation, ARE binding activity and enhanced stabilization of Nrf2 by inhibition of ubiquitination. Knockdown of Nrf2 abolished the effect of EX4 on increased insulin secretion. Inhibition of PKCdelta attenuated Nrf2 translocation and antioxidative gene expression by EX4 treatment. We suggest that EX4 activates and stabilizes Nrf2 through PKCdelta activation, contributing to the increase of antioxidant gene expression and consequently improving beta cell function in the presence of oxidative stress. PMID- 27939243 TI - Habitat-related variation in composition of the essential oil of Seseli rigidum Waldst. & Kit. (Apiaceae). AB - Plant specialised metabolites like essential oils are highly variable depending on genetic and various ecological factors. The aim of the present work was to characterise essential oils of the species Seseli rigidum Waldst. & Kit. (Apiaceae) in various organs on the individual and populational levels. Geographical variability and the impact of climate and soil type on essential oil composition were also investigated. Individually sampled essential oils of roots, aerial parts and fruits of plants from seven populations were analysed by GC-FID and GC-MS. The investigated populations showed high interpopulational and especially intrapopulational variability of essential oil composition. In regard to the variability of essential oils, different chemotypes were defined. The essential oils of S. rigidum roots represented a falcarinol chemotype, oils of aerial parts constituted an alpha-pinene or alpha-pinene/sabinene chemotype and fruit essential oils can be characterised as belonging to a complex sabinene/alpha-pinene/beta-phellandrene/falcarinol/germacrene B chemotype. At the species level, analysis of variance (ANOVA), principal component analysis (PCA) and canonical discriminant analysis (CDA) showed that the plant part exerted the strongest influence on the composition of essential oils. Climate had a high impact on composition of the essential oils of roots, aerial parts and fruits, while influence of the substrate was less pronounced. The variations in main compounds of essential oils based on climate or substrate were complex and specific to the plant part. PMID- 27939244 TI - Effect of dietary n-3 fatty acids supplementation on fatty acid metabolism in atorvastatin-administered SHR.Cg-Leprcp/NDmcr rats, a metabolic syndrome model. AB - The effects of cholesterol-lowering statins, which substantially benefit future cardiovascular events, on fatty acid metabolism have remained largely obscured. In this study, we investigated the effects of atorvastatin on fatty acid metabolism together with the effects of TAK-085 containing highly purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl ester on atorvastatin-induced n-3 polyunsaturated fatty acid lowering in SHR.Cg Leprcp/NDmcr (SHRcp) rats, as a metabolic syndrome model. Supplementation with 10mg/kg body weight/day of atorvastatin for 17 weeks significantly decreased plasma total cholesterol and very low density lipoprotein cholesterol. Atorvastatin alone caused a subtle change in fatty acid composition particularly of EPA and DHA in the plasma, liver or erythrocyte membranes. However, the TAK 085 consistently increased both the levels of EPA and DHA in the plasma, liver and erythrocyte membranes. After confirming the reduction of plasma total cholesterol, 300mg/kg body weight/day of TAK-085 was continuously administered for another 6 weeks. Supplementation with TAK-085 did not decrease plasma total cholesterol but significantly increased the EPA and DHA levels in both the plasma and liver compared with rats administered atorvastatin only. Supplementation with atorvastatin alone significantly decreased sterol regulatory element-binding protein-1c, Delta5- and Delta6-desaturases, elongase-5, and stearoyl-coenzyme A (CoA) desaturase-2 levels and increased 3-hydroxy-3-methylglutaryl-CoA reductase mRNA expression in the liver compared with control rats. TAK-085 supplementation significantly increased stearoyl-CoA desaturase-2 mRNA expression. These results suggest that long-term supplementation with atorvastatin decreases the EPA and DHA levels by inhibiting the desaturation and elongation of n-3 fatty acid metabolism, while TAK-085 supplementation effectively replenishes this effect in SHRcp rat liver. PMID- 27939245 TI - Evaluation of a modified cleaning procedure in the prevention of carbapenem resistant Acinetobacter baumannii clonal spread in a burn intensive care unit using a high-sensitivity luminometer. AB - BACKGROUND: Enhanced environmental cleaning practices are among the most accepted measures for controlling the spread of carbapenem-resistant Acinetobacter baumannii (CR-Ab). AIM: To evaluate the impact of heightened cleaning on an ongoing CR-Ab outbreak in a burn intensive care unit (BICU) of an Italian teaching hospital, where chlorhexidine-60% isopropyl alcohol was applied as a complementary disinfectant on high-touch surfaces. METHODS: Compliance with the microbial limit proposed for the BICU by AFNOR-NF-S90-351 (20 colony-forming units/100cm2) was assessed by plate count, and compared with the results obtained with intracellular adenosine triphosphate (ATP) detection. Genotyping was performed using pulsed-field gel electrophoresis. FINDINGS: During the standard cleaning regimen, three out of 23 samples (13%) gave results over the AFNOR limit and five (21.7%) showed unacceptable ATP levels with 100 relative light units/100cm2 as the benchmark limit (sensibility 86.4%, specificity 92.2%). Following improvement of the cleaning procedure, only two samples out of 50 (4%) did not satisfy the microbiological criteria and seven (14%) exceeded the ATP limit. In a successive phase, eight of 30 samples collected showed unacceptable results (27%). CONCLUSIONS: Adding chlorhexidine-60% isopropyl alcohol as complementary disinfectant proved to be effective for reducing environmental microbial contamination, ATP levels and CR-Ab infection/colonization in patients admitted to the BICU. Real-time monitoring by ATP assay was useful for managing the cleaning schedule and reducing hospital infections, although the calculated values must be interpreted as cleanliness indicators rather than risk indicators. PMID- 27939246 TI - Knockout of P2Y12 aggravates experimental autoimmune encephalomyelitis in mice via increasing of IL-23 production and Th17 cell differentiation by dendritic cells. AB - Experimental autoimmune encephalomyelitis (EAE), a common model of multiple sclerosis (MS), is mainly mediated by CD4+ T cells with demyelination and neurodegeneration of central nervous system (CNS). The loss of P2Y12 receptor might be associated with the pathogenesis of MS/EAE, but its potential mechanism is still not clear. In this study, more severe EAE developed in P2Y12-knockout (P2Y12-KO) mice compared to WT mice. Knockout of P2Y12 increased expression of IL 17A in the sera and proportion of Th17 cells in spleen and CNS. However, in vitro studies showed that P2Y12 did not influence cell differentiation and proliferation of CD4+ T cells. In bone marrow-derived dendritic cells (BMDCs), loss of P2Y12 significantly increased the production of IL-23 in contrast to the wild-type (WT) BMDCs. FACS analysis indicated that the culture supernatant from P2Y12-deficient DCs promoted more naive CD4+ T cells to differentiate into Th17 cells. Our finding demonstrated that genetic deletion of P2Y12 receptor broke the balance of Th subtypes by affecting the cytokine profile of BMDCs and resulted in the aggravated EAE, which suggested that P2Y12 may be a potential target in treating MS. PMID- 27939248 TI - Deep brain stimulation during early adolescence prevents microglial alterations in a model of maternal immune activation. AB - In recent years schizophrenia has been recognized as a neurodevelopmental disorder likely involving a perinatal insult progressively affecting brain development. The poly I:C maternal immune activation (MIA) rodent model is considered as a neurodevelopmental model of schizophrenia. Using this model we and others demonstrated the association between neuroinflammation in the form of altered microglia and a schizophrenia-like endophenotype. Therapeutic intervention using the anti-inflammatory drug minocycline affected altered microglia activation and was successful in the adult offspring. However, less is known about the effect of preventive therapeutic strategies on microglia properties. Previously we found that deep brain stimulation of the medial prefrontal cortex applied pre-symptomatically to adolescence MIA rats prevented the manifestation of behavioral and structural deficits in adult rats. We here studied the effects of deep brain stimulation during adolescence on microglia properties in adulthood. We found that in the hippocampus and nucleus accumbens, but not in the medial prefrontal cortex, microglial density and soma size were increased in MIA rats. Pro-inflammatory cytokine mRNA was unchanged in all brain areas before and after implantation and stimulation. Stimulation of either the medial prefrontal cortex or the nucleus accumbens normalized microglia density and soma size in main projection areas including the hippocampus and in the area around the electrode implantation. We conclude that in parallel to an alleviation of the symptoms in the rat MIA model, deep brain stimulation has the potential to prevent the neuroinflammatory component in this disease. PMID- 27939247 TI - Salsalate treatment following traumatic brain injury reduces inflammation and promotes a neuroprotective and neurogenic transcriptional response with concomitant functional recovery. AB - Neuroinflammation plays a critical role in the pathogenesis of traumatic brain injury (TBI). TBI induces rapid activation of astrocytes and microglia, infiltration of peripheral leukocytes, and secretion of inflammatory cytokines. In the context of modest or severe TBI, such inflammation contributes to tissue destruction and permanent brain damage. However, it is clear that the inflammatory response is also necessary to promote post-injury healing. To date, anti-inflammatory therapies, including the broad class of non-steroidal anti inflammatory drugs (NSAIDs), have met with little success in treatment of TBI, perhaps because these drugs have inhibited both the tissue-damaging and repair promoting aspects of the inflammatory response, or because inhibition of inflammation alone is insufficient to yield therapeutic benefit. Salsalate is an unacetylated salicylate with long history of use in limiting inflammation. This drug is known to block activation of NF-kappaB, and recent data suggest that salsalate has a number of additional biological activities, which may also contribute to its efficacy in treatment of human disease. Here, we show that salsalate potently blocks pro-inflammatory gene expression and nitrite secretion by microglia in vitro. Using the controlled cortical impact (CCI) model in mice, we find that salsalate has a broad anti-inflammatory effect on in vivo TBI induced gene expression, when administered post-injury. Interestingly, salsalate also elevates expression of genes associated with neuroprotection and neurogenesis, including the neuropeptides, oxytocin and thyrotropin releasing hormone. Histological analysis reveals salsalate-dependent decreases in numbers and activation-associated morphological changes in microglia/macrophages, proximal to the injury site. Flow cytometry data show that salsalate changes the kinetics of CCI-induced accumulation of various populations of CD11b-positive myeloid cells in the injured brain. Behavioral assays demonstrate that salsalate treatment promotes significant recovery of function following CCI. These pre clinical data suggest that salsalate may show promise as a TBI therapy with a multifactorial mechanism of action to enhance functional recovery. PMID- 27939249 TI - Activation of MU-opioid receptor and Toll-like receptor 4 by plasma from morphine treated mice. AB - In this study, we quantified the ability of opioids present in biological samples to activate the MU-opioid receptor and TLR4 using cell-based assays. Each assay was standardised, in the presence of plasma, using morphine, its MU receptor active metabolite morphine-6 glucuronide (M6G) and its MU receptor-inactive, but TLR4-active metabolite morphine-3 glucuronide (M3G). Specificity was verified using antagonists. Morphine- and M6G-spiked plasma samples exhibited MU receptor activation, which M3G-spiked plasma lacked. In contrast, M3G showed moderate but consistent activation of TLR-4. Plasma samples were collected at a number of time points from mice administered morphine (1 or 10mg/kg every 12h for 3days) or saline. Morphine administration led to intermittent MU receptor activation, reversed by MU receptor antagonists, and to TRL4 activation at time points where M3G is measured in plasma. Interestingly, this protocol of morphine administration also led to TLR4-independent NF-kappaB activation, at time points where M3G was not detected, presumably via elevation of circulating cytokines including, but not limited to, TNFalpha. Circulating TNFalpha was increased after three days of morphine administration, and TNFalpha mRNA elevated in the spleen of morphine-treated mice. PMID- 27939250 TI - "Molecular" MR imaging at high fields. AB - Magnetic resonance imaging (MRI) and spectroscopy (MRS) have contributed considerably to clinical radiology, and a variety of MR techniques have been developed to evaluate pathological processes as well as normal tissue biology at the cellular and molecular level. However, in comparison to nuclear imaging, MRI has relatively poor sensitivity for detecting true molecular changes or for detecting the presence of targeted contrast agents, though these remain under active development. In recent years very high field (7T and above) MRI systems have been developed for human studies and these provide new opportunities and technical challenges for molecular imaging. We identify 5 types of intrinsic contrast mechanisms that do not require the use of exogenous agents but which can provide molecular and cellular information. We can derive information on tissue composition by (i) imaging different nuclei, especially sodium (ii) exploiting chemical shift differences as in MRS (iii) exploiting specific relaxation mechanisms (iv) exploiting tissue differences in the exchange rates of molecular species such as amides or hydroxyls and (v) differences in susceptibility. The increased signal strength at higher fields enables higher resolution images to be acquired, along with increased sensitivity to detecting subtle effects caused by molecular changes in tissues. PMID- 27939251 TI - Muscle Mass and Body Fat in Relation to Cardiovascular Risk Estimation and Lipid Lowering Eligibility. AB - This cross-sectional population-based study aimed to evaluate the relationships of muscle-mass and body-fat phenotypes to 10-yr risk of cardiovascular disease (CVD) events and eligibility for lipid management. Participants were Korean adults (N = 7315; 3163 men, 4152 women) aged 40-79 yr, free from stroke and coronary heart disease, who provided complete data for estimating 10-yr CVD risk and body composition during the Fifth Korea National Health and Nutrition Examination Survey (2009-2010). Four levels of combined muscle mass and body fat were determined using sex-specific quintiles of appendicular skeletal muscle mass divided by height squared, and sex-specific quintiles of total body fat percentage. Ten-year CVD risk was calculated using Pooled Cohort Equations and Framingham risk scores. Lipid-lowering medication eligibility was determined using American College of Cardiology/American Heart Association (ACC/AHA) and Adult Treatment Panel (ATP) III guidelines. Compared with the reference group, the risk of CVD events was higher in men with low muscle mass, high body fat, or the 2 factors combined. CVD risk was lower in women with low muscle mass, higher in women with high body fat, and nonsignificant in women with the 2 factors. Participants with low muscle mass and high body fat had higher odds for medication eligibility using the ACC/AHA guidelines but not the ATP III guidelines. Higher estimated 10-yr CVD risk was associated with combined phenotypes of low muscle mass and high fat in men but not in women. Also, the relationship of these phenotypes to lipid-lowering medication eligibility was guideline-specific. PMID- 27939252 TI - A Matter of Time: Small RNAs Regulate the Duration of Epigenetic Inheritance. AB - Small RNAs are increasingly emerging as transgenerational carriers of epigenetic information in Caenorhabditis elegans and in other organisms. Recent studies have identified factors that are required for the inheritance of small RNAs and for heritable RNAi in worms, which typically persist for a finite number of generations. We examine here recent insights into the mechanisms that control the duration of transgenerational inheritance of small RNAs. We discuss current understanding of two types of regulatory mechanisms: those that prolong RNAi inheritance through amplification and maintenance of heritable small RNAs, and those that limit the persistence of ancestral RNAi by, for example, employing negative feedback loops to reset the transmission of epigenetic information. Collectively, these machineries result in the precise and intricate regulation of small RNA inheritance across generations. PMID- 27939253 TI - Hippocampal sclerosis and associated focal cortical dysplasia-related epilepsy in neurofibromatosis type I. AB - Neurofibromatosis type I (NF1) is a relatively common disorder associated with a range of neurologic sequelae. Refractory epilepsy occurs in 4-13% of NF1 patients. Hippocampal sclerosis and focal cortical dysplasia, both well-defined epilepsy-related entities, have been described in a subset of cases. To our knowledge, there has been only one other series describing coexistent focal cortical dysplasia and hippocampal sclerosis in the setting of NF1. We report two such patients who presented with intractable seizures requiring epilepsy surgery. Histologically, the hippocampal sclerosis specimen met criteria for the International League Against Epilepsy (ILAE) hippocampal sclerosis subtypes Ia and II respectively. The associated focal cortical dysplasia observed within the resected temporal lobe were both consistent with ILAE focal cortical dysplasia type IIIa (e.g. associated with a secondary lesion). Post-operatively, both patients had recurrence of habitual seizures, with one case continuing to have intractable seizures following two subsequent temporal lobectomies. Although hippocampal sclerosis association with focal cortical dysplasia is well document in epilepsy, it has been rarely described in the setting of neurofibromatosis type I. Although prior surgical series have shown good epilepsy surgery outcomes within neurofibromatosis type I, these two cases did not. PMID- 27939254 TI - Early introduction of clozapine after neuroleptic malignant syndrome may prevent malignant catatonia: A case report. PMID- 27939255 TI - Outbreaks of Invasive Kingella kingae Infections in Daycare Facilities: Approach to Investigation and Management. PMID- 27939256 TI - Do Growing Rods for Idiopathic Early Onset Scoliosis Improve Activity and Participation for Children? AB - OBJECTIVE: To investigate whether growing rod surgery for children with progressive idiopathic early onset scoliosis (EOS) effects activity and participation, and investigate factors that may affect this. STUDY DESIGN: Multicenter retrospective cohort study using prospectively collected data on 60 children with idiopathic EOS and significant scoliosis (defined as a Cobb angle >40 degrees ). Thirty underwent brace treatment, and 30, growth rod surgery. Questionnaire and radiographic data were recorded at 1 year. The validated Activities Scale for Kids performance version (ASKp) questionnaire was used to measure activity and participation. RESULTS: In the brace group, Cobb angle increased from 60 degrees to 68 degrees . There was no change in ASKp score. In the operative group, Cobb angle decreased from 67 degrees to 45 degrees . ASKp decreased from 91 to 88 (P < .01). Presence of spinal pain correlated with greater reduction in activity and participation scores in both groups, as did occurrence of complications in the operative group (P < .05). Both treatments permitted growth of the immature spine. CONCLUSIONS: In children with significant idiopathic EOS (Cobb angle>40 degrees ), growth rod surgery was associated with a reduction in activity and participation and Cobb angle, whereas brace treatment was associated with an increase in Cobb angle and no change in activity and participation. Pain was the most important factor affecting activity and participation in both groups. PMID- 27939257 TI - Comparisons of Office and 24-Hour Ambulatory Blood Pressure Monitoring in Children with Obstructive Sleep Apnea. AB - OBJECTIVE: To compare office blood pressure (BP) and 24-hour ambulatory BP (ABP) monitoring to facilitate the diagnosis and management of hypertension in children with obstructive sleep apnea (OSA). STUDY DESIGN: Children aged 4-16 years with OSA-related symptoms were recruited from a tertiary referral medical center. All children underwent overnight polysomnography, office BP, and 24-hour ABP studies. Multiple linear regression analyses were applied to elucidate the association between the apnea-hypopnea index and BP. Correlation and consistency between office BP and 24-hour ABP were measured by Pearson correlation, intraclass correlation, and Bland-Altman analyses. RESULTS: In the 163 children enrolled (mean age, 8.2 +/- 3.3 years; 67% male). The prevalence of systolic hypertension at night was significantly higher in children with moderate-to-severe OSA than in those with primary snoring (44.9% vs 16.1%, P = .006). Pearson correlation and intraclass correlation analyses revealed associations between office BP and 24 hour BP, and Bland-Altman analysis indicated an agreement between office and 24 hour BP measurements. However, multiple linear regression analyses demonstrated that 24-hour BP (nighttime systolic BP and mean arterial pressure), unlike office BP, was independently associated with the apnea-hypopnea index, after adjustment for adiposity variables. CONCLUSIONS: Twenty-four-hour ABP is more strongly correlated with OSA in children, compared with office BP. PMID- 27939258 TI - Mucopolysaccharidosis Type I Newborn Screening: Best Practices for Diagnosis and Management. PMID- 27939259 TI - Oxygen Saturation and Heart Rate Ranges in Very Preterm Infants Requiring Respiratory Support at Birth. AB - OBJECTIVE: To evaluate the changes in preductal oxygen saturation (SpO2) and heart rate in preterm infants receiving continuous positive airway pressure (CPAP) and/or positive-pressure ventilation (PPV) at birth. STUDY DESIGN: A prospective observational study at birth of infants aged <32 weeks separated into 2 gestational age (GA) groups: 230/7-276/7 weeks (group 1) and 280/7-316/7 weeks (group 2). Infants received delayed cord clamping (DCC) in accordance with institutional protocol. CPAP and/or PPV was applied at the clinical team's discretion. SpO2 and heart rate were recorded every minute for 10 minutes. Preductal SpO2 was targeted according to published nomograms. For heart rate, the goal was to maintain a stable heart rate >100 bpm. RESULTS: The study cohort comprised 96 group 1 infants (mean GA, 26 +/- 1 weeks; mean birth weight, 818 +/- 208 g) and 173 group 2 infants (mean GA, 30 +/- 1 weeks; mean birth weight, 1438 +/- 374 g). In general, infants requiring respiratory support reached target values for heart rate and SpO2 more slowly than the published nomograms for spontaneously breathing preterm infants without respiratory support. Infants receiving CPAP reached SpO2 and heart rate targets faster than infants receiving PPV. In group 1, but not group 2 infants, DCC resulted in higher SpO2 and heart rate. CONCLUSION: SpO2 and heart rate do not quickly and reliably reach the values achieved by spontaneously breathing preterm infants not requiring respiratory support. PMID- 27939260 TI - The effects of active video games on patients' rehabilitative outcomes: A meta analysis. AB - A meta-analysis on Active Video Games (AVG) as a rehabilitative tool does not appear to be available. This meta-analytic review synthesizes the effectiveness of AVGs on patients' rehabilitative outcomes. Ninety-eight published studies on AVGs and rehabilitation were obtained in late 2015 with 14 meeting the following inclusion criteria: 1) data-based English articles; 2) randomized-controlled trials investigating AVG's effect on rehabilitative outcome(s); and 3) >=1 comparison present in each study. Data extraction for comparisons was completed for three age categories: 1) youth/young adults (5-25years-old); 2) middle-aged adults (40-65years-old); and 3) older adults (>=65years-old). Comprehensive Meta Analysis software calculated effect size (ES; Hedge's g). Comparison group protocols often employed another non-AVG experimental treatment. Control group protocols implemented standard care. AVGs demonstrated a large positive effect on balance control over control among youth/young adults (ES=0.81, p<0.01). Further, AVGs resulted in small positive effects on middle-aged adults' balance control over control (ES=0.143, p=0.48) and comparison (ES=0.14, p=0.53), with similar results in older adults compared to control (ES=0.16, p=0.27). Notably, AVG's effect on balance control versus comparison among older adults was small yet negative (ES=-0.12, p=0.63). AVGs were also used to enhance general physical functioning (GPF) among middle-aged and older adults. Versus control and comparison, AVGs had no effect on middle-aged adults' GPF (ES=-0.054 and -0.046, respectively) or older adults' GPF (ES=0.04 and 0.002, respectively). Finally, AVGs had a moderate effect on older adults' falls efficacy versus control (ES=0.61, p<0.05). Findings favor AVGs for youth/young adult balance control rehabilitation and falls efficacy promotion in older adults. PMID- 27939262 TI - Sedentary time assessed by actigraphy and mortality: The Rotterdam Study. AB - Research suggests that sedentary behavior is a risk factor for mortality. However, most studies rely on questionnaires, which are prone to reporting error. We examined the association between sedentary time assessed by actigraphy and mortality among 1839 participants, aged 45-98years, from the prospective population-based Rotterdam Study, enrolled between 2004 and 2007. Participants wore an actigraph around the wrist for seven days. Sedentary time was evaluated continuously, per 1h/day increase, and categorically in three groups (<8, 8-11, >=11h/day). The lowest category was used as reference. Mortality risks were examined using Cox proportional hazard models, adjusted for confounders and biological risk factors. We examined the association between sedentary behavior and mortality over and beyond other activity measures (including physical activity (PA) and activities of daily living (ADL)) in a final model. During 11years of follow-up (median: 7.5years, interquartile range: 6.6-8.3years), 212 participants (11.5%) died. In the multivariable model, the hazard ratio (HR) and 95% confidence interval (95% CI) per 1 more hour/day sedentary time was 1.09 (1.00, 1.18). The HR (95% CI) after adjustment for PA and ADL was 1.04 (0.96, 1.13). Participants sedentary for >=11h/day had a higher mortality risk (HR: 1.80, 95% CI: 1.14, 2.84) than those sedentary <8h/day, in the multivariable model. After adjusting for PA and ADL, this association was clearly attenuated (HR: 1.50, 95% CI: 0.93, 2.41). In conclusion, our study suggests that sedentary behavior is a risk factor for mortality. Further investigation is needed to examine whether this association is distinct from the effect of other measures of activity. PMID- 27939261 TI - Changes in heavy drinking following onset of health problems in a U.S. general population sample. AB - Heavy episodic drinking is a well-established risk factor for heart disease, diabetes, certain cancers, stroke, hypertension and injuries, however, little is known about whether health problems precipitate changes in subsequent drinking patterns. Retrospective cohort analyses of heavy drinking by decade were conducted using data from the 2010 U.S. National Alcohol Survey (n=5240). Generalized estimating equations models were used to predict any, monthly, and weekly heavy (5+) drinking occasions across decades of life following a diagnosis of hypertension, heart problems, diabetes, stroke, cancer, or serious injury. Experiencing heart problems was associated with higher odds of reduced weekly heavy drinking (adjusted odds ratio (ORadj)=3.5; 95% confidence interval (CI); 1.7-7.4). The onset of diabetes was also associated with higher odds of reducing any heavy drinking over the decade (ORadj=1.7; 95% CI; 1.1-2.6). Cancer survivors were less likely to report no heavy drinking (ORadj=0.5; 95% CI; 0.3-0.8) or no weekly heavy drinking (ORadj=0.3; 95% CI; 0.2-0.7). Hypertension, stroke and injury were not found to have any significant associations. Reduced heavy drinking was more likely to be reported by Black drinkers following heart problems and Whites following a diabetes diagnosis. Increased heavy drinking following a cancer diagnosis was significant among women and Whites. Future studies on alcohol's heath and mortality risks should take into consideration effects of health problems on drinking patterns. Additionally, study results support increased prevention efforts targeting heavy drinking among cancer survivors, especially White women, and individuals with or being treated for hypertension. PMID- 27939264 TI - Preconception health behaviours: A scoping review. AB - Preconception health refers to the health of males and females at any point in time prior to a potential pregnancy. A goal of preconception health research is to use preventive behaviour and healthcare to optimize the health of future offspring that result from both planned and unplanned pregnancies. This paper briefly reviews evidence of the importance of various preconception health behaviours, and examines the extent to which specific preconception health behaviours have been included in recent studies of such knowledge, behaviours, and intentions. To describe this recent research in highly developed countries, a scoping review of the literature was completed of studies published within the past seven years. A total of 94 studies on preconception health were identified and reviewed: (a) 15 examined knowledge and attitudes, (b) 68 studied behaviours, (c) 18 examined interventions designed to improve knowledge or behaviour, and (d) no studies examined intentions to engage in preconception health behaviours. Over 40% of studies examining preconception health behaviour focussed exclusively on folic acid. Overall, folic acid, alcohol, and cigarettes have consistently been topics of focus, while exposure to harmful environmental substances, stress, and sleep have been largely neglected. Despite strong evidence for the importance of men's health during the preconception period, only 11% of all studies included male participants. Based on existing gaps in the research, recommendations are provided, such as including men in future research, assessing a wider variety of behaviours, consideration of behavioural intentions, and consideration of the relationships between preconception health knowledge, intentions, and behaviour. PMID- 27939263 TI - Objective reports versus subjective perceptions of crime and their relationships to accelerometer-measured physical activity in Hispanic caretaker-child dyads. AB - Crime and safety are commonly cited barriers to physical activity (PA). We had three objectives, 1) describe the association between objective crime measures and perceptions of crime, 2) analyze the relationships between each type of crime and accelerometer-measured physical activity in caretakers and young children (ages 3-5years), and 3) explore for early gender differences in the relationship between crime and physical activity in young children. Data are from the cross sectional baseline data of an ongoing randomized controlled trial in Nashville, Tennessee spanning September 2012 through May 2014. Data was analyzed from 480 Hispanic dyads (adult caretaker and 3-5year old child). Objective crime rate was assessed in ArcGIS and perception of crime was measured by caretaker agreement with the statement "The crime rate in my neighborhood makes it unsafe to go on walks." The primary outcome was accelerometer-measured physical activity over seven consecutive days. Objective and perceived crime were significantly positively correlated. Caretaker vigorous PA was significantly related to perceptions of crime; however, its relationship to objective crime was not significant. Child PA was not significantly related to caretaker perceptions of crime. However, interactions suggested that the relationship between crime rate and PA was significantly more negative for girls than for boys. Objective and subjective measures of crime rate are expected to be important correlates of PA, but they appear to have complex relationships that are different for adults than they are for young children, as well as for young girls compared to boys, and research has produced conflicting findings. PMID- 27939265 TI - Global participation in sport and leisure-time physical activities: A systematic review and meta-analysis. AB - This review aimed to determine the most popular physical activities performed by children, adolescents, and adults globally. Statistic bureau websites and article databases Scopus, ProQuest, SPORTDiscus, and Science Direct were searched between November 17th, 2014 and April 31st, 2015. Eligible studies were published in the last 10years with participation rates for specific physical activities among individuals five years or older. Data extraction for included articles (n=64) was assessed independently and agreed upon by two authors. A random-effects model was used to calculate participation rates in specific activities for each age group and region. In total 73,304 articles were retrieved and 64 articles representing 47 countries were included in the final meta-analysis. Among adults, walking was the most popular activity in the Americas (18.9%; 95% CI 10.2 to 32.5), Eastern Mediterranean (15.0%; 95% CI 5.8 to 33.6), Southeast Asia (39.3%; 95% CI 0.9 to 98.0) and Western Pacific (41.8%; 95% CI 25.2 to 60.6). In Europe and Africa, soccer (10.0%; 95% CI 6.5 to 15.1) and running (9.3%; 95% CI 0.9 to 53.9), respectively, were top activities. Child and adolescent participation results were highly dependent upon region. American youth team sport participation was high, while youth from the Eastern Mediterranean and Western Pacific were more likely to report participation in lifelong physical activities. Global data for adults reflects a consistent pattern of participation in running and walking. Among all age groups and regions soccer was popular. In children and adolescents, preferences were variable between regions. PMID- 27939266 TI - Perceived neighborhood environmental attributes associated with leisure-time and transport physical activity in Mexican adults. AB - Environmental factors have been associated with specific physical activity domains, including leisure-time and transport physical activity, in some high income countries. Few studies have examined the environmental correlates for domain-specific physical activity in low-and middle-income countries, and results are inconsistent. We aimed to estimate the associations between perceived environment and self-reported leisure-time walking, moderate-to-vigorous leisure time physical activity and transport physical activity among adults living in Cuernavaca, Mexico. A population-based study of adults 20 to 64years old was conducted in Cuernavaca, Mexico in 2011 (n=677). Leisure and transport physical activity was measured using the International Physical Activity Questionnaire - Long Form. Perceptions of neighborhood environment were obtained by questionnaire. Hurdle regression models estimated the association between environmental perceptions and participation and time spent in each physical activity domain. High perceived aesthetics were positively correlated with participation and time spent in leisure-time walking and moderate-to-vigorous physical activity. SES differences existed for aesthetics in relation to participation in leisure-time walking. Participation in transport physical activity was positively associated with easy access to large parks, while closer distance to large parks was a negative correlate for participation and time-spent in this physical activity domain. Results suggest that perceived environmental characteristics related with physical activity are domain specific. High perceived aesthetics were an important correlate for leisure-time activities among Mexican adults, suggesting that policy strategies aimed at improving this environmental perception may be warranted. Patterns of associations between environmental correlates and transport physical activity differed from those reported in commonly studied high income countries. PMID- 27939267 TI - Are children living on dead-end streets more active? Near-home street patterns and school-going children's time spent outdoors in Dhaka, Bangladesh. AB - This study aimed to investigate relationships between near-home street patterns and children's time spent outdoors (TSO). Participants were 60 (n=60) school-age Dhaka children, 7-11years old (16 girls and 44 boys) selected by a two-phase cluster sampling method. Data were collected from September 2010 to June 2011 by visiting each of 60 children's homes. Children's mean TSOs (in minutes) were reported by parents' face-to-face interviews, and near-home street pattern data were collected by systematic direct observations. The researchers also collected data on seven socio-demographic variables and three neighborhood built environment variables. A backward selection based multiple linear regression was used to examine association between children's TSO and near-home street patterns. Results (adjusted R2=0.66 for weekdays and 0.68 for weekend) suggested that children's TSO were significantly associated with near-home street type: dead-end instead of through streets (28min on weekdays, p<0.01 and 66min on weekend, p<0.01). The width of the street, level of its branching and availability of an open space or playground near the house are also positively associated with TSO. Near-home street features significantly contribute to TSO in school-going children of Dhaka. PMID- 27939268 TI - The efficiency and safety of fibrin sealant for reducing blood loss in primary total hip arthroplasty: A systematic review and meta-analysis. AB - OBJECTIVE: Total hip arthroplasty (THA) is associated with substantial blood loss. The objective of present systematic review and meta-analysis is to provide evidence from randomized controlled trials (RCTs) on the efficiency and safety of administration of fibrin sealant (FS) for reducing blood loss in patients undergoing primary THA. METHODS: Potential relevant studies were identified from electronic databases including Medline, PubMed, Embase, ScienceDirect, web of science and Cochrane Library. Gray academic studies were also identified from the reference list of included studies. There was no language restriction. Pooling of data was carried out by using RevMan 5.1. RESULTS: Six randomized controlled trials (RCTs) met the inclusion criteria. Current meta-analysis indicated that there were significant differences in terms of total blood loss (MD = -153.77, 95% CI: -287.21 to -20.34, P = 0.02), postoperative hemoglobin level (MD = -0.25, 95% CI: -0.46 to -0.05, P = 0.02) and transfusion rate (RD = -0.12, 95% CI: -0.22 to -0.03, P = 0.01) between groups. No significant differences were found regarding the incidence of deep venous thrombosis (DVT) (RD = 0.00, 95% CI: 0.01to 0.01, P = 0.51) or other side effects. CONCLUSION: Administration of fibrin sealant in total hip arthroplasty may reduce total blood loss, postoperative hemoglobin decline and transfusion requirements. Moreover, no adverse effect was related to FS. Due to the limited quality of the evidence currently available, higher quality RCTs are required. PMID- 27939269 TI - Biological properties of Hertia cheirifolia L. flower extracts and effect of the nopol on alpha-glucosidase. AB - In screening for antioxidant and alpha-glucosidase inhibitors from the extracts of Hertia cheirifolia L. flowers, the petroleum ether extract showed interesting antioxidant activity and inhibitory effect on the activity of alpha-glucosidase. The fractionation of this extract resulted in the isolation of a compound which is characterized by NMR and ESI-MS as a nopol. The nopol exhibited potent alpha glucosidase inhibitory potential with IC50 value of 220MUM. The kinetic evaluation indicated that it acts as a non-competitive inhibitor. A molecular docking study proved that the nopol presented a strong affinity with amino acid residues of alpha-glucosidase. PMID- 27939270 TI - Characterization, antioxidant activity and immunomodulatory activity of polysaccharides from the swollen culms of Zizania latifolia. AB - The swollen culms of Zizania latifolia have been used as a vegetable and traditional herbal medicine in China, Japan, Korea and Southeast Asia countries. Up to date, there is little information about the polysaccharides from the swollen culms of Zizania latifolia and their potential bioactivities. In the present study, water extractable polysaccharide (ZLPs-W) and alkali extractable polysaccharide (ZLPs-A) was sequentially prepared from the swollen culms of Zizania latifolia. Both of ZLPs-W and ZLPs-A was found to be non-starch polydisperse heterpolysaccharide with beta-type glycosidic linkage. ZLPs-W with triple helix conformation mainly composed of GalA, Glc and Gal. ZLPs-A without triple helix conformation mainly composed of Glc, Gal, Xyl and Ara. In in vitro antioxidant assay, ZLPs-W and ZLPs-A exhibited good scavenging activities. The EC50 of DPPH radical, superoxide radical and hydroxy radical scavenging activities for ZLPs-A is 1.87, 1.13 and 0.38mg/mL compared with that for ZLPs-W is 2.95, 3.99 and 0.5mg/mL, respectively. Moreover, in vitro cell assay revealed that ZLPs-W without cytotoxicity has higher immunomodulatory activity than ZLPs-A in terms of stimulation of phagocytic ability and NO production in murine macrophage RAW 264.7. At the treated concentration of 400MUg/mL and 100MUg/mL, ZLPs-W induced a highest phagocytosis index (1.76) and NO product (29.12MUmol/L), respectively. The results suggest that polysaccharide from the swollen culms of Zizania latifolia could be explored as potential natural antioxidant and immunomodulatory agents in medicine or functional food fields. PMID- 27939271 TI - Biocompatibility of ionic liquids towards protein stability: A comprehensive overview on the current understanding and their implications. AB - Over the past years since the discovery of ionic liquids (ILs), there is an increased demand to consider ILs as novel biocompatible co-solvents for proteins. Due to their tunable physical properties ILs can adjust themselves in any required experimental conditions starting from protein extraction to enzyme catalysis at elevated temperature. In recent years, large numbers of ILs have been synthesized and their effect on protein stability has been illustrated. With the rapid growth in various kinds of ILs, our understanding of protein stability in ILs has substantially increased. It is not necessary that a particular IL that is biocompatible to a protein will behave same for the other. Therefore, it is extremely essential to collect the literature dealing with the direct involvement of ILs in protein folding/unfolding studies under the same roof. This review focuses the tremendous accomplishments achieved in recent years in the field of protein stability in ILs. We hope that this would also help to set a stage where we can identify, explore and compare the mechanistic behavior of protein folding/unfolding in ILs. This review will surely bring a new boost in protein folding studies from the chemical biology perspective. PMID- 27939272 TI - Sodium alginate and gum acacia hydrogels of ZnO nanoparticles show wound healing effect on fibroblast cells. AB - An ideal biomaterial for wound dressing applications should possess antibacterial and anti-inflammatory properties without any toxicity to the host cells while providing the maximum healing activity. Zinc oxide nanoparticles (ZnONPs) possess antimicrobial activity and enhance wound healing, but the questions regarding their safety arise before application to the biological systems. We synthesized ZnONPs-loaded-sodium alginate-gum acacia hydrogels (SAGA-ZnONPs) by cross linking hydroxyl groups of the polymers sodium alginate and gum acacia with the aldehyde group of gluteradehyde. Here, we report the wound healing properties of sodium alginate/gum acacia/ZnONPs, circumventing the toxicity of ZnONPs simultaneously. We demonstrated the concentration-dependent zones of inhibition in treated cultures of Pseudomonas aerigunosa and Bacillus cereus and biocompatability on peripheral blood mononuclear/fibroblast cells. SAGA-ZnONPs hydrogels showed a healing effect at a low concentration of ZnONPs using sheep fibroblast cells. Our findings suggest that high concentrations of ZnONPs were toxic to cells but SAGA ZnONPs hydrogels significantly reduced the toxicity and preserved the beneficial antibacterial and healing effect. PMID- 27939273 TI - Dimerization of Tyr136Cys alpha-synuclein prevents amyloid transformation of wild type alpha-synuclein. AB - Expression of human alpha-synuclein in E. coli cells is known to result in a mixture of the wild type alpha-synuclein and the protein containing Tyr136Cys substitution due to the translational error. The amount of Cys136 alpha-synuclein (Cys136-AS) may reach approximately 50% of the recombinant protein. The wild-type and Cys136-containing fractions of alpha-synuclein were separated using thiol Sepharose, and their properties were investigated. In the absence of reducing agents, Cys136-AS forms dimers due to the disulfide bonding. Both wild-type and Cys136 alpha-synuclein preparations are prone to aggregate during prolonged incubation under shaking at pH 4 and 37 degrees C, but only the wild-type alpha synuclein produces amyloid aggregates. The aggregates produced by either monomeric or dimeric Cys136-AS do not exhibit amyloid properties according to the test with Thioflavin T. Moreover, an admixture of dimeric Cys136-AS prevents the amyloid transformation of the wild-type alpha-synuclein. CD spectroscopy analysis revealed an enhanced content of alpha-helical structures in the aggregates produced by dimeric Cys136-AS. The admixture of Cys136-AS in preparations of human recombinant alpha-synuclein can be a source of erroneous interpretation of experiments on amyloid transformation of this protein. PMID- 27939274 TI - Helional-induced activation of human olfactory receptor 2J3 promotes apoptosis and inhibits proliferation in a non-small-cell lung cancer cell line. AB - Studies within the last decade have localized the functional expression of olfactory receptors (ORs) to cells outside of the olfactory epithelium. In human hepatocarcinoma and prostate cancer cells, the activation of ORs by odors modulates elementary physiological processes and leads to an inhibitory effect on proliferation. Cells of the respiratory tract are in direct contact with the surrounding air, in which a myriad of volatile molecules, especially odors, are present. Non-small-cell lung cancer (NSCLC) has a high prevalence, a high mortality rate and is difficult to treat. NSCLC cells are nearly resistant to common chemotherapeutic approaches, and surgical resection provides the only possible chance of a cure for most patients. New approaches for the treatment of NSCLC are the focus of many current studies. Thus, it is of interest to characterize the functional expression of ORs in cancer cells of the lung and to investigate the impact of ORs on pathophysiological processes. In the present study, we demonstrate that the expression of OR2J3 and cytosolic Ca2+ increase via the activation of the agonist helional in the NSCLC cell line A549. We further investigated the underlying pathway. Helional triggers phoshoinositol-3 kinase (PI3K), signaling the release of intracellular Ca2+ and phosphorylation of ERK. We observed that OR2J3 activation induces apoptosis and inhibits cell proliferation and migration in long-term stimulus experiments with helional. Our study provides the first evidence of the functional expression of an OR in NSCLC cells and its putative therapeutic impact. PMID- 27939275 TI - "No Country for Old Men" With ST-segment Elevation Myocardial Infarction. PMID- 27939276 TI - Imminent Paradoxical Embolism Diagnosed by Computed Tomography. PMID- 27939279 TI - Handing Over. PMID- 27939278 TI - Usefulness of right ventricular and right atrial two-dimensional speckle tracking strain to predict late arrhythmic events in adult patients with repaired Tetralogy of Fallot. AB - OBJECTIVE: To determine whether right ventricular and/or atrial speckle tracking strain is associated with previous arrhythmic events in patients with repaired tetralogy of Fallot. METHODS AND RESULTS: We studied right ventricular and atrial strain in 100 consecutive patients with repaired tetralogy of Fallot referred for routine echocardiographic evaluation. Patients were divided into two groups, one with previous documentation of arrhythmias (n=26) and one without arrhythmias, in a median follow-up of 22 years. Patients with arrhythmias were older (p<0.001) and had surgical repair at an older age (p=0.001). They also had significantly reduced right ventricular strain (-14.7+/-5.5 vs. -16.9+/-4.0%, p=0.029) and right atrial strain (19.1+/-7.7% vs. 25.8+/-11.4%, p=0.001). Neither right ventricular nor right atrial strain were independent predictors of the presence of a history of documented arrhythmias, which was associated with age at correction and with the presence of residual defects. In a subanalysis after excluding 23 patients who had had more than one corrective surgery, right ventricular strain was an independent predictor of the presence of previous arrhythmic events (OR 1.19, 95% CI 1.02-1.38, p=0.025). Right atrial strain was also an independent predictor after adjustment (OR 0.93, 95% CI 0.87-0.99, p=0.029). The ideal cut-off for right ventricular strain was -15.3% and for right atrial strain 23.0%. CONCLUSIONS: Compared with conventional echocardiographic parameters, strain measures of the right heart are associated with the presence of arrhythmic events, and may be useful for risk stratification of patients with repaired tetralogy of Fallot, although a prospective study is required. PMID- 27939277 TI - Thrombus and Plaque Erosion Characterized by Optical Coherence Tomography in Patients With Vasospastic Angina. AB - INTRODUCTION AND OBJECTIVES: Vasospastic angina (VSA) can result in endothelial damage and thrombus formation. The aim of this study was to evaluate the incidence of thrombus and plaque characteristics at coronary spasm segments compared with nonspasm segments by using optical coherence tomography (OCT) in patients with suspected VSA. METHODS: One hundred and eighty-three patients with suspected VSA were enrolled in this study. The ergonovine provocation test was performed in all patients for the diagnosis of VSA except in patients with spontaneous spasm. All target lesions were analyzed by OCT. Plaque erosion was defined as the presence of attached thrombus overlying an intact fibrous cap and visualized plaque on multiple adjacent OCT frames. RESULTS: One hundred and nine spasm segments (93 patients) were compared with 55 nonspasm segments (39 patients). Thrombus was more frequently seen at spasm segments than at nonspasm segments (28.4% vs 7.3%; P = .026) and thrombus size was larger at spasm segments than at nonspasm segments (0.26 +/- 0.50 mm2 vs 0.04 +/- 0.01 mm2; P = .023). Thin-cap fibroatheroma was more frequently seen at nonspasm segments than at spasm segments (16.4% vs 1.8%; P = .006). Plaque erosion was more prevalent at spasm segments than at nonspasm segments (25.7% vs 5.4%; P = .001). CONCLUSIONS: Thrombus and plaque erosion were more common at spasm segments than at nonspasm segments assessed by OCT in patients with suspected VSA. These findings suggest the potential benefit and treatment role of antiplatelet therapy in vasospastic angina. PMID- 27939280 TI - Multicenter trial of an internal joint stabilizer for the elbow. AB - BACKGROUND: Our primary efficacy objective was to evaluate the effectiveness of the internal joint stabilizer of the elbow (IJS-E) in maintaining concentric location of the elbow during and after removal of the device in the treatment of persistent or recurrent instability after elbow fracture or dislocations, or both. The secondary study objectives were to assess range of motion, Broberg Morrey functional score, Broberg-Morrey categorical rating, the Disabilities of the Arm, Shoulder and Hand score, and the rate of complications and adverse events after the use of IJS-E. METHODS: Twenty-four patients were studied in a multicenter, nonrandomized, prospective, single-arm study. The IJS-E was used to provide temporary stabilization of the elbow joint and allow a functional range of motion while ligaments and fractures healed. RESULTS: The elbow remained concentrically aligned in 23 of 24 patients. One coronoid-deficient elbow did not maintain concentric reduction. At the last evaluation a minimum of 6 months after device removal, the mean arc of elbow flexion was 119 degrees (range, 80 degrees -150 degrees ; standard deviation [SD], 18 degrees ), and the mean arc of forearm rotation was 151 degrees (range, 90 degrees -190 degrees ; SD, 24 degrees ). The mean and median Broberg-Morrey scores were 93 and 97, respectively. Categorically the results were excellent in 14, good in 8, fair in 1, and poor in 1. The mean Disabilities of the Arm, Shoulder and Hand score was 16 (range, 0-68; SD, 18). CONCLUSION: The IJS-E maintains concentric reduction, allows elbow motion, and avoids the inconveniences and pin problems of percutaneous fixation. PMID- 27939281 TI - Reverse shoulder arthroplasty after radial-to-axillary nerve transfer for axillary nerve palsy with concomitant irreparable rotator cuff tear. PMID- 27939282 TI - A minimally interactive and reproducible method for abdominal aortic aneurysm quantification in 3D ultrasound and computed tomography with implicit template deformations. AB - The maximum diameter of abdominal aortic aneurysm (AAA) is a key quantification parameter for disease assessment. Although it is routinely measured on 2D ultrasound images, using a volumetric approach is expected to improve measurement reproducibility. In this work, 3D-ultrasound or computed tomography imaging of patients with AAA was combined with a minimally interactive 3D segmentation based on implicit template deformation. Segmentation usability and reproducibility were evaluated on 81 patients, showing a mean measurement time of [2;8]min per case, and Dice coefficients of 0.87+/-0.12 for 3D-US and 0.81+/-0.08 for CT. Quantification parameters included a diameter measurement from 3D-US and CT volumes with respective confidence intervals of 0.51 [-2.5;3.52]mm and 1.00 [ 1.68;3.67]mm. Additional volume measurements showed confidence intervals of 0.91 [-4.17;5.99]ml for 3D-US and 4.10 [-4.11;12.30]ml for CT. PMID- 27939283 TI - Global vision of druggability issues: applications and perspectives. AB - During the preliminary stage of a drug discovery project, the lack of druggability information and poor target selection are the main causes of frequent failures. Elaborating on accurate computational druggability prediction methods is a requirement for prioritizing target selection, designing new drugs and avoiding side effects. In this review, we describe a survey of recently reported druggability prediction methods mainly based on networks, statistical pocket druggability predictions and virtual screening. An application for a frequent mutation of p53 tumor suppressor is presented, illustrating the complementarity of druggability prediction approaches, the remaining challenges and potential new drug development perspectives. PMID- 27939284 TI - Contribution of a rapid influenza diagnostic test to manage hospitalized patients with suspected influenza. AB - AIM: To evaluate the performances of the Alere i influenza A&B test and to appraise its contribution to patient management. METHODS: In total, 267 samples were tested. Influenza A and B PCR was performed as the reference. For each positive result, the supervising physician was contacted to collect data regarding patient management. FINDINGS: The overall sensitivity and specificity of the Alere i were 91.4% and 97.6% for influenza A and 54.5% and 98.8% for influenza B, respectively. More specifically, when used in the emergency room (ER), the test helped avoid 10.7% of hospitalizations, 46.4% of antibiotic prescriptions and 42.9% of additional investigations for positive patients. The test was also helpful in instituting the prescription of oseltamivir and patient isolation. CONCLUSION: Alere i influenza A&B is a rapid, sensitive and specific diagnostic test for influenza A. Sensitivity for influenza B was poor. Its usefulness was more important when patients were still in the ER. PMID- 27939285 TI - Performance of a MALDI-TOF MS-based imipenem hydrolysis assay incorporating zinc sulfate. AB - A MALDI-TOF MS1-based imipenem hydrolysis assay was modified by adding ZnSO4. This improved detection of metallo-beta-lactamase producing strains without compromising detection of other carbapenemase types. Using 129 genetically characterized Gram-negative bacilli, the sensitivity and specificity were 98.5% (95% confidence interval [CI]: 91.9-99.7%) and 100% (95% CI: 94.3-100%), respectively. PMID- 27939286 TI - Leishmania infantum mimotopes and a phage-ELISA assay as tools for a sensitive and specific serodiagnosis of human visceral leishmaniasis. AB - Serological methods used to diagnose visceral leishmaniasis (VL) are considered minimally invasive, but they present problems related with their sensitivity and/or specificity. In this study, a subtractive selection using the phage display technology against antibodies from healthy subjects living in endemic and non-endemic areas of disease, as well as from Chagas disease patients and those developing active VL, was developed. The aim of this study was to select bacteriophage-fused epitopes to be used in the serodiagnosis of human VL. Eight phage clones were selected after the bio-panning rounds, and their reactivity was evaluated in a phage-ELISA assay against a human serological panel. A wild-type clone and the recombinant K39-based immunochromatographic test were used as controls. In the results, it was shown that all clones showed an excellent performance to serologically identify VL patients, demonstrating the feasibility of the isolated phages for developing a specific and sensitive serodiagnosis of human VL. PMID- 27939287 TI - Serotypes, antimicrobial resistance and genotypes of Streptococcus pneumoniae associated with infections in cancer patients in Brazil. AB - We sought to characterize pneumococcal isolates associated with bacteremia, pneumonia and meningitis in cancer patients and to estimate the coverage of the available pneumococcal vaccines. Fifty isolates recovered from 49 patients attending a cancer reference center over a 1-year period were analyzed. The prevalent serotypes were: 23F (12%), 6A (8%), 3, 4, 20, and 23A (6% each). All isolates were susceptible to chloramphenicol, levofloxacin, rifampicin, and vancomycin. Resistance or reduced susceptibility to penicillin made up 14%, and one isolate was also intermediately resistant to ceftriaxone. The three (6%) erythromycin-resistant isolates presented the M or cMLSB phenotypes and harbored the mef(A/E) gene exclusively or along with the erm(B) gene. Twenty-two (44%) isolates were closely related to 11 international clones, being strongly associated with penicillin non-susceptibility. Combined immunization with the 13 valent conjugate and the 23-valent polysaccharide vaccines might contribute to reduce (76%) the burden of the pneumococcal infections in the population investigated. PMID- 27939290 TI - The DisVis and PowerFit Web Servers: Explorative and Integrative Modeling of Biomolecular Complexes. AB - Structure determination of complex molecular machines requires a combination of an increasing number of experimental methods with highly specialized software geared toward each data source to properly handle the gathered data. Recently, we introduced the two software packages PowerFit and DisVis. These combine high resolution structures of atomic subunits with density maps from cryo-electron microscopy or distance restraints, typically acquired by chemical cross-linking coupled with mass spectrometry, respectively. Here, we report on recent advances in both GPGPU-accelerated software packages: PowerFit is a tool for rigid body fitting of atomic structures in cryo-electron density maps and has been updated to also output reliability indicators for the success of fitting, through the use of the Fisher z-transformation and associated confidence intervals; DisVis aims at quantifying the information content of distance restraints and identifying false-positive restraints. We extended its analysis capabilities to include an analysis of putative interface residues and to output an average shape representing the putative location of the ligand. To facilitate their use by a broad community, they have been implemented as web portals harvesting both local CPU resources and GPGPU-accelerated EGI grid resources. They offer user-friendly interfaces, while minimizing computational requirements, and provide a first interactive view of the results. The portals can be accessed freely after registration via http://milou.science.uu.nl/services/DISVIS and http://milou.science.uu.nl/services/POWERFIT. PMID- 27939288 TI - Epidemiology and characteristics of Escherichia coli sequence type 131 (ST131) from long-term care facility residents colonized intestinally with fluoroquinolone-resistant Escherichia coli. AB - The objective of this study was to evaluate molecular and epidemiologic factors associated with Escherichia coli sequence type 131 (ST131) among long-term care facility (LTCF) residents who acquired gastrointestinal tract colonization with fluoroquinolone-resistant E. coli (FQREC). Colonizing isolates from 37 residents who newly developed FQREC colonization at three LTCFs from 2006 to 2008 were evaluated. Twenty-nine (78%) of 37 total FQREC colonizing isolates were ST131. Most ST131 isolates had a distinctive combination of gyrA and parC replacement mutations. The ST131 and non-ST131 isolates differed significantly for the prevalence of many individual virulence factors but not for the proportion that qualified molecularly as extraintestinal pathogenic E. coli (ExPEC) or aggregate virulence factor scores. E. coli ST131 was highly prevalent among LTCF residents with FQREC colonization. Future studies should determine the risk factors for infection among ST131-colonized residents, and assess the potential for increased transmissibility of ST131 in the long-term care setting. PMID- 27939289 TI - Intensification: A Resource for Amplifying Population-Genetic Signals with Protein Repeats. AB - Large-scale genome sequencing holds great promise for the interpretation of protein structures through the discovery of many, rare functional variants in the human population. However, because protein-coding regions are under high selective constraints, these variants occur at low frequencies, such that there is often insufficient statistics for downstream calculations. To address this problem, we develop the Intensification approach, which uses the modular structure of repeat protein domains to amplify signals of selection from population genetics and traditional interspecies conservation. In particular, we are able to aggregate variants at the codon level to identify important positions in repeat domains that show strong conservation signals. This allows us to compare conservation over different evolutionary timescales. It also enables us to visualize population-genetic measures on protein structures. We make available the Intensification results as an online resource (http://intensification.gersteinlab.org) and illustrate the approach through a case study on the tetratricopeptide repeat. PMID- 27939291 TI - Structures of the Karyopherins Kap121p and Kap60p Bound to the Nuclear Pore Targeting Domain of the SUMO Protease Ulp1p. AB - The budding yeast small ubiquitin-like modifier (SUMO) protease Ulp1p catalyzes both the processing of newly synthesized SUMO to its mature form and the deconjugation of SUMO from target proteins, thereby regulating a wide range of cellular processes including cell division, DNA repair, DNA replication, transcription, and mRNA quality control. Ulp1p is localized primarily at the nuclear pore complex (NPC) through interactions involving the karyopherins Kap121p and Kap95p-Kap60p heterodimer and a subset of nuclear pore-associated proteins. The sequestration of Ulp1p at the nuclear periphery is crucial for the proper control of protein desumoylation. To gain insights into the role of the karyopherins in regulating the localization of Ulp1p, we have determined the crystal structures of Kap121p and Kap60p bound to the N-terminal non-catalytic domain of Ulp1p that is necessary and sufficient for NPC targeting. Contrary to a previous proposal that Ulp1p is tethered to the transport channel of the NPC through unconventional interactions with the karyopherins, our structures reveal that Ulp1p has canonical nuclear localization signals (NLSs): (1) an isoleucine lysine-NLS (residues 51-55) that binds to the NLS-binding site of Kap121p, and (2) a classical bipartite NLS (residues 154-172) that binds to the major and minor NLS-binding sites of Kap60p. Ulp1p also binds Kap95p directly, and the Ulp1p-Kap95p binding is enhanced by the importin-beta-binding domain of Kap60p. GTP-bound Gsp1p (the yeast Ran ortholog) and the exportin Cse1p cooperate to release Ulp1p from the karyopherins, indicating that the stable sequestration of Ulp1p to the NPC would require a karyopherin-independent mechanism to anchor Ulp1p at the NPC. PMID- 27939293 TI - Telomeric Retrotransposon HeT-A Contains a Bidirectional Promoter that Initiates Divergent Transcription of piRNA Precursors in Drosophila Germline. AB - PIWI-interacting RNAs (piRNAs) provide the silencing of transposable elements in the germline. Drosophila telomeres are maintained by transpositions of specialized telomeric retroelements. piRNAs generated from sense and antisense transcripts of telomeric elements provide telomere length control in the germline. Previously, we have found that antisense transcription of the major telomeric retroelement HeT-A is initiated upstream of the HeT-A sense transcription start site. Here, we performed a deletion analysis of the HeT-A promoter and show that common regulatory elements are shared by sense and antisense promoters of HeT-A. Therefore, the HeT-A promoter is a bidirectional promoter capable of processive sense and antisense transcription. Ovarian small RNA data show that a solo HeT-A promoter within an euchromatic transgene initiates the divergent transcription of transgenic reporter genes and subsequent processing of these transcripts into piRNAs. These events lead to the formation of a divergent unistrand piRNA cluster at solo HeT-A promoters, in contrast to endogenous telomeres that represent strong dual-strand piRNA clusters. Solo HeT-A promoters are not immunoprecipitated with heterochromatin protein 1 (HP1) homolog Rhino, a marker of the dual-strand piRNA clusters, but are associated with HP1 itself, which provides piRNA-mediated transcriptional repression of the reporter genes. Unlike endogenous dual-strand piRNA clusters, the solo HeT-A promoter does not produce overlapping transcripts. In a telomeric context, however, bidirectional promoters of tandem HeT-A repeats provide a read-through transcription of both genomic strands, followed by Rhi binding. These data indicate that Drosophila telomeres share properties of unistrand and dual-strand piRNA clusters. PMID- 27939292 TI - Structural Basis of Arp2/3 Complex Inhibition by GMF, Coronin, and Arpin. AB - The evolutionarily conserved Arp2/3 complex plays a central role in nucleating the branched actin filament arrays that drive cell migration, endocytosis, and other processes. To better understand Arp2/3 complex regulation, we used single particle electron microscopy to compare the structures of Arp2/3 complex bound to three different inhibitory ligands: glia maturation factor (GMF), Coronin, and Arpin. Although the three inhibitors have distinct binding sites on Arp2/3 complex, they each induced an "open" nucleation-inactive conformation. Coronin promoted a standard (previously described) open conformation of Arp2/3 complex, with the N-terminal beta-propeller domain of Coronin positioned near the p35/ARPC2 subunit of Arp2/3 complex. GMF induced two distinct open conformations of Arp2/3 complex, which correlated with the two suggested binding sites for GMF. Furthermore, GMF synergized with Coronin in inhibiting actin nucleation by Arp2/3 complex. Arpin, which uses VCA-related acidic (A) motifs to interact with the Arp2/3 complex, induced the standard open conformation, and two new masses appeared at positions near Arp2 and Arp3. Furthermore, Arpin showed additive inhibitory effects on Arp2/3 complex with Coronin and GMF. Together, these data suggest that Arp2/3 complex conformation is highly polymorphic and that its activities can be controlled combinatorially by different inhibitory ligands. PMID- 27939295 TI - Shedding light on the puzzle of drug-membrane interactions: Experimental techniques and molecular dynamics simulations. AB - Lipid membranes work as barriers, which leads to inevitable drug-membrane interactions in vivo. These interactions affect the pharmacokinetic properties of drugs, such as their diffusion, transport, distribution, and accumulation inside the membrane. Furthermore, these interactions also affect their pharmacodynamic properties with respect to both therapeutic and toxic effects. Experimental membrane models have been used to perform in vitro assessment of the effects of drugs on the biophysical properties of membranes by employing different experimental techniques. In in silico studies, molecular dynamics simulations have been used to provide new insights at an atomistic level, which enables the study of properties that are difficult or even impossible to measure experimentally. Each model and technique has its advantages and disadvantages. Hence, combining different models and techniques is necessary for a more reliable study. In this review, the theoretical backgrounds of these (in vitro and in silico) approaches are presented, followed by a discussion of the pharmacokinetic and pharmacodynamic properties of drugs that are related to their interactions with membranes. All approaches are discussed in parallel to present for a better connection between experimental and simulation studies. Finally, an overview of the molecular dynamics simulation studies used for drug-membrane interactions is provided. PMID- 27939294 TI - Distinct Contributions of Tryptophan Residues within the Dimerization Domain to Nanog Function. AB - The level of the transcription factor Nanog directly determines the efficiency of mouse embryonic stem cell self-renewal. Nanog protein exists as a dimer with the dimerization domain composed of a simple repeat region in which every fifth residue is a tryptophan, the tryptophan repeat (WR). Although WR is necessary to enable Nanog to confer LIF-independent self-renewal, the mechanism of dimerization and the effect of modulating dimerization strength have been unclear. Here we couple mutagenesis with functional and dimerization assays to show that the number of tryptophans within the WR is linked to the strength of homodimerization, Sox2 heterodimerization and self-renewal activity. A reduction in the number of tryptophan residues leads initially to a gradual reduction in activity before a precipitous reduction in activity occurs upon reduction in tryptophan number below eight. Further functional attrition follows subsequent tryptophan number reduction with substitution of all tryptophan residues ablating dimerization and self-renewal function completely. A strong positional influence of tryptophans exists, with residues at the WR termini contributing more to Nanog function, particularly at the N-terminal end. Limited proteolysis demonstrates that a structural core of Nanog encompassing the homeodomain and the tryptophan repeat can support LIF-independent colony formation. These results increase understanding of the molecular interactions occurring between transcription factor subunits at the core of the pluripotency gene regulatory network and will enhance our ability to control pluripotent cell self-renewal and differentiation. PMID- 27939296 TI - Risk factors for Clonorchis sinensis infection transmission in humans in northern Vietnam: A descriptive and social network analysis study. AB - Clonorchis sinensis is major fish-borne trematode, endemic in North Vietnam. Risk factors described so far include individual eating behaviors and environmental factors. Here, additional to conventional risk factors, we report on socially influenced liver fluke transmission in endemic communities. A cross-sectional study on risk factors and fish sharing networks was conducted in 4 villages of Gia Thinh Commune, Ninh Binh Province. A total of 510 residents in 272 households were recruited for risk factor analysis while 220 households, 28 fishermen and 10 fish-sellers were enrolled for social network study. Fecal examination for C. sinensis eggs was performed. Average C. sinensis infection rate at Gia Thinh commune was 16.5% (range 2% to 34.4%). Higher infection rates were significantly associated with males, lower educational levels, eating raw fish, and location of the villages. Social network analysis (SNA) showed a strong positive correlation between ego network size (number of households in fish sharing network) and quantity of raw fish consumed (r=0.603, P<0.05). The infection rate in people who ate raw-fish caught from a nearby river was significantly higher than those who consumed fish taken from farmed ponds (P<0.05). The amount of raw-fish meal consumed per resident/year was significantly higher in villages that had a strong network of sharing raw-fish food (P<0.001). This study reports for the first time on fish-food sharing among neighbors, proximity to water bodies, frequency of eating raw fish from natural water bodies and low education were key risk factors in C. sinensis infection transmission in northern Vietnam. PMID- 27939297 TI - Health and Social Care workers' perceptions of NPS use in Northern Ireland. AB - BACKGROUND: The EU Early Warning System currently monitors more than 560 new psychoactive substances, far outweighing the total number of illicit drugs under international control. Due to the recent emergence of NPS and rapidly changing nature of the market, evidence about the way in which the emerging drugs are managed in health and social care settings is limited. METHODS: The study adopted a mixed methods design, utilising a cross sectional survey and telephone interviews to capture data from staff working in drug and alcohol related services in statutory and voluntary sectors, across the five Health and Social Care (HSC) Trust areas in Northern Ireland. 196 staff participated in the survey and 13 participated in follow up in telephone interviews between August and November 2015. RESULTS: Study respondents reported that addressing NPS related issues with service users was a key aspect of their daily role and function. Levels of injecting behaviours were also viewed as relatively high by study participants. Almost all workers used harm reduction as their primary approach when working with service users and the majority of respondents called for additional practical training in relation to addressing drug interactions and intervening with NPS related issues. PMID- 27939298 TI - Reasons for missed appointments with a hepatitis C outreach clinic: A qualitative study. AB - BACKGROUND: Non-attendance in drug service hepatitis C outreach clinics means clients miss the opportunity of being given lifestyle advice and referral to hospital for assessment and treatment. A similar problem is experienced in other services throughout the UK. A qualitative study was undertaken to investigate the problem. METHODS: Clients with a history of not attending the outreach clinic were invited to participate during a routine drug clinic appointment. A contact details sheet with a preferred telephone number was completed by those agreeing to take part. Verbal consent was taken and a telephone interview took place. The participants were remunerated for taking part with a five pounds high street voucher. The 'framework method' was used to analyse the data with key themes identified. RESULTS: Twenty-eight telephone interviews were undertaken from April to June 2012. All the clients gave 'prima-facie' reasons for non-attendance including 'not a priority' and 'forgot'. However, the study indicates these are insufficient to explain the various experiences and influences. Underlying reasons that impacted upon attendance were identified. These reasons relate to (i) client characteristics e.g. 'priority' to score drugs and the 'cost of travel' and (ii) clinic service e.g. 'difficult journey' to the clinic and timing of the 'appointment'. The reasons operated within a complex context where other factors had an impact including addiction, welfare policy, stigma and the nature of hepatitis C itself. CONCLUSION: The study revealed that beneath apparently simple explanations for non-attendance, such as clients' chaotic lifestyle resulting in them forgetting or not being bothered to attend, there were far more complex and varied underlying reasons. This has important implications for drug policy including the need to better incorporate clients' perspectives. Policy that is based only on the simple, surface reasons is unlikely to be effective. PMID- 27939299 TI - Reply. PMID- 27939300 TI - Characterization of FcgammaRIIIA effector cells used in in vitro ADCC bioassay: Comparison of primary NK cells with engineered NK-92 and Jurkat T cells. AB - Antibody-dependent cell-mediated cytotoxicity (ADCC) is an important mechanism of action (MOA) of several therapeutic antibody drugs and evaluation in ADCC bioassays is important in antibody drug development and maintenance. Three types of effector cells now routinely used in bioassay evaluation of ADCC are natural killer cells from human donors (FcgammaRIIIA+primary NK), FcgammaRIIIA engineered NK-92 cells and FcgammaRIIIA/NFAT-RE/luc2 engineered Jurkat T cells. Engineered effector cells were developed to address need for improved precision and accuracy of classic NK cell ADCC bioassays. The main purpose of our study was to rationalize which of these ADCC effector cells best simulate the expected response in human subjects and to identify which effector cells and assays best fit ADCC bioassay needs during antibody drug development. We characterized differences between the effector cells and compared ADCC biological activities using the well-known humanized IgG1 antibody drug, trastuzumab. The three effector cell types studied expressed either V-158 or F-158 allotype of FcgammaRIIIA, hence six cell preparations were compared. Our results demonstrate highest surface expression of FcgammaRIIIA in primary NK and engineered NK-92 (V 158) cells with nearly all expressed on the cell surface. In contrast, expression in engineered Jurkat T cells was low with only a small percentage expressed on the cell surface. Studies evaluating binding of trastuzumab to effector cells demonstrated the highest affinity of FcgammaRIIIA in primary NK and NK-92 (V-158) cells. ADCC cytotoxicity studies showed greatest trastuzumab potency in primary NK and engineered NK-92 (V-158) cells and negligible cell lysis obtained using engineered Jurkat T cells. In contrast, the engineered Jurkat T (V-158) cells responded as effectively as primary NK (V/V) cells to nuclear factor of activated T cells (NFAT2) activation upon binding of trastuzumab to FcgammaRIIIA, demonstrating similar ADCC pathway activation in these cells despite the low surface expression of FcgammaRIIIA and its low affinity for trastuzumab. Dose response range of trastuzumab in activation of NFAT2 (measured as pNFAT2 dephosphorylation) was very similar to response in classic ADCC assay for primary and NK-92 cells and to response in ADCC reporter assay for Jurkat T effector cells, bridging the assays. Trastuzumab potency in ADCC reporter assay using the engineered Jurkat T cells was close to that seen using either primary NK or engineered NK-92 cells in classic ADCC assay. In summary, all three effector cell systems differentially express FcgammaRIIIA and provide dose-dependent ADCC pathway activity, yet only primary NK and engineered NK-92 cells are capable of inducing ADCC-mediated cell lysis. Engineered Jurkat T effector cells have value to assure antibody manufacturing consistency and in other applications where accuracy and precision are important. For functional assessment of ADCC activity, primary NK or NK-92 (V-158) cells better reflect the physiologically relevant ADCC mechanism of action. As an engineered cell line, NK-92 cells may behave more reproducibly than primary NK, but this must be balanced with the objective for biological relevance in decisions on which NK cells to use in assay. PMID- 27939301 TI - Accurate quantitation for in vitro refolding of single domain antibody fragments expressed as inclusion bodies by referring the concomitant expression of a soluble form in the periplasms of Escherichia coli. AB - Single domain antibody fragments from two species, a camel VHH (PM1) and a shark VNAR (A6), were derived from inclusion bodies of E. coli and refolded in vitro following three refolding recipes for comparing refolding efficiencies: three step cold dialysis refolding (TCDR), one-step hot dialysis refolding (OHDR), and one-step cold dialysis refolding (OCDR), as these fragments were expressed as 'a soluble form' either in cytoplasm or periplasm, but the amount were much less than those expressed as 'an insoluble form (inclusion body)' in cytoplasm and periplasm. In order to verify the refolding efficiencies from inclusion bodies correctly, proteins purified from periplasmic soluble fractions were used as reference samples. These samples showed far-UV spectra of a typical beta-sheet dominant structure in circular dichroism (CD) spectroscopy and so did the refolded samples as well. As the maximal magnitude of ellipticity in millidegrees (thetamax) observed at a given wave length was proportional to the concentrations of the respective reference samples, we could draw linear regression lines for the magnitudes vs. sample concentrations. By using these lines, we measured the concentrations for the refolded PM1 and A6 samples purified from solubilized cytoplasmic insoluble fractions. The refolding efficiency of PM1 was almost 50% following TCDR and 40% and 30% following OHDR and OCDR, respectively, whereas the value of A6 was around 30% following TCDR, and out of bound for quantitation following the other two recipes. The ELISA curves, which were derived from the refolded samples, coincided better with those obtained from the reference samples after converting the values from the protein-concentrations at recovery to the ones of refolded proteins using recovery ratios, indicating that such a correction gives better results for the accurate measure of the ELISA curves than those without correction. Our method require constructing a dual expression system, expressed both in periplasm as a soluble form and cytoplasm as an insoluble form; application of the different refolding recipes due to sequence-by sequence-difference could be precisely monitored using CD spectra with the concomitant soluble samples as a reference. PMID- 27939302 TI - Postnatal maturation of mouse medullo-spinal cerebrospinal fluid-contacting neurons. AB - The central canal along the spinal cord (SC.) and medulla is characterized by the presence of a specific population of neurons that contacts the cerebrospinal fluid (CSF). These medullo-spinal CSF-contacting neurons (CSF-cNs) are identified by the selective expression of the polycystin kidney disease 2-like 1 ionic channel (PKD2L1 or polycystin-L). In adult, they have been shown to express doublecortin (DCX) and Nkx6.1, two markers of juvenile neurons along with the neuron-specific nuclear protein (NeuN) typically expressed in mature neurons. They were therefore suggested to remain in a rather incomplete maturation state. The aim of this study was to assess whether such juvenile state is stable in postnatal animals or whether CSF-cNs may reach maturity at older stages than neurons in the parenchyma. We show, in the cervical SC. and the brainstem that, in relation to age, CSF-cN density declines and that their cell bodies become more distant from the cc, except in its ventral part. Moreover, in adults (from 1month) by comparison with neonatal mice, we show that CSF-cNs have evolved to a more mature state, as indicated by the increase in the percentage of cells positive for NeuN and of its level of expression. In parallel, CSF-cNs exhibit, in adult, lower DCX immunoreactivity and do not express PSA-NCAM and TUC4, two neurogenic markers. Nevertheless, CSF-cNs still share in adult characteristics of juvenile neurons such as the presence of phospho-CREB and DCX while NeuN expression remained low. This phenotype persists in 12-month-old animals. Thus, despite a pursuit of neuronal maturation during the postnatal period, CSF-cNs retain a durable low differentiated state. PMID- 27939303 TI - Prostate cancer diagnostics: Clinical challenges and the ongoing need for disruptive and effective diagnostic tools. AB - The increased incidence and the significant health burden associated with carcinoma of the prostate have led to substantial changes in its diagnosis over the past century. Despite technological advancements, the management of prostate cancer has become progressively more complex and controversial for both early and late-stage disease. The limitations and potential harms associated with the use of prostate-specific antigen (PSA) as a diagnostic marker have stimulated significant investigation of numerous novel biomarkers that demonstrate varying capacities to detect prostate cancer and can decrease unnecessary biopsies. However, only a few of these markers have been approved for specific clinical settings while the others have not been adequately validated for use. This review systematically and critically assesses ongoing issues and emerging challenges in the current state of prostate cancer diagnostic tools and the need for disruptive next generation tools based on analysis of combinations of these biomarkers to enhance predictive accuracy which will benefit clinical diagnostics and patient welfare. PMID- 27939305 TI - Use of Liraglutide in the Real World and Impact at 36 Months on Metabolic Control, Weight, Lipid Profile, Blood Pressure, Heart Rate, and Renal Function. AB - PURPOSE: An observational retrospective study was conducted by 2 diabetes clinics in Italy to assess patterns of use and long-term effectiveness of liraglutide on established and emerging parameters. METHODS: Data from 261 patients with type 2 diabetes who started treatment with liraglutide between 2010 and 2014 were collected. Hierarchical linear regression models were applied to assess trends over time of clinical parameters. Factors associated with higher likelihood of dropout were identified through multivariate logistic analysis. FINDINGS: Liraglutide was initiated as a switch in 42.5% of patients and as an add-on in 49.8%; in 7.7% of the patients initiation of liraglutide was associated with a reduction in the number of pharmacologic agents. A statistically significant reduction after 36 months was found for the following parameters (mean change [95% CIs]): glycosylated hemoglobin (HbA1c; -1.01% [1.34% to -0.68%]), fasting blood glucose (-27.5 [-40.6 to -14.4] mg/dL), weight (-2.9 [-4.5 to -1.3] kg), body mass index (-1.13 [-1.76 to -0.50] kg/m2), waist circumference (-1.74 [-3.85 to -0.37] cm), and LDL-C (-24.7 [-36.67 to -12.8] mg/dL). Improvements in systolic (-3.5 mm Hg) and diastolic (-2.3 mm Hg) blood pressures were observed at 24 months. Albuminuria was reduced by -16.6 mg/L during 36 months, although statistical significance was not reached. Glomerular filtration rate and heart rate were unchanged. Reductions in HbA1c between -0.6% and -1.3% were obtained in specific subgroups. Treatment was effective also in patients with >20 years of diabetes duration, although the likelihood of dropout was 6% higher for each additional year of disease duration (RR = 1.06; 95% CI, 1.01-1.12). The likelihood of dropout was almost four times higher for subjects treated with insulin (RR = 3.82; 95% CI, 1.22-11.96) and more than twice for those treated with sulfonylureas (RR = 2.39; 95% CI, 1.16-4.94) compared with patients not treated with these agents. IMPLICATIONS: Liraglutide used in routine clinical conditions maintains its effectiveness on metabolic control and weight after 3 years. Improvements in terms of metabolic control were found when liraglutide was used as both switch and add-on treatment. In addition, improvements were sustained when liraglutide replaced sulfonylureas or insulin. Diabetes duration had no impact on drug efficacy. Long-term benefits relative to blood pressure and LDL-C were also found, which could not be entirely explained by antihypertensive/lipid-lowering treatment intensification. No major effect on renal parameters was documented. Diabetes duration and some concomitant treatments were associated with a higher likelihood of liraglutide discontinuation. These data can contribute to improve appropriateness and cost effectiveness profile of liraglutide. PMID- 27939306 TI - Association of h-index of Editorial Board Members and Impact Factor among Radiology Journals. AB - RATIONALE AND OBJECTIVES: h-Index has been proposed as a useful bibliometric measure for quantifying research productivity. In this current study, we analyzed h-indices of editorial board members of Radiology journals and tested the hypothesis that editorial board members of Radiology journals with higher impact factors (IF) have higher h-indices. MATERIALS AND METHODS: Sixty-two Radiology journals with IF >1 were included. Editorial board members were identified using the journals' websites. Editors' affiliations and research fields of interest were used to distinguish investigators with similar names. Bibliometric indices including number of publications, total citations, citations per publication, and h-index for each editorial board member were obtained using the Web of Science database. Chi-square or Wilcoxon rank-sum tests were used to test for differences in bibliographic measures or demographics between groups. RESULTS: Among the editorial boards of 62 journals, the median [interquartile range] board h-index was 26 [18, 31] and had 36 [17, 56] members. The median journal IF was 2.27 [1.74, 3.31]. We identified a total of 2204 distinct editors; they had a median [interquartile range] h-index of 23 [13, 35], 120 [58, 215] total publications, 1938 [682, 4634] total citations, and an average of 15.7 [9.96, 24.8] citations per publication. The boards of journals with IF above the median had significantly higher h-indices (P = .002), total publications (P = .01), and total and average citations (both any [P = .003, .009] and nonself-citations [P = .001, .002]) than journals below the median. CONCLUSIONS: Our data indicate that board members of Radiology journals with higher IF have greater h-indices compared to lower IF journals. PMID- 27939304 TI - Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration. AB - BACKGROUND: The potential for global collaborations to better inform public health policy regarding major non-communicable diseases has been successfully demonstrated by several large-scale international consortia. However, the true public health impact of familial hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large scale, robust data on the burden of FH worldwide. METHODS: The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. CONCLUSIONS: The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients. PMID- 27939307 TI - Papain wound dressings obtained from poly(vinyl alcohol)/calcium alginate blends as new pharmaceutical dosage form: Preparation and preliminary evaluation. AB - Transparent, soft, flexible, mechanically resistant films, which are ideal for use as wound dressings were prepared in the presence of 2% papain, a proteolytic enzyme that can play a role in the chemical debridement of the skin and can accelerate the healing process. The films, based on poly(vinyl alcohol):calcium alginate blends with increasing concentrations of polysaccharide (10, 20, and 30% v/v), were obtained by casting method. FTIR and DSC analyses were performed to assess the composition and miscibility of blends. Mechanical properties such as tensile strength, elasticity modulus, and elongation at breakpoint were evaluated. The influence of different concentrations of calcium alginate on physical attributes of films like wettability, swelling capacity and mechanical properties was determined. The stability of papain in the films was assessed indirectly by hemolytic activity assay employing direct contact method and confirmed by technique based on blood agar diffusion. Preliminary cytotoxicity was evaluated with the XTT method. The results showed that at the polymer concentrations tested, the blends were miscible. The increase in the content of the calcium alginate increased the wettability and swelling capacity of the films, which is desirable in wound dressings. On the other hand, mechanical resistance decreased without causing breakage of the films during the swelling tests. The hemolytic activity of the films was maintained during the studied period, suggesting the stability of papain in the proposed formulations. Cellular viability indicated that the films were non-toxic. The analysis of the results showed that it is possible to prepare interactive and bioactive wound dressing containing papain from blends of PVA and calcium alginate polymers. PMID- 27939308 TI - Phenylanthraquinones and flavone-C-glucosides from the disjunct Bulbinella in New Zealand. AB - The genera Bulbine, Bulbinella and Kniphofia produce phenylanthraquinones and are mostly found in southern Africa, although a disjunct group of Bulbinella species endemic to New Zealand also contain phenylanthraquinones as reported herein. The sub-Antarctic megaherb B. rossii yielded sulphated phenylanthraquinones, including a phenylanthraquinone found to carry a sulphated glycoside substituent, 4'-O-demethylknipholone-4'-beta-D-xylopyranosyl-3"-sulphate. A sensitive HPLC method was used to analyse 5 of the 6 New Zealand Bulbinella species, all of which contained phenylanthraquinones. Leaves and roots had different profiles, but species were not distinct. Roots were rich in sulphated and free phenylanthraquinones (0.27 +/- 0.09% dry wt), whereas leaves typically only contained free knipholone (0.14 +/- 0.01%). Localisation of phenylanthraquinones to the stele and peel was observed in roots. Two flavone-C-glucosides were found in leaves of Bulbinella. PMID- 27939310 TI - Opposing Activities of Aurora B Kinase and B56-PP2A Phosphatase on MKlp2 Determine Abscission Timing. AB - After cleavage furrow ingression during cytokinesis, nascent daughter cells remain connected by an intercellular bridge (ICB) and the midbody [1, 2]. The midbody becomes an assembly platform for ESCRT complexes that split apart the plasma membrane (PM) anchored to the ICB and complete abscission, which is the final step of cell division [3-5]. Aurora B governs abscission by regulating its timing as a checkpoint [6-10]. However, the underlying mechanisms for this process remain unknown. Here, we reveal the mechanism controlling abscission through integration of Aurora B kinase and B56-bound PP2A phosphatase activities on the kinesin motor protein MKlp2. We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton at the ICB through its previously uncharacterized lipid association motif (LAM). MKlp2 recruits Aurora B to the ICB [11-15]. In turn, Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878. Strikingly, a phospho-resistant MKlp2 S878A mutant overcomes Aurora-B-mediated abscission blockade. Thus, abscission is determined by the balance of Aurora B and B56-PP2A activities on MKlp2 S878 within the LAM. Together, these findings establish a key mechanism for Aurora B regulation of abscission in mammalian cells. PMID- 27939309 TI - Adhesion-Dependent Wave Generation in Crawling Cells. AB - Dynamic actin networks are excitable. In migrating cells, feedback loops can amplify stochastic fluctuations in actin dynamics, often resulting in traveling waves of protrusion. The precise contributions of various molecular and mechanical interactions to wave generation have been difficult to disentangle, in part due to complex cellular morphodynamics. Here we used a relatively simple cell type-the fish epithelial keratocyte-to define a set of mechanochemical feedback loops underlying actin network excitability and wave generation. Although keratocytes are normally characterized by the persistent protrusion of a broad leading edge, increasing cell-substrate adhesion strength results in waving protrusion of a short leading edge. We show that protrusion waves are due to fluctuations in actin polymerization rates and that overexpression of VASP, an actin anti-capping protein that promotes actin polymerization, switches highly adherent keratocytes from waving to persistent protrusion. Moreover, VASP localizes both to adhesion complexes and to the leading edge. Based on these results, we developed a mathematical model for protrusion waves in which local depletion of VASP from the leading edge by adhesions-along with lateral propagation of protrusion due to the branched architecture of the actin network and negative mechanical feedback from the cell membrane-results in regular protrusion waves. Consistent with our model simulations, we show that VASP localization at the leading edge oscillates, with VASP leading-edge enrichment greatest just prior to protrusion initiation. We propose that the mechanochemical feedbacks underlying wave generation in keratocytes may constitute a general module for establishing excitable actin dynamics in other cellular contexts. PMID- 27939312 TI - Caribbean Spiny Lobster Fishery Is Underpinned by Trophic Subsidies from Chemosynthetic Primary Production. AB - The Caribbean spiny lobster, Panulirus argus, is one of the most valuable fisheries commodities in the Central American region, directly employing 50,000 people and generating >US$450 million per year [1]. This industry is particularly important to small island states such as The Bahamas, which exports more lobster than any other country in the region [1]. Several factors contribute to this disproportionally high productivity, principally the extensive shallow-water banks covered in seagrass meadows [2], where fishermen deploy artificial shelters for the lobsters to supplement scarce reef habitat [3]. The surrounding seabed communities are dominated by lucinid bivalve mollusks that live among the seagrass root system [4, 5]. These clams host chemoautotrophic bacterial symbionts in their gills that synthesize organic matter using reduced sulfur compounds, providing nutrition to their hosts [6]. Recent studies have highlighted the important role of the lucinid clam symbiosis in maintaining the health and productivity of seagrass ecosystems [7, 8], but their biomass also represents a potentially abundant, but as yet unquantified, food source to benthic predators [9]. Here we undertake the first analysis of Caribbean spiny lobster diet using a stable isotope approach (carbon, nitrogen, and sulfur) and show that a significant portion of their food (~20% on average) is obtained from chemosynthetic primary production in the form of lucinid clams. This nutritional pathway was previously unrecognized in the spiny lobster's diet, and these results are the first empirical evidence that chemosynthetic primary production contributes to the productivity of commercial fisheries stocks. PMID- 27939313 TI - The Adult Body Plan of Indirect Developing Hemichordates Develops by Adding a Hox Patterned Trunk to an Anterior Larval Territory. AB - Many animals are indirect developers with distinct larval and adult body plans [1]. The molecular basis of differences between larval and adult forms is often poorly understood, adding a level of uncertainty to comparative developmental studies that use data from both indirect and direct developers. Here we compare the larval and adult body plans of an indirect developing hemichordate, Schizocardium californicum [2]. We describe the expression of 27 transcription factors with conserved roles in deuterostome ectodermal anteroposterior (AP) patterning in developing embryos, tornaria larvae, and post-metamorphic juveniles and show that the tornaria larva of S. californicum is transcriptionally similar to a truncated version of the adult. The larval ectoderm has an anterior molecular signature, while most of the trunk, defined by the expression of hox1 7, is absent. Posterior ectodermal activation of Hox is initiated in the late larva prior to metamorphosis, in preparation for the transition to the adult form, in which the AP axis converges on a molecular architecture similar to that of the direct developing hemichordate Saccoglossus kowalevskii. These results identify a molecular correlate of a major difference in body plan between hemichordate larval and adult forms and confirm the hypothesis that deuterostome larvae are "swimming heads" [3]. This will allow future comparative studies with hemichordates to take into account molecular differences caused by early life history evolution within the phylum. Additionally, comparisons with other phyla suggest that a delay in trunk development is a feature of indirect development shared across distantly related phyla. PMID- 27939311 TI - Diversity in Morphology and Locomotory Behavior Is Associated with Niche Expansion in the Semi-aquatic Bugs. AB - Acquisition of new ecological opportunities is a major driver of adaptation and species diversification [1-4]. However, how groups of organisms expand their habitat range is often unclear [3]. We study the Gerromorpha, a monophyletic group of heteropteran insects that occupy a large variety of water surface associated niches, from small puddles to open oceans [5, 6]. Due to constraints related to fluid dynamics [7-9] and exposure to predation [5, 10], we hypothesize that selection will favor high speed of locomotion in the Gerromorpha that occupy water-air interface niches relative to the ancestral terrestrial life style. Through biomechanical assays and phylogenetic reconstruction, we show that only species that occupy water surface niches can generate high maximum speeds. Basally branching lineages with ancestral mode of locomotion, consisting of tripod gait, achieved increased speed on the water through increasing midleg length, stroke amplitude, and stroke frequency. Derived lineages evolved rowing as a novel mode of locomotion through simultaneous sculling motion almost exclusively of the midlegs. We demonstrate that this change in locomotory behavior significantly reduced the requirement for high stroke frequency and energy expenditure. Furthermore, we show how the evolution of rowing, by reducing stroke frequency, may have eliminated the constraint on body size, which may explain the evolution of larger Gerromorpha. This correlation between the diversity in locomotion behaviors and niche specialization suggests that changes in morphology and behavior may facilitate the invasion and diversification in novel environments. PMID- 27939314 TI - 17th Century Variola Virus Reveals the Recent History of Smallpox. AB - Smallpox holds a unique position in the history of medicine. It was the first disease for which a vaccine was developed and remains the only human disease eradicated by vaccination. Although there have been claims of smallpox in Egypt, India, and China dating back millennia [1-4], the timescale of emergence of the causative agent, variola virus (VARV), and how it evolved in the context of increasingly widespread immunization, have proven controversial [4-9]. In particular, some molecular-clock-based studies have suggested that key events in VARV evolution only occurred during the last two centuries [4-6] and hence in apparent conflict with anecdotal historical reports, although it is difficult to distinguish smallpox from other pustular rashes by description alone. To address these issues, we captured, sequenced, and reconstructed a draft genome of an ancient strain of VARV, sampled from a Lithuanian child mummy dating between 1643 and 1665 and close to the time of several documented European epidemics [1, 2, 10]. When compared to vaccinia virus, this archival strain contained the same pattern of gene degradation as 20th century VARVs, indicating that such loss of gene function had occurred before ca. 1650. Strikingly, the mummy sequence fell basal to all currently sequenced strains of VARV on phylogenetic trees. Molecular clock analyses revealed a strong clock-like structure and that the timescale of smallpox evolution is more recent than often supposed, with the diversification of major viral lineages only occurring within the 18th and 19th centuries, concomitant with the development of modern vaccination. PMID- 27939316 TI - Mechanical Constraints on Flight at High Elevation Decrease Maneuvering Performance of Hummingbirds. AB - High-elevation habitats offer ecological advantages including reduced competition, predation, and parasitism [1]. However, flying organisms at high elevation also face physiological challenges due to lower air density and oxygen availability [2]. These constraints are expected to affect the flight maneuvers that are required to compete with rivals, capture prey, and evade threats [3-5]. To test how individual maneuvering performance is affected by elevation, we measured the free-flight maneuvers of male Anna's hummingbirds in a large chamber translocated to a high-elevation site and then measured their performance at low elevation. We used a multi-camera tracking system to identify thousands of maneuvers based on body position and orientation [6]. At high elevation, the birds' translational velocities, accelerations, and rotational velocities were reduced, and they used less demanding turns. To determine how mechanical and metabolic constraints independently affect performance, we performed a second experiment to evaluate flight maneuvers in an airtight chamber infused with either normoxic heliox, to lower air density, or nitrogen, to lower oxygen availability. The hypodense treatment caused the birds to reduce their accelerations and rotational velocities, whereas the hypoxic treatment had no significant effect on maneuvering performance. Collectively, these experiments reveal how aerial maneuvering performance changes with elevation, demonstrating that as birds move up in elevation, air density constrains their maneuverability prior to any influence of oxygen availability. Our results support the hypothesis that changes in competitive ability at high elevations are the result of mechanical limits to flight performance [7]. PMID- 27939315 TI - A Feathered Dinosaur Tail with Primitive Plumage Trapped in Mid-Cretaceous Amber. AB - In the two decades since the discovery of feathered dinosaurs [1-3], the range of plumage known from non-avialan theropods has expanded significantly, confirming several features predicted by developmentally informed models of feather evolution [4-10]. However, three-dimensional feather morphology and evolutionary patterns remain difficult to interpret, due to compression in sedimentary rocks [9, 11]. Recent discoveries in Cretaceous amber from Canada, France, Japan, Lebanon, Myanmar, and the United States [12-18] reveal much finer levels of structural detail, but taxonomic placement is uncertain because plumage is rarely associated with identifiable skeletal material [14]. Here we describe the feathered tail of a non-avialan theropod preserved in mid-Cretaceous (~99 Ma) amber from Kachin State, Myanmar [17], with plumage structure that directly informs the evolutionary developmental pathway of feathers. This specimen provides an opportunity to document pristine feathers in direct association with a putative juvenile coelurosaur, preserving fine morphological details, including the spatial arrangement of follicles and feathers on the body, and micrometer scale features of the plumage. Many feathers exhibit a short, slender rachis with alternating barbs and a uniform series of contiguous barbules, supporting the developmental hypothesis that barbs already possessed barbules when they fused to form the rachis [19]. Beneath the feathers, carbonized soft tissues offer a glimpse of preservational potential and history for the inclusion; abundant Fe2+ suggests that vestiges of primary hemoglobin and ferritin remain trapped within the tail. The new finding highlights the unique preservation potential of amber for understanding the morphology and evolution of coelurosaurian integumentary structures. PMID- 27939317 TI - Regional Growth Rate Differences Specified by Apical Notch Activities Regulate Liverwort Thallus Shape. AB - Plants have undergone 470 million years of evolution on land and different groups have distinct body shapes. Liverworts are the most ancient land plant lineage and have a flattened, creeping body (the thallus), which grows from apical cells in an invaginated "notch." The genetic mechanisms regulating liverwort shape are almost totally unknown, yet they provide a blueprint for the radiation of land plant forms. We have used a combination of live imaging, growth analyses, and computational modeling to determine what regulates liverwort thallus shape in Marchantia polymorpha. We find that the thallus undergoes a stereotypical sequence of shape transitions during the first 2 weeks of growth and that key aspects of global shape depend on regional growth rate differences generated by the coordinated activities of the apical notches. A "notch-drives-growth" model, in which a diffusible morphogen produced at each notch promotes specified isotropic growth, can reproduce the growth rate distributions that generate thallus shape given growth suppression at the apex. However, in surgical experiments, tissue growth persists following notch excision, showing that this model is insufficient to explain thallus growth. In an alternative "notch-pre patterns-growth" model, a persistently acting growth regulator whose distribution is pre-patterned by the notches can account for the discrepancies between growth dynamics in the notch-drives-growth model and real plants following excision. Our work shows that growth rate heterogeneity is the primary shape determinant in Marchantia polymorpha and suggests that the thallus is likely to have zones with specialized functions. PMID- 27939318 TI - Successful Geriatric Rehabilitation: Effects on Patients' Outcome of a National Program to Improve Quality of Care, the SINGER Study. AB - OBJECTIVE: To determine whether the implementation of a national program to improve quality of care in geriatric rehabilitation (GR) in the Netherlands improves successful GR in terms of independence in activities of daily living (ADL), discharge destination, and length of stay. DESIGN: Prospective longitudinal study, comparing 2 consecutive cohorts: at the start of implementation (n = 386) and at 1 year after implementation (n = 357) of this program. SETTING/PARTICIPANTS: Included were 16 skilled nursing facilities, 743 patients (median age 80 years, interquartile range 72-85; 64.5% females) indicated for GR and their health care professionals (elderly care physicians, physiotherapists, and nursing staff). INTERVENTION: National program to stimulate self-organizing capacity to develop integrated care to improve GR service delivery in 4 domains: alignment with patients' (care) needs, care coordination, team cooperation, and quality of care. MEASUREMENTS: Data on patients' characteristics, functional outcomes at admission and discharge, length of stay, and discharge destination were collected via an online questionnaire sent to health care professionals. The primary outcome measure was successful rehabilitation defined as independence in ADL (Barthel Index >=15), discharge home, and a short length of stay (lowest 25% per diagnostic group). Generalized estimating equation analysis was used to adjust for age, gender, and clustering effects in the total population and for the 2 largest diagnostic subgroups, traumatic injuries and stroke. RESULTS: In the total population, at 1 year postimplementation there was 12% more ADL independence [odds ratio (OR) 1.59, 95% confidence interval (CI) 1.00-2.54]. Although successful rehabilitation (independence in ADL, discharge home, short length of stay) was similar in the 2 cohorts, patients with traumatic injuries were more successful 1 year postimplementation (OR 1.61, 95% CI 1.01-2.54). In stroke patients, successful rehabilitation was similar between the cohorts, but with more independence in ADL in the follow-up cohort (OR 1.99, 95% CI 1.09-3.63). CONCLUSIONS: This study shows that 1-year after the implementation of the Dutch national program to improve quality of care there was more independence in ADL at discharge, but the combined outcome of successful GR (independence in ADL, discharge home, short length of stay) was only significantly improved in patients with traumatic injuries. PMID- 27939319 TI - Ability of Lactobacillus kefiri LKF01 (DSM32079) to colonize the intestinal environment and modify the gut microbiota composition of healthy individuals. AB - BACKGROUND: Probiotics have been observed to positively influence the host's health, but to date few data about the ability of probiotics to modify the gut microbiota composition exist. AIMS: To evaluate the ability of Lactobacillus kefiri LKF01 DSM32079 (LKEF) to colonize the intestinal environment of healthy subjects and modify the gut microbiota composition. METHODS: Twenty Italian healthy volunteers were randomized in pre-prandial and post-prandial groups. Changes in the gut microbiota composition were detected by using a Next Generation Sequencing technology (Ion Torrent Personal Genome Machine). RESULTS: L. kefiri was recovered in the feces of all volunteers after one month of probiotic administration, while it was detected only in three subjects belonging to the pre-prandial group and in two subjects belonging to the post-prandial group one month after the end of probiotic consumption. After one month of probiotic oral intake we observed a reduction of Bilophila, Butyricicomonas, Flavonifractor, Oscillibacter and Prevotella. Interestingly, after the end of probiotic administration Bacteroides, Barnesiella, Butyricicomonas, Clostridium, Haemophilus, Oscillibacter, Salmonella, Streptococcus, Subdoligranolum, and Veillonella were significantly reduced if compared to baseline samples. CONCLUSION: L. kefiri LKF01 showed a strong ability to modulate the gut microbiota composition, leading to a significant reduction of several bacterial genera directly involved in the onset of pro-inflammatory response and gastrointestinal diseases. PMID- 27939320 TI - MinION as part of a biomedical rapidly deployable laboratory. AB - Fast turnaround times are of utmost importance for biomedical reconnaissance, particularly regarding dangerous pathogens. Recent advances in sequencing technology and its devices allow sequencing within a short time frame outside stationary laboratories close to the epicenter of the outbreak. In our study, we evaluated the portable sequencing device MinION as part of a rapidly deployable laboratory specialized in identification of highly pathogenic agents. We tested the device in the course of a NATO live agent exercise in a deployable field laboratory in hot climate conditions. The samples were obtained from bio terroristic scenarios that formed part of the exercise and contained unknown bacterial agents. To simulate conditions of a resource-limited remote deployment site, we operated the sequencer without internet access. Using a metagenomic approach, we were able to identify the causative agent in the analyzed samples. Furthermore, depending on the obtained data, we were able to perform molecular typing down to strain level. In our study we challenged the device and discuss advances as well as remaining limitations for sequencing biological samples outside of stationary laboratories. Nevertheless, massive parallel sequencing as a non-selective methodology yields important information and is able to support outbreak investigation - even in the field. PMID- 27939321 TI - Transfer of a three step mAb chromatography process from batch to continuous: Optimizing productivity to minimize consumable requirements. AB - The goal of this study was to adapt a batch mAb purification chromatography platform for continuous operation. The experiments and rationale used to convert from batch to continuous operation are described. Experimental data was used to design chromatography methods for continuous operation that would exceed the threshold for critical quality attributes and minimize the consumables required as compared to batch mode of operation. Four unit operations comprising of Protein A capture, viral inactivation, flow-through anion exchange (AEX), and mixed-mode cation exchange chromatography (MMCEX) were integrated across two Cadence BioSMB PD multi-column chromatography systems in order to process a 25L volume of harvested cell culture fluid (HCCF) in less than 12h. Transfer from batch to continuous resulted in an increase in productivity of the Protein A step from 13 to 50g/L/h and of the MMCEX step from 10 to 60g/L/h with no impact on the purification process performance in term of contaminant removal (4.5 log reduction of host cell proteins, 50% reduction in soluble product aggregates) and overall chromatography process yield of recovery (75%). The increase in productivity, combined with continuous operation, reduced the resin volume required for Protein A and MMCEX chromatography by more than 95% compared to batch. The volume of AEX membrane required for flow through operation was reduced by 74%. Moreover, the continuous process required 44% less buffer than an equivalent batch process. This significant reduction in consumables enables cost effective, disposable, single-use manufacturing. PMID- 27939322 TI - Two populations of TSPO binding sites in oral cancer SCC-15 cells. AB - Oral cancer mortality and morbidity rates remain high. The main inducer of oral cancer is cigarette smoke (CS). Translocator protein 18kDa (TSPO) was shown to play a role in carcinogenesis. We characterized TSPO binding sites in human oral cancer cell line SCC-15 and examined effect of CS on TSPO binding. We exposed SCC 15 human squamous cells to cigarette smoke. [3H]PK 11195 binding results were assessed in cells confluent for one day. To characterize the number of population sites, a custom written Matlab program compared Pearson linear correlation coefficients between all points in the Scatchard plot. Using [3H]PK 11195 as a radio ligand, we found that TSPO binding sites are not uniform, but separated into two sub-populations, one with high affinity (respective Kd and Bmax values of 1.40+/-0.08nM and 1586+/-48 fmol/mg protein), another with lower affinity (respective Kd and Bmax values of 61+/-5nM and 26260+/-1050 fmol/mg protein). We demonstrate rapid decrease in TSPO binding to the high affinity site induced by exposure to CS; specifically, significant 36% decrease in binding after 30min CS exposure (p<0.05), and 69% decrease after 2h CS exposure (p<0.05). Association between TSPO and CS exposure may contribute to understanding the underlying mechanism of oral carcinogenesis. PMID- 27939323 TI - Anatomic and Ultrasonic Study Based on Selective Tibial Neurotomy. AB - BACKGROUND: Selective tibial neurotomy (STN) was considered as an effective procedure for the treatment of spastic feet. It is also widely used for treating obese calves in some Asian countries. This study aimed to provide morphologic measurement data and theoretical support for the operation and intraoperative localization. METHODS: Fifty lower legs from 20 embalmed cadavers and 5 fresh corpses were dissected to observe and record the relationship of 4 branches of the tibial nerve, as well as the length, width, and thickness of the triceps surae. An ultrasonic transducer was also used to measure the thickness of muscles of 50 volunteers and acquire the ultrasonic image of muscles and nerve branches. RESULTS: Anatomic results showed that the tibial nerve gave off 4 branches in a proximal to distal direction: the medial sural cutaneous nerve, the motor branches innervating the medial and lateral gastrocnemius, and the motor branch innervating the soleus. These nerve branches had 8 patterns of origin. A significant finding was that the nerve innervating the soleus consisted of 2 branches. Ultrasonic measurement results showed that the thickness of the gastrocnemius and the soleus were positively related to the circumference of the calf. CONCLUSIONS: The calf circumference was positively related to the thickness of the soleus and the gastrocnemius. Diverging patterns of tibial nerve branches were multiple, and caution should be used to prevent damaging other branches. Tibial nerve, branches, and diverging sites could be seen clearly in the ultrasonic image. A preoperational ultrasonic examination is recommended. PMID- 27939324 TI - Understanding the role of the Parkinson's disease nurse specialist in the delivery of apomorphine therpy. AB - Optimal care of Parkinson's disease (PD) patients should involve a multidisciplinary team (MDT) of which a PD nurse specialist (PDNS) is a key member. The role of a PDNS is particularly prominent in the care of advanced PD patients suitable for apomorphine because, in addition to nursing skills, apomorphine treatment requires liaison, training, interaction and coordination with patients, caregivers and other members of the MDT as well as the interface with primary care physicians. The therapeutic success of apomorphine therapy depends not only upon the pharmacologic drug response, but also on how well the patient understands his/her disease and how to handle the therapy. In this respect, a PDNS is a vital member of the MDT who provides education and training, support, and is available for consultation when problems arise. In this article, we review the literature on the contribution of PDNSs in both continuous subcutaneous apomorphine infusion and intermittent subcutaneous apomorphine injection and highlight the various beneficial aspects of PDNS care, supported by scientific evidence when available. Despite a low level of published evidence, there is strong clinical evidence that the impact of PDNSs on the management of apomorphine therapy is vital and indispensable for the success of this treatment. PMID- 27939325 TI - The efficacy of apomorphine - A non-motor perspective. AB - Non-motor features have a great impact on progression and quality of life in individuals with Parkinson's disease. Current treatments for PD are limited and apomorphine is one of the advanced therapies available with advantageous effects on motor complications. Several studies have suggested that apomorphine has potential benefits in PD patients beyond its established role in the treatment of motor fluctuations and levodopa-induced dyskinesia. This review examines the efficacy of apomorphine in the treatment of non-motor symptoms (NMS), describing recent studies that highlight its possible effect on cognition. Despite a limited number of studies, the available evidence shows that apomorphine has an overall beneficial effect on NMS of PD patients, including neuropsychiatric symptoms, sleep disturbances, pain, urinary dysfunction, and impulse control disorders. If the effects of apomorphine on amyloid deposition are confirmed in the future, its place in the armamentarium of PD treatment could see a shift towards younger and non-demented PD patients. PMID- 27939326 TI - Quantitative demonstration of the efficacy of night-time apomorphine infusion to treat nocturnal hypokinesia in Parkinson's disease using wearable sensors. AB - BACKGROUND: Nocturnal hypokinesia/akinesia is one of the common night-time symptoms in patients with Parkinson's disease (PD), negatively affecting quality of life of patients and caregivers. The recognition of this problem and treatment options are limited in clinical practice. OBJECTIVES: To evaluate the efficacy of nocturnal apomorphine infusion, using a wearable sensor, in patients who are already on daytime continuous subcutaneous apomorphine infusion and still suffer from nocturnal hypokinesia. METHODS: Nocturnal parameters in 10 PD patients before and during nocturnal infusion were assessed over two nights at their homes, using a wearable sensor (trunk). Nocturnal parameters included number, velocity, acceleration, degree, and duration of rolling over, and number of times they got out of bed. Correlations with validated clinical rating scales were performed. RESULTS: Following nocturnal apomorphine infusion (34.8 +/- 6.5 mg per night), there were significant improvements in the number of turns in bed (p = 0.027), turning velocity (p = 0.046), and the degree of turning (p = 0.028) in PD patients. Significant improvements of Modified Parkinson's Disease Sleep Scale (p = 0.005), the axial score of Unified Parkinson's Disease Rating Scale (p = 0.013), and Nocturnal Akinesia Dystonia and Cramp Scale (p = 0.014) were also observed. CONCLUSION: Our study was able to demonstrate quantitatively the efficacy of nocturnal apomorphine infusion in PD patients with nocturnal hypokinesia and demonstrated the feasibility of using wearable sensors to yield objective and quantifiable outcomes in a clinical trial setting. More studies are needed to determine the long-term efficacy of this treatment in a large prospective cohort of PD patients. PMID- 27939327 TI - Survival implications of time to surgical treatment of endometrial cancers. AB - BACKGROUND: Optimal care for women with endometrial cancers often involves transfer of care from diagnosing physicians (eg, obstetrician-gynecologists) to treating physicians (eg, gynecologic oncologists.) It is critical to determine the effect of time to treatment on cancer outcomes to set best practices guidelines for referral processes. OBJECTIVE: We sought to determine the impact of time from diagnosis of endometrial cancer to surgical treatment on mortality and to characterize those patients who may be at highest risk for worsened survival related to surgical timing. STUDY DESIGN: The National Cancer Database was queried for incident endometrial cancers in adults from 2003 through 2012. Cancers were classified as low risk (grade 1 or 2 endometrioid histologies) or high risk (nonendometrioid and grade 3 endometrioid histologies) and analyzed separately. Demographic, clinicopathologic, and health system factors were collected. Unadjusted and adjusted hazard ratios for mortality were calculated by interval between diagnosis and surgery. Linear regression of patient and health care system characteristics was performed on diagnosis-to-surgery interval. RESULTS: For low-risk cancers (N = 140,078), surgery in the first and second weeks after diagnosis was independently associated with mortality risk (hazard ratio, 1.4; 95% confidence interval, 1.3-1.5; and hazard ratio, 1.1; 95% confidence interval, 1.0-1.2, respectively). The 30-day postoperative mortality was significantly higher among patients undergoing surgery in the first or second week postdiagnosis, compared to patients treated in the third or fourth week postdiagnosis (0.7% vs 0.4%; P < .001). Mortality risk was also significantly higher than baseline when time between diagnosis and surgery was >8 weeks. Independent associations with added time to surgery of at least 1 week were seen with black race (1.1 weeks; 95% confidence interval, 0.9-1.4), uninsurance (1.3 weeks; 95% confidence interval, 1.1-1.5), Medicaid insurance (1.7 weeks; 95% confidence interval, 1.5-1.9), and Charlson-Deyo comorbidity score >1 (1.0 weeks; 95% confidence interval, 0.8-1.2). For high-risk cancers (N = 68,360), surgery in the first and second weeks after diagnosis was independently associated with mortality risk (hazard ratio, 1.5; 95% confidence interval, 1.3-1.6; and hazard ratio, 1.2; 95% confidence interval, 1.1-1.2, respectively). The 30-day postoperative mortality was significantly higher among patients undergoing surgery in the first or second week postdiagnosis, compared to patients treated in the third or fourth week postdiagnosis (2.5% vs 1.0%; P < .001). Surgery after the third week postdiagnosis was not associated with a statistically significant increase in the adjusted risk of mortality. Independent associations with added time to surgery of at least 1 week were seen with uninsurance (1.4 weeks; 95% confidence interval, 0.9-1.9) and Medicaid insurance (1.4 weeks; 95% confidence interval, 1.1-1.7). CONCLUSION: Surgery in the first 2 weeks after diagnosis of endometrial cancer was associated with worsened survival associated with elevated perioperative mortality and treatment in low-volume hospitals. Delay in surgical treatment was a risk factor for mortality in low-risk cancers only and was likely associated with poor access to specialty care. We suggest that the target interval between diagnosis and treatment of endometrial cancers be <=8 weeks; however, referral to an experienced surgeon and adequate preoperative optimization should be prioritized over expedited surgery. PMID- 27939328 TI - A longitudinal study of sleep duration in pregnancy and subsequent risk of gestational diabetes: findings from a prospective, multiracial cohort. AB - BACKGROUND: Both short and prolonged sleep duration have been linked to impaired glucose metabolism. Sleep patterns change during pregnancy, but prospective data are limited on their relation to gestational diabetes. OBJECTIVE: We sought to prospectively examine the trimester-specific (first and second trimester) association between typical sleep duration in pregnancy and subsequent risk of gestational diabetes, as well as the influence of compensatory daytime napping on this association. STUDY DESIGN: In the prospective, multiracial Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort, 2581 pregnant women reported their typical sleep duration and napping frequency in the first and second trimesters. Diagnosis of gestational diabetes (n = 107; 4.1%) was based on medical records review. Adjusted relative risks with 95% confidence intervals for gestational diabetes were estimated with Poisson regression, adjusting for demographics, prepregnancy body mass index, and other risk factors. RESULTS: From the first and second trimester, sleep duration and napping frequency declined. Sleeping duration in the second but not first trimester was significantly related to risk of gestational diabetes. The association between second-trimester sleep and gestational diabetes differed by prepregnancy obesity status (P for interaction = .04). Among nonobese but not obese women, both sleeping >8-9 hours or <8-9 hours were significantly related to risk of gestational diabetes: 5-6 hours (adjusted relative risk, 2.52; 95% confidence interval, 1.27-4.99); 7 hours (adjusted relative risk, 2.01; 95% confidence interval, 1.09-3.68); or >=10 hours (adjusted relative risk, 2.17; 95% confidence interval, 1.01-4.67). Significant effect modification by napping frequency was also observed in the second trimester (P for interaction = .03). Significant and positive association between reduced sleep (5-7 hours) and gestational diabetes was observed among women napping rarely/never (adjusted relative risk, 2.48; 95% confidence interval, 1.20-5.13), whereas no comparable associations were observed among women napping most/sometimes. CONCLUSION: Our data suggest a U-shaped association between sleep duration and gestational diabetes, and that napping and prepregnancy obesity status may modify this association. PMID- 27939329 TI - Pelvic floor morphometry and function in women with and without puborectalis avulsion in the early postpartum period. AB - BACKGROUND: Pelvic floor muscles are subject to considerable stretching during vaginal birth. In 13-36% of women, stretching results in avulsion injury whereby the puborectalis muscle disconnects from its insertion points on the pubis bone. Until now, few studies have investigated the effect of this lesion on pelvic floor muscles in the early postpartum period. OBJECTIVE: The primary aim of this study was to compare pelvic floor muscle morphometry and function in primiparous women with and without puborectalis avulsion in the early postpartum period. Our secondary objective was to compare the 2 groups for pelvic floor disorders and impact on quality of life. STUDY DESIGN: In all, 52 primiparous women diagnosed with (n = 22) or without (n = 30) puborectalis avulsion injury were assessed at 3 months postpartum. Pelvic floor muscle morphometry was evaluated with 3-/4 dimensional transperineal ultrasound at rest, maximal contraction, and Valsalva maneuver. Different parameters were measured in the midsagittal and axial planes: bladder neck position, levator plate angle, anorectal angle, and levator hiatus dimensions. The dynamometric speculum was used to assess pelvic floor muscle function including: passive properties (passive forces and stiffness) during dynamic stretches, maximal strength, speed of contraction, and endurance. Pelvic floor disorder-related symptoms (eg, urinary incontinence, vaginal and bowel symptoms) and impact on quality of life were evaluated with the International Consultation on Incontinence Questionnaire and the Pelvic Floor Impact Questionnaire-Short Form. Pelvic Organ Prolapse Quantification was also assessed. RESULTS: In comparison to women without avulsion, women with avulsion presented an enlarged hiatus area at rest, maximal contraction, and Valsalva maneuver (P <= .013) and all other ultrasound parameters were found to be significantly altered during maximal contraction (P <= .014). They showed lower passive forces at maximal and 20-mm vaginal apertures as well as lower stiffness at 20-mm aperture (P <= .048). Significantly lower strength, speed of contraction, and endurance were also found in women with avulsion (P <= .005). They also presented more urinary incontinence symptoms (P = .040) whereas vaginal and bowel symptoms were found to be similar in the 2 groups. Pelvic Organ Prolapse Quantification revealed greater anterior compartment descent in women with avulsion (P <= .010). The impact of pelvic floor disorders on quality of life was found to be significantly higher in women with avulsion (P = .038). CONCLUSION: This study confirms that pelvic floor muscle morphometry and function are impaired in primiparous women with puborectalis avulsion in the early postpartum period. Moreover, it highlights specific muscle parameters that are altered such as passive properties, strength, speed of contraction, and endurance. PMID- 27939330 TI - Food allergy to millet and cross-reactivity with rice, corn and other cereals. PMID- 27939331 TI - Teamwork, Soft Skills, and Research Training. AB - We provide a list of soft skills that are important for collaboration and teamwork, based on our own experience and from an opinion survey of team leaders. Each skill can be learned to some extent. We also outline workable short courses for graduate schools to strengthen teamwork and collaboration skills among research students. PMID- 27939332 TI - Phylogenetic relationship and genotypic variability in Anaplasma marginale strains causing anaplasmosis in India. AB - Anaplasma marginale is a tick borne rickesttsial parasite known to cause bovine anaplasmosis. There are prevalence reports from different parts of India, however, information regarding genetic diversity and phylogenetic association of the Indian strains are unknown. In the current study, 965 cattle blood samples from two states of India, Seemandhra and Telangana, were investigated for the presence of A. marginale by PCR using major surface protein 4 gene (msp4). We found an overall infection of 16.4%, with 3.4% prevalence in Seemandhra and 22.2% in Telangana. Sequence analysis of the 24 cloned msp4 gene indicated genetic diversity among Indian clinical strains of A. marginale which may be due to evolutionary pressure or migration of strains. Phylogenetic association analysis revealed that most of the strains showed close proximity with strains from Mexico and other strains showed closeness to strains reported from countries like Brazil, Zimbabwe, Prico and Hungary. This is the first report from India, identifying heterogeneous population of A. marginale strains causing anaplasmosis, and such data can play an important role in designing new control policies. PMID- 27939333 TI - Association between Cx37 rs1764390 polymorphism and susceptibility to sepsis in Chinese population. AB - In this study, we aimed to explore the possible relationship between a functional single-nucleotide polymorphism (SNP) rs1764390 in Cx37 and sepsis. We also investigated the difference of Cx37 expression in septic patients and healthy controls. A case-control study was performed in 215 septic patients and in 260 healthy controls. Genotyping of the rs1764390 polymorphism was performed by sequencing method. The expression of Cx37 in peripheral blood mononuclear cells (PBMCs) from septic patients and healthy controls was determined by real-time PCR and western-blotting. Plasma levels of NO, IL-6, and C reactive protein (CRP) were also detected in septic patients and healthy controls. The frequencies of GG genotype and the rs1764390 G allele were significantly higher in septic patients than in healthy controls. We also observed a decreased expression of Cx37 protein in septic patients compared to the healthy controls accompanied by increased plasma levels of NO, IL-6 and CRP. Furthermore, the carriers of rs1764390 G allele showed higher levels of NO, IL-6 and CRP in septic patients. The rs1764390 G allele is associated with increased susceptibility to sepsis, which may be involved in the process of sepsis via mediating the plasma levels of NO, IL-6 and CRP. PMID- 27939334 TI - Clinical importance of intraoperative peritoneal cytology in patients with pancreatic cancer. AB - BACKGROUND: The clinical importance of intraoperative peritoneal cytology in patients with pancreatic cancer remains incompletely understood. METHODS: Peritoneal washing samples were collected from 411 consecutive patients with pancreatic ductal adenocarcinoma from 1996 to 2014. Of the 411 patients, 335 underwent macroscopically curative resection and 76 with noncurative factors did not undergo resection. We compared long-term outcomes between patients with positive cytology (cytology+) and those with negative cytology (cytology-) and investigated the importance of clinicopathologic factors. RESULTS: Of 335 patients with curative resection, 300 (89.6%) were cytology- and 35 (10.4%) were cytology+. The median overall survival of cytology+ patients was less than that of cytology- patients (16 vs 31 months, respectively; P < .0001). The median overall survival of cytology+ patients with noncurative factors was significantly worse than that of cytology+ patients with curative resection (6.9 vs 16.0 months, respectively; P = .0023). The median disease-free survival of cytology+ patients was less than that of cytology- patients (6.5 vs 16 months, respectively; P < .0001). In the multivariate analysis, cytology+ was an independent prognostic factor for overall survival and disease-free survival. CONCLUSION: Cytology+ without noncurative factors was a predictive factor for a poor prognosis. Therefore, it is important to regard patients with pancreatic cancer characterized by cytology+ as a special group that may warrant more aggressive adjuvant therapy. PMID- 27939336 TI - Adjuvant Chemotherapy is Indicated in Patients with Lower Grade Glioma. PMID- 27939335 TI - Calcium signalling induced by in vitro exposure to silicium dioxide nanoparticles in rat pulmonary artery smooth muscle cells. AB - The development and use of nanomaterials, especially engineered nanoparticles (NP), is expected to provide many benefits. But at the same time the development of such materials is also feared because of their potential human health risks. Indeed, NP display some characteristics similar to ultrafine environmental particles which are known to exert deleterious cardiovascular effects including pro-hypertensive ones. In this context, the effect of NP on calcium signalling, whose deregulation is often involved in hypertensive diseases, remain poorly described. We thus assessed the effect of SiO2 NP on calcium signalling by fluorescence imaging and on the proliferation response in rat pulmonary artery smooth muscle cells (PASMC). In PASMC, acute exposure to SiO2 NP, from 1 to 500MUg/mL, produced an increase of the [Ca2+]i. In addition, when PASMC were exposed to NP at 200MUg/mL, a proliferative response was observed. This calcium increase was even greater in PASMC isolated from rats suffering from pulmonary hypertension. The absence of extracellular calcium, addition of diltiazem or nicardipine (L-type voltage-operated calcium channel inhibitors both used at 10MUM), and addition of capsazepine or HC067047 (TRPV1 and TRPV4 inhibitors used at 10MUM and 5MUM, respectively) significantly reduced this response. Moreover, this response was also inhibited by thapsigargin (SERCA inhibitor, 1MUM), ryanodine (100MUM) and dantrolene (ryanodine receptor antagonists, 10MUM) but not by xestospongin C (IP3 receptor antagonist, 10MUM). Thus, NP induce an intracellular calcium rise in rat PASMC originating from both extracellular and intracellular calcium sources. This study also provides evidence for the implication of TRPV channels in NP induced calcium rise that may highlight the role of these channels in the deleterious cardiovascular effects of NP. PMID- 27939337 TI - Analysis of Global Radiotherapy Needs and Costs by Geographic Region and Income Level. AB - Recent years have seen various reviews on the lack of access to radiotherapy often based on geographic regions of the world such as Africa, Asia Pacific, Europe, Latin America and North America. Countries are often defined by their national income per capita levels based on World Bank definitions of high income, upper middle income, lower middle income and low income. Within the world regions, there are significant variations in gross national income (GNI) per capita among the different countries, and even within similar income levels, large variations exist. This report presents the actual status of radiotherapy and analyses the current needs and costs to provide full access in the different regions of the world. Actual coverage of the needs ranges from 34% in Africa to over 92% in Europe to about double the needs in North America. In line with this, proportional additional investments and operational costs are as high as more than 200% in Africa to almost none in North America. Two world regions face substantial challenges: Africa, based on the important demands to build new capacity and subsequently to maintain operational capability; and Asia Pacific, due to its high population density, translating into large absolute needs in radiotherapy treatments and resources, and hence in associated costs. With the data highlighting a large variability of GNI/capita even within similar income levels in the various world regions, it is expected that additional investment in resources and costs may be more dependent on income level of the country than on the GNI group or the geographic region of the world. PMID- 27939338 TI - Clinical Characteristics, Health Care Utilization and Costs Among Men with Primary or Secondary Hypogonadism in a US Commercially Insured Population. AB - INTRODUCTION: Hypogonadism is broadly associated with increases in chronic comorbid conditions and health care costs. Little is known about the specific impact of primary and secondary hypogonadism on health care costs. AIM: To characterize the health care cost and utilization burden of primary and secondary hypogonadism in a population of US men with commercial insurance. METHODS: Newly diagnosed patients with International Classification of Diseases, Ninth Revision, Clinical Modification codes associated with specific medical conditions known to have a high prevalence of testosterone deficiency (ie, relating to primary or secondary hypogonadism) or who had fills for testosterone replacement therapy from January 1, 2007 through April 30, 2013 were identified in administrative claims data from the HealthCore Integrated Research Database. A cohort of patients without hypogonadism was matched on demographics and comorbidities. The matched hypogonadism and non-hypogonadism cohorts (n = 5,777 in each cohort) were compared during a 12-month follow-up period. MAIN OUTCOME MEASURES: Direct health care expenditures and utilization were assessed for all causes and for hypogonadism-related claims. Costs included out-of-pocket patient expenditures and those paid by the insurer. RESULTS: Hypogonadism and matched non-hypogonadism cohorts were similar in demographics (mean age = 50 years) and diagnosed comorbid conditions in the 12 months preceding the index date. In the year after the index date, mean all-cause expenditures for patients with hypogonadism increased by 62% (from $5,425 to $8,813) compared with 25% for the matched controls (from $4,786 to $5,992; P < .01 for follow-up difference between groups). Approximately 16% of total mean costs ($1,377), primarily outpatient and pharmacy costs, were identifiable as related to hypogonadism. CONCLUSION: These data from a population of US men with commercial insurance coverage showed a greater resource use burden for patients with primary and secondary hypogonadism compared with similar patients without hypogonadism. Additional management might be required to address unmet need and decrease the cost burden for patients with hypogonadism. PMID- 27939339 TI - Unusual case of duodenobiliary fistula complicating Crohn's disease successfully treated with Adalimumab. AB - Crohn's disease (CD) is characterized by transmural inflammation of the gastrointestinal tract, which predisposes to the formation of fistula. Duodenal involvement occurs in less than 5% of cases and often leads to clinically relevant strictures. However, fistula formation in the duodenum is exceptional. Herein, we report an unusual case of duodenobiliary fistula due to CD occurring in a 65-year-old patient who was successfully treated by anti-tumor necrosis factor (TNF) agents. This case report highlights the efficacy of anti-TNF alpha agents in the treatment of a bilioenteric fistula because it increases the probability of clinical remission and mucosal healing and therefore reduces the need for surgical treatment which may be associated morbidity. PMID- 27939340 TI - Deletion of the serotonin receptor type 7 disrupts the acquisition of allocentric but not egocentric navigation strategies in mice. AB - Spatial navigation is achieved through both egocentric (body-centered) and allocentric (externally-centered) strategies but decline with age, especially allocentric strategies. A better understanding of the neurobiological mechanisms underlying these strategies would allow the development of new treatments to mitigate this deterioration. Among them, the modulation of 5-HT7 receptor (5 HT7R) may constitute a potential strategy. Indeed, this receptor is known to play a role in spatial navigation, however its precise role in egocentric and allocentric strategies remains unclear. Here, we first examined the effect of 5 HT7 genetic invalidation (knock-out (KO) mice) in two versions of a water cross maze task in which only egocentric or allocentric strategies were efficient to solve the task. Our results demonstrated that KO mice are able to learn an allocentric strategy. However, contrary to wild-type mice (WT mice), the acquisition rate was slower compared to the task requiring the acquisition of an egocentric strategy. Mice were then trained in a third version of the water maze, allowing the use of both egocentric and allocentric strategies. When facing conflicting spatial information, both KO and WT mice preferentially used an egocentric strategy. However, only WT mice displayed a greater latency to achieve the task. This suggests that WT mice are able to learn both information in parallel, but not KO mice (i.e. only learning an egocentric strategy). Altogether, these results provide evidence for the essential role of the 5HT7R in the acquisition of an allocentric strategy and in the ability to learn concomitantly both strategies. PMID- 27939341 TI - The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in male rats. AB - Methamphetamine (meth) addiction is a costly burden to both the individual user and society as a whole. Establishing effective pharmacotherapies to treat meth dependence is needed to help solve this health problem. The study reported herein examined the effects of varenicline, a partial alpha4beta2 and full alpha7 nicotinic acetylcholine receptor agonist, on meth self-administration and reinstatement in male Sprague-Dawley rats. Following indwelling jugular catheter surgery, rats were either trained to self-administer meth or saline on a variable ratio (VR) 3 schedule of reinforcement. Self-administration sessions (2h duration; 19 total sessions) were conducted daily. The effect of varenicline pretreatment on meth and saline self-administration was then determined using a within-study design. All rats received varenicline (0.0, 0.3, 1.0, and 3.0mg/kg) prior to 4 different test sessions. Dose order was randomly assigned and each test was separated by 2 standard self-administration sessions to assess stability of responding. Fifteen extinction sessions (no meth available) followed the last test. Extinction was followed by meth-primed (0.3mg/kg IP) reinstatement tests to examine the effect of varenicline on meth-seeking behavior. All rats again received all doses of varenicline over 4 separate reinstatement tests performed on 4 consecutive days. Varenicline did not alter self-administration of meth or saline. Additionally, the 0.3 and 1.0 doses of varenicline non-specifically increased active lever responding during the reinstatement test sessions. This latter finding suggests that varenicline may increase relapse liability and should not be utilized as pharmacotherapy to treat meth dependence. PMID- 27939342 TI - Costs and hospital procedures in an urology department of a tertiary hospital. Analysis of groups related by their diagnosis. AB - INTRODUCTION: The health care system has management tools available in hospitals that facilitate the assessment of efficiency through the study of costs and management control in order to make a better use of the resources. OBJECTIVE: The aim of the study was the calculation and analysis of the total cost of a urology department, including ambulatory, hospitalization and surgery activity and the drafting of an income statement where service costs are compared with income earned from the Government fees during 2014. MATERIAL AND METHODS: From the information recorded by the Economic Information System of the Department of Health, ABC and top-down method of cost calculation was applied by process care activity. The cost results obtained were compared with the rates established for ambulatory and hospital production in the Tax Law of the Generalitat Valenciana. The production was structured into outpatient (external and technical consultations) and hospital stays and surgeries (inpatient). RESULTS: A total of 32,510 outpatient consultations, 7,527 techniques, 2,860 interventions and 4,855 hospital stays were made during 2014. The total cost was 7,579,327?; the cost for outpatient consultations was 1,748,145?, 1,229,836 Euros for technical consultations, 2,621,036? for surgery procedures and 1,980,310? for hospital admissions. Considered as income the current rates applied in 2014 (a total of 15,035,843?), the difference between income and expenditure was 7,456,516?. CONCLUSIONS: The economic balance was positive with savings over 50% and a mean adjusted hospitalization stay rate (IEMAC) rate of 0.67 (33% better than the standard). CMA had a favorable impact on cost control. PMID- 27939343 TI - Stress-induced change in serum BDNF is related to quantitative family history of alcohol use disorder and age at first alcohol use. AB - Previous research in animal models suggests that brain-derived neurotrophic factor (BDNF) is involved in stress-modulated alcohol consumption. However, relatively few studies have investigated this issue in humans, and results of existing studies have been heterogeneous. The primary aim of the current study was to examine the within-subjects effect of acute stress (timed math plus cold pressor) on serum BDNF levels (DeltaBDNF: post- minus pre-stress) in healthy social drinkers (N=68, 20 male). A secondary aim was to explore which heritable and environmental factors in our limited sample might exert the greatest influences on DeltaBDNF. Importantly, presence versus absence of the BDNF Val66Met polymorphism (rs6265), which has often been discounted in studies of human serum BDNF, was included as a between-subjects control variable in all statistical analyses. Our results indicated that acute stress decreased serum BDNF. Further, multiple regression analyses revealed that quantitative family history of alcohol use disorder (qFH) and age at first alcohol use together accounted for 15% of the variance in DeltaBDNF. Thus, the influences of qFH and age at first alcohol use may explain some of the heterogeneity that exists in previous studies of human serum BDNF. These results parallel findings in animal models and suggest that stress-related changes in serum BDNF are influenced by both heritable (qFH) and environmental (early alcohol consumption) factors. PMID- 27939344 TI - A Puf RNA-binding protein encoding gene PlM90 regulates the sexual and asexual life stages of the litchi downy blight pathogen Peronophythora litchii. AB - Sexual and asexual reproduction are two key processes in the pathogenic cycle of many filamentous pathogens. However in Peronophythora litchii, the causal pathogen for the litchi downy blight disease, critical regulator(s) of sexual or asexual differentiation has not been elucidated. In this study, we cloned a gene named PlM90 from P. litchii, which encodes a putative Puf RNA-binding protein. We found that PlM90 was highly expressed during asexual development, and much higher than that during sexual development, while relatively lower during cyst germination and plant infection. By polyethylene glycol (PEG)-mediated protoplast transformation, we generated three PlM90-silenced transformants and found a severely impaired ability in sexual spore production and a delay in stages of zoospore release and encystment. However, the pathogenicity of P. litchii was not affected by PlM90-silencing. Therefore we conclude that PlM90 specifically regulates the sexual and asexual differentiation of P. litchii. PMID- 27939346 TI - Coating lanthanide nanoparticles with carbohydrate ligands elicits affinity for HeLa and RAW264.7 cells, enhancing their photodamaging effect. AB - Lanthanide nanoparticles (LNPs) conjugated with monosaccharides were synthesized as a photon energy-upconverting nanodevice with affinity to cancer cells. The conjugates were designed to selectively damage the cancer cells containing protoporphyrin IX, a photosensitizer endogenously synthesized from priorly administrated 5-aminolevlunic acid (ALA), by a highly tissue-penetrative near infrared (NIR) irradiation. First of all, the affinities of monosaccharides toward cells (HeLa, RAW264.7, and MKN45) were assessed by a novel cell aggregation assay with trivalent monosaccharide-citric acid conjugates. As a result, HeLa exhibited high affinity for glucose, while RAW264.7 for glucose, galactose, mannose, and fucose. A similar cell-monosaccharide affinity was microscopically observed when the cells were mixed with monosaccharide-LNP conjugates and rinsed, in which the high affinity LNP probes luminesced on the cells. The high affinity monosaccharide-LNPs showed greater photodamaging effects than the unmodified LNP toward the corresponding cells, when the cells were pretreated with ALA and irradiated by NIR. This study demonstrates that carbohydrates can be used as selective ligands for cancer cells in a photodynamic therapy with LNP. PMID- 27939345 TI - Influence of chain length on the activity of tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4). AB - Here we report a series of close analogues of our recently published scaffold based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R1 and R2, and an aromatic group in R3. While contraction/elongation of the guanidine carrying side chains (R1 and R2) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2 ylmethyl moiety (R3) resulted in an EC50 of 61MUM (mixture of diastereoisomers) against wild-type CXCR4; thus, the antagonistic activity of these tripeptidomimetics seems to be amenable to optimization of the aromatic moiety. Moreover, for analogues carrying a naphth-2-ylmethyl substituent, we observed that a Pictet-Spengler like cyclization side reaction depended on the nature of the R1 substituent. PMID- 27939347 TI - Coumarins and other fused bicyclic heterocycles with selective tumor-associated carbonic anhydrase isoforms inhibitory activity. AB - Herein we report for the first time a series of 2-benzamido-N-(2-oxo-4 (methyl/trifluoromethyl)-2H-chromen-7-yl) benzamide 3a-f and substituted quinazolin-4(3H)-ones and 2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxides (5, 6, 8 and 10a-c) as selective inhibitors of the tumor associated hCA IX and XII isoforms. Among the compounds reported the trifluoromethyl derivative 3d resulted the most potent against these CA isoforms with KIs of 10.9 and 6.7nM. PMID- 27939348 TI - Synthesis of novel C4-benzazole naphthalimide derivatives with potent anti-tumor properties against murine melanoma. AB - Novel C4-benzazole naphthalimide derivatives were synthesized and tested in vitro and in vivo as anti-cancer drugs. Among these synthetic molecules, compounds 9 and 10 exhibited cytotoxicity against murine B16F10 melanoma cells. In addition, the above-mentioned compounds significantly suppressed lung tumor metastasis with no visible sign of toxicity. PMID- 27939350 TI - Quantifying the history dependency of muscle recovery from a fatiguing intermittent task. AB - Muscle fatigue and recovery are complex processes influencing muscle force generation capacity. While fatigue reduces this capacity, recovery acts to restore the unfatigued muscle state. Many factors can potentially affect muscle recovery, and among these may be a task dependency of recovery following an exercise. However, little has been reported regarding the history dependency of recovery after fatiguing contractions. We examined the dependency of muscle recovery subsequent to four different histories of fatiguing muscle contractions, imposed using two cycle times (30 and 60s) during low to moderate levels (15% and 25% of maximum voluntary contraction (MVC)) of intermittent static exertions involving index finger abduction. MVC and low-frequency electrical stimulation (LFES) measures (i.e., magnitude, rise and relaxation rates) of muscle capacity were used, all of which indicated a dependency of muscle recovery on the muscle capacity state existing immediately after fatiguing exercise. This dependency did not appear to be modified by either the cycle time or exertion level leading to that state. These results imply that the post-exercise rate of recovery is primarily influenced by the immediate post-exercise muscle contractile status (estimated by MVC and LFES measures). Such results may help improve existing models of muscle recovery, facilitating more accurate predictions of localized muscle fatigue development and thereby helping to enhance muscle performance and reduce the risk of injury. PMID- 27939349 TI - An initial negative round of targeted biopsies in men with highly suspicious multiparametric magnetic resonance findings does not exclude clinically significant prostate cancer-Preliminary experience. AB - BACKGROUND: Targeted prostate biopsies are changing the landscape of prostate cancer (PCa) diagnosis with the degree of suspicion on multiparametric magnetic resonance imaging (mpMRI) being a strong predictor of targeted biopsy outcome. Data regarding the rate and potential causes of false-negative magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion-targeted biopsy in patients with highly suspicious mpMRI findings are lacking. OBJECTIVES: To determine the rate of clinically significant PCa detection in repeat targeted biopsy or surgery in patients with highly suspicious mpMRI findings and in an initial negative MRI TRUS fusion-targeted biopsy. MATERIALS AND METHODS: In this single-center, retrospective study of prospectively generated data, men with highly suspicious lesions (Likert 5 score) on mpMRI and an initial negative MRI-TRUS fusion targeted biopsy were reviewed. The rate of PCa detection in a subsequent MRI-TRUS fusion-targeted biopsy or radical prostatectomy was determined. Tumors in the intermediate- and high-risk groups according to the National Comprehensive Cancer Network criteria were considered clinically significant. RESULTS: A total of 32 men with 38 Likert 5 lesions were identified. Repeat targeted biopsy or surgery detected cancer in 42% (16/38) of the Likert 5 lesions with initial negative targeted biopsy. Most of these cancers were intermediate- (69%; 11/16) or high risk (25%; 4/16) tumors. CONCLUSION: A negative round of targeted biopsies does not exclude clinically significant PCa in men with highly suspicious mpMRI findings. Patients with imaging-pathology disagreement should be carefully reviewed and considered for repeat biopsy or for strict surveillance. PMID- 27939351 TI - Prescribing joint co-ordinates during model preparation to improve inverse kinematic estimates of elbow joint angles. AB - To appropriately use inverse kinematic (IK) modelling for the assessment of human motion, a musculoskeletal model must be prepared 1) to match participant segment lengths (scaling) and 2) to align the model's virtual markers positions with known, experimentally derived kinematic marker positions (marker registration). The purpose of this study was to investigate whether prescribing joint co ordinates during the marker registration process (within the modelling framework OpenSim) will improve IK derived elbow kinematics during an overhead sporting task. To test this, the upper limb kinematics of eight cricket bowlers were recorded during two testing sessions, with a different tester each session. The bowling trials were IK modelled twice: once with an upper limb musculoskeletal model prepared with prescribed participant specific co-ordinates during marker registration - MRPC - and once with the same model prepared without prescribed co ordinates - MR; and by an established direct kinematic (DK) upper limb model. Whilst both skeletal model preparations had strong inter-tester repeatability (MR: Statistical Parametric Mapping (SPM1D)=0% different; MRPC: SPM1D=0% different), when compared with DK model elbow FE waveform estimates, IK estimates using the MRPC model (RMSD=5.2+/-2.0 degrees , SPM1D=68% different) were in closer agreement than the estimates from the MR model (RMSD=44.5+/-18.5 degrees , SPM1D=100% different). Results show that prescribing participant specific joint co-ordinates during the marker registration phase of model preparation increases the accuracy and repeatability of IK solutions when modelling overhead sporting tasks in OpenSim. PMID- 27939352 TI - Age- and region-related changes in the biomechanical properties and composition of the human ureter. AB - The ureter has been largely overlooked heretofore in the study of the biomechanics of soft biological tissues, although there has been significant motivation to use its biomechanical properties as inputs to mathematical models of ureteral function. Herein, we used histological analysis for quantification of collagen contents and thickness/area of ureteral layers, with concomitant geometrical analysis of zero-stress and no-load states, and inflation/extension testing to biomechanically characterize with the Fung-type model the ureters from cadavers. The effects of age and gender on the regional distribution of those properties were examined. Tissue properties did not differ (p>0.05) between the left and right ureter. Regional heterogeneity was established that was profoundly age-related but seldom gender-related, based on the following evidence: 1) In younger subjects, the axial stress-circumferential strain curves of upper ureter were shifted to smaller stresses and model parameter a2 representing axial stiffness was smallest (p<0.05), i.e. upper ureter was the least stiff region axially; 2) upper ureter underwent axial stiffening with advanced age, evidenced by the increasing (p<0.05) parameter a2, and the stress-strain curves were uniformly exhibited along the ureter, evidenced by the non-varying (p>0.05) parameters C,a1,a2,anda4; 3) aging raised (p<0.05) the collagen content of upper ureter to favor a near-uniform regional distribution; 4) wall thickness increased with age, unlike the opening angle and residual strains, reflecting the thickening of outer (muscular) vs. inner (mucosal) layers in aged subjects, with significant differences (p<0.05) in some regions; and 5) gender affected little (p>0.05) the opening angle and morphometry of no-load and zero-stress states. PMID- 27939353 TI - Three-dimensional diastolic blood flow in the left ventricle. AB - Three-dimensional blood flow in a human left ventricle is studied via a computational analysis with magnetic resonance imaging of the cardiac motion. Formation, growth and decay of vortices during the myocardial dilation are analyzed with flow patterns on various diametric planes. They are dominated by momentum transfer during flow acceleration and deceleration through the mitral orifice. The posterior and anterior vortices form an asymmetric annular vortex at the mitral orifice, providing a smooth transition for the rapid inflow to the ventricle. The development of core vortex accommodates momentum for deceleration and for acceleration at end diastolic atrial contraction. The rate of energy dissipation and that of work done by viscous stresses are small; they are approximately balanced with each other. The kinetic energy flux and the rate of work done by pressure delivered to blood from ventricular dilation is well balanced by the total energy influx at the mitral orifice and the rate change of kinetic energy in the ventricle. PMID- 27939354 TI - Antinociceptive effect of tebanicline for various noxious stimuli-induced behaviours in mice. AB - Tebanicline (ABT-594), an analogue of epibatidine, exhibits potent antinociceptive effects and high affinity for the nicotinic acetylcholine receptor in the central nervous system. We assessed whether tebanicline exerts an effect on various noxious stimuli and mediates the nicotine receptor or opioid receptor through stimulation. The antinociceptive effects of tebanicline were determined by noxious chemical, thermal and mechanical stimuli-induced behaviours in mice. Tebanicline had dose-dependent analgesic effects in formalin, hot-plate and tail-pressure tests. By contrast, the antinociceptive effect of tebanicline was not demonstrated in the tail-flick assay. Pre-treatment with mecamylamine, a nicotinic acetylcholine receptor antagonist, blocked the effects of tebanicline in formalin, tail-pressure and hot-plate tests. Moreover, pre-treatment with naloxone, an opioid receptor antagonist, only partially inhibited the effects of tebanicline in formalin and tail-pressure tests. Tebanicline produced antinociception in persistent chemical (formalin), acute thermal (hot-plate, but not tail-flick) and mechanical (tail-pressure) pain states. Moreover, tebanicline stimulated the nicotinic acetylcholine receptor and opioid receptor. PMID- 27939355 TI - 5-HT1A receptor (HTR1A) 5' region haplotypes significantly affect protein expression in vitro. AB - The aim of this study was to explore the role of two SNPs (rs6295 & rs113195492) in the HTR1A gene promoter region that regulates the expression of the 5-HT1A receptor. A fragment spanning from -551 to +672 of HTR1A (Transcription start site +1) was cloned into the pGL-3 Basic Vector and three haplotype plasmids composed of two SNPs were constructed. HEK-293 cells and the SK-N-SH cells were transfected with the three plasmids, and the relative fluorescence intensity was measured. In HEK-293 cells, there was a significant difference when the relative fluorescence intensity of plasmid 1-1 was compared to that of plasmid 2-1. However, no significant difference was observed when the luciferase expression of plasmid 2-1 and plasmid 3-1 was analyzed. We also found that the expression trend of the SK-N-SH cells was similar to the HEK-293 cells, but the overall relative fluorescence intensity of the SK-N-SH cells was lower than that of the HEK-293 cells. Our finding showed that the rs6295 SNP, as a suspected variant that indicates susceptibility to schizophrenia, exhibited a higher transcriptional activity. The influence of the rs113195492 locus on schizophrenia needs to be explored further. PMID- 27939356 TI - The origins of rimmed vacuoles and granulovacuolar degeneration bodies are associated with the Wnt signaling pathway. AB - Inclusion-body myositis (IBM) and Alzheimer's disease (AD) are biochemically characterized by the presence of aggregated beta-amyloid protein and tau protein. In addition, both diseases are pathologically characterized by vacuolar changes, including rimmed vacuoles (RVs) in IBM and granulovacuolar degeneration (GVD) in AD. Previously, we demonstrated that RVs and GVD bodies are associated with a set of common molecules, leading us to speculate that both RVs and GVD bodies originate from similar structures on the plasma membrane of muscle cells and neuronal cells, namely, the neuromuscular junction (NMJ) and the postsynaptic spine especially in terms of Wnt signaling pathway. In this study, we investigated the presence of components of NMJ in RVs and/or postsynaptic spine in GVD bodies respectively by immunohistochemistry and immunofluorescence. The antigens probed included the following: (1) dishevelled (Dvl) family proteins (Dvl1, Dvl2 and Dvl3), (2) NMJ-associated proteins (low density lipoprotein related protein 4 [Lrp4], heat shock protein 70 [Hsp70], beta-catenin, phospho beta-catenin, rapsyn, P21-activated kinase 1 [PAK1], adenomatous polyposis coli [APC] and ADP-ribosylation factor 6 [Arf6]), (3) a lipid raft-associated molecule (phosphatidylinositol 4, 5-bisphosphate [PIP2]), and (4) other proteins [prion, glycogen-synthase kinase 3beta (GSK-3beta)]. In all cases of sporadic IBM examined, RVs were immunopositive for Dvl3, Hsp70, beta-catenin, PIP2, APC, prion and GSK-3beta. In all cases of AD examined, GVD bodies were immunopositive for Dvl3, phospho-beta-catenin, rapsyn, APC and PIP2. These findings show that RVs and GVD bodies share common molecules associated with the Wnt signaling pathway, indicating that these structures share a common structural and functional origin. PMID- 27939357 TI - alpha-Isocubebenol alleviates scopolamine-induced cognitive impairment by repressing acetylcholinesterase activity. AB - alpha-Isocubebenol (ICO) isolated from Schisandra chinensis fruit was recently shown to exert neuroprotective properties with significant anti-neuroinflammatory effects. Here, we present evidence of the novel effects of ICO on alleviation of cognitive impairment. To confirm these effects, ICR mice were pretreated with two different doses of ICO for 3 weeks and scopolamine (SP) to induce memory impairment for the last 7days of the period. A passive avoidance test showed that ICO pretreatment recovered memory impairment in SP treated mice, although there was no difference between the two doses. Acetylcholinesterase (AChE) activity was significantly decreased in the SP+ICO treated group compared with the SP+Vehicle treated group. Additionally, significant recovery of the number of apoptotic cells and the ratio of apoptosis proteins (Bcl-2/Bax) were detected in the SP+ICO treated group than the SP+Vehicle treated group. Moreover, ICO treatment attenuated the decrease of ERK phosphorylation by SP treatment. These results indicate that ICO from S. chinensis fruit could be applied as an active pharmaceutical ingredient for cognitive improvement in Alzheimer's disease (AD). PMID- 27939358 TI - The new ESPEN diagnostic criteria for malnutrition predict overall survival in hospitalised patients. AB - BACKGROUND: In 2015 the European Society for Clinical Nutrition and Metabolism (ESPEN) presented new consensus criteria for the diagnosis of malnutrition. Whereas most previous definitions were based on involuntary weight loss and/or a low BMI, the ESPEN definition added Fat Free Mass Index (FFMI) to the set of criteria. AIM: To study the predictive value of the new ESPEN diagnostic criteria for malnutrition on survival, with specific focus on the additional value of FFMI. METHODS: Included were 335 hospitalized adult patients of the VU University Medical Center Amsterdam (60% female, age 58 +/- 18 y). Three sets of criteria for malnutrition were used to study the predictive value for survival: Dutch definition for malnutrition, ESPEN diagnostic criteria for malnutrition and ESPEN diagnostic criteria for malnutrition without FFMI criterion. The association between malnutrition and three-months and one-year overall survival was analyzed by log rank tests and Cox regression. In multivariate analyses, adjustments were made for gender, age, care complexity and length of stay. RESULTS: Ninety patients (27%) were classified as malnourished by any of the sets of criteria; malnourished patients had significant lower survival rates than non-malnourished patients at three months (84% vs 94%; p = 0.01) and one year (76% vs 87%; p = 0.02). After adjustments, malnutrition remained significantly associated with three-months survival for the Dutch definition for malnutrition (HR:2.25, p = 0.04) and the ESPEN diagnostic criteria for malnutrition (HR:2.76, p = 0.02). Malnutrition remained significantly associated with one-year survival for the ESPEN diagnostic criteria for malnutrition (HR:2.17, p < 0.02) and the ESPEN diagnostic criteria for malnutrition without FFMI (HR:2.66, p < 0.01). CONCLUSION: The new ESPEN definition for malnutrition is predictive for both three-months and one-year survival in a general hospital population, whereas definitions without FFMI are predictive for either three-months or one year survival. PMID- 27939359 TI - A story of metformin-butyrate synergism to control various pathological conditions as a consequence of gut microbiome modification: Genesis of a wonder drug? AB - The most widely prescribed oral anti-diabetic agent today in the world today is a member of the biguanide class of drugs called metformin. Apart from its use in diabetes, it is currently being investigated for its potential use in many diseases such as cancer, cardiovascular diseases, Alzheimer's disease, obesity, comorbidities of diabetes such as retinopathy, nephropathy to name a few. Numerous in-vitro and in-vivo studies as well as clinical trials have been and are being conducted with a vast amount of literature being published every day. Numerous mechanisms for this drug have been proposed, but they have been unable to explain all the actions observed clinically. It is of interest that insulin has a stimulatory effect on cellular growth. Metformin sensitizes the insulin action but believed to be beneficial in cancer. Like -wise metformin is shown to have beneficial effects in opposite sets of pathological scenario looking from insulin sensitization point of view. This requires a comprehensive review of the disease conditions which are claimed to be affected by metformin therapy. Such a comprehensive review is presently lacking. In this review, we begin by examining the history of metformin before it became the most popular anti-diabetic medication today followed by a review of its relevant molecular mechanisms and important clinical trials in all areas where metformin has been studied and investigated till today. We also review novel mechanistic insight in metformin action in relation to microbiome and elaborate implications of such aspect in various disease states. Finally, we highlight the quandaries and suggest potential solutions which will help the researchers and physicians to channel their research and put this drug to better use. PMID- 27939361 TI - Deja vecu for news events but not personal events: A dissociation between autobiographical and non-autobiographical episodic memory processing. AB - In deja vu, the feeling that what we are currently experiencing we have experienced before is fleeting and is not accepted as true. In contrast, in deja vecu or "recollective confabulation", the sense of deja vu is persistent and convincing, and patients genuinely believe that they have lived through the current moment at some previous time. In previous reports of cases of deja vecu, both personal events and non-personal, world events gave rise to this experience. In this paper we describe a patient whose deja vecu experiences are entirely restricted to non-personal events, suggesting that autobiographical and non autobiographical episodic memory processing can dissociate. We suggest that this dissociation is secondary to differences in the degree to which personal and emotional associations are formed for these two different types of event, and offer a two-factor theory of deja vecu. PMID- 27939362 TI - Autonomic, endocrine and behavioural responses to thunder in laboratory and companion dogs. AB - Dogs are highly sensitive to sound stimuli, especially fireworks, firearms, and thunder, and therefore these sounds are used as models of stress reactivity in dogs. Companion and laboratory dogs may respond differently to stressful stimuli, due to differences in management and their relationship with humans. Therefore, the reactivity of beagle dogs (laboratory) and companion dogs to an acute acoustic stress model was studied by analysing the heart rate variability (HRV; cardiac interval values), serum cortisol levels and various behavioural parameters. Eight beagles and six privately owned dogs with no history of phobia to thunder were used. The sound stimulus consisted of a standardized recording of thunder for 2.5min with a maximum intensity of 103-104dB. To evaluate the HRV, cardiac intervals were recorded using a frequency meter (Polar RS800CX model), and later the data were analysed using CardioSeries 2.4.1 software. In both laboratory and companion dogs, thunder promoted an increase in the power of the LF band of the cardiac interval spectrum, in the LF/HF ratio and in the HR, and a decrease in the power of the HF band of the cardiac interval spectrum. Companion dogs showed higher cortisol levels, than beagles, independently of the time point studied and a significant increase in the cortisol levels 15min after acoustic stress, while beagles did not show any alterations in their cortisol levels in response to the sound. On the other hand, beagles showed higher scores in the trembling, hiding, vigilance, running, salivation, bolting and startle parameters than companion dogs. Our results showed that independently of the sound stimulus, companion dogs had higher cortisol levels than laboratory dogs. Furthermore, the sound stimulus induced a marked autonomic imbalance towards sympathetic predominance in both laboratory and companion dogs. However a significant increase in the cortisol was observed only in companion dogs. On the other hand, in general the behavioural response was more pronounced in laboratory dogs than in companion dogs. PMID- 27939363 TI - Sex differences in biological response to peer rejection and performance challenge across development: A pilot study. AB - A pilot study of sex differences in biological response to peer rejection and performance challenges across development was conducted. Participants were 59 typically-developing children (ages 8-17; 58% girls); 59 children completed one challenge: 37 completed both challenges. Following a habituation session, participants completed peer rejection (exclusion challenges) and/or performance (speech, arithmetic, tracing) stress sessions. Saliva cortisol and alpha amylase (AA) were measured throughout. Post-pubertal girls showed increased AA and equivalent cortisol output in response to rejection vs. performance; pre-pubertal girls showed heightened cortisol and AA response to performance vs. rejection. Boys showed similar biological responses across puberty, with pre- and post pubertal boys demonstrating heightened cortisol, but equivalent AA output in response to performance vs. rejection stressors. Although results are preliminary, they suggest increases in relative sensitivity to rejection vs. performance stressors and malleability of stress response across development in girls, but stability of stress response across development in boys. Future, larger-scale, longitudinal studies are needed. PMID- 27939364 TI - Intracellular signalling and plasma hormone profiles associated with the expression of unconditioned and conditioned fear and anxiety in female rats. AB - There is considerable overlap in the neural regions and intracellular signalling pathways implicated in anxiety and fear, although less is known in females. Here, we investigated whether unconditioned and conditioned fear are associated with distinct patterns of expression of extracellular signal-regulated kinase-1 and -2 (ERK1/2), protein kinase B (Akt), and calcineurin (CaN) (proteins that are key regulators of the expression of and/or memory processes of fear and anxiety) in the dorsal and ventral hippocampus, medial prefrontal cortex, and amygdala (important regions in neural fear circuitry) of adult female rats, and used a multivariate approach to find patterns of signalling that might discriminate between the different states of fear. To isolate fear to the conditioned cue from generalized fear to the test context, rats were conditioned to an auditory tone (i.e. tone paired with footshock) and twenty-four hours later exposed to a novel context in the presence or absence of the conditioned cue. A third group that was exposed to the conditioning context without undergoing fear conditioning was included to control for unconditioned responses to the testing procedures, which are anxiogenic. A discriminate function analysis and MANOVA determined that hippocampal signalling best discriminated the three groups from each other. The addition of values for plasma concentrations of corticosterone and progesterone (as indices of activation of the hypothalamic-pituitary-adrenal stress axis) to statistical analyses increased the separation of the three groups. There was high degree of association among the three signalling molecules in the four brain regions within each group. There was an absence of the associations between the medial prefrontal cortex and the amygdala in the cued fear recall group that were strong for the non-conditioned group. These results demonstrated unique neuronal and hormonal signalling profiles associated with unconditioned, generalized, and conditioned fear expression in females and highlight the importance of including appropriate comparisons to best discriminate between these different emotional states. PMID- 27939360 TI - Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer. AB - Breast cancer is a leading cause of morbidity and mortality in women. Both Epidemiological and experimental studies indicate a positive correlation between alcohol consumption and the risk of breast cancer. While alcohol exposure may promote the carcinogenesis or onset of breast cancer, it may as well enhance the progression and aggressiveness of existing mammary tumors. Recent progress in this line of research suggests that alcohol exposure is associated with invasive breast cancer and promotes the growth and metastasis of mammary tumors. There are multiple potential mechanisms involved in alcohol-stimulated progression and aggressiveness of breast cancer. Alcohol may increase the mobility of cancer cells by inducing cytoskeleton reorganization and enhancing the cancer cell invasion by causing degradation and reconstruction of the extracellular matrix (ECM). Moreover, alcohol may promote the epithelial-mesenchymal transition (EMT), a hallmark of malignancy, and impair endothelial integrity, thereby increasing the dissemination of breast cancer cells and facilitating metastasis. Furthermore, alcohol may stimulate tumor angiogenesis through the activation of cytokines and chemokines which promotes tumor growth. Additionally, alcohol may increase the cancer stem cell population which affects neoplastic cell behavior, aggressiveness, and the therapeutic response. Alcohol can be metabolized in the mammary tissues and breast cancer cells which produces reactive oxygen species (ROS), causing oxidative stress. Recent studies suggest that the epidermal growth factor receptor (EGFR) family, particularly ErbB2 (a member of this family), is involved in alcohol-mediated tumor promotion. Breast cancer cells or mammary epithelial cells over-expressing ErbB2 are more sensitive to alcohol's tumor promoting effects. There is considerable cross-talk between oxidative stress and EGFR/ErbB2 signaling. This review further discusses how the interaction between oxidative stress and EGFR/ErbB2 signaling contributes to the cellular and molecular events associated with breast cancer aggressiveness. We also discuss the potential therapeutic approaches for cancer patients who drink alcoholic beverages. PMID- 27939365 TI - Direct eye contact enhances mirroring of others' movements: A transcranial magnetic stimulation study. AB - Direct eye contact is a powerful social cue to regulate interpersonal interactions. Previous behavioral studies showed a link between eye contact and motor mimicry, indicating that the automatic mimicry of observed hand movements is significantly enhanced when direct eye contact exists between the observer and the observed model. In the present study, we aim to investigate the neurophysiological basis of the previously reported behavioral enhancements. Here, transcranial magnetic stimulation (TMS) was applied to assess changes in cortico-motor excitability at the level of the primary motor cortex (M1) to explore whether and how the motor system is facilitated from observing others' hand movements and, in particular, how this process is modulated by eye contact. To do so, motor evoked potentials (MEPs) were collected from two hand muscles while participants received single-pulse TMS and naturally observed video clips of an actor showing hand opening movements or static hands. During the observation, either direct or averted eye gaze was established between the subject and the observed actor. Our findings show a clear effect of eye gaze on observation-induced motor facilitation. This indicates that the mapping or 'mirroring' of others' movements is significantly enhanced when movement observation is accompanied by direct eye gaze compared to averted eye gaze. Our results support the notion that eye contact is a powerful social signal with the ability to direct human non-verbal social behavior. Furthermore, our findings are important for understanding the role of the mirror motor system in the mapping of socially relevant actions. PMID- 27939366 TI - Interpreting experience enhances early attentional processing, conflict monitoring and interference suppression along the time course of processing. AB - To explore how interpreting experience may modulate young adults' executive functioning, the present study conducted two ERP studies using the Flanker task, and recruited university students of more or less interpreting experience. Experiment 1 revealed that participants of more interpreting experience exhibited larger N1 and N2 amplitudes in both congruent and incongruent conditions, which, according to previous research, are respectively evidence for advantages in early attentional processing and monitoring. As for the response time (RT) data, a smaller interference effect for the group of more interpreting experience was obtained, showing an advantage in inhibition. The P3 results were quite mixed, with the results of the first half P3 time window mainly supporting a monitoring advantage, and the results of the second half mainly supporting an inhibition advantage. Experiment 2 replicated Experiment 1 with two participant groups more closely matched in age and L2 AoA. The pattern of the results was similar to that in Experiment 1, except that the inhibition advantage from the P3 component appeared earlier, and that the inhibition advantage in RT data was only marginally significant. Both experiments have produced results that can be integrated into a coherent whole along the time course of processing, indicating that interpreting experience may enhance early attentional processing, conflict monitoring and interference suppression, with the latter two as parts of inhibitory control. PMID- 27939367 TI - Naming unique entities in the semantic variant of primary progressive aphasia and Alzheimer's disease: Towards a better understanding of the semantic impairment. AB - While the semantic variant of primary progressive aphasia (svPPA) is characterized by a predominant semantic memory impairment, episodic memory impairments are the clinical hallmark of Alzheimer's disease (AD). However, AD patients also present with semantic deficits, which are more severe for semantically unique entities (e.g. a famous person) than for common concepts (e.g. a beaver). Previous studies in these patient populations have largely focused on famous-person naming. Therefore, we aimed to evaluate if these impairments also extend to other semantically unique entities such as famous places and famous logos. In this study, 13 AD patients, 9 svPPA patients, and 12 cognitively unimpaired elderly subjects (CTRL) were tested with a picture-naming test of non-unique entities (Boston Naming Test) and three experimental tests of semantically unique entities assessing naming of famous persons, places, and logos. Both clinical groups were overall more impaired at naming semantically unique entities than non-unique entities. Naming impairments in AD and svPPA extended to the other types of semantically unique entities, since a CTRL>AD>svPPA pattern was found on the performance of all naming tests. Naming famous places and famous persons appeared to be most impaired in svPPA, and both specific and general semantic knowledge for these entities were affected in these patients. Although AD patients were most significantly impaired on famous-person naming, only their specific semantic knowledge was impaired, while general knowledge was preserved. Post-hoc neuroimaging analyses also showed that famous person naming impairments in AD correlated with atrophy in the temporo-parietal junction, a region functionally associated with lexical access. In line with previous studies, svPPA patients' impairment in both naming and semantic knowledge suggest a more profound semantic impairment, while naming impairments in AD may arise to a greater extent from impaired lexical access, even though semantic impairment for specific knowledge is also present. These results highlight the critical importance of developing and using a variety of semantically-unique-entity naming tests in neuropsychological assessments of patients with neurodegenerative diseases, which may unveil different patterns of lexical-semantic deficits. PMID- 27939368 TI - Dissociating oral motor capabilities: Evidence from patients with movement disorders. AB - Abnormal articulation rate is a frequent symptom in neurogenic speech disorders. Performance rates in speech-like or nonspeech tasks involving the vocal motor apparatus are commonly accepted predictors of speech motor function in general and of articulation rate in particular. However, theoretical arguments and behavioral observations in populations with disordered speech indicate that different oral motor behaviors may be governed by distinct mechanisms. The objective of the present study was to expand our knowledge of the relationship between speech movements, on the one hand, and speech-like and nonspeech oral motor behaviors, on the other, by using a rate paradigm. 130 patients with neurological movement disorders of different origins and 130 neurologically healthy subjects participated in the study. Rate data was collected in a speech task (oral reading/repetition), in speech-like tasks (rapid syllable repetitions), and in nonspeech tasks (rapid single articulator movements of the tongue/lips). The main analyses involved a multiple single-case method, by which we tested for differences among each patient's performance rates on the three task types. The results disclosed statistically significant (classical and strong) dissociations between movement rates obtained from the speech task and those obtained from speech-like and nonspeech oral motor tasks in a number of patients. The findings can be interpreted as reflecting major differences in task demands and underlying control mechanisms. The validity of diagnostic indices for speech obtained from speech-like or nonspeech tasks must thus be called into question. PMID- 27939370 TI - Lymphaticoperitoneal and Lymphaticopleural Shunting to Treat Lymphedema; a New Therapeutic Approach. AB - Lymphedema is a common and progressive disease which causes deterioration of the quality of life of the patients, and still, there is no gold standard therapeutic option. In this article, we discuss about our new approach to deal with management of lymphedema which is lymphatic drainage by a subcutaneous channel which is designed as lymphaticoperitoneal and lymphaticopleural shunts for lower and upper extremity lymphedema, respectively. PMID- 27939371 TI - Phlegmasia Cerulea Dolens as an Unusual Presentation of Ruptured Abdominal Aortic Aneurysm into the Inferior Vena Cava. AB - The aim of this case study is to report a case of unusual manifestation of ruptured abdominal aortic aneurysm (AAA) involving an aortocaval fistula (ACF) as phlegmasia cerulea dolens (PCD). A 58-year-old male presented with acute signs of PCD of the right lower limb, confirmed on duplex ultrasonography. Computed tomography angiography revealed a 65-mm ruptured AAA with a large ACF. Successful emergent surgical repair was performed, using implantation of an aortobi-iliac graft with primary closure of the fistula and associated venous thrombectomy. PCD revealing a ruptured AAA with ACF is rare. Knowledge of this original entity might be the most important factor on the outcome. PMID- 27939369 TI - Hippocampal structure predicts cortical indices of reactivation of related items. AB - One of the key components of relational memory is the ability to bind together the constituent elements of a memory experience, and this ability is thought to be supported by the hippocampus. Previously we had shown that these relational bindings can be used to reactivate the cortical processors of an absent item in the presence of a relationally bound associate (Walker et al., 2014). Specifically, we recorded the event-related optical signal (EROS) when presenting the scene of a face-scene pair during a preview period immediately preceding a test display, and demonstrated reactivation of a face-processing cortical area (the superior temporal sulcus, STS) for scenes that had been previously paired with faces, relative to scenes that had not. Here we combined the EROS measures during the same preview paradigm with anatomical estimates of hippocampal integrity (structural MRI measures of hippocampal volume and diffusion tensor imaging measures of mean fractional anisotropy and diffusivity) to provide evidence that the hippocampus is mediating this reactivation phenomenon. The study was run in a sample of older adults aged 55-87, taking advantage of the high amount of hippocampal variability present in aging. We replicated the functional reactivation of STS during the preview period, specific to scenes previously paired with faces. Crucially, we also found that this phenomenon is correlated with structural hippocampus integrity. Both STS reactivation and hippocampal structure predicted subsequent recognition performance. These data support the theory that relational memory is sustained by an interaction between hippocampal and cortical sensory processing regions, and that these functions may be at the basis of episodic memory changes in normal aging. PMID- 27939372 TI - Diagnostic performance of CT cerebral blood volume colour maps for evaluation of acute infarcts; comparison with diffusion-weighted MRI within 12hours of major stroke onset. AB - BACKGROUND AND PURPOSE: Recent developments in treatment of ischemic stroke increased importance of defining limits of ischemic insult by imaging. Some studies postulated that CTP is a promising technique, which can discriminate between ischemic core and penumbra. In this study, we sought to evaluate diagnostic performance of CTP-CBV colour maps, regarded as a marker of acute infarct; in comparison with DWI. MATERIALS AND METHODS: We retrospectively analyzed 48 patients with CTA proved major ischemic stroke within 12hours of onset, they had DWI and CTP exams within 1hour of each other, regardless of order. DWI sizes were calculated. Sensitivity, specificity, PPV and NPV of CBV colour maps for identification of acute infarcts were calculated. ROC curve was constructed. RESULTS: CBV colour maps missed a lot of small infarcts that were identified by DWI with an overall diagnostic accuracy of (62.5%) and low sensitivity (38.5%) for patients whom DWI size<70mL. Area under curve was 0.79. DWI size was an only predictor of abnormal CBV colour maps (P=0.005). CONCLUSIONS: Assuming direct equivalence of DWI and CBV-based core might be unrealistic for individual patients in clinical practice. CBV colour maps are highly specific for acute infarcts, but with lack of sufficient sensitivity; particularly for small sized infarcts. PMID- 27939374 TI - Mesenchymal stromal cell-secreted chemerin is a novel immunomodulatory molecule driving the migration of ChemR23-expressing cells. AB - BACKGROUND: Mesenchymal stromal cells (MSCs) are multipotent cells characterized by broad immunomodulatory properties exploited for the treatment of inflammatory disorders. However, the efficacy of MSC-based therapy is highly variable and tightly linked to MSC culture conditions and treatment schedule. Thus, the identification of novel key molecules regulating MSC immunomodulatory activities in vivo might constitute a crucial step toward the optimization of currently available clinical protocols. In this regard, herein, we sought to determine whether the newly identified chemotactic protein, chemerin, plays a role in MSC mediated regulation of inflammation. METHODS: Chemerin production by human MSCs was investigated under different culture conditions using enzyme-linked immunosorbent assay (ELISA). After purification, MSC-secreted chemerin was identified using mass spectrometry analysis and the biological activity of secreted isoforms was evaluated using migration assay. RESULTS: Bone marrow derived MSCs secrete chemerin and express its receptors ChemR23 and CCRL2. Chemerin production is dependent on culture conditions and increases upon stimulation with inflammatory cytokines. In particular, platelet lysate (PL)-MSCs produce higher levels of chemerin compared with fetal bovine serum (FBS)-MSCs. Furthermore, chemerin is secreted by MSCs as an inactive precursor, which can be converted into its active form by exogenous chemerin-activating serine and cysteine proteases. DISCUSSION: Our data indicate that, in response to various inflammatory stimuli, MSCs secrete high amounts of inactive chemerin, which can then be activated by inflammation-induced tissue proteases. In light of these initial findings, we propose that further analysis of chemerin functions in vivo might constitute a crucial step toward optimizing MSC-based therapy for inflammatory diseases. PMID- 27939375 TI - Targeted Delivery of Interferon Gamma Using a Recombinant Fusion Protein of a Fibrin Clot-Binding Peptide With Interferon Gamma for Cancer Gene Therapy. AB - Accelerated formation of fibrin clots in a tumor microenvironment can be used for targeted delivery of interferon gamma (IFNgamma) to tumor cells. Here, we selected cysteine-arginine-glutamic acid-lysine-alanine (CREKA) as the fibrin clot-binding peptide and designed 2 types of fusion proteins for tumor targeting. The CREKA peptide was fused to IFNgamma's C-terminus, with or without a matrix metalloproteinase-2 (MMP2)-cleavable linker (IFNgamma-mmp-CREKA or IFNgamma CREKA, respectively). The former was designed to release IFNgamma from IFNgamma mmp-CREKA bound to fibrin clots, to ensure IFNgamma's function in the tumor milieu. IFNgamma-activated sequence-dependent reporter gene expression in B16-BL6 cells revealed that the biological activities of IFNgamma-CREKA and IFNgamma were comparable, whereas that of IFNgamma-mmp-CREKA was approximately 60% that of IFNgamma. Plasma concentrations of IFNgamma-CREKA and IFNgamma-mmp-CREKA remained at effective levels for at least 4 weeks after gene transfer into mice. After gene transfer to tumor-bearing mice, intratumoral concentration of IFNgamma in pCpG-IFNgamma-mmp-CREKA group was tended to be higher than those of the other groups. Inhibition of colon-26 tumor growth was significantly more with gene transfer of IFNgamma-mmp-CREKA than with IFNgamma or IFNgamma-CREKA. These results indicate that targeted delivery of IFNgamma to fibrin clots through IFNgamma-mmp-CREKA fusion can enhance the therapeutic efficacy of IFNgamma in cancer gene therapy. PMID- 27939373 TI - Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation. AB - BACKGROUND & AIMS: Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in beta-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications. METHODS: We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation. RESULTS: Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with beta-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively. CONCLUSIONS: Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA. PMID- 27939377 TI - Draft genome of a South African strain of Pectobacterium carotovorum subsp. brasiliense. AB - The draft genome of Pectobacterium carotovorum subsp. brasiliense (Pcb) which causes blackleg of potato was submitted to the NCBI and released with reference number NZ_LGRF00000000.1. The estimated genome size based on the draft genome assembly is 4,820,279bp from 33 contigs ranging in length from 444 to 1,660,019 nucleotides. The genome annotation showed 4250 putative genes, 4114 CDS and 43 pseudo-genes. Three complete rRNA gene species were detected: nine 5S, one 16S and one 23S. Other partial rRNA gene fragments were also identified, nine 16S rRNA and three 23S rRNA. A total of 69 tRNA genes and one ncRNA gene were also annotated in this genome. PMID- 27939376 TI - The Promises of Quantitative Proteomics in Precision Medicine. AB - Precision medicine approach has a potential to ensure optimum efficacy and safety of drugs at individual patient level. Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models could play a significant role in precision medicine by predicting interindividual variability in drug disposition and response. In order to develop robust PBPK/PD models, it is imperative that the critical physiological parameters affecting drug disposition and response and their variability are precisely characterized. Currently used PBPK/PD modeling software, for example, Simcyp and Gastroplus, encompass information such as organ volumes, blood flows to organs, body fat composition, glomerular filtration rate, etc. However, the information on the interindividual variability of the majority of the proteins associated with PK and PD, for example, drug metabolizing enzymes, transporters, and receptors, are not fully incorporated into these PBPK modeling platforms. Such information is significant because the population factors such as age, genotype, disease, and gender can affect abundance or activity of these proteins. To fill this critical knowledge gap, mass spectrometry-based quantitative proteomics has emerged as an important technique to characterize interindividual variability in the protein abundance of drug metabolizing enzymes, transporters, and receptors. Integration of these quantitative proteomics data into in silico PBPK/PD modeling tools will be crucial toward precision medicine. PMID- 27939379 TI - Epithelial Barriers in Murine Skin during Herpes Simplex Virus 1 Infection: The Role of Tight Junction Formation. AB - Herpes simplex virus 1 has to overcome skin or mucosa barriers to infect its human host. The impact of the various barrier functions on successful viral invasion is not known. On ex vivo infection of murine skin, we observed efficient invasion only via the basal epidermal layer when the dermis was removed. Here, we investigated how wounding and intercellular junction formation control successful viral entry. After wounding of skin samples or removal of the stratum corneum, infected cells were rarely detected. On the basis of infection studies in epidermis from IFN-stimulated mice, we assume that mechanical wounding does not lead to an antiviral state that impedes infection. When we infected human skin equivalents, we observed entry only into unstratified keratinocytes or after wounding of fully stratified cultures. Reduced infection of keratinocytes after calcium-induced stratification confirmed the impact of junction formation. To assess the effect of functional tight junctions, stratified cultures of polarity regulator partitioning-defective-3- or E-cadherin-deficient keratinocytes were infected. As the number of infected cells strongly increased with enhanced paracellular permeability, we conclude that the formation of functional tight junctions interferes with viral entry indicating that next to the stratum corneum tight junctions are a major physical barrier for herpes simplex virus 1 invasion into tissue. PMID- 27939378 TI - MYO5A Gene Is a Target of MITF in Melanocytes. PMID- 27939380 TI - Effect of Omalizumab on Blood Basophil Counts in Patients with Chronic Idiopathic/Spontaneous Urticaria. PMID- 27939381 TI - Impact of Elevated End-Diastolic Pulmonary Regurgitation Gradient on Worse Clinical Outcomes in Hospitalized Patients With Heart Failure. AB - The echo Doppler end-diastolic pulmonary regurgitation (EDPR) gradient correlates well with catheter-derived pulmonary artery diastolic pressure. An elevated EDPR gradient is associated with worse clinical outcomes in patients with stable coronary artery disease. However, the prognostic significance of EDPR gradient in patients with heart failure (HF) is unclear. The aim of the present study was to investigate the prognostic impact of EDPR gradient in HF. We retrospectively examined 751 consecutive hospitalized patients with acute HF. Those with acute coronary syndrome or in-hospital death and those without accessible EDPR gradient data at discharge were excluded. Finally, 265 patients were examined and divided into 2 groups according to EDPR gradient (cutoff 9 mm Hg). Adverse events were defined as worsening HF and death. Patients with elevated EDPR gradient had higher B-type natriuretic peptide, lower age, and lower left ventricular ejection fraction at discharge than those with nonelevated EDPR gradient. During a median follow-up of 429 days, elevated EDPR gradient was independently associated with adverse events (hazard ratio 2.34, 95% CI 1.44 to 3.78, p <0.001) after adjustment for confounders. In conclusion, echo Doppler EDPR gradient might be a noninvasive predictor of clinical outcomes in hospitalized patients with HF. PMID- 27939384 TI - Reply. PMID- 27939382 TI - Incidence, Predictors, and Mid-Term Outcomes of Percutaneous Closure Failure After Transfemoral Aortic Valve Implantation Using an Expandable Sheath (from the Optimized Transcatheter Valvular Intervention [OCEAN-TAVI] Registry). AB - The aim of this study was to evaluate the incidence, predictors, and outcomes of percutaneous closure device (PCD) failure during transfemoral transcatheter aortic valve implantation (TAVI) with an Edwards Sapien-XT prosthesis using an expandable sheath (eSheath). From October 2013 to April 2016, 1,215 patients who underwent TAVI were prospectively enrolled in the Optimized Transcatheter Valvular Intervention (OCEAN-TAVI) registry. Of these, 478 patients underwent transfemoral TAVI with Sapien-XT prosthesis using an eSheath and percutaneous closure with a Perclose ProGlide system. We evaluated the predictors of PCD failure and whether it affected the clinical outcomes. Patients were aged 85 years (interquartile range 82 to 88 years). PCD failure occurred in 36 patients (8%). Sheath-to-femoral artery ratio (SFAR) (per 1 increase) (odds ratio 5.40, 95% confidence interval 1.28 to 22.92, p = 0.022) predicted PCD failure in a multivariate model. The sensitivity-specificity curves identified an SFAR threshold of 1.03; the area under the curve for SFAR as a predictor of PCD failure was 0.629. The PCD failure group did not have a higher rate of 30-day mortality (0% vs 1%, p = 0.52) or mid-term (365-day) mortality (log-rank test p = 0.85) compared with the PCD success group in the Kaplan-Meier analysis. In conclusion, PCD failures occurred in 8% of the patients and were not associated with 30-day or mid-term mortality rates after percutaneous transfemoral TAVI. The SFAR threshold of 1.03 was useful for predicting PCD failures. PMID- 27939385 TI - Meta-Analysis of Randomized Trials of Long-Term All-Cause Mortality in Patients With Non-ST-Elevation Acute Coronary Syndrome Managed With Routine Invasive Versus Selective Invasive Strategies. AB - Randomized trials and meta-analyses demonstrated that a routine invasive strategy improves outcomes in patients with non-ST-elevation acute coronary syndrome (NSTE ACS) compared to a selective invasive strategy. Benefit was driven primarily by a reduction in the risk of myocardial infarction. However, the impact of either strategy on long-term mortality is unknown. Trials that compared a routine invasive strategy versus a selective invasive strategy in patients with NSTE-ACS and reported data on all-cause mortality >=1 year were included. Summary odds ratios (OR) were constructed using Peto's model for all-cause mortality using the longest available follow-up data. Subgroup analysis was performed for follow-up at 1 to <=5 years and >5 years. Eight trials with 6,657 patients were available for analysis. At a mean of 10.3 years, the risk of all-cause mortality was similar with both strategies (28.5% vs 28.5%; OR 1.00, 95% confidence interval [CI] 0.90 to 1.12, p = 0.97). This effect was similar on subgroup analysis for follow-up at 1 to <=5 years (OR 0.89, 95% CI 0.77 to 1.04, p = 0.15) and >5 years (OR 1.02, 95% CI 0.90 to 1.14, p = 0.79). There was no difference in treatment effect across various study-level covariates such as age, gender, diabetes, and positive troponin (all P for interaction >0.05). In conclusion, in patients with NSTE-ACS, both routine invasive and selective invasive strategies have a similar risk of all-cause mortality at ~10 years. This illustrates there are still opportunities to change the trajectory of mortality events among invasively treated patients with NSTE-ACS. PMID- 27939383 TI - Recent Trends in Management and Inhospital Outcomes of Acute Myocardial Infarction in Renal Transplant Recipients. AB - Renal transplant recipients (RTR) are at high risk of cardiovascular events including acute myocardial infarction (AMI). We evaluated recent trends in AMI admissions in 9,243 RTR with functioning grafts using data from the 2003 to 2011 Nationwide Inpatient Sample database. Findings were compared with those of patients with end-stage renal disease without transplantation (ESRD-NRT, n = 160,932) and those without advanced kidney disease (non-ESRD/RT, n = 5,640,851) admitted with AMI. RTR comprised 0.2% of AMI admissions with increasing numbers during the study period (adjusted odds ratio [aOR] 1.04; 95% confidence interval [CI] 1.04 to 1.05; ptrend <0.001). Overall, 29.3% of admissions in RTR were for acute ST-segment elevation myocardial infarction (STEMI). Compared with non ESRD/RT, history of renal transplantation was independently associated with a decreased likelihood of STEMI at presentation (aOR 0.73; 95% CI 0.65 to 0.80; p <0.001). Inhospital mortality among RTR admitted for NSTEMI decreased from 3.8% in 2003 to 2.1% in 2011 (aOR 0.85; 95% CI 0.78 to 0.93; p <0.001), whereas that for STEMI remained unchanged (7.6% in 2003; 9.3% in 2011, aOR 0.97; 95% CI 0.90 to 1.03; p = 0.36). Rates of percutaneous coronary interventions were higher, and inhospital mortality was lower among RTR compared with ESRD-NRT (p <0.001 for both). Treatment strategies appeared largely unchanged during the course of this study with the exception of an increase in primary percutaneous coronary intervention among RTR admitted with STEMI. In conclusion, RTR were frequently admitted with AMI, particularly NSTEMI, and were found to have multiple coronary artery disease risk factors despite their younger age. Compared with other forms of renal replacement therapy, renal transplant was associated with lower inhospital mortality. PMID- 27939386 TI - Impact of an Interaction Between Clopidogrel and Selective Serotonin Reuptake Inhibitors. AB - Clopidogrel is a pro-drug that requires activation by the cytochrome P450 (CYP) enzyme system. Patients receiving clopidogrel are often treated with selective serotonin reuptake inhibitors (SSRIs) for co-existing depression. SSRIs that inhibit the CYP2C19 enzyme have the potential to reduce the effectiveness of clopidogrel. Using 5 US databases (1998 to 2013), we conducted a cohort study of adults who initiated clopidogrel while being treated with either an SSRI that inhibits CYP2C19 (fluoxetine and fluvoxamine) or a noninhibiting SSRI. Patients were matched by propensity score and followed for as long as they were exposed to both clopidogrel and the index SSRI group (primary analysis) or for 180 days after clopidogrel initiation (sensitivity analysis). Outcomes included a composite ischemic event (myocardial infarction, ischemic stroke, or a revascularization procedure) and a composite major bleeding event (gastrointestinal bleed or hemorrhagic stroke). The final propensity score matched cohort comprised 9,281 clopidogrel initiators on CYP2C19-inhibiting SSRIs and 44,278 clopidogrel initiators on a noninhibiting SSRIs. Compared with those treated with a noninhibiting SSRI, patients on a CYP2C19-inhibiting SSRI had an increased risk of ischemic events (hazard ratio [HR] 1.12; 95% confidence interval [CI] 1.01 to 1.24), which was more pronounced in patients >=65 years (HR 1.22; 95% CI 1.00 to 1.48). The HR for major bleeding was 0.76 (95% CI 0.50 to 1.17). In conclusion, the findings from this large, population-based study suggest that being treated with a CYP2C19-inhibiting SSRI when initiating clopidogrel may be associated with slight decrease in effectiveness of clopidogrel. PMID- 27939387 TI - Combining electron microscopy with single molecule DNA fiber approaches to study DNA replication dynamics. AB - Replication stress is a crucial driver of genomic instability. Understanding the mechanisms of replication stress response is instrumental to improve diagnosis and treatment of human disease. Electron microscopy (EM) is currently the technique of choice to directly visualize a high number of replication intermediates and to monitor their remodeling upon stress. At the same time, DNA fiber analysis is useful to gain mechanistic insight on how genotoxic agents perturb replication fork dynamics genome-wide at single-molecule resolution. Combining these techniques has proven invaluable to achieve a comprehensive view of the mechanisms that ensure error-free processing of damaged replication forks. Here, we review how EM and single-molecule DNA fiber approaches can be used together to shed light into the mechanisms of replication stress response and discuss important cautions to be taken into account when comparing results obtained by EM and DNA fiber. PMID- 27939388 TI - Pax2 is persistently expressed by GABAergic neurons throughout the adult rat dorsal horn. AB - The transcription factor Pax2 is required for the differentiation of GABAergic neurons in the mouse dorsal horn. Pax2 continues to be expressed in the adult murine spinal cord and has been used as a presumed marker of GABAergic neurons in the superficial dorsal horn of the adult mouse, although a strict association between adult Pax2 expression and presence of GABA throughout the dorsal horn has not been firmly established. Moreover, whether Pax2 is selectively expressed in GABAergic dorsal horn neurons also in the rat is unknown. Here, immunofluorescent labeling of Pax2 and GABA in the lumbar spinal cord of adult rats was used to investigate this issue. Indeed, essentially all GABA immunoreactive neurons in laminae I-V were immunolabeled for Pax2. Conversely, essentially all Pax2 immunopositive neurons in these laminae exhibited somatic GABA immunolabeling. These results indicate persistent Pax2 expression in GABAergic neurons in the adult rat dorsal horn, supporting the hypothesis that Pax2 may be required for the maintenance of a GABAergic phenotype in mature inhibitory dorsal horn neurons in the rat. Furthermore, Pax2 may be used as a selective and specific general somatic marker of such neurons. PMID- 27939389 TI - Synthesis of silica-PAMAM dendrimer nanoparticles as promising carriers in Neuro blastoma cells. AB - Mesoporous silica carriers are emerging as therapeutic drug delivery systems. The objective of this study was to develop a formulation for synthesizing silica PAMAM dendrimer hybrid nanoparticles with sol-gel technique. Subsequently, black carrot anthocyanins were encapsulated and investigated for their capability in terms of inhibiting the proliferative effects of neuroblastoma (Neuro 2A). In this context, particle size distributions were ascertained followed by thermal analysis (DSC), scanning electron microscopy and encapsulation efficiency. Subsequently, in vitro release kinetics was determined along with cytotoxicity of empty and anthocyanin doped hybrid nanoparticles. The lowest particle size was 134.8 nm with a zeta potential of +19.78 mV which enhanced electrostatic interaction with the cell membrane in the cytotoxicity analyses. As the anthocyanin content was totally released at the end of 6 days, the cytotoxicity was observed for 134 h, reaching an inhibition of 87.9%. On the other hand, Neuro 2A cells incubated with empty nanoparticles exhibited a high proliferation indicating that hybrid nanoparticles were not toxic to the cells and the inhibitory effect was associated with the anthocyanins. PMID- 27939390 TI - PCSK9 inhibition and diabetes: turning to Mendel for clues. PMID- 27939391 TI - Into the unknown: Trump's stance on health. PMID- 27939392 TI - Research digest. PMID- 27939393 TI - The ecological cost of continued use of endocrine-disrupting chemicals. PMID- 27939394 TI - The challenges of harmonising the iodine supply across Europe. PMID- 27939395 TI - Do microplastic loads reflect the population demographics along the southern African coastline? AB - Plastic pollution is a major anthropogenic contaminant effecting the marine environment and is often associated with high human population densities and industrial activities. The microplastic (63 to 5000MUm) burden of beach sediment and surf-zone water was investigated at selected sites along the entire length of the South African coastline. It was predicted that samples collected in areas of high population density, would contain a higher microplastic burden than those along coasts that demonstrate very low population densities. With the exception of water column microplastics within Richard's Bay Harbour (413.3+/ 77.53particles.m-3) and Durban Harbour (1200+/-133.2particles.m-3), there were no significant spatial differences in microplastic loads. This supports the theory that harbours act as a source of microplastics for the surrounding marine environment. Additionally, the absence of any spatial variation highlights the possible long range distribution of microplastic pollutants by large scale ocean currents. PMID- 27939397 TI - On the origins of organology: Franz Joseph Gall and a girl named Bianchi. AB - Franz Joseph Gall (1758-1828) introduced a new theory of mind and brain at the end of the eighteenth century, which he referred to as organology, dealing with mental functions and their cortical localizations. Gall wrote that observations regarding the verbal learning capacities of his schoolmates brought about his new way of thinking. This widely accepted view, however, requires qualification. Although Gall's experiences and observations as a schoolboy were relevant, especially for his craniology, these childhood memories might have been recalled and reinterpreted after he had started to think about the faculties of mind specifically after he had met Bianchi, a 5-year-old girl with a special talent for music. PMID- 27939398 TI - Intradural extramedullary Ewing's sarcoma: A case report and review of the literature. AB - INTRODUCTION: Extra-skeletal Ewing's sarcomas are very rare lesions to the spine surgeon, with the intradural, extramedullary lesions being even rarer. Herein we present a patient with an intradural, extramedullary form of Ewing's sarcoma and review the relevant literature. The medical records, operative reports, radiographical studies and histological examinations of a single patient are retrospectively reviewed. CASE REPORT: A 31-year old male presented with back pain, right-leg progressive paraparesis, and inability to walk. Both motor and sensory disturbances were revealed on the right leg at the clinical examination. Lumbar MRI showed two lesions. The first one was an intradural, extramedullary lesion at the L2-L3 level, while the second was smaller, located at the bottom of the dural sac. The patient underwent gross total resection of the L2-L3 lesion after a bilateral laminectomy. Histological examination was compatible with Ewing's sarcoma, and was verified by molecular analysis. No other extra-skeletal or skeletal lesion was found. A chemotherapy scheme was tailored to the patients' histological diagnosis. The patient presented with local recurrence and bone metastasis 2 years after his initial diagnosis. A second operation was performed and the follow up of the patient showed no disease progression 18 months after revision surgery. CONCLUSION: The spine surgeon should be aware of the existence of such rare entities, in order to timely fulfill the staging process and institute the proper therapy. The management of patients with extra-skeletal Ewing's sarcomas involves professionals as members of a multidisciplinary team, all of which should co-operate for the patient's optimal outcome. PMID- 27939396 TI - A Role for Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1alpha in Nucleus Accumbens Neuron Subtypes in Cocaine Action. AB - BACKGROUND: Molecules critically involved in cocaine behavioral plasticity are known to regulate and interact with peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). In addition, the PGC-1alpha promoter has binding sites for early growth response 3 (Egr3), which plays a dynamic role in cocaine action in nucleus accumbens (NAc) medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor D1 (D1-MSN) versus D2 (D2-MSN). However, the role of PGC-1alpha in NAc in cocaine action is unknown. METHODS: PGC-1alpha messenger RNA and protein were examined in NAc after repeated cocaine exposure. Binding of Egr3 to and histone methylation at the PGC-1alpha promoter was examined in NAc using chromatin immunoprecipitation after repeated cocaine. PGC 1alpha ribosome-associated messenger RNA in MSN subtypes was assessed after repeated cocaine using D1-Cre-RiboTag and D2-Cre-RiboTag lines. Finally, PGC 1alpha was expressed in NAc D1-MSNs versus D2-MSNs using a Cre-inducible adeno associated virus and Cre lines during cocaine conditioned place preference and cocaine-induced locomotion. RESULTS: Repeated cocaine increased PGC-1alpha levels and increased Egr3 binding and H3K4me3 at the PGC-1alpha promoter in NAc. Increased PGC-1alpha occurred in D1-MSNs, while D2-MSNs showed reduced levels. Viral-mediated expression of PGC-1alpha in D1-MSNs enhanced behavioral responses to cocaine, while expression in D2-MSNs blunted these behaviors. CONCLUSIONS: We demonstrate a novel role for PGC-1alpha in NAc in cocaine action. PGC-1alpha is enhanced in NAc D1-MSNs, specifically after cocaine exposure. These data are consistent with increased active methylation and Egr3 binding at the PGC-1alpha promoter. Finally, we demonstrate a bidirectional role for PGC-1alpha in mediating behavioral plasticity to cocaine through D1-MSNs versus D2-MSNs. PMID- 27939399 TI - Necrotizing Enterocolitis in Anorexia Nervosa: A Case Report and Review of the Literature. PMID- 27939401 TI - Immune-checkpoint blockade in cisplatin-ineligible patients with urothelial cancer. PMID- 27939402 TI - Bilateral posterior uveitis associated with Zika virus infection. PMID- 27939400 TI - Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. AB - BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17.2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2.7 months (2.1 to 4.2). Median overall survival was 15.9 months (10.4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech. PMID- 27939403 TI - Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations. AB - BACKGROUND: Ikaros, which is encoded by IKZF1, is a transcriptional factor that play a critical role in hematopoiesis. Somatic IKZF1 alterations are known to be involved in the pathogenesis of leukemia in human subjects. Recently, immunodeficiency caused by germline IKZF1 mutation has been described. OBJECTIVE: We sought to describe the clinical and immunologic phenotypes of Japanese patients with heterozygous IKZF1 mutations. METHODS: We performed whole-exome sequencing in patients from a dysgammaglobulinemia or autoimmune disease cohort and used a candidate gene approach in 4 patients. Functional and laboratory studies, including detailed lymphopoiesis/hematopoiesis analysis in the bone marrow, were performed. RESULTS: Nine patients from 6 unrelated families were identified to have heterozygous germline mutations in IKZF1. Age of onset was 0 to 20 years (mean, 7.4 years). Eight of 9 patients presented with dysgammaglobulinemia accompanied by B-cell deficiency. Four of 9 patients had autoimmune disease, including immune thrombocytopenic purpura, IgA vasculitis, and systemic lupus erythematosus. Nonautoimmune pancytopenia was observed in 1 patient. All of the mutant Ikaros protein demonstrated impaired DNA binding to the target sequence and abnormal diffuse nuclear localization. Flow cytometric analysis of bone marrow revealed reduced levels of common lymphoid progenitors and normal development of pro-B to pre-B cells. CONCLUSIONS: Germline heterozygous IKZF1 mutations cause dysgammaglobulinemia; hematologic abnormalities, including B-cell defect; and autoimmune diseases. PMID- 27939404 TI - Proliferation and apoptosis in subcutaneous adipose tissue of lactating cows with different genetic merit for milk yield. AB - The aim of this study was to investigate the adipocyte size and fate in subcutaneous fat (scAT) of cows diverging for genetic merit at mid lactation stage, when anabolic activity increases and animals are in a state of positive energy balance. Twenty mid lactation cows (180+/-20days in milk) grouped according to the Estimated Breeding Values (EBV) for milk yield in plus (EBVp) and minus (EBVm) variants were selected. Average of adipocytes area, proliferation and apoptotic labelling index as well as DLK-1 expression, a marker of pre-adipocytes, were immunohistochemically evaluated in scAT biopsies. In EBVp cows, the BCS was lower (P<0.01) whereas milk yield, protein, fat yield (P<0.001) and plasma free fatty acid concentration (P<0.05) were higher. The scAT of EBVp cows showed a significantly (P<0.001) higher frequency between 500 and 3000MUm2 classes in comparison to EBVm cows, that showed a significantly (P<0.01) higher apoptotic labeling index. The immunohistochemical reaction showed DLK-1 positivity in scAT of EBVp cows. Taking together, the data indicate a link between milk yield genetic merit of cows, scAT morphology and function, suggesting greater dynamics and metabolic flexibility in EBVp cows. PMID- 27939405 TI - FOXP3+ regulatory T cell ameliorates microvasculature in the rejection of mouse orthotopic tracheal transplants. AB - Microvascular loss may be a root cause of chronic rejection in lung transplants, which leads to the bronchiolitis obliterans syndrome. Previous research implicates T regulatory cell (Treg) as a key component of immune modulation, however, Treg has never been examined as a reparative mediator to salvage microvasculature during transplantation. Here, we reconstituted purified Tregs in to allografts, and serially monitored allografts for tissue oxygenation, microvascular perfusion for four weeks. We demonstrated that Tregs reconstitution of allografts significantly improve tissue oxygenation, microvascular flow, epithelial repair, number of CD4+CD25highFOXP3+ Tregs, followed by an upregulation of proinflammatory, angiogenic and regulatory genes, while prevented subepithelial deposition of CD4+T cells at d10, and collagen at d28 post transplantation. Altogether, these findings concluded that Treg-mediated immunotherapy has potential to preserve microvasculature and rescue allograft from sustained hypoxic/ischemic phase, limits airway tissue remodeling, and therefore may be a useful therapeutic tool to prevent chronic rejection after organ transplantation. PMID- 27939408 TI - Expression of Concern: "Importance of the PMMA viscoelastic rheology on the reduction of the leakage risk during osteoporotic bone augmentation: A numerical leakage model through a porous media" [J. Mech. Behav. Biomed. Mater. 65 (2017) 29-41]. PMID- 27939407 TI - Higher body mass index and anti-drug antibodies predict the discontinuation of anti-TNF agents in Korean patients with axial spondyloarthritis. AB - OBJECTIVE: The development of anti-drug antibodies (ADAbs) against tumor necrosis factor (TNF) inhibitors is a likely explanation for the failure of TNF-inhibitors in patients with spondyloarthritis (SpA). Our study determined the existence and clinical implications of ADAbs in axial SpA patients. METHODS: According to the Assessment of SpondyloArthritis International Society classification criteria for axial SpA, patients treated with adalimumab or infliximab were recruited consecutively. Serum samples were collected at enrollment to measure ADAb and drug levels. RESULTS: Of 100 patients, the mean duration of current TNF inhibitor use was 22.3+/-17.9 months. ADAbs were detected in 5 of 72 adalimumab users compared to 5 of 28 infliximab users (6.9% vs. 17.9%). ADAb-positive patients had a significantly higher body mass index than ADAb-negative patients among both adalimumab (28.4+/-5.9kg/m2 vs. 24.3+/-2.9kg/m2, respectively, p=0.01) and infliximab users (25.9+/-2.8kg/m2 vs. 22.6+/-2.8kg/m2, respectively, p=0.02). During the median 15-month follow-up period, drug discontinuation occurred more frequently in the ADAb-positive group than the ADAb-negative group (30.0% vs. 6.5%, respectively, p=0.04). In logistic regression, ADAb positivity (OR=5.85, 95% CI 1.19-28.61, p=0.029) and BMI (OR=4.35, 95% CI 1.01-18.69, p=0.048) were associated with a greater risk of stopping TNF inhibitor treatment. CONCLUSIONS: Our result suggests that the presence of ADAbs against adalimumab and infliximab as well as a higher BMI can predict subsequent drug discontinuation in axial SpA patients. PMID- 27939406 TI - Safety of immunotherapy with glutaraldehyde modified allergen extracts in children and adults. AB - BACKGROUND: Glutaraldehyde-modified natural allergen extracts show significant reduction in the IgE-binding capacity and proteolytic activity. This allows the administration of higher doses in a shorter period of time, and to mix different allergen extracts. OBJECTIVE: Evaluate the safety of different concentrations and mixtures of glutaraldehyde-modified allergen extracts in a large group of paediatric and adult patients undergoing specific immunotherapy treatment. MATERIALS AND METHODS: 1855 patients (1156 adults and 699 children), suffering from rhinoconjunctivitis and/or asthma, participated in an observational multicentre cohort study, to evaluate the safety of immunotherapy using vaccines containing modified allergen extracts. Patients were monosensitised, or polysensitised, and received a therapeutic vaccine containing polymerised allergen extracts adsorbed onto aluminium hydroxide. Safety was assessed by recording all side reactions related to immunotherapy. RESULTS: The clinically relevant local reactions totalled 120, (90 immediate and 30 delayed) (1.02% of injections). Of them, 31 (0.26% of injections) occurred in children (26 immediate and 5 delayed) and 89 (0.76% of injections) in adults (64 immediate and 25 delayed). There were 38 systemic reactions. Eleven reactions were immediate (9 of grade 1 and 2 of grade 2) and 27 delayed (22 of grade 1 and 5 of grade 2). There were seven grade 2 systemic reactions (0.06% of the injections). No differences (P>0.05) in the number of reactions were observed between adults and children and between treatments were found in systemic reactions. All systemic reactions were mild and resolved spontaneously without the need of medication. CONCLUSION: Specific immunotherapy using natural modified allergen vaccines is safe to treat allergic patients, even at higher doses and in mixtures of unrelated allergen extracts. The percentage of adverse reactions detected is lower than those reported in the literature with native unmodified allergen extracts. PMID- 27939409 TI - Cost-Effectiveness of Arthroscopic Rotator Cuff Repair Versus Reverse Total Shoulder Arthroplasty for the Treatment of Massive Rotator Cuff Tears in Patients With Pseudoparalysis and Nonarthritic Shoulders. AB - PURPOSE: To determine the most cost-effective treatment strategy for patients with massive rotator cuff tears and pseudoparalysis of the shoulder without osteoarthritis of the glenohumeral joint (PP without OA). Specifically, we aimed to compare arthroscopic rotator cuff repair (ARCR) versus reverse total shoulder arthroplasty (RTSA) and investigate the effect of patient age on this decision. METHODS: A Markov decision model was used to compare 3 treatment strategies for addressing PP without OA: (1) ARCR with option to arthroscopically revise once, (2) ARCR with immediate conversion to RTSA on potential failure, and (3) primary RTSA. Hypothetical patients were cycled through the model according to transition probabilities, meanwhile accruing financial costs, utility for time in health states, and disutilities for surgical procedures. Utilities were derived from the Short Form-6D scale and expressed as quality-adjusted life-years. Model parameters were derived from the literature and from expert opinion, and thorough sensitivity analyses were conducted. TreeAge Pro 2015 software was used to construct and assess the Markov model. RESULTS: For the base-case scenario (60 year-old patient), ARCR with conversion to RTSA on potential failure was the most cost-effective strategy when we assumed equal utility for the ARCR and RTSA health states. Primary RTSA became cost-effective when the utility of RTSA exceeded that of ARCR by 0.04 quality-adjusted life-years per year. Age at decision did not substantially change this result. CONCLUSIONS: Primary ARCR with conversion to RTSA on potential failure was found to be the most cost-effective strategy for PP without OA. This result was independent of age. Primary ARCR with revision ARCR on potential failure was a less cost-effective strategy. LEVEL OF EVIDENCE: Level IV, economic and decision analysis. PMID- 27939410 TI - Collet-Sicard syndrome secondary to viral infection with influenza A (H1N1). PMID- 27939412 TI - Investigation of kinetic-order sensitivities in metabolic reaction networks. AB - Kinetic-order sensitivity (the ratio of relative change in a dependent variable to the relative change in a kinetic order in a power-law-type differential equation) has recently become an important indicator in metabolic pathway analysis using mathematical models with parameter values determined from time series data on cellular metabolite concentrations. Here, we discuss a potential problem in calculating kinetic-order sensitivities. When the steady-state metabolite concentration is less than unity, a slight increase in the kinetic order changes the metabolite concentration in the incorrect direction, yielding a kinetic-order sensitivity value with an incorrect sign. This is caused by a property of the power-law function (y=Xn): when X is less than unity, y decreases for a larger positive n or for a smaller absolute value of negative n. We propose two solutions. The first is to directly calculate the kinetic-order sensitivities and then reverse the sign of the relevant value if a steady-state metabolite concentration less than unity is involved. The second involves calculation of the kinetic-order sensitivities after setting all metabolite concentrations to values greater than unity (e.g., by changing the units from mM to MUM). The latter method changes the absolute values of the kinetic-order sensitivities according to the magnitude of a multiplication factor, because kinetic-order sensitivities do not have unique values. Nevertheless, since the normalized absolute values exhibit an almost identical distribution, it should not be difficult to identify which kinetic order has greater effect, although kinetic order rankings may change slightly under different calculation conditions. PMID- 27939411 TI - Identification of novel mutations in Japanese ovarian clear cell carcinoma patients using optimized targeted NGS for clinical diagnosis. AB - OBJECTIVE: Ovarian clear cell carcinoma (OCCC) is an aggressive ovarian cancer with a higher frequency in Japan and often becomes chemorefractory disease. Reliable genetic diagnosis is essential to affirm the success of precision medicine for OCCC treatment. The aim of this study is, therefore, to identify novel mutations in OCCCs and develop a feasible clinical next generation sequencing (NGS) approach using formalin-fixed paraffin-embedded (FFPE) rather than preferable but not always available fresh frozen (FF) samples. METHODS: We optimized and evaluated exome analyses of 409 cancer-related genes using FFPE and FF DNA and analyzed NGS data to identify somatic mutations in Japanese OCCCs. RESULTS: Sufficient and good quality DNAs from FFPE samples were extracted from 18 (FIGO Stage I: 12) out of 29 pairs of matched normal and OCCC for NGS (63%). The fine quality of extracted DNAs depended on the length of storage period (<2years storage). We also identified 45 somatic mutations in 34 genes including unreported variants from those FFPE DNA, in which somatic mutations in the PIK3CA gene was the most common (28%) as previously reported. Seven genes (PIK3CA, ARID1A, CTNNB1, CSMD3, LPHN3, LRP1B, and TP53) were mutated in at least two independent OCCCs. FF samples from 3 out of those 18 OCCCs were available and 13 out of 14 FFPE somatic mutations were confirmed. CONCLUSIONS: We successfully identified novel genetic alterations in Japanese OCCCs and demonstrated a feasible clinical diagnostic procedure using targeted NGS for OCCC FFPE samples. PMID- 27939413 TI - Comprehensive mitigation framework for concurrent application of multiple clinical practice guidelines. AB - In this work we propose a comprehensive framework based on first-order logic (FOL) for mitigating (identifying and addressing) interactions between multiple clinical practice guidelines (CPGs) applied to a multi-morbid patient while also considering patient preferences related to the prescribed treatment. With this framework we respond to two fundamental challenges associated with clinical decision support: (1) concurrent application of multiple CPGs and (2) incorporation of patient preferences into the decision making process. We significantly expand our earlier research by (1) proposing a revised and improved mitigation-oriented representation of CPGs and secondary medical knowledge for addressing adverse interactions and incorporating patient preferences and (2) introducing a new mitigation algorithm. Specifically, actionable graphs representing CPGs allow for parallel and temporal activities (decisions and actions). Revision operators representing secondary medical knowledge support temporal interactions and complex revisions across multiple actionable graphs. The mitigation algorithm uses the actionable graphs, revision operators and available (and possibly incomplete) patient information represented in FOL. It relies on a depth-first search strategy to find a valid sequence of revisions and uses theorem proving and model finding techniques to identify applicable revision operators and to establish a management scenario for a given patient if one exists. The management scenario defines a safe (interaction-free) and preferred set of activities together with possible patient states. We illustrate the use of our framework with a clinical case study describing two patients who suffer from chronic kidney disease, hypertension, and atrial fibrillation, and who are managed according to CPGs for these diseases. While in this paper we are primarily concerned with the methodological aspects of mitigation, we also briefly discuss a high-level proof of concept implementation of the proposed framework in the form of a clinical decision support system (CDSS). The proposed mitigation CDSS "insulates" clinicians from the complexities of the FOL representations and provides semantically meaningful summaries of mitigation results. Ultimately we plan to implement the mitigation CDSS within our MET (Mobile Emergency Triage) decision support environment. PMID- 27939415 TI - Retraction notice to Green Synthesis of Silver nanoparticles from Gloriosa superba.L Leaf extract and their catalytic activity [SAA 115C 388-392]. PMID- 27939414 TI - Decreased expression of IL-27 in moderate-to-severe psoriasis and its anti inflammation role in imiquimod-induced psoriasis-like mouse model. AB - BACKGROUND: Psoriasis is a high-incident T-cell-mediated autoimmune disease mainly affecting the skin. Interleukin (IL)-27 is a novel member of the IL-6/IL 12 cytokine family, which plays a versatile role in the differentiation and function of distinct T cell subsets. Previous studies uncovered that IL-27 promoted the onset of psoriasis through enhancing the differentiation of T helper (Th) 1 cells. However, the role of IL-27 in other psoriasis-related Th lineages, especially Th17 cells, remains elusive. OBJECTS: The study aimed to investigate the role of IL-27 in the progression of psoriasis and its underlying mechanisms, particularly its influence on Th1 and Th17. METHODS: IL-27 and IL-27 receptor alpha (IL-27Ralpha) expressions in normal and lesional skin were determined by immunohistochemistry and western blot analysis. Serum levels of IL-27 and IL-10 were measured by ELISA. Expression levels of IL-27 and IL-27 receptor (IL-27R) mRNA in the skin tissue and peripheral blood mononuclear cells (PBMC) were assessed by quantitative polymerase chain reaction (PCR) analysis. To explore the function of IL-27 in vivo, we used imiquimod (IMQ)-induced psoriasis mouse model. We treated mice with IL-27 or its antagonist, evaluated disease severity and detected the cytokine secretion from splenic CD4+ T cells by flow cytometric analysis and the expression levels of IL-17 and IFN-gamma in serum and skin lesion. RESULTS: The expression levels of IL-27 and IL-27Ralpha were significantly reduced in the moderate-to-severe psoriatic lesions, along with a consistent decrease in serum IL-27 levels, compared with those of healthy control subjects. Moreover, subcutaneous administration of IL-27 recombinant protein lessened severity of IMQ-induced psoriasis-like cutaneous lesions, whereas IL 27p28 antagonist exaggerated the disease severity. Further analysis revealed that IL-27 significantly repressed IL-17 secretion from CD4+ T lymphocytes. Also administration of IL-27 decreased IL-17A level while IL-27p28 antagonist increased IL-17A level in serum and psoriasis-like lesion in the IMQ-treated mice. CONCLUSION: Our results suggest that IL-27 might predominantly play a protective role in the pathogenesis of psoriasis through abrogating Th17 differentiation. The potential therapeutic benefit of harnessing IL-27 in treating psoriasis awaits future investigation. PMID- 27939416 TI - The tearing patient. PMID- 27939417 TI - [Quality of life after robotic prostatectomy: Impact of BMI and age on urinary incontinence]. AB - INTRODUCTION: Data evaluating risk factors for urinary incontinence (UI) and quality of life (QoL) after robotic-assisted radical prostatectomy are scarce. The objective of our study was to explore the impact of age and body mass index (BMI) on postoperative incontinence, and the impact of such incontinence and urinary symptoms on QoL. MATERIAL AND METHODS: Two hundred and seventy two patients undergoing robotic-assisted radical prostatectomy answered the questionnaires ICIQ-UI short-form (evaluating UI) and EORTC QoL PR25 (evaluating QoL) in the preoperative setting, then at 1, 3, 12 et 24 months after surgery. Data regarding bother due to UI and urinary symptoms were extrapolated and calculated from the EORT PR25 questionnaire. The modification of ICIQ, of the bother from UI and of urinary symptoms was compared between the preoperative and the early (1-3 months) and late postoperative period (12-24 months). Differences of these scores were explored across non-obese and obese patients, as well as across different age groups. Chi-squared and logistic regression models were performed to test the association between BMI, age and ICIQ score, the bother from UI and urinary symptom score. RESULTS: Median age was 64 years and median BMI was 26.4kg/m2. After surgery, all scores (ICIQ, bother from UI and urinary symptoms) were significantly modified and worsened compared to preoperative values; in particular, median ICIQ passed from 1 to 10, 20% of patients were highly bothered by their urinary symptoms (compared to 2% in the preoperative setting) and the urinary score symptom passed from 8% to 33%. We observed a progressive amelioration of all scores of late controls (12-24 months), with a significantly improved QoL. Across BMI groups, we did not observe any significant difference in terms of modification of ICIQ, of the bother from UI or of urinary symptoms. Moreover, on multivariate logistic regression, BMI was not a risk factor for UI at neither 1 month (P>0.35) nor 12 months (P=0.35). On the other hand, age was significantly associated to an increased risk of UI in the immediate postoperative period on multivariate analysis (P<0.001). Indeed, the rate of patients with an ICIQ>=1 in the immediate postoperative period was higher in men>60 years old compared to younger men<60 years (96% vs 78%, P<0.001). When exploring the QoL scores, we did not observe any significant association between age and QoL, with the exception of an inversion correlation between age and urinary symptoms at 1 month after surgery (P=0.01). CONCLUSION: In this study, after robotic-assisted radical prostatectomy, older men appear to be at increased risk of immediate postoperative incontinence when compared to their younger counterparts, although their QoL is less likely to be bothered. BMI instead was not significantly associated to either urinary incontinence nor to QoL scores as bother form UI and urinary symptoms. LEVEL OF EVIDENCE: 4. PMID- 27939419 TI - Traditional medicine among people of Pakistani descent in the capital region of Copenhagen. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Studies show that ethnic minorities continue to use their cultural traditional medicines also after migration to the West. Research in this field is necessary, given that little is known about traditional medicines' impact on health-related problems. This study sheds light on the issue through a qualitative study among ethnic Pakistanis residing in Denmark. AIM OF THE STUDY: The study addresses perception, knowledge and attitudes regarding the use of medicinal plants among Pakistanis living in Copenhagen. We furthermore document and identify the medicinal plants used in households. MATERIALS AND METHODS: Data were collected through in-depth, semi-structured interviews with sixteen ethnic Pakistanis aged 30-80 years. Interviews were transcribed verbatim and analysed through Emerson's two-phased analysis method. Medicinal plant products in the interviewees' households were collected, photographed, identified and deposited at Museum of Natural Medicine at University of Copenhagen. RESULTS: A total number of 121 Pakistani traditional medicines were identified, and found to represent both medicinal plants and foods. The average number of quoted Pakistani Traditional Medicines was 18 (N=16). Interviewees independently reported the same traditions for preparation and consumption of Pakistani traditional medicines. Factors that play a role in choosing to use Pakistani traditional medicines are frequent visits to Pakistan, belief in the healing power of totkas (homemade medicinal preparation), religious knowledge and the occurrence of recent illness within the family. Further, the upkeep of traditional use depends on the availability of Pakistani traditional medicines. CONCLUSION: The study enhanced understanding of ethnic Pakistanis' perception and continued use of traditional medicines within the household after migration to the West. In the context of Western biomedicine, little is known of the potential toxicity and side-effects of many of the Pakistani traditional medicines found to be used in households in Copenhagen. PMID- 27939418 TI - Loudness and pitch perception using Dynamically Compensated Virtual Channels. AB - Reducing power consumption is important for the development of smaller cochlear implant (CI) speech processors. Simultaneous electrode stimulation may improve power efficiency by minimizing the required current applied to a given electrode. Simultaneous in-phase stimulation on adjacent electrodes (i.e. virtual channels) can be used to elicit pitch percepts intermediate to the ones provided by each of the physical electrodes in isolation. Virtual channels are typically implemented in monopolar stimulation mode, producing broad excitation patterns. Focused stimulation may reduce the excitation patterns, but is inefficient in terms of power consumption. To create a more power efficient virtual channel, we developed the Dynamically Compensated Virtual Channel (DC-VC) using four adjacent electrodes. The two central electrodes are current steered using the coefficient alpha (034 (c-statistic, 0.98). This model also performed well in small for gestational age infants (c-statistic, 0.998). DISCUSSION: The development of a point-of-care mechanism to allow widespread implementation of postnatal gestational age prediction tools that make use of hemoglobin or non mass spectromietry-derived metabolites could serve areas where antenatal gestational age dating is not routinely available. PMID- 27939427 TI - A developmental study of glutamatergic neuron populations in the ventrobasal and the lateral geniculate nucleus of the thalamus: Comparing Genetic Absence Rats from Strasbourg (GAERS) and normal control wistar rats. AB - An imbalance of GABAergic inhibition and glutamatergic excitation is suspected to be the cause of absence epileptic seizures. Absence seizures are known to be generated in thalamocortical circuitry. In the present study we used light microscopy immunohistochemistry to quantify the density of glutamate+ve neurons at two developmental stages (P10 and P60) in two thalamic nuclei, the ventrobasal (VB) and lateral geniculate nucleus (LGN) in Wistar rats and compared the results with similar data obtained from genetic absence epilepsy rats from Strasbourg (GAERS). Rats were perfused transcardially with glutaraldehyde and paraformaldehyde fixative, then samples from VB and LGN were removed from each animal and sectioned. The glutamatergic neurons were labelled using light microscopic glutamate immunohistochemistry. The disector method was used to quantify the glutamate+ve neurons in VB and LGN of GAERS and Wistar rats. The data were statistically analyzed. The distribution of the glutamate+ve neurons in the VB thalamic nucleus showed a significant reduction in the neuronal profiles per unit thalamic area from P10 to P60 in both Wistar and GAERS. The decrease was greater in the GAERS compared to the Wistar animals. However, in the LGN no reduction was observed either in the Wistar or in the GAERS. Comparing the density of glutamate+ve neurons in the VB thalamic nucleus of P10 of Wistar animals with of P10 GAERS showed statistically significant greater densities of these neurons in GAERS than in the Wistar rats. However no significant difference was present at P60 between the Wistar and GAERS animals. The disproportional decrease in GAERS may be related to the onset of absence seizures or may be related to neurogenesis of absence epilepsy. PMID- 27939426 TI - Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer. AB - : Artemisinin (ARS) and its derivatives, which are clinically used antimalarial agents, have shown antitumor activities. Their therapeutic potencies, however, are limited by their low solubility and poor bioavailability. Here, through a pharmacophore hybridization strategy, we synthesized ARS-drug conjugates, in which the marketed chemotherapeutic agents chlorambucil, melphalan, flutamide, aminoglutethimide, and doxifluridine, were separately bonded to Dihydroartemisinin (DHA) through various linkages. Of these, the artemisinin melphalan conjugate, ARS4, exhibited most toxicity to human ovarian cancer cells but had low cytotoxicity to normal cells. ARS4 inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis, and inhibition of migration; these effects were stronger than those of its parent drugs, DHA and melphalan. Furthermore, ARS4 modulated the expression of proteins involved in cell cycle progression, apoptosis, and the epithelial-mesenchymal transition (EMT). Moreover, in mice, ARS4 inhibited growth and intraperitoneal dissemination and metastasis of ovarian cancer cells without observable toxic effects. Our results provide a basis for development of the compound as a chemotherapeutic agent. RESEARCH IN CONTEXT: Artemisinin compounds have recently received attention as anticancer agents because of their clinical safety profiles and broad efficacy. However, their therapeutic potencies are limited by low solubility and poor bioavailability. Here, we report that ARS4, an artemisinin melphalan conjugate, possesses marked in-vitro and in-vivo antitumor activity against ovarian cancer, the effects of which are stronger than those for its parent drugs, Dihydroartemisinin and melphalan. In mice, ARS4 inhibits localized growth of ovarian cancer cells and intraperitoneal dissemination and metastasis without appreciable host toxicity. Thus, for patients with ovarian cancer, ARS4 is a promising chemotherapeutic agent. PMID- 27939429 TI - Prevalence of Hepatitis C Screening in an HIV Primary Care Clinic. PMID- 27939428 TI - Perceived exertion is as effective as the perceptual strain index in predicting physiological strain when wearing personal protective clothing. AB - OBJECTIVE: The perceptual strain index (PeSI) has been shown to overcome the limitations associated with the assessment of the physiological strain index (PSI), primarily the need to obtain a core body temperature measurement. The PeSI uses the subjective scales of thermal sensation and perceived exertion (RPE) to provide surrogate measures of core temperature and heart rate, respectively. Unfortunately, thermal sensation has shown large variability in providing an estimation of core body temperature. Therefore, the primary aim of this study was to determine if thermal comfort improved the ability of the PeSI to predict the PSI during exertional-heat stress. METHODS: Eighteen healthy males (age: 23.5years; body mass: 79.4kg; maximal aerobic capacity: 57.2ml.kg-1.min-1) wore four different chemical/biological protective garments while walking on treadmill at a low (<325W) or moderate (326-499W) metabolic workload in environmental conditions equivalent to wet bulb globe temperatures 21, 30 or 37 degrees C. Trials were terminated when heart rate exceeded 90% of maximum, when core body temperature reached 39 degrees C, at 120min or due to volitional fatigue. Core body temperature, heart rate, thermal sensation, thermal comfort and RPE were recorded at 15min intervals and at termination. Multiple statistical methods were used to determine the most accurate perceptual predictor. RESULTS: Significant moderate relationships were observed between the PeSI (r=0.74; p<0.001), the modified PeSI (r=0.73; p<0.001) and unexpectedly RPE (r=0.71; p<0.001) with the PSI, respectively. The PeSI (mean bias: -0.8+/-1.5 based on a 0-10 scale; area under the curve: 0.887), modified PeSI (mean bias: -0.5+/-1.4 based on 0-10 scale; area under the curve: 0.886) and RPE (mean bias: -0.7+/-1.4 based on a 0 10 scale; area under the curve: 0.883) displayed similar predictive performance when participants experienced high-to-very high levels of physiological strain. CONCLUSIONS: Modifying the PeSI did not improve the subjective prediction of physiological strain. However, RPE provided an equally accurate prediction of physiological strain, particularly when high-to-very high levels of strain were observed. Therefore, given its predictive performance and user-friendliness, the evidence suggests that RPE in isolation is a practical and cost-effective tool able to estimate physiological strain during exertional-heat stress under these work conditions. PMID- 27939430 TI - Implications of the thyroid hormone on neuronal development with special emphasis on the calmodulin-kinase IV pathway. AB - Thyroid hormones influence brain development through regulation of gene expression. This is especially true for Ca2+-dependent regulation since a major pathway is controlled by the Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) which in turn is induced by the thyroid hormone T3. In addition, CaMKIV is involved in regulation of alternative splicing of a number of protein isoforms, among them PMCA1a, the neuronal specific isoform of the plasma membrane calcium pump. On the other hand, hypothyroidism or CaMKIV deficiency can have a severe influence on brain development. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. PMID- 27939431 TI - Crosstalk between different family members: IL27 recapitulates IFNgamma responses in HCC cells, but is inhibited by IL6-type cytokines. AB - Interleukin-27 (IL27) is a type-I-cytokine of the IL6/IL12 family predominantly secreted by activated macrophages and dendritic cells. In the liver, IL27 expression was observed to be upregulated in patients with hepatitis B, and sera of hepatocellular carcinoma (HCC) patients contain significantly elevated levels of IL27 compared to healthy controls or patients with hepatitis and/or liver cirrhosis. In this study, we show that IL27 induces STAT1 and STAT3 phosphorylation in 5 HCC lines and 3 different types of non-transformed liver cells. We were especially interested in the relevance of the IL27-induced STAT3 activation in liver cells. Thus, we compared the IL27 responses with those induced by IFNgamma (STAT1-dominated response) or IL6-type cytokines (IL6, hyper IL6 (hy-IL6) or OSM) (STAT3-dominated response) by microarray analysis and find that in HCC cells, IL27 induces an IFNgamma-like, STAT1-dependent transcriptional response, but we do not find an effective STAT3-dependent response. Validation experiments corroborate the finding from the microarray evaluation. Interestingly, the availability of STAT1 seems critical in the shaping of the IL27 response, as the siRNA knock-down of STAT1 revealed the ability of IL27 to induce the acute-phase protein gamma-fibrinogen, a typical IL6 family characteristic. Moreover, we describe a crosstalk between the signaling of IL6 type cytokines and IL27: responses to the gp130-engaging cytokine IL27 (but not those to IFNs) can be inhibited by IL6-type cytokine pre-stimulation, likely by a SOCS3-mediated mechanism. Thus, IL27 recapitulates IFNgamma responses in liver cells, but differs from IFNgamma by its sensitivity to SOCS3 inhibition. PMID- 27939432 TI - Regulation of microRNA expression in vascular smooth muscle by MRTF-A and actin polymerization. AB - The dynamic properties of the actin cytoskeleton in smooth muscle cells play an important role in a number of cardiovascular disease states. The state of actin does not only mediate mechanical stability and contractile function but can also regulate gene expression via myocardin related transcription factors (MRTFs). These transcriptional co-activators regulate genes encoding contractile and cytoskeletal proteins in smooth muscle. Regulation of small non-coding microRNAs (miRNAs) by actin polymerization may mediate some of these effects. MiRNAs are short non-coding RNAs that modulate gene expression by post-transcriptional regulation of target messenger RNA. In this study we aimed to determine a profile of miRNAs that were 1) regulated by actin/MRTF-A, 2) associated with the contractile smooth muscle phenotype and 3) enriched in muscle cells. This analysis was performed using cardiovascular disease-focused miRNA arrays in both mouse and human cells. The potential clinical importance of actin polymerization in aortic aneurysm was evaluated using biopsies from mildly dilated human thoracic aorta in patients with stenotic tricuspid or bicuspid aortic valve. By integrating information from multiple qPCR based miRNA arrays we identified a group of five miRNAs (miR-1, miR-22, miR-143, miR-145 and miR-378a) that were sensitive to actin polymerization and MRTF-A overexpression in both mouse and human vascular smooth muscle. With the exception of miR-22, these miRNAs were also relatively enriched in striated and/or smooth muscle containing tissues. Actin polymerization was found to be dramatically reduced in the aorta from patients with mild aortic dilations. This was associated with a decrease in actin/MRTF-regulated miRNAs. In conclusion, the transcriptional co-activator MRTF A and actin polymerization regulated a subset of miRNAs in vascular smooth muscle. Identification of novel miRNAs regulated by actin/MRTF-A may provide further insight into the mechanisms underlying vascular disease states, such as aortic aneurysm, as well as novel ideas regarding therapeutic strategies. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. PMID- 27939433 TI - Measuring Ca2+ inside intracellular organelles with luminescent and fluorescent aequorin-based sensors. AB - GFP-Aequorin Protein (GAP) can be used to measure [Ca2+] inside intracellular organelles, both by luminescence and by fluorescence. The low-affinity variant GAP3 is adequate for ratiometric imaging in the endoplasmic reticulum and Golgi apparatus, and it can be combined with conventional synthetic indicators for simultaneous measurements of cytosolic Ca2+. GAP is bioorthogonal as it does not have mammalian homologues, and it is robust and functionally expressed in transgenic flies and mice, where it can be used for Ca2+ measurements ex vivo and in vivo to explore animal models of health and disease. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. PMID- 27939434 TI - Reconstruction of randomly under-sampled spectra for in vivo13C magnetic resonance spectroscopy. AB - PURPOSE: Over the past decade, many techniques have been developed to reduce radiofrequency (RF) power deposition associated with proton decoupling in in vivo Carbon-13 (13C) magnetic resonance spectroscopy (MRS). In this work we propose a new strategy that uses data under-sampling to achieve reduction in RF power deposition. MATERIALS AND METHODS: Essentially, proton decoupling is required only during randomly selected segments of data acquisition. By taking advantage of the sparse spectral pattern of the carboxylic/amide region of in vivo13C spectra of brain, we developed an iterative algorithm to reconstruct spectra from randomly under-sampled data. Fully sampled data were used as references. Reconstructed spectra were compared with the fully sampled references and evaluated using residuals and relative signal intensity errors. RESULTS: Numerical simulations and in vivo experiments at 7Tesla demonstrated that this novel decoupling and data processing strategy can effectively reduce decoupling power deposition by greater than 30%. CONCLUSION: This study proposes and evaluates a novel approach to acquire 13C data with reduced proton decoupling power deposition and reconstruct in vivo13C spectra of carboxylic/amide metabolite signals using randomly under-sampled data. Because proton decoupling is not needed over a significant portion of data acquisition, this novel approach can effectively reduce the required decoupling power and thus SAR. It opens the possibility of performing in vivo13C experiments of human brain at very high magnetic fields. PMID- 27939435 TI - Brain imaging: Comparison of T1W FLAIR BLADE with conventional T1W SE. AB - INTRODUCTION: Although T1 weighted spin echo (T1W SE) images are widely used to study anatomical details and pathologic abnormalities of the brain, its role in delineation of lesions and reduction of artifacts has not been thoroughly investigated. BLADE is a fairly new technique that has been reported to reduce motion artifacts and improve image quality. OBJECTIVE: The primary objective of this study is to compare the quality of T1-weighted fluid attenuated inversion recovery (FLAIR) images with BLADE technique (T1W FLAIR BLADE) and the quality of T1W SE images in the MR imaging of the brain. The goal is to highlight the advantages of the two sequences as well as which one can better reduce flow and motion artifacts so that the imaging of the lesions will not be impaired. MATERIALS AND METHODS: Brain examinations with T1W FLAIR BLADE and T1W SE sequences were performed on 48 patients using a 1.5T scanner. These techniques were evaluated by two radiologists based on: a) a qualitative analysis i.e. overall image quality, presence of artifacts, CSF nulling; and b) a quantitative analysis of signal-to-noise ratios (SNR), contrast-to-noise ratios (CNR) and Relative Contrast. The statistical analysis was performed using the Kruskal Wallis non-parametric system. RESULTS: In the qualitative analysis, BLADE sequences had a higher scoring than the conventional sequences in all the cases. The overall image quality was better on T1W FLAIR BLADE. Motion and flow-related artifacts were lower in T1W FLAIR BLADE. Regarding the SNR measurements, T1W SE appeared to have higher values in the majority of cases, whilst T1W-FLAIR BLADE had higher values in the CNR and Relative Contrast measurements. CONCLUSION: T1W FLAIR BLADE sequence appears to be superior to T1W SE in overall image quality and reduction of motion and flow-pulsation artifacts as well as in nulling CSF and has been preferred by the clinicians. T1W FLAIR BLADE may be an alternative approach in brain MRI imaging. PMID- 27939436 TI - MR imaging findings in mild traumatic brain injury with persistent neurological impairment. AB - : Traumatic brain injury (TBI) is a widespread cause of neurologic disability, with >70% of cases being mild in severity. Magnetic resonance imaging provides objective biomarkers in the diagnosis of brain injury by detecting brain lesions resulting from trauma. This paper reports on the detection rates of presumed trauma-related pathology using fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted imaging (SWI) in TBI patients with chronic, persistent symptoms. METHODS: 180 subjects with persistent neurobehavioral symptoms following head trauma referred by personal injury attorneys and 94 asymptomatic, age-matched volunteers were included in the study. 83% of TBI subjects were classified as mild. RESULTS: TBI subjects had a significantly greater number of lesions detected by FLAIR than controls (42% vs. 22%) and more lesions detected by SWI than controls (28% vs. 3%). To reduce the confounding effects of aging, we examined mild TBI subjects <45years of age, which reduced the rate of lesions detected by FLAIR (26% vs. 2%) and SWI (15% vs. 0%). This younger group, which contained few age-related lesions, also demonstrated that subcortical lesions on FLAIR are more specific for TBI than deeper lesions. CONCLUSIONS: While the presence of litigation in mild TBI cases with incomplete recovery has been associated with greater expression of symptomatology and, by extension, poorer outcomes, this study shows that mild TBI patients in litigation with chronic, persistent symptoms may have associated brain injury underlying their symptoms detectable by MRI biomarkers. PMID- 27939438 TI - Emission characteristic of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) from medical waste incinerators (MWIs) in China in 2016: A comparison between higher emission levels of MWIs and lower emission levels of MWIs. AB - Emission characteristic of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) from 12 medical waste incinerators (MWIs) which have a total yearly capacity of 523 440 ton medical waste and accounted for 8.1% of total yearly capacity of 246 MWIs in China were studied. The congeners profile, emissions and toxic equivalent concentrations (TEQ) indicators of PCDD/Fs in stack gas from two groups of MWIs were researched, and the possible formation mechanisms of PCDD/Fs from MWIs were preliminarily discussed. The results of present study were summarized as follows. (1) The total concentrations and TEQ of PCDD/Fs in stack gas from MWIs were 0.516-122.803 ng Nm-3 and 0.031-3.463 ng I TEQ Nm-3, respectively. (2) 1,2,3,4,6,7,8-H7CDF, O8CDD, O8CDF and 1,2,3,4,6,7,8 H7CDD were the indicatory PCDD/Fs of MWI source, which could be used to apportion the sources of PCDD/Fs in environmental medium in China. (3) The emission factors of PCDD/Fs from MWIs ranged from 32.7 to 4900.0 ng I-TEQ ton-1 with a mean of 1923.6 ng I-TEQ ton-1. (4) The gas emissions of PCDD/Fs from researched 12 MWIs and all of MWIs in China in 2016 were 37.742 and 465.951 mg I-TEQ year-1, respectively. (5) 1,2,3,7,8,9-H6CDF and 1,2,3,4,7,8-H6CDF were effective TEQ indicators for the real-time monitoring of the PCDD/Fs emission. (6) The congeners profile and factor composition of PCDD/Fs in stack gas from two groups of MWIs were researched based on positive matrix factorization (PMF) model, and the possible formation mechanisms of PCDD/Fs from MWIs were preliminarily discussed. PMID- 27939439 TI - Early prosthetic valve infective endocarditis in the elderly: Changes over a 28 year period (1987-2014). PMID- 27939437 TI - The dual enzyme LRRK2 hydrolyzes GTP in both its GTPase and kinase domains in vitro. AB - The evolutionarily conserved enzyme encoded by the leucine-rich repeat kinase 2 gene, LRRK2, harbors both a Rab-like GTPase domain and a serine/threonine protein kinase domain. Pathogenic mutations in either the GTPase or kinase domain can cause neurodegeneration and Parkinson disease. No high-resolution structure of the human LRRK2 kinase domain is available but the most common mutation, G2019S in the kinase domain, is predicted to alter the ATP-binding pocket structure and interaction with divalent cations. Here we find that the manganese-bound kinase domain acquires a robust ability to utilize both GTP as well as ATP in autophosphorylation of the GTPase domain and phosphorylation of peptide substrates in vitro. The G2019S LRRK2 mutation increases the efficiency of GTP mediated kinase activity ten-fold compared to WT LRRK2 activity. Moreover, GTP dependent phosphorylation alters autophosphorylation-site preference in vitro. While additional studies are required to determine the physiological relevance of these observations, LRRK2 is one of the only known kinases to be able to utilize GTP as a phospho-donor at physiological levels in vitro, and thus one of the only known proteins to be able to hydrolyze GTP in two distinct domains within the same protein. PMID- 27939440 TI - Correlation study between genotype and phenotype: Success or failure? PMID- 27939441 TI - Cardiovascular risk factors, nonvalvular atrial fibrillation and retinal vein occlusion. AB - OBJECTIVES: To analyse the importance of cardiovascular risk factors, ultrasound findings in the supra-aortic trunk and the presence of anticoagulated nonvalvular atrial fibrillation (NVAF) in patients with retinal vein occlusion (RVO) and in a control group. PATIENTS AND METHODS: A cross-sectional study was conducted of all patients with RVO consecutively referred to the office of internal medicine, comparing them with a control group. We analysed clinical, electrocardiographic and ultrasound variables. RESULTS: We studied 212 patients (114 men and 98 women) with RVO and 212 controls (95 men and 117 women) of similar ages. Arterial hypertension, dyslipidaemia and diabetes mellitus were significantly more prevalent in the patients with RVO than in the controls (73.6 vs. 50%, 64.6 vs. 48.6% and 27.8 vs. 12.3%, respectively). We observed arteriosclerotic lesions in the supra-aortic trunk in 55% of the patients with RVO. The patients with RVO and NVAF had a greater burden of cardiovascular risk factors than the controls with NVAF. There were no differences in terms of the international normalised ratio or in the use of direct anticoagulants between the cases and controls with NVAF. CONCLUSIONS: Cardiovascular risk factors (especially arterial hypertension) and arteriosclerotic involvement of the supra-aortic trunk are highly prevalent in RVO. Anticoagulation does not appear to be effective in preventing RVO. PMID- 27939442 TI - Neuroma of the distal posterior interosseous nerve as a cause of persistent dorsal wrist pain. AB - Dorsal wrist pain is a very common cause of complaint in the clinical practice of the hand surgeon. Such pain can frequently be related to traumatic, inflammatory or degenerative diseases, but sometimes its origin is far away from these common causes. A rare case is reported of chronic dorsal wrist pain of neuropathic origin, due to a pre-capsular neuroma of the posterior interosseous nerve. Possible causes, diagnostic hints, and treatment options are thoroughly discussed. PMID- 27939445 TI - Changes in adipose tissue cellular composition during obesity and aging as a cause of metabolic dysregulation. AB - Adipose tissue represents complex endocrine organ containing several different cellular populations including adipocytes, pre-adipocytes, mesenchymal stem cells, macrophages and lymphocytes. It is well establishing that these populations are not static but alter during obesity and aging. Changes in cellular populations alter inflammatory status and other common metabolic complications arise, therefore adipose tissue cellular composition helps dictate its endocrine and regulatory function. During excessive weight gain in obese individuals and as we age there is shift towards increase populations of inflammatory macrophages with a decrease of regulatory T cell. This altered cellular composition promote chronic low grade inflammation negatively affecting mesenchymal stem cell progenitor self-renewal, which result in deterioration of adipogenesis and increased cellular stress in adipocytes. All these changes promote metabolic disorders including age- or obese-related insulin resistance leading to type 2 diabetes. PMID- 27939446 TI - Classification Systems of Secondary Active Transporters. AB - Membrane-bound solute carrier (SLC) transporter proteins are vital to the human body, as they sustain homeostasis by moving soluble molecule as nutrients, drugs, and waste across lipid membranes. Of the 430 identified secondary active transporters in humans, 30% are still orphans, and systematic research has been requested to elaborate on their possible involvement in diseases and their potential as drug targets. To enable this, the various classification systems in use must be understood and used correctly. In this review, we describe how various classification systems for human SLCs are constructed, and how they overlap and differ. To facilitate communication between researchers and to avoid ambiguities, everyone must clearly state which classification system they are referring to when writing scientific articles. PMID- 27939443 TI - Anxiety symptoms and disorders among adults living with HIV and AIDS: A critical review and integrative synthesis of the empirical literature. AB - There are over 35 million people worldwide infected with the Human Immunodeficiency Virus (HIV) and its progression to Acquired Immunodeficiency Syndrome (AIDS; WHO, 2014). With the advent of combined antiretroviral therapy (i.e., cART) in 1996, persons living with HIV/AIDS (PLWHA) now have much longer life expectancies. However, living with HIV remains challenging, as it is associated with a number of significant and recurrent (chronic) stressors including physical pain, side effects of cART, social stigma, and discrimination, among other social stressors. Presumably, as a result of these types of stressors, a disproportionately high number of PLWHA struggle with clinically significant psychiatric symptoms and disorders. Although much scientific and clinical attention has focused on depressed mood and psychopathology among PLWHA, there has been comparably less focus on anxiety and its disorders. The paucity of work in this area is concerning from a public health perspective, as anxiety symptoms and disorders are the most common class of psychiatric disorders and often maintain a large negative impact on life functioning. PMID- 27939444 TI - The influence of vitamins E and C and exercise on brain aging. AB - Age-related declines in motor and cognitive function have been associated with increases in oxidative stress. Accordingly, interventions capable of reducing the oxidative burden would be capable of preventing or reducing functional declines occurring during aging. Popular interventions such as antioxidant intake and moderate exercise are often recommended to attain healthy aging and have the capacity to alter redox burden. This review is intended to summarize the outcomes of antioxidant supplementation (more specifically of vitamins C and E) and exercise training on motor and cognitive declines during aging, and on measures of oxidative stress. Additionally, we will address whether co-implementation of these two types of interventions can potentially further their individual benefits. Together, these studies highlight the importance of using translationally-relevant parameters for interventions and to study their combined outcomes on healthy brain aging. PMID- 27939448 TI - Topographic distribution of serotonin-immunoreactive urethral endocrine cells and their relationship with calcitonin gene-related peptide-immunoreactive nerves in male rats. AB - We investigated the topographic distribution and morphology of serotonin (5-HT) immunoreactive endocrine cells in the urethra of male rats, and focused on their relationship with peptidergic nerve fibers immunoreactive for calcitonin gene related peptide (CGRP). Urethral endocrine cells immunoreactive for 5-HT were densely distributed in the epithelial layers of the prostatic part, but were sparsely distributed in the membranous and spongy parts of urethra. Distribution of urethral endocrine cells with 5-HT immunoreactivity in the prostatic part was restricted from the internal urethral orifice to the region of seminal colliculus. 5-HT-immunoreactive endocrine cells were also observed in the ductal epithelial layers of coagulating glands, prostatic glands, and seminal vesicles. 5-HT-immunoreactive endocrine cells were triangular or flask in shape and possessed an apical projection extending toward the urethral lumen, and basal or lateral protrusions intruding between other epithelial cells were also detected in some cells. Double immunolabeling for 5-HT and CGRP revealed that CGRP immunoreactive nerve fibers attached to urethral endocrine cells with 5-HT immunoreactivity in the prostatic part. These results suggest that urethral endocrine cells may release 5-HT in response to luminal stimuli, and that these cells and CGRP-immunoreactive nerves may regulate each other by an axon reflex mechanism. PMID- 27939447 TI - Differential response and withdrawal profile of glucocorticoid-treated human trabecular meshwork cells. AB - The goal of the study was to examine secreted protein response and withdrawal profiles from cultured human trabecular meshwork (HTM) cells following short- and long-term glucocorticoid treatment. Primary cultures of five human HTM cell strains isolated from 5 different individual donor eyes were tested. Confluent HTM cells were differentiated in culture media containing 1% FBS for at least one week, and then treated with Dexamethasone (Dex, 100 nM) 3 times/week for 1 or 4 weeks. Cell culture supernatants were collected 3 times per week for 8 weeks. Secretion profiles of myocilin (MYOC), matrix metalloproteinase-2 (MMP2) and fibronectin (FN) were determined by Western blot analysis and MMP2 activity by zymography. Dex treatment reduced MMP2 expression and activity, returning to normal levels shortly after Dex withdrawal in 5 HTM cell strains. All five cell strains significantly upregulated MYOC in response to Dex treatment by an average of 17-fold, but recovery to basal levels after Dex withdrawal took vastly different periods of time depending on cell strain and treatment duration. Dex treatment significantly increased FN secretion in all strains but one, which decreased FN secretion in the presence of Dex. Interestingly, secretion of FN and MYOC negatively correlated during a 4 week recovery period following 4 weeks of Dex treatment. Taken together, the time course and magnitude of response and recovery for three different secreted, extracellular matrix-associated proteins varied greatly between HTM cell strains, which may underlie susceptibility to glucocorticoid-induced ocular hypertension. PMID- 27939450 TI - Comparative histochemistry of posterior lingual salivary glands of mouse. AB - Normal posterior deep and superficial salivary glands of tongue were examined in male mice by means of light microscopical histochemistry and neurohistology. Both glands showed acini and simple ducts. Demilunes were present in the superficial gland. Disulphides and neutral mucosubstances occurred in acini and demilunes. Tryptophan staining was seen in acini of the deep gland and demilunes, whereas acid mucosubstances were exclusively localised in the superficial gland. Dehydrogenase activities were widespread. Strong esterase activity occurred throughout the parenchyma of the deep gland and in demilunes; it was variably inhibited by E600, apart from acinar apical regions in the deep gland. Lipase was confined to acini of the deep gland and demilunes. Acid phosphatase staining was similarly localised; it was also seen in periluminal ductal rims of the deep gland, in which ouabain-sensitive Na,K-ATPase was localised basolaterally. Staining for alkaline phosphatase decorated occasional myoepithelial-like arrangements and interstitial capillaries. Acetylcholinesterase was associated with nerve fibres embracing glandular parenchyma. Adrenergic fibres were not seen. The results suggest that the acini of the posterior deep lingual gland secrete neutral glycoproteins, whereas the ducts transport ions and absorb luminal material. The posterior superficial lingual gland mainly secretes acid glycoproteins. Both glands produce lingual lipase, receive cholinergic-type innervation and have inconspicuous myoepithelium. PMID- 27939449 TI - Involvement of PI3K and PKA pathways in mouse tongue epithelial differentiation. AB - In mice, tongue epithelial differentiation is mainly regulated by the interactions among various signalling molecules including Fgf signalling pathways. However, the subsequent signalling modulations for epithelial maturation, initiated by Fgf signalling, remain to be elucidated. Therefore, we employed an in vitro tongue organ cultivation system along with the applications of various pharmacological inhibitors against the intracellular signalling molecules of Fgf signalling pathways, including H89, LY294002, PD98059, and U0126. Following treatments with LY294002 and H89, inhibitors for PI3K and PKA, respectively, the decreased thickness of the tongue epithelium was observed along with the alteration in cell proliferative and apoptotic patterns. Meanwhile, cultivated tongues treated with MEK inhibitor U0126 or PD98059 showed significantly decreased cell proliferation in the tongue epithelium and the mesenchyme. Based on these results, we suggest that the tongue epithelium is differentiated into multiple epithelial cell layers via the PI3K and PKA pathways in tissue-specific manner during the epithelial-mesenchymal interactions. PMID- 27939452 TI - MHC Bias by T Cell Receptors: Genetic Evidence for MHC and TCR Coevolution. AB - Major histocompatibility complex (MHC) restriction is a fundamental tenet of T cell biology, but the underlying mechanisms have remained controversial. The extent to which T cell receptors (TCRs) are biased towards MHC proteins in particular has been widely discussed. In a recent paper, Sharon et al. report direct evidence for coevolution between TCR and MHC genes, helping to explain how MHC compatibility and bias can be encoded within TCRs. PMID- 27939451 TI - Transcriptional Regulation of Tissue-Resident Lymphocytes. AB - Numerous innate and adaptive immune cells reside in non-lymphoid tissues, where they contribute to barrier immunity, tissue homeostasis, and immune regulation. These tissue-resident populations do not recirculate in the blood or lymphatics and adopt a unique phenotype that is distinct from immune cells in the circulation. Tissue residency has been predominantly described for memory CD8+ T cells [tissue-resident memory T cells (TRM)], but it is now clear that CD4 T cells, regulatory T (Treg) cells, various innate T cells, and innate lymphoid cells (ILCs) can establish residence in non-lymphoid tissues. Here we highlight distinct and common features of tissue-resident lymphocytes, with a focus on the transcriptional programs that have recently been shown to guide the establishment of tissue residency. PMID- 27939453 TI - TLR3 and skin features. PMID- 27939454 TI - Skin and brain repair: New prospects in the life of a couple. PMID- 27939455 TI - The role of myofibroblasts in wound healing. AB - The importance of proper skin wound healing becomes evident when our body's repair mechanisms fail, leading to either non-healing (chronic) wounds or excessive repair (fibrosis). Chronic wounds are a tremendous burden for patients and global healthcare systems and are on the rise due to their increasing incidence with age and diabetes. Curiously, these same risk factors also sign responsible for the development of hypertrophic scarring and organ fibrosis. Activated repair cells - myofibroblasts - are the main producers and organizers of extracellular matrix which is needed to restore tissue integrity after injury. Too many myofibroblasts working for too long cause tissue contractures that ultimately obstruct organ function. Insufficient myofibroblast activation and activities, in turn, prevents normal wound healing. This short review puts a spotlight on the myofibroblast for those who seek therapeutic targets in the context of dysregulated tissue repair. "Keep your myofibroblasts in balance" is the message. PMID- 27939456 TI - Modelling atopic dermatitis during the morphogenetic process involved in reconstruction of a human epidermis. AB - Most crucial role of epidermis is to maintain efficient barrier between the organism and its environment. This barrier is however perturbed in inflammatory skin conditions like atopic dermatitis (AD), one common chronic disease. This review depicts characteristics of a model intending to reproduce epidermal features of AD in vitro. Firstly, methyl-beta-cyclodextrin (MbetaCD) during reconstruction of epidermis was used to deplete cholesterol from plasma membrane because this condition reproduces characteristics of AD at transcriptomic level in monolayer cultures. Major changes are confirmed after same treatment inside reconstructed human epidermis (RHE). However, since early treatment do not reveal impairment to reconstruct a functional epidermal barrier and given the importance of the Th2 dysregulated immune response in AD, cholesterol-depleted RHE at day 11 of reconstruction were then incubated with three Th2-related cytokines (IL-4, IL 13 and IL-25) previously reported as playing important roles in the development of AD, as well as altering overall function of epidermal barrier. When combining both treatments, essential epidermal features of AD are observed. Indeed, RHE then exhibit spongiosis, disappearing granular layer, alteration of barrier function, as well as dysregulated expression levels for genes involved in AD pathogenesis. Moreover, while trying to identify individual roles for each component used to create AD-like alterations, incubation with IL-4 following cholesterol depletion from plasma membrane was found inducing most of the reported alterations. This model suggests potential for better investigations of epidermal AD features and may be considered for eventual in vitro screening of cosmetics or therapeutic compounds. PMID- 27939457 TI - Skin fibrosis: Models and mechanisms. AB - Matrix synthesis, deposition and remodeling are complex biological processes that are critical in development, maintenance of tissue homeostasis and repair of injured tissues. Disturbances in the regulation of these processes can result in severe pathological conditions which are associated with tissue fibrosis as e.g. in Scleroderma, cutaneous Graft-versus-Host-Disease, excessive scarring after trauma or carcinogenesis. Therefore, finding efficient treatments to limit skin fibrosis is of major clinical importance. However the pathogenesis underlying the development of tissue fibrosis is still not entirely resolved. In recent years progress has been made unraveling the complex cellular and molecular mechanisms that determine fibrosis. Here we provide an overview of established and more recently developed mouse models that can be used to investigate the mechanisms of skin fibrosis and to test potential therapeutic approaches. PMID- 27939458 TI - Evidence for physiological and pathological roles for sensory nerves in the microvasculature and skin. AB - This review highlights the progress from the initial finding of neurogenic inflammation up to the most recent development in the field of sensory nerves research, focusing on their roles in the microvasculature and the skin. Recent discovery of Transient Receptor Potential (TRP) channels highlight their important roles in detecting a range of environmental stimuli, including chemical and temperature. This provides us novel mechanisms for driving neurogenic inflammation upstream of neuropeptide release in addition to promising potential therapeutic targets in various diseases, including pain, itching and skin inflammation. PMID- 27939459 TI - Molecular mechanisms of pruritus. AB - Pruritus is an unpleasant sensation that evokes the urgent desire to scratch. It is a symptom derived from many nervous system disorders that affects a large population of humans and is treated by a variety of pharmacological agents with variable access. Chronic itch is a huge unmet health problem which affect upward 20% of people worldwide. The mechanisms underlying the chronic pruritus are complex. Studies of the neurobiology, neurophysiology and cellular biology of itch have gradually been clarifying the mechanism of chronic itch both peripherally and centrally. The discussion has been focused on pruriceptive nerves and their receptors as well as the cytokines/chemokines that play major roles in itch induction. Though it is historically hypothesized that pain convey signal generated with the stimuli under high intensity, and itch transduces signal from the same nerves of pain but under low intensity, recently, with the identification of distinct itch specific sensory afferent fibers the theory has twisted the "intensity" to a existence of a complete separation of pain and itch pathways. This review helps to understand the unique properties of itch signaling pathways and their clinical importance of the itch perception and pruritic diseases. PMID- 27939460 TI - Exploring the "brain-skin connection": Leads and lessons from the hair follicle. AB - Research into how the central nervous system (CNS) and the skin of mammals are physiologically connected and how this "brain-skin connection" may be therapeutically targeted in clinical medicine has witnessed a renaissance. A key element in this development has been the discovery that mammalian skin and its appendages, namely human scalp hair follicles (HFs), not only are important, long underestimated target tissues for classical neurohormones, neurotrophins and neuropeptides, but also are eminent peripheral tissue sources for the production and/or release of these neuromediators. This essay summarizes the many different levels of biology at which human scalp HFs respond to and generate a striking variety of neurohormones, and portrays HFs as prototypic, cyclically remodelled miniorgans that utilize these neurohormones to autoregulate their growth, hair shaft production, rhythmic organ transformation, pigmentation, mitochondrial energy metabolism, and immune status. The essay also explores how preclinical research on human scalp HFs can be exploited to unveil and explore "novel" and clinically as yet untapped, but most likely ancestral functions of neurohormones within mammalian epithelial biology that still impact substantially on human skin physiology. Arguably, systematic investigation of the "brain-skin connection" is one of the most intriguing current research frontiers in investigative dermatology, not the least since it has reversed the traditional CNS focus in studying the interactions between two key organ systems by placing the skin epithelium on center stage. PMID- 27939461 TI - Preeclampsia: Prevalence and perinatal repercussions in a University Hospital in Rio de Janeiro, Brazil. AB - Preeclampsia (PE) prevalence studies in Brazil are both scarce and not divided in accordance with gestational age at delivery. We accessed PE prevalence according to delivery before 34, 37 and 42weeks in a cross-sectional study including 4464 single deliveries. PE was diagnosed in 301 cases (6.74%); Prevalence of PE was 0.78%; 1.92% and 6.74% according to deliveries before 34, 37 and 42weeks. PE was associated with fetal death, prematurity and small for gestational age newborns. PMID- 27939462 TI - Survey of healthcare professionals regarding adjustment of antihypertensive medication(s) in the postnatal period in women with hypertensive disorders of pregnancy. AB - Hypertensive disorders of pregnancy affect approximately one in ten pregnancies and often persist postpartum. Their postnatal course can be unpredictable and complications may occur, hence control remains important but is informed by little evidence. Clinicians from UK primary and secondary healthcare were invited to complete a survey regarding antihypertensive adjustment postpartum. The response rate was 101/390 (26%). Labetalol was the commonest antihypertensive used. Most participants reported following national guidelines when reducing, although not increasing, antihypertensive medications. The results suggest an unwarranted and unjustifiable variation in management - underlining the evidence gap - additional research is needed to inform the standardisation of care. PMID- 27939463 TI - The effects of hydroxychloroquine on endothelial dysfunction. AB - Hydroxychloroquine is an anti-malarial drug which, due to its anti-inflammatory and immunomodulatory effects, is widely used for the treatment of autoimmune diseases. In a model of systemic lupus erythematosus hydroxychloroquine has been shown to exert protective endothelial effects. In this study, we aimed to investigate whether hydroxychloroquine was endothelial protective in an in vitro model of TNF-alpha and preeclamptic serum induced dysfunction. We showed that hydroxychloroquine significantly reduced the production of TNF-alpha and preeclamptic serum induced endothelin-1 (ET-1). Hydroxychloroquine also significantly mitigated TNF-alpha induced impairment of angiogenesis. These findings support the further assessment of hydroxychloroquine as an adjuvant therapy in preeclampsia. PMID- 27939464 TI - Remote monitoring of blood pressure to reduce the risk of preeclampsia related complications with an innovative use of mobile technology. AB - OBJECTIVE: Assess suitability of remote self-monitoring of blood pressure with an innovative use of technology in detecting raised blood pressure in pregnancy. STUDY DESIGN: Assess ease of use and safety of the newly developed kit which included a Bluetooth enabled blood pressure machine and an android based mobile phone. The phone was modified to have only one application in it which showed the blood pressure readings with a traffic light system. The study was a proof of concept for wider use of the kit. We provided 50 women who were admitted with the kit. We assessed ease of use of the blood pressure machine and accuracy of readings including remote transfer to a computer. MAIN OUTCOME MEASURE: Technological feasibility and acceptance by women. RESULTS: The technology provides accurate data and visual cues including safe remote transfer instantaneously. 90% of the women agreed that the Kit was simple to use and 78% would prefer this model of testing at home. CONCLUSION: In a relatively resource rich setting the machine can reduce the number of patient visits for women who are at risk for preeclampsia. In resource poor settings it helps to triage resources to women who need it the most. It also is a valuable tool for research. Studies of the Kit in both developed and developing world will be needed to show reduction in perinatal and maternal morbidity or mortality secondary to preeclampsia. PMID- 27939465 TI - Antiretrovirals causing severe pre-eclampsia. AB - BACKGROUND: Extremely low birth weight infants (ELBW) (?1000g) at our tertiary hospital have a much higher HIV exposure rate than bigger babies and are mainly delivered due to complications of pre-eclampsia. Studies investigating the effect of HIV or antiretroviral therapy on pre-eclampsia, a partially immune-mediated disease have produced contradictory results. OBJECTIVE: To determine if there was an association between pre-eclampsia and HIV and/or antiretrovirals in the mothers of ELBW infants. STUDY DESIGN: A prospective database was maintained for all ELBW infants born from August 2011 till January 2013. Data included maternal information such as HIV status, antiretroviral medication (duration and type) and mode and indication for delivery. RESULTS: Of the 195 mothers who delivered ELBW infants, 46 (24%) were HIV positive. This is significantly different to the 17% HIV prevalence in mothers with bigger children (p=0.02). The main indication (59%) for delivery of the infant was hypertension related with the majority of these (94%) being classified as pre-eclampsia. Although HIV on its own showed no association (p=0.13), mothers who received greater than 4weeks of antiretrovirals were more likely to develop severe pre-eclampsia (p=0.007). CONCLUSION: The debate about ARVs and PET is not yet over. We postulate that in a small group of susceptible women, ARVs may trigger early severe PET. It is unclear from our study if this would be due on a toxic or immune basis. PMID- 27939466 TI - The utility of first trimester uterine artery Doppler, placental volume and PAPP A levels alone and in combination to predict preeclampsia. AB - In this study, we aimed to evaluate the detection of pre-eclampsia (PE) by integrating uterine artery Doppler, placental volume, and pregnancy-associated plasma protein A (PAPP-A) levels in the first trimester. We prospectively recruited 602 women that underwent 11-13weeks' aneuploidy screening. The mean pulsatility index (PI) of the uterine arteries and the placental volume were measured by ultrasonography. Measurement of PAPP-A levels has been performed at the same day of ultrasonographic examinations. The 90th percentile of uterine artery PI and the 10th percentile of placental volume and PAPP-A levels were used as cut-offs. Uterine artery PI, placental volume, and PAPP-A levels had similar sensitivities in predicting PE (53.66%, 63.41%, and 70.73%, respectively). Use of the parameters in combination had better sensitivity. If one parameter was positive, the sensitivity was 92.68% with 85.20% specificity. If at least two parameters were positive, the sensitivity was 85.37% with 98.89% specificity. In conclusion, the combination of increased PI of uterine artery with low placental volume and low PAPP-A levels in the first trimester achieved better results than either test alone in the prediction of PE. PMID- 27939467 TI - A protocol for developing, disseminating, and implementing a core outcome set for pre-eclampsia. AB - BACKGROUND: Pre-eclampsia is a serious complication of pregnancy and contributes to maternal and offspring mortality and morbidity. Randomised controlled trials evaluating therapeutic interventions for pre-eclampsia have reported many different outcomes and outcome measures. Such variation contributes to an inability to compare, contrast, and combine individual studies, limiting the usefulness of research to inform clinical practice. The development and use of a core outcome set would help to address these issues ensuring outcomes important to all stakeholders, including patients, will be collected and reported in a standardised fashion. METHODS: An international steering group including healthcare professionals, researchers, and patients, has been formed to guide the development of this core outcome set. Potential outcomes will be identified through a comprehensive literature review and semi-structured interviews with patients. Potential core outcomes will be entered into an international, multi perspective online Delphi survey. All key stakeholders, including healthcare professionals, researchers, and patients will be invited to participate. The modified Delphi method encourages whole and stakeholder group convergence towards consensus 'core' outcomes. Once core outcomes have been agreed upon it is important to determine how they should be measured. The truth, discrimination, and feasibility assessment framework will assess the quality of potential outcome measures. High quality outcome measures will be associated with core outcomes. Mechanisms exist to disseminate and implement the resulting core outcome set within an international context. DISCUSSION: Embedding the core outcome set within future clinical trials, systematic reviews, and clinical practice guidelines could make a profound contribution to advancing the usefulness of research to inform clinical practice, enhance patient care, and improve maternal and offspring outcomes. The infrastructure created by developing a core outcome set for pre-eclampsia could be leveraged in other settings, for example selecting research priorities and clinical practice guideline development. PROSPECTIVE REGISTRATION: [1] Core Outcome Measures in Effectiveness Trials (COMET) registration number: 588. [2] International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42015015529. PMID- 27939468 TI - Benchmarking the Hypertensive Disorders of Pregnancy. AB - INTRODUCTION: The Hypertensive Disorders of Pregnancy (HDP) affect 7-10% of pregnancies worldwide and are one of the leading causes of mortality and morbidity in the perinatal period. An accurate assessment of mortality and morbidity is essential to provide effective care and treatment and benchmarking of these issues is required to enhance outcomes and define standards. AIM: To benchmark outcomes for women and babies following a diagnosis of hypertension between obstetric units in similar settings. METHODS: Utilising a set of pre defined clinical indicators, Individual Patient Data analysis techniques applied to the medical records of all women diagnosed with a HDP over a 12month period at six obstetric units within Australia and Canada. Statistical analysis included contingency table sand means testing oas appropriate utilising IBM SPSS V.18. RESULTS: Overall HDP rate of 7.6% of all deliveries, with a 3.0% preeclampsia rate. Outcomes differed significantly between units and did not cluster within any individual unit. PMID- 27939469 TI - Red blood cell distribution width: A simple parameter in preeclampsia. AB - OBJECTIVE: Preeclampsia is a serious disease and a leading cause of maternal and perinatal mortality and morbidity. Red blood cell distribution width (RDW), a measure of anisocytosis, is used as an inflammation marker in hypertension and cardiovascular diseases. Although the relationship between RDW and hypertension has been well documented, the association between preeclampsia and RDW is not clear. We aimed to investigate the relationship between RDW and preeclampsia and its severity. MATERIALS AND METHODS: One hundred eighteen pregnant women with preeclampsia and one hundred twenty uncomplicated pregnant women were included in the study. Blood samples for routine CBC and RDW levels were analyzed. RESULTS: The RDW values were significantly higher in preeclampsia group compared with the control group (15.23+/-1.96 vs 14.48+/-1.70, p<0.05). We also confirmed that RDW levels were significantly higher in severe preeclampsia group than mild preeclampsia group in subgroup analyses (15.08+/-2.07, 15.92+/-1.99, p<0.05). CONCLUSION: Our study showed that there is an association between RDW and preeclampsia and also its severity. RDW, a marker which is easy, inexpensive and calculated as a part of blood cell count, can be used as a significant diagnostic and prognostic marker in patient with preeclampsia like the other cardiovascular diseases. PMID- 27939470 TI - Butorphanol use in laboring patients with preeclampsia or chronic hypertension. AB - OBJECTIVE: The American College of Obstetricians and Gynecologists (ACOG) recommends against the use of butorphanol in patients diagnosed with preeclampsia or chronic hypertension secondary to a theoretical concern that the drug will further elevate blood pressures. No past study has examined the drug's potential to elevate blood pressures in laboring patients. METHODS: In this retrospective cohort study all chronic hypertensive and preeclamptic patients who underwent an induction of labor and delivered a viable, singleton pregnancy between the dates of 1/1/2013 and 12/31/2014 at a single academic hospital were included. RESULTS: The use of butorphanol in chronically hypertensive patients during labor was not associated with the presence of severe range blood pressures during labor (OR=0.92 95% CI: (0.04-19.34) P=0.96). In preeclamptic patients there was similarly no change in the frequency of severe range blood pressures with the use of the drug (OR=0.59 95% CI: (0.19-1.83) P=0.36). CONCLUSION: In laboring patients with chronic hypertension or preeclampsia butorphanol is not associated with severe range blood pressures, and therefore it is a reasonable option for providing pain relief in these populations. PMID- 27939471 TI - Maternal and fetal morbidity following discontinuation of antihypertensive drugs in mild to moderate chronic hypertension: A 4-year observational study. AB - OBJECTIVE: To assess maternal and fetal morbidity in women with mild to moderate chronic hypertension on antihypertensive drug therapy compared to cessation of therapy. METHODS: This was a prospective observational study included 222 women with mild to moderate chronic hypertension (systolic blood pressure of 140 159mmHg or diastolic blood pressure of 90-109mmHg) who were divided into two groups based on antihypertensive drug intake, treatment group (n=104) who received methyl dopa, and non-treatment group (n=118) who used only low dose aspirin. Patients were followed to assess maternal and fetal outcome. RESULTS: There were significant differences between the two groups regarding the development of severe hypertension (p<0.001), renal impairment (p<0.001), ECG changes (p<0.001), placental abruption (p<0.05), repeated hospital admissions (p<0.001), preterm delivery (p<0.05) and neonatal ICU admission (p<0.05) with higher occurrence in the non-treatment group. There were no significant differences between the two groups in terms of the development of preeclampsia, hepatic impairment, mode of delivery, venous thromboembolism, small for gestational age, intrauterine fetal demise or neonatal mortality (p>0.05). CONCLUSION: Maternal and fetal morbidity is increased following cessation of antihypertensive drug use in patients with mild to moderate chronic hypertension. Further larger studies are warranted to confirm or refute our findings. PMID- 27939472 TI - Total oxidative and anti-oxidative status, and ADAMTS-12 levels in placenta previa and early-onset severe preeclampsia. AB - AIM: This study was carried out due to the discussions in the literature stating that the inverse association between placenta previa (PP) and preeclampsia (PE). The aim of this study was to determine whether total antioxidant status (TAS), and total oxidant status (TOS) and ADAMTS-12 levels differ among early-onset (<34th gestational week) severe PE (EOS-PE), PP and uncomplicated pregnancies. METHODS: In this case-control study, serum samples obtained from 26 pregnant with EOS-PE, 31 pregnant with PP, and 32 healthy patients with uncomplicated pregnancies (control group). RESULTS: TOS levels were significantly higher in the EOS-PE than in the control group and PP groups (p=0.002, p=0.05, respectively). TAS levels were significantly lower in the EOS-PE than in the control (p<0.001). Although TAS levels were lower in the EOS-PE group than in the PP group, the differences were not statistically significant (p=0.09). There were no significant differences in the ADAMTS-12 levels of the groups. DISCUSSION: The data in this study suggested that the balance between oxidative and anti oxidative substances were comparable and normal in pregnancies complicated by PP when compared to normal pregnancies without placentation abnormality. In support of this, we encountered no case with PE and fetal growth restriction in our study groups suggesting normal placental angiogenesis. Contrarily, EOS-PE was associated with decreased TAS and increased TOS levels in the maternal serum. PMID- 27939473 TI - Bedside cardiovascular maternal interrogation in the first trimester to predict different phenotypes of hypertensive disorders in pregnancy. AB - OBJECTIVE: The aim is to evaluate if maternal cardiovascular indices, in the first trimester of pregnancy, might be useful to differentiate women who develop different hypertensive disorders of pregnancy (HDP). STUDY DESIGN: Method: 1399 pregnant women attending screening for chromosomal aneuploidies were recruited. The following parameters were measured: Doppler Velocimetry of uterine arteries; Peripheral blood pressure; Aortic Pressure derived from applanation tonometry. Primary outcome were: women who developed HDP associated with newborns with an appropriate weight for local gestational age standards (AGA) and women that developed HDP associated with a newborn weight below the 10th centile (SGA). RESULTS: Mean UtA PI was significantly higher in the HDP-SGA compared with controls. HDP-AGA showed a higher rate of family history of hypertension and a higher BMI. In HDP-AGA Brachial and Aortic mean pressure were higher than controls. The most significant contributors for all forms of HDP were mean UtA PI for HDP-SGA and mean arterial blood pressure for HDP-AGA. The multivariate logistic regression for HDP-SGA shows an AUC 0.88, whereas the AUC for the prediction of HDP-AGA group was 0.71. CONCLUSION: HDP-SGA were characterized by significantly higher values of UtA-PI, whereas HDP-AGA by mean aortic and brachial pressure and risk factors for endothelial dysfunction. PMID- 27939474 TI - Evaluation of fetal hypermethylated RASSF1A in pre-eclampsia and its relationship with placental protein-13, pregnancy associated plasma protein-A and urine protein. AB - OBJECTIVES: Cell free fetal DNA (cffDNA) and its hypermethylated RASSF1A gene signify a recent advancement in non-invasive prenatal diagnosis of feto-placental anomalies like pre-eclampsia. The study uses hypermethylated RASSF1A gene to quantify cffDNA and to assess its relationship with placental and urine proteins in pre-eclampsia cases. DESIGN AND METHODS: DNA was isolated from plasma samples of clinically diagnosed cases of pre-eclampsia (n=103) and normal pregnancy (n=616) from 21weeks of gestation. Through methylation sensitive enzyme (BstUI) digestion; followed by real time-polymerase chain reaction (RT-PCR), quantification of hypermethylated RASSF1A was done. Immunoassays determined: placental protein-13 (pp-13) and pregnancy associated plasma protein A (PAPP-A) and pyrogallol red molybdate assay for 24h urine protein. RESULTS: Highly significant differences between control and pre-eclampsia cases for hypermethylated RASSF1A concentrations were found; Group I: 33+/-7.35 vs 74.46+/ 16.71, Group II: 53.75+/-16.65 vs 244.22+/-35.68, Group III: 93.25+/-19.08 vs 412.31+/-80.18, Group IV: 144.30+/-18.13 vs 1056.89+/-153.78, Group V: 307.55+/ 40.76 vs 2763.76+/-259.76copies/ml. Multivariate Pearson's correlation analysis of hypermethylated RASSF1A with pp-13, PAPP-A and urine proteins showed positive and very highly significant (P<0.001) associations. CONCLUSIONS: Diagnostic potential of fetal specific, hypermethylated RASSF1A was evaluated. Its positive relationship with placental and urine proteins submit the case for considering it as a reliable marker for pre-eclampsia. PMID- 27939475 TI - Trophoblast mitochondrial function is impaired in preeclampsia and correlates negatively with the expression of soluble fms-like tyrosine kinase 1. AB - Preeclampsia is a common medical complication of pregnancy that is associated with significant morbidity and mortality to the mother and the baby. Extensive human epidemiological and experimental studies suggest that excess placental soluble fms-like tyrosine kinase 1, a potent anti-angiogenic factor leads to the maternal hypertension, proteinuria and other systemic complications of preeclampsia. To evaluate the mechanisms of the aberrant placental sFlt1 expression, we studied the role of mitochondrial dysfunction as one possible etiological factor. Here, using human placental samples, we demonstrate that both the activity and expression of a mitochondrial electron transport chain enzyme cytochrome C oxidase (COX) is diminished in the syncytiotrophoblast layer of the chorionic villi from preeclamptic subjects. In addition, there was an inverse correlation between mitochondrial COX enzyme activity and placental sFlt1 expression. Functional in situ enzyme chemistry with electron microscopy also confirmed impaired mitochondrial function in preeclampsia. Ultrastructural and morphometric analysis of mitochondria using electron microscopy demonstrated, that mitochondria are smaller in both the syncytiotrophoblast and cytotrophoblast layers of preeclamptic tissue. The etiology of the mitochondrial dysfunction in preeclampsia as a cause or effect of the placental anti-angiogenic state remains to be elucidated in future studies. PMID- 27939477 TI - The paternal polymorphism rs5370 in the EDN1 gene decreases the risk of preeclampsia. AB - OBJECTIVE: To evaluate whether the maternal, paternal or the combined maternal/paternal contribution of SNP rs5370 of the EDN1 gene is associated with preeclampsia and drove its expression in placenta. STUDY DESIGN: This case control study included 61 preeclamptic patients and their partners and 49 healthy pregnant women and their partners. The population was sub-divided into three groups: women-only, men-only and combined (women/men). The analysis included genotyping of rs5370 in mothers and fathers and evaluating the expression profile of the EDN1 gene in placenta. Comparisons of categorical variables were performed using chi-square and/or Fisher's exact tests. The intergroup comparisons were analysed with the Mann-Whitney U test. The association between the polymorphism and the disease was evaluated through multivariate regression analysis. Spearman's correlation was performed to test the relationship between pre gestational history and clinical features of the affected patients with EDN1 gene expression. RESULTS: The analysis of paternal risk factors associated with preeclampsia revealed no differences between groups. A negative association between SNP rs5370 and preeclampsia was found in men group (OR 0.42; CI 95% 0.18 0.94, p=0.034) but not in women or combined groups. The adjustment for paternal protective factors increased the observed negative association, and the opposite was observed in the presence of paternal risk factors. The expression of the EDN1 gene in the placenta was significantly higher in the group of cases and was not associated with the rs5370 polymorphism. CONCLUSION: The paternal rs5370 polymorphism decreases the risk for preeclampsia and is not associated with placental expression of the EDN1 gene. PMID- 27939476 TI - Differences in cardiovascular function comparing prior preeclamptics with nulliparous controls. AB - OBJECTIVE: The objective of the current study was to evaluate cardiovascular function; including blood pressure, cardiac output, pulse wave velocity and vascular compliance in nonpregnant nulliparous women compared to women with a history of preterm preeclampsia. STUDY DESIGN: This was a case control study. Blood pressure was measured using the Finapres Pro. Baseline cardiac output was determined by echocardiography. Pulse wave velocity was estimated using simultaneous electrocardiographic tracings and ultrasound determined arterial flow waveforms and calculated as estimated distance divided by the time interval between EKG r-wave peak and ultrasound derived peak popliteal artery flow. During volume challenge, 500mL of lactated Ringers solution was infused through an indwelling antecubital catheter over 10min. Cardiac output and blood pressure during and 15min after the infusion were estimated using the Finapres Pro. MAIN OUTCOME MEASURES: Indices of arterial stiffness and vascular compliance. RESULTS: Previous preeclamptics exhibited a significant increase in pulse pressure and cardiac output in response to volume challenge when compared with nulliparous controls. Prior preeclamptics had a strong positive correlation between blood pressure indices (r=0.50-0.68, p?0.01) and pulse pressure (r=0.58, P=0.008) with pulse wave velocity that was not evident in control women. CONCLUSIONS: In women with prior preterm preeclampsia a relationship between blood pressure, intravascular volume and arterial stiffness, is evident in the nonpregnant state and in the absence of hypertension or overt cardiovascular disease. This supports an overarching hypothesis that nonpregnant physiology is an important contributor to pregnancy adaptations. PMID- 27939479 TI - Assessing progression from mild to severe preeclampsia in expectantly managed preterm parturients. AB - OBJECTIVE: To identify factors associated with shortened latency in expectantly managed women diagnosed with preeclampsia without severe features between 23 0/7 and 35 6/7weeks' gestation. METHODS: This was a retrospective cohort study performed at a large community-based hospital between 2009 and 2014, evaluating all mothers between 23 0/7 and 35 6/7weeks' gestation with a diagnosis of preeclampsia without severe features. We collected maternal demographics, symptoms, vital signs and laboratory values within six hours of admission. Maternal and neonatal outcomes were stratified by latency period of less than or greater than/equal to seven days (<7d or ?7d). RESULTS: Overall mean latency was 7.6+/-12.1days. When stratifying subjects to <7d or ?7d latency, neither maternal demographics nor gestational age at diagnosis differed between groups. For subjects with ?7d latency, pregnancy was prolonged by a mean of 24days compared to the <7d latency group (34 1/7 vs 30 4/7weeks GA, P=0.001). Systolic blood pressure greater than 160mmHg within the first six hours of hospital presentation correlated with a more than 3-fold risk for requiring delivery within seven days of diagnosis (OR 3.26 95% CI 1.40-7.58). CONCLUSION: Within our cohort of preterm women admitted with preeclampsia without severe features, elevated systolic blood pressure on admission conveyed significant risk for delivery within seven days. PMID- 27939478 TI - Gelsolin is an endogenous inhibitor of syncytiotrophoblast extracellular vesicle shedding in pregnancy. AB - BACKGROUND: Preeclampsia, a pregnancy-specific inflammatory disorder, is characterized by high levels of anti-angiogenic protein, soluble fms-like tyrosine kinase 1 (sFlt1), in the maternal circulation. sFlt1 producing molecular machinery is present in syncytiotrophoblast extracellular vesicles that are released by the placenta into maternal plasma during normal pregnancy, a process greatly accelerated in preeclampsia. We hypothesized that syncytiotrophoblast extracellular vesicles exposes cytoplasmic actin to plasma resulting in depletion of plasma gelsolin (pGSN), an abundant plasma protein that scavenges circulating actin and other pro-inflammatory mediators. OBJECTIVE: To test whether pGSN levels would be lower in preeclampsia and to assess whether recombinant human plasma gelsolin (rhpGSN) may promote placental health by decreasing shedding of syncytiotrophoblast extracellular vesicles. METHODS: We tested pGSN levels in third trimester plasma samples from women with preeclampsia and non-hypertensive pregnancies. We then assessed whether rhpGSN may act as a negative regulator of syncytial shedding in placental explant culture and dynamic mechanical stretch studies. RESULTS: pGSN levels fall in late pregnancy and decline further in preeclampsia patients. Recombinant human pGSN (rhpGSN) at 100MUg/ml limits spontaneous syncytiotrophoblast vesicle release and sFlt1 protein dissemination by normal placental explants. Higher rhpGSN doses (500MUg/ml) also limit syncytiotrophoblast vesicle and sFlt1 dissemination from preeclamptic placental explants. rhpGSN also mitigates syncytiotrophoblast vesicle during dynamic mechanical stretch. CONCLUSIONS: 1) pGSN, an anti-inflammatory factor of maternal origin is reduced in preeclampsia and may contribute to disease progression and 2) exogenous rhpGSN supplementation can limit the dissemination of toxic syncytiotrophoblast vesicle that characterizes the disease state. PMID- 27939481 TI - Aspirin adherence during high-risk pregnancies, a questionnaire study. AB - OBJECTIVE: Aspirin reduces the risk of recurrent hypertensive disorders of pregnancy (HD) and fetal growth restriction (FGR). This study examined the non adherence rates of aspirin in women with high-risk pregnancies. STUDY DESIGN: All consecutive women between 24 and 36weeks gestation with an indication for aspirin use during pregnancy were invited for this study. A survey was used which included two validated questionnaires, the simplified medication adherence questionnaire (SMAQ) and the Beliefs and Behaviour Questionnaire (BBQ). MAIN OUTCOME MEASURES: To determine the non-adherence rates of aspirin, and to identify the beliefs and behavior concerning aspirin. RESULTS: Indications for aspirin use during pregnancy were previous HD, FGR, intrauterine fetal death or current maternal disease. Non-adherence rates according to the SMAQ and BBQ were 46.3% and 21.4% respectively. No differences in demographic background or obstetrical characteristics between adherent and non-adherent women could be demonstrated. CONCLUSIONS: Adherence for aspirin in this high-risk population cannot be taken for granted. The non-adherence rates in pregnant women are comparable with the non-adherence rates for aspirin in the non-pregnant population. PMID- 27939480 TI - Long term effects of gestational hypertension and pre-eclampsia on kidney function: Record linkage study. AB - OBJECTIVE: To assess the long term effects of hypertensive disorders of pregnancy on renal function. DESIGN: Cohort study where exposure was gestational hypertension or preeclampsia in the first pregnancy. Normotensive women formed the comparison group. SETTING: Aberdeen, Scotland. PARTICIPANTS: All women with date of birth on or before 30th June 1969 and at least their first singleton delivery recorded in the Aberdeen Maternity and Neonatal Databank. METHODS: Participants were linked to the Renal Biochemistry Register, Scottish Morbidity Records, Scottish Renal Registry and National Register for deaths. MAIN OUTCOME MEASURES: Occurrence of chronic kidney disease (CKD) as identified from renal function tests in later life, hospital admissions or death from kidney disease or recorded as receiving renal replacement therapy. RESULTS: CKD was diagnosed in 7.5% and 5.2% of women who previously had GH and PE respectively compared to 3.9% in normotensive women. The unadjusted odds ratio (95% confidence interval) of having CKD in PE was 2.04 (1.53, 2.71) and that for GH was 1.37 (1.15, 1.65), while the adjusted odds ratio (95% confidence interval) of CKD was 1.93 (1.44, 2.57) and 1.36 (1.13, 1.63) in women with PE and GH respectively. Kaplan-Meier curves of survival time to development of chronic kidney disease revealed that women with preeclampsia were susceptible to kidney function impairment earliest, followed by those with gestational hypertension. CONCLUSIONS: There was an increased subsequent risk of CKD associated with hypertensive disorders of pregnancy. Women with GH and PE were also found to have CKD earlier than normotensive women. PMID- 27939482 TI - Magnesium sulphate prevents lipopolysaccharide-induced cell death in an in vitro model of the human placenta. AB - OBJECTIVES: To determine if magnesium sulphate (MgSO4) prevents lipopolysaccharide (LPS)-induced cell death in an in vitro model of the human placenta. STUDY DESIGN: BeWo choriocarcinoma cells were treated with increasing concentrations of LPS (10-1000ng/ml) and MgSO4 ranging from 1 mM to 100 mM for 24 or 48h. For co-treatments, cells were pre-treated with 1mM MgSO4 for 1h and 200ng/ml LPS was then added for the remaining 48h. To assess viability an MTT assay was carried out along with nuclear staining to assess pyknotic nuclei. The expression of the pro-inflammatory cytokine TNF-alpha was examined by real-time PCR. RESULTS: MgSO4 had a dose dependent effect of cell viability with a narrow therapeutic window. MgSO4 (1mM) protected against adverse effects of LPS on cell viability by preventing LPS-induced decreases in cell viability (MTT assay) and protecting against LPS-induced pyknotic changes in nuclear membrane. MgSO4 also inhibited the elevated TNF-alpha mRNA expression induced by LPS. CONCLUSIONS: MgSO4 preserves BeWo cell viability following an inflammatory insult and reduces the mRNA expression of the inflammatory cytokine TNF-alpha. These data elucidate a potential therapeutic pathway by which MgSO4 may be protective in pre eclampsia. PMID- 27939483 TI - Sex differences in early growth during the first three years of life in offspring from mothers with pregnancy-induced hypertension. AB - OBJECTIVES: Newborns born to mothers with pregnancy-induced hypertension (PIH) are thought to be at high risk for lifestyle-related diseases, such as obesity and hypertension, in adulthood. STUDY DESIGN: A longitudinal study of 78 pregnant women with PIH and their newborns, who visited Okayama University Hospital from 2009 to 2013. MAIN OUTCOME MEASURES: We investigated the change in growth of offspring born to mothers with PIH and compared it with the standard growth curve in Japanese to examine whether there was rapid catch-up growth during the first 3years of life. RESULTS: Subjects were 78 pregnant women with PIH and their offspring, who visited Okayama University Hospital from 2009 to 2013. Valid responses were obtained from 29 of 78 (37.1%) women. Body weight and length at birth were at the third percentile or less in females, and at the 10th percentile or less, in males. When body weight and length were compared at 6months, 18months, and 3years old between male and female toddlers, male toddlers slowly caught up until 3years old, but female toddlers rapidly caught up in the first 6months. Furthermore, in newborns with fetal growth restriction caused by the intrauterine environment of PIH, differences in physical development between male and female toddlers were more remarkable. CONCLUSIONS: There is a significant sex difference in catch-up growth during the first 3years, which might be involved in lifestyle-related diseases in adulthood, suggesting continuous follow-up is necessary, especially for female offspring. PMID- 27939484 TI - Strong inhibitory effect of pre-eclampsia serum on angiogenesis detected in vitro by human cell-based angiogenesis tests. AB - OBJECTIVE: To explore in vitro angiogenic properties of maternal and umbilical cord blood sera from women with symptomatic pre-eclampsia in comparison with sera from women with normotensive pregnancies. STUDY DESIGN: Maternal and umbilical blood serum samples were collected from eleven primiparous women with pre eclampsia and ten healthy gestational-age-matched primiparous controls. The samples were tested for tubule formation in two different types of in vitro angiogenesis tests. The first test (fibroblast-HUVEC) showed effects on angiogenesis and the second test (hASC-HUVEC), in addition to angiogenesis, also showed effects on vasculogenesis. The pro-angiogenic and inhibitory properties of the samples were microscopically quantified after immunostaining tubular structures, using markers for von Willebrand factor (vWf) and collagen IV. RESULTS: Serum samples from pre-eclamptic women inhibited tubule formation in both models, while those from normal pregnancy didn't. Umbilical blood samples were inhibitory both after pre-eclampsia and normal pregnancy. In the fibroblast HUVEC model the inhibition was stronger after preeclampsia pregnancy, and the difference between groups was statistically significant. In the pre-eclampsia group a correlation between the inhibitory effect of umbilical blood and birth weight adjusted to gestational age was found. No clear correlation between sera from pregnant women and corresponding umbilical sera was found. CONCLUSION: The strong inhibitory effect of maternal serum samples on tubule formation reflects the anti-angiogenic state that is present in pre-eclampsia. PMID- 27939485 TI - Postpartum physiology, psychology and paediatric follow up study (P4 Study) - Study protocol. AB - BACKGROUND: Women who have had hypertension in pregnancy are at greater risk of long term cardiovascular disease (CVD). Little is known about their cardiovascular risk postpartum or the effects on the woman's mental health and the outcomes of their infants. In this project we will study the physiological and psychological health of women and the physical health and development of their infants six months, two years and five years after birth. We will establish normal blood pressure (BP) and metabolic function for women who were normotensive in pregnancy and use these to assess women who had gestational hypertension (GH) or preeclampsia (PE). DESIGN/METHODS: Women will be asked to participate if they have given birth in the preceding six months. They will be excluded if they had diabetes, hypertension, renal or other serious maternal disease prior to pregnancy or congenital anomaly in the pregnancy. We will recruit 292 women who were normotensive and their babies, 100 who had GH and 100 who had PE and their babies. They will be assessed at six months, two and five years after birth. At each assessment mothers will have their blood pressure (BP) assessed peripherally with a liquid crystal sphygmomanometer and 24h ambulatory blood pressure monitoring (ABPM), and centrally with non-invasive applanation tonometry. Additional physiological testing will include: body composition; energy balance; vascular compliance; cardiac function; liver and renal function, lipids and biochemistry; glucose and insulin; and urinalysis. Psychological status will be assessed with validated self-report questionnaires for depression, anxiety, post traumatic stress disorder (PTSD) and mother-infant bonding. The babies will have a medical examination by a paediatrician at each assessment. Their behavioural development will be assessed with an Ages and Stages Questionnaire completed by their mother at each assessment and a developmental assessment by a child psychologist at two and five years. CONCLUSIONS: This study will re-define normal BP and other physiological parameters for young parous women thereby permitting a more sensitive assessment of post-partum BP and other cardiovascular risk markers in women who have had GH or PE. It will also determine the extent, if any, of psychological disorders in these women and developmental or other concerns in their babies. TRIALS REGISTRATION: Australian and New Zealand Clinical Trials Registry Number: ACTRN12613001260718. PMID- 27939486 TI - Changes in cerebral autoregulation in the second half of pregnancy and compared to non-pregnant controls. AB - OBJECTIVE: The mechanism by which pregnancy affects the cerebral circulation is unknown, but it has a central role in the development of neurological complications in preeclampsia, which is believed to be related to impaired autoregulation. We evaluated the cerebral autoregulation in the second half of pregnancy, and compared this with a control group of healthy, fertile non pregnant women. METHODS: In a prospective cohort analysis, cerebral blood flow velocity of the middle cerebral artery (determined by transcranial Doppler), blood pressure (noninvasive arterial volume clamping), and end-tidal carbon dioxide (EtCO2) were simultaneously collected for 7min. The autoregulation index (ARI) was calculated. ARI values of 0 and 9 indicated absent and perfect autoregulation, respectively. ANOVA and Pearson's correlation coefficient were used, with p<0.05 considered significant. RESULTS: A total of 76 pregnant and 18 non-pregnant women were included. The ARI did not change during pregnancy, but pregnant women had a significantly higher ARI than non-pregnant controls (ARI 6.7+/-0.9 vs. 5.3+/-1.4, p<0.001). This remained significant after adjusting for EtCO2 (p<0.001). CONCLUSION: Cerebral autoregulation functionality is enhanced in the second half of pregnancy, when compared to non-pregnant fertile women, even after controlling for EtCO2. The autoregulation does not change with advancing gestational age. PMID- 27939487 TI - Cerebrospinal fluid levels of tau and phospho-tau-181 proteins during pregnancy. AB - OBJECTIVES: During pregnancy various interactions occur between structural alterations of the maternal brain and placental metabolism. The aim of the present study was to investigate whether cerebrospinal fluid concentrations of tau and phospho-tau-181 protein vary during normal pregnancy and in women with preeclampsia and HELLP syndrome. STUDY DESIGN: We measured cerebrospinal fluid biomarkers, tau and phospho-tau-181 protein levels in 90 pregnant women electively assigned for regional anaesthesia during pregnancy or for cesarean section using enzyme-linked immunosorbent assays. RESULTS: Cerebrospinal fluid concentrations for tau and phospho-tau-181 in 66 women with normal pregnancy were 308.5+/-117.3pg/mL and 50.5+/-16.7pg/mL, respectively. Blood pressure, liver function, clotting activity and kidney function were significantly different in eleven women with preeclampsia and HELLP syndrome. The weight of the newly born (p<0.001; HR: 0.998), the weight of the placenta (p=0.018) and concentrations for phospho-tau-181 (p=0.043; HR: 1.211) correlated significantly with the disease. CONCLUSION: Mean concentrations of cerebrospinal fluid tau and phospho-tau-181 protein during pregnancy were evaluated. Phospho-tau-181 protein concentrations correlated with placental function supporting the hypothesis that altered expression of neuronal factors during pregnancy may affect development of the placenta. PMID- 27939489 TI - Evaluation of the level of thiol-disulphide homeostasis in patients with mild and severe preeclampsia. PMID- 27939488 TI - First and second trimester immune biomarkers in preeclamptic and normotensive women. AB - INTRODUCTION: Circulating immune markers may be associated with preeclampsia but further investigations in early pregnancy and among preeclampsia subtypes are warranted. We examined immune markers in 208 preeclamptic women and 411 normotensive controls. METHODS: Our study was nested within the Collaborative Perinatal Project. A total of 242 women had first trimester serum samples and 392 had second trimester serum samples. Preeclampsia was defined as hypertension >20weeks of gestation with proteinuria or pulmonary edema, oliguria, or convulsions. Preterm preeclampsia was defined as preeclampsia with delivery less than 37weeks of gestation. Associations between immune markers RANTES, interleukin (IL)-6, IL4, IL5, IL12, IL10, IL8, IL1-beta, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and beta, transforming growth factor (TGF)-beta and preeclampsia were explored using a modified version of cox regression developed to address data with non-detectable levels. Models were adjusted for body mass index, gestational age of blood sampling, fetal sex, smoking, socioeconomic status and maternal age. RESULTS: In first trimester samples, IL-12 was associated with preeclampsia (p=0.0255). IFN-gamma (p=0.0063), IL1-beta (p=0.0006), IL5 (p=0.0422) and TNFr (p=0.0460) were associated with preterm preeclampsia only. In second trimester samples, IL1-beta was associated with preeclampsia (p=0.0180) and term preeclampsia (p=0.0454). After correction for multiple comparisons, only IL1-beta remained associated with preterm preeclampsia in the first trimester (p=0.0288). DISCUSSION: Elevated first trimester IL1-beta appears to be associated with preterm preeclampsia. However, few associations were observed in the second trimester. Systemic immune markers alone may not be useful for preeclampsia prediction. PMID- 27939490 TI - Elevated circulatingadenosine deaminase activity in women with preeclampsia: association with pro-inflammatory cytokine production and uric acid levels. AB - OBJECTIVE: Preeclampsia is a specific disorder of human pregnancy that is associated with hyperuricemia and higher levels of pro-inflammatory cytokines. Adenosine deaminase (ADA) is an enzyme present in all human tissues, and is considered an indicator of cellular inflammation. In the present study we assess whether adenosine deaminase (ADA) activity is altered in women with preeclampsia (PE) and contributes to elevated levels of uric acid and pro-inflammatory cytokine production. STUDY DESIGN: The population studied consisted of 60 women with PE, 30 normotensive pregnant women (NT) and 20 non-pregnant women (NP). Uric acid concentration and ADA activity were determined in the serum. Peripheral blood mononuclear cells (PBMCs) were isolated and evaluated for intracellular nuclear transcription factor kappa B (NF-kappaB) levels and for endogenous tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) production. The data were evaluated with parametric or non-parametric tests with significance set at P<0.05. RESULTS: ADA levels were higher in the PE group compared with the NT and NP groups (P<0.001). A positive correlation between ADA and uric acid levels was identified in women with PE (P<0.001). Endogenous production of IL 1beta and TNF-alpha, as well as intracellular NF-kappaB levels, were higher in PBMCs from the PE group than from NT and NP women (P<0.01) and correlated with the ADA concentration in preeclamptic women (P<0.01). CONCLUSION: An elevation in ADA activity in women with PE may contribute to their increased levels of uric acid and pro-inflammatory immune activity. PMID- 27939491 TI - Validation of the Withings BP-800 in pregnancy and impact of maternal characteristics on the accuracy of blood pressure measurement. AB - OBJECTIVE: Firstly, to validate the Withings BP-800 automated device for use in pregnancy and, secondly, to assess the impact of maternal somatometric and demographic variables on the accuracy of the device. DESIGN: Prospective observational study. SETTING: Kings College Hospital, London, UK. POPULATION: Forty-seven women of any gestation. METHODS: Validation: The British Hypertension Society (BHS) Protocol (1993) was used for the validation of the Withings BP-800. Two trained observers took nine sequential same arm measurements alternating between the Withings BP-800 and the mercury sphygmomanometer. Assessment of factors affecting the disagreement between the two devices: The associations between discrepancies in the measured systolic and diastolic blood pressure by the two devices and potential predictors of discrepancy and/or possible confounders of associations including age, gestational age, ethnicity, body mass index and arm circumference were investigated using two-level mixed effects models to take into account the repeated measurements. MAIN OUTCOME MEASURES: Accuracy of the Withings BP-800 based on the grading criteria of the BHS Protocol (1993). RESULTS: The Withings BP-800 failed to meet the validation criteria of the BHS protocol for pregnancy and preeclampsia. Inter-device discrepancy was significantly associated with larger arm circumferences and was more pronounced with diastolic blood pressure. This relationship was independent of other maternal characteristics. CONCLUSIONS: The Withings BP-800 cannot be recommended for the measurement of blood pressure in pregnancy or preeclampsia. The inaccuracy of the Withings BP-800 increases when used in patients with larger arm circumferences with a propensity to over-read. PMID- 27939492 TI - Prevalence of pregnancy hypertensive disorders in Mongolia. AB - OBJECTIVE: To estimate the prevalence of preeclampsia in a contemporary population of Mongolian women living in urban and rural areas. We determined the sensitivity and specificity of diagnosis based on established diagnostic criteria and assessed whether local diagnostic criteria were similar to those used in the US. STUDY DESIGN: Cross-sectional study of urban and nomadic pregnant women recruited in Ulaanbaatar (n=136) and rural provinces (n=85). MAIN OUTCOME MEASURES: Preeclampsia defined as hypertension new to pregnancy after 20weeks and proteinuria (or protein creatinine ratio ?0.3 and dipstick reading>+1) or in the absence of proteinuria, hypertension and onset of: renal insufficiency, impaired liver function, thrombocytopenia, pulmonary edema, cerebral/visual symptoms. Prevalence of preeclampsia based on established criteria was compared with prevalence based on local physician's diagnosis. RESULTS: Prevalence of local physician diagnosed preeclampsia was 9.5% (13.2% urban, 3.5% rural). Prevalence based on established diagnostic criteria was 4.1% (4.4% urban, 3.5% rural). Sensitivity of physician's diagnosis was 23.8%, specificity was 98.0%, false negative rate was 2.0% and false positive rate was 76.2%. While prevalence based on local physician's diagnosis was over double that based on diagnostic criteria, overdiagnosis did not result in adverse effects. Women fulfilling diagnostic criteria for preeclampsia had babies with higher birth weights than women who did not (p-value=0.006). CONCLUSION: The 4.1% prevalence of preeclampsia in Mongolia was consistent with global estimates of 2-8%, suggesting the pathophysiology of preeclampsia here may be similar to that found globally. Sensitivity of physician's diagnosis was low, specificity was high. PMID- 27939493 TI - Hypertensive disease in pregnancy in Botswana: Prevalence and impact on perinatal outcomes. AB - OBJECTIVES: Perinatal morbidity in sub-Saharan Africa has been attributed to infection, obstetric emergencies, and preterm birth, but less is known about hypertension in pregnancy. Our objective was to characterize the prevalence of hypertension in pregnancy and the impact of hypertension on perinatal outcomes in sub-Saharan Africa. STUDY DESIGN: We performed surveillance of obstetric records at eight of the largest public hospitals in Botswana. Women were included in this analysis if they were HIV-uninfected and had singleton gestations and at least one prenatal blood pressure measurement. MAIN OUTCOME MEASURES: We measured stillbirth, preterm birth, small for gestational age, and neonatal death in women with and without hypertension in pregnancy. RESULTS: We included 14,170 pregnancies. Hypertension occurred in 3156 (22.2%) women, with 602 (19.1%) defined as severe. Severe hypertension increased risk of stillbirth (RR 4.4; 95% CI 3.2-6.2), preterm birth (RR 2.5; 95% CI 2.2-2.8), small for gestational age (RR 2.7; 95% CI 2.3-3.1) and neonatal death (RR 5.1; 95% CI 2.9-5.6). Non-severe hypertension increased risk of stillbirth (RR 2.0; 95% CI 1.5-2.7), preterm birth (RR 1.2; 95% CI 1.1-1.3), and small for gestational age (RR 1.6; 95% CI 1.4-1.8). Perinatal outcomes were worse in women with hypertension who had spontaneous preterm birth compared to those who underwent iatrogenic preterm delivery. CONCLUSIONS: Hypertension in pregnancy is common in Botswana and leads to a large number of adverse outcomes. Improved management of hypertension in pregnancy may improve perinatal morbidity and mortality. PMID- 27939496 TI - Necessity is the mother of invention: Alternative techniques in living-related lobar transplantation come to the mainstream. PMID- 27939494 TI - Features of endothelial dysfunction and morphofunctional changes of the uteroplacental complex in experimentally induced pre-eclampsia. AB - BACKGROUND: Pre-eclampsia is considered to be a severe complication of pregnancy. Theoretical investigation of its etiology and pathogenesis, development of strategies for its prevention and treatment are conditioned by the development of appropriate experimental models of this pathology. METHODS: The study involved Wistar rat lines weighing 220-240g. Experimental pre-eclampsia was modeled by replacing drinking water consumed by pregnant female rats with 1.8% NaCl solution throughout gestation. Arterial pressure, protein concentration in urine and tissue hydration extent were measured on the 1st and 21st days of gestation. Uteroplacental blood flow, vasodilating and antithrombotic endothelial functions were also assessed. For pathomorphological and immunohistochemical investigation murine monoclonal antibodies against vascular endothelial growth factor (VEGF), polyclonal rabbit antibodies against inducible and endothelial NO-synthases were used. RESULTS: Replacing drinking water with 1.8% NaCl solution in female rats throughout gestation elevates arterial pressure, causes proteinuria and edema, impairs vasodilating and antithrombotic endothelial properties, and suppresses uteroplacental blood circulation. A morphological examination of the animals revealed the signs of focal duodenitis, spasms of myometrium arteries with no invasion of syncytiotrophoblast into its walls which also involved a raised VEGF and reduced eNOS expression in the endothelium of myometrial vessels, as well as cytoplasmic expression of iNOS in the cells of inflammatory infiltrate. CONCLUSIONS: These findings make it possible to conclude that replacing drinking water with 1.8% NaCl solution causes a number of changes typical of pre-eclampsia and, therefore, can be regarded as an experimental model of this pathologic condition. PMID- 27939497 TI - Adoption of short-term mechanical circulatory support as a viable rescue effort for patients with refractory cardiogenic shock. PMID- 27939495 TI - Development and impact of arrhythmias after the Norwood procedure: A report from the Pediatric Heart Network. AB - OBJECTIVES: The study objective was to determine the predictors of new-onset arrhythmia among infants with single-ventricle anomalies during the post-Norwood hospitalization and the association of those arrhythmias with postoperative outcomes (ventilator time and length of stay) and interstage mortality. METHODS: After excluding patients with preoperative arrhythmias, we used data from the Pediatric Heart Network Single Ventricle Reconstruction Trial to identify risk factors for tachyarrhythmias (atrial fibrillation, atrial flutter, supraventricular tachycardia, junctional ectopic tachycardia, and ventricular tachycardia) and atrioventricular block (second or third degree) among 544 eligible patients. We then determined the association of arrhythmia with outcomes during the post-Norwood hospitalization and interstage period, adjusting for identified risk factors and previously published factors. RESULTS: Tachyarrhythmias were noted in 20% of subjects, and atrioventricular block was noted in 4% of subjects. Potentially significant risk factors for tachyarrhythmia included the presence of modified Blalock-Taussig shunt (P = .08) and age at Norwood (P = .07, with risk decreasing each day at age 8-20 days); the only significant risk factor for atrioventricular block was undergoing a concomitant procedure at the time of the Norwood (P = .001), with the greatest risk being in those undergoing a tricuspid valve procedure. Both tachyarrhythmias and atrioventricular block were associated with longer ventilation time and length of stay (P < .001 for all analyses). Tachyarrhythmias were not associated with interstage mortality; atrioventricular block was associated with mortality among those without a pacemaker in the unadjusted analysis (hazard ratio, 2.3; P = .02), but not after adding covariates. CONCLUSIONS: Tachyarrhythmias are common after the Norwood procedure, but atrioventricular block may portend a greater risk for interstage mortality. PMID- 27939499 TI - Nuance need not be subtle. PMID- 27939498 TI - Elective primary aortic root replacement with and without hemiarch repair in patients with no previous cardiac surgery. AB - OBJECTIVE: Excellent outcomes have been established for elective aortic root replacement (ARR). It is less clear whether extending the repair into the proximal aortic arch with hypothermic circulatory arrest increases risk. We examined the early outcomes of elective, primary ARR, with and without hemiarch replacement, in patients without previous cardiac surgery. METHODS: Over a 4-year period, 140 non-redo patients (median age, 54 years) underwent elective, primary ARR for root aneurysms; 119 patients (85%) had hemiarch replacement, and 21 (15%) had only ascending aortic replacement. Valve-sparing ARR was performed in 41 cases (29.3%) and valve-replacing ARR in 99 (70.7%). Moderate hypothermic circulatory arrest and antegrade cerebral perfusion were used in 118 (99%) hemiarch repairs. RESULTS: There were no operative deaths or permanent strokes. Complications included temporary renal dialysis (n = 1; 4.8%), transient neurologic deficit (n = 2; 9.5%), and tracheostomy (n = 2; 9.5%) after ascending aortic repair and bleeding requiring reoperation (n = 4; 3.4%), pericardial effusion requiring drainage (n = 9; 7.6%), and tracheostomy (n = 2; 1.7%) after hemiarch replacement. No stroke was observed in the hemiarch group (P = .022; univariate analysis). The extent of the repair into the proximal arch did not appear to be associated with any adverse effect. CONCLUSIONS: In non-redo patients, elective primary ARR has excellent early outcomes, regardless of whether repair extends into the proximal arch. Additional elective hemiarch replacement with moderate hypothermic circulatory arrest and antegrade cerebral perfusion has a low risk of neurologic complications and should be performed if necessary. Long-term data are needed to compare the rates of reintervention in the aortic arch in patients with or without proximal arch replacement. PMID- 27939501 TI - Discussion. PMID- 27939500 TI - The times are a-changin'-Rapidly! PMID- 27939503 TI - Toward pragmatic innovation. PMID- 27939502 TI - Magnetic resonance imaging assessment of cardiac function in a swine model of hibernating myocardium 3 months following bypass surgery. AB - OBJECTIVE: Clinical studies demonstrate delayed recovery of hibernating myocardium (HM) following coronary artery bypass graft (CABG) surgery. Cardiac magnetic resonance (CMR) imaging is effective in identifying HM in clinical settings. Our animal model of HM shows partial but incomplete functional recovery 1 month following CABG using echocardiography. This study uses CMR imaging to determine completeness of recovery 3 months post-CABG. METHODS: Swine (N = 12) underwent left anterior descending artery (LAD) 1.5-cm constrictor placement creating a territory of HM over 12 weeks. CMR at 12 weeks confirmed hibernation without infarction (N = 12). Off-pump left internal thoracic artery (LITA) to the LAD was performed in 9 animals. Three animals were killed as HM controls. CMR imaging was repeated in revascularized animals before death at 1 (n = 4) or 3 months (n = 5). CMR imaging was performed at baseline and with dobutamine infusion (5 MUg/kg/min). RESULTS: Twelve weeks after constrictor placement, CMR imaging confirmed viability in LAD region and LAD stenosis in all animals. In HM, wall thickening is reduced at baseline but with contractile reserve present during dobutamine infusion. Following revascularization, CMR imaging confirmed patent LITA graft (n = 9). Analysis of baseline regional function shows incomplete recovery of HM following CABG, with reduced contractile reserve at both 1 and 3 months post-CABG. CONCLUSIONS: CMR imaging provides accurate spatial resolution of regional contractile function and confirms the presence of HM at 12 weeks following instrumentation of the LAD. Three months following CABG, partial recovery of HM with contractile reserve is present in the single LAD territory. PMID- 27939504 TI - Anti-inflammatory effects on ischemia/reperfusion-injured lung transplants by the cluster of differentiation 26/dipeptidylpeptidase 4 (CD26/DPP4) inhibitor vildagliptin. AB - OBJECTIVES: We showed previously that stromal cell-derived factor 1 (SDF-1) is a substrate of cluster of differentiation 26/dipeptidylpeptidase 4 (CD26/DPP4) and exerts regenerative properties on acute lung ischemia-reperfusion injury on CD26/DPP4 inhibition. Here, we extend our studies to test whether an intermediate recovery of lung transplants from ischemia/reperfusion injury by CD26/DPP4 inhibition can be achieved for up to 14 days. METHODS: Syngeneic mouse lung transplantation (Tx) was performed in C57BL/6 and in CD26-/- mice by applying 18 hours of cold ischemia. Donor lungs were preconditioned with saline or the CD26/DPP4 inhibitor vildagliptin (1 MUg/mL [3 MUM]). In vitro, the influence of vildagliptin and SDF-1 on the macrophage cell line RAW 264.7 was tested. Transplants were analyzed up to 14 days after Tx for the expression of SDF-1, tumor necrosis factor-alpha (TNF-alpha), interleukin-10, intercellular adhesion molecule-1 (ICAM-1), immune cell infiltration, and oxygenation. RESULTS: Cold ischemic time of 18 hours with vildagliptin preconditioning elevated lung SDF-1 levels (P = .0011) and increased interleukin-10-producing macrophages (P = .0165) compared with the control. SDF-1 reduced macrophage-derived TNF-alpha (P = .0248) in vitro. Five hours after Tx, vildagliptin significantly reduced macrophages and neutrophils (P = .0306), decreased ICAM-1 expression (P = .002), and improved transplant oxygenation (P = .0181). Seven days after Tx, grafts were preserved on CD26/DPP4-inhibition: perivascular macrophages (P = .0046) and TNF-alpha (P = .0013) were reduced as well as T and B cells. ICAM-1 was absent in CD26/DPP4 inhibited grafts at all time points. CONCLUSIONS: This study proves an intermediate improvement of ischemia/reperfusion-injured lung transplants by the CD26/DPP4-inhibitor vildagliptin up to 14 days. Enhanced levels of SDF-1 induced an anti-inflammatory effect on a cellular and protein level, and render CD26/DPP4 inhibition preconditioning effective for the protection from lung ischemia/reperfusion injury. PMID- 27939505 TI - Thinkers needed to improve biventricular assist device outcome. PMID- 27939506 TI - Structural studies of RNA-protein complexes: A hybrid approach involving hydrodynamics, scattering, and computational methods. AB - The diverse functional cellular roles played by ribonucleic acids (RNA) have emphasized the need to develop rapid and accurate methodologies to elucidate the relationship between the structure and function of RNA. Structural biology tools such as X-ray crystallography and Nuclear Magnetic Resonance are highly useful methods to obtain atomic-level resolution models of macromolecules. However, both methods have sample, time, and technical limitations that prevent their application to a number of macromolecules of interest. An emerging alternative to high-resolution structural techniques is to employ a hybrid approach that combines low-resolution shape information about macromolecules and their complexes from experimental hydrodynamic (e.g. analytical ultracentrifugation) and solution scattering measurements (e.g., solution X-ray or neutron scattering), with computational modeling to obtain atomic-level models. While promising, scattering methods rely on aggregation-free, monodispersed preparations and therefore the careful development of a quality control pipeline is fundamental to an unbiased and reliable structural determination. This review article describes hydrodynamic techniques that are highly valuable for homogeneity studies, scattering techniques useful to study the low-resolution shape, and strategies for computational modeling to obtain high-resolution 3D structural models of RNAs, proteins, and RNA-protein complexes. PMID- 27939507 TI - Suppression of T cells by myeloid-derived suppressor cells in cancer. AB - Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells defined by their immunosuppression. Elevated levels of certain soluble cytokines in tumor microenvironment, such as IL-6 and IL-10, contribute to the recruitment and accumulation of tumor-associated MDSCs. In turn, MDSCs secret IL 6 and IL-10 and form a positive self-feedback to promote self-expansion. MDSCs also release other soluble cytokines such as TGF-beta and chemokines to exert their suppressive function by induction of regulatory T cells. Exhaustion of some amino acids by MDSCs with many secretory enzymes or membrane transporters as well as their metabolites leads to blockage of T cells development. The interaction of membrane molecules on MDSCs and T cells leads inactivation and apoptosis of T cells. There may be one or some dominant mechanism(s) by which MDSCs impair the immune system in different tumor microenvironment. Thus, it is important to identify the subpopulations of MDSCs and clarify the dominant mechanism(s) through which MDSCs inhibit antitumor immunity in order to establish a more individual immunotherapy by eliminating MDSCs-mediated suppression. Currently studies concentrated on therapeutic strategies targeting MDSCs have obtained promising results. However, more studies are needed to demonstrate their clinical safety and efficacy. PMID- 27939508 TI - Time-lapse morphokinetic assessment has low to moderate ability to predict euploidy when patient- and ovarian stimulation-related factors are taken into account with the use of clustered data analysis. AB - OBJECTIVE: To study whether time-lapse morphokinetic (TLM) assessment predicts ploidy status when patient- and ovarian stimulation-related factors are taken into account. DESIGN: Retrospective cohort study. SETTING: Private IVF clinic. PATIENT(S): In total, 103 consecutive patients (415 blastocysts) were included. All embryos were individually cultured in a time-lapse incubator from intracytoplasmic sperm injection up to trophectoderm biopsy. Following trophectoderm biopsy on day 5 or 6, blastocysts were vitrified and 23 TLM parameters were analyzed. INTERVENTION(S): Correlations between patient- and ovarian stimulation-related factors and TLM parameters were tested in a multilevel mixed-effects linear regression model and assessed by means of intraclass correlation coefficient (ICC). MAIN OUTCOME MEASURE(S): Predictive ability of TLM parameters for euploidy. RESULT(S): The majority of TLM parameters had ICCs of 16%-47%. None of the patient- or ovarian stimulation-related factor had any systematic effect on any TLM parameter; however, body mass, total FSH dose, duration of infertility, number of previous cycles, antral follicle count, ovarian stimulation protocol, and E2 on the trigger day had a significant impact on some TLM parameters. With the use of multilevel mixed-effects logistic regression analysis, of the ten TLM parameters that were initially noted to be significantly different among euploid and aneuploid blastocysts in the univariate analysis, only five remained significant. However, the areas under the receiver operating characteristic curves at regression analysis were low, ranging from 0.55 to 0.63. CONCLUSION(S): Five TLM parameters, all related to timing of blastocyst development, have limited ability to predict euploidy when patient- and ovarian stimulation-related factors are taken into account. PMID- 27939509 TI - Dynamics of PAHs and derived organic compounds in a soil-plant mesocosm spiked with 13C-phenanthrene. AB - Polycyclic Aromatic Hydrocarbons (PAHs) are ubiquitous and persistent soil pollutants. Their fate and the influence of the plant rhizosphere on their dynamics has been extensively studied, but studies mainly focused on their dissipation rate. We conducted a plant-soil mesocosm experiment to study the fate and distribution of PAHs or derived compounds in the extractable fraction, the residual soil, the shoot biomass and the root biomass. The experiment was conducted for 21 days using ryegrass and a forest soil spiked with 13C-labeled phenanthrene (PHE), using combined IRMS and NanoSIMS for analyses. Almost 90% of the initial extractable PHE content was dissipated within 3 weeks, but no rhizospheric effect was highlighted on PHE dissipation. More than 40% of 13C-PHE was still in the soil at the end of the experiment, but not as PHE or PAH-derived compounds. Therefore it was under the form of new compounds (metabolites) and/or had been incorporated into the microbial biomass. About 0.36% of the initial 13C PHE was recovered in the root and shoot tissues, representing similar 13C enrichment (E13C) as in the soil (E13C ~ 0.04 at.%). Using NanoSIMS, 13C was also localized at the microscale in the roots and their close environment. Global 13C enrichment confirmed the results obtained by IRMS. Some hotspots of 13C enrichment were found, with a high 32S/12C14N ratio. Comparing the ratios, sizes and shapes of these hotspots suggested that they could be bacteria. PMID- 27939510 TI - Purification, antitumor and immunomodulatory activity of polysaccharides from soybean residue fermented with Morchella esculenta. AB - Crude polysaccharides (MPS) from soybean residue fermented with Morchella esculenta were extracted and purified by DEAE Sephadex A-50 chromatography and Sephadex G-100 size-exclusion chromatography in sequence. Three main fractions MP 1, MP-3 and MP-4 were obtained during the purification steps. The recovery rates based on MPS used were 26.2%, 29.1% and 18.7% for MP-1, MP-3 and MP-4 respectively. The monosaccharide composition, ultraviolet spectrum, infrared spectrum and NMR of the three fractions were analyzed. Furthermore, the influence of polysaccharides fractions upon activation of macrophage cells (RAW 264.7), antitumor activities of the human hepatocellular cell line (HepG-2) and human cervical carcinoma cells (Hela) in vitro were evaluated. The results indicated that the proliferation of MP-3 on RAW 264.7 was 313.57% at 25MUg/mL, which is high while MP-1 had a higher growth inhibition effect on HepG-2 cells of 68.01% at concentration of 50MUg/mL. The fractions of MP-1, MP-3 and MP-4 induced apoptosis in HepG-2 cells and Hela cells by arresting cell cycle progression at the G0/G1 phase. These findings suggest that the purified polysaccharides fractions may be a potent candidate for human hepatocellular and cervical carcinoma treatment and prevention in functional foods and pharmacological fields. PMID- 27939511 TI - From rotten grapes to industrial exploitation: Komagataeibacter europaeus SGP37, a micro-factory for macroscale production of bacterial nanocellulose. AB - Bacterial nanocellulose (BNC), being ultrapure and unique in its properties, is a booming and ageless precursor of several breakthrough technologies of materials sciences; however, its low yield and high cost has created a challenge for its usage at industrial level. Herein, we report a novel, high yielding bacterial cell factory Komagataeibacter europaeus SGP37, isolated from rotten grapes, for the production of high quality and value added BNC. The strain was kinetically analyzed to evaluate BNC production under different physiological conditions and had demonstrated the production of 9.98+/-0.24gL-1 BNC at the expense of 12.08+/ 1.94gL-1 sugar following 2 weeks of cultivation, thus having the conversion yield of 0.82g BNC/g sugar which seems to be the maximum reported yield so far. The analysis of produced pellicle using FTIR, 13C CP MAS NMR, FE-SEM, XRD and TGA had shown similar structural, morphological and chemical characteristics with that of bacterial nanocellulose. Thus, K. europaeus SGP37 appears to be a potential strain and may offer a promising platform for industrial scale production of nanocelluloses. PMID- 27939512 TI - Frailty and the Role of Obliterative versus Reconstructive Surgery for Pelvic Organ Prolapse: A National Study. AB - PURPOSE: We sought to determine whether frailty affects the type of pelvic organ prolapse surgery performed and the odds of postoperative complications. MATERIALS AND METHODS: This is a retrospective cohort study of women who underwent obliterative and reconstructive surgery for pelvic organ prolapse in ACS (American College of Surgeons) NSQIP(r) (National Surgical Quality Improvement Program) from 2005 to 2013. We quantified frailty using NSQIP-FI (Frailty Index) and applied logistic regression models predicting the type of procedure (colpocleisis) and the odds of postoperative complications. RESULTS: We identified a total of 12,731 women treated with pelvic organ prolapse repair, of which 5.3% were colpocleisis procedures, from 2005 to 2013. Among women undergoing colpocleisis, the average age was 79.2 years and 28.5% had a NSQIP-FI of 0.18 or higher, indicating frailty. Women undergoing colpocleisis procedures had higher odds of being frail (NSQIP-FI 0.18 vs 0 OR 1.9, 95% CI 1.4-2.6) and were older (age 85+ vs less than 65 years OR 486.4, 95% CI 274.6-861.7). For all types of pelvic organ prolapse procedures, frailty increased the odds of complications (NSQIP-FI 0.18 vs 0 OR 2.8, 95% CI 1.8-3.0), after adjusting for age and type of pelvic organ prolapse procedure. CONCLUSIONS: For pelvic organ prolapse surgery, age rather than frailty is more strongly associated with the type of procedure performed. However, frailty is more strongly associated with postoperative complications than age. Furthermore, incorporating frailty into preoperative decision making is important to improve expectations and outcomes among older women considering pelvic organ prolapse surgery. PMID- 27939513 TI - Lung Toxicity after Lenalidomide Treatment in a Patient with Multiple Myeloma. PMID- 27939514 TI - New oral anticoagulants in patients with chronic kidney disease. AB - Patients with chronic kidney disease (CKD) develop bleeding and thrombotic tendencies, so the indication of anticoagulation at the onset of atrial fibrillation (AF) is complex. AF is the most common chronic cardiac arrhythmia, and thromboembolism and ischemic stroke in particular are major complications. In recent years, new oral anticoagulant drugs have been developed, and they have shown superiority over the classical AVK in preventing stroke, systemic embolism and bleeding risk, constituting an effective alternative to those resources. PMID- 27939515 TI - Impact of an emergency medicine pharmacist on time to thrombolysis in acute ischemic stroke: strength of association. PMID- 27939516 TI - Nonrheumatic myopericarditis post acute streptococcal pharyngitis: An uncommon cause of sore throat with ST segment elevation. AB - Nonrheumatic myopericarditis is an uncommon complication of acute pharyngitis caused by Group A Streptococcal infection (GAS). While the natural history of carditis complicating acute rheumatic fever is well established, the incidence, pathophysiology and clinical course of nonrheumatic myopericarditis are ill defined. Advances in rapid bedside testing for both myocardial injury and GAS pharyngitis have allowed for increasing recognition of this uncommon complication in patients presenting with a sore throat with associated chest discomfort. We describe a case of a 34years old man with GAS pharyngitis complicated by acute myopericarditis who presented with chest pain, ST segment elevation on electrocardiogram, and elevated cardiac biomarkers. PMID- 27939517 TI - Pyelonephritis following phenazopyridine use. AB - We present a case of pyelonephritis following the extended andsolitary use of over-the-counter phenazopyridine in a forty-year-oldfemale. The patient initially had uncomplicated cystitis signs andsymptoms which partially resolved with phenazopyridine and therefore she continued use. She presented to the emergency department with systemicsigns and symptoms of acute pyelonephritis. As phenazopyridine is devoidof antibacterial properties this allowed the lower urinary tractinfection to progress to acute pyelonephritis requiring intravenousantibiotics. Better patient education may preclude this complication. PMID- 27939518 TI - Failure rate of prehospital chest decompression after severe thoracic trauma. AB - INTRODUCTION: Chest decompression can be performed by different techniques, like needle thoracocentesis (NT), lateral thoracostomy (LT), or tube thoracostomy (TT). The aim of this study was to report the incidence of prehospital chest decompression and to analyse the effectiveness of these techniques. MATERIAL AND METHODS: In this retrospective case series study, all medical records of adult trauma patients undergoing prehospital chest decompression and admitted to the resuscitation area of a level-1 trauma center between 2009 and 2015 were reviewed and analysed. Only descriptive statistics were applied. RESULTS: In a 6-year period 24 of 2261 (1.1%) trauma patients had prehospital chest decompression. Seventeen patients had NT, six patients TT, one patient NT as well as TT, and no patients had LT. Prehospital successful release of a tension pneumothorax was reported by the paramedics in 83% (5/6) with TT, whereas NT was effective in 18% only (3/17). In five CT scans all thoracocentesis needles were either removed or extrapleural, one patient had a tension pneumothorax, and two patients had no pneumothorax. No NT or TT related complications were reported during hospitalization. CONCLUSION: Prehospital NT or TT is infrequently attempted in trauma patients. Especially NT is associated with a high failure rate of more than 80%, potentially due to an inadequate ratio between chest wall thickness and catheter length as previously published as well as a possible different pathophysiological cause of respiratory distress. Therefore, TT may be considered already in the prehospital setting to retain sufficient pleural decompression upon admission. PMID- 27939520 TI - Tapping into Salmonella typhimurium LT2 genome in a quest to explore its therapeutic arsenal: A metabolic network modeling approach. AB - S. typhimurium, the classical broad-host-range serovar is a widely distributed cause of food-borne illness. Escalating antibiotic resistance and potential of conjugal transmission to other pathogens attributable to its broad spectrum host specificities have aided S. typhimurium to emerge as a global health threat. To keep pace with ever evolving bacterial defenses, there is dire need to restock the antibiotic pipeline. Genome scale metabolic reconstructions present immense possibilities to decipher physiological properties of an organism using constraint-based methods The systems-level approaches of genome scale metabolic networks interrogation open up new avenues of drug target identification against deadly infectious diseases. We performed flux balance analysis and minimization of metabolic adjustment studies of genome scale reconstruction model of S. typhimurium targeted at identifying large number of metabolites with a potential to be utilized as therapeutic drug targets. These constraint based approaches initially predict a set of genes indispensable to bacterial survival by performing gene knockout studies which are then prioritized through a multistep process. Metabolites involved in l-rhamnose biosynthesis, peptidoglycan biosynthesis, fatty acid biosynthesis, and folate biosynthesis pathways were prioritized as candidate drug targets. This study provides a general therapeutic approach which can be effectively applied to other pathogens as well. PMID- 27939519 TI - 13-Ethylberberine reduces HMGB1 release through AMPK activation in LPS-activated RAW264.7 cells and protects endotoxemic mice from organ damage. AB - High mobility group box 1 (HMGB1), a highly conserved non-histone DNA-binding protein, plays an important role in the pathogenesis of sepsis. Previously, the authors reported 13-ethylberberine (13-EBR) has anti-inflammatory and antibacterial effects. However, the effect of 13-EBR on HMGB1 release was not investigated. In the present study, it was hypothesized 13-EBR might reduce HMGB1 release by activating AMPK under septic conditions. The results obtained showed 13-EBR significantly reduced HMGB1 release from LPS-activated RAW264.7 cells, and that this reduction was reversed by silencing p38, or AMPK, or by co-treating cells with p38 MAPKinase inhibitor. 13-EBR increased the phosphorylations of p38 and AMPK, and the phosphorylation of p38 by 13-EBR was inhibited by AMPK-siRNA, indicating AMPK acted upstream of p38. In the lung tissues of LPS-treated mice, 13-EBR administration significantly increased p-AMPK but reduced inducible nitric oxide synthase (iNOS) protein levels. Hematoxylin and eosin staining revealed 13 EBR significantly reduced LPS-induced lung and liver damage. In addition, 13-EBR inhibited NF-kB in LPS-activated RAW264.7 cells, and in LPS-treated mice, 13-EBR administration significantly increased survival. Furthermore, co-administration of 13-EBR plus LPS prevented LPS-induced aortic rings hypocontractile response to phenylephrine in vitro. Taken together, these results indicate 13-EBR might offer a means of treating sepsis through AMPK activation. PMID- 27939521 TI - The clinical significance and biological function of olfactomedin 4 in triple negative breast cancer. AB - Olfactomedin 4 abnormal expression has been observed in several types of human cancer, but the status of olfactomedin 4 in triple negative breast cancer is still unknown. The aim of our study is to explore the clinical significance and biological function of olfactomedin 4 in triple negative breast cancer. The mRNA and protein expression of olfactomedin 4 in triple negative breast cancer tissues and cell lines was detected, and the correlation between olfactomedin 4 expression and clinicopathological factors was analyzed by immunohistochemistry. The biological function of olfactomedin 4 on tumor-metastasis was explored by Transwell migration assay and invasion assay in vitro. In our results, olfactomedin 4 mRNA and protein expression is decreased in triple-negative breast cancer tissues and cell lines. Olfactomedin 4 protein low-expression associated with lymph node metastasis, distant metastasis, clinical stage and poor prognosis of triple-negative breast cancer patients. Up-regulation of olfactomedin 4 suppresseed triple-negative breast cancer cells migration and invasion, and reduced cell metastasis-associated protein MMP 9 expression. In conclusion, olfactomedin 4 is a novel biomarker of triple-negative breast cancer for predicting prognosis and developing targeted molecular therapies. PMID- 27939522 TI - Induction of acetylation and bundling of cellular microtubules by 9-(4 vinylphenyl) noscapine elicits S-phase arrest in MDA-MB-231 cells. AB - Noscapine is an alkaloid present in the latex of Papaver somniferum. It has been known for its anticancer efficacy and lack of severe toxicities to normal tissues. Structural alterations in noscapine core architecture have produced a number of potent analogues of noscapine. Here, we report an unusual activity of a novel noscapine analogue, 9-(4-vinylphenyl)noscapine (VinPhe-Nos) on cancer cells. As we reported earlier, VinPhe-Nos inhibited MDA-MB-231 cell proliferation with an IC50 of 6MUM. The present study elucidated a possible antiproliferative mechanism of action of VinPhe-Nos. The noscapinoid significantly inhibited clonogenic propagation of MDA-MB-231 cells. However, unlike the majority of tubulin-binding agents, it did not induce mitotic arrest; instead, it prolonged S phase. Although prolonged presence of the drug show some disruption of cellular microtubule architecture, it did not affect microtubule recovery after cold induced depolymerization. VinPhe-Nos, nevertheless, induced acetylation and bundling of microtubules. Our data suggest that rational modification of parent compound can alter its mechanism of action on cell cycle and that VinPhe-Nos can be investigated further as a less-toxic, S-phase-preferred, cytostatic anticancer agent. PMID- 27939523 TI - Effect of Praeruptorin C on 3-nitropropionic acid induced Huntington's disease like symptoms in mice. AB - Huntington's disease (HD) is an autosomal dominant inherited disease characterized by movement, psychiatric, and cognitive disorders. Previous research suggests that Praeruptorin C (Pra-C), an effective component in the root of Peucedanum praeruptorum dunn, a traditional Chinese medicine, may function in neuroprotection. The present study was conducted to evaluate the effectiveness of Pra-C in the treatment of HD-like symptoms in a 3-nitropropionic acid (3-NP) mouse model, and to explore the possible mechanism of the drug's activity. We treated 3-NP-injected mice with two different doses of Pra-C (1.5 and 3.0mg/kg) for 3 days. Motor behavior was tested using the open field test (OFT) and rotarod test, while psychiatric symptoms were tested using the forced swimming test (FST) and tail suspension test (TST). We found that Pra-C alleviated the motor deficits and depression-like behavior in the 3-NP-treated mice, and protected neurons from excitotoxicity. Western blot analysis revealed that Pra-C upregulated BDNF, DARPP32, and huntingtin protein in the striatum of 3-NP mice. These results taken together suggest that Pra-C may have therapeutic potential with respect to the movement, psychiatric, and cognitive symptoms of HD. PMID- 27939524 TI - Neem oil (Azadirachta indica A. Juss) affects the ultrastructure of the midgut muscle of Ceraeochrysa claveri (Navas, 1911) (Neuroptera: Chrysopidae). AB - Cytomorphological changes, by means of ultrastructural analyses, have been used to determine the effects of the biopesticide neem oil on the muscle fibers of the midgut of the predator Ceraeochrysa claveri. Insects, throughout the larval period, were fed eggs of Diatraea saccharalis treated with neem oil at a concentration of 0.5%, 1% or 2%. In the adult stage, the midgut was collected from female insects at two stages of adulthood (newly emerged and at the start of oviposition) and processed for ultrastructural analyses. In the newly emerged insects obtained from neem oil treatments, muscle fibers showed a reduction of myofilaments as well as swollen mitochondria and an accumulation of membranous structures. Muscular fibers responded to those cellular injuries with the initiation of detoxification mechanisms, in which acid phosphatase activity was observed in large vesicles located at the periphery of the muscle fiber. At the start of oviposition in the neem oil treated insects, muscle fibers exhibited signs of degeneration, containing vacant areas in which contractile myofilaments were reduced or completely absent, and an accumulation of myelin structures, a dilatation of cisternae of sarcoplasmic reticulum, and mitochondrial swelling and cristolysis were observed. Enzymatic activity for acid phosphatase was present in large vesicles, indicating that mechanisms of lytic activity during the cell injury were utilized but insufficient for recovery from all the cellular damage. The results indicate that the visceral muscle layer is also the target of action of neem oil, and the cytotoxic effects observed may compromise the function of that organ. PMID- 27939525 TI - The risk of developing cardiovascular disease in Bangladesh: does diabetes mellitus matter? Which socioeconomic status does it impact? A cross sectional study. AB - The elevation of blood pressure levels has been recognized as a determinant of the risk for several common cardiovascular diseases. This work explores the evidence of disparities in the form of association between hypertension and diabetes mellitus in different socioeconomic statuses (SESs) at household level. A population sample of 7561 individuals aged >=35 years from the 2011 Bangladesh Demographic Health Survey (BDHS) was used for this study. Concentration indexes are used to measure the disparities of myocardial infarction and diabetes mellitus with SES. A two-level hierarchical logit model was used to examine the effects of participants and household SES accompanied by other explanatory variables on having hypertension. Then, the analysis is stratified by SES groups to examine how the overall effect of diabetes mellitus on hypertension may vary with SES. Finally, predictive margins are determined to understand the predictive probability of diabetes and SES of having hypertension as a risk factor of developing cardiovascular disease. The descriptive summary measures of SES inequality indicate that prevalence of hypertension and diabetes was higher among high SES. The multivariate analysis covering all samples reveals that there is a strong association between diabetes and hypertension (P < .01). Likewise, after stratifying, it is evident that in high SES, there is a strong association between individuals with diabetes mellitus and hypertension development; they have around four-fold higher chance of being affected by hypertension in comparison to individuals with normal fasting plasma glucose (P < .01). Moreover, there are strong associations between individuals in low and medium SESs having diabetes and having hypertension (P < .01); the likelihood of having hypertension is almost double compared to individuals who have no diabetes. The result of this study also shed light on the chance of an increase in prevalence of hypertension in prediabetes individuals and in medium and high SES groups, although the association is statistically insignificant (P > .05). Finally, the predictive analysis reveals that the predictive margin of having hypertension is high among individuals belonging to the high SES (23%; CI, 20-23) and diabetic patients with high SES (37%; CI, 33-47). Contrary to other developed countries, hypertension in Bangladesh is prevalent among all SES, and the likelihood is high among diabetic patients in the medium and high SES. Hence, urgent preventive measures are needed to control the impending comorbidity of diabetes and developing cardiovascular disease risk. PMID- 27939526 TI - Sensitive detection of hemodynamic failure during orthostatic stress in patients with diabetic polyneuropathy using a mini laser Doppler blood flowmeter. AB - Autonomic dysfunction in diabetes is serious but often underestimated. The purpose of this study was to evaluate hemodynamics within the important initial phase just after standing, which cannot be evaluated by conventional instruments for orthostatic hypotension. Earlobe blood flow (EBF), which indirectly reflects the blood pressure response on standing, was evaluated using a mini laser Doppler flowmeter during standing from the sitting position in 58 healthy controls and 56 diabetic patients categorized as without (11), mild (27), and advanced diabetic polyneuropathy (18). The response area of the EBF waveform within 30 seconds after standing was calculated. An increased response area indicates poor recovery of EBF. Response area increased significantly with the degree of neuropathy (P < .001 for linear trend). Orthostatic hypotension was detected in two patients in the mild neuropathy group. The present approach may be sensitive and practical for detecting autonomic dysfunction not detected with the conventional orthostatic test. PMID- 27939527 TI - Nitric oxide production by peritoneal macrophages from aged rats: A short term and direct modulation by citrulline. AB - Citrulline has anti-inflammatory properties and exerts beneficial effects on various impaired functions in aging. However, there are few data on citrulline action on immune function in aged populations. The objective of the study was to evaluate citrulline ability, after in vivo and in vitro administration, to modulate macrophage functions in aged rats and the possible pathways involved. Twenty-one-month-old Sprague-Dawley rats (n = 27) received a citrulline supplementation at 5 g/kg/d for 5 days, or an isonitrogenous diet, and peritoneal macrophages were cultured with or without LPS. In the in vitro study, macrophages from 22-month-old rats (n = 16) were cultured with or without LPS, citrulline and inhibitors of different inflammatory pathways (n = 8/conditions). Nitric oxide (NO) and tumor necrosis factor alpha (TNFalpha) production were measured in both in vivo and in vitro studies. Citrulline decreased NO production variability by peritoneal macrophages after in vivo administration (p = 0.0034) and downregulated NO production by 22% after in vitro administration (95% CI: [6%; 35%]; p = 0.0394), without any direct effect on TNFalpha production. None of the transductional pathways explored seem to be involved. Citrulline slightly modulates NO production in vivo and in vitro, suggesting a possible action through modulation of arginine metabolism in macrophages rather than a direct transductional effect. The pleiotropic effects of citrulline in aging could be due, at least in part, to the anti-inflammatory effect of citrulline. PMID- 27939528 TI - Peroxisome Proliferator Activated Receptor Beta (PPARbeta) activity increases the immune response and shortens the early phases of skeletal muscle regeneration. AB - Peroxisome Proliferator-Activated Receptor Beta (PPARbeta) is a transcription factor playing an important role in both muscle myogenesis and remodeling, and in inflammation. However, its role in the coordination of the transient muscle inflammation and reparation process following muscle injury has not yet been fully determined. We postulated that activation of the PPARbeta pathway alters the early phase of the muscle regeneration process, i.e. when immune cells infiltrate in injured muscle. Tibialis anteriors of C57BL6/J mice treated or not with the PPARbeta agonist GW0742 were injected with cardiotoxin (or with physiological serum for the contralateral muscle). Muscle regeneration was monitored on days 4, 7, and 14 post-injury. We found that treatment of mice with GW0742 increased, at day 4 post-damage, the recruitment of immune cells (M1 and M2 macrophages) and upregulated the expression of the anti-inflammatory cytokine IL-10 and TGF-beta mRNA. Those effects were accompanied by a significant increase at day 4 of myogenic regulatory factors (Pax7, MyoD, Myf5, Myogenin) mRNA in GW0742-treated mice. However, we showed an earlier return (7 days vs 14 days) of Myf5 and Myogenin to basal levels in GW0742- compared to DMSO-treated mice. Differential effects of GW0742 observed during the regeneration were associated with variations of PPARbeta pathway activity. Collectively, our findings indicate that PPARbeta pathway activity shortens the early phases of skeletal muscle regeneration by increasing the immune response. PMID- 27939529 TI - Exploring the biodiversity of two groups of Oenococcus oeni isolated from grape musts and wines: Are they equally diverse? AB - One hundred and four Oenococcus oeni isolates were characterised by the carbohydrate fermentation (CH) profile and DNA fingerprinting. Forty-four isolates came from grape must, and 60 from wines sampled at the end of alcoholic fermentation or during malolactic fermentation. The grape must isolates fermented more CH than the wine isolates. In genotypical terms, no clear boundary between grape must and wine isolates was found. Diversities were deduced by considering the isolates of grape must and of wine separately and jointly. By considering only CH fermentation abilities, the group of grape must isolates gave higher diversity index (DICH) values than those isolated from wine; i.e., these isolates were metabolically more diverse. The contrary occurred when the DNA fingerprints were used to calculate DIRAPD-VNTR: wine isolates were genotypically more diverse than grape must ones. With a polyphasic approach, which considered metabolic and genotypic data, the diversity index of both isolate groups (from grape must and wine) was the same, 0.993, which was slightly lower than that calculated from all the isolates (0.997). PMID- 27939531 TI - Technical note: In vitro digestibility of amylase-treated, ash-corrected neutral detergent fiber, with addition of sodium sulfite, at 240 hours with or without rumen fluid reinoculation. AB - Long-term in vitro fermentation (240 h) evaluating amylase-treated, ash-corrected neutral detergent fiber, with addition of sodium sulfite (aNDFom) digestibility is required to quantify the indigestible fiber fraction. It is commonly accepted to inoculate rumen fluid more than one time during such fermentations, every 96 h or at 120 h. However, no studies have been conducted to verify if the reinoculation is actually required to properly carry out the fermentation process. The current study aims to evaluate the effects of these procedures on aNDFom digestibility at 240 h. The study was conducted on a total of 24 forage samples (8 alfalfa hays, 8 grass hays, and 8 corn silages). Samples were digested in triplicate at 240 h in vitro. Rumen fluid was added twice (at 96 and 192 h) in treatment 1, after 120 h in treatment 2, whereas no addition was made in treatment 3. At the end of the fermentations, residual aNDFom was quantified to calculate digestibility. Among treatments, no difference was found in digestibility of aNDFom. Moreover, treatment 1 resulted in higher variability compared with other treatments. Results obtained in the current study show that subsequent addition of rumen fluid is not necessary for a proper estimation of aNDFom digestibility, and can be avoided. PMID- 27939532 TI - Associations between exposure to bovine herpesvirus 1 (BoHV-1) and milk production, reproductive performance, and mortality in Irish dairy herds. AB - As cost-benefit analyses are required to prioritize and promote disease control and eradication programs within a jurisdiction, national data relating to disease related production losses are particularly useful. The objectives of the current study were to use Irish bovine herpesvirus 1 (BoHV-1) prevalence data in dairy herds, obtained by bulk milk sampling on 4 occasions over the 2009 lactation, to document associations between milk production, fertility performance, mortality, and BoHV-1 herd status. Bulk milk (n = 305) antibody ELISA was used to classify farms as positive or negative in terms of endemic BoHV-1. Cow-level (milk parameters only) and herd-level performance data were sourced from the Irish Cattle Breeding Federation. Ordinary linear and negative binomial regressions were used to investigate associations between milk, fertility, and mortality performance and herd-level BoHV-1 results (both categorical and continuous variables). Only slight effects on the rates of carryover cows, nonpregnant cows, and total deaths were highlighted with increasing ELISA sample/positive (%) values (incidence rate ratio = 1.001). Multiparous cows in herds BoHV-1 bulk milk antibody positive recorded a reduction in milk yield per cow per year of 250.9 L in the multivariable linear model. Milk fat and protein yields were also affected by herd BoHV-1 status, again highlighting sub-optimal milk production in BoHV-1 bulk milk-positive herds. The current study has highlighted an economical method of investigating losses due to endemic infection using repeated bulk milk sampling over a single lactation. These data can contribute to analyzing the cost benefit of applying BoHV-1 control strategies both on farm and at a national level. PMID- 27939530 TI - Diverse Mesorhizobium bacteria nodulate native Astragalus and Oxytropis in arctic and subarctic areas in Eurasia. AB - Rhizobia nodulating native Astragalus and Oxytropis spp. in Northern Europe are not well-studied. In this study, we isolated bacteria from nodules of four Astragalus spp. and two Oxytropis spp. from the arctic and subarctic regions of Sweden and Russia. The phylogenetic analyses were performed by using sequences of three housekeeping genes (16S rRNA, rpoB and recA) and two accessory genes (nodC and nifH). The results of our multilocus sequence analysis (MLSA) of the three housekeeping genes tree showed that all the 13 isolates belonged to the genus Mesorhizobium and were positioned in six clades. Our concatenated housekeeping gene tree also suggested that the isolates nodulating Astragalus inopinatus, Astragalus frigidus, Astragalus alpinus ssp. alpinus and Oxytropis revoluta might be designated as four new Mesorhizobium species. The 13 isolates were grouped in three clades in the nodC and nifH trees. 15N analysis suggested that the legumes in association with these isolates were actively fixing nitrogen. PMID- 27939534 TI - Linear and nonlinear genetic relationships between type traits and productive life in US dairy goats. AB - Linear or nonlinear genetic relationships between productive life and functional productive life at 72 mo, with final score (SCO), stature, strength, dairyness (DAI), teat diameter, rear legs (side view), rump angle, rump width (RUW), fore udder attachment (FUA), rear udder height, rear udder arch, udder depth (UDD), suspensory ligament (SUS), and teat placement, as well as heritabilities and correlations were estimated from multibreed US dairy goat records. Productive life was defined as the total days in production until 72 mo of age (PL72) for goats having the opportunity to express the trait. Functional productive life (FPL72) was analyzed by incorporating first lactation milk yield, fat yield, protein yield, and SCO in the statistical model. Heritabilities and correlations were estimated using linear mixed models with pedigree additive genetic relationships and ASReml software. Nonlinearity of genetic relationships was assessed based on second-degree polynomial (quadratic) regression models, with the breeding values of PL72 or FPL72 as responses and the breeding values for each type trait (linear and quadratic) as predictor variables. Heritability estimates were 0.19, 0.14, 0.18, 0.20, 0.14, 0.07, 0.28, 0.20, 0.15, 0.13, 0.25, 0.18, 0.20, 0.21, 0.21, and 0.32 for PL72, FPL72, SCO, stature, strength, DAI, teat diameter, rear legs, rump angle, RUW, FUA, rear udder height, rear udder arch, UDD, SUS, and teat placement, respectively. The type traits SCO, RUW, and FUA were the most correlated with PL72 and FPL72, so these may be used as selection criteria to increase longevity in dairy goats. An increase in the coefficient of determination >1% for the second degree, compared with that for the linear model for either PL72 or FPL72, was taken as evidence of a nonlinear genetic relationship. Using this criterion, PL72 showed maximum values at intermediate scores in DAI, UDD, and RUW, and maximum values at extreme scores in FUA and SUS, whereas FPL72 showed maximum values at intermediate scores in DAI and UDD, and maximum values at extreme scores in FUA, RUW, and SUS. Selecting for increased SCO, RUW, and FUA will lead to an increase of FPL72 in goats. Consideration of nonlinear relationships between DAI, FUA, RUW, SUS, and UDD may help in the design of more efficient breeding programs for dairy goats using conformation traits. PMID- 27939533 TI - Effect of incomplete milking on milk production rate and composition with 2 daily milkings. AB - The primary aim of this study was to assess the effects of incomplete milking on milk secretion and milk composition at the quarter level. Twelve cows were enrolled beginning at 5 d in milk and remained on study through 47 d in milk. Half of each contralateral udder was incompletely milked (treatment), detaching the teat cup early to leave approximately 30% of the total milk yield behind. This target milk remaining in the gland was based on weekly calibration milking measurements of quarter total milk yield. Control quarters were milked completely until milk flow had decreased to 0 kg/min based on visual assessment. Harvested milk yield was measured twice daily at each milking, and milk components (fat, protein, lactose, solids nonfat, milk urea nitrogen) and somatic cell count, were measured twice weekly at the quarter level. The experimental unit in this design was the half-udder, and a mixed-model approach was used to assess the main and interactive effects of experiment week and treatment on milk production rate, milk remaining in the gland, and milk composition. The effect of treatment on milk production rate was significant, with the average control half-udder producing 0.97 kg/h and the treatment half-udder 0.73 kg/h. The effect of week on milk production rate and the interaction of week * treatment were also significant. The effect of treatment on milk remaining in the gland was significant, illustrating that an increase in milk remaining in the cisternal compartment had been achieved. We detected a significant decrease in milk lactose percentage in treatment half-udders, and a significant increase in somatic cell count (log10). The increase was relatively small, from a geometric mean of 26,300 cells/mL in control quarters to 48,300 cells/mL in treatment quarters. The decrease in milk production rate in treatment half-udders supports current knowledge about how mammary epithelial cell secretion, proliferation, and apoptosis are modulated by autocrine-paracrine factors. PMID- 27939535 TI - Increased feeding frequency increased milk fat yield and may reduce the severity of subacute ruminal acidosis in higher-risk cows. AB - The objectives of this study were to determine whether feeding behavior is different between cows at higher or lower risk for subacute ruminal acidosis (SARA) and whether increasing feeding frequency could be used to reduce the severity of SARA in higher-risk cows. In preliminary studies, 16 ruminally cannulated lactating cows were fed high-grain diets once per day to increase the risk of SARA. After a 17-d diet adaptation, ruminal pH was measured every 30 s over 24 h. Cows were classified as higher-risk (n = 7) or lower-risk (n = 9) for SARA based on an acidosis index (area of pH <5.8/dry matter intake). Feeding behavior was recorded every 5 min over the same 24 h. The 24-h observation period was analyzed in 3 periods of 8 h after feeding. Although there was no significant difference in overall dry matter intake, higher-risk cows spent more time eating in the first 8-h period after feeding than lower-risk cows (186 vs. 153 min) and less time eating in the third 8-h period (19 vs. 43 min). In the primary experiment, 8 ruminally cannulated lactating cows were fed a high-grain diet once per day (1*; 0800 h) or 3 times per day (3*; 0800, 1500, and 2000 h) in a crossover design with 21-d periods (16 d of treatment adaptation and 5 d of data collection). Rumen pH and feeding behavior were measured over 72 h. Behavior data were summarized separately for the 3 periods (0800 to 1500, 1500 to 2200, and 2200 to 0800 h). Four cows were categorized as higher-risk and 4 as lower-risk, based on their acidosis index. The 3* feeding reduced eating time between 0800 and 1500 h (99 vs. 145 min) and increased eating time between 2200 and 0800 h (76 vs. 43 min) for all cows, regardless of category, compared with 1* feeding. For higher-risk cows, 3* feeding reduced the area below pH 5.8 (51 vs. 98 pH * min/d), but it did not affect rumen pH for the lower-risk cows. Milk yield was not different between groups, but 3* feeding increased milk fat yield (1.22 vs. 1.08 kg/d) for all cows, regardless of category, compared to 1* feeding. Our results suggest that cows at higher risk for SARA eat less evenly throughout the day; increasing feeding frequency may reduce the severity of SARA in higher-risk cows and may also increase milk fat yield. PMID- 27939536 TI - Determination of energy and protein requirements for crossbred Holstein * Gyr preweaned dairy calves. AB - The objective was to quantify the energy and protein nutritional requirements of Holstein * Gyr crossbred preweaned dairy calves until 64 d of age. Thirty-nine Holstein * Gyr crossbred male calves with an average initial live weight (mean +/ SEM; for all next values) of 36 +/- 1.0 kg were used. Five calves were slaughtered at 4 d of life to estimate the animals' initial body composition (reference group). The remaining 34 calves were distributed in a completely randomized design in a 3 * 2 factorial arrangement consisting of 3 levels of milk (2, 4, or 8 L/d) and 2 levels of starter feed (presence or absence in diet). At 15 and 45 d of life, 4 animals from each treatment were subjected to digestibility trials with total collection of feces (for 72 h) and urine (for 24 h). At 64 d of age, all animals were slaughtered, their gastro-intestinal tract was washed to determine the empty body weight (EBW; kg), and their body tissues were sampled for subsequent analyses. The net energy requirement for maintenance was estimated using an exponential regression between metabolizable energy intake and heat production (both in Mcal/EBW0.75 per d) and was 74.3 +/- 5.7 kcal/EBW0.75 per d, and was not affected by inclusion of starter feed in the diet. The metabolizable energy requirement for maintenance was determined at the point of zero energy retention in the body and was 105.2 +/- 5.8 kcal/EBW0.75 per d. The net energy for gain was estimated using the EBW and the empty body gain (EBG; kg/d) as 0.0882 +/- 0.0028 * EBW0.75 * EBG0.9050+/-0.0706. The metabolizable energy efficiency for gain (kg) of the milk was 57.4 +/- 3.45%, and the kg of the starter feed was 39.3 +/- 2.09%. The metabolizable protein requirement for maintenance was 3.52 +/- 0.34 g/BW0.75 per d. The net protein required for each kilogram gained was estimated as 119.1 +/- 32.9 * EBW0.0663+/ 0.059. The metabolizable protein efficiency for gain was 77 +/- 8.5% and was not affected by inclusion of starter feed in the diet. In conclusion, the energy efficiency for gain of milk is higher than that of starter and the net protein required per unit protein gain increases with empty body weight. PMID- 27939537 TI - Short communication: Early-lactation, but not mid-lactation, bovine lactoferrin preparation increases epithelial barrier integrity of Caco-2 cell layers. AB - Bovine lactoferrin is an important milk protein with many health-promoting properties, including improving intestinal barrier integrity. Dysfunction of this barrier, commonly referred to as "leaky gut," has been linked to inflammatory and autoimmune diseases. With some processing techniques, lactoferrin isolated from milk collected at the start of the milking season (early lactation) may have lower purity than that isolated from milk collected during the rest of the milking season (mid-lactation) and could result in differences in bioactivity based on the stage of lactation. We compared reversed-phase HPLC chromatographs of early-lactation and mid-lactation preparations and found that both had large chromatograph peaks at the time predicted for lactoferrin. The notable difference between the 2 chromatographs was a much larger peak in the early-lactation lactoferrin sample that was determined to be angiogenin. Angiogenin was first identified due to its ability to induce new blood vessel formation, but is now known to be involved in numerous physiological processes. Then, we compared the effects of early-lactation and mid-lactation lactoferrin preparations in 2 bioassays: trans-epithelial electrical resistance (TEER), a measure of intestinal barrier integrity, and peripheral blood mononuclear cell cytokine secretion, a measure of immune-stimulatory properties. We found that early-lactation lactoferrin increased TEER across Caco-2 cell layers compared with control from 10 to 48 h, mid-lactation lactoferrin did not alter TEER. We also found that early-lactation lactoferrin reduced the amount of IL-8 produced by peripheral blood mononuclear cells (compared with those treated with control medium) to a greater extent than mid-lactation lactoferrin. A pro-inflammatory chemokine, IL-8 is also known to decrease barrier function. These results suggest that the decrease in IL-8 production in the presence of early-lactation lactoferrin may be the mechanism by which it increases TEER. The anti-inflammatory effect of early lactation lactoferrin may be related to the presence of angiogenin, which is known to suppress inflammatory responses. This work indicates that products rich in angiogenin may have intestinal health benefits, and further work to investigate this is warranted. PMID- 27939538 TI - Effects of forage provision to dairy calves on growth performance and rumen fermentation: A meta-analysis and meta-regression. AB - A meta-analysis of the potential effect of forage provision on growth performance and rumen fermentation of dairy calves was conducted using published data from the literature (1998-2016). Meta-regression was used to evaluate the effects of different forage levels, forage sources, forage offering methods, physical forms of starter, and grain sources on the heterogeneity of the results. We considered 27 studies that reported the effects of forage provision to dairy calves. Estimated effect sizes of forage were calculated on starter feed intake, average daily gain (ADG), feed efficiency (FE), body weight (BW), and rumen fermentation parameters. Intake of starter feed, ADG, BW, ruminal pH, and rumen molar proportion of acetate increased when supplementing forage but FE decreased. Heterogeneity (the amount of variation among studies) was significant for intake of starter feed, ADG, FE, final BW, and rumen fermentation parameters. Improving overall starter feed intake was greater in calves offered alfalfa hay compared with those offered other types of forages. During the milk feeding and overall periods, improving ADG was greater for calves fed a high level of forage (>10% in dry matter) compared with those fed a low level of forage (<=10% in dry matter) diets. The advantages reported in weight gain at a high level of forage could be due to increased gut fill. Improving overall ADG was lower for calves offered forages with textured starter feed compared with ground starter feed. The meta regression analysis revealed that changes associated with forage provision affect FE differently for various forage sources and forage offering methods during the milk-feeding period. Forage sources also modulated the effect of feeding forage on ruminal pH during the milk-feeding period. In conclusion, forage has the potential to affect starter feed intake and performance of dairy calves, but its effects depend on source, level, and method of forage feeding and physical form of starter feed independently of grain sources included in the starter feed. PMID- 27939539 TI - Effectiveness of a standardized footbath protocol for prevention of digital dermatitis. AB - A footbath is the most common herd-level approach to control digital dermatitis (DD) in intensive dairy farming. However, wide variation in footbath design and protocols suggests a gap between evidence-based management practices and on-farm implementation. The objective was to evaluate effectiveness of a standardized footbath protocol in decreasing prevalence of active DD lesions in lactating dairy cattle. The protocol was based on current scientific literature, including footbath design and management. The M-stage classification system was used to score DD lesions. Scores were also combined into a simplified scoring system: no lesions (M0), active lesions (M1, M2, and M4.1), and chronic lesions (M3 and M4). A controlled intervention trial was conducted on 9 farms over 22 wk. Each farm served as its own control with data collected for 10 wk before and 12 wk after intervention. A total of 1,978 lactating cattle were assessed biweekly for DD lesions and leg cleanliness in the milking parlor. Lactating cattle were also inspected in the trimming chute at 3 time points: start, intervention, and end of trial. Intervention consisted of implementing an automated footbath that measured 3 m long, 0.50 m wide, held a fluid depth of 0.15 m, along with a weekly footbath protocol using 5% CuSO4 for 4 consecutive milkings, with footbath content replaced at a maximum of 200 cow passes. Multilevel logistic regression models for repeated measures were used to evaluate effects of the standardized footbath protocol in preventing active DD lesions. For the purpose of analysis, farms' within-herd prevalence of active DD lesions (at baseline) was assessed and categorized as low (<15%) or high (>=15%). Farms with low or high within-herd prevalence of active DD lesions at trial outset had a mean cow-level prevalence of active DD lesions of 8% (range, 2 to 13) and 31% (range, 18 to 43), respectively. At milking parlor inspections, apparent prevalence of active DD lesions decreased from the time of footbath intervention, but this effect interacted with the farms' baseline prevalence of active DD lesions. In that regard, on farms with high prevalence of active DD at baseline, apparent prevalence of active DD lesions decreased after intervention, whereas on farms with low prevalence of active DD at baseline, apparent prevalence of active DD lesions did not change. At the cow level, poor leg cleanliness was associated with higher prevalence of active DD lesions. At trimming chute inspections, prevalence of active DD lesions decreased from start to the end of the trial (22 and 14%, respectively); concurrently, prevalence of feet with no DD lesions (M0) increased (39 and 48%). We concluded that on farms with high DD prevalence, implementation of proper footbath design and improvement of footbathing management will decrease prevalence of active DD lesions and increase prevalence of feet without DD lesions. In addition, improving cow cleanliness will further result in control of active DD lesions. PMID- 27939540 TI - Including nonadditive genetic effects in mating programs to maximize dairy farm profitability. AB - We compared the outcome of mating programs based on different evaluation models that included nonadditive genetic effects (dominance and heterozygosity) in addition to additive effects. The additive and dominance marker effects and the values of regression on average heterozygosity were estimated using 632,003 single nucleotide polymorphisms from 7,902 and 7,510 Holstein cows with calving interval and production (milk, fat, and protein yields) records, respectively. Expected progeny values were computed based on the estimated genetic effects and genotype probabilities of hypothetical progeny from matings between the available genotyped cows and the top 50 young genomic bulls. An index combining the traits based on their economic values was developed and used to evaluate the performance of different mating scenarios in terms of dollar profit. We observed that mating programs with nonadditive genetic effects performed better than a model with only additive effects. Mating programs with dominance and heterozygosity effects increased milk, fat, and protein yields by up to 38, 1.57, and 1.21 kg, respectively. The inclusion of dominance and heterozygosity effects decreased calving interval by up to 0.70 d compared with random mating. The average reduction in progeny inbreeding by the inclusion of nonadditive genetic effects in matings compared with random mating was between 0.25 to 1.57 and 0.64 to 1.57 percentage points for calving interval and production traits, respectively. The reduction in inbreeding was accompanied by an average of A$8.42 (Australian dollars) more profit per mating for a model with additive, dominance, and heterozygosity effects compared with random mating. Mate allocations that benefit from nonadditive genetic effects can improve progeny performance only in the generation where it is being implemented, and the gain from specific combining abilities cannot be accumulated over generations. Continuous updating of genomic predictions and mate allocation programs are required to benefit from nonadditive genetic effects in the long term. PMID- 27939541 TI - Invited review: Phenotypes to genetically reduce greenhouse gas emissions in dairying. AB - Phenotypes have been reviewed to select for lower-emitting animals in order to decrease the environmental footprint of dairy cattle products. This includes direct selection for breath measurements, as well as indirect selection via indicator traits such as feed intake, milk spectral data, and rumen microbial communities. Many of these traits are expensive or difficult to record, or both, but with genomic selection, inclusion of methane emission as a breeding goal trait is feasible, even with a limited number of registrations. At present, methane emission is not included among breeding goals for dairy cattle worldwide. There is no incentive to include enteric methane in breeding goals, although global warming and the release of greenhouse gases is a much-debated political topic. However, if selection for reduced methane emission became a reality, there would be limited consensus as to which phenotype to select for: methane in liters per day or grams per day, methane in liters per kilogram of energy-corrected milk or dry matter intake, or a residual methane phenotype, where methane production is corrected for milk production and the weight of the cow. We have reviewed the advantages and disadvantages of these traits, and discuss the methods for selection and consequences for these phenotypes. PMID- 27939542 TI - Lama glama alphaS1-casein: Identification of new polymorphisms in the CSN1S1 gene. AB - South American camelids have been poorly genetically investigated and little information is available in llamas (Lama glama) regarding the diversity of the caseins at the protein and gene level. Exon skipping and duplication events previously reported in the alphaS1-casein gene (CSN1S1) led us to investigate the genetic variability at this locus. Seventy-two positive clones for the alphaS1 casein transcripts were analyzed and randomly sequenced. The comparative analysis of the sequences revealed 2 transitions, c.366A>G and c.690T>C, at the 10th nucleotide of exon 12 and 94 bp of exon 19, respectively. These SNP are responsible for 2 amino acid changes, Ile->Val in position 86 and Tyr->His in position 194 of the mature protein. Both polymorphisms clarify the genetic events behind the protein variants A and B. This result was confirmed by isoelectric focusing analysis of llama milk samples. Quick methods based on PCR-RFLP and allele-specific PCR were set up for allelic discrimination in a population of 128 animals. Based on genotyping results, 4 haplotypes were observed and the estimated frequencies indicated B as the most common haplotype (0.629) in the investigated population. These data add knowledge to the genetic variability of a species little investigated, and open opportunity for new investigation in the field of milk protein for South American camelids, including the possibility, in the future, to select alleles with favorable characteristics. PMID- 27939543 TI - The cow pedogram-Analysis of gait cycle variables allows the detection of lameness and foot pathologies. AB - Changes in gait characteristics are important indicators in assessing the health and welfare of cattle. The aim of this study was to detect unilateral hind limb lameness and foot pathologies in dairy cows using 2 high-frequency accelerometers (400 Hz). The extracted gait cycle variables included temporal events (kinematic outcome = gait cycle, stance phase, and swing phase duration) and several peaks (kinetic outcome = foot load, toe-off). The study consisted of 2 independent experiments. Experiment 1 was carried out to compare the pedogram variables between the lateral claw and respective metatarsus (MT; n = 12) in sound cows (numerical rating system <3, n = 12) and the differences of pedogram variables across limbs within cows between lame cows (numerical rating system >=3, n = 5) and sound cows (n = 12) using pedogram data that were visually compared with the synchronized cinematographic data. Experiment 2 was carried out to determine the differences across limbs within cows between cows with foot lesions (n = 12) and without foot lesions (n = 12) using only pedogram data. A receiver operator characteristic analysis was used to determine the performance of selected pedogram variables at the cow level. The pedogram of the lateral claw of sound cows revealed similarities of temporal events (gait cycle duration, stance and swing phases) but higher peaks (toe-off and foot load) as compared with the pedogram of the respective MT. In both experiments, comparison of the values between groups showed significantly higher values in lame cows and cows with foot lesions for all gait cycle variables. The optimal cutoff value of the relative stance phase duration for identifying lame cows was 14.79% and for cows with foot lesions was 2.53% with (both 100% sensitivity and 100% specificity) in experiments 1 and 2, respectively. The use of accelerometers with a high sampling rate (400 Hz) at the level of the MT is a promising tool to indirectly measure the kinematic variables of the lateral claw and to detect unilateral hind limb lameness and hind limb pathologies in dairy cows and is highly accurate. PMID- 27939544 TI - Effect of feeding warm-season annuals with orchardgrass on ruminal fermentation and methane output in continuous culture. AB - A 4-unit, dual-flow continuous culture fermentor system was used to assess nutrient digestibility, volatile fatty acids (VFA) production, bacterial protein synthesis, and methane (CH4) output of warm-season annual grasses. Treatments were randomly assigned to fermentors in a 4 * 4 Latin square design using 7 d for adaptation to treatment and 3 d for sample collection. Treatments were (1) 100% orchardgrass (Dactylis glomerata L.; ORD); (2) 50% orchardgrass + 50% Japanese millet [Echinochloa esculenta (A. Braun) H. Scholz; MIL]; (3) 50% orchardgrass + 50% brown midrib sorghum * sudangrass (Sorghum bicolor L. Moench * S. bicolor var. sudanense; SSG]; or (4) 50% orchardgrass + 25% millet + 25% sorghum * sudangrass (MIX). Fermentors were fed 60 g of dry matter (DM)/d in equal portions of herbage 4 times daily (0730, 1030, 1400, and 1900 h). To replicate a typical 12-h pasture rotation, fermentors were fed the orchardgrass at 0730 and 1030 h and the individual treatment herbage (orchardgrass, Japanese millet, sorghum * sudangrass, or 50:50 Japanese millet and sorghum * sudangrass) at 1400 and 1900 h. Gas samples for CH4 analysis were collected 6 times daily at 0725, 0900, 1000, 1355, 1530, and 1630 h. Fermentor pH was determined at the time of feeding, and fermentor effluent samples for NH3-N and VFA analyses were taken daily at 1030 h on d 8, 9, and 10. Samples were also analyzed for DM, organic matter (OM), crude protein, and fiber fractions to determine nutrient digestibilities. Bacterial efficiency was estimated by dividing bacterial N by truly digested OM. True DM and OM digestibilities and pH were not different among treatments. Apparent OM digestibility was greater in ORD than in MIL and SSG. The concentration of propionate was greater in ORD than in SSG and MIX, and that of butyrate was greatest in ORD and MIL. Methane output was greatest in MIL, intermediate in ORD, and lowest in SSG and MIX. Nitrogen intake did not differ across treatments, whereas bacterial N efficiency per kilogram of truly digestible OM was greatest in MIL, intermediate in SSG and MIX, and lowest in ORD. True crude protein digestibility was greater in ORD versus MIL, and ORD had lower total N, non-NH3 N, bacterial N, and dietary N in effluent flows than MIL. Overall, we detected little difference in true nutrient digestibility; however, SSG and MIX provided the lowest acetate to propionate ratio and lower CH4 output than MIL and ORD. Thus, improved warm-season annual pastures (i.e., brown midrib sorghum * sudangrass) could provide a reasonable alternative to orchardgrass pastures during the summer months when such perennial cool-season grass species have greatly reduced productivity. PMID- 27939545 TI - Short communication: Calving site selection of multiparous, group-housed dairy cows is influenced by site of a previous calving. AB - A calving cow and her newborn calf appear to have an attracting effect on periparturient cows, which may potentially influence the functionality of future motivation-based calving pen designs. In this pilot study we examined whether calving site selection of group-housed Holstein dairy cows was affected by the site of a previous calving. Ten multiparous cows moved to 1 of 2 group pens 11 (range = 4-27) d before calving were included. Each pen consisted of an open area (9 * 9 m) connected to 6 secluded areas (4.5 * 3 m each), where cows could move freely between all areas. Time of calving, location of the breaking of the amniotic sac, as well as the place of birth were recorded. In all but 1 case cows calved within a distance of 1 cow length from where the previous calving took place, suggesting that the cows did not select calving site at random. These preliminary observations indicate that choice of calving site may be affected by the site of a previous calving, potentially explained by the presence of amniotic fluids. PMID- 27939546 TI - Evaluation of the effects of colostrum replacer supplementation of the milk replacer ration on the occurrence of disease, antibiotic therapy, and performance of pre-weaned dairy calves. AB - The objective of this study was to evaluate the effects of colostrum supplementation of the milk replacer ration on disease occurrence, antibiotic therapy, and performance of pre-weaned dairy calves with adequate transfer of passive immunity. Two hundred and two 1-d-old Holstein dairy calves were assigned to 1 of 2 groups after arrival to a dairy calf rearing facility. Calves assigned to the control group (n = 100) received milk replacer (28% crude protein and 20% crude fat) without colostrum inclusion twice daily. Calves assigned to the treatment group (n = 102) received 150 g of supplemental colostrum replacer powder added to their milk replacer twice daily for the first 14 d of life. Before group assignment, serum samples were collected from all calves to confirm transfer of passive immunity. Calves were evaluated daily until weaning (56 d of life) for signs of clinical disease as well as any treatment with antibiotics. Presentation of clinical disease and antibiotic treatment was recorded daily by personnel blinded to treatment allocation. Adequate transfer of passive immunity was confirmed in all calves at the start of the study and mean serum IgG values were similar among calves from treatment and control groups. The odds ratios of having abnormal feces and abnormal respiration during the pre-weaning period for calves from the treatment group were 0.15 and 0.46 the odds ratios of calves from the control group, respectively. The odds ratios of receiving antibiotic therapy during the pre-weaning period for calves from the treatment group were 0.09 the odds ratios of calves from the control group. Mean body weight and average daily gain at weaning were not significantly different among calves from the treatment and control groups. Colostrum replacer supplementation of the milk replacer ration was effective in reducing antibiotic therapy and occurrence of disease during the pre-weaning period. PMID- 27939547 TI - Genetic evaluation for bovine tuberculosis resistance in dairy cattle. AB - Genetic evaluations for resistance to bovine tuberculosis (bTB) were calculated based on British national data including individual animal tuberculin skin test results, postmortem examination (presence of bTB lesions and bacteriological culture for Mycobacterium bovis), animal movement and location information, production history, and pedigree records. Holstein cows with identified sires in herds with bTB breakdowns (new herd incidents) occurring between the years 2000 and 2014 were considered. In the first instance, cows with a positive reaction to the skin test and a positive postmortem examination were defined as infected. Values of 0 and 1 were assigned to healthy and infected animal records, respectively. Data were analyzed with mixed models. Linear and logit function heritability estimates were 0.092 and 0.172, respectively. In subsequent analyses, breakdowns were split into 2-mo intervals to better model time of exposure and infection in the contemporary group. Intervals with at least one infected individual were retained and multiple intervals within the same breakdown were included. Healthy animal records were assigned values of 0, and infected records a value of 1 in the interval of infection and values reflecting a diminishing probability of infection in the preceding intervals. Heritability and repeatability estimates were 0.115 and 0.699, respectively. Reliabilities and across time stability of the genetic evaluation were improved with the interval model. Subsequently, 2 more definitions of "infected" were analyzed with the interval model: (1) all positive skin test reactors regardless of postmortem examination, and (2) all positive skin test reactors plus nonreactors with positive postmortem examination. Estimated heritability was 0.085 and 0.089, respectively; corresponding repeatability estimates were 0.701 and 0.697. Genetic evaluation reliabilities and across time stability did not change. Correlations of genetic evaluations for bTB with other traits in the current breeding goal were mostly not different from zero. Correlation with the UK Profitable Lifetime Index was moderate, significant, and favorable. Results demonstrated the feasibility of a national genetic evaluation for bTB resistance. Selection for enhanced resistance will have a positive effect on profitability and no antagonistic effects on current breeding goal traits. Official genetic evaluations are now based on the interval model and the last bTB trait definition. PMID- 27939548 TI - Using plant wax markers to estimate the diet composition of grazing Holstein dairy cows. AB - The objective of this study was to test whether diet selection of dairy cows under grazing conditions could be estimated using plant wax markers. Furthermore, differences between 2 cow strains and the effect of concentrate supplementation on plant species selection were investigated. The experiment was a study with a crossover design performed on an organic farm with 12 Swiss Holstein cows and 12 New Zealand Holstein cows. Both experimental periods consisted of a 21-d adaptation and a 7-d measurement period. All cows grazed full time in a rotational stocking system and received either no concentrate or 6 kg/d of a commercial cereal-grain mix. Representative herbage samples of each grazed paddock were taken and botanical composition of subsamples was manually determined. The average proportions of the plant species were 27.8% Lolium perenne, 6.1% Dactylis glomerata, 10.4% Trifolium repens, and 9.0% Taraxacum officinale. Other grass species were merged as "other grass" (38.2%) and other forb species as "other forbs" (8.5%). n-Alkanes, long-chain fatty acids, and long chain alcohols (LCOH) were analyzed in the samples of plant species, concentrate, and feces from each cow. A linear discriminant analysis indicated that diet components were differentiated best with LCOH (96%) and worst with the combination of all marker groups together (12%). For each marker, the fecal marker recovery (FR) relative to dosed ytterbium was determined in 2 ways. Estimation of diet composition was performed with the software "EatWhat," and results were compared with botanical composition with the Aitchison distance. The results indicate that the diet composition of grazing dairy cows can be estimated using plant wax markers. Additionally, the calculation of FR led to mostly reliable results, yet this approach needs further validation. The most accurate estimation was achieved with the marker combination of n-alkanes and LCOH with a correction for FR. Less accurate estimations were achieved with long-chain fatty acids alone or in combination with n-alkanes. No difference relating to diet selection between the 2 cow strains was recorded, but supplemented cows apparently ingested higher proportions of T. repens than nonsupplemented cows. Awareness that supplementation influences selection behavior of grazing dairy cows may lead to adaptations in botanical composition of the pasture according to the demand of the animals. PMID- 27939549 TI - Effect of sources of calcium salts of fatty acids on production, nutrient digestibility, energy balance, and carryover effects of early lactation grazing dairy cows. AB - The objective of our study was to investigate the effects of sources of calcium salts of fatty acids (FA) on production, nutrient digestibility, energy balance, and carryover effects of early lactation grazing dairy cows. Treatment diets were offered from 3 to 16 wk postpartum (the treatment period), in which all cows grazed elephantgrass (Pennisetum purpureum 'Cameroon') and treatments were added to a concentrate supplement. The treatments were (1) control (concentrate without supplemental fat); (2) concentrate with calcium salts of soybean FA (CSSO); and (3) concentrate with calcium salts of palm FA (CSPO). From 17 to 42 wk postpartum (the carryover period), all cows received a common diet fed as a total mixed ration. During the treatment period, CSPO increased milk yield, milk fat yield, 3.5% fat-corrected milk, energy-corrected milk, and cumulative milk yield compared with control and CSSO. Treatment CSSO increased the yield of milk but did not affect 3.5% fat-corrected milk or energy-corrected compared with control. Also, CSSO decreased milk fat yield, dry matter intake, neutral detergent fiber digestibility, and body weight and body condition loss. Compared with control, both CSSO and CSPO increased feed efficiency (3.5% fat-corrected milk:dry matter intake), and CSPO increased feed efficiency compared with CSSO. When considering energy partitioning (as % energy intake), CSPO increased energy partitioning toward milk and increased energy mobilized from body reserves compared with control and CSSO. Furthermore, CSSO tended to reduce the mobilization of energy from body reserves compared with control. In the carryover period, no differences in milk composition were observed among treatments. A treatment by time interaction was observed during the carryover period for milk yield because cows on CSPO maintained higher production compared with control and CSSO cows until 30 wk postpartum; CSSO had a lower carryover effect sustaining higher milk yield compared with control until 25 wk postpartum. In conclusion, supplementation with CSPO was an effective strategy to increase energy intake and yields of milk and milk solids and it had a greater carryover effect. Supplementation with CSSO resulted in lower mobilization of reserves and less variation in body weight and body condition throughout lactation. PMID- 27939551 TI - Antimicrobial treatment of clinical mastitis in the eastern United States: The influence of dairy farmers' mastitis management and treatment behavior and attitudes. AB - To assess both the behaviors and social variables related to antimicrobial therapy for clinical mastitis, we sent a survey to 1,700 dairy farms in Michigan, Pennsylvania, and Florida in January and February 2013. The survey included questions related to 7 major areas: sociodemographic and farm characteristics, milking proficiency, milking systems, cow environment, infected cow monitoring and treatment, farm labor, and attitudes toward mastitis and related antimicrobial use. The overall response rate was 41% (21% in Florida, 39% in Michigan, and 45% in Pennsylvania). Herd size ranged from 9 to 5,800 cows. Only a small proportion of herds frequently or always cultured milk samples for bacteriology from cows with a high somatic cell count (17%), cows with clinical mastitis (18%), or bulk tank milk (13%). Likewise, only 56% of herds frequently or always maintained records of all treated cows and 49% reviewed records before administering mastitis treatments. Multivariate analysis determined that use of treatment records was associated with increased likelihood of frequent use for both intramammary (IMA) and systemic (SYA) administration of antimicrobial drugs for therapy of clinical mastitis. As would be expected, use of natural (organic) therapies was associated with decreased use of IMA, as was the respondent being a member of an Amish community. Lower levels of education and the use of bacterins to control Staphylococcus aureus mastitis were also associated with decreased IMA, whereas increased use of IMA at dry off and the belief that "bad luck" plays a role in mastitis problems were associated with increased IMA. Use of an internal teat sealant, the respondent being the sole proprietor, being from Michigan, use of conductivity to measure subclinical mastitis, the respondent placing increasing importance on decreasing antibiotic residues in cull cows, and having financial incentives for employees linked to somatic cell count were associated with increased use of SYA for the treatment of clinical mastitis. Use of sand or mattresses for bedding were associated with decreased SYA. These findings highlight the need to improve the acceptance of practices that are consistent with prudent antimicrobial use for the treatment of clinical mastitis on dairy farms. Additionally, the willingness of dairy farmers to administer antimicrobial drugs for the treatment of clinical mastitis is associated with other mastitis-related practices and attitudes. PMID- 27939550 TI - Invited review: Microbe-mediated aflatoxin decontamination of dairy products and feeds. AB - Aspergillus flavus, Aspergillus parasiticus, and Aspergillus nomius contaminate corn, sorghum, rice, peanuts, tree nuts, figs, ginger, nutmeg, and milk. They produce aflatoxins, especially aflatoxin B1, which is classified as a Group 1 carcinogen by the International Agency for Research on Cancer. Many studies have focused on aflatoxin removal from food or feed, especially via microbe-mediated mechanisms-either adsorption or degradation. Of the lactic acid bacteria, Lactobacillus rhamnosus GG efficiently binds aflatoxin B1, and a peptidoglycan in the bacterium cell wall plays an important role. This ability of L. rhamnosus GG should be applied to the removal of aflatoxin B1. Aflatoxin can be removed using other aflatoxin-degrading microorganisms, including bacterial and fungal strains. This review explores microbe-associated aflatoxin decontamination, which may be used to produce aflatoxin-free food or feed. PMID- 27939552 TI - Intramammary infusion of Escherichia coli lipopolysaccharide negatively affects feed intake, chewing, and clinical variables, but some effects are stronger in cows experiencing subacute rumen acidosis. AB - Feeding high-grain diets increases the risk of subacute rumen acidosis (SARA) and adversely affects rumen health. This condition might impair the responsiveness of cows when they are exposed to external infectious stimuli such as lipopolysaccharide (LPS). The main objective of this study was to evaluate various responses to intramammary LPS infusion in healthy dairy cows and those experimentally subjected to SARA. Eighteen early-lactating Simmental cows were subjected to SARA (n = 12) or control (CON; n = 6) feeding conditions. Cows of the control group received a diet containing 40% concentrates (DM basis) throughout the experiment. The intermittent SARA feeding regimen consisted in feeding the cows a ration with 60% concentrate (DM basis) for 32 d, consisting of a first SARA induction for 8 d, switched to the CON diet for 7 d, and re induction during the last 17 d. On d 30 of the experiment, 6 SARA (SARA-LPS) and 6 CON (CON-LPS) cows were intramammary challenged once with a single dose of 50 MUg of LPS from Escherichia coli (O26:B6), whereas the other 6 SARA cows (SARA PLA) received 10 mL of sterile saline solution as placebo. To confirm the induction of SARA, the reticular pH was continuously monitored via wireless pH probes. The DMI remained unchanged between SARA and CON cows during the feeding experiment, but was reduced in both treatment groups receiving the LPS infusion compared with SARA-PLA, whereby a significant decline was observed for cows of the SARA-LPS treatment (-38%) compared with CON-LPS (-19%). The LPS infusion did not affect the reticuloruminal pH dynamics, but significantly enhanced ruminal temperature and negatively affected chewing behavior. The ruminal temperature increased after the LPS infusion and peaked about 1 h earlier in SARA-LPS cows compared with the cows of the CON-LPS treatment. Moreover, a significant decline in milk yield was found in SARA-LPS compared with CON-LPS following the LPS infusion. Cows receiving LPS had elevated somatic cell counts, protein, and fat contents in milk as well as decreased lactose contents and pH following the LPS infusion, whereby the changes in milk constituents were more pronounced in SARA LPS than CON-LPS cows. Rectal temperature and pulse rate were highest 6 h after LPS infusion, but rumen contractions were not affected by the LPS infusion. The data suggest that a single intramammary LPS infusion induced fever and negatively affected feed intake, chewing activity, rectal temperature, and milk yield and composition, whereby these effects were more pronounced in SARA cows. PMID- 27939553 TI - Anatomical characteristics of teats and premilking bacterial counts of teat skin swabs of primiparous cows exposed to different types of bedding. AB - Bacterial populations of teat skin are associated with risk of intramammary infection and may be influenced by anatomical characteristics of teats. The objective of this study was to evaluate associations of selected anatomical characteristics of teats with bacterial counts of teat skin of cows exposed to different types of bedding. Primarily primiparous Holstein cows (n = 128) were randomly allocated to 4 pens within a single barn. Each pen contained 1 type of bedding [new sand (NES), recycled sand (RS), deep-bedded manure solids (DBMS), and shallow-bedded manure solids over foam core mattresses (SBMS)]. During a single farm visit udders (n = 112) were scored for hygiene and 1 front (n = 112) and 1 rear teat (n = 111) of each enrolled cow were scored for hyperkeratosis (HK). Teat length, teat barrel diameter, and teat apex diameter were measured and teat skin swabs were systematically collected for microbiological analysis. Linear type evaluation data for udders of each cow were retrieved for each cow. Teat position (front or rear) was associated with occurrence of clinical mastitis during the 12 mo before the farm visit and more cases occurred in front quarters. The proportion of udders that were classified as clean (score 1 or 2) was 68, 82, 54, and 95% for cows housed in pens containing NES, RS, SBMS, and DBMS, respectively. No association was found between HK score and teat position and no association was found between HK score and teat skin bacterial count. Bacterial counts of teat skin swabs from front teats of cows in pens containing RS and SBMS were significantly less than those of rear teats of cows in pens containing DBMS or NES. Teat skin bacterial counts were significantly greater for swabs obtained from teats of cows with udder hygiene scores of 3 and 4 as compared with swabs obtained from cows with cleaner udders. Of all udder conformation traits evaluated, only narrower rear teat placement was positively associated with bacterial counts on teat skin. PMID- 27939554 TI - Using the Malthus programme to predict the recruitment of patients to MR-linac research trials in prostate and lung cancer. AB - In this study, we used evidence-based mathematical modelling to predict the patient cohort for MR-linac to assess its feasibility in a time of austerity. We discuss our results and the implications of evidence-based radiotherapy demand modelling tools such as Malthus on the implementation of new technology and value based healthcare. PMID- 27939555 TI - Exome array analysis suggests an increased variant burden in families with schizophrenia. AB - The exome array assays rare-but-recurrent, likely deleterious, exonic variants and represents an intermediary between single nucleotide polymorphism (SNP) arrays and sequencing for genetic association studies. Multiplex families with multiple affected individuals may be enriched for disease-associated variants of this class compared to unrelated populations. We present an exome array study of schizophrenia in 99 multiplex families (n=341, including 118 cases) from the Western Australian Family Study of Schizophrenia (WAFSS). Compared to 55,726 individuals from the DIAGRAM sample not selected for schizophrenia, overall allele frequency of exome variants was higher in the WAFSS (P<2.2E-16). This was pronounced in variants nominally associated (P<0.05) with schizophrenia. Genes harbouring variants present only in WAFSS cases were enriched (FDR-corrected P=0.05) for membership of the 'extracellular matrix (ECM) - receptor interaction' biological pathway, adding to evidence that processes affecting the composition or turnover of ECM may contribute to neuropsychiatric disease. We did not find individual variants significantly associated with schizophrenia, although like previous studies, power to detect associations of small effect size was low. Cases did not exhibit a higher burden of variants compared to their unaffected relatives and the finding of previous exome chip studies of unrelated samples that 'schizophrenia gene-sets' were enriched for case-only variants was not replicated in the WAFSS. The higher frequency of moderately rare, exonic variants in these multiplex families compared to a population-based sample may account for some of their genetic liability to schizophrenia, and adds to evidence for a role of exome array variants from previous studies of unrelated samples. PMID- 27939556 TI - The potential impact of reducing indoor tanning on melanoma prevention and treatment costs in the United States: An economic analysis. AB - BACKGROUND: Indoor tanning is associated with an increased risk of melanoma. The US Food and Drug Administration proposed prohibiting indoor tanning among minors younger than 18 years. OBJECTIVE: We sought to estimate the health and economic benefits of reducing indoor tanning in the United States. METHODS: We used a Markov model to estimate the expected number of melanoma cases and deaths averted, life-years saved, and melanoma treatment costs saved by reducing indoor tanning. We examined 5 scenarios: restricting indoor tanning among minors younger than 18 years, and reducing the prevalence by 20%, 50%, 80%, and 100%. RESULTS: Restricting indoor tanning among minors younger than 18 years was estimated to prevent 61,839 melanoma cases, prevent 6735 melanoma deaths, and save $342.9 million in treatment costs over the lifetime of the 61.2 million youth age 14 years or younger in the United States. The estimated health and economic benefits increased as indoor tanning was further reduced. LIMITATIONS: Limitations include the reliance on available data and not examining compliance to indoor tanning laws. CONCLUSIONS: Reducing indoor tanning has the potential to reduce melanoma incidence, mortality, and treatment costs. These findings help quantify and underscore the importance of continued efforts to reduce indoor tanning and prevent melanoma. PMID- 27939558 TI - A new global strategy for the elimination of schistosomiasis. AB - Mass drug administration utilising a single oral dose of 40mg/kg of praziquantel (PZQ) has been endorsed and advocated by the World Health Organisation (WHO) for the global control and elimination of schistosomiasis. However, this strategy is failing primarily because the drugs are not getting to the people who need them the most. The current global coverage is 20%, the drug compliance rate is less than 50%, and the drug efficacy is approximately 50%. Thus in reality, only about 5% of the reservoir human population is actually receiving intermittent chemotherapy. Despite claims that more of the drug will soon be made available the current strategy is inherently flawed and will not lead to disease elimination. We discuss the many practical issues related to this global strategy, and advocate for an integrated control strategy targeting the life cycle and the most at-risk. Moreover, we discuss how an integrated control package for schistosomiasis should fit within a larger integrated health package for rural and remote villages in the developing world. A holistic health system approach is required to achieve sustainable control and ultimately disease elimination. PMID- 27939557 TI - The administration of multipotent stromal cells at precancerous stage precludes tumor growth and epithelial dedifferentiation of oral squamous cell carcinoma. AB - Multipotent stromal cells (MSCs) are envisioned as a powerful therapeutic tool. As they home into tumors, secrete trophic and vasculogenic factors, and suppress immune response their role in carcinogenesis is a matter of controversy. Worldwide oral squamous cell carcinoma (OSCC) is the fifth most common epithelial cancer. Our aim was to determine whether MSC administration at precancerous stage modifies the natural progression of OSCC. OSCC was induced in Syrian hamsters by topical application of DMBA in the buccal pouch. At papilloma stage, the vehicle or 3*106 allogenic bone marrow-derived MSCs were locally administered. Four weeks later, the lesions were studied according to: volume, stratification (histology), proliferation (Ki-67), apoptosis (Caspase 3 cleaved), vasculature (ASMA), inflammation (Leukocyte infiltrate), differentiation (CK1 and CK4) and gene expression profile (mRNA). Tumors found in individuals that received MSCs were smaller than those presented in the vehicle group (87+/-80 versus 54+/-62mm3, p<0.05). The rate of proliferation was two times lower and the apoptosis was 2.5 times higher in lesions treated with MSCs than in untreated ones. While the laters presented dedifferentiated cells, the former maintained differentiated cells (cytokeratin and gene expression profile similar to normal tissue). Thus, MSC administration at papilloma stage precludes tumor growth and epithelial dedifferentiation of OSCC. PMID- 27939559 TI - Posterior Vault Distance of Ciliary Sulcus-Implanted Three-piece Intraocular Lenses According to Ciliary Sulcus Diameter. AB - PURPOSE: To investigate the correlation among preoperative biometry data, postoperative ciliary sulcus diameter, posterior vault distance, and effective lens position of ciliary sulcus-implanted intraocular lenses (IOLs). DESIGN: Retrospective interventional case series. METHODS: Twenty-six eyes of 26 patients underwent phacoemulsification with implantation of a ZA9003 IOL (Abbott Medical Optics Inc, Santa Ana, California, USA) in the ciliary sulcus. We analyzed correlations among preoperative biometry data and ultrasound biomicroscopy measurements, ciliary sulcus diameter, posterior vault distance, and effective lens position. Regression analyses were performed to identify which combination of preoperative biometry data, average corneal power (keratometry [K]), anterior chamber depth (ACD), and axial length (AL) was best for predicting effective lens position. RESULTS: The sulcus diameter was shorter in eyes that had a steep cornea and shorter AL. The posterior vault distance was negatively correlated with sulcus diameter in subjects who had shorter postoperative time intervals (<=24 months) (R2 = 0.336 and P = .038). The posterior vault distance decreased with each passing postoperative month (R2 = 0.158 and P = .045). The R2 value for predicting the effective lens positions of sulcus-implanted IOLs based on the entire average K, ACD, and AL was higher than those based on parts of these values. CONCLUSIONS: The effective lens position of sulcus-implanted IOLs can be affected by sulcus diameter, and lens position can change, especially in the early postoperative period. We recommend using the entire average K, ACD, and AL to predict the effective position of sulcus-implanted IOLs. PMID- 27939560 TI - Drusen-like Deposits in Young Adults Diagnosed With Systemic Lupus Erythematosus. AB - PURPOSE: To determine the prevalence of drusen-like deposits (DLDs) and choroidal changes in patients with systemic lupus erythematosus (SLE), with or without glomerulonephritis; and to correlate ocular findings with systemic features. DESIGN: Case-control study. METHODS: Sixty patients with SLE (age, 18-55 years; 30 with and 30 without SLE-related glomerulonephritis) and 60 age- and sex matched healthy controls were enrolled. All patients underwent noninvasive multimodal imaging that included fundus photography, near-infrared reflectance, blue autofluorescence, blue reflectance, and spectral-domain optical coherence tomography (SDOCT). Images were analyzed for the prevalence of DLDs. Distribution, size, and number of DLDs were measured. Correlations between ocular findings and systemic features were analyzed. Subfoveal choroidal thickness (SCT) was measured using the SDOCT. RESULTS: Drusen-like deposits were detected in 40% of SLE subjects and 3.33% of controls (P < .0001). Compared with other techniques, SDOCT detected the largest number of affected subjects. In eyes with DLDs, small, medium, and large lesions were found in 75%, 50%, and 42% of cases, respectively. Drusen-like deposits were located in the nasal, temporal, inferior, superior, and central regions of the posterior pole in 83%, 75%, 67%, 54%, and 25% of eyes, respectively. The prevalence of DLDs in patients with SLE was similar regardless of renal involvement, but patients with glomerulonephritis had more DLDs per eye, larger deposits, and DLDs in >3 quadrants (P < .001, P = .03, P = .009, respectively). Subfoveal choroidal thickness was greater in patients with SLE (P = .002). CONCLUSIONS: Drusen-like deposits in patients with SLE were independent of renal disease and were best detected with SDOCT. Lupus-related glomerulonephritis was associated with more fundus abnormalities and a screening SDOCT should be considered in all patients with SLE. Drusen-like deposits in the absence of glomerulonephritis may support the recent proposal that complement alteration is the primary cause of these lesions. PMID- 27939562 TI - Results in Combined Cataract Surgery With Prosthetic Iris Implantation in Patients With Previous Iridocyclectomy for Iris Melanoma. AB - PURPOSE: To present visual and functional results following implantation of iris prosthesis combined with cataract surgery in eyes with previous iridocyclectomy for iris melanoma or presumed iris melanoma. DESIGN: Retrospective noncomparative case series. METHODS: Sixteen patients (16 eyes) with iris defects after iridocyclectomy for iris melanoma in 15 cases and iris adenoma in 1 case underwent prosthetic iris device implantation surgery. Prosthetic iris implantation was combined with phacoemulsification and intraocular lens (IOL) implantation. The visual acuity, subjective glare and photophobia reduction, anatomic outcome, and complications were reviewed. RESULTS: Best-corrected visual acuity was improved in 13 eyes (81.25%), remained stable in 2 eyes (12.25%), and decreased in 1 eye (6.25%). Photophobia and glare improved in every case except for 1 (93.75%). Notably, after surgery 12 patients (75.00%) reported no photophobia and 10 patients (62.50%) reported no glare. The median postoperative follow-up was 29.5 months, with a minimum of 5 months and a maximum of 189 months. All iris devices were in the correct position, and all eyes achieved the desired anatomic result. The IOL optic edges were covered in all areas by either residual iris or opaque portions of a prosthetic iris device. CONCLUSIONS: In patients who have undergone previous iridocyclectomy for presumed iris melanoma, combined cataract surgery and iris prosthesis placement, with or without iris reconstruction, can lead to visual improvement as well as reduction of both glare and photophobia. PMID- 27939563 TI - Generalized predictive control for a coupled four tank MIMO system using a continuous-discrete time observer. AB - This paper deals with the problem of the observer based control design for a coupled four-tank liquid level system. For this MIMO system's dynamics, motivated by a desire to provide precise and sensorless liquid level control, a nonlinear predictive controller based on a continuous-discrete observer is presented. First, an analytical solution from the model predictive control (MPC) technique is developed for a particular class of nonlinear MIMO systems and its corresponding exponential stability is proven. Then, a high gain observer that runs in continuous-time with an output error correction time that is updated in a mixed continuous-discrete fashion is designed in order to estimate the liquid levels in the two upper tanks. The effectiveness of the designed control schemes are validated by two tests; The first one is maintaining a constant level in the first bottom tank while making the level in the second bottom tank to follow a sinusoidal reference signal. The second test is more difficult and it is made using two trapezoidal reference signals in order to see the decoupling performance of the system's outputs. Simulation and experimental results validate the objective of the paper. PMID- 27939561 TI - Phakic Intraocular Collamer Lens (Visian ICL) Implantation for Correction of Myopia in Spectacle-Aversive Special Needs Children. AB - PURPOSE: A subset of children with high anisometropia or isoametropia and neurobehavioral disorders have chronic difficulties with spectacle or contact lens wear. We report the results of refractive surgery in a series of these children treated using bilateral or unilateral intraocular collamer lens (Visian ICL) implantation for moderate to high myopia. DESIGN: Prospective nonrandomized cohort study. METHODS: Clinical course and outcome data were collated prospectively for 40 implanted eyes in 23 children (mean age 10.2 +/- 5.3 years, range, 1.8-17 years). Myopia ranged from -3.0 to -14.5 diopters (D), mean -9.2 +/ 3.5 D. Goal refraction was plano to +1 D. Correction was achieved by sulcus implantation of a Visian ICL (STAAR Surgical, Monrovia, California, USA) under general anesthesia. Mean follow-up was 15.1 months (range, 6-22 months). RESULTS: Thirty-five eyes (88%) were corrected to within +/-1.0 D of goal refraction; the other 5 (12%) were corrected to within 1.5 D. Uncorrected distance visual acuity improved substantially in all eyes (from mean 20/1050 [logMAR 1.72] to mean 20/42 [logMAR 0.48]). Spherical regression at last follow-up was an average of +0.59 D. Visuomotor comorbidities (eg, amblyopia, nystagmus, foveopathy, optic neuropathy) accounted for residual postoperative subnormal visual acuity. Thirteen of the 23 children (57%) had a neurobehavioral disorder (eg, developmental delay/intellectual disability/mental retardation, Down syndrome, cerebral palsy, autism spectrum disorder). Eighty-five percent (11/13) of those children were reported to have enhanced visual awareness, attentiveness, or social interactions. Endothelial cell density was measureable in 6 cooperative children (10 eyes), showing an average 1% decline. Central corneal thickness, measured in all children, increased an average of 8 MUm. Two children (8%) required unplanned return to the operating room on the first postoperative day to alleviate pupillary block caused by a nonpatent iridotomy. No other complications were encounterd. CONCLUSION: Visian ICL implantation improves visual function in special needs children who have moderate to high myopia and difficulties wearing glasses or contact lenses. PMID- 27939564 TI - Nonlinear stabilization for a class of time delay systems via inverse optimality approach. AB - This paper is devoted to obtain a stabilizing optimal nonlinear controller based on the well known Control Lyapunov-Krasovskii Functional (CLKF) approach, aimed to solve the inverse optimality problem for a class of nonlinear time delay systems. To determine sufficient conditions for the Bellman's equation solution of the system under consideration, the CLKF and the inverse optimality approach are considered in this paper. In comparison with previous results, this scheme allows us to obtain less conservative controllers, implying energy saving (in terms of average power consumption for a specific thermo-electrical process). Sufficient delay-independent criteria in terms of CLKF is obtained such that the closed-loop nonlinear time-delay system is guaranteed to be local Asymptotically Stable. To illustrate the effectiveness of the theoretical results, a comparative study with an industrial PID controller tuned by the Ziegler-Nichols methodology (Z-N) and a Robust-PID tuned by using the D-partition method is presented by online experimental tests for an atmospheric drying process with time delay in its dynamics. PMID- 27939565 TI - Adaptive MPC based on MIMO ARX-Laguerre model. AB - This paper proposes a method for synthesizing an adaptive predictive controller using a reduced complexity model. This latter is given by the projection of the ARX model on Laguerre bases. The resulting model is entitled MIMO ARX-Laguerre and it is characterized by an easy recursive representation. The adaptive predictive control law is computed based on multi-step-ahead finite-element predictors, identified directly from experimental input/output data. The model is tuned in each iteration by an online identification algorithms of both model parameters and Laguerre poles. The proposed approach avoids time consuming numerical optimization algorithms associated with most common linear predictive control strategies, which makes it suitable for real-time implementation. The method is used to synthesize and test in numerical simulations adaptive predictive controllers for the CSTR process benchmark. PMID- 27939566 TI - Move Suppression Calculations for Well-Conditioned MPC. AB - Several popular tuning strategies applicable to Model Predictive Control (MPC) schemes such as GPC and DMC have previously been developed. Many of these tuning strategies require an approximate model of the controlled process to be obtained, typically of the First Order Plus Dead Time type. One popular method uses such a model to analytically calculate an approximate value of the move suppression coefficient to achieve a desired condition number for the regularized system dynamic matrix; however it is not always accurate and tends to under-estimate the required value. In this paper an off-line method is presented to exactly calculate the move suppression coefficient required to achieve a desired condition number directly from the unregularized system dynamic matrix. This method involves an Eigendecomposition of the system dynamic matrix - which may be too unwieldy in some cases -and a simpler analytical expression is also derived. This analytical expression provides a guaranteed tight upper bound on the required move suppression coefficient yielding a tuning formula which is easy to apply, even in on-line situations. Both methods do not require the use of approximate or reduced order process models for their application. Simulation examples and perturbation studies illustrate the effectiveness of the methods in both off-line and on-line MPC configurations. It is shown that accurate conditioning and improved closed loop robustness can be achieved. PMID- 27939567 TI - Improved PI-PD control design using predictive functional optimization for temperature model of a fluidized catalytic cracking unit. AB - Proportional-integral-derivative (PID) control is widely used in industry because of its simple structure and convenient implementation. However, PID control is suitable for small time delay systems; while if too large delay is encountered, PID control may not obtain the desired performance. Proportional-integral proportional-derivative (PI-PD) control is a modified of PID control and can get improved control performance; however, due to the complex controller parameter tuning, the PI-PD control is used in a limited scope. Inspired by the advantage of predictive functional control (PFC), a new PI-PD control design using PFC optimization is proposed in this paper. The proposed method not only inherits the advantage of PFC, which does well in coping with the time delay, but also has the same structure as the PI-PD controller. The proposed method is tested on the preheated temperature control of crude oil in a fluidized catalytic cracking unit. The results show that the proposed controller improves control performance compared with typical PID control and PI-PD control. PMID- 27939568 TI - CLFs-based optimization control for a class of constrained visual servoing systems. AB - In this paper, we use the control Lyapunov function (CLF) technique to present an optimized visual servo control method for constrained eye-in-hand robot visual servoing systems. With the knowledge of camera intrinsic parameters and depth of target changes, visual servo control laws (i.e. translation speed) with adjustable parameters are derived by image point features and some known CLF of the visual servoing system. The Fibonacci method is employed to online compute the optimal value of those adjustable parameters, which yields an optimized control law to satisfy constraints of the visual servoing system. The Lyapunov's theorem and the properties of CLF are used to establish stability of the constrained visual servoing system in the closed-loop with the optimized control law. One merit of the presented method is that there is no requirement of online calculating the pseudo-inverse of the image Jacobian's matrix and the homography matrix. Simulation and experimental results illustrated the effectiveness of the method proposed here. PMID- 27939569 TI - Benign phyllodes tumours of the breast: (Over) treatment of margins - A literature review. AB - BACKGROUND: Phyllodes tumours form a small group of fibroepithelial breast lesions (2-3%). They are classified as benign, borderline, or malignant. (1). Benign phyllodes tumours are the largest subgroup of phyllodes tumours (50-80%), (2) A margin of 1 cm has been suggested as standard of care for all groups of phyllodes tumours.3-6 METHODS: We performed a literature review from January 2009 to April 2016 including the non-English literature. We compared studies taking a 1 mm margin, 10 mm margin and studies with focal margin involvement. RESULTS: We included 12 studies with overall 1702 patients. The range of therapeutic margins differed widely between studies. There is no consensus between studies what constitutes a clear or involved margin. There was a high percentage of margin involvement for benign phyllodes tumours (7.6-43.7%). Despite these inconsistencies, the recurrence rate after excision of benign phyllodes tumours was low in most studies (112 recurrences of 1052 benign phyllodes tumours - 11%; range 0-43%). There is no difference of the recurrence rate between studies aiming for a 10 mm margin (7.9%) compared to a 1 mm margin (5.7%) (p 0.124). The recurrence rate increases when there are tumour cells at the margin (12.9%) (p 0.006). CONCLUSION: There is no difference in recurrence rates between a 1 and a 10 mm margin. 1 mm is an acceptable margin for benign phyllodes tumours. The recurrence rate increases if there is focal margin involvement. PMID- 27939570 TI - Effects of different combinations of nanocrystallization technologies on avanafil nanoparticles: in vitro, in vivo and stability evaluation. AB - The study investigated the effects of different combined top-down and bottom-up nanocrystallization technologies on particle size and solid state of avanafil nanoparticles. Combined antisolvent precipitation-ultrasonication (sonoprecipitation) technique was adopted to prepare 18 formulas according to 32.21 factorial design using 3 stabilizers; Tween 80, polyvinyl alcohol (PVA) and Pluronic F68 at different concentrations with different cryoprotectants. Particle size analysis of the lyophilized formulas showed that Tween 80 was an effective nanoparticles stabilizer in contrast to Pluronic F68 and PVA which failed to prevent nanoparticles flocculation when they were used at high concentration. The combined effects of nanonization and amorphism contributed to the improvement in solubility. Further processing of the sonoprecipitated formulas by high pressure homogenization (HPH) (modified NANOEDGETM technology) resulted in further size reduction of PVA-stabilized particles, while it stimulated flocculation of Tween stabilized nanoparticles. Nevertheless, all of the homogenized formulas partially retrieved their crystallinity which reduced their solubility. Non-homogenized formula 2E composed of 1:2 (avanafil: Tween) with glucose as cryoprotectant, exhibited 13.68- and 2.59-fold improvement in solubility and in vitro dissolution, respectively. This formula had oral bioavailability of 137.02% relative to Spedra(r) tablets and it maintained its nanosize, amorphism and dissolution behavior over 6 months of storage under stress conditions. PMID- 27939571 TI - Ex vivo encapsulation of dexamethasone sodium phosphate into human autologous erythrocytes using fully automated biomedical equipment. AB - Erythrocyte-based drug delivery systems are emerging as potential new solutions for the release of drugs into the bloodstream. The aim of the present work was to assess the performance of a fully automated process (EDS) for the ex-vivo encapsulation of the pro-drug dexamethasone sodium phosphate (DSP) into autologous erythrocytes in compliance with regulatory requirements. The loading method was based on reversible hypotonic hemolysis, which allows the opening of transient pores in the cell membrane to be crossed by DSP. The efficiency of encapsulation and the biochemical and physiological characteristics of the processed erythrocytes were investigated in blood samples from 34 healthy donors. It was found that the processed erythrocytes maintained their fundamental properties and the encapsulation process was reproducible. The EDS under study showed greater loading efficiency and reduced variability compared to previous EDS versions. Notably, these results were confirmed using blood samples from Ataxia Telangiectasia (AT) patients, 9.33+/-1.40 and 19.41+/-2.10mg of DSP (mean+/-SD, n=134) by using 62.5 and 125mg DSP loading quantities, respectively. These results support the use of the new EDS version 3.2.0 to investigate the effect of erythrocyte-delivered dexamethasone in regulatory trials in patients with AT. PMID- 27939573 TI - Age, ageing and their influence on waste management behaviour. PMID- 27939572 TI - Integration of Biomass Formulations of Genome-Scale Metabolic Models with Experimental Data Reveals Universally Essential Cofactors in Prokaryotes. AB - The composition of a cell in terms of macromolecular building blocks and other organic molecules underlies the metabolic needs and capabilities of a species. Although some core biomass components such as nucleic acids and proteins are evident for most species, the essentiality of the pool of other organic molecules, especially cofactors and prosthetic groups, is yet unclear. Here we integrate biomass compositions from 71 manually curated genome-scale models, 33 large-scale gene essentiality datasets, enzyme-cofactor association data and a vast array of publications, revealing universally essential cofactors for prokaryotic metabolism and also others that are specific for phylogenetic branches or metabolic modes. Our results revise predictions of essential genes in Klebsiella pneumoniae and identify missing biosynthetic pathways in models of Mycobacterium tuberculosis. This work provides fundamental insights into the essentiality of organic cofactors and has implications for minimal cell studies as well as for modeling genotype-phenotype relations in prokaryotic metabolic networks. PMID- 27939574 TI - Effect of Perioperative Pregabalin on Postoperative Quality of Recovery in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting (OPCABG): A Prospective, Randomized, Double-Blind Trial. AB - OBJECTIVES: Use of pregabalin is increasing in cardiac surgical patients. However, studies using comprehensive scoring systems are lacking on the drug's impact on postoperative recovery. The authors tested the hypothesis that perioperative oral pregabalin improves the postoperative quality of recovery as assessed using the Quality of Recovery (QoR-40) questionnaire in patients undergoing off-pump coronary artery bypass grafting (OPCABG). DESIGN: This was a randomized, double-blind, placebo-controlled study. SETTINGS: Tertiary-care hospital. PARTICIPANTS: Patients undergoing OPCABG. INTERVENTIONS: Patients were assigned randomly to the following 2 groups: the pregabalin group (those who received pregabalin, 150 mg capsule orally, 1 hour before surgery and 2 days postoperatively [75 mg twice a day] starting after extubation; n = 37); and the control group (those who received 2 similar-looking multivitamin capsules at similar times; n = 34). The QoR-40 scores were noted preoperatively and 24 hours after extubation. MEASUREMENTS AND MAIN RESULTS: Both groups were comparable in terms of preoperative patient characteristics and baseline QoR-40 scores. Global scores were significantly improved in the pregabalin group compared with the control group in the postoperative period (177+/-9 v 170+/-9; p = 0.002). QoR-40 values in the dimensions of emotional state (p = 0.005), physical comfort (p = 0.04), and pain (p = 0.02) were improved in the pregabalin group. CONCLUSIONS: Perioperative pregabalin improved postoperative quality of recovery as assessed using the QoR-40 questionnaire in patients undergoing OPCABG. Perioperative pregabalin offered advantages beyond better pain control, such as improved physical comfort and better emotional state; therefore, the drug's use in the perioperative period is recommended. PMID- 27939575 TI - Receptor-interacting protein 2 (RIP2) gene polymorphisms are associated with increased risk of subclinical atherosclerosis and clinical and metabolic parameters. The Genetics of Atherosclerotic Disease (GEA) Mexican study. AB - The receptor-interacting protein 2 (Rip2) is a serine/threonine kinase involved in multiple nuclear factor-kappaB (NFkappaB) activation pathways and is a key regulator of cellular lipid metabolism and cardiovascular disease. The aim of the present study was to evaluate the role of RIP2 gene polymorphisms as susceptibility markers for subclinical atherosclerosis (SA). Using an informatics analysis, four RIP2 gene polymorphisms with predicted functional effects (rs2293808, rs43133, rs431264, and rs16900627) were selected. The polymorphisms were genotyped in 405 individuals with SA (calcium score>0 assessed by computed tomography) and 1099 controls (calcium score=0). Clinical, anthropometric, tomographic and biochemical traits were measured. The association between the RIP2 polymorphisms and SA was evaluated using logistic regression analyses. Pair wise linkage disequilibrium (LD, D') estimations between polymorphisms and haplotype reconstruction were performed with Haploview version 4:1. Under different models adjusted by age, gender, body mass index, hypertension, diabetes mellitus, smoking habit, total cholesterol, HDL-cholesterol, LDL-cholesterol and triglyceride levels, rs43133 (OR=1.43, 95% CI: 1.05-1.94, P=0.022), and rs16900627 (OR=1.59, 95% CI: 1.00-2.54, Pdom=0.048 and OR=1.60, 95% CI: 1.05 2.54, Padd=0.028) were associated with increased risk of developing SA. Moreover, rs2293808, and rs431264 were associated with clinical or metabolic parameters in SA individuals and in healthy controls. The four polymorphisms were in high linkage disequilibrium and the GAAG haplotype was associated with increased risk of developing SA (OR=1.47, P=0.027). This study shows for the first time, that RIP2 polymorphisms are associated with increased risk of SA and with some clinical and metabolic parameters. PMID- 27939576 TI - Advanced glycation end products interfere with gastric smooth muscle contractile marker expression via the AGE/RAGE/NF-kappaB pathway. AB - Excessive production of advanced glycation end products (AGE) has been implicated in the pathogenesis of diabetic complications. Smooth muscle (SM) phenotype transition is involved in diabetes-associated gastric motility dysfunction. We investigated whether AGE interfere with gastric antral SM contractile marker expression. Sixteen Sprague-Dawley rats were randomly divided into control and streptozotocin-induced diabetic groups. Sixteen weeks after streptozotocin administration, gastric antral SM strip contractility in the groups were measured. The gastric tissue expression of AGE was tested. Primary cultured gastric smooth muscle cells (SMCs) were used in complementary in vitro studies. In the presence and absence of AGE, SMCs were transfected with myocardin plasmid or treated with nuclear factor-kappaB (NF-kappaB) inhibitor or anti-RAGE antibody. Diabetic rats showed weakness of SM strip contractility and decreased expression of SM contractile marker genes (myosin heavy chains [MHC], alpha actin, calponin) as compared with the control group. Gastric antral SM layer Nepsilon-(carboxymethyl) lysine (CML) level, the major AGE compound, were increased in the diabetic rats. AGE downregulated SM contractile markers and myocardin expression in a concentration-dependent manner. Myocardin overexpression prevented these results. AGE treatment activated NF-kappaB in SMCs. The NF-kappaB inhibitor BAY 11-7082 and anti-RAGE antibody blocked the effects of AGE on myocardin downregulation. AGE may induce the development of gastric dysmotility by downregulating SM contractile proteins and myocardin expression via the AGE/RAGE/NF-kappaB pathway. PMID- 27939577 TI - Utility of the Roche Cobas 4800 for detection of high-risk human papillomavirus in formalin-fixed paraffin-embedded oropharyngeal squamous cell carcinoma. AB - Clinical laboratories are expected to reliably identify human papilloma virus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) for prognostic and potential therapeutic applications. In addition to surrogate p16 immunohistochemistry (IHC) testing, DNA-based HPV-specific testing strategies are widely utilized. Recognizing the efficiency of the Roche Cobas 4800 platform for testing gynecological cytology specimens for high-risk HPV, we elected to evaluate the potential utility of this platform for testing formalin-fixed paraffin-embedded (FFPE) OPSCC tissue. Using the Roche Linear Array assay for comparison, we tested twenty-eight samples (16 primary OPSCC, 2 lymph node metastases from primary OPSCC, 1 oral tongue carcinoma, 3 benign squamous papillomas, and 3 non-oropharyngeal carcinoma tissues). Excluding two invalid results, the Roche Cobas 4800 testing resulted in excellent inter-assay concordance (25/26, 96.2%) and 100% concordance for HPV-16/HPV-18 positive samples. This data suggests that the Roche Cobas 4800 platform may be a cost effective method for testing OPSCC FFPE tissues in a clinical molecular pathology laboratory setting. PMID- 27939578 TI - Disseminated aspergillosis in an immunocompetent patient with detectable bis(methylthio)gliotoxin and negative galactomannan. AB - BACKGROUND: Disseminated invasive aspergillosis is an exceptional finding in immunocompetent hosts. As in immunocompromised patients, it has high mortality rates. Early diagnostic methods are required in order to properly manage the patient. Bis(methylthio)gliotoxin (bmGT) is a novel biomarker, useful in onco hematological patients. CASE REPORT: A 70-year-old male, with non-insulin dependent type II diabetes mellitus and a past surgery history of aortic valve replacement with coronary by-pass five years ago, was seen in the emergency department with blurred vision. Three days later, endogen endophthalmitis was diagnosed in the ophthalmology clinic. During admission for the vitrectomy, he suffered an ischemia of the right lower limb. A thoracic computed tomography revealed a mycotic aneurysm of the ascending thoracic aorta and parietal thrombus. The ascending aorta was replaced and abundant brittle material of infectious appearance, found between the aortic valve graft and the aneurysm, was removed. Aspergillus fumigatus sensu stricto grew in both vitreous and aorta cultures. BmGT was detected in two serum samples obtained prior to intravenous antifungal treatment, which was then reduced after voriconazole treatment was started. CONCLUSIONS: Disseminated invasive aspergillosis is a severe disease regardless of the immune status of the patient. This case report suggests that bmGT could be a suitable early diagnostic biomarker, not only in neutropenic patients, but also in immunocompetent hosts. PMID- 27939579 TI - Fear Erasure Facilitated by Immature Inhibitory Neuron Transplantation. AB - Transplantation of embryonic gamma-aminobutyric acid (GABA)ergic neurons has been shown to modify disease phenotypes in rodent models of neurologic and psychiatric disorders. However, whether transplanted interneurons modulate fear memory remains largely unclear. Here, we report that transplantation of embryonic interneurons into the amygdala does not alter host fear memory formation. Yet approximately 2 weeks after transplantation, but not earlier or later, extinction training produces a marked reduction in spontaneous recovery and renewal of fear response. Further analyses reveal that transplanted interneurons robustly form functional synapses with neurons of the host amygdala and exhibit similar developmental maturation in electrophysiological properties as native amygdala interneurons. Importantly, transplanted immature interneurons reduce the expression of perineuronal nets, promote long-term synaptic plasticity, and modulate both excitatory and inhibitory synaptic transmissions of the host circuits. Our findings demonstrate that transplanted immature interneurons modify amygdala circuitry and suggest a previously unknown strategy for the prevention of extinction-resistant pathological fear. PMID- 27939580 TI - MicroRNA-101 Regulates Multiple Developmental Programs to Constrain Excitation in Adult Neural Networks. AB - A critical feature of neural networks is that they balance excitation and inhibition to prevent pathological dysfunction. How this is achieved is largely unknown, although deficits in the balance contribute to many neurological disorders. We show here that a microRNA (miR-101) is a key orchestrator of this essential feature, shaping the developing network to constrain excitation in the adult. Transient early blockade of miR-101 induces long-lasting hyper excitability and persistent memory deficits. Using target site blockers in vivo, we identify multiple developmental programs regulated in parallel by miR-101 to achieve balanced networks. Repression of one target, NKCC1, initiates the switch in gamma-aminobutyric acid (GABA) signaling, limits early spontaneous activity, and constrains dendritic growth. Kif1a and Ank2 are targeted to prevent excessive synapse formation. Simultaneous de-repression of these three targets completely phenocopies major dysfunctions produced by miR-101 blockade. Our results provide new mechanistic insight into brain development and suggest novel candidates for therapeutic intervention. PMID- 27939581 TI - Expression of Terminal Effector Genes in Mammalian Neurons Is Maintained by a Dynamic Relay of Transient Enhancers. AB - Generic spinal motor neuron identity is established by cooperative binding of programming transcription factors (TFs), Isl1 and Lhx3, to motor-neuron-specific enhancers. How expression of effector genes is maintained following downregulation of programming TFs in maturing neurons remains unknown. High resolution exonuclease (ChIP-exo) mapping revealed that the majority of enhancers established by programming TFs are rapidly deactivated following Lhx3 downregulation in stem-cell-derived hypaxial motor neurons. Isl1 is released from nascent motor neuron enhancers and recruited to new enhancers bound by clusters of Onecut1 in maturing neurons. Synthetic enhancer reporter assays revealed that Isl1 operates as an integrator factor, translating the density of Lhx3 or Onecut1 binding sites into transient enhancer activity. Importantly, independent Isl1/Lhx3- and Isl1/Onecut1-bound enhancers contribute to sustained expression of motor neuron effector genes, demonstrating that outwardly stable expression of terminal effector genes in postmitotic neurons is controlled by a dynamic relay of stage-specific enhancers. PMID- 27939582 TI - New Transgenic Mouse Lines for Selectively Targeting Astrocytes and Studying Calcium Signals in Astrocyte Processes In Situ and In Vivo. AB - Astrocytes exist throughout the nervous system and are proposed to affect neural circuits and behavior. However, studying astrocytes has proven difficult because of the lack of tools permitting astrocyte-selective genetic manipulations. Here, we report the generation of Aldh1l1-Cre/ERT2 transgenic mice to selectively target astrocytes in vivo. We characterized Aldh1l1-Cre/ERT2 mice using imaging, immunohistochemistry, AAV-FLEX-GFP microinjections, and crosses to RiboTag, Ai95, and new Cre-dependent membrane-tethered Lck-GCaMP6f knockin mice that we also generated. Two to three weeks after tamoxifen induction, Aldh1l1-Cre/ERT2 selectively targeted essentially all adult (P80) brain astrocytes with no detectable neuronal contamination, resulting in expression of cytosolic and Lck GCaMP6f, and permitting subcellular astrocyte calcium imaging during startle responses in vivo. Crosses with RiboTag mice allowed sequencing of actively translated mRNAs and determination of the adult cortical astrocyte transcriptome. Thus, we provide well-characterized, easy-to-use resources with which to selectively study astrocytes in situ and in vivo in multiple experimental scenarios. PMID- 27939585 TI - A Strength-Based Approach to Care. PMID- 27939584 TI - Linking Electrical Stimulation of Human Primary Visual Cortex, Size of Affected Cortical Area, Neuronal Responses, and Subjective Experience. AB - Electrical brain stimulation (EBS) complements neural measurements by probing the causal relationship between brain and perception, cognition, and action. Many fundamental questions about EBS remain unanswered, including the spatial extent of cortex responsive to stimulation, and the relationship between the circuitry engaged by EBS and the types of neural responses elicited by sensory stimulation. Here, we measured neural responses and the effects of EBS in primary visual cortex in four patients implanted with intracranial electrodes. Using stimulation, behavior, and retinotopic mapping, we show the relationship between the size of affected cortical area and the magnitude of electrical charge. Furthermore, we show that the spatial location of electrically induced visual sensations is matched to the receptive field of the cortical site measured with broadband field potentials, and less so with event related potentials. Together, these findings broaden our knowledge about the mechanism of EBS and the neuromodulation of the human brain. PMID- 27939583 TI - Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2alpha Signaling as a Generalizable Mechanism for Dystonia. AB - Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2alpha signaling in DYT1 dystonia, a rare inherited generalized form, through a genome-wide RNAi screen. Subsequent experiments including patient derived cells and a mouse model support both a pathogenic role and therapeutic potential for eIF2alpha pathway perturbations. We further find genetic and functional evidence supporting similar pathway impairment in patients with sporadic cervical dystonia, due to rare coding variation in the eIF2alpha effector ATF4. Considering also that another dystonia, DYT16, involves a gene upstream of the eIF2alpha pathway, these results mechanistically link multiple forms of dystonia and put forth a new overall cellular mechanism for dystonia pathogenesis, impairment of eIF2alpha signaling, a pathway known for its roles in cellular stress responses and synaptic plasticity. PMID- 27939586 TI - Use of Biomarkers to Predict Readmission for Congestive Heart Failure. AB - Acute decompensated heart failure (ADHF) is a major reason for repeated hospitalizations. Identifying those patients with ADHF at risk for readmission is critical so that preventive interventions can be implemented. Biomarkers such as B-type natriuretic peptide (BNP), high-sensitivity troponin I, and galectin-3 (Gal-3) assessed at discharge may be useful, although their role in predicting short-term readmission is not well defined in the literature. We enrolled and had follow-up data for 101 participants admitted to our facility from April 2013 to March 2015 with a primary diagnosis of ADHF. Gal-3, high-sensitivity troponin I, and BNP were obtained within 48 hours before hospital discharge after management of ADHF. Gal-3 was assessed using 2 commercially available assays. We compared subjects who were and were not readmitted. Discharge BNP was found to be a significant predictor of 30- and 60-day readmission (area under the curve [AUC] 0.69 [p = 0.046], AUC 0.7 [p = 0.005], respectively). The addition of Gal-3 to discharge BNP provided significantly improved prediction of 60-day readmission. Gal-3 alone was found to be a significant predictor of 60-day readmission in patients with preserved ejection fraction (AUC 0.85, p <0.001). The net reclassification improvement was 55.2 (p = 0.037). Using multivariate analysis, for every 100 pg/L BNP increase, the probability of readmission increased by approximately 10%, and for every 1-ng/ml Gal-3 increase, the probability further increased 8%. A statistically significant net reclassification improvement was not found on examination of 30-day readmission. In conclusion, measurement of both Gal-3 and BNP at hospital discharge provides significant prediction of hospital readmission within 60 days. When combined, the prediction of readmission is significantly improved. PMID- 27939587 TI - Helminth glycomics - glycan repertoires and host-parasite interactions. AB - Glycoproteins and glycolipids of parasitic helminths play important roles in biology and host-parasite interaction. This review discusses recent helminth glycomics studies that have been expanding our insights into the glycan repertoire of helminths. Structural data are integrated with biological and immunological observations to highlight how glycomics advances our understanding of the critical roles that glycans and glycan motifs play in helminth infection biology. Prospects and challenges in helminth glycomics and glycobiology are discussed. PMID- 27939588 TI - Ascaris phylogeny based on multiple whole mtDNA genomes. AB - Ascaris lumbricoides and A. suum are two parasitic nematodes infecting humans and pigs, respectively. There has been considerable debate as to whether Ascaris in the two hosts should be considered a single or two separate species. Previous studies identified at least three major clusters (A, B and C) of human and pig Ascaris based on partial cox1 sequences. In the present study, we selected major haplotypes from these different clusters to characterize their whole mitochondrial genomes for phylogenetic analysis. We also undertook coalescent simulations to investigate the evolutionary history of the different Ascaris haplotypes. The topology of the phylogenetic tree based on complete mitochondrial genomic sequences was found to be similar to partial cox1 sequencing, but the support at internal nodes was higher in the former. Coalescent simulations suggested the presence of at least two divergence events: the first one occurring early in the Neolithic period which resulted in a differentiated population of Ascaris in pigs (cluster C), the second occurring more recently (~900 generations ago), resulting in clusters A and B which might have been spread worldwide by human activities. PMID- 27939589 TI - Dose related effects of LPS on endometrial epithelial cell populations from dioestrus cows. AB - Lipopolysaccharides (LPS) from Gram negative bacteria are involved in the pathogeny of uterine diseases in cows. This study aimed to investigate LPS effects on the growth of bovine endometrial epithelial cells (bEEC) and relationships between LPS response and tissue characteristics. Uteri from 35 females were characterized for parity and stage of oestrous cycle. Densities of glandular tissue (dGT), CD11b+ cells and Ki67+ cells were measured in the endometrial tissue. Cells from 13 dioestrus cows were exposed to 0, 2, 4, 8, 12, 16 or 24MUg/mL LPS. Effects of parity and stage of the oestrous cycle on tissue characteristics and effects of LPS dosage, cow and tissue characteristics on changes in cell numbers were analyzed by ANOVA. The dGT was higher in metoestrus and dioestrus samples than in pro-oestrus ones whereas densities of CD11b+ and Ki67+ cells were higher at pro-oestrus (p<0.05-p<0.01). LPS influenced bEEC populations in a dose related manner. An increase in number of live cells was observed for dosages ranging from 2 to 12MUg/mL LPS (p<0.0001 vs controls). No effect was found on numbers and frequencies of dead cells. With higher dosages, the numbers of live cells did not increase but the numbers of dead did increase. No relationships were observed between cow or tissue characteristics and growth patterns or frequencies of viable bEEC in controls nor in the response to LPS. To conclude this model is suitable for further studies on dysregulations induced by LPS in endometrial tissue. PMID- 27939590 TI - Lymph Node Fluorescence During Robot-Assisted Radical Prostatectomy With Indocyanine Green: Prospective Dosing Analysis. AB - OBJECTIVE: To prospectively assess the ideal dosing and the value of fluorescent sentinel lymph node (LN) detection with indocyanine green (ICG) for the detection of LN metastases in intermediate- and high-risk patients undergoing robot assisted prostatectomy and extended pelvic LN dissection (ePLND). PATIENTS AND METHODS: Twenty patients received transperineal prostatic injections of ICG. Patients were cycled through 5 doses (1.25, 2.5, 3.75, 5, and 7.5 mg) so optimal ICG dosing could be discovered early. RESULTS: ICG injection was able to identify fluorescent LN (FLN) packets in all 20 patients. Compared to the higher ICG doses, the 1.25 and 2.5 mg doses had fewer FLN packets and were abandoned after 1 dose each. The median number of FLN packets was 4.0, 6.0, and 4.5 for the respective doses of 3.75, 5.0, and 7.5 mg. The external iliac group was the most common site of fluorescence in 27.2% of patients, followed by the common iliac (21.3%), obturator (20.3%), internal iliac (18.5%), and node of Cloquet (7.7%). Seven (35%) of 20 patients had node-positive disease. Of the 5 patients that had fluorescent tissue outside of our ePLND template, 1 had a positive node present in the anterior bladder neck fat. Across all patients, ICG had 62% sensitivity, 50% specificity, 8% positive predictive value, and 95% negative predictive value in detecting LN metastases. CONCLUSION: The low sensitivity of ICG for the detection of LN metastases highlights why FLN dissection with ICG does not represent an alternative to ePLND. PMID- 27939591 TI - Re: Can calcitonin nasal spray reduce the risk of recurrence of central giant cell granuloma of the jaws? PMID- 27939592 TI - Evaluation of the accuracy of linear measurements on multi-slice and cone beam computed tomography scans to detect the mandibular canal during bilateral sagittal split osteotomy of the mandible. AB - The aim of this study was to compare the accuracy of linear measurements of the distance between the mandibular cortical bone and the mandibular canal using 64 detector multi-slice computed tomography (MSCT) and cone beam computed tomography (CBCT). It was sought to evaluate the reliability of these examinations in detecting the mandibular canal for use in bilateral sagittal split osteotomy (BSSO) planning. Eight dry human mandibles were studied. Three sites, corresponding to the lingula, the angle, and the body of the mandible, were selected. After the CT scans had been obtained, the mandibles were sectioned and the bone segments measured to obtain the actual measurements. On analysis, no statistically significant difference was found between the measurements obtained through MSCT and CBCT, or when comparing the measurements from these scans with the actual measurements. It is concluded that the images obtained by CT scan, both 64-detector multi-slice and cone beam, can be used to obtain accurate linear measurements to locate the mandibular canal for preoperative planning of BSSO. The ability to correctly locate the mandibular canal during BSSO will reduce the occurrence of neurosensory disturbances in the postoperative period. PMID- 27939593 TI - Dietary Patterns and Clinical Outcomes in Chronic Kidney Disease: The CKD.QLD Nutrition Study. AB - OBJECTIVE: Emerging evidence suggests that dietary patterns are associated with survival in people with chronic kidney disease (CKD). This study evaluated the relationship between dietary habits and renal-related clinical outcomes in an established CKD cohort. DESIGN: Prospective cohort study. SETTING: Three outpatient nephrology clinics in Queensland, Australia. SUBJECTS: A total of 145 adult patients with Stage 3 or 4 CKD (estimated glomerular filtration rate 15-59 mL/minute/1.73 m2). INTERVENTION: Dietary intake was measured using 24-hour recall and the HeartWise Dietary Habits Questionnaire (DHQ), which evaluates 10 components of dietary patterns in relation to cooking habits and intake of food groups. MAIN OUTCOME MEASURE: The primary outcome was a composite end point of all-cause mortality, commencement of dialysis, and doubling of serum creatinine. Secondary outcome was all-cause mortality alone. Multivariate cox regression analyses calculated hazard ratios (HRs) for associations between DHQ domains and occurrence of composite outcome and adjusted for confounders, including comorbidities and renal function. RESULTS: Over a median follow-up of 36 months, 32% (n = 47) reached the composite end point, of which 21% died (n = 30). Increasing DHQ score was associated with a lower risk of the composite end point with increasing intake of fruits and vegetables (HR: 0.61; 95% CI, 0.39-0.94) and limiting alcohol consumption (HR, 0.79; 95% CI: 0.65-0.96). For the secondary outcome of all-cause mortality, there was a significant association with adequate intake of fruits and vegetables (HR: 0.35; 95% CI, 0.15-0.83). CONCLUSION: Healthy dietary patterns consisting of adequate fruits and vegetables and limited alcohol consumption are associated with a delay in CKD progression and improved survival in patients with Stage 3 or 4 CKD. PMID- 27939594 TI - In Response to Risk Determinants of Acute Mountain Sickness by Lawrence and Reid. PMID- 27939595 TI - Fabrication of size-controlled linoleic acid particles and evaluation of their in vitro lipotoxicity. AB - The biological activities of fatty acids (FAs) can differ with size even for lipids of similar compositions. The aim of this study was to develop size controlled FA particles and to evaluate their toxicity as a function of size. Well-stabilized nano- and microscale linoleic acid (LA) were fabricated based on specific physical factors. Then, resulting LAs were characterized by size distribution, surface charge, assembly structure, composition, and serum effects. The sizes of the nano- (LAnano) and microscale (LAmicro) LAs, determined by electron microscopy, were 109 nm and 12 MUm, respectively. LAnano, a multilamellar structure as determined by cryo-electron microscopy, was rapidly internalized into cells via free fatty acid receptor 3. After internalization, LAnano, but not LAmicro, induced nuclear translocation of fatty acid binding protein 4 (FABP4). Translocation of FABP4 into the nucleus then induced expression of the FA metabolism-related genes InsR and AdipoR1. Their expression was significantly increased in the presence of only LAnano. Cytotoxicity was also significantly increased in cells treated with LAnano, but not LAmicro, as indicated by the endoplasmic reticulum stress markers CHOP and GRP78. Therefore, our results demonstrated that FAs with the same composition but varying in size can cause different cellular responses. PMID- 27939596 TI - Unb-DPC: Identify mycobacterial membrane protein types by incorporating un-biased dipeptide composition into Chou's general PseAAC. AB - This study investigates an efficient and accurate computational method for predicating mycobacterial membrane protein. Mycobacterium is a pathogenic bacterium which is the causative agent of tuberculosis and leprosy. The existing feature encoding algorithms for protein sequence representation such as composition and translation, and split amino acid composition cannot suitably express the mycobacterium membrane protein and their types due to biasness among different types. Therefore, in this study a novel un-biased dipeptide composition (Unb-DPC) method is proposed. The proposed encoding scheme has two advantages, first it avoid the biasness among the different mycobacterium membrane protein and their types. Secondly, the method is fast and preserves protein sequence structure information. The experimental results yield SVM based classification accurately of 97.1% for membrane protein types and 95.0% for discriminating mycobacterium membrane and non-membrane proteins by using jackknife cross validation test. The results exhibit that proposed model achieved significant predictive performance compared to the existing algorithms and will lead to develop a powerful tool for anti-mycobacterium drugs. PMID- 27939597 TI - A forecast for extinction debt in the presence of speciation. AB - Predicting biodiversity relaxation following a disturbance is of great importance to conservation biology. Recently-developed models of stochastic community assembly allow us to predict the evolution of communities on the basis of mechanistic processes at the level of individuals. The neutral model of biodiversity, in particular, has provided closed-form solutions for the relaxation of biodiversity in isolated communities (no immigration or speciation). Here, we extend these results by deriving a relaxation curve for a neutral community in which new species are introduced through the mechanism of random fission speciation (RFS). The solution provides simple closed-form expressions for the equilibrium species richness, the relaxation time and the species-individual curve, which are good approximation to the more complicated formulas existing for the same model. The derivation of the relaxation curve is based on the assumption of a broken-stick species-abundance distribution (SAD) as an initial community configuration; yet for commonly observed SADs, the maximum deviation from the curve does not exceed 10%. Importantly, the solution confirms theoretical results and observations showing that the relaxation time increases with community size and thus habitat area. Such simple and analytically tractable models can help crystallize our ideas on the leading factors affecting biodiversity loss. PMID- 27939599 TI - I like the old stuff better than the new stuff? Subjective experiences of new psychoactive substances. AB - BACKGROUND: Over the past decade, monitoring systems have identified the rapid emergence of new psychoactive substances (NPS). While the use of many NPS is minimal and transitory, little is known about which products have potential for capturing the attention of significant proportions of the drug consuming market. The aim of this study was to explore self-reported experiences of three commonly used NPS classes within the Australian context (synthetic cathinones, hallucinogenic phenethylamines and hallucinogenic tryptamines) relative to traditional illicit drug counterparts. METHODS: Frequent psychostimulant consumers interviewed for the Australian Ecstasy and related Drugs Reporting System (EDRS) (n=1208) provided subjective ratings of the pleasurable and negative (acute and longer-term) effects of substances used in the last six months on the last occasion of use, and the likelihood of future use. RESULTS: Stimulant-type NPS (e.g., mephedrone, methylone) were rated less favourably than ecstasy and cocaine in terms of pleasurable effects and likelihood of future use. DMT (a hallucinogenic tryptamine) showed a similar profile to LSD in terms of pleasurable effects and the likelihood of future use, but negative effects (acute and comedown) were rated lower. Hallucinogenic phenethylamines (e.g., 2C-B) showed a similar negative profile to LSD, but were rated as less pleasurable and less likely to be used again. CONCLUSION: The potential for expanded use of stimulant-type NPS may be lower compared to commonly used stimulants such as ecstasy and cocaine. In contrast, the potential of DMT may be higher relative to LSD given the comparative absence of negative effects. PMID- 27939600 TI - A rapid monitoring method for inorganic arsenic in rice flour using reversed phase-high performance liquid chromatography-inductively coupled plasma mass spectrometry. AB - A new rapid monitoring method by means of high performance liquid chromatography inductively coupled plasma mass spectrometry (HPLC-ICP-MS) following the heat assisted extraction was developed for measurement of total inorganic arsenic species in rice flour. As(III) and As(V) eluted at the same retention time and completely separated from organoarsenic species by an isocratic elution program on a reversed phase column. Therefore, neither ambiguous oxidation of arsenite to arsenate nor the integration of two peaks were necessary to determine directly the target analyte inorganic arsenic. Rapid injection allowed measuring 3 replicates within 6min and this combined with a quantitative extraction of all arsenic species from rice flour by a 15min HNO3-H2O2 extraction makes this the fastest laboratory based method for inorganic arsenic in rice flour. PMID- 27939598 TI - Alternative roles for oxidized mCs and TETs. AB - Ten-eleven-translocation (TET) proteins oxidize 5-methylcytosine (5mC) to form stable or transient modifications (oxi-mCs) in the mammalian genome. Genome-wide mapping and protein interaction studies have shown that 5mC and oxi-mCs have unique distribution patterns and alternative roles in gene expression. In addition, oxi-mCs may interact with specific chromatin regulators, transcription factors and DNA repair proteins to maintain genomic integrity or alter DNA replication and transcriptional elongation rates. In this review we will discuss recent advances in our understanding of how TETs and 5hmC exert their epigenetic function as tumor suppressors by playing alternative roles in transcriptional regulation and genomic stability. PMID- 27939601 TI - Methacrylate-bonded covalent-organic framework monolithic columns for high performance liquid chromatography. AB - Covalent-organic frameworks (COFs) are a newfangled class of intriguing microporous materials. Considering their unique properties, COFs should be promising as packing materials for high performance liquid chromatography (HPLC). However, the irregular shape and sub-micrometer size of COFs synthesized via the traditional methods render the main obstacles for the application of COFs in HPLC. Herein, we report the preparation of methacrylate-bonded COF monolithic columns for HPLC to overcome the above obstacles. The prepared COF bonded monolithic columns not only show good homogeneity and permeability, but also give high column efficiency, good resolution and precision for HPLC separation of small molecules including polycyclic aromatic hydrocarbons, phenols, anilines, nonsteroidal anti-inflammatory drugs and benzothiophenes. Compared with the bare polymer monolithic column, the COF bonded monolithic columns show enhanced hydrophobic, pi-pi and hydrogen bond interactions in reverse phase HPLC. The results reveal the great potential of COF bonded monoliths for HPLC and COFs in separation sciences. PMID- 27939602 TI - Child-resistant and tamper-resistant packaging: A systematic review to inform tobacco packaging regulation. AB - OBJECTIVE: We aimed to investigate the effects of special packaging (child resistant, adult-friendly) and tamper-resistant packaging on health and behavioral outcomes in order to identify research gaps and implications for packaging standards for tobacco products. METHODS: We searched seven databases for keywords related to special and tamper-resistant packaging, consulted experts, and reviewed citations of potentially relevant studies. 733 unique papers were identified. Two coders independently screened each title and abstract for eligibility. They then reviewed the full text of the remaining papers for a second round of eligibility screening. Included studies investigated a causal relationship between type of packaging or packaging regulation and behavioral or health outcomes and had a study population composed of consumers. Studies were excluded on the basis of publication type, if they were not peer-reviewed, and if they had low external validity. Two reviewers independently coded each paper for study and methodological characteristics and limitations. Discrepancies were discussed and resolved. RESULTS: The review included eight studies: four assessing people's ability to access the contents of different packaging types and four evaluating the impact of packaging requirements on health-related outcomes. Child-resistant packaging was generally more difficult to open than non child-resistant packaging. Child-resistant packaging requirements have been associated with reductions in child mortality. CONCLUSIONS: Child-resistant packaging holds the expectation to reduce tobacco product poisonings among children under six. PMID- 27939603 TI - Acyl/free carnitine ratio is a risk factor for hepatic steatosis after pancreatoduodenectomy and total pancreatectomy. AB - OBJECTIVES: Hepatic steatosis, one of the most frequent long-term complications of pancreatectomy, influences not only hepatic function but also survival rate. However, its risk factors and pathogenesis have not been established. The purpose of this study was to clarify the risk factors for hepatic steatosis after pancreatectomy. METHODS: In this retrospective study of 21 patients who had undergone pancreatectomy (19 cases of pancreatoduodenectomy and 2 cases of total pancreatectomy), serum carnitine concentrations, fractions of carnitine, and hepatic attenuation on computed tomography images were analyzed with the aim of identifying risk factors for hepatic steatosis. RESULTS: Thirteen (61.9%) of the 21 patients were diagnosed as having hypocarnitinemia after pancreatectomy. Average hepatic attenuation was as low as 42.2HU (+/-21.3 SD). A high ratio of acyl/free carnitine was associated with less pronounced hepatic attenuation according to both univariate (P < 0.001) and multivariate (P = 0.020) regression analyses. CONCLUSIONS: The serum carnitine concentrations were low after pancreatectomy in some patients. The statistical analyses suggest that a high ratio of acyl/free carnitine is an independent risk factor for hepatic steatosis after pancreatectomy. PMID- 27939604 TI - Antigen retrieval prior to on-tissue digestion of formalin-fixed paraffin embedded tumour tissue sections yields oxidation of proline residues. AB - MALDI-mass spectrometry imaging (MALDI-MSI) has been shown to allow the study of protein distribution and identification directly within formalin-fixed paraffin embedded (FFPE) tissue sections. However, direct protein identification from tissue sections remains challenging due to signal interferences and/or existing post-translational or other chemical modifications. The use of antigen retrieval (AR) has been demonstrated for unlocking proteins prior to in situ enzymatic digestion and MALDI-MSI analysis of FFPE tissue sections. In the work reported here, the identification of proline oxidation, which may occur when performing the AR protocol, is described. This facilitated and considerably increased the number of identified peptides when adding proline oxidation as a variable modification to the MASCOT search criteria. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann. PMID- 27939605 TI - Dynamics of the Escherichia coli proteome in response to nitrogen starvation and entry into the stationary phase. AB - Nitrogen is needed for the biosynthesis of biomolecules including proteins and nucleic acids. In the absence of fixed nitrogen prokaryotes such as E. coli immediately ceases growth. Ammonium is the preferred nitrogen source for E. coli supporting the fastest growth rates. Under conditions of ammonium limitation, E. coli can use alternative nitrogen sources to supply ammonium ions and this reprogramming is led by the induction of the NtrC regulon. Here we used label free proteomics to determine the dynamics of E. coli proteins expression in response to ammonium starvation in both the short (30min) and the longer (60min) starvation. Protein abundances and post-translational modifications confirmed that activation of the NtrC regulon acts as the first line of defense against nitrogen starvation. The ribosome inactivating protein Rmf was induced shortly after ammonium exhaustion and this was preceded by induction of other ribosome inactivating proteins such as Hpf and RaiA supporting the hypothesis that ribosome shut-down is a key process during nitrogen limitation stress. The proteomic data revealed that growth arrest due to nitrogen starvation correlates with the accumulation of proteins involved in DNA condensation, RNA and protein catabolism and ribosome hibernation. Collectively, these proteome adaptations will result in metabolic inactive cells which are likely to exhibit multidrug tolerance. PMID- 27939606 TI - Typing of colon and lung adenocarcinoma by high throughput imaging mass spectrometry. AB - In advanced tumor stages, diagnosis is frequently made from metastatic tumor tissue. In some cases, the identification of the tumor of origin may be difficult by histology alone. In this setting, immunohistochemical and molecular biological methods are often required. In a subset of tumors definite diagnosis cannot be achieved. Thus, additional new diagnostic methods are required for precise tumor subtyping. Mass spectrometric methods are of special interest for the discrimination of different tumor types. We investigated whether it is possible to discern adenocarcinomas of colon and lung using high-throughput imaging mass spectrometry on formalin-fixed paraffin-embedded tissue microarrays. 101 primary adenocarcinoma of the colon and 91 primary adenocarcinoma of the lung were used to train a Linear Discriminant Analysis model. Results were validated on an independent set of 116 colonic and 75 lung adenocarcinomas. In the validation cohort 109 of 116 patients with colonic and 67 of 75 patients with lung adenocarcinomas were correctly classified. The ability to define proteomic profiles capable to discern different tumor types promises a valuable tool in cancer diagnostics and might complement current approaches. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann. PMID- 27939607 TI - Proteomic profiles of thyroid tumors by mass spectrometry-imaging on tissue microarrays. AB - The current study proposes the successful use of a mass spectrometry-imaging technology that explores the composition of biomolecules and their spatial distribution directly on-tissue to differentially classify benign and malignant cases, as well as different histotypes. To identify new specific markers, we investigated with this technology a wide histological Tissue Microarray (TMA) based thyroid lesion series. Results showed specific protein signatures for malignant and benign specimens and allowed to build clusters comprising several proteins with discriminant capabilities. Among them, FINC, ACTB1, LMNA, HSP7C and KAD1 were identified by LC-ESI-MS/MS and found up-expressed in malignant lesions. These findings represent the opening of further investigations for their translation into clinical practice, e.g. for setting up new immunohistochemical stainings, and for a better understanding of thyroid lesions. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann. PMID- 27939608 TI - Structural and functional studies of Escherichia coli aggregative adherence fimbriae (AAF/V) reveal a deficiency in extracellular matrix binding. AB - Enteroaggregative Escherichia coli (EAEC) is an emerging cause of acute and persistent diarrhea worldwide. The pathogenesis of different EAEC stains is complicated, however, the early essential step begins with attachment of EAEC to intestinal mucosa via aggregative adherence fimbriae (AAFs). Currently, five different variants have been identified, which all share a degree of similarity in the gene organization of their operons and sequences. Here, we report the solution structure of Agg5A from the AAF/V variant. While preserving the major structural features shared by all AAF members, only Agg5A possesses an inserted helix at the beginning of the donor strand, which together with altered surface electrostatics, renders the protein unable to interact with fibronectin. Hence, here we characterize the first AAF variant with a binding mode that varies from previously described AAFs. PMID- 27939610 TI - Changes in Malaria Epidemiology in Africa and New Challenges for Elimination. AB - Although the burden of Plasmodium falciparum malaria is gradually declining in many parts of Africa, it is characterized by spatial and temporal variability that presents new and evolving challenges for malaria control programs. Reductions in the malaria burden need to be sustained in the face of changing epidemiology whilst simultaneously tackling significant pockets of sustained or increasing transmission. Large-scale, robust surveillance mechanisms that measure rather than estimate the actual burden of malaria over time from large areas of the continent where such data are lacking need to be prioritized. We review these fascinating developments, caution against complacency, and make the case that improving the extent and quality of malaria surveillance is vital for Africa as she marches on towards elimination. PMID- 27939611 TI - High concentration of trichlorfon (1mM) disrupts axonal cytoskeleton and decreases the expression of plasticity-related proteins in SH-SY5Y cells. AB - Some organophosphorus compounds (OPs) induce a neurodegenerative disorder known as organophosphate-induced delayed neuropathy (OPIDN), which is related to irreversible inhibition of neuropathy target esterase (NTE) and impairment of neurite outgrowth. The present study addresses the effects of trichlorfon, mipafox (neuropathic model) and paraoxon (non-neuropathic model) on neurite outgrowth and neuroplasticity-related proteins in retinoic-acid-stimulated SH SY5Y cells, a cellular model widely used to study the neurotoxicity of OPs. Mipafox (20MUM) decreased cellular differentiation and the expression of neurofilament 200 (NF-200), growth associated- (GAP-43) and synaptic proteins (synapsin I and synaptophysin); whereas paraoxon (300MUM) induced no effect on cellular differentiation, but significant decrease of NF-200, GAP-43, synapsin I and synaptophysin as compared to controls. However, the effects of paraoxon on these proteins were significantly lower than the effects of mipafox. In conclusion, axonal cytoskeletal proteins, as well as axonal plasticity-related proteins are more effectively affected by neuropathic (mipafox) than by non neuropathic (paraoxon) OPs, suggesting that they might play a role in the mechanism of OPIDN. At high concentration (1mM), trichlorfon induced effects similar to those of the neuropathic OP, mipafox (20MUM), but also caused high inhibition of AChE. Therefore, these effects are unlikely to occur in humans at non-lethal doses of trichlorfon. PMID- 27939609 TI - EPCR and Malaria Severity: The Center of a Perfect Storm. AB - Severe malaria due to Plasmodium falciparum infection causes nearly half a million deaths per year. The different symptomatology and disease manifestations among patients have hampered understanding of severe malaria pathology and complicated efforts to develop targeted disease interventions. Infected erythrocyte sequestration in the microvasculature plays a critical role in the development of severe disease, and there is increasing evidence that cytoadherent parasites interact with host factors to enhance the damage caused by the parasite. The recent discovery that parasite binding to endothelial protein C receptor (EPCR) is associated with severe disease has suggested new mechanisms of pathology and provided new avenues for severe malaria adjunctive therapy research. PMID- 27939612 TI - In vitro testing of basal cytotoxicity: Establishment of an adverse outcome pathway from chemical insult to cell death. AB - In this paper, an in vitro basal cytotoxicity testing strategy is described for new chemical entities that lack any pre-existing information on potential toxicity. Special attention is paid to the selection of the cellular system, cytotoxicity assay and exposure conditions. This approach is based on a newly proposed generic adverse outcome pathway from chemical insult to cell death that consists of 3 steps, including initial cell injury, mitochondrial dysfunction and cell demise. The suggested strategy to consider in vitro basal cytotoxicity as a first step in evaluating the toxicity of new chemical entities can be placed in a tiered strategy that could be continued by evaluating more specific types of toxicity. PMID- 27939614 TI - Comparing direct and video laryngoscopy for urgent intubation during chest compression. PMID- 27939615 TI - Fibroepithelial polyp of external auditory canal. PMID- 27939613 TI - Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. AB - Nonalcoholic steatohepatitis (NASH) is an emerging health crisis with no approved therapies. Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, shows promise in NASH trials. However, the precise mechanisms mediating OCA effects and impact on cholesterol metabolism are not fully understood. We explored the pharmaco-toxicological effects of OCA on patho-physiological pathways in hepatocytes using a previously described perfused organotypic liver system that allows culture in near-physiological insulin/glucose milieus, and exhibits drug responses at clinically-relevant concentrations. Primary hepatocytes experienced 48-hour exposure to OCA at concentrations approximating therapeutic (0.5MUM) and supratherapeutic (10MUM) levels. Global transcriptomics by RNAseq was complimented by cellular viability (MTT), CYP activity assays, and secreted FGF19 levels in the media. Dose-dependent, transcriptional effects suggested suppression of bile acid synthesis (?CYP7A1, ?CYP27A1) and increased bile efflux (?ABCB4, ?ABCB11, ?OSTA, ?OSTB). Pleiotropic effects included suppression of TGFbeta and IL-6 signaling pathways, and signatures suggestive of HDL suppression (?SCARB1, ?ApoAI, ?LCAT) and LDL elevation (?ApoB, ?CYP7A1). OCA exhibited direct FXR-mediated effects with increased FGF19 secretion. Transcriptomics revealed regulation of metabolic, anti-inflammatory, and anti-fibrotic pathways beneficial in NASH, and predicted cholesterol profiles consistent with clinical findings. Follow-up studies under lipotoxic/inflammatory conditions would corroborate these effects in a disease-relevant environment. PMID- 27939616 TI - Defibrotide in Severe Sinusoidal Obstruction Syndrome: Medicine and Economic Issues. AB - In Europe, Defitelio (defibrotide) has a Market Authorization in curative treatment of severe sinusoidal obstruction syndrome (SOS) but not in prophylaxis (2013). In France, defibrotide has had a compassionate-use program since 2009. Today, the high cost of defibrotide remains a major hurdle for hospital budgets. Medicine and economic issues were evaluated for the 39 hospitals of the French Public Assistance-Hospitals of Paris (AP-HP). We analyzed literature reviews, consumption, and expenditures through AP-HP data in 2014 and patient profiles with defibrotide in the corresponding diagnostic-related groups (DRGs) and consulted a board of hematologists. Finally, 18 publications were selected. Between 2011 and 2014 consumption increased to ?5.2M. In 2014, 80 patients receiving defibrotide were mainly ascribed to the DRG "hematopoietic stem cell transplantation" levels 3 or 4. The tariffs attributed to drugs (?3544 to 4084) cover a small part of treatment costs (?97,524 for an adult). French experts thus recommended a harmonization of indications in prophylaxis (off-label use), improvement of pretransplant care, and optimization of the number of vials used. The economic impact led experts to change their practices. They recommended the restriction of defibrotide use to SOS curative treatment and to high-risk situations in prophylaxis. PMID- 27939617 TI - Hypoxia mimetic induces lipid accumulation through mitochondrial dysfunction and stimulates autophagy in murine preadipocyte cell line. AB - BACKGROUND: Hypoxia occurs within adipose tissue of obese human and mice. However, its role in adipose tissue regulation is still controversial. METHODS: We used murine preadipocyte 3T3-L1 cells and hypoxia was induced by using hypoxia mimetic agents, as CoCl2. To study adipocyte differentiation, we evaluated the adipocyte markers (PPARgamma, C/EBPalpha and aP2), and a preadipocyte marker (pref-1) by qPCR, western blotting and immunofluorescence. Lipid accumulation was evaluated by Oil red-O assay and perilipin levels by western blotting and immunofluorescence. The effect of CoCl2 in microRNA, miR-27a and miR-27b, levels was evaluated by qPCR. We also assessed the mitochondrial membrane potential and reactive oxygen species (ROS), superoxide and ATP production. The effect of hypoxia mimetic in autophagy was determined by LC3B and p62 level evaluation by western blotting. RESULTS: Our results show that the hypoxia mimetic cobalt chloride increases lipid accumulation with no expression of PPARgamma2. Furthermore, using qPCR we observed that the hypoxia mimetic increases microRNAs miR-27a and miR-27b, which are known to block PPARgamma2 expression. In contrast, cobalt chloride induces mitochondrial dysfunction, and increases ROS production and autophagy. Moreover, an antioxidant agent, glutathione, prevents lipid accumulation induced by hypoxia mimetic indicating that ROS are responsible for hypoxia-induced lipid accumulation. CONCLUSIONS: All these results taken together suggest that hypoxia mimetic blocks differentiation and induces autophagy. Hypoxia mimetic also induces lipid accumulation through mitochondrial dysfunction and ROS accumulation. GENERAL SIGNIFICANCE: This study highlights the importance of adipocyte response to hypoxia, which might impair adipocyte metabolism and compromise adipose tissue function. PMID- 27939618 TI - Pharmaceutical salt of BM635 with improved bioavailability. AB - BM635 is a small molecule endowed with outstanding anti-mycobacterial activity (minimum inhibitory concentration of 0.12MUM against M. tuberculosis H37Rv) identified during a hit-to-lead campaign. Its poor aqueous solubility together with its high lipophilicity led to low exposure in vivo. Indeed, the half-life in vivo of BM635 was 1h, allowing a reasonable maximum concentration (Cmax=1.62MUM) and a moderate bioavailability (46%). The present study aimed to develop salt forms of BM635 with pharmaceutically accepted hydrochloric, methanesulphonic, phosphoric, tartaric, and citric acids to overcome these drawbacks. BM635 salts (BM635-HCl, BM635-Mes, BM635-PA, BM635-TA and BM635-CA) were evaluated for physicochemical as well as biopharmaceutical attributes. PMID- 27939619 TI - Formulation and characterization of an apigenin-phospholipid phytosome (APLC) for improved solubility, in vivo bioavailability, and antioxidant potential. AB - The apigenin-phospholipid phytosome (APLC) was developed to improve the aqueous solubility, dissolution, in vivo bioavailability, and antioxidant activity of apigenin. The APLC synthesis was guided by a full factorial design strategy, incorporating specific formulation and process variables to deliver an optimized product. The design-optimized formulation was assayed for aqueous solubility, in vitro dissolution, pharmacokinetics, and antioxidant activity. The pharmacological evaluation was carried out by assessing its effects on carbon tetrachloride-induced elevation of liver function marker enzymes in a rat model. The antioxidant activity was assessed by studying its effects on the liver antioxidant marker enzymes. The developed model was validated using the design optimized levels of formulation and process variables. The physical-chemical characterization confirmed the formation of phytosomes. The optimized formulation demonstrated over 36-fold higher aqueous solubility of apigenin, compared to that of pure apigenin. The formulation also exhibited a significantly higher rate and extent of apigenin release in dissolution studies. The pharmacokinetic analysis revealed a significant enhancement in the oral bioavailability of apigenin from the prepared formulation, compared to pure apigenin. The liver function tests indicated that the prepared phytosome showed a significantly improved restoration of all carbon tetrachloride-elevated rat liver function marker enzymes. The prepared formulation also exhibited antioxidant potential by significantly increasing the levels of glutathione, superoxide dismutase, catalase, and decreasing the levels of lipid peroxidase. The study shows that phospholipid based phytosome is a promising and viable strategy for improving the delivery of apigenin and similar phytoconstituents with low aqueous solubility. PMID- 27939620 TI - PLGA/SBA-15 mesoporous silica composite microparticles loaded with paclitaxel for local chemotherapy. AB - In this work, high surface area mesoporous silica (SBA-15) was loaded with paclitaxel (taxol, PTX) and was further entrapped into poly(lactic acid-co glycolic acid) (PLGA) microparticles (MPs). A modified solvent evaporation emulsion method was used in order to formulate the composite microparticles with sizes of 8-12MUm. PTX loaded SBA-15 as well as the PLGA/PTX-SBA-15 composites were characterized in terms of their morphology, crystal structure and thermal properties. Drug content, loading efficiency, particle size and the in-vitro drug release kinetics of the PLGA/PTChi-SBA-15 microspheres were also investigated. The in vitro release studies were carried out using Simulated Body Fluid (SBF) at 37 degrees C revealing that the prepared formulations present higher dissolution rate than pure PTX and sustained pattern which is ideal for anticancer carriers. Modeling and data analysis of the in vitro drug release was also investigated. It was also shown that all microparticles have low cytotoxicity in HUVE cells. Finally, it was found that drug loaded microparticles are very effective in Human Cervical Adenocarcinoma (HeLa) cells. PMID- 27939621 TI - The relationship between foot and ankle symptoms and risk of developing knee osteoarthritis: data from the osteoarthritis initiative. AB - OBJECTIVE: To investigate whether foot and/or ankle symptoms increase the risk of developing (1) knee symptoms and (2) symptomatic radiographic knee osteoarthritis (OA). DESIGN: 1020 Osteoarthritis Initiative (OAI) participants who were at-risk of knee OA, but were without knee symptoms or radiographic knee OA, were investigated. Participants indicated the presence and laterality of foot/ankle symptoms at baseline. The main outcome was development of knee symptoms (pain, aching or stiffness in and around the knee on most days of the month for at least 1 month in the past year). A secondary outcome was development of symptomatic radiographic knee OA (symptoms plus Kellgren and Lawrence [KL] grade >=2), over the subsequent 4 years. Associations between foot/ankle symptoms and study outcomes were assessed by logistic regression models. RESULTS: Foot/ankle symptoms in either or both feet significantly increased the odds of developing knee symptoms (adjusted odds ratio (OR) 1.55, 95% confidence interval (CI) 1.10 to 2.19), and developing symptomatic radiographic knee OA (adjusted OR 3.28, 95% CI 1.69 to 6.37). Based on laterality, contralateral foot/ankle symptoms were associated with developing both knee symptoms (adjusted OR 1.68, 95% CI 1.05 to 2.68) and symptomatic radiographic knee OA (adjusted OR 3.08, 95% CI 1.06 to 8.98), whilst bilateral foot/ankle symptoms were associated with developing symptomatic radiographic knee OA (adjusted OR 4.02, 95% CI 1.76 to 9.17). CONCLUSION: In individuals at-risk of knee OA, the presence of contralateral foot/ankle symptoms in particular increases risk of developing both knee symptoms and symptomatic radiographic knee OA. PMID- 27939622 TI - A systematic review and evidence synthesis of qualitative studies to identify primary care clinicians' barriers and enablers to the management of osteoarthritis. AB - OBJECTIVE: Primary care management of osteoarthritis (OA) is variable and often inconsistent with clinical practice guidelines (CPGs). This study aimed to identify and synthesize available qualitative evidence on primary care clinicians' views on providing recommended management of OA. DESIGN: Eligibility criteria included full reports published in peer-reviewed journals, with data collected directly from primary care clinicians using qualitative methods for collection and analysis. Five electronic databases (MEDLINE, Cochrane Central Register, EMBASE, CINAHL and PsychInfo) were searched to August 2016. Two independent reviewers identified eligible reports, conducted critical appraisal (based on Critical Appraisal Skills Programme (CASP) criteria), and extracted data. Three reviewers independently, then collaboratively, synthesized and interpreted data through an inductive and iterative process to derive new themes. The Confidence in Evidence from Reviews of Qualitative research (CERQual) approach was used to determine a confidence profile for each finding. RESULTS: Eight studies involving approximately 83 general practitioners (GPs), 24 practice nurses, 12 pharmacists and 10 physical therapists, from Australia, France, United Kingdom, Germany and Mexico were included. Four barriers were identified as themes 1) OA is not that serious, 2) Clinicians are, or perceive they are, under prepared, 3) Personal beliefs at odds with providing recommended practice, and 4) Dissonant patient expectations. No themes were enablers. Confidence ratings were moderate or low. CONCLUSIONS: Synthesising available data revealed barriers that collectively point towards a need to address clinician knowledge gaps, and enhance clinician communication and behaviour change skills to facilitate patient adherence, enable effective conversations and manage dissonant patient expectations. REGISTRATION: PROSPERO (http://www.crd.york.ac.uk/PROSPERO) [4/11/2015, CRD42015027543]. PMID- 27939624 TI - Winter monsoon variability and its impact on aerosol concentrations in East Asia. AB - We investigate the relationship between winter aerosol concentrations over East Asia and variability in the East Asian winter monsoon (EAWM) using GEOS-Chem 3-D global chemical transport model simulations and ground-based aerosol concentration data. We find that both observed and modeled surface aerosol concentrations have strong relationships with the intensity of the EAWM over northern (30-50 degrees N, 100-140 degrees E) and southern (20-30 degrees N, 100 140 degrees E) East Asia. In strong winter monsoon years, compared to weak winter monsoon years, lower and higher surface PM2.5 concentrations by up to 25% are shown over northern and southern East Asia, respectively. Analysis of the simulated results indicates that the southward transport of aerosols is a key process controlling changes in aerosol concentrations over East Asia associated with the EAWM. Variability in the EAWM is found to play a major role in interannual variations in aerosol concentrations; consequently, changes in the EAWM will be important for understanding future changes in wintertime air quality over East Asia. PMID- 27939623 TI - Factors associated with meniscal body extrusion on knee MRI in overweight and obese women. AB - OBJECTIVE: To determine factors associated with higher degree of meniscal body extrusion in overweight and obese women at high risk of knee osteoarthritis (OA). DESIGN: We used baseline data of the PRevention of knee Osteoarthritis in Overweight Females (PROOF) study, Netherlands, comprising overweight or obese women aged 50-60 years, free of clinical knee OA. All subjects completed a questionnaire on knee complaints and physical activity, underwent physical examination, radiography, and 1.5 T magnetic resonance imaging (MRI) of both knees. Using the mid-coronal MRI slice, one blinded observer measured tibial plateau width and meniscal body extrusion of both menisci in both knees. The association between baseline factors and meniscal extrusion, were analyzed with a random effects regression model. In addition, we used a fixed effect regression model for evaluation of knee-specific factors. RESULTS: Mean age of the included women (n = 395) was 55.7 years and mean body mass index (BMI) 32.4 kg/m2. Of all knees, 23% had an absolute medial meniscus body extrusion >=3.0 mm and 4% had lateral meniscus body extrusion >=3.0 mm. In the multivariable model, the medial meniscus extrusion was increased by 0.44 mm (95% confidence interval [CI] 0.11, 0.77) when a medial meniscus tear was present, by 0.20 mm per 5 kg/m2 (95% CI 0.05, 0.35) increase in BMI and by 0.25 in the presence of mild knee symptoms (95% CI 0.05 to 0.44). Kellgren-Lawrence (KL) grade >=1 and tibia width were associated with increased both medial and lateral extrusion. CONCLUSION: In women, ipsilateral meniscus tear and high BMI are factors associated with medial meniscus body extrusion. PMID- 27939625 TI - Characteristics of air quality and sources affecting fine particulate matter (PM2.5) levels in the City of Red Deer, Canada. AB - With concern about levels and exceedances of Canadian and provincial standards and objectives for fine particulate matter (PM2.5) in recent years, an investigation of air quality characteristics and potential local and long-range sources influencing PM2.5 concentrations was undertaken in the City of Red Deer, Alberta. The study covered the period May 2009 to December 2015. Comparatively higher concentrations of PM2.5 were observed in winter (mean: 11.6 MUg/m3, median: 10 MUg/m3) than in summer (mean: 9.0 MUg/m3, median: 7.0 MUg/m3). Exceedances of the 1 h Alberta Ambient Air Quality objective (3-31 times per year > 80 MUg/m3) and the 24 h Canada-Wide Standard (2-11 times per year > 30 MUg/m3) were found at the Red Deer Riverside air monitoring station, particularly in 2010, 2011 and 2015. Positive matrix factorization (PMF) followed by multiple linear regression (MLR) analysis identified a mixed industry/agriculture factor as the dominant contributor to PM2.5 (39.3%), followed by an O3-rich (biogenic) factor (26.4%), traffic (19.3%), biomass burning (10.5%) and a mixed urban factor (4.4%). In addition to local traffic, the mixed industry/agriculture factor - inferred as mostly upstream oil and gas emission sources surrounding Red Deer - was identified as another potentially important source contributing to wintertime high PM2.5 pollution days. These findings offer useful preliminary information about current PM2.5 sources and their potential contributions in Red Deer; and this information can support policy makers in the development of particulate matter control strategies if required. PMID- 27939626 TI - MiR-34a, a promising novel biomarker for benzene toxicity, is involved in cell apoptosis triggered by 1,4-benzoquinone through targeting Bcl-2. AB - Exposure to benzene is inevitable, and concerns regarding the adverse health effects of benzene have been raised. Most investigators found that benzene exposure induced hematotoxicity. In this regard, Our study aimed to explore a novel potential biomarker of adverse health effects following benzene exposure and the toxic mechanisms of benzene metabolites in vitro. This study consisted of 314 benzene-exposed workers and 288 control workers, an air benzene concentration of who were 2.64 +/- 1.60 mg/m3 and 0.05 +/- 0.01 mg/m3, respectively. In this population-based study, miR-34a expression was elevated in benzene-exposed workers. The correlation of miR-34a with the airborne benzene concentration, S phenylmercapturic acid (S-PMA) and trans, trans-muconic acid (t, t-MA), all of which reflect benzene exposure, was found. Correlation analysis indicated that miR-34a was associated with peripheral blood count, alanine transaminase (ALT) and oxidative stress. Furthermore, multivariate analysis demonstrated that miR 34a expression was strongly associated with white blood cell count (structure loadings = 0.952). In population-based study, miR-34a had the largest contribution to altered peripheral blood counts, which reflect benzene-induced hematotoxicity. The role of miR-34a in benzene toxicity was assessed using lentiviral vector transfection. Results revealed that 1,4-benzoquinone induced abnormal cell apoptosis and simultaneously upregulated miR-34a accompanied with decreased Bcl-2. Finally, inhibition of miR-34a elevated Bcl-2 and decreased 1,4 benzoquinone-induced apoptosis. In conclusion, miR-34a was observed to be involved in benzene-induced hematotoxicity by targeting Bcl-2 and could be regarded as a potential novel biomarker for benzene toxicity. PMID- 27939627 TI - Hydrology and phosphorus transport simulation in a lowland polder by a coupled modeling system. AB - Modeling the rain-runoff processes and phosphorus transport processes in lowland polders is critical in finding reasonable measures to alleviate the eutrophication problem of downstream rivers and lakes. This study develops a lowland Polder Hydrology and Phosphorus modeling System (PHPS) by coupling the WALRUS-paddy model and an improved phosphorus module of a Phosphorus Dynamic model for lowland Polder systems (PDP). It considers some important hydrological characteristics, such as groundwater-unsaturated zone coupling, groundwater surface water feedback, human-controlled irrigation and discharge, and detailed physical and biochemical cycles of phosphorus in surface water. The application of the model in the Jianwei polder shows that the simulated phosphorus matches well with the measured values. The high precision of this model combined with its low input data requirement and efficient computation make it practical and easy to the water resources management of Chinese polders. Parameter sensitivity analysis demonstrates that Kuptake, cQ2, cW1, and cQ1 exert a significant effect on the modeled results, whereas KresuspensionMax, Ksettling, and Kmineralization have little effect on the modeled total phosphorus. Among the three types of uncertainties (i.e., parameter, initial condition, and forcing uncertainties), forcing uncertainty produces the strongest effect on the simulated phosphorus. Based on the analysis result of annual phosphorus balance when considering the high import from irrigation and fertilization, lowland polder is capable of retaining phosphorus and reducing phosphorus export to surrounding aquatic ecosystems because of their special hydrological regulation regime. PMID- 27939628 TI - Light absorption enhancement of black carbon from urban haze in Northern China winter. AB - Atmospheric black carbon (BC) is an important pollutant for both air quality and Earth's energy balance. Estimates of BC climate forcing remain highly uncertain, e.g., due to the mixing with non-absorbing components. Non-absorbing aerosols create a coating on BC and may thereby act as a lens which may enhance the light absorption. However, this absorption enhancement is poorly constrained. To this end a two-step solvent dissolution protocol was employed to remove both organic and inorganic coatings, and then investigate their effects on BC light absorption. Samples were collected at a severely polluted urban area, Jinan, in the North China Plain (NCP) during February 2014. The BC mass absorption cross section (MAC) was measured for the aerosol samples before and after the solvent decoating treatment, and the enhancement of MAC (EMAC) from the coating effect was defined as the ratio. A distinct diurnal pattern for the enhancement was observed, with EMAC 1.3 +/- 0.3 (1 S.D.) in the morning, increasing to 2.2 +/- 1.0 in the afternoon, after that dropping to 1.5 +/- 0.8 in the evening-night. The BC absorption enhancement primarily was associated with urban-scale photochemical production of nitrate and sulfate aerosols. In addition to that, regional-scale haze plume with increasing sulfate levels strengthened the absorption enhancement. These observations offer direct evidence for an increased absorption enhancement of BC due to severe air pollution in China. PMID- 27939629 TI - Microplastics and mesoplastics in fish from coastal and fresh waters of China. AB - Plastic pollution is a growing global concern. In the present study, we investigated plastic pollution in 21 species of sea fish and 6 species of freshwater fish from China. All of the species were found to ingest micro- or mesoplastics. The average abundance of microplastics varied from 1.1 to 7.2 items by individual and 0.2-17.2 items by gram. The average abundance of mesoplastics varied from 0.2 to 3.0 items by individual and 0.1-3.9 items by gram. Microplastics were abundant in 26 species, accounting for 55.9-92.3% of the total number of plastics items in each species. Thamnaconus septentrionalis contained the highest abundance of microplastics (7.2 items/individual). The average abundance of plastics in sea benthopelagic fishes was significantly higher than in freshwater benthopelagic fishes by items/individual. The plastics were dominanted by fiber in shape, transparent in color and cellophane in composition. The proportion of plastics in the stomach to the intestines showed great variation in different species, ranging from 0.5 to 1.9 by items/individual. The stomach of Harpodon nehereus and intestines of Pampus cinereus contained the highest number of plastics, (3.3) and (2.7), respectively, by items/individual. Our results suggested that plastic pollution was widespread in the investigated fish species and showed higher abundance in comparison with worldwide studies. The ingestion of plastics in fish was closely related to the habitat and gastrointestinal tract structure. We highly recommend that the entire gastrointestinal tract and digestion process be used in future investigations of plastic pollution in fish. PMID- 27939630 TI - Endosulfan inhibits proliferation through the Notch signaling pathway in human umbilical vein endothelial cells. AB - Our previous research showed that endosulfan triggers the extrinsic coagulation pathway by damaging endothelial cells and causes hypercoagulation of blood. To identify the mechanism of endosulfan-impaired endothelial cells, we treated human umbilical vein endothelial cells (HUVECs) with different concentrations of endosulfan, with and without an inhibitor for Notch, N-[N-(3, 5 difluorophenacetyl)-1-alanyl]S-Phenylglycinet-butylester (DAPT, 20 MUM), or a reactive oxygen species (ROS) scavenger, N-Acetyl-l-cysteine (NAC, 3 mM), for 24 h. The results showed that endosulfan could inhibit cell viability/proliferation by increasing the release of lactate dehydrogenase (LDH), arresting the cell cycle in both S and G2/M phases, and inducing apoptosis in HUVECs. We also found that endosulfan can damage microfilaments, microtubules, and nuclei; arrest mitosis; remarkably increase the expressions of Dll4, Notch1, Cleaved-Notch1, Jagged1, Notch4, Hes1, and p21; and significantly induce ROS and malondialdehyde production in HUVECs. The presence of DAPT antagonized the above changes of cycle arrest, proliferation inhibition, and expressions of Dll4, Notch1, Cleaved Notch1, Hes1, and p21 caused by endosulfan; however, NAC could attenuate LDH release; ROS and malondialdehyde production; apoptosis; and the expression levels of Dll4, Notch1, Cleaved-Notch1, Notch4, and Hes1 induced by endosulfan. These results demonstrated that endosulfan inhibited proliferation through the Notch signaling pathway as a result of oxidative stress. In addition, endosulfan can damage the cytoskeleton and block mitosis, which may add another layer of toxic effects on endothelial cells. PMID- 27939631 TI - Ecotoxicological effects and mechanism of CuO nanoparticles to individual organisms. AB - Copper oxide nanoparticles (CuO NPs) are used extensively in a variety of applications such as antimicrobial agent, photo-catalyst and gas sensors. The expanding production and widespread utilization of CuO NPs may pose risks to individual organisms and ecosystem. Comprehensive understanding the CuO NPs induced adverse effects and their underlying mechanism are of great importance to assess the environmental risk of CuO NPs and to expand their use safely. However, toxic effects of CuO NPs to individual organisms and the mechanism of their action are still deficient and ambiguities. To ensure the safely use of CuO NPs, more attention should be paid on the long-term and chronic effects of CuO NPs at low concentration. Efforts should be devoted to develop techniques to differentiate toxicities induced by CuO NPs or dissolved Cu2+, and to reduce the toxicity of CuO NPs by controlling the particle diameter, modifying surface characteristic, selecting proper exposure route and regulating the release of Cu2+ from CuO NPs. This review provides a brief overview of toxicity of CuO NPs to individual organisms with a broad range of taxa (microorganisms, algae, plants, invertebrates and vertebrates) and to discuss the underlying toxicity mechanisms including oxidative stress, dynamic unbalance and coordination effects. PMID- 27939632 TI - Investigation of road salts and biotic stressors on freshwater wetland communities. AB - The application of road deicing salts has led to the salinization of freshwater ecosystems in northern regions worldwide. Increased chloride concentrations in lakes, streams, ponds, and wetlands may negatively affect freshwater biota, potentially threatening ecosystem services. In an effort to reduce the effects of road salt, operators have increased the use of salt alternatives, yet we lack an understanding of how these deicers affect aquatic communities. We examined the direct and indirect effects of the most commonly used road salt (NaCl) and a proprietary salt mixture (NaCl, KCl, MgCl2), at three environmentally relevant concentrations (150, 470, and 780 mg Cl-/L) on freshwater wetland communities in combination with one of three biotic stressors (control, predator cues, and competitors). The communities contained periphyton, phytoplankton, zooplankton, and two tadpole species (American toads, Anaxyrus americanus; wood frogs, Lithobates sylvaticus). Overall, we found the two road salts did not interact with the natural stressors. Both salts decreased pH and reduced zooplankton abundance. The strong decrease in zooplankton abundance in the highest NaCl concentration caused a trophic cascade that resulted in increased phytoplankton abundance. The highest NaCl concentration also reduced toad activity. For the biotic stressors, predatory stress decreased whereas competitive stress increased the activity of both tadpole species. Wood frog survival, time to metamorphosis, and mass at metamorphosis all decreased under competitive stress whereas toad time to metamorphosis increased and mass at metamorphosis decreased. Road salts and biotic stressors can both affect freshwater communities, but their effects are not interactive. PMID- 27939633 TI - Sequential biodegradation of complex naphtha hydrocarbons under methanogenic conditions in two different oil sands tailings. AB - Methane emissions in oil sands tailings ponds are sustained by anaerobic biodegradation of unrecovered hydrocarbons. Naphtha (primarily C6-C10; n- iso- and cycloalkanes) is commonly used as a solvent during bitumen extraction process and its residue escapes to tailings ponds during tailings deposition. To investigate biodegradability of hydrocarbons in naphtha, mature fine tailings (MFT) collected from Albian and CNRL tailings ponds were amended with CNRL naphtha at ~0.2 wt% (~2000 mg L-1) and incubated under methanogenic conditions for ~1600 d. Microbial communities in both MFTs started metabolizing naphtha after a lag phase of ~100 d. Complete biodegradation/biotransformation of all n alkanes (except partial biodegradation of n-octane in CNRL MFT) followed by major iso-alkanes (2-methylpentane, 3-methylhexane, 2- and 4-methylheptane, iso-nonanes and 2-methylnonane) and a few cycloalkanes (derivatives of cyclopentane and cyclohexane) was observed during the incubation. 16S rRNA gene pyrosequencing showed dominance of Peptococcaceae and Anaerolineaceae in Albian MFT and Anaerolineaceae and Syntrophaceae in CNRL MFT bacterial communities with co domination of Methanosaetaceae and "Candidatus Methanoregula" in archaeal populations during active biodegradation of hydrocarbons. The findings extend the known range of hydrocarbons susceptible to methanogenic biodegradation in petroleum-impacted anaerobic environments and help refine existing kinetic model to predict greenhouse gas emissions from tailings ponds. PMID- 27939635 TI - Reciprocal effects of pesticides and pathogens on amphibian hosts: The importance of exposure order and timing. AB - Ecological communities are increasingly exposed to natural and anthropogenic stressors. While the effects of individual stressors have been broadly investigated, there is growing evidence that multiple stressors are frequently encountered underscoring the need to examine interactive effects. Pesticides and infectious diseases are two common stressors that regularly occur together in nature. Given the documented lethal and sublethal effects of each stressor on individuals, there is the potential for interactive effects that alter disease outcomes and pesticide toxicity. Using larval wood frogs (Lithobates sylvaticus), we examined the reciprocal interaction between insecticides (carbaryl and thiamethoxam) and the viral pathogen ranavirus by testing whether: (1) prior ranavirus infection influences pesticide toxicity and (2) sublethal pesticide exposure increases susceptibility to and transmission of ranavirus. We found that prior infection with ranavirus increased pesticide toxicity; median lethal concentration (LC50) estimates were reduced by 72 and 55% for carbaryl and thiamethoxam, respectively. Importantly, LC50 estimates were reduced to concentrations found in natural systems. This is the first demonstration that an infection can alter pesticide toxicity. We also found that prior pesticide exposure exacerbated disease-induced mortality by increasing mortality rates, but effects on infection prevalence and transmission of the pathogen were minimal. Collectively, our results underscore the importance of incorporating complexity (i.e. order and timing of exposures) into research examining the interactions between natural and anthropogenic stressors. Given the environmental heterogeneity present in nature, such research will provide a more comprehensive understanding of how stressors affect wildlife. PMID- 27939634 TI - Prior knowledge-based approach for associating contaminants with biological effects: A case study in the St. Croix River basin, MN, WI, USA. AB - Evaluating potential adverse effects of complex chemical mixtures in the environment is challenging. One way to address that challenge is through more integrated analysis of chemical monitoring and biological effects data. In the present study, water samples from five locations near two municipal wastewater treatment plants in the St. Croix River basin, on the border of MN and WI, USA, were analyzed for 127 organic contaminants. Known chemical-gene interactions were used to develop site-specific knowledge assembly models (KAMs) and formulate hypotheses concerning possible biological effects associated with chemicals detected in water samples from each location. Additionally, hepatic gene expression data were collected for fathead minnows (Pimephales promelas) exposed in situ, for 12 d, at each location. Expression data from oligonucleotide microarrays were analyzed to identify functional annotation terms enriched among the differentially-expressed probes. The general nature of many of the terms made hypothesis formulation on the basis of the transcriptome-level response alone difficult. However, integrated analysis of the transcriptome data in the context of the site-specific KAMs allowed for evaluation of the likelihood of specific chemicals contributing to observed biological responses. Thirteen chemicals (atrazine, carbamazepine, metformin, thiabendazole, diazepam, cholesterol, p cresol, phenytoin, omeprazole, ethyromycin, 17beta-estradiol, cimetidine, and estrone), for which there was statistically significant concordance between occurrence at a site and expected biological response as represented in the KAM, were identified. While not definitive, the approach provides a line of evidence for evaluating potential cause-effect relationships between components of a complex mixture of contaminants and biological effects data, which can inform subsequent monitoring and investigation. PMID- 27939636 TI - Comparative study of species sensitivity distributions based on non-parametric kernel density estimation for some transition metals. AB - Transition metals in the fourth period of the periodic table of the elements are widely widespread in aquatic environments. They could often occur at certain concentrations to cause adverse effects on aquatic life and human health. Generally, parametric models are mostly used to construct species sensitivity distributions (SSDs), which result in comparison for water quality criteria (WQC) of elements in the same period or group of the periodic table might be inaccurate and the results could be biased. To address this inadequacy, the non-parametric kernel density estimation (NPKDE) with its optimal bandwidths and testing methods were developed for establishing SSDs. The NPKDE was better fit, more robustness and better predicted than conventional normal and logistic parametric density estimations for constructing SSDs and deriving acute HC5 and WQC for transition metals in the fourth period of the periodic table. The decreasing sequence of HC5 values for the transition metals in the fourth period was Ti > Mn > V > Ni > Zn > Cu > Fe > Co > Cr(VI), which were not proportional to atomic number in the periodic table, and for different metals the relatively sensitive species were also different. The results indicated that except for physical and chemical properties there are other factors affecting toxicity mechanisms of transition metals. The proposed method enriched the methodological foundation for WQC. Meanwhile, it also provided a relatively innovative, accurate approach for the WQC derivation and risk assessment of the same group and period metals in aquatic environments to support protection of aquatic organisms. PMID- 27939637 TI - First molecular evidence of mixed infections of Anaplasma species in dogs in Henan, China. AB - In recent years, tick-borne diseases like anaplasmosis have become widespread worldwide threatening the health of both human and animals. Dogs play an important role in the epidemiology of several zoonotic tick-borne pathogens by acting as reservoirs. In this study, the status of Anaplasma phagocytophilum, A. platys, A. bovis and A. ovis infection were assessed in dogs in Henan, China, with PCR and phylogenetic analyses. Nested PCRs on 243 blood samples collected from dogs from different sampling sites revealed that thirty-three (13.6%) dogs were positive for one or more pathogens. The prevalence of Anaplasma spp. in stray dogs was 40.7% (24/59), which was much higher than that of pet dogs (4.0%, 7/175). The prevalence for A. ovis, A. bovis and A. phagocytophilum was 6.2%, 4.1% and 0.4%, respectively and mixed-infection of these three pathogens was found in only one stray dog (prevalence, 0.4%). None of the dogs was positive for A. platys. Phylogenetic analyses classified A. phagocytophilum into two distinct groups (East Asia and south Africa group, Europe and America group), whereas A. ovis and A. bovis showed a general classification into two groups (cluster 1 and cluster 2), respectively. The isolate (KX190783) of A. ovis from a stray dog fell in a clade with a human isolate from Cyprus (FJ460443) and shared 99.8% similarity with it. To the best of our knowledge, this study is the first report to identify A. bovis and A. ovis DNA in dogs in China and the mixed-infection of the three Anaplasma spp. (A. phagocytophilum, A. bovis and A. ovis) in dogs. PMID- 27939638 TI - Proteome-Scale Investigation of Protein Allosteric Regulation Perturbed by Somatic Mutations in 7,000 Cancer Genomes. AB - The allosteric regulation triggering the protein's functional activity via conformational changes is an intrinsic function of protein under many physiological and pathological conditions, including cancer. Identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes that they alter during tumor initiation and progression is a central challenge for cancer genomes in the post-genomic era. Here, we mapped more than 47,000 somatic missense mutations observed in approximately 7,000 tumor normal matched samples across 33 cancer types into protein allosteric sites to prioritize the mutated allosteric proteins and we tested our prediction in cancer cell lines. We found that the deleterious mutations identified in cancer genomes were more significantly enriched at protein allosteric sites than tolerated mutations, suggesting a critical role for protein allosteric variants in cancer. Next, we developed a statistical approach, namely AlloDriver, and further identified 15 potential mutated allosteric proteins during pan-cancer and individual cancer-type analyses. More importantly, we experimentally confirmed that p.Pro360Ala on PDE10A played a potential oncogenic role in mediating tumorigenesis in non-small cell lung cancer (NSCLC). In summary, these findings shed light on the role of allosteric regulation during tumorigenesis and provide a useful tool for the timely development of targeted cancer therapies. PMID- 27939639 TI - Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis. AB - Intellectual disability (ID) is a common neurodevelopmental disorder exhibiting extreme genetic heterogeneity, and more than 500 genes have been implicated in Mendelian forms of ID. We performed exome sequencing in a large family affected by an autosomal-dominant form of mild syndromic ID with ptosis, growth retardation, and hypotonia, and we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members. BRPF1 encodes a protein modifier of two histone acetyltransferases associated with ID: KAT6A (also known as MOZ or MYST3) and KAT6B (MORF or MYST4). The mRNA transcript was not significantly reduced in affected fibroblasts and most likely produces a truncated protein (p.Val351Glyfs*8). The protein variant shows an aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation. We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype. Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency. We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5. We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency. PMID- 27939641 TI - Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease. AB - Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-beta-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells. PMID- 27939642 TI - Exercise interventions to improve sleep in cancer patients: A systematic review and meta-analysis. AB - Exercise leads to several positive outcomes in oncology. However, the question as to whether exercise is a valuable option for improving patients' sleep, which is frequently disturbed in cancer patients, remains unanswered. The aims of this study were to conduct a systematic review and meta-analysis of randomized and non randomized clinical trials that have investigated the effect of exercise on sleep outcomes, assessed subjectively and objectively. Relevant studies, published before May 2016, were traced through a systematic search of PubMed, Embase, PsycINFO, SportDiscus and Cochrane library databases. The review looked at twenty one trials, including 17 randomized controlled trials. Most interventions were home-based aerobic walking programs and breast cancer patients were the subgroup most represented. Sleep variables were most commonly used as secondary outcomes in the reviewed studies. Studies were highly heterogeneous in terms of methodology. The qualitative review of available evidence suggested a beneficial effect of exercise interventions on sleep in several studies (48%). However, the meta-analysis conducted on RCTs revealed no significant effect either on subjective or on objective sleep measures. This lack of significant effect could be due, at least in part, to a floor effect. More rigorous studies are needed to assess the effect of exercise interventions in cancer patients, in particular randomized controlled trials conducted in patients with clinically significant sleep disturbances at baseline. PMID- 27939640 TI - Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation. AB - Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome. PMID- 27939643 TI - Commentary on topic: Should all tests of cognitive function - Learning, memory, attention - Be eliminated from the required protocols for developmental neurotoxicity testing? AB - The attached manuscript by Dr. Herr is a Commentary on Topic: Should All Tests of Cognitive Function - Learning, Memory, Attention - be Eliminated From the Required Protocols for Developmental Neurotoxicity Testing? PMID- 27939644 TI - Unexpected primary bone lymphoma. PMID- 27939645 TI - [Dermoscopy and reflectance confocal microscopy examination of pigmented fungiform papillae of the tongue]. PMID- 27939646 TI - [Contribution of reflectance confocal microscopy in the diagnosis of conjunctival melanoma]. PMID- 27939647 TI - Intolerance of uncertainty, not just right experiences, and compulsive checking: Test of a moderated mediation model on a non-clinical sample. AB - OBJECTIVE: Intolerance of uncertainty (IU) and not just right experiences (NJREs) have been claimed putative vulnerability factors for obsessive-compulsive disorder (OCD). The aim of the present study was to test whether IU could represent a trans-diagnostic construct accountable for OC checking behaviors and whether NJREs could embody an OCD-specific criterion through which IU operates. METHOD: One hundred and eighty-eight Italian community individuals completed self report measures of IU, NJREs, OC symptoms, worry, anxiety, and depression. Mediation and moderated mediation models were tested using a bootstrapping approach, wherein IU was included as the independent variable as well as the moderator; checking behaviors were entered as the dependent variable; and NJRE severity was included as a mediator. RESULTS: The main findings highlighted that NJREs were a mediator of the relationship between IU and checking behaviors; nonetheless, in connection with medium levels of IU, NJREs no longer mediated the path. Furthermore, IU did not emerge to moderate the mediation. CONCLUSION: Despite their preliminary nature, the present results might be a hint for future research, as theoretical integration may represent a way to go for better understanding OCD etiology and phenomenology. PMID- 27939649 TI - CD98 promotes vascular smooth muscle cell accumulation in atherosclerosis to confer plaque stability. PMID- 27939648 TI - Clinically speaking, psychological abuse matters. AB - BACKGROUND: The adverse effects of intimate partner violence (IPV) on mental health are well-established, except in the cases of psychological abuse and men's victimization. This research study examines the prevalence and the independent contribution of psychological IPV on mental health for both genders. METHODS: The initial sample comprises 661 college students from a Portuguese public university, who completed an e-survey. Statistical analysis focused on a subsample (n=364), 23% of which were men, after removing cases of physical and/or sexual abuse. RESULTS: A total of 75% of men and 72% of women reported lifetime psychological victimization and no differences were found for sociodemographic factors, including gender. However, women reported significantly more instigations of psychological abusive acts (OR =5.41, 95% CI=1.88-15.55). Multivariate linear regression models revealed that post-traumatic stress symptoms-PTSS (beta=.51; p<.001), depression (beta=.34; p<.001) and anxiety (beta=.22; p<.001)-were predicted by psychological IPV. The strongest relationship was established between psychological IPV and PTSS, and the final model accounts for 28.6% of the variance (F(6357)=23.86, p<.001). CONCLUSIONS: This article provides an empirical basis to recognize the unique and serious impact of psychological IPV on mental health, and recommends screening psychological IPV as part of the clinical routine, developing a gender-inclusive approach, and implementing evidence-based protocols tailored to the needs of these victims. PMID- 27939650 TI - The increased number of tumor-associated macrophage is associated with overexpression of VEGF-C, plays an important role in Kazakh ESCC invasion and metastasis. AB - Tumor associated macrophages (TAMs) play an important role in the growth, progression, and metastasis of tumors. The distribution of TAMs in Kazakh esophageal squamous cell carcinoma (ESCC) is not determined. We aimed to investigate the role of TAMs in the occurrence and progression of Kazakh ESCC. CD163 was used as the TAM marker, and immunohistochemistry (IHC) counts were used to quantify the density of TAMs in tumor nest and surrounding stroma. IHC staining was used to evaluate the expression of vascular endothelial growth factor C (VEGF-C) in Kazakh ESCC and cancer adjacent normal (CAN) tissues. The density of TAMs in Kazakh ESCCs tumor nest and stromal was significantly higher than that in CAN tissues. The increased number of CD163-positive TAMs in tumor nest and tumor stromal was positively associated with Kazakh ESCC lymph node metastasis and clinical stage progression. Meanwhile, the expression of VEGF-C in Kazakh ESCCs was significantly higher than that in CAN tissues. Overexpression of VEGF-C in Kazakh ESCCs was significantly associated with gender, depth of tumor invasion, lymph node metastasis and tumor clinical stage. The increased number of TAMs, either in the tumor nests or tumor stroma was positively correlated with the overexpression of VEGF-C, which may promote lymphangiogenesis and play an important role in the invasion and metastasis of Kazakh ESCC. PMID- 27939651 TI - Reproducibility and validity of the Nintendo Wii Balance Board for measuring shoulder sensorimotor control in prone lying. AB - INTRODUCTION: For the lower limbs, the Nintendo Wii Balance Board (NWBB) has been widely used to measure postural control. However, this has not been performed for upper limb measurements. Further, the NWBB has shown to produce more background noise with decreasing loads, which may be of concern when used for upper limb testing. The aim was to investigate reproducibility and validity of the NWBB. METHODS: A test-retest design was performed with 68 subjects completing three different prone lying, upper limb weight-bearing balance tasks on a NWBB: two arms, eyes closed (1) one-arm, non-dominant/non-injured (2) and one-arm, dominant/injured (3). Each task was repeated three times over the course of two test sessions with a 30-min break in between. Further, the level of background noise from a NWBB was compared with a force platform through systematic loading of both boards with increasing deadweights ranging from 5 to 90kg. RESULTS: Test retest reproducibility was high with ICCs ranging from 0.95 to 0.97 (95% CI 0.92 to 0.98). However, systematic bias and tendencies for funnel effects in the Bland Altman plots for both one-armed tests were present. The concurrent validity of the NWBB was low (CCC 0.17 (95% CI 0.12-0.22)) due to large differences between the NWBB and force platform in noise sensitivity at low deadweights (especially below 50kg). CONCLUSION: The NWBB prone lying, shoulder sensorimotor control test was highly reproducible. Though, concurrent validity of the NWBB was poor compared to a force platform. Further investigation of the impact of the background noise, especially at low loads, is needed. PMID- 27939652 TI - Balance and mobility training with or without concurrent cognitive training does not improve posture, but improves reaction time in healthy older adults. AB - BACKGROUND AND AIMS: The purpose was to determine whether balance and mobility training (BMT) or balance and mobility plus cognitive training (BMT+C) would reduce postural sway and reaction time (RT) and maintain these improvements after a 12-week follow-up in healthy older adults. METHODS: Participants were allocated to the BMT (n=15; age: 70.2+/-3.2), BMT+C (n=14; age:68.7+/-5.5), or control group (n=13; age: 66.7+/-4.2). The BMT group trained one-on-one, 3*/wk for 12 weeks on a balance obstacle course. The BMT+C group trained one-on-one, 3*/week for 12 weeks on a balance obstacle course while completing cognitive tasks. Participants stood on a force plate for 30s in feet-apart (FA) and semi-tandem (ST) positions while completing simple RT and choice RT tasks at baseline, at the 12-week post-training, and at the 12-week follow-up. Participants were instructed to stand as still as possible while verbally responding as fast as possible to the auditory cues. RESULTS: No group differences in center of pressure (COP) Area, COP Velocity, or Sample Entropy of the COP displacement were shown after the training or 12-week follow-up, but the BMT and BMT+C showed faster RT after training and maintained these improvements at the 12-week follow-up compared to the control group. No differences in postural sway or RT emerged between the BMT and BMT+C groups. CONCLUSION: Both training groups improved RT after the interventions and sustained these improvements over 12 weeks, but showed no reductions in postural sway. Multi-task balance training likely results in reduced attention demand. PMID- 27939653 TI - Experimental infection of adult Scapharca broughtonii with Ostreid herpesvirus SB strain. AB - We investigated the susceptibility of ark shell, Scapharca broughtonii, adults to Ostreid herpesvirus SB strain (OsHV-1-SB) through experimental infection by intramuscular injection assays. Results showed the onset of mortality occurred at 3days post injection, one day after the water turbidity became evident in rearing tanks. The mortality curves for the challenged group were similar to those observed at affected hatcheries. Histological lesions, herpesvirus-like particles and high OsHV-1-SB quantities were detected in challenged ark shells. This is the first study to successfully reproduce OsHV-1 disease in Arcoida species, and very few studies in adult bivalves (over 24months old). PMID- 27939654 TI - Racial and Ethnic Minorities at Increased Risk for Gastric Cancer in a Regional US Population Study. AB - BACKGROUND AND AIMS: Limited data are available on risk factors for gastric cancer in the United States. We aimed to characterize risk for gastric cancer based on race/ethnicity and additional established risk factors. METHODS: We conducted a retrospective cohort study from 2008 to 2014 from an integrated health care system in Southern California to assess incidence of gastric cancer by race/ethnicity. We then conducted an age- and sex-matched case-cohort study to evaluate additional risk factors: Helicobacter pylori infection, tobacco use, family history, obesity, language, and socioeconomic status. Subgroup analysis was performed for language and socioeconomic status by race/ethnicity. RESULTS: The incidence of gastric cancer in the reference (non-Hispanic white) population was 8.2 (95% confidence interval [CI], 7.7-8.7) cases per 100,000 person-years. Incidence values for Asians, Hispanics, and non-Hispanic black persons were higher: 12.7 (95% CI, 11.1-14.3), 12.7 (95% CI, 11.7-13.7), and 11.8 (95% CI, 10.3-13.2) cases per 100,000 person-years, respectively (all P < .0001). In logistic regression analysis, we found race/ethnicity to be an independent risk factor for gastric cancer; the odds ratio (OR) for non-Hispanic black persons was 1.5 (95% CI, 1.22-1.72; P < .0001), the OR for Hispanics was 1.4 (95% CI, 1.22 1.57; P < .0001), and the OR for Asians was 1.5 (95% CI, 1.28-1.81; P < .0001), compared with the non-Hispanic white population. Other independent risk factors included infection with H pylori (OR, 4.6; 95% CI, 3.8-5.7), smoking history (OR, 1.4; 95% CI, 1.3-1.6), and family history of gastric cancer (OR, 3.4; 95% CI, 2.6 4.4) (all P < .0001). Non-English language was a significant risk factor for gastric cancer in Asians (P = .05). Higher annual median income was associated with reduced risk (OR, 0.84; 95% CI, 0.75-0.95; P = .0004). CONCLUSIONS: In a population study in Southern California, we found racial/ethnic minorities to have a 40%-50% increase in risk of gastric cancer compared with the non-Hispanic white population. In addition to H pylori infection, smoking, family history, and low socioeconomic status were also associated with increased risk. Further characterization of high-risk groups may identify populations appropriate for targeted screening. PMID- 27939655 TI - A new in situ model to study erosive enamel wear, a clinical pilot study. AB - OBJECTIVES: To develop an in situ model for erosive wear research which allows for more clinically relevant exposure parameters than other in situ models and to show tooth site-specific erosive wear effect of an acid challenge of orange juice on enamel. METHODS: This pilot study included 6 edentulous volunteers wearing full dentures with 13 embedded enamel samples The study consisted of two control runs: habitual diet only for 30days, and two experimental runs: habitual diet plus 125ml orange juice four times per day (consumed over 4m). In the first experimental run subjects were instructed to take the drink in their mouth and promptly swallow it. In the second experimental run subjects take the drink in their mouth and hold each 25ml for 30s, moving it around their mouth before swallowing. Sample enamel surface loss was measured using non-contact surface profilometry. RESULTS: Drinking of orange juice additional to the habitual diet, caused significant but low increased erosive wear at buccal, palatal and lingual specimens. Significantly higher levels of tissue loss were found on all surfaces in the swishing experiment but molars (especially occlusal specimens in mandibular molars), palatal specimens sited in upper anterior teeth and lingual specimens in lower anterior teeth were most affected. CONCLUSION: The model showed clinically relevant patterns of erosive tooth wear as seen clinically in erosive wear patients. CLINICAL SIGNIFICANCE: The model could have many applications to study clinically erosive wear for specific diets or consumption patterns and to test preventive measures. PMID- 27939656 TI - Clinical audit of posterior three-unit fixed-movable resin-bonded fixed partial dentures - A retrospective, preliminary clinical investigation. AB - BACKGROUND: Two-unit cantilevered resin-bonded fixed partial dentures (RBFPDs) have higher retention rates over longer span fixed-fixed RBFPDs. It has been hypothesized that interabutment stresses associated with fixed-fixed designs cause prosthesis debonds therefore for the replacement of molar-sized and longer spans, non-rigid connectors have been used to allow independent movement between two abutment teeth. OBJECTIVES: This preliminary study evaluates the clinical longevity and subjects' satisfaction of three-unit fixed-movable (FM3) RBFPDs provided at a dental teaching hospital. MATERIALS AND METHODS: Subjects who had received FM3 RBFPD(s) in the posterior region were clinically reviewed for complications. History of any debonds and subjects' satisfaction to the prosthesis was recorded. Time-to-debond (retention rate) and time-to-loss (survival rate) of these prostheses were presented in life tables. RESULTS: Ninety-eight prostheses in 84 subjects were examined. Their mean service life was 31.8 months (SD 11.5, range 3-67 months). Twenty-two prostheses had a history of debond, resulting in a retention proportion of 77.6%; seventeen of these were rebonded and still present at the time of review. One prosthesis was lost after extraction of a periodontally-involved abutment tooth, giving a survival proportion of 93.9%. High subject satisfaction and no adverse outcome were reported. CONCLUSION: Three-unit fixed-movable RBFPDs have a shorter success than two-unit cantilevered RBFPDs. However, non-rigid connectors allow the possibility of rebonding giving satisfactory short-term survival rate. Further research is needed to investigate their long-term efficacy. CLINICAL SIGNIFICANCE: Three-unit fixed-movable RBFPDs incorporating non-rigid connectors may be a feasible option for replacement of molar-size pontic in the posterior region. PMID- 27939657 TI - Prevention of secondary caries using silver diamine fluoride treatment and casein phosphopeptide-amorphous calcium phosphate modified glass-ionomer cement. AB - OBJECTIVE: To study the effect of silver diamine fluoride (SDF) treatment and incorporating casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) into a glass-ionomer cement (GIC) to prevent secondary caries. METHOD: A cervical cavity was prepared on 32 premolars for the following restoration groups: group 1, conventional GIC restoration; group 2, SDF (38%) treatment and conventional GIC restoration; group 3, CPP-ACP (3%) modified GIC; and group 4, SDF treatment and CPP-ACP modified GIC. The restored teeth were thermal-cycled before undergoing a multi-species cariogenic biofilm challenge. The restored teeth were examined by micro-computed tomography (micro-CT), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDX) and Fourier transform infrared (FTIR) spectroscopy. Data were analyzed by two-way ANOVA. RESULTS: Micro-CT determined outer lesion depths for groups 1-4 were: 123+/-6MUm, 87+/-7MUm, 79+/-3MUm and 68+/-5MUm respectively. An interaction effect on the outer lesion depth was found between the restorative materials and SDF treatment (p<0.001). Both SDF treatment and modification with CPP-ACP had a significant effect on outer lesion depth (p<0.001). SEM/EDX showed an increase of calcium and phosphorus at the root dentine adjacent to the restoration in groups 3 and 4 (CPP-ACP modified GIC). FTIR revealed that SDF treatment and CPP-ACP modified GIC had a significant effect on amide I-to-hydrogen phosphate ratio on the material-root interface (p=0.001). CONCLUSION: SDF treatment and incorporation of CPP-ACP into GIC restorative material can prevent secondary root caries development. CLINICAL SIGNIFICANCE: The results provide useful information to dentists in formulating clinical management protocols and material when treating root caries. PMID- 27939658 TI - Solution and surface chemistry of the Se(IV)-Fe(0) reactions: Effect of initial solution pH. AB - Aspects of solution and solid-phase reactions between selenite (Se(IV)) and nanoscale zero-valent iron (nZVI) were investigated. Experimental results on the effects of initial solution pH, formation and evolution of nZVI corrosion products, and speciation of selenium in nZVI were presented. In general, the rate of Se(IV) removal decreases with increasing initial pH. The observed rate constants of Se(IV) removal decreased from 0.3530 to 0.0364 min-1 as pH increased from 4.0 to 10.0. Composition and morphology of nZVI corrosion products and selenium species were characterized using scanning electron microscopy (SEM), X ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). Results confirmed that Se(IV) was reduced to Se(0) and Se(-II) by nZVI. Lower solution pH favored further reduction of Se(0) to Se(-II). Amorphous FeOOH, magnetite/maghemite (Fe3O4/gamma-Fe2O3) and ferrous hydroxide (Fe(OH)2) were identified as the main corrosion products. Under alkaline conditions, the corrosion products were mainly of Fe(OH)2 along with small amounts of Fe3O4, while nZVI in acidic solutions was oxidized to mostly Fe3O4 and amorphous FeOOH. Furthermore, these corrosion products acted as intermediates for electron transfer and reactive/sorptive sites for Se(IV) adsorption and reduction, thus played a crucial role in the removal of aqueous Se(IV). PMID- 27939660 TI - Cometabolic biodegradation of 1,2,3-trichloropropane by propane-oxidizing bacteria. AB - 1,2,3-Trichloropropane (TCP) is an emerging groundwater pollutant and suspected human carcinogen. TCP, a recalcitrant contaminant, has been detected in the subsurface near TCP manufacture facilities and many superfund sites. Considering the toxicity and the occurence of TCP, there is a need to seek for cost-effective treatment technologies for TCP-contaminated sites. This paper investigated TCP biodegradation by propane-oxidizing bacteria (PrOB) which are known to express propane monooxygenase (PrMO). PrMO can cometabolically degrade many different contaminants. Four PrOB, Rhodococus jostii RHA1, Mycobacterium vaccae JOB5, Rhodococcus rubber ENV425 and one isolate Sphingopyxis sp. AX-A were examined for their ability to degrade TCP. All the four PrOB resting cells were able to degrade TCP. Strain JOB5 exhibited the best TCP degradation ability (vinitial = 9.7 +/- 0.7 MUg TCP (mg protein)-1h-1). No TCP was degraded in the presence of acetylene (an inhibitor for PrMO), suggesting that PrMO might be responsible for TCP degradation. Furthermore, competitive inhibition was observed between propane and TCP, and between trichloroethylene (TCE) and TCP. PMID- 27939661 TI - 30+ year evolution of Cu in the surface sediment of Lake Poyang, China. AB - Poyang Lake, the largest freshwater lake in China, is increasingly experiencing Cu crises. Combining field data, laboratory experiments, and long-term simulations, we retrieved 30 + year evolution of Cu in surface sediments (SCu). SCu evolution between 1983 and 2015 may be separated into two distinguishable periods. During the first period (1983-2003), SCu underwent a continuous increase at a mean rate of 1.80 mg/kg/yr; however, since 2003 it displayed a stepwise reduction tendency. The average SCu concentration of the entire lake in 2015 fell to 54.26 mg/kg, which is approximately 30.01% lower than that in 2003. The operation of Three Gorges Dam (TGD) markedly altered the river-lake relationship, pulled more deposited Cu along with sediment out toward the Yangtze River, and made the regions of high SCu emanate from the southeastern lake extend northwestward between 2003 and 2015. SCu in the reserves showed significant inter annual variations, with the exception of the Jiangxi Whitebait Spawning Reserve (JWSR), where SCu generally has not been significantly impacted and has displayed no departure from the 30 + year mean of 30.57 mg/kg. The National Germplasm Reserve (NGR) and Nanjishan National Nature Reserve (NNNR) were detected with the highest SCu, with the peak concentrations, respectively, of 123.15 mg/kg and 103.1 mg/kg. PMID- 27939659 TI - Lead and cadmium contamination and exposure risk assessment via consumption of vegetables grown in agricultural soils of five-selected regions of Pakistan. AB - Rapid urbanization and industrialization result in serious contamination of soil with toxic metals such as lead (Pb) and cadmium (Cd), which can lead to deleterious health impacts in the exposed population. This study aimed to investigate Pb and Cd contamination in agricultural soils and vegetables in five different agricultural sites in Pakistan. The metal transfer from soil-to-plant, average daily intake of metals, and health risk index (HRI) were also characterized. The Pb concentrations for all soils were below the maximum allowable limits (MAL 350 mg kg-1) set by State Environmental Protection Administration of China (SEPA), for soils in China, while Cd concentrations in the soils were exceeded the MAL (61.7-73.7% and 4.39-34.3%) set by SEPA (0.6 mg kg-), and European Union, (1.5 mg kg-1) respectively. The mean Pb concentration in edible parts of vegetables ranged from 1.8 to 11 mg kg-1. The Pb concentrations for leafy vegetables were higher than the fruiting and pulpy vegetables. The Pb concentrations exceeded the MAL (0.3 mg kg-1) for leafy vegetables and the 0.1 mg kg-1 MAL for fruity and rooty/tuber vegetables set by FAO/WHO-CODEX. Likewise, all vegetables except Pisum sativum (0.12 mg kg-1) contained Cd concentrations that exceeded the MAL set by SEPA. The HRI values for Pb and Cd were <1 for both adults and children for most of the vegetable species except Luffa acutangula, Solanum lycopersicum, Benincasa hispada, Momordi charantia, Aesculantus malvaceae, Cucumis sativus, Praecitrullus fistulosus, Brassica oleracea, and Colocasia esculanta for children. Based on these results, consumption of these Pb and Cd contaminated vegetables poses a potential health risk to the local consumers. PMID- 27939662 TI - Influence of iron precipitated condition and light intensity on microalgae activated sludge based wastewater remediation. AB - The indigenous microalgae-activated sludge (MAAS) process during remediation of municipal wastewater was investigated by studying the influence of iron flocculation step and light intensity. In addition, availability of total phosphorous (P) and photosynthetic activity was examined in fed-batch and batch mode under northern climatic conditions and limited lighting. This was followed by a semi-continuous operation with 4 d of hydraulic retention time and mean cell residence time of 6.75 d in a photo-bioreactor (PBR) with varying P availability. The fed-batch condition showed that P concentrations of 3-4 mg L-1 were effective for photosynthetic chl. a development in iron flocculated conditions. In the PBR, the oxygen evolution rate increased with increase in the concentration of MAAS (from 258 to 573 mg TSS L-1) at higher surface photosynthetic active radiation (250 and 500 MUmol m-2 s-1). Additionally, the rate approached a saturation phase at low MAAS (110 mg L-1) with higher light intensities. Semi-continuous operation with luxury P uptake and effective P condition showed stable average total nitrogen removal of 88 and 92% respectively, with residual concentrations of 3.77 and 2.21 mg L-1. The corresponding average P removal was 68 and 59% with residual concentrations of 2.32 and 1.75 mg L-1. The semi-continuous operation produced a rapidly settleable MAAS under iron flocculated condition with a settling velocity of 92-106 m h-1 and sludge volume index of 31-43 ml g-1 in the studied cases. PMID- 27939663 TI - Heat-activated persulfate oxidation of methyl- and ethyl-parabens: Effect, kinetics, and mechanism. AB - We evaluated the degradation of methylparaben (MeP) and ethylparaben (EtP), two representative parabens, using the heat-activated persulfate system in a laboratory. Both sulfate and hydroxyl radicals contributed to the removal of the two parabens. The degradations of both MeP and EtP were improved by increasing the heating temperature or persulfate dose in accordance with a pseudo-first order reaction model. The oxidation efficiency of parabens was found to be pH dependent; decreasing in the order pH 5.0 > 7.0 > 9.0. The presence of chloride, bicarbonate, or humic acid was found to inhibit the degradation of the two parabens to some extent because of competition for the reactive radicals, with humic acid having the most serious effect. Dealkylation of the methyl unit, decarboxylation of the carboxylic group, and subsequent hydrolysis are proposed to be involved in the degradation pathway of MeP. The results suggest that the heat-activated persulfate system might be efficiently applied in the treatment of paraben-containing water samples. This was also supported by the results of applying this system to treat a real water sample containing both MeP and EtP. PMID- 27939664 TI - Catalytic ozonation of Orange-G through highly interactive contributions of hematite and SBA-16 - To better understand azo-dye oxidation in nature. AB - Hematite-SBA-16 mixture (HS) exhibited high catalytic activity in Orange-G (OG) ozonation in water. Total OG discoloration was achieved in half the time required with hematite or SBA-16 alone, all UV-Vis bands disappeared in less than 2 min. Liquid chromatography- Mass spectrometry (LC-MS) revealed that OG ozonation triggers via both hydroxylation and desulfonation of the aromatic rings into specific intermediates. Prolonged ozonation in the presence of hematite and SBA 16 alone resulted in different distributions of common derivatives. The latter were not detected after 25 min ozonation with HS. Stochastic modeling of the evolution in time of the UV-Vis bands of OG revealed strong binary interaction between the initial pH and catalyst concentration. This was explained in terms of reciprocal contributions of: i. the catalytic properties of hematite in spite of its low porosity; ii. the high specific surface area of SBA-16 for adsorption and surface reaction notwithstanding its low intrinsic catalytic activity. The weak basicity of SBA-16 surface seems to play a key-role in adsorption. These findings are of great interest for envisaging flexible oxidative treatments, where Fe3+ containing soils or mixtures of sand and rust may also act as catalyst for total mineralization of various azo-dyes, regardless to their structures. PMID- 27939665 TI - Musk xylene induces malignant transformation of human liver cell line L02 via repressing the TGF-beta signaling pathway. AB - Musk xylene (MX) is a widely used synthetic nitro musk. Although the persistence and bioaccumulation of the synthetic musks are of concern since the nineteenth century, knowledge concerning the toxicity and environmental risks, especially the carcinogenicity is still limited. In the present study, the normal human hepatic cell line L02 was used to investigate the long-term carcinogenicity of MX. L02 cells were exposed to MX with different concentrations (10, 100, and 1000 MUg/L) for 24 h, then with conventional culture. After MX exposure for 24 h, some irregular fusiform, protuberances and multinucleated cells were observed. Indefinite cell proliferation, ability of anchorage-independent proliferation and increase of migration and invision were also observed in subsequent experiments, which suggested the positive effects of MX on cell malignant transformation in vitro. Moreover, the up-regulated protein expression of some oncogenes (C-myc and PCNA) in each time points furthermore supported this conclusion. Meanwhile, decreased protein expression level of TGF-beta and the downstream proteins, SMAD4 coupled with P15 were observed in MX-treated cells. In addition, after culturing for 20 passages, the proportion of cells in the G0/G1 phase was decreased. These results demonstrated that the TGF-beta signaling pathway regulated indefinite cell proliferation might be responsible for the oncogenesis of MX. PMID- 27939666 TI - The mechanisms by which phenanthrene affects the photosynthetic apparatus of cucumber leaves. AB - Phenanthrene is a polycyclic aromatic hydrocarbon (PAH) that is widely distributed in the environment and seriously affects the growth and development of plants. To clarify the mechanisms of the direct effects of phenanthrene on the plant photosynthetic apparatus, we measured short-term phenanthrene-treated cucumber leaves. Phenanthrene inhibited Rubisco carboxylation activity, decreasing photosynthesis rates (Pn). And phenanthrene inhibited photosystem II (PSII) activity, thereby blocking photosynthetic electron transport. The inhibition of the light and dark reactions decreased the photosynthetic electron transport rate (ETR) and increased the excitation pressure (1-qP). Under high light, the maximum photochemical efficiency of photosystem II (Fv/Fm) in phenanthrene-treated cucumber leaves decreased significantly, but photosystem I (PSI) activity (Delta I/Io) did not. Phenanthrene also caused a J-point rise in the OJIP curve under high light, which indicated that the acceptor side of PSII QA to QB electron transfer was restricted. This was primarily due to the net degradation of D1 protein, which is caused by the accumulation of reactive oxygen species (ROS) in phenanthrene-treated cucumber leaves under high light. This study demonstrated that phenanthrene could directly inhibit photosynthetic electron transport and Rubisco carboxylation activity to decrease net Pn. Under high light, phenanthrene caused the accumulation of ROS, resulting in net increases in D1 protein degradation and consequently causing PSII photoinhibition. PMID- 27939667 TI - A review of odour impact criteria in selected countries around the world. AB - Exposure to environmental odour can result in annoyance, health effects and depreciation of property values. Therefore, many jurisdictions classify odour as an atmospheric pollutant and regulate emissions and/or impacts from odour generating activities at a national, state or municipal level. In this work, a critical review of odour regulations in selected jurisdictions of 28 countries is presented. Individual approaches were identified as: comparing ambient air odour concentration and individual chemicals statistics against impact criteria (maximum impact standard); using fixed and variable separation distances (separation distance standard); maximum emission rate for mixtures of odorants and individual chemical species (maximum emission standard); number of complaints received or annoyance level determined via community surveys (maximum annoyance standard); and requiring use of best available technologies (BAT) to minimize odour emissions (technology standard). The comparison of model-predicted odour concentration statistics against odour impact criteria (OIC) is identified as one of the most common tools used by regulators to evaluate the risk of odour impacts in planning stage assessments and is also used to inform assessment of odour impacts of existing facilities. Special emphasis is given to summarizing OIC (concentration percentile and threshold) and the manner in which they are applied. The way short term odour peak to model time-step mean (peak-to-mean) effects is also captured. Furthermore, the fundamentals of odorant properties, dimensions of nuisance odour, odour sampling and analysis methods and dispersion modelling guidance are provided. Common elements of mature and effective odour regulation frameworks are identified and an integrated multi-tool strategy is recommended. PMID- 27939668 TI - Hexavalent chromium availability and phytoremediation potential of Cichorium spinosum as affect by manure, zeolite and soil ageing. AB - Cichorium spinosum (spiny chicory) is a wild edible vegetable, and a possible suitable species for Cr(VI)-phytoremediation. There are three approaches for altering Cr(VI) dynamics: reduction to Cr(III) by organic matter addition, soil ageing, and Cr(VI) retention by high binding capacity materials added to soil, e.g., zeolite. Our aim was to assess spiny chicory as a phytoremediation species in relation to these three methods of altering Cr(VI) soil dynamics. There were 5 treatments: control (C); soil with 100 mg kg-1 Cr(VI) (S); soil with zeolite plus 100 mg kg-1 Cr(VI) (Z); soil with manure plus 100 mg kg-1 Cr(VI) (M); and soil added with 100 mg kg-1 Cr(VI) one year before this experiment (AS, "aged soil"). In soil, Cr(VI) was higher at S, while Z, M and AS were lower. In plant, Cr(VI) at Z, S, and AS were similar and significantly higher than M. This indicates that added manure decrease Cr(VI) availability to chicory due to the formation of organometallic complexes. However, chicory uptake amounted to 0.26-0.40 kg Cr(VI) ha-1 for Z, S, and AS, while uptake at M was lower. In conclusion, manure addition was more successful in decreasing Cr(VI) bioavailability, but it also slowed Cr(VI)-phytoremediation process. PMID- 27939669 TI - Photodegradation of methylene blue by photocatalyst of D-A-D type polymer/functionalized multi-walled carbon nanotubes composite under visible light irradiation. AB - A donor-acceptor-donor (D-A-D) type monomer (3,6-bis(2-(3,4-ethylenedioxy- thiophene))pyridazine) (EPE) with pyridazine as intermediate unit (acceptor) and 3,4-ethylenedioxythiophene (EDOT) as sealing unit (donor) was successfully synthesized. The functionalized multi-walled carbon nanotubes (f-MWCNT) was covalently linked with polymer chain via chemical oxidative polymerization of monomer EPE to form poly(EPE)/f-MWCNT composite. The prepared composite was characterized by Fourier transform infrared spectroscopy (FT-IR), Ultraviolet visible absorption spectra (UV-vis), X-ray diffraction (XRD), Energy-dispersive X ray spectroscopy (EDS), and Field emission scanning electron microscope (FESEM), respectively. The photocatalytic activity of poly(EPE)/f-MWCNT was investigated toward degrading methylene blue (MB) dye solution (1 * 10-5 M) under visible light irradiation. As expected, the degradation efficiency of poly(EPE)/f-MWCNT is significantly higher than that of either pure poly(EPE) or poly(EPE)/MWCNT for MB dye, especially the kinetic constant of poly(EPE)/f-MWCNT is more than 6 times of poly(EPE)/MWCNT. Besides, the reactive oxygen species trapping experiments indicate that the degradation of MB over the poly(EPE)/f-MWCNT composite mainly results from holes oxidation. Moreover, the enhancement of the photodegradation rate is mainly attributed to the superior stability, strong light absorption ability, and highly effective photo-generated electron-hole pairs of the poly(EPE)/f-MWCNT composite. A reasonable mechanism for the enhanced reactivity was proposed. PMID- 27939670 TI - Identification and characterization of a catechol-o-methyltransferase cDNA in the catfish Heteropneustes fossilis: Tissue, sex and seasonal variations, and effects of gonadotropin and 2-hydroxyestradiol-17beta on mRNA expression. AB - Catechol-O-methyltransferase (COMT) is involved in the methylation and inactivation of endogenous and xenobiotic catechol compounds, and serves as a common biochemical link in the catecholamine and catecholestrogen metabolism. Studies on cloning, sequencing and function characterization comt gene in lower vertebrates like fish are fewer. In the present study, a full-length comt cDNA of 1442bp with an open-reading frame (ORF) of 792bp, and start codon (ATG) at nucleotide 162 and stop codon (TAG) at nucleotide 953 was isolated and characterized in the stinging catfish Heteropneustes fossilis (accession No. KT597925). The ORF codes for a protein of 263 amino acid residues, which is also validated by the catfish transcriptome data analysis. The catfish Comt shared conserved putative structural regions important for S-adenosyl methionine (AdoMet)- and catechol-binding, transmembrane regions, two glycosylation sites (N 65 and N-91) at the N-terminus and two phosphorylation sites (Ser-235 and Thr 240) at the C-terminus. The gene was expressed in all tissues examined and the expression showed significant sex dimorphic distribution with high levels in females. The transcript was abundant in the liver, brain and gonads and low in muscles. The transcripts showed significant seasonal variations in the brain and ovary, increased progressively to the peak levels in spawning phase and then declined. The brain and ovarian comt mRNA levels showed periovulatory changes after in vivo and in vitro human chorionic gonadotropin (hCG) treatments with high fold increases at 16 and 24h in the brain and at 16h in the ovary. The catecholestrogen 2-hydroxyE2 up regulated ovarian comt expression in vitro with the highest fold increase at 16h. The mRNA and protein was localized in the follicular layer of the vitellogenic follicles and in the cytoplasm of primary follicles. The data were discussed in relation to catecholamine and catecholestrogen-mediated functions in the brain and ovary of the stinging catfish. PMID- 27939671 TI - The Chemokine Receptor CX3CR1 Defines Three Antigen-Experienced CD8 T Cell Subsets with Distinct Roles in Immune Surveillance and Homeostasis. AB - Infections induce pathogen-specific T cell differentiation into diverse effectors (Teff) that give rise to memory (Tmem) subsets. The cell-fate decisions and lineage relationships that underlie these transitions are poorly understood. Here, we found that the chemokine receptor CX3CR1 identifies three distinct CD8+ Teff and Tmem subsets. Classical central (Tcm) and effector memory (Tem) cells and their corresponding Teff precursors were CX3CR1- and CX3CR1high, respectively. Viral infection also induced a numerically stable CX3CR1int subset that represented ~15% of blood-borne Tmem cells. CX3CR1int Tmem cells underwent more frequent homeostatic divisions than other Tmem subsets and not only self renewed, but also contributed to the expanding CX3CR1- Tcm pool. Both Tcm and CX3CR1int cells homed to lymph nodes, but CX3CR1int cells, and not Tem cells, predominantly surveyed peripheral tissues. As CX3CR1int Tmem cells present unique phenotypic, homeostatic, and migratory properties, we designate this subset peripheral memory (tpm) cells and propose that tpm cells are chiefly responsible for the global surveillance of non-lymphoid tissues. PMID- 27939672 TI - Dynamic Changes in Chromatin Accessibility Occur in CD8+ T Cells Responding to Viral Infection. AB - In response to acute infection, naive CD8+ T cells expand, differentiate into effector cells, and then contract to a long-lived pool of memory cells after pathogen clearance. During chronic infections or in tumors, CD8+ T cells acquire an "exhausted" phenotype. Here we present genome-wide comparisons of chromatin accessibility and gene expression from endogenous CD8+ T cells responding to acute and chronic viral infection using ATAC-seq and RNA-seq techniques. Acquisition of effector, memory, or exhausted phenotypes was associated with stable changes in chromatin accessibility away from the naive T cell state. Regions differentially accessible between functional subsets in vivo were enriched for binding sites of transcription factors known to regulate these subsets, including E2A, BATF, IRF4, T-bet, and TCF1. Exhaustion-specific accessible regions were enriched for consensus binding sites for NFAT and Nr4a family members, indicating that chronic stimulation confers a unique accessibility profile on exhausted cells. PMID- 27939673 TI - Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung. AB - Allergic disease originates in early life and polymorphisms in interleukin-33 gene (IL33) and IL1RL1, coding for IL-33R and decoy receptor sST2, confer allergy risk. Early life T helper 2 (Th2) cell skewing and allergy susceptibility are often seen as remnants of feto-maternal symbiosis. Here we report that shortly after birth, innate lymphoid type 2 cells (ILC2s), eosinophils, basophils, and mast cells spontaneously accumulated in developing lungs in an IL-33-dependent manner. During the phase of postnatal lung alveolarization, house dust mite exposure further increased IL-33, which boosted cytokine production in ILC2s and activated CD11b+ dendritic cells (DCs). IL-33 suppressed IL-12p35 and induced OX40L in neonatal DCs, thus promoting Th2 cell skewing. Decoy sST2 had a strong preventive effect on asthma in the neonatal period, less so in adulthood. Thus, enhanced neonatal Th2 cell skewing to inhaled allergens results from postnatal hyperactivity of the IL-33 axis during a period of maximal lung remodeling. PMID- 27939674 TI - Loss of Bladder Epithelium Induced by Cytolytic Mast Cell Granules. AB - Programmed death and shedding of epithelial cells is a powerful defense mechanism to reduce bacterial burden during infection but this activity cannot be indiscriminate because of the critical barrier function of the epithelium. We report that during cystitis, shedding of infected bladder epithelial cells (BECs) was preceded by the recruitment of mast cells (MCs) directly underneath the superficial epithelium where they docked and extruded their granules. MCs were responding to interleukin-1beta (IL-1beta) secreted by BECs after inflammasome and caspase-1 signaling. Upon uptake of granule-associated chymase (mouse MC protease 4 [mMCPT4]), BECs underwent caspase-1-associated cytolysis and exfoliation. Thus, infected epithelial cells require a specific cue for cytolysis from recruited sentinel inflammatory cells before shedding. PMID- 27939676 TI - Multi-omics approach to study global changes in a triclosan-resistant mutant strain of Acinetobacter baumannii ATCC 17978. AB - Acinetobacter baumannii AB042, a triclosan-resistant mutant strain, was examined for modulated gene expression using whole-genome sequencing, transcriptomics and proteomics in order to understand the mechanism of triclosan resistance as well as its impact on A. baumannii. Data revealed modulated expression of the fatty acid metabolism pathway, co-factors known to play a role in the synthesis of fatty acids, as well as several transcriptional regulators. The membrane composition of the mutant revealed a decrease in C18 with a corresponding increase in C16 fatty acids compared with the parent strain A. baumannii ATCC 17978. These data indicate that A. baumannii responds to triclosan by altering the expression of genes involved in fatty acid metabolism, antibiotic resistance and amino acid metabolism. PMID- 27939675 TI - Repurposing the anticancer drug mitomycin C for the treatment of persistent Acinetobacter baumannii infections. AB - Acinetobacter baumannii is an emergent opportunistic bacterial pathogen responsible for recalcitrant infections owing to its high intrinsic tolerance to most antibiotics; therefore, suitable strategies to treat these infections are needed. One plausible approach is the repurposing of drugs that are already in use. Among them, anticancer drugs may be especially useful due their cytotoxic activities and ample similarities between bacterial infections and growing tumours. In this work, the effectiveness of four anticancer drugs on the growth of A. baumannii ATTC BAA-747 was evaluated, including the antimetabolite 5 fluorouracil and three DNA crosslinkers, namely cisplatin, mitomycin C (MMC) and merphalan. MMC was the most effective drug, having a minimum inhibitory concentration for 50% of growth in Luria-Bertani medium at ca. 7 ug/mL and completely inhibiting growth at 25 ug/mL. Hence, MMC was tested against a panel of 21 clinical isolates, including 18 multidrug-resistant (MDR) isolates, 3 of which were sensitive only to colistin. The minimum inhibitory concentrations and minimum bactericidal concentrations of MMC in all tested strains were found to be similar to those of A. baumannii ATCC BAA-747, and MMC also effectively killed stationary-phase, persister and biofilm cells. Moreover, MMC was able to increase survival of the insect larvae Galleria mellonella against an otherwise lethal A. baumannii infection from 0% to >=53% for the antibiotic-sensitive A. baumannii ATCC BAA-747 strain and the MDR strains A560 and A578. Therefore, MMC is highly effective at killing the emergent opportunistic pathogen A. baumannii. PMID- 27939677 TI - Detection of the high-risk clone ST131 of Escherichia coli carrying the colistin resistance gene mcr-1 and causing acute peritonitis. PMID- 27939678 TI - Response to Letter to the Editor re: 'Executive dysfunction and balance function post-stroke: a cross-sectional study'. PMID- 27939679 TI - The Role of Negotiation in Consultation-Liaison Psychiatry. PMID- 27939680 TI - Research on biological therapies in systemic lupus erythematosus. PMID- 27939681 TI - Hepcidin and ferritin levels in Still's disease. PMID- 27939682 TI - Treatment of cognitive impairment in Parkinson disease. PMID- 27939683 TI - Left pleural effusion secondary to splenic infarctions in a patient with liver cirrhosis. PMID- 27939684 TI - Malonylome analysis of rhizobacterium Bacillus amyloliquefaciens FZB42 reveals involvement of lysine malonylation in polyketide synthesis and plant-bacteria interactions. AB - : Using the combination of affinity enrichment and high-resolution LC-MS/MS analysis, we performed a large-scale lysine malonylation analysis in the model representative of Gram-positive plant growth-promoting rhizobacteria (PGPR), Bacillus amyloliquefaciens FZB42. Altogether, 809 malonyllysine sites in 382 proteins were identified. The bioinformatic analysis revealed that lysine malonylation occurs on the proteins involved in a variety of biological functions including central carbon metabolism, fatty acid biosynthesis and metabolism, NAD(P) binding and translation machinery. A group of proteins known to be implicated in rhizobacterium-plant interaction were also malonylated; especially, the enzymes responsible for antibiotic production including polyketide synthases (PKSs) and nonribosomal peptide synthases (NRPSs) were highly malonylated. Furthermore, our analysis showed malonylation occurred on proteins structure with higher surface accessibility and appeared to be conserved in many bacteria but not in archaea. The results provide us valuable insights into the potential roles of lysine malonylation in governing bacterial metabolism and cellular processes. BIOLOGICAL SIGNIFICANCE: Although in mammalian cells some important findings have been discovered that protein malonylation is related to basic metabolism and chronic disease, few studies have been performed on prokaryotic malonylome. In this study, we determined the malonylation profiles of Bacillus amyloliquefaciens FZB42, a model organism of Gram-positive plant growth-promoting rhizobacteria. FZB42 is known for the extensive investigations on its strong ability of producing antimicrobial polyketides and its potent activities of stimulating plant growth. Our analysis shows that malonylation is highly related to the polyketide synthases and the proteins involved bacterial interactions with plants. The results not only provide one of the first malonylomes for exploring the biochemical nature of bacterial proteins, but also shed light on the better understanding of bacterial antibiotic biosynthesis and plant-microbe interaction. PMID- 27939685 TI - Regionally Restricted Hox Function in Adult Bone Marrow Multipotent Mesenchymal Stem/Stromal Cells. AB - Posterior Hox genes (Hox9-13) are critical for patterning the limb skeleton along the proximodistal axis during embryonic development. Here we show that Hox11 paralogous genes, which developmentally pattern the zeugopod (radius/ulna and tibia/fibula), remain regionally expressed in the adult skeleton. Using Hoxa11EGFP reporter mice, we demonstrate expression exclusively in multipotent mesenchymal stromal cells (MSCs) in the bone marrow of the adult zeugopod. Hox positive cells express PDGFRalpha and CD51, are marked by LepR-Cre, and exhibit colony-forming unit fibroblast activity and tri-lineage differentiation in vitro. Loss of Hox11 function leads to fracture repair defects, including reduced cartilage formation and delayed ossification. Hox mutant cells are defective in osteoblastic and chondrogenic differentiation in tri-lineage differentiation experiments, and these defects are zeugopod specific. In the stylopod (humerus and femur) and sternum, bone marrow MSCs express other regionally restricted Hox genes, and femur fractures heal normally in Hox11 mutants. Together, our data support regional Hox expression and function in skeletal MSCs. PMID- 27939687 TI - Spatial distribution, risk assessment and source identification of heavy metals in sediments of the Yangtze River Estuary, China. AB - The aim of this study was to determine the spatial distribution, potential risks and sources of seven heavy metals in sediments of the Yangtze River Estuary. Analyses of 55 sediment samples revealed that the distributions of metals within the YRE were determined by the combined effects of their sources, hydrodynamic conditions, pH and Eh. According to the geoaccumulation index (Igeo) and sediment quality guidelines, Pb, Cd and Cr were present at low levels of pollution, with Cd posing the largest ecological risk. Positive Factor Matrix (PMF) results indicated that Hg, Zn, As, Pb and Cr mainly originated from natural geological background sources, while Cu originated from anthropogenic activities and atmospheric deposition was the source of Cd. These three sources contributed to 53.0%, 32.8% and 14.2%, respectively of total heavy metal concentrations. These results suggest that reducing the emission of Cd would promote a reduction of potential risks in sediments of the YRE. PMID- 27939686 TI - Mesenchymal Cell Invasion Requires Cooperative Regulation of Persistent Microtubule Growth by SLAIN2 and CLASP1. AB - Microtubules regulate signaling, trafficking, and cell mechanics, but the respective contribution of these functions to cell morphogenesis and migration in 3D matrices is unclear. Here, we report that the microtubule plus-end tracking protein (+TIP) SLAIN2, which suppresses catastrophes, is not required for 2D cell migration but is essential for mesenchymal cell invasion in 3D culture and in a mouse cancer model. We show that SLAIN2 inactivation does not affect Rho GTPase activity, trafficking, and focal adhesion formation. However, SLAIN2-dependent catastrophe inhibition determines microtubule resistance to compression and pseudopod elongation. Another +TIP, CLASP1, is also needed to form invasive pseudopods because it prevents catastrophes specifically at their tips. When microtubule growth persistence is reduced, inhibition of depolymerization is sufficient for pseudopod maintenance but not remodeling. We propose that catastrophe inhibition by SLAIN2 and CLASP1 supports mesenchymal cell shape in soft 3D matrices by enabling microtubules to perform a load-bearing function. PMID- 27939688 TI - Microplastic pollution in the marine waters and sediments of Hong Kong. AB - The presence of plastic waste with a diameter of less than 5mm ("microplastics") in marine environments has prompted increasing concern in recent years, both locally and globally. We conducted seasonal surveys of microplastic pollution in the surface waters and sediments from Deep Bay, Tolo Harbor, Tsing Yi, and Victoria Harbor in Hong Kong between June 2015 and March 2016. The average concentrations of microplastics in local coastal waters and sediments respectively ranged from 51 to 27,909particles per 100m3 and 49 to 279particles per kilogram. Microplastics of different shapes (mainly fragments, lines, fibers, and pellets) were identified as polypropylene, low-density polyethylene, high density polyethylene, a blend of polypropylene and ethylene propylene, and styrene acrylonitrile by means of Attenuated Total Reflectance - Fourier Transform Infrared Spectroscopy. This is the first comprehensive study to assess the spatial and temporal variations of microplastic pollution in Hong Kong coastal regions. PMID- 27939689 TI - AAV-mediated IL-10 gene transfer counteracts inflammation in the hypothalamic arcuate nucleus and obesity induced by high-fat diet. AB - Consumption of high-fat diet (HFD) induces energy imbalance and consequently obesity. In the pathogenesis of obesity, HFD triggers inflammation in the hypothalamus including arcuate nucleus (ARC). Interleukin-10 (IL-10) is a representative anti-inflammatory cytokine, known to ameliorate the adipose tissue inflammation and insulin resistance in obesity. However, the effect of IL-10 on the hypothalamic inflammation remains less defined. We here report the effect of over-expression of murine IL-10 using adeno-associated virus (AAV) vector on the inflammation in ARC and feeding behavior in HFD-induced obese (DIO) mice. DIO mice exhibited reduced POMC expression and elevated IKKs (IkappaB kinases) and SOCS3 expression in ARC. Overexpression of mIL-10 using AAV vector ameliorated obesity in parallel with restoration of ARC POMC expression in DIO mice. Moreover, IL-10 treatment suppressed IKKs activation and SOCS3 expression in ARC of DIO mice. These results suggest that IL-10 gene transfer provides an effective approach for counteracting HFD-induced inflammation and leptin resistance in ARC to prevent progression of obesity. PMID- 27939690 TI - Urban fine particulate matter exposure causes male reproductive injury through destroying blood-testis barrier (BTB) integrity. AB - Blood-testis barrier (BTB) provides a suitable microenvironment for germ cells that is required for spermatogenesis. Exposure to particulate matter (PM) is recognized to occasion male reproductive impairment, but the mechanism of which remains unclear. Male Sprague-Dawley (SD) rats were used to establish animal models with PM2.5 exposure concentration of 0, 10, and 20mg/kg.b.w. once a day for four weeks. Success rate of mating, sperm quality, epididymal morphology, expressions of spermatogenesis markers, superoxide dismutases (SOD) activity and expression in testicular tissues, and expressions of BTB junction proteins were detected. In addition, in vitro experiments were also performed. After PM2.5 treatment, reactive oxygen species (ROS) production and apoptosis of Sertoli cells were analyzed. Our results indicated that after PM2.5 exposure male rats presented inferior uberty and sperm quality, with decreased expressions of spermatogenesis markers, escalated SOD activity and expression levels, and reduced expressions of tight junction, adherens junction, and gap junction proteins in testicular tissues. Meantime, PM2.5-treated Sertoli cells displayed increased SOD production and apoptosis. PM2.5 exposure engenders male reproductive function injury through breaking BTB integrity. PMID- 27939691 TI - Frequency-dependent, transient effects of subthalamic nucleus deep brain stimulation on methamphetamine-induced circling and neuronal activity in the hemiparkinsonian rat. AB - Methamphetamine-induced circling is used to quantify the behavioral effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in hemiparkinsonian rats. We observed a frequency-dependent transient effect of DBS on circling, and quantified this effect to determine its neuronal basis. High frequency STN DBS (75-260Hz) resulted in transient circling contralateral to the lesion at the onset of stimulation, which was not sustained after the first several seconds of stimulation. Following the transient behavioral change, DBS resulted in a frequency-dependent steady-state reduction in pathological ipsilateral circling, but no change in overall movement. Recordings from single neurons in globus pallidus externa (GPe) and substantia nigra pars reticulata (SNr) revealed that high frequency, but not low frequency, STN DBS elicited transient changes in both firing rate and neuronal oscillatory power at the stimulation frequency in a subpopulation of GPe and SNr neurons. These transient changes were not sustained, and most neurons exhibited a different response during the steady-state phase of DBS. During the steady-state, DBS produced elevated neuronal oscillatory power at the stimulus frequency in a majority of GPe and SNr neurons, and the increase was more pronounced during high frequency DBS than during low frequency DBS. Changes in oscillatory power during both transient and steady-state DBS were highly correlated with changes in firing rates. These results suggest that distinct neural mechanisms were responsible for transient and sustained behavioral responses to STN DBS. The transient contralateral turning behavior following the onset of high frequency DBS was paralleled by transient changes in firing rate and oscillatory power in the GPe and SNr, while steady-state suppression of ipsilateral turning was paralleled by sustained increased synchronization of basal ganglia neurons to the stimulus pulses. Our analysis of distinct frequency dependent transient and steady-state responses to DBS lays the foundation for future mechanistic studies of the immediate and persistent effects of DBS. PMID- 27939692 TI - Behavioral effects of chronic stress in the Fmr1 mouse model for fragile X syndrome. AB - Fragile X Syndrome (FXS) is a pervasive developmental disorder due to a mutation in the FMR1 X-linked gene. Despite its clear genetic cause, the expression of FXS symptoms is known to be modulated by environmental factors, including stress. Furthermore, several studies have shown disturbances in stress regulatory systems in FXS patients and Fmr1 mice. These studies have mostly focused on the hormonal responses to stress, using the acute exposure to a single type of stressor. Hence, little is known about the behavioral effects of stress in FXS, and the importance of the nature of the stressing procedure, especially in the context of a repeated exposure that more closely resembles real life conditions. Here we evaluated the effects of chronic exposure to different types of stress (i.e., either repeated restraint or unpredictable stress) on the behavioral phenotype of adult Fmr1 mice. Our results demonstrated that chronic stress induced deficits in social interaction and working memory only in WT mice and the impact of stress depended on the type of stressors and the specific behavior tested. Our data suggest that the behavioral sensitivity to stress is dramatically reduced in FXS, opening new views on the impact of gene-environment interactions in this pathology. PMID- 27939693 TI - Influence of concentration on distribution properties of stretched-DNA in the MEC studied with fluorescence imaging and drop shape analyzing. AB - Stretching and manipulating DNA efficiently is significant for exploring the properties and applications of single DNA molecules. Here, the influence of concentrations of buffer and DNA on properties of stretched DNA molecules in the molecular evaporation combing (MEC) is investigated systematically with the single molecule fluorescence imaging microscopy and the high-precision drop shape analyzing technology. The stretched degree and uniformity of combed DNA molecules decrease as the buffer concentration are increased from 7 to 20mM. When the buffer concentration changes from 12 to 15mM, the stretched DNA molecules are apt to form a ringlike pattern. During the MEC process, there exist two kinds of evaporation modes, i.e., the constant contact angle mode and the constant contact radius mode. The former only takes effect in the lower concentration of buffer and DNA, enabling the uniform stretching. While the latter plays the leading role in the higher concentration, promoting the formation of the ringlike pattern of DNA molecules. PMID- 27939694 TI - Understanding the anaerobic biodegradability of food waste: Relationship between the typological, biochemical and microbial characteristics. AB - In this study, an extensive characterisation of food waste (FW) was performed with the aim of studying the relation between FW characteristics and FW treatability through an anaerobic digestion process. In addition to the typological composition (paper, meat, fruits, vegetables contents, etc) and the physicochemical characteristics, this study provides an original characterisation of microbial populations present in FW. These intrinsic populations can actively participate to aerobic and anaerobic degradation with the presence of Proteobacteria and Firmicutes species for the bacteria and of Ascomycota phylum for the fungi. However, the characterisation of FW bacterial and fungi community shows to be a challenge because of the biases generated by the non-microbial DNA coming from plant and by the presence of mushrooms in the food. In terms of relations, it was demonstrated that some FW characteristics as the density, the volatile solids and the fibres content vary as a function of the typological composition. No direct relationship was demonstrated between the typological composition and the anaerobic biodegradability. However, the Pearson's matrix results reveal that the anaerobic biodegradation potential of FW was highly related to the total chemical oxygen demand (tCOD), the total solid content (TS), the high weight organic matter molecules soluble in water (SOLW>1.5 kDa) and the C/N ratio content. These relations may help predicting FW behaviour through anaerobic digestion process. Finally, this study also showed that the storage of FW before collection, that could induce pre-biodegradation, seems to impact several biochemical characteristics and could improve the biodegradability of FW. PMID- 27939695 TI - AG311, a small molecule inhibitor of complex I and hypoxia-induced HIF-1alpha stabilization. AB - Cancer cells have a unique metabolic profile and mitochondria have been shown to play an important role in chemoresistance, tumor progression and metastases. This unique profile can be exploited by mitochondrial-targeted anticancer therapies. A small anticancer molecule, AG311, was previously shown to possess anticancer and antimetastatic activity in two cancer mouse models and to induce mitochondrial depolarization. This study defines the molecular effects of AG311 on the mitochondria to elucidate its observed efficacy. AG311 was found to competitively inhibit complex I activity at the ubiquinone-binding site. Complex I as a target for AG311 was further established by measuring oxygen consumption rate in tumor tissue isolated from AG311-treated mice. Cotreatment of cells and animals with AG311 and dichloroacetate, a pyruvate dehydrogenase kinase inhibitor that increases oxidative metabolism, resulted in synergistic cell kill and reduced tumor growth. The inhibition of mitochondrial oxygen consumption by AG311 was found to reduce HIF-1alpha stabilization by increasing oxygen tension in hypoxic conditions. Taken together, these results suggest that AG311 at least partially mediates its antitumor effect through inhibition of complex I, which could be exploited in its use as an anticancer agent. PMID- 27939696 TI - STC2 as a novel mediator for Mus81-dependent proliferation and survival in hepatocellular carcinoma. AB - Methyl methansulfonate and UV sensitive gene clone 81 (Mus81) is a critical DNA repair gene that has been implicated in development of several cancers including hepatocellular carcinoma (HCC). However, whether Mus81 can affect proliferation and survival of HCC remains unknown. In the present study, we demonstrated that the knockdown of Mus81 was associated with suppressed proliferation and elevated apoptosis of HCC cells in vitro and in vivo. Multilayered screenings, including DNA microarray, high content screen, and real-time PCR validation, identified STC2 as a proliferation-facilitating gene significantly down-regulated in HCC cells upon Mus81 knockdown. STC2 expression was also closely correlated to Mus81 expression in HCC tissues. More importantly, the restoration of STC2 expression recovered the compromised cell proliferation and survival in Mus81 depleted HCC cells. Furthermore, Mus81 knockdown was associated with the activation of APAF1, APC, and PTEN pathways and concurrent inhibition of MAPK pathway through decreasing STC2 expression. In conclusion, Mus81 knockdown suppresses proliferation and survival of HCC cells likely by downregulating STC2 expression, implicating Mus81 as a therapeutic target for HCC. PMID- 27939697 TI - Genetic and functional analysis of TBK1 variants in Korean patients with sporadic amyotrophic lateral sclerosis. AB - The TANK-binding kinase 1 (TBK1) gene has recently been identified as a novel causative gene of amyotrophic lateral sclerosis (ALS). This study aims to determine the frequency and spectrum of TBK1 variants and their functional implications in Korean patients with sporadic ALS (sALS). TBK1 sequences were analyzed in 129 consecutive patients with sALS using either multigene panel or exome sequencing. One frameshift (c.1414delA) and 3 missense variants of uncertain significance in TBK1 were found in 4 patients each. In vitro functional studies revealed that the c.1414delA (p.Ile472Serfs*8) variant was associated with reduced mRNA expression of TBK1. Moreover, protein expression of this variant in patient-derived fibroblasts disrupted binding to autophagy adapter proteins and inhibited the function of TBK1 in HEK293T cells. In contrast, the 3 other missense variants of uncertain significance showed normal mRNA expression and no abnormalities in protein function. Based on these findings, the frequency of pathogenic TBK1 variants in Korean sALS patients was estimated to be 0.8% (1/129). In conclusion, pathogenic variants in TBK1 are rare but could be responsible for sALS in a small number of Korean patients. PMID- 27939698 TI - What success can teach us about failure: the plasma metabolome of older adults with superior memory and lessons for Alzheimer's disease. AB - As the world population ages, primary prevention of age-related cognitive decline and disability will become increasingly important. Prevention strategies are often developed from an understanding of disease pathobiology, but models of biological success may provide additional useful insights. Here, we studied 224 older adults, some with superior memory performance (n = 41), some with normal memory performance (n = 109), and some with mild cognitive impairment or Alzheimer's disease (AD; n = 74) to understand metabolomic differences which might inform future interventions to promote cognitive health. Plasma metabolomics revealed significant differential abundance of 12 metabolites in those with superior memory relative to controls (receiver operating characteristic area under the curve [AUC] = 0.89) and the inverse abundance pattern in the mild cognitive impairment, AD (AUC = 1.0) and even preclinical AD groups relative to controls (AUC = 0.97). The 12 metabolites are components of key metabolic pathways regulating oxidative stress, inflammation, and nitric oxide bioavailability. These findings from opposite ends of the cognitive continuum highlight the role of these pathways in superior memory abilities and whose failure may contribute to age-related memory impairment. These pathways may be targeted to promote successful cognitive aging. PMID- 27939699 TI - ERN, theta power, and risk for anxiety problems in preschoolers. AB - The Error Related Negativity (ERN) is a neural marker of performance monitoring that has been inconsistently linked to anxiety risk in children. One avenue for understanding inconsistencies is to investigate other neural dynamics linked to ERN. In this study, we investigated interactions between ERN and power in the theta frequency band, which is associated with attentional control and theorized to contribute ERN, in association with childhood anxiety risk. Fifty-nine 3-year old children provided usable EEG data during a modified go/no-go task. Associations between ERN and anxious behaviors in preschoolers were moderated by theta power during incorrect trials. Specifically, when theta power was low, greater ERN predicted more social withdrawal; when theta power was high, ERN and social withdrawal were unrelated. Our findings suggest that ERN and theta may jointly contribute to anxiety risk in early childhood. PMID- 27939701 TI - Anger and aggression problems in veterans are associated with an increased acoustic startle reflex. AB - Anger and aggression are frequent problems in deployed military personnel. A lowered threshold of perceiving and responding to threat can trigger impulsive aggression. This can be indicated by an exaggerated startle response. Fifty-two veterans with anger and aggression problems (Anger group) and 50 control veterans were tested using a startle experiment with 10 startle probes and 10 prepulse trials, presented in a random order and with a random interval between the trials. Predictors (demographics, Trait Anger, State Anger, Harm Avoidance and Anxious Arousal) for the startle response within the Anger group were tested. Increased EMG responses were found to the startle probes in the Anger Group compared to the Control group, but not to the prepulse trials. Furthermore, Harm Avoidance and State Anger predicted the increased startle reflex within the Anger group, whereas Trait Anger was negatively related to the startle reflex. These findings indicate that threat reactivity is increased in anger and aggression problems. These problems are not only caused by an anxious predisposition, the degree of anger also predicts the startle reflex. PMID- 27939700 TI - Is the link between depressed mood and heart rate variability explained by disinhibited eating and diet? AB - Consistently it has been reported that a depressed mood and low heart rate variability (HRV) are linked. However, studies have not considered that the association might be explained by dietary behaviour. The resting inter-beat interval data of 266 adults (Study 1: 156 (51M), Study 2: 112 (38M)) were recorded for six minutes and quantified using linear (HF power: 0.15-0.4Hz) and nonlinear indices (Sample entropy). Participants also completed the Profile of Mood States and the Three Factor Eating questionnaires. The Alternative Healthy Eating Index was used to quantify diet quality. In study 1 mood was associated with HRV; an effect partially mediated by diet. Study 2 replicated the finding: disinhibited eating (the tendency to lose control over one's eating) and diet sequentially mediated the association between mood and HRV. Diet plays a role in the link between mood and HRV and studies should consider the influence of this factor. PMID- 27939702 TI - Fear and disgust in women: Differentiation of cardiovascular regulation patterns. AB - Both fear and disgust facilitate avoidance of threat. From a functional view, however, cardiovascular responses to fear and disgust should differ as they prepare for appropriate behavior to protect from injury and infection, respectively. Therefore, we examined the cardiovascular responses to fear and contamination-related disgust in comparison to an emotionally neutral state induced with auditory scripts and film clips in female participants. Ten emotion and motivation self-reports and ninecardiovascular response factors derived from 23 cardiovascular variables served as dependent variables. Self-reports confirmed the specific induction of fear and disgust. In addition, fear and disgust differed in their cardiovascular response patterning. For fear, we observed specific increases in factors indicating vasoconstriction and cardiac pump function. For disgust, we found specific increases in vagal cardiac control and decreases in myocardial contractility. These findings provide support for the cardiovascular specificity of fear and disgust and are discussed in terms of a basic emotions approach. PMID- 27939705 TI - Embryonic axon guidance: insights from Drosophila and other insects. AB - During embryonic development, growing axons are guided by cellular signaling pathways that control a series of individual axon guidance decisions. In Drosophila, two major pathways (Netrin-Frazzled/DCC and Slit-Robo) regulate axon guidance in the embryonic ventral nerve cord, including the critical decision of whether or not to cross the midline. Studies in the fruit fly have revealed a complex picture of precise regulation and cross-talk between these pathways. In addition, Robo receptors in Drosophila have diversified their activities to regulate additional axon guidance decisions in the developing embryo. Here, I discuss recent advances in understanding roles and regulation of the Net-Fra and Slit-Robo signaling pathways in Drosophila, and examine the evolutionary conservation of these signaling mechanisms across insects and other arthropods. PMID- 27939703 TI - Tackling Bet v 1 and associated food allergies with a single hybrid protein. AB - BACKGROUND: Allergy vaccines should be easily applicable, safe, and efficacious. For Bet v 1-mediated birch pollen and associated food allergies, a single wild type allergen does not provide a complete solution. OBJECTIVE: We aimed to combine immunologically relevant epitopes of Bet v 1 and the 2 clinically most important related food allergens from apple and hazelnut to a single hybrid protein, termed MBC4. METHODS: After identification of T cell epitope-containing parts on each of the 3 parental allergens, the hybrid molecule was designed to cover relevant epitopes and evaluated in silico. Thereby a mutation was introduced into the hybrid sequence, which should alter the secondary structure without compromising the immunogenic properties of the molecule. RESULTS: MBC4 and the parental allergens were purified to homogeneity. Analyses of secondary structure elements revealed substantial changes rendering the hybrid de facto nonreactive with patients' serum IgE. Nevertheless, the protein was monomeric in solution. MBC4 was able to activate T-cell lines from donors with birch pollen allergy and from mice immunized with the parental allergens. Moreover, on immunization of mice and rabbits, MBC4 induced cross-reactive IgG antibodies, which were able to block the binding of human serum IgE. CONCLUSION: Directed epitope rearrangements combined with a knowledge-based structural modification resulted in a protein unable to bind IgE from allergic patients. Still, properties to activate specific T cells or induce blocking antibodies were conserved. This suggests that MBC4 is a suitable vaccine candidate for the simultaneous treatment of Bet v 1 and associated food allergies. PMID- 27939704 TI - Neuronal migration during development and the amyloid precursor protein. AB - The Amyloid Precursor Protein (APP) is the source of amyloid peptides that accumulate in Alzheimer's disease. However, members of the APP family are strongly expressed in the developing nervous systems of invertebrates and vertebrates, where they regulate neuronal guidance, synaptic remodeling, and injury responses. In contrast to mammals, insects express only one APP ortholog (APPL), simplifying investigations into its normal functions. Recent studies have shown that APPL regulates neuronal migration in the developing insect nervous system, analogous to the roles ascribed to APP family proteins in the mammalian cortex. The comparative simplicity of insect systems offers new opportunities for deciphering the signaling mechanisms by which this enigmatic class of proteins contributes to the formation and function of the nervous system. PMID- 27939707 TI - Synapsin-based approaches to brain plasticity in adult social insects. AB - Development of the mushroom bodies continues after adult eclosion in social insects. Synapsins, phosphoproteins abundant in presynaptic boutons, are not required for development of the nervous system but have as their primary function modulation of synaptic transmission. A monoclonal antibody against a conserved region of Drosophila synapsin labels synaptic structures called microglomeruli in the mushroom bodies of adult social insects, permitting studies of microglomerular volume, density, and number. The results point to multiple forms of brain plasticity in social insects: age-based and experience-based maturation that results in a decrease in density coupled with an increase in volume of individual microglomeruli in simultaneous operation with shorter term changes in density produced by specific life experiences. PMID- 27939706 TI - Long-term fluorescence live imaging of Tribolium castaneum embryos: principles, resources, scientific challenges and the comparative approach. AB - Light sheet-based fluorescence microscopy became an important tool in insect developmental biology due to its high acquisition speed, low photo-bleaching rate and the high survival probability of the specimens. Initially applied to document the embryogenesis of Drosophila melanogaster, it is now used to investigate the embryonic morphogenesis of emerging model organisms such as the red flour beetle Tribolium castaneum. Here, we discuss the principles of light sheet-based fluorescence microscopy and outline Tribolium as a model organism for developmental biology. We summarize labeling options and present two custom-made transgenic lines suitable for live imaging. Finally, we highlight studies on Tribolium that address scientific questions with fluorescence live imaging and discuss the comparative approach to investigate insect morphogenesis in an evolutionary context. PMID- 27939708 TI - Applications of phylogenetics to solve practical problems in insect conservation. AB - Phylogenetic approaches have much promise for the setting of conservation priorities and resource allocation. There has been significant development of analytical methods for the measurement of phylogenetic diversity within and among ecological communities as a way of setting conservation priorities. Application of these tools to insects has been low as has been the uptake by conservation managers. A critical reason for the lack of uptake includes the scarcity of detailed phylogenetic and species distribution data from much of insect diversity. Environmental DNA technologies offer a means for the high throughout collection of phylogenetic data across landscapes for conservation planning. PMID- 27939709 TI - Advances using molecular data in insect systematics. AB - The size of molecular datasets has been growing exponentially since the mid 1980s, and new technologies have now dramatically increased the slope of this increase. New datasets include genomes, transcriptomes, and hybrid capture data, producing hundreds or thousands of loci. With these datasets, we are approaching a consensus on the higher level insect phylogeny. Huge datasets can produce new challenges in interpreting branch support, and new opportunities in developing better models and more sophisticated partitioning schemes. Dating analyses are improving as we recognize the importance of careful fossil calibration selection. With thousands of genes now available, coalescent methods have come of age. Barcode libraries continue to expand, and new methods are being developed for incorporating them into phylogenies with tens of thousands of individuals. PMID- 27939710 TI - Insect phylogenetics in the digital age. AB - Insect systematists have long used digital data management tools to facilitate phylogenetic research. Web-based platforms developed over the past several years support creation of comprehensive, openly accessible data repositories and analytical tools that support large-scale collaboration, accelerating efforts to document Earth's biota and reconstruct the Tree of Life. New digital tools have the potential to further enhance insect phylogenetics by providing efficient workflows for capturing and analyzing phylogenetically relevant data. Recent initiatives streamline various steps in phylogenetic studies and provide community access to supercomputing resources. In the near future, automated, web based systems will enable researchers to complete a phylogenetic study from start to finish using resources linked together within a single portal and incorporate results into a global synthesis. PMID- 27939711 TI - Testing cospeciation through large-scale cophylogenetic studies. AB - Insects are involved in a multitude of interactions with other organisms, which make them ideal models for large-scale cophylogenetic studies. Once phylogenies of interacting lineages have been inferred, there are a number of questions we may wish to ask, such as what was the relationship between the partners in the past? Have they co-evolved for thousands or millions of years, or has one of the partners switched among different host species? To answer such questions, researchers may conduct cophylogenetic analysis, to explore the relationships between the phylogenies of interacting lineages and determine whether the match is significant or find explanations for observed differences. When combined with dating analyses, cophylogenetic analyses may support cospeciation of the partners or phylogenetic tracking. As they may reveal dynamics of host-pathogen coevolution, cophylogenetic studies may also help tackle global health issues (e.g. document the spread of disease causing pathogens). Cophylogenetic studies of parasitoids and their insect hosts may also help identify effective biocontrol agents. With the advent of next generation sequencing technologies and keeping in mind that systematic errors may occur, cophylogenetics will benefit from better resolved trees, allowing more accurate reconciliation. However as trees become larger, current algorithms also become more computationally challenging. Nevertheless, both theoretical and methodological developments are leading to more accurate and powerful tests of cospeciation through cophylogenetic analysis. PMID- 27939712 TI - A review of methods for analysing insect structures - the role of morphology in the age of phylogenomics. AB - Techniques currently used in insect morphology are outlined briefly. Scanning electron microscopy (SEM) and microphotography are used mainly for documenting external features, the former providing more information on tiny surface structures and the latter on coloration, transparency and degree of sclerotization. A broad spectrum of methods is now available for anatomical studies: histological serial sections, confocal laser scanning microscopy (CLSM), light-sheet fluorescence microscopy (LSFM), serial block-face scanning electron microscopy (SBFSEM), dual beam scanning electron microscopy (FIB-SEM), nuclear magnetic resonance imaging (NMRI), and MU-computed tomography (micro-CT). The use of SBFSEM and FIB-SEM is restricted to extremely small samples. NMRI is used mainly in in vivo studies. Micro-computed tomography, in combination with computer-based reconstruction, has greatly accelerated the acquisition of high quality data in a phylogenetic context. Morphology will continue to play a vital role in phylogenetic and evolutionary investigations. It provides independent data for checking the plausibility of molecular phylogenies and is the only source of information for placing extinct taxa. It is the necessary basis for reconstructing character evolution on the phenotypic level and for developing complex evolutionary scenarios. Computer-based anatomical ontologies are an additional future perspective of morphological work. PMID- 27939714 TI - The rapidly changing landscape of insect phylogenetics. AB - Insect phylogenetics is being profoundly changed by many innovations. Although rapid developments in genomics have center stage, key progress has been made in phenomics, field and museum science, digital databases and pipelines, analytical tools, and the culture of science. The importance of these methodological and cultural changes to the pace of inference of the hexapod Tree of Life is discussed. The innovations have the potential, when synthesized and mobilized in ways as yet unforeseen, to shine light on the million or more clades in insects, and infer their composition with confidence. There are many challenges to overcome before insects can enter the 'phylocognisant age', but because of the promise of genomics, phenomics, and informatics, that is now an imaginable future. PMID- 27939713 TI - Incorporating fossils into hypotheses of insect phylogeny. AB - Fossils represent stem and crown lineages, and their inclusion in phylogenetic reconstruction influences branch lengths, topology, and divergence time estimation. In addition, paleontological data may inform trends in morphological evolution as well as biogeographic history. Here we review the incorporation of fossils in studies of insect evolution, from morphological analyses to combined 'total evidence' node dating analyses. We discuss challenges associated with fossil based phylogenetics, and suggest best practices for use in tree reconstruction. PMID- 27939715 TI - Museums are biobanks: unlocking the genetic potential of the three billion specimens in the world's biological collections. AB - Museums and herbaria represent vast repositories of biological material. Until recently, working with these collections has been difficult, due to the poor condition of historical DNA. However, recent advances in next-generation sequencing technology, and subsequent development of techniques for preparing and sequencing historical DNA, have recently made working with collection specimens an attractive option. Here we describe the unique technical challenges of working with collection specimens, and innovative molecular methods developed to tackle them. We also highlight possible applications of collection specimens, for taxonomy, ecology and evolution. The application of next-generation sequencing methods to museum and herbaria collections is still in its infancy. However, by giving researchers access to billions of specimens across time and space, it holds considerable promise for generating future discoveries across many fields. PMID- 27939717 TI - Editorial overview: Insect phylogenetics: an expanding toolbox to resolve evolutionary questions. PMID- 27939716 TI - Democratizing evolutionary biology, lessons from insects. AB - The engagement of the public in the scientific process is an old practice. Yet with recent advances in technology, the role of the citizen scientist in studying evolutionary processes has increased. Insects provide ideal models for understanding these evolutionary processes at large scales. This review highlights how insect-based citizen science has led to the expansion of specimen collections and reframed research questions in light of new observations and unexpected discoveries. Given the rapid expansion of human-modified (and inhabited) environments, the degree to which the public can participate in insect based citizen science will allow us to track and monitor evolutionary trends at a global scale. PMID- 27939719 TI - Editorial overview: Neuroscience: Back to the future in the developing insect nervous system. PMID- 27939720 TI - Effects of Mediterranean diet in patients with recurring colds and frequent complications. AB - INTRODUCTION: In recent years, traditional diets enriched with fresh plant-based foods have been gradually abandoned, increasing the consumption of animal foods and highly processed food. The aim of this study was to assess the effects of a nutritional intervention with a Traditional Mediterranean Diet in patients with recurring colds (RC) and frequent inflammatory complications (IC). METHODS: Prospective before-after comparison study of 63 girls and 65 boys aged 1-5 years were included over a year in the nutritional programme "Learning to eat from the Mediterranean". We studied clinical and therapeutic variables and various anthropometric parameters. RESULTS: All the studied indicators (number of catarrhal episodes CB, degree of intensity, emergency and hospital admissions) showed a positive and statistically significant evolution, evidenced from the first weeks of starting treatment, until the end of the year, after which 53.9% of patients had no CB, 25% had only one, and 16.4% had two episodes, compared to the 4.64 episodes on average in the previous year. Antibiotic use decreased by 87.4%, from 3.85+/-1.27 times/patient/year to 0.49+/-0.79 (p<0.001). Symptomatic treatment decreased by 56.7%, from 7.03+/-2.76 to 3.05+/-1.69 (p<0.001). The satisfaction of the families was very high. The Kidmed index, which assesses the quality of the Mediterranean Diet, increased from 7.8 to 10.9 points. CONCLUSION: The adoption of a Traditional Mediterranean Diet could be a major contribution to the improvement of patients with recurring colds and frequent inflammatory complications. PMID- 27939718 TI - Origins of glial cell populations in the insect nervous system. AB - Glia of vertebrates and invertebrates alike represents a diverse population of cells in the nervous system, divided into numerous classes with different structural and functional characteristics. In insects, glia fall within three basic classes: surface, cell body, and neuropil glia. Due to the glial subclass specific markers and genetic tools available in Drosophila, it is possible to establish the progenitor origin of these different populations and reconstruct their migration and differentiation during development. We review, and posit when appropriate, recently elucidated aspects of glial developmental dynamics. In particular, we focus on the relationships between mature glial subclasses of the larval nervous system (primary glia), born in the embryo, and glia of the adult (secondary glia), generated in the larva. PMID- 27939722 TI - The effects of linalool on the excitability of central neurons of snail Caucasotachea atrolabiata. AB - Linalool is a major constituent of the essential oil of several plant species and possesses several biological activities. In this work, we studied the effects of linalool on excitability of central neurons of land snail Caucasotachea atrolabiata and tried to elucidate the underlying mechanisms. The lower concentration of linalool (0.1mM) showed suppressive action on spontaneous activity and pentylenetetrazole-induced epileptiform activity. These effects were associated with elevation of the action potential threshold and reduction of action potential rising phase, supporting the inhibitory action of linalool on Na+ channels. At this concentration it also prolonged the post stimulus inhibitory period that can take part in its antiepileptic effect and apparently results from increased action potential duration and indirect augmentation of Ca2+-activated K+ currents. At higher concentration, however, linalool (0.4mM) increased the neuronal excitability and induced epileptiform activity. The modulatory effects on action potential waveform during preconvulsive period suggest that the recent effect is mainly dependent on the suppression of outward potassium currents underlying repolarization phase and afterhyperpolarization. The linalool-induced epileptiform activity was abolished by Ca2+ channel blockers, nifedipine and nickel chloride, and selective inhibitor of protein kinase C, chelerythrine, suggesting that Ca2+ inward currents and protein kinase C (PKC) activity are required for linalool-induced epileptiform activity. Our results support the antiepileptic activity of linalool at lower dose, but it shows epileptogenic activity when applied directly on snail neurons at higher dose. Linalool may also be a potential therapeutic agent for activating PKC. PMID- 27939721 TI - A bioenergetics assay for studying the effects of environmental stressors on mitochondrial function in vivo in zebrafish larvae. AB - Mitochondria, an integral component of cellular energy metabolism and other key functions, are extremely vulnerable to damage by environmental stressors. Although methods to measure mitochondrial function in vitro exist, sensitive, medium- to high-throughput assays that assess respiration within physiologically relevant whole organisms are needed to identify drugs and/or chemicals that disrupt mitochondrial function, particularly at sensitive early developmental stages. Consequently, we have developed and optimized an assay to measure mitochondrial bioenergetics in zebrafish larvae using the XFe24 Extracellular Flux Analyzer. To prevent larval movement from confounding oxygen consumption measurements, we relied on MS-222-based anesthetization. We obtained stable measurement values in the absence of effects on average oxygen consumption rate and subsequently optimized the use of pharmacological agents for metabolic partitioning. To confirm assay reproducibility we demonstrated that triclosan, a positive control, significantly decreased spare respiratory capacity. We then exposed zebrafish from 5 hours post-fertilization (hpf) to 6days post fertilization (dpf) to three polycyclic aromatic hydrocarbons (PAHs) - benzo(a)pyrene (BaP), phenanthrene (Phe), and fluoranthene (FL) - and measured various fundamental parameters of mitochondrial respiratory chain function, including maximal respiration, spare respiratory capacity, mitochondrial and non mitochondrial respiration. Exposure to all three PAHs decreased spare respiratory capacity and maximal respiration. Additionally, Phe exposure increased non mitochondrial respiration and FL exposure decreased mitochondrial respiration and increased non-mitochondrial respiration. Overall, this whole organism-based assay provides a platform for examining mitochondrial dysfunction in vivo at critical developmental stages. It has important implications in biomedical sciences, toxicology and ecophysiology, particularly to examine the effects of environmental chemicals and/or drugs on mitochondrial bioenergetics. PMID- 27939723 TI - Transcriptomic characterization of zebrafish larvae in response to mercury exposure. AB - Mercury is a widespread toxicant in aquatic environment that can cause deleterious effects on fish. Although a number of mercury-regulated genes have been investigated in adult fish, the transcriptional responses of fish larvae to acute mercury exposure are not well understood. In this study, RNA sequencing was used to examine the transcriptional changes in developing zebrafish larvae under a low concentration of mercuric chloride exposure from 24 to 120hpf. Our initial results showed that a total of 142.59 million raw reads were obtained from sequencing libraries and about 86% of the processed reads were mapped to the reference genome of zebrafish. Differential expression analysis identified 391 up and 87 down-regulated genes. Gene ontology enrichment analysis revealed that most of the differential expressed genes are closely related to the regulation of cellular process, metabolic process, multicellular organismal process, biological regulation, pigmentation, and response to stimulus. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis demonstrated that antigen processing and presentation was the most significantly enriched pathway. Moreover, we characterized a novel and sensitive mercury-induced ABCB (ATP- binding cassette B subfamily) transporter gene - abcb5. This gene is localized on zebrafish chromosome 16 and contains a 4014bp open-reading frame. The deduced polypeptide is composed of 1337 amino acids and possesses most of functional domains and critical residues defined in human and mouse ABCB5/Abcb5. Functional analysis in vitro demonstrated that overexpression of zebrafish abcb5 gene can significantly decrease the cytotoxicity of mercury in LLC-PK1 cells, implying it is a potential efflux transporter of mercury. Thus, these findings provide useful insights to help further understand the transcriptional response and detoxification ability of zebrafish larvae following acute exposure to mercury. PMID- 27939724 TI - WAFs lead molting retardation of naupliar stages with down-regulated expression profiles of chitin metabolic pathway and related genes in the copepod Tigriopus japonicus. AB - Oil pollution is considered being disastrous to marine organisms and ecosystems. As molting is critical in the developmental process of arthropods in general and copepods, in particular, the impact will be adverse if the target of spilled oil is on molting. Thus, we investigated the harmful effects of water accommodated fractions (WAFs) of crude oil with an emphasis on inhibition of chitin metabolic pathways related genes and developmental retardation in the copepod Tigriopus japonicus. Also, we analysed the ontology and domain of chitin metabolic pathway genes and mRNA expression patterns of developmental stage-specific genes. Further, the developmental retardation followed by transcriptional modulations in nuclear receptor genes (NR) and chitin metabolic pathway-related genes were observed in the WAFs-exposed T. japonicus. As a result, the developmental time was found significantly (P<0.05) delayed in response to 40% WAFs in comparison with that of control. Moreover, the NR gene, HR3 and chitinases (CHT9 and CHT10) were up-regulated in N4-5 stages, while chitin synthase genes (CHS-1, CHS-2-1, and CHS-2-2) down-regulated in response to WAFs. In brief, a high concentration of WAFs repressed nuclear receptor genes but elicited activation of some of the transcription factors at low concentration of WAFs, resulting in suppression of chitin synthesis. Thus, we suggest that WAF can lead molting retardation of naupliar stages in T. japonicus through down-regulations of chitin metabolism. These findings will provide a better understanding of the mode of action of chitin biosynthesis associated with molting mechanism in WAF-exposed T. japonicus. PMID- 27939726 TI - The use of visually guided behaviour in children with Developmental Coordination Disorder (DCD) when crossing a virtual road. AB - The ability to safely cross a road is a perceptual-motor skill that involves coordination between a pedestrian's perception of the approaching vehicles and their locomotive capability to execute the road crossing action. Developmental Coordination Disorder (DCD) is a chronic disorder that is characterised by significant motor difficulties that impact on daily living, including a reduced ability to perform visually guided actions. A total of 25 typically developing primary school aged children and 25 age- and gender-matched children with DCD were presented with a virtual desktop task that required them to select suitable temporal crossing gaps between vehicles a stream of traffic approaching at either 20mph, 30mph or 40mph from the near-side (one-lane) or both near+far-sides (two lane). A best-PEST staircase procedure was used to measure the temporal gaps that children accepted and the maximum likelihood value was taken after nine reversals as each participant's threshold. Typically developing children accepted temporal gaps that were sufficient to execute a safe crossing for vehicles approaching at 20mph and 30mph, but insufficient for vehicles approaching at 40mph. In contrast, children with DCD selected insufficient temporal crossing gaps across all approach speeds, which if translated to the roadside would have resulted in collision. These findings add to our understanding of the difficulties that children with DCD appear to have with visually guided behaviour and suggest the potential impact on one aspect of daily functioning that could have significant consequences. PMID- 27939725 TI - Response of oxidative stress transcripts in the brain of wild yellow perch (Perca flavescens) exposed to an environmental gradient of methylmercury. AB - Methylmercury (MeHg) exposure and adverse health effects in fishes have been documented, but the molecular mechanisms involved in toxicity have not been fully characterized. The objectives of the current study were to (1) determine whether total Hg (THg) in the muscle was predictive of MeHg concentrations in the brain of wild female yellow perch (Perca flavescens) collected from four lakes in Kejimkujik National Park, a known biological mercury (Hg) hotspot in Nova Scotia, Canada and (2) to determine whether transcripts involved in the oxidative stress response were altered in abundance in fish collected across five lakes representing a MeHg gradient. In female yellow perch, MeHg in whole brain (0.38 to 2.00MUg/g wet weight) was positively associated with THg in muscle (0.18 to 2.13MUg/g wet weight) (R2=0.61, p<0.01), suggesting that muscle THg may be useful for predicting MeHg concentrations in the brain. Catalase (cat) mRNA levels were significantly lower in brains of perch collected from lakes with high Hg when compared to those individuals from lakes with relatively lower Hg (p=0.02). Other transcripts (cytochrome c oxidase, glutathione peroxidase, glutathione-s transferase, heat shock protein 70, protein disulfide isomerase, and superoxide dismutase) did not show differential expression in the brain over the gradient. These findings suggest that MeHg may be inversely associated with catalase mRNA abundance in the central nervous system of wild fishes. PMID- 27939727 TI - Elevated expression of miR-24-3p is a potentially adverse prognostic factor in colorectal adenocarcinoma. AB - OBJECTIVES: Several miRNAs are aberrantly expressed in cancer. miR-24-3p is involved in cancer-related cellular processes, including cell cycle control, cell growth, proliferation, and apoptosis. In this study, we examined the potential diagnostic and prognostic significance of miR-24-3p expression in colorectal adenocarcinoma. DESIGN AND METHODS: Total RNA was isolated from 182 colorectal adenocarcinoma specimens and 86 paired non-cancerous colorectal mucosae. After polyadenylation of 2MUg total RNA and reverse transcription into first-strand cDNA using an oligo-dT-adapter primer, miR-24-3p expression was quantified using an in-house-developed reverse-transcription real-time quantitative PCR method, based on the SYBR Green chemistry. SNORD43 (RNU43) was used as a reference gene. RESULTS: miR-24-3p levels do not significantly differ between colorectal adenocarcinoma and non-cancerous colorectal mucosae. Thus, miR-24-3p expression cannot be used for diagnostic purposes. However, high miR-24-3p expression predicts poor disease-free survival (DFS) and overall survival (OS) of colorectal adenocarcinoma patients. Multivariate Cox regression analysis confirmed that miR 24-3p overexpression is a significant predictor of relapse in colorectal adenocarcinoma and that its prognostic significance is independent of other established prognostic factors and treatment of patients. Of note, miR-24-3p overexpression retains its rather unfavorable prognostic value in the subgroup of patients with advanced yet locally restricted colorectal adenocarcinoma (T3) and in those without distant metastasis (M0). Moreover, miR-24-3p overexpression is a potentially unfavorable prognosticator for patients who were not treated with radiotherapy. CONCLUSIONS: Strong expression of miR-24-3p predicts poor DFS and OS of colorectal adenocarcinoma patients, independently of clinicopathological parameters that are currently used for prognosis in this human malignancy. PMID- 27939728 TI - Comparative Analysis of Dentinal Erosion after Passive Ultrasonic Irrigation versus Irrigation with Reciprocating Activation: An Environmental Scanning Electron Study. AB - INTRODUCTION: The aim of this study was to assess ex vivo the erosive effects of passive ultrasonic irrigation versus irrigation with reciprocating activation on the dentinal surface of the root canal at 3 predetermined levels using environmental scanning electron microscopy. METHODS: Ten roots of mandibular premolars were prepared using the ProTaper Universal system (Dentsply Maillefer, Ballaigues, Switzerland). The specimens were embedded in flasks cleaved longitudinally, and indentations were made 3.0, 6.0, and 9.0 mm from the apex. The specimens in the control group (n = 10) were cleaned in an ultrasonic bath containing 2.5% sodium hypochlorite and 17% EDTA and then dried. Then, environmental scanning electron microscopic images were obtained at magnification * 800. The specimens were then reassembled in their flasks, and the NaOCl and EDTA solutions were activated according to the conditions established for the experimental groups (ie, the passive ultrasonic irrigation group [n = 5] and the EasyClean (Easy Equipamentos Odontologicos, Belo Horizonte, MG, Brazil) group, irrigation with reciprocating activation with the EasyClean instrument [n = 5]). The specimens of both experimental groups were analyzed in the same manner as in the control group. Analysis of the dentinal surface topography was conducted using the 3D Roughness Reconstruction program (Phenom-World BV, Eindhoven, the Netherlands) as a means for assessing erosion. The data were evaluated by means of the Kruskal-Wallis, Student-Newman-Keuls, and Mann-Whitney tests. RESULTS: In the EasyClean group, the degree of dentinal erosion at 3.0 mm was significantly higher than at 9.0 mm. In the other comparisons, there was no statistically significant difference (P < .05). CONCLUSIONS: The final irrigation techniques tested were equivalent in relation to the degree of erosion caused to the dentinal surface. PMID- 27939729 TI - Nonsteroidal Anti-inflammatory Drugs for Managing Postoperative Endodontic Pain in Patients Who Present with Preoperative Pain: A Systematic Review and Meta analysis. AB - INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been commonly used to treat endodontic postoperative pain. The purpose of this study was to address the following Population, Intervention, Comparator, Outcome, Timing, Study design and setting question: in patients with preoperative pain who undergo initial orthograde endodontic treatment, what is the comparative efficacy of NSAIDS compared with non-narcotic analgesics or placebo in reducing postoperative pain and the incidence of adverse events. METHODS: Ovid MEDLINE (1946-December 15, 2015), the Cochrane Database of Systematic Reviews (2005-December 15, 2015), and the Cochrane Central Register of Controlled Trials (to December 15, 2015) were searched using included drugs, indications, and study designs as search terms. Hand searches in texts were also conducted. Two independent reviewers assessed eligibility for inclusion, extracted data, and assessed quality using the risk of bias tool. L'Abbe plots were used for qualitative review. Where applicable, meta-analysis was conducted on the pooled effect size (ES). RESULTS: Two thousand two hundred eighty-four studies were identified through the database searches; 405 full-text articles were assessed. Fifteen articles met the inclusion criteria; qualitative analysis revealed all studies had a moderate to high risk of bias. Ibuprofen was the most studied NSAID. The L'Abbe plots showed that NSAIDS are effective at relieving postoperative endodontic pain overall. Meta-analysis showed that ibuprofen 600 mg is more effective than placebo at 6 hours postoperatively (ES = 10.50, P = .037), and ibuprofen 600 mg + acetaminophen 1000 mg combination is more effective than placebo (ES = 34.89, P = .000) but not significantly different than ibuprofen (ES = 13.94, P = .317). Five studies reported patients experiencing adverse events such as drowsiness, dizziness, nausea, and emesis; 2 studies reported that patients experienced no adverse events. CONCLUSIONS: A combination of ibuprofen 600 mg and acetaminophen 1000 mg is more effective than placebo but not significantly different than ibuprofen 600 mg at 6 hours postoperatively. Ibuprofen 600 mg is more effective than placebo at 6 hours postoperatively; however, there are insufficient data to recommend the most effective NSAID, dose amount, or dose interval for the relief of postoperative endodontic pain of longer duration in patients with preoperative pain. PMID- 27939730 TI - Viral MicroRNAs Identified in Human Dental Pulp. AB - INTRODUCTION: MicroRNAs (miRs) are a family of noncoding RNAs that regulate gene expression. They are ubiquitous among multicellular eukaryotes and are also encoded by some viruses. Upon infection, viral miRs (vmiRs) can potentially target gene expression in the host and alter the immune response. Although prior studies have reported viral infections in human pulp, the role of vmiRs in pulpal disease is yet to be explored. The purpose of this study was to examine the expression of vmiRs in normal and diseased pulps and to identify potential target genes. METHODS: Total RNA was extracted and quantified from normal and inflamed human pulps (N = 28). Expression profiles of vmiRs were then interrogated using miRNA microarrays (V3) and the miRNA Complete Labeling and Hyb Kit (Agilent Technologies, Santa Clara, CA). To identify vmiRs that were differentially expressed, we applied a permutation test. RESULTS: Of the 12 vmiRs detected in the pulp, 4 vmiRs (including those from herpesvirus and human cytomegalovirus) were differentially expressed in inflamed pulp compared with normal pulp (P < .05). Using bioinformatics, we identified potential target genes for the differentially expressed vmiRs. They included key mediators involved in the detection of microbial ligands, chemotaxis, proteolysis, cytokines, and signal transduction molecules. CONCLUSIONS: These data suggest that miRs may play a role in interspecies regulation of pulpal health and disease. Further research is needed to elucidate the mechanisms by which vmiRs can potentially modulate the host response in pulpal disease. PMID- 27939731 TI - Association of Unfinished Root Canal Treatments with the Risk of Pneumonia Hospitalization. AB - INTRODUCTION: The objective of root canal treatments (RCTs) is to control pulpal diseases and salvage infected teeth by eradicating microorganisms within the root canal system. However, an unfinished RCT can leave a space for bacterial accumulation, which can leak into the oral cavity and then aspirate into the lower respiratory tract and the lungs, causing infection. This study investigated the association of unfinished RCTs with the possible risk of pneumonia hospitalization using a nationwide population-based database. METHODS: After a matching process, we recruited 116,490 subjects who received an initiated RCT and had no history of pneumonia before 2005 and observed until the end of 2011. An unfinished RCT was operationally defined as an endodontic session that was started on a tooth but had no subsequent completion records. Cox proportional hazards models and subgroup analyses were used to estimate the association of unfinished RCTs on the risk of pneumonia hospitalization. RESULTS: In total, 1285 subjects were hospitalized for pneumonia during 2005 to 2011 with an overall pneumonia hospitalization incidence rate of 0.22% per person year. After adjusting for confounding factors, the adjusted pneumonia hospitalization hazard ratio for subjects who had unfinished RCTs was 1.40 (95% confidence interval, 1.24-1.59) compared with subjects without unfinished RCTs (P < .0001). For middle aged patients, the hazard ratio was 1.81 (95% confidence interval, 1.45-2.24). CONCLUSIONS: Patients with unfinished RCTs had a higher risk of pneumonia hospitalization. Thus, dentists are advised to complete endodontic treatments once started. PMID- 27939732 TI - Ion Release, Microstructural, and Biological Properties of iRoot BP Plus and ProRoot MTA Exposed to an Acidic Environment. AB - INTRODUCTION: This study evaluated how exposing the novel calcium silicate nanoparticulate bioceramic iRoot BP Plus (Innovative Bioceramix, Vancouver, Canada) to an acidic environment affects ion release from this material and alters MC3T3-E1 preosteoblast viability on and attachment to this material. These factors were compared against those of ProRoot MTA under similar conditions. METHODS: Each material was exposed to phosphate-buffered saline (pH = 7.4) or butyric acid (pH = 5.4) for 5 days. Trace metal elements within the 2 materials and released ions were identified using inductively coupled plasma optical emission spectroscopy. The microstructures and elemental compositions of MTA and iRoot BP Plus after treatment with butyric acid were determined using scanning electron microscopy with an energy-dispersive X-ray spectrometer. Furthermore, the viability of MC3T3-E1 cells on and their levels of attachment to the materials after the butyric acid treatment were compared. RESULTS: iRoot BP Plus contained fewer toxic metal elements than MTA. Under acidic conditions, both materials displayed similar ion release abilities, with increased release of Si and Ca ions. Substantial changes in microstructure, including reduced apatite formation, were observed for both materials after exposure to acidic pH. Furthermore, exposing iRoot BP Plus and MTA to an acidic environment increased and decreased MC3T3-E1 cell viability on these materials, respectively. MC3T3-E1 cell attachment to both materials was not significantly affected by acidic pH. CONCLUSIONS: iRoot BP Plus seems more biologically appropriate for application in an inflamed acidic environment than ProRoot MTA. PMID- 27939734 TI - External Cervical Resorption: A Comparison of the Diagnostic Efficacy Using 2 Different Cone-beam Computed Tomographic Units and Periapical Radiographs. AB - INTRODUCTION: The aim of this study was to compare the diagnostic efficacy of 2 cone-beam computed tomographic (CBCT) units with parallax periapical (PA) radiographs for the detection and classification of simulated external cervical resorption (ECR) lesions. METHODS: Simulated ECR lesions were created on 13 mandibular teeth from 3 human dry mandibles. PA and CBCT scans were taken using 2 different units, Kodak CS9300 (Carestream Health Inc, Rochester, NY) and Morita 3D Accuitomo 80 (J Morita, Kyoto, Japan), before and after the creation of the ECR lesions. The lesions were then classified according to Heithersay's classification and their position on the root surface. Sensitivity, specificity, positive predictive values, negative predictive values, and receiver operator characteristic curves as well as the reproducibility of each technique were determined for diagnostic accuracy. RESULTS: The area under the receiver operating characteristic value for diagnostic accuracy for PA radiography and Kodak and Morita CBCT scanners was 0.872, 0.99, and 0.994, respectively. The sensitivity and specificity for both CBCT scanners were significantly better than PA radiography (P < .001). There was no statistical difference between the sensitivity and specificity of the 2 scanners. The percentage of correct diagnoses according to the tooth type was 87.4% for the Kodak scanner, 88.3% for the Morita scanner, and 48.5% for PA radiography.The ECR lesions were correctly identified according to the tooth surface in 87.8% Kodak, 89.1% Morita and 49.4% PA cases. The ECR lesions were correctly classified according to Heithersay classification in 70.5% of Kodak, 69.2% of Morita, and 39.7% of PA cases. CONCLUSIONS: This study revealed that both CBCT scanners tested were equally accurate in diagnosing ECR and significantly better than PA radiography. CBCT scans were more likely to correctly categorize ECR according to the Heithersay classification compared with parallax PA radiographs. PMID- 27939733 TI - Mesoporous Calcium Silicate Nanoparticles with Drug Delivery and Odontogenesis Properties. AB - INTRODUCTION: Calcium silicate (CS) -based materials play an important role in the development of endodontic materials that induce bone/cementum tissue regeneration and inhibit bacterial viability. The aim of this study was to prepare novel mesoporous CS (MesoCS) nanoparticles that have osteogenic, drug delivery, and antibacterial characteristics for endodontic materials and also have an excellent ability to develop apatite mineralization. METHODS: The MesoCS nanoparticles were prepared using sol-gel methods. In addition, the mesoporous structure, specific surface area, pore volume, and morphology of the MesoCS nanoparticles were analyzed. The apatite mineralization ability, in vitro odontogenic differentiation, drug delivery, and antibacterial properties of the MesoCS nanoparticles were further investigated. RESULTS: The results indicate that the 200-nm-sized MesoCS nanoparticles synthesized using a facile template method exhibited a high specific surface area and pore volume with internal mesopores (average pore size = 3.05 nm). Furthermore, the MesoCS nanoparticles can be used as drug carriers to maintain sustained release of gentamicin and fibroblast growth factor-2 (FGF-2). The MesoCS-loaded FGF-2 might stimulate more odontogenic-related protein than CS because of the FGF-2 release. CONCLUSIONS: Based on this work, it can be inferred that MesoCS nanoparticles are potentially useful endodontic materials for biocompatible and osteogenic dental pulp tissue regenerative materials. PMID- 27939735 TI - Comparative Micro-computed Tomographic Evaluation of the Sealing Quality of ProRoot MTA and MTA Angelus Apical Plugs Placed with Various Techniques. AB - INTRODUCTION: This study compared the effects of different mixing and placement techniques on sealing of ProRoot MTA (Dentsply Maillefer, Ballaigues, Switzerland) and MTA Angelus (Solucoes Odontologicas, Londrina, Brazil) apical plugs using micro-computed tomographic (micro-CT) imaging. METHODS: Standardized divergent open apex models were created using 120 extracted maxillary incisors and divided into 8 groups (n = 15). ProRoot MTA and MTA Angelus were mixed manually or mechanically and introduced to form apical plugs by hand condensation or indirect ultrasonic activation for 10 seconds. The samples were scanned using micro-CT imaging, and volumetric analysis of the voids between the dentin walls and the apical plugs and the porosity inside MTA was performed. RESULTS: Irrespective of the mixing and placement techniques used, the voids between the dentin walls and the apical plugs in the MTA Angelus groups were greater than those in the ProRoot MTA groups (P < .05). The mechanically mixed groups were significantly less porous than the manually mixed groups (P < .05). Combined mechanical mixing and indirect ultrasonic activation yielded a less porous structure for both types of MTA than combined manual mixing and hand condensation (P < .05). Marginal adaptation for ProRoot MTA, both mixed and placed manually, was greater than for MTA Angelus (P < .05), but no difference was found when indirect ultrasonic activation was performed (P > .05). CONCLUSIONS: ProRoot MTA showed better marginal adaptation than MTA Angelus. Mechanically mixed products had better handling characteristics than the manually mixed product. Indirect ultrasonic activation did improve the adaptation of manually mixed MTA Angelus to the dentin walls. PMID- 27939736 TI - Efficacy of XP-endo Finisher File in Removing Calcium Hydroxide from Simulated Internal Resorption Cavity. AB - INTRODUCTION: The aim of this study was to evaluate the effect of supplementary use of XP-endo Finisher file, passive ultrasonic activation (PUI), EndoActivator (EA), and CanalBrush (CB) on the removal of calcium hydroxide (CH) paste from simulated internal resorption cavities. METHODS: The root canals of 110 extracted single-rooted teeth with straight canals were prepared up to size 50. The specimens were split longitudinally, and standardized internal resorption cavities were prepared with burs. The cavities and root canals were filled with CH paste. The specimens were divided into 5 groups as follows: XP-endo Finisher, EA, PUI, CB, and syringe irrigation (SI). The root canals were irrigated with 5.25% NaOCl and 17% EDTA for 2 minutes, respectively. Apart from the SI group, both solutions were activated by using tested techniques for 1 minute. The quantity of CH remnants on resorption cavities was scored. Data were analyzed by using Kruskal-Wallis H and Mann-Whitney U tests. RESULTS: XP-endo Finisher and PUI removed significantly more CH than SI, EA, and CB (P < .05), showing no significant difference between them (P > .05). Differences among SI, EA, and CB were also non-significant (P > .05). CONCLUSIONS: None of the tested techniques render the simulated internal resorption cavities free of CH debris. XP-endo Finisher and PUI were superior to SI, CB, and EA. PMID- 27939737 TI - Interaction between Octenidine-based Solution and Sodium Hypochlorite: A Mass Spectroscopy, Proton Nuclear Magnetic Resonance, and Scanning Electron Microscopy based Observational Study. AB - INTRODUCTION: Octenisept (OCT; Schulke & Mayr, Nordersdedt, Germany), an antimicrobial, antibiofilm agent and a promising root canal irrigant, can be potentially combined with sodium hypochlorite (NaOCl) during endodontic treatment. The aim of this study was first to identify the precipitate formed on the interaction between OCT and NaOCl and secondly to compare its effect on dentinal tubules with that of precipitate formed on combining chlorhexidine (CHX) and NaOCl. METHODS: This observational study was conducted in 3 stages. Initially, the color changes and precipitate formation were assessed when the test solution 0.1% OCT and 5.2% NaOCl were mixed. Color changes were compared with those observed when 2% CHX was mixed with 5.2% NaOCl. The residue obtained on combining OCT and NaOCl was subjected to proton nuclear magnetic resonance (1H NMR) and mass spectrometric (MS) analysis. In the final stage, dentinal surfaces irrigated alternatively with OCT and NaOCl were compared using scanning electron microscopy (SEM) with the dentinal surface irrigated with CHX and NaOCl. RESULTS: The OCT-NaOCl mixture changed in color from initial milky white to transparent over time, whereas the CHX-NaOCl mixture showed an immediate peach-brown discoloration. 1H NMR and MS analysis established that the whitish precipitate obtained on combining OCT and NaOCl solutions correlated with the structure of phenoxyethanol (PE). SEM revealed dense precipitate occluding the dentinal tubules with the CHX and NaOCl group, whereas the precipitate was sparse and partially occluded in the OCT and NaOCl group. CONCLUSIONS: The whitish precipitate formed with the OCT-NaOCl mixture was identified as PE, a compound already present in OCT, and it partly occluded the dentinal tubules. PMID- 27939738 TI - Effect of the Association of Nonsteroidal Anti-inflammatory and Antibiotic Drugs on Antibiofilm Activity and pH of Calcium Hydroxide Pastes. AB - INTRODUCTION: The objective of the present study was to evaluate the in vitro antibiofilm activity and pH of calcium hydroxide associated with different nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: The groups analyzed were as follows: group 1, calcium hydroxide paste with propylene glycol; group 2, calcium hydroxide paste with propylene glycol + 5% diclofenac sodium; group 3, calcium hydroxide paste with propylene glycol + 5% ibuprofen; group 4, calcium hydroxide paste with propylene glycol + 5% ciprofloxacin; and group 6, positive control (without medication). For analysis of the pH, the pastes were inserted into tubes and immersed in flasks containing ultrapure water. At the time intervals of 3, 24, 72, and 168 hours, the pH was measured with a calibrated pH meter. For microbial analysis, biofilm was induced in 30 bovine dentin blocks for 21 days. Subsequently, the pastes were placed on the blocks with biofilm for 7 days. Afterward, the pastes were removed by irrigation with sterile water, and the specimens were analyzed with a laser scanning confocal microscope with the 50 MUL Live/Dead BacLight Bacterial Viability solution L7012 Kit (Molecular Probes, Inc, Eugene, OR). Data were subjected to statistical analysis at a significance level of 5%. RESULTS: The highest pH values were found for calcium hydroxide associated with ciprofloxacin in all periods analyzed. With the exception of pure calcium hydroxide paste, the other groups showed statistically significant differences (P < .05) in comparison with the positive control. CONCLUSIONS: The association of NSAIDs or antibiotic did not interfere with the pH of calcium hydroxide paste and increased the antimicrobial action of calcium hydroxide paste against Enterococcus faecalis biofilm formation. PMID- 27939740 TI - Influence of Atopy in the Outcome of Avulsed and Replanted Teeth during 5 Years of Follow-up. AB - INTRODUCTION: The goal of replantation after dental avulsion is to maintain the tooth in its socket. Presence of vital periodontal ligament cells on the root surface of the replanted tooth and the immunologic status of the patient are factors that protect against root resorption. It is known that dental constituents play an active role in root resorption by inducing specific and non specific immune responses; however, little information exists regarding the influence of the acquired immune response on replantation. Therefore, the aim of this study was to evaluate the 5-year outcome of replantation in non-atopic and atopic patients. METHODS: Clinical and radiographic examinations were performed in 62 replanted teeth during a 5-year period. The evaluation of atopy was based on the patients' personal and family histories and skin prick test results. The chi2 and the Z tests were used to assess the association between atopy and the outcome of the replanted teeth (P < .05). RESULTS: There were significant differences between the 1-year and 5-year outcomes of the replanted teeth (P < .05) and atopic and non-atopic patients who had their teeth extracted because of inflammatory or replacement root resorption after 5 years (P < .05). CONCLUSIONS: Being atopic may offer the advantage of loss of fewer teeth because of replacement resorption, whereas being non-atopic may create an advantage of loss of fewer teeth because of inflammatory root resorption during the first 5 years after trauma. PMID- 27939739 TI - Characterization of a Vascular Endothelial Growth Factor-loaded Bioresorbable Delivery System for Pulp Regeneration. AB - INTRODUCTION: Vascular endothelial growth factor (VEGF) is a signal protein that stimulates angiogenesis and vasculogenesis and has been used in tissue regeneration and pulp regeneration experimental models. The purpose of this study was to develop a delivery system composed of a biodegradable fiber and controlled release of VEGF to promote cell viability and secure an adequate blood supply for the survival of human stem cells of the apical papilla (SCAP) favoring endodontic regenerative procedures. METHODS: We developed a polydioxanone fiber, 50 MUm in diameter, loaded with VEGF at a linear concentration of 12.2 ng/cm. Cytotoxic effects of the VEGF-loaded fiber (VF) on SCAP and mouse fibroblasts were assessed by using a multiparametric assay kit (XTT-NR-CVDE [Xenometrix, Allschwil, Switzerland]). We evaluated VF-induced mRNA expression of downstream growth factors by using a human growth factor Taqman array in real-time polymerase chain reaction. We also assessed the in vivo subcutaneous reaction of C57BL/6 mice to implants of VF alone and human root fragments (10 mm in length) filled with VF after 10, 20, and 45 days. Statistical analyses were performed by using analysis of variance and Student t tests or non-parametric alternatives. RESULTS: Enzyme linked immunosorbent assay verified detectable concentrations of released VEGF in solution for 25 days. No cytotoxicity was observed on SCAP and mouse fibroblasts treated with VEGF. In addition, VEGF treatment also induced the expression of additional growth factors with roles in tissue and blood vessel formation and neuroprotective function. Implantation of VF and root fragments filled with VF showed biocompatibility in vivo, promoting new blood vessels and connective tissue formation into the root canal space with negligible inflammation. CONCLUSIONS: Our results show that the VF used in this study is biocompatible and may be a promising scaffold for additional optimization and use in endodontic regenerative procedures. PMID- 27939741 TI - Proteomic Analysis Reveals GMP Synthetase as p53 Repression Target in Liver Cancer. AB - Disruption of the tumor-suppressive p53 network is a key event in human malignancies, including primary liver cancer. In response to different types of stress, p53 mediates several antiproliferative cellular outcomes, such as cell cycle arrest, apoptosis, and senescence, by activation or repression of its target genes. Metabolic alterations initiating or being part of the p53 response have become an actively studied research area in the p53 field, with several aspects that still remain to be elucidated. Herein, we identified GMP synthetase (GMPS), a key enzyme of de novo purine biosynthesis, as an important p53 repression target using a large-scale proteomics approach. This p53-mediated repression of GMPS could be validated by immunoblotting in Sk-Hep1, HepG2, and HuH6 cells. Moreover, we found GMPS transcriptionally repressed in a p21 dependent manner and its repression maintained in the context of p53-mediated cellular senescence. More important, direct knockdown of GMPS by RNA interference resulted in reduced cell viability and was sufficient to trigger cellular senescence. Finally, by comparing murine hepatocellular carcinomas, which developed in p53 wild-type (+/+) versus p53 null (-/-) mice, we observed higher GMPS expression in the latter, supporting the in vivo relevance of our findings. We conclude that repression of GMPS by p53 through p21 is a functionally relevant part of the p53-mediated senescence program limiting tumor cell growth in liver cancer. PMID- 27939742 TI - Long-Term Primary Patency Rate After Nitinol Self-Expandable Stents Implantation in Long, Totally Occluded Femoropopliteal (TASC II C & D) Lesions. AB - BACKGROUND: Endovascular therapy for long femoropopliteal lesions using percutaneous transluminal balloon angioplasty or first-generation of peripheral stents has been associated with unacceptable one-year restenosis rates. However, with recent advances in equipment and techniques, a better primary patency rate is expected. This study was conducted to detect the long-term primary patency rate of nitinol self-expandable stents implanted in long, totally occluded femoropopliteal lesions TransAtlantic Inter-Society Census (TASC II type C & D), and determine the predictors of reocclusion or restenosis in the stented segments. METHODS: The demographics, clinical, anatomical, and procedural data of 213 patients with 240 de novo totally occluded femoropopliteal (TASC II type C & D) lesions treated with nitinol self-expandable stents were retrospectively analysed. Of these limbs, 159 (66.2%) presented with intermittent claudication, while 81 (33.8%) presented with critical limb ischaemia. The mean-time of follow up was 36+/-22.6 months, (range: 6.3-106.2 months). Outcomes evaluated were, primary patency rate and predictors of reocclusion or restenosis in the stented segments. RESULTS: The mean age of the patients was 70.9+/-9.3 years, with male gender 66.2%. Mean pre-procedural ABI was 0.45+/-0.53. One-hundred-and-seventy five (73%) lesions were TASC II type C, while 65 (27%) were type D lesions. The mean length of the lesions was 17.9+/-11.3mm. Procedure related complications occurred in 10 (4.1%) limbs. There was no periprocedural mortality. Reocclusion and restenosis were detected during follow-up in 45 and 30 limbs respectively, and all were re-treated by endovascular approach. None of the patients required major amputation. Primary patency rates were 81.4+/-1.1%, 77.7+/-1.9% and 74.4+/ 2.8% at 12, 24, and 36 months respectively. Male gender, severe calcification, and TASC II D lesion were independent predictors for reocclusion, while predictors of restenosis were DM, smoking and TASC II D lesions. CONCLUSIONS: Treatment of long, totally occluded femoropopliteal (TASC II C & D) lesions with nitinol self-expandable stents is safe and is associated with highly acceptable long-term primary patency rates. PMID- 27939743 TI - Effects of Ethnicity on the Prevalence of Obstructive Sleep Apnoea in Patients with Acute Coronary Syndrome: A Pooled Analysis of the ISAACC Trial and Sleep and Stent Study. AB - BACKGROUND: Obstructive sleep apnoea (OSA) is an emerging risk factor for acute coronary syndrome (ACS). We sought to determine the effects of ethnicity on the prevalence of OSA in patients presenting with ACS who participated in an overnight sleep study. METHODS: A pooled analysis using patient-level data from the ISAACC Trial and Sleep and Stent Study was performed. Using the same portable diagnostic device, OSA was defined as an apnoea-hypopnoea index of >=15 events per hour. RESULTS: A total of 1961 patients were analysed, including Spanish (53.6%, n=1050), Chinese (25.5%, n=500), Indian (12.0%, n=235), Malay (6.1%, n=119), Brazilian (1.7%, n=34) and Burmese (1.2%, n=23) populations. Significant differences in body mass index (BMI) were found among the various ethnic groups, averaging from 25.3kg/m2 for Indians and 25.4kg/m2 for Chinese to 28.6kg/m2 for Spaniards. The prevalence of OSA was highest in the Spanish (63.1%), followed by the Chinese (50.2%), Malay (47.9%), Burmese (43.5%), Brazilian (41.2%), and Indian (36.1%) patients. The estimated odds ratio of BMI on OSA was highest in the Chinese population (1.17; 95% confidence interval: 1.10-1.24), but was not significant in the Spanish, Burmese or Brazilian populations. The area under the curve (AUC) for the Asian patients (ranging from 0.6365 to 0.6692) was higher than that for the Spanish patients (0.5161). CONCLUSION: There was significant ethnic variation in the prevalence of OSA in patients with ACS. The magnitude of the effect of BMI on OSA was greater in the Chinese population than in the Spanish patients. PMID- 27939744 TI - Which Mechanism is Effective on the Hyperamylasaemia After Coronary Artery Bypass Surgery? AB - BACKGROUND AND AIM: Acute pancreatitis is one of the less frequently diagnosed lethal abdominal complications of cardiac surgery. The incidence of early postoperative period hyperamylasaemia was reported to be 30-70% of patients who underwent coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). The mechanism of pancreatic enzyme elevation after cardiac surgery is not clear. Our aim was to determine the relationship between ischaemia associated temporary renal dysfunction and elevation of pancreatic enzymes after CABG. METHODS: Forty-one consecutive patients undergoing CABG under CPB were prospectively studied to determine serum total amylase, phospholipase A2, macroamylase, Cystatin C and urine NAG levels. RESULTS: Hyperamylasaemia was observed in 88% of the cases, with a distribution of 6% at the beginning of cardioplegic arrest, 5% at the 20th minute after cardioplegic arrest, 7% at the 40th minute after cardioplegic arrest, 14% when the heart was re-started, 26% at the 6th hour of intensive care and 30% at the 24th hour of intensive care. All of these patients had asymptomatic isolated hyperamylasaemia, and none of them presented with clinical pancreatitis. As indicators of renal damage; Cystatin C and NAG levels were higher compared to baseline values. CONCLUSION: Amylase began to rise during initial extracorporeal circulation and reached a maximum level postoperatively at 6 and 24hours. Decreased amylase excretion is the main reason for post CABG hyperamylasaemia. PMID- 27939745 TI - The Effect of Left Ventricular Assist Device Implantation on Serum Albumin, Total Protein and Body Mass: A Short-Term, Longitudinal Follow-Up Study. AB - BACKGROUND: Cardiac cachexia and low serum albumin levels are poor prognostic signs in advanced heart failure, while overweight patients or patients who gain weight after treatment have more favourable outcomes. Weight gain following LVAD implantation is common, while the dynamic changes in body mass or serum proteins have not been studied adequately. Our aim was to study short-term changes in serum albumin, total protein and body weight following LVAD implantation and to compare these changes with heart failure patients treated medically. MATERIALS AND METHODS: A total of 15 patients scheduled for LVAD implantation and 15 patients receiving medical treatment were prospectively enrolled. Anthropometric and laboratory data for the patients were obtained at baseline and at first and sixth months after LVAD implantation. RESULTS: Anthropometric, demographic and clinical characteristics between two groups were similar at baseline. Both serum albumin (3.59+/-0.71 vs. 4.17+/-0.46g/dl, p=0.01) and total protein (6.45+/-0.80 vs. 7.12+/-0.35g/dl, p<0.01) levels were significantly lower in LVAD group at baseline. Both total protein and serum albumin levels increased significantly in LVAD group (final total protein 7.60+/-0.62g/dl and serum albumin 4.20+/ 0.46g/dl; p<0.01 for both), while there was a nonsignificant small decrease in serum albumin in medical group. The change in serum albumin, but not total protein was significantly different between LVAD and medical groups at the sixth month. Body weight initially decreased in LVAD group at first month but was nonsignificantly higher compared to baseline and medical group at the sixth month. There was a moderate correlation between the percentage weight gain and percentage increase in serum albumin in LVAD group at six months (r=0.44). CONCLUSIONS: In suitable patients with advanced heart failure, LVAD treatment can correct hypoalbuminaemia associated with heart failure within six months after implantation. PMID- 27939746 TI - Non-Invasive Assessment of Pulmonary Vascular Resistance in Pulmonary Hypertension: Current Knowledge and Future Direction. AB - Pulmonary Hypertension (PHT) is relatively common, dangerous and under recognised. Pulmonary hypertension is not a diagnosis in itself; it is caused by a number of differing diseases each with different treatments and prognoses. Therefore, timely and accurate recognition of the underlying cause for PHT is essential for appropriate management. This is especially true for patients with Pulmonary Arterial Hypertension (PAH) in the current era of disease-specific drug therapy. Measurement of Pulmonary Vascular Resistance (PVR) helps separate pre capillary from post-capillary PHT, and is measured with right heart catheterisation (RHC). Echocardiography has been used to derive a number of non invasive surrogates for PVR, with varying accuracy. Ultimately, the goal of non invasive assessment of PVR is to separate PHT due to left heart disease from PHT due to increased PVR, to help streamline investigation and subsequent treatment. In this review, we summarise the physiology and pathophysiology of pulmonary blood flow, the various causes of pulmonary hypertension, and non-invasive surrogates for PVR. PMID- 27939748 TI - The length of a short sperm: Elongation and shortening during spermiogenesis in Cotesia congregata (Hymenoptera, Braconidae). AB - The spermatozoon of the parasitoid wasp Cotesia congregata is an extremely short gamete measuring less than 7 MUm; it is as yet the shortest flagellated sperm to be identified. The mature sperm consists of an acrosome, surrounded by an extra cellular coat, a condensed nucleus, two uncoiled mitochondrial derivatives and a short axoneme. Testes of young adults contain a continuum of differentiation stages. Initially, the flagellum is approximately 5 MUm long. It conserves its length in round, elongated and mature spermatids, but is reduced to less than 3 MUm in mature spermatozoa. The nucleus is 2 MUm in diameter when round, 10 MUm long when it becomes a long boat-hull shaped filament, and then reduces to 3.6 MUm. Thus, during development the gamete reaches a total length of 15 MUm before finally reducing to less than half that length. Some traits of mature sperm anatomy are similar to related species of the Braconidae family, but others seem to be specific and could be due to the shortness of the cell. This uncommon elongation and subsequent shortening of such a tiny flagellated cell constitutes a model for both nucleus and cilium development. PMID- 27939747 TI - Maximum pain on visual analog scales in spinal disorders. AB - BACKGROUND CONTEXT: Determining pain intensity is largely dependent on the patient's report. PURPOSE: The objective of this study was to test the hypothesis that patients initially reporting a pain score of 10 out of 10 on the visual analog scale (VAS) would experience symptom improvement to a degree similar to patients reporting milder pain. STUDY DESIGN: This study is a retrospective chart review. PATIENT SAMPLE: A total of 6,779 patients seeking care for spinal disorders were included in the study. OUTCOME MEASURES: The outcome measures used in the study were pain scores on the VAS pain scale, smoking status, morbid depression, gender, and the presence of known secondary gain. MATERIALS AND METHODS: Patients with lumbar degenerative disk disease with or without spinal stenosis who reported a VAS pain score of 10 out of 10 were identified. Changes in reported VAS pain, patient age, smoking status, morbid depression, gender, and the presence of known secondary gain were examined. RESULTS: A total of 160 individuals (2.9%) reported a maximum pain score of 10 out of 10 on a VAS at their initial presentation. The patients had a median improvement of 3 points in reported VAS pain between the first visit and the last follow-up appointment. The odds to improve by at least 40% on the VAS were 1.500 (95% confidence interval 1.090-2.065) compared with patients reporting submaximal pain. The proportion of patients with identifiable secondary gain was higher (p=.001) than that of patients with submaximal pain. Patients whose pain scores improved dramatically (ie, at least 4 points on the VAS) tended to be older (p=.001), to less often have secondary gain from their disease (p=.007), and to have a negative current smoking status (p=.002). Patients whose pain remained 10 out of 10 during the course of treatment smoked more frequently (p=.016). CONCLUSIONS: Our analysis supports the need to consider the influence of secondary gain on the patients' reported VAS pain scores. Maximum pain seems to be a more acute phenomenon with some likelihood to significantly improve. PMID- 27939750 TI - The GEP: Crowd-Sourcing Big Data Analysis with Undergraduates. AB - The era of 'big data' is also the era of abundant data, creating new opportunities for student-scientist research partnerships. By coordinating undergraduate efforts, the Genomics Education Partnership produces high-quality annotated data sets and analyses that could not be generated otherwise, leading to scientific publications while providing many students with research experience. PMID- 27939749 TI - Mining the Unknown: Assigning Function to Noncoding Single Nucleotide Polymorphisms. AB - One of the formative goals of genetics research is to understand how genetic variation leads to phenotypic differences and human disease. Genome-wide association studies (GWASs) bring us closer to this goal by linking variation with disease faster than ever before. Despite this, GWASs alone are unable to pinpoint disease-causing single nucleotide polymorphisms (SNPs). Noncoding SNPs, which represent the majority of GWAS SNPs, present a particular challenge. To address this challenge, an array of computational tools designed to prioritize and predict the function of noncoding GWAS SNPs have been developed. However, fewer than 40% of GWAS publications from 2015 utilized these tools. We discuss several leading methods for annotating noncoding variants and how they can be integrated into research pipelines in hopes that they will be broadly applied in future GWAS analyses. PMID- 27939751 TI - Estimating axonal strain and failure following white matter stretch using contactin-associated protein as a fiduciary marker. AB - Axonal injury occurs during trauma when tissue-scale loads are transferred to individual axons. Computational models are used to understand this transfer and predict the circumstances that cause injury. However, these findings are limited by a lack of validating experimental work examining the mechanics of axons in their in situ state. As a first step towards validation for dynamic stretch, we use contactin-associated protein (Caspr), expressed at the nodes of Ranvier, as a fiduciary marker of quasistatic axonal stretch. We measured changes in the distance between immunolabled Caspr pairs along axons as a function of tissue level stretch in chick embryo spinal cords harvested from different developmental periods. We then identified and characterized broken axons and adapted a kinematic model published previously by our group (Singh et al., 2015) to estimate average strain thresholds for axon mechanical failure. The distance between Caspr pairs increased with stretch, though not as much as predicted by simple continuum mechanics. For equivalent tissue stretch, greater numbers of broken axons were found at later stages of development. In adapting our kinematic model to predict a breaking threshold strain, we found that breaking thresholds decrease with development stage. When thresholds were split and classified based on kinematic behavior, non-affine, uncoupled axons had higher strain thresholds than affine, coupled axons, corroborating thresholds predicted from in vitro and in vivo preparations. These results provide a valuable launching point for generating more accurate multi-scale models in primary central nervous system injury. PMID- 27939752 TI - Influence of patellar position on the knee extensor mechanism in normal and crouched walking. AB - Patella alta is common in cerebral palsy, especially in patients with crouch gait. Correction of patella alta has been advocated in the treatment of crouch, however the appropriate degree of correction and the implications for knee extensor function remain unclear. Therefore, the goal of this study was to assess the impact of patellar position on quadriceps and patellar tendon forces during normal and crouch gait. To this end, a lower extremity musculoskeletal model with a novel 12 degree of freedom knee joint was used to simulate normal gait in a healthy child, as well as mild (23 deg min knee flexion in stance), moderate (41 deg), and severe (67 deg) crouch gait in three children with cerebral palsy. The simulations revealed that quadriceps and patellar tendon forces increase dramatically with crouch, and are modulated by patellar position. For example with a normal patellar tendon position, peak patellar tendon forces were 0.7 times body weight in normal walking, but reached 2.2, 3.2 and 5.4 times body weight in mild, moderate and severe crouch. Moderate patella alta acted to reduce quadriceps and patellar tendon loads in crouch gait, due to an enhancement of the patellar tendon moment arms with alta in a flexed knee. In contrast, patella baja reduced the patellar tendon moment arm in a flexed knee and thus induced an increase in the patellar tendon loads needed to walk in crouch. Functionally, these results suggest that patella baja could also compromise knee extensor function for other flexed knee activities such as chair rise and stair climbing. The findings are important to consider when using surgical approaches for correcting patella alta in children who exhibit crouch gait patterns. PMID- 27939753 TI - A head-to-head comparison between CT- and IVUS-derived coronary blood flow models. AB - The goal of this work is to compare coronary hemodynamics as predicted by computational blood flow models derived from two imaging modalities: coronary computed tomography angiography (CCTA) and intravascular ultrasound integrated with angiography (IVUS). Criteria to define boundary conditions are proposed to overcome the dissimilar anatomical definition delivered by both modalities. The strategy to define boundary conditions is novel in the present context, and naturally accounts for the flow redistribution induced by the resistance of coronary vessels. Hyperemic conditions are assumed to assess model predictions under stressed hemodynamic environments similar to those encountered in Fractional Flow Reserve (FFR) calculations. As results, it was found that CCTA models predict larger pressure drops, higher average blood velocity and smaller FFR. Concerning the flow rate at distal locations in the major vessels of interest, it was found that CCTA predicted smaller flow than IVUS, which is a consequence of a larger sensitivity of CCTA models to coronary steal phenomena. Comparisons to in-vivo measurements of FFR are shown. PMID- 27939754 TI - Increasing NO level regulates apoptosis and inflammation in macrophages after 2 chloroethyl ethyl sulphide challenge. AB - Generation of nitric oxide (NO) in cellular compartments acts in a redox dependent manner to counteract oxidative stress either by directly acting as an antioxidant through scavenging superoxide anions (O2-), to form peroxynitrite (ONOO-) or acting as a signaling molecule, altering gene expression that triggers various physiological processes. However, the molecular mechanisms of macrophage activation and NO production leads to apoptosis and inflammation after 2 chloroethyl ethyl sulphide (CEES) exposure remains unclear. We showed that CEES exposure in macrophages increased the O2- production. Also CEES exposure transiently increases the NO production and ONOO- accumulation via expression of inducible NO synthase (iNOS). Simultaneously, CEES exposure caused a significant reduction in cellular antioxidants and modulate lipid peroxidation (LPO), and protein carbonylation (PC) reactions, which was correlated with the increased level of NO and ONOO- accumulation. Mechanistic studies showed the DNA damage, 8 oxoGDNA glycosylase (OGG1) down regulation and 8-hydroxydeoxyguanosine (8-OHdG) accumulations in DNA, which was also confirmed by phosphorylation of ATM, ATR and H2A.X. Elevated levels of NO/ONOO- plays an important role in apoptosis, and alteration of cell cycle regulatory proteins in macrophages after CEES exposure. Moreover, CEES exposure to macrophage cells enhanced the transcriptional activities of inflammatory mediators such as TNFalpha, IL-1alpha, ICAM, CX3CL1, CCL8, and CXCL10, which were linked with NO/ONOO- accumulation. These results showed a mechanistic explanation of how NO/ONOO- cooperate to conduct apoptosis and inflammatory signals in macrophages after CEES challenged. Further, the protective effects of NO/ONOO- inhibitors may provide the basis for the development of a therapeutic strategy to counteract exposure to CEES. PMID- 27939755 TI - NF-Y in cancer: Impact on cell transformation of a gene essential for proliferation. AB - NF-Y is a ubiquitous heterotrimeric transcription factor with a binding affinity for the CCAAT consensus motif, one of the most common cis-acting element in the promoter and enhancer regions of eukaryote genes in direct (CCAAT) or reverse (ATTGG) orientation. NF-Y consists of three subunits, NF-YA, the regulatory subunit of the trimer, NF-YB, and NF-YC, all required for CCAAT binding. Growing evidence in cells and animal models support the notion that NF-Y, driving transcription of a plethora of cell cycle regulatory genes, is a key player in the regulation of proliferation. Proper control of cellular growth is critical for cancer prevention and uncontrolled proliferation is a hallmark of cancer cells. Indeed, during cell transformation aberrant molecular pathways disrupt mechanisms controlling proliferation and many growth regulatory genes are altered in tumors. Here, we review bioinformatics, molecular and functional evidence indicating the involvement of the cell cycle regulator NF-Y in cancer-associated pathways. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani. PMID- 27939756 TI - Plant NF-Y transcription factors: Key players in plant-microbe interactions, root development and adaptation to stress. AB - NF-Ys are heterotrimeric transcription factors composed by the NF-YA, NF-YB and NF-YC subunits. In plants, NF-Y subunits are encoded by multigene families whose members show structural and functional diversifications. An increasing number of NF-Y genes has been shown to play key roles during different stages of root nodule and arbuscular mycorrhizal symbiosis, as well as during the interaction of plants with pathogenic microorganisms. Individual members of the NF-YA and NF-YB families have also been implicated in the development of primary and lateral roots. In addition, different members of the NF-YA and NF-YB gene families from mono- and di-cotyledonous plants have been involved in plant responses to water and nutrient scarcity. This review presents the most relevant and striking results concerning these NF-Y subunits. A phylogenetic analysis of the functionally characterized NF-Y genes revealed that, across plant species, NF-Y proteins functioning in the same biological process tend to belong to common phylogenetic groups. Finally, we discuss the forthcoming challenges of plant NF-Y research, including the detailed dissection of expression patterns, the elucidation of functional specificities as well as the characterization of the potential NF-Y-mediated epigenetic mechanisms by which they control the expression of their target genes. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani. PMID- 27939757 TI - The CCAAT-binding complex (CBC) in Aspergillus species. AB - BACKGROUND: The CCAAT binding complex (CBC), consisting of a heterotrimeric core structure, is highly conserved in eukaryotes and constitutes an important general transcriptional regulator. Scope of the review. In this review we discuss the scientific history and the current state of knowledge of the multiple gene regulatory functions, protein motifs and structure of the CBC in fungi with a special focus on Aspergillus species. Major conclusions and general significance. Initially identified as a transcriptional activator of respiration in Saccharomyces cerevisiae, in other fungal species the CBC was found to be involved in highly diverse pathways, but a general rationale for its involvement was missing. Subsequently, the CBC was found to sense reactive oxygen species through oxidative modifications of cysteine residues in order to mediate redox regulation. Moreover, via interaction with the iron-sensing bZIP transcription factor HapX, the CBC was shown to mediate adaptation to both iron starvation and iron excess. Due to the control of various pathways in primary and secondary metabolism the CBC is of crucial importance for fungal virulence in both animal and plant hosts as well as antifungal resistance. Consequently, CBC-mediated control affects biological processes that are of high interest in biotechnology, agriculture and infection medicine. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani. PMID- 27939758 TI - Assessment of Hemodynamic Compromise Using Computed Tomography Perfusion in Combination with 123I-IMP Single-Photon Emission Computed Tomography without Acetazolamide Challenge Test. AB - OBJECTIVES: The acetazolamide challenge test in conjunction with 123I-IMP single photon emission computed tomography (SPECT) is a known method of assessing cerebrovascular reserve capacity. In this study, we investigated whether CT perfusion in combination with resting state 123I-IMP SPECT could be used instead of the acetazolamide challenge test to evaluate hemodynamic compromise in patients with atherosclerotic occlusive disease. METHODS: Twenty consecutive patients with unilateral internal carotid artery or middle cerebral artery steno occlusive disease were enrolled. 123I-IMP SPECT was performed with and without the acetazolamide challenge test, and with CT perfusion. Cerebral blood flow (CBF), cerebral blood volume, and mean transit time (MTT) obtained by CT perfusion were compared with CBF and cerebrovascular reactivity (CVR) obtained by 123I-IMP SPECT. RESULTS: The asymmetry ratio of MTT as measured by CT perfusion showed a strong correlation with the CVR to acetazolamide as measured by 123I-IMP SPECT (rho = -.780, P <.001). Based on the CBF obtained through 123I-IMP SPECT and the MTT obtained through CT perfusion, hemodynamic compromise was detected with high sensitivity (1.000) and specificity (.929), and a cutoff value of 30% was found to be suitable for the asymmetry ratio of MTT. MTT prolongation was significantly improved after revascularization surgery in hemodynamic compromise (P = .028). CONCLUSION: MTT as measured by CT perfusion in combination with CBF as measured by resting state 123I-IMP SPECT may be useful for evaluating hemodynamic compromise as an alternative to the acetazolamide challenge test. PMID- 27939759 TI - FHA domains: Phosphopeptide binding and beyond. AB - Forkhead-associated (FHA) domains are small phosphopeptide recognition modules found in eubacterial and eukaryotic, but not archeal, genomes. Although they were originally found in forkhead-type transcription factors, they have now been identified in many other signaling proteins. FHA domains share a remarkably conserved fold despite very low sequence conservation. They only have five conserved amino acids that are important for binding to phosphorylated epitopes. Recent work from several laboratories has demonstrated that FHA domains can mediate many interactions that do not depend on their ability to recognize a phosphorylated threonine. In this review, we present structural and biochemical work that has unveiled novel interaction interfaces on FHA domains. We discuss how these non-canonical interactions modulate the recognition of phosphorylated and non-phosphorylated substrates, as well as protein oligomerization - events that collectively determine FHA function. PMID- 27939761 TI - High relative deoxyribonucleic acid content of trophectoderm biopsy adversely affects pregnancy outcomes. AB - OBJECTIVE: To evaluate the association between relative DNA content of the trophectoderm biopsy and pregnancy outcomes. DESIGN: Retrospective cohort study. SETTING: Academic-affiliated private practice. PATIENT(S): This study included patients undergoing their first single embryo transfer after trophectoderm biopsy and comprehensive chromosome screening (CCS) at a single center between January 2010 and February 2014. INTERVENTION(S): In phase 1 of the study, a standard curve was developed to estimate the relative DNA content of trophectoderm biopsies. Phase 2 of the study examined reproductive outcomes in patients undergoing single embryo transfer after trophectoderm biopsy and CCS. Samples were divided into quartiles according to their relative DNA content, and clinical outcomes were compared. MAIN OUTCOME MEASURE(S): Chemical pregnancy rate, clinical implantation rate, ongoing pregnancy rate, live birth rate. RESULT(S): The quartile of highest relative DNA content had a significantly lower live birth rate when compared with the other three quartiles (relative risk 0.84, 95% confidence interval 0.75-0.95). There was no difference between the quartiles regarding age, body mass index, ovarian response, or endometrial thickness. Among those patients who had a live birth, there was no difference in hCG levels, gestational age at delivery, or birth weight with respect to biopsy DNA content. CONCLUSION(S): Trophectoderm biopsies with the highest relative DNA content are associated with lower live birth rates after single embryo transfer. Possible explanations for this phenomenon include diminished accuracy of the euploid diagnosis vs. a mechanical impact of the biopsy. Regardless of the cause, the outcomes emphasize the importance of obtaining appropriately sized trophectoderm biopsies for CCS. PMID- 27939760 TI - Rad4 recognition-at-a-distance: Physical basis of conformation-specific anomalous diffusion of DNA repair proteins. AB - Since Robert Brown's first observations of random walks by pollen particles suspended in solution, the concept of diffusion has been subject to countless theoretical and experimental studies in diverse fields from finance and social sciences, to physics and biology. Diffusive transport of macromolecules in cells is intimately linked to essential cellular functions including nutrient uptake, signal transduction, gene expression, as well as DNA replication and repair. Advancement in experimental techniques has allowed precise measurements of these diffusion processes. Mathematical and physical descriptions and computer simulations have been applied to model complicated biological systems in which anomalous diffusion, in addition to simple Brownian motion, was observed. The purpose of this review is to provide an overview of the major physical models of anomalous diffusion and corresponding experimental evidence on the target search problem faced by DNA-binding proteins, with an emphasis on DNA repair proteins and the role of anomalous diffusion in DNA target recognition. PMID- 27939763 TI - Advanced age does not affect abdominal wall reconstruction outcomes using acellular dermal matrix: A comparative study using propensity score analysis. AB - BACKGROUND: We hypothesized that elderly patients (>=65 years) experience worse outcomes following abdominal wall reconstruction (AWR) for hernia or oncologic resection. METHODS: We included all consecutive patients who underwent complex AWR using acellular dermal matrix (ADM) between 2005 and 2015. Propensity score analysis was performed for risk adjustment in multivariable analysis and for one to-one matching. The primary outcome was hernia recurrence; the secondary outcomes included surgical site occurrence (SSO) and bulging. RESULTS: Mean follow-up for the 511 patients was 31.4 months; 184 (36%) patients were elderly. The elderly and non-elderly groups had similar rates of hernia recurrence (7.6% vs 10.1%, respectively; p = 0.43) and SSO (24.5% vs 23.5%, respectively; p = 0.82). Bulging occurred significantly more often in elderly patients (6.5% vs 2.8%, respectively; p = 0.04). After adjustment through the propensity score, which included 130 pairs, these results persisted. CONCLUSIONS: Contrary to our hypothesis, elderly patients did not have worse outcomes in AWR with ADM. Surgeons should not deny elderly patients AWR solely because of their age. PMID- 27939762 TI - Estrogen stabilizes hypoxia-inducible factor 1alpha through G protein-coupled estrogen receptor 1 in eutopic endometrium of endometriosis. AB - OBJECTIVE: To investigate whether G protein-coupled estrogen receptor (GPER, also known as GPR30 and GPER1) stabilizes hypoxia-inducible factor 1alpha (HIF-1alpha) in eutopic endometrium (EuEM) of endometriosis. DESIGN: Immunohistochemical analysis and experimental in vitro study. SETTING: University hospital. PATIENT(S): Patients with or without endometriosis. INTERVENTION(S): The EuEM and normal control endometrium (CoEM) were obtained by curettage. Primary cultured endometrial stromal cells (ESCs) were treated with 17beta-E2, G1, or G15. MAIN OUTCOME MEASURE(S): The EuEM and CoEM were collected for immunohistochemistry. Western blot, polymerase chain reaction, ELISA, and dual luciferase experiments were used to detect expression of GPER, HIF-1alpha, vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP9) in ESCs. Estradiol and G1 were used as agonists of GPER, G15 as an antagonist. Migration of ESCs and endothelial tube formation of human umbilical vein endothelial cells cultured in medium collected from ESCs were measured. RESULT(S): Protein levels of GPER and HIF-1alpha were higher in EuEM than in CoEM. Protein levels of HIF-1alpha but not HIF-1alpha mRNA levels increased concurrently with GPER after E2 and G1 treatment. Furthermore, expression and activity of VEGF and MMP9 increased under E2 and G1 stimulation. However, these effects disappeared when GPER was blocked. CONCLUSION(S): G protein-coupled estrogen receptor stabilizes HIF-1alpha and thus promotes HIF-1alpha-induced VEGF and MMP9 in ESCs, which play critical roles in endometriosis. PMID- 27939765 TI - Parasitological and transcriptomic comparison of Strongyloides ratti infections in natural and in suboptimal permissive hosts. AB - The nematode genus Strongyloides consists of fairly species-specific small intestinal parasites of various vertebrates, among them the human pathogen S. stercoralis. Between the parthenogenetic parasitic generations these worms can also form single facultative sexual free-living generations. In addition to their primary hosts, several species can also live more or less well in other permissive hosts, which are sometimes not very closely related with the normal host. For example, S. stercoralis can also infect dogs and non-human primates. Here we compare the infection and reproductive success over time and the gene expression profiles as determined by quantitative sequencing of S. ratti parasitizing in its natural host rat and in the permissive host gerbil. We show that in gerbils fewer infective larvae successfully establish in the host, but those that do accomplish this survive and reproduce for longer and produced a higher proportion of males during the first two month of infection. Globally, the gene expression profiles in the two hosts are very similar. Among the relatively few differentially expressed genes, astacin-like and acetylcholinesterase genes are prominently represented. In the future it will be interesting to see if these changes in the suboptimal host are indeed ecologically sensible responses to the different host. PMID- 27939766 TI - Evolutionary developmental biology (evo-devo) of cestodes. AB - Cestodes (tapeworms) have complex adaptations to their obligatory parasitic life style. Among these adaptations, they show many evolutionary innovations in their development, including complex life-cycles with multiple hosts and life-stages, several independent origins of asexual reproduction, and the evolution of segmentation as a mean to generate massive reproductive output. Therefore, cestodes offer many opportunities for the investigation of the evolutionary origins of developmental novelties (evo-devo). However, cestodes have not been exploited as major models for evo-devo research due to the considerable technical difficulties involved in their study. In this review, a panoramic view is given of classical aspects, methods and hypothesis of cestode development, together with recent advances in phylogenetics, genomics, culture methods, and comparative analysis of cestode gene expression. Together with the availability of powerful models for related free-living flatworms, these developments should encourage the incorporation of these fascinating parasites into the first-line of evo-devo research. PMID- 27939764 TI - Elevated BMI and antibodies to citrullinated proteins interact to increase rheumatoid arthritis risk and shorten time to diagnosis: A nested case-control study of women in the Nurses' Health Studies. AB - OBJECTIVE: Overweight/obesity and anti-citrullinated protein antibodies (ACPA) increase rheumatoid arthritis (RA) risk. We investigated the relationship between body mass index (BMI) and ACPA, tested for an interaction between BMI and ACPA for RA risk, and examined effects of BMI and ACPA on time to RA diagnosis. DESIGN: Within the Nurses' Health Studies, blood samples were collected before diagnosis from medical record-confirmed incident RA cases and matched controls. Multiplex assays measured 7 ACPA subtypes (biglycan, clusterin, enolase, fibrinogen, histone 2A, histone 2B, and vimentin). Logistic regression analyses tested the association of BMI and ACPA and for a multiplicative interaction between BMI groups (>=25 vs. <25kg/m2) and ACPA positivity (>=2 vs. <2 subtypes), adjusting for age, smoking, alcohol use, and HLA-shared epitope. In case-only analyses, log-rank tests compared time from blood draw to RA onset by cross classified BMI/ACPA status. RESULTS: Among 255 pre-RA cases and 778 matched controls, 15.7% vs. 2.1% (p<0.001) had >=2 ACPA and 49.4% vs. 40.2% (p<0.01) were overweight/obese. Continuous BMI was not associated with presence of >=2 ACPA [OR per kg/m2 unit BMI: 1.03 (95% CI: 0.97-1.09)]. However, there was a multiplicative interaction between elevated BMI and the presence of >=2 ACPA for RA risk (p = 0.027). Women with BMI>=25kg/m2 and >=2 ACPA had OR 22.7 (95% CI: 6.64-77.72) for RA. Median time to RA differed by BMI/ACPA group (overall log rank p<0.001) and was shortest among women with >=2 ACPA and BMI>=25kg/m2 [45.0 months, IQR: 17.5-72.5] and longest in women with <2 ACPA and BMI<25kg/m2 [125.0 months, IQR: 72.0-161.0] (pairwise log-rank p = 0.002). CONCLUSION: Elevated BMI and presence of ACPA interacted to increase RA risk. Time to RA onset was shortest among overweight/obese women with >=2 ACPA. PMID- 27939767 TI - Molecular and biochemical characterisation and recognition by the immune host of the enolase of the abomasal nematode parasite Teladorsagia circumcincta. AB - A 1299 bp full length cDNA encoding Teladorsagia circumcincta enolase (TeciENO) was cloned, expressed in Escherichia coli and the recombinant protein purified and its kinetic properties determined. Helminth enolase sequences were used to construct a phylogenetic tree. The predicted protein consisted of 433 amino acids and was present as a single band of about 50 kDa on SDS-PAGE. Multiple alignments of the protein sequence of TeciENO with homologues from other helminths showed 98% similarity with Haemonchus contortus enolase, 78-95% similarity to other nematode sequences and 72-75% similarity to cestode and trematode enolases. Substrate binding sites and conserved regions were identified and were completely conserved in other homologues. The optimum pH for TeciENO activity at 25 degrees C was pH 7, the Km for 2-phophoglycerate 0.09 +/- 0.04 mM and the Vmax was 604 +/ 6 nmol min-1 mg-1 protein (both mean +/- SD, n = 2). TeciENO activity was inhibited by 11.5% by 1 mM citrate (p < 0.001). Antibodies in both serum and saliva from field-immune, but not nematode-naive, sheep recognised recombinant TeciENO in enzyme-linked immunosorbent assays. The recognition of the recombinant protein by antibodies generated by exposure of sheep to native enolase indicates similar antigenicity of the two proteins. PMID- 27939768 TI - Zika virus in Asia. AB - Zika virus (ZIKV) is an emerging mosquito-borne virus that was first isolated from a sentinel rhesus monkey in the Zika Forest in Uganda in 1947. In Asia, the virus was isolated in Malaysia from Aedes aegypti mosquitoes in 1966, and the first human infections were reported in 1977 in Central Java, Indonesia. In this review, all reported cases of ZIKV infection in Asia as of September 1, 2016 are summarized and some of the hypotheses that could currently explain the apparently low incidence of Zika cases in Asia are explored. PMID- 27939769 TI - CARD14-Mediated Activation of Paracaspase MALT1 in Keratinocytes: Implications for Psoriasis. AB - Mutations in caspase recruitment domain-containing protein 14(CARD14) have been linked to susceptibility to psoriasis. CARD14 is an intracellular scaffold protein that regulates proinflammatory gene expression. Recent studies have offered novel insights into the mechanisms of CARD14-mediated signaling in keratinocytes and the molecular impact of psoriasis-associated CARD14 mutations. CARD14 forms a signaling complex with BCL10 and the paracaspase MALT1, and this process is enhanced upon pathogenic CARD14 mutation, culminating in the activation of MALT1 protease activity and psoriasis-associated gene expression. This review summarizes the current knowledge of CARD14/MALT1-mediated signaling in keratinocytes and its therapeutic implications in psoriasis. PMID- 27939770 TI - Evolutionary developmental transition from median to paired morphology of vertebrate fins: Perspectives from twin-tail goldfish. AB - Vertebrate morphology has been evolutionarily modified by natural and/or artificial selection. The morphological variation of goldfish is a representative example. In particular, the twin-tail strain of ornamental goldfish shows highly diverged anal and caudal fin morphology: bifurcated anal and caudal fins. Recent molecular developmental genetics research revealed that a stop codon mutation in one of the two recently duplicated chordin genes is important for the highly diverged fin morphology of twin-tail goldfish. However, some issues still need to be discussed in the context of evolutionary developmental biology (evo-devo). For example, the bifurcated anal and caudal fins of twin-tail goldfish provided early researchers with insights into the origin of paired fins (pectoral and pelvic fins), but no subsequent researchers have discussed this topic. In addition, although the fossil jawless vertebrate species Euphanerops is also known to have had a bifurcated anal fin, how the bifurcated anal fin of twin-tail goldfish is related to that of fossil jawless vertebrate species has never been investigated. In this review, we present an overview of the early anatomical and embryological studies of twin-tail goldfish. Moreover, based on the similarity of embryonic features between the secondarily bifurcated competent stripe in twin-tail goldfish and the trunk bilateral competent stripes in conventional gnathostomes, we hypothesized that they share the same molecular developmental mechanisms. We also postulate that the bifurcated anal fin of Euphanerops might be caused by the same type of modification of dorsal-ventral patterning that occurs in the twin tail goldfish, unlike the previously suggested evolutionary process that required the co-option of paired fin developmental mechanisms. Understanding the molecular developmental genetics of twin-tail goldfish allows us to further investigate the evolutionary developmental mechanisms of the origin of paired fins. PMID- 27939771 TI - Speckle-Tracking Echocardiography and Advanced Interatrial Block. PMID- 27939772 TI - Price and cost: An unfriendly relationship in the institutions of the National Health Service. PMID- 27939773 TI - Shame and eating psychopathology in Portuguese women: Exploring the roles of self judgment and fears of receiving compassion. AB - Shame has been for long associated with the development and maintenance of body image and eating-related difficulties. However, the mechanisms underlying this association remain unclear. Therefore, the current study sought to examine the mechanisms of self-judgment and fears of receiving compassion from others in the association between external shame and disordered eating, while controlling for body mass index (BMI). Participants in this study were 400 women from the general population, aged between 18 and 55 years old. Correlation analyses revealed significant and positive relationships between external shame, self-judgment, fears of receiving compassion from others and eating psychopathology. A path analysis confirmed that, when controlling for the effect of BMI, external shame has a direct effect on disordered eating severity, and also an indirect effect, mediated by higher levels of self-judgment and increased fears of receiving others' kindness and compassion. Results showed the plausibility of the tested model which explained 36% of the variance of disordered eating. These findings seem to support that women who perceive that others view them negatively tend to be defensive and engage in maladaptive emotion regulation strategies (such as harsh critical attitudes towards the self and being resistant to others' compassion), which may trigger maladaptive eating attitudes and behaviours. The current research appears to be an innovative study in the field of body image and eating-related psychopathology and seems to represent a new avenue for future research and for the development of intervention programs. PMID- 27939774 TI - Exploring food reward and calorie intake in self-perceived food addicts. AB - Previous research indicates that many people perceive themselves to be addicted to food. These 'self-perceived food addicts' may demonstrate aberrant eating patterns which put them at greater risk of overeating. However this is yet to be empirically investigated. The current study investigated whether self-perceived food addicts would exhibit higher food reward and calorie intake in a laboratory context relative to self-perceived non-addicts. A secondary aim was to investigate whether self-perceived food addicts would demonstrate increased food liking and/or increased hunger ratings. Finally, we explored whether self perceived food addicts demonstrate patterns of aberrant eating, beyond that predicted by measures of trait dietary disinhibition and restraint. Female participants (self-perceived food addicts n = 31, non-addicts n = 29) completed measures of hunger, food reward (desire-to-eat, willingness-to-pay ratings, and an operant response task) and liking for high- and low-fat foods. Participants completed all measures when they were hungry, and again when they were satiated after consuming a fixed-lunch meal. Finally, participants were provided with ad libitum access to high-and low-fat foods. Results indicated that self-perceived food addicts consumed more calories from high-fat food compared to non-addicts, despite the absence of any between-group differences in hunger or overall liking ratings. Self-perceived food addicts also displayed higher desire-to-eat ratings across foods compared to non-addicts, but groups did not differ on other measures of food reward. However, the differences in calorie intake and desire-to-eat between self-perceived food addicts and non-addicts were no longer significant after controlling for dietary disinhibition and restraint. These findings suggest that self-perceived food addicts experience food as more rewarding and have a tendency to overeat. However, this may be attributable to increased dietary disinhibition and decreased restraint rather than reflecting a unique pattern of aberrant eating behaviour. PMID- 27939775 TI - Potential of an outranking multi-criteria approach to support the participatory assessment of land management actions. AB - We evaluated the potential of an outranking Multi-Criteria Decision Analysis approach for assisting in the participatory assessment of dryland management actions implemented in the San Simon watershed, in southeastern Arizona, USA. We compared an outranking-facilitated assessment of actions with a simple and direct (baseline) ranking of the same actions by the participating stakeholders in terms of: 1) internal homogeneity of each assessment approach, (2) similarity of individual assessments between methods, and (3) effects of the use of implicit/explicit assessment criteria. The actions assessed combined various management approaches, including livestock management (rotation, resting), vegetation management (grass seeding, brush control), and hydraulic structures (dams, dykes). The outranking-facilitated assessment discriminated better between actions and reduced the variability of results between individual stakeholders as compared with the direct ranking of actions. In general, the two assessments significantly differed in the relative preference of the five management actions assessed, yet both assessments identified rotational grazing combined with vegetation management (grass seeding and brush control) as the most preferred management action in the study area. The comparative analysis revealed inconsistencies between the use of implicit and explicit assessment criteria. Our findings highlight the opportunities offered by outranking approaches to help capture, structure, and make explicit stakeholder perspectives in the framework of a participatory environmental assessment process, which may facilitate the understanding of the multiple preferences involved. The outranking integration process, which resembles a voting procedure, proved simple and transparent, with potential for contributing to stakeholder engagement and trust in participatory assessment. PMID- 27939776 TI - Magnetic susceptibility as a simple tracer for fluvial sediment source ascription during storm events. AB - Sediment tracing using a single tracer, low frequency magnetic susceptibility (Xlf), was used to apportion suspended sediment to geologically defined source areas and to interpret sediment source changes during flood events in the degraded catchment of the Vuvu River, a headwater tributary of the Mzimbubu River, South Africa. The method was tested as a simple tool for use by catchment managers concerned with controlling erosion. The geology of the 58 km2 catchment comprises two distinct formations: basalt in the upper catchment with a characteristically high magnetic susceptibility and shales with a low magnetic susceptibility in the lower catchment. Application of an unmixing model incorporating a Monte Carlo uncertainty analysis showed that Xlf provided a means to assign the proportion of each geological province contributing to the river's sediment load. Grab water samples were collected at ten-minute intervals during flood events for subsequent analysis of suspended sediment concentration and the magnetic susceptibility of the filtered sediment. Two floods are presented in detail, the first represents a significant event at the start of the wet season (max. discharge 32 m3 s-1); the second was a smaller flood (max discharge 14 m3 s 1) that occurred a month later. Suspended sediment concentrations during the twelve monitored events showed a characteristic decline over the wet season. The main source of suspended sediment was shown to be from the mudstones in the lower catchment, which contributed 86% of the total measured load. The sediment dynamics during the two floods monitored in detail were quite different from each other. In the first the sediment concentration was high (11 g L-1), peaking after the flood peak. The Xlf value increased during the event, indicating that contribution to the sediment load from basalt in the upper catchment increased during the recession limb. In the second, smaller flood the sediment peak (6 g L 1) coincided with the flood peak. Low Xlf values indicated that mudstones in the lower catchment soils dominated the sediment load throughout the entire event. Sediment tracing using a single property (Xlf) was thus used effectively to study changing sediment sources both between and during a flood event in a catchment with strongly contrasting magnetic signatures in different areas. The results support the use of magnetic susceptibility as a simple and cheap tool to determine sediment provenance that can be used to guide catchment restoration in similar environments. PMID- 27939777 TI - BRAF mutations in sarcomatoid and large cell carcinoma of the lung. PMID- 27939778 TI - Pericytic mimicry (extravascular migratory metastasis) in neoplasia. PMID- 27939779 TI - Comparative immunomorphology of testicular Sertoli and sertoliform tumors. AB - Sertoli cell (SC) and sertoliform tumors of the testis are very uncommon; for this reason their differential diagnosis and classification can be challenging. We applied an extensive immunophenotypic panel that included androgenic hormones, enzymes and receptors, neuroendocrine, lineage and genitourinary markers to a series of these lesions to determine if and which immunostains can aid in their diagnostic workup. Study cases included: 2 androgen insensitivity syndrome associated SC adenomas, 3 SC tumors (SCT) not otherwise specified (SCT-NOS), 3 sclerosing SCT, 2 large cell calcifying SCT, 1 SCT with heterologous sarcomatous elements, 1 malignant SCT, and 1 sertoliform rete testis adenoma (sertoliform RTA). We found that SCT-NOS and variants with sclerosis showed a phenotype akin to atrophic seminiferous tubules characterized by gain of expression of pankeratin, calretinin, CD56, which are negative in normal SC. Distinctive phenotypes were identified in: sclerosing SCT: androgen receptors (AR) + (strong)/PAX2/PAX8+ (subset)/S100+/inhibin-; large cell calcifying SCT: calretinin+ (strong)/S100+/AR-; sertoliform RTA: PAX2/PAX8+/pankeratin+/inhibin-. Androgenic hormones and enzymes did not show diagnostic utility. A panel of calretinin, inhibin, pankeratin, S100, PAX2/PAX8, and AR consistently allowed distinction between variants of Sertoli and sertoliform tumors. PMID- 27939780 TI - BRAF mutations in sarcomatoid and large cell carcinoma of the lung-reply. PMID- 27939781 TI - Pericytic mimicry (extravascular migratory metastasis) in neoplasia-reply. PMID- 27939784 TI - What is the value of cover letters in scientific journals with high impact factors and how important should they be in Radiologia? PMID- 27939786 TI - Dynamic nonlinear focal shift in amplitude modulated moderately focused acoustic beams. AB - The phenomenon of the displacement of the position of the pressure, intensity and acoustic radiation force maxima along the axis of focused acoustic beams under increasing driving amplitudes (nonlinear focal shift) is studied for the case of a moderately focused beam excited with continuous and 25kHz amplitude modulated signals, both in water and tissue. We prove that in amplitude modulated beams the linear and nonlinear propagation effects coexist in a semi-period of modulation, giving place to a complex dynamic behavior, where the singular points of the beam (peak pressure, rarefaction, intensity and acoustic radiation force) locate at different points on axis as a function of time. These entire phenomena are explained in terms of harmonic generation and absorption during the propagation in a lossy nonlinear medium both for a continuous and an amplitude modulated beam. One of the possible applications of the acoustic radiation force displacement is the generation of shear waves at different locations by using a focused mono-element transducer excited by an amplitude modulated signal. PMID- 27939785 TI - Inhibition of collagen synthesis by IWR-1 in normal and keloid-derived skin fibroblasts. AB - AIMS: Keloid is a benign tumor that is characterized by the hyperproliferation of dermal fibroblasts and excessive deposition of extracellular matrix (ECM) especially the collagen. Aberrant activation of Wnt/beta-catenin signaling is implicated in the pathogenesis of keloid. In this study, we investigated the effects of IWR-1, a small molecule inhibitor for Wnt/beta-catenin signaling via the inhibition of tankyrase, on production of collagen and matrix metalloproteinase (MMP) in dermal fibroblasts. MAIN METHODS: We cultured human normal skin- and keloid-derived fibroblasts, then treated with IWR-1. The effects of IWR-1 on collagen and MMP production were determined by Western blot, ELISA and zymography. KEY FINDINGS: IWR-1 significantly suppressed the proliferation and migration of both the normal and keloid fibroblasts. IWR-1 also inhibited the production and secretion of type I collagen from the fibroblasts. In addition, IWR-1 significantly increased the expression of MMPs, such as MMP-1, MMP-3 and MMP-13, along with the increase of gelatinase activity. These results suggest that inhibitory effect of IWR-1 on collagen production may be related with the increased MMP activity. SIGNIFICANCE: This study provides the possible action mechanism of IWR-1 on regulation of collagen expression, on which to base further investigation for preventing skin fibrotic diseases such as keloid. PMID- 27939787 TI - A rheological model for immersed corrugated elastic plates. AB - The influence of surface imperfections on the propagation of guided waves in an immersed elastic plate can be interpreted by means of a rheological model. The corrugated surface is modeled by a very thin interface, similar to a Jones spring model, which replaces the continuity boundary conditions at the liquid - corrugated solid-plate interface. As the surrounding liquid is considered to be perfect, only one complex stiffness is used for the model of Jones. The selection of the plate guided mode and the test frequency are motivated by the detectability and non-interference with other modes. The spring stiffness is obtained by a best fit procedure, between the analytical solution and the results obtained by the finite elements method (FEM). One way ensuring the agreement of the two approaches, rheological and FEM, is to consider angular resonances provided by the transmission coefficients. Small changes in the parameters of the roughness keep the positions of the angular resonances of the plate practically unchanged, while at the same time large variations of the half width of the transmission coefficient curve is observed. The effect of corrugation parameters on the guided modes in the plate can be predicted by using the rheological model with the deduced spring complex stiffness. PMID- 27939783 TI - Structural Basis for Regulation and Specificity of Fructooligosaccharide Import in Streptococcus pneumoniae. AB - Streptococcus pneumoniae is dependent on carbohydrate uptake for colonization and pathogenesis, and dedicates over a third of its transport systems to their uptake. The ability of the pneumococcus to utilize fructooligosaccharides (FOSs) is attributed to the presence of one of two types of FOS ATP-binding cassette (ABC) transporters. Strains encoding SfuABC are only able to utilize short-chain FOSs, while strains encoding FusABC can utilize both short- and long-chain FOSs. The crystal structures of the substrate-binding protein FusA in its open and closed conformations bound to FOSs, and solution scattering data of SfuA, delineate the structural basis for import of short- and long-chain FOSs. The structure of FusA identifies an EF hand-like calcium-binding motif. This is shown to be essential for translocation of FOSs in FusABC and forms the basis for the definition of a new class of substrate-binding proteins that regulate substrate translocation by calcium. PMID- 27939788 TI - Combined phase screen aberration correction and minimum variance beamforming in medical ultrasound. AB - In recent years, applying adaptive beamforming to ultrasound imaging improves image quality in terms of resolution and contrast. One of the best adaptive beamformers in this field is the minimum variance (MV) beamformer which presents better resolution and edge definition compared to the traditional delay-and-sum (DAS) beamformer. However, in real situations, sound-velocity inhomogeneities cause phase aberration which leads to ambiguity in targets' location and degradation in resolution. This effect is a fundamental obstacle to utilize advantages of MV beamformer, although, in aberrating medium MV beamformer results in better performance compared to DAS. In this paper, two different levels of phase screens have been applied to simulate aberrator layers located close to the transducer. Also, prior to beamforming process, a conventional correction technique based on phase screen model is used. Simulations are performed in majority resolution of MV which has the lowest robustness. The results demonstrate that applying this correction method can retrieve the efficiency of the MV beamformer. Moreover, the method improves the performance of the MV in both terms of resolution and contrast. As corrected MV achieved at least 22% improvement in sidelobe reduction and 24% increase in contrast to noise ratio (CNR) with respect to the DAS corrected data. Also, according to experimental dataset 17% enhancement in CNR is yielded by MV. PMID- 27939782 TI - What makes you tic? Translational approaches to study the role of stress and contextual triggers in Tourette syndrome. AB - Tourette syndrome (TS) is a neurodevelopmental condition characterized by multiple, recurring motor and phonic tics. Rich empirical evidence shows that the severity of tics and associated manifestations is increased by several stressors and contextual triggers; however, the neurobiological mechanisms responsible for symptom exacerbation in TS remain poorly understood. This conceptual gap partially reflects the high phenotypic variability in tics, as well as the existing difficulties in operationalizing and standardizing stress and its effects in a clinical setting. Animal models of TS may be highly informative tools to overcome some of these limitations; these experimental preparations have already provided critical insights on key aspects of TS pathophysiology, and may prove useful to identify the neurochemical alterations induced by different stressful contingencies. In particular, emerging knowledge on the role of contextual triggers in animal models of TS may inform the development of novel pharmacological interventions to reduce tic fluctuations in this disorder. PMID- 27939789 TI - Feasibility study of ultrasonic elliptical vibration-assisted reaming of carbon fiber reinforced plastics/titanium alloy stacks. AB - The production of high quality bolt holes, especially on the carbon fiber reinforced plastics/titanium alloy (CFRP/Ti) stacks, is essential to the manufacturing process in order to facilitate part assembly and improve the component mechanical integrity in aerospace industry. Reaming is widely used as a mandatory operation for bolt holes to meet the strict industry requirements. In this paper, the ultrasonic elliptical vibration-assisted reaming (UEVR) which is considered as a new method for finish machining of CFRP/Ti stacked holes is studied. The paper outlines an analysis of tool performance and hole quality in UEVR compared with that in conventional reaming (CR). Experimental results show that the quality of holes was significantly improved in UEVR. This is substantiated by monitoring cutting force, hole geometric precision and surface finish. The average thrust forces and torque in UEVR were decreased over 30% and 60% respectively. It is found that, during first 45 holes, better diameter tolerance (IT7 vs. IT8), smaller diameter difference of CFRP and Ti holes (around 3MUm vs. 12MUm), better geometrical errors were achieved in UEVR as compared to CR. As for surface finish, both of the average roughness and hole surface topography in UEVR were obviously improved. PMID- 27939790 TI - Thallium bromide iodide crystal acoustic anisotropy examination. AB - Thallium bromide iodide crystal also known as KRS-5 is the well known material used in far infrared radiation applications for optical windows and lenses fabrication. The main advantage of this material is the transparency in wide band of wavelengths from 0.53 to 50MUm. Despite such advantages as transparency and large acousto-optic figure of merit values, KRS-5 is rarely used in acousto optics. Nevertheless this material seems to be promising for far infrared acousto optic applications. The acoustic and acousto-optic properties of KRS-5 needed for the full use in optoelectronics are not well understood to date. In this paper the detailed examination of thallium bromide iodide crystal acoustic properties is presented. PMID- 27939791 TI - Dynamic system model for ultrasonic lubrication in perpendicular configuration. AB - Ultrasonic lubrication can be achieved by superimposing ultrasonic vibrations onto the relative sliding velocity between two surfaces. Ultrasonic vibrations are typically generated by a piezoelectric actuator. Relative to the macroscopic velocity, the vibrations can be longitudinal, transverse, or perpendicular. Often considered as a purely interfacial effect, ultrasonic lubrication is in fact a system phenomenon incorporating the dynamics of the actuator, sliding surfaces, and surrounding structure. This article presents a dynamic system model for ultrasonic lubrication configured in perpendicular mode, as experimentally measured with a modified pin-on-disc tribometer. The framework includes a lumped parameter, dynamic model for the tribometer, an electromechanical model for the piezoelectric transducer used to generated the ultrasonic vibrations in the tribometer, and a "cube" model for the contact mechanics between asperities. Electrical impedance, system vibrations, and friction reduction are examined. Results show a strong match between experiments and simulations with errors lower than 10%. A parametric study is conducted to investigate the influence of driving voltage, macroscopic velocity, driving frequency, and signal waveform on ultrasonic friction reduction. PMID- 27939793 TI - Validating an image-based fNIRS approach with fMRI and a working memory task. AB - In the current study, we extend a previous methodological pipeline by adding a novel image reconstruction approach to move functional near-infrared (fNIRS) signals from channel-space on the surface of the head to voxel-space within the brain volume. We validate this methodology by comparing voxel-wise fNIRS results to functional magnetic resonance imaging (fMRI) results from a visual working memory (VWM) task using two approaches. In the first approach, significant voxel wise correlations were observed between fNIRS and fMRI measures for all experimental conditions across brain regions in the fronto-parieto-temporal cortices. In the second approach, we conducted separate multi-factorial ANOVAs on fNIRS and fMRI measures and then examined the correspondence between main and interaction effects within common regions of interest. Both fMRI and fNIRS showed similar trends in activation within the VWM network when the number of items held in working memory increases. These results validate the image-based fNIRS approach. PMID- 27939794 TI - Studying cyto and myeloarchitecture of the human cortex at ultra-high field with quantitative imaging: R1, R2* and magnetic susceptibility. AB - In this manuscript, the use of quantitative imaging at ultra-high field is evaluated as a mean to study cyto and myelo-architecture of the cortex. The quantitative contrasts used are the longitudinal relaxation rate (R1), apparent transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM). The quantitative contrasts were computed using high resolution in-vivo (0.65mm isotropic) brain data acquired at 7T. The performance of the different quantitative approaches was evaluated by visualizing the contrast between known highly myelinated primary sensory cortex regions and the neighbouring cortex. The transition from the inner layers to the outer layers (from white matter to the pial surface) of the human cortex, which is known to have varying cyto- and myelo architecture, was evaluated. The across cortex and through depth behaviour observed for the different quantitative maps was in good agreement between the different subjects, clearly allowing the differentiation between different Brodmann regions, suggesting these features could be used for individual cortical brain parcellation. While both R1 and R2* maps decrease monotonically from the white matter to the pial surface due to the decrease of myelin and iron between these regions, magnetic susceptibility maps have a more complex behaviour reflecting its opposing sensitivity to myelin and iron concentration. PMID- 27939792 TI - Brain metastasis: Unique challenges and open opportunities. AB - The metastasis of cancer to the central nervous system (CNS) remains a devastating clinical reality, carrying an estimated survival time of less than one year in spite of recent therapeutic breakthroughs for other disease contexts. Advances in brain metastasis research are hindered by a number of factors, including its complicated nature and the difficulty of modeling metastatic cancer growth in the unique brain microenvironment. In this review, we will discuss the clinical challenge, and compare the merits and limitations of the available models for brain metastasis research. Additionally, we will specifically address current knowledge on how brain metastases take advantage of the unique brain environment to benefit their own growth. Finally, we will explore the distinctive metabolic and chemical characteristics of the brain and how these paradoxically represent barriers to establishment of brain metastasis, but also provide ample supplies for metastatic cells' growth in the brain. We envision that multi disciplinary innovative approaches will open opportunities for the field to make breakthroughs in tackling unique challenges of brain metastasis. PMID- 27939795 TI - Traumatic Anterior Cerebral Artery Pseudoaneurysmal Epistaxis. AB - BACKGROUND: Pseudoaneurysmal epistaxis is a rare but emergent condition. We report a case of traumatic anterior cerebral artery pseudoaneurysmal epistaxis and review the published literature. CASE DESCRIPTION: A 49-year-old man sustained severe head trauma. He was diagnosed with multiple skull bone fractures, left subdural hematoma, subarachnoid hemorrhage, pneumocephalus, and right frontal hematoma. Subdural hematoma evacuation was done at a local hospital. In the following months, he experienced repeated epistaxis that required nasal packing to stop the bleeding. Digital subtraction angiography showed an anterior cerebral artery pseudoaneurysm protruding into the posterior ethmoid sinus. Embolization of the aneurysm was performed with microcoils, and the parent artery was occluded by thrombosis. The patient presented 1 month later with another epistaxis episode. Digital subtraction angiography showed recanalization of the parent artery and recurrence of the aneurysm. The parent artery was occluded for the second time with coils and Onyx embolic agent. CONCLUSIONS: Pseudoaneurysmal epistaxis is rare, and this is the first report of an anterior cerebral artery pseudoaneurysm that manifested with epistaxis. Endovascular intervention has become the first choice of treatment for this disease. The high recurrence rate is the main disadvantage of endovascular intervention. Aneurysm trapping with bypass surgery is another treatment option. PMID- 27939796 TI - Feasibility Analysis for Treatment of Giant Intracranial Benign Tumor by Delayed Operation in Infancy. AB - OBJECTIVE: The survival rate and prognosis in infants with giant intracranial tumors are significantly worse than in older children. This study aimed to analyze the feasibility of delayed operation for infants with giant intracranial benign tumor by evaluating the initial clinical presentations, expectant treatment measures, perioperative vital signs, and recuperation after surgery. PATIENTS AND DATA: We reviewed 3 infant patients (average age, 9.33 months; range, 5-12 months) with giant intracranial benign tumors during January 2015 and April 2016. The maximum sections of tumors were 38 * 50 mm, 57 * 39 mm, and 55 * 67 mm, respectively. All clinical presentations, neuroimaging, and laboratory examinations were recorded. RESULTS: Obstructive hydrocephalus was observed in 2 infants; ventriculoperitoneal shunts were placed in both before the delayed tumor resection. The disease progressed rapidly in the infant with teratoma and surgery was performed 4 months after placement of the ventriculoperitoneal shunt. The other 2 patients had experienced a 12-month growth and developmental phase and later underwent operations. Gross total resection was achieved in all patients. The pathologic results were consistent with the preoperative diagnosis. During a period of high-quality postoperative care, they remained stable and were discharged without any complications or neurologic deficits, and continued to improve toward their baseline. CONCLUSIONS: Delayed operation enabled infant patients to gain a better physical state, with a stage of full preoperative preparation that may reduce intraoperative/postoperative morbidity and mortality. PMID- 27939798 TI - Diplopia and Sjogren's disease: A rare case report. AB - Sjogren's syndrome is a chronic autoimmune disorder which affects the exocrine glands with lymphocytic infiltration, and occasionally involves central nervous system. It is usually rare and manifests as a lesion in the trigeminal nerve. Our case discusses the involvement of the oculomotor and abducens nerves along with the prevalence of such cases as seen on literature review. We describe a case of a middle aged woman who presented with ophthalmoplegic symptoms. The symptoms resolved in response to steroid therapy and serum analysis was positive for anti SSA antibodies. Increasing use of imaging modalities has enabled identifying cranial nerve enhancements easily. Correlating this to serum analysis, as in our case; has helped identify more cases of third and sixth cranial nerve involvement than was previously known to occur with primary Sjogren's syndrome. PMID- 27939797 TI - Spinal Diffusion Tensor Imaging in Evaluation of Preoperative and Postoperative Severity of Cervical Spondylotic Myelopathy: Systematic Review of Literature. AB - BACKGROUND: Diffusion tensor imaging (DTI) is increasingly investigated as a potential diagnostic and prognostic tool for symptomatic degenerative cervical pathology; however, it is yet to be validated for this purpose. OBJECTIVE: To investigate the association of preoperative DTI signal changes and postoperative outcomes in patients with cervical spondylotic myelopathy (CSM). METHODS: We performed a systematic literature review using PubMed for clinical studies using DTI in adults undergoing operative management for CSM. Data on preoperative clinical status, preoperative DTI metrics, and postoperative clinical outcomes were abstracted. Preoperative DTI parameters were correlated with preoperative severity and postoperative outcomes and pooled across studies. RESULTS: Nine studies met inclusion criteria for 238 patients who underwent operative management with mean follow-up time 310 days. Higher preoperative fractional anisotropy (FA) at the level of maximal compression correlates strongly with a higher preoperative modified Japanese Orthopaedic Association (mJOA) score (n = 192 patients, rho = 0.62, P < 0.001). Higher preoperative FA is associated with less postoperative mJOA change (n = 27, rho = -0.42, P = 0.02) but a greater recovery rate (n = 93, rho = 0.32, P < 0.001). Preoperative FA correlated with lower Neck Disability Index (n = 15, rho = -0.61, P = 0.04). Preoperative fiber tract ratio had a large positive correlation with a postoperative recovery rate (n = 20, rho = 0.61, P = 0.005). When reported, an apparent diffusion coefficient showed an inverse correlation compared with FA. CONCLUSION: DTI is associated with preoperative severity and postoperative outcomes in CSM patients, suggesting that DTI may become useful in identifying those most likely to benefit from operative intervention (Level 3 Evidence). Prospective trials with standardized DTI acquisition techniques and patient selection are required for higher-level evidence. PMID- 27939799 TI - The consequence of regional gradients of P-gp and CYP3A4 for drug-drug interactions by P-gp inhibitors and the P-gp/CYP3A4 interplay in the human intestine ex vivo. AB - Intestinal P-gp and CYP3A4 work coordinately to reduce the intracellular concentration of drugs, and drug-drug interactions (DDIs) based on this interplay are of clinical importance and require pre-clinical investigation. Using precision-cut intestinal slices (PCIS) of human jejunum, ileum and colon, we investigated the P-gp/CYP3A4 interplay and related DDIs with P-gp inhibitors at the different regions of the human intestine with quinidine (Qi), dual substrate of P-gp and CYP3A4, as probe. All the P-gp inhibitors increased the intracellular concentrations of Qi by 2.1-2.6 fold in jejunum, 2.6-3.8 fold in ileum but only 1.2-1.3 fold in colon, in line with the different P-gp expression in these intestinal regions. The selective P-gp inhibitors (CP100356 and PSC833) enhanced 3-hydroxy-quinidine (3OH-Qi) in jejunum and ileum, while dual inhibitors of P-gp and CYP3A4 (verapamil and ketoconazole) decreased the 3OH-Qi production, despite of the increased intracellular Qi concentration, due to inhibition of CYP3A4. The outcome of DDIs based on P-gp/CYP3A4 interplay, shown as remarkable changes in the intracellular concentration of both the parent drug and the metabolite, varied among the intestinal regions, probably due to the different expression of P-gp and CYP3A4, and were different from those found in rat PCIS, which may have important implications for the disposition and toxicity of drugs and their metabolites. PMID- 27939800 TI - Changes in blood pressure and heart rate during sedation with ketamine in the pediatric ED. AB - BACKGROUND: Ketamine is commonly used in the emergency department for short, painful procedures. We describe changes in blood pressure (BP) and heart rate (HR) during procedural sedation with ketamine, as these changes have not been well described in children. METHODS: We performed a secondary analysis of a prospective, observational study involving children aged 8 to 18 years who received procedural sedation with ketamine in a pediatric emergency department. Serial vital signs and sedation scores were recorded from baseline until recovery from ketamine procedural sedation. Time of orthopedic manipulation was also recorded. Linear mixed-effect models were used to evaluate changes in systolic BP (SBP), diastolic BP (DBP), and HR using 3 sedation strata: presedation (baseline), sedated (ketamine administered and patient deeply sedated), and recovery (ketamine administered with patient minimally sedated), controlling for age and weight. RESULTS: Sixty children were enrolled; 10 were excluded due to missing manipulation time. A total of 394 observations were recorded. Mean sedated SBP, DBP, and HR were 8 mm Hg, 4 mm Hg, and 13 beats/min higher than presedation SBP (P<.001), DBP (P<.01), and HR (P<.001), respectively. Mean sedated SBP and DBP were 3 and 4 mm Hg higher than SBP (P=.006) and DBP (P<.01) during recovery. Manipulation increased mean SBP by 5 mm Hg (P<.001), mean DBP by 7 mm Hg (P<.001), and mean HR by 1 beat/min (P=.35). CONCLUSIONS: Ketamine administered during procedural sedation for painful procedures causes a statistically significant but modest increase in SBP, DBP, and HR. Orthopedic manipulation further increases BP. PMID- 27939801 TI - First cases of calcium pyrophosphate deposition disease after zoledronic acid therapy. AB - A number of medications promote the development of calcium pyrophosphate deposition disease (CPDD). We report 2 cases of acute CPDD after intravenous zoledronic acid therapy. Case #1: a 63-year-old female was admitted for vertebroplasty at the site of an osteoporotic fracture. She received an intravenous infusion of zoledronic acid 5mg on the day after the procedure. Acute CPDD developed in her right knee 24hours later. Findings from joint aspiration and standard radiography confirmed the diagnosis. Case #2: this 79-year-old woman had a history of CPDD was on glucocorticoid and hydroxychloroquine therapy for lupus. She was given an intravenous infusion of zoledronic acid 5mg as prophylaxis of glucocorticoid-induced osteoporosis. Joint pain and a fever developed later on the same day. After 5 days, she had arthritis of the right wrist, laboratory evidence of systemic inflammation, and hypocalcemia. Radiographs showed evidence of CPDD. A Medline search identified 6 cases of bisphosphonate-related CPDD, including 2 due to pamidronate, 2 to etidronate, 1 to alendronic acid, and 1 to neridronic acid. The features were similar to those in our patients, with a short time to onset, systemic inflammation in many cases, a tendency toward hypocalcemia, and radiographs that often showed evidence of CPDD. Bisphosphonate-induced CPDD is a rare eventuality that should nevertheless be borne in mind by rheumatologists. Also, in patients with CPDD while taking bisphosphonate therapy, a role for the drug in the symptoms should be considered. PMID- 27939803 TI - History of trachoma. PMID- 27939802 TI - Improving ultrasound for appendicitis through standardized reporting of secondary signs. AB - OBJECTIVE: Our aim was to implement a standardized US report that included secondary signs of appendicitis (SS) to facilitate accurate diagnosis of appendicitis and decrease the use of computed tomography (CT) and admissions for observation. METHODS: A multidisciplinary team implemented a quality improvement (QI) intervention in the form of a standardized US report and provided stakeholders with monthly feedback. Outcomes including report compliance, CT use, and observation admissions were compared pretemplate and posttemplate. RESULTS: We identified 387 patients in the pretemplate period and 483 patients in the posttemplate period. In the posttemplate period, the reporting of SS increased from 5.4% to 79.5% (p<0.001). Despite lower rates of appendix visualization (43.9% to 32.7%, p<0.001) with US, overall CT use (8.5% vs 7.0%, p=0.41) and the negative appendectomy rate remained stable (1.0% vs 1.0%, p=1.0). CT utilization for patients with an equivocal ultrasound and SS present decreased (36.4% vs 8.9%, p=0.002) and admissions for observations decreased (21.5% vs 15.3%, p=0.02). Test characteristics of RLQ US for appendicitis also improved in the posttemplate period. CONCLUSION: A focused QI initiative led to high compliance rates of utilizing the standardized US report and resulted in lower CT use and fewer admissions for observation. Study of a Diagnostic Test Level of Evidence: 1. PMID- 27939805 TI - Medical ethics and ophthalmology. PMID- 27939804 TI - An ophthalmologist Nobel Prize Winner. PMID- 27939806 TI - Implantable collamer lens for correction of ametropia in eyes with corneal scarring. AB - CASES: Two cases are reported in which implantation of a collagen copolymer phakic intraocular lens (implantable collamer lens) corrected refractive errors in eyes with corneal scarring. A previous accident, in both cases, resulted in a central linear scar on the surface of the cornea of one eye. In the first patient, a corneal scar was visible in the left eye. The distance corrected visual acuity was 0.3 (-7.75 -4*160 degrees ). An uncorrected distance visual acuity of 0.25 was obtained by implanting an implantable collamer lens. In the second patient an oblique corneal scar was visible in the right eye. The distance corrected visual acuity was 0.25 (-8.75 -1.25*8 degrees ), and after implantation of the implantable collamer lens, uncorrected distance visual acuity was 0.25. DISCUSSION: The indications of the implantable collamer lens should be reviewed and possibly expanded. PMID- 27939808 TI - First report of NDM-1-producing Klebsiella pneumoniae imported from Africa to Italy: Evidence of the need for continuous surveillance. AB - OBJECTIVES: NDM-producing Enterobacteriaceae are considered emergent on the African continent and have been increasingly reported in recent years. In contrast, strains producing NDM-type enzymes have been rarely reported in Italy, usually associated with sporadic cases or small outbreaks. Here we report two cases of infection caused by NDM-1-producing Klebsiella pneumoniae (NDM-KP) in two unrelated patients returned from travel to Egypt. CASE REPORTS: The two patients had been previously hospitalised for a short period in two different Egyptian hospitals. In our institution in Italy, NDM-KP isolates were detected from surgical wound drainage (patient #1) and respiratory secretions and blood cultures (patient #2). Rectal swabs of both patients were persistently positive for NDM-KP. In both cases, NDM-1-producing isolates exhibited a multidrug resistant phenotype, being susceptible only to tigecycline and colistin. Analysis by multilocus sequence typing (MLST) revealed that the two K. pneumoniae isolates were not clonally related, belonging to different sequence types (STs), namely ST15 from patient #1 and ST11 from patient #2. CONCLUSIONS: To the best of our knowledge, this is the first report of NDM-producing isolates imported from Africa to Italy, with no obvious link to the Indian subcontinent. Our experience confirms that Egypt is an emergent source of NDM-producing Enterobacteriaceae, thus representing a cause of concern for Mediterranean countries. Owing to its geographical position, Italy is a first-line European checkpoint with respect to African countries and plays a pivotal role in limiting the dissemination of high risk clones, especially considering the latest strong migration flows. PMID- 27939809 TI - Prevalence of macrolide-lincosamide resistance and multidrug resistance phenotypes in streptococcal isolates causing infections in European hospitals: Evaluation of the in vitro activity of oritavancin and comparator agents. AB - The aim of this study was to evaluate the prevalence of resistance to erythromycin alone (M) and to erythromycin and clindamycin (cMLSB) as well as multidrug resistance (MDR) phenotypes (resistance to at least three classes of drugs) among clinical enterococci from European countries and adjacent geographic regions. The in vitro activity of oritavancin against these isolates was also evaluated. A total of 2569 streptococci collected from 12 European countries as well as Russia, Turkey and Israel were included. A total of 9.8%, 8.1% and 6.4% of beta-haemolytic streptococci (BHS) displayed M, cMLSB and MDR phenotypes, respectively. Oritavancin (99.4-100.0% susceptible) demonstrated modal minimum inhibitory concentration (MIC) (0.03mg/L) and MIC50 (0.03mg/L) values that were the same for all BHS or subsets, including MDR. The oritavancin MIC50 value of 0.06mg/L against Streptococcus dysgalactiae was similar to those of daptomycin and penicillin (MIC50<=0.06mg/L for both). Among viridans group streptococci (VGS), 28.3%, 12.7% and 11.6% showed M, cMLSB and MDR phenotypes, respectively. Oritavancin (99.9-100.0% susceptible; MIC50/90, <=0.008/0.06mg/L) exhibited potent in vitro activity against VGS and resistant subsets, as did vancomycin (MIC50/90, 0.5/0.5-1mg/L), daptomycin (MIC50/90, 0.25-0.5/0.5-1mg/L) and linezolid (MIC50/90, 0.5-1/1mg/L). In conclusion, rates of resistance phenotypes were higher in VGS than BHS. Oritavancin demonstrated in vitro potencies that were similar to or greater than those of comparators against this recent collection of streptococci, including drug-resistant subsets, from European and adjacent countries. PMID- 27939807 TI - Whipple-specific complications result in prolonged length of stay not accounted for in ACS-NSQIP Surgical Risk Calculator. AB - BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Surgical Risk Calculator was developed to help counsel patients regarding estimated postoperative risk for a variety of surgical complications. This retrospective single institutional study examined the calculator's ability to accurately predict complications and length of hospital stay (LOS) in patients who had undergone a Pancreaticoduodenectomy (PD) at our institution. METHODS: 165 patients at Washington University School of Medicine who underwent a PD from 8/2011 to 7/2013 were included. Surgical complication risk as determined by the ACS-NSQIP Surgical Risk Calculator were compared to actual 30 day complications. PD complications not accounted for by the calculator were compared to those without PD-specific complications. RESULTS: Overall predicted LOS was significantly shorter than actual duration of hospitalization (median 8.5 vs. 8.0 days; p < 0.001). 38% patients (n = 62) with Whipple-specific complication demonstrated a significant increase in LOS (8.0 vs. 12.2 days; p < 0.0001). DISCUSSION: A large proportion of complications experienced after PD are pancreas-specific, accounting for the difference in predicted vs. actual LOS and providing rationale for future development of PD specific risk models. PMID- 27939810 TI - The acute social defeat stress and nest-building test paradigm: A potential new method to screen drugs for depressive-like symptoms. AB - Psychosocial stress can cause mental conditions such as depression in humans. To develop drug therapies for the treatment of depression, it is necessary to use animal models of depression to screen drug candidates that exhibit anti depressive effects. Unfortunately, the present methods of drug screening for antidepressants, the forced-swim test and tail-suspension test, are limiting factors in drug discovery because they are not based on the constructive validity of objective phenotypes in depression. Previously, we discovered that the onset of nest building is severely delayed in mice exposed to subchronic mild social defeat stress (sCSDS). Therefore, a novel paradigm combining acute social defeat stress (ASDS) and the nest-building test (SNB) were established for the efficient screening of drugs for depressive-like symptoms. Since ASDS severely delayed the nest-building process as shown in chronically social defeated mice, we sought to rescue the delayed nest-building behavior in ASDS mice. Injecting a specific serotonin 2a receptor antagonist (SR-46349B), the nest-building deficit exhibited by ASDS mice was partially rescued. On the other hand, a selective serotonin reuptake inhibitor (fluoxetine) did not rescue the nest-building deficit in ASDS mice. Therefore, we conclude that the SNB paradigm is an another potential behavioral method for screening drugs for depressive-like symptoms including attention deficit, anxiety, low locomotion, and decreased motivation. PMID- 27939811 TI - Integrating knowledge exchange and the assessment of dryland management alternatives - A learning-centered participatory approach. AB - The adoption of sustainable land management strategies and practices that respond to current climate and human pressures requires both assessment tools that can lead to better informed decision-making and effective knowledge-exchange mechanisms that facilitate new learning and behavior change. We propose a learning-centered participatory approach that links land management assessment and knowledge exchange and integrates science-based data and stakeholder perspectives on both biophysical and socio-economic attributes. We outline a structured procedure for a transparent assessment of land management alternatives, tailored to dryland management, that is based on (1) principles of constructivism and social learning, (2) the participation of stakeholders throughout the whole assessment process, from design to implementation, and (3) the combination of site-specific indicators, identified by local stakeholders as relevant to their particular objectives and context conditions, and science-based indicators that represent ecosystem services of drylands worldwide. The proposed procedure follows a pattern of eliciting, challenging, and self-reviewing stakeholder perspectives that aims to facilitate learning. The difference between the initial baseline perspectives and the final self-reviewed stakeholder perspectives is used as a proxy of learning. We illustrate the potential of this methodology by its application to the assessment of land uses in a Mediterranean fire-prone area in East Spain. The approach may be applied to a variety of socio ecological systems and decision-making and governance scales. PMID- 27939813 TI - Trypanosoma cruzi induces cellular proliferation in the trophoblastic cell line BeWo. AB - Congenital transmission of Trypanosoma cruzi (T. cruzi) is partially responsible for the progressive globalization of Chagas disease. During congenital transmission the parasite must cross the placental barrier where the trophoblast, a continuous renewing epithelium, is the first tissue in contact with the parasite. The trophoblast turnover implies cellular proliferation, differentiation and apoptotic cell death. The epithelial turnover is considered part of innate immunity. We previously demonstrated that T. cruzi induces cellular differentiation and apoptosis in this tissue. Here we demonstrate that T. cruzi induces cellular proliferation in a trophoblastic cell line. We analyzed the cellular proliferation in BeWo cells by determining DNA synthesis by BrdU incorporation assays, mitotic index, cell cycle analysis by flow cytometry, as well as quantification of nucleolus organizer regions by histochemistry and expression of the proliferation markers PCNA and Ki67 by Western blotting and/or immunofluorescence. Additionally, we determined the ERK1/2 MAPK pathway activation by the parasite by Western blotting. PMID- 27939812 TI - Bis(monoacylglycero)phosphate inhibits TLR4-dependent RANTES production in macrophages. AB - Toll-like receptor 4 (TLR4) is the receptor for bacterial lipopolysaccharide (LPS) triggering production of pro-inflammatory cytokines which help eradicate the bacteria but could also be harmful when overproduced. The signaling activity of TLR4 is modulated by cholesterol level in cellular membranes, which in turn is affected by bis(monoacylglycero)phosphate (BMP), a phospholipid enriched in late endosomes. We found that exogenously added BMP isomers become incorporated into the plasma membrane and intracellular vesicles of macrophages and strongly reduced LPS-stimulated production of a chemokine RANTES, which was correlated with inhibition of interferon regulatory factor 3 (IRF3) controlling Rantes expression. To investigate the mechanism underlying the influence of BMP on TLR4 signaling we applied Laurdan and studied the impact of BMP incorporation on lipid packing, a measure for membrane order. Enrichment of model and cellular membranes with BMP significantly reduced their order and the reduction was maintained during stimulation of cells with LPS. This effect of BMP was abolished by enrichment of macrophages with cholesterol. In parallel, the inhibitory effect of BMP exerted on the TLR4-dependent phosphorylation of IRF3 was also reversed. Taken together our results indicate that BMP reduces the order of macrophage membranes which contributes to the inhibition of TLR4-dependent RANTES production. PMID- 27939814 TI - Visualizing viable Mycobacterium tuberculosis in sputum to monitor isolation measures. PMID- 27939815 TI - Patient factors associated with 30-day complications after partial nephrectomy: A contemporary update. AB - INTRODUCTION: Patient-level factors associated with perioperative complications after partial nephrectomy (PN) have not been well described in a contemporary series. METHODS: Single-institution retrospective study evaluating patients undergoing open, laparoscopic, and robotic PN between 2001 and 2012. Univariable and multivariable logistic regression models were evaluated to assess factors associated with complications within 30 days of surgery. RESULTS: We identified 1,763 patients who underwent 1,773 PNs between 2001 and 2012. From 2001 to 2006, 766 PNs were performed (85% open, 15% laparoscopic, and<1% robotic); in contrast, from 2007 to 2012, 1,007 PNs were performed (75% open, 8% laparoscopic, and 17% robotic); P<0.001. Overall, 241 (14%) PNs resulted in an early surgical complication. Patients undergoing a minimally invasive approach had smaller tumors (P<0.001), were less likely to have a solitary kidney (P<0.001), and had a lower Charlson score (P = 0.004). On multivariable analysis, factors independently associated with an increased risk of any complication included male sex (odds ratio [OR] = 1.40), solitary kidney (OR = 1.71), estimated glomerular filtration rate (OR = 2.89 for estimated glomerular filtration rate<30), Charlson score (OR = 1.97 for Charlson score>=3), and tumor size (OR = 1.12 for each 1-cm increase in tumor size); meanwhile, laparoscopic and robotic approaches were associated with a lower risk for complication (OR = 0.017 and 0.016, respectively), all P< 0.05. CONCLUSION: Several patient-level factors are associated with 30-day complications after PN, regardless of surgical approach. These data may inform counseling before PN, including potential identification and selection of high-risk surgical candidates for percutaneous ablative approaches. PMID- 27939816 TI - Light reflection from crystal platelets in iridophores determines green or brown skin coloration in Takydromus lizards. AB - Brown and green are the most commonly imitated colors in prey animals because both colors occur in a range of habitats. Many researchers have evaluated survival with respect to background color matching, but the pigment cell mechanisms underlying such coloration are not known. Dorsal coloration of East Asian Takydromus lizards has shifted from green to brown or from brown to green on multiple occasions during the diversification of the genus, thus giving us an opportunity to examine the cellular mechanisms of background color matching. Brown and green skin were found to differ with respect to the morphological characteristics of iridophores, with different thicknesses of the reflecting platelets and the cytoplasmic spacing between platelets, despite a shared vertical arrangement of pigment cells, i.e., xanthophores in the upper layer, iridophores in the middle layer, and melanophores at the bottom of the dermal layer, among the different Takydromus lizards. Iridophores of brown skin reflected longer wavelengths of light than those of green skin, which may be attributed to the thicker platelets and longer distances between platelets in brown skin. We discuss the potential role of genetic and intracellular mechanisms explaining the thickness and orientation of the light-reflecting platelets of iridophores in Takydromus lizards. PMID- 27939817 TI - Late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH) due to mutation of SLC34A3/NPT2c. AB - OBJECTIVE: To identify a genetic basis for markedly reduced bone density and multiple fractures in an adult patient with hypophosphatemia and hypercalciuria. SUBJECTS: A 54-year-old Vietnamese man, his unaffected two daughters and wife. METHODS: We performed biochemical studies and sequenced the SLC34A3 gene using genomic DNA from peripheral blood mononuclear cells. RESULTS: Biochemical evaluation of the proband revealed hypophosphatemia with increased renal phosphate wasting, hypercalciuria, low serum parathyroid hormone (PTH) and an elevated serum 1,25(OH)2D level. Mutation analysis of SLC34A3 gene revealed that the patient was a compound heterozygote for two nonsynonymous nucleotide substitutions: a novel c.571G>A (p.G191S) damaging mutation and the previously reported c.200G>A (p.R67H) polymorphism, consistent with the clinical diagnosis of late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH). His wife and older daughter both carried the p.R67H polymorphism, while his younger daughter was compound heterozygous for p.R67H and p.G191S. CONCLUSIONS: HHRH is an uncommon autosomal recessive disease that generally manifests in childhood as rickets or nephrolithiasis, but an adult onset phenotype may occur in heterozygous carriers of SLC34A3 mutations. The severe presentation of this proband in adulthood with marked nephrolithiasis, multiple fractures and low bone density emphasizes the importance of measuring the serum phosphorus level in patients with suspected but unexplained osteoporosis and/or recurrent renal stones. The recognition of late-onset HHRH facilitates timely institution of appropriate therapy. PMID- 27939818 TI - Medical School Surgical Boot Camps: A Systematic Review. AB - PURPOSE: Many medical schools have begun to offer surgical boot camps to senior medical students. The aim of the present study is to systematically review the literature and evidence surrounding medical school surgical boot camps to direct future research into the effectiveness of boot camps. METHODS: A systematic review was conducted, searching MEDLINE, EMBASE, PsycINFO, CINAHL, and ERIC. The review was conducted according to the PICOTS structure, with an intervention of a surgical boot camp for senior medical students entering surgical residencies. RESULTS: The search resulted in 5351 database hits, from which we identified 10 published studies that met the inclusion criteria. Two reviews were identified that met the PICOTS criteria but were excluded from data synthesis. Boot camps increase the confidence and competence of medical students entering their surgical internships. There is no objective assessment of the effect of boot camps on the clinical performance of interns. CONCLUSIONS: Despite the success of medical school surgical boot camps, no objective data exist to show that boot camps translate into improved performance during internship. PMID- 27939819 TI - RT-PCR using glycoprotein target is more sensitive for the detection of Ebola virus in clinical samples. AB - The recent largest ever Ebola virus disease (EVD) outbreak in West Africa has been of worldwide concern, causing huge economic losses and constituting serious threat to the local residents and health care workers. Rapid detection of Ebola virus (EBOV) using RT-PCR has been suggested to be of great value in stopping the outbreak, because it is highly sensitive and specific and can return results within hours. In this study, 210 clinical samples, including 109 blood and 101 nasopharyngeal swab samples were used to compare the performance of glycoprotein (GP) and nucleoprotein (NP) gene targets for the detection of EBOV. The analytical sensitivity of both assays were 10 molecules/MUL. For clinical samples, the sensitivity of the assay targeting GP gene is higher than that of NP gene (respectively 98% and 94%) and the specificities for both targets were 100%. In addition, the positive samples in the RT-PCR assay targeting GP showed lower cycle threshold values and higher virus loads than NP gene. PMID- 27939820 TI - Colistin-resistant Enterobacteriaceae infections: clinical and molecular characterization and analysis of in vitro synergy. AB - We described 27 polyclonal colistin-resistant Enterobacteriaceae (MIC 4-16 MUg/mL) infections (12 pneumonia, 12 urinary tract infection (UTI), two Bacteremia, and one skin/soft tissue infection) in which 74% harbored KPC. The isolates were polyclonal, 6 STs were identified and the colistin resistance was due to chromosome mutations. Eight patients with UTI received monotherapy, and combination therapy was given to 19 patients. Overall mortality was 37%. In vitro synergy using time-kill assay was observed in 14 of 19 (74%) isolates tested; the synergistic effect was observed for almost all isolates for the combination of three drugs: colistin, amikacin, and tigecycline. The Kaplan-Meier survival curve showed no significant difference comparing combination therapy with 2, 3, or more drugs and risk factors associated with death were dialysis and shock. These findings reinforce the fact that colistin in combination with other classes of drugs can be useful in treating infections caused by colistin-resistant CRE. PMID- 27939821 TI - Multimodal Imaging of Neurometabolic Pathology due to Traumatic Brain Injury. AB - The impact of traumatic brain injury (TBI) involves a combination of complex biochemical processes beginning with the initial insult and lasting for days, months and even years post-trauma. These changes range from neuronal integrity losses to neurotransmitter imbalance and metabolite dysregulation, leading to the release of pro- or anti-apoptotic factors which mediate cell survival or death. Such dynamic processes affecting the brain's neurochemistry can be monitored using a variety of neuroimaging techniques, whose combined use can be particularly useful for understanding patient-specific clinical trajectories. Here, we describe how TBI changes the metabolism of essential neurochemical compounds, summarize how neuroimaging approaches facilitate the study of such alterations, and highlight promising ways in which neuroimaging can be used to investigate post-TBI changes in neurometabolism. PMID- 27939822 TI - Construction and characterization of monoclonal antibodies against the extracellular domain of B-lymphocyte antigen CD20 using DNA immunization method. AB - To date, several new anti-CD20 monoclonal antibodies (mAbs) have been developed for potential efficacies compared with familiar mAb rituximab. Despite the recent advances in development of anti-CD20 mAbs for the treatment of B cell malignancies, the efforts should be continued to develop novel antibodies with improved properties. However, the development of mAbs against CD20 as a multi transmembrane protein is challenging due to the difficulty of providing a lipid environment that can maintain native epitopes. To overcome this limitation, we describe a simple and efficient DNA immunization strategy for the construction of a novel anti-CD20 mAb with improved anti-tumour properties. Using a DNA immunization strategy that includes intradermal (i.d.) immunization with naked plasmid DNA encoding the CD20 gene, we generated the hybridoma cell line D4, which secretes functional mAbs against an extracellular epitope of CD20. Immunocytochemistry analysis and a cell-based enzyme-linked immunosorbent assay using a Burkitt's lymphoma cell line showed that D4 mAbs are capable of binding to native extracellular epitopes of CD20. Moreover, the binding specificity of D4 mAbs was determined by western blot analysis. Cell proliferation was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected by the annexin V/propidium iodide staining and dye exclusion assay. The results showed that D4 anti-CD20 mAbs produced by DNA immunization exhibit potent growth inhibitory activity and have superior direct B cell cytotoxicity compared to rituximab. We propose that antibody-induced apoptosis is one of the mechanisms of cell growth inhibition. Taken together, the data reported here open the path to DNA-based immunization for generating pharmacologically active monoclonal antibodies against CD20. In addition, the data support future in vivo animal testing and subsequent procedures to produce a potential therapeutic mAb. PMID- 27939823 TI - The combined effect of resveratrol and diphenyleneiodonium on irradiation-induced injury to the hematopoietic system. AB - Both resveratrol(Res) and diphenyleneiodonium(DPI) have been shown to have radioprotective effects on hematopoietic system injury. However, the cooperative effect of Res and DPI are unknown. In this study, we explored the radioprotective effect of the combination of Res and DPI both in vitro and in vivo. Our results showed that the combined treatment of Res and DPI was more effective in protecting irradiated BMMNCs in terms of cell viability, colony-forming ability, and reconstitution ability in vitro compared with Res or DPI treatment alone. However, in mice, the combination of Res and DPI had no enhanced protection on 4Gy total body irradiation (TBI)-induced hematopoietic system injury, including TBI-induced myelosuppression, induction of the splenic index, and increases in HSC/HPC numbers and the colony-forming ability of BMCs,compared to Res or DPI alone. An exception was the number of BMCs. These studies illustrated the inconsistency between experiments carried out in vitro and in vivo and suggest an interaction between Res or DPI in vivo. PMID- 27939824 TI - Pulmonary platelet accumulation induced by catecholamines: Its involvement in lipopolysaccharide-induced anaphylaxis-like shock. AB - Intravenously injected lipopolysaccharides (LPS) rapidly induce pulmonary platelet accumulation (PPA) and anaphylaxis-like shock (ALS) in mice. Macrophages reportedly release catecholamines rapidly upon stimulation with LPS. Here, we examined the involvement of macrophage-derived catecholamines in LPS-induced PPA and ALS. A catecholamine or Klebsiella O3 (KO3) LPS was intravenously injected into mice, with 5-hydroxytryptamine in the lung being measured as a platelet marker. The tested catecholamines induced PPA, leading to shock. Their minimum shock-inducing doses were at the nmol/kg level. The effects of epinephrine and norepinephrine were inhibited by prazosin (alpha1 antagonist) and by yohimbine (alpha2 antagonist), while dopamine's were inhibited only by prazosin. Use of synthetic adrenergic alpha1- and/or alpha2-agonists, platelet- or macrophage depleted mice, a complement C5 inhibitor and C5-deficient mice revealed that (a) alpha2-receptor-mediated PPA and shock depend on both macrophages and complements, while alpha1-receptor-mediated PPA and shock depend on neither macrophages nor complements, (b) the PPA and ALS induced by KO3-LPS depend on alpha1- and alpha2-receptors, macrophages, and complements, and (c) KO3-LPS induced PPA is preceded by catecholamines decreasing in serum. Together, these results suggest the following. (i) Catecholamines may stimulate macrophages and release complement C5 via alpha2-receptors. (ii) Macrophage-derived catecholamines may mediate LPS-induced PPA and ALS. (iii) Moderate PPA may serve as a defense mechanism to remove excess catecholamines from the circulation by promoting their rapid uptake, thus preventing excessive systemic effects. (iv) The present findings might provide an insight into possible future pharmacological strategies against such diseases as shock and acute respiratory distress syndrome. PMID- 27939825 TI - Long-term Clinical Outcomes of Endodontically Treated Teeth Restored with or without Fiber Post-retained Single-unit Restorations. AB - INTRODUCTION: The aim of the present study was to evaluate both survival and failure rates of endodontically treated teeth restored with or without fiber post retained restorations after a mean observation period of at least 5 years. METHODS: A total of 144 single-rooted and multirooted teeth in 100 subjects were endodontically treated following a predetermined aseptic protocol and restored with either a fiber post and a composite core or a composite filling without intraradicular retention. A fiber post was cemented when the teeth presented with only 1 wall and/or less than one third of the remaining height of the clinical crown. After a comprehensive treatment plan, the teeth were restored with either a direct composite restoration or a single-unit crown. Endodontically treated teeth supporting fixed and removable dental prostheses and telescopic crowns were excluded from the analysis. Success was defined as tooth survival without any treatment of biological and/or technical complications. RESULTS: The overall tooth survival rate was 89.6% after a mean observation time of 8.8 +/- 2.3 years. The survival rate of teeth with a fiber post amounted to 94.3%, and for teeth without a post, it was 76.3% (P < .001). The main reason for tooth loss was root fracture (9.7%). No loss of post retention was observed. Successfully treated teeth without any biological and/or technical complications and requiring no additional treatment during the entire observation period amounted to 79.9%. CONCLUSIONS: Endodontically treated teeth restored with fiber posts and either a direct composite restoration or a single-unit crown yielded higher survival and success rates compared with teeth restored without fiber posts. Vertical fractures of roots not containing a post represented a frequently encountered and serious problem. PMID- 27939826 TI - In Vitro Efficacy of XP-endo Finisher with 2 Different Protocols on Biofilm Removal from Apical Root Canals. AB - INTRODUCTION: The purpose of this study was to evaluate the effectiveness of the XP-endo Finisher (XPF; FKG Dentaire SA, La Chaux-de-Fonds, Switzerland) in biofilm removal in comparison with conventional needle irrigation (CNI) and passive ultrasonic irrigation (PUI) using an infected tooth model with an artificial apical groove. METHODS: Fifty-four extracted human single-rooted premolars were selected. Each tooth was split longitudinally into 2 halves, with a groove made in the apical segment of the canal wall. After growing mixed bacteria biofilm for 4 weeks, the split halves were reassembled and instrumented using Vortex Blue files (Dentsply Tulsa Dental, Tulsa, OK) to size 40/.06. The instrumented teeth were randomly assigned to 6 groups (n = 8) according to the final irrigation protocol. Three different techniques (CNI, PUI, and XPF) were performed each with either continuous irrigation or 3-step irrigation. Scanning electron microscopic images were taken to evaluate the amount of residual biofilm inside and outside the groove. RESULTS: Robust growth of biofilm was observed in each canal of the controls after 4 weeks. XPF showed the best biofilm removal efficacy inside and outside the groove followed by PUI and CNI (P < .05). The XPF 2 group using the 3-step protocol showed better antibiofilm efficiency than the XPF 1 group with continuous irrigation inside the groove (P < .05). CONCLUSIONS: The XP-endo Finisher, as an irrigation agitation technique, may help to remove biofilm from hard-to-reach areas in the root canal system. The 3-step irrigation protocol was more effective than continuous irrigation when XPF was used. PMID- 27939827 TI - The role of arterial elasticity and cardiovascular peripheral resistance as clinically relevant indices of health status in people with psychosis. AB - OBJECTIVE: Hypertension is one of the most important risk factors for cardiovascular disease (CVD). Systolic and diastolic blood pressure (BP) are higher in people with psychosis compared to the general population, but there is little research into measures of the elasticity of the arterial wall (pulse pressure; PP) and peripheral resistance (mean arterial pressure; MAP). PP and MAP can provide an additional perspective on the functioning of the circulatory system. This study investigated PP and MAP in people with psychosis, using factors known to be related to PP and MAP in the general population. METHOD: Participants included 1421 people aged 18-64years, from the second Australian national survey of psychosis, untreated with antihypertensive medication. We tested the interaction and main effects between age and gender on PP, MAP, systolic BP and diastolic BP. Odds ratios were calculated in people exceeding the at-risk thresholds for PP and MAP. Multiple linear regression was used to test whether factors associated with at-risk PP and MAP in the general population were similarly associated in the psychosis population. RESULTS: The interaction effect between age and gender on PP, MAP, systolic BP and diastolic BP was not statistically significant. Variables that retained significance in the regression model in explaining higher PP and MAP were: male gender, higher age, and having a family history of hypertension. CONCLUSION: Clinicians monitoring and treating CV risk in this population need to ensure that they have recorded whether there is a family history of hypertension, and should be especially, more vigilant in men and in older patients. PMID- 27939828 TI - Understanding the role of thalamic circuits in schizophrenia neuropathology. PMID- 27939829 TI - Association of the polygenic risk score for schizophrenia with mortality and suicidal behavior - A Danish population-based study. AB - BACKGROUND: It is unknown whether an increased genetic liability to schizophrenia influences the risk of dying early. The aim of the study was to determine whether the genetic predisposition to schizophrenia is associated with the risk of dying early and experience a suicide attempt. METHOD: Case control study, Denmark. The main measure was the mortality rate ratios (MRR) for deaths and odds ratios (OR) for multiple suicide attempts, associated with one standard deviations increase of the polygenic risk-score for schizophrenia (PRS). RESULTS: We replicated the high mortality MRR=9.01 (95% CI: 3.56-22.80), and high risk of multiple suicide attempts OR=33.16 (95% CI: 20.97-52.43) associated with schizophrenia compared to the general population. However, there was no effect of the PRS on mortality MRR=1.00 (95% CI 0.71-1.40) in the case-control setup or in cases only, MRR=1.05 (95% CI 0.73-1.51). Similar, no association between the PRS and multiple suicide attempts was found in the adjusted models, but in contrast, family history of mental disorders was associated with both outcomes. CONCLUSIONS: A genetic predisposition for schizophrenia, measured by PRS, has little influence on the excess mortality or the risk of suicide attempts. In contrast there is a strong significant effect of family history of mental disorders. Our findings could reflect that the common variants detected by recent PRS only explain a small proportion of risk of schizophrenia, and that future, more powerful PRS instruments may be able to predict excess mortality within this disorder. PMID- 27939830 TI - In vitro toxicological assessment of an organosulfur compound from Allium extract: Cytotoxicity, mutagenicity and genotoxicity studies. AB - Garlic (Allium sativum) and onion (Allium cepa) are being used in the food industry as flavoring but also for their antimicrobial activities. These activities are mainly derived from the organosulfur compounds (OSCs). Propyl propane thiosulfinate (PTS) is an OSC with potential use in the active packaging, but its safety should be guaranteed before being commercialized. The aim of this work was to investigate for the first time the cytotoxicity of PTS as well as its in vitro mutagenic/genotoxic potential using the following battery of genotoxicity tests:(1)the bacterial reverse-mutation assay in S. typhimurium (Ames test, OECD 471, 1997); (2) the micronucleus test (MN, OECD 487, 2016); (3) the mouse lymphoma thymidine-kinase assay (MLA, OECD 476, 2015), and (4) the comet assay (standard and modified with restriction enzymes). The results revealed that PTS was not mutagenic neither in the Ames test nor in MLA. However, genotoxic effects were recorded in the MN test on mammalian cells (L5178YTk+/ cells) after PTS exposure at the highest concentration tested (17.25 MUM) without S9, and also its metabolites (+S9, from 20 MUM). Moreover, in the comet assay, PTS induced DNA breaks damage in Caco-2 cells at the highest concentration tested (280 MUM) but it did not induce oxidative DNA damage. PMID- 27939831 TI - Persistent alterations in immune cell populations and function from a single dose of perfluorononanoic acid (PFNA) in C57Bl/6 mice. AB - Perfluorononanoic acid (PFNA) is a perfluoroalkyl substance (PFAS) that is structurally related to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Whereas PFOA and PFOS are known immunotoxicants, PFNA is less well characterized. Our previous study showed that PFNA has immunomodulatory effects on leukocyte populations and immune function. The present studies sought to determine whether, and to what degree, the immune system recovered 28 days after PFNA exposure. None of the parameters measured had fully recovered. A few parameters had partially recovered, including decreased spleen size and the decreased ratio of the CD4+/CD8+ double-positive population in thymus. The majority of effects of PFNA remained unchanged 28 days after exposure, including decreased proportion of intact thymocytes (as determined by FSC vs SSC), alterations in the ratios of immune cell populations in spleen and the CD4+, CD8+ and double-negative populations in thymus. Notably, PFNA markedly increased the TNFalpha response to LPS in vivo, and no recovery was evident 28 days after exposure. The effect of PFNA on CD4+ T cells, CD8+ T cells and CD19+ cells was more pronounced in females. The current study demonstrates that a single high dose exposure to PFNA (e.g. as might occur accidentally in an occupational setting) has long-lasting effects on the immune system. PMID- 27939833 TI - Orthoses for osteoarthritis: A narrative review. AB - Orthoses for osteoarthritis represent splints, taping, sleeves, unloading knee braces and insoles. This review of the effectiveness of these orthoses involved a search for articles published up to 2015 in MEDLINE via PubMed, with a focus on Osteoarthritis Research Society International, American College of Rheumatology and European League Against Rheumatology international recommendations. Evidence for splinting effectiveness in patients with thumb-base osteoarthritis is now provided. Splints for thumb-base osteoarthritis decrease pain and functional disability. Weaker evidence was found for knee bracing, including taping, sleeves and unloading braces. Low rate of observance and safety results should be considered before using current unloading knee braces for knee osteoarthritis. For insoles, data remain controversial. Orthoses for interphalangeal or hip osteoarthritis have not been investigated in a randomized trial. Regardless, if indicated in daily clinical practice, bracing must be checked by a healthcare professional to insure the suitability of the device. Patients using bracing must be educated. Patient education should include knowledge of the aims and modalities of the treatment as well as knowledge of potential side effects. Patients should be encouraged to contact the therapist if adjustment is needed, with poor tolerance or with questions about the device. PMID- 27939832 TI - Morbidity and mortality of very low birth weight infants in Taiwan-Changes in 15 years: A population based study. AB - BACKGROUND/PURPOSE: Very low birth weight (VLBW) infants account for over 50% of perinatal deaths in Taiwan. This study aimed to identify changes in parental characteristics, perinatal conditions, mortality, and major neonatal morbidities for VLBW infants in Taiwan, and to highlight the challenges faced by patients, families, and caregivers. METHODS: We conducted a retrospective cohort study to investigate the mortality and morbidity of VLBW infants registered in the Taiwan Premature Infant Follow-up Network from 1997 through 2011. The exclusion criteria included congenital anomalies and chromosome anomalies. Continuous data was represented as mean +/- SD, and changes over time in the variables were tested using one-way analysis of variance, with p < 0.05 considered statistically significant. RESULTS: A total of 13,159 VLBW infants were enrolled. We found significant increases over time in the parental age and educational level, in vitro fertilization, first livebirth, multiple births, maternal transfer, cesarean section, and complete antenatal steroid use. Apgar scores at 1 minute and 5 minutes after birth increased, and the intubation rate decreased gradually. Decreasing mortality over time for each successive period was demonstrated. Incidence of some morbidities increased, such as respiratory distress syndrome and patent ductus arteriosus; in contrast, incidence of others decreased, such as sepsis, necrotizing enterocolitis, intraventricular hemorrhage, and chronic lung disease. However, retinopathy of prematurity (ROP) incidence remained constant. CONCLUSION: Although the mortality and most of the morbidity of VLBW infants improved over time, the incidence of ROP remained constant. This requires us to further evaluate our strategy for preventing ROP in the future. PMID- 27939835 TI - Vesicoureteral Reflux Index: Predicting Primary Vesicoureteral Reflux Resolution in Children Diagnosed after Age 24 Months. AB - PURPOSE: The Vesicoureteral Reflux Index is a validated tool that reliably predicts spontaneous resolution of reflux or at least 2 grades of improvement for patients diagnosed before age 24 months. We evaluated the Vesicoureteral Reflux Index in children older than 2 years. MATERIALS AND METHODS: Patients younger than 18 years who were diagnosed with primary vesicoureteral reflux after age 24 months and had undergone 2 or more voiding cystourethrograms were identified. Disease severity was scored using the Vesicoureteral Reflux Index, a 6-point scale based on gender, reflux grade, ureteral abnormalities and reflux timing. Proportional subdistribution hazard models for competing risks identified variables associated with resolution/improvement at different time points. RESULTS: A total of 21 males and 250 females met inclusion criteria. Mean +/- SD age was 4.0 +/- 2.1 years and patients had a median vesicoureteral reflux grade of 2. The Vesicoureteral Reflux Index score improved by 1 point in 1 patient (100%), 2 points in 25 (67.6%), 3 points in 48 (37%), 4 points in 18 (21.4%) and 5 to 6 points in 4 (18.2%). Female gender (p = 0.005) and vesicoureteral reflux timing (late filling, p = 0.002; early/mid filling, p <0.001) independently predicted nonresolution. Median resolution time based on Vesicoureteral Reflux Index score was 2 months or less in 15.6% of patients (95% CI 11.0-13.8), 3 months in 34.7% (95% CI 25.4-44.1), 4 months in 55.9% (95% CI 40.1 to infinity) and 5 months or more in 30.3% (95% CI 29.5 to infinity). High grade (IV or V) reflux was not associated with resolution at any point. Ureteral abnormalities were associated with lack of resolution in the first 12 to 18 months (HR 0.29, 95% CI 0.29-0.80) but not in later followup. Vesicoureteral Reflux Index scores of 3, 4 and 5 were significantly associated with lack of resolution/improvement compared to scores of 2 or less (p = 0.031). CONCLUSIONS: The Vesicoureteral Reflux Index reliably predicts primary vesicoureteral reflux improvement/resolution in children diagnosed after age 24 months. Spontaneous resolution/improvement is less likely as Vesicoureteral Reflux Index score and time from diagnosis increase. PMID- 27939834 TI - Focus on the role of Caveolin and Cavin protein families in liposarcoma. AB - The identification of ancillary biomarkers useful to improve diagnosis is a major challenge for adipocytic liposarcoma (LPS), the most common type among soft tissue sarcomas affecting adulthood. Recent findings have reported the expression of some proteins belonging to Caveolin and Cavin families as a critical hallmark distinctive of the least aggressive, well-differentiated LPS tumors. These proteins are involved in the biogenesis, morphology and function of caveolae, minute bulb-shaped domains of the plasma membrane that play a crucial role in the adipose tissue by controlling hormone-dependent uptake of nutrients and contributing to the maintenance of tissue integrity. In light of this, in this paper we covered different topics, including metabolism, hypoxia and cell mechanoprotection, to outline the rationale for considering a deeper investigation of Caveolin and Cavin protein members in LPS neoplasms as an opportunity to identify pro-differentiating mechanisms that could counteract tumor growth. PMID- 27939837 TI - Exploration and exploitation of Victorian science in Darwin's reading notebooks. AB - Search in an environment with an uncertain distribution of resources involves a trade-off between exploitation of past discoveries and further exploration. This extends to information foraging, where a knowledge-seeker shifts between reading in depth and studying new domains. To study this decision-making process, we examine the reading choices made by one of the most celebrated scientists of the modern era: Charles Darwin. From the full-text of books listed in his chronologically-organized reading journals, we generate topic models to quantify his local (text-to-text) and global (text-to-past) reading decisions using Kullback-Liebler Divergence, a cognitively-validated, information-theoretic measure of relative surprise. Rather than a pattern of surprise-minimization, corresponding to a pure exploitation strategy, Darwin's behavior shifts from early exploitation to later exploration, seeking unusually high levels of cognitive surprise relative to previous eras. These shifts, detected by an unsupervised Bayesian model, correlate with major intellectual epochs of his career as identified both by qualitative scholarship and Darwin's own self commentary. Our methods allow us to compare his consumption of texts with their publication order. We find Darwin's consumption more exploratory than the culture's production, suggesting that underneath gradual societal changes are the explorations of individual synthesis and discovery. Our quantitative methods advance the study of cognitive search through a framework for testing interactions between individual and collective behavior and between short- and long-term consumption choices. This novel application of topic modeling to characterize individual reading complements widespread studies of collective scientific behavior. PMID- 27939836 TI - Luteinizing Hormone-Releasing Hormone Agonists are Superior to Subcapsular Orchiectomy in Lowering Testosterone Levels of Men with Prostate Cancer: Results from a Randomized Clinical Trial. AB - PURPOSE: Recent evidence suggests that reaching the lowest achievable levels of testosterone with androgen deprivation therapy delays disease progression and increases overall survival in men with advanced prostate cancer. The aim of this analysis was to compare posttreatment serum testosterone levels between patients undergoing subcapsular orchiectomy and patients treated with the luteinizing hormone-releasing hormone agonist triptorelin. MATERIALS AND METHODS: In this randomized clinical trial we included 58 consecutive hormone naive men diagnosed with advanced prostate cancer at Herlev and Gentofte University Hospital, Herlev, Denmark from September 2013 to March 2015. Followup was 48 weeks. Participants were randomly assigned 1:1 to subcapsular orchiectomy or triptorelin 22.5 mg given as 24-week depot injections. Androgen status was measured by liquid chromatography-tandem mass spectrometry prior to treatment and after 12, 24 and 48 weeks. Between group differences in achieved hormone levels were analyzed by longitudinal Tobit regression. RESULTS: Triptorelin injections resulted in 29% lower testosterone levels (95% CI 17.2-41.7) compared to subcapsular orchiectomy (p <0.001). A significantly higher proportion of men receiving triptorelin had testosterone levels less than 20 ng/dl at 12 and 48 weeks compared to men undergoing orchiectomy (97% vs 79% and 100% vs 87%, respectively, p <0.05). There was no detectable difference in the adrenal androgen reduction between the treatment groups. CONCLUSIONS: The use of 24-week depot triptorelin injections results in significantly lower testosterone levels compared to subcapsular orchiectomy. To our knowledge this is the first randomized study to demonstrate a difference in treatment effect between surgical and medical castration on testosterone levels. PMID- 27939838 TI - Eye movements reveal a dissociation between memory encoding and retrieval in adults with autism. AB - People with Autism Spectrum Disorder (ASD) exhibit subtle deficits in recollection, which have been proposed to arise from encoding impairments, though a direct link has yet to be demonstrated. In the current study, we used eye tracking to obtain trial-specific measures of encoding (eye movement patterns) during incidental (natural viewing) and intentional (strategic) encoding conditions in adults with ASD and typical controls. Using this approach, we tested the degree to which differences in encoding might contribute to recollection impairments, or whether group differences in memory primarily emerge at retrieval. Following encoding of scenes, participants were asked to distinguish between old and similar lure scenes and provide 'remember'/'familiar' responses. Intentional encoding increased eye movements and subsequent recollection in both groups to a similar degree, but the ASD group were impaired overall at the memory task and used recollection less frequently. In controls, eye movements at encoding predicted subsequent correct responses and subsequent recollection on a trial-by-trial basis, as expected. In contrast, despite a similar pattern of eye movements during encoding in the two groups, eye movements did not predict trial-by-trial subsequent memory in ASD. Furthermore, recollection was associated with lower similarity between encoding- and retrieval related eye movements in the ASD group compared to the control group. The eye tracking results therefore provide novel evidence for a dissociation between encoding and recollection-based retrieval in ASD. PMID- 27939839 TI - Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells. AB - Tamoxifen is a standard endocrine therapy for estrogen receptor positive breast cancer patients. Despite its success, development of resistance mechanisms is still a serious clinical problem. Deregulation of survival signaling pathways play a key role in tamoxifen resistance, being upregulation of Rac1-PAK1 signaling pathway one of the most important. Here, we report the development of the breast cancer cell model MCF7::C1199 having Rac1 enhanced activity with the aim of evaluating the role of Rac1 in acquired endocrine resistance. These cells not only showed distinctive features of Rac1-regulated process as increased migration and proliferation rates, but also showed that upregulation of Rac1 activity triggered a hormonal-independent and tamoxifen resistant phenotype. We also demonstrated that PAK1 activity increases in response to Tamoxifen, increasing phosphorylation levels of estrogen receptor at Ser305, a key phosphorylation site involved in tamoxifen resistance. Finally, we evaluated the effect of 1A-116, a specific Rac1 inhibitor developed by our group, in tamoxifen resistant cells. 1A-116 effectively restored tamoxifen anti-proliferative effects, switched off PAK1 activity and decreased estrogen receptor phospho Ser305 levels. Since combination schemes of novel targeted agents with endocrine therapy could be potential new strategies to restore tamoxifen sensibility, these results show that inhibition of Rac1-PAK1 signaling pathway may provides benefits to revert resistance mechanisms in endocrine therapies. PMID- 27939840 TI - Niclosamide inhibits lytic replication of Epstein-Barr virus by disrupting mTOR activation. AB - Infection with the oncogenic gamma-herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause several severe malignancies in humans. Inhibition of the lytic replication of EBV and KSHV eliminates the reservoir of persistent infection and transmission, consequently preventing the occurrence of diseases from the sources of infection. Antiviral drugs are limited in controlling these viral infectious diseases. Here, we demonstrate that niclosamide, an old anthelmintic drug, inhibits mTOR activation during EBV lytic replication. Consequently, niclosamide effectively suppresses EBV lytic gene expression, viral DNA lytic replication and virion production in EBV-infected lymphoma cells and epithelial cells. Niclosamide exhibits cytotoxicity toward lymphoma cells and induces irreversible cell cycle arrest in lytically EBV infected cells. The ectopic overexpression of mTOR reverses the inhibition of niclosamide in EBV lytic replication. Similarly, niclosamide inhibits KSHV lytic replication. Thus, we conclude that niclosamide is a promising candidate for chemotherapy against the acute occurrence and transmission of infectious diseases of oncogenic gamma-herpesviruses. PMID- 27939841 TI - Meeting report: Third Summer School on Innovative Approaches for Identification of Antiviral Agents (IAAASS). AB - The third Summer School on Innovative Approaches for Identification of Antiviral Agents (IAAASS) was held from September 28th to October 2nd, 2016 at the Sardegna Ricerche Research Park in Santa Margherita di Pula, Sardinia, Italy. The school brought together graduate students and postdoctoral fellows early in their careers with a faculty of internationally recognized experts, to encourage the sharing of knowledge and experience in virology research and drug development in an informal and interactive environment. The first IAAASS was held in Sardinia in 2012 and the second in 2014. The meetings provide a unique combination of plenary lectures on topics in virology, biochemistry, molecular modeling, crystallography and medicinal chemistry with small group sessions, in which students have the opportunity to ask questions and put forward their own ideas, and senior researchers offer advice, based on their own experience. This report summarizes presentations and presentations at the 3rd IAAASS. PMID- 27939842 TI - Atopic characteristics of patients with vocal cord dysfunction. PMID- 27939843 TI - Reply to the letter: 'Physical activity and survival in breast cancer: What were missing?' by Wu H, Wang D, and Ruan X. PMID- 27939844 TI - Physical activity and survival in breast cancer: What were missing? PMID- 27939845 TI - Soluble PD-L1 and prognosis of patients with hepatocellular carcinoma. PMID- 27939847 TI - Open-tension free three-dimensional Cooper ligament repair for femoral hernia. AB - BACKGROUND: The objective of this study was to investigate the outcome of modified three-dimensional (3D) anterior polypropylene mesh technique for recurrent inguinal and femoral hernias. METHODS: This study was designed as a prospective cohort clinical trial and 75 patients with femoral hernia and/or recurrent hernia were recruited between 2005 and 2014. Patients were operated upon using a modified 3D anterior polypropylene mesh technique. RESULTS: Sixty three femoral and 12 recurrent hernias in 75 patients were treated by a single surgeon through a 9-year period using a modified 3D polypropylene mesh, fashioned by the same surgeon. Forty-six female and 29 male patients, with a mean age of 43.6 years, were evaluated for postoperative chronic pain, wound issues, and recurrences. Any complications or complaints were recorded through office visits and by telephone calls. Urinary retention in one patient and wound infections in two patients were treated within 2 weeks postoperatively. Six patients had wound swelling (2 patients with hematoma and 4 with seroma) in early term (2 weeks to 2 months) and were treated by simple drainage and compression. No chronic pain or recurrent hernia was detected. CONCLUSION: Modified 3D anterior polypropylene mesh technique allows anatomical support for the potential hernia area and can be confidently applied with low morbidity and recurrence rate. PMID- 27939848 TI - Development and validation of a simple and robust HPLC method with UV detection for quantification of the hepatitis C virus inhibitor daclatasvir in human plasma. AB - Daclatasvir is an inhibitor of hepatitis C virus NS5A protein that is used for the therapy of chronic hepatitis. So far, published methods for analysis of daclatasvir in plasma are exclusively based on mass spectrometry, which is not always available in standard clinical laboratories. Thus, we wished to develop and validate a simple, but still reliable and sensitive high-performance liquid chromatography (HPLC) assay with UV detection for the quantification of daclatasvir, feasible for a wide-spread clinical routine use. The method consisted of solid-phase extraction of daclatasvir using Waters Oasis HLB 1cc cartridges, reversed-phase liquid chromatography with a Waters XTerra RP18 (150mm*4.6mm, 3.5MUm) column and a mobile phase of ammonium acetate buffer (pH 5.0, 10mM) and acetonitrile (56:44, v/v), and UV detection at 318nm. This assay proved to be sensitive (lower limit of quantification of 0.05MUg/mL), linear (correlation coefficients >=0.997), specific (no interference with various potentially co-administrated drugs), reproducible (both intra-day and inter-day coefficients of variation <=8.9%), and accurate (deviations ranged from -2.2 to 8.0% and from -6.5 to 9.2% for intra-day and inter-day assays, respectively). The method was applied to therapeutic monitoring of patients undergoing daclatasvir therapy for hepatitis C and showed to be reliable and robust. Thus, this method provides a simple, sensitive, precise, and reproducible assay for dosing daclatasvir that can be readily adaptable to routine use by clinical laboratories with standard equipment. In addition, the stability of daclatasvir in plasma was evaluated under various conditions, including after the heating procedure required for inactivation of infectious viruses and in different light exposure conditions. These studies evidenced photo-instability of the compound under sunlight exposure over time. Thus, blood sampling and the whole handling procedure have to be performed quickly and with minimal light exposure. PMID- 27939846 TI - Using a computer simulation for teaching communication skills: A blinded multisite mixed methods randomized controlled trial. AB - OBJECTIVES: To assess advanced communication skills among second-year medical students exposed either to a computer simulation (MPathic-VR) featuring virtual humans, or to a multimedia computer-based learning module, and to understand each group's experiences and learning preferences. METHODS: A single-blinded, mixed methods, randomized, multisite trial compared MPathic-VR (N=210) to computer based learning (N=211). Primary outcomes: communication scores during repeat interactions with MPathic-VR's intercultural and interprofessional communication scenarios and scores on a subsequent advanced communication skills objective structured clinical examination (OSCE). Multivariate analysis of variance was used to compare outcomes. SECONDARY OUTCOMES: student attitude surveys and qualitative assessments of their experiences with MPathic-VR or computer-based learning. RESULTS: MPathic-VR-trained students improved their intercultural and interprofessional communication performance between their first and second interactions with each scenario. They also achieved significantly higher composite scores on the OSCE than computer-based learning-trained students. Attitudes and experiences were more positive among students trained with MPathic VR, who valued its providing immediate feedback, teaching nonverbal communication skills, and preparing them for emotion-charged patient encounters. CONCLUSIONS: MPathic-VR was effective in training advanced communication skills and in enabling knowledge transfer into a more realistic clinical situation. PRACTICE IMPLICATIONS: MPathic-VR's virtual human simulation offers an effective and engaging means of advanced communication training. PMID- 27939849 TI - A squalene synthase protein degradation method for improved sesquiterpene production in Saccharomyces cerevisiae. AB - Sesquiterpenes are C15 isoprenoids with utility as fragrances, flavours, pharmaceuticals, and potential biofuels. Microbial fermentation is being examined as a competitive approach for bulk production of these compounds. Competition for carbon allocation between synthesis of endogenous sterols and production of the introduced sesquiterpene limits yields. Achieving balance between endogenous sterols and heterologous sesquiterpenes is therefore required to achieve economical yields. In the current study, the yeast Saccharomyces cerevisiae was used to produce the acyclic sesquiterpene alcohol, trans-nerolidol. Nerolidol production was first improved by enhancing the upstream mevalonate pathway for the synthesis of the precursor farnesyl pyrophosphate (FPP). However, excess FPP was partially directed towards squalene by squalene synthase (Erg9p), resulting in squalene accumulation to 1% biomass; moreover, the specific growth rate declined. In order to re-direct carbon away from sterol production and towards the desired heterologous sesquiterpene, a novel protein destabilisation approach was developed for Erg9p. It was shown that Erg9p is located on endoplasmic reticulum and lipid droplets through a C-terminal ER-targeted transmembrane peptide. A PEST (rich in Pro, Glu/Asp, Ser, and Thr) sequence-dependent endoplasmic reticulum-associated protein degradation (ERAD) mechanism was established to decrease cellular levels of Erg9p without relying on inducers, repressors or specific repressing conditions. This improved nerolidol titre by 86% to ~100mgL-1. In this strain, squalene levels were similar to the wild-type control strain, and downstream ergosterol levels were slightly decreased relative to the control, indicating redirection of carbon away from sterols and towards sesquiterpene production. There was no negative effect on cell growth under these conditions. Protein degradation is an efficient mechanism to control carbon allocation at flux-competing nodes in metabolic engineering applications. This study demonstrates that an engineered ERAD mechanism can be used to balance flux competition between the endogenous sterol pathway and an introduced bio-product pathways at the FPP node. The approach of protein degradation in general might be more widely applied to improve metabolic engineering outcomes. PMID- 27939850 TI - Grazing of particle-associated bacteria-an elimination of the non-viable fraction. AB - Quantification of bacteria being grazed by microzooplankton is gaining importance since they serve as energy subsidies for higher trophic levels which consequently influence fish production. Hence, grazing pressure on viable and non-viable fraction of free and particle-associated bacteria in a tropical estuary controlled mainly by protist grazers was estimated using the seawater dilution technique. In vitro incubations over a period of 42h showed that at the end of 24h, growth coefficient (k) of particle-associated bacteria was 9 times higher at 0.546 than that of free forms. Further, 'k' value of viable cells on particles was double that of free forms at 0.016 and 0.007, respectively. While bacteria associated with particles were grazed (coefficient of removal (g)=0.564), the free forms were relatively less grazed indicating that particle-associated bacteria were exposed to grazers in these waters. Among the viable and non-viable forms, 'g' of non-viable fraction (particle-associated bacteria=0.615, Free=0.0086) was much greater than the viable fraction (particle-associated bacteria=0.056, Free=0.068). Thus, grazing on viable cells was relatively low in both the free and attached states. These observations suggest that non-viable forms of particle-associated bacteria were more prone to grazing and were weeded out leaving the viable cells to replenish the bacterial standing stock. Particle colonization could thus be a temporary refuge for the "persistent variants" where the viable fraction multiply and release their progeny. PMID- 27939852 TI - Effects of perforation size on the success rate of tympanoplasty using a cartilage graft. PMID- 27939851 TI - Age-Specific Prevalence of Hoarding and Obsessive Compulsive Disorder: A Population-Based Study. AB - OBJECTIVE: Little is known about the age-specific prevalence of hoarding and obsessive compulsive symptoms (OCS), particularly in older age groups. The objectives of this study were to estimate the age-specific prevalence, severity, and relationships between hoarding and OCS in males and females using a large population-based sample. METHODS: We assessed the age-specific prevalence rates of hoarding disorder (HD) and OC disorder (OCD) in males and females (at various age ranges between 15 and 97 years) from the Netherlands Twins Register (N = 15,194). Provisional HD and OCD diagnoses were made according to Diagnostic and Statistical Manual of Mental Health Disorders, 5th Edition, criteria using self report measures. We also assessed hoarding and OCS severity in the various age groups and explored specific hoarding and OCS patterns (e.g., difficulty discarding, excessive acquisition, clutter, checking, washing, perfectionism, and obsessions) with age. RESULTS: Prevalence of provisional HD diagnoses (2.12%) increased linearly by 20% with every 5 years of age (z = 13.8, p < 0.0001) and did not differ between males and females. Provisional OCD diagnoses were most common in younger individuals and in individuals over age 65. Co-occurring OCD increased hoarding symptom severity (coefficient: 4.5; SE: 0.2; 95% CI: 4.1-4.9; t = 22.0, p < 0.0001). Difficulty discarding for HD and checking behaviors for OCD appeared to drive most increases in these diagnoses in older ages. CONCLUSION: Increased prevalence and severity of HD with age appears to be primarily driven by difficulties with discarding. Increases in OCD prevalence with older age were unexpected and of potential clinical relevance. PMID- 27939854 TI - Bayesian analysis of high-resolution ultrasonography and guided fine needle aspiration cytology in diagnosis of palpable thyroid nodules. AB - INTRODUCTION: To evaluate diagnostic accuracy of high-resolution ultrasonography in differentiation of benign and malignant thyroid nodules in comparison to results of guided fine needle aspiration cytology based on the Bayes rule. OBJECTIVE: To assess the validity of ultrasonography results of thyroid nodules in comparison to guided fine needle aspiration cytology findings. METHODS: This study was done on randomly chosen 80 patients presented with palpable thyroid nodules, undergone real-time sonographic evaluation of thyroid nodules to characterize features, internal consistency, margins, echotexture, calcification, peripheral lucent halo and vascularity. Ultrasonography guided fine needle aspiration cytology studies of thyroid nodules were done. RESULTS: Palpable thyroid nodules were highly prevalent in fourth and fifth decades of life with female-male ratio, 4:1. Solid internal consistency was demonstrated by 75% malignant nodules. Hypoechogenicity and intra-nodular micro-calcifications were observed in 92% malignant nodules; 83% malignant nodules had intra-nodular vascularity and absence of peripheral halo. The pre-test prevalence of malignant nodules in the targeted population was 17.5%. As type I error, 2.5% false positive cases and as type II error, 5.0% false-negative cases were detected. Values of sensitivity and specificity of the ultrasonography test were 71.43 and 96.97%, respectively. CONCLUSION: Malignant thyroid nodules demonstrated ultrasonography characteristics of hypoechoic texture, intra-nodular micro calcifications, solid consistency, internal vascularity and absence of peripheral halo. The ultrasonography test has 92.5% diagnostic accuracy to differentiate malignant from benign lesions in comparison to the gold standard fine needle aspiration cytology test. PMID- 27939855 TI - Intraoral excision of a huge retropharyngeal lipoma causing dysphagia and obstructive sleep apnea. PMID- 27939853 TI - Effects of distractors on upright balance performance in school-aged children with attention deficit hyperactivity disorder, preliminary study. AB - INTRODUCTION: Attention deficit hyperactivity disorder is a common impairing neuropsychiatric disorder with onset in early childhood. Almost half of the children with attention deficit hyperactivity disorder also experience a variety of motor-related dysfunctions ranging from fine/gross motor control problems to difficulties in maintaining balance. OBJECTIVES: The main purpose of this study was to investigate the effects of distractors two different auditory distractors namely, relaxing music and white noise on upright balance performance in children with attention deficit hyperactivity disorder. METHODS: We compared upright balance performance and the involvement of different sensory systems in the presence of auditory distractors between school-aged children with attention deficit hyperactivity disorder (n=26) and typically developing controls (n=20). Neurocom SMART Balance Master Dynamic Posturography device was used for the sensory organization test. Sensory organization test was repeated three times for each participant in three different test environments. RESULTS: The balance scores in the silence environment were lower in the attention deficit hyperactivity disorder group but the differences were not statistically significant. In addition to lower balance scores the visual and vestibular ratios were also lower. Auditory distractors affected the general balance performance positively for both groups. More challenging conditions, using an unstable platform with distorted somatosensory signals were more affected. Relaxing music was more effective in the control group, and white noise was more effective in the attention deficit hyperactivity disorder group and the positive effects of white noise became more apparent in challenging conditions. CONCLUSION: To the best of our knowledge, this is the first study evaluating balance performance in children with attention deficit hyperactivity disorder under the effects of auditory distractors. Although more studies are needed, our results indicate that auditory distractors may have enhancing effects on upright balance performance in children with attention deficit hyperactivity disorder. PMID- 27939856 TI - An assessment of domain-general metacognitive responding in rhesus monkeys. AB - Metacognition is the ability to monitor and control one's cognition. Monitoring may involve either public cues or introspection of private cognitive states. We tested rhesus monkeys (Macaca mulatta) in a series of generalization tests to determine which type of cues control metacognition. In Experiment 1, monkeys learned a perceptual discrimination in which a "decline-test" response allowed them to avoid tests and receive a guaranteed small reward. Monkeys declined more difficult than easy tests. In Experiments 2-4, we evaluated whether monkeys generalized this metacognitive responding to new perceptual tests. Monkeys showed a trend toward generalization in Experiments 2 & 3, and reliable generalization in Experiment 4. In Experiments 5 & 6, we presented the decline-test response in a delayed matching-to-sample task. Memory tests differed from perceptual tests in that the appearance of the test display could not control metacognitive responding. In Experiment 6, monkeys made prospective metamemory judgments before seeing the tests. Generalization across perceptual tests with different visual properties and mixed generalization from perceptual to memory tests provide provisional evidence that domain-general, private cues controlled metacognition in some monkeys. We observed individual differences in generalization, suggesting that monkeys differ in use of public and private metacognitive cues. PMID- 27939858 TI - A Quick Reference on Magnesium. AB - This article serves as a quick reference on the distribution, handling, and supplementation of magnesium. It also lists the manifestations and causes of magnesium deficit and provides criteria for the diagnosis of a magnesium deficit. PMID- 27939859 TI - Fluid Therapy for Pediatric Patients. AB - Young puppies and kittens have unique physiologic needs in regards to fluid therapy, which must address hydration, vascular fluid volume, electrolyte disturbances, or hypoglycemia. Pediatric patients have a higher fluid requirement compared with adults and can rapidly progress from mild dehydration to hypovolemia. Simultaneously, their small size makes overhydration a real possibility. Patient size complicates fluid administration because catheters used in larger pets may be difficult to place. Routes of fluid administration used in the neonate or pediatric patient include oral, subcutaneous, intraperitoneal, intraosseous, and intravenous. Clinicians should be aware of the pros and cons of each route. PMID- 27939860 TI - A Quick Reference on Hyperkalemia. AB - The clinical signs of hyperkalemia usually are less evident than hypokalemia. Arrhythmia and bradycardia could be the first changes noticed. Most cases of persistent hyperkalemia are associated with renal retention of potassium. Common causes for hyperkalemia include hypoadrenocorticism, ruptured bladder, and urethral or bilateral ureteral obstruction. Drug such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, potassium-sparing diuretics, and nonsteroidal antiinflammatory drugs can also lead to hyperkalemia. PMID- 27939857 TI - Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. AB - We recently discovered that forebrain activation of the IL-1 receptor/Toll-like receptor (IL-1R1/TLR4) innate immunity signal plays a pivotal role in neuronal hyperexcitability underlying seizures in rodents. Since this pathway is activated in neurons and glia in human epileptogenic foci, it represents a potential target for developing drugs interfering with the mechanisms of epileptogenesis that lead to spontaneous seizures. The lack of such drugs represents a major unmet clinical need. We tested therefore novel therapies inhibiting the IL-1R1/TLR4 signaling in an established murine model of acquired epilepsy. We used an epigenetic approach by injecting a synthetic mimic of micro(mi)RNA-146a that impairs IL1R1/TLR4 signal transduction, or we blocked receptor activation with antiinflammatory drugs. Both interventions when transiently applied to mice after epilepsy onset, prevented disease progression and dramatically reduced chronic seizure recurrence, while the anticonvulsant drug carbamazepine was ineffective. We conclude that IL-1R1/TLR4 is a novel potential therapeutic target for attaining disease-modifications in patients with diagnosed epilepsy. PMID- 27939861 TI - Fluid and Electrolyte Therapy During Vomiting and Diarrhea. AB - Fluid therapy is generally the most life saving and important therapeutic measure in a critical pet suffering from dehydration due to gastrointestinal losses (vomiting and/or diarrhea). Fluid therapy should be personalized to the patient's history, complaint, physical examination and laboratory findings. It is directed to the patients needs and modified based of the physical and laboratory findings until fluid therapy resuscitation end points are achieved. PMID- 27939863 TI - A Quick Reference on Respiratory Alkalosis. AB - Respiratory alkalosis, or primary hypocapnia, occurs when alveolar ventilation exceeds that required to eliminate the carbon dioxide produced by tissues. Concurrent decreases in Paco2, increases in pH, and compensatory decreases in blood HCO3- levels are associated with respiratory alkalosis. Respiratory alkalosis can be acute or chronic, with metabolic compensation initially consisting of cellular uptake of HCO3- and buffering by intracellular phosphates and proteins. Chronic respiratory alkalosis results in longer-lasting decreases in renal reabsorption of HCO3-; the arterial pH can approach near-normal values. PMID- 27939862 TI - A Quick Reference on Respiratory Acidosis. AB - Respiratory acidosis, or primary hypercapnia, occurs when carbon dioxide production exceeds elimination via the lung and is mainly owing to alveolar hypoventilation. Concurrent increases in Paco2, decreases in pH and compensatory increases in blood HCO3- concentration are associated with respiratory acidosis. Respiratory acidosis can be acute or chronic, with initial metabolic compensation to increase HCO3- concentrations by intracellular buffering. Chronic respiratory acidosis results in longer lasting increases in renal reabsorption of HCO3-. Alveolar hypoventilation and resulting respiratory acidosis may also be associated with hypoxemia, especially evident when patients are inspiring room air (20.9% O2). PMID- 27939864 TI - A Quick Reference on Hypokalemia. AB - Hypokalemia is more common than hyperkalemia and usually is caused by excessive losses of potassium from the kidneys or gastrointestinal tract. Serum potassium should be investigated in patients developing chronic or frequent vomiting or diarrhea, marked polyuria, muscle weakness, or unexpected cardiac arrhythmias, as well as in those undergoing therapy with insulin, diuretics, or total parenteral nutrition. Clinical signs develop when serum potassium deficit is moderate or severe. PMID- 27939866 TI - Natural pyrethrins induces apoptosis in human hepatocyte cells via Bax- and Bcl-2 mediated mitochondrial pathway. AB - Natural pyrethrins have been widely used for pest control in organic farming and for residential indoor pest managements. Although the specific mechanisms underlying their activity are incompletely understood, natural pesticides are considered the safest based on their target specificity and rapid degradation in the environment. Here, we used in vitro bioassays to characterize the cytotoxic effects of natural pyrethrins and attempted to delineate the cellular and molecular mechanisms of their cytotoxicity against human hepatocytes. The results demonstrate that natural pyrethrins reduce cell viability and enhance apoptosis in HepG2 cells. In addition, the current data indicate that natural pyrethrins cause a reduction in the mitochondrial membrane potential (Deltapsim), increase reactive oxygen species production, and up-regulate the Bax/Bcl-2 expression, leading to the release of cytochrome-c into the cytosol, activation of caspase-9 and caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP). Taken together, the results indicate that natural pyrethrins has potentially exert adverse effects on human health by inducing caspase-dependent apoptosis in hepatocytes through Bax- and Bcl-2-mediated mitochondrial pathway. PMID- 27939867 TI - The importance of nucleoside hydrolase enzyme (NH) in studies to treatment of Leishmania: A review. AB - Leishmania is a genus of trypanosomes, which are responsible for leishmaniasis disease, a major trypanosome infection in humans. In recent years, published studies have shown that the search for new drugs for Leishmania treatments has intensified. Through technique modeling it has been possible to develop new compounds, which act as nucleoside hydrolase (NH) inhibitors. The effect of these enzymes is the hydrolysis of certain RNA nucleotides, which include uridine and inosine, necessary for the protozoa to transform certain nucleosides obtained from infected individuals into nucleobases for the preparation of their DNA. The obtention of NH inhibitors is very important to eliminate leishmaniasis disease in infected individuals. The aim of this study is to discuss the research and development of new agents for the treatment of Leishmania, and to stimulate the formulation of new NH inhibitors. PMID- 27939865 TI - PITX2 DNA Methylation as Biomarker for Individualized Risk Assessment of Prostate Cancer in Core Biopsies. AB - Hypermethylation of the paired-like homeodomain transcription factor 2 (PITX2) gene is a strong predictor of the risk of biochemical recurrence in patients with prostate cancer (PCa) after radical prostatectomy. We investigate whether PITX2 methylation is feasible for individualized risk assessment in prostate core biopsies before surgery. A quantitative, methylation-specific real-time PCR was used to measure PITX2 in three cohorts: i) matched samples of neoplastic and nonneoplastic tissue from 24 patients with PCa, ii) a well-characterized cohort of 300 patients with PCa after radical prostatectomy, and iii) core biopsy specimens from 32 patients with PCa and 31 patients with benign prostatic disease. PITX2 methylation discriminated between neoplastic and nonneoplastic tissue in patients with PCa (P < 0.001). In the second cohort, PITX2 methylation significantly correlated with clinicopathologic parameters, and PITX2 hypermethylation predicted an increased risk of biochemical recurrence in univariate Cox proportional hazards regression analysis (hazard ratio, 1.77; P = 0.046) and Kaplan-Meier analysis (P = 0.043). In 753 prostate biopsies, 720 (95.6%) were applicable for analysis, rendering the assay feasible for diagnostic biopsies. PITX2 methylation was furthermore significantly increased in tumor positive biopsies and strongly correlated with International Society of Urological Pathology (ISUP) grade groups. This study indicates that the PITX2 methylation assay is feasible in prostate biopsies and might add valuable prognostic information for risk assessment in a presurgical diagnostic setting. PMID- 27939868 TI - Locating the Seventh Cervical Spinous Process: Accuracy of the Thorax-Rib Static Method and the Effects of Clinical Data on Its Performance. AB - OBJECTIVES: The aim of this study was to assess the thorax-rib static method (TRSM), a palpation method for locating the seventh cervical spinous process (C7SP), and to report clinical data on the accuracy of this method and that of the neck flexion-extension method (FEM), using radiography as the gold standard. METHODS: A single-blinded, cross-sectional diagnostic accuracy study was conducted. One hundred and one participants from a primary-to-tertiary health care center (63 men, 56 +/- 17 years of age) had their neck palpated using the FEM and the TRSM. A single examiner performed both the FEM and TRSM in a random sequence. Radiopaque markers were placed at each location with the aid of an ultraviolet lamp. Participants underwent chest radiography for assessment of the superimposed inner body structure, which was located by using either the FEM or the TRSM. RESULTS: Accuracy in identifying the C7SP was 18% and 33% (P = .013) with use of the FEM and the TRSM, respectively. The cumulative accuracy considering both caudal and cephalic directions (C7SP +/- 1SP) increased to 58% and 81% (P = .001) with use of the FEM and the TRSM, respectively. Age had a significant effect on the accuracy of FEM (P = .027) but not on the accuracy of TRSM (P = .939). Sex, body mass, body height, and body mass index had no significant effects on the accuracy of both the FEM (P = .209 or higher) and the TRSM (P = .265 or higher). CONCLUSIONS: The TRMS located the C7SP more accurately compared with the FEM at any given level of anatomic detail, although both still underperformed in terms of acceptable accuracy for a clinical setting. PMID- 27939869 TI - Ammonium conversion and its feedback effect on methane oxidation of Methylosinus sporium. AB - Ammonium (NH4+) is not only nitrogen source that can support methanotrophic growth, but also it can inhibit methane (CH4) oxidation by competing with CH4 for the active site of methane monooxygenase. NH4+ conversion and its feedback effect on the growth and activity of methanotrophs were evaluated with Methylosinus sporium used as a model methanotroph. Nitrogen sources could affect the CH4 derived carbon distribution, which varied with incubation time and nitrogen concentrations. More CH4-derived carbon was incorporated into biomass in the media with NH4+-N, compared to nitrate-nitrogen (NO3--N), as sole nitrogen source at the nitrogen concentrations of 10-18 mmol L-1. Although ammonia (NH3) oxidation activity of methanotrophs was considerably lower, only accounting for 0.01-0.06% of CH4 oxidation activity in the experimental cultures, NH4+ conversion could lead to the pH decrease and toxic intermediates accumulation in the their habits. Compared with NH4+, nitrite (NO2-) accumulation in the NH4+ conversion of methanotroph had stronger inhibition on its activity, especially the joint inhibition of NO2- accumulation and the pH decrease during the NH4+-N conversion. These results suggested that more attention should be paid to the feedback effects of NH4+ conversion by methanotrophs to understand effects of NH4+ on CH4 oxidation in the environments. PMID- 27939870 TI - Effect of pH on lactic acid production from acidogenic fermentation of food waste with different types of inocula. AB - Effect of acidic pH (4, 5, 6 and uncontrolled) on lactic acid (LA) fermentation from food waste was investigated by batch fermentation experiments using methanogenic sludge, fresh food waste and anaerobic activated sludge as inocula. Results showed that due to the increase of hydrolysis, substrate degradation rate and enzyme activity, the optimal LA concentration and yield were obtained at pH 5, regardless of the inoculum used. The highest LA concentration (28.4g/L) and yield (0.46g/g-TS) were obtained with fresh food waste as inoculum. Moreover, after the substrate was completely utilized, the lactic acid bacteria population sharply decreased, and the LA produced was converted to volatile fatty acids (VFAs) at pH 6 within a short period. The VFA components varied with the inoculum supplied. Microbial community analysis using high-throughput pyrosequencing revealed that diversity decreased and a high abundance of Lactobacillus (83.4 98.5%) accumulated during fermentation with all inocula. PMID- 27939871 TI - Bridged polysilsesquioxane-based wide-bore monolithic capillary columns for hydrophilic interaction chromatography. AB - The synthesis and characterization of large-bore silica-based monolithic capillary columns (0.32mm*150mm) are presented. Columns were prepared by acidic hydrolysis of a mixture containing tetramethoxysilane (TMOS) and 1,2 bis(trimethoxysilyl)ethane (BTME) in different molar ratios in the presence of polyethylene glycol and urea. The monoliths were modified by zwitterionic monomer [2-(methacryloyloxy)ethyl]-dimethyl-(3-sulfopropyl)-ammonium hydroxide via 3 (trimethoxysilyl)propyl methacrylate. Prepared stationary phases were evaluated by scanning electron microscopy and chromatographic separation of nucleobases and their derivatives in the HILIC mode. The best chromatographic results were obtained with the column prepared from the reaction mixture containing BTME and TMOS in a 1:4 molar ratio. The permeability of such column reached 1.68*10-14m2 and the efficiency, expressed as a height equivalent of the theoretical plate, did not exceed 10.5MUm for the tested compounds. The columns were successfully applied to HILIC separation of native and labeled oligosaccharides and glycans released from bovine ribonuclease B and human immunoglobulin G. PMID- 27939872 TI - HPTLC fingerprint profile, in vitro antioxidant and evaluation of antimicrobial compound produced from Brevibacillus brevis-EGS9 against multidrug resistant Staphylococcus aureus. AB - In the present study, in vitro antimicrobial activity of Brevibacillus brevis EGS9 against multi drug resistant Staphylococcus aureus (MDRSA) and to investigate the antimicrobial, antioxidant activity and HPTLC finger print profile of Brevibacillus brevis EGS9. Primary screening was done using by cross streak method against multi drug resistant Staphylococcus aureus. The bioactive metabolites were extracted from Brevibacillus brevis EGS9 using ethyl acetate extraction. Ethyl acetate extract showed significant antimicrobial activity against Escherichia coli (20.2 +/- 0.1) mm, Candida albicans (19.2 +/- 0.3) mm and Bacillus cereus (18.6 +/- 0.2) mm respectively. Forty three UTI bacterial strains were isolated from mid-urine samples of 50 males and 50 females. Escherichia coli were more predominant (48%) followed by Klebsilla pneumonia (29%), Pseudomonas aeruginosa (17%), Staphylococcus aureus (4%) and Enterobacter faecalis (6%). The ethyl acetate extract was examined to evaluate antibacterial properties against isolated UTIs bacterial pathogens. The results were revealed that the maximum zone was measured in Escherichia coli (18.1 +/- 0.4) mm and minimum zone of inhibition was shown against Pseudomonas aeruginosa (10.6 +/- 0.3) mm. Based on the results obtained, the extract of Brevibacillus brevis EGS9 exhibited dose dependent manner of antioxidant activity. The DPPH scavenging activity of lowest concentration at 25 MUg/ml and high concentration at 1000 MUg/ml was measured at 2.4% and 39.5% respectively. HPTLC finger print profile was showed the active compounds present in crude extract, which may responsible for the antioxidant prospective. These results showed that, the significant antimicrobial properties against pathogen; this work will be helpful to explore the active compound identification in the field of pharmaceutical research and able to produce new drug molecules against pathogens. PMID- 27939873 TI - Letter to the editor on 'The necessity of overhaul in perception of microbiological culture methods'. AB - Unarguably, clinical microbiology has got a boost from NGS technology, but in the process of this transition it has suffered a huge setback. Computational biology can find the microbial genomic variations and can link it to drug resistance, but it has so far underestimated the crucial role of microbial culture medium. The constituents and growth conditions of the medium have been documented to shuffle genomic, epigenetic and metabolic aspects of the bacterial pathogens. Ignoring these in vitro-driven evolutions and attributing the variations as normal bacterial features, responsible for drug resistance is a huge mistake. Unfortunately, it has been the trend since the inception of NGS in microbiology arena. No wonder, drug resistance is spreading unrestrained like wildfire and drug discovery is lagging behind. The urgent need to standardize culture medium by simulating it to human physiological conditions can salvage the situation and result in correct interpretations. PMID- 27939874 TI - Discovery of potent inhibitors targeting Vibrio harveyi LuxR through shape and e pharmacophore based virtual screening and its biological evaluation. AB - Quorum sensing is widely recognized as an efficient mechanism in the regulation and production of several virulence factors, biofilm formation and stress responses. For this reason, quorum sensing circuit is emerging as a novel drug target for the development of anti-infective. Recently, cinnamaldehyde derivatives have been found to interfere with master quorum sensing transcriptional regulator and thereby decreasing the DNA binding ability of LuxR. However, the exact mode of cinnamaldehyde binding with LuxR and receptor interaction still remains inconclusive. In the current study, combined method of molecular docking and molecular dynamics simulations were performed to investigate the binding mode, dynamic and energy aspects of cinnamaldehyde derivatives into the binding site of LuxR. Based on the experimental and computational evidences, LuxR-3,4-dichloro-cinnamaldehyde complex was chosen for the development of e-pharmacophore model. Further, shape and e-pharmacophore based virtual screening were performed against ChemBridge database to find potent and suitable ligands for LuxR. By comparing the results of shape and e pharmacophore based virtual screening; best 9 hit molecules were selected for further studies including ADMET prediction, molecular dynamics simulations and Prime MM-GBSA calculations. From the 9 hit molecules, the top most compound 3 (2,4-dichlorophenyl)-1-(1H-pyrrol-2-yl)-2-propen-1-one (ChemBridge-7364106) was selected for in vitro assays using Vibrio harveyi. The result revealed that ChemBridge-7364106 significantly reduced the bioluminescence production in a dose dependent manner. In addition, ChemBridge-7364106 showed a significant inhibition in biofilm formation and motility in V. harveyi. The results from the study suggest that ChemBridge-7364106 could serve as an anti-quorum sensing molecule for V. harveyi. PMID- 27939875 TI - Segmental Infantile Hemangioma With Minimal or Arrested Growth in LUMBAR Syndrome. PMID- 27939876 TI - Strategies used by Patients with Type 1 Diabetes to Avoid Hypoglycemia in a 24*1 Hour Marathon: Comparison with the Amounts of Carbohydrates Estimated by a Customizable Algorithm. AB - OBJECTIVES: The preferred countermeasure to avoid exercise-related hypoglycemia was investigated in a group of patients with type 1 diabetes participating in a stressful event, a 24*1-hour relay marathon. The carbohydrates actually consumed were compared to those estimated for each patient by applying a customizable algorithm, Exercise Carbohydrates Requirement Estimating Software (ECRES), based on patient's usual therapy and diet and on the exercise characteristics. METHODS: Glycemia was tested at the start, middle and end of the races. Usual therapies and diets and the adopted countermeasures were recorded in detail. RESULTS: We studied 19 patients who walked/ran 10.4+/-2.8 km with a heart rate of 167+/-11 beats per minute. Of the 19 patients, 7 patients reduced the administered insulin (premeal bolus or basal infusion rate). Glycemia fell by the end of the races (p=0.006; median -1.8 mmol?L-1; interquartile range -0.4 mmol?L-1 to -5.3 mmol?L 1), despite 9 patients being hyperglycemic at the start. Of the patients, 14 concluded the race with glycemia on target, and 4 patients were hyperglycemic. Amounts of carbohydrates actually consumed (median 30 g; interquartile range 0 g to 71 g) were not significantly different from those estimated by ECRES (median 38 g; interquartile range 24 g to 68 g), the 2 quantities being significantly related (R=0.64; p=0.003). ECRES estimated lower carbohydrate levels (-13 g) than the amounts actually consumed by the 4 patients who concluded their exercises with hyperglycemia. CONCLUSIONS: Patients preferred to consume extra carbohydrates to avoid the possible exercise-induced hypoglycemia. ECRES would provide satisfactory estimates of the carbohydrate requirements, even for a stressful condition, and almost equal to the quantities consumed following medical advice. PMID- 27939877 TI - Effect of Exercise and Antidepressants on Skeletal Outcomes in Adolescent Girls With Anorexia Nervosa. AB - PURPOSE: We examined the relationships between malnutrition, lifestyle factors, and bone health in anorexia nervosa (AN) via dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). METHODS: Seventy adolescent girls with AN and 132 normal-weighted controls underwent pQCT tibial measures including trabecular volumetric bone mineral density (vBMD), cortical vBMD, and cortical thickness. Participants with AN underwent DXA measures of the axial skeleton. We assessed the association of DXA and pQCT measures with clinical and lifestyle variables. RESULTS: Body mass index Z-score and ideal body weight percentage were positively correlated with trabecular vBMD, cortical CSA, and section modulus (p < .04). Exercise was associated with all pQCT measures but only with hip BMD by DXA. In AN, the use of antidepressants was associated with lower pQCT measures (p < .03). CONCLUSIONS: Antidepressants may negatively, and exercise positively, influence BMD in adolescents with eating disorders. These findings offer a provocative look at two longstanding questions. PMID- 27939878 TI - Components of Interventions That Improve Transitions to Adult Care for Adolescents With Type 1 Diabetes. AB - Adolescents with type 1 diabetes struggle with glycemic control with decline further exacerbated by transfer from pediatric to adult care. The purpose of this systematic review/meta-analysis was to examine which components of transition programs are effective in improving outcomes following transfer. We searched six databases for studies that assessed the efficacy of a transition program on diabetes outcomes. Studies reporting hemoglobin A1c (HbA1c) or its change for the intervention versus control group pretransition and posttransition were pooled using a random effects meta-analysis model. Of 4,689 studies identified, 18 (1 randomized control trial, 6 quasi-experimental, 1 prospective, and 10 retrospective cohort) met inclusion criteria. Findings represent data from 3,382 youth with type 1 diabetes (52% male, age 16-23 years) undergoing transition. Programs varied and included transition coordinators (n = 7), transition clinics (n = 10), and group education meetings (n = 5). Average age of transfer was 17.7 years. All but one study reported improvement/maintenance of HbA1c posttransition. However, pooling data from four studies with a control group (418 youth), there were no differences in HbA1c at 12 months (-.11 [95% confidence interval: -.31, .08]). Of other outcomes studied (clinic attendance [n = 12], severe hypoglycemia [n = 8], and diabetic ketoacidosis [n = 7]), transition programs showed greatest consistency in reducing diabetic ketoacidosis episodes. Findings suggest that transition interventions may be effective in maintaining glycemic control and reducing diabetic ketoacidosis episodes posttransition. Further research is needed to determine which program types are most effective. PMID- 27939879 TI - Trends in Adolescent Overweight Perception and Its Association With Psychosomatic Health 2002-2014: Evidence From 33 Countries. AB - PURPOSE: Perceiving oneself as overweight is common and strongly associated with adolescents' subjective well-being. The prevalence of overweight perceptions and their impact on well-being may have increased over the past decade due to an increase in the salience of weight-related issues. This study examines trends (2002-2014) in the prevalence of adolescent overweight perceptions and their association with psychosomatic complaints. METHODS: Data from 15-year-old adolescents were obtained between 2002 and 2014 in four rounds of the Health Behaviour in School-aged Children study in 33 countries in Europe and North America (N = 187,511). Design-adjusted logistic regressions were used to quantify changes in overweight perceptions over time. Linear modeling was used to assess change in the association between perceived overweight and self-reported psychosomatic complaint burden, adjusting for overweight status. RESULTS: Among boys, 10 of 33 countries saw an increase in overweight perceptions between 2002 and 2014, with Russia, Estonia, and Latvia showing the most pronounced year-on year increases. Only England, France, Germany, and Norway saw an increase in the positive association between overweight perceptions and psychosomatic complaints among boys. Among girls, most countries (28/33) saw no change in the prevalence of overweight perceptions, with the prevalence over 40% in most nations. However, in 12 countries, the association between overweight perceptions and psychosomatic complaints increased among girls, with particularly strong changes seen in Scotland and Norway. CONCLUSIONS: Evidence is presented which suggests that for adolescent girls in 12 Northern and Western European countries and for boys in four perceiving oneself as overweight may be increasingly deleterious for psychosomatic health. PMID- 27939880 TI - Adolescent Cigarette Smoking Perceptions and Behavior: Tobacco Control Gains and Gaps Amidst the Rapidly Expanding Tobacco Products Market From 2001 to 2015. AB - PURPOSE: The aim of the study was to determine whether adolescents' intentions to smoke, cigarette smoking behavior, and specific perceptions of cigarette smoking are different in 2015 versus 2001. METHODS: Data from two California school-based studies (Xage = 14) were compared: one conducted in 2001-2002 ("2001"), N = 395; the second in 2014-2015 ("2015"); N = 282. RESULTS: In 2015, more participants reported it was very unlikely they would smoke (94% vs. 65%) and that they never smoked (95% vs. 74%); they reported perceiving less likelihood of looking more mature (17% vs. 28%) and greater likelihood of getting into trouble (86% vs. 77%), having a heart attack (76% vs. 69%), and contracting lung cancer (85% vs. 78%) from smoking (p < .001). Perceptions of short-term health problems and addiction were similar in 2001 and 2015. CONCLUSIONS: Findings suggest that adolescents in 2015 perceived greater risks compared to those in 2001 even amidst the rapidly changing tobacco product landscape. In addition to continuing messages of long-term health risks, prevention efforts should include messages about addiction and short-term health and social risks. PMID- 27939881 TI - DeltaN-ASPP2, a novel isoform of the ASPP2 tumor suppressor, promotes cellular survival. AB - ASPP2 is a tumor suppressor that works, at least in part, through enhancing p53 dependent apoptosis. We now describe a new ASPP2 isoform, DeltaN-ASPP2, generated from an internal transcription start site that encodes an N-terminally truncated protein missing a predicted 254 amino acids. DeltaN-ASPP2 suppresses p53 target gene transactivation, promoter occupancy, and endogenous p53 target gene expression in response to DNA damage. Moreover, DeltaN-ASPP2 promotes progression through the cell cycle, as well as resistance to genotoxic stress-induced growth inhibition and apoptosis. Additionally, we found that DeltaN-ASPP2 expression is increased in human breast tumors as compared to adjacent normal breast tissue; in contrast, ASPP2 is suppressed in the majority of these breast tumors. Together, our results provide insight into how this new ASPP2 isoform may play a role in regulating the ASPP2-p53 axis. PMID- 27939883 TI - Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors. AB - Ligand-dependent activation of Notch signaling is required to maintain the stem cell niche of normal intestinal epithelium. However, the precise role of Notch signaling in the maintenance of the intestinal tumor stem cell niche and the importance of the RBPJ-independent non-canonical pathway in intestinal tumors remains unknown. Here we show that Notch signaling was activated in LGR5+ve cells of APC-deficient mice intestinal tumors. Accordingly, Notch ligands, including Jag1, Dll1, and Dll4, were expressed in these tumors. In vitro studies using tumor-derived organoids confirmed the intrinsic Notch activity-dependent growth of tumor cells. Surprisingly, the targeted deletion of Jag1 but not RBPJ in LGR5+ve tumor-initiating cells resulted in the silencing of Hes1 expression, disruption of the tumor stem cell niche, and dramatic reduction in the proliferation activity of APC-deficient intestinal tumors in vivo. Thus, our results highlight the importance of ligand-dependent non-canonical Notch signaling in the proliferation and maintenance of the tumor stem cell niche in APC-deficient intestinal adenomas. PMID- 27939884 TI - WIP promotes in-vitro invasion ability, anchorage independent growth and EMT progression of A549 lung adenocarcinoma cells by regulating RhoA levels. AB - Cancer cell migration and invasion involves actin cytoskeleton reorganization, which is regulated by the WASP (Wiskott Aldrich Syndrome Protein) family of proteins such as WASP, N-WASP (Neural-WASP) and WASP interacting protein (WIP). In this study, we found that the expression of WIP was significantly upregulated in metastatic A5-RT3 cells compared to its parental non-tumorigenic HaCaT cells. Using A549 human lung adenocarcinoma cell line as the model system, we found that WIP regulates cell invasion, proliferation and anchorage-independent growth. Expression of WIP was enhanced during TGF-beta1 induced epithelial-mesenchymal transition (EMT) and overexpression of WIP accelerated EMT while knocking down WIP attenuated EMT associated morphological changes. Knocking down WIP expression in A549 cells significantly reduced RhoA levels and WIP was found to interact with RhoA suggesting that WIP might be executing its function by regulating RhoA. Acquisition of invasive, proliferative properties and anoikis resistance is the central step in metastasis indicating a novel function of WIP in cancer progression. PMID- 27939882 TI - Clusterin and Pycr1 alterations associate with strain and model differences in susceptibility to experimental pancreatitis. AB - : Acute pancreatitis has several underlying etiologies, and results in consequences ranging from mild to complex multi-organ failure. The wide range of pathology suggests a genetic predisposition for progression. We compared the susceptibility to acute pancreatitis in BALB/c and FVB/N mice, coupled with proteomic analysis, in order to identify potential protein associations with pancreatitis progression. METHODS: Pancreatitis was induced in BALB/c and FVB/N mice by administration of cerulein or feeding a choline-deficient, ethionine supplemented (CDE) diet. Histology and changes in serum amylase were examined. Proteome profiling in cerulein-treated mice was performed using 2-dimensional differential in gel electrophoresis (2D-DIGE) followed by mass spectrometry analysis and biochemical validation. RESULTS: Male and female FVB/N mice manifested more severe cerulein-induced pancreatitis as compared with BALB/c mice, but both strains were similarly susceptible to CDE-induced pancreatitis. Few of the 2D-DIGE alterations were validated by immunoblotting. Clusterin was markedly up-regulated after cerulein-induced pancreatitis in FVB/N but less-so in BALB/c mice. Pyrroline-5-carboxylate reductase (Pycr1), an enzyme involved in proline biosynthesis, had higher basal levels in FVB/N male and female mouse pancreata compared with BALB/c pancreata, and was relatively more resistant to degradation in FVB/N pancreata. However, serum and pancreas tissue proline levels were similar in the two strains. CONCLUSION: FVB/N is more susceptible than BALB/c mice to cerulein-induced but not CDE-induced pancreatitis. Most of the 2D DIGE alterations in the two strains likely relate to posttranslational modifications rather than protein level differences. Clusterin levels increase dramatically in association with pancreatitis severity, while Pycr1 is higher in FVB/N versus BALB/c pancreata basally and after induction of pancreatitis. Changes in proline metabolism may represent a novel potential genetic modifier in the context of pancreatitis. PMID- 27939886 TI - ClbM is a versatile, cation-promiscuous MATE transporter found in the colibactin biosynthetic gene cluster. AB - Multidrug transporters play key roles in cellular drug resistance to toxic molecules, yet these transporters are also involved in natural product transport as part of biosynthetic clusters in bacteria and fungi. The genotoxic molecule colibactin is produced by strains of virulent and pathobiont Escherichia coli and Klebsiella pneumoniae. In the biosynthetic cluster is a multidrug and toxic compound extrusion protein (MATE) proposed to transport the prodrug molecule precolibactin across the cytoplasmic membrane, for subsequent cleavage by the peptidase ClbP and cellular export. We recently determined the X-ray structure of ClbM, and showed preliminary data suggesting its specific role in precolibactin transport. Here, we define a functional role of ClbM by examining transport capabilities under various biochemical conditions. Our data indicate ClbM responds to sodium, potassium, and rubidium ion gradients, while also having substantial transport activity in the absence of alkali cations. PMID- 27939885 TI - Tescalcin is a potential target of class I histone deacetylase inhibitors in neurons. AB - Class I histone deacetylase (HDAC) inhibitors are believed to have positive effects on neurite outgrowth, synaptic plasticity, and neurogenesis in adult brain. However, the downstream molecular targets of class I HDAC inhibitors in neurons are not clear. Although class I HDAC inhibitors are thought to broadly promote transcription of many neuronal genes through enhancement of histone acetylation, the affected gene set may include unidentified genes that are essential for neuronal survival and function. To identify novel genes that are targets of class I HDAC inhibitors, we used a microarray to screen transcripts from neuronal cultures and evaluated changes in protein and mRNA expression following treatment with four HDAC inhibitors. We identified tescalcin (Tesc) as the most strongly up-regulated gene following treatment with class I HDAC inhibitors in neurons. Moreover, hippocampal neurons overexpressing TESC showed a greater than 5-fold increase in the total length of neurites and number of branch points compared with controls. These findings highlight a potentially important role for TESC in mediating the neuroprotective effect of class I HDAC inhibitors. TESC may also be involved in the development of brain and neurodegenerative diseases through epigenetic mechanisms. PMID- 27939887 TI - B7-H3 regulates lipid metabolism of lung cancer through SREBP1-mediated expression of FASN. AB - B7-H3 is a glycoprotein overexpressed in cancer, but its functional contribution in this setting remains poorly understood. In the present study, we identified that the overexpression of B7-H3 in lung cancer resulted in aberrant lipid metabolism via SREBP-1/FASN signaling pathway. Immunohistochemical analysis of tissue microarrays revealed that approximately 80.4% (37/46) of lung cancer tissues were positive for B7-H3 accompanying poor prognosis. Notably, Oil red O staining and total triglyceride assay exhibited that down-regulation of B7-H3 decreased lipid synthesis in lung cancer A549 and H446 cell lines. Mechanistic investigations showed that B7-H3 modulated the expression of FASN, a fatty acid synthase, specifically. Furthermore, deletion of B7-H3 down-regulated the mRNA and protein levels of SREBP-1, a transcription factor governing the expression of FASN. Finally, correlation analysis between expression levels of B7-H3 and FASN exhibited a positive correlation in clinical lung cancer tissues. Overall, we conclude that B7-H3 hijacks SREBP-1/FASN signaling mediating abnormal lipid metabolism in lung cancer. Our finding provides new insights into the function and mechanism of B7-H3 in the development of lung cancer. PMID- 27939888 TI - Chaperone-mediated autophagy promotes lung cancer cell survival through selective stabilization of the pro-survival protein, MCL1. AB - Autophagy is a dynamic recycling system using lysosomal proteolysis that produces new proteins and energy for cellular renovation and homeostasis. Although macroautophagy is known to serve as a survival pathway in many cancer cells, the role of chaperone-mediated autophagy (CMA), a selective protein degradation system, in cancer is not fully understood. Here, we demonstrated that lysosomal proteolysis, but not macroautophagy, attenuated apoptosis induced by the tyrosine kinase inhibitor, crizotinib, in the non-small-cell lung cancer (NSCLC) cell line, EBC1. In EBC1 cells, crizotinib induced BIM-dependent apoptosis, which was enhanced by inhibition of lysosomal proteolysis. Moreover, degradation of the pro survival protein, MCL1, by the ubiquitin-proteasome system was induced by inhibition of lysosomal proteolysis, and by inhibition of the expression of the CMA mediators, HSC70 (heat shock cognate protein 70 kDa) and LAMP2A (lysosome membrane protein type 2A), suggesting the existence of a CMA-mediated MCL1 stabilization system in cancer cells. Indeed, the same MCL1 stabilization system was also observed in several NSCLC cell lines; in these cells, their specific molecular-targeted drug or ABT-263 (Navitoclax), the specific inhibitor of BCL-2 and BCL-XL, but not of MCL1, effectively induced apoptosis in combination with CMA inhibition. Therefore, our results indicate a novel mechanism of MCL1 stabilization in lung cancers by CMA, and a candidate efficient combination chemotherapy method against lung cancers. PMID- 27939889 TI - Trigonella foenum-graecum alleviates airway inflammation of allergic asthma in ovalbumin-induced mouse model. AB - Trigonella foenum-graecum, a member oldest medicinal plant in the fabaceae (legumes) family, is used as a herb, spice, and vegetable, and known for its olfactory, laxative, and galactogogue effects. However, the inhibitory effect of Trigonella foenum-graecum on allergic inflammatory response remains unclear, therefore, we investigated the precise role of Trigonella foenum-graecum in the allergic asthma and revealed the effects of Trigonella foenum-graecum in regulating airway inflammation and its possible mechanism. Allergic asthma was initiated in BALB/c mice by sensitized with OVA emulsified in aluminum on days 1 and 14, then aerosol challenged with OVA on days 27, 28 and 29. Some mice were administered Trigonella foenum-graecum by oral gavage before challenge. Then mice were evaluated for the presence of airway inflammation, production of allergen specific cytokine response and lung pathology. Trigonella foenum-graecum significantly ameliorated the number of inflammatory cells in BALF and alleviated lung inflammation. It also reduced the collagen deposition and goblet cells. Meanwhile, Trigonella foenum-graecum treatment evidently decreased the high expression of Th2 cytokines and increased the Th1 cytokines in BALF and lung homogenates. Trigonella foenum-graecum showed a significant inhibition of serum IgE and anti-OVA IgG1. In this study, our data suggest that Trigonella foenum graecum has a significant anti-inflammatory effect and it may prove to be an efficacious therapeutic regent on allergic asthma. PMID- 27939891 TI - Inactivation of the VID27 gene prevents suppression of the doa4 degradation defect in doa4Delta did3Delta double mutant. AB - Ubiquitination is a key regulatory mechanism that affects numerous cellular processes. This modification is reversible. Deubiquitinating enzymes (DUBs) remove the ubiquitin tag from modified proteins. DUB Doa4 is involved in deubiquitination of conjugates at the late endosome/pre vacuolar compartment. A genetic screen led to isolation of seven extragenic suppressors of the doa4 phenotypic abnormalities. Remarkably, cloned Doa4-independent degradation (DID) genes encode the class E vacuolar protein-sorting factors involved in membrane protein trafficking. Here we provide evidence that inactivation of Vid27 (vacuolar import and degradation) prevents suppression of the doa4 phenotype by did3 mutation. Vid27 is a cytoplasmic protein essential for delivery of fructose 1,6-bisphosphatase into VID vesicles. Thus, our data revealed another connection between Doa4 and vacuolar protein sorting. PMID- 27939890 TI - Lumican-null mice are susceptible to aging and isoproterenol-induced myocardial fibrosis. AB - With aging and stress, the myocardium undergoes structural remodeling, often leading to fibrosis. The purpose of this study is to examine whether lumican, one of the class II small leucine-rich proteoglycans, has a protective role in cardiac remodeling and fibrosis. In attempts to elucidate the hypothesis that lumican may have a protective role in cardiac remodeling and fibrosis, we compared the cardiac phenotypes of young (3-month-old) and elder (6-month- and 12 month-old) lumican-null (Lum-/-) mice. Extra-cellular matrix remodeling and apoptosis are examined to determine the roles of lumican on age-dependent cardiac fibrosis induced by isoproterenol. Compared to wild type littermates, Lum-/- mice exhibited higher mortality due to significantly impaired systolic function, which was associated with an increase of atrial natriuretic peptide (ANP) secreted by the ventricles in response to excessive stretching of myocytes. Masson's Trichrome and silver stains showed significantly more severe ventricle fibrosis in Lum-/- mice. Interestingly, rate of cell death mediated via apoptosis illustrated by the expression of caspase 3 and TUNEL assay was lower in Lum-/- mice after isoproterenol infusion. In addition, Lum-/- mice exhibited higher levels of TGF-beta, collagen I/III, and membrane-type matrix metalloproteinase-1 (MT1-MMP/MMP-14) during cardiac remodeling. This study shows that alternations of lumican might be implicated in the pathogenesis of cardiac fibrosis and suggests lumican as novel targets for cardiac fibrosis therapy. Further studies are required to define the mechanism by which lumican modulates cardiac remodeling. PMID- 27939892 TI - Ras mutants enhance the ability of cells to anticipate future lethal stressors. AB - Organisms integrate information of current environmental stressors and can adjust themselves against harmful events that might occur in the future. The molecular processes that lead to such "anticipatory" behaviors, although of great interest, are mostly unexplored and the minimal genetic requirements for reconfiguring key signaling networks in order either to create or to strengthen such vital "anticipatory" capabilities is largely unknown. We identified new "anticipatory" phenotypes in yeast cells by evolving yeast strains that strongly associate a present modest stress with a future deadly one. Whole genome sequencing and classic genetic analysis revealed that two dominant negative ras2 alleles (ras2 K23N and ras2-G17C) displayed a strong "anticipatory" ability being highly resistant to oxidative stress, extremely thermotolerant and long lived only following an initial mild heat shock. We suggest that such "anticipatory" phenotypes can be easily evolved by a single point mutation in a key signaling protein, the Ras2 small GTPase, and we propose a molecular model describing how specific ras2 alleles, and not null ras2 mutants, or mutations in other components of the Ras/cAMP pathway, can enhance the "predictive ability" of cells for future lethal stressors. PMID- 27939893 TI - Use of flecainide in combination antiarrhythmic therapy in patients with arrhythmogenic right ventricular cardiomyopathy. AB - BACKGROUND: Antiarrhythmic therapy is commonly used for suppression of arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) in conjunction with implantable cardioverter-defibrillators and catheter ablation. The efficacy of combination flecainide and sotalol/metoprolol therapy for patients refractory to single agents and/or catheter ablation has not been well established. OBJECTIVE: The purpose of this study was to describe our experience with the addition of flecainide in combination with sotalol/metoprolol for treatment of arrhythmias in patients with ARVC. METHODS: We reviewed all patients within our genetic arrhythmia program with a definite diagnosis of ARVC (45 patients) and identified 8 patients treated with a combination of flecainide with sotalol/metoprolol after failure of single-agent therapy and/or catheter ablation. These patients were monitored with at least yearly clinic visits and device interrogations focused on the detection of major ventricular arrhythmias. RESULTS: Of the 8 patients reviewed, 6 demonstrated excellent arrhythmia control after initiation of combination therapy with flecainide and sotalol/metoprolol. These patients have been arrhythmia-free for an average of 35.5 months. Two patients have demonstrated recurrent arrhythmias despite combination therapy and have undergone repeat epicardial and endocardial ablation. Recurrence was noted to occur within 2 months of therapy. Patients were diverse with regard to the severity of disease as well as in the presence of genetic mutations. CONCLUSION: The addition of flecainide in combination with sotalol/metoprolol may be an effective antiarrhythmic strategy for the control of ventricular arrhythmias in patients with ARVC refractory to single-agent therapy and/or catheter ablation. PMID- 27939894 TI - Review: Fetal-maternal communication via extracellular vesicles - Implications for complications of pregnancies. AB - The maternal physiology experiences numerous changes during pregnancy which are essential in controlling and maintaining maternal metabolic adaptations and fetal development. The human placenta is an organ that serves as the primary interface between the maternal and fetal circulation, thereby supplying the fetus with nutrients, blood and oxygen through the umbilical cord. During gestation, the placenta continuously releases several molecules into maternal circulation, including hormones, proteins, RNA and DNA. Interestingly, the presence of extracellular vesicles (EVs) of placental origin has been identified in maternal circulation across gestation. EVs can be categorised according to their size and/or origin into microvesicles (~150-1000 nm) and exosomes (~40-120 nm). Microvesicles are released by budding from the plasmatic membrane, whereas exosome release is by fusion of multivesicular bodies with the plasmatic membrane. Exosomes released from placental cells have been found to be regulated by oxygen tension and glucose concentration. Furthermore, maternal exosomes have the ability to stimulate cytokine release from endothelial cells. In this review, we will discuss the role of EVs during fetal-maternal communication during gestation with a special emphasis on exosomes. PMID- 27939895 TI - Misplaced Intrauterine Device Found on Laparoscopy. PMID- 27939897 TI - Endometrial Cystic Atrophy. PMID- 27939896 TI - Feasibility, Safety, and Prediction of Complications for Minimally Invasive Myomectomy in Women With Large and Numerous Myomata. AB - OBJECTIVE: To assess perioperative outcomes and identify predictors of complications for minimally invasive surgery (MIS) myomectomy in a cohort of women with large and numerous myomata. DESIGN: Case-control study (Canadian Task Force classification II-2). SETTING: Academic tertiary care medical center. PATIENTS: Women undergoing MIS myomectomy performed by 3 high-volume surgeons between April 2011 and December 2014. INTERVENTIONS: Characteristics were compared between women who experienced complications and those who did not. Factors predictive of complications were then identified. MEASUREMENTS AND MAIN RESULTS: A total of 221 women underwent an MIS myomectomy, 47.5% via a laparoscopic approach and 52.5% via robotic surgery. The mean +/- SD specimen weight was 408.1 +/- 384.9 g, uterine volume was 586.1 +/- 534.1 cm3, dominant myoma diameter was 9.6 +/- 5.1 cm, and number of myomata removed was 4.5 +/- 4.1. The most common complications were hemorrhage >1000 mL (8.6%) and blood transfusion (4.1%). The conversion rate was 1.8%. A dominant myoma diameter of >=12 cm and a uterine volume of >=750 cm3 increased the odds of complications (odds ratio [OR], 7.44; 95% confidence interval [CI], 2.03-31.84; p = .004 and OR, 6.15; 95% CI, 1.55-30.02; p = .014 respectively). A receiver operating characteristic curve considering dominant myoma diameter and uterine volume had an area under the curve of 0.81. A combination of dominant myoma diameter of >=10 cm and uterine volume of 600 cm3 predicted complications with 79% sensitivity and 79% specificity. CONCLUSION: Our cohort had large and numerous myomata with high specimen weights, but complications were comparable to those reported in previous studies of MIS myomectomy with less complex pathology. Hemorrhage and transfusion accounted for the majority of complications, and a combination of dominant myoma diameter and uterine volume was predictive of complications. Both factors can be easily defined before surgery and may be used to guide patient counseling, referrals, and implementation of preventative measures for hemorrhage and transfusion. PMID- 27939898 TI - Portomesenteric Vein Thrombosis After Excision of Parasitic Peritoneal Myomas. AB - An enlargement of multiple asymptomatic pelvic masses was detected during a regular checkup of a 39-year-old woman. Twelve years earlier, she had undergone laparoscopic-assisted myomectomy, at which time an uncontained manual extraction of a posterior intramural myoma was performed. This was followed by 2 uneventful cesarean deliveries after spontaneous conceptions. Diagnostic imaging revealed at least 3 abdominal masses, 1 of which received its major blood supply from the inferior mesenteric artery. Gasless single-port laparoscopic excision of the peritoneal masses, was performed along with laparoscopic-assisted vaginal hysterectomy and bilateral salpingo- oophorectomy. The masses were histopathologically diagnosed as parasitic peritoneal myomas. The patient's immediate postoperative course was uneventful; however, on day 6 after surgery, she complained of severe periumbilical abdominal pain and vomiting. Anticoagulant therapy was initiated after hematologic examination revealed an elevated D-dimer level and dynamic computed tomography angiography showed portomesenteric vein thrombosis. Vaginal stump bleeding, which occurred 17 days after the initiation of anticoagulant therapy, was managed conservatively, and there was no recurrence of venous thrombosis in the year after surgery. To avoid significant morbidities and potential mortality when parasitic peritoneal myomas with aberrant neovascularization are excised, attention should be given to the perioperative development of venous thromboembolic events in rare locations. PMID- 27939899 TI - High-Content Imaging Platform for Profiling Intracellular Signaling Network Activity in Living Cells. AB - Essential characteristics of cellular signaling networks include a complex interconnected architecture and temporal dynamics of protein activity. The latter can be monitored by Forster resonance energy transfer (FRET) biosensors at a single-live-cell level with high temporal resolution. However, these experiments are typically limited to the use of a couple of FRET biosensors. Here, we describe a FRET-based multi-parameter imaging platform (FMIP) that allows simultaneous high-throughput monitoring of multiple signaling pathways. We apply FMIP to monitor the crosstalk between epidermal growth factor receptor (EGFR) and insulin-like growth factor-1 receptor signaling, signaling perturbations caused by pathophysiologically relevant EGFR mutations, and the effects of a clinically important MEK inhibitor (selumetinib) on the EGFR network. We expect that in the future the platform will be applied to develop comprehensive models of signaling networks and will help to investigate the mechanism of action as well as side effects of therapeutic treatments. PMID- 27939900 TI - MRSA Isolates from United States Hospitals Carry dfrG and dfrK Resistance Genes and Succumb to Propargyl-Linked Antifolates. AB - Antibiotic resistance is a rapidly evolving health concern that requires a sustained effort to understand mechanisms of resistance and to develop new agents that overcome those mechanisms. The dihydrofolate reductase (DHFR) inhibitor, trimethoprim (TMP), remains one of the most important orally administered antibiotics. However, resistance through chromosomal mutations and mobile, plasmid-encoded insensitive DHFRs threatens the continued use of this agent. We are pursuing the development of new propargyl-linked antifolate (PLA) DHFR inhibitors designed to evade these mechanisms. While analyzing contemporary TMP resistant clinical isolates of methicillin-resistant and sensitive Staphylococcus aureus, we discovered two mobile resistance elements, dfrG and dfrK. This is the first identification of these resistance mechanisms in the United States. These resistant organisms were isolated from a variety of infection sites, show clonal diversity, and each contain distinct resistance genotypes for common antibiotics. Several PLAs showed significant activity against these resistant strains by direct inhibition of the TMP resistance elements. PMID- 27939901 TI - Readmission of ICU patients: A quality indicator? AB - PURPOSE: Readmission rate is frequently proposed as a quality indicator because it is related to both patient outcome and organizational efficiency. Currently available studies are not clear about modifiable factors as tools to reduce readmission rate. MATERIAL AND METHODS: In a 14year retrospective cohort study of 19,750 ICU admissions we identified 1378 readmissions (7%). A multivariate logistic regression analysis for determinants of readmission within 24h, 48h, 72h and any time during hospital admission was performed with adjustment for patients' characteristics and initial admission severity scores. RESULTS: In all models with different time points, patients with older age, a medical and emergency surgery initial admission and patients with higher SOFA score have a higher risk of readmission. Immunodeficiency was a predictor only in the at any time model. Confirmed infection was predicted in all models except the 24h model. Last day noradrenaline treatment was predicted in the 24 and 48h model. Mechanical ventilation on admission independently protected for readmission, which can be explained by the large number of cardiac surgery patients. All multivariate models had a moderate performance with the highest AUC of 0.70. CONCLUSIONS: Readmission can be predicted with moderate precision and independent variables associated with readmission are age, severity of disease, type of admission, infection, immunodeficiency and last day noradrenaline use. The latter factor is the only one that can be modified and therefore readmission rate does not meet the criteria to be used as a useful quality indicator. PMID- 27939902 TI - Cilostazol protects against microvascular brain injury in a rat model of type 2 diabetes. AB - Cilostazol, a pluripotent phosphodiesterase III-specific inhibitor with anti platelet and vasculogenic effects, is useful for preventing recurrent brain vascular events, particularly in stroke patients with diabetes mellitus (DM). However, it is unclear whether cilostazol affects autoregulatory responses in small cerebral arteries. Thus, we investigated the effect of cilostazol on diabetic brain vasculopathy in a model of type II DM using male OLETF rats. OLETF rats were treated with either cilostazol (CG) or vehicle (VG) and subjected to microangiography with monochromatic synchrotron radiation to investigate middle cerebral artery (MCA) vasoreactivity following an injection of acetylcholine (Ach). Ach administration led to MCA diameter contraction in the VG, but MCA dilation in the CG. We also evaluated morphological changes in the small intracranial vessels and found that in the CG, the endothelial cell structure in the small artery was not destroyed. Moreover, protein levels of phosphorylated endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) were higher in each evaluated brain region in CG rats vs. VG rats. Our results suggest that cilostazol could potentially improve autoregulatory responses in the small cerebral arteries by increasing eNOS phosphorylation and VEGF expression in DM, and thus, may act as a neurovascular protectant. PMID- 27939903 TI - Multifunctional polycationic photosensitizer conjugates with rich hydroxyl groups for versatile water-soluble photodynamic therapy nanoplatforms. AB - Photodynamic therapy (PDT) has already shown immense potential in antitumor fields due to its low systemic toxicity and negligible drug resistance. However, the clinical application of current photosensitizers is still restricted by the low singlet oxygen yield or insolubility. Herein, series of star-like hydroxyl rich polycations (Pc-PGEA/Pc) with flanking phthalocyanine (Pc) were proposed for effective water-soluble photosensitizers. The designed Pc-PGEA/Pc polymers consist of one Pc core and four ethanolamine and Pc-difunctionalized poly(glycidyl methacrylate) arms. The strong pi-pi stacking and hydrophobicity of introduced Pc units drive the amphipathic Pc-PGEA/Pc polymers to self-assemble into well-defined cationic nanoparticles. Such Pc-PGEA/Pc nanoparticles present impressive photodynamic therapy effects under moderate irradiation and remarkable photoacoustic imaging (PAI) ability. These kinds of nanoparticles also exhibit good performance as gene vectors. The PAI ability given by the proper wavelength absorbance of Pc units provides one promising method for PAI-guided combined antitumor therapy. The present work would contribute valuable information for the development of new strategies of visible antitumor therapy. PMID- 27939904 TI - Mitochondria-targeting "Nanoheater" for enhanced photothermal/chemo-therapy. AB - In this work, mitochondria-targeting gold nanostar (AuNS) and anticarcinogen DOX were co-encapsulated in hyaluronic acid (HA) protective shell for tumor-targeting synergistic photothermal/chemo-therapy. Cationic peptide R8 and mitochondria targeting pro-apoptotic peptide TPP-KLA were co-decorated on AuNS to form AuNS pep via Au-S bonds. Then, electronegative HA was further coated on the surface via electrostatic interaction for cancer cell targeting. During the coating process, DOX was also introduced via electrostatic interaction to obtain a versatile nanoplatform AuNS-pep/DOX@HA. It was found that the nanoplatform could be internalized into tumor cells via CD44 receptor-mediated recognition. Followed digestion by hyaluronidase (HAase), the therapeutic nanoplatform was able to release DOX for chemotherapy and mitochondria-targeting nanoheater AuNS-pep for near infrared (NIR) light triggered subcellular photothermal therapy (PTT). This tumor-targeting nanoplatform AuNS-pep/DOX@HA displayed prominent non-resistant or resistant tumor inhibition both in vitro and in vivo. PMID- 27939905 TI - Quadratus lumborum block intramuscular approach for pediatric surgery. PMID- 27939906 TI - Hypoperfusion in response to epinephrine in local anaesthetics: Investigation of dependence on epinephrine concentration, spread of hypoperfusion and time to maximal cutaneous vasoconstriction. AB - OBJECTIVES: The present study aimed to examine hypoperfusion in response to epinephrine following the administration of a local anaesthetic. The concentration of epinephrine that causes maximal hypoperfusion, the spread of hypoperfusion in the tissue and the time to the stabilization of hypoperfusion were investigated. METHODS: Blood perfusion was monitored using laser Doppler velocimetry and laser speckle contrast imaging of random-pattern advancement flaps (1 * 4 cm) or intact skin on the pig flank. Epinephrine was either injected cumulatively (0.1, 1.0, 10 or 100 MUg/ml) after injecting 20 mg/ml lidocaine, to determine the concentration response, or given as a single dose (12.5 MUg/ml epinephrine+20 mg/ml lidocaine). Control experiments were performed with saline or lidocaine (without epinephrine). RESULTS: Increasing concentrations of epinephrine resulted in a gradual decrease in skin perfusion, approaching a minimum after injecting 10 MUg/ml. The area of hypoperfusion was 12 mm in radius, and the time from the injection to the stabilization of hypoperfusion was approximately 120 s. After the administration of 10 MUg/ml epinephrine in flaps with small pedicle, 25% blood perfusion still remained. CONCLUSIONS: Local anaesthetic with an epinephrine concentration of approximately 10 MUg/ml appears to be adequate for vasoconstriction before surgery. Incisions were required to be delayed only for 2 min following local anaesthetic with epinephrine in pigs. The remaining 25% blood perfusion observed after the administration of epinephrine supports the use of epinephrine in flaps with a small pedicle. Obviously, these experimental findings must be clinically assessed before being considered for infiltration anaesthesia during plastic surgery procedures. PMID- 27939907 TI - Effect of interfragmentary gap on the mechanical behavior of mandibular angle fracture with three fixation designs: A finite element analysis. AB - BACKGROUND: The aim of this study was to simulate stress and strain distribution numerically on a normal mandible under physiological occlusal loadings. The results were compared with those of mandibles that had an angle fracture stabilized with different fixation designs under the same loadings. The amount of displacement at two interfragmentary gaps was also studied. MATERIALS AND METHODS: A three-dimensional (3D) virtual mandible was reconstructed with an angle fracture that had a fracture gap of either 0.1 or 1 mm. Three types of plate fixation designs were used: Type I, a miniplate was placed across the fracture line following the Champy technique; Type II, two miniplates were used; and Type III, a reconstruction plate was used on the inferior border of the mandible. Loads of 100 and 500 N were applied to the models. The maximum von Mises stress, strain, and displacement were computed using finite element analysis. The results from the control and experimental groups were analyzed and compared. RESULTS: The results demonstrated that high stresses and strains were distributed to the condylar and angular areas regardless of the loading position. The ratio of the plate/bone average stress ranged from 215% (Type II design) to 848% (Type I design) irrespective of the interfragmentary gap size. With a 1-mm fracture gap, the ratio of the plate/bone stress ranged from 204% (Type II design) to 1130% (Type I design). All strains were well below critical bone strain thresholds. Displacement on the cross-sectional mapping at fracture interface indicated that uneven movement occurred in x, y, and z directions. CONCLUSIONS: Interfragmentary gaps between 0.1 and 1 mm did not have a substantial effect on the average stress distribution to the fractured bony segments; however, they had a greater effect on the stress distribution to the plates and screws. Type II fixation was the best mechanical design under bite loads. Type I design was the least stable system and had the highest stress distribution and the largest displacement at the fracture site. PMID- 27939908 TI - Sutureless microvascular anastomosis with the aid of heparin loaded poloxamer 407. AB - BACKGROUND: Anastomosis with tissue adhesives is an alternative method for conventional anastomosis. However, this method has several technical challenges. It requires the use of suture to prevent leakage into lumen and precise application onto all surfaces of the anastomosis site. To solve these problems, poloxamer 407 (P 407) was previously used as a stent. In this study, we made heparinized P 407 (h-P 407) as a new formula. We aimed to successfully use h-P 407 as a stent in sutureless anastomosis in a rat abdominal aorta model. METHODS: Sixty Sprague-Dawley rats were used. In the first group, end-to-end anastomoses were performed with suture; in the second and third groups, sutureless anastomoses were performed with 2-octyl cyanoacrylate. As an intraluminal stent, P 407 was used in the second group, and h-P 407 was used in the third group. Anastomosis time was measured. Lumen width, intimal hyperplasia, and foreign body reaction were assessed histologically. Velocity flow rates and vessel diameters were measured radiologically. Burst strength was measured, and the results were statistically evaluated. RESULTS: Sutureless anastomosis was more rapid than conventional anastomosis. Lumen width was narrower in the suture group. Inflammation and foreign body reaction were more severe in the suture group. There was no radiologic and biomechanical difference between the groups. We found that intimal hyperplasia was less in h-P 407 than in P 407. CONCLUSION: h-P407 can be successfully used as an intraluminal stent for sutureless microvascular anastomosis with tissue adhesives. PMID- 27939909 TI - Liver failure after long-limb gastric bypass. AB - Liver failure is reported with increasing frequency in patients who underwent bariatric surgery for morbid obesity. In most cases, liver transplantation is the only possible treatment to avoid fatal outcome. Although most cases are observed after older bariatric surgery techniques characterized by high malabsorption rates, we report on a 38-year-old woman who developed liver failure seven months after long-limb gastric bypass. PMID- 27939910 TI - Identification of microRNAs as biomarkers for cholangiocarcinoma detection: A diagnostic meta-analysis. AB - BACKGROUND: Cholangiocarcinoma (CCA) is a common biliary malignancy that results in high mortality and poor survival rates. The diagnostic capacity of miRNAs in CCA detection is still controversial. Current meta-analysis evaluate the evidence on the capacity of miRNAs for CCA diagnosis. METHODS: A systematic literature search for relevant articles in PubMed, Embase and Web of science database up to 10 April 2016 was conducted. The pooled sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR, respectively), diagnostic odds ratio (DOR) and area under the curve (AUC) were pooled to assess the overall diagnostic value of miRNA. Subgroup analysis was further applied to explore the between study heterogeneity. Publication bias was assessed with Deeks' funnel plot. Statistical analysis was carried out using RevMan 5.2 and MetaDisc 1.4. RESULTS: A total of 501 patients and 248 controls from 14 studies in 8 articles were included in this meta-analysis. The pooled sensitivity and specialty were 0.83 (0.80-0.86) and 0.79 (0.75-0.83), respectively. The pooled PLR was 3.96 (2.64 5.94), NLR was 0.25 (0.19-0.34), DOR was 18.1 (9.79-33.5) and pooled AUC was 0.88 (0.85-0.90). Subgroup analyses indicated that the serum miRNA assays showed highly accurate CCA diagnosis. The diagnostic capacity was more accurate in Caucasians than in Asians. CONCLUSIONS: The miRNA assays are promising diagnostic tools for CCA detection with moderate accuracy. However, further prospective studies were needed to confirm this results before clinical application. PMID- 27939911 TI - "Unscrambling what's in your head": A mixed method evaluation of clinical supervision for midwives. AB - BACKGROUND: As a strategy to promote workforce sustainability a number of midwives working in one health district in New South Wales, Australia were trained to offer a reflective model of clinical supervision. The expectation was that these midwives would then be equipped to facilitate clinical supervision for their colleagues with the organisational aim of supporting professional development and promoting emotional well-being. AIM: To identify understanding, uptake, perceptions of impact, and the experiences of midwives accessing clinical supervision. METHOD: Mixed Methods. In phase one 225 midwives were invited to complete a self-administered survey. Descriptive and inferential statistics were used to analyse the data. In phase two 12 midwives were interviewed. Thematic analysis was used to deepen understanding of midwives' experiences of receiving clinical supervision. RESULTS: Sixty percent of midwives responding in phase one had some experience of clinical supervision. Findings from both phases were complementary with midwives reporting a positive impact on their work, interpersonal skills, situational responses and career goals. Midwives described clinical supervision as a formal, structured and confidential space for 'safe reflection' that was valued as an opportunity for self-care. Barriers included misconceptions, perceived work related pressures and a sense that taking time out was unjustifiable. CONCLUSION: Education, awareness raising and further research into reflective clinical supervision, to support emotional well-being and professional midwifery practice is needed. In addition, health organisations need to design, implement and evaluate strategies that support the embedding of clinical supervision within midwives' clinical practice. PMID- 27939912 TI - Effects of mastication on human somatosensory processing: A study using somatosensory-evoked potentials. AB - The aim of the present study was to investigate the effects of mastication on somatosensory processing using somatosensory-evoked potentials (SEPs). Fourteen healthy subjects received a median nerve stimulation at the right wrist under two conditions: Mastication and Control. SEPs were recorded in five sessions for approximately seven minutes: Pre, Post 1, 2, 3, and 4. Subjects were asked to chew gum for five minutes after one session in Mastication. Control included the same five sessions. The amplitudes and latencies of P14, N20, P25, N35, P45, and N60 components at C3', frontal N30 component at Fz, and P100 and N140 components at Pz were analyzed. The amplitude of P45-N60 was significantly smaller at Post 1, 2, 3, and 4 than at Pre in Control, but not in Mastication. The latency of P25 was significantly longer at Post 2, 3, and 4 than at Pre in Control, but not in Mastication. The latency of P100 was significantly longer at Post 2 than at Pre in Control, but not in Mastication. These results suggest the significant effects of mastication on the neural activity of human somatosensory processing. PMID- 27939914 TI - Corrigendum to "Dynamics of an SIR model with vaccination dependent on past prevalence with high order distributed delay" [BioSystems 129 (2015) 50-65]. PMID- 27939913 TI - Non-structural cancellous bone graft and headless compression screw fixation for treatment of scaphoid waist non-union. AB - PURPOSE: Scaphoid fracture commonly occurs around the mid-third of the scaphoid, and non-union of this fracture has several treatment options. The authors performed autologous cancellous bone graft from the iliac crest and headless compression screw fixation for the treatment of Mack-Lichtman type II scaphoid waist non-union. The purpose of this study was to determine whether this procedure was effective in achieving bony union and restoration of alignment. METHODS: Medical records and radiographs of 30 patients who underwent cancellous bone graft and headless compression screw fixation for non-union of scaphoid waist fracture were retrospectively reviewed. There were 28 men and 2 women, with a mean age of 32.8 years (range: 21-63). The mean time to surgery was 10 months (range: 3-25) and mean follow-up was 37.5 months (range: 15-52). The authors analyzed bony union, lateral intrascaphoid angle, scapholunate angle, radiolunate angle and scaphoid length on radiographs and evaluated the Modified Mayo wrist score (MMWS) as a functional outcome. RESULTS: Bony union was achieved in all cases. The lateral intrascaphoid angle improved from 40 degrees to 32 degrees (P<0.001). The scapholunate angle also improved from 61 degrees to 56 degrees (P=0.009). The radiolunate angle decreased from 8 degrees to 4 degrees (P=0.048) and scaphoid length increased from 22mm to 26mm (P<0.001) postoperatively. Wrist motion and MMWS improved significantly at last follow-up. However, there were no significant differences between scaphoid deformity correction angle and pre- to post-operative difference in MMWS. CONCLUSIONS: Non structural autologous cancellous bone graft from the iliac crest and headless screw fixation provided reliable results and can be one of the effective treatment options for patients with symptomatic Mack-Lichtman type II non-union in the mid-third of the scaphoid. LEVEL OF EVIDENCE: Level III. PMID- 27939915 TI - Acute kidney failure due to polyarteritis nodosa. PMID- 27939916 TI - Capecitabine, a possible reason of sudden cardiac death. PMID- 27939917 TI - Corrigendum to "Increased central microglial activation associated with peripheral cytokine levels in premanifest Huntington's disease gene carriers" [Neurobiol. Dis. 83 (2015) 115-121]. PMID- 27939918 TI - Corrigendum to "NCX1 and NCX3: Two new effectors of delayed preconditioning in brain ischemia" [Neurobiol. Dis. 45 (2012) 616-623]. PMID- 27939919 TI - Peptide nucleic acid probe-based fluorescence melting curve analysis for rapid screening of common JAK2, MPL, and CALR mutations. AB - BACKGROUND: We developed and evaluated the feasibility of peptide nucleic acid (PNA)-based fluorescence melting curve analysis (FMCA) to detect common mutations in myeloproliferative neoplasms (MPNs). METHODS: We have set up two separate reactions of PNA-based FMCA: JAK2 V617F &CALR p.Leu367fs*46 (set A) and MPL W515L/K &CALR p.Lys385fs*47 (set B). Clinical usefulness was validated with allele-specific real-time PCR, fragment analysis, Sanger sequencing in 57 BCR ABL1-negative MPNs. RESULTS: The limit of detection (LOD) of PNA-based FMCA was approximately 10% for each mutation and interference reactions using mixtures of different mutations were not observed. Non-specific amplification was not observed in normal control. PNA-based FMCA was able to detect all JAK2 V617F (n=20), CALR p.Leu367fs*46 (n=10) and p.Lys385fs*47 (n=8). Three of six MPL mutations were detected except three samples with low mutant concentration in out of LOD. JAK2 exon 12 mutations (n=7) were negative without influencing V617F results. Among six variant CALR exon 9 mutations, two were detected by this method owing to invading of probe binding site. CONCLUSIONS: PNA-based FMCA for detecting common JAK2, MPL, and CALR mutations is a rapid, simple, and sensitive technique in BCR-ABL1-negative MPNs with >10% mutant allele at the time of initial diagnosis. PMID- 27939920 TI - Gamma-glutamyl transferase and atrial fibrillation in patients with coronary artery disease. AB - BACKGROUND: The association between gamma-glutamyl transferase (GGT) and atrial fibrillation (AF) in patients with coronary artery disease (CAD) is uncertain. METHODS: This study included 5501 consecutive patients with CAD, all of whom had baseline GGT measurements available. The primary endpoint was presence of AF. RESULTS: Overall 809 patients (14.7%) had AF on hospital admission. Patients with AF had significantly higher GGT activity compared with patients in sinus rhythm (median [25th-75th percentile]: 52.0 [32.9-96.0] U/L versus 34.8 [23.8-55.9] U/L, P<0.001). The prevalence of AF increased from 8.6% of patients in the first GGT decile to 30.3% of patients in the tenth decile (P<0.001). After multivariable adjustment, GGT activity remained independently associated with the probability of the presence of AF (adjusted adds ratio=1.66, 95% confidence interval 1.53 1.81, P<0.001 for each standard deviation increment in the GGT logarithmic scale). GGT predicted the probability of AF with an area under the receiver operating characteristic (ROC) curve of 0.6496, 95% confidence interval 0.6287 to 0.6705, P<0.001 indicating moderate strength to discriminate between patients with and without AF. CONCLUSIONS: In patients with CAD, elevated GGT activity is independently associated with the presence of AF. GGT may be a circulating marker of the risk for AF. PMID- 27939921 TI - Regulation of oxidative phosphorylation through each-step activation (ESA): Evidences from computer modeling. AB - The mechanisms responsible for matching of the highly varying ATP demand by ATP supply in muscle are of primary importance for pure science, sport science and medicine. According to the traditional opinion ATP supply is activated by elevated ADP and Pi resulting from ATP hydrolysis during intensive work. Theoretical studies using the computer model of oxidative phosphorylation (OXPHOS) and the entire cell bioenergetic system developed by the author and co workers lead to the each-step-activation (ESA) mechanism of the regulation of the system in skeletal muscle, heart and other tissues during work transitions. According to ESA not only ATP usage, but also all OXPHOS complexes (complex I, complex III, complex IV, ATP synthase, ATP/ADP carrier, Pi carrier), NADH supply block and (anaerobic) glycolysis are directly activated by some cytosolic factor/mechanism during rest- or low-to-high work transitions. ESA conception results from large increase in oxygen consumption (VO2) and ATP turnover flux accompanied by only moderate or no changes in metabolite (ADP, Pi, PCr, NADH) concentrations during work transitions in skeletal muscle and heart and from the uniform distribution among OXPHOS complexes of the metabolic control over VO2, as defined within Metabolic Control Analysis. Several theoretical studies carried out using the discussed computer model of the cell bioenergetic system are overviewed. It is demonstrated that this model, involving the ESA mechanism, is able to explain numerous, apparently unrelated to each other, properties of the system. PMID- 27939922 TI - Duration adaptation modulates EEG correlates of subsequent temporal encoding. AB - Repetitive exposure to relatively long or short sensory events has been shown to shorten or lengthen the perceived duration of a subsequent event. However, the neural basis of this phenomenon, called duration adaptation, remains unclear. In this study, we used electroencephalography (EEG) to investigate whether duration adaptation could modulate the subsequent temporal encoding represented by the contingent negative variation (CNV). Participants were asked to reproduce the duration of a test stimulus after adapting duration (Experiment 1) or after anchor duration (Experiment 2). We found that both adapting duration and anchor duration affected the reproduction duration of a subsequently presented test stimulus. The simultaneously recorded event-related potentials (ERPs) revealed that test stimuli evoked clearly identifiable N1, P2 and CNV components in the fronto-central scalp. Further analyses showed that the CNV amplitude was modulated by duration adaptation: adaptation to shorter duration (200ms) increased whereas adaptation to longer duration (800ms) decreased the CNV amplitude. These findings suggest that the neural correlates of temporal encoding represented by the CNV amplitude reflect the duration aftereffect. Additionally, the duration adaptation effect observed on the P2 component also suggests an early expectancy effect on subsequent encoding processes. Finally, no effect of anchor duration was observed on the CNV amplitude, which implies that different mechanisms underlie the duration aftereffect and the anchor effect. PMID- 27939923 TI - CD98 siRNA-loaded nanoparticles decrease hepatic steatosis in mice. AB - Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid hepatic accumulation. Here, we investigated whether a reduction of CD98 expression mediated by CD98 siRNA-loaded nanoparticles (NPs) could attenuate liver disease markers in a mouse model of NAFLD. NPs were generated using a double emulsion/solvent evaporation technique. Mice fed a high fat diet for 8 weeks to induce fatty liver were treated with vein tail injections of CD98 siRNA loaded NPs. In vitro, HepG2 treated with CD98 siRNA-loaded NPs showed significant downregulation of CD98 leading to a significant decrease of major pro inflammatory cytokines and markers. In vivo, CD98 siRNA-loaded NPs strongly decreased all markers of NAFLD, including the blood levels of ALT and lipids accumulation, fibrosis evidence and pro-inflammatory cytokines. In conclusion, our results indicate that CD98 appears to function as a key actor/inducer in NAFLD, and that our NPs approach may offer a new targeted therapeutic for this disease. PMID- 27939924 TI - Clues on the function of Manduca sexta perilipin 2 inferred from developmental and nutrition-dependent changes in its expression. AB - Cellular triglycerides (TG) are stored in cytosolic lipid droplets (LDs). Perilipins (PLIN) are a group of LD-proteins that play important roles in the assembly and transport of LDs and in TG metabolism. Two members of the PLIN family are found in insects (PLIN1 & 2 or Lsd1 & 2). We have cloned and expressed Manduca sexta PLIN2 (MsPLIN2), and studied developmental and nutritional changes in the expression of PLIN2. Nutritional changes induced fast alterations in PLIN2 mRNA and protein levels in fat body and midgut of the feeding larvae. The relationship observed between PLIN2 expression and TG synthesis in both larval fat body and midgut suggests that PLIN2 is needed when tissues are accumulating TG. However, when the fat body was storing TG at maximal capacity, MsPLIN2 levels declined. This unexpected finding suggests the occurrence of alternative mechanism/s to shield TG from the action of lipases in M. sexta LDs. In addition, it implies that the cellular level of lipid storage could be modulating MsPLIN2 expression and/or degradation. The study also confirmed that MsPLIN2 was most abundant in the adult fat body, which is characterized by a high rate of TG hydrolysis and lipid mobilization. Whether MsPLIN2 is directly involved in lipolysis and/or the secretion of lipids in the fat body of adult of M. sexta is unknown at this time. Nonetheless, the coexistence of high PLIN2 and lipolysis levels suggests a complex role for MsPLIN2. Altogether, we found that MsPLIN2 is needed when the synthesis of glycerides, DG and TG, is active even if the insect is accumulating or consuming TG. PMID- 27939926 TI - Galen Wagner, M.D., Ph.D. (1939-2016) as international mentor of young investigators in electrocardiology. AB - This paper describes a substantial part of the international mentoring network of students and young investigators in electrocardiology that developed around Dr. Galen Wagner (1939-2016), including many experiences of his mentees and co mentors. The paper is meant to stimulate thinking about international mentoring as a means to achieve important learning experiences and personal development of young investigators, to intensify international scientific cooperation, and to stimulate scientific production. PMID- 27939927 TI - Special issue of the Journal of Electrocardiology to commemorate Dr. Galen Wagner (1939-2016). PMID- 27939925 TI - A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression. AB - INTRODUCTION: We hypothesized that common Alzheimer's disease (AD)-associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression. METHODS: Expression microarrays on temporal cortex and cerebellum from ~400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis. RESULTS: A variant within a DNase hypersensitive site 5' of TREM2, rs9357347-C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 * 10-3 and 4.6 * 10-2, respectively). Meta-analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 * 10-2 and 3.5 * 10-3, Bonferroni-corrected P = 6.7 * 10-2 and 7.1 * 10 3, respectively). DISCUSSION: Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome-wide association study meta-analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD. PMID- 27939929 TI - Molecular dynamics simulation of salt rejection through silicon carbide nanotubes as a nanostructure membrane. AB - Salt rejection phenomenon was investigated using armchair silicon carbide (SiC) nanotubes under applied electric fields. The systems included the (7,7) and (8,8) SiC nanotubes surrounded by silicon nitride membrane immersed in a 0.4mol/L aqueous solution of sodium chloride. Results of molecular dynamics (MD) simulations for selective separation of Na+ and Cl- ions showed that the (7,7) SiC nanotube is suitable for separation of cations and the (8,8) SiC nanotube can be used for separating anions. The water desalination by SiC nanotubes was demonstrated by potential of mean force for Na+ and Cl- ions in each SiC nanotube. Furthermore, the ionic current, ion residence time, and the radial distribution functions of species were measured to evaluate the properties of the system. Based on the results of this research, the studied SiC nanotubes can be recommended as a nanostructure model for water desalination. PMID- 27939928 TI - How Vial Geometry Variability Influences Heat Transfer and Product Temperature During Freeze-Drying. AB - Vial design features can play a significant role in heat transfer between the shelf and the product and, consequently, in the final quality of the freeze-dried product. Our objective was to investigate the impact of the variability of some geometrical dimensions of a set of tubing vials commonly used for pharmaceuticals production on the distribution of the vial heat transfer coefficients (Kv) and its potential consequence on product temperature. Sublimation tests were carried out using pure water and 8 combinations of chamber pressure (4-50 Pa) and shelf temperature (-40 degrees C and 0 degrees C) in 2 freeze-dryers. Kv values were individually determined for 100 vials located in the center of the shelf. Vial bottom curvature depth and contact area between the vial and the shelf were carefully measured for 120 vials and these data were used to calculate Kv distribution due to variability in vial geometry. At low pressures commonly used for sensitive products (below 10 Pa), the vial-shelf contact area appeared crucial for explaining Kv heterogeneity and was found to generate, in our study, a product temperature distribution of approximately 2 degrees C during sublimation. Our approach provides quantitative guidelines for defining vial geometry tolerance specifications and product temperature safety margins. PMID- 27939930 TI - Proliferating miller indices of C20 fullerene device under DFT-NEGF regime. AB - We present ab-initio scrutiny of electron transport through C20 fullerene cleaved with gold electrodes having unique set of miller orientations. The three families of miller indices {100}, {110} and {111} are considered with four exclusive device models for elucidating electronic transport under applied potential of - 2 to +2V. Thereafter, the quantum calculations employing DFT-NEGF are performed for envisaging density of states, transmission function, energy levels, molecular orbitals, charge transfer. These electronic transfer parameters lead to the study of its two electrical parameters: current and conductance. We conclude that in molecular-devices of constituted miller family {110}, HOMO-LUMO gap are inversely proportional to extent of charge carriers. While for miller devices {100} and {111}, the situation is fully contrasting with HOMO-LUMO gap being directly proportional to its charge carriers. Another important conclusion is that the gold electrodes having miller family {100} and {111} are providing equal opportunity to fullerene molecule to imply its behavior while electrodes of miller family {110} are over shadowing the performance of fullerene molecule. PMID- 27939932 TI - Meshing molecular surfaces based on analytical implicit representation. AB - We develop an algorithm for meshing molecular surfaces that is based on patch wise meshing using an advancing-front method adapted to the particular case of molecular surfaces. We focus on the solvent accessible surface (SAS) and the solvent excluded surface (SES). The essential ingredient is a newly developed analysis of such surfaces in [18] that allows to describe all SES-singularities a priori and therefore a complete characterization of the SES. In addition, an algorithm for filling molecular inner holes is proposed based on the pre-computed data structures of molecular surfaces. PMID- 27939931 TI - Probing the stereospecificity of tyrosyl- and glutaminyl-tRNA synthetase with molecular dynamics. AB - The stereospecificity of aminoacyl-tRNA synthetases helps exclude d-amino acids from protein synthesis and could perhaps be engineered to allow controlled d amino acylation of tRNA. We use molecular dynamics simulations to probe the stereospecificity of the class I tyrosyl- and glutaminyl-tRNA synthetases (TyrRS, GlnRS), including wildtype enzymes and three point mutants suggested by three different protein design methods. l/d binding free energy differences are obtained by alchemically and reversibly transforming the ligand from L to D in simulations of the protein-ligand complex. The D81Q mutation in Escherichia coli TyrRS is homologous to the D81R mutant shown earlier to have inverted stereospecificity. D81Q is predicted to lead to a rotated ligand backbone and an increased, not a decreased l-Tyr preference. The E36Q mutation in Methanococcus jannaschii TyrRS has a predicted l/d binding free energy difference DeltaDeltaG of just 0.5+/-0.9kcal/mol, compared to 3.1+/-0.8kcal/mol for the wildtype enzyme (favoring l-Tyr). The ligand ammonium position is preserved in the d-Tyr complex, while the carboxylate is shifted. Wildtype GlnRS has a similar preference for l glutaminyl adenylate; the R260Q mutant has an increased preference, even though Arg260 makes a large contribution to the wildtype DeltaDeltaG value. PMID- 27939933 TI - Investigating carbohydrate based ligands for galectin-3 with docking and molecular dynamics studies. AB - Galectin-3 (Gal-3) is a carbohydrate binding protein that is overexpressed in several types of cancers, including pancreatic cancer, which makes it a good target for both imaging and therapeutic drug design. A ligand library specialized for 18F positron emission tomography (PET) has been investigated with molecular dynamics (MD) and free energy methods to determine the relative binding energies of various potential ligands. Our results suggest that traditional docking methods can give good results when complemented by molecular dynamics and free energy methods for these types of ligands. Available experimental binding affinities for a small number of the tested compounds show very good agreement with the calculated energies and provide the rational approach for design of Gal 3 ligands with even higher affinity. PMID- 27939934 TI - Radiation-induced clustered DNA lesions: Repair and mutagenesis. AB - Clustered DNA lesions, also called Multiply Damaged Sites, is the hallmark of ionizing radiation. It is defined as the combination of two or more lesions, comprising strand breaks, oxidatively generated base damage, abasic sites within one or two DNA helix turns, created by the passage of a single radiation track. DSB clustered lesions associate DSB and several base damage and abasic sites in close vicinity, and are assimilated to complex DSB. Non-DSB clustered lesions comprise single strand break, base damage and abasic sites. At radiation with low Linear Energy Transfer (LET), such as X-rays or gamma-rays clustered DNA lesions are 3-4 times more abundant than DSB. Their proportion and their complexity increase with increasing LET; they may represent a large part of the damage to DNA. Studies in vitro using engineered clustered DNA lesions of increasing complexity have greatly enhanced our understanding on how non-DSB clustered lesions are processed. Base excision repair is compromised, the observed hierarchy in the processing of the lesions within a cluster leads to the formation of SSB or DSB as repair intermediates and increases the lifetime of the lesions. As a consequence, the chances of mutation drastically increase. Complex DSB, either formed directly by irradiation or by the processing of non-DSB clustered lesions, are repaired by slow kinetics or left unrepaired and cause cell death or pass mitosis. In surviving cells, large deletions, translocations, and chromosomal aberrations are observed. This review details the most recent data on the processing of non-DSB clustered lesions and complex DSB and tends to demonstrate the high significance of these specific DNA damage in terms of genomic instability induction. PMID- 27939936 TI - Spatial and seasonal variations, sources, air-soil exchange, and carcinogenic risk assessment for PAHs and PCBs in air and soil of Kutahya, Turkey, the province of thermal power plants. AB - Atmospheric and concurrent soil samples were collected during winter and summer of 2014 at 41 sites in Kutahya, Turkey to investigate spatial and seasonal variations, sources, air-soil exchange, and associated carcinogenic risks of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs). The highest atmospheric and soil concentrations were observed near power plants and residential areas, and the wintertime concentrations were generally higher than ones measured in summer. Spatial distribution of measured ambient concentrations and results of the factor analysis showed that the major contributing PAH sources in Kutahya region were the coal combustion for power generation and residential heating (48.9%), and diesel and gasoline exhaust emissions (47.3%) while the major PCB sources were the coal (thermal power plants and residential heating) and wood combustion (residential heating) (45.4%), and evaporative emissions from previously used technical PCB mixtures (34.7%). Results of fugacity fraction calculations indicated that the soil and atmosphere were not in equilibrium for most of the PAHs (88.0% in winter, 87.4% in summer) and PCBs (76.8% in winter, 83.8% in summer). For PAHs, deposition to the soil was the dominant mechanism in winter while in summer volatilization was equally important. For PCBs, volatilization dominated in summer while deposition was higher in winter. Cancer risks associated with inhalation and accidental soil ingestion of soil were also estimated. Generally, the estimated carcinogenic risks were below the acceptable risk level of 10-6. The percentage of the population exceeding the acceptable risk level ranged from <1% to 16%, except, 32% of the inhalation risk levels due to PAH exposure in winter at urban/industrial sites were >10-6. PMID- 27939937 TI - Public health implications of environmental noise associated with unconventional oil and gas development. AB - Modern oil and gas development frequently occurs in close proximity to human populations and increased levels of ambient noise have been documented throughout some phases of development. Numerous studies have evaluated air and water quality degradation and human exposure pathways, but few have evaluated potential health risks and impacts from environmental noise exposure. We reviewed the scientific literature on environmental noise exposure to determine the potential concerns, if any, that noise from oil and gas development activities present to public health. Data on noise levels associated with oil and gas development are limited, but measurements can be evaluated amidst the large body of epidemiology assessing the non-auditory effects of environmental noise exposure and established public health guidelines for community noise. There are a large number of noise dependent and subjective factors that make the determination of a dose response relationship between noise and health outcomes difficult. However, the literature indicates that oil and gas activities produce noise at levels that may increase the risk of adverse health outcomes, including annoyance, sleep disturbance, and cardiovascular disease. More studies that investigate the relationships between noise exposure and human health risks from unconventional oil and gas development are warranted. Finally, policies and mitigation techniques that limit human exposure to noise from oil and gas operations should be considered to reduce health risks. PMID- 27939935 TI - Catalase deletion promotes prediabetic phenotype in mice. AB - Hydrogen peroxide is produced endogenously and can be toxic to living organisms by inducing oxidative stress and cell damage. However, it has also been identified as a signal transduction molecule. By metabolizing hydrogen peroxide, catalase protects cells and tissues against oxidative damage and may also influence signal transduction mechanisms. Studies suggest that acatalasemic individuals (i.e., those with very low catalase activity) have a higher risk for the development of diabetes. We now report catalase knockout (Cat-/-) mice, when fed a normal (6.5% lipid) chow, exhibit an obese phenotype that manifests as an increase in body weight that becomes more pronounced with age. The mice demonstrate altered hepatic and muscle lipid deposition, as well as increases in serum and hepatic triglycerides (TGs), and increased hepatic transcription and protein expression of PPARgamma. Liver morphology revealed steatosis with inflammation. Cat-/- mice also exhibited pancreatic morphological changes that correlated with impaired glucose tolerance and increased fasting serum insulin levels, conditions consistent with pre-diabetic status. RNA-seq analyses revealed a differential expression of pathways and genes in Cat-/- mice, many of which are related to metabolic syndrome, diabetes, and obesity, such as Pparg and Cidec. In conclusion, the results of the present study show mice devoid of catalase develop an obese, pre-diabetic phenotype and provide compelling evidence for catalase (or its products) being integral in metabolic regulation. PMID- 27939938 TI - Effects of sediment-associated CuO nanoparticles on Cu bioaccumulation and oxidative stress responses in freshwater snail Bellamya aeruginosa. AB - Copper oxide nanoparticles (CuO-NPs) may pose high ecological risks to aquatic ecosystems. While sediments are the final destinations for CuO-NPs, little is known about the potential ecotoxicity of sediment-associated CuO-NPs on freshwater deposit-feeding macroinvertebrates. The gastropod Bellamya aeruginosa was chosen as an ecotoxicological test species. Adult snails were exposed to Cu (180MUg/g dry weight (DW)) added to sediments in the form of CuO-NPs, CuO microparticles (CuO-MPs, size control), and CuSO4 (solubility control) for 7, 14, and 28days, Cu burdens in different tissues and biomarkers of oxidative stress were determined to understand Cu accumulation differences among tissues, potential mechanisms of Cu uptake, time-effect relationships, particle size effects, and the relative contribution of toxicity from CuO-NPs and its soluble Cu ions. There was no difference in Cu ion concentrations in porewaters between the CuO-NPs and CuO-MPs treatments. In addition, relatively low Cu ion concentrations in porewater might indicate their remarkably low solubility. The hepatopancreas and gonad of B. aeruginosa are the primary target tissues for Cu accumulation. Cu accumulation in the hepatopancreas and gonad from CuSO4 treatments was consistently higher than that from the CuO-NPs and CuO-MPs treatments. After long-term exposure, Cu accumulation was higher from CuO-NPs than from CuO-MPs, especially, the Cu accumulation rate from CuO-NPs was greater than that from CuSO4. Short-term exposure to the three Cu forms caused oxidative stress to the hepatopancreas. CuO-MPs did not cause oxidative damage. Long-term exposure to CuO-NPs and CuSO4 resulted in oxidative damage. Overall, prolonged exposure to CuO-NPs will increase the ecotoxicity risk to B. aeruginosa. Although there was no difference in Cu accumulation between the CuO-NPs and CuO-MPs treatments after 14days of exposure, pronounced oxidative damage was caused by exposure to CuO-NPs but not to CuO-MPs, implying that toxicity of CuO-NPs could be attributed to specific nanoparticulate effects. PMID- 27939940 TI - Expression of ER-alpha and ER-beta during peri-implantation period in uterus is essential for implantation and decidualization in golden hamster. AB - AIMS: The role of estrogen in embryo implantation in golden hamster (Mesocricetus auratus) is still ambiguous. In order to clarify it, we investigated the spatial distribution and expression of estrogen receptors, ER-alpha and ER-beta in the uterus of pregnant hamster during peri-implantation period and identified the effect of estrogen receptor antagonist ICI-182,780 on the embryo implantation. MAIN METHODS: We performed in vivo experiments on early pregnant hamsters involving treatment with ICI-182,780, an estrogen receptor antagonist. Immunohistochemistry, western blot analysis and quantitative PCR were employed to evaluate the spatio-temporal distribution and expression of ER-alpha and ER-beta in the uterus of normal early pregnant and treated hamsters. KEY FINDINGS: Results showed that embryo implantation was completely absent in ICI-182,780 treated uterine horn while, normal implantation occurred in control and vehicle treated horns. Both the receptors were differentially expressed in the uterus of hamster from day 1 (D1) to day7 (D7). In contrast, treated horns without any implantation site showed no trace of any receptors. Protein and mRNA expression of both the receptors were high around the day of implantation while, ER-beta expression was up-regulated on D7 of embryo implantation. P value?0.05 is considered significant. SIGNIFICANCE: Spatio-temporal expression of ERs in the uterus during peri-implantation period have crucial role for endometrium receptivity and implantation in hamster. Recurrent implantation failure is the devastating problem among the desirable couple and is mainly due to defect in endometrium receptivity. This study may provide a new insight to manage the problem of idiopathic infertility. PMID- 27939939 TI - CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets. AB - CD38 is an ectoenzyme that catalyzes the conversion of beta-nicotinamide adenine dinucleotide (beta-NAD) to cyclic adenosine diphosphoribose (cADPR) and adenosine diphosphoribose (ADPR) and NADP to nicotinic acid adenine dinucleotide phosphate (NAADP) and adenosine diphosphoribose-2'-phosphate (ADPR-P). The metabolites of NAD and NADP have roles in calcium signaling in different cell types including airway smooth muscle (ASM) cells. In ASM cells, inflammatory cytokines augment CD38 expression and to a greater magnitude in cells from asthmatics, indicating a greater capacity for the generation of cADPR and ADPR in ASM from asthmatics. CD38 deficient mice develop attenuated airway responsiveness to inhaled methacholine following allergen sensitization and challenge compared to wild-type mice indicating its potential role in asthma. Regulation of CD38 expression in ASM cells is achieved by mitogen activated protein kinases, specific isoforms of PI3 kinases, the transcription factors NF-kappaB and AP-1, and post transcriptionally by microRNAs. This review will focus on the role of CD38 in intracellular calcium regulation in ASM, contribution to airway inflammation and airway hyperresponsiveness in mouse models of allergic airway inflammation, the transcriptional and post-transcriptional mechanisms of regulation of expression, and outline approaches to inhibit its expression and activity. PMID- 27939941 TI - The Toxin-Antitoxin System DarTG Catalyzes Reversible ADP-Ribosylation of DNA. AB - The discovery and study of toxin-antitoxin (TA) systems helps us advance our understanding of the strategies prokaryotes employ to regulate cellular processes related to the general stress response, such as defense against phages, growth control, biofilm formation, persistence, and programmed cell death. Here we identify and characterize a TA system found in various bacteria, including the global pathogen Mycobacterium tuberculosis. The toxin of the system (DarT) is a domain of unknown function (DUF) 4433, and the antitoxin (DarG) a macrodomain protein. We demonstrate that DarT is an enzyme that specifically modifies thymidines on single-stranded DNA in a sequence-specific manner by a nucleotide type modification called ADP-ribosylation. We also show that this modification can be removed by DarG. Our results provide an example of reversible DNA ADP ribosylation, and we anticipate potential therapeutic benefits by targeting this enzyme-enzyme TA system in bacterial pathogens such as M. tuberculosis. PMID- 27939942 TI - Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM. AB - Ataxia-telangiectasia mutated (ATM) regulates the DNA damage response as well as DNA double-strand break repair through homologous recombination. Here we show that ATM is hyperactive when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is chemically inhibited or when the DNA-PKcs gene is deleted in human cells. Pre-incubation of ATM protein with active DNA-PKcs also significantly reduces ATM activity in vitro. We characterize several phosphorylation sites in ATM that are targets of DNA-PKcs and show that phospho mimetic mutations at these residues significantly inhibit ATM activity and impair ATM signaling upon DNA damage. In contrast, phospho-blocking mutations at one cluster of sites increase the frequency of apoptosis during normal cell growth. DNA-PKcs, which is integral to the non-homologous end joining pathway, thus negatively regulates ATM activity through phosphorylation of ATM. These observations illuminate an important regulatory mechanism for ATM that also controls DNA repair pathway choice. PMID- 27939943 TI - The Mitotic Checkpoint Complex Requires an Evolutionary Conserved Cassette to Bind and Inhibit Active APC/C. AB - The Spindle Assembly Checkpoint (SAC) ensures genomic stability by preventing sister chromatid separation until all chromosomes are attached to the spindle. It catalyzes the production of the Mitotic Checkpoint Complex (MCC), which inhibits Cdc20 to inactivate the Anaphase Promoting Complex/Cyclosome (APC/C). Here we show that two Cdc20-binding motifs in BubR1 of the recently identified ABBA motif class are crucial for the MCC to recognize active APC/C-Cdc20. Mutating these motifs eliminates MCC binding to the APC/C, thereby abolishing the SAC and preventing cells from arresting in response to microtubule poisons. These ABBA motifs flank a KEN box to form a cassette that is highly conserved through evolution, both in the arrangement and spacing of the ABBA-KEN-ABBA motifs, and association with the amino-terminal KEN box required to form the MCC. We propose that the ABBA-KEN-ABBA cassette holds the MCC onto the APC/C by binding the two Cdc20 molecules in the MCC-APC/C complex. PMID- 27939944 TI - A SUMO-Dependent Protein Network Regulates Chromosome Congression during Oocyte Meiosis. AB - During Caenorhabditis elegans oocyte meiosis, a multi-protein ring complex (RC) localized between homologous chromosomes, promotes chromosome congression through the action of the chromokinesin KLP-19. While some RC components are known, the mechanism of RC assembly has remained obscure. We show that SUMO E3 ligase GEI 17/PIAS is required for KLP-19 recruitment to the RC, and proteomic analysis identified KLP-19 as a SUMO substrate in vivo. In vitro analysis revealed that KLP-19 is efficiently sumoylated in a GEI-17-dependent manner, while GEI-17 undergoes extensive auto-sumoylation. GEI-17 and another RC component, the kinase BUB-1, contain functional SUMO interaction motifs (SIMs), allowing them to recruit SUMO modified proteins, including KLP-19, into the RC. Thus, dynamic SUMO modification and the presence of SIMs in RC components generate a SUMO-SIM network that facilitates assembly of the RC. Our results highlight the importance of SUMO-SIM networks in regulating the assembly of dynamic protein complexes. PMID- 27939945 TI - Substitution of the precursor peptide prevents anti-prM antibody-mediated antibody-dependent enhancement of dengue virus infection. AB - Antibody-dependent enhancement (ADE) is currently considered as the mechanism underlying the pathogenesis of severe dengue disease. Many studies have shown that precursor (pr) peptide-specific antibodies do not efficiently neutralize infection but potently promote ADE of dengue virus (DENV) infection. To explore the effect of pr peptide substitution on neutralization and ADE of DENV infection, the rabbit anti-prM polyclonal antibodies (pAbs) and anti-JEVpr/DENV-M pAbs were prepared, and the neutralization and ADE of these two pAbs were further compared. Here, we report that both anti-JEVpr/DENV-M and anti-prM pAbs exhibited broad cross-reactivity and only partial neutralization with four DENV serotypes and immature DENV. Rabbit anti-prM pAbs showed a significant enhancement in a broad range of serum dilutions. However, there was no statistically significant difference in the enhancing activity of rabbit anti-JEVpr/DENV-M pAbs at various levels of dilution. These results demonstrate that anti-prM antibody-mediated ADE can be prevented by JEV pr peptide replacement. The present study contribute further to research on the pathogenesis of DENV infection. PMID- 27939947 TI - Single colonic polyp as a presentation of mantle cell lymphoma. PMID- 27939946 TI - Stargardt disease-associated mutation spectrum of a Russian Federation cohort. AB - ABCA4-associated mutation screening is extensively performed in European, African, American and several other populations for various retinopathies. However, it has not been well studied in a Russian cohort. Using next-generation (325 genes inherited disease panel) and Sanger sequencing technologies for the first time we documented the spectrum of genetic variations in a Russian retinopathy cohort of 51 patients from 10 ethnic groups. We found ABCA4 variations in 70.5% cases and one case with BEST1 variation. Multiple ABCA4 variations, ABCA4 + RDH12, and ABCA4 + BEST1 variations are also observed and the disease severity is found proportionate to the variation burden. Ten novel ABCA4 variations are detected of which 8 belongs to non-Slavonian population. Most of the detected known variations are found in European and American Stargardt disease populations. No retinopathy causing variation is detected in 14 (27%) cases suggesting that in this Russian retinopathies cohort the causal variants could be in genes that are not covered by our 325 gene panel. Therefore, whole genome/exome analysis is required to identify novel retinopathy associated genes and provide better disease management for this heterogeneous cohort. PMID- 27939948 TI - Catastrophic antiphospholipid antibody syndrome presenting as severe ischaemic colitis. PMID- 27939950 TI - A critical review of the ESCAPE project for estimating long-term health effects of air pollution. AB - The European Study of Cohorts for Air Pollution Effects (ESCAPE) is a13-nation study of long-term health effects of air pollution based on subjects pooled from up to 22 cohorts that were intended for other purposes. Twenty-five papers have been published on associations of various health endpoints with long-term exposures to NOx, NO2, traffic indicators, PM10, PM2.5 and PM constituents including absorbance (elemental carbon). Seven additional ESCAPE papers found moderate correlations (R2=0.3-0.8) between measured air quality and estimates based on land-use regression that were used; personal exposures were not considered. I found no project summaries or comparisons across papers; here I conflate the 25 ESCAPE findings in the context of other recent European epidemiology studies. Because one ESCAPE cohort contributed about half of the subjects, I consider it and the other 18 cohorts separately to compare their contributions to the combined risk estimates. I emphasize PM2.5 and confirm the published hazard ratio of 1.14 (1.04-1.26) per 10MUg/m3 for all-cause mortality. The ESCAPE papers found 16 statistically significant (p<0.05) risks among the125 pollutant-endpoint combinations; 4 each for PM2.5 and PM10, 1 for PM absorbance, 5 for NO2, and 2 for traffic. No PM constituent was consistently significant. No significant associations were reported for cardiovascular mortality; low birthrate was significant for all pollutants except PM absorbance. Based on associations with PM2.5, I find large differences between all-cause death estimates and the sum of specific-cause death estimates. Scatterplots of PM2.5 mortality risks by cause show no consistency across the 18 cohorts, ostensibly because of the relatively few subjects. Overall, I find the ESCAPE project inconclusive and I question whether the efforts required to estimate exposures for small cohorts were worthwhile. I suggest that detailed studies of the large cohort using historical exposures and additional cardiovascular risk factors might be productive. PMID- 27939952 TI - Toxico-vigilance - An inevitable prerequisite to keep a watch on toxins around you. AB - India has got a handful of poison centers to compensate about 1.25 billion population of India. Hence, a lot of under-reporting of poisoning cases occurs due to limited resources. Gujarat being an upcoming industrial centre of India has got many key industries like textiles, automobiles, chemicals, diamonds, pharmaceuticals etc. This magnificent industrial growth has resulted upon increased exposure of various hazardous chemicals among the general and working population. This study reflects trends of poisoning observed in a poison center named Center For Education Awareness and Research On Chemicals and Health (CEARCH) at Ahmedabad. A retrospective study of around 659 cases were analytically analyzed which have been reported at CEARCH. Variables considered for analysis are age, gender, route of exposure, intention, agent group, agent subgroup and agent name. Out of which 274 cases of females, 384 cases were of males and one case of a transgender was reported. Maximum poisoning cases reported were of pesticides (57.35%) followed by pharmaceuticals (21.24%), industrial chemicals (6.22%), metals (5%), substance of abuse (3.94%), plant poisons (1.82%), household chemicals (1.36%), mixture of more than one agent (1.36%), herbicides (0.75%), animal poisons (0.45%), bacterial poisons (0.30%) and other poisons (0.15%). The data analysis reports that among all the routes of exposure, Oral route (94%) is the major route of exposure followed by inhalation (4%), dermal and injections respectively clearly emphasizing the need for appropriate steps towards the protection of the most vulnerable populations from the consequences of the pervasive poisons exposure. PMID- 27939951 TI - Effects of personalised exposure on self-rated electromagnetic hypersensitivity and sensibility - A double-blind randomised controlled trial. AB - BACKGROUND: Previous provocation experiments with persons reporting electromagnetic hypersensitivity (EHS) have been criticised because EHS persons were obliged to travel to study locations (seen as stressful), and that they were unable to select the type of signal they reported reacting to. In our study we used mobile exposure units that allow double-blind exposure conditions with personalised exposure settings (signal type, strength, duration) at home. Our aim was to evaluate whether subjects were able to identify exposure conditions, and to assess if providing feedback on personal test results altered the level of self-reported EHS. METHODS: We used double-blind randomised controlled exposure testing with questionnaires at baseline, immediately before and after testing, and at two and four months post testing. Participants were eligible if they reported sensing either radiofrequency or extremely low frequency fields within minutes of exposure. Participants were visited at home or another location where they felt comfortable to undergo testing. Before double-blind testing, we verified together with participants in an unblinded exposure session that the exposure settings were selected were ones that the participant responded to. Double-blind testing consisted of a series of 10 exposure and sham exposures in random sequence, feedback on test results was provided directly after testing. RESULTS: 42 persons participated, mean age was 55years (range 29-78), 76% were women. During double-blind testing, no participant was able to correctly identify when they were being exposed better than chance. There were no statistically significant differences in the self-reported level of EHS at follow-up compared to baseline, but during follow-up participants reported reduced certainty in reacting within minutes to exposure and reported significantly fewer symptoms compared to baseline. CONCLUSION: Our results suggest that a subgroup of persons exist who profit from participation in a personalised testing procedure. PMID- 27939949 TI - From the exposome to mechanistic understanding of chemical-induced adverse effects. AB - The exposome encompasses an individual's exposure to exogenous chemicals, as well as endogenous chemicals that are produced or altered in response to external stressors. While the exposome concept has been established for human health, its principles can be extended to include broader ecological issues. The assessment of exposure is tightly interlinked with hazard assessment. Here, we explore if mechanistic understanding of the causal links between exposure and adverse effects on human health and the environment can be improved by integrating the exposome approach with the adverse outcome pathway (AOP) concept that structures and organizes the sequence of biological events from an initial molecular interaction of a chemical with a biological target to an adverse outcome. Complementing exposome research with the AOP concept may facilitate a mechanistic understanding of stress-induced adverse effects, examine the relative contributions from various components of the exposome, determine the primary risk drivers in complex mixtures, and promote an integrative assessment of chemical risks for both human and environmental health. PMID- 27939953 TI - Delineation of the mechanisms of tendon gliding resistance within the carpal tunnel. AB - BACKGROUND: Forceful, high-velocity, and repetitive manual hand tasks contribute to the onset of carpal tunnel syndrome. This study aimed to isolate and identify mechanisms that contribute to tendon gliding resistance in the carpal tunnel. METHODS: Eight human cadaver hands (four pairs) were used. Tendon gliding resistance (force, energy, and stiffness) was measured under different conditions: with intact and with divided subsynovial connective tissue, at 2mm/s and 60mm/s tendon excursion velocity, and with and without relaxation time before tendon excursion. RESULTS: Subsynovial connective tissue stretching substantially contributed to increased gliding resistance force and energy during higher tendon excursion velocities, and subsynovial connective tissue stiffening was observed. Poroelastic properties of the tendon (and possibly the subsynovial connective tissue) also appear to be involved because relaxation time significantly increased gliding resistance force and energy (P<0.01), and the difference in energy and force between high- and low-velocity tendon excursions increased with relaxation time (P=0.01 and P<0.01). Lastly, without relaxation time, no difference in force and energy was observed (P=0.06 and P=0.60), suggesting contact friction. INTERPRETATION: These findings are consistent with the hypothesis that the mechanics of tendon motion within the carpal tunnel are affected by the integrity of the subsynovial connective tissue. While not tested here, in carpal tunnel syndrome this tissue is known to be the fibrotic, thickened, and less-fluid-permeable. An extrapolation of our findings suggests that these changes in the subsynovial connective tissue of carpal tunnel syndrome patients could increase contact friction and carpal tunnel pressure. PMID- 27939954 TI - New tools for redox biology: From imaging to manipulation. AB - Redox reactions play a key role in maintaining essential biological processes. Deviations in redox pathways result in the development of various pathologies at cellular and organismal levels. Until recently, studies on transformations in the intracellular redox state have been significantly hampered in living systems. The genetically encoded indicators, based on fluorescent proteins, have provided new opportunities in biomedical research. The existing indicators already enable monitoring of cellular redox parameters in different processes including embryogenesis, aging, inflammation, tissue regeneration, and pathogenesis of various diseases. In this review, we summarize information about all genetically encoded redox indicators developed to date. We provide the description of each indicator and discuss its advantages and limitations, as well as points that need to be considered when choosing an indicator for a particular experiment. One chapter is devoted to the important discoveries that have been made by using genetically encoded redox indicators. PMID- 27939955 TI - Corrigendum to "Ossification of the posterior ligament is mediated by osterix via inhibition of the beta-catenin signaling pathway" [Exp. Cell Res. 349 (2016) 53 59]. PMID- 27939957 TI - Time course of disassociation of bone formation signals with bone mass and bone strength in sclerostin antibody treated ovariectomized rats. AB - Sclerostin antibodies increase bone mass by stimulating bone formation. However, human and animal studies show that bone formation increases transiently and returns to pre-treatment level despite ongoing antibody treatment. To understand its mechanism of action, we studied the time course of bone formation, correlating the rate and extent of accrual of bone mass and strength after sclerostin antibody treatment. Ovariectomized (OVX) rats were treated with a sclerostin-antibody (Scle-ab) at 20mg/kg sc once weekly and sacrificed at baseline and 2, 3, 4, 6, and 8weeks post-treatment. In Scle-ab treated rats, serum PINP and OCN rapidly increased at week 1, peaked around week 3, and returned to OVX control levels by week 6. Transcript analyses from the distal femur revealed an early increase in bone formation followed by a sustained decrease in bone resorption genes. Lumbar vertebral (LV) osteoblast surface increased 88% by week 2, and bone formation rate (BFR/BS) increased 138% by week 4. Both parameters were below OVX control by week 8. Bone formation was primarily a result of modeling based formation. Endocortical and periosteal BFR/BS peaked around week 4 at 313% and 585% of OVX control, respectively. BFR/BS then declined but remained higher than OVX control on both surfaces through week 8. Histomorphometric analyses showed LV-BV/TV did not further increase after week 4, while BMD continued to increase at LV, mid femur (MF), and femoral neck (FN) through week 8. Biomechanical tests showed a similar improvement in bone strength through 8weeks in MF and FN, but bone strength plateaued between weeks 6 and 8 for LV. Our data suggest that bone formation with Scle-ab treatment is rapid and modeling formation dominated in OVX rats. Although transient, the bone formation response persists longer in cortical than trabecular bone. PMID- 27939956 TI - Maternal vitamin D biomarkers are associated with maternal and fetal bone turnover among pregnant women consuming controlled amounts of vitamin D, calcium, and phosphorus. AB - Vitamin D plays a central role in calcium homeostasis; however, its relationship with bone turnover during pregnancy remains unclear due to a lack of studies that have rigorously controlled for vitamin D and other nutrients known to influence bone metabolism. Similarly, prior investigations of the effect of pregnancy on bone turnover relative to the nonpregnant state may have been confounded by varying intakes of these nutrients. Nested within a controlled intake study, the present investigation sought to quantify associations between maternal vitamin D biomarkers and biochemical markers of bone turnover among pregnant (versus nonpregnant) women and their fetuses under conditions of equivalent and adequate intakes of vitamin D and related nutrients. Changes in markers of bone turnover across the third trimester were also examined. Healthy pregnant (26-29 wk gestation; n=26) and nonpregnant (n=21) women consumed 511IU vitamin D/d, 1.6g calcium/d, and 1.9g phosphorus/d for 10weeks while participating in a controlled feeding study featuring two choline doses. Based on linear mixed models adjusted for influential covariates (e.g., BMI, ethnicity, and season), pregnant women had 50-150% higher (P<0.001) concentrations of bone resorption markers than nonpregnant women. Among pregnant women, increases in maternal 25(OH)D across the study period were associated (P<0.020) with lower osteocalcin and deoxypyridinoline at study-end, and higher fetal osteocalcin. In addition, maternal free 25(OH)D, 1,25(OH)2D and 24,25(OH)2D tended to be negatively associated (P<=0.063) with maternal NTx at study-end, and maternal free 25(OH)D and 24,25(OH)2D were positively associated (P<=0.021) with fetal CTx. Similarly, maternal 3-epi-25(OH)D3 was negatively related (P<=0.037) to maternal NTx and deoxypyridinoline at study-end. These declines in bone resorption markers resulting from higher vitamin D biomarker concentrations among pregnant women coincided with increases in their albumin-corrected serum calcium concentrations, indicating that calcium transfer to the fetus was uncompromised. Notably, none of these associations achieved statistical significance among nonpregnant women. Overall, our study findings suggest that achieving higher maternal concentrations of vitamin D biomarkers might attenuate third-trimester bone resorption while ensuring sufficient calcium delivery to the fetus. PMID- 27939958 TI - The impact of antimicrobial photodynamic therapy on peri-implant disease: What mechanisms are involved in this novel treatment? AB - According to the American Academy of Implant Dentistry, 3 million Americans have dental implants, and this number is growing by 500,000 each year. Proportionally, the number of biological complications is also increasing. Among them, peri implant disease is considered the most common cause of implant loss after osseointegration. In this context, microorganisms residing on the surfaces of implants and their prosthetic components are considered to be the primary etiologic factor for peri-implantitis. Some research groups have proposed combining surgical and non-surgical therapies with systemic antibiotics. The major problem associated with the use of antibiotics to treat peri-implantitis is that microorganisms replicate very quickly. Moreover, inappropriate prescription of antibiotics is not only associated with potential resistance but also and most importantly with the development of superinfections that are difficult to eradicate. Although antimicrobial photodynamic therapy (aPDT) was discovered several years ago, aPDT has only recently emerged as a possible alternative therapy against different oral pathogens causing peri-implantitis. The mechanism of action of aPDT is based on a combination of a photosensitizer drug and light of a specific wavelength in the presence of oxygen. The reaction between light and oxygen produces toxic forms of oxygen species that can kill microbial cells. This mechanism is crucial to the efficacy of aPDT. To help us understand conflicting data, it is necessary to know all the particularities of the etiology of peri-implantitis and the aPDT compounds. We believe that this review will draw attention to new insights regarding the impact of aPDT on peri-implant disease. PMID- 27939960 TI - Synthesis and in-vitro anti-leishmanial activity of (4-arylpiperazin-1-yl)(1 (thiophen-2-yl)-9H-pyrido[3,4-b]indol-3-yl)methanone derivatives. AB - In the present study, we have reported synthesis and biological evaluation of a series of fifteen 1-(thiophen-2-yl)-9H-pyrido[3,4-b]indole derivatives against both promastigotes and amastigotes of Leishmania parasites responsible for visceral (L. donovani) and cutaneous (L. amazonensis) leishmaniasis. Among these reported analogues, compounds 7b, 7c, 7f, 7g, 7i, 7j, 7m, 7o displayed potent activity (15.55, 7.70, 7.00, 3.80, 14.10, 9.25, 3.10, 4.85MUM, respectively) against L. donovani promastigotes than standard drugs miltefosine (15.70MUM) and pentamidine (32.70MUM) with good selectivity index. In further, in-vitro evaluation against amastigote forms, two compounds 7g (8.80MUM) and 7i (7.50MUM) showed significant inhibition of L. donovani amastigotes. Standard drug amphotericin B is also used as control to compare inhibition potency of compounds against both promastigote (0.24MUM) and amastigote (0.05MUM) forms. PMID- 27939959 TI - Age-related differences in the structural complexity of subcortical and ventricular structures. AB - It has been well established that the volume of several subcortical structures decreases in relation to age. Different metrics of cortical structure (e.g., volume, thickness, surface area, and gyrification) have been shown to index distinct characteristics of interindividual differences; thus, it is important to consider the relation of age to multiple structural measures. Here, we compare age-related differences in subcortical and ventricular volume to those differences revealed with a measure of structural complexity, quantified as fractal dimensionality. Across 3 large data sets, totaling nearly 900 individuals across the adult lifespan (aged 18-94 years), we found greater age-related differences in complexity than volume for the subcortical structures, particularly in the caudate and thalamus. The structural complexity of ventricular structures was not more strongly related to age than volume. These results demonstrate that considering shape-related characteristics improves sensitivity to detect age-related differences in subcortical structures. PMID- 27939961 TI - Investigating the use of a Gammatone filterbank for a cochlear implant coding strategy. AB - BACKGROUND: Contemporary speech processing strategies in cochlear implants (CIs) such as the Advanced Combination Encoder (ACE) use a standard Fast Fourier Transform (FFT) filterbank to extract envelopes. The assignment of the FFT bins to approximate the frequency resolution of the basilar membrane is only partly based on physiology, especially since the bins are distributed linearly below 1000Hz and logarithmically above 1000Hz. NEW METHOD: A Gammatone filterbank which provides a closer approximation to the bandwidths of filters in the human auditory system could replace the standard FFT filterbank in the ACE strategy. An infinite impulse response (IIR) all-pole design of the Gammatone filterbank was compared to the FFT filterbank with 128, 256 and 512 points resolutions and the effect of the frequency boundaries of the filters was also investigated. RESULTS: Melodic contour identification (MCI) and just noticeable difference (JND) experiments, both involving synthetic clarinet notes in octaves 3 and 4, were conducted with 6 normal hearing (NH) participants using noise vocoded stimuli; and 10 CI recipients just performed the MCI experiment. The MCI results for both NH and CI subjects, showed a significant effect of the filterbank on the percentage correct responses of the participants. COMPARISON WITH EXISTING METHODS: The Gammatone filterbank can better resolve the harmonics of tested synthetic clarinet notes which led to better performances in the MCI experiment. CONCLUSIONS: The total delay of the Gammatone filterbank can be made smaller than the delay of the FFT filterbank with the same frequency resolution at low frequencies. PMID- 27939962 TI - Method for testing sustained attention in touchscreen operant chambers in rats. AB - BACKGROUND: Sustained attention, the ability to detect rare and unpredictable events, is central to cognitive performance. This construct can be tested in rodents using a Sustained Attention Task (SAT), where rats are trained to detect an unpredictably occurring signal (a brief light presentation) from non-signal events. The traditional version of this task utilizes an operant chamber with a central panel light for the signal and two retractable response levers. Adaptation of SAT to the increasingly popular touchscreen operant chambers, which do not have levers or fixed lights, could enhance the versatility of the task. NEW METHOD: Here we developed a touchscreen version of SAT where the light signal is presented in the center of the touchscreen, followed by a tone to indicate the beginning of the response period. Rats indicate their choice during this period by touching their nose to one of two touchscreen response areas. The remaining parameters were kept similar to the traditional version. RESULTS: Rats acquired touchscreen SAT at a similar rate to the traditional version. As with the traditional version, shorter stimulus durations on the signaled trials reduced accuracy and the presence of a distractor (a flashing houselight) disrupted performance on the touchscreen version. COMPARISON TO EXISTING METHOD: Collectively, these data suggest that the touchscreen version is comparable to the traditional version of the SAT, and is an equally valid way of measuring sustained attention. CONCLUSIONS: Many researchers with touchscreen chambers could easily implement our modifications in order to study sustained attention. PMID- 27939965 TI - Editorial Comment. PMID- 27939963 TI - Introducing Euro-Glo, a rare earth metal chelate with numerous applications for the fluorescent localization of myelin and amyloid plaques in brain tissue sections. AB - : The vast majority of fluorochromes are organic in nature and none of the few existing chelates have been applied as histological tracers for localizing brain anatomy and pathology. NEW METHOD: In this study we have developed and characterized a Europium chelate with the ability to fluorescently label normal and pathological myelin in control and toxicant-exposed rats, as well as the amyloid plaques in aged AD/Tg mice. RESULTS: This study demonstrates how Euro-Glo can be used for the detailed labeling of both normal myelination in the control rat as well as myelin pathology in the kainic acid exposed rat. In addition, this study demonstrates how E-G will label the shell of amyloid plaques in an AD/Tg mouse model of Alzheimer's disease a red color, while the plaque core appears blue in color. The observed E-G staining pattern is compared with that of well characterized tracers specific for the localization of myelin (Black-Gold II), degenerating neurons (Fluoro-Jade C), A-beta aggregates (Amylo-Glo) and glycolipids (PAS). COMPARISONS WITH EXISTING METHODS: This study represents the first time a rare earth metal (REM) chelate has been used as a histochemical tracer in the brain. This novel tracer, Euro-Glo (E-G), exhibits numerous advantages over conventional organic fluorophores including high intensity emission, high resistance to fading, compatibility with multiple labeling protocols, high Stoke's shift value and an absence of bleed-through of the signal through other filters. CONCLUSIONS: Euro-Glo represents the first fluorescent metal chelate to be used as a histochemical tracer, specifically to localize normal and pathological myelin as well as amyloid plaques. PMID- 27939964 TI - Sustainable biobutanol production from pineapple waste by using Clostridium acetobutylicum B 527: Drying kinetics study. AB - Present investigation explores the use of pineapple peel, a food industry waste, for acetone-butanol-ethanol (ABE) production using Clostridium acetobutylicum B 527. Proximate analysis of pineapple peel shows that it contains 35% cellulose, 19% hemicellulose, and 16% lignin on dry basis. Drying experiments on pineapple peel waste were carried out in the temperature range of 60-120 degrees C and experimental drying data was modeled using moisture diffusion control model to study its effect on ABE production. The production of ABE was further accomplished via acid hydrolysis, detoxification, and fermentation process. Maximum total sugar release obtained by using acid hydrolysis was 97g/L with 95 97% and 10-50% removal of phenolics and acetic acid, respectively during detoxification process. The maximum ABE titer obtained was 5.23g/L with 55.6% substrate consumption when samples dried at 120 degrees C were used as a substrate (after detoxification). PMID- 27939966 TI - Prediction of Clinical Outcomes in Prenatal Hydronephrosis: Importance of Gravity Assisted Drainage. AB - PURPOSE: In infants with SFU (Society for Fetal Urology) grade 3-4 congenital hydronephrosis, 99mTc-mercaptoacetyltriglycine diuretic renography assesses differential function and drainage half-time. We routinely also include the percent of radiotracer drained after 30 minutes of diuresis as well as after 15 minutes with the patient in the upright position. We investigated whether any 1 or more of these parameters on initial diuretic renography predicts persistent or worsening drainage parameters. MATERIALS AND METHODS: Infants 6 months or younger with grade 3-4 congenital hydronephrosis who presented between January 2009 and December 2014 were identified from billing data and included in analysis if they underwent at least 1 baseline diuretic renography. Those with structural anomalies were excluded from study. Baseline and followup differential function, diuresis half-time, clearance at 30 minutes and clearance with the patient upright were abstracted and comparisons were made between those with initially indeterminate diuresis half-time who underwent pyeloplasty vs those showing spontaneous improvement. RESULTS: A total of 74 patients (82 renal units) with presumed ureteropelvic junction obstruction met inclusion/exclusion criteria. All 10 renal units with initial diuresis half-time less than 5 minutes resolved spontaneously and all 25 renal units with initial diuresis half-time greater than 75 minutes underwent pyeloplasty. Therefore, we defined the indeterminate group as the 47 renal units with initial half-time between 5 and 75 minutes. Of those 47 renal units with indeterminate initial diuresis half-time 23 (47%) underwent pyeloplasty and 25 (53%) resolved spontaneously. Indications for pyeloplasty included worsening in 17 cases, persistent obstruction in 4 and urinary tract infection in 1. Among renal units with indeterminate drainage clearance while upright and clearance at 30 minutes were the only variables that differed significantly between surgical cases and those that resolved spontaneously. CONCLUSIONS: Radiotracer clearance with the patient upright and clearance at 30 minutes are more predictive of surgical management than diuresis half-time or differential function for renal units with indeterminate drainage. They should be included in the standard assessment of ureteropelvic junction obstruction. PMID- 27939967 TI - The effect of preoperative serum triglycerides and high-density lipoprotein cholesterol levels on the prognosis of breast cancer. AB - OBJECTIVES: Although dyslipidemia has been documented to be associated with several types of cancer including breast cancer, it remains uncertainty the prognostic value of serum lipid in breast cancer. The purpose of this study is to evaluate the association between the preoperative plasma lipid profile and the prognostic of breast cancer patients. METHODS: The levels of preoperative serum lipid profile (including cholesterol [CHO], Triglycerides [TG], high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C], apolipoprotein A-I [ApoAI], and apolipoprotein B [ApoB]) and the clinical data were retrospectively collected and reviewed in 1044 breast cancer patients undergoing operation. Kaplan-Meier method and the Cox proportional hazards regression model were used in analyzing the overall survival [OS] and disease free survival [DFS]. RESULTS: Combining the receiver-operating characteristic and Kaplan-Meier analysis, we found that preoperative lower TG and HDL-C level were risk factors of breast cancer patients. In multivariate analyses, a decreased HDL C level showed significant association with worse OS (HR: 0.528; 95% CI: 0.302 0.923; P = 0.025), whereas a decreased TG level showed significant association with worse DFS (HR: 0.569; 95% CI: 0.370-0.873; P = 0.010). CONCLUSIONS: Preoperative serum levels of TG and HDL-C may be independent factor to predict outcome in breast cancer patient. PMID- 27939968 TI - Goblet cells and intestinal Alkaline phosphatase expression (IAP) during the development of the rat small intestine. AB - This study aimed to evaluate the temporal and spacial distribution of the mucins produced by goblet cells and intestinal alkaline phosphatase (IAP) expression during the development of the small intestine of the rat. Intestines were removed from rats on the 15th, 17th and 18th days of intratuterine life (i.u.) and on the 3rd, 10th, 17th and 25th days after birth (a.b.). Intestines were processed for routine histological procedures and sections were submitted to histochemistry using PAS to stain neutral glycoproteins and Alcian blue for acidic glycoproteins, as well as immunohistochemistry to detect IAP. In rats, glycoprotein production was seen to begin in the intestinal epithelium cell at around the 17th day of i.u. life; however, this production was not accompanied by morphological indications of the presence of goblet cells. By the 18th i.u. day, the villus epithelium was undergoing differentiation and the first goblet cells could be identified from this time. At around the 10th day a.b., both compartments of the small intestine were detected; i.e. the villi and the crypts. At this timepoint, goblet cells were present in the villi, and also in the upper regions of the crypts. On the 3rd, 10th 17th and 25th days a.b., the presence of the goblet cells increased and presented regional differences in the sections evaluated. IAP was not detected during i.u. life, but was weakly detected in the cells of the villi from the 3rd day a.b., along the entire extension of the villi. On the 10th day, IAP was detected at the tip of the villi, while on the 25th day, it was detected along the extension of the villi, but with a weaker intensity. In conclusion, a temporal and spacial distribution of goblet cells and IAP activity occurs during the development of the small intestine, suggesting a possible regulatory control in accordance with the suckling and weaning phases of food intake in the rat's life. PMID- 27939969 TI - U.S. military service and the prevalence of metabolic syndrome: Findings from a cross-sectional analysis of the Cooper Center Longitudinal Study, 1979-2013. AB - U.S. military service confers both health benefits and risks potentially associated with a clustering of cardiovascular risk factors called metabolic syndrome. However, the association between prior military service and metabolic syndrome has not sufficiently been examined. The purpose of the study was to compare the prevalence of metabolic syndrome by prior military service status. Among 42,370 men (887 with prior military service) examined from 1979 to 2013 at the Cooper Clinic (Dallas, TX), we used a cross-sectional study design to examine the association between military service and metabolic syndrome. First, an unadjusted log binomial regression model was performed by regressing the prevalence of metabolic syndrome on prior service. This was followed by performing Kleinbaum's modeling strategy for assessing confounding. The same methodology was used to explore the association between individual metabolic syndrome risk factors and prior service. Prior military service was not significantly associated with the prevalence of metabolic syndrome (PR=0.98, 0.89 1.07). None of the variables explored were identified as confounders. Participants with prior military service had lower prevalence of both elevated levels of triglycerides (PR=0.89, 0.80-0.99) and low levels of high-density lipoprotein-cholesterol (PR=0.78, 0.70-0.88). They had a higher prevalence of elevated resting systolic blood pressure (PR=1.23, 1.12-1.35). However, none of these associations were significant after adjusting for identified confounders: age; cardiorespiratory fitness; and exam year. Study findings indicate that military service was not independently associated with the prevalence of metabolic syndrome or its components. Future research is warranted longitudinally assessing the impact of military service on long-term outcomes. PMID- 27939970 TI - Quantifying bicycle network connectivity. AB - The intent of this study was to compare bicycle network connectivity for different types of bicyclists and different neighborhoods. Connectivity was defined as the ability to reach important destinations, such as grocery stores, banks, and elementary schools, via pathways or roads with low vehicle volumes and low speed limits. The analysis was conducted for 28 neighborhoods in Seattle, Washington under existing conditions and for a proposed bicycle master plan, which when complete will provide over 700 new bicycle facilities, including protected bike lanes, neighborhood greenways, and multi-use trails. The results showed different levels of connectivity across neighborhoods and for different types of bicyclists. Certain projects were shown to improve connectivity differently for confident and non-confident bicyclists. The analysis showed a positive correlation between connectivity and observed utilitarian bicycle trips. To improve connectivity for the majority of bicyclists, planners and policy makers should provide bicycle facilities that allow immediate, low-stress access to the street network, such as neighborhood greenways. The analysis also suggests that policies and programs that build confidence for bicycling could greatly increase connectivity. PMID- 27939971 TI - Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis. AB - BACKGROUND: Studies that have investigated the association between vitamin D receptor (VDR) gene polymorphisms and intervertebral disc degeneration (IDD) have yielded inconsistent results. METHODS: To investigate the association between VDR gene polymorphisms and IDD, a systematic literature search for relevant published studies was performed on PubMed, Embase, Web of Science, Cochrane library, Wan Fang, and CNKI databases. A random effects model was used for heterogeneous data; while a fixed effect model was used for homogenous data. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the strength of the association. RESULTS: We observed no association between VDR FokI, TaqI-ApaI polymorphisms and IDD. However, on subgroup analysis by ethnicity, VDR FokI mutation was associated with a significantly lower risk for IDD [dominant model: OR = 0.78, 95% CI = 0.65-0.93; heterozygote model: OR = 0.76, 95% CI = 0.63-0.92; allele model: OR = 0.86, 95% CI = 0.75-0.98] among Caucasians. CONCLUSION: These results suggest that the VDR FokI polymorphism may be associated with IDD among Caucasians. However, the association between VDR TaqI-ApaI polymorphisms and IDD in Asians is still not clear. Further well-designed studies are needed to arrive at a definitive conclusion. PMID- 27939972 TI - Opisthorchiasis in Western Siberia: Epidemiology and distribution in human, fish, snail, and animal populations. AB - Opisthorchiasis is a widespread helminth infection in Russia. The largest opisthorchiasis endemic focus in the world is the Ob river watershed in Western Siberia. The main causative agent of this condition is the liver fluke, Opisthorchis felineus. In addition, another liver fluke species in the Opisthorchiidae family, Metorchis bilis, causes a symptomatically similar disease, metorchiasis. Despite a long research history going back to 1927, opisthorchiasis remains a serious problem in Russia, and numerous questions related to the epidemiology of these liver fluke infections and their patterns of distribution in Western Siberia, the causes of high prevalence in different populations, and the prognosis of the epidemiological situation remain to be answered. In this review, we first briefly describe the life cycle of O. felineus and then summarize the available published data on the epidemiological aspects of O. felineus infection among populations in Western Siberia. Additionally, the geographical distribution and rates of infection with the two major small liver flukes, O. felineus and M. bilis, in the intermediate (Bithyniidae snails and cyprinid fish) and definitive (humans, wild and domestic carnivorous animals and birds) hosts are described to assess their role in the transmission cycle. Moreover, species in the genus Opisthorchis and the genus Metorchis that have been reported in carnivorous mammals and birds in Western Siberia are listed and their potential to serve as the agents of opisthorchiasis transmission is discussed. PMID- 27939973 TI - Quantitative FRET studies and integrative modeling unravel the structure and dynamics of biomolecular systems. AB - Forster Resonance Energy Transfer (FRET) combined with single-molecule spectroscopy probes macromolecular structure and dynamics and identifies coexisting conformational states. We review recent methodological developments in integrative structural modeling by satisfying spatial restraints on networks of FRET pairs (hybrid-FRET). We discuss procedures to incorporate prior structural knowledge and to obtain optimal distance networks. Finally, a workflow for hybrid FRET is presented that automates integrative structural modeling and experiment planning to put hybrid-FRET on rails. To test this workflow, we simulate realistic single-molecule experiments and resolve three protein conformers, exchanging at 30MUs and 10ms, with accuracies of 1-3A RMSD versus the target structure. Incorporation of data from other spectroscopies and imaging is also discussed. PMID- 27939974 TI - Revision surgeries following artificial disc replacement of cervical spine. AB - OBJECTIVE: We investigated causes and results of revision surgeries after artificial disc replacement of cervical spine (C-ADR). METHODS: Twenty-one patients (mean age: 52.8) who underwent revision surgery after C-ADR and who had a minimum 2-year of follow-up were included into this study. The mean time between the primary and revision surgeries was 21 months. During their primary surgeries, 14 patients underwent single level C-ADR, 2 two-level C-ADR, and 5 two level hybrid surgery for 16 radiculopathy, 3 myelopathy, and 2 adjacent segment diseases. Causes for revision surgeries were at least one of the followings: 17 poor patient selections, 7 insufficient decompressions, 7 malpositions, 6 subsidences, 3 osteolysis, and 1 postoperative infection. RESULTS: Sixteen patients underwent anterior removal of C-ADR, one-level discectomy and fusion (N = 11), two-level discectomy (N = 3) or one-level corpectomy (N = 2) and fusion. Three patients of keel type C-ADR with heterotopic ossification underwent posterior laminoforaminotomy and fusion. Two patients underwent combined procedures due to infection or severe subsidence and osteolysis. At the 2-year follow-up, neck (7.3 vs 1.6) and arm (7.0 vs 1.3) visual analog scales and Neck Disability Index score (46.7 vs 16.32) were improved (all, p < 0.05). According to Odom's criteria, 86% of the patients were satisfied and 91% achieved solid fusion. No major complications developed except for transient dysphagia in 6 patients (29%). CONCLUSIONS: In this small case series, revision surgeries provided successful outcomes in failed C-ADR without major complications. Careful patient selection and meticulous surgical techniques are important to avoid disappointing clinical outcome or even failure of C-ADR. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 27939975 TI - Neuroprotection and secondary damage following spinal cord injury: concepts and methods. AB - Neuroprotection refers to the attenuation of pathophysiological processes triggered by acute injury to minimize secondary damage. The development of neuroprotective treatments represents a major goal in the field of spinal cord injury (SCI) research. In this review, we discuss the strengths and limitations of the methodologies employed to assess secondary damage and neuroprotection in preclinical models of traumatic SCI. We also discuss modelling issues and how new tools might be exploited to study secondary damage and neuroprotection. PMID- 27939976 TI - Inhibiting medial septal cholinergic neurons with DREADD alleviated anxiety-like behaviors in mice. AB - Cholinergic neurons in the medial septum (MS) participate in a variety of cognitive and emotional behaviors. Some studies but not others show that lesions or inhibition of the MS reduce anxiety-like behaviors and locomotive exploration in rats. However, these conclusions come from manipulations that are either irreversible or non-specific to cholinergic neurons, casting doubt on their validity. With DREADD (designer receptors exclusively activated by designer drugs), we temporarily and reversibly inhibited cholinergic neurons in the MS. We observed consistent anxiolytic effects of MS cholinergic inhibition in the novelty-suppressed feeding test, the marble burying test and the elevated plus maze test, as well as increased exploratory activities in the open field test. These findings confirm an excitatory role of the MS cholinergic neurons in the control of innate anxiety, and reconcile conflicting findings from previous studies using irreversible lesions or non-specific inhibition. PMID- 27939977 TI - Melatonin ameliorates amygdala-dependent emotional memory deficits in Tg2576 mice by up-regulating the CREB/c-Fos pathway. AB - The effects of melatonin on spatial memory deficits in Alzheimer's disease (AD) have been thoroughly investigated. Our previous study demonstrated that melatonin rescues hippocampus-dependent spatial memory deficits by arresting hippocampal pathological progression in an animal model of AD, which occurs via the inhibition of GSK3beta and an increase in c-Fos. Based on the interaction between the amygdala and hippocampus, it is important to determine whether melatonin also improves amygdala-dependent emotional memory to understand the mechanism of melatonin amelioration of memory deficits in AD. The basolateral amygdala (BLA) is essential for the processing of emotions, including cued fear conditioning and anxiety. In the present study, we intraperitoneally injected Tg2576 mice with melatonin for 4 months and measured amygdala-dependent emotional memory using cued fear conditioning and a step-down passive avoidance test; the expression of c-Fos, Arc, phosphorylated CREB (pCREB) and other related genes were subsequently measured using Real-time polymerase chain reaction (RT-PCR) and Western blot in BLA. Our findings suggest that melatonin ameliorates amygdala-dependent emotional memory in AD via up-regulation of the pCREB/c-Fos pathway. PMID- 27939978 TI - alpha1-Adrenergic receptor downregulates hepatic FGF21 production and circulating FGF21 levels in mice. AB - Fibroblast growth factor 21 (FGF21) is primarily secreted by the liver as an endocrine hormone and is suggested as a promising target for the treatment of metabolic diseases. FGF21 acts centrally to exert its effects on energy expenditure and body weight via the sympathetic nervous system in mice. Here we show that intraperitoneal injection of phentolamine (an alpha-adrenergic receptor antagonist, 5mg/kg) significantly increased plasma FGF21 levels compared with the saline controls in C57BL6J mice, whereas alprenolol (a beta-adrenergic receptor antagonist, 6mg/kg) had no effect. In addition, intraperitoneal injection of prazosin (an alpha1-adrenergic receptor antagonist, 5mg/kg) significantly increased plasma FGF21 levels compared with the controls, whereas yohimbine (an alpha2-adrenergic receptor antagonist, 5mg/kg) had no effect. Moreover, the treatment with prazosin significantly increased the expression of hepatic FGF21, while having no effect on the expression of hepatic PPARalpha and PPARgamma. After a 5-h fast, intraperitoneal injection of prazosin significantly increased plasma FGF21 levels and impaired glucose tolerance compared with controls. These findings suggest that alpha1-adrenergic receptor downregulates the expression of hepatic FGF21 and plasma FGF21 levels independently of feeding and hepatic PPARalpha and PPARgamma expression in mice, and that the increases in circulating FGF21 levels might be related to impaired glucose tolerance. PMID- 27939979 TI - The expression of amphetamine sensitization is dissociable from anxiety and aversive memory: Effect of an acute injection of amphetamine. AB - The repeated administration of amphetamine can lead to locomotor sensitization. Although the repeated administration of amphetamine has been associated with anxiety and impaired working memory, it is uncertain if expression of amphetamine sensitization is associated with modifications of emotional memories. To address this issue, rats were injected once daily with amphetamine for five consecutive days (1.5mg/kg). After four days of withdrawal, rats were delivered an acute amphetamine injection to assess the expression of sensitization. A single exposure to an elevated plus maze (EPM), 24h after the last injection of amphetamine, showed that amphetamine sensitization is not accompanied by anxiety. Next, aversive memory was assessed using an 11day inter-trial interval between the EPM Trial 1 and EPM Trial 2. Rats administered with saline showed a percentage of open arms time (% OAT) in Trial 2 that was comparable to Trial 1, demonstrating a reduction in the retrieval of aversive memory. However, rats sensitized after the EPM Trial 1 showed a significant decrease in the % OAT in Trial 2. Importantly, a decrease in the % OAT in Trial 2 compared to Trial 1 was also observed after a single injection of amphetamine 24h before Trial 2. These results show a facilitation in the retrieval of aversive memory, and suggest that a previous amphetamine injection is enough to produce a protracted activation of neural circuits necessary for the retrieval of aversive memory. PMID- 27939980 TI - Corticospinal circuit plasticity in motor rehabilitation from spinal cord injury. AB - Restoring corticospinal function after spinal cord injury is a significant challenge as the corticospinal tract elicits no substantive, spontaneous regeneration, and its interruption leaves a permanent deficit. The corticospinal circuit serves multiple motor and sensory functions within the mammalian nervous system as the direct link between isocortex and spinal cord. Maturation of the corticospinal circuit involves the refinement of projections within the spinal cord and a subsequent refinement of motor maps within the cortex. The plasticity of these cortical motor maps mirrors the acquisition of skilled motor learning, and both the maps and motor skills are disrupted following injury to the corticospinal tract. The motor cortex exhibits the capacity to incorporate changes in corticospinal projections induced by both spontaneous and therapeutic mediated plasticity of corticospinal axons through appropriate rehabilitation. An understanding of the mechanisms of corticospinal plasticity in motor learning will undoubtedly help inform strategies to improve motor rehabilitation after spinal cord injury. PMID- 27939981 TI - 5-HT7 receptor-mediated fear conditioning and possible involvement of extracellular signal-regulated kinase. AB - Fear conditioning is a valuable behavioral paradigm for studying the neural basis of emotional learning and memory. The present study examined the involvement of extracellular signal-regulated kinase 1/2 (ERK) signaling on the serotonin (5 HT)7 receptor-mediated fear conditioning. Conditioning was performed in a trial in which a tone was followed by an electrical foot-shock. Context- and tone dependent fear were examined in tests conducted 24 and 48h after conditioning, respectively. The selective 5-HT7 receptor antagonist 2a-[4-(4-phenyl-1,2,3,6 tetrahydropyridyl)butyl]-2a,3,4,-tetrahydrobenzo(c,d)indol-2-(1H)-one (DR4004) (5mg/kg), when administered intraperitoneally (i.p.) immediately after conditioning, caused a significant decrease in both context- and tone-dependent fear responses (freezing behavior). A significant increase in ERK activity was observed in the amygdala of mice that displayed context- or tone-dependent fear responses, and these changes were also inhibited by the administration of DR4004 (5mg/kg, i.p.) immediately after conditioning. In contrast, the increase in hippocampal ERK activity in mice that displayed context-dependent fear responses was further enhanced by the administration of DR4004 (5mg/kg, i.p.). These results suggest that 5-HT7 receptor-mediated ERK signaling may play a significant role in the processes of emotional learning and memory. PMID- 27939982 TI - Prognosis of patients with BRCA1-associated ovarian carcinomas depends on TP53 accumulation status in tumor cells. AB - OBJECTIVE: TP53 mutation is the most frequent molecular event in BRCA1-associated ovarian carcinomas. TP53 status may be a confounding factor in the evaluation of clinical importance of other proteins. We aimed to evaluate the clinical significance of BRCA1 mutations with respect to the TP53 accumulation status in 159 high-grade ovarian carcinomas. METHODS: Statistical analyses were done with the Kaplan-Meier method, log-rank test, the Cox's and logistic regression models for all patients, and in subgroups with and without TP53 accumulation (TP53+ and TP53-, respectively). RESULTS: Forty of 159 ovarian carcinomas (25.2%) were diagnosed in patients with BRCA1 germline mutations; 102 tumors (64.2%) were TP53+ and 57 (37.8%) were TP53-. Among patients with TP53+ carcinomas, BRCA1 carriers had increased odds of recurrence compared with sporadic cases (HR 2.25, P=0.003; median disease-free survival time 7.7 vs. 18.4months, respectively). In the smaller TP53- subgroup, BRCA1 mutation reduced the risk of death by 46% (HR 0.54, P=0.099, median overall survival time 42.7 vs. 28.1months), but beyond the border of significance. When the TP53 status was not taken into account, BRCA1 mutations did not show any significance, however, there was a trend toward increased odds of complete remission for women with BRCA1 mutations compared to non-carriers (OR 2.47, P=0.064). Taxane-platinum therapy showed advantage over the platinum-cyclophosphamide one in the entire group of patients and in the TP53+ subgroup. CONCLUSIONS: Our results suggest that the TP53 accumulation status determines the prognosis of BRCA1 mutation carriers with high-grade ovarian carcinomas. PMID- 27939983 TI - American College of Surgeons Clinical Congress 2016. PMID- 27939984 TI - Risk of cervical intra-epithelial neoplasia and invasive cancer of the cervix in DES daughters. AB - OBJECTIVE: Women exposed to diethylstilbestrol in utero (DES) have an increased risk of clear cell adenocarcinoma (CCA) of the vagina and cervix, while their risk of non-CCA invasive cervical cancer is still unclear. METHODS: We studied the risk of pre-cancerous (CIN) lesions and non-CCA invasive cervical cancer in a prospective cohort of 12,182 women with self-reported DES exposure followed from 2000 till 2008. We took screening behavior carefully into account. Incidence was obtained through linkage with the Netherlands Nationwide Pathology database (PALGA). General population data were also derived from PALGA. RESULTS: The incidence of CIN1 was increased (Standardized Incidence Ratio (SIR)=2.8, 95% Confidence Interval (CI)=2.3 to 3.4), but no increased risk was observed for CIN2+ (CIN2, CIN3 or invasive cancer) compared to the screened general population (SIR=1.1, 95% CI=0.95 to1.4). Women with DES-related malformations had increased risks of both CIN1 and CIN2+ (SIR=4.1, 95%CI=3.0 to 5.3 and SIR=1.5, 95%CI=1.1 to 2.0, respectively). For CIN2+, this risk increase was largely restricted to women with malformations who were more intensively screened. CONCLUSIONS: An increased risk of CIN1 among DES daughters was observed, especially in women with DES related malformations, probably mainly due to screening. The risk of CIN2+ (including cancer) was not increased. However, among DES daughters with DES related malformations a true small risk increase for non-CCA cervical cancer cannot be excluded. PMID- 27939985 TI - Dihydroartemisinin protects against alcoholic liver injury through alleviating hepatocyte steatosis in a farnesoid X receptor-dependent manner. AB - Alcoholic liver disease (ALD) is a common etiology of liver diseases, characterized by hepatic steatosis. We previously identified farnesoid X receptor (FXR) as a potential therapeutic target for ALD. Dihydroartemisinin (DHA) has been recently identified to possess potent pharmacological activities on liver diseases. This study was aimed to explore the impact of DHA on ALD and further elaborate the underlying mechanisms. Gain- or loss-of-function analyses of FXR were applied in both in vivo and in vitro studies. Results demonstrated that DHA rescued FXR expression and activity in alcoholic rat livers. DHA also reduced serodiagnostic markers of liver injury, including aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase. DHA improved alcohol-induced liver histological lesions, expression of inflammation genes, and inflammatory cell infiltration. In addition, DHA not only attenuated hyperlipidemia but also reduced hepatic steatosis through regulating lipogenesis and lipolysis genes. In vitro experiments further consolidated the concept that DHA ameliorated ethanol-caused hepatocyte injury and steatosis. Noteworthily, DHA effects were reinforced by FXR agonist obeticholic acid or FXR expression plasmids but abrogated by FXR antagonist Z-guggulsterone or FXR siRNA. In summary, DHA significantly improved alcoholic liver injury by inhibiting hepatic steatosis, which was dependent on its activation of FXR in hepatocytes. PMID- 27939986 TI - Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis. AB - Liver fibrosis, resulting from chronic and persistent injury to the liver, is a worldwide health problem. Advanced liver fibrosis results in cirrhosis, liver failure and even hepatocellular cancer (HCC), often eventually requiring liver transplantation, poses a huge health burden on the global community. However, the specific pathogenesis of liver fibrosis remains not fully understood. Numerous basic and clinical studies have provided evidence that epigenetic modifications, especially DNA methylation, might contribute to the activation of hepatic stellate cells (HSCs), the pivotal cell type responsible for the fibrous scar in liver. Here, reduced representation bisulfite sequencing (RRBS) and bisulfite pyrosequencing PCR (BSP) analysis identified hypermethylation status of Septin9 (Sept9) gene in liver fibrogenesis. Sept9 protein was dramatically decreased in livers of CCl4-treated mice and immortalized HSC-T6 cells exposed to TGF-beta1. Nevertheless, the suppression of Sept9 could be blocked by DNMT3a-siRNA and DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-azadC). Overexpressed Sept9 attenuated TGF-beta1-induced expression of myofibroblast markers alpha-SMA and Col1a1, accompanied by up-regulation of cell apoptosis-related proteins. Conversely, RNAi-mediated silencing of Sept9 enhanced accumulation of extracellular matrix. These observations suggested that Sept9 contributed to alleviate liver fibrosis might partially through promoting activated HSCs apoptosis and this anti-fibrogenesis effect might be blocked by DNMT-3a mediated methylation of Sept9. Therefore, pharmacological agents that inhibit Sept9 methylation and increase its expression could be considered as valuable treatments for liver fibrosis. PMID- 27939987 TI - Clozapine-induced agranulocytosis: Evidence for an immune-mediated mechanism from a patient-specific in-vitro approach. AB - Use of the atypical antipsychotic clozapine (CZP) is compromised by the risk of potentially fatal agranulocytosis/granulocytopenia (CIAG). To address this, we have established a simple, personalized cell culture-based strategy to identify CIAG-susceptible patients, hypothesizing that an immunogenic and possibly haptene based mechanism underlies CIAG pathophysiology. To detect a putative haptene induced response to CZP in vitro exposure, a traditional lymphocyte stimulation assay was adapted and applied to patient-specific peripheral blood-derived mononuclear cells (PBMC). 6 patients with a history of CIAG, 6 patients under CZP treatment (without CIAG) and 12 matched healthy controls were studied. In vitro CZP exposure, even at strikingly low levels, resulted in significantly increased proliferation rates only in CIAG patients' PBMC. Other parameters including cell viability and mitogen-induced proliferation were also affected by in vitro CZP exposure, yet there was no significant difference between the groups. This personalized approach is a starting point for further investigations into a putative haptene-based mechanism underlying CIAG development, and may facilitate the future development of predictive testing. PMID- 27939988 TI - AmTAR2: Functional characterization of a honeybee tyramine receptor stimulating adenylyl cyclase activity. AB - The biogenic monoamines norepinephrine and epinephrine regulate important physiological functions in vertebrates. Insects such as honeybees do not synthesize these neuroactive substances. Instead, they employ octopamine and tyramine for comparable physiological functions. These biogenic amines activate specific guanine nucleotide-binding (G) protein-coupled receptors (GPCRs). Based on pharmacological data obtained on heterologously expressed receptors, alpha- and beta-adrenergic-like octopamine receptors are better activated by octopamine than by tyramine. Conversely, GPCRs forming the type 1 tyramine receptor clade (synonymous to octopamine/tyramine receptors) are better activated by tyramine than by octopamine. More recently, receptors were characterized which are almost exclusively activated by tyramine, thus forming an independent type 2 tyramine receptor clade. Functionally, type 1 tyramine receptors inhibit adenylyl cyclase activity, leading to a decrease in intracellular cAMP concentration ([cAMP]i). Type 2 tyramine receptors can mediate Ca2+ signals or both Ca2+ signals and effects on [cAMP]i. We here provide evidence that the honeybee tyramine receptor 2 (AmTAR2), when heterologously expressed in flpTM cells, exclusively causes an increase in [cAMP]i. The receptor displays a pronounced preference for tyramine over octopamine. Its activity can be blocked by a series of established antagonists, of which mianserin and yohimbine are most efficient. The functional characterization of two tyramine receptors from the honeybee, AmTAR1 (previously named AmTYR1) and AmTAR2, which respond to tyramine by changing cAMP levels in opposite direction, is an important step towards understanding the actions of tyramine in honeybee behavior and physiology, particularly in comparison to the effects of octopamine. PMID- 27939989 TI - Identification of demethylincisterol A3 as a selective inhibitor of protein tyrosine phosphatase Shp2. AB - Shp2 is a classical non-receptor protein tyrosine phosphatase (PTP) involved in many human diseases such as Noonan syndrome and tumors, and identified as a potential therapeutic target. In order to find a potent and selective Shp2 inhibitor, we screened a diverse collection of the secondary metabolites from endophyte fungi using an in vitro enzyme assay, and finally identified a potent Shp2 inhibitor, HLP46 (demethylincisterol A3) from Pestalotiopsis sp. HLP46 was reported to have anti-tumor and anti-inflammation activity previously. We provide the first evidence that HLP46 is an inhibitor of the Shp2. HLP46 shows high selective inhibition of Shp2 over Shp1, PTP1B, Lyp, STEP, PTPRA and Cdc25b. Enzymatic kinetic analyses showed that HLP46 is a non-competitive inhibitor of Shp2. HLP46 interrupts Gab1-Shp2 association and blocked Shp2-dependent activation of the Ras/ERK signal pathway induced by EGF. Furthermore, HLP46 decreased Src activation and inhibit tumor cell migration and invasion. As expected, HLP46 has no effect on the Shp2-independent activation of ERK induced by PMA or on the activation of the PI3K/Akt pathway. We testified therapeutic efficacy targeting both Shp2 and PI3K in MCF7 cells. HLP46 does not show any synergistic inhibition with PI3K inhibitor in suppressing cell growth. Collectively, these results suggest that HLP46 is a selective Shp2 inhibitor and could inhibit Shp2-dependent cell signaling in human cells. PMID- 27939990 TI - Apomorphine prevents LPS-induced IL-23 p19 mRNA expression via inhibition of JNK and ATF4 in HAPI cells. AB - Inflammation has been reported to be closely related to exaggeration of cerebral ischemia and neurodegenerative diseases. Microglia, resident immune cells in the central nervous system, can be activated in response to neuronal injury and produce proinflammatory cytokines, resulting in further aggravation of neuronal injury. Interleukin (IL)-23, which consists of p19 and IL-12 p40 subunits, has been shown to be involved in brain injury associated with neuroinflammation. Apomorphine (Apo), a nonselective dopamine receptor agonist, has been used for clinical therapy of Parkinson's disease. Besides the pharmacological effect, Apo is known to have pleiotropic biological functions. In this study, to elucidate the effect of Apo on lipopolysaccharide (LPS)-induced IL-23 p19 mRNA expression in microglial cell line HAPI cells, we pretreated cells with various concentrations of Apo (10 - 30MUM) for 8, 16, and 24h, followed by exposure to LPS (100ng/ml). Pretreatment with Apo dose- and time-dependently suppressed the induction of IL-23 p19 mRNA. However, this effect of Apo was exerted independently of dopamine receptors. JNK and ATF4, an endoplasmic reticulum (ER) stress-inducible transcription factor, were involved in expression of LPS-induced IL-23 p19 mRNA. Pretreatment with Apo (30MUM) for 24h inhibited LPS-induced activation of JNK and the nuclear accumulation of ATF4. Thapsigargin (Tg), an ER stress inducer, stimulated IL-23 p19 mRNA expression via an ATF4 dependent mechanism. We also found that Apo inhibited Tg-induced ATF4 accumulation and IL 23 p19 mRNA expression. Taken together, our findings suggest that Apo exerts anti inflammatory effects through inhibition of JNK and ATF4 signaling pathways. PMID- 27939991 TI - Protective effect of 3H-1, 2-dithiole-3-thione on cellular model of Alzheimer's disease involves Nrf2/ARE signaling pathway. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator for a battery of genes encoding detoxifying and antioxidative enzymes. 3H-1, 2-dithiole 3-thione (D3T), a potent free radical scavenger, is able to activate Nrf2 signaling pathway. In the present study, N2a/APPswe cells were used as the Alzheimer's disease (AD) cellular model and we investigated the protective effect of D3T on N2a/APPswe cells and the potential mechanisms. Our assays demonstrated that D3T was able to attenuate reactive oxygen species generation, increase MMP level as well as decrease MDA content. Furthermore, treatment of the cells with 40MUM D3T for 24h, showed significant suppression of Abeta level in N2a/APPswe cells. The current study also found that D3T significantly upregulated the Nrf2 mRNA level and protein expression, and subsequently enhanced mRNA expression of HO-1 and NQO1 in N2a/APPswe cells. Meanwhile, down-regulation of Nrf2 by small interference RNA abolished cytoprotection of D3T. Taken together, these results demonstrate that D3T provides neuroprotection in vitro model and therefore may be a potential complement for AD therapy. PMID- 27939992 TI - Dioxin-metabolizing genes in relation to effects of prenatal dioxin levels and reduced birth size: The Hokkaido study. AB - OBJECTIVES: We investigated the effects of maternal polymorphisms in 3 genes encoding dioxin-metabolizing enzymes in relation to prenatal dioxin levels on infant birth size in Japan. METHODS: We examined the relationship between dioxin exposure and birth size in relation to the polymorphisms in the genes encoding aromatic hydrocarbon receptor (AHR [G>A, Arg554Lys]), cytochrome P450 (CYP) 1A1 (T6235C), and glutathione S-transferase mu 1 (GSTM1; Non-null/null) in 421 participants using multiple linear regression models. RESULTS: In mothers carrying the GSTM1 null genotype, a ten-fold increase in total dioxin toxic equivalency was correlated with a decrease in birth weight of -345g (95% confidence interval: -584, -105). CONCLUSIONS: We observed adverse effects of maternal GSTM1 null genotype on birth weight in the presence of dioxins exposure during pregnancy. PMID- 27939993 TI - Long-term exposure to urban air pollution and the relationship with life expectancy in cohort of 3.5 million people in Silesia. AB - Air pollution is considered to be one of the most important environmental health determinants. The studies constitute an attempt to explain the role of air pollutants in the impact on the length of life of the 3.5 million people living in the cities of the Silesia province in Poland. The association between the long term inhalation exposure to PM10, benzo(a)pyrene, cadmium and lead in the period from 1989 to 2008 and length of life in the year 2014 of the inhabitants of 19 cities of the Silesia province has been estimated. The Pearson linear regression method was applied to calculate the relation between exposure to specific pollutants and length of life. In order to determine the influence of the mixture of the pollutants the multiple regression analysis was carried out. The studies have confirmed the significant correlations between the chronic exposure of Silesia province residents to PM10 and benzo(a)pyrene and their length of life. The stronger correlation was demonstrated in case of the long-term exposure to the mixture of examined air pollutants. Differentiated exposure of the inhabitants of the Silesia province to air pollutants results in existing inequalities in the life expectancy of men and women among the cities. PMID- 27939995 TI - At what scale and extent environmental gradients and climatic changes influence stream invertebrate communities? AB - In a context of increasing landscape modifications and climatic changes, scale hierarchy becomes an ever more crucial issue to integrate in the analysis of drivers and stressors of biological communities, especially in river networks. To cope with this issue, we developed (i) spatial hierarchical models of functional diversity of stream invertebrate communities to assess the relative influence of local- vs. regional-scale factors in structuring community assembly, and (ii) analysis of metacommunity elements to determine the ecological processes behind the structuring. The spatial structuring of benthic invertebrate communities was investigated over 568 sites in South-eastern France. Community structure was mainly driven by the altitudinal gradient and spring flow variation at broad scales, with functional diversity gradually decreasing with elevation and being maximized at intermediate levels of flow variability. According to the 'elements of metacommunity structure' analysis, the prevailing influence of the altitudinal gradient was also supported by a Clementsian structuration of invertebrate communities. Conversely, the influence of observed climatic changes in temperature and rainfall was weak and observed only at fine scales. As a result, natural environmental filters were stronger drivers of the functional diversity of communities than human-induced stressors (e.g. water pollution and hydromorphological alterations). More broadly, our results suggest that management needs to embrace the possibilities of gathering high spatial and taxonomical resolution data when analysing and predicting flow variation and climate change effects in order to preserve and restore functionally diverse communities. Moreover, to develop environmental flow schemes or restoration and climate change adaptation strategies for freshwater communities, local and regional processes need to be addressed simultaneously; equally responsible as drivers of community diversity. PMID- 27939994 TI - Oxidative stress responses in relationship to persistent organic pollutant levels in feathers and blood of two predatory bird species from Pakistan. AB - To date, knowledge of persistent organic pollutant (POP) mediated oxidative stress responses in avian species is rather limited. We therefore investigated whether exposure to polybrominated diphenyl ethers (PBDEs) and organochlorine pesticides (OCPs) in two predatory bird species, namely black kite (Milvus migrans) and spotted owlet (Athene brama), was associated to activities of antioxidant enzymes, such as glutathione peroxidase (GPx), glutathione S transferase (GST), glutathione reductase (GR) and catalase (CAT), or expression of GPx and superoxide dismutase (SOD) genes. As part of this investigation, we evaluated whether feathers were suitable to reflect internal body burdens and their associated oxidative stress effects. p,p'-DDE was unanimously recorded with highest concentrations in feathers and blood of both species. In general, the non significant associations reflect that feathers are not always a suitable indicator for internal body burdens of POPs, depending on the feather type and the age of the bird. The activity of GST and GR was significantly higher in spotted owlet whereas GPx and CAT was higher (albeit not significant) in spotted owlet and black kite respectively. In comparison, mRNA expression of GPx, SOD and Cu,ZnSOD was significantly higher in black kite. Regression analysis showed that the activity of GST and GR was significantly associated with p,p'-DDE in blood of spotted owlet. Similarly, activity of CAT and GR was significantly correlated with BDE-100 in feathers of spotted owlet. In comparison, mRNA expression of SOD was found significantly associated with ?PBDEs in blood of spotted owlet as well as p,p'-DDE in feathers of black kite. Significant associations of various POPs with biological responses may suggest that POP exposure may be contributing to oxidative stress in the studied bird of prey species. This first investigation indicates the necessity for further research on cause-effect relationships between POP exposures and changes in general health of free ranging birds. PMID- 27939996 TI - Effects of environmentally-relevant antibiotic mixtures on marine microalgal growth. AB - As of 2008, approximately 48% of Americans use prescription drugs within any given 30-day period. Many pharmaceutical compounds are not fully metabolized by the human body, nor fully removed by wastewater treatment systems, before release into the environment. As a result, a vast array of pharmaceuticals has been detected in marine and freshwater organisms, sediments, and waters, with unintended effects on non-target organisms, and limited studies of environmental effects. The antibiotics sulfamethoxazole (SMX), and trimethoprim (TRI), often prescribed together to treat bacterial infections, have been detected worldwide in marine and estuarine environments at concentrations up to 765-870ng/L each. Little research has examined sub-lethal effects of antibiotic mixtures at environmentally-relevant concentrations on marine organisms. We examined the effects of mixtures of these two antibiotics on three marine microalgal species with wide geographic ranges: Isochrysis galbana, Chaetoceros neogracile, and Nannochloropsis oculata. In separate simulations using a temperature/light controlled set-up, we measured the growth response for each species to environmentally-relevant levels of SMX and TRI. N. oculata growth was significantly reduced by mixture treatments of both drugs (p<0.05), by TRI (p<0.001), and by SMX (p<0.001), whereas only aggregated SMX levels significantly reduced growth for the other two species (p<0.005). The exposure time at which growth rates were affected varied across species, with significant reduction in growth focused in the latter half of the experimental period for C. neogracile and N. oculata (Days 15 and 6 respectively), and midway through the experimental period for I. galbana (by Day 3). This study finds that important marine primary producers respond to the presence of SMX and TRI in the water, offering an understanding of environmental consequences of anthropogenic pharmaceuticals contaminants, and specifically the suite of antibiotics, that are released into marine ecosystems at an ever-growing rate, and highlighting potential cascading effects through trophic levels. PMID- 27939997 TI - Soil phosphorus loss in tile drainage water from long-term conventional- and non tillage soils of Ontario with and without compost addition. AB - Recent ascertainment of tile drainage a predominant pathway of soil phosphorus (P) loss, along with the rise in concentration of soluble P in the Lake Erie, has led to a need to re-examine the impacts of agricultural practices. A three-year on-farm study was conducted to assess P loss in tile drainage water under long term conventional- (CT) and non-tillage (NT) as influenced by yard waste leaf compost (LC) application in a Brookston clay loam soil. The effects of LC addition on soil P loss in tile drainage water varied depending on P forms and tillage systems. Under CT, dissolved reactive P (DRP) loss with LC addition over the study period was 765g P ha-1, 2.9 times higher than CT without LC application, due to both a 50% increase in tile drainage flow volume and a 165% increase in DRP concentration. Under NT, DRP loss in tile drainage water with LC addition was 1447gPha-1, 5.3 times greater than that for NT without LC application; this was solely caused by a 564% increase in DRP concentration. However, particulate P loads in tile drainage water with LC application remained unchanged, relative to non-LC application, regardless of tillage systems. Consequently, LC addition led to an increase in total P loads in tile drainage water by 57 and 69% under CT and NT, respectively. The results indicate that LC application may become an environmental concern due to increased DRP loss, particularly under NT. PMID- 27939998 TI - Cochlear implantation in autistic children with profound sensorineural hearing loss. AB - INTRODUCTION: Cochlear implants have become the method of choice for the treatment of severe-to-profound hearing loss in both children and adults. Its benefits are well documented in the pediatric and adult population. Also deaf children with additional needs, including autism, have been covered by this treatment. OBJECTIVE: The aim of this study was to assess the benefits from cochlear implantation in deafened children with autism as the only additional disability. METHODS: This study analyzes data of six children. The follow-up time was at least 43 months. The following data were analyzed: medical history, reaction to music and sound, Ling's six sounds test, onomatopoeic word test, reaction to spoken child's name, response to requests, questionnaire given to parents, sound processor fitting sessions and data. RESULTS: After cochlear implantation each child presented other communication skills. In some children, the symptoms of speech understanding were observed. No increased hyperactivity associated with daily use cochlear implant was observed. The study showed that in autistic children the perception is very important for a child's sense of security and makes contact with parents easier. CONCLUSION: Our study showed that oral communication is not likely to be a realistic goal in children with cochlear implants and autism. The implantation results showed benefits that varied among those children. The traditional methods of evaluating the results of cochlear implantation in children with autism are usually insufficient to fully assess the functional benefits. These benefits should be assessed in a more comprehensive manner taking into account the limitations of communication resulting from the essence of autism. It is important that we share knowledge about these complex children with cochlear implants. PMID- 27939999 TI - 24-Methylenecyclopropane steroidal inhibitors: A Trojan horse in ergosterol biosynthesis that prevents growth of Trypanosoma brucei. AB - A new class of steroidal therapeutics based on phylogenetic-guided design of covalent inhibitors that target parasite-specific enzymes of ergosterol biosynthesis is shown to prevent growth of the protozoan-Trypanosoma brucei, responsible for sleeping sickness. In the presence of approximately 15+/-5MUM 26,27-dehydrolanosterol, T. brucei procyclic or blood stream form growth is inhibited by 50%. This compound is actively converted by the parasite to an acceptable substrate of sterol C24-methyl transferase (SMT) that upon position specific side chain methylation at C26 inactivates the enzyme. Treated cells show dose-dependent depletion of ergosterol and other 24beta-methyl sterols with no accumulation of intermediates in contradistinction to profiles typical of tight binding inhibitor treatments to azoles showing loss of ergosterol accompanied by accumulation of toxic 14-methyl sterols. HEK cells accumulate 26,27 dehydrolanosterol without effect on cholesterol biosynthesis. During exposure of cloned TbSMT to 26,27-dehydrozymosterol, the enzyme is gradually inactivated (kcat/kinact=0.13min-1/0.08min-1; partition ratio of 1.6) while 26,27 dehydrolanosterol binds nonproductively. GC-MS analysis of the turnover product and bound intermediate released as a C26-methylated diol (C3-OH and C24-OH) confirmed substrate recognition and covalent binding to TbSMT. This study has potential implications for design of a novel class of chemotherapeutic leads functioning as mechanism-based inhibitors of ergosterol biosynthesis to treat neglected tropical diseases. PMID- 27940002 TI - Coronary calcium scores: From histology to preventive cardiology. PMID- 27940003 TI - Predictors for left ventricular dysfunction in patients with non-ST-segment elevation myocardial infarction. PMID- 27940000 TI - Impact of dietary phytol on lipid metabolism in SCP2/SCPX/L-FABP null mice. AB - In vitro studies suggest that liver fatty acid binding protein (L-FABP) and sterol carrier protein-2/sterol carrier protein-x (SCP2/SCPx) gene products facilitate uptake and metabolism and detoxification of dietary-derived phytol in mammals. However, concomitant upregulation of L-FABP in SCP2/SCPx null mice complicates interpretation of their physiological phenotype. Therefore, the impact of ablating both the L-FABP gene and SCP2/SCPx gene (L-FABP/SCP2/SCPx null or TKO) was examined in phytol-fed female wild-type (WT) and TKO mice. TKO increased hepatic total lipid accumulation, primarily phospholipid, by mechanisms involving increased hepatic levels of proteins in the phospholipid synthetic pathway. Concomitantly, TKO reduced expression of proteins in targeting fatty acids towards the triacylglycerol synthetic pathway. Increased hepatic lipid accumulation was not associated with any concomitant upregulation of membrane fatty acid transport/translocase proteins involved in fatty acid uptake (FATP2, FATP4, FATP5 or GOT) or cytosolic proteins involved in fatty acid intracellular targeting (ACBP). In addition, TKO exacerbated dietary phytol-induced whole body weight loss, especially lean tissue mass. Since individually ablating SCPx or SCP2/SCPx elicited concomitant upregulation of L-FABP, these findings with TKO mice help to resolve the contributions of SCP2/SCPx gene ablation on dietary phytol-induced whole body and hepatic lipid phenotype independent of concomitant upregulation of L-FABP. PMID- 27940001 TI - Utilization of multiple substrates by butyrate kinase from Listeria monocytogenes. AB - Listeria monocytogenes, the causative agent of listeriosis, can build up to dangerous levels in refrigerated foods potentially leading to expensive product recalls. An important aspect of the bacterium's growth at low temperatures is its ability to increase the branched-chain fatty acid anteiso C15:0 content of its membrane at lower growth temperatures, which imparts greater membrane fluidity. Mutants in the branched-chain alpha-keto dehydrogenase (bkd) complex are deficient in branched-chain fatty acids (BCFAs,) but these can be restored by feeding C4 and C5 branched-chain carboxylic acids (BCCAs). This suggests the presence of an alternate pathway for production of acyl CoA precursors for fatty acid biosynthesis. We hypothesize that the alternate pathway is composed of butyrate kinase (buk) and phosphotransbutyrylase (ptb) encoded in the bkd complex which produce acyl CoA products by their sequential action through the metabolism of carboxylic acids. We determined the steady state kinetics of recombinant His tagged Buk using 11 different straight-chain and BCCA substrates in the acyl phosphate forming direction. Buk demonstrated highest catalytic efficiency with pentanoate as the substrate. Low product formation observed with acetate (C2) and hexanoate (C6) as the substrates indicates that Buk is not involved in either acetate metabolism or long chain carboxylic acid activation. We were also able to show that Buk catalysis occurs through a ternary complex intermediate. Additionally, Buk demonstrates a strong preference for BCCAs at low temperatures. These results indicate that Buk may be involved in the activation and assimilation of exogenous carboxylic acids for membrane fatty acid biosynthesis. PMID- 27940004 TI - Early repolarization syndrome and Brugada syndrome: Similar or different? PMID- 27940005 TI - Cardiotoxicity of capecitabine: Captions not to bin. PMID- 27940006 TI - Prediction of thromboembolic events for patients with non-valvular atrial fibrillation; CHA2DS2-VASc-UA2-VitD. PMID- 27940007 TI - Capecitabine cardiotoxicity: How to limit life-threatening events. PMID- 27940008 TI - What should be the optimal revascularization strategy for left main stem coronary artery disease? PMID- 27940011 TI - Pediatric Intracranial Hypertension. AB - Primary (idiopathic) intracranial hypertension has been considered to be a rare entity, but with no precise estimates of the pediatric incidence in the United States. There have been attempts to revise the criteria over the years and adapt the adult criteria for use in pediatrics. The clinical presentation varies with age, and symptoms tending to be less obvious in younger individuals. In the prepubertal population, incidentally discovered optic disc edema is relatively common. By far the most consistent symptom is headache; other symptoms include nausea, vomiting tinnitus, and diplopia. Treatment mainstays include weight loss when appropriate and acetazolamide. Furosemide may exhibit a synergistic benefit when used in conjunction with acetazolamide. Surgical interventions are required relatively infrequently, but include optic nerve sheath fenestration and cerebrospinal fluid shunting. Pain and permanent vision loss are the two major complications of this disorder and these manifestations justify aggressive treatment. Once intracranial hypertension has resolved, up to two thirds of patients develop a new or chronic headache type that is different from their initial presenting headache. PMID- 27940010 TI - Resolution of pericardial constriction with anakinra; possible role of C reactive protein. PMID- 27940009 TI - No protection of heart, kidneys and brain by remote ischemic preconditioning before transfemoral transcatheter aortic valve implantation: Interim-analysis of a randomized single-blinded, placebo-controlled, single-center trial. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) reduces myocardial injury and improves clinical outcome in patients undergoing coronary revascularization, but only in the absence of propofol-anesthesia. We investigated whether RIPC provides protection of heart, kidneys and brain and improves outcome in patients undergoing transfemoral transcatheter aortic valve implantation (TF-TAVI). METHODS: Patients undergoing TF-TAVI were randomized to receive RIPC (3cycles of 5min left upper arm ischemia and 5min reperfusion) or placebo. The primary endpoint was myocardial injury, reflected by the area under the curve for serum troponin I concentrations (AUC-TnI) over the first 72h. Secondary endpoints included the incidences of periprocedural myocardial infarction, delayed gadolinium enhancement on postprocedural cardiac MRI, acute kidney injury, periprocedural stroke, and the incidence and volume of new lesions on postprocedural cerebral MRI. All-cause and cardiovascular mortality and major adverse cardiac and cerebrovascular events (MACCE) were assessed over 1-year follow-up. A prespecified interim-analysis was performed after the last patient had completed 1-year follow-up (NCT02080299). RESULTS: 100 consecutive patients were enrolled between September 2013 and June 2015. There were no significant between-group differences in the primary endpoint of peri-interventional myocardial injury (ratio RIPC/placebo AUC-TnI: 0.87, 95% CI: 0.57-1.34, p=0.53) or the secondary endpoints of cardiac, renal and cerebral impairment. There was no significant treatment effect in subgroup-analyses of patients undergoing cardiac or cerebral MRI. Mortality and MACCE did not differ. No RIPC-related adverse events were observed. CONCLUSIONS: RIPC did neither protect heart, kidneys and brain nor improve clinical outcome in patients undergoing TF-TAVI. PMID- 27940012 TI - Molecular crowding improves bead-based padlock rolling circle amplification. AB - Bead-based padlock rolling circle amplification (RCA), an ultrasensitive and accurate DNA detection technique, was conducted in a molecular crowding environment created by poly(ethylene glycol) (PEG). The number of RCA products generated increased and exhibited a bell-shaped dependence on PEG concentration. Experiments using magnetic beads suggested that facilitation of DNA ligation and hybridization is the main reason for the observed increase. Selectivity of the technique was retained in the presence of PEG. This technique is simple and can be utilized to detect target DNA with high accuracy and sensitivity in a variety of areas such as medical diagnosis and food analysis. PMID- 27940013 TI - Domain-specific free thiol variant characterization of an IgG1 by reversed-phase high-performance liquid chromatography mass spectrometry. AB - Measurement of free thiols in antibody therapeutics is important for product development and assessment of critical quality attributes. Earlier studies demonstrated fast separation of free thiol variants of IgG1 using reversed-phase high performance liquid chromatography (RP-HPLC) with diphenyl resin. Here, we report using N-tert-butylmaleimide (NtBM) alkylation followed by RP-HPLC and online mass spectrometry for rapid total and domain-specific free thiol characterization of IgG1. By increasing hydrophobicity, NtBM alkylation improves separation of free thiol variants from disulfide-linked main peak species. The unique mass shift by NtBM alkylation offers unambiguous characterization of free thiol variants by online mass spectrometry. Variant peaks separated by RP-HPLC were antibody molecules containing two NtBM-alkylated cysteines, corresponding to IgG1 containing two free thiols before alkylation. Further characterization of the collected fractions of variants by peptide mapping revealed that each variant contained unpaired cysteines located in specific IgG1 domains (CH1, CH3, VH and VL domains). Total molecular-level and domain-specific free thiol content measured by this method correlate well with orthogonal differential alkylation peptide mapping analysis, which measures free thiol level at individual cysteine residues. This method provides high throughput quantitation of total and domain specific free thiol content in IgG1 molecules, facilitating rapid, comprehensive product and manufacturing process characterization. PMID- 27940014 TI - Are we missing dextropropoxyphene? PMID- 27940015 TI - Atypical Chlamydia Psittaci Pneumonia. Four Related Cases. PMID- 27940016 TI - Metals and metastasis: Exploiting the role of metals in cancer metastasis to develop novel anti-metastatic agents. AB - Metastasis is currently the leading cause of cancer related death and is the most feared and difficult to treat outcome for cancer patients. This complex process is regulated by a plethora of signaling pathways and molecules that control cell proliferation, invasion, motility and adhesion. Many of these vital processes that enable metastasis to occur are influenced by metals, which play crucial roles in the function of numerous proteins and enzymes. Importantly, an excess of essential metals such as iron and copper is often associated with carcinogenesis and metastatic disease. As such, metals have emerged as promising and viable therapeutic targets for a new generation of anti-cancer and anti-metastatic agents. Further, the unique properties of metals, including their abilities to redox cycle or to mimic other metals, can also be utilized to more effectively target aggressive and metastatic cancer cells. This review will provide an overview of the role that metals play in the metastatic progression of cancer and the development of novel therapies that either target or utilize metal ions as part of their mechanism of action to inhibit metastasis. PMID- 27940017 TI - Honokiol, a potential therapeutic agent, induces cell cycle arrest and program cell death in vitro and in vivo in human thyroid cancer cells. AB - Thyroid cancer is the most common endocrine malignancy, the global incidence rate of which is rapidly rising. Surgery and radioiodine therapies are common and effective treatments only for nonmetastasized primary tumors. Therefore, effective treatment modalities are imperative for patients with radioiodine resistant thyroid cancer. Honokiol, a biophenolic compound derived from Magnolia spp., has been shown have diverse biological and pharmacological activities, including anti-inflammatory, antioxidative, antiangiogenic, and anticancer properties. In the present study, three human thyroid cancer cell lines, namely anaplastic, follicular, and poorly differentiated thyroid cancer cells, were used to evaluate the chemotherapeutic activity of honokiol. Cell viability, cell cycle, apoptosis, and autophagy induction were determined through flow cytometry and western blot analysis. We found that honokiol treatment can suppress cell growth, induce cell cycle arrest, and enhance the induction of caspase-dependent apoptosis and autophagy in cancer cells. Moreover, honokiol treatment modulated signaling pathways including Akt/mTOR, ERK, JNK, and p38 in the studied cells. In addition, the antitumorigenic activity of honokiol was also confirmed in vitro and in vivo. Our data provide evidence that honokiol has a unique application in chemotherapy for human thyroid cancers. PMID- 27940018 TI - Reversible recovery of neuronal structures depends on the degree of neuronal damage after global cerebral ischemia in mice. AB - It has been observed by in vivo imaging that damaged neuronal structures can be reversibly restored after ischemic insults with the application of timely therapeutic interventions. However, what degree of neuronal damage can be restored and the time frame for reversible recovery of neuronal structures remain unclear. Here, transcranial two-photon imaging, histological staining and electron microscopy were used to investigate the reversible recovery of neuronal structures from dendrites to soma after different durations of global cerebral ischemia in mice. Intravital imaging revealed that the damage to dendritic structures was reversible when ischemia time was <1h, but they became difficult to restore after >3h of ischemia. Data from fixed YFP brain slice and Golgi staining indicated that the damage of dendritic structures progressively extended to deeper dendritic shafts with the extension of ischemia time. Furthermore, longer duration of ischemia caused an increasing number of degenerating neurons. Importantly, significant chromatin margination and karyopyknosis of neuron were observed after 6h of ischemia. These data suggested that neuronal structures could be reversibly restored when ischemia time was <1h, but irreversible and progressive damage to neurons occurred with longer duration of ischemia. Consistently, behavioral performance of post-ischemic animals experienced an ischemia time-dependent recovery. Taken together, our data suggested that recovery of neuronal structures following ischemia was dependent on the duration of ischemia, and prevention of neuronal loss is a key target for therapeutic interventions in ischemic stroke. PMID- 27940019 TI - The habenula as a critical node in chronic stress-related anxiety. AB - The habenula is activated in response to stressful and aversive events, resulting in exploratory inhibition. Although possible mechanisms for habenula activation have been proposed, the effects of chronic stress on the habenular structure have never been studied. Herein, we assessed changes in volume, cell density and dendritic structure of habenular cells after chronic stress exposure using stereological and 3D morphological analysis. This study shows for the first time that there is a hemispherical asymmetry in the medial habenula (MHb) of the adult rat, with the right MHb containing more neurons than its left counterpart. Additionally, it shows that chronic stress induces a bilateral atrophy of both the MHb and the lateral habenula (LHb). This atrophy was accompanied by a reduction of the number of neurons in the right MHb and the number of glial cells in the bilateral LHb, but not by changes in the dendritic arbors of multipolar neurons. Importantly, these structural changes were correlated with elevated levels of serum corticosterone and increased anxious-like behavior in stressed animals. To further assess the role of the habenula in stress-related anxiety, bilateral lesions of the LHb were performed; interestingly, in lesioned animals the chronic stress protocol did not trigger increases in circulating corticosterone or anxious-like behavior. This study highlights the role of the habenula in the stress responses and how its sub-regions are structurally impacted by chronic stress with physiological and behavioral consequences. PMID- 27940021 TI - The extraordinary longevity of kleptoplasts derived from the Ross Sea haptophyte Phaeocystis antarctica within dinoflagellate host cells relates to the diminished role of the oxygen-evolving Photosystem II and to supplementary light harvesting by mycosporine-like amino acid/s. AB - The haptophyte Phaeocystis antarctica and the novel Ross Sea dinoflagellate that hosts kleptoplasts derived from P. antarctica (RSD; R.J. Gast et al., 2006, J. Phycol. 42 233-242) were compared for photosynthetic light harvesting and for oxygen evolution activity. Both chloroplasts and kleptoplasts emit chlorophyll a (Chl a) fluorescence peaking at 683nm (F683) at 277K and at 689 (F689) at 77K. Second derivative analysis of the F689 band at 77K revealed two individual contributions centered at 683nm (Fi-683) and at 689 (Fi-689). Using the p nitrothiophenol (p-NTP) treatment of Kobayashi et al. (Biochim. Biophys. Acta 423 (1976) 80-90) to differentiate between Photosystem (PS) II and I fluorescence emissions, we could identify PS II as the origin of Fi-683 and PS I as the origin of Fi-689. Both emissions could be excited not only by Chl a-selective light (436nm) but also by mycosporine-like amino acids (MAAs)-selective light (345nm). This suggests that a fraction of MAAs must be proximal to Chls a and, therefore, located within the plastids. On the basis of second derivative fluorescence spectra at 77K, of p-NTP resolved fluorescence spectra, as well as of PSII-driven oxygen evolution activities, PS II appears substantially less active (~1/5) in dinoflagellate kleptoplasts than in P. antarctica chloroplasts. We suggest that a diminished role of PS II, a known source of reactive oxygen species, and a diminished dependence on nucleus-encoded light-harvesting proteins, due to supplementary light-harvesting by MAAs, may account for the extraordinary longevity of RSD kleptoplasts. PMID- 27940022 TI - Population-attributable fraction of hypertension associated with obesity, abdominal obesity, and the joint effect of both in the Central Provinces of Iran. AB - The prevalence of obesity has been increasing in Iran over the past decade. This study aimed to determine the population-attributable fraction (PAF) of hypertension associated with obesity, abdominal obesity, and the joint effect of both in the central provinces of Iran. Prevalence of hypertension was extracted from the Iranian Ministry of Health Non-Communicable Disease Risk Factor InfoBase 2009. Measure of association between obesity and hypertension was extracted from Tehran Lipid and Glucose Study, for males and females, in order to calculate the PAF of hypertension associated with obesity. Age standardization of the reported prevalence of obesity was done using the World Health Organization method. The PAF of hypertension associated with the joint effect of obesity and abdominal obesity in females was highest in Semnan Province: 22.7 [95% confidence interval (CI): 4.2-35.6], followed by Qom 21.09 (95% CI: 3.7-33.1), and Yazd 20.3 (95% CI: 3.5-32.1). In males, the highest PAF was observed in Qom Province 31.07 (95% CI: 16.7-41.1), followed by Semnan 29.6 (95% CI: 15.9-39.3), Qazvin 25.9 (95% CI: 13.7-34.5), Tehran 24.2 (95% CI: 12.7-32.3), and Isfahan 20.4 (95% CI: 3.5-27.4). Prevalence of hypertension is higher in more developed provinces. PAFs suggest that a sizable share of hypertension in these provinces is associated with obesity. It is recommended that health promotion programs focus on obesity in the provinces with a higher share of hypertension due to obesity. PMID- 27940020 TI - Subunit NDUFV3 is present in two distinct isoforms in mammalian complex I. AB - Complex I (NADH:ubiquinone oxidoreductase) is the first enzyme of the electron transport chain in mammalian mitochondria. Extensive proteomic and structural analyses of complex I from Bos taurus heart mitochondria have shown it comprises 45 subunits encoded on both the nuclear and mitochondrial genomes; 44 of them are different and one is present in two copies. The bovine heart enzyme has provided a model for studying the composition of complex I in other mammalian species, including humans, but the possibility of additional subunits or isoforms in other species or tissues has not been explored. Here, we describe characterization of the complexes I purified from five rat tissues and from a rat hepatoma cell line. We identify a~50kDa isoform of subunit NDUFV3, for which the canonical isoform is only ~10kDa in size. We combine LC-MS and MALDI-TOF mass spectrometry data from two different purification methods (chromatography and immuno-purification) with information from blue native PAGE analyses to show the long isoform is present in the mature complex, but at substoichiometric levels. It is also present in complex I in cultured human cells. We describe evidence that the long isoform is more abundant in both the mitochondria and purified complexes from brain (relative to in heart, liver, kidney and skeletal muscle) and more abundant still in complex I in cultured cells. We propose that the long 50kDa isoform competes with its canonical 10kDa counterpart for a common binding site on the flavoprotein domain of complex I. PMID- 27940024 TI - Influence of category coherence and type of base-rate acquisition on property generalization. AB - Category coherence involves identifying similarities between social categories, such as jobs and hobbies, and is primarily used for generalizing or drawing inferences about their properties. Category coherence is also used for drawing inferences from explicit information, such as base rates. For example, people generalize the properties of groups or brands from multiple sources (e.g., survey results and the share market in periodicals). However, generalizing the properties of categories using explicit base-rate information may not always involve category coherence; rather, it may involve directly analyzing base-rate information. Therefore, this study attempts to distinguish between conditions in which people use category coherence and explicit base-rate information. Specifically, we proposed that people acquiring explicit base-rate knowledge described as a percentage-would generalize a category's properties according to its base rate; however, for base-rate information acquired via direct observation, the inductive strength in generalizing properties would be greater for categories with high levels of coherence. Our results (Experiment 1 and Experiment 2) validated these two predictions. Finally, the interaction between category coherence and type of base-rate acquisition was discussed. PMID- 27940023 TI - Adaptive diversification in heterogeneous environments. AB - The role of environmental heterogeneity in the evolution of biological diversity has been studied only for simple types of heterogeneities and dispersals. This article broadens previous results by considering heterogeneities and dispersals that are structured by several environmental factors. It studies the evolution of a metapopulation, living in a network of patches connected by dispersal, under the effects of mutation, selection and migration. First, it is assumed that patches are equally connected and that they carry habitats characterized by several factors exerting selection pressures on several individual traits. Habitat factors may vary in the environment independently or they may be correlated. It is shown that correlations between habitat factors promote adaptive diversification and that this effect may be modified by trait interactions on survival. Then, it is assumed that patches are structured by two crossed factors, called the row and column factors, such that patches are more connected when they occur in the same row or in the same column. Environmental patterns in which each habitat appears in each row the same number of times and appears in each column the same number of times are found to hinder adaptive diversification. PMID- 27940025 TI - Priming biological motion changes extrapersonal space categorization. AB - Recent results have shown that the way we categorize space varies as a function of the frame of reference. If the reference frame (RF) is another person vs. an object, the distance is judged as reduced. It has been suggested that such an effect is due to the spontaneous processing of the other's motor potentialities. To investigate the impact of movement representation on space perception, we used biological motion displays as a prime for a spatial categorization task. In Exp. 1, participants were presented with a point-light walker or a scrambled motion, and then judged the location ("Near" or "Far") of a target with a human body or an inanimate object as RF. In Exp. 2, participants were primed with point-light walkers of different speeds: a runner, a normal walker and a slow walker. In Exp. 3 they were primed with a point-light display depicting a human body sitting down on or standing up from a chair, with a human body RF either oriented or not oriented towards the target. Results showed a reduced judged distance when the human body RF was primed with a point-light walker (Exp. 1). Furthermore, we found an additional reduction of the judged distance when priming with a runner (Exp. 2). Finally, Exp. 3 showed that the human body RF has to be target oriented as a precondition for priming effects of the point-light walker. PMID- 27940026 TI - The effect of cue content on retrieval from autobiographical memory. AB - It has long been argued that personal memories are usually generated in an effortful search process in word-cueing studies. However, recent research (Uzer, Lee, & Brown, 2012) shows that direct retrieval of autobiographical memories, in response to word cues, is common. This invites the question of whether direct retrieval phenomenon is generalizable beyond the standard laboratory paradigm. Here we investigated prevalence of direct retrieval of autobiographical memories cued by specific and individuated cues versus generic cues. In Experiment 1, participants retrieved memories in response to cues from their own life (e.g., the names of friends) and generic words (e.g., chair). In Experiment 2, participants provided their personal cues two or three months prior to coming to the lab (min: 75days; max: 100days). In each experiment, RT was measured and participants reported whether memories were directly retrieved or generated on each trial. Results showed that personal cues elicited a high rate of direct retrieval. Personal cues were more likely to elicit direct retrieval than generic word cues, and as a consequence, participants responded faster, on average, to the former than to the latter. These results challenge the constructive view of autobiographical memory and suggest that autobiographical memories consist of pre stored event representations, which are largely governed by associative mechanisms. These demonstrations offer theoretically interesting questions such as why are we not overwhelmed with directly retrieved memories cued by everyday familiar surroundings? PMID- 27940027 TI - Foscarnet resistance mutations mapping to atypical domains of the cytomegalovirus DNA polymerase gene. AB - Human cytomegalovirus UL54 DNA polymerase gene mutations that confer foscarnet resistance in clinical practice typically cluster in the amino terminal 2, palm and finger domains. Exposure to foscarnet in cell culture selected for mutations elsewhere in UL54, including amino acid substitutions S290R in the amino terminal 1 domain and E951D in the palm 2 domain. These are newly confirmed to confer foscarnet resistance and slightly decreased ganciclovir susceptibility. Other emergent substitutions N495K, T552N and T838A are known to confer foscarnet resistance, while additional ones Q783R and V798A only slightly affected susceptibility. An expanded set of domains is involved in foscarnet resistance and its genotypic diagnosis. PMID- 27940028 TI - Viral-bacterial co-infections in the respiratory tract. AB - Preceding or concurrent viral respiratory tract infection can predispose to secondary bacterial co-infection throughout the airway. The mechanisms by which viruses promote these superinfections are diverse and replete. Whereas we understand much as to how viruses damage the airway and dysregulate both innate and acquired immune responses which, in turn, supports bacterial growth, adherence and invasion into normally sterile sites within the respiratory tract, new information regarding these co-infections is being gained from recent advances in microbiome research and our enhanced appreciation of the contribution of bacterial biofilms, among others. The advanced understanding obtained by continued research efforts in all aspects of viral-bacterial co-infections of the respiratory tract will allow us to devise novel approaches for disease prevention as well as to develop more effective therapeutics. PMID- 27940029 TI - sFlt-1, PlGF, sFlt-1/PlGF ratio and uterine artery Doppler for preeclampsia diagnostics. AB - BACKGROUND AND OBJECTIVE: Angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) play a key role in the pathogenesis of preeclampsia. Uterine artery (UA) blood flow is important for preeclamptic pregnancy outcome, but small amount of evidence suggests UA dopplerometry for preeclampsia diagnostics and management. The aim of our study was to compare the value of angiogenic factors and UA dopplerometry in preeclampsia diagnosis and determine cut-off values to obtain the highest sensitivity and specificity of the parameter. MATERIALS AND METHODS: We performed a case controlled study of 72 pregnant women with preeclampsia and 72 healthy matched controls. SFlt-1 and PlGF were measured in serum samples, the sFlt-1/PlGF ratio was calculated and UA pulsatility (PI) and resistance (RI) indexes were registered. RESULTS: Significantly higher levels of sFlt-1, sFlt-1/PlGF ratio and mean UAPI and UARI and lower levels of PlGF were found in preeclampsia group when compared to controls. The highest sensitivity and specificity for preeclampsia had SFlt-1/PlGF and PlGF with the cut-off values of >=35 (sensitivity of 95.8% and specificity of 96.2%, respectively) and <=138.6pg/mL (sensitivity of 95.8% and specificity of 93.7%, respectively). For diagnostics of early-onset preeclampsia, all factors sFlt-1, PlGF and sFlt-1/PlGF had equal significance with the cut-off values of >=7572pg/mL (specificity of 97.5%, sensitivity 92.3%), <=100.5pg/mL (specificity 96.2%, sensitivity of 100%) and >=54.6 (specificity 97.5%, sensitivity 97.5%) respectively. CONCLUSIONS: The sFlt-1/PlGF ratio and PlGF are superior to sFlt-1, UAPI and UARI for preeclampsia diagnosis. For early onset preeclampsia diagnostics either sFlt-1 or PlGF is sufficient. PMID- 27940030 TI - Designing of experiments for evaluating the interactions of influencing factors on the photocatalytic activity of NiS and SnS2: Focus on coupling, supporting and nanoparticles. AB - Synergistic photocatalytic activity of SnS2 and NiS supported was observed by coupling and supporting the semiconductors onto clinoptilolite nanoparticles (NC). Formation of electrical double layer at the semiconductors' interface in the coupled semiconductors significantly prevented from electron/hole recombination which in turn enhanced the photodegradation activity. Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) confirmed enhancement in charge transfer efficiency of the coupled/supported system with respect to the mono-component systems. Consequently the coupled/supported system showed the best photodegradation activity in degradation of metronidazole (MZ). The response surface methodology (RSM) showed that irradiation time, solution pH and interactions of time-CMZ and time-pH are the most important factors in MZ degradation. The best degradation extent was obtained at pH 4, catalyst dosage of 3gL-1, 3mgL-1 of MZ at irradiation time of 270min. R2 of 0.9743 confirmed that the data predicted by RSM well agree with the experimental results. Catalyst dosage and irradiation time had synergistic effect and initial pH and CMZ had an antagonistic effect on the response, meaning that increasing in time and catalyst dosage and decreasing in pH and CMZ decreased MZ photodegradation. Sharp decrease in the UV-Vis absorption at 319nm and increase in the intensity at 240 and 206nm during the process confirmed converting the nitro group and nitrogen existing in MZ to nitrite ion. PMID- 27940031 TI - PEGylated chitosan protected silver nanoparticles as water-borne coating for leather with antibacterial property. AB - Development of eco-labeled and effectively antibacterial coatings for final leather products has been desiderated both by industry and by consumers. Herein, PEGylated chitosan modified silver nanoparticles (PEG-g-CS@AgNPs) were prepared and characterized by UV-vis spectroscopy, transmission electron microscopy and dynamic light scattering. The antimicrobial activity of such silver nanoparticles was investigated against Gram-negative Escherichia coli (E. coli) and Gram positive Staphylococcus aureus (S. aureus), exhibiting much lower minimum inhibitory concentration (MIC) than chitosan or PEG-g-CS. Water-borne coating was formed by immobilizing the PEG-g-CS@AgNPs onto the leather surface through the electrostatic interaction between amino groups of chitosan and carboxyl groups of leather collagen. Scanning electron microscopy and water contact angle were employed to study the coating's morphology and hydrophilicity, respectively. After coating, leather samples showed significantly high bactericidal efficiency with reusability after release of dead cells from the coating by simply water washing. The excellent antibacterial property of PEG-g-CS@AgNPs coating was ascribed to the combination of bacteria-resistance and bacteria-release by PEGylation, and dual bacteria-killing based on chitosan and Ag+ release. PMID- 27940032 TI - Comprehensive study on enhanced photocatalytic activity of heterojunction ZnS NiS/zeolite nanoparticles: Experimental design based on response surface methodology (RSM), impedance spectroscopy and GC-MASS studies. AB - In the present work, coupled and supported NiS and ZnS onto the mechanically prepared clinoptilolite nanoparticles (NC) was prepared and characterized by XRD, FTIR, SEM-EDX, X-ray mapping, DRS, BET, cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) techniques. The obtained catalysts were used in photodegradation of metronidazole (MZ). The mole ratio of NiS/ZnS affects the degradation activity of the obtained catalysts so the best activity was obtained for the NZ4-NC (NiS1.0-ZnS5.2/NC, containing 1.0 and 5.2W% of NiS and ZnS, respectively and mole ratio of ZnS/NiS about 4) catalyst. The simultaneous effects of the experimental parameters were studied using central composite design combined with response surface methodology (RSM). Results of CV and EIS have good agreement with photodegradation results, so the coupled NiS-ZnS NC system with significant enhancement in charge transfer with respect to the monocomponent systems showed the best photodegradation activity. The best degradation extent of MZ was obtained at a run including pH 2, catalyst dose of 3gL-1, 4mgL-1 of MZ at irradiation time of 150min. The high correlation coefficient (R2=0.9883) for the second-order polynomial model, showed that the data predicted using RSM were in good agreement with the experimental results. Change of initial pH of MZ solution from 5.5 to 4.1 during 150min, confirms formation of acidic degradation intermediates. PMID- 27940034 TI - N-doped nanoporous carbon as efficient catalyst for nitrobenzene reduction in sulfide-containing aqueous solutions. AB - Metal-free N-doped porous carbon (NC) materials have been demonstrated to be promising catalysts in contaminated environment remediation. Two NC materials (NC 1 and NC-2) were prepared by sol-gel routes. Their catalytic properties were investigated for the reduction of nitrobenzene (NB) in sulfide-containing aqueous solution. Both NC-1 and NC-2 can efficiently catalyze the reduction of NB to aniline (AN) under ambient conditions, but also can be reused for more than 5 times. The reaction fits excellently to the pseudo-first-order kinetic. Compared with NC-1 material, NC-2 shows much higher removal efficiency (rate constant kobs: 0.283h-1vs. 2.50h-1). The important features of NC material, including high specific surface area, suitable surface functional groups (especially nitrogen containing groups), and enhanced electron transfer ability, should be mainly factors for its excellent catalytic activity. This work demonstrates that N-doped carbon materials have great potential for degradation of NB to AN in the natural aquatic environment. PMID- 27940033 TI - Ultrasound-induced gelation of fluorenyl-9-methoxycarbonyl-l-lysine(fluorenyl-9 methoxycarbonyl)-OH and its dipeptide derivatives showing very low minimum gelation concentrations. AB - Four l-Lysine(Lys)-l-glutamic acid(Glu) dipeptide derivatives (1-4) and their precursor-a single fluorenyl-9-methoxycarbonyl(Fmoc)-l-Lys(Fmoc)-OH amino acid (5) were demonstrated as gelators to gelate a variety of alcohols and aromatic solvents under the sonication conditions. Compared to the routine heating-cooling protocol, the ultrasound substantially brought down the minimum gelation concentrations (MGCs) of the resulting organogels. The Fourier transform infrared spectroscopy (FT-IR) and fluorescence studies revealed that the pi-pi stacking and hydrogen bonding act as major driving forces for the self-assembly of these lysine-based gelators into supramolecular fibrous three dimensional (3D) network, where the more the Fmoc protecting groups, the gelators are more responsive to ultrasound-stimulus and more conducive to an ordered molecular arrangement reinforcing the intermolecular forces. Moreover, the ultrasound-triggered organogels of 5 exhibited the thixotropic property. Upon imposing a mechanical shear, its gels with the fibrous 3D network structure were unraveled into sols. However, after standing quiescently over time, these sols returned to the gels showing a more ordered lamella-like packing structure as evidenced by scanning electron microscopy (SEM) and X-ray diffraction (XRD) analyses. PMID- 27940035 TI - One-pot synthesis of binary metal organic frameworks (HKUST-1 and UiO-66) for enhanced adsorptive removal of water contaminants. AB - In this study, binary metal organic frameworks (MOFs) with HKUST-1 and UiO-66 have been synthesized in a one-pot process. The synthesized MOFs were characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), N2 adsorption, and thermogravimetric analysis (TGA). The meso-porosity and thermal stability of the binary MOFs were higher than those of single HKUST-1 or UiO-66. The synthesized MOF hybrids were then tested for adsorptive removal of methylene blue (MB) from wastewater in terms of kinetic and isothermal adsorption as compared to a commercially available activated carbon (AC). All the synthesized MOFs showed significant removal of MB under a wide range of pH. The adsorption capacities of HKUST-1 are higher than UiO-66 and commercial AC while the binary MOFs presented an even higher adsorption capacity than single MOFs. This is the first time that binary HKUST-1 and UiO-66 MOFs have been successfully synthesized and demonstrated enhanced adsorptive removal of contaminants. PMID- 27940036 TI - Maternal history of child maltreatment and maternal depression risk in the perinatal period: A longitudinal study. AB - Existing research is limited, with only a few studies considering each single type and multiple types of child maltreatment (CM) as well as multiple assessments of maternal depression throughout the perinatal period. The purpose of the study was to assess each type and accumulative types of CM in relation to the risk of maternal depression throughout the perinatal period. In total, 276 pregnant women were recruited from the prenatal clinic at a general hospital in China. Maternal CM history and depression risk were assessed at late pregnancy, postpartum week 1, and postpartum week 4 using the Childhood Trauma Questionnaire (CTQ) and Edinburgh Postnatal Depression Scale (EPDS). The GEE showed that physical and emotional neglect and multiple types of CM were associated with higher overall depression risk across the perinatal period. The multinomial regression models showed physical neglect and multiple types of CM predicted higher risk of both antepartum and postpartum depression. Emotional and sexual abuse and emotional neglect predicted antepartum depression risk, while none of the three types of CM predicted postpartum depression risk. Physical abuse did not predict antepartum and postpartum depression risk. The findings suggest that maternal history of child physical and emotional neglect play significant roles in perinatal depression risk with physical neglect as the most important predictor. Routine screening for maternal CM history and depression risk in prenatal clinics is needed to aid in the early detection and treatment of depression. PMID- 27940037 TI - The G-Quadruplex-Specific RNA Helicase DHX36 Regulates p53 Pre-mRNA 3'-End Processing Following UV-Induced DNA Damage. AB - Pre-mRNA 3'-end processing, the process through which almost all eukaryotic mRNAs acquire a poly(A) tail is generally inhibited during the cellular DNA damage response leading to a profound impact on the level of protein expression since unprocessed transcripts at the 3'-end will be degraded or unable to be transported to the cytoplasm. However, a compensatory mechanism involving the binding of the hnRNP H/F family of RNA binding proteins to an RNA G-quadruplex (G4) structure located in the vicinity of a polyadenylation site has previously been described to allow the transcript encoding the p53 tumour suppressor protein to be properly processed during DNA damage and to provide the cells with a way to react to DNA damage. Here we report that the DEAH (Asp-Glu-Ala-His) box RNA helicase DHX36/RHAU/G4R1, which specifically binds to and resolves parallel stranded G4, is necessary to maintain p53 pre-mRNA 3'-end processing following UV induced DNA damage. DHX36 binds to the p53 RNA G4, while mutation of the G4 impairs the ability of DHX36 to maintain pre-mRNA 3'-end processing. Stabilization of the p53 RNA G4 with two different G4 ligands (PNADOTASQ and PhenDC3), which is expected from previous studies to prevent DHX36 from binding and unwinding G4s, also impairs p53 pre-mRNA 3'-end processing following UV. Our work identifies DHX36 as a new actor in the compensatory mechanisms that are in place to ensure that the mRNAs encoding p53 are still processed following UV. PMID- 27940038 TI - Increased levels of legumain in plasma and plaques from patients with carotid atherosclerosis. AB - BACKGROUND AND AIMS: The cysteine protease legumain has been shown to be up regulated in unstable atherosclerotic plaques. This study aims to further elucidate legumain in atherosclerosis, by examining legumain in plasma and carotid plaques from patients with carotid stenosis. Furthermore, legumain secretion from monocyte-derived macrophages treated with atherogenic lipids during macrophage polarization was studied. METHODS: Plasma levels of legumain from patients with carotid stenosis (n = 254), healthy controls (n = 91), and secreted from monocyte-derived macrophages were assessed by enzyme-linked immunosorbent assay. Quantitative PCR and immunoblotting of legumain were performed on isolated plaques and legumain localization was visualized by immunohistochemistry and fluorescence microscopy. Monocyte-derived macrophages polarized to M1 or M2 macrophages were treated with VLDL, oxLDL or cholesterol crystals (CC) and the level of legumain analysed. RESULTS: Patients with carotid stenosis had significantly higher levels of plasma legumain compared with healthy controls (median 2.0 versus 1.5 ng/ml, respectively; p = 0.003), although there was no correlation between the level of legumain and the degree of stenosis, and legumain was not an independent factor to identify patients with carotid plaques. Moreover, patients with symptoms the last 2 months had higher expressions of mature legumain, cystatin C and E/M, and the macrophage markers CD80 (M1) and CD163 (M2). Legumain co-localized with both M1 and M2 macrophages within plaques, whereas legumain mRNA expression was significantly higher (p < 0.0001) in plaques compared to non-atherosclerotic arteries (controls). Furthermore, in vitro studies showed significantly increased secretion of legumain from pro inflammatory M1 compared to pro-resolving M2 macrophages (p = 0.014), and particularly in M1 treated with CC. In plaques, legumain was localized to structures resembling foam cells. CONCLUSIONS: Legumain is increased in both plasma and plaques of patients with carotid stenosis and might be a new and early biomarker of atherosclerosis. PMID- 27940039 TI - Management strategy for congenital thumb differences in paediatric patients. AB - Congenital thumb anomalies are common and have a major impact given the specific functional role of the thumb. They may occur alone or as part of a multiple congenital anomaly syndrome. The primary goal of surgical management is to improve or restore pincer grip. In patients with 'congenital' trigger thumb, the A1 pulley must be released if the interphalangeal joint remains in fixed flexion. Thumb duplication is generally managed by reconstruction of the thumb from the predominant (ulnar-based) digit; the accessory (radial-based) digit is excised after collection of its tissue components needed for the reconstruction programme. Thumb aplasia requires pollicisation of the index finger by island flap transfer of the second ray to give it the shape, position, and function of a thumb. Among patterns of digital hypoplasia, some require reconstruction of the existing thumb and others excision of the rudimentary thumb followed by pollicisation. In patients with aplasia of multiple hand digits, a toe transfer may be considered when there is no natural tendency to develop digital prehension at the hand. PMID- 27940040 TI - Geniposide ameliorates cognitive deficits by attenuating the cholinergic defect and amyloidosis in middle-aged Alzheimer model mice. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory deficits and cognitive decline. Amyloid-beta (Abeta) deposition and cholinergic defect are widely thought to be the underlying mechanism of learning and memory impairment. Geniposide, which is the main active component of the traditional Chinese herbal Gardenia jasminoides Ellis, elicits neuroprotective effects by alleviating inflammation responses and oxidative damages. In this study, we investigated the protective effect of geniposide on levels of cholinergic markers, RAGE, RAGE-dependent signalling pathways and amyloid accumulation in the APPswe/PS1dE9 AD model mouse. Geniposide suppressed MAPK signaling over-activation mediated by Abeta-RAGE interaction, resulting in reduced Abeta accumulation and amelioration of cholinergic deficits in the cerebral hippocampus. Furthermore, geniposide inhibited the toxic effect of oligomeric Abeta1-42 induced cholinergic deficit by increasing ChAT levels and activity but decreasing AChE activity in cultured primary hippocampal neurons. These results indicated that geniposide enhanced cholinergic neurotransmission, which likely contributes to its memory enhancing effect. PMID- 27940041 TI - Thermosensitive nanofibers loaded with ciprofloxacin as antibacterial wound dressing materials. AB - To obtain wound dressings which could be removed easily without secondary injuries, we prepared thermoresponsive electrospun fiber mats containing poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA). Blend fibers of PDEGMA and poly(l-lactic acid-co-epsilon-caprolactone) (P(LLA-CL) were fabricated via electrospinning, and analogous fibers containing the antibiotic ciprofloxacin (CIF) were also prepared. Smooth cylindrical fibers were obtained, albeit with a small amount of beading visible for the ciprofloxacin-loaded fibers. X-ray diffraction showed the drug to exist in the amorphous physical form post electrospinning. The composite fibers showed distinct thermosensitive properties and gave sustained release of CIF over more than 160h in vitro. The fibers could promote the proliferation of fibroblasts, and by varying the temperature cells could easily be attached to and detached from the fibers. Antibacterial tests demonstrated that fibers loaded with ciprofloxacin were effective in inhibiting the growth of E. coli and S. aureus. In vivo investigations on rats indicated that the composite PDEGMA/P(LLA-CL) fibers loaded with CIF had much more potent wound healing properties than a commercial gauze and CIF-loaded fibers made solely of P(LLA-CL). These results demonstrate the potential of PDEGMA/P(LLA CL)/ciprofloxacin fibers as advanced wound dressing materials. PMID- 27940042 TI - Interrelationship among steroid hormones, energetics and vocalisation in the Bombay night frog (Nyctibatrachus humayuni). AB - In vertebrates, the increase in plasma androgens and corticosteroids is essential for the expression of reproductive behaviour. In male anurans, the interaction between hypothalamus-pituitary-gonadal and hypothalamus-pituitary-interrenal axes plays a pivotal role in calling behaviour and energy mobilisation through the secretion of testosterone and corticosterone respectively. To explain the association among body condition, testosterone, corticosterone and calling behaviour the energetic-hormone-vocalisation (EHV) model has been proposed. The model predicts that with continued participation in chorus activity within and across nights, levels of circulating androgens, corticosterone and vocal effort tend to increase and should be positively correlated in calling males. Consequently, decreasing energy reserves should be inversely correlated with corticosterone level in calling males. Depleted energy reserves lead to the peaking of circulating corticosterone, which suppresses androgen production and calling behaviour. In the present study, we used Nyctibatrachus humayuni with unique reproductive behaviour to test the model by quantifying calling behaviour and urinary metabolites of testosterone and corticosterone. We also computed the body condition index (BCI) to assess the association among energetics, levels of testosterone, corticosterone and calling behaviour. The results show that calling males had higher levels of urinary testosterone metabolites (UTM) than non calling males indicating the importance of testosterone in controlling the calling behaviour. Surprisingly, urinary corticosterone metabolite (UCM) levels were comparable between calling and non-calling males. Further, calling males had higher body condition estimates than non-calling males. The vocal effort was neither associated with UTM, UCM nor BCI. However, a positive association was observed between UTM and UCM levels in calling males indicating the requirement of higher energy for advertisement. Analysis of UTM and UCM levels throughout the breeding season revealed that breeding basal of UTM was significantly higher than that of UCM. Interestingly, UCM levels were maintained at a lower threshold during the breeding season. These observations are in line with some of the predictions of EHV model. PMID- 27940043 TI - Gonadotropin subunits of the characiform Astyanax altiparanae: Molecular characterization, spatiotemporal expression and their possible role on female reproductive dysfunction in captivity. AB - To better understand the endocrine control of reproduction in Characiformes and the reproductive dysfunctions that commonly occur in migratory fish of this order when kept in captivity, we chose Astyanax altiparanae, which has asynchronous ovarian development and multiple spawning events, as model species. From A. altiparanae pituitary total RNA, we cloned the full-length cDNAs coding for the follicle-stimulating hormone beta subunit (fshb), the luteinizing hormone beta subunit (lhb), and the common gonadotropin alpha subunit (gpha). All three sequences showed the highest degree of amino acid identity with other homologous sequences from Siluriformes and Cypriniformes. Real-time, quantitative PCR analysis showed that gpha, fshb and lhb mRNAs were restricted to the pituitary gland. In situ hybridization and immunofluorescence, using specific-developed and characterized polyclonal antibodies, revealed that both gonadotropin beta subunits mRNAs/proteins are expressed by distinct populations of gonadotropic cells in the proximal pars distalis. No marked variations for lhb transcripts levels were detected during the reproductive cycle, and 17alpha,20beta-dihydroxy 4-pregnen-3-one plasma levels were also constant, suggesting that the reproductive dysfunction seen in A. altiparanae females in captivity are probably due to a lack of increase of Lh synthesis during spawning season. In contrast, fshb transcripts changed significantly during the reproductive cycle, although estradiol-17beta (E2) levels remained constant during the experiment, possibly due to a differential regulation of E2 synthesis. Taken together, these data demonstrate the putative involvement of gonadotropin signaling on the impairment of the reproductive function in a migratory species when kept in captivity. Future experimental studies must be carried to clarify this hypothesis. All these data open the possibility for further basic and applied studies related to reproduction in this fish model. PMID- 27940044 TI - Immunochromatographic detection of the heat-labile enterotoxin of enterotoxigenic Escherichia coli with cross-detection of cholera toxin. AB - Here, we report the development of an immunochromatographic test strip that can detect heat-labile enterotoxin (LT) produced by enterotoxigenic Escherichia coli. Five types of monoclonal antibody (mAb)-producing hybridomas were isolated: three mAbs were A subunit specific and two were B subunit specific. Four mAbs also cross-reacted with both LT proteins derived from swine and human E. coli strains, but only one mAb 57B9 additionally cross-reacted with cholera toxin. Thus, mAb 57B9 was used to form a gold colloid-conjugated antibody for the immunochromatographic test by combination with polyclonal anti-LT rabbit IgG. This test strip detected not only LT in the culture supernatant of LT gene positive strains, but also cholera toxin in the culture supernatant of Vibrio cholerae. These results indicate that this test strip is suitable for the diagnosis of both enterotoxigenic E. coli and V. cholerae infection. PMID- 27940045 TI - Transfer of the bone morphogenetic protein 4 gene into rat periodontal ligament by in vivo electroporation. AB - OBJECTIVE: Regulation of alveolar bone metabolism is required in clinical dentistry. The aim of the present study was to establish a method for gene transfer into the periodontal ligament (PDL) by in vivo electroporation with a plasmid vector and to investigate the effects of BMP-4 transfer into the PDL. DESIGN: Plasmids containing mouse BMP-4 cDNA (pCAGGS-BMP4) were transfected into cultured rat PDL cells by in vitro electroporation, and BMP-4 production and secretion were detected by immunocytochemistry and western blotting. Next, pCAGGS BMP4 was injected into the PDL of rats, and electroporation was performed in vivo, using original paired-needle electrodes. BMP-4 expression was examined by immunohistochemical staining 3, 7, 14, 21, and 28days after electroporation. Control groups were injected with pCAGGS by electroporation, injected with pCAGGS BMP4 without electroporation, or subjected to neither injection nor electroporation. RESULTS: In vitro-transfected rat PDL cells exhibited production and secretion of the mature-form BMP-4. After in vivo electroporation of pCAGGS BMP4, site-specific BMP-4 expression peaked on day 3, gradually decreased until day 14, and was absent by day 21. We observed no unfavorable effects such as inflammation, degeneration, or necrosis. CONCLUSIONS: Gene transfer by electroporation with plasmid DNA vectors has several advantages over other methods, including the non-viral vector, non-immunogenic effects, site-specific expression, simplicity, cost-effectiveness, and limited histological side effects. Our results indicate that the method is useful for gene therapy targeting the periodontal tissue, which regulates alveolar bone remodeling. PMID- 27940046 TI - Electrical impedance myography for discriminating traumatic peripheral nerve injury in the upper extremity. AB - OBJECTIVE: To evaluate the potential of electrical impedance myography (EIM), which is sensitive to the changes in muscle structure and physiology, in discriminating traumatic peripheral nerve injury (TPNI) in the upper extremity. To identify factors that primarily influence muscle atrophy secondary to nerve injury. METHODS: Thirty-nine patients with TPNI underwent EIM measurement and standard electromyography tests for multiple muscles in the upper extremity. The side-to-side differences in EIM parameters were calculated for each subject and compared with the compound motor action potential (CMAP) amplitude, which is a measure of injury severity, and the time since injury. RESULTS: The reactance and phase values of the affected muscles were consistently lower than those of healthy muscles, with an average side-to-side difference of approximately -50% (p<0.001) and -45% (p<0.001), respectively. The CMAP amplitude, rather than the time since injury, had a greater effect on the side-to-side difference of phase values. CONCLUSIONS: EIM discriminates TPNI by revealing asymmetries in reactance and phase values. The severity of injury had a larger influence than the time since injury on muscle atrophy secondary to nerve injury. SIGNIFICANCE: These results demonstrate the putative use of EIM in discriminating TPNI and deserves further study. PMID- 27940047 TI - Myoclonus subtypes in tertiary referral center. Cortical myoclonus and functional jerks are common. AB - OBJECTIVE: To evaluate the accuracy of clinical phenotyping of myoclonus patients and to determine differentiating clinical characteristics between cortical (CM), subcortical (SCM), spinal (SM), peripheral (PM) myoclonus, and functional jerks (FJ). METHODS: Clinical notes for all patients with myoclonus over an 8-year period (2006-2014) were reviewed retrospectively. We used the conclusion of electrophysiological testing as definite diagnosis of myoclonus or FJ. RESULTS: 85 patients were identified suffering from CM (34%), SCM (11%), SM (6%), PM (2%), and 47% FJ. The clinical diagnosis of myoclonus was confirmed by electrophysiological testing in 74% and its subtype in 78% of cases. CM was characterized by an early age of onset, facial myoclonus, and provocation by action. Differentiating features of FJ were an abrupt onset, preceding contributing events and provocation by a supine position. CONCLUSION: The majority of clinical myoclonic jerk cases were functional in our heterogeneous tertiary clinic cohort. CM was the main anatomical myoclonic subtype. Clinical diagnosis was accurate in the majority of cases, although electrophysiological testing was important to verify the clinical classification. SIGNIFICANCE: In patients with jerky movements a functional diagnosis should be considered. Determination of the myoclonic subtypes is important to initiate tailored treatment. PMID- 27940048 TI - Automated spike detection in EEG. PMID- 27940049 TI - Erratum. PMID- 27940050 TI - Empowerment evaluation: An approach that has literally altered the landscape of evaluation. AB - The quest for credible and actionable evidence to improve decision making, foster improvement, enhance self-determination, and promote social betterment is now a global phenomenon. Evaluation theorists and practitioners alike have responded to and overcome the challenges that limited the effectiveness and usefulness of traditional evaluation approaches primarily focused on seeking rigorous scientific knowledge about social programs and policies. No modern evaluation approach has received a more robust welcome from stakeholders across the globe than empowerment evaluation. Empowerment evaluation has been a leader in the development of stakeholder involvement approaches to evaluation, setting a high bar. In addition, empowerment evaluation's respect for community knowledge and commitment to the people's right to build their own evaluation capacity has influenced the evaluation mainstream, particularly concerning evaluation capacity building. Empowerment evaluation's most significant contributions to the field have been to improving evaluation use and knowledge utilization. PMID- 27940051 TI - Attenuated JNK signaling in multidrug-resistant leukemic cells. Dual role of MAPK in cell survival. AB - Having found previously that leukemic cells with multidrug resistant (MDR) phenotype, but not their sensitive counterparts, exhibit collateral sensitivity to cold stress in a P-gp-dependent manner, our aim was to study the signaling pathways involved in this phenomenon in sensitive (L1210) and resistant cells (L1210R and CBMC-6). It was observed that the acquisition of MDR phenotype by leukemic cells or their transfection with the extrussion pump, P-gp, modifies the activation profile and regulation of Mitogen-Activated Protein Kinases (MAPK) in cells exposed to low temperatures. More specifically, cold stress provoked the activation of c-Jun N-terminal kinase (JNK) in sensitive cells, while attenuated JNK signaling was observed in MDR cells. This effect was also observed, although with less intensity, in P-gp-transfected cells. Using pharmacological inhibitors to determine the role of MAPK in leukemic cell survival in physiological conditions or under cold stress, a dual temperature-dependent role was observed for JNK in MDR cell survival. At 37 degrees C JNK is necessary for the survival of parental, resistant and P-gp-transfected cells; however, the use of inhibitors of either extracellular signal-regulated protein kinase (ERK) or JNK significantly counteracts cold-induced death of resistant and P-gp-transfected cells, supporting a role for ERK and JNK in cold-stress induced cell death. Finally, a connectivity model concerning MAPK is proposed, summarizing how cold stress and MDR-1 might trigger apoptosis in resistant cell lines. These findings on MDR cells may assist in the design of specific therapeutic strategies to complement current chemotherapy. PMID- 27940052 TI - Lipopolysaccharide and heat stress impair the estradiol biosynthesis in granulosa cells via increase of HSP70 and inhibition of smad3 phosphorylation and nuclear translocation. AB - LPS and heat stress have been shown to exert various toxic effects in animals, as they induce estradiol biosynthesis dysfunction in granulosa cells (GCs) and result in low reproductive performance. However, there is limited information regarding their detailed mechanisms. In the present study, primary cultured porcine GCs were treated with LPS (1000ng/mL for 48h), or heat stress (41 degrees C for 3h), in vitro, with or without the HSP70 inhibitor VER155008 (10MUM), to investigate their potential mechanisms. To mimic the spike in HSP70 from LPS and heat stress, treatments with only the HSP70 activator STA-4783 (10MUM for 3h or 48h) were also performed. We found that LPS and heat stress treatments could significantly reduce the expressions of FSHR and CYP19A1; associated with a reduction in estradiol concentrations; and increased in HSP70 expression both at mRNA and protein levels. While, VER155008 attenuation of LPS and heat stress induced HSP70 upregulation can restore the expressions of FSHR and CYP19A1. Furthermore, STA-4783 treatment alone can mimic the effects of LPS and heat stress treatments. Following immunofluorescence staining and western blot analysis showed that Smad3 phosphorylation and nuclear translocation were also inhibited by LPS, heat stress and STA-4783 treatments. We also examined the interactions between HSP70 and Smad3 by yeast two-hybrid screening, the results revealed that HSP70 indirectly interacted with Smad3. Thus, our results suggested that LPS and heat stress could impair estradiol biosynthesis in GCs via increased HSP70 and indirect inhibition of Smad3 phosphorylation and nuclear translocation. PMID- 27940053 TI - Paeonol alleviates epirubicin-induced renal injury in mice by regulating Nrf2 and NF-kappaB pathways. AB - Renal injury is a dose-dependent side effect of epirubicin that limits its clinical application in the field of tumor chemotherapy. Paeonol is an active ingredient with a variety of biological activities, including the prevention of multiple antineoplastic-induced toxicities. In the present study, we assessed the renoprotective effect of paeonol on epirubicin-induced nephrotoxicity and investigated the underlying mechanism. Renal function, kidney histology, oxidative stress, nitrative stress, inflammation, apoptotic proteins and the effects on signaling pathways were investigated. Paeonol lowered the levels of biomarkers of renal injury, relieved histopathological alterations, alleviated oxidative stress and nitrative stress, and ameliorated inflammation. Moreover, paeonol inhibited epirubicin-induced apoptosis by suppressing the activation of caspase-9 and caspase-3, the Bax/Bcl-2 imbalance and cytochrome c release. Further studies suggest that paeonol up-regulates the Nrf2/HO-1 pathway by increasing the expression of Nrf2 and HO-1 and down-regulates the NF-kappaB pathway by reducing IkappaBalpha degradation and blocking the p-NF-kappaB nuclear translocation. In conclusion, paeonol alleviates epirubicin-induced renal injury in mice by regulating the Nrf2 and NF-kappaB signaling pathways. PMID- 27940054 TI - Betaine attenuates memory impairment after water-immersion restraint stress and is regulated by the GABAergic neuronal system in the hippocampus. AB - GABA mediated neuronal system regulates hippocampus-dependent memory and stress responses by controlling plasticity and neuronal excitability. Here, we demonstrate that betaine ameliorates water-immersion restraint stress (WIRS) induced memory impairments. This improvement was inhibited by a betaine/GABA transporter-1 (GABA transporter-2: GAT2) inhibitor, NNC 05-2090. In this study, we investigated whether memory amelioration by betaine was mediated by the GABAergic neuronal system. Adult male mice were co-administered betaine and GABA receptor antagonists after WIRS. We also examined whether memory impairment after WIRS was attenuated by GABA receptor agonists. The memory functions were evaluated using a novel object recognition test 3-6 days after WIRS and/or the step-down type passive avoidance test at 7-8 days. The co-administration of the GABAA receptor antagonist bicuculline (1mg/kg) or the GABAB receptor antagonist phaclofen (10mg/kg) 1h after WIRS suppressed the memory-improving effects induced by betaine. Additionally, the administration of the GABAA receptor agonist muscimol (1mg/kg) or the GABAB receptor agonist baclofen (10mg/kg) 1h after WIRS attenuated memory impairments. These results were similar to the data observed with betaine. The treatment with betaine after WIRS significantly decreased the expression of GABA transaminase, and this effect was partially blocked by NNC 05 2090 in the hippocampus. WIRS caused a transient increase in hippocampal GABA levels and the changes after WIRS were not affected by betaine treatment in an in vivo microdialysis study. These results suggest that the beneficial effects of betaine may be mediated in part by changing the GABAergic neuronal system. PMID- 27940055 TI - The effects of sildenafil citrate on uterine angiogenic status and serum inflammatory markers in an L-NAME rat model of pre-eclampsia. AB - Pre-eclampsia (PE), a hypertensive disorder of pregnancy, is detrimental to both mother and foetus. There is currently no effective treatment, but we have shown that Sildenafil Citrate (SC) improve various foetal outcomes in Nomega-nitro-L arginine methyl ester (L-NAME) rat model of PE. Therefore, we aimed to investigate the effects of SC on a uterine angiogenic status and serum inflammatory markers in an L-NAME rat model of PE. One hundred and twenty adult nulliparous pregnant female Sprague-Dawley rats were used for the study. These were divided into five equal groups; the pregnant control, early and late onset PE and respective SC treated animals. Hypertension was manifested by considerably increased systolic blood pressure and placental lipid peroxidative marker (thiobarbituric acid reactive substances) and also we assessed the activities of plasma nitric oxide level, serum inflammatory marker (TGF-beta and IFN-gamma) and uterine angiogenic status (VEGF and sFlt-1) at two stages of PE. The administration of SC decreased systolic blood pressure, placental lipid peroxidation product and altered uterine angiogenic status; increased plasma nitric oxide levels in an early and late onset L-NAME model of PE. In addition, histological findings of SC treated preeclamptic rat placenta support the biochemical findings of this study. Our findings revealed that SC enhanced plasma NO levels and uterine angiogenic status in an L-NAME model of PE at two gestational stages. PMID- 27940056 TI - Terpenoids as anti-colon cancer agents - A comprehensive review on its mechanistic perspectives. AB - Multistep model of colon carcinogenesis has provided the framework to advance our understanding of the molecular basis of colon cancer. This multistage process of carcinogenesis takes a long period to transform from a normal epithelial cell to invasive carcinoma. Thus, it provides enough time to intervene the process of carcinogenesis especially through dietary modification. In spite of the in-depth understanding of the colon cancer etiology and pathophysiology and its association with diet, colon cancer remains a major cause of cancer mortality worldwide. Phytochemicals and their derivatives are gaining attention in cancer prevention and treatment strategies because of cancer chemotherapy associated adverse effects. Being the largest group of phytochemicals traditionally used for medicinal purpose in India and China, terpenoids are recently being explored as anticancer agents. Anticancer properties of terpenoids are associated with various mechanisms like counteraction of oxidative stress, potentiating endogenous antioxidants, improving detoxification potential, disrupting cell survival pathways and inducing apoptosis. This review gives a comprehensive idea of naturally occurring terpenoids as useful agents for the prevention of colon cancer with reference to their classes, sources and molecular targets. Based on the explored molecular targets further research in colon cancer chemoprevention is warranted. PMID- 27940057 TI - Epigallocatechin-3-gallate inhibits adipogenesis through down-regulation of PPARgamma and FAS expression mediated by PI3K-AKT signaling in 3T3-L1 cells. AB - Epigallocatechin-3-gallate (EGCG), a major component in green tea, functions as extensive bioactivities including anti-inflammation, anti-oxidation, and anti cancer. However, little is known about its anti-adipogenesis and underlying mechanisms. The purport of this study sought to investigate effects of EGCG on 3T3-L1 preadipocyte differentiation and to explore its possible mechanisms. The 3T3-L1 cells were induced to differentiate under the condition of pro-adipogenic cocktail with or without indicated EGCG concentrations (10, 50, 100, 200uM) for 2, 4, 6 and 8 days, respectively. Also, another batch of 3T3-L1 cells was induced under the optimal EGCG concentration (100uM) with or without SC3036 (PI3K activator, 10uM) or SC79 (AKT activator, 0.5uM) for 8 days. Subsequently, the cell viability was examined by MTT assay and the cell morphology was visualized by Oil red O staining. Finally, the mRNA levels including peroxisome proliferator activated receptor gamma (PPARgamma) and fatty acid synthase (FAS) were detected by quantitative real time PCR, while the protein levels of PPARgamma, FAS, phosphatidylinositol 3 kinase (PI3K), insulin receptor substrate1(IRS1), AKT, and p-AKT were measured by immunoblotting analysis. Our results showed that EGCG inhibited adipogenesis of 3T3-L1 preadipocyte in a concentration-dependent manner. Moreover, the inhibitory effects were reversed by SC3036 or SC79, suggesting that the inhibitory effects of EGCG are mediated by PI3K-AKT signaling to down-regulate PPARgamma and FAS expression levels. The findings shed light on EGCG anti-adipogenic effects and its underlying mechanism and provide a novel preventive-therapeutic potential for obesity subjects as a compound from Chinese green tea. PMID- 27940058 TI - Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis. AB - The importance of cyclooxygenase and lipoxygenase pathways and the consequent eicosanoid synthesis in the physiology and pathophysiology of the intestinal epithelium is currently being established. Each eicosanoid (prostanoid, leukotriene, hydroxyeicosatetraenoic acid) preferentially recognizes one or more receptors coupled to one or more signal-transduction processes. This overview focuses on the role of eicosanoid receptors in the maintenance of intestinal epithelium physiology through the control of proliferation/differentiation/apoptosis processes. Furthermore, it is reported that the role of these receptors on the regulation of the barrier function of the intestinal epithelium have arisen through the regulation of absorption/secretion processes, tight-junction state and the control of the intestinal immune response. Also, this review considers the implication of AA cascade in the disruption of epithelial homeostasis during inflammatory bowel diseases and colorectal cancer as well as the therapeutic values and potential of the eicosanoid receptors as novel targets for the treatments of the pathologies above mentioned. PMID- 27940059 TI - Use of the levonorgestrel 52-mg intrauterine system in adolescent and young adult solid organ transplant recipients: a case series. AB - This case series reports on the safety and efficacy of the levonorgestrel 52-mg intrauterine system in adolescent and young adult solid organ transplant recipients. All patients used the device for contraception, with no documented cases of disseminated pelvic infection or unplanned pregnancy. PMID- 27940060 TI - Dialysis in Children and Adolescents: The Pediatric Nephrology Perspective. AB - The care of children with end-stage renal disease (ESRD) is highly specialized and often poorly understood by nonpediatric providers and facility/institution administrators. As such, this position paper has been created to offer provider, facility, and institutional guidance regarding the components of care necessary for children receiving dialysis. Key differences between adult and pediatric dialysis units are highlighted. Responsibilities and expectations of the members of the interdisciplinary dialysis team are outlined as they pertain specifically to the care of pediatric dialysis patients. Physical and staffing requirements of the dialysis facility are reviewed, again focusing on unique needs and challenges faced by the pediatric dialysis care team. Among these, vascular access options and proper planning of ESRD care are underscored. Pediatric quality-of-life metrics differ significantly from adult quality variables, and proper tools for assessment must be used. Endorsed by the Council of the American Society of Pediatric Nephrology (ASPN), this position paper serves as a reference tool for the provision of care to pediatric patients with ESRD. PMID- 27940062 TI - Outcome Reporting Bias: A Pervasive Problem in Published Meta-analyses. PMID- 27940061 TI - Hemodialyzer Reuse and Gram-Negative Bloodstream Infections. AB - BACKGROUND: Clusters of bloodstream infections caused by Burkholderia cepacia and Stenotrophomonas maltophilia are uncommon, but have been previously identified in hemodialysis centers that reprocessed dialyzers for reuse on patients. We investigated an outbreak of bloodstream infections caused by B cepacia and S maltophilia among hemodialysis patients in clinics of a dialysis organization. STUDY DESIGN: Outbreak investigation, including matched case-control study. SETTING & PARTICIPANTS: Hemodialysis patients treated in multiple outpatient clinics owned by a dialysis organization. PREDICTORS: Main predictors were dialyzer reuse, dialyzer model, and dialyzer reprocessing practice. OUTCOMES: Case patients had a bloodstream infection caused by B cepacia or S maltophilia; controls were patients without infection dialyzed at the same clinic on the same day as a case; results of environmental cultures and organism typing. RESULTS: 17 cases (9 B cepacia and 8 S maltophilia bloodstream infections) occurred in 5 clinics owned by the same dialysis organization. Case patients were more likely to have received hemodialysis with a dialyzer that had been used more than 6 times (matched OR, 7.03; 95% CI, 1.38-69.76) and to have been dialyzed with a specific reusable dialyzer (Model R) with sealed ends (OR, 22.87; 95% CI, 4.49 infinity). No major lapses during dialyzer reprocessing were identified that could explain the outbreak. B cepacia was isolated from samples collected from a dialyzer header-cleaning machine from a clinic with cases and was indistinguishable from a patient isolate collected from the same clinic, by pulsed-field gel electrophoresis. Gram-negative bacteria were isolated from 2 reused Model R dialyzers that had undergone the facility's reprocessing procedure. LIMITATIONS: Limited statistical power and overmatching; few patient isolates and dialyzers available for testing. CONCLUSIONS: This outbreak was likely caused by contamination during reprocessing of reused dialyzers. Results of this and previous investigations demonstrate that exposing patients to reused dialyzers increases the risk for bloodstream infections. To reduce infection risk, providers should consider implementing single dialyzer use whenever possible. PMID- 27940064 TI - Erratum to 'Encoding of low-quality DNA profiles as genotype probability matrices for improved profile comparisons, relatedness evalation and database searches'. Forensic Science International: Genetics (2016) 227-239. PMID- 27940063 TI - Automated Reminders and Physician Notification to Promote Immunosuppression Adherence Among Kidney Transplant Recipients: A Randomized Trial. AB - BACKGROUND: Immunosuppression nonadherence increases the risk for kidney transplant loss after transplantation. Wireless-enabled pill bottles have created the opportunity to monitor medication adherence in real time. Reminders may help patients with poor memory or organization. Provision of adherence data to providers may motivate patients to improve adherence and help providers identify adherence barriers. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: Kidney transplant recipients (n=120) at a single center. INTERVENTION: Participants were provided wireless pill bottles to store tacrolimus and record bottle openings. Participants were randomly assigned 1:1:1 to adherence monitoring with customized reminders (including alarms, texts, telephone calls, and/or e-mails), monitoring with customized reminders plus provider notification (every 2 weeks, providers received notification if adherence decreased to <90% during that period), or wireless pill bottle use alone (control). OUTCOMES: The main outcome was bottle-measured tacrolimus adherence during the last 90 days of the 180-day trial. A secondary outcome was tacrolimus whole-blood concentrations at routine clinical visits. MEASUREMENTS: Adherence for the primary outcome was assessed via wireless pill bottle openings. RESULTS: Mean participant age was 50 years; 60% were men, and 40% were black. Mean adherence was 78%, 88%, and 55% in the reminders, reminders-plus notification, and control arms (P<0.001 for comparison of each intervention to control). Mean tacrolimus levels were not significantly different between groups. LIMITATIONS: The study did not assess clinical end points. Participants and study coordinators were not blinded to intervention arm. CONCLUSIONS: Provider notification and customized reminders appear promising in helping patients achieve better medication adherence, but these strategies require evaluation in trials powered to detect differences in clinical outcomes. PMID- 27940065 TI - Identification of Trypanosoma cruzi Discrete Typing Units (DTUs) in Latin American migrants in Barcelona (Spain). AB - Trypanosoma cruzi, the causative agent of Chagas disease, is divided into six Discrete Typing Units (DTUs): TcI-TcVI. We aimed to identify T. cruzi DTUs in Latin-American migrants in the Barcelona area (Spain) and to assess different molecular typing approaches for the characterization of T. cruzi genotypes. Seventy-five peripheral blood samples were analyzed by two real-time PCR methods (qPCR) based on satellite DNA (SatDNA) and kinetoplastid DNA (kDNA). The 20 samples testing positive in both methods, all belonging to Bolivian individuals, were submitted to DTU characterization using two PCR-based flowcharts: multiplex qPCR using TaqMan probes (MTq-PCR), and conventional PCR. These samples were also studied by sequencing the SatDNA and classified as type I (TcI/III), type II (TcII/IV) and type I/II hybrid (TcV/VI). Ten out of the 20 samples gave positive results in the flowcharts: TcV (5 samples), TcII/V/VI (3) and mixed infections by TcV plus TcII (1) and TcV plus TcII/VI (1). By SatDNA sequencing, we classified the 20 samples, 19 as type I/II and one as type I. The most frequent DTU identified by both flowcharts, and suggested by SatDNA sequencing in the remaining samples with low parasitic loads, TcV, is common in Bolivia and predominant in peripheral blood. The mixed infection by TcV-TcII was detected for the first time simultaneously in Bolivian migrants. PCR-based flowcharts are very useful to characterize DTUs during acute infection. SatDNA sequence analysis cannot discriminate T. cruzi populations at the level of a single DTU but it enabled us to increase the number of characterized cases in chronically infected patients. PMID- 27940067 TI - Enhanced alcohol-drinking behavior associated with active ghrelinergic and serotoninergic neurons in the lateral hypothalamus and amygdala. AB - Central ghrelin is required for the rewarding properties of drug abuse. We investigated whether alcohol affects ghrelinergic, dopaminergic, and serotoninergic neurons and growth hormone secretagogue receptor 1A (GHS-R1A) levels in the reward system of the brain. Alcohol-naive C57BL/6J mice received 2g/kg ethanol (EtOH) intraperitoneally (i.p.). Plasma ghrelin levels decreased between 1 and 4h. We investigated the effects of EtOH administration on plasma ghrelin levels in two different animal models at 1, 3, and 10months of age. Plasma ghrelin levels decreased following the EtOH treatment in 1- and 3-month old short-term (1-day) alcohol vapor-exposed (STA) mice. In contrast, EtOH administration increased plasma ghrelin levels in 1- and 3-month-old long-term (20-day) alcohol vapor-exposed (LTA) mice. In vivo ghrelin release in the lateral hypothalamus (LH) increased in STA and LTA mice after the i.p. administration of EtOH. EtOH increased in vivo dopamine (DA), but not serotonin (5-HT) release in the LH of STA mice, and increased in vivo DA and 5-HT release in the LH of LTA mice. GHS-R1A mRNA expression and GHS-R1A protein levels in the LH were increased in LTA mice. The number of GHS-R1A-immunoreactive cells was greater in the LH and amygdala of LTA mice. These results support the neurobiological correlation between the development of drinking behavior and activation of ghrelinergic and serotonergic neurons in the LH. The activation of ghrelinergic systems in the amygdala may also induce an increase in 5-HT release in the LH during long-term alcohol intake. PMID- 27940066 TI - Fasciola hepatica demonstrates high levels of genetic diversity, a lack of population structure and high gene flow: possible implications for drug resistance. AB - Fasciola hepatica, the liver fluke, is a trematode parasite of considerable economic importance to the livestock industry and is a re-emerging zoonosis that poses a risk to human health in F. hepatica-endemic areas worldwide. Drug resistance is a substantial threat to the current and future control of F. hepatica, yet little is known about how the biology of the parasite influences the development and spread of resistance. Given that F. hepatica can self fertilise and therefore inbreed, there is the potential for greater population differentiation and an increased likelihood of recessive alleles, such as drug resistance genes, coming together. This could be compounded by clonal expansion within the snail intermediate host and aggregation of parasites of the same genotype on pasture. Alternatively, widespread movement of animals that typically occurs in the UK could promote high levels of gene flow and prevent population differentiation. We identified clonal parasites with identical multilocus genotypes in 61% of hosts. Despite this, 84% of 1579 adult parasites had unique multilocus genotypes, which supports high levels of genotypic diversity within F. hepatica populations. Our analyses indicate a selfing rate no greater than 2%, suggesting that this diversity is in part due to the propensity for F. hepatica to cross-fertilise. Finally, although we identified high genetic diversity within a given host, there was little evidence for differentiation between populations from different hosts, indicating a single panmictic population. This implies that, once those emerge, anthelmintic resistance genes have the potential to spread rapidly through liver fluke populations. PMID- 27940068 TI - Drug decriminalization and the price of illicit drugs. AB - BACKGROUND: This study is an empirical assessment of the impact of the drug decriminalization policy followed by Portugal in July 2001, on the price of illicit drugs. METHODS: The analysis is performed using a difference-in differences approach and the Synthetic Control Method in order to construct a synthetic control unit from a convex combination of countries. RESULTS: The results suggest that the prices of opiates and cocaine in the post-treatment period did not decrease in the sequence of the policy change. CONCLUSION: We conclude that the drug decriminalization policy seems to have caused no harm through lower illicit drugs prices, which would lead to higher drug usage and dependence. PMID- 27940070 TI - On the antiquity of Legg-Calve-Perthes disease: Skeletal evidence in Iron Age Italy. AB - Legg-Calve-Perthes is a very rare disease involving childhood osteochondrosis of the femoral head due to interruption of its blood supply. The etiology is unknown. The signs of the pathology are well described in the literature but few paleopathological cases have been reported, mostly dating from Late Antiquity to Early Middle Ages. Here we report on morphometric and radiological analyses of a skeleton from the Etruscan necropolis of Spina (Ferrara, Italy, 6th-3rd century BCE), to our knowledge the most ancient case of Legg-Calve-Perthes disease published thus far. PMID- 27940069 TI - Cardiovascular effects of exogenous adrenomedullin and CGRP in Ramp and Calcrl deficient mice. AB - Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) are potent vasodilator peptides and serve as ligands for the G-protein coupled receptor (GPCR) calcitonin receptor-like receptor (CLR/Calcrl). Three GPCR accessory proteins called receptor activity-modifying proteins (RAMPs) modify the ligand binding affinity of the receptor such that the CLR/RAMP1 heterodimer preferably binds CGRP, while CLR/RAMP2 and CLR/RAMP3 have a stronger affinity for AM. Here we determine the contribution of each of the three RAMPs to blood pressure control in response to exogenous AM and CGRP by measuring the blood pressure of mice with genetic reduction or deletion of the receptor components. Thus, the cardiovascular response of Ramp1-/-, Ramp2+/-, Ramp3-/-, Ramp1-/-/Ramp3-/- double knockout (dKO), and Calcrl+/- mice to AM and CGRP were compared to wildtype mice. While under anesthesia, Ramp1-/- male mice had significantly higher basal blood pressure than wildtype males; a difference which was not present in female mice. Additionally, anesthetized Ramp1-/-, Ramp3-/-, and Calcrl+/- male mice exhibited significantly higher basal blood pressure than females of the same genotype. The hypotensive response to intravenously injected AM was greatly attenuated in Ramp1 /- mice, and to a lesser extent in Ramp3-/- and Calcrl+/- mice. However, Ramp1-/ /Ramp3-/- dKO mice retained some hypotensive response to AM. These results suggest that the hypotensive effect of AM is primarily mediated through the CLR/RAMP1 heterodimer, but that AM signaling via CLR/RAMP2 and CLR/RAMP3 also contributes to some hypotensive action. On the other hand, CGRP's hypotensive activity seems to be predominantly through the CLR/RAMP1 heterodimer. With this knowledge, therapeutic AM or CGRP peptides could be designed to cause less hypotension while maintaining canonical receptor-RAMP mediated signaling. PMID- 27940071 TI - Analysis of plant soil seed banks and seed dispersal vectors: Its potential and limits for forensic investigations. AB - Plant seeds exhibit many species-specific traits, thus potentially being especially helpful for forensic investigations. Seeds of a broad range of plant species occur in soil seed banks of various habitats and may become attached in large quantities to moving objects. Although plant seeds are now routinely used as trace evidence in forensic practice, only scant information has been published on this topic in the scientific literature. Thus, the standard methods remain unknown to specialists in such botanical subjects as plant ecology and plant geography. These specialists, if made aware of the forensic uses of seeds, could help in development of new, more sophisticated approaches. We aim to bridge the gap between forensic analysts and botanists. Therefore, we explore the available literature and compare it with our own experiences to reveal both the potential and limits of soil seed bank and seed dispersal analysis in forensic investigations. We demonstrate that habitat-specific and thus relatively rare species are of the greatest forensic value. Overall species composition, in terms of species presence/absence and relative abundance can also provide important information. In particular, the ecological profiles of seeds found on any moving object can help us identify the types of environments through which the object had travelled. We discuss the applicability of this approach to various European environments, with the ability to compare seed samples with georeferenced vegetation databases being particularly promising for forensic investigations. We also explore the forensic limitations of soil seed bank and seed dispersal vector analyses. PMID- 27940072 TI - Optimising crime scene temperature collection for forensic entomology casework. AB - The value of minimum post-mortem interval (minPMI) estimations in suspicious death investigations from insect evidence using temperature modelling is indisputable. In order to investigate the reliability of the collected temperature data used for modelling minPMI, it is necessary to study the effects of data logger location on the accuracy and precision of measurements. Digital data logging devices are the most commonly used temperature measuring devices in forensic entomology, however, the relationship between ambient temperatures (measured by loggers) and body temperatures has been little studied. The placement of loggers in this study in three locations (two outdoors, one indoors) had measurable effects when compared with actual body temperature measurements (simulated with pig heads), some more significant than others depending on season, exposure to the environment and logger location. Overall, the study demonstrated the complexity of the question of optimal logger placement at a crime scene and the potential impact of inaccurate temperature data on minPMI estimations, showing the importance of further research in this area and development of a standard protocol. Initial recommendations are provided for data logger placement (within a Stevenson Screen where practical), situations to avoid (e.g. placement of logger in front of windows when measuring indoor temperatures), and a baseline for further research into producing standard guidelines for logger placement, to increase the accuracy of minPMI estimations and, thereby, the reliability of forensic entomology evidence in court. PMID- 27940073 TI - Novel application of three-dimensional technologies in a case of dismemberment. AB - This case study reports the novel application of three-dimensional technologies such as micro-CT and 3D printing to the forensic investigation of a complex case of dismemberment. Micro-CT was successfully employed to virtually align severed skeletal elements found in different locations, analyse tool marks created during the dismemberment process, and virtually dissect a charred piece of evidence. High resolution 3D prints of the burnt human bone contained within were created for physical visualisation to assist the investigation team. Micro-CT as a forensic radiological method provided vital information and the basis for visualisation both during the investigation and in the subsequent trial making it one of the first examples of such technology in a UK court. PMID- 27940074 TI - ACC GABA levels are associated with functional activation and connectivity in the fronto-striatal network during interference inhibition in patients with borderline personality disorder. AB - Impulsivity often develops from disturbed inhibitory control, a function mainly regulated by gamma-Aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC) and the fronto-striatal system. In this study, we combined MRS GABA measurements and fMRI to investigate neurochemical and neurofunctional correlates of interference inhibition, further emphasizing the direct relationship between those two systems, as well as their relations to impulsivity in patients with BPD. In addition to BOLD activation, task-dependent functional connectivity was assessed by a generalized psychophysiological interactions approach. Full factorial analyses were performed via SPM to examine the main effect (within group associations) as well as the interaction term (group differences in the association slope). The UPPS scales were used to evaluate impulsivity traits. Compared to healthy controls (HCs), BPD patients exhibited significantly less ACC caudate functional connectivity during interference inhibition. ACC GABA levels in BPD patients but not in HCs were positively related to the magnitude of activation in several fronto-striatal regions (e.g. ACC, frontal regions, putamen, caudate,) and the strength of ACC-caudate functional connectivity during interference inhibition. The strength of the correlations of GABA with connectivity significantly differs between the two groups. Moreover, among all the UPPS impulsivity subscales, UPPS sensation seeking in the BPD group was related to GABA and was also negatively related to the task-dependent BOLD activation and functional connectivity in the fronto-striatal network. Finally, mediation analyses revealed that the magnitude of activation in the caudate and the strength of ACC-caudate functional connectivity mediated the relationship between ACC GABA levels and UPPS sensation seeking in patients with BPD. Our findings suggest a disconnectivity of the fronto-striatal network in BPD patients during interference inhibition, particularly for patients with higher impulsivity. The ACC GABAergic system seems to play a crucial role in regulating regional BOLD activations and functional connectivity in this network, which are further associated with impulsive sensation seeking in BPD. PMID- 27940075 TI - Decoding eye-of-origin outside of awareness. AB - In the primary visual cortex of many mammals, ocular dominance columns segregate information from the two eyes. Yet under controlled conditions, most human observers are unable to correctly report the eye to which a stimulus has been shown, indicating that this information is lost during subsequent processing. This study investigates whether eye-of-origin information is available in the pattern of electrophysiological activity evoked by visual stimuli, recorded using EEG and decoded using multivariate pattern analysis. Observers (N=24) viewed sine wave grating and plaid stimuli of different orientations, shown to either the left or right eye (or both). Using a support vector machine, eye-of-origin could be decoded above chance at around 140 and 220ms post stimulus onset, yet observers were at chance for reporting this information. Other stimulus features, such as binocularity, orientation, spatial pattern, and the presence of interocular conflict (i.e. rivalry), could also be decoded using the same techniques, though all of these were perceptually discriminable above chance. A control analysis found no evidence to support the possibility that eye dominance was responsible for the eye-of-origin effects. These results support a structural explanation for multivariate decoding of electrophysiological signals - information organised in cortical columns can be decoded, even when observers are unaware of this information. PMID- 27940076 TI - A rapid assessment for predicting drug-induced hepatotoxicity using zebrafish. AB - INTRODUCTION: Zebrafish have been used as a model to access drug-induced hepatotoxicity. However, individual differences occur in the liver development of zebrafish. METHODS: We used a transgenic line of zebrafish that expressed enhanced green fluorescent protein (EGFP) in the liver and then used a calculation of the liver index area, a potentially new endpoint of hepatotoxicity, to evaluate drug-induced liver injury. To further validate the reliability of the liver area index as a quick evaluation of zebrafish liver function damage, the liver area index level was correlated with hepatic transaminase activities using the Pearson correlation coefficient and confirmed by histopathology. RESULTS: Zebrafish larvae treated with high doses of the known mammalian hepatotoxic drugs carbaryl, isoniazide, and pyrazinamide showed significantly decreased liver area index levels, which are suggestive of liver injury and correspond with the higher alanine transaminase (ALT) and aspartate transaminase (AST) activities and histological liver alterations. The results showed a significant negative correlation between the degree of liver injury and the liver area index level. DISCUSSION: Our data support the use of the liver area index as a reliable and comparable indicator to screen hepatotoxic agents using the zebrafish model. PMID- 27940077 TI - The discriminative stimulus effects of i.v. nicotine in rhesus monkeys: Pharmacokinetics and apparent pA2 analysis with dihydro-beta-erythroidine. AB - Quantitative analysis of antagonism is infrequently used to identify nAChRs mediating behavioral effects. Here, nicotine (0.032 mg/kg i.v.) was established as a discriminative stimulus in rhesus monkeys responding under a fixed ratio 5 schedule; pharmacokinetics and underlying nAChR mechanism(s) were examined. When measured up to 4 h in venous blood, the training dose resulted in the following mean pharmacokinetic parameters: nicotine Cmax = 71.7 ng/ml, t1/2 = 116 min, and clearance = 6.25 ml/min/kg; cotinine Cmax = 191 ng/ml; and 3OH-cotinine Cmax = 63 ng/ml. The ED50 value of nicotine to produce discriminative stimulus effects was 0.013 mg/kg. Epibatidine and varenicline increased drug-lever responding to 97% and 95%, respectively (ED50 values = 0.00015 and 0.031 mg/kg, respectively), whereas cocaine, midazolam, and morphine produced no more than 28% drug appropriate responding. Mecamylamine and dihydro-beta-erythroidine (DHbetaE) dose dependently attenuated the discriminative stimulus effects of the nicotine training dose, whereas methyllycaconitine (MLA) did not. DHbetaE (0.1 and 0.32) produced rightward shifts of the nicotine and varenicline dose-response functions; Schild plots fitted through individual data resulted in slopes that were not different from unity; the apparent pA2 calculated for DHbetaE did not significantly differ in the presence of nicotine (6.58) or varenicline (6.45). Compared to human cigarette smoking, nicotine blood levels after 0.032 mg/kg nicotine i.v. took a similar time to reach maximal concentration, levels at Cmax were similar to smoking 2-3 cigarettes, while average nicotine levels were comparable to smoking 5-6 cigarettes. Apparent pA2 analysis with DHbetaE under these conditions is consistent with nicotine and varenicline acting through the same nAChRs to produce discriminative stimulus effects. PMID- 27940078 TI - Biochar increases nitrogen retention and lowers greenhouse gas emissions when added to composting poultry litter. AB - Biochar has intrinsic and nascent structural and sorption properties that may alter the physical and chemical properties of a composting mixture thus influencing the production of greenhouse gases [GHGs; nitrous oxide (N2O) and methane (CH4)]. In this study, contrasting biochars produced from greenwaste (GWB) or poultry litter (PLB) were incorporated into a composting mixture containing poultry litter and straw, and GHG emissions were measured in situ during composting using Fourier Transform Infrared Spectroscopy (FTIR). Emissions of N2O from the biochar-amended composting mixtures decreased significantly (P<0.05) soon after commencement of the composting process compared with the non amended control. The cumulative emissions of N2O over 8weeks in the GWB composting mixture (GWBC), PLB composting mixture (PLBC) and control (no biochar) were 4.2, 5.0 and 14.0gN2O-Nkg-1 of total nitrogen (TN) in composting mixture, respectively (P<0.05). The CH4 emissions were significantly (P<0.05) lower in the GWBC and PLBC treatments than the control during the period from day 8 to day 36, when anaerobic conditions likely prevailed. The cumulative CH4 emissions were 12, 18 and 80mg CH4-Ckg-1 of total carbon (TC) for the GWBC, PLBC and control treatments, respectively, though due to wide variation between replicates this difference was not statistically significant. The cumulative N2O and CH4 emissions were similar between the GWBC and PLBC despite differences in properties of the two biochars. X-ray Photoelectron Spectroscopy (XPS) analysis and SEM imaging of the composted biochars indicated the presence of iron oxide compounds and amine-NH3 on the surface and pores of the biochars (PLB>GWB). The change in nitrogen (N) functional groups on the biochar surface after composting is evidence for sorption and/or reaction with N from labile organic N, mineral N, and gaseous N (e.g. N2O). The concentration of NH4+ increased during the thermophilic phase and then decreased during the maturation phase, while NO3- accumulated during the maturation phase. Total N retained was significantly (P<0.05) higher in the PLBC (740g) and the GWBC (660g) relative to the control (530g). The TC retained was significantly higher in the GWBC (10.0kg) and the PLBC (8.5kg) cf. the control (6.0kg). Total GHG emissions across the composting period were 50, 63 and 183kg CO2-eqt-1 of initial mass of GWBC, PLBC and control (dry weight basis) respectively. These results support the co-composting of biochar to lower net emissions of GHGs while increasing N retention (and fertiliser N value) in the mature compost. PMID- 27940079 TI - Leaching of electrodic powders from lithium ion batteries: Optimization of operating conditions and effect of physical pretreatment for waste fraction retrieval. AB - Experimental results of leaching tests using waste fractions obtained by mechanical pretreatment of lithium ion batteries (LIB) were reported. Two physical pretreatments were performed at pilot scale in order to recover electrodic powders: the first including crushing, milling, and sieving and the second granulation, and sieving. Recovery yield of electrodic powder was significantly influenced by the type of pretreatment. About 50% of initial LIB wastes was recovered by the first treatment (as electrodic powder with size <0.5mm, Sample 1), while only 37% of powder with size <1mm (Sample 2) can be recovered by the second treatment. Chemical digestion put in evidence the heterogeneity of recovered powders denoting different amounts of Co, Mn, and Ni. Leaching tests of both powders were performed in order to determine optimized conditions for metal extraction. Solid/liquid ratios and sulfuric acid concentrations were changed according to factorial designs at constant temperature (80 degrees C). Optimized conditions for quantitative extraction (>99%) of Co and Li from Sample 1 are 1/10g/mL as solid/liquid ratio and +50% stoichiometric excess of acid (1.1M). Using the same solid/liquid ratio, +100% acid excess (1.2M) is necessary to extract 96% of Co and 86% of Li from Sample 2. Best conditions for leaching of Sample 2 using glucose are +200% acid excess (1.7M) and 0.05M glucose concentration. Optimized conditions found in this work are among the most effective reported in the literature in term of Co extraction and reagent consumption. PMID- 27940081 TI - Optimization of in vitro release of an anticonvulsant using nanocapsule-based thermogels. AB - Controlling the release rate of anticonvulsant drugs can have a significant effect on the efficacy of these drugs and the safety with which they can be administered to patients. This study investigated in vitro release of the anticonvulsant ethosuximide from nanocapsule-based N,O-carboxymethyl chitosan and hyaluronan-methylcellulose hydrogels using two experimental designs: a one-factor at-a-time method and an optimization method employing a Taguchi design. Using the first method, the release rate of the drug was significantly reduced compared with other delivery systems. With the second method, when the drug was blended into a hyaluronan-methylcellulose hydrogel the release rate was similarly reduced, with full release occurring after three days. Scanning electron microscopy, Fourier-transform infrared spectroscopy, and ultraviolet-visible spectrophotometry were used to study the drug encapsulation, and two mathematical models for evaluating encapsulation efficiency were developed. The results of this study show promise for use of nanoencapsulated thermoresponsive hydrogels in clinical delivery of anticonvulsants. PMID- 27940082 TI - Sucrose esters as biocompatible surfactants for penetration enhancement: An insight into the mechanism of penetration enhancement studied using stratumcorneum model lipids and Langmuir monolayers. AB - Up to now, the molecular mechanism of the penetration enhancing effect of sucrose esters (SEs) on stratumcorneum (SC) has not been explained in details. In this study, variety of surface sensitive techniques, including surface pressure-area (pi-A) isotherms, infrared reflection-absorption spectroscopy (IRRAS), and Brewster angle microscopy (BAM), have been used to investigate interactions between SEs and SC intercellular lipids. A monolayer of the mixture of ceramide AS C18:18, stearic acid and cholesterol in the molar ratio of 1:1:0.7 on an aqueous subphase is a good model to mimic a single layer of intercellular SC lipids. The pi-A isotherms of mixed monolayers and parameters derived from the curves demonstrated the interaction between nonionic surfactants such as SEs and SC lipids. With increasing SE concentration, the resultant monolayer films became more fluid and better compressible. IRRAS measurements showed that SEs disordered the acyl chains of SC lipids, and the BAM images demonstrated the modification of the domain structures in SC monolayers. Longer chain-SE has a stronger disordering effect and is better miscible with ceramides in comparison to SE with a shorter hydrophobic part. In conclusion, this study demonstrates the disordering effect of SEs on the biomimetic SC model, pointing out that small changes in the structure of surfactant may have a strong influence on a penetration enhancement of lipophilic drugs through intercellular lipids of skin. PMID- 27940080 TI - Sex specific recruitment of a medial prefrontal cortex-hippocampal-thalamic system during context-dependent renewal of responding to food cues in rats. AB - Renewal, or reinstatement, of responding to food cues after extinction may explain the inability to resist palatable foods and change maladaptive eating habits. Previously, we found sex differences in context-dependent renewal of extinguished Pavlovian conditioned responding to food cues. Context-induced renewal involves cue-food conditioning and extinction in different contexts and the renewal of conditioned behavior is induced by return to the conditioning context (ABA renewal). Male rats showed renewal of responding while females did not. In the current study we sought to identify recruitment of key neural systems underlying context-mediated renewal and sex differences. We examined Fos induction within the ventromedial prefrontal cortex (vmPFC), hippocampal formation, thalamus and amygdala in male and female rats during the test for renewal. We found sex differences in vmPFC recruitment during renewal. Male rats in the experimental condition showed renewal of responding and had more Fos induction within the infralimbic and prelimbic vmPFC areas compared to controls that remained in the same context throughout training and testing. Females in the experimental condition did not show renewal or an increase in Fos induction. Additionally, Fos expression differed between experimental and control groups and between the sexes in the hippocampal formation, thalamus and amygdala. Within the ventral subiculum, the experimental groups of both sexes had more Fos compared to control groups. Within the dorsal CA1 and the anterior region of the paraventricular nucleus of the thalamus, in males, the experimental group had higher Fos induction, while both females groups had similar number of Fos positive neurons. Within the capsular part of the central amygdalar nucleus, females in the experimental group had higher Fos induction, while males groups had similar amounts. The differential recruitment corresponded to the behavioral differences between males and females and suggests the medial prefrontal cortex hippocampal-thalamic system is a critical site of sex differences during renewal of appetitive Pavlovian responding to food cues. These findings provide evidence for novel neural mechanisms underlying sex differences in food motivation and contextual processing in associative learning and memory. The results should also inform future molecular and translational work investigating sex differences and maladaptive eating habits. PMID- 27940083 TI - Statistical investigation of simulated fed intestinal media composition on the equilibrium solubility of oral drugs. AB - Gastrointestinal fluid is a complex milieu and it is recognised that gut drug solubility is different to that observed in simple aqueous buffers. Simulated gastrointestinal media have been developed covering fasted and fed states to facilitate in vitro prediction of gut solubility and product dissolution. However, the combination of bile salts, phospholipids, fatty acids and proteins in an aqueous buffered system creates multiple phases and drug solubility is therefore a complex interaction between these components, which may create unique environments for each API. The impact on solubility can be assessed through a statistical design of experiment (DoE) approach, to determine the influence and relationships between factors. In this paper DoE has been applied to fed simulated gastrointestinal media consisting of eight components (pH, bile salt, lecithin, sodium oleate, monoglyceride, buffer, salt and pancreatin) using a two level D-optimal design with forty-four duplicate measurements and four centre points. The equilibrium solubility of a range of poorly soluble acidic (indomethacin, ibuprofen, phenytoin, valsartan, zafirlukast), basic (aprepitant, carvedilol, tadalafil, bromocriptine) and neutral (fenofibrate, felodipine, probucol, itraconazole) drugs was investigated. Results indicate that the DoE provides equilibrium solubility values that are comparable to literature results for other simulated fed gastrointestinal media systems or human intestinal fluid samples. For acidic drugs the influence of pH predominates but other significant factors related to oleate and bile salt or interactions between them are present. For basic drugs pH, oleate and bile salt have equal significance along with interactions between pH and oleate and lecithin and oleate. Neutral drugs show diverse effects of the media components particularly with regard to oleate, bile salt, pH and lecithin but the presence of monoglyceride, pancreatin and buffer have significant but smaller effects on solubility. There are fourteen significant interactions between factors mainly related to the surfactant components and pH, indicating that the solubility of neutral drugs in fed simulated media is complex. The results also indicate that the equilibrium solubility of each drug can exhibit individualistic behaviour associated with the drug's chemical structure, physicochemical properties and interaction with media components. The utility of DoE for fed simulated media has been demonstrated providing equilibrium solubility values comparable with similar in vitro systems whilst also providing greater information on the influence of media factors and their interactions. The determination of a drug's gastrointestinal solubility envelope provides useful limits that can potentially be applied to in silico modelling and in vivo experiments. PMID- 27940084 TI - Considerations for the development of in vitro dissolution tests to reduce or replace preclinical oral absorption studies. AB - The pharmaceutical development of new chemical entities can be hampered by their solubility and/or dissolution limitations. Currently, these properties are characterised mostly during in vivo pre-clinical studies. The development of appropriate in vitro methods to study the solubility and dissolution properties in preclinical species would lead to a significant reduction or replacement of the animal experiments at this stage of development. During clinical development, media simulating the human gastrointestinal tract fluids are commonly used and a similar approach mimicking laboratory animals' gastrointestinal tract fluids would impact on the preclinical stage of development. This review summarises the current knowledge regarding the gastrointestinal physiology of the most common laboratory animals, and animal simulated gastric and intestinal media are proposed. PMID- 27940086 TI - Effects of Ginkgo biloba on dementia: An overview of systematic reviews. AB - OBJECTIVE: To assess the cumulative evidence on the efficacy and effectiveness of Ginkgo biloba extract (GbE) in the treatment of dementia. DESIGN: Overview of systematic reviews. METHODS: PubMed/MEDLINE, EMBASE, Cochrane, and Google Scholar were searched in June 2016. Systematic reviews (SRs) of randomized controlled trials (RCTs) evaluating the effects of GbE on different outcomes in people with dementia or cognitive impairment were included. Methodological quality of the included SRs was assessed using the AMSTAR tool. The quality of evidence of the primary studies was assessed using GRADE. RESULTS: Twelve SRs with meta-analyses met the eligibility criteria. The quality of the evidence reported in these SRs varies ranging from low to moderate level. Overall, the available evidence suggests that GbE has potentially beneficial effects over placebo on cognitive performance, activities of daily living, and clinical global impression in the treatment of dementia at doses greater than 200mg/day (usually 240mg/day) administrated for 22 weeks or longer, and that GbE appears to be safe for human consumption. No sufficient evidence supports the favorable effects of GbE administrated for less than 22 weeks. The available evidence consistently indicates that a dose less than 200mg/day of GbE may not be adequate to yield clinical relevant effects in the treatment of dementia. CONCLUSIONS: GbE has potentially beneficial effects for people with dementia when it is administered at doses greater than 200mg/day for at least 5 months. Given the lower quality of the evidence, further rigorously-designed, multicenter-based, large-scale RCTs are warranted. PMID- 27940087 TI - Does contingency in adults' responding influence 12-month-old infants' social referencing? AB - In two experiments we examined the influence of contingent versus non-contingent responding on infant social referencing behavior. EXPERIMENT 1: Forty 12-month old infants were exposed to an ambiguous toy in a social referencing situation. In one condition an unfamiliar adult who in a previous play situation had responded contingently to the infant's looks gave the infant positive information about the toy. In the other condition an unfamiliar adult who previously had not responded contingently delivered the positive information. EXPERIMENT 2: Forty eight 12-month-old infants participated in Experiment 2. In this experiment it was examined whether the familiarity of the adult influences infants' reactions to contingency in responding. In one condition a parent who previously had responded contingently to the infant's looks provided positive information about the ambiguous toy, and in the other condition a parent who previously had not responded contingently provided the positive information. The infants looked more at the contingent experimenter in Experimenter 1, and also played more with the toy after receiving positive information from the contingent experimenter. No differences in looking at the parent and in playing with the toy were found in Experiment 2. The results indicate that contingency in responding, as well as the familiarity of the adult, influence infants' social referencing behavior. PMID- 27940085 TI - Learning and memory improvement and neuroprotection of Gardenia jasminoides (Fructus gardenia) extract on ischemic brain injury rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gardenia jasminoides Ellis is a traditional Chinese medicine (TCM) that containing a variety of effective active ingredients and exhibits diverse pharmacological functions, such as anti-inflammatory, antioxidant and nerve protection. AIM OF THE STUDY: This study investigated the effect of Gardenia jasminoides extract (GJE) and Geniposide on learning and memory improvement and neuroprotection in a rat model with chronic cerebral ischemia, as well as explore the underlying mechanisms. MATERIALS AND METHODS: The crude GJE was prepared using the methods of water extraction and alcohol precipitation, and refined by macroporous adsorption resin. The chronic cerebral ischemia model was simulated by permanent occlusion of bilateral common carotid arteries in rats. GJE was taken at three doses groups (150mg/kg, 100mg/kg, 50mg/kg), Geniposide group (50mg/kg), and oral administration for 30 days. Memory function was assessed using Morris water maze test. The morphological changes of hippocampus and related parts of brain in rats by Hematoxylin and Eosin (HE) staining were observed. Moreover, the levels of Acetylcholin Esterase (AchE), Nitric Oxide Synthase (NOS), Malondialdehyde (MDA), Superoxide Dismutase (SOD) in the brain tissue were quantified. RESULTS: GJE contained 27% gardenoside and 72% total iridoid glycoside. The chronic cerebral ischemia rat model has been proved successfully. The memory function of the rats assessed using Morris water maze test showed that GJE significantly shortened the escape latency of rats, but had no significant improvement on the number of times crossing the platform and the percentage of time spent in the target quadrant. HE staining showed that the apoptosis and necrosis of the cortex and hippocampus in the GJE group were significantly reduced. In addition, it was found that GJE could significantly improved the content of SOD, inhibited NOS and AchE activity in brain tissue, but did not show a significant reduction in the content of MDA. The effect of medium dosage of GJE was the best among these three dose groups and also better than Geniposide according to the results of all the detection index. CONCLUSIONS: GJE had the functions of learning and memory improvement and the neuroprotection on chronic cerebral ischemia model rats. The mechanisms were found to be strongly correlated with antioxygen free radical, reduction of NO toxicity and AChE activity, and brain neuron protective effect. GJE could be able to play a better effect on improving chronic cerebral ischemia than Geniposide. PMID- 27940088 TI - Vitamin A differentially regulates cytokine expression in respiratory epithelial and macrophage cell lines. AB - Vitamin A is an essential nutrient for the protection of children from respiratory tract disease. Supplementation with vitamin A is frequently prescribed in the clinical setting, in part to combat deficiencies among children in developing countries, and in part to treat respiratory infections in clinical trials. This vitamin influences immune responses via multiple, and sometimes seemingly contradictory mechanisms. For example, in separate reports, vitamin A was shown to decrease Th17 T-cell activity by downregulating IL-6, and to promote B cell production of IgA by upregulating IL-6. To explain these apparent contradictions, we evaluated the effects of retinoic acid (RA), a key metabolite of vitamin A, on cell lines of respiratory tract epithelial cells (LETs) and macrophages (MACs). When triggered with LPS or Sendai virus, a mouse respiratory pathogen, these two cell lines experienced opposing influences of RA on IL-6. Both IL-6 protein production and transcript levels were downregulated by RA in LETs, but upregulated in MACs. RA also increased transcript levels of MCP-1, GMCSF, and IL-10 in MACs, but not in LETs. Conversely, when LETs, but not MACs, were exposed to RA, there was an increase in transcripts for RARbeta, an RA receptor with known inhibitory effects on cell metabolism. Results help explain past discrepancies in the literature by demonstrating that the effects of RA are cell target dependent, and suggest close attention be paid to cell-specific effects in clinical trials involving vitamin A supplements. PMID- 27940089 TI - The ancient cytokine IL-17D is regulated by Nrf2 and mediates tumor and virus surveillance. AB - Early stage immune responses can dictate the severity and outcome of inflammatory processes such as tumor growth and viral infection. Cytokines such as the interleukin 17 (IL-17) family and cellular stress defense (e.g., anti-oxidant) pathways have evolved early and regulate disease surveillance in vertebrates and invertebrates as far back as Caenorhabditis elegans. Our group has recently found a new role for nuclear factor erythroid-derived 2-like 2 (Nrf2) in regulating early anti-cancer immune responses by inducing IL-17D and recruiting natural killer (NK) cells. In this Cytokine Stimulus, we discuss recent findings that encourage boosting the Nrf2/IL-17D/NK cell axis for the treatment of cancer and viral infection. PMID- 27940090 TI - Serological signatures of clinical cure following successful treatment with sodium stibogluconate in Ethiopian visceral leishmaniasis. AB - BACKGROUND: In Ethiopia, visceral leishmaniasis (VL) is a growing public health threat. Among the key challenges in VL control in Ethiopia is lack of an effective test of cure. The recommended test of cure is parasite detection. As sterile cure is not expected with the current widely used drugs, the value of parasite detection as test of cure is questionable. Moreover, the sampling is invasive, requires a well-equipped facility and highly skilled personnel, which are all hardly found in endemic set-ups. OBJECTIVE: Our aim was to assess the value of sCD40L, MMP9 and IL-10 serum levels as signature biomarkers of clinical cure in VL cases from Ethiopia. METHODS: A total of 45 VL cases before and after treatment and 30 endemic healthy controls were included in the study. Sandwich ELISA was used to measure serum levels of sCD40L, MMP9 and IL-10. RESULT: The mean sCD40L, MMP9 and IL-10 serum levels changed significantly at clinical cure. At individual case level sCD40L and MMP9 showed an increasing trend. Yet, the degree of increase in serum level of MMP9 seems to be affected by nutritional status of the individual VL case. The mean IL-10 serum level was significantly reduced at clinical cure. As seen on case by case basis, all demonstrated a declining trend except that two VL cases had a high IL10 level at clinical cure. CONCLUSION: Our result is suggestive of the possibility of developing a signature biomarker to monitor VL treatment in Ethiopia using one or a combination of parameters. PMID- 27940092 TI - Crystal structures of an archaeal thymidylate kinase from Sulfolobus tokodaii provide insights into the role of a conserved active site Arginine residue. AB - Thymidylate kinase (TMK) is a key enzyme that plays an important role in DNA synthesis. Therefore, it serves as an attractive therapeutic target for the development of antibacterial, antiparasitic and anticancer drugs. Herein, we report the biochemical characterization and crystal structure determination of thymidylate kinase from a hyperthermophilic organism Sulfolobus tokodaii (StTMK) in its apo and ADP-bound forms. Our study describes the first three-dimensional structure of an archaeal TMK. StTMK is a thermostable enzyme with optimum activity at 80 degrees C. Despite the overall similarity to homologous TMKs, StTMK structures revealed several residue substitutions at the active site. However, enzyme assays demonstrated specificity to its natural substrates ATP and dTMP. Analysis of the structures also revealed multiple conformational states of Arg93 which is located at the reaction centre and is a part of the highly conserved DRX motif. Only one of these states was found to be suitable for the proper positioning of the alpha-phosphate group of dTMP at the active site. Computational alanine scanning and MM/PBSA binding energy calculation revealed the importance of Arg93 side chain in substrate binding. Subsequent site directed mutagenesis at this position to an Ala resulted in the loss of activity. Thus, the computational and biochemical studies reveal the importance of Arg93 for enzyme function, while the different conformational states of Arg93 observed in the structural studies imply its regulatory role in the catalytically competent placement of dTMP. PMID- 27940093 TI - Valve microstructure and phylomineralogy of New Zealand chitons. AB - The microstructure and mineralogy of chiton valves has been largely ignored in the literature and only described in 29 species to date. Eight species: Acanthochitona zelandica, Notoplax violacea (Family Acanthochitonidae, Suborder Acanthochitonina, Order Chitonida), Chiton glaucus, Onithochiton neglectus, Sypharochiton spelliserpentis, Sypharochiton sinclairi (Family Chitonidae, Suborder, Chitonina, Order Chitonida), Ischnochiton maorianus (Family Ischnochitonidae, Suborder Chitonina, Order Chitonida), and Leptochiton inquinatus (Family Leptochitonidae, Suborder Lepidopleurina, Order Lepidopleurida) were collected from the Otago Peninsula, South Island, New Zealand. The valves of these chitons were analysed with X-ray diffractometry, Raman spectrometry, and Scanning Electron Micrography (SEM) to determine their mineralogy and microstructure. Both the XRD and Raman data show that the valves consisted solely of aragonite. The observed microstructures of the valves were complex, typically composed of four to seven sublayers, and varied among species. The dorsal layer, the tegmentum, of each species was granular and the ventral layer, the articulamentum, was predominately composed of a spherulitic sublayer, a crossed lamellar sublayer, and an acicular sublayer. The chitonids Sypharochiton pelliserpentis and S. sinclairi had the most complex microstructure layering with three crossed lamellar, two spherulitic sublayers, and a ventral acicular sublayer while the acanthochitonids Acanthochitona zelandica and Notoplax violacea as well as the ischnochitonid Ischnochiton maorianus had the simplest structure with one spherulitic, one crossed lamellar sublayer, and a ventral acicular sublayer. Terminal valves were less complex than intermediate valves and tended to be dominated by the crossed lamellar structure. The leptochitonid Leptochiton inquinatus generated a unique crossed lamellar sublayer different from the other analysed chitonids. Acanthochitona zelandica is the only analysed chitonid that utilizes two different crossed lamellar structures. Clearly, many of these properties do not reflect the currently recognized polyplacophoran phylogeny. PMID- 27940094 TI - Commentary on "Development and External Validation of a Model Predicting Death After Surgery in Patients With a Ruptured Abdominal Aortic Aneurysm". PMID- 27940095 TI - The epidemiology, prognosis, and trends of severe traumatic brain injury with presenting Glasgow Coma Scale of 3. AB - PURPOSE: To characterize trends and prognosis of severe traumatic brain injury (TBI). METHODS: This 5-year multicenter retrospective study included patients with TBI and Glasgow Coma Scale of 3. We analyzed demographic and clinical characteristics and mortality using Pearson chi2 tests, Cochran-Armitage trend tests, and stepwise logistic regression. Analyses were stratified by vehicular and fall etiologies; other etiologies were excluded (24%). RESULTS: Included were 481 patients. Fall-related injuries increased 58% (P=.001) but vehicular etiology did not change (P=.63). The characteristics of the populations changed over time; with falls, the population became older and increasingly presented with normal vital signs, whereas with vehicular etiology, the population became younger, with more alcohol-related injury (P<.05 for all). Mortality from falls increased substantially from 25% to 63% (P<.001), whereas death from vehicular injures remained statistically unchanged but with a downward trend (50%-38%, P=.28). Predictors of mortality included injury severity and age at least 65 years for both groups. Additional variables that were prognostic were abnormal vital signs and subdural hematoma for vehicular injuries, and sex for fall injuries. CONCLUSIONS: The epidemiology of severe TBI is changing. These epidemiologic data may be used for management and resource decisions, monitoring, and directing injury prevention measures. PMID- 27940096 TI - Molecular dynamics and protein interaction studies of lipopeptide (Iturin A) on alpha- amylase of Spodoptera litura. AB - The small mottled willow moth (Spodoptera litura) is one of the best-known agricultural pest insects. To understand the insecticidal activity, we have selected iturin A compound produced by Bacillus amyloliquefaciens RHNK22 which showed the strongest and most common inhibitory effect on the Spodoptera litura protein. In this work we have identified the action of iturin A on alpha- amylase is a major digestive enzyme of Spodoptera litura using docking studies. A 3D model of alpha- amylase from Spodoptera litura was generated using 2HPH as a template with the help of Modeller7v7. With the aid of the molecular mechanics and molecular dynamics methods, the final model is obtained and is further checked by Procheck and Verify 3D graph programs, which showed that the final refined model is reliable. With this model, a adjustable docking study was performed with iturin A using GOLD software. The results indicated that ARG 18, THR15, LEU42 in alpha- amylase are important determinant residues in binding as they have strong hydrogen bonding interactions with iturin A. These hydrogen binding interactions play an important role for the stability of the complex. PMID- 27940097 TI - Evolution of group-wise cooperation: Is direct reciprocity insufficient? AB - Group-wise cooperation, or cooperation among three or more individuals, is an integral part of human societies. It is likely that group-wise cooperation also played a crucial role in the survival of early hominins, who were confronted with novel environmental challenges, long before the emergence of Homo sapiens. However, previous theoretical and empirical studies, focusing mainly on modern humans, have tended to suggest that evolution of cooperation in sizable groups cannot be explained by simple direct reciprocity and requires some additional mechanisms (reputation, punishment, etc.), which are cognitively too demanding for early hominins. As a partial resolution of the paradox, our recent analysis of a stochastic evolutionary model, which considers the effect of random drift, has revealed that evolution of group-wise cooperation is more likely to occur in larger groups when an individual's share of the benefit produced by one cooperator does not decrease with increasing group size (i.e., goods are non rivalrous). In this paper, we further extend our previous analysis to explore possible consequences of introducing rare mistakes in behavior or imperfect information about behavior of others on the model outcome. Analyses of the extended models show that evolution of group-wise cooperation can be facilitated by large group size even when individuals intending to cooperate sometimes fail to do so or when all the information about the past behavior of group members is not available. We argue, therefore, that evolution of cooperation in sizable groups does not necessarily require other mechanisms than direct reciprocity if the goods to be produced via group-wise cooperation are non-rivalrous. PMID- 27940098 TI - Plasma transport of ergocalciferol and cholecalciferol and their 25-hydroxylated metabolites in dairy cows. AB - In cattle, there are 2 significant forms of vitamin D: ergocalciferol (ERG) from fungi on roughage and cholecalciferol (CHO) from vitamin supplements or endogenous synthesis in the skin. The hypothesis of the present study is that vitamin D from the 3 sources is transported in different plasma fractions in the body. This is hypothesized to explain the lower efficiency of ERG compared to CHO in securing a sufficient plasma status of 25-hydroxyvitamin D and explain the inefficient excretion of dietary CHO into milk compared to endogenous CHO. Twenty vitamin D-depleted cows were assigned to 5 treatments: D2, housed indoor and fed 625-MUg/d (25.000 IU) ERG; D3, housed indoor and fed 625-MUg/d CHO; D2+D3, housed indoor and fed 625-MUg/d ERG and 625-MUg/d CHO; SUN, let out for daily pasture to facilitate CHO synthesis from sunlight; and D2+SUN, fed 625-MUg/d ERG and let out for daily pasture. Blood samples were taken twice weekly and plasma fractionated by ultracentrifugation into 3 fractions: light lipoprotein (LLP), heavy lipoprotein (HLP), and protein and analyzed for content of ERG and CHO and their liver derived metabolites 25-hydroxyergocalciferol (25ERG) and 25 hydroxycholecalciferol (25CHO), respectively. Liver biopsies were taken on the last day of the study to asses gene expression related to vitamin D metabolism. During 4 wk of study, the vitamin D status in plasma increased to 19.3 to 22.8 ng/mL 25ERG in ERG-treated cows with the highest concentration in D2 (P <= 0.05) and to 25.0 to 33.4 ng/mL 25CHO in pasture or CHO-treated cows with the highest concentration in SUN (P <= 0.01). In plasma fractions, CHO was mainly found in the HLP fraction, whereas 25CHO was almost exclusively found in the protein fraction, probably due to its reported high binding affinity to vitamin D-binding protein. About 70% to 90% of 25ERG was found in the protein fraction and the remaining 25ERG was found in HLP, whereas ERG was found in both HLP and LLP fractions. In liver tissue, the expression of vitamin D-25-hydroxylase was lower in D2+D3 (P <= 0.05) and SUN (P <= 0.05) than that in the remaining groups, and the vitamin D receptor was expressed in the liver to a larger extent in D2+SUN than that in D2+D3 (P <= 0.05) and SUN (P <= 0.05). In conclusion, different plasma transport mechanisms may explain the lower physiological efficiency of ERG compared to CHO in securing the vitamin D status in plasma but do not explain the lower efficiency of synthetic CHO compared to endogenous CHO from sunlight or UV light in securing a high CHO content in milk. PMID- 27940099 TI - A novel method for assessing chronic cortisol concentrations in dogs using the nail as a source. AB - Cortisol, a glucocorticoid secreted in response to stress, is used to assess adrenal function and mental health in clinical settings. Current methods assess cortisol sources that reflect short-term secretion that can vary with current stress state. Here, we present a novel method for the extraction and quantification of cortisol from the dog nail using solid phase extraction coupled to enzyme-linked immunosorbent assay. Validation experiments demonstrated accuracy (r = 0.836, P < 0.001) precision (15.1% coefficients of variation), and repeatability (14.4% coefficients of variation) with this method. Furthermore, nail cortisol concentrations were positively correlated to an established hair cortisol method (r = 0.736, P < 0.001). Nail cortisol concentrations did not differ with dog sex, breed, age, or weights; however, sample size limitations may preclude statistical significance. Nail cortisol may provide information on cortisol secretion integrated over the time corresponding to nail growth and may be useful as a tool for diagnosing stress and adrenal disorders in dogs. PMID- 27940091 TI - Pathogenesis of NEC: Role of the innate and adaptive immune response. AB - Necrotizing enterocolitis (NEC) is a devastating disease in premature infants with high case fatality and significant morbidity among survivors. Immaturity of intestinal host defenses predisposes the premature infant gut to injury. An abnormal bacterial colonization pattern with a deficiency of commensal bacteria may lead to a further breakdown of these host defense mechanisms, predisposing the infant to NEC. Here, we review the role of the innate and adaptive immune system in the pathophysiology of NEC. PMID- 27940100 TI - The effect of different anesthetics on tumor cytotoxicity by natural killer cells. AB - A number of retrospective studies have suggested that choice of anesthetic drugs during surgical tumor resection might affect tumor recurrence/metastasis, or outcome of patients. The recent study showed that volatile anesthetics-based general anesthesia was associated with the worse outcomes than intravenous anesthetics-based general anesthesia. However, the underlying mechanism is yet to be determined. Because natural killer (NK) cells are implicated as important immune cells for tumor recurrence/metastasis in the perioperative period, we examined the effect of different anesthetics on NK cell-mediated tumor cytotoxicity. Because adhesion molecule leukocyte function-associated antigen-1 (LFA-1) is functionally important in NK cells and is inhibited by commonly used volatile anesthetics isoflurane and sevoflurane, we hypothesized that these anesthetics would attenuate NK cell-mediated cytotoxicity. Using human NK cell line NK92-MI cells and tumor cell line K562 cells as a model system, we performed cytotoxicity, proliferation, conjugation and degranulation assays. Lytic granule polarization was also assessed. We showed that isoflurane, sevoflurane and LFA-1 inhibitor BIRT377 attenuated cytotoxicity, and reduced conjugation and polarization, but not degranulation of NK cells. Our data suggest that isoflurane and sevoflurane attenuated NK cell-mediated cytotoxicity at least partly by their LFA-1 inhibition in vitro. Whether or not isoflurane and sevoflurane attenuate NK cell-mediated tumor cytotoxicity in patients needs to be determined in the future. PMID- 27940101 TI - Normal saline solution versus other viscous solutions for submucosal injection during endoscopic mucosal resection: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: EMR is being increasingly practiced for the removal of large colorectal polyps. A variety of solutions such as normal saline solution (NS) and other viscous and hypertonic solutions (VS) have been used as submucosal injections for EMR. A systematic review and meta-analysis is presented comparing the efficacy and adverse events of EMR performed using NS versus VS. METHODS: Two independent reviewers conducted a search of all databases for human, randomized controlled trials that compared NS with VS for EMR of colorectal polyps. Data on complete en bloc resection, presence of residual lesions, and adverse events were extracted using a standardized protocol. Pooled odds ratio (OR) estimates along with 95% confidence intervals (CI) were calculated using fixed effect or random effects models. RESULTS: Five prospective, randomized controlled trials (504 patients) met the inclusion criteria. The mean polyp sizes were 20.84 mm with NS and 21.44 mm with VS. On pooled analysis, a significant increase in en bloc resection (OR, 1.91; 95% CI, 1.11-3.29; P = .02; I2 = 0%) and decrease in residual lesions (OR, 0.54; 95% CI, 0.32-0.91; P = .02; I2 = 0%) were noted in VS compared with NS. There was no significant difference in the rate of overall adverse events between the 2 groups. CONCLUSIONS: Use of VS during EMR leads to higher rates of en bloc resection and lower rates of residual lesions compared with NS, without any significant difference in adverse events. Endoscopists could consider using VS for EMR of large colorectal polyps and NS for smaller polyps because there is no significant difference in the outcomes with lesions <2 cm. PMID- 27940102 TI - Association of environmental enrichment and locomotor stimulation in a rodent model of cerebral palsy: Insights of biological mechanisms. AB - Several physiotherapy approaches are used with different aims in the treatment of cerebral palsy (CP), such as the early stimulation and the locomotor training, but their biological effects, isolated or combined, are not completely known. In animals models, these strategies can be compared, with due translational restrictions, to the environmental enrichment (EE), that involves the enhancement of animal's physical and social environment, and locomotor stimulation (LS), that can be performed using the treadmill adapted for rats. This study was designed to describe which biological and functional mechanisms underlying rehabilitative process in clinical practice. Male rat pups were initially divided in two groups: control (healthy) and submitted to a CP model. Then, pups were divided in eight groups: CP, CPEE, CPLS, CPEELS and its respectively control groups. Functional outcomes were assessed at the postnatal day (P) 31 and P52. The tibialis anterior and soleus muscles, tibia bone parameters, the expression of synaptophysin in the primary motor cortex (M1) and ventral horn (VH) of the spinal cord, were evaluated. The association of therapies was able to improve the functional assessments and musculoskeletal parameters. Isolated therapies presented complementary benefits in CP, but the association of therapies proved to be a fundamental and effective strategy to functional recovery, besides alter positively all biological tissues evaluated in this study. PMID- 27940103 TI - Management and risk factor of stenosis after endoscopic submucosal dissection for colorectal neoplasms. AB - BACKGROUND AND AIM: Although endoscopic submucosal dissection (ESD) enables en bloc removal of large colorectal neoplasms, the incidence of stenosis after ESD and its risk factors have not been well described. This study aimed to determine the risk factors of stenosis and verify the surveillance and treatment of stenosis. METHODS: This retrospective study included 822 patients, with a total of 912 consecutive colorectal lesions, who underwent ESD from September 2003 to May 2015. The main outcome measures were incidence of stenosis and its relationship with the clinicopathologic factors in surveillance. RESULTS: Surveillance endoscopy was performed 6 months after ESD. Four of the 822 patients (0.49%) developed stenosis and required unanticipated endoscopy. The other 908 cases in 818 patients showed no symptoms or only slight abdominal discomfort (that was controlled with medication) and did not require any dilation or steroid therapies. Post-ESD stenosis was observed in 11.1% (2/18) of patients with circumferential resection between >=90% and <100% and in 50% (2/4) of patients with circumferential resection of 100%. Among the 50 cases with a circumferential mucosal defect >=75%, a circumferential mucosal defect >=90% was a significant risk factor (P = .005). Four patients with stenosis were treated successfully by endoscopic dilation. CONCLUSIONS: Circumferential mucosal defect of more than 90% is a significant risk factor for stenosis after colorectal ESD. Surveillance endoscopy 6 months after ESD is recommended to assess for development of stenosis. Defects smaller than 90% do not require close endoscopic follow-up or prophylactic measures for prevention of post-ESD stenosis. (UMIN clinical trial registration number: UMIN000015754.). PMID- 27940104 TI - Ozone and hypertensive disorders of pregnancy in Florida: Identifying critical windows of exposure. AB - INTRODUCTION: Ozone (O3) has been linked to hypertensive disorders of pregnancy (HDP). However, inconsistent results have been reported, and no study has examined the critical exposure windows during pregnancy. MATERIALS AND METHODS: We used Florida birth vital statistics records to investigate the association between HDP and O3 exposure among 655,529 pregnancies with conception dates between 2005 and 2007. Individual O3 exposure was assessed at mothers' home address at the time of delivery using the Hierarchical Bayesian space-time statistical model. We examined the association during three predefined exposure windows including trimester 1, trimester 2, and trimesters 1&2, as well as in each week of the first two trimesters using distributed lag models. RESULTS: Pregnancies with HDP had a higher mean exposure to O3 (39.07 in trimester 1, 39.02 in trimester 2, and 39.06 in trimesters 1&2, unit: ppb) than those without HDP (38.65 in trimester 1, 38.57 in trimester 2, and 38.61 in trimesters 1&2, unit: ppb). In the adjusted logistic regression model, increased odds of HDP were observed for each 5 ppb increase in O3 (ORTrimester1=1.04, 95% CI: 1.03, 1.06; ORTrimester2=1.03, 95% CI: 1.02, 1.04; ORTrimester1&2=1.07, 95% CI: 1.05, 1.08). In the distributed lag models, elevated odds of HDP were observed with increased O3 exposure during the 1st to 24th weeks of gestation, with higher odds during early pregnancy. CONCLUSIONS: O3 exposure during pregnancy is related to increased odds of HDP, and early pregnancy appears to be a potentially critical window of exposure. PMID- 27940105 TI - Occupational airborne exposure in relation to Chronic Obstructive Pulmonary Disease (COPD) and lung function in individuals without childhood wheezing illness: A 50-year cohort study. AB - BACKGROUND: Evidence from longitudinal population-based studies relating occupational exposure to the full range of different forms of airborne pollutants and lung function and airway obstruction is limited. OBJECTIVE: To relate self reported COPD and lung function impairment to occupational exposure to different forms of airborne chemical pollutants in individuals who did not have childhood wheeze. METHODS: A prospective cohort study was randomly selected in 1964 at age 10-15 years and followed up in 1989, 1995, 2001 and 2014 (aged 58-64) by spirometry and respiratory questionnaire. Occupational histories were recorded in 2014 and occupational exposures assigned using an airborne chemical job exposure matrix. The risk of COPD and lung function impairment was analyzed in subjects, who did not have childhood wheeze, using logistic and linear regression and linear mixed effects models. RESULTS: 237 subjects without childhood wheeze (mean age 60.6 years, 47% male) were analyzed. There was no association between any respiratory outcomes and exposure to gases, fibers, mists or mineral dusts and no consistent associations with exposure to fumes. Reduced FEV1 was associated with longer duration (years) of exposure to any of the six main pollutant forms - vapors, gases, dusts, fumes, fibers and mists (VGDFFiM) with evidence of a dose response relationship (p-trend=0.004). Exposure to biological dusts was associated with self-reported COPD and FEV1= 4 + 5). Relative to grade group I, the unadjusted risks of PCSM and bone metastasis were significantly associated with prognostic grade groupings for both biopsy and prostatectomy samples (all p<0.01). Pairwise comparisons within Gleason sums collapsed within grade group V were not significant; however, this analysis was limited by a small representation of men with Gleason pattern >= 4 + 5. CONCLUSIONS: The prognostic grade grouping system is associated with risk of PCSM and metastasis across management strategies, including definitive therapy, conservative management, and primary androgen deprivation. PATIENT SUMMARY: A five-level reporting system for prostate cancer pathology is associated with the risk of late prostate cancer endpoints. PMID- 27940156 TI - Tbx20 drives cardiac progenitor formation and cardiomyocyte proliferation in zebrafish. AB - Tbx20 is a T-box transcription factor that plays essential roles in the development and maintenance of the heart. Although it is expressed by cardiac progenitors in all species examined, an involvement of Tbx20 in cardiac progenitor formation in vertebrates has not been previously described. Here we report the identification of a zebrafish tbx20 mutation that results in an inactive, truncated protein lacking any functional domains. The cardiac progenitor population is strongly diminished in this mutant, leading to the formation of a small, stretched-out heart. We found that overexpression of Tbx20 results in an enlarged heart with significantly more cardiomyocytes. Interestingly, this increase in cell number is caused by both enhanced cardiac progenitor cell formation and the proliferation of differentiated cardiomyocytes, and is dependent upon the activity of Tbx20's T-box and transcription activation domains. Together, our findings highlight a previously unappreciated role for Tbx20 in promoting cardiac progenitor formation in vertebrates and reveal a novel function for its activation domain in cardiac cell proliferation during embryogenesis. PMID- 27940157 TI - Pa2G4 is a novel Six1 co-factor that is required for neural crest and otic development. AB - Mutations in SIX1 and in its co-factor, EYA1, underlie Branchiootorenal Spectrum disorder (BOS), which is characterized by variable branchial arch, otic and kidney malformations. However, mutations in these two genes are identified in only half of patients. We screened for other potential co-factors, and herein characterize one of them, Pa2G4 (aka Ebp1/Plfap). In human embryonic kidney cells, Pa2G4 binds to Six1 and interferes with the Six1-Eya1 complex. In Xenopus embryos, knock-down of Pa2G4 leads to down-regulation of neural border zone, neural crest and cranial placode genes, and concomitant expansion of neural plate genes. Gain-of-function leads to a broader neural border zone, expanded neural crest and altered cranial placode domains. In loss-of-function assays, the later developing otocyst is reduced in size, which impacts gene expression. In contrast, the size of the otocyst in gain-of-function assays is not changed but the expression domains of several otocyst genes are reduced. Together these findings establish an interaction between Pa2G4 and Six1, and demonstrate that it has an important role in the development of tissues affected in BOS. Thereby, we suggest that pa2g4 is a potential candidate gene for BOS. PMID- 27940158 TI - Inactivation of maternal Hif-1alpha at mid-pregnancy causes placental defects and deficits in oxygen delivery to the fetal organs under hypoxic stress. AB - A critical transition occurs near mid-gestation of mammalian pregnancy. Prior to this transition, low concentrations of oxygen (hypoxia) signaling through Hypoxia Inducible Factor (HIF) functions as a morphogen for the placenta and fetal organs. Subsequently, functional coupling of the placenta and fetal cardiovascular system for oxygen (O2) transport is required to support the continued growth and development of the fetus. Here we tested the hypothesis that Hif-1alpha is required in maternal cells for placental morphogenesis and function. We used Tamoxifen-inducible Cre-Lox to inactivate Hif-1alpha in maternal tissues at E8.5 (MATcKO), and used ODD-Luciferase as a reporter of hypoxia in placenta and fetal tissues. MATcKO of Hif-1alpha reduced the number of uterine natural killer (uNK) cells and Tpbpa-positve trophoblast cells in the maternal decidua at E13.5 -15.5. There were dynamic changes in all three layers of E13.5-15.5 MATcKO placenta. Of note was the under-development of the labyrinth at E15.5 associated with reduced Ki67 and increased TUNEL staining consistent with reduced cell proliferation and increased apoptosis. Labyrinth defects were particularly evident in placentas connected to effectively HIF-1alpha heterozygous null embryos. MATcKO had no effect on basal ODD-Luciferase activity in fetal organs (heart, liver, brain) at any stage, but at E13.5-15.5 resulted in enhanced induction of the ODD-Luciferase hypoxia reporter when the dam's inspired O2 was reduced to 8% for 4 hours. MATcKO also slowed the growth after E13.5 of fetuses that were effectively heterozygous for Hif-1alpha, with most being non viable at E15.5. The hearts of these E15.5 fetuses were abnormal with reduction in size, thickened epicardium and mesenchymal septum. We conclude that maternal HIF-1alpha is required for placentation including recruitment of uNK and trophoblast cells into the maternal decidua and other trophoblast cell behaviors. The placental defects render the fetus vulnerable to O2 deprivation after mid gestation. PMID- 27940159 TI - Dmrt1 is necessary for male sexual development in zebrafish. AB - The dmrt1 (doublesex and mab-3 related transcription factor 1) gene is a key regulator of sex determination and/or gonadal sex differentiation across metazoan animals. This is unusual given that sex determination genes are typically not well conserved. The mechanisms by which zebrafish sex is determined have remained elusive due to the lack of sex chromosomes and the complex polygenic nature of sex determination in domesticated strains. To investigate the role of dmrt1 in zebrafish sex determination and gonad development, we isolated mutations disrupting this gene. We found that the majority of dmrt1 mutant fish develop as fertile females suggesting a complete male-to-female sex reversal in mutant animals that would have otherwise developed as males. A small percentage of mutant animals became males, but were sterile and displayed testicular dysgenesis. Therefore zebrafish dmrt1 functions in male sex determination and testis development. Mutant males had aberrant gonadal development at the onset of gonadal sex-differentiation, displaying reduced oocyte apoptosis followed by development of intersex gonads and failed testis morphogenesis and spermatogenesis. By contrast, female ovaries developed normally. We found that Dmrt1 is necessary for normal transcriptional regulation of the amh (anti Mullerian hormone) and foxl2 (forkhead box L2) genes, which are thought to be important for male or female sexual development respectively. Interestingly, we identified one dmrt1 mutant allele that co-operates with a linked segregation distorter locus to generate an apparent XY sex determination mechanism. We conclude that dmrt1 is dispensable for ovary development but necessary for testis development in zebrafish, and that dmrt1 promotes male development by transcriptionally regulating male and female genes as has been described in other animals. Furthermore, the strong sex-ratio bias caused by dmrt1 reduction-of function points to potential mechanisms through which sex chromosomes may evolve. PMID- 27940160 TI - Neural stem/progenitor cells on collagen with anchored basic fibroblast growth factor as potential natural nerve conduits for facial nerve regeneration. AB - : Introducing neural stem/progenitor cells (NS/PCs) for repairing facial nerve injuries could be an alternative strategy for nerve gap reconstruction. However, the lack of success associated with current methods of applying NS/PCs to neurological disease is due to poor engraftment following transplantation into the host tissue. In this work, we developed rat-tail collagen-based nerve conduits to repair lengthy facial nerve defects, promoting NS/PC proliferation in the natural nerve conduits with anchored bFGF to improve the therapeutic effects of cell transplantation. In vitro studies showed that heparinized collagen prevented leakage of bFGF and NS/PCs expended in the rat-tail collagen gel with the anchored bFGF. The natural nerve conduits were implanted to connect 8-mm facial nerve defects in rats. The repair outcomes including vibrissae movements, electrophysiological tests, immunohistochemistry and remyelination analysis of regenerated nerve were evaluated. At 12weeks after implantation, only natural nerve conduits treated group showed Hoechst labeled NS/PCs. Besides, the natural nerve conduit significantly promoted functional recovery and nerve growth, which was similar to those of the gold standard, an autograft. The animal experiment results suggesting that the natural nerve conduits were valuable for facial nerve reconstruction. STATEMENT OF SIGNIFICANCE: Neural stem/progenitor cells (NS/PCs) were beneficial for the treatment of nervous system diseases. However, after transplantation, the beneficial was limited because the number of living NS/PCs decreased rapidly due to insufficient signaling molecules, such as growth factors, in the microenvironments surrounding transplanted cells. In the present study, we constructed collagen-based nerve conduit with anchored bFGF to achieve higher numbers of NS/PCs for repairing facial nerve injury. Compared with other methods involving neutral salt treatment or dialysis, the fabrication method of collagen scaffolds was simple, low-cost and safe, requiring a relatively short time to prepare. At 12weeks after transplantation, the functional and histological results of natural nerve conduits treated group showed significant similarities to the gold standard method of nerve autografting. PMID- 27940161 TI - Moldable elastomeric polyester-carbon nanotube scaffolds for cardiac tissue engineering. AB - : Polymer biomaterials are used to construct scaffolds in tissue engineering applications to assist in mechanical support, organization, and maturation of tissues. Given the flexibility, electrical conductance, and contractility of native cardiac tissues, it is desirable that polymeric scaffolds for cardiac tissue regeneration exhibit elasticity and high electrical conductivity. Herein, we developed a facile approach to introduce carbon nanotubes (CNTs) into poly(octamethylene maleate (anhydride) 1,2,4-butanetricarboxylate) (124 polymer), and developed an elastomeric scaffold for cardiac tissue engineering that provides electrical conductivity and structural integrity to 124 polymer. 124 polymer-CNT materials were developed by first dispersing CNTs in poly(ethylene glycol) dimethyl ether porogen and mixing with 124 prepolymer for molding into shapes and crosslinking under ultraviolet light. 124 polymers with 0.5% and 0.1% CNT content (wt) exhibited improved conductivity against pristine 124 polymer. With increasing the CNT content, surface moduli of hybrid polymers were increased, while their bulk moduli were decreased. Furthermore, increased swelling of hybrid 124 polymer-CNT materials was observed, suggesting their improved structural support in an aqueous environment. Finally, functional characterization of engineered cardiac tissues using the 124 polymer-CNT scaffolds demonstrated improved excitation threshold in materials with 0.5% CNT content (3.6+/-0.8V/cm) compared to materials with 0% (5.1+/-0.8V/cm) and 0.1% (5.0+/-0.7V/cm), suggesting greater tissue maturity. 124 polymer-CNT materials build on the advantages of 124 polymer elastomer to give a versatile biomaterial for cardiac tissue engineering applications. STATEMENT OF SIGNIFICANCE: Achieving a high elasticity and a high conductivity in a single cardiac tissue engineering material remains a challenge. We report the use of CNTs in making electrically conductive and mechanically strong polymeric scaffolds in cardiac tissue regeneration. CNTs were incorporated in elastomeric polymers in a facile and reproducible approach. Polymer-CNT materials were able to construct complicated scaffold structures by injecting the prepolymer into a mold and crosslinking the prepolymer under ultraviolet light. CNTs enhanced electrical conductivity and structural support of elastomeric polymers. Hybrid polymeric scaffolds containing 0.5wt% CNTs increased the maturation of cardiac tissues fabricated on them compared to pure polymeric scaffolds. The cardiac tissues on hybrid polymer-CNT scaffolds showed earlier beating than those on pure polymer scaffolds. In the future, fabricated polymer-CNT scaffolds could also be used to fabricate other electro-active tissues, such neural and skeletal muscle tissues. In the future, fabricated polymer-CNT scaffolds could also be used to fabricate other electro active tissues, such as neural and skeletal muscle tissues. PMID- 27940162 TI - Osteoinductive recombinant silk fusion proteins for bone regeneration. AB - : Protein polymers provide a unique opportunity for tunable designs of material systems due to the genetic basis of sequence control. To address the challenge of biomineralization interfaces with protein based materials, we genetically engineered spider silks to design organic-inorganic hybrid systems. The spider silk inspired domain (SGRGGLGGQG AGAAAAAGGA GQGGYGGLGSQGT)15 served as an organic scaffold to control material stability and to allow multiple modes of processing, whereas the hydroxyapatite binding domain VTKHLNQISQSY (VTK), provided control over osteogenesis. The VTK domain was fused either to the N-, C- or both terminals of the spider silk domain to understand the effect of position on material properties and mineralization. The addition of the VTK domain to silk did not affect the physical properties of the silk recombinant constructs, but it had a critical role in the induction of biomineralization. When the VTK domain was placed on both the C- and N-termini the formation of crystalline hydroxyapatite was significantly increased. In addition, all of the recombinant proteins in film format supported the growth and proliferation of human mesenchymal stem cells (hMSCs). Importantly, the presence of the VTK domain enhanced osteoinductive properties up to 3-fold compared to the control (silk alone without VTK). Therefore, silk-VTK fusion proteins have been shown suitable for mineralization and functionalization for specific biomedical applications. STATEMENT OF SIGNIFICANCE: Organic-inorganic interfaces are integral to biomaterial functions in many areas of repair and regeneration. Several protein polymers have been investigated for this purpose. Despite their success the limited options to fine-tune their material properties, degradation patterns and functionalize them for each specific biomedical application limits their application. Various studies have shown that the biological performance of such proteins can be improved by genetic engineering. The present study provides data relating protein design parameters and functional outcome quantified by biomineralization and human mesenchymal stem cell differentiation. As such, it helps the design of osteoinductive recombinant biomaterials for bone regeneration. PMID- 27940163 TI - Synergistic antitumor efficacy of redox and pH dually responsive micelleplexes for co-delivery of camptothecin and genes. AB - : Challenges remain to load and deliver two or multiple drugs of complementary effects for synergistic cancer therapies. In the current study, multiarmed amphiphilic copolymers of 4-arm poly(ethylene glycol) (PEG) and polyaspartate (PAsp) are created for conjugation of camptothecin (CPT) and condensation with tumor necrosis factor-alpha (TNF) plasmids. Diethylenetriamine (DET) is grafted on PAsp, and CPT is conjugated onto PAsp(DET) by disulfide linkages to form hydrophobic cores of micelles, followed by condensation with TNF plasmids to form micelleplexes. The cis-aconitic linkers are introduced between PEG and PAsp(DET) to remove PEG shells in response to acidic pH, resulting in destabilized micelleplexes and prompted endosomal escape into the cytosol. The micelleplex disintegration in response to reductive stimuli in the cytosol leads to an efficient CPT release and pDNA disassociation. The co-delivery of CPT with TNF plasmids enhances the gene transfection of micelleplexes at low N/P ratios, and shows synergetic cytotoxicities to tumor cells with 2.5 and 8 folds lower IC50s compared with those after treatment with CPT or TNF alone, respectively. The micelleplex treatment on 4T1 tumor models dramatically extends the animal survival and suppresses the tumor growth with 2.3 and 3 folds lower in volume compared with CPT or TNF treatment alone, respectively. Histological and biochemical analyses display TNF expressions in tumor tissues after micelleplex treatment, resulting in significantly larger necrotic regions in tumors, higher cell apoptosis rates, and no obvious sign of tumor metastasis in lungs compared with other treatment. Therefore, the multifunctional micelleplexes based on multiarmed PEG-PAsp(DET) copolymers offer the targeted drug/gene delivery, dually responsive drug/gene release and synergistic antitumor efficacy, holding great promises for combination therapies. STATEMENT OF SIGNIFICANCE: Micelleplexes are constructed from multiarmed amphiphilic copolymers with conjugation of captothecin (CPT) and condensation of tumor necrosis factor-alpha (TNF) plasmid. The pH/redox stimuli realize co-delivery of CPT and pDNA in a sequential manner of folate-mediated endocytosis, endosomal escape induced by PEG cleavage, reduction-sensitive release of CPT in cytosol, and pDNA release from disintegrated polyplexes after CPT release. Compared with CPT or TNF treatment alone, the micelleplexes achieve 2.5 and 8 folds higher cytotoxicities to tumor cells, and suppress the tumor growth with 2.3 and 3 folds lower in volume, respectively. It demonstrates a feasible strategy to develop multifunctional micelleplexes with simultaneous drug conjugation and pDNA condensation, dually responsive drug/gene release and synergistic antitumor efficacy, holding great promise for combinational therapies. PMID- 27940164 TI - RANKL release from self-assembling nanofiber hydrogels for inducing osteoclastogenesis in vitro. AB - PURPOSE: To develop a nanofiber hydrogel (NF-hydrogel) for sustained and controlled release of the recombinant receptor activator of NF-kB ligand; (RANKL) and to characterize the release kinetics and bioactivity of the released RANKL. METHODS: Various concentrations of fluorescently-labelled RANKL protein were added to NF-hydrogels, composed of Acetyl-(Arg-Ala-Asp-Ala)4-CONH2 [(RADA)4] of different concentrations, to investigate the resulting in vitro release rates. The nano-structures of NF-hydrogel, with and without RANKL, were determined using atomic force microscopy (AFM). Released RANKL was further analyzed for changes in secondary and tertiary structure using CD spectroscopy and fluorescent emission spectroscopy, respectively. Bioactivity of released RANKL protein was determined using NFATc1 gene expression and tartrate resistant acid phosphatase (TRAP) activity of osteoclast cells as biomarkers. RESULTS: NF-hydrogel concentration dependent sustained release of RANKL protein was measured at concentrations between 0.5 and 2%(w/v). NF-hydrogel at 2%(w/v) concentration exhibited a sustained and slow-release of RANKL protein up to 48h. Secondary and tertiary structure analyses confirmed no changes to the RANKL protein released from NF hydrogel in comparison to native RANKL. The results of NFATc1 gene mRNA expression and TRAP activities of osteoclast, showed that the release process did not affect the bioactivity of released RANKL. CONCLUSIONS: This novel study is the first of its kind to attempt in vitro characterization of NF-hydrogel based delivery of RANKL protein to induce osteoclastogenesis. We have shown the self assembling NF-hydrogel peptide system is amenable to the sustained and controlled release of RANKL locally; that could in turn increase local concentration of RANKL to induce osteoclastogenesis, for application to the controlled mobilization of tooth movement in orthodontic procedures. STATEMENT OF SIGNIFICANCE: Orthodontic tooth movement (OTM) occurs through controlled application of light forces to teeth, facilitating the required changes in the surrounding alveolar bone through the process of bone remodelling. The RANKL system regulates alveolar bone remodelling and controls root resorption during OTM. The use of exogenous RANKL to accelerate OTM has not been attempted to date because large quantities of RANKL for systemic therapy may subsequently cause serious systemic loss of skeletal bone. The controlled and sustained local release of RANKL from a carrier matrix could maximize its therapeutic benefit whilst minimizing systemic side effects. In this study a NF-hydrogel was used for sustained and controlled release of RANKL and the release kinetics and biofunctionality of the released RANKL was characterized. Our results provide fundamental insight for further investigating the role of RANKL NF-hydrogel release systems for inducing osteoclastogenesis in vivo. PMID- 27940165 TI - Study of the pH-sensitive mechanism of tumor-targeting liposomes. AB - Currently, the phosphatidylethanolamine-based, pH-sensitive, liposome drug delivery system has been widely developed for efficient, targeted cancer therapy. However, the mechanism of pH sensitivity was unclear; it is a main obstacle in controlling the preparation of pH-sensitive liposomes (PSLs).Therefore, our research is aimed at clarifying the pH-response mechanism of the various molecules that compose liposomes. We chose the small pH-sensitive molecules oleic acid (OA), linoleic acid (LA) and cholesteryl hemisuccinate (CHEMS) and the fundamental lipids cholesterol and phosphatidylethanolamine (PE) as test molecules. The PSLs were prepared using the thin-film hydration method and characterized in detail at various pH values (pH 5.0, 6.0 and 7.4), including particle size, zeta-potential, drug encapsulation efficiency and drug loading. The surface structure was observed by transmission electron microscopy (TEM), and the electrical conductivity of the liposome dispersion was also tested. The calorimetric analysis was conducted by Nano-differential scanning calorimetry (Nano-DSC). The in vitro drug release profile showed that PSLs exhibit good pH sensitivity. At neutral pH, the particle size was approximately 150nm, and it dramatically increased at pH 5.0. The zeta-potential increased as the pH decreased. The Nano-DSC results showed that cholesterol and CHEMS can both increase the stability and phase transfer temperature of PSLs. Conductivity increased to a maximum at pH 5.0 and was rather low at pH 7.4. In conclusion, results show that the three kinds of liposomes have pH responsive release characteristics in acidic pH. The OA-PSLs have a pH sensitive point of 5. Since CHEMS has a cholesterol-like structure, it can stabilizes the phospholipid bilayer under neutral conditions as shown in the Nano-DSC data, and because it has a special steroidal rigid structure, it exhibits better pH response characteristics under acidic conditions. PMID- 27940166 TI - Structural, textural and morphological characteristics of tannins from Acacia mearnsii encapsulated using sol-gel methods: Applications as antimicrobial agents. AB - Tannins from Acacia mearnsii were encapsulated using four different sol-gel methods acid (SGAR), basic (SGBR), silicate (SGSR) and non-hydrolytic (SGNHR) routes. The hybrid materials were analyzed using a set of techniques to characterize their structure, texture and morphology. The antimicrobial performance of the encapsulated materials was evaluated against different microorganisms (Staphylococcus aureus, Escherichia coli, Aspergillus niger and Candida sp.). The data showed that the encapsulation route significantly affects the characteristics of the resulting hybrid materials. Better functional performances were obtained using the silicate route, which produced mesoporous materials with a small surface area (0.96m2g-1) and small particle size (<1nm). These characteristics promoted the gradual release of tannins in an aqueous medium and improved their interactions with microorganisms. Furthermore, the process demonstrated the preservation of tannins after synthesis and increased antimicrobial activity (via a controlled tannin release), as demonstrated by the moderate activity against filamentous fungi and yeast. PMID- 27940167 TI - Inverse hexagonal and cubic micellar lyotropic liquid crystalline phase behaviour of novel double chain sugar-based amphiphiles. AB - The lyotropic phase behaviour of a library of sugar-based amphiphiles was investigated using high-throughput small-angle X-ray scattering (SAXS). Double unsaturated-chain monosaccharide amphiphiles formed inverse hexagonal and cubic micellar (Fd3m) lyotropic phases under excess water conditions. A galactose-oleyl amphiphile from the library was subsequently formulated into hexosome nanoparticles, which have potential uses as drug delivery vehicles. The nanoparticles were shown to be stable at elevated temperatures and non-cytotoxic up to at least 200MUgmL-1. PMID- 27940168 TI - Developing a non-fouling hybrid microfluidic device for applications in circulating tumour cell detections. AB - Non-specific cell adsorption is a challenge in sensitive detections using microfluidic systems, such as detecting circulating tumour cells from blood samples. In this report, we present a new strategy to study the combined effects of surface hydrophilicity/hydrophobicity, electric charges and roughness on surface non-fouling properties of a PDMS/SU-8 microfluidic system. To achieve this, microchannel surfaces were modified by poly(amidoamine) generation 4 and generation 7, dendrimers that rendered surfaces negatively and positively charged at pH 7.4, respectively. Water contact angle, atomic force microscopy (AFM) and microscopy were used to characterize and confirm surface modifications, and the non-fouling performance of the resulting surfaces was tested using both live and dead CCRM-CEM cancer cells. Our results show that for live cells, electric charges of a surface is the most important factor affecting the non-fouling features of the surface in microfluidic systems; in contrast, for dead cells, surface hydrophilicity is the most important factor affecting surface non-fouling properties. However, surface roughness does not seem to be as important for both live and dead cells under the experimental conditions used in this study. These results also highlight the importance of different considerations when designing a lab-on-a-chip microfluidic system for high sensitivity biosensing and detection applications. PMID- 27940169 TI - Aging modifies daily variation of antioxidant enzymes and oxidative status in the hippocampus. AB - BACKGROUND: Aging is a complex and multifactorial biological process that leads to the progressive deterioration of physiological systems, including the circadian system. In addition, oxidative stress has been associated with the aging of the normal brain and the development of late-onset neurodegenerative diseases. Even though, functional weakening of circadian rhythms and antioxidant function has been observed during aging, the mechanisms by which the circadian system signaling and oxidative stress are interrelated have not yet been elucidated. The objectives of this study were to evaluate the consequences of aging on the temporal organization of the antioxidant defense system and oxidative status as well as to analyze the endogenous clock activity, in the hippocampus of aged rats. METHODS: Young adults (3-month-old) or older (22-month old) male Holtzman rats were maintained under constant darkness conditions, during 15days before the sacrifice. Levels of catalase (CAT) and glutathione peroxidase (GPx) mRNA and activity, reduced glutathione (GSH), lipoperoxidation (LPO) and BMAL1 protein were analyzed in hippocampus samples isolated every 4h during a 24-h period. Locomotor activity was recorded during 20days before the experiment. RESULTS: Our results show that aging modifies temporal patterns of CAT and GPx expression and activity in the hippocampus in a different way. On the one hand, it abolishes the oscillating CAT expression and specific enzymatic activity while, on the other, it increases the mesor of circadian GPx activity rhythm (p<0.01). Additionally, we observed increased GSH (p<0.05) and reduced LPO (p<0.01) levels in the hippocampus of aged rats. Moreover, the nocturnal locomotor activity was reduced in the older animals in comparison to the young adult rats (p<0.01). Interestingly, the 22month-old animals became arrhythmic and showed a marked fragmentation as well as a significant decline in daily locomotor activity when they were maintained under constant darkness conditions (p<0.05). Aging also abolished circadian rhythms of the core clock BMAL1 protein. CONCLUSION: The loss of temporal organization of the antioxidant enzymes activity, the oxidative status and the cellular clock machinery could result in a temporally altered antioxidant defense system in the aging brain. Learning about how aging affects the circadian system and the expression of genes involved in the antioxidant defense system could contribute to the design of new strategies to improve the quality of life of older people and also to promote a healthy aging. PMID- 27940171 TI - Treatment of elderly patients: The challenge of the future. PMID- 27940170 TI - Short term methionine restriction increases hepatic global DNA methylation in adult but not young male C57BL/6J mice. AB - Despite well-documented evidence for lifespan extension by methionine restriction (MR), underlying mechanisms remain unknown. As methionine can alter S adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), the substrate and product of DNA methyltransferase-1 (DNMT1), we hypothesized that MR diet alters DNA methylation. Young (8-week-old) and adult (1-year-old) male C57BL/6J mice were fed diets with different levels of methionine (0.12%-MR, 0.84%-CD) for 12weeks. Functional indicators of DNA methylation, including global methylation (GM), gene-specific methylation (GSM) and LINE-1 methylation; and biochemical factors affecting DNA methylation, SAH, SAM, and DNMT1 were assessed in different tissues. MR altered DNA methylation depending on the age of intervention. While MR had no effect on hepatic GM in young animals, it increased GM by 27% over CD in adults (p<0.01). In comparison with young animals, hepatic GM levels were 17% lower in CD adults (p<0.05), but not different in MR adults. The MR-induced increase in hepatic GM was associated with a 38% decrease in SAH levels in adults (p<0.001), with SAH and GM levels being negatively correlated (r2=0.33, p<0.001). No changes were observed in DNMT protein levels in liver. In adipose tissue, MR caused a 6% decline in GM in adults (p<0.05), a corresponding 2-fold increase in SAH (p<0.05), and a 2-fold decrease in DNMT1 (p<0.01). MR caused both increases and decreases in GSM of liver and adipose. No changes were observed in LINE-1. Together, these findings provide evidence for protective effects of MR diet on hepatic DNA hypomethylation in adults, apparently mediated by SAH. These findings also indicate that altered DNA methylation might be playing a role in benefits conferred by MR diet. PMID- 27940172 TI - Biomaterials to suppress cancer stem cells and disrupt their tumoral niche. AB - Lack of improvement in the treatment options of several types of cancer can largely be attributed to the presence of a subpopulation of cancer cells with stem cell signatures and to the tumoral niche that supports and protects these cells. This review analyses the main strategies that specifically modulate or suppress cancer stem cells (CSCs) and the tumoral niche (TN), focusing on the role of biomaterials (i.e. implants, nanomedicines, etc.) in these therapies. In the case of CSCs, we discuss differentiation therapies and the disruption of critical cellular signaling networks. For the TN, we analyze diverse strategies to modulate tumor hypervascularization and hypoxia, tumor extracellular matrix, and the inflammatory and tumor immunosuppressive environment. Due to their capacity to control drug disposition and integrate diverse functionalities, biomaterial-based therapies can provide important benefits in these strategies. We illustrate this by providing case studies where biomaterial-based therapies either show CSC suppression and TN disruption or improved delivery of major modulators of these features. Finally, we discuss the future of these technologies in the framework of these emerging therapeutic concepts. PMID- 27940174 TI - Assessment of evertor weakness in patients with chronic ankle instability: Functional versus isokinetic testing. AB - BACKGROUND: Ankle sprain is the most common sport-related injury and eccentric weakness of ankle evertors is regarded as a significant muscular deficit related to chronic ankle instability. However, the eccentric performance of the evertors is rarely assessed by clinicians because procedures used for research purposes (i.e. isokinetic tests) are not easily applicable in daily practice. METHODS: The present study assessed the ability of two different testing procedures to distinguish between groups of 12 healthy subjects or 12 patients suffering from chronic ankle instability. On the one hand, the strength of evertors was assessed with a goldstandard isokinetic procedure. On the other hand, we assessed the ability of the subjects to control ankle inversion during weight bearing (functional standing test). FINDINGS: Data showed no significant difference between groups for isokinetic peak torque values normalized to body weight. Conversely, the functional test revealed a significantly impaired ability to control ankle inversion during weight bearing in subjects with chronic ankle instability. INTERPRETATION: This suggests that this easy-to-apply functional test is better suited compared to isokinetic testing procedures to assess weakness of evertors in patients suffering from chronic ankle instability. Moreover, this test may also be used to objectively monitor improvements during rehabilitation or progression in prevention protocols. PMID- 27940173 TI - The bio-physics of condensation of divalent cations into the bacterial wall has implications for growth of Gram-positive bacteria. AB - BACKGROUND: The anionic-polyelectrolyte nature of the wall of Gram-positive bacteria has long been suspected to be involved in homeostasis of essential cations and bacterial growth. A better understanding of the coupling between the biophysics and the biology of the wall is essential to understand some key features at play in ion-homeostasis in this living system. METHODS: We consider the wall as a polyelectrolyte gel and balance the long-range electrostatic repulsion within this structure against the penalty entropy required to condense cations around wall polyelectrolytes. The resulting equations define how cations interact physically with the wall and the characteristic time required for a cation to leave the wall and enter into the bacterium to enable its usage for bacterial metabolism and growth. RESULTS: The model was challenged against experimental data regarding growth of Gram-positive bacteria in the presence of varying concentration of divalent ions. The model explains qualitatively and quantitatively how divalent cations interact with the wall as well as how the biophysical properties of the wall impact on bacterial growth (in particular the initiation of bacterial growth). CONCLUSION: The interplay between polymer biophysics and the biology of Gram positive bacteria is defined for the first time as a new set of variables that contribute to the kinetics of bacterial growth. GENERAL SIGNIFICANCE: Providing an understanding of how bacteria capture essential metal cations in way that does not follow usual binding laws has implications when considering the control of such organisms and their ability to survive and grow in extreme environments. PMID- 27940175 TI - Implication of protein kinase C of the left intermediate medial mesopallium in memory impairments induced by early prenatal morphine exposure in one-day old chicks. AB - Previously we reported that prenatal morphine exposure during embryonic days 5-8 can cause cognitive deficits of one-trial passive avoidance learning (PAL) in one day old chicks. Because protein kinase C (PKC) has been associated with memory capacity, we investigated the effects of prenatal morphine exposure on PKC isoforms expression in the left intermediate medial mesopallium (IMM) of chick brain at a time when memory tests were performed at 30, 120 and 360min respectively following training in PAL paradigm. We found that the level of PKCalpha in the membrane fractions in left IMM was decreased but that in the cytosol fractions showed a increased trend in prenatally morphine-exposed chicks with impaired long-term memory (120 and 360min). Moreover, the translocation of PKC delta from cytosol to membrane in left IMM was shown in prenatal morphine group which had significantly impaired long-term memory at 360min after training. Furthermore, there were no statistical differences between the two groups regarding the expressions of PKCalpha and PKC delta in the membrane fraction, although their levels in the cytosol fraction of prenatal morphine group which showed impaired intermediate-term memory at 30min after training, were quite different from that of prenatal saline group. Taken together, these results indicate that PKCalpha and PKC delta in the left IMM are differentially involved in the impairments of long-term memory induced by prenatal morphine exposure. Neither PKCalpha nor PKC delta in left IMM may be associated with the disruption of intermediate-term memory of chicks prenatally exposed to morphine. PMID- 27940176 TI - Clinical presentation and outcome of twenty cases of Invasive Meningococcal Disease due to Serogroup C - Clonal complex 11 in the Florence province, Italy, 2015-2016. PMID- 27940177 TI - [Use of high-flow nasal cannula in infants with bronchiolitis in a pediatric emergency department]. AB - High-flow nasal cannula oxygen therapy (HFNC) is a technique for noninvasive ventilation commonly used in pediatric intensive care units for respiratory distress, particularly in acute bronchiolitis. HFNC was introduced in the pediatric emergency department of the Reims university hospital for the treatment of infants with moderate to severe acute viral bronchiolitis. This retrospective observational study aimed to investigate the use of HFNC in a pediatric emergency ward, describing the groups of infants with acute viral bronchiolitis to be treated either with conventional oxygen therapy or with HFNC therapy. A total of 89 infants aged less than 6 months were included between December 2013 and April 2014. The choice of the type of oxygen used belonged to the pediatrician, according to his or her assessment of the clinical severity of the patient's condition, guided by a protocol of HFNC use for the treatment of moderate to severe bronchiolitis and limited by the availability of a single device in the department. Eighty-nine infants were included; 64% were boys. Fifty-seven infants (64%) had no medical history. At admission, 39 infants (46.4%) had tachypnea and 75 (84.3%) intercostal indrawing. RSV was found in 75 infants (97.4% of infants had a positive respiratory virology test). Seventy-six infants (85.4%) were treated with conventional oxygen therapy and 13 (14.6%) with HFNC. At admission, the mean weight for infants treated with HFNC was lower (P=0.03), the oxygen saturation level was 86.7% versus 93.5% (P=0.03) for conventional oxygen therapy. Moreover, modified Wood's score was higher and the mean PCO2 was 61.1 versus 49.9mmHg (P<0.01). Six infants treated with conventional oxygen therapy (7.9%) and six with HFNC (46.1%) were then transferred to an intensive care unit. HFNC therapy in the pediatric emergency ward seems to be an advantageous therapeutic option in the early treatment of infants with moderate to severe bronchiolitis, but further studies are needed to specify its indications and effectiveness. PMID- 27940178 TI - Resurgence of Neisseria meningitidis serogroup W ST-11 (cc11) in Madagascar, 2015 2016. AB - The resurgence of invasive meningococcal disease caused by Neisseria meningitidis serogroup W with sequence type ST-11 (cc11) was observed in Madagascar in 2015 2016. Three cases were investigated in this study. Molecular characterization of the strains suggests the local transmission of a single genotype that may have been circulating for years. PMID- 27940179 TI - The CYP2B6 G516T polymorphism influences CD4+ T-cell counts in HIV-positive patients receiving antiretroviral therapy in an ethnically diverse region of the Amazon. AB - OBJECTIVES: Cytochrome P450 (CYP) enzyme polymorphisms seem to significantly influence the variability of the responses to certain antiretroviral drugs and their toxicity levels. The objective of this study was to evaluate the influence of the CYP2B6 G516T polymorphism on hepatic, renal, immunological, and viral marker changes in HIV-1-positive patients receiving treatment in an ethnically diverse region of the Amazon. METHODS: CYP2B6 G516T genotyping was performed by real-time PCR (RT-PCR) in samples from 185 patients. Urea, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), CD4+/CD8+ T-cell counts, and HIV-1 plasma viral load were measured. RESULTS: The polymorphic CYP2B6 G516T allele frequency was 0.36, which is different from the frequencies in other ethnic groups. The polymorphic genotype was associated with changes in the urea and ALT levels, although the median values were within the normal range. The TT genotype was also associated with significantly lower CD4+ T-cell counts in patients using efavirenz. CONCLUSIONS: The CYP2B6 G516T polymorphism seems to affect the response to efavirenz treatment by reducing CD4+ T-cell counts in patients with a high degree of miscegenation who use this antiretroviral agent. PMID- 27940180 TI - The Lifestyle Intervention for the Treatment of Diabetes study (LIFT Diabetes): Design and baseline characteristics for a randomized translational trial to improve control of cardiovascular disease risk factors. AB - The prevalence of type 2 diabetes continues to increase in minority and underserved patients, who are also more likely to have poorer control of diabetes and related risk factors for complications. Although the Look AHEAD trial has demonstrated improved risk factor control among overweight or obese diabetes patients who received an intensive lifestyle intervention, translating such findings into accessible programs is a major public health challenge. The purpose of this paper is to report the design and baseline characteristics of the Lifestyle Interventions for the Treatment of Diabetes study (LIFT Diabetes). The overall goal is to test the impact of a community-based lifestyle weight loss (LWL) intervention adapted from Look AHEAD on cardiovascular disease risk at 12 months and 24-months among minority and lower income diabetes patients. Secondary outcomes include body weight, physical activity, medication use, cost, resource utilization, and safety. The primary hypothesis being tested is that the LWL will result in 10% relative reduction in CVD risk compared to the DSM. We have randomized 260 overweight or obese adults with diabetes one of two 12-month interventions: a LWL condition delivered by community health workers or a diabetes self-management (DSM) education condition. The baseline demographic characteristics indicate that our sample is predominantly female, obese, low income, and ethnic minority. Translating evidence-based, lifestyle strategies, and targeting minority and underserved patients, will yield, if successful, a model for addressing the burden of diabetes and may favorably impact health disparities. PMID- 27940183 TI - Randomized controlled dissemination study of community-to-clinic navigation to promote CRC screening: Study design and implications. AB - INTRODUCTION: Regular screening facilitates early diagnosis of colorectal cancer (CRC) and reduction of CRC morbidity and mortality. Screening rates for minorities and low-income populations remain suboptimal. Provider referral for CRC screening is one of the strongest predictors of adherence, but referrals are unlikely among those who have no clinic home (common among poor and minority populations). METHODS/STUDY DESIGN: This group randomized controlled study will test the effectiveness of an evidence based tailored messaging intervention in a community-to-clinic navigation context compared to no navigation. Multicultural, underinsured individuals from community sites will be randomized (by site) to receive CRC screening education only, or education plus navigation. In Phase I, those randomized to education plus navigation will be guided to make a clinic appointment to receive a provider referral for CRC screening. Patients attending clinic appointments will continue to receive navigation until screened (Phase II) regardless of initial arm assignment. We hypothesize that those receiving education plus navigation will be more likely to attend clinic appointments (H1) and show higher rates of screening (H2) compared to those receiving education only. Phase I group assignment will be used as a control variable in analysis of screening follow-through in Phase II. Costs per screening achieved will be evaluated for each condition and the RE-AIM framework will be used to examine dissemination results. CONCLUSION: The novelty of our study design is the translational dissemination model that will allow us to assess the real-world application of an efficacious intervention previously tested in a randomized controlled trial. PMID- 27940182 TI - Design of a randomized controlled trial for genomic carrier screening in healthy patients seeking preconception genetic testing. AB - Population-based carrier screening is limited to well-studied or high-impact genetic conditions for which the benefits may outweigh the associated harms and costs. As the cost of genome sequencing declines and availability increases, the balance of risks and benefits may change for a much larger number of genetic conditions, including medically actionable additional findings. We designed an RCT to evaluate genomic clinical sequencing for women and partners considering a pregnancy. All results are placed into the medical record for use by healthcare providers. Through quantitative and qualitative measures, including baseline and post result disclosure surveys, post result disclosure interviews, 1-2year follow up interviews, and team journaling, we are obtaining data about the clinical and personal utility of genomic carrier screening in this population. Key outcomes include the number of reportable carrier and additional findings, and the comparative cost, utilization, and psychosocial impacts of usual care vs. genomic carrier screening. As the study progresses, we will compare the costs of genome sequencing and usual care as well as the cost of screening, pattern of use of genetic or mental health counseling services, number of outpatient visits, and total healthcare costs. This project includes novel investigation into human reactions and responses from would-be parents who are learning information that could both affect a future pregnancy and their own health. PMID- 27940181 TI - An intervention to reduce sitting and increase light-intensity physical activity at work: Design and rationale of the 'Stand & Move at Work' group randomized trial. AB - BACKGROUND: American workers spend 70-80% of their time at work being sedentary. Traditional approaches to increase moderate-vigorous physical activity (MVPA) may be perceived to be harmful to productivity. Approaches that target reductions in sedentary behavior and/or increases in standing or light-intensity physical activity [LPA] may not interfere with productivity and may be more feasible to achieve through small changes accumulated throughout the workday METHODS/DESIGN: This group randomized trial (i.e., cluster randomized trial) will test the relative efficacy of two sedentary behavior focused interventions in 24 worksites across two states (N=720 workers). The MOVE+ intervention is a multilevel individual, social, environmental, and organizational intervention targeting increases in light-intensity physical activity in the workplace. The STAND+ intervention is the MOVE+ intervention with the addition of the installation and use of sit-stand workstations to reduce sedentary behavior and enhance light intensity physical activity opportunities. Our primary outcome will be objectively-measured changes in sedentary behavior and light-intensity physical activity over 12months, with additional process measures at 3months and longer term sustainability outcomes at 24months. Our secondary outcomes will be a clustered cardiometabolic risk score (comprised of fasting glucose, insulin, triglycerides, HDL-cholesterol, and blood pressure), workplace productivity, and job satisfaction DISCUSSION: This study will determine the efficacy of a multi level workplace intervention (including the use of a sit-stand workstation) to reduce sedentary behavior and increase LPA and concomitant impact on cardiometabolic health, workplace productivity, and satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02566317 (date of registration: 10/1/2015). PMID- 27940184 TI - SiRNA-mediated in vivo gene knockdown by acid-degradable cationic nanohydrogel particles. AB - Cationic nanohydrogel particles have become an attractive tool for systemic siRNA delivery, but improvement of their in vivo tolerance is desirable, especially to prevent potential long term side effects by tissue and cellular accumulation. Here, we designed novel ketal cross-linked cationic nanohydrogel particles that were assessed for reduced tissue accumulation and robust siRNA delivery in vitro and in vivo. An oligo-amine cross-linker equipped with a ketal moiety in its core was synthesized and applied to nanohydrogel cross-linking of self-assembled reactive ester block copolymers in DMSO. The resulting acid-sensitive cationic nanoparticles spontaneously disassembled over time in acidic milieu, as investigated by dynamic light scattering. Fluorescent correlation spectroscopy showed effective complexation with siRNA as well as its release upon particle degradation at endosomal pH. These properties resulted in an enhanced in vitro gene knockdown for the acid-degradable cationic nanoparticles compared to their non-degradable spermine analogues. In a murine liver fibrosis model enhanced carrier and payload accumulation in the fibrotic tissue facilitated sequence specific gene knockdown and prevented fibrosis progression. Long-term monitoring of the carrier in the body showed an enhanced clearance for the acid-degradable carrier, even after multiple dosing. Therefore, these acid-degradable cationic nanohydrogel particles can be considered as promising siRNA carriers for in vivo purposes towards therapeutic applications. PMID- 27940185 TI - Surrogacy of progression free survival for overall survival in metastatic breast cancer studies: Meta-analyses of published studies. AB - PURPOSE: PFS is often used as a surrogate endpoint for OS in metastatic breast cancer studies. We have evaluated the association of treatment effect on PFS with significant HROS (and how this association is affected by other factors) in published prospective metastatic breast cancer studies. METHODS: A systematic literature search in PubMed identified prospective metastatic breast cancer studies. Treatment effects on PFS were determined using hazard ratio (HRPFS), increase in median PFS (DeltaMEDPFS) and % increase in median PFS (%DeltaMEDPFS). Diagnostic accuracy of PFS measures (HRPFS, DeltaMEDPFS and %DeltaMEDPFS) in predicting significant HROS was assessed using receiver operating characteristic (ROC) curves and classification tree approach (CART). RESULTS: Seventy-four cases (i.e., treatment to control comparisons) from 65 individual publications were identified for the analyses. Of these, 16 cases reported significant treatment effect on HROS at 5% level of significance. Median number of deaths reported in these cases were 153. Area under the ROC curve (AUC) for diagnostic measures as HRPFS, DeltaMEDPFS and %DeltaMEDPFS were 0.69, 0.70 and 0.75, respectively. Classification tree results identified %DeltaMEDPFS and number of deaths as diagnostic measure for significant HROS. Only 7.9% (3/39) cases with DeltaMEDPFS shorter than 48.27% reported significant HROS. There were 7 cases with DeltaMEDPFS of 48.27% or more and number of deaths reported as 227 or more - of these 5 cases reported significant HROS. CONCLUSION: %DeltaMEDPFS was found to be a better diagnostic measure for predicting significant HROS. Our analysis results also suggest that consideration of total number of deaths may further improve its diagnostic performance. Based on our study results, the studies with 50% improvement in median PFS are more likely to produce significant HROS if the total number of OS events at the time of analysis is 227 or more. PMID- 27940186 TI - Patient Navigation in Medically Underserved Areas study design: A trial with implications for efficacy, effect modification, and full continuum assessment. AB - BACKGROUND: The Patient Navigation in Medically Underserved Areas study objectives are to assess if navigation improves: 1) care uptake and time to diagnosis; and 2) outcomes depending on patients' residential medically underserved area (MUA) status. Secondary objectives include the efficacy of navigation across 1) different points of the care continuum among patients diagnosed with breast cancer; and 2) multiple regular screening episodes among patients who did not obtain breast cancer diagnoses. DESIGN/METHODS: Our randomized controlled trial was implemented in three community hospitals in South Chicago. Eligible participants were: 1) female, 2) 18+years old, 3) not pregnant, 4) referred from a primary care provider for a screening or diagnostic mammogram based on an abnormal clinical breast exam. Participants were randomized to 1) control care or 2) receive longitudinal navigation, through treatment if diagnosed with cancer or across multiple years if asymptomatic, by a lay health worker. Participants' residential areas were identified as: 1) established MUA (before 1998), 2) new MUA (after 1998), 3) eligible/but not designated as MUA, and 4) affluent/ineligible for MUA. Primary outcomes include days to initially recommended care after randomization and days to diagnosis for women with abnormal results. Secondary outcomes concern days to treatment initiation following a diagnosis and receipt of subsequent screening following normal/benign results. DISCUSSION: This intervention aims to assess the efficacy of patient navigation on breast cancer care uptake across the continuum. If effective, the program may improve rates of early cancer detection and breast cancer morbidity. PMID- 27940187 TI - Study adaptation, design, and methods of a web-based PTSD intervention for women Veterans. AB - Women Veterans are a rapidly growing population with high risk of exposure to potentially traumatizing events and PTSD diagnoses. Despite the dissemination of evidence-based treatments for PTSD in the VA, most women Veteran VA users underutilize these treatments. Web-based PTSD treatment has the potential to reach and engage women Veterans with PTSD who do not receive treatment in VA settings. Our objective is to modify and evaluate Delivery of Self Training and Education for Stressful Situations (DESTRESSS), a web-based cognitive-behavioral intervention for PTSD, to target PTSD symptoms among women Veterans. The specific aims are to: (1) obtain feedback about DESTRESS, particularly on its relevance and sensitivity to women, using semi-structured interviews with expert clinicians and women Veterans with PTSD, and make modifications based on this feedback; (2) conduct a pilot study to finalize study procedures and make further refinements to the intervention; and (3) conduct a randomized clinical trial (RCT) evaluating a revised, telephone-assisted DESTRESS compared to telephone monitoring only. We describe the results from the first two aims, and the study design and procedures for the ongoing RCT. This line of research has the potential to result in a gender-sensitive, empirically-based, online treatment option for women Veterans with PTSD. PMID- 27940188 TI - Effectiveness of adjunctive, personalised psychosocial intervention for non response to opioid agonist treatment: Study protocol for a pragmatic randomised controlled trial. AB - INTRODUCTION: Opioid use disorder (OUD) is a debilitating and relapsing psychiatric disorder; opioid agonist therapy (OAT) is the front-line, evidence supported treatment. A substantial number of patients relapse or continue to use heroin or other illicit drugs during OAT. There is considerable heterogeneity in the OAT-resistant sub-population, with many behavioural moderators of treatment response. We have developed a personalised psychosocial intervention (PSI) targeting these individuals. A formulation-guided assessment is linked to a toolkit of motivational, cognitive/behavioural and social support techniques. Change methods have been adapted from evidence-supported psychological therapies and are idiosyncratically tailored to the need and response. METHODS: In this single-centre, 18-week, parallel group, pragmatic randomised clinical trial, we will determine the clinical and cost-effectiveness of the PSI as an adjunctive intervention during OAT, in comparison to opioid agonist treatment-as-usual. We plan to recruit 368 adults. The primary outcome measure is the proportion of participants categorised as 'responders' at the end of the intervention (defined as self-reported abstinence from heroin and cocaine with no positive biological drug tests during the 28days prior to the endpoint). Secondary outcomes include: percentage of days abstinent from heroin and cocaine in the 28days before follow up; treatment retention; therapy compliance; health and social functioning; exploratory genetic biomarkers; and analyses of treatment moderation and mediation. CONCLUSIONS: This pragmatic controlled trial determines the effectiveness and cost-effectiveness of a personalised PSI for non-responding patients during OAT. Our intervention applies motivational, cognitive/behavioural and social support techniques adapted from evidence-based therapies. Findings will inform stratified delivery of OAT. PMID- 27940189 TI - Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. AB - BACKGROUND: The global burden of sepsis is estimated as 15 to 19 million cases annually, with a mortality rate approaching 60% in low-income countries. METHODS: In this retrospective before-after clinical study, we compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a 7-month period (treatment group) with a control group treated in our ICU during the preceding 7 months. The primary outcome was hospital survival. A propensity score was generated to adjust the primary outcome. RESULTS: There were 47 patients in both treatment and control groups, with no significant differences in baseline characteristics between the two groups. The hospital mortality was 8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group (P < .001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI, 0.04-0.48; P = .002). The Sepsis-Related Organ Failure Assessment score decreased in all patients in the treatment group, with none developing progressive organ failure. All patients in the treatment group were weaned off vasopressors, a mean of 18.3 +/- 9.8 h after starting treatment with the vitamin C protocol. The mean duration of vasopressor use was 54.9 +/- 28.4 h in the control group (P < .001). CONCLUSIONS: Our results suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine, are effective in preventing progressive organ dysfunction, including acute kidney injury, and in reducing the mortality of patients with severe sepsis and septic shock. Additional studies are required to confirm these preliminary findings. PMID- 27940190 TI - Percent Emphysema and Daily Motor Activity Levels in the General Population: Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: COPD is associated with reduced physical capacity. However, it is unclear whether pulmonary emphysema, which can occur without COPD, is associated with reduced physical activity in daily life, particularly among people without COPD and never smokers. We hypothesized that greater percentage of emphysema-like lung on CT scan is associated with reduced physical activity assessed by actigraphy and self-report. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants free of clinical cardiovascular disease from the general population. Percent emphysema was defined as percentage of voxels < -950 Hounsfield units on full-lung CT scans. Physical activity was measured by wrist actigraphy over 7 days and a questionnaire. Multivariable linear regression was used to adjust for age, sex, race/ethnicity, height, weight, education, smoking, pack-years, and lung function. RESULTS: Among 1,435 participants with actigraphy and lung measures, 47% had never smoked, and 8% had COPD. Percent emphysema was associated with lower activity levels on actigraphy (P = .001), corresponding to 1.5 hour less per week of moderately paced walking for the average participant in quintile 2 vs 4 of percent emphysema. This association was significant among participants without COPD (P = .004) and among ever (P = .01) and never smokers (P = .03). It was also independent of coronary artery calcium and left ventricular ejection fraction. There was no evidence that percent emphysema was associated with self-reported activity levels. CONCLUSIONS: Percent emphysema was associated with decreased physical activity in daily life objectively assessed by actigraphy in the general population, among participants without COPD, and nonsmokers. PMID- 27940191 TI - The Power of Flash Mob Research: Conducting a Nationwide Observational Clinical Study on Capillary Refill Time in a Single Day. AB - BACKGROUND: Capillary refill time (CRT) is a clinical test used to evaluate the circulatory status of patients; various methods are available to assess CRT. Conventional clinical research often demands large numbers of patients, making it costly, labor-intensive, and time-consuming. We studied the interobserver agreement on CRT in a nationwide study by using a novel method of research called flash mob research (FMR). METHODS: Physicians in the Netherlands were recruited by using word-of-mouth referrals, conventional media, and social media to participate in a nationwide, single-day, "nine-to-five," multicenter, cross sectional, observational study to evaluate CRT. Patients aged >= 18 years presenting to the ED or who were hospitalized were eligible for inclusion. CRT was measured independently (by two investigators) at the patient's sternum and distal phalanx after application of pressure for 5 s (5s) and 15 s (15s). RESULTS: On October 29, 2014, a total of 458 investigators in 38 Dutch hospitals enrolled 1,734 patients. The mean CRT measured at the distal phalanx were 2.3 s (5s, SD 1.1) and 2.4 s (15s, SD 1.3). The mean CRT measured at the sternum was 2.6 s (5s, SD 1.1) and 2.7 s (15s, SD 1.1). Interobserver agreement was higher for the distal phalanx (kappa value, 0.40) than for the sternum (kappa value, 0.30). CONCLUSIONS: Interobserver agreement on CRT is, at best, moderate. CRT measured at the distal phalanx yielded higher interobserver agreement compared with sternal CRT measurements. FMR proved a valuable instrument to investigate a relatively simple clinical question in an inexpensive, quick, and reliable manner. PMID- 27940193 TI - Nano-shape varied cerium oxide nanomaterials rescue human dental stem cells from oxidative insult through intracellular or extracellular actions. AB - : Cerium oxide nanomaterials (CeNMs), due to their excellent scavenging properties of reactive oxygen species (ROS), have gained great promise for therapeutic applications. A high level of ROS often degrades the potential of stem cells in terms of survivability, maintenance and lineage differentiation. Here we hypothesize the CeNMs may play an important role in protecting the capacity of stem cells against the oxidative insult, and the suppression mechanism of ROS level may depend on the internalization of CeNMs. We synthesized CeNMs with different directional shapes (aspect ratios) by a pH-controlled hydrothermal method, and treated them to stem cells derived from human dental pulp at various doses. The short CeNMs (nanoparticles and nanorods) were internalized rapidly to cells whereas long CeNMs (nanowires) were slowly internalized, which led to different distributions of CeNMs and suppressed the ROS levels either intracellularly or extracellularly under the H2O2-exposed conditions. Resultantly, the stem cells, when dosed with the CeNMs, were rescued to have excellent cell survivability; the damages in intracellular components including DNA fragmentation, lipid rupture and protein degradation were significantly alleviated. The findings imply that the ROS-scavenging events of CeNMs need special consideration of aspect ratio-dependent cellular internalization, and also suggest the promising use of CeNMs to protect stem cells from the ROS-insult environments, which can ultimately improve the stem cell potential for tissue engineering and regenerative medicine uses. STATEMENT OF SIGNIFICANCE: Oxidative stress governs many stem cell functions like self renewal and lineage differentiation, and the biological conditions involving tissue repair and disease cure where stem cell therapy is often needed. Here we demonstrate the unique role of cerium oxide nanomaterials (CeNMs) in rescuing stem cell survivability, migration ability, and intracellular components from oxidative stress. In particular, we deliver a novel finding that nano morphologically varied CeNMs show different mechanisms in their scavenging reactive oxygen species either intracellularly or extracellularly, and this is related with their different cellular internalizations. We used human dental pulp stem cells for the model study and proved the CeNMs were effective in controlling ROS level by means of scavenging intracellularly or extracellularly, which ultimately led to improving the intact therapeutic potential of stem cells. This work touches an important biological issue of nanomaterial interactions with stem cells under the conditions related with oxidative stress and the resultant damage. The correlation of shape factor in therapeutic nanomaterials with stem cell interaction and the oxidative stress-related functions will provide informative ideas in the design of CeNMs for cellular therapy. PMID- 27940192 TI - 3D bioprinting of urethra with PCL/PLCL blend and dual autologous cells in fibrin hydrogel: An in vitro evaluation of biomimetic mechanical property and cell growth environment. AB - OBJECTIVE: Urethral stricture is a common condition seen after urethral injury. The currently available treatments are inadequate and there is a scarcity of substitute materials used for treatment of urethral stricture. The traditional tissue engineering of urethra involves scaffold design, fabrication and processing of multiple cell types. METHODS: In this study, we have used 3D bioprinting technology to fabricate cell-laden urethra in vitro with different polymer types and structural characteristics. We hypothesized that use of PCL and PLCL polymers with a spiral scaffold design could mimic the structure and mechanical properties of natural urethra of rabbits, and cell-laden fibrin hydrogel could give a better microenvironment for cell growth. With using an integrated bioprinting system, tubular scaffold was formed with the biomaterials; meanwhile, urothelial cells (UCs) and smooth muscle cells (SMCs) were delivered evenly into inner and outer layers of the scaffold separately within the cell laden hydrogel. RESULTS: The PCL/PLCL (50:50) spiral scaffold demonstrated mechanical properties equivalent to the native urethra in rabbit. Evaluation of the cell bioactivity in the bioprinted urethra revealed that UCs and SMCs maintained more than 80% viability even at 7days after printing. Both cell types also showed active proliferation and maintained the specific biomarkers in the cell-laden hydrogel. CONCLUSION: These results provided a foundation for further studies in 3D bioprinting of urethral constructs that mimic the natural urethral tissue in mechanical properties and cell bioactivity, as well a possibility of using the bioprinted construct for in vivo study of urethral implantation in animal model. SIGNIFICANCE OF STATEMENTS: The 3D bioprinting is a new technique to replace traditional tissue engineering. The present study is the first demonstration that it is feasible to create a urethral construct. Two kinds of biomaterials were used and achieved mechanical properties equivalent to that of native rabbit urethra. Bladder epithelial cells and smooth muscle cells were loaded in hydrogel and maintained sufficient viability and proliferation in the hydrogel. The highly porous scaffold could mimic a natural urethral base membrane, and facilitate contacts between the printed epithelial cells and smooth muscle cells on both sides of the scaffold. These results provided a strong foundation for future studies on 3D bioprinted urethra. PMID- 27940194 TI - Endocytosis of cerium oxide nanoparticles and modulation of reactive oxygen species in human ovarian and colon cancer cells. AB - : Cerium oxide nanoparticles (nanoceria) are widely reported to be cytocompatible and modulate intracellular reactive oxygen species (ROS) in a range of different cell types. In this study, nanoceria (d=7 and 94nm) synthesised by flame spray pyrolysis did not affect the proliferation of SKOV3 human ovarian and WiDr human colon cancer cell lines over a 72h treatment period. The cellular accumulation of nanoceria was uniform and increased up to 24h post-treatment before decreasing. The uptake of nanoceria in both cell lines was energy-dependent and was found to occur via non-specific pathways as well as clathrin-coated vesicles and caveolae. Nanoceria were localised predominantly in the cytoplasm and, to a lesser extent, with clathrin, caveolin-1 and lysosomes. The intracellular trafficking varied with particle size, treatment time and cell type. The larger nanoceria were found to scavenge intracellular ROS to a greater extent than the smaller nanoceria, and ROS scavenging was found to increase with treatment time. Together these data demonstrated that the diameter of the nanoceria and the cell types determined their mechanisms of uptake and intracellular localisation, as well as their ROS scavenging effects. STATEMENT OF SIGNIFICANCE: Cerium oxide nanoparticles (nanoceria) are a promising biomaterial that can catalytically scavenge reactive oxygen species (ROS). Modulation of ROS may potentially minimise the inflammatory effects of cancer. However, the antioxidant properties of nanoceria are reported to be pH-dependent and, thus, dependent on their mechanisms of endocytosis. This study is the first to examine the effects of particle size on the uptake and intracellular trafficking of flame spray-synthesised nanoceria in human cancer cells. This study demonstrated that the particle diameter, treatment time and cell type determined the mechanisms of uptake and intracellular localisation of nanoceria, as well as their ROS scavenging effects. This study highlighted the importance of testing new nanoparticle systems rather than making assumptions based on previous uptake studies. PMID- 27940195 TI - Differential integrin expression regulates cell sensing of the matrix nanoscale geometry. AB - : The nanoscale geometry and topography of the extra-cellular matrix (ECM) is an important parameter controlling cell adhesion and phenotype. Similarly, integrin expression and the geometrical maturation of adhesions they regulate have been correlated with important changes in cell spreading and phenotype. However, how integrin expression controls the nanoscale sensing of the ECM geometry is not clearly understood. Here we develop a new nanopatterning technique, electrospun nanofiber lithography (ENL), which allows the production of a quasi-2D fibrous nanopattern with controlled dimensions (250-1000nm) and densities. ENL relies on electrospun fibres to act as a mask for the controlled growth of protein resistant polymer brushes. SEM, AFM and immunofluorescence imaging were used to characterise the resulting patterns and the adsorption of the extra-cellular matrix protein fibronectin to the patterned fibres. The control of adhesion formation was studied, as well as the remodelling and deposition of novel matrix. Cell spreading was found to be regulated by the size of fibres, similarly to previous observations made on circular nanopatterns. However, cell shape and polarity were more significantly affected. These changes correlated with important cytoskeleton reorganisation, with a gradual decrease in stress fibre formation as the pattern dimensions decrease. Finally, the differential expression of alphavbeta3 and alpha5beta1 integrins in engineered cell lines was found to be an important mediator of cell sensing of the nanoscale geometry of the ECM. STATEMENT OF SIGNIFICANCE: The novel nanofiber patterns developed in this study, via ENL, mimic the geometry and continuity of natural matrices found in the stroma of tissues, whilst preserving a quasi-2D character (to facilitate imaging and for comparison with other 2D systems such as micropatterned monolayers and circular nanopatches generated by colloidal lithography). These results demonstrate that the nanoscale geometry of the ECM plays an important role in regulating cell adhesion and that this is modulated by integrin expression. This is an important finding as it implies that the knowledge of the biochemical context underlying the integrin-mediated adhesive machinery of specific cell types should allow better design of biomaterials and biointerfaces. Indeed, changes in integrin expression are often associated with the control of cell proliferation and differentiation. PMID- 27940196 TI - Single-probe multistate detection of DNA via aggregation-induced emission on a graphene oxide platform. AB - : Graphene and graphene oxides (GO), or their reduced forms, have been introduced in a variety of biosensing platforms and have exhibited enhanced performance levels in these forms. We herein report a DNA sensing platform consisting of aggregation-induced emission (AIE) molecules and complementary DNA (comDNA) adsorbed on GO. We experimentally turned the AIE molecule on and off by adjusting its distance, which correlates with DNA structures as shown in our computational results, from the GO sheet, which quenches depending on its distance from the graphene plane. The changes in florescence are reproducible, which demonstrates the probe's ability to identify the binding state of the DNA. Our molecular dynamics simulation results reveal strong pi-pi interactions between single strand DNA (ssDNA) and GO, which enable the ssDNA molecule to move closer to the graphene oxide. This reduces the center of mass and binding free energies in the simulation. When hybridized with comDNA, the increased distance, evidenced by the reduced interaction, eliminates the quenching effect and turns on the AIE molecule. Our protocol use of the AIE molecule as a probe thus avoids the complicated steps involved in covalent functionalization and allows the rapid and label-free detection of DNA molecules. STATEMENT OF SIGNIFICANCE: A simple, rapid method of fluorescent measurement of DNA hybridization in the presence of graphene (oxide) is presented. Conventional fluorescent dyes offer high performance in biosensors. However, labeling procedures are synthetically demanding in time and resources making it less cost-effective. Molecules with aggregation-induced-emission (AIE) property have advantages over traditional fluorescent molecules because of their intrinsic preference for detection as a turn-on probe and their single-molecule detection ability. Previous work has shown AIE dyes act as excellent "label-free" bioprobes with high sensitivity but with limited selectivity. Graphene oxide (GO) with its unique optical properties and affinity to different kinds of biomolecules can be used as an auxiliary to enhance selectivity of AIE dyes. In this work, we report a label-free strategy to detect DNA of particular sequence by water-soluble AIE probes with the aid of GO, supported by the computational explanations for this phenomenon. PMID- 27940198 TI - Osteoclast differentiation from human blood precursors on biomimetic calcium phosphate substrates. AB - : The design of synthetic bone grafts to foster bone formation is a challenge in regenerative medicine. Understanding the interaction of bone substitutes with osteoclasts is essential, since osteoclasts not only drive a timely resorption of the biomaterial, but also trigger osteoblast activity. In this study, the adhesion and differentiation of human blood-derived osteoclast precursors (OCP) on two different micro-nanostructured biomimetic hydroxyapatite materials consisting in coarse (HA-C) and fine HA (HA-F) crystals, in comparison with sintered stoichiometric HA (sin-HA, reference material), were investigated. Osteoclasts were induced to differentiate by RANKL-containing supernatant using cell/substrate direct and indirect contact systems, and calcium (Ca++) and phosphorus (P5+) in culture medium were measured. We observed that OCP adhered to the experimental surfaces, and that osteoclast-like cells formed at a rate influenced by the micro- and nano-structure of HA, which also modulate extracellular Ca++. Qualitative differences were found between OCP on biomimetic HA-C and HA-F and their counterparts on plastic and sin-HA. On HA-C and HA-F cells shared typical features of mature osteoclasts, i.e. podosomes, multinuclearity, tartrate acid phosphatase (TRAP)-positive staining, and TRAP5b enzyme release. However, cells were less in number compared to those on plastic or on sin-HA, and they did not express some specific osteoclast markers. In conclusion, blood-derived OCP are able to attach to biomimetic and sintered HA substrates, but their subsequent fusion and resorptive activity are hampered by surface micro-nano-structure. Indirect cultures suggest that fusion of OCP is sensitive to topography and to extracellular calcium. STATEMENT OF SIGNIFICANCE: The novelty of the paper is the differentiation of human blood-derived osteoclast precursors, instead of mouse-derived macrophages as used in most studies, directly on biomimetic micro-nano structured HA-based surfaces, as triggered by osteoblast-produced factors (RANKL/OPG), and influenced by chemistry and topography of the substrate(s). Biomimetic HA-surfaces, like those obtained in calcium phosphate cements, are very different from the conventional calcium phosphate ceramics, both in terms of topography and ion exchange. The role of these factors in modulating precursors' differentiation and activity is analysed. The system is closely reproducing the physiological process of attachment of host cells and further maturation to osteoclasts toward resorption of the substrate, which occurs in vivo after filling bone defects with the calcium phosphate grafts. PMID- 27940197 TI - Delivery vehicle effects on bone regeneration and heterotopic ossification induced by high dose BMP-2. AB - : Bone morphogenetic protein-2 (BMP-2), delivered on absorbable collagen sponge, is frequently used to treat bone defects. However, supraphysiological BMP-2 doses are common and often associated with complications such as heterotopic ossification and inflammation, causing pain and impaired mobility. This has prompted investigations into strategies to spatially control bone regeneration, for example growth factor delivery in appropriate scaffolds. Our objective was to investigate the spatiotemporal effects of high dose BMP-2 on bone regeneration as a function of the delivery vehicle. We hypothesized that an alginate delivery system would spatially restrict bone formation compared to a collagen sponge delivery system. In vitro, BMP-2 release was accelerated from collagen sponge compared to alginate constructs. In vivo, bone regeneration was evaluated over 12weeks in critically sized rat femoral segmental defects treated with 30MUg rhBMP-2 in alginate hydrogel or collagen sponge, surrounded by perforated nanofiber meshes. Total bone volume, calculated from micro-CT reconstructions, was higher in the alginate group at 12weeks. Though bone volume within the central defect region was greater in the alginate group at 8 and 12weeks, heterotopic bone volume was similar between groups. Likewise, mechanical properties from ex vivo torsional testing were comparable between groups. Histology corroborated these findings and revealed heterotopic mineralization at 2weeks post-surgery in both groups. Overall, this study recapitulated the heterotopic ossification associated with high dose BMP-2 delivery, and demonstrated that the amount and spatial pattern of bone formation was dependent on the delivery matrix. STATEMENT OF SIGNIFICANCE: Alginate hydrogel-based BMP-2 delivery has induced better spatiotemporal bone regeneration in animals, compared to clinically used collagen sponge, at lower BMP-2 doses. Lack of clear dose response relationships for BMP-2 vis-a-vis bone regeneration has contributed to the use of higher doses clinically. We investigated the potential of the alginate system, with comparatively favorable BMP-2 release-kinetics, to reduce heterotopic ossification and promote bone regeneration, when used with a high BMP 2 dose. While defect mineralization improved with alginate hydrogel, the initial high-release phase and likely early tissue exposure to BMP-2 appeared sufficient to induce heterotopic ossification. The characterization presented here should provide the framework for future evaluations of strategies to optimize bone formation and minimize adverse effects of high dose BMP-2 therapy. PMID- 27940199 TI - Nodular lymphoid hyperplasia complicated with ileal Burkitt's lymphoma in an adult patient with selective IgA deficiency. AB - INTRODUCTION: Primary lymphomas of the small intestine are rare. Burkitt's lymphoma (BL) occurs sporadically in adults. Nodular lymphoid hyperplasia (NLH) is a rare disorder characterized by diffuse nodular lesions, which represent hyperplastic lymphoid follicles, and it is often associated with immunodeficiency syndromes. PRESENTATION OF CASE: We present a 38-year-old male patient in a state of surgical emergency, suspected of Crohn's disease, who had an unusual combination of NLH and BL of the proximal ileum. Furthermore, retrospectively analyzed documentation revealed selective IgA deficiency. DISCUSSION: Association between NLH and intestinal lymphomas in patients with immunodeficiency syndromes was indicated before. This case report supports the notion on NLH as a transition state between immunodeficiency and intestinal lymphomas. CONCLUSION: This is one of the first case reports which presents the combination of NHL and BL. The awareness of the existence of this rare combination, especially in young adult males, can improve the diagnostic accuracy and the treatment management. PMID- 27940200 TI - Polyunsaturated fatty acids and suicide risk in mood disorders: A systematic review. AB - Deficiency of omega-3 polyunsaturated fatty acids (PUFAs) and an alteration between the ratio of omega-3 and omega-6 PUFAs may contribute to the pathogenesis of bipolar disorder and unipolar depression. Recent epidemiological studies have also demonstrated an association between the depletion of PUFAs and suicide. Our aim was to investigate the relationship between PUFAs and suicide; assess whether the depletion of PUFAs may be considered a risk factor for suicidal behavior; in addition to detailing the potential use of PUFAs in clinical practice. We performed a systematic review on PUFAs and suicide in mood disorders, searching MedLine, Excerpta Medica, PsycLit, PsycInfo, and Index Medicus for relevant epidemiological, post-mortem, and clinical studies from January 1997 to September 2016. A total of 20 articles from peer-reviewed journals were identified and selected for this review. The reviewed studies suggest that subjects with psychiatric conditions have a depletion of omega-3 PUFAs compared to control groups. This fatty acid depletion has also been found to contribute to suicidal thoughts and behavior in some cases. However, large epidemiological studies have generally not supported this finding, as the depletion of omega-3 PUFAs was not statistically different between controls and patients diagnosed with a mental illness and/or who engaged in suicidal behavior. Increasing PUFA intake may be relevant in the treatment of depression, however in respect to the prevention of suicide, the data is currently not supportive of this approach. Changes in levels of PUFAs may however be a risk factor to evaluate when assessing for suicide risk. Clinical studies should be conducted to prospectively assess whether prescriptive long-term use of PUFAs in PUFA-deficient people with depression, may have a preventative role in attenuating suicide. PMID- 27940201 TI - Development of real-time immuno-PCR for the quantitative detection of mycobacterial PstS1 in tuberculosis patients. AB - A novel indirect real-time immuno-polymerase chain reaction (RT-I-PCR) assay, an evolution of I-PCR, was developed for the quantitative detection of Mycobacterium tuberculosis PstS1 (Rv0934) with a wide dynamic range of 10ng/mL to 1pg/mL in body fluids of tuberculosis (TB) patients, which may monitor the dynamics of disease. PMID- 27940202 TI - The intellectual disability protein PAK3 regulates oligodendrocyte precursor cell differentiation. AB - Oligodendrocyte and myelin deficits have been reported in mental/psychiatric diseases. The p21-activated kinase 3 (PAK3), a serine/threonine kinase, whose activity is stimulated by the binding of active Rac and Cdc42 GTPases is affected in these pathologies. Indeed, many mutations of Pak3 gene have been described in non-syndromic intellectual disability diseases. Pak3 is expressed mainly in the brain where its role has been investigated in neurons but not in glial cells. Here, we showed that PAK3 is highly expressed in oligodendrocyte precursors (OPCs) and its expression decreases in mature oligodendrocytes. In the developing white matter of the Pak3 knockout mice, we found defects of oligodendrocyte differentiation in the corpus callosum and to a lesser extent in the anterior commissure, which were compensated at the adult stage. In vitro experiments in OPC cultures, derived from Pak3 knockout and wild type brains, support a developmental and cell-autonomous role for PAK3 in regulating OPC differentiation into mature oligodendrocytes. Moreover, we did not detect any obvious alterations of the proliferation or migration of Pak3 null OPCs compared to wild type. Overall, our data highlight PAK3 as a new regulator of OPC differentiation. PMID- 27940203 TI - Cooperative synthesis of dopamine by non-dopaminergic neurons as a compensatory mechanism in the striatum of mice with MPTP-induced Parkinsonism. AB - Since the late 80s it has been repeatedly shown that besides dopaminergic neurons, the brain contains so-called monoenzymatic neurons possessing one of the enzymes of dopamine (DA) synthesis, tyrosine hydroxylase (TH) or aromatic l-amino acid decarboxylase (AADC). However, the data on the existence of monoenzymatic neurons in the striatum remain controversial, and little is known about their functional significance. The aim of this study was to test our hypothesis that monoenzymatic TH-containing neurons produce DA in cooperation with the neurons containing AADC, which might help to compensate DA deficiency under the failure of the nigrostriatal dopaminergic system. Using a combination of techniques: retrograde tracing, qPCR and immunolabeling for TH, AADC and MAP2, we showed that the striatum of mice with normal and degraded dopaminergic system comprises of monoenzymatic TH- and AADC-containing neurons. To provide evidence for cooperative synthesis of DA, we used an ex vivo model of inhibiting of DA synthesis by blocking transport of l-DOPA, produced in monoenzymatic TH containing neurons, to neurons containing AADC by means of l-leucine, a competitive inhibitor of the membrane transporter of large neutral amino acids, and l-DOPA. With this original approach, cooperative synthesis of DA in the striatum was proven in MPTP-treated mice but not in the control. Furthermore, we demonstrated that the proportion of DA produced through cooperative synthesis in the striatum of MPTP-treated mice increases as the degradation of dopaminergic system proceeds. An increase in the proportion of cooperative synthesis of DA alongside degradation of the dopaminergic system is also proved by an increase of both TH gene expression and the number of TH-immunoreactive structures in the striatum. Thus, these data suggest that the cooperative synthesis of DA in the degraded striatum is an up-regulated compensatory reaction, which plays an increasing role as DA deficiency rises, and might be considered among the principal mechanisms of neuroplasticity in neurodegenerative diseases. PMID- 27940205 TI - Re-calculating! Navigating through the osteosarcoma treatment roadblock. AB - The survival rates for patients with osteosarcoma have remained almost static for the past three decades. Current standard of care therapy includes chemotherapies such as doxorubicin, cisplatin, and methotrexate along with complete surgical resection and surgery with or without ifosfamide and etoposide for relapse, though outcomes are hoped to be improved through clinical trials. Additionally, increased understanding of the genetics, signaling pathways and microenvironmental factors driving the disease have led to the identification of promising agents and potential paths towards translation of an exciting array of novel targeted therapies. Here, we review the mechanism of action of these emerging therapies and how, with clinical translation, they can potentially improve the survival rates for osteosarcoma patients in the near future. PMID- 27940204 TI - Potentiation of hepatic stellate cell activation by extracellular ATP is dependent on P2X7R-mediated NLRP3 inflammasome activation. AB - Purinergic receptor P2x7 (P2x7R) is a key modulator of liver inflammation and fibrosis. The present study aimed to investigate the role of P2x7R in hepatic stellate cells activation. Lipopolysaccharide (LPS) or the conditioned medium (CM) from LPS-stimulated RAW 264.7 mouse macrophages was supplemented to human hepatic stellate cells, LX-2 for 24h and P2x7R selective antagonist A438079 (10MUM) was supplemented to LX-2 cells 1h before LPS or CM stimulation. In addition LX-2 cells were primed with LPS for 4h and subsequently stimulated for 30min with 3mM of adenosine 5'-triphosphate (ATP). A438079 was supplemented to LX 2 cells 10min prior to ATP. Directly treated with LPS on LX-2 cells, mRNA expressions of interleukin (IL)-1beta, IL-18 and IL-6 were increased, as well as mRNA expressions of P2x7R, caspase-1, apoptosis-associated speck-like protein containing CARD (ASC) and NOD-like receptor family, pyrin domain containing 3 (NLRP3) mRNA. LPS also increased alpha-smooth muscle actin (alpha-SMA) and type I collagen mRNA expressions, as well as collagen deposition. Interestingly treatment of LX-2 cells with LPS-activated CM exhibited the greater increase of above factors than those in LX-2 cells directly treated with LPS. Pretreatment of A438079 on LX-2 cells stimulated by LPS or LPS-activated CM both suppressed IL 1beta mRNA expression. LPS combined with ATP dramatically increased protein synthesis and cleavage of IL-1beta and its mRNA level than those in HSC treated with LPS or ATP alone. Additionally LX-2 cells primed with LPS and subsequently stimulated for 30min with ATP greatly increased mRNA and protein expression of caspase-1, NLRP3 and P2x7R, as well as liver fibrosis markers, alpha-SMA and type I collagen. These events were remarkably suppressed by A438079 pretreatment. siRNA against P2x7R reduced protein expression of NLRP3 and alpha-SMA, and suppressed deposition and secretion of type I collagen. The involvement of P2X7R mediated NLRP3 inflammasome activation in IL-1beta production of HSC might contribute to ECM deposition and suggests that blockade of the P2x7R-NLRP3 inflammasome axis represents a potential therapeutic target to liver fibrosis. PMID- 27940206 TI - Hydroxytyrosol ameliorates metabolic, cardiovascular and liver changes in a rat model of diet-induced metabolic syndrome: Pharmacological and metabolism-based investigation. AB - Metabolic syndrome is a clustering of interrelated risk factors for cardiovascular disease and diabetes. The Mediterranean diet has been proposed as an important dietary pattern to confer cardioprotection by attenuating risk factors of metabolic syndrome. Hydroxytyrosol (HT) is present in olive fruit and oil, which are basic constituents of the Mediterranean diet. In this study, we have shown that treatment with HT (20mg/kg/d for 8 weeks) decreased adiposity, improved impaired glucose and insulin tolerance, improved endothelial function with lower systolic blood pressure, decreased left ventricular fibrosis and resultant diastolic stiffness and reduced markers of liver damage in a diet induced rat model of metabolic syndrome. These results were accompanied by reduced infiltration of monocytes/macrophages into the heart with reduced biomarkers of oxidative stress. Furthermore, in an HRMS-based metabolism study of HT, we have identified 24 HT phase I and II metabolites, six of them being over produced in high-starch, low-fat diet fed rats treated with HT compared to obese rats on high-carbohydrate, high-fat diet. These results provide direct evidence for cardioprotective effects of hydroxytyrosol by attenuation of metabolic risk factors. The implications of altered metabolism of HT in high-carbohydrate, high fat diet fed obese rats warrant further investigation. PMID- 27940207 TI - Chromosome folding and its regulation in health and disease. AB - There are many ways in which cells may not adequately behave or respond to their environment, and the molecular mechanisms leading to these defects are as diverse as they are many. In this review, we report on how spatial chromatin organization contributes to the proper expression of genes, relating how CTCF-one of its main architects-contributes to gene regulation. We also touch on the emerging role of long noncoding RNAs in shaping chromatin organization and activity. The HOX gene clusters have been used as paradigm in the study of various biological pathways, and the overview we provide gives emphasis to what research on these loci has revealed about chromatin architecture and its regulation in the control of gene expression. PMID- 27940208 TI - H3K27 methylation: a promiscuous repressive chromatin mark. AB - Polycomb Repressive Complex 2 (PRC2) is a multiprotein complex that catalyzes the methylation of lysine 27 on histone H3 (H3K27me). This histone modification is a feature of facultative heterochromatin in many eukaryotes and maintains transcriptional repression established during early development. Understanding how PRC2 targets regions of the genome to be methylated remains poorly understood. Different cell types can show disparate patterns of H3K27me, and chromatin perturbations, such as loss of marks of constitutive heterochromatin, can cause redistribution of H3K27me, implying that DNA sequence, per se, is not sufficient to define the distribution of this mark. Emerging information supports the idea that the chromatin context-including histone modifications, DNA methylation, transcription, chromatin structure and organization within the nucleus-informs PRC2 target selection. PMID- 27940209 TI - An integrated model for motor control of song in Serinus canaria. AB - Birdsong is a learned motor behavior controlled by an interconnected structure of neural nuclei. This pathway is bilaterally organized, with anatomically indistinguishable structures in each brain hemisphere. In this work, we present a computational model whose variables are the average activities of different neural nuclei of the song system of oscine birds. Two of the variables are linked to the air sac pressure and the tension of the labia during canary song production. We show that these time dependent gestures are capable of driving a model of the vocal organ to synthesize realistic canary like songs. PMID- 27940210 TI - Magnetic orientation in C. elegans relies on the integrity of the villi of the AFD magnetosensory neurons. AB - The magnetic field of the earth provides many organisms with sufficient information to successfully navigate through their environments. While evidence suggests the widespread use of this sensory modality across many taxa, it remains an understudied sensory modality. We have recently showed that the nematode C. elegans orients to earth-strength magnetic fields using the first pair of described magnetosensory neurons, AFDs. The AFD cells are a pair of ciliated sensory neurons crowned by fifty villi known to be implicated in temperature sensation. We investigated the potential importance of these subcellular structures for the performance of magnetic orientation. We show that ciliary integrity and villi number are essential for magnetic orientation. Mutants with impairments AFD cilia or villi structure failed to orient to magnetic fields. Similarly, C. elegans larvae possessing immature AFD neurons with fewer villi were also unable to orient to magnetic fields. Larvae of every stage however retained the ability to orient to thermal gradients. To our knowledge, this is the first behavioral separation of magnetic and thermal orientation in C. elegans. We conclude that magnetic orientation relies on the function of both cilia and villi in the AFD neurons. The role of villi in multiple sensory transduction pathways involved in the sensory transduction of vectorial stimuli further supports the likely role of the villi of the AFD neurons as the site for magnetic field transduction. The genetic and behavioral tractability of C. elegans make it a promising system for uncovering potentially conserved molecular mechanisms by which animals across taxa detect and orient to magnetic fields. PMID- 27940211 TI - Fibrin/fibrinogen degradation products (FDP) at hospital admission predict neurological outcomes in out-of-hospital cardiac arrest patients. AB - OBJECTIVE: This study aimed to test the hypothesis that coagulation, fibrinolytic markers and disseminated intravascular coagulation (DIC) score (International Society on Thrombosis and Haemostasis) at hospital admission of out-of-hospital cardiac arrest (OHCA) patients can predict neurological outcomes 1 month after cardiac arrest. METHODS: In this retrospective, observational analysis, data were collected from the Sapporo Utstein Registry and medical records at Hokkaido University Hospital. We included patients who experienced OHCA with successful return of spontaneous circulation (ROSC) between 2006 and 2012 and were transferred to Hokkaido University Hospital. From medical records, we collected information about the following coagulation and fibrinolytic factors at hospital admission: platelet count; prothrombin time; activated partial thromboplastin time; plasma levels of fibrinogen, D-dimer, fibrin/fibrinogen degradation products (FDP), and antithrombin; and calculated DIC score. Favorable neurological outcomes were defined as a cerebral performance category 1-2. RESULTS: We analyzed data for 315 patients. Except for fibrinogen level, all coagulation variables, fibrinolytic variables, and DIC score were associated with favorable neurological outcomes. In the receiver operating characteristic curve analysis, FDP level had the largest area under the curve (AUC; 0.795). In addition, the AUC of FDP level was larger than that of lactate level. CONCLUSIONS: All of the coagulation and fibrinolytic markers, except for fibrinogen level, and DIC score at hospital admission, were associated with favorable neurological outcomes. Of all of the variables, FDP level was most closely associated with favorable neurological outcomes in OHCA patients who successfully achieved ROSC. PMID- 27940213 TI - Whole genome sequencing of Fowl aviadenovirus A - a causative agent of gizzard erosion and ulceration, in adult laying hens. AB - Gizzard erosion and ulceration (GEU) caused by fowl aviadenovirus serotype 1 (FAdV-1) of the species Fowl aviadenovirus A (FAdV-A) represents an economically important problem in poultry production. The disease affects mostly young chicken broilers or layers before production. In this study, an unusual GEU outbreak in a flock of laying hens at 38weeks of age is described. The affected flock showed elevated mortality rates, with the highest number of dead birds appearing between the 39th and 40th week of life, with a subsequent reduction in laying performance and decreased total egg weight. Post-mortem examination showed the presence of erosion in multiple areas of the gizzard, with wall perforation in the proximity of the interventriculus. FAdV antibodies were detected in all examined sera with an ELISA assay. The virus was isolated from pathologically altered gizzards. PCR, subsequent sequencing and phylogenetic analysis of the partial hexon gene confirmed the presence of FAdV-A DNA. To investigate the molecular background of FAdV-A which causes GEU in adult hens, whole genome sequencing was performed on two FAdV-A strains - strain W-15, obtained from the outbreak described in this study and strain 61/11z, isolated from a GEU outbreak in 3-week-old broiler chickens in 2011. The genome size of FAdV-A W-15 is 43,849bp. Genome sequence and genome organization resembles those of the reference, apathogenic CELO strain and the newly sequenced GEU strain, 61/11z. Most amino acid changes, between CELO and GEU strains, were observed in ORF0, ORF1, ORF14, IVa2, polymerase, pIIIa, penton base and fiber-2. Analysis conducted on the translated ORFs revealed that W-15 and 61/11z are nearly identical, with the highest rate of amino acid mutations in pTP, 100K, ORF9 and ORF10. In this study, the occurrence of GEU, caused by FAdV-1 infection, in adult layer chickens and the effects of such infection on egg production parameters are described in detail. Moreover, the whole genome sequences of two pathogenic, GEU inducing FAdV-A strains have been provided and characterized for the first time, which in the future will help to pinpoint the viral factors involved in pathogenicity. PMID- 27940212 TI - The categories, frequencies, and stability of idiosyncratic eye-movement patterns to faces. AB - The spatial pattern of eye-movements to faces considered typical for neurologically healthy individuals is a roughly T-shaped distribution over the internal facial features with peak fixation density tending toward the left eye (observer's perspective). However, recent studies indicate that striking deviations from this classic pattern are common within the population and are highly stable over time. The classic pattern actually reflects the average of these various idiosyncratic eye-movement patterns across individuals. The natural categories and respective frequencies of different types of idiosyncratic eye movement patterns have not been specifically investigated before, so here we analyzed the spatial patterns of eye-movements for 48 participants to estimate the frequency of different kinds of individual eye-movement patterns to faces in the normal healthy population. Four natural clusters were discovered such that approximately 25% of our participants' fixation density peaks clustered over the left eye region (observer's perspective), 23% over the right eye-region, 31% over the nasion/bridge region of the nose, and 20% over the region spanning the nose, philthrum, and upper lips. We did not find any relationship between particular idiosyncratic eye-movement patterns and recognition performance. Individuals' eye movement patterns early in a trial were more stereotyped than later ones and idiosyncratic fixation patterns evolved with time into a trial. Finally, while face inversion strongly modulated eye-movement patterns, individual patterns did not become less distinct for inverted compared to upright faces. Group-averaged fixation patterns do not represent individual patterns well, so exploration of such individual patterns is of value for future studies of visual cognition. PMID- 27940214 TI - Extensive genetic diversity among populations of the malaria mosquito Anopheles moucheti revealed by population genomics. AB - Malaria vectors are exposed to intense selective pressures due to large-scale intervention programs that are underway in most African countries. One of the current priorities is therefore to clearly assess the adaptive potential of Anopheline populations, which is critical to understand and anticipate the response mosquitoes can elicit against such adaptive challenges. The development of genomic resources that will empower robust examinations of evolutionary changes in all vectors including currently understudied species is an inevitable step toward this goal. Here we constructed double-digest Restriction Associated DNA (ddRAD) libraries and generated 6461 Single Nucleotide Polymorphisms (SNPs) that we used to explore the population structure and demographic history of wild caught Anopheles moucheti from Cameroon. The genome-wide distribution of allelic frequencies among samples best fitted that of an old population at equilibrium, characterized by a weak genetic structure and extensive genetic diversity, presumably due to a large long term effective population size. Estimates of FST and Linkage Disequilibrium (LD) across SNPs reveal a very low genetic differentiation throughout the genome and the absence of segregating LD blocks among populations, suggesting an overall lack of local adaptation. Our study provides the first investigation of the genetic structure and diversity in An. moucheti at the genomic scale. We conclude that, despite a weak genetic structure, this species has the potential to challenge current vector control measures and other rapid anthropogenic and environmental changes thanks to its great genetic diversity. PMID- 27940215 TI - HTLV-1aA introduction into Brazil and its association with the trans-Atlantic slave trade. AB - INTRODUCTION: Human T-lymphotropic virus (HTLV) is an endemic virus in some parts of the world, with Africa being home to most of the viral genetic diversity. In Brazil, HTLV-1 is endemic amongst Japanese and African immigrant populations. Multiple introductions of the virus in Brazil from other epidemic foci were hypothesized. The long terminal repeat (LTR) region of HTLV-1 was used to infer the origin of the virus in Brazil, using phylogenetic analysis. METHODS: LTR sequences were obtained from the HTLV-1 database (http://htlv1db.bahia.fiocruz.br). Sequences were aligned and maximum-likelihood and Bayesian tree topologies were inferred. Brazilian specific clusters were identified and molecular-clock and coalescent models were used to estimate each cluster's time to the most recent common ancestor (tMRCA). RESULTS: Three Brazilian clusters were identified with a posterior probability ranged from 0.61 to 0.99. Molecular clock analysis of these three clusters dated back their respective tMRCAs between the year 1499 and the year 1668. Additional analysis also identified a close association between Brazilian sequences and new sequences from South Africa. CONCLUSION: Our results support the hypothesis of a multiple introductions of HTLV-1 into Brazil, with the majority of introductions occurring in the post-Colombian period. Our results further suggest that HTLV-1 introduction into Brazil was facilitated by the trans-Atlantic slave trade from endemic areas of Africa. The close association between southern African and Brazilian sequences also suggested that greater numbers of the southern African Bantu population might also have been part of the slave trade than previously thought. PMID- 27940216 TI - Incidence, prevalence, natural course and prognosis of patellofemoral osteoarthritis: the Cohort Hip and Cohort Knee study. AB - OBJECTIVE: To examine the proportion of isolated patellofemoral osteoarthritis (PFOA) compared to tibiofemoral osteoarthritis (TFOA) in middle-aged participants with early osteoarthritis (OA) symptoms of the knee; to describe the natural course of PFOA compared with that of TFOA and to identify whether patients with PFOA have a different phenotype compared to patients with TFOA, or with combined PFOA and TFOA (combined osteoarthritis (COA)). DESIGN: Participants with early OA symptoms of the knee were selected, completed questionnaires, underwent physical examination, and had knee radiographs at baseline, and at 2 and 5 years follow up. Based on radiographs, participants were classified as having isolated TFOA, isolated PFOA, COA, or no radiographic OA. Multivariate logistic regression was used to identify participant characteristics associated with a specific group of OA at 2 years follow-up. RESULTS: The cohort comprised 845 participants (mean age 55.9 years). At baseline, 116 had PFOA, none had TFOA or COA. Of these 116 participants, 66.3% had developed COA at 5 years follow-up. At 2 years follow-up, PFOA, TFOA and COA were present in 77 (10.8%), 39 (5.5%) and 83 (11.6%) participants, respectively. Multivariate regression analyses at 2 years follow-up showed that participants with radiographic PFOA or TFOA were not significantly different from each other with respect to signs and symptoms. CONCLUSIONS: These results suggest that OA is more likely to start in the patellofemoral joint and then progress to COA in individuals with symptoms of early knee OA. No differences in TFOA and PFOA phenotypes were determined with respect to signs and symptoms. PMID- 27940217 TI - Ants and antlions: The impact of ecology, coevolution and learning on an insect predator-prey relationship. AB - A behavioural ecological approach to the relationship between pit-digging larval antlions and their common prey, ants, provides yet another example of how the specific ecological niche that species inhabit imposes selection pressures leading to unique behavioural adaptations. Antlions rely on multiple strategies to capture prey with a minimal expenditure of energy and extraordinary efficiency while ants employ several different strategies for avoiding capture, including rescue of trapped nestmates. Importantly, both ants and antlions rely heavily on their capacity for learning, a tool that sometimes is overlooked in predator-prey relationships, leading to the implicit assumption that behavioural adaptations are the result of fixed, hard-wired responses. Nonetheless, like hard-wired responses, learned behaviour, too, is uniquely adapted to the ecological niche, a reminder that the expression of associative learning is species-specific. Beyond the study of ants and antlions, per se, this particular predator-prey relationship reveals the important role that the capacity to learn plays in coevolutionary arms races. PMID- 27940219 TI - Anoctamin2 (TMEM16B) forms the Ca2+-activated Cl- channel in the retinal pigment epithelium. AB - Chloride channels (Cl channels) play an essential role for the retinal pigment epithelium (RPE). They provide a plasma membrane conductance for Cl- important for transepithelial transport and volume regulation. Ca2+-dependent chloride channels (CaCC) in the RPE were found to adapt Cl- transport to specific needs by increasing intracellular free Ca2+. Although a variety of Cl channels have been identified in the RPE, the molecular identity of the CaCC remains controversial. Sagittal sections of mouse retina were stained against anoctamin2 (Ano2) and analyzed by confocal microscopy. Membrane currents from ARPE-19 cells and primary murine RPE cells were recorded in the whole-cell configuration of the patch-clamp technique. Expression of Ano2 was assessed via immunocytochemistry, PCR and western-blot and down-regulated via siRNA approaches. In the mouse retina, Ano2 was found in the basolateral membrane of the RPE. In primary mouse RPE cells, Ano2 was localized predominantly in the cell membrane. Ano2 mRNA and protein were also detected in rat and primate RPE as well as ARPE-19 cells. Whole-cell currents were elicited by increasing intracellular free Ca2+ via ATP application. These currents were identified as Cl- currents by their reversal potential and blocker sensitivity. Knock-down of Ano2 by siRNA decreased both the Ca2+ dependent chloride conductance and protein expression of Ano2. The biophysical and pharmacological properties of CaCC in ARPE-19 and primary mouse RPE cells resemble those described in previous publications using RPE cells from different species. The siRNA knock-down suggests that Ano2 contributes to Ca2+-dependent chloride conductance in the RPE. PMID- 27940218 TI - Multiplex assay reliability and long-term intra-individual variation of serologic inflammatory biomarkers. AB - BACKGROUND: Circulating cytokines, chemokines, and soluble cytokine receptors can serve as biomarkers of inflammation and immune dysregulation. Good reliability of multiplex platforms, which allow for simultaneous, comprehensive biomarker assessment, is critical for their utility in epidemiologic studies. We examined the reliability of the Meso-Scale Discovery (MSD) platform to simultaneously quantitate 15 cytokines and chemokines and the Luminex platform (R&D Systems) to quantitate 5 soluble receptors and 2 chemokines and cytokines and evaluated long term within-person correlation of these biomarkers. METHODS: The detectability and reliability of these assay systems were assessed using the same external controls across plates and archived sera from 250 HIV- men in the Multicenter AIDS Cohort Study. Using up to four visits per person from 1984 to 2009, age adjusted intraclass correlation coefficients (ICC) of biomarkers with >80% detectability (CCL11, CXCL8, CXCL10, CCL2, CCL4, CCL13, CCL17, CXCL13, IL-10, IL 12p70, IL-6, TNF-alpha, BAFF, sCD14, sCD27, sgp130, sIL-2Ralpha, and sTNF-R2) were obtained using linear mixed models. RESULTS: Most biomarkers were detectable in 80% of control samples; IFN-gamma, GM-CSF, and IL-2 were undetectable in >20% of samples. Among the HIV-uninfected men, most biomarkers showed fair to strong within-person correlation (ICC>0.40) up to 15years. The ICC for CXCL8 was good in the short term but decreased with increasing time between visits, becoming lower (ICC<0.40) after 8years. CONCLUSIONS: These multiplexed assays showed acceptable reliability for use in epidemiologic research, despite some technical variability and limitations in cytokine quantitation. Most biomarkers displayed moderate-to excellent intra-individual variability over the long term, suggesting their utility in prospective studies investigating etiologic associations with diverse chronic conditions. PMID- 27940220 TI - An Acrodermatitis Enteropathica-Associated Zn Transporter, ZIP4, Regulates Human Epidermal Homeostasis. AB - Acrodermatitis enteropathica is an autosomal recessive disorder characterized by scaly eczematous dermatosis accompanied by alopecia and diarrhea. Various mutations in the SLC39A4 gene (ZIP4), which encodes a zinc transporter, are responsible for this disorder. However, the molecular mechanism underlying the involvement of ZIP4 in the pathogenesis of this condition has yet to be established. In this study, we report the role of ZIP4 in human epidermis. ZIP4 is predominantly expressed in human keratinocytes, and its expression is dramatically reduced on epidermal differentiation. ZIP4 knockdown in human keratinocytes down-regulates zinc (Zn) levels and the transcriptional activity of a key epidermal Zn-binding protein, DeltaNp63, and dysregulates epidermal differentiation in a reconstituted human skin model, resulting in the appearance of proliferating keratinocytes even in the uppermost layers of the skin. We verified that, among the amino acid residues in its Zn-binding motif, Cys205 is critical for the processing and nuclear distribution of DeltaNp63 and, therefore, Zn-dependent transcriptional activity. Our results suggest that ZIP4 is essential for maintaining human epidermal homeostasis through the regulation of Zn dependent DeltaNp63 activity and can provide insight into the molecular mechanisms responsible for the cutaneous symptoms observed in Acrodermatitis enteropathica patients. PMID- 27940221 TI - Prenatal Risk Factors for Infantile Hemangioma Development. PMID- 27940222 TI - Vasotocin increases dominance in the weakly electric fish Brachyhypopomus gauderio. AB - Animals establish social hierarchies through agonistic behavior. The recognition of the own and others social ranks is crucial for animals that live in groups to avoid costly constant conflicts. Weakly electric fish are valuable model systems for the study of agonistic behavior and its neuromodulation, given that they display conspicuous electrocommunication signals that are generated by a very well-known electromotor circuit. Brachyhypopomus gauderio is a gregarious electric fish, presents a polygynous breeding system, morphological and electrophysiological sexual dimorphism during the breeding season, and displays a typical intrasexual reproduction-related aggression. Dominants signal their social status by increasing their electric organ discharge (EOD) rate after an agonistic encounter (electric dominance). Subordinates only occasionally produce transient electric signals (chirps and offs). The hypothalamic neuropeptide arginine-vasotocin (AVT) and its mammalian homologue, arginine- vasopressin (AVP) are key modulators of social behavior across vertebrates. In this study, we focus on the role of AVT on dominance establishment in Brachyhypopomus gauderio by analyzing the effects of pharmacological manipulations of the AVT system in potential dominants. AVT exerts a very specific direct effect restricted only to EOD rate, and is responsible for the electric dominance. Unexpectedly, AVT did not affect the intensity of aggression in either contender. Nor was the time structure affected by AVT administration. We also present two interesting examples of the interplay between contenders by evaluating how AVT modulations, even when directed to one individual, affect the behavior of the dyad as a unit. First, we found that V1a AVT receptor antagonist Manning Compound (MC) induces a reversion in the positive correlation between dominants' and subordinates' attack rates, observed in both control and AVT treated dyads, suggesting that an endogenous AVT tone modulates aggressive interactions. Second, we confirmed that AVT administered to dominants induces an increase in the submissive transient electric signals in subordinates. PMID- 27940223 TI - MOPS and coxsackievirus B3 stability. AB - Study of coxsackievirus B3 strain 28 (CVB3/28) stability using MOPS to improve buffering in the experimental medium revealed that MOPS (3-morpholinopropane-1 sulfonic acid) increased CVB3 stability and the effect was concentration dependent. Over the pH range 7.0-7.5, virus stability was affected by both pH and MOPS concentration. Computer-simulated molecular docking showed that MOPS can occupy the hydrophobic pocket in capsid protein VP1 where the sulfonic acid head group can form ionic and hydrogen bonds with Arg95 and Asn211 near the pocket opening. The effects of MOPS and hydrogen ion concentrations on the rate of virus decay were modeled by including corresponding parameters in a recent kinetic model. These results indicate that MOPS can directly associate with CVB3 and stabilize the virus, possibly by altering capsid conformational dynamics. PMID- 27940224 TI - The calmodulin antagonist W-7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride) inhibits DENV infection in Huh-7 cells. AB - Dengue virus (DENV) replicative cycle occurs in the endoplasmic reticulum where calcium ions play an important role in cell signaling. Calmodulin (CaM) is the primary sensor of intracellular Ca2+ levels in eukaryotic cells. In this paper, the effect of the calmodulin antagonist W-7 in DENV infection in Huh-7 cells was evaluated. W7 inhibited viral yield, NS1 secretion and viral RNA and protein synthesis. Moreover, luciferase activity, encoded by a DENV replicon, was also reduced. A decrease in the replicative complexes formation was clearly observed in W7 treated cells. Docking simulations suggest 2 possible mechanisms of action for W7: the direct inhibition of NS2B-NS3 activity and/or inhibition of the interaction between NS2A with Ca2+-CaM complex. This last possibility was supported by the in vitro interaction observed between recombinant NS2A and CaM. These results indicate that Ca2+-CaM plays an important role in DENV replication. PMID- 27940225 TI - Migration and interaction tracking for quantitative analysis of phagocyte pathogen confrontation assays. AB - Invasive fungal infections are emerging as a significant health risk for humans. The innate immune system is the first line of defense against invading micro organisms and involves the recruitment of phagocytes, which engulf and kill pathogens, to the site of infection. To gain a quantitative understanding of the interplay between phagocytes and fungal pathogens, live-cell imaging is a modern approach to monitor the dynamic process of phagocytosis in time and space. However, this requires the processing of large amounts of video data that is tedious to be performed manually. Here, we present a novel framework, called AMIT (algorithm for migration and interaction tracking), that enables automated high throughput analysis of multi-channel time-lapse microscopy videos of phagocyte pathogen confrontation assays. The framework is based on our previously developed segmentation and tracking framework for non-rigid cells in brightfield microscopy (Brandes et al., 2015). We here present an advancement of this framework to segment and track different cell types in different video channels as well as to track the interactions between different cell types. For the confrontation assays of polymorphonuclear neutrophils (PMNs) and Candida glabrata considered in this work, the main focus lies on the correct detection of phagocytic events. To achieve this, we introduced different PMN states and a state-transition model that represents the basic principles of phagocyte-pathogen interactions. The framework is validated by a direct comparison of the automatically detected phagocytic activity of PMNs to a manual analysis and by a qualitative comparison with previously published analyses (Duggan et al., 2105; Essig et al., 2015). We demonstrate the potential of our algorithm by comprehensive quantitative and multivariate analyses of confrontation assays involving human PMNs and the fungus C. glabrata. PMID- 27940226 TI - Direct and simultaneous estimation of cardiac four chamber volumes by multioutput sparse regression. AB - Cardiac four-chamber volume estimation serves as a fundamental and crucial role in clinical quantitative analysis of whole heart functions. It is a challenging task due to the huge complexity of the four chambers including great appearance variations, huge shape deformation and interference between chambers. Direct estimation has recently emerged as an effective and convenient tool for cardiac ventricular volume estimation. However, existing direct estimation methods were specifically developed for one single ventricle, i.e., left ventricle (LV), or bi ventricles; they can not be directly used for four chamber volume estimation due to the great combinatorial variability and highly complex anatomical interdependency of the four chambers. In this paper, we propose a new, general framework for direct and simultaneous four chamber volume estimation. We have addressed two key issues, i.e., cardiac image representation and simultaneous four chamber volume estimation, which enables accurate and efficient four-chamber volume estimation. We generate compact and discriminative image representations by supervised descriptor learning (SDL) which can remove irrelevant information and extract discriminative features. We propose direct and simultaneous four chamber volume estimation by the multioutput sparse latent regression (MSLR), which enables jointly modeling nonlinear input-output relationships and capturing four-chamber interdependence. The proposed method is highly generalized, independent of imaging modalities, which provides a general regression framework that can be extensively used for clinical data prediction to achieve automated diagnosis. Experiments on both MR and CT images show that our method achieves high performance with a correlation coefficient of up to 0.921 with ground truth obtained manually by human experts, which is clinically significant and enables more accurate, convenient and comprehensive assessment of cardiac functions. PMID- 27940228 TI - Mexican consumers' perceptions and attitudes towards farm animal welfare and willingness to pay for welfare friendly meat products. AB - Increasing concerns about farm animal welfare have led to an increase in the availability of welfare-friendly-products (WFP), but little is known about how much more consumers are willing-to-pay (WTP) for WFP or about their buying trends in Latin America. In this study, a survey was given to 843 meat consumers in the city of Toluca, Mexico. The results show that consumers were interested in farm animal welfare issues and their ethical, sociological and economic implications, as in Europe. The people surveyed also conveyed a high level of empathy with animal feelings and emotions, however they clearly demanded more information and regulations related to farm animal welfare. The majority of respondents expressed that they were WTP more for properly certified WFP, but mostly based on the benefits in terms of product quality and human health. If the demand for WFP begins to increase in Mexico, the supply chain should consider a certification system to guarantee product origin based on current conditions. PMID- 27940227 TI - Comparison of Warner-Bratzler shear force values between round and square cross section cores for assessment of beef Longissimus tenderness. AB - The objective of this experiment was to determine whether there is a difference between Warner-Blatzler shear force values of round (WBSF) and square (WBsSF) cross-section cores for assessment of beef tenderness. To compare the effect of core sampling, Longissimus thoracis muscles were obtained from 43 beef carcasses at 1, 14, and 28days postmortem. For each sample, tenderness was assessed by a trained sensory panel and by WBSF and WBsSF techniques. There was a strong and linear relationship (R2=0.77) between WBSF and WBsSF, but the average shear force of square cores were (P<0.05) greater than those of round cores. The WBsSF had greater repeatability (R=0.85 vs 0.81) and explained slightly more of the variation in sensory panel perception of beef tenderness (76% vs 74%) than WBSF. The results indicate that WBsSF seems to be a more precise method of measuring shear force, being little more sensitive for detecting tenderness differences than WBSF. PMID- 27940229 TI - Peripheral Non-atherosclerotic Arterial Disorders: What Radiologists Need to Know. AB - Peripheral non-atherosclerotic arterial disorders (NAADs) are a heterogeneous group of rather uncommon conditions that tend to manifest in subjects without atherosclerosis. Each of these conditions has distinctive pathophysiology; however, there are some common clinical and radiological characteristics and in some cases a common treatment approach that unifies these conditions to a specific group, hence the NAADs. Clinicians and radiologists often fail to recognize NAADs, and there might be a delay in the management of such patients; this may result in seriously adverse outcomes that could otherwise have been avoided or minimized. Knowledge of these conditions and of their radiological appearances is therefore important to help establish a correct diagnosis to allow the prompt initiation of treatment. The purpose of this pictorial review is to present a selection of NAADs cases and to discuss the radiological characteristics and the most common lines of therapeutic approaches. PMID- 27940230 TI - Lung Mass in Smokers. AB - RATIONALE AND OBJECTIVE: Emphysema is characterized by airspace dilation, inflammation, and irregular deposition of elastin and collagen in the interstitium. Computed tomographic studies have reported that lung mass (LM) may be increased in smokers, a finding attributed to inflammatory and parenchymal remodeling processes observed on histopathology. We sought to examine the epidemiologic and clinical associations of LM in smokers. MATERIALS AND METHODS: Baseline epidemiologic, clinical, and computed tomography (CT) data (n = 8156) from smokers enrolled into the COPDGene Study were analyzed. LM was calculated from the CT scan. Changes in lung function at 5 years' follow-up were available from 1623 subjects. Regression analysis was performed to assess for associations of LM with forced expiratory volume in 1 second (FEV1) and FEV1 decline. RESULTS: Subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 chronic obstructive pulmonary disease had greater LM than either smokers with normal lung function or those with GOLD 2-4 chronic obstructive pulmonary disease (P < 0.001 for both comparisons). LM was predictive of the rate of the decline in FEV1 (decline per 100 g, -4.7 +/- 1.7 mL/y, P = 0.006). CONCLUSIONS: Our cross sectional data suggest the presence of a biphasic radiological remodeling process in smokers: the presence of such nonlinearity must be accounted for in longitudinal computed tomographic studies. Baseline LM predicts the decline in lung function. PMID- 27940231 TI - Superior Abdominal 4D Flow MRI Data Consistency with Adjusted Preprocessing Workflow and Noncontrast Acquisitions. AB - RATIONALE AND OBJECTIVES: To assess the impact of an alternative preprocessing workflow on noncontrast- and contrast-enhanced abdominal four-dimensional flow magnetic resonance imaging (4D flow MRI) data consistency. MATERIALS AND METHODS: Twenty patients with cirrhosis and portal hypertension (5 women; 53 +/- 10 years old) underwent 4D flow MRI at 3.0T before and after administration of 0.03 mmol/kg of gadofosveset trisodium with velocity sensitivities of 100 and 50 cm/s for arterial and venous flow quantifications, respectively. 4D flow MRI data were preprocessed using the conventional workflow (workflow 1), applying noise filters prior to eddy current correction, and an alternative workflow (workflow 2), first correcting for eddy currents and using noise filtering only if needed for anti aliasing. Vessel segmentation quality was ranked by independent reviewers and compared via Wilcoxon signed-rank tests. Flow quantification and conservation of mass at two portal and one arterial branch points were compared via paired t tests. RESULTS: Segmentation quality was significantly higher for workflow 2 (P < 0.05) with excellent interobserver agreement (kappa = 0.92). Workflow 2 resulted in larger flow values (P < 0.05) with improved conservation of mass (7.3 +/- 6.1% vs. 27.7 +/- 25.0%, P < 0.001 [portal]; 10.7 +/- 9.0% vs. 21.7 +/- 21.6%, P = 0.02 [arterial]). Peak velocities and abdominal aortic flow were similar (P > 0.05). Noncontrast acquisitions yielded significantly smaller portal flow values (P < 0.05) with improved conservation of mass (5.8 +/- 4.7% vs. 8.7 +/- 6.9%, P = 0.05 [portal]; 6.2 +/- 4.5% vs. 13.7 +/- 10.2%, P = 0.03 [arterial]). CONCLUSIONS: Superior abdominal 4D flow MRI data consistency was obtained by applying eddy current correction before any other data manipulation, using noise masking and velocity anti-aliasing cautiously, and using noncontrast acquisitions. PMID- 27940232 TI - Improving Image Quality of Coronary Computed Tomography Angiography Using Patient Weight and Height-Dependent Scan Trigger Threshold. AB - RATIONALE AND OBJECTIVES: We aim to improve the image quality of coronary computed tomography angiography (CCTA) by using personalized weight and height dependent scan trigger threshold. MATERIALS AND METHODS: This study was divided into two parts. First, we performed and analyzed the 100 scheduled CCTA data, which were acquired by using body mass index-dependent Smart Prep sequence (trigger threshold ranged from 80 Hu to 250 Hu based on body mass index). By identifying the cases of high quality image, a linear regression equation was established to determine the correlation among the Smart Prep threshold, height, and body weight. Furthermore, a quick search table was generated for weight and height-dependent Smart Prep threshold in CCTA scan. Second, to evaluate the effectiveness of the new individual threshold method, an additional 100 consecutive patients were divided into two groups: individualized group (n = 50) with weight and height-dependent threshold and control group (n = 50) with the conventional constant threshold of 150 HU. Image quality was compared between the two groups by measuring the enhancement in coronary artery, aorta, left and right ventricle, and inferior vena cava. By visual inspection, image quality scores were performed to compare between the two groups. RESULTS: Regression equation between Smart Prep threshold (K, Hu), height (H, cm), and body weight (BW, kg) was K = 0.811 * H + 1.917 * BW - 99.341. When compared to the control group, the individualized group presented an average overall increase of 12.30% in enhancement in left main coronary artery, 12.94% in proximal right coronary artery, and 10.6% in aorta. Correspondingly, the contrast-to-noise ratios increased by 26.03%, 27.08%, and 23.17%, respectively, and by 633.1% in contrast between aorta and left ventricle. Meanwhile, the individualized group showed an average overall decrease of 22.7% in enhancement of right ventricle and 32.7% in inferior vena cava. There was no significant difference of the image noise between the two groups (P > .05). By visual inspection, the image quality score of the individualized group was higher than that of the control group. CONCLUSION: Using personalized weight and height-dependent Smart Prep threshold to adjust scan trigger time can significantly improve the image quality of CCTA. PMID- 27940233 TI - Protective immune response in mice induced by a suicidal DNA vaccine encoding NTPase-II gene of Toxoplasma gondii. AB - DNA-based alphaviral RNA replicon vectors, also called suicidal DNA vectors, have been employed to alleviate biosafety concerns attribution to its ability to induce apoptotic cell death of the transfected cells. Toxoplasma gondii nucleoside triphosphate hydrolase-II (TgNTPase-II), which facilitates the parasite to salvage purines from the host cell for survival and replication, have been demonstrated to be a potential vaccine candidate for toxoplasmosis. Herein, we evaluated the immunogenic potential of a suicidal DNA vaccine encoding TgNTPase-II gene, pDREP-TgNTPase-II, delivered intramuscularly in combination with electroporation. Immunization of mice with pDREP-TgNTPase-II elicited specific humoral responses, with high IgG antibody titers and a mixed IgG1/IgG2a response. The cellular immune response was associated with high level production of IFN-gamma, IL-2, IL-10 cytokines and low level IL-4 production as well as the increase of the percentage of CD8+ T cells, indicating that a Th1 predominant response was elicited. Furthermore, mice vaccinated with this suicidal DNA vaccine displayed partial protection against acute infection with the virulent RH strain as well as chronic infection with PRU cyst, which shows 77.7% and 71.4% reduction in brain cyst burden in comparison to PBS and pDREP-eGFP control group, respectively. Based on the cellular and antibody responses, the suicidal DNA vaccine elicited a Th1-predominant immune response against T. gondii challenge. PMID- 27940234 TI - Construction of iron-polymer-graphene nanocomposites with low nonspecific adsorption and strong quenching ability for competitive immunofluorescent detection of biomarkers in GM crops. AB - We developed a new immunofluorescent biosensor by utilizing a novel nanobody (Nb) and iron-polymer-graphene nanocomposites for sensitive detection of 5 enolpyruvylshikimate-3-phosphate synthase from Agrobacdterium tumefaciens strain CP4 (CP4-EPSPS), which considered as biomarkers of genetically modified (GM) crops. Specifically, we prepared iron doped polyacrylic hydrazide modified reduced graphene nanocomposites (Fe@RGO/PAH) by in-situ polymerization approach and subsequent a one-pot reaction with hydrazine. The resulting Fe@RGO/PAH nanocomposites displayed low nonspecific adsorption to analytes (11% quenching caused by nonspecific adsorption) due to electrostatic, energetic and steric effect of the nanocomposites. After Nb immobilizing, the as-prepared Fe@RGO/PAH/Nbs showed good selectivity and high quenching ability (92% quenching) in the presence of antigen (Ag) and polyethylene glycol (PEG) modified CdTe QDs (Ag/QDs@PEG), which is a nearly 4 fold than that of the unmodified GO in same condition. The high quenching ability of Fe@RGO/PAH/Nbs can be used for detection of CP4-EPSPS based on competitive immunoassay with a linearly proportional concentration range of 5-100ng/mL and a detection limit of 0.34ng/mL. The good stability, reproducibility and specificity of the resulting immunofluorescent biosensor are demonstrated and might open a new window for investigation of fluorescent sensing with numerous multifunctional graphene based materials. PMID- 27940235 TI - Chemically modified cellulose strips with pyridoxal conjugated red fluorescent gold nanoclusters for nanomolar detection of mercuric ions. AB - One-pot approach was adopted for the synthesis of highly luminescent near infrared (NIR)-emitting gold nanoclusters (AuNCs) using bovine serum albumin (BSA) as a protecting agent. The vitamin B6 cofactor pyridoxal was conjugated with the luminescent BSA-AuNCs through the free amines of BSA and then employed for the nanomolar detection of Hg2+ in aqueous medium via selective fluorescence quenching of AuNCs. This nano-assembly was successfully applied for the real sample analysis of Hg2+ in fish, tap water and river water. The study also presents chemically-modified cellulosic paper strips with the pyridoxal conjugated BSA-AuNCs for detecting Hg2+ ion up to 1nM. PMID- 27940237 TI - Simultaneous detection of MCF-7 and HepG2 cells in blood by ICP-MS with gold nanoparticles and quantum dots as elemental tags. AB - In this work, we demonstrate a novel method based on inductively coupled plasma mass spectrometry (ICP-MS) detection with gold nanoparticles (Au NPs) and quantum dots (QDs) labeling for the simultaneous counting of two circulating tumor cell lines (MCF-7 and HepG2 cells) in human blood. MCF-7 and HepG2 cells were captured by magnetic beads coupled with anti-EpCAM and then specifically labeled by CdSe QDs-anti-ASGPR and Au NPs-anti-MUC1, respectively, which were used as signal probes for ICP-MS measurement. Under the optimal experimental conditions, the limits of detection of 50 MCF-7, 89 HepG2 cells and the linear ranges of 200 40000 MCF-7, 300-30000 HepG2 cells were obtained, and the relative standard deviations for seven replicate detections of 800 MCF-7 and HepG2 cells were 4.6% and 5.7%, respectively. This method has the advantages of high sensitivity, low sample consumption, wide linear range and can be extended to the simultaneous detection of multiple CTC lines in human peripheral blood. PMID- 27940236 TI - Engineering anatase hierarchically cactus-like TiO2 arrays for photoelectrochemical and visualized sensing platform. AB - This work described that one-step synthesis three dimensional anatase hierarchically cactus-like TiO2 arrays (AHCT) and their application in constructing a novel photoelectrochemical (PEC) and visualized sensing platform based on molecular imprinting technique, which reports its result with the prussian blue (PB) electrode served as the electrochromic indicator for the detection of glycoprotein (RNase B). The AHCT arrays were perpendicularly grown on FTO substrate with tunable sizes, offering many advantages, such as large contact area, rapid charge electron separation and transport. A possible formation process of the interesting AHCT arrays has been investigated based on time-dependent experiment. In addition, the PEC and visualized sensing platform was constructed based on the molecularly imprinted polymer modified AHCT arrays. Specifically, in the proposed system, the more RNase B being, the more insulating layer was formed on the surface of AHCT arrays that impeded the harvesting of light and electron transfer, resulting in the reduction of photocurrent. When upon light illumination, the photogenerated electrons flow through an external circuit to PB, leading to the reduction of PB to prussian white (PW), which is transparent. The rate of decolourization of PB is proportional to the concentration of RNase B. In this way, a visualized PEC sensing platform that gives its quantitative information could be performed by monitoring the change of color intensity. Under optimal conditions, the protocol possessed a detection range of 0.5pM to 2MUM (r=0.997) and the limit of detection was 0.12 pM toward RNase B. Our method eliminates the need for sophisticated instruments and high detection expenses, making it possible to be a reliable alternative in resource constrained regions. PMID- 27940238 TI - A flexible and miniaturized hair dye based photodetector via chemiluminescence pathway. AB - A flexible and miniaturized metal semiconductor metal (MSM) biomolecular photodetector was developed as the core photocurrent system through chemiluminescence for hydrogen peroxide sensing. The flexible photocurrent sensing system was manufactured on a 30-um-thick crystalline silicon chip by chemical etching process, which produced a flexible silicon chip. A surface texturization design on the flexible device enhanced the light-trapping effect and minimized reflectivity losses from the incident light. The model protein streptavidin bound to horseradish peroxidase (HRP) was successfully immobilized onto the sensor surface through high-affinity conjugation with biotin. The luminescence reaction occurred with luminol, hydrogen peroxide and HRP enzyme, and the emission of light from the catalytic reaction was detected by underlying flexible photodetector. The chemiluminescence in the miniaturized photocurrent sensing system was successfully used to determine the hydrogen peroxide concentration in real-time analyses. The hydrogen peroxide detection limit of the flexible MSM photodetector was 2.47mM. The performance of the flexible MSM photodetector maintained high stability under bending at various bending radii. Moreover, for concave bending, a significant improvement in detection signal intensity (14.5% enhancement compared with a flat configuration) was observed because of the increased photocurrent, which was attributed to enhancement of light trapping. Additionally, this detector was used to detect hydrogen peroxide concentrations in commercial hair dye products, which is a significant issue in the healthcare field. The development of this novel, flexible and miniaturized MSM biomolecular photodetector with excellent mechanical flexibility and high sensitivity demonstrates the applicability of this approach to future wearable sensor development efforts. PMID- 27940239 TI - Label-free electrochemical aptasensor for adenosine detection based on cascade signal amplification strategy. AB - In this work, a simple and highly sensitive label-free electrochemical aptasensor for adenosine detection was developed based on target-aptamer binding triggered nicking endonuclease-assisted strand-replacement DNA polymerization and rolling circle amplification (RCA) strategy. The magnetic beads (MB) probe, which was attached the aptamer of adenosine and mDNA, was firstly fabricated. In the presence of adenosine, mDNA was released from MB upon recognition of the aptamer to target adenosine. The released mDNA as the primer activated autonomous DNA polymerization/nicking process and accompanied by the continuous release of replicated DNA fragments. Subsequently, numerous released DNA fragments were captured on the working electrode, and then as initiators to trigger the downstream RCA process leading to the formation of a long ssDNA concatemer for loading large amounts of Ru(NH3)63+. Therefore, a conspicuously amplified electrochemical signal through the developed dual-amplification strategy could be achieved. This method exhibited a high sensitivity toward adenosine with a detection limit of 0.032nM. Also, it exhibited high selectivity to different nucleoside families and good reproducibility. This design opens new horizons for integrating different disciplines, presenting a versatile tool for ultrasensitive detecting organic small molecules in medical research and clinical diagnosis. PMID- 27940240 TI - Advances in biosensor development for the screening of antibiotic residues in food products of animal origin - A comprehensive review. AB - Antibiotic residues may be found in food of animal origin, since veterinary drugs are used for preventive and curative purposes to treat animals. The control of veterinary drug residues in food is necessary to ensure consumer safety. Screening methods are the first step in the control of antibiotic residues in food of animal origin. Conventional screening methods are based on different technologies, microbiological methods, immunological methods or physico-chemical methods (e.g. thin-layer chromatography, HPLC, LC-MS/MS). Screening methods should be simple, quick, inexpensive and specific, with low detection limits and high sample throughput. Biosensors can meet some of these requirements. Therefore, the development of biosensors for the screening of antibiotic residues has been increasing since the 1980s. The present review provides extensive and up to-date findings on biosensors for the screening of antibiotic residues in food products of animal origin. Biosensors are constituted of a bioreceptor and a transducer. In the detection of antibiotic residues, even though antibodies were the first bioreceptors to be used, new kinds of bioreceptors are being developed more and more (enzymes, aptamers, MIPs); their advantages and drawbacks are discussed in this review. The different categories of transducers (electrochemical, mass-based biosensors, optical and thermal) and their potential applications for the screening of antibiotic residues in food are presented. Moreover, the advantages and drawbacks of the different types of transducers are discussed. Lastly, outlook and the future development of biosensors for the control of antibiotic residues in food are highlighted. PMID- 27940241 TI - Electrospun manganese (III) oxide nanofiber based electrochemical DNA nanobiosensor for zeptomolar detection of dengue consensus primer. AB - Nanoscale biosensors, owing to their high-sensitivity and extremely low limits-of detection, have enabled the realization of highly complex and sophisticated miniaturized platforms for several important healthcare applications, the most predominant one being disease diagnosis. In particular, nanomaterial facilitated electrochemical detection of DNA hybridization has had an exceptional impact on fields such as genetics and cancerous mutation detection Here we report an ultrasensitive electrochemical platform using electrospun semi-conducting Manganese (III) Oxide (Mn2O3) nanofibers for DNA Hybridization detection. The proposed platform coalesces the inherent advantages of metal-oxide nanofibers and electrochemical transduction techniques, resulting in label-free zeptomolar detection of DNA hybridization. As proof of concept, we demonstrate zeptomolar detection of Dengue consensus primer (limit of detection: 120*10-21M) both in control as well as spiked serum samples. Our reported detection limit is superior in comparison with previously reported electrochemical DNA hybridization sensors for Dengue virus detection, spanning both labeled and label-free transductions. This ultra-sensitivity, we believe, is a result of synthesizing a low bandgap electrospun metal-oxide nanomaterial corresponding to a specific oxidation state of Manganese. This methodology can be extended for detection of any hybridization of interest by simply adapting an appropriate functionalization protocol and thus is very generic in nature. PMID- 27940242 TI - Co-translational protein folding: progress and methods. AB - Proteins are synthesized as linear polymers and have to fold into their native structure to fulfil various functions in the cell. Folding can start co translationally when the emerging peptide is still attached to the ribosome and is guided by the environment of the polypeptide exit tunnel and the kinetics of translation. Major questions are: When does co-translational folding begin? What is the role of the ribosome in guiding the nascent peptide towards its native structure? How does translation elongation kinetics modulate protein folding? Here we suggest how novel structural and biophysical approaches can help to probe the interplay between the ribosome and the emerging peptide and present future challenges in understanding co-translational folding. PMID- 27940243 TI - SigCH, an extracytoplasmic function sigma factor of Porphyromonas gingivalis regulates the expression of cdhR and hmuYR. AB - Extracytoplasmic function (ECF) sigma factors play an important role in the bacterial response to various environmental stresses. Porphyromonas gingivalis, a prominent etiological agent in human periodontitis, possesses six putative ECF sigma factors. So far, information is limited on the ECF sigma factor, PGN_0319. The aim of this study was to investigate the role of PGN_0319 (SigCH) of P. gingivalis, focusing on the regulation of hmuY and hmuR, which encode outer membrane proteins involved in hemin utilization, and cdhR, a transcriptional regulator of hmuYR. First, we evaluated the gene expression profile of the sigCH mutant by DNA microarray. Among the genes with altered expression levels, those involved in hemin utilization were downregulated in the sigCH mutant. To verify the microarray data, quantitative reverse transcription PCR analysis was performed. The RNA samples used were obtained from bacterial cells grown to early log phase, in which sigCH expression in the wild type was significantly higher than that in mid-log and late-log phases. The expression levels of hmuY, hmuR, and cdhR were significantly decreased in the sigCH mutant compared to wild type. Transcription of these genes was restored in a sigCH complemented strain. Compared to the wild type, the sigCH mutant showed reduced growth in log phase under hemin-limiting conditions. Electrophoretic mobility shift assays showed that recombinant SigCH protein bound to the promoter region of hmuY and cdhR. These results suggest that SigCH plays an important role in the early growth of P. gingivalis, and directly regulates cdhR and hmuYR, thereby playing a potential role in the mechanisms of hemin utilization by P. gingivalis. PMID- 27940244 TI - Pomegranate ellagitannins stimulate the growth of Akkermansia muciniphila in vivo. AB - Results from our previous human pomegranate extract (POM extract) intervention study demonstrated that about seventy percent of participants were able to form urolithin A from ellagitannins in the intestine (urolithin A producers). Urolithin A formation was associated with a high proportion of Akkermansia muciniphila in fecal bacterial samples as determined by 16S rRNA sequencing. Here we investigated whether A. muciniphila counts increased in stool samples collected after the POM extract intervention compared to baseline stool samples using real-time PCR. In addition, we performed in vitro culture studies to determine the effect of POM extract and ellagic acid on the growth of A. muciniphila and to analyze ellagic acid metabolites formed in the culture broth by high-performance liquid chromatography. Supplementation of culture broth with 10 MUM of ellagic acid did not change A. muciniphila growth while the addition of 0.18 mg/ml and 0.28 mg/ml of POM extract to the culture broth inhibited the growth of A. muciniphila significantly. Incubation of A. muciniphila with POM extract resulted in formation of ellagic acid and incubation of A. muciniphila with ellagic acid demonstrated hydrolysis of ellagic acid to metabolites different from urolithin A. The in vitro culture studies with A. muciniphila partially explain our in vivo findings that the presence of A. muciniphila was associated with breakdown of ellagic acid for further metabolism by other members of the microbiota. This is the first report of the role of A. muciniphila in ellagitannin hydrolysis. However, we conclude that enzymes from other bacteria must be involved in the formation of urolithin A in the human intestine. PMID- 27940245 TI - Recurrent obstructive acute pyelonephritis: A rare form of Actinotignum (Actinobaculum) schaalii infection in a HIV-1 infected patient. AB - Actinobaculum schaalii is a rarely reported, anaerobic, Gram-positive bacterium which role as uropathogen is emerging. We report here the case of a 47 year old HIV-1 infected woman presented with five recurrent episodes of obstructive pyelonephritis in the context of multiple renal stones. No bacteria was found until the fifth episode, during which prolonged urinary cultures as well as 16S rDNA sequencing allowed the diagnosis of A. schaalii infection. She had developed a life-threatening condition with severe renal failure. A right nephrectomy was performed and found that the intrarenal stones were attributed to the antiretroviral therapy. The renal parenchyma corresponded to an end-stage renal disease with chronic pyelonephritis without abcesses or granules. The situation improved after six months of amoxicillin therapy. PMID- 27940246 TI - Improving the energy balance of grass-based anaerobic digestion through combined harvesting and pretreatment. AB - An important challenge that has to be addressed to achieve sustainable anaerobic digestion of lignocellulosic substrates is the development of energy and cost efficient pretreatment methods. Technologies orientated to simultaneously harvest and mechanically pretreat the biomass at the field could meet these criteria as they can potentially reduce the energy losses. The objective of this study was to elucidate the effect of two full-scale harvesting machines to enhance the biogas production and subsequently, improve energy balance. The performances of Disc mower and Excoriator were assessed on meadow and cultivated grass silages. The results showed that relatively high methane production can be achieved from meadow and cultivated grass harvested in different seasons. The findings indicated that the bioenergy production can be improved based on the selection of the appropriate harvesting technology. More specifically, Excoriator, which cuts and subsequently applies shearing forces on harvested biomass, enhanced the methane production up to 10% and the overall energy budget was improved proportionally to the driving speed increase. PMID- 27940247 TI - SDF-1 Blockade Enhances Anti-VEGF Therapy of Glioblastoma and Can Be Monitored by MRI. AB - Despite the approval of antiangiogenic therapy for glioblastoma multiforme (GBM) patients, survival benefits are still limited. One of the resistance mechanisms for antiangiogenic therapy is the induction of hypoxia and subsequent recruitment of macrophages by stromal-derived factor (SDF)-1alpha (CXCL-12). In this study, we tested whether olaptesed pegol (OLA-PEG, NOX-A12), a novel SDF-1alpha inhibitor, could reverse the recruitment of macrophages and potentiate the antitumor effect of anti-vascular endothelial growth factor (VEGF) therapy. We also tested whether magnetic resonance imaging (MRI) with ferumoxytol as a contrast agent could provide early information on macrophage blockade. Orthotopic human G12 glioblastomas in nude mice and rat C6 glioblastomas were employed as the animal models. These were treated with bevacizumab or B-20, both anti-VEGF antibodies. Rats were MR imaged with ferumoxytol for macrophage detection. Tumor hypoxia and SDF-1alpha expression were elevated by VEGF blockade. Adding OLA-PEG to bevacizumab or B-20 significantly prolonged the survival of rodents bearing intracranial GBM compared with anti-VEGF therapy alone. Intratumoral CD68+ tumor associated macrophages (TAMs) were increased by VEGF blockade, but the combination of OLA-PEG + VEGF blockade markedly lowered TAM levels compared with VEGF blockade alone. MRI with ferumoxytol as a contrast agent noninvasively demonstrated macrophage reduction in OLA-PEG + anti-VEGF-treated rats compared with VEGF blockade alone. In conclusion, inhibition of SDF-1 with OLA-PEG inhibited the recruitment of TAMs by VEGF blockage and potentiated its antitumor efficacy in GBM. Noninvasive MRI with ferumoxytol as a contrast agent provides early information on the effect of OLA-PEG in reducing TAMs. PMID- 27940248 TI - Integrin-Targeted Hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography for Imaging Tumor Progression and Early Response in Non-Small Cell Lung Cancer. AB - Integrins play an important role in tumor progression, invasion and metastasis. Therefore we aimed to evaluate a preclinical imaging approach applying alphanubeta3 integrin targeted hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography (FMT-XCT) for monitoring tumor progression as well as early therapy response in a syngeneic murine Non-Small Cell Lung Cancer (NSCLC) model. Lewis Lung Carcinomas were grown orthotopically in C57BL/6 J mice and imaged in vivo using a alphanubeta3 targeted near-infrared fluorescence (NIRF) probe. alphanubeta3-targeted FMT-XCT was able to track tumor progression. Cilengitide was able to substantially block the binding of the NIRF probe and suppress the imaging signal. Additionally mice were treated with an established chemotherapy regimen of Cisplatin and Bevacizumab or with a novel MEK inhibitor (Refametinib) for 2 weeks. While MUCT revealed only a moderate slowdown of tumor growth, alphanubeta3 dependent signal decreased significantly compared to non-treated mice already at one week post treatment. alphanubeta3 targeted imaging might therefore become a promising tool for assessment of early therapy response in the future. PMID- 27940249 TI - Mason type III radial head fractures treated by anatomic radial head arthroplasty: Is this a safe treatment option? AB - BACKGROUND: Radial head fractures make up approximately 3% of all fractures and they are the most common elbow fracture in adults. Replacement through arthroplasty is the recommended treatment in the context of unstable elbow injury and comminuted radial head fracture. The midterm clinical, functional, and radiographic results in patients treated with anatomic radial head arthroplasty for a Mason type III radial head fracture are presented. MATERIAL AND METHODS: We performed a retrospective search of our facility's prospective trauma database to identify all skeletally mature patients who were treated by primary radial head replacement or open reduction and internal fixation following an acute radial head fracture. Inclusion criteria were Mason type III fractures and anatomic radial head arthroplasty (RHA). All the patients included were evaluated using a standard postoperative protocol including clinical and radiographic evaluation at 1, 3 and 12 months of follow-up. All the patients were reviewed clinically at an average of 30 months' follow-up. RESULTS: Forty-one subjects (32 Mason type III and 9 Mason IV fractures) were treated with anatomic RHA (Acumed, Hillsboro, OR, USA). Of these, two patients (1 Mason type III and 1 Mason type IV) were excluded from the analysis because severe cognitive impairment. Moreover, we decided to exclude the subjects with a Mason type IV fracture to obtain a more homogeneous sample. Therefore, 31 patients with a Mason type III fracture were included in this study. Based on the Mayo Elbow Performance Score, excellent results were obtained in 24 (77%) patients, good in 3 (10%) and fair in 4 (13%) patients. Heterotopic ossification was reported in 8 patients (26% of cases). The final elbow flexion-extension range of motion was of 112 degrees , with a mean flexion of 125 degrees . The final forearm rotational range of motion was 134 degrees with a mean pronation of 68 degrees and a mean supination of 66 degrees . DISCUSSION: Anatomic radial head replacement leads to a good functional recovery, even in the presence of severe instability, such as coronoid fractures and LUCL injury. However, patients should be informed of the high number of adverse events (mainly heterotopic ossification) following this treatment. LEVEL OF EVIDENCE: Therapeutic IV. PMID- 27940250 TI - Comparative study on the treatment of Rockwood type III acute acromioclavicular dislocation: Clinical results from the TightRope(r) technique vs. K-wire fixation. AB - BACKGROUND AND HYPOTHESIS: The aim of this study was to address the inconsistency regarding the operative treatment of Rockwood type III acromioclavicular joint separation. We compared results after single- and double TightRope(r) reduction with results after acromioclavicular transfixation via K-wires only and additional ligament augmentation in acute acromioclavicular (AC) joint separations graded Rockwood type III, and hypothesized that the TightRope(r) technique leads to better clinical and radiological results. MATERIALS AND METHODS: We conducted a retrospective clinical cohort study and included 42 consecutive patients (mean age 43 years [24-66]) diagnosed and operatively treated between 2004 and 2012 (mean follow-up was 54.6 months [15-118]). Specific shoulder scores as well as scores reflecting the patients' overall mental and physical health status were used. Radiological evaluation was also performed. RESULTS: The SF12 test revealed comparability between all subgroups. Specific shoulder tests and a visual analogue scale demonstrated comparable results. Radiographic measurements showed a significant reduction in the AC distance and CC distance after surgery in all subgroups. The early complication rate was 9.5% for all patients, while late complications occurred in 14.3% of all cases. CONCLUSIONS: Compared to the established methods, the operative TightRope(r) procedures represent a safe alternative in Rockwood III injuries. All investigated techniques predominantly led to good and excellent clinical results in acute Rockwood type III AC joint instabilities. Avoidance of material removal and shorter hospital stays appear to speak in favour for the TightRope(r) technique. LEVEL OF EVIDENCE: IV. PMID- 27940251 TI - Lung metastases of diffuse giant cell tumour of the fibular tendon sheath at the ankle: A case report. AB - Diffuse giant cell tumours of the tendon sheaths are described in the literature as locally aggressive soft-tissue tumours. We report the case of a 56-year-old male with a history of multiple surgical procedures for a giant cell tumour of the fibular tendon sheath at the right ankle. The multiple recurrences prompted monitoring by positron-emission tomography, which showed lung tumours. Biopsies confirmed that the tumours were metastases from the giant cell tumour of the tendon sheath. In patients with recurrent and/or diffuse giant cell tumour, positron-emission tomography is an effective monitoring tool. PMID- 27940252 TI - The relationship between the striatal dopamine transporter and novelty seeking and cognitive flexibility in opioid dependence. AB - Novelty seeking (NS) is a core personality trait that primes the susceptibility to drug addiction. Striatal dopamine activity contributes to cognitive flexibility, an important cognitive strategy to inhibit impulsivity and compulsive drug-seeking behavior. Evidence supports the association between dopamine and NS. Opioid-dependent patients show higher levels of NS, and repeated opioid exposure can cause cognitive deficits including poor cognitive flexibility and impaired impulse control. However, in opioid-dependent patients, the link between NS, striatal dopamine activity, and cognitive flexibility is still unclear. We recruited 22 opioid-dependent individuals and 30 age- and sex-matched healthy controls. Single-photon emission computed tomography with [99mTc]TRODAT-1 as a ligand was used to measure the striatal dopamine transporter (DAT) availability. The Trail Making Test (TMT) was performed to assess cognitive flexibility. Cloninger's Tridimensional Personality Questionnaire (TPQ) was used to measure NS. We found that in opioid-dependent patients, the striatal DAT availability was lower and negatively associated with TMT Part B/Part A. Moreover, an inverted-U shape significantly matched the scores of NS as a function of the striatal DAT availability, with maximum NS potential in the midrange of the DAT availability. An extra sum-of-squares F test was conducted, indicating that a quadratic model fitted the association between the DAT and NS better than a linear model did. In brief, in opioid-dependent patients, the striatal DAT availability is nonlinearly linked to NS and linearly linked to cognitive flexibility. The role of the striatal DAT in the transition from controlled to compulsive opioid use warrants further research. PMID- 27940253 TI - Heterogeneous spatial representation by different subpopulations of neurons in the subiculum. AB - The subiculum is a pivotal structure located in the hippocampal formation that receives inputs from grid and place cells and that mediates the output from the hippocampus to cortical and sub-cortical areas. Previous studies have demonstrated the existence of boundary vector cells (BVC) in the subiculum, as well as exceptional stability during recordings conducted in the dark, suggesting that the subiculum is involved in the coding of allocentric cues and also in path integration. In order to better understand the role of the subiculum in spatial processing and the coding of external cues, we recorded subicular units in freely moving rats while performing two experiments: the "size experiment" in which we modified the arena size, and the "barrier experiment" in which we inserted new barriers in a familiar open field thus dividing the enclosure into four comparable sub-chambers. We hypothesized that if physical boundaries were deterministic of the firing of subicular units a strong spatial replication pattern would be found in most spatially modulated units. In contrast, our results demonstrate heterogeneous space coding by different cell types: place cells, barrier-related units and BVC. We also found units characterized by narrow spike waveforms, most likely belonging to axonal recordings, that showed grid like patterns. Our data indicate that the subiculum codes space in a flexible manner, and that it is involved in the processing of allocentric information, external cues and path integration, thus broadly supporting spatial navigation. PMID- 27940254 TI - Apa2H1, the first head domain of Apa2 trimeric autotransporter adhesin, activates mouse bone marrow-derived dendritic cells and immunization with Apa2H1 protects against Actinobacillus pleuropneumoniae infection. AB - Actinobacillus pleuropneumoniae is the causative pathogen of porcine pleuropneumonia, which results in large economic losses in the pig industry worldwide. There are, however, no effective subunit vaccines are available in the market owing to the various serotypes and the absence of cross-protection against this pathogen. Therefore, the selection of protective components is of great significance for vaccine development. We previously showed that trimeric autotransporter adhesins are important virulence factors of A. pleuropneumoniae. To determine the potential role in vaccine development of the functional head domain (Apa2H1) of Apa2, a trimeric autotransporter adhesin found in A. pleuropneumoniae, we obtained nature-like trimeric Apa2H1 using a prokaryotic expression system and co-culture of Apa2H1 with bone marrow derived dendritic cells (BMDCs) in vitro resulted in maturation of BMDCs, characterised by the up regulation of CD83, MHC-II, CCR7, ICAM-I and the increased expression of factors related to B lymphoid cells stimulation, such as proliferation-inducing ligand (APRIL), B lymphocyte stimulator (BLyS) and B cell activating factor (BAFF). The in vivo results showed that vaccination with Apa2H1 resulted in the robust production of antigen-specific antibodies, modestly induced mixed Th1 and Th2 immunity, impaired bacterial colonization and dissemination, and improved mouse survival rates. This study is the first to show that Apa2H1 is antigenic and can be used as a component of a subunit vaccine against A. pleuropneumoniae infection, providing valuable reference material for the development of an effective vaccine against A. pleuropneumoniae. PMID- 27940256 TI - Enhanced expression of TREM-1 in splenic cDCs in lupus prone mice and it was modulated by miRNA-150. AB - Over activation of conventional dendritic cells (cDCs) contributes to the development of systemic lupus erythematosus (SLE). Triggering receptor expressed on myeloid cells 1 (TREM-1) is emerging as a potent amplifier of the inflammatory responses. We sought to determine the expression level of TREM-1 on cDCs in a mice model of SLE and to identify miRNA which could modulate TREM-1 expression. In the present study, TREM-1 expression in splenocytes and on cDCs was strongly up-regulated in vivo, and was enhanced with LPS stimulation in vitro. Blockade of TREM-1 signal impaired the TLR4-induced cytokines production. These indicated that TREM-1 potently amplified the function of TLR4 which enhanced the inflammation responses. A common set of dysregulated miRNAs (miRNA-98, -150 and 494) were identified in splenocytes of mice. Moreover, the results of bioinformatics and the immunoblotting, demonstrated that miRNA-150 inhibited the expression of TREM-1. Together, these data suggested that TREM-1 signaling pathway may be a therapeutic target to prevent the effects of the inflammatory cDCs in SLE and miRNA-150 serves as the important regulator. PMID- 27940255 TI - Arsenic trioxide is an immune adjuvant in liver cancer treatment. AB - Tumor cells are inhibited effectively by As2O3in vitro and in vivo, although the underlying immune regulatory mechanisms remain unknown. Regulatory T cells play a key role in tumor immune escape. In the present study, we aimed to assess the in vivo effects of As2O3 on the immune status in hepatic cancer and its in vitro regulatory role in cytokine-induced killers(CIKs)cytotoxicity. In a tumor H22 xenograft model of hepatic cancer, we demonstrated that As2O3 treatment decreased tumor volumes and weights, and improved survival by reducing Tregs infiltration into the tumor. Moreover, our data indicated that the exact immune regulatory mechanism of As2O3 might involve elevated CD3+T lymphocyte amounts more than reduced Tregs levels. Furthermore, As2O3 significantly improved CIKs cytotoxicity in vitro by decreasing CD4+T lymphocytes and Tregs, and increasing CD8+T lymphocytes. Our results suggested that As2O3 might act as an immune adjuvant in liver carcinoma treatment by increasing T lymphocytes and decreasing Treg infiltrated into the tumor. PMID- 27940257 TI - Variables influencing the efficiency and interpretation of reverse transcription quantitative PCR (RT-qPCR): An empirical study using Bacteriophage MS2. AB - Reverse transcription, quantitative PCR (RT-qPCR) is a sensitive method for quantification of specific RNA targets, but the first step of the assay, reverse transcription, is notoriously variable and sensitive to reaction conditions. In this study, we used purified Bacteriophage MS2 genomic RNA as a model virus target to test two different RT enzymes (SuperScript II and SuperScript III), two RT-priming strategies (gene-specific primers and random hexamers), and varying background RNA concentrations (0-50ngMUl-1) to determine how these variables influence the efficiency of reverse transcription over a range of target concentrations (101-107 copies MUl-1). The efficiency of the RT reaction was greatly improved by increasing both background RNA and primer concentrations, but the benefit provided by background RNA was source dependent. At a given target concentration, similar RT efficiencies were achieved with gene-specific primers and random hexamers, but the latter required much higher concentrations. With random hexamers, we observed a systematic variation in RT reaction efficiency as a function of target concentration. Using an RNA standard curve that was also subject to RT effectively normalized for this systematic variability, but the assay accuracy depended critically on the length of the standard RNA extending to the 3' end of the qPCR target site. Our results shed some light on previous contradictory conclusions in the literature, and provide insights that may aid in the design of RT-qPCR assays and the design of synthetic RNA standards when full length material is not available. PMID- 27940258 TI - Evolution of structural abnormalities in the rat brain following in utero exposure to maternal immune activation: A longitudinal in vivo MRI study. AB - Genetic and environmental risk factors for psychiatric disorders are suggested to disrupt the trajectory of brain maturation during adolescence, leading to the development of psychopathology in adulthood. Rodent models are powerful tools to dissect the specific effects of such risk factors on brain maturational profiles, particularly when combined with Magnetic Resonance Imaging (MRI; clinically comparable technology). We therefore investigated the effect of maternal immune activation (MIA), an epidemiological risk factor for adult-onset psychiatric disorders, on rat brain maturation using atlas and tensor-based morphometry analysis of longitudinal in vivo MR images. Exposure to MIA resulted in decreases in the volume of several cortical regions, the hippocampus, amygdala, striatum, nucleus accumbens and unexpectedly, the lateral ventricles, relative to controls. In contrast, the volumes of the thalamus, ventral mesencephalon, brain stem and major white matter tracts were larger, relative to controls. These volumetric changes were maximal between post-natal day 50 and 100 with no differences between the groups thereafter. These data are consistent with and extend prior studies of brain structure in MIA-exposed rodents. Apart from the ventricular findings, these data have robust face validity to clinical imaging findings reported in studies of individuals at high clinical risk for a psychiatric disorder. Further work is now required to address the relationship of these MRI changes to behavioral dysfunction and to establish thier cellular correlates. PMID- 27940259 TI - Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent. AB - Systemic inflammation evokes an array of brain-mediated responses including fever, anorexia and taste aversion. Both fever and anorexia are prostaglandin dependent but it has been unclear if the cell-type that synthesizes the critical prostaglandins is the same. Here we show that pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not of COX-1, attenuates inflammation-induced anorexia. Mice with deletions of COX-2 selectively in brain endothelial cells displayed attenuated fever, as demonstrated previously, but intact anorexia in response to peripherally injected lipopolysaccharide (10MUg/kg). Whereas intracerebroventricular injection of a cyclooxygenase inhibitor markedly reduced anorexia, deletion of COX-2 selectively in neural cells, in myeloid cells or in both brain endothelial and neural cells had no effect on LPS-induced anorexia. In addition, COX-2 in myeloid and neural cells was dispensable for the fever response. Inflammation-induced conditioned taste aversion did not involve prostaglandin signaling at all. These findings collectively show that anorexia, fever and taste aversion are triggered by distinct routes of immune-to-brain signaling. PMID- 27940260 TI - Clinically proven drug targets differentially expressed in the prefrontal cortex of schizophrenia patients. AB - BACKGROUND: Due to the heterogeneous nature of schizophrenia, understanding the genetic risk for the disease is a complex task. Gene expression studies have proven to be more reliable than association studies as they are consistently replicated in a tissue specific manner. METHODS: Using RNA-Seq we analysed gene expression in the frontal cortex of 24 individuals with schizophrenia and 25 unaffected controls. RESULTS: We identified 1146 genes that were differentially expressed in schizophrenia, approximately 60% of which were up-regulated and 366 of 1146 (32%) also have aberrant DNA methylation (p=2.46*10-39). The differentially expressed genes were significantly overrepresented in several pathways including inflammatory (p=8.7*10-3) and nitric oxide pathways (p=9.2*10 4). Moreover, these genes were significantly enriched for those with a druggable genome (p=0.04). We identified a number of genes that are significantly up regulated in schizophrenia as confirmed in other gene expression studies using different brain tissues. Of the 349 genes associated with schizophrenia from the Psychiatric Genomics Consortium we identified 16 genes that are significant from our list of differentially expressed genes. CONCLUSIONS: Our results identified biological functional genes that are differentially expressed in schizophrenia. A subset of these genes are clinically proven drug targets. We also found a strong pattern of differentially expressed immune response genes that may reflect an underlying defect in schizophrenia. PMID- 27940261 TI - Exploring the Parents' Attitudes and Perceptions About School Breakfast to Understand Why Participation Is Low in a Rural Midwest State. AB - OBJECTIVE: To explore parental attitudes and perceptions about the school breakfast program in a state with low school breakfast participation. DESIGN: A cross-sectional study design that used an online survey completed by parents supplemented with district data from a state department of education. The survey included quantitative and qualitative components. SETTING: A rural Midwestern state with low school breakfast participation. PARTICIPANTS: Parents and caregivers of children in grades 1-12 were recruited through schools to complete a survey (n = 7,209). MAIN OUTCOME MEASURES: Participation in a school breakfast program. ANALYSIS: A generalized estimating equation model was used to analyze the data and account for the possible correlation among students from the same school district. Open-end survey items were coded. RESULTS: Parents identified several structural and logistic barriers in response to open-ended survey items. Factors associated with breakfast participation include perceived benefits, stigma related to those for whom breakfast is intended, and the importance of breakfast. CONCLUSIONS AND IMPLICATIONS: Interventions should be designed to test whether changing parent perceptions and decreasing stigma will lead to increased breakfast participation. Policy, systems, and environment changes addressing the structural and logistic barriers also may have the potential to increase participation. PMID- 27940262 TI - The marine-derived pachycladin diterpenoids as novel inhibitors of wild-type and mutant EGFR. AB - Epidermal growth factor receptor (EGFR) is a key player in proliferation and metastasis of various cancers. Discovery of novel EGFR inhibitors is still an urgent clinical oncology unmet need. Pachycladins are eunicellin-based diterpenoids isolated from the soft coral Cladiella pachycladous species. This study evaluated the anticancer activity of pachycladins A-E against diverse breast and cervical cancer cells. Pachycladin A (1) potently inhibited the proliferation of multiple cancer cell lines, without being cytotoxic to non cancerous cells. The antiproliferative activity of 1 is mediated through cytostatic mechanisms rather than inducing apoptosis, as evidenced by lack of TUNEL response. Additionally, 1 arrested cell cycle in either G1 or G2/M phase, according to the cancer type, which induced caspase-dependent and independent apoptosis only after prolonged treatment. Meanwhile, 1 potently decreased microvessel formation and endothelial cell migration, suggesting its potential antiangiogenic activity. Different kinase profiling platforms revealed the exquisite potency and selectivity of 1 towards EGFR, even compared to other members of the EGFR family. In cancer cells, the antiproliferative activity of 1 was associated with suppression of EGFR activation and its downstream effectors. Interestingly, 1 significantly inhibited the drug-resistant T790M EGFR mutant, which is believed to be an attractive feature of EGFR inhibitors. Docking studies characterized the structural determinants required for efficient wild and mutant EGFR inhibition. Overlay studies of 1 with known EGFR inhibitors provided future guidance to chemically improve its binding affinity. Together, the anticancer activity of 1 is mediated by direct effects on tumor growth and angiogenesis, selectively via deactivating EGFR signaling, providing an excellent scaffold to control EGF-dependent cancers. PMID- 27940264 TI - Lincosamides: Chemical structure, biosynthesis, mechanism of action, resistance, and applications. AB - Lincomycin and its derivatives are antibiotics exhibiting biological activity against bacteria, especially Gram-positive ones, and also protozoans. Lincomycin and its semi-synthetic chlorinated derivative clindamycin are widely used in clinical practice. Both antibiotics are bacteriostatic, inhibiting protein synthesis in sensitive bacteria; however, at higher concentrations, they may be bactericidal. Clindamycin is usually much more active than lincomycin in the treatment of bacterial infections, in particular those caused by anaerobic species; it can also be used for the treatment of important protozoal diseases, e.g. malaria, most effectively in combination with other antibiotic or non antibiotic antimicrobials (primaquine, fosfidomycin, benzoyl peroxide). Chemical structures of lincosamide antibiotics and the biosynthesis of lincomycin and its genetic control have been summarized and described. Resistance to lincomycin and clindamycin may be caused by methylation of 23S ribosomal RNA, modification of the antibiotics by specific enzymes or active efflux from the bacterial cell. PMID- 27940265 TI - Influence of the type of work shift in Female Sexual Function Index of healthcare sector female workers. AB - OBJECTIVE: To determine the influence of the type of work shift over the sexual function of healthcare sector female workers. METHODOLOGY: Quantitative, cross sectional and correlation type of study. Universe composed of a high complexity hospital female workers aged between 20 and 64 years old who worked in Day Shifts (DS) and Rotating Shifts (RS). Bio-social-demographic profile of 365 female workers was characterized by means of the Female Sexual Function Index (FSFI). Statistical analysis was carried out using SPSS v.19.0 Software and univariate, bivariate and multivariate analyses were applied. Mann-Whitney's non-parametric test was employed, altogether with Chi Square Test, Fisher's exact test and logistic regression with p-value<0.05. RESULTS: 36, 5 years old mean age (10, 65 SD); 43,2% belongs to DS and 56,7% belongs to RS. General FSFI scored 27, 86 points (6, 11 SD), with an mean of 27,47 points (6,82 SD) for DS and 28,16 points (5,51 SD) for the RS. Variables that might affect FSFI in the case of RS were the Health Service Assistant category, with 7, 11 OR; 2, 051-24,622 IC; p=0,002 and chronic disease with 2, 226 OR; 1093-4533 IC; p=0,027. Protective variables for DS, the use of hormonal contraceptive method with 0,322 OR; 0,145-0,713 IC; p=0,005 and non- hormonal contraceptive method with 0,229 OR; 0,09-0,586 IC; p=0,002. CONCLUSION: There was no significant FSFI difference per shift. A protective factor for DS and two Risk factors for RS were identified. PMID- 27940266 TI - Aggregated oviposition in Rhodnius prolixus, sensory cues and physiological consequences. AB - Females of the haematophagous bug Rhodnius prolixus attach their eggs in clusters on substrates related to their hosts, such as nests or avian feathers. Because the hosts are an enormous food resource as well as potential predators, the choice of the site and pattern of oviposition could have an important adaptive value. Here we investigated proximate and a potential ultimate cause of this aggregated pattern of laid eggs. First, we studied proximal causes by analyzing the use of chemical or physical cues associated with aggregated oviposition in R. prolixus. For all terrestrial organisms there is a trade-off between exchange of respiratory gases and water loss. Particularly, insect eggs are highly susceptible to this trade-off because they do not obtain water from the environment, hence our second objective is to study the possible mechanisms involved in dehydration resistance in this species. Therefore we examined the dynamics of change in CO2 release rate (MCO2), and water loss rate (MH2O) in relation to embryo development as energetic demands increase, and tested the energetic or hygric efficiency hypothesis as a potential ultimate cause of aggregated oviposition. This hypothesis states that grouped eggs consume less energy or lose less water than equal numbers of isolated eggs, the latter being more susceptible to dehydration. Results indicated the use of physical external cues such as dummy eggs or edges of the oviposition substrates, but we did not find any chemical cues associated with the aggregated pattern of oviposition. There are no energetic or hygric benefits associated with egg's aggregated pattern. However, when we analyzed the MCO2 and MH2O change in relation to embryo development, we found a fairly constant and low MH2O albeit a clear increase in MCO2, suggesting a tightly control of egg's desiccation tolerance. This high resistance to desiccation coupled with a temporal strategy of hatching allows R. prolixus embryos to successfully develop and hatch under harsh environmental conditions. PMID- 27940263 TI - Using bacterial genomes and essential genes for the development of new antibiotics. AB - The shrinking antibiotic development pipeline together with the global increase in antibiotic resistant infections requires that new molecules with antimicrobial activity are developed. Traditional empirical screening approaches of natural and non-natural compounds have identified the majority of antibiotics that are currently available, however this approach has produced relatively few new antibiotics over the last few decades. The vast amount of bacterial genome sequence information that has become available since the sequencing of the first bacterial genome more than 20years ago holds potential for contributing to the discovery of novel antimicrobial compounds. Comparative genomic approaches can identify genes that are highly conserved within and between bacterial species, and thus may represent genes that participate in key bacterial processes. Whole genome mutagenesis studies can also identify genes necessary for bacterial growth and survival under different environmental conditions, making them attractive targets for the development of novel inhibitory compounds. In addition, transcriptomic and proteomic approaches can be used to characterize RNA and protein levels on a cellular scale, providing information on bacterial physiology that can be applied to antibiotic target identification. Finally, bacterial genomes can be mined to identify biosynthetic pathways that produce many intrinsic antimicrobial compounds and peptides. In this review, we provide an overview of past and current efforts aimed at using bacterial genomic data in the discovery and development of novel antibiotics. PMID- 27940268 TI - Transcription activation activity of ERD15 protein from Morus indica. AB - Early Responsive to Dehydration (ERD) genes are described as rapid response mediators of dehydration stress. Recently, ERD15 has emerged as a novel stress induced transcription factor which might be involved in mediating distinct stress responses in plants. In order to determine whether mulberry ERD15 can act as functional transcription factor, yeast-based assays were performed. Mulberry ERD15 was found to drive high level reporter gene expression in yeast which suggests it may function as a transcription factor. However, due to lack of an identifiable DNA binding domain, deletion analysis was carried out to determine the putative region of the protein involved in mediating protein-DNA interaction. Our results indicate that the region between 70 and 100 amino acids is critical in conferring transcription activation activity and might harbor the DNA binding region of ERD15. PMID- 27940267 TI - Nitric oxide protects carbon assimilation process of watermelon from boron induced oxidative injury. AB - Nitric oxide (NO) mediates plant response to a variety of abiotic stresses; however, limited information is available on its effect on boron (B)-stressed watermelon plants. The present study investigates the mechanism through which NO protects watermelon seedlings from B deficiency and toxicity stresses. Five days old watermelon seedlings were exposed to B (0, 0.5 and 10 mg L-1) alone or with 75 MUmole of NO donor sodium nitroprusside (SNP) for 30 days. Both low and high B concentrations in the media altered nutrient accumulation and impaired various physiological processes of watermelon seedlings, leading to a significant reduction in biomass production. The plants exposed to B deficient or toxic concentrations had 66 and 69% lower shoot dry weight, respectively compared with optimum B levels. B toxicity-induced growth inhibition of watermelon seedlings was associated with high B translocation to shoot tissues, which caused lipid membrane peroxidation (12% increase) and chlorophyll destruction (25% reduction). In contrast, B deficiency accelerated generation of reactive oxygen species (ROS), specifically OH-1 and induced cellular oxidative injury. Exogenously applied SNP promoted leaf chlorophyll, photosynthesis and consequently biomass production in B-stressed watermelon seedlings by reducing B accumulation, lipid membrane peroxidation and ROS generation. It also activated antioxidant enzymes such as SOD, POD and APX, and protected the seedlings from ROS-induced cellular burst. PMID- 27940269 TI - Hydrogen sulfide alleviates mercury toxicity by sequestering it in roots or regulating reactive oxygen species productions in rice seedlings. AB - Soil mercury (Hg) contamination is a major factor that affects agricultural yield and food security. Hydrogen sulfide (H2S) plays multifunctional roles in mediating a variety of responses to abiotic stresses. The effects of exogenous H2S on rice (Oryza sativa var 'Nipponbare') growth and metabolism under mercuric chloride (HgCl2) stress were investigated in this study. Either 100 or 200 MUM sodium hydrosulfide (NaHS, a donor of H2S) pretreatment improved the transcription of bZIP60, a membrane-associated transcription factor, and then enhanced the expressions of non-protein thiols (NPT) and metallothioneins (OsMT 1) to sequester Hg in roots and thus inhibit Hg transport to shoots. Meanwhile, H2S promoted seedlings growth significantly even in the presences of Hg and superoxide dismutase (SOD, EC 1.15.1.1) or catalase (CAT, EC 1.11.1.6) inhibitors, diethyldithiocarbamate (DDC) or 3-amino-1,2,4-triazole (AT). H2S might act as an antioxidant to inhibit or scavenge reactive oxygen species (ROS) productions for maintaining the lower MDA and H2O2 levels, and thereby preventing oxidative damages. All these results indicated H2S effectively alleviated Hg toxicity by sequestering it in roots or by regulating ROS in seedlings and then thus significantly promoted rice growth. PMID- 27940270 TI - Zinc and selenium accumulation and their effect on iron bioavailability in common bean seeds. AB - Common beans (Phaseolus vulgaris) are the most important legume crops. They represent a major source of micronutrients and a target for essential trace mineral enhancement (i.e. biofortification). To investigate mineral accumulation during seed maturation and to examine whether it is possible to biofortify seeds with multi-micronutrients without affecting mineral bioavailability, three common bean cultivars were treated independently with zinc (Zn) and selenium (Se), the two critical micronutrients that can be effectively enhanced via fertilization. The seed mineral concentrations during seed maturation and the seed Fe bioavailability were analyzed. Common bean seeds were found to respond positively to Zn and Se treatments in accumulating these micronutrients. While the seed pods showed a decrease in Zn and Se along with Fe content during pod development, the seeds maintained relatively constant mineral concentrations during seed maturation. Selenium treatment had minimal effect on the seed accumulation of phytic acid and polyphenols, the compounds affecting Fe bioavailability. Zinc treatment reduced phytic acid level, but did not dramatically affect the concentrations of total polyphenols. Iron bioavailability was found not to be greatly affected in seeds biofortified with Se and Zn. In contrast, the inhibitory polyphenol compounds in the black bean profoundly reduced Fe bioavailability. These results provide valuable information for Se and Zn enhancement in common bean seeds and suggest the possibility to biofortify with these essential nutrients without greatly affecting mineral bioavailability to increase the food quality of common bean seeds. PMID- 27940271 TI - Expression profiles and hormonal regulation of tobacco NtEXGT gene and its involvement in abiotic stress response. AB - Despite the intensive study of xyloglucan endotransglucosylases/hydrolases, their multifaceted role in plant growth regulation in changing environmental conditions is not yet clarified. The functional role of the large number of genes encoding this group of enzymes is also still unclear. NtEXGT gene encodes one of xyloglucan endotransglucosylases/hydrolases (XTHs) of Nicotiana tabacum L. The highest level of NtEXGT gene expression was detected in young flowers and leaves near the shoot apex. Expression of the NtEXGT gene in leaves was induced by cytokinins, auxins, brassinosteroids and gibberellins. NtEXGT gene was also up regulated by salinity, drought, cold, cadmium and 10 MUM abscisic acid treatments and down-regulated in response to 0 degrees C and 100 MUM abscisic acid. Pretreatment of leaves with fluridone contributed to smaller increase in the level of NtEXGT transcripts in response to drought stress. These data suggest that NtEXGT gene is ABA-regulated and probably implicated in ABA-dependent signaling in response to stress factors. 35S::NtEXGT plants of tobacco showed higher rate of root growth under salt-stress conditions, greater frost and heat tolerance as compared with the wild type tobacco plants. PMID- 27940272 TI - Cost Utility Analysis of Topical Steroids Compared With Dietary Elimination for Treatment of Eosinophilic Esophagitis. AB - BACKGROUND & AIMS: Topical corticosteroids or dietary elimination are recommended as first-line therapies for eosinophilic esophagitis, but data to directly compare these therapies are scant. We performed a cost utility comparison of topical corticosteroids and the 6-food elimination diet (SFED) in treatment of eosinophilic esophagitis, from the payer perspective. METHODS: We used a modified Markov model based on current clinical guidelines, in which transition between states depended on histologic response simulated at the individual cohort-member level. Simulation parameters were defined by systematic review and meta-analysis to determine the base-case estimates and bounds of uncertainty for sensitivity analysis. Meta-regression models included adjustment for differences in study and cohort characteristics. RESULTS: In the base-case scenario, topical fluticasone was about as effective as SFED but more expensive at a 5-year time horizon ($9261.58 vs $5719.72 per person). SFED was more effective and less expensive than topical fluticasone and topical budesonide in the base-case scenario. Probabilistic sensitivity analysis revealed little uncertainty in relative treatment effectiveness. There was somewhat greater uncertainty in the relative cost of treatments; most simulations found SFED to be less expensive. CONCLUSIONS: In a cost utility analysis comparing topical corticosteroids and SFED for first-line treatment of eosinophilic esophagitis, the therapies were similar in effectiveness. SFED was on average less expensive, and more cost effective in most simulations, than topical budesonide and topical fluticasone, from a payer perspective and not accounting for patient-level costs or quality of life. PMID- 27940273 TI - GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis. AB - GPR4 is a proton-sensing G protein-coupled receptor that can be activated by extracellular acidosis. It has recently been demonstrated that activation of GPR4 by acidosis increases the expression of numerous inflammatory and stress response genes in vascular endothelial cells (ECs) and also augments EC-leukocyte adhesion. Inhibition of GPR4 by siRNA or small molecule inhibitors reduces endothelial cell inflammation. As acidotic tissue microenvironments exist in many types of inflammatory disorders, including inflammatory bowel disease (IBD), we examined the role of GPR4 in intestinal inflammation using a dextran sulfate sodium (DSS)-induced acute colitis mouse model. We observed that GPR4 mRNA expression was increased in mouse and human IBD tissues when compared to control intestinal tissues. To determine the function of GPR4 in intestinal inflammation, wild-type and GPR4-deficient mice were treated with 3% DSS for 7days to induce acute colitis. Our results showed that the severity of colitis was decreased in GPR4-deficient DSS-treated mice in comparison to wild-type DSS-treated mice. Clinical parameters, macroscopic disease indicators, and histopathological features were less severe in the DSS-treated GPR4-deficient mice than the DSS treated wild-type mice. Endothelial adhesion molecule expression, leukocyte infiltration, and isolated lymphoid follicle (ILF) formation were reduced in intestinal tissues of DSS-treated GPR4-null mice. Collectively, our results suggest GPR4 provides a pro-inflammatory role in the inflamed gut as the absence of GPR4 ameliorates intestinal inflammation in the acute experimental colitis mouse model. PMID- 27940275 TI - Nurses' experiences of working in organizations undergoing restructuring: A metasynthesis of qualitative research studies. AB - BACKGROUND: Health care organizations worldwide undergo continual reconfiguration and structural changes in order to optimize the use of resources, reduce costs, and improve the quality of treatment. OBJECTIVE: The objective of this study was to synthesize qualitative studies of how nurses experience working in organizations undergoing structural changes. DESIGN: The review is designed as a metasynthesis and follows the guidelines put forth by Sandelowski and Barroso for synthesizing qualitative research. DATA SOURCES: From January to April 2015, literature searches were conducted in the CINAHL, PubMed, ProQuest, and Web of Science databases for the period from 1994 to 2014. REVIEW METHODS: A total of 762 articles were found and screened, 12 of which were included in the review after being appraised using a specially designed reading guide. The inclusion criteria were qualitative studies in English, German, Norwegian, Swedish, or Danish on nurses' experiences with being employed in organizations undergoing structural changes. The data were then analyzed in a metasummary and metasynthesis. RESULTS: Four overall categories that illustrate how nurses experience working in organizations undergoing structural changes were identified: nursing management, emotional responses, nursing work, and colleagues. Generally, nurses seemed to describe their experiences working in organizations undergoing structural changes in a negative way, as all of the included articles reported that nurses experience an increased workload due to restructuring. However, some of the articles reported that nurses also experience a certain joy associated with the nursing work despite the negative consequences of the structural changes. CONCLUSIONS: The findings can be seen as a paradox because former research has shown that an increased workload reduces the pleasure in working. Further research on this topic is needed to ensure a better working environment for nurses. PMID- 27940274 TI - Direct Conversion of Human Fibroblasts into Neural Progenitors Using Transcription Factors Enriched in Human ESC-Derived Neural Progenitors. AB - Early human embryonic stem cell (hESC)-derived neural populations consist of various embryonic neural progenitors (ENPs) with broad neural developmental propensity. Here, we sought to directly convert human somatic cells into ENP-like phenotypes using hESC-ENP-enriched neural transcription factors (TFs). We demonstrated that induced ENP could be efficiently converted from human fibroblasts using two TF combinations. The iENPs exhibit cellular and molecular characteristics resembling hESC-ENPs and can give rise to astrocytes, oligodendrocytes, and functional neuronal subtypes of the central and peripheral nervous system. Nevertheless, our analyses further revealed that these two iENP populations differ in terms of their proliferation ability and neuronal propensity. Finally, we demonstrated that the iENPs can be induced from fibroblasts from patients with Huntington's disease and Alzheimer's disease, and the diseased iENPs and their neuronal derivatives recapitulated the hallmark pathological features of the diseases. Collectively, our results point toward a promising strategy for generating iENPs from somatic cells for disease modeling and future clinical intervention. PMID- 27940277 TI - POINT: Should Acute Fluid Resuscitation Be Guided Primarily by Inferior Vena Cava Ultrasound for Patients in Shock? Yes. PMID- 27940276 TI - Maximal Inspiratory Pressure: Does the Choice of Reference Values Actually Matter? AB - BACKGROUND: Single-point measurements of maximal inspiratory pressure (MIP) are frequently used to suggest muscle weakness in clinical practice. Although there is a large variability in "mean" predicted MIP depending on the chosen reference values, it remains unclear whether those discrepancies actually impact on the prevalence of weakness, that is, MIP below the lower limit of normal. METHODS: A total of 1,729 subjects (50.1% men, aged 20 to 94 years) who underwent MIP measurements in a clinical laboratory comprised the study group. MIP was predicted according to the most frequently cited regression equations as of August 2015. Pretest probability of weakness was defined by a cluster of clinical and physiologic variables. RESULTS: Prevalence of weakness ranged from 33.4 to 66.9%. Set 2 equations agreed well in indicating weakness (kappa [95% CI] ranging from 0.81 [0.79-0.83] to 0.83 [0.81-0.85]; P < .01). There was closer agreement between higher pretest probability of weakness and low MIP according to set 2 equations compared with set 1 equations. Thus, a significant fraction of subjects with abnormal MIP according to set 1 equations but preserved MIP according to set 2 equations had higher pretest probability of weakness (P < .05). CONCLUSIONS: The choice of MIP reference values strongly impacts on the prevalence of weakness. Some specific equations relate better to clinical and physiologic indicators of weakness, suggesting that they might be particularly useful to screen subjects for advanced respiratory neuromuscular assessment. PMID- 27940278 TI - Short-term Effects of Supplemental Oxygen on 6-Min Walk Test Outcomes in Patients With COPD: A Randomized, Placebo-Controlled, Single-blind, Crossover Trial. AB - BACKGROUND: The acute effect of supplemental oxygen during exercise has been shown to differ largely among patients with COPD. It is unknown what factors influence oxygen response. METHODS: In a randomized, single-blind fashion, 124 patients with COPD underwent one 6-min walk test on supplemental oxygen (6MWTO2) and one 6-min walk test on room air after a practice 6-min walk test. Both gases were delivered via standard nasal prongs (2 L/min). For analyses, patients were stratified on the basis of PaO2 values and compared: (1) 34 patients with resting hypoxemia (HYX); (2) 43 patients with exercise-induced hypoxemia (EIH); and (3) 31 patients with normoxemia (NOX). RESULTS: Oxygen supplementation resulted in an increase in the 6-min walk distance in the total cohort (27 +/- 42 meters; P < .001) and in the subgroups of HYX (37 +/- 40 meters; P < .001) and EIH (28 +/- 44 meters; P < .001) but not in the NOX subgroup (15 +/- 43 meters; P = .065). Forty two percent of patients with HYX and 47% of patients with EIH improved their 6 min walk distance to a clinically relevant extent (>= 30 meters) by using oxygen. These oxygen responders were characterized by significantly lower 6-min walk distance using room air compared with patients without a relevant response (306 +/- 106 meters vs 358 +/- 113 meters; P < .05). Although oxygen saturation was significantly higher during 6MWTO2 compared with the 6-min walk test on room air in all 3 subgroups, it dropped to < 88% during 6MWTO2 in 73.5% of patients with HYX. CONCLUSIONS: In contrast to patients with NOX, patients with HYX and EIH generally benefit from supplemental oxygen by increasing exercise capacity. However, less than one-half of patients reached the threshold of clinically relevant improvements. These oxygen responders were characterized by significantly lower exercise capacity levels. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00886639; URL: www.clinicaltrials.gov. PMID- 27940279 TI - Rebuttal From Dr Kory. PMID- 27940280 TI - Rebuttal From Dr Schmidt. PMID- 27940281 TI - COUNTERPOINT: Should Acute Fluid Resuscitation Be Guided Primarily by Inferior Vena Cava Ultrasound for Patients in Shock? No. PMID- 27940282 TI - Sub-chronic 90-day toxicity of neamine in SD rats and its anti-liver cancer activity in vitro and in vivo. AB - Neamine, an inhibitor of angiogenin (ANG), is a new investigative anticancer drug currently in preclinical stage. Here we report the 90-day sub-chronic toxicity of neamine in SD rats and its anti-liver cancer activity in vitro and in vivo. Neamine has a No Observed Adverse Effect Level (NOAEL) of 12 and 16mg.kg-1.d-1 for female and male rats, respectively. No mortality was found. The adverse effects included increased organ coefficients of spleen and kidney, increased BUN in both female and male rats at high dose, increased CR and decreased organ coefficients of heart and liver in male rats at high dose. All of which, except the kidney coefficient and BUN in males, returned to normal levels after 28-day recovery. Histopathological examination revealed vacuolar degeneration of glomerulus, degeneration of renal tubules and cast in the kidneys, which were also recovered except in males of high-dosing group. These results indicate that kidney is the most susceptible organ for neamine toxicity. Tissue microarray analysis validated that ANG is up-regulated in hepatocellular carcinoma accompanied by increased nuclear translocation, suggesting that ANG is a possible target for drug development in liver cancer treatment. Neamine blocked nuclear translocation of ANG in HUVEC and HepG2 cells, and inhibited ANG-stimulated cell proliferation without affecting basal level cell proliferation. Neamine also inhibited progression of HepG2 xenografts in athymic mice accompanied by decreased angiogenesis and cancer cell proliferation. These results suggest that neamine is a specific ANG inhibitor with low toxicity and high anti-liver cancer efficacy. PMID- 27940283 TI - Effects of cryopreservation on the epigenetic profile of cells. AB - Effective cryopreservation protocols are essential for long-term storage of cells and their subsequent clinical application. Freezing protocols are generally considered as safe; however, putative effects on epigenetic marks have not yet been studied in detail. While post-thaw cell survival rates have been used to evaluate the success of cryopreservation protocols, increasing evidence suggests that freezing may be associated with deviations from the physiological epigenetic marks with putative long-term effects on the cells and/or their derivatives. A better understanding of the underlying mechanisms would be beneficial for improving safety and effectiveness of freezing protocols. The purpose of this review is to provide current information regarding epigenetic alterations (DNA methylation and histone modification patterns) associated with cryopreservation. PMID- 27940284 TI - Alamethicin for using in bioavailability studies? - Re-evaluation of its effect. AB - A major pathway for the elimination of drugs is the biliary and renal excretion following the formation of more hydrophilic secondary metabolites such as glucuronides. For in vitro investigations of the phase II metabolism, hepatic microsomes are commonly used in the combination with the pore-forming peptide alamethicin, also to give estimates for the in vivo situation. Thus, alamethicin may represent a neglected parameter in the characterization of microsomal in vitro assays. In the present study, the influence of varying alamethicin concentrations on glucuronide formation of selected phenolic compounds was investigated systematically. A correlation between the alamethicin impact and the lipophilicity of the investigated substrates was analyzed as well. Lipophilicity was determined by the logarithm of the octanol-water partition coefficient. For every substrate, a distinct alamethicin concentration could be detected leading to a maximal glucuronidation activity. Further increase of the alamethicin application led to negative effects. The differences between the maximum depletion rates with and without alamethicin addition varied between 2.7% and 18.2% depending on the substrate. A dependence on the lipophilicity could not be confirmed. Calculation of the apparent intrinsic clearance led to a more than 2 fold increase using the most effective alamethicin concentration compared to the alamethicin free control. PMID- 27940285 TI - Potency of marbofloxacin for pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida: Comparison of growth media. AB - Pharmacodynamic properties of marbofloxacin were established for six isolates each of the pig respiratory tract pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Three in vitro indices of potency were determined; Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC) and Mutant Prevention Concentration (MPC). For MIC determination Clinical Laboratory Standards Institute guidelines were modified in three respects: (1) comparison was made between two growth media, an artificial broth and pig serum; (2) a high inoculum count was used to simulate heavy clinical bacteriological loads; and (3) five overlapping sets of two-fold dilutions were used to improve accuracy of determinations. Similar methods were used for MBC and MPC estimations. MIC and MPC serum:broth ratios for A. pleuropneumoniae were 0.79:1 and 0.99:1, respectively, and corresponding values for P. multocida were 1.12:1 and 1.32:1. Serum protein binding of marbofloxacin was 49%, so that fraction unbound (fu) serum MIC values were significantly lower than those predicted by correction for protein binding; fu serum:broth MIC ratios were 0.40:1 (A. pleuropneumoniae) and 0.50:1 (P. multocida). For broth, MPC:MIC ratios were 13.7:1 (A. pleuropneumoniae) and 14.2:1 (P. multocida). Corresponding ratios for serum were similar, 17.2:1 and 18.8:1, respectively. It is suggested that, for dose prediction purposes, serum data might be preferable to potency indices measured in broths. PMID- 27940286 TI - Recombinant expression, characterization, and application of a phospholipase B from Fusarium oxysporum. AB - In this study, a gene encoding a putative lipase from Fusarium oxysporum was optimized via codon optimization and expressed in Pichia pastoris KM71. The gene product was identified as a phospholipase B (PLB). The engineered P. pastoris was further cultured in a 3.6-L bioreactor. After optimization of the induction conditions, this system produced 6.6mgmL-1 protein and 6503.8UmL-1 PLB activity in the culture medium. Efficient expression of this PLB in P. pastoris should reduce the costs of production and application. The purified enzyme, with a specific activity of 1170Umg-1, was optimally active at pH 5.0 and 55 degrees C. The results of a degumming experiment performed using the recombinant PLB showed that the phosphorus content of a test oil was decreased from 75.88ppm to 3.3ppm in 2h under optimal reaction conditions. This study provides a basis for the industrial use of F. oxysporum PLB in oil degumming applications. PMID- 27940287 TI - Fast onset of action of glycopyrronium compared with tiotropium in patients with moderate to severe COPD - A randomised, multicentre, crossover trial. AB - BACKGROUND: Long-acting bronchodilators, including anticholinergics glycopyrronium and tiotropium, are central to symptomatic management of chronic obstructive pulmonary disease (COPD). In patients with moderate to severe COPD, glycopyrronium has demonstrated comparable efficacy to open-label and single blinded tiotropium, but with faster onset of bronchodilation. The FAST study assessed the efficacy of glycopyrronium compared with tiotropium in serial spirometry and body plethysmography assessments to further characterize the earlier onset of action associated with glycopyrronium. METHODS: In this German multicentre, randomised, double-blinded, double-dummy, cross-over study, patients with moderate-to-severe COPD received single-dose of glycopyrronium 44 MUg and tiotropium 18 MUg via the Breezhaler(r) and Handihaler(r) devices, respectively. Primary objective was to demonstrate superiority of glycopyrronium over tiotropium in terms of improvement in forced expiratory volume in 1 s as assessed by the area under the curve from 0 to 2 h (FEV1 AUC 0-2h). Secondary endpoints were functional residual capacity (FRC), residual volume (RV), inspiratory capacity (IC), and specific airway resistance (sRaw), all measured by body plethysmography. RESULTS: Of the 152 patients randomised, 99.3% completed the study. After inhalation of the single dose, glycopyrronium demonstrated superiority over tiotropium in early bronchodilation as assessed by improvement in FEV1 AUC0-2h (least squares mean treatment difference = 37 mL; 95% CI: 16, 59 mL; p < 0.01) and FEV1 at 15 min post-dose (least square mean treatment difference = 36 mL; 95% CI: 14, 58 mL; p < 0.01). Both treatments showed similar improvements in FRCpleth, RV, and IC. Glycopyrronium showed statistically significant improvement in sRaw compared with tiotropium over the first 90 min after dosing, with the difference of 0.184 kPa * s at 90 min post-dose (95% CI: 0.315,0.054 kPa * s; p < 0.01). CONCLUSIONS: Glycopyrronium was superior to tiotropium in terms of early bronchodilation. Although both glycopyrronium and tiotropium showed similar improvements in static lung volume parameters, glycopyrronium reduced specific airway resistance faster than tiotropium, which could in part explain the earlier FEV1 response seen with glycopyrronium. TRIAL REGISTRATION: ClinicalTrials.govNCT01922271. PMID- 27940288 TI - Binarized cross-approximate entropy in crowdsensing environment. AB - OBJECTIVES: Personalised monitoring in health applications has been recognised as part of the mobile crowdsensing concept, where subjects equipped with sensors extract information and share them for personal or common benefit. Limited transmission resources impose the use of local analyses methodology, but this approach is incompatible with analytical tools that require stationary and artefact-free data. This paper proposes a computationally efficient binarised cross-approximate entropy, referred to as (X)BinEn, for unsupervised cardiovascular signal processing in environments where energy and processor resources are limited. METHODS: The proposed method is a descendant of the cross approximate entropy ((X)ApEn). It operates on binary, differentially encoded data series split into m-sized vectors. The Hamming distance is used as a distance measure, while a search for similarities is performed on the vector sets. The procedure is tested on rats under shaker and restraint stress, and compared to the existing (X)ApEn results. RESULTS: The number of processing operations is reduced. (X)BinEn captures entropy changes in a similar manner to (X)ApEn. The coding coarseness yields an adverse effect of reduced sensitivity, but it attenuates parameter inconsistency and binary bias. A special case of (X)BinEn is equivalent to Shannon's entropy. A binary conditional entropy for m =1 vectors is embedded into the (X)BinEn procedure. CONCLUSION: (X)BinEn can be applied to a single time series as an auto-entropy method, or to a pair of time series, as a cross-entropy method. Its low processing requirements makes it suitable for mobile, battery operated, self-attached sensing devices, with limited power and processor resources. PMID- 27940289 TI - Combination of visual and symbolic knowledge: A survey in anatomy. AB - In medicine, anatomy is considered as the most discussed field and results in a huge amount of knowledge, which is heterogeneous and covers aspects that are mostly independent in nature. Visual and symbolic modalities are mainly adopted for exemplifying knowledge about human anatomy and are crucial for the evolution of computational anatomy. In particular, a tight integration of visual and symbolic modalities is beneficial to support knowledge-driven methods for biomedical investigation. In this paper, we review previous work on the presentation and sharing of anatomical knowledge, and the development of advanced methods for computational anatomy, also focusing on the key research challenges for harmonizing symbolic knowledge and spatial 3D data. PMID- 27940290 TI - The relationship between systemic inflammation and stoma formation following anterior resection for rectal cancer: A cross-sectional study. AB - INTRODUCTION: There is evidence that temporary defunctioning stoma formation in patients undergoing anterior resection reduces the risk of anastomotic leakage. The aim of the present study was to investigate the relationship between stoma formation, the postoperative systemic inflammatory response and complications following anterior resection for rectal cancer. METHODS: Data was recorded prospectively for patients who underwent anterior resection for histologically proven rectal cancer, from 2008 to 2015 at a single centre, n = 167. Patients had routine preoperative and postoperative blood sampling including serum C-reactive protein (CRP). Postoperative complications including anastomotic leakage were recorded. RESULTS: Of the 167 patients, the majority were male (61%) and over 65 years old (56%) with node negative disease (60%). 36 patients (22%) underwent preoperative neoadjuvant treatment. 100 patients (60%) had a stoma formed at the time of surgery. Stoma formation was significantly associated with male sex (69% vs. 50%, p = 0.017), neoadjuvant chemoradiotherapy (30% vs 9%, p = 0.001) and open surgery (71% vs. 55%, p = 0.040). Of those 100 patients who had a stoma formed, 80 had it reversed. Permanent stoma was significantly associated with increasing age (p = 0.011), exceeding the established CRP threshold of 150 mg/L on postoperative day 4 (67% vs 37%, p = 0.039), higher incidence of postoperative complications (76% vs 47%, p = 0.035), anastomotic leakage (24% vs 2%, p = 0.003) and higher Clavien Dindo score (p = 0.036). CONCLUSIONS: There was no significant association between stoma formation during anterior resection and the postoperative systemic inflammatory response. However, in these patients both the postoperative systemic inflammatory response and complications were associated with permanent stoma. PMID- 27940291 TI - Open retromuscular mesh repair versus onlay technique of incisional hernia: A randomized controlled trial. AB - INTRODUCTION: The aim of this prospective randomized clinical study was to compare and analyze the results of two methods of treatment of incisional hernia: open retromuscular mesh repair and onlay technique. METHODS: 180 patients who underwent open elective surgery for middle primary incisional hernia were randomized into two groups. The retomuscular mesh repair was used in the first group and the onlay technique - in the second group. Several preoperative and intraoperative factors, also wound complications (wound infection, hematoma, seroma) and hernia recurrence rate were determined and compared between the groups. RESULTS: The operative time was significantly longer in the retromuscular group compared with the onlay group (P < 0.001). In the retromuscular group 17 (22.1%) wound complications were observed, in the onlay group-39 (50.0%) wound complications. The difference was statistically significance (P < 0.001). Seroma was the most frequent postoperative wound complication, ranging from 16.9% to 41.0% among the groups, respectively (P = 0.0013). No significantly difference has been found between groups by wound infection and hematoma. 2 (2.6%) case of hernia recurrence was marked in retromuscular group and 4 (5.1%) case of hernia recurrence - in onlay group. But there was no statistically significantly difference between the two groups. CONCLUSION: Our research shows no significant difference in frequency of hernia recurrence between retromuscular mesh repair and onlay technique for treatment of incisional hernia. The usage of the retromuscular mesh repair is associated with significantly less wound complications than onlay technique. That can be considered as an advantage of retromuscular method, which makes it more preferential than onlay method. PMID- 27940292 TI - Lobectomy vs total thyroidectomy - Have we resolved the debate? PMID- 27940293 TI - A simple, rapid and cost-effective process for production of latex clearing protein to produce oligopolyisoprene molecules. AB - Aiming at finding feasible alternatives for rubber waste disposal, the partial enzymatic degradation of poly(cis-1,4-isoprene)-containing materials represents a potential solution. The use of rubber-degrading enzymes and the biotransformation of rubber into new materials is limited by the high costs associated with the production and purification of the enzyme and the complexity of the process. This study presents a simple and low-cost procedure to obtain purified latex clearing protein (Lcp), an enzyme capable of cleaving the double bonds of poly(cis-1,4 isoprene) in presence of oxygen to produce different size of oligomers with terminal aldehyde and ketone groups, respectively. The gene coding for Lcp1VH2 from Gordonia polyisoprenivorans strain VH2 was overexpressed in Escherichia coli C41 (DE3), and by using an auto-induction medium high protein yields were obtained. The cultivation process was described and compared with an IPTG inducible medium previously used. Purification of the enzyme was performed using salting out precipitation with ammonium sulfate. Different salt concentrations and pH were tested in order to find the optimal for purification, obtaining a concentration of 60mg Lcp per l. The enzymatic activity of the purified enzyme was measured by an oxygen consumption assay in the presence of polyisoprene latex. Volumetric activities of 0.16Uml-1 were obtained at optimal conditions of temperature and pH. The results showed an active and partial purified fraction of Lcp1VH2, able to cleave the backbone of poly(cis-1,4-isoprene) and to produce degradation products that were identified with staining methodologies (Schiff reagent for aldehyde groups and 2,4-DNPH for carbonyl groups) and characterized using nuclear magnetic resonance (NMR). Thirteen different storage conditions were tested for the purified enzyme analyzing the enzymatic activity after 1 and 3 months. Lcp1VH2, as an ammonium sulfate precipitate, was stable, easy to handle and sufficiently active for further analysis. The described methodology offers the possibility to upscale the process and to produce large amounts of this protein. PMID- 27940294 TI - Long-term performance and bacterial community dynamics in biocovers for mitigating methane and malodorous gases. AB - The long-term performance of lab-scale biocovers for the simulation of engineered landfill cover soils was evaluated. Methane (CH4), trimethylamine (TMA), and dimethyl sulfide (DMS) were introduced into the biocovers as landfill gases for 134 days and the removal performance was evaluated. The biocover systems were capable of simultaneously removing methane, TMA, and DMS. Methane was mostly eliminated in the top layer of the systems, while TMA and DMS were removed in the bottom layer. Overall, the methane removal capacity and efficiency were 224.8+/ 55.6g-CH4m-2d-1 and 66.6+/-12.8%, respectively, whereas 100% removal efficiencies of both TMA and DMS were achieved. Using quantitative PCR and pyrosequencing assay, the bacterial and methanotrophic communities in the top and bottom layers were analyzed along with the removal performance of landfill gases in the biocovers. The top and bottom soil layers possessed distinct communities from the original inoculum, but their structure dynamics were different from each other. While the structures of the bacterial and methanotrophic communities showed little change in the top layer, both communities in the bottom layer were considerably shifted by adding TMA and DMA. These findings provide information that can extend the understanding of full-scale biocover performance in landfills. PMID- 27940296 TI - Induction of type 1 iodothyronine deiodinase expression inhibits proliferation and migration of renal cancer cells. AB - Type 1 iodothyronine deiodinase (DIO1) regulates peripheral metabolism of thyroid hormones that control cellular proliferation, differentiation and metabolism. The significance of DIO1 in cancer is unknown. In this study we hypothesized that diminished expression of DIO1, observed in renal cancer, contributes to the carcinogenic process in the kidney. Here, we demonstrate that ectopic expression of DIO1 in renal cancer cells changes the expression of genes controlling cell cycle, including cyclin E1 and E2F5, and results in inhibition of proliferation. The expression of genes encoding collagens (COL1A1, COL4A2, COL5A1), integrins (ITGA4, ITGA5, ITGB3) and transforming growth factor-beta-induced (TGFBI) is significantly altered in renal cancer cells with induced expression of DIO1. Finally, we show that overexpression of DIO1 inhibits migration of renal cancer cells. In conclusion, we demonstrate for the first time that loss of DIO1 contributes to renal carcinogenesis and that its induced expression protects cells against cancerous proliferation and migration. PMID- 27940295 TI - Altering the central carbon metabolism of HEK293 cells: Impact on recombinant glycoprotein quality. AB - The accumulation of metabolic by-products remains a critical challenge in the development of mammalian cells culture processes as it impacts cellular growth, productivity and product quality. Although the overexpression of the PYC2 gene was shown to significantly improve the nutrient metabolism efficiency of mammalian cells, its impact on recombinant protein quality has not been investigated yet. In this study, we assess the effect of this metabolic engineering strategy on the quality of a recombinant therapeutic glycoprotein, the human interferon alpha2b (IFNalpha2b). As inferred from densitometry analysis of SDS-PAGE gels, PYC2-overexpressing cells sustained a higher percentage of intact glycosylated IFNalpha2b at the late stage of batch cultures, which was correlated with prolonged viability and reduced accumulation of waste metabolites. Contrarily to the IFNalpha2b produced by the PYC2 cells, LC-MS analysis confirmed the presence of less glycosylated IFNalpha2b as well as the occurrence of proteolytic cleavage in the IFNalpha2b produced in the parental cells. Taken together, these results indicate that PYC2-overexpression in mammalian cells leads to extended favorable conditions for glycosylation and offer an attractive approach to mass-produce high-quality recombinant proteins. PMID- 27940297 TI - Increased levels of enzymes involved in local estradiol synthesis in chronic obstructive pulmonary disease. AB - INTRODUCTION: Steroid hormones are involved in lung development, pulmonary inflammation, and lung cancer. Estrogen signaling and exposure may play a role in pulmonary disorders, including COPD. In both genders, estrogens can be generated locally in the lungs and this contributes importantly to the tissue exposure to these steroids. OBJECTIVE: To characterize and assess differences in localization of estrogen receptors and enzymes involved in the local generation of estrogens in COPD. METHODS: Estrogen Receptor alpha (ERalpha/ESR1), Estrogen Receptor beta (ERbeta/ESR2) and G-protein-coupled estrogen receptor 1 (GPER) were explored by real-time (RT)-PCR analysis (mRNA expression), immunohistochemistry and western blotting in controls and COPD patients. mRNA expression of the enzymes involved in the local estrogen generation - i.e. aromatase (CYP19A1), 17beta hydroxysteroid dehydrogenases (17beta-HSDs) 1, 2, 4, 5, 7 and 12, steroid sulfatase (STS) and sulfotransferase (SULT1E1) - were analyzed by RT-PCR. RESULTS: ERalpha, ERbeta and GPER were expressed in lung tissue, but no differences were observed between patients and controls. The main enzymes involved in local estrogen generation were also present in both normal and COPD lung tissue. In lungs of COPD patients compared with controls, we observed increased expression of the enzymes 17beta-HSD type 1 and aromatase (positive association), both involved in the local synthesis of active estrogens. CONCLUSION: All ER subtypes are present in the lung. The shift in local mRNA level of estrogen metabolic enzymes suggests that exposure to estrogens is involved in the pathogenesis of COPD. PMID- 27940299 TI - GPER/ERK&AKT/NF-kappaB pathway is involved in cadmium-induced proliferation, invasion and migration of GPER-positive thyroid cancer cells. AB - The higher incidence of thyroid cancer in women during reproductive years compared with men and the increased risk associated with the therapeutic use of estrogen have strongly suggested that estrogen may be involved in the occurrence and development of thyroid cancer. Cadmium (Cd) is a potent metalloestrogen that disrupts the endocrine system by mimicking the effects of 17beta-estradiol (E2). In the present study, we demonstrate that similar to E2 and G1, a specific agonist for G protein-coupled estrogen receptor (GPER), Cd induces the proliferation, invasion and migration of human WRO and FRO thyroid cancer cells that have endogenous GPER. Moreover, like E2 and G1, Cd leads to a rapid activation of ERK/AKT, and then nuclear translocation of NF-kappaB, increased expression of cyclin A and D1, and secretion of IL-8, all of which are significantly attenuated by GPER blockage or knock-down in both WRO and FRO cells. Furthermore, the Cd-induced proliferation, invasion and migration are suppressed either by specific inhibitors for GPER, ERK, AKT and NF-kappaB, or by knock-down of GPER. These results suggest that GPER/ERK&AKT/NF-kappaB signaling pathway is involved in the Cd-induced proliferation, invasion and migration of GPER-positive thyroid cancer cells. PMID- 27940298 TI - Cell signaling pathways in the adrenal cortex: Links to stem/progenitor biology and neoplasia. AB - The adrenal cortex is a dynamic tissue responsible for the synthesis of steroid hormones, including mineralocorticoids, glucocorticoids, and androgens in humans. Advances have been made in understanding the role of adrenocortical stem/progenitor cell populations in cortex homeostasis and self-renewal. Recently, large molecular profiling studies of adrenocortical carcinoma (ACC) have given insights into proteins and signaling pathways involved in normal tissue homeostasis that become dysregulated in cancer. These data provide an impetus to examine the cellular pathways implicated in adrenocortical disease and study connections, or lack thereof, between adrenal homeostasis and tumorigenesis, with a particular focus on stem and progenitor cell pathways. In this review, we discuss evidence for stem/progenitor cells in the adrenal cortex, proteins and signaling pathways that may regulate these cells, and the role these proteins play in pathologic and neoplastic conditions. In turn, we also examine common perturbations in adrenocortical tumors (ACT) and how these proteins and pathways may be involved in adrenal homeostasis. PMID- 27940300 TI - Molecular regulation of LHCGR expression by miR-122 during follicle growth in the rat ovary. AB - We have previously reported that LHCGR expression in the ovary is regulated through a post-transcriptional mechanism involving an mRNA binding protein designated as LRBP, which is regulated, at least in part, by a non-coding RNA, miR-122. Our present study examined the regulatory role of miR-122 in FSH-induced LHCGR expression during follicle development. Treatment of rat granulosa cells concurrently with FSH and 17beta estradiol showed, as expected, a time-dependent increase in LHCGR mRNA levels as well as hCG-induced progesterone production. However, miR-122 expression was decreased during the early time periods, which preceded the increased expression of LHCGR mRNA. The role of miR-122 in FSH induced LHCGR mRNA expression was then examined by overexpressing miR-122 prior to FSH stimulation by infecting granulosa cells with an adenoviral vector containing a miR-122 insert (AdmiR-122). Pretreatment with AdmiR-122 resulted in complete abrogation of FSH- mediated upregulation of LHCGR. AdmiR-122 also blocked FSH-induced decrease in LRBP expression and increased the binding of LHCGR mRNA to LRBP. Based on these results, we conclude that miR-122 plays a regulatory role in LHCGR expression by modulating LRBP levels during FSH-induced follicle growth. PMID- 27940301 TI - Elevated plasma levels of copeptin linked to diabetic retinopathy in type 2 diabetes. AB - BACKGROUND: The arginine vasopressin (AVP) system has been postulated to play a role in glucose homeostasis, insulin resistance, and diabetes mellitus in human and animal studies. The aim of this study was to evaluate the role of plasma copeptin in Chinese patients with type 2 diabetes mellitus (T2DM) with and without diabetic retinopathy (DR). METHOD: Plasma copeptin concentrations were determined in 281 patients with T2DM. At baseline, demographic and clinical information including presence of DR and vision-threatening DR (VTDR) was collected. The relationship between copeptin and DR or VTDR was investigated using logistic regression. RESULTS: T2DM participants with DR or VTDR had significantly higher plasma copeptin concentrations on admission (P < 0.0001). Receiver operating characteristics to predict DR and VDTR demonstrated areas under the curve for copeptin of 0.784 (95% confidence interval [CI] 0.724-0.844) and 0.834 (95% CI 0.781-0.904), respectively, which were superior to those for the homeostasis model assessment of insulin resistance (DR AUC 0.736, 95% CI 0.676-0.797; VTDR AUC 0.754, 95% CI 0.703-0.828; P < 0.01). Multivariate logistic regression analysis adjusted for common DR risk factors showed plasma copeptin concentrations >=28.6 pmol/L (>3rd quartile) to be an independent marker of DR (OR 3.68, 95% CI 2.04-6.79; P < 0.0001) and VTDR (OR 4.32, 95% CI 2.12-8.14; P < 0.0001). CONCLUSIONS: We found that increased plasma copeptin concentrations were an independent marker of DR and VDTR in Chinese patients with T2DM, suggesting a possible role of copeptin in the pathogenesis of DR complications. PMID- 27940302 TI - Leydig progenitor cells in fetal testis. AB - Testicular Leydig cells play pivotal roles in masculinization of organisms by producing androgens. At least two distinct Leydig cell populations sequentially emerge in the mammalian testis. Leydig cells in the fetal testis (fetal Leydig cells) appear just after initial sex differentiation and induce masculinization of male fetuses. Although there has been a debate on the fate of fetal Leydig cells in the postnatal testis, it has been generally believed that fetal Leydig cells regress and are completely replaced by another Leydig cell population, adult Leydig cells. Recent studies revealed that gene expression patterns are different between fetal and adult Leydig cells and that the androgens produced in fetal Leydig cells are different from those in adult Leydig cells in mice. Although these results suggested that fetal and adult Leydig cells have distinct origins, several recent studies of mouse models support the hypothesis that fetal and adult Leydig cells arise from a common progenitor pool. In this review, we first provide an overview of previous knowledge, mainly from mouse studies, focusing on the cellular origins of fetal Leydig cells and the regulatory mechanisms underlying fetal Leydig cell differentiation. In addition, we will briefly discuss the functional differences of fetal Leydig cells between human and rodents. We will also discuss recent studies with mouse models that give clues for understanding how the progenitor cells in the fetal testis are subsequently destined to become fetal or adult Leydig cells. PMID- 27940303 TI - Neural representation of a melodic motif: Effects of polyphonic contexts. AB - In music, a melodic motif is often played repeatedly in different pitch ranges and at different times. Event-related potential (ERP) studies have shown that the mismatch negativity (MMN) reflects memory trace processing that encodes two separate melodic lines ("voices") with different motifs. Here we investigated whether a single motif presented in two voices is encoded as a single entity or two separate entities, and whether motifs overlapping in time impede or enhance encoding strength. Electroencephalogram (EEG) from 11 musically-trained participants was recorded while they passively listened to sequences of 5-note motifs where the 5th note either descended (standard) or ascended (deviant) relative to the previous note (20% deviant rate). Motifs were presented either in one pitch range, or alternated between two pitch ranges, creating an "upper" and a "lower" voice. Further, motifs were either temporally isolated (silence in between), or temporally concurrent with two tones overlapping. When motifs were temporally isolated, MMN amplitude in the one-pitch-range condition was similar to that in the two-pitch-range upper voice. In contrast, no MMN, but P3a, was observed in the two-pitch-range lower voice. When motifs were temporally concurrent and presented in two pitch ranges, MMN exhibited a more posterior distribution in the upper voice, but again, was absent in the lower voice. These results suggest that motifs presented in two separate voices are not encoded entirely independently, but hierarchically, causing asymmetry between the upper and lower voice encoding even when no simultaneous pitches are presented. PMID- 27940304 TI - The structure of polymer carriers controls the efficacy of the experimental combination treatment of tumors with HPMA copolymer conjugates carrying doxorubicin and docetaxel. AB - The tumor-specific targeting of cancerostatics using polymer drug carriers represents a potential strategy to achieve an effective treatment with reduced side toxicity. Synthetic water-soluble copolymers based on N-(2 hydroxypropyl)methacrylamide (HPMA) are carriers with tunable architecture and drug loading, tumor-specific accumulation of the drug, and its controlled release. We describe a combination treatment of murine EL4 T cell lymphoma with HPMA-based star conjugates (Mw 250,000gmol-1) of doxorubicin (Dox) or docetaxel (Dtx) designed for enhanced tumor accumulation and combination therapy. Although the combination of linear conjugates (Mw=28,000gmol-1) containing Dox or Dtx resulted in an additive effect in the treatment of the lymphoma, the opposite was observed in the combination of two star conjugates with Dox or Dtx, as the star Dtx conjugate decreased the treatment efficacy of the star Dox conjugate. The Dtx conjugate alone was virtually ineffective in the reduction of tumor growth or survival time extension; thus, a curative effect could be solely attributed to the Dox-containing conjugate. When Dtx was delivered to the tumor on the same polymer carrier as Dox, the efficacy of the Dox-induced treatment was reduced to a lesser extent. No reduction was found when Dtx was delivered by a linear polymer or applied as a free drug. The phenomenon was strictly related to the enhanced permeability and retention (EPR) effect, as it was not observed in BCL1 leukemia, a model without EPR. The diminished treatment outcome in the combination therapy with the two star conjugates was underlined by the significantly decreased accumulation of Dox in the tumor. The use of the drug free polymer carrier instead of the Dtx-containing star conjugate did not reduce the treatment efficacy of the Dox conjugate. Thus, the physicochemical characteristics of the polymer carrier designed for tumor-specific drug delivery systems control the activity of the respective drug, leading to changes within the tumor microenvironment that can determine ultimate efficacy of the combination therapy. PMID- 27940305 TI - Thioredoxins Play a Crucial Role in Dynamic Acclimation of Photosynthesis in Fluctuating Light. AB - Sunlight represents the energy source for photosynthesis and plant growth. When growing in the field, plant photosynthesis has to manage strong fluctuations in light intensities. Regulation based on the thioredoxin (Trx) system is believed to ensure light-responsive control of photosynthetic reactions in the chloroplast. However, direct evidence for a role of this system in regulating dynamic acclimation of photosynthesis in fluctuating conditions is largely lacking. In this report we show that the ferredoxin-dependent Trxs m1 and m2 as well as the NADPH-dependent NTRC are both indispensable for photosynthetic acclimation in fluctuating light intensities. Arabidopsis mutants with combined deficiency in Trxs m1 and m2 show wild-type growth and photosynthesis under constant light condition, while photosynthetic parameters are strongly modified in rapidly alternating high and low light. Two independent trxm1m2 mutants show lower photosynthetic efficiency in high light, but surprisingly significantly higher photosynthetic efficiency in low light. Our data suggest that a main target of Trx m1 and m2 is the NADP-malate dehydrogenase involved in export of excess reductive power from the chloroplast. The decreased photosynthetic efficiency in the high-light peaks may thus be explained by a reduced capacity of the trxm1m2 mutants in the rapid light activation of this enzyme. In the ntrc mutant, dynamic responses of non-photochemical quenching of excitation energy and plastoquinone reduction state both were strongly attenuated in fluctuating light intensities, leading to a massive decrease in PSII quantum efficiency and a specific decrease in plant growth under these conditions. This is likely due to the decreased ability of the ntrc mutant to control the stromal NADP(H) redox poise. Taken together, our results indicate that NTRC is indispensable in ensuring the full range of dynamic responses of photosynthesis to optimize photosynthesis and maintain growth in fluctuating light, while Trxs m1 and m2 are indispensable for full activation of photosynthesis in the high-light periods but negatively affect photosynthetic efficiency in the low-light periods of fluctuating light. PMID- 27940306 TI - Generation of Targeted Point Mutations in Rice by a Modified CRISPR/Cas9 System. PMID- 27940310 TI - Acute hunger modifies responses on the Three Factor Eating Questionnaire hunger and disinhibition, but not restraint, scales. AB - It is widely assumed that responses on the Three Factor Eating Questionnaire (TFEQ) represent long-term (trait) attitudes to eating behaviour. However, the questionnaire requires agreement with a number of food related statements, and it is possible that some are easier to agree with when assessed hungry than sated. To test this potential state-dependency, participants completed a 100 mm visual analogue scale rating of their current hunger at the time they completed the TFEQ. Data were collected from two cohorts: Cohort 1 (507 women and 119 men) completed both measures on paper, while the hunger rating was computerised in Cohort 2 (179 women). Regression analysis revealed significant effects of rated hunger on scores on the hunger (TFEQ-H) and disinhibition (TFEQ-D) but not restraint (TFEQ-R) subscales, with higher TFEQ-H and TFEQ-D scores when participants were more hungry. In addition, 61 women and two men from Cohort 1 completed the measures on two separate occasions. Here, scores on TFEQ-H were higher on days when these participants were hungrier, but no differences in TFEQ D or TFEQ-R were found. Overall these data suggest TFEQ-H could be interpreted as an indirect measure of current hunger, that scores on TFEQ-D are partly moderated by hunger but TFEQ-R is a more trait-like measure of restraint. PMID- 27940309 TI - Bacterial aminoacyl phospholipids - Biosynthesis and role in basic cellular processes and pathogenicity. AB - The bacterial cell membrane accomplishes the controlled exchange of molecules with the extracellular space and mediates specific interactions with the environment. However, the cytoplasmic membrane also includes vulnerable targets for antimicrobial agents. A common feature of cationic antimicrobial peptides (CAMPs) produced by other bacteria or by the host immune system is to utilize the negative charge of bacterial phospholipids such as phosphatidylglycerol (PG) or cardiolipin (CL) for initial adherence and subsequent penetration into the membrane bilayer. To resist cationic antimicrobials many bacteria integrate positive charges into the membrane surface. This is accomplished by aminoacylation of negatively charged (PG) or (CL) with alanine, arginine, or lysine residues. The Multiple Peptide Resistance Factor (MprF) of Staphylococcus aureus is the prototype of a highly conserved protein family of aminoacyl phosphatidylglycerol synthases (aaPGSs) which modify PG or CL with amino acids. MprF is an oligomerizing membrane protein responsible for both, synthesis of lysyl phosphatidylglycerol (LysPG) in the inner leaflet of the cytoplasmic membrane and translocation of LysPG to the outer leaflet. This review focuses on occurrence, synthesis and function of bacterial aminoacyl phospholipids (aaPLs) and on the role of such lipids in basic cellular processes and pathogenicity. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. PMID- 27940308 TI - Structure, inhibition, and regulation of essential lipid A enzymes. AB - The Raetz pathway of lipid A biosynthesis plays a vital role in the survival and fitness of Gram-negative bacteria. Research efforts in the past three decades have identified individual enzymes of the pathway and have provided a mechanistic understanding of the action and regulation of these enzymes at the molecular level. This article reviews the discovery, biochemical and structural characterization, and regulation of the essential lipid A enzymes, as well as continued efforts to develop novel antibiotics against Gram-negative pathogens by targeting lipid A biosynthesis. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. PMID- 27940311 TI - Behavioural measures of child's eating temperament and their link with BMI. AB - Rothbart's model of temperament, defined as individual differences in reactivity and self-regulation, has a strong heuristic value with applications in a wide variety of children's outcomes. Our objective was to test Rothbart's model applied to children's food behaviours and BMI outcome through behavioural measures. Our hypotheses, according to Rothbart's model, were as follows: (i) self-regulation in eating modulates appetite reactivity; (ii) appetite reactivity increases the risk of excess BMI, whereas self-regulation in eating limits this risk. One hundred and four children aged between 7 and 12 years completed four behavioural tasks to assess scores for two components of appetite reactivity (i.e. appetite arousal and appetite persistence) and two components of self regulation in eating (i.e. self-regulation in eating without hunger and self regulation in eating speed). Their heights and weights were measured in order to calculate their BMI-for-age. T-tests and regression analysis were used to verify our hypotheses. None of the scores of self-regulation in eating was directly associated with BMI but we observed a significant impact of self-regulation in eating without hunger on appetite arousal (p-value = 0.04), together with a modest but significant association between appetite persistence and BMI (p-value = 0.02). We can thus conclude that our behavioural measures could be used for the determination of the child's eating temperament. Further studies are needed to investigate how to use these measures to improve the treatment of overweight in children. PMID- 27940312 TI - The migrant suitcase: Food, belonging and commensality among Indian migrants in The Netherlands. AB - The Migrant Suitcase is a metaphor to understand how social remittances are taken, brought back and transformed. Migrants bring with them different cultural norms, food and eating practices. In this paper I review the concept of social remittances in light of material culture, food and eating practices and examine the linkages between food, belonging, commensality and care and then provide empirical examples from the suitcases of Indian migrants. This paper is based on 30 in-depth interviews conducted among Indian migrants living in The Netherlands. The main themes from the data included food from home, cooking practices, food sharing and family relationships. Migrants' sense of belonging was intrinsically related to the food they brought from home and the memories it generates. The practices of cooking and sensorial experiences surrounding them demonstrate the place and home making processes. Commensality with co-ethnics led to a sense of community and stronger community bonds. Commensality with other non-Indian groups was perceived to be problematic. The exchanges of food, eating practices, and care create a sense of 'co-presence' in lives migrants and their transnational families. PMID- 27940307 TI - Comparison of oscillatory activity in subthalamic nucleus in Parkinson's disease and dystonia. AB - OBJECTIVES: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been successfully used to treat both Parkinson's disease (PD) and dystonia. Local field potentials (LFPs) recorded from the STN of PD patients demonstrate prominent beta frequency band activity. It is unclear whether such activity occurs in the STN in dystonia, and, if not, whether dystonia has another distinctive neural population activity in the STN. METHODS: Twelve patients with PD, and eight patients with dystonia underwent DBS electrode implantation targeting the STN. Seven dystonia patients were off medication and one was on aripiprazole and clonazepam. LFPs were recorded from the DBS electrodes in PD in the on/off medication states and in dystonia. Power spectra and temporal dynamics measured by the with Lempel-Ziv complexity of the LFPs were compared among these states. RESULTS: Normalised power spectra and Lempel-Ziv complexity of subthalamic LFPs differed between dystonia off and PD on/off, and between PD off and on over the low frequency, beta and high gamma bands. Patients with dystonia and off medication had lower beta power but higher low frequency and high gamma power than PD. Spectral power in the low beta frequency (11-20Hz) range was attenuated in medicated PD. CONCLUSION: The results suggest that dystonia and PD are characterized by different patterns of oscillatory activities even within the same nucleus, and exaggerated beta activity may relate to hypo-dopaminergic status. PMID- 27940313 TI - An experimental analysis of the affect regulation model of binge eating. AB - There is research suggesting that binge eating may serve an affect regulation function. However, experimental evidence supporting this model in adults is sparse and studies have been mixed regarding whether negative affect impacts objective energy intake. This study examined the impact of a real-time interpersonal stressor on laboratory test meal intake between individuals endorsing recent objective binge eating (>=1*/week) and those denying disordered eating. Generalized linear modeling was used to compare individuals with recent binge eating (BE group; n = 52) to those denying recent eating pathology (HC group; n = 51) on test meal intake following a stressor (stressful condition) or neutral stimulus (non-stressful condition). Moderated mediation analyses were used to examine whether negative affect mediated the impact of condition on intake differently between BE and HC groups. The BE group did not have significantly higher energy intake than the HC group in the stressful verses non stressful condition. However, the BE group was more likely to engage in extreme intake (i.e., over- or under-consumption) than the HC group in the stressful versus non-stressful condition (p = 0.02). Changes in negative affect did not significantly mediate the relationship between condition and intake extremes for the BE group. The results indicate that both over- and under-consumption are triggered by stress among individuals with recent binge eating. Continued research investigating both binge eating and restriction as a means of affect regulation in binge-eating samples is encouraged. PMID- 27940315 TI - A high-fat high-sugar diet-induced impairment in place-recognition memory is reversible and training-dependent. AB - A high-fat high-sugar (HFHS) diet is associated with cognitive deficits in people and produces spatial learning and memory deficits in rodents. Notable, such diets rapidly impair place-, but not object-recognition memory in rats within one week of exposure. Three experiments examined whether this impairment was reversed by removal of the diet, or prevented by pre-diet training. Experiment 1 showed that rats switched from HFHS to chow recovered from the place-recognition impairment that they displayed while on HFHS. Experiment 2 showed that control rats ("Untrained") who were exposed to an empty testing arena while on chow, were impaired in place-recognition when switched to HFHS and tested for the first time. However, rats tested ("Trained") on the place and object task while on chow, were protected from the diet-induce deficit and maintained good place recognition when switched to HFHS. Experiment 3 examined the conditions of this protection effect by training rats in a square arena while on chow, and testing them in a rectangular arena while on HFHS. We have previously demonstrated that chow rats, but not HFHS rats, show geometry-based reorientation on a rectangular arena place-recognition task (Tran & Westbrook, 2015). Experiment 3 assessed whether rats switched to the HFHS diet after training on the place and object tasks in a square area, would show geometry-based reorientation in a rectangular arena. The protective benefit of training was replicated in the square arena, but both Untrained and Trained HFHS failed to show geometry-based reorientation in the rectangular arena. These findings are discussed in relation to the specificity of the training effect, the role of the hippocampus in diet-induced deficits, and their implications for dietary effects on cognition in people. PMID- 27940314 TI - Predicting dietary intake among children classified as overweight or at risk for overweight: Independent and interactive effects of parenting practices and styles. AB - Using baseline data from a randomized controlled pediatric obesity prevention trial, this study sought to examine general parenting style as a potential moderator of the association between feeding-specific parenting practices and child dietary intake. Four hundred and twenty-one parent-child dyads served as participants (49% girls and 93% mothers). Children were, on average, 6.6 years old and either overweight or at-risk for overweight (mean BMI percentile = 84.9). Data were collected in participants' homes. Study staff measured children's height and weight. Parents completed questionnaires designed to assess general parenting styles (authoritative, authoritarian and permissive) and child feeding practices (restriction and monitoring). Child dietary intake was assessed using a 24-h recall system. Outcomes were daily servings of fruits and vegetables, sugar sweetened beverages (SSB), and unhealthy snacks. Results were as follows: Permissive parenting was inversely associated with fruit and vegetable consumption, and parental monitoring was inversely associated with SSB consumption. There were no other main effects of parenting style or feeding practice on child dietary consumption. Authoritarian parenting moderated the association between restriction and SSB intake (a marginally significant effect after correcting for multiple comparisons). Restriction was inversely associated with SSB consumption when authoritarianism was high but unassociated with SSB consumption when authoritarianism was low. Findings indicate that the parenting practice of monitoring child dietary intake was associated with more healthful consumption regardless of parenting style; interventions may thus benefit from encouraging parental monitoring. The parenting strategy of restricting child dietary intake, in contrast, was associated with lower SSB intake in the context of higher parental authoritarianism but inconsequential in the context of lower parental authoritarianism. This exploratory finding warrants further investigation. PMID- 27940316 TI - Proteomic analysis of the adaptative response of Mucor spp. to cheese environment. AB - : In the cheese industry context, Mucor species exhibit an ambivalent behavior as some species are essential "technological" organisms of some cheeses while others can be spoiling agents. Previously, we observed that cheese "technological" species exhibited higher optimal growth rates on cheese related matrices than on synthetic media. This growth pattern combined with morphological differences raise the question of their adaptation to cheese. In this study, using a comparative proteomic approach, we described the metabolic pathways of three Mucor strains considered as "technological" or "contaminant" in the cheese environment (M. lanceolatus UBOCC-A-109153, M. racemosus UBOCC-A-109155, M. circinelloides CBS 277-49) as well as a non-cheese related strain (M. endophyticus CBS 385-95). Overall, 15.8 to 19.0% of the proteomes showed a fold change >=1.6 in Potato Dextrose Agar (PDA) versus Cheese Agar (CA), a cheese mimicking-medium. The 289 differentially expressed proteins identified by LC MS MS analysis were mostly assigned to energy and amino-acid metabolisms in PDA whereas a higher diversity of biological processes was observed for cheese related strains in CA. Surprisingly, the vast majority (72.9%) of the over accumulated proteins were different according to the considered medium and strain. These results strongly suggest that the observed better adaptative response of "technological" strains to cheese environment is mediated by species specific proteins. BIOLOGICAL SIGNIFICANCE: The Mucor genus consists of a multitude of poorly known species. In the food context, few species are known for their positive role in the production of various food products, including cheese, while others are spoiling agents. The present study focused on the analysis of morphological and proteome differences of various Mucor spp. representative strains known as either positively (hereafter referred as "technological") or negatively (hereafter referred as "contaminant") associated with cheese or non related to cheese (endophyte) on two different media, a synthetic medium and a cheese-mimicking medium. The main goal was to assess if adaptative traits of "technological" strains to the cheese environment could be identified. This work was based on observations we did in a recently published physiological study (Morin-Sardin et al., 2016). One of the important innovative aspects lies in the use for the first time of an extensive 2-DE approach to compare proteome variations for 4 strains on two different media. Results obtained offered an insight in the metabolic mechanisms associated with growth on a given medium and showed that adaptation to cheese environment is probably supported by species specific proteins. The obtained data represent an essential step point for more targeted studies at the genomic and transcriptomic levels. PMID- 27940317 TI - The role of alexithymia and gastrointestinal-specific anxiety as predictors of treatment outcome in irritable bowel syndrome. AB - In a previous investigation irritable bowel syndrome (IBS) was associated more to alexithymia than gastrointestinal-specific anxiety (GSA). In this study their independent contribution in predicting treatment outcome was longitudinally investigated. Consecutive 150 IBS patients were evaluated for IBS symptoms, alexithymia, GSA, and psychological distress with validated scales after as-usual treatment for 6-12months. The primary treatment outcome was improvement measured with the IBS-Severity Scoring System that showed 111 patients who improved and 39 who did not improve. Improvement was associated to both alexithymia (d=1.27) and GSA (d=4.63) but only alexithymia showed overtime stability by hierarchical regression, controlled for co-variables. A series of logistic and linear regressions showed that baseline alexithymia, but not GSA, independently predicted both post-treatment improvement status (Cox & Snell R2=0.15; overall classification rate=74%) and symptom change (23% of explained variance). Although alexithymia and GSA were closely related IBS symptoms, only alexithymia was found to be a stable trait and a stronger predictor of treatment outcome than GSA. Since no treatment was established to be definitely effective for IBS, clinicians might improve treatment outcome by identifying patients with high alexithymia, attempting to improve their coping skills, emotional regulation, and affective awareness. PMID- 27940318 TI - Individual differences in Affective Neuroscience Personality Scale (ANPS) primary emotional traits and depressive tendencies. AB - BACKGROUND: The present study investigated individual differences in the Affective Neuroscience Personality Scales (ANPS), representing measures of primary emotional systems, and depressive tendencies in two independent samples. METHODS: In order to be able to find support for a continuum model with respect to the relation of strength in the cross-species "affective neuroscience" taxonomy of primary emotional systems, we investigated ANPS measured personality traits in a psychologically mostly healthy population (n=614 participants) as well as a sample of clinically depressed people (n=55 depressed patients). RESULTS: In both normal and depressed samples robust associations appeared between higher FEAR and SADNESS scores and depressive tendencies. A similar - albeit weaker - association was observed with lower SEEKING system scores and higher depressive tendencies, an effect again seen in both samples. LIMITATIONS: The study is of cross-sectional nature and therefore only associations between primary emotional systems and depressive tendencies were evaluated. CONCLUSIONS: These results show that similar associations between ANPS monitored primary emotional systems and tendencies toward depression can be observed in both healthy and depressed participants. This lends support for a continuum of affective changes accompanying depression, potentially reflecting differences in specific brain emotional system activities in both affectively normal as well as clinically depressed individuals. PMID- 27940319 TI - Trade-offs between data resolution, accuracy, and cost when choosing information to plan reserves for coral reef ecosystems. AB - Conservation planners must reconcile trade-offs associated with using biodiversity data of differing qualities to make decisions. Coarse habitat classifications are commonly used as surrogates to design marine reserve networks when fine-scale biodiversity data are incomplete or unavailable. Although finely classified habitat maps provide more detail, they may have more misclassification errors, a common problem when remotely-sensed imagery is used. Despite these issues, planners rarely consider the effects of errors when choosing data for spatially explicit conservation prioritizations. Here we evaluate trade-offs between accuracy and resolution of hierarchical coral reef habitat data (geomorphology and benthic substrate) derived from remote sensing, in spatial planning for Kubulau District, Fiji. For both, we use accuracy information describing the probability that a mapped habitat classification is correct to design marine reserve networks that achieve habitat conservation targets, and demonstrate inadequacies of using habitat maps without accuracy data. We show that using more detailed habitat information ensures better representation of biogenic habitats (i.e. coral and seagrass), but leads to larger and more costly reserves, because these data have more misclassification errors, and are also more expensive to obtain. Reduced impacts on fishers are possible using coarsely classified data, which are also more cost-effective for planning reserves if we account for data collection costs, but using these data may under-represent reef habitats that are important for fisheries and biodiversity, due to the maps low thematic resolution. Finally, we show that explicitly accounting for accuracy information in decisions maximizes the chance of successful conservation outcomes by reducing the risk of missing conservation representation targets, particularly when using finely classified data. PMID- 27940321 TI - Monitoring infants by automatic video processing: A unified approach to motion analysis. AB - A unified approach to contact-less and low-cost video processing for automatic detection of neonatal diseases characterized by specific movement patterns is presented. This disease category includes neonatal clonic seizures and apneas. Both disorders are characterized by the presence or absence, respectively, of periodic movements of parts of the body-e.g., the limbs in case of clonic seizures and the chest/abdomen in case of apneas. Therefore, one can analyze the data obtained from multiple video sensors placed around a patient, extracting relevant motion signals and estimating, using the Maximum Likelihood (ML) criterion, their possible periodicity. This approach is very versatile and allows to investigate various scenarios, including: a single Red, Green and Blue (RGB) camera, an RGB-depth sensor or a network of a few RGB cameras. Data fusion principles are considered to aggregate the signals from multiple sensors. In the case of apneas, since breathing movements are subtle, the video can be pre processed by a recently proposed algorithm which is able to emphasize small movements. The performance of the proposed contact-less detection algorithms is assessed, considering real video recordings of newborns, in terms of sensitivity, specificity, and Receiver Operating Characteristic (ROC) curves, with respect to medical gold standard devices. The obtained results show that a video processing based system can effectively detect the considered specific diseases, with increasing performance for increasing number of sensors. PMID- 27940320 TI - MiR-212-3p inhibits LPS-induced inflammatory response through targeting HMGB1 in murine macrophages. AB - Sepsis is a major cause of mortality in seriously ill patients characterized by a series of severe systemic inflammatory responses due to an infection. Thus, there is a critically need to search more accurate biomarkers and targets for diagnosis and treatment of sepsis. Our study showed that miR-212-3p was up-regulated in LPS treated macrophage RAW264.7 cells. Overexpression of miR-212-3p in RAW264.7 cells led to suppression of pro-inflammatory cytokines (TNF-alpha and IL-6) induced by LPS. Bioinformatic predictions and experimental researches both revealed that HMGB1 was a direct target of miR-212-3p. Meanwhile, the results showed that overexpression of miR-212-3p inhibited the cytoplasmic translocation of HMGB1 in LPS-induced RAW264.7 cells. Subsequently, transfection of the pcDNA3.1/HMGB1 plasmid, which produced HMGB1 overexpression, exhibited similar effects as the LPS-induced macrophage inflammatory response and markedly activated the MAPKs including p38, ERK and JNK phosphorylation. Furthermore, we also found that the phosphorylation of p38 MAPK and ERK was downregulated by miR-212-3p mimics upon LPS injection. In conclusion, these results reveal that miR-212-3p directly targets HMGB1 to suppress inflammatory response in LPS-induced RAW264.7 cells. All our findings indicate that miR-212-3p may act as a potential pharmacological target for promising and effective therapeutic intervention in microbial infection in the future. PMID- 27940322 TI - An improved approach for measuring the tonic stretch reflex response of spastic muscles. AB - We propose a new method for detecting the onset of the stretch reflex response for assessment of spasticity based on the Tonic Stretch Reflex Threshold (TSRT). Our strategy relies on a three-stage approach to detect the onset of the reflex EMG activity: (i) Reduction of baseline activity by means of Empirical Mode Decomposition; (ii) Extraction of the complex envelope of the EMG signal by means of Hilbert Transform (HT) and; iii) A double threshold decision rule. Simulated and real EMG data were used to evaluate and compare our method (TSRT-EHD) against three other popular methods described in the literature to assess TSRT ('Kim', 'Ferreira' and 'Blanchette'). Four different groups of signals containing simulated evoked stretch reflex EMG activities were generated: groups A and B without spontaneous EMG activity at rest and signal-to-noise ratio (SNR) of 10dB and 20dB respectively; groups C and D with spontaneous EMG activity at rest, as observed frequently in spastic muscles, and SNR of 10dB and 20dB respectively. The results with simulated data showed a significantly higher accuracy of TSRT EHD for detecting the onset of the reflex EMG activity in groups C and D when compared to the other methods. Analyses using real data from five post stroke spastic subjects demonstrated that the TSRTs generated by each method were dramatically different from one another. Nevertheless, only TSRT-EHD provided valid measures across all subjects. PMID- 27940324 TI - Effects of memantine added to risperidone on the symptoms of schizophrenia: A randomized double-blind, placebo-controlled clinical trial. AB - The "glutamate hypothesis of schizophrenia" has changed attitudes in the development of new medications. This study aimed to evaluate the effects of 20mg of memantine per day (as a NMDA receptor antagonist) added to risperidone among male patients with schizophrenia. In a randomized placebo-controlled, double blind clinical trial, 46 adult male patients with schizophrenia were evaluated in both intervention and control groups at weeks 0, 6 and 12. The positive and negative symptoms scale and the mini mental status examination were used to assess positive, negative and cognitive symptoms and general psychopathology. The mean age of the patients was 44.8 for the intervention group and 45.3 for the control group, and the mean times since diagnosis were 23.5 and 25.7 years in the intervention and the control group, respectively. Positive and general psychopathologic symptoms showed no significant differences between the two groups at baseline or after treatment; while negative symptoms improved significantly in the intervention group at week 12. Cognitive function was also significantly improved in the intervention group at weeks 6 and 12. Memantine is supported as an effective adjunct treatment to improve negative and cognitive symptoms in patients with schizophrenia. PMID- 27940323 TI - Serum lipid changes following the onset of depressive symptoms in postmenopausal women. AB - A cross-sectional association between depression and serum low-density lipoprotein cholesterol (LDL-c) has been noted in psychiatric literature, raising the question of temporality: does low LDL-c predict depression, does depression lead to changes in LDL-c levels, or is this relationship bidirectional? In a previous longitudinal analysis of postmenopausal women ages 50-79 who participated in the Women's Health Initiative (WHI), we detected an association between low LDL-c and the subsequent onset of depressive symptoms (HR=1.25, 95% CI 1.05-1.49, p=0.01). This current study uses the WHI cohort to explore the question of temporality in the opposite direction, examining the influence of depressive symptoms on subsequent changes in LDL-c levels. This study provides no evidence to suggest an association between depression and subsequent changes in LDL-c level (-2.78mg/dL, 95% CI=-7.49 to 1.92, p=0.25), nor was any association detected for total cholesterol, HDL, or triglyceride changes over time. Further, this study demonstrates that the relationship between depression and serum LDL changes is not mediated by changes in weight, exercise, or energy intake. PMID- 27940325 TI - Predictors and mental health outcomes of potentially traumatic event exposure. AB - The aims were two-fold: to examine prevalence and correlates of lifetime potentially traumatic event (PTE) exposure and to explore the relationships between PTE exposure and mental health outcomes (i.e., trauma related distress, alcohol use quantity and frequency, depression symptoms, and anxiety symptoms) within a large sample of college freshmen. 6120 participants, consisting of three cohorts of incoming freshman at a large southeastern university, completed an online assessment battery measuring a multitude of factors including PTEs, personality, relationships (i.e., parental and peer), and mental health. The majority (81.8%) of participants endorsed experiencing at least one PTE within their lifetime and 39.0% reported at least one interpersonal trauma (i.e., physical assault, sexual assault, other unwanted or uncomfortable sexual situation). The average number of PTE categories endorsed was 1.71 (SD=1.30), and 8.7% of participants reported experiencing four or more separate PTE categories pre-college entry. Female gender and peer deviance were consistently associated with PTE exposure and symptoms of psychopathology. Furthermore, a history of interpersonal PTE exposure was associated with increased alcohol use (i.e., frequency and quantity), trauma related distress, depressive symptoms, and anxiety symptoms. The data demonstrate high prevalence PTE exposure among young adults and the clinical significance of a PTE history. PMID- 27940326 TI - MicroRNA-132 attenuates neurobehavioral and neuropathological changes associated with intracerebral hemorrhage in mice. AB - Recent studies suggest that microRNA-132 (miR-132) potentiates the cholinergic blockade of inflammatory reactions by targeting acetylcholinesterase (AChE) and affords robust protection against ischemia-induced neuronal death. However, the role of miR-132 in intracerebral hemorrhage (ICH) remains unexplored. This study aimed to determine whether miR-132 participates in the process and launches an anti-inflammatory response in a mouse model of ICH. To establish a relationship between miR-132 and ICH-induced neuronal inflammation and death, we used unilateral stereotaxic injections to deliver lentiviruses encoding miR-132, anti miR-132 or an empty lentiviral vector directly into the right caudate nuclei of 192 living male C57BL/6 mice. Fourteen days later, ICH was induced by injection of autologous blood into these three groups. Neurodeficits, brain edema, blood brain barrier (BBB) integrity, inflammatory reactions, together with cell death were assessed after ICH. Compared with the control group, the mice overexpressing miR-132 in the brain responded with attenuated neurological deficits and brain edema. The counts of activated microglia and the expression of proinflammatory cytokines were also decreased in these mice. Additionally, BBB integrity improved, and the extent of neuronal death decreased in ICH mice injected with lentivirus encoding miR-132. On the contrary, a decrease of miR-132 expression aggravated the severity of inflammation and increased cell apoptosis. Overall, these findings support a protective role of miR-132 in a mouse model of ICH, providing new opportunities for therapeutic intervention. PMID- 27940328 TI - Phylogeny mandalas of birds using the lithographs of John Gould's folio bird books. AB - The phylogeny mandala, which is a circular phylogeny with photos or drawings of species, is a suitable way to show visually how the biodiversity has developed in the course of evolution as clarified by the molecular phylogenetics. In this article, in order to demonstrate the recent progress of avian molecular phylogenetics, six phylogeny mandalas of various taxonomic groups of birds are presented with the lithographs of John Gould's folio bird books; i.e., (1) whole Aves, (2) Passeriformes, (3) Paradisaeidae in Corvoidea (Passeriformes), (4) Meliphagoidea (Passeriformes), (5) Trochili in Apodiformes, and (6) Galliformes. PMID- 27940327 TI - Peptide vaccines in cancer-old concept revisited. AB - Synthetic peptide vaccines aim to elicit and expand tumor-specific T cells capable of controlling or eradicating the tumor. Despite the high expectations based on preclinical studies, the results of clinical trials using peptide vaccines have been disappointing. Thus, many researchers in the field have considered peptide vaccines as outdated and no longer viable for cancer therapy. However, recent progress in understanding the critical roles of immune adjuvants, modes of vaccine administration and T cell dynamics has lead to a rebirth of this approach and reconsidering the use of peptide vaccines for treating malignant disorders. PMID- 27940329 TI - Restructuring higher taxonomy using broad-scale phylogenomics: The living Ophiuroidea. AB - The power and throughput of next-generation sequencing is instigating a major transformation in our understanding of evolution and classification of life on our planet. The new trees of life are robust and comprehensive. Here we provide a landmark phylogeny of the living ophiuroids and use it as the basis for a major revision of the higher classification of this class of marine invertebrates. We used an exon-capture system to generate a 1484 exon (273kbp) data-matrix from DNA extracted from ethanol-preserved museum samples. We successfully obtained an average of 90% of our target sequence from 576 species spread across the known taxonomic diversity. The topology of the major lineages was robust to taxon sampling, exon-sampling, models and methods. However, estimates of node age were much less precise, varying by about a quarter of mean age. We used a combination of phylogenetic distinctiveness and temporal-banding to guide our revision of the family-level classification. Empirically, we determined that limiting family crown age to 110+/-10Ma (mid Cretaceous) selected phylogenetically distinct nodes while minimising disruption to the existing taxonomy. The resulting scheme of 32 families and six orders considerably expands the number of higher taxa. The families are generally longitudinally widespread across the world's oceans, although 17 are largely confined to temperate and equatorial latitudes and six to relatively shallow water (less than 1000m depth). PMID- 27940330 TI - In the shadows: Phylogenomics and coalescent species delimitation unveil cryptic diversity in a Cerrado endemic lizard (Squamata: Tropidurus). AB - The recognition of cryptic diversity within geographically widespread species is gradually becoming a trend in the highly speciose Neotropical biomes. The statistical methods to recognise such cryptic lineages are rapidly advancing, but have rarely been applied to genomic-scale datasets. Herein, we used phylogenomic data to investigate phylogenetic history and cryptic diversity within Tropidurus itambere, a lizard endemic to the Cerrado biodiversity hotspot. We applied a series of phylogenetic methods to reconstruct evolutionary relationships and a coalescent Bayesian species delimitation approach (BPP) to clarify species limits. The BPP results suggest that the widespread nominal taxon comprises a complex of 5 highly supported and geographically structured cryptic species. We highlight and discuss the different topological patterns recovered by concatenated and coalescent species tree methods for these closely related lineages. Finally, we suggest that the existence of cryptic lineages in the Cerrado is much more common than traditionally thought, highlighting the value of using NGS data and coalescent techniques to investigate patterns of species diversity. PMID- 27940331 TI - Cryptic lineage diversity in the zoonotic pathogen Angiostrongylus cantonensis. AB - Delimitation of species is still a necessity among parasitic pathogens especially where morphological characters provide limited discernibility. Identification of cryptic lineages (independently evolving lineages that are morphologically similar) is critical as there could be lineage-specific traits that are of epidemiological importance. Angiostrongylus cantonensis is a zoonotic pathogen that can cause eosinophilic meningitis in humans. Recent reports of single marker sequence divergence hint at the potential for cryptic diversity in this lungworm. However, to definitively address if single marker divergence corresponds to independent evolving lineages, a multilocus approach is necessary. Using multilocus data, our goal was to determine if there were cryptic lineages within Thailand, a country plagued by several outbreaks and isolated cases of A. cantonensis infection. We analyzed the genetic structure of A. cantonensis samples collected from snails, Achatina fulica, across provinces in Thailand. Multilocus data (mitochondrial sequence data and 12 nuclear microsatellites) and individual based analyses were used to test for cryptic lineages. We found strong linkage disequilibrium patterns between mitochondrial haplotypes and nuclear identified genetic clusters. There were clearly two divergent and independent clades. Moreover, within each clade, the data suggested additional substructure where individual provinces were likely to harbor unique genetic clusters. The results indicate there are at minimum two and possibly up to eight cryptic lineages within the assumed single species of A. cantonensis. Importantly, the two main clades do not show geographic affiliation and can be found in sympatry. With recent studies highlighting A. cantonensis strain diversity in pathogenicity and infectivity, it will be important to determine if these critical epidemiological traits are associated with specific lineages. PMID- 27940332 TI - Evolutionary history of a keystone pollinator parallels the biome occupancy of angiosperms in the Greater Cape Floristic Region. AB - The Greater Cape Floristic Region (GCFR) in South Africa has been extensively investigated for its phenomenal angiosperm diversity. A key emergent pattern is the occurrence of older plant lineages in the southern Fynbos biome and younger lineages in the northern Succulent Karoo biome. We know practically nothing, however, about the evolutionary history of the animals that pollinate this often highly-specialized flora. In this study, we explore the evolutionary history of an important GCFR fly pollinator, Megapalpus capensis, and ask whether it exhibits broadly congruent genetic structuring and timing of diversification to flowering plants within these biomes. We find that the oldest M. capensis lineages originated in Fynbos during the Miocene, while younger Succulent Karoo lineages diverged in the Pliocene and correspond to the proposed age of this recent biome. A strong signature of population expansion is also recovered for flies in this arid biome, consistent with recent colonization. Our first investigation into the evolutionary history of GCFR pollinators thus supports a recent origin of the SK biome, as inferred from angiosperm phylogenies, and suggests that plants and pollinators may have co-diverged within this remarkable area. PMID- 27940334 TI - Obesity in Middle Age Increases Risk of Later Heart Failure in Women-Results From the Prospective Population Study of Women and H70 Studies in Gothenburg, Sweden. AB - OBJECTIVE: Obesity has been shown to be a risk factor for heart failure (HF), but whether the association varies by age is not understood. The aim was to examine the impact of obesity/overweight on the risk of developing heart failure in women of different ages by analysing prospective data from 2 population studies. METHODS: Data were obtained from the Population Study of Women in Gothenburg and the Gerontologic and Geriatric Population Studies concerning body mass index (BMI) collected in 1980 or later. Follow-up ended in 2006. Cox proportional hazard methods were used to determine associations between developing HF and BMI in 2574 women, 1243 aged 26-65 years and 1331 aged 66-76 years, at baseline. RESULTS: Women aged 26-65 years at baseline with BMI >=30 kg/m2 had an increased risk of developing HF (hazard ratio [HR] 2.61, 95% confidence interval [CI] 1.56 4.35) even when controlling for age, glucose, smoking, alcohol consumption, serum triglycerides, and systolic blood pressure (reference group: women with BMI 18.5 22.4 kg/m2). Obese women aged 66-76 years at baseline did not show increased risk of developing HF (HR 0.55, 95% CI 0.23-1.29). CONCLUSIONS: Obesity in middle-age women increases their risk of developing HF later in life. In contrast, obesity later in life shows no association with HF. PMID- 27940333 TI - Marked phylogeographic structure of Gentoo penguin reveals an ongoing diversification process along the Southern Ocean. AB - Two main hypotheses have been debated about the biogeography of the Southern Ocean: (1) the Antarctic Polar Front (APF), acting as a barrier between Antarctic and sub-Antarctic provinces, and (2) the Antarctic Circumpolar Current (ACC), promoting gene flow among sub-Antarctic areas. The Gentoo penguin is distributed throughout these two provinces, separated by the APF. We analyzed mtDNA (HVR1) and 12 microsatellite loci of 264 Gentoo penguins, Pygoscelis papua, from 12 colonies spanning from the Western Antarctic Peninsula and the South Shetland Islands (WAP) to the sub-Antarctic Islands (SAI). While low genetic structure was detected among WAP colonies (mtDNA FST=0.037-0.133; microsatellite FST=0.009 0.063), high differentiation was found between all SAI and WAP populations (mtDNA FST=0.678-0.930; microsatellite FST=0.110-0.290). These results suggest that contemporary dispersal around the Southern Ocean is very limited or absent. As predicted, the APF appears to be a significant biogeographical boundary for Gentoo penguin populations; however, the ACC does not promote connectivity in this species. Our data suggest demographic expansion in the WAP during the last glacial maximum (LGM, about 20kya), but stability in SAI. Phylogenetic analyses showed a deep divergence between populations from the WAP and those from the SAI. Therefore, taxonomy should be further revised. The Crozet Islands resulted as a basal clade (3.57Mya), followed by the Kerguelen Islands (2.32Mya) as well as a more recent divergence between the Falkland/Malvinas Islands and the WAP (1.27Mya). Historical isolation, local adaptation, and past climate scenarios of those Evolutionarily Significant Units may have led to different potentials to respond to climate changes. PMID- 27940335 TI - Comparison Between the Kansas City Cardiomyopathy Questionnaire and New York Heart Association in Assessing Functional Capacity and Clinical Outcomes. AB - OBJECTIVE: The Kansas City Cardiomyopathy Questionnaire (KCCQ) has emerged as a patient-centered heart failure-specific health status measure. It currently lacks routine and widespread use in clinical practice and trials. The purpose of this study was to examine the correlation between KCCQ and cardiopulmonary exercise testing (CPET) parameters and clinical outcomes, compared with the New York Heart Association functional classification (NYHA). METHODS AND RESULTS: We performed a single-centered observational analysis of 432 patients who presented to the Heart Failure Department, completed the KCCQ, and underwent CPET. The 1-year clinical outcome assessed was a composite of mortality, heart failure hospitalization, and need for heart transplantation or left ventricular assist device. In the KCCQ, the physical limitation domain had a correlation with peak VO2 similar to NYHA (r = 0.48; P < .001; and r = -0.48; P < .001; respectively), and slightly better correlation with ventilatory threshold (r = 0.42; P < .001; and r = -0.40; P < .001; respectively). According to model validation, the KCCQ physical limitation domain and NYHA were similar predictors of peak VO2 (r2 = 0.229; and r2 = 0.227; respectively). KCCQ predicted the specified 1-year clinical outcome (hazard ratio 0.75, 95% confidence interval 0.69-0.82; P < .001) and provided incremental predictive ability when added to a model that included NYHA, with a net reclassification index of 76.1% (P < .001). CONCLUSIONS: KCCQ and NYHA provide similar assessment of functional capacity. KCCQ predicts 1-year clinical outcomes, providing incremental value over NYHA. These findings support its routine use in clinical care, as well as its potential to serve as a measure in clinical trials. PMID- 27940336 TI - Myocardial T1 Measurement Predicts Beneficial LV Remodeling After Long-Term Heart Failure Therapy. AB - BACKGROUND: The myocardial longitudinal relaxation time (T1) on cardiac magnetic resonance imaging (CMR) can quantify myocardial fibrosis in the presence or absence of visually detectable late gadolinium (Gd) enhancement (LGE). Mineralocorticoid receptor antagonist (MRA) treatment produces beneficial remodeling in nonischemic dilated cardiomyopathy (NIDCM). We assessed the hypothesis that interstitial myocardial fibrosis measured with the use of CMR predicts left ventricular (LV) beneficial remodeling in NIDCM after heart failure (HF) treatment including MRAs. METHODS AND RESULTS: Twelve patients with NIDCM, on stable beta-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor-blocking therapy, were studied before and after 6-29 months of treatment with MRAs, by means of CMR assessment of LV structure, function, and T1 from standard Look-Locker sequences (T1LL). All patients had depressed cardiac function, dilated left ventricles, and no visual LGE. After adding MRA to HF treatment, the LV ejection fraction increased and the LV end-systolic volume index (LV end-systolic volume/m2) decreased in all patients (P < .0001). This this was inversely proportional to the baseline myocardial T1LL (r = -0.65; P = .02). CONCLUSION: Myocardial T1LL, in the absence of visually detectable LGE, was quantitatively related to the degree of beneficial LV remodeling achieved in response to adding MRA to a HF regimen. PMID- 27940337 TI - Immobilization of levan-xylanase nanohybrid on an alginate bead improves xylanase stability at wide pH and temperature. AB - Despite the sustainable availability, levan, a fructose based natural polysaccharide has not received significant attention in the development of enzyme immobilization technology. Herein, we prepared levan-xylanase (LXy) nanohybrid and characterized by scanning electron microscopy, particle size analyzer and zeta potential. To prevent the enzyme leakage from the nanohybrid, LXy was immobilized onto an alginate beads (NaAlg). Immobilization yield was optimized using a statistical method, central composite design. A maximum immobilization yield of 95.3% was achieved at 2.13% (w/v) of sodium alginate, 2.14% (w/v) of calcium chloride, 64min of curation time and 1.4mm bead size. Immobilized LXy retains nearly 80% of the enzyme activity at a wide range of temperature (20-90 degrees C) and pH (3-10). Immobilization of LXy onto NaAlg increases the activation energy from 28.50Jmol-1K-1 to 39.38Jmol-1K-1. Collectively, this result implies that LXy immobilized onto NaAlg increases the enzyme stability and retains its activity. PMID- 27940338 TI - The effect of alpha-ketoglutaric acid on tyrosinase activity and conformation: Kinetics and molecular dynamics simulation study. AB - Alpha-ketoglutaric acid (AKG) is naturally found in organisms and is a well-known intermediate in the production of ATP or GTP in the Krebs cycle. We elucidated the effects of AKG on tyrosinase activity and conformation via methods of inhibition kinetics integrated with molecular dynamics (MD) simulations. AKG was found to be a reversible inhibitor of tyrosinase (IC50=15+/-0.5mM) and induced parabolic slope mixed-type inhibition. Based on our newly established equation, the dissociation constant (Kislope) was determined to be 7.93+/-0.31mM. The spectrofluorimetry studies showed that AKG mainly induced regional changes in the active site of tyrosinase, which reflects the flexibility of the active site. The computational docking and molecular dynamics (MD) simulations further demonstrated that AKG could interact with several residues near the substrate binding site located in the tyrosinase active site pocket. Our study provides insight into the mechanism by which energy-producing intermediates such as AKG inhibit tyrosinase through its ketone groups. Also, AKG could be a potential natural antipigmentation agent due to its non-toxic property. PMID- 27940339 TI - Characterization of an arylsulfatase from a mutant library of Pseudoalteromonas carrageenovora arylsulfatase. AB - A library of Pseudoalteromonas carrageenovora arylsulfatase mutants was constructed by introducing random mutagenesis using error-prone PCR. After screening, one mutant strain was obtained whose arylsulfatase had improved thermal stability. Protein sequence analysis revealed one amino acid substitution of H260L. The mutant arylsulfatase (named H260L) retained higher residual activity than wild-type enzyme (named WT) after incubation at 45, 50, 55 and 60 degrees C for 60min. Thermal inactivation analysis showed that the half-life (t1/2) value at 55 degrees C for H260L was 40.6min, while that of WT was 9.1min. When p-nitrophenyl sulfate was used as a substrate, the optimal reaction temperature and pH for the mutant enzyme were 55 degrees C and pH 8.0, respectively. H260L was stable over the pH range of 6.0-9.0. Inhibition assay with EDTA indicated that metal ions play an important role during the catalytic process of the mutant enzyme. The desulfation ratio against agar of Gracilaria lemaneiformis was 82%. PMID- 27940340 TI - Inhibition of tyrosinase by fumaric acid: Integration of inhibition kinetics with computational docking simulations. AB - Fumaric acid (FA), which is naturally found in organisms, is a well known intermediate of the citric acid cycle. We evaluated the effects of FA on tyrosinase activity and structure via enzyme kinetics and computational simulations. FA was found to be a reversible inhibitor of tyrosinase and its induced mechanism was the parabolic non-competitive inhibition type with IC50=13.7+/-0.25mM and Kislope=12.64+/-0.75mM. We newly established the equation for the dissociation constant (Kislope) for the parabolic inhibition type in this study. Kinetic measurements and spectrofluorimetry studies showed that FA induced regional changes in the active site of tyrosinase. One possible binding site for FA was identified under the condition without L-DOPA. The computational docking simulations further revealed that FA can interact with HIS263 and HIS85 at the active site. Furthermore, four important hydrogen bonds were found to be involved with the docking of FA on tyrosinase. Our study provides insight into the mechanism by which dicarboxylic acids such as FA inhibit tyrosinase. By inhibiting tyrosinase and its central role in pigment production, FA is a potential natural antipigmentation agent. PMID- 27940341 TI - Composition quantification of electron-transparent samples by backscattered electron imaging in scanning electron microscopy. AB - The contrast of backscattered electron (BSE) images in scanning electron microscopy (SEM) depends on material parameters which can be exploited for composition quantification if some information on the material system is available. As an example, the In-concentration in thin InxGa1-xAs layers embedded in a GaAs matrix is analyzed in this work. The spatial resolution of the technique is improved by using thin electron-transparent specimens instead of bulk samples. Although the BSEs are detected in a comparably small angular range by an annular semiconductor detector, the image intensity can be evaluated to determine the composition and local thickness of the specimen. The measured intensities are calibrated within one single image to eliminate the influence of the detection and amplification system. Quantification is performed by comparison of experimental and calculated data. Instead of using time-consuming Monte-Carlo simulations, an analytical model is applied for BSE-intensity calculations which considers single electron scattering and electron diffusion. PMID- 27940342 TI - Social learning within a community of practice: Investigating interactions about evaluation among zoo education professionals. AB - The accessibility and ubiquity of zoos and aquariums-which reach over 700 million people worldwide annually-make them critical sites for science and environmental learning. Through educational offerings, these sites can generate excitement and curiosity about nature and motivate stewardship behavior, but only if their programs are high quality and meet the needs of their audiences. Evaluation is, therefore, critical: knowing what works, for whom, and under what conditions must be central to these organizations. Yet, many zoo and aquarium educators find evaluation to be daunting, and they are challenged to implement evaluations and/or use the findings iteratively in program development and improvement. This article examines how zoo education professionals engage with one another in a learning community related to evaluation. We use a communities of practice lens and social network analysis to understand the structure of this networked learning community, considering changes over time. Our findings suggest that individuals' roles in a networked learning community are influenced by factors such as communicative convenience and one's perceptions of others' evaluation expertise, which also contribute to forming and sustaining professional relationships. This study illuminates how project-based professional networks can become communities of practice. PMID- 27940343 TI - Factors contributing to eviction from permanent supportive housing: Lessons from HUD-VASH. AB - INTRODUCTION: Eviction from housing is associated with several negative outcomes, further exacerbated among high-need populations requiring financial and supportive services to maintain housing stability. This study investigated risk and protective factors-both characteristics and precipitating events of tenant eviction-informing permanent supportive housing (PSH) programs' efforts to identify tenants at risk and intervene. METHODS: Using administrative data for a cohort of 20,146 Veterans participating in PSH, this study assessed differences in Veterans who exited the program due to eviction and Veterans who exited because they accomplished their goals. A series of logistic regressions identified patterns of health services use that may signal imminent eviction. RESULTS: Veterans with a drug use disorder and those who received inpatient, emergency, or outpatient care related to mental/behavioral health and substance use conditions proximal to program exit had greater risk for eviction. Receipt of outpatient primary medical care and supportive services was generally protective against eviction. The likelihood of eviction was greatest for Veterans with acute care use within 30days of exit. DISCUSSION: PSH providers may use these correlates of eviction to identify Veterans in need of an intervention to prevent eviction. Future work should focus on operationalizing these findings and identifying appropriate interventions. PMID- 27940344 TI - Melatonin influences NO/NOS pathway and reduces oxidative and nitrosative stress in a model of hypoxic-ischemic brain damage. AB - In this work, using a rat model combining ischemia and hypobaric hypoxia (IH), we evaluate the relationships between the antioxidant melatonin and the cerebral nitric oxide/nitric oxide synthase (NO/NOS) system seeking to ascertain whether melatonin exerts its antioxidant protective action by balancing this key pathway, which is highly involved in the cerebral oxidative and nitrosative damage underlying these pathologies. The application of the IH model increases the expression of the three nitric oxide synthase (NOS) isoforms, as well as nitrogen oxide (NOx) levels and nitrotyrosine (n-Tyr) impacts on the cerebral cortex. However, melatonin administration before IH makes nNOS expression response earlier and stronger, but diminishes iNOS and n-Tyr expression, while both eNOS and NOx remain unchanged. These results were corroborated by nicotine adenine dinucleotide phosphate diaphorase (NADPH-d) staining, as indicative of in situ NOS activity. In addition, the rats previously treated with melatonin exhibited a reduction in the oxidative impact evaluated by thiobarbituric acid reactive substances (TBARS). Finally, IH also intensified glial fibrillary acidic protein (GFAP) expression, reduced hypoxia-inducible factor-1alpha (HIF-1alpha), but did not change nuclear factor kappa B (NF-kappaB); meanwhile, melatonin did not significantly affect any of these patterns after the application of the IH model. The antioxidant melatonin acts on the NO/NOS system after IH injury balancing the release of NO, reducing peroxynitrite formation and protecting from nitrosative/oxidative damage. In addition, this paper raises questions concerning the classical role of some controversial molecules such as NO, which are of great consequence in the final fate of hypoxic neurons. We conclude that melatonin protects the brain from hypoxic/ischemic-derived damage in the first steps of the ischemic cascade, influencing the NO/NOS pathway and reducing oxidative and nitrosative stress. PMID- 27940345 TI - Characterization of S-nitrosoglutathione reductase from Brassica and Lactuca spp. and its modulation during plant development. AB - Cellular homeostasis of S-nitrosoglutathione (GSNO), a major cache of nitric oxide bioactivity in plants, is controlled by the NADH-dependent S nitrosoglutathione reductase (GSNOR) belonging to the family of class III alcohol dehydrogenases (EC 1.1.1.1). GSNOR is a key regulator of S-nitrosothiol metabolism and is involved in plant responses to abiotic and biotic stresses. This study was focused on GSNOR from two important crop plants, cauliflower (Brassica oleracea var. botrytis, BoGSNOR) and lettuce (Lactuca sativa, LsGSNOR). Both purified recombinant GSNORs were characterized in vitro and found to exists as dimers, exhibit high thermal stability and substrate preference towards GSNO, although both enzymes have dehydrogenase activity with a broad range of long chain alcohols and omega-hydroxy fatty acids in presence of NAD+. Data on enzyme affinities to their cofactors NADH and NAD+ obtained by isothermal titration calorimetry suggest the high affinity to NADH might underline the GSNOR capacity to function in the intracellular environment. GSNOR activity and gene expression peak during early developmental stages of lettuce and cauliflower at 20 and 30 days after germination, respectively. GSNOR activity was also measured in four other Lactuca spp. genotypes with different degree of resistance to biotrophic pathogen Bremia lactucae. Higher GSNOR activities were found in non-infected plants of susceptible genotypes L. sativa UCDM2 and L. serriola as compared to resistant genotypes. GSNOR and GSNO were localized by confocal laser scanning microscopy in vascular bundles and in epidermal and parenchymal cells of leaf cross-sections. The presented results bring new insight in the role of GSNOR in the regulation of S-nitrosothiol levels in plant growth and development. PMID- 27940346 TI - Spectator no more, the role of the membrane in regulating ion channel function. AB - A pressure gradient across a curved lipid bilayer leads to a lateral force within the bilayer. Following ground breaking work on eukaryotic ion channels, it is now known that many proteins sense this change in the lateral tension and alter their functions in response. It has been proposed that responding to pressure differentials may be one of the oldest signaling mechanisms in biology. The most well characterized mechanosensing ion channels are the bacterial ones which open when the pressure differential hits a threshold. Recent studies on one of these channels, MscS, have developed a simple molecular model for how they sense and adapt to pressure. Biochemical and structural studies on mechanosensitive channels from eukaryotes have disclosed pressure sensing mechanisms. In this review, we highlight these findings and discuss the potential for a general model for pressure sensing. PMID- 27940347 TI - Proteasome inhibitors in cancer therapy: Treatment regimen and peripheral neuropathy as a side effect. AB - Proteasomal system plays an important role in protein turnover, which is essential for homeostasis of cells. Besides degradation of oxidized proteins, it is involved in the regulation of many different signaling pathways. These pathways include mainly cell differentiation, proliferation, apoptosis, transcriptional activation and angiogenesis. Thus, proteasomal system is a crucial target for treatment of several diseases including neurodegenerative diseases, cystic fibrosis, atherosclerosis, autoimmune diseases, diabetes and cancer. Over the last fifteen years, proteasome inhibitors have been tested to highlight their mechanisms of action and used in the clinic to treat different types of cancer. Proteasome inhibitors are mainly used in combinational therapy along with classical chemo-radiotherapy. Several studies have proved their significant effects but serious side effects such as peripheral neuropathy, limits their use in required effective doses. Recent studies focus on peripheral neuropathy as the primary side effect of proteasome inhibitors. Therefore, it is important to delineate the underlying mechanisms of peripheral neuropathy and develop new inhibitors according to obtained data. This review will detail the role of proteasome inhibition in cancer therapy and development of peripheral neuropathy as a side effect. Additionally, new approaches to prevent treatment limiting side effects will be discussed in order to help researchers in developing effective strategies to overcome side effects of proteasome inhibitors. PMID- 27940348 TI - PEG-functionalized zinc oxide nanoparticles induce apoptosis in breast cancer cells through reactive oxygen species-dependent impairment of DNA damage repair enzyme NEIL2. AB - We find that PEG functionalized ZnO nanoparticles (NP) have anticancer properties primarily because of ROS generation. Detailed investigation revealed two consequences depending on the level of ROS - either DNA damage repair or apoptosis - in a time-dependent manner. At early hours of treatment, NP promote NEIL2-mediated DNA repair process to counteract low ROS-induced DNA damage. However, at late hours these NP produce high level of ROS that inhibits DNA repair process, thereby directing the cell towards apoptosis. Mechanistically at low ROS conditions, transcription factor Sp1 binds to the NEIL2 promoter and facilitates its transcription for triggering a 'fight-back mechanism' thereby resisting cancer cell apoptosis. In contrast, as ROS increase during later hours, Sp1 undergoes oxidative degradation that decreases its availability for binding to the promoter thereby down-regulating NEIL2 and impairing the repair mechanism. Under such conditions, the cells strategically switch to the p53-dependent apoptosis. PMID- 27940349 TI - Autophagy as a regulator of cardiovascular redox homeostasis. AB - Autophagy is a highly regulated process involving the removal of damaged proteins and organelles from cells and tissues through a lysosomal-mediated pathway. Accumulating evidence suggests that autophagy is necessary to maintain redox homeostasis. Here, we explore the connection between autophagy and reactive oxygen species (ROS). In particular, we discuss how oxidant-dependent signaling can modulate autophagic flux and how autophagy can, in turn, modulate ROS levels. Finally, we discuss how a decline or disruption of autophagy might contribute to redox-dependent cardiovascular pathology and help fuel the age-dependent decline in cardiovascular function. PMID- 27940351 TI - Unexpected marked seizure improvement in paediatric epilepsy surgery candidates. AB - PURPOSE: Epilepsy surgery is performed based on the assumption that medical refractory epilepsy will continue. Rarely seizure freedom occurs before surgery is performed, while the patient is being evaluated as an epilepsy surgery candidate. The aim of this study was to describe the number of children withdrawn from an epilepsy surgery programme due to unexpected seizure improvement. METHODS: We retrospectively studied 173 children under 18 years with medical refractory epilepsy referred for epilepsy surgery between 1996 and 2010. Medical records were reviewed in 2012 and 2015. RESULTS: At the first evaluation point in 2012, 13 patients were withdrawn from the epilepsy surgery programme due to unexpected marked improvement. In 2015, 6 of them were still seizure free. They had unexpected seizure freedom due to change in AED treatment (n=3) or after a febrile episode (n=3). The mean number of years they had had seizures was 3.4 years (range 0.6-6.2 years) and the number of seizures at inclusion was 209 per month (range 6-750 per month). The duration of follow-up was 6.6 years after inclusion into the epilepsy surgery programme (range 4.0-13.0 years). The aetiology of the epilepsy for these patients was heterotopia (n=1), focal cortical dysplasia (n=3), infarction (n=1) and unknown, with normal MRI (n=1). They all had an IQ in the normal range. Two of the remaining 7 children were operated later. CONCLUSION: Unexpected seizure control may occur during epilepsy surgery evaluation. PMID- 27940352 TI - Gray matter network differences between behavioral variant frontotemporal dementia and Alzheimer's disease. AB - We set out to study whether single-subject gray matter (GM) networks show disturbances that are specific for Alzheimer's disease (AD; n = 90) or behavioral variant frontotemporal dementia (bvFTD; n = 59), and whether such disturbances would be related to cognitive deficits measured with mini-mental state examination and a neuropsychological battery, using subjective cognitive decline subjects as reference. AD and bvFTD patients had a lower degree, connectivity density, clustering, path length, betweenness centrality, and small world values compared with subjective cognitive decline. AD patients had a lower connectivity density than bvFTD patients (F = 5.79, p = 0.02; mean +/- standard deviation bvFTD 16.10 +/- 1.19%; mean +/- standard deviation AD 15.64 +/- 1.02%). Lasso logistic regression showed that connectivity differences between bvFTD and AD were specific to 23 anatomical areas, in terms of local GM volume, degree, and clustering. Lower clustering values and lower degree values were specifically associated with worse mini-mental state examination scores and lower performance on the neuropsychological tests. GM showed disease-specific alterations, when comparing bvFTD with AD patients, and these alterations were associated with cognitive deficits. PMID- 27940350 TI - Responses to reductive stress in the cardiovascular system. AB - There is a growing appreciation that reductive stress represents a disturbance in the redox state that is harmful to biological systems. On a cellular level, the presence of increased reducing equivalents and the lack of beneficial fluxes of reactive oxygen species can prevent growth factor-mediated signaling, promote mitochondrial dysfunction, increase apoptosis, and decrease cell survival. In this review, we highlight the importance of redox balance in maintaining cardiovascular homeostasis and consider the tenuous balance between oxidative and reductive stress. We explain the role of reductive stress in models of protein aggregation-induced cardiomyopathies, such as those caused by mutations in alphaB crystallin. In addition, we discuss the role of NADPH oxidases in models of heart failure and ischemia-reperfusion to illustrate how oxidants may mediate the adaptive responses to injury. NADPH oxidase 4, a hydrogen peroxide generator, also has a major role in promoting vascular homeostasis through its regulation of vascular tone, angiogenic responses, and effects on atherogenesis. In contrast, the lack of antioxidant enzymes that reduce hydrogen peroxide, such as glutathione peroxidase 1, promotes vascular remodeling and is deleterious to endothelial function. Thus, we consider the role of oxidants as necessary signals to promote adaptive responses, such as the activation of Nrf2 and eNOS, and the stabilization of Hif1. In addition, we discuss the adaptive metabolic reprogramming in hypoxia that lead to a reductive state, and the subsequent cellular redistribution of reducing equivalents from NADH to other metabolites. Finally, we discuss the paradoxical ability of excess reducing equivalents to stimulate oxidative stress and promote injury. PMID- 27940354 TI - Pharmacogenetic association of MBL2 and CD95 polymorphisms with grade 3 infection following adjuvant therapy for breast cancer with doxorubicin and cyclophosphamide. AB - Life-threatening infection as an adverse reaction to cytotoxic therapy of cancer remains a major problem, potentially limiting efficacy. Administration of colony stimulation factors benefits only a minority of patients, and improved stratification guidelines are needed to identify those patients likely to benefit. We investigated single nucleotide polymorphisms (SNPs) in two genes related to immune function to identify associations with severe infection following treatment of breast cancer with doxorubicin and cyclophosphamide. CD95 mediates the extrinsic apoptosis pathway in haematopoietic cells and a CD95 promoter SNP (rs2234767) has been shown to result in reduced expression of the receptor. MBL2 activates the classical complement pathway in the presence of pathogens and independently of antibodies. Numerous SNPs have been described including a promoter SNP (rs7096206) which results in decreased expression of the protein. Homozygotes for the CD95 minor allele were more likely to experience a grade 3 infection than heterozygote and homozygote wild-type patients (29%, 3% and 5%, respectively p=0.048). CD95 minor allele homozygotes also had higher basal white blood cell and neutrophil counts compared with wild-type allele carriers, which was sustained throughout therapy. There was an allele-dose association between the MBL2 SNP and grade 3 infection, with 2, 8 and 17% of wild type homozygotes, heterozygotes and minor allele homozygotes, respectively, experiencing grade 3 infection (p=0.02). These associations demonstrate the utility of a pharmacogenetic approach to identify individuals more likely to acquire a life-threatening infection during chemotherapy. The apparent association with a CD95 SNP and a mild neutrophilia merits further investigation. PMID- 27940355 TI - Temporary ovarian suppression during chemotherapy to preserve ovarian function and fertility in breast cancer patients: A GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology. AB - The development of premature ovarian failure and subsequent infertility are possible consequences of chemotherapy use in pre-menopausal women with early stage breast cancer. Among the available strategies for fertility preservation, pharmacological protection of the ovaries using luteinising hormone-releasing hormone analogues (LHRHa) during chemotherapy has the potential to restore ovarian function and fertility after anticancer treatments; however, the possible efficacy and clinical application of this strategy has been highly debated in the last years. Following the availability of new data on this controversial topic, the Panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guideline on fertility preservation in cancer patients decided to apply the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology around the relevant and current question on the clinical utility of temporary ovarian suppression with LHRHa during chemotherapy as a strategy to preserve ovarian function and fertility in breast cancer patients. To answer this question, preservation of ovarian function and fertility were judged as critical outcomes for the decision-making. Three possible outcomes of harm were identified: LHRHa-associated toxicities, potential antagonism between concurrent LHRHa and chemotherapy, and lack of the prognostic impact of chemotherapy-induced premature ovarian failure. According to the GRADE evaluation conducted, the result was a strong positive recommendation in favour of using this option to preserve ovarian function and fertility in breast cancer patients. The present manuscript aims to update and summarise the evidence for the use of this strategy in light of the new data published up to January 2016, according to the GRADE process. PMID- 27940353 TI - White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies. AB - We investigated cognitive function, axonal/white matter (WM) changes and glymphatic function of vascular dementia using a multiple microinfarction (MMI) model in retired breeder (RB) rats. The MMI model induces significant (p < 0.05) cognitive decline that worsens with age starting at 2 weeks, which persists until at least 6 weeks after MMI. RB rats subjected to MMI exhibit significant axonal/WM damage identified by decreased myelin thickness, oligodendrocyte progenitor cell numbers, axon density, synaptic protein expression in the cortex and striatum, cortical neuronal branching, and dendritic spine density in the cortex and hippocampus compared with age-matched controls. MMI evokes significant dilation of perivascular spaces as well as water channel dysfunction indicated by decreased Aquaporin-4 expression around blood vessels. MMI-induced glymphatic dysfunction with delayed cerebrospinal fluid penetration into the brain parenchyma via paravascular pathways as well as delayed waste clearance from the brain. The MMI model in RB rats decreases Aquaporin-4 and induces glymphatic dysfunction which may play an important role in MMI-induced axonal/WM damage and cognitive deficits. PMID- 27940356 TI - Locoregional treatment and overall survival of men with T1a,b,cN0M0 breast cancer: A population-based study. AB - BACKGROUND: Male breast cancer (MaBC) is an understudied disease; information about locoregional treatment and outcomes in patients with early stage is unknown. We aimed to analyse patient characteristics, locoregional treatment and overall survival (OS) of T1a,b,cN0M0 male breast cancer. METHODS: We evaluated men with T1a,b,cN0M0 breast cancer reported to Surveillance, Epidemiology, and End Results program from 1988 to 2012. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. RESULTS: We included 1263 patients. Median age was 66 years (range 27-103). Median follow-up was 62 months (range 1-294). OS at 5 and 10 years were 85.1% and 66.5%, respectively. Distribution according to tumour sub-stage was: T1a 6.5%, T1b 20.7% and T1c 72.8%. Mastectomy was performed in >74% of patients of each tumour size group and overall 44.1% had >5 lymph nodes examined (LNE). Univariate analysis showed that patients with T1c, no surgery and 0 LNE had worse prognosis. In multivariate analysis, older age (hazard ratio [HR] 11.09), grade 3/4 tumours (HR 1.7), no surgery (HR 3.3), 0 LNE (HR 5.1) and unmarried patients (HR 1.7) had significantly shorter OS. There were no differences in OS between breast conservation versus mastectomy and 1-5 LNE versus > 5 LNE. CONCLUSION: Men with early breast cancer have a favourable OS. However, older age, higher grade, no breast surgery, no LNE and unmarried status emerged as poor prognostic characteristics. Efforts to decrease the high rates of mastectomy and extensive LNE should be taken given similar OS observed with breast conservation and 1-5 LNE, respectively. PMID- 27940357 TI - The regulation of high insulin levels on ovary apoptosis in early pregnant mice. AB - Studies have shown that metabolic syndrome is associated with reproductive problems. Women with metabolic syndrome, characterized by hyperinsulinemia, have common ovarian dysfunction, but the mechanism remains elusive. The aim of this research is to explore the effects of high levels of insulin on ovary function during early pregnancy. Mice in the high insulin-exposed group were given a subcutaneous injection of human recombinant insulin. After insulin treatment, changes in various hormones were tested using ELISA kits which showed hormones secreted by the ovary were significantly altered in the insulin group. TUNEL staining showed less TUNEL-positive cells in the insulin group. A significant decrease in Bax and an increase in Bcl2 in the ovary were found in the insulin group by immunohistochemical studies. Western blotting showed the expressions of apoptosis related proteins in the ovaries from the insulin group were obviously altered. In addition, expression of p-Akt proteins in the ovaries from the insulin group was significantly upregulated. Moreover, the Akt inhibitor LY294002 reversed the anti-apoptotic effects of high insulin in the ovary tissues in early pregnancy mice. All of these results showed that insulin impaired ovarian function during early pregnancy and ovarian apoptosis is imbalanced under the role of insulin. The PI3K/AKT signalling pathway might participate in this process. PMID- 27940358 TI - Dimerization of the antimicrobial peptide arenicin plays a key role in the cytotoxicity but not in the antibacterial activity. AB - The beta-hairpin antimicrobial peptides arenicins from marine polychaeta Arenicola marina exhibit a broad spectrum of antimicrobial activity and high cytotoxicity. In this study the biological activities of arenicin-1 and its therapeutically valuable analog Ar-1[V8R] were investigated. The peptide Ar 1[V8R] displays significantly reduced cytotoxicity against mammalian cells relative to the wild-type arenicin-1. At the same time, both peptides exhibit similar antibacterial activities and kinetics of bacterial membrane permeabilization. Comparative NMR analysis of the peptides spatial structures in water and membrane-mimicking environment showed that Ar-1[V8R] in contrast to arenicin has significantly lower dimerization propensity. Thus, dimerization of the antimicrobial peptide arenicin plays a key role in the cytotoxicity but not in the antibacterial activity. PMID- 27940359 TI - The new obesity-associated protein, neuronal growth regulator 1 (NEGR1), is implicated in Niemann-Pick disease Type C (NPC2)-mediated cholesterol trafficking. AB - Neuronal growth regulator 1 (NEGR1) is a newly identified raft-associated protein, which has recently been spotlighted as a new locus related to human obesity. Niemann-Pick disease Type C2 (NPC2) protein functions as a key player in the intracellular cholesterol trafficking, and its defect is linked to a fatal human neurodegenerative disease, NPC. In this study, we identified that NEGR1 interacts with NPC2 and increases its protein stability. Ectopically expressed NEGR1 proteins relieved an abnormal cholesterol accumulation in endosomal compartments. Importantly, NEGR1-defective mouse embryonic fibroblast cells exhibit increased cholesterol levels and triglyceride contents. These findings provide the first insight into the role of NEGR1 in intracellular cholesterol homeostasis, possibly explaining the missing link between NEGR1 with human obesity. PMID- 27940360 TI - A new fluorescence-based method to monitor the pH in the thylakoid lumen using GFP variants. AB - The DeltapH-dependent/Tat pathway is unique for using only the proton motive force for driving proteins transport across the thylakoid membrane in chloroplasts. 9-aminoacridine fluorescence quenching is widely used to monitor the DeltapH developed across the thylakoid membrane in the light. However, this method suffers from limited sensitivity to low DeltapH values and to spurious fluorescence signals due to membrane binding. In order to develop a more sensitive method for monitoring the real pH of the thylakoid lumen without these problems we transformed Arabidopsis thaliana with a ratiometric pH-sensitive GFP variant (termed pHluorin) targeted to the lumen by the prOE17 transit peptide. Positive transgenic plants displayed localization of pHluorin in the chloroplast by confocal microscopy, and fractionation experiments revealed that it is in the lumen. The pHluorin signal was the strongest in very young plants and diminished as the plants matured. The pHluorin released from the lumen displayed the expected fluorescence intensity changes in response to pH titration. The fluorescence signal in isolated chloroplasts responded to illumination in a manner consistent with light-dependent lumen acidification. Future experiments will exploit the use of this new pH-indicating probe of the thylakoid lumen to examine the influence of the thylakoid DeltapH on ATP synthesis and protein transport. PMID- 27940361 TI - Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down regulating CCL2 expression in both in vivo and in vitro Parkinson's disease models. AB - The abnormality of nuclear receptor-related protein 1 (Nurr1) in expression and function can contribute to neurodegeneration of dopaminergic neurons and occurrence of Parkinson's disease (PD). However, its related mechanism in PD is still unknown. In this study, we found that Nurr1 was down-regulated and CCL2 was up-regulated in PD patients and PD mice. CCL2 promoted apoptosis and secretion of TNF-alpha and IL-1beta in SH-SY5Y cells and inhibited cell viability while knockdown of CCL2 exerted the opposite effects. Nurr1 overexpression inhibited apoptosis, the release of TNF-alpha and IL-1beta and promoted viability in alpha Syn-treated SH-SY5Y cells, which was markedly promoted by CCL2 antibody and dramatically reversed by CCL2. Nurr1 overexpression negatively regulated CCL2 expression in vivo and in vitro. Furthermore, Nurr1 overexpression remarkably relieved MPTP-induced movement disorder and spatial memory deficits and played neuroprotective and anti-inflammatory roles in MPTP-induced PD mice by down regulating CCL2 in vivo. In conclusion, Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 in both in vivo and in vitro PD models, contributing to developing mechanism-based and neuroprotective strategies against PD. PMID- 27940363 TI - Evidence for presynaptically silent synapses in the immature hippocampus. AB - Silent synapses show NMDA receptor (NMDAR)-mediated synaptic responses, but not AMPAR-mediated synaptic responses. A prevailing hypothesis states that silent synapses contain NMDARs, but not AMPARs. However, alternative presynaptic hypotheses, according to which AMPARs are present at silent synapses, have been proposed; silent synapses show slow glutamate release via a fusion pore, and glutamate spillover from the neighboring synaptic terminals. Consistent with these presynaptic hypotheses, the peak glutamate concentrations at silent synapses have been estimated to be ?170 MUM, much lower than those seen at functional synapses. Glutamate transients predicted based on the two presynaptic mechanisms have been shown to activate only high-affinity NMDARs, but not low affinity AMPARs. Interestingly, a previous study has developed a new approach to distinguish between the two presynaptic mechanisms using dextran, an inert macromolecule that reduces the diffusivity of released glutamate: postsynaptic responses through the fusion pore mechanism, but not through the spillover mechanism, are potentiated by reduced glutamate diffusivity. Therefore, we reasoned that if the fusion pore mechanism underlies silent synapses, dextran application would reveal AMPAR-mediated synaptic responses at silent synapses. In the present study, we recorded AMPAR-mediated synaptic responses at the CA3-CA1 synapses in neonatal rats in the presence of blockers for NMDARs and GABAARs. Bath application of dextran revealed synaptic responses at silent synapses. GYKI53655, a selective AMPAR-antagonist, completely inhibited the unsilenced synaptic responses, indicating that the unsilenced synaptic responses are mediated by AMPARs. The dextran-mediated reduction in glutamate diffusivity would also lead to the activation of metabotropic glutamate receptors (mGluRs), which might induce unsilencing via the activation of unknown intracellular signaling. Hence, we determined whether mGluR-blockers alter the dextran-induced unsilencing. However, dextran application continued to produce significant synaptic unsilencing in the presence of a cocktail of the blockers for all subtypes of mGluRs. Our findings provide evidence that slowed glutamate diffusion produces synaptic unsilencing by enhancing the peak glutamate occupancy of pre existing AMPARs, supporting the fusion pore mechanism of silent synapses. PMID- 27940364 TI - Rigor and replication: Toward improved best practices in human electrophysiology research. PMID- 27940362 TI - STAT3 stimulates adipogenic stem cell proliferation and cooperates with HMGA2 during the early stage of differentiation to promote adipogenesis. AB - Signal transducer and activator of transcription 3 (STAT3) is abundantly expressed in the adipose tissue of obese mice and humans, but the role of STAT3 in adipogenesis is still not fully understood. In the present study, we discovered an activation of STAT3 during the early differentiation stage of mouse 3T3-L1 preadipocytes. Stat3 knockdown using siRNA blocked cell cycle progression of both preadipoctes and early differentiating cells. Moreover, accumulation of lipid droplets was inhibited by Stat3 knockdown. Importantly, in the nucleus of early differentiating cells, we demonstrated that STAT3 protein co-localized with high-mobility-group protein AT-hook 2 (HMGA2), which was reported to promote adipogenesis in a previous study. Taken together, our data indicate that STAT3 and HMGA2 cooperatively promote adipogenesis which highlight a more detail understanding of STAT3 related transcription factor network during adipogenesis. PMID- 27940365 TI - The role of language skills and internationalization in nursing degree programmes: A literature review. AB - Globalization and internationalization have had major influences on higher education, including nursing education. Since the signing of the Bologna declaration, many institutions in Europe have adopted English as the "scientific lingua franca", and have instated courses and entire degree programmes taught in English. Several countries in the European Union also offer nursing degree programmes in English. With the rise of multilingualism in Europe, new challenges have become apparent in multilingual education. The Content and Language Integrated Learning (CLIL) approach has emerged as a new, innovative way to learn languages. The approach has become mainstream in primary and secondary education with proven success, and has also spread to higher education. Nurses are required to develop their linguistic skills such that they can communicate well with their patients and colleagues. Due to globalization, nurses are faced with increasingly diverse patients, presenting new challenges in nursing education concerning linguistic and transcultural preparation of students. Although CLIL is becoming more widely accepted in many academic faculties, it has not yet been studied sufficiently in the nursing education context. PMID- 27940366 TI - Identification and functional analysis of dual-specificity MAP kinase phosphatase 6 gene (dusp6) in response to immune challenges in Japanese flounder Paralichthys olivaceus. AB - Dual-specificity phosphatase 6 (Dusp6) is a member of mitogen-activated protein kinase (MAPK) phosphatases that play crucial roles in regulating MAPK signaling and immune response. The immunological relevance of Dusp6 in fish, however, remains largely uncharacterized. In the present study, a full-length Japanese flounder dusp6 cDNA ortholog, termed PoDusp6, was identified and characterized from Paralichthys olivaceus. The deduced PoDusp6 protein is comprised of 383 amino acids with a conserved N-terminal regulatory rhodanese homology domain and a C-terminal catalytic domain. Immunofluorescence microscopy revealed that PoDusp6 protein is mainly localized in cytoplasm. Sequence analysis indicates that PoDusp6 is highly conserved (>70% identity) throughout the evolution from teleost to mammals. In unstimulated conditions, PoDusp6 mRNA was present in all examined tissues and showed the highest expression in Japanese flounder head kidney macrophages (HKMs). Immune challenge experiments revealed that the expression of PoDusp6 was down-regulated at the early stage after LPS and poly(I:C) stimulations but significantly up-regulated at the later stage in the HKMs. The similar expression pattern was also observed in the Japanese flounder immune-related tissues including head kidney, gill and spleen upon bacterial challenge with Edwardsiella tarda. Overexpression of PoDusp6 in Japanese flounder FG-9307 cells led to a significant down-regulation of proinflammatory cytokine genes IL-1beta, TNF-alpha and IFN-gamma, and antiviral gene Mx. Interestingly, inhibition of Dusp6 activity also down-regulated the LPS-induced IL-beta gene expression but did not affected on the LPS-induced IFN-gamma and TNF-alpha expression in the HKMs. Our findings suggest that the expression of PoDusp6 is modulated by immune stimuli and PoDusp6 may act as an essential modulator in fish inflammatory response. PMID- 27940368 TI - Work environment characteristics associated with quality of care in Dutch nursing homes: A cross-sectional study. AB - BACKGROUND: A lack of relationship between direct care staffing levels and quality of care, as found in prior studies, underscores the importance of considering the quality of the work environment instead of only considering staff ratios. Only a few studies, however, have combined direct care staffing with work environment characteristics when assessing the relationship with quality of care in nursing homes. OBJECTIVES: To examine the relationship between direct care staffing levels, work environment characteristics and perceived quality of care in Dutch nursing homes. DESIGN: Cross-sectional, observational study in cooperation with the Dutch Prevalence Measurement of Care Problems. SETTINGS: Twenty-four somatic and 31 psychogeriatric wards from 21 nursing homes in the Netherlands. PARTICIPANTS: Forty-one ward managers and 274 staff members (registered nurses or certified nurse assistants) from the 55 participating wards. METHODS: Ward rosters were discussed with managers to obtain an insight into direct care staffing levels (i.e, total direct care staff hours per resident per day). Participating staff members completed a questionnaire on work environment characteristics (i.e., ward culture, team climate, communication and coordination, role model availability, and multidisciplinary collaboration) and they rated the quality of care in their ward. Data were analyzed using multilevel linear regression analyses (random intercept). Separate analyses were conducted for somatic and psychogeriatric wards. RESULTS: In general, staff members were satisfied with the quality of care in their wards. Staff members from psychogeriatric wards scored higher on the statement 'In the event that a family member had to be admitted to a nursing home now, I would recommend this ward'. A better team climate was related to better perceived quality of care in both ward types (p<=0.020). In somatic wards, there was a positive association between multidisciplinary collaboration and agreement by staff of ward recommendation for a family member (p=0.028). In psychogeriatric wards, a lower score on market culture (p=0.019), better communication/coordination (p=0.018) and a higher rating for multidisciplinary collaboration (p=0.003) were significantly associated with a higher grade for overall quality of care. Total direct care staffing, adhocracy culture, hierarchy culture, as well as role model availability were not significantly related to quality of care. CONCLUSIONS: Our findings suggest that team climate may be an important factor to consider when trying to improve quality of care. Generating more evidence on which work environment characteristics actually lead to better quality of care is needed. PMID- 27940367 TI - The B-cell translocation gene 1 (CgBTG1) identified in oyster Crassostrea gigas exhibit multiple functions in immune response. AB - B-cell translocation gene 1 (BTG1) is a member of the anti-proliferative gene family, which plays important roles in regulation of cell cycle. In the present study, a B-cell translocation gene 1 molecule homologue (designed CgBTG1) are identified and characterized in oyster Crassostrea gigas. CgBTG1 contains a conserved BTG domain with Box A and Box B motifs, and it shares high similarities with both BTG1 and BTG2 proteins in vertebrates. CgBTG1 mRNA is predominantly expressed in hemocytes, and its expression level in hemocytes is significantly up regulated at 6 h (5.40-fold, p < 0.01) post Vibrio splendidus stimulation. The apoptosis rate of oyster hemocytes is significantly decreased (p < 0.05) after CgBTG1 interfered by dsRNA (dsCgBTG1). This is indicated that CgBTG1 participated in the regulation of oyster hemocytes apoptosis. Furthermore, CgBTG1 could also induce the apoptosis of cancer cells (HeLa, A549 and BEL7402) in vitro. Compared with normal oysters, both vessel-like structures and muscle fibers in CgBTG1 interfered oysters are severely damaged after V. splendidus challenge in paraffin section, considering that CgBTG1 possessed an analogous feature of angiogenesis for maintenance of vessel-like structures in adductor muscle of oyster. The results suggests that CgBTG1 is a multi-functional molecule involved in the immune response of C. gigas against pathogen infection, which provides more clues for intensive studies of BTG family proteins in invertebrates. PMID- 27940369 TI - The biological standard of living in pre-modern Korea: Determinants of height of militia recruits during the Choson dynasty. AB - This paper extends the research on the biological standard of living in the Korean peninsula back to pre-modern times. Drawing on militia rosters of the Choson Dynasty from the sixteenth to eighteenth centuries, we tentatively conclude that the final height of Korean men during this period was 166cm and thus slightly above that of modern North Korean men (165cm). On the other hand, the average height of modern South Korean men is 172cm, 6cm more than what we tentatively estimate for pre-modern Korean men. Regression analysis of the height of pre-modern Korean men finds that un-free Koreans ("slaves") were significantly shorter by about 0.6-0.7cm than commoners, whereas the average height of recruits suffering from smallpox did not differ significantly from that of other recruits. Moreover, regional, as opposed to birth-dummy, variables account, and to a significant degree, for most of the differences in height. Whether or not this is a result of socioeconomic differences across provinces or a result of other regionally-varying factors remains an open question. PMID- 27940371 TI - Women recovering from social rejection: The effect of the person and the situation on a hormonal mechanism of affiliation. AB - Rejection can motivate either affiliation or withdrawal. In order to study how personality and situational variables influence whether women will be motivated to affiliate versus withdraw, we manipulate social feedback (rejection vs. acceptance) and opportunity for face-to-face interaction (blocked vs. face-to face) and measure the individual difference variables rejection sensitivity and social anxiety. We test how these variables affect endogenous progesterone and cortisol concentrations, which are presumed to signal motivational responses to rejection. We find that three-way interactions involving social feedback, opportunity for face-to-face interactions, and either social anxiety or rejection sensitivity significantly predict progesterone change, but not cortisol change. Both interactions are driven by sharp progesterone decreases for women high in social anxiety/rejection sensitivity who have been rejected and who have no opportunity to reaffiliate in a face-to-face interaction. This progesterone change may be a physiological marker of motivation for social avoidance following rejection for women who cannot reaffiliate and who are particularly socially anxious or sensitive to rejection. PMID- 27940370 TI - Protein-crystal interface mediates cell adhesion and proangiogenic secretion. AB - The nanoscale materials properties of bone apatite crystals have been implicated in breast cancer bone metastasis and their interactions with extracellular matrix proteins are likely involved. In this study, we used geologic hydroxyapatite (HAP, Ca10(PO4)6(OH)2), closely related to bone apatite, to investigate how HAP surface chemistry and nano/microscale topography individually influence the crystal-protein interface, and how the altered protein deposition impacts subsequent breast cancer cell activities. We first utilized Forster resonance energy transfer (FRET) to assess the molecular conformation of fibronectin (Fn), a major extracellular matrix protein upregulated in cancer, when it adsorbed onto HAP facets. Our analysis reveals that both low surface charge density and nanoscale roughness of HAP facets individually contributed to molecular unfolding of Fn. We next quantified cell adhesion and secretion on Fn-coated HAP facets using MDA-MB-231 breast cancer cells. Our data show elevated proangiogenic and proinflammatory secretions associated with more unfolded Fn adsorbed onto nano rough HAP facets with low surface charge density. These findings not only deconvolute the roles of crystal surface chemistry and topography in interfacial protein deposition but also enhance our knowledge of protein-mediated breast cancer cell interactions with apatite, which may be implicated in tumor growth and bone metastasis. PMID- 27940372 TI - Arterial Phase with CAIPIRINHA-Dixon-TWIST (CDT)-Volume-Interpolated Breath-Hold Examination (VIBE) in Detecting Hepatic Metastases. AB - PURPOSE: To evaluate lesion enhancement performance of Multi-Arterial CAIPIRINHA Dixon-TWIST-Volume-Interpolated Breath-Hold Examination (MA-CDT-VIBE) for the detection of hepatic metastases. MATERIALS AND METHODS: Thirty-one patients with suspicious hepatic metastases were enrolled in this retrospective study. Two independent radiologists scored visualization of each lesion on a scale of 1 (poor visualization) to 11 (excellent visualization) on 11 sets of images. These included 6 hepatic arterial sub-phases acquired in one breath-hold, 1 series of the mean of 6 hepatic arterial sub-phases, 3 subtracted arterial sub-phases, and 1 portal venous phase. The phases with good (score 8-10) and excellent (score 11) lesion visualization were identified, and the number of lesions seen on each of these phases was compared to the number of lesions that was seen best on the equivalent-to-conventional single arterial phase as well as to those that were see best on the mean of 6 hepatic arterial sub-phases. Inter-reader agreement was also calculated. RESULTS: The MA-CDT-VIBE was successfully acquired in 25 patients with hypervascular metastases (96 lesions) and 6 patients with hypovascular metastases (13 lesions). In case of hypervascular metastases, the 6th/6 arterial sub-phase had excellent lesion visualization (sore of 11) in 56 and 44 lesions for the 2 readers, respectively. Good lesion visualization (score of 8-10) was recorded in 5th/6 arterial subphases, in 81 and 67 lesions for the 2 readers, respectively. In case of hypovascular metastases, the portal venous phase had excellent lesion visualization (sore of 11) in all 13 lesions for the 2 readers. Good lesion visualization (score of 8-10) was recorded in 12 and 13 lesions on the 5th/6 and 6th/6 arterial subphases, respectively. More hypervascular lesions scored good (score of 8-10) and excellent (score of 11) on the 5th/6 and 6th/6 phases of MA-CDT-VIBE compared with the equivalent-to conventional single arterial phase (3rd/6) and the set with mean of 6 hepatic arterial sub-phases. The results were statistically significant (t test, P<.0001). Inter-reader agreement was good for hypervascular lesions (kappa=0.627, P<.0001) and excellent for hypovascular lesions (kappa=1.0, P<.0001), respectively. CONCLUSIONS: The MA-CDT-VIBE improves lesion conspicuity by providing a wide observation window for hypervascular lesions. For hypovascular lesions, the advantage of multiple arterial sub-phases over the portal venous phase is not apparent. PMID- 27940373 TI - Clinical Features of Brain Metastases in Small Cell Lung Cancer: an Implication for Hippocampal Sparing Whole Brain Radiation Therapy. AB - PURPOSE: To assess the clinical features and distribution of brain metastases (BMs) of small cell lung cancer (SCLC) in the hippocampal and perihippocampal region, with the purpose of exploring the viability of hippocampal-sparing whole brain radiation therapy (HS-WBRT) on reducing neurocognitive deficits. METHODS: This was a retrospective analysis of the clinical characteristics and patterns of BMs in patients with SCLC. Associations between the clinical characteristics and hippocampal metastases (HMs)/perihippocampal metastases (PHMs) were evaluated in univariate and multivariate regression analyses. RESULTS: A total of 1594 brain metastatic lesions were identified in 180 patients. Thirty-two (17.8%) patients were diagnosed with BMs at the time of primary SCLC diagnosis. The median interval between diagnosis of primary SCLC and BMs was 9.3 months. There were 9 (5.0%) and 22 (12.2%) patients with HMs and PHMs (patients with BMs located in or within 5 mm around the hippocampus), respectively. In the univariate and multivariate analysis, the number of BMs was the risk factor for HMs and PHMs. Patients with BMs>=5 had significantly higher risk of HMs (odds ratio [OR] 7.892, 95% confidence interval [CI] 1.469-42.404, P=.016), and patients with BMs>=7 had significantly higher risk of PHMs (OR 5.162, 95% CI 2.017-13.213, P=.001). Patients with extracranial metastases are also associated with HMs. CONCLUSIONS: Our results indicate that patients with nonoligometastatic disease are significantly associated with HMs and PHMs. The incidence of PHMs may be acceptably low enough to perform HS-WBRT for SCLC. Our findings provide valuable clinical data to assess the benefit of HS-WBRT in SCLC patients with BMs. PMID- 27940374 TI - Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages. AB - BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) may have extra-hepatic effects on cholesterol homeostasis of vascular macrophages. In this study, we aimed to investigate PCSK9 role on the anti-atherogenic process of ATP binding cassette transporter A1 (Abca1)-mediated cholesterol efflux. METHODS: Abca1-mediated cholesterol efflux was evaluated by a radioisotopic technique in mouse peritoneal macrophages (MPM) from wild-type (WT) or LDL receptor knock-out (Ldlr-/-) mice exposed to human recombinant PCSK9, in the presence of liver X receptor/retinoid X receptor (LXR/RXR) ligands or acetylated LDL (AcLDL) to stimulate Abca1 expression. Protein and gene expression was evaluated by Western blot and quantitative real time PCR, respectively. RESULTS: PCSK9 inhibited Abca1 mediated cholesterol efflux induced by LXR/RXR agonists in WT MPM (-55%, p < 0.05) but not in Ldlr-/- MPM. This effect was fully abrogated by the co incubation with an anti-PCSK9 antibody. The inhibition of Abca1-dependent efflux induced by PCSK9 was associated with a reduction of Abca1 protein expression only in WT cells. Abca1 gene expression was significantly downregulated by PCSK9 in WT macrophages (-64%, p < 0.001) and, to a lesser extent, in MPM lacking Ldlr (-35%, p < 0.001). The inhibitory effect on Abca1-mediated efflux was also confirmed in AcLDL-treated macrophages. PCSK9 had a marginal or no effect on the expression of the lipid transporters Sr-b1 and Abcg1. CONCLUSIONS: PCSK9 plays a direct role on Abca1-mediated cholesterol efflux through a downregulation of Abca1 gene and Abca1 protein expression. This extrahepatic effect may influence relevant steps in the pathogenesis of atherosclerosis, such as foam cell formation. PMID- 27940375 TI - Elevated 1-h post-load plasma glucose levels in subjects with normal glucose tolerance are associated with a pro-atherogenic lipid profile. AB - BACKGROUND AND AIMS: Evidence suggests that plasma glucose concentration >=155 mg/dl at 1h during an oral glucose tolerance test (OGTT) (NGT 1 h-high) predicts both development of type 2 diabetes (T2DM) and cardiovascular events, among adults with normal glucose tolerance (NGT). An atherogenic lipid profile is detectable in subjects with impaired glucose tolerance (IGT) and T2DM. Whether individuals with NGT-1h-high also exhibit a pro-atherogenic lipid profile is still uncertain. METHODS: The study cohort includes 1011 non-diabetic Caucasian adults participating in the CATAMERI study. All participants were submitted to anthropometrical evaluation before undergoing an OGTT. Subjects were categorized into NGT 1 h-low (1 h glucose < 155 mg/dl), NGT 1 h-high, IGT, and newly diagnosed T2DM. Lipid profile includes triglycerides, total and HDL cholesterol, apolipoprotein B (ApoB) and ApoA-1. RESULTS: 510 subjects were NGT 1 h-low, 211 NGT 1 h-high, 232 IGT and 58 were newly diagnosed T2DM. Triglyceride and ApoB levels were significantly higher in NGT 1 h-high, IGT and T2DM subjects compared to NGT 1 h-low, and HDL cholesterol was significantly lower. Triglycerides-to-HDL cholesterol ratio was significantly higher in NGT 1 h-high, IGT and T2DM groups compared with NGT 1 h-low individuals. The ApoB/ApoA-1 ratio was significantly higher in NGT 1 h-high, IGT and T2DM groups than in the NGT 1 h-low group. NGT 1 h-high, IGT and T2DM subjects exhibited reduced LDL/ApoB ratio compared with NGT 1 h-low. Noticeably, there were no significant differences in ApoB/ApoA-1 and LDL/ApoB ratios when comparing NGT 1 h-high with IGT and T2DM. CONCLUSIONS: Individuals with NGT 1-h-high exhibited an atherogenic lipid pattern qualitatively and quantitatively similar to that observed in individuals with IGT and newly diagnosed T2DM. PMID- 27940376 TI - Prevalence and severity of arterial calcifications in pseudoxanthoma elasticum (PXE) compared to hospital controls. Novel insights into the vascular phenotype of PXE. AB - BACKGROUND AND AIMS: Pseudoxanthoma elasticum (PXE) is a monogenetic disorder with progressive calcifications of the skin, the Bruch's membrane in the eyes and the arterial wall. Vascular disease is considered to be very prevalent, but the whole-body distribution of arterial calcifications in PXE is unknown. We aimed to systematically investigate arterial calcifications in PXE. METHODS: We included 104 PXE patients from the Dutch PXE cohort and 93 hospital controls. All subjects underwent full-body low-dose CT scans without contrast. To investigate the prevalence and severity of arterial calcification per arterial location, CT scans were scored using a reproducible semi-quantitative scale with four calcification categories (interobserver kappa 0.54-0.99). RESULTS: PXE patients (38/104 males) were 54 +/- 13 years and controls (45/93 males) 54 +/- 16 years old. Arterial calcifications were significantly more common in PXE patients in the intracranial internal carotid artery (75% vs. 44%), the arteries of the arms (20% vs. 3%), the femoral-popliteal arteries (74% vs. 44%) and the subpopliteal arteries (84% vs. 38%). In these arteries, calcification scores also indicated more severe calcification. No significant differences in prevalence of arterial calcification were observed in other arterial beds such as the coronary arteries (45% vs. 43%, p = 0.776), the carotid arteries (52% vs. 46%, p = 0.476) and the abdominal aorta (71% vs. 63%, p = 0.287). Analyses using patients younger than 55 years only, showed similar differences in prevalence of arterial calcifications between PXE patients and controls, with most pronounced calcifications in the arteries of the lower legs (67% vs. 8%). Similar patterns were observed in those without concomitant diabetes or renal dysfunction. CONCLUSIONS: In PXE, a vascular phenotype can be identified with a distribution of arterial calcifications that is clearly distinct from hospital controls and involves arterial calcifications in the legs, the intracranial internal carotid arteries and the arteries of the arms. PMID- 27940377 TI - Using simulation to interpret experimental data in terms of protein conformational ensembles. AB - In their biological environment, proteins are dynamic molecules, necessitating an ensemble structural description. Molecular dynamics simulations and solution state experiments provide complimentary information in the form of atomically detailed coordinates and averaged or distributions of structural properties or related quantities. Recently, increases in the temporal and spatial scale of conformational sampling and comparison of the more diverse conformational ensembles thus generated have revealed the importance of sampling rare events. Excitingly, new methods based on maximum entropy and Bayesian inference are promising to provide a statistically sound mechanism for combining experimental data with molecular dynamics simulations. PMID- 27940378 TI - PPARgamma activation ameliorates postoperative cognitive decline probably through suppressing hippocampal neuroinflammation in aged mice. AB - Neuroinflammation plays a key role in many neurodegenerative disorders, including postoperative cognitive decline (POCD). Growing evidence has demonstrated that activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma) attenuates the inflammatory response and improves cognitive dysfunction associated with many neuropsychiatric disorders. We hypothesize that down regulation of PPARgamma is linked to neuroinflammation and the subsequent cognitive deficits observed in an animal model of POCD. In the present study, the POCD animal model was established by performing an exploratory laparotomy under isoflurane anesthesia in 20-month-old male C57BL/6 mice. Behavioral tests, inflammatory biomarkers, including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-1beta, ionized calcium-binding adaptor molecule 1 (IBA1)-positive cells, as well as glial fibrillary acidic protein (GFAP) positive cells and brain-derived neurotrophic factor (BDNF), were measured. Herein, we showed that surgery induced profound impairment in cognition that was associated with significant decreases in PPARgamma and BDNF expression, and significant increases in IL-1beta, IBA1-positive cells, and GFAP-positive cells in the hippocampus. As expected, the PPARgamma agonist pioglitazone attenuated the surgery-induced inflammatory changes and rescued the associated cognitive impairment. However, these beneficial effects were abolished by the PPARgamma specific antagonist GW9662, suggesting a pivotal role of the PPARgamma pathway in the pathogenesis of POCD. Taken together, our results provide evidence that down regulation of PPARgamma may be involved in neuroinflammation and subsequent POCD, and suggest that activation of PPARgamma by pioglitazone may represent a new way to prevent or treat POCD. PMID- 27940379 TI - Native thymic extracellular matrix improves in vivo thymic organoid T cell output, and drives in vitro thymic epithelial cell differentiation. AB - Although the thymus is a primary lymphoid organ, its function is compromised by an age-induced loss of resident epithelial cells, which results in reduced naive T cell output. This has important implications for immune recovery in aged and elderly patients following damage from cytoablative therapies. As thymic architecture plays a crucial role in naive T cell development, a tissue specific scaffold that provides essential supporting matrix may assist in stem cell-based thymus regeneration to recreate complex organoids. Here we investigate thymus decellularization approaches that preserve major extracellular matrix components and support thymic epithelial cells for the generation of a functional thymic microenvironment with improved T cell output. We also established an in vitro, serum-free culture system that both maintains a progenitor thymic epithelial cell pool and drives their differentiation in the presence of decellularized thymic matrix. This approach enables further dissection of key cellular and niche components involved in thymic epithelial stem cell maintenance and T cell production. PMID- 27940381 TI - Antimicrobial resistance challenged with metal-based antimicrobial macromolecules. AB - Antimicrobial resistance threatens the achievements of science and medicine, as it deactivates conventional antimicrobial therapeutics. Scientists respond to the threat by developing new antimicrobial platforms to prevent and treat infections from these resistant strains. Metal-based antimicrobial macromolecules are emerging as an alternative to conventional platforms because they combine multiple mechanisms of action into one platform due to the distinctive properties of metals. For example, metals interact with intracellular proteins and enzymes, and catalyse various intracellular processes. The macromolecular architecture offers a means to enhance antimicrobial activity since several antimicrobial moieties can be conjugated to the scaffold. Further, these macromolecules can be fabricated into antimicrobial materials for contact-killing medical implants, fabrics, and devices. As volatilization or leaching out of the antimicrobial moieties from the macromolecular scaffold is reduced, these medical implants, fabrics, and devices can retain their antimicrobial activity over an extended period. Recent advances demonstrate the potential of metal-based antimicrobial macromolecules as effective platforms that prevent and treat infections from resistant strains. In this review these advances are thoroughly discussed within the context of examples of metal-based antimicrobial macromolecules, their mechanisms of action and biocompatibility. PMID- 27940380 TI - Biomimetic biodegradable artificial antigen presenting cells synergize with PD-1 blockade to treat melanoma. AB - Biomimetic materials that target the immune system and generate an anti-tumor responses hold promise in augmenting cancer immunotherapy. These synthetic materials can be engineered and optimized for their biodegradability, physical parameters such as shape and size, and controlled release of immune-modulators. As these new platforms enter the playing field, it is imperative to understand their interaction with existing immunotherapies since single-targeted approaches have limited efficacy. Here, we investigate the synergy between a PLGA-based artificial antigen presenting cell (aAPC) and a checkpoint blockade molecule, anti-PD1 monoclonal antibody (mAb). The combination of antigen-specific aAPC based activation and anti-PD-1 mAb checkpoint blockade induced the greatest IFN gamma secretion by CD8+ T cells in vitro. Combination treatment also acted synergistically in an in vivo murine melanoma model to result in delayed tumor growth and extended survival, while either treatment alone had no effect. This was shown mechanistically to be due to decreased PD-1 expression and increased antigen-specific proliferation of CD8+ T cells within the tumor microenvironment and spleen. Thus, biomaterial-based therapy can synergize with other immunotherapies and motivates the translation of biomimetic combinatorial treatments. PMID- 27940382 TI - Polyplexes assembled from self-peptides and regulatory nucleic acids blunt toll like receptor signaling to combat autoimmunity. AB - Autoimmune diseases occur when the immune system incorrectly recognizes self molecules as foreign; in the case of multiple sclerosis (MS), myelin is attacked. Intriguingly, new studies reveal toll-like receptors (TLRs), pathways usually involved in generating immune responses against pathogens, play a significant role in driving autoimmune disease in both humans and animal models. We reasoned polyplexes formed from myelin self-antigen and regulatory TLR antagonists might limit TLR signaling during differentiation of myelin-specific T cells, inducing tolerance by biasing T cells away from inflammatory phenotypes. Complexes were formed by modifying myelin peptide with cationic amino acids to create peptides able to condense the anionic nucleic-acid based TLR antagonist. These immunological polyplexes eliminate synthetic polymers commonly used to condense polyplexes and do not rely on gene expression; however, the complexes mimic key features of traditional polyplexes such as tunable loading and co-delivery. Using these materials and classic polyplex analysis techniques, we demonstrate condensation of both immune signals, protection from enzymatic degradation, and tunable physicochemical properties. We show polyplexes reduce TLR signaling, and in primary dendritic cell and T cell co-culture, reduce myelin-driven inflammation. During mouse models of MS, these tolerogenic polyplexes improve the progression, severity, and incidence of disease. PMID- 27940384 TI - The profile of adsorbed plasma and serum proteins on methacrylic acid copolymer beads: Effect on complement activation. AB - Polymer beads made of 45% methacrylic acid co methyl methacrylate (MAA beads) promote vascular regenerative responses in contrast to control materials without methacrylic acid (here polymethyl methacrylate beads, PMMA). In vitro and in vivo studies suggest that MAA copolymers induce differences in macrophage phenotype and polarization and inflammatory responses, presumably due to protein adsorption differences between the beads. To explore differences in protein adsorption in an unbiased manner, we used high resolution shotgun mass spectrometry to identify and compare proteins that adsorb from human plasma or serum onto MAA and PMMA beads. From plasma, MAA beads adsorbed many complement proteins, such as C1q, C4 related proteins and the complement inhibitor factor H, while PMMA adsorbed proteins, such as albumin, C3 and apolipoproteins. Because of the differences in complement protein adsorption, follow-up studies focused on using ELISA to assess complement activation. When incubated in serum, MAA beads generated significantly lower levels of soluble C5b9 and C3a/C3adesarg in comparison to PMMA beads, indicating a decrease in complement activation with MAA beads. The differences in adsorbed protein on the two materials likely alter subsequent cell-material interactions that ultimately result in different host responses and local vascularization. PMID- 27940385 TI - Proteomic analysis reveals contrasting stress response to uranium in two nitrogen fixing Anabaena strains, differentially tolerant to uranium. AB - : Two strains of the nitrogen-fixing cyanobacterium Anabaena, native to Indian paddy fields, displayed differential sensitivity to exposure to uranyl carbonate at neutral pH. Anabaena sp. strain PCC 7120 and Anabaena sp. strain L-31 displayed 50% reduction in survival (LD50 dose), following 3h exposure to 75MUM and 200MUM uranyl carbonate, respectively. Uranium responsive proteome alterations were visualized by 2D gel electrophoresis, followed by protein identification by MALDI-ToF mass spectrometry. The two strains displayed significant differences in levels of proteins associated with photosynthesis, carbon metabolism, and oxidative stress alleviation, commensurate with their uranium tolerance. Higher uranium tolerance of Anabaena sp. strain L-31 could be attributed to sustained photosynthesis and carbon metabolism and superior oxidative stress defense, as compared to the uranium sensitive Anabaena sp. strain PCC 7120. SIGNIFICANCE: Uranium responsive proteome modulations in two nitrogen-fixing strains of Anabaena, native to Indian paddy fields, revealed that rapid adaptation to better oxidative stress management, and maintenance of metabolic and energy homeostasis underlies superior uranium tolerance of Anabaena sp. strain L-31 compared to Anabaena sp. strain PCC 7120. PMID- 27940383 TI - In vitro characterization and in vivo ultrasound molecular imaging of nucleolin targeted microbubbles. AB - Nucleolin (NCL) plays an important role in tumor vascular development. An increased endothelial expression level of NCL has been related to cancer aggressiveness and prognosis and has been detected clinically in advanced tumors. Here, with a peptide targeted to NCL (F3 peptide), we created an NCL-targeted microbubble (MB) and compared the performance of F3-conjugated MBs with non targeted (NT) MBs both in vitro and in vivo. In an in vitro study, F3-conjugated MBs bound 433 times more than NT MBs to an NCL-expressing cell line, while pretreating cells with 0.5 mM free F3 peptide reduced the binding of F3 conjugated MBs by 84%, n = 4, p < 0.001. We then set out to create a method to extract both the tumor wash-in and wash-out kinetics and tumor accumulation following a single injection of targeted MBs. In order to accomplish this, a series of ultrasound frames (a clip) was recorded at the time of injection and subsequent time points. Each pixel within this clip was analyzed for the minimum intensity projection (MinIP) and average intensity projection (AvgIP). We found that the MinIP robustly demonstrates enhanced accumulation of F3-conjugated MBs over the range of tumor diameters evaluated here (2-8 mm), and the difference between the AvgIP and the MinIP quantifies inflow and kinetics. The inflow and clearance were similar for unbound F3-conjugated MBs, control (non-targeted) and scrambled control agents. Targeted agent accumulation was confirmed by a high amplitude pulse and by a two-dimensional Fourier Transform technique. In summary, F3-conjugated MBs provide a new imaging agent for ultrasound molecular imaging of cancer vasculature, and we have validated metrics to assess performance using low mechanical index strategies that have potential for use in human molecular imaging studies. PMID- 27940386 TI - Could PANSS be a useful tool in the determining of the stages of schizophrenia? A clinically operational approach. AB - Staging in schizophrenia might be an important approach for the better treatment and rehabilitation of patients. The purpose of this study was to empirically devise a staging approach in a sample of stabilized patients with schizophrenia. One hundred and seventy patients aged >=18 years (mean = 40.7, SD = 11.6) diagnosed by DSM-5 criteria were evaluated with the Positive and Negative Syndrome Scale (PANSS). Principal components analysis (PCA) with varimax rotation was used. The model was examined in the total sample and separately across a hypothesized stage of illness based on three age groups and between the two sexes. The PCA revealed a six factor structure for the total sample: 1) Negative, 2) Positive, 3) Depression and anxiety, 4) Excitement and Hostility, 5) Neurocognition and 6) Disorganization. The separate PCAs by stage of illness and sex revealed different patterns and quality of symptomatology. The Negative and Positive factors were stable across all examined groups. The models corresponding to different stages differed mainly in terms of neurocognition and disorganization and their interplay. Catatonic features appear more prominent in males while in females neurocognition takes two forms; one with disorganization and one with stereotype thinking with delusions. This study suggests that the three arbitrary defined stages of illness (on the basis of age) seem to reflect a progress from a preserved insight and more coherent mental functioning to disorganization and eventually neurocognitive impairment. Sexes differ in terms of the relationship of psychotic features with neurocognition. These results might have significant research and clinical implications. PMID- 27940387 TI - Beyond methamphetamine: Documenting the implementation of the Matrix model of substance use treatment for opioid users in a South African setting. AB - INTRODUCTION: The Matrix model of substance use treatment has been evaluated extensively in the United States as an effective treatment for methamphetamine use disorders. Since 2007, the Matrix model has been implemented in Cape Town, South Africa, where one in four treatment-seeking individuals are primarily opioid rather than stimulant users. Yet, there has been limited data on the application of the Matrix model for other types of substance use disorders in a resource-limited setting. METHODS: We compared primary opioid and primary methamphetamine users seeking treatment at the first certified Matrix model substance use treatment site in Cape Town, South Africa from 2009 to 2014 (n=1863) on engagement in treatment, an important early predictor of later substance use treatment outcomes, and urine-verified abstinence at treatment exit. RESULTS: Compared to primary opioid users, primary methamphetamine users had over 50% greater odds of initiating treatment (defined as attending at least one treatment session following intake; OR=1.55; 95%CI: 1.24-1.94), and 4.5 times greater odds of engaging in treatment (i.e., attending at least four treatment sessions; OR=4.48; 95%CI: 2.27-8.84). There were no significant differences in rates of urine-verified abstinence at treatment exit. CONCLUSIONS: Results suggest primary opioid users may experience additional barriers to treatment initiation and engagement in the Matrix model of substance use treatment, yet those who enter treatment are equally as likely to be abstinent at treatment exit compared to primary methamphetamine users. Findings highlight the need for additional strategies to optimize treatment initiation and engagement among primary opioid users in this setting, for instance by integrating medication assisted treatment (e.g., methadone). PMID- 27940388 TI - The impact of sleep and psychiatric symptoms on alcohol consequences among young adults. AB - OBJECTIVE: Independent lines of research have documented links between psychiatric symptoms and poor sleep quality, psychiatric symptoms and alcohol use, and alcohol use and poor sleep quality. The current study examined the synergistic effect of poor sleep quality and psychiatric symptoms on alcohol related consequences in heavy-drinking young adults. METHOD: Matriculating college students reporting at least one heavy drinking episode over the first nine weeks of the semester (N=385, 52% female) were categorized as experiencing 'good' (n=280) versus 'poor' sleep quality (n=105) and screening 'positive' (n=203) or 'negative' (n=182) for a psychiatric disorder. Sleep quality was assessed using the Pittsburgh Sleep Quality Index; psychiatric diagnosis was assessed using the Psychiatric Diagnostic Screening Questionnaire; and alcohol related consequences were assessed using the Brief Young Adult Alcohol Consequences Questionnaire. General linear models were used to examine the main effects and interaction between sleep quality and psychiatric symptoms on alcohol related consequences. RESULTS: Sleep quality moderated the association between psychiatric screen and alcohol-related consequences among heavy-drinking college students, such that psychiatric symptoms were associated with more alcohol related consequences in the context of poor sleep quality. CONCLUSIONS: The combination of poor sleep quality and psychiatric symptoms is associated with increased alcohol-related consequences among heavy-drinking college students. Given the significant interaction between these symptoms, healthcare providers are encouraged to screen for the presence of sleep and psychiatric disorders among heavy-drinking young adults and to provide empirically-supported treatments as appropriate. PMID- 27940390 TI - Impact of nonadherence on complication risks and healthcare costs in patients newly-diagnosed with diabetes. AB - AIMS: To investigate the association between nonadherence to diabetes treatment and the occurrence of diabetes complications. METHODS: Our study retrospectively identified adherence and nonadherence to diabetes treatment in patients during the first year of observation after new diagnoses of type 2 diabetes enrolled in commercial database from 52 health insurers in Japan. Participants were insurance enrollees with type 2 diabetes who received healthcare between 2005 and 2013, and who could be tracked for more than 12months from the initiation of diabetes treatment. We compared the occurrence of diabetes-related complications (retinopathy, nephropathy, neuropathy, ischemic heart disease, cerebrovascular disease, and chronic arterial occlusion) and all-cause healthcare expenditure during the second to eighth years. RESULTS: We identified 1784 nonadherent patients and 9547 adherent patients. Cox proportional hazard models showed that the occurrence of microvascular complications was significantly higher in the nonadherent group: the hazard ratios (95% confidence intervals) for retinopathy, nephropathy, and neuropathy were 2.04 (1.57-2.66), 1.91 (1.35-2.72), and 1.83 (1.02-3.27), respectively. However, no significant differences were observed between the adherent and nonadherent groups for the macrovascular complications (ischemic heart disease, cerebrovascular disease, and chronic arterial occlusion). In addition, the nonadherent group had a significantly higher cumulative healthcare expenditure than the adherent group during the second-to fifth-year period (p=0.029) and the second-to-sixth-year period (p=0.009) after treatment initiation. CONCLUSIONS: Nonadherence in the first year of diabetes may increase the incidence of complications and result in higher expenditures for patients and payers. PMID- 27940389 TI - Silk based bioinks for soft tissue reconstruction using 3-dimensional (3D) printing with in vitro and in vivo assessments. AB - In the field of soft tissue reconstruction, custom implants could address the need for materials that can fill complex geometries. Our aim was to develop a material system with optimal rheology for material extrusion, that can be processed in physiological and non-toxic conditions and provide structural support for soft tissue reconstruction. To meet this need we developed silk based bioinks using gelatin as a bulking agent and glycerol as a non-toxic additive to induce physical crosslinking. We developed these inks optimizing printing efficacy and resolution for patient-specific geometries that can be used for soft tissue reconstruction. We demonstrated in vitro that the material was stable under physiological conditions and could be tuned to match soft tissue mechanical properties. We demonstrated in vivo that the material was biocompatible and could be tuned to maintain shape and volume up to three months while promoting cellular infiltration and tissue integration. PMID- 27940392 TI - Visual perception and visual mental imagery of emotional faces generate similar expression aftereffects. AB - What is the relationship between visual perception and visual mental imagery of emotional faces? We investigated this question using a within-emotion perceptual adaptation paradigm in which adaptation to a strong version of an expression was paired with a test face displaying a weak version of the same emotion category. We predicted that within-emotion adaptation to perception and imagery of expressions would generate similar aftereffects, biasing perception of weak emotional test faces toward a more neutral value. Our findings confirmed this prediction. Adaptation to mental images yielded aftereffects that inhibited emotion recognition of test expressions, as participants were less accurate at recognising these stimuli compared to baseline. While the same inhibitory effect was observed when expressions were visually perceived, the size of the aftereffects was greater for perception than imagery. These findings suggest the existence of expression-selective neural mechanisms that subserve both visual perception and visual mental imagery of emotional faces. PMID- 27940391 TI - Online professional development for digitally differentiated nurses: An action research perspective. AB - Professional development opportunities for nurses are increasingly being offered in the online environment and therefore it is imperative that learning designers, nurse educators and healthcare organisations consider how best to support staff to enable Registered Nurses to capitalise on the resources available. Research participants explored educational strategies to support digitally differentiated nurses' engagement with professional development activities in an online environment through a participatory action research project that collected data over a 16 month period through six focus groups before being analysed thematically. The reality of work-based, e-learning while managing clinical workloads can be problematic however specific measures, such as having a quiet space and computer away from the clinical floor, access to professional development resources from anywhere and at any time, can be effective. A 'one size-fits-all' approach to resources offered will not meet the needs of diverse staffing groups whereas heutagogical learning offers tangible benefits to Registered Nurses seeking professional development opportunities in this context. Apparent proficiency with technological skills may not reflect a Registered Nurse's actual ability in this environment and face-to-face support offered regularly, rather than remedially, can be beneficial for some staff. Implementing specific strategies can result in successful transition to the online environment. PMID- 27940394 TI - Assessment of ovarian reserve after hysterectomy: Laparoscopic vs. non laparoscopic surgery. AB - OBJECTIVES: To evaluate changes of ovarian reserve after hysterectomy by comparing serum anti-Mullerian hormone (AMH) levels following laparoscopic hysterectomy (LH) to those of non-laparoscopic hysterectomy (non-LH). METHODS: Prospectively, serum AMH levels were measured pre-operatively (AMH0), 7days (AMH1), 2 months (AMH2), and 6 months (AMH3) after LH (total laparoscopic hysterectomy or laparoscopy-assisted vaginal hysterectomy) and non-LH (vaginal hysterectomy or abdominal hysterectomy) in 91 premenopausal women (LH=60, non LH=31). Changes of serum AMH levels were compared between the two groups. RESULTS: AMH0 was similar between the two groups (P=0.400). Also, AMH1, AMH2, and AMH3 were not different between the two groups (P=0.333, 0.534, and 0.726). A significant decrease of serum AMH level (30% decreases from AMH0) at 7days, 2 months, and 6 months was observed in 44.4%, 34.8%, and 40% of all patients. Interestingly, the incidence of a significant decrease of serum AMH levels at postoperative 2 months was considerably higher in LH group compare to non-LH group (43.9% vs. 20.0%, P=0.042). Multivariate analysis revealed that laparoscopic hysterectomy was an independent risk factor for the significant decrease of serum AMH at postoperative 2 months (Hazard ratio 4.147, 95% confidence interval 1.139-15.097). CONCLUSION: Laparoscopic hysterectomy, which is associated with electro-thermal vessel ligation, might have negative effect on ovarian reserve after surgery. More large-scaled, long-term follow-up study is required. PMID- 27940393 TI - Chronic adnexal torsion: An under-recognized disease entity. AB - OBJECTIVE: To clarify the incidence, clinical background and surgical characteristics of chronic adnexal torsion in comparison to acute adnexal torsion. STUDY DESIGN: The patients were divided into three categories based on the period from the onset of symptoms to surgical management: acute (<=24h), subacute (2days) and chronic adnexal torsions (>=3days). Cases, in which the onset of symptoms was unspecified, were included in the chronic adnexal torsion group. Then, a retrospective comparative study of acute (49 patients) and chronic adnexal torsion (45 patients) was performed. Laparoscopic surgery was performed as a primary surgical procedure. RESULTS: In chronic adnexal torsion, surgery was performed at a median of 9days (range: 3-270days) after the onset of symptoms. The apparent onset of symptoms was not noted in 2 cases. All cases with acute adnexal torsion received emergency surgery. In contrast, emergency surgery was performed only in 13 patients with chronic adnexal torsion. Patients with chronic adnexal torsion were significantly older than those with acute adnexal torsion. Isolated tubal torsion was more frequent in chronic adnexal torsion. With the exception of 2 cases with chronic adnexal torsion in which laparotomic conversion was required due to severe adhesion, and 2 cases with acute adnexal torsion with advanced gestational age, who were managed by initial laparotomy, laparoscopic surgery was successful. Unilateral salpingo-oophorectomy was the most frequent surgical procedure in both groups. When confined to the patients who expressed a wish for adnexal preservation, adnexal cystectomy or detorsion was possible in 60.9% of the acute torsion cases and 57.1% of the chronic adnexal torsion cases. Severe necrosis of the adnexal tissue and extensive pelvic adhesion were the more frequent associated conditions in chronic adnexal torsion. Among the patients who were successfully managed by laparoscopic surgery, the duration of surgery was significantly longer in the patients with chronic adnexal torsion. Severe necrosis that makes a pathological diagnosis difficult was the most frequent finding in cases of chronic adnexal torsion. CONCLUSION: Chronic adnexal torsion still represents a diagnostic and therapeutic challenge that should be recognized as a distinct and more frequently encountered disease entity. PMID- 27940395 TI - The effectiveness of gynaecology teaching associates in teaching pelvic examination to medical students: a randomised controlled trial. AB - OBJECTIVES: To assess whether teaching female pelvic examinations using gynaecological teaching associates (GTAs); women who are trained to give instruction and feedback on gynaecological examination technique, improves the competence, confidence and communication skills of medical students compared to conventional teaching. STUDY DESIGN: Randomised controlled trial. SETTING: Ten University of Birmingham (UoB) affiliated teaching hospitals in the UK. POPULATION: 492 final year medical students. METHODS: GTA teaching of gynaecological examination compared with conventional pelvic manikin based teaching at the start of a five week clinical placement in obstetrics and gynaecology (O&G). MAIN OUTCOME MEASURES: Student's perception of their confidence was measured on a 10cm visual analogue scale (VAS). Domains of competence were measured by a senior clinical examiner using a standardised assessment tool which utilised 10cm VAS and by a GTA using a four point Likert scale. Assessors were blinded to the allocated teaching intervention. RESULTS: 407/492 (83%) students completed both the intervention and outcome assessment. Self-reported confidence was higher in students taught by GTAs compared with those taught on manikins (median score GTA 6.3; vs. conventional 5.8; p=0.03). Competence was also higher in those taught by GTAs when assessed by an examiner (median global score GTA 7.1 vs. conventional 6.0; p<0.001) and by a GTA (p<0.001). CONCLUSIONS: GTA teaching of female pelvic examination at the start of undergraduate medical student O&G clinical placements improves their confidence and competence compared with conventional pelvic manikin based teaching. GTAs should be introduced into undergraduate medical curricula to teach pelvic examination. PMID- 27940397 TI - Individualisation of intervention for tubal ectopic pregnancy: historical perspectives and the modern evidence based management of ectopic pregnancy. AB - Historically, ectopic pregnancy was a life-threatening condition where diagnosis was possible only at post mortem or laparotomy and maternal mortality was up to 90%. The evolution in the management of ectopic pregnancy has meant that diagnosis can be made using non-invasive techniques with an aim to identify the ectopic gestation before tubal rupture. This enables health care professionals to offer management options that consider not only maternal mortality, but morbidity and fertility outcomes as well. In spite of this, diagnostic techniques and management options are not without limitations. Research is currently focused on new tests with a single diagnostic capability, diagnostic and treatment algorithms and safe methods of triaging patients. This article aims to review the current literature on the diagnosis and management of ectopic pregnancy and to formulate a pathway to help individualise care and achieve the best possible outcome. PMID- 27940396 TI - Immunohistochemical expression pattern of metastasis suppressor KISS-1 protein in adenomyosis lesions and normal endometrium. AB - OBJECTIVE: Kisspeptins are multifunctional peptides; it has been shown that they act as inhibitors of tumor metastasis in a range of cancers and that they are also involved in cell invasion through regulation of matrix metalloproteinases (MMPs). The aim of this study was to investigate the expression of KISS-1 protein in adenomyosis lesions compared with matched eutopic endometrium, as well as with endometrium from patients without adenomyosis. STUDY DESIGN: In this comparative, non-interventional study, adenomyosis and corresponding eutopic endometrium samples from women with histologically proven adenomyosis after hysterectomy, and eutopic endometrium samples from women without adenomyosis were analysed. Expression of KISS-1 protein was analyzed immunohistochemically in formalin fixed, paraffin-embedded adenomyotic tissue specimens (n=29), matched eutopic endometrium from the same patients (n=29) and normal endometrium from patients without adenomyosis (n=29). RESULTS: Using a semi-quantitative immunohistochemical score, we found that KISS-1 protein expression was higher in the adenomyotic as compared with matched eutopic glandular endometrium (p<0.05), in which in turn KISS-1 protein expression was higher than those from patients without adenomyosis (p<0.001). The inverse correlation was found in the stroma, between adenomyosis lesions and matched eutopic endometrium (p<0.01), while no statistically significant correlation was found in KISS-1 protein expression in the stroma between patients with and without adenomyosis. CONCLUSIONS: KISS-1 protein expression appears to be up-regulated in adenomyotic as compared with eutopic glandular endometrium of patients with, as well as women without adenomyosis. These findings are suggestive of the involvement of KISS-1 protein in the pathogenesis and maintenance of adenomyosis. Future studies should investigate whether KISS1 protein could be used as a marker for early and minimally invasive detection of adenomyosis, based on its differential protein expression pattern in the eutopic endometrium of patients with and without adenomyosis. PMID- 27940398 TI - Therapeutic role of nitric oxide as emerging molecule. AB - NO has many physiological roles; in inflammation, pain, rheumatoid arthritis, immune system, gastroprotection, as antioxidant and reported to be a free radical scavenger.Intensive research on the biological functions of NO and other reactive nitrogen oxide species demands exogenous sources of NO donors as research tools and pharmaceuticals. Since the mid-1980s, the development of new NO donors has offered several advantages over theprevious NO donors, such as spontaneous release of NO, donation of NO under controlled rates, and even the targeting of NO to certain tissues. Nitric oxide releasing derivatives of conventional NSAIDs have been synthesized not only to avoid gastrotoxicity, but also for making them fit for topical delivery, targeting them to brain and increase their analgesic and anti-inflammatory activity. "Hybrid nitrates" have vital role in different like NSAIDs, Anti-platelet, Antileukemic, Glaucoma, Antihypertensive, Antimalarial etc. PMID- 27940399 TI - A technique to record the sedentary to walk movement during free living mobility: A comparison of healthy and stroke populations. AB - BACKGROUND: Hesitation between moving from a sedentary posture (lying/sitting) to walking is a characteristic of mobility impaired individuals, as identified from laboratory studies. Knowing the extent to which this hesitation occurs during everyday life would benefit rehabilitation research. This study aimed to quantify this transition hesitation through a novel approach to analysing data from a physical activity monitor based on a tri-axial accelerometer and compare results from two populations; stroke patients and age-matched unimpaired controls. METHODS: Stroke patients living at home with early supported discharge (n=34, 68.9YO+/-11.8) and age-matched controls (n=30, 66.8YO+/-10.5) wore a physical activity monitor for 48h. The outputs from the monitor were then used to determine the transitions from sedentary to walking. The time delay between a sedentary posture ending and the start of walking classified four transition types: 1) fluent (<=2s), 2) hesitant (>2s<=10s), 3) separated (>10s) and 4) a change from sedentary with no registered walking to a return to sedentary. RESULTS: Control participants initiated walking after a sedentary posture on 92% of occasions. Most commonly (43%) this was a fluent transition. In contrast stroke patients walked after changing from a sedentary posture on 68% of occasions with only 9% of transitions classed as fluent, (p<0.05). DISCUSSION/ CONCLUSION: A new data analysis technique reports the frequency of walking following a change in sedentary position in stroke patients and healthy controls and characterises this transition according to the time delay before walking. This technique creates opportunities to explore everyday mobility in greater depth. PMID- 27940400 TI - Synthesis and antibacterial activities of novel pleuromutilin derivatives with a substituted pyrimidine moiety. AB - The alarming growth of multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) has become a major global health hazard. Therefore, urgent demand for new antibiotics with a unique mechanism of action is very necessary. The present study reports the design, synthesis, and antibacterial studies of a series of novel pleuromutilin derivatives with substituted 6-amino pyrimidine moieties. Most of the tested compounds exhibited highly potent anti-MRSA or Staphylococcus aureus (S. aureus) activities. 14-O-[(4,6-Diamino -pyrimidine-2-yl) thioacetyl] mutilin (3) and 14-O-[(2-((3R)-3-Hydroxymethylpiperidine-1-yl)-acetamido-6 aminopyrimidine-2-yl) thioacetyl] mutilin (5h) were the most active compounds and showed higher antibacterial activities. Compound 3 displayed rapid bactericidal activity and affected bacterial growth with the same manner as tiamulin fumarate. Docking experiments for compounds 3 and 5h carried out on the peptidyl transferase center (PTC) of 23S rRNA provided the information about the binding model. In vivo mouse systemic infection experimental results confirmed the therapeutic efficacy of compound 3, with ED50 of 4.22 mg/kg body weight against MRSA. PMID- 27940402 TI - CaMKIIdelta meditates phenylephrine induced cardiomyocyte hypertrophy through store-operated Ca2+ entry. AB - Evidence suggests that store-operated Ca2+ entry (SOCE) is involved in the hypertrophy of cardiomyocytes. The signaling mechanisms of SOCE contributing to cardiac hypertrophy following phenylephrine (PE) stimulation are not fully understood. Ca2+/calmodulin-dependent protein kinase II delta (CaMKIIdelta) plays an important role in regulating intracellular Ca2+ hemostasis and function in the cardimyocytes. This study is aimed to determine the role of CaMKIIdelta in regulating the PE-induced myocardial hypertrophy and the associated molecular signaling mechanisms. We used primary cultures of neonatal cardimyocytes isolated from the left ventricle of Sprague Dawley rats to investigate the effects of CaMKIIdelta on myocardial hypertrophy and intracellular Ca2+ mobilization. We found that the expression of CaMKIIdelta was enhanced in PE-induced hypertrophic cardiomyocytes. CaMKIIdelta siRNA, CaMKII inhibitor KN93, and SOCE blocker BTP2 attenuated the increase in the expression of CaMKIIdelta and normalized the hypertrophic markers, atrial natriuretic peptide and brain natriuretic peptide, and size of cardiomyocytes induced by PE stimulation. The protein level of stromal interaction molecule 1 and Orai1, the essential components of the SOCE, is also enhanced in hypertrophic cardiomyocytes, which were normalized by CaMKIIdelta siRNA and KN93 treatment. Hypertrophic cardiomyocytes showed an increase in the peak of Ca2+ transient following store depletion, which was inhibited by SOCE blocker BTP2, CaMKIIdelta siRNA, and KN93. The Ca2+ currents through Ca2+ release-activated Ca2+ channels were increased in PE-treated cardiomyocytes and were attenuated by CaMKIIdelta siRNA and KN93. These data indicate that PE-induced myocardial hypertrophy requires a complex signaling pathway that involves activation of both CaMKIIdelta and SOCE. In conclusion, these studies reveal that up-regulation of CaMKIIdelta may contribute to the PE induced myocardial hypertrophy through the activation of SOCE expressed in the cardiomyocytes. PMID- 27940401 TI - DNA damage induced by NADPH cytochrome P450 reductase-activated idarubicin in sensitive and multidrug resistant MCF7 breast cancer cells. AB - BACKGROUND: Idarubicin (IDA) is one of clinically important anticancer drugs belonging to the anthracycline antibiotic family. The aim of this study was to examine DNA damage induced by NADPH cytochrome P450 reductase (CPR)-activated IDA in human sensitive MCF7 and multidrug resistant MCF7/DOX500 (overexpressing P-gp) breast adenocarcinoma cells. METHODS: The evaluation of DNA fragmentation caused by single strand breaks (SSB) and double strand breaks (DSB) was performed using terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) test. Additionally, DSB formation was examined using H2AX histone phosphorylation assays. RESULTS: It was found that IDA alone and CPR-activated used at IC90 caused a higher level of DNA strand breaks in sensitive MCF7 cells detected by TUNEL assessments (p=0.0011 for IDA alone and p=0.0109 for IDA reductively activated, Kruskal-Wallis test) and gamma-H2AX-positive staining (p=0.0003 for IDA alone and p=0.0193 for IDA reductively activated, Kruskal-Wallis test) than in multidrug resistant MCF7/DOX500 cells. However, no changes were observed in the percentage of TUNEL-positive and DSB-positive cells for MCF7 as well as MCF7/DOX500 cells in the case of IDA alone and the drug pretreated in the presence of the activating system. CONCLUSIONS: The obtained results suggest that CPR-activation of IDA does not significantly change the cellular DNA damage response of studied sensitive MCF7 and multidrug resistant MCF7/DOX500 breast cancer cells, even if the results concerning the interaction of IDA undergoing CPR activation with naked DNA showed the important differences in comparison with the drug alone (non-activated). PMID- 27940403 TI - Markers of sympathetic nervous system activity associate with complex plasma lipids in metabolic syndrome subjects. AB - BACKGROUND AND AIMS: Plasma sphingolipids including ceramides, and gangliosides are associated with insulin resistance (IR) through effects on insulin signalling and glucose metabolism. Our studies of subjects with metabolic syndrome (MetS) showed close relationships between IR and sympathetic nervous system (SNS) activity including arterial norepinephrine (NE). We have therefore investigated possible associations of IR and SNS activity with complex lipids that are involved in both insulin sensitivity and neurotransmission. METHODS: We performed a cross-sectional assessment of 23 lipid classes/subclasses (total 339 lipid species) by tandem mass spectrometry in 94 overweight untreated subjects with IR (quantified by HOMA-IR, Matsuda index and plasma insulin). RESULTS: Independently of IR parameters, several circulating complex lipids associated significantly with arterial NE and NEFA (non-esterified fatty acids) and marginally with heart rate (HR). After accounting for BMI, HOMA-IR, systolic BP, age, gender, and correction for multiple comparisons, these associations were significant (p < 0.05): NE with ceramide, phosphatidylcholine, alkyl- and alkenylphosphatidylcholine and free cholesterol; NEFA with mono- di- and trihexosylceramide, GM3 ganglioside, sphingomyelin, phosphatidylcholine, alkyl- and alkenylphosphatidylcholine, phosphatidylinositol and free cholesterol; HR marginally (p = or <0.1>0.05) with ceramide, GM3 ganglioside, sphingomyelin, lysophosphatidylcholine, phosphatidylinositol, lysophosphatidylinositol and free cholesterol. Multiple subspecies of these lipids significantly associated with NE and NEFA. None of the IR biomarkers associated significantly with lipid classes/subclasses after correction for multiple comparisons. CONCLUSIONS: This is the first demonstration that arterial norepinephrine and NEFA, that reflect both SNS activity and IR, associate significantly with circulating complex lipids independently of IR, suggesting a role for such lipids in neural mechanisms operating in MetS. PMID- 27940404 TI - Got bacteria? The astounding, yet not-so-surprising, microbiome of human milk. AB - Contrary to long-held dogma, human milk is not sterile. Instead, it provides infants a rich source of diverse bacteria, particularly microbes belonging to the Staphylococcus, Streptococcus, and Pseudomonas genera. Very little is known about factors that influence variation in the milk microbiome among women and populations, although time postpartum, delivery mode, and maternal factors such as diet and antibiotic use might be important. The origins of the bacteria in milk are thought to include the maternal gastrointestinal tract (via an entero mammary pathway) and through bacterial exposure of the breast during nursing. Currently, almost nothing is known about whether variation in microbe consumption by the infant via human milk and that of the mammary gland, itself, impacts short term and/or long-term infant and maternal health although several studies suggest this is likely. We urge the clinical and public health communities to be patient, however, in order to allow human milk and lactation researchers to first understand what constitutes 'normal' in terms of the milk microbiome (as well as factors that impact microbial community structure) prior to jumping the gun to investigate if and how this important source of microbes impacts maternal and infant health. PMID- 27940405 TI - Dietary and enteral interventions for Crohn's disease. AB - It is now widely acknowledged that the intestinal bacterial flora together with genetic predisposing factors significantly contribute to the immunopathogenesis of inflammatory bowel disease (IBD) as reflected by mucosal immune dysregulation. Recently, there has been an increased interest in nutraceutical therapies, including probiotics, prebiotics and synbiotics. Other dietary interventions with low carbohydrate diet, omega-3 polyunsaturated fatty acids and glutamine have been attempted to downregulate the gut inflammatory response and thereby alleviate gastrointestinal symptoms. Enteral nutrition has been widely used as induction and maintenance therapies in the management of Crohn's disease (CD). In this review, a critical assessment of the results of clinical trial outcomes and meta-analyses was conducted to evaluate the efficacy of dietary and enteral interventions for CD. PMID- 27940406 TI - Nanoscale sensors for assuring the safety of food products. AB - As far as chemical analysis is concerned, foods are among the most difficult matrices to work with because they are complex, heterogeneous substances with a high degree of variety. Assaying foods for trace levels of chemical and microbiological substances is a challenge that often requires the application of time-consuming, expensive analytical instrumentation in dedicated facilities populated by highly trained personnel. Therefore there is a continued demand for new analytical technologies that can detect small concentrations of chemicals or microbes in a more cost- and time-effective manner, preferably in the field, on the production line, and/or non-destructively, with little to no sample pre treatment, and possibly by individuals with scant scientific training. In the last decade, nanotechnology - a branch of science that takes advantage of the unique chemical and physical properties of matter on the nanoscale - has created new opportunities for both qualitative and quantitative detection of vapors/gasses, small molecules, biopolymers, and even living microbes in a fraction of the time and expense of traditional analytical techniques. This article offers a focused review of recent progress in nanotechnology-enabled biosensing as applied to foods and related matrices, paying particular attention to trends in the field, recent breakthroughs, and current areas of need. Special focus is paid to two primary categories of nanobiosensors - optical and electrochemical - and the discussion includes a comparison of their various strengths and weaknesses as they pertain ensuring the safety of the food supply. PMID- 27940407 TI - Electricity generation and microbial community in response to short-term changes in stack connection of self-stacked submersible microbial fuel cell powered by glycerol. AB - Stack connection (i.e., in series or parallel) of microbial fuel cell (MFC) is an efficient way to boost the power output for practical application. However, there is little information available on short-term changes in stack connection and its effect on the electricity generation and microbial community. In this study, a self-stacked submersible microbial fuel cell (SSMFC) powered by glycerol was tested to elucidate this important issue. In series connection, the maximum voltage output reached to 1.15 V, while maximum current density was 5.73 mA in parallel. In both connections, the maximum power density increased with the initial glycerol concentration. However, the glycerol degradation was even faster in parallel connection. When the SSMFC was shifted from series to parallel connection, the reactor reached to a stable power output without any lag phase. Meanwhile, the anodic microbial community compositions were nearly stable. Comparatively, after changing parallel to series connection, there was a lag period for the system to get stable again and the microbial community compositions became greatly different. This study is the first attempt to elucidate the influence of short-term changes in connection on the performance of MFC stack, and could provide insight to the practical utilization of MFC. PMID- 27940408 TI - Carbohydrate structure: the rocky road to automation. AB - With the introduction of intuitive graphical software, structural biologists who are not experts in crystallography are now able to build complete protein or nucleic acid models rapidly. In contrast, carbohydrates are in a wholly different situation: scant automation exists, with manual building attempts being sometimes toppled by incorrect dictionaries or refinement problems. Sugars are the most stereochemically complex family of biomolecules and, as pyranose rings, have clear conformational preferences. Despite this, all refinement programs may produce high-energy conformations at medium to low resolution, without any support from the electron density. This problem renders the affected structures unusable in glyco-chemical terms. Bringing structural glycobiology up to 'protein standards' will require a total overhaul of the methodology. Time is of the essence, as the community is steadily increasing the production rate of glycoproteins, and electron cryo-microscopy has just started to image them in precisely that resolution range where crystallographic methods falter most. PMID- 27940409 TI - Fates and furies: Using novels to support the education of nurses and family therapists. PMID- 27940410 TI - Evaluating the forensic application of 19 target microRNAs as biomarkers in body fluid and tissue identification. AB - RNA-based body fluid and tissue identification has evolved as a promising and reliable new technique to classify type and source of biological evidence in crime cases. In particular, mRNA-based approaches are currently on the rise to replace conventional protein-based methods and are increasingly implemented into forensic casework. However, degradation of these nucleic acid molecules can cause issues on laboratory scale and need to be considered for a credible investigation. For this reason, the analysis of miRNAs using qPCR has been proposed to be a sensitive and specific approach to identify the origin of a biological trace taking advantage of their small size and resistance to degradation. Despite the straightforward workflow of this method, suitable endogenous controls are inevitable when performing real-time PCR to ensure accurate normalization of gene expression data in order to allow a meaningful interpretation. In this regard, we have validated reference genes for a set of forensically relevant body fluids and tissues (blood, saliva, semen, vaginal secretions, menstrual blood and skin) and tested 15 target genes aiming to identify abovementioned sample types. Our data showed that preselected endogenous controls (miR26b, miR92 and miR484) and miR144, initially selected as potential marker for the detection of menstrual blood, were the most stable expressed genes among our set of samples. Normalizing qPCR data with these four validated references revealed that only five miRNA markers are necessary to differentiate between the six different cell types selected in this study. Nevertheless, our observations in the present study indicate that miRNA analysis methods may not provide straightforward data interpretation strategies required for an implementation in forensic casework. PMID- 27940411 TI - Can mastication in children with cerebral palsy be analyzed by clinical observation, dynamic ultrasound and 3D kinematics? AB - The aim of this study was to explore the feasibility of the Mastication Observation and Evaluation (MOE) instrument, dynamic ultrasound and 3D kinematic measurements to describe mastication in children with spastic cerebral palsy and typically developing children. Masticatory movements during five trials of eating a biscuit were assessed in 8 children with cerebral palsy, spastic type (mean age 9.08years) and 14 typically developing children (mean age 9.01years). Differences between trials were tested (t-test) and the mastication of individual children with cerebral palsy was analyzed. MOE scores ranged from 17 to 31 (median 24) for the children with cerebral palsy and from 28 to 32 (median 31) for the typically developing children. There was an increased chewing cycle duration, a smaller left-right and up-down tongue displacement and larger anterior mandible movements for the trials (n=40) of cerebral palsy children (p<0.000 for all comparisons) compared to the trials of typically developing children (n=70). The MOE captures differences in mastication between individual children with cerebral palsy. The MOE items 'jaw movement' and 'fluency and coordination' showed the most similarity with the objective measurements. Objective measurements of dynamic ultrasound and 3D kinematics complemented data from the MOE instrument. PMID- 27940412 TI - Linking wine lactic acid bacteria diversity with wine aroma and flavour. AB - In the last two decades knowledge on lactic acid bacteria (LAB) associated with wine has increased considerably. Investigations on genetic and biochemistry of species involved in malolactic fermentation, such as Oenococcus oeni and of Lactobacillus have enabled a better understand of their role in aroma modification and microbial stability of wine. In particular, the use of molecular techniques has provided evidence on the high diversity at species and strain level, thus improving the knowledge on wine LAB taxonomy and ecology. These tools demonstrated to also be useful to detect strains with potential desirable or undesirable traits for winemaking purposes. At the same time, advances on the enzymatic properties of wine LAB responsible for the development of wine aroma molecules have been undertaken. Interestingly, it has highlighted the high intraspecific variability of enzymatic activities such as glucosidase, esterase, proteases and those related to citrate metabolism within the wine LAB species. This genetic and biochemistry diversity that characterizes wine LAB populations can generate a wide spectrum of wine sensory outcomes. This review examines some of these interesting aspects as a way to elucidate the link between LAB diversity with wine aroma and flavour. In particular, the correlation between inter- and intra-species diversity and bacterial metabolic traits that affect the organoleptic properties of wines is highlighted with emphasis on the importance of enzymatic potential of bacteria for the selection of starter cultures to control MLF and to enhance wine aroma. PMID- 27940413 TI - Single vs multiple-spore inoculum effect on growth kinetic parameters and modeled probabilities of growth and aflatoxin B1 production of Aspergillus flavus on pistachio extract agar. AB - The objective of the present study was to assess the differences in modeled growth/AFB1 production probability and kinetic growth parameters for Aspergillus flavus inoculated as single spores or in a concentrated inoculation point (~500 spores). The experiment was carried out at 25 degrees C and at two water activities (0.85 and 0.87) on pistachio extract agar (3%). Binary data obtained from growth and AFB1 studies were modeled using linear logistic regression analysis. The radial growth curve for each colony was fitted to a linear model for the estimation of the lag phase for growth and the mycelial growth rate. In general, radial growth rate and lag phase for growth were not normally distributed and both of them were affected by the inoculation type, with the lag phase for growth being more affected. Changing from the multiple spore to the single spore inoculation led to a delay of approximately 3-5days on the lag phase and higher growth rates for the multiple spore experiment were found. The same trend was observed on the probability models, with lower predicted probabilities when colonies came up from single spores, for both growth and AFB1 production probabilities. Comparing both types of models, it was concluded that a clear overestimation of the lag phase for growth occurred using the linear model, but only in the multiple spore experiment. Multiple spore inoculum gave very similar estimated time to reach some set probabilities (t10, t50 and t100) for growth or AFB1 production due to the abruptness of the logistic curve developed. The observed differences suggest that inoculum concentration greatly affects the outcome of the predictive models, the estimated times to growth/AFB1 production being much earlier for the concentrated inoculum than for a single spore colony (up to 9days). Thus the number of spores used to generate data in predictive mycology experiments should be carefully controlled in order to predict as accurately as possible the fungal behavior in a foodstuff. PMID- 27940414 TI - Cold stress increases salt tolerance of the extremophytes Eutrema salsugineum (Thellungiella salsuginea) and Eutrema (Thellungiella) botschantzevii. AB - A comparative study was performed to analyze the effect of cold acclimation on improving the resistance of Arabidopsis thaliana, Eutrema salsugineum and Eutrema botschantzevii plants to salt stress. Shoot FW, sodium and potassium accumulation, metabolite content, expression of proton pump genes VAB1, VAB2,VAB3, VP2, HA3 and genes encoding ion transporters SOS1, HKT1, NHX1, NHX2, NHX5 located in the plasma membrane or tonoplast were determined just after the cold treatment and the onset of the salt stress. In the same cold-acclimated E. botschantzevii plants, the Na+ concentration after salt treatment was around 80% lower than in non-acclimated plants, whereas the K+ concentration was higher. As a result of cold acclimation, the expression of, VAB3, NHX2, NHX5 genes and of SOS1, VP2, HA3 genes was strongly enhanced in E. botschantzevii and in E. salsugineum plants correspondently. None of the 10 genes analyzed showed any expression change in A. thaliana plants after cold acclimation. Altogether, the results indicate that cold-induced adaptation to subsequent salt stress exists in the extremophytes E. botschantzevii and to a lesser extend in E. salsugineum and is absent in Arabidopsis. This phenomenon may be attributed to the increased expression of ion transporter genes during cold acclimation in the Eutrema species. PMID- 27940415 TI - Impact of Terminalia chebula Retz. against Aedes aegypti L. and non-target aquatic predatory insects. AB - Aedes aegypti Linn is one of the most important mosquito species. The vectors are responsible for causing deadly diseases like dengue and dengue hemorrhagic fever. Several chemical pesticides used to control these dengue vectors caused severe toxic significances on human health and other non-target beneficial insects. Therefore the current investigation has been made to access the bio-efficacy of the crude seed extracts of T. chebula against the dengue vector Ae. aegypti. The GC-MS analysis of crude seed extracts of T. chebula identified nine chemical compounds with major peak area in the 1,2,3-Benzenetriol (61.96%), followed by Tridecanoic acid (09.55%). Ae. aegypti larvae showed dose dependent mortality rate was observed between the treatments. Prominent protection rate at greater concentrations of 100ppm and moderate protection at 75 and 50ppm was observed in the repellent assay. Lethal concentration (LC50 and LC90) of fourth instar larvae of Ae. aegypti was observed in 138 and 220ppm concentration respectively. Similarly, the seed extracts showed 100% adulticidal activity at the concentration of 400ppm at 30min of exposure time. Phytochemicals present in the seed extracts of T. chebula significantly affects the major portions of the midgut tissues of Ae. aegypti at the concentration of 100ppm. The toxicological evaluation of seed extracts also proved non-toxic towards the A. bouvieri and Tx. splendens aquatic predatory insects. Hence, the present result suggest that bio rational plant derived T. chebula could be incorporated in the dengue vector control and have no adverse effects on non-target beneficial insects. PMID- 27940417 TI - The right to medicalization? Invited commentary on Karsoho et al. (2016). PMID- 27940416 TI - Social anxiety and suicidal ideation: Test of the utility of the interpersonal psychological theory of suicide. AB - Social anxiety is related to greater suicidality, even after controlling for depression and other psychopathology. The Interpersonal-Psychological Theory of Suicide (IPTS; Joiner, 2005) proposes that people are vulnerable to wanting to die by suicide if they experience both perceived burdensomeness (sense that one is a burden to others) and thwarted belongingness (a greater sense of alienation from others). Socially anxious persons may be especially vulnerable to these interpersonal factors. The current study tested whether interpersonal IPTS components independently and additively mediate the social anxiety-suicidal ideation (SI) relation among 780 (80.5% female) undergraduates. Social anxiety was significantly, robustly related to SI and to thwarted belongingness and perceived burdensomeness. Social anxiety was indirectly related to SI via thwarted belongingness and perceived burdensomeness. The sum of these indirect effects was significant. Moderated mediation analyses indicated that perceived burdensomeness only mediated the relation between social anxiety and SI at higher levels of thwarted belongingness. Findings highlight that difficulties in interpersonal functioning may serve as potential pathways through which social anxiety may lead to greater suicidality. Findings highlight that difficulties in interpersonal functioning may serve as potential pathways through which social anxiety may lead to greater suicidality. PMID- 27940418 TI - Toxoplasmosis versus lymphoma: Cerebral lesion characterization using DSC-MRI revisited. AB - OBJECTIVE: CNS toxoplasmosis and lymphoma are often indistinguishable by conventional contrast-enhanced MRI. There is limited literature on the diagnostic efficacy of dynamic susceptibility contrast (DSC) MRI for differentiating these entities. This study assesses the clinical utility of relative cerebral blood volume (rCBV) for making a diagnosis and determines rCBV thresholds for differentiation using contemporary DSC-MRI. PATIENTS AND METHODS: Thirteen patients with 25 lesions (13 toxoplasmosis and 12 lymphoma) and pre-treatment DSC MRI were identified retrospectively. Volumetric regions of interest of segmented enhancement were used to extract mean rCBV normalized to normal-appearing white matter for each lesion. We compared average mean rCBV between all toxoplasmosis and lymphoma lesions using a general mixed model. Three models were also compared for evaluating rCBV-based disease status in each patient: 1) mean rCBV of each lesion using a generalized estimating equation, 2) volume-weighted mean rCBV, and 3) maximum mean rCBV of all lesions using logistic regression. RESULTS: The average mean rCBV for all toxoplasmosis lesions was 0.98 (95% CI 0.55-1.41) compared to 2.07 (95% CI 1.71-2.43) for all lymphoma lesions, a significant difference (1.09, 95% CI 0.53-1.65, p=0.0013). For the three models used to evaluate rCBV-based disease status in each patient, a significant relationship was observed, with an optimal rCBV threshold of approximately 1.5 for distinguishing lymphoma from toxoplasmosis in each model. CONCLUSION: RCBV derived from contemporary DSC-MRI is helpful for distinguishing between cerebral toxoplasmosis and cerebral lymphoma on an individual patient basis and may facilitate more timely initiation of appropriate directed therapy. PMID- 27940419 TI - Novel CLK1 inhibitors based on N-aryloxazol-2-amine skeleton - A possible way to dual VEGFR2 TK/CLK ligands. AB - BACKGROUND: Inhibitors of CLK protein kinases suppress cell growth and induce apoptosis by modulating pre-mRNA splicing in cancer. CLK family kinases are also involved in alternative splicing and RNA processing in Duchenne muscular dystrophy, Alzheimer's disease, HIV-1, and influenza virus. Small inhibitors are valuable tools for better understanding the molecular mechanisms of splicing and may serve as seeds for a novel class of therapeutics. ACHIEVEMENTS: Here we describe a discovery of four novel CLK1 inhibitors possessing N-aryloxazol-2 amine skeleton. Their activity against CLK1 (IC50: 20, 30, 40 and 80 nM) and some other CMGC kinases, predicted CLK binding poses, synthesis and physico-chemical characteristics are also stated. Additionally analysis of all PDB available CLK structures and interactions of their ligands was performed. There are only few powerful dual CLK/VEGFR inhibitors known in the literature. We proposed that our inhibitors have similar binding places and interactions in CLK1, 3 and VEGFR2 TK mostly due to the joint N-aryloxazol-2-amine pharmacophoric fragment. One of our N-aryloxazol-2-amines already proved a good activity against both VEGFR2 and CLK1 enzymes (23/80 nM, resp). We proposed that the presented class of compounds has a potential to be developed in dual VEGFR2/CLK clinical compounds with prospective synergy to treat cancer. PMID- 27940420 TI - Effect of combined treatment with supercritical CO2 and rosemary on microbiological and physicochemical properties of ground pork stored at 4 degrees C. AB - The effect of combined treatment with supercritical CO2 (2000psi, 35 degrees C for 2h) and rosemary powder (2.5% and 5.0% (w/w)) on microbiological and physicochemical properties of ground pork stored at 4 degrees C was investigated. The changes in total viable count, pH, total volatile base nitrogen (TVB-N), lipid oxidation and instrumental color (CIE L*, a*, b*) were analyzed during a week period of refrigerated storage. It was found that microbial populations were reduced by supercritical CO2 treatment, with the more pronounced effect being achieved by combined treatment with supercritical CO2 and 5.0g rosemary powder/100g meat. Supercritical CO2 treatment for 2h could accelerate lipid oxidation of ground pork during refrigerated storage, whereas combination with rosemary can significantly slow down the increase of oxidation rate. Combined treatment of supercritical CO2 and rosemary significantly increased L* and b* values of the ground pork, while the a*, pH and TVB-N value were not affected as compared to the treatment with supercritical CO2 alone. The results of this study indicate that combined treatment of supercritical CO2 and rosemary may be useful in the meat industry to enhance the storage stability of ground pork treated with long time exposure of supercritical CO2 during refrigerated storage. PMID- 27940421 TI - Estimation of the intramuscular fat content of m. longissimus thoracis in crossbred beef cattle based on live animal measurements. AB - The objective of this study was to determine the usefulness of live animal measurements in estimating the intramuscular fat (IMF) content of m. longissimus thoracis (MLT) in beef cattle. Live animal measurements were performed in young crossbred bulls (96) and steers (59), the offspring of Holstein-Friesian (HF) cows and beef bulls (Limousin, Hereford and Charolais), at the end of the fattening period. The content of intramuscular fat was determined in samples from MLT by chemical analyses. A prediction model was developed by stepwise regression. In the validation model, the values of R2=0.74, RMSE=0.37% were determined. The results indicate that selected biometric (chest width, chest girth) ultrasound measurements (thickness of subcutaneous rump and back fat) and selected blood parameters (triglycerides) can be used to predict IMF content with satisfactory precision and accuracy. The analyzed parameters could constitute a valuable tool in the process of selecting beef quality traits and determining the slaughter value of young beef cattle. PMID- 27940422 TI - Data-as-a-Service Platform for Delivering Healthy Lifestyle and Preventive Medicine: Concept and Structure of the DAPHNE Project. AB - BACKGROUND: Overweight and obesity is related to many health problems and diseases. The current obesity epidemic, which is a major health problem, is closely related to a lack of physical activity, high levels of sedentary behavior, and increased energy intake; with evidence to show increasing incidence of these issues in the younger population. Tackling obesity and its comorbid conditions requires a holistic approach encompassing attention on physical activity, healthy diet, and behavioral activation in order to enable and maintain meaningful and long-term weight loss and weight maintenance. OBJECTIVE: The objective of the Data-as-a-Service Platform for Healthy Lifestyle and Preventive Medicine (DAPHNE) project is to develop a breakthrough information communications technology (ICT) platform for tracking health, weight, physical activity, diet, lifestyle, and psychological components within health care systems, whereby the platform and clinical support is linked. METHODS: The DAPHNE platform aims to deliver personalized guidance services for lifestyle management to the citizen/patient by means of (1) advanced sensors and mobile phone apps to acquire and store continuous/real-time data on lifestyle aspects, behavior, and surrounding environment; (2) individual models to monitor their health and fitness status; (3) intelligent data processing for the recognition of behavioral trends; and (4) specific services for personalized guidance on healthy lifestyle and disease prevention. It is well known that weight loss and maintenance of weight loss are particularly difficult. This tool will address some of the issues found with conventional treatment/advice in that it will collect data in real time, thereby reducing reliability issues known with recalling events once they have passed and will also allow adjustment of behavior through timely support and recommendations sent through the platform without the necessity of formal one-to one visits between patient and clinician. Patient motivation/compliance is a particular issue with conventional weight loss regimes; DAPHNE aims to increase the individuals' awareness of their own behavior and fosters their accountability. RESULTS: The project has been funded and the research work has started. Results for the validation of the different components is due imminently. CONCLUSIONS: In contrast with previous existing solutions, the DAPHNE project tackles the obesity problem from a clinical point of view, designing the different interfaces for its use by patients (adults and children), physicians, and caregivers. A specific design for children and adolescent patients treated for obesity has been followed, guided by pediatric physicians at hospitals in Europe. The final clinical validation of the DAPHNE platform will be carried out in different European hospitals, testing the platform in both adolescents and adults. PMID- 27940423 TI - Impact of Structured Rounding Tools on Time Allocation During Multidisciplinary Rounds: An Observational Study. AB - BACKGROUND: Recent research has shown evidence of disproportionate time allocation for patient communication during multidisciplinary rounds (MDRs). Studies have shown that patients discussed later during rounds receive lesser time. OBJECTIVE: The aim of our study was to investigate whether disproportionate time allocation effects persist with the use of structured rounding tools. METHODS: Using audio recordings of rounds (N=82 patients), we compared time allocation and communication breakdowns between a problem-based Subjective, Objective, Assessment, and Plan (SOAP) and a system-based Handoff Intervention Tool (HAND-IT) rounding tools. RESULTS: We found no significant linear dependence of the order of patient presentation on the time spent or on communication breakdowns for both structured tools. However, for the problem-based tool, there was a significant linear relationship between the time spent on discussing a patient and the number of communication breakdowns (P<.05)--with an average of 1.04 additional breakdowns with every 120 seconds in discussion. CONCLUSIONS: The use of structured rounding tools potentially mitigates disproportionate time allocation and communication breakdowns during rounds, with the more structured HAND-IT, almost completely eliminating such effects. These results have potential implications for planning, prioritization, and training for time management during MDRs. PMID- 27940425 TI - Where the Wild Things Aren't: Loss of Biodiversity, Emerging Infectious Diseases, and Implications for Diagnosticians. PMID- 27940428 TI - Update From the Editors to Our Readers. PMID- 27940427 TI - Discrepancies Between Clinical Diagnoses and Autopsy Findings in Critically Ill Children: A Prospective Study. AB - OBJECTIVES: To evaluate the discrepancies between clinical and autopsy diagnoses in patients who died in the pediatric intensive care units (PICUs) of a tertiary care university hospital. METHODS: A prospective study of all consecutive autopsies discussed at monthly mortality conferences over 5 years. Discrepancies between premortem and autopsy diagnoses were classified according to modified Goldman et al criteria. RESULTS: From January 1, 2011, to December 31, 2015, a total of 2,679 children were admitted to the two PICUs of our hospital; 257 (9.6%) died, 150 (58.4%) underwent autopsy, and 123 were included. Complete concordance between clinical and postmortem diagnoses was observed in 86 (69.9%) patients; 20 (16.3%) had a class I discrepancy, and eight (6.5%) had a class II discrepancy. Comparing 2011 and 2015, the rate of major discrepancies decreased from 31.6% to 15%. CONCLUSIONS: Our results emphasize the importance of autopsy to clarify the cause of death and its potential contribution to improvement of team performance and quality of care. PMID- 27940426 TI - Laboratory Tests Ordering Pattern by Medical Residents From a Brazilian University Hospital. AB - OBJECTIVES: The adequacy of laboratory test orders by medical residents is a longstanding issue. The aim of this study is to analyze the number, types, and pattern of repetition of tests ordered by medical residents. METHODS: We studied all tests ordered over a 1-year period for inpatients of an internal medicine ward in a university hospital. Types, results, and repetition pattern of tests were analyzed in relation to patients' diagnoses. RESULTS: We evaluated 117,666 tests, requested for 1,024 inpatients. The mean number of tests was 9.5 per day. The test repetition pattern was similar, regardless of patients' diagnoses, previous test results, or duration of stay. The probability of an abnormal result after a sequence of three normal tests was lower than 25%, regardless of the diagnosis. CONCLUSIONS: Number of tests and repetition were both high, imposing costs, discomfort, and risks to patients, thus warranting further investigation. PMID- 27940429 TI - Is it Time to Find a Role for Uric Acid Levels in the Prevention and Management of Hypertension. PMID- 27940432 TI - Marian Hughes. PMID- 27940433 TI - Morality and non-medical drug use. PMID- 27940434 TI - Is caviar a risk factor for being a millionaire? PMID- 27940435 TI - E-cigarettes are major threat to young people's health, says US surgeon general. PMID- 27940436 TI - Doctors' leader calls for government to rethink plans to replace Human Rights Act. PMID- 27940442 TI - Poverty and abortion complications in Peru. PMID- 27940443 TI - Women's health is not in focus in disaster zones: lessons from the Nepal earthquake. PMID- 27940444 TI - Geometric morphometric analysis of craniofacial growth between the ages of 12 and 14 in normal humans. AB - Aim: There is great variation of growth among individuals. The question whether patients with different skeletal discrepancies grow differently is biologically interesting but also important in designing clinical trials. The aim of the present study was to evaluate whether growth direction depends on the initial craniofacial pattern. Subjects and method: The sample consisted of 350 lateral cephalograms of 175 subjects (91 females and 84 males) followed during normal growth without any orthodontic treatment. The examined ages were 12 (T1) and 14 (T2) years. The cephalograms were obtained from the American Association of Orthodontists Foundation (AAOF) Craniofacial Growth Legacy Collection (Burlington, Fels, Iowa, and Oregon growth studies). We digitally traced 15 curves on each cephalogram, comprehensively covering the craniofacial skeleton, and located 127 points on the curves, 117 of which were sliding semilandmarks and 10 fixed. Procrustes alignment, principal component analysis and two-block partial least squares analysis were performed, after sliding the semilandmarks to minimize bending energy. Results: The first 10 principal components (PCs) described approximately 71 per cent of the total shape variance. PC1 was related to shape variance in the vertical direction (low/high angle skeletal pattern) and PC2 was mainly related to shape variance in the anteroposterior direction (Class II/Class III pattern). PC3 was mainly related to the shape variance of the mandibular angle. All subjects shared a similar growth trajectory in shape space. We did not find any correlation between the initial shape and the magnitude of shape change between T1 and T2, but males showed a greater shape change than females. The direction of shape change was moderately correlated to the initial shape (RV coefficient: 0.14, P < 0.001). Conclusions: The initial shape of the craniofacial complex covaried weakly with the direction of shape change during growth. PMID- 27940446 TI - The 100 000 Genomes Project: What it means for paediatrics. PMID- 27940447 TI - How Well Do Laboratories Adhere to Recommended Clinical Guidelines for the Management of Myocardial Infarction? The Italian Experience. PMID- 27940445 TI - Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2. AB - The liver has an intrinsic capacity to regenerate in response to injury or surgical resection. Nevertheless, circumstances in which hepatocytes are unresponsive to proliferative signals result in impaired regeneration and hepatic failure. As the Hippo pathway has a canonical role in the maintenance of liver size, we investigated whether it could serve as a therapeutic target to support regeneration. Using a standard two-thirds partial hepatectomy (PH) model in young and aged mice, we demonstrate that the Hippo pathway is modulated across the phases of liver regeneration. The activity of the core kinases MST1 and LATS1 increased during the early hypertrophic phase and returned to steady state levels in the proliferative phase, coinciding with activation of YAP1 target genes and hepatocyte proliferation. Moreover, following PH in aged mice, we demonstrate that Hippo signaling is anomalous in non-regenerating livers. We provide pre clinical evidence that silencing the Hippo core kinases MST1 and MST2 with siRNA provokes hepatocyte proliferation in quiescent livers and rescues liver regeneration in aged mice following PH. Our data suggest that targeting the Hippo core kinases MST1/2 has therapeutic potential to improve regeneration in non regenerative disorders. PMID- 27940450 TI - Identification and Characterization of Cardiac Troponin T Fragments in Serum of Patients Suffering from Acute Myocardial Infarction. AB - BACKGROUND: Cardiac troponin T (cTnT) is the preferred biomarker for the diagnosis of acute myocardial infarction (AMI). It has been suggested that cTnT is present predominantly in fragmented forms in human serum following AMI. In this study, we have used a targeted mass spectrometry assay and epitope mapping using Western blotting to confirm this hypothesis. METHODS: cTnT was captured from the serum of 12 patients diagnosed with AMI using an immunoprecipitation technique employing the M11.7 catcher antibody and fractionated with SDS-PAGE. Coomassie-stained bands of 4 patients at 37, 29, and 16 kDa were excised from the gel, digested with trypsin, and analyzed on a Q Exactive instrument set on targeted Selected Ion Monitoring mode with data-dependent tandem mass spectrometry (MS/MS) for identification. Western blotting employing 3 different antibodies was used for epitope mapping. RESULTS: Ten cTnT peptides of interest were targeted. By using MS/MS, all of these peptides were identified in the 37 kDa, intact, cTnT band. In the 29- and 16-kDa fragment bands, 8 and 4 cTnT specific peptides were identified, respectively. Some of these peptides were "semitryptic," meaning that their C-termini were not formed by trypsin cleavage. The C-termini of these semitryptic peptides represent the C-terminal end of the cTnT molecules present in these bands. These results were confirmed independently by epitope mapping. CONCLUSIONS: Using LC-MS, we have succeeded in positively identifying the 29- and 16-kDa fragment bands as cTnT-derived products. The amino acid sequences of the 29- and 16-kDa fragments are Ser79-Trp297 and Ser79-Gln199, respectively. PMID- 27940451 TI - The 2016 BJA/PGA special issue: a selection of six educational reviews. PMID- 27940449 TI - Next Generation Sequencing of Circulating Cell-Free DNA for Evaluating Mutations and Gene Amplification in Metastatic Breast Cancer. AB - BACKGROUND: Breast cancer tissues are heterogeneous and show diverse somatic mutations and somatic copy number alterations (CNAs). We used a novel targeted next generation sequencing (NGS) panel to examine cell-free DNA (cfDNA) to detect somatic mutations and gene amplification in women with metastatic breast cancer (MBC). METHODS: cfDNA from pretreated patients (n = 42) and 9 healthy controls were compared with matched lymphocyte DNA by NGS, using a custom 158 amplicon panel covering hot-spot mutations and CNAs in 16 genes, with further validation of results by droplet digital PCR. RESULTS: No mutations were identified in cfDNA of healthy controls, whereas exactly half the patients with metastatic breast cancer had at least one mutation or amplification in cfDNA (mean 2, range 1-6) across a total of 13 genes. Longitudinal follow up showed dynamic changes to mutations and gene amplification in cfDNA indicating clonal and subclonal response to treatment that was more dynamic than cancer antigen 15-3 (CA15-3). Interestingly, at the time of blood sampling disease progression was occurring in 7 patients with erb-b2 receptor tyrosine kinase 2 (ERBB2) gene amplification in their cfDNA and 3 of these patients were human epidermal growth factor receptor 2 (HER2) negative at diagnosis, suggesting clonal evolution to a more aggressive phenotype. Lastly, 6 patients harbored estrogen receptor 1 (ESR1) mutations in cfDNA, suggesting resistance to endocrine therapy. Overall 9 of 42 patients (21%) had alterations in cfDNA that could herald a change in treatment. CONCLUSIONS: Targeted NGS of cfDNA has potential for monitoring response to targeted therapies through both mutations and gene amplification, for analysis of dynamic tumor heterogeneity and stratification to targeted therapy. PMID- 27940452 TI - Perioperative goal-directed haemodynamic therapy based on flow parameters: a concept in evolution. AB - Haemodynamic management incorporating direct or surrogate stroke volume monitoring has experienced a rapid evolution, because of emergence of the "goal directed therapy" concept and technological developments aimed at providing a parameter leading to the goal. Nonetheless, consensus on both definitions of the ideal "goal" and strategies for achieving it remain elusive. For this review, we first consider basic physiological and patient monitoring factors relevant to the concept of "fluid responsiveness", and then focus upon randomized controlled trials and meta-analyses involving goal-directed haemodynamic therapy based on various flow parameters. Finally, we discuss the current status of noninvasive methods for monitoring fluid responsiveness. PMID- 27940448 TI - Bone Turnover Markers in the Diagnosis and Monitoring of Metabolic Bone Disease. AB - BACKGROUND: Disorders of bone metabolism, most notably osteoporosis, are highly prevalent and predispose to fractures, causing high patient morbidity and mortality. Diagnosis and monitoring of bone metabolic defects can present a major challenge as these disorders are largely asymptomatic and radiographic measures of bone mass respond slowly to changes in bone physiology. CONTENT: Bone turnover markers (BTMs) are a series of protein or protein derivative biomarkers released during bone remodeling by osteoblasts or osteoclasts. BTMs can offer prognostic information on fracture risk that supplements radiographic measures of bone mass, but testing using BTMs has to take into account the large number of preanalytic factors and comorbid clinical conditions influencing BTM levels. BTMs respond rapidly to changes in bone physiology, therefore, they have utility in determining patient response to and compliance with therapies for osteoporosis. SUMMARY: BTMs are a useful adjunct for the diagnosis and therapeutic monitoring of bone metabolic disorders, but their use has to be tempered by the known limitations in their clinical utility and preanalytic variables complicating interpretation. PMID- 27940454 TI - Acute traumatic coagulopathy: pathophysiology and resuscitation. AB - Acute Traumatic Coagulopathy occurs immediately after massive trauma when shock, hypoperfusion, and vascular damage are present. Mechanisms for this acute coagulopathy include activation of protein C, endothelial glycocalyx disruption, depletion of fibrinogen, and platelet dysfunction. Hypothermia and acidaemia amplify the endogenous coagulopathy and often accompany trauma. These multifactorial processes lead to decreased clot strength, autoheparinization, and hyperfibrinolysis. Furthermore, the effects of aggressive crystalloid administration, haemodilution from inappropriate blood product transfusion, and prolonged surgical times may worsen clinical outcomes. We review normal coagulation using the cell-based model of haemostasis and the pathophysiology of acute traumatic coagulopathy. Developed trauma systems reduce mortality, highlighting critical goals for the trauma patient in different phases of care. Once patients reach a trauma hospital, certain triggers reliably indicate when they require massive transfusion and specialized trauma care. These triggers include base deficit, international normalized radio (INR), systolic arterial pressure, haemoglobin concentration, and temperature. Early identification for massive transfusion is critically important, as exsanguination in the first few hours of trauma is a leading cause of death. To combat derangements caused by massive haemorrhage, damage control resuscitation is a technique that addresses each antagonist to normal haemostasis. Components of damage control resuscitation include damage control surgery, permissive hypotension, limited crystalloid administration, haemostatic resuscitation, and correction of hyperfibrinolysis. PMID- 27940455 TI - Sepsis for the anaesthetist. AB - Sepsis is as a dysregulated systemic response to infection. Morbidity and mortality of the syndrome are very high worldwide. Recent definitions have redefined criteria for sepsis. The new definition (Sepsis-3) classifies sepsis as infection with organ dysfunction (the old 'severe sepsis'). Septic patients are at risk for secondary injuries, thus aggressive source control, resuscitation, and antibiotic therapy are the mainstays of management. Central to sepsis physiology is vasodilated shock. Many patients respond to i.v. fluid therapy. Pathophysiology also includes energy failure, or a cellular inability to oxidize fuel, and immune incompetence, often manifest by susceptibility to superinfections. Sepsis treatment is optimized by timely resuscitation and control of infection. Early recognition and resuscitation are associated with improved outcomes, although no single resuscitation end point is as good as overall patient assessment. Dynamic resuscitation metrics might be useful to avoid overinfusion of fluid therapies. Antibiotics should treat likely pathogens, with broader coverage for sicker patients (e.g. those with septic shock). Avoidance of iatrogenic injury, such as ventilator-induced lung injury from large tidal volumes, helps to prevent subsequent tissue damage and worsened systemic response. Single-agent therapies to block the systemic response have not fulfilled promise in sepsis, probably because part of the complex syndrome is adaptive. However, early aggressive care based on bundles is associated with improved outcomes. Research opportunities include understanding the role of neurological, endocrine, immune, and metabolic pathophysiology in the syndrome. PMID- 27940456 TI - Perioperative cognitive protection. AB - There is significant evidence that many older surgical patients experience at least a transient decrease in cognitive function. Although there is still equipoise regarding the degree, duration, and mechanism of cognitive dysfunction, there is a concurrent need to provide best-practice clinical evidence. The two major cognitive disorders seen after surgery are postoperative delirium and postoperative cognitive dysfunction. Delirium is a public health problem; millions of dollars are spent annually on delirium-related medical resource use and prolonged hospital stays. Postoperative cognitive dysfunction is a research construct that historically signifies decline in performance on a neuropsychiatric test or group of tests and begins days to weeks after surgery. This review focuses on the current state of information gathered by several interdisciplinary stakeholder groups. Although there is still a need for high level evidence to guide clinical practice, there is an emerging literature that can guide practitioners. PMID- 27940457 TI - Enhanced recovery after surgery for primary hip and knee arthroplasty: a review of the evidence. AB - Enhanced recovery after surgery (ERAS) protocols produce significant clinical and economic benefits in a range of surgical subspecialties. There is a long tradition of applying clinical pathways to the perioperative care of joint arthroplasty patients. Enhanced recovery after surgery represents the next step in the evolution of standardized care. To date, reports of full ERAS pathways for hip or knee arthroplasty are lacking. In this narrative review, we present the evidence base that can be usefully applied to constructing ERAS pathways for hip or knee arthroplasty. The history and rationale for applying ERAS to joint arthroplasty are explained. Evidence demonstrates improved outcomes after joint arthroplasty when a standardized approach to care is implemented. The efficacy of individual ERAS components in hip or knee replacement is considered, including preoperative education, intraoperative anaesthetic techniques, postoperative analgesia, and early mobilization after joint arthroplasty. Interventions lacking high-quality evidence are identified, together with recommendations for future research. Based on currently available evidence, we present a model ERAS pathway that can be applied to perioperative care of patients undergoing hip or knee arthroplasty. PMID- 27940453 TI - Perioperative management of the bleeding patient. AB - Perioperative bleeding remains a major complication during and after surgery, resulting in increased morbidity and mortality. The principal causes of non vascular sources of haemostatic perioperative bleeding are a preexisting undetected bleeding disorder, the nature of the operation itself, or acquired coagulation abnormalities secondary to haemorrhage, haemodilution, or haemostatic factor consumption. In the bleeding patient, standard therapeutic approaches include allogeneic blood product administration, concomitant pharmacologic agents, and increasing application of purified and recombinant haemostatic factors. Multiple haemostatic changes occur perioperatively after trauma and complex surgical procedures including cardiac surgery and liver transplantation. Novel strategies for both prophylaxis and therapy of perioperative bleeding include tranexamic acid, desmopressin, fibrinogen and prothrombin complex concentrates. Point-of-care patient testing using thromboelastography, rotational thromboelastometry, and platelet function assays has allowed for more detailed assessment of specific targeted therapy for haemostasis. Strategic multimodal management is needed to improve management, reduce allogeneic blood product administration, and minimize associated risks related to transfusion. PMID- 27940458 TI - Blood Calcification Propensity, Cardiovascular Events, and Survival in Patients Receiving Hemodialysis in the EVOLVE Trial. AB - BACKGROUND AND OBJECTIVES: Patients receiving hemodialysis are at risk of cardiovascular events. A novel blood test (T50 test) determines the individual calcification propensity of blood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: T50 was determined in 2785 baseline serum samples of patients receiving hemodialysis enrolled in the Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) trial and the T50 results were related to patient outcomes. RESULTS: Serum albumin, bicarbonate, HDL cholesterol, and creatinine were the main factors positively/directly and phosphate was the main factor negatively/inversely associated with T50. The primary composite end point (all cause mortality, myocardial infarction [MI], hospitalization for unstable angina, heart failure, or peripheral vascular event [PVE]) was reached in 1350 patients after a median follow-up time of 619 days. After adjustments for confounding, a lower T50 was independently associated with a higher risk of the primary composite end point as a continuous measure (hazard ratio [HR] per 1 SD lower T50, 1.15; 95% confidence interval [95% CI], 1.08 to 1.22; P<0.001). Furthermore, lower T50 was associated with a higher risk in all-cause mortality (HR per 1 SD lower T50, 1.10; 95% CI, 1.02 to 1.17; P=0.001), MI (HR per 1 SD lower T50, 1.38; 95% CI, 1.19 to 1.60; P<0.001), and PVE (HR per 1 SD lower T50, 1.22; 95% CI, 1.05 to 1.42; P=0.01). T50 improved risk prediction (integrated discrimination improvement and net reclassification improvement, P<0.001 and P=0.001) of the primary composite end point. CONCLUSIONS: Blood calcification propensity was independently associated with the primary composite end point, all-cause mortality, MI, and PVE in the EVOLVE study and improved risk prediction. Prospective trials should clarify whether T50-guided therapies improve outcomes. PMID- 27940459 TI - A Multicenter Cohort Study of Histologic Findings and Long-Term Outcomes of Kidney Disease in Women Who Have Been Pregnant. AB - BACKGROUND AND OBJECTIVES: For many women pregnancy is the first contact with health services, thus providing an opportunity to identify renal disease. This study compares causes and long-term renal outcomes of biopsy-proven renal disease identified during pregnancy or within 1 year postpartum, with nonpregnant women. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Native renal biopsies (1997-2012), in women of childbearing age (16 to <50 years), from 21 hospitals were studied. The pregnancy-related diagnosis group included those women with abnormal urinalysis/raised creatinine identified during pregnancy or within 1 year postpartum. Pregnancy-related and control biopsies were matched for age and ethnicity (black versus nonblack). RESULTS: One hundred and seventy-three pregnancy-related biopsies (19 antenatal, 154 postpregnancy) were identified and matched with 1000 controls. FSGS was more common in pregnancy-related biopsies (32.4%) than controls (9.7%) (P<0.001) but there were no differences in Columbia classification. Women with a pregnancy-related diagnosis were younger (32.1 versus 34.2 years; P=0.004) and more likely to be black (26.0% versus 13.3%; P<0.001) than controls, although there were no differences in ethnicities in women with FSGS. The pregnancy-related group (excluding antenatal biopsies) was more likely to have a decline in Chronic Kidney Disease Epidemiology Collaboration eGFR in the follow-up period than the control group (odds ratio, 1.67; 95% confidence interval, 1.03 to 2.71; P=0.04), and this decline appeared to be more rapid (-1.33 versus -0.56 ml/min per 1.73 m2 per year, respectively; P=0.045). However, there were no differences between groups in those who required RRT or who died. CONCLUSIONS: Pregnancy is an opportunity to detect kidney disease. FSGS is more common in women who have been pregnant than in controls, and disease identified in pregnancy or within 1 year postpartum is more likely to show a subsequent decline in renal function. Further work is required to determine whether pregnancy initiates, exacerbates, or reveals renal disease. PMID- 27940460 TI - Minimal Change Disease. AB - Minimal change disease (MCD) is a major cause of idiopathic nephrotic syndrome (NS), characterized by intense proteinuria leading to edema and intravascular volume depletion. In adults, it accounts for approximately 15% of patients with idiopathic NS, reaching a much higher percentage at younger ages, up to 70%-90% in children >1 year of age. In the pediatric setting, a renal biopsy is usually not performed if presentation is typical and the patient responds to therapy with oral prednisone at conventional doses. Therefore, in this setting steroid sensitive NS can be considered synonymous with MCD. The pathologic hallmark of disease is absence of visible alterations by light microscopy and effacement of foot processes by electron microscopy. Although the cause is unknown and it is likely that different subgroups of disease recognize a different pathogenesis, immunologic dysregulation and modifications of the podocyte are thought to synergize in altering the integrity of the glomerular basement membrane and therefore determining proteinuria. The mainstay of therapy is prednisone, but steroid-sensitive forms frequently relapse and this leads to a percentage of patients requiring second-line steroid-sparing immunosuppression. The outcome is variable, but forms of MCD that respond to steroids usually do not lead to chronic renal damage, whereas forms that are unresponsive to steroids may subsequently reveal themselves as FSGS. However, in a substantial number of patients the disease is recurrent and requires long-term immunosuppression, with significant morbidity because of side effects. Recent therapeutic advances, such as the use of anti-CD20 antibodies, have provided long-term remission off-therapy and suggest new hypotheses for disease pathogenesis. PMID- 27940461 TI - Comparative analysis of MazEF and HicAB toxin-antitoxin systems of the cyanobacterium, Anabaena sp. PCC7120. AB - Anabaena PCC7120 has two annotated toxin-antitoxin systems: MazEF and HicAB. Overexpression of either of the toxins severely inhibited the growth of Escherichia coli BL21(plysS)(DE3). Of the two Anabaena toxins, MazF exhibited higher toxicity than HicA as evidenced by (i) 100-fold lower viability upon overexpression of MazF compared to HicA; (ii) complete loss of cell viability within 1 h of induction of MazF expression, as against >103 colony forming units mL-1 in case of HicA; (iii) inability to maintain the MazF overexpressing plasmid in E. coli cells; and (iv) neutralisation of the toxin was effective at the molar ratio of 1:1.9 for MazF:MazE and 13:1 for HicA:HicB, indicating higher antitoxin requirement for neutralisation of MazF. The growth inhibitory effect of MazF was found to be higher in lag phase cultures compared to mid-logarithmic phase cultures of E. coli, while the reverse was true for HicA. The results suggest possible distinct roles for MazEF and HicAB systems of Anabaena. PMID- 27940462 TI - Molecular variability and genetic relationship among Brazilian strains of the sugarcane smut fungus. AB - Sporisorium scitamineum is the fungus that causes sugarcane smut disease. Despite of the importance of sugarcane for Brazilian agribusiness and the persistence of the pathogen in most cropping areas, genetic variation studies are still missing for Brazilian isolates. In this study, sets of isolates were analyzed using two molecular markers (AFLP and telRFLP) and ITS sequencing. Twenty-two whips were collected from symptomatic plants in cultivated sugarcane fields of Brazil. A total of 41 haploid strains of compatible mating types were selected from individual teliospores and used for molecular genetic analyses. telRFLP and ITS analyses were expanded to six Argentine isolates, where the sugarcane smut was first recorded in America. Genetic relationship among strains suggests the human mediated dispersal of S. scitamineum within the Brazilian territory and between the two neighboring countries. Two genetically distinct groups were defined by the combined analysis of AFLP and telRFLP. The opposite mating-type strains derived from single teliospores were clustered together into these main groups, but had not always identical haplotypes. telRFLP markers analyzed over two generations of selfing and controlled outcrossing confirmed the potential for emergence of new variants and occurrence of recombination, which are relevant events for evolution of virulence and environmental adaptation. PMID- 27940463 TI - Characterization of the Cag pathogenicity island in Helicobacter pylori from naturally infected rhesus macaques. AB - Helicobacter pylori commonly infects the epithelial layer of the human stomach and in some individuals causes peptic ulcers, gastric adenocarcinoma or gastric lymphoma. Helicobacter pylori is a genetically diverse species, and the most important bacterial virulence factor that increases the risk of developing disease, versus asymptomatic colonization, is the cytotoxin associated gene pathogenicity island (cagPAI). Socially housed rhesus macaques are often naturally infected with H. pylori similar to that which colonizes humans, but little is known about the cagPAI. Here we show that H. pylori strains isolated from naturally infected rhesus macaques have a cagPAI very similar to that found in human clinical isolates, and like human isolates, it encodes a functional type IV secretion system. These results provide further support for the relevance of rhesus macaques as a valid experimental model for H. pylori infection in humans. PMID- 27940465 TI - GacA regulates the PTSNtr-dependent control of cyst formation in Azotobacter vinelandii. AB - Azotobacter vinelandii forms cysts resistant to desiccation and produces polyhydroxybutyrate (PHB), alginate and alkylresorcinols (ARs) that are components of mature cysts. The expression of genes involved in the synthesis of these compounds is under the control of the GacA-RsmA global regulatory system where the RsmA protein represses the translation of mRNAs involved in the synthesis of these polymers. The synthesis of PHB and ARs is also controlled by the Nitrogen-regulated phosphotransferase system (PTSNtr) global regulatory system. When unphosphorylated, the Enzyme IIANtr (EIIANtr) protein impairs the synthesis of PHB and ARs. Here we show that cells of gacA mutants, as well as mutants that carry the EIIANtr protein in its unphosphorylated state, have similar encysting negative phenotypes. Interestingly, we found that in the gacA mutant strain, the EIIANtr protein was present in its unphosphorylated state. These data indicated that in addition to the GacA-RsmA system, GacA controls polymer synthesis and encystment by controlling the phosphorylation of the EIIANtr, revealing a previously unrecognized link between GacA and PTSNtr. PMID- 27940464 TI - Determination of fungal community diversity in fresh and traditional Chinese fermented pepper by pyrosequencing. AB - Fermented pepper is one of the traditional Chinese fermented vegetables. The production mainly relies on the fermentation by natural microorganisms. This fermentation system is a unique and dynamic microecological environment, and involved microbial communities are very complex. In this study, 454 pyrosequencing was first used to investigate the fungal communities in fresh pepper and different fermentation phases. The results showed that fungal communities in fresh pepper (sample M_0) were more abundant than later fermented phases. Taxa in proportions >0.01% could be assigned to 21 different genera. Taxa in proportions >1% were Trichosporon 24.11%, Rhodotorula 7.4%, Cladosporium 4.26%, Debarvomvces 3.94%, Mucor 2.51% and Cryptococcus 1.86%. There were a large number of unknown fungi (47.99%) in the sample waiting to be identified. Along with the fermentation, microbial communities became less diverse. Hanseniaspora and Pichia became the dominant fungal genera, while Trichosporon decreased from a maximum 24.11% to a minimum 0.1%. On the seventh fermentation day, the percentage of Hanseniaspora reached 89.3%. On the 20th fermentation day, taxa in proportions >1% were Hanseniaspora 69.25%, Unclassified 12.23%, Pichia 8.95%, Debaryomyces 6.22% and Rhodotorula 1.31%. PMID- 27940467 TI - Effects of environmental variation during seed production on seed dormancy and germination. AB - The environment during seed production has major impacts on the behaviour of progeny seeds. It can be shown that for annual plants temperature perception over the whole life history of the mother can affect the germination rate of progeny, and instances have been documented where these affects cross whole generations. Here we discuss the current state of knowledge of signal transduction pathways controlling environmental responses during seed production, focusing both on events that take place in the mother plant and those that occur directly as a result of environmental responses in the developing zygote. We show that seed production environment effects are complex, involving overlapping gene networks active independently in fruit, seed coat, and zygotic tissues that can be deconstructed using careful physiology alongside molecular and genetic experiments. PMID- 27940469 TI - Regulatory gateways for cell-specific gene expression in C4 leaves with Kranz anatomy. AB - C4 photosynthesis is a carbon-concentrating mechanism that increases delivery of carbon dioxide to RuBisCO and as a consequence reduces photorespiration. The C4 pathway is therefore beneficial in environments that promote high photorespiration. This pathway has evolved many times, and involves restricting gene expression to either mesophyll or bundle sheath cells. Here we review the regulatory mechanisms that control cell-preferential expression of genes in the C4 cycle. From this analysis, it is clear that the C4 pathway has a complex regulatory framework, with control operating at epigenetic, transcriptional, post transcriptional, translational, and post-translational levels. Some genes of the C4 pathway are regulated at multiple levels, and we propose that this ensures robust expression in each cell type. Accumulating evidence suggests that multiple genes of the C4 pathway may share the same regulatory mechanism. The control systems for C4 photosynthesis gene expression appear to operate in C3 plants, and so it appears that pre-existing mechanisms form the basis of C4 photosynthesis gene expression. PMID- 27940471 TI - Genomic Variation of Inbreeding and Ancestry in the Remaining Two Isle Royale Wolves. AB - Inbreeding, relatedness, and ancestry have traditionally been estimated with pedigree information, however, molecular genomic data can provide more detailed examination of these properties. For example, pedigree information provides estimation of the expected value of these measures but molecular genomic data can estimate the realized values of these measures in individuals. Here, we generate the theoretical distribution of inbreeding, relatedness, and ancestry for the individuals in the pedigree of the Isle Royale wolves, the first examination of such variation in a wild population with a known pedigree. We use the 38 autosomes of the dog genome and their estimated map lengths in our genomic analysis. Although it is known that the remaining wolves are highly inbred, closely related, and descend from only 3 ancestors, our analyses suggest that there is significant variation in the realized inbreeding and relatedness around pedigree expectations. For example, the expected inbreeding in a hypothetical offspring from the 2 remaining wolves is 0.438 but the realized 95% genomic confidence interval is from 0.311 to 0.565. For individual chromosomes, a substantial proportion of the whole chromosomes are completely identical by descent. This examination provides a background to use when analyzing molecular genomic data for individual levels of inbreeding, relatedness, and ancestry. The level of variation in these measures is a function of the time to the common ancestor(s), the number of chromosomes, and the rate of recombination. In the Isle Royale wolf population, the few generations to a common ancestor results in the high variance in genomic inbreeding. PMID- 27940470 TI - Jasmonates: biosynthesis, metabolism, and signaling by proteins activating and repressing transcription. AB - The lipid-derived phytohormone jasmonate (JA) regulates plant growth, development, secondary metabolism, defense against insect attack and pathogen infection, and tolerance to abiotic stresses such as wounding, UV light, salt, and drought. JA was first identified in 1962, and since the 1980s many studies have analyzed the physiological functions, biosynthesis, distribution, metabolism, perception, signaling, and crosstalk of JA, greatly expanding our knowledge of the hormone's action. In response to fluctuating environmental cues and transient endogenous signals, the occurrence of multilayered organization of biosynthesis and inactivation of JA, and activation and repression of the COI1 JAZ-based perception and signaling contributes to the fine-tuning of JA responses. This review describes the JA biosynthetic enzymes in terms of gene families, enzymatic activity, location and regulation, substrate specificity and products, the metabolic pathways in converting JA to activate or inactivate compounds, JA signaling in perception, and the co-existence of signaling activators and repressors. PMID- 27940472 TI - Population Differences at MHC Do Not Explain Enhanced Resistance of Song Sparrows to Local Parasites. AB - Infectious disease represents an emerging threat to natural populations, particularly when hosts are more susceptible to novel parasites (allopatric) than to parasites from the local area (sympatric). This pattern could arise through evolutionary processes (host populations become adapted to their local parasites and genetically differentiated from other populations at immune-related loci) and/or through ecological interactions (host individuals develop resistance to local parasites through previous exposure). The relative importance of these candidate mechanisms remains unclear. In jawed vertebrates, genes of the major histocompatibility complex (MHC) play a fundamental role in immunity and are compelling candidates for spatially varying selection. We recently showed that song sparrows (Melospiza melodia) are more susceptible to allopatric than to sympatric strains of malaria (Plasmodium). In the current study, to determine whether population differences at MHC explain this pattern, we characterized the peptide-binding regions of MHC (classes I and II) of birds that did or did not become infected in the previous experiment. We recovered up to 4 alleles per individual at class I, implying at least 2 loci, and up to 26 alleles per individual at class II, implying at least 13 loci. Individuals with more class I alleles were less likely to become infected by Plasmodium, consistent with parasite-mediated balancing selection. However, we found no evidence for population genetic differentiation at either class of MHC, based on 36 individuals sequenced. Resistance to sympatric parasites previously described for this system likely stems from individuals' prior immune experience, not from population differentiation and locally protective alleles at MHC. PMID- 27940473 TI - Chromosomal Mapping of Transposable Elements of the Rex Family in the Bristlenose Catfish, Ancistrus (Siluriformes, Loricariidae), from the Amazonian Region. AB - Repetitive DNA sequences are present in the genome of basically every known organism, and transposable elements (TE) are one of the most representative sequences involved in chromosomal rearrangements and the genomic evolution of eukaryotes. In fish, the non-LTR retrotransposon TEs, Rex1, Rex3, and Rex6, are widely distributed in fish genomes and are the best-characterized TEs in several species. In the current study, three of these retroelements were physically mapped, through fluorescent in situ hybridization (FISH), in 7 species (71 specimens) of the genus Ancistrus, known as bristlenose catfish: Ancistrus ranunculus, Ancistrus sp. 1 "Purus," Ancistrus sp. 2 "Catalao," Ancistrus dolichopterus, Ancistrus maximus, Ancistrus aff. dolichopterus, and Ancistrus dubius. Rex1, Rex3, and Rex6 showed a cluster distribution, mainly in the terminal and pericentromeric portions, in heterochromatic and euchromatic regions, and did not occur in sexual chromosomes; however, the number and position of the clusters varied between species. This TE distribution suggests its implication in the karyotypic evolution of these species, without affecting the rise of sexual chromosome systems in Ancistrus, in view of their chromosomal variation. PMID- 27940474 TI - Phylogeography of the Small Indian Civet and Origin of Introductions to Western Indian Ocean Islands. AB - The biogeographic dynamics affecting the Indian subcontinent, East and Southeast Asia during the Plio-Pleistocene has generated complex biodiversity patterns. We assessed the molecular biogeography of the small Indian civet (Viverricula indica) through mitogenome and cytochrome b + control region sequencing of 89 historical and modern samples to (1) establish a time-calibrated phylogeography across the species' native range and (2) test introduction scenarios to western Indian Ocean islands. Bayesian phylogenetic analyses identified 3 geographic lineages (East Asia, sister-group to Southeast Asia and the Indian subcontinent + northern Indochina) diverging 3.2-2.3 million years ago (Mya), with no clear signature of past demographic expansion. Within Southeast Asia, Balinese populations separated from the rest 2.6-1.3 Mya. Western Indian Ocean populations were assigned to the Indian subcontinent + northern Indochina lineage and had the lowest mitochondrial diversity. Approximate Bayesian computation did not distinguish between single versus multiple introduction scenarios. The early diversification of the small Indian civet was likely shaped by humid periods in the Late Pliocene-Early Pleistocene that created evergreen rainforest barriers, generating areas of intra-specific endemism in the Indian subcontinent, East, and Southeast Asia. Later, Pleistocene dispersals through drier conditions in South and Southeast Asia were likely, giving rise to the species' current natural distribution. Our molecular data supported the delineation of only 4 subspecies in V. indica, including an endemic Balinese lineage. Our study also highlighted the influence of prefirst millennium AD introductions to western Indian Ocean islands, with Indian and/or Arab traders probably introducing the species for its civet oil. PMID- 27940476 TI - Trametinib after disease reactivation under dabrafenib in Erdheim-Chester disease with both BRAF and KRAS mutations. AB - Major advances have been made in understanding the pathogenesis of Erdheim Chester disease (ECD) leading to novel treatment strategies. Targeted therapies such as BRAF inhibition have shown a significant impact on disease management, emphasizing the importance of the activated mitogen-associated protein kinase pathway in this disease. However, incomplete responsiveness, potentially limiting adverse effects, and the occurrence of treatment resistance to BRAF inhibition observed in other BRAF-mutant malignancies imply the importance of therapeutic strategies beyond BRAF inhibition. We report a patient with ECD who carried the BRAFV600E mutation and developed treatment resistance under BRAF inhibition despite initial treatment response. Genetic analyses of a newly developing ECD lesion revealed a somatic KRASQ61H mutation without the presence of BRAFV600E Accordingly, the addition of MEK-inhibiting trametinib to BRAF-inhibiting dabrafenib was able to overcome acquired partial treatment resistance. This is the first report of treatment resistance as a result of a secondary MAPK pathway activating mutation during BRAF inhibition in ECD. This case contributes to the ongoing efforts of simultaneous BRAF/MEK inhibition as a promising strategy in ECD. PMID- 27940475 TI - The intestinal microbiota in allogeneic hematopoietic cell transplant and graft versus-host disease. AB - Hematopoietic cell transplantation (HCT) is a critical treatment of patients with high-risk hematopoietic malignancies, hematological deficiencies, and other immune diseases. In allogeneic HCT (allo-HCT), donor-derived T cells recognize host tissues as foreign, causing graft-versus-host disease (GVHD) which is a main contributor to morbidity and mortality. The intestine is one of the organs most severely affected by GVHD and research has recently highlighted the importance of bacteria, particularly the gut microbiota, in HCT outcome and in GVHD development. Loss of intestinal bacterial diversity is common during the course of HCT and is associated with GVHD development and treatment with broad-spectrum antibiotics. Loss of intestinal diversity and outgrowth of opportunistic pathogens belonging to the phylum Proteobacteria and Enterococcus genus have also been linked to increased treatment-related mortality including GVHD, infections, and organ failure after allo-HCT. Experimental studies in allo-HCT animal models have shown some promising results for prebiotic and probiotic strategies as prophylaxis or treatment of GVHD. Continuous research will be important to define the relation of cause and effect for these associations between microbiota features and HCT outcomes. Importantly, studies focused on geographic and cultural differences in intestinal microbiota are necessary to define applicability of new strategies targeting the intestinal microbiota. PMID- 27940477 TI - Distinct regulatory networks control the development of macrophages of different origins in zebrafish. AB - Macrophages are key components of the innate immune system and play pivotal roles in immune response, organ development, and tissue homeostasis. Studies in mice and zebrafish have shown that tissue-resident macrophages derived from different hematopoietic origins manifest distinct developmental kinetics and colonization potential, yet the genetic programs controlling the development of macrophages of different origins remain incompletely defined. In this study, we use zebrafish, where tissue-resident macrophages arise from the rostral blood island (RBI) and ventral wall of dorsal aorta (VDA), the zebrafish hematopoietic tissue equivalents to the mouse yolk sac and aorta-gonad-mesonephros for myelopoiesis, to address this issue. We show that RBI- and VDA-born macrophages are orchestrated by distinctive regulatory networks formed by the E-twenty-six (Ets) transcription factors Pu.1 and Spi-b, the zebrafish ortholog of mouse spleen focus forming virus proviral integration oncogene B (SPI-B), and the helix-turn helix DNA-binding domain containing protein Irf8. Epistatic studies document that during RBI macrophage development, Pu.1 acts upstream of Spi-b, which, upon induction by Pu.1, partially compensates the function of Pu.1. In contrast, Pu.1 and Spi-b act in parallel and cooperatively to regulate the development of VDA derived macrophages. Interestingly, these two distinct regulatory networks orchestrate the RBI- and VDA-born macrophage development largely by regulating a common downstream gene, Irf8. Our study indicates that macrophages derived from different origins are governed by distinct genetic networks formed by the same repertoire of myeloid-specific transcription factors. PMID- 27940479 TI - Prevalence and correlates of self-reported chronic non-communicable diseases in Botswana: a cross-sectional study. AB - BACKGROUND: The purpose of this paper is to estimate the prevalence of self reported chronic non-communicable diseases and their correlates in Botswana. This is a nationally representative, cross-sectional survey. METHODS: This is a cross sectional study of respondents aged 10-64 years using data from the Botswana AIDS Impact Survey IV conducted in 2013. Three self-reported non-communicable diseases, namely, hypertension, diabetes and asthma were used. Multivariate logistic regression models were used to identify their correlates. RESULTS: Out of the 2153 participants, the prevalence rates of hypertension, diabetes and asthma were 14.2%, 3.3% and 5.3%, respectively. The study found that among other factors, older populations are at a much higher risk of having more than one non communicable disease. After controlling for other covariates, the ORs of self reported non-communicable disease was highest among older respondents aged 50 years and over (AOR=12.01, p<0.001) followed by richer respondents (AOR=1.86, p<=0.025). The ORs were also higher among females (AOR=1.83, p<0.001) and urban village residents (AOR=1.41, p=0.038). CONCLUSIONS: It is evident that chronic non-communicable diseases are likely to increase in the future due to the rise in the old age population resulting from fertility transition and improvement in life expectancy in Botswana. Therefore urgent and holistic intervention programmes are required to halt the problem. Failure to act now is likely to result in high morbidity and mortality. PMID- 27940478 TI - Splicing factor gene mutations in hematologic malignancies. AB - Alternative splicing generates a diversity of messenger RNA (mRNA) transcripts from a single mRNA precursor and contributes to the complexity of our proteome. Splicing is perturbed by a variety of mechanisms in cancer. Recurrent mutations in splicing factors have emerged as a hallmark of several hematologic malignancies. Splicing factor mutations tend to occur in the founding clone of myeloid cancers, and these mutations have recently been identified in blood cells from normal, healthy elderly individuals with clonal hematopoiesis who are at increased risk of subsequently developing a hematopoietic malignancy, suggesting that these mutations contribute to disease initiation. Splicing factor mutations change the pattern of splicing in primary patient and mouse hematopoietic cells and alter hematopoietic differentiation and maturation in animal models. Recent developments in this field are reviewed here, with an emphasis on the clinical consequences of splicing factor mutations, mechanistic insights from animal models, and implications for development of novel therapies targeting the precursor mRNA splicing pathway. PMID- 27940480 TI - Sex disparities in outcomes among adults on long-term antiretroviral treatment in northern Nigeria. AB - BACKGROUND: There are conflicting reports of sex differences in HIV treatment outcomes in Africa. We investigated sex disparities in treatment outcomes for adults on first line antiretroviral treatment (ART) in Nigeria. METHODS: We compared clinical and immunologic responses to ART between HIV-infected men (n=205) and women (n=140) enrolled in an ART program between June 2004 and December 2007, with follow-up through June 2014. We employed Kaplan-Meier estimates to examine differences in time to immunologic failure and loss to follow-up (LTFU), and generalized estimating equations to assess changes in CD4+ count by sex. RESULTS: Men had lower baseline mean CD4+ count compared to women (327.6 cells/uL vs 413.4, respectively, p<0.01). Women had significantly higher rates of increase in CD4+ count than men, even after adjusting for confounders, p<0.0001. There was no significant difference in LTFU by sex: LTFU rate was 2.47/1000 person-months (95% CI 1.6-3.9) in the first five years for men vs 1.98/1000 person-months (95% CI (1.3-3.0) for women. There was no difference in time to LTFU by sex over the study period. CONCLUSIONS: Women achieved better long-term immune response to ART at baseline and during treatment, but had similar rates of long-term retention in care to men. Targeted efforts are needed to improve immune outcomes in men in our setting. PMID- 27940481 TI - Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters. AB - The farnesoid X receptor (FXR) plays critical roles in plasma cholesterol metabolism, in particular HDL-cholesterol (HDL-C) homeostasis. Obeticholic acid (OCA) is a FXR agonist being developed for treating various chronic liver diseases. Previous studies reported inconsistent effects of OCA on regulating plasma cholesterol levels in different animal models and in different patient populations. The mechanisms underlying its divergent effects have not yet been thoroughly investigated. The scavenger receptor class B type I (SR-BI) is a FXR modulated gene and the major receptor for HDL-C. We investigated the effects of OCA on hepatic SR-BI expression and correlated such effects with plasma HDL-C levels and hepatic cholesterol efflux in hyperlipidemic hamsters. We demonstrated that OCA induced a time-dependent reduction in serum HDL-C levels after 14 days of treatment, which was accompanied by a significant reduction of liver cholesterol content and increases in fecal cholesterol in OCA-treated hamsters. Importantly, hepatic SR-BI mRNA and protein levels in hamsters were increased to 1.9- and 1.8-fold of control by OCA treatment. Further investigations in normolipidemic hamsters did not reveal OCA-induced changes in serum HDL-C levels or hepatic SR-BI expression. We conclude that OCA reduces plasma HDL-C levels and promotes transhepatic cholesterol efflux in hyperlipidemic hamsters via a mechanism involving upregulation of hepatic SR-BI. PMID- 27940484 TI - Cohort Profile: The Jiaxing Birth Cohort in China. PMID- 27940483 TI - Do gifts increase consent to home-based HIV testing? A difference-in-differences study in rural KwaZulu-Natal, South Africa. AB - Background: Despite the importance of HIV testing for controlling the HIV epidemic, testing rates remain low. Efforts to scale up testing coverage and frequency in hard-to-reach and at-risk populations commonly focus on home-based HIV testing. This study evaluates the effect of a gift (a US$5 food voucher for families) on consent rates for home-based HIV testing. Methods: We use data on 18 478 individuals (6 418 men and 12 060 women) who were successfully contacted to participate in the 2009 and 2010 population-based HIV surveillance carried out by the Wellcome Trust's Africa Health Research Institute in rural KwaZulu-Natal, South Africa. Of 18 478 potential participants contacted in both years, 35% (6 518) consented to test in 2009, and 41% (7 533) consented to test in 2010. Our quasi-experimental difference-in-differences approach controls for unobserved confounding in estimating the causal effect of the intervention on HIV-testing consent rates. Results: Allocation of the gift to a family in 2010 increased the probability of family members consenting to test in the same year by 25 percentage points [95% confidence interval (CI) 21-30 percentage points; P < 0.001]. The intervention effect persisted, slightly attenuated, in the year following the intervention (2011). Conclusions: In HIV hyperendemic settings, a gift can be highly effective at increasing consent rates for home-based HIV testing. Given the importance of HIV testing for treatment uptake and individual health, as well as for HIV treatment-as-prevention strategies and for monitoring the population impact of the HIV response, gifts should be considered as a supportive intervention for HIV-testing initiatives where consent rates have been low. PMID- 27940485 TI - Epidemiology, the International Epidemiological Association and the International Journal of Epidemiology: a personal chronicle. PMID- 27940482 TI - Quantitative structural characterization of phosphatidylinositol phosphates from biological samples. AB - The aspects of cellular metabolism controlled by phosphatidylinositol phosphates (PtdInsPs) have been broadly expanded, and these phospholipids have drawn tremendous attention as pleiotropic signaling molecules. PtdInsPs analysis using LC/MS/MS has remained challenging due to the strong hydrophilicity of these lipids. Multiple reaction monitoring (MRM) or a neutral loss scan has been performed to quantitatively measure PtdInsPs after chemical derivatization on the phosphate groups of inositol moieties. Only predefined PtdInsPs can be measured in MRM mode, and fatty acyl compositions of sn-1 and sn-2 positions of PtdInsPs cannot be obtained from a neutral loss scan. In our present study, we developed a simple LC/MS/MS method for structural identification of sn-1 and sn-2 fatty acids of PtdInsPs and their relative quantitation. Precursor ion scans of sn-1 monoacylglycerols (MAGs) of PtdInsPs provided structural information about the lipids, and ammonium adduction enhanced signal intensities of PtdInsPs. The relative amount of observed PtdInsPs in biological samples could be compared using chromatographic peak areas from the neutral loss scans. Using precursor ion scans of sn-1 MAG and neutral loss scans of headgroups, major PtdInsPs in cells and tissues were successfully identified with structural information of sn-1 and sn-2 fatty acids, and their relative amounts in different samples were compared. PMID- 27940486 TI - Moist smokeless tobacco (Snus) use and risk of Parkinson's disease. AB - Background: Cigarette smoking is associated with a lower risk of Parkinson's disease. It is unclear what constituent of tobacco smoke may lower the risk. Use of Swedish moist smokeless tobacco (snus) can serve as a model to disentangle what constituent of tobacco smoke may lower the risk. The aim of this study was to determine whether snus use was associated with a lower risk of Parkinson's disease. Methods: Individual participant data were collected from seven prospective cohort studies, including 348 601 men. We used survival analysis with multivariable Cox regression to estimate study-specific relative risk of Parkinson's disease due to snus use, and random-effects models to pool estimates in a meta-analysis. The primary analyses were restricted to never-smokers to eliminate the potential confounding effect of tobacco smoking. Results: During a mean follow-up time of 16.1 years, 1199 incident Parkinson's disease cases were identified. Among men who never smoked, ever-snus users had about 60% lower Parkinson's disease risk compared with never-snus users [pooled hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.28-0.61]. The inverse association between snus use and Parkinson's disease risk was more pronounced in current (pooled HR 0.38, 95% CI 0.23-0.63), moderate-heavy amount (pooled HR 0.41, 95% CI 0.19-0.90) and long-term snus users (pooled HR 0.44, 95% CI 0.24-0.83). Conclusions: Non smoking men who used snus had a substantially lower risk of Parkinson's disease. Results also indicated an inverse dose-response relationship between snus use and Parkinson's disease risk. Our findings suggest that nicotine or other components of tobacco leaves may influence the development of Parkinson's disease. PMID- 27940488 TI - Survival of surgery for recurrent biliary tract cancer: a single-center experience and systematic review of literature. AB - Background: For recurrent biliary tract cancer, chemotherapy is the standard treatment. However, the efficacy of surgery is unknown. Here, the prognostic benefit of surgery for recurrent biliary tract cancer was investigated. Methods: Data of 206 patients who underwent surgery for biliary tract cancer between 2005 and 2015 were retrospectively analyzed. Of these, 107 recurrent patients were divided into two groups, surgery (n = 14) and non-surgery (n = 93) groups. In the latter group, 45 patients received chemotherapy and 48 received best supportive care. Results: Of the total 121 sites of recurrence, the liver was the most common (n = 41), followed by locoregional recurrence (n = 32) and lymph nodes (n = 18). Surgery was performed in the 14 patients with recurrence, comprising nine patients with intrahepatic cholangiocarcinoma, three with perihilar cholangiocarcinoma, one with distal cholangiocarcinoma and one with gallbladder carcinoma. Survival after recurrence was significantly better after surgery than after chemotherapy or best supportive care (38% vs. 5.3% vs. 0% at 3 years and 19% vs. 5.3% vs. 0% at 5 years; P < 0.0001). Multivariate analysis identified the residual status of the primary tumor (hazard ratio = 1.58, 95% confidence interval = 1.00-2.44; P = 0.047), time to recurrence >=1 year (hazard ratio = 0.62, 95% confidence interval = 0.39-0.97; P = 0.037) and surgery for recurrence (hazard ratio = 0.32, 95% confidence interval = 0.14-0.62; P < 0.001) as independent prognostic factors. Conclusions: Surgery for recurrent biliary tract cancer may prolong survival in patients with time to recurrence >=1 year. PMID- 27940489 TI - Predictive factors of late biochemical recurrence after radical prostatectomy. AB - Objective: To assess the characteristics of biochemical recurrence in the late period (>5 years after radical prostatectomy) and the differences in the predictors of biochemical recurrence in different periods, we conducted a multicenter retrospective study. Methods: We reviewed 478 men who underwent radical prostatectomy for clinically localized prostate cancer. All of the patients were followed up for at least 5 years. The cohort was then divided into three groups; no recurrence group, recurrence <5 years after surgery group and recurrence >=5 years after surgery group. The background characteristics of each group were compared using the chi2 test. A Cox multivariate regression analysis was performed to determine the predictors of biochemical recurrence in each period. Results: Biochemical recurrence occurred in 135 men. In 113 (84%) of the patients, biochemical recurrence occurred at <5 years after surgery; in 22 (16%), it occurred at >=5 years after surgery. The proportion of men with a low preoperative prostate-specific antigen level was significantly larger in the latter group (P = 0.0023). A preoperative prostate-specific antigen level and a positive surgical margin were significant predictors of biochemical recurrence at <5 years after surgery (hazard ratio: 1.03 and 3.20). A positive surgical margin was also a significant predictor of biochemical recurrence at >=5 years after surgery (hazard ratio: 3.03); however, a high preoperative prostate-specific antigen level was not. Conclusions: Biochemical recurrence occurred at >=5 years after surgery in 16% of the patients. A positive surgical margin predicted biochemical recurrence in both the early and late periods. PMID- 27940490 TI - Exploiting native forces to capture chromosome conformation in mammalian cell nuclei. AB - Mammalian interphase chromosomes fold into a multitude of loops to fit the confines of cell nuclei, and looping is tightly linked to regulated function. Chromosome conformation capture (3C) technology has significantly advanced our understanding of this structure-to-function relationship. However, all 3C-based methods rely on chemical cross-linking to stabilize spatial interactions. This step remains a "black box" as regards the biases it may introduce, and some discrepancies between microscopy and 3C studies have now been reported. To address these concerns, we developed "i3C", a novel approach for capturing spatial interactions without a need for cross-linking. We apply i3C to intact nuclei of living cells and exploit native forces that stabilize chromatin folding. Using different cell types and loci, computational modeling, and a methylation-based orthogonal validation method, "TALE-iD", we show that native interactions resemble cross-linked ones, but display improved signal-to-noise ratios and are more focal on regulatory elements and CTCF sites, while strictly abiding to topologically associating domain restrictions. PMID- 27940491 TI - Capturing native interactions: intrinsic methods to study chromatin conformation. PMID- 27940493 TI - STUDY ON A STEP-ADVANCED FILTER MONITOR FOR CONTINUOUS RADON PROGENY MEASUREMENT. AB - Traditional fixed-filter radon progeny monitors are usually clogged with the loading of dust and cannot be used for radon progeny continuous measurement for long period. To solve this problem, a step-advanced filter (SAF) monitor for radon progeny measurement was developed. This monitor automatically roll and stop the filter at each interview. Radon progeny is collected on a 'fresh' filter at a flowrate of 3 L/min. At the same time, alpha and beta particles emitted from filter are recorded by a PIPS detector. A newly developed alpha-beta spectrum method was used for radon progeny concentration calculation. The 218Po, 214Pb and 214Bi concentrations as well as equilibrium equivalent concentration (EEC) could be worked out at the same time. The lower level limit detection of this monitor is 0.48 Bq m-3 (EEC) for 1h interval. Comparison experiments were carried out in the radon chamber at the National Institute of Metrology of China. The measurement results of this SAF monitor are consistent with EQF3220 (SARAD GmbH, Germany), and the uncertainty is smaller. Due to its high sensitivity, the periodical variation of radon progeny concentration can be easily observed by this monitor. The SAF moniter is suitable for continuous measurement in both indoor and outdoor environments. PMID- 27940494 TI - Evaluation of Imaging Dose From Different Image Guided Systems During Head and Neck Radiotherapy: A Phantom Study. AB - This work evaluated and compared the absorbed doses to selected organs in the head and neck region from the three image guided radiotherapy systems: cone-beam computed tomography (CBCT) and kilovoltage (kV) planar imaging using the On-board Imager(r) (OBI) as well as the ExacTrac(r) X-ray system, all available on the Varian Novalis TX linear accelerator. The head and neck region of an anthropomorphic phantom was used to simulate patients' head within the imaging field. Nanodots optically stimulated luminescent dosemeters were positioned at selected sites to measure the absorbed doses. CBCT was found to be delivering the highest dose to internal organs while OBI-2D gave the highest doses to the eye lenses. The setting of half-rotation in CBCT effectively reduces the dose to the eye lenses. Daily high-quality CBCT verification was found to increase the secondary cancer risk by 0.79%. PMID- 27940496 TI - Treatment of Acute Necrotizing Eosinophilic Myocarditis With Immunosuppression and Mechanical Circulatory Support. PMID- 27940495 TI - Extracorporeal Membrane Oxygenation in New York State: Trends, Outcomes, and Implications for Patient Selection. AB - BACKGROUND: Utilization of extracorporeal membrane oxygenation (ECMO) is expanding despite limited outcome data defining appropriate use. METHODS AND RESULTS: To quantify determinants of early and 1-year survival after ECMO in adult patients, we conducted a retrospective cohort analysis of 1286 patients aged >=18 years who underwent ECMO in New York State from 2003 to 2014. Median follow-up time was 4.9 months (range, 0-12 months). ECMO utilization increased from 13 patients in 8 hospitals in 2003 to 330 patients in 30 hospitals in 2014. Compared with patients undergoing ECMO before 2009, later patients were older (54.4 versus 52.3 years; P=0.013) and more likely to have major comorbidity including chronic kidney disease (25.2% versus 13.2%; P=0.02) and liver disease (20.0% versus 10.7%; P=0.001). In the overall cohort, 30-day mortality was 52.2% (95% confidence interval, 49.5-54.9). Mortality at 30 days was 65.2% for patients aged >=75 years (n=73/112) and 74.6% in patients who required cardiopulmonary resuscitation (n=91/122). Survival at 1 year was 38.4% (95% confidence interval, 35.7-41.0). The 30-day mortality and 1-year survival improved across the study period. In multivariable analysis, earlier year of ECMO, lower hospital volume, indication for ECMO after a cardiac procedure, cardiopulmonary resuscitation before ECMO placement, and age >65 years were independent predictors of worse survival. CONCLUSIONS: Outcomes of ECMO have improved despite increasing comorbidity. Extreme mortality after ECMO in elderly patients and patients requiring cardiopulmonary resuscitation indicates that less invasive therapeutic or palliative modalities may be more appropriate in this end-of-life setting. PMID- 27940492 TI - Silencing CHALCONE SYNTHASE in Maize Impedes the Incorporation of Tricin into Lignin and Increases Lignin Content. AB - Lignin is a phenolic heteropolymer that is deposited in secondary-thickened cell walls, where it provides mechanical strength. A recent structural characterization of cell walls from monocot species showed that the flavone tricin is part of the native lignin polymer, where it is hypothesized to initiate lignin chains. In this study, we investigated the consequences of altered tricin levels on lignin structure and cell wall recalcitrance by phenolic profiling, nuclear magnetic resonance, and saccharification assays of the naturally silenced maize (Zea mays) C2-Idf (inhibitor diffuse) mutant, defective in the CHALCONE SYNTHASE Colorless2 (C2) gene. We show that the C2-Idf mutant produces highly reduced levels of apigenin- and tricin-related flavonoids, resulting in a strongly reduced incorporation of tricin into the lignin polymer. Moreover, the lignin was enriched in beta-beta and beta-5 units, lending support to the contention that tricin acts to initiate lignin chains and that, in the absence of tricin, more monolignol dimerization reactions occur. In addition, the C2-Idf mutation resulted in strikingly higher Klason lignin levels in the leaves. As a consequence, the leaves of C2-Idf mutants had significantly reduced saccharification efficiencies compared with those of control plants. These findings are instructive for lignin engineering strategies to improve biomass processing and biochemical production. PMID- 27940497 TI - Implementation of Ultraviolet Radiation Safety Measures for Outdoor Workers. AB - Ultraviolet radiation (UVR) poses a major risk for outdoor workers, putting them at greater risk for skin cancer. In the general population, the incidence of both melanoma and nonmelanoma skin cancers is increasing. It is estimated that 90% of skin cancers in Canada are directly attributable to UVR exposure, making this cancer largely preventable with the appropriate precautions. A scoping review was conducted on the barriers and facilitators to UVR safety in outdoor workers to elucidate why these precautions are not in use currently. We discuss these results according to the Hierarchy of Controls as a means to outline effective and feasible prevention strategies for outdoor workers. In doing so, this review may be used to inform the design of future workplace interventions for UVR safety in outdoor workers to decrease the risk of skin cancer in this vulnerable population. PMID- 27940498 TI - Archelosaurian Color Vision, Parietal Eye Loss, and the Crocodylian Nocturnal Bottleneck. AB - Vertebrate color vision has evolved partly through the modification of five ancestral visual opsin proteins via gene duplication, loss, and shifts in spectral sensitivity. While many vertebrates, particularly mammals, birds, and fishes, have had their visual opsin repertoires studied in great detail, testudines (turtles) and crocodylians have largely been neglected. Here I examine the genomic basis for color vision in four species of turtles and four species of crocodylians, and demonstrate that while turtles appear to vary in their number of visual opsins, crocodylians experienced a reduction in their color discrimination capacity after their divergence from Aves. Based on the opsin sequences present in their genomes and previous measurements of crocodylian cones, I provide evidence that crocodylians have co-opted the rod opsin (RH1) for cone function. This suggests that some crocodylians might have reinvented trichromatic color vision in a novel way, analogous to several primate lineages. The loss of visual opsins in crocodylians paralleled the loss of various anatomical features associated with photoreception, attributed to a "nocturnal bottleneck" similar to that hypothesized for Mesozoic mammals. I further queried crocodylian genomes for nonvisual opsins and genes associated with protection from ultraviolet light, and found evidence for gene inactivation or loss for several of these genes. Two genes, encoding parietopsin and parapinopsin, were additionally inactivated in birds and turtles, likely co-occurring with the loss of the parietal eye in these lineages. PMID- 27940499 TI - The effects of adolescent methylphenidate exposure on the behavioral and brain derived neurotrophic factor response to nicotine. AB - This study analyzed the interaction of adolescent methylphenidate on the behavioral response to nicotine and the effects of these drug treatments on brain derived neurotrophic factor in the nucleus accumbens and hippocampus in male and female Sprague-Dawley rats. Animals were intraperitoneal administered 1 mg/kg methylphenidate or saline using a "school day" regimen (five days on, two days off) beginning on postnatal day (P)28 and throughout behavioral testing. In Experiment 1, animals were intraperitoneal administered 0.5 mg/kg (free base) nicotine or saline every second day for 10 days from P45-P63 and tested after a three-day drug washout on the forced swim stress task on P67-P68. Results revealed that adolescent methylphenidate blunted nicotine behavioral sensitization. However, methylphenidate-treated rats given saline during sensitization demonstrated decreased latency to immobility and increased immobility time on the forced swim stress task in males that was reduced by nicotine. In Experiment 2, a different set of animals were conditioned to nicotine (0.6 mg/kg free base) or saline using the conditioned place preference behavioral paradigm from P44-P51, and given a preference test on P52. On P53, the nucleus accumbens and hippocampus were analyzed for brain-derived neurotrophic factor. Methylphenidate enhanced nicotine-conditioned place preference in females and nicotine produced conditioned place preference in males and females pre exposed to saline in adolescence. In addition, methylphenidate and nicotine increased nucleus accumbens brain-derived neurotrophic factor in females and methylphenidate enhanced hippocampus brain-derived neurotrophic factor in males and females. Methylphenidate adolescent exposure using a clinically relevant dose and regimen results in changes in the behavioral and brain-derived neurotrophic factor responses to nicotine in adolescence that are sex-dependent. PMID- 27940501 TI - Predicting Sexual Harassment From Hostile Sexism and Short-Term Mating Orientation: Relative Strength of Predictors Depends on Situational Priming of Power Versus Sex. AB - Previous research has shown that short-term mating orientation (STMO) and hostile sexism (HS) selectively predict different types of sexual harassment. In a priming experiment, we studied the situational malleability of those effects. Male participants could repeatedly send sexist jokes (gender harassment), harassing remarks (unwanted sexual attention), or nonharassing messages to a (computer-simulated) female target. Before entering the laboratory, participants were unobtrusively primed with the concepts of either sexuality or power. As hypothesized, sexuality priming strengthened the link between STMO and unwanted sexual attention, whereas power priming strengthened the link between HS and gender harassment. Practical implications are discussed. PMID- 27940500 TI - Binge ethanol drinking during adolescence modifies cocaine responses in mice. AB - Binge ethanol drinking is an emerging pattern of excessive consumption among adolescents and young adults. Repeated ethanol intoxication has negative consequences during critical periods of brain development. Therefore, binge ethanol intake represents a vulnerability factor that promotes subsequent manifestations of neuropsychiatric disorders. In this study, we investigated the effects of oral binge ethanol intake during adolescence on the subsequent effects of cocaine in C57BL/6 mice. Firstly, we evaluated the oral ethanol intake of two binge ethanol procedures with different ethanol concentrations (20% v/v versus 30%, v/v). The highest ethanol intake was found in mice exposed to the lower ethanol concentration (20% v/v). In a second experiment, mice exposed to binge ethanol procedure were evaluated to study the effects of cocaine on locomotor activity, behavioural sensitization, and the reinforcing effects of cocaine in the self-administration paradigm. Mice exposed to ethanol binging showed discrete detrimental effects in responses to cocaine in the different experiments evaluated. Our findings revealed that the pattern of binge ethanol consumption in adolescent mice here evaluated produced a weak facilitation of cocaine responses. The present study highlights the importance of interventions to limit the deleterious effects of binge ethanol drinking during adolescence. PMID- 27940502 TI - Ulrich Erich Otto Schirrmacher. PMID- 27940505 TI - A Previously Healthy Adolescent With Acute Encephalopathy and Decorticate Posturing. AB - A 14-year-old previously healthy female was transferred from a local emergency department after being found unresponsive at home. Parental questioning revealed she had fever and pharyngitis 2 weeks before presentation. Past mental health history was negative, including concern for past or present suicidal ideation/attempts, suspected substance use, or toxic ingestion. In the emergency department, she was orotracheally intubated due to a Glasgow Coma Scale of 3. She was hemodynamically stable and euglycemic. Electrocardiogram showed sinus tachycardia. She underwent a noncontrast head computed tomography that was normal and subsequently underwent a lumbar puncture. She had a seizure and was given a loading dose of diazepam and fosphenytoin that led to cessation of extremity movements. She was subsequently transferred to the PICU for additional evaluation. Initial examination without sedation or analgesia demonstrated dilated and minimally responsive pupils, intermittent decorticate posturing, and bilateral lower extremity rigidity and clonus, consistent with a Glasgow Coma Scale of 5. Serum studies were unremarkable with the exception of mild leukocytosis. Chest radiograph only showed atelectasis. She was empirically started on antibiotics to cover for meningitis pending final cerebral spinal fluid test results. The pediatric neurology team was consulted for EEG monitoring, and the patient was eventually sent for computed tomography angiogram and magnetic resonance angiogram/venogram. We will review diagnostic evaluation and management of an adolescent patient with acute encephalopathy with decorticate posturing of unclear etiology. PMID- 27940504 TI - A Population Intervention to Improve Outcomes in Children With Medical Complexity. AB - BACKGROUND AND OBJECTIVES: Children with medical complexity experience frequent interactions with the medical system and often receive care that is costly, duplicative, and inefficient. The growth of value-based contracting creates incentives for systems to improve their care. This project was designed to improve the health, health care value, and utilization for a population-based cohort of children with neurologic impairment and feeding tubes. METHODS: A freestanding children's hospital and affiliated accountable care organization jointly developed a quality improvement initiative. Children with a percutaneous feeding tube, a neurologic diagnosis, and Medicaid, were targeted for intervention within a catchment area of >300 000 children receiving Medicaid. Initiatives included standardizing feeding tube management, improving family education, and implementing a care coordination program. RESULTS: Between January 2011 and December 2014, there was an 18.0% decrease (P < .001) in admissions and a 31.9% decrease (P < .001) in the average length of stay for children in the cohort. Total inpatient charges were reduced by $11 764 856. There was an 8.2% increase (P < .001) in the percentage of children with weights between the fifth and 95th percentiles. The care coordination program enrolled 58.3% of the cohort. CONCLUSIONS: This population-based initiative to improve the care of children with medical complexity showed promising results, including a reduction in charges while improving weight status and implementing a care coordination program. A concerted institutional initiative, in the context of an accountable care organization, can be part of the solution for improving outcomes and health care value for children with medical complexity. PMID- 27940506 TI - Improving Pediatric Asthma Outcomes in a Community Emergency Department. AB - BACKGROUND: Asthma triggers >775 000 emergency department (ED) visits for children each year. Approximately 80% of these visits occur in community EDs. We performed this study to measure effects of partnership with a community ED on pediatric asthma care. METHODS: For this quality improvement initiative, we implemented an evidence-based pediatric asthma guideline in a community ED. We included patients whose clinical impression in the medical decision section of the electronic health record contained the words asthma, bronchospasm, or wheezing. We reviewed charts of included patients 12 months before guideline implementation (August 2012-July 2013) and 19 months after guideline implementation (August 2013-February 2015). Process measures included the proportion of children who had an asthma score recorded, the proportion who received steroids, and time to steroid administration. The outcome measure was the proportion of children who needed transfer for additional care. RESULTS: In total, 724 patients were included, 289 during the baseline period and 435 after guideline implementation. Overall, 64% of patients were assigned an asthma score after guideline implementation. During the baseline period, 60% of patients received steroids during their ED visit, compared with 76% after guideline implementation (odds ratio 2.2; 95% confidence interval, 1.6-3.0). After guideline implementation, the mean time to steroids decreased significantly, from 196 to 105 minutes (P < .001). Significantly fewer patients needed transfer after guideline implementation (10% compared with 14% during the baseline period) (odds ratio 0.63; 95% confidence interval, 0.40-0.99). CONCLUSIONS: Our study shows that partnership between a pediatric tertiary care center and a community ED is feasible and can improve pediatric asthma care. PMID- 27940503 TI - Inhibition of nonsense-mediated RNA decay by ER stress. AB - Nonsense-mediated RNA decay (NMD) selectively degrades mutated and aberrantly processed transcripts that contain premature termination codons (PTC). Cellular NMD activity is typically assessed using exogenous PTC-containing reporters. We overcame some inherently problematic aspects of assaying endogenous targets and developed a broadly applicable strategy to reliably and easily monitor changes in cellular NMD activity. Our new method was genetically validated for distinguishing NMD regulation from transcriptional control and alternative splicing regulation, and unexpectedly disclosed a different sensitivity of NMD targets to NMD inhibition. Applying this robust method for screening, we identified NMD-inhibiting stressors but also found that NMD inactivation was not universal to cellular stresses. The high sensitivity and broad dynamic range of our method revealed a strong correlation between NMD inhibition, endoplasmic reticulum (ER) stress, and polysome disassembly upon thapsigargin treatment in a temporal and dose-dependent manner. We found little evidence of calcium signaling mediating thapsigargin-induced NMD inhibition. Instead, we discovered that of the three unfolded protein response (UPR) pathways activated by thapsigargin, mainly protein kinase RNA-like endoplasmic reticulum kinase (PERK) was required for NMD inhibition. Finally, we showed that ER stress compounded TDP-43 depletion in the up-regulation of NMD isoforms that had been implicated in the pathogenic mechanisms of amyotrophic lateral sclerosis and frontotemporal dementia, and that the additive effect of ER stress was completely blocked by PERK deficiency. PMID- 27940507 TI - Titanium Dioxide in Toothpaste Causing Yellow Nail Syndrome. AB - Yellow nail syndrome (YNS) is an uncommon disorder, the classic triad of which consists of yellow nails, lymphedema, and respiratory symptoms. Few pediatric cases have been reported. We report a 9-year-old girl with yellowish nail discoloration for 1 year accompanied by respiratory symptoms, including chronic cough, recurrent pneumonia, bronchiectasis, and chronic sinusitis. The patient was diagnosed with YNS. Knowing that a relationship between YNS and titanium has been reported, we collected her nail clippings and detected titanium in them by energy dispersive radiograph fluorescence. This patient's titanium exposure may have come from her habit of swallowing children's toothpaste. With meticulous avoidance of swallowing toothpaste, she had amelioration of her yellow nail discoloration as well as diminution of her respiratory symptoms. We reevaluated her nail clippings for titanium 3 years later, and no titanium was detected. This observation suggests that avoiding titanium exposure could alleviate the symptoms of YNS. This is the first report of YNS in a pediatric patient that demonstrates a relationship between YNS and titanium. We review the previous reports of pediatric patients with YNS. PMID- 27940508 TI - Persistent Pulmonary Hypertension of the Newborn in Late Preterm and Term Infants in California. AB - BACKGROUND AND OBJECTIVES: There are limited epidemiologic data on persistent pulmonary hypertension of the newborn (PPHN). We sought to describe the incidence and 1-year mortality of PPHN by its underlying cause, and to identify risk factors for PPHN in a contemporary population-based dataset. METHODS: The California Office of Statewide Health Planning and Development maintains a database linking maternal and infant hospital discharges, readmissions, and birth and death certificates from 1 year before to 1 year after birth. We searched the database (2007-2011) for cases of PPHN (identified by International Classification of Diseases, Ninth Revision codes), including infants >=34 weeks' gestational age without congenital heart disease. Multivariate Poisson regression was used to identify risk factors associated with PPHN; results are presented as risk ratios, 95% confidence intervals. RESULTS: Incidence of PPHN was 0.18% (3277 cases/1 781 156 live births). Infection was the most common cause (30.0%). One year mortality was 7.6%; infants with congenital anomalies of the respiratory tract had the highest mortality (32.0%). Risk factors independently associated with PPHN included gestational age <37 weeks, black race, large and small for gestational age, maternal preexisting and gestational diabetes, obesity, and advanced age. Female sex, Hispanic ethnicity, and multiple gestation were protective against PPHN. CONCLUSIONS: This risk factor profile will aid clinicians identifying infants at increased risk for PPHN, as they are at greater risk for rapid clinical deterioration. PMID- 27940509 TI - Families' Priorities Regarding Hospital-to-Home Transitions for Children With Medical Complexity. AB - BACKGROUND: National health care policy recommends that patients and families be actively involved in discharge planning. Although children with medical complexity (CMC) account for more than half of pediatric readmissions, scalable, family-centered methods to effectively engage families of CMC in discharge planning are lacking. We aimed to systematically examine the scope of preferences, priorities, and goals of parents of CMC regarding planning for hospital-to-home transitions and to ascertain health care providers' perceptions of families' transitional care goals and needs. METHODS: We conducted semistructured interviews with parents and health care providers at a tertiary care hospital. Interviews were continued until thematic saturation was reached. Interviews were audio recorded, transcribed verbatim, and analyzed to identify emergent themes via a general inductive approach. RESULTS: Thirty-nine in-depth interviews were conducted, including 23 with family caregivers of CMC and 16 with health care providers. Families' priorities, preferences, and goals for hospital to-home transitions aligned with 7 domains: effective engagement with health care providers, respect for families' discharge readiness, care coordination, timely and efficient discharge processes, pain and symptom control, self-efficacy to support recovery and ongoing child development, and normalization and routine. These domains also emerged in interviews with health care providers, although there were minor differences in themes discussed. CONCLUSIONS: Although CMC have diverse transitional care needs, their families' priorities, preferences, and goals aligned with 7 domains that bridged their hospital admission with reestablishment of a home routine. This research provides essential foundational data to engage families in discharge planning, guiding the operationalization of national health policy recommendations. PMID- 27940511 TI - The Outcomes of Very Preterm Infants: Is It Time to Ask Different Questions? PMID- 27940510 TI - Oxygen Saturation Targets in Preterm Infants and Outcomes at 18-24 Months: A Systematic Review. AB - CONTEXT: The optimal oxygen saturation target for extremely preterm infants remains unclear. OBJECTIVE: To systematically review evidence evaluating the effect of lower (85%-89%) versus higher (91%-95%) pulse oxygen saturation (Spo2) target on mortality and neurodevelopmental impairment (NDI) at 18 to 24 months. DATA SOURCES: Electronic databases and all published randomized trials evaluating lower versus higher Spo2 target in preterm infants. STUDY SELECTION: A total of 2896 relevant citations were identified; 5 trials were included in the final analysis. DATA EXTRACTION: Data from 5 trials were analyzed for quality of evidence and risk of bias. LIMITATIONS: Limitations include heterogeneity in age at enrollment and comorbidities between trials and change in oximeter algorithm midway through 3 trials. RESULTS: There was no difference in the incidence of primary outcome (death/NDI at 18-24 months) in the 2 groups; risk ratio,1.05, 95% confidence interval 0.98-1.12, P = .18. Mortality before 18 to 24 months was higher in the lower-target group (risk ratio,1.16, 95% confidence interval 1.03 1.31, P = .02). Rates of NDI and severe visual loss did not differ between the 2 groups. Proportion of time infants spent outside the target range while on supplemental oxygen ranged from 8.2% to 27.4% <85% and 8.1% to 22.4% >95% with significant overlap between the 2 groups. CONCLUSIONS: There was no difference in primary outcome between the 2 Spo2 target groups. The collective data suggest that risks associated with restricting the upper Spo2 target limit to 89% outweigh the benefits. The quality of evidence was moderate. We speculate that a wider target range (lower alarm limit, 89% and upper, 96%) may increase time spent within range, but the safety profile of this approach remains to be determined. PMID- 27940513 TI - The Tobacco 21 Movement and Electronic Nicotine Delivery System Use Among Youth. PMID- 27940512 TI - Announcements Versus Conversations to Improve HPV Vaccination Coverage: A Randomized Trial. AB - OBJECTIVE: Improving provider recommendations is critical to addressing low human papillomavirus (HPV) vaccination coverage. Thus, we sought to determine the effectiveness of training providers to improve their recommendations using either presumptive "announcements" or participatory "conversations." METHODS: In 2015, we conducted a parallel-group randomized clinical trial with 30 pediatric and family medicine clinics in central North Carolina. We randomized clinics to receive no training (control), announcement training, or conversation training. Announcements are brief statements that assume parents are ready to vaccinate, whereas conversations engage parents in open-ended discussions. A physician led the 1-hour, in-clinic training. The North Carolina Immunization Registry provided data on the primary trial outcome: 6-month coverage change in HPV vaccine initiation (>=1 dose) for adolescents aged 11 or 12 years. RESULTS: The immunization registry attributed 17 173 adolescents aged 11 or 12 to the 29 clinics still open at 6-months posttraining. Six-month increases in HPV vaccination coverage were larger for patients in clinics that received announcement training versus those in control clinics (5.4% difference, 95% confidence interval: 1.1%-9.7%). Stratified analyses showed increases for both girls (4.6% difference) and boys (6.2% difference). Patients in clinics receiving conversation training did not differ from those in control clinics with respect to changes in HPV vaccination coverage. Neither training was effective for changing coverage for other vaccination outcomes or for adolescents aged 13 through 17 (n = 37 796). CONCLUSIONS: Training providers to use announcements resulted in a clinically meaningful increase in HPV vaccine initiation among young adolescents. PMID- 27940514 TI - Should School Boards Discontinue Support for High School Football? AB - A pediatrician is asked by her local school board to help them decide whether to discontinue their high school football program. She reviews the available evidence on the risks of football and finds it hopelessly contradictory. Some scholars claim that football is clearly more dangerous than other sports. Others suggest that the risks of football are comparable to other sports, such as lacrosse, ice hockey, or soccer. She finds very little data on the long-term sequelae of concussions. She sees claims that good coaching and a school culture that prioritizes the health of athletes over winning can reduce morbidity from sports injuries. In this paper, 3 experts also review the evidence about sports risks and discuss what is known and not known about the science and the ethics of high school football. PMID- 27940515 TI - Closing the Gap: Improving Access to Mental Health Care Through Enhanced Training in Residency. PMID- 27940516 TI - Molecular Genetics of Neurodegenerative Dementias. AB - Neurodegenerative dementias are clinically heterogeneous, progressive diseases with frequently overlapping symptoms, such as cognitive impairments and behavior and movement deficits. Although a majority of cases appear to be sporadic, there is a large genetic component that has yet to be fully explained. Here, we review the recent genetic and genomic findings pertaining to Alzheimer's disease, frontotemporal dementia, Lewy body dementia, and prion dementia. In this review, we describe causal and susceptibility genes identified for these dementias and discuss recent research pertaining to the molecular function of these genes. Of particular interest, there is a large overlap in clinical phenotypes, genes, and/or aggregating protein products involved in these diseases, as well as frequent comorbid presentation, indicating that these dementias may represent a continuum of syndromes rather than individual diseases. PMID- 27940517 TI - Tau Positron Emission Tomography Imaging. AB - Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia among the elderly population. The good correlation between the density and neocortical spread of neurofibrillary tangles (NFTs) and the severity of cognitive impairment offers an opportunity to use a noninvasive imaging technique such as positron emission tomography (PET) for early diagnosis and staging of the disease. PET imaging of NFTs holds promise not only as a diagnostic tool but also because it may enable the development of disease modifying therapeutics for AD. In this review, we focus on the structural diversity of tau PET tracers, the challenges related to identifying high-affinity and highly selective NFT ligands, and recent progress in the clinical development of tau PET radioligands. PMID- 27940518 TI - Radial Spokes-A Snapshot of the Motility Regulation, Assembly, and Evolution of Cilia and Flagella. AB - Propulsive forces generated by cilia and flagella are used in events that are critical for the thriving of diverse eukaryotic organisms in their environments. Despite distinctive strokes and regulations, the majority of them adopt the 9+2 axoneme that is believed to exist in the last eukaryotic common ancestor. Only a few outliers have opted for a simpler format that forsakes the signature radial spokes and the central pair apparatus, although both are unnecessary for force generation or rhythmicity. Extensive evidence has shown that they operate as an integral system for motility control. Recent studies have made remarkable progress on the radial spoke. This review will trace how the new structural, compositional, and evolutional insights pose significant implications on flagella biology and, conversely, ciliopathy. PMID- 27940519 TI - Austerity Resistant Social Policies to Protect Employment. AB - During the worse phase of the economic downturn, few social policies resisted to the austerity measures imposed to Italy by the European Union. Among them, the most important is the Wage Supplementation Fund, to protect workers and entrepreneurs from bankruptcy and unemployment. Adopting a realist methodology we studied the social mechanisms which are the roots of some political and administrative choices in that period; the public policy decision making approach gave us a theoretical base. Some main mechanisms have been discovered: technical and economic mechanisms overcame politics, social attitudes pushed political choices, the fear of political and social instability drove all parties. PMID- 27940520 TI - Exploring the Benefit/Risk Associated with Antiangiogenic Agents for the Treatment of Non-Small Cell Lung Cancer Patients. AB - Following the approval of bevacizumab, an antibody targeting VEGF-A, for advanced non-squamous non-small cell lung cancer (NSCLC) in 2006, intensive efforts were put into the clinical development of antiangiogenic agents for NSCLC. Currently, the other antiangiogenic agents approved for NSCLC are ramucirumab, a VEGF receptor-2 (VEGFR-2)-targeting antibody indicated for both squamous and non squamous NSCLC in the United States, and nintedanib, an anti-VEGFR-1/2/3, platelet-derived growth factor receptor-alpha/beta, fibroblast growth factor receptor-1/2/3 angiokinase inhibitor indicated for adenocarcinoma of the lung in the European Union. Many other antiangiogenic agents are being evaluated in phase III trials for NSCLC, including aflibercept, sunitinib, sorafenib, cediranib, and vandetanib. Although many of the same signaling pathways are targeted by these novel agents, mixed efficacy results have been observed in these trials. Moreover, safety issues have raised concerns about using antiangiogenic agents in this patient population, and fatal bleeding events have been reported. Importantly, although no biomarker has yet been validated for antiangiogenic agents in NSCLC, biomarkers that show potential include circulating levels of short VEGF-A isoforms, expression of neuropilin-1 and VEGFR-1 in tumors and plasma, genetic variants in VEGF-A and VEGFR, and tumor protein p53 mutations (with the latter having been shown to correlate with increased levels of VEGF-A transcripts). This review provides an overview of the clinical benefit and risk associated with the use of antiangiogenic agents for NSCLC, and summarizes the research to date on the identification of predictive biomarkers for antiangiogenic therapies. Clin Cancer Res; 23(5); 1137-48. (c)2016 AACR. PMID- 27940521 TI - Incidence, risk factors and associated mortality of central line-associated bloodstream infections at an intensive care unit in northern India. AB - Objective: To evaluate the incidence, risk factors and associated mortality of central line-associated bloodstream infection (CLABSI) in an adult intensive care unit (ICU) in India. Design: This prospective observational study was conducted over a period of 16 months at a tertiary care referral medical center. Setting: We conducted this study over a period of 16 months at a tertiary care referral medical center. Participants: All patients with a central venous catheter (CVC) for >48 h admitted to the ICU were enrolled. Intervention and main outcome measures: Patient characteristics included were underlying disease, sequential organ failure assessment (SOFA), acute physiology and chronic health evaluation (APACHE II) scores and outcome. Statistical analysis of risk factors for their association with mortality was also done. Results: There were 3235 inpatient-days and 2698 catheter-days. About 46 cases of CLABSI were diagnosed during the study period. The overall rate of CLABSI was 17.04 per 1000 catheter-days and 14.21 per 1000 inpatient-days. The median duration of hospitalization was 23.5 days while the median number of days that a CVC was in place was 17.5. The median APACHE II and SOFA scores were 17 and 10, respectively. Klebsiella pneumoniae was the most common organism (n = 22/55, 40%). Immunosuppressed state and duration of central line more than 10 days were significant factors for developing CLABSI. SOFA and APACHE II scores showed a tendency towards significance for mortality. Conclusions: Our results underscore the need for strict institutional infection control measures. Regular training module for doctors and nurses for catheter insertion and maintenance with a checklist on nurses' chart for site inspection and alerts in all shifts are some measures planned at our center. PMID- 27940523 TI - The impact of child restraint legislation on the incidence of severe paediatric injury in Chile. AB - BACKGROUND: The objective of this study is to determine the association between Chile's 2005 child restraint legislation (CRL) and the incidence of severe paediatric motor vehicle-related injury. METHODS: We analysed motor vehicle injury data from Chile's Road Safety Commission from 2000 to 2012 to determine the association between Chile's 2005 CRL and severe paediatric injury. Using Poisson time-series models we assessed the effect of the law on two outcome variables: (1) severely injured children per vehicle fleet; and (2) severely injured children per population. RESULTS: Chile's 2005 CRL is significantly associated with a 24% reduction in severely injured children per vehicle, and 19% reduction in severely injured children per population in the 1st year of its enactment. In 2007 this law is also significantly associated with a 17% decrease in severely injured children per vehicle, and with an 11% decrease in severely injured children per population. However, this legislation had a short-term effect since no reductions in severely injured children per vehicle were observed after 2009 and no reductions for severely injured children per population were registered after 2008. CONCLUSIONS: This is the first study to examine the association between CRL and severe paediatric injury in a Latin-American country. This study suggests that Chile's CRL was only effective in the short term. To support this type of reforms in the long term, other measures such as police enforcement, public information campaigns and involvement of public health professionals in educating parents about the benefits of using child restraints should be considered. PMID- 27940525 TI - Liminality and the Limits of Law in Health Research Regulation: What are we Missing in the Spaces in-Between? AB - This article fundamentally challenges the way in which law currently regulates human health research. It invokes the anthropological concept of liminality-the quality of in-between-ness-to suggest deeper ways of understanding ongoing challenges in delivering acceptable and effective regulation of research involving human participants. In stark contrast to the structural regulatory spaces constructed by law, the metaphor of the liminal space is explored to explain what is lost through our failure to see health research regulation as an inherently human experiential process, involving potentially profound transformative events for participants and researchers alike. The implications for the future of health research regulation are then examined. In particular, the analysis calls into question key features of the current regulatory paradigm, and demands that we reconsider our own demands of law in this context. The argument is made that health research is a liminal process and that we fail to treat it as such. This requires a rethink of corollary regulation also in processual terms. Ultimately, the charge is to undertake a radical reimagining of regulatory space to accommodate and promote liminal regulatory spaces. PMID- 27940533 TI - An Introduction to Coherent Multidimensional Spectroscopy. AB - Coherent multidimensional spectroscopy is a field that has drawn much attention as an optical analogue to multidimensional nuclear magnetic resonance imaging. Coherent multidimensional spectroscopic techniques produce spectra that show the magnitude of an optical signal as a function of two or more pulsed laser frequencies. Spectra can be collected in either the frequency or the time domain. In addition to improving resolution and overcoming spectral congestion, coherent multidimensional spectroscopy provides the ability to investigate and conduct studies based upon the relationship between different peaks. The purpose of this paper is to provide a general introduction to the area of coherent multidimensional spectroscopy, to provide a brief overview of current experimental approaches, and to discuss some emerging developments in this relatively young field. PMID- 27940522 TI - Quality management: where is the evidence? Developing an indicator-based approach in Kenya. AB - Introduction: The 2030 Sustainable Development Agenda emphasizes the importance of quality of care in the drive to achieve universal health coverage. Despite recent progress, challenges in service delivery, efficiency and resource utilization in the health sector remain. Objective: The Ministry of Health Department of Standards and Regulations sought to operationalize the Kenya Quality Assurance Model for Health. To this end, the European Practice Assessment (EPA) was adapted to the area of Reproductive and Maternal and Neonatal Health. Methods: The adaptation process made use of a ten step-modified RAND Corporation/University of California Los Angeles (UCLA) Appropriateness Method. The steps included a scoping workshop, definition of five critical domains of quality in the Kenyan context ('People, Management, Clinical Care, Quality & Safety, Interface between inpatients and outpatients care'), a review of policy documents, management and clinical guidelines, grey and scientific literature to identify indicators in use in the Kenyan health system and an expert panel process to rate their feasibility and validity. Results: The resulting 278 indicators, clustered across the five domains, were broken-down into 29 dimensions and assigned measure specifications. A set of data collection tools were developed to furnish the indicators and piloted at two health facilities. They were subsequently finalized for use in 30 health facilities in 3 counties. Conclusions: The integrative and indicator-based aspects of the EPA process could be readily adapted to facilitate the operationalization of a practical quality assurance approach in Kenya. PMID- 27940534 TI - The Academic Tree of Howard V. Malmstadt: From Early Scientific Exploration to Modern Analytical Chemistry. AB - Over the last several decades, science has benefited tremendously by the implementation of digital electronic components for analytical instrumentation. A pioneer in this area of scientific inquiry was Howard Malmstadt. Frequently, such revolutions in scientific history can be viewed as a series of discoveries without a great deal of attention as to how mentorship shapes the careers and methodologies of those who made great strides forward for science. This paper focuses on the verifiable relationships of those who are connected through the academic tree of Malmstadt and how their experiences and the context of world events influenced their scientific pursuits. Particular attention is dedicated to the development of American chemistry departments and the critical role played by many of the individuals in the tree in this process. PMID- 27940535 TI - Investigation of the Matrix Effect on the Accuracy of Quantitative Analysis of Trace Metals in Liquids Using Laser-Induced Breakdown Spectroscopy with Solid Substrates. AB - The detection limit of trace metals in liquids has been improved greatly by laser induced breakdown spectroscopy (LIBS) using solid substrate. A paper substrate and a metallic substrate were used as a solid substrate for the detection of trace metals in aqueous solutions and viscous liquids (lubricating oils) respectively. The matrix effect on quantitative analysis of trace metals in two types of liquids was investigated. For trace metals in aqueous solutions using paper substrate, the calibration curves established for pure solutions and mixed solutions samples presented large variation on both the slope and the intercept for the Cu, Cd, and Cr. The matrix effects among the different elements in mixed solutions were observed. However, good agreement was obtained between the measured and known values in real wastewater. For trace metals in lubricating oils, the matrix effect between the different oils is relatively small and reasonably negligible under the conditions of our experiment. A universal calibration curve can be established for trace metals in different types of oils. The two approaches are verified that it is possible to develop a feasible and sensitive method with accuracy results for rapid detection of trace metals in industrial wastewater and viscous liquids by laser-induced breakdown spectroscopy. PMID- 27940536 TI - Residential area and physical activity: A multi-level study of 68,000 adults in Stockholm County. AB - AIM: To determine whether there are systematic differences in physical activity between residential areas after extensive control for sociodemographic factors at the individual level. METHODS: Multi-level regressions of walking/bicycling, sedentary activities, household work and exercise were carried out in a representative sample of 68,303 adults in 39 residential areas in Stockholm County, first adjusting at the individual level for country of birth, sex, age, education, occupational class and income. The type of housing was then considered at the individual level or, for walking/bicycling and exercise, at both the individual and area levels (as a measure of area density). RESULTS: After adjustment for sociodemographic factors, differences between residential areas remained in walking/bicycling, corresponding to 0.27 SD, or 50 min/week between the most and least active areas. Forty per cent of this difference could be explained by the type of housing at the area level. For sedentary activities and household work, respectively, much of the variation that remained after adjustment for sociodemographic factors was, in turn, explained by the type of housing at the individual level, leaving a difference of 0.16 SD (80 min/week) and 0.13 SD (60 min/week), respectively. For exercise, the corresponding difference was 0.11 SD (11 min/week, not sensitive to housing). CONCLUSIONS: Area level factors may influence walking/bicycling. High area density was associated with more activity. However, high density also comes with a type of housing (apartments) that is associated with less household work and, surprisingly, more sedentary activities, introducing a challenging trade-off. The differences in exercise were smaller than for all other types of activities. PMID- 27940537 TI - Psychometric analysis of the Salutogenic Health Indicator Scale (SHIS) in adolescents. AB - AIM: The aim of this study was to test the psychometric properties of the Salutogenic Health Indicator Scale (SHIS) in an adolescent population. METHODS: The investigation was performed among Swedish students aged 13-15 years ( n = 817; 58% girls). The SHIS was assessed for respondent acceptability, and its psychometric properties were evaluated according to classical test theory (regarding unidimensionality, targeting, reliability, and external construct validity). RESULTS: The adolescents found it easy to complete the questionnaire, which was completed in an average of 4 minutes. Exploratory factor analysis, which is based on polychoric correlations, identified one factor, supporting the instrument's unidimensionality. Floor/ceiling effects were ? 3.3%. Reliability estimates yielded a Cronbach's alpha value of 0.93; the test-retest reliability ( n = 50; 2-week interval) coefficients were 0.89 for the total SHIS score and 0.52 0.79 for item scores. Spearman correlations with other variables were based on a priori expectations (self-rated general health, 0.595; depressive symptoms, 0.773; anxiety, -0.577; and sleep problems, 0.519). CONCLUSIONS: Our observations support both the acceptability and the psychometric properties of the SHIS as a brief, unidimensional assessment tool for salutogenic health in adolescents. Further studies using modern test theory are needed to better understand the measurement properties of the SHIS, including the functioning of its response categories and its comparability between adolescents and adults. PMID- 27940539 TI - Contribution of Pentose Catabolism to Molecular Hydrogen Formation by Targeted Disruption of Arabinose Isomerase (araA) in the Hyperthermophilic Bacterium Thermotoga maritima. AB - : Thermotoga maritima ferments a broad range of sugars to form acetate, carbon dioxide, traces of lactate, and near theoretic yields of molecular hydrogen (H2). In this organism, the catabolism of pentose sugars such as arabinose depends on the interaction of the pentose phosphate pathway with the Embden-Myerhoff and Entner-Doudoroff pathways. Although the values for H2 yield have been determined using pentose-supplemented complex medium and predicted by metabolic pathway reconstruction, the actual effect of pathway elimination on hydrogen production has not been reported due to the lack of a genetic method for the creation of targeted mutations. Here, a spontaneous and genetically stable pyrE deletion mutant was isolated and used as a recipient to refine transformation methods for its repair by homologous recombination. To verify the occurrence of recombination and to assess the frequency of crossover events flanking the deleted region, a synthetic pyrE allele, encoding synonymous nucleotide substitutions, was used. Targeted inactivation of araA (encoding arabinose isomerase) in the pyrE mutant was accomplished using a divergent, codon-optimized Thermosipho africanus pyrE allele fused to the T. maritima groES promoter as a genetic marker. Mutants lacking araA were unable to catabolize arabinose in a defined medium. The araA mutation was then repaired using targeted recombination. Levels of synthesis of H2 using arabinose-supplemented complex medium by wild-type and araA mutant cell lines were compared. The difference between strains provided a direct measurement of H2 production that was dependent on arabinose consumption. Development of a targeted recombination system for genetic manipulation of T. maritima provides a new strategy to explore H2 formation and life at an extremely high temperature in the bacterial domain. IMPORTANCE: We describe here the development of a genetic system for manipulation of Thermotoga maritima T. maritima is a hyperthermophilic anaerobic bacterium that is well known for its efficient synthesis of molecular hydrogen (H2) from the fermentation of sugars. Despite considerable efforts to advance compatible genetic methods, chromosome manipulation has remained elusive and hindered use of T. maritima or its close relatives as model hyperthermophiles. Lack of a genetic method also prevented efforts to manipulate specific metabolic pathways to measure their contributions to H2 yield. To overcome this barrier, a homologous chromosomal recombination method was developed and used to characterize the contribution of arabinose catabolism to H2 formation. We report here a stable genetic method for a hyperthermophilic bacterium that will advance studies on the basic and synthetic biology of Thermotogales. PMID- 27940538 TI - Distribution and Differential Survival of Traditional and Alternative Indicators of Fecal Pollution at Freshwater Beaches. AB - : Alternative indicators have been developed that can be used to identify host sources of fecal pollution, yet little is known about how their distribution and fate compare to traditional indicators. Escherichia coli and enterococci were widely distributed at the six beaches studied and were detected in almost 95% of water samples (n = 422) and 100% of sand samples (n = 400). Berm sand contained the largest amount of E. coli (P < 0.01), whereas levels of enterococci were highest in the backshore (P < 0.01). E. coli and enterococci were the lowest in water, using a weight-to-volume comparison. The gull-associated Catellicoccus marimammalium (Gull2) marker was found in over 80% of water samples, regardless of E. coli levels, and in 25% of sand samples. Human-associated Bacteroides (HB) and Lachnospiraceae (Lachno2) were detected in only 2.4% of water samples collected under baseflow and post-rain conditions but produced a robust signal after a combined sewage overflow, despite low E. coli concentrations. Burdens of E. coli and enterococci in water and sand were disproportionately high in relation to alternative indicators when comparing environmental samples to source material. In microcosm studies, Gull2, HB, and Lachno2 quantitative PCR (qPCR) signals were reduced twice as quickly as those from E. coli and enterococci and approximately 20% faster than signals from culturable E. coli High concentrations of alternative indicators in source material illustrated their high sensitivity for the identification of fecal sources; however, differential survival and the potential for long-term persistence of traditional fecal indicators complicate the use of alternative indicator data to account for the levels of E. coli and enterococci in environmental samples. IMPORTANCE: E. coli and enterococci are general indicators of fecal pollution and may persist in beach sand, making their use problematic for many applications. This study demonstrates that gull fecal pollution is widespread at Great Lakes beaches, whereas human and ruminant contamination is evident only after major rain events. An exploration of sand as a reservoir for indicators found that E. coli was ubiquitous, while gull host markers were detected in only 25% of samples. In situ sand beach microcosms provided decay rate constants for E. coli and enterococci relative to alternative indicators, which establish comparative benchmarks that would be helpful to distinguish recent from past pollution. Overall, alternative indicators are useful for identifying sources and assessing potentially high health risk contamination events; however, beach managers should be cautious in attempting to directly link their detection to the levels of E. coli or enterococci. PMID- 27940541 TI - Insecticidal Specificity of Cry1Ah to Helicoverpa armigera Is Determined by Binding of APN1 via Domain II Loops 2 and 3. AB - Bacillus thuringiensis Cry1Ah protein is highly toxic against Helicoverpa armigera but shows no toxicity against Bombyx mori larvae. In contrast, the closely related Cry1Ai toxin showed the opposite phenotype: high activity against B. mori but no toxicity against H. armigera. Analysis of binding of Cry1Ah to brush border membrane vesicle (BBMV) proteins from H. armigera and B. mori by surface plasmon resonance revealed association of toxin binding with insect specificity. Pulldown experiments identified aminopeptidase N1 (APN1) as a Cry1Ah binding protein that was not observed in the assays using B. mori BBMV proteins. The APN1 Cry1Ah binding region was narrowed to the region from A548 to S798 (fragment H3) by expressing four different APN1 fragments in Escherichia coli and analyzing Cry1Ah binding by ligand blot. Binding competition experiments of Cry1Ah to APN1 fragment H3 using synthetic peptides corresponding to four predicted domain II loop regions showed that loop 2 and loop 3 have additive effects on binding to APN1 fragment H3. Moreover, switching of loop 2 and loop 3 regions from Cry1Ah to Cry1Ai toxins showed that loop 2 and loop 3 are both involved in specificity and toxicity against H. armigera IMPORTANCE: Domain II loop regions have been shown to be involved in binding to larval gut proteins mediating insect specificity. The modification of loop regions is a direct and effective method to construct new Cry toxin variants to increase toxicity or modify specificity. Our results show that the exchange of loop regions from one toxin into another is a successful scheme for modification of B. thuringiensis Cry toxin specificity. PMID- 27940540 TI - Relationships and Evolution of Double-Stranded RNA Totiviruses of Yeasts Inferred from Analysis of L-A-2 and L-BC Variants in Wine Yeast Strain Populations. AB - : Saccharomyces cerevisiae killer strains secrete a protein toxin active on nonkiller strains of the same (or other) yeast species. Different killer toxins, K1, K2, K28, and Klus, have been described. Each toxin is encoded by a medium size (1.5- to 2.3-kb) M double-stranded RNA (dsRNA) located in the cytoplasm. M dsRNAs require L-A helper virus for maintenance. L-A belongs to the Totiviridae family, and its dsRNA genome of 4.6 kb codes for the major capsid protein Gag and a minor Gag-Pol protein, which form the virions that separately encapsidate L-A or the M satellites. Different L-A variants exist in nature; on average, 24% of their nucleotides are different. Previously, we reported that L-A-lus was specifically associated with Mlus, suggesting coevolution, and proposed a role of the toxin-encoding M dsRNAs in the appearance of new L-A variants. Here we confirm this by analyzing the helper virus in K2 killer wine strains, which we named L-A-2. L-A-2 is required for M2 maintenance, and neither L-A nor L-A-lus shows helper activity for M2 in the same genetic background. This requirement is overcome when coat proteins are provided in large amounts by a vector or in ski mutants. The genome of another totivirus, L-BC, frequently accompanying L-A in the same cells shows a lower degree of variation than does L-A (about 10% of nucleotides are different). Although L-BC has no helper activity for M dsRNAs, distinct L-BC variants are associated with a particular killer strain. The so called L-BC-lus (in Klus strains) and L-BC-2 (in K2 strains) are analyzed. IMPORTANCE: Killer strains of S. cerevisiae secrete protein toxins that kill nonkiller yeasts. The "killer phenomenon" depends on two dsRNA viruses: L-A and M. M encodes the toxin, and L-A, the helper virus, provides the capsids for both viruses. Different killer toxins exist: K1, K2, K28, and Klus, encoded on different M viruses. Our data indicate that each M dsRNA depends on a specific helper virus; these helper viruses have nucleotide sequences that may be as much as 26% different, suggesting coevolution. In wine environments, K2 and Klus strains frequently coexist. We have previously characterized the association of Mlus and L-A-lus. Here we sequence and characterize L-A-2, the helper virus of M2, establishing the helper virus requirements of M2, which had not been completely elucidated. We also report the existence of two specific L-BC totiviruses in Klus and K2 strains with about 10% of their nucleotides different, suggesting different evolutionary histories from those of L-A viruses. PMID- 27940542 TI - Arsenic Detoxification by Geobacter Species. AB - : Insight into the mechanisms for arsenic detoxification by Geobacter species is expected to improve the understanding of global cycling of arsenic in iron-rich subsurface sedimentary environments. Analysis of 14 different Geobacter genomes showed that all of these species have genes coding for an arsenic detoxification system (ars operon), and several have genes required for arsenic respiration (arr operon) and methylation (arsM). Genes encoding four arsenic repressor-like proteins were detected in the genome of G. sulfurreducens; however, only one (ArsR1) regulated transcription of the ars operon. Elimination of arsR1 from the G. sulfurreducens chromosome resulted in enhanced transcription of genes coding for the arsenic efflux pump (Acr3) and arsenate reductase (ArsC). When the gene coding for Acr3 was deleted, cells were not able to grow in the presence of either the oxidized or reduced form of arsenic, while arsC deletion mutants could grow in the presence of arsenite but not arsenate. These studies shed light on how Geobacter influences arsenic mobility in anoxic sediments and may help us develop methods to remediate arsenic contamination in the subsurface. IMPORTANCE: This study examines arsenic transformation mechanisms utilized by Geobacter, a genus of iron-reducing bacteria that are predominant in many anoxic iron-rich subsurface environments. Geobacter species play a major role in microbially mediated arsenic release from metal hydroxides in the subsurface. This release raises arsenic concentrations in drinking water to levels that are high enough to cause major health problems. Therefore, information obtained from studies of Geobacter should shed light on arsenic cycling in iron-rich subsurface sedimentary environments, which may help reduce arsenic-associated illnesses. These studies should also help in the development of biosensors that can be used to detect arsenic contaminants in anoxic subsurface environments. We examined 14 different Geobacter genomes and found that all of these species possess genes coding for an arsenic detoxification system (ars operon), and some also have genes required for arsenic respiration (arr operon) and arsenic methylation (arsM). PMID- 27940543 TI - BspK, a Serine Protease from the Predatory Bacterium Bdellovibrio bacteriovorus with Utility for Analysis of Therapeutic Antibodies. AB - : The development of therapeutic and diagnostic antibodies is a rapidly growing field of research, being the fastest expanding group of products on the pharmaceutical market, and appropriate quality controls are crucial for their application. We have identified and characterized the serine protease termed BspK (Bdellovibrio serine protease K) from Bdellovibrio bacteriovorus and here show its activity on antibodies. Mutation of the serine residue at position 230 rendered the protease inactive. Further investigations of BspK enzymatic characteristics revealed autoproteolytic activity, resulting in numerous cleavage products. Two of the autoproteolytic cleavage sites in the BspK fusion protein were investigated in more detail and corresponded to cleavage after K28 and K210 in the N- and C-terminal parts of BspK, respectively. Further, BspK displayed stable enzymatic activity on IgG within the pH range of 6.0 to 9.5 and was inhibited in the presence of ZnCl2 BspK demonstrated preferential hydrolysis of human IgG1 compared to other immunoglobulins and isotypes, with hydrolysis of the heavy chain at position K226 generating two separate Fab fragments and an intact IgG Fc domain. Finally, we show that BspK preferentially cleaves its substrates C terminally to lysines similar to the protease LysC. However, BspK displays a unique cleavage profile compared to several currently used proteases on the market. IMPORTANCE: The rapid development of novel therapeutic antibodies is partly hindered by difficulties in assessing their quality and safety. The lack of tools and methods facilitating such quality controls obstructs and delays the process of product approval, eventually affecting the patients in need of treatment. These difficulties in product evaluations indicate a need for new and comprehensive tools for such analysis. Additionally, recent concerns raised regarding the limitations of established products on the market (e.g., trypsin) further highlight a general need for a larger array of proteases with novel cleavage profiles to meet current and future needs, within both the life science industry and the academic research community. PMID- 27940544 TI - Influences of pH and Iron Concentration on the Salivary Microbiome in Individual Humans with and without Caries. AB - : This study aimed to identify the differences in the oral microbial communities in saliva from patients with and without caries by performing sequencing with the Illumina MiSeq platform, as well as to further assess their relationships with environmental factors (salivary pH and iron concentration). Forty-three volunteers were selected, including 21 subjects with and 22 without caries, from one village in Gansu, China. Based on 966,255 trimmed sequences and clustering at the 97% similarity level, 1,303 species-level operational taxonomic units were generated. The sequencing data for the two groups revealed that (i) particular distribution patterns (synergistic effects or competition) existed in the subjects with and without caries at both the genus and species levels and (ii) both the salivary pH and iron concentration had significant influences on the microbial community structure. IMPORTANCE: The significant influences of the oral environment observed in this study increase the current understanding of the salivary microbiome in caries. These results will be useful for expanding research directions and for improving disease diagnosis, prognosis, and therapy. PMID- 27940545 TI - Dynamics of Virus Distribution in a Defined Swine Production Network Using Enteric Viruses as Molecular Markers. AB - : Modern swine production systems represent complex and dynamic networks involving numerous stakeholders. For instance, livestock transporters carry live animals between fattening sites, abattoirs, and other premises on a daily basis. This interconnected system may increase the risk of microbial spread within and between networks, although little information is available in that regard. In the present study, a swine network composed of 10 finishing farms, one abattoir, and three types of stakeholders (veterinarians, livestock transporters, and nutritional technicians) in Quebec, Canada, was selected to investigate specific vectors and reservoirs of enteric viruses. Environmental samples were collected from the premises over a 12-month period. Samples were screened using targeted reverse transcription-PCR and sequencing of two selected viral markers, group A rotaviruses (RVA) and porcine astroviruses (PoAstV), both prevalent and genetically heterogeneous swine enteric viruses. The results revealed frequent contamination of farm sites (21.4 to 100%), livestock transporter vehicles (30.6 to 68.8%) and, most importantly, the abattoir yard (46.7 to 94.1%), depending on the sample types. Although high levels of strain diversity for both viruses were found, identical PoAstV and RVA strains were detected in specific samples from farms, the abattoir yard, and the livestock transporter vehicle, suggesting interconnections between these premises and transporters. Overall, the results from this study underscore the potential role of abattoirs and livestock transport as a reservoir and transmission route for enteric viruses within and between animal production networks, respectively. IMPORTANCE: Using rotaviruses and astroviruses as markers of enteric contamination in a swine network has revealed the potential role of abattoirs and livestock transporters as a reservoir and vectors of enteric pathogens. The results from this study highlight the importance of tightening biosecurity measures. For instance, implementing sanitary vacancy between animal batches and emphasizing washing, disinfection, and drying procedures on farms and for transportation vehicles, as well as giving limited access and circulation of vehicles throughout the production premises, are some examples of measures that should be applied properly. The results also emphasize the need to closely monitor the dynamics of enteric contamination in the swine industry in order to better understand and potentially prevent the spread of infectious diseases. This is especially relevant when a virulent and economically damaging agent is involved, as seen with the recent introduction of the porcine epidemic diarrhea virus in the country. PMID- 27940548 TI - Robert Lockhart Johnston. PMID- 27940546 TI - Discovery of Polyesterases from Moss-Associated Microorganisms. AB - : The growing pollution of the environment with plastic debris is a global threat which urgently requires biotechnological solutions. Enzymatic recycling not only prevents pollution but also would allow recovery of valuable building blocks. Therefore, we explored the existence of microbial polyesterases in microbial communities associated with the Sphagnum magellanicum moss, a key species within unexploited bog ecosystems. This resulted in the identification of six novel esterases, which were isolated, cloned, and heterologously expressed in Escherichia coli The esterases were found to hydrolyze the copolyester poly(butylene adipate-co-butylene terephthalate) (PBAT) and the oligomeric model substrate bis[4-(benzoyloxy)butyl] terephthalate (BaBTaBBa). Two promising polyesterase candidates, EstB3 and EstC7, which clustered in family VIII of bacterial lipolytic enzymes, were purified and characterized using the soluble esterase substrate p-nitrophenyl butyrate (Km values of 46.5 and 3.4 MUM, temperature optima of 48 degrees C and 50 degrees C, and pH optima of 7.0 and 8.5, respectively). In particular, EstC7 showed outstanding activity and a strong preference for hydrolysis of the aromatic ester bond in PBAT. Our study highlights the potential of plant-associated microbiomes from extreme natural ecosystems as a source for novel hydrolytic enzymes hydrolyzing polymeric compounds. IMPORTANCE: In this study, we describe the discovery and analysis of new enzymes from microbial communities associated with plants (moss). The recovered enzymes show the ability to hydrolyze not only common esterase substrates but also the synthetic polyester poly(butylene adipate-co-butylene terephthalate), which is a common material employed in biodegradable plastics. The widespread use of such synthetic polyesters in industry and society requires the development of new sustainable technological solutions for their recycling. The discovered enzymes have the potential to be used as catalysts for selective recovery of valuable building blocks from this material. PMID- 27940547 TI - Modeling Stochastic Variability in the Numbers of Surviving Salmonella enterica, Enterohemorrhagic Escherichia coli, and Listeria monocytogenes Cells at the Single-Cell Level in a Desiccated Environment. AB - : Despite effective inactivation procedures, small numbers of bacterial cells may still remain in food samples. The risk that bacteria will survive these procedures has not been estimated precisely because deterministic models cannot be used to describe the uncertain behavior of bacterial populations. We used the Poisson distribution as a representative probability distribution to estimate the variability in bacterial numbers during the inactivation process. Strains of four serotypes of Salmonella enterica, three serotypes of enterohemorrhagic Escherichia coli, and one serotype of Listeria monocytogenes were evaluated for survival. We prepared bacterial cell numbers following a Poisson distribution (indicated by the parameter lambda, which was equal to 2) and plated the cells in 96-well microplates, which were stored in a desiccated environment at 10% to 20% relative humidity and at 5, 15, and 25 degrees C. The survival or death of the bacterial cells in each well was confirmed by adding tryptic soy broth as an enrichment culture. Changes in the Poisson distribution parameter during the inactivation process, which represent the variability in the numbers of surviving bacteria, were described by nonlinear regression with an exponential function based on a Weibull distribution. We also examined random changes in the number of surviving bacteria using a random number generator and computer simulations to determine whether the number of surviving bacteria followed a Poisson distribution during the bacterial death process by use of the Poisson process. For small initial cell numbers, more than 80% of the simulated distributions (lambda = 2 or 10) followed a Poisson distribution. The results demonstrate that variability in the number of surviving bacteria can be described as a Poisson distribution by use of the model developed by use of the Poisson process. IMPORTANCE: We developed a model to enable the quantitative assessment of bacterial survivors of inactivation procedures because the presence of even one bacterium can cause foodborne disease. The results demonstrate that the variability in the numbers of surviving bacteria was described as a Poisson distribution by use of the model developed by use of the Poisson process. Description of the number of surviving bacteria as a probability distribution rather than as the point estimates used in a deterministic approach can provide a more realistic estimation of risk. The probability model should be useful for estimating the quantitative risk of bacterial survival during inactivation. PMID- 27940549 TI - Repression of telomerase gene promoter requires human-specific genomic context and is mediated by multiple HDAC1-containing corepressor complexes. AB - The human telomerase reverse transcriptase (hTERT) gene is repressed in most somatic cells, whereas the expression of the mouse mTert gene is widely detected. To understand the mechanisms of this human-specific repression, we constructed bacterial artificial chromosome (BAC) reporters using human and mouse genomic DNAs encompassing the TERT genes and neighboring loci. Upon chromosomal integration, the hTERT, but not the mTert, reporter was stringently repressed in telomerase-negative human cells in a histone deacetylase (HDAC)-dependent manner, replicating the expression of their respective endogenous genes. In chimeric BACs, the mTert promoter became strongly repressed in the human genomic context, but the hTERT promoter was highly active in the mouse genomic context. Furthermore, an unrelated herpes simplex virus-thymidine kinase (HSV-TK) promoter was strongly repressed in the human, but not in the mouse, genomic context. These results demonstrated that the repression of hTERT gene was dictated by distal elements and its chromatin environment. This repression depended on class I HDACs and involved multiple corepressor complexes, including HDAC1/2-containing Sin3B, nucleosome remodeling and histone deacetylase (NuRD), and corepressor of RE1 silencing transcription factor (CoREST) complexes. Together, our data indicate that the lack of telomerase expression in most human somatic cells results from its repressive genomic environment, providing new insight into the mechanism of long-recognized differential telomerase regulation in mammalian species.-Cheng, D., Zhao, Y., Wang, S., Zhang, F., Russo, M., McMahon, S. B., Zhu, J. Repression of telomerase gene promoter requires human-specific genomic context and is mediated by multiple HDAC1-containing corepressor complexes. PMID- 27940550 TI - COX-2-dependent and independent effects of COX-2 inhibitors and NSAIDs on proatherogenic changes in human monocytes/macrophages. AB - It is the second decade of controversy regarding the cardiovascular effects of cyclo-oxygenase-2 (COX-2) inhibitors. At this time, celecoxib is the only available COX-2-specific inhibitor for treatment of pain and inflammation. Therefore, the present study was designed primarily to determine the impact of celecoxib on cholesterol handling (uptake via scavenger receptors and efflux from the cells) and foam cell formation in human THP-1 macrophages, followed by comparison to rofecoxib and other non-steroidal anti-inflammatory drugs (NSAIDs). THP-1 human macrophages and peripheral blood mononuclear cells were incubated with: celecoxib, rofecoxib, naproxen (at 5, 10, 25 uM) and acetaminophen (0.5 mM, 1 mM)+/-oxidized low-density lipoprotein (oxLDL, 25 ug/mL). Scavenger receptors: CD36, LOX-1, SR-A1, and CXCL16 and cholesterol efflux proteins: ATP-binding cassette transporter (ABC) A1 and G1, and 27-hydroxylase were detected. The adhesion of monocytes to cultured endothelial cells with/ without COX-2 inhibitors/NSAIDs was also analyzed. The presence of celecoxib and rofecoxib (at high concentrations) significantly decreased expression of 27-hydroxylase and ABCA1, interfering with normal cholesterol outflow from macrophages. Acetaminophen and the non-specific COX inhibitor naproxen had no significant effect on these proteins. Only celecoxib had a profound effect on the class B scavenger receptor CD36 and the class E receptor LOX1. We demonstrate that in contrast to celecoxib, rofecoxib and naproxen increased adhesive properties of monocytes to endothelial cells. This work might contribute to our understanding of multiple mechanisms underlying elevated cardiovascular risk upon the use of COX-2 inhibitors and uncover new possibilities to enhance the safety profile of existing COX-2 inhibitors. PMID- 27940551 TI - Management of alcohol misuse in patients with liver diseases. AB - Excessive alcohol use not only causes alcoholic liver disease (ALD) but also increases the risk of liver-related mortality in patients who already have other chronic liver diseases. Screening for alcohol misuse or alcohol use disorder (AUD) among patients with underlying liver disease is essential. This clinical review covers what is known about ALD, the impact of alcohol in patients with underlying liver diseases, current management of alcohol misuse and AUD, and the management of alcohol misuse and AUD specifically in patients with liver diseases. Several treatment options for alcohol misuse and AUD exist such as psychosocial intervention and behavioral and pharmacological therapies. The strategies used in the treatment of alcohol misuse and AUD are still applicable in those who consume alcohol and have underlying liver disease. However, certain medications still need to be carefully used due to potentially worsening already compromised liver function. Screening of ongoing alcohol use in subjects with liver disease is important, and prompt intervention is needed to prevent the associated morbidity and mortality from the detrimental effects of continued alcohol use on underlying liver disease. Considering alcoholism is a complex disease, probably a multidisciplinary approach combining psychotherapy and comprehensive medical care will be the most effective. Future research could focus on identifying additional treatment options for addressing the psychotherapy component since the self-determination and will to quit drinking alcohol can play such a crucial role in promoting abstinence. PMID- 27940552 TI - And-1 coordinates with CtIP for efficient homologous recombination and DNA damage checkpoint maintenance. AB - To prevent genomic instability, cells respond to DNA lesions by blocking cell cycle progression and initiating DNA repair. Homologous recombination repair of DNA breaks requires CtIP-dependent resection of the DNA ends, which is thought to play a key role in activation of CHK1 kinase to induce the cell cycle checkpoint. But the mechanism is still not fully understood. Here, we establish that And-1, a replisome component, promotes DNA-end resection and DNA repair by homologous recombination. Mechanistically, And-1 interacts with CtIP and regulates CtIP recruitment to DNA damage sites. And-1 localizes to sites of DNA damage dependent on MDC1-RNF8 pathway, and is required for resistance to many DNA-damaging and replication stress-inducing agents. Furthermore, we show that And-1-CtIP axis is critically required for sustained ATR-CHK1 checkpoint signaling and for maintaining both the intra-S- and G2-phase checkpoints. Our findings thus identify And-1 as a novel DNA repair regulator and reveal how the replisome regulates the DNA damage induced checkpoint and genomic stability. PMID- 27940555 TI - The CSRP2BP histone acetyltransferase drives smooth muscle gene expression. AB - The expression of nearly all smooth muscle genes are controlled by serum response factor binding sites in their promoter regions. However, SRF alone is not sufficient for regulating smooth muscle cell development. It associates with other cardiovascular specific cofactors to regulate smooth muscle gene expression. Previously, we showed that the transcription co-factor CRP2 was a regulator of smooth muscle gene expression. Here, we report that CSRP2BP, a coactivator for CRP2, is a histone acetyltransferase and a driver of smooth muscle gene expression. CSRP2BP directly interacted with SRF, CRP2 and myocardin. CSRP2BP synergistically activated smooth muscle gene promoters in an SRF dependent manner. A combination of SRF, GATA6 and CRP2 required CSRP2BP for robust smooth muscle gene promoter activity. Knock-down of Csrp2bp in smooth muscle cells resulted in reduced smooth muscle gene expression. We conclude that the CSRP2BP histone acetyltransferase is a coactivator for CRP2 that works synergistically with SRF and myocardin to regulate smooth muscle gene expression. PMID- 27940558 TI - Simultaneous detection of mRNA transcription and decay intermediates by dual colour single mRNA FISH on subcellular resolution. AB - The detection of mRNAs undergoing transcription or decay is challenging, because both processes are fast. However, the relative proportion of an mRNA in synthesis or decay increases with mRNA size and decreases with mRNA half-life. Based on this rationale, I have exploited a 22 200 nucleotide-long, short-lived endogenous mRNA as a reporter for mRNA metabolism in trypanosomes. The extreme 5? and 3? ends were labeled with red- and green-fluorescent Affymetrix(r) single mRNA FISH probes, respectively. In the resulting fluorescence images, yellow spots represent intact mRNAs; red spots are mRNAs in transcription or 3?-5? decay, and green spots are mRNAs in 5?-3? degradation. Most red spots were nuclear and insensitive to transcriptional inhibition and thus likely transcription intermediates. Most green spots were cytoplasmic, confirming that the majority of cytoplasmic decay in trypanosomes is 5?-3?. The system showed the expected changes at inhibition of transcription or translation and RNAi depletion of the trypanosome homologue to the 5?-3? exoribonuclease Xrn1. The method allows to monitor changes in mRNA metabolism both on cellular and on population/tissue wide levels, but also to study the subcellular localization of mRNA transcription and decay pathways. I show that the system is applicable to mammalian cells. PMID- 27940557 TI - And-1 is required for homologous recombination repair by regulating DNA end resection. AB - Homologous recombination (HR) is a major mechanism to repair DNA double-strand breaks (DSBs). Although tumor suppressor CtIP is critical for DSB end resection, a key initial event of HR repair, the mechanism regulating the recruitment of CtIP to DSB sites remains largely unknown. Here, we show that acidic nucleoplasmic DNA-binding protein 1 (And-1) forms complexes with CtIP as well as other repair proteins, and is essential for HR repair by regulating DSB end resection. Furthermore, And-1 is recruited to DNA DSB sites in a manner dependent on MDC1, BRCA1 and ATM, down-regulation of And-1 impairs end resection by reducing the recruitment of CtIP to damage sites, and considerably reduces Chk1 activation and other damage response during HR repair. These findings collectively demonstrate a hitherto unknown role of MDC1->And-1->CtIP axis that regulates CtIP-mediated DNA end resection and cellular response to DSBs. PMID- 27940556 TI - The Drosophila telomere-capping protein Verrocchio binds single-stranded DNA and protects telomeres from DNA damage response. AB - Drosophila telomeres are sequence-independent structures maintained by transposition to chromosome ends of three specialized retroelements rather than by telomerase activity. Fly telomeres are protected by the terminin complex that includes the HOAP, HipHop, Moi and Ver proteins. These are fast evolving, non conserved proteins that localize and function exclusively at telomeres, protecting them from fusion events. We have previously suggested that terminin is the functional analogue of shelterin, the multi-protein complex that protects human telomeres. Here, we use electrophoretic mobility shift assay (EMSA) and atomic force microscopy (AFM) to show that Ver preferentially binds single stranded DNA (ssDNA) with no sequence specificity. We also show that Moi and Ver form a complex in vivo. Although these two proteins are mutually dependent for their localization at telomeres, Moi neither binds ssDNA nor facilitates Ver binding to ssDNA. Consistent with these results, we found that Ver-depleted telomeres form RPA and gammaH2AX foci, like the human telomeres lacking the ssDNA binding POT1 protein. Collectively, our findings suggest that Drosophila telomeres possess a ssDNA overhang like the other eukaryotes, and that the terminin complex is architecturally and functionally similar to shelterin. PMID- 27940560 TI - Nucleosome-free DNA regions differentially affect distant communication in chromatin. AB - Communication between distantly spaced genomic regions is one of the key features of gene regulation in eukaryotes. Chromatin per se can stimulate efficient enhancer-promoter communication (EPC); however, the role of chromatin structure and dynamics in this process remains poorly understood. Here we show that nucleosome spacing and the presence of nucleosome-free DNA regions can modulate chromatin structure/dynamics and, in turn, affect the rate of EPC in vitro and in silico. Increasing the length of internucleosomal linker DNA from 25 to 60 bp results in more efficient EPC. The presence of longer nucleosome-free DNA regions can positively or negatively affect the rate of EPC, depending upon the length and location of the DNA region within the chromatin fiber. Thus the presence of histone-free DNA regions can differentially affect the efficiency of EPC, suggesting that gene regulation over a distance could be modulated by changes in the length of internucleosomal DNA spacers. PMID- 27940562 TI - A cost effective 5? selective single cell transcriptome profiling approach with improved UMI design. AB - Single cell RNA sequencing approaches are instrumental in studies of cell-to-cell variability. 5? selective transcriptome profiling approaches allow simultaneous definition of the transcription start size and have advantages over 3? selective approaches which just provide internal sequences close to the 3? end. The only currently existing 5? selective approach requires costly and labor intensive fragmentation and cell barcoding after cDNA amplification. We developed an optimized 5? selective workflow where all the cell indexing is done prior to fragmentation. With our protocol, cell indexing can be performed in the Fluidigm C1 microfluidic device, resulting in a significant reduction of cost and labor. We also designed optimized unique molecular identifiers that show less sequence bias and vulnerability towards sequencing errors resulting in an improved accuracy of molecule counting. We provide comprehensive experimental workflows for Illumina and Ion Proton sequencers that allow single cell sequencing in a cost range comparable to qPCR assays. PMID- 27940564 TI - The AibR-isovaleryl coenzyme A regulator and its DNA binding site - a model for the regulation of alternative de novo isovaleryl coenzyme A biosynthesis in Myxococcus xanthus. AB - Isovaleryl coenzyme A (IV-CoA) is an important building block of iso-fatty acids. In myxobacteria, IV-CoA is essential for the formation of signaling molecules involved in fruiting body formation. Leucine degradation is the common source of IV-CoA, but a second, de novo biosynthetic route to IV-CoA termed AIB (alternative IV-CoA biosynthesis) was recently discovered in M. xanthus. The AIB operon contains the TetR-like transcriptional regulator AibR, which we characterize in this study. We demonstrate that IV-CoA binds AibR with micromolar affinity and show by gelshift experiments that AibR interacts with the promoter region of the AIB-operon once IV-CoA is present. We identify an 18-bp near perfect palindromic repeat as containing the AibR operator and provide evidence that AibR also controls an additional genomic locus coding for a putative acetyl CoA acetyltransferase. To elucidate atomic details, we determined crystal structures of AibR in the apo, the IV-CoA- and the IV-CoA-DNA-bound state to 1.7 A, 2.35 A and 2.92 A, respectively. IV-CoA induces partial unfolding of an alpha helix, which allows sequence-specific interactions between AibR and its operator. This study provides insights into AibR-mediated regulation and shows that AibR functions in an unusual TetR-like manner by blocking transcription not in the ligand-free but in the effector-bound state. PMID- 27940565 TI - Differentially expressed genes and gene networks involved in pig ovarian follicular atresia. AB - Ovarian folliculogenesis corresponds to the development of follicles leading to either ovulation or degeneration, this latter process being called atresia. Even if atresia involves apoptosis, its mechanism is not well understood. The objective of this study was to analyze global gene expression in pig granulosa cells of ovarian follicles during atresia. The transcriptome analysis was performed on a 9,216 cDNA microarray to identify gene networks and candidate genes involved in pig ovarian follicular atresia. We found 1,684 significantly regulated genes to be differentially regulated between small healthy follicles and small atretic follicles. Among them, 287 genes had a fold-change higher than two between the two follicle groups. Eleven genes (DKK3, GADD45A, CAMTA2, CCDC80, DAPK2, ECSIT, MSMB, NUPR1, RUNX2, SAMD4A, and ZNF628) having a fold-change higher than five between groups could likely serve as markers of follicular atresia. Moreover, automatic confrontation of deregulated genes with literature data highlighted 93 genes as regulatory candidates of pig granulosa cell atresia. Among these genes known to be inhibitors of apoptosis, stimulators of apoptosis, or tumor suppressors INHBB, HNF4, CLU, different interleukins (IL5, IL24), TNF associated receptor (TNFR1), and cytochrome-c oxidase (COX) were suggested as playing an important role in porcine atresia. The present study also enlists key upstream regulators in follicle atresia based on our results and on a literature review. The novel gene candidates and gene networks identified in the current study lead to a better understanding of the molecular regulation of ovarian follicular atresia. PMID- 27940567 TI - A life course approach to health literacy: the role of gender, educational attainment and lifetime cognitive capability. AB - Objective: social inequalities in health are believed to arise in part because individuals make use of social and economic resources in order to improve survival. In recent years, health literacy has received increased attention as a factor that can help explain differences in health outcomes. However, examination of life course predictors of health literacy has been limited. Methods: life course data from the Wisconsin Longitudinal Study 1957-2011 were used to examine predictors of health literacy in old age (N = 2,122), using the Newest Vital Sign. Generalised structural equation modelling was used to model pathways to health literacy. Results: predictors of health literacy included educational attainment, and adolescent cognitive and non-cognitive skills, and, in men, rate of cognitive decline from middle to later life. Discussion: numerous studies have documented health literacy issues among older adults, and recommendations have been made for ways to improve health literacy for this population. This study reports on risk factors across the life course that are associated with health literacy later in life, identifying possible intervention targets to reduce risk of poor health as people age. Our results suggest that a range of life course factors, beginning in early life, predict health literacy. Further research studying health literacy over the life course is warranted. PMID- 27940566 TI - Glucose regulates the intrinsic inflammatory response of the heart to surgically induced hypothermic ischemic arrest and reperfusion. AB - We investigated the isolated working rat heart as a model to study early transcriptional remodeling induced in the setting of open heart surgery and stress hyperglycemia. Hearts of male Sprague Dawley rats were cold-arrested in Krebs-Henseleit buffer and subjected to 60 min normothermic reperfusion in the working mode with buffer supplemented with noncarbohydrate substrates plus glucose (25 mM) or mannitol (25 mM; osmotic control). Gene expression profiles were determined by microarray analysis and compared with those of nonperfused hearts. Perfused hearts displayed a transcriptional signature independent from the presence of glucose showing a more than twofold increase in expression of 71 genes connected to inflammation, cell proliferation, and apoptosis. These transcriptional alterations were very similar to the ones taking place in the hearts of open heart surgery patients. Prominent among those alterations was the upregulation of the three master regulators of metabolic reprogramming, MYC, NR4A1, and NR4A2. Targeted pathway analysis revealed an upregulation of metabolic processes associated with the proliferation and activation of macrophages and fibroblasts. Glucose potentiated the upregulation of a subset of genes associated with polarization of tissue reparative M2-like macrophages, an effect that was lost in perfused hearts from rats rendered insulin resistant by high-sucrose feeding. The results expose the heart as a significant source of proinflammatory mediators released in response to stress associated with cardiac surgery with cardiopulmonary bypass, and suggest a major role for glucose as a signal in the determination of resident cardiac macrophage polarization. PMID- 27940568 TI - Can consultant geriatrician led comprehensive geriatric assessment in the emergency department reduce hospital admission rates? A systematic review. AB - Objective: economic and demographic pressures are driving a need to reassess the way in which we care for older patients presenting to emergency departments (EDs). This systematic review seeks to assess the extent to which performing comprehensive geriatric assessment (CGA) in the ED can reduce admission rates. Design: systematic search of both published and unpublished literature to identify studies reporting admission rates following the introduction of consultant geriatrician led teams performing CGA in the ED. Changes in inpatient length of stay and subsequent readmission rates were identified as secondary outcome measures. Results: five studies with a total of 28,434 participants were included. All of the studies reported statistically significant reductions in admission rates (ranging between 2.6 and 19.7%). However, variation in the degree of changes leads to uncertainty as to the financial viability of the intervention. No studies have yet examined the clinical effects of performing CGA within the ED. The results were far more varied with regards to inpatient length of stay and readmission rates, indicating that complex local factors, such as the design of community support services, may play an important role. Conclusion: consultant geriatrician led teams performing CGA within the ED can reduce admissions rates among older patients. It is unclear as to what impact such interventions have upon readmission rates or inpatient length of stay. Future research is needed to assess the clinical outcomes and financial viability of such admissions avoidance teams. PROSPERO registration number: CRD42016038840. PMID- 27940569 TI - Factors influencing the probability of a diagnosis of autism spectrum disorder in girls versus boys. AB - In order to shed more light on why referred girls are less likely to be diagnosed with autism spectrum disorder than boys, this study examined whether behavioral characteristics influence the probability of an autism spectrum disorder diagnosis differently in girls versus boys derived from a multicenter sample of consecutively referred children aged 2.5-10 years. Based on information from the short version of the Developmental, Dimensional and Diagnostic Interview and the Autism Diagnostic Observation Schedule, 130 children (106 boys and 24 girls) received a diagnosis of autism spectrum disorder according to Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.) criteria and 101 children (61 boys and 40 girls) did not. Higher overall levels of parent-reported repetitive and restricted behavior symptoms were less predictive of an autism spectrum disorder diagnosis in girls than in boys (odds ratio interaction = 0.41, 95% confidence interval = 0.18-0.92, p = 0.03). In contrast, higher overall levels of parent-reported emotional and behavioral problems increased the probability of an autism spectrum disorder diagnosis more in girls than in boys (odds ratio interaction = 2.44, 95% confidence interval = 1.13-5.29, p = 0.02). No differences were found between girls and boys in the prediction of an autism spectrum disorder diagnosis by overall autistic impairment, sensory symptoms, and cognitive functioning. These findings provide insight into possible explanations for the assumed underidentification of autism spectrum disorder in girls in the clinic. PMID- 27940570 TI - Attention and written expression in school-age, high-functioning children with autism spectrum disorders. AB - High-functioning children with autism spectrum disorders often find writing challenging. These writing difficulties may be specific to autism spectrum disorder or to a more general clinical effect of attention disturbance, as these children are often comorbid for attention-deficit/hyperactivity disorder (ADHD) symptomatology (and children with attention-deficit/hyperactivity disorder often also find writing challenging). To examine this issue, this study investigated the role of attention disturbance on writing in 155 school-age children across four diagnostic groups: high-functioning autism spectrum disorder (HFASD) with lower ADHD symptoms (HFASD-L), HFASD with higher ADHD symptoms (HFASD-H), ADHD symptoms but no autism spectrum disorder symptoms, and typical development. Both HFASD subgroups and the ADHD group displayed lower word production writing scores than the typical development group, but the clinical groups did not differ. The HFASD-H and ADHD groups had significantly lower theme development and text organization writing scores than the typical development group, but the HFASD-L and typical development groups were not significantly different. The findings support prior research reporting writing problems in children with autism spectrum disorder but also suggest that children with HFASD-H may be at greater risk for writing difficulties than children with HFASD-L. Better understanding the role of attention in writing development could advance methods for assessment and intervention for children with high-functioning autism spectrum disorder at risk for writing difficulties. PMID- 27940571 TI - Assertive Community Treatment For People With Alcohol Dependence: A Pilot Randomized Controlled Trial. AB - Aims: A pilot randomized controlled trial (RCT) to assess the feasibility and potential efficacy of assertive community treatment (ACT) in adults with alcohol dependence. Methods: Single blind, individually randomized, pilot RCT of 12 months of ACT plus treatment as usual (TAU) versus TAU alone in adults (age 18+ years) with alcohol dependence and a history of previous unsuccessful alcohol treatment attending specialist community alcohol treatment services. ACT aimed to actively engage participants for 12 months with assertive, regular, minimum weekly contact. ACT was combined with TAU. TAU comprised access to the full range of services provided by the community teams. Primary outcome is mean drinks per drinking day and percent days abstinent at 12 months follow up. Analysis of covariance was conducted using 80% confidence intervals, appropriate in the context of a pilot trial. Results: A total of 94 participants were randomized, 45 in ACT and 49 in TAU. Follow-up was achieved with 98 and 88%, respectively at 12 months. Those in ACT had better treatment engagement, and were more often seen in their homes or local community than TAU participants. At 12 months the ACT group had more problems related to drinking and lower quality of life than TAU but no differences in drinking measures. The ACT group had a higher percentage of days abstinent but lower quality of life at 6 months. The ACT group had less unplanned healthcare use than TAU. Conclusions: An trial of ACT was feasible to implement in an alcohol dependent treatment population. Trial registration: ISRCTN22775534. PMID- 27940574 TI - Robin Priscott. PMID- 27940573 TI - Knee Osteoarthritis Is Associated With Previous Meniscus and Anterior Cruciate Ligament Surgery Among Elite College American Football Athletes. AB - BACKGROUND: Football puts athletes at risk for knee injuries such meniscus and anterior cruciate ligament (ACL) tears, which are associated with the development of osteoarthritis (OA). Previous knee surgery, player position, and body mass index (BMI) may be associated with knee OA. HYPOTHESIS: In elite football players undergoing knee magnetic resonance imaging at the National Football League's Invitational Combine, the prevalence of knee OA is associated with previous knee surgery and BMI. STUDY DESIGN: Retrospective cohort. LEVEL OF EVIDENCE: Level 4. METHODS: A retrospective review was performed of all participants of the National Football League Combine from 2005 to 2009 who underwent magnetic resonance imaging of the knee because of prior knee injury, surgery, or knee-related symptoms or concerning examination findings. Imaging studies were reviewed for evidence of OA. History of previous knee surgery-including ACL reconstruction, meniscal procedures, and articular cartilage surgery-and position were recorded for each athlete. BMI was calculated based on height and weight. RESULTS: There was a higher prevalence of OA in knees with a history of previous knee surgery (23% vs 4.0%, P < 0.001). The prevalence of knee OA was 4.0% in those without previous knee surgery, 11% in those with a history of meniscus repair, 24% of those with a history of ACL reconstruction, and 27% of those with a history of partial meniscectomy. Among knees with a previous ACL reconstruction, the rate of OA doubled in tibiofemoral compartments in which meniscal surgery was performed. BMI >30 kg/m2 was also associated with a higher risk of OA ( P = 0.007) but player position was not associated with knee OA. CONCLUSIONS: Previous knee surgery, particularly ACL reconstruction and partial meniscectomy, and elevated BMI are associated with knee OA in elite football players. Future research should investigate ways to minimize the risk of OA after knee surgery in these athletes. CLINICAL RELEVANCE: Treatment of knee injuries in football athletes should consider chondroprotection, including meniscal preservation and cartilage repair, when possible. PMID- 27940575 TI - mda-7/IL-24 Mediates Cancer Cell-Specific Death via Regulation of miR-221 and the Beclin-1 Axis. AB - Melanoma differentiation-associated gene-7/IL-24 (mda-7/IL-24) displays broad spectrum anticancer activity in vitro, in vivo in preclinical animal models, and in a phase I/II clinical trial in patients with advanced cancers without harming normal cells or tissues. Here we demonstrate that mda-7/IL-24 regulates a specific subset of miRNAs, including cancer-associated miR-221. Either ectopic expression of mda-7/IL-24 or treatment with recombinant His-MDA-7 protein resulted in downregulation of miR-221 and upregulation of p27 and PUMA in a panel of cancer cells, culminating in cell death. Mda-7/IL-24-induced cancer cell death was dependent on reactive oxygen species induction and was rescued by overexpression of miR-221. Beclin-1 was identified as a new transcriptional target of miR-221, and mda-7/IL-24 regulated autophagy through a miR-221/beclin-1 feedback loop. In a human breast cancer xenograft model, miR-221-overexpressing MDA-MB-231 clones were more aggressive and resistant to mda-7/IL-24-mediated cell death than parental clones. This is the first demonstration that mda-7/IL-24 directly regulates miRNA expression in cancer cells and highlights the novelty of the mda-7/IL-24-miR-221-beclin-1 loop in mediating cancer cell-specific death. Cancer Res; 77(4); 949-59. (c)2016 AACR. PMID- 27940576 TI - Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling. AB - Despite the high incidence of oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K, PI3K inhibitors have yielded little clinical benefit for breast cancer patients. Recent epidemiologic studies have suggested a therapeutic benefit from aspirin intake in cancers harboring oncogenic PIK3CA Here, we show that mutant PIK3CA-expressing breast cancer cells have greater sensitivity to aspirin-mediated growth suppression than their wild-type counterparts. Aspirin decreased viability and anchorage-independent growth of mutant PIK3CA breast cancer cells independently of its effects on COX-2 and NF kappaB. We ascribed the effects of aspirin to AMP-activated protein kinase (AMPK) activation, mTORC1 inhibition, and autophagy induction. In vivo, oncogenic PIK3CA driven mouse mammary tumors treated daily with aspirin resulted in decreased tumor growth kinetics, whereas combination therapy of aspirin and a PI3K inhibitor further attenuated tumor growth. Our study supports the evaluation of aspirin and PI3K pathway inhibitors as a combination therapy for targeting breast cancer. Cancer Res; 77(3); 790-801. (c)2016 AACR. PMID- 27940577 TI - Pyocyanin degradation by a tautomerizing demethylase inhibits Pseudomonas aeruginosa biofilms. AB - The opportunistic pathogen Pseudomonas aeruginosa produces colorful redox-active metabolites called phenazines, which underpin biofilm development, virulence, and clinical outcomes. Although phenazines exist in many forms, the best studied is pyocyanin. Here, we describe pyocyanin demethylase (PodA), a hitherto uncharacterized protein that oxidizes the pyocyanin methyl group to formaldehyde and reduces the pyrazine ring via an unusual tautomerizing demethylation reaction. Treatment with PodA disrupts P. aeruginosa biofilm formation similarly to DNase, suggesting interference with the pyocyanin-dependent release of extracellular DNA into the matrix. PodA-dependent pyocyanin demethylation also restricts established biofilm aggregate populations experiencing anoxic conditions. Together, these results show that modulating extracellular redox active metabolites can influence the fitness of a biofilm-forming microorganism. PMID- 27940578 TI - Suppressing relaxation in superconducting qubits by quasiparticle pumping. AB - Dynamical error suppression techniques are commonly used to improve coherence in quantum systems. They reduce dephasing errors by applying control pulses designed to reverse erroneous coherent evolution driven by environmental noise. However, such methods cannot correct for irreversible processes such as energy relaxation. We investigate a complementary, stochastic approach to reducing errors: Instead of deterministically reversing the unwanted qubit evolution, we use control pulses to shape the noise environment dynamically. In the context of superconducting qubits, we implement a pumping sequence to reduce the number of unpaired electrons (quasiparticles) in close proximity to the device. A 70% reduction in the quasiparticle density results in a threefold enhancement in qubit relaxation times and a comparable reduction in coherence variability. PMID- 27940579 TI - Quantum optical circulator controlled by a single chirally coupled atom. AB - Integrated nonreciprocal optical components, which have an inherent asymmetry between their forward and backward propagation direction, are key for routing signals in photonic circuits. Here, we demonstrate a fiber-integrated quantum optical circulator operated by a single atom. Its nonreciprocal behavior arises from the chiral interaction between the atom and the transversally confined light. We demonstrate that the internal quantum state of the atom controls the operation direction of the circulator and that it features a strongly nonlinear response at the single-photon level. This enables, for example, photon number dependent routing and novel quantum simulation protocols. Furthermore, such a circulator can in principle be prepared in a coherent superposition of its operational states and may become a key element for quantum information processing in scalable integrated optical circuits. PMID- 27940580 TI - Crystal structure of unlinked NS2B-NS3 protease from Zika virus. AB - Zika virus (ZIKV) has rapidly emerged as a global public health concern. Viral NS2B-NS3 protease processes viral polyprotein and is essential for the virus replication, making it an attractive antiviral drug target. We report crystal structures at 1.58-angstrom resolution of the unlinked NS2B-NS3 protease from ZIKV as free enzyme and bound to a peptide reversely oriented at the active site. The unlinked NS2B-NS3 protease adopts a closed conformation in which NS2B engages NS3 to form an empty substrate-binding site. A second protease in the same crystal binds to the residues K14K15G16E17 from the neighboring NS3 in reverse orientation, resisting proteolysis. These features of ZIKV NS2B-NS3 protease may accelerate the discovery of structure-based antiviral drugs against ZIKV and related pathogenic flaviviruses. PMID- 27940582 TI - Active sites in heterogeneous ice nucleation-the example of K-rich feldspars. AB - Ice formation on aerosol particles is a process of crucial importance to Earth's climate and the environmental sciences, but it is not understood at the molecular level. This is partly because the nature of active sites, local surface features where ice growth commences, is still unclear. Here we report direct electron microscopic observations of deposition growth of aligned ice crystals on feldspar, an atmospherically important component of mineral dust. Our molecular scale computer simulations indicate that this alignment arises from the preferential nucleation of prismatic crystal planes of ice on high-energy (100) surface planes of feldspar. The microscopic patches of (100) surface, exposed at surface defects such as steps, cracks, and cavities, are thought to be responsible for the high ice nucleation efficacy of potassium (K)-feldspar particles. PMID- 27940581 TI - Precursor processing for plant peptide hormone maturation by subtilisin-like serine proteinases. AB - Peptide hormones that regulate plant growth and development are derived from larger precursor proteins by proteolytic processing. Our study addressed the role of subtilisin-like proteinases (SBTs) in this process. Using tissue-specific expression of proteinase inhibitors as a tool to overcome functional redundancy, we found that SBT activity was required for the maturation of IDA (INFLORESCENCE DEFICIENT IN ABSCISSION), a peptide signal for the abscission of floral organs in Arabidopsis We identified three SBTs that process the IDA precursor in vitro, and this processing was shown to be required for the formation of mIDA (the mature and bioactive form of IDA) as the endogenous signaling peptide in vivo. Hence, SBTs act as prohormone convertases in plants, and several functionally redundant SBTs contribute to signal biogenesis. PMID- 27940583 TI - The effect of ethnicity and genetic ancestry on the epidemiology, clinical features and outcome of systemic lupus erythematosus. AB - In this in-depth review, we examine the worldwide epidemiology of SLE and summarize current knowledge on the influence of race/ethnicity on clinical manifestations, disease activity, damage accumulation and outcome in SLE. Susceptibility to SLE has a strong genetic component, and trans-ancestral genetic studies have revealed a substantial commonality of shared genetic risk variants across different genetic ancestries that predispose to the development of SLE. The highest increased risk of developing SLE is observed in black individuals (incidence 5- to 9-fold increased, prevalence 2- to 3-fold increased), with an increased risk also observed in South Asians, East Asians and other non-white groups, compared with white individuals. Black, East Asian, South Asian and Hispanic individuals with SLE tend to develop more severe disease with a greater number of manifestations and accumulate damage from lupus more rapidly. Increased genetic risk burden in these populations, associated with increased autoantibody reactivity in non-white individuals with SLE, may explain the more severe lupus phenotype. Even after taking into account socio-economic factors, race/ethnicity remains a key determinant of poor outcome, such as end-stage renal failure and mortality, in SLE. Community measures to expedite diagnosis through increased awareness in at-risk racial/ethnic populations and ethnically personalized treatment algorithms may help in future to improve long-term outcomes in SLE. PMID- 27940584 TI - Interleukin-22 drives the proliferation, migration and osteogenic differentiation of mesenchymal stem cells: a novel cytokine that could contribute to new bone formation in spondyloarthropathies. AB - Objectives.: The SpAs are genetically and therapeutically linked to IL-23, which in turn regulates IL-22, a cytokine that has been implicated in the regulation of new bone formation in experimental models. We hypothesize that IL-22, a master regulator of stem cells in other niches, might also regulate human mesenchymal stem cell (MSC) osteogenesis. Methods.: The effects of IL-22 on in vitro MSC proliferation, migration and osteogenic differentiation were evaluated in the presence or absence of IFN-gamma and TNF (to ascertain IL-22 activity in pro inflammatory environments). Colorimetric XTT assay, trans-well migration assays, quantitative real-time PCR (qRT-PCR) for MSC lineage markers and osteogenesis assays were used. Results.: Combined treatment of MSC with IL-22, IFN-gamma and TNF resulted in increased MSC proliferation ( P = 0.008) and migration ( P = 0.04), an effect that was not seen in cells treated with IL-22 alone and untreated cells. Osteogenic and adipogenic, but not chondrogenic, transcription factors were upregulated by IL-22 alone ( P < 0.05). MSC osteogenesis was enhanced following IL-22 exposure ( P = 0.03, measured by calcium production). The combination of IFN-gamma and TNF with or without IL-22 suppressed MSC osteogenesis ( P = 0.03). Conclusion.: This work shows that IL-22 is involved in human MSC proliferation/migration in inflammatory environments, with MSC osteogenesis occurring only in the absence of IFN-gamma/TNF. These effects of IL 22 on MSC function is a novel pathway for exploring pathological, post inflammation osteogenesis in human SpA. PMID- 27940585 TI - Adult primary angiitis of the central nervous system: isolated small-vessel vasculitis represents distinct disease pattern. AB - Objectives: We aimed to identify whether presentations and outcomes in adult patients with isolated small-vessel primary angiitis of the CNS (PACNS) would differ from other patients with large/medium-vessel involvement. Methods: In the French PACNS cohort, we compared the characteristics, treatments and outcomes of patients with isolated small-vessel disease (normal CT, MR and/or conventional angiograms, brain biopsy positive for vasculitis) with other patients who had large/medium-vessel involvement (vessel abnormalities on CT, MR or conventional angiograms). A good functional outcome was defined as a modified Rankin scale ?2 at last follow-up, regardless of the occurrence of relapse. Results: Among the 102 patients in the cohort, 26 (25%) had isolated small-vessel PACNS, whereas the 76 others demonstrated large/medium-vessel involvement. Patients with isolated small-vessel PACNS had more seizures (P < 0.0001), cognitive (P = 0.02) or consciousness impairment (P = 0.03) and more dyskinesias (P = 0.002) but less focal deficits (P = 0.0002) than other PACNS patients. They also had more abnormal cerebrospinal fluid analysis (P = 0.008) and gadolinium enhancements on MRI (P = 0.001) but less frequent acute ischaemic lesions (P < 0.0001) than patients with large/medium-vessel involvement. Treatments and modified Rankin scale at last follow-up did not differ between groups. Thirty-two (31%) patients relapsed; 14 (54%) with isolated small-vessel PACNS vs 18 (24%) with large/medium vessel involvement (P = 0.004). Eight patients died, with no difference between the groups (P = 0.97). Conclusion: In our cohort, adult patients with isolated small-vessel PACNS presented some distinct disease features and relapsed more often than other PACNS patients who had large/medium-vessel involvement. Functional outcomes and mortality did not differ. PMID- 27940587 TI - The impact of socio-economic status in rheumatoid arthritis. PMID- 27940586 TI - Patterns of interstitial lung disease and mortality in rheumatoid arthritis. AB - Objective: To characterize a cohort of patients with RA who have interstitial lung disease (ILD) and to assess the utility of previously developed mortality staging systems [gender, age, lung physiology (GAP) and ILD-GAP]. Methods: All patients with RA and ILD seen at the Mayo Clinic from 1998 to 2014 were identified and manually screened for study inclusion. RA disease characteristics and pulmonary findings including high-resolution CT and pulmonary function testing were evaluated. Survival was estimated using Kaplan-Meier methods. GAP and ILD-GAP models were evaluated using c-statistics and standardized incidence ratios. Results: The study included 181 patients with RA-associated ILD (96% Caucasian; 48% females; 37% never-smokers). The mean age at ILD diagnosis was 67.4 years ( s . d . 9.9). The median time from RA diagnosis to ILD was 4.9 years (range -10.9-48.1). The median follow-up was 3.1 years (range 0.01-14.8). Age, RA disease duration and low initial diffusing capacity for carbon monoxide were predictive of premature mortality in multivariate modelling. Sex, smoking status, obstructive lung disease, seropositivity and erosive disease were not associated with mortality. The 5-year survival rate was 59.7% (95% CI 51.5, 69.2). Survival did not differ between usual interstitial pneumonia, non-specific interstitial pneumonia and organizing pneumonia ( P = 0.42). The GAP model performed well in this cohort for both discrimination and calibration (c-statistic 0.71, standardized incidence ratio 0.97). Conclusion: In this large single-centre cohort of patients with RA-ILD, most patients were seropositive and had a history of smoking. ILD most commonly occurred after the RA diagnosis. Mortality was high and did not differ among the types. The GAP model may be useful in assessing mortality risk. PMID- 27940588 TI - A multicentre study of 95 biopsy-proven cases of renal disease in primary Sjogren's syndrome. AB - Objective.: Renal involvement is a rare event during primary SS (pSS). We aimed to describe the clinico-biological and histopathological characteristics of pSS related nephropathy and its response to treatment. Methods.: We conducted a French nationwide, retrospective, multicentre study including pSS patients fulfilling American-European Consensus Group criteria or enlarged American European Consensus Group criteria, and with biopsy-proven renal involvement. Results.: A total of 95 patients were included (median age 49 years). An estimated glomerular filtration rate (eGFR) of <60 ml/min was found in 82/95 patients (86.3%). Renal biopsy demonstrated tubulointerstitial nephritis (TIN) in 93 patients (97.9%), and frequent (75%) plasma cell infiltrates. Glomerular lesions were found in 22 patients (23.2%), mainly related to cryoglobulin. The presence of anti-SSA (76.8%) and anti-SSB (53.8%) antibodies was particularly frequent among patients with TIN and was associated with a worse renal prognosis. Eighty-one patients (85.3%) were treated, with CSs in 80 (98.8%) and immunosuppressive agents (mostly rituximab) in 21 cases (25.9%). Despite marked interstitial fibrosis at initial biopsy, kidney function improved significantly during the 12-month period following diagnosis (final eGFR 49.9 vs 39.8 ml/min/1.73 m 2 at baseline, P < 0.001). No proven benefit of immunosuppressive agents over steroid therapy alone was found in this study. Conclusion.: Renal involvement of pSS is mostly due to TIN with marked T, B and especially plasma cell infiltration. Renal dysfunction is usually isolated but can be severe. Use of CSs can improve the eGFR, but further studies are needed to define the best therapeutic strategy in this disease. PMID- 27940590 TI - Primary myocardial disease in scleroderma-a comprehensive review of the literature to inform the UK Systemic Sclerosis Study Group cardiac working group. AB - Cardiac disease is prevalent in SSc and associated with a poor prognosis. Differentiating primary myocardial disease (SSc-cardiomyopathy) from ischaemic heart disease is difficult and the disease phenotype most at risk is unclear. A comprehensive literature review was performed to inform the UK Systemic Sclerosis Study Group for cardiac disease tasked with producing a best practice pathway for the management of cardiac disease in SSc. This review describes the prevalence of SSc-cardiomyopathy, its associated greater mortality and various manifestations (e.g. heart failure, arrhythmias and diastolic dysfunction). The limited evidence suggests SSc-cardiomyopathy is associated with other poor prognostic indicators, including diffuse cutaneous disease, positive SSc-specific serology, black ethnicity, older age at disease onset, tendon friction rubs, abnormal nail-fold capillaroscopy and worse quality-of-life scores. Differentiating SSc cardiomyopathy from ischaemic heart disease requires well-planned studies. Non invasive investigative techniques are improving the understanding of its pathophysiological basis. PMID- 27940589 TI - IL37 dampens the IL1beta-induced catabolic status of human OA chondrocytes. AB - Objective: A crucial feature of OA is cartilage degradation. This process is mediated by pro-inflammatory cytokines, among other factors, via induction of matrix-degrading enzymes. Interleukin 37 (IL37) is an anti-inflammatory cytokine and is efficient in blocking the production of pro-inflammatory cytokines during innate immune responses. We hypothesize that IL37 is therapeutic in treating the inflammatory cytokine cascade in human OA chondrocytes and can act as a counter regulatory cytokine to reduce cartilage degradation in OA. Methods: Human OA cartilage was obtained from patients undergoing total knee or hip arthroplasty. Immunohistochemistry was applied to study IL37 protein expression in cartilage biopsies from OA patients. Induction of IL37 expression by IL1beta, OA synovium conditioned medium and TNFalpha was investigated in human OA chondrocytes. Adenoviral overexpression of IL37 followed by IL1beta stimulation was performed to investigate the anti-inflammatory potential of IL37. Results: IL37 expression was detected in cartilage biopsies of OA patients and induced by IL1beta. After IL1beta stimulation, increased IL1beta, IL6 and IL8 expression was observed in OA chondrocytes. Elevated IL37 levels diminished the IL1beta-induced IL1beta , IL6 and IL8 gene levels and IL1beta and IL8 protein levels. In addition to the reduction in pro-inflammatory cytokine expression, IL37 reduced MMP1 , MMP3 , MMP13 and disintegrin and metalloproteinase with thrombospondin motifs 5 gene levels and MMP3 and MMP13 protein levels. Conclusion: IL37 is induced by IL1beta, and IL37 itself reduced IL1beta, IL6 and IL8 production, indicating that IL37 is able to induce a counter-regulatory anti-inflammatory feedback loop in chondrocytes. In addition, IL37 dampens catabolic enzyme expression. This supports IL37 as a potential therapeutic target in OA. PMID- 27940591 TI - Granulomatosis with polyangiitis according to geographic origin and ethnicity: clinical-biological presentation and outcome in a French population. AB - Objectives: Granulomatosis with polyangiitis (GPA) mainly affects white Europeans, but rarely GPA may also affect non-Europeans. This study aimed to describe GPA clinical-biological presentation and outcome in black sub-Saharan Africans and Afro-Caribbeans and in North Africans. Methods: Among 914 GPA patients included in the French Vasculitis Study Group database, geographic origin and ethnicity were known for 760. Clinical-biological presentations and outcomes of white Europeans vs black sub-Saharans and Afro-Caribbeans and vs North Africans were analysed. Results: Among the 760 patients, 689 (91%) were white Europeans, 33 (4.3%) were North Africans and 22 (2.9%) were sub-Saharans (n = 8) or Afro-Caribbeans (French West Indies, n = 14). Black sub-Saharans and Afro Caribbeans, compared with white Europeans, were significantly younger at GPA diagnosis (P = 0.003), had more frequent central nervous system involvement (P = 0.02), subglottic stenosis (P = 0.002) and pachymeningitis (P = 0.009), and tended to have more frequent chondritis and retroorbital tumour. Median serum creatinine levels and Birmingham Vasculitis Activity Score were significantly lower in sub-Saharans and Afro-Caribbeans (P = 0.002 and P = 0.003, respectively). In contrast, in comparison with white Europeans, North Africans had only less frequent arthralgias (P = 0.004). Time to relapse was shorter for black sub-Saharans and Afro-Caribbeans compared with white Europeans [adjusted HR = 1.96 (95% CI: 1.09, 3.51) (P = 0.02)], and did not differ for North Africans. In contrast, overall survival was not significantly different according to ethnicity. Conclusion: Our findings indicated different GPA clinical presentations in white Europeans and sub-Saharans and Afro-Caribbeans, with black patients having more frequent severe granulomatous manifestations. In addition, time to relapse was significantly shorter for black sub-Saharans and Afro Caribbeans compared with white Europeans. PMID- 27940593 TI - Chronic hepatitis E in a patient with rheumatoid arthritis treated with adalimumab and methotrexate. PMID- 27940592 TI - CD3Z hypermethylation is associated with severe clinical manifestations in systemic lupus erythematosus and reduces CD3zeta-chain expression in T cells. AB - Objective: The importance of hypomethylation in SLE is well recognized; however, the significance of hypermethylation has not been well characterized. We screened hypermethylated marks in SLE and investigated their possible implications. Methods: DNA methylation marks were screened in SLE whole-blood DNA by microarray, and two marks ( CD3Z and VHL hypermethylations) were confirmed by a methylation single-base extension method in two independent ethnic cohorts consisting of 207 SLE patients and 151 controls. The correlation with clinical manifestations and the genetic influence on those epigenetic marks were analysed. Results: Two epigenetic marks, CD3Z and VHL hypermethylation, were significantly correlated with SLE: CD3Z hypermethylation (odds ratio = 7.76; P = 1.71 * 10 -13 ) and VHL hypermethylation (odds ratio = 3.77; P = 3.20 * 10 -8 ), and the increased CD3Z methylation was correlated with downregulation of the CD3zeta chain in SLE T cells. In addition, less genetic influence on CD3Z methylation relative to VHL methylation was found in analyses of longitudinal and twin samples. Furthermore, a higher CD3Z methylation level was significantly correlated with a higher SLE disease activity index and more severe clinical manifestations, such as proteinuria, haemolytic anaemia and thrombocytopenia, whereas VHL hypermethylation was not. Conclusion: CD3Z hypermethylation is an SLE risk factor that can be modified by environmental factors and is associated with more severe SLE clinical manifestations, which are related to deranged T cell function by downregulating the CD3zeta-chain. PMID- 27940594 TI - The comparison of magnetic resonance imaging and radiographs to assess structural progression over 5 years in hand osteoarthritis. AB - Objective: . The aim was to explore the agreement between 1.0 T MRI and conventional radiography (CR) to detect progression of hand OA over 5 years and the associations between structural progression and incident joint tenderness. Methods: Paired radiographs and paired MRIs of the second-fifth IP joints of the dominant hand from 69 hand OA patients were read for osteophytes, joint space narrowing and erosions. Patients with two or more joints demonstrating progression of any structural feature(s) were classified as progressors per imaging modality. Agreement between methods to detect progressors was evaluated with kappa and intraclass correlation coefficients. At the joint level, the associations between methods to detect progression were explored with generalized estimating equations. Likewise, we analysed the associations between progression per imaging modality and incident pain. Results: MRI (58.0%) and CR (62.3%) detected similar numbers of progressors. The agreement between methods to detect progressors was good (kappa = 0.61). We found good agreement between methods regarding the number of progressive joints (intraclass correlation coefficient = 0.61, 95% CI: 0.43, 0.76). At the joint level, MRI progression was associated with radiographic progression (P < 0.001). Incident joint tenderness was more common in joints with progression by MRI and CR, but statistically significance was not reached. Conclusion: Both 1.0 T MRI and CR detect a similar amount of progression over 5 years in patients with hand OA, although not in exactly the same joints. As CR assesses more joints for a lower cost, CR should be the imaging modality of choice rather than 1.0 T MRI in observational studies with a long period of follow-up. PMID- 27940595 TI - The association of vascular risk factors with visual loss in giant cell arteritis. AB - Objective: Blindness is a recognized complication of GCA; however, the frequency of and risk factors for this complication have not been firmly established. The aim of this study was to examine the incidence and determinants of blindness in patients with GCA, using a large international cohort. Methods: The analysis was conducted among subjects recruited into the Diagnosis and Classification Criteria in Vasculitis Study. The study captures consecutive patients presenting to clinic based physicians. New-onset blindness was assessed 6 months after diagnosis by completion of the Vasculitis Damage Index. Logistic regression analysis was used to assess the association between blindness and clinical variables. Results: Of 433 patients with GCA from 26 countries, 7.9% presented with blindness in at least one eye at 6 months. Risk factors identified at baseline for blindness at 6 months were identified and included prevalent stroke [odds ratio (OR) = 4.47, 95% CI: 1.30, 15.41] and peripheral vascular disease (OR = 10.44, 95% CI: 2.94, 37.03). Conclusion: This is the largest study to date of subjects with incident GCA and confirms that blindness remains a common complication of disease and is associated with established vascular disease. : Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov , NCT01066208. PMID- 27940596 TI - Predicting cardiopulmonary involvement in patients with systemic sclerosis: complementary value of nailfold videocapillaroscopy patterns and disease-specific autoantibodies. AB - Objective: To evaluate the prevalence of anti-extractable nuclear antigen (anti ENA) antibodies in Dutch SSc patients and the predictive power of the combination of specific anti-ENA antibodies and nailfold videocapillaroscopy (NVC) patterns to improve identification of patients with high risk for cardiopulmonary involvement. Methods: A total of 287 patients (79%) from the Leiden SSc-Cohort had data available on NVC-pattern (no SSc-specific, early, active, late) and anti ENA antibodies. Associations between anti-ENA/NVC combinations with cardiopulmonary parameters were explored using logistic regression. Results: Prevalence of ACA was 37%, anti-Scl-70 24%, anti-RNP 9%, anti-RNAPIII 5%, anti fibrillarin 4%, anti-Pm/Scl 3%, anti-Th/To 0.3% and anti-Ku 1.4%. NVC showed a SSc-specific pattern in 88%: 10% early, 42% active and 36% late. The prevalence of different NVC patterns was equally distributed among specific anti-ENA antibodies, except for the absence of early pattern in anti-RNP positive patients. Fifty-one percent had interstitial lung disease (ILD), 59% had decreased diffusion capacity for carbon monoxide and 16% systolic pulmonary artery pressure >35 mmHg (sPAP?). Regardless of ENA-subtype, NVC-pattern showed a stable association with presence of ILD or sPAP?. For ILD, the odds ratios (ORs) were 1.3-1.4 ( P < 0.05 for analyses with anti-RNAPIII, anti-RNP). For diffusion capacity for carbon monoxide, the OR was 1.5 ( P < 0.05 for analyses with ACA, anti-Scl-70, anti-RNAPIII, anti-RNP). For sPAP?, the ORs were 2.2-2.4 ( P < 0.05 for analyses with anti-RNAPIII, anti-RNP). Conclusion: In Dutch SSc patients, all SSc-specific auto-antibodies were found, with ACA and anti-Scl-70 being the most prevalent. Strikingly, the association between NVC-pattern and heart/lung involvement was independent of specific anti-ENA antibodies, which might indicate microangiopathy is an important cause of organ involvement. PMID- 27940597 TI - Analysis of anti-topoisomerase I antibodies in patients with systemic sclerosis before and after autologous stem cell transplantation. AB - Objectives: To evaluate the effect of autologous stem cell transplantation (aSCTrans) on antibody (Ab) reactivity towards topo I in patients with SSc, and to see whether it may correlate with clinical outcome after aSCTrans. Methods: Eighteen anti-topo/Scl70-positive patients with SSc in whom non-myeloablative aSCTrans had been performed were analysed. Seven patients showed good response without relapse for several years (group 1), eight primarily responded but later relapsed and three did not respond (group 2). A total of 74 sera were analysed at different time points and tested by ELISA against full length ( fl ) topo I, truncated ( tr ) topo I and a previously identified immunodominant epitope covering amino acid 489-573. Results: Eighty-three percent had IgG Abs to topo fl and topo tr . Ab reactivity significantly decreased after aSCTrans, but remained positive in 10 of the 11 patients followed for up to 24 months. The decrease did not correlate with the clinical outcome after aSCTrans. Fifty-six percent of the patients reacted with topo489-573, and reactivity was nearly confined to group 2. There was no correlation between Ab reactivity towards topo fl or topo489-573 and the modified Rodnan Skin Score before aSCTrans or its decrease after aSCTrans. Conclusions: Although aSCTrans is a good treatment option in patients with progressive SSc, it does not abrogate Ab reactivity towards topo I. The presence of anti-topo489-573 Abs before aSCTrans may indicate a less favourable course after aSCTrans. PMID- 27940598 TI - Regression of microangiopathy in antisynthetase syndrome. PMID- 27940600 TI - The Prion-Like Behavior of Assembled Tau in Transgenic Mice. AB - Tauopathies constitute neurodegenerative diseases that are characterized by the intracellular deposition of filaments made of hyperphosphorylated tau protein. The pattern of tau deposition in Alzheimer's disease follows a stereotypical progression, with the first lesions appearing in the locus coeruleus and entorhinal cortex, from where they appear to spread to the hippocampus and neocortex. Propagation of pathological tau is also characteristic of argyrophilic grain disease, where the lesions seem to spread through distinct regions of the limbic system. In chronic traumatic encephalopathy, tauopathy appears to spread from the neocortex to the brainstem. These findings implicate neuron-to-neuron propagation of tau aggregates. Isoform compositions and morphologies of tau filaments can differ between tauopathies, which is consistent with the existence of distinct tau strains. Here, we review recent findings that support prion-like mechanisms in the pathogenesis of tauopathies through the experimental use of transgenic mice. PMID- 27940599 TI - Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules. AB - Tau aggregation is linked to multiple neurodegenerative disorders that are collectively termed tauopathies. Small molecules are powerful probes of the aggregation process, helping to reveal the key steps and serving as diagnostics and reporters. Moreover, some of these small molecules may have potential as therapeutics. This review details how small molecules and chemical biology have helped to elucidate the mechanisms of tau aggregation and how they are being used to detect and prevent tau aggregation. In addition, we comment on how new insights into tau prions are changing the approach to small molecule discovery. PMID- 27940602 TI - Huntington's Disease: Mechanisms of Pathogenesis and Therapeutic Strategies. AB - Huntington's disease is a late-onset neurodegenerative disease caused by a CAG trinucleotide repeat in the gene encoding the huntingtin protein. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Finally, we outline some of the therapeutic strategies that are currently being pursued to slow down the disease. PMID- 27940603 TI - A rare case of plexiform angiomyxoid myofibroblastic tumor in the stomach which was diagnosed at the earliest stage in the literature. AB - Plexiform angiomyxoid myofibroblastic tumor (PAMT) is a rare gastric mesenchymal entity with a peculiar plexiform pattern, bland spindle cells and myxoid stroma rich in arborizing blood vessels. Here we report a 44-year-old Chinese woman with PAMT. Initially she was admitted for removal of a gastric antral'polyp' found on a routine examination 5 months previously. Our gastroscopy showed a 0.8 * 0.8 cm polyp-like mass in the antrum which protruded into the lumen. Endoscopic submucosal dissection (ESD) was performed to remove this mass en bloc. The specimen was carefully examined by pathologists, and the correct diagnosis of PAMT was finally made. The tumor in this case depicted typical histopathological and immunohistochemical features of gastric PAMT. This PAMT was not only the smallest on endoscopic examination in the literature but also-unlike the already reported PAMTs-exhibited a focal hyperechogenic lesion on endoscopic ultrasonography (EUS). This information highlights its value on how to identify a PAMT at its early stage. PMID- 27940601 TI - Binding Sites for Amyloid-beta Oligomers and Synaptic Toxicity. AB - In Alzheimer's disease (AD), insoluble and fibrillary amyloid-beta (Abeta) peptide accumulates in plaques. However, soluble Abeta oligomers are most potent in creating synaptic dysfunction and loss. Therefore, receptors for Abeta oligomers are hypothesized to be the first step in a neuronal cascade leading to dementia. A number of cell-surface proteins have been described as Abeta binding proteins, and one or more are likely to mediate Abeta oligomer toxicity in AD. Cellular prion protein (PrPC) is a high-affinity Abeta oligomer binding site, and a range of data delineates a signaling pathway leading from Abeta complexation with PrPC to neuronal impairment. Further study of Abeta binding proteins will define the molecular basis of this crucial step in AD pathogenesis. PMID- 27940604 TI - Rates of hospitalization among African American and Caucasian American patients with Crohn's disease seen at a tertiary care center. AB - BACKGROUND: There is equivocal evidence regarding differences in the clinical course and outcomes of Crohn's disease (CD) among African Americans compared with Caucasian Americans. We sought to analyze whether African Americans with CD are more likely to be hospitalized for CD-related complications when compared with Caucasian Americans with CD. METHODS: We conducted a retrospective cohort study including 909 African Americans and Caucasian Americans with CD who were seen at our tertiary care Inflammatory Bowel Disease (IBD) referral center between 2000 and 2013. We calculated the rate of hospitalization for CD-related complications among African Americans and Caucasian Americans separately. Zero-inflated Poisson regression models with robust variance estimates were used to estimate crude and multivariable adjusted rate ratios (RR) for CD-related hospitalizations. Multivariable adjusted models included adjustment for age, sex, duration of CD, smoking and CD therapy. RESULTS: The cumulative rate of CD-related hospital admissions was higher among African American patients compared with Caucasian American patients (395.6/1000 person-years in African Americans vs. 230.4/1000 person-years in Caucasian Americans). Unadjusted and multivariable adjusted rate ratios for CD-related hospitalization comparing African Americans and Caucasian Americans were 1.59 (95% confidence interval [95%CI]: 1.10-2.29; P=0.01) and 1.44 (95%CI: 1.02-2.03; P=0.04), respectively. CONCLUSIONS: African Americans with CD followed at a tertiary IBD-referral center had a higher rate for CD-related hospitalizations compared with Caucasian Americans. Future studies should examine whether socioeconomic status and biologic markers of disease status could explain the higher risk observed among African Americans. PMID- 27940605 TI - Temporal Processing Development in Chinese Primary School-Aged Children With Dyslexia. AB - This study aimed to investigate the development of visual and auditory temporal processing among children with and without dyslexia and to examine the roles of temporal processing in reading and reading-related abilities. A total of 362 Chinese children in Grades 1-6 were recruited from Taiwan. Half of the children had dyslexia, and the other half were typically developing children who matched the dyslexic group on age, intelligence, and gender. Our results indicate that for typically developing children, the visual and auditory modalities follow the same developmental trend: The children in first and second grades performed significantly worse than the older children. Among the children with dyslexia, however, significant improvements in the visual modality were observed with increasing age. Furthermore, although both modalities were important for all reading-related abilities and for Chinese character reading in first and second grades, the visual modality significantly predicted only orthographic knowledge and Chinese character reading in third and fourth grades. In contrast, the auditory modality affected only phonological awareness. In fifth and sixth grades, only visual temporal processing slightly contributed to the orthographic knowledge and Chinese character reading of the dyslexic group. Also, the relationship between temporal processing and Chinese character reading is strongly influenced by age. PMID- 27940606 TI - Childhood Abuse and Current Intimate Partner Violence: A Population Study in Hong Kong. AB - Previous studies have established that childhood violence victimization is associated with current experience of intimate partner violence (IPV). Existing literature, however, focused exclusively on female survivors and physical IPV and relied on non-representative samples. The present study examined the associations between life adversities and IPV using a representative sample of 1,239 men and women aged between 18 and 97. Participants provided information on their demographic characteristics, lifetime history of adverse life events, and past year IPV. Results show that IPV is common with 32.8% of the participants having reported past year psychological aggression, 4.5% reported physical abuse, and 1.1% reported injury. Various life adversities were also common with 21.7% having reported family disruption, 6% having experienced abuse or witnessing violence, and 2.1% life-threatening events. Logistic regression analyses revealed that experiencing abuse or witnessing violence in childhood is associated with a greater risk of past year psychological aggression, physical assault, and injury. Results were significant even after controlling for demographics and other life adversities. Family disruption in childhood was associated with increased risk of past year injury, but the association diminished after controlling for the rest of the variables. Experience of life-threatening events was not associated with any form of past year IPV. Altogether, our results point out that childhood victimization, especially physical abuse by parents, is associated with future long-term risk of IPV. This highlights the importance of early prevention and intervention for child abuse. PMID- 27940608 TI - Surface defects generated by intrinsic origins on 4H-SiC epitaxial wafers observed by scanning electron microscopy. AB - Surface defects with intrinsic origins in an epitaxial layer on 4H-SiC wafers were observed by scanning electron microscopy. Commercially available 4H-SiC epitaxial wafers with 4 degrees or 8 degrees off-axis angles from the [0001] direction toward the [112-0] direction were used in this experiment. Various types of defects, including micropipes, pits, carrots, stacking faults and wide terrace and high step structures, were observed and clearly identified. The defects are presented as a catalog that can be used in the identification of surface defects. PMID- 27940609 TI - Surface defects generated by extrinsic origins on 4H-SiC epitaxial-wafers observed by scanning electron microscopy. AB - Surface defects on 4H-SiC wafers with an epitaxial layer grown by chemical vapor deposition (CVD) were observed using scanning electron microscopy (SEM). Commercially available epitaxial-wafers with four or eight deg-off surface from the [0001] toward the [112-0] directions were used for this experiment. 3C-SiC particles, triangular-defects, comets, obtuse-triangular-shaped-defects and micro holes were identified in the SEM images. This paper can be considered as a catalog of SEM images and descriptions of various surface defects for 4H-SiC wafers with a CVD-grown epilayer. PMID- 27940607 TI - Synergistic drug combinations from electronic health records and gene expression. AB - Objective: Using electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding. Method: We applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis. Results: From EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence. Conclusions: This is a proof of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing. PMID- 27940610 TI - RPAN: rice pan-genome browser for ~3000 rice genomes. AB - A pan-genome is the union of the gene sets of all the individuals of a clade or a species and it provides a new dimension of genome complexity with the presence/absence variations (PAVs) of genes among these genomes. With the progress of sequencing technologies, pan-genome study is becoming affordable for eukaryotes with large-sized genomes. The Asian cultivated rice, Oryza sativa L., is one of the major food sources for the world and a model organism in plant biology. Recently, the 3000 Rice Genome Project (3K RGP) sequenced more than 3000 rice genomes with a mean sequencing depth of 14.3*, which provided a tremendous resource for rice research. In this paper, we present a genome browser, Rice Pan genome Browser (RPAN), as a tool to search and visualize the rice pan-genome derived from 3K RGP. RPAN contains a database of the basic information of 3010 rice accessions, including genomic sequences, gene annotations, PAV information and gene expression data of the rice pan-genome. At least 12 000 novel genes absent in the reference genome were included. RPAN also provides multiple search and visualization functions. RPAN can be a rich resource for rice biology and rice breeding. It is available at http://cgm.sjtu.edu.cn/3kricedb/ or http://www.rmbreeding.cn/pan3k. PMID- 27940611 TI - Analysis of Annotation and Differential Expression Methods used in RNA-seq Studies in Crustacean Systems. AB - In the field of crustacean biology, usage of RNA-seq to study gene expression is rapidly growing. Major advances in sequencing technology have contributed to the ability to examine complex patterns of genome activity in a wide range of organisms that are extensively used for comparative physiology, ecology and evolution, environmental monitoring, and commercial aquaculture. Relative to insect and vertebrate model organisms, however, information on the organization of crustacean genomes is virtually nonexistent, making de novo transcriptome assembly, annotation and quantification problematic and challenging. We present here a summary of the methodologies and software analyses employed in 23 recent publications, which describe de novo transcriptome assembly, annotation, and differential gene expression in a variety of crustacean experimental systems. We focus on establishing a series of best practices that will allow for investigators to produce datasets that are understandable, reproducible, and of general utility for related analyses and cross-study comparisons. PMID- 27940612 TI - Introduction to Symposium: New Frontiers in the Integrative Study of Animal Behavior: Nothing in Neuroscience Makes Sense Except in the Light of Behavior. PMID- 27940613 TI - Evaluation of Possible Proximate Mechanisms Underlying the Kinship Theory of Intragenomic Conflict in Social Insects. AB - Kinship theory provides a universal framework in which to understand the evolution of altruism, but there are many molecular and genetic mechanisms that can generate altruistic behaviors. Interestingly, kinship theory specifically predicts intragenomic conflict between maternally-derived alleles (matrigenes) and paternally-derived alleles (patrigenes) over the generation of altruistic behavior in cases where the interests of the matrigenes and patrigenes are not aligned. Under these conditions, individual differences in selfish versus altruistic behavior are predicted to arise from differential expression of the matrigenes and patrigenes (parent-specific gene expression or PSGE) that regulate selfish versus altruistic behaviors. As one of the leading theories to describe PSGE and genomic imprinting, kinship theory has been used to generate predictions to describe the reproductive division of labor in social insect colonies, which represents an excellent model system to test the hypotheses of kinship theory and examine the underlying mechanisms driving it. Recent studies have confirmed the predicted differences in the influence of matrigenes and patrigenes on reproductive division of labor in social insects, and demonstrated that these differences are associated with differences in PSGE of key genes involved in regulating reproductive physiology, providing further support for kinship theory. However, the mechanisms mediating PSGE in social insects, and how PSGE leads to differences in selfish versus altruistic behavior, remain to be determined. Here, we review the available supporting evidence for three possible epigenetic mechanisms (DNA methylation, piRNAs, and histone modification) that may generate PSGE in social insects, and discuss how these may lead to variation in social behavior. PMID- 27940614 TI - Host Competence: An Organismal Trait to Integrate Immunology and Epidemiology. AB - The new fields of ecological immunology and disease ecology have begun to merge, and the classic fields of immunology and epidemiology are beginning to blend with them. This merger is occurring because the integrative study of host-parasite interactions is providing insights into disease in ways that traditional methods have not. With the advent of new tools, mathematical and technological, we could be on the verge of developing a unified theory of infectious disease, one that supersedes the barriers of jargon and tradition. Here we argue that a cornerstone of any such synthesis will be host competence, the propensity of an individual host to generate new infections in other susceptible hosts. In the last few years, the emergence of systems immunology has led to novel insight into how hosts control or eliminate pathogens. Most such efforts have stopped short of considering transmission and the requisite behaviors of infected individuals that mediate it, and few have explicitly incorporated ecological and evolutionary principles. Ultimately though, we expect that the use of a systems immunology perspective will help link suborganismal processes (i.e., health of hosts and selection on genes) to superorganismal outcomes (i.e., community-level disease dynamics and host-parasite coevolution). Recently, physiological regulatory networks (PRNs) were cast as whole-organism regulatory systems that mediate homeostasis and hence link suborganismal processes with the fitness of individuals. Here, we use the PRN construct to develop a roadmap for studying host competence, taking guidance from systems immunology and evolutionary ecology research. We argue that PRN variation underlies heterogeneity in individual host competence and hence host-parasite dynamics. PMID- 27940617 TI - Functional (Secondary) Adaptation to an Aquatic Life in Vertebrates: An Introduction to the Symposium. AB - One of the great transformations in evolution of vertebrates has been the return to the aquatic environment after the conquest of terrestrial ecosystems. With structural and physiological characteristics adapted to function on land, the various non-piscine taxa had to modify these characteristics to perform in water. Secondary aquatic vertebrates successfully transformed mechanisms for feeding, locomotion, osmoregulation, and sensory systems to function and thrive in an aqueous environment. This symposium emphasized the changes that had to be acquired to operate in the water with morphologies previously evolved to function on land. It brought together researchers working on different aspects of functional biology and on various taxa in order to illustrate the diversity in the required adaptations: the numerous convergences as well as the specific adaptive traits. The collection of talks, posters, and of the contributions to this special volume highlights recent advances in the understanding of the functional adaptations associated to secondary adaptation to an aquatic lifestyle in vertebrates. PMID- 27940615 TI - The Role of VIP in Social Behavior: Neural Hotspots for the Modulation of Affiliation, Aggression, and Parental Care. AB - Although the modulation of social behaviors by most major neurochemical systems has been explored, there are still standouts, including the study of vasoactive intestinal polypeptide (VIP). VIP is a modulator of circadian, reproductive, and seasonal rhythms and is well known for its role in reproductive behavior, as it is the main vertebrate prolactin-releasing hormone. Originally isolated as a gut peptide, VIP and its cognate receptors are present in virtually every brain area that is important for social behavior, including all nodes of the core "social behavior network" (SBN). Furthermore, VIP cells show increased transcriptional activity throughout the SBN in response to social stimuli. Using a combination of comparative and mechanistic approaches in socially diverse species of estrildid finches and emberizid sparrows, we have identified neural "hotspots" in the SBN that relate to avian affiliative behavior, as well as neural "hotspots" that may represent critical nodes underlying a trade-off between aggression and parental care. Specifically, we have found that: (1) VIP fiber densities and VIP receptor binding in specific brain sites, such as the lateral septum, medial extended amygdala, arcopallium, and medial nidopallium, correlate with species and/or seasonal differences in flocking behavior, and (2) VIP cells and fibers within the anterior hypothalamus-caudocentral septal circuit relate positively to aggression and negatively to parental care while VIP elements in the mediobasal hypothalamus relate negatively to aggression and positively to parental care. Thus, while a given behavior or social context likely activates VIP circuitry throughout the SBN and beyond, key brain sites emerge as potential "hotspots" for the modulation of affiliation, aggression, and parental care. PMID- 27940618 TI - From Teeth to Baleen and Raptorial to Bulk Filter Feeding in Mysticete Cetaceans: The Role of Paleontological, Genetic, and Geochemical Data in Feeding Evolution and Ecology. AB - The origin of baleen and filter feeding in mysticete cetaceans occurred sometime between approximately 34 and 24 million years ago and represents a major macroevolutionary shift in cetacean morphology (teeth to baleen) and ecology (raptorial to filter feeding). We explore this dramatic change in feeding strategy by employing a diversity of tools and approaches: morphology, molecules, development, and stable isotopes from the geological record. Adaptations for raptorial feeding in extinct toothed mysticetes provide the phylogenetic context for evaluating morphological apomorphies preserved in the skeletons of stem and crown edentulous mysticetes. In this light, the presence of novel vascular structures on the palates of certain Oligocene toothed mysticetes is interpreted as the earliest evidence of baleen and points to an intermediate condition between an ancestral condition with teeth only and a derived condition with baleen only. Supporting this step-wise evolutionary hypothesis, evidence from stable isotopes show how changes in dental chemistry in early toothed mysticetes tracked the changes in diet and environment. Recent discoveries also demonstrate how this transition was made possible by radical changes in cranial ontogeny. In addition, genetic mutations and the possession of dental pseudogenes in extant baleen whales support a toothed ancestry for mysticetes. Molecular and morphological data also document the dramatic developmental shifts that take place in extant fetal baleen whales, in skull development, resorption of a fetal dentition and growth of baleen. The mechanisms involved in this complex evolutionary transition that entails multiple, integrated aspects of anatomy and ecology are only beginning to be understood, and future work will further clarify the processes underlying this macroevolutionary pattern. PMID- 27940616 TI - Dissecting the Transcriptional Patterns of Social Dominance across Teleosts. AB - In many species, under varying ecological conditions, social interactions among individuals result in the formation of dominance hierarchies. Despite general similarities, there are robust differences among dominance hierarchies across species, populations, environments, life stages, sexes, and individuals. Understanding the proximate mechanisms underlying the variation is an important step toward understanding the evolution of social behavior. However, physiological changes associated with dominance, such as gonadal maturation and somatic growth, often complicate efforts to identify the specific underlying mechanisms. Traditional gene expression analyses are useful for generating candidate gene lists, but are biased by choice of significance cut-offs and difficult to use for between-study comparisons. In contrast, complementary analysis tools allow one to both test a priori hypotheses and generate new hypotheses. Here we employ a meta-analysis of high-throughput expression profiling experiments to investigate the gene expression patterns that underlie mechanisms and evolution of behavioral social phenotypes. Specifically, we use a collection of datasets on social dominance in fish across social contexts, sex, and species. Using experimental manipulation to produce female dominance hierarchies in the cichlid Astatotilapia burtoni, heralded as a genomic model of social dominance, we generate gene lists, and assess molecular gene modules. In the dominant female gene expression profile, we demonstrate a strong pattern of up-regulation of genes previously identified as having male-biased expression and furthermore, compare expression biases between male and female dominance phenotypes. Using a threshold-free approach to identify correlation throughout ranked gene lists, we query previously published datasets associated with maternal behavior, alternative reproductive tactics, cooperative breeding, and sex-role reversal to describe correlations among these various neural gene expression profiles associated with different instances of social dominance. These complementary approaches capitalize on the high-throughput gene expression profiling from similar behavioral phenotypes in order to address the mechanisms associated with social dominance behavioral phenotypes. PMID- 27940619 TI - "On the Fence" versus "All in": Insights from Turtles for the Evolution of Aquatic Locomotor Specializations and Habitat Transitions in Tetrapod Vertebrates. AB - Though ultimately descended from terrestrial amniotes, turtles have deep roots as an aquatic lineage and are quite diverse in the extent of their aquatic specializations. Many taxa can be viewed as "on the fence" between aquatic and terrestrial realms, whereas others have independently hyperspecialized and moved "all in" to aquatic habitats. Such differences in specialization are reflected strongly in the locomotor system. We have conducted several studies to evaluate the performance consequences of such variation in design, as well as the mechanisms through which specialization for aquatic locomotion is facilitated in turtles. One path to aquatic hyperspecialization has involved the evolutionary transformation of the forelimbs from rowing, tubular limbs with distal paddles into flapping, flattened flippers, as in sea turtles. Prior to the advent of any hydrodynamic advantages, the evolution of such flippers may have been enabled by a reduction in twisting loads on proximal limb bones that accompanied swimming in rowing ancestors, facilitating a shift from tubular to flattened limbs. Moreover, the control of flapping movements appears related primarily to shifts in the activity of a single forelimb muscle, the deltoid. Despite some performance advantages, flapping may entail a locomotor cost in terms of decreased locomotor stability. However, other morphological specializations among rowing species may enhance swimming stability. For example, among highly aquatic pleurodiran turtles, fusion of the pelvis to the shell appears to dramatically reduce motions of the pelvis compared to freshwater cryptodiran species. This could contribute to advantageous increases in aquatic stability among predominantly aquatic pleurodires. Thus, even within the potential constraints of a body plan in which the body is encased by a shell, turtles exhibit diverse locomotor capacities that have enabled diversification into a wide range of aquatic habitats. PMID- 27940620 TI - How to Build a Deep Diver: The Extreme Morphology of Mesoplodonts. AB - Mesoplodont beaked whales are extreme divers, diving for over 45 mins and to depths of over 800 m. These dives are of similar depth and duration to those of the giant sperm whale (Physeter macrocephalus) whose body mass can be 50 times larger. Velten et al. (2013) provided anatomical data that demonstrated that on board oxygen stores were sufficient to aerobically support the extreme dives of mesoplodonts if their diving metabolic rates are low. Because no physiological data yet exist, we utilized an anatomical approach-the body composition technique to examine the relative metabolic rates of mesoplodonts. We utilized a systematic mass dissection protocol to compare the body composition of mesoplodonts with those of two short duration, shallow divers-the harbor porpoise (Phocoena phocoena) and bottlenose dolphin (Tursiops truncatus). We then investigated the body composition of two other extreme divers, the southern elephant seal (Mirounga leonina) and P. macrocephalus using data from the literature. Our results demonstrate that extreme divers invest a smaller percentage of their total body mass (TBM) in metabolically expensive brain and viscera, and a larger percent of their TBM in inexpensive integument, bone, and muscle, than do the shallow divers. Deep divers also share features of their locomotor muscle that contribute to relatively low tissue metabolic rates and high oxygen storage capacity, including large muscle fiber diameters, low mitochondrial volume densities, and high myoglobin concentrations. One feature of the locomotor muscle of mesoplodonts, though, is unique among deep divers investigated to date. Rather than having an endurance athlete's muscle fiber profile, dominated by slow oxidative fibers, mesoplodonts possess a sprinter's profile, dominated by fast glycolytic fibers. Velten et al. (2013) hypothesized that these fibers are likely inactive during routine swimming and provide a large, metabolically inexpensive oxygen store for the slow oxidative fibers to aerobically power swimming. We suggest that future anatomical analyses, coupled with performance data transduced through tagging studies, will enhance our understanding of the extreme diving capabilities of marine mammals. PMID- 27940622 TI - Errata. PMID- 27940623 TI - Errata. PMID- 27940624 TI - Anti-adalimumab antibodies in psoriasis: lack of clinical utility and laboratory evidence. AB - OBJECTIVE: Adalimumab has proven effective in psoriasis; however, secondary failure may result from the drug's immunogenicity. Prevalence data on the immunogenicity of biologicals, and of adalimumab in particular, are highly variable. We investigated the prevalence of anti-adalimumab antibodies and the association with clinical indexes and tumour necrosis factor alpha (TNFalpha) serum levels in psoriatic patients. DESIGN: Case-control, longitudinal. SETTING: Single centre. PARTICIPANTS: Patient groups: I (n=20) receiving biological therapies after switching from adalimumab; II (n=30) ongoing adalimumab therapy; III (n=30) novel adalimumab therapy; IV (n=15) biological therapies other than adalimumab.Healthy subjects: (group V; n=15) never treated with immunosuppressants or biologicals. INTERVENTIONS: All groups were tested at enrolment. Group II was also tested at 12 months, and group III at 1, 3, and 6 months. PRIMARY AND SECONDARY OUTCOME MEASURES: Standard clinical evaluations (Psoriasis Area Severity Index (PASI)), blood samples and two-site ELISA-based measurement of serum adalimumab trough levels, anti-adalimumab antibodies and TNFalpha. RESULTS: The false-positive rate was 23% for adalimumab detection and 22% for anti-adalimumab antibodies in patients naive to adalimumab. Spurious positivity for anti-adalimumab antibodies (one-time-point positivity in group III during follow-up) accounted for 33% of the total. The prevalence of anti-drug antibodies was highest (87%) in group I patients. No correlations were found between the presence of anti-adalimumab antibodies or adalimumab levels and changes in PASI scores. CONCLUSIONS: High variability of results, high prevalence of false-positives and lack of association between anti-adalimumab antibodies and TNFalpha level/PASI score limit this assay's usefulness. Accurate clinical evaluation is key to early identification of treatment failures. PMID- 27940625 TI - Effect of the number of request calls on the time from call to hospital arrival: a cross-sectional study of an ambulance record database in Nara prefecture, Japan. AB - OBJECTIVES: In Japan, ambulance staff sometimes must make request calls to find hospitals that can accept patients because of an inadequate information sharing system. This study aimed to quantify effects of the number of request calls on the time interval between an emergency call and hospital arrival. DESIGN AND SETTING: A cross-sectional study of an ambulance records database in Nara prefecture, Japan. CASES: A total of 43 663 patients (50% women; 31.2% aged 80 years and over): (1) transported by ambulance from April 2013 to March 2014, (2) aged 15 years and over, and (3) with suspected major illness. PRIMARY OUTCOME MEASURES: The time from call to hospital arrival, defined as the time interval from receipt of an emergency call to ambulance arrival at a hospital. RESULTS: The mean time interval from emergency call to hospital arrival was 44.5 min, and the mean number of requests was 1.8. Multilevel linear regression analysis showed that ~43.8% of variations in transportation times were explained by patient age, sex, season, day of the week, time, category of suspected illness, person calling for the ambulance, emergency status at request call, area and number of request calls. A higher number of request calls was associated with longer time intervals to hospital arrival (addition of 6.3 min per request call; p<0.001). In an analysis dividing areas into three groups, there were differences in transportation time for diseases needing cardiologists, neurologists, neurosurgeons and orthopaedists. CONCLUSIONS: The study revealed 6.3 additional minutes needed in transportation time for every refusal of a request call, and also revealed disease-specific delays among specific areas. An effective system should be collaboratively established by policymakers and physicians to ensure the rapid identification of an available hospital for patient transportation in order to reduce the time from the initial emergency call to hospital arrival. PMID- 27940626 TI - Pay More Attention: a national mixed methods study to identify the barriers and facilitators to ensuring equal access to high-quality hospital care and services for children and young people with and without learning disabilities and their families. AB - INTRODUCTION: Despite evidence of health inequalities for adults with intellectual disability (ID) there has yet to be a comprehensive review of how well hospital services are meeting the needs of children and young people (CYP) with ID and their families. We do not know how relevant existing recommendations and guidelines are to CYP, whether these are being applied in the paediatric setting or what difference they are making. Evidence of parental dissatisfaction with the quality, safety and accessibility of hospital care for CYP with ID exists. However, the extent to which their experience differs from parents of CYP without ID is not known and the views and experiences of CYP with ID have not been investigated. We will compare how services are delivered to, and experienced by CYP aged 5-15 years with and without ID and their families to see what inequalities exist, for whom, why and under what circumstances. METHODS AND ANALYSIS: We will use a transformative, mixed methods case study design to collect data over four consecutive phases. We will involve CYP, parents and hospital staff using a range of methods; interviews, parental electronic diary, hospital and community staff questionnaire, patient and parent satisfaction questionnaire, content analysis of hospital documents and a retrospective mapping of patient hospital activity. Qualitative data will be managed and analysed using NVivo and quantitative data will be analysed using parametric and non-parametric descriptive statistics. ETHICS AND DISSEMINATION: The study will run from December 2015 to November 2018. We have Health Authority Approval (IRAS project ID: 193932) for phase 1 involving staff only and ethical and Health Authority Approval for phases 2-4 (IRAS project ID: 178525). We will disseminate widely to relevant stakeholders, using a range of accessible formats, including social media. We will publish in international peer-reviewed journals and present to professional, academic and lay audiences through national and international conferences. PMID- 27940628 TI - What determines duration of palliative care before death for patients with advanced disease? A retrospective cohort study of community and hospital palliative care provision in a large UK city. AB - OBJECTIVE: For patients with advanced cancer, several randomised controlled trials have shown that access to palliative care at least 6 months before death can improve symptoms, reduce unplanned hospital admissions, minimise aggressive cancer treatments and enable patients to make choices about their end-of-life care, including exercising the choice to die at home. This study determines in a UK population the duration of palliative care before death and explores influencing factors. DESIGN: This retrospective cohort study analysed referrals to three specialist palliative care services; a hospital-based inpatient palliative care team, and two community-based services (hospices). For each patient referred to any of the above services we identified the date of first referral to that team and calculated the median interval between first referral and death. We also calculated how referral time varied by age, sex, diagnosis and type of palliative care service. PARTICIPANTS: 4650 patients referred to specialist palliative care services in Leeds UK between April 2012 and March 2014. RESULTS: Median age of the sample was 75 years. 3903 (84.0%) patients had a diagnosis of cancer. Age, diagnosis and place of referral were significant predictors of duration of palliative care before death. Age was independently associated (J=2 672 078, z=-392046.14, r=0.01) with duration of palliative care regardless of diagnosis. Patients over 75 years have 29 fewer days of palliative care than patients under 50. Patients with non-cancer diagnoses have 13 fewer days of palliative care than patients with cancer. Additionally, patients referred to hospital palliative care receive 24.5 fewer days palliative care than those referred to community palliative care services. CONCLUSIONS: The current timing of referral to palliative care may limit the benefits to patients in terms of improvements in end-of-life care, particularly for older patients and patients with conditions other than cancer. PMID- 27940627 TI - Automatic identification of type 2 diabetes, hypertension, ischaemic heart disease, heart failure and their levels of severity from Italian General Practitioners' electronic medical records: a validation study. AB - OBJECTIVES: The Italian project MATRICE aimed to assess how well cases of type 2 diabetes (T2DM), hypertension, ischaemic heart disease (IHD) and heart failure (HF) and their levels of severity can be automatically extracted from the Health Search/CSD Longitudinal Patient Database (HSD). From the medical records of the general practitioners (GP) who volunteered to participate, cases were extracted by algorithms based on diagnosis codes, keywords, drug prescriptions and results of diagnostic tests. A random sample of identified cases was validated by interviewing their GPs. SETTING: HSD is a database of primary care medical records. A panel of 12 GPs participated in this validation study. PARTICIPANTS: 300 patients were sampled for each disease, except for HF, where 243 patients were assessed. OUTCOME MEASURES: The positive predictive value (PPV) was assessed for the presence/absence of each condition against the GP's response to the questionnaire, and Cohen's kappa was calculated for agreement on the severity level. RESULTS: The PPV was 100% (99% to 100%) for T2DM and hypertension, 98% (96% to 100%) for IHD and 55% (49% to 61%) for HF. Cohen's kappa for agreement on the severity level was 0.70 for T2DM and 0.69 for hypertension and IHD. CONCLUSIONS: This study shows that individuals with T2DM, hypertension or IHD can be validly identified in HSD by automated identification algorithms. Automatic queries for levels of severity of the same diseases compare well with the corresponding clinical definitions, but some misclassification occurs. For HF, further research is needed to refine the current algorithm. PMID- 27940630 TI - Positive predictive value of cardiac examination, procedure and surgery codes in the Danish National Patient Registry: a population-based validation study. AB - OBJECTIVE: Danish medical registries are widely used for cardiovascular research, but little is known about the data quality of cardiac interventions. We computed positive predictive values (PPVs) of codes for cardiac examinations, procedures and surgeries registered in the Danish National Patient Registry during 2010 2012. DESIGN: Population-based validation study. SETTING: We randomly sampled patients from 1 university hospital and 2 regional hospitals in the Central Denmark Region. PARTICIPANTS: 1239 patients undergoing different cardiac interventions. MAIN OUTCOME MEASURE: PPVs with medical record review as reference standard. RESULTS: A total of 1233 medical records (99% of the total sample) were available for review. PPVs ranged from 83% to 100%. For examinations, the PPV was overall 98%, reflecting PPVs of 97% for echocardiography, 97% for right heart catheterisation and 100% for coronary angiogram. For procedures, the PPV was 98% overall, with PPVs of 98% for thrombolysis, 92% for cardioversion, 100% for radiofrequency ablation, 98% for percutaneous coronary intervention, and 100% for both cardiac pacemakers and implantable cardiac defibrillators. For cardiac surgery, the overall PPVs was 99%, encompassing PPVs of 100% for mitral valve surgery, 99% for aortic valve surgery, 98% for coronary artery bypass graft surgery, and 100% for heart transplantation. The accuracy of coding was consistent within age, sex, and calendar year categories, and the agreement between independent reviewers was high (99%). CONCLUSIONS: Cardiac examinations, procedures and surgeries have high PPVs in the Danish National Patient Registry. PMID- 27940629 TI - Provider and service-user perspectives of volunteer health-worker service provision in Ayeyarwady Region, Myanmar: a qualitative study. AB - OBJECTIVES: To explore perspectives and reported experiences of service users, community providers and policymakers related to volunteer health-worker services provision in a rural area of Myanmar. METHODS: A qualitative interview study was conducted in rural communities with 54 service users and 17 community providers in Ayeyarwady Region, Myanmar, and with 14 national managers and policymakers in Yangon Myanmar. Topics included reasons for seeking health services, views and experiences, and comparison with experiences of other services. Data were analysed thematically using deductive and inductive coding. RESULTS: Accessibility and affordability were important to all participants. Service users described the particular relevance of trust, familiarity and acceptability in choosing a provider. Perceived quality and effectiveness were necessary for trust to develop. Perceived value of volunteers was a cross-cutting dimension, which was interpreted differently by different participants. CONCLUSIONS: Results suggest that volunteers are appropriate and valued, and support 'availability', 'accessibility' and 'acceptability' as dimensions of health services access in this setting. However, social complexities should be considered to ensure effective service delivery. Further research into trust-building, developing quality perceptions and resulting service-user choices would be useful to inform effective policy and planning. PMID- 27940631 TI - Gut feelings in the diagnostic process of Spanish GPs: a focus group study. AB - OBJECTIVES: The gut feelings of doctors can act as triggers and modulators of the diagnostic process. This study explored the existence, significance, determinants and triggers of gut feelings among Spanish general practitioners. DESIGN: Qualitative study using focus groups. Thematic content analysis. SETTING: Primary healthcare centres in Majorca (Spain). PARTICIPANTS: 20 purposively sampled general practitioners working in Majorca. RESULTS: General practitioners were aware of the existence of gut feelings in their diagnostic reasoning process and recognised 2 kinds of gut feelings: a sense of alarm and a sense of reassurance. A previous physician-patient relationship and the physician's experience had a strong perceived influence on the appearance of gut feelings. The physicians attached great significance to gut feelings, and considered them as a characteristic of the primary care working style and as a tool available in their diagnostic process. The physicians thought that the notion of gut feelings and their relevance can be transmitted to students and trainees. They tended to follow their gut feelings, although they were not sure of their accuracy. CONCLUSIONS: Spanish general practitioners in our study recognise the presence and role of gut feelings in their diagnostic reasoning process. Future research should examine the diagnostic accuracy of gut feelings and how to teach about gut feelings in the training of general practitioners. PMID- 27940632 TI - Association between meteorological factors and bacillary dysentery incidence in Chaoyang city, China: an ecological study. AB - OBJECTIVES: To quantify the relationship between meteorological factors and bacillary dysentery incidence. DESIGN: Ecological study. SETTING: We collected bacillary dysentery incidences and meteorological data of Chaoyang city from the year 1981 to 2010. The climate in this city was a typical northern temperate continental monsoon. All meteorological factors in this study were divided into 4 latent factors: temperature, humidity, sunshine and airflow. Structural equation modelling was used to analyse the relationship between meteorological factors and the incidence of bacillary dysentery. MATERIAL: Incidences of bacillary dysentery were obtained from the Center for Disease Control and Prevention of Chaoyang city, and meteorological data were collected from the Bureau of Meteorology in Chaoyang city. PRIMARY OUTCOME MEASURES: The indexes including chi2, root mean square error of approximation (RMSEA), comparative fit index (CFI), standardised root mean square residual (SRMR) and goodness-of-fit index (GFI) were used to evaluate the goodness-of-fit of the theoretical model to the data. The factor loads were used to explore quantitative relationship between bacillary dysentery incidences and meteorological factors. RESULTS: The goodness-of-fit results of the model showing that RMSEA=0.08, GFI=0.84, CFI=0.88, SRMR=0.06 and the chi2 value is 231.95 (p=0.0) with 15 degrees of freedom. Temperature and humidity factors had positive correlations with incidence of bacillary dysentery, with the factor load of 0.59 and 0.78, respectively. Sunshine had a negative correlation with bacillary dysentery incidence, with a factor load of -0.15. CONCLUSIONS: Humidity and temperature should be given greater consideration in bacillary dysentery prevention measures for northern temperate continental monsoon climates, such as that of Chaoyang. PMID- 27940634 TI - Effectiveness of medicines authentication technology to detect counterfeit, recalled and expired medicines: a two-stage quantitative secondary care study. AB - OBJECTIVES: To identify the authentication and detection rate of serialised medicines using medicines authentication technology. DESIGN AND INTERVENTION: 4192 serialised medicines were entered into a hospital dispensary over two separate 8-week stages in 2015. Medicines were authenticated using secure external database cross-checking, triggered by the scanning of a two-dimensional data matrix with a unit specific 12-digit serial code. 4% of medicines included were preprogrammed with a message to identify the product as either expired, pack recalled, product recalled or counterfeit. SETTING: A site within a large UK National Health Service teaching hospital trust. PARTICIPANTS: Accredited checking staff, pharmacists and dispensers in a pharmacy department. PRIMARY OUTCOME MEASURES: Authentication and detection rate of counterfeit expired and recalled medicines. RESULTS: The operational detection rate of counterfeit, recalled and expired medicines scanned as a combined group was 81.4% (stage 1 (S1)) and 87% (stage 2 (S2)). The technology's technical detection rate (TDR) was 100%; however, not all medicines were scanned and of those that were scanned not all that generated a warning message were quarantined. Owing to an operational authentication rate (OAR) of 66.3% (over both stages), only 31.8% of counterfeit medicines, 58% of recalled drugs and 64% of expired medicines were detected as a proportion of those entered into the study. Response times (RTs) of 152 ms (S1) and 165 ms (S2) were recorded, meeting the falsified medicines directive-mandated 300 ms limit. CONCLUSIONS: TDRs and RTs were not a limiting factor in this study. The suboptimal OAR poses significant quality and safety issues with this detection approach. Authentication at the checking stage, however, demonstrated higher OARs. There is a need for further qualitative research to establish the reasons for less than absolute authentication and detection rates in the hospital environment to improve this technology in preparation for the incumbent European Union regulative deadline. PMID- 27940633 TI - Supporting underserved patients with their medicines: a study protocol for a patient/professional coproduced education intervention for community pharmacy staff to improve the provision and delivery of Medicine Use Reviews (MURs). AB - INTRODUCTION: Community pharmacy increasingly features in global strategies to modernise the delivery of primary healthcare. Medicine Use Reviews (MURs) form part of the English Government's medicines management strategy to improve adherence and reduce medicine waste. MURs provide space for patient-pharmacist dialogue to discuss the well-known problems patients experience with medicine taking. However, 'underserved' communities (eg, black and minority ethnic communities, people with mental illness), who may benefit the most, may not receive this support. This study aims to develop, implement and evaluate an e learning education intervention which is coproduced between patients from underserved communities and pharmacy teams to improve MUR provision. METHODS AND ANALYSIS: This mixed-methods evaluative study will involve a 2-stage design. Stage 1 involves coproduction of an e-learning resource through mixed patient professional development (n=2) and review (n=2) workshops, alongside informative semistructured interviews with patients (n=10) and pharmacy staff (n=10). Stage 2 involves the implementation and evaluation of the intervention with community pharmacy staff within all community pharmacies within the Nottinghamshire geographical area (n=237). Online questionnaires will be completed at baseline and postintervention (3 months) to assess changes in engagement with underserved communities and changes in self-reported attitudes and behaviour. To triangulate findings, 10 pharmacies will record at baseline and postintervention, details of actual numbers of MURs performed and the proportion that are from underserved communities. Descriptive and inferential statistics will be used to analyse the data. The evaluation will also include a thematic analysis of one-to-one interviews with pharmacy teams to explore the impact on clinical practice (n=20). Interviews with patients belonging to underserved communities, and who received an MUR, will also be conducted (n=20). ETHICS AND DISSEMINATION: The study has received ethical approval from the NHS Research Ethics Committee (East Midlands Derby) and governance clearance through the NHS Health Research Authority. Following the evaluation, the educational intervention will be freely accessible online. PMID- 27940635 TI - Young people's experiences of persistent musculoskeletal pain, needs, gaps and perceptions about the role of digital technologies to support their co-care: a qualitative study. AB - OBJECTIVE: To investigate young people's experiences of persistent musculoskeletal pain, including care needs and current service gaps as well as perceptions about the role of digital technologies to support their co-care. METHODS: A qualitative study employing two independent data collection modes: in depth individual semistructured interviews and focus groups. SETTING: Community settings throughout Australia. PARTICIPANTS: Participants were included if they had experienced persistent musculoskeletal pain of >3-month duration with an average of >=3 on the visual analogue scale over the preceding 3 months, including non-specific conditions (eg, low back pain) and specific conditions (eg, juvenile idiopathic arthritis and other systemic arthritides), with/without pre-existing or current diagnosed mental health conditions. 23 young people (87.0% women; mean (SD) age: 20.8 (2.4) years) from across 6 Australian jurisdictions participated. Almost two-thirds of participants with persistent musculoskeletal pain reported comorbid mental health conditions. MAIN OUTCOME MEASURES: Inductive and deductive approaches to analyse and derive key themes from verbatim transcripts. RESULTS: Participants described their daily experiences of living with persistent musculoskeletal pain, their fears and the challenges imposed by the invisibility of pain, and the two-way relationship between their pain and mental well-being. A lack of relevant and accessible information and resources tailored to young people's unique needs, integrated and youth-relevant healthcare services and adequately skilled healthcare practitioners were identified as key care gaps. Participants strongly advocated for the use of digital technologies to improve access to age-appropriate resources and support for co-care. CONCLUSIONS: Young people living with persistent musculoskeletal pain described the absence of age-appropriate pain services and clearly articulated their perceptions on the role of, and opportunities provided by, digital technologies to connect with and support improved pain healthcare. Innovative and digitally-enabled models of pain care are likely to be helpful for this group. PMID- 27940636 TI - Ultrasonographic reference values for peripheral nerves and nerve roots in the normal population of children and adolescents: study protocol for an observational-prospective trial. AB - BACKGROUND: High-resolution ultrasonography is a new and promising technique to evaluate peripheral and spinal nerves. Its validity as a diagnostic tool in neurological diseases has been demonstrated in adults. Up to now no reference values have been published in children and adolescents although this technique would be ideal in this population as it is fast and non-invasive. METHODS/DESIGN: Our aim is to generate ultrasonographic reference values for several peripheral nerves (median, ulnar, radial, tibial, sural, peroneal and tibial nerve) as well as for the spinal nerves C5 and C6 and the vagus nerve in children and adolescents. In an observational prospective study, we will recruit 205 children and adolescents aged between >=2 and <=18 years without neuromuscular symptoms/signs and without a history of neuromuscular disease. After the collection of demographic and anthropometric data (height, weight, body mass index, age, gender and handedness) and a neurologic examination, a high resolution ultrasonography of peripheral and spinal nerves at several anatomic landmarks will be performed. These data will be used to estimate age-dependent percentile curves and to evaluate inter-rater, intrarater and interequipment reliability of the measurements. ETHICS AND DISSEMINATION: This study was approved by the local ethics committee (EKNZ 2015-210). The findings from this study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT02570802, pre-results publication. PMID- 27940638 TI - Our current approach to root cause analysis: is it contributing to our failure to improve patient safety? AB - BACKGROUND: Despite over a decade of efforts to reduce the adverse event rate in healthcare, the rate has remained relatively unchanged. Root cause analysis (RCA) is a process used by hospitals in an attempt to reduce adverse event rates; however, the outputs of this process have not been well studied in healthcare. This study aimed to examine the types of solutions proposed in RCAs over an 8 year period at a major academic medical institution. METHODS: All state reportable adverse events were gathered, and those for which an RCA was performed were analysed. A consensus rating process was used to determine a severity rating for each case. A qualitative approach was used to categorise the types of solutions proposed by the RCA team in each case and descriptive statistics were calculated. RESULTS: 302 RCAs were reviewed. The most common event types involved a procedure complication, followed by cardiopulmonary arrest, neurological deficit and retained foreign body. In 106 RCAs, solutions were proposed. A large proportion (38.7%) of RCAs with solutions proposed involved a patient death. Of the 731 proposed solutions, the most common solution types were training (20%), process change (19.6%) and policy reinforcement (15.2%). We found that multiple event types were repeated in the study period, despite repeated RCAs. CONCLUSIONS: This study found that the most commonly proposed solutions were weaker actions, which were less likely to decrease event recurrence. These findings support recent attempts to improve the RCA process and to develop guidance for the creation of effective and sustainable solutions to be used by RCA teams. PMID- 27940637 TI - An Optimized Chromatographic Strategy for Multiplexing In Parallel Reaction Monitoring Mass Spectrometry: Insights from Quantitation of Activated Kinases. AB - Reliable quantitation of protein abundances in defined sets of cellular proteins is critical to numerous biological applications. Traditional immunodetection based methods are limited by the quality and availability of specific antibodies, especially for site-specific post-translational modifications. Targeted proteomic methods, including the recently developed parallel reaction monitoring (PRM) mass spectrometry, have enabled accurate quantitative measurements of up to a few hundred specific target peptides. However, the degree of practical multiplexing in label-free PRM workflows remains a significant limitation for the technique. Here we present a strategy for significantly increasing multiplexing in label free PRM that takes advantage of the superior separation characteristics and retention time stability of meter-scale monolithic silica-C18 column-based chromatography. We show the utility of the approach in quantifying kinase abundances downstream of previously developed active kinase enrichment methodology based on multidrug inhibitor beads. We examine kinase activation dynamics in response to three different MAP kinase inhibitors in colorectal carcinoma cells and demonstrate reliable quantitation of over 800 target peptides from over 150 kinases in a single label-free PRM run. The kinase activity profiles obtained from these analyses reveal compensatory activation of TGF-beta family receptors as a response to MAPK blockade. The gains achieved using this label-free PRM multiplexing strategy will benefit a wide array of biological applications. PMID- 27940640 TI - Evidence, expertise, and facts in a "post-truth" society. PMID- 27940639 TI - Microanalysis of video from the operating room: an underused approach to patient safety research. PMID- 27940641 TI - Educational and Gender Differences in Health Behavior Changes After a Gateway Diagnosis. AB - OBJECTIVE: Hypertension represents a gateway diagnosis to more serious health problems that occur as people age. We examine educational differences in three health behavior changes people often make after receiving this diagnosis in middle or older age, and test whether these educational differences depend on (a) the complexity of the health behavior change and (b) gender. METHOD: We use data from the Health and Retirement Study and conduct logistic regression analysis to examine the likelihood of modifying health behaviors post diagnosis. RESULTS: We find educational differences in three behavior changes-antihypertensive medication use, smoking cessation, and physical activity initiation-after a hypertension diagnosis. These educational differences in health behaviors were stronger among women compared with men. DISCUSSION: Upon receiving a hypertension diagnosis, education is a more important predictor of behavior changes for women compared with men, which may help explain gender differences in the socioeconomic gradient in health in the United States. PMID- 27940642 TI - New insights into the role of the porcine intestinal yeast, Kazachstania slooffiae, in intestinal environment of weaned piglets. AB - Kazachstania slooffiae is a porcine intestinal yeast whose role in the intestinal environment is largely unexplored. Therefore, the impact of K. slooffiae on growth performance, intestinal microbial metabolites and the microbiota of weaned piglets was investigated in this study. Forty-eight German Landrace pigs were weaned at day 27 or 28 of life and grouped into one control and three treatment groups. During the 5-week experiment, piglets had ad libitum access to feed and water. On days 5, 6 and 7 post weaning, pigs were orally supplemented with either placebo or K. slooffiae cells once a day. Faecal samples collected on days 5-8, 14, 21 and 28 post weaning were used for microbiological and chemical analyses. Between groups, there were no significant differences in the incidence of diarrhoea, pH and growth performance. Total yeasts and K. slooffiae correlated positively with total short-chain fatty acids, acetic, propionic, n-butyric, i valeric and valeric acids, and negatively with pH. Pyrosequencing of the bacterial intestinal community revealed that K. slooffiae significantly affected the composition of the microbiota. The results of this study suggest that K. slooffiae may play an important role in the porcine digestive system, especially in the critical weaning period. PMID- 27940643 TI - Marine heatwaves and optimal temperatures for microbial assemblage activity. AB - The response of microbial assemblages to instantaneous temperature change was measured in a seasonal study of the coastal waters of the western English Channel. On 18 occasions between November 1999 and December 2000, bacterial abundance was assessed and temperature responses determined from the incorporation of 3H leucine, measured in a temperature gradient from 5 degrees C to 38 degrees C. Q10 values varied, being close to 2 in spring and summer but were >3 in autumn. There was a seasonal pattern in the assemblage optimum temperature (Topt), which was out of phase with sea surface temperature. In July, highest 3H-leucine incorporation rates were measured at temperatures that were only 2.8 degrees C greater than ambient sea surface temperature but in winter, Topt was ~20 degrees C higher than the ambient sea surface temperature. Sea surface temperatures for the adjacent English Channel and Celtic Sea for 1982 2014 have periodically been >3 degrees C higher than climatological mean temperatures. This suggests that discrete periods of anomalously high temperatures might be close to, or exceed, temperatures at which maximum microbial assemblage activity occurs. The frequency and magnitude of marine heatwaves are likely to increase as a consequence of anthropogenic climate change and extreme temperatures may influence the role of bacterial assemblages in biogeochemical processes. PMID- 27940645 TI - Biogeography of soil Thaumarchaeota in relation to soil depth and land usage. AB - Although Thaumarchaeota are important contributors to ammonia oxidation in terrestrial habitats, distributions of ammonia oxidizers along soil depth profiles are poorly understood, especially in relation to distinct land usages. Leveraging the close proximity of forest, field and agricultural plots at the RARE: Charitable Research Reserve, we examined soil thaumarchaeotal biogeography at three different depths (0-15, 15-30 and 30-45 cm) from plots within areas of contrasting land usage. Data from high-throughput sequencing of thaumarchaeotal 16S rRNA gene sequences demonstrated that OTU richness was affected significantly by depth and land-use type. Specifically, thaumarchaeotal diversity was higher in soils from forest sites than from field sites, and lower within 0-15 cm soils than either 15-30 cm or 30-45 cm soils. Soil land-use type influenced the relative abundance of the Soil Crenarchaeota Group (SCG), with a lower relative abundance of SCG in forest sites compared to field sites. At the OTU level, thaumarchaeotal communities changed with increasing soil depth for agricultural soils, in contrast to homogeneous depth profiles generated from forest site samples. Soil pH was the strongest factor impacting thaumarchaeotal community composition and, importantly, the evenness of archaeal taxa. Nitrogen, carbon and soil texture shaped thaumarchaeotal community composition among field site samples. PMID- 27940644 TI - Rhizosphere microbiomes of potato cultivated in the High Andes show stable and dynamic core microbiomes with different responses to plant development. AB - The rhizosphere hosts a rich microflora supporting plant nutrition and health. We examined bacterial rhizosphere microbiota of Solanum tuberosum grown in its center of origin, the Central Andean Highlands, at different vegetation stages and sites at altitudes ranging from 3245 to 4070 m.a.s.l., differing in soil characteristics, climate and the agricultural practices by 454 sequence analysis of 16S rRNA genes. We observed that the taxonomic composition of bacteria repeatedly occurring at particular stages of plant development was almost unaffected by highly diverse environmental conditions. A detailed statistical analysis on the operational taxonomic unit (OTU) level, representing bacterial species, revealed a complex community structure of the rhizosphere. We identified an opportunistic microbiome which comprises OTUs that occur randomly or under specific environmental conditions. In contrast, core microbiome members were found at all sites. The 'stable' component of the core microbiome consisted of few ubiquitous OTUs that were continuously abundant in all samples and vegetation stages, whereas the 'dynamic' component comprised OTUs that were enriched at specific vegetation stages. PMID- 27940646 TI - An improved protocol with a highly degenerate primer targeting copper-containing membrane-bound monooxygenase genes for community analysis of methane- and ammonia oxidizing bacteria. AB - The copper-containing membrane-bound monooxygenase (CuMMO) family comprises key enzymes for methane or ammonia oxidation: particulate methane monooxygenase (PMMO) and ammonia monooxygenase (AMO). To comprehensively amplify CuMMO genes, a two-step PCR strategy was developed using a newly designed tagged highly degenerate primer (THDP; degeneracy = 4608). Designated THDP-PCR, the technique consists of primary CuMMO gene-specific PCR followed by secondary PCR with a tag as a single primer. No significant bias in THDP-PCR amplification was found using various combinations of template mixtures of pmoA and amoA genes, which encode key subunits of the pMMO and AMO enzymes, respectively, from different microbes. THDP-PCR was successfully applied to nine different environmental samples and revealed relatively high contents of complete ammonia oxidation (Comammox) related bacteria and a novel group of the CuMMO family. The levels of freshwater cluster methanotrophs obtained by THDP-PCR were much higher than those obtained by conventional methanotroph-specific PCR. The THDP-PCR strategy developed in this study can be extended to other functional gene-based community analyses, particularly when the target gene sequences lack regions of high consensus for primer design. PMID- 27940647 TI - Gaia and her microbiome. AB - The Gaia hypothesis, proposed 50 years ago, posits that the Earth's biosphere, atmosphere, hydrosphere and lithosphere interact as a cybernetic system, maintaining the long-term habitability of the planet. The resulting chemical composition of the atmosphere, oceans and crust is unique as compared to the other planets of our solar system, and due to the presence of life. Together these components comprise the biosphere, the life support system of the planet, with most of the essential processes carried out by microbes. Over a half of the elements in the periodic table are now known to have some biological role with many having complex biogeochemical cycles. The global microbiome inhabits a wide range of environments including deep into the Earth's crust, with a population of ~1030 cells and more than a trillion species. Deep sequencing projects have revealed hitherto unknown phyla and 'microbial dark matter'. The discoveries of conductive pili and cable bacteria have demonstrated that microbes transfer electrons to and from external sources, sometimes over significant distances, while research on quorum sensing and the plethora of microbial volatile organic substances have provided new insights into how microbes communicate. These advances in microbiology have expanded our understanding how Gaia could actually work. PMID- 27940649 TI - Avoidance of steroids in the reversible cerebral vasoconstriction syndrome. PMID- 27940648 TI - Endovascular treatment improves cognition after stroke: A secondary analysis of REVASCAT trial. AB - OBJECTIVE: To investigate the effect of endovascular treatment on cognitive function as a prespecified secondary analysis of the REVASCAT (Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours) trial. METHODS: REVASCAT randomized 206 patients with anterior circulation proximal arterial occlusion stroke to Solitaire thrombectomy or best medical treatment alone. Patients with established dementia were excluded from enrollment. Cognitive function was assessed in person with Trail Making Test (TMT) Parts A and B at 3 months and 1 year after randomization by an investigator masked to treatment allocation. Test completion within 5 minutes, time of completion (seconds), and number of errors were recorded. RESULTS: From November 2012 to December 2014, 206 patients were enrolled in REVASCAT. TMT was assessed in 82 of 84 patients undergoing thrombectomy and 86 of 87 control patients alive at 3 months and in 71 of 79 patients undergoing thrombectomy and 72 of 78 control patients alive at 1 year. Rates of timely TMT-A completion were similar in both treatment arms, although patients undergoing thrombectomy required less time for TMT-A completion and had higher rates of error-free TMT-A performance. Thrombectomy was also associated with a higher probability of timely TMT-B completion (adjusted odds ratio 3.17, 95% confidence interval 1.51-6.66 at 3 months; and adjusted ratio 3.66, 95% confidence interval 1.60-8.35 at 1 year) and shorter time for TMT-B completion. Differences in TMT completion times between treatment arms were significant in patients with good functional outcome but not in those who were functionally dependent (modified Rankin Scale score >2). Poorer cognitive outcomes were significantly associated with larger infarct volume, higher modified Rankin Scale scores, and worse quality of life. CONCLUSIONS: Thrombectomy improves TMT performance after stroke, especially among patients who reach good functional recovery. CLINICALTRIALSGOV IDENTIFIER: NCT01692379. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with stroke from acute anterior circulation proximal arterial occlusion, thrombectomy improves performance on the TMT at 3 months. PMID- 27940650 TI - Autopsy validation of 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of DLB. AB - OBJECTIVE: To conduct a validation study of 123I-N-fluoropropyl-2b-carbomethoxy 3b-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT dopaminergic imaging in the clinical diagnosis of dementia with Lewy bodies (DLB) with autopsy as the gold standard. METHODS: Patients >60 years of age with dementia who had undergone 123I FP-CIT imaging in research studies and who had donated their brain tissue to the Newcastle Brain Tissue Resource were included. All had structured clinical research assessments, and clinical diagnoses were applied by consensus panels using international diagnostic criteria. All underwent 123I-FP-CIT imaging at baseline, and scans were rated as normal or abnormal by blinded raters. Patients were reviewed in prospective studies and after death underwent detailed autopsy assessment, and neuropathologic diagnoses were applied with the use of standard international criteria. RESULTS: Fifty-five patients (33 with DLB and 22 with Alzheimer disease) were included. Against autopsy diagnosis, 123I-FP-CIT had a balanced diagnostic accuracy of 86% (sensitivity 80%, specificity 92%) compared with clinical diagnosis, which had an accuracy of 79% (sensitivity 87%, specificity 72%). Among patients with DLB, 10% (3 patients) met pathologic criteria for Lewy body disease but had normal 123I-FP-CIT imaging. CONCLUSIONS: This large autopsy analysis of 123I-FP-CIT imaging in dementia demonstrates that it is a valid and accurate biomarker for DLB, and the high specificity compared with clinical diagnosis (20% higher) is clinically important. The results need to be replicated with patients recruited from a wider range of settings, including movement disorder clinics and general practice. While an abnormal 123I-FP-CIT scan strongly supports Lewy body disease, a normal scan does not exclude DLB with minimal brainstem involvement. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 123I-FP-CIT dopaminergic neuroimaging accurately identifies patients with DLB. PMID- 27940651 TI - Glucocorticoid-associated worsening in reversible cerebral vasoconstriction syndrome. AB - OBJECTIVE: Factors predicting poor outcome in patients with the reversible cerebral vasoconstriction syndrome (RCVS) have not been identified. METHODS: In this single-center retrospective study, we analyzed the clinical, brain imaging, and angiography data in 162 patients with RCVS. Univariable and multivariable regression analysis were performed to identify predictors of persistent (nontransient) clinical worsening, radiologic worsening, early angiographic progression, and poor discharge outcome (modified Rankin Scale score 4-6). RESULTS: The mean age was 44 +/- 13 years; 78% of patients were women. Persistent clinical worsening occurred in 14% at 6.6 +/- 4.1 days after symptom onset, radiologic worsening in 27% (mainly new infarcts), and angiographic progression in 15%. Clinical worsening correlated with angiographic progression and new nonhemorrhagic lesions. Age and sex did not independently predict any type of worsening. Infarction on baseline imaging predicted poor outcome. Prior serotonergic antidepressant use predicted clinical and angiographic worsening but not poor outcome. Intra-arterial vasodilator therapy independently predicted clinical worsening and poor discharge outcome but was offered to more severe cases. Glucocorticoid treatment proved to be an independent predictor of clinical, imaging, and angiographic worsening and poor outcome. Of the 23 patients with clinical worsening, 17 received glucocorticoids (15 within the preceding 2 days). There were no significant differences in baseline brain lesions and angiographic abnormalities between glucocorticoid-treated and untreated patients. CONCLUSION: Patients with RCVS at risk for worsening can be identified on basis of baseline features. Iatrogenic factors such as glucocorticoid exposure may contribute to worsening. PMID- 27940652 TI - Pulmonary hyalinizing granuloma presenting with dysphagia: a rare presentation. AB - A 25-year-old man presented with a 2-month history of dysphagia and past history of pulmonary and intestinal tuberculosis. A barium swallow showed a point of constriction 42 mm above the gastroesophageal junction. Computed tomography revealed large opacities in bilateral lung fields, encroaching more on the esophagus. The lesion progressively compressed the esophagus as it moved inferiorly. A right posterolateral thoracotomy was performed for sub-anatomical resection of the mass. A biopsy revealed homogenous whirling hyalinized collagen fibers, highly suggestive of pulmonary hyalinizing granuloma, with no evidence of malignancy. Pulmonary hyalinizing granuloma should be considered in the differential diagnosis of longstanding dysphagia. PMID- 27940653 TI - Hair follicle stem cell cultures reveal self-organizing plasticity of stem cells and their progeny. AB - Understanding how complex tissues are formed, maintained, and regenerated through local growth, differentiation, and remodeling requires knowledge on how single cell behaviors are coordinated on the population level. The self-renewing hair follicle, maintained by a distinct stem cell population, represents an excellent paradigm to address this question. A major obstacle in mechanistic understanding of hair follicle stem cell (HFSC) regulation has been the lack of a culture system that recapitulates HFSC behavior while allowing their precise monitoring and manipulation. Here, we establish an in vitro culture system based on a 3D extracellular matrix environment and defined soluble factors, which for the first time allows expansion and long-term maintenance of murine multipotent HFSCs in the absence of heterologous cell types. Strikingly, this scheme promotes de novo generation of HFSCs from non-HFSCs and vice versa in a dynamic self-organizing process. This bidirectional interconversion of HFSCs and their progeny drives the system into a population equilibrium state. Our study uncovers regulatory dynamics by which phenotypic plasticity of cells drives population-level homeostasis within a niche, and provides a discovery tool for studies on adult stem cell fate. PMID- 27940655 TI - Abdominal self-stabbing: A case report. AB - While abdominal stabbings are frequently associated with homicides, abdominal self-stabbing is uncommon and poses a challenge for the investigators. In cases of sharp force trauma, the presence of hesitation cuts over the neck and extremities help to distinguish self-inflicted injuries from homicides. Hesitation cuts are not associated with self-inflicted sharp force injuries to the abdomen, and thus are of limited use in distinguishing suicidal from homicidal abdominal stab wounds. In this study, we present a case of self inflicted abdominal stabbing along with a detailed review of literature to help elucidate such cases. PMID- 27940654 TI - Endothelial basement membrane laminin 511 is essential for shear stress response. AB - Shear detection and mechanotransduction by arterial endothelium requires junctional complexes containing PECAM-1 and VE-cadherin, as well as firm anchorage to the underlying basement membrane. While considerable information is available for junctional complexes in these processes, gained largely from in vitro studies, little is known about the contribution of the endothelial basement membrane. Using resistance artery explants, we show that the integral endothelial basement membrane component, laminin 511 (laminin alpha5), is central to shear detection and mechanotransduction and its elimination at this site results in ablation of dilation in response to increased shear stress. Loss of endothelial laminin 511 correlates with reduced cortical stiffness of arterial endothelium in vivo, smaller integrin beta1-positive/vinculin-positive focal adhesions, and reduced junctional association of actin-myosin II In vitro assays reveal that beta1 integrin-mediated interaction with laminin 511 results in high strengths of adhesion, which promotes p120 catenin association with VE-cadherin, stabilizing it at cell junctions and increasing cell-cell adhesion strength. This highlights the importance of endothelial laminin 511 in shear response in the physiologically relevant context of resistance arteries. PMID- 27940656 TI - Is being in paid work beyond state pension age beneficial for health? Evidence from England using a life-course approach. AB - BACKGROUND: Given the current policy emphasis in many Western societies on extending working lives, we investigated the health effects of being in paid work beyond state pension age (SPA). Until now, work has largely focused on the health of those who exit the labour force early. METHODS: Our data come from waves 2-4 of the English Longitudinal Study of Ageing, including the life history interview at wave 3. Using logistic and linear regression models, we assessed the longitudinal associations between being in paid work beyond SPA and 3 measures of health (depression, a latent measure of somatic health and sleep disturbance) among men aged 65-74 and women aged 60-69. Our analyses controlled for baseline health and socioeconomic characteristics, as well as for work histories and health in adulthood and childhood. RESULTS: Approximately a quarter of women and 15% of men were in paid work beyond SPA. Descriptive bivariate analyses suggested that men and women in paid work were more likely to report better health at follow-up. However, once baseline socioeconomic characteristics as well as adulthood and baseline health and labour market histories were accounted for, the health benefits of working beyond SPA were no longer significant. CONCLUSIONS: Potential health benefits of working beyond SPA need to be considered in the light of the fact that those who report good health and are more socioeconomically advantaged are more likely to be working beyond SPA to begin with. PMID- 27940657 TI - Long-term excess mortality associated with diabetes following acute myocardial infarction: a population-based cohort study. PMID- 27940658 TI - Cutting Edge: IL-10 Is Essential for the Generation of Germinal Center B Cell Responses and Anti-Plasmodium Humoral Immunity. AB - IL-10 is a pleiotropic cytokine expressed during malaria, a disease characterized by short-lived, parasite-specific Ab responses. The role of IL-10 in regulating B cell responses during malaria is not known. In this study we report that IL-10 is essential for anti-Plasmodium humoral immunity. We identify that germinal center (GC) B cell reactions, isotype-switched Ab responses, parasite control, and host survival require B cell-intrinsic IL-10 signaling. IL-10 also indirectly supports humoral immunity by suppressing excessive IFN-gamma, which induces T-bet expression in B cells. Genetic ablation of either IFN-gamma signaling or T-bet expression in B cells substantially enhanced GC B cell responses and anti Plasmodium Ab production. Together, our data show that B cell-intrinsic IL-10 enhances whereas B cell-intrinsic IFN-gamma and T-bet suppress GC B cell responses and anti-Plasmodium humoral immunity. These data identify critical immunoregulatory circuits in B cells that may be targeted to promote long-lived humoral immunity and resistance to malaria. PMID- 27940661 TI - South Africa's Supreme Court overturns ruling allowing physician assisted suicide. PMID- 27940660 TI - MARCH1 E3 Ubiquitin Ligase Dampens the Innate Inflammatory Response by Modulating Monocyte Functions in Mice. AB - Ubiquitination was recently identified as a central process in the pathogenesis and development of numerous inflammatory diseases, such as obesity, atherosclerosis, and asthma. Treatment with proteasomal inhibitors led to severe side effects because ubiquitination is heavily involved in a plethora of cellular functions. Thus, new players regulating ubiquitination processes must be identified to improve therapies for inflammatory diseases. In addition to their role in adaptive immunity, endosomal MHC class II (MHCII) molecules were shown to modulate innate immune responses by fine tuning the TLR4 signaling pathway. However, the role of MHCII ubiquitination by membrane associated ring-CH-type finger 1 (MARCH1) E3 ubiquitin ligase in this process remains to be assessed. In this article, we demonstrate that MARCH1 is a key inhibitor of innate inflammation in response to bacterial endotoxins. The higher mortality of March1 /- mice challenged with a lethal dose of LPS was associated with significantly stronger systemic production of proinflammatory cytokines and splenic NK cell activation; however, we did not find evidence that MARCH1 modulates LPS or IL-10 signaling pathways. Instead, the mechanism by which MARCH1 protects against endotoxic shock rests on its capacity to promote the transition of monocytes from Ly6CHi to Ly6C+/- Moreover, in competitive bone marrow chimeras, March1-/- monocytes and polymorphonuclear neutrophils outcompeted wild-type cells with regard to bone marrow egress and homing to peripheral organs. We conclude that MARCH1 exerts MHCII-independent effects that regulate the innate arm of immunity. Thus, MARCH1 might represent a potential new target for emerging therapies based on ubiquitination reactions in inflammatory diseases. PMID- 27940659 TI - Endogenous Nur77 Is a Specific Indicator of Antigen Receptor Signaling in Human T and B Cells. AB - Distinguishing true Ag-stimulated lymphocytes from bystanders activated by the inflammatory milieu has been difficult. Nur77 is an immediate early gene whose expression is rapidly upregulated by TCR signaling in murine T cells and human thymocytes. Nur77-GFP transgenes serve as specific TCR and BCR signaling reporters in murine transgenic models. In this study, we demonstrate that endogenous Nur77 protein expression can serve as a reporter of TCR and BCR specific signaling in human PBMCs. Nur77 protein amounts were assessed by immunofluorescence and flow cytometry in T and B cells isolated from human PBMCs obtained from healthy donors that had been stimulated by their respective Ag receptors. We demonstrate that endogenous Nur77 is a more specific reporter of Ag specific signaling events than the commonly used CD69 activation marker in both human T and B cells. This is reflective of the disparity in signaling pathways that regulate the expression of Nur77 and CD69. Assessing endogenous Nur77 protein expression has great potential to identify Ag-activated lymphocytes in human disease. PMID- 27940663 TI - Infusion Medication Error Reduction by Two-Person Verification: A Quality Improvement Initiative. AB - OBJECTIVE: Errors made in the administration of intravenous medication can lead to catastrophic harm. The frequency of hospital settings in which medication pumps are being used are increasing. We sought to improve medication safety by implementing a 2-person verification system before medication administration. METHODS: Our quality improvement initiative took place in an anesthesia radiology imaging service at a tertiary pediatric hospital. Key drivers included frequent educational meetings with clinicians, written reminders, display of visual reminders, constant feedback in the clinical areas that carried out the processes, and sharing of knowledge on displayed run charts. A multidisciplinary team conducted a series of tests of changes to address the interventions. Data were collected and entered into a database by an independent and impartial data collector. Data were analyzed via run charts and statistical process control methods. RESULTS: The team ran 24 plan-do-study-act ramps. The rate of 2-person verification of infusion pump programming increased from 0% to 90% and was sustained. Overall, 4 errors were rectified before the medication was administered to the patient. There was no delay in case starts (>90% before and during the project). This project played a key role, as part of a larger initiative within the department of anesthesia, in reducing medication errors. CONCLUSIONS: A brief 2-person verification approach can reduce medication errors due to inaccurate infusion pump programming. This improvement was achieved with the use of plan-do-study-act cycles. The impact can be significant and will promote a hospital safety culture. PMID- 27940662 TI - Deep-targeted exon sequencing reveals renal polymorphisms associate with postexercise hypotension among African Americans. AB - We found variants from the Angiotensinogen-Converting Enzyme (ACE), Angiotensin Type 1 Receptor (AGTR1), Aldosterone Synthase (CYP11B2), and Adducin (ADD1) genes exhibited intensity-dependent associations with the ambulatory blood pressure (BP) response following acute exercise, or postexercise hypotension (PEH). In a validation cohort, we sequenced exons from these genes for their associations with PEH Obese (30.9 +/- 3.6 kg m-2) adults (n = 23; 61% African Americans [AF], 39% Caucasian) 42.0 +/- 9.8 years with hypertension (139.8 +/- 10.4/84.6 +/- 6.2 mmHg) completed three random experiments: bouts of vigorous and moderate intensity cycling and control. Subjects wore an ambulatory BP monitor for 19 h. We performed deep-targeted exon sequencing using the Illumina TruSeq Custom Amplicon kit. Variant genotypes were coded as number of minor alleles (#MA) and selected for further statistical analysis based upon Bonferonni or Benjamini Yekutieli multiple testing corrected p-values under time adjusted linear models for 19 hourly BP measurements per subject. After vigorous intensity over 19 h among ACE, AGTR1, CYP11B2, and ADD1 variants passing multiple testing thresholds, as the #MA increased, systolic (SBP) and/or diastolic BP decreased 12 mmHg (P = 4.5E-05) to 30 mmHg (P = 6.4E-04) among AF only. In contrast, after moderate intensity over 19 h among ACE and CYP11B2 variants passing multiple testing thresholds, as the #MA increased, SBP increased 21 mmHg (P = 8.0E-04) to 22 mmHg (P = 8.2E-04) among AF only. In this replication study, ACE, AGTR1, CYP11B2, and ADD1 variants exhibited associations with PEH after vigorous, but not moderate intensity exercise among AF only. Renal variants should be explored further with a multi-level "omics" approach for associations with PEH among a large, ethnically diverse sample of adults with hypertension. PMID- 27940664 TI - Inhaled Laninamivir Octanoate as Prophylaxis for Influenza in Children. AB - BACKGROUND: A single 20-mg dose of inhaled laninamivir octanoate is an effective treatment of influenza. However, the efficacy of laninamivir octanoate for the prevention of influenza in children <10 years of age has not yet been established. METHODS: We conducted a double-blind, multicenter, randomized, placebo-controlled study to determine whether the efficacy of a single 20-mg dose of inhaled laninamivir octanoate to prevent the development of influenza was superior to that of placebo as prophylaxis for influenza in pediatric (<10 years) household members of index cases. Eligible subjects without influenza, in contact with an influenza-infected index case living in the same household, were blindly randomly assigned in a 1:1 ratio to receive 20 mg of laninamivir octanoate or placebo. The primary end point was the proportion of subjects who developed clinical influenza during a 10-day period. RESULTS: A total of 343 subjects were randomly assigned, with 341 subjects included in the full analysis set for the primary analysis. The proportions of subjects who developed clinical influenza were 11% (18/171) in the laninamivir octanoate group and 19% (33/170) in the placebo group (P = .02). The relative risk reduction was 45.8% (95% confidence interval, 7.5% to 68.2%). The incidence of adverse events was similar in both groups. CONCLUSIONS: A single 20-mg dose of inhaled laninamivir octanoate was effective and well tolerated as prophylaxis for influenza. PMID- 27940665 TI - Recurrent Immune Thrombocytopenia After Influenza Vaccination: A Case Report. AB - Immune thrombocytopenia (ITP) is an isolated autoimmune condition, often preceded by a viral infection. Vaccines, mainly the measles-mumps-rubella vaccine, have also been associated with an increased risk of developing the disease. Although some case reports of ITP after influenza immunization in adults have been published, epidemiologic studies examining the role of the influenza vaccine as a trigger of ITP have not conclusively proven causality. We report a child with 3 occurrences of ITP, each within 1 week of receiving the influenza trivalent inactivated vaccine. He recovered fully in-between the episodes, and no further episodes have occurred since discontinuation of seasonal influenza vaccination. To the best of our knowledge, this report is the first showing, with high probability, the influenza vaccine as a cause for ITP in a pediatric patient. PMID- 27940666 TI - RASopathies Are Associated With Delayed Puberty; Are They Associated With Precocious Puberty Too? AB - RASopathies, such as Noonan, Costello, and cardio-facio-cutaneous syndromes, are developmental disorders caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. Mutations that cause Noonan syndrome have been associated with delayed puberty. Here we report 4 patients with either Costello or cardio-facio-cutaneous syndrome who developed precocious puberty, suggesting complex regulation of the hypothalamic-pituitary-gonadal axis and the timing of puberty by the rat sarcoma-mitogen-activated protein kinase pathway. Additional study of the timing of puberty among patients with RASopathies is warranted to ascertain the incidence of delayed and precocious puberty in these conditions and to examine genotype-phenotype correlations, which may provide insight into pathways that regulate the timing of puberty. PMID- 27940667 TI - Management and Outcomes of Previously Healthy, Full-Term, Febrile Infants Ages 7 to 90 Days. AB - BACKGROUND: There is considerable variation in the approach to infants presenting to the emergency department and outpatient clinics with fever without a source. We set out to describe the current clinical practice regarding culture acquisition on febrile young infants and review the outcomes of infants with and without cultures obtained. METHODS: This study analyzed Kaiser Permanente Northern California's electronic medical record to identify all febrile, full term, previously healthy infants born between July 1, 2010, and June 30, 2013, presenting for care between 7 and 90 days of age. RESULTS: During this 3-year study, 96 156 full-term infants were born at Kaiser Permanente Northern California. A total of 1380 infants presented for care with a fever with an incidence rate of 14.4 (95% confidence interval: 13.6-15.1) per 1000 full term births. Fifty-nine percent of infants 7 to 28 days old had a full evaluation compared with 25% of infants 29 to 60 days old and 5% of infants 61 to 90 days old. Older infants with lower febrile temperatures presenting to an office setting were less likely to have a culture. In the 30 days after fevers, 1% of infants returned with a urinary tract infection. No infants returned with bacteremia or meningitis. CONCLUSIONS: Fever in a medical setting occurred in 1.4% of infants in this large cohort. Forty-one percent of febrile infants did not have any cultures including 24% less than 28 days. One percent returned in the following month with a urinary tract infection. There was no delayed identification of bacteremia or meningitis. PMID- 27940668 TI - Reliable Pregnancy Testing Before Intravenous Cyclophosphamide: A Quality Improvement Study. AB - BACKGROUND AND OBJECTIVE: Cyclophosphamide is a teratogenic medication used in the treatment of adolescents with autoimmune disorders. This adolescent population is sexually active, does not receive adequate contraceptive care, and is at risk for unintended pregnancy. We undertook a quality improvement initiative to improve rates of pregnancy screening before intravenous cyclophosphamide administration in our adolescent girl patients. METHODS: Data were collected from the electronic medical record. The primary outcome was completion of a urine pregnancy test before intravenous cyclophosphamide infusion in girls aged 12 to 21 years between July 2011 and June 2015. Data were reviewed quarterly and an iterative quality improvement approach was used. Interventions included staff education, electronic order set updates, and a Maintenance of Certification project. Interrupted time series analysis and multivariable mixed effects logistic regression were used to evaluate trends over time and to adjust for potential confounders. RESULTS: Thirty girls received 153 cyclophosphamide infusions during the study. Pregnancy testing before medication administration increased from 25% to 100% by study completion. Infusions in the last time period were significantly more likely to be accompanied by a pregnancy test versus those in the first time period (odds ratio: 17.7; 95% confidence interval [CI]: 3.1 101.6) after adjustment for patient age, managing service, infusion setting, and insurance type. CONCLUSIONS: Our institution achieved a significant increase in standard pregnancy screening in adolescent girls receiving intravenous cyclophosphamide. The interventions most valuable in increasing screening rates were updating electronic order sets, educating staff, and physician engagement in the Maintenance of Certification program. PMID- 27940669 TI - Association of Gestational Age With Verbal Ability and Spatial Working Memory at Age 11. AB - BACKGROUND: Although children born very preterm (gestation <32 weeks) have an increased risk of cognitive impairment compared with full-term children (39-41 weeks), the risk for children born moderately (32-33 weeks) to late preterm (34 36 weeks) and early term (37-38 weeks) is unclear. This study describes the relationship between gestational age and cognitive outcomes at 11 years and the trajectory of deficits in verbal ability from age 3 to 11 years. METHODS: Cognitive ability was assessed by using the Spatial Working Memory test from the Cambridge Neuropsychological Test Automated Working Battery (n = 11 395) and British Ability Scale Verbal Similarities test (n = 11 889) in the UK Millennium Cohort Study. Each gestational group was compared with the full-term group by using differences in z scores and odds ratios for delay (scoring >=1 SD below the mean). RESULTS: Very and moderately preterm children demonstrated significantly lower working memory scores compared with full-term children (adjusted difference -0.2 to -0.6) and were more likely to be delayed. There was no significant relationship between late-preterm or early-term birth and working memory (adjusted differences < -0.1), or between gestational age and verbal ability at 11 years. There appears to be a general attenuation in odds ratios as the child ages. CONCLUSIONS: Very preterm children exhibited working memory deficits at 11 years. However, the absence of delayed verbal skills at 11 years despite earlier delays could indicate "catch-up" effects. PMID- 27940670 TI - Environmental Enteric Dysfunction and Growth Failure/Stunting in Global Child Health. AB - Approximately 25% of the world's children aged <5 years have stunted growth, which is associated with increased mortality, cognitive dysfunction, and loss of productivity. Reducing by 40% the number of stunted children is a global target for 2030. The pathogenesis of stunting is poorly understood. Prenatal and postnatal nutritional deficits and enteric and systemic infections clearly contribute, but recent findings implicate a central role for environmental enteric dysfunction (EED), a generalized disturbance of small intestinal structure and function found at a high prevalence in children living under unsanitary conditions. Mechanisms contributing to growth failure in EED include intestinal leakiness and heightened permeability, gut inflammation, dysbiosis and bacterial translocation, systemic inflammation, and nutrient malabsorption. Because EED has multiple causal pathways, approaches to manage it need to be multifaceted. Potential interventions to tackle EED include: (1) reduction of exposure to feces and contact with animals through programs such as improved water, sanitation, and hygiene; (2) breastfeeding and enhanced dietary diversity; (3) probiotics and prebiotics; (4) nutrient supplements, including zinc, polyunsaturated fatty acids, and amino acids; (5) antiinflammatory agents such as 5-aminosalicyclic acid; and (6) antibiotics in the context of acute malnutrition and infection. Better understanding of the underlying causes of EED and development of noninvasive, practical, simple, and affordable point-of-care diagnostic tools remain key gaps. "Omics" technologies (genomics, epigenomics, transcriptomics, proteomics, and metabolomics) and stable isotope techniques (eg, 13C breath tests) targeted at children and their intestinal microbiota will enhance our ability to successfully identify, manage, and prevent this disorder. PMID- 27940671 TI - Case Report: Cystinuria and Polycystic Kidney Disease. AB - Cystinuria and polycystic kidney disease are 2 genetic disorders that affect the genitourinary tract but rarely together. This case report presents 2 pediatric patients diagnosed with polycystic kidney disease and cystinuria requiring surgical treatment. Both subjects presented acutely with stone disease. Imaging studies and stone analysis established the diagnoses. Although coexistence of these 2 conditions is rare, cystinuria should be considered in the differential diagnosis when evaluating patients with cystic disease who develop renal calculi. PMID- 27940672 TI - Validation of a Parent-Reported Experience Measure of Integrated Care. AB - OBJECTIVES: The objectives of this study were to design and validate a survey measuring the parents' and caregivers' experiences of integration of their child's care across providers. METHODS: After review of the literature on care coordination and integration, we solicited input regarding care experiences from focus groups of families with children with chronic conditions. These data informed a 95-item pilot survey that included elements from a care integration measure designed for adult care experiences. The survey was then administered to parents of children who had had at least 1 primary care appointment and 2 specialty care appointments in the previous 12 months. Psychometric analyses were used to establish scales through exploratory factor analysis, internal consistency using Cronbach's alpha, test-retest reliability using Spearman's rank correlation coefficient, and known-group validity according to chi2 tests. All research activities were institutional review board approved. RESULTS: The pilot survey was completed as either a Web or mail survey by 255 participants. After excluding nonrating or screening questions and items not applicable to a large percentage of participants, 26 experience items were included in the exploratory factor analysis. The final survey contained 19 experience items in 5 scales: access, communication, family impact, care goal creation, and team functioning. Psychometric analyses supported these 5 scales. CONCLUSIONS: This project developed and validated a survey with 19 experience items, plus additional demographic and health needs and usage items. The Pediatric Integrated Care Survey can be used in quality improvement efforts to measure family-reported experience of pediatric care integration. PMID- 27940673 TI - Can a Flavored Spray (Pill Glide) Help Children Swallow Their Medicines? A Pilot Study. AB - Pediatric pharmacists are constantly faced with the challenges of supporting children and caregivers for whom the difficulties of swallowing medicines can be a daily struggle. Most medicines are only available as tablets and capsules, and where liquid alternatives exist, these products often have issues with palatability and high costs. The objective of this study was to evaluate whether the swallowing spray, Pill Glide, could help children in taking their solid and liquid medicines. This open label pilot study compared the spray with a behavioral approach alone, the current standard of care at the pediatric hospital. Patients were children on long-term drug therapies, either transitioning from liquid preparations to tablets and capsules, or known to be experiencing swallowing difficulties. Using age-adapted diaries, patients self reported the difficulty of taking medicines on a 6-point hedonic scale for 2 weeks before the intervention, and then for 1 week while using Pill Glide. Data were analyzed from 10 children aged 6 to 16 years, with an average burden of 3.5 tablets per day. Pill Glide (strawberry was the most popular flavor) was shown to significantly decrease the overall medicine taking difficulty score by 0.93 (range, 0.33-1.53), almost 1 hedonic face point on the scale used (P = .002). There was insufficient data for liquid medicines. Pill Glide could help children with pill swallowing, thus improving patient acceptability of medicines and potentially adherence. It could also be implemented as a useful cost-saving intervention because solid dosage forms are cheaper. PMID- 27940675 TI - Socioeconomic Gaps in Parents' Discipline Strategies From 1988 to 2011. AB - BACKGROUND AND OBJECTIVES: The prevalence of corporal punishment is high in the United States despite a 1998 American Academy of Pediatrics policy statement urging against its use. The current study tests whether the socioeconomic difference in its use by parents has changed over the past quarter century. It goes on to test whether socioeconomic differences in the use of nonphysical discipline have also changed over time. METHODS: Data are drawn from 4 national studies conducted between 1988 and 2011. Each asked how often a kindergarten-aged child was spanked in the past week and what the parents would do if the child misbehaved, with physical discipline, time-out, and talking to child as possible responses. We use regression models to estimate parents' responses to these questions at the 90th, 50th, and 10th percentiles of the income and education distributions and t tests to compare estimates across cohorts. RESULTS: The proportion of mothers at the 50th income-percentile who endorse physical discipline decreased from 46% to 21% over time. Gaps between the 90th and 10th income-percentiles were stable at 11 and 18 percentage points in 1988 and 2011. The percentage of mothers at the 10th income-percentile endorsing time-outs increased from 51% to 71%, and the 90/10 income gap decreased from 23 to 14 percentage points between 1998 and 2011. CONCLUSIONS: Decline in popular support for physical discipline reflects real changes in parents' discipline strategies. These changes have occurred at all socioeconomic levels, producing for some behaviors a significant reduction in socioeconomic differences. PMID- 27940674 TI - Reliability and Validity of a Two-Question Alcohol Screen in the Pediatric Emergency Department. AB - BACKGROUND AND OBJECTIVE: A multisite study was conducted to determine the psychometric properties of the National Institute of Alcohol Abuse and Alcoholism (NIAAA) 2-question alcohol screen within pediatric emergency departments (PEDs). METHODS: Participants (N = 4838) included 12- to 17-year-old subjects treated in 1 of the 16 participating PEDs across the United States. A criterion assessment battery (including the NIAAA 2-question alcohol screen and other measures of alcohol, drug use, and risk behaviors) was self-administered on a tablet computer. A subsample (n = 186) was re-administered the NIAAA 2-question screen 1 week later to assess test-retest reliability. RESULTS: Moderate to good test retest reliability was demonstrated. A classification of moderate risk or higher on the screen had the best combined sensitivity and specificity for determining a diagnosis of alcohol use disorder (AUD) for all students. Any past year drinking among middle school students increased the odds of a diagnosis of an AUD according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria, whereas the optimal cutoff for high school ages was >=3 drinking days in the past year. The optimal cutoff for drinking days determining a positive Alcohol Use Disorders Identification Test score among middle school subjects was >=1 drinking day, whereas the optimal cutoff for high school subjects was >=2 drinking days. CONCLUSIONS: The NIAAA 2-question screen is a brief, valid approach for alcohol screening in PEDs. A positive screen suggests that referral for further evaluation is indicated to determine if an adolescent has an AUD. PMID- 27940676 TI - Solitary Participation in the "Choking Game" in Oregon. AB - OBJECTIVE: The purpose of this study was to compare characteristics of youth who participate in the choking game alone versus those who participate in a group. METHODS: Lifetime prevalence estimates were obtained from the 2011 (n = 5682) and 2013 (n = 15 150) Oregon Healthy Teens survey. The 2011 and 2013 data sets were merged (N = 20 832) to compare youth who participate alone versus those who participate in a group in the choking game. Multivariate modeling was conducted to examine individual characteristics of young people who engaged in the choking game alone versus those who engaged in the game in a group. RESULTS: In 2011, 3.8% of eighth-grade participants reported a lifetime prevalence of choking game participation; 3.7% reported lifetime prevalence of participation in 2013. In the merged 2011/2013 data set, 17.6% (n = 93) of choking game participants indicated that they had participated alone. Compared with those who reported participating in a group, youth who participated alone had significantly higher rates of suicide contemplation (odds ratio: 4.58; P < .001) and poor mental health (odds ratio: 2.13; P < .05). CONCLUSIONS: Youth who participate alone in the choking game are a particularly high risk group, exhibiting substantially higher rates of suicidal ideation and poorer mental health compared with youth who participate in the choking game in a group. Adolescent health care providers should be aware of these associations, assess whether prevention messaging is appropriate, and be prepared to explain the high risks of morbidity and mortality associated with participation. PMID- 27940677 TI - Mother- and Father-Adolescent Relationships and Early Sexual Intercourse. AB - OBJECTIVES: To assess the prospective associations between mother-adolescent and father-adolescent relationship quality and early sexual intercourse initiation (ie, <=16 years) among a large sample of Dutch adolescents. METHODS: Two waves of data from the Rotterdam Youth Monitor, a longitudinal study in the Netherlands, were used. The analysis sample consisted of 2931 adolescents aged 12 to 16 years (Meanage@T1 = 12.5 years, SD = 0.61; Meanage@T2 = 14.3 years, SD = 0.60). Variables were assessed by means of self-report questionnaires. Prospective associations between mother-adolescent and father-adolescent relationships and early sexual initiation were assessed by logistic regression analyses, stratified by gender, controlling for various potential confounders. RESULTS: We found that only girls (not boys) having a higher-quality relationship with mothers were significantly less likely to have initiated early sexual intercourse between T1 and T2. Bivariate findings showed that both girls and boys having a higher quality relationship with their father at T1 were significantly less likely to have engaged in early sexual intercourse between T1 and T2, but when assessed multivariately, these associations were no longer significant, neither for boys nor for girls. CONCLUSIONS: Our findings suggest that a higher-quality relationship between adolescents and their parents, especially between mothers and daughters, may help to protect against early sexual initiation. Pediatricians and other health care professionals should be able to explain to parents that early sexual intercourse initiation can be associated with negative health outcomes, but that parents can play an important role in promoting healthy sexual behaviors. PMID- 27940678 TI - Growth Trajectories of Refugee and Nonrefugee Children in the United States. AB - BACKGROUND AND OBJECTIVES: Limited data examine longitudinal nutrition outcomes of refugee children after United States resettlement. Among refugee children, our aims were to (1) assess the changes in weight-based nutritional status between baseline (0-3 months) and 10-24 months after arrival and (2) compare the BMI (BMIz) or weight-for-length z score (WFLz) trajectories to nonrefugee children for up to 36 months after arrival. METHODS: We conducted a retrospective study of refugees aged 0-16 years from Washington and Pennsylvania and compared them with an age and sex-matched nonrefugee low-income sample from Washington. Data included anthropometric measurements from the initial screening medical visit and subsequent primary care visits. Multilevel linear mixed-effects regression models evaluated the change in BMIz or WFLz trajectory. RESULTS: The study included 512 refugee and 1175 nonrefugee children. The unadjusted prevalence of overweight/obesity increased from 8.9% to 20% (P < .001) for 2- to 16-year-old refugees from baseline to 10-24 months. Refugees (2-16 years old) had a steeper increase in their BMIz per 12 months compared with nonrefugees (coefficient 0.18 vs 0.03; P < .001). Refugees <2 years old had a less steep increase in their WFLz per 12 months compared with nonrefugees (coefficient 0.12 vs 0.36, P = .002). CONCLUSIONS: Older refugee children exhibited a higher risk of obesity than nonrefugees, whereas refugees <2 years old exhibited a slower increase in their risk of obesity than nonrefugee children. All age groups experienced increasing obesity prevalence. Targeted and culturally tailored obesity prevention interventions may mitigate health and nutrition inequities among refugee children. PMID- 27940680 TI - Wernicke Encephalopathy in Adolescents After Bariatric Surgery: Case Report and Review. AB - Roughly 1% of all weight loss surgery is performed in adolescents. There is strong evidence demonstrating significant postsurgical weight loss, improvement in quality of life, and reduction in comorbidities such as hypertension and diabetes. Reports of postoperative complications in adolescents are few because of the small sample size in most series. Despite vitamin supplementation, nutritional deficiencies requiring hospitalization occur occasionally after Roux en-Y gastric bypass. Wernicke encephalopathy, a triad of ophthalmoplegia, ataxia, and altered mental status, is a serious consequence of thiamine (vitamin B1) deficiency. Few cases of Wernicke encephalopathy after weight loss surgery have been reported in the literature and even fewer in the pediatric population. Here we describe a teenage girl who develops vomiting after Roux-en-Y gastric bypass and presented with nystagmus, irritability, and ataxia. The clinical presentation, diagnosis, and treatment of Wernicke encephalopathy in adolescents after bariatric surgery are discussed. PMID- 27940679 TI - BMI Development and Early Adolescent Psychosocial Well-Being: UK Millennium Cohort Study. AB - BACKGROUND AND OBJECTIVES: The underlying influences on different patterns of BMI development are not well understood, and psychosocial outcomes linked to BMI development have been little investigated. Objectives were to identify BMI developmental trajectories across the first decade of life, examine early life predictors of trajectory membership, and investigate whether being on a particular BMI trajectory is associated with markers of psychosocial well-being. METHODS: We used latent class analysis to derive BMI trajectories by using data collected at ages 3, 5, 7, and 11 years on 16 936 participants from the Millennium Cohort Study. Regression models were used to estimate predictors of BMI trajectory membership and their psychosocial correlates. RESULTS: Four trajectories were identified: 83.8% had an average "stable" nonoverweight BMI, 0.6% were in a "decreasing" group, 13.1% had "moderate increasing" BMIs, and 2.5% had "high increasing" BMIs. Predictors of "moderate" and "high" increasing group membership were smoking in pregnancy (odds ratios [ORs] = 1.17 and 1.97, respectively), maternal BMI (ORs = 1.10 and 1.14), skipping breakfast (ORs = 1.66 and 1.76), nonregular bedtimes (ORs = 1.22 and 1.55). Children in the "moderate" and "high" increasing groups had worse scores for emotional symptoms, peer problems, happiness, body satisfaction, and self-esteem, and those in the "high increasing" group were more likely to have tried alcohol and cigarettes. CONCLUSIONS: Several potentially modifiable early life factors including smoking in pregnancy, skipping breakfast, and bedtime routines were important predictors of BMI development in the overweight and obese range, and high BMI growth was linked to worse psychosocial well-being. PMID- 27940681 TI - Resilience in Adolescence, Health, and Psychosocial Outcomes. AB - OBJECTIVES: This study was designed to determine whether black adolescents from disadvantaged backgrounds who have an unrelenting determination to succeed would, as adults, show "skin-deep resilience" by faring well in psychosocial domains but also show a heightened chance of having a chronic disease, specifically type 2 diabetes. METHODS: Secondary data analyses were executed with the use of waves 1 and 4 of the US Longitudinal Study of Adolescent to Adult Health (Add Health). At wave 1, when participants were age 16, data were obtained on a behavioral style termed "striving." Striving includes high aspirations, unwavering persistence, investment in education, and avoidance of activities that sidetrack success. At wave 4, when participants were age 29, college graduation, personal income, symptoms of depression, and type 2 diabetes status were assessed. RESULTS: Black and non-Hispanic white youth who displayed striving during adolescence evinced, at age 29, a higher likelihood of college graduation, greater personal income, and fewer symptoms of depression than did nonstrivers. Among black participants, the findings were consistent with the "skin-deep resilience" pattern for type 2 diabetes. High-striving black adolescents in the most disadvantaged families had a greater likelihood of developing type 2 diabetes during adulthood than did similar high-striving black adolescents living in more privileged families. The skin-deep resilience pattern did not emerge among non-Hispanic white participants. CONCLUSIONS: This study is the first to show that an unrelenting determination to succeed among black adolescents from disadvantaged backgrounds forecasts an elevated risk of developing type 2 diabetes during adulthood. PMID- 27940682 TI - Definitions and Assessment Approaches for Emergency Medical Services for Children. AB - Pediatric Life Support (PLS) courses and instructional programs are educational tools developed to teach resuscitation and stabilization of children who are critically ill or injured. A number of PLS courses have been developed by national professional organizations for different health care providers (eg, pediatricians, emergency physicians, other physicians, prehospital professionals, pediatric and emergency advanced practice nurses, physician assistants). PLS courses and programs have attempted to clarify and standardize assessment and treatment approaches for clinical practice in emergency, trauma, and critical care. Although the effectiveness of PLS education has not yet been scientifically validated, the courses and programs have significantly expanded pediatric resuscitation training throughout the United States and internationally. Variability in terminology and in assessment components used in education and training among PLS courses has the potential to create confusion among target groups and in how experts train educators and learners to teach and practice pediatric emergency, trauma, and critical care. It is critical that all educators use standard terminology and patient assessment to address potential or actual conflicts regarding patient evaluation and treatment. This article provides a consensus of several organizations as to the proper order and terminology for pediatric patient assessment. The Supplemental Information provides definitions for terms and nomenclature used in pediatric resuscitation and life support courses. PMID- 27940684 TI - Cytokine Elevation in Sudden Death With Respiratory Syncytial Virus: A Case Report of 2 Children. AB - Respiratory syncytial virus (RSV) is the most common viral cause of bronchiolitis and pneumonia in young children worldwide. Premature birth, bronchopulmonary dysplasia, congenital heart disease, and Down syndrome are risk factors for high mortality and prolonged morbidity after RSV infection. Conversely, many previously healthy, full-term children are also admitted to the hospital because of RSV, and some of them experience severe sequelae or die due to the virus. Various complications of RSV infection have been reported, such as encephalopathy, encephalitis, and cardiomyopathy. However, the pathogenesis of serious cases in children without an underlying disease has not been elucidated. In this report, we present 2 RSV-related deaths of children who were born at full term and developed normally up to the age of 19 months. Their cardiopulmonary arrests occurred within half a day after the onset of symptoms, such as cough and high fever. Many postmortem examinations were performed to investigate their unexpected deaths. Histopathological examinations revealed extensive bronchiolitis and mild pneumonia accompanying airway obstruction. Immunostaining revealed the presence of the virus mainly in bronchial epithelia, but not in alveoli. Complete brain edema was prominent, and encephalopathy was developing. Blood tests revealed that the IL-6 level was elevated more than >200-fold above normal, despite a normal C-reactive protein level. Because IL-6 may reflect the severity of bronchial epithelial damage and contribute to brain edema, an extreme elevation of IL-6 may predict the risk for sudden death in children with RSV infection. PMID- 27940683 TI - Modification of an Established Pediatric Asthma Pathway Improves Evidence-Based, Efficient Care. AB - OBJECTIVE: In September 2011, an established pediatric asthma pathway at a tertiary care children's hospital underwent significant revision. Modifications included simplification of the visual layout, addition of evidence-based recommendations regarding medication use, and implementation of standardized admission criteria. The objective of this study was to determine the impact of the modified asthma pathway on pathway adherence, percentage of patients receiving evidence-based care, length of stay, and cost. METHODS: Cases were identified by using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Data were analyzed for 24 months before and after pathway modification. Statistical process control was used to examine changes in processes of care, and interrupted time series was used to examine outcome measures, including length of stay and cost in the premodification and postmodification periods. RESULTS: A total of 5584 patients were included (2928 premodification; 2656 postmodification). Pathway adherence was high (79%-88%) throughout the study period. The percentage of patients receiving evidence-based care improved after pathway modification, and the results were sustained for 2 years. There was also improved efficiency, with a 30-minute (10%) decrease in emergency department length of stay for patients admitted with asthma (P = .006). There was a nominal (<10%) increase in costs of asthma care for patients in the emergency department (P = .04) and no change for those admitted to the hospital. CONCLUSIONS: Modification of an existing pediatric asthma pathway led to sustained improvement in provision of evidence-based care and patient flow without adversely affecting costs. Our results suggest that continuous re evaluation of established clinical pathways can lead to changes in provider practices and improvements in patient care. PMID- 27940685 TI - Prenatal Iron Deficiency, Neonatal Ferritin, and Infant Cognitive Function. AB - OBJECTIVE: To investigate the impact of prenatal maternal iron deficiency (ID) on cord blood serum ferritin (CBSF) concentration and infant cognitive and motor development. METHODS: Our prospective cohort study included 636 mother-singleton child pairs from 828 eligible pregnant women who were enrolled during their first antenatal care (ANC) visit in Allada, Benin, into a clinical trial comparing the efficacy of mefloquine and sulfadoxine-pyrimethamine. Venous blood samples of women were assessed for ferritin and hemoglobin concentrations at the first and second ANC visits (occurring at least 1-month apart) and at delivery. Women were prescribed daily iron and folic acid supplements throughout pregnancy. Hematologic examinations were repeated for cord blood at birth. At age 1 year, cognitive and motor functions of children were assessed by using the Mullen Scales of Early Learning. RESULTS: The prevalence of prenatal ID at first and second ANC visits, and at delivery was 30.5%, 34.0%, and 28.4%, respectively. CBSF concentrations were similar between ID and non-ID pregnant women. Neither prenatal ID nor CBSF concentration was associated with poor cognitive or gross motor function of children at age 1 year. CBSF concentrations were lower among mothers who had ID anemia (IDA) at delivery compared with non-IDA pregnant women (adjusted mean difference: -0.2 [95% confidence interval: -0.4 to -0.0]). CONCLUSIONS: In a malaria-endemic region, ID in pregnancy in the context of iron supplementation is neither associated with CBSF concentration nor with infant cognitive and motor development. Prenatal IDA around the time of delivery is associated with lower CBSF concentrations. PMID- 27940686 TI - School-Age Outcomes of Early Intervention for Preterm Infants and Their Parents: A Randomized Trial. AB - OBJECTIVE: To examine the child and parental outcomes at school age of a randomized controlled trial of a home-based early preventative care program for infants born very preterm and their caregivers. METHODS: At term-equivalent age, 120 infants born at a gestational age of <30 weeks were randomly allocated to intervention (n = 61) or standard care (n = 59) groups. The intervention included 9 home visits over the first year of life focusing on infant development, parental mental health, and the parent-infant relationship. At 8 years' corrected age, children's cognitive, behavioral, and motor functioning and parental mental health were assessed. Analysis was by intention to treat. RESULTS: One hundred children, including 13 sets of twins, attended follow-up (85% follow-up of survivors). Children in the intervention group were less likely to have mathematics difficulties (odds ratio, 0.42; 95% confidence interval [CI], 0.18 to 0.98; P = .045) than children in the standard care group, but there was no evidence of an effect on other developmental outcomes. Parents in the intervention group reported fewer symptoms of depression (mean difference, -2.7; 95% CI, -4.0 to -1.4; P < .001) and had reduced odds for mild to severe depression (odds ratio, 0.14; 95% CI, 0.03 to 0.68; P = .0152) than parents in the standard care group. CONCLUSIONS: An early preventive care program for very preterm infants and their parents had minimal long-term effects on child neurodevelopmental outcomes at the 8-year follow-up, whereas primary caregivers in the intervention group reported less depression. PMID- 27940687 TI - Survival and Neurodevelopmental Outcomes of Preterms Resuscitated With Different Oxygen Fractions. AB - BACKGROUND AND OBJECTIVES: Stabilization of preterm infants after birth frequently requires oxygen supplementation. At present the optimal initial oxygen inspiratory fraction (Fio2) for preterm stabilization after birth is still under debate. We aimed to compare neurodevelopmental outcomes of extremely preterm infants at 24 months corrected age randomly assigned to be stabilized after birth with an initial Fio2 of 0.3 versus 0.6 to 0.65 in 3 academic centers from Spain and the Netherlands. METHODS: Randomized, controlled, double-blinded, multicenter, international clinical trial enrolling preterm infants <32 weeks' gestation assigned to an initial Fio2 of 0.3 (Lowox group) or 0.6 to 0.65 (Hiox group). During stabilization, arterial pulse oxygen saturation and heart rate were continuously monitored and Fio2 was individually titrated to keep infants within recommended ranges. At 24 months, blinded researchers used the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) to assess visual acuity, neurosensory deafness, and language skills. RESULTS: A total of 253 infants were recruited and 206 (81.4%) completed follow-up. No differences in perinatal characteristics, oxidative stress, or morbidities during the neonatal period were assessed. Mortality at hospital discharge or when follow-up was completed didn't show differences between the groups. No differences regarding Bayley-III scale scores (motor, cognitive, and language composites), neurosensorial handicaps, cerebral palsy, or language skills between groups were found. CONCLUSIONS: The use of an initial lower (0.3) or higher (0.6-0.65) Fio2 during stabilization of extremely preterm infants in the delivery room does not influence survival or neurodevelopmental outcomes at 24 months. PMID- 27940688 TI - Self-Regulation and Sleep Duration, Sleepiness, and Chronotype in Adolescents. AB - OBJECTIVE: To determine whether shorter school-night sleep duration, greater daytime sleepiness, and greater eveningness chronotype were associated with lower self-regulation among adolescents. METHODS: An online survey of 7th- to 12th grade students in 19 schools in Fairfax County, Virginia Public Schools was conducted in 2015. Self-regulation was measured with the Behavior Rating Inventory of Executive Function, 2nd edition, Screening Self-Report Form. Sleep measures included school night-sleep duration (hours between usual bedtime and wake time), daytime sleepiness (Sleepiness Scale in the Sleep Habits Survey, tertiles), and chronotype (Morningness-Eveningness Scale for Children, continuous score and tertiles). Sociodemographic factors and mental health conditions were analyzed as potential confounders. RESULTS: Among 2017 students surveyed, the mean age was 15.0 years (range, 12.1-18.9 years), and 21.7% slept <7 hours on school nights. In regression models adjusted for confounders, there was a significant independent association between self-regulation and both chronotype (P < .001) and daytime sleepiness (P < .001) but not sleep duration (P = .80). Compared with those in the lowest tertile of daytime sleepiness, those in the highest tertile had lower (0.59 SD units; 95% confidence interval, 0.48-0.71) self-regulation, as did those in the eveningness tertile of chronotype compared with those in the morningness tertile (0.35 SD units lower; 95% confidence interval, 0.24-0.46). CONCLUSIONS: Among adolescents, greater daytime sleepiness and greater eveningness chronotype were independently associated with lower self regulation, but shorter sleep duration was not. Aspects of sleep other than school-night sleep duration appear to be more strongly associated with self regulation. PMID- 27940689 TI - School Entry Requirements and Coverage of Nontargeted Adolescent Vaccines. AB - BACKGROUND: Low human papillomavirus (HPV) vaccination coverage is an urgent public health problem requiring action. To identify policy remedies to suboptimal HPV vaccination, we assessed the relationship between states' school entry requirements and adolescent vaccination. METHODS: We gathered data on states' school entry requirements for adolescent vaccination (tetanus, diphtheria, and pertussis [Tdap] booster; meningococcal; and HPV) from 2007 to 2012 from Immunization Action Coalition. The National Immunization Survey-Teen provided medical record-verified vaccination data for 99 921 adolescents. We calculated coverage (among 13- to 17-year-olds) for individual vaccinations and concomitant vaccination. HPV vaccination outcomes were among female adolescents. Analyses used weighted longitudinal multivariable models. RESULTS: States with requirements for Tdap booster and meningococcal vaccination had 22 and 24 percentage point increases in coverage for these vaccines, respectively, compared with other states (both P < .05). States with HPV vaccination requirements had <1 percentage point increase in coverage for this vaccine (P < .05). Tdap booster and meningococcal vaccination requirements, respectively, were associated with 8 and 4 percentage point spillover increases for HPV vaccination coverage (both P < .05) and with increases for concomitant vaccination (all P < .05). CONCLUSIONS: Ensuring all states have meningococcal vaccination requirements could improve the nation's HPV vaccination coverage, given that many states already require Tdap booster but not meningococcal vaccination for school entry. Vaccination programs and clinicians should capitalize on changes in adolescent vaccination, including concomitant vaccination, that may arise after states adopt vaccination requirements. Additional studies are needed on the effects of HPV vaccination requirements and opt-out provisions. PMID- 27940690 TI - Developmental Outcomes of Preterm Infants With Neonatal Hypoglycemia. AB - BACKGROUND AND OBJECTIVES: Neonatal hypoglycemia has been associated with abnormalities on brain imaging and a spectrum of developmental delays, although historical and recent studies show conflicting results. We compared the cognitive, academic, and behavioral outcomes of preterm infants with neonatal hypoglycemia with those of normoglycemic controls at 3 to 18 years of age. METHODS: A secondary analysis of data from the Infant Health and Development Program, a national, multisite, randomized controlled longitudinal intervention study of long-term health and developmental outcomes in preterm infants. Of the 985 infants enrolled in the Infant Health and Development Program, 745 infants had glucose levels recorded. Infants were stratified into 4 groups by glucose level. By using standardized cognitive, academic, and behavioral assessments performed at 3, 8, and 18 years of age, we compared groups after adjusting for intervention status, birth weight, gestational age, sex, severity of neonatal course, race, maternal education, and maternal preconception weight. RESULTS: No significant differences were observed in cognitive or academic skills between the control and effected groups at any age. Participants with more severe neonatal hypoglycemia reported fewer problem behaviors at age 18 than those without hypoglycemia. CONCLUSIONS: No significant differences in intellectual or academic achievement were found between preterm infants with and without hypoglycemia. A statistical difference was found in behavior at age 18, with hypoglycemic children showing fewer problematic behaviors than normoglycemic children. This difference was not clinically meaningful. Using extended outcomes, our results are consistent with previous studies that found no significant neurodevelopmental outcomes associated with neonatal hypoglycemia in preterm-born children. PMID- 27940691 TI - Seizure Treatment in Children Transported to Tertiary Care: Recommendation Adherence and Outcomes. AB - BACKGROUND AND OBJECTIVES: Convulsive seizures account for 15% of pediatric air transports. We evaluated seizure treatment received in community hospital emergency departments among transported patients for adherence to recommended management. METHODS: This study was a retrospective cohort study of children transported for an acute seizure to a tertiary pediatric hospital from 2010 to 2013. Seizure treatment was evaluated for adherence to recommended management. The primary outcome was intubation. RESULTS: Among 126 events, 61% did not receive recommended acute treatment. The most common deviation from recommended care was administration of >2 benzodiazepine doses. Lack of adherence to recommended care was associated with a greater than twofold increased risk of intubation (relative risk 2.4; 95% confidence interval, 1.4-4.13) and 1.5-fold increased risk of admission to the ICU (relative risk 1.65; 95% confidence interval, 1.24-2.16). Duration of ventilation was commonly <24 hours (87%) for patients who did or did not receive recommended acute seizure care. Among events treated initially with a benzodiazepine, only 32% received a recommended weight based dosage, and underdosing was most common. CONCLUSIONS: Adherence to evidence based recommended acute seizure treatment during initial care of pediatric patients using medical air transportation was poor. Intubation was more common when patients did not receive recommended acute seizure care. Educational efforts with a sustained quality focus should be directed to increase adherence to appropriate pediatric seizure treatment of children in community emergency departments. PMID- 27940693 TI - Use of Food Allergy Panels by Pediatric Care Providers Compared With Allergists. AB - BACKGROUND AND OBJECTIVE: Immunoglobullin E (IgE)-mediated food allergies affect 5% to 8% of children. Serum IgE levels assist in diagnosing food allergies but have low positive predictive value. This can lead to misinterpretation, overdiagnosis, and unnecessary dietary elimination. Use of IgE food allergen panels has been associated with increased cost and burden. The scale of use of these panels has not been reported in the medical literature. METHODS: We conducted a retrospective review of a commercial laboratory database associated with a tertiary care pediatric academic medical center for food IgE tests ordered by all provider types during 2013. RESULTS: A total of 10 794 single-food IgE tests and 3065 allergen panels were ordered. Allergists ordered the majority of single-food IgE tests (58.2%) whereas 78.8% of food allergen panels were ordered by primary care providers (PCPs) (P < .001). Of all IgE tests ordered by PCPs, 45.1% were panels compared with 1.2% of orders placed by allergists (P < .001). PCPs in practice for >15 years ordered a higher number of food allergen panels (P < .05) compared with PCPs with less experience. Compared with allergists, PCPs ordered more tests for unlikely causes of food allergies (P < .001). Total cost of IgE testing and cost per patient were higher for PCPs compared with allergists. CONCLUSIONS: Review of food allergen IgE testing through a high volume outpatient laboratory revealed PCPs order significantly more food allergen panels, tests for uncommon causes of food allergy, and generate higher cost per patient compared with allergists. These results suggest a need for increased education of PCPs regarding proper use of food IgE tests. PMID- 27940692 TI - Severe Hemolysis and Pulmonary Hypertension in a Neonate With Upshaw-Schulman Syndrome. AB - Pulmonary involvement is extremely rare in thrombotic thrombocytopenic purpura. In this report, we present a girl patient with congenital thrombotic thrombocytopenic purpura, known as Upshaw-Schulman syndrome (USS), complicated with severe hemolysis and pulmonary hypertension (PH). The assay results of a disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13 (ADAMTS13) activity measured by FRETS-VWF73 and ADAMTS13-act-ELISA were different. Hyperbilirubinemia (total bilirubin, 25.3 mg/dL) interfered strongly with the FRETS-VWF73 assay. Plasma levels of ADAMTS13 activity by act-ELISA were <0.5% of normal. The diagnosis of USS was confirmed by ADAMTS13 gene analysis, which showed compound heterozygous mutations of p.G139Vfs*17 and p.I673F. The p.G139Vfs*17 mutation was previously unreported, and its effect in splicing was confirmed by reverse transcription polymerase chain reaction. The patient received oxygen therapy for PH and exchange blood transfusion for severe hemolysis. The PH resolved without specific treatment. Based on these findings, the PH may have been caused by free hemoglobin that scavenged nitrogen oxide or platelet thrombi in the lungs caused by ADAMTS13 deficiency. Thus, severe PH can occur in neonatal patients with USS, and severe hemolysis might result in overestimation of ADAMTS 13 activity. Both possibilities are important for the diagnosis and management of USS. PMID- 27940694 TI - Anthropometric Charts for Infants Born Between 22 and 29 Weeks' Gestation. AB - OBJECTIVES: Using a large, racially diverse US dataset, we aimed primarily to: (1) fit and validate sex-specific birth weight and head circumference for gestational age charts for infants born at 22 to 29 weeks' gestation; and (2) fit race-specific birth weight and head circumference for gestational age charts. METHODS: We used data collected between 2006 and 2014 on 183 243 singleton infants without congenital malformations with gestational age between 22 weeks, 0 days and 29 weeks, 6 days from 852 US members of the Vermont Oxford Network. For the sex-specific charts, the final sample size included 156 587 infants who survived hospital discharge. From these 156 587, we abstracted a subset of 47 005 infants to fit sex-specific charts separately for white, black, and Asian infants. For all charts, we applied quantile regression models to predict infants' birth weight and head circumference percentiles from gestational age expressed in days. RESULTS: We successfully validated the overall sex-specific charts. Over most of the gestational age range, black infants, either girls or boys, had the lowest predicted birth weight as compared with white and Asian infants for many percentiles. CONCLUSIONS: We fitted and validated new sex specific charts using a recent, large, and racially diverse dataset. Future steps include using these charts to examine associations of weight and head circumference at birth with mortality and morbidity. PMID- 27940695 TI - Intravenous Versus Oral Antibiotics for Postdischarge Treatment of Complicated Pneumonia. AB - BACKGROUND AND OBJECTIVES: Postdischarge treatment of complicated pneumonia includes antibiotics administered intravenously via a peripherally inserted central venous catheter (PICC) or orally. Antibiotics administered via PICC, although effective, may result in serious complications. We compared the effectiveness and treatment-related complications of postdischarge antibiotics delivered by these 2 routes. METHODS: This multicenter retrospective cohort study included children >=2 months and <18 years discharged with complicated pneumonia between 2009 and 2012. The main exposure was the route of postdischarge antibiotic administration, classified as PICC or oral. The primary outcome was treatment failure. Secondary outcomes included PICC complications, adverse drug reactions, other related revisits, and a composite of all 4 outcomes, termed "all related revisits." RESULTS: Among 2123 children, 281 (13.2%) received antibiotics via PICC. Treatment failure rates were 3.2% among PICC and 2.6% among oral antibiotic recipients and were not significantly different between the groups in across-hospital-matched analysis (matched odds ratio [OR], 1.26; 95% confidence interval [CI], 0.54 to 2.94). PICC complications occurred in 7.1%. Adverse drug reactions occurred in 0.6% of children; PICC antibiotic recipients had greater odds of adverse drug reaction in across hospital matched analysis (matched OR, 19.1; 95% CI, 4.2 to 87.3). The high rate of PICC complications and differences in adverse drug reactions contributed to higher odds of the composite outcome of all related revisits among PICC antibiotic recipients (matched OR, 4.71; 95% CI, 2.97 to 7.46). CONCLUSIONS: Treatment failure rates between PICC and oral antibiotics did not differ. Children with complicated pneumonia should preferentially receive oral antibiotics at discharge when effective oral options are available. PMID- 27940696 TI - Screening in Primary Care: What Is the Best Way to Identify At-Risk Youth for Substance Use? AB - BACKGROUND: It is important to improve primary care providers' capability to identify youth at risk for alcohol and other drug use. To our knowledge, this is the first study to use Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria to compare screeners for youth for both alcohol and marijuana, given that these are the most frequently used substances by this age group. METHODS: We compared the psychometric performance of 4 screeners: the National Institute on Alcohol Abuse and Alcoholism Screening Guide (NIAAA SG), the Alcohol Use Disorders Identification Test, the Car-Relax-Alone-Forget-Family and Friends-Trouble (CRAFFT) screener, and the Personal Experience Screening Questionnaire Problem Severity Scale (PESQ-PS) in identifying alcohol and marijuana use outcomes. Youth age 12 through 18 (N = 1573; 27% black, 51% Hispanic) were screened with the NIAAA SG, followed by a Web survey that included the other screeners and outcomes. RESULTS: Sensitivity for alcohol outcomes indicated that the NIAAA SG (0.87) did not perform as well as the CRAFFT (0.97) or PESQ-PS (0.97) screeners but performed better than the Alcohol Use Disorders Identification Test (0.70). The pattern for sensitivity across screeners for marijuana outcomes was similar. CONCLUSIONS: An important tradeoff in primary care settings is precision versus practicality. Because of brevity and focus on frequency of drinking, the NIAAA SG offers ease of administration and is good at identifying youth with probably problematic drinking levels. The PESQ-PS and the CRAFFT correctly identify more at-risk youth for alcohol and marijuana than the NIAAA SG. Future work is needed to elucidate how to efficiently and accurately identify at-risk youth in the primary care setting, including determining the best cutoff points to use to increase sensitivity. PMID- 27940697 TI - Familial Congenital Facial Synkinesis Due to 12q Duplication: A Case Report and Literature Review. AB - Inverse Marcus Gunn phenomenon is a rare form of congenital facial synkinesis in which jaw movement temporarily elicits ptosis, either unilateral or bilateral. This phenomenon is presumed to result from dysinnervation of facial muscles during development of the nervous system. We describe 2 brothers, both with inverse Marcus Gunn phenomenon in the context of multiple other congenital anomalies, all presumed secondary to a chromosomal abnormality involving 12q duplication and 1p36 deletion. Although a handful of familial cases of congenital facial synkinesis have been previously described, this is the first in which a genetic abnormality has been identified. Of the 4 genetic abnormalities previously described in association with congenital facial synkinesis (based on isolated case reports), 1 also involved duplication at the long arm of chromosome 12. We conclude that duplication of >=1 of the roughly 44 protein-coding genes in the ~6.3-Mb overlap region between the previously published case and our 2 patients is a likely genetic cause of congenital facial synkinesis. PMID- 27940698 TI - Use of Low-Value Pediatric Services Among the Commercially Insured. AB - BACKGROUND: Claims-based measures of "low-value" pediatric services could facilitate the implementation of interventions to reduce the provision of potentially harmful services to children. However, few such measures have been developed. METHODS: We developed claims-based measures of 20 services that typically do not improve child health according to evidence-based guidelines (eg, cough and cold medicines). Using these measures and claims from 4.4 million commercially insured US children in the 2014 Truven MarketScan Commercial Claims and Encounters database, we calculated the proportion of children who received at least 1 low-value pediatric service during the year, as well as total and out-of pocket spending on these services. We report estimates based on "narrow" measures designed to only capture instances of service use that were low-value. To assess the sensitivity of results to measure specification, we also reported estimates based on "broad measures" designed to capture most instances of service use that were low-value. RESULTS: According to the narrow measures, 9.6% of children in our sample received at least 1 of the 20 low-value services during the year, resulting in $27.0 million in spending, of which $9.2 million was paid out-of pocket (33.9%). According to the broad measures, 14.0% of children in our sample received at least 1 of the 20 low-value services during the year. CONCLUSIONS: According to a novel set of claims-based measures, at least 1 in 10 children in our sample received low-value pediatric services during 2014. Estimates of low value pediatric service use may vary substantially with measure specification. PMID- 27940699 TI - Mechanistic Pathways From Early Gestation Through Infancy and Neurodevelopment. AB - OBJECTIVE: To identify pathways through which pre- and postnatal factors directly or indirectly affect infant neurodevelopment at 12 months of age among Filipino infants. METHODS: The Bayley Scales of Infant Development, third edition was used to assess the development of 314 infants of mothers enrolled in a trial examining the safety and efficacy of praziquantel during pregnancy. Maternal covariates included socioeconomic status, iron and nutritional status, cognitive performance, and alcohol intake. Infant covariates included birth weight and feeding practices, longitudinal growth and nutritional status, hemoglobin and iron status captured at birth, and 6 and 12 months of age. Multivariable regression and structural equation modeling were used to identify significant factors associated with infant development. RESULTS: In regression models, maternal education, cognition, and iron status as well as infant weight-for-age z score (WAZ), weight-for-length z-score, and WAZ gains were significantly associated with infant development at 12 months of age. Structural equation modeling demonstrated a direct effect of maternal cognition on most subscales of infant development and indirect effects on expressive language through effects on infant WAZ. Maternal iron status was a stronger predictor of infant cognition subscale scores than was infant iron status. Exclusive breastfeeding had a direct influence on expressive language rather than acting through improved infant iron or nutritional status. CONCLUSIONS: We identified key modifiable risk factors for impaired neurodevelopment, including prenatal risk factors such as maternal iron status. Integrated nutritional interventions that impact both maternal and infant nutritional status are likely to positively affect infant neurodevelopment through identified pathways. PMID- 27940702 TI - Promoting Health Literacy for Children and Adolescents. PMID- 27940701 TI - National Trends in the Prevalence and Treatment of Depression in Adolescents and Young Adults. AB - OBJECTIVES: This study examined national trends in 12-month prevalence of major depressive episodes (MDEs) in adolescents and young adults overall and in different sociodemographic groups, as well as trends in depression treatment between 2005 and 2014. METHODS: Data were drawn from the National Surveys on Drug Use and Health for 2005 to 2014, which are annual cross-sectional surveys of the US general population. Participants included 172 495 adolescents aged 12 to 17 and 178 755 adults aged 18 to 25. Time trends in 12-month prevalence of MDEs were examined overall and in different subgroups, as were time trends in the use of treatment services. RESULTS: The 12-month prevalence of MDEs increased from 8.7% in 2005 to 11.3% in 2014 in adolescents and from 8.8% to 9.6% in young adults (both P < .001). The increase was larger and statistically significant only in the age range of 12 to 20 years. The trends remained significant after adjustment for substance use disorders and sociodemographic factors. Mental health care contacts overall did not change over time; however, the use of specialty mental health providers increased in adolescents and young adults, and the use of prescription medications and inpatient hospitalizations increased in adolescents. CONCLUSIONS: The prevalence of depression in adolescents and young adults has increased in recent years. In the context of little change in mental health treatments, trends in prevalence translate into a growing number of young people with untreated depression. The findings call for renewed efforts to expand service capacity to best meet the mental health care needs of this age group. PMID- 27940700 TI - Acceptability of Family-Centered Advanced Care Planning for Adolescents With HIV. AB - BACKGROUND AND OBJECTIVE: Small pilot studies support the appropriateness of engaging adolescents with chronic or life-limiting illnesses in pediatric advance care planning (pACP). We do not yet know if pACP is acceptable, feasible, and worthwhile, even if emotionally intense, in a fully powered randomized controlled trial. METHODS: We conducted a prospective 2-arm randomized controlled trial at 6 US urban hospitals. Adolescent/family member dyads were randomized to receive the 1-session-a-week 3-session FAmily-CEntered Advance Care Planning (FACE) pACP intervention (1, ACP Survey; 2, Goals of Care Conversation/Treatment Preferences; 3, Completion of Advance Directive) or active comparator (1, Developmental History; 2, Safety Tips; 3, Nutrition/Exercise). The Satisfaction Questionnaire was administered to participants independently after each session by a blinded research assistant. RESULTS: We enrolled 53% of eligible participants and intervened with 97 adolescent/family dyads. Adolescents ranged in age from 14 to 21 years; 54% were male individuals; 93% African American; and 73% perinatally infected. Attendance was 99% for all 3 sessions in each arm. At session 3, FACE adolescents and family dyad members, respectively, found the session useful (98%, 98%) and helpful (98%, 100%), despite feelings of sadness (25%, 17%). FACE adolescents' improvement in the total subscale A score (useful, helpful, like a load off my mind, satisfied, something I needed to do, courageous, worthwhile) was better than control adolescents at session 3 (beta = 1.16, P = .02). There were no adverse events. CONCLUSIONS: FACE enabled worthwhile conversations, while simultaneously eliciting intense emotions. No participants withdrew, 99% of those enrolled completed each session, and there were no adverse events, evidence of pACP's feasibility, acceptability, and safety. PMID- 27940703 TI - Use of Gastroesophageal Reflux Medications in Premature Infants After NICU Discharge. AB - OBJECTIVES: To describe the epidemiology and management of gastroesophageal reflux (GER) medications started in the first year of life for premature infants. METHODS: Retrospective review of a cohort of infants <=35 weeks' gestation presenting for care by 168 days of age to a 30-site network between 2005 and 2009 (n = 2217) and followed to 3 years of age. Medication frequency, types, and duration of use were assessed. Logistic regression identified factors associated with treatment. RESULTS: Thirty-seven percent (812) were prescribed GER medications with 77% begun after NICU discharge. Ninety percent (727) received histamine-2 receptor antagonists, 33% (269) proton pump inhibitors, 22% (182) prokinetics; 40% (325) received >1 medication. Outpatient medication was initiated at 95 +/- 69 days of life for total of 294 +/- 249 days (interquartile ratio: 117-359). Feeding issues (adjusted odds ratio [aOR] 2.05, 95% confidence interval [CI]: 1.24-3.39) were associated with outpatient initiation. Forty-three percent (322) of infants started before 6 months were still on at 1 year of age associated with gestational age <32 weeks (aOR 1.76, 95% CI: 1.16-2.67), chronic lung disease (aOR 2.59, 95% CI: 1.29-5.22), and reactive airways disease (aOR 1.67, 95% CI: 1.05-2.65). CONCLUSIONS: Of the 37% of the cohort on GER medications, 77% were started after NICU discharge with prolonged use of medications. Feeding difficulties were associated with starting medication and markers of chronic lung disease with continuation of treatment. With uncertain evidence of efficacy, use of these medications in a high-risk population should be carefully evaluated. PMID- 27940704 TI - Planned Birth Before 39 Weeks and Child Development: A Population-Based Study. AB - OBJECTIVE: To investigate the association of gestational age and mode of birth with early child development. METHODS: Population-based record linkage cohort study was conducted among 153 730 live-born infants of >=32 weeks' gestation with developmental assessments at school age, in New South Wales, Australia, 2002 to 2007. Children were assessed in 5 domains: physical health and well-being, language and cognition, social competence, emotional maturity, and general knowledge and communication. Children scoring in the bottom 10% of national domains were considered developmentally vulnerable, and children developmentally vulnerable for >=2 domains were classified as developmentally high risk (DHR), the primary outcome. Robust multivariable Poisson models were used to obtain individual and combined adjusted relative risks (aRRs) of gestational age and mode of birth for DHR children. RESULTS: Overall, 9.6% of children were DHR. The aRR (95% confidence interval) of being DHR increased with decreasing gestational age (referent: 40 weeks); 32 to 33 weeks 1.25 (1.08-1.44), 34 to 36 weeks 1.26 (1.18-1.34), 37 weeks 1.17 (1.10-1.25), 38 weeks 1.06 (1.01-1.10), 39 weeks 0.98 (0.94-1.02), >=41 weeks 0.99 (0.94-1.03), and for labor induction or prelabor cesarean delivery (planned birth; referent: vaginal birth after spontaneous labor), 1.07 (1.04-1.11). The combined aRR for planned birth was 1.26 (1.18-1.34) at 37 weeks and 1.13 (1.08-1.19) at 38 weeks. CONCLUSIONS: Early (at <39 weeks) planned birth is associated with an elevated risk of poor child development at school age. The timing of planned birth is modifiable, and strategies to inform more judicious decision-making are needed to ensure optimal child health and development. PMID- 27940705 TI - Epidemiology of Invasive Early-Onset Neonatal Sepsis, 2005 to 2014. AB - BACKGROUND: Group B Streptococcus (GBS) and Escherichia coli have historically dominated as causes of early-onset neonatal sepsis. Widespread use of intrapartum prophylaxis for GBS disease led to concerns about the potential adverse impact on E coli incidence. METHODS: Active, laboratory, and population-based surveillance for culture-positive (blood or cerebrospinal fluid) bacterial infections among infants 0 to 2 days of age was conducted statewide in Minnesota and Connecticut and in selected counties of California and Georgia during 2005 to 2014. Demographic and clinical information were collected and hospital live birth denominators were used to calculate incidence rates (per 1000 live births). We used the Cochran-Amitage test to assess trends. RESULTS: Surveillance identified 1484 cases. GBS was most common (532) followed by E coli (368) and viridans streptococci (280). Eleven percent of cases died and 6.3% of survivors had sequelae at discharge. All-cause (2005: 0.79; 2014: 0.77; P = .05) and E coli (2005: 0.21; 2014: 0.18; P = .25) sepsis incidence were stable. GBS incidence decreased (2005: 0.27; 2014: 0.22; P = .02). Among infants <1500 g, incidence was an order of magnitude higher for both pathogens and stable. The odds of death among infants <1500 g were similar for both pathogens but among infants >=1500 g, the odds of death were greater for E coli cases (odds ratio: 7.0; 95% confidence interval: 2.7-18.2). CONCLUSIONS: GBS prevention efforts have not led to an increasing burden of early-onset E coli infections. However, the stable burden of E coli sepsis and associated mortality underscore the need for interventions. PMID- 27940707 TI - Management of Fever in Young Infants: Evidence Versus Common Practice. PMID- 27940708 TI - Zika as a Catalyst for Social Change. PMID- 27940706 TI - Preschool ADHD Diagnosis and Stimulant Use Before and After the 2011 AAP Practice Guideline. AB - OBJECTIVE: To evaluate the change in the diagnosis of attention deficit/hyperactivity disorder (ADHD) and prescribing of stimulants to children 4 to 5 years old after release of the 2011 American Academy of Pediatrics guideline. METHODS: Electronic health record data were extracted from 63 primary care practices. We included preventive visits from children 48 to 72 months old receiving care from January 2008 to July 2014. We compared rates of ADHD diagnosis and stimulant prescribing before and after guideline release using logistic regression with a spline and clustering by practice. Patterns of change (increase, decrease, no change) were described for each practice. RESULTS: Among 87 067 children with 118 957 visits before the guideline and 56 814 with 92 601 visits after the guideline, children had an ADHD diagnosis at 0.7% (95% confidence interval [CI], 0.7% to 0.8%) of visits before and 0.9% (95% CI, 0.8% to 0.9%) after guideline release and had stimulant prescriptions at 0.4% (95% CI, 0.4% to 0.4%) of visits in both periods. A significantly increasing preguideline trend in ADHD diagnosis ended after guideline release. The rate of stimulant medication use remained constant before and after guideline release. Patterns of change from before to after the guideline varied significantly across practices. CONCLUSIONS: Release of the 2011 guideline that addressed ADHD in preschoolers was associated with the end of an increasing rate of diagnosis, and the rate of prescribing stimulants remained constant. These are reassuring results given that a standardized approach to diagnosis was recommended and stimulant treatment is not first-line therapy for this age group. PMID- 27940709 TI - Variations in State Laws Governing School Reintegration Following Concussion. AB - OBJECTIVE: We sought to examine the prevalence, scope, and specificity of provisions governing school reintegration in current state concussion laws. METHODS: State concussion laws as of May 2016 were independently assessed and classified by 2 trained coders. Statutes were classified as "Return-to-Learn" (RTL) laws if they contained language mandating institutional action at the state, district, or school level related to academic reintegration of youth who have sustained a concussion. All statutes classified as RTL laws were further analyzed to determine scope, required actions, and delineation of responsibility. RESULTS: RTL laws were uncommon, present in only 8 states. Most (75%) of these laws held schools responsible for RTL management but mandated RTL education for school personnel was less frequent, present in only one-quarter of the laws. None of the RTL laws provided guidance on support of students with persistent postconcussive symptoms, and only 1 recommended an evidence-based standard for RTL guidelines. CONCLUSIONS: Our review of state concussion laws indicates scant and vague legal guidance regarding RTL. These findings suggest an opportunity for legislative action on the issue of RTL, and reveal the need for better integration of laws and research, so that laws reflect existing best-practice recommendations and remain current as the evidence base develops. PMID- 27940710 TI - Trends in Access to Health Care Services for US Children: 2000-2014. AB - BACKGROUND AND OBJECTIVE: Recent years have witnessed substantial gains in health insurance coverage for children, but few studies have examined trends across a diverse set of access indicators. We examine US children's access to health services and whether trends vary by race/ethnicity and income. METHODS: Analysis of 178 038 children ages 0 to 17 from the 2000 to 2014 National Health Interview Survey. Trends are examined for health insurance and 5 access indicators: no well child visit in the year, no doctor office visit, no dental visit, no usual source of care, and unmet health needs. Logistic regression models add controls for sociodemographics and child health status. Statistical interactions test whether trends vary by race/ethnicity and income. RESULTS: Among all children, uninsured rates declined from 12.1% in 2000 to 5.3% in 2014, with improvement across all 5 access indicators. Along with steep declines in the uninsured rate, Hispanic children had sizeable improvement for no doctor office (19.8% to 11.9%), no dental visit (43.2% to 21.8%), and no usual source of care (13.9% to 6.3%). Black children and those in poor and near-poor families also had large gains. Results from adjusted statistical interaction models showed more improvement for black and Hispanic children versus whites for 3 of 5 access indicators and for children in poor and near-poor families for 4 of 5 access indicators. CONCLUSIONS: Children's access to health services has improved since 2000 with greater gains in vulnerable population groups. Findings support a need for continued support of health insurance for all children. PMID- 27940712 TI - Strengthening Early Intervention for Very Preterm Infants. PMID- 27940711 TI - Diagnosis and Medication Treatment of Pediatric Hypertension: A Retrospective Cohort Study. AB - BACKGROUND AND OBJECTIVES: Pediatric hypertension predisposes children to adult hypertension and early markers of cardiovascular disease. No large-scale studies have examined diagnosis and initial medication management of pediatric hypertension and prehypertension. The objective of this study was to evaluate diagnosis and initial medication management of pediatric hypertension and prehypertension in primary care. METHODS: Retrospective cohort study aggregating electronic health record data on >1.2 million pediatric patients from 196 ambulatory clinics across 27 states. Demographic, diagnosis, blood pressure (BP), height, weight, and medication prescription data extracted. Main outcome measures include proportion of pediatric patients with >=3 visits with abnormal BPs, documented hypertension and prehypertension diagnoses, and prescribed antihypertensive medications. Marginal standardization via logistic regression produced adjusted diagnosis rates. RESULTS: Three hundred ninety-eight thousand seventy-nine patients, ages 3 to 18, had >=3 visits with BP measurements (48.9% girls, 58.6% <10 years old). Of these, 3.3% met criteria for hypertension and 10.1% for prehypertension. Among practices with >=50 eligible patients, 2813 of 12 138 patients with hypertension (23.2%; 95% confidence interval, 18.2%-28.2%) and 3990 of 38 874 prehypertensive patients (10.2%; 95% confidence interval, 8.2% 12.2%) were diagnosed. Age, weight, height, sex, and number and magnitude of abnormal BPs were associated with diagnosis rates. Of 2813 diagnosed, persistently hypertensive patients, 158 (5.6%) were prescribed antihypertensive medication within 12 months of diagnosis (angiotensin-converting enzyme inhibitors/angiotensin receptive blockers [35%], diuretics [22%], calcium channel blockers [17%], and beta-blockers [10%]). CONCLUSIONS: Hypertension and prehypertension were infrequently diagnosed among pediatric patients. Guidelines for diagnosis and initial medication management of abnormal BP in pediatric patients are not routinely followed. PMID- 27940714 TI - Influenza Prophylaxis in Children: Could a Single Dose of One Drug Be an Option? PMID- 27940713 TI - Randomized Exposure to Food Advertisements and Eating in the Absence of Hunger Among Preschoolers. AB - BACKGROUND: Preschoolers in the United States are heavily exposed to unhealthy food advertisements. Whether such exposure promotes cued eating has not been documented in this age group. METHODS: Randomized experiment among 60 children, aged 2 to 5 years, recruited in 2015-2016 from New Hampshire and Vermont. Children completed the experiment at a behavioral laboratory. Children were provided with a healthy snack to consume upon arrival then randomized to view a 14-minute TV program embedded with advertisements for either a food or a department store. Children were provided 2 snack foods to consume ad libitum while viewing the TV program; 1 of those snacks was the food advertised. Eating in the absence of hunger (EAH) was operationalized as the kilocalories of snack foods consumed. t tests were used to compare EAH by advertisement condition; linear regression models assessed effect modification by the child's age, sex, BMI percentile, and parental feeding restriction. RESULTS: Mean age was 4.1 (SD 0.9) years, 55% of children were male, 80% were non-Hispanic white, and 20% were overweight or obese. There were no differences in child or socioeconomic characteristics by advertisement condition. Child BMI was not related to EAH. Mean kilocalories consumed during the EAH phase was greater among children exposed to the food advertisements (126.8, SD: 58.5) versus those exposed to the nonfood advertisements (97.3, SD: 52.3; P = .04), an effect driven by greater consumption of the advertised food (P < .01). There was no evidence of effect modification. CONCLUSIONS: Findings suggest that food advertisement exposure may encourage obesogenic-eating behaviors among the very young. PMID- 27940715 TI - Transcutaneous Bilirubinometry in Jaundiced Neonates: A Randomized Controlled Trial. AB - BACKGROUND: For evaluation of jaundiced neonates, serum bilirubin (SB) or transcutaneous bilirubinometry (TcB) is used. Few data are available on the quantitative reduction of blood sampling by using TcB. METHODS: We conducted a randomized controlled trial in hospitalized jaundiced neonates >=32 weeks' gestational age. In the intervention group, TcB was used and in the control group the decision to obtain a blood sample for SB was based on visual and clinical assessment. Outcome measure was the number of blood samples before phototherapy. When TcB was <50 umol/L below the threshold for phototherapy, SB was obtained. The decision to start treatment was always based on an SB value. RESULTS: A total of 430 were randomized and included in the intention-to-treat analysis: 213 in the TcB group and 217 in the control group. In the TcB group, 104 (48.4%) had at least 1 blood sample taken for SB, versus 172 (79.3%) in the control group (difference 30.5%, 95% confidence interval 21.5-38.7, P < .001). The number of blood draws was significantly reduced by 38.5% (0.9 +/- 1.1 vs 1.3 +/- 1.0, difference -0.5, 95% confidence interval -0.7 to -0.3, P < .001). Peak of bilirubin value, indications for phototherapy, or exchange transfusion and hospitalization length were not different between groups. CONCLUSIONS: The use of TcB in jaundiced neonates is feasible and safe, resulting in a reduction of more than one-third in blood draws. PMID- 27940717 TI - Inhaled Corticosteroids for Bronchopulmonary Dysplasia: A Meta-analysis. AB - CONTEXT: Bronchopulmonary dysplasia (BPD) in preterm infants remains a major health burden despite many therapeutic interventions. Inhaled corticosteroids (IC) may be a safe and effective therapy. OBJECTIVE: To assess the safety and efficacy of IC for prevention or treatment of BPD or death in preterm infants. DATA SOURCES: PubMed, the Cochrane Library, Embase, and CINAHL from their inception until November 2015 together with other relevant sources. STUDY SELECTION: Randomized controlled trials of ICs versus placebo for either prevention or treatment of BPD. DATA EXTRACTION: This meta-analysis used a random effects model with assessment of quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Thirty-eight trials were identified, and 16 met inclusion criteria. ICs were associated with a significant reduction in death or BPD at 36 weeks' postmenstrual age (risk ratio [RR] = 0.86, 95% confidence interval [CI] 0.75 to 0.99, I2 = 0%, P = .03; 6 trials, n = 1285). BPD was significantly reduced (RR = 0.77, 95% CI 0.65 to 0.91, I2 = 0%, 7 trials, n = 1168), although there was no effect on death (RR = 0.97, 95% CI 0.42 to 2.2, I2 = 50%, 7 trials, n = 1270). No difference was found for death or BPD at 28 days' postnatal age. The use of systemic steroids was significantly reduced in treated infants (13 trials, n = 1537, RR = 0.87, 95% CI 0.76 to 0.98 I2 = 3%,). No significant differences were found in neonatal morbidities and other adverse events. LIMITATIONS: Long-term follow-up data are awaited from a recent large randomized controlled trial. CONCLUSIONS: Very preterm infants appear to benefit from ICs with reduced risk for BPD and no effect on death, other morbidities, or adverse events. Data on long-term respiratory, growth, and developmental outcomes are eagerly awaited. PMID- 27940718 TI - Flavored Electronic Cigarette Use and Smoking Among Youth. AB - BACKGROUND AND OBJECTIVE: Flavored electronic cigarettes (e-cigarettes) are not prohibited in the United States, and e-cigarette flavors proliferate on the market. This study sought to examine flavored e-cigarette use and its association with smoking among youth. METHODS: Estimates of flavored e-cigarette use from the 2014 National Youth Tobacco Survey were investigated. A logistic regression model was used to assess whether flavored e-cigarette use was associated with (1) intention to initiate cigarette use among never-smoking youth (n = 16 471), (2) intention to quit tobacco use among current-smoking youth (n = 1338), and (3) perception of tobacco's danger among all respondents (n = 21 491). RESULTS: A total of 2017 respondents reported using e-cigarettes in the last 30 days, of whom 1228 (60.9%) reported using flavored e-cigarettes. Among never-smoking youth, 55.6% (288) of current e-cigarette users reported using flavored e cigarettes. Among current smokers, 68.4% (495) of current e-cigarette users reported using flavored e-cigarettes. Compared with not using e-cigarettes in the past 30 days, using flavored e-cigarettes was associated with higher odds of intention to initiate cigarette use among never-smoking youth (adjusted odds ratio [aOR] = 5.7; P < .0001), lower odds of intention to quit tobacco use among current-smoking youth (aOR = 0.6; P = .006), and a lower prevalence of perception of tobacco's danger among all respondents (aOR = 0.5; P < .0001). CONCLUSIONS: Flavored e-cigarette use is associated with increased risks of smoking among youth. Comprehensive tobacco control and prevention strategies that address flavored e-cigarette products are critically needed to reduce tobacco use among youth. PMID- 27940719 TI - Implications of Poverty for Practices Serving Suburban Families. PMID- 27940716 TI - Mental Health Conditions and Medical and Surgical Hospital Utilization. AB - OBJECTIVE: Mental health conditions are prevalent among children hospitalized for medical conditions and surgical procedures, but little is known about their influence on hospital resource use. The objectives of this study were to examine how hospitalization characteristics vary by presence of a comorbid mental health condition and estimate the association of a comorbid mental health condition with hospital length of stay (LOS) and costs. METHODS: Using the 2012 Kids' Inpatient Database, we conducted a retrospective, nationally representative, cross sectional study of 670 161 hospitalizations for 10 common medical and 10 common surgical conditions among 3- to 20-year-old patients. Associations between mental health conditions and hospital LOS were examined using adjusted generalized linear models. Costs of additional hospital days associated with mental health conditions were estimated using hospital cost-to-charge ratios. RESULTS: A comorbid mental health condition was present in 13.2% of hospitalizations. A comorbid mental health condition was associated with a LOS increase of 8.8% (from 2.5 to 2.7 days, P < .001) for medical hospitalizations and a 16.9% increase (from 3.6 to 4.2 days, P < .001) for surgical hospitalizations. For hospitalizations in this sample, comorbid mental health conditions were associated with an additional 31 729 (95% confidence interval: 29 085 to 33 492) hospital days and $90 million (95% confidence interval: $81 to $101 million) in hospital costs. CONCLUSIONS: Medical and surgical hospitalizations with comorbid mental health conditions were associated with longer hospital stay and higher hospital costs. Knowledge about the influence of mental health conditions on pediatric hospital utilization can inform clinical innovation and case-mix adjustment. PMID- 27940720 TI - Should Neonatologists Give Opinions Withdrawing Life-sustaining Treatment? AB - An infant has a massive intracranial hemorrhage. She is neurologically devastated and ventilator-dependent. The prognosis for pulmonary or neurologic recovery is bleak. The physicians and parents face a choice: withdraw the ventilator and allow her to die or perform a tracheotomy? The parents cling to hope for recovery. The physician must decide how blunt to be in communicating his own opinions and recommendations. Should the physician try to give just the facts? Or should he also make a recommendation based on his own values? In this article, experts in neonatology, decision-making, and bioethics discuss this situation and the choice that the physician faces. PMID- 27940721 TI - Weight Change Nomograms for the First Month After Birth. AB - OBJECTIVE: Clinicians expect newborns to surpass birth weight by age 10 to 14 days, yet few studies have examined the natural history of weight change in the weeks after birth. We sought to determine the distribution of weight loss and subsequent regain during the first month, the proportion not surpassing birth weight by 14 and 21 days, and whether findings differed by delivery mode. METHODS: For 161 471 singleton neonates delivered at >=36 weeks' gestation at Kaiser Permanente Northern California Medical Centers between 2009 and 2013 and weighing 2000 to 5000 g at birth, we extracted daily weights from inpatient electronic records and weights from outpatient visits in the first month. Quantile regression appropriate for repeated measures was used to estimate percentiles of weight change as a function of time after birth, stratified by delivery mode. RESULTS: After exclusions, weight data were analyzed from 143 889 newborns (76% born vaginally). Based on percentile estimates, 50% of newborns were at or above birth weight at 9 and 10 days after vaginal and cesarean delivery, respectively. Among those delivered vaginally, 14% and 5% were not back to birth weight by 14 and 21 days, respectively. For those delivered by cesarean, 24% and 8% were not back to birth weight by 14 and 21 days, respectively. CONCLUSIONS: It is not uncommon for newborns to be below birth weight 10 to 14 days after delivery. A larger percentage of newborns delivered by cesarean had yet to regain birth weight at every time point through 1 month. PMID- 27940722 TI - Reflections From a Member of the AAP Committee That Prepared "Guidance for Effective Discipline". PMID- 27940723 TI - Can We Go Beyond Care Process Measures to a New Child Health Policy? PMID- 27940724 TI - Use of Reflux Medications in Premature Infants After Hospital Discharge. PMID- 27940725 TI - Childhood Hypertension: An Underappreciated Epidemic? PMID- 27940726 TI - Depression Is a Deadly Growing Threat to Our Youth: Time to Rally. PMID- 27940728 TI - Cummings JJ, Polin RA, COMMITTEE ON FETUS AND NEWBORN. Oxygen Targeting in Extremely Low Birth Weight Infants. Pediatrics. 2016;138(2):e20161576. PMID- 27940729 TI - It Takes a Full-Service Village to Treat Children With ADHD. PMID- 27940727 TI - Modern Management of Preterm Infants Prevents Adverse Developmental Outcomes From Hypoglycemia. PMID- 27940730 TI - Helping Children and Families Deal With Divorce and Separation. AB - For the past several years in the United States, there have been more than 800 000 divorces and parent separations annually, with over 1 million children affected. Children and their parents can experience emotional trauma before, during, and after a separation or divorce. Pediatricians can be aware of their patients' behavior and parental attitudes and behaviors that may indicate family dysfunction and that can indicate need for intervention. Age-appropriate explanation and counseling for the child and advice and guidance for the parents, as well as recommendation of reading material, may help reduce the potential negative effects of divorce. Often, referral to professionals with expertise in the social, emotional, and legal aspects of the separation and its aftermath may be helpful for these families. PMID- 27940731 TI - Recognition and Management of Medical Complexity. AB - Children with medical complexity have extensive needs for health services, experience functional limitations, and are high resource utilizers. Addressing the needs of this population to achieve high-value health care requires optimizing care within the medical home and medical neighborhood. Opportunities exist for health care providers, payers, and policy makers to develop strategies to enhance care delivery and to decrease costs. Important outcomes include decreasing unplanned hospital admissions, decreasing emergency department use, ensuring access to health services, limiting out-of-pocket expenses for families, and improving patient and family experiences, quality of life, and satisfaction with care. This report describes the population of children with medical complexity and provides strategies to optimize medical and health outcomes. PMID- 27940732 TI - Youth Participation and Injury Risk in Martial Arts. AB - The martial arts can provide children and adolescents with vigorous levels of physical exercise that can improve overall physical fitness. The various types of martial arts encompass noncontact basic forms and techniques that may have a lower relative risk of injury. Contact-based sparring with competitive training and bouts have a higher risk of injury. This clinical report describes important techniques and movement patterns in several types of martial arts and reviews frequently reported injuries encountered in each discipline, with focused discussions of higher risk activities. Some of these higher risk activities include blows to the head and choking or submission movements that may cause concussions or significant head injuries. The roles of rule changes, documented benefits of protective equipment, and changes in training recommendations in attempts to reduce injury are critically assessed. This information is intended to help pediatric health care providers counsel patients and families in encouraging safe participation in martial arts. PMID- 27940733 TI - Addressing Early Childhood Emotional and Behavioral Problems. AB - Emotional, behavioral, and relationship problems can develop in very young children, especially those living in high-risk families or communities. These early problems interfere with the normative activities of young children and their families and predict long-lasting problems across multiple domains. A growing evidence base demonstrates the efficacy of specific family-focused therapies in reducing the symptoms of emotional, behavioral, and relationship symptoms, with effects lasting years after the therapy has ended. Pediatricians are usually the primary health care providers for children with emotional or behavioral difficulties, and awareness of emerging research about evidence-based treatments will enhance this care. In most communities, access to these interventions is insufficient. Pediatricians can improve the care of young children with emotional, behavioral, and relationship problems by calling for the following: increased access to care; increased research identifying alternative approaches, including primary care delivery of treatments; adequate payment for pediatric providers who serve these young children; and improved education for pediatric providers about the principles of evidence-based interventions. PMID- 27940735 TI - Reaffirmation of AAP Clinical Practice Guideline: The Diagnosis and Management of the Initial Urinary Tract Infection in Febrile Infants and Young Children 2-24 Months of Age. PMID- 27940734 TI - Addressing Early Childhood Emotional and Behavioral Problems. AB - More than 10% of young children experience clinically significant mental health problems, with rates of impairment and persistence comparable to those seen in older children. For many of these clinical disorders, effective treatments supported by rigorous data are available. On the other hand, rigorous support for psychopharmacologic interventions is limited to 2 large randomized controlled trials. Access to psychotherapeutic interventions is limited. The pediatrician has a critical role as the leader of the medical home to promote well-being that includes emotional, behavioral, and relationship health. To be effective in this role, pediatricians promote the use of safe and effective treatments and recognize the limitations of psychopharmacologic interventions. This technical report reviews the data supporting treatments for young children with emotional, behavioral, and relationship problems and supports the policy statement of the same name. PMID- 27940736 TI - Early-Onset Neonatal Sepsis: A Continuing Problem in Need of Novel Prevention Strategies. PMID- 27940737 TI - "Skin Deep Resilience" Among Disadvantaged Blacks: Critical Questions, Elusive Answers. PMID- 27940738 TI - The Timing of Planned Delivery: Strengthening the Case for 39 Weeks. PMID- 27940739 TI - The Uncertain Future of Human Papillomavirus Vaccination School Requirements. PMID- 27940740 TI - Evaluation and Referral for Developmental Dysplasia of the Hip in Infants. AB - Developmental dysplasia of the hip (DDH) encompasses a wide spectrum of clinical severity, from mild developmental abnormalities to frank dislocation. Clinical hip instability occurs in 1% to 2% of full-term infants, and up to 15% have hip instability or hip immaturity detectable by imaging studies. Hip dysplasia is the most common cause of hip arthritis in women younger than 40 years and accounts for 5% to 10% of all total hip replacements in the United States. Newborn and periodic screening have been practiced for decades, because DDH is clinically silent during the first year of life, can be treated more effectively if detected early, and can have severe consequences if left untreated. However, screening programs and techniques are not uniform, and there is little evidence-based literature to support current practice, leading to controversy. Recent literature shows that many mild forms of DDH resolve without treatment, and there is a lack of agreement on ultrasonographic diagnostic criteria for DDH as a disease versus developmental variations. The American Academy of Pediatrics has not published any policy statements on DDH since its 2000 clinical practice guideline and accompanying technical report. Developments since then include a controversial US Preventive Services Task Force "inconclusive" determination regarding usefulness of DDH screening, several prospective studies supporting observation over treatment of minor ultrasonographic hip variations, and a recent evidence-based clinical practice guideline from the American Academy of Orthopaedic Surgeons on the detection and management of DDH in infants 0 to 6 months of age. The purpose of this clinical report was to provide literature-based updated direction for the clinician in screening and referral for DDH, with the primary goal of preventing and/or detecting a dislocated hip by 6 to 12 months of age in an otherwise healthy child, understanding that no screening program has eliminated late development or presentation of a dislocated hip and that the diagnosis and treatment of milder forms of hip dysplasia remain controversial. PMID- 27940742 TI - Author's Response: RE: comment. PMID- 27940741 TI - RE: Menstrual Management for Adolescents With Disabilities. PMID- 27940743 TI - Do We Need Another Set of Growth Charts for Premature Infants? PMID- 27940744 TI - Adolescent Chronotype and Self-Regulation: The Power of When. PMID- 27940745 TI - Oxygen Redux. PMID- 27940746 TI - Expanding Concussion Laws Not Necessary for Return to Learning After Concussion. PMID- 27940747 TI - Disclosure of Adverse Events in Pediatrics. AB - Despite increasing attention to issues of patient safety, preventable adverse events (AEs) continue to occur, causing direct and consequential injuries to patients, families, and health care providers. Pediatricians generally agree that there is an ethical obligation to inform patients and families about preventable AEs and medical errors. Nonetheless, barriers, such as fear of liability, interfere with disclosure regarding preventable AEs. Changes to the legal system, improved communications skills, and carefully developed disclosure policies and programs can improve the quality and frequency of appropriate AE disclosure communications. PMID- 27940749 TI - Orthoptists as Physician Extenders. PMID- 27940750 TI - Choosing Wrong. PMID- 27940748 TI - Out-of-Home Placement for Children and Adolescents With Disabilities-Addendum: Care Options for Children and Adolescents With Disabilities and Medical Complexity. AB - Children and adolescents with significant intellectual and developmental disabilities and complex medical problems require safe and comprehensive care to meet their medical and psychosocial needs. Ideally, such children and youth should be cared for by their families in their home environments. When this type of arrangement is not possible, there should be exploration of appropriate, alternative noncongregate community-based settings, especially alternative family homes. Government funding sources exist to support care in the community, although there is variability among states with regard to the availability of community programs and resources. It is important that families are supported in learning about options of care. Pediatricians can serve as advocates for their patients and their families to access community-based services and to increase the availability of resources to ensure that the option to live in a family home is available to all children with complex medical needs. PMID- 27940751 TI - Achieving High Adolescent HPV Vaccination Coverage. AB - BACKGROUND AND OBJECTIVE: Despite national recommendations for adolescent human papillomavirus (HPV) vaccination, rates have lagged behind those of other adolescent vaccines. We implemented interventions and examined rates of vaccination coverage in a large, urban, safety net health care system to understand whether our tactics for achieving high rates of adolescent vaccination were successful. METHODS: Denver Health is an integrated urban safety net health system serving >17 000 adolescents annually. The process for achieving high vaccination rates in our health system includes "bundling" of vaccines, offering vaccines at every visit, and standard orders. Data from vaccine registry and utilization statistics were used to determine vaccination rates in adolescents aged 13 to 17 years from 2004 to 2014, and these findings were compared with state and national rates for 2013. Regression analysis was used to identify characteristics associated with vaccination. RESULTS: In 2013 (N = 11 463), HPV coverage of >=1 dose was 89.8% (female subjects) and 89.3% (male subjects), compared with national rates of 57.3% and 34.6%. Rates of HPV coverage (>=3 doses) were 66.0% for female subjects and 52.5% for male subjects, versus 37.6% and 13.9% nationally. For both sexes, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed, vaccine coverage was 95.9% (86.0% nationally), and meningococcal conjugate vaccine coverage was 93.5% (77.8% nationally). Female subjects, Hispanic subjects, non-English speakers, and teenagers <200% below the federal poverty level were more likely to have received 3 doses of HPV. CONCLUSIONS: Through low-cost, system-wide standard procedures, Denver Health achieved adolescent vaccination rates well above national coverage rates. Avoiding missed opportunities for vaccination and normalizing the HPV vaccine were key procedures that contributed to high coverage rates. PMID- 27940752 TI - Improving Guideline-Based Care of Acute Asthma in a Pediatric Emergency Department. AB - BACKGROUND AND OBJECTIVE: Rapid repetitive administration of short-acting beta agonists (SABA) is the most effective means of reducing acute airflow obstruction in asthma. Little evidence exists that assesses process measures (ie, timeliness) and outcomes for asthma. We used quality improvement (QI) methods to improve emergency department care in accordance with national guidelines including timely SABA administration and use of asthma severity scores. METHODS: The Model for Improvement was used and interventions were targeted at 4 key drivers: knowledge, engagement, decision support, and workflow enhancement. Time series analysis was performed and outcomes assessed on statistical process control charts. RESULTS: Asthma severity scoring increased from 0% to >95% in triage and to >75% for repeat scores. Time to first SABA (T1) improved by 32.8 minutes (47%). T1 for low severity patients improved by 17.6 minutes (28%). T1 for high severity patients improved by 3.1 minutes to 18.1 minutes (15%). Time to third SABA (T3) improved by 30 minutes (24%). T3 for low severity patients improved by 42.5 minutes (29%) and T3 for high severity patients improved by 21 minutes (23%). Emergency department length of stay for low severity patients discharged to home improved by 29.3 minutes (15%). The number of asthma-related visits between 48-hour return hospitalizations increased from 114 to 261. The admission rate decreased 6.0%. CONCLUSIONS: We implemented standardized asthma severity scoring with high rates of compliance, improved timely administration of beta-agonist treatments, demonstrated early improvements in Emergency department length of stay, and reduced admission rates without increasing unplanned return admissions. PMID- 27940753 TI - A 5-Year-Old With Fever, Headache, Neck Stiffness, and Leg Pain. AB - A 5-year-old boy presented with fever, headache, fatigue, neck stiffness, and 2 episodes of nocturnal urinary incontinence, prompting a visit to the emergency department. He had experienced intermittent frontal headaches and leg and buttock pain for several months, which had worsened over the previous 2 weeks. His history was notable for a spinal hemangioma with vascular tract, but he was otherwise healthy. On examination, he was febrile and tachycardic. He held his neck slightly rotated to the right with limited range of motion in all directions due to pain. No focal neurologic deficits were noted, and sensation and deep tendon reflexes were intact bilaterally. He was able to bear weight on both legs. There was no spinal tenderness or limitation in range of motion of his back and hips. There were no cutaneous manifestations, including no sacral dimple. A complete blood count with differential revealed leukocytosis of 31.98 * 103/uL (78.6% neutrophils, 16% bands). C-reactive protein was elevated at 2.4 mg/dL (0-1 mg/dL), and serum electrolytes, liver function tests, uric acid, and lactate dehydrogenase were within normal limits for age. Blood cultures were obtained before admission. Here we present his case, diagnostic evaluation, ultimate diagnosis, and complications. PMID- 27940754 TI - Perceptions of e-Cigarettes and Noncigarette Tobacco Products Among US Youth. AB - BACKGROUND: Electronic cigarettes (e-cigarettes) are now the most commonly used tobacco product among US youth. The extent to which perceptions of e-cigarettes' harm and addictiveness differ from those of other products remains unknown, as does whether these perceptions have changed over time. METHODS: Data from the 2012 and 2014 National Youth Tobacco Survey, a repeated cross-sectional survey of grade 6 to 12 students, were used. Cross-tabulations and logistic regression models were used to describe correlates of perceptions of harm and addictiveness of e-cigarettes, cigars, and smokeless tobacco compared with cigarettes. Trends in perceptions of e-cigarettes' harm among different demographic groups were also assessed. RESULTS: In 2014, 73.0% believed that e-cigarettes were less harmful than cigarettes, compared with 20.2% for smokeless tobacco and 25.8% for cigars. By comparison, 47.1% believed that e-cigarettes were less addictive than cigarettes, compared with only 14.0% for smokeless tobacco and 31.5% for cigars. Use of each product was associated with a perception of decreased harm and addictiveness in adjusted analyses, as was being male, being a non-Hispanic white, and residing with a household member who used that product. Between 2012 and 2014, increasing numbers of US youth thought they were able to assess the relative harm of e-cigarettes and increasingly believed that e-cigarettes are less harmful than cigarettes. CONCLUSIONS: Most US youth view e-cigarettes as less harmful and addictive than cigarettes. Far fewer think similarly about cigars and smokeless tobacco. Increases in e-cigarettes' perceived safety mirrors rapid increases observed in their use. Perceived safety correlates with use of each tobacco product. PMID- 27940755 TI - Lysine Restriction and Pyridoxal Phosphate Administration in a NADK2 Patient. AB - We report the case of a 10-year-old Spanish girl with mutations in NADK2 Prenatal central nervous system abnormalities showed ventriculomegaly, colpocephaly, and hypoplasia of the corpus callosum. At birth, axial hypotonia, uncoordinated movements, microcephaly, and generalized cerebellar atrophy were detected. Metabolic investigations revealed high lysine, lactate, and pipecolic acid levels in blood and cerebrospinal fluid. Pyruvate carboxylase and pyruvate dehydrogenase activity in fibroblasts were normal. Beginning at birth she received biotin, thiamine, and carnitine supplementation. A lysine-restricted diet was started when she was 1 month old. Because pipecolic acid was high, pyridoxine was added to treatment. At 3 years old, astatic myoclonic epilepsy appeared, with no response to levetiracetam. We switched pyridoxine to pyridoxal phosphate, with electroclinical improvement. Because the activity of mitochondrial respiratory chain complexes III and IV was slightly low in muscle, other cofactors such as ubidecarenone, idebenone, vitamin E, and creatine were added to the treatment. At 8 years old, plasma acylcarnitine testing was performed, and high levels of 2 trans, 4-cis-decadienoylcarnitine were found. Whole exome sequencing identified a homozygous splice site mutation in NADK2 (c.956+6T>C; p.Trp319Cysfs*21). This substitution generates exon skipping, leading to a truncated protein. In fact, NADK2 messenger RNA and the corresponding protein were almost absent. Now, at 10 years of age she presents with ataxia and incoordination. She has oromotor dysphasia but is able to understand fluid language and is a very friendly girl. We hypothesize that the patient's clinical improvement could be due to her lysine restricted diet together with cofactors and pyridoxal phosphate administration. PMID- 27940757 TI - Atypical Leydig Cell Tumor in Children: Report of 2 Cases. AB - Leydig cell tumors (LCTs) are rare cord-stromal tumors that may occur in testis or ovaries and may produce androgens or estrogens. The majority has been found in men between the ages of 20 and 60 years. Adults with androgen-secreting LCTs are usually asymptomatic; feminizing syndromes may result from the production of estradiol or the peripheral aromatization of testosterone. In children, LCTs usually present between 5 and 10 years of age with isosexual precocious pseudopuberty or gynecomastia. We report 2 cases of LCT in prepubertal boys presenting with advanced unilateral pubarche and testicular volume asymmetry. Both subjects had normal penis size for age; no axillary hair or other signs of puberty were present. Height velocity was normal, and bone age was coincident with chronological age. Androgen levels were normal, as well as estrogen, corticotropin, and cortisol concentration. Testicular ultrasound demonstrated a testicular mass. Histology examination revealed a well-differentiated LCT. This is the first report of 2 pediatric patients with LCT presenting with advanced pubarche in absence of systemic hyperandrogenism. We hypothesize that the neoplastic cells may locally produce high levels of androgens or androgen-like bioactivity molecules that are responsible for the clinical manifestation. We suggest that a testicular ultrasound should be obtained in all children presenting with unilateral pubarche, with or without hyperandrogenism. PMID- 27940756 TI - Complementary and Alternative Medicine and Influenza Vaccine Uptake in US Children. AB - BACKGROUND: Complementary and alternative medicine (CAM) is increasingly used in the United States. Although CAM is mostly used in conjunction with conventional medicine, some CAM practitioners recommend against vaccination, and children who saw naturopathic physicians or chiropractors were less likely to receive vaccines and more likely to get vaccine-preventable diseases. Nothing is known about how child CAM usage affects influenza vaccination. METHODS: This nationally representative study analyzed ~9000 children from the Child Complementary and Alternative Medicine File of the 2012 National Health Interview Survey. Adjusting for health services use factors, it examined influenza vaccination odds by ever using major CAM domains: (1) alternative medical systems (AMS; eg, acupuncture); (2) biologically-based therapies, excluding multivitamins/multiminerals (eg, herbal supplements); (3) multivitamins/multiminerals; (4) manipulative and body based therapies (MBBT; eg, chiropractic manipulation); and (5) mind-body therapies (eg, yoga). RESULTS: Influenza vaccination uptake was lower among children ever (versus never) using AMS (33% vs 43%; P = .008) or MBBT (35% vs 43%; P = .002) but higher by using multivitamins/multiminerals (45% vs 39%; P < .001). In multivariate analyses, multivitamin/multimineral use lost significance, but children ever (versus never) using any AMS or MBBT had lower uptake (respective odds ratios: 0.61 [95% confidence interval: 0.44-0.85]; and 0.74 [0.58-0.94]). CONCLUSIONS: Children who have ever used certain CAM domains that may require contact with vaccine-hesitant CAM practitioners are vulnerable to lower annual uptake of influenza vaccination. Opportunity exists for US public health, policy, and medical professionals to improve child health by better engaging parents of children using particular domains of CAM and CAM practitioners advising them. PMID- 27940758 TI - Neonatal Morbidity After Maternal Use of Antidepressant Drugs During Pregnancy. AB - OBJECTIVES: To estimate the rate of admissions to NICUs, as well as infants' morbidity and neonatal interventions, after exposure to antidepressant drugs in utero. METHODS: Data on pregnancies, deliveries, prescription drug use, and health status of the newborn infants were obtained from the Swedish Medical Birth Register, the Prescribed Drug Register, and the Swedish Neonatal Quality Register. We included 741 040 singletons, born between July 1, 2006, and December 31, 2012. Of the infants, 17 736 (2.4%) had mothers who used selective serotonin reuptake inhibitors (SSRIs) during pregnancy. Infants exposed to an SSRI were compared with nonexposed infants, and infants exposed during late pregnancy were compared with those exposed during early pregnancy only. The results were analyzed with logistic regression analysis. RESULTS: After maternal use of an SSRI, 13.7% of the infants were admitted to the NICU compared with 8.2% in the population (adjusted odds ratio: 1.5 [95% confidence interval: 1.4-1.5]). The admission rate to the NICU after treatment during late pregnancy was 16.5% compared with 10.8% after treatment during early pregnancy only (adjusted odds ratio: 1.6 [95% confidence interval: 1.5-1.8]). Respiratory and central nervous system disorders and hypoglycemia were more common after maternal use of an SSRI. Infants exposed to SSRIs in late pregnancy compared with early pregnancy had a higher risk of persistent pulmonary hypertension (number needed to harm: 285). CONCLUSIONS: Maternal use of antidepressants during pregnancy was associated with increased neonatal morbidity and a higher rate of admissions to the NICU. The absolute risk for severe disease was low, however. PMID- 27940759 TI - Human Parechovirus as a Cause of Isolated Pediatric Acute Liver Failure. AB - Among infants, almost half of acute liver failure cases are classified as indeterminate, whereas only a small number of cases show a documented viral infection. We present the first reported case of isolated acute hepatic failure in an infant in the setting of a human parechovirus (HPeV) infection. HPeV also may have been contributory to the posttransplant complication of 2 intussusceptions. This is a 10-month-old girl who presented with only symptoms of fussiness and was noted to have progressive decline in synthetic liver function as well as worsening coagulopathy requiring a liver transplant. The acute liver failure was in the setting of a positive serum RNA HPeV, subtype 3 (HPeV-3), after extensive diagnostic testing with genetic, autoimmune, and infectious causes otherwise negative. After liver transplantation, the postoperative course was complicated by both an ileal-ileal intussusception as well as a jejunal intussusception. Viral testing in pediatric acute liver failure is often performed, but the workup is frequently incomplete. This case report would support more extensive viral testing in this population of patients. In the setting of HPeV, clinicians could be alerted to the possibility of delayed gastrointestinal pathology in the posttransplant phase. Wider use of routine HPeV testing may more clearly define the variable clinical presentations and outcomes. PMID- 27940760 TI - Risk Factors for Bicycling Injuries in Children and Adolescents: A Systematic Review. AB - CONTEXT: Child and adolescent bicycling is beneficial, but injuries occur and can be severe and costly. OBJECTIVE: To systematically review the individual and environmental factors associated with bicycling injury risk in children and adolescents. DATA SOURCES: Fourteen electronic databases were searched. STUDY SELECTION: Two authors independently assessed potentially relevant articles for eligibility. The inclusion criteria were as follows: bicyclists younger than 20 years old; examined individual and environmental characteristics of bicycling crashes; compared injured and uninjured bicyclists or bicyclists with different types or severity of injury; study designs with a predetermined comparison group; and published in English from January 1990 to May 2015. The exclusion criteria were outcomes related to helmet use, helmet legislation, or mountain biking, and comparisons of census-based injury rates. DATA EXTRACTION: Data on study design, setting, population, injury definitions, injury risk factors, and results were extracted. Risk of bias was assessed by using the Newcastle-Ottawa Scales. RESULTS: Fourteen articles were included. Lower socioeconomic status, riding on the road, riding in rural compared with urban areas, and riding on the sidewalk were associated with bicycling injury. Bicycling safety education did not protect children against future injury. Injuries related to a motor vehicle collision were more severe than other bicycling injuries. LIMITATIONS: Study heterogeneity prevented meta-analyses. Study quality was affected by inadequate definitions of study groups and self-reported data. CONCLUSIONS: Lower socioeconomic status and riding location were associated with bicycling injury and severity increased with motor vehicle collisions. The bicycling environment is a promising avenue for prevention. PMID- 27940761 TI - Tetanus and Occam's Razor: Almost Forgotten but Not Gone: A Case Report. AB - Tetanus is a rare disease in industrialized countries, largely due to the highly protective effect of immunization. We present a case of tetanus in a formerly preterm infant with myelomeningocele repaired in utero, who presented at 44 days of age with poor feeding, lethargy, and increased tone. His symptoms progressed despite a course of antibiotics for presumed meningitis. At 73 days of age (on 29th day of hospitalization), a clinical diagnosis of tetanus was made based on the presence of risus sardonicus, trismus, and generalized hypertonicity. Consequently, tetanus immune globulin, muscle relaxants, and metronidazole were administered. Five months later, the infant has had complete resolution of the hypertonicity, has regained normal jaw movement and swallowing, and is regaining oral feeding skills. This case involved a delay in diagnosis despite clinical symptoms and signs classic, in retrospect, for tetanus, highlighting the importance of recognizing the constellation of symptoms that should lead us to consider this rare diagnosis. PMID- 27940762 TI - Pediatric Chronic Pain: Biopsychosocial Assessment and Formulation. AB - Chronic pain in children is an increasingly recognized clinical problem with alarmingly high prevalence rates found in some populations. Although it is not understood why some children experience high levels of pain, the subjective experience of chronic pain (including its site, intensity, quality, unpleasantness, and associated suffering) has long been believed to result from interactions between multiple contributors, including nociceptive, affective, sociocultural, behavioral, and cognitive. Regardless of whether the antecedent of chronic pain is known or unknown, similar patterns of symptoms, behaviors, and disability are often seen. Historically, however, there has been an unhelpful tendency to dichotomize chronic pain as either physical or functional in origin. However, recent studies strongly support a biopsychosocial basis to all pain, revealing its sensory emotional nature by showing that large distributed neural networks are accessed during nociceptive processing. The development and maintenance of chronic pain involve long-term changes in multiple integrated peripheral, spinal, and brain regions interacting in a complex way to shape the individual's experience. Hence, chronic pain from any cause cannot be viewed as a purely physical or psychological phenomenon, nor should it be expected that a unimodal approach to treatment will succeed. It follows that when assessing children and young people with chronic pain, information on a wide range of developmentally relevant dimensions, conveniently classified as biological, psychological, and sociocultural, should be gathered to formulate the potential causes, contributors, and effects of pain to devise an appropriate multimodal management plan. PMID- 27940763 TI - Childhood Victims of Snakebites: 2000-2013. AB - BACKGROUND: Snakebites are not a reportable condition (to state health departments), and 1 major assessment of US children with snakebites was published 50 years ago. Increasing urbanization, population shifts south and west, newer antivenom therapy, and the importation of exotic snakes may have changed snakebites. Poison control centers are often consulted on treatment and collect surveillance data. METHODS: Generic codes for venomous, nonvenomous, and unknown snakebites were used to characterize victims aged <=18 years reported to US poison control centers between 2000 and 2013. Data included demographic characteristics, snake types, and outcomes. RESULTS: Callers reported 18 721 pediatric snakebites (annual mean, 1337). Two-thirds were male (n = 12 688 [68%]), with a mean age of 10.7 years. One-half of the snakebites were venomous (n = 9183 [49%]), with copperheads (n = 3602 [39%]) and rattlesnakes (n = 2859 [31%]) the most frequently identified. Reported copperhead bites increased 137% and unknown crotalids (venomous) increased 107%. Exotic (nonnative) exposures were reported in 2% of cases. All 50 states reported snakebites, but one-quarter occurred in Texas and Florida. Rates for total snakebites and venomous snakebites were highest in West Virginia, Oklahoma, and Louisiana. One-fifth required ICU admission. Limited data for 28% of bites for antivenom treatment suggests increasing use. Four victims died. CONCLUSIONS: The epidemiology of pediatric snakebites is changing. One-half of the reported exposures were venomous, and copperhead bites and exotic species are being reported more frequently. Although snakebite-related deaths are rare, ICU admission is common. Antivenom treatment is incompletely reported, but its use is increasing. PMID- 27940764 TI - Home Health Nursing Care and Hospital Use for Medically Complex Children. AB - BACKGROUND AND OBJECTIVE: Home health nursing care (HH) may be a valuable approach to long-term optimization of health for children, particularly those with medical complexity who are prone to frequent and lengthy hospitalizations. We sought to assess the relationship between HH services and hospital use in children. METHODS: Retrospective, matched cohort study of 2783 hospitalized children receiving postdischarge HH services by BAYADA Home Health Care across 19 states and 7361 matched controls not discharged to HH services from the Children's Hospital Association Case Mix database between January 2004 and September 2012. Subsequent hospitalizations, hospital days, readmissions, and costs of hospital care were assessed over the 12-month period after the initial hospitalization. Nonparametric Wilcoxon signed rank tests were used for comparisons between HH and non-HH users. RESULTS: Although HH cases had a higher percentage of complex chronic conditions (68.5% vs 65.4%), technology assistance (40.5% vs 35.7%), and neurologic impairment (40.7% vs 37.3%) than matched controls (P <= .003 for all), 30-day readmission rates were lower in HH patients (18.3% vs 21.5%, P = .001). At 12 months after the index admission, HH patients averaged fewer admissions (0.8 vs 1.0, P < .001), fewer days in the hospital (6.4 vs 6.6, P < .001), and lower hospital costs ($22 511 vs $24 194, P < .001) compared with matched controls. CONCLUSIONS: Children discharged to HH care experienced less hospital use than children with similar characteristics who did not use HH care. Further investigation is needed to understand how HH care affects the health and health services of children. PMID- 27940765 TI - Management of Children With Hereditary Angioedema Due to C1 Inhibitor Deficiency. AB - Hereditary angioedema (HAE) is a potentially life-threatening inherited disease characterized by attacks of skin swelling, severe abdominal pain, and upper airway swelling. Attacks typically begin in childhood, but the appropriate diagnosis is often missed. Attacks do not respond to epinephrine, antihistamines, or glucocorticoids. Recently, many effective drugs have been approved for treatment of adults with HAE, and the Medical Advisory Board of the HAE Patient's Association has developed and reported treatment recommendations for adults. Only 1 medication is approved for treatment of children <12 years of age, and there are no reported consensus recommendations for treatment of young children in the United States. The 11-member Medical Advisory Board, with extensive experience in the treatment of children, in concert with the leaders of the HAE Patient's Association, has developed these consensus recommendations to help in recognition, diagnosis, treatment of attacks, and prophylaxis of children with HAE. PMID- 27940767 TI - Effective Neurally Adjusted Ventilatory Assist (NAVA) Ventilation in a Child With Jeune Syndrome. AB - Jeune syndrome (asphyxiating thoracic dystrophy) is a rare skeletal dysplasia mainly characterized by dystrophy of the thoracic cage. Neurally adjusted ventilatory assist (NAVA) is a respiratory support in which pressure assistance is provided in proportion to and synchronous with the electrical activity of the diaphragm. We present the case of a 4-month-old infant with asphyxiating thoracic dystrophy and respiratory failure successfully ventilated with NAVA. In this case, NAVA improved patient-ventilator synchrony, reducing endotracheal secretion and gastric overdistention. The reduction of breathing effort and the improvement in enteral feeding tolerance and weight gain made the patient eligible for thoracic surgical correction. PMID- 27940766 TI - Phototherapy and Risk of Type 1 Diabetes. AB - BACKGROUND AND OBJECTIVE: Increases in both phototherapy use and the incidence of type 1 diabetes mellitus (DM-1) have been reported. One large study has suggested a strong association between them. Our objective was to quantify any association between neonatal phototherapy and DM-1 in a northern California integrated health care system. METHODS: This retrospective cohort study included 499 642 children born at >=35 weeks' gestation in 15 Kaiser Permanente Northern California hospitals from 1995 to 2011 and followed until March 31, 2014. We ascertained phototherapy, bilirubin levels, and other covariates from electronic records. We identified DM-1 cases using a diabetes registry and inpatient and outpatient diagnoses. We used traditional and propensity-adjusted Cox models to quantify associations. RESULTS: Phototherapy use increased from 2.7% in 1995 to 16.0% in 2011. DM-1 was diagnosed in 37 of 39 406 children who had received phototherapy (15.1 per 100 000 person-years; mean follow-up 6.2 years) and 712 of 460 236 who had not (18.8 per 100 000 person-years; mean follow-up 8.2 years). There was no evidence of increasing diabetes incidence. We found no association between phototherapy and DM-1 in either unadjusted analyses (incidence rate ratio 0.81; 95% confidence interval, 0.56 to 1.12) or analyses adjusted for hyperbilirubinemia and other covariates (hazard ratio 1.06; 95% confidence interval, 0.78 to 1.45). DM-1 incidence was most strongly associated with race and ethnicity, with whites at highest risk (25.6 per 100 000) and Asians at lowest risk (8.9 per 100 000). CONCLUSIONS: We found no evidence of increased DM 1 risk in children who had received phototherapy. PMID- 27940768 TI - Case Report of a Severe Recurrent Tongue Self-Injury in an Infant With Dystonia. AB - Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both that are typically patterned, twisting, and sometimes tremulous. It is often initiated or worsened by voluntary action and associated with overflow muscle activation. In this article we report a case of severe oromandibular dystonia, which is a specific form of dystonia characterized by involuntary, action-induced tonic or clonic spasms of the masticatory, lingual, and pharyngeal musculature. Episodes of repeated tongue biting in a 17-month-old girl caused her to stay in the PICU for 4 weeks. These episodes were the consequence of dystonia induced by a perinatal stroke. We highlight the specific dental management that enabled us to treat the child without extractions. Facing this type of complex illness, we insist on the importance of interdisciplinary work with the goal of avoiding outdated techniques. The use of botulinum toxin seemed relevant. PMID- 27940769 TI - Progressive Aortic Stenosis in Homozygous Familial Hypercholesterolemia After Liver Transplant. AB - Early onset coronary artery disease and aortic calcifications are characteristic features of patients with homozygous familial hypercholesterolemia. Standard medical therapy includes dietary modification, pharmacotherapy, and lipoprotein apheresis to lower serum low-density lipoprotein cholesterol (LDL-C). Liver transplant is a surgical option for the treatment of homozygous familial hypercholesterolemia and can lead to normal cholesterol levels. Vascular calcifications are known to progress despite standard medical therapy and have been reported after liver transplant in the setting of rejection. We present the first report of progressive severe aortic valve stenosis in a patient despite liver transplant with normalization of lipid levels and no history of graft rejection. PMID- 27940770 TI - A Quality Improvement Initiative: Improving the Frequency of Inpatient Electronic Prescribing. AB - OBJECTIVE: To improve the frequency of electronic prescribing (e-prescribing) of discharge prescriptions at a children's hospital via a bundle of quality improvement interventions. METHODS: Surveys and focus groups were conducted with patient families and pediatric residents to identify barriers and propose solutions to e-prescribing. These data were used to generate a series of interventions, including the following: (1) provider education; (2) changes in patient registration workflow; and (3) electronic health record changes to improve the frequency of e-prescribing on the pediatric hospital medicine (PHM) service. The primary outcome measure was the e-prescribing frequency, with a balance measure of e-prescribing errors. RESULTS: From July 2014 through June 2015, e-prescribing frequency on the PHM service improved from a median of 7.4% to 48.9% (P < .001) and was sustained for an additional 6 months (July 2015 December 2015), surpassing meaningful use targets with associated US News and World Report hospital ranking points. The frequency of PHM prescription errors remained unchanged, and in comparison, the resident outpatient clinic revealed no statistically significant change in e-prescribing frequency during this time period. CONCLUSIONS: Engaging front-line providers in hospital-wide initiatives and quality improvement interventions can directly affect hospital metrics in programs such as meaningful use and US News and World Report, as shown through successful improvement in PHM e-prescribing frequency. Future studies are necessary to determine whether increased e-prescribing frequency affects patient outcomes and compliance. PMID- 27940771 TI - The AAP Resilience in the Face of Grief and Loss Curriculum. AB - A career in pediatrics can bring great joy and satisfaction. It can also be challenging and lead some providers to manifest burnout and depression. A curriculum designed to help pediatric health providers acquire resilience and adaptive skills may be a key element in transforming times of anxiety and grief into rewarding professional experiences. The need for this curriculum was identified by the American Academy of Pediatrics Section on Medical Students, Residents and Fellowship Trainees. A working group of educators developed this curriculum to address the professional attitudes, knowledge, and skills essential to thrive despite the many stressors inevitable in clinical care. Fourteen modules incorporating adult learning theory were developed. The first 2 sections of the curriculum address the knowledge and skills to approach disclosure of life altering diagnoses, and the second 2 sections focus on the provider's responses to difficult patient care experiences and their needs to develop strategies to maintain their own well-being. This curriculum addresses the intellectual and emotional characteristics patient care medical professionals need to provide high quality, compassionate care while also addressing active and intentional ways to maintain personal wellness and resilience. PMID- 27940772 TI - HIV-Associated Cognitive Impairment in Perinatally Infected Children: A Meta analysis. AB - CONTEXT: Research shows, conclusively, that perinatal HIV infection has negative effects on cognitive functioning of children and adolescents. However, the extent of these cognitive impairments is unknown. Current literature does not document specific cognitive domains most affected in HIV-infected children and adolescents. OBJECTIVE: To systematically review and meta-analyze the degree of cognitive impairment, and the specific cognitive domains affected, in children and adolescents with perinatally acquired HIV infection. DATA SOURCES: We systematically searched 5 electronic bibliographic databases, namely: PubMed, PsychINFO, Academic Search Premier, Scopus, and WorldCat, by using a search protocol specifically designed for this study. STUDY SELECTION: Studies were selected on the basis of set a priori eligibility criteria. Titles, abstracts, and full texts were assessed by 2 independent reviewers. DATA EXTRACTION: Data from included studies were extracted into Microsoft Excel by 2 independent reviewers. RESULTS: Twenty-two studies were identified for inclusion in the systematic review and of this, 6 studies were included in the meta-analysis. Results from the meta-analysis indicated that working memory and executive function were the domains most affected by the HIV virus. LIMITATIONS: Only 27% of the included studies were suitable to enter into the meta-analysis. There was significant geographic bias in published studies, with only 32% (7/22) of included studies from sub-Saharan Africa. CONCLUSIONS: The evidence supports an association between HIV infection in children and adolescents and cognitive impairment in the domains of working memory, executive function and processing speed, with effect size estimates also providing some support for deficits in visual memory and visual-spatial ability. PMID- 27940773 TI - Psychiatric Disorders and Trends in Resource Use in Pediatric Hospitals. AB - OBJECTIVE: To describe recent, 10-year trends in pediatric hospital resource use with and without a psychiatric diagnosis and examine how these trends vary by type of psychiatric and medical diagnosis cooccurrence. METHODS: A retrospective, longitudinal cohort analysis using hospital discharge data from 33 tertiary care US children's hospitals of patients ages 3 to 17 years from January 1, 2005 through December 31, 2014. The trends in hospital discharges, hospital days, and total aggregate costs for each psychiatric comorbid group were assessed by using multivariate generalized estimating equations. RESULTS: From 2005 to 2014, the cumulative percent growth in resource use was significantly (all P < .001) greater for children hospitalized with versus without a psychiatric diagnosis (hospitalizations: +137.7% vs +26.0%; hospital days: +92.9% vs 5.9%; and costs: +142.7% vs + 18.9%). During this time period, the most substantial growth was observed in children admitted with a medical condition who also had a cooccurring psychiatric diagnosis (hospitalizations: +160.5%; hospital days: +112.4%; costs: +156.2%). In 2014, these children accounted for 77.8% of all hospitalizations for children with a psychiatric diagnosis; their most common psychiatric diagnoses were developmental disorders (22.3%), attention-deficit/hyperactivity disorder (18.1%), and anxiety disorders (14.2%). CONCLUSIONS: The 10-year rise in pediatric hospitalizations in US children's hospitals is 5 times greater for children with versus without a psychiatric diagnosis. Strategic planning to meet the rising demand for psychiatric care in tertiary care children's hospitals should place high priority on the needs of children with a primary medical condition and cooccurring psychiatric disorders. PMID- 27940774 TI - Venovenous ECMO for Congenital Diaphragmatic Hernia: Role of Ductal Patency and Lung Recruitment. AB - We report a case of antenatally diagnosed left-sided congenital diaphragmatic hernia, managed on venovenous extracorporeal membrane oxygenation with an hemodynamic and ventilation strategy aimed at preventing left and right ventricular dysfunction. Keeping the ductus arteriosus open with prostaglandin infusion and optimizing lung recruitment were effective in achieving hemodynamic stabilization and an ideal systemic oxygen delivery. The patient was discharged from the hospital and had normal development at 1 year of age. The combination of ductal patency and lung recruitment has not been previously reported as a strategy to stabilize congenital diaphragmatic hernia patients undergoing venovenous extracorporeal membrane oxygenation. We believe that this approach may deserve further evaluation in prospective studies. PMID- 27940775 TI - Mental and Physical Health of Children in Foster Care. AB - BACKGROUND AND OBJECTIVES: Each year, nearly 1% of US children spend time in foster care, with 6% of US children placed in foster care at least once between their birth and 18th birthday. Although a large literature considers the consequences of foster care placement for children's wellbeing, no study has used a nationally representative sample of US children to compare the mental and physical health of children placed in foster care to the health of children not placed in foster care. METHODS: We used data from the 2011-2012 National Survey of Children's Health, a nationally representative sample of noninstitutionalized children in the United States, and logistic regression models to compare parent reported mental and physical health outcomes of children placed in foster care to outcomes of children not placed in foster care, children adopted from foster care, children across specific family types (eg, single-mother households), and children in economically disadvantaged families. RESULTS: We find that children in foster care are in poor mental and physical health relative to children in the general population, children across specific family types, and children in economically disadvantaged families. Some differences are explained by adjusting for children's demographic characteristics, and nearly all differences are explained by also adjusting for the current home environment. Additionally, children adopted from foster care, compared with children in foster care, have significantly higher odds of having some health problems. CONCLUSIONS: Children in foster care are a vulnerable population in poor health, partially as a result of their early life circumstances. PMID- 27940776 TI - Risk Factors for Sleep-Related Infant Deaths in In-Home and Out-of-Home Settings. AB - BACKGROUND AND OBJECTIVE: Multiple environmental risk factors are associated with sleep-related infant deaths. Little is known about differences in risk factors for deaths occurring in-home and out-of-home. We sought to compare risk factors for in-home and out-of-home infant deaths. METHODS: We conducted a cross sectional analysis of sleep-related infant deaths from 2004 to 2014 in the National Child Fatality Review and Prevention database. The main exposure was setting (in-home versus out-of-home) at time of death. Primary outcomes were known risk factors: sleep position, sleep location (eg, crib), objects in the environment, and bed sharing. Risk factors for in-home versus out-of-home deaths were compared using the chi2 test and multivariate logistic regressions. RESULTS: A total of 11 717 deaths were analyzed. Infants who died out-of-home were more likely to be in a stroller/car seat (adjusted odds ratio, 2.6; 95% confidence interval, 2.1-3.4; P < .001) and other locations (adjusted odds ratio, 1.9; 95% confidence interval, 1.5-2.3; P < .001), and placed prone (adjusted odds ratio, 1.1; 95% confidence interval, 1.02-1.27; P = .02). Bed sharing was less common out-of-home (adjusted odds ratio, 0.7; 95% confidence interval, 0.6-0.7; P < .001). There were no differences in sleeping in an adult bed/on person, on a couch/ chair, or objects in the sleep environment. CONCLUSIONS: Sleep-related infant deaths in the out-of-home setting have higher odds of having certain risk factors, such as prone placement for sleep and location in a stroller/car seat, rather than in a crib/bassinet. Caregivers should be educated on the importance of placing infants to sleep supine in cribs/bassinets to protect against sleep related deaths, both in and out of the home. PMID- 27940777 TI - Newborn Pulse Oximetry Screening: Which Algorithm Is Best? PMID- 27940779 TI - Neuropsychological Follow-up After Neonatal ECMO. AB - OBJECTIVE: To assess the longitudinal development of intelligence and its relation to school performance in a nationwide cohort of neonatal extracorporeal membrane oxygenation (ECMO) survivors and evaluate predictors of outcome at 8 years of age. METHODS: Repeated measurements assessed intelligence of neonatal ECMO survivors at 2, 5, and 8 years (n = 178) with the use of validated, standardized instruments. Selective attention (n = 148) and type of education were evaluated in the 8-year-olds. RESULTS: Intelligence remained stable and average across development (mean +/- SD IQ: at 2 years, 102 +/- 18; at 5 years, 100 +/- 17; and at 8 years, 99 +/- 17 [P = .15]). Children attending regular education without the need for help (n = 101; mean z score: -1.50 +/- 1.93) performed significantly better on the selective attention task compared with those children who needed extra help (n = 65; mean z score: -2.54 +/- 3.18) or those attending special education (n = 13; mean z score: -4.14 +/- 3.63) (P = .03). However, only children attending special education had below-average intelligence (mean IQ: 76 +/- 15), compared with average intelligence for those attending regular education, both with help (mean IQ: 95 +/- 15) and without help (mean IQ: 105 +/- 16). Compared with children with other diagnoses, children with congenital diaphragmatic hernia (CDH) scored significantly lower on both IQ (CDH, mean IQ: 93 +/- 20; meconium aspiration syndrome, mean IQ: 100 +/- 15; other diagnoses, mean IQ: 100 +/- 19 [P = .04]) and selective attention (CDH, mean z score: -3.48 +/- 3.46; meconium aspiration syndrome, mean z score: -1.60 +/- 2.13; other diagnoses, mean z score: -1.65 +/- 2.39 [P = .002]). CONCLUSIONS: For the majority of neonatal ECMO survivors, intelligence testing alone did not identify those at risk for academic problems. We propose internationally standardized follow-up protocols that focus on long-term, problem-oriented neuropsychological assessment. PMID- 27940778 TI - Trends in Susceptibility to Smoking by Race and Ethnicity. AB - OBJECTIVES: Examine racial/ethnic differences in smoking susceptibility among US youth nonsmokers over time and age. METHODS: We used nationally representative samples of youths who never tried cigarettes (N = 143 917; age, 9-21, mean, 14.01 years) from National Youth Tobacco Survey, 1999 to 2014. We used time-varying effect modeling to examine nonlinear trends in smoking susceptibility adjusted for demographics, living with smokers, and exposure to tobacco advertising. RESULTS: Compared with non-Hispanic whites (NHWs), Hispanics were more susceptible to smoking from 1999 to 2014 (highest adjusted odds ratio [aOR], 1.67 in 2012). Non-Hispanic blacks were less susceptible to smoking than NHWs from 2000 to 2009 (lowest aOR, 0.80 in 2003-2005). Non-Hispanic Asian Americans were less susceptible to smoking from 2000 to 2009 (aOR, 0.83), after which they did not differ from NHWs. Other non-Hispanics were more susceptible to smoking than NHWs from 2012 to 2014 (highest aOR, 1.40 in 2014). Compared with NHWs, non Hispanic blacks and other non-Hispanics were more susceptible to smoking at ages 11 to 13 (highest aOR, 1.22 at age 11.5 ) and 12 to 14 (highest aOR, 1.27 at age 12 ), respectively. Hispanics were more susceptible to smoking throughout adolescence peaking at age 12 (aOR, 1.60) and age 16.5 (aOR, 1.46). Non-Hispanic Asian Americans were less susceptible to smoking at ages 11 to 15 (lowest aOR, 0.76 at ages 11-13 ). CONCLUSIONS: Racial/ethnic disparities in smoking susceptibility persisted over time among US youth nonsmokers, especially at ages 11 to 13 . Interventions to combat smoking susceptibility are needed. PMID- 27940780 TI - Childcare Attendance and Obesity Risk. AB - BACKGROUND AND OBJECTIVES: Several observational studies have revealed that children who receive nonparental childcare are at increased risk of obesity. However, this may be due to unmeasured confounding or selection into different types of childcare. It is not well established whether this association reflects a causal effect of childcare attendance on obesity risk. We examined the effect of attending childcare on children's BMI z scores, using nationally representative data of ~10 700 children followed from age 9 months through kindergarten entry. METHODS: We first employed ordinary least squares regression to evaluate longitudinal associations between childcare attendance at 24 months and BMI z scores at kindergarten entry, controlling for child, family, and neighborhood characteristics. Because type of childcare is associated with unobserved confounding factors, we repeated the analysis by using 2 quasi experimental approaches: (1) individual fixed effect models, which control for all observed and unobserved time-invariant confounders; and (2) instrumental variable (IV) analysis. RESULTS: At 24 months, 48.7% of children were in nonparental childcare, and 35.1% of children were overweight/obese at kindergarten entry. In ordinary least squares models, compared with children in parental care, children in nonparental childcare at 24 months had higher BMI z scores at kindergarten entry (0.08 [SE 0.03], P = .01). By contrast, fixed effects and IV models revealed no significant effect of childcare on BMI z score (fixed effects model: beta = 0.02 [SE 0.02], P = .62); IV model: beta = 1.12 [SE 0.76], P = .14). CONCLUSIONS: We found no consistent associations between nonparental childcare and obesity. Previously reported significant associations may be confounded by unobserved family circumstances resulting in selection into different types of childcare. PMID- 27940781 TI - Inheritance Patterns of Infantile Hemangioma. AB - BACKGROUND AND OBJECTIVE: Infantile hemangioma (IH) includes, among its other risk factors, familial clustering, but a definitive understanding of IH's inheritance model and genetic basis is lacking. Our objective was to collect IH pedigrees in Finland, to study the inheritance patterns of IH within these families, and to analyze the characteristics of familial IHs. METHODS: We identified 185 patients with IH who visited our vascular anomaly clinic between 2004 and 2007. Based on hospital records and a questionnaire sent to these patients and their families, IH characteristics and family history of IH were studied. We compared characteristics between patients with positive (familial) and negative (sporadic) IH family history. Families with positive IH family history were further interviewed for extended pedigree data. RESULTS: One-third of our IH cohort's families reported a family history positive for IH, with IH characteristics and perinatal data between the familial and sporadic cases being similar. IH patients with affected first-degree relatives reported higher long term discomfort rates than the sporadic cases. Of the 40 families interviewed, 11 included >=4 IH-affected family members; these were most commonly first-degree relatives (63%). Segregation patterns match with autosomal dominant inheritance with an incomplete penetrance or maternal transmission. We also present a case of monozygotic twins that manifest identical IHs. CONCLUSIONS: Based on this large number of IH pedigrees, we suggest at least 2 possible mechanisms of inheritance: autosomal dominant and maternal transmission. This study highlights the need for additional genetic studies to define inheritance of this common disease. PMID- 27940783 TI - Outcomes of Nosocomial Viral Respiratory Infections in High-Risk Neonates. AB - BACKGROUND AND OBJECTIVE: Neonatal respiratory disease, particularly bronchopulmonary dysplasia, remains one of the leading causes of morbidity and mortality in newborn infants. Recent evidence suggests nosocomially acquired viral respiratory tract infections (VRTIs) are not uncommon in the NICU. The goal of this study was to assess the association between nosocomial VRTIs, neonatal respiratory disease, and the health care related costs. METHODS: A matched case control study was conducted in 2 tertiary NICUs during a 6-year period in Nottingham, United Kingdom. Case subjects were symptomatic neonatal patients with a confirmed real-time polymerase chain reaction diagnosis of a VRTI. Matched controls had never tested positive for a VRTI. Multivariable logistic regression was used to test for associations with key respiratory outcomes. RESULTS: There were 7995 admissions during the study period, with 92 case subjects matched to 183 control subjects. Baseline characteristics were similar, with a median gestation of 29 weeks. Rhinovirus was found in 74% of VRTIs. During VRTIs, 51% of infants needed escalation of respiratory support, and case subjects required significantly more respiratory pressure support overall (25 vs 7 days; P < .001). Case subjects spent longer in the hospital (76 vs 41 days; P < .001), twice as many required home oxygen (37%; odds ratio: 3.94 [95% confidence interval: 1.92 8.06]; P < .001), and in-hospital care costs were significantly higher (L49 664 [$71 861] vs L22 155 [$32 057]; P < .001). CONCLUSIONS: Nosocomial VRTIs in neonatal patients are associated with significant greater respiratory morbidity and health care costs. Prevention efforts must be explored. PMID- 27940784 TI - Parental Refusal of Surgery in an Infant With Tricuspid Atresia. AB - We present a case of a fetal diagnosis of tricuspid atresia (TA). The pregnant woman and her husband requested that the baby be treated with only palliative care. The cardiologist did not think it would be appropriate to withhold life prolonging surgery once the infant was born. The neonatologist argued that outcomes for TA are similar to those for hypoplastic left heart syndrome, and the standard practice at the institution was to allow parents to choose surgery or end-of-life care for those infants. The team requested an ethics consultation to assist in determining whether forgoing life-prolonging interventions in this case would be ethically supportable. In this article, we ask a pediatric intensivist, a pediatric cardiologist, and a neonatologist to discuss the ethics of withholding life-sustaining treatment of a baby with TA. PMID- 27940782 TI - Third Trimester Brain Growth in Preterm Infants Compared With In Utero Healthy Fetuses. AB - BACKGROUND AND OBJECTIVES: Compared with term infants, preterm infants have impaired brain development at term-equivalent age, even in the absence of structural brain injury. However, details regarding the onset and progression of impaired preterm brain development over the third trimester are unknown. Our primary objective was to compare third-trimester brain volumes and brain growth trajectories in ex utero preterm infants without structural brain injury and in healthy in utero fetuses. As a secondary objective, we examined risk factors associated with brain volumes in preterm infants over the third-trimester postconception. METHODS: Preterm infants born before 32 weeks of gestational age (GA) and weighing <1500 g with no evidence of structural brain injury on conventional MRI and healthy pregnant women were prospectively recruited. Anatomic T2-weighted brain images of preterm infants and healthy fetuses were parcellated into the following regions: cerebrum, cerebellum, brainstem, and intracranial cavity. RESULTS: We studied 205 participants (75 preterm infants and 130 healthy control fetuses) between 27 and 39 weeks' GA. Third-trimester brain volumes were reduced and brain growth trajectories were slower in the ex utero preterm group compared with the in utero healthy fetuses in the cerebrum, cerebellum, brainstem, and intracranial cavity. Clinical risk factors associated with reduced brain volumes included dexamethasone treatment, the presence of extra-axial blood on brain MRI, confirmed sepsis, and duration of oxygen support. CONCLUSIONS: These preterm infants exhibited impaired third-trimester global and regional brain growth in the absence of cerebral/cerebellar parenchymal injury detected by using conventional MRI. PMID- 27940785 TI - School-Located Influenza Vaccinations: A Randomized Trial. AB - OBJECTIVE: Assess impact of offering school-located influenza vaccination (SLIV) clinics using both Web-based and paper consent upon overall influenza vaccination rates among elementary school children. METHODS: We conducted a cluster randomized trial (stratified by suburban/urban districts) in upstate New York in 2014-2015. We randomized 44 elementary schools, selected similar pairs of schools within districts, and allocated schools to SLIV versus usual care (control). Parents of children at SLIV schools were sent information and vaccination consent forms via e-mail, backpack fliers, or both (depending on school preferences) regarding school vaccine clinics. Health department nurses conducted vaccine clinics and billed insurers. For all children registered at SLIV/control schools, we compared receipt of influenza vaccination anywhere (primary outcome). RESULTS: The 44 schools served 19 776 eligible children in 2014-2015. Children in SLIV schools had higher influenza vaccination rates than children in control schools county-wide (54.1% vs 47.4%, P < .001) and in suburban (61.9% vs 53.6%, P < .001) and urban schools (43.9% vs 39.2%; P < .001). Multivariate analyses (controlling for age, grade, vaccination in previous season) confirmed bivariate findings. Among parents who consented for SLIV, nearly half of those notified by backpack fliers and four-fifths of those notified by e-mail consented online. In suburban districts, SLIV did not substitute for primary care influenza vaccination. In urban schools, some substitution occurred. CONCLUSIONS: SLIV raised seasonal influenza vaccination rates county-wide and in both suburban and urban settings. SLIV did not substitute for primary care vaccinations in suburban settings where pediatricians often preorder influenza vaccine but did substitute somewhat in urban settings. PMID- 27940786 TI - Long-term Behavioral Problems in Children With Severe Malaria. AB - BACKGROUND: Severe malaria in children is associated with long-term neurocognitive impairment, but it is unclear whether it is associated with long term behavioral problems. METHODS: Children <5 years old with cerebral malaria (CM) or severe malarial anemia (SMA) treated at Mulago Hospital, Kampala, Uganda were assessed for behavioral outcomes at 0, 6, 12, and 24 months using the Child Behavior Checklist. Sample sizes at 0, 12, and 24 months were 122, 100, and 80 in the CM group, 130, 98, and 81 in the SMA group, and 149, 123, and 90 in healthy community control (CC) children, respectively. Age adjusted z-scores for behavioral outcomes were computed using scores for the CC group. Study groups were compared using regression models adjusted for age, nutritional status, preschool education, and socioeconomic status. RESULTS: At 12 months, children with SMA had higher z-scores than CC children for internalizing (mean difference, 0.49; SE, 0.14; P = .001), externalizing (mean difference, 0.49; SE, 0.15; P = .001), and total problems (mean difference, 0.51; SE, 0.15; P < .001). Children with CM had higher adjusted z-scores than CC children for externalizing problems (mean difference, 0.39; SE, 0.15; P = .009) but not internalizing or total problems. At 24 months, children with CM or SMA both had increased internalizing and externalizing behavioral problems compared with CC children (P <= .05 for all). CONCLUSIONS: CM and SMA are associated with long-term internalizing and externalizing behavioral problems in children. They may contribute substantially to mental health morbidity in children <5 years old in malaria endemic areas. PMID- 27940787 TI - Congenital Diaphragmatic Hernia Defect Size and Infant Morbidity at Discharge. AB - BACKGROUND AND OBJECTIVE: Survival for infants with congenital diaphragmatic hernia (CDH) has gradually improved, yet substantial burden of disease remains. Although larger CDH defect sizes increase mortality, the association between defect size and morbidity has not been reported. Our objective was to evaluate the association of defect size with pulmonary, neurologic, and gastrointestinal morbidity at the time of hospital discharge. METHODS: An international, prospective cohort study was performed. Patient demographics, intraoperative defect size, and clinical outcomes were reviewed. The primary outcome was morbidity at the time of discharge, which entailed supplemental oxygen requirement, abnormal neurologic clinical and radiographic findings, gastroesophageal reflux, supplemental nutrition, or pulmonary-, neurologic-, or gastrointestinal-related medications. RESULTS: A total of 3665 patients were included in the study cohort. Overall survival was 70.9%, and 84.0% of survivors were discharged from the hospital (16.0% transferred). Median age at discharge was 38 days (interquartile range [IQR] 23-69) and ranged from 22 (IQR 16-32) days for "A" (smallest) defects to 89 (IQR 64-132) days for "D" (largest) defects (P < .001). Of those discharged from the hospital, 1522 (74.2%) had pulmonary (n = 660, 30.2%), neurologic (n = 446, 20.4%), or gastrointestinal (n = 1348, 61.7%) morbidities, and multiple morbidities were diagnosed in 701 (34.7%) patients. On multivariable regression analyses incorporating key patient characteristics, defect size was consistently the greatest predictor of overall morbidity, hospital length of stay, and duration of ventilation. CONCLUSIONS: Infants with CDH are commonly discharged with >=1 major morbidities. The size of the diaphragmatic defect appears to be the most reliable indicator of a patient's hospital course and discharge burden of disease. PMID- 27940788 TI - Urine Concentration and Pyuria for Identifying UTI in Infants. AB - BACKGROUND: Varying urine white blood cell (WBC) thresholds have been recommended for the presumptive diagnosis of urinary tract infection (UTI) among young infants. These thresholds have not been studied with newer automated urinalysis systems that analyze uncentrifuged urine that might be influenced by urine concentration. Our objective was to determine the optimal urine WBC threshold for UTI in young infants by using an automated urinalysis system, stratified by urine concentration. METHODS: Retrospective cross-sectional study of infants aged <3 months evaluated for UTI in the emergency department with paired urinalysis and urine culture. UTI was defined as >=50 000 colony-forming units/mL from catheterized specimens. Test characteristics were calculated across a range of WBC and leukocyte esterase (LE) cut-points, dichotomized into specific gravity groups (dilute <1.015; concentrated >=1.015). RESULTS: Twenty-seven thousand infants with a median age of 1.7 months were studied. UTI prevalence was 7.8%. Optimal WBC cut-points were 3 WBC/high-power field (HPF) in dilute urine (likelihood ratio positive [LR+] 9.9, likelihood ratio negative [LR-] 0.15) and 6 WBC/HPF (LR+ 10.1, LR- 0.17) in concentrated urine. For dipstick analysis, positive LE has excellent test characteristics regardless of urine concentration (LR+ 22.1, LR- 0.12 in dilute urine; LR+ 31.6, LR- 0.22 in concentrated urine). CONCLUSIONS: Urine concentration should be incorporated into the interpretation of automated microscopic urinalysis in young infants. Pyuria thresholds of 3 WBC/HPF in dilute urine and 6 WBC/HPF in concentrated urine are recommended for the presumptive diagnosis of UTI. Without correction of specific gravity, positive LE by automated dipstick is a reliably strong indicator of UTI. PMID- 27940789 TI - To Trust or Not to Trust? An Introduction to Entrustable Professional Activities. PMID- 27940790 TI - Leading by Example and Design: The Joseph St Geme Jr Leadership Award, 2016. PMID- 27940791 TI - Indoor Environmental Control Practices and Asthma Management. AB - Indoor environmental exposures, particularly allergens and pollutants, are major contributors to asthma morbidity in children; environmental control practices aimed at reducing these exposures are an integral component of asthma management. Some individually tailored environmental control practices that have been shown to reduce asthma symptoms and exacerbations are similar in efficacy and cost to controller medications. As a part of developing tailored strategies regarding environmental control measures, an environmental history can be obtained to evaluate the key indoor environmental exposures that are known to trigger asthma symptoms and exacerbations, including both indoor pollutants and allergens. An environmental history includes questions regarding the presence of pets or pests or evidence of pests in the home, as well as knowledge regarding whether the climatic characteristics in the community favor dust mites. In addition, the history focuses on sources of indoor air pollution, including the presence of smokers who live in the home or care for children and the use of gas stoves and appliances in the home. Serum allergen-specific immunoglobulin E antibody tests can be performed or the patient can be referred for allergy skin testing to identify indoor allergens that are most likely to be clinically relevant. Environmental control strategies are tailored to each potentially relevant indoor exposure and are based on knowledge of the sources and underlying characteristics of the exposure. Strategies include source removal, source control, and mitigation strategies, such as high-efficiency particulate air purifiers and allergen-proof mattress and pillow encasements, as well as education, which can be delivered by primary care pediatricians, allergists, pediatric pulmonologists, other health care workers, or community health workers trained in asthma environmental control and asthma education. PMID- 27940792 TI - Establishing a Standard Protocol for the Voiding Cystourethrography. AB - The voiding cystourethrogram (VCUG) is a frequently performed test to diagnose a variety of urologic conditions, such as vesicoureteral reflux. The test results determine whether continued observation or an interventional procedure is indicated. VCUGs are ordered by many specialists and primary care providers, including pediatricians, family practitioners, nephrologists, hospitalists, emergency department physicians, and urologists. Current protocols for performing and interpreting a VCUG are based on the International Reflux Study in 1985. However, more recent information provided by many national and international institutions suggests a need to refine those recommendations. The lead author of the 1985 study, R.L. Lebowitz, agreed to and participated in the current protocol. In addition, a recent survey directed to the chairpersons of pediatric radiology of 65 children's hospitals throughout the United States and Canada showed that VCUG protocols vary substantially. Recent guidelines from the American Academy of Pediatrics (AAP) recommend a VCUG for children between 2 and 24 months of age with urinary tract infections but did not specify how this test should be performed. To improve patient safety and to standardize the data obtained when a VCUG is performed, the AAP Section on Radiology and the AAP Section on Urology initiated the current VCUG protocol to create a consensus on how to perform this test. PMID- 27940793 TI - Media and Young Minds. AB - Infants, toddlers, and preschoolers are now growing up in environments saturated with a variety of traditional and new technologies, which they are adopting at increasing rates. Although there has been much hope for the educational potential of interactive media for young children, accompanied by fears about their overuse during this crucial period of rapid brain development, research in this area still remains limited. This policy statement reviews the existing literature on television, videos, and mobile/interactive technologies; their potential for educational benefit; and related health concerns for young children (0 to 5 years of age). The statement also highlights areas in which pediatric providers can offer specific guidance to families in managing their young children's media use, not only in terms of content or time limits, but also emphasizing the importance of parent-child shared media use and allowing the child time to take part in other developmentally healthy activities. PMID- 27940794 TI - Media Use in School-Aged Children and Adolescents. AB - This policy statement focuses on children and adolescents 5 through 18 years of age. Research suggests both benefits and risks of media use for the health of children and teenagers. Benefits include exposure to new ideas and knowledge acquisition, increased opportunities for social contact and support, and new opportunities to access health-promotion messages and information. Risks include negative health effects on weight and sleep; exposure to inaccurate, inappropriate, or unsafe content and contacts; and compromised privacy and confidentiality. Parents face challenges in monitoring their children's and their own media use and in serving as positive role models. In this new era, evidence regarding healthy media use does not support a one-size-fits-all approach. Parents and pediatricians can work together to develop a Family Media Use Plan (www.healthychildren.org/MediaUsePlan) that considers their children's developmental stages to individualize an appropriate balance for media time and consistent rules about media use, to mentor their children, to set boundaries for accessing content and displaying personal information, and to implement open family communication about media. PMID- 27940796 TI - The Neurologist's Role in Supporting Transition to Adult Health Care. PMID- 27940795 TI - Children and Adolescents and Digital Media. AB - Today's children and adolescents are immersed in both traditional and new forms of digital media. Research on traditional media, such as television, has identified health concerns and negative outcomes that correlate with the duration and content of viewing. Over the past decade, the use of digital media, including interactive and social media, has grown, and research evidence suggests that these newer media offer both benefits and risks to the health of children and teenagers. Evidence-based benefits identified from the use of digital and social media include early learning, exposure to new ideas and knowledge, increased opportunities for social contact and support, and new opportunities to access health promotion messages and information. Risks of such media include negative health effects on sleep, attention, and learning; a higher incidence of obesity and depression; exposure to inaccurate, inappropriate, or unsafe content and contacts; and compromised privacy and confidentiality. This technical report reviews the literature regarding these opportunities and risks, framed around clinical questions, for children from birth to adulthood. To promote health and wellness in children and adolescents, it is important to maintain adequate physical activity, healthy nutrition, good sleep hygiene, and a nurturing social environment. A healthy Family Media Use Plan (www.healthychildren.org/MediaUsePlan) that is individualized for a specific child, teenager, or family can identify an appropriate balance between screen time/online time and other activities, set boundaries for accessing content, guide displays of personal information, encourage age-appropriate critical thinking and digital literacy, and support open family communication and implementation of consistent rules about media use. PMID- 27940801 TI - Systematic Review and Evidence-Based Guidelines for the Management of Patients with Positional Plagiocephaly. PMID- 27940799 TI - Standardization of Inpatient Handoff Communication. AB - Handoff communication is identified as an integral part of hospital care. Throughout medical communities, inadequate handoff communication is being highlighted as a significant risk to patients. The complexity of hospitals and the number of providers involved in the care of hospitalized patients place inpatients at high risk of communication lapses. This miscommunication and the potential resulting harm make effective handoffs more critical than ever. Although hospitalized patients are being exposed to many handoffs each day, this report is limited to describing the best handoff practices between providers at the time of shift change. PMID- 27940798 TI - Handoffs: Transitions of Care for Children in the Emergency Department. AB - Transitions of care (ToCs), also referred to as handoffs or sign-outs, occur when the responsibility for a patient's care transfers from 1 health care provider to another. Transitions are common in the acute care setting and have been noted to be vulnerable events with opportunities for error. Health care is taking ideas from other high-risk industries, such as aerospace and nuclear power, to create models of structured transition processes. Although little literature currently exists to establish 1 model as superior, multiorganizational consensus groups agree that standardization is warranted and that additional work is needed to establish characteristics of ToCs that are associated with clinical or practice outcomes. The rationale for structuring ToCs, specifically those related to the care of children in the emergency setting, and a description of identified strategies are presented, along with resources for educating health care providers on ToCs. Recommendations for development, education, and implementation of transition models are included. PMID- 27940800 TI - The Use of Systemic and Topical Fluoroquinolones. AB - Appropriate prescribing practices for fluoroquinolones, as well as all antimicrobial agents, are essential as evolving resistance patterns are considered, additional treatment indications are identified, and the toxicity profile of fluoroquinolones in children has become better defined. Earlier recommendations for systemic therapy remain; expanded uses of fluoroquinolones for the treatment of certain infections are outlined in this report. Prescribing clinicians should be aware of specific adverse reactions associated with fluoroquinolones, and their use in children should continue to be limited to the treatment of infections for which no safe and effective alternative exists or in situations in which oral fluoroquinolone treatment represents a reasonable alternative to parenteral antimicrobial therapy. PMID- 27940802 TI - The Diagnosis of UTI: Concentrating on Pyuria. PMID- 27940803 TI - In the Absence of Clear Causation, Casting a Wider Net for Prevention. PMID- 27940804 TI - SIDS and Other Sleep-Related Infant Deaths: Updated 2016 Recommendations for a Safe Infant Sleeping Environment. AB - Approximately 3500 infants die annually in the United States from sleep-related infant deaths, including sudden infant death syndrome (SIDS; International Classification of Diseases, 10th Revision [ICD-10], R95), ill-defined deaths (ICD 10 R99), and accidental suffocation and strangulation in bed (ICD-10 W75). After an initial decrease in the 1990s, the overall death rate attributable to sleep related infant deaths has not declined in more recent years. Many of the modifiable and nonmodifiable risk factors for SIDS and other sleep-related infant deaths are strikingly similar. The American Academy of Pediatrics recommends a safe sleep environment that can reduce the risk of all sleep-related infant deaths. Recommendations for a safe sleep environment include supine positioning, the use of a firm sleep surface, room-sharing without bed-sharing, and the avoidance of soft bedding and overheating. Additional recommendations for SIDS reduction include the avoidance of exposure to smoke, alcohol, and illicit drugs; breastfeeding; routine immunization; and use of a pacifier. New evidence is presented for skin-to-skin care for newborn infants, use of bedside and in-bed sleepers, sleeping on couches/armchairs and in sitting devices, and use of soft bedding after 4 months of age. The recommendations and strength of evidence for each recommendation are included in this policy statement. The rationale for these recommendations is discussed in detail in the accompanying technical report (www.pediatrics.org/cgi/doi/10.1542/peds.2016-2940). PMID- 27940805 TI - SIDS and Other Sleep-Related Infant Deaths: Evidence Base for 2016 Updated Recommendations for a Safe Infant Sleeping Environment. AB - Approximately 3500 infants die annually in the United States from sleep-related infant deaths, including sudden infant death syndrome (SIDS), ill-defined deaths, and accidental suffocation and strangulation in bed. After an initial decrease in the 1990s, the overall sleep-related infant death rate has not declined in more recent years. Many of the modifiable and nonmodifiable risk factors for SIDS and other sleep-related infant deaths are strikingly similar. The American Academy of Pediatrics recommends a safe sleep environment that can reduce the risk of all sleep-related infant deaths. Recommendations for a safe sleep environment include supine positioning, use of a firm sleep surface, room-sharing without bed sharing, and avoidance of soft bedding and overheating. Additional recommendations for SIDS risk reduction include avoidance of exposure to smoke, alcohol, and illicit drugs; breastfeeding; routine immunization; and use of a pacifier. New evidence and rationale for recommendations are presented for skin to-skin care for newborn infants, bedside and in-bed sleepers, sleeping on couches/armchairs and in sitting devices, and use of soft bedding after 4 months of age. In addition, expanded recommendations for infant sleep location are included. The recommendations and strength of evidence for each recommendation are published in the accompanying policy statement, "SIDS and Other Sleep-Related Infant Deaths: Updated 2016 Recommendations for a Safe Infant Sleeping Environment," which is included in this issue. PMID- 27940806 TI - Treatment for Ulnar Neuritis Around the Elbow in Adolescent Baseball Players: Factors Associated With Poor Outcome. AB - BACKGROUND: Ulnar neuritis around the elbow is one of the injuries seen in throwing athletes. Outcomes of nonsurgical treatment and factors associated with failure outcomes have not been reported. PURPOSE: To investigate the outcomes of treatments for ulnar neuritis in adolescent baseball players. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We assessed 40 male baseball players with a mean age of 15.0 years (range, 13-17 years) who presented with ulnar neuritis. There were 19 pitchers and 21 fielders whose throwing side was affected. All patients had elbow pain, and 13 patients had hand numbness on the ulnar side. The mean Kerlan-Jobe Orthopaedic Clinic (KJOC) overhead athlete shoulder and elbow score was 52.5 at the first follow-up visit (n = 36 patients). Thirteen patients were identified with ulnar nerve subluxation, and 23 patients had concomitant elbow ulnar collateral ligament (UCL) injury. All patients underwent nonsurgical treatment, which included rehabilitation exercises and prohibition of throwing. If the nonsurgical treatment failed, we recommended surgical treatment. We investigated the outcomes of the nonsurgical and surgical treatments. Return to sports was evaluated, combined with factors associated with return to sports in nonsurgical treatment by univariate and multivariate statistical analysis. RESULTS: The mean follow-up period was 23.6 months (range, 6-39 months). After nonsurgical treatment, 24 patients (60%) returned to the previous competition level after a mean of 2.4 months. Two patients returned to a recreational level. One patient gave up playing baseball at 2 months. The remaining 13 patients underwent surgery and returned to sports after a mean of 2.0 months postoperatively, and 12 had no limitation of sports activities. Multivariate logistical regression analysis demonstrated that hand numbness, ulnar nerve subluxation, and UCL injury were associated with failure of nonsurgical treatment ( P < .05). In addition, KJOC score of <45 at the first follow-up tended to be associated with poor outcomes of nonsurgical treatment ( P = .06). CONCLUSION: Hand numbness on the ulnar side, ulnar nerve subluxation, and UCL injury are strong predictors of poor outcomes after nonsurgical treatment for ulnar neuritis, and surgery provides excellent results. PMID- 27940809 TI - EuroCMR 2016 Congress Report: separating facts from myths. PMID- 27940807 TI - Sex-Based Differences in Cognitive Deficits and Symptom Reporting Among Acutely Concussed Adolescent Lacrosse and Soccer Players. AB - BACKGROUND: Research on the acute effects of a concussion among lacrosse players is limited, and postconcussion patterns between male and female athletes have yet to be clearly established. Differences in the style of play and protective gear worn among male and female lacrosse players potentially confound a direct comparison of sex-based differences in this population. PURPOSE: To explore sex based differences in postconcussive neurocognitive functioning and symptom reporting outcomes in concussed adolescent male and female lacrosse players compared with a group of soccer players. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 224 adolescent lacrosse players (112 male, 112 female) aged 13 to 17 years (mean [+/-SD] age, 15.43 +/- 1.09 years) were included in this study. A comparison group of soccer players was added and matched to lacrosse players based on age and sex to address confounding sport differences in male and female versions of lacrosse. All athletes underwent baseline and postinjury testing within 3 days of an injury using the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) tool. Data were analyzed at baseline using a multivariate analysis of variance (MANOVA) with sport and sex as between-participant factors. A 2 * 2 * 2 mixed-factorial MANOVA was also conducted for sex and sport comparisons at baseline versus after a concussion. Ancillary analyses evaluated sex-based differences in exceeded reliable change indices (RCIs) using an independent-samples t test and established postinjury cutoff scores reflective of a protracted recovery using chi-square tests. RESULTS: All athletes had a significantly worse cognitive profile and greater endorsement of symptoms after an injury ( F5,216 = 30.30, P < .001, etarho2 = .41). Sport yielded a significant main effect ( F5,216 = 2.36, P = .04, etarho2 = .05), but subsequent univariate analyses were nonsignificant ( P > .05) across all neurocognitive and symptom outcome variables. Likewise, there were no significant interaction effects for sport * time ( F5,216 = 1.46, P = .21, etarho2 = .03) or sport * sex * time ( F5,216 = 2.09, P = .07, etarho2 = .05), indicating that lacrosse and soccer players respond similarly on neurocognitive testing and symptom reporting after sustaining a concussion. Regarding sex-based differences, female athletes had a significantly greater neurocognitive decline and increased symptoms after a concussion relative to male athletes, regardless of the sport type (sex * time interaction effect: F5,216 = 3.86, P = .002, etarho2 = .08), with the relationship between concussions and sex demonstrating a medium- to large-sized effect. Female athletes demonstrated a significantly greater number of exceeded RCIs ( t(216.16) = -3.732, P < .001), with 59% of male and 74% of female athletes with at least 1 RCI decline. Approximately 13% of male athletes, compared with 30% of female athletes, demonstrated scores indicative of protracted recovery at a 75% sensitivity (chi2 (1, N = 224) = 9.43, P = .002). CONCLUSION: Athletes performed more poorly on computerized cognitive screening tools and reported greater symptoms after an acute concussion relative to their baseline performance. Female sex may be a modifier of an acute concussion outcome, given that female athletes in this study performed significantly worse than male athletes across all neurocognitive measures and reported greater symptoms relative to their baseline testing compared with male athletes, regardless of the sport played. Female athletes were also more likely than male athletes to demonstrate scores on neurocognitive testing that exceeded reliable change cutoffs and were predictive of a protracted recovery. The practical significance of these findings should be further verified by prospective longitudinal research given the medium- to large-sized effect demonstrated for the overall relationship between sex and concussions. PMID- 27940808 TI - Frontiers in precision medicine: genes and their modulation by miRNAs. PMID- 27940810 TI - CMRI during percussive ventilation: a breath-taking strategy. PMID- 27940811 TI - A new study has identified a more precise magnetic resonance imaging technique for assessing dilated cardiomyopathy patients. PMID- 27940812 TI - CMR; a long story short. PMID- 27940813 TI - The Institute of Model Animals of Wuhan University, China. PMID- 27940814 TI - Arterial switch to 12 o'clock associated with reduced coronary reserve in adolescence. PMID- 27940815 TI - Genetic cardiovascular risk prediction: are we already there? PMID- 27940816 TI - Erratum for the Report "Coordination-induced weakening of ammonia, water, and hydrazine X-H bonds in a molybdenum complex" by M. J. Bezdek, S. Guo, and P. J. Chirik. PMID- 27940817 TI - Erratum for the Editorial "A comprehensive nuclear test ban" by E. J. Moniz. PMID- 27940818 TI - The broadening reach of frustrated Lewis pair chemistry. AB - The revelation that combinations of Lewis acids and bases for which dative bonding is impeded can activate dihydrogen led to the concept of "frustrated Lewis pairs" (FLPs). Over the past decade, a range of FLP systems and substrate molecules have precipitated a paradigm change in main-group chemistry and metal free catalysis. The FLP motif has also found application in a growing body of chemical problems in organic synthesis, transition metal and free radical chemistry, materials, enzymatic models, and surface chemistry. The current state of FLP chemistry is assessed herein, and the outlook for the future considered. PMID- 27940819 TI - Lifeline for refugee scholars. PMID- 27940820 TI - News at a glance. PMID- 27940821 TI - Corals tie stronger El Ninos to climate change. PMID- 27940822 TI - Worries, confusion after cancer trial deaths. PMID- 27940823 TI - U.S. Congress wants to know the weather weeks ahead. PMID- 27940824 TI - AIDS epidemic nears control in three African countries. PMID- 27940825 TI - Perovskite solar cells gear up to go commercial. PMID- 27940826 TI - Carbon monoxide, the silent killer, may have met its match. PMID- 27940828 TI - When DNA and culture clash. PMID- 27940827 TI - Curator resigns after sexual misconduct investigations. PMID- 27940829 TI - Qatar's genome effort slowly gears up. PMID- 27940830 TI - Calling all kid scientists. PMID- 27940831 TI - A fast radio boom. PMID- 27940832 TI - Why does time seem to fly when we're having fun? PMID- 27940833 TI - Swimming in polluted waters. PMID- 27940834 TI - Encoding vocal culture. PMID- 27940835 TI - The smoking gun of the ice ages. PMID- 27940836 TI - What life scientists should know about security threats. PMID- 27940837 TI - Enhancing reproducibility for computational methods. PMID- 27940838 TI - Instilling integrity. PMID- 27940839 TI - Respect for the ancients. PMID- 27940840 TI - Now is the time to protect the Arctic. PMID- 27940841 TI - Substituting minutes for money. PMID- 27940842 TI - Birds of a feather sing together. PMID- 27940843 TI - Catching a break in polyphenol synthesis. PMID- 27940845 TI - Mapping genetic adaptations to pollution. PMID- 27940844 TI - An edge that is hard to get rid of. PMID- 27940847 TI - Super sensitive, not so silly, putty. PMID- 27940848 TI - A mitochondrial target for slowing PD. PMID- 27940846 TI - Engineering cells to regulate glucose. PMID- 27940849 TI - Diseases emerge when forests degrade. PMID- 27940850 TI - Cooperation between frustrated partners. PMID- 27940851 TI - Aspects of the design. PMID- 27940853 TI - Probing the intergalactic magnetic field. PMID- 27940852 TI - Crafting chiral boron building blocks. PMID- 27940854 TI - Beating the curse of the parasite. PMID- 27940855 TI - A laboratory model of viral speciation. PMID- 27940856 TI - Time is a subjective experience. PMID- 27940857 TI - Pacemaker of the ice ages, 40 years on. PMID- 27940858 TI - Inhibiting calcium uptake ubiquitously. PMID- 27940859 TI - Steel goes for the quick draw. PMID- 27940860 TI - mRNA quality control. PMID- 27940861 TI - Blocking PI3Kgamma makes cold tumors hot. PMID- 27940862 TI - How fiber feeds a healthy gut. PMID- 27940863 TI - Housemates. PMID- 27940864 TI - An on-chip cold-atom gravimeter. PMID- 27940865 TI - Forcing iron to bond to bismuth. PMID- 27940866 TI - Sensitive electromechanical sensors using viscoelastic graphene-polymer nanocomposites. AB - Despite its widespread use in nanocomposites, the effect of embedding graphene in highly viscoelastic polymer matrices is not well understood. We added graphene to a lightly cross-linked polysilicone, often encountered as Silly Putty, changing its electromechanical properties substantially. The resulting nanocomposites display unusual electromechanical behavior, such as postdeformation temporal relaxation of electrical resistance and nonmonotonic changes in resistivity with strain. These phenomena are associated with the mobility of the nanosheets in the low-viscosity polymer matrix. By considering both the connectivity and mobility of the nanosheets, we developed a quantitative model that completely describes the electromechanical properties. These nanocomposites are sensitive electromechanical sensors with gauge factors >500 that can measure pulse, blood pressure, and even the impact associated with the footsteps of a small spider. PMID- 27940867 TI - Synthesis of resveratrol tetramers via a stereoconvergent radical equilibrium. AB - Persistent free radicals have become indispensable in the synthesis of organic materials through living radical polymerization. However, examples of their use in the synthesis of small molecules are rare. Here, we report the application of persistent radical and quinone methide intermediates to the synthesis of the resveratrol tetramers nepalensinol B and vateriaphenol C. The spontaneous cleavage and reconstitution of exceptionally weak carbon-carbon bonds has enabled a stereoconvergent oxidative dimerization of racemic materials in a transformation that likely coincides with the biogenesis of these natural products. The efficient synthesis of higher-order oligomers of resveratrol will facilitate the biological studies necessary to elucidate their mechanism(s) of action. PMID- 27940868 TI - A general, modular method for the catalytic asymmetric synthesis of alkylboronate esters. AB - Alkylboron compounds are an important family of target molecules, serving as useful intermediates, as well as end points, in fields such as pharmaceutical science and organic chemistry. Facile transformation of carbon-boron bonds into a wide variety of carbon-X bonds (where X is, for example, carbon, nitrogen, oxygen, or a halogen), with stereochemical fidelity, renders the generation of enantioenriched alkylboronate esters a powerful tool in synthesis. Here we report the use of a chiral nickel catalyst to achieve stereoconvergent alkyl-alkyl couplings of readily available racemic alpha-haloboronates with organozinc reagents under mild conditions. We demonstrate that this method provides straightforward access to a diverse array of enantioenriched alkylboronate esters, in which boron is bound to a stereogenic carbon, and we highlight the utility of these compounds in synthesis. PMID- 27940869 TI - Robust spin-polarized midgap states at step edges of topological crystalline insulators. AB - Topological crystalline insulators are materials in which the crystalline symmetry leads to topologically protected surface states with a chiral spin texture, rendering them potential candidates for spintronics applications. Using scanning tunneling spectroscopy, we uncover the existence of one-dimensional (1D) midgap states at odd-atomic surface step edges of the three-dimensional topological crystalline insulator (Pb,Sn)Se. A minimal toy model and realistic tight-binding calculations identify them as spin-polarized flat bands connecting two Dirac points. This nontrivial origin provides the 1D midgap states with inherent stability and protects them from backscattering. We experimentally show that this stability results in a striking robustness to defects, strong magnetic fields, and elevated temperature. PMID- 27940870 TI - Midbrain dopamine neurons control judgment of time. AB - Our sense of time is far from constant. For instance, time flies when we are having fun, and it slows to a trickle when we are bored. Midbrain dopamine neurons have been implicated in variable time estimation. However, a direct link between signals carried by dopamine neurons and temporal judgments is lacking. We measured and manipulated the activity of dopamine neurons as mice judged the duration of time intervals. We found that pharmacogenetic suppression of dopamine neurons decreased behavioral sensitivity to time and that dopamine neurons encoded information about trial-to-trial variability in time estimates. Last, we found that transient activation or inhibition of dopamine neurons was sufficient to slow down or speed up time estimation, respectively. Dopamine neuron activity thus reflects and can directly control the judgment of time. PMID- 27940872 TI - Mind the gap: Neural coding of species identity in birdsong prosody. AB - Juvenile songbirds learn vocal communication from adult tutors of the same species but not from adults of other species. How species-specific learning emerges from the basic features of song prosody remains unknown. In the zebra finch auditory cortex, we discovered a class of neurons that register the silent temporal gaps between song syllables and are distinct from neurons encoding syllable morphology. Behavioral learning and neuronal coding of temporal gap structure resisted song tutoring from other species: Zebra finches fostered by Bengalese finch parents learned Bengalese finch song morphology transposed onto zebra finch temporal gaps. During the vocal learning period, temporal gap neurons fired selectively to zebra finch song. The innate temporal coding of intersyllable silent gaps suggests a neuronal barcode for conspecific vocal learning and social communication in acoustically diverse environments. PMID- 27940873 TI - The long-run poverty and gender impacts of mobile money. AB - Mobile money, a service that allows monetary value to be stored on a mobile phone and sent to other users via text messages, has been adopted by the vast majority of Kenyan households. We estimate that access to the Kenyan mobile money system M PESA increased per capita consumption levels and lifted 194,000 households, or 2% of Kenyan households, out of poverty. The impacts, which are more pronounced for female-headed households, appear to be driven by changes in financial behavior-in particular, increased financial resilience and saving-and labor market outcomes, such as occupational choice, especially for women, who moved out of agriculture and into business. Mobile money has therefore increased the efficiency of the allocation of consumption over time while allowing a more efficient allocation of labor, resulting in a meaningful reduction of poverty in Kenya. PMID- 27940871 TI - Dopamine neurons encode performance error in singing birds. AB - Many behaviors are learned through trial and error by matching performance to internal goals. Yet neural mechanisms of performance evaluation remain poorly understood. We recorded basal ganglia-projecting dopamine neurons in singing zebra finches as we controlled perceived song quality with distorted auditory feedback. Dopamine activity was phasically suppressed after distorted syllables, consistent with a worse-than-predicted outcome, and was phasically activated at the precise moment of the song when a predicted distortion did not occur, consistent with a better-than-predicted outcome. Error response magnitude depended on distortion probability. Thus, dopaminergic error signals can evaluate behaviors that are not learned for reward and are instead learned by matching performance outcomes to internal goals. PMID- 27940874 TI - Transient compartmentalization of RNA replicators prevents extinction due to parasites. AB - The appearance of molecular replicators (molecules that can be copied) was probably a critical step in the origin of life. However, parasitic replicators would take over and would have prevented life from taking off unless the replicators were compartmentalized in reproducing protocells. Paradoxically, control of protocell reproduction would seem to require evolved replicators. We show here that a simpler population structure, based on cycles of transient compartmentalization (TC) and mixing of RNA replicators, is sufficient to prevent takeover by parasitic mutants. TC tends to select for ensembles of replicators that replicate at a similar rate, including a diversity of parasites that could serve as a source of opportunistic functionality. Thus, TC in natural, abiological compartments could have allowed life to take hold. PMID- 27940878 TI - Following my lucky star. PMID- 27940875 TI - beta-cell-mimetic designer cells provide closed-loop glycemic control. AB - Chronically deregulated blood-glucose concentrations in diabetes mellitus result from a loss of pancreatic insulin-producing beta cells (type 1 diabetes, T1D) or from impaired insulin sensitivity of body cells and glucose-stimulated insulin release (type 2 diabetes, T2D). Here, we show that therapeutically applicable beta-cell-mimetic designer cells can be established by minimal engineering of human cells. We achieved glucose responsiveness by a synthetic circuit that couples glycolysis-mediated calcium entry to an excitation-transcription system controlling therapeutic transgene expression. Implanted circuit-carrying cells corrected insulin deficiency and self-sufficiently abolished persistent hyperglycemia in T1D mice. Similarly, glucose-inducible glucagon-like peptide 1 transcription improved endogenous glucose-stimulated insulin release and glucose tolerance in T2D mice. These systems may enable a combination of diagnosis and treatment for diabetes mellitus therapy. PMID- 27940879 TI - Field testing of ICHD-3 beta criteria of periictal headaches in patients with focal epilepsy - a prospective diary study. AB - Background To date we are lacking prospective data for field testing of ICHD-3 beta criteria for periictal headache (PIH). Methods Patients with focal epilepsy diagnosed by means of prolonged video-EEG monitoring completed a paper-pencil diary for three months and recorded seizures and headaches on a daily basis. According to ICHD-3 beta, we classified PIH, defined as headache present on a day with at least one seizure, as "7.6 headache related to epileptic seizure", "7.6.1 hemicrania epileptica" or "7.6.2 postictal headache". In addition, we compared the ICHD-3 beta diagnoses to the diagnoses according to ICHD-2. Results Thirty two patients completed the diary. Data analysis included 2,668 patient days, 300 seizures and 37 episodes of PIH. Two of these episodes (5.4%) were classified as headache related to seizure, three (8.1%) fulfilled both the criteria of headache related to seizure and hemicrania epileptica and four (10.8%) were postictal headaches. Twenty eight episodes (75.7%) did not fulfil any of the ICHD-3 beta criteria of seizure-related headaches, mostly because headache onset was before seizure onset. Applying ICHD-2 criteria allowed only one single episode of PIH to be classified as postictal headache. Discussion Our study is the first to present prospective field testing data of the ICHD-3 beta criteria for three types of seizure-related headaches. The majority of PIH episodes do not fulfil any of these criteria. One quarter can be classified according to ICHD-3 beta, whereas purely clinical diagnosis of PIH is markedly restricted in ICHD-2 because of mandatory electroencephalographic evidence. PMID- 27940876 TI - The genomic landscape of rapid repeated evolutionary adaptation to toxic pollution in wild fish. AB - Atlantic killifish populations have rapidly adapted to normally lethal levels of pollution in four urban estuaries. Through analysis of 384 whole killifish genome sequences and comparative transcriptomics in four pairs of sensitive and tolerant populations, we identify the aryl hydrocarbon receptor-based signaling pathway as a shared target of selection. This suggests evolutionary constraint on adaptive solutions to complex toxicant mixtures at each site. However, distinct molecular variants apparently contribute to adaptive pathway modification among tolerant populations. Selection also targets other toxicity-mediating genes and genes of connected signaling pathways; this indicates complex tolerance phenotypes and potentially compensatory adaptations. Molecular changes are consistent with selection on standing genetic variation. In killifish, high nucleotide diversity has likely been a crucial substrate for selective sweeps to propel rapid adaptation. PMID- 27940880 TI - CGRP in human models of primary headaches. AB - Objective To review the role of CGRP in human models of primary headaches and to discuss methodological aspects and future directions. Discussion Provocation experiments demonstrated a heterogeneous CGRP migraine response in migraine patients. Conflicting CGRP plasma results in the provocation experiments are likely due to assay variation; therefore, proper validation and standardization of an assay is needed. To what extent CGRP is involved in tension-type headache and cluster headache is unknown. Conclusion Human models of primary headaches have elucidated the role of CGRP in headache pathophysiology and sparked great interest in developing new treatment strategies using CGRP antagonists and antibodies. Future studies applying more refined human experimental models should identify biomarkers of CGRP-induced primary headache and reveal whether CGRP provocation experiments could be used to predict efficacy of CGRP antagonists in migraine patients. PMID- 27940882 TI - An Investigation of a Computerized Sequential Depression Module of the MMPI-2. AB - The current study investigated the utility and validity of a computerized "depression" module of the Minnesota Multiphasic Personality Inventory-Second version (MMPI-2), with and without sequential testing rules, with a college student sample. Participants completed one of three MMPI-2 test-retest administrations (i.e., conventional-conventional, conventional-module, or conventional-sequential module) as well as 15 criterion measures across two testing sessions exactly 1 week apart. The findings pointed to statistically significant and clinically meaningful time-savings in administering selected MMPI 2 scales (for both full-length and variable-length versions). Criterion measures rationally selected to represent similar (depression, anhedonia, anxiety) and dissimilar (behavioral, thought, and somatic dysfunction) psychological constructs were administered to assess the convergent and discriminant validity of the depression module. The criterion correlations suggested minimal differences in discriminant and convergent validity across administration modes, suggesting limited to no impact of administering targeted MMPI-2 scales in terms of construct validity. PMID- 27940881 TI - Long-term predictors of remission in patients treated for medication-overuse headache at a specialized headache center: A prospective cohort study. AB - Objective To evaluate long-term predictors of remission in patients with medication-overuse headache (MOH) by prospective cohort study. Background Knowledge regarding long-term predictors of MOH outcome is limited. Methods Two hundred and forty MOH patients recruited from 2000 to 2005 were included in a one year follow-up study and then subsequently followed until 31 December 2013. The median follow-up was three years (interquartile range, three years). Predictive values of selected variables were assessed by the Cox proportional hazard regression model. Results At the end of follow-up, 102 (42.5%) patients were in remission. The most important predictors of remission were lower number of headache days per month before the one-year follow-up (HR-hazard ratio = 0.936, 95% confidence interval (CI) 0.884-0.990, p = 0.021) and efficient initial drug withdrawal (HR = 0.136, 95% CI 0.042-0.444, p = 0.001). Refractory MOH was observed in seven (2.9%) and MOH relapse in 131 patients (54.6%). Conclusions Outcome at the one-year follow-up is a reliable predictor of MOH long-term remission. PMID- 27940883 TI - The Link Between Clinically Validated Patient Safety Indicators and Clinical Outcomes. AB - There is a paucity of evidence on the association between clinically validated Patient Safety Indicators (PSIs) and inpatient length of stay, mortality, and 30 day unplanned readmission. The authors perform a retrospective analysis of patient discharges from an academic medical center comprising 6 hospitals from July 2012 to June 2014. Multivariable regression models are used to assess the relationship between length of stay, mortality, and 30-day unplanned readmission and the presence of a clinically validated PSI. Cases flagged with a clinically validated PSI are associated with a statistically greater length of stay, 30-day unplanned readmission, and mortality as compared to cases without a PSI. This study demonstrates a strong association between clinically validated PSIs and patient outcomes. The findings have important implications in policy and practice as health care reform dictates improvement in the experience of care, health of populations, and per capita costs. PMID- 27940884 TI - The Cultivation of Chinese Health Care Professionals. PMID- 27940886 TI - Alfred Wilson McKenzie. PMID- 27940887 TI - Machine learning and computer vision approaches for phenotypic profiling. AB - With recent advances in high-throughput, automated microscopy, there has been an increased demand for effective computational strategies to analyze large-scale, image-based data. To this end, computer vision approaches have been applied to cell segmentation and feature extraction, whereas machine-learning approaches have been developed to aid in phenotypic classification and clustering of data acquired from biological images. Here, we provide an overview of the commonly used computer vision and machine-learning methods for generating and categorizing phenotypic profiles, highlighting the general biological utility of each approach. PMID- 27940889 TI - Rusty Gage: A plastic approach to neuroscience. PMID- 27940890 TI - Longitudinal Growth and Neuropsychological Functioning at Age 7 in Moderate and Late Preterms. AB - OBJECTIVE: To determine the association between longitudinal growth measures (height, weight, head circumference, and extent of catch-up growth) and neuropsychological functioning at 7 years in moderately and late preterm children. METHODS: This study was part of a prospective, community-based cohort study. Data on growth were obtained from records on routine assessments in well child centers until age 4 years and in a research setting at 7 years. Neuropsychological functioning was assessed at age 7 years. We assessed associations of growth with neuropsychological functioning and determined odds ratios for impaired neuropsychological functioning. All analyses were corrected for maternal education. RESULTS: We included 234 children. Median gestational age was 34 weeks (P25-75: 33-35 weeks), and mean birth weight was 2.2 kg (+/- 0.5 kg). Short stature at all ages was associated with poorer motor, IQ, and attention scores and led to increased risks of impaired motor skills and low IQ. Lower weight at 1 and 4 years was associated with poorer IQ scores. Increased weight gain between age 4 and 7 years was, however, associated with poorer motor, IQ, and attention scores. Decreased head circumference gain in the first year of life was associated with poorer motor and attention scores and led to an increased risk of impaired motor and attention skills. CONCLUSIONS: In moderately and late preterm children, poorer growth in the first 7 years is associated with poorer neuropsychological functioning. Regarding height, short stature was also associated with a higher likelihood of clinically relevant impaired neuropsychological functioning. PMID- 27940891 TI - Researchers', Regulators', and Sponsors' Views on Pediatric Clinical Trials: A Multinational Study. AB - BACKGROUND AND OBJECTIVE: The last decade has seen dramatic changes in the regulatory landscape to support more trials involving children, but child specific challenges and inequitable conduct across income regions persist. The goal of this study was to describe the attitudes and opinions of stakeholders toward trials in children, to inform additional strategies to promote more high quality, relevant pediatric trials across the globe. METHODS: Key informant semi structured interviews were conducted with stakeholders (researchers, regulators, and sponsors) who were purposively sampled from low- to middle-income countries and high-income countries. The transcripts were thematically analyzed. RESULTS: Thirty-five stakeholders from 10 countries were interviewed. Five major themes were identified: addressing pervasive inequities (paucity of safety and efficacy data, knowledge disparities, volatile environment, double standards, contextual relevance, market-driven forces, industry sponsorship bias and prohibitive costs); contending with infrastructural barriers (resource constraints, dearth of pediatric trial expertise, and logistical complexities); navigating complex ethical and regulatory frameworks ("draconian" oversight, ambiguous requirements, exploitation, excessive paternalism and precariousness of coercion versus volunteerism); respecting uniqueness of children (pediatric research paradigms, child-appropriate approaches, and family-centered empowerment); and driving evidence-based child health (advocacy, opportunities, treatment access, best practices, and research prioritization). CONCLUSIONS: Stakeholders acknowledge that changes in the regulatory environment have encouraged more trials in children, but they contend that inequities and political, regulatory, and resource barriers continue to exist. Embedding trials as part of routine clinical care, addressing the unique needs of children, and streamlining regulatory approvals were suggested. Stakeholders recommended increasing international collaboration, establishing centralized trials infrastructure, and aligning research to child health priorities to encourage trials that address global child health care needs. PMID- 27940888 TI - Constitutive centromere-associated network controls centromere drift in vertebrate cells. AB - Centromeres are specified by sequence-independent epigenetic mechanisms, and the centromere position may drift at each cell cycle, but once this position is specified, it may not be frequently moved. Currently, it is unclear whether the centromere position is stable. To address this question, we systematically analyzed the position of nonrepetitive centromeres in 21 independent clones isolated from a laboratory stock of chicken DT40 cells using chromatin immunoprecipitation combined with massive parallel sequencing analysis with anti CENP-A antibody. We demonstrated that the centromere position varies among the clones, suggesting that centromere drift occurs during cell proliferation. However, when we analyzed this position in the subclones obtained from one isolated clone, the position was found to be relatively stable. Interestingly, the centromere drift was shown to occur frequently in CENP-U- and CENP-S deficient cells. Based on these results, we suggest that the centromere position can change after many cell divisions, but this drift is suppressed in short-term cultures, and the complete centromere structure contributes to the suppression of the centromere drift. PMID- 27940893 TI - AAP Council on Communications and Media. Virtual Violence. Pediatrics. 2016;138(1):e20161298. PMID- 27940892 TI - Protecting Children Through Research. PMID- 27940894 TI - Witt M, Kvist N, Jorgensen MH, et al. Prophylactic Dosing of Vitamin K to Prevent Bleeding. Pediatrics. 2016;137(5):e20154222. PMID- 27940895 TI - Boikos, C, De Serres G, Lands LC, et al. Safety of Live-Attenuated Influenza Vaccination in Cystic Fibrosis. Pediatrics. 2014;134(4):e983. PMID- 27940897 TI - CORRIGENDUM to Abnormal thymic maturation and lymphoproliferation in MRL Faslpr/lpr mice can be partially reversed by synthetic oligonucleotides: implications for systemic lupus erythematosus and autoimmune lymphoproliferative syndrome. PMID- 27940898 TI - The effect of damping in prosthetic ankle and knee joints on the biomechanical outcomes: A literature review. AB - BACKGROUND: Given the growing number of variable-damping prosthetic knee and ankle components and broad number of potential biomechanical outcomes, a systematic review is needed to assess advantages of damped knee and ankle units over non-damped prostheses. OBJECTIVES: This study provides an overview of the biomechanical outcomes associated with the use of prosthetic knees and ankles with damping mechanisms in individuals with lower limb amputation. STUDY DESIGN: Literature review. METHODS: A systematic search was performed through PubMed, Science Direct, Web of Science, Cochrane, and Scopus databases from June 1994 to March 2016. The level of evidence of each article was assessed using a 13-element checklist for evaluating non-randomized controlled trials for quality assessment. Afterward, the studies were classified as A-level, B-level, or C-level based on total score and positive scores from certain key categories. RESULTS: In total, 22 papers remained for the quality assessment based on the inclusion criteria. In total, 15 studies scored sufficiently high quality scores to be classified. One article scored as A-level, eight as B-level, and six as C-level. In total, 10 studied knees and 5 examined ankles. Sample sizes ranged from 5 to 28 subjects. CONCLUSION: Available studies were evaluated in detail and biomechanical outcomes were extracted from the studies that met criteria. Results of this review indicate that study methodology and outcome measures were heterogeneous across reviewed papers. This could be an explanation for inconsistent findings of the reviewed studies. Only self-selected gait speed showed a consistent difference when dampers were applied to the leg. Thus, further research is required in this area. Clinical relevance This study provides an overview of evidence related to prosthetic knee and foot/ankle components with damping attachments. Research related to biomechanical outcomes is of great importance for researchers and practitioners in this area. The studies drew mixed conclusions, but walking speed was consistently different for damped versus non-damped components. PMID- 27940896 TI - Effect of diabetes mellitus on the clinical outcome of lower limb arterial bypass surgery: A propensity score analysis. AB - Objectives Diabetic patients who undergo lower limb arterial bypass surgery are considered to have a worse clinical outcome compared to non-diabetics. The aim of the study was to test this hypothesis after applying propensity score matching analysis. Patients and methods A total of 113 consecutive lower limb bypass procedures (55 diabetic and 58 non-diabetic) were evaluated regarding their clinical outcome. Endpoints of the study included amputation-free survival, limb salvage, patency and patients' survival up to 36 months post-procedure. After propensity score matching analysis, two new groups, diabetic and non-diabetic, of 31 limbs in each one were created, both equivalent regarding all baseline characteristics. Results Between the propensity score matching groups, the amputation-free survival was 68.8% in the non-diabetic and 37.7% in the diabetic group at 36 months ( p = 0.004). Similarly, the survival was 88.6% and 57.6%, respectively, in the two groups at the same time point ( p = 0.01). On the contrary, no difference was found in patency (58.3% vs. 56%) and in limb salvage rate (74.1% vs. 60.8%). Conclusions Lower limbs arterial bypass surgery has similar results regarding patency and limb salvage rate in diabetic and non diabetic patients. On the contrary, mortality is worse in diabetic patients, this affecting negatively their amputation-free survival. PMID- 27940899 TI - Prospective randomized controlled study of patient compliance in using a compression stocking: Importance of recommendations of the practitioner as a factor for better compliance. AB - Background Patient compliance is the cornerstone of compression therapy success. However, there has been up to now no tool to assess it other than self-reporting by the patient, which is not reliable. Material and methods Forty active females classified C2S were enrolled to wear compression stockings (CS) providing a pressure of 15-20 mmHg at the ankle. A thermal probe was inserted in the stocking (Thermotrack(r)), recording the skin temperature every 20 min for four weeks. The patients were randomized in two groups of 20: - Group 1: Receiving minimal recommendations by their physician at the office. - Group 2: Receiving in-depth recommendations by the physician reinforced with SMS message which were repeated once a week for four weeks. The basic CEAP classification and the quality of life (QoL) were recorded before and after four weeks. Results The two groups are similar for age, symptoms and type of CS. The analysis of the thermal curves showed a significant increase (+33%) in the average wearing time daily in the group 2: 8 h vs. 5.6 h (group1) p < 0.01. The average number of days worn per week is also increased: 3.4 (group 1) vs. 4.8 (group 2), thus improving patient compliance from 48.5% to 70% as a direct result of the physician recommendations ( p < 0.001). Conclusion This is the first study assessing the real compliance in CVD patients of using compression. It shows that better and repeated recommendations by the practitioner result in an increase in time the compression is used by 33%. The study also suggests that the number of days the compression stocking is worn is a good criterion of patient compliance. PMID- 27940900 TI - Prevalence and Correlates of Late Initiation of Smokeless Tobacco in US Firefighters. AB - Introduction: Prevalence rates of smokeless tobacco (SLT) use and late initiation among firefighters (ie, starting use as an adult after joining the fire service) are remarkably high, 10.5% and 26.0%, respectively. The purpose of this study is to examine characteristics associated with late SLT initiation in a sample comprised of male career firefighters from two large cohort studies. Methods: We examined correlates of late SLT initiation in a secondary analysis of data combining the baseline evaluations of two published firefighter health studies with 1474 male career firefighters in the United States. Results: Fourteen percent of participants were current SLT users. Among this group, the unadjusted rate of firefighters who initiated SLT use after joining the fire service was 15.9%, while the age-standardized rate was 38.2%; this is substantially higher than the national adjusted late initiation rate among adult males (0.8%). In addition, firefighters demonstrated higher rates of late SLT initiation (15.9% unadjusted; 18.4% age-standardized) when compared to males in the military overall (13.8%). Conclusions: The exceptionally high prevalence of SLT use overall and late initiation in the fire service suggest that joining the fire service in the United States is a risk factor for SLT use. There is a need to develop interventions aimed at reducing SLT use in the fire service that are specifically tailored for this occupational group. Implications: The high prevalence of late SLT initiation (ie, starting use as an adult after joining the fire service) among firefighters should be addressed by both researchers and fire service organizations given the significant health risks associated with SLT and its impact on occupational readiness. There is a need for developing intervention programs aimed at reducing SLT use in the fire service. Interventions would need to be specifically tailored for this occupational group and their unique culture, given that joining the fire service appears to be a risk factor for SLT initiation among firefighters who did not use tobacco prior to joining the fire service. PMID- 27940901 TI - Structured Trauma-Focused CBT and Unstructured Play/Experiential Techniques in the Treatment of Sexually Abused Children: A Field Study With Practicing Clinicians. AB - Structured, trauma-focused cognitive-behavioral therapy (CBT) techniques are widely considered an effective intervention for children who experienced sexual abuse. However, unstructured (i.e., nondirective) play/experiential techniques have a longer history of widespread promotion and are preferred by many practicing clinicians. No evidence is available, however, to determine how the integration of these techniques impacts treatment outcome. In this study, community-based clinicians who received training in a structured, trauma-focused cognitive-behavioral intervention administered pretreatment and posttreatment evaluations to 260 sexually abused children presenting with elevated posttraumatic stress. In addition, they completed a questionnaire describing the treatment techniques implemented with each child. Overall, significant improvement was observed for each of the six clinical outcomes. Regression analyses indicated that technique selection was a significant factor in posttreatment outcome for posttraumatic stress, dissociation, anxiety, and anger/aggression. In general, a greater utilization of the structured CBT techniques was related to lower posttreatment scores, whereas a higher frequency of play/experiential techniques was associated with higher posttreatment scores. However, no interaction effects were observed. The implication of these findings for clinical practice and future research are examined. PMID- 27940902 TI - Religion and Spiritual Care in Pediatric Intensive Care Unit: Parental Attitudes Regarding Physician Spiritual and Religious Inquiry. AB - OBJECTIVE: Parents of seriously ill children require attention to their spiritual needs, especially during end-of-life care. The objective of this study was to characterize parental attitudes regarding physician inquiry into their belief system. Materials and Main Results: A total of 162 surveys from parents of children hospitalized for >48 hours in pediatric intensive care unit in a tertiary academic medical center were analyzed. Forty-nine percent of all respondents and 62% of those who identified themselves as moderate to very spiritual or religious stated that their beliefs influenced the decisions they made about their child's medical care. Although 34% of all respondents would like their physician to ask about their spiritual or religious beliefs, 48% would desire such enquiry if their child was seriously ill. Those who identified themselves as moderate to very spiritual or religious were most likely to welcome the discussion ( P < .001). Two-thirds of the respondents would feel comforted to know that their child's physician prayed for their child. One-third of all respondents would feel very comfortable discussing their beliefs with a physician, whereas 62% would feel very comfortable having such discussions with a chaplain. CONCLUSION: The study findings suggest parental ambivalence when it comes to discussing their spiritual or religious beliefs with their child's physicians. Given that improved understanding of parental spiritual and religious beliefs may be important in the decision-making process, incorporation of the expertise of professional spiritual care providers may provide the optimal context for enhanced parent-physician collaboration in the care of the critically ill child. PMID- 27940903 TI - Does Who I Am or How I Regulate Matter? Consequences of Manipulation of Emotion Regulation Strategies. AB - This study experimentally examined the affective and social consequences of emotion regulation in men and women from young adulthood to old age. Participants were instructed to reappraise, suppress, or given no instructions while recalling a negative memory about their romantic relationship. Participants were 191 adults in a Trinidadian lifespan sample. Engaging in suppression resulted in higher relationship satisfaction, particularly for women, whereas engaging in reappraisal reduced negative affect for middle-aged versus younger adults. Reappraisal was, however, particularly consequential for young women who experienced higher levels of negative affect compared with men of the same age and older aged women. Regardless of instructions, older adults experienced higher relationship satisfaction, higher positive and lower negative affect than younger aged adults. Results are discussed considering the positivity effect for older adults, and how the current and historical climate of Trinidad influences the way women regulate their emotions. PMID- 27940904 TI - Predicting Zambian Grandmothers' Sensitivity Toward Their Grandchildren. AB - Whereas child care by grandmothers is widespread in the African cultural context, few studies have examined predictors of the quality of grandmaternal care in Africa. In the current study, we collected observational data to investigate predictors of the quality of grandmother-grandchild interactions in Zambia. Data were collected from 46 grandmothers and their 12 to 27-month-old infant grandchildren. The results revealed that grandmothers with fewer children and those who enjoyed the grandparenting tasks more were more sensitive in their interactions with their grandchildren. Unexpectedly, parenting beliefs favoring sensitive parenting predicted lower observed sensitivity in grandmothers. Further, grandmothers with a more individualistic cultural orientation were more intrusive toward their grandchildren. The results underscore the importance of time and emotional resources as predictors of sensitive parenting among grandmothers. PMID- 27940907 TI - Commentary on: Polyurethane Implants in 2-Stage Breast Reconstruction: 9-Year Clinical Experience. PMID- 27940908 TI - Polyurethane Implants in 2-Stage Breast Reconstruction: 9-Year Clinical Experience. AB - BACKGROUND: Capsular contracture (CC) is a major complication of breast surgery with smooth and textured implants. Polyurethane (PU) foam-coated breast implants were developed to decrease the incidence of CC. OBJECTIVES: The authors determined the incidence of CC following 2-stage breast reconstruction using PU foam-covered implants, with and without radiation therapy. METHODS: The records of 92 patients who received 115 PU implants were retrospectively reviewed. The rates of CC over time were compared for irradiated and nonirradiated groups with a Kaplan-Meier analysis and log-rank test. CC rates also were analyzed with respect to age. RESULTS: The median follow-up time for patients was 103.3 months. Nine patients experienced unilateral Baker grade III or IV fibrous CC, including 6 patients from the irradiated group and 3 patients from the nonirradiated group. The overall cumulative incidence of CC at 9 years was 8.1%. In the irradiated and nonirradiated groups, the 9-year cumulative incidence was 10.7% and 5.5%, respectively. CC occurred within 3 years in the irradiated group and within 7 years in the nonirradiated group. The incidence of CC appeared to be higher among younger patients. CONCLUSIONS: Radiation therapy increases the risk of high-grade CC with textured or smooth implants. PU implants are associated with a much lower cumulative incidence of CC following 2-stage breast reconstruction, even when radiotherapy is performed. LEVEL OF EVIDENCE 3. PMID- 27940909 TI - Love, not war, drove the Mesozoic marine revolution. PMID- 27940910 TI - Antibiotic discovery is a walk in the park. PMID- 27940911 TI - Climate variation drives dengue dynamics. AB - Dengue, a viral infection transmitted between people by mosquitoes, is one of the most rapidly spreading diseases in the world. Here, we report the analyses covering 11 y (2005-2015) from the city of Guangzhou in southern China. Using the first 8 y of data to develop an ecologically based model for the dengue system, we reliably predict the following 3 y of dengue dynamics-years with exceptionally extensive dengue outbreaks. We demonstrate that climate conditions, through the effects of rainfall and temperature on mosquito abundance and dengue transmission rate, play key roles in explaining the temporal dynamics of dengue incidence in the human population. Our study thus contributes to a better understanding of dengue dynamics and provides a predictive tool for preventive dengue reduction strategies. PMID- 27940912 TI - Kinetic isotope effects reveal early transition state of protein lysine methyltransferase SET8. AB - Protein lysine methyltransferases (PKMTs) catalyze the methylation of protein substrates, and their dysregulation has been linked to many diseases, including cancer. Accumulated evidence suggests that the reaction path of PKMT-catalyzed methylation consists of the formation of a cofactor(cosubstrate)-PKMT-substrate complex, lysine deprotonation through dynamic water channels, and a nucleophilic substitution (SN2) transition state for transmethylation. However, the molecular characters of the proposed process remain to be elucidated experimentally. Here we developed a matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) method and corresponding mathematic matrix to determine precisely the ratios of isotopically methylated peptides. This approach may be generally applicable for examining the kinetic isotope effects (KIEs) of posttranslational modifying enzymes. Protein lysine methyltransferase SET8 is the sole PKMT to monomethylate histone 4 lysine 20 (H4K20) and its function has been implicated in normal cell cycle progression and cancer metastasis. We therefore implemented the MS-based method to measure KIEs and binding isotope effects (BIEs) of the cofactor S-adenosyl-l-methionine (SAM) for SET8-catalyzed H4K20 monomethylation. A primary intrinsic 13C KIE of 1.04, an inverse intrinsic alpha secondary CD3 KIE of 0.90, and a small but statistically significant inverse CD3 BIE of 0.96, in combination with computational modeling, revealed that SET8 catalyzed methylation proceeds through an early, asymmetrical SN2 transition state with the C-N and C-S distances of 2.35-2.40 A and 2.00-2.05 A, respectively. This transition state is further supported by the KIEs, BIEs, and steady-state kinetics with the SAM analog Se-adenosyl-l-selenomethionine (SeAM) as a cofactor surrogate. The distinct transition states between protein methyltransferases present the opportunity to design selective transition-state analog inhibitors. PMID- 27940913 TI - Roles of density-dependent growth and life history evolution in accounting for fisheries-induced trait changes. AB - The relative roles of density dependence and life history evolution in contributing to rapid fisheries-induced trait changes remain debated. In the 1930s, northeast Arctic cod (Gadus morhua), currently the world's largest cod stock, experienced a shift from a traditional spawning-ground fishery to an industrial trawl fishery with elevated exploitation in the stock's feeding grounds. Since then, age and length at maturation have declined dramatically, a trend paralleled in other exploited stocks worldwide. These trends can be explained by demographic truncation of the population's age structure, phenotypic plasticity in maturation arising through density-dependent growth, fisheries induced evolution favoring faster-growing or earlier-maturing fish, or a combination of these processes. Here, we use a multitrait eco-evolutionary model to assess the capacity of these processes to reproduce 74 y of historical data on age and length at maturation in northeast Arctic cod, while mimicking the stock's historical harvesting regime. Our results show that model predictions critically depend on the assumed density dependence of growth: when this is weak, life history evolution might be necessary to prevent stock collapse, whereas when a stronger density dependence estimated from recent data is used, the role of evolution in explaining fisheries-induced trait changes is diminished. Our integrative analysis of density-dependent growth, multitrait evolution, and stock specific time series data underscores the importance of jointly considering evolutionary and ecological processes, enabling a more comprehensive perspective on empirically observed stock dynamics than previous studies could provide. PMID- 27940915 TI - Tolerance checkpoint bypass permits emergence of pathogenic T cells to neuromyelitis optica autoantigen aquaporin-4. AB - Aquaporin-4 (AQP4)-specific T cells are expanded in neuromyelitis optica (NMO) patients and exhibit Th17 polarization. However, their pathogenic role in CNS autoimmune inflammatory disease is unclear. Although multiple AQP4 T-cell epitopes have been identified in WT C57BL/6 mice, we observed that neither immunization with those determinants nor transfer of donor T cells targeting them caused CNS autoimmune disease in recipient mice. In contrast, robust proliferation was observed following immunization of AQP4-deficient (AQP4-/-) mice with AQP4 peptide (p) 135-153 or p201-220, peptides predicted to contain I Ab-restricted T-cell epitopes but not identified in WT mice. In comparison with WT mice, AQP4-/- mice used unique T-cell receptor repertoires for recognition of these two AQP4 epitopes. Donor T cells specific for either determinant from AQP4 /-, but not WT, mice induced paralysis in recipient WT and B-cell-deficient mice. AQP4-specific Th17-polarized cells induced more severe disease than Th1-polarized cells. Clinical signs were associated with opticospinal infiltrates of T cells and monocytes. Fluorescent-labeled donor T cells were detected in CNS lesions. Visual system involvement was evident by changes in optical coherence tomography. Fine mapping of AQP4 p201-220 and p135-153 epitopes identified peptides within p201-220 but not p135-153, which induced clinical disease in 40% of WT mice by direct immunization. Our results provide a foundation to evaluate how AQP4 specific T cells contribute to AQP4-targeted CNS autoimmunity (ATCA) and suggest that pathogenic AQP4-specific T-cell responses are normally restrained by central tolerance, which may be relevant to understanding development of AQP4-reactive T cells in NMO. PMID- 27940916 TI - Hierarchical CRMP2 posttranslational modifications control NaV1.7 function. AB - Voltage-gated sodium channels are crucial determinants of neuronal excitability and signaling. Trafficking of the voltage-gated sodium channel NaV1.7 is dysregulated in neuropathic pain. We identify a trafficking program for NaV1.7 driven by hierarchical interactions with posttranslationally modified versions of the binding partner collapsin response mediator protein 2 (CRMP2). The binding described between CRMP2 and NaV1.7 was enhanced by conjugation of CRMP2 with small ubiquitin-like modifier (SUMO) and further controlled by the phosphorylation status of CRMP2. We determined that CRMP2 SUMOylation is enhanced by prior phosphorylation by cyclin-dependent kinase 5 and antagonized by Fyn phosphorylation. As a consequence of CRMP2 loss of SUMOylation and binding to NaV1.7, the channel displays decreased membrane localization and current density, and reduces neuronal excitability. Preventing CRMP2 SUMOylation with a SUMO impaired CRMP2-K374A mutant triggered NaV1.7 internalization in a clathrin dependent manner involving the E3 ubiquitin ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4) and endocytosis adaptor proteins Numb and epidermal growth factor receptor pathway substrate 15. Collectively, our work shows that diverse modifications of CRMP2 cross-talk to control NaV1.7 activity and illustrate a general principle for regulation of NaV1.7. PMID- 27940914 TI - Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide. AB - Major depressive disorder (MDD) is a substantial burden to patients, families, and society, but many patients cannot be treated adequately. Rodent experiments suggest that the neuropeptide galanin (GAL) and its three G protein-coupled receptors, GAL1-3, are involved in mood regulation. To explore the translational potential of these results, we assessed the transcript levels (by quantitative PCR), DNA methylation status (by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL system in postmortem brains from depressed persons who had committed suicide and controls. Transcripts for all four members were detected and showed marked regional variations, GAL and galanin receptor 1 (GALR1) being most abundant. Striking increases in GAL and GALR3 mRNA levels, especially in the noradrenergic locus coeruleus and the dorsal raphe nucleus, in parallel with decreased DNA methylation, were found in both male and female suicide subjects as compared with controls. In contrast, GAL and GALR3 transcript levels were decreased, GALR1 was increased, and DNA methylation was increased in the dorsolateral prefrontal cortex of male suicide subjects, however, there were no changes in the anterior cingulate cortex. Thus, GAL and its receptor GALR3 are differentially methylated and expressed in brains of MDD subjects in a region- and sex-specific manner. Such an epigenetic modification in GALR3, a hyperpolarizing receptor, might contribute to the dysregulation of noradrenergic and serotonergic neurons implicated in the pathogenesis of MDD. Thus, one may speculate that a GAL3 antagonist could have antidepressant properties by disinhibiting the firing of these neurons, resulting in increased release of noradrenaline and serotonin in forebrain areas involved in mood regulation. PMID- 27940918 TI - Computational design of a homotrimeric metalloprotein with a trisbipyridyl core. AB - Metal-chelating heteroaryl small molecules have found widespread use as building blocks for coordination-driven, self-assembling nanostructures. The metal chelating noncanonical amino acid (2,2'-bipyridin-5yl)alanine (Bpy-ala) could, in principle, be used to nucleate specific metalloprotein assemblies if introduced into proteins such that one assembly had much lower free energy than all alternatives. Here we describe the use of the Rosetta computational methodology to design a self-assembling homotrimeric protein with [Fe(Bpy-ala)3]2+ complexes at the interface between monomers. X-ray crystallographic analysis of the homotrimer showed that the design process had near-atomic-level accuracy: The all atom rmsd between the design model and crystal structure for the residues at the protein interface is ~1.4 A. These results demonstrate that computational protein design together with genetically encoded noncanonical amino acids can be used to drive formation of precisely specified metal-mediated protein assemblies that could find use in a wide range of photophysical applications. PMID- 27940917 TI - Probing conformational dynamics of an enzymatic active site by an in situ single fluorogenic probe under piconewton force manipulation. AB - Unraveling the conformational details of an enzyme during the essential steps of a catalytic reaction (i.e., enzyme-substrate interaction, enzyme-substrate active complex formation, nascent product formation, and product release) is challenging due to the transient nature of intermediate conformational states, conformational fluctuations, and the associated complex dynamics. Here we report our study on the conformational dynamics of horseradish peroxidase using single-molecule multiparameter photon time-stamping spectroscopy with mechanical force manipulation, a newly developed single-molecule fluorescence imaging magnetic tweezers nanoscopic approach. A nascent-formed fluorogenic product molecule serves as a probe, perfectly fitting in the enzymatic reaction active site for probing the enzymatic conformational dynamics. Interestingly, the product releasing dynamics shows the complex conformational behavior with multiple product releasing pathways. However, under magnetic force manipulation, the complex nature of the multiple product releasing pathways disappears and more simplistic conformations of the active site are populated. PMID- 27940921 TI - Carotid artery dissection associated with long styloid process. PMID- 27940922 TI - Peripheral vascular intervention is better than tibial bypass for critical limb ischemia. PMID- 27940920 TI - Evolution of a mass spectrometry-grade protease with PTM-directed specificity. AB - Mapping posttranslational modifications (PTMs), which diversely modulate biological functions, represents a significant analytical challenge. The centerpiece technology for PTM site identification, mass spectrometry (MS), requires proteolytic cleavage in the vicinity of a PTM to yield peptides for sequencing. This requirement catalyzed our efforts to evolve MS-grade mutant PTM directed proteases. Citrulline, a PTM implicated in epigenetic and immunological function, made an ideal first target, because citrullination eliminates arginyl tryptic sites. Bead-displayed trypsin mutant genes were translated in droplets, the mutant proteases were challenged to cleave bead-bound fluorogenic probes of citrulline-dependent proteolysis, and the resultant beads (1.3 million) were screened. The most promising mutant efficiently catalyzed citrulline-dependent peptide bond cleavage (kcat/KM = 6.9 * 105 M-1?s-1). The resulting C-terminally citrullinated peptides generated characteristic isotopic patterns in MALDI-TOF MS, and both a fragmentation product y1 ion corresponding to citrulline (176.1030 m/z) and diagnostic peak pairs in the extracted ion chromatograms of LC-MS/MS analysis. Using these signatures, we identified citrullination sites in protein arginine deiminase 4 (12 sites) and in fibrinogen (25 sites, two previously unknown). The unique mass spectral features of PTM-dependent proteolytic digest products promise a generalized PTM site-mapping strategy based on a toolbox of such mutant proteases, which are now accessible by laboratory evolution. PMID- 27940919 TI - Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium. AB - A major unresolved issue in the cloning of mammals by somatic cell nuclear transfer (SCNT) is the mechanism by which the process fails after embryos are transferred to the uterus of recipients before or during the implantation window. We investigated this problem by using RNA sequencing (RNA-seq) to compare the transcriptomes in cattle conceptuses produced by SCNT and artificial insemination (AI) at day (d) 18 (preimplantation) and d 34 (postimplantation) of gestation. In addition, endometrium was profiled to identify the communication pathways that might be affected by the presence of a cloned conceptus, ultimately leading to mortality before or during the implantation window. At d 18, the effects on the transcriptome associated with SCNT were massive, involving more than 5,000 differentially expressed genes (DEGs). Among them are 121 genes that have embryonic lethal phenotypes in mice, cause defects in trophoblast and placental development, and/or affect conceptus survival in mice. In endometria at d 18, <0.4% of expressed genes were affected by the presence of a cloned conceptus, whereas at d 34, ~36% and <0.7% of genes were differentially expressed in intercaruncular and caruncular tissues, respectively. Functional analysis of DEGs in placental and endometrial tissues suggests a major disruption of signaling between the cloned conceptus and the endometrium, particularly the intercaruncular tissue. Our results support a "bottleneck" model for cloned conceptus survival during the periimplantation period determined by gene expression levels in extraembryonic tissues and the endometrial response to altered signaling from clones. PMID- 27940923 TI - Prognostic value of an increase in post-exercise ankle-brachial index. AB - Prior studies have assessed the prognostic value of a decrease, not an increase, of the post-exercise ankle-brachial index (ABI) among patients with normal resting results. Thus, we sought to evaluate the prognostic significance of an increase in post-exercise ABI among these patients. From a single center vascular laboratory database between September 2005 and January 2010, we retrospectively identified 1437 consecutive patients with a normal resting ABI (1.00-1.40) and available post-exercise results. We classified them into group 1 (normal subjects; post-exercise ABI drop ? 20%, 58%) and group 2 (post-exercise ABI increase, 42%) after excluding those with an ABI drop > 20% (peripheral artery disease) as they had known disease ( n=192). The primary outcome was to assess the risk of ischemic events, defined as a composite of unadjudicated death, stroke, or myocardial infraction (MACE). Associations between groups and outcomes were examined using multivariable Cox proportional hazard and propensity analyses. Both groups had similar prevalence of cardiovascular comorbidities. In unadjusted analysis, group 2 was more likely to have MACE ( p = 0.001). After adjusting for all baseline characteristics, an increase in post-exercise ABI compared to normal subjects was associated with a higher MACE (adjusted HR: 1.70, 95% CI: 1.14-2.53; p=0.009). This association stayed statistically significant after propensity matching (adjusted HR: 1.80, 95% CI: 1.17-2.76; p=0.007). This hypothesis-generating analysis showed that an increase in post-exercise ABI appears to identify a population with a higher risk for MACE. A prospective study of this association and mechanisms of risk should be conducted. PMID- 27940924 TI - Evidence-Based Interventions for Increasing Work Participation for Persons With Various Disabilities. AB - Title I of the Americans With Disabilities Act prohibits discrimination in employment; however, 26 years later, employment rates for persons with disabilities hover at 34%. This systematic review investigates the effectiveness of evidence-based interventions to increase employment for people with various disabilities. Forty-six articles met the inclusion criteria for evidence-based interventions. The majority of studies assessed interventions for persons with mental health disabilities. Strong evidence was found for ongoing support and work-related social skills training prior to and during competitive employment for persons with mental health disabilities. Moderate evidence supported simulation and use of assistive technology, especially apps for cueing and peer support to increase work participation for persons with intellectual disabilities, neurological/cognitive disabilities, and autism spectrum disorder. Many of the strategies to increase work participation were appropriate for occupational therapy intervention. Suggestions were made for research, specifically looking at more rigorous evaluation of strategies in the long term. PMID- 27940925 TI - Neonatal nurses' response to a hypothetical premature birth situation: What if it was my baby? AB - BACKGROUND:: Evolving technology and scientific advancement have increased the chances of survival of the extremely premature baby; however, such survival can be associated with some severe long-term morbidities. RESEARCH QUESTION:: The research investigates the caregiving and ethical dilemmas faced by neonatal nurses when caring for extremely premature babies (defined as <=24 weeks' gestation). This article explores the issues arising for neonatal nurses when they considered the philosophical question of 'what if it was me and my baby', or what they believed they would do in the hypothetical situation of going into premature labour and delivering an extremely premature baby. PARTICIPANTS:: Data were collected via a questionnaire to Australian neonatal nurses and semi structured interviews with 24 neonatal nurses in New South Wales, Australia. ETHICAL CONSIDERATIONS:: Relevant ethical approvals have been obtained by the researchers. FINDINGS:: A qualitative approach was used to analyse the data. The theme 'imagined futures' was generated which comprised three sub-themes: 'choice is important', 'not subjecting their own baby to treatment' and 'nurses and outcome predictions'. The results offer an important and unique understanding into the perceptions of nursing staff who care for extremely premature babies and their family, see them go home and witness their evolving outcomes. The results show that previous clinical and personal experiences led the nurses in the study to choose to have the belief that if in a similar situation, they would choose not to have their own baby resuscitated and subjected to the very treatment that they provide to other babies. CONCLUSION:: The theme 'imagined futures' offers an overall understanding of how neonatal nurses imagine what the life of the extremely premature baby and his or her family will be like after discharge from neonatal intensive care. The nurses' past experience has led them to believe that they would not want this life for themselves and their baby, if they were to deliver at 24 weeks' gestation or less. PMID- 27940929 TI - Erratum. PMID- 27940927 TI - Adeno-Associated Virus-Mediated Gene Transfer into Taste Cells In Vivo. AB - The sense of taste is achieved by cooperation of many signaling molecules expressed in taste cells, which code and transmit information on quality and intensity of taste to the nervous system. Viral vector-mediated gene transfer techniques have been proven to be useful to study and control function of a gene product in vivo However, there is no transduction method for taste cells in live animals. Here, we have established a method for inducing foreign gene expression in mouse taste cells in vivo by recombinant adeno-associated virus (AAV) vector. First, using enhanced green fluorescent protein (EGFP) as a reporter, we screened 6 AAV serotypes along with a recombinant lentivirus vector for their ability to transduce taste cells. One week after viral injection into the submucosa of the tongue, EGFP expression in fungiform taste cells was observed only in animals injected with AAV-DJ, a synthetic serotype. Next, time course of AAV-DJ-mediated EGFP expression in fungiform taste cells was evaluated. Intragemmal EGFP signals appeared after a delay, rapidly increased until 7 days postinjection, and gradually decreased over the next few weeks probably because of the cell turnover. Finally, the taste cell types susceptible to AAV-DJ transduction were characterized. EGFP expression was observed in PLCbeta2-immunoreactive type II and aromatic l-amino acid decarboxylase (AADC)-immunoreactive type III taste cells as well as in cells immunonegative for both PLCbeta2 and AADC, demonstrating that AAV-DJ does not discriminate functional taste cell types. In conclusion, the method established in this study will be a promising tool to study the mechanism of taste. PMID- 27940933 TI - Management of functional Sprint Fidelis leads at cardiac resynchronization therapy-defibrillator generator replacement: a novel option for preventing inappropriate shocks from lead failure in fragile patients with high risk of sudden death. AB - Aims: In patients with a functional Sprint Fidelis lead at generator replacement, the manufacturer recommended to either continue to use the existing lead or replace it with a new lead. For those patients who continue to use a functional Fidelis lead, the risk of inappropriate shocks remains present if the lead fails in the future. We evaluated the feasibility of an alternative approach at the time of cardiac resynchronization therapy-defibrillator (CRT-D) generator replacement in patients with a functional bipolar left ventricular (LV) lead for prevention of inappropriate shocks from future Fidelis lead failure. Methods and results: During the procedure, the pace/sense IS-1 connection pin of the functional Fidelis lead was intentionally inserted into the LV port of the new CRT-D generator, while the existing bipolar LV lead IS-1 connection pin was inserted into the right ventricular (RV) pace/sense port. After such switching, the existing bipolar LV lead was used for functional LV pacing/sensing, while the Fidelis lead was used for functional RV pacing and high voltage shock only and could no longer be used for the purpose of sensing and detecting. This approach precluded oversensing and inappropriate shocks should the functional Fidelis lead fail in the future. Six fragile patients, who were not considered suitable candidates for lead replacement, underwent the alternative approach. During a follow-up of 35 +/- 23 months, the CRT-D system functioned normally in five patients. The Fidelis lead fractured in one patient 7 months after generator replacement. The malfunction was detected promptly and the defected lead was replaced. No inappropriate detections or shock was triggered. Conclusions: In CRT D patients with a functional Fidelis lead and a bipolar LV lead, switching of the Fidelis lead pace/sense IS-1 pin with the bipolar LV lead IS-1 pin at generator replacement did not affect normal system function. This novel approach may be valuable in fragile patients with high risk of sudden death for prevention of inappropriate shocks triggered by oversensing from a malfunctioning Fidelis lead. PMID- 27940934 TI - Adverse outcomes in patients with atrial fibrillation and peripheral arterial disease: a report from the EURObservational research programme pilot survey on atrial fibrillation. AB - Aims: Peripheral arterial disease (PAD) is highly prevalent in general population. Data on the prevalence of symptomatic PAD in patients with atrial fibrillation (AF) are limited, and the impact of PAD on adverse outcomes in AF patients is controversial. Our aims were: (i) to define the prevalence of symptomatic PAD in European AF patients and describe its associated clinical risk factors and (ii) to establish the relationship of PAD to adverse events in AF, especially all-cause death. Methods and results: Atrial fibrillation patients enrolled in the EORP-AF Pilot study with data about PAD status were included in this analysis. Event rates were determined at 1-year follow-up. Peripheral arterial disease was recorded in 328 (11%) patients. Age (P < 0.0001), hypertension (P = 0.0059), diabetes mellitus (P = 0.0001), chronic heart failure (P < 0.0001), previous stroke/transient ischaemic attack (P = 0.0060), and antiplatelet drug treatment (P = 0.0001) were associated with the presence of PAD, while female gender was inversely associated (P = 0.0002). Peripheral arterial disease patients had higher absolute rates of both cardiovascular (CV) and all-cause death (both P < 0.0001). On Kaplan-Meier analysis, risk of all cause death was higher in PAD patients compared with those without PAD (P < 0.0001), but PAD did not emerge as an independent risk factor for mortality on Cox regression analysis. A lower risk of all-cause death was associated with the prescription of statins (P = 0.0019), angiotensin-converting enzyme inhibitors (P = 0.0008), and calcium-channel blockers (P = 0.0071). Conclusion: Peripheral arterial disease is prevalent in 11% of AF patients and related to various atherosclerotic risk factors. Even if PAD is associated with higher risk of all cause death on univariate analysis, this risk was significantly lowered and was no longer evident after adjusting for the use of CV prevention drugs. PMID- 27940935 TI - Left atrial fibrosis quantification by late gadolinium-enhanced magnetic resonance: a new method to standardize the thresholds for reproducibility. AB - Aims: Identification of left atrial (LA) fibrosis through late gadolinium enhanced cardiac magnetic resonance (LGE-CMR) remains controversial due to the heterogeneity and lack of reproducibility of proposed methods. Our aim is to describe a normalized, reproducible, standardized method to evaluate LA fibrosis through LGE-CMR. Methods and results: Electrocardiogram- and respiratory-gated 3 Tesla LGE-CMR was performed in 10 healthy young volunteers and 30 patients with atrial fibrillation (AF): 10 with paroxysmal AF, 10 with persistent AF, and 10 with a previous AF ablation procedure. Local image intensity ratio (IIR) of the LA was calculated as the absolute pixel intensity to mean blood pool intensity ratio. The healthy atrial tissue threshold was defined in young healthy volunteers (upper limit of normality set at IIR tissue mean plus 2 SDs). Dense atrial scarring was characterized in patients with previous radiofrequency induced scarring (post-AF ablation patients). Validation groups consisted of patients with paroxysmal and persistent AFs. The upper limit of normal IIR was 1.20; IIR values higher than 1.32 (60% of mean maximum pixel intensity in post ablation patients) were considered dense scar. Image intensity ratio values between 1.2 and 1.32 identified interstitial fibrosis. Patients with paroxysmal and persistent AFs had less atrial fibrotic tissue compared with post-ablation patients. Endocardial bipolar voltage was correlated to IIR values. Conclusions: An IIR of 1.2 identifies the upper limit of normality in healthy young individuals. An IIR of >1.32 defines dense atrial fibrosis in post-ablation patients. Our results provide a consistent, comparable, and normalized tool to assess atrial arrhythmogenic substrate. PMID- 27940937 TI - Risk factors for transmission of Middle East respiratory syndrome coronavirus infection during the 2015 outbreak in South Korea. AB - Background: Transmission heterogeneity was observed during the 2015 South Korean outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Only 22 of 186 cases transmitted the infection, and 5 super-spreading events caused 150 transmissions. We investigated the risk factors for MERS-CoV transmission. Methods: Epidemiological reports were used to classify patients as non-spreaders, spreaders (1-4 transmission), or those associated with super spreading event (>=4 transmissions). Logistic regression analyses were used to evaluate the factors that influenced MERS-CoV transmission. Results: Compared to non-spreaders, spreaders exhibited a longer interval from symptom onset to isolation (7 days vs. 3 days) and more frequent pre-isolation pneumonia diagnoses (68.2% vs. 17.1%). Spreaders also exhibited higher values for pre-isolation contacts (149 vs. 17.5), pre-isolation hospitalization (68.2% vs. 16.5%), and emergency room visits (50% vs. 7.3%). Spreaders exhibited lower cycle thresholds for the upE and ORF1a genes (22.7 vs. 27.2 and 23.7 vs. 27.9, respectively). Transmission was independently associated with the cycle threshold (odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.75-0.96) and pre-isolation hospitalization or emergency room visits (OR: 6.82, 95% CI: 2.06-22.84). The spreaders with >=4 transmissions exhibited higher values for pre-isolation contacts (777 vs. 78), pre-isolation emergency room visits (100% vs. 35.3%), and doctor-shopping (100% vs. 47.1%), compared to other spreaders. Conclusions: These findings indicate that transmission is determined by host infectivity and the number of contacts, whereas super-spreading events were determined by the number of contacts and hospital visits. These relationships highlight the importance of rapidly enforcing infection control measures to prevent outbreaks. PMID- 27940939 TI - Japanese Media and the HPV Vaccine Saga. PMID- 27940936 TI - HIV Infection, Immunosuppression, and Age at Diagnosis of Non-AIDS-Defining Cancers. AB - Background: It is unclear whether immunosuppression leads to younger ages at cancer diagnosis among people living with human immunodeficiency virus (PLWH). A previous study found that most cancers are not diagnosed at a younger age in people with AIDS, with the exception of anal and lung cancers. This study extends prior work to include all PLWH and examines associations between AIDS, CD4 count, and age at cancer diagnosis. Methods: We compared the median age at cancer diagnosis between PLWH in the North American AIDS Cohort Collaboration on Research and Design and the general population using data from the Surveillance, Epidemiology and End Results Program. We used statistical weights to adjust for population differences. We also compared median age at cancer diagnosis by AIDS status and CD4 count. Results: After adjusting for population differences, younger ages at diagnosis (P < .05) were observed for PLWH compared with the general population for lung (difference in medians = 4 years), anal (difference = 4), oral cavity/pharynx (difference = 2), and kidney cancers (difference = 2) and myeloma (difference = 4). Among PLWH, having an AIDS-defining event was associated with a younger age at myeloma diagnosis (difference = 4; P = .01), and CD4 count <200 cells/uL (vs >=500) was associated with a younger age at lung cancer diagnosis (difference = 4; P = .006). Conclusions: Among PLWH, most cancers are not diagnosed at younger ages. However, this study strengthens evidence that lung cancer, anal cancer, and myeloma are diagnosed at modestly younger ages, and also shows younger ages at diagnosis of oral cavity/pharynx and kidney cancers, possibly reflecting accelerated cancer progression, etiologic heterogeneity, or risk factor exposure in PLWH. PMID- 27940942 TI - Transient myocarditis associated with acute Zika virus infection. AB - Zika virus outbreak is spreading in America. This emerging infection is associated with neurological complication. We report the first travel-acquired Zika acute infection complicated with myocarditis imported in Mainland France. We recommand an electrocardiogram and an troponin if any cardiac symptoms are present in a patient with acute Zika infection. PMID- 27940938 TI - Ebola Virus Persistence in Breast Milk After No Reported Illness: A Likely Source of Virus Transmission From Mother to Child. AB - A 9-month-old infant died from Ebola virus (EBOV) disease with unknown epidemiological link. While her parents did not report previous illness, laboratory investigations revealed persisting EBOV RNA in the mother's breast milk and the father's seminal fluid. Genomic analysis strongly suggests EBOV transmission to the child through breastfeeding. PMID- 27940945 TI - From Care to Cure: Demonstrating a Model of Clinical Patient Navigation for Hepatitis C Care and Treatment in High-Need Patients. AB - The NYC Department of Health implemented a patient navigation program, Check Hep C, to address patient and provider barriers to HCV care and potentially lifesaving treatment. Services were delivered at two clinical care sites and two sites that linked patients to off-site care. Working with a multidisciplinary care team, patient navigators provided risk assessment, health education, treatment readiness and medication adherence counseling, and medication coordination. Between March 2014 and January 2015, 388 participants enrolled in Check Hep C, 129 (33%) initiated treatment, and 119 (91% of initiators) had sustained virologic response (SVR). Participants receiving on-site clinical care had higher odds of initiating treatment than those linked to off-site care. Check Hep C successfully supported high-need participants through HCV care and treatment, and SVR rates demonstrate the real-world ability of achieving high cure rates using patient navigation care models. PMID- 27940946 TI - Systematic Review and Meta-Analysis of Acute Kidney Injury Associated with Concomitant Vancomycin and Piperacillin/tazobactam. AB - Concomitant vancomycin and piperacillin/tazobactam may be associated with increased acute kidney injury (AKI) compared to vancomycin without piperacillin/tazobactam. A systematic search of Medline, Cochrane Library, and Scopus through October 2016 using ["vancomycin" and "piperacillin" and "tazobactam"] and ["AKI" or "acute renal failure" or "nephrotoxicity"] and registered meta-analysis (PROSPERO: CRD42016041646) with relevant scenarios was performed. From 307 results, fourteen observational studies totaling 3549 patients were analyzed. Concomitant vancomycin and piperacillin/tazobactam was associated with AKI in unadjusted (odds ratio (OR) 3.12, 95% confidence interval (CI) 2.04-4.78) and adjusted (aOR 3.11, 95% CI 1.77-5.47) analyses. Similar findings were seen assessing studies in adults (aOR 3.15, 95% CI 1.72-5.76), children (OR 4.55, 95% CI 2.71-10.21), and when <50% of patients received care in an intensive care unit (aOR 3.04, 95% CI 1.49-6.22) but not >=50% (aOR 2.83, 95% CI 0.74-10.85). Increased AKI with concomitant vancomycin and piperacillin/tazobactam should be considered when determining beta-lactam therapy. PMID- 27940944 TI - Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae: Laboratory Detection and Impact on Mortality. AB - Background: Polymyxins including colistin are an important "last-line" treatment for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp). Increasing use of colistin has led to resistance to this cationic antimicrobial peptide. Methods: A cohort nested within the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRACKLE) was constructed of patients with infection, or colonization with CRKp isolates tested for colistin susceptibility during the study period of December, 2011 to October, 2014. Reference colistin resistance determination as performed by broth macrodilution was compared to results from clinical microbiology laboratories (Etest) and to polymyxin resistance testing. Each patient was included once, at the time of their first colistin-tested CRKp positive culture. Time to 30-day in-hospital all-cause mortality was evaluated by Kaplan-Meier curves and Cox proportional hazard modeling. Results: In 246 patients with CRKp, 13% possessed ColR CRKp. ColR was underestimated by Etest (very major error rate = 35%, major error rate = 0.4%). A variety of rep-PCR strain types were encountered in both the ColS and the ColR groups. Carbapenem resistance was mediated primarily by blaKPC-2 (46%) and blaKPC 3 (50%). ColR was associated with increased hazard for in-hospital mortality (aHR 3.48; 95% confidence interval, 1.73-6.57; P < .001). The plasmid-associated ColR genes, mcr-1 and mcr-2 were not detected in any of the ColR CRKp. Conclusions: In this cohort, 13% of patients with CRKp presented with ColR CRKp. The apparent polyclonal nature of the isolates suggests de novo emergence of ColR in this cohort as the primary factor driving ColR. Importantly, mortality was increased in patients with ColR isolates. PMID- 27940947 TI - Increased Sexually Transmitted Disease Testing Among Sexually Active Persons Receiving Medical Care for Human Immunodeficiency Virus Infection in the United States, 2009-2013. AB - Background: Current guidelines recommend that all sexually active human immunodeficiency virus (HIV)-infected persons be tested at least annually for syphilis, chlamydia, and gonorrhea. We examined temporal trends in syphilis, chlamydia, and gonorrhea testing among sexually active HIV-infected adults receiving medical care in the United States during 2009-2013. Methods: Using medical record data from the Medical Monitoring Project, a population-based HIV surveillance system, we assessed the proportion of adults receiving HIV medical care who were tested for syphilis, chlamydia, and gonorrhea in the past 12 months by year and stratified by sex and sexual behavior, age, and race/ethnicity. Results: During 2009-2013, the proportion of sexually active HIV-infected adults receiving medical care who were tested in the past year for all 3 examined sexually transmitted diseases (STDs) increased from 20% to 36% (PTREND < .01). Overall testing for syphilis increased from 55% to 65% (PTREND < .01), and significant increases were noted for the following subgroups: men who have sex with men (58% to 69%), non-Hispanic whites (48% to 64%), and all age groups with the exception of persons aged 18-29 year. Overall testing for chlamydia and gonorrhea increased from 22% to 42% (PTREND < .01), and significant increases were noted for most subgroups. Conclusions: STD testing significantly increased among sexually active HIV-infected adults receiving medical care; however, the majority of persons were not tested for all 3 STDs in 2013. While increased testing indicates progress, testing remained far below recommended guidelines. Our findings suggest enhanced efforts may be warranted to screen all sexually active HIV-infected adults for syphilis, chlamydia, and gonorrhea. PMID- 27940949 TI - Trojan triplets: RNA-based pathomechanisms for muscle dysfunction in Huntington's disease. PMID- 27940950 TI - A GC-rich sequence feature in the 3' UTR directs UPF1-dependent mRNA decay in mammalian cells. AB - Up-frameshift protein 1 (UPF1) is an ATP-dependent RNA helicase that has essential roles in RNA surveillance and in post-transcriptional gene regulation by promoting the degradation of mRNAs. Previous studies revealed that UPF1 is associated with the 3' untranslated region (UTR) of target mRNAs via as-yet unknown sequence features. Herein, we aimed to identify characteristic sequence features of UPF1 targets. We identified 246 UPF1 targets by measuring RNA stabilization upon UPF1 depletion and by identifying mRNAs that associate with UPF1. By analyzing RNA footprint data of phosphorylated UPF1 and two CLIP-seq data of UPF1, we found that 3' UTR but not 5' UTRs or open reading frames of UPF1 targets have GC-rich motifs embedded in high GC-content regions. Reporter gene experiments revealed that GC-rich motifs in UPF1 targets were indispensable for UPF1-mediated mRNA decay. These findings highlight the important features of UPF1 target 3' UTRs. PMID- 27940951 TI - APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context. AB - APOBEC3A/B cytidine deaminase is responsible for the majority of cancerous mutations in a large fraction of cancer samples. However, its role in heritable mutagenesis remains very poorly understood. Recent studies have demonstrated that both in yeast and in human cancerous cells, most APOBEC3A/B-induced mutations occur on the lagging strand during replication and on the nontemplate strand of transcribed regions. Here, we use data on rare human polymorphisms, interspecies divergence, and de novo mutations to study germline mutagenesis and to analyze mutations at nucleotide contexts prone to attack by APOBEC3A/B. We show that such mutations occur preferentially on the lagging strand and on nontemplate strands of transcribed regions. Moreover, we demonstrate that APOBEC3A/B-like mutations tend to produce strand-coordinated clusters, which are also biased toward the lagging strand. Finally, we show that the mutation rate is increased 3' of C->G mutations to a greater extent than 3' of C->T mutations, suggesting pervasive trans-lesion bypass of the APOBEC3A/B-induced damage. Our study demonstrates that 20% of C->T and C->G mutations in the TpCpW context-where W denotes A or T, segregating as polymorphisms in human population-or 1.4% of all heritable mutations are attributable to APOBEC3A/B activity. PMID- 27940952 TI - HapCUT2: robust and accurate haplotype assembly for diverse sequencing technologies. AB - Many tools have been developed for haplotype assembly-the reconstruction of individual haplotypes using reads mapped to a reference genome sequence. Due to increasing interest in obtaining haplotype-resolved human genomes, a range of new sequencing protocols and technologies have been developed to enable the reconstruction of whole-genome haplotypes. However, existing computational methods designed to handle specific technologies do not scale well on data from different protocols. We describe a new algorithm, HapCUT2, that extends our previous method (HapCUT) to handle multiple sequencing technologies. Using simulations and whole-genome sequencing (WGS) data from multiple different data types-dilution pool sequencing, linked-read sequencing, single molecule real-time (SMRT) sequencing, and proximity ligation (Hi-C) sequencing-we show that HapCUT2 rapidly assembles haplotypes with best-in-class accuracy for all data types. In particular, HapCUT2 scales well for high sequencing coverage and rapidly assembled haplotypes for two long-read WGS data sets on which other methods struggled. Further, HapCUT2 directly models Hi-C specific error modalities, resulting in significant improvements in error rates compared to HapCUT, the only other method that could assemble haplotypes from Hi-C data. Using HapCUT2, haplotype assembly from a 90* coverage whole-genome Hi-C data set yielded high resolution haplotypes (78.6% of variants phased in a single block) with high pairwise phasing accuracy (~98% across chromosomes). Our results demonstrate that HapCUT2 is a robust tool for haplotype assembly applicable to data from diverse sequencing technologies. PMID- 27940954 TI - Frailty and cardiac rehabilitation: A call to action from the EAPC Cardiac Rehabilitation Section. AB - Frailty is a geriatric syndrome characterised by a vulnerability status associated with declining function of multiple physiological systems and loss of physiological reserves. Two main models of frailty have been advanced: the phenotypic model (primary frailty) or deficits accumulation model (secondary frailty), and different instruments have been proposed and validated to measure frailty. However measured, frailty correlates to medical outcomes in the elderly, and has been shown to have prognostic value for patients in different clinical settings, such as in patients with coronary artery disease, after cardiac surgery or transvalvular aortic valve replacement, in patients with chronic heart failure or after left ventricular assist device implantation. The prevalence, clinical and prognostic relevance of frailty in a cardiac rehabilitation setting has not yet been well characterised, despite the increasing frequency of elderly patients in cardiac rehabilitation, where frailty is likely to influence the onset, type and intensity of the exercise training programme and the design of tailored rehabilitative interventions for these patients. Therefore, we need to start looking for frailty in elderly patients entering cardiac rehabilitation programmes and become more familiar with some of the tools to recognise and evaluate the severity of this condition. Furthermore, we need to better understand whether exercise-based cardiac rehabilitation may change the course and the prognosis of frailty in cardiovascular patients. PMID- 27940953 TI - Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles. AB - Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA2 enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA2. We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA2 activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA2-lowering alleles. Results Lp-PLA2 activity was decreased by 64% ( p = 2.4 * 10-25) with carriage of any of the four loss-of-function variants, by 45% ( p < 10-300) for every allele inherited at Val279Phe, and by 2.7% ( p = 1.9 * 10-12) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA2 activity by 65% ( p < 10-300). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA2 activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74 1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions In a large scale human genetic study, none of a series of Lp-PLA2-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA2 is unlikely to be a causal risk factor. PMID- 27940955 TI - Increased Vascular Permeability Measured With an Albumin-Binding Magnetic Resonance Contrast Agent Is a Surrogate Marker of Rupture-Prone Atherosclerotic Plaque. AB - BACKGROUND: Compromised structural integrity of the endothelium and higher microvessel density increase vascular permeability. We investigated whether vascular permeability measured in vivo by magnetic resonance imaging using the albumin-binding contrast agent, gadofosveset, is a surrogate marker of rupture prone atherosclerotic plaque in a rabbit model. METHODS AND RESULTS: New Zealand white rabbits (n=10) were rendered atherosclerotic by cholesterol-diet and endothelial denudation. Plaque rupture was triggered with Russell's viper venom and histamine. Animals were imaged pre-triggering, at 3 and 12 weeks, to quantify plaque area, vascular permeability, vasodilation, and stiffness and post triggering to identify thrombus. Plaques identified on the pretrigger scans were classified as stable or rupture-prone based on the absence or presence of thrombus on the corresponding post-trigger magnetic resonance imaging, respectively. All rabbits had developed atherosclerosis, and 60% had ruptured plaques. Rupture-prone plaques had higher vessel wall relaxation rate (R1; 2.30+/ 0.5 versus 1.86+/-0.3 s-1; P<0.001), measured 30 minutes after gadofosveset administration, and higher R1/plaque area ratio (0.70+/-0.06 versus 0.47+/-0.02, P= 0.01) compared with stable plaque at 12 weeks. Rupture-prone plaques had higher percent change in R1 between the 3 and 12 weeks compared with stable plaque (50.80+/-7.2% versus 14.22+/-2.2%; P<0.001). Immunohistochemistry revealed increased vessel wall albumin and microvessel density in diseased aortas and especially in ruptured plaque. Electron microscopy showed lack of structural integrity in both luminal and microvascular endothelium in diseased vessels. Functionally, the intrinsic vasodilation of the vessel wall decreased at 12 weeks compared with 3 weeks (18.60+/-1.0% versus 23.43+/-0.8%; P<0.001) and in rupture prone compared with stable lesions (16.40+/-2.0% versus 21.63+/-1.2%; P<0.001). Arterial stiffness increased at 12 weeks compared with 3 weeks (5.00+/-0.1 versus 2.53+/-0.2 m/s; P<0.001) both in animals with stable and rupture-prone lesions. CONCLUSIONS: T1 mapping using an albumin-binding contrast agent (gadofosveset) could quantify the changes in vascular permeability associated with atherosclerosis progression and rupture-prone plaques. PMID- 27940956 TI - Effects of Liraglutide on Reperfusion Injury in Patients With ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: Liraglutide, a glucagon-like peptide-1 analog, was reported to reduce reperfusion injury in mice. We planned to evaluate the effects of liraglutide on reperfusion injury in patients with acute ST-segment-elevation myocardial infarction treated with primary percutaneous coronary intervention. METHODS AND RESULTS: A total of 96 patients with ST-segment-elevation myocardial infarction undergoing emergency primary percutaneous coronary intervention were randomized to receive either subcutaneous liraglutide or placebo. Study treatment was commenced 30 minutes before intervention (1.8 mg) and maintained for 7 days after the procedure (0.6 mg for 2 days, 1.2 mg for 2 days, followed by 1.8 mg for 3 days). The salvage index was calculated from myocardial area at risk, measured during the index admission (35+/-12 hours), and final infarct size measured at 91+/-5 days after primary percutaneous coronary intervention by cardiac magnetic resonance. At 3 months, the primary end point, a higher salvage index was found in the liraglutide group than in the placebo group in 77 patients evaluated with cardiac magnetic resonance (0.66+/-0.14 versus 0.55+/-0.15; P=0.001). The final infarct size was lower in the liraglutide group than that in the placebo group (15+/-12 versus 21+/-15 g; P=0.05). Serum high-sensitivity C-reactive protein level was lower in the liraglutide group (P<0.001). During a 6-month follow-up period, no difference was observed in the incidence of major adverse cardiovascular event. Safety and tolerability were similar among the 2 groups. CONCLUSIONS: Our study provides evidence that liraglutide improves myocardial salvage and infarct size after ST-segment-elevation myocardial infarction, possibly by reducing reperfusion injury, making it a promising treatment for evaluation in larger trials. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02001363. PMID- 27940957 TI - Magnetic Resonance-Augmented Cardiopulmonary Exercise Testing: Comprehensively Assessing Exercise Intolerance in Children With Cardiovascular Disease. AB - BACKGROUND: Conventional cardiopulmonary exercise testing can objectively measure exercise intolerance but cannot provide comprehensive evaluation of physiology. This requires additional assessment of cardiac output and arteriovenous oxygen content difference. We developed magnetic resonance (MR)-augmented cardiopulmonary exercise testing to achieve this goal and assessed children with right heart disease. METHODS AND RESULTS: Healthy controls (n=10) and children with pulmonary arterial hypertension (PAH; n=10) and repaired tetralogy of Fallot (n=10) underwent MR-augmented cardiopulmonary exercise testing. All exercises were performed on an MR-compatible ergometer, and oxygen uptake was continuously acquired using a modified metabolic cart. Simultaneous cardiac output was measured using a real-time MR flow sequence and combined with oxygen uptake to calculate arteriovenous oxygen content difference. Peak oxygen uptake was significantly lower in the PAH group (12.6+/-1.31 mL/kg per minute; P=0.01) and trended toward lower in the tetralogy of Fallot group (13.5+/-1.29 mL/kg per minute; P=0.06) compared with controls (16.7+/-1.37 mL/kg per minute). Although tetralogy of Fallot patients had the largest increase in cardiac output, they had lower resting (3+/-1.2 L/min per m2) and peak (5.3+/-1.2 L/min per m2) values compared with controls (resting 4.3+/-1.2 L/min per m2 and peak 6.6+/-1.2 L/min per m2) and PAH patients (resting 4.5+/-1.1 L/min per m2 and peak 5.9+/-1.1 L/min per m2). Both the PAH and tetralogy of Fallot patients had blunted exercise induced increases in arteriovenous oxygen content difference. However, only the PAH patients had significantly reduced peak values (6.9+/-1.3 mlO2/100 mL) compared with controls (8.4+/-1.4 mlO2/100 mL; P=0.005). CONCLUSIONS: MR augmented cardiopulmonary exercise testing is feasible in both healthy children and children with cardiac disease. Using this novel technique, we have demonstrated abnormal exercise patterns in oxygen uptake, cardiac output, and arteriovenous oxygen content difference. PMID- 27940958 TI - Is Liraglutide Associated With Myocardial Protection in ST-Elevation Myocardial Infarction? PMID- 27940959 TI - Exercise Magnetic Resonance Imaging Is a Gas. PMID- 27940960 TI - Imaging the Permeable Endothelium: Predicting Plaque Rupture in Atherosclerotic Rabbits. PMID- 27940963 TI - Lipid Peroxidation and Altered Antioxidant Profiles with Pediatric HIV Infection and Antiretroviral Therapy in Addis Ababa, Ethiopia. AB - HIV- and highly active antiretroviral therapy (HAART)-associated elevations in oxidative stress likely play a role in incomplete immune reconstitution, opportunistic infections and non-AIDS co-morbidities. We aimed to test the hypothesis that children living with HIV exhibit elevated markers of oxidative stress and reduced antioxidant profiles and that HAART-therapy will exacerbate these differences. HIV-positive HAART-naive (n = 50) and HAART-treated (n = 50) and HIV-negative control (n = 50) participants, 3-15 years of age, were recruited from Black Lion Hospital in Ethiopia. Serum malondialdehyde (MDA) and bilirubin were higher and vitamin C and zinc were lower in HAART-naive and HAART-treated compared with HIV-negative subjects and higher in HAART-treated compared with HAART-naive subjects. Uric acid was higher in HAART-naive compared with HAART treated and HIV-negative subjects. Differences in MDA and several antioxidants were also observed across treatment regimens. Thus, children living with HIV exhibited systemic elevations in oxidative stress and reduction in antioxidants, which are exacerbated with HAART therapy. PMID- 27940961 TI - IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer. AB - IMPs, also known as insulin-like growth factor 2 (IGF2) messenger RNA (mRNA) binding proteins (IGF2BPs), are highly conserved oncofetal RNA-binding proteins (RBPs) that regulate RNA processing at several levels, including localization, translation, and stability. Three mammalian IMP paralogs (IMP1-3) have been identified that are expressed in most organs during embryogenesis, where they are believed to play an important role in cell migration, metabolism, and stem cell renewal. Whereas some IMP2 expression is retained in several adult mouse organs, IMP1 and IMP3 are either absent or expressed at very low levels in most tissues after birth. However, all three paralogs can be re-expressed upon malignant transformation and are found in a broad range of cancer types where their expression often correlates with poor prognosis. IMPs appear to resume their physiological functions in malignant cells, which not only contribute to tumor progression but participate in the establishment and maintenance of tumor cell hierarchies. This review summarizes our current understanding of the functions of IMPs during normal development and focuses on a series of recent observations that have provided new insight into how their physiological functions enable IMPs to play a potentially key role in cancer stem cell maintenance and tumor growth. PMID- 27940962 TI - RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1. AB - The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double strand breaks (DSBs) dependent on E2F1 and ATM kinase activity and promotes DSB repair through homologous recombination (HR), and its loss results in genome instability. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1, and BRG1 to DSBs. This knock-in mutation also impairs DNA repair, increases genomic instability, and renders mice hypersensitive to IR. Importantly, depletion of RB in osteosarcoma and breast cancer cell lines results in sensitivity to DNA-damaging drugs, which is further exacerbated by poly-ADP ribose polymerase (PARP) inhibitors. We uncovered a novel, nontranscriptional function for RB in HR, which could contribute to genome instability associated with RB loss. PMID- 27940964 TI - Chronic exposure to water-pipe smoke induces cardiovascular dysfunction in mice. AB - Water-pipe tobacco smoking is becoming prevalent in all over the world including Western countries. There are limited data on the cardiovascular effects of water pipe smoke (WPS), in particular following chronic exposure. Here, we assessed the chronic cardiovascular effects of nose-only WPS exposure in C57BL/6 mice. The duration of the session was 30 minutes/day, 5 days/week for 6 consecutive months. Control mice were exposed to air. WPS significantly increased systolic blood pressure. The relative heart weight and plasma concentrations of troponin-I and B type natriuretic peptide were increased in mice exposed to WPS. Arterial blood gas analysis showed that WPS caused a significant decrease in [Formula: see text] and an increase in [Formula: see text] WPS significantly shortened the thrombotic occlusion time in pial arterioles and venules and increased the number of circulating platelet. Cardiac lipid peroxidation, measured as thiobarbituric acid reactive substances, was significantly increased, while superoxide dismutase activity, total nitric oxide activity, and glutathione concentration were reduced by WPS exposure. Likewise, immunohistochemical analysis of the heart revealed an increase in the expression of inducible nitric oxide synthase and cytochrome c by cardiomyocytes of WPS-exposed mice. Moreover, hearts of WPS-exposed mice showed the presence of focal interstitial fibrosis. WPS exposure significantly increased heart DNA damage assessed by Comet assay. We conclude that chronic nose-only exposure to WPS impairs cardiovascular homeostasis. Our findings provide evidence that long-term exposure to WPS is harmful to the cardiovascular system and supports interventions to control the spread of WPS, particularly amid youths.NEW & NOTEWORTHY No data are available on the chronic cardiovascular effects of water pipe smoke (WPS). Our findings provide experimental evidence that chronic exposure to WPS increased blood pressure, relative heart weight, troponin I, and B-type natriuretic peptide in plasma and induced hypoxemia, hypercapnia, and thrombosis. Moreover, WPS caused cardiac oxidative stress, DNA damage, and fibrosis. PMID- 27940966 TI - Statins for primary prevention of cardiovascular disease : Patients need better tools to navigate divergent recommendations. PMID- 27940965 TI - High aminopeptidase A activity contributes to blood pressure control in ob/ob mice by AT2 receptor-dependent mechanism. AB - Obesity is assumed to be a major cause of human essential hypertension; however, the mechanisms responsible for weight-related increase in blood pressure (BP) are not fully understood. The prevalence of hypertension induced by obesity has grown over the years, and the role of the renin-angiotensin-aldosterone system (RAAS) in this process continues to be elucidated. In this scenario, the ob/ob mice are a genetic obesity model generally used for metabolic disorder studies. These mice are normotensive even though they present several metabolic conditions that predispose them to hypertension. Although the normotensive trait in these mice is associated with the poor activation of sympathetic nervous system by the lack of leptin, we demonstrated that ob/ob mice present massively increased aminopeptidase A (APA) activity in the circulation. APA enzyme metabolizes angiotensin (ANG) II into ANG III, a peptide associated with intrarenal angiotensin type 2 (AT2) receptor activation and induction of natriuresis. In these mice, we found increased ANG-III levels in the circulation, high AT2 receptor expression in the kidney, and enhanced natriuresis. AT2 receptor blocking and APA inhibition increased BP, suggesting the ANG III-AT2 receptor axis as a complementary BP control mechanism. Circulating APA activity was significantly reduced by weight loss independently of leptin, indicating the role of fat tissue in APA production. Therefore, in this study we provide new data supporting the role of APA in BP control in ob/ob mouse strain. These findings improve our comprehension about obesity-related hypertension and suggest new tools for its treatment.NEW & NOTEWORTHY In this study, we reported an increased angiotensin III generation in the circulation of ob/ob mice caused by a high aminopeptidase A activity. These findings are associated with an increased natriuresis found in these mice and support the role of renin-angiotensin aldosterone system as additional mechanism regulating blood pressure in this genetic obese strain. PMID- 27940968 TI - Psychological distress: a long-lasting matter of the heart. PMID- 27940967 TI - The challenge of frailty and sarcopenia in heart failure with preserved ejection fraction. AB - Frailty is a clinical state in which there is an increase in an individual's vulnerability for developing increased dependency and/or mortality when exposed to stressors. Frailty is often accompanied by heart failure with preserved ejection fraction (HFpEF), and frailty is likely to affect its clinical features and outcomes. Frail patients with HFpEF are frequently associated with sarcopenia (ie, muscle loss and weakness), which is a major component of the pathophysiology of frailty. Sarcopenia is a systemic skeletal muscle disease that impairs the function of limb skeletal muscles, as well as respiratory muscles, and this results in further functional decline. In addition, sarcopenia may contribute to cardiovascular remodelling and dysfunction, leading to the development of HFpEF through several metabolic and endocrine abnormalities. Although there is no established strategy for frail patients with HFpEF, a multidisciplinary approach, including various types of muscular training and nutritional intervention, may provide beneficial effects for these patients. PMID- 27940969 TI - David Kells O'Donel Calderwood. PMID- 27940971 TI - Foreword: Cancer Prevention Can Start Early and Last a Lifetime. PMID- 27940974 TI - Potential Intervention Targets in Utero and Early Life for Prevention of Hormone Related Cancers. AB - Hormone-related cancers have long been thought to be sensitive to exposures during key periods of sexual development, as shown by the vulnerability to such cancers of women exposed to diethylstilbestrol in utero. In addition to evidence from human studies, animal studies using new techniques, such as gene knockout models, suggest that an increasing number of cancers may be hormonally related, including liver, lung, and bladder cancer. Greater understanding of sexual development has also revealed the "mini-puberty" of early infancy as a key period when some sex hormones reach levels similar to those at puberty. Factors driving sex hormones in utero and early infancy have not been systematically identified as potential targets of intervention for cancer prevention. On the basis of sex hormone pathways, we identify common potentially modifiable drivers of sex hormones, including but not limited to factors such as obesity, alcohol, and possibly nitric oxide. We review the evidence for effects of modifiable drivers of sex hormones during the prenatal period and early infancy, including measured hormones as well as proxies, such as the second-to-fourth digit length ratio. We summarize the gaps in the evidence needed to identify new potential targets of early life intervention for lifelong cancer prevention. PMID- 27940973 TI - Annual Economic Burden of Productivity Losses Among Adult Survivors of Childhood Cancers. AB - BACKGROUND AND OBJECTIVES: Although adult survivors of childhood cancers have poorer health and greater health limitations than other adults, substantial gaps remain in understanding the economic consequences of surviving childhood cancer. Therefore, we estimated the economic burden of productivity losses among adult survivors of childhood cancers. METHODS: We examined health status, functional limitations, and productivity loss among adult survivors of childhood cancers (n = 239) diagnosed at <=14 years of age compared with adults without a history of cancer (n = 304 265) by using the 2004-2014 National Health Interview Survey. We estimated economic burden using the productivity loss from health-related unemployment, missed work days, missed household productivity, and multivariable regression models controlling for age, sex, race/ethnicity, education, comorbidities, and survey year. RESULTS: Childhood cancer survivorship is associated with a substantial economic burden. Adult survivors of childhood cancers are more likely to be in poorer health, need assistance with personal care and routine needs, have work limitations, be unable to work because of health, miss more days of work, and have greater household productivity loss compared with adults without a history of cancer (all P < .05). The annual productivity loss for adult survivors of childhood cancer is $8169 per person compared with $3083 per person for individuals without a history of cancer. CONCLUSIONS: These findings underscore the importance of efforts to reduce the health and economic burden among adult survivors of childhood cancer. In addition, this study highlights the potential productivity losses that could be avoided during adulthood from the prevention of childhood cancer in the United States. PMID- 27940972 TI - Opportunities During Early Life for Cancer Prevention: Highlights From a Series of Virtual Meetings With Experts. AB - Compelling evidence suggests that early life exposures can affect lifetime cancer risk. In 2014, the Centers for Disease Control and Prevention's (CDC's) Cancer Prevention Across the Lifespan Workgroup hosted a series of virtual meetings with select experts to discuss the state of the evidence linking factors during the prenatal period and early childhood to subsequent risk of both pediatric and adult cancers. In this article, we present the results from a qualitative analysis of the meeting transcripts and summarize themes that emerged from our discussions with meeting participants. Themes included the state of the evidence linking early life factors to cancer risk, research gaps and challenges, the level of evidence needed to support taking public health action, and the challenges of communicating complex, and sometimes conflicting, scientific findings to the public. Opportunities for collaboration among public health agencies and other stakeholders were identified during these discussions. Potential next steps for the CDC and its partners included advancing and building upon epidemiology and surveillance work, developing and using evidence from multiple sources to inform decision-making, disseminating and communicating research findings in a clear and effective way, and expanding collaborations with grantees and other partners. As the science on early life factors and cancer risk continues to evolve, there are opportunities for collaboration to translate science into actionable public health practice. PMID- 27940975 TI - Maternal Anthropometry and Mammographic Density in Adult Daughters. AB - OBJECTIVE: We examined the relation between maternal anthropometry and mammographic density in the adult daughter using prospectively collected data. METHODS: Our study included a total of 700 mother-daughter dyads participating in an adult follow-up of women born in 2 US birth cohorts: the Child Health and Development Study and the Boston, Massachusetts, and Providence, Rhode Island sites of the National Collaborative Perinatal Project. RESULTS: We observed an increased percent breast density at a mean age of 43.1 years in the daughters of mothers who gained 5 kg or less during pregnancy compared with mother-daughter pairs in which the mother gained 5 to 10 kg (beta = 4.8, 95% confidence interval: 1.0 to 8.6). The daughters of mothers who were overweight at the time of conception (prepregnancy BMI >=25) and who gained >5 kg during pregnancy had a lower percent density (beta = -3.2, 95% confidence interval: -6.2 to -0.2) compared with mothers with a BMI <25 at conception who gained >5 kg. CONCLUSIONS: We did not find any strong and consistent patterns between maternal anthropometry and the daughter's breast density, a strong predictor of breast cancer risk. A modest association between low gestational weight gain and increased breast density 40 years later in the daughter was observed, even after accounting for adult body size, and if confirmed, possible mechanisms need to be further elucidated. PMID- 27940976 TI - The Diethylstilbestrol Legacy: A Powerful Case Against Intervention in Uncomplicated Pregnancy. PMID- 27940978 TI - Environmental and Economic Strategies for Primary Prevention of Cancer in Early Life. AB - This article summarizes the evidence for environmental toxic exposures contributing to cancers in early life, focusing on the most common cancer sites in this age group. It provides examples of widespread avoidable exposures to human carcinogens through air, water, and food and then describes recent examples of successful initiatives to reduce exposure to chemicals linked to these cancer sites, through government policy, industry initiatives, and consumer activism. State government initiatives to reduce toxic chemical exposures have made important gains; the Toxics Use Reduction Act of Massachusetts is now 25 years old and has been a major success story. There are a growing number of corporate initiatives to eliminate toxics, especially carcinogens, from the products they manufacture and sell. Another important opportunity for cancer prevention is provided by online databases that list chemicals, their toxicity, and lower toxicity alternatives; these can be used by businesses, health care institutions, consumers, and workers to reduce exposures to chemicals of concern. The article concludes by inviting pediatricians and public health professionals to include elimination of carcinogen exposures in their work to promote primary prevention of cancer in early life. PMID- 27940980 TI - Family-based Breast Cancer Prevention Efforts in Adolescence. PMID- 27940977 TI - Childhood Leukemia: A Preventable Disease. AB - In contrast to most pediatric cancers, there is a growing body of literature, nationally and internationally, that has implicated the role of several environmental indoor and outdoor hazards in the etiology of childhood leukemia. For example, exposures to solvents, traffic, pesticides, and tobacco smoke have consistently demonstrated positive associations with the risk of developing childhood leukemia. Intake of vitamins and folate supplementation during the preconception period or pregnancy has been demonstrated to have a protective effect. Despite the strength of these findings, the dissemination of this knowledge to clinicians has been limited. Some children may be more vulnerable than others as documented by the high and increasing incidence of childhood leukemia in Hispanics. To protect children's health, it is prudent to establish programs to alter exposure to those factors with well-established associations with leukemia risk rather than to suspend judgment until no uncertainty remains. This is particularly true because other serious health outcomes (both negative and positive) have been associated with the same exposures. We draw from historical examples to put in perspective the arguments of association versus causation, as well as to discuss benefits versus risks of immediate and long-term preventive actions. PMID- 27940979 TI - Disparities in the Context of Opportunities for Cancer Prevention in Early Life. AB - Persistent health disparities are a major contributor to disproportionate burden of cancer for some populations. Health disparities in cancer incidence and mortality may reflect differences in exposures to risk factors early in life. Understanding the distribution of exposures to early life risk and protective factors for cancer across different populations can shed light on opportunities to promote health equity at earlier developmental stages. Disparities may differentially influence risk for cancer during early life and create opportunities to promote health equity. Potential risk and protective factors for cancer in early life reveal patterns of disparities in their exposure. These disparities in exposures can manifest in downstream disparities in risk for cancer. These risk and protective factors include adverse childhood experiences; maternal alcohol consumption in pregnancy; childhood obesity; high or low birth weight; benzene exposure; use of assisted reproductive technologies; pesticide and insecticide exposure; isolated cryptorchidism; early pubertal timing; exposure to radiation; exposure to tobacco in utero and in early life; allergies, asthma, and atopy; and early exposure to infection. Disparities on the basis of racial and ethnic minority status, economic disadvantage, disability status, sex, geography, and nation of origin can occur in these risk and protective factors. Vulnerable populations experience disproportionally greater exposure to risk factors in early life. Addressing disparities in risk factors in early life can advance opportunities for prevention, promote health equity, and possibly reduce risk for subsequent development of cancer. PMID- 27940982 TI - Empowering Pediatricians to Prevent Chronic Disease Across Generations. PMID- 27940983 TI - Labeling Cancer Risk Factors as Lifestyle Limits Prevention Activities Across the Life Span. PMID- 27940984 TI - Concluding Commentary: Children in All Cancer Prevention Policy Decisions. PMID- 27940981 TI - The Association Between Adverse Childhood Experiences and Risk of Cancer in Adulthood: A Systematic Review of the Literature. AB - CONTEXT: Adverse childhood experiences (ACEs) can affect health and well-being across the life course. OBJECTIVE: This systematic review summarizes the literature on associations between ACEs and risk of cancer in adulthood. DATA SOURCES: We searched PubMed to identify relevant publications published on or before May 31, 2015. STUDY SELECTION: We included original research quantifying the association between ACEs and adult cancer incidence. Case reports and reviews were excluded. DATA ABSTRACTION: Two reviewers independently abstracted and summarized key information (eg, ACE type, cancer type, risk estimates) from included studies and resolved all discrepancies. RESULTS: Twelve studies were included in the review. In studies in which ACE summary scores were calculated, significant associations were observed between the scores and an increased risk of cancer in adulthood. Of the different types of ACEs examined, physical and psychological abuse victimization were associated with risk of any cancer in 3 and 2 studies, respectively. Two studies also reported significant associations with regard to sexual abuse victimization (1 for cervical cancer and 1 for any cancer). However, 2 other studies reported no significant associations between childhood sexual or physical abuse and incidence of cervical or breast cancer. LIMITATIONS: Because of heterogeneity across studies, we were unable to compute a summary effect estimate. CONCLUSIONS: These findings suggest that childhood adversity in various forms may increase a person's cancer risk. Further research is needed to understand the mechanisms driving this relationship and to identify opportunities to prevent and mitigate the deleterious effects of early adversity on long-term health. PMID- 27940986 TI - Consumption of artificially sweetened beverages during pregnancy is associated with a twofold higher risk of infant being overweight at 1 year. PMID- 27940987 TI - Ten doctors are charged in Texas hospital referral bribery scheme. PMID- 27940985 TI - Military personnel sustaining Lisfranc injuries have high rates of disability separation. AB - OBJECTIVES: Lisfranc injuries are relatively uncommon midfoot injuries disproportionately affecting young, active males. Previous studies in civilian populations have reported relatively good results with operative treatment. However, treatment results have not been specifically examined in military personnel, who may have higher physical demands than the general population. The purpose of this study was to examine rates of return to military duty following surgical treatment of isolated Lisfranc injuries. METHODS: Surgical records and radiographic images from all active duty US military personnel treated for an isolated Lisfranc injury between January 2005 and July 2014 were examined. Demographic information, injury data, surgical details and subsequent return to duty information were recorded. The primary outcome was ability to return to unrestricted military duty following treatment. The secondary outcome was secondary conversion to a midfoot arthrodesis following initial open reduction internal fixation. RESULTS: Twenty-one patients meeting inclusion criteria were identified. Median patient age was 23 years, and mean follow-up was 43 months. Within this cohort, 14 patients were able to return to military service, while seven required a disability separation from the armed forces. Of the 18 patients who underwent initial fixation, eight were subsequently revised to midfoot arthrodesis for persistent pain. DISCUSSION: Military personnel sustaining Lisfranc injuries have high rates of persistent pain and disability, even after optimal initial surgical treatment. Military surgeons should counsel patients on the career-threatening nature of this condition and high rates of secondary procedures. PMID- 27940997 TI - Real-Time, Label-Free Detection of Local Exocytosis Outside Pancreatic beta Cells Using Laser Tweezers Raman Spectroscopy. AB - The examination of insulin (Ins) exocytosis at the single-cell level by conventional methods, such as electrophysiological approaches, total internal reflection imaging, and two-photon imaging technology, often requires an invasive microelectrode puncture or label. In this study, high concentrations of glucose and potassium chloride were used to stimulate beta cell Ins exocytosis, while low concentrations of glucose and calcium channel blockers served as the blank and negative control, respectively. Laser tweezers Raman spectroscopy (LTRS) was used to capture the possible Raman scattering signal from a local zone outside of the cell edge. The results show that the frequencies of the strong signals from the local zones outside the cellular edge in the stimulated groups are greater than those of the control. The Raman spectra from the cellular edge, Ins and cell membrane were compared. Thus, local Ins exocytosis activity outside pancreatic beta cells might be observed indirectly using LTRS, a non-invasive optical method. PMID- 27940999 TI - Taking the lead: Supporting staff in coping with grief and loss in dementia care. AB - Healthcare providers working with people living with dementia often experience a profound sense of grief when the person they support dies or moves to an alternative level of care. Unattended staff grief can impact healthcare leaders by reducing quality of care, increasing staff turnover and absenteeism, lowering morale, and creating a greater risk of long-term staff health problems. Organizational and self-care strategies can mitigate these challenges. PMID- 27940998 TI - Decreased circulating BMP-9 levels in patients with Type 2 diabetes is a signature of insulin resistance. AB - Bone morphogenetic protein 9 (BMP-9) has been demonstrated to improve glucose homoeostasis in diabetic mice. However, no report has demonstrated the relationship of circulating BMP-9 levels with insulin resistance (IR) or Type 2 diabetes mellitus (T2DM) in humans. The objective of the present study was to investigate the relationship between BMP-9 and IR in cross-sectional and interventional studies. Circulating BMP-9 levels were analysed by ELISA in 280 well-characterized individuals. Two-hour oral glucose tolerance test (OGTT) and euglycaemic-hyperinsulinaemic clamp (EHC) were performed in 20 healthy subjects. Acute IR was induced by lipid infusion for 4 h in 20 healthy volunteers. Real time (RT)-PCR and Western blotting were used to assess mRNA and protein expression of BMP-9. The effect of a glucagon-like peptide-1 (GLP-1) receptor agonist (PEX168) on circulating BMP-9 was investigated in a 24-week treatment trial. Circulating BMP-9 levels were significantly higher in healthy subjects than in newly diagnosed patients with T2DM. Circulating BMP-9 negatively correlated with HbA1c, fasting blood glucose (FBG), OGTT, the area under the curve for glucose (AUCglucose) and homoeostasis model assessment of insulin resistance (HOMA-IR). Multivariate regression analyses showed that BMP-9 levels were independently associated with non-esterified fatty acid (NEFA) and AUCglucose Both hyperinsulinaemia and lipid infusion decreased circulating BMP-9 levels. BMP-9 mRNA and protein expressions were significantly decreased in muscle and adipose tissues of T2DM patients. In the placebo treated group, BMP-9 levels continued to decline over time, whereas in the PEX 168 treated groups BMP-9 levels remained stable. Our data suggest that BMP-9 is likely to play an important role in IR in humans. PMID- 27941000 TI - Appropriate ethics review is required. AB - Health leaders manage many types of risk. One type of risk that may be underrecognized is the ethical risk in the many projects and activities that are done regularly besides research (eg, program evaluation, quality improvement, and health innovation). Applying clinical, personal, professional, and organizational ethics can help address the risks but are insufficient by themselves or in combination. Each different type of project or activity requires an ethics review that is appropriate for that activity. Health leaders must first acknowledge that ethical risks exist in many of the activities occurring in their organization and then support the different types of ethics review required to adequately protect and respect people and their information. PMID- 27941001 TI - Implicit and Explicit Evaluations of Sexual Aggression Predict Subsequent Sexually Aggressive Behavior in a Sample of Community Men. AB - The current longitudinal study explored the extent to which implicit and explicit evaluations of sexual aggression predict subsequent sexually aggressive behavior. Participants (248 community men recruited online) completed measures of implicit and explicit evaluations and self-reported sexually aggressive behavior at two time points, approximately 4 months apart. Implicit and explicit evaluations of sexual aggression at Wave 1 had small significant and independent predictive relationships with sexually aggressive behavior at Wave 2, while controlling for sexually aggressive behavior at Wave 1. This is the first study to test whether implicit and explicit evaluations predict subsequent sexually aggressive behavior. Our findings are consistent with the possibility that both implicit and explicit evaluations may be relevant for understanding and preventing subsequent sexually aggressive behavior. If these findings can be replicated, evaluations of sexual aggression should be studied with more rigorous methodology (e.g., experimental design) and correctional/forensic populations, and possibly addressed in risk assessment and interventions. PMID- 27941002 TI - Reducing Stigma and Punitive Attitudes Toward Pedophiles Through Narrative Humanization. AB - Stigmatization and societal punitiveness about pedophilia have a range of potential consequences, such as the social isolation of people with sexual interest in children, and the formation of policies that are not consistent with empirical research findings. Previous research has shown that people with pedophilic sexual interests use societal thinking to self-stigmatize, which in turn may actually serve to increase their risk of committing a sexual offense. In this study, we compared two attitudinal interventions (first-person narrative vs. expert opinion) using a student sample ( N = 100). It was hypothesized that both interventions would lead to reductions in stigmatization and punitive attitudes about pedophiles on an explicit (self-report) level but that only the narrative intervention would lead to reductions of these constructs at the implicit level. Our findings supported both hypotheses. We further discuss the role of narrative humanization in this area and offer suggestions for further research based upon the theoretical and methodological implications of the findings. PMID- 27941003 TI - Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia. AB - Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to immunotherapy. We show that the murine tumor lines B16 and MC38 differed in their ability to consume oxygen and produce hypoxic environments, which correlated with their sensitivity to checkpoint blockade. Metformin, a broadly prescribed type II diabetes treatment, inhibited oxygen consumption in tumor cells in vitro and in vivo, resulting in reduced intratumoral hypoxia. Although metformin monotherapy had little therapeutic benefit in highly aggressive tumors, combination of metformin with PD-1 blockade resulted in improved intratumoral T-cell function and tumor clearance. Our data suggest tumor hypoxia acts as a barrier to immunotherapy and that remodeling the hypoxic tumor microenvironment has potential to convert patients resistant to immunotherapy into those that receive clinical benefit. Cancer Immunol Res; 5(1); 9-16. (c)2016 AACR. PMID- 27941005 TI - 68 years--a record breaking thoracoplasty? PMID- 27941006 TI - Constructing diagnostic likelihood: clinical decisions using subjective versus statistical probability. AB - BACKGROUND: Although physicians are highly trained in the application of evidence based medicine, and are assumed to make rational decisions, there is evidence that their decision making is prone to biases. One of the biases that has been shown to affect accuracy of judgements is that of representativeness and base rate neglect, where the saliency of a person's features leads to overestimation of their likelihood of belonging to a group. This results in the substitution of 'subjective' probability for statistical probability. METHODS: This study examines clinicians' propensity to make estimations of subjective probability when presented with clinical information that is considered typical of a medical condition. The strength of the representativeness bias is tested by presenting choices in textual and graphic form. Understanding of statistical probability is also tested by omitting all clinical information. RESULTS: For the questions that included clinical information, 46.7% and 45.5% of clinicians made judgements of statistical probability, respectively. Where the question omitted clinical information, 79.9% of clinicians made a judgement consistent with statistical probability. There was a statistically significant difference in responses to the questions with and without representativeness information (chi2 (1, n=254)=54.45, p<0.0001). CONCLUSIONS: Physicians are strongly influenced by a representativeness bias, leading to base-rate neglect, even though they understand the application of statistical probability. One of the causes for this representativeness bias may be the way clinical medicine is taught where stereotypic presentations are emphasised in diagnostic decision making. PMID- 27941004 TI - Optimization of Peptide Vaccines to Induce Robust Antitumor CD4 T-cell Responses. AB - Substantial evidence indicates that immunotherapy is a feasible and effective approach for the treatment of numerous types of cancer. Among various immunotherapy options, peptide vaccines to generate antitumor T cells appear as promising candidates, because of their cost effectiveness and ease of implementation. Nevertheless, most peptide vaccines are notorious for being weekly immunogenic and, thus, optimization of the vaccination strategy is essential to achieve therapeutic effectiveness. In addition, effective peptide vaccines must stimulate both CD8 cytotoxic and CD4 helper T lymphocytes. Our group has been successful in designing effective peptide vaccination strategies for inducing CD8 T-cell responses in mouse tumor models. Here, we describe a somewhat similar, but distinct, peptide vaccination strategy capable of generating vast CD4 T-cell responses by combining synthetic peptides with toll like receptor (TLR) agonists and OX40/CD40 costimulation. This vaccination strategy was efficient in overcoming immune tolerance to a self-tumor-associated antigen and generated significant antitumor effects in a mouse model of malignant melanoma. The optimized peptide vaccine also allowed the expansion of adoptively transferred CD4 T cells without the need for lymphodepletion and IL2 administration, generating effective antimelanoma responses through the enhancement of proliferative and antiapoptotic activities of CD4 T cells. These results have practical implications in the design of more effective T-cell-based immunotherapies. Cancer Immunol Res; 5(1); 72-83. (c)2016 AACR. PMID- 27941007 TI - Age-adjusted D-dimer excludes pulmonary embolism and reduces unnecessary radiation exposure in older adults: retrospective study. AB - BACKGROUND: Patients in whom a diagnosis of pulmonary embolism (PE) is suspected and whose D-dimers are elevated frequently require CT pulmonary angiogram (CTPA) for diagnosis. Because D-dimer rises with age, an age-adjusted D-dimer threshold may prevent unnecessary radiation exposure from CTPA in older patients. OBJECTIVE: To determine the efficacy and safety of implementing an age-adjusted D dimer threshold to exclude PE. DESIGN, SETTINGS AND PATIENTS: Retrospective comparison of conventional and age-adjusted D-dimer thresholds in 1000 consecutive patients who had both D-dimer and CTPA. MAIN OUTCOME MEASURES: Conventional and age-adjusted D-dimer thresholds for excluding PE were <250 ng/mL and 5* age for patients older than 50 years, respectively. We defined patients as unlikely to have PE using the revised Geneva score (RGS) and two different categories of clinical risk: RGS <=5 and RGS <=10. RESULTS: We diagnosed PE by CTPA in 244 (24.4%) patients. 3/86 patients (3.5%) whose D-dimer was below the conventional threshold of 250 ng/mL had PE (RGS 3, 9 and 14), all of which were judged to be light clot load (group 1). 3/108 patients (2.8%) whose D-dimer lay between 250 ng/mL and the age-adjusted threshold had PE (RGS 6, 8 and 9), all of which were again judged to be light clot load (group 2). 62/108 group 2 patients with RGS <=5 were considered unlikely to have PE as were 102/108 using the RGS clinical risk category <=10. None of the 62 patients with RGS <=5 had PE while 3/102 patients with RGS <=10 had PE. 236/806 patients (29.3%) whose D-dimer was above the age-adjusted threshold had PE (group 3). CONCLUSIONS: In a consecutive series of 1000 patients, an RGS <=5 and an age-adjusted D-dimer would have led to 62 fewer CTPA at a cost of no missed PEs. PMID- 27941009 TI - The SfaNI restriction-modification system from Enterococcus faecalis NEB215 is located on a putative mobile genetic element. PMID- 27941008 TI - Genetic polymorphisms of UTS2 rs2890565 Ser89Asn in cardiac hypertrophy in Chinese Han population. AB - OBJECTIVE: Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli, some of which might finally lead up to a maladaptive state. Clinical evidence, in vitro and in vivo studies have implicated urotensin II (U-II/UTS2) in the development of cardiac hypertrophy, contributing to the (patho)-physiological regulation of cardiovascular homeostasis in humans. Several genes are associated with left ventricular hypertrophy; considering these, our objective was to evaluate the possible role of UTS2 gene polymorphisms (Thr21Met and Ser89Asn) in the genetic susceptibility to cardiac hypertrophy in a Chinese population. METHODS: A case-control study was designed to compare the distribution of alleles and genotypes between three groups: case group 1 (subjects with hypertension and cardiac hypertrophy, n=265), case group 2 (subjects with hypertension, without cardiac hypertrophy, n=768), and the control group (subjects neither with hypertension nor with cardiac hypertrophy, n=416). The detection of UTS2 gene polymorphisms was achieved with the PCR restriction fragment length polymorphism technique. RESULTS: We did not identify statistically significant differences between the three groups, neither with regard to the frequency of genotype/variant at the Ser89Asn locus nor at the Thr21Met locus. When stratified by sex, differences in genotype distribution of polymorphism Ser89Asn were only seen in female subjects in both the additive tested inheritance model (OR=0.507, 95% CI 0.249 to 1.032, p=0.032) and the recessive tested inheritance model (OR=0.475, 95% CI 0.239 to 0.945, p=0.034) between case group 2 (subjects with hypertension, without cardiac hypertrophy) and the control group (subjects neither with hypertension nor with cardiac hypertrophy). When stratified by sex, for female subjects with cardiac hypertrophy, we identified statistically significant differences in left ventricular posterior wall thickness for variant genotypes at the Ser89Asn locus (AA vs GG: 1.2500 (1.2000, 1.3750) vs 1.2500 (1.2000, 1.3750), p=0.03) and (AG+AA vs GG: 1.2000 (1.2000, 1.3000) vs 1.2000 (1.1000, 1.2000), p=0.01). CONCLUSIONS: Ser89Asn (S89N) polymorphisms of the UTS2 gene were associated with hypertension in a Chinese female population. Additionally, we demonstrated that genotype Asn89Asn was associated with left ventricular posterior wall thickness for subjects with hypertension and cardiac hypertrophy in a Chinese female population. PMID- 27941010 TI - A local cryotherapy with percutaneous tumour removal as a successful treatment option in patient with tricuspid valve fibroelastoma papillare. PMID- 27941011 TI - Out-of-hospital cardiac arrest: The need for continuing education. PMID- 27941012 TI - Implantation of magnesium-bioresorbable scaffolds in a bifurcation under optical coherence tomography guidance. PMID- 27941013 TI - Transcatheter repair of persistent tricuspid regurgitation after MitraClip with the TriCinch system: interventional valve treatment toward the surgical standard. PMID- 27941014 TI - Myocardial crystallization arising from a mitral annulus calcification. PMID- 27941015 TI - Non-invasive FFRCT revealing severe inducible ischaemia in an anomalous right coronary artery. PMID- 27941016 TI - Limitations of the SCORE-guided European guidelines on cardiovascular disease prevention. PMID- 27941017 TI - Early stentframe thrombosis complicating transcatheter valve in transcatheter valve implantation. PMID- 27941018 TI - Prognostic assessment of stable coronary artery disease as determined by coronary computed tomography angiography: a Danish multicentre cohort study. AB - Aims: To examine the 3.5 year prognosis of stable coronary artery disease (CAD) as assessed by coronary computed tomography angiography (CCTA) in real-world clinical practice, overall and within subgroups of patients according to age, sex, and comorbidity. Methods and results: This cohort study included 16,949 patients (median age 57 years; 57% women) with new-onset symptoms suggestive of CAD, who underwent CCTA between January 2008 and December 2012. The endpoint was a composite of late coronary revascularization procedure >90 days after CCTA, myocardial infarction, and all-cause death. The Kaplan-Meier estimator was used to compute 91 day to 3.5 year risk according to the CAD severity. Comparisons between patients with and without CAD were based on Cox-regression adjusted for age, sex, comorbidity, cardiovascular risk factors, concomitant cardiac medications, and post-CCTA treatment within 90 days. The composite endpoint occurred in 486 patients. Risk of the composite endpoint was 1.5% for patients without CAD, 6.8% for obstructive CAD, and 15% for three-vessel/left main disease. Compared with patients without CAD, higher relative risk of the composite endpoint was observed for non-obstructive CAD [hazard ratio (HR): 1.28; 95% confidence interval (CI): 1.01-1.63], obstructive one-vessel CAD (HR: 1.83; 95% CI: 1.37-2.44), two-vessel CAD (HR: 2.97; 95% CI: 2.09-4.22), and three vessel/left main CAD (HR: 4.41; 95% CI :2.90-6.69). The results were consistent in strata of age, sex, and comorbidity. Conclusion: Coronary artery disease determined by CCTA in real-world practice predicts the 3.5 year composite risk of late revascularization, myocardial infarction, and all-cause death across different groups of age, sex, or comorbidity burden. PMID- 27941019 TI - Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1. AB - Aims: To describe the incidence and identify predictors of sudden death (SD), major conduction defects and sustained ventricular tachyarrhythmias (VTA) in myotonic dystrophy type 1 (DM1). Methods and results: We retrospectively enrolled 1388 adults with DM1 referred to six French medical centres between January 2000 and October 2013. We confirmed their vital status, classified all deaths, and determined the incidence of major conduction defects requiring permanent pacing and sustained VTA. We searched for predictors of overall survival, SD, major conduction defects, and sustained VTA by Cox regression analysis. Over a median 10-year follow-up, 253 (18.2%) patients died, 39 (3.6%) suddenly. Analysis of the cardiac rhythm at the time of the 39 SD revealed sustained VTA in 9, asystole in 5, complete atrioventricular block in 1 and electromechanical dissociation in two patients. Non-cardiac causes were identified in the five patients with SD who underwent autopsies. Major conduction defects developed in 143 (19.3%) and sustained VTA in 26 (2.3%) patients. By Cox regression analysis, age, family history of SD and left bundle branch block were independent predictors of SD, while age, male sex, electrocardiographic conduction abnormalities, syncope, and atrial fibrillation were independent predictors of major conduction defects; non sustained VTA was the only predictor of sustained VTA. Conclusions: SD was a frequent mode of death in DM1, with multiple mechanisms involved. Major conduction defects were by far more frequent than sustained VTA, whose only independent predictor was a personal history of non-sustained VTA. ClinicalTrials.gov no: NCT01136330. PMID- 27941020 TI - Contractility sensor-guided optimization of cardiac resynchronization therapy: results from the RESPOND-CRT trial. AB - Aims: Although cardiac resynchronization therapy (CRT) is effective in patients with systolic heart failure (HF) and a wide QRS interval, a substantial proportion of patients remain non-responsive. The SonR contractility sensor embedded in the right atrial lead enables individualized automatic optimization of the atrioventricular (AV) and interventricular (VV) timings. The RESPOND-CRT study investigated the safety and efficacy of the contractility sensor system in HF patients undergoing CRT. Methods and results: RESPOND-CRT was a prospective, randomized, double-blinded, multicentre, non-inferiority trial. Patients were randomized (2:1, respectively) to receive weekly, automatic CRT optimization with SonR vs. an Echo-guided optimization of AV and VV timings. The primary efficacy endpoint was the rate of clinical responders (patients alive, without adjudicated HF-related events, with improvement in New York Heart Association class or quality of life), at 12 months. The study randomized 998 patients. Responder rates were 75.0% in the SonR arm and 70.4% in the Echo arm (mean difference, 4.6%; 95% CI, -1.4% to 10.6%; P < 0.001 for non-inferiority margin -10.0%) (Table 2). At an overall mean follow-up of 548 +/- 190 days SonR was associated with a 35% risk reduction in HF hospitalization (hazard ratio, 0.65; 95% CI, 0.46-0.92; log-rank P = 0.01). Conclusion: Automatic AV and VV optimization using the contractility sensor was safe and as effective as Echo-guided AV and VV optimization in increasing response to CRT. ClinicalTrials.gov number: NCT01534234. PMID- 27941021 TI - Phospholipase Cgamma1 (PLCgamma1) Controls Osteoclast Numbers via Colony stimulating Factor 1 (CSF-1)-dependent Diacylglycerol/beta-Catenin/CyclinD1 Pathway. AB - Phospholipases Cgamma (PLCgamma) 1 and 2 are a class of highly homologous enzymes modulating a variety of cellular pathways through production of inositol 1,4,5 trisphosphate and diacylglycerol (DAG). Our previous studies demonstrated the importance of PLCgamma2 in osteoclast (OC) differentiation by modulating inositol 1,4,5-trisphosphate-mediated calcium oscillations and the up-regulation of the transcription factor NFATc1. Surprisingly, despite being expressed throughout osteoclastogenesis, PLCgamma1 did not compensate for PLCgamma2 deficiency. Because both isoforms are activated during osteoclastogenesis, it is plausible that PLCgamma1 modulates OC development independently of PLCgamma2. Here, we utilized PLCgamma1-specific shRNAs to delete PLCgamma1 in OC precursors derived from wild type (WT) mice. Differently from PLCgamma2, we found that PLCgamma1 shRNA significantly suppresses OC differentiation by limiting colony-stimulating factor 1 (CSF-1)-dependent proliferation and beta-catenin/cyclinD1 levels. Confirming the specificity toward CSF-1 signaling, PLCgamma1 is recruited to the CSF-1 receptor following exposure to the cytokine. To understand how PLCgamma1 controls cell proliferation, we turned to its downstream effector, DAG. By utilizing cells lacking the DAG kinase zeta, which have increased DAG levels, we demonstrate that DAG modulates CSF-1-dependent proliferation and beta catenin/cyclinD1 levels in OC precursors. Most importantly, the proliferation and osteoclastogenesis defects observed in the absence of PLCgamma1 are normalized in PLCgamma1/DAG kinase zeta double null cells. Taken together, our study shows that PLCgamma1 controls OC numbers via a CSF-1-dependent DAG/beta-catenin/cyclinD1 pathway. PMID- 27941022 TI - Basic Residues of beta-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12). AB - Many members of the serine protease inhibitor (serpin) family are activated by glycosaminoglycans (GAGs). Visceral adipose tissue-derived serpin (vaspin), serpin A12 of the serpin family, and its target protease kallikrein 7 (KLK7) are heparin-binding proteins, and inhibition of KLK7 by vaspin is accelerated by heparin. However, the nature of GAG binding to vaspin is not known. Here, we measured vaspin binding of various glycosaminoglycans and low molecular weight heparins by microscale thermophoresis and analyzed acceleration of protease inhibition by these molecules. In addition, basic residues contributing to heparin binding and heparin activation were identified by a selective labeling approach. Together, these data show that vaspin binds heparin with high affinity (KD = 21 +/- 2 nm) and that binding takes place at a basic patch on top of beta sheet A and is different from other heparin-binding serpins. Mutation of basic residues decreased heparin binding and activation of vaspin. Similarly, reactive center loop insertion into sheet A decreased heparin binding because it disturbs the basic cluster. Finally, using vaspin-overexpressing keratinocyte cells, we show that a significant part of secreted vaspin is bound in the extracellular matrix on the cell surface. Together, basic residues of central beta-sheet A contribute to heparin binding and activation of vaspin. Thus, binding to GAGs in the extracellular matrix can direct and regulate vaspin interaction with target proteases or other proteins and may play an important role in the various beneficial functions of vaspin in different tissues. PMID- 27941023 TI - Loss of Cardiolipin Leads to Perturbation of Acetyl-CoA Synthesis. AB - Cardiolipin (CL), the signature phospholipid of mitochondrial membranes, plays an important role in mitochondrial processes and bioenergetics. CL is synthesized de novo and undergoes remodeling in the mitochondrial membranes. Perturbation of CL remodeling leads to the rare X-linked genetic disorder Barth syndrome, which shows disparities in clinical presentation. To uncover biochemical modifiers that exacerbate CL deficiency, we carried out a synthetic genetic array screen to identify synthetic lethal interactions with the yeast CL synthase mutant crd1Delta. The results indicated that crd1Delta is synthetically lethal with mutants in pyruvate dehydrogenase (PDH), which catalyzes the conversion of pyruvate to acetyl-CoA. Acetyl-CoA levels were decreased in the mutant. The synthesis of acetyl-CoA depends primarily on the PDH-catalyzed conversion of pyruvate in the mitochondria and on the PDH bypass in the cytosol, which synthesizes acetyl-CoA from acetate. Consistent with perturbation of the PDH bypass, crd1Delta cells grown on acetate as the sole carbon source exhibited decreased growth, decreased acetyl-CoA, and increased intracellular acetate levels resulting from decreased acetyl-CoA synthetase activity. PDH mRNA and protein levels were up-regulated in crd1Delta cells, but PDH enzyme activity was not increased, indicating that PDH up-regulation did not compensate for defects in the PDH bypass. These findings demonstrate for the first time that CL is required for acetyl-CoA synthesis, which is decreased in CL-deficient cells as a result of a defective PDH bypass pathway. PMID- 27941024 TI - Endosomal Phosphatidylinositol 3-Phosphate Promotes Gephyrin Clustering and GABAergic Neurotransmission at Inhibitory Postsynapses. AB - The formation of neuronal synapses and the dynamic regulation of their efficacy depend on the proper assembly of the postsynaptic neurotransmitter receptor apparatus. Receptor recruitment to inhibitory GABAergic postsynapses requires the scaffold protein gephyrin and the guanine nucleotide exchange factor collybistin (Cb). In vitro, the pleckstrin homology domain of Cb binds phosphoinositides, specifically phosphatidylinositol 3-phosphate (PI3P). However, whether PI3P is required for inhibitory postsynapse formation is currently unknown. Here, we investigated the role of PI3P at developing GABAergic postsynapses by using a membrane-permeant PI3P derivative, time-lapse confocal imaging, electrophysiology, as well as knockdown and overexpression of PI3P-metabolizing enzymes. Our results provide the first in cellula evidence that PI3P located at early/sorting endosomes regulates the postsynaptic clustering of gephyrin and GABAA receptors and the strength of inhibitory, but not excitatory, postsynapses in cultured hippocampal neurons. In human embryonic kidney 293 cells, stimulation of gephyrin cluster formation by PI3P depends on Cb. We therefore conclude that the endosomal pool of PI3P, generated by the class III phosphatidylinositol 3 kinase, is important for the Cb-mediated recruitment of gephyrin and GABAA receptors to developing inhibitory postsynapses and thus the formation of postsynaptic membrane specializations. PMID- 27941026 TI - Cooperative DnaA Binding to the Negatively Supercoiled datA Locus Stimulates DnaA ATP Hydrolysis. AB - Timely initiation of replication in Escherichia coli requires functional regulation of the replication initiator, ATP-DnaA. The cellular level of ATP-DnaA increases just before initiation, after which its level decreases through hydrolysis of DnaA-bound ATP, yielding initiation-inactive ADP-DnaA. Previously, we reported a novel DnaA-ATP hydrolysis system involving the chromosomal locus datA and named it datA-dependent DnaA-ATP hydrolysis (DDAH). The datA locus contains a binding site for a nucleoid-associating factor integration host factor (IHF) and a cluster of three known DnaA-binding sites, which are important for DDAH. However, the mechanisms underlying the formation and regulation of the datA IHF.DnaA complex remain unclear. We now demonstrate that a novel DnaA box within datA is essential for ATP-DnaA complex formation and DnaA-ATP hydrolysis. Specific DnaA residues, which are important for interaction with bound ATP and for head-to-tail inter-DnaA interaction, were also required for ATP-DnaA-specific oligomer formation on datA Furthermore, we show that negative DNA supercoiling of datA stabilizes ATP-DnaA oligomers, and stimulates datA-IHF interaction and DnaA ATP hydrolysis. Relaxation of DNA supercoiling by the addition of novobiocin, a DNA gyrase inhibitor, inhibits datA function in cells. On the basis of these results, we propose a mechanistic model of datA-IHF.DnaA complex formation and DNA supercoiling-dependent regulation for DDAH. PMID- 27941025 TI - A Novel Rac1-GSPT1 Signaling Pathway Controls Astrogliosis Following Central Nervous System Injury. AB - Astrogliosis (i.e. glial scar), which is comprised primarily of proliferated astrocytes at the lesion site and migrated astrocytes from neighboring regions, is one of the key reactions in determining outcomes after CNS injury. In an effort to identify potential molecules/pathways that regulate astrogliosis, we sought to determine whether Rac/Rac-mediated signaling in astrocytes represents a novel candidate for therapeutic intervention following CNS injury. For these studies, we generated mice with Rac1 deletion under the control of the GFAP (glial fibrillary acidic protein) promoter (GFAP-Cre;Rac1flox/flox). GFAP Cre;Rac1flox/flox (Rac1-KO) mice exhibited better recovery after spinal cord injury and exhibited reduced astrogliosis at the lesion site relative to control. Reduced astrogliosis was also observed in Rac1-KO mice following microbeam irradiation-induced injury. Moreover, knockdown (KD) or KO of Rac1 in astrocytes (LN229 cells, primary astrocytes, or primary astrocytes from Rac1-KO mice) led to delayed cell cycle progression and reduced cell migration. Rac1-KD or Rac1-KO astrocytes additionally had decreased levels of GSPT1 (G1 to S phase transition 1) expression and reduced responses of IL-1beta and GSPT1 to LPS treatment, indicating that IL-1beta and GSPT1 are downstream molecules of Rac1 associated with inflammatory condition. Furthermore, GSPT1-KD astrocytes had cell cycle delay, with no effect on cell migration. The cell cycle delay induced by Rac1-KD was rescued by overexpression of GSPT1. Based on these results, we propose that Rac1-GSPT1 represents a novel signaling axis in astrocytes that accelerates proliferation in response to inflammation, which is one important factor in the development of astrogliosis/glial scar following CNS injury. PMID- 27941027 TI - The lipid droplet-associated protein perilipin 3 facilitates hepatitis C virus driven hepatic steatosis. AB - Hepatitis C virus (HCV) is an enveloped RNA virus responsible for 170 million cases of viral hepatitis worldwide. Over 50% of chronically infected HCV patients develop hepatic steatosis, and steatosis can be induced by expression of HCV core protein (core) alone. Additionally, core must associate with cytoplasmic lipid droplets (LDs) for steatosis development and viral particle assembly. Due to the importance of the LD as a key component of hepatic lipid storage and as a platform for HCV particle assembly, it seems this dynamic subcellular organelle is a gatekeeper in the pathogenesis of viral hepatitis. Here, we hypothesized that core requires the host LD scaffold protein, perilipin (PLIN)3, to induce hepatic steatosis. To test our hypothesis in vivo, we have studied core-induced hepatic steatosis in the absence or presence of antisense oligonucleotide mediated knockdown of PLIN3. PLIN3 knockdown blunted HCV core-induced steatosis in transgenic mice fed either chow or a moderate fat diet. Collectively, our studies demonstrate that the LD scaffold protein, PLIN3, is essential for HCV core-induced hepatic steatosis and provide new insights into the pathogenesis of HCV. PMID- 27941029 TI - Deubiquitylating enzymes in receptor endocytosis and trafficking. AB - In recent times, our knowledge of the roles ubiquitin plays in multiple cellular processes has expanded exponentially, with one example being the role of ubiquitin in receptor endocytosis and trafficking. This has prompted a multitude of studies examining how the different machinery involved in the addition and removal of ubiquitin can influence this process. Multiple deubiquitylating enzymes (DUBs) have been implicated either in facilitating receptor endocytosis and lysosomal degradation or in rescuing receptor levels by preventing endocytosis and/or promoting recycling to the plasma membrane. In this review, we will discuss in detail what is currently known about the role of DUBs in regulating the endocytosis of various transmembrane receptors and ion channels. We will also expand upon the role DUBs play in receptor sorting at the multivesicular body to determine whether a receptor is recycled or trafficked to the lysosome for degradation. Finally, we will briefly discuss how the DUBs implicated in these processes may contribute to the pathogenesis of a range of diseases, and thus the potential these have as therapeutic targets. PMID- 27941030 TI - Molecular mechanisms of ROS production and oxidative stress in diabetes. AB - Oxidative stress and chronic inflammation are known to be associated with the development of metabolic diseases, including diabetes. Oxidative stress, an imbalance between oxidative and antioxidative systems of cells and tissues, is a result of over production of oxidative-free radicals and associated reactive oxygen species (ROS). One outcome of excessive levels of ROS is the modification of the structure and function of cellular proteins and lipids, leading to cellular dysfunction including impaired energy metabolism, altered cell signalling and cell cycle control, impaired cell transport mechanisms and overall dysfunctional biological activity, immune activation and inflammation. Nutritional stress, such as that caused by excess high-fat and/or carbohydrate diets, promotes oxidative stress as evident by increased lipid peroxidation products, protein carbonylation and decreased antioxidant status. In obesity, chronic oxidative stress and associated inflammation are the underlying factors that lead to the development of pathologies such as insulin resistance, dysregulated pathways of metabolism, diabetes and cardiovascular disease through impaired signalling and metabolism resulting in dysfunction to insulin secretion, insulin action and immune responses. However, exercise may counter excessive levels of oxidative stress and thus improve metabolic and inflammatory outcomes. In the present article, we review the cellular and molecular origins and significance of ROS production, the molecular targets and responses describing how oxidative stress affects cell function including mechanisms of insulin secretion and action, from the point of view of possible application of novel diabetic therapies based on redox regulation. PMID- 27941028 TI - Intra-abdominal Candida spp infection in acute abdomen in a quality assurance (QA)-certified academic setting. AB - AIMS: To evaluate the contribution of light microscopy to detecting Candida spp infection in patients with complicated intra-abdominal infections (IAIs) admitted for acute abdomen to a quality assurance (QA)-certified surgical emergency ward. METHODS: We conducted a retrospective study (2008-2012) of 809 abdominal intraoperative or biopsy tissue specimens obtained from patients admitted with acute abdomen and microbiological samples positive for Candida spp. Demographic data, mortality, comorbidities, specimen type, microscopy results, special histological staining performed, antimicrobial therapy were collected and analysed. Any comments at the multidisciplinary team meeting was recorded in minutes of and approved. RESULTS: Sixty-six patients with complicated IAIs due to Candida spp were identified (39 male, 27 female, mean+/-SD age 75+/-20 years). Candida albicans was isolated in 35 cases and Candida non-albicans spp in 31 cases. Candida spp were isolated from blood in 50% of all selected microbiological specimens. Patients were stratified according to Candida spp (albicans vs non-albicans), underlying cancer disease and no previous antimicrobial administration, and a positive correlation with C. albicans isolation was found (p=0.009 and p=0.048, respectively). Out of 41 cases with microscopic evaluation, we identified yeast forms, pseudohyphae or both, indicative of Candida spp, in 23. Identification of Candida spp in histological specimens was higher in C. albicans cases than in C. non-albicans cases (73% vs 37.5%). Microscopy allowed prompt treatment of all patients. CONCLUSIONS: Light microscopy still has great diagnostic significance, being a solid QA step. It provides rapid information and clues in patients who may harbour impaired defence mechanisms, concurrent chronic conditions and/or cancer. PMID- 27941031 TI - Protein degradation, the main hub in the regulation of cellular polyamines. AB - Ornithine decarboxylase (ODC) is the first and rate-limiting enzyme in the biosynthesis of polyamines, low-molecular-mass aliphatic polycations that are ubiquitously present in all living cells and are essential for fundamental cellular processes. Most cellular polyamines are bound, whereas the free pools, which regulate cellular functions, are subjected to tight regulation. The regulation of the free polyamine pools is manifested by modulation of their synthesis, catabolism, uptake and excretion. A central element that enables this regulation is the rapid degradation of key enzymes and regulators of these processes, particularly that of ODC. ODC degradation is part of an autoregulatory circuit that responds to the intracellular level of the free polyamines. The driving force of this regulatory circuit is a protein termed antizyme (Az). Az stimulates the degradation of ODC and inhibits polyamine uptake. Az acts as a sensor of the free intracellular polyamine pools as it is expressed via a polyamine-stimulated ribosomal frameshifting. Az binds to monomeric ODC subunits to prevent their reassociation into active homodimers and facilitates their ubiquitin-independent degradation by the 26S proteasome. In addition, through a yet unidentified mechanism, Az inhibits polyamine uptake. Interestingly, a protein, termed antizyme inhibitor (AzI) that is highly homologous with ODC, but retains no ornithine decarboxylating activity, seems to regulate cellular polyamines through its ability to negate Az. Overall, the degradation of ODC is a net result of interactions with regulatory proteins and possession of signals that mediate its ubiquitin-independent recognition by the proteasome. PMID- 27941032 TI - Correction: Channel-transporter complexes: an emerging theme in cell signalling. PMID- 27941033 TI - Response to: 'Pleural mesothelioma and occupational and non-occupational asbestos exposure: a case-control study with quantitative risk assessment' by Ferrante et al. PMID- 27941034 TI - Pleural mesothelioma and asbestos exposure: a case-control study with quantitative risk assessment-response to Marsh and Benson's letter. PMID- 27941036 TI - The miracle of face transplantation after 10 years. AB - INTRODUCTION: At the 10th year anniversary of the first face transplantation, there are currently 36 patients worldwide, who are the recipients of faces coming from human donors. AREAS OF AGREEMENT: Despite the initial debates and ethical concerns, face transplantation became a clinical reality with satisfactory functional outcomes. AREAS OF CONTROVERSY: The areas of controversy still include the impact of lifelong immunosuppression on otherwise healthy patients as well as the selection process of face transplant candidates. GROWING POINTS: Other concerns include financial support for this new generation of transplants as well as social reintegration and patients return to work after face transplantation. AREAS TIMELY FOR DEVELOPING RESEARCH: Based on over 20 years of research experience in the field of vascularized composite allotransplantation, and clinical experience as a leading surgeon of the US first face transplantation, this review will summarize the well-known facts as well as unexpected outcomes and challenges of face transplantation. PMID- 27941037 TI - China: the tipping point in tobacco control. AB - BACKGROUND: Tobacco control in China, the world's largest producer and consumer of tobacco, began in the 1980s with the first national prevalence survey and a conference on tobacco held in Tianjin. Since then, there have been dozens of research papers, partial restrictions on smoking and tobacco advertising, public education campaigns, and the ratification of the World Health Organization Framework Convention on Tobacco Control, but progress has been slow. The state owned tobacco industry remains a major obstacle to tobacco control. RECENT DEVELOPMENTS: In the last few years, tobacco control efforts have accelerated beyond expectations. The triggering event was the publication on tobacco by the Chinese Central Party School, the ideological think tank of the Communist Party, followed by a spate of activity: directives to government officials; regulations issued by the Ministry of Education, the People's Liberation Army and the Healthy City Standards; tobacco clauses in national advertising and philanthropy laws; the creation of a Smoke-free Beijing; an increase in tobacco taxation; and a national smoke-free law currently in draft. AREAS TIMELY FOR POLICY RESEARCH AND ACTION: There is a crucial need for China to build upon these recent developments, in accepting the economic research evidence of the debit of tobacco to the economy; in implementing robust, comprehensive legislation; in increasing cigarette price through taxation and, most challenging of all, to tackle the power and influence of the state tobacco monopoly over tobacco control. PMID- 27941038 TI - Globalizing and crowdsourcing biomedical research. AB - INTRODUCTION OR BACKGROUND: Crowdfunding and crowdsourcing of medical research has emerged as a novel paradigm for many biomedical disciplines to rapidly collect, process and interpret data from high-throughput and high-dimensional experiments. The novelty and promise of these approaches have led to fundamental discoveries about RNA mechanisms, microbiome dynamics and even patient interpretation of test results. However, these methods require robust training protocols, uniform sampling methods and experimental rigor in order to be useful for subsequent research efforts. Executed correctly, crowdfunding and crowdsourcing can leverage public resources and engagement to generate support for scientific endeavors that would otherwise be impossible due to funding constraints and or the large number of participants needed for data collection. SOURCES OF DATA: We conducted a comprehensive literature review of scientific studies that utilized crowdsourcing and crowdfunding to generate data. We also discuss our own experiences conducting citizen-science research initiatives (MetaSUB and PathoMap) in ensuring data robustness, educational outreach and public engagement. AREAS OF AGREEMENT: We demonstrate the efficacy of crowdsourcing mechanisms for revolutionizing microbiome and metagenomic research to better elucidate the microbial and genetic dynamics of cities around the world (as well as non-urban areas). Crowdsourced studies have been able to create an improved and unprecedented ability to monitor, design and measure changes at the microbial and macroscopic scale. Thus, the use of crowdsourcing strategies has dramatically altered certain genomics research to create global citizen-science initiatives that reveal new discoveries about the world's genetic dynamics. AREAS OF CONTROVERSY: The effectiveness of crowdfunding and crowdsourcing is largely dependent on the study design and methodology. One point of contention for the present discussion is the validity and scientific rigor of data that are generated by non-scientists. Selection bias, limited sample sizes and limitations for scientists in enforcing standardized protocols are all challenges for those who engage in citizen-science initiatives. GROWING POINTS: Despite the aforementioned concerns, crowdsourced data allow for greater inroads into the field of personalized medicine, whereby community members take an active role in generating data about their personal and environmental health. AREAS TIMELY FOR DEVELOPING RESEARCH: Crowdsourced viral and metagenomic studies are the next step in elucidating the genomic and epigenomic characterization of urban population health. PMID- 27941039 TI - Targeted response? An exploration of why ambulance services find government targets particularly challenging. AB - INTRODUCTION OR BACKGROUND: Ambulance services have historically found their targets particularly challenging. This article explores some areas of this multifaceted problem. SOURCES OF DATA: Research articles, government publications and published audit data. AREAS OF AGREEMENT: Demand is increasing in many areas of healthcare, but whilst hospitals saw a 7% increase in demand in recent times, ambulance services saw nearly double that. The services ambulance trusts provide have evolved from that of a transport service to that of a mobile health provider, and they have become victims of their own success. AREAS OF CONTROVERSY: Ambulance targets have never evolved to match evolving care. Ambulance personnel strive to avoid hospital attendance where appropriate, but this can be difficult for a 24-hour service, when not all referral pathways have 24-hour referral systems. GROWING POINTS: We discuss why demand might be growing disproportionately for ambulance services, and challenge the appropriateness of the targets themselves. AREAS TIMELY FOR DEVELOPING RESEARCH: Possible formats for revised ambulance targets are discussed. PMID- 27941041 TI - Advances in the recognition and management of hereditary cancer. AB - INTRODUCTION: Constitutional mutations in genes controlling DNA repair, cell cycle regulation and cell apoptosis can determine an individual's tendency to develop cancer. Hereditary cancer predisposition syndromes present with multiple cancers at a young age and underlie a significant burden of morbidity and mortality. Recent advances in the recognition and management of hereditary cancer will be illustrated with specific examples of developments in diagnosis and treatment. SOURCES OF DATA: Key recent published literature. AREAS OF AGREEMENT: The identification of individuals with hereditary cancer offers important opportunities for cancer prevention, early intervention and personalized management. AREAS OF CONTROVERSY: Individuals at risk of hereditary cancer remain under-recognized. There is a need to develop evidence-based guidelines for the recognition and management of hereditary cancer predisposition conditions. GROWING POINTS: The study of Mendelian cancer susceptibility syndromes has added to our understanding of hereditary and sporadic cancers and facilitated the development of targeted agents directed against cancer-driving mutations. Increasingly, cancer patients with constitutional gene mutations treated with targeted therapies have improved clinical outcomes. AREAS FOR TIMELY RESEARCH: Building the infrastructure to enable constitutional gene mutation testing to become integrated into routine cancer care, including the parallel development of robust referral pathways alongside genomic sequencing technologies. PMID- 27941040 TI - Genetic predisposition to prostate cancer. AB - INTRODUCTION: Prostate cancer (PrCa) is the commonest non-cutaneous cancer in men in the UK. Epidemiological evidence as well as twin studies points towards a genetic component contributing to aetiology. SOURCES OF DATA: Key recently published literature. AREAS OF AGREEMENT: A family history of PrCa doubles the risk of disease development in first-degree relatives. Linkage and genetic sequencing studies identified rare moderate-high-risk gene loci, which predispose to PrCa development when altered by mutation. Genome-wide association studies have identified common single-nucleotide polypmorphisms (SNPs), which confer a cumulative risk of PrCa development with increasing number of risk alleles. There are emerging data that castrate-resistant disease is associated with mutations in DNA repair genes. AREAS OF CONTROVERSY: Linkage studies investigating possible high-risk loci leading to PrCa development identified possible loci on several chromosomes, but most have not been consistently replicated by subsequent studies. Germline SNPs related to prostate specific antigen (PSA) levels and to normal tissue radiosensitivity have also been identified though not all have been validated in subsequent studies. GROWING POINTS: Utilizing germline SNP profiles as well as identifying high-risk genetic variants could target screening to high risk groups, avoiding the drawbacks of PSA screening. AREAS TIMELY FOR DEVELOPING RESEARCH: Incorporating genetics into PrCa screening is being investigated currently using both common SNP profiles and higher risk rare variants. Knowledge of germline genetic defects will allow the development of targeted screening programs, preventive strategies and the personalized treatment of PrCa. PMID- 27941043 TI - Does Racial/Ethnic Identity Influence the Effectiveness of a Community Health Worker Intervention for African American and Latino Adults With Type 2 Diabetes? AB - BACKGROUND: Community health worker (CHW) interventions are known to be an effective strategy to improve health behaviors and outcomes in relation to diabetes, particularly for racial/ethnic communities. Although understanding the function of identity with same race/ethnicity among clients of CHW interventions could contribute to more effective program design, few studies have explored whether levels of racial/ethnic identity among participants can influence the effectiveness of CHW interventions. AIMS: We tested the relationship between level of racial/ethnic identity and changes in hemoglobin A1c and diabetes self efficacy among low-income African American and Latino adults with type 2 diabetes who participated in a CHW intervention. METHODS: Data came from a randomized controlled trial of the CHW intervention with a 6-month delayed control group design for 164 African American and Latino adults in Detroit, Michigan. Racial/ethnic identity was created from two items and classified into high, moderate, and low. We combined the two arms (immediate and delayed) into one because there was no significant difference in baseline characteristics, other than age and postintervention self-efficacy, and multivariable linear regression models were applied in the analysis. RESULTS: Possession of high racial/ethnic identity was associated with greater improvement both in hemoglobin A1c and diabetes self-efficacy at 6 months. Moreover, among those with high hemoglobin A1c at preintervention, higher racial/ethnic identity had a greater impact on hemoglobin A1c improvement, compared with those with lower identity. CONCLUSIONS: This study suggests the importance of considering racial/ethnic identity of the participants in designing and operating the CHW intervention for racial/ethnic minority population. PMID- 27941042 TI - Apophyseal injuries in children's and youth sports. AB - INTRODUCTION: The authors reviewed the current English literature regarding apophyseal injuries affecting young athletes, to highlight the frequency and characteristics of these injuries, to clarify risk factors and specific prevention measures, and to identify future research objectives. SOURCES OF DATA: The authors performed a comprehensive search of the medical literature, using the Medline database, including all English articles. Various combinations of the Keywords 'injury', 'sports', 'athletic injuries', 'avulsion fractures', 'physeal', 'physis', 'apophysis', 'apophysitis', 'growth plate' were used. AREAS OF AGREEMENT: Growth benefits from a moderate physical activity. AREAS OF CONTROVERSY: Growth deficit may occur in young athletes involved in intensive practice of sport following apophysitis. GROWING POINTS: Apophyseal injuries occurring during sport are less common than overall rate of injuries affecting the adolescent population. Growth disturbance occurs only rarely after an apophyseal injury. AREAS TIMELY FOR DEVELOPING RESEARCH: Further studies should consider analytical as well as descriptive components of apophyseal injuries, to allow the identification of new possible risk factors and preventive measures and to help early detection and proper treatment as well. PMID- 27941044 TI - In vivo ocular biomechanical compliance in thyroid eye disease. AB - BACKGROUND/AIMS: To compare the ocular biomechanical properties in patients with thyroid eye disease (TED) and healthy participants using a non-contact Scheimpflug-based tonometer (CorVis ST). METHODS: All eyes were examined by slit lamp biomicroscopy, corneal tomography and the CorVis ST (CST). Patients with TED were examined by a fellowship trained oculoplastics specialist to determine status and assess severity. The outputs from CST and additionally derived parameters, including maximum orbital deformation (MOD), were compared between healthy participants and patients with TED using Student's t-test. Furthermore, a multiple linear regression analysis was used to control for various factors known to influence ocular biomechanical responses to an air pulse. RESULTS: This study included 20 patients with TED and compared them with a cohort of 152 healthy participants. The mean age of patients with TED was 46.7+/-19.0 years and the mean age of healthy participants was 35.9+/-13.8 years (p=0.03). There were no statistically significant differences in gender distributions between both groups (p>0.05). Several CST parameters were significantly different between groups (p<0.05). Of note, however, MOD was significantly lower in patients with TED (0.16+/-0.04 mm) compared with the healthy participants (0.25+/-0.05 mm, p<0.001). This dissimilarity remained even after controlling for the various cofactors. Receiver-operating characteristic analysis revealed an area under the curve of 0.91+/-0.04 (95% CI 0.84 to 0.98, p<0.001) for MOD. CONCLUSIONS: The in vivo ocular biomechanics as measured by the CST reflects a reduced orbital compliance. This method of ocular biomechanical assessment may aid in the categorisation of TED severity and assist in monitoring and/or diagnosing TED. PMID- 27941045 TI - Single-step transepithelial versus alcohol-assisted photorefractive keratectomy in the treatment of high myopia: a comparative evaluation over 12 months. AB - BACKGROUND/AIMS: To evaluate refractive outcomes of single-step transepithelial photorefractive keratectomy (TransPRK) versus alcohol-assisted PRK (EtOH-PRK) for the correction of high myopia. METHODS: This was a retrospective non-randomised comparative study conducted at the American University of Beirut Medical Center, Beirut, Lebanon. Eyes with myopia (spherical equivalent (SE) larger than -6.00 D) that had undergone EtOH-PRK treatment combined with mitomycin C and TransPRK (SE: -7.53+/-0.90 D and -7.24+/-0.77 D, p=0.062), using the Schwind Amaris excimer laser, were included. 59 eyes (37 patients) that had single-step TransPRK were compared with 59 eyes (36 patients) that had EtOH-PRK. Visual and refractive outcomes, including analysis of astigmatism, and corneal higher order aberrations (HOAs) at 6.0 mm optical zone, were compared for 12 months postoperatively. RESULTS: Baseline characteristics were similar between the two groups (p>0.05). The SE deviation from target (SEDT) at 1 week, 1, 3, 6 and 12 months follow-up visits were similar between groups (p=0.428). At 12 months, 81.3% and 73.3% of eyes that had undergone TransPRK and EtOH-PRK, respectively, were between +/-0.50 D SEDT (p=0.381). Mean cylinder power was 0.33+/-0.26 D versus 0.41+/-0.30 D at 12 months follow-up (p=0.140). The mean success index was 0.50+/-0.50 for the TransPRK group and 0.49+/-0.52 for the EtOH-PRK group (p=0.939), while the absolute mean angle of error was 7.81 degrees +/-61.98 degrees vs 13.12 degrees +/-71.86 degrees (p=0.667), respectively. The change in total, spherical and comatic corneal HOAs were similar in both groups at 12 months (p>0.05). Haze was similar between both groups; two eyes had +1 haze at 12 months in the TransPRK group versus zero eyes among the EtOH-PRK group (p=0.154). CONCLUSIONS: Single step TransPRK for high myopia with or without astigmatism appears to yield similar visual, refractive and safety results as EtOH-PRK. PMID- 27941046 TI - Topical 1% 5-fluoruracil as a sole treatment of corneoconjunctival ocular surface squamous neoplasia: long-term study. AB - AIMS: To report long-term clinical outcome of topical 1% 5-fluoruracil (5-FU) as a sole treatment of ocular surface squamous neoplasia (OSSN). METHODS: 41 patients affected by OSSN were included. Each patient underwent full ophthalmological examination at baseline, with cytological or histological confirmation. Patients were treated by topical chemotherapy with 1% 5-FU four times a day for 4 weeks. One course was defined as 4 weeks of topical chemotherapy. Adjunctive courses were administered after 1 month of chemotherapy free interval. RESULTS: Mean follow-up was 105+/-32 months (range 60-171 months). Complete tumour regression was achieved in 34 cases (83%) after a mean of 1.5 courses (range, 1-3 courses). Univariate analysis revealed that complete response was significantly related to tumour thickness <1.5 mm (p=0.005), lack of fornix or tarsal involvement (p=0.015 and p=0.009, respectively) and the absence of multifocality (p=0.002). Histopathological diagnosis (intraepithelial neoplasia vs squamous cell carcinoma, p=0.019) and American Joint Committee on Cancer (AJCC) classification (T1 vs T2 or T3) (p=0.028) were also related to incomplete tumour response. In a multivariate analysis, just tumour thickness >1.5 mm (p=0.045) and multifocality (p=0.023) were correlated with incomplete tumour response. Transient and reversible low-to-mild local side effects were documented in 19 (48%) eyes. CONCLUSION: Topical 5-FU, as a sole therapy, is a long-term safe and effective treatment for patients affected by preinvasive OSSN and for a limited proportion (50%) of invasive OSSN. PMID- 27941047 TI - Cataract surgery in children with retinopathy of prematurity (ROP): surgical outcomes. AB - PURPOSE: To report the outcomes of cataract surgery in children with retinopathy of prematurity (ROP). METHODS: A retrospective case review of all children diagnosed with ROP from January 2001 to December 2014 was done and those who underwent cataract surgery were included in the study. Details of ROP and cataract treatment, postoperative complications and outcomes were analysed. RESULTS: Of the 2258 children diagnosed to have ROP, 28 eyes of 22 children were included, 14 boys and 8 girls. Mean age at cataract surgery was 18.9 months (range 2 months to 12 years). Most common grade of ROP was stage 4 (13 eyes). Nineteen eyes underwent retinal surgery, scleral buckle (one eye) and laser (three eyes). Five eyes showed spontaneous regression. Mean duration for the development of cataract postretinal surgery was 7.76 months (range 2-32 months). Nine eyes did not receive a primary intraocular lens (IOL). Intraoperative posterior capsular rupture occurred in two eyes. Postoperative complications included visual axis opacification (four), secondary glaucoma (two) and IOL capture (one). Postoperative visual acuity assessment was possible in 23 eyes, 11 had better than 20/200 vision. Eleven patients had a follow-up of at least 2 years and the mean myopic shift at 2 years was -3.07 D in pseudophakes and -8.75 D in aphakes. CONCLUSIONS: Cataracts may develop in children with ROP regardless of the modality of intervention. Postoperative complications and refractive changes are similar to those in eyes without ROP. PMID- 27941048 TI - The association between skin autofluorescence and mean deviation in patients with open-angle glaucoma. AB - BACKGROUND: It has been suggested that local and systemic oxidative stress levels are causal risk factors for glaucoma. AIM: To evaluate the effect of age on the role of systemic oxidative stress in open-angle glaucoma (OAG). METHODS: This study included 502 eyes of 251 Japanese patients with OAG. Systemic oxidative stress was assessed with skin autofluorescence (SAF), an indicator of advanced glycogen end products. We selected the youngest and oldest patients by quartile (<=58 and >=74 years old, respectively) and determined the univariate correlation between SAF and mean deviation (MD) of the visual field in both eyes of each group. We also investigated the association between SAF and glaucoma in the youngest group with a logistic regression analysis. RESULTS: The younger subjects with OAG with high SAF had significantly lower better-eye MD than the younger subjects with normal SAF (p<0.01), but the older subjects had similar better-eye MD regardless of SAF level. Furthermore, SAF was negatively correlated with MD in the youngest subjects (better eye: r=-0.35, p<0.01, worse eye: r=-0.28, p=0.02), but not in the older subjects. Finally, mixed-effects regression analysis showed that SAF contributed to the MD in the younger patients with OAG (p=0.01). CONCLUSIONS: We found that the relationship between systemic oxidative stress and visual field loss was strongest in relatively young patients with OAG, suggesting that the potential benefit of antioxidant therapies to combat systemic oxidative stress might be dependent on the age of the patient. PMID- 27941049 TI - Understanding the reasons for loss to follow-up in patients with glaucoma at a tertiary referral teaching hospital in Korea. AB - BACKGROUND/AIMS: To assess the reasons and factors for discontinuation of follow up among patients with glaucoma at a tertiary referral teaching hospital in Seoul, Korea. METHODS: We identified all adult patients with glaucoma (>=18 years), who had visited the glaucoma clinic of Seoul National University Hospital between April 2012 and March 2014 and had missed an appointment by at least 12 months. These patients were traced via cellular phone, and their true status and reasons for discontinuation of follow-up were documented. RESULTS: A total of 6848 patients with glaucoma (3512 men and 3336 women) were considered. Among them, 247 (3.61%) had missed a scheduled appointment by 12 months or more. Among 230 (93.1%) who were successfully traced, 4 (1.7%) had died and 96 (41.7%) had self-transferred to another glaucoma clinic. Of the 130 patients left, 123 (94.6%) had treatment and follow-up interruptions, and 7 (5.4%) had been treated with alternative medicine. The two main reasons cited for treatment and follow-up interruptions were lack of understanding regarding the necessity of follow-up (46.3%) and unawareness of appointment schedule (30.9%). In stepwise linear regression analysis, older age (p=0.001. beta=0.13), male gender (p=0.013, beta=0.08) and lower baseline intraocular pressure (p=0.005, beta=0.11) were independently associated with follow-up loss involving treatment interruptions. CONCLUSIONS: This study's results emphasise the need for ongoing educational support and improved appointment notification, especially for the elderly, men and patients with low baseline intraocular pressure. PMID- 27941050 TI - Effects of ocular and systemic factors on the progression of glaucomatous visual field damage in various sectors. AB - BACKGROUND/AIM: To investigate the effects of ocular and systemic risk factors for glaucomatous progression in different sectors of the visual field (VF). METHOD: 409 eyes from 268 patients with 10 reliable VFs from the Japanese Archive of Multicentral Databases in Glaucoma (JAMDIG) were investigated. VFs were divided into six sectors (mean total deviation (mTD)s20+, mTDs10-20 and mTDs0-10, >20 degrees , 10-20 degrees and <10 degrees in the superior hemifield, respectively; and mTDi20+, mTDi10-20 and mTDi0-10, >20 degrees , 10-20 degrees and <10 degrees in the inferior hemifield, respectively). The relationship between sectorial progression rate and eight variables (age, mTD at baseline VF, average intraocular pressure (IOP), SD of IOP, systemic hypertension, migraine, family history of glaucoma and smoking status) was investigated. RESULT: The mTD progression rate was -0.21 dB/year. Older age was related to progression of mTDs20+, mTDs10-20, mTDi20+ and mTDi10-20. Mean IOP was not related to progression in any VF sector; however, a larger SD of IOP was related to progression of mTDs20+, mTDi0-10, mTDi10-20 and mTDi20+. Smoking status was related to progression in all inferior VF sectors (mTDi0-10, mTDi10-20 and mTDi20+). CONCLUSIONS: Smoking status is related to glaucomatous VF progression in all sectors of the inferior hemifield. PMID- 27941051 TI - Vascular risk in obesity: Facts, misconceptions and the unknown. AB - Obesity is a major burden on healthcare systems worldwide due to the association with numerous complications, arguably the most important of which are the development of type 2 diabetes and cardiovascular disease. Both are thought to develop from similar origins and occur at variable rates in obese individuals, including those with similar body mass indices. This phenomenon is likely a result of an increased susceptibility for the storage of excess fat in the wrong place, namely, ectopic fat surrounding the liver, pancreas and muscles. This triggers a concatenation of events leading to insulin resistance and inflammation which culminate in an increased atherothrombotic potential due to the dysfunction of vascular endothelial cells causing accelerated atherosclerotic plaque formation and a pro-thrombotic phenotype. The degree of weight loss following different interventions is well documented but it is less widely known what effect weight loss by various means has on the deleterious process mentioned above, in particular their effects on cardiovascular events. This review summarises the processes leading to increased vascular risk in obesity and examines the effects of currently available weight loss strategies on reversing these processes and how this translates to cardiovascular disease. PMID- 27941053 TI - Patient characteristics related to metabolic disorders and chronic complications in type 2 diabetes mellitus patients hospitalized at the Qingdao Endocrine and Diabetes Hospital from 2006 to 2012 in China. AB - OBJECTIVE: To study the clinical characteristics related to metabolic disorders and complications in type 2 diabetes mellitus patients hospitalized in the Qingdao Endocrine and Diabetes Hospital from 2006 to 2012 in Qingdao, China. PATIENT POPULATION AND METHODS: Data from 14,289 (51% males) type 2 diabetes mellitus patients hospitalized between 2006 and 2012 were collected and analysed. Information on patients' demographic, anthropometric, laboratory and disease histories were extracted from electronic medical records. RESULTS: The mean age of the patients was 60.5 years, with median diabetes duration of 9.0 years. Mean haemoglobin A1c was 8.4%, where <30.0% of patients had haemoglobin A1c <7.0%. In all, 34.5% of patients had low-density lipoprotein cholesterol lower than 2.6 mmol/L and 31.9% had hypertriglyceridaemia. Retinopathy was diagnosed in 51.1% of patients, nephropathy in 21.6%, neuropathy in 50.4%, hypertension in 77.4%, coronary heart disease in 27.6% and peripheral vascular disease in 58.6%. Once hospitalized, 71.1% of patients underwent insulin injection treatments, either mono-therapy or combined with other anti-diabetic drugs. Metformin was prescribed to 36.9% of patients, followed by acarbose 29.9%, thiazolidinediones 18.1%, meglitinides 14.8% and sulfonylureas 10.7%. CONCLUSION: Inadequate control of hyperglycaemia, poor metabolic profiles and diabetic complications were common challenges for long-term diabetes management in Chinese patients with type 2 diabetes mellitus. PMID- 27941054 TI - Tetrahydrobiopterin rescues impaired responses of cerebral resistance arterioles during type 1 diabetes. AB - Our goal was to test the hypothesis that administration of tetrahydrobiopterin (BH4) would improve impaired endothelial nitric oxide synthase-dependent dilation of cerebral arterioles during type 1 diabetes. In addition, we examined the influence of BH4 on levels of superoxide in brain tissue. In vivo diameter of cerebral arterioles in nondiabetic and diabetic rats was measured in response to endothelial nitric oxide synthase-dependent agonists (acetylcholine and adenosine 5'-diphosphate) and an endothelial nitric oxide synthase-independent agonist (nitroglycerine) before and during application of BH4 (1.0 uM). We also measured levels of superoxide from cortex tissue in nondiabetic and diabetic rats under basal states and during BH4 Acetylcholine and adenosine 5'-diphosphate dilated cerebral arterioles in nondiabetic rats, but this vasodilation was significantly impaired in diabetic rats. In contrast, nitroglycerine produced similar vasodilation in nondiabetic and diabetic rats. Application of BH4 did not enhance vasodilation in nondiabetic rats but improved impaired cerebral vasodilation in diabetic rats. Basal superoxide levels were increased in cortex tissue from diabetic rats, and BH4 reduced these levels to that found in nondiabetic rats. Thus, BH4 is an important mediator of endothelial nitric oxide synthase-dependent responses of cerebral arterioles in diabetes and may have therapeutic potential for the treatment of cerebral vascular disease. PMID- 27941055 TI - White matter injury induced by diabetes in acute stroke is clinically relevant: A preliminary study. AB - The importance of white matter injury induced by diabetes in stroke severity and prognosis is largely unknown. We aimed to investigate the relationship between diabetes-related white matter injury beyond stroke lesions with acute neurological deficits and clinical outcome after stroke. In total, 36 stroke patients within 3-7 days after onset were enrolled. Neurological deficits on admission were assessed by National Institute of Health Stroke Score, and poor outcome at 3 months was defined as modified Rankin score >2. White matter tracts were compared between patients with diabetic and non-diabetic stroke using fractional anisotropy from diffusion tensor imaging. Regional white matter abnormality with decreased fractional anisotropy was observed in diabetic patients (n = 18) when compared to non-diabetic patients (n = 18). Decreased fractional anisotropy in ipsilesional distal corticospinal tract was independently associated with higher National Institute of Health Stroke Score motor component score (beta = -0.444, p = 0.005), and decreased fractional anisotropy in contralesional superior longitudinal fasciculus I was independently related to poor outcome (odds ratio, 0.900; p = 0.033). Our findings suggested that only white matter injury induced by diabetes in specific tracts like corticospinal tract and superior longitudinal fasciculus beyond stroke lesions has clinically relevant, providing insight into the mechanism of stroke recovery under the diabetic condition. PMID- 27941056 TI - A non-exercise method to determine cardiorespiratory fitness identifies females predicted to be at 'high risk' of type 2 diabetes. AB - This study examined the relationship between cardiorespiratory fitness determined by a non-exercise testing method for estimating fitness and predicted risk of developing type 2 diabetes mellitus using five risk assessments/questionnaires (Leicester Diabetes Risk Score, QDiabetes, Cambridge Risk Score, Finnish Diabetes Risk Score and American Diabetes Association Diabetes Risk Test). Retrospective analysis was performed on 330 female individuals with no prior diagnosis of cardiovascular disease or type 2 diabetes mellitus who participated in the Prosiect Sir Gar workplace initiative in Carmarthenshire, South Wales. Non exercise testing method for estimating fitness (expressed as metabolic equivalents) was calculated using a validated algorithm, and females were grouped accordingly into fitness quintiles <6.8 metabolic equivalents (Quintile 1), 6.8 7.6 metabolic equivalents (Quintile 2), 7.6-8.6 metabolic equivalents (Quintile 3), 8.6-9.5 metabolic equivalents (Quintile 4), >9.5 metabolic equivalents (Quintile 5). Body mass index, waist circumference, and HbA1c all decreased between increasing non-exercise testing method for estimating fitness quintiles (p < 0.05), as did risk prediction scores in each of the five assessments/questionnaires (p < 0.05). The proportion of females in Quintile 1 predicted at 'high risk' was between 20.9% and 81.4%, depending on diabetes risk assessment used, compared to none of the females in Quintile 5. A calculated non exercise testing method for estimating fitness <6.8 metabolic equivalents could help to identify females at 'high risk' of developing type 2 diabetes mellitus as predicted using five risk assessments/questionnaires. PMID- 27941052 TI - Role of endoplasmic reticulum stress signalling in diabetic endothelial dysfunction and atherosclerosis. AB - It is well established that diabetes mellitus accelerates atherosclerotic vascular disease. Endothelial injury has been proposed to be the initial event in the pathogenesis of atherosclerosis. Endothelium not only acts as a semi selective barrier but also serves physiological and metabolic functions. Diabetes or high glucose in circulation triggers a series of intracellular responses and organ damage such as endothelial dysfunction and apoptosis. One such response is high glucose-induced chronic endoplasmic reticulum stress in the endothelium. The unfolded protein response is an acute reaction that enables cells to overcome endoplasmic reticulum stress. However, when chronically persistent, endoplasmic reticulum stress response could ultimately lead to endothelial dysfunction and atherosclerosis. Herein, we discuss the scientific advances in understanding endoplasmic reticulum stress-induced endothelial dysfunction, the pathogenesis of diabetes-accelerated atherosclerosis and endoplasmic reticulum stress as a potential target in therapies for diabetic atherosclerosis. PMID- 27941057 TI - Interdisciplinary treatment of diabetic foot wounds in the elderly: Low risk of amputations and mortality and good chance of being mobile with good quality of life. AB - AIMS: A major proportion of patients with diabetic foot syndrome are older than 65 years. Little is known about outcomes of these elderly patients. METHODS: We analysed 245 treatment cases in an observational single-centre study for comorbidities and outcomes over a 6-month period. RESULTS: In all, 122 patients had peripheral arterial disease which was significantly increasing with age (n = 245, df = 1, chi2 = 23.06, p ? 0.0001). Increasing age correlated positively with decreasing rate of revascularisations (n = 122, df = 1, chi2 = 4.23, p = 0.039). In total, 23 (9.3%) patients died in the observation period. In-hospital mortality was 2.8%, percentage of major amputations 2.8%. In the invasively treated subgroup, 13 out of 67 patients died within the observation period. Death after revascularisation was independent of age (n = 67, df = 1, chi2 = 2.05, p = 0.153). Mobility decreased in the whole study group with increasing age. The risk of decrease with age was not influenced by revascularisation status. CONCLUSION: With careful interdisciplinary evaluation, elderly patients with diabetic foot syndrome can be treated with favourable outcome. Mobility before and after treatment deserves more attention as a predictor of treatment success and outcome parameter. PMID- 27941059 TI - Revascularization of Unprotected Left Main Coronary Artery Disease: Implications of Evolving Data on Clinical Practice. PMID- 27941058 TI - Acute effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate responses to intraduodenal glucose infusion in type 2 diabetes. AB - AIM: To evaluate the effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate during an intraduodenal glucose infusion in type 2 diabetes. METHODS: Nine subjects with type 2 diabetes were randomised to receive intravenous exenatide or saline control in a crossover design. Glucose (3 kcal min-1) was infused via an intraduodenal manometry catheter for 60 min. Blood pressure, heart rate, and the frequency and amplitude of duodenal pressure waves were measured at regular intervals. Gastrointestinal symptoms were monitored using 100 mm visual analogue scales. RESULTS: During intraduodenal glucose infusion (0-60 min), diastolic (p(0-60) = 0.03) and mean arterial (p(0-60) = 0.03) blood pressures and heart rate (p(0-60) = 0.06; p(0 120) = 0.03)) were higher with exenatide compared to placebo. The increase in the area under the curve for diastolic blood pressure and mean arterial blood pressure was related directly to the suppression of the duodenal motility index with exenatide compared to control (p = 0.007 and 0.04, respectively). CONCLUSION: In type 2 diabetes, intravenous exenatide increases mean arterial blood pressure and heart rate during an intraduodenal glucose infusion, supporting the need for further research with exenatide for its potential use in postprandial hypotension. PMID- 27941060 TI - Effects of a structured exercise programme in sedentary dogs with chronic diarrhoea. AB - The aim of this investigation was to evaluate the effects of a structured exercise programme in sedentary dogs with chronic diarrhoea. Twenty-two dogs were enrolled in the study. All dogs received oral prednisolone (1 mg/kg/day for 14 days, followed by a tapering dosage) for 10 weeks. After four weeks of prednisolone treatment, dogs were assigned to either the exercise or control group (n=11 each). Owners of dogs in the exercise group were instructed to guide their dogs in structured exercise training (low-intensity to moderate-intensity aerobic and resistance exercise three to five days per week). After 10 weeks of prednisolone treatment with concomitant 6 weeks of complementary exercise, the Canine Inflammatory Bowel Disease Activity Index (CIBDAI) score had decreased significantly in the exercise group (from 8.8+/-1.5 at the start of the exercise programme to 2.4+/-1.5; P<0.001); no such change was observed in the control group (from 9.2+/-0.9 to 9.2+/-1.1). CIBDAI scores differed significantly between the groups at the end of the 10-week study period (P<0.001). The exercise programme affected all six CIBDAI parameters significantly; bodyweight (P<0.001, adjusted r2=0.722) was most affected. A structured exercise programme may have positive effects on clinical symptoms in sedentary dogs with chronic diarrhoea. PMID- 27941061 TI - Perceptions of responsibility and capability for treating wildlife casualties in UK veterinary practices. PMID- 27941062 TI - Can there be science without philosophy? AB - Over the last few decades, philosophy has gained an increasingly bad reputation among working scientists. Prominent researchers have suggested, in various forms and degrees of mockery, that philosophy has little or nothing positive to contribute to science. This essay provides a response to these allegations. We begin by examining, and ultimately questioning, an influential argument purporting to undermine the significance of a philosophical approach to science. Next, we offer some biomedical examples where philosophical speculation plays a prominent role. We conclude by arguing that, when understood in the appropriate context, philosophical reflection is an important-indeed, integral-ingredient of healthy scientific inquiry. PMID- 27941063 TI - Prognostic implications of adding urine output to serum creatinine measurements for staging of acute kidney injury after major surgery: a cohort study. AB - BACKGROUND: Current guidelines recommend staging acute kidney injury (AKI) according to the serum creatinine (SCr) or urine output (UO) criteria that achieve the highest stage. There is little information about the implications of adding UO to SCr measurements for staging AKI outside intensive care units and after cardiac surgery. METHODS: We performed a cohort study of all adults without end-stage renal disease who underwent major noncardiac surgery between January 2005 and March 2011 in Calgary, AB, Canada. Participants required at least two SCr and UO measurements to be included. We examined the implications of adding UO to SCr to stage AKI based on Kidney Disease: Improving Global Outcomes criteria. Logistic and linear regression models were used to examine the associations between AKI stage and 30-day mortality or hospital length of stay (LOS), respectively. RESULTS: A total of 4229 (17%) surgical patients had sufficient SCr and UO measurements for inclusion in the cohort. The apparent incidence of postoperative AKI substantially increased with the addition of UO to SCr criteria (8.1% with SCr alone versus 64.0% with SCr and UO). Mortality for a given stage of AKI was lower when UO was added to SCr criteria (0.3, 3.2, 1.9 and 3.0% for no AKI and Stages 1, 2 and 3, respectively) versus with SCr alone (1.2, 4.2, 15.4 and 12.8%). However, among participants without AKI based on the SCr criterion, the odds of mortality and mean LOS both significantly increased with lower UO. Models that reclassified AKI stage based on UO in addition SCr criteria had the best discrimination for mortality and LOS. CONCLUSIONS: Adding UO to SCr criteria substantially increases the apparent incidence of AKI on hospital wards and significantly changes the prognostic implications of AKI identification and staging. These measures should not be considered equivalent criteria in AKI staging. PMID- 27941065 TI - Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism. AB - BACKGROUND: Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL) cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies. METHODS: We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)-apolipoprotein B-100 (apoB), intermediate density lipoprotein-apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling. RESULTS: Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB (P<0.001 and P.032, respectively), intermediate-density lipoprotein-apoB (P=0.021 and P=.002, respectively), and LDL-apoB (P<0.001, both interventions). Evolocumab but not atorvastatin decreased the production rate of intermediate-density lipoprotein apoB (P=0.043) and LDL-apoB (P<0.001), which contributed to the reduction in the plasma pool sizes of these lipoprotein particles. The reduction in LDL-apoB and LDL-cholesterol concentrations was significantly greater with combination versus either monotherapy (P<0.001). Whereas evolocumab but not atorvastatin lowered the concentration of free PCSK9, atorvastatin lowered the lathosterol/campesterol ratio (a measure of cholesterol synthesis/absorption) and apoC-III concentration. Both interventions decreased plasma apoE, but neither significantly altered lipoprotein lipase and cholesteryl ester protein mass or measures of insulin resistance. CONCLUSIONS: In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 monoclonal antibodies incremental to statins in on-going clinical end point trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02189837. PMID- 27941067 TI - Association Between Preterm Birth and Lower Adult Height in Women. AB - We examined whether being born preterm was associated with changes in adult anthropometry in women. We assessed data on 201,382 women (born in 1973-1988) from the Swedish Birth Register. The mean age was 26.0 years. Of the women in our cohort, 663 were born very preterm (<32 weeks of gestation), 8,247 were born moderately preterm (at least 32 weeks but <37 weeks), and 192,472 were born at term (37-41 weeks). Subgroup analyses were carried out among siblings and also after adjustment for maternal anthropometric data. Statistical tests were 2 sided. Decreasing gestational age was associated with lower height (-1.1 mm per week of gestation; P < 0.0001), so that women who were born very preterm were on average 12 mm shorter than women who were born moderately preterm (P < 0.0001) and 17 mm shorter than women born at term (P < 0.0001). Compared with women who were born at term, those who were born very preterm had 2.9 times higher odds of short stature (<155.4 cm), and those born moderately preterm had 1.43 times higher odds. Subgroup analyses showed no differences between women born moderately preterm and those born at term but accentuated differences from women born very preterm. Among siblings (n = 2,388), very preterm women were 23 mm shorter than those born at term (P = 0.003), with a 20-mm difference observed in subgroup analyses (n = 27,395) that were adjusted for maternal stature (P < 0.001). A shorter final height was associated with decreasing gestational age, and this association was particularly marked in women born very preterm. PMID- 27941066 TI - Thrombus Aspiration in ST-Segment-Elevation Myocardial Infarction: An Individual Patient Meta-Analysis: Thrombectomy Trialists Collaboration. AB - BACKGROUND: Thrombus aspiration during percutaneous coronary intervention (PCI) for the treatment of ST-segment-elevation myocardial infarction (STEMI) has been widely used; however, recent trials have questioned its value and safety. In this meta-analysis, we, the trial investigators, aimed to pool the individual patient data from these trials to determine the benefits and risks of thrombus aspiration during PCI in patients with ST-segment-elevation myocardial infarction. METHODS: Included were large (n>=1000), randomized, controlled trials comparing manual thrombectomy and PCI alone in patients with ST-segment-elevation myocardial infarction. Individual patient data were provided by the leadership of each trial. The prespecified primary efficacy outcome was cardiovascular mortality within 30 days, and the primary safety outcome was stroke or transient ischemic attack within 30 days. RESULTS: The 3 eligible randomized trials (TAPAS [Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction], TASTE [Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia], and TOTAL [Trial of Routine Aspiration Thrombectomy With PCI Versus PCI Alone in Patients With STEMI]) enrolled 19 047 patients, of whom 18 306 underwent PCI and were included in the primary analysis. Cardiovascular death at 30 days occurred in 221 of 9155 patients (2.4%) randomized to thrombus aspiration and 262 of 9151 (2.9%) randomized to PCI alone (hazard ratio, 0.84; 95% confidence interval, 0.70-1.01; P=0.06). Stroke or transient ischemic attack occurred in 66 (0.8%) randomized to thrombus aspiration and 46 (0.5%) randomized to PCI alone (odds ratio, 1.43; 95% confidence interval, 0.98-2.10; P=0.06). There were no significant differences in recurrent myocardial infarction, stent thrombosis, heart failure, or target vessel revascularization. In the subgroup with high thrombus burden (TIMI [Thrombolysis in Myocardial Infarction] thrombus grade >=3), thrombus aspiration was associated with fewer cardiovascular deaths (170 [2.5%] versus 205 [3.1%]; hazard ratio, 0.80; 95% confidence interval, 0.65 0.98; P=0.03) and with more strokes or transient ischemic attacks (55 [0.9%] versus 34 [0.5%]; odds ratio, 1.56; 95% confidence interval, 1.02-2.42, P=0.04). However, the interaction P values were 0.32 and 0.34, respectively. CONCLUSIONS: Routine thrombus aspiration during PCI for ST-segment-elevation myocardial infarction did not improve clinical outcomes. In the high thrombus burden group, the trends toward reduced cardiovascular death and increased stroke or transient ischemic attack provide a rationale for future trials of improved thrombus aspiration technologies in this high-risk subgroup. CLINICAL TRIAL REGISTRATION: URLs: http://www.ClinicalTrials.gov http://www.crd.york.ac.uk/prospero/. Unique identifiers: NCT02552407 and CRD42015025936. PMID- 27941068 TI - Targeted Maximum Likelihood Estimation for Causal Inference in Observational Studies. AB - Estimation of causal effects using observational data continues to grow in popularity in the epidemiologic literature. While many applications of causal effect estimation use propensity score methods or G-computation, targeted maximum likelihood estimation (TMLE) is a well-established alternative method with desirable statistical properties. TMLE is a doubly robust maximum-likelihood based approach that includes a secondary "targeting" step that optimizes the bias variance tradeoff for the target parameter. Under standard causal assumptions, estimates can be interpreted as causal effects. Because TMLE has not been as widely implemented in epidemiologic research, we aim to provide an accessible presentation of TMLE for applied researchers. We give step-by-step instructions for using TMLE to estimate the average treatment effect in the context of an observational study. We discuss conceptual similarities and differences between TMLE and 2 common estimation approaches (G-computation and inverse probability weighting) and present findings on their relative performance using simulated data. Our simulation study compares methods under parametric regression misspecification; our results highlight TMLE's property of double robustness. Additionally, we discuss best practices for TMLE implementation, particularly the use of ensembled machine learning algorithms. Our simulation study demonstrates all methods using super learning, highlighting that incorporation of machine learning may outperform parametric regression in observational data settings. PMID- 27941071 TI - MyD88 adapter-like (Mal) is phosphorylated by Bruton's tyrosine kinase during TLR2 and TLR4 signal transduction. PMID- 27941070 TI - Phosphorylation of PP1 regulator Sds22 by PLK1 ensures accurate chromosome segregation. PMID- 27941069 TI - Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors: A Pooled Analysis of 13 Case-Control Studies. AB - Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation. PMID- 27941073 TI - Erratum: Differences and similarities in rheumatology speciality training programmes across European countries. PMID- 27941072 TI - Is it time to revisit the role of ultrasound in rheumatoid arthritis management? AB - For over a decade, a large number of studies have highlighted the benefits of ultrasound (US) in the diagnosis and management of rheumatic diseases, especially rheumatoid arthritis (RA). However, its benefits in routine practice have been less studied and trials examining US as part of various clinical strategies are just emerging, with recent randomised trials examining the added value of US in tight-control paradigms. The conclusions of these trials have raised questions on the role of US in RA management. This Viewpoint analyses the recent studies, and discusses potential limitations in study designs as well as the methodological challenges of assessing the added value of an imaging technique. PMID- 27941074 TI - Cartilage rings contribute to the proper embryonic tracheal epithelial differentiation, metabolism, and expression of inflammatory genes. AB - The signaling cross talk between the tracheal mesenchyme and epithelium has not been researched extensively, leaving a substantial gap of knowledge in the mechanisms dictating embryonic development of the proximal airways by the adjacent mesenchyme. Recently, we reported that embryos lacking mesenchymal expression of Sox9 did not develop tracheal cartilage rings and showed aberrant differentiation of the tracheal epithelium. Here, we propose that tracheal cartilage provides local inductive signals responsible for the proper differentiation, metabolism, and inflammatory status regulation of the tracheal epithelium. The tracheal epithelium of mesenchyme-specific Sox9Delta/Delta mutant embryos showed altered mRNA expression of various epithelial markers such as Pb1fa1, surfactant protein B (Sftpb), secretoglobulin, family 1A, member 1 (Scgb1a1), and trefoil factor 1 (Tff1). In vitro tracheal epithelial cell cultures confirmed that tracheal chondrocytes secrete factors that inhibit club cell differentiation. Whole gene expression profiling and ingenuity pathway analysis showed that the tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and transforming growth factor-beta (TGF-beta) signaling pathways were significantly altered in the Sox9 mutant trachea. TNF-alpha and IFN gamma interfered with the differentiation of tracheal epithelial progenitor cells into mature epithelial cell types in vitro. Mesenchymal knockout of Tgf-beta1 in vivo resulted in altered differentiation of the tracheal epithelium. Finally, mitochondrial enzymes involved in fat and glycogen metabolism, cytochrome c oxidase subunit VIIIb (Cox8b) and cytochrome c oxidase subunit VIIa polypeptide 1 (Cox7a1), were strongly upregulated in the Sox9 mutant trachea, resulting in increases in the number and size of glycogen storage vacuoles. Our results support a role for tracheal cartilage in modulation of the differentiation and metabolism and the expression of inflammatory-related genes in the tracheal epithelium by feeding into the TNF-alpha, IFN-gamma, and TGF-beta signaling pathways. PMID- 27941075 TI - deltabetagamma-ENaC is inhibited by CFTR but stimulated by cAMP in Xenopus laevis oocytes. AB - The epithelial sodium channel (ENaC) and the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel critically regulate airway surface liquid by driving fluid absorption and secretion, respectively. Their functional interplay is complex and incompletely understood. ENaC is a heteromeric channel with three well-characterized subunits (alpha, beta, and gamma). In humans, an additional delta-ENaC subunit exists in lung and several other tissues, where it may replace the alpha-subunit to form deltabetagamma-ENaC. Little is known about the physiological role of deltabetagamma-ENaC and its possible interaction with CFTR. The aim of the present study was to investigate the effect of human CFTR on human deltabetagamma-ENaC heterologously expressed in Xenopus laevis oocytes. In oocytes coexpressing deltabetagamma-ENaC and CFTR the ENaC-mediated amiloride sensitive whole cell current (DeltaIami) was reduced by ~50% compared with that measured in oocytes expressing deltabetagamma-ENaC alone. Moreover, basal level of proteolytic ENaC activation was reduced in the presence of CFTR. The inhibitory effect of CFTR on deltabetagamma-ENaC was due to a combination of decreased average open probability (Po) and reduced channel expression at the cell surface. Interestingly, in oocytes expressing deltabetagamma-ENaC, increasing intracellular [cAMP] by IBMX and forskolin increased DeltaIami by ~50%. This stimulatory effect was not observed for human and rat alphabetagamma ENaC and was independent of CFTR coexpression and coactivation. Experiments with a mutant channel (deltabetaS520Cgamma-ENaC) which can be converted to a channel with a Po of nearly 1 suggested that cAMP activates deltabetagamma-ENaC by increasing Po In conclusion, our results demonstrate that deltabetagamma-ENaC is inhibited by CFTR but activated by cAMP. PMID- 27941076 TI - Airway smooth muscle tone increases airway responsiveness in healthy young adults. AB - Force adaptation, a process whereby sustained spasmogenic activation (viz., tone) of airway smooth muscle (ASM) increases its contractile capacity, has been reported in isolated ASM tissues in vitro, as well as in mice in vivo. The objective of the present study was to assess the effect of tone on airway responsiveness in humans. Ten healthy volunteers underwent methacholine challenge on two occasions. One challenge consisted of six serial doses of saline followed by a single high dose of methacholine. The other consisted of six low doses of methacholine 5 min apart followed by a higher dose. The cumulative dose was identical for both challenges. After both methacholine challenges, subjects took a deep inspiration (DI) to total lung capacity as another way to probe ASM mechanics. Responses to methacholine and the DI were measured using a multifrequency forced oscillation technique. Compared with a single high dose, the challenge preceded by tone led to an elevated response measured by respiratory system resistance (Rrs) and reactance at 5 Hz. However, there was no difference in the increase in Rrs at 19 Hz, suggesting a predominant effect on smaller airways. Increased tone also reduced the efficacy of DI, measured by an attenuated maximal dilation during the DI and an increased renarrowing post-DI. We conclude that ASM tone increases small airway responsiveness to inhaled methacholine and reduces the effectiveness of DI in healthy humans. This suggests that force adaptation may contribute to airway hyperresponsiveness and the reduced bronchodilatory effect of DI in asthma. PMID- 27941078 TI - High HIV incidence among young black men who have sex with men: constructing a retrospective cohort from a community health programme. AB - OBJECTIVES: We sought to calculate HIV incidence in a retrospective cohort of young (13-29 years old) black men who have sex with men (YBMSM) accessing repeated HIV-antibody testing in a mid-size city in the USA. METHODS: We aggregated site-specific HIV-antibody testing results from the project's inception among YBMSM who received an initial negative result and accessed at least one additional HIV-antibody test. From these data, we assessed number of seroconversions and person-years and calculated HIV incidence using a mid-P exact test to estimate 95% CIs. RESULTS: Five seroconversions were documented over 42.3 person-years (the mean age at first onsite test: 19.7 years), resulting in an HIV incidence rate of 11.8% (95% CI 4.3% to 26.2%). The mean age at seroconversion was 20.4 (+/-3.0) years. CONCLUSIONS: Even in mid-size cities with low HIV prevalence rates in the general population, HIV incidence among YBMSM may be high. Community-based HIV-antibody testing organisations serving YBMSM should be encouraged and trained to track repeated HIV testing and calculate HIV incidence rates. Increased resources should be deployed to develop and encourage regular HIV testing in community health sites serving YBMSM. PMID- 27941077 TI - Posttranslational modification of beta-catenin is associated with pathogenic fibroblastic changes in bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD) is a common complication of premature birth. The histopathology of BPD is characterized by an arrest of alveolarization with fibroblast activation. The Wnt/beta-catenin signaling pathway is important in early lung development. When Wnt signaling is active, phosphorylation of beta catenin by tyrosine kinases at activating sites, specifically at tyrosine 489 (Y489), correlates with nuclear localization of beta-catenin. We examined fetal lung tissue, lung tissue from term newborns, and lung tissue from infants who died with BPD; we found nuclear beta-catenin phosphorylation at Y489 in epithelial and mesenchymal cells in fetal tissue and BPD tissue, but not in the lungs of term infants. Using a 3D human organoid model, we found increased nuclear localization of beta-catenin phosphorylated at Y489 (p-beta-cateninY489) after exposure to alternating hypoxia and hyperoxia compared with organoids cultured in normoxia. Exogenous stimulation of the canonical Wnt pathway in organoids was sufficient to cause nuclear localization of p-beta-cateninY489 in normoxia and mimicked the pattern of alpha-smooth muscle actin (alpha-SMA) expression seen with fibroblastic activation from oxidative stress. Treatment of organoids with a tyrosine kinase inhibitor prior to cyclic hypoxia-hyperoxia inhibited nuclear localization of p-beta-cateninY489 and prevented alpha-SMA expression by fibroblasts. Posttranslational phosphorylation of beta-catenin is a transient feature of normal lung development. Moreover, the persistence of p-beta cateninY489 is a durable marker of fibroblast activation in BPD and may play an important role in BPD disease pathobiology. PMID- 27941080 TI - Drug-drug interactions in patients receiving tyrosine kinase inhibitors. AB - Rationale Tyrosine kinase inhibitors are increasingly used in the treatment of cancer. Drug interactions involving tyrosine kinase inhibitors are commonly encountered in clinical practice. The objective of this study was to describe the frequency of tyrosine kinase inhibitor-associated drug interactions among a cohort of oncology patients. Methods Adult patients were included who presented to either of two outpatient oncology practices and were prescribed a tyrosine kinase inhibitor during 2 January 2013 to 1 January 2015. Demographic and medication data were abstracted from electronic medical records. Lexicomp(r), Micromedex Solutions(r), and medication labeling were utilized to identify potential interactions between tyrosine kinase inhibitors and concomitant medications. Interactions were then assessed by the investigators for clinical significance. The primary outcome was the frequency of significant drug interactions involving tyrosine kinase inhibitors and concomitant medications. Secondary outcomes included describing the nature and clinical impact of interactions, and describing interactions by medication class. Results A total of 356 patients were identified for analysis, in whom 244 potential interactions were identified, and 109 (44.7%) of which were considered severe. Decreased tyrosine kinase inhibitor absorption due to acid suppressive therapy and CYP3A4 interactions were the most frequent mechanisms of potential subtherapeutic and supratherapeutic concentrations, respectively. Potential clinical consequences included QTc prolongation ( n = 53, 48.6%), decreased tyrosine kinase inhibitor concentration ( n = 53, 48.6%), and increased tyrosine kinase inhibitor concentration ( n = 3, 2.8%). Conclusions Safer alternative therapy and/or more frequent clinical monitoring should be considered if an interaction poses a significant risk of increased tyrosine kinase inhibitor toxicity or decreased tyrosine kinase inhibitor efficacy. Oncology pharmacists can play a role in screening for tyrosine kinase inhibitor-associated interactions, recommending alternative therapies or dosing strategies, and monitoring tyrosine kinase inhibitor efficacy and toxicity. PMID- 27941079 TI - The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 3: The Clinical Guidelines. AB - Background: The current paper introduces the actual International College of Neuro-Psychopharmacology clinical guidelines for the treatment of bipolar disorder. Concept and structure of the guidelines: The current clinical guidelines are based on evidence-based data, but they also intend to be clinically useful, while a rigid algorithm was developed on the basis of firm evidence alone. Monotherapy was prioritized over combination therapy. There are separate recommendations for each of the major phases of bipolar disorder expressed as a 5-step algorithm. Discussion: The current International College of Neuro-Psychopharmacology clinical guidelines for the treatment of bipolar disorder are the most up-to-date guidance and are as evidence based as possible. They also include recommendations concerning the use of psychotherapeutic interventions, again on the basis of available evidence. This adherence of the workgroup to the evidence in a clinically oriented way helped to clarify the role of specific antidepressants and traditional agents like lithium, valproate, or carbamazepine. The additional focus on specific clinical characteristics, including predominant polarity, mixed features, and rapid cycling, is also a novel approach. Many issues need further studies, data are sparse and insufficient, and many questions remain unanswered. The most important and still unmet need is to merge all the guidelines that concern different phases of the illness into a single one and in this way consider BD as a single unified disorder, which is the real world fact. However, to date the research data do not permit such a unified approach. PMID- 27941082 TI - Parental Perceptions of Pediatric Pain and POTS-Related Disability. AB - Adolescents with postural orthostatic tachycardia syndrome (POTS) often have pain and functional impairment. This study evaluated how parental attributions of children's symptoms relate to child functional impairment. Adolescents with chronic pain and clinical symptoms suggestive of autonomic dysfunction (fatigue, dizziness, nausea) that attended a multidisciplinary chronic pain clinic completed measures of depression, anxiety, and functioning (n = 141). Parents of 114 of these patients completed the Parent Pain Attribution Questionnaire (PPAQ), a measure indicating the extent they believe physical and psychosocial factors account for their child's health condition. Patients were retrospectively grouped as to whether or not they had significant POTS on tilt table testing (n = 37). Greater parental attribution to physical causes was associated with increased levels of functional disability whether patients had POTS ( r = 0.45, P = .006) or not ( r = 0.25, P = .03). These results suggest that providers should advocate a more comprehensive family-oriented rehabilitative approach to treatment. PMID- 27941083 TI - Prediabetes in Obese Adolescents. PMID- 27941081 TI - A Multivariate Mixture Model to Estimate the Accuracy of Glycosaminoglycan Identifications Made by Tandem Mass Spectrometry (MS/MS) and Database Search. AB - We present a statistical model to estimate the accuracy of derivatized heparin and heparan sulfate (HS) glycosaminoglycan (GAG) assignments to tandem mass (MS/MS) spectra made by the first published database search application, GAG-ID. Employing a multivariate expectation-maximization algorithm, this statistical model distinguishes correct from ambiguous and incorrect database search results when computing the probability that heparin/HS GAG assignments to spectra are correct based upon database search scores. Using GAG-ID search results for spectra generated from a defined mixture of 21 synthesized tetrasaccharide sequences as well as seven spectra of longer defined oligosaccharides, we demonstrate that the computed probabilities are accurate and have high power to discriminate between correctly, ambiguously, and incorrectly assigned heparin/HS GAGs. This analysis makes it possible to filter large MS/MS database search results with predictable false identification error rates. PMID- 27941084 TI - Persistent Gaps in Appropriate Use of Empiric Acyclovir in Neonates. AB - The use of empiric acyclovir for suspected neonatal herpes simplex virus (HSV) infection has been debated for years. To identify the gap in the decision to initiate empiric acyclovir, we performed a retrospective chart review and administered a survey to pediatricians to assess current practices regarding evaluation for possible HSV infection. Seventy infants received empiric acyclovir over a 1-year period; of these, 3 infants (4.3%) had positive HSV testing. Fourteen infants were identified as "high-risk" for HSV infection; of these, 13 infants had incomplete testing. Survey results revealed uncertainty in the decision to initiate acyclovir and in the composition of complete diagnostic testing. This study confirmed the clinical uncertainty in the decision to initiate empiric acyclovir. Using this chart review and survey as a baseline, future efforts will focus on a quality improvement project to reduce empiric acyclovir use in low-risk infants and to ensure complete diagnostic evaluation in high-risk infants. PMID- 27941085 TI - A Healthy Infant Incidentally Presenting With Low SpO2: The Pitfalls of Pulse Oximetry. PMID- 27941086 TI - Onychocryptosis in the Pediatric Patient. PMID- 27941088 TI - Initial Results of an Evidence-Based Safe Patient Handling and Mobility Program to Decrease Hospital Worker Injuries. AB - The rate for musculoskeletal injuries among health care workers is one of the highest for all industrial sectors in the United States; these injuries often occur during manual handling (i.e., lifting, moving, transferring, and repositioning) of patients. The following article describes the process used to complete a comprehensive assessment, as well as the planning, implementation, and initial evaluation of a quality improvement program to reduce work-related musculoskeletal disorders (WMSD) among health care workers employed by a rural Midwest hospital. Key elements for WMSD injury reduction were identified and compared across literature sources, national standards, and current state and federal legislative requirements for hospitals. The program used a multi-factor design that included evidence-based interventions (i.e., those supported by emerging evidence) to create a comprehensive Safe Patient Handling and Mobility (SPHM) program intended to address the unique needs of the organization. Initial program results are reviewed as well as significant considerations and challenges for SPHM programs. PMID- 27941087 TI - Enhancing the Safety Climate and Reducing Violence Against Staff in Closed Hospital Wards. AB - This study examined the effectiveness of an intervention program to enhance unit safety climate and minimize employee risk of injury from patient violence. The intervention program, including a 3-day workshop, was offered to personnel on maximum security units of an Israeli psychiatric hospital. Safety climate was examined before and after the implementation of the intervention, and incidents of patient violence were investigated. Six months after the intervention, a significant improvement in employees' perceptions of management's commitment to safety as well as a marginally significant improvement in communication about safety issues were found. This study demonstrated that an intervention program to enhance safety climate was associated with a decrease in the number of aggressive incidents. The researchers concluded that this intervention program is likely to return a sense of safety to workers and reduce workplace violence. PMID- 27941089 TI - Evaluation of Stress Experienced by Emergency Telecommunications Personnel Employed in a Large Metropolitan Police Department. AB - Emergency telecommunications personnel (ETCP) form the hub of police agencies and persistently deal with distressing situations on a daily basis, making them highly susceptible to psychological and physiological ailments. To date, few studies have examined the necessity or feasibility of implementing a resilience training intervention for ETCP. In this study, the authors assessed baseline psychological data from the ETCP of a large police department to determine the differences in baseline measures for ETCP and police officers. Participants included ETCP ages 29 to 64 years ( n = 19). Results showed that ETCP self reported greater levels of psychological stress compared with police officers ( p < .05) for the majority of measures; ETCP experience excessive levels of stress and greater prevalence of chronic disease. Consideration should be given to piloting resilience interventions within this group to manage stress; improve health, performance, and decision making; and decrease the prevalence of chronic disease. PMID- 27941092 TI - Molecular phylogeny, biogeography and ecological niche modelling of Cardiocrinum (Liliaceae): insights into the evolutionary history of endemic genera distributed across the Sino-Japanese floristic region. AB - BACKGROUND AND AIMS: The patterns of evolutionary assembly in the Sino-Japanese floristic region (SJFR) remain largely unknown due to a lack of integrative multidimensional studies throughout the region. To address this issue, we elucidated the evolutionary history of Cardiocrinum (Liliaceae), a genus containing four taxa distributed across the SJFR. METHODS: Fifty-four populations were sampled throughout the geographical range of Cardiocrinum to assess genetic structure, analyse phylogenetic relationships and reconstruct ancestral area based on six chloroplast DNA (cpDNA) fragments and three low copy nuclear genes (LCNG). Ecological niche modelling was used to examine the potential range shifts of Cardiocrinum in response to climatic change. KEY RESULTS: The molecular data showed high genetic similarity in the cpDNA (98.37 %) and LCNG (94.53 %) sequences. The biogeographical analyses revealed that the ancestor of Cardiocrinum diversified during the late Miocene (approx. 7.32 Mya) in Central China. The ancestor of the C. giganteum lineage dispersed westward to the Himalayas and south-west China with the split between C. giganteum and C. giganteum var. yunnanense occurring around 4.11 Mya consistent with the period of orogeny of the Hengduan Mountains. Some populations of the C. cathayanum lineage dispersed eastward to south Japan via the land bridge approx. 4.97 Mya, providing opportunities for allopatric speciation of C. cordatum The predicted suitable habitats of Cardiocrinum have become smaller and more fragmented since the Last Glacial Maximum. CONCLUSIONS: Our study provides evidence of a biogeographical pattern of dispersal from Central China to the Himalayas in the west and Japan in the east for genera distributed across the SJFR, and highlights that the orogeny of the Hengduan Mountains and fluctuations of the sea level of the East China Sea played important roles in promoting species divergence. PMID- 27941091 TI - Underexplored biodiversity of Eastern Mediterranean biota: systematics and evolutionary history of the genus Aubrieta (Brassicaceae). AB - BACKGROUND AND AIMS: Aubrieta is a taxonomically difficult genus from the Brassicaceae family with approximately 20 species centred in Turkey and Greece. Species boundaries and their evolutionary history are poorly understood. Therefore, we analysed bio- and phylogeographic relationships and evaluated morphological variation to study the evolution of this genus. METHODS: Phylogenetic analyses of DNA sequence variation of nuclear-encoded loci and plastid DNA were used to unravel phylogeographic patterns. Morphometric analyses were conducted to study species delimitation. DNA sequence-based mismatch distribution and climate-niche analyses were performed to explain various radiations in space and time during the last 2.5 million years. KEY RESULTS: Species groups largely show non-overlapping distribution patterns in the eastern Mediterranean and Asia Minor. We recognized 20 species and provide evidence for overlooked species, thereby highlighting taxonomical difficulties but also demonstrating underexplored species diversity. The centre of origin of Aubrieta is probably Turkey, from which various clades expanded independently towards Asia Minor, south to Lebanon and west to Greece and the Balkans during the Pleistocene. CONCLUSIONS: Pleistocene climatic fluctuations had a pronounced effect on Aubrieta speciation and radiation during the last 1.1 million years in the Eastern Mediterranean and Asia Minor. In contrast to many other Brassicaceae, speciation processes did not involve excessive formation of polyploids, but displayed formation of diploids with non-overlapping present-day distribution areas. Expansions from the Aubrieta centre of origin and primary centre of species diversity showed adaptation trends towards higher temperature and drier conditions. However, later expansion and diversification of taxa from within the second centre of species diversity in Greece started ~0.19 Mya and were associated with a general transition of species adaptation towards milder temperatures and less dry conditions. PMID- 27941093 TI - Seed-predator satiation and Janzen-Connell effects vary with spatial scales for seed-feeding insects. AB - BACKGROUND AND AIMS: The Janzen-Connell model predicts that common species suffer high seed predation from specialized natural enemies as a function of distance from parent trees, and consequently as a function of conspecific density, whereas the predator satiation hypothesis predicts that seed attack is reduced due to predator satiation at high seed densities. Pre-dispersal predation by insects was studied while seeds are still on parent trees, which represents a frequently overlooked stage in which seed predation occurs. METHODS: Reproductive tree density and seed production were investigated from ten Quercus serrata populations located in south-west China, quantifying density-dependent pre dispersal seed predation over two years by three insect groups. KEY RESULTS: Acorn infestation was nearly twice as high in the low-seed year as that in the high-seed year, with considerable spatio-temporal variation in the direction and magnitude of density-dependent pre-dispersal seed predation evident. Across whole populations of trees, a high density of reproductive trees caused predator satiation and reduced insect attack in the high-seed year. Within individual trees, and consistent with the Janzen-Connell model, overall insect seed predation was positively correlated with seed production in the low-seed year. In addition, there was variation among insect taxa, with positive density-dependent seed predation by Curculio weevils in the high-seed year and moths in the low seed year, but apparent density independence by Cyllorhynchites weevils in both years. CONCLUSIONS: The overall trend of negative density-dependent, pre dispersal seed predation suggests that predator satiation limited the occurrence of Janzen-Connell effects across Q. serrata populations. Such effects may have large impacts on plant population dynamics and tree diversity, depending on the extent to which they are reduced by counteracting positive density-dependent predation for seeds on individual trees and other factors affecting successful recruitment. PMID- 27941090 TI - Modulation of host plant immunity by Tobamovirus proteins. AB - Background: To establish successful infection, plant viruses produce profound alterations of host physiology, disturbing unrelated endogenous processes and contributing to the development of disease. In tobamoviruses, emerging evidence suggests that viral-encoded proteins display a great variety of functions beyond the canonical roles required for virus structure and replication. Among these, their modulation of host immunity appears to be relevant in infection progression. Scope: In this review, some recently described effects on host plant physiology of Tobacco mosaic virus (TMV)-encoded proteins, namely replicase, movement protein (MP) and coat protein (CP), are summarized. The discussion is focused on the effects of each viral component on the modulation of host defense responses, through mechanisms involving hormonal imbalance, innate immunity modulation and antiviral RNA silencing. These effects are described taking into consideration the differential spatial distribution and temporality of viral proteins during the dynamic process of replication and spread of the virus. Conclusion: In discussion of these mechanisms, it is shown that both individual and combined effects of viral-encoded proteins contribute to the development of the pathogenesis process, with the host plant's ability to control infection to some extent potentially advantageous to the invading virus. PMID- 27941095 TI - 100-million-year-old conifer tissues from the mid-Cretaceous amber of Charente (western France) revealed by synchrotron microtomography. AB - BACKGROUND AND AIMS: Terrestrial plant remains in fossilized tree resin are relatively common. However, histology and preservation of plants entombed in Cretaceous ambers remain poorly known. We report an exquisitely preserved conifer leafy axis from 100-million-year-old opaque amber of western France that is assignable to Glenrosa carentonensis Moreau, Neraudeau, Tafforeau & Depre. The purpose of this paper is to discuss the taphonomy and the use of microtomography for studies of palaeobotanical remains in amber. METHODS: A leafy axis was examined using propagation phase-contrast X-ray synchrotron microtomography with voxel sizes of 14.9, 1.4, and 0.7 MUm. KEY RESULTS: The conifer leafy axis described is preserved in three dimensions. Despite desiccation of the specimen within the surrounding amber, the cuticle, as well as most of inner tissues, is preserved in three dimensions down to the cellular level. Epidermis, palisade parenchyma, spongy parenchyma, transfusion tracheids and vascular bundles are clearly distinguished. CONCLUSIONS: Gross morphology and histology of the specimen were revealed using synchrotron microtomography, allowing an unprecedented resolution for the study of soft-bodied plants entombed in amber. The study reveals a peculiar combination of authigenic and duripartic preservation as well as permineralization, and highlights the complexity of taphonomic processes that can occur in amber inclusions. This fossil demonstrates the difficulty of studying amber-preserved plant remains under certain conditions. PMID- 27941097 TI - A comparative study of cognitive behavioural therapy and shared reading for chronic pain. AB - The case for psychosocial interventions in relation to chronic pain, one of the most common health issues in contemporary healthcare, is well-established as a means of managing the emotional and psychological difficulties experienced by sufferers. Using mixed methods, this study compared a standard therapy for chronic pain, cognitive behavioural therapy (CBT), with a specific literature based intervention, shared reading (SR) developed by national charity, The Reader. A 5-week CBT group and a 22-week SR group for patients with chronic pain ran in parallel, with CBT group members joining the SR group after the completion of CBT. In addition to self-report measures of positive and negative affect before and after each experience of the intervention, the 10 participants kept twice-daily (12-hourly) pain and emotion diaries. Qualitative data were gathered via literary-linguistic analysis of audio/video-recordings and transcriptions of the CBT and SR sessions and video-assisted individual qualitative interviews with participants. Qualitative evidence indicates SR's potential as an alternative or long-term follow-up or adjunct to CBT in bringing into conscious awareness areas of emotional pain otherwise passively suffered by patients with chronic pain. In addition, quantitative analysis, albeit of limited pilot data, indicated possible improvements in mood/pain for up to 2 days following SR. Both findings lay the basis for future research involving a larger sample size. PMID- 27941094 TI - The Fusarium crown rot pathogen Fusarium pseudograminearum triggers a suite of transcriptional and metabolic changes in bread wheat (Triticum aestivum L.). AB - Background and Aims: Fusarium crown rot caused by the fungal pathogen Fusarium pseudograminearum is a disease of wheat and barley, bearing significant economic cost. Efforts to develop effective resistance to this disease have been hampered by the quantitative nature of resistance and a lack of understanding of the factors associated with resistance and susceptibility. Here, we aimed to dissect transcriptional responses triggered in wheat by F. pseudograminearum infection. Methods: We used an RNA-seq approach to analyse host responses during a compatible interaction and identified >2700 wheat genes differentially regulated after inoculation with F. pseudograminearum . The production of a few key metabolites and plant hormones in the host during the interaction was also analysed. Key Results: Analysis of gene ontology enrichment showed that a disproportionate number of genes involved in primary and secondary metabolism, signalling and transport were differentially expressed in infected seedlings. A number of genes encoding pathogen-responsive uridine-diphosphate glycosyltransferases (UGTs) potentially involved in detoxification of the Fusarium mycotoxin deoxynivalenol (DON) were differentially expressed. Using a F. pseudograminearum DON-non-producing mutant, DON was shown to play an important role in virulence during Fusarium crown rot. An over-representation of genes involved in the phenylalanine, tryptophan and tyrosine biosynthesis pathways was observed. This was confirmed through metabolite analyses that demonstrated tryptamine and serotonin levels are induced after F. pseudograminearum inoculation. Conclusions: Overall, the observed host response in bread wheat to F. pseudograminearum during early infection exhibited enrichment of processes related to pathogen perception, defence signalling, transport and metabolism and deployment of chemical and enzymatic defences. Additional functional analyses of candidate genes should reveal their roles in disease resistance or susceptibility. Better understanding of host responses contributing to resistance and/or susceptibility will aid the development of future disease improvement strategies against this important plant pathogen. PMID- 27941098 TI - From Face/Off to the face race: the case of Isabelle Dinoire and the future of the face transplant. AB - Isabelle Dinoire, the world's first face transplant recipient has died, 11 years after the procedure that brought her unwanted fame and media attention. While medical debates centre mainly on ethical and medical concerns like immunosuppressant use, the psychological hazards of face transplants are still being overlooked. Using medical and media reports and examining the gendering of clinical and patient narratives, this article argues we need to look again at face transplants and their motivation for individuals as well as society. PMID- 27941096 TI - Maintenance of mixed mating after the loss of self-incompatibility in a long lived perennial herb. AB - BACKGROUND AND AIMS: Many hermaphroditic plants avoid self-fertilization by means of a molecular self-incompatibility (SI) system, a complex trait that is difficult to evolve but relatively easy to lose. Loss of SI is a prerequisite for an evolutionary transition from obligate outcrossing to self-fertilization, which may bring about rapid changes in the genetic diversity and structure of populations. Loss of SI is also often followed by the evolution of a 'selfing syndrome', with plants having small flowers, little nectar and few pollen grains per ovule. Here, we document the loss of SI in the long-lived Spanish toadflax Linaria cavanillesii, which has led to mixed mating rather than a transition to a high rate of selfing and in which an outcrossing syndrome has been maintained. METHODS: We performed crosses within and among six populations of L. cavanillesii in the glasshouse, measured floral traits in a common-garden experiment, performed a pollen-limitation experiment in the field and conducted population genetic analyses using microsatellites markers. KEY RESULTS: Controlled crosses revealed variation in SI from fully SI through intermediate SI to fully self compatible (SC). Flowers of SC individuals showed no evidence of a selfing syndrome. Although the SC population of L. cavanillesii had lower within population genetic diversity than SI populations, as expected, population differentiation among all populations was extreme and represents an FST outlier in the distribution for both selfing and outcrossing species of flowering plants. CONCLUSIONS: Together, our results suggest that the transition to SC in L. cavanillesii has probably been very recent, and may have been aided by selection during or following a colonization bottleneck rather than in the absence of pollinators. We find little indication that the transition to SC has been driven by selection for reproductive assurance under conditions currently prevailing in natural populations. PMID- 27941101 TI - Feasibility of Malaria Diagnosis and Management in Burkina Faso, Nigeria, and Uganda: A Community-Based Observational Study. AB - BACKGROUND: Malaria-endemic countries are encouraged to increase, expedite, and standardize care based on parasite diagnosis and treat confirmed malaria using oral artemisinin-based combination therapy (ACT) or rectal artesunate plus referral when patients are unable to take oral medication. METHODS: In 172 villages in 3 African countries, trained community health workers (CHWs) assessed and diagnosed children aged between 6 months and 6 years using rapid histidine rich protein 2 (HRP2)-based diagnostic tests (RDTs). Patients coming for care who could take oral medication were treated with ACTs, and those who could not were treated with rectal artesunate and referred to hospital. The full combined intervention package lasted 12 months. Changes in access and speed of care and clinical course were determined through 1746 random household interviews before and 3199 during the intervention. RESULTS: A total of 15 932 children were assessed: 6394 in Burkina Faso, 2148 in Nigeria, and 7390 in Uganda. Most children assessed (97.3% [15 495/15 932]) were febrile and most febrile cases (82.1% [12 725/15 495]) tested were RDT positive. Almost half of afebrile episodes (47.6% [204/429]) were RDT positive. Children eligible for rectal artesunate contributed 1.1% of episodes. The odds of using CHWs as the first point of care doubled (odds ratio [OR], 2.15; 95% confidence interval [CI], 1.9 2.4; P < .0001). RDT use changed from 3.2% to 72.9% (OR, 80.8; 95% CI, 51.2 127.3; P < .0001). The mean duration of uncomplicated episodes reduced from 3.69 +/- 2.06 days to 3.47 +/- 1.61 days, Degrees of freedom (df) = 2960, Student's t (t) = 3.2 (P = .0014), and mean duration of severe episodes reduced from 4.24 +/- 2.26 days to 3.7 +/- 1.57 days, df = 749, t = 3.8, P = .0001. There was a reduction in children with danger signs from 24.7% before to 18.1% during the intervention (OR, 0.68; 95% CI, .59-.78; P < .0001). CONCLUSIONS: Provision of diagnosis and treatment via trained CHWs increases access to diagnosis and treatment, shortens clinical episode duration, and reduces the number of severe cases. This approach, recommended by the World Health Organization, improves malaria case management. CLINICAL TRIALS REGISTRATION: ISRCTN13858170. PMID- 27941102 TI - Impact of Improving Community-Based Access to Malaria Diagnosis and Treatment on Household Costs. AB - BACKGROUND: Community health workers (CHWs) were trained in Burkina Faso, Nigeria, and Uganda to diagnose febrile children using malaria rapid diagnostic tests, and treat positive malaria cases with artemisinin-based combination therapy (ACT) and those who could not take oral medicines with rectal artesunate. We quantified the impact of this intervention on private household costs for childhood febrile illness. METHODS: Households with recent febrile illness in a young child in previous 2 weeks were selected randomly before and during the intervention and data obtained on household costs for the illness episode. Household costs included consultation fees, registration costs, user fees, diagnosis, bed, drugs, food, and transport costs. Private household costs per episode before and during the intervention were compared. The intervention's impact on household costs per episode was calculated and projected to districtwide impacts on household costs. RESULTS: Use of CHWs increased from 35% of illness episodes before the intervention to 50% during the intervention (P < .0001), and total household costs per episode decreased significantly in each country: from US Dollars (USD) $4.36 to USD $1.54 in Burkina Faso, from USD $3.90 to USD $2.04 in Nigeria, and from USD $4.46 to USD $1.42 in Uganda (all P < .0001). There was no difference in the time used by the child's caregiver to care for a sick child (59% before intervention vs 51% during intervention spent <=2 days). Using the most recent population figures for each study district, we estimate that the intervention could save households a total of USD $29 965, USD $254 268, and USD $303 467, respectively, in the study districts in Burkina Faso, Nigeria, and Uganda. CONCLUSIONS: Improving access to malaria diagnostics and treatments in malaria-endemic areas substantially reduces private household costs. The key challenge is to develop and strengthen community human resources to deliver the intervention, and ensure adequate supplies of commodities and supervision. We demonstrate feasibility and benefit to populations living in difficult circumstances. CLINICAL TRIALS REGISTRATION: ISRCTN13858170. PMID- 27941103 TI - Training Community Health Workers to Manage Uncomplicated and Severe Malaria: Experience From 3 Rural Malaria-Endemic Areas in Sub-Saharan Africa. AB - BACKGROUND: Use of community health workers (CHWs) to increase access to diagnosis and treatment of malaria is recommended by the World Health Organization. The present article reports on training and performance of CHWs in applying these recommendations. METHODS: Two hundred seventy-nine CHWs were trained for 3-5 days in Burkina Faso, Nigeria, and Uganda, and 19 were certified to diagnose and treat only uncomplicated malaria and 235 to diagnose and treat both uncomplicated and severe malaria. Almost 1 year after training, 220 CHWs were assessed using standard checklists using facility staff responses as the reference standard. RESULTS: Training models were slightly different in the 3 countries, but the same topics were covered. The main challenges noticed were the low level of education in rural areas and the involvement of health staff in the supervision process. Overall performance was 98% (with 99% in taking history, 95% in measuring temperature, 85% for measuring respiratory rates, 98% for diagnosis, 98% for classification, and 99% for prescribing treatment). Young, single, new CHWs performed better than their older, married, more experienced counterparts. CONCLUSIONS: Training CHWs for community-based diagnosis and treatment of uncomplicated and severe malaria is possible with basic and refresher training and close supervision of CHWs' performance. CLINICAL TRIALS REGISTRATION: ISRCTRS13858170. PMID- 27941104 TI - Motivation of Community Health Workers in Diagnosing, Treating, and Referring Sick Young Children in a Multicountry Study. AB - BACKGROUND: Community health workers (CHWs) are an important element of care provision for a wide range of conditions, but their turnover rate is high. Many studies have been conducted on health workers' motivation, focusing on formal sector staff but not CHWs. Although CHWs are easy to recruit, motivating and retaining them for service delivery is difficult. This article investigates factors influencing CHW motivation and retention in health service delivery. METHODS: Quantitative and qualitative data were collected to identify the key factors favoring motivation and retention of CHWs as well as those deterring them. We interviewed 47, 25, and 134 CHWs in Burkina Faso, Nigeria, and Uganda, respectively, using a structured questionnaire. Focus group discussions (FGDs) were also conducted with CHWs, community participants, and facility health workers. RESULTS: Except for Burkina Faso, most CHWs were female. Average age was between 38 and 41 years, and most came from agricultural communities. The majority (52%-80%) judged they had a high to very high level of satisfaction, but most CHWs (approximately 75%) in Burkina Faso and Uganda indicated that they would be prepared to leave the job, citing income as a major reason. Community recognition and opportunities for training and supervision were major incentives in all countries, but the volume of unremunerated work, at a time when both malaria-positive cases and farming needs were at their peak, was challenging. CONCLUSIONS: Most CHWs understood the volunteer nature of their position but desired community recognition and modest financial remuneration. CLINICAL TRIALS REGISTRATION: ISRCTN13858170. PMID- 27941105 TI - Compliance With Malaria Rapid Diagnostic Testing by Community Health Workers in 3 Malaria-Endemic Countries of Sub-Saharan Africa: An Observational Study. AB - BACKGROUND: The World Health Organization recommends that all malaria management be based on parasitological identification. We monitored performance of trained community health workers (CHWs) in adhering to this recommendation to restrict artemisinin-based combination therapies (ACTs) to positive rapid diagnostic test (RDT)-confirmed cases in children in 3 malaria-endemic sub-Saharan African countries. METHODS: In 33 villages in Burkina Faso, 45 villages in Nigeria, and 84 villages in Uganda, 265 CHWs were trained over a minimum of 3 days to diagnose malaria using RDTs (prepare, read, record results, and inform the patient about results) and treat RDT-confirmed uncomplicated malaria cases with ACTs. In Nigeria, CHWs were also taught to obtain a thick blood smear. Spent RDT kits and prepared blood slides were collected and interpreted independently in Burkina Faso and Nigeria to confirm CHWs' diagnoses. Interviews were held with 12 of 17 CHWs who prescribed ACTs for patients with RDT-negative test results, and with 16 of 29 caregivers to determine factors related to noncompliance. RESULTS: Of 12 656 patients treated with ACTs in the participating countries (5365 in Burkina Faso, 1648 in Nigeria, and 5643 in Uganda), 29 patients (8 from Burkina Faso, 17 from Nigeria, 4 from Uganda) were RDT negative. The small number of RDT-negative ACT-treated cases limits statistical analysis. Only a few CHWs were involved, and they were more likely to be traders rather than farmers (odds ratio [OR], 6.15; 95% confidence interval [CI], 2.09-18.07; P = .0004). RDT-negative children who were treated with ACTs had a significantly higher probability of residing in a village other than that of the CHW (OR, 3.85; 95% CI, 1.59-9.30; P = .0018). Parental pressure was identified in interviews with parents. CONCLUSIONS: Noncompliance with results of RDT tests is relatively rare when CHWs are trained and well supervised. CLINICAL TRIALS REGISTRATION: ISRCTN13858170. PMID- 27941106 TI - Compliance With Referral Advice After Treatment With Prereferral Rectal Artesunate: A Study in 3 Sub-Saharan African Countries. AB - BACKGROUND: Children aged <5 years were enrolled in a large study in 3 countries of sub-Saharan Africa because they had danger signs preventing them from being able to take oral medications. We examined compliance and factors associated with compliance with referral advice for those who were treated with rectal artesunate. METHODS: Patient demographic data, speed of accessing treatment after danger signs were recognized, clinical symptoms, malaria microscopy, treatment-seeking behavior, and compliance with referral advice were obtained from case record forms of 179 children treated with prereferral rectal artesunate in a multicountry study. We held focus group discussions and key informant interviews with parents, community health workers (CHWs), and facility staff to understand the factors that deterred or facilitated compliance with referral advice. RESULTS: There was a very high level of compliance (90%) among patients treated with prereferral rectal artesunate. Age, symptoms at baseline (prostration, impaired consciousness, convulsions, coma), and malaria status were not related to referral compliance in the analysis. CONCLUSIONS: Teaching CHWs to diagnose and treat young children with prereferral rectal artesunate is feasible in remote communities of Africa, and high compliance with referral advice can be achieved. PMID- 27941107 TI - Malaria Rapid Diagnostic Tests and Malaria Microscopy for Guiding Malaria Treatment of Uncomplicated Fevers in Nigeria and Prereferral Cases in 3 African Countries. AB - BACKGROUND: The World Health Organization recommends that malaria treatment be based on demonstration of the infecting Plasmodium parasite specie. Malaria rapid diagnostic tests (RDTs) are recommended at community points of care because they are accurate and rapid. We report on parasitological results in a malaria study in selected rural communities in 3 African countries. METHODS: In Nigeria, community health workers (CHWs) performed RDTs (SD-Bioline) and thick blood smears on all children suspected to have malaria. Malaria RDT-positive children able to swallow received artemisinin-based combination therapy (Coartem). In all countries, children unable to take oral drugs received prereferral rectal artesunate irrespective of RDT result and were referred to the nearest health facility. Thick blood smears and RDTs were usually taken at hospital admission. In Nigeria and Burkina Faso, RDT cassettes and blood smears were re-read by an experienced investigator at study end. RESULTS: Trained CHWs enrolled 2148 children in Nigeria. Complete parasitological data of 1860 (86.6%) enrollees were analyzed. The mean age of enrollees was 30.4 +/- 15.7 months. The prevalence of malaria parasitemia in the study population was 77.8% (1447/1860), 77.6% (1439/1855), and 54.1% (862/1593) by RDT performed by CHWs vs an expert clinical research assistant vs microscopy (gold standard), respectively. Geometric mean parasite density was 6946/uL (range, 40-436 450/uL). There were 49 cases of RDT false-negative results with a parasite density range of 40-54 059/uL. False negative RDT results with high parasitemia could be due to non-falciparum infection or result from a prozone effect. Sensitivity and specificity of SD Bioline RDT results as read by CHWs were 94.3% and 41.6%, respectively, while the negative and positive predictive values were 86.1% and 65.6%, respectively. The level of agreement in RDT reading by the CHWs and experienced research staff was 86.04% and kappa statistic of 0.60. The malaria parasite positivity rate by RDT and microscopy among children with danger signs in the 3 countries was 67.9% and 41.8%, respectively. CONCLUSIONS: RDTs are useful in guiding malaria management and were successfully used for diagnosis by trained CHWs. However, false-negative RDT results were identified and can undermine confidence in results and control efforts. PMID- 27941108 TI - Quantifying and Valuing Community Health Worker Time in Improving Access to Malaria Diagnosis and Treatment. AB - BACKGROUND: Community health workers (CHWs) are members of a community who are chosen by their communities as first-line, volunteer health workers. The time they spend providing healthcare and the value of this time are often not evaluated. Our aim was to quantify the time CHWs spent on providing healthcare before and during the implementation of an integrated program of diagnosis and treatment of febrile illness in 3 African countries. METHODS: In Burkina Faso, Nigeria, and Uganda, CHWs were trained to assess and manage febrile patients in keeping with Integrated Management of Childhood Illness recommendations to use rapid diagnostic tests, artemisinin-based combination therapy, and rectal artesunate for malaria treatment. All CHWs provided healthcare only to young children usually <5 years of age, and hence daily time allocation of their time to child healthcare was documented for 1 day (in the high malaria season) before the intervention and at several time points following the implementation of the intervention. Time spent in providing child healthcare was valued in earnings of persons with similar experience. RESULTS: During the high malaria season of the intervention, CHWs spent nearly 50 minutes more in daily healthcare provision (average daily time, 30.2 minutes before the intervention vs 79.5 minutes during the intervention; test for difference in means P < .01). On average, the daily time spent providing healthcare during the intervention was 55.8 minutes (Burkina Faso), 77.4 minutes (Nigeria), and 72.2 minutes (Uganda). Using the country minimum monthly salary, CHWs' time allocated to child healthcare for 1 year was valued at US Dollars (USD) $52 in Burkina Faso, USD $295 in Nigeria, and USD $141 in Uganda. CONCLUSIONS: CHWs spend up to an hour and a half daily on child healthcare in their communities. These data are informative in designing reward systems to motivate CHWs to continue providing good-quality services. CLINICAL TRIALS REGISTRATION: ISRCTN13858170. PMID- 27941111 TI - Combining an antiviral with rituximab in EBV-related haemophagocytic lymphohistiocytosis led to rapid viral clearance; and a comprehensive review. AB - Epstein-Barr virus (EBV)-related haemophagocytic lymphohistiocytosis (EBVr-HLH) has a better prognosis when the virus is rapidly cleared, but the best antiviral approach is controversial. We present a patient to whom the therapeutic standard rituximab was co-administered with valacyclovir and an HLH-specific treatment with favourable viral and clinical responses. We conducted an extensive literature review and contacted several world reference centres and experts to inquire about their approaches and experience. We conclude that antivirals are infrequently used for EBVr-HLH, despite their laboratory-proven and likely clinical beneficial effect on some EBV-related diseases. However, the role of antivirals remains obscure. Concerns about their lack of efficacy are based on observational data and reports of the cellular tropism of EBV. Therefore, the adjunct use of antivirals may be considered when myelotoxicity is not the primary concern, and related outcomes should be systematically recorded to produce higher quality evidence. PMID- 27941109 TI - Assessing Acceptability of a Diagnostic and Malaria Treatment Package Delivered by Community Health Workers in Malaria-Endemic Settings of Burkina Faso, Nigeria, and Uganda. AB - BACKGROUND: The efficacy of artemisinin-based combination therapy (ACT) and rectal artesunate for severe malaria in children is proven. However, acceptability of a package of interventions that included use of malaria rapid diagnostic tests (RDTs), ACTs, and rectal artesunate when provided by community health workers (CHWs) is uncertain. This study assessed acceptability of use of CHWs for case management of malaria using RDTs, ACTs, and rectal artesunate. METHODS: The study was carried out in Burkina Faso, Nigeria, and Uganda in 2015 toward the end of an intervention using CHWs to provide diagnosis and treatment. Focus group discussions (FGDs) and key informant interviews (KIIs) were conducted with parents of sick children, community leaders, and health workers to understand whether they accepted the package for case management of malaria using CHWs. Transcripts from FGDs and KII recordings were analyzed using content analysis. The findings were described, interpreted, and reported in the form of narratives. RESULTS: Treatment of malaria using the CHWs was acceptable to caregivers and communities. The CHWs were perceived to be accessible, diligent, and effective. There were no physical, social, or cultural barriers to accessing the CHWs' services. Respondents were extremely positive about the intervention and were concerned that CHWs had limited financial and nonfinancial incentives that would reduce their motivation and willingness to continue. CONCLUSIONS: Treatment of malaria using CHWs was fully accepted. CHWs should be compensated, trained, and well supervised. CLINICAL TRIALS REGISTRATION: ISRCTN13858170. PMID- 27941112 TI - Antisynthetase syndrome (ASS) presenting as acute respiratory distress syndrome (ARDS) in a patient without myositis features. AB - A woman aged 61 years presented to the emergency room with a 1-week history of dyspnoea on exertion and dry cough. X-ray of the chest showed diffuse interstitial opacities and was started on antibiotics and furosemide, and despite these measures, patient's respiratory status worsened, prompting endotracheal intubation. CT of the chest showed diffuse bilateral ground glass opacities and underwent bronchoscope with trans-bronchial biopsy that showed chronic bronchitis. Pt was empirically started on intravenous steroids due to concerns for interstitial lung disease (ILD). Autoimmune work up was sent and underwent video-assisted thoracoscopic surgery-guided biopsy of the lung that showed non specific interstitial pattern with fibrosis. The patient was diagnosed as having antisynthetase syndrome with pulmonary involvement (ILD) as the cause of her acute respiratory failure. Azathioprine was started as steroid-sparing agent and was weaned off the ventilator to a tracheostomy collar and discharged to long term rehabilitation centre. PMID- 27941114 TI - Posterior scleritis presenting as conjunctivitis in a child. AB - A 14-year-old male child presented with redness and decreased vision in the right eye for 7 days. He was being treated for viral conjunctivitis for right eye at a local hospital. His visual acuity was 6/24 OD and 6/9 OS. Slit-lamp examination revealed diffuse conjunctival congestion in the right eye. Dilated fundus examination revealed mild disc hyperaemia and retinal striae in both the eyes. A peripapillary serous detachment of macula in the right eye was seen on optical coherence tomography. B scan ultrasonography revealed increased scleral thickening and characteristic 'T' sign in both the eyes. Investigations revealed no other relevant systemic association. A diagnosis of bilateral posterior scleritis was made. The patient was started on topical steroids and oral non steroidal anti-inflammatory drugs. Within 2 weeks of therapy the visual acuity improved to 6/6, the serous detachment resolved and retinal striae reduced in both the eyes. PMID- 27941113 TI - Forgetting to remember: hypoglycaemic encephalopathy. AB - A 37-year-old woman with a history of poorly controlled type 1 diabetes presented acutely with a decreased Glasgow Coma Scale and a diagnosis of hypoglycaemic brain injury. Her MRI highlighted bilateral hippocampi diffusion restriction and T2 hyperintensity. Clinically, she had a marked cognitive deficit, particularly of short-term, anterograde amnesia. She was managed conservatively and with intensive rehabilitation. PMID- 27941110 TI - Pre-referral Rectal Artesunate Treatment by Community-Based Treatment Providers in Ghana, Guinea-Bissau, Tanzania, and Uganda (Study 18): A Cluster-Randomized Trial. AB - BACKGROUND: If malaria patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate prior to hospital referral can prevent death and disability. The goal is to reduce death from malaria by having rectal artesunate treatment available and used. How best to do this remains unknown. METHODS: Villages remote from a health facility were randomized to different community-based treatment providers trained to provide rectal artesunate in Ghana, Guinea-Bissau, Tanzania, and Uganda. Prereferral rectal artesunate treatment was provided in 272 villages: 109 through community-based health workers (CHWs), 112 via trained mothers (MUMs), 25 via trained traditional healers (THs), and 26 through trained community-chosen personnel (COMs); episodes eligible for rectal artesunate were established through regular household surveys of febrile illnesses recording symptoms eligible for prereferral treatment. Differences in treatment coverage with rectal artesunate in children aged <5 years in MUM vs CHW (standard-of-care) villages were assessed using the odds ratio (OR); the predictive probability of treatment was derived from a logistic regression analysis, adjusting for heterogeneity between clusters (villages) using random effects. RESULTS: Over 19 months, 54 013 children had 102 504 febrile episodes, of which 32% (31 817 episodes) had symptoms eligible for prereferral therapy; 14% (4460) children received treatment. Episodes with altered consciousness, coma, or convulsions constituted 36.6% of all episodes in treated children. The overall OR of treatment between MUM vs CHW villages, adjusting for country, was 1.84 (95% confidence interval [CI], 1.20-2.83; P = .005). Adjusting for heterogeneity, this translated into a 1.67 higher average probability of a child being treated in MUM vs CHW villages. Referral compliance was 81% and significantly higher with CHWs vs MUMs: 87% vs 82% (risk ratio [RR], 1.1 [95% CI, 1.0-1.1]; P < .0001). There were more deaths in the TH cluster than elsewhere (RR, 2.7 [95% CI, 1.4-5.6]; P = .0040). CONCLUSIONS: Prereferral episodes were almost one-third of all febrile episodes. More than one-third of patients treated had convulsions, altered consciousness, or coma. Mothers were effective in treating patients, and achieved higher coverage than other providers. Treatment access was low. CLINICAL TRIALS REGISTRATION: ISRCTN58046240. PMID- 27941115 TI - Congenital dacryocystocele. PMID- 27941117 TI - Treating Sick Young Infants With Only Fast Breathing With Oral Amoxicillin in Resource-Limited Settings: Taking the High Road? PMID- 27941116 TI - Greater Coronary Heart Disease Risk With Lower Intensity and Longer Duration Smoking Compared With Higher Intensity and Shorter Duration Smoking: Congruent Results Across Diverse Cohorts. AB - Introduction: Relative risks (RRs) for coronary heart disease (CHD) by cigarettes/day exhibit a concave pattern, implying the RR increase with each additional cigarette/day consumed decreases with greater intensity. Interpreting this pattern faces limitations, since cigarettes/day alone does not fully characterize smoking-related exposure. A more complete understanding of smoking and CHD risk requires a more comprehensive representation of smoking. Methods: Using Poisson regression, we applied a RR model in pack-years and cigarettes/day to analyze two diverse cohorts, the US Agricultural Health Study, with 4396 CHD events and 1 425 976 person-years of follow-up, and the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, with 5979 CHD events and 486 643 person years. Results: In both cohorts, the concave RR pattern with cigarettes/day was consistent with cigarettes/day modifying a linear RR association for CHD by pack years within categories of cigarettes/day, indicating that strength of the pack years association depended on cigarettes/day (p < .01). For example, at 50 pack years (365 000 total cigarettes), estimated RRs of CHD were 2.1 for accrual at 20 cigarettes/day and 1.5 for accrual at 50 cigarettes/day. Conclusions: RRs for CHD increased with pack-years with smoking intensities affecting the strength of association. For equal pack-years, smoking fewer cigarettes/day for longer duration was more deleterious than smoking more cigarettes/day for shorter duration. We have now observed inverse smoking intensity effects in multiple cohorts with differing smoking patterns and other characteristics, suggesting a common underlying phenomenon. Implications: Risk of CHD increases with pack-years of smoking, but accrual intensity strongly influences the strength of the association, such that smoking fewer cigarettes/day for longer duration is more deleterious than smoking more cigarettes/day for shorter duration. This observation offers clues to better understanding biological mechanisms, and reinforces the importance of cessation rather than smoking less to reduce CHD risk. PMID- 27941118 TI - Reply to Johnson. PMID- 27941119 TI - Ambulatory Treatment of Fast Breathing in Young Infants Aged <60 Days: A Double Blind, Randomized, Placebo-Controlled Equivalence Trial in Low-Income Settlements of Karachi. AB - : (See the Editorial Commentary by Jehan and Qazi on pages 190-1) BACKGROUND: Integrated Management of Childhood Illness recommends that young infants with isolated fast breathing be referred to a hospital for antibiotic treatment, which is often impractical in resource-limited settings. Additionally, antibiotics may be unnecessary for physiologic tachypnea in otherwise well newborns. We tested the hypothesis that ambulatory treatment with oral amoxicillin for 7 days was equivalent (similarity margin of 3%) to placebo in young infants with isolated fast breathing in primary care settings where hospital referral is often unfeasible. METHODS: This randomized equivalence trial was conducted in 4 primary health centers of Karachi, Pakistan. Infants presenting with isolated fast breathing and oxygen saturation >=90% were randomly assigned to receive either oral amoxicillin or placebo twice daily for 7 days. Enrolled infants were followed on days 1-8, 11, and 14. The primary outcome was treatment failure by day 8, analyzed per protocol. The trial was stopped by the data safety monitoring board due to higher treatment failure rate and the occurrence of 2 deaths in the placebo arm in an interim analysis. RESULTS: Four hundred twenty-three infants fulfilled per protocol criteria in the amoxicillin arm and 426 in the placebo arm. Twelve infants (2.8%) had treatment failure in the amoxicillin arm and 25 (5.9%) in the placebo arm (risk difference, 3.1; P value .04). Two infants in the placebo arm died, whereas no deaths occurred in the amoxicillin arm. Other adverse outcomes, as well as the proportions of relapse, were evenly distributed across both study arms. CONCLUSIONS: This trial failed to show equivalence of placebo to amoxicillin in the management of isolated fast breathing without hypoxemia or other clinical signs of illness in term young infants. CLINICAL TRIALS REGISTRATION: NCT01533818. PMID- 27941120 TI - Haemoglobin discordances in twins: due to differences in timing of cord clamping? AB - OBJECTIVE: Our objective was to study the differences in haemoglobin (Hb) at birth in dichorionic (DC) versus monochorionic (MC) twins in relation to birth order and mode of delivery. METHODS: All consecutive DC twin pregnancies and uncomplicated MC twin pregnancies with two live-born twins delivered at our centre were included in this retrospective cohort study. Hb levels at birth and on day 2 were evaluated in association with birth order and mode of delivery. The occurrence of polycythaemia (venous haematocrit >65%) was also recorded. RESULTS: A total of 300 DC and 290 MC twin pairs were included. In DC and MC twins delivered vaginally, second-born twins had a higher Hb level at birth compared with their co-twin (mean Hb level 16.7 vs 15.9 g/dL (p<0.01) in DC twins and 17.8 vs 16.1 g/dL (p<0.01) in MC twins). In twins delivered through caesarean section, no intertwin differences in Hb levels were detected. Polycythaemia occurred significantly more often in second-born twins compared with first-born twins delivered vaginally: 10 (5%) vs 2 (1%) (p=0.02) in DC twins and 20 (12%) vs 2 (1%) (p<0.01) in MC twins. CONCLUSIONS: Second-born DC and MC twins delivered vaginally have higher Hb levels at birth compared with first-born twins. Intertwin Hb differences in MC twins may partly be related to blood transfusion through the vascular anastomoses. Since DC twins do not have anastomoses, other factors may lead to Hb differences, including differences in timing of umbilical cord clamping. PMID- 27941121 TI - A Novel Copolymer-Based Functional SPECT/MR Imaging Agent for Asialoglycoprotein Receptor Targeting. AB - The aim of this study is to develop a copolymer-based single-photon emission computed tomography/magnetic resonance (SPECT/MR) dual-modality imaging agent that can be labeled with both technetium-99m (99mTc) and gadolinium (Gd) and target asialoglycoprotein receptor (ASGPR) via galactose. Monomers of N-p vinylbenzyl-6-(2-(4-dimethylamino)benzaldehydehydrazono) nicotinate (VNI) for labeling of 99mTc, 5,8-bis(carboxymethyl)-3-oxo-11-(2-oxo-2-((4 vinylbenzyl)amino)ethyl)-1-(4-vinylphenzyl)-2,5,8,11-tetraazatridecan-13-oic acid (V2DTPA) for labeling of Gd, and vinylbenzyl-O-beta-d-galactopyranosyl-d gluconamide (VLA) for targeting ASGPR were synthesized, respectively. Then the copolymer P(VLA-co-VNI-co-V2DTPA) (pVLND2) was synthesized and characterized by gel permeation chromatography, dynamic light scattering, and high-performance liquid chromatography analysis. After labeling with 99mTc and Gd simultaneously, the radiochemical purity, toxicity, relaxivity (r1), and in vivo SPECT/MR imaging in mice were evaluated. Single-photon emission computed tomography/magnetic resonance imaging and biodistribution results showed that pVLND2 could target ASGPR well. The significantly improved signal to noise ratio was observed in mice liver during MR imaging. All the results suggest that this novel kind of copolymer has the potential to be further developed as a functional SPECT/MR imaging agent. PMID- 27941122 TI - First PET Imaging Studies With 63Zn-Zinc Citrate in Healthy Human Participants and Patients With Alzheimer Disease. AB - Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). 63Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD. Dynamic PET imaging of the brain was performed for 30 minutes following intravenous administration of 63Zn-zinc citrate (~330 MBq). Subsequently, body PET images were acquired. Urine and venous blood were analyzed to give information on urinary excretion and pharmacokinetics. Regional cerebral 63Zn clearances were compared with 11C-Pittsburgh Compound B (11C-PiB) and 18F fluorodeoxyglucose (18F-FDG) imaging data. 63Zn-zinc citrate was well tolerated in human participants with no adverse events monitored. Tissues of highest uptake were liver, pancreas, and kidney, with moderate uptake being seen in intestines, prostate (in males), thyroid, spleen, stomach, pituitary, and salivary glands. Moderate brain uptake was observed, and regional dependencies were observed in 63Zn clearance kinetics in relationship with regions of high amyloid-beta plaque burden (11C-PiB) and 18F-FDG hypometabolism. In conclusion, zinc transport was successfully imaged in human participants using the PET probe 63Zn-zinc citrate. Primary sites of uptake in the digestive system accent the role of zinc in gastrointestinal function. Preliminary information on zinc kinetics in patients with AD evidenced regional differences in clearance rates in correspondence with regional amyloid-beta pathology, warranting further imaging studies of zinc homeostasis in patients with AD. PMID- 27941123 TI - The RNA-induced transcriptional silencing complex targets chromatin exclusively via interacting with nascent transcripts. AB - Small RNAs regulate chromatin modification and transcriptional gene silencing across the eukaryotic kingdom. Although these processes have been well studied, fundamental mechanistic aspects remain obscure. Specifically, it is unclear exactly how small RNA-loaded Argonaute protein complexes target chromatin to mediate silencing. Here, using fission yeast, we demonstrate that transcription of the target locus is essential for RNA-directed formation of heterochromatin. However, high transcriptional activity is inhibitory; thus, a transcriptional window exists that is optimal for silencing. We further found that pre-mRNA splicing is compatible with RNA-directed heterochromatin formation. However, the kinetics of pre-mRNA processing is critical. Introns close to the 5' end of a transcript that are rapidly spliced result in a bistable response whereby the target either remains euchromatic or becomes fully silenced. Together, our results discount siRNA-DNA base pairing in RNA-mediated heterochromatin formation, and the mechanistic insights further reveal guiding paradigms for the design of small RNA-directed chromatin silencing studies in multicellular organisms. PMID- 27941125 TI - Histatin 1 Enhances Cell Adhesion to Titanium in an Implant Integration Model. AB - Cellular adhesion is essential for successful integration of dental implants. Rapid soft tissue integration is important to create a seal around the implant and prevent infections, which commonly cause implant failure and can result in bone loss. In addition, soft tissue management is important to obtain good dental aesthetics. We previously demonstrated that the salivary peptide histatin 1 (Hst1) causes a more than 2-fold increase in the ability of human adherent cells to attach and spread on a glass surface. Cells treated with Hst1 attached more rapidly and firmly to the substrate and to each other. In the current study, we examine the potential application of Hst1 for promotion of dental implant integration. Our results show that Hst1 enhances the attachment and spreading of soft tissue cell types (oral epithelial cells and fibroblasts) to titanium (Ti) and hydroxyapatite (HAP), biomaterials that have found wide applications as implant material in dentistry and orthopedics. For improved visualization of cell adhesion to Ti, we developed a novel technique that uses sputtering to deposit a thin, transparent layer of Ti onto glass slides. This approach allows detailed, high-resolution analysis of cell adherence to Ti in real time. Furthermore, our results suggest that Hst1 has no negative effects on cell survival. Given its natural occurrence in the oral cavity, Hst1 could be an attractive agent for clinical application. Importantly, even though Hst1 is specific for saliva of humans and higher primates, it stimulated the attachment and spreading of canine cells, paving the way for preclinical studies in canine models. PMID- 27941126 TI - Evolution of Resistance Against CRISPR/Cas9 Gene Drive. AB - CRISPR/Cas9 gene drive (CGD) promises to be a highly adaptable approach for spreading genetically engineered alleles throughout a species, even if those alleles impair reproductive success. CGD has been shown to be effective in laboratory crosses of insects, yet it remains unclear to what extent potential resistance mechanisms will affect the dynamics of this process in large natural populations. Here we develop a comprehensive population genetic framework for modeling CGD dynamics, which incorporates potential resistance mechanisms as well as random genetic drift. Using this framework, we calculate the probability that resistance against CGD evolves from standing genetic variation, de novo mutation of wild-type alleles, or cleavage repair by nonhomologous end joining (NHEJ)-a likely by-product of CGD itself. We show that resistance to standard CGD approaches should evolve almost inevitably in most natural populations, unless repair of CGD-induced cleavage via NHEJ can be effectively suppressed, or resistance costs are on par with those of the driver. The key factor determining the probability that resistance evolves is the overall rate at which resistance alleles arise at the population level by mutation or NHEJ. By contrast, the conversion efficiency of the driver, its fitness cost, and its introduction frequency have only minor impact. Our results shed light on strategies that could facilitate the engineering of drivers with lower resistance potential, and motivate the possibility to embrace resistance as a possible mechanism for controlling a CGD approach. This study highlights the need for careful modeling of the population dynamics of CGD prior to the actual release of a driver construct into the wild. PMID- 27941127 TI - Leprosy in a patient infected with HIV. AB - A 60-year-old Nigerian man, who had lived in Europe for 30 years but had returned home frequently, presented with right frontalis muscle weakness and right ulnar nerve palsy, without skin lesions. Neurophysiology showed a generalised neuropathy with demyelinating features. Blood tests were positive for HIV, with a normal CD4 count. There was nerve thickening both clinically and on MRI. Nerve biopsy showed chronic endoneuritis and perineuritis (indicating leprosy) without visible mycobacteria. His neuropathy continued to deteriorate (lepra reaction) before starting treatment with WHO multidrug therapy, highly active antiretroviral therapy and corticosteroids. There are 10 new cases of leprosy diagnosed annually in the UK. Coinfection with HIV is rare but paradoxically does not usually adversely affect the outcome of leprosy or change treatment. However, permanent nerve damage in leprosy is common despite optimal therapy. Leprosy should be considered in patients from endemic areas who present with mononeuritis multiplex. PMID- 27941124 TI - A phosphorylation-deubiquitination cascade regulates the BRCA2-RAD51 axis in homologous recombination. AB - Homologous recombination (HR) is one of the major DNA double-strand break (DSB) repair pathways in mammalian cells. Defects in HR trigger genomic instability and result in cancer predisposition. The defining step of HR is homologous strand exchange directed by the protein RAD51, which is recruited to DSBs by BRCA2. However, the regulation of the BRCA2-RAD51 axis remains unclear. Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2. Overexpression of UCHL3 renders breast cancer cells resistant to radiation and chemotherapy, while depletion of UCHL3 sensitizes cells to these treatments, suggesting a determinant role of UCHL3 in cancer therapy. Overall, we identify UCHL3 as a novel regulator of DNA repair and reveal a model in which a phosphorylation-deubiquitination cascade dynamically regulates the BRCA2-RAD51 pathway. PMID- 27941128 TI - Development of a liquid chromatography tandem mass spectrometry method for the simultaneous measurement of voriconazole, posaconazole and itraconazole. AB - Background Azole-based antifungals are the first-line therapy for some of the most common mycoses and are now also being used prophylactically to protect immunocompromised patients. However, due to variability in both their metabolism and bioavailability, therapeutic drug monitoring is essential to avoid toxicity but still gain maximum efficacy. Methods Following protein precipitation of serum with acetonitrile, 20 uL of extract was injected onto a 2.1 * 50 mm Waters Atlantis dC18 3 um column. Detection was via a Waters Quattro Premier XE tandem mass spectrometer operating in ESI-positive mode. Multiple reaction monitoring (MRM) detected two product ions for each compound and one for each isotopically labelled internal standard. Ion suppression, linearity, stability, matrix effects, recovery, imprecision, lower limits of measuring interval and detection were all assessed. Results Optimal chromatographic separation was achieved using gradient elution over 8 minutes. Voriconazole, posaconazole and itraconazole eluted at 1.71, 2.73 and 3.41 min, respectively. The lower limits of measuring interval for all three compounds was 0.1 mg/L. The assay was linear to 10 mg/L for voriconazole (R2 = 0.995) and 5 mg/L for posaconazole (R2 = 0.990) and itraconazole (R2 = 0.991). The assay was both highly accurate and precise with % bias of voriconazole, posaconazole and itraconazole, respectively, when compared with previous NEQAS samples. The intra-assay precision (CV%) was 1.6%, 2.5% and 1.9% for voriconazole, posaconazole and itraconazole, respectively, across the linear range. Conclusion A simple and robust method has been validated for azole antifungal therapeutic drug monitoring. This new assay will result in a greatly improved sample turnaround time and will therefore vastly increase the clinical utility of azole antifungal drug monitoring. PMID- 27941130 TI - The EULAR points to consider for health professionals undertaking musculoskeletal ultrasound for rheumatic and musculoskeletal diseases. PMID- 27941131 TI - Genome-wide association study identifies variants in HORMAD2 associated with tonsillectomy. AB - BACKGROUND: Inflammation of the tonsils is a normal response to infection, but some individuals experience recurrent, severe tonsillitis and massive hypertrophy of the tonsils in which case surgical removal of the tonsils may be considered. OBJECTIVE: To identify common genetic variants associated with tonsillectomy. METHODS: We used tonsillectomy information from Danish health registers and carried out a genome-wide association study comprising 1464 patients and 12 019 controls of Northwestern European ancestry, with replication in an independent sample set of 1575 patients and 1367 controls. RESULTS: The variant rs2412971, intronic in HORMAD2 at chromosome 22q12.2, was robustly associated with tonsillectomy (OR=1.22; p=1.48*10-9) and is highly correlated with SNPs previously found to be associated with IgA nephropathy, Crohn's disease (CD) and early onset inflammatory bowel disease (IBD). The risk allele for tonsillectomy corresponded to increased risk of IgA nephropathy and decreased risk of CD and IBD. We further performed lookup analyses of the top SNP for outcomes related to tonsillectomy in the combined discovery and replication sample and found that rs2412971 was associated with acute tonsillitis (OR=1.19; p=7.82*10-4), chronic disease of the tonsils (OR=1.19; p=2.32*10-6) and appendectomy (OR=1.18; p=1.13*10-3). CONCLUSIONS: We identified and replicated a genetic association at 22q12.2 with tonsillectomy. Further functional investigation is required to illuminate whether the molecular mechanisms underlying the genetic association involve general lymphoid hyper-reaction throughout the mucosa-associated lymphoid tissue system. PMID- 27941132 TI - Health Outcomes of a Series of Bonny Method of Guided Imagery and Music Sessions: A Systematic Review. AB - Background: The Bonny Method of Guided Imagery and Music (GIM) is a music centered approach to exploring consciousness for personal growth and transformation. Applications have been reported in a variety of clinical and nonclinical contexts. Objective: The purpose of this study was to review evidence that a series of Bonny Method of GIM sessions may promote positive health outcomes in adults. Methods: This systematic review examined randomized and nonrandomized controlled trials and repeated measures designs that reported psychological or physiological outcomes following a series of at least six individual Bonny Method of GIM sessions. Researchers assessed each study for risk of bias and computed effect sizes for outcome variables. Results: Of 270 non duplicate titles retrieved, nine met criteria for inclusion, and eight had moderate or low risk of bias. These included 275 participants 18-78 years of age representing a variety of populations. Multiple studies measured anxiety, depression, mood disturbance, interpersonal problems, quality of life, sense of coherence, and/or psychiatric symptoms and found medium to large effect sizes. Four included physiological measures (systolic and diastolic blood pressure, beta endorphin, cortisol, and pain) and reported medium to large effect sizes, none of which were replicated across studies in this review. Conclusions: Evidence is promising that a series of Bonny Method of GIM sessions may be effective for improving both psychological and physiological health and may be therapeutically indicated for adults seeking treatment with medical, mental health, and nonclinical needs. Further research is needed to replicate findings within outcomes and populations. PMID- 27941134 TI - Heartbeat: Evidence, Experts and Trustworthy Guidelines. PMID- 27941133 TI - Letter regarding: Absence of skin discoloration after transarterial embolization of a subcutaneous auricular arteriovenous malformation with PHIL. PMID- 27941135 TI - Cardiovascular highlights from non-cardiology journals. PMID- 27941129 TI - Update of EULAR recommendations for the treatment of systemic sclerosis. AB - The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE 5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc. PMID- 27941138 TI - Examining Neuropathology: Beginning a Dialogue. PMID- 27941139 TI - Prognostic Biomarkers in Spinal Chordoma: A Systematic Review. PMID- 27941137 TI - Tubular Aggregates and Cylindrical Spirals Have Distinct Immunohistochemical Signatures. AB - Tubular aggregates and cylindrical spirals are 2 distinct ultrastructural abnormalities observed in muscle biopsies that have similar histochemical staining characteristics on light microscopy. Both are found in a wide range of disorders. Recently, a number of genetic mutations have been reported in conditions with tubular aggregates in skeletal muscle. It is widely accepted that tubular aggregates arise from the sarcoplasmic reticulum, but the origin of cylindrical spirals has been less clearly defined. We describe the histopathological features of myopathies with tubular aggregates, including a detailed immunohistochemical analysis of congenital myasthenic syndromes with tubular aggregates due to mutations in GFPT1 and DPAGT1, and myopathies with cylindrical spirals. Our findings support the notion that cylindrical spirals, like tubular aggregates, derive primarily from the sarcoplasmic reticulum; however, immunohistochemistry indicates that different molecular components of the sarcoplasmic reticulum may be involved and can be used to distinguish between these different inclusions. The immunohistochemical differences may also help to guide genetic testing. PMID- 27941141 TI - Tenascin-C is associated with cored amyloid-beta plaques in Alzheimer disease and pathology burdened cognitively normal elderly. PMID- 27941142 TI - Passing the Mantle. PMID- 27941143 TI - Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). AB - It is important to realize that leishmaniasis guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The IDSA and ASTMH consider adherence to these guidelines to be voluntary, with the ultimate determinations regarding their application to be made by the physician in the light of each patient's individual circumstances. PMID- 27941144 TI - Diagnosis and Clinical Management of Schistosoma haematobium-Schistosoma bovis Hybrid Infection in a Cluster of Travelers Returning From Mali. AB - Ten Belgian travelers returned from Mali with a Schistosoma haematobium Schistosoma bovis hybrid infection, confirmed by DNA sequencing from eggs. Clinical symptoms and laboratory findings resembled those of classic acute schistosomiasis, but the detected eggs were morphologically unusual. PMID- 27941151 TI - Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). AB - It is important to realize that leishmaniasis guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The IDSA and ASTMH consider adherence to these guidelines to be voluntary, with the ultimate determinations regarding their application to be made by the physician in the light of each patient's individual circumstances. PMID- 27941154 TI - Controlling skeletal muscle CPT-I malonyl-CoA sensitivity: the importance of AMPK independent regulation of intermediate filaments during exercise. AB - The obligatory role of carnitine palmitoyltransferase-I (CPT-I) in mediating mitochondrial lipid transport is well established, a process attenuated by malonyl-CoA (M-CoA). However, the necessity of reducing M-CoA concentrations to promote lipid oxidation has recently been challenged, suggesting external regulation on CPT-I. Since previous work in hepatocytes suggests the involvement of the intermediate filament fraction of the cytoskeleton in regulating CPT-I, we investigated in skeletal muscle if CPT-I sensitivity for M-CoA inhibition could be regulated by the intermediate filaments, and whether AMP-activated protein kinase (AMPK) could be involved in this process. Chemical disruption (3,3' iminodipropionitrile, IDPN) of the intermediate filaments did not alter mitochondrial respiration or sensitivity for numerous substrates (palmitoyl-CoA, ADP, palmitoyl carnitine and pyruvate). In contrast, IDPN reduced CPT-I sensitivity for M-CoA inhibition in permeabilized muscle fibers, identifying M CoA kinetics as a specific target for intermediate filament regulation. Importantly, exercise mimicked the effect of IDPN on M-CoA sensitivity, suggesting that intermediate filament disruption in vivo is physiologically important for CPT-I regulation. To ascertain a potential mechanism, since AMPK is activated during exercise, AMPK beta1beta2-KO mice were utilized in an attempt to ablate the observed exercise response. Unexpectedly, these mice displayed drastic attenuation in resting M-CoA sensitivity, such that exercise and IDPN could not further alter M-CoA sensitivity. These data suggest that AMPK is not required for the regulation of the intermediate filament interaction with CPT-I. Altogether, these data highlight that M-CoA sensitivity is important for regulating mitochondrial lipid transport. Moreover, M-CoA sensitivity appears to be regulated by intermediate filament interaction with CPT-I, a process that is important when metabolic homeostasis is challenged. PMID- 27941155 TI - Work status in MS: A proxy measure for comprehensive MS management. PMID- 27941158 TI - The experience of spirituality from the perspective of people living with dementia: A systematic review and meta-synthesis. AB - Spirituality is an important aspect of humanity. Concerned with deriving meaning from events, and connection with others, it provides a mechanism for some to cope with illness and disability. While spiritual support is recognised as important, little is known about the spiritual needs of those people experiencing dementia. This meta-synthesis considers the experiences of spirituality from the perspective of people living with a diagnosis of dementia. Using a review protocol, key words from a preliminary scoping review were used to direct database searches in November 2013. A total of 667 papers were initially identified. However, following careful quality review assessment a final eight papers were selected. Findings demonstrated the ongoing importance of spirituality to people living with dementia and its importance as a means of finding hope, meaning and linkage with past, present and future. Expression of spirituality through faith practices, contact with faith communities, and the impact of dementia on these, were also highlighted. PMID- 27941156 TI - Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis. AB - OBJECTIVE: The benefits of pancreatic enzyme replacement therapy (PERT) in chronic pancreatitis (CP) are inadequately defined. We have undertaken a systematic review and meta-analysis of randomised controlled trials of PERT to determine the efficacy of PERT in exocrine pancreatic insufficiency (EPI) from CP. DESIGN: Major databases were searched from 1966 to 2015 inclusive. The primary outcome was coefficient of fat absorption (CFA). Effects of PERT versus baseline and versus placebo, and of different doses, formulations and schedules were determined. RESULTS: A total of 17 studies (511 patients with CP) were included and assessed qualitatively (Jadad score). Quantitative data were synthesised from 14 studies. PERT improved CFA compared with baseline (83.7+/-6.0 vs 63.1+/-15.0, p<0.00001; I2=89%) and placebo (83.2+/-5.5 vs 67.4+/-7.0, p=0.0001; I2=86%). PERT improved coefficient of nitrogen absorption, reduced faecal fat excretion, faecal nitrogen excretion, faecal weight and abdominal pain, without significant adverse events. Follow-up studies demonstrated that PERT increased serum nutritional parameters, improved GI symptoms and quality of life without significant adverse events. High-dose or enteric-coated enzymes showed a trend to greater effectiveness than low-dose or non-coated comparisons, respectively. Subgroup, sensitive and meta-regression analyses revealed that sample size, CP diagnostic criteria, study design and enzyme dose contributed to heterogeneity; data on health inequalities were lacking. CONCLUSIONS: PERT is indicated to correct EPI and malnutrition in CP and may be improved by higher doses, enteric coating, administration during food and acid suppression. Further studies are required to determine optimal regimens, the impact of health inequalities and long-term effects on nutrition. PMID- 27941159 TI - Identifying barriers to diagnosing dementia following incentivisation and policy pressures: General practitioners' perspectives. AB - Overcoming barriers to earlier diagnosis of dementia in primary care is a core ambition of several government initiatives in the UK, with incentives put in place to promote earlier recognition by general practitioners and referral to specialists. This study was designed to explore general practitioners' opinions concerning barriers to diagnosing dementia, following implementation of strategies aimed at reducing them. The study involved in-depth, semi-structured interviews with 13 general practitioners from seven practices in North London or the West Midlands. Thematic analysis of interview transcripts was carried out using the Framework approach. We identified four major themes: organisational factors, clinician-related factors, patient-related factors and societal influences. The study findings revealed barriers previously unidentified in the literature which warrant further investigation, including the limits of diagnostic tools, lack of cultural applicability of these tools, and prioritisation of severe over mildly symptomatic patients by dementia services. PMID- 27941157 TI - Association between high-sensitivity troponin T and cardiovascular risk in individuals with and without metabolic syndrome: The ARIC study. AB - Background Metabolic syndrome (MetS) is associated with increased risk for cardiovascular disease, but there is heterogeneity in this risk. We evaluated whether high-sensitivity troponin T (hs-cTnT), a marker associated with cardiovascular disease, can stratify risk in MetS. Methods We evaluated associations between MetS (and groups with similar number of MetS components) and incident heart failure hospitalization, coronary heart disease, stroke and death using hs-cTnT categories after adjusting for risk factors/markers between 1996 and 2011 in 8204 individuals in the Atherosclerosis Risk In Communities study. Results The mean age of the population was 63 years (56% women, 19% Blacks). hs cTnT levels were higher with MetS and with increasing MetS components. In individuals with MetS, higher hs-cTnT levels were associated with increased hazard ratios for heart failure, coronary heart disease and death. Within each number of MetS components, higher hs-cTnT was associated with progressively higher heart failure, coronary heart disease and death hazards. The association was particularly strong for heart failure. With increasing hs-cTnT categories, the hazard ratios (95% confidence interval) for heart failure in individuals with MetS increased gradually from 1.68 (1.31-2.16) to 3.76 (2.69-5.26) ( p-trend < 0.001) compared with those with MetS and hs-cTnT < 5 ng/l; and respective hazard ratios with increasing hs-cTnT categories in those with all five MetS components ranged from 2.22 (1.17-4.21) to 4.23 (1.89-9.50) ( p-trend 0.004) compared with those with all five MetS components and hs-cTnT < 5 ng/l. However, mostly there were no significant interactions of hs-cTnT with MetS or its components. Conclusion hs-cTnT is useful for identifying MetS patients with increased hazards for coronary heart disease, death and particularly heart failure. PMID- 27941160 TI - Association between exposure to ambient particulate matter and chronic obstructive pulmonary disease: results from a cross-sectional study in China. AB - OBJECTIVE: The association between exposure to ambient particles with a median aerodynamic diameter less than 10/2.5 um (particulate matter, PM10/2.5) and COPD remains unclear. Our study objective was to examine the association between ambient PM10/2.5 concentrations and lung functions in adults. METHODS: A cross sectional study was conducted in southern China. Seven clusters were randomly selected from four cities across Guangdong province. Residents aged >=20 years in the participating clusters were randomly recruited; all eligible participants were examined with a standardised questionnaire and spirometry. COPD was defined as a post-bronchodilator FEV1/FVC less than 70%. Atmosphere PM sampling was conducted across the clusters along with our survey. RESULTS: Of the subjects initially recruited, 84.4% (n=5993) were included for analysis. COPD prevalence and atmosphere PM concentration varied significantly among the seven clusters. COPD prevalence was significantly associated with elevated PM concentration levels: adjusted OR 2.416 (95% CI 1.417 to 4.118) for >35 and <=75 ug/m3 and 2.530 (1.280 to 5.001) for >75 ug/m3 compared with the level of <=35 ug/m3 for PM2.5; adjusted OR 2.442 (95% CI 1.449 to 4.117) for >50 and <=150 ug/m3 compared with the level of <=50 ug/m3 for PM1. A 10 ug/m3 increase in PM2.5 concentrations was associated with a 26 mL (95% CI -43 to -9) decrease in FEV1, a 28 mL (-49 to 8) decrease in FVC and a 0.09% decrease (-0.170 to -0.010) in FEV1/FVC ratio. The associations of COPD with PM10 were consistent with PM2.5 but slightly weaker. CONCLUSIONS: Exposure to higher PM concentrations was strongly associated with increased COPD prevalence and declined respiratory function. TRIAL REGISTRATION NUMBER: ChiCTR-OO-14004264; Post-results. PMID- 27941162 TI - Sequential Revision of Belief, Trust Type, and the Order Effect. AB - Objective To investigate how people's sequential adjustments to their position are impacted by the source of the information. Background There is an extensive body of research on how the order in which new information is received affects people's final views and decisions as well as research on how they adjust their views in light of new information. Method Seventy college-aged students, 60% of whom were women, completed one of eight different randomly distributed booklets prepared to create the eight different between-subjects treatment conditions created by crossing the two levels of information source with the four level of order conditions. Based on the information provided, participants estimated the probability of an attack, the dependent measure. Results Confirming information from an expert intelligence officer significantly increased the attack probability from the initial position more than confirming information from a longtime friend. Conversely, disconfirming information from a longtime friend decreased the attack probability significantly more than the same information from an intelligence officer. Conclusion It was confirmed that confirming and disconfirming evidence were differentially affected depending on information source, either an expert or a close friend. The difference appears to be due to the existence of two kinds of trust: cognitive-based imbued to an expert and affective-based imbued to a close friend. Application Purveyors of information need to understand that it is not only the content of a message that counts but that other forces are at work such as the order in which information is received and characteristics of the information source. PMID- 27941163 TI - Effects of Accumulating Work Shifts on Performance-Based Fatigue Using Multiple Strength Measurements in Day and Night Shift Nurses and Aides. AB - Objective This study aimed to examine the effects of accumulating nursing work on maximal and rapid strength characteristics in female nurses and compare these effects in day versus night shift workers. Background Nurses exhibit among the highest nonfatal injury rates of all occupations, which may be a consequence of long, cumulative work shift schedules. Fatigue may accumulate across multiple shifts and lead to performance impairments, which in turn may be linked to injury risks. Method Thirty-seven nurses and aides performed isometric strength-based performance testing of three muscle groups, including the knee extensors, knee flexors, and wrist flexors (hand grip), as well as countermovement jumps, at baseline and following exposure to three 12-hour work shifts in a four-day period. Variables included peak torque (PT) and rate of torque development (RTD) from isometric strength testing and jump height and power output. Results The rigorous work period resulted in significant decreases (-7.2% to -19.2%) in a large majority (8/9) of the isometric strength-based measurements. No differences were noted for the day versus night shift workers except for the RTD at 200 millisecond variable, for which the night shift had greater work-induced decreases than the day shift workers. No changes were observed for jump height or power output. Conclusions A compressed nursing work schedule resulted in decreases in strength-based performance abilities, being indicative of performance fatigue. Application Compressed work schedules involving long shifts lead to functional declines in nurse performance capacities that may pose risks for both the nurse and patient quality of care. Fatigue management plans are needed to monitor and regulate increased levels of fatigue. PMID- 27941164 TI - Single nucleotide polymorphisms of IFNgamma (+874 A/T) and IFNgammaR1 (-56 C/T) in Iranian patients with TB. AB - BACKGROUND: Two important genes for controlling TB are IFNgamma and IFNgammaR1. However, little information exists regarding genetic susceptibility of the Iranian TB population. METHODS: We investigated the single nucleotide polymorphisms (SNPs) in genes of IFNgamma (+874 A/T) and IFNgammaR1 (-56 C/T) and serum level of IFNgamma and their influence on TB in patients; 300 patients with TB and 300 healthy controls were enrolled in this study. PCR-restriction fragment length polymorphism was used to identify SNPs and serum level of IFNgamma was measured by ELISA. RESULTS: The allelic and the genotypic form of IFNgamma+874 A/T SNP of the studied population were not significant (p>0.05). Allele T frequencies of IFNgammaR1 -56 C/T promoter region in patients with pulmonary TB (PTB) or extrapulmonary TB (EPTB) were significantly greater than allele C. The 56 TT motif of IFNgammaR1 is associated with both forms of TB (p<0.05). The serum level of IFNgamma was significantly higher in patients with TB than in controls, but there was no significant difference between serum level of IFNgamma and the studied genotypes (p>0.05). CONCLUSIONS: The cause of active TB in the patients seems to be due to the lack of effective IFNgamma function or the lack of effective signaling connection between IFNgamma and its receptor in presence of 56 C/T polymorphism in promoter region of IFNgammaR1 gene. PMID- 27941165 TI - Leishmania recombinant antigen modulates macrophage effector function facilitating early clearance of intracellular parasites. AB - BACKGROUND: Immunmodulation combined with chemotherapy has emerged as an alternative to treat infections. The study evaluates immunomodulatory properties of a Leishmania recombinant protein (rA6) in activating macrophages and clearing intracellular parasites. METHODS: The rA6 from a previously identified cDNA clone was analyzed for inducing the production of nitric oxide (NO) and reactive oxygen species (ROS) in macrophages, post and prior to infection with promastigotes by Griess method and flow cytometry. Phagocytosis and killing by treated macrophages was evaluated using Staphylococcus aureus as an index organism. Intracellular clearance of PKH67-labeled parasites from treated macrophages was assessed flowcytometrically. Combined effect of rA6 with miltefosine/AmBisome in reducing intracellular amastigotes was examined microscopically. RESULTS: Treatment with rA6 post infection caused increased production of NO with increased number of macrophages producing NO and ROS coupled with enhanced phagocytic and killing capacity. Antigen stimulated macrophages expressed high level of iNOS and TNF alpha mRNA. It synergized with miltefosine and AmBisome and facilitated early clearance of intracellular amastigotes at sub-optimal drug doses. CONCLUSION: The study demonstrates immunomodulatory potential of rA6 and presents first evidence on synergism between rA6 and anti-leishmanial drugs, thus placing it as a promising candidate for adjunct therapy. PMID- 27941166 TI - Study of commonly used organophosphate pesticides that induced oxidative stress and apoptosis in peripheral blood lymphocytes of rats. AB - In a previous study, we have found that organophosphate (OP) pesticides such as chlorpyrifos (CPF), methyl parathion (MPT), and malathion (MLT) significantly induced genotoxicity in peripheral blood lymphocytes of rats. To explore the mechanism of OP-induced genotoxicity, we measured the formation of DNA interstrand cross-links (DICs) and apoptosis in peripheral blood lymphocytes of rats. Peripheral blood lymphocytes of rats were treated with CPF, MPT, and MLT individually and in combination at concentrations of 0.1 and 0.25 LC50 for 2, 4, 8, and 12 h at 37 degrees C. Lipid peroxidation (LPO) was measured as a biomarker of oxidative stress. Apoptosis induced by CPF, MPT, and MLT individually and in combination was determined by measuring the intracellular level of active caspase 3 and caspase-9 by spectrofluorimetry. We found significant dose- and time dependent increases in LPO, DICs formation and increase of intracellular active caspase-3 and caspase-9 in exposed peripheral blood lymphocytes of rats. These findings suggest that the studied pesticides have potential to induce oxidative stress, cause DNA adduct formation, and cause failure of adduct repair, which leads to apoptosis that is partially mediated by activation of intracellular caspase-3 and caspase-9. PMID- 27941161 TI - Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems. AB - Endothelial cells that form the inner layer of blood and lymphatic vessels are important regulators of vascular functions and centrally involved in the pathogenesis of vascular diseases. In addition to the vascular endothelial growth factor (VEGF) receptor pathway, the angiopoietin (Ang)-Tie system is a second endothelial cell specific ligand-receptor signalling system necessary for embryonic cardiovascular and lymphatic development. The Ang-Tie system also regulates postnatal angiogenesis, vessel remodelling, vascular permeability and inflammation to maintain vascular homoeostasis in adult physiology. This system is implicated in numerous diseases where the vasculature has an important contribution, such as cancer, sepsis, diabetes, atherosclerosis and ocular diseases. Furthermore, mutations in the TIE2 signalling pathway cause defects in vascular morphogenesis, resulting in venous malformations and primary congenital glaucoma. Here, we review recent advances in the understanding of the Ang-Tie signalling system, including cross-talk with the vascular endothelial protein tyrosine phosphatase (VE-PTP) and the integrin cell adhesion receptors, focusing on the Ang-Tie system in vascular development and pathogenesis of vascular diseases. PMID- 27941167 TI - Protective effects of dietary selenium and vitamin C in barium-induced cardiotoxicity. AB - Several metals including barium (Ba) known as environmental pollutants provoke deleterious effects on human health. The present work pertains to the potential ability of selenium (Se) and/or vitamin C, used as nutritional supplements, to alleviate the toxic effects induced by barium chloride (BaCl2) in the heart of adult rats. Animals were randomly divided into seven groups of six each: group 1, serving as negative controls, received distilled water; group 2 received in their drinking water BaCl2 (67 ppm); group 3 received both Ba and Se (sodium selenite 0.5 mg kg-1 of diet); group 4 received both Ba and vitamin C (200 mg kg-1 bodyweight) via force feeding; group 5 received Ba, Se, and vitamin C; and groups 6 and 7, serving as positive controls, received either Se or vitamin C for 21 days. The exposure of rats to BaCl2 caused cardiotoxicity as monitored by an increase in malondialdehyde, hydrogen peroxide, and advanced oxidation protein product levels, a decrease in Na+-K+ adenosine triphosphatase (ATPase), Mg2+ ATPase, and acetylcholinesterase activities and in antioxidant defense system (catalase, glutathione peroxidase, superoxide dismutase, glutathione, and nonprotein thiols). Plasma lactate dehydrogenase and creatine kinase activities, total cholesterol, triglyceride, and low-density lipoprotein-cholesterol levels increased, while high-density lipoprotein-cholesterol level decreased. Coadministration of Se and/or vitamin C restored the parameters indicated above to near control values. The histopathological findings confirmed the biochemical results. Se and vitamin C may be a promising therapeutic strategy for Ba-induced heart injury. PMID- 27941168 TI - Wogonoside exerts growth-suppressive effects against T acute lymphoblastic leukemia through the STAT3 pathway. AB - Wogonoside is the main flavonoid of the traditional Chinese medicinal herb Scutellaria baicalensis Georgi and has been found to induce growth suppression in myelogenous leukemia cells. However, its activity in T acute lymphoblastic leukemia (T-ALL) is still unclear. In this study, T-ALL cell lines MOLT-3 and Jurkat were exposed to different concentrations of wogonoside for 48 h, and cell viability, cell cycle distribution, and apoptosis were measured. The involvement of signal transducers and activators of transcription 3 (STAT3) signaling in the activity of wogonoside was checked. The in vivo effect of wogonoside on T-ALL growth was investigated in a xenograft mouse model. Wogonoside significantly inhibited the viability of MOLT-3 and Jurkat cells, with the IC50 (the half maximal concentration) of 68.5 +/- 3.8 and 52.6 +/- 4.3 MUM, respectively. However, healthy T lymphocytes were unaffected. Wogonoside-treated Jurkat cells exhibited a G1-phase cell cycle arrest and significant apoptosis, which was coupled with inactivation of STAT3 signaling. Overexpression of constitutively active STAT3 reversed wogonoside-mediated growth suppression and apoptosis and restored the expression of cyclin D1, Mcl-1, and Bcl-xL. In vivo studies demonstrated that wogonoside retarded tumor growth and suppressed STAT3 phosphorylation in Jurkat xenografts. In conclusion, wogonoside suppresses the growth of T-ALL through the STAT3 pathway and may have therapeutic benefits in this disease. PMID- 27941170 TI - Management of traumatic patellar dislocation in a regional hospital in Hong Kong. AB - INTRODUCTION: The role of surgery for acute patellar dislocation without osteochondral fracture is controversial. The aim of this study was to report the short-term results of management of patellar dislocation in our institute. METHODS: Patients who were seen in our institution with patella dislocation from January 2011 to April 2014 were managed according to a standardised management algorithm. Pretreatment and 1-year post-treatment International Knee Documentation Committee score, Tegner activity level scale score, and presence of apprehension sign were analysed. RESULTS: A total of 41 patients were studied of whom 20 were first-time dislocators and 21 were recurrent dislocators. Among the first-time dislocators, there was a significant difference between patients who received conservative treatment versus surgical management. The conservative treatment group had a 33% recurrent dislocation rate, whereas there were no recurrent dislocations in the surgery group. There was no difference in Tegner activity level scale score or apprehension sign before and 1 year after treatment, however. Among the recurrent dislocators, there was a significant difference between those who received conservative treatment and those who underwent surgery. The recurrent dislocation rate was 71% in the conservative treatment group versus 0% in the surgery group. There was also significant improvement in International Knee Documentation Committee score from 67.7 to 80.0 (P=0.02), and of apprehension sign from 62% to 0% (P<0.01). CONCLUSIONS: A management algorithm for patellar dislocation is described. Surgery is preferable to conservative treatment in patients who have recurrent patellar dislocation, and may also be preferable for those who have an acute dislocation. PMID- 27941171 TI - The role of season and climate in the incidence of congenital hypothyroidism in Kerman province, Southeastern Iran. AB - BACKGROUND: Congenital hypothyroidism (CH) is a common endocrine disease and an important cause of mental retardation. The purpose of this study was to investigate the probable role of season and climatic factors in the incidence of CH in Kerman province, Iran. METHODS: Incidence data were collected from the CH screening program files from 2005 to 2011 in Kerman province, a number of 288,437 infants were included in the study. Climate data were collected from the Meteorological Office. The relations were tested by chi2-test, Pearson correlation, and negative binomial regression. RESULTS: The overall incidence of CH in Kerman province was 2.68 per 1000 births. There was a significant difference in both the monthly and seasonal incidence of CH (p<0.05). There were a few significant, but weak correlation between some climatic factors and the incidence of CH in some regions, but the results were inconsistent. CONCLUSIONS: It seems like there is no clear relation between CH incidence and climate factors, in Kerman Province. However, CH incidence was highest in October (Autumn) and lowest in June (Summer). PMID- 27941169 TI - Nilotinib attenuates endothelial dysfunction and liver damage in high-cholesterol fed rabbits. AB - Nilotinib is an oral potent tyrosine kinase inhibitor that has diverse biological activities. However, its effects on hypercholesterolemia and associated disorders have not been studied yet. The present study explored the effect of nilotinib on atherosclerosis progression, endothelial dysfunction, and hyperlipidemia associated hepatic injury in high-cholesterol (HC)-fed rabbits. Rabbits were classified into four groups: control, nilotinib, HC, and HC + nilotinib groups. Rabbits were fed either a regular diet or an HC-enriched diet for 8 weeks. By the end of the eighth week, blood and tissue samples were obtained for biochemical, histological, immunohistochemical, and in vitro analyses. Results indicated that the HC diet induced a significant elevation in the serum lipid parameters (triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high density lipoprotein cholesterol), lactate dehydrogenase, and nitric oxide content. Endothelial dysfunction was evident through the impairment of acetylcholine-induced relaxation of isolated aortas and the histopathological lesions of the aortic specimen. Moreover, HC significantly increased serum malondialdehyde. Liver damage was clear through increase in serum transaminases and alkaline phosphatase, and it was further supported by histopathological examination. HC increased the expression of platelet-derived growth factor receptor (PDGFR)-B in both aorta and liver tissues. Interestingly, nilotinib administration retarded atherosclerosis progression and attenuated all of the aforementioned parameters. These data suggest that nilotinib may counteract atherosclerosis development, vascular dysfunction, and hepatic damage in HC-fed rabbits through interfering with PDGF-B. PMID- 27941172 TI - Elevated endogenous secretory receptor for advanced glycation end products (esRAGE) levels are associated with circulating soluble RAGE levels in diabetic children. AB - BACKGROUND: Advanced glycation end products (AGEs) and the receptor for AGE (RAGE) play an important role in the development of diabetic vascular complications. This study aimed at investigating the relationship between the soluble form of RAGE (sRAGE), endogenous secretory RAGE (esRAGE), and pentosidine in childhood diabetes. METHODS: The study included 18 children with type 1 diabetes mellitus (T1DM), 10 with type 2 DM (T2DM), and 22 age-matched, non diabetic children (control). RESULTS: Serum sRAGE levels in the T1DM (2557.7 pg/mL) were significantly higher than both T2DM (1956.4 pg/mL) and control (1658.5 pg/mL). The circulating levels of esRAGE in T1DM and T2DM children were similar, but significantly higher than those of control. Serum pentosidine levels in the T1DM group were positively correlated with serum sRAGE and esRAGE levels, but not with anthropometric or biochemical measurements. The duration of diabetes and esRAGE levels were independent predictors of the circulating sRAGE levels. CONCLUSIONS: Unlike adults, children with diabetes exhibit high circulating esRAGE levels, and both sRAGE and esRAGE levels are correlated with pentosidine levels. These results suggest that circulating sRAGE and esRAGE in children may be surrogate markers for progressive glucose toxicity in pediatric patients with childhood-onset diabetes. PMID- 27941173 TI - Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2. AB - BACKGROUND: Heterozygous loss-of-function mutations in the natriuretic peptide receptor B gene (NPR2) are responsible for short stature in patients without a distinct phenotype. Some of these patients have been treated with recombinant human growth hormone (rhGH) therapy with a variable response. CASE PRESENTATION: The proband was a healthy boy who presented at the age of 5.1 years with familial short stature (height SDS of -3.1). He had a prominent forehead, a depressed nasal bridge, centripetal fat distribution and a high-pitched voice resembling that of children with GH deficiency. His hormonal evaluation showed low insulin like growth factor-1 (IGF-1) but a normal GH peak at a stimulation test. During the first year of rhGH treatment, his growth velocity increased from 3.4 to 10.4 cm/year (height SDS change of +1.1). At the last visit, he was 8.8 years old and still on treatment, his growth velocity was 6.4 cm/year and height SDS was -1.8. RESULTS: We identified through exome sequencing a novel heterozygous loss-of function NPR2 mutation (c.2905G>C; p.Val969Leu). Cells cotransfected with the p.Val969Leu mutant showed a significant decrease in cyclic guanosine monophosphate (cGMP) production compared to the wild type (WT), suggesting a dominant negative effect. CONCLUSIONS: This case reveals a novel heterozygous loss-of-function NPR2 mutation responsible for familial short stature and the good response of rhGH therapy in this patient. PMID- 27941174 TI - Nocturnal levels of chemerin and progranulin in adolescents: influence of sex, body mass index, glucose metabolism and sleep. AB - BACKGROUND: Adipokines have been implicated in obesity, insulin resistance and sleep regulation. However, the role of chemerin and progranulin, two recently described adipokines, in the context of sleep remains unclear. The aim of this study was to compare nocturnal serum chemerin and progranulin levels between overweight/obese and normal-weight adolescents and to assess variations by sex, across different sleep stages and in relation to glucose metabolism. METHODS: The study sample included 34 overweight/obese and 32 normal-weight adolescents from secondary schools and the Leipzig Research Center for Civilization Diseases (LIFE) Child study cohort. We obtained longitudinal serum adipokine levels during in-laboratory polysomnography followed by an oral glucose tolerance test. RESULTS: Overweight/obese adolescents had significantly higher mean nocturnal serum chemerin area under the curve (AUC) levels (348.2+/-133.3 vs. 241.7+/-67.7 vs. ng/mL*h, p<0.001) compared to normal-weight controls. In detail, higher chemerin AUC levels in obese/overweight subjects were exclusively due to increased levels in females. No overall difference for serum progranulin AUC was found between the groups. However, when assessing sex-specific levels, serum progranulin AUC levels were ~30% higher in overweight/obese males compared to overweight/obese females. Of note, nocturnal serum chemerin and progranulin AUC did not exhibit a correlation with markers of glucose metabolism or sleep stages. CONCLUSIONS: Collectively, we report a sexual dimorphism in nocturnal progranulin and chemerin levels, which may help explain underlying differences in energy balance and body composition between males and females in the context of obesity. PMID- 27941175 TI - A case of hypercalcaemic crisis secondary to coexistence of primary hyperparathyroidism and Graves' disease. AB - A 46 year-old female patient presented to the hospital with ongoing and progressively increasing fatigue, severe nausea and vomiting, loss of appetite, constipation, palpitations and somnolence. Laboratory evaluation revealed a severe hypercalcaemia and overt hyperthyroidism. She was diagnosed with primary hyperparathyroidism accompanied by Graves' disease. The patient underwent total thyroidectomy and right inferior parathyroid gland adenoma excision on the 24th day of her admission to the hospital after calcium levels and free thyroid hormone levels were brought to normal ranges. We suggest that a possibility of simultaneous thyrotoxicosis and primary hyperparathyroidism in cases presenting with a hypercalcaemic crisis should be considered. PMID- 27941177 TI - Effect of the autonomic nervous system on cancer progression depends on the type of tumor: solid are more affected then ascitic tumors. AB - OBJECTIVES: A number of recently published studies have shown that the sympathetic nervous system may influence cancer progression. There are, however, some ambiguities about the role of the parasympathetic nerves in the modulation of growth of different tumor types. Moreover, tumor models used for investigation of the autonomic neurotransmission role in the processes related to the cancer growth and progression are mainly of the solid nature. The knowledge about the nervous system involvement in the modulation of the development and progression of malignant ascites is only fragmental. Therefore, the aim of the present article was to summarize the results of our experimental studies focused on the elucidation of the role of the autonomic nervous system in the modulation of tumor growth in animals. We are summarizing data from studies, in which not only different experimental approaches in order to influence the autonomic neurotransmission, but also different tumor models have been used. METHODS: Three different types of tumor models, namely solid rat intra-abdominal fibrosarcoma, solid murine subcutaneous melanoma, and rat ascites hepatoma, and three types of interventions have been used in order to modulate the autonomic neurotransmission, specifically chemical sympathectomy, subdiaphragmatic vagotomy, or the electric stimulation of the vagus nerve. RESULTS: We have proved a strong stimulatory effect of the sympathetic nerves on the development and growth in both solid tumors, rat fibrosarcoma as well as murine melanoma, and significant inhibitory impact on the survival time of tumor-bearing animals. The progression of ascites hepatoma in rats was not influenced by chemical sympathectomy. Modulation of parasympathetic signalization by vagotomy or vagal nerve stimulation does not affect fibrosarcoma and ascites hepatoma growth and survival of the tumor-bearing rats. CONCLUSIONS: Based on the obtained data, it seems that the solid types of tumors are suitable substrate for the direct action of neurotransmitters released especially from the sympathetic nerves. In contrast, it appears that the malignant ascites are not under the direct autonomic nerves control; however, an indirect action via the immune functions modulation cannot be excluded. PMID- 27941176 TI - Protective effects of boron and vitamin E on ethylene glycol-induced renal crystal calcium deposition in rat. AB - OBJECTIVES: Kidney stone disease is a common form of renal disease. Antioxidants, such as vitamin E (Vit E) and boron, are substances that reduce the damage caused by oxidation. METHODS: Adult male rats were divided into 5 groups (n=6). In group 1, rats received standard food and water for 28 days (control group); in group 2, standard rodent food and water with 0.75% ethylene glycol/d (dissolved in drinking water) (EG Group); in group 3, similar to group 2, with 3 mg of boron/d (dissolved in water) (EG+B Group); in group 4, similar to group 2, with 200 IU of vitamin E injected intraperitoneally on the first day and the 14th day, (EG+Vit E Group); in group 5, mix of groups 3 and 4, respectively (EG+B+Vit E Group). RESULTS: Kidney sections showed that crystals in the EG group increased significantly in comparison with the control group. Crystal calcium deposition score in groups of EG+B (160), EG+Vit E, and EG+B+Vit E showed a significant decrease compared to EG group. Measurement of the renal tubules area and renal tubular epithelial histological score showed the highest significant dilation in the EG group. Tubular dilation in the EG+B+Vit E group decreased compared to the EG+B and EG+Vit E groups. CONCLUSIONS: Efficient effect of boron and Vit E supplements, separately and in combination, has a complimentary effect in protection against the formation of kidney stones, probably by decreasing oxidative stress. PMID- 27941178 TI - Alternative renin-angiotensin system pathways in adipose tissue and their role in the pathogenesis of obesity. AB - Adipose tissue expresses all the renin-angiotensin system (RAS) components that play an important role in the adipogenesis, lipid and glucose metabolism regulation in an auto/paracrine manner. The classical RAS has been found to be over-activated during the adipose tissue enlargement, thus elevated generation of angiotensin II (Ang II) may contribute to the obesity pathogenesis. The contemporary view on the RAS has become more complex with the discovery of alternative pathways, including angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor, (pro)renin receptor, as well as angiotensin IV(Ang IV)/AT4 receptor. Ang-(1-7) via Mas receptor counteracts with most of the deleterious effects of the Ang II-mediated by AT1 receptor implying its beneficial role in the glucose and lipid metabolism, oxidative stress, inflammation, and insulin resistance. Pro(renin) receptor may play a role (at least partial) in the pathogenesis of the obesity by increasing the local production of Ang II in adipose tissue as well as triggering signal transduction independently of Ang II. In this review, modulation of alternative RAS pathways in adipose tissue during obesity is discussed and the involvement of Ang-(1-7), (pro)renin and AT4 receptors in the regulation of adipose tissue homeostasis and insulin resistance is summarized. PMID- 27941179 TI - Flaxseed oil supplementation manipulates correlations between serum individual mol % free fatty acid levels and insulin resistance in type 2 diabetics. Insulin resistance and percent remaining pancreatic beta-cell function are unaffected. AB - OBJECTIVES: Elevated total serum free fatty acids (FFAs) concentrations have been suggested, controversially, to enhance insulin resistance and decrease percent remaining beta-cell function. However, concentrations of individual serum FFAs have never been published in terms of their relationship (correlation) to homeostatic model assessment-insulin resistance (HOMA-IR) and percent remaining beta-cell function (HOMA-%beta) in the type 2 diabetics (T2Ds). Alpha-linolenic acid consumption has a negative correlation with the insulin resistance, which in turn is negatively correlated with the remaining beta-cell function. The primary objective was to test the hypothesis that there would be different relationship (correlation) between the blood serum individual free FFA mol % levels and HOMA IR and/or HOMA-%beta in T2D. The secondary objective was to test the hypothesis that flaxseed oil, previously being shown to be ineffective in the glycemic control in T2Ds, may alter these correlations in a statistically significant manner as well as HOMA-IR and/or HOMA-%beta. METHODS: Patients were recruited via a newspaper advertisement and two physicians have been employed. All the patients came to visit one and three months later for a second visit. At the second visit, the subjects were randomly assigned (double blind) to flaxseed or safflower oil treatment for three months, until the third visit. RESULTS: Different statistically significant correlations or trends towards among some serum individual free FFA mol % levels and HOMA-IR and HOMA-%beta, pre- and post flaxseed and safflower oil supplementation were found. However, flaxseed oil had no impact on HOMA-IR or HOMA-%beta despite statistically significant alterations in correlations compared to baseline HOMA-IR. CONCLUSIONS: The obtained data indicate that high doses of flaxseed oil have no statistically significant effect on HOMA-IR or HOMA-%beta in T2Ds, probably due to the additive effects of negative and positive correlations. PMID- 27941181 TI - Hypogonadotropic hypogonadism in a female patient with congenital arhinia. AB - The association of anosmia and congenital hypogonadotropic hypogonadism (CHH) is well described; however, congenital arhinia is a malformation associated with CHH that occurs much more rarely. There have been three reports of male patients with hypogonadism and congenital arhinia in the literature to date. We present the first case of arhinia associated with CHH in a female patient. A 14 years and 8 months female with congenital arhinia presented with delayed puberty. Physical examination and laboratory evaluation were consistent with hypogonadotropic hypogonadism. She had no other hormone deficiencies and brain magnetic resonance imaging demonstrated a normal pituitary gland. Abdominal ultrasound showed a prepubertal uterus and ovaries. She was subsequently started on sex steroid treatment to induce secondary sexual characteristics. This case demonstrates that abnormalities of nasal development may provide an early diagnostic clue to hypogonadotropic hypogonadism, particularly in female patients who would not manifest classic signs of CHH in infancy (micropenis and cryptorchidism). Early diagnosis of CHH and timely initiation of sex steroid therapy is important to prevent comorbidities related to pubertal delay. PMID- 27941180 TI - Sympathectomized tumor-bearing mice survive longer but develop bigger melanomas. AB - OBJECTIVES: Previously we have shown that 20 days after the tumor cells injection smaller melanomas have been developed in chemically sympathectomized mice in comparison with animals having intact sympathetic nervous system. However, it is known that chemical sympathectomy reduces the sympathetic neurotransmission only temporarily. In the present study, we monitored the survival of the sympathectomized mice with melanoma with an attempt to find out how long the suppressing effect of sympathectomy on the melanoma growth may endure. METHODS: The chemical sympathectomy was performed by intraperitoneal injection of neurotoxin 6-hydroxydopamine in male C57BL/6J mice. Seven days later, the animals were injected subcutaneously with B16-F10 melanoma cells. Then, melanoma development, survival of the tumor-bearing mice and weight of the developed tumor mass were analyzed. RESULTS: Sympathectomy delayed the development of the palpable tumors (18th day vs.14th day) and significantly prolonged the survival of the tumor-bearing mice (median 34 days vs. 29 days). However, the weight of the developed melanoma was significantly increased in the sympathectomized mice in comparison with the animals having intact sympathetic nervous system. CONCLUSIONS: The data of the present study showed that effect of the chemical sympathectomy, performed before the tumor growth induction, persisted even at the time when sympathetic nerves started to regenerate that resulted in a prolonged survival of the mice with melanoma. However, comparing to our previous study, in which we have shown a reduced tumor mass in earlier stages of the tumor growth, specifically 20 days after melanoma cells injection, now we indicate that in later stages of the melanoma progression, the tumor mass was significantly increased in sympathectomized animals. These contra-intuitive findings may indicate that interventions affecting the sympathetic nervous system may exert complex effect on the tumor progression. Based on these data we may suggest that the potential therapeutic interventions affecting the sympathetic signaling in the tumor tissue and its microenvironment should attenuate the sympathetic neurotransmission not only temporarily but till the complete regression of the tumor tissue. PMID- 27941182 TI - Paramedic and midwifery student exposure to workplace violence during clinical placements in Australia - A pilot study. AB - Objectives: The objective of this pilot study was to identify the type of workplace violence experienced by undergraduate paramedic and midwifery students. Methods: The study used a cross-sectional methodology with the self-administered paper-based Paramedic Workplace Violence Exposure Questionnaire to elicit undergraduate paramedic and midwife responses to workplace violence whilst on clinical placements. There were 393 students eligible for inclusion in the study. A convenience sample was used. The anonymous questionnaire took 10 to 20 minutes to complete. Descriptive statistics are used to summarise the data with a two tailed t-test used to compare groups. Results: The main form of workplace violence was verbal abuse 18% and intimidation 17%. There was a statistically significant difference between midwifery and paramedic students for intimidation (t(134)=-3.143, CI: -0.367 to -0.082, p=0.002) and between females and males for sexual harassment (t(134)=2.029, CI: 0.001 to 0.074, p=0.045), all other results were not statistically different. Conclusions: This pilot study is the first of its kind in Australia and internationally to identify exposure rates of workplace violence by undergraduate paramedic students during clinical placements and one of very few to identify midwifery students' exposure rates of workplace violence. The study identified that students were exposed to a range of workplace violence acts from verbal abuse through to sexual harassment. These findings highlight a need for investigation of workplace violence exposure of medical, nursing and allied health students during the clinical phase of their studies. PMID- 27941183 TI - Development of a Brazilian Portuguese adapted version of the Gap-Kalamazoo communication skills assessment form. AB - Objective: The goal of this study was to translate, adapt and validate the items of the Gap-Kalamazoo Communication Skills Assessment Form for use in the Brazilian cultural setting. Methods: The Gap-Kalamazoo Communication Skills Assessment Form was translated into Portuguese by two independent bilingual Brazilian translators and was reconciled by a third bilingual healthcare professional. The translated text was then assessed for content using a modified Delphi technique and adjusted as needed to assure content validity. A total of nine phrases in the completed tool were adjusted. The final tool was then used to assess videotaped simulations as a means of validation. Response process was assessed using exploratory factor analysis and internal structure was assessed via Cronbach's Alpha (internal consistency) and Intraclass Correlation (test retest reliability and inter-rater reliability). Results: One hundred and four (104) videotaped communication skills simulations were assessed by 38 subjects (6 staff physicians, 4 faculty physicians, 8 resident physicians, 4 professional actors with experience in simulation, and 16 other allied healthcare professionals). Measures of Internal consistency (Cronbach's alpha = 0.818) and test-retest reliability (intra-class correlation coefficient = 0.942) were high. Exploratory factor analysis confirmed the uni-dimensionality of the instrument. Conclusions: Our results support the validity and reliability of the Brazilian Gap-Kalamazoo Communication Skills Assessment Form when used among Brazilian medical residents. The Brazilian version of Gap-Kalamazoo Communication Skills Assessment Form was found to be adequate both in the linguistic and technical aspects. The use of this instrument in Brazilian medical education can enhance the assessment of physician-patient-team relationships on an ongoing basis. PMID- 27941184 TI - Should we be more aware of endometrial cancer in adolescents? AB - Although endometrial cancer is generally diagnosed in women after menopause, it may incidentally develop in young women or even in adolescents. Diagnostic tools should be applied in young teenage girls complaining of abnormal genital bleeding, particularly those with hereditary cancer syndromes (such as Cowden or Lynch syndromes). Adolescents affected by polycystic ovary syndrome and obesity may also be at increased risk for the development of atypical endometrial hyperplasia and endometrial cancer, and should be carefully managed when the distressing symptoms occur. In the present article, we briefly summarize the principal clinical correlates associated with endometrial cancer in adolescents. PMID- 27941186 TI - Mixed Gonadal Dysgenesis with an unusual "inverted" Y chromosome. AB - Mixed gonadal dysgenesis is a rare disorder of sex development associated with sex chromosome aneuploidy and mosaicism of the Y chromosome. It is characterized by a unilateral non-palpable (usually intra-abdominal) testis, a contralateral streak gonad and persistent mullerian structures. The clinical presentation can vary from a typical male to female phenotype including all degrees of cryptorchidism, labial fusion, clitoromegaly, epispadias and hypospadias. It is the second most common cause of ambiguous genitalia in the neonatal period. We report a case of Mixed Gonadal Dysgenesis with an inverted Y chromosome. PMID- 27941185 TI - Fetus in Fetu: Two Cases and Literature Review. AB - Fetus in fetu is a rare cause of abdominal mass in infants wherein a parasitic twin grows inside a host. The true etiology is unclear. Various theories have been postulated. We report two cases of retroperitoneal fetus in fetu in female infants. PMID- 27941187 TI - Factors related to compliance with palivizumab prophylaxis for respiratory syncytial virus (RSV) infection - data from Poland. AB - AIM: To evaluate compliance and health outcomes in children receiving palivizumab prophylaxis and to identify factors that could impact parental compliance with the recommended regimen of palivizumab immunoprophylaxis. MATERIAL AND METHODS: A retrospective, multicentre, non-interventional study of children enrolled in the Polish National Programme for Respiratory Syncytial Virus (RSV) Immunoprophylaxis who received >=1 dose of palivizumab during two consecutive RSV seasons (I: 2008 2009, II: 2009-2010). For each child qualified to receive palivizumab, the following data were collected: sociodemographic factors, clinical characteristics at enrolment, and in the course of palivizumab prophylaxis. RESULTS: One thousand twenty-one infants were enrolled into the Registry at 29 sites across Poland and received a total of 3,241 palivizumab injections (average: 3.2 doses per child). The incidence of adverse reactions was 3.33%; nervousness was the most frequently reported event (1.23%). Overall, 771 (75.5%) children received all of their expected injections, whereas 635 (62.2%) children received their injections within the appropriate interdose interval. Compliance was lower in male infants. None of the other demographic, social, or clinical factors seemed to impact compliance. Non-compliant children had a higher rate of hospitalisation due to respiratory illness (22% vs 9.9%, p<0.0001, and 18.4% vs 9.5%, p<0.0001, for compliance defined by the number of expected injections received and by the interdose interval, respectively). CONCLUSIONS: Palivizumab prophylaxis was conducted in accordance with recommendations and was well tolerated in at-risk infants. Non-compliance was higher among male infants and was related with a higher rate of hospitalisation due to respiratory illness. PMID- 27941188 TI - Arthrogryposis multiplex congenital - multidisciplinary care - including own experience. AB - Arthrogryposis multiplex congenital (AMC) is a heterogeneous disorder, characterized by nonprogressive multiple intra-articular contractures, which can be recognized at birth. The prevalence in Europe is estimated at about 1 per 12,000. Etiopathogenesis of arthrogryposis is multifactorial. Symptoms of some forms of arthrogryposis can be found in the clinical presentation of selected genetic disorders, e.g. Pena Shokeir syndrome. Arthrogryposis can also result from environmental factors such as medication, trauma or chronic illness during pregnancy, as well as from oligohydramnios or abnormal structure of the uterus. In this particular disorder prenatal diagnosis is crucial, because it determines the level of hospital reference during the delivery of the affected child. The highest reference degree hospital is preferential, with staff prepared for the multidisciplinary approach to the treatment of the newborn. The key to success is rehabilitation treatment and it should be initiated as soon as possible. In a substantial number of cases, physical therapy can replace invasive corrective surgery, but even when orthopedic treatment is required, it should always be preceded and followed by rehabilitation. PMID- 27941189 TI - Clinical evaluation of children with ulcerative colitis treated between 2013-2015 - own experience. AB - AIM: Evaluation of the changes in the endoscopic, laboratory and clinical status in children with ulcerative colitis (UC) with regard to the duration of the disease. MATERIAL AND METHODS: 91 children with UC were involved in the study. Each of them had colonoscopy and their laboratory values were tested. We assessed the colonoscopy results by the Paris classification and by the Baron score. Moreover, demographic, clinical and anthropometric data were collected. We divided our patients into five subgroups depending on the duration of the disease. In order to assess the changes in the variables, we conducted the Mann Whitney U test. RESULTS: The most numerous group were patients whose disease had lasted between 1 and 2.5 years. At the time of assessment 39.6% did not have inflammation lesions in the mucosa and 60.4% were in sustained clinical remission. At the time of diagnosis 55% of the participants had pancolitis or extensive colitis and 66% had ulcers or ulcerations in the mucosa. We found a statistically significant decrease in the extension of the disease between the patient at diagnosis and the patient during the first year after diagnosis, with p=0.049, but there were no statistically significant differences in the activity of the inflammatory changes between those groups. No significant changes were found in laboratory values, apart from those pertaining to faecal calprotectin (FC). During our study 95% of the patients were exposed to mesalazin, 66% to corticosteroids, 57% to immunosuppressants and 10% to biologics. 20% of our patients were exposed to steroids more than once. CONCLUSIONS: The changes observed during colonoscopy in children with UC have a widespread localization and varied aggression. With the duration of the disease, inflammatory lesions tend to acquire more and more of the surface in the colon, but are not characterized by a progression of their activity. The issue requires further well designed studies. PMID- 27941190 TI - Assessment of induction therapy with infliximab in children with moderate to severe ulcerative colitis: a multi-center study. AB - THE AIM OF THE STUDY: Assessment of clinical and endoscopic efficacy of induction therapy with infliximab in children with ulcerative colitis. MATERIAL AND METHODS: This is a retrospective analysis of medical records of pediatric patients with moderate to severe UC who had received at least one infusion of infliximab in Polish pediatric academic clinical centers from 2003 to 2013. The primary endpoint was clinical remission rate at week 10, (PUCAI score <10 points) while the secondary endpoints were: clinical response rate (>19-points decrease in PUCAI), mucosal response rate (defined as an improvement of the Baron score), and mucosal healing rate (Baron score 0 or 1). RESULTS: 44 patients, at mean age of 14+/-3.9 years, were included into the study. 38 (86%) patients completed induction therapy regimen with infliximab and were finally included into the analysis. Clinical response and remission rates at week 10 there were 36% and 25% respectively. There was significant drop of PUCAI (58.31+/-15.5 vs. 24.23+/ 23.83) and Baron score (2.63+/-0.49 vs. 1.44+/-0.99) at this time point. Mucosal response and mucosal healing rate were 57% and 48% respectively. Infliximab failure defined as non-clinical and non-mucosal response at week 10, occurred in 16 patients. Infliximab-associated adverse events occurred in 3 patients, with all severe hypersensitivity reactions to infliximab. CONCLUSIONS: Infliximab induction therapy was safe and effective in Polish moderate to severe UC pediatric patients with 50% rate of mucosal improvement. However, clinical response rate was lower than previously reported. PMID- 27941191 TI - Diagnostic and therapeutic management of children with lysosomal acid lipase deficiency (LAL-D). Review of the literature and own experience. AB - Lysosomal acid lipase deficiency may present at any age (in infants, children and adults). Its presenting features commonly include elevated serum transaminase activity levels, hypercholesterolemia, fatty liver, progressive liver fibrosis, and cirrhosis. Nonspecific clinical manifestations can lead to a delay in the diagnosis of both children and adults. The early development of fibrosis and cirrhosis suggests that the lysosomal accumulation of cholesterol esters and triglycerides in the liver is a potent inducer of fibrosis. Elevated levels of low-density lipoprotein-cholesterol or low levels of high-density lipoprotein cholesterol with elevated transaminase activity should raise the suspicion of lysosomal acid lipase deficiency in the diagnostic workup. Still, some patients may not present with abnormal triglyceride and cholesterol concentrations. Early onset LAL-D has a different clinical presentation, with acute symptoms, including liver failure, and can be confused with many other metabolic conditions or with lymphohistiocytosis. The dried blood spot test enables rapid diagnosis and should be widely applied when the cause of liver disease remains unknown. PMID- 27941192 TI - Clinical presentations of Wilson disease among Polish children. AB - INTRODUCTION: Wilson disease (WD) may present from early childhood up to the eighth decade, presenting with variable hepatic and neuropsychiatric symptoms. Establishing the diagnosis is straightforward if the major clinical and laboratory features are present. However, clinical phenotypes are highly varied and early, proper diagnosis can be challenging. AIM: The aim of our study was to analyze clinical presentations and diagnostic tests of Polish pediatric patients with WD. METHODS: We retrospectively analyzed medical history of 156 patients with confirmed diagnosis of WD treated at our Institute from 1996 till March 2016. RESULTS: The mean age at onset of symptoms was 10.15+/-4.23 years of age. Hepatic presentation was the most common one (94.23%) with either liver failure (16.03%) or more frequently increased transaminases (78.2%). In 90.26% cases ceruloplasmin serum concentration was <=0,2 g/l, in 51.93% patients basal urinary copper excretion was >100 MUg/24 h. Mutation analysis was performed in 155 (99.36%) cases. The most common mutation was p.H1069Q. CONCLUSIONS: Wilson disease can present with only significantly increased transaminases activity and hepatomegaly or liver failure, but neurological symptoms are very rare in children. Diagnostic approach is challenging due to wide spectrum of clinical presentations in a high variable degree of severity. Genetic screening is supportive, ceruloplasmin and urinary copper excretion are valuable tests in the majority of patients but do not allow to exclude WD. PMID- 27941193 TI - Comparison of 72-hour fecal fat quantification and the 13C-mixed triglyceride breath test in assessing pancreatic exocrine sufficiency in children with chronic pancreatitis. AB - INTRODUCTION: Chronic pancreatitis (CP) in children is still a rare, although increasingly recognized entity. Over the duration of the disease several complications can be observed, two of which are major ones: endo- and exocrine insufficiency. In the medical care of children with CP it is crucial to diagnose the decreased endo- and exocrine function of the pancreas, in order to preserve patients from malnutrition and the failure to thrive. The aim of the study was to compare the usefulness of two indirect methods of assessing the pancreas exocrine function in children with CP. MATERIAL AND METHODS: Ninety one patients with CP were enrolled in the study (41 boys, 50 girls, aged 2-17.8 years). Only Patients who had had both the 72-hour fecal fat quantification and the 13C-mixed triglyceride breath test (13C -MTBT) performed were selected. We compared the results of both tests for sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) in detecting exocrine pancreatic insufficiency. RESULTS: Out of 91 patients, 12 were diagnosed with exocrine pancreatic insufficiency (EPI). The sensitivity of the fecal fat quantification was 50%, the specificity for the test was 100%. PPV and NPV were 100% and 93%, respectively. 13C-MTBT had the sensitivity of 42% and the specificity of 99%. PPV and NPV for the breath test were of 83% and 92%, respectively. No statistically significant discrepancy between the values obtained was found. CONCLUSIONS: Although the 72-hour fecal fat quantification remains the gold standard in detecting EPI, both of the methods that had been investigated were shown to be comparable regarding sensitivity, specificity, PPV and NPV in assessing pancreas exocrine sufficiency in children with CP. Due to the easier execution of the breath test, both for the patient and for medical personnel, its importance may increase. PMID- 27941194 TI - [Genetic mutations as a cause of acute recurrent pancreatitis in children - case report and literature review]. AB - Acute recurrent pancreatitis is not common in children. The epidemiology, etiology and clinical presentation of pediatric acute recurrent pancreatitis are not well understood. The etiology is diverse and multifactorial, with many cases being idiopathic. The most common etiology of acute recurrent pancreatitis in children are genetic factors, biliary duct disorders, anatomic anomalies of the pancreatobiliary system and metabolic diseases. Mutations are most commonly found in the cationic trypsynogen gene (PRSS1), the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cystic fibrosis transmembrane conductance regulator gene (CFTR). The case described here is that of a 6-year-old boy, without a family history of pancreatitis, who was hospitalized several times over 5 years, with epigastric pain and high serum levels of amylase and lipase. Genetic testing showed a heterozygous variation, c.194+2T>C (IVS3+2T>C) in the SPINK1 gene and variation c.1210-34TG(11) T(5) (IVS8-5T+(TG)11) in the CFTR gene. Other etiological factors also occurred leading to the initiation and relapses of the disease. PMID- 27941195 TI - Mucoceles of minor salivary glands in children. Own clinical observations. AB - INTRODUCTION: Mucoceles are benign lesions associated with the pathology of the oral mucosa of minor salivary glands. Two types of cysts are distinguished depending on their pathogenesis. Most often they occur as a result of mechanical trauma and mucus extravasation into tissues or obstruction of the gland ducts. AIM: The aim of the study was to present our own experiences regarding mucoceles of minor salivary glands in the oral cavity taking into account how frequently the individual types of cysts occur in children. MATERIAL AND METHODS: The research was carried out based on medical files from the years 2005-2015. These were: medical case records, operating books and the medical registry of patients treated at the Clinic of Maxillofacial Surgery, Frederic Chopin Clinical Regional Hospital in Rzeszow. In that period 64 children and teenagers, 28 girls and 36 boys were treated. What was considered was the age and gender of the patients, the reason for their appointment with a doctor, the location, size and histopathological type of the cysts, as well as the course and results of the diagnostic and therapeutic process. RESULTS: In the group analyzed, the reasons for referral to the Clinic were: in 25 patients accidental ascertainment of a non symptomatic tumor in the oral cavity during examination by a dentist, pediatrician or laryngologist which had not caused any discomfort to the children; in 13 patients concern had been raised by a gradually increasing tumor; in 18 cases there was an increased tissue tension surrounding the tumor, while in 3 children red oedema was observed in the oral cavity (suspicion of abscess). The most frequent mucocele location was the lower lip (34 children). The most frequent size was 2.1-3 cm (28 children). The most frequent histological type was MEP. All the patients were treated at the Clinic in the one-day surgery mode, with good outcome. CONCLUSIONS: Mucocele ascertainment in children's oral cavity could be made accidentally in routine pediatric examination, therefore it is necessary to extend pediatricians' knowledge about small salivary gland mucoceles. The most frequent type of MEP could be related to different types of trauma in the oral mucose. PMID- 27941196 TI - Gluten-containing products in the diet of infants in nutritional recommendations a retrospective view and conclusions for the future. AB - The discussion on the optimal timing of the introduction of gluten products and their quantity into the diet of infants in order to reduce the risk of the development of undesirable reactions to gluten, including celiac disease, has been going on for years. The aim of this study was to present how the relevant Polish nutritional recommendations in this regard had changed over the last fifty years. PMID- 27941197 TI - [Immune-Mediated Inflammatory Diseases and accompanying comorbidities]. AB - Immune-Mediated Inflammatory Diseases (IMIDs) are a group of unrelated conditions that share common inflammatory pathways with immune dysregulation and imbalance in inflammatory cytokines. The aetiology of these conditions is unknown. IMIDs encompassing disorders as diverse as asthma, type 1 and 2 diabetes mellitus, inflammatory bowel diseases (IBD) Crohn disease and ulcerative colitis, rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis (Ps), psoriatic arthritis (PsA), uveitis, juvenile idiopathic arthritis (JIA). IMIDs are associated with relative over-expression of cytokines such as TNF alpha. TNF alpha blockers are licensed for clinical use in IMIDs conditions such as RA, Ps, PsA, uveitis, IBD, AS, JIA. In patients with spondyloarthritis extra-articular manifestations are frequently observed e g psoriasis, uveitis, and IBD. Such conditions should be managed in collaboration with rheumatologists, gastroenterologists and dermatologists by drugs effective in all conditions. TNF alpha blockers could be a such alternative. Screening and treatment of accompanying comorbidities is very important in patients with IMIDs. PMID- 27941198 TI - [Clinical and ultrasound assessment of the disease activity in patients with rheumatoid arthritis]. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease, leading to irreversible joint destruction and deformities. The adequate assessment of the disease activity enables the correct choice of therapy and evaluation of the treatment efficacy. The aim of the study was to compare different methods of assessment of the disease activity, using clinical data and ultrasonography (US) of joints, in patients with RA, in daily clinical practice. MATERIAL AND METHODS: The study group consisted of 68 patients with RA. The clinical assessment of the disease activity was performed using the Disease Activity Score based on evaluation of 28 joints (DAS28). Ultrasonography (US) examination of joints was performed in 24 small joints, evaluating hypertrophy and vascularity of the synovium. Ability to perform daily activities was measured using the modified Health Assessment Questionnaire (M-HAQ) Results: There were statistically significant correlations between the grade of synovial vascularity of joints and parameters of clinical activity [tender joints count (TJC), swollen joints count (SJC), DAS28] and laboratory acute phase parameters (ESR, CRP). The grade of synovial hypertrophy was significantly associated with SJC and DAS28, and not with laboratory parameters. M-HAQ value was significantly associated only with TJC. CONCLUSIONS: In RA patients an assessment of the disease activity should be performed taking into consideration several parameters, clinical activity, laboratory parameters, US and quality of life assessment. US examination enables verification of synovial inflammatory activity, which is not always possible in clinical examination. PMID- 27941199 TI - [Peripheral nerves phenolisation in spasticity management - forgotten art or interesting perspective?] AB - INTRODUCTION: Spasticity is one of the most common obstacles in the process of rehabilitation after permanent central nervous system injury. Statistics show that the problem affects more than 12 billion people all over the world. Treatment of spasticity is necessary for proper rehabilitation, prevention of secondary disability, pain management and also strongly influences quality of life. Nowadays the most common formula used for the treatment of local spasticity is injection of botulinum toxin. Years ago and also nowadays physicians all over the world successfully used phenol as the chemodenervating factor. This technique today almost forgot in Poland but still used in other countries. MATERIALS AND METHODS: Peripheral nerves phenolisation had been used in STOCER (Konstancin) since 1965. The procedure was performed once in 59 patients, twice in 13 patients and three times in 7 patients. Evaluation was based on clinical presentation completed with patient self evaluation form. RESULTS: Good - 36 cases (45%), moderate - 34 cases (43%), bad - 9 cases (12%). CONCLUSION: Peripheral nerve phenolisation seems to be an interesting alternative to botulinum toxin in the management of spasticity. PMID- 27941201 TI - [Peripheral nerves alcoholization in the spasticity managament]. AB - INTRODUCTION: Spasticity is velocity dependent increased resistance to passive lengthening of the muscle. Mild spasticity doesn't require treatment, but severe impede with hygiene, constrict range of motion and mobility, interfere with gait pattern and can be the cause of pain and discomfort. Proper spasticity management is crucial for correct rehabilitation. THE AIM OF THE STUDY: The assesment of chemodenervation with ethyl alcohol in spasticity treatment. MATERIAL AND METHODS: 13 patients (5 female, 8 male) age 18-68 yrs (mean 46,8+/-13,3). Qualification to the procedure requiered high level of spasticity (mean 3,4 +/- 0,5 in Ashworth scale), no response for pharmacological treatment, low level in Bartel scale. Patients were evaluated with VAS pain scale, EQ-5D before, day after and 6 weeks after procedure. RESULTS: Ashworth scale before procedure: 3-4 (mean 3.44+/-0.52), after procedure: 0-3 (mean 2.0+/-1.26), 6 weeks after procedure: 1-3 (mean 2.0+/-1.0). VAS before procedure: 0-4 (mean 1.49+/-1.9), after procedure: 0-2 (mean 1.33+/-1.0), 6 weeks after procedure (mean 1.0+/-1.0). Bartel scale before procedure: 0-16 (mean 9.25+/-6.7), after procedure: 0-16 (mean 6.0+/-8.71), 6 weeks after procedure: 0-16 (mean 9.25+/-6.7). EQ-5D results showed on Fig 5-19. CONCLUSION: Results shows improvement in every examinated aspect (decrease in spasticity level, decrease in pain, increase in quality of life and disability scale). PMID- 27941200 TI - [Neurologopedic treatment in dysarthria cases. Diagnosis and therapy]. AB - INTRODUCTION: The article is devoted to the problems of diagnosis and neurologopedic therapy of hospitalized persons suffering from dysarthria. MATERIAL AND METHODS: The research presented in the article was conducted on a group of 49 patients (people aged 18-95, including 26 men and 23 women) who were diagnosed and underwent logopedic therapy in the department of Neurological Rehabilitation in the Independent Public Teaching Hospital no 4 in lublin in 2014. In the neurologopedic diagnostics the following methods were used: the analysis of the medical record (information cards containing medical diagnosis, mriri, ct head scanning, eeg ), clinical interview and clinical observations, The Robertson Dysarthria Profile, Dysarthria Scale by mirecka and gustaw, scale of deficiency depth, w. Lucki's package of tests to examine cognitive processes in the patients with brain damages, tests to examine aphasia by j. Szumska, tests to examine aphasia by m. Szepietowska and h. Misztal, author's questionnaire to examine dysarthria and aphasia, experimental tests to examine pragnosia and dysphagia. RESULTS: In the group of 49 patients dysarthria was diagnosed among 22 persons as the only speech disorder and in the group of 27 patients other speech disorders (aphasia, pragnosia, interpersonal communication disorders) co-occurred with dysarthria. Dysphagia was diagnosed among 21 patients. CONCLUSIONS: Neurologopedic diagnostics and therapy of the dysarthric patients should constitute an integral part of the complex improving treatment (in addition to medical, rehabilitation and psychological procedures). PMID- 27941202 TI - [Autoimmunization and carcinogenesis]. AB - The connections between autoimmunization and carcinogenesis have been observed in many patients' cases for numerous years. Various autoimmune diseases precede the diagnosis of neoplasm, however the mechanisms of autoimmunization may also be useful in anti-cancer defence. This review presents the analysis of links between the mentioned processes and their possible application in modern anti neoplasmatic immunotherapy. PMID- 27941204 TI - [Lublin - the capital of polish speech and language therapy. Half a century of slt education in UMCS]. AB - Lublin is the capital of Polish speech and language therapy (SLT) and this fact is justified by both historical as well as support in evaluating the potential of science - research and teaching, particularly in connection with the activities of the Department of Logopedics/SLT and Applied Linguistics of University of Maria Curie-Sklodowska and Polish Logopedic Society. The article discusses the history of the formation of SLT in Poland, strongly associated with Lublin, and also presents Lublin SLT educational traditions and the current teaching and research activities of the Department of Logopedics/SLT and Applied Linguistics of UMCS. PMID- 27941203 TI - [Diagnosis and therapy of steroid-induced hyperglycemia based on literature reports]. AB - The increase of the incidence of autoimmune diseases leads to a growing number of patients treated with immunosuppressants. One of the main group of drugs used in immunosuppression are glucocorticoids, which are connected with a significant risk of glucose tolerance disorders. It seems that a decisive role in the hyperglycemic activity plays a reduction of peripheral glucose uptake at the level of skeletal muscle, but in case of higher doses of glucocorticosteroids, stimulation of hepatic glucose production can be dominant. The diagnosis of glucocorticoid-induced diabetes is not different from the generally accepted criteria. There are not commonly accepted diagnostic and therapeutic rules in this area. The majority of hyperglycaemia cases in patients treated with high doses of glucocorticosteroids occur within the first 48 hours after start of glucocorticoids therapy. The closely monitoring of glucose profile should be performed in this time period. In the case of prolonged glucocorticoids treatment, regularly assessment of postprandial glucose and periodically performed oral glucose tolerance test is recommended. The diagnostic significance of glycated hemoglobin in this area has been not yet determined. The therapeutic targets are adequate as for type 2 diabetes. Pharmacological treatment should be implemented when glucose values reach up above 12mmol/l (216mg/dl) twice a day. The therapeutic hopes are connected with the use of new classes of drugs, in particular with incretin-drugs, especially with glucagon-like peptide (GLP) -1 receptor agonists. When the therapy goals are not able to achieve, the insulin treatment should be implemented. PMID- 27941206 TI - [Psychosomatic issues in the rehabilitation of motor organs]. AB - The relation between bodily health and mental health has been observed since ancien Times. Ancient teachers of the art of medicine advised to treat a person not an illness. Facination with the discoveries concerning the cell was the reason why investigation of somatic illnesses concentrated more and more on exploring physiology , ignoring mental aspects. Psychoanalysis, on the other hand considered mental sphere as the source of all illnesses. Although psychoanalitical approach is still controversial psychologists and doctors are still trying to find relations between personality traits and illnesses. Investigating psychological factors in etiology of motor organs disorders is not common but significant for the treatment. The paper presents disorders of mental adjustment which seem particularly important in rehabilitation of motor organs. They are illustrated by descriptions of case studies from clinical practice. PMID- 27941205 TI - [Between mind and body. Psychologicall methods for patients with musculoskeletal pain]. AB - According to the currently prevailing trends in medicine in restoring the psychosomatic unity of human, it is important to ask the question about the function and role of psychology in the rehabilitation of patients with chronic musculoskeletal disorder, MSD. In this article authors present the theoretical basis of psychical and body rehabilitation of patients with MSD. In the first part of this article, problem of the prevalence of MSD in population, its biological, psychological and social components and its impact on the economy of the country, have been discussed. Secondly, there was a focus on the mental representation of the body and its role as a psychophysical integrating unit. The following sections discuss therapeutic methods, like cognitive-behavioral therapy and chosen body work methods as complex rehabilitation of patients with musculoskeletal pain. PMID- 27941207 TI - [Psychological rehabilitation in patients with ischemic heart disease in the last 30 years]. AB - Cardiological rehabilitation is one of the basic methods used in the treatment of cardiovascular diseases including ischemic heart disease. Complex cardiological rehabilitation consists of clinical assessment, pharmacotherapy, kinesitherapy, psychological rehabilitation, assessment of cardiovascular risk factors prevalence, lifestyle modification and health education of patients. The paper presents methods of psychological therapy applied at different stages of psychological rehabilitation in traditional clinical procedure in patients with ischemic heart disease. In the mid 90-ties of the 20th century new, invasive diagnostic and treatment methods of cardiovascular diseases were introduced. Along with application of modern methods of invasive treatment methods of psychological rehabilitation changed towards crisis intervention. PMID- 27941208 TI - [Current views on the interaction between the treatment of osteoporosis and cardiovascular diseases]. AB - The most common medical conditions after menopause are osteoporosis and atherosclerotic disease. Traditionally these two conditions were considered unrelated and their coexistence has been attributed to independent processess exclusively reated to age. The possible link between cardiovascular disease and osteoporosis stimulates today to analyse not only the evidence of a possible association, but also to identify mutual beneficial and adverse effects of drugs used in these two diseases. That's why, the focus on the interference between osteoporosis treatment and drugs used for atherosclerosis is made. Moreover side effects of cardiological drug considering bones are analysed. Additionally possible advantages of selected drugs used for cardiovascular diseases on osteoporosis prevention are evaluated. Drugs used for osteoporosis treatment may heave adverse effects on cardiovascular system. The article has detailed analyses of current drug classes, such as the bisphosphonates, strontium ranelate as well as a review of the controversy surrounding hormone replacement therapy (HRT) and the selective oestrogen receptor modulators (SERMs). Lastly discussion of adverse effects on the heart of calcium and drugs influencing calcium metabolism such as vitamin D, parathormone and calcitonin is performed. PMID- 27941209 TI - [Subcutaneous methotrexate in psoriasis and psoriatic arthritis treatment]. AB - Methotrexate (MTX) plays a crucial role in the treatment of moderate-to-severe psoriasis. Thanks to numerous long-term observations and control clinical studies its safety and efficacy profile is well-established. Oral route of administration is the most common but data indicate the benefits of subcutaneous injections of MTX. Recent studies have revealed that bioavailability of oral MTX show interindividual differencies and decreases with the dose. In many cases to control disease activity MTX exceeding 15 mg/week is needed. On the other hand high doses of MTX increase the risk of gastro-intestinal side effects, and in some patients, may by ineffective. Bioavailability of subcutaneous MTX is linear and predictable. Studies show that methotrexate in this formulation is more efficacious. Thus it seems reasonable to switch from oral to subcutaneous route of MTX administration specially in patients with treatment failure with MTX or/and with gastrointestinal intolerance. Therapeutic success with this formulation may contribute to postpone the use of much more expensive biologic therapies. Formulation consisting prefilled syringe with high concentration of MTX and pre-attached needleis especially suitable for methotrexate subcutaneousself-administration. PMID- 27941210 TI - [Contemporary diagnostics of the primary Sjogren's syndrome]. AB - Primary Sjogren's syndrome is one of the most common systemic autoimmune disorders, whose diagnosis is very often delayed. In most cases it is a mild disease with symptoms such as dryness and musculoskeletal pain and fatigue but 20 40% of patients suffer from severe systemic manifestations. Extraglandular manifestations can be the first sign of the disease, therefore it is very important to diagnose them as early as possible. Classification criteria established by the American-European Consensus Group (AECG) have been applied in primary Sjogren's syndrome diagnosis since 2002. They took both subjective - dryness of eyes and mouth - and objective tests - imaging and functional tests of salivary glands, ocular tests, histopathologic test of minor salivary glands and presence of typical autoantibodies - into account. New classification criteria proposed in 2012 by the American College of Rheumatology (ACR) include objective tests only. Most recent research data suggest that noninvasive ultrasound examination of salivary gland should be included in the diagnostics process of Sjogren's syndrome due to its high specificity values which are comparable to those obtained from minor salivary glands biopsy. Also, it is important to evaluate disease activity in patients with primary Sjogren's syndrome using a score index - ESSDAI (EULAR Sjogren's Syndrome Disease Activity Index). PMID- 27941211 TI - [Immunity and cancer associated thrombosis]. AB - In cancer patients, thrombosis is commonly found complication. There are many established risk factors which may be responsible for thrombosis in this group of patients. Especially the factors connected with treatment and the cancer itself, seem to be significant in the pathogenesis of thromboembolism. On the other hand, the reactions between cancer, hemostasis and immunological system seem to be important in initiation of the thrombotic process. In this review, on the basis of current literature, we have analyzed the relationship between neoplasmatic thrombosis and immunological disorders. The lack of balance between immunological system and haemostasis in neoplasms is the key issue to solve, in order to correct the long term cancer survival. PMID- 27941212 TI - Coexistence of systemic sclerosis and sarcoidosis. AB - Coexistence of systemic sclerosis (SSc) and sarcoidosis (SA) is rarely reported; 21 cases only were reported in the English medical literature before 2011. It is suggested that low incidence of overlap syndrome of SSc with SA is resulted from different immune mechanisms involved in pathogenesis of the diseases. In SSc patients, a role of Th2 lymphocytes is suggested while in patients with SA such role is attributed to Th1 lymphocytes. The paper presents a 47-year-old woman suffering from SSc for over 6 years. CT scan of the lungs revealed the nodulus of the right lung and enlarged mediastinal lymphatic nodes. Pathologic evaluation of the nodulus provided basis for diagnosis of sarcoidosis. Diagnosis of SSc was based on clinical and capilaroscopic evaluation as well as detection of anti topoisomerase I antibodies. In the course of the disease, fibrosis of the lung, pulmonary hypertension and cardiac abnormalities with rhythm disturbances were developed. Treatment included cyclophosphamide, mycophenolate mofetil, sildenafil, losartan. Stabilization of the general state of the patient was achieved. PMID- 27941213 TI - Senescence associated macrophages and "macroph-aging": are they pieces of the same puzzle? PMID- 27941214 TI - Calcium alterations signal either to senescence or to autophagy induction in stem cells upon oxidative stress. AB - Intracellular calcium ([Ca2+]i) has been reported to play an important role in autophagy, apoptosis and necrosis, however, a little is known about its impact in senescence. Here we investigated [Ca2+]i contribution to oxidative stress-induced senescence of human endometrium-derived stem cells (hMESCs). In hMESCs sublethal H2O2-treatment resulted in a rapid calcium release from intracellular stores mediated by the activation of PLC/IP3/IP3R pathway. Notably, further senescence development was accompanied by persistently elevated [Ca2+]i levels. In H2O2 treated hMESCs, [Ca2+]i chelation by BAPTA-AM (BAPTA) was sufficient to prevent the expansion of the senescence phenotype, to decrease endogenous reactive oxygen species levels, to avoid G0/G1 cell cycle arrest, and finally to retain proliferation. Particularly, loading with BAPTA attenuated phosphorylation of the main DNA damage response members, including ATM, 53BP1 and H2A.X and reduced activation of the p53/p21/Rb pathway in H2O2-stimulated cells. Next, we revealed that BAPTA induced an early onset of AMPK-dependent autophagy in H2O2-treated cells as confirmed by both the phosphorylation status of AMPK/mTORC1 pathway and the dynamics of the LC3 lipidization. Summarizing the obtained data we can assume that calcium chelation is able to trigger short-term autophagy and to prevent the premature senescence of hMESCs under oxidative stress. PMID- 27941217 TI - Implementation and verification of an enhanced algorithm for the automatic computation of RR-interval series derived from 24 h 12-lead ECGs. AB - An important tool in early diagnosis of cardiac dysfunctions is the analysis of electrocardiograms (ECGs) obtained from ambulatory long-term recordings. Heart rate variability (HRV) analysis became a significant tool for assessing the cardiac health. The usefulness of HRV assessment for the prediction of cardiovascular events in end-stage renal disease patients was previously reported. The aim of this work is to verify an enhanced algorithm to obtain an RR interval time series in a fully automated manner. The multi-lead corrected R peaks of each ECG lead are used for RR-series computation and the algorithm is verified by a comparison with manually reviewed reference RR-time series. Twenty four hour 12-lead ECG recordings of 339 end-stage renal disease patients from the ISAR (rISk strAtification in end-stage Renal disease) study were used. Seven universal indicators were calculated to allow for a generalization of the comparison results. The median score of the indicator of synchronization, i.e. intraclass correlation coefficient, was 96.4% and the median of the root mean square error of the difference time series was 7.5 ms. The negligible error and high synchronization rate indicate high similarity and verified the agreement between the fully automated RR-interval series calculated with the AIT Multi-Lead ECGsolver and the reference time series. As a future perspective, HRV parameters calculated on this RR-time series can be evaluated in longitudinal studies to ensure clinical benefit. PMID- 27941218 TI - Insight into the electrical properties and chain conformation of spherical polyelectrolyte brushes by dielectric spectroscopy. AB - We report here a dielectric study on three kinds of anionic spherical polyelectrolyte brush (SPBs, consisting of a polystyrene (PS) core and three different poly (acrylic acid) chains grafted onto the core) suspensions over a frequency ranging from 40 Hz to 110 MHz. The relaxation behavior of the SPB suspensions shows significant changes in the brush-layer properties when the mass fraction of SPBs and the pH of the suspensions change. Two definite relaxations related to the interfacial polarization are observed around 100 kHz and 10 MHz. A single-layer spherical-shell model is applied to describe the SPB suspensions wherein the suspended SPB is modeled as a spherical-shell composite particle in which an insulated PS sphere is surrounded by a conducting ion-permeable shell (the polyelectrolyte chain layer). We developed the curve-fitting procedure to analyze the dielectric spectrum in order to obtain the dielectric properties of the components of the SPBs, especially the properties of the polyelectrolyte brush. Based on this method and model, the permittivity and conductivity of the brush layer, zeta potential, etc are calculated. The ordered orientation of the water molecules in the layer leads to an additional electrical dipole moment; increasing pH causes the brush layer to swell. In addition, the repulsive force between the SPB particles are evaluated using the brush-layer thickness, which is obtained by fitting dielectric spectra, combined with relative theoretical formulas. Increasing PH values or SPB concentration would improve the stability of the SPBs dispersion. PMID- 27941219 TI - V-T theory for the self-intermediate scattering function in a monatomic liquid. AB - In V-T theory the atomic motion is harmonic vibrations in a liquid-specific potential energy valley, plus transits, which move the system rapidly among the multitude of such valleys. In its first application to the self intermediate scattering function (SISF), V-T theory produced an accurate account of molecular dynamics (MD) data at all wave numbers q and time t. Recently, analysis of the mean square displacement (MSD) resolved a crossover behavior that was not observed in the SISF study. Our purpose here is to apply the more accurate MSD calibration to the SISF, and assess the results. We derive and discuss the theoretical equations for vibrational and transit contributions to the SISF. The time evolution is divided into three successive intervals: the vibrational interval when the vibrational contribution alone accurately accounts for the MD data; the crossover when the vibrational contribution saturates and the transit contribution becomes resolved; and the diffusive interval when the transit contribution alone accurately accounts for the MD data. The resulting theoretical error is extremely small at all q and t. V-T theory is compared to mode-coupling theories for the MSD and SISF, and to recent developments in Brownian motion experiments and theory. PMID- 27941215 TI - RelA NF-kappaB subunit activation as a therapeutic target in diffuse large B-cell lymphoma. AB - It has been well established that nuclear factor kappa-B (NF-kappaB) activation is important for tumor cell growth and survival. RelA/p65 and p50 are the most common NF-kB subunits and involved in the classical NF-kB pathway. However, the prognostic and biological significance of RelA/p65 is equivocal in the field. In this study, we assessed RelA/p65 nuclear expression by immunohistochemistry in 487 patients with de novo diffuse large B-cell lymphoma (DLBCL), and studied the effects of molecular and pharmacological inhibition of NF-kB on cell viability. We found RelA/p65 nuclear expression, without associations with other apparent genetic or phenotypic abnormalities, had unfavorable prognostic impact in patients with stage I/II DLBCL. Gene expression profiling analysis suggested immune dysregulation and antiapoptosis may be relevant for the poorer prognosis associated with p65 hyperactivation in germinal center B-cell-like (GCB) DLBCL and in activated B-cell-like (ABC) DLBCL, respectively. We knocked down individual NF-kappaB subunits in representative DLBCL cells in vitro, and found targeting p65 was more effective than targeting other NF-kappaB subunits in inhibiting cell growth and survival. In summary, RelA/p65 nuclear overexpression correlates with significant poor survival in early-stage DLBCL patients, and therapeutic targeting RelA/p65 is effective in inhibiting proliferation and survival of DLBCL with NF-kappaB hyperactivation. PMID- 27941216 TI - Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling. AB - : Clinical data identify age as a factor for severe liver fibrosis. We evaluate whether and how aging modulates the fibrotic response in a mouse model. Liver fibrosis was induced by CCl4 injections (thrice weekly for 2 weeks) in 7 weeks- and 15 months-old mice (young and old, respectively). Livers were analyzed for fibrosis, inflammation and remodeling 48 and 96 hours after the last injection. Old mice developed more severe fibrosis compared to young ones as evaluated by sirius red morphometry. Expression of pro-fibrogenic genes was equally induced in the two age-groups but enhanced fibrolysis in young mice was demonstrated by a significantly higher Mmp13 induction and collagenase activity. While fibrosis resolution occurred in young mice within 96 hours, no significant fibrosis attenuation was observed in old mice. Although recruitment of monocytes-derived macrophages was similar in young and old livers, young macrophages had globally a remodeling phenotype while old ones, a pro-fibrogenic phenotype. Moreover, we observed a higher proportion of thick fibers and enhanced expression of enzymes involved in collagen maturation in old mice. CONCLUSION: Impaired fibrolysis of a matrix less prone to remodeling associated with a pro-inflammatory phenotype of infiltrated macrophages contribute to a more severe fibrosis in old mice. PMID- 27941220 TI - Facet-mediated growth of silver nanoparticles on biaxial calcium fluoride nanorod arrays. AB - The surface orientation of metal nanoparticles is critical to their physical and chemical properties. This study aims on the understanding of the effect of surface orientation as well as heterogeneous epitaxy of metal nanoparticles at an interface between two materials with a large lattice mismatch. Silver nanoparticles of different diameters were grown on arrays of calcium fluoride (CaF2) nanorods using oblique angle deposition as a model system for this study. Scanning electron microscopy and transmission electron microscopy (TEM) imaging were used to verify that the nanoparticles were selectively grown on the desired {111} facets of the nanorod tips. Using selected area diffraction and dark field imaging in TEM, it was shown that the nanoparticles were grown at a (111) orientation at the CaF2 interface with large lattice strains. Thus biaxially textured CaF2 nanorod arrays can be used as a catalytic support. PMID- 27941221 TI - Remarkable cycle-activated capacity increasing in onion-like carbon nanospheres as lithium battery anode material. AB - Onion-like carbon nanospheres (OCNSs) with an average diameter of 43 nm were produced on a large scale via a combustion method and examined as an anode material for lithium ion batteries. The OCNSs exhibit a remarkable electrochemical cycling behavior and a capacity much higher than that of graphite. The capacity increases significantly with increasing charge-discharge cycles and reaches a value of 178% of the initial value (from 586 mA h g-1to 1045 mA h g-1) after 200 cycles. Further investigation provides unambiguous experimental evidence that such a remarkable capacity increase is related to the stable onion-like structure of the OCNSs and to the existence of large numbers of disordered/short graphitic fragments, which gradually provide more active sites for Li ion storage. The unique electrochemical performance of OCNSs provides a new way to design a high-performance anode material for rechargeable batteries. PMID- 27941222 TI - Analyzing spinodal decomposition of an anisotropic fluid mixture. AB - Spinodal decomposition leads to spontaneous fluctuations of the local concentration. In the early stage, the resulting pattern provides explicit information about the material properties of the mixture. In the case of two isotropic fluids, the static structure factor shows the characteristic ring shape. If one component is a liquid crystal, the pattern is typically anisotropic and the structure factor is more complex. Using numerical methods, we investigate how structure factors can be used to extract information about material properties like the diffusion constant or the isotropic and the anisotropic contributions to the interfacial tension. The method is based on momenta taken from structure factors in the early stage of the spinodal demixing. We perform phase field calculations for an isotropic and an anisotropic spinodal decomposition. A comparison of the extracted results with analytic values is made. The calculations show that linear modes dominate in the beginning of the growth process, while non-linear modes grow monotonously in the region of the k space for which damping is predicted by the linearized theory. As long as non linear modes are small enough, linearized theory can be applied to extract material properties from the structure factor. PMID- 27941223 TI - Dual-channel current valve in a three terminal zigzag graphene nanoribbon junction. AB - We theoretically propose a dual-channel current valve based on a three terminal zigzag graphene nanoribbon (ZGNR) junction driven by three asymmetric time dependent pumping potentials. By means of the Keldysh Green's function method, we show that two asymmetric charge currents can be pumped in the different left right terminals of the device at a zero bias, which mainly stems from the single photon-assisted pumping approximation and the valley valve effect in a ZGNR p-n junction. The ON and OFF states of pumped charge currents are crucially dependent on the even-odd chain widths of the three electrodes, the pumping frequency, the lattice potential and the Fermi level. Two-tunneling spin valves are also considered to spatially separate and detect 100% polarized spin currents owing to the combined spin pump effect and the valley selective transport in a three terminal ZGNR ferromagnetic junction. Our investigations might be helpful to control the spatial and spin degrees of freedom of electrons in graphene pumping devices. PMID- 27941224 TI - Selective coherent phonon-mode generation in single-wall carbon nanotubes. AB - The pulse-train technique within ultrafast pump-probe spectroscopy is theoretically investigated to excite a specific coherent phonon mode while suppressing the other phonon modes generated in single-wall carbon nanotubes (SWNTs). In particular, we focus on the selectivity of the radial breathing mode (RBM) and the G-band for a given SWNT. We find that if the repetition period of the pulse train matches with the integer multiple of the RBM phonon period, the RBM amplitude can be maintained while the amplitudes of the other modes are suppressed. As for the G-band, when we apply a repetition period of a half integer multiple of the RBM period, the RBM can be suppressed because of destructive interference, while the G-band still survives. It is also possible to keep the G-band and suppress the RBM by applying a repetition period that matches with the integer multiple of the G-band phonon period. However, in this case we have to use a large number of laser pulses having a property of "magic ratio" of the G-band and RBM periods. PMID- 27941225 TI - The 3D Kasteleyn transition in dipolar spin ice: a numerical study with the conserved monopoles algorithm. AB - We study the three-dimensional Kasteleyn transition in both nearest neighbours and dipolar spin ice models using an algorithm that conserves the number of excitations. We first limit the interactions range to nearest neighbours to test the method in the presence of a field applied along [Formula: see text], and then focus on the dipolar spin ice model. The effect of dipolar interactions, which is known to be greatly self screened at zero field, is particularly strong near full polarization. It shifts the Kasteleyn transition to lower temperatures, which decreases ~0.4 K for the parameters corresponding to the best known spin ice materials, [Formula: see text] and [Formula: see text]. This shift implies effective dipolar fields as big as 0.05 T opposing the applied field, and thus favouring the creation of 'strings' of reversed spins. We compare the reduction in the transition temperature with results in previous experiments, and study the phenomenon quantitatively using a simple molecular field approach. Finally, we relate the presence of the effective residual field to the appearance of string ordered phases at low fields and temperatures, and we check numerically that for fields applied along [Formula: see text] there are only three different stable phases at zero temperature. PMID- 27941226 TI - Estimating head and neck tissue dose from x-ray scatter to physicians performing x-ray guided cardiovascular procedures: a phantom study. AB - Physicians performing x-ray guided interventional procedures have a keen interest in radiation safety. Radiation dose to tissues and organs of the head and neck are of particular interest because they are not routinely protected by wearable radiation safety devices. This study was conducted to facilitate estimation of radiation dose to tissues of the head and neck of interventional physicians based on the dose recorded by a personal dosimeter worn on the left collar. Scatter beam qualities maximum energy and HVL were measured for 40 scatter beams emitting from an anthropomorphic patient phantom. Variables of the scatter beams included scatter angle (35 degrees and 90 degrees ), primary beam peak tube potential (60, 80, 100, and 120 kVp), and 5 Cu spectral filter thicknesses (0-0.9 mm). Four reference scatter beam qualities were selected to represent the range of scatter beams realized in a typical practice. A general radiographic x-ray tube was tuned to produce scatter-equivalent radiographic beams and used to simultaneously expose the head and neck of an anthropomorphic operator phantom and radiochromic film. The geometric relationship between the x-ray source of the scatter equivalent beams and the operator phantom was set to mimic that between a patient and physician performing an invasive cardiovascular procedure. Dose to the exterior surface of the operator phantom was measured with both 3 * 3 cm2 pieces of film and personal dosimeters positioned at the location of the left collar. All films were scanned with a calibrated flatbed scanner, which converted the film's reflective density to dose. Films from the transverse planes of the operator phantom provided 2D maps of the dose distribution within the phantom. These dose maps were normalized by the dose at the left collar, providing 2D percent of left collar dose (LCD) maps. The percent LCD maps were overlain with bony anatomy CT images of the operator phantom and estimates of percent LCD to the left, right and whole brain, brain stem, lenses of the eyes, and carotid arteries were calculated. Per expectation, results indicated greater percent dose to superficial versus deep tissues and increasing percent dose to deep tissues with increasing scatter-equivalent beam energy and HVL. The results enable estimation of the scatter dose to tissues of the head and neck of interventional physicians based on occupational dose measured by a personal dosimeter worn at the collar outside the protective apron. PMID- 27941228 TI - Topological phase transition and evolution of edge states in In-rich InGaN/GaN quantum wells under hydrostatic pressure. AB - Combining the k . p method with the third-order elasticity theory, we perform a theoretical study of the pressure-induced topological phase transition and the pressure evolution of topologically protected edge states in InN/GaN and In-rich InGaN/GaN quantum wells. We show that for a certain range of the quantum well parameters, thanks to a negative band gap pressure coefficient, it is possible to continuously drive the system from the normal insulator state through the topological insulator into the semimetal phase. The critical pressure for the topological phase transition depends not only on the quantum well thickness but also on the width of the Hall bar, which determines the coupling between the edge states localized at the opposite edges. We also find that in narrow Hall bar structures, near the topological phase transition, a significant Rashba-type spin splitting of the lower and upper branches of the edge state dispersion curve appears. This effect originates from the lack of the mirror symmetry of the quantum well potential caused by the built-in electric field, and can be suppressed by increasing the Hall bar width. When the pressure increases, the energy dispersion of the edge states becomes more parabolic-like and the spin splitting decreases. A further increase of pressure leads to the transition to a semimetal phase, which occurs due to the closure of the indirect 2D bulk band gap. The difference between the critical pressure at which the system becomes semimetallic, and the pressure for the topological phase transition, correlates with the variation of the pressure coefficient of the band gap in the normal insulator state. PMID- 27941227 TI - Comparison of cardiac magnetic resonance imaging and bio-impedance spectroscopy for the assessment of fluid displacement induced by external leg compression. AB - Heart failure is marked by frequent hospital admissions, often as a consequence of pulmonary congestion. Current gold standard techniques for thoracic fluid measurement require invasive heamodynamic access and therefore they are not suitable for continuous monitoring. Changes in thoracic impedance (TI) may enable non-invasive early detection of congestion and prevention of unplanned hospitalizations. However, the usefulness of TI to assess thoracic fluid status is limited by inter-subject variability and by the lack of reliable normalization methods. Indicator dilution methods allow absolute fluid volume estimation; cardiac magnetic resonance (CMR) has been recently proposed to apply indicator dilution methods in a minimally-invasive manner. In this study, we aim to compare bio-impedance spectroscopy (BIS) and CMR for the assessment of thoracic fluid status, and to determine their ability to detect fluid displacement induced by a leg compression procedure in healthy volunteers. A pressure gradient was applied across each subject's legs for 5 min (100-60 mmHg, distal to proximal). Each subject underwent a continuous TI-BIS measurement during the procedure, and repeated CMR-based indicator dilution measurements on a 1.5 T scanner at baseline, during compression, and after pressure release. The Cole-Cole and the local density random walk models were used for parameter extraction from TI-BIS and indicator dilution measurements, respectively. Intra-thoracic blood volume index (ITBI) derived from CMR, and extracellular fluid resistance (R E) from TI BIS, were considered as thoracic fluid status measures. Eight healthy volunteers were included in this study. An increase in ITBI of 45.2 +/- 47.2 ml m-2 was observed after the leg inflation (13.1 +/- 15.1% w.r.t. baseline, p < 0.05), while a decrease of -0.84 +/- 0.39 Omega in R E (-1.7 +/- 0.9% w.r.t. baseline, p < 0.05) was observed. ITBV and R E normalized by body mass index were strongly inversely correlated (r = -0.93, p < 0.05). In conclusion, an acute fluid displacement to the thoracic circulation was induced in healthy volunteers. Significant changes were observed in the considered thoracic fluid measures derived from BIS and CMR. Good correlation was observed between the two measurement techniques. Further clinical studies will be necessary to prospectively evaluate the value of a combination of the two techniques for prediction of re-hospitalizations after admission for heart failure. PMID- 27941229 TI - First-principles investigations into the thermodynamics of cation disorder and its impact on electronic structure and magnetic properties of spinel Co(Cr1-x Mn x )2O4. AB - Cation disorder over different crystallographic sites in spinel oxides is known to affect their properties. Recent experiments on Mn doped multiferroic [Formula: see text] indicate that a possible distribution of Mn atoms among tetrahedrally and octahedrally coordinated sites in the spinel lattice give rise to different variations in the structural parameters and saturation magnetisations in different concentration regimes of Mn atoms substituting the Cr. A composition dependent magnetic compensation behaviour points to the role conversions of the magnetic constituents. In this work, we have investigated the thermodynamics of cation disorder in [Formula: see text] system and its consequences on the structural, electronic and magnetic properties, using results from first principles electronic structure calculations. We have computed the variations in the cation-disorder as a function of Mn concentration and the temperature and found that at the annealing temperature of the experiment many of the systems exhibit cation disorder. Our results support the interpretations of the experimental results regarding the qualitative variations in the sub-lattice occupancies and the associated magnetisation behaviour, with composition. We have analysed the variations in structural, magnetic and electronic properties of this system with variations in the compositions and the degree of cation disorder from the variations in their electronic structures and by using the ideas from crystal field theory. Our study provides a complete microscopic picture of the effects that are responsible for composition dependent behavioural differences of the properties of this system. This work lays down a general framework, based upon results from first-principles calculations, to understand and analyse the substitutional magnetic spinel oxides [Formula: see text] in presence of cation disorder. PMID- 27941230 TI - The possible role of the vagal nervous system in the recovery of the blood pressure control after cardiac arrest: a porcine model study. AB - Previous studies have proved that the baroreceptor reflex (baroreflex) control of heart rate can be used for stratification of post-infarction population and, in general, cardiovascular disease populations. Many methods have been proposed to estimate the so-called baroreflex sensitivity (BRS) expressed as ms mmhg-1. Most of the studies that exploit BRS focus mainly on acute myocardial infarction (AMI) and there are no important works that investigate the role of BRS immediately after cardiac arrest (CA). The present work is a continuation of the published work of Ristagno et al (2014 Shock 41 72-8). In particular, the main objectives are: (1) to study the evolution of BRS after CA and following cardiopulmonary resuscitation (CPR); (2) to verify if the recovery of cardiovascular stability and arterial blood pressure is accompanied by a recovery of BR in a porcine model; (3) to investigate the possible causes of the BRS variations in response to CA and following cardiopulmonary resuscitation. All the BRS estimators adopted in this study show a significant decrease after CA. However, partial recovery is obtained in the last hours of post resuscitation. Analysis of impulse response showed a decrease in peak delay after CA and was significantly shorter 4 hours after CPR. This finding hints at a compensation mechanism: a faster response when baroreflex gain is not fully restored. The increase in the speed of baroreflex response is in line with the hypothesis of a key role of the parasympathetic nervous system, which is known to act at a higher firing rate. PMID- 27941231 TI - Printed highly conductive Cu films with strong adhesion enabled by low-energy photonic sintering on low-Tg flexible plastic substrate. AB - Copper (Cu) films and circuits were fabricated by screen-printing Cu nanoink on low-Tg (glass transition temperature) flexible plastic substrates (PEN and PET) instead of widely used high-Tg polyimide (PI) substrate. Photonic sintering of printed Cu films was carried out using intensive pulsed light (IPL). Low resistivities of 28 MUOmega . cm on PEN and 44 MUOmega . cm on PET were obtained without damaging the substrates. The sintered Cu films exhibited strong adhesion to PEN and PET substrates, with measured adhesion strength of 5B by the ASTM D3359 international standard, whereas the top part of the copper film on the PI substrate was stripped off during the adhesion test. The sintered Cu films also showed excellent stability in harsh conditions and mechanical flexibility in rolling tests. The underlying mechanisms of the high conductivity and strong adhesion on PEN and PET substrates with low-energy IPL sintering were investigated. Simple circuits and radio frequency identification antennas were made by screen-printing Cu nanoink and IPL sintering, demonstrating the technique's feasibility for practical applications. PMID- 27941232 TI - iTrack: instrumented mobile electrooculography (EOG) eye-tracking in older adults and Parkinson's disease. AB - Detection of saccades (fast eye-movements) within raw mobile electrooculography (EOG) data involves complex algorithms which typically process data acquired during seated static tasks only. Processing of data during dynamic tasks such as walking is relatively rare and complex, particularly in older adults or people with Parkinson's disease (PD). Development of algorithms that can be easily implemented to detect saccades is required. This study aimed to develop an algorithm for the detection and measurement of saccades in EOG data during static (sitting) and dynamic (walking) tasks, in older adults and PD. Eye-tracking via mobile EOG and infra-red (IR) eye-tracker (with video) was performed with a group of older adults (n = 10) and PD participants (n = 10) (?50 years). Horizontal saccades made between targets set 5 degrees , 10 degrees and 15 degrees apart were first measured while seated. Horizontal saccades were then measured while a participant walked and executed a 40 degrees turn left and right. The EOG algorithm was evaluated by comparing the number of correct saccade detections and agreement (ICC2,1) between output from visual inspection of eye-tracker videos and IR eye-tracker. The EOG algorithm detected 75-92% of saccades compared to video inspection and IR output during static testing, with fair to excellent agreement (ICC2,1 0.49-0.93). However, during walking EOG saccade detection reduced to 42-88% compared to video inspection or IR output, with poor to excellent (ICC2,1 0.13-0.88) agreement between methodologies. The algorithm was robust during seated testing but less so during walking, which was likely due to increased measurement and analysis error with a dynamic task. Future studies may consider a combination of EOG and IR for comprehensive measurement. PMID- 27941233 TI - Large magnetocaloric effect and near-zero thermal hysteresis in the rare earth intermetallic Tb1-x Dy x Co2 compounds. AB - We report the magnetocaloric effect in a Tb1-x Dy x Co2 compound which exhibits a wide working temperature window around the Curie temperature (T C) and delivers a large refrigerant capacity (RC) with near-zero thermal hysteresis. Specifically, the wide full width at half maxima ([Formula: see text]) can reach up to 62 K and the RC value changes from 216.5 to 274.3 J Kg-1 when the external magnetic field increases to 5 T. Such magnetocaloric effects are attributed to a magnetic and structural transition from a paramagnetic and cubic phase to a ferromagnetic (M S along [1 1 1] direction) and rhombohedral phase or ferromagnetic (M S along [0 0 1] direction) and tetragonal phase. PMID- 27941235 TI - Strong spin Seebeck effect in Kondo T-shaped double quantum dots. AB - We investigate, taking a theoretical approach, the thermoelectric and spin thermoelectric properties of a T-shaped double quantum dot strongly coupled to two ferromagnetic leads, focusing on the transport regime in which the system exhibits the two-stage Kondo effect. We study the dependence of the (spin) Seebeck coefficient, the corresponding power factor and the figure of merit on temperature, leads' spin polarization and dot level position. We show that the thermal conductance fulfills a modified Wiedemann-Franz law, also in the regime of suppression of subsequent stages of the Kondo effect by the exchange field resulting from the presence of ferromagnets. Moreover, we demonstrate that the spin thermopower is enhanced at temperatures corresponding to the second stage of Kondo screening. Very interestingly, the spin-thermoelectric response of the system is found to be highly sensitive to the spin polarization of the leads. In some cases spin polarization of the order of 1% is sufficient for a strong spin Seebeck effect to occur. This is explained as a consequence of the interplay between the two-stage Kondo effect and the exchange field induced in the double quantum dot. Due to the possibility of tuning the exchange field by the choice of gate voltage, the spin thermopower may also be tuned to be maximal for desired spin polarization of the leads. All calculations are performed with the aid of the numerical renormalization group technique. PMID- 27941234 TI - Thermal symmetry of healthy feet: a precursor to a thermal study of diabetic feet prior to skin breakdown. AB - Early identification of areas of inflammation may aid prevention of diabetic foot ulcers. A new bespoke thermal camera system has been developed to thermally image feet at risk. Hotspots (areas at least 2.2 degrees C hotter than the contralateral site) may indicate areas of inflammation prior to any apparent visual signs. This article describes the thermal pattern and symmetry of 103 healthy pairs of feet. 68% of participants were thermally symmetric at the 33 foot sites measured. 32% of participants had at least one hotspot, but hotspots overall only accounted for 5% of the measurements made. Refinements to the definition of hotspots are proposed when considering feet at risk of ulceration. PMID- 27941236 TI - ScVO4 under non-hydrostatic compression: a new metastable polymorph. AB - The high-pressure (HP) behaviour of scandium vanadate (ScVO4) is investigated under non-hydrostatic compression. The compound is studied by means of synchrotron-based powder x-ray diffraction (XRD) and optical-absorption techniques. The occurrence of a non-reversible phase transition is detected. The transition is from the zircon structure to the fergusonite-type structure and takes place around 6 GPa with nearly 10% volume discontinuity. XRD measurements on the pressure cycled sample confirm for the first time that the fergusonite type ScVO4 can be recovered as the metastable phase at ambient conditions. Raman spectroscopic measurements verify the metastable phase to be of a fergusonite type phase. Theoretical calculations also corroborate the experimental findings. The fergusonite phase is found to be stiffer than the ambient-pressure zircon phase, as indicated by the observed experimental and theoretical bulk moduli. The optical properties and lattice-dynamics calculation of the fergusonite ScVO4 are discussed. At ambient pressure the band gap of the zircon (fergusonite)-type ScVO4 is 2.75 eV (2.3 eV). This fact suggests that the novel metastable polymorph of ScVO4 can have applications in green technologies; for instance, it can be used as photocatalytic material for hydrogen production by water splitting. PMID- 27941238 TI - Detecting free-living steps and walking bouts: validating an algorithm for macro gait analysis. AB - Research suggests wearables and not instrumented walkways are better suited to quantify gait outcomes in clinic and free-living environments, providing a more comprehensive overview of walking due to continuous monitoring. Numerous validation studies in controlled settings exist, but few have examined the validity of wearables and associated algorithms for identifying and quantifying step counts and walking bouts in uncontrolled (free-living) environments. Studies which have examined free-living step and bout count validity found limited agreement due to variations in walking speed, changing terrain or task. Here we present a gait segmentation algorithm to define free-living step count and walking bouts from an open-source, high-resolution, accelerometer-based wearable (AX3, Axivity). Ten healthy participants (20-33 years) wore two portable gait measurement systems; a wearable accelerometer on the lower-back and a wearable body-mounted camera (GoPro HERO) on the chest, for 1 h on two separate occasions (24 h apart) during free-living activities. Step count and walking bouts were derived for both measurement systems and compared. For all participants during a total of almost 20 h of uncontrolled and unscripted free-living activity data, excellent relative (rho ? 0.941) and absolute (ICC(2,1) ? 0.975) agreement with no presence of bias were identified for step count compared to the camera (gold standard reference). Walking bout identification showed excellent relative (rho ? 0.909) and absolute agreement (ICC(2,1) ? 0.941) but demonstrated significant bias. The algorithm employed for identifying and quantifying steps and bouts from a single wearable accelerometer worn on the lower-back has been demonstrated to be valid and could be used for pragmatic gait analysis in prolonged uncontrolled free-living environments. PMID- 27941237 TI - Disentangling the health benefits of walking from increased exposure to falls in older people using remote gait monitoring and multi-dimensional analysis. AB - Falls and physical deconditioning are two major health problems for older people. Recent advances in remote physiological monitoring provide new opportunities to investigate why walking exercise, with its many health benefits, can both increase and decrease fall rates in older people. In this paper we combine remote wearable device monitoring of daily gait with non-linear multi-dimensional pattern recognition analysis; to disentangle the complex associations between walking, health and fall rates. One week of activities of daily living (ADL) were recorded with a wearable device in 96 independent living older people prior to completing 6 months of exergaming interventions. Using the wearable device data; the quantity, intensity, variability and distribution of daily walking patterns were assessed. At baseline, clinical assessments of health, falls, sensorimotor and physiological fall risks were completed. At 6 months, fall rates, sensorimotor and physiological fall risks were re-assessed. A non-linear multi dimensional analysis was conducted to identify risk-groups according to their daily walking patterns. Four distinct risk-groups were identified: The Impaired (93% fallers), Restrained (8% fallers), Active (50% fallers) and Athletic (4% fallers). Walking was strongly associated with multiple health benefits and protective of falls for the top performing Athletic risk-group. However, in the middle of the spectrum, the Active risk-group, who were more active, younger and healthier were 6.25 times more likely to be fallers than their Restrained counterparts. Remote monitoring of daily walking patterns may provide a new way to distinguish Impaired people at risk of falling because of frailty from Active people at risk of falling from greater exposure to situations were falls could occur, but further validation is required. Wearable device risk-profiling could help in developing more personalised interventions for older people seeking the health benefits of walking without increasing their risk of falls. PMID- 27941239 TI - The influence of circumferential resection margins on survival following rectal cancer surgery. AB - BACKGROUND AND AIMS: A negative (R0) circumferential resection margin (CRM) is described as one of the most important factor that decrease the rate of local recurrence in rectal cancer. The primary outcome of the study was the status of the CRM, while the secondary outcomes were local recurrence and overall survival. METHODS: Study includes 192 patients with rectal cancer operated between January 2012 and December 2013 in our Institute. The incidence of positive CRM and its impact on the survival rates after oncologic surgical resection were investigated along with factors that determine positive CRM. R1 was defined as a distance of <= 1 mm between the tumor and the resection margin. RESULTS: The R1 rate was 3.6 % (7 cases). Nine patients (4.68%) developed local recurrence during a median followup period of 720 days. A positive CRM was found to be a risk factor of local recurrence (p-value = 0.031) and it decreased the overall survival (p value=0.001). pT4 stage (p-value=0.008) and vascular invasion (p-value=0.005) are factors that play significant roles in determining CRM positivity. In case of inferior rectal tumours abdomino-perineal resection (APR) determines significantly higher (p-value=0.048) rates of positive CRM than anterior resection (AR) of the rectum. CONCLUSIONS: Positive CRM affects overall survival and local recurrence in rectal cancer. pT4 stage and vascular invasion play determinant roles in determine CRM status. APR is a risk factor for positive CRM in inferior rectal tumors. KEY WORDS: Abdomino-perineal resection, Circumferential resection margins, Local recurrence, Rectal cancer, Overall survival. PMID- 27941240 TI - Surgical treatment of chronic multivascular mesenteric ischemia in a patient with antiphospholipid syndrome, abdominal aortic aneurism, and renal cancer: when planning overwhelms complexity. AB - : Chronic mesenteric ischemia is a clinical condition caused by obstructive or occlusive disease of the mesenteric vessels, with potentially lethal consequences. We describe a case of open multiple revascularization in a patient affected by antiphospholipid syndrome and diffuse atherosclerosis, with an abdominal aortic aneurism, a contracted kidney, a renal cancer affecting the contralateral kidney, and as a consequence, a chronic renal failure and hypertension. We revascularized the celiac trunk, the superior and inferior mesenteric arteries, and the right renal artery using saphenous grafts; the aneurism was corrected, and the renal tumor was treated by radiofrequency ablation. Despite the invasiveness and complexity, the surgical strategy adopted allowed to save the patient's life, to treat the chronic mesenteric ischemia and the renal cancer, and to improve the chronic renal insufficiency and hypertension. KEY WORDS: Graft, Mesenteric ischemia, Occlusion, Revascularization. PMID- 27941242 TI - The interferon paradox: can inhibiting an antiviral mechanism advance an HIV cure? AB - While antiretroviral therapy (ART) has improved the quality of life and increased the life span of many HIV-infected individuals, this therapeutic strategy has several limitations, including a lack of efficacy in fully restoring immune function and a requirement for life-long treatment. Two studies in this issue of the JCI use a humanized mouse model and demonstrate that type I interferon (IFN) is induced early during HIV infection and that type I IFN-associated gene signatures persist, even during ART. Importantly, blockade of type I IFN improved immune function, reduced the HIV reservoir, and caused a delay in viral rebound after ART interruption. Together, these two studies support further evaluation of IFN blockade as a supplement to ART. PMID- 27941241 TI - PAX6 maintains beta cell identity by repressing genes of alternative islet cell types. AB - Type 2 diabetes is thought to involve a compromised beta cell differentiation state, but the mechanisms underlying this dysfunction remain unclear. Here, we report a key role for the TF PAX6 in the maintenance of adult beta cell identity and function. PAX6 was downregulated in beta cells of diabetic db/db mice and in WT mice treated with an insulin receptor antagonist, revealing metabolic control of expression. Deletion of Pax6 in beta cells of adult mice led to lethal hyperglycemia and ketosis that were attributed to loss of beta cell function and expansion of alpha cells. Lineage-tracing, transcriptome, and chromatin analyses showed that PAX6 is a direct activator of beta cell genes, thus maintaining mature beta cell function and identity. In parallel, we found that PAX6 binds promoters and enhancers to repress alternative islet cell genes including ghrelin, glucagon, and somatostatin. Chromatin analysis and shRNA-mediated gene suppression experiments indicated a similar function of PAX6 in human beta cells. We conclude that reduced expression of PAX6 in metabolically stressed beta cells may contribute to beta cell failure and alpha cell dysfunction in diabetes. PMID- 27941244 TI - beta Cells led astray by transcription factors and the company they keep. AB - Pancreatic beta cells have one of the highest protein secretion burdens in the body, as these cells must synthesize and secrete insulin in proportion to postprandial rises in blood glucose. Remarkably, it is now becoming clear that adult beta cells retain plasticity and can dedifferentiate into embryonic fates or adopt alternate islet endocrine cell identities. This property is especially important, because changes in cell fate alter beta cell function and could form the basis for defects in insulin secretion that occur early in the pathogenesis of the most prevalent form of beta cell dysfunction, type 2 diabetes. In this issue, three different studies provide complementary perspectives on how the transcription factors NK2 homeobox 2 (NKX2.2), paired box 6 (PAX6), and LIM domain-binding protein 1 (LDB1) serve to maintain mature adult beta cell identity, revealing clues as to how adult beta cells can partially dedifferentiate or become reprogrammed into other islet endocrine cells. PMID- 27941243 TI - Targeting type I interferon-mediated activation restores immune function in chronic HIV infection. AB - Chronic immune activation, immunosuppression, and T cell exhaustion are hallmarks of HIV infection, yet the mechanisms driving these processes are unclear. Chronic activation can be a driving force in immune exhaustion, and type I interferons (IFN-I) are emerging as critical components underlying ongoing activation in HIV infection. Here, we have tested the effect of blocking IFN-I signaling on T cell responses and virus replication in a murine model of chronic HIV infection. Using HIV-infected humanized mice, we demonstrated that in vivo blockade of IFN-I signaling during chronic HIV infection diminished HIV-driven immune activation, decreased T cell exhaustion marker expression, restored HIV-specific CD8 T cell function, and led to decreased viral replication. Antiretroviral therapy (ART) in combination with IFN-I blockade accelerated viral suppression, further decreased viral loads, and reduced the persistently infected HIV reservoir compared with ART treatment alone. Our data suggest that blocking IFN-I signaling in conjunction with ART treatment can restore immune function and may reduce viral reservoirs during chronic HIV infection, providing validation for IFN-I blockade as a potential therapy for HIV infection. PMID- 27941245 TI - Prolonged red cell storage before transfusion increases extravascular hemolysis. AB - BACKGROUND: Some countries have limited the maximum allowable storage duration for red cells to 5 weeks before transfusion. In the US, red blood cells can be stored for up to 6 weeks, but randomized trials have not assessed the effects of this final week of storage on clinical outcomes. METHODS: Sixty healthy adult volunteers were randomized to a single standard, autologous, leukoreduced, packed red cell transfusion after 1, 2, 3, 4, 5, or 6 weeks of storage (n = 10 per group). 51-Chromium posttransfusion red cell recovery studies were performed and laboratory parameters measured before and at defined times after transfusion. RESULTS: Extravascular hemolysis after transfusion progressively increased with increasing storage time (P < 0.001 for linear trend in the AUC of serum indirect bilirubin and iron levels). Longer storage duration was associated with decreasing posttransfusion red cell recovery (P = 0.002), decreasing elevations in hematocrit (P = 0.02), and increasing serum ferritin (P < 0.0001). After 6 weeks of refrigerated storage, transfusion was followed by increases in AUC for serum iron (P < 0.01), transferrin saturation (P < 0.001), and nontransferrin bound iron (P < 0.001) as compared with transfusion after 1 to 5 weeks of storage. CONCLUSIONS: After 6 weeks of refrigerated storage, transfusion of autologous red cells to healthy human volunteers increased extravascular hemolysis, saturated serum transferrin, and produced circulating nontransferrin bound iron. These outcomes, associated with increased risks of harm, provide evidence that the maximal allowable red cell storage duration should be reduced to the minimum sustainable by the blood supply, with 35 days as an attainable goal.REGISTRATION. ClinicalTrials.gov NCT02087514. FUNDING: NIH grant HL115557 and UL1 TR000040. PMID- 27941247 TI - Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs. AB - Despite the efficient suppression of HIV-1 replication that can be achieved with combined antiretroviral therapy (cART), low levels of type I interferon (IFN-I) signaling persist in some individuals. This sustained signaling may impede immune recovery and foster viral persistence. Here we report studies using a monoclonal antibody to block IFN-alpha/beta receptor (IFNAR) signaling in humanized mice (hu mice) that were persistently infected with HIV-1. We discovered that effective cART restored the number of human immune cells in HIV-1-infected hu-mice but did not rescue their immune hyperactivation and dysfunction. IFNAR blockade fully reversed HIV-1-induced immune hyperactivation and rescued anti-HIV-1 immune responses in T cells from HIV-1-infected hu-mice. Finally, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1 reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1-infected hu mice. We conclude that low levels of IFN-I signaling contribute to HIV-1 associated immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a potential strategy to enhance immune recovery and reduce HIV-1 reservoirs in individuals with sustained elevations in IFN-I signaling during suppressive cART. PMID- 27941246 TI - LIM domain-binding 1 maintains the terminally differentiated state of pancreatic beta cells. AB - The recognition of beta cell dedifferentiation in type 2 diabetes raises the translational relevance of mechanisms that direct and maintain beta cell identity. LIM domain-binding protein 1 (LDB1) nucleates multimeric transcriptional complexes and establishes promoter-enhancer looping, thereby directing fate assignment and maturation of progenitor populations. Many terminally differentiated endocrine cell types, however, remain enriched for LDB1, but its role is unknown. Here, we have demonstrated a requirement for LDB1 in maintaining the terminally differentiated status of pancreatic beta cells. Inducible ablation of LDB1 in mature beta cells impaired insulin secretion and glucose homeostasis. Transcriptomic analysis of LDB1-depleted beta cells revealed the collapse of the terminally differentiated gene program, indicated by a loss of beta cell identity genes and induction of the endocrine progenitor factor neurogenin 3 (NEUROG3). Lineage tracing confirmed that LDB1-depleted, insulin negative beta cells express NEUROG3 but do not adopt alternate endocrine cell fates. In primary mouse islets, LDB1 and its LIM homeodomain-binding partner islet 1 (ISL1) were coenriched at chromatin sites occupied by pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1), forkhead box A2 (FOXA2), and NK2 homeobox 2 (NKX2.2) - factors that co-occupy active enhancers in 3D chromatin domains in human islets. Indeed, LDB1 was enriched at active enhancers in human islets. Thus, LDB1 maintains the terminally differentiated state of beta cells and is a component of active enhancers in both murine and human islets. PMID- 27941250 TI - Impaired prohormone processing: a grand unified theory for features of Prader Willi syndrome? AB - Prader-Willi syndrome (PWS) is a complex disorder that manifests with an array of phenotypes, such as hypotonia and difficulties in feeding during infancy and reduced energy expenditure, hyperphagia, and developmental delays later in life. While the genetic cause has long been known, it is still not clear how mutations at this locus produce this array of phenotypes. In this issue of the JCI, Burnett and colleagues used a comprehensive approach to gain insight into how PWS associated mutations drive disease. Using neurons derived from PWS patient induced pluripotent stem cells (iPSCs) and mouse models, the authors provide evidence that neuroendocrine PWS-associated phenotypes may be linked to reduced expression of prohormone convertase 1 (PC1). While these compelling results support a critical role for PC1 deficiency in PWS, more work needs to be done to fully understand how and to what extent loss of this prohormone processing enzyme underlies disease manifestations in PWS patients. PMID- 27941248 TI - Pancreatic beta cell identity requires continual repression of non-beta cell programs. AB - Loss of beta cell identity, the presence of polyhormonal cells, and reprogramming are emerging as important features of beta cell dysfunction in patients with type 1 and type 2 diabetes. In this study, we have demonstrated that the transcription factor NKX2.2 is essential for the active maintenance of adult beta cell identity as well as function. Deletion of Nkx2.2 in beta cells caused rapid onset of a diabetic phenotype in mice that was attributed to loss of insulin and downregulation of many beta cell functional genes. Concomitantly, NKX2.2 deficient murine beta cells acquired non-beta cell endocrine features, resulting in populations of completely reprogrammed cells and bihormonal cells that displayed hybrid endocrine cell morphological characteristics. Molecular analysis in mouse and human islets revealed that NKX2.2 is a conserved master regulatory protein that controls the acquisition and maintenance of a functional, monohormonal beta cell identity by directly activating critical beta cell genes and actively repressing genes that specify the alternative islet endocrine cell lineages. This study demonstrates the highly volatile nature of the beta cell, indicating that acquiring and sustaining beta cell identity and function requires not only active maintaining of the expression of genes involved in beta cell function, but also continual repression of closely related endocrine gene programs. PMID- 27941251 TI - Stored blood: how old is too old? AB - Transfusion of rbc is a routine, often lifesaving procedure that depends on a stored supply of blood. In the US, 42 days is the maximum duration allowed for rbc storage; however, several lines of evidence indicate that patients that receive blood at the upper end of this storage limit are at a higher risk of morbidity and mortality. In this issue of the JCI, Rapido and colleagues evaluated the effects of transfusing one unit of blood close to the storage limit into healthy adults. Compared to those that received rbc stored for five weeks or less, those that received blood stored for six weeks showed several effects associated with increased harm, including disruption in iron handling, increased extravascular hemolysis, and the formation of circulating non-transferrin-bound iron. Together, the results of this study suggest that current maximum storage durations should be carefully reevaluated. PMID- 27941249 TI - Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader Willi syndrome. AB - Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p-/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p-/m+ mice. Nhlh2 deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p-/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency. PMID- 27941252 TI - Antenatal Health Care and Postnatal Dental Check-Ups Prevent Early Childhood Caries. AB - The first stage of early childhood caries (ECC) is infection by mutans streptococci, of which the primary infection source is the child's mother. Early intervention programs including antenatal and postnatal phases are effective for reducing ECC. This study was conducted to assess the respective effects of antenatal health care and postnatal care such as regular dental check-ups on reducing ECC among 3-year-old Japanese children. This nested case-control study of 155 three-year-old children (49.0% boys) was conducted at a dental clinic that provides collaborative health services with the Obstetrics and Gynecology Clinic, Okayama. Child characteristics and the mothers' antenatal data were collected retrospectively from the dental charts. They were divided into two groups: caries free children (n = 77) and children without ECC (n = 78). Most of the children (81.9%) received regular check-ups with topical fluoride application. Most of the mothers reported morning sickness during pregnancy (81.3%), normal delivery (72.9%), and used antenatal health care (80.6%). Over half (55.5%) were primigravida. Adjusted odds ratio (AOR) and 95% confidential interval (95% CI) were computed to assess the strength of association using logistic regression analysis. Receiving antenatal health care (AOR, 3.27; 95% CI, 1.30-8.24) and child's having regular check-ups (AOR, 3.42; 95% CI, 1.35-8.69) were significantly associated with caries-free status among three-year old children. For ECC prevention, antenatal health care is as effective as regular check-ups up to three years of age. The results of this retrospective study demonstrate that maternal health education during pregnancy is effective for ECC prevention. PMID- 27941253 TI - Fermented Food Consumption and Psychological Distress in Pregnant Women: A Nationwide Birth Cohort Study of the Japan Environment and Children's Study. AB - Health benefits of fermented foods are attracting attention worldwide, and they have been traditionally eaten in Japan. Moreover, a recent study showed the association between the higher intake of yogurt and lower prevalence of depressive symptoms during pregnancy. Psychological problems, such as anxiety and depression, during pregnancy are serious health concerns and may increase the risk of adverse outcomes in children. In this study, we explored the association between fermented food consumption and psychological distress in 10,129 pregnant Japanese women, using the fixed data of the Japan Environment and Children's Study (JECS), an ongoing nation-wide birth cohort study. Food consumption was assessed with a semi-quantitative food frequency questionnaire (FFQ), and the Kessler 6-item psychological distress scale (K6) was administered to eligible women during their second or third trimester to eliminate overlap with the period of hyperemesis gravidarum. The mean median gestation in the subjects was 24.8 weeks. In total, 9,030 subjects completed the K6 questionnaire and FFQ. Importantly, the prevalence of the K6 score of >= 13 was 3.1% (280 subjects). This value was lower compared to precedent studies, which may reflect that cooperative and health conscious subject participated in the survey. The multivariate logistic regression analysis indicates that the intake of yogurt, lactic acid beverages, cheese, Japanese pickles, miso soup, or fermented soybeans was not significantly associated with a K6 score of >= 13. In conclusion, the present cohort study shows no association between fermented food consumption and psychological distress symptoms during the second or third trimester of pregnancy. PMID- 27941254 TI - Rapid and Simultaneous Quantitation of Amoxicillin and Clavulanic Acid in Human Plasma and Urine by Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry and Its Application to a Pharmacokinetic Study. AB - Rapid, accurate and sensitive ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) methods were developed and validated for the simultaneous quantitation of amoxicillin and clavulanic acid in human plasma and urine samples. Amoxicillin and clavulanic acid in both plasma and urine were extracted using a solid-phase extraction method. The compounds were separated on an Acquity UPLC HSS T3 column (2.1 * 100 mm, 1.8 MUm). Ampicillin was used as the internal standard (IS) in plasma, while amoxicillin-d4 and sulbactam were used as ISs in urine. The lower limit of quantitation was 0.0500 and 0.0250 MUg/mL for amoxicillin and clavulanic acid in plasma, and 0.0500 MUg/mL for both analytes in urine. The established methods were validated in terms of selectivity, precision, accuracy, linearity, matrix effect, recovery, carryover, interaction, dilution integrity and stability, and successfully applied to a pharmacokinetic study of amoxicillin sodium and clavulanate potassium (10:1) injection in healthy volunteers. PMID- 27941256 TI - Acceleration of Vaporization, Atomization, and Ionization Efficiencies in Inductively Coupled Plasma by Merging Laser-Ablated Particles with Hydrochloric Acid Gas. AB - To accelerate the vaporization, atomization, and ionization efficiencies in laser ablation inductively coupled plasma mass spectrometry, we merged HCl gas with laser-ablated particles before introduction into the plasma, to convert their surface constituents from oxides to lower-melting chlorides. When particles were merged with HCl gas generated from a HCl solution at 200 degrees C, the measured concentrations of elements in the particles were 135% higher on average than the concentrations in particles merged with ultrapure water vapor. Particle corrosion and surface roughness were observed by scanning electron microscopy, and oxide conversion to chlorides was confirmed by X-ray photoelectron spectroscopy. Under the optimum conditions, the recoveries of measured elements improved by 23% on average, and the recoveries of elements with high-melting oxides (Sr, Zr, and Th) improved by as much as 36%. These results indicate that vaporization, atomization, and ionization in the ICP improved when HCl gas was merged with the ablated particles. PMID- 27941255 TI - Determination of Glycoproteins by a Self-Assembled 4-Mercaptophenylboronic Acid Film on a Quartz Crystal Microbalance. AB - Glycosylation plays an important part in many biological processes. However, many glycoproteins are either of low abundance or covered by other components in biological samples. Hence, developing new methods to measure the glycoproteins with both high efficiency and low detection limit is important. In this work, a self-assembled 4-mercaptophenylboronic acid film was coated on a quartz crystal microbalance chip. By optimizing the reaction time and the concentration of 4 mercaptophenylboronic acid, a sensor that specifically responded to glycoproteins was created. Then, several parameters for the prepared sensor were investigated and the working curve for representative glycoprotein-transferrin was established. The linearity range was from 50 to 400 ng/mL and the detection limit was 21.0 ng/mL. The sensor was used to detect transferrin in artificial urine samples. This sensor has a low detection limit of glycoproteins requiring only a small amount of samples, and thus has potential applications in both pharmaceutical and medical areas. PMID- 27941257 TI - A Near Infrared Fluorescent Probe for Sensitive Determination of Human Serum Albumin. AB - A fluorescent probe 1 has been successfully developed to determine human serum albumin (HSA). Probe 1 expresses a dramatic fluorescence enhancement to HSA without interference from other amino acids. Under the optimal conditions, the calibration graphs are linear over the range of 0 - 13.3 MUg/mL with the limit of determination of 0.61 MUg/mL. Thus, this probe shows high sensitivity and selectivity to HSA. PMID- 27941258 TI - Oxime Based Selective Fluorescent Sensor for Arsenate Ion in a Greener Way with Bio-Imaging Application. AB - A newly designed oxime based probe, 2,4-dihydroxyacetophenone-oxime (DHAO), was found to recognize H2AsO4- selectively with ~3 fold "turn-on" fluorescence enhancement and LOD of 29 MUM, K = (2.10 +/- 0.54) * 104 M-1 in purely aqueous medium. The structures of the DHAO and its adduct with H2AsO4- were optimized by DFT calculations. Intracellular imaging of As(V) in HepG2 cells demonstrate the possibilities of in vitro/in vivo applications for selective monitoring of such species. PMID- 27941259 TI - Direct Determination of Cadmium in Seawater by Standard Addition ICP-QMS/QMS with an ORC. AB - A method for direct and precise determination of Cd in seawater by ICP-QMS/QMS was developed, where a high matrix introducing unit permitted the direct introduction of seawater without clogging the cones while the matrix effect of seawater was canceled by standard addition. NH3 gas was selected as the reaction gas for removing the MoO interferences with the measurement of Cd isotopes, effectively improving the signal to background ratio. The lower limit of detection obtained at 114Cd was 0.0002 ng mL-1, which is enough for the determination of Cd in natural seawater. The validity of the present method was confirmed by the analysis of two certified reference materials, i.e. NASS-5 and NASS-6, whose observed values of Cd concentration agreed with the certified values. The analytical figures of merit of the present method were comparable to or better than those reported for direct analysis of seawater. PMID- 27941261 TI - A Novel Spectrofluorometric Probe for the Determination of Peroxynitrite Anion Scavenging Activity of Biothiols and Amino Acids. AB - In this study, a novel fluorometric method for the determination of peroxynitrite anion (ONOO-) scavenging (PAS) activity of amino acids and biothiols, which can mostly trap peroxynitrite in vivo, is described. This assay is based on the conversion of a gentisic acid probe to its non-fluorescent oxidation products with ONOO-. The attenuation of the fluorescence intensity (FI) of the probe upon peroxynitrite attack is diminished with antioxidants, the difference in FI being related to the PAS activity of the antioxidants. The IC50 (50% inhibitive concentration) values of biothiols, amino acids and tissue homogenates were estimated, in comparison with the reference Pyrogallol Red (PR) bleaching method. PR is the most suitable and frequently used dye to determine PAS activity, but is relatively insensitive. The developed fluorometric assay is highly sensitive to allow determinations of the PAS activity of amino acids. PMID- 27941260 TI - A Membrane-integrated Microfluidic Device to Study Permeation of Nanoparticles through Straight Micropores toward Rational Design of Nanomedicines. AB - Nanoparticles have been widely utilized to deliver drugs from blood vessels to target tissues. A crucial issue concerning nanoparticle-based drug delivery is to discuss the relationship between experimentally-obtained permeability and physical parameters. Although nanoparticles can permeate vascular pores, because the size and shape of the pores are essentially non-uniform, conventional animal testing and recent cell-based microfluidic devices are unable to precisely evaluate the effects of physical parameters (e.g. pore size and nanoparticle size) on permeation. In this study, we present a membrane-integrated microfluidic device to study permeation of nanoparticles through straight micropores. Porous membranes possessing uniform straight pores were utilized. The effects of pore size and pressure difference across the pores on nanoparticle permeation were examined. The experimentally determined permeability coefficient of 1.0 MUm-pore membrane against 100 nm-diameter nanoparticles agreed well with the theoretical value obtained for convectional permeation. Our method can be utilized to clarify the relationship between the experimentally-obtained permeability and physical parameters, and will help rational design of nanomedicines. PMID- 27941262 TI - Online Preconcentration Procedure for Chromium Speciation and Determination in Industrial Water Samples Using Flame Atomic Absorption Spectrometry. AB - An online preconcentration system based on solid-phase extraction was developed for speciation and determinations of Cr in industrial water samples using flame atomic absorption spectrometry. A minicolumn packed with Amberlite XAD-16 loaded with salicylic acid was used to preconcentrate chromium species. All flow and chemical parameters that influence sorption were studied. The preconcentration factor and detection limit for the preconcentration time of 120 s were 79 and 0.10 MUg L-1, respectively. The concentration of Cr(VI) species was calculated by the difference of the total Cr and Cr(III). The relative standard deviation (RSD) (five replicate of measurements) for 50 and 100 MUg L-1 Cr(III) solution was 1.2 and 1.0% respectively. The accuracy of the method was verified by analyzing a standard reference material (NIST SRM 1640a, trace elements in natural water). The proposed preconcentration method was successfully applied to the determination of Cr species in industrial water samples with satisfactory results. PMID- 27941263 TI - Determination of the Acid-Base Dissociation Constant of Acid-Degradable Hexamethylenetetramine by Capillary Zone Electrophoresis. AB - The acid-base equilibrium of hexamethylenetetramine (hexamine) was analyzed with its effective electrophoretic mobility by capillary zone electrophoresis. Although hexamine is degradable in a weakly acidic aqueous solution, and the degraded products of ammonia and formaldehyde can be formed, the effective electrophoretic mobility of hexamine was measured in the pH range between 2.8 and 6.9. An acid-base dissociation equilibrium of the protonated hexamine was analyzed based on the mobility change, and an acid dissociation constant of pKa = 4.93 +/- 0.01 (mean +/- standard error, ionic strength: 0.020 mol dm-3) was determined. The monoprotic acid-base equilibrium of hexamine was confirmed through comparisons of its electrophoretic mobility with the N-ethylquinolinium ion and with the monocationic N-ethyl derivative of hexamine, as well as a slope analysis of the dissociation equilibrium. PMID- 27941264 TI - A Sensitive Precolumn Derivatization Method for Determination of Piperazine in Vortioxetine Hydrobromide Using a C8 Column and High-Performance Liquid Chromatography-Mass Spectrometry. AB - A rapid and sensitive high-performance liquid chromatography-mass spectrometry method was established to determine the trace residues of piperazine in vortioxetine hydrobromide. The presence of piperazine was determined by precolumn derivatization with dansyl chloride. Chromatographic separation was performed on a Waters SunFire C8 column (150 * 4.6 mm, 3.5 MUm) in gradient elution mode, using formic acid and acetonitrile as mobile phase. Detection was performed in a single quadrupole mass spectrometer in single ion monitoring mode using positive ionization. An m/z value of 553 was selected for monitoring disubstituted piperazine by DNS-Cl. Linearity, accuracy, and precision were found to be acceptable over the piperazine concentration range of 0.3525 - 2.35 ng mL-1. The limit of detection and limit of quantification of piperazine were 0.1175 and 0.3525 ng mL-1, respectively, which complied with the requirements of qualitative and quantitative analyses. The method was deemed sensitive and efficient. PMID- 27941266 TI - Adamantane-based Bidendate Metal Complexes in Crystalline and Solution State. AB - Bidentate organic molecules with imidazole or benzimidazole moieties connected to a rigid 1,3-diphenyladamantane spacer are simple and unique building blocks that facilitate the assembly of supramolecular architectures in the solid state via metal-coordination. Single-crystal X-ray analysis revealed that the complexation of bidentate ligand-bearing imidazole moieties with cobalt(II) or cadmium(II) ions in methanol/chloroform produced complexes that showed doubly-interpenetrated two-dimensional (2D) sheets through the formation of coordination bonds between the cobalt or cadmium metal centers and the nitrogen atoms of the imidazole groups. In the complexation of another ligand bearing a bulky benzimidazole group with cobalt(II) ion generated in methanol/chloroform, extended zigzag one dimensional (1D) chains were formed, indicating that the molecular shape and bulkiness of the ligand design are crucial in the control of coordination polymers. The crystallization solutions were subjected to cold-spray ionization mass spectrometry (CSI-MS), and ion peaks derived from complexes with metal ligand 1:2 and 1:1 were observed in complexation with ligands bearing the imidazole and benzimidazole moieties, respectively. The metal-ligand ratio in the CSI-MS analysis was identical to that found in the single-crystal X-ray analysis of an independent molecule. In addition, coordination oligomers with large molecular weight were detected as part of the obtained coordination polymers observed by CSI-MS/MS. PMID- 27941265 TI - 24 T High-Resolution and -Sensitivity Solid-State NMR Measurements of Low-Gamma Half-Integer Quadrupolar Nuclei 35Cl and 37Cl. AB - Solid-state NMR observations of low-gamma half-integer quadrupolar nuclei, 35Cl and 37Cl, were demonstrated using a 24 T hybrid magnet (1H resonance frequency of 1.02 GHz) comprised of the high-temperature (HTS) and low-temperature (LTS) superconductors, and compared with results using a 14.1 T standard NMR magnet. While at 24 T the linewidth is 1.7 times narrower than that at 14.1 T, the gain in the sensitivity is 7.0 times because of enhanced polarization, reduced linewidth, and the use of larger rotor. A simple theoretical model was used to rationalize the sensitivity enhancements. The ratio of 35Cl and 37Cl quadrupolar couplings agrees well with the ratio of quadrupolar moments, and no isotope dependent chemical shift has been observed. In addition, the 3QMAS spectrum of 35Cl is shown to demonstrate the high sensitivity rendered by the 24 T spectrometer. PMID- 27941267 TI - A Simple Method for Ion Channel Recordings Using Fine Gold Electrode. AB - The artificial bilayer single-channel recording technique is commonly used to observe detailed pharmacological properties of various ion channel proteins. It permits easy control of the solution and membrane lipid composition, and is also compatible with pharmacological screening devices. However, its use is limited due to low measurement efficiency. Here, we develop a novel artificial bilayer single-channel recording technique in which bilayers are made and channels are reconstituted into the membranes by contacting a gold electrode to the lipid solution interface. Using this technique, we measured the single-channel currents of two channel-forming peptides, gramicidin and alamethicin, and a channel forming protein, alpha-hemolysin. This technique requires only one action, allowing the technique to potentially be combined with high-throughput screening devices. PMID- 27941268 TI - Rapid Detection of Cat Cystatin C (cCys-C) Using Immuno-Pillar Chips. AB - We demonstrated a rapid immunoassay for detection of cat cystatin C (cCys-C) which is an important marker for chronic kidney disease in cats, using immuno pillar chips. The required amount of reagent solution is 200 times smaller than that for the conventional ELISA in the 96-well microplate (0.5 MUL versus 100 MUL). In addition, the total assay time in the proposed method is more than 12 times shorter than in the conventional method (20 min versus 240 min). The limit of detection in the new method of 3 ng mL-1 is comparable to that of the conventional method (1 ng mL-1) and it is in the clinically relevant range. PMID- 27941269 TI - Duplex PCR-RFLP for the Simultaneous Genotyping of Single Nucleotide Polymorphisms in ADH1B and ALDH2 Genes. AB - Single nucleotide polymorphisms (SNPs) in ADH1B and ALDH2, which encode alcohol dehydrogenase 1B and aldehyde dehydrogenase 2, respectively, are responsible for ethanol-metabolizing activity and alcohol-related disease. We developed a simple and rapid polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method for the simultaneous genotyping of the genes in a single-tube reaction. Using an alkaline lysate of a human hair root as a template, SNP-containing regions of each gene were PCR-amplified simultaneously. The PCR products were directly applied to double restriction digestion, followed by agarose gel band analysis. The duplex PCR-RFLP allows for the simultaneous and accurate determination of the SNP genotypes of ADH1B and ALDH2 within 1.2 h. PMID- 27941270 TI - Synergistic Ion-pair Extraction of Strontium Ion with Tri-n-octylphosphine Oxide and Dicyclohexano-18-crown-6. AB - The co-use of two neutral ligands, tri-n-octylphosphine oxide (TOPO) and dicyclohexano-18-crown-6 (DC18C6), for ion-pair extraction of divalent strontium (Sr2+) with bis(trifluoromethanesulfonyl)imide anion (Tf2N-) showed unique synergistic effect. The extracted species in use of a single ligand is Sr(TOPO)32+.2Tf2N- or Sr(DC18C6)2+.2Tf2N-, whereas the co-use resulted in extraction enhancement based on additional formation of Sr(DC18C6)(TOPO)2+.2Tf2N- and Sr(DC18C6)(TOPO)22+.2Tf2N-. PMID- 27941271 TI - Tube Radial Distribution Flow Separation in a Microchannel Using an Ionic Liquid Aqueous Two-Phase System Based on Phase Separation Multi-Phase Flow. AB - Ionic liquid aqueous two-phase systems were delivered into a capillary tube to achieve tube radial distribution flow (TRDF) or annular flow in a microspace. The phase diagram, viscosity of the phases, and TRDF image of the 1-butyl-3 methylimidazolium chloride and NaOH system were examined. The TRDF was formed with inner ionic liquid-rich and outer ionic liquid-poor phases in the capillary tube. The phase configuration was explained using the viscous dissipation principle. We also examined the distribution of rhodamine B in a three-branched microchannel on a microchip with ionic liquid aqueous two-phase systems for the first time. PMID- 27941272 TI - Development of a Novel and Rapid Fully Automated Genetic Testing System. AB - We have developed a rapid genetic testing system integrating nucleic acid extraction, purification, amplification, and detection in a single cartridge. The system performs real-time polymerase chain reaction (PCR) after nucleic acid purification in a fully automated manner. RNase P, a housekeeping gene, was purified from human nasal epithelial cells using silica-coated magnetic beads and subjected to real-time PCR using a novel droplet-real-time-PCR machine. The process was completed within 13 min. This system will be widely applicable for research and diagnostic uses. PMID- 27941273 TI - Development of Electrochemical Oxygen Demand Measurement Cells Using a Diamond Electrode. AB - Electrolytic cells for electrochemical oxygen demand (ECOD) measurements based on total electrolytic decomposition at a boron-doped diamond (BDD) electrode were developed for rapid measurement of organic pollutants at low concentrations. Using improved electrolytic cells designed for efficient mass transfer, the ECOD for 10 MUM potassium hydrogen phthalate (theoretical ECOD: 2.3 mg-O2 L-1) was determined in a relatively short electrolysis time. Thus, ECOD measurements using these cells would be useful for estimating organic water pollution in industrial waste and lake water. PMID- 27941275 TI - Increased Postural Sway and Changes in the Neuromuscular Activities of the Ankle Stabilizing Muscles at Ovulation in Healthy Young Women. AB - Lateral ankle sprains are one of the most common injuries among the physically active subjects. Ankle inversion-eversion laxity is greater and dynamic postural control is less in women compared with men. The purpose of this study was to examine differences in postural sway and its effects on the neuromuscular activities of the ankle stabilizing muscles during the menstrual cycle in young women. Fourteen young women with regular menstrual cycles participated in this experiment. Postural sway and electromyographic signals of the lateral gastrocnemius, peroneus longus (PL), and tibialis anterior (TA) were recorded while the participants performed eight different balance tasks at ovulation and early follicular phase during one full menstrual cycle. Significantly greater postural sway in the two most difficult balance tasks was observed at ovulation compared to that in the early follicular phase (p < 0.001). A similar pattern was also observed in terms of PL activity, while TA activity was significantly greater in the most difficult balance task at ovulation. In addition, TA-PL co contraction (TA/PL ratio) was significantly higher at ovulation compared with that in the follicular phase in the two most difficult balance tasks (p < 0.01). Young women could benefit from increased understanding of the varying neuromuscular activation patterns throughout the menstrual cycle. The results of this study suggest that health professionals should be aware of the physiological effects and the shifts in neuromuscular strategies in each menstrual cycle phase in order to prevent increased risk of lower extremity injury. PMID- 27941277 TI - ? PMID- 27941276 TI - ABCB1 Is Upregulated in Acquisition of Taxane Resistance: Lessons from Esophageal Squamous Cell Carcinoma Cell Lines. AB - Esophageal cancer is one of the common malignancies worldwide, particularly in eastern African and Asian countries including Japan. Taxane (paclitaxel or docetaxel) is one of the effective chemotherapeutic reagents for patients with esophageal cancer, but acquisition of chemoresistance frequently occurs; this is one of the most frequent causes for therapeutic failure. In this study, we established three taxane resistant esophageal squamous cell carcinoma cell lines and explored possible mechanisms for the acquisition of chemoresistance. Microarray analyses indicated that the ABCB1 (ATP binding cassette subfamily B member 1) gene was significantly upregulated in taxane resistant esophageal cancer cell lines. Moreover, we found that siRNA mediated ABCB1 knockdown successfully restored drug sensitivity in both paclitaxel and docetaxel resistant esophageal cancer cell lines. In conclusion, we propose that ABCB1 might play a pivotal role in acquisition of taxane resistance and could be a promising target for treatment of patients with esophageal cancer after acquisition of taxane resistance. PMID- 27941278 TI - Long-term follow-up results of a phase I/II study of melphalan, prednisolone and bortezomib in Japanese transplant-ineligible multiple myeloma patients (JPN-102). AB - The phase I/II study of melphalan-prednisolone-bortezomib (MPB) therapy in Japanese patients with previously untreated multiple myeloma (MM) who are ineligible for hematopoietic stem cell transplantation (JPN-102 trial) (registered between July 2008 and March 2011) showed an overall response rate in the MPB arm equivalent to that of the VISTA trial. In this study, we followed up the clinical data of 92 of the 101 patients registered in the JPN-102 trial to clarify the long-term outcomes of MPB therapy. The median follow-up period was 50.8 (0.9-66.1) months. The median age of this cohort was 72 (48-84) years. The median progression-free survival was 25.7 (95%CI: 21.3-33.9) months and the overall survival rates at 1, 3 and 5 years were 98, 86 and 76%, respectively. There was no significant difference in either progression-free survival or overall survival when comparing a total bortezomib amount of 39 mg/m2 or more being administered versus less than 39 mg/m2. The outcomes of the JPN-102 cohort appeared, at a minimum, to not be inferior to those of the MPB cohort in the VISTA trial. A prospective trial is needed to establish the MPB regimen as being suitable for Japanese patients with multiple myeloma. PMID- 27941279 TI - Post-allogeneic stem cell transplant extramedullary relapse of acute megakaryoblastic leukemia initially detected by elevated WT1 mRNA levels in peripheral blood. AB - An 18-year-old male was admitted to our hospital for fever, and was diagnosed with acute megakaryoblastic leukemia (AML M7) based on the presence of CD42a and CD61 positive myeloblasts in peripheral blood (PB). Induction chemotherapy at our hospital resulted in complete remission (CR). Subsequently, he underwent unrelated HLA-DR one locus-mismatched allogeneic bone marrow (BM) transplantation. Although CR was maintained without development of graft-versus host disease (GvHD), the WT1 mRNA level in PB was elevated on post-transplant day 134. As BM aspiration performed 1 week later confirmed maintenance of CR, and because the WT1 mRNA level in BM was not high in comparison with PB, we suspected extramedullary relapse. PET-CT demonstrated a thymic tumor and a gastric tumor with abnormal accumulation of FDG, and biopsy confirmed both to be extramedullary relapse of AML M7. Induction chemotherapy following local radiation therapy achieved a second CR, following which he received HLA haploidentical peripheral blood stem cell transplantation on day 256 after the first transplant. The patient is currently surviving free from both relapse and GvHD. High WT1 mRNA levels in PB as compared with BM should raise suspicion of extramedullary relapse, and PET-CT is very useful for whole body evaluation in such cases. PMID- 27941280 TI - Rapidly progressive autoimmune pancytopenia successfully treated with steroids. AB - A 73-year-old woman was admitted to our hospital because of pancytopenia. Bone marrow aspiration showed increased cellularity with no dysplastic change. Laboratory tests revealed increased reticulated erythrocytes and reticulated platelets, positive direct Coombs test, and hemolysis. These findings led to the diagnosis of Evans syndrome. Relatively decreased mature neutrophils in the bone marrow aspirate raised the possibility of autoimmune neutropenia. Antineutrophil antibody was detected by the 6 cell-lineage immunofluorescence test, consistent with the diagnosis of autoimmune neutropenia. The patient had no underlying diseases, and was therefore considered to have idiopathic autoimmune pancytopenia. Due to rapid progression of the disease, prednisolone was administered at an initial dose of 0.5 mg/kg per day and the pancytopenia improved promptly. PMID- 27941281 TI - Development of AML without karyotype abnormalities including the Ph chromosome in a CML patient on second-generation TKI therapy. AB - A 58-year-old man was diagnosed with accelerated phase chronic myelogenous leukemia (CML). He was treated with dasatinib and followed-up; 6 months later, he achieved a complete molecular response. Seventeen months after this therapy, he developed pancytopenia, and was examined. His diagnosis was Ph-negative acute myeloid leukemia (AML) with no karyotype abnormalities. He was administered two courses of induction chemotherapy, and during the first remission, he received allogeneic hematopoietic stem cell transplantation. Treatment with a tyrosine kinase inhibitor (TKI) achieved a successful outcome. However, approximately 10% of CML cases develop clonal cytogenetic changes in Ph-negative cells during TKI treatment, and rarely, cases of Ph-negative myelodysplastic syndrome or AML are reported. Furthermore, similar to our case, CML patients developing AML with Ph negative and normal chromosome abnormalities have been reported. We suggest vigilant monitoring during TKI therapy and stress the importance of further analysis based on similar accumulated cases. PMID- 27941282 TI - Donor cell leukemia with bone marrow necrosis. AB - A 60-year-old man with myelodysplastic syndrome underwent allogeneic transplantation of female umbilical cord blood in 2010 and sustained a complete remission. He experienced severe pain in his left hip joint and was admitted to the orthopedic surgery division of our institution in February 2015. After admission, he was suspected to have hemophagocytic syndrome (HPS) and was thus transferred to the hematology division. Bone marrow aspiration revealed hyper cellular marrow filled with abnormal collapsed cells, consistent with bone marrow necrosis (BMN). As there was no evidence of infection, collagen disease, or occult cancer, he was diagnosed with HPS of unknown origin and treated with dexamethasone, cyclosporine A, and etoposide according to the HLH-2004 protocol. Although his general condition and laboratory findings showed amelioration, morphologically abnormal cells appeared in peripheral blood two weeks after treatment. Bone marrow aspiration showed BMN with increased abnormal cells, positive for CD117 and MPO. Sex chromosome FISH analysis revealed donor chimerism and cytogenetic analysis showed 46XX, +1, der (1;7) (q10;q10). He was diagnosed with donor cell leukemia (DCL) and received salvage chemotherapy. However, he died because of severe pneumonia and sepsis without neutrophil recovery at day 68. We herein report this rare case of DCL with BMN. PMID- 27941283 TI - Efficacy of pomalidomide in a multiple myeloma patient requiring hemodialysis. AB - A 67-year-old male patient developed multiple myeloma with acute renal failure caused by myeloma kidney. Although a very good partial response was achieved with bortezomib with dexamethasone (BD) therapy under temporary dialysis, relapse occurred 3 years later. Thalidomide was added to the BD therapy but was discontinued because of drug-induced eczema. Subsequently, bone lesions and chromosomal abnormalities appeared. Because renal failure progressed with increased serum free light chain levels, maintenance hemodialysis was introduced. Administration of lenalidomide showed no effect due to intolerance. BD therapy was re-started, but diffuse ground-glass opacity with pleural effusion was observed in both lungs, leading to the discontinuation of this treatment. Subsequently, pomalidomide with low-dose dexamethasone (PD) therapy was begun under hemodialysis. Seven cycles of PD therapy maintained disease stability. However, a dosage adjustment was needed because of pancytopenia. Maintaining the therapeutic effect apparently required a pomalidomide dose of 4 mg/day in this case. These findings suggest that pomalidomide is useful in relapsed or refractory advanced myeloma, with careful dose reductions and supportive care, even for patients with renal failure requiring hemodialysis. PMID- 27941284 TI - Overview. PMID- 27941285 TI - Basics of cancer immunotherapy. AB - The immune system is the body's defense against infectious organisms and other invaders including cancer cells. Cancer immunotherapy, which employs our own immune systems to attack cancer cells, is now emerging as a promising modality of cancer treatment based upon the clinical successes of immune checkpoint blockade and adoptive T cell transfer. In hematologic malignancies, clinical application of anti-PD-1 mAb and CAR (chimeric antigen receptor) T therapy is now being extensively tested in Hodgkin's disease, multiple myeloma, and CD19+ acute lymphocytic leukemia. In sharp contrast to conventional anti-cancer reagents which directly kill cancer cells, cancer immunotherapy activates various types of immune effector cells to attack cancer cells. However, more than half of the treated patients showed no activation of anti-tumor CD8+ killer T cells and CD4+ helper T cells and failed to respond to immune therapies such as immune checkpoint blockade, even when administered in combination regimens. Thus, development of novel immunotherapies to achieve more effective activation of anti cancer immunity and immuno-monitoring of biomarkers, allowing proper evaluation of immune responses in cancer patients in order to detect responders, are urgent issues. Additionally, we must pay attention to characteristic immunological side effects not observed following treatment with conventional anti-cancer reagents. Herein, we present a summary outline and discuss the future direction of cancer immunotherapy. PMID- 27941286 TI - Adoptive immunotherapy utilizing cancer antigen-specific T-cell receptors. AB - Synthetic immunology based on rapidly-advancing gene-engineering and immunobiology has made novel anticancer adoptive immunotherapies, using gene modified T lymphocytes to express cancer antigen-specific receptors, a reality. Various technological innovations have overcome recent difficulties and achieved clear and long-lasting clinical efficacy against tumors, while seeking more powerful effector gene-modified T cells has yielded serious treatment-related adverse events. In this article, along with introducing our clinical trial for a novel anti-leukemia adoptive immunotherapy regimen using gene-modified autologous lymphocytes to express leukemia antigen Wilms Tumor 1(WT1)-specific T cell receptor (TCR) against refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we provide an overview of the current status of this emerging treatment option and discuss its future form in the context of neoantigens encoded by mutated genes in cancer cells and immune checkpoint inhibitors. PMID- 27941287 TI - Adoptive immunotherapy utilizing anti-CD19 chimeric antigen receptor T-cells for B-cell malignancies. AB - Genetically modified T-cells with forced expression of anti-CD19 chimeric antigen receptor (CD19 CAR) have demonstrated promising clinical results for relapsed and refractory B cell malignancies in early clinical trial settings. The first beneficial tumor regressions were identified among approximately half of CLL patients in 2011. Similarly, CD19 CAR T-cells achieved remissions in about 80% of aggressive B-cell lymphomas in 2012. Furthermore, in 2013 this cellular therapy showed an extremely high rate of efficacy against refractory CD19 positive acute lymphoid leukemia, which had been regarded as the most difficult to treat hematologic disease. Recently, despite the absence of CD19 expression by neoplastic plasma cells, patients with refractory multiple myeloma achieved stringent complete remission after this therapy coupled with high dose chemotherapy and autologous stem cell transplantation. However, there are significant toxicities. Cytokine releasing syndrome and neurotoxicity are recognized as life-threatening adverse events. Although phase I/II clinical trials have just started in Japan, given the exciting results obtained to date, this cellular therapy is expected to be a novel breakthrough immunotherapy for treating refractory B-cell malignancies. PMID- 27941288 TI - Regulation of adoptive immunotherapy. AB - Adoptive immunotherapy using chimeric antigen receptor (CAR)-modified T cells has provided a major breakthrough in the treatment of hematological malignancies. In Japan, it is expected that CD19 CAR-T cell therapy will be introduced earlier in clinical B cell malignancy settings and/or that a novel CAR-T cell therapy will be developed for non-B cell malignancies. The "Act on the Safety of Regenerative Medicine" and the "Revised Pharmaceutical Affairs Act" were promulgated in 2014. Both Acts were very important to the introduction and development of CAR-T therapy in Japan. "Specified cell products" produced according to the former Act can be used in clinical research projects, while "regenerated medical products" produced according to the latter Act can be used in clinical trials, having been launched on the market. In this chapter, we will summarize the regulations pertaining to adoptive immunotherapy on the basis of these two essential Acts. PMID- 27941289 TI - Immune-checkpoint inhibitors in hematologic malignancies. AB - Immuno-checkpoint inhibitors are one of the most promising immunotherapies for various advanced cancers including hematologic malignancies. Recently, enhanced signaling of the PD-1/CTLA4 pathway has emerged as a critical mechanism by which tumors can escape the anti-tumor immune response. PD-1-blocking antibodies have been used to enhance immunity in several malignancies and obtain durable responses, especially in patients with heavily treated relapsed/refractory Hodgkin lymphoma. Currently, several clinical trials including single agent or combination therapies for hematologic malignancies, such as Hodgkin lymphoma, B cell lymphomas and multiple myeloma, are ongoing. The results of ongoing and future clinical trials may establish a new treatment paradigm for hematologic malignancies. PMID- 27941291 TI - ? PMID- 27941290 TI - Recent advances and future challenges in cancer immunotherapy. AB - Remarkable advances have been made in cancer immunotherapy. Recent treatment strategies, especially chimeric antigen receptor-T (CAR-T) cell therapy and immune checkpoint inhibitors, reportedly achieve higher objective responses and better survival rates than previous immunotherapies for patients with treatment resistant malignancies, creating a paradigm shift in cancer treatment. Several clinical trials of cancer immunotherapy for patients with various malignancies are ongoing. However, those with certain malignancies, such as low-immunogenic cancers, cannot be successfully treated with T-cell immunotherapy, and subsets of immunotherapy-treated patients relapse, meaning that more effective immunotherapeutic strategies are needed for such patients. Furthermore, the safety, convenience, and cost of cancer immunotherapy need to be improved in the near future. Herein, we discuss recent advances and future challenges in cancer immunotherapy, i.e., the identification of neoantigens for the development of individualized immunotherapies, the development of new CAR-T cell therapies, including so-called armored CAR-T cells that can induce greater clinical effects and thereby achieve longer survival, the development of off-the-shelf treatment regimens using non-self cells or cell lines, and effective cancer immunotherapy combinations. PMID- 27941292 TI - ? PMID- 27941293 TI - ? PMID- 27941294 TI - ? PMID- 27941295 TI - MR Spectroscopy to Distinguish between Supratentorial Intraventricular Subependymoma and Central Neurocytoma. AB - PURPOSE: The purpose of this study was to discriminate supratentorial intraventricular subependymoma (SIS) from central neurocytoma (CNC) using magnetic resonance spectroscopy (MRS). METHODS: Single-voxel proton MRS using a 1.5T or 3T MR scanner from five SISs, five CNCs, and normal controls were evaluated. They were examined using a point-resolved spectroscopy. Automatically calculated ratios comparing choline (Cho), N-acetylaspartate (NAA), myoinositol (MI), and/or glycine (Gly) to creatine (Cr) were determined. Evaluation of Cr to unsuppressed water (USW) was also performed. Mann-Whitney U test was carried out to test the significance of differences in the metabolite ratios. Detectability of lactate (Lac) and alanine (Ala) was evaluated. RESULTS: Although a statistically significant difference (P < 0.0001) was observed in Cho/Cr among SIS, control spectra, and CNC, no statistical difference was noted between SIS and control spectra (P = 0.11). Statistically significant differences were observed in NAA/Cr between SIS and CNC (P = 0.04) or control spectra (P < 0.0001). A statistically significant difference was observed in MI and/or Gly to Cr between SIS and control spectra (P = 0.03), and CNC and control spectra (P < 0.0006). There were no statistical differences between SIS and CNC for MI and/or Gly to Cr (P = 0.32). Significant statistical differences were found between SIS and control spectra (P < 0.0053), control spectra and CNC (P < 0.0016), and SIS and CNC (P < 0.0083) for Cr to USW. Lac inverted doublets were confirmed in two SISs. Triplets of Lac and Ala were detected in four spectra of CNC. CONCLUSION: The present study showed that MRS can be useful in discriminating SIS from CNC. PMID- 27941296 TI - Investigation of the Longitudinal Relaxation Time of Rat Tibial Cortical Bone Using SWIFT. AB - Sweep imaging with Fourier transform (SWIFT) method has been developed to image tissues with very short T2 values, such as cortical bone. The purpose of this study was to measure the T1 value of the rat cortical bone. It was approximately 120 ms on 7.04T. This result could thus be useful for studying bony tissue according to the SWIFT method in the future. PMID- 27941297 TI - Serum levels of ochratoxin A in dogs with chronic kidney disease (CKD): a retrospective study. AB - Ochratoxin A (OTA) is a mycotoxin produced by secondary metabolism of several fungi belonging to the genera Aspergillus and Penicillium. OTA is potentially nephrotoxic, neurotoxic, immunotoxic and carcinogenic in several animal species and in humans. This toxin has been detected in several human food and animal feed. The aim of this study was to determine OTA in blood samples of healthy and affected by chronic kidney disease (CKD) dogs. CKD group showed higher incidence of OTA-positivity than healthy dogs (96 vs. 56%) and a significantly higher median value of OTA plasma concentration (0.008 vs. 0.144 ng/ml). No significant correlation was observed between OTA levels and creatinine values in CKD dogs. This is the first study regarding OTA detection in plasma samples of healthy and CKD dogs; the presence of this toxin is higher in nephropatic patients but is not yet clear, if it is correlated with progression of the disease. PMID- 27941298 TI - Degenerative myelopathy in the Collie breed: a retrospective immunohistochemical analysis of superoxide dismutase 1 in an affected Rough Collie, and a molecular epidemiological survey of the SOD1: c.118G>A mutation in Japan. AB - Canine degenerative myelopathy (DM) is an adult-onset, progressive neurodegenerative disease that occurs in multiple dog breeds. A DM-associated mutation of the canine superoxide dismutase 1 (SOD1) gene, designated as c.118G>A (p.E40K), has been implicated as one of pathogenetic determinants of the disease in many breeds, but it remains to be determined whether the c.118G>A mutation is responsible for development or progression of DM in Collies. Previously, a Rough Collie was diagnosed clinically and histopathologically as having DM in Japan, suggesting the possibility that the Collie breed may be predisposed to DM due to the high frequency of c.118G>A in Japan. In this study, accumulation and aggregate formation of SOD1 protein were retrospectively demonstrated in the spinal cord of the DM-affected dog by immunohistochemical analysis. Furthermore, a molecular epidemiological survey revealed a high carrier rate (27.6%) and mutant allele frequency (0.138) of c.118G>A in a population of Collies in Japan, suggesting that the Collie breed may be predisposed to DM associated with c.118G>A, and the prevention of DM in Collies in Japan should be addressed through epidemiological and genetic testing strategies. PMID- 27941299 TI - Long-Term Efficacy of Implantable Cardioverter Defibrillator in Repaired Tetralogy of Fallot - Role of Anti-tachycardia Pacing. AB - BACKGROUND: Tetralogy of Fallot (TOF) is one of the common congenital heart diseases (CHD) in implantable cardioverter defibrillator (ICD) recipients, but few studies have reported the long-term outcomes of and the anti-tachycardia pacing (ATP) efficacy in repaired TOF.Methods and Results:Twenty-one repaired TOF patients with an ICD implanted between April 2003 and March 2015 were investigated retrospectively. ICD therapy and clinical outcome were analyzed. Mean patient age was 39+/-11 years; 62% were male; and mean age at repair surgery was 9.4+/-6.8 years. During a median follow-up of 5.6 years (range, 2.6-8.4 years), no patients died. Appropriate ATP were delivered in 11 patients (52%), with appropriate shocks in 5 patients (24%) and inappropriate shocks in 5 patients (24%). The success rate of ATP was 98% for fast ventricular tachycardia (VT; cycle length <=320 ms) and 98% for slow VT (cycle length >320 ms). ATP effectiveness increased from 81.5% with the first ATP attempt to 93.7% with the second ATP attempt, to 97.5% with the third ATP attempt, and to 98.6% with the fourth or successive ATP attempt (P<0.0001, Cochran-Armitage trend test). CONCLUSIONS: ATP was highly effective in repaired TOF regardless of VT cycle length. Multiple ATP attempts could have an important role in VT termination, and the novel subcutaneous ICD without ATP capability should be used carefully. PMID- 27941300 TI - Reperfusion Damage - A Story of Success, Failure, and Hope. AB - Tissue salvage of severely ischemic myocardium requires timely reperfusion by thrombolysis, angioplasty, or bypass. However, recovery of left ventricular function is rare. It may be absent or, even worse, reperfusion can induce further damage. Laboratory studies have shown convincingly that reperfusion can increase injury over and above that attributable to the pre-existing ischemia, precipitating arrhythmias, suppressing the recovery of contractile function ("stunning") and possibly even causing cell death in potentially salvable ischemic tissue. The mechanisms of reperfusion injury have been widely studied and, in the laboratory, it can be attenuated or prevented. Disappointingly, this is not the case in the clinic, particularly after thrombolysis or primary angioplasty. In contrast, excellent results have been achieved by surgeons by means of cardioplegia and hypothermia. For the interventionist, the issue is more complex as, contrary to cardiac surgery where the cardioplegia can be applied before ischemia and the heart can be stopped, during an angioplasty the heart still has to beat to support the circulation. We analyze in detail all these issues. PMID- 27941301 TI - Circulation Journal Has Changed Its Style. PMID- 27941302 TI - Effects of downregulating TEAD4 transcripts by RNA interference on early development of bovine embryos. AB - Transcription factor TEA domain family transcription factor 4 (Tead4) is one of the key factors involved in the differentiation of the trophectoderm (TE) in murine embryos. However, knowledge on the roles of TEAD4 in preimplantation development during bovine embryos is currently limited. This study examined the transcript and protein expression patterns of TEAD4 and attempted to elucidate the functions of TEAD4 during bovine preimplantation development using RNA interference. TEAD4 mRNA was found to be upregulated between the 16-cell and morula stages, and nuclear localization of the TEAD4 protein was detected at the morula stage, as well as in subsequent developmental stages. TEAD4 downregulation did not affect embryonic development until the blastocyst stage, and TEAD4 downregulated embryos were capable of forming the TE under both 5% and 21% O2 conditions. Results of gene expression analysis showed that TEAD4 downregulation did not affect the expression levels of POU class 5 transcription factor 1 (OCT 4), NANOG, caudal-type homeobox 2 (CDX2), GATA binding protein 3 (GATA3), and interferon-tau (IFNT). In conclusion, TEAD4 might be dispensable for development until the blastocyst stage and TE differentiation in bovine embryos. PMID- 27941303 TI - Report of the American Heart Association (AHA) Scientific Sessions 2016, New Orleans. AB - The American Heart Association (AHA) Scientific Sessions 2016 were held on November 12-16 at the Ernest N. Morial Convention Center, New Orleans, LA. This 5 day event featured cardiovascular clinical practice covering all aspects of basic, clinical, population, and translational content. One of the hot topics at AHA 2016 was precision medicine. The key presentations and highlights from the AHA Scientific Sessions 2016, including "precision medicine" as one of the hot topics, are herein reported. PMID- 27941305 TI - Molecular characterization and phylogeny of Linguatula serrata (Pentastomida: Linguatulidae) based on the nuclear 18S rDNA and mitochondrial cytochrome c oxidase I gene. AB - Linguatula serrata, a cosmopolitan parasite, is commonly known as tongue worm belonging to the subclass Pentastomida.We collected the nymphal stage of the worm from mesenteric lymph nodes of cattle and identified these as L. serrata based on morphology and morphometry. The 18S rDNA sequences showed no intraspecific variation, although cox1 sequences showed 99.7-99.9% homology. In the phylogenies inferred from both gene loci, members of the genus Linguatula (order Porocephalida) were closer to those of the order Cephalobaenida than to those of Porocephalida, reflecting a mismatch with the corresponding morphology-based taxonomy. Accordingly, analyses of additional gene loci using a larger number of taxa across the Pentastomida should be undertaken to determine an accurate phylogenetic position within the Arthropoda. PMID- 27941304 TI - Lactoferrin ameliorates corticosterone-related acute stress and hyperglycemia in rats. AB - We aimed to assess the effects of lactoferrin (Lf) on glycemic regulatory responses under restraint stress (RS) in rats. Bovine Lf (bLf, 100 mg/kg) was intraperitoneally administered to rats before oral saline administration or oral glucose tolerance test (OGTT) following 60 min of RS load. In the case of oral saline administration, RS significantly raised plasma glucose, but bLf did not affect the level. Plasma glucose in OGTT showed an overall lower transition in the bLf group, and the levels at 30 and 180 min or the area under the curve (AUC) were significantly decreased. Although bLf suppressed an increase in plasma corticosterone during RS, the levels of plasma insulin, epinephrine and glucagon were not changed by the bLf treatment. PMID- 27941307 TI - Calcium inhibition as an intracellular signal for actin-myosin interaction. AB - Intracellular signaling pathways include both the activation and the inhibition of biological processes. The activation of Ca2+ regulation of actin-myosin interactions was examined first, whereas it took 20 years for the author to clarify the inhibitory mode by using Physarum polycephalum, a lower eukaryote. This review describes the investigation of the inhibitory mode since 1980. The inhibitory effect of Ca2+ on myosin was detected chemically by ATPase assays and mechanically by in vitro motility assays. The Ca2+-binding ability of Physarum myosin is as high as that of scallop myosin. Ca2+ inhibits Physarum myosin, whereas it activates scallop myosin. We cloned cDNA of the myosin heavy chain and light chains to express a hybrid of Physarum and scallop myosin, and found that the Ca-binding light chain (CaLc), which belongs to an alkali light chain class, plays a major role in Ca inhibition. The role of CaLc was confirmed by mutating its EF-hand, Ca-binding structure and expressing Physarum myosin as a recombinant protein. Thus, the data obtained by classical protein purification were confirmed by the results obtained with the modern recombinant techniques. However, there are some discrepancies that remain to be solved as described in Section XII. PMID- 27941308 TI - Both the transglycosylase and transpeptidase functions in plastid penicillin binding protein are essential for plastid division in Physcomitrella patens. AB - Class A penicillin-binding proteins (PBPs) are active in the final step of bacterial peptidoglycan biosynthesis. They possess a transglycosylase (TG) domain to polymerize the glycan chains and a transpeptidase (TP) domain to catalyze peptide cross-linking. We reported that knockout of the Pbp gene in the moss Physcomitrella patens (DeltaPpPbp) results in a macrochloroplast phenotype by affecting plastid division. Here, expression of PpPBP-GFP in DeltaPpPbp restored the wild-type phenotype and GFP fluorescence was observed mainly in the periphery of each chloroplast. Stable transformants expressing Anabaena PBP with the plastid-targeting sequence, or PpPBP replacing the Anabaena TP domain exhibited partial recovery, while chloroplast number was recovered to that of wild-type plants in the transformant expressing PpPBP replacing the Anabaena TG domain. Transient expression experiments with site-directed mutagenized PpPBP showed that mutations in the conserved amino acids in both domains interfered with phenotype recovery. These results suggest that both TG and TP functions are essential for function of PpPBP in moss chloroplast division. PMID- 27941309 TI - Gene interaction at seed-awning loci in the genetic background of wild rice. AB - Seed awning is one of the important traits for successful propagation in wild rice. During the domestication of rice by ancient humans, plants with awnless seeds may have been selected because long awns hindered collection and handling activities. To investigate domestication of awnless rice, QTL analysis for seed awning was first carried out using backcross recombinant inbred lines between Oryza sativa Nipponbare (recurrent parent) and O. rufipogon W630 (donor parent). Two strong QTLs were detected in the same regions as known major seed-awning loci, An-1 and RAE2. Subsequent causal mutation surveying and fine mapping confirmed that O. rufipogon W630 has functional alleles at both loci. The gene effects and interactions at these loci were examined using two backcross populations with reciprocal genetic backgrounds of O. sativa Nipponbare and O. rufipogon W630. As awn length in wild rice varied among seeds even in the same plant, awn length was measured based on spikelet position. In the genetic background of cultivated rice, the wild alleles at An-1 and RAE2 had awning effects, and plants having both wild homozygous alleles produced awns whose length was about 70% of those of the wild parent. On the other hand, in the genetic background of wild rice, the substitution of cultivated alleles at An-1 and RAE2 contributed little to awn length reduction. These results indicate that the domestication process of awnless seeds was complicated because many genes are involved in awn formation in wild rice. PMID- 27941306 TI - Peroxisome biogenesis and human peroxisome-deficiency disorders. AB - Peroxisome is a single-membrane-bounded ubiquitous organelle containing a hundred different enzymes that catalyze various metabolic pathways such as beta-oxidation of very long-chain fatty acids and synthesis of plasmalogens. To investigate peroxisome biogenesis and human peroxisome biogenesis disorders (PBDs) including Zellweger syndrome, more than a dozen different complementation groups of Chinese hamster ovary (CHO) cell mutants impaired in peroxisome biogenesis are isolated as a model experimental system. By taking advantage of rapid functional complementation assay of the CHO cell mutants, successful cloning of PEX genes encoding peroxins required for peroxisome assembly invaluably contributed to the accomplishment of cloning of pathogenic genes responsible for PBDs. Peroxins are divided into three groups: 1) peroxins including Pex3p, Pex16p and Pex19p, are responsible for peroxisome membrane biogenesis via Pex19p- and Pex3p-dependent class I and Pex19p- and Pex16p-dependent class II pathways; 2) peroxins that function in matrix protein import; 3) those such as Pex11pbeta are involved in peroxisome division where DLP1, Mff, and Fis1 coordinately function. PMID- 27941310 TI - Smad3-mSin3A-HDAC1 Complex is Required for TGF-beta1-Induced Transcriptional Inhibition of PPARgamma in Mouse Cardiac Fibroblasts. AB - BACKGROUND: We have recently demonstrated that activated transforming growth factor-beta (TGF-beta) signaling suppresses myocardial peroxisome proliferator activated receptor gamma (PPARgamma) expression in the pressure overloaded heart. In this study, we aim to further define the molecular mechanisms that underlie TGF-beta-induced PPARgamma transcriptional inhibition. METHODS: Adult mouse cardiac fibroblasts were isolated and cultured. PPARgamma promoter activity was measured by the dual-Luciferase reporter assay. Interactions between transcription factors and the target gene were identified. RESULTS: In cultured cardiac fibroblasts transfected with a plasmid containing a human PPARgamma promoter, co-transfection of Smad3 and Smad4, but not Smad2, plasmids significantly enhanced TGF-beta1-induced inhibition of PPARgamma promoter activity. Promoter deletion analysis and site-directed mutagenesis assays defined two Smad binding elements on the promoter of the PPARgamma gene. Utilizing chromatin immunoprecipitation analysis and DNA-affinity precipitation methods, we demonstrated that the transcriptional regulatory complex consisting of Smad3, mSin3A and HDAC1 bound to the promoter of the PPARgamma gene in cardiac fibroblasts in response to TGF-beta1 stimulation. Either silencing endogenous mSin3A expression by Lentivirus-mediated transduction of mSin3A shRNA or pretreatment with the specific HDAC1 inhibitor MS-275 effectively attenuated TGF beta-induced transcriptional suppression of PPARgamma. CONCLUSION: These results suggest that TGF-beta1-induced inhibition of PPARgamma transcription depends on formation of a functional transcriptional regulatory complex that includes Smad3, mSin3A and HDAC1 at the PPARgamma promoter. PMID- 27941311 TI - beta-Klotho as a Negative Regulator of the Peptide Transporters PEPT1 and PEPT2. AB - BACKGROUND/AIMS: beta-Klotho, a transmembrane protein expressed in several tissues including the brain and the kidney, is critically important for inhibition of 1,25(OH)2D3 formation by FGF23. The extracellular domain of Klotho protein could be cleaved off, thus being released into blood or cerebrospinal fluid. Soluble klotho is a beta-glucuronidase participating in the regulation of several ion channels and carriers. The present study explored the effect of beta Klotho protein on the peptide transporters PEPT1 and PEPT2. METHODS: cRNA encoding PEPT1 or PEPT2 was injected into Xenopus laevis oocytes and glycine glycine (2 mM)-induced inward current (IGly) taken as measure of glycine-glycine transport. Measurements were made without or with prior 24 h treatment with soluble beta-Klotho protein (30 ng/ml) in the absence and presence of beta glucuronidase inhibitor D-saccharic acid 1,4-lactone monohydrate (DSAL,10 uM). Ussing chamber experiments were employed to determine electrogenic peptide transport across intestinal epithelia of klotho deficient (kl-/-) and corresponding wild type (kl+/+) mice. RESULTS: IGly was observed in PEPT1 and in PEPT2 expressing oocytes but not in water injected oocytes. In both, PEPT1 and PEPT2 expressing oocytes IGly was significantly decreased by treatment with soluble beta-Klotho protein. As shown for PEPT1, beta-klotho protein decreased significantly the maximal transport rate without significantly modifying the affinity of the carrier. The effect of beta-Klotho on PEPT1 was reversed by DSAL. Intestinal IGly was significantly larger in kl-/- than in kl+/+ mice. CONCLUSION: beta-Klotho participates in the regulation of the peptide transporters PEPT1 and PEPT2. PMID- 27941312 TI - Single-Incision Laparoscopic Colectomy: A Case Match Study for Stage IV Colon Cancer. AB - BACKGROUND: Utilization of single-incision laparoscopic surgery for the management of colon cancer has increased; however, the feasibility of single incision laparoscopic colectomy (SILC) for patients with stage IV colon cancer (ST4) has not been well examined. METHODS: Fifty-four patients with ST4 could be identified who electively underwent single-incision laparoscopic surgery. In a matched pairs design, 54 patients were then chosen out of a collective of 275 patients undergoing single-incision laparoscopic surgery for stages 0-III colon cancer (ST0-3). Short-term clinical outcomes were assessed, and the overall survival status in ST4 patients was assessed. RESULTS: The mean length of skin incision was 2.85 cm, and the median operating time and estimated blood loss were 156.1 min and 50.5 g respectively. The mean number of harvested lymph nodes was 20.7. All differences between short-time outcomes were not significant in both groups. The postoperative complication rate was significantly higher and postoperative hospital stay was significantly longer in ST4 patients. The 1-year overall survival rate was 78.5% in ST4 patients. In patients with complication, only postoperative stay was significantly prolonged compared with patients without complication. CONCLUSIONS: Our study indicated mid-term oncological and clinical safety of SILC for patients with ST4. PMID- 27941313 TI - Enhanced Recovery after Elective Colorectal Surgery - Reasons for Non-Compliance with the Protocol. AB - BACKGROUND/AIMS: Enhanced recovery after surgery (ERAS) protocols for elective colorectal surgery reduce the intensity of postoperative complications, hospital stays and costs. Improvements in clinical outcome are directly proportional to the adherence to the recommended pathway (compliance). The aim of the present study was to analyze reasons for the non-compliance of colorectal surgeries with the ERAS protocol. METHODS: A consecutive cohort of patients undergoing elective colorectal surgery was prospectively analyzed with regards to the surgery's compliance with the ERAS protocol. The reason for every single protocol deviation was documented and the decision was categorized based on whether it was medically justified or not. RESULTS: During the 8-month study period, 76 patients were included. The overall compliance with 22 ERAS items was 76% (96% in the preoperative, 82% in the perioperative, and 63% in the postoperative period). The decision to deviate from the clinical pathway was mainly a medical decision, while patients and nurses were responsible in 26 and 14% of the cases, respectively. However, reasons for non-compliance were medically justified in 78% of the study participants. CONCLUSION: 'Non-compliance' with the ERAS protocol was observed mostly in the postoperative period. Most deviations from the pathway were decided by doctors and in a majority of cases it appeared that they were due to a medical necessity rather than non-compliance. However, almost a quarter of deviations that were absolutely required are still amenable to improvement. PMID- 27941314 TI - AntimiR-30b Inhibits TNF-alpha Mediated Apoptosis and Attenuated Cartilage Degradation through Enhancing Autophagy. AB - OBJECTIVE: Cell death plays an important role in the pathology associated with inflammatory diseases such as osteoarthritis. It has been reported that autophagy can protect cells against tumour necrosis factor-alpha (TNF-alpha)-induced apoptosis. This study aimed to determine the potential role of microRNA-30b (miR 30b) in TNF-alpha-induced apoptosis, autophagy and differentiation in the chondrogenic ADTC5 cell line. METHODS: To analyse the effect of TNF-alpha on the viability of ADTC5 cells, cell counting kit-8 and Hoechst 33342 staining were employed and the expression levels of caspase-3 and -9 were assessed. Autophagy was examined by analysing the levels of LC3B-II and p62 and quantitating GFP-LC3B by fluorescence microscopy. A luciferase reporter assay investigated the putative binding sites of miR-30b. The effects of miR-30b and antimiR-30b on autophagy, apoptosis and osteogenic differentiation of TNF-alpha-treated cells were determined by autophagosome, apoptosis and alkaline phosphatase assays, respectively. RESULTS: TNF-alpha exposure decreased cell viability, increased apoptosis and positively regulated autophagy in ADTC5 cells. A direct interaction was detected between miR-30b and the mRNA 3'-UTRs of autophagy genes BECN1 and ATG5. Overexpression of miR-30b downregulated autophagy genes and upregulated pro apoptotic gene expression in TNF-alpha-treated cells, while treatment with antimiR-30b had the inverse effect. Overexpression of miR-30b also downregulated ECM degradation and anti-miR-30b reverse TNF-alpha-induced ECM degradation. CONCLUSIONS: Anti-miR-30b enhanced autophagy and attenuated cartilage degradation and played a protective role in TNF-alpha-induced apoptosis of ATDC5 cells. Anti miR-30b may therefore elevate cellular survival during inflammation and has therapeutic potential for inflammatory diseases such as osteoarthritis. PMID- 27941315 TI - Laparoscopic versus Open Surgery for Diverticulitis: A Systematic Review and Meta Analysis. AB - BACKGROUND/AIMS: The study aimed to perform a meta-analysis comparing laparoscopic and open surgery for diverticulitis. METHODS: Studies comparing the outcomes of laparoscopic surgery versus open surgery for diverticulitis that reported quantitative data were included. Outcome measures were mortality and morbidity rates and length of hospital stay. RESULTS: Four randomized controlled trials - 3 prospective and 21 retrospective - were included in the analysis. The total numbers of patients ranged from 5 to 14,562 in the laparoscopic groups and from 4 to 110,172 in the open surgery groups, and the mean patient age ranged from 38.9 to 78 years. Overall analysis revealed that laparoscopic surgery was associated with lower mortality (pooled OR 0.40, 95% CI 0.25-0.63, p < 0.001) and a lower overall morbidity rate (pooled OR 0.65, 95% CI 0.51-0.82, p < 0.001) than open surgery. Laparoscopic surgery was associated with a higher anastomotic bleeding rate, but lower rates of ileus, anastomotic leakage, small bowel obstruction, wound infection, fascial dehiscence and intra-abdominal abscesses. Length of hospital stay was less with laparoscopic surgery. CONCLUSIONS: The current meta-analysis supports the use of laparoscopy for the treatment of diverticulitis. The results, however, should be interpreted with caution. PMID- 27941316 TI - The Utility of Neutrophil to Lymphocyte Ratio as a Predictor of Intervention in Acute Diverticulitis. AB - BACKGROUND: Neutrophil to lymphocyte ratio (NLR) is a novel biomarker that has been recently studied in diverticulitis. The primary aim of this study was to assess the accuracy of NLR in predicting which patients had complicated diverticulitis and which patients required a radiological or surgical intervention. The accuracy of NLR was compared to C-reactive protein (CRP), white blood cell (WBC) count, neutrophil count and white cell to lymphocyte ratio (WLR). METHODS: Details of all patients admitted with acute diverticulitis over an 18-month period were collected prospectively. Median CRP, WBC, neutrophil count, WLR and NLR values at initial presentation were compared using the Mann Whitney U test. The diagnostic accuracy of each test was assessed using receiver operating characteristic curve analysis. Optimal cut-off points were determined for each biomarker using Youden's Index (J). RESULTS: CRP, WBC, neutrophil count, WLR and NLR had variable accuracy in predicting complicated diverticulitis. NLR had the greatest accuracy of the 5 biomarkers in predicting the need for intervention with an area under the curve of 0.79 (p < 0.0001). The optimal cut off point for NLR was 5.34 (J = 0.45). CONCLUSION: NLR was more accurate than CRP, WBC, neutrophil count and WLR in predicting the need for intervention. This cost-neutral, readily available biomarker can easily be calculated from the complete blood count and is a useful adjunct to CT. PMID- 27941318 TI - Early Detection of Desiccation and Curettage Failure in the Treatment of Basal Cell Carcinoma. AB - BACKGROUND/AIMS: Basal cell carcinoma (BCC) is a malignant neoplasm of keratinocytes. Electrodessication and curettage (ED&C) published cure rates vary widely, and the authors of this study are unaware of any previous literature which has attempted to rapidly identify treatment failures. OBJECTIVE: To identify BCC ED&C failures by histologically analyzing the fragments produced by the third round of curettage. METHODS: The monitoring of routine therapy of 862 cases of BCC that were treated by ED&C followed by the submission of cautery fragments of the third round of curettage for histological and immunohistochemical testing. RESULTS: Of the 862 cases, 764 (89%) had no residual BCC seen in their curetting. Of these patients, zero recurrences (0%) were noted. Forty-eight of the 862 cases had residual BCC seen in their curetting and elected to receive no additional therapy. Eighteen (38%) had a recurrence detected. Fifty of the 862 cases had residual BCC seen in their curetting and elected for immediate re-excision. Thirty-five (70%) had histological evidence of residual BCC. LIMITATIONS: The study was performed at a single center with 2 years of follow-up. CONCLUSION: Pathological examination of curettage fragments in combination with immunohistochemistry testing appears to be beneficial in predicting which patients are likely to have recurrence of BCC after ED&C. PMID- 27941317 TI - Clinical Analysis of Stercoral Perforation without Mortality. AB - AIMS: This study was designed to review the clinical features of stercoral colonic perforation and to evaluate the appropriate intraoperative procedures and postoperative management to achieve the best surgical outcomes. METHODS: Between January 2009 and December 2015, 12 patients with stercoral perforation confirmed surgically and pathologically were included in this study, and their medical records were reviewed retrospectively. RESULTS: The enrolled patients included 2 men and 10 women; their mean age was 73.8 years. Abdomino-pelvic CT was an important diagnostic tool, which revealed fecalomas, extraluminal air and pericolic fat stranding in all patients. Hartmann's operation was performed in all patients, with a mean operation time of 239.3 min. Perforation site was in the left colon, mainly in the sigmoid colon. Intraoperative hypotension developed in 8 cases (66.7%). Postoperatively, all patients needed intensive care for 6.5 days and 6 patients needed the administration of inotropic agents for 3.0 days postoperatively. Disseminated intravascular coagulation developed in 10 cases (83.3%). There was no surgical mortality. CONCLUSION: Colorectal surgeons should be aware of the possibility of stercoral perforation, despite its rare incidence. Deep understanding of this potentially fatal disease by surgeons could reduce surgical mortality and improve postoperative outcomes. PMID- 27941319 TI - The Vigabatrin Induced Retinal Toxicity is Associated with Photopic Exposure and Taurine Deficiency: An In Vivo Study. AB - BACKGROUND/AIMS: Retinal toxicity is one of the most commonly discussed and concerning adverse effects of vigabatrin (VGB). The present study explored the relationship between the VGB elicited retinal toxicity, photopic exposure, and taurine deficiency, aiming at screening for risk factors to minimize the adverse effects of VGB. METHODS: The effects of VGB on function and morphology of mouse retinas were examined via a series of in vivo tests, including electroretinography (ERG), Spectral domain optical coherence tomography (SD-OCT), and optokinetic testing. Moreover, VGB-treated mice were in addition treated with taurine to verify possible protective effects against retinal toxicity. RESULTS: A close relationship between VGB induced retinal toxicity and light exposure was observed. The VGB-treated mice which were reared in darkness preserved better visual function and retinal architectures as verified by the optokinetic tests, OCT and ERG examinations. The retinal taurine level of the VBG-treated mice which were exposed to light were significantly lower than that of the VBG mice reared in darkness. Furthermore, several in vivo evidence provided by our research confirmed that the VGB induced morphological and functional impairments could be partially alleviated by taurine treatment. The present study showed the retinal toxicity of VGB by in vivo measurements. CONCLUSION: The VGB induced retinal toxicity is closely associated with photopic exposure and taurine deficiency. Patients who are taking VGB might benefit from minimization of light exposure and dietetic taurine supplements. PMID- 27941320 TI - Necroptosis Induced by Ad-HGF Activates Endogenous C-Kit+ Cardiac Stem Cells and Promotes Cardiomyocyte Proliferation and Angiogenesis in the Infarcted Aged Heart. AB - BACKGROUND/AIMS: The discovery of c-kit+ cardiac stem cells (CSCs) provided us with new therapeutic targets to repair the damaged heart. However, the precise mechanisms regulating CSC proliferation and differentiation in the aged heart remained elusive. Necroptosis, a type of regulated cell death, has recently been shown to occur following myocardial infarction (MI); however, its effect on c kit+ CSCs remains unknown. We investigated the effects of hepatocyte growth factor (HGF) and necroptosis on the proliferation and differentiation of endogenous c-kit+ CSCs in aged rat hearts following MI. METHODS: The c-kit+ CSCs and HGF/p-Met expression levels in neonatal, adult and aged rats were compared using immunofluorescence and Western blotting. Immediately after MI, adenovirus carrying the HGF gene (Ad-HGF) was injected into the left ventricular wall surrounding the infarct areas of the aged rat heart. The proliferation and differentiation of the endogenous c-kit+ CSCs were studied using immunofluorescence. The signalling pathways were analysed via Western blotting and ELISA. RESULTS: HGF/p-Met expression levels and c-kit+ CSC abundance gradually decreased with age. Ad-HGF promoted c-kit+ CSC differentiation into precursor cells of cardiomyocyte, endothelial and smooth muscle cell lineages and enhanced cardiomyocyte proliferation and angiogenesis in aged rats; these effects were reversed by the inhibition of necroptosis. Ad-HGF administration induced necroptosis by increasing the expression of receptor interacting protein kinase (RIP) 1 and receptor interacting protein kinase (RIP) 3 proteins in the infarcted heart. Moreover, Ad-HGF-induced necroptosis increased high-mobility group box 1 protein (HMGB1) levels and enhanced the abundance of c-kit+ cells in the bone marrow, which may partly account for the beneficial effect of necroptosis on the c-kit+ CSCs. CONCLUSION: Ad-HGF-induced necroptosis facilitated aged heart repair after MI by promoting c-kit+ CSC proliferation and differentiation. These findings may lead to the development of new methods for the treatment of ischaemic heart disease in aged populations. PMID- 27941321 TI - Outcome of Gastric Cancer Surgery in Patients with Chronic Kidney Disease. AB - BACKGROUND: The influence of chronic kidney disease (CKD) on the outcome of gastric cancer surgery has rarely been reported. METHODS: Retrospectively collected clinicopathological data on patients who underwent elective gastrectomy between January 2007 and December 2014 were analyzed (n = 500). The patients were divided into 2 groups based on the preoperative estimated glomerular filtration rate (eGFR): a non-CKD group (eGFR >=60 ml/min/1.73 m2, n = 392) and a CKD group (eGFR <60 ml/min/1.73 m2, n = 108). Short- and long-term results of the surgery were compared. RESULTS: There was no significant difference between the 2 groups in terms of the overall morbidity rate (p = 0.215), and in any kind of postoperative complication, including infectious and cardiovascular complications. Additionally, there was no significant difference in the morbidity rate irrespective of the type of gastrectomy and the extent of lymph node dissection. The 3-year relapse-free survival rates in the non-CKD and CKD groups were 92.1 and 92.0%, respectively, in stage I disease (p = 0.640), 81.4 and 73.7%, respectively, in stage II disease (p = 0.825), and 35.9 and 31.9%, respectively, in stage III disease (p = 0.784). CONCLUSION: CKD did not affect the short- and long-term outcomes in patients after gastric cancer surgery. PMID- 27941323 TI - Immunogenicity and Safety of Pandemic Influenza H5N1 Vaccines in Healthy Adults through Meta-Analysis. AB - BACKGROUND: There are sporadic cases and local outbreaks of H5N1 avian influenza virus worldwide every year. The World Health Organization (WHO) has paid close attention to the avian influenza epidemic trend. Avian influenza vaccines (AIV) are considered to be useful when an epidemic occurs. However, the use of AIV for humans is not yet widespread. METHODS: This study assessed the immunogenicity and safety of pandemic influenza H5N1 vaccines with inactivated whole virus, split virus and subunit virus vaccines for healthy adults. We searched the databases of the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Excerpata Medica Database (EMBASE) and China National Knowledge Infrastructure (CNKI). The data from randomized trials regarding the immunogenicity and safety of AIV with or without different types of adjuvants for healthy adults (with an age range from 18 to 60 years) were collected. RESULTS: According to this study, the most effective doses of H5N1 AIV ranged from 3.75 ug to 7.5 ug Hemagglutinin (HA) antigen. Aluminium adjuvants were administered with the same vaccine dose as a no adjuvant group and induced the same immune effects. However, novel adjuvants (MF59 and AS03) were used with a smaller dose of vaccine than the no-adjuvant groups and successfully stimulated the body to produce more effective antibodies. CONCLUSION: All of the H5N1 AIV surveyed in this study were well tolerated without serious adverse reactions. PMID- 27941322 TI - Serum Bicarbonate Is Associated with Heart Failure in the Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: Low serum bicarbonate concentrations are associated with mortality and kidney disease progression. Data regarding associations between bicarbonate and cardiovascular disease (CVD) are scarce. METHODS: We performed a cohort study of 6,229 adult participants from the Multi-Ethnic Study of Atherosclerosis, a community-based cohort free of CVD at baseline. Serum bicarbonate was measured at baseline. Cardiovascular outcomes were defined as: (1) subclinical CVD (left ventricular mass [LVM] and aortic pulse pressure [PP] measured at baseline), (2) incident atherosclerotic cardiovascular events (CVE; composite of myocardial infarction, resuscitated cardiac arrest, stroke, coronary heart disease death, and stroke death), and (3) incident heart failure. RESULTS: During a median (interquartile range) follow-up of 8.5 (7.7-8.6) years, 331 (5.3%) participants had an incident CVE and 174 (2.8%) developed incident heart failure. We stratified analyses by use of diuretics because we observed a significant interaction between diuretic use and bicarbonate with study outcomes. Among diuretic nonusers, with adjustment, bicarbonate >=25 mEq/L was associated with an estimated 3.0 g greater LVM (95% CI 0.5-5.0) and 1.0 mm Hg higher aortic PP (95% CI 0.4-2.0) compared to bicarbonate 23-24 mEq/L. Each 1 mEq/L of bicarbonate increase was associated with a 13% higher risk of incident heart failure (hazards ratio 1.13, 95% CI 1.01-2.11). Among diuretic users, higher bicarbonate was not associated with CVD. Bicarbonate was not associated with incident atherosclerotic CVE irrespective of diuretic use. CONCLUSION: Among nonusers of diuretics in a large community-based study, higher serum bicarbonate concentrations are associated with subclinical CVD and new heart failure. PMID- 27941324 TI - Jagged1/Notch3 Signaling Modulates Hemangioma-Derived Pericyte Proliferation and Maturation. AB - BACKGROUND: The Notch signaling pathway has been implicated in the pericyte phenotype, but its exact roles in hemangioma-derived pericytes (Hem-pericytes) remain ill defined. METHODS: Hem-pericytes were stimulated by immobilized recombinant Jagged1. The potential mechanisms of Notch-induced Hem-pericytes growth arrest were investigated by cell cycle assay, and the role of the Notch in promoting Hem-pericyte maturation was also analyzed by real-time PCR and western blot. RESULTS: Activation of Notch3 in Hem-pericytes significantly reduced cell proliferation and inhibited cell cycle transition. This event was associated with an increase in the levels of p21Cip1. Knockdown of p21Cip1 resulted in a significant rescue of Notch-induced cell growth arrest and an entry into the cell cycle. We showed that Jagged1 activation of Notch3 signaling upregulated the expression of the pericyte contractile markers smooth muscle myosin heavy chain (smMHC) and alpha-smooth muscle actin (alphaSMA), concomitant with an increase in the expression of myocardin in Hem-pericytes. We further revealed that the endothelial-derived Jagged1 modulated the Hem-pericyte phenotype via a contact dependent mechanism. CONCLUSIONS: Our results demonstrated that Jagged1 activation of Notch3 resulted in a significant decrease in cell proliferation while concomitantly promoting Hem-pericyte maturation. These data provide initial evidence that Notch induces a quiescent phenotype in Hem-pericytes. PMID- 27941325 TI - Arterial Iron Content Is Increased in Patients with High Plasma Ferritin Levels. AB - The association between increased amounts of stored iron and development of cardiovascular disease (CVD) has been recognized for many years. However, basic information on iron content in human arteries is limited. We envision that associations between body iron content and CVD are based on the accumulation of iron in the arteries, possibly leading to the dysfunction of cellular biochemical pathways. This study addresses the very fundamental question of whether there is a relation between body iron content and the level of iron accumulated in arterial tissue. The iron content in human nonatherosclerotic artery samples from patients with high and low body-iron contents estimated from the plasma ferritin concentration were determined by inductively coupled plasma mass spectroscopy in tissue extracts and by histological staining, using a modified Perls reaction to display iron deposits. We found that the arteries contained small but measurable levels of iron. The iron content was significantly higher in tissue from patients with high plasma ferritin (p = 0.026). Histological staining showed the presence of iron deposits. Our results suggest that iron does accumulate in arterial tissue in accordance to the level of stored body iron. Further studies are needed on the distribution of iron in excess to explain the relationship between stored iron and the development of atherosclerosis. PMID- 27941326 TI - Conversion from Brand-Name Neoral to the Generic Ciqorin in Stable Renal Transplant Recipients. AB - BACKGROUND/AIMS: Transplant physicians and patients are often reluctant to change to generic versions of immunosuppressive drugs with a narrow therapeutic index, such as ciclosporin (CsA). Thus, in routine follow-up for kidney transplant patients receiving CsA maintenance immunosuppressive therapy in our center, we evaluated the exchangeability of the brand name, Neoral, and the recently approved CsA generic formulation, Ciqorin. METHODS: We assessed the complete 12-h CsA pharmacokinetic profile and direct measurement of glomerular filtration rate (mGFR) of 10 patients receiving stable doses of Neoral (138 +/- 43 mg/day), at least 6 months after kidney transplantation (Neoral 1). The same evaluations were repeated 10 days after conversion to Ciqorin on a milligram-to-milligram basis and 10 days after reinstituting Neoral (Neoral 2). RESULTS: The mean CsA area under the concentration-time curve increased slightly after switching from Neoral to Ciqorin (p = 0.03), but did not change significantly after Neoral was reintroduced (Neoral 1: 2,234 +/- 783, Ciqorin: 2,452 +/- 767, Neoral 2: 2,472 +/ 784 ng * h/mL). There were no appreciable differences between the 2 CsA formulations in trough levels, maximum concentrations, or time to reach maximum concentrations. In all patients, renal function remained stable throughout the monitoring period (mGFR, Neoral 1: 52.0 +/- 16.2; Ciqorin: 55.0 +/- 19.0; Neoral 2: 55.8 +/- 18.9 mL/min/1.73 m2), as did urinary and hematochemical parameters. CONCLUSIONS: In stable kidney transplant recipients, switching from Neoral to Ciqorin resulted in similar pharmacokinetic parameters and did not change renal allograft function, reassuring physicians and patients regarding the exchangeability of reference and generic CsA formulations. PMID- 27941327 TI - Reduced Erythrocyte Survival in Uremic Patients Under Hemodialysis or Peritoneal Dialysis. AB - BACKGROUND/AIMS: Recent observations in end-stage renal disease (ESRD)-patients on hemodialysis revealed that anemia is, in part, due to stimulated suicidal erythrocyte death or eryptosis leading to accelerated clearance of circulating erythrocytes. The present study explored whether eryptosis is similarly enhanced in patients on peritoneal dialysis (PD). METHODS: Measurements were made in freshly drawn erythrocytes from healthy volunteers (n=38), and ESRD patients on hemodialysis (HD; n=18) or on PD (n=22). Both, HD patients and PD patients suffered from anemia despite increased reticulocyte numbers. RESULTS: The percentage of phosphatidylserine-exposing erythrocytes was significantly higher in HD patients than in healthy volunteers and significantly higher in PD patients than in healthy volunteers and HD patients. In PD patients, the percentage of phosphatidylserine-exposing erythrocytes was positively correlated with dialysis volume. The increase in phosphatidylserine exposure was in both, HD and PD patients, paralleled by increase of reactive oxygen species and ceramide abundance. In both, HD and PD patients, a positive correlation was observed between the percentage of phosphatidylserine-exposing erythrocytes and both, erythropoietin dosage and the percentage of reticulocytes. CONCLUSIONS: Similar to HD patients, PD patients suffer from enhanced eryptosis, which is paralleled by oxidative stress and enhanced ceramide abundance contributing to the anemia of uremic patients. PMID- 27941329 TI - Advantages of Early Preventive Ileostomy Closure after Total Mesorectal Excision Surgery for Rectal Cancer: An Institutional Retrospective Study of 123 Consecutive Patients. AB - BACKGROUND/AIM: Preventive ileostomy is frequently constructed to minimizethe consequences of anastomotic leakage after resection of rectal cancer. There is no consensus regarding the best timing for temporary stoma closure after proctectomy for rectal cancer. This retrospective study sought to determine whether the timing of stoma closure influenced postoperative outcomes. METHODS: Subjects were 123 patients with rectal cancer undergoing laparoscopic or open total mesorectal excision surgery with preventive ileostomy from 2012 to 2015. They were divided into 2 groups according the timing of stoma closure: the standard group who had closure within 90 (60-120) days (n = 78) and the late group who had closure after 180 (150-210) days (n = 45). RESULTS: There was no significant difference in operative time, operative blood loss or postoperative complications between the 2 groups. Timing of postoperative fasting and length of hospital stay was similar in both groups. Adjuvant chemotherapy was not a risk factor for postoperative complications after stoma closure. CONCLUSIONS: There was no significant difference between different timings of temporary stoma closure in relation to postoperative complications. Delayed stoma closure showed no benefit in prevention of morbidity. Early closure is safe and can provide better quality of life for patients. PMID- 27941328 TI - Upper-Extremity Function Predicts Adverse Health Outcomes among Older Adults Hospitalized for Ground-Level Falls. AB - BACKGROUND: Despite National Surgical Quality Improvement guidelines to integrate frailty into surgical elder assessments, a quick, accurate, and simple frailty assessment tool suitable for busy clinical settings is still not available. Recently, we have demonstrated that a simple upper-extremity function (UEF) test based on wearable sensors could identify frailty with high agreement with conventional assessments by testing 20-s repetitive elbow flexion and extension. OBJECTIVE: We examined whether UEF parameters are sensitive for predicting adverse health outcomes in bedbound older adults admitted to hospital due to ground-level fall injuries. STUDY DESIGN: Frailty was assessed in 101 eligible older adults (age: 79 +/- 9 years) admitted to a trauma setting using the UEF test at the time of admission. All participants were followed up for 2 months using phone calls and chart reviews. The measured health outcomes included (1) discharge disposition (favorable: discharge home or rehabilitation; unfavorable: discharge to skilled nursing facility or death), (2) hospital length of stay, (3) 30-day readmission, (4) 60-day readmission, and (5) 30-day prospective falls. Multivariate analyses were used to identify independent predictors of adverse health outcomes based on participants' demographic parameters (i.e., age, gender, and body mass index [BMI]) and UEF index. RESULTS: Based on the UEF frailty status, 53 (52%) of the participants were frail and 48 (48%) were non-frail. Among all adverse health outcomes, age was only a significant predictor of 30-day prospective falls (p = 0.023). On the other hand, the UEF index was a significant predictor of all measured outcomes except hospital length of stay (p < 0.010). Among the UEF parameters, those indicating slowness, weakness, and exhaustion had the highest effect sizes to predict an unfavorable discharge disposition (p < 0.010; effect size = 0.65-0.92). CONCLUSION: The results of this study suggest that a 20-s UEF test is practical in the trauma setting and could be used as a quick measure for predicting adverse events and outcomes among bedbound patients after discharge. Assessing frailty using UEF may assist in objective triage, treatment, and post-discharge decision-making with regard to geriatric trauma patients. PMID- 27941331 TI - Interleukin-17RA Promotes Humoral Responses and Glomerular Injury in Experimental Rapidly Progressive Glomerulonephritis. AB - BACKGROUND/AIMS: Interleukin (IL)-17A and IL-17F are proinflammatory cytokines, which signal through a receptor complex consisting of IL-17RA and IL-17RC subunits. We sought to define the role of IL-17RA expression by leukocytes and stromal cells in nephritogenic immunity and injury in experimental glomerulonephritis. METHODS: Glomerulonephritis was induced in wild-type and IL 17RA-deficient (IL-17RA-/-) mice by sheep anti-mouse glomerular basement membrane globulin. Renal injury and immune responses were assessed at day 21. Glomerulonephritis was induced in bone marrow (BM) chimeric mice, with either BM or tissue cell (TC) deficiency of IL-17RA. To assess humoral responses, WT and IL 17RA-/- mice were sensitized to sheep globulin and euthanized 10 days later. RESULTS: IL-17RA-/- mice had reduced glomerular crescent formation, neutrophils and macrophages compared to wild-type mice, while nephritic BM-TC+ mice developed less glomerular segmental necrosis. IL-17RA expression was required in both BM and TC for maximal systemic interferon-gamma expression. Antigen-specific humoral immune responses were impaired in the absence of IL-17RA. Compared to BM+TC+ mice, glomerular IgG and C3 deposition was reduced in BM+TC- and BM-TC+ mice, respectively. Humoral immunity was also impaired in BM- and TC-deficient chimeras. BM+TC- mice had fewer B cells expressing CXCR5, while IL-17RA-/- mice had abnormal germinal centre development after immunization, with reduced follicular B cell and follicular helper T-cell CXCR5 expression, explaining the impaired humoral immunity. CONCLUSION: IL-17RA contributes to experimental glomerulonephritis, with IL-17RA expression on both leukocytes and stromal cells being required for the full expression of nephritogenic humoral immunity. PMID- 27941330 TI - Hyperosmolarity and Benzalkonium Chloride Differently Stimulate Inflammatory Markers in Conjunctiva-Derived Epithelial Cells in vitro. AB - Tear hyperosmolarity is known to cause ocular surface inflammation in dry eye syndrome. Benzalkonium chloride (BAK), an eyedrop preservative, is known to induce dry eye in long-term-treated patients. Analyzing the modulation of the proinflammatory potential of hyperosmolarity in the presence of BAK on the conjunctiva could give new insights into the effect of this preservative on the disease. In a hyperosmolar model on a conjunctiva-derived cell line, and in the presence of BAK, we evaluated key inflammatory markers [CCL2, IL-8, IL-6, macrophage migration inhibitory factor (MIF) and intercellular adhesion molecule (ICAM)-1] as well as the osmoprotectant element nuclear factor of activated T cells (NFAT)5 using ELISA, RT-qPCR or immunofluorescence staining. Hyperosmolarity highly stimulated CCL2 and NFAT5 in these cells. BAK alone only increased IL-6 expression. The stress-combined condition stimulated CCL2, NFAT5, MIF and IL-8 secretion. ICAM-1 was not modulated by any of the conditions tested. In this model, hyperosmolarity and BAK induced the release of different proinflammatory mediators, and, when combined, they lead to the release of additional inflammatory cytokines. This in vitro study highlights the importance of avoiding long-term ophthalmic treatments containing BAK, as tear film hyperosmolarity can be a result of its detergent action. PMID- 27941332 TI - Overexpression of TGF-beta Inducible microRNA-143 in Zebrafish Leads to Impairment of the Glomerular Filtration Barrier by Targeting Proteoglycans. AB - BACKGROUND: TGF-beta is known as an important stress factor of podocytes in glomerular diseases. Apart from activation of direct pro-apoptotic pathways we wanted to analyze micro-RNA (miRs) driven regulation of components involved in the integrity of the glomerular filtration barrier induced by TGF-beta. Since miR 143-3p (miR-143) is described as a TGF-beta inducible miR in other cell types, we examined this specific miR and its ability to induce glomerular pathology. METHODS: We analyzed miR-143 expression in cultured human podocytes after stimulation with TGF-beta. We also microinjected zebrafish eggs with a miR-143 mimic or with morpholinos specific for its targets syndecan and versican and compared phenotype and proteinuria development. RESULTS: We detected a time dependent, TGF-beta inducible expression of miR-143 in human podocytes. Targets of miR-143 relevant in glomerular biology are syndecans and versican, which are known components of the glycocalyx. We found that syndecan 1 and 4 were predominantly expressed in podocytes while syndecan 3 was largely expressed in glomerular endothelial cells. Versican could be detected in both cell types. After injection of a miR-143 mimic in zebrafish larvae, syndecan 3, 4 and versican were significantly downregulated. Moreover, miR-143 overexpression or versican knockdown by morpholino caused loss of plasma proteins, edema, podocyte effacement and endothelial damage. In contrast, knockdown of syndecan 3 and syndecan 4 had no effects on glomerular filtration barrier. CONCLUSION: Expression of versican and syndecan isoforms is indispensable for proper barrier function. Podocyte-derived miR-143 is a mediator for paracrine and autocrine cross talk between podocytes and glomerular endothelial cells and can alter expression of glomerular glycocalyx proteins. PMID- 27941333 TI - Randomized Controlled Trial of Hepatic Portal Reocclusion as a New Option for Detecting Bile Leakage during Hepatic Resection. AB - BACKGROUND/AIMS: To explore the possibility and feasibility of hepatic portal reocclusion for detecting bile leakage during hepatectomy. METHODS: Data were prospectively collected from 200 patients who underwent hepatectomy alone for removal of various benign or malignant tumors between March 2014 and November 2014. The surgical procedure used a conventional method for all patients, and one additional step (hepatic portal reocclusion) was included in group B. The postoperative outcomes of the patients in group A (subjected to the traditional procedure) and group B (subjected to hepatic portal reocclusion) were compared during the same period, and the incidence rates of postoperative bile leakage and other complications in the 2 groups were also analyzed. RESULTS: The incidence of postoperative bile leakage in group B was significantly lower than that in group A (1.0 vs. 9.2%, p = 0.009), although no significant differences in postoperative indicators of liver dysfunction and other complications were observed between the 2 groups (p > 0.05). CONCLUSIONS: Hepatic portal reocclusion effectively reduced the incidence of bile leakage compared to the traditional procedure, without significantly affecting liver function. Therefore, this method might be an alternative to other tests for bile leakage. PMID- 27941334 TI - Synergistic Effect of Lipoprotein-Associated Phospholipase A2 with Classical Risk Factors on Coronary Heart Disease: A Multi-Ethnic Study in China. AB - AIMS: We evaluated the synergistic effect of lipoprotein-associated phospholipase A2 (Lp-PLA2) in association with classical risk factors in predicting coronary heart disease (CHD) and demonstrated the diagnostic value of Lp-PLA2 for predicting coronary stenotic lesions in subjects with CHD. METHODS: Blood samples were acquired from 911 consecutive adult subjects (662 males and 249 females) from 11 ethnic groups. Lp-PLA2 plasma levels were detected using a commercially available turbidimetric immunoassay (TIA). CHD in patients was confirmed using coronary angiography, and the severity of coronary atherosclerosis was assessed using the Gensini scoring system. RESULTS: A binary logistic regression was performed to analyse the relationships between Lp-PLA2 and other risk factors. A multivariate logistic regression analysis revealed that Lp-PLA2 levels were significantly associated with CHD (OR, 1.882; 95% CI, 1.369-2.587, p=0.000).The area under the receiver operating characteristic curve for Lp-PLA2 was 0.589 (95%CI, 0.549-0.629, p=0.000).The synergism between Lp-PLA2 and other risk factors was also investigated. The proportion of CHD attributable to the interaction between Lp-PLA2 and age was as high as 64%. CONCLUSIONS: Lp-PLA2 levels in human plasma were positively associated with the severity of CHD, and there was a clear positive interaction between Lp-PLA2 and classical risk factors in predicting CHD. PMID- 27941335 TI - Mechanisms Underlying Endothelin-1 Level Elevations Caused by Excessive Fluoride Exposure. AB - OBJECTIVE: To explore the mechanisms underlying endothelin-1 (ET-1) elevations induced by excessive fluoride exposure. METHODS: We measured serum and bone fluoride ion content and plasma ET-1 levels and compared these parameters among different groups in an animal model. We also observed morphological changes in the aorta and endothelium of rabbits. In cell experiments, human umbilical vein endothelial cells (HUVECs) were treated with varying concentrations of NaF for 24h, with or without 10 uM U0126 pretreatment for 1 h. ET-1 levels in culture fluid and intracellular reactive oxygen species (ROS) levels, as well as ET1 gene, endothelin-converting enzyme-1 (ECE-1), extracellular signal-regulating kinase 1/2 (ERK1/2), pERK1/2 expression levels and RAS activation were measured and compared among the groups. RESULTS: Plasma ET-1 levels of rabbits increased significantly in fluorinated groups compared with those in the control group. The rabbit thoracic aortas became slightly hardened in fluorinated groups compared with those in the control group, and some vacuoles were present in the endothelial cell cytoplasm of the rabbits in fluorinated groups. In our cell experiments, ET1 gene and ECE-1 expression levels in HUVECs and ET-1 expression levels in the cell culture supernatants increased significantly in some experimental groups compared with those in the control group. These trends paralleled the changes in intracellular ROS levels, RAS activation, and the pERK1/2-to-ERK1/2 ratio. After U0126 was added, ECE-1 expression and ET-1 levels decreased significantly. CONCLUSION: Excessive fluoride exposure leads to characteristic endothelial damage (vacuoles), thoracic aorta hardening, and plasma ET-1 level elevations in rabbits. In addition, the ROS-RAS-MEK1/2 pERK1/2/ERK1/2 pathway plays a crucial-and at least partial-role in ET-1 over expression, which is promoted by excessive fluoride exposure. PMID- 27941338 TI - Does Serum HCO3 Predict Risk for Cardiovascular Disease? PMID- 27941336 TI - A Feed-Forward Regulatory Loop between HuR and the Long Noncoding RNA HOTAIR Promotes Head and Neck Squamous Cell Carcinoma Progression and Metastasis. AB - BACKGROUND/AIMS: The lncRNA Homeobox (HOX) transcript antisense RNA (HOTAIR) is overexpressed in numerous cancers. HuR is also overexpressed during tumourigenesis and is abnormally present within the cytoplasm, where it binds to AU-rich elements in the 3'UTRs of target mRNA and post-transcriptionally regulates the expression of its target genes. However, whether HOTAIR is regulated and the mechanisms by which it affects head and neck squamous cell carcinoma (HNSCC) are not well understood. METHODS: MTT, cell cycle arrest and apoptotic assays were used to examine the effects of HOTAIR and HuR on cell viability in SCC25 and FaDu cells. Wound healing and transwell invasion analysis were performed to detect the effects of HOTAIR and HuR on cell migration and invasion. The interaction between HuR and HOTAIR was confirmed via qRT-PCR, western blots, luciferase reporter and RIP assays. Finally, qRT-PCR analysis was used to detect the levels of HuR and HOTAIR in HNSCC tumours and adjacent normal tissues. RESULTS: Knockdown of HOTAIR and HuR decreased cell viability, cellular migration and invasion. Moreover, HuR interacted and stabilized HOTAIR stability and thus promoted HOTAIR expression. Notably, HOTAIR acted as a miRNA sponge for HuR. HuR also reinforced HOTAIR sponge activity through miRNA recruitment, thus enhancing HuR expression in turn. Finally, HuR and HOTAIR levels were positively correlated and significantly up-regulated in tumours samples. CONCLUSION: We demonstrated the existence of a regulatory loop in which the expression of HOTAIR and HuR is reciprocally and temporally regulated during the metastasis and progression of HNSCC. PMID- 27941337 TI - CXCL12 Regulates the Cholinergic Locus and CHT1 Through Akt Signaling Pathway. AB - BACKGROUND: CXCL12 is pivotal for cholinergic neurons, and it induces the expressions of several genes that are essential for synthesis and storage of acetylcholine(ACh), specifically choline acetyltransferase, vesicular ACh transporter (VAChT), and choline transporter. The present study explored the impact of pharmacological Akt inhibition upon cholinergic gene expression. METHODS: Western blotting was employed to determine the level of p-AKT, RT-PCR to check the mRNA levels of and CHT1(choline transporter1),VAChT and ChAT, ELISA to decipher the secretion of ACh and the activity of choline acetyltransferase. RESULTS: Here we demonstrated, in the rat pheochromocytoma cell line PC12 and in primary rat neuronal cultures, that CXCL12-evoked up-regulation of CHT1, VAChT and ChAT was mediated by Akt. Inhibition of Akt by the pharmacological inhibitor GSK690693 eliminated CXCL12-stimulated increases in cholinergic gene expression. Moreover, treatment with GSK690693 reversed CXCL12-evoked increases in choline acetyltransferase activity and ACh production. CONCLUSION: Our results suggest that CXCL12 contributes to cholinergic gene expression via Akt signaling pathway. PMID- 27941339 TI - Overexpression of CXCR7 Is a Novel Prognostic Indicator in Gastric Cancer. AB - BACKGROUND: Among several candidate genes that promote peritoneal dissemination extracted by comprehensive expression analysis of both in vivo selected metastatic cell lines and patients with gastric cancer, we focused on the chemokine (C-X-C motif) receptor (CXCR7) and explored its clinicopathological significance in gastric cancer. METHODS: CXCR7 expression was evaluated by microarray data in the Singapore cohort (n = 196) and by immunohistochemistry and reverse transcription quantitative real-time polymerase chain reaction in the Japanese cohort (n = 195). The biological function of CXCR7 in gastric cancer was explored using gene set enrichment analysis (GSEA). RESULTS: CXCR7 expression was upregulated in tumor tissues compared to normal tissues. High CXCR7 mRNA expression was associated with peritoneal dissemination and poor prognosis in the Singapore cohort. Consistent with this, the high CXCR7 mRNA expression group showed significantly poorer prognosis and a more aggressive disease course than the low expression group in the Japanese cohort. High CXCR7 mRNA expression and peritoneal dissemination were clinically relevant. GSEA revealed that CXCR7 was significantly enriched in gene expression signatures associated with tumor progression. CONCLUSIONS: CXCR7 may be a prognostic indicator and therapeutic target for gastric cancer with peritoneal dissemination. PMID- 27941340 TI - Salvianolic Acid B Ameliorates Hyperglycemia and Dyslipidemia in db/db Mice through the AMPK Pathway. AB - BACKGROUND/AIMS: Salvianolic acid B (Sal B), a major polyphenolic compound of Salvia miltiorrhiza Bunge, has been shown to possess potential antidiabetic activities. However, the action mechanism of SalB in type 2 diabetes has not been investigated extensively. The present study was designed to investigate the effects of Sal B on diabetes-related metabolic changes in a spontaneous model of type 2 diabetes, as well as its potential molecular mechanism. METHODS: Male C57BL/KsJ-db/db mice were orally treated with Sal B (50 and 100 mg/kg) or metformin (positive drug, 300 mg/kg) for 6 weeks. RESULTS: Both doses of Sal B significantly decreased fasting blood glucose, serum insulin, triglyceride and free fatty acid levels, reduced hepatic gluconeogenic gene expression and improved insulin intolerance in db/db mice. High dose Sal B also significantly improved glucose intolerance, increased hepatic glycolytic gene expression and muscle glycogen content, and ameliorated histopathological alterations of pancreas, similar to metformin. Sal B treatment resulted in increased phosphorylated AMP-activated protein kinase (p-AMPK) protein expression in skeletal muscle and liver, increased glucose transporter 4 (GLUT4) and glycogen synthase protein expressions in skeletal muscle, and increased peroxisome proliferator-activated receptor alpha (PPARalpha) and phosphorylated acetyl CoA carboxylase (p-ACC) protein expressions in liver. CONCLUSION: Our data suggest that Sal B displays beneficial effects in the prevention and treatment of type 2 diabetes at least in part via modulation of the AMPK pathway. PMID- 27941342 TI - Should the Surgical Management of Buschke-Lowenstein Tumors Be Aggressive? About 10 Cases. AB - AIMS: Buschke-Lowenstein tumor (BLT) of the anal margin is a histologically benign tumor whose degeneration can lead to a deadly local evolution because of difficult and late diagnosis. The objective of this study was to report our experience and propose a therapeutic strategy for these rare tumors. METHODS: From 1996 to 2014, 10 men with a median age of 45 years (25-64) were treated for a BLT of the anal margin with a first local excision possibly followed by rectal amputation. RESULTS: Local perianal excision was curative in 6 cases without recurrence. The median follow-up time was 94.5 months (5-175). In 4 patients, local excision was followed by an early recurrence, justifying a complementary abdominoperineal excision (APE) of the rectum. Two patients who benefited from complementary resection are currently free from recurrence. Even if the postoperative course was uneventful, 2 died from recurrence and disease progression within 5 and 11 postoperative months each. CONCLUSION: Macroscopic surgical evaluation of local tumoral invasion and extensive radical resection appears to be associated with long-term survival without recurrence. When recurrence occurs, APE of the rectum seems to be the only curative alternative. Based on low level of evidence, surgical excision is currently the only standard treatment for these lesions. PMID- 27941341 TI - Sulodexide Reduces the Proinflammatory Effect of Serum from Patients with Peripheral Artery Disease in Human Arterial Endothelial Cells. AB - BACKGROUND/AIMS: Dysfunction of the arterial endothelial cells promotes the progression of atherosclerosis. We studied how exposure of human arterial endothelial cells to atherosclerotic serum from patients with peripheral artery disease changes the secretory activity of these cells, and whether that reaction is modified by sulodexide. METHODS: Endothelial cells in in vitro culture were exposed to standard culture medium +/- 100pg/mL Interleukin-1(IL-1) or to medium supplemented with 20% atherosclerotic serum. Afterwards, the expression of genes responsible for the synthesis of Interleukin-6 (IL-6), Vascular Cell Adhesion Protein-1 (VCAM-1) and Von Willebrand Factor (VWF) was evaluated, together with the secretion of these compounds. Additionally, the effect of sulodexide on these processes was studied. RESULTS: Atherosclerotic serum stimulated the expression of IL6, VCAM-1 and VWF genes in endothelial cells, which was followed by increased secretion of these compounds by 179%, 121% and 116%, respectively. Sulodexide (0.5 LRU/mL) reduced atherosclerotic serum-induced increased expression of genes for IL-6 (-32%), VCAM-1 (-20%) and VWF (-42%), and lowered secretion of these molecules: IL-6 (-27%), VCAM-1(-27%), VWF (-25%). Sulodexide also reduced, in a dose- dependent manner, secretion of IL6 from unstimulated and stimulated with IL-1 endothelial cells. CONCLUSIONS: Atherosclerotic serum induces proinflammatory and prothrombotic phenotype in arterial endothelium, which is partially reduced by sulodexide, via inhibition of genes expression, and in consequence lower secretory activity. PMID- 27941343 TI - Detection of Prostate Cancer Metastasis by Whole Body Magnetic Resonance Imaging Combined with Bone Scintigraphy and PSA Levels. AB - BACKGROUND/AIMS: The combined role of whole-body magnetic resonance imaging (WB MRI), bone scintigraphy and prostate specific antigen (PSA) were considered in predicting metastases and prognosis of prostate cancer (PCa). METHODS: Totally 38 PCa patients underwent WB-MRI, bone scintigraphy and PSA detections, and 34 benign prostate hyperplasia (BPH) patients were checked with PSA. Pearson correlations were performed to determine associations among PSA, apparent diffusion coefficient (ADC) and Gleason scoring. Specificity and sensitivity were for comparison of diagnostic accuracies. Patients' baseline PSA, PSA nadir and time to the prostate-specific antigen nadir (TTPN) were analyzed, and Kaplan Meier survival curves were also established. RESULTS: ADC values were negatively correlated with PSA levels (rs = -0.389, P = 0.016) and Gleason scores (rs = 0.432, P = 0.006), while PSA levels were positively correlated with Gleason scoring (rs = 0.493, P = 0.002). Diagnostic efficacy of whole body-diffusion weighted imaging (WB-DWI) combined with PSA seemed the most favorable, and bone scintigraphy was advantageous in identifying bone metastasis. PSA levels (> 61.60 ug/L), Gleason scores (> 6) and ADC (< 0.81 * 10-3 mm2/s) could all predict pessimistic prognosis (HR = 7.65; HR = 6.09; HR = 7.28). Smaller PSA nadir (<= 1.0 ug/L) and longer TTPN (> 3 months) were associated with increased 5-year survival rate (P < 0.05). CONCLUSIONS: The combined efficacies of WB-MRI, bone scintigraphy and PSA levels were desired in identifying PCa lesions and prognosis. PMID- 27941345 TI - Pulmonary Hypertension Is Associated with Mortality and Cardiovascular Events in Chronic Kidney Disease Patients. AB - BACKGROUND: We evaluated the prevalence, determinants and prognosis value of pulmonary hypertension (PH) in non-dialysis chronic kidney disease (CKD) patients. METHODS: This is a prospective study with stages 3-5 non-dialysis dependent CKD patients. PH was estimated by Doppler echocardiography and defined as a pulmonary artery systolic pressure above 35 mm Hg. RESULTS: Three hundred fifty-three patients were recruited, of whom 94 (26.6%) had PH. Prevalence of PH increased with the decline of renal function: 21.6, 24.1, and 31.7% in stages 3, 4, and 5, respectively. Independent predictors of PH were age, estimated glomerular filtration rate (eGFR), history of cardiovascular (CV) events, the presence of an arteriovenous fistulae (AVF), and left ventricular (systolic and diastolic) dysfunction. Over a median follow-up of 22 months, 71 patients died (20%). After multivariate adjustment for age, gender, previous CV disease, diastolic and systolic dysfunction, PH remained as an independent predictor of all-cause mortality (hazards ratio [HR] 1.84, 95% CI 1.06-3.18, p = 0.02). One hundred patients (28%) had a new onset CV event. After adjustment for age, gender, previous CV disease, systolic and diastolic dysfunction, PH maintains its independent association with CV events (HR 2.77, 95% CI 2.00-3.25, p < 0.001). CONCLUSIONS: PH prevalence rises as kidney function declines. Main determinants of PH are age, eGFR, previous CV disease, the presence of an AVF and left ventricular systolic or diastolic dysfunction. PH is an independent predictor of all-cause mortality and CV events. PMID- 27941344 TI - Routine Colonoscopy after Acute Uncomplicated Diverticulitis - Challenging a Putative Indication. AB - BACKGROUND AND AIMS: Most international guidelines recommend performing a routine colonoscopy after the conservative management of acute diverticulitis, mainly to rule out a colorectal malignancy; however, data to support these recommendations are scarce and conflicting. This study is aimed at determining the rate of advanced colonic neoplasia (ACN) found by colonoscopy, and hence the need for routine colonoscopy after CT-diagnosed acute diverticulitis. METHODS: We retrospectively analyzed all patients hospitalized for acute diverticulitis between July 2008 and June 2013. Patients who underwent colonoscopy more than 1 year after the acute episode were excluded. Advanced adenoma (AA) was defined as an adenoma with: (i) >=10 mm, (ii) >=25% villous features, or (iii) high-grade dysplasia. ACN included cases of colorectal cancer (CRC) and AA. RESULTS: Of the 364 selected patients, 252 (69%) underwent colonoscopy (51% women, median age 55 +/- 11 years). Adenomatous polyps were evident in 14.7% patients; 5.1% had AA and 3.2% had CRC. Patients with complicated diverticulitis had a higher number of ACN compared to those with uncomplicated diverticulitis (20.9 vs. 5.7%, p = 0.003). On multivariate analysis, age >=50 years (OR 8.12, 95% CI 2.463-45.112; p = 0.017) and abscess on CT (OR 3.15, 95% CI 1.586-11.586; p = 0.036) were identified as significant risk factors for ACN. CONCLUSIONS: Patients with diverticulitis complicated with abscess have a higher risk of ACN on follow-up colonoscopy. The prevalence of ACN in patients with uncomplicated diverticulitis is quite similar to the average-risk population, and therefore an episode of CT diagnosed uncomplicated diverticulitis, per se, does not seem to be a recommendation for colonoscopy. PMID- 27941346 TI - Prospective Evaluation of Discharge Trends after Colorectal Surgery within an Enhanced Recovery after Surgery Pathway. AB - INTRODUCTION: Enhanced recovery after surgery (ERAS) pathways proved to reduce complications, length of hospital stay and costs after colorectal surgery. Standardized discharge criteria have been established that are fulfilled after complete medical recovery is achieved. This study aimed to assess the timing of complete medical recovery in relation to the timing of actual discharge, and to assess reasons for prolonged hospital stay within an ERAS pathway. METHODS: One hundred fourteen consecutive patients undergoing elective colorectal surgery within an ERAS pathway were included in this prospective analysis. Fulfillment of discharge criteria was assessed daily and reasons for prolonged hospital stay were documented. RESULTS: Thirty percent of patients went home on the day that all discharge criteria were met. Overall, patients were discharged at a median of 2 days (interquartile range 1-3) after fulfillment of discharge criteria. Reasons for delayed discharge were (1) organizational in 20%; (2) patient or surgeon unwilling in 29%; and (3) because the patient was deemed to be discharged too soon distance from the operation in 51%. CONCLUSION: In this observational study, only 30% of patients were discharged on the day all recovery criteria were met. The main reason for continued hospitalization was surgeon- or patient-related reluctance or 'precaution'; thus, better and more of general information seems to be necessary. PMID- 27941347 TI - Feasibility of Shape-Memory Ni/Ti Alloy Wire Containing Tube Elevators for Transcrestal Detaching Maxillary Sinus Mucosa: Ex Vivo Study. AB - BACKGROUND: Osteotome sinus floor elevation is a less invasive approach to augment an insufficient alveolar bone at the posterior maxilla for dental implantation. However, this approach has some limitations due to the lack of sinus lift tools available for clinical use and the small transcrestal access to the maxillary sinus floor. We recently invented shape-memory Ni/Ti alloy wire containing tube elevators for transcrestal detaching maxillary sinus mucosa, and developed goat ex vivo models for direct visualizing the effectiveness of detaching sinus mucosa in real time during transcrestal maxillary sinus floor elevation. METHODS: We evaluated our invented elevators, namely elevator 012 and elevator 014, for their effectiveness for transcrestal detaching maxillary sinus mucosa using the goat ex vivo models. We measured the length of sinus mucosa detached in mesial and distal directions or buccal and palatal directions, and the space volume created by detaching maxillary sinus mucosa in mesial, distal, buccal and palatal directions using the invented elevators. RESULTS: Elevator 012 had a shape-memory Ni/Ti alloy wire with a diameter of 0.012 inch, while elevator 014 had its shape-memory Ni/Ti alloy wire with a diameter of 0.014 inch. Elevator 012 could detach the goat maxillary sinus mucosa in the mesial or distal direction for 12.1+/-4.3 mm, while in the buccal or palatal direction for 12.5+/ 6.7 mm. The elevator 014 could detach the goat maxillary sinus mucosa for 23.0+/ 4.9 mm in the mesial or distal direction, and for 19.0+/-8.1 mm in the buccal or palatal direction. An average space volume of 1.7936+/-0.2079 ml was created after detaching the goat maxillay sinus mucosa in both mesial/distal direction and buccal/palatal direction using elevator 012; while the average space volume created using elevator 014 was 1.8764+/-0.2366 ml. CONCLUSION: Both two newly invented tube elevators could effectively detach the maxillary sinus mucosa on the goat ex vivo sinus models. Moreover, elevator 014 has advantages over the elevator 012 for the capability to detach sinus mucosa. PMID- 27941349 TI - Lipotoxic Palmitate Impairs the Rate of beta-Oxidation and Citric Acid Cycle Flux in Rat Neonatal Cardiomyocytes. AB - BACKGROUND/AIMS: Diabetic hearts exhibit intracellular lipid accumulation. This suggests that the degree of fatty acid oxidation (FAO) in these hearts is insufficient to handle the elevated lipid uptake. We previously showed that palmitate impaired the rate of FAO in primary rat neonatal cardiomyocytes. Here we were interested in characterizing the site of FAO impairment induced by palmitate since it may shed light on the metabolic dysfunction that leads to lipid accumulation in diabetic hearts. METHODS: We measured fatty acid oxidation, acetyl-CoA oxidation, and carnitine palmitoyl transferase (Cpt1b) activity. We measured both forward and reverse aconitase activity, as well as NAD+ dependent isocitrate dehydrogenase activity. We also measured reactive oxygen species using the 2', 7'-Dichlorofluorescin Diacetate (DCFDA) assay. Finally we used thin layer chromatography to assess diacylglycerol (DAG) levels. RESULTS: We found that palmitate significantly impaired mitochondrial beta-oxidation as well as citric acid cycle flux, but not Cpt1b activity. Palmitate negatively affected net aconitase activity and isocitrate dehydrogenase activity. The impaired enzyme activities were not due to oxidative stress but may be due to DAG mediated PKC activation. CONCLUSION: This work demonstrates that palmitate, a highly abundant fatty acid in human diets, causes impaired beta-oxidation and citric acid cycle flux in primary neonatal cardiomyocytes. This metabolic defect occurs prior to cell death suggesting that it is a cause, rather than a consequence of palmitate mediated lipotoxicity. This impaired mitochondrial metabolism can have important implications for metabolic diseases such as diabetes and obesity. PMID- 27941348 TI - Protective Effects of 2-Dodecyl-6-Methoxycyclohexa-2,5 -Diene-1,4-Dione Isolated from Averrhoa Carambola L. (Oxalidaceae) Roots on High-Fat Diet-Induced Obesity and Insulin Resistance in Mice. AB - BACKGROUND/AIMS: The roots of Averrhoa carambola L. (Oxalidaceae) have long been used as a traditional Chinese medicine for the treatment of diabetes and diabetes related diseases. 2-dodecyl-6-methoxycycyclohexa-2,5-1,4-dione (DMDD) has been isolated from A. carambola L. roots, and this study was carried out to investigate the potential beneficial effects of DMDD on obesity and insulin resistance induced by a high-fat diet (HFD) in mice. METHODS: C57BL/6J mice were fed a HFD for 16 weeks and orally administered DMDD (12.5, 25, or 50 mg/kg of body weight per day) and metformin (280 mg/kg of body weight per day) for the last 4 weeks. RESULTS: The body weights and adipose tissue weights as well as the serum levels of blood glucose, total cholesterol, triglycerides, free fatty acids, insulin, interleukin-6, and tumor necrosis factor-alpha were significantly decreased by DMDD, and the expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor (Myd88) in the epididymal adipose tissue was downregulated by DMDD. In contrast, insulin sensitivity was enhanced. The results of the glucose tolerance tests, insulin tolerance tests, and insulin release tests indicated that there was a marked improvement in insulin secretion, and the areas under the curve corresponding to the three tests were also significantly decreased by DMDD. The activities of superoxide dismutase and glutathione peroxidase were simultaneously enhanced, whereas the content of malondialdehyde was decreased by DMDD in the liver homogenates of the C57BL/6J mice. In addition, hepatic steatosis and adipocyte hypertrophy, as assessed by H&E staining of liver and adipose tissues, were significantly improved by DMDD. CONCLUSION: These data suggest that MDD has potential benefits for the treatment of HFD-induced obesity and insulin resistance, and its effects may be associated with improvements in lipid metabolism and inhibition of the expression of TLR4 in adipose tissues. PMID- 27941350 TI - Pentraxin 3 Activates JNK Signaling and Regulates the Epithelial-To-Mesenchymal Transition in Renal Fibrosis. AB - BACKGROUND/AIMS: Tubulointerstitial fibrosis can lead to end-stage renal disease. Pentraxin 3 (PTX3) is an acute phase protein produced by resident and innate immunity cells. We investigated the effect of PTX3 on cultured human proximal tubular epithelial (HK-2) cells and a rat unilateral ureteral obstruction (UUO) model of renal fibrosis. METHODS: Gain-of-function experiments were used to examine the effect of recombinant human PTX3 (Rh-PTX3) on HK-2 cells. Cell proliferation (MTT assay) and in vitro cell migration were measured. The levels of PTX3, p-JNK, and EMT markers were measured using immunohistochemistry, RT-PCR, and western blotting in UUO rats and HK-2 cells. RESULTS: HK-2 cells treated with Rh PTX3 did not affect cell viability, but significantly increased cell migration. Moreover, Rh-PTX3 increased the expression of snail, slug, N-cadherin, and vimentin, decreased the expression of E-cadherin, and increased the phosphorylation of JNK. SP600126 (a specific JNK inhibitor) enhanced the effects of Rh-PTX3. Rats with UUO exhibited time-dependent increased levels of PTX3, p JNK, and vimentin, and decreased expression of E-cadherin. CONCLUSIONS: Our results suggest that PTX3 induces cell migration via upregulation of EMT in a JNK dependent mechanism, and highlight the role of PTX3 in the pathogenesis renal fibrosis. PMID- 27941351 TI - Anti-Cancer Effect of Cap-Translation Inhibitor 4EGI-1 in Human Glioma U87 Cells: Involvement of Mitochondrial Dysfunction and ER Stress. AB - BACKGROUND: Cancer cells are frequently addicted to deregulated oncogenic protein translation that usually arises as a consequence of increased signaling flux from eIF4F activation. The small molecule 4EG-I, a potent inhibitor of translation initiation through disrupting eIF4E/eIF4G interaction, has been shown to exert anticancer effects in animal models of human cancers. METHODS: Here, we extensively investigated the anticancer activity of 4EGI-1 in human glioma U87 cells. The anti-cancer effects of 4EGI-1 were measured by cell viability, lactate dehydrogenase (LDH) release, TUNEL staining, flow cytometry and western blot analysis in vitro, and also examined in a U87 xenograft model in vivo. The potential underlying molecular mechanisms were investigated by measuring mitochondrial function and ER stress. RESULTS: We found that 4EGI-1 impaired the assembly of the eIF4F complex and decreased the expression of the eIF4E regulated proteins. The results of TUNEL staining and flow cytometry showed that 4EGI-1 treatment induced apoptotic cell death in a dose-dependent manner. Furthermore, 4EGI-1-induced apoptosis in U87 cells was associated with mitochondrial dysfunction and activation of the intrinsic mitochondrial pathway, which was dependent on the induction of the pro-apoptotic protein Bax. In addition, 4EGI-1 treatment triggered ER stress, which was evidenced by morphological changes of ER lumen and ER calcium release, as well as the dose-dependent increases in the expression of ER stress related proteins. Moreover, knockdown of the ER chaperone GRP-78 through siRNA was shown to partially reverse the 4EGI-1-induced ER stress in U87 cells. In vivo, 4EGI-1 strongly inhibited growth of U87 glioma xenografts without any apparent organ related toxicities. CONCLUSION: These data indicate that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for human glioma therapy. PMID- 27941352 TI - A Comparison Study: The Risk Factors in the Lifestyles of Thyroid Cancer Patients and Healthy Adults of South Korea. AB - BACKGROUND: In South Korea, there has been a rapid increase in thyroid cancer diagnoses, and the thyroid cancer incidence rate is the highest in the world. This study explored possible risk factors that may influence the development of thyroid cancer by comparing life habits of thyroid cancer patients and healthy adults. OBJECTIVE: The aims of this study were to identify lifestyle and habit differences in thyroid cancer patients and healthy adults and to investigate risk factors that influence the development of thyroid cancer. METHODS: The study was designed as a retrospective comparison survey study of thyroid cancer patient group and healthy adult group. One hundred two thyroid cancer patients in a university hospital and 115 healthy adults were recruited for this study. Data were analyzed using descriptive statistics, chi test/t test, and logistic regression with SPSS program. RESULTS: Previous smoking history, lower physical activity level, higher stress, and unhealthy eating habits (consumption of instant food products) were shown to be risk factors in the development of thyroid cancer. CONCLUSION: Based on the results of this study comparing thyroid cancer patients and healthy adults, it is recommended to encourage an increase in physical activity, minimize both direct and indirect exposure to smoking, develop healthy eating habits of consuming more vegetables, and effectively manage stress levels. IMPLICATIONS FOR PRACTICE: Lifestyle preferences and habits may influence the development of thyroid cancer. It is imperative to identify and modify the risk factors in order to prevent thyroid cancer development. PMID- 27941353 TI - Cancer Survivors' Experiences and Explanations of Postcancer Fatigue: An Analysis of Online Blogs. AB - BACKGROUND: Postcancer fatigue (PCF) is a form of chronic fatigue that is very common and can persist for years among disease-free cancer survivors. Despite this, PCF remains underreported and often goes untreated. OBJECTIVE: The aim of this study is to explore PCF from the perspective of cancer survivors via online blogs, with a focus on their experiences and personal explanations of PCF. METHODS: An online search identified 15 recent blogs written by cancer survivors who specifically discussed their PCF. Thematic analysis was used to analyze blog content. RESULTS: Bloggers explained PCF as a severe and unpredictable symptom in their lives. They identified anxiety, emotional trauma, and cancer side effects to be the key causal factors of their PCF. Coping strategies adopted by bloggers included diet, exercise, acceptance and reducing workload to manage their fatigue. CONCLUSIONS: Online blogs are a rich source of qualitative data that can give unique insight into issues faced by cancer survivors. Bloggers' accounts confirmed that PCF is a complex issue that can be a significant source of frustration in their everyday lives. This study highlighted that bloggers with PCF appear to have some coping strategies and understanding of PCF, yet these are not always consistent with current medical and psychological knowledge. IMPLICATIONS FOR PRACTICE: This study has demonstrated that blogs can offer valuable information to existing knowledge of cancer survivors' experiences and explanations of PCF. The findings may assist healthcare professionals with educating patients about PCF and with increasing the legitimacy, awareness, and understanding of PCF. PMID- 27941354 TI - The endothelial glycocalyx and perioperative lung injury. AB - PURPOSE OF REVIEW: Ventilator-induced lung injury is a major contributor to perioperative lung injury. The end-expiratory lung volume, regional lung overdistension, and tidal recruitment are known to be the main factors causing subsequent alveolar damage and inflammation. The alveolar-capillary membrane including the endothelial glycocalyx as an integral part of the vascular endothelium seems to play a major role in different kinds of lung injury. RECENT FINDINGS: Recent studies underline the pivotal importance of the endothelial glycocalyx in lung injury. The glycocalyx regulates and modulates plasma endothelial cell interactions. Several triggers are known to deteriorate the gylcocalyx such as fluid overload, ischemia, and TRALI. The clinical manifestation is inflammation, capillary leak, and edema formation. Breakdown of the endothelial gylcocalyx is of gaining importance in the context of one-lung ventilation, known to be a major risk factor for postoperative lung injury. Studies suggest that volatile anesthetics may have a protective influence on the endothelial glycocalyx of pulmonary capillaries and reduce ischemia-reperfusion injury. This might be of clinical relevance for postoperative outcome. SUMMARY: This review focuses on the involvement of the pulmonary endothelial glycocalyx in the context of perioperative lung injury. The pathophysiological mechanisms and trigger factors of glycocalyx deterioration are discussed, and prevention strategies are taken into consideration. PMID- 27941355 TI - Managing nonalcoholic fatty liver disease in patients living with HIV. AB - PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) is common among patients living with HIV and may lead to liver-related morbidity and mortality. RECENT FINDINGS: The prevalence of NAFLD among patients with HIV is increasingly well described due to new noninvasive techniques to quantify hepatic steatosis and fibrosis. Patients with HIV may be at increased risk of disease progression, though high-quality natural history studies are not available. The high rates of metabolic syndrome, dyslipidemia and insulin resistance may partially account for this excess risk, though the impact of HIV itself, antiretroviral medications and dysregulation of the gut-liver axis likely play important roles. Treatment of NAFLD in patients with HIV is poorly studied. Current recommendations include diet and lifestyle modifications, HIV viral suppression and limitation of hepatotoxic medications as possible. In addition, there are a large number of novel medications now in clinical trials designed to target the accumulation of hepatic fat, oxidative stress, inflammation and/or fibrosis, which will revolutionize this field. SUMMARY: Although additional work is needed to understand the natural history of NAFLD in patients with HIV and identify those at highest risk, novel treatment approaches are now being tested in this population. We may soon have effective treatments to combat this epidemic. PMID- 27941356 TI - Abdominal compartment syndrome and the open abdomen: any unresolved issues? AB - PURPOSE OF REVIEW: This article reviews the key principles of abdominal compartment syndrome and the open abdomen, exploring some of the unresolved issues. It reviews new concepts in care. RECENT FINDINGS: Recent use of peritoneal resuscitation, and benefits of mesh-mediated traction are discussed. Abdominal compartment syndrome remains a result of complex interaction between general haemorrhage, sepsis and fluid resuscitation. Improved resuscitation and sepsis control has decreased but not abolished the need for the open abdomen and progression for abdominal compartment syndrome. Fourth-generation abdominal wall dressings need to be combined with a dynamic closure system; currently, negative pressure wound therapy at the index open abdomen coupled with mesh-mediated tractions offers the best outcome. SUMMARY: The key to optimizing outcome is early abdominal closure within 7 days because failure to do so will increase morbidity, mortality and fistulae formation. Novel techniques complementing existing de-resuscitation techniques are discussed. PMID- 27941357 TI - Nutrient deficiencies prior to bariatric surgery. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an update of recent additions to our understanding of the prevalence of nutrient deficiencies and the potential role of preoperative weight loss in contributing to these deficiencies in obese individuals planning to undergo bariatric surgery. RECENT FINDINGS: Recent reports that have included bariatric surgery candidates from sites around the world have shown consistent deficiencies in a variety of nutrients. Although protein-energy malnutrition is uncommon preoperatively, micronutrient deficiencies occur commonly with multiple deficiencies often present in the same individual. No difference in the prevalence of deficiency between men and women is apparent, and a standard profile of susceptibility to deficiency has not been identified. In the only studies that have evaluated dietary intake of total energy, macronutrients and micronutrients preoperatively, despite an excess of calories ingested, micronutrient intake tends to be lower than recommended. SUMMARY: A high prevalence of micronutrient deficiencies, especially vitamin D, folate, B12 and iron, is present in obese individuals being considered for bariatric surgery. Despite high-caloric intake, the deficiencies present appear to be related to the poor quality of the diet and low micronutrient intake. These findings strengthen prior recommendations of routine preoperative nutritional screening. Because a standard profile of susceptibility to deficiency has not been identified, extensive nutritional screening, including micronutrient testing, should be considered in all patients in the preoperative setting. Finally, we recommend early supplementation of vitamins and minerals based on laboratory assessment and incorporation of a program to optimize eating behaviors prior to surgery. PMID- 27941358 TI - Simvastatin adjunct therapy for negative symptoms of schizophrenia: a randomized double-blind placebo-controlled trial. AB - We investigated the effects of simvastatin adjunctive therapy on the negative symptoms of schizophrenia. In this double-blind trial, inpatients with chronic schizophrenia were clinically stabilized on a constant dose of risperidone for at least 4 weeks before the study and were then randomized to receive risperidone (4 6 mg/day) plus either simvastatin (40 mg/day) (n=33) or placebo (n=33) for 8 weeks. The Positive and Negative Syndrome Scale was used to measure the negative, positive, and general symptoms of schizophrenia at baseline and every 2 weeks. The Hamilton Depression Rating Scale and the Extrapyramidal Symptom Rating Scale were used to measure depression and extrapyramidal symptoms at baseline and week 8. Difference in change in negative symptoms score from the baseline to week 8 was considered the single primary outcome. At baseline, negative symptoms scores were higher than positive symptoms scores in both simvastatin and placebo groups. There was no baseline difference between the two groups in terms of any of the measured variables. Compared with the placebo group, the simvastatin group showed a significantly higher reduction in negative symptoms scores from baseline to week 8 [mean difference: 95% confidence interval=-1.42 (-2.32 to -0.52), P=0.003]. Similar findings were observed for total scores [mean difference: 95% confidence interval=-1.85 (-2.87 to -0.83), P=0.001]. The results were not significant for positive symptoms or general psychopathology scores. We found a favorable effect of simvastatin on negative symptoms of patients with schizophrenia; however, future studies are warranted to confirm these results. PMID- 27941359 TI - Short article: Capsule endoscopy in graft-versus-host disease. AB - INTRODUCTION: The gold standard in the diagnosis of gastrointestinal graft-versus host disease (GVHD) after allogenic hematopoietic stem cell transplantation is conventional endoscopy with histopathological assessment. The role of capsule endoscopy (CE) is uncertain. The aim of the present study was to investigate the accuracy of CE in this setting, comparing the clinical, endoscopic and histological data. METHODS: This was a retrospective single-centre study that included 57 (mean age: 47.18+/-15.05 years, 57.89% men) patients presenting with GVHD who underwent a valid CE and histopathological analysis by conventional endoscopy between January 2004 and July 2016. The endoscopic scored findings, clinical data and histopathological diagnosis were compared using duodenal histology as the gold standard. RESULTS: CE detected mild (n=4, 7.02%), moderate (n=6, 10.53%) and severe (n=21, 36.84%) grades, with a higher diagnostic yield than conventional endoscopy (54.39 vs. 28.07%, P<0.001). A positive CE predicted positive histology (80.64 vs. 15.38%, P<0.001) with a sensitivity, specificity, negative predictive value and accuracy of 86.21, 78.57, 84.62 and 82.46%. This procedure detected more mild-to-moderate histological lesions than conventional endoscopy (8.77 vs. 3.51%, P=0.25). In addition, 16% of patients with a previous normal endoscopy with biopsies had a pathological CE and there were eight (25.81%) patients with positive CE images unreachable by conventional endoscopy. CONCLUSION: CE is a useful device in GVHD, achieving high accuracy values and diagnostic yield. However, its results may be interpreted in conjunction with clinical and histological features, particularly in mild-to-moderate stages. PMID- 27941360 TI - Food and Drug Administration Efforts to Mitigate Contact Lens Discomfort. AB - The premarket review of contact lenses and accessories by the FDA involves the assessment of nonclinical and clinical information in support of clearance or approval of marketing applications. The review process for these medical devices, including attributes, which may contribute to comfort for lens wearers, is summarized, as are mechanisms by which FDA continues to assess and improve recommendations through the review process and through collaboration with external entities. PMID- 27941361 TI - Treatment strategies for endometrial cancer: current practice and perspective. AB - PURPOSE OF REVIEW: Endometrial cancer incidence is increasing in North America and is a major cause of morbidity and mortality in women. We review recent literature published on treatment of endometrial cancer and highlight areas of active interest. RECENT FINDINGS: There has been movement toward minimal invasive surgery at diagnosis; lymph node staging remains controversial and continues to be investigated. Progress has been made to establish consensus on endometrial cancer risk classification to promote consistency for future trial design. Molecular characterization of endometrial cancer and its integration into clinicopathological profiling to develop predictive biomarkers for treatment selection are active areas of research. Optimal adjuvant treatment strategy in high-risk endometrial cancer remains to be defined with recognition of treatment related toxicity. Despite encouraging results in drug development for treatment of advanced/recurrent endometrial cancer, no targeted therapies beyond hormonal therapy are approved. There is an urgent need for scientifically validated therapy with predictive biomarkers. SUMMARY: Our understanding of endometrial cancer has evolved through improvements in molecular biology, allowing improved definition of target-specific therapies. The precise role and sequence of conventional and targeted therapies, including immunotherapy, will require careful attention to the design of clinical trials with translational emphasis to allow the discovery, validation, and implementation of predictive biomarkers into clinical care. PMID- 27941362 TI - Molecular characterization of endometrial cancer and therapeutic implications. AB - PURPOSE OF REVIEW: This article reviews the emerging comprehensive genomic classification of endometrial carcinoma and discusses the therapeutic implications of these subgroups. RECENT FINDINGS: Comprehensive, multiplatform evaluation of endometrial cancers by the Cancer Genome Atlas stratified the molecular aberrations into four distinct subtypes: POLE mutations, microsatellite instability, copy-number low/microsatellite stable, and copy-number high/'serous like.' POLE-mutant tumors have a favorable prognosis and may often be overtreated. Microsatellite instability hypermutated tumors commonly have alterations in the phosphatidylinositide 3-kinases/AKT/mechanistic target of rapamycin pathway and limiting targeted therapy to this group may lead to greater response rates. Copy-number low/microsatellite stable tumors represent the majority of grade 1 and grade 2 endometrioid cancers and have an intermediate prognosis, few TP53 mutations, but frequent mutations in genes involved with Wingless-related integration site signaling. Approximately 25% of high-grade endometrioid tumors have mutational profiles that classify as copy-number high/'serous-like' and might benefit from treatment approaches similar to those for serous tumors. SUMMARY: Molecular characterization of endometrial cancer classifies tumors into prognostically significant subtypes with a broad range of therapeutic implications. PMID- 27941363 TI - Cancer genomics and clinical practice: how can we close the gap more quickly? PMID- 27941364 TI - Airway Management in the 21st Century. PMID- 27941365 TI - Management of the Airway in Challenging Patients Undergoing Upper Endoscopic Procedures. PMID- 27941366 TI - Anatomic Approach to Airway Management of the Syndromic Child. PMID- 27941367 TI - The Bariatric Airway. PMID- 27941370 TI - Meta-Analysis of Therapeutic Hypothermia for Traumatic Brain Injury in Adult and Pediatric Patients. AB - OBJECTIVE: Therapeutic hypothermia has been used to attenuate the effects of traumatic brain injuries. However, the required degree of hypothermia, length of its use, and its timing are uncertain. We undertook a comprehensive meta-analysis to quantify benefits of hypothermia therapy for traumatic brain injuries in adults and children by analyzing mortality rates, neurologic outcomes, and adverse effects. DATA SOURCES: Electronic databases PubMed, Google Scholar, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov and manual searches of studies were conducted for relevant publications up until February 2016. STUDY SELECTION: Forty-one studies in adults (n = 3,109; age range, 18-81 yr) and eight studies in children (n = 454; age range, 3 mo to 18 yr) met eligibility criteria. DATA EXTRACTION: Baseline patient characteristics, enrollment time, methodology of cooling, target temperature, duration of hypothermia, and rewarming protocols were extracted. DATA SYNTHESIS: Risk ratios with 95% CIs were calculated. Compared with adults who were kept normothermic, those who underwent therapeutic hypothermia were associated with 18% reduction in mortality (risk ratio, 0.82; 95% CI, 0.70-0.96; p = 0.01) and a 35% improvement in neurologic outcome (risk ratio, 1.35; 95% CI, 1.18-1.54; p < 0.00001). The optimal management strategy for adult patients included cooling patients to a minimum of 33 degrees C for 72 hours, followed by spontaneous, natural rewarming. In contrast, adverse outcomes were observed in children who underwent hypothermic treatment with a 66% increase in mortality (risk ratio, 1.66; 95% CI, 1.06-2.59; p = 0.03) and a marginal deterioration of neurologic outcome (risk ratio, 0.90; 95% CI, 0.80-1.01; p = 0.06). CONCLUSIONS: Therapeutic hypothermia is likely a beneficial treatment following traumatic brain injuries in adults but cannot be recommended in children. PMID- 27941369 TI - Pulmonary Arterial Compliance in Acute Respiratory Distress Syndrome: Clinical Determinants and Association With Outcome From the Fluid and Catheter Treatment Trial Cohort. AB - OBJECTIVES: Pulmonary vascular dysfunction is associated with adverse prognosis in patients with the acute respiratory distress syndrome; however, the prognostic impact of pulmonary arterial compliance in acute respiratory distress syndrome is not established. DESIGN, SETTING, PATIENTS: We performed a retrospective analysis of 363 subjects with acute respiratory distress syndrome who had complete baseline right heart catheterization data from the Fluid and Catheter Treatment Trial to test whether pulmonary arterial compliance at baseline and over the course of treatment predicted mortality. MAIN RESULTS: Baseline pulmonary arterial compliance (hazard ratio, 1.18 per interquartile range of 1/pulmonary arterial compliance; 95% CI, 1.02-1.37; p = 0.03) and pulmonary vascular resistance (hazard ratio, 1.28 per interquartile range; 95% CI, 1.07-1.53; p = 0.006) both modestly predicted 60-day mortality. Baseline pulmonary arterial compliance remained predictive of mortality when pulmonary vascular resistance was in the normal range (p = 0.02). Between day 0 and day 3, pulmonary arterial compliance increased in acute respiratory distress syndrome survivors and remained unchanged in nonsurvivors, whereas pulmonary vascular resistance did not change in either group. The resistance-compliance product (resistance-compliance time) increased in survivors compared with nonsurvivors, suggesting improvements in right ventricular load. CONCLUSIONS: Baseline measures of pulmonary arterial compliance and pulmonary vascular resistance predict mortality in acute respiratory distress syndrome, and pulmonary arterial compliance remains predictive even when pulmonary vascular resistance is normal. Pulmonary arterial compliance and right ventricular load improve over time in acute respiratory distress syndrome survivors. Future studies should assess the impact of right ventricular protective acute respiratory distress syndrome treatment on right ventricular afterload and outcome. PMID- 27941371 TI - Survival Benefit and Cost Savings From Compliance With a Simplified 3-Hour Sepsis Bundle in a Series of Prospective, Multisite, Observational Cohorts. AB - OBJECTIVES: To determine mortality and costs associated with adherence to an aggressive, 3-hour sepsis bundle versus noncompliance with greater than or equal to one bundle element for severe sepsis and septic shock patients. DESIGN: Prospective, multisite, observational study following three sequential, independent cohorts, from a single U.S. health system, through their hospitalization. SETTING: Cohort 1: five tertiary and six community hospitals. Cohort 2: single tertiary, academic medical center. Cohort 3: five tertiary and four community hospitals. PATIENTS: Consecutive sample of all severe sepsis and septic shock patients (defined: infection, >= 2 systemic inflammatory response syndrome, and hypoperfusive organ dysfunction) identified by a quality initiative. The exposure was full 3-hour bundle compliance. Bundle elements are as follows: 1) blood cultures before antibiotics; 2) parenteral antibiotics administered less than or equal to 180 minutes from greater than or equal to two systemic inflammatory response syndrome "and" lactate ordered, or less than or equal to 60 minutes from "time-zero," whichever occurs earlier; 3) lactate result available less than or equal to 90 minutes postorder; and 4) 30 mL/kg IV crystalloid bolus initiated less than or equal to 30 minutes from "time-zero." Main outcomes were in-hospital mortality (all cohorts) and total direct costs (cohorts 2 and 3). MEASUREMENTS AND MAIN RESULTS: Cohort 1: 5,819 total patients; 1,050 (18.0%) bundle compliant. Mortality: 604 (22.6%) versus 834 (26.5%); CI, 0.9-7.1%; adjusted odds ratio, 0.72; CI, 0.61-0.86; p value is less than 0.001. Cohort 2: 1,697 total patients; 739 (43.5%) bundle compliant. Mortality: 99 (13.4%) versus 171 (17.8%), CI, 1.0-7.9%; adjusted odds ratio, 0.60; CI, 0.44 0.80; p value is equal to 0.001. Mean costs: $14,845 versus $20,056; CI, -$4,798 to -5,624; adjusted beta, -$2,851; CI, -$4,880 to -822; p value is equal to 0.006. Cohort 3: 7,239 total patients; 2,115 (29.2%) bundle compliant. Mortality: 383 (18.1%) versus 1,078 (21.0%); CI, 0.9-4.9%; adjusted odds ratio, 0.84; CI, 0.73-0.96; p value is equal to 0.013. Mean costs: $17,885 versus $22,108; CI, $2,783 to -5,663; adjusted beta, -$1,423; CI, -$2,574 to -272; p value is equal to 0.015. CONCLUSIONS: In three independent cohorts, 3-hour bundle compliance was associated with improved survival and cost savings. PMID- 27941372 TI - Early and Delayed 18F-FCH PET/CT Imaging in Parathyroid Adenomas. AB - Preoperative localization with Tc-sestaMIBI or ultrasound is a common prerequisite for successful minimally invasive parathyroid adenoma (PA) surgery. SPECT/CT with Tc-sestaMIBI and PET/CT with F-FCH offer the possibility of attenuation correction and coregistration of functional and anatomical images providing more accurate PA localization. F-FCH PET/CT is used predominantly in patients with prostate cancer and is under investigation in PA. We report the case of a 43-year-old man with early FCH uptake in a cystic PA with delayed washout at 60 minutes. PMID- 27941373 TI - Added Value of Combined Semi-Quantitative and Visual [123I]FP-CIT SPECT Analyses for the Diagnosis of Dementia With Lewy Bodies. AB - PURPOSE OF THE REPORT: To assess the validity of a semi-quantitative I-FP-CIT SPECT method, compared to the commonly used visual analysis, in patients with probable dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We also studied DLB specific uptake impairment pattern and correlation of uptake in the presence or absence of parkinsonism. MATERIALS AND METHODS: Among 1202 scans performed at our center from 2003 to 2015, we identified 93 subjects with probable DLB (mean age 76.9 +/- 6.8 years, 37% women) and 18 with AD (mean age 76.9 +/- 8.1 years, 50% women). Independent visual and semi-quantitative assessments based on previously established on-site reference values (including volumes-of-interest uptake, caudate-to-putamen ratio and striatal asymmetry index) were performed and compared between both groups. RESULTS: Visual staging was considered abnormal in 96.8% of DLB patients, whereas 97.8% of subjects had an abnormal semi-quantitative assessment. Combining both methods yielded a 100% sensitivity. Patients with DLB exhibited a more pronounced impairment of putaminal uptake when associated with parkinsonism, whereas a more diffuse pattern and significantly higher uptake values were observed in the subgroup of DLB patients without parkinsonism (resp. striatal uptake 1.61 +/- 0.66 vs. 2.28 +/- 0.52, P = 0.01). A minority of AD subjects show minimal alterations of presynaptic dopaminergic transport (striatal uptake 3.07 +/- 0.41), values being always significantly higher than those from DLB patients, irrespective of the presence of parkinsonism (P < 0.0001) or not (P = 0.002). CONCLUSIONS: Additional use of semi-quantitative analysis allows a higher discrimination of DLB from AD and demonstrates a specific pattern of degeneration in DLB patients according to their motor phenotype. PMID- 27941375 TI - Diffuse Subcutaneous Fat Involvement in a Marginal Zone Lymphoma. AB - Marginal zone lymphoma (MZL) is usually considered not avid for FDG. We report a case of a 57-year-old man with an MZL suspected for transformation. FDG-PET/CT showed a diffuse atypical involvement of subcutaneous fat, without sign suggestive for a transformation. No cutaneous involvement was clinically evident. A random subcutaneous biopsy was performed and showed the presence of MZL. PMID- 27941374 TI - Delayed Gastric Emptying in Advanced Parkinson Disease: Correlation With Therapeutic Doses. AB - INTRODUCTION: Gastrointestinal dysfunction is often described in patients with Parkinson disease (PD), and gastrointestinal symptoms are usually attributed to gastroparesis. The consequent delayed gastric emptying (GE) may be an important pharmacokinetic mechanism underlying some of the response fluctuations that develop after long-term levodopa (L-dopa) therapy.The aim of this prospective study was to assess GE time by a liquid meal scintigraphy, in PD patients, and to correlate them with demographic, clinical, and therapeutic data. METHODS: Scintigraphy with radiolabeled albumin nanocolloids added to acidified orange juice was performed in 51 consecutive PD patients 1 hour after their usual dopaminergic therapy first dose and after a 12-hour fast. Demographic, neurologic, gastrointestinal, and pharmacologic data were collected. RESULTS: Fifty-one patients were divided into 2 groups using the cutoff point obtained in normal subjects (40 minutes): group 1 included 29 patients with GE T1/2 of 27.60 +/- 7.30 minutes (normal), group 2 showed a GE T1/2 of 84.90 +/- 53.80 minutes (delayed). The most striking significant difference between the 2 groups was the dopa-decarboxylase inhibitor mean dose that was significantly higher in the group of patients with delayed GE (201.32 +/- 97.26 vs 127.65 +/- 79.74; P = 0.005). CONCLUSIONS: The impairment of gastric motility, frequently represented in PD patients, occurs in approximately 42% of patients with motor complications. A mechanism that may explain the GE delay is the effect of L-dopa on dopaminergic receptors in the stomach. Therefore, the dosage of dopa-decarboxylase inhibitor, increasing the L-dopa concentration, may contribute to GE delay and its consequent effect on drug delivery and efficacy. PMID- 27941376 TI - Paraneoplastic Syndrome With Anti-NMDAR Encephalitis Associated With Ovarian Teratomas. AB - We report on a 33-year-old woman who had a paraneoplastic syndrome with anti-N methyl-d-aspartate receptor encephalitis, associated with ovarian teratomas. She presented with acute onset seizures, grandiosity, elevated mood, disorganized thoughts, and paranoia. Cerebral spinal fluid analysis revealed anti-N-methyl-d aspartate receptor antibodies. A PET/CT was requested, which identified a possible fat and calcification containing right adnexal lesion on the noncontrast CT portion, which was suspicious for a teratoma. Subsequent ultrasound revealed bilateral masses consistent with teratomas. She underwent laparoscopic removal of these masses, which were both confirmed to be mature cystic teratomas on pathology. After surgery, her symptoms progressively improved. PMID- 27941377 TI - 68Ga-PSMA PET/CT Imaging in Multiple Myeloma. AB - The potential applications of Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT in the imaging of prostate cancer are now well established. A few case reports regarding the potential use of Ga-PSMA PET/CT in nonprostate cancer malignancies are also published. Apparently, the tumor neoangiogenesis is the mechanism attributed to increased Ga-PSMA uptake in the tumor sites in nonprostatic malignancies. We describe the use of Ga-PSMA PET/CT in imaging multiple myeloma. The intense Ga-PSMA avidity of the lesions also opens up the possibility of theranostics with Lu-PSMA. PMID- 27941379 TI - Can we improve transurethral resection of the bladder tumour for nonmuscle invasive bladder cancer? AB - PURPOSE OF REVIEW: The recurrence rate in patients with nonmuscle invasive bladder cancer is high, and the quality of transurethral resection of the bladder (TURB) tumour influences recurrence risk. We review new methods that aim to improve the effectiveness of TURB, and highlight studies of the past year. RECENT FINDINGS: Several approaches have been explored: bipolar resection is well tolerated and efficient; however, surgical outcomes are not clearly superior to monopolar resection; en-bloc resection seems feasible and well tolerated, and has the potential to improve the quality of tissue for histopathology; enhancement techniques such as photodynamic diagnosis, narrow band imaging, and Image1 S improve tumour detection, whereas photodynamic diagnosis reduces recurrence rates; high-resolution imaging modality such as confocal laser endomicroscopy may provide histopathologic information. Additionally, optical coherence tomography, Raman spectroscopy, multiphoton microscopy and ultraviolet autofluorescence microscopy, molecular imaging, and photoacoustic imaging are techniques that are in development. SUMMARY: Recent advances in resection methods and image enhancement techniques have been studied to improve the quality of TURB, but more evidence is still needed before these techniques can be implemented in daily practice. PMID- 27941378 TI - Prognostic Value of Metabolic Parameters of 18F-FDG PET/CT and Apparent Diffusion Coefficient of MRI in Hepatocellular Carcinoma. AB - BACKGROUND: The aim of this study was to predict the survival of patients with hepatocellular carcinoma (HCC) by examining metabolic PET parameters, apparent diffusion coefficients (ADCs), and clinical parameters. METHODS: We retrospectively reviewed 52 patients with pathologically confirmed HCC (age, 57.9 +/- 10.7 years; 43 men) who underwent MRI and F-FDG PET/CT. The tumor-to-normal liver SUV ratio (TLR), the mean ADC of each tumor, and other clinical data were obtained. Survival analysis was performed. RESULTS: Thirty-two patients died during the follow-up period. There was an inverse correlation between the mean SUV and the mean ADC of a tumor (r = -0.402, P = 0.020). Among HCC patients, disease-specific survival was significantly associated with each of the following factors: high TLR (TLR >= 2; hazard ratio [HR], 3.78; P = 0.001), high mean ADC (mean ADC >= 1.250 * 10 mm/s; HR, 0.45; P = 0.028), AFP >= 400 ng/mL (HR, 3.48; P = 0.001), PIVKA-II >= 100mAU/mL (HR, 6.39; P = 0.011), tumor size (HR, 1.13; P < 0.001), number of tumors (HR, 2.16; P = 0.031), tumor stage (HR, 3.08; P < 0.001), and surgery for initial treatment (HR, 0.06; P < 0.001). The results of multivariate analysis show that DSS was significantly associated with each of the following factors: TLR >= 2 (HR, 2.46; P = 0.044), PIVKA-II >= 100mAU/mL (HR, 5.11; P = 0.037), tumor stage (HR, 3.01; P < 0.001), and surgery for initial treatment (HR, 0.04; P < 0.001). CONCLUSIONS: High TLRs and low mean ADCs were associated with poor outcomes. The TLR was an independent prognostic factor in patients with HCC, but the mean ADC was not. A negative correlation was found between the mean ADC and the mean SUV of a tumor. PMID- 27941382 TI - Russian Keratoprosthesis in Stevens-Johnson Syndrome. AB - PURPOSE: To evaluate the efficacy and safety of Moscow Eye Microsurgery Complex in Russia (MICOF) keratoprosthesis (KPro) implantation in patients with Stevens Johnson syndrome (SJS). METHODS: This was a retrospective case series. Fourteen eyes of 13 patients with SJS underwent KPro implantation at the Chinese People's Liberation Army General Hospital between April 1, 2000, and December 24, 2014. The visual outcome, KPro retention rate, and incidence of postoperative complications and their management were recorded and investigated. RESULTS: The mean age and follow-up duration were 61.5 +/- 17.3 years (range: 27-87 yrs) and 62 +/- 39.1 months (range: 13-144 mo). Thirteen eyes (92.9%) achieved a best corrected visual acuity of 20/200 or better, and 8 eyes (57.1%) achieved a best corrected visual acuity of 20/40 or better after surgery. However, 71.4% (10/14) experienced visual decline because of different postoperative complications. Common complications included corneal melting, glaucoma, vitritis, superficial tissue overgrowth, and retroprosthetic membrane, and the incidence of these complications was 71.4%, 28.6%, 35.7%, 14.3%, and 28.6%, respectively. After repair and autoauricular cartilage reinforcement, all cases had stable anatomical retention at the last visit. CONCLUSIONS: The MICOF KPro improved vision of patients with SJS, but lifelong surveillance is necessitated because of a high rate of postoperative complications. Corneal melting was the main reason for KPro failure. Infectious endophthalmitis and glaucoma were the main risk factors for visual loss. PMID- 27941383 TI - Autologous Blood Versus Fibrin Glue in Pterygium Excision With Conjunctival Autograft Surgery. AB - PURPOSE: To evaluate graft stability and recurrence rate between fibrin glue and autologous blood in pterygium conjunctival autograft surgery. METHODS: A prospective, randomized, single-blinded clinical trial to assess the efficacy of autologous blood in place of fibrin glue in pterygium surgery. A total of 120 eyes of 111 patients were randomized according to pterygium morphology, to undergo pterygium surgery with autografting using either autologous blood or fibrin glue. All patients were operated by a single surgeon; 58 eyes were operated using fibrin glue and 62 eyes had a conjunctival autograft with autologous blood. Patients were seen on postoperative day 1, 1 week, 1 month, 6 months, and 1 year after surgery. Graft stability and pterygium recurrence were graded by an independent observer who was masked to the method of treatment. RESULTS: All 120 eyes completed the 1-year follow-up. Graft loss was seen only in the autologous blood group. Of the 62 eyes in this group, a total of 15 (24.2%) grafts dislodged. Recurrence was calculated after excluding grafts that were dislodged. Of the 105 patients, there were a total of 7 recurrences, 2 (3.4%) from the fibrin adhesive method and 5 (10.6%) from the autologous blood method. This was not statistically significant (P = 0.238). CONCLUSIONS: Autologous blood does not exhibit similar graft stability seen with fibrin glue. Although the recurrence rate may not be significant, careful patient selection and a standard method needs to be laid out before the use of this method is widely accepted. PMID- 27941385 TI - Comparison of Topical Low-Molecular-Weight Heparin-Taurocholate and Bevacizumab for Treatment and Prevention of Corneal Neovascularization. AB - PURPOSE: To compare the therapeutic and preventive effects of topically administered 7-taurocholic acid-conjugated low-molecular-weight heparin (LHT7) and bevacizumab in experimentally induced corneal neovascularization (CoNV). METHODS: CoNV was induced using sutures in the right eyes of 24 mice. To investigate the therapeutic effects, CoNV was allowed to develop for 1 week before treatment. To ascertain the preventive effects, the treatments were applied immediately after the suture. In each experiment, 12 eyes were divided into 3 groups and treated topically using bevacizumab (bevacizumab group), LHT7 (LHT7 group), and normal saline (control group). The treatments were instilled 3 times daily for 2 weeks. The CoNV area was measured before instillation and after 1 and 2 weeks after instillation. RESULTS: In the investigation of therapeutic effects, the CoNV area had decreased significantly 1 week after treatment in the bevacizumab group (1.58-0.75 mm; P = 0.036) and LHT7 group (1.38-0.74 mm; P = 0.018). Two weeks after treatment, the CoNV area was significantly smaller in the bevacizumab groups (0.60 mm; P = 0.005) and LHT7 group (0.64 mm; P = 0.015) than in the control group (1.68 mm), but the bevacizumab group did not differ significantly from the LHT7 group. In the experiment addressing the preventive effects, CoNV was less developed in the bevacizumab group (0.70 mm; P = 0.003) and LHT7 group (0.54 mm; P = 0.003) than in the control group (1.75 mm), and the CoNV area was smaller in the LHT7 group than in the bevacizumab group (P = 0.021). CONCLUSIONS: The effects of LHT7 on CoNV regression are comparable to those of bevacizumab. Topical administration of LHT7 prevents CoNV more effectively than bevacizumab. PMID- 27941384 TI - Characterization of the Corneal Subbasal Nerve Plexus in Limbal Stem Cell Deficiency. AB - PURPOSE: To quantify the changes in the subbasal nerve plexus in patients with limbal stem cell deficiency (LSCD) using in vivo laser scanning confocal microscopy. METHODS: In this retrospective cross-sectional comparative study, confocal images of 51 eyes of 37 patients with LSCD collected between 2010 and 2015 by the Heidelberg Retina Tomograph III Rostock Corneal Module Confocal Microscope were analyzed. Two independent observers evaluated the scans of the central cornea. Seventeen normal eyes of 13 subjects served as controls. Total subbasal nerve density (SND), density of long nerves (ie, nerves 200 MUm or longer), and the degree of tortuosity were quantified. RESULTS: The mean (+/-SD) total SND and long nerve density were 48.0 +/- 34.2 and 9.7 +/- 10.9 nerves/mm, respectively, in all eyes with LSCD and 97.3 +/- 29.9 and 35.3 +/- 25.3 nerves/mm, respectively, in eyes of the control group (P < 0.001 for both comparisons). Compared with SND in control subjects, SND was reduced by 34.9% in the early stage, 54.0% in the intermediate stage, and 73.5% in the late stage of LSCD. The degrees of nerve tortuosity were significantly greater in patients with LSCD than in control subjects and differed among the early, intermediate, and late stages of LSCD. Reductions in total SND and long nerve density were positively correlated with the severity of LSCD. CONCLUSIONS: Reductions in total SND and long nerve density were accompanied by increases in nerve tortuosity in eyes with LSCD. These parameters could be used as quantifiable measures of LSCD severity. PMID- 27941386 TI - Ten-Year Clinical Outcome of the First Patient Undergoing Descemet Membrane Endothelial Keratoplasty. AB - PURPOSE: To describe the 10-year clinical outcome of the first patient worldwide who underwent Descemet membrane endothelial keratoplasty (DMEK). METHODS: In 2006, a 63-year-old man presented at the Melles Cornea Clinic, Rotterdam, with bilateral Fuchs endothelial dystrophy and cataract. After phacoemulsification, in vivo DMEK was performed in the left eye and 10 months later in the right eye. Best spectacle-corrected visual acuity (BSCVA), endothelial cell density, pachymetry, and complications were recorded every 6 months over a 10-year period. RESULTS: BSCVA in the left eye improved from 20/60 (0.3) before surgery to 20/17 (1.2) at 1 month, and remained stable over 10 years, ranging from 20/20 (1.0) to 20/13 (1.5). BSCVA in the right eye improved from 20/50 (0.4) preoperative and 20/60 (0.3) at 1 month to 20/25 (0.8) at 3 months and 20/17 (1.2) at 6 months, ranging from 20/25 (0.8) to 20/17 (1.2) over 9 years. Both eyes underwent YAG laser-capsulotomy to manage posterior capsule opacification at 5 and 4 years after DMEK, respectively. Endothelial cell density in the right and left eyes, respectively, decreased by 43% and 45% at 1 year, 52% and 59% at 5 years, and 72% and 68% at 10/9 years, respectively. No intraoperative or postoperative complications occurred; at the last follow-up, both corneas were clear. CONCLUSIONS: The first DMEK patient worldwide may show all short and long-term characteristics of this endothelial keratoplasty technique: outstanding patient satisfaction, quick visual recovery, low incidence of complications, and graft longevity. Published studies in the past decade would suggest that this case was the start of a new era in corneal transplantation. PMID- 27941387 TI - Clinical Findings of Anterior Segment Spectral Domain Optical Coherence Tomography Images in Cytomegalovirus Corneal Endotheliitis. AB - PURPOSE: To evaluate the morphological characteristics of posterior corneal regions including keratic precipitates in eyes with cytomegalovirus (CMV) corneal endotheliitis using anterior segment spectral domain optical coherence tomography (SD-OCT). METHODS: Thirteen eyes of 13 patients with polymerase chain reaction proven CMV corneal endotheliitis were included in this study. Slit-lamp images and anterior segment SD-OCT images of the posterior cornea were obtained to analyze the clinical characteristics of corneal structures and keratic precipitates. Morphological changes in the posterior cornea throughout the course of an antiviral treatment were also investigated. RESULTS: Anterior SD-OCT images showed protruding structures at the posterior cornea. These protruding structures exhibited dendritic, dome-shaped, quadrangular, or saw-tooth appearance, and reflectivity of these structures was high. Reflectivity of posterior corneal images including the endothelium and deep stromal corneal regions were also high (76.9%). Because corneal inflammation and corneal edema improved, the protruding structures and high-intensity regions of posterior corneal images were resolved after a course of antiviral treatment. CONCLUSIONS: The anterior segment SD-OCT examination represents a useful noninvasive alternative to diagnose and monitor CMV corneal endotheliitis. PMID- 27941389 TI - Factors modulating the inflammatory response in acute gouty arthritis. AB - PURPOSE OF REVIEW: Gout is a common debilitating form of arthritis and despite our extensive knowledge on the pathogenesis its prevalence is still rising quickly. In the current review, we provide a concise overview of recent discoveries in factors tuning the inflammatory response to soluble uric acid and monosodium urate crystals. RECENT FINDINGS: It appears that soluble uric acid has a much larger role to play than just being a risk factor for gout. It may have widespread consequences for systemic inflammation and the development of metabolic syndrome. Additionally, a specific gout-related gut microbiome might not only provide us with a new diagnostic tool, but also highlights possible new therapeutic targets. Furthermore, several recent publications further elucidated the roles of mitochondrial dysfunction, production of reactive oxygen species, autophagy, and AMP-dependent protein kinase in monosodium urate-induced NLRP3 inflammasome activation. Finally, neutrophils have been shown to be involved in both the promotion and resolution of gouty inflammation. A new alpha-1 antitrypsin fusion protein may limit the proinflammatory effects of neutrophil derived serine proteases. SUMMARY: Together, these studies provide us with many new insights in the pathogenesis of gout, important new treatment targets, and a rationale to further study the role of soluble uric acid in inflammatory diseases. PMID- 27941390 TI - Mesenchymal stem cells for the management of rheumatoid arthritis: immune modulation, repair or both? AB - PURPOSE OF REVIEW: Mesenchymal stromal/stem cells (MSCs) have potent anti inflammatory and immunomodulatory properties, in addition to their ability to form cartilage and bone. The purpose of this review is to highlight recent developments and current knowledge gaps in our understanding of the protective effects of MSCs against inflammatory arthritis, and to discuss their clinical exploitation for the treatment of rheumatoid arthritis (RA). RECENT FINDINGS: The weight of evidence for protective mechanisms of exogenously administered MSCs is on immunomodulatory effects, including inhibition of dendritic cell maturation, polarization of macrophages to an anti-inflammatory phenotype, and activation of regulatory T cells, thereby dampening inflammation and preventing joint damage. Evidence for direct effects on tissue repair is scant. Recent studies have identified MSC subsets in vivo and an important question is whether MSCs in their native tissues have similar immunoregulatory functions. Recent proof-of-concept clinical studies have shown a satisfactory safety profile of allogeneic MSC therapy in RA patients with promising trends for clinical efficacy. SUMMARY: Allogeneic MSCs could be effective in RA. Larger, multicentre clinical studies are needed to provide robust evidence, and MSC treatment at early stages of RA should be explored to 'reset' the immune system. PMID- 27941391 TI - Mechanobiological implications of articular cartilage crystals. AB - PURPOSE OF REVIEW: Calcium crystals exist in both pathological and normal articular cartilage. The prevalence of these crystals dramatically increases with age, and crystals are typically found in osteoarthritic cartilage and synovial fluid. Relatively few studies have examined the effects of crystals on cartilage biomechanics or chondrocyte mechanotransduction. The purpose of this review is to describe how crystals could influence cartilage biomechanics and mechanotransduction in osteoarthritis. RECENT FINDINGS: Crystals are found in both loaded and unloaded regions of articular cartilage. Exogenous crystals, in combination with joint motion, result in substantial joint inflammation. Articular cartilage vesicles promote crystal formation, and these vesicles are found near the periphery of chondrocytes. Crystallographic studies report monoclinic symmetry for synthetic crystals, suggesting that crystals will have a large stiffness compared with the cartilage extracellular matrix, the pericellular matrix, or the chondrocyte. This stiffness imbalance may cause crystal-induced dysregulation of chondrocyte mechanotransduction promoting both aging and osteoarthritis chondrocyte phenotypes. SUMMARY: Because of their high stiffness compared with cartilage matrix, crystals likely alter chondrocyte mechanotransduction, and high concentrations of crystals within cartilage may alter macroscale biomechanics. Future studies should focus on understanding the mechanical properties of joint crystals and developing methods to understand how crystals affect chondrocyte mechanotransduction. PMID- 27941392 TI - A new era of quality measurement in rheumatology: electronic clinical quality measures and national registries. AB - PURPOSE OF REVIEW: This article reviews the evolution of quality measurement in rheumatology, highlighting new health-information technology infrastructure and standards that are enabling unprecedented innovation in this field. RECENT FINDINGS: Spurred by landmark legislation that ties physician payment to value, the widespread use of electronic health records, and standards such as the Quality Data Model, quality measurement in rheumatology is rapidly evolving. Rather than relying on retrospective assessments of care gathered through administrative claims or manual chart abstraction, new electronic clinical quality measures (eCQMs) allow automated data capture from electronic health records. At the same time, qualified clinical data registries, like the American College of Rheumatology's Rheumatology Informatics System for Effectiveness registry, are enabling large-scale implementation of eCQMs across national electronic health record networks with real-time performance feedback to clinicians. Although successful examples of eCQM development and implementation in rheumatology and other fields exist, there also remain challenges, such as lack of health system data interoperability and problems with measure accuracy. SUMMARY: Quality measurement and improvement is increasingly an essential component of rheumatology practice. Advances in health information technology are likely to continue to make implementation of eCQMs easier and measurement more clinically meaningful and accurate in coming years. PMID- 27941401 TI - New Standards of Care in Ischemic Stroke. AB - BACKGROUND: Ischemic arterial strokes of the ophthalmic artery and its branches and posterior cerebral artery are common causes of visual disability. Etiologies of stroke affecting the retina, optic nerve, optic radiation, and visual cortex overlap with other types of ischemic strokes. Stenosis of the internal carotid is the most common cause of central retinal artery occlusion (CRAO). One-fourth of patients with CRAO have cerebral strokes. We report recent developments in the acute treatment and secondary prevention of ischemic stroke of relevance to clinicians who encounter patients with acute vision loss. EVIDENCE ACQUISITION: A search of Pubmed and practice guidelines over the past 5 years was performed, with a focus on significant changes in treatment and prevention of ischemic stroke. RESULTS: Recent randomized controlled trials provide Level I evidence for the use of endovascular therapy with current stent retriever devices for patients with large vessel anterior circulation occlusions within 6 hours of presentation. Number needed to treat to achieve one additional patient with an independent functional outcome was in the range of 3-7, and benefit was additive to that of intravenous tissue plasminogen activator alone. Paroxysmal atrial fibrillation (AF) is a major cause of cryptogenic stroke with incidence expected to rise with the aging population. Since 2014, prolonged 30-day cardiac monitoring has been recommended as a part of transient ischemic attack and stroke workup in patients with cryptogenic stroke. Even longer term monitoring of 6 months to 1 year with external and implantable loop recorders improves rates of diagnosing AF. First available in 2010, the novel anticoagulants-dabigatran, apixaban, rivaroxaban, and edoxaban-have been compared with warfarin in the prevention of stroke in patients with nonvalvular AF. Apixaban demonstrated superiority in safety and efficacy, with the novel anticoagulants as a group having favorable risk-benefit profile at higher dosages compared with standard warfarin therapy. CONCLUSIONS: Endovascular therapy is now standard of care for eligible patients with anterior large vessel occlusions. Prolonged cardiac monitoring is recommended for patients with cryptogenic stroke. The novel anticoagulants are an alternative to warfarin in patients with AF. PMID- 27941393 TI - Use of rosuvastatin in HIV-associated chronic obstructive pulmonary disease. AB - OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is more prevalent in HIV infected individuals and is associated with persistent inflammation. Therapies unique to HIV are lacking. We performed a pilot study of the 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitor rosuvastatin to determine effects on lung function. DESIGN: Randomized, placebo-controlled, triple-blinded trial. METHODS: HIV-infected individuals with abnormal lung function were recruited from an ongoing lung function study. Participants were randomized to 24 weeks of placebo (n = 11) or rosuvastatin (n = 11) using an adaptive randomization based on change in peripheral C-reactive protein levels at 30 days of treatment. Forced expiratory volume in 1 s (FEV1) and diffusing capacity for carbon monoxide (DLco)%-predicted were compared to baseline at 24 weeks in the two groups using a Wilcoxon rank-sum test. The %-predicted change at 24 weeks in pulmonary function variables was compared between groups using simulated randomization tests. RESULTS: The placebo group experienced a significant decline in FEV1%-predicted (P = 0.027), and no change in DLco%-predicted over 24 weeks. In contrast, FEV1% predicted remained stable in the rosuvastatin group, and DLco%-predicted increased significantly (P = 0.027). There was no significant difference in absolute change in either measure between placebo and rosuvastatin groups. CONCLUSION: In a pilot study, the use of rosuvastatin for 24 weeks appeared to slow worsening of airflow obstruction and to improve DLco in HIV-infected individuals with abnormal lung function, although comparison of absolute changes between the groups did not reach significance. This study is the first to test a therapy for COPD in an HIV-infected population, and large-scale clinical trials are needed. PMID- 27941394 TI - Virological efficacy of 24-week fozivudine-based regimen in ART-naive patients from Tanzania and Cote d'Ivoire. AB - OBJECTIVE: Use of zidovudine (ZDV) in antiretroviral therapy is limited by toxicity and twice daily (b.i.d.) dosing. Fozivudine (FZD) is a ZDV prodrug, which is activated intracellularly to ZDV-monophosphate especially in mononuclear cells but not in bone marrow cells. FZD promises improved myelotoxicity and once daily (o.d.) dosing. DESIGN: Randomized clinical trial. METHODS: We conducted an open-label, phase II, proof-of-concept trial investigating three different FZD doses (800 mg o.d., 600 mg b.i.d., 1200 mg o.d.) versus ZDV (300 mg b.i.d.) in combination with lamivudine and efavirenz in HIV-infected, ART-naive patients from Tanzania and Cote d'Ivoire. The primary objective was to demonstrate virological efficacy after 24 weeks in intent-to treat and per-protocol analysis. Secondary endpoints included safety and pharmacokinetic outcomes. RESULTS: Of 119 participants included in the intent-to treat analysis, HIV RNA less than 50 copies/ml at 24 weeks was observed in 64 of 88 (73%) patients in the combined FZD arms versus 24 of 31 (77%) in the ZDV arm (RR 0.94, 95% confidence interval 0.75 1.18). In the per-protocol analysis, responses were 64 of 77 (87%) versus 23 of 29 (79%), respectively (RR 1.09, 95% confidence interval 0.89-1.34). Outcomes were similar between FZD arms. Overall, treatments were well tolerated. Severe or worse anaemia occurred in two cases (one related to FZD, one to ZDV), grade III/IV neutropenia was less frequent in FZD compared with ZDV arms (22 versus 42%, P = 0.035). Pharmacokinetic analysis supported o.d. administration of FZD. CONCLUSION: Virological 24-week efficacy was demonstrated in b.i.d. and o.d. administered FZD-based regimens. Reduced myelotoxicity of FZD needs to be confirmed in a larger trial. PMID- 27941402 TI - Nonarteritic Ischemic Optic Neuropathy Associated With Clomiphene Citrate Use. PMID- 27941403 TI - Central Retinal Artery Occlusion and Cerebral Infarction Following Stem Cell Injection for Baldness. PMID- 27941406 TI - Do Maintenance of Certification Activities Promote Positive Changes in Clinical Practice? PMID- 27941405 TI - Optimizations for the Electrically-Evoked Stapedial Reflex Threshold Measurement in Cochlear Implant Recipients. AB - OBJECTIVE: The electrically-evoked stapedial reflex threshold (eSRT) has proven to be useful in setting upper stimulation levels of cochlear implant recipients. However, the literature suggests that the reflex can be difficult to observe in a significant percentage of the population. The primary goal of this investigation was to assess the difference in eSRT levels obtained with alternative acoustic admittance probe tone frequencies. DESIGN: A repeated-measures design was used to examine the effect of 3 probe tone frequencies (226, 678, and 1000 Hz) on eSRT in 23 adults with cochlear implants. RESULTS: The mean eSRT measured using the conventional probe tone of 226 Hz was significantly higher than the mean eSRT measured with use of 678 and 1000 Hz probe tones. The mean eSRT were 174, 167, and 165 charge units with use of 226, 678, and 1000 Hz probe tones, respectively. There was not a statistically significant difference between the average eSRTs for probe tones 678 and 1000 Hz. Twenty of 23 participants had eSRT at lower charge unit levels with use of either a 678 or 1000 Hz probe tone when compared with the 226 Hz probe tone. Two participants had eSRT measured with 678 or 1000 Hz probe tones that were equal in level to the eSRT measured with a 226 Hz probe tone. Only 1 participant had an eSRT that was obtained at a lower charge unit level with a 226 Hz probe tone relative to the eSRT obtained with a 678 and 1000 Hz probe tone. CONCLUSIONS: The results of this investigation demonstrate that the use of a standard 226 Hz probe tone is not ideal for measurement of the eSRT. The use of higher probe tone frequencies (i.e., 678 or 1000 Hz) resulted in lower eSRT levels when compared with the eSRT levels obtained with use of a 226 probe tone. In addition, 4 of the 23 participants included in this study did not have a measureable eSRT with use of a 226 Hz probe tone, but all of the participants had measureable eSRT with use of both the 678 and 1000 Hz probe tones. Additional work is required to understand the clinical implication of these changes in the context of cochlear implant programming. PMID- 27941404 TI - Dichotic Digits Test Performance Across the Ages: Results From Two Large Epidemiologic Cohort Studies. AB - OBJECTIVES: The Dichotic Digits test (DDT) has been widely used to assess central auditory processing but there is limited information on observed DDT performance in a general population. The purpose of the study was to determine factors related to DDT performance in a large cohort spanning the adult age range. DESIGN: The study was cross-sectional and subjects were participants in the Epidemiology of Hearing Loss Study (EHLS), a population-based investigation of age-related hearing loss, or the Beaver Dam Offspring Study (BOSS), a study of aging in the adult offspring of the EHLS members. Subjects seen during the 4th EHLS (2008 to 2010) or the 2nd BOSS (2010 to 2013) examination were included (N = 3655 participants [1391 EHLS, 2264 BOSS]; mean age = 61.1 years, range = 21 to 100 years). The free and right ear-directed recall DDTs were administered using 25 sets of triple-digit pairs with a 70 dB HL presentation level. Pure-tone audiometric testing was conducted and the pure-tone threshold average (PTA) at 0.5, 1, 2, and 4 kHz was categorized using the worse ear: no loss = PTA <= 25 dB HL; mild loss = 25 < PTA <= 40 dB HL; moderate or marked loss = PTA > 40 dB HL. Cognitive impairment was defined as a Mini-Mental State Examination score < 24 (maximum = 30) or a self- or proxy-reported history of dementia or Alzheimer's disease. Demographic information was self-reported. General linear models were fit and multiple linear regression was performed. RESULTS: The mean total free recall DDT score was 76.7% (range = 21.3 to 100%). Less than 10% of the participants had a total free recall score below 60% correct. The mean right ear directed recall score was 98.4% with 69% of the participants scoring 100% and another 15.5% scoring 98.7% (1 incorrect digit). In multivariable modeling of the total free recall scores, the predicted mean free recall score was 1 percentage point lower for every 5-year increase in age, 2.3 percentage points lower in males than females, 8.7 percentage points lower in participants with less than a high school degree than in those with college degrees, 6.8 percentage points lower in participants with a moderate or marked hearing loss compared with no hearing loss, and 8.3 percentage points lower in participants with cognitive impairment compared with those without cognitive impairment. These 5 factors were independently and significantly related to performance and accounted for 22.7% of the total variability in free recall scores. CONCLUSIONS: Substantial variation in the total free recall DDT scores but very little variation in the right ear directed recall DDT scores was observed. Age, sex, education, hearing loss severity, and cognitive impairment were found to be significantly related to DDT scores but explained less than 25% of the total variability in total free recall scores. The right ear-directed recall DDT by itself may not be of benefit in assessing central auditory processing in a general population because of its limited variability but further evaluation of factors potentially related to free recall DDT variability may prove useful. PMID- 27941407 TI - Invited Commentary Related to: "Does a Staged Posterior Approach Have a Negative Effect on OTA 43C Fracture Outcomes?" PMID- 27941410 TI - Response to Comment on "Neutrophil to Lymphocyte Ratio as a Predictive Marker of Vestibular Schwannoma Growth". PMID- 27941411 TI - Developmental Trajectories of Bottle-Feeding During Infancy and Their Association with Weight Gain. AB - OBJECTIVE: To describe patterns of bottle-feeding across the first year postpartum and explore whether bottle-feeding trajectories are differentially associated with infant weight gain. METHOD: Data came from 1291 mothers who participated in the Infant Feeding Practices Study 2. Mothers completed a prenatal questionnaire and monthly surveys of infant feeding and growth between birth and 12 months. Group-based trajectory mixture modeling was used to describe developmental trajectories of bottle-feeding intensities across the first year. Growth curve modeling was used to explore associations between bottle-feeding intensity trajectory group membership and weight-for-age z-score (WAZ) trajectories from birth to 12 months. RESULTS: Four qualitatively distinct trajectories of bottle-feeding were identified: (1) High-Stable: ~100% of feeds from bottles across infancy; (2) Rapid-Increase: <30% of feeds from bottles during the neonatal assessment, increasing to ~100% by 6 months; (3) Gradual Increase: <10% of feeds from bottles during the neonatal assessment, gradually increasing to ~100% by 12 months; and (4) Low-Stable: <5% of feeds from bottles across the majority of infancy. Bottle-feeding groups had significantly different WAZ trajectories across infancy; by 12 months, the High-Stable and Rapid-Increase groups had significantly higher WAZs compared with the Gradual-Increase and Low Stable groups (p < .001). The association between bottle-feeding group membership and WAZ trajectories was not confounded by sociodemographic characteristics or the extent to which infants received breast milk. CONCLUSION: High-intensity bottle use during early infancy may place infants at higher risk for excess weight gain. Supports and policies that help mothers delay high-intensity bottle use until later infancy are warranted. PMID- 27941412 TI - Examining Associations of Functional Deficits and Mood States With Empathic Responses of Stroke Family Caregivers. AB - BACKGROUND: Stroke is one of the most prevalent chronic illnesses worldwide. Family caregivers can make a significant contribution toward patients' recovery. However, the patient's functional deficits and the caregiver's mood states can impact the caregiver's motivation to engage in empathic responses toward patients. Clinicians need help in recognizing patients at risk for not receiving empathic responses from family caregivers who are pivotal in long-term help and emotional support. OBJECTIVE: The aim of this study was to examine possible associations of family caregiver perceptions of functional deficits of patients who are poststroke and caregiver mood states with their empathic responses toward patients who are poststroke. METHODOLOGY: As guided by Davis' organizational model on empathy, we conducted a correlational descriptive study of associations among patient functional deficits, caregiver mood states, and caregiver empathic responses toward patients who are poststroke. Participants were requested to complete four questionnaires. RESULTS: Caregiver fatigue was the only mood state significantly associated with their empathic responses toward patients who are poststroke. CONCLUSIONS: The results of the current study contribute to the current state of the literature on poststroke care at home by highlighting the impact of caregiver mood states, particularly caregiver fatigue, on their empathic responses toward patients who are poststroke. Recommendations for clinical practice and future studies were made based on this study's results. PMID- 27941413 TI - Agitation in Patients Recovering From Traumatic Brain Injury: Nursing Management. AB - This article reviews clinical and research literature regarding the nursing management of agitation after severe traumatic brain injury. Neuroscience nurses in acute rehabilitation settings use an evidence-based approach to perform multifaceted assessments and implement effective individualized plans of care. These essential efforts minimize the effects of agitation and help patients achieve optimal outcomes. PMID- 27941414 TI - Intraoperative Measurements and Tools to Assess Stability. AB - Knee stability is the ability for the joint to maintain an appropriate functional position throughout its range of motion. Knee instability can be defined as excessive laxity during activities of daily living. Intraoperative knee laxity can be affected by implant design, alignment of components, and soft-tissue balancing. Soft-tissue balance is a major contributor to knee instability. Mechanical balancing instruments can be classified as spacer blocks or joint distraction devices. Conventional wisdom favors rectangular and equal flexion extension gaps. However, knee balance is elusive even with mechanical balancing instruments. First-generation electronic balancing devices are equivalent in concept to spacer blocks instrumented with force sensors. Second-generation electronic balancing devices are equivalent in concept to mechanical distraction devices instrumented with pressure and displacement sensors. Electronic ligament balancers can be useful in documenting intraoperative knee laxity for quantifiable correlation with postoperative outcomes, thus directly relating postoperative stability to surgical balance, and may predict outcomes and knee stability. PMID- 27941415 TI - Implementation of Patient-reported Outcome Measures in Total Knee Arthroplasty. AB - Patient-reported outcome measures (PROMs) has emerged as a strategy to improve the outcome of total knee arthroplasty. The use of PROMs in routine clinical practice has accelerated because health care in the United States is shifting from a volume-based to a value-based reimbursement system in which quality is increasingly being measured using PROMs. Electronic, internet-based platforms, such as Functional and Outcomes Research for Comparative Effectiveness in Total Joint Replacement, currently exist which offer turn-key solutions for PROM collection, trending, analysis, and benchmarking for busy clinicians. Successful systems provide real-time trended PROM scores that inform shared decision making, optimize patient care, and enable comparisons among practices. PMID- 27941416 TI - Strategies to Improve Total Knee Arthroplasty: A Multidisciplinary Research Conference. PMID- 27941417 TI - Is There Any Association Between Use of Antidepressants and Preeclampsia or Gestational Hypertension?: A Systematic Review of Current Studies. AB - OBJECTIVE: Hypertension in pregnant women is an important medical problem, which can cause morbidity and mortality in the fetus. This study reviewed the current literature examining the potential relationship between use of antidepressants during pregnancy and preeclampsia or gestational hypertension. METHODS: PubMed was searched for English-language reports between January 1, 1995, and December 31, 2015, by using combinations of key words pregnancy, pregnancy complications, preeclampsia, gestational hypertension, and antidepressants. Studies that reported the diagnosis of preeclampsia or gestational hypertension and use of antidepressant were included in the review. RESULTS: A total of 7 relevant studies that met the review criteria were examined. The studies reported that compared with nonusers adjusted relative risk of preeclampsia or gestational hypertension in antidepressant users was 1.28 to 1.53 for any antidepressant, 1.05 to 3.16 for selective serotonin reuptake inhibitors, 1.49 to 1.95 for selective serotonin-norepinephrine reuptake inhibitors, and 0.35 to 3.23 for tricyclic antidepressants. Consistently, antidepressant use during the second trimester of pregnancy was associated with increased risk of preeclampsia or gestational hypertension. However, possible contribution of severity, type, and comorbidity of underlying anxiety or depressive disorders is unclear in the current studies. CONCLUSIONS: Although some studies have suggested a moderately increased risk in pregnancy-specific hypertensive disorders with antidepressant treatment, the current data do not allow a definitive conclusion on this topic, because the studies have many methodological limitations. In addition, the effects of untreated depression or anxiety disorders cannot be disentangled from the results. PMID- 27941418 TI - Comparative Risk of Ventricular Arrhythmia and Sudden Cardiac Death Across Antidepressants in Patients With Depressive Disorders. AB - OBJECTIVE: We aimed to evaluate the risk of ventricular arrhythmia (VA) and/or sudden cardiac death (SCD) associated with antidepressant use. METHODS: A cohort study was conducted using data from Taiwan's National Health Insurance Research Database from 2001 to 2012. A total of 793,460 new antidepressant users with depressive disorders were enrolled in the study. Outcomes were defined as the first principal diagnosis of VA or SCD in the emergency department or hospital discharge records. Cox proportional hazards models with stratification of propensity score deciles were used to evaluate the relative risk of VA/SCD for antidepressants compared with selective serotonin reuptake inhibitors (SSRIs). RESULTS: A total of 245 VA/SCD events occurred. The incidence rate of VA/SCD among antidepressant users was 1.5 per 1000 person-years (95% confidence interval [CI], 1.3-1.7). Compared with SSRIs, the risk of VA/SCD was significantly lower for tricyclic or tetracyclic antidepressant (TCAs) (adjusted hazards ratio [aHR], 0.54; 95% CI, 0.36-0.83), but not other antidepressant classes. However, use of moderate- to high-dose TCAs carried a higher risk than low-dose TCAs (aHR, 4.37; 95% CI, 1.23-15.60). Antidepressant polypharmacy was associated with an increased risk of VA/SCD (aHR, 1.63; 95% CI, 1.07-2.49). CONCLUSIONS: There was no difference in VA/SCD risk across antidepressant classes except that TCAs were associated with a lower risk than SSRIs. However, the observed comparative risk of TCAs might be attributable to low-dose TCA use, which is quite common in current clinical practice. It would be of importance to carry out further investigations to scrutinize the influence of antidepressants on VA/SCD. PMID- 27941419 TI - Adjunctive Brexpiprazole as a Novel Effective Strategy for Treating Major Depressive Disorder: A Systematic Review and Meta-Analysis. AB - PURPOSE/BACKGROUND: Brexpiprazole was approved for adjunctive treatment of major depressive disorder (MDD) in 2015. Because only a small number of randomized controlled trials have investigated the use of brexpiprazole in MDD, we performed a meta-analysis. METHODS/PROCEDURES: We systematically searched literatures in PubMed, Cochrane Library database, EMBASE, Google Scholar, and clinicaltrials.gov up to January 2016. The primary efficacy measure was the mean change in total Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline. Secondary efficacy measures were the mean change in total Hamilton Rating Scale for Depression (17 items) score from baseline and the response (>=50% reduction in MADRS total score) and remission (MADRS total score <= 10 with >=50% reduction) rates. FINDINGS/RESULTS: Four studies fulfilled the inclusion criteria and were included in the analysis. Brexpiprazole showed superior efficacy over placebo with effect sizes (mean differences) of -1.76 (95% confidence interval [CI], 2.45 to -1.07) for MADRS and -1.21 (95% CI, -1.71 to -0.72) for the 17-item Hamilton Rating Scale for Depression. The risk ratios for response and remission were 1.57 (95% CI, 1.29-1.91) and 1.55 (95% CI, 1.22-1.96), respectively. The incidences of discontinuation due to adverse events, akathisia, and weight increase were higher in the brexpiprazole group than in the placebo group, with risk ratios of 3.44 (95% CI, 1.52-7.80), 3.39 (95% CI, 2.08-5.51), and 4.36 (95% CI, 2.45-7.77), respectively, and the incidence of akathisia was related to the brexpiprazole dose. IMPLICATIONS/CONCLUSIONS: Although our results suggest that brexpiprazole could be an effective adjunctive agent for MDD, they should be cautiously translated into clinical practice because the meta-analysis was based on only a handful of randomized controlled trials. PMID- 27941420 TI - The Natural History of Petroclival Meningiomas: A Volumetric Study. AB - OBJECTIVES: This study characterizes primary petroclival meningioma growth rates, before intervention, using volumetric analysis. In addition, predictors of growth are analyzed. METHODS: Patients with previously untreated petroclival meningiomas were retrospectively reviewed (1999-2015). Image analysis software was used to perform volumetric analyses of tumor size and growth. Three-dimensional segmentation volumetric analyses were compared with volumes estimated utilizing three orthogonal dimensions. Tumor growth was defined as a 15% increase in volume. RESULTS: Thirty-four patients who underwent at least two magnetic resonance imaging (MRI) studies before intervention were included. The mean age was 55.2 years, and 65.7% were women. The mean tumor volume at presentation was 5.6 cm (range, 0.1-25.8 cm) as determined from segmentation volumetric analysis. At a mean follow-up of 44.5 months (range, 3.7-125.1 mo), 88.2% of tumors grew. The mean annual volumetric growth rate was 2.38 cm/yr (-0.63 to 25.9 cm/yr). Tumor volume, T2 hyperintensity within the tumor, peritumoral edema, and ataxia and/or cerebellar symptoms at presentation were all significantly associated with greater rates of tumor growth. Ultimately, 10 (29.4%) patients underwent treatment during the follow-up period. CONCLUSION: Our experience demonstrates that the vast majority (88%) of untreated petroclival meningiomas grow; the mean volumetric growth rate was noted to be 2.38 cm/yr. We found a significant association between increased growth rate and larger tumor size at diagnosis, T2 hyperintensity within the tumor, peritumoral edema, and the presence of ataxia and/or cerebellar symptoms. PMID- 27941422 TI - Improving breast cancer screening in a federally qualified health center with a team of nursing leaders. AB - To improve breast cancer screening in a federally qualified health center, NPs developed a collaborative team of nurses to implement innovative strategies that improved mammography rates from 23% to 40% over a 12-month period. Through shared expertise, this team led the way in translating mammography guidelines into clinical practice. PMID- 27941424 TI - Characterization of Neurologic and Ophthalmologic Safety of Oral Administration of Tedizolid for Up to 21 Days in Healthy Volunteers. AB - BACKGROUND: Antibacterials that inhibit protein synthesis may be associated with mitochondrial toxicity, manifested as serious optic or peripheral neuropathy or myelosuppression. Tedizolid is a novel oxazolidinone antibacterial that may have reduced the potential for mitochondrial toxicity. STUDY QUESTION: Based on the results of 2 studies (NCT01623401 and NCT00671814) conducted early in the tedizolid development program, what is the potential for drug-induced optic and peripheral neuropathies with tedizolid treatment? METHODS: Two phase-1 studies were conducted in healthy volunteers. The first was an open-label study in which subjects received 200 mg of oral tedizolid phosphate once daily for 10 days. The second was a double-blind, placebo- and active-controlled, dose-escalating (multiple-administration) study in which subjects received 200, 300, or 400 mg of oral tedizolid phosphate once daily or 600 mg of oral linezolid twice daily or oral placebo for 21 days. Overall safety and tolerability were assessed, and extensive ophthalmologic and neurologic assessments were performed in both studies. RESULTS: In these 2 studies in healthy subjects, tedizolid administered for up to 21 days was not associated with drug-related ophthalmologic or neurologic adverse events. Incidences of adverse events involving the eye or the nervous system were generally low, and no clinically meaningful changes in ophthalmologic or neurologic test results were recorded during either study. CONCLUSIONS: Using an extensive battery of ophthalmologic tests and detailed neurologic clinical examination, there was no evidence of clinical or subclinical neurologic or ophthalmologic changes suggestive of peripheral or optic neuropathy in healthy volunteers who received therapeutic and supratherapeutic doses of oral tedizolid for periods of up to 21 days. PMID- 27941425 TI - Treatment of subperiosteal abscesses in children: is drainage of the intramedullary canal required? AB - Acute osteomyelitis can be successfully treated with antibiotics alone. Surgery is utilized after failure of antibiotic treatment or if an abscess is present. Limited evidence exists with regard to whether intramedullary drainage is required in addition to the drainage of the subperiosteal abscess. We reviewed our 9-year experience of treating subperiosteal abscesses identifying 68 patients. Thirty patients underwent both intramedullary and abscess drainage, whereas 38 patients underwent drainage of the abscess alone at the initial procedure. Our analysis demonstrated a statistical significance (P=0.012) and odds ratio of 6.46 in favor of an intramedullary drainage to decrease risk for need for repeat surgical treatment. PMID- 27941423 TI - A Systemic Inflammation Mortality Risk Assessment Contingency Table for Severe Sepsis. AB - OBJECTIVES: We tested the hypothesis that a C-reactive protein and ferritin-based systemic inflammation contingency table can track mortality risk in pediatric severe sepsis. DESIGN: Prospective cohort study. SETTING: Tertiary PICU. PATIENTS: Children with 100 separate admission episodes of severe sepsis were enrolled. INTERVENTIONS: Blood samples were attained on day 2 of sepsis and bi weekly for biomarker batch analysis. A 2 * 2 contingency table using C-reactive protein and ferritin thresholds was developed. MEASUREMENTS AND MAIN RESULTS: A C reactive protein of 4.08 mg/dL and a ferritin of 1,980 ng/mL were found to be optimal cutoffs for outcome prediction at first sampling (n = 100) using the Youden index. PICU mortality was increased in the "high-risk" C-reactive protein greater than or equal to 4.08 mg/dL and ferritin greater than or equal to 1,980 ng/mL category (6/13 [46.15%]) compared with the "intermediate-risk" C-reactive protein greater than or equal to 4.08 mg/dL and ferritin less than 1,980 ng/mL or C-reactive protein less than 4.08 mg/dL and ferritin greater than or equal to 1,980 ng/mL categories (2/43 [4.65%]), and the "low-risk" C-reactive protein less than 4.08 mg/dL and ferritin less than 1,980 ng/mL category (0/44 [0%]) (odds ratio, 36.43 [95% CI, 6.16-215.21]). The high-risk category was also associated with the development of immunoparalysis (odds ratio, 4.47 [95% CI, 1.34-14.96]) and macrophage activation syndrome (odds ratio, 24.20 [95% CI, 5.50-106.54]). Sixty-three children underwent sequential blood sampling; those who were initially in the low-risk category (n = 24) and those who subsequently migrated (n = 19) to the low-risk category all survived, whereas those who remained in the "at-risk" categories had increased mortality (7/20 [35%]; p < 0.05). CONCLUSIONS: A C-reactive protein- and ferritin-based contingency table effectively assessed mortality risk. Reduction in systemic inflammation below a combined threshold C reactive protein of 4.08 mg/dL and ferritin of 1,980 ng/mL appeared to be a desired response in children with severe sepsis. PMID- 27941426 TI - Pancreatic Fat Is Associated With Metabolic Syndrome and Visceral Fat but Not Beta-Cell Function or Body Mass Index in Pediatric Obesity. AB - OBJECTIVE: Adolescents with obesity have increased risk of type 2 diabetes and metabolic syndrome (MetS). Pancreatic fat has been related to these conditions; however, little is known about associations in pediatric obesity. The present study was designed to explore these associations further. METHODS: We examined 116 subjects, 90 with obesity. Anthropometry, MetS, blood samples, and oral glucose tolerance tests were assessed using standard techniques. Pancreatic fat fraction (PFF) and other fat depots were quantified using magnetic resonance imaging. RESULTS: The PFF was elevated in subjects with obesity. No association between PFF and body mass index-standard deviation score (BMI-SDS) was found in the obesity subcohort. Pancreatic fat fraction correlated to Insulin Secretion Sensitivity Index-2 and Homeostatic Model Assessment of Insulin Resistance in simple regression; however, when using adjusted regression and correcting for BMI SDS and other fat compartments, PFF correlated only to visceral adipose tissue and fasting glucose. Highest levels of PFF were found in subjects with obesity and MetS. CONCLUSIONS: In adolescents with obesity, PFF is elevated and associated to MetS, fasting glucose, and visceral adipose tissue but not to beta cell function, glucose tolerance, or BMI-SDS. This study demonstrates that conclusions regarding PFF and its associations depend on the body mass features of the cohort. PMID- 27941427 TI - Belatacept Compared With Tacrolimus for Kidney Transplantation: A Propensity Score Matched Cohort Study. AB - BACKGROUND: Although tacrolimus is the basis of most maintenance immunosuppression regimens for kidney transplantation, concerns about toxicity have made alternative agents, such as belatacept, attractive to clinicians. However, limited data exist to directly compare outcomes with belatacept-based regimens to tacrolimus. METHODS: We performed a propensity score matched cohort study of adult kidney transplant recipients transplanted between May 1, 2001, and December 31, 2015, using national transplant registry data to compare patient and allograft survival in patients discharged from their index hospitalization on belatacept-based versus tacrolimus-based regimens. RESULTS: In the primary analysis, we found that belatacept was not associated with a statistically significant difference in risk of patient death (hazard ratio, 0.84; 95% confidence interval [CI], 0.61-1.15, P = 0.28) or allograft loss (hazard ratio, 0.83; 95% CI, 0.62-1.11; P = 0.20) despite an increased risk of acute rejection in the first year posttransplant (odds ratio, 3.12; 95% CI, 2.13-4.57; P < 0.001). These findings were confirmed in additional sensitivity analyses that accounted for use of belatacept in combination with tacrolimus, transplant center effects, and differing approaches to matching. CONCLUSIONS: Belatacept appears to have similar longitudinal risk of mortality and allograft failure compared with tacrolimus-based regimens. These data are encouraging but require confirmation in prospective randomized controlled trials. PMID- 27941429 TI - Vascularized Composite Allograft Preservation: Ubi Sumus? PMID- 27941428 TI - Machine-Learning Algorithms Predict Graft Failure After Liver Transplantation. AB - BACKGROUND: The ability to predict graft failure or primary nonfunction at liver transplant decision time assists utilization of scarce resource of donor livers, while ensuring that patients who are urgently requiring a liver transplant are prioritized. An index that is derived to predict graft failure using donor and recipient factors, based on local data sets, will be more beneficial in the Australian context. METHODS: Liver transplant data from the Austin Hospital, Melbourne, Australia, from 2010 to 2013 has been included in the study. The top 15 donor, recipient, and transplant factors influencing the outcome of graft failure within 30 days were selected using a machine learning methodology. An algorithm predicting the outcome of interest was developed using those factors. RESULTS: Donor Risk Index predicts the outcome with an area under the receiver operating characteristic curve (AUC-ROC) value of 0.680 (95% confidence interval [CI], 0.669-0.690). The combination of the factors used in Donor Risk Index with the model for end-stage liver disease score yields an AUC-ROC of 0.764 (95% CI, 0.756-0.771), whereas survival outcomes after liver transplantation score obtains an AUC-ROC of 0.638 (95% CI, 0.632-0.645). The top 15 donor and recipient characteristics within random forests results in an AUC-ROC of 0.818 (95% CI, 0.812-0.824). CONCLUSIONS: Using donor, transplant, and recipient characteristics known at the decision time of a transplant, high accuracy in matching donors and recipients can be achieved, potentially providing assistance with clinical decision making. PMID- 27941430 TI - Long-term Persistence of Innate Lymphoid Cells in the Gut After Intestinal Transplantation. AB - BACKGROUND: Little is known about innate lymphoid cell (ILC) populations in the human gut, and the turnover of these cells and their subsets after transplantation has not been described. METHODS: Intestinal samples were taken from 4 isolated intestine and 3 multivisceral transplant recipients at the time of any operative resection, such as stoma closure or revision. ILCs were isolated and analyzed by flow cytometry. The target population was defined as being negative for lineage markers and double-positive for CD45/CD127. Cells were further stained to define ILC subsets and a donor-specific or recipient-specific HLA marker to analyze chimerism. RESULTS: Donor-derived ILCs were found to persist greater than 8 years after transplantation. Additionally, the percentage of cells thought to be lymphoid tissue inducer cells among donor ILCs was far higher than that among recipient ILCs. CONCLUSIONS: Our findings demonstrate that donor-derived ILCs persist long-term after transplantation and support the notion that human lymphoid tissue inducer cells may form in the fetus and persist throughout life, as hypothesized in rodents. Correlation between chimerism and rejection, graft failure, and patient survival requires further study. PMID- 27941431 TI - Role of Circulating MicroRNAs in the Immunopathogenesis of Rejection After Pediatric Lung Transplantation. AB - BACKGROUND: Acute rejection (AR) and development of chronic rejection, bronchiolitis obliterans syndrome (BOS) remain major limiting factors for lung transplantation (LTx). This retrospective study is to identify differentially expressed circulating microRNAs (miRNAs) that associate with development of AR and BOS in pediatric lung transplant recipients (LTxR). METHODS: We determined the circulating levels of 7 selected candidate miRNAs in 14 LTxR with AR, 7 with BOS, and compared them against 13 stable pediatric LTxR at 1, 6, and 12 months after LTx. In addition, 6 AR, 7 BOS, and 8 stable pediatric LTxR, 16 AR, 17 BOS, and 16 stable adult LTxR were included for validation. RESULTS: MiR-10a, -195, 133b were significantly lower in AR and miR-144, -142-5p, -155 were higher in AR compared to stable (P < 0.05). In addition, circulating levels of miR-134, -10a, 195, -133b were significantly lower and miR-144, -142-5p, -155 were higher (P < 0.05) with development of BOS. The receiver-operating characteristic demonstrated that miR-142-5p, miR-155, and miR-195 strongly discriminated patients with AR from stable LTxR (P < 0.001 for all comparisons): miR-142-5p (area under the curve [AUC], 0.854), miR-155 (AUC, 0.876), and miR-195 (AUC, 0.872). Further, miR 10a, miR-142-5p, miR-144, and miR-155 strongly discriminated BOS from stable LTxR (P < 0.001 for all comparisons). CONCLUSIONS: We demonstrated that differential expression of circulating miRNAs occurs in LTxR with AR and BOS, suggesting that they can provide not only important clues to pathogenesis but also may serve as potential noninvasive biomarkers for AR and BOS after pediatric LTx. PMID- 27941432 TI - Immune Reconstitution After HCV Clearance With Direct Antiviral Agents: Potential Consequences for Patients With HCC? AB - Recent introduction of all-oral direct-acting antiviral (DAA) treatment has revolutionized care of patients with chronic hepatitis C virus infection. Because patients with different liver disease stages have been treated with great success including those awaiting liver transplantation, therapy has been extended to patients with hepatocellular carcinoma as well. From observational studies among compensated cirrhotic hepatitis C patients treated with interferon-containing regimens, it would have been expected that the rate of hepatocellular carcinoma occurrence is markedly decreased after a sustained virological response. However, recently 2 studies have been published reporting markedly increased rates of tumor recurrence and occurrence after viral clearance with DAA agents. Over the last decades, it has been established that chronic antigen stimulation during persistent infection with hepatitis C virus is associated with continuous activation and impaired function of several immune cell populations, such as natural killer cells and virus-specific T cells. This review therefore focuses on recent studies evaluating the restoration of adaptive and innate immune cell populations after DAA therapy in patients with chronic hepatitis C virus infection in the context of the immune responses in hepatocarcinogenesis. PMID- 27941433 TI - Kidney Fibrosis: Origins and Interventions. AB - All causes of renal allograft injury, when severe and/or sustained, can result in chronic histological damage of which interstitial fibrosis and tubular atrophy are dominant features. Unless a specific disease process can be identified, what drives interstitial fibrosis and tubular atrophy progression in individual patients is often unclear. In general, clinicopathological factors known to predict and drive allograft fibrosis include graft quality, inflammation (whether "nonspecific" or related to a specific diagnosis), infections, such as polyomavirus-associated nephropathy, calcineurin inhibitors (CNI), and genetic factors. The incidence and severity of chronic histological damage have decreased substantially over the last 3 decades, but it is difficult to disentangle what effects individual innovations (eg, better matching and preservation techniques, lower CNI dosing, BK viremia screening) may have had. There is little evidence that CNI-sparing/minimization strategies, steroid minimization or renin angiotensin-aldosterone system blockade result in better preservation of intermediate-term histology. Treatment of subclinical rejections has only proven beneficial to histological and functional outcome in studies in which the rate of subclinical rejection in the first 3 months was greater than 10% to 15%. Potential novel antifibrotic strategies include antagonists of transforming growth factor-beta, connective tissue growth factor, several tyrosine kinase ligands (epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor), endothelin and inhibitors of chemotaxis. Although many of these drugs are mainly being developed and marketed for oncological indications and diseases, such as idiopathic pulmonary fibrosis, a number may hold promise in the treatment of diabetic nephropathy, which could eventually lead to applications in renal transplantation. PMID- 27941435 TI - Conformational Variants of HLA-I Antigens on Luminex Single Antigen Beads. PMID- 27941434 TI - Mortality and Graft Loss Attributable to Readmission After Kidney Transplantation: Immediate and Long-term Risk. AB - BACKGROUND: After kidney transplantation, early readmission is independently associated with graft loss and mortality. The mechanism of this association is poorly understood. Understanding the timeline of risk, that is, during the readmission hospitalization versus periods postreadmission, will provide additional insights. METHODS: We used national registry data to study 56 076 adult Medicare-primary first-time kidney transplant recipients from December 1999 to October 2011. Piecewise Cox proportional hazard models were used to estimate the association between graft loss, mortality, and readmission for 2 periods: readmission hospitalization and postreadmission. RESULTS: During the readmission hospitalization, graft loss was substantially higher (deceased donor kidney transplant [DDKT] without delayed graft function [DGF] hazard ratio: 24.634.447.9, P < 0.001; with DGF: 10.815.221.4, P < 0.001; live donor kidney transplant [LDKT]: 18.136.774.2, P < 0.001) and mortality was substantially higher (DDKT without DGF: 14.120.830.7, P < 0.001; with DGF: 9.0312.818.0, P < 0.001; LDKT: 9.0018.241.3, P < 0.001). Immediately after readmission discharge, graft loss (DDKT without DGF: 2.082.402.77, P < 0.001; with DGF: 1.832.142.51, P < 0.001; LDKT: 2.002.503.13, P < 0.001), and mortality (DDKT without DGF: 2.162.432.73, P < 0.001; with DGF: 1.832.162.88, P < 0.001; LDKT: 1.902.342.88, P < 0.001) remained elevated, but much less so. After readmission, the hazard of graft loss remained, but decreased 19% per year for DDKT recipients (time varying coefficient 0.780.810.85, P < 0.001) and 14% per year for LDKT recipients (0.790.860.93, P < 0.001). The hazard of mortality remained, but decreased 14% per year for DDKT recipients (0.830.860.89, P < 0.001) and 9% per year for LDKT recipients (0.850.910.98, P < 0.001). CONCLUSIONS: In conclusion, readmission is most strongly associated with graft loss and mortality during the readmission hospitalization, but also portends a lasting, albeit attenuated, risk postreadmission. PMID- 27941436 TI - MyD88 Inhibitors and the Continuing Challenge of TLR Antagonism. PMID- 27941437 TI - Activation of Fibrinolysis, But Not Coagulation, During End-Ischemic Ex Situ Normothermic Machine Perfusion of Human Donor Livers. AB - BACKGROUND: Ex situ normothermic machine perfusion (NMP) can be performed after traditional static cold preservation to assess graft function and viability before transplantation. It is unknown whether this results in activation of coagulation and fibrinolysis, as may occur upon graft reperfusion in vivo. METHODS: Twelve donor livers declined for transplantation underwent 6 hours of end-ischemic NMP using a heparinized plasma-based perfusion fluid. Concentration of prothrombin fragment F1 + 2 (marker of coagulation activation), D-dimer, plasmin-antiplasmin complex, tissue plasminogen activator and plasminogen activator inhibitor-1 (markers for fibrinolysis) and alanine aminotransferase (ALT) (marker of ischemia-reperfusion [I/R] injury) were measured in perfusion fluid at regular intervals. Liver biopsies were examined for the presence of fibrin, using light microscopy after Maurits, Scarlet and Blue staining. RESULTS: No significant increase in prothrombin F1 + 2 was noted during NMP. D-dimer and plasmin-antiplasmin complex levels increased soon after start of NMP and D-dimer concentrations correlated significantly with levels of tissue plasminogen activator. In livers displaying good function during NMP, perfusate levels of ALT and D-dimers were low (<=3500 ng/mL), whereas significantly higher D-dimer levels (>3500 ng/mL) were in found in livers with poor graft function. Activation of fibrinolysis correlated significantly with the degree of I/R injury, as reflected by ALT levels. CONCLUSIONS: End-ischemic ex situ NMP results in activation of fibrinolysis, but not of coagulation. Markers of fibrinolysis activation correlate significantly with markers of I/R injury. High concentrations of D dimer early after start of NMP can be considered a marker of severe I/R injury and a predictor of poor liver graft function. PMID- 27941439 TI - Report of the 22nd Annual Congress of the International Liver Transplantation Society. AB - The 2016 Annual Congress of the International Liver Transplantation Society was held in Seoul, South Korea in May. The 22nd Congress marked the largest multidisciplinary liver transplantation meeting in Asia since 2010. The principal themes were living donation, allocation, immunosuppression, machine preservation, novel treatment of hepatitis C, and expansion of the deceased-donor allograft pool. This report presents select abstracts from the scientific sessions within the context of the published literature to serve as a quick reference. PMID- 27941438 TI - Low Measured Hepatic Artery Flow Increases Rate of Biliary Strictures in Deceased Donor Liver Transplantation: An Age-Dependent Phenomenon. AB - BACKGROUND: This study was conducted to determine effect of lower measured hepatic arterial (HA) flow (<400 mL/min) on biliary complications and graft survival after deceased donor liver transplantation. Hepatic artery is the main blood supply to bile duct and lack of adequate HA flow is thought to be a risk factor for biliary complications. METHODS: A retrospective review of 1300 patients who underwent deceased donor liver transplantation was performed. Patients with arterial complications were excluded to eliminate potential contribution to biliary complications from HA thrombosis. Patients were divided into low (<400 mL/min; N = 201) and high (>=400 mL/min; N = 1099) HA flow groups. Incidence of biliary complications and graft survival were analyzed. RESULTS: HA flows less than 400 mL/min were associated with increased rate of biliary strictures in younger donors (<50 years old), and in patients with duct-to-duct anastomoses (P = 0.028). Lower HA flows were associated with decreased graft survival (P = 0.013). Donor older than 50 years was associated with increased rate of biliary strictures (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.14-2.45; P = 0.0085) and graft failure (HR, 1.68; 95% CI, 1.35-2.1; P <0.0001) on multivariate analyses. HA flow less than 400 mL/min was associated with biliary strictures (HR, 1.53; 95% CI, 1.04-2.24; P = 0.0297) on univariate analysis only. CONCLUSIONS: HA flow less than 400 mL/min was associated with higher rate of biliary strictures in younger donors with duct-to-duct reconstruction and lower graft survival. A consideration should be given to increase the intraoperative HA flow to prevent biliary strictures in such patients. PMID- 27941440 TI - Financial Burden Borne by Laparoscopic Living Kidney Donors. AB - BACKGROUND: Living kidney donors have donation-related out-of-pocket costs (direct costs) and/or ongoing daily expenses while losing income (indirect costs). Yet there is little information about how much of a subjective burden these constitute for the donors. METHODS: From December 2003 through December 2014, we surveyed donors 6 months postdonation to determine their financial burden related to donation (on a scale of 1 to 10) and what resources were used to cover expenses. RESULTS: Of 1136 surveyed, 796 (70%) responded. Among respondents, mean age at donation was 43.6 +/- 10.6 years, 64% were women, 96% were white, and 53% were related by blood to their recipient. Overall, 26% scored their financial burden as 5 or higher; 8% scored it as 8 or higher. Increased expenses were associated with a higher reported burden; however, significant burden was reported by some with no out-of-pocket expenses (presumably due to lost wages and continuing expenses). The burden was scored as 5 or higher by 27% of those employed outside the home (n = 660), 15% homemakers, 13% retirees, 40% students; 28% unemployed; and 26% whose occupation was unknown. Over half (51%) of those receiving a local or (means-tested) national grant still reported moderate to severe burden. Besides grants, donors used a variety of sources to help offset expenses: dipped into savings, borrowed from friends or family, took out a loan, and/or had a fundraiser. Those with the highest burden reported using the most additional sources. CONCLUSIONS: Donors should not have to incur costs or a financial burden to donate; the transplant community should strive to make donation financially neutral. PMID- 27941442 TI - Why Suffering? PMID- 27941441 TI - Live Donors of the Initial Observational Study of Uterus Transplantation Psychological and Medical Follow-Up Until 1 Year After Surgery in the 9 Cases. AB - BACKGROUND: The first prospective observational study of uterus transplantation was initiated in 2013 with live donation to 9 women with absolute uterine factor infertility. We explored the medical complications and psychosocial wellbeing of the donors during the first postoperative year. METHODS: Complications were registered and graded according to the Clavien-Dindo (C-D) classification. Symptoms related to the surgery were registered. Data on length of hospital stay, sick leave, socioeconomic parameters, and life events were obtained. Psychological evaluations (Psychological General Well-Being, Dyadic Adjustment Scale, Hospital Anxiety and Depression Scale [HADS], SF-36) questionnaires focusing on quality of life, mood, and relationship, were conducted at inclusion and at 3, 6, and 12 months after uterus donation. RESULTS: One major surgical complication (C-D IIIb) occurred. A ureteric-vaginal fistula developed 2 weeks after uterus procurement. The fistula was surgically repaired. Two self-reported and transient complications (C-D I) were noted (nocturia, meralgia paresthetica). Hospital stays of all donors were 6 days and median sick leave was 56 days (range, 14-132). At inclusion, median scores exceeded the normative values of the Swedish population in Psychological General Well-Being and Dyadic Adjustment Scale. HADS-Anxiety was detected preoperatively in 1 donor. Two donors exceeded 10-point declines in SF-36 summary scores and increased their HADS scores by 6 points during the observation period. All donors returned to their predonation levels of physical health. CONCLUSIONS: The results support that it is feasible to retrieve a uterus safely from a live donor. Further studies are needed to better evaluate the method. PMID- 27941444 TI - Etc. PMID- 27941443 TI - NCF @ Work. PMID- 27941445 TI - What Is Your Life Song? PMID- 27941446 TI - Clinical Nurses Specialists' Spheres of Influence. PMID- 27941447 TI - Nursing in the Church. PMID- 27941448 TI - Student TXT. PMID- 27941449 TI - Toxic Teaching. PMID- 27941450 TI - Entering Into Suffering: Becoming a Transformed and Transforming Healer. AB - Learning how to respond to suffering is a significant challenge for healthcare providers. This interdisciplinary paper relays a Pedagogy of Suffering Model, based on research following a suffering interview project with undergraduate nursing students. The model is compared to the Gospel account of an encounter between Jesus and a Syrophoenician woman (Mark 7:24-30), supporting biblical and theological soundness of the model's transformative tasks for learning how to respond to suffering. The model can guide development of learning experiences that deepen understanding of compassionate interventions for those who suffer. PMID- 27941451 TI - End-of-Life Nursing Care and Education: End-of-Life Nursing Education: Past and Present. AB - The dying experience is forever carried in the life story of those for whom the nurse cares. A goal of end-of-life nursing education is to produce nurses who are comfortable with death and dying and who have had the opportunity to reflect on their thoughts and feelings about end-of-life care. This article reviews the history, development, and teaching methods of end-of-life care, offering recommendations for future education. PMID- 27941452 TI - Use of Simulation in End-of-Life Care Education. AB - Death and dying encompasses the period when individuals present with a limited prognosis and are near death or have recently died. Using simulation to educate nurses on end-of-life (EOL) care helps focus more on the needs of the learner rather than the patient, and allows the learner to process feelings in preparation for a real experience. Incorporating simulation with a spiritual perspective is essential and needed in EOL nursing care. PMID- 27941453 TI - The Pad Project: A Global Initiative Uniting Women. AB - The Pad Project is a women's health program used to educate women on their monthly menstrual cycles. Through this ministry, women who do not have access to menstrual hygiene products are given sustainable hygienic kits to promote menstrual health. This unique health education program also integrates stories from the gospel to illustrate Christ's love and caring commitment toward women and women's health. PMID- 27941454 TI - Accelerated RN-to-BSN Service-Learning Program Serves the Vulnerable. AB - The definition, implementation, and benefits support the value of service learning for nursing education. However, accelerated RN-to-BSN programs may have difficulty requiring service-learning experiences. This article offers a biblical rationale for service with vulnerable populations and an example of how service learning is implemented into the curriculum of an accelerated, nontraditional, online/onsite RN-BSN completion program at a Christian university. PMID- 27941455 TI - Respite Care for Families of Children with Disabilities: A University/Faith Community Model. AB - Families of children with disabilities or special healthcare needs report respite care as a great need, yet availability of such care is scarce. A partnership developed between a nursing school in the Southeast and a faith community, to provide respite care and summer camps, resulted in a win-win situation for families, children, interprofessional students and educators, the faith community, and volunteers. This article explains the need for respite, how schools of nursing and faith communities can partner, and the benefits to all stakeholders. PMID- 27941456 TI - Writing the Persona Poem. PMID- 27941457 TI - Is It Okay To Cry with Patients? PMID- 27941458 TI - Are We Losing the Calling to Care for Others? PMID- 27941459 TI - Writing Habits: Training for the Details of Nursing. PMID- 27941461 TI - Resources. PMID- 27941460 TI - Who Is Your Battle Buddy? PMID- 27941462 TI - PulseBeats. PMID- 27941463 TI - Understanding Spiritual Care: The Faith-Hope-Love Model of Spiritual Wellness. AB - Spiritual care has been associated with positive patient outcomes. Although nurses want to provide spiritual care, many have difficulty conceptualizing spiritual care outside of religion and religious activities. The Faith-Hope-Love Model of Spiritual Wellness, a theoretical model of spirituality and spiritual well-being, grounded in Christian theology and biblical text, can help nurses provide spiritual support to patients and families from multiple faith traditions or those without a faith background. Spirituality concepts are discussed, and description of how spirituality is related to finding meaning and purpose in life along with a summary of the spiritual needs identified from healthcare literature and the Bible, are provided. PMID- 27941464 TI - End of Life in a Haitian American, Faith-Based Community: Caring for Family and Communal Unity. AB - This article presents two models resulting from a grounded theory study of the end-of-life decision-making process for Haitian Americans. Successful access to this vulnerable population was achieved through the faith-based community. The first model describes this faith-based community of Haitian Americans. The second model describes the process used by families in this community who must make end of-life healthcare decisions. Implications for nursing practice and caring science include a need to improve the congruence between the nursing care provided at this vulnerable time and the cultural values of a population. PMID- 27941467 TI - Cellular and molecular profiling of graft injury post renal transplantation. AB - PURPOSE OF REVIEW: Continues advancements in assessing methods for biomolecules that have assisted to identify surrogate candidate biomarkers that can be used to monitor the transplanted organ. These high-throughput methods can help researchers to significantly speed up the identification and the validation steps, which are crucial factors for biomarker discovery efforts. However, this task in transplantation confronts multiple limitations. The review summarizes main findings using 'omics approaches in the evaluation of different types of allograft injury with the overarching aim of evaluating the next steps for transferring the available data to the clinical setting. RECENT FINDINGS: Significant discoveries have been made about the molecular and cellular mechanisms that associate with graft injury that may lead to early biomarkers of graft injury (prediction and diagnosis) with the goal of improving long-term outcomes by extending the lifespan of the graft and/or identifying new therapeutic targets. SUMMARY: Common efforts among researchers are needed for transferring biomarkers to the clinical setting and, moreover, elucidate pathways that may allow for early interventions to avoid fibrosis progression and graft loss. Large and prospective studies for validation of current available data under strict analytical evaluation are needed to move biomarkers from the discovery phase to validation and clinical implementation. PMID- 27941468 TI - Liver perfusion devices: how close are we to widespread application? AB - PURPOSE OF REVIEW: Ex-situ liver machine perfusion has been the focus of increasing interest over the past decade as a means to improve the quality of livers for transplantation and the applicability of liver transplantation in general. The present review aims to evaluate the experimental basis for liver machine perfusion and the significance of recent reports on its clinical application. RECENT FINDINGS: Although liver machine perfusion has been studied experimentally over a range of temperatures, clinical liver transplant work that has been performed to date has been done using either hypothermic machine perfusion (0-12 degrees C), HMP or normothermic machine perfusion (35-38 degrees C, NMP). Both HMP and NMP have been studied clinically in the context of phase I trials demonstrating the feasibility of their application. It has also been shown through a small number of cases that NMP may serve as a useful means to evaluate initially discarded livers to determine viability for subsequent transplantation. SUMMARY: Although initial clinical results are promising, higher level evidence is still needed to justify more widespread application of machine perfusion in human liver transplantation. PMID- 27941469 TI - Periorbital Dermoid Cyst With Unique Trichilemmal Differentiation. AB - The authors describe a 4-year-old girl presenting with a 2-year history of a superomedial eyelid "bump" that appeared cystic on MRI. The clinical diagnosis was dermoid cyst, possibly of conjunctival origin. Following excision, histology showed a cyst that contained keratin and lanugo hairs in its lumen with sebaceous glands and chronic inflammation in its fibrous wall. An unanticipated finding was the presence of a trichilemmal (pilar) variety of epithelial lining that stained positively for calretinin, an immunostain that identifies trichilemmal epithelium. To the authors' knowledge this is the first case of a dermoid cyst with trichilemmal lining. This study was conducted in compliance with the rules and regulations of the Health Insurance Portability and Accountability Act and in conformity with the Oslo declaration. PMID- 27941470 TI - Simbu Ptosis: An Outreach Approach to Myogenic Ptosis in Eastern Highlands of Papua New Guinea-Experience and Results From a High-Volume Oculoplastic Surgical Camp. AB - PURPOSE: To present the results of a high-volume oculoplastic surgical outreach in a remote region of Simbu Province in the Eastern Highlands of Papua New Guinea. The authors describe the clinical features and evaluation and treatment of a novel ptosis syndrome found in this area. DESIGN: A team of 4 international ophthalmologists and 3 local doctors and 3 local nurses involved in a high-volume field intervention for all patients presenting with a bilateral ptosis to Mingende Rural Hospital. METHODS: Patients were systematically evaluated and treated during a 6-day surgical outreach and followed daily for 1 week and as needed via telemedicine. Visiting surgeons provided skills-transfer instruction for 3 local doctors and 3 nurses. Data collected included demographic information, history of present illness, past medical history, family history, social history, and a complete ophthalmologic and targeted neurologic evaluation. Patients were offered surgical intervention if they met criteria for safe eyelid elevation and could present for follow ups. Detailed notes of patient geographic location, history, and risk factors were collected in addition to pre- and postoperative photos. MAIN OUTCOME MEASURES: Efficient triage and treatment of all patients referred to the remote oculoplastic clinic. RESULTS: A total of 97 patients presented to the camp; of these, 87 underwent complete evaluation. There were 72 patients with ptosis, of which 60 were found to be of Simbu-type. These patients were grouped clinically by degree of ptosis: mild, moderate, and severe. Thirty-eight patients had moderate ptosis of which 34 underwent surgical intervention. Eleven patients with mild ptosis were counseled and observed. The 10 patients with severe ptosis and 2 with moderate ptosis were treated medically with ptosis crutches manufactured on site. A new technique for creating ptosis crutch glasses was developed. CONCLUSIONS: A new variant of progressive myogenic ptosis was identified. A high-volume oculoplastic surgical camp is an efficient way to systematically evaluate and treat this new entity. Skills-transfer training for local doctors and staff ensured continuity of care for the surgical patients. PMID- 27941471 TI - The Brow Fat Pad Suspension Suture: Safety Profile and Clinical Observations. AB - PURPOSE: To evaluate the safety, subjectively assess outcome, and emphasize surgical pearls and critical clinical observations of upper blepharoplasty performed in conjunction with the brow fat pad suspension suture procedure, previously referred to as a "browpexy variant" or "brassiere suture procedure." METHODS: A retrospective 4-year analysis of patients who underwent the brow fat pad suspension suture with upper blepharoplasty was performed. Adjunctive procedures (brow lift and ptosis repair) were categorized. The surgical technique is detailed with emphasis placed on nuances to aid in optimal outcome. RESULTS: Two hundred and sixteen patients (149 women and 47 men) underwent upper blepharoplasty with the brow fat pad suspension suture. The average patient age is 54 years and follow up is 11 months. One hundred patients had adjudicative brow lift or ptosis repair, and in 20 patients the blepharoplasty was a revision procedure. Subjective assessment of outcome showed excellent aesthetic results with improved brow projection, and enhanced lateral tarsal platform show and eyebrow/eyelid contour. Surgical complications were infrequent and patient satisfaction was high. CONCLUSIONS: This initial large series description of the brow fat pad suspension suture demonstrates that it is a safe adjunct to upper blepharoplasty, which the authors believe subjectively improves overall outcome. Evidence-based quantitative assessments of objective measures of surgical results are currently underway. PMID- 27941472 TI - Isolation of Methicillin-resistant Staphylococcus aureus and Multidrug-resistant Elizabethkingia meningoseptica From Neonates Within Minutes of Birth. PMID- 27941473 TI - Roll-plate Alone Does Demonstrate Colonization in Silicone Neonatal Catheters. PMID- 27941474 TI - In Reply: Roll-plate Alone Does Demonstrate Colonization in Silicone Neonatal Catheters. PMID- 27941475 TI - Denouement. PMID- 27941477 TI - Diaphragm-Sparing Nerve Blocks for Shoulder Surgery. AB - Shoulder surgery can result in significant postoperative pain. Interscalene brachial plexus blocks (ISBs) constitute the current criterion standard for analgesia but may be contraindicated in patients with pulmonary pathology due to the inherent risk of phrenic nerve block and symptomatic hemidiaphragmatic paralysis. Although ultrasound-guided ISB with small volumes (5 mL), dilute local anesthetic (LA) concentrations, and LA injection 4 mm lateral to the brachial plexus have been shown to reduce the risk of phrenic nerve block, no single intervention can decrease its incidence below 20%. Ultrasound-guided supraclavicular blocks with LA injection posterolateral to the brachial plexus may anesthetize the shoulder without incidental diaphragmatic dysfunction, but further confirmatory trials are required. Ultrasound-guided C7 root blocks also seem to offer an attractive, diaphragm-sparing alternative to ISB. However, additional large-scale studies are needed to confirm their efficacy and to quantify the risk of periforaminal vascular breach. Combined axillary suprascapular nerve blocks may provide adequate postoperative analgesia for minor shoulder surgery but do not compare favorably to ISB for major surgical procedures. One intriguing solution lies in the combined use of infraclavicular brachial plexus blocks and suprascapular nerve blocks. Theoretically, the infraclavicular approach targets the posterior and lateral cords, thus anesthetizing the axillary nerve (which supplies the anterior and posterior shoulder joint), as well as the subscapular and lateral pectoral nerves (both of which supply the anterior shoulder joint), whereas the suprascapular nerve block anesthetizes the posterior shoulder. Future randomized trials are required to validate the efficacy of combined infraclavicular-suprascapular blocks for shoulder surgery. PMID- 27941478 TI - Asynchrony Between Ventilator Flow and Pressure Waveforms and the Capnograph on Drager Anesthesia Workstations: A Case Report. AB - Modern anesthesia workstations display capnography, flow-time, and pressure-time waveforms in real time. We observed that at certain ventilator settings (10 breaths/min) on Drager workstations, the expiratory phase of the capnograph overlaps both the inspiratory and the expiratory phases of ventilation. This discrepancy disappears at respiratory rates of 16 breaths/min. This synchronous respiratory monitoring display at respiratory rates 16 breaths/min is not physiologically correct, because it implies a synchronization of waveforms that is not actually present. This again becomes asynchronous once the respiratory rate is increased to >18 breaths/min. Such an artifact may not affect the patient's safety in most cases but may mislead clinicians when synchrony between flow/pressure and capnography is needed for diagnostic purposes. We wish to share this discrepancy with clinicians and notify the manufacturer so that potential solutions may be found. PMID- 27941476 TI - Effect of CYP Inducers/Inhibitors on Topiramate Concentration: Clinical Value of Therapeutic Drug Monitoring. AB - BACKGROUND: This study investigated the pharmacokinetic interactions between topiramate (TPM) and concomitant antiepileptic drugs and evaluated the therapeutic concentration range of TPM and the effect of the achieved plasma concentration on the retention rate of TPM therapy. METHODS: A total of 1217 plasma samples obtained from 610 patients were retrospectively investigated, and the concentration-to-dose ratio (CD ratio) of TPM was compared among patients on various antiepileptic drug regimens. In addition, the therapeutic concentration of TPM was reviewed in patients on long-term therapy, and factors influencing the retention rate of TPM were analyzed by the Kaplan-Meier method. RESULTS: Among patients using hepatic enzyme inducers (phenytoin, phenobarbital, and carbamazepine), the CD ratio was reduced by 45.4% in adults and 33.3% in children. Patients taking phenytoin concomitantly had a significantly lower CD ratio than patients taking phenobarbital or carbamazepine. Among noninducers, concomitant use of stiripentol increased the CD ratio. In 276 patients who remained on TPM therapy for more than 2 years, the mean therapeutic concentration was 5.1 mcg/mL (15.0 MUmol/L). The estimated retention day was significantly higher for patients with a TPM concentration >5 mcg/mL than that for patients with a concentration <5 mcg/mL (945 versus 802 days; P = 0.007 by the log-rank test). Also, patients without hepatic enzyme inducers had a significantly higher retention rate than patients using such inducers (P = 0.002). CONCLUSIONS: Concomitant use of hepatic enzyme inducers markedly reduced the plasma TPM concentration and can decrease its antiepileptic effect. A therapeutic concentration of >5 mcg/mL TPM was significantly associated with continuation of therapy, and therapeutic drug monitoring can be helpful. PMID- 27941480 TI - The Role of Simulation in Planning Intraoperative Magnetic Resonance Imaging Guided Neurosurgical Procedures: A Case Report. AB - Simulation of the actual procedure is a simple and yet effective method of increasing patient safety and reducing the rate of unexpected adverse effects. We present our experience with 2 cases of preprocedural simulation on healthy volunteers that were performed in the intraoperative magnetic resonance imaging suite. During one of the cases, we also simulated a scenario of sudden cardiac arrest. Such an approach helped us to refine the procedures and coordinate the work of different teams within the intraoperative magnetic resonance imaging suite as well as improve the quality of patient management. PMID- 27941481 TI - Anesthetic Considerations for Pneumonectomy With Left Atrial Resection on Cardiopulmonary Bypass in a Patient With Lung Cancer: A Case Report. AB - Cases of pneumonectomy plus atrial resection for lung cancer have been reported in the surgical literature, but not the anesthesia literature. To achieve curative resection, cardiopulmonary bypass (CPB) may be necessary. Although CPB may complicate the management of these high-risk patients, these cases should always be undertaken in a center where it is immediately available. Here, we discuss the anesthetic management of a 70-year-old man with left lower lobe lung cancer invading the left inferior pulmonary vein and left atrium. PMID- 27941482 TI - Iatrogenic Cardiac Tamponade During Endovascular Aortic and Mesenteric Stent Grafting: A Case Report. AB - The authors report a case of left ventricular perforation and cardiac tamponade in a patient undergoing endovascular aortic and mesenteric stent grafting. During the procedure, the anesthetist noticed a sudden increase in central venous pressure and a decrease in blood pressure. Cardiac tamponade was suspected and confirmed by transesophageal echocardiography. Pericardiotomy resulted only in temporary stabilization. Emergency sternotomy revealed left ventricular perforation. Both anesthetists and radiologists have to be aware of such rare but severe complications of interventional procedures. PMID- 27941485 TI - Anesthetic Management of a Tracheoesophageal Fistula in a Patient With a Large Uncorrected Aortopulmonary Window: A Case Report. AB - Aortopulmonary window is a rare form of congenital heart disease that requires significant anesthetic considerations. Cardiac involvement is a well-known comorbidity identified in patients with tracheoesophageal fistula (TEF). Identification of coexisting lesions, specifically congenital heart disease, is crucial before undergoing repair of a TEF. Understanding the complex physiology and expected changes occurring during the anesthetic and surgical intervention for correction of TEF with a significant unrepaired shunting defect is crucial to prevent hemodynamic instability. We present the anesthetic management of a 1-day old neonate with a postnatally diagnosed aortopulmonary window for correction of a TEF. PMID- 27941486 TI - Lipid Emulsion Rescue of Amniotic Fluid Embolism-Induced Cardiac Arrest: A Case Report. AB - Amniotic fluid embolism (AFE) is a rare and often fatal complication that occurs in the peripartum period. We present a patient with an AFE who developed disseminated intravascular coagulation and cardiovascular collapse who may have benefitted from intravascular lipid emulsion rescue. This is the first published case in which lipid emulsion was a part of the successful treatment of AFE. PMID- 27941488 TI - No Differences Between Alter G-Trainer and Active and Passive Recovery Strategies on Isokinetic Strength, Systemic Oxidative Stress and Perceived Muscle Soreness After Exercise-Induced Muscle Damage. AB - Cooke, MB, Nix, C, Greenwood, L, and Greenwood, M. No Differences Between Alter G Trainer and Active and Passive Recovery Strategies on Isokinetic Strength, Systemic Oxidative Stress and Perceived Muscle Soreness After Exercise-Induced Muscle Damage. J Strength Cond Res 32(3): 736-747, 2018-The incidence of muscle injuries is prevalent in elite sport athletes and weekend warriors and strategies that safely and effectively hasten recovery are highly desirable. The purpose of this study was to examine the differences between 3 recovery methods after eliciting muscle damage in recreationally active men relative to maximal isokinetic contractions, perceived muscle soreness, and psychological mood states. Twenty-five recreationally active men (22.15 +/- 3.53 years, 75.75 +/- 11.91 kg, 180.52 +/- 7.3 cm) were randomly matched by V[Combining Dot Above]O2 peak (53.86 +/- 6.65 ml.kg.min) and assigned to one of 3 recovery methods: anti gravity treadmill (G-Trainer) (N = 8), conventional treadmill (N = 8) or static stretching (N = 9). Recovery methods were performed 30 minutes, 24, 48, and 72 hours after a 45-minute downhill run. Following eccentrically biased running, no significant differences were noted in isokinetic knee flexion and extension peak torque, systemic markers of muscle damage, oxidative stress and lipid peroxidation such as serum creatine kinase (CK), superoxide dismutase (SOD), and malondialdehyde (MDA), respectively, and subjective ratings of perceived muscle soreness between recovery methods. The G-Trainer group did however display a higher mood state as indicated by the Profile of Mood State global scores at 24 hours postexercise when compared to the conventional treadmill recovery group (p = 0.035). The improved mood state after the use of the anti-gravity treadmill may provide clinical relevance to other populations. PMID- 27941489 TI - Reproducibility of the Internal Load and Performance-Based Responses to Simulated Amateur Boxing. AB - Thomson, ED and Lamb, KL. Reproducibility of the internal load and performance based responses to simulated amateur boxing. J Strength Cond Res 31(12): 3396 3402, 2017-The aim of this study was to examine the reproducibility of the internal load and performance-based responses to repeated bouts of a three-round amateur boxing simulation protocol (boxing conditioning and fitness test [BOXFIT]). Twenty-eight amateur boxers completed 2 familiarization trials before performing 2 complete trials of the BOXFIT, separated by 4-7 days. To characterize the internal load, mean (HRmean) and peak (HRpeak) heart rate, breath-by-breath oxygen uptake (V[Combining Dot Above]O2), aerobic energy expenditure, excess carbon dioxide production (CO2excess), and ratings of perceived exertion were recorded throughout each round, and blood lactate determined post-BOXFIT. Additionally, an indication of the performance-based demands of the BOXFIT was provided by a measure of acceleration of the punches thrown in each round. Analyses revealed there were no significant differences (p > 0.05) between repeated trials in any round for all dependent measures. The typical error (coefficient variation %) for all but 1 marker of internal load (CO2excess) was 1.2-16.5% and reflected a consistency that was sufficient for the detection of moderate changes in variables owing to an intervention. The reproducibility of the punch accelerations was high (coefficient of variance % range = 2.1-2.7%). In general, these findings suggest that the internal load and performance-based efforts recorded during the BOXFIT are reproducible and, thereby, offer practitioners a method by which meaningful changes impacting on performance could be identified. PMID- 27941490 TI - Excess Blood Flow Response to Acute Resistance Exercise in Individuals Who are Obese or Nonobese. AB - Lipford, GF, Evans, RK, Acevedo, EO, Wolfe, LG, and Franco, RL. Excess blood flow response to acute resistance exercise in individuals who are obese or nonobese. J Strength Cond Res 31(11): 3120-3127, 2017-Resistance exercise (RE) is a commonly recommended treatment option for obese individuals. However, little is known regarding alterations in vasodilatory responses to RE, which could impair exercise tolerance. No studies to date have compared microvascular vasodilatory capacity, assessed by excess blood flow (EBF), responses in individuals who are obese or nonobese following acute RE. The purpose of the study was to evaluate EBF before and up to 24-hour after a single RE bout in obese (n = 18, 38.1 +/- 7.64% body fat) and nonobese (n = 10, 23.6 +/- 4.03% body fat) individuals who volunteered to participate. Each subject completed a leg flexion and knee extension one repetition maximum (1RM) test, and subsequently completed 4 sets of 8 repetitions at 85% of 1RM. Excess blood flow, adiponectin, and tumor necrosis factor alpha (TNF-alpha) were evaluated at baseline (PRE-RE), immediately after (POST-RE), and 1 (POST-1) and 24 (POST-24) hours after exercise. A repeated measures analysis of variance revealed a significant interaction for EBF between the 2 groups (p = 0.029). The estimated marginal means plot suggested that obese individuals had a significant increase in POST-RE EBF in comparison with PRE-RE EBF (428.54 +/- 261.59 vs. 547.00 +/- 311.15 ml/100 ml/min.s; p = 0.046). In addition, EBF significantly decreased at POST-24 in comparison with POST-RE in the obese individuals (547.00 +/- 311.15 vs. 389.33 +/- 252.32 ml/100 ml/min.s; p = 0.011). Changes in EBF were not related to adiponectin or TNF-alpha. An acute bout of RE resulted in an opposite EBF response between nonobese and obese individuals immediately after RE. Furthermore, only the obese individuals displayed a significant increase in EBF immediately after RE, which was significantly reduced 24 hours after the RE bout. Microvascular vasodilatory capacity may alter the adaptive exercise response associated with RE, requiring alterations to frequency, intensity, and/or duration that are specific to populations of various body composition profiles. PMID- 27941492 TI - Effects of a Modified German Volume Training Program on Muscular Hypertrophy and Strength. AB - Amirthalingam, T, Mavros, Y, Wilson, GC, Clarke, JL, Mitchell, L, and Hackett, DA. Effects of a modified German volume training program on muscular hypertrophy and strength. J Strength Cond Res 31(11): 3109-3119, 2017-German Volume Training (GVT), or the 10 sets method, has been used for decades by weightlifters to increase muscle mass. To date, no study has directly examined the training adaptations after GVT. The purpose of this study was to investigate the effect of a modified GVT intervention on muscular hypertrophy and strength. Nineteen healthy men were randomly assign to 6 weeks of 10 or 5 sets of 10 repetitions for specific compound resistance exercises included in a split routine performed 3 times per week. Total and regional lean body mass, muscle thickness, and muscle strength were measured before and after the training program. Across groups, there were significant increases in lean body mass measures, however, greater increases in trunk (p = 0.043; effect size [ES] = -0.21) and arm (p = 0.083; ES = -0.25) lean body mass favored the 5-SET group. No significant increases were found for leg lean body mass or measures of muscle thickness across groups. Significant increases were found across groups for muscular strength, with greater increases in the 5-SET group for bench press (p = 0.014; ES = -0.43) and lat pull-down (p = 0.003; ES = -0.54). It seems that the modified GVT program is no more effective than performing 5 sets per exercise for increasing muscle hypertrophy and strength. To maximize hypertrophic training effects, it is recommended that 4-6 sets per exercise be performed, as it seems gains will plateau beyond this set range and may even regress due to overtraining. PMID- 27941491 TI - Low-Intensity Sprint Training With Blood Flow Restriction Improves 100-m Dash. AB - Behringer, M, Behlau, D, Montag, JCK, McCourt, ML, and Mester, J. Low-intensity sprint training with blood flow restriction improves 100-m dash. J Strength Cond Res 31(9): 2462-2472, 2017-We investigated the effects of practical blood flow restriction (pBFR) of leg muscles during sprint training on the 100-m dash time in well-trained sport students. Participants performed 6 * 100-m sprints at 60 70% of their maximal 100-m sprinting speed twice a week for 6 weeks, either with (intervention group [IG]; n = 12) or without pBFR (control group [CG]; n = 12). The 100-m dash time significantly decreased more in the IG (-0.38 +/- 0.24 seconds) than in the CG (-0.16 +/- 0.17 seconds). The muscle thickness of the rectus femoris increased only in the IG, whereas no group-by-time interactions were found for the muscle thickness of the biceps femoris and the biceps brachii. The maximal isometric force, measured using a leg press, did not change in either group. However, the rate of force development improved in the IG. Growth hormone, testosterone, insulin-like growth factor 1, and cortisol concentrations did not significantly differ between both groups at any measurement time point (pre, 1 minute, 20 minutes, 120 minutes, and 24 hours after the 6 all-out sprints of the first training session). The muscle damage marker h-FABP increased significantly more in the CG than in the IG. The pBFR improved the 100-m dash time significantly more than low-intensity sprint interval training alone. Other noted benefits of training with pBFR were a decreased level of muscle damage, a greater increase of the rectus femoris muscle thickness, and a higher rate of force development. However, the tested hormones were unable to explain the additional beneficial effects. PMID- 27941493 TI - Early infant diagnosis of HIV: review of current and innovative practices. AB - PURPOSE OF REVIEW: Only 51% of HIV-exposed infants receive an HIV test between 4 and 6 weeks of age, with even lower repeat testing rates at older ages, and only 49% of infants tested are initiated on antiretroviral therapy. The purpose of this article is to discuss potential solutions for increasing coverage of early infant diagnosis (EID), decreasing turnaround time for result return, improving linkages to care and treatment and fulfilling the objective of improving outcomes for HIV-infected children. RECENT FINDINGS: Differences in HIV testing guidelines have emerged in different countries, with some recommending HIV testing at birth. Although EID programs are not yet optimal, some solutions have proven successful including the use of short message service printers, community-based interventions and support and education of mothers. Birth and EID point-of-care testing have emerged as potential game changers for improving EID programs. SUMMARY: For EID programs to impact on child health outcomes, by preventing HIV associated morbidity and mortality, and provide more value than a mere surveillance tool, efforts need to be aligned toward the implementation of a comprehensive set of interventions that take cognizance of different contexts, epidemiology and health systems, and that are backed by political and community support. PMID- 27941494 TI - Specialty Plastic Surgical Care and the Accountable Care Act. PMID- 27941495 TI - Evaluation of 2 Purification Methods for Isolation of Human Adipose-Derived Stem Cells Based on Red Blood Cell Lysis With Ammonium Chloride and Hypotonic Sodium Chloride Solution. AB - BACKGROUND: The present study was conducted to compare 2 purification methods for isolation of human adipose-derived stromal vascular fraction or stem cells (ADSCs) based on red blood cell (RBC) lysis with 155 mM ammonium chloride (NH4Cl) and hypotonic sodium chloride (NaCl) solution, and try to develop a safe, convenient, and cost-effective purification method for clinical applications. METHODS: Adipose-derived stem cells and RBC were harvested from the fatty and fluid portions of liposuction aspirates, respectively. The suitable concentration of hypotonic NaCl solution on RBC lysis for purification of ADSCs was developed by RBC osmotic fragility test and flow cytometry analysis. The effects of 155 mM NH4Cl or 0.3% NaCl solution on ADSCs proliferation and RBC lysis efficiency were examined by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide assay and lysis efficiency test, respectively. In addition, the adipogenic and osteogenic capabilities, phenotype and genetic stability of ADSCs were evaluated by oil red staining, alkaline phosphatase activity measurement, flow cytometry, and karyotype analysis, respectively. RESULTS: Sodium chloride solution in 0.3% concentration effectively removed RBCs and did not influence the survival of ADSCs in the 10-minute incubation time. The lysis efficiency did not differ significantly between 0.3% NaCl and 155 mM NH4Cl. Moreover, the adipogenic and osteogenic capabilities, surface marker expression and karyotype of the ADSCs were not affected by lysis solutions or by lysis per se. However, the proliferation capacity in the 0.3% NaCl group was superior to that in 155 mM NH4Cl group. CONCLUSIONS: Our data suggest that 0.3% NaCl solution is useful for isolating ADSCs from liposuction aspirate for clinical applications with safety, convenience, and cost-effect. PMID- 27941496 TI - Comment to "Orange Peel Excision of Gland: A Novel Surgical Technique for Treatment of Gynecomastia". PMID- 27941497 TI - The role of nociceptive input and tissue injury on stress regulation in borderline personality disorder. AB - Approximately 60% to 90% of patients with borderline personality disorder (BPD) show nonsuicidal self-injurious behavior (NSSI) with cutting being the most frequently applied method. One of NSSI's functions is to reduce aversive tension. Previous studies have found a tension-reducing effect of painful tissue injury by an incision. It is still unclear whether this effect is based on the effect of tissue injury or the effect of pain experience, or both. The aim of this study was to determine whether tissue injury leads to a stronger stress reduction than a sole pain stimulus in patients with BPD. After stress induction, 57 BPD patients and 60 healthy controls (HCs) received either an incision or a non tissue-injuring mechanical nociceptive stimulus ("blade") typically perceived as painful or a non-nociceptive tactile sham stimulus (blunt end of scalpel). Participants were unaware of which procedure was applied. For stress assessment, subjective and objective parameters were measured. As immediate response to the stimulus application, we found greater stress reduction after both painful stimuli (incision and blade) in BPD patients but no difference in stress decrease between the tissue-injuring incision and the non-tissue-injuring pain stimulus (blade). Compared with HCs, incision and blade were followed by greater immediate decrease of arousal in BPD patients. Our findings confirm that among BPD patients, the nociceptive input leads to stress reduction. In contrast, the impact of tissue damage on stress reduction was relatively small. In addition, the results suggest that painful stimuli lead to a greater stress reduction in BPD patients compared with HCs. PMID- 27941498 TI - Neuropathic pain after spinal cord injury: the impact of sensorimotor activity. PMID- 27941500 TI - Nurse gender and its influence on emergency department triage-upsides and downsides of registry data. PMID- 27941499 TI - Risk factors for neuropathic pain in diabetes mellitus. PMID- 27941501 TI - Isoflurane Sedation on the ICU in Cardiac Arrest Patients Treated With Targeted Temperature Management: An Observational Propensity-Matched Study. AB - OBJECTIVE: Targeted temperature management after cardiac arrest requires deep sedation to prevent shivering and discomfort. Compared to IV sedation, volatile sedation has a shorter half-life and thus may allow more rapid extubation and neurologic assessment. DESIGN: Observational analysis of clinical data. SETTING: University hospital, medical ICU. PATIENTS: Four hundred thirty-two cardiac arrest survivors underwent targeted temperature management; of those, 110 were treated with volatile sedation using an anesthetic conserving device and isoflurane, and 322 received standard IV sedation. INTERVENTION: No intervention. MEASUREMENT AND MAIN RESULTS: A matched pairs analysis revealed that time on ventilator (difference of median, 98.5 hr; p = 0.003) and length of ICU stay (difference of median, 4.5 d; p = 0.006) were significantly shorter in patients sedated with isoflurane when compared with IV sedation although no differences in neurologic outcome (45% of patients with cerebral performance category 1-2 in both groups) were observed. Significant hypercapnia occurred more frequently during anesthetic conserving device use (6.4% vs 0%; p = 0.021). CONCLUSIONS: Volatile sedation is feasible in cardiac arrest survivors. Prospective controlled studies are necessary to confirm the beneficial effects on duration of ventilation and length of ICU stay observed in our study. Our data argue against a major effect on neurologic outcome. Close monitoring of PaCO2 is necessary during sedation via anesthetic conserving device. PMID- 27941502 TI - Update on the Protective Role of Regulatory T Cells in Myocardial Infarction: A Promising Therapy to Repair the Heart. AB - Myocardial infarction (MI) remains one of the leading causes of heart failure development and death worldwide. To date, interventional and pharmacological therapies are effective in reducing the onset of heart failure and promoting survival. However, progressive maladaptive remodeling post-MI persists in a large fraction of patients resulting in poor prognosis. Immune cell responses and an inflammatory environment largely contribute to adverse cardiac remodeling post MI. CD4FOXP3 regulatory T cells (Tregs) are known for their immunosuppressive capacity and have been successfully implemented in multiple preclinical studies of permanent and ischemia-reperfusion MI. In this review, we highlight the important cardioprotective role of Tregs at the cardiac tissue, cellular, and molecular level, as well as the most prominent pharmacological venues that could be used to exploit Tregs as a novel therapeutic intervention to lessen myocardial injury post-MI. PMID- 27941503 TI - The "Facemask Blinder": A Technique for Optimizing Anxiolysis in Children Undergoing Facial Laceration Repair. AB - We present the case of a 7-year-old boy with a forehead laceration that required suture repair. The child was anxious and uncooperative, and the initial plan was to administer intranasal midazolam to facilitate the repair. However, a facemask blinder was first implemented as a visual barrier to block the child's view of any anxiety-provoking stimuli and appeared to improve the child's cooperation with the procedure. Intranasal midazolam was not administered, and the laceration was cleaned and repaired successfully. In conjunction with adequate local anesthesia and distraction techniques, the facemask blinder helped to facilitate the completion of the laceration repair without the need for any physical restraint or pharmacologic anxiolysis or sedation. PMID- 27941504 TI - Surrogate outcomes. PMID- 27941505 TI - Perceptions of the Canadian occupational performance measure in enhancing the client-centered approach in the rehabilitation process: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this qualitative systematic review is to identify whether the use of the Canadian occupational performance measure (COPM) enhances the perceived experience of a client-centered approach throughout the rehabilitation process. Specifically the review questions are:How do healthcare professionals and their clients perceive the use of the COPM as an instrument to enhance the client-centered approach in the rehabilitation process?Does the use of the COPM provide a more client-centered approach and more involvement in the rehabilitation process, as experienced by the client and professionals?How do the clients and/or the professionals perceive the usability of the COPM in regard to facilitating the client-centered approach in specific settings or phases of the rehabilitation process? PMID- 27941506 TI - Relationship between birth weight or fetal growth rate and postnatal allergy: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this systematic review is to synthesize the best available evidence on the relationship between size at birth or fetal growth and postnatal allergy. Specifically, this review aims to assess evidence regarding relationships between absolute birth weight at term, birth weight corrected for gestational age, expressed as relative to population or customized growth data, or fetal growth measures and physician-diagnosed or parent- and self-reported postnatal clinical allergic disease (eczema/atopic dermatitis, hay fever/rhinitis, allergic asthma or anaphylaxis).The specific review question is: what is the association between the absolute birth weight at full-term or birth weight relative to population or customized data and corrected for gestational age or direct measures of fetal growth, and physician-diagnosed or parent- and self-reported clinical allergic disease (eczema/atopic dermatitis, hay fever/rhinitis, allergic asthma or anaphylaxis)? PMID- 27941507 TI - Perceptions of the influence of social media and therapeutic relationships on nurses: a systematic review protocol of qualitative evidence. AB - REVIEW QUESTION/OBJECTIVE: The objective of the review is to explore the perceptions of the influence social media has on professional boundaries and therapeutic relationships between nurses and their patients and families. PMID- 27941508 TI - Effectiveness of caregiver-provided cognitive interventions on cognition, social functioning and quality of life among older adults with major neurocognitive disorder: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this systematic review is to synthesize the best available evidence on the effectiveness of individual cognitive interventions (CIs) provided by caregivers on cognition, social functioning and quality of life among older adults (>=65 years) with major neurocognitive disorder (NCD).The review questions are as follows:What is the best available evidence on the effectiveness of individual CIs provided by caregivers on cognitive domains such as memory, problem-solving and verbal fluency among older adults (>=65 years) with major NCD?What is the best available evidence regarding the effectiveness of individual CIs provided by caregivers on the social functioning and quality of life among older adults (>=65 years) with major NCD? PMID- 27941509 TI - Perceptions of patients, significant others and health professionals of the role of significant others in programs for chronic non-malignant pain patients: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to identify and synthesize the perceptions of patients, significant others and health professionals regarding the role of significant others in chronic pain programs or healthcare regimens that target patients with chronic non-malignant pain. More specifically, the objective is to identify the role of significant others in chronic pain programs and healthcare regimens for adult patients with chronic non malignant pain in primary, secondary or tertiary healthcare settings. PMID- 27941510 TI - Effectiveness and user experience of web-based interventions for increasing physical activity in people with multiple sclerosis: a comprehensive systematic review protocol. AB - REVIEW QUESTIONS/OBJECTIVES: The overall aim of this comprehensive systematic review is to explore the use of web-based interventions for increasing physical activity levels in people with a diagnosis of multiple sclerosis (MS).The quantitative objectives are to identify:The qualitative objectives are to. PMID- 27941511 TI - A comparison between dexmedetomidine and propofol on extubation times in postoperative adult cardiac surgery patients: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this systematic review is to synthesize the best available evidence regarding the effects of dexmedetomidine compared to propofol on time to extubation, intensive care unit (ICU) length of stay (LOS), hospital LOS and mortality in postoperative adult cardiac surgery patients.The specific review question is as follows:What is the effectiveness of dexmedetomidine compared to propofol on times to extubation, ICU LOS, hospital LOS and mortality in postoperative adults undergoing cardiac surgery? PMID- 27941512 TI - Experiences of midwives and nurses in policy development in low- and middle income countries: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to identify, appraise and synthesize the qualitative evidence on the experiences of midwives' and nurses' involvement in policy development in low- and middle-income countries (LMICs). This qualitative review seeks to address the following question:What are midwives' and nurses' experiences of being involved in policy development in LMICs? PMID- 27941513 TI - Experiences and needs of families with a relative admitted to an adult intensive care unit: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of the proposed review is to determine the best available qualitative evidence to guide healthcare workers when providing care and support for families of relatives in an adult intensive care unit (ICU). The specific objective is to explore the experiences and needs of families with a relative in an adult ICU. PMID- 27941514 TI - Effective treatment of Madura foot: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to determine the best available evidence on the effective treatment of Madura foot. More specifically, the objectives are to identify. PMID- 27941515 TI - Parents' and families' experiences of palliative and end-of-life neonatal care in neonatal settings: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The overall objective of this systematic review is to identify, critically appraise and synthesize the parents' and families' experiences of palliative and end-of-life neonatal care at facilities/services globally. The specific review question is: what are parents' and families' experiences of palliative and end-of-life neonatal care? PMID- 27941516 TI - The use of non-invasive thermometers in healthcare facilities: a scoping review protocol. AB - REVIEW OBJECTIVE AND QUESTIONS: The objective of the review is to map the available evidence to provide an overview of the use of non-invasive thermometers in the general context of health care. The specific questions, in regards to the available international published and unpublished literature, are. PMID- 27941517 TI - Effectiveness of school-based family asthma educational programs in quality of life and asthma exacerbations in asthmatic children aged five to 18: a systematic review. AB - BACKGROUND: Asthma is a common, chronic, non-communicable respiratory disease that affects millions of children worldwide. Asthma exacerbations can range from mild to severe and can have an unfavorable impact on the quality of life of children and their caregivers. Asthma exacerbations often result in absenteeism from school or work, activity intolerance and emergency hospital visits. One strategy to address this health issue in an attempt to improve health outcomes is school-based asthma educational programs. A review of the literature revealed that previous systematic reviews have examined similar topics on the effectiveness of school-based asthma educational programs that have included collaborative efforts between parents and schools. No systematic reviews were found that examined the effectiveness of school-based asthma educational programs that exclusively included children and their caregivers. Research has not been systematically reviewed to determine the effectiveness of a school-based asthma educational program within a familial context. OBJECTIVES: To identify the best available evidence on the effectiveness of school-based family asthma educational programs that exclusively included both children and caregivers on the quality of life and number of asthma exacerbations of children aged five to 18 years with a clinical diagnosis of asthma. INCLUSION CRITERIA TYPES OF PARTICIPANTS: Children aged five to 18 years of any gender, race or ethnicity with a clinical diagnosis of asthma and their caregivers. TYPES OF INTERVENTION(S): School-based family asthma educational programs. TYPES OF STUDIES: Randomized controlled trials. OUTCOMES: Quality of life and the number of asthma exacerbations measured by either missed days from school or work, and/or physical activity intolerance, and/or emergency hospital visits. SEARCH STRATEGY: The search strategy aimed to find both published and unpublished studies from inception of the database to August 21, 2015. METHODOLOGICAL QUALITY: Quantitative papers selected for retrieval were assessed by two independent reviewers for methodological validity before inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute. DATA EXTRACTION: Data were extracted from articles included in the review using the standardized data extraction tool from the Joanna Briggs Institute. The data extracted included specific details about the populations, interventions, study methods and outcomes of significance to the review question and its specific objectives. DATA SYNTHESIS: Due to the heterogeneity among the included studies, statistical pooling and meta-analysis was not possible. Results are presented in narrative form. RESULTS: Six studies examining the intervention were included in this review. All six of the included studies were randomized controlled trials (RCTs). All six studies compared the effects of school-based asthma education to no school-based asthma education/usual care on quality of life and number of asthma exacerbations. Three out of four RCTs showed that children who participated in school-based family asthma educational programs demonstrated a statistically significant improvement in overall quality of life (P < 0.05). All six studies showed improvement in the number of asthma exacerbations that resulted in one or all of the measured outcomes of either missed days from school or work, physical activity intolerance and/or decreased emergency hospital visits. CONCLUSION: School-based family asthma educational programs for children that include caregivers can have a positive impact on the quality of life and asthma management of children with asthma. Other outcomes that can be positively affected by school-based family asthma educational programs include absenteeism from school or work, physical activity intolerance and emergency hospital visits as result of asthma exacerbations. PMID- 27941518 TI - Effectiveness and experience of arts-based pedagogy among undergraduate nursing students: a mixed methods systematic review. AB - BACKGROUND: To develop well rounded professional nurses, educators need diverse pedagogical approaches. There is growing interest in arts-based pedagogy (ABP) as the arts can facilitate reflection, create meaning and engage healthcare students. However, the emerging body of research about ABP needs to be systematically examined. OBJECTIVES: To synthesize the best available evidence on the effectiveness of ABP in enhancing competencies and learning behaviors in undergraduate nursing education and to explore nursing students' experiences with art-based pedagogy. INCLUSION CRITERIA TYPES OF PARTICIPANTS: The review considered studies that included participants who are undergraduate nursing students. TYPES OF INTERVENTION(S)/PHENOMENA OF INTEREST: The qualitative (QL) component considered studies investigating nursing students' experiences of ABP, and the quantitative (QN) component considered studies evaluating the effectiveness of ABP in undergraduate nursing education. TYPES OF STUDIES: The QL component considered QL studies including designs such as phenomenology, grounded theory, ethnography, action research and feminist research. The QN component considered studies that examined the effectiveness of ABP including designs such as randomized controlled trials, non-randomized controlled trials, quasi experimental, before and after studies, prospective and retrospective cohort studies, case-control studies, analytical cross-sectional studies, case series, individual case reports and descriptive cross-sectional studies. OUTCOMES: The following QN outcomes of ABP were assessed: knowledge acquisition, level of empathy, attitudes toward others, emotional states, reflective practice, self transcendence, cognitive/ethical maturity, learning behaviors and students' perspectives of ABP. SEARCH STRATEGY: An extensive three-step search strategy was conducted for primary research studies published between January 1, 1994 and April 7, 2015. The strategy included searching CINAHL, MEDLINE, ERIC, PsycINFO, Academic Search Complete, Arts and Humanities Citation Index, Art Full Text, Scopus, ProQuest Dissertations and Theses, A&I, and gray literature. Only studies published in English were included. METHODOLOGICAL QUALITY: Two reviewers assessed all studies for methodological quality using appropriate critical appraisal checklists from the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI) or the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI). DATA EXTRACTION: Data were extracted from included articles using the standardized data extraction tool from JBI-QARI or JBI-MAStARI. DATA SYNTHESIS: Qualitative studies were pooled through a meta-synthesis. Data from the QN studies were combined using a narrative synthesis as a meta-analysis was not possible. The researchers used a segregated mixed methods approach to integrate the QL and QN components. RESULTS: Twenty-one QL studies of high methodological quality were included. The two synthesized findings revealed that art forms could create meaning and inspire learning in undergraduate nursing education and that ABP can develop important learner outcomes/competencies for professional nursing. These synthesized findings received a moderate ConQual rating. Fifteen experimental/quasi experimental studies of moderate methodological quality were included. The narrative synthesis suggested that ABP improved nursing students' knowledge acquisition, level of empathy, attitude toward others, emotional states, level of reflective practice, learning behaviors and aspects of cognitive/ethical maturity. In five cross-sectional studies, the majority of students had a positive perspective of ABP. When the QL and QN findings were interpreted as a whole, ABP appeared to facilitate learning in the cognitive and affective domains and may be especially useful in addressing the affective domain. CONCLUSION: Nurse educators should consider using ABP as students found that this approach offered a meaningful way of learning and resulted in the development of important competencies for professional nursing. The QN studies provide a very low level of evidence that ABP improved students' knowledge acquisition, level of empathy, attitude toward others, emotional states, level of reflective practice, learning behaviors and aspects of cognitive/ethical maturity. Although the QN findings can inform future research, the evidence is not robust enough to demonstrate improved outcomes. PMID- 27941519 TI - Quality of life among adults following bariatric and body contouring surgery: a systematic review. AB - BACKGROUND: Weight loss following bariatric surgery is associated with significant improvements in obesity-related comorbidities, body satisfaction and psychosocial outcomes, at least in the short term. However, in the context of extreme weight loss, body image and appearance may worsen again because the "excess" or "loose" skin can lead to both functional and profound dissatisfaction with appearance. These concerns have led to an increasing uptake of post bariatric surgery, "body-contouring" procedures but the implications for quality of life (QoL) have not been thoroughly considered. OBJECTIVE/PURPOSE: The objective was to identify the best available evidence regarding the QoL outcomes for adults following bariatric and body contouring surgery. INCLUSION CRITERIA TYPES OF PARTICIPANTS: The review considered studies involving people aged 18 years and beyond who underwent bariatric surgery and body contouring surgery. TYPES OF INTERVENTIONS: The review considered studies that evaluated bariatric surgery as well as body contouring surgery. TYPES OF STUDIES: The review considered both experimental and epidemiological study designs. OUTCOMES: The primary outcomes were QoL as measured by validated tools at less than two years, two to five years and more than five years following body contouring surgery. The secondary outcomes were adverse events, unsatisfactory aesthetic appearance and weight gain. SEARCH STRATEGY: Six databases were searched, including Cochrane Central, MEDLINE, Embase, Web of Science, PsycINFO and CINAHL. Studies published from 1954 to 2014 were considered. Additional searches for unpublished studies were undertaken in BIOSIS citation index, Register of Current Controlled Trials and Global Health Observatory. METHODOLOGICAL QUALITY: The methodological quality of eligible studies was assessed independently by two reviewers using the Joanna Briggs Institute quality assessment tool. DATA EXTRACTION: Data extraction from the included studies was undertaken and summarized independently by two reviewers using the standardized Joanna Briggs Institute data extraction tool. DATA SYNTHESIS: Studies were too heterogeneous and could not be pooled in statistical meta-analysis. Therefore, the data results are presented as a narrative summary in relation to the outcomes of interest. RESULTS: Nine quantitative studies (four comparable cohort studies, including two group design and two four-group designs and five descriptive or case-series studies) were included in the review. The included studies reported significant clinical improvements in appearance, wellbeing and QoL. These included primary outcomes pointing to body image satisfaction, improved self-esteem and confidence, improved physical function/pain and improved social function. The secondary outcomes were related to adverse events in the early postoperative period and reported wound healing problems, including seromas, partial necrosis, dehiscence, hematoma and anemia because of blood loss. Also, some data sets shed light on appearance-related distress and body dysphoria post surgery associated with visible scars and contour deformities. CONCLUSION: Body contouring surgery has been shown to have positive benefits, especially in relation to improved wellbeing, function and QoL. However, adjustment to changing body image following body contouring is both challenging and empowering and seems to be a transitional process. PMID- 27941520 TI - Self-management for patients with inflammatory bowel disease in a gastroenterology ward in China: a best practice implementation project. AB - BACKGROUND: Globally, there is an increasing incidence of inflammatory bowel disease. It is very important for patients to be involved with self-management that can optimize personal heath behavior to control the disease. OBJECTIVES: The aim of this project was to increase nursing staff knowledge of inflammatory bowel disease discharge guidance, and to improve the quality of education for discharged patients, thereby improving their self-management. METHODS: A baseline audit was conducted by interviewing 30 patients in the gastroenterology ward of Huadong Hospital, Fudan University. The project utilized the Joanna Briggs Institute's Practical Application of Clinical Evidence System and Getting Research Into Practice audit tools for promoting quality of education and self management of patients with inflammatory bowel disease. Thirty patients were provided with written materials, which included disease education and information regarding self-management. A post-implementation audit was conducted. RESULTS: There was improvement of education prior to discharge and dietary consultancy in the gastroenterology ward. Self-management plans utilizing written materials only were not sufficient for ensuring sustainability of the project. CONCLUSIONS: Comprehensive self-management education can make a contribution to improving awareness of the importance of self-management for patients with inflammatory bowel disease. PMID- 27941521 TI - Prevention, assessment and management of post-dialysis fatigue in patients attending in-center hemodialysis: a best practice implementation project. AB - BACKGROUND: The hemodialysis (HD) population experiences a myriad of disease related symptoms that are often not recognized and/or not treated. Post-dialysis fatigue is a frequent complaint of HD patients following a dialysis session, and there is currently no evidence-based approach to alleviate this problem. OBJECTIVES: The object of this best practice implementation project was to implement evidence-based strategies for the prevention, assessment and management of post-dialysis fatigue, with a view to lessening the disease burden experienced by in-center HD patients. METHODS: The project used the Joanna Briggs Institute's Practical Application of Clinical Evidence System and Getting Research Into Practice audit tool for promoting change in clinical practice. A baseline audit was conducted, followed by implementation of evidence-based strategies with a focus on staff and patient education. A follow-up audit was performed to assess the effects of the interventions on compliance with best practice. RESULTS: The baseline audit showed that there was no evidence-based approach to prevention, assessment and management of post-dialysis fatigue in place, with only two of the 11 audit criteria showing compliance greater than 50%. Education programs for nursing staff and patients were established, along with the implementation of additional strategies to prevent, assess and manage post-dialysis fatigue. The follow-up audit showed a dramatic increase in the utilization of evidence-based strategies, with ten of the 11 audit criteria achieving above 75% compliance. CONCLUSION: An evidence-based program to prevent, assess and manage post-dialysis fatigue was successfully implemented. Future studies may reveal if this project has lessened the disease burden experienced by in-center HD patients. PMID- 27941522 TI - Nystagmus and central vestibular disorders. AB - PURPOSE OF REVIEW: This review will cover the recent advances in clinical and laboratory features, pathophysiology, and treatment of central vestibular disorders. RECENT FINDINGS: Several features and mechanisms of central nystagmus have been identified over the years. Application of head impulse tests and vestibular evoked myogenic potentials has expanded our understanding of altered processing of canal-driven and otolith-driven vestibular signals in lesions involving the central vestibular structures. Integrated approach based on the symptoms and neurotologic signs enhances the diagnostic accuracy of acute vascular vertigo. Identification of isolated central vestibular syndromes has improved the diagnosis of central vertigo and our understanding of anatomic and functional organization of the central vestibular structures. SUMMARY: With the developments of clinical and laboratory neurotology, the spectrum of central vestibular disorders has expanded markedly over the years. PMID- 27941523 TI - 3-D spatial memory and navigation: functions and disorders. AB - PURPOSE OF REVIEW: The aim of this review is to report on the specialized neuronal systems mediating spatial orientation and navigation discovered in animal experiments. These findings have important implications for the clinical management of patients with vestibular disorders or dementia and for translational research in these fields. RECENT FINDINGS: The following anatomically and functionally separate, but nevertheless cooperative cell types have been characterized: angular head velocity cells and head direction cells, which depend on vestibular input and interact with place cells and grid cells, which represent position and distance. The entire system is thought to encode internal cognitive maps whose spatial data can be utilized for navigation and orientation. Flying and swimming species use spatial orientation and navigation isotropically, i.e., in the earth-horizontal and vertical directions, whereas ground-based species, including humans, perform better in the earth-horizontal plane (anisotropically). Examples of clinical disorders with deficits of spatial orientation and navigation are bilateral peripheral vestibulopathy, mild cognitive impairment, and dementia. SUMMARY: Testing spatial orientation and navigation should become an integral part of routine neurological examinations, especially in the elderly. Also desirable are the further development and standardization of simple and reliable smart phone-based bedside tests to measure these functions in patients. PMID- 27941524 TI - Neuroprotection and visual function after optic neuritis. AB - PURPOSE OF REVIEW: This article discusses the advantages and pitfalls of testing neuroprotective treatment strategies in patients suffering from optic neuritis. RECENT FINDINGS: Spectral domain optical coherence tomography now permits for automated segmentation of individual retinal layers. The peripapillary retinal nerve fibre layer (pRNFL) has been used in 13 of the 15 trials reviewed. Twelve trials also made use of electrophysiology. Overestimation of good visual recovery in the past has recently been recognized. Assessment of low contrast visual acuity and colour vision are now mainstream. SUMMARY: The availability of highly accurate and robust trial outcome measures has facilitated research on this topic. A single long-term structural outcome measurement of the pRNFL is sufficient. For shorter term, assessments of the ganglion cell/inner plexiform layer and axonal birefringence are promising. Longitudinal blood levels of neurofilament proteins permit to recognize axonal loss at presentation and monitor changes longitudinally. Inner nuclear layer volume changes relate to inflammatory disease activity.Pitfalls are related to the timing of events. Hyperacute recruitment is needed for future trials. The onset of demyelination is not known, which complicates timing of electrophysiological recordings. Optic disc oedema precludes the use of the pRNFL from the affected eye as a baseline variable. The concomitant use of corticosteroids complicates interpretation of trial data. PMID- 27941525 TI - Alcohol-Sensitive Generalized Dystonia. AB - We report the case of a 29-year-old male patient with a generalized and progressive dystonia that led him unable to stand. Multiple antidystonic treatments were tried without benefit. Alcohol test was positive with a dramatic improvement. To the best of our knowledge, this is the first reported case of generalized dystonia without other clinical manifestations sensitive to alcohol. PMID- 27941526 TI - Epigallocatechin Gallate Extends Therapeutic Window of Recombinant Tissue Plasminogen Activator Treatment for Brain Ischemic Stroke: A Randomized Double Blind and Placebo-Controlled Trial. AB - OBJECTIVES: Recombinant tissue plasminogen activator (rt-PA) is a safe and effective treatment for acute brain ischemia stroke, albeit with a narrow therapeutic window. We aimed to assess the effect of epigallocatechin gallate (EGCG) in extending the rt-PA treatment window in this clinical trial among stroke patients. METHODS: Patients were randomly assigned according to their onset-to-treatment time (OTT) and were then treated with rt-PA simultaneously with EGCG or placebo. Treatment outcome was assessed by the National Institutes of Health stroke scale (NIHSS) and plasma levels of matrix metalloproteinases (MMP)-2 and 9. RESULTS: Administration of EGCG significantly improved treatment outcomes of patients in the delayed OTT strata, as evidenced by improved NIHSS scores. This improved treatment outcome was likely attributed to reduction in plasma levels of both MMP-2 and 9, as indicated by strong linear correlations between both MMPs and NIHSS scores in all patients. CONCLUSIONS: Epigallocatechin gallate could potentially be used as a supplement of traditional rt-PA treatment among stroke patients, particularly those with delayed OTT, to extend the otherwise narrow therapeutic window and improve the outcome in late stroke treatment. PMID- 27941527 TI - Striatal Dopamine Transporter Modulation After Rotigotine: Results From a Pilot Single-Photon Emission Computed Tomography Study in a Group of Early Stage Parkinson Disease Patients. AB - INTRODUCTION: Several in vitro data have reported negative interference by dopamine-agonists on the expression of dopamine transporter (DAT), whereas the majority of imaging studies have shown that neither L-dopa nor dopamine-agonists interfere with DAT availability. As yet, there are no in vivo studies on DAT expression after treatment with rotigotine. METHODS: We evaluated presynaptic nigrostriatal function in 8 patients with de novo Parkinson disease (age, 59 +/- 6.2 years; male/female sex, 5/3) using 123-I- N-omega-fluoropropyl-2-beta carbomethoxy-3-beta-(4-iodophenyl)nortropane (FP-CIT) single-photon emission computed tomography before and after 3 months of treatment with rotigotine (mean dose, 7.75 +/- 1.98 mg). For data analysis, specific (left and right caudate, left and right putamen) to nonspecific (occipital cortex) binding ratios, putamen to-caudate ratios, and asymmetry indices were calculated. RESULTS: After rotigotine, motor symptoms improved in all patients (Unified Parkinson Disease Rating Scale III mean score, 11.88 +/- 2.59 vs 7.63 +/- 1.92 on therapy; P = 0.0022). Striatal FP-CIT levels showed a significant improvement in every patient at the follow-up scan. Comparisons between before and after treatment in the whole group revealed a significant improvement in FP-CIT uptake in both caudate and putamen (P < 0.001 in each nucleus). Putamen-to-caudate ratio and asymmetry indices did not show any significant difference before and after treatment. DISCUSSION: Although the study population was small, we found DAT overexpression after chronic treatment with rotigotine, presumably related to its pharmacological profile. The DAT upregulation by rotigotine in an opposite direction with respect to early Parkinson disease compensatory mechanisms might reduce the risk of dyskinesia, but it could imply less motor benefit because of less stimulation by the dopamine itself on dopaminergic receptors. PMID- 27941528 TI - Efficacy of the Treatments Used in Multiple Sclerosis: From Meta-analysis to Number Needed to Treat. AB - : The aim of this study was to analyze the efficacy of drugs used in relapsing remitting multiple sclerosis, first- and second-line drugs, using the number needed to treat (NNT) as a measure of efficacy. METHODS: Data from randomized clinical trials were analyzed for 3 categories of clinical efficacy outcomes: relapse, change in Expanded Disability Status Scale, and number of new lesions in magnetic resonance imaging. Meta-analysis results are expressed as odds ratios. RESULTS: The global odds ratio was 0.41 (95% confidence interval [CI], 0.34 0.49). For analyzed clinical outcomes, the odds ratio was less for second-line drugs (odds ratio, 2.0). For all studied clinical conditions, in the control group, 47 of 100 patients do not get benefits, compared with 25 (95% CI, 18-32 patients) of 100 for the active treatment group. The NNT was 5 patients (95% CI, 4-7 patients). For the proportion of patients free of relapses, in the control group, 56 of 100 patients had a relapse at 2 years, compared with 37 of 100 patients in the treatment group, with an NNT of 6 patients (95% CI, 5-8 patients). CONCLUSIONS: Active treatments produced statistically significant improvements compared with placebo. PMID- 27941529 TI - CHANGE OF CHOROIDAL VOLUME IN UNTREATED CENTRAL SEROUS CHORIORETINOPATHY. AB - PURPOSE: Choroidal hyperpermeability plays a central role in the pathophysiology of central serous chorioretinopathy (CSC). In active CSC undergoing treatment, choroidal thickness decreases if subretinal fluid (SRF) resolves. This study aimed to investigate the change in choroidal thickness and volume in eyes with untreated CSC. METHODS: The authors retrospectively analyzed 27 eyes with treatment-naive CSC (25 patients), who had a follow-up of 4 to 6 weeks. Retinal and choroidal volume and SRF were segmented manually and calculated using the Spectralis OCT built-in software (Spectralis; Heidelberg Engineering). RESULTS: In treatment-naive eyes with CSC, an increase in SRF was significantly associated with an increase in choroidal thickness and volume (rho = 0.93, P < 0.01). Eyes with greater baseline choroidal volume showed a significantly greater decrease in SRF during follow-up (rho = -0.47, P = 0.03). CONCLUSION: In this study, an increase in SRF was associated with an increase in both choroidal thickness and volume in eyes with treatment-naive CSC. Eyes with thicker baseline choroidal volume showed a greater reduction in SRF. PMID- 27941530 TI - SHORT-TERM EFFECTS OF EXERCISE ON OPTIC NERVE AND MACULAR PERFUSION MEASURED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To evaluate the effects of exercise on optic nerve and macular perfusion using optical coherence tomography angiography. METHODS: Thirteen eyes of 13 healthy volunteers were examined using a high-speed and high-resolution spectral domain optical coherence tomography XR Avanti with a split-spectrum amplitude decorrelation angiography algorithm. Blood pressure, heart rate, the mean area of the foveal avascular zone , and flow density on the optic nerve head and macula, before and after exercise were measured and analyzed. RESULTS: Mean patient age was 27.3 +/- 3.5 years. Heart rate, systolic and diastolic blood pressure increased significantly after exercise (P < 0.001). The mean area of the foveal avascular zone did not change significantly after exercise (before: 0.27 +/- 0.07 mm; after: 0.26 +/- 0.07 mm; P = 0.10). The peripapillary and the parafoveal flow density decreased significantly after exercise (peripapillary: before: 65.1 +/- 2.1; after: 62.3 +/- 3.0; P < 0.001 and parafoveal: before: 56.7 +/- 1.3; after: 55.6 +/- 1.5; P = 0.007). CONCLUSION: Increased physical activity induced significant changes in optic nerve and macular perfusion, which were measured using split-spectrum amplitude-decorrelation angiography optical coherence tomography angiography. In studies that aim to evaluate optic nerve and macular perfusion using optical coherence tomography angiography, it should be strongly recommended that patients rest before imaging is performed and that data concerning systemic circulation including blood pressure and pulse is included within the evaluation. PMID- 27941531 TI - Hallux valgus deformity correction without fusion in children with cerebral palsy. AB - : This study aimed to evaluate the outcomes of nonarthrodesis surgical treatment of hallux valgus (HV) deformity in children with cerebral palsy using radiographic and gait analysis parameters. There were 25 patients who had hallux valgus correction in 39 feet. The mean age at surgery was 15+/-2.8 years and the mean follow-up duration was 14.6 months. The first metatarsal osteotomy was performed in nine feet, bunionectomy in 25 feet, and Aiken osteotomy in 32 feet. None had metatarsophalangeal joint fusion. We observed a significant correlation between HV correction and other foot and ankle gait parameters. Our study showed correction of HV deformity at short-term follow-up without fusion of the metatarsophalangeal joint. LEVEL OF EVIDENCE: Level IV Therapeutic Studies. PMID- 27941532 TI - Modification of the alignment between the tibial tubercle and the trochlear groove induced by temporary hemiepiphysiodesis for lower extremity angular deformities: a trigonometric analysis. AB - : This study aimed to predict the modification of the alignment between the tibial tubercle (TT) and the trochlear groove (TG) that occurs during femoral or tibial hemiepiphysiodesis. MRI scans of 541 knees were retrospectively reviewed to determine the distances between the cranial insertion of the patellar tendon on the TT and the femoral physis (FP)/tibial physis (TP). Thereafter, we developed a trigonometric formula to calculate the predicted change of the TT-TG distance that occurs during hemiepiphysiodesis around the knee using both the planned angular correction as well as the length between the physis (both distal femoral and proximal tibial) and the insertion of the patellar tendon of the TT. This study showed that TT-FP and TT-TP distances vary very little with sex and age during growth and the mean values of FP-TT and TP-TT distances (55 and 7 mm, respectively) can thus be used in clinical settings for calculating a rough estimate of the translation of the TT position that will occur during 'guided growth'. On this subject, one can expect a 1 mm simultaneous lateral or medial transfer of the TT for every 1 degrees of angular correction during distal femoral hemiepiphysiodesis. For proximal tibial hemiepiphysiodesis, an angular correction of 8 degrees should roughly translate into a simultaneous 1 mm transfer of the TT. This study puts forward the hypothesis that a simultaneous modification of the TT-TG distance has to be expected following hemiepiphysiodesis, whether femoral or tibial. LEVEL OF EVIDENCE: III. PMID- 27941533 TI - Congenital insensitivity to pain in one family. AB - Congenital insensitivity to pain (CIP) is a rare autosomal recessive genetic disease caused by mutation in several different genes. The diagnosis requires the combined skills and cooperation of pediatricians, neurologists, radiologists, pathologists, and orthopedic surgeons. Orthopedic manifestations of CIP include delayed diagnosis of fractures, nonunions, Charcot arthropathy, avascular necrosis, osteomyelitis, joint dislocations, and heterotopic ossifications. We present case reports of two brothers with CIP with various orthopedic manifestations and methods of surgical treatment with 10 years of follow-up. PMID- 27941534 TI - Safety and efficacy of sublaminar bands and Ponte osteotomies in rigid deformity: preliminary results in a prospective series of 20 neuromuscular scoliosis patients. AB - This prospective cohort study investigated radiographic outcomes and complications over time in patients with rigid neuromuscular scoliosis treated with sublaminar bands and Ponte osteotomies. Twenty consecutive patients with neuromuscular scoliosis were treated with sublaminar bands in addition to Ponte osteotomies at and around the apex of the deformity and prospectively included. All curves were rigid, with less than 30% reduction on preoperative bending films. Cobb angle, pelvic obliquity, and shoulder obliquity were significantly corrected (P<0.01). Normal thoracic kyphosis was achieved for 85% of patients at the last follow-up. No intraoperative complications were observed. The association between Ponte osteotomies and sublaminar bands appears to be efficient for the management of rigid neuromuscular deformities in children and adolescents. No death and no permanent neurological impairment, as well as no sublaminar bands associated events were recorded. PMID- 27941535 TI - Estimation of Mycophenolic Acid Area Under the Curve With Limited-Sampling Strategy in Chinese Renal Transplant Recipients Receiving Enteric-Coated Mycophenolate Sodium. AB - BACKGROUND: The enteric-coated mycophenolate sodium (EC-MPS), whose active constituent is mycophenolic acid (MPA), has been widely clinically used for organ transplant recipients. However, its absorption is delayed due to its special designed dosage form, which results in difficulty to monitor the exposure of the MPA in patients receiving the EC-MPS. This study was aimed at developing a relatively practical and precise model with limited sampling strategy to estimate the 12-hour area under the concentration-time curve (AUC0-12 h) of MPA for Chinese renal transplant recipients receiving EC-MPS. METHODS: A total of 36 Chinese renal transplant recipients receiving the EC-MPS and tacrolimus were recruited in this study. The time point was 2 weeks after the transplantation for all the patients. The MPA concentrations were measured with enzyme-multiplied immunoassay technique for 11 blood specimens collected predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after the morning dose of EC-MPS. The measured AUC was calculated with these 11 points of MPA concentrations with the linear trapezoidal rule. Limited sampling strategy was used to develop models for estimated AUC in the model group (n = 18). The bias and precision of different models were evaluated in the validation group (n = 18). RESULTS: C4 showed the strongest correlation with the measured AUC. The best 3 time point equation was 6.629 + 8.029 * C0 + 0.592 * C3 + 1.786 * C4 (R = 0.910; P < 0.001), whereas the best 4 time point equation was 3.132 + 5.337 * C0 + 0.735 * C3 + 1.783 * C4 + 3.065 * C8 (R = 0.959; P < 0.001). When evaluated in the validation group, the 4 time point model had a much better performance than the 3 time point model: for the 4 time point model: R = 0.873, bias = 0.505 [95% confidence interval (CI), 10.159 to 11.170], precision = 13.370 (95% CI, 5.186-21.555), and 77.8% of estimated AUCs was within 85%-115% of the measured AUCs; for the 3 time point model: R = 0.573, bias = 6.196 (95% CI, -10.627 to 23.018), precision = 21.286 (95% CI, 8.079-34.492), and 50.0% of estimated AUCs was within 85%-115% of the measured AUCs. CONCLUSIONS: It demanded at least 4 time points to develop a relatively reliable model to estimate the exposure of MPA in renal transplant recipients receiving the EC-MPS. The long time span needed restricted its application, especially for the outpatients, but it could be a useful tool to guide the personalized prescription for the inpatients. PMID- 27941536 TI - LC-MS/MS Analysis of Erythrocyte Thiopurine Nucleotides and Their Association With Genetic Variants in Patients With Neuromyelitis Optica Spectrum Disorders Taking Azathioprine. AB - BACKGROUND: Azathioprine is a first-line drug in treating neuromyelitis optica spectrum disorders (NMOSD). To exhibit its bioactivity, azathioprine needs to be converted to thiopurine nucleotides (TPNs) including 6-thioguanine nucleotides (6 TGNs) and 6-methylmercaptopurine nucleotides (6-MMPNs) that are affected by genetic polymorphisms. This study aims to develop an LC-MS/MS method for the analysis of erythrocyte concentrations of TPNs and to evaluate their associations with variants of various genes (MTHFR, TPMT, HLA, SLC29A1, SLC28A2, SLC28A3, ABCB1, and ABCC4) in patients with NMOSD. METHODS: Erythrocyte 6-TGNs and 6-MMPNs were converted to their free bases 6-thioguanine and 6-methylmercaptopurine derivative by 1-hour acid hydrolysis at 95 degrees C. An LC-MS/MS method was developed, validated, and used to study 32 patients with NMOSD to determine these free bases. Genetic variants were identified by MassARRAY (Sequenom) and multiple SNaPshot techniques. The associations between genetic variants and the concentrations of TPNs or the 6-MMPNs:6-TGNs ratio were evaluated by PLINK software using linear regression. RESULTS: Methanol and water were used for separation with a total run time of 6.5 minutes. The lowest limit of quantification was 0.1 MUmol/L with an injection volume of 10 MUL. rs10868138 (SLC28A3) was associated with a higher erythrocyte concentration of 6-TGNs (P = 0.031), whereas rs12378361 (SLC28A3) was associated with a lower erythrocyte concentration of 6-TGNs (P = 0.0067). rs507964 (SLC29A1) was significantly associated with a lower erythrocyte concentration of 6-MMPNs (P = 0.024) and a lower 6-MMPNs:6-TGNs ratio (P = 0.029). CONCLUSIONS: An LC-MS/MS method for the analysis of erythrocyte TPNs was developed, validated, and used to study 32 patients with NMOSD. SLC29A1 and SLC28A3 were associated with the erythrocyte concentrations of TPNs and 6-MMPNs:6-TGNs ratio. Further studies are needed to confirm these results. PMID- 27941537 TI - Autophagy inhibitors chloroquine and LY294002 enhance temozolomide cytotoxicity on cutaneous melanoma cell lines in vitro. AB - Patients with metastatic melanoma are difficult to treat and have a very poor prognosis because of high resistance to therapy. Recent evidence indicates that tumors could overcome death through autophagy, a survival mechanism, which cancer cells use under lack of energy and nutrient deprivation. Melanoma cells have different sensitivity to temozolomide (TMZ) treatment. In this study, we showed that the combination of autophagy inhibitors chloroquine or LY294002 and TMZ induced enhanced cytotoxicity of alkylating agents on human melanoma cell lines. All assays were performed on patient-derived melanoma cell lines. The effectiveness of the combined treatment of TMZ and autophagy inhibitors was determined using an MTT assay. Next, we analyzed the expression mRNA level of Beclin 1, LC3B, and p62/STSQM1 and the relative expression of LC3B protein under combined treatment. Autophagic flux was determined by analysis of colocalization of Lysotracker Red and LC3B puncta. Apoptosis was measured by Annexin V/PI staining. Cell cycle analyses were carried out by flow cytometry. We showed that autophagy inhibition could enhance melanoma cell death combined with TMZ therapy. Chloroquine synergistically enhanced the TMZ-induced growth arrest and increased the G0/G1 population in Mel Z and Mel IL cell lines, but not Mel MTP. The expression analysis showed that autophagy involvement in TMZ enhanced cytotoxicity. Furthermore, LY294002, an early-stage autophagy, and PI3K inhibitor were found to exert similar effects. Both chloroquine and LY294002 improved the cytotoxic effect of TMZ treatment, making this combination applicable as a potent antitumor treatment for metastatic melanoma. PMID- 27941538 TI - NF1 and Neurofibromin: Emerging Players in the Genetic Landscape of Desmoplastic Melanoma. AB - Neurofibromatosis type I (NF1), a monogenic disorder with an autosomal dominant mode of inheritance, is caused by alterations in the NF1 gene which codes for the protein neurofibromin. Functionally, NF1 is a tumor suppressor as it is GTPase activating protein that negatively regulates the MAPK pathway. More recently, much attention has focused on the role of NF1 and neurofibromin in melanoma as mutations in NF1 have been found to constitute 1 of the 4 distinct genomic categories of melanoma, with the other 3 comprising BRAF, NRAS, and "triple-wild type" subtypes. In this review, we parse the literature on NF1 and neurofibromin with a view to clarifying and gaining a better understanding of their precise role/s in melanomagenesis. We begin with a historic overview, followed by details regarding structure and function and characterization of neural crest development as a model for genetic reversion in neoplasia. Melanogenesis in NF1 sets the stage for the discussion on the roles of NF1 and neurofibromin in neural crest derived neoplasms including melanoma with particular emphasis on NF1 and neurofibromin as markers of melanocyte dedifferentiation in desmoplastic melanoma. PMID- 27941539 TI - Primary Salivary Gland Type Tumors of the Thymus. AB - The existence of primary salivary gland type tumors (SGTs), similar to those occurring in the major salivary glands, is well known in the thoracic cavity. When they occur in this anatomic area, these tumors more commonly arise from the lung. However, the existence of these tumors primarily affecting the thymus, although recognized in the literature, is rather not well documented or known. In addition, contrary to the primary lung SGTs, which are predominantly of the malignant type, these tumors when occur in thymus encompass a wider spectrum of biology ranging from benign to low grade, and high grade malignancy. The recognition of SGTs in the thymus, even though rare, is important to properly address treatment and prognosis. Herein, we will discuss the numerous benign a malignant SGTs that have been described in the thymus and highlight the difficulty that these tumors may pose when occurring in the thymic area. PMID- 27941540 TI - New and Emerging Diagnostic and Prognostic Immunohistochemical Biomarkers in Prostate Pathology. AB - The diagnosis of minimal prostatic adenocarcinoma can be challenging on prostate needle biopsy, and immunohistochemistry may be used to support the diagnosis of cancer. The International Society of Urologic Pathology currently recommends the use of the basal cell markers high-molecular-weight cytokeraratin and p63, and alpha-methylacyl-coenzyme-A racemase. However, there are caveats associated with the interpretation of these markers, particularly with benign mimickers. Another issue is that of early detection of presence and progression of disease and prediction of recurrence after clinical intervention. There remains a lack of reliable biomarkers to accurately predict low-risk cancer and avoid over treatment. As such, aggressive forms of prostate cancer may be missed and indolent disease may be subjected to unnecessary radical therapy. New biomarker discovery promises to improve early detection and prognosis and to provide targets for therapeutic interventions. In this review, we present the emerging immunohistochemical biomarkers of prostate cancer PTEN, ERG, FASN, MAGI-2, and SPINK1, and address their diagnostic and prognostic advantages and limitations. PMID- 27941541 TI - Cytopathology of Follicular Cell Nodules. AB - The detection of thyroid nodules, consisting of different diseases, represents a common finding in population. Their evaluation and diagnosis are mostly achieved with fine-needle aspiration cytology (FNAC). Even though the majority of thyroid nodules are correctly diagnosed, a total of 25% to 30% of them are classified "indeterminate" comprising lesions with varying risk of malignancy and different types of management. Although the number of thyroid FNACs, including small lesions, is increasing due to the reliance upon sonographic and cytologic interpretations, there are issues concerning cytomorphologic interpretation and interobserver reproducibility. Different classification systems have tried to better define the criteria for inclusion in specific categories and to therefore reduce the rate of indeterminate diagnoses such as atypia of undetermined significance, follicular neoplasms, and suspicious for malignancy. However, the support of ancillary techniques (eg, immunocytochemistry and molecular analysis) are reshaping morphologic diagnoses made on materials obtained from FNAC. PMID- 27941542 TI - Pathophysiology of IgA Nephropathy. AB - Immunoglobulin (Ig)A nephropathy is the most prevalent primary chronic glomerular disease in the world. Studies of molecular and cellular interactions involved in the pathogenesis of IgA nephropathy have revealed several inherent abnormalities in the production and subsequent handling of IgA1. In patients with this disease, altered glycan structures in the unique hinge region of the heavy chains of IgA1 molecules lead to the exposure of antigenic determinants, which are recognized by naturally occurring antiglycan antibodies of the IgG and/or IgA1 isotype. In addition, due to a homing abnormality there is a gradual shift of mucosal IgA1 producing lymphoplasma cells from mucosal lymphoid tissue to bone marrow resulting in excess production of mucosal-type IgA1 in the systemic circulation. As a result, nephritogenic immune complexes form in the circulation and deposit in the glomerular mesangium. Deposited immune complexes induce proliferation of resident mesangial cells with increased production of extracellular matrix proteins. A number of inflammatory cytokines produced by the mesangial cells damage the filtration barrier resulting in hematuria and proteinuria ultimately leading to progressive renal damage. PMID- 27941543 TI - Is Routine Histopathologic Examination Necessary Following Tonsillectomy and/or Adenoidectomy Procedures in Pediatric Patients? AB - Tonsillectomy and/or adenoidectomy is the most common surgical procedure in ENT practice and the malignancy rate of tonsillar tissue is very rare. The purpose of the present study is to investigate the necessity of routine histopathologic examinations following tonsillectomy and/or adenoidectomy surgeries. A total of 385 patients between the age of 5 and 16 years who were admitted to our ENT clinic and underwent adenoidectomy and/or tonsillectomy between October 2008 and July 2015 participated in the study. Patient data such as age, sex, indication for surgery, and histopathologic findings were recorded prospectively. Histopathologic findings were analyzed for hyperplastic lymphoid parenchyma and malignancy. No malignancies were detected in the studied patients and all had hyperplastic lymphoid parenchyma. Unilateral tonsillar swelling, significant lesions on the tonsil or adenoid tissue, malignancy history in the head and neck region, or a mass in the neck region with weight loss must be examined histopathologically; however, we conclude that there is no need to perform histopathologic examination for patients for whom there is no clinical suspicion. A meta-analysis is needed in this regard. PMID- 27941545 TI - Microcephaly and Zika Virus Infection. PMID- 27941544 TI - Large Dentigerous Cyst Associated to Maxillary Canine. AB - Dentigerous cysts are defined as a cyst originated by separation of the follicle of dental crown of a tooth unerupted. Although most dentigerous cysts are considered developmental cysts, some cases seem to have an inflammatory origin. The aim of this study was to show a case of an 8-year-old patient, male, presenting a lesion in maxilla with large proportions. Computed tomography scans showed a hypodense image, well-defined, associated to unerupted teeth. The case was treated by enucleation of the lesion under local anesthesia. Histopathological examination confirmed the diagnostic suspicious of dentigerous cyst. Currently, 3-year follow-up period showed no signs of recurrence, and it was observed eruption of the teeth associated to the lesion. This case highlights the importance of the association between clinical and radiographic analysis together to the surgical findings, aiming the best treatment for the patient. PMID- 27941546 TI - An Analysis of Mandibular Symphyseal Graft Sufficiency for Alveolar Cleft Bone Grafting. AB - The purpose of this study was to evaluate the sufficiency of the mandibular symphysis as a donor site for unilateral and bilateral alveolar grafting, measuring both the alveolar cleft volume and maximum bone graft volume that can be harvested from the mandibular symphysis using 3-dimensional computed tomography (CT) and software in children and adults. Computed tomography data obtained from 20 unilateral and bilateral cleft lip palates patients in the preoperative period were used in this study. The patients were divided into 2 groups: children (female, n = 5; male, n = 5) and adults (female, n = 5; male, n = 5). The required bone graft volume for grafting and the maximum bone graft volume that can be harvested from the mandibular symphysis were measured based on cone beam CT data and software. The average required bone graft volume (cleft volume) for unilateral alveolar grafting was 963.51 +/- 172.31 mm in the children and 1001.21 +/- 268.16 mm in the adults. The average required bone graft volume for bilateral alveolar grafting was 1457.82 +/- 148.18 mm in the children and 2189.59 +/- 600.97 mm in the adults. The average the mandibular symphysis bone graft volume was 819.29 +/- 330.85 mm in the children and 2164.9 +/- 1095.86 mm in the adults. The results demonstrated that the mandibular symphysis region provided an adequate bone volume for alveolar grafting in adults with unilateral alveolar clefts. However, it is difficult to standardize these results, due to cleft volume and graft volume that could be harvested from the mandibular symphysis are highly variable among individuals. PMID- 27941547 TI - Nasal Septal Schwannoma: Advances in Diagnosis and Treatment. AB - The nasal septum is one of the rarest sites of origin of schwannomas. Recently, as the authors experienced a patient with nasal septal schwannoma completely removed by transnasal endoscopic approach, the authors tried to review all the literatures reported since Berlucchi's report in 2000. To the best of our knowledge, only 18 patients with nasal septal schwannoma in the literatures written by English-language have been reported. The purpose of this study is to describe our recent experience and thoroughly review our collected patients with nasal septal schwannoma with particular emphasis on therapeutic options. Additionally, it is to describe the changes in clinical symptoms, diagnosis, and treatment of nasal septal schwannoma by comparing our data with Berlucchi's data. Based on our review, the authors suggest some conclusions. First, since common symptoms were nonspecific like other intranasal tumors, the authors should keep in mind that nasal septal schwannoma is included in the differential diagnosis of unilateral nasal mass pathologies with a high degree of suspicion on the basis of the endoscopic findings. Second, although there is no diagnostic computed tomography (CT) finding of nasal septal schwannoma, CT scan with contrast enhancement is helpful in defining the origin and location of the tumor and the involvement of vital structures. Third, combined immunohistochemical staining for S-100 protein, calretinin, and CD56 in addition to the light microscopic findings can be very useful as a simple, easy, and reliable method for definite diagnosis. Last, transnasal endoscopic surgery is the most suitable approach for treating any size and location of nasal septal schwannomas. PMID- 27941548 TI - Nasal Septal Chain Suture: A New Suturing Technique. AB - As a new technique for suturing the nasal septum, the nasal septal chain suture has been described in this study, and compared with nasal packing and the quilting suture technique in terms of patient comfort after septoplasty. A total of 75 patients were evaluated in 3 groups: Merocel nasal packing group, absorbable quilting suture group, and nonabsorbable nasal septal chain suture group. The symptoms of these patients were evaluated using the nasal obstruction symptom evaluation (NOSE) scale and rhinomanometry measurements. The NOSE scale values were significantly higher on the postoperative 1st and 3rd days in the nasal packing group (P < 0.001 and P < 0.001, respectively). The nasal resistance was significantly lower (P = 0.011) and the nasal airflow significantly higher (P < 0.001) in the suture groups on the postoperative 3rd day. The use of nasal packing was found to shorten the surgery duration significantly (P < 0.001), while there was no difference between the 2 suture groups (P = 1.000). There was significantly severe pain during the removal of the nasal packing when compared to the nasal septal chain suture removal (P < 0.001), but there was no difference in the bleeding (P = 0.460). Overall, nasal septal sutures significantly improve patient comfort during the postoperative period, when compared to nasal packing, with an earlier return to nasal respiration. The nasal septal chain suture that has been described in this study for the first time can be an alternative to nasal packing and the nasal septal suture techniques currently in use, since both absorbable and nonabsorbable materials can be used, it is easy to remove, and there is no pain during the suture removal. PMID- 27941549 TI - A Surface-Based Spatial Registration Method Based on Sense Three-Dimensional Scanner. AB - OBJECTIVE: The purpose of this study was to investigate the feasibility of a surface-based registration method based on a low-cost, hand-held Sense three dimensional (3D) scanner in image-guided neurosurgery system. METHODS: The scanner was calibrated prior and fixed on a tripod before registration. During registration, a part of the head surface was scanned at first and the spatial position of the adapter was recorded. Then the scanner was taken off from the tripod and the entire head surface was scanned by moving the scanner around the patient's head. All the scan points were aligned to the recorded spatial position to form a unique point cloud of the head by the automatic mosaic function of the scanner. The coordinates of the scan points were transformed from the device space to the adapter space by a calibration matrix, and then to the patient space. A 2-step patient-to-image registration method was then performed to register the patient space to the image space. RESULTS: The experimental results showed that the mean target registration error of 15 targets on the surface of the phantom was 1.61+/-0.09 mm. In a clinical experiment, the mean target registration error of 7 targets on the patient's head surface was 2.50+/-0.31 mm, which was sufficient to meet clinical requirements. CONCLUSIONS: It is feasible to use the Sense 3D scanner for patient-to-image registration, and the low-cost Sense 3D scanner can take the place of the current used scanner in the image guided neurosurgery system. PMID- 27941551 TI - Double Thyroglossal Duct Cysts in an Adult. AB - Double thyroglossal duct cysts (TDCs) are a very rare congenital malformation. Herein, we report a rare case of double TDCs, one below the hyoid bone and the other at the base of the tongue. Clinicians should be aware that TDCs can occur as multiple cystic lesions. Preoperative radiological examinations should be performed for an accurate diagnosis of double TDCs. PMID- 27941552 TI - Modified Heavy Wire Twister as an Efficient Screw Holder and Screw Driver in Maxillofacial Surgery. PMID- 27941550 TI - Examining Velopharyngeal Closure Patterns Based on Anatomic Variables. AB - The purpose of this study was to use three-dimensional magnetic resonance imaging to correlate velopharyngeal closure patterns with velopharyngeal anatomic structural characteristics. Thirty-eight participants (18 females and 20 males) between 19 and 32 years of age participated in the study. Participants were evaluated using magnetic resonance imaging and nasopharyngoscopy to determine closure pattern type and their relationship to anatomic characteristics believed to influence velopharyngeal closure. Structural anatomic measures were completed in the vertical (nasopharyngeal length) and horizontal (nasopharyngeal width) planes. Anterior to posterior dimensions of pharyngeal depth, posterior pharyngeal wall thickness, velar length, effective velar length, and adenoid thickness were also completed. Velar length and adenoid thickness varied based on closure patterns, with coronal closure pattern demonstrating significantly larger values than circular closure pattern. There were no statistically significant differences for effective velar length, pharyngeal depth, nasopharyngeal length, posterior pharyngeal wall thickness, and nasopharyngeal width based on the type of closure pattern. Closure patterns varied by sex, with females demonstrating more circular closure patterns than males who demonstrated more coronal closure patterns. Nasopharyngeal length, velar length, and nasopharyngeal width also varied by sex, with males demonstrating significantly larger values than females. Statistically significant differences were observed in velopharyngeal anatomic structural measures and sex during evaluations of closure patterns. These preliminary findings indicate that the length of the velum and thickness of the adenoids may have the greatest impact on velopharyngeal closure patterns. PMID- 27941553 TI - The Transcranial Stab Wound and the Life-Saving Zygomatic Arch Clinical Report. AB - A 58-year-old man presented to the neurosurgical emergencies for a transzygomatic transcranial stab wound with a retained broken knife. The patient was neurologically intact. After radiographic evaluation the knife was found to be penetrating the temporal lobe, neighboring the intracavernous portion of the carotid artery. The patient was successfully managed in a conservative way. No abnormalities were seen at 12 months of follow-up. Dealing with penetrating head injuries is a usual condition in neurosurgical practice. Some situations are though really challenging, especially when the offending object is still in place, with a close connection to vital structures. This clinical reports an unusual penetrating head injury, highlighting the importance of careful radiographic evaluation and trying to discuss clear management options. PMID- 27941554 TI - Genetic Etiology in Nonsyndromic Mandibular Prognathism. AB - Mandibular prognathism (MP) is considered to be a cranial-facial disorder resulting from the interaction between genes and environment. Recent studies have demonstrated that susceptible chromosomal regions and candidate genes may be responsible for MP. In this study, the authors present current views on the effect of genetic components in nonsystematic mandibular prognathism, in order to clarify the genetic etiology of MP. Data source were Electronic databases, manual searching, and reference lists checking, up to April 2016. Study selection, level of evidence assessment, and data extraction were done by 2 individuals in duplicate. Ninety-one studies were retrieved in initial electronic and manual search, and based on the established inclusion and exclusion criteria, 15 were selected for the review. In result, loci 1p36, 1q32.2, 1p22.3, 4p16.1, 6q25, 19p13, 14q24.3, 14q31.1, and 14q31.2 were thought to harbor genes that confer susceptibility to MP. Genes Matrilin-1, ADAMTS1, COL2A1, and EPB41 seemed to be strongly associated with MP while gene of growth hormone receptor was in dispute. Genetic components appeared to be associated with MP. However, in view of the variety of populations and results in related publications, further studies are necessary to clarify the genetic etiology of MP. PMID- 27941555 TI - What Postoperative Outcome Measures Link Joint Stability to Patient Satisfaction? AB - Total knee arthroplasty is a common, effective treatment for disabling arthritis of the knee. However, not all patients receiving total knee arthroplasty achieve what is considered an optimal outcome, and not all patients report high satisfaction with their results. Because the focus of attention increasingly turns to optimizing outcomes and utilization of healthcare resources, it is worthwhile to review the array of available tools and techniques for quantifying postoperative outcomes after knee arthroplasty and identify how these might be used to guide refinement of the treatment to achieve even better and more predictable outcomes. This review summarizes current methods for assessing postoperative outcomes on a biomechanical basis, organizes them into three complementary domains, and suggests how these domains must be linked to address the titular question. PMID- 27941557 TI - Performance of 4 Immunohistochemical Phosphohistone H3 Antibodies for Marking Mitotic Figures in Breast Cancer. AB - BACKGROUND: Phosphohistone H3 (PHH3) has been suggested to facilitate and improve mitotic activity assessment in breast cancer and other tumor entities, but the reliability of respective immunohistochemical antibodies has not yet been compared for routine purposes. Our aim was to test the performance of 4 different PHH3 antibodies on a series of highly proliferating breast cancers with good preservation of morphology. METHODS: Four commercially available PHH3 antibodies were tested on 9 grade 3 invasive breast cancers processed in the same batch. We analyzed the number of antibody stained and nonstained mitotic figures as well as the total of cells observed in 10 high power fields per tumor to calculate sensitivity, specificity, and accuracy of the respective antibodies for staining mitotic figures, taking morphologically defined mitotic figures as gold standard. RESULTS: Sensitivity, specificity, and accuracy of the respective PHH3 antibodies for staining mitotic figures were 54.51%, 99.98%, and 98.79% for Cell Marque, 87.48%, 67.62%, and 67.47% for Epitomics, 98.62%, 99.73%, and 99.49% for Merck 06 570, and 99.74%, 99.52%, and 99.51% for Merck 09-797, respectively. Sensitivity was lowest for telophase. In statistical analysis, the Cell Marque antibody demonstrated significantly lower sensitivity and Epitomics substantially lower sensitivity and specificity than Merck 06-570 and Merck 09-797 antibodies (P<0.0001, respectively). CONCLUSIONS: Performance and reliability varied significantly between the 4 tested antibodies. For faster identification of mitotic hot spots and as potential marker in digital image analysis, the Merck antibodies seem to be most suitable. PMID- 27941556 TI - Preclinical Evaluation of Photoacoustic Imaging as a Novel Noninvasive Approach to Detect an Orthopaedic Implant Infection. AB - INTRODUCTION: Diagnosing prosthetic joint infection (PJI) poses significant challenges, and current modalities are fraught with low sensitivity and/or potential morbidity. Photoacoustic imaging (PAI) is a novel ultrasound-based modality with potential for diagnosing PJI safely and noninvasively. MATERIALS: In an established preclinical mouse model of bioluminescent Staphylococcus aureus PJI, fluorescent indocyanine green (ICG) was conjugated to beta-cyclodextrin (CDX ICG) or teicoplanin (Teic-ICG) and injected intravenously for 1 week postoperatively. Daily fluorescent imaging and PAI were used to localize and quantify tracer signals. Results were analyzed using 2-way analysis of variance. RESULTS: Fluorescence clearly localized to the site of infection and was significantly higher with Teic-ICG compared with CDX-ICG (P = 0.046) and ICG alone (P = 0.0087). With PAI, the photoacoustic signal per volumetric analysis was substantially higher and better visualized with Teic-ICG compared with CDX ICG and ICG alone, and colocalized well with bioluminescence and fluorescence imaging. CONCLUSION: Photoacoustic imaging successfully localized PJI in this proof-of-concept study and demonstrates potential for clinical translation in orthopaedics. PMID- 27941558 TI - Increased Immunoglobulin G4-positive Plasma Cells in Lymphadenoma of the Salivary Gland: An Immunohistochemical Comparison Among Lymphoepithelial Lesions. AB - BACKGROUND: Lymphadenoma (LA) of the salivary gland, nonsebaceous type, is an uncommon benign lymphoepithelial neoplasm. The histogenesis of the lymphoid component of LA is under debate as in Warthin's tumor. A recent study has described immunoglobulin (Ig) class switching to IgG4 in a subset of Warthin's tumors. The aim of this study is to evaluate IgG4 status of LA and presume the role of IgG4 status in pathogenesis of LA. MATERIALS AND METHODS: The distribution of IgG-positive and IgG4-positive cells was compared by immunohistochemistry among 15 lymphoepithelial lesions of the salivary gland (8 LAs, 3 lymphoepithelial carcinomas, and 4 lymphoepithelial cysts). Epstein-Barr virus in situ hybridization was also performed. RESULTS: IgG-positive and IgG4 positive plasma cells were observed in all cases, but to a remarkable degree (IgG4>100/hpf) in 2 of 8 LAs. The IgG4 plasma cells in LA were distributed in interfollicular areas and in the vicinity of epithelial nests. Among all cases, the mean number of IgG4 plasma cells was not correlated with the presence of germinal centers (12/15) or Epstein-Barr virus positivity (2/15). CONCLUSIONS: Increased IgG4 plasma cells in LA suggest involvement of an immune reaction in the pathogenesis of LA similar to Warthin's tumor. PMID- 27941560 TI - Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine: Part 4: Tissue Tools for Quality Assurance in Immunohistochemistry. AB - The numbers of diagnostic, prognostic, and predictive immunohistochemistry (IHC) tests are increasing; the implementation and validation of new IHC tests, revalidation of existing tests, as well as the on-going need for daily quality assurance monitoring present significant challenges to clinical laboratories. There is a need for proper quality tools, specifically tissue tools that will enable laboratories to successfully carry out these processes. This paper clarifies, through the lens of laboratory tissue tools, how validation, verification, and revalidation of IHC tests can be performed in order to develop and maintain high quality "fit-for-purpose" IHC testing in the era of precision medicine. This is the final part of the 4-part series "Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine." PMID- 27941561 TI - Sporadic Burkitt Lymphoma Presenting as Intestinal Polyposis in a Child. PMID- 27941559 TI - Expression of CAS/CSE1L, the Cellular Apoptosis Susceptibility Protein, Correlates With Neoplastic Progression in Barrett's Esophagus. AB - BACKGROUND: Identifying the molecular switch responsible for the neoplastic progression of Barrett's esophagus (BE) and initiation of adenocarcinoma (ADC) is clinically essential and it will have a profound impact on patient diagnosis, prognosis, and treatment. The cellular apoptosis susceptibility gene CAS/CSE1L is overexpressed in various cancers, including a rare report on esophageal ADC; however, its expression in BE neoplasia has not been addressed. MATERIALS AND METHODS: We investigated the expression of the CAS/CSE1L protein immunohistochemically in 56 esophageal resection specimens for ADC arising in BE. For each specimen, a full representative section of the invasive ADC was selected to include, when possible, BE, low-grade dysplasia (LGD) and high-grade dysplasia (HGD). Samples were stained for CAS/CSE1L expression using a rabbit polyclonal antibody recognizing the N-terminus of human CAS/CSE1L. Protein expression levels were measured using the Allred semiquantitative scoring system. The data were evaluated using chi statistical analysis. Gene expression Omnibus was queried for CAS/CSE1L and BE neoplasia. RESULTS: We found minimal to absent CAS/CSE1L in all BE tissue samples; however, CAS/CSE1L was upregulated in 60% of LGD and overexpressed in HGD and ADC. The results were statistically significant (P<0.05). The localization of CAS/CSE1L protein was nuclear in BE; it became nuclear and cytoplasmic in LGD and HGD, and predominantly cytoplasmic in ADC. A similar progressive increase was observed for CAS/CSE1L gene expression. CONCLUSION: These findings show changes in CAS/CSE1L during BE progression. CAS/CSE1L may represent a potential marker for dysplasia/carcinoma. PMID- 27941563 TI - The Role of Collagen IV and Cytokeratin 5/6 Immunohistochemistry in Identifying Subtypes of Hereditary Epidermolysis Bullosa. AB - Hereditary epidermolysis bullosa (EB) constitute a genodermatosis group with variable clinical severity. Biopsies diagnosed as EB in the last 4 years were retrieved from the database of the king Khalid University Hospital and military hospital lab at Saudi Arabia. The current study was performed to examine the diagnostic usefulness of immunohistochemistry, as compared with electron microscopic examination, for subclassification of HEB. Fourteen cases were studied. Collagen IV immunostain was located above the blister in all dystrophic EB cases, and below the blister in all cases of epidermolytic and junctional EB. Cytokeratin 5/6 was visible above the blister in all cases of dystrophic and junctional types EB. In 2 out of 4 cases of epidermolytic EB, cytokeratin 5/6 was seen only above the cleft, whereas 1 case revealed positivity above and below the blister. One epidermolytic EB case showed scattered fragments of keratinocytes inside the blister. PMID- 27941562 TI - Clear Cell Variant of Calcifying Epithelial Odontogenic Tumor: A Case Report and Preliminary Immunohistochemical Study of the SHH Pathway. PMID- 27941564 TI - Paired Box 5 (PAX5) Expression in Poorly Differentiated Neuroendocrine Carcinoma of the Gastrointestinal and Pancreatobiliary Tract: Diagnostic and Potentially Therapeutic Implications. AB - Paired Box 5 (PAX5), a well-established B-cell marker, is preferentially expressed in small cell lung carcinoma and regulates the transcription of c-Met, offering a potential for therapeutic target. Its expression in poorly differentiated neuroendocrine carcinoma (PDNEC) of the digestive system has not been systemically evaluated. Archived pathology materials from 38 PDNEC in the gastrointestinal (GI) and pancreatobiliary (PB) tract were reviewed. Representative tumor sections were subject to immunohistochemical stain for PAX5, c-Met, and CD20. The extent of the staining [focal (<10%), patchy (10% to 50%), and diffuse (>50%)] and intensity (1+ to 3+) was evaluated. In total, 38 cases of well-differentiated neuroendocrine tumors from GI/PB tract served as controls. Nuclear PAX5 staining was observed in 16 (42%) cases in total, in 46% (11/24) of large cell neuroendocrine carcinoma, 67% (4/6) of small cell neuroendocrine carcinoma, and 13% (1/8) of mixed adenoneuroendocrine carcinoma, with diffuse (8), patchy (4), or focal (4) staining. The intensity was 3+ (2), 2+ (6), and 1+ (8). PAX5 expression was common in ampullary (4/5) and gastroesophageal junctional/esophageal (5/9) PDNEC. Two (5%) of 38 well-differentiated neuroendocrine tumors were positive for PAX5. Three PAX5 positive PDNEC showed weak cytoplasmic c-Met immunolabeling. CD20 was negative in all tumors. Our data show that PAX5 is commonly expressed in PDNEC of the GI/PB tract including small cell neuroendocrine carcinoma. This observation warrants a cautious approach when interpreting small biopsy of poorly differentiated neoplasms, especially when lymphoma is considered in the differentials. Further study of PAX5/c-Met signaling pathway and its potential therapeutic value in GI/PB PDNEC is warranted. PMID- 27941565 TI - Clinicopathologic Correlates of Helicobacter pylori in Gastric Mucosa. PMID- 27941566 TI - Folate Receptor Alpha Expression in Platinum Resistant/Refractory Ovarian Carcinomas and Primary Endocervical Adenocarcinomas. AB - INTRODUCTION: Treatment of advanced stage ovarian carcinoma is challenging, and despite surgical treatment and chemotherapy, the 5-year survival rate is estimated around 30%. Early recurrence and resistance to platinum-based chemotherapy are associated with poor prognosis and limited response to available second-line chemotherapy. The relative incidence of endocervical adenocarcinoma (EAC) compared with squamous cell carcinoma is increasing. Although the first line treatment modality for early stage EAC is surgical resection, for locally advanced disease chemoradiation or neoadjuvant chemotherapy is used. Recently, folate along with its receptor alpha (FRA) has been studied as a potential target in gynecologic malignancy. The objective of this study was to elucidate FRA expression in chemotherapy resistant ovarian cancer and primary EAC. METHODS: FRA expression was evaluated in tissue samples in an epithelial ovarian tumor microarray and 2 study groups: platinum resistant ovarian cancer and primary EAC. Staining intensity was analyzed with a semiquantitative staining algorithm. RESULTS: FRA expression was positive in 32 of 40 (80%) ovarian tumors in the control group. In the platinum resistant ovarian cancer group, FRA was expressed in all 30 samples with moderate to strong staining. None of the EAC samples stained positive for FRA expression. CONCLUSIONS: FRA expression occurs frequently in epithelial ovarian cancer. Our data supports that FRA expressions are maintained after chemotherapy treatment. Folate targeted therapies may be most useful in patients with chemotherapy resistant disease based on high levels of FRA expression in these tumors. There is likely no benefit to folate therapy as an adjuvant treatment in EAC. PMID- 27941567 TI - A Serous Peritoneal Cancer Revealing Itself With Double Breast Cancer Metastases in 2 Different Periods. AB - A 72-year-old woman presented with a mass on the right axilla. This was thought to be an occult breast cancer case, and the patient was treated with modified radical mastectomy, followed by hormonotherapy. Two years later she presented with incarcerated umbilical hernia. Pathology revealed Sister Mary Joseph's nodule inside the hernia sac. Further evaluation revealed that the primary tumor was papillary serous carcinoma of the peritoneal surface. The patient received adjuvant chemotherapy. Two years later the metastatic tumor was located on the other breast. The disease progressed gradually, and the patient eventually died from disseminated disease. This case is extraordinary in that it first presented with axillary metastasis without abdominal involvement and then later metastasized to the other breast after a long disease-free period. PMID- 27941568 TI - The Family of beta-Catenin Ovarian Tumors. PMID- 27941569 TI - HPV-associated oropharyngeal squamous cell carcinoma. AB - Human papillomavirus (HPV) can infect the tonsillar tissues of the oropharynx and is associated with oropharyngeal squamous cell carcinoma. This article provides an overview to guide primary care providers in screening patients for oropharyngeal cancer and making appropriate referrals. The article also reviews available HPV vaccines and immunization adherence rates. PMID- 27941570 TI - Assessing acquired rhabdomyolysis in adults. AB - The presentation of patients with rhabdomyolysis is variable and can range in severity from asymptomatic serum elevations of creatine kinase to life threatening electrolyte disturbances and acute kidney injury. Clinicians must have a high suspicion for rhabdomyolysis and be familiar with the risk factors for developing this condition. This article focuses on prompt recognition and evidence-based approaches to diagnose and treat rhabdomyolysis. PMID- 27941571 TI - Clinical and Histopathological Features of Post Burn Pruritus. AB - The aim of the study was to evaluate the clinical and histopathological characteristics of patients with post burn pruritus. The authors took skin samples from 62 burn patients with or without pruritus. The measured skin condition includes thickness and paresthesia. Various clinical features were rated on patient assessment scale (PSAS) and observer scar assessment scale. The samples were stained with hematoxylin & eosin, Masson's trichrome, Verhoeff's elastic, and toluidine blue stain. The stained samples were analyzed in terms of epidermal thickness, mononuclear cell infiltration, collagen bundles, elastic fibers, and mast cell distribution. A total of 62 patients were divided into group A (43 patients with pruritus) and group B (19 patients without). The mean (+/-SD) intensity of itch in group A patients was 4.58 (+/-3.24). Group A patients had thickened epidermises and higher scores on the PSAS and observer scar assessment scale, especially on the PSAS score. Sensations, including stinging and electric shock sensations, were more frequent in group A than in group B. Histological analysis revealed that group A patients had thinner collagen bundles and more increased mast cell counts, while others did not. Patients suffering from post burn pruritus had distinctive clinical and histopathological features, such as prominent mast cell deposition and thin collagen bundles, compared with group B patients. These results may help better understand post burn pruritus. PMID- 27941572 TI - A CASE OF FULL-THICKNESS MACULAR HOLE IN EYE WITH FOCAL CHOROIDAL EXCAVATION. AB - PURPOSE: To report an association between a Stage 4 full-thickness macular hole and focal choroidal excavation. METHODS: Case report. RESULTS: A 46-year-old male patient with high myopia was referred for macular hole surgery and found to have an associated focal choroidal excavation. The patient underwent uneventful combined procedure with closure of macular hole. CONCLUSION: Successful macular hole surgery can be achieved even in the presence of focal choroidal excavation. PMID- 27941573 TI - In-Flight Injuries Involving Children on Commercial Airline Flights. AB - BACKGROUND: More than 3 billion passengers are transported every year on commercial airline flights worldwide, many of whom are children. The incidence of in-flight medical events (IFMEs) affecting children is largely unknown. This study seeks to characterize pediatric IFMEs, with particular focus on in-flight injuries (IFIs). METHODS: We reviewed the records of all IFMEs from January 2009 to January 2014 involving children treated in consultation with a ground-based medical support center providing medical support to commercial airlines. RESULTS: Among 114 222 IFMEs, we identified 12 226 (10.7%) cases involving children. In flight medical events commonly involved gastrointestinal (35.4%), infectious (20.3%), neurological (12.2%), allergic (8.6%), and respiratory (6.3%) conditions. In addition, 400 cases (3.3%) of IFMEs involved IFIs. Subjects who sustained IFIs were younger than those involved in other medical events (3 [1-8] vs 7 [3-14] y, respectively), and lap infants were overrepresented (35.8% of IFIs vs 15.9% of other medical events). Examples of IFIs included burns, contusions, and lacerations from falls in unrestrained lap infants; fallen objects from the overhead bin; and trauma to extremities by the service cart or aisle traffic. CONCLUSIONS: Pediatric IFIs are relatively infrequent given the total passenger traffic but are not negligible. Unrestrained lap children are prone to IFIs, particularly during meal service or turbulence, but not only then. Children occupying aisle seats are vulnerable to injury from fallen objects, aisle traffic, and burns from mishandled hot items. The possible protection from using in-flight child restraints might extend beyond takeoff and landing operations or during turbulence.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 27941574 TI - Comparison Between Retrograde and Antegrade Peripheral Venous Cannulation in Intensive Care Unit Patients: Assessment of Thrombus Formation. AB - BACKGROUND: Antegrade cannulation of peripheral veins is the usual practice. Blood stasis between a catheter and the wall of the vein or at its tip in addition to catheter-induced phlebitis may initiate a thrombosis. The use of retrograde ventriculojugular shunts against the direction of the blood flow with resultant decrease in the incidence of venous thrombosis encouraged us to compare retrograde versus conventional antegrade peripheral venous cannulation. METHODS: Monocentric, nonblinded, prospective observational cohort of 40 intensive care unit patients receiving 2 peripheral venous catheters in upper limbs, 1 inserted in the direction of blood flow (antegrade cannula) and the other inserted in an opposite direction to blood flow (retrograde cannula). Daily ultrasound assessment of the angle between the catheter and the vascular wall was done to detect onset and progression of thrombus formation. RESULTS: The study included 40 patients, aged 46.7 +/- 10.132 years. The incidence of thrombus formation was 100% in both techniques. The onset time of thrombus formation between the catheter and the wall of a vein was significantly longer with the retrograde catheters than with the antegrade catheters with median time (interquartile range [range]) 6 days (5-6.75 [4-8]) with 95% confidence interval (CI), 5.58-6.42 vs 3 days (3-4 [2-5]) with 95% CI (2.76-3.24), respectively, with a P value <.001. The time needed by the recently detected thrombus to reach the catheter tip determined by ultrasound with or without catheter failure was significantly longer in the retrograde catheters than in the antegrade catheter with median time (interquartile range [range]) 9 days (8-9 [7-10]) with 95% CI, 8.76-9.24 vs 4 days (4-5 [3-6]) with 95% CI, 3.76-4.24, respectively, with a P value <.001. CONCLUSIONS: Retrograde cannulation did not decrease the incidence of thrombus formation, but significantly increased the onset time until thrombus formation and prolonged the time needed by the newly formed thrombus to reach the catheter tip compared with conventional antegrade cannulation. PMID- 27941575 TI - Prediction of Opioid Analgesic Efficacy by Measurement of Pupillary Unrest. AB - BACKGROUND: Pupillary unrest under ambient light (PUAL) is the fluctuation in pupil diameter in time around a mean value. PUAL is augmented by light and diminished by administration of opioids. We hypothesized that, because pupillary unrest is a marker of opioid effect, low levels of PUAL may be associated with reduced opioid efficacy, as measured by changes in the numerical rating scale (NRS) pain scores of patients in the postanesthesia care unit (PACU). METHODS: We used an infrared pupillometer to measure PUAL in patients recovering from ambulatory surgery at 2 different institutions. At both sites, PUAL was quantified using spectral analysis of the Fourier transform of pupil diameter versus time. We measured PUAL and pain scores before and after opioid administration. Protocols for total capture time and lighting conditions varied between the 2 sites. Correlations between PUAL and change in NRS scores were examined using significance testing of Pearson correlation coefficients. Correlations between change in PUAL and change in NRS scores were also examined. Patients were divided into high and low PUAL groups, and high and low response to opioid. A Fisher exact test was used to determine whether there was a significant association between PUAL and opioid response. RESULTS: For patients with pain in the PACU, low levels of pupillary unrest before opioid therapy were associated with minimal or no reduction in pain scores after opioid administration. We noted a significant correlation at both sites between PUAL and pain score reduction with opioids (r = 0.59, P = .0053, and r = 0.57, P = .022.) The Fisher exact test confirmed that patients with PUAL levels above the mean had a more beneficial analgesic effect from opioids than those with low PUAL levels (P = .018). We also noted that change in PUAL was significantly correlated with change in pain score at both sites (r = 0.56, P = .03 and r = 0.55, P = .01). CONCLUSIONS: We observe that the pretreatment magnitude of PUAL is correlated with the analgesic response to opioid therapy, and that patients who exhibit higher levels of PUAL change after opioid administration have a more beneficial analgesic effect from opioids. Larger studies with uniform measurement protocols are required to confirm these preliminary results. PMID- 27941576 TI - Sedation of Patients With Disorders of Consciousness During Neuroimaging: Effects on Resting State Functional Brain Connectivity. AB - BACKGROUND: To reduce head movement during resting state functional magnetic resonance imaging, post-coma patients with disorders of consciousness (DOC) are frequently sedated with propofol. However, little is known about the effects of this sedation on the brain connectivity patterns in the damaged brain essential for differential diagnosis. In this study, we aimed to assess these effects. METHODS: Using resting state functional magnetic resonance imaging 3T data obtained over several years of scanning patients for diagnostic and research purposes, we employed a seed-based approach to examine resting state connectivity in higher-order (default mode, bilateral external control, and salience) and lower-order (auditory, sensorimotor, and visual) resting state networks and connectivity with the thalamus, in 20 healthy unsedated controls, 8 unsedated patients with DOC, and 8 patients with DOC sedated with propofol. The DOC groups were matched for age at onset, etiology, time spent in DOC, diagnosis, standardized behavioral assessment scores, movement intensities, and pattern of structural brain injury (as assessed with T1-based voxel-based morphometry). RESULTS: DOC were associated with severely impaired resting state network connectivity in all but the visual network. Thalamic connectivity to higher-order network regions was also reduced. Propofol administration to patients was associated with minor further decreases in thalamic and insular connectivity. CONCLUSIONS: Our findings indicate that connectivity decreases associated with propofol sedation, involving the thalamus and insula, are relatively small compared with those already caused by DOC-associated structural brain injury. Nonetheless, given the known importance of the thalamus in brain arousal, its disruption could well reflect the diminished movement obtained in these patients. However, more research is needed on this topic to fully address the research question. PMID- 27941577 TI - Stress, Illness Perceptions, Behaviors, and Healing in Venous Leg Ulcers: Findings From a Prospective Observational Study. AB - OBJECTIVE: The aim of the study was to investigate the impact of stress, illness perceptions, and behaviors on healing of venous leg ulcers. METHODS: A prospective observational study of 63 individuals for 24 weeks investigated possible psychosocial predictors of healing. There were two indices of healing: rate of change in ulcer area and number of weeks to heal. Psychological variables were assessed at baseline using self-report measures (Perceived Stress Scale, Hospital Anxiety and Depression Scale, Revised Illness Perception Questionnaire, adapted Summary of Diabetes Self-Care Activities, Adherence Questionnaire, and Short-Form Health Survey). RESULTS: Controlling for sociodemographic and clinical variables, for the 24 weeks, a slower rate of change in ulcer area was predicted by greater stress (standardized beta = -0.61, p = .008), depression (standardized beta = -0.51, p = .039), and holding negative perceptions or beliefs about the ulcer (standardized beta = -1.4, p = .045). By 24 weeks, 69% of ulcers had closed. A more negative emotional response to the ulcer at baseline (i.e., emotional representation of the ulcer) was associated with a greater number of weeks to heal (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.41 0.95, p = .028). Higher educational attainment (HR = 3.22, 95% CI = 1.37-7.55, p = .007) and better adherence to compression bandaging (HR = 1.41, 95% CI = 1.06 1.88, p = .019) were associated with fewer weeks to heal. No other psychosocial variable (stress, perceptions about the ulcer, health behaviors) predicted weeks to heal. CONCLUSIONS: Alongside ulcer-related predictors, psychological and sociodemographic factors were associated with healing. Future research should explore mediating mechanisms underlying these associations and develop interventions to target these variables. PMID- 27941579 TI - Early Life Stress, FKBP5 Polymorphisms, and Quantitative Glycemic Traits. AB - OBJECTIVE: Early life stress (ELS) has been shown to influence health later in life. Functioning of the hypothalamic-pituitary-adrenal axis, regulated partly by FKBP5 gene, may moderate these effects. We examined whether FKBP5 single nucleotide polymorphisms (SNPs) interact with ELS on Type 2 diabetes, cardiovascular disease, and quantitative glycemic traits. METHODS: A total of 1728 Helsinki Birth Cohort Study participants born from 1934 to 1944 were genotyped for FKBP5 SNPs (rs1360780, rs9394309, rs9470080) and were administered a 2-hour (75 g) oral glucose tolerance test and a questionnaire on physician diagnosed and medication use for chronic diseases at a mean age of 61.5 years. Of the participants, 273 had been exposed to ELS, operationalized as separation from their parents, at a mean age of 4.7 years due to evacuations during World War II. RESULTS: ELS interacted with FKBP5 SNPs in the analyses of fasting (rs1360780, p = .015), 30-minute (rs1360780, p = .031; rs9394309, p = .041) and incremental insulin (rs1360780, p = .032; rs9394309, p = .028; rs9470080, p = .043), insulin area under the curve (rs1360780, p = .044), and impaired fasting glucose (rs9470080, p = .049); among carriers of at least one copy of minor allele, but not among major allele homozygotes, insulin values were higher, as were the odds for impaired fasting glucose if they had been separated compared with if they had not. Corresponding associations were found with a haplotype formed by minor alleles in all three SNPs for fasting, 30-minute, and incremental insulin (p < .05). CONCLUSIONS: FKBP5 polymorphisms in combination with ELS exposure predict higher insulin and glucose values in midlife. Our findings support the role for hypothalamic-pituitary-adrenal axis dysregulation in health-related metabolic outcomes. PMID- 27941580 TI - An Attachment-Based Model of the Relationship Between Childhood Adversity and Somatization in Children and Adults. AB - OBJECTIVE: An attachment model was used to understand how maternal sensitivity and adverse childhood experiences are related to somatization. METHODS: We examined maternal sensitivity at 6 and 18 months and somatization at 5 years in 292 children in a longitudinal cohort study. We next examined attachment insecurity and somatization (health anxiety, physical symptoms) in four adult cohorts: healthy primary care patients (AC1, n = 67), ulcerative colitis in remission (AC2, n = 100), hospital workers (AC3, n = 157), and paramedics (AC4, n = 188). Recall of childhood adversity was measured in AC3 and AC4. Attachment insecurity was tested as a possible mediator between childhood adversity and somatization in AC3 and AC4. RESULTS: In children, there was a significant negative relationship between maternal sensitivity at 18 months and somatization at age 5 years (B = -3.52, standard error = 1.16, t = -3.02, p = .003), whereas maternal sensitivity at 6 months had no significant relationship. In adults, there were consistent, significant relationships between attachment insecurity and somatization, with the strongest findings for attachment anxiety and health anxiety (AC1, beta = 0.51; AC2, beta = 0.43). There was a significant indirect effect of childhood adversity on physical symptoms mediated by attachment anxiety in AC3 and AC4. CONCLUSIONS: Deficits in maternal sensitivity at 18 months of age are related to the emergence of somatization by age 5 years. Adult attachment insecurity is related to somatization. Insecure attachment may partially mediate the relationship between early adversity and somatization. PMID- 27941582 TI - Accepting the Torch. PMID- 27941583 TI - Current Endoscopic Approaches for the Treatment of Barrett Esophagus. AB - Barrett esophagus (BE) is the only identifiable premalignant condition for esophageal adenocarcinoma (EAC), a cancer associated with a poor 5-year survival rate. The stepwise pathologic progression of BE to invasive cancer provides an opportunity to halt progression and potentially decrease incidence and ultimately the morbidity and mortality related to this lethal cancer. Endoscopic eradication therapy (EET) in patients at increased risk of progression to invasive EAC (intramucosal EAC, high-grade dysplasia, and low-grade dysplasia) is a practice that is endorsed by multiple societies and has replaced esophagectomy as the standard of care for these patients. Although the effectiveness, safety, and durability of EET have been demonstrated in several studies, this review addresses the several challenges with EET that need to be considered to optimize patient outcomes. Finally, the critical role of training, competence, and quality indicators in EET are emphasized in this era of value-based health care practice. PMID- 27941584 TI - In Reply. PMID- 27941587 TI - To The Editor. PMID- 27941586 TI - Geometric Torsion in Adolescent Idiopathic Scoliosis: A Surgical Outcomes Study of Lenke Type 1 Patients. AB - STUDY DESIGN: Consecutive case series analysis. OBJECTIVE: To evaluate the surgical outcomes of patients with thoracic adolescent idiopathic scoliosis (AIS) in relation to different degrees of geometric torsion. SUMMARY OF BACKGROUND DATA: AIS is a three-dimensional (3D) deformity of the spine. A 3D classification of AIS, however, remains elusive because there is no widely accepted 3D parameter in the clinical practice. Recently, a new method of estimating geometric torsion has been proposed and detected two potential new 3D subgroups based on geometric torsion values. METHODS: This is an analysis of 93 patients with Lenke type-1 deformity from our institution. 3D reconstructions were obtained using biplanar radiographs both pre- and postoperatively. Geometric torsion was computed using a novel technique by approximating local arc lengths at the neutral vertebra in the thoracolumbar segment. An inter- and intragroup statistical analysis was performed to compare clinical indices of patients with different torsion values. A qualitative assessment was also performed on each patient by two senior staff surgeons. RESULTS: Statistically significant differences were observed in clinical indices between high (2.85 mm) and low torsion (0.83 mm) Lenke type 1 subgroups. Preoperatively, the high torsion group showed higher Cobb angle values in the thoracic segment (71.18 degrees vs. 63.74 degrees ), as well as higher angulation in the thoracolumbar plane of maximum deformity (67.79 degrees vs. 53.30 degrees ). Postoperatively, a statistically significant difference was found in the orientation of the plane of maximum deformity in the thoracolumbar segment between the high and low torsion groups (47.95 degrees vs. 30.03 degrees ). Results from the qualitative evaluation of surgical results showed different results between the two staff surgeons. CONCLUSION: These results suggest a link between preoperative torsion values and surgical outcomes within Lenke type 1 deformities. These results will need to be validated by an independent group, as it is a single-center study. LEVEL OF EVIDENCE: 4. PMID- 27941588 TI - Cardiac rehabilitation after transcatheter aortic valve implantation compared to patients after valve replacement. AB - AIMS: To evaluate feasibility, safety, and outcome of an exercise-based residential cardiac rehabilitation program in transcatheter aortic valve implantation (TAVI) patients compared to elderly patients after surgical valve replacement (sAVR). METHODS: From January 2010 to January 2013, 65 consecutive TAVI and 70 sAVR older than 70 years were enrolled. Six-min walk test (6MWT) distance, Barthel index, Morse Fall Scale (MFS) on admission and discharge, Cumulative Illness Rated State-Comorbidity Index (CIRS-CI), and echocardiography were assessed. Patients underwent a 3-week intensive cardiac rehabilitation program. RESULTS: Compared with sAVR, TAVI had worse CIRS-CI (4.8 +/- 1.5 vs. 3.4 +/- 1.5; P = 0.00001), left ventricle ejection fraction (55.3 +/- 9 vs. 59.2 +/- 7.7; P = 0.008), Barthel index (67 +/- 24 vs. 79 +/- 21; P = 0.0018), and MFS (36 +/- 22 vs. 25 +/- 19; P = 0.002) on admission and at discharge (Barthel index 85 +/- 17 vs. 93 +/- 14; P = 0.005 and MFS 30 +/- 20 vs. 20 +/- 12; P = 0.0001), despite a significant improvement at discharge of Barthel index (85 +/- 17 vs. 67 +/- 24; P = 0.001) and MFS (36 +/- 22 vs. 30 +/- 20; P > 0.01). TAVI attended safely cardiac rehabilitation, but tolerated a significantly lower workload and had reduced 6MWT both on admission and discharge compared with sAVR (162 +/- 87vs. 216 +/- 82; P = 0.00001, and 240 +/- 92 vs. 33295; P = 0.00001, respectively), despite a net improvement at discharge in 6MWT (240 +/- 92 vs. 162 +/- 92; P < 0.001). CONCLUSION: Intensive cardiac rehabilitation after TAVI is safe, well tolerated, and leads to a net improvement in disability, risk of falls, and exercise capacity, similar to that observed in less disabled sAVR patients, favoring home discharge and relatively independent life at home. A persistent higher disability, comorbidity profile, and risk of falls at discharge characterize TAVI patients compared with sAVR patients of similar age. PMID- 27941589 TI - Treatment of stroke with early imaging and revascularization: when to be aggressive? AB - Neuroimaging has a key role in the assessment and treatment of acute stroke. Cerebral computer tomography is the first step to differentiate hemorragic from ischemic stroke and to detect, in the latter, early signs representative of the lesion severity and predicting a possible hemorrhagic infarction after thrombolytic treatment.Advanced neuroimaging techniques are relevant in the assessment of the ischemic and/or hypo-perfused area, being an essential tool in uncertain situations or when the time of symptoms onset is unavailable, increasing the efficacy and safety of endovenous thrombolysis by enlarging its therapeutic window and leading to more accurate selection of patients to be treated.Moreover, advanced neuroimaging may be of help in choosing the patients to be submitted to endovascular treatment when occlusion of an intracranial artery is documented, either after intravenous thrombolysis or as a primary approach.Here we describe the impact of neuroimaging in the decisional process in acute ischemic stroke, presenting the literature evidence on the topic, especially regarding the recent trials on endovascular treatment. PMID- 27941591 TI - M2A and M2C Macrophage Subsets Ameliorate Inflammation and Fibroproliferation in Acute Lung Injury Through Interleukin 10 Pathway. AB - The role of M2 macrophages in the resolution and fibroproliferation of acute lung injury (ALI) is poorly understood. In this study, we investigated the effects of two M2 macrophage subtypes, M2a induced by interleukin (IL)-4/IL-13 and M2c induced by IL-10/transforming growth factor -beta, on the pathogenesis of ALI. M2a and M2c were adoptively transferred into lipopolysaccharide-induced ALI mice model. Data showed that Vybrant-labeled macrophages appeared in the lungs of ALI mice. Subsequently, we observed that both subsets significantly reduced lung inflammation and injury including a reduction of neutrophil influx into the lung and an augmentation of apoptosis. Interestingly, M2c macrophages more effectively suppressed indices of lung injury than M2a macrophages. M2c macrophages were also more effective than M2a in reduction of lung fibrosis. In addition, we found that M2c but not M2a macrophages increased IL-10 level in lung tissues of the recipient ALI mice partially mediated by activating the JAK1/STAT3/suppressor of cytokine signaling 3 signaling pathway. After blocking IL-10, these superior effects of M2c over M2a were abolished. These data imply that M2c are more potent than M2a macrophages in protecting against lung injury and subsequent fibrosis due to their ability to produce IL-10. Therefore, reprogramming macrophages to M2c subset may be a novel treatment modality with transitional potential. PMID- 27941590 TI - Traumatic Hemothorax Blood Contains Elevated Levels of Microparticles that are Prothrombotic but Inhibit Platelet Aggregation. AB - OBJECTIVES: Autotransfusion of shed blood from traumatic hemothorax is an attractive option for resuscitation of trauma patients in austere environments. However, previous analyses revealed that shed hemothorax (HX) blood is defibrinated, thrombocytopenic, and contains elevated levels of D-dimer. Mixing studies with normal pooled plasma demonstrated hypercoagulability, evoking concern for potentiation of acute traumatic coagulopathy. We hypothesized that induction of coagulopathic changes by shed HX blood may be due to increases in cellular microparticles (MP) and that these may also affect recipient platelet function. METHODS: Shed HX blood was obtained from 17 adult trauma patients under an Institutional Review Board approved prospective observational protocol. Blood samples were collected every hour up to 4 h after thoracostomy tube placement. The corresponding plasma was isolated and frozen for analysis. The effects of shed HX frozen plasma (HFP) and isolated HX microparticles (HMP) on coagulation and platelet function were assessed through mixing studies with platelet-rich plasma at various dilutions followed by analysis with thromboelastometry (ROTEM), platelet aggregometry (Multiplate), enzyme-linked immunosorbent assays, and flow cytometry. Furthermore, HFP was assessed for von Willebrand factor antigen levels and multimer content, and plasma-free hemoglobin. RESULTS: ROTEM analysis demonstrated that diluted HFP and isolated HMP samples decreased clotting time, clotting formation time, and increased alpha angle, irrespective of sample concentrations, when compared with diluted control plasma. Isolated HMP inhibited platelet aggregation in response to adenosine diphosphate, arachidonic acid, and collagen. HFP contained elevated levels of fibrin-degradation products and tissue factor compared with control fresh frozen plasma samples. MP concentrations in HFP were significantly increased and enriched in events positive for phosphatidylserine, tissue factor, CD235, CD45, CD41a, and CD14. von Willebrand factor (vWF) multimer analysis revealed significant loss of high molecular weight multimers in HFP samples. Plasma-free hemoglobin levels were 8-fold higher in HFP compared with fresh frozen plasma. CONCLUSION: HFP induces plasma hypercoagulability that is likely related to increased tissue factor and phosphatidylserine expression originating from cell-derived MP. In contrast, platelet dysfunction is induced by HMP, potentially aggravated by depletion of high molecular weight multimers of vWF. Thus, autologous transfusion of shed traumatic hemothorax blood may induce a range of undesirable effects in patients with acute traumatic coagulopathy. PMID- 27941592 TI - Pathological Role and Diagnostic Value of Endogenous Host Defense Peptides in Adult and Neonatal Sepsis: A Systematic Review. AB - BACKGROUND: Sepsis is a systemic host response to an infection leading to organ failure. This is associated with dynamic expression of endogenous host defense peptides. Dysregulation of these peptides is associated with septic morbidity and mortality. METHODS: We performed a systematic search of articles indexed in PubMed, ISI Web of Knowledge, EmBase, and Scopus database from inception to October 2016. Both preclinical and clinical studies investigating the role of host defense peptides in pathogenesis and as biomarkers for sepsis were included. RESULTS: Of the available literature, cathelicidin, defensin, and hepcidin are among the best-characterized peptides. These regulate immune response, and crosstalk with pyroptosis and coagulation cascades. The applicability of these peptides as septic biomarkers has been investigated in vitro and in vivo studies. However, numerous studies were based on endotoxemia without an infection, jeopardizing interpretation of the outcomes. Cathelicidin and defensin were frequently reported in adult sepsis while hepcidin in neonatal sepsis. The expression level of these peptides is significantly associated with septic condition. Most of the studies employed a cross-sectional design, precluding the establishment of a temporal relationship between candidate peptide biomarkers and sepsis. CONCLUSIONS: Innate defense peptides have been insufficiently evaluated as either diagnostic or prognostic biomarkers. In the future, evaluation of host defense peptides as septic biomarkers may employ a longitudinal design and consider a panel of multiple peptides. PMID- 27941593 TI - Low-Dose Sodium Nitrite Fluid Resuscitation Prevents Lethality From Crush Syndrome by Improving Nitric Oxide Consumption and Preventing Myoglobin Cytotoxicity in Kidney in A Rat Model. AB - OBJECTIVE: Crush syndrome (CS) is a serious medical condition characterized by muscle cell damage resulting from pressure. CS has a high mortality, even when patients receive fluid therapy. We examined whether administration of NaNO2 containing fluid can improve survival in a rat model of CS. DESIGN: The CS model was generated by subjecting anesthetized rats to bilateral hind limb compression with a rubber tourniquet for 5 h. Rats were then randomly divided into six groups: sham; CS with no treatment; CS with normal saline treatment; CS with normal saline + 25 mEq/L bicarbonate treatment; and CS with normal saline + 200 or 500 MUmol/kg NaNO2. MEASUREMENTS AND MAIN RESULTS: Blood and tissue samples were collected for histological and biochemical analyses at predetermined time points before and after reperfusion. Ischemic compression of rat hind limbs reduced nitrite content in the crushed muscle, and subsequent reperfusion resulted in reactive oxygen species-induced circulatory dysfunction and systemic inflammation. Rats treated with 200 MUmol/kg NaNO2 showed increased nitric oxide (NO) levels, blood circulation, and neoangiogenesis, decreased generation of reactive oxygen species, and suppression of the inflammatory response, leading to complete recovery. CONCLUSIONS: Treatment with 200 MUmol/kg NaNO2 prevents muscle damage induced by ischemia reperfusion via the protective effects of NO and suppression of systemic inflammation, thereby increasing survival rates in CS. PMID- 27941594 TI - The Sweetener-Sensing Mechanisms of the Ghrelin Cell. AB - Carbohydrate administration decreases plasma levels of the 'hunger hormone' ghrelin. The ghrelin cell is co-localized with the sweet taste receptor subunit, TAS1R3, and the gustatory G-protein, gustducin, both involved in the sensing of sweeteners by entero-endocrine cells. This study investigated the role of gustducin-mediated sweet taste receptor signaling on ghrelin secretion in a gastric ghrelinoma cell line, tissue segments and mice. The monosaccharide d glucose and low-intensity sweetener oligofructose (OFS) decreased (p < 0.001) ghrelin secretion while the high-intensity sweetener sucralose increased (p < 0.001) ghrelin secretion in vitro. These effects were not mediated via the sweet taste receptor or glucose transporters (the sodium-dependent glucose cotransporter SGLT-1 and GLUT2). The effect of these compounds was mimicked ex vivo in gastric and jejunal segments from both wild type (WT) and alpha-gustducin knockout (alpha-gust-/-) mice. In vivo, the sensing of d-glucose was polarized since intragastric but not intravenous administration of d-glucose decreased (p < 0.05) ghrelin levels in an alpha-gustducin independent manner which involved inhibition of duodenal ghrelin release. In contrast, neither OFS nor sucralose affected ghrelin secretion in vivo. In conclusion, alpha-gustducin-mediated sweet taste receptor signaling does not play a functional role in the sensing of carbohydrates, or low- or high-intensity sweeteners by the ghrelin cell. PMID- 27941596 TI - Chlorophyll-a Estimation Around the Antarctica Peninsula Using Satellite Algorithms: Hints from Field Water Leaving Reflectance. AB - Ocean color remote sensing significantly contributes to our understanding of phytoplankton distribution and abundance and primary productivity in the Southern Ocean (SO). However, the current SO in situ optical database is still insufficient and unevenly distributed. This limits the ability to produce robust and accurate measurements of satellite-based chlorophyll. Based on data collected on cruises around the Antarctica Peninsula (AP) on January 2014 and 2016, this research intends to enhance our knowledge of SO water and atmospheric optical characteristics and address satellite algorithm deficiency of ocean color products. We collected high resolution in situ water leaving reflectance (+/-1 nm band resolution), simultaneous in situ chlorophyll-a concentrations and satellite (MODIS and VIIRS) water leaving reflectance. Field samples show that clouds have a great impact on the visible green bands and are difficult to detect because NASA protocols apply the NIR band as a cloud contamination threshold. When compared to global case I water, water around the AP has lower water leaving reflectance and a narrower blue-green band ratio, which explains chlorophyll-a underestimation in high chlorophyll-a regions and overestimation in low chlorophyll-a regions. VIIRS shows higher spatial coverage and detection accuracy than MODIS. After coefficient improvement, VIIRS is able to predict chlorophyll a with 53% accuracy. PMID- 27941595 TI - Achieving HIV-1 Control through RNA-Directed Gene Regulation. AB - HIV-1 infection has been transformed by combined anti-retroviral therapy (ART), changing a universally fatal infection into a controllable infection. However, major obstacles for an HIV-1 cure exist. The HIV latent reservoir, which exists in resting CD4+ T cells, is not impacted by ART, and can reactivate when ART is interrupted or ceased. Additionally, multi-drug resistance can arise. One alternate approach to conventional HIV-1 drug treatment that is being explored involves gene therapies utilizing RNA-directed gene regulation. Commonly known as RNA interference (RNAi), short interfering RNA (siRNA) induce gene silencing in conserved biological pathways, which require a high degree of sequence specificity. This review will provide an overview of the silencing pathways, the current RNAi technologies being developed for HIV-1 gene therapy, current clinical trials, and the challenges faced in progressing these treatments into clinical trials. PMID- 27941597 TI - Maternal Vitamin D Status and Adverse Birth Outcomes in Children from Rural Western Kenya. AB - Maternal plasma 25-hydroxyvitamin D (25(OH)D) status and its association with pregnancy outcomes in malaria holoendemic regions of sub-Saharan Africa is poorly defined. We examined this association and any potential interaction with malaria and helminth infections in an ongoing pregnancy cohort study in Kenya. The association of maternal plasma 25(OH)D status with pregnancy outcomes and infant anthropometric measurements at birth was determined in a subset of women (n = 63). Binomial and linear regression analyses were used to examine associations between maternal plasma 25(OH)D and adverse pregnancy outcomes. Fifty-one percent of the women had insufficient (<75 nmol/L) and 21% had deficient (<50 nmol/L) plasma 25(OH)D concentration at enrollment. At birth, 74.4% of the infants had insufficient and 30% had deficient plasma 25(OH)D concentrations, measured in cord blood. Multivariate analysis controlling for maternal age and body mass index (BMI) at enrollment and gestational age at delivery found that deficient plasma 25(OH)D levels were associated with a four-fold higher risk of stunting in neonates (p = 0.04). These findings add to the existing literature about vitamin D and its association with linear growth in resource-limited settings, though randomized clinical trials are needed to establish causation. PMID- 27941598 TI - Standardization, Calibration, and Evaluation of Tantalum-Nano rGO-SnO2 Composite as a Possible Candidate Material in Humidity Sensors. AB - The present study focuses the development and the evaluation of humidity sensors based on reduced graphene oxide-tin oxide (rGO-SnO2) nanocomposites, synthesized by a simple redox reaction between GO and SnCl2. The physico-chemical characteristics of the nanocomposites were analyzed by XRD, TEM, FTIR, and Raman spectroscopy. The formation of SnO2 crystal phase was observed through XRD. The SnO2 crystal phase anchoring to the graphene sheet was confirmed through TEM images. For the preparation of the sensors, tantalum substrates were coated with the sensing material. The sensitivity of the fabricated sensor was studied by varying the relative humidity (RH) from 11% to 95% over a period of 30 days. The dependence of the impedance and of the capacitance with RH of the sensor was measured with varying frequency ranging from 1 kHz to 100 Hz. The long-term stability of the sensor was measured at 95% RH over a period of 30 days. The results proved that rGO-SnO2 nanocomposites are an ideal conducting material for humidity sensors due to their high sensitivity, rapid response and recovery times, as well as their good long-term stability. PMID- 27941599 TI - Marine Algae as a Potential Source for Anti-Obesity Agents. AB - Obesity is a major epidemic that poses a worldwide threat to human health, as it is also associated with metabolic syndrome, type 2 diabetes and cardiovascular disease. Therapeutic intervention through weight loss drugs, accompanied by diet and exercise, is one of the options for the treatment and management of obesity. However, the only approved anti-obesity drug currently available in the market is orlistat, a synthetic inhibitor of pancreatic lipase. Other anti-obesity drugs are still being evaluated at different stages of clinical trials, while some have been withdrawn due to their severe adverse effects. Thus, there is a need to look for new anti-obesity agents, especially from biological sources. Marine algae, especially seaweeds are a promising source of anti-obesity agents. Four major bioactive compounds from seaweeds which have the potential as anti-obesity agents are fucoxanthin, alginates, fucoidans and phlorotannins. The anti-obesity effects of such compounds are due to several mechanisms, which include the inhibition of lipid absorption and metabolism (e.g., fucoxanthin and fucoidans), effect on satiety feeling (e.g., alginates), and inhibition of adipocyte differentiation (e.g., fucoxanthin). Further studies, especially testing bioactive compounds in long-term human trials are required before any new anti-obesity drugs based on algal products can be developed. PMID- 27941600 TI - Application of Fast Dynamic Allan Variance for the Characterization of FOGs-Based Measurement While Drilling. AB - The stability of a fiber optic gyroscope (FOG) in measurement while drilling (MWD) could vary with time because of changing temperature, high vibration, and sudden power failure. The dynamic Allan variance (DAVAR) is a sliding version of the Allan variance. It is a practical tool that could represent the non stationary behavior of the gyroscope signal. Since the normal DAVAR takes too long to deal with long time series, a fast DAVAR algorithm has been developed to accelerate the computation speed. However, both the normal DAVAR algorithm and the fast algorithm become invalid for discontinuous time series. What is worse, the FOG-based MWD underground often keeps working for several days; the gyro data collected aboveground is not only very time-consuming, but also sometimes discontinuous in the timeline. In this article, on the basis of the fast algorithm for DAVAR, we make a further advance in the fast algorithm (improved fast DAVAR) to extend the fast DAVAR to discontinuous time series. The improved fast DAVAR and the normal DAVAR are used to responsively characterize two sets of simulation data. The simulation results show that when the length of the time series is short, the improved fast DAVAR saves 78.93% of calculation time. When the length of the time series is long ( 6 * 10 5 samples), the improved fast DAVAR reduces calculation time by 97.09%. Another set of simulation data with missing data is characterized by the improved fast DAVAR. Its simulation results prove that the improved fast DAVAR could successfully deal with discontinuous data. In the end, a vibration experiment with FOGs-based MWD has been implemented to validate the good performance of the improved fast DAVAR. The results of the experience testify that the improved fast DAVAR not only shortens computation time, but could also analyze discontinuous time series. PMID- 27941602 TI - Aerodynamic Drag Analysis of 3-DOF Flex-Gimbal GyroWheel System in the Sense of Ground Test. AB - GyroWheel is an innovative device that combines the actuating capabilities of a control moment gyro with the rate sensing capabilities of a tuned rotor gyro by using a spinning flex-gimbal system. However, in the process of the ground test, the existence of aerodynamic disturbance is inevitable, which hinders the improvement of the specification performance and control accuracy. A vacuum tank test is a possible candidate but is sometimes unrealistic due to the substantial increase in costs and complexity involved. In this paper, the aerodynamic drag problem with respect to the 3-DOF flex-gimbal GyroWheel system is investigated by simulation analysis and experimental verification. Concretely, the angular momentum envelope property of the spinning rotor system is studied and its integral dynamical model is deduced based on the physical configuration of the GyroWheel system with an appropriately defined coordinate system. In the sequel, the fluid numerical model is established and the model geometries are checked with FLUENT software. According to the diversity and time-varying properties of the rotor motions in three-dimensions, the airflow field around the GyroWheel rotor is analyzed by simulation with respect to its varying angular velocity and tilt angle. The IPC-based experimental platform is introduced, and the properties of aerodynamic drag in the ground test condition are obtained through comparing the simulation with experimental results. PMID- 27941603 TI - Analysis of Metabolites in Stem Parasitic Plant Interactions: Interaction of Cuscuta-Momordica versus Cassytha-Ipomoea. AB - Cuscuta and Cassytha are two well-known stem parasitic plant genera with reduced leaves and roots, inducing haustoria in their stems. Their similar appearance in the field has been recognized, but few comparative studies on their respective plant interactions are available. To compare their interactions, we conducted a metabolite analysis of both the Cassytha-Ipomoea and the Cuscuta-Momordica interaction. We investigated the energy charge of the metabolites by UFLC (ultra high performance liquid chromatography), and conducted GC-MS (gas chromatography mass spectrometry) analysis for polar metabolites (e.g., saccharides, polyols) and steroids. The energy charge after parasitization changed considerably in Cassytha but not in Cusucta. Cuscuta changed its steroid pattern during the plant interaction, whereas Cassytha did not. In the polar metabolite analysis, the laminaribiose increase after parasitization was conspicuous in Cuscuta, but not in Cassytha. This metabolite profile difference points to different lifestyles and parasitic strategies. PMID- 27941601 TI - Two New Diphenylketones and a New Xanthone from Talaromyces islandicus EN-501, an Endophytic Fungus Derived from the Marine Red Alga Laurencia okamurai. AB - Two new diphenylketones (1 and 2), a new xanthone (3), and a known xanthone analogue (4) were isolated and identified from Talaromyces islandicus EN-501, an endophytic fungus obtained from the fresh collected marine red alga Laurencia okamurai. Their structures were elucidated on the basis of NMR spectroscopic and X-ray crystallographic analysis. The joint isolation of benzophenones and xanthones from the same fungal strain supports the biogenesis of xanthones via a benzophenone intermediate. It is worth mentioning that xanthones 3 and 4 have a methyl group at C-6 and C-2, respectively, which is uncommon compared with typical xanthones usually having a methyl group at C-8. Compounds 1-4 exhibited potent antioxidative activities against DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonate) radicals with IC50 values ranging from 0.58 to 6.92 MUg/mL, which are stronger than that of the positive controls BHT (butylated hydroxytoluene) and ascorbic acid. Compounds 1, 3, and 4 also showed inhibitory activities against several pathogenic bacteria. PMID- 27941604 TI - Modeling of a Robust Confidence Band for the Power Curve of a Wind Turbine. AB - Having an accurate model of the power curve of a wind turbine allows us to better monitor its operation and planning of storage capacity. Since wind speed and direction is of a highly stochastic nature, the forecasting of the power generated by the wind turbine is of the same nature as well. In this paper, a method for obtaining a robust confidence band containing the power curve of a wind turbine under test conditions is presented. Here, the confidence band is bound by two curves which are estimated using parametric statistical inference techniques. However, the observations that are used for carrying out the statistical analysis are obtained by using the binning method, and in each bin, the outliers are eliminated by using a censorship process based on robust statistical techniques. Then, the observations that are not outliers are divided into observation sets. Finally, both the power curve of the wind turbine and the two curves that define the robust confidence band are estimated using each of the previously mentioned observation sets. PMID- 27941606 TI - Stereoselective Fluorescence Quenching in the Electron Transfer Photooxidation of Nucleobase-Related Azetidines by Cyanoaromatics. AB - Electron transfer involving nucleic acids and their derivatives is an important field in bioorganic chemistry, specifically in connection with its role in the photo-driven DNA damage and repair. Four-membered ring heterocyclic oxetanes and azetidines have been claimed to be the intermediates involved in the repair of DNA (6-4) photoproduct by photolyase. In this context, we examine here the redox properties of the two azetidine isomers obtained from photocycloaddition between 6-aza-1,3-dimethyluracil and cyclohexene. Steady-state and time-resolved fluorescence experiments using a series of photoreductants and photooxidants have been run to evaluate the efficiency of the electron transfer process. Analysis of the obtained quenching kinetics shows that the azetidine compounds can act as electron donors. Additionally, it appears that the cis isomer is more easily oxidized than its trans counterpart. This result is in agreement with electrochemical studies performed on both azetidine derivatives. PMID- 27941605 TI - Screening the Expression Changes in MicroRNAs and Their Target Genes in Mature Cementoblasts Stimulated with Cyclic Tensile Stress. AB - Cementum is a thin layer of cementoblast-produced mineralized tissue covering the root surfaces of teeth. Mechanical forces, which are produced during masticatory activity, play a paramount role in stimulating cementoblastogenesis, which thereby facilitates the maintenance, remodeling and integrity of cementum. However, hitherto, the extent to which a post-transcriptional modulation mechanism is involved in this process has rarely been reported. In this study, a mature murine cementoblast cell line OCCM-30 cells (immortalized osteocalcin positive cementoblasts) was cultured and subjected to cyclic tensile stress (0.5 Hz, 2000 ustrain). We showed that the cyclic tensile stress could not only rearrange the cell alignment, but also influence the proliferation in an S-shaped manner. Furthermore, cyclic tensile stress could significantly promote cementoblastogenesis-related genes, proteins and mineralized nodules. From the miRNA array analyses, we found that 60 and 103 miRNAs were significantly altered 6 and 18 h after the stimulation using cyclic tensile stress, respectively. Based on a literature review and bioinformatics analyses, we found that miR-146b-5p and its target gene Smad4 play an important role in this procedure. The upregulation of miR-146b-5p and downregulation of Smad4 induced by the tensile stress were further confirmed by qRT-PCR. The direct binding of miR-146b-5p to the three prime untranslated region (3' UTR) of Smad4 was established using a dual luciferase reporter assay. Taken together, these results suggest an important involvement of miR-146b-5p and its target gene Smad4 in the cementoblastogenesis of mature cementoblasts. PMID- 27941607 TI - Comparative Study of Green Sub- and Supercritical Processes to Obtain Carnosic Acid and Carnosol-Enriched Rosemary Extracts with in Vitro Anti-Proliferative Activity on Colon Cancer Cells. AB - In the present work, four green processes have been compared to evaluate their potential to obtain rosemary extracts with in vitro anti-proliferative activity against two colon cancer cell lines (HT-29 and HCT116). The processes, carried out under optimal conditions, were: (1) pressurized liquid extraction (PLE, using an hydroalcoholic mixture as solvent) at lab-scale; (2) Single-step supercritical fluid extraction (SFE) at pilot scale; (3) Intensified two-step sequential SFE at pilot scale; (4) Integrated PLE plus supercritical antisolvent fractionation (SAF) at pilot scale. Although higher extraction yields were achieved by using PLE (38.46% dry weight), this extract provided the lowest anti-proliferative activity with no observed cytotoxic effects at the assayed concentrations. On the other hand, extracts obtained using the PLE + SAF process provided the most active rosemary extracts against both colon cancer cell lines, with LC50 ranging from 11.2 to 12.4 ug/mL and from 21.8 to 31.9 ug/mL for HCT116 and HT-29, respectively. In general, active rosemary extracts were characterized by containing carnosic acid (CA) and carnosol (CS) at concentrations above 263.7 and 33.9 mg/g extract, respectively. Some distinct compounds have been identified in the SAF extracts (rosmaridiphenol and safficinolide), suggesting their possible role as additional contributors to the observed strong anti-proliferative activity of CA and CS in SAF extracts. PMID- 27941609 TI - Pentacoordinate and Hexacoordinate Mn(III) Complexes of Tetradentate Schiff-Base Ligands Containing Tetracyanidoplatinate(II) Bridges and Revealing Uniaxial Magnetic Anisotropy. AB - Crystal structures and magnetic properties of polymeric and trinuclear heterobimetallic MnIII...PtII...MnIII coordination compounds, prepared from the Ba[Pt(CN)4] and [Mn(L4A/B)(Cl)] (1a/b) precursor complexes, are reported. The polymeric complex [{Mn(L4A)}2{MU4-Pt(CN)4}]n (2a), where H2L4A = N,N'-ethylene bis(salicylideneiminate), comprises the {Mn(L4A)} moieties covalently connected through the [Pt(CN)4]2- bridges, thus forming a square-grid polymeric structure with the hexacoordinate MnIII atoms. The trinuclear complex [{Mn(L4B)}2{MU Pt(CN)4}] (2b), where H2L4B = N,N'-benzene-bis(4-aminodiethylene salicylideneiminate), consists of two [{Mn(L4B)} moieties, involving pentacoordinate MnIII atoms, bridged through the tetracyanidoplatinate (II) bridges to which they are coordinated in a trans fashion. Both complexes possess uniaxial type of magnetic anisotropy, with D (the axial parameter of zero-field splitting) = -3.7(1) in 2a and -2.2(1) cm-1 in 2b. Furthermore, the parameters of magnetic anisotropy 2a and 2b were also thoroughly studied by theoretical complete active space self-consistent field (CASSCF) methods, which revealed that the former is much more sensitive to the ligand field strength of the axial ligands. PMID- 27941608 TI - Mutations in the Mitochondrial ND1 Gene Are Associated with Postoperative Prognosis of Localized Renal Cell Carcinoma. AB - We analyzed mutations in the mitochondrial ND1 gene to determine their association with clinicopathological parameters and postoperative recurrence of renal cell carcinoma (RCC) in Japanese patients. Among 62 RCC cases for which tumor pathology was confirmed by histopathology, ND1 sequencing revealed the presence of 30 mutation sites in 19 cases. Most mutations were heteroplasmic, with 16 of 19 cases harboring one or more heteroplasmic sites. Additionally, 12 sites had amino acid mutations, which were frequent in 10 of the cases. The 5 year recurrence-free survival (RFS) rate was significantly worse in patients with tumors >40 mm in diameter (p = 0.0091), pathological T (pT) stage >=3 (p = 0.0122), Fuhrman nuclear atypia grade >=III (p = 0.0070), and ND1 mutations (p = 0.0006). Multivariate analysis using these factors revealed that mutations in ND1 were significantly associated with the 5-year RFS rate (p = 0.0044). These results suggest a strong correlation between the presence of ND1 mutations in cancer tissue and postoperative recurrence of localized RCC in Japanese patients. PMID- 27941610 TI - Subcritical Butane Extraction of Wheat Germ Oil and Its Deacidification by Molecular Distillation. AB - Extraction and deacidification are important stages for wheat germ oil (WGO) production. Crude WGO was extracted using subcritical butane extraction (SBE) and compared with traditional solvent extraction (SE) and supercritical carbon dioxide extraction (SCE) based on the yield, chemical index and fatty acid profile. Furthermore, the effects of the molecular distillation temperature on the quality of WGO were also investigated in this study. Results indicated that WGO extracted by SBE has a higher yield of 9.10% and better quality; at the same time, its fatty acid composition has no significant difference compared with that of SE and SCE. The molecular distillation experiment showed that the acid value, peroxide value and p-anisidine value of WGO were reduced with the increase of the evaporation temperatures, and the contents of the active constituents of tocopherol, polyphenols and phytosterols are simultaneously decreased. Generally, the distillation temperature of 150 degrees C is an appropriate condition for WGO deacidification with the higher deacidification efficiency of 77.78% and the higher retention rate of active constituents. PMID- 27941611 TI - Transcriptional Response of Silkworm (Bombyx mori) Eggs to O2 or HCl Treatment. AB - Diapause is a common biological phenomenon that occurs in many organisms, including fish, insects, and nematodes. In the silkworm (Bombyx mori), diapause generally occurs in the egg stage. Treatment with O2, HCl, or other compounds can prevent egg diapause. Here, we characterized the transcriptomic responses of newly laid eggs treated with O2 or HCl. Digital gene expression analysis showed that 610 genes in O2-treated eggs and 656 in HCl-treated eggs were differentially expressed. Of these, 343 genes were differentially expressed in both treatments. In addition to trehalases, sorbic acid dehydrogenases, and some enzymes involved in the carbohydrate metabolism, we also identified heat shock proteins, cytochrome P450, and GADD45, which are related to stress tolerance. Gene ontology enrichment analysis showed differentially expressed genes in O2-treated eggs were involved in oxidoreductase activity as well as in binding, catalytic, and metabolic processes. The Kyoto Encyclopedia of Genes and Genomes analysis showed that the pathways for ribosome biogenesis, spliceosome, and circadian rhythm were significantly enriched in HCl-treated eggs. The reliability of the data was confirmed by qRT-PCR analysis. Our results improved the understanding of the mechanism of diapause blocking in silkworm eggs treated with O2 or HCl and identified novel molecular targets for future studies. PMID- 27941612 TI - Chemical Variability and Biological Activities of Eucalyptus spp. Essential Oils. AB - Many plant species produce mixtures of odorous and volatile compounds known as essential oils (EOs). These mixtures play important roles in Nature and have been utilized by mankind for different purposes, such as pharmaceuticals, agrochemicals, aromatherapy, and food flavorants. There are more than 3000 EOs reported in the literature, with approximately 300 in commercial use, including the EOs from Eucalyptus species. Most EOs from Eucalyptus species are rich in monoterpenes and many have found applications in pharmaceuticals, agrochemicals, food flavorants, and perfumes. Such applications are related to their diverse biological and organoleptic properties. In this study, we review the latest information concerning the chemical composition and biological activities of EOs from different species of Eucalyptus. Among the 900 species and subspecies of the Eucalyptus genus, we examined 68 species. The studies associated with these species were conducted in 27 countries. We have focused on the antimicrobial, acaricidal, insecticidal and herbicidal activities, hoping that such information will contribute to the development of research in this field. It is also intended that the information described in this study can be useful in the rationalization of the use of Eucalyptus EOs as components for pharmaceutical and agrochemical applications as well as food preservatives and flavorants. PMID- 27941613 TI - Cellular Localization and Regulation of Expression of the PLET1 Gene in Porcine Placenta. AB - The placenta expressed transcript 1 (PLET1) gene, which is expressed in placentas of pigs and mice, has been found to have a potential role in trophoblast cell fate decision in mice. Results of this study showed that the porcine PLET1 mRNA and protein were expressed exclusively in trophoblast cells on Days 15, 26, 50, and 95 of gestation (gestation length in the pig is 114 days), indicating that the PLET1 could be a useful marker for porcine trophoblast cells. Additionally, PLET1 protein was found to be redistributed from cytoplasm to the apical side of trophoblast cells as gestation progresses, which suggests a role of PLET1 in the establishment of a stable trophoblast and endometrial epithelial layers. In addition, two transcripts that differ in the 3' UTR length but encode identical protein were identified to be generated by the alternative cleavage and polyadenylation (APA), and the expression of PLET1-L transcript was significantly upregulated in porcine placentas as gestation progresses. Furthermore, we demonstrated the interaction between the miR-365-3p and PLET1 gene using luciferase assay system. Our findings imply an important role of PLET1 in the placental development in pigs. PMID- 27941614 TI - Supercritical CO2 Foaming of Radiation Cross-Linked Isotactic Polypropylene in the Presence of TAIC. AB - Since the maximum foaming temperature window is only about 4 degrees C for supercritical CO2 (scCO2) foaming of pristine polypropylene, it is important to raise the melt strength of polypropylene in order to more easily achieve scCO2 foaming. In this work, radiation cross-linked isotactic polypropylene, assisted by the addition of a polyfunctional monomer (triallylisocyanurate, TAIC), was employed in the scCO2 foaming process in order to understand the benefits of radiation cross-linking. Due to significantly enhanced melt strength and the decreased degree of crystallinity caused by cross-linking, the scCO2 foaming behavior of polypropylene was dramatically changed. The cell size distribution, cell diameter, cell density, volume expansion ratio, and foaming rate of radiation-cross-linked polypropylene under different foaming conditions were analyzed and compared. It was found that radiation cross-linking favors the foamability and formation of well-defined cell structures. The optimal absorbed dose with the addition of 2 wt % TAIC was 30 kGy. Additionally, the foaming temperature window was expanded to about 8 degrees C, making the handling of scCO2 foaming of isotactic polypropylene much easier. PMID- 27941615 TI - Mechanisms of Body Weight Reduction by Black Tea Polyphenols. AB - Obesity is one of the most common nutritional diseases worldwide. This disease causes health problems, such as dyslipidemia, hyperglycemia, hypertension and inflammation. There are drugs used to inhibit obesity. However, they have serious side effects outweighing their beneficial effects. Black tea, commonly referred to as "fermented tea", has shown a positive effect on reducing body weight in animal models. Black tea polyphenols are the major components in black tea which reduce body weight. Black tea polyphenols are more effective than green tea polyphenols. Black tea polyphenols exert a positive effect on inhibiting obesity involving in two major mechanisms: (i) inhibiting lipid and saccharide digestion, absorption and intake, thus reducing calorie intake; and (ii) promoting lipid metabolism by activating AMP-activated protein kinase to attenuate lipogenesis and enhance lipolysis, and decreasing lipid accumulation by inhibiting the differentiation and proliferation of preadipocytes; (iii) blocking the pathological processes of obesity and comorbidities of obesity by reducing oxidative stress. Epidemiological studies of the health relevance between anti obesity and black tea polyphenols consumption remain to be further investigated. PMID- 27941616 TI - miR-429 Inhibits Differentiation and Promotes Proliferation in Porcine Preadipocytes. AB - MicroRNAs (miRNAs) are crucial regulatory molecules for adipogenesis. They contribute to the controlling of proliferation and differentiation of preadipocytes. Previous studies revealed an important role of miR-429 in cell invasion, migration, and apoptosis. Our previous work has shown that the expression of miR-429 in subcutaneous fat can be observed in newly born (3-day old) Rongchang piglets rather than their adult counterparts (180-day-old). This expression pattern suggests that miR-429 might be functionally related to postnatal adipogenesis. However, we currently lack a mechanistic understanding of miR-429 within the context of preadipocyte differentiation. In this study, we investigated the function of miR-429 in porcine subcutaneous and intramuscular preadipocyte proliferation and differentiation. In our porcine preadipocyte differentiation model, miR-429 expression decreased remarkably upon adipogenic induction. Overexpression of miR-429 notably down-regulated the expression of adipogenic marker genes: PPARgamma, aP2, FAS and impaired the triglyceride accumulation, while the expression of lipolytic gene ATGL was not affected. In addition, we observed that miR-429 significantly promoted the proliferation of porcine preadipocytes. We also found that miR-429 could directly bind to the 3' UTRs of KLF9 and p27, which have been well documented to promote preadipocyte differentiation and repress cell cycle progression. Taken together, our data support a novel role of miR-429 in regulating porcine preadipocyte differentiation and proliferation, and KLF9 and p27 are potent targets of miR-429 during these processes. PMID- 27941617 TI - Concrete Infill Monitoring in Concrete-Filled FRP Tubes Using a PZT-Based Ultrasonic Time-of-Flight Method. AB - Concrete-filled fiber-reinforced polymer tubes (CFFTs) have attracted interest for their structural applications in corrosive environments. However, a weak interfacial strength between the fiber-reinforced polymer (FRP) tube and the concrete infill may develop due to concrete shrinkage and inadequate concrete compaction during concrete casting, which will destroy the confinement effect and thereby reduce the load bearing capacity of a CFFT. In this paper, the lead zirconate titanate (PZT)-based ultrasonic time-of-flight (TOF) method was adopted to assess the concrete infill condition of CFFTs. The basic idea of this method is that the velocity of the ultrasonic wave propagation in the FRP material is about half of that in concrete material. Any voids or debonding created along the interface between the FRP tube and the concrete will delay the arrival time between the pairs of PZT transducers. A comparison of the arrival times of the PZT pairs between the intact and the defected CFFT was made to assess the severity of the voids or the debonding. The feasibility of the methodology was analyzed using a finite-difference time-domain-based numerical simulation. Experiments were setup to validate the numerical results, which showed good agreement with the numerical findings. The results showed that the ultrasonic time-of-flight method is able to detect the concrete infill condition of CFFTs. PMID- 27941619 TI - Black Crowberry (Empetrum nigrum L.) Flavonoids and Their Health Promoting Activity. AB - Nowadays, much research attention is focused on underutilized berry crops due to the high antioxidant activity of fruits. Black crowberry (Empetrum nigrum L.) represents an important source of flavonols (quercetin, rutin, myricetin, naringenin, naringin, morin, and kaempferol) and anthocyanins. The fruit components could be utilised as natural colourants or as a part of functional foods and, because of the high antioxidant activity, the berries of black crowberry can be used in the treatment of diseases accompanied with inflammation, or as an effective antibacterial and antifungal remedy. Moreover, the reduction of lipid accumulation and total cholesterol as well as an improvement of postprandial hyperglycaemia have been proven. This review summarizes for the first time the main antioxidants (flavonoids) of black crowberry fruits, with a focus on their health promoting activity. PMID- 27941620 TI - The First Finding of Six Instars of Larvae in Heteroptera and the Negative Correlation between Precipitation and Number of Individuals Collected in Sea Skaters of Halobates (Heteroptera: Gerridae). AB - This study, conducted during a scientific cruise, MR15-04, aims, first, to examine species and larval/adult components of Halobates (Heteroptera: Gerridae) inhabiting the tropical Indian Ocean of 4 degrees 00' S-7 degrees 00' S, 101 degrees 00' E-103 degrees 00' E and, second, to examine the correlative relationship between precipitation just before collection and the number of sea skaters collected in November and December 2015. Near Sumatra (50 km south-west), larvae and adults of four species of Halobates (Halobates germanes White, 1883; Halobates micans Eschscholtz, 1822; Halobates princeps White, 1883; undescribed species: Halobates sp.) were collected. Adults of an undescribed species had about a 5 mm long body in a gourd-like shape. One male adult specimen of H. princeps was collected. Body length, body width, and head width was measured in all specimens of Halobates. Six larval stages were detected in all three species of sea skaters as the first finding for Heteropteran insects. There was a negative correlation between amount of precipitation for 19 h before collection and the number of Halobates individuals collected by the neuston net. Death or (positive or passive) sinking by sea skaters could be due to occasional rain fall on the sea surface. PMID- 27941622 TI - Synthesis and Determination of Physicochemical Properties of New 3-(4 Arylpiperazin-1-yl)-2-hydroxypropyl 4-Alkoxyethoxybenzoates. AB - Nine new dihydrochloride salts of 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4 alkoxyethoxybenzoates were designed and synthesized. The physicochemical properties such as lipophilicity index (log kw) and dissociation constant (pKa) were experimentally determined and compared to the software calculated data. The lipophilicity index was determined by means of reversed-phase high performance liquid chromatography (RP-HPLC). The pKa values were determined by means of capillary zone electrophoresis. The "drug-likeness" properties according to the Lipinski Rule of Five and prediction of possible blood-brain barrier penetration were computed and discussed. PMID- 27941618 TI - Aquaporins in the Spinal Cord. AB - Aquaporins (AQPs) are water channel proteins robustly expressed in the central nervous system (CNS). A number of previous studies described the cellular expression sites and investigated their major roles and function in the brain and spinal cord. Among thirteen different mammalian AQPs, AQP1 and AQP4 have been mainly studied in the CNS and evidence has been presented that they play important roles in the pathogenesis of CNS injury, edema and multiple diseases such as multiple sclerosis, neuromyelitis optica spectrum disorders, amyotrophic lateral sclerosis, glioblastoma multiforme, Alzheimer's disease and Parkinson's disease. The objective of this review is to highlight the current knowledge about AQPs in the spinal cord and their proposed roles in pathophysiology and pathogenesis related to spinal cord lesions and injury. PMID- 27941621 TI - Relevance of MicroRNA200 Family and MicroRNA205 for Epithelial to Mesenchymal Transition and Clinical Outcome in Biliary Tract Cancer Patients. AB - Extensive stromal interaction is one reason for the dismal outcome of biliary tract cancer (BTC) patients. Epithelial to mesenchymal transition (EMT) is involved in tumor invasion and metastasis and is partly regulated by microRNAs (miRs). This study explores the expression of anti-EMT miR200 family (miR141, 200a/b/c, -429) and miR205 as well as the EMT-related proteins E-cadherin and vimentin in a panel of BTC cell lines and clinical specimens by quantitative real time polymerase chain reaction, Western blot and immunohistochemistry, respectively. MicroRNA expression was correlated to (i) the expression patterns of E-cadherin and vimentin; (ii) clinicopathological characteristics; and (iii) survival data. MicroRNA-200 family and miR205 were expressed in all BTC cells and clinical specimens. E-cadherin and vimentin showed a mutually exclusive expression pattern in both, in vitro and in vivo. Expression of miR200 family members positively correlated with E-cadherin and negatively with vimentin expression in BTC cells and specimens. High expression of miR200 family members (but not miR205) and E-cadherin was associated with longer survival, while low miR200 family and high vimentin expression was a predictor of unfavorable survival. Overall, the current study demonstrates the relevance of the miR200 family in EMT of BTC tumors and suggests these miRs as predictors for positive outcome. PMID- 27941623 TI - Identification of Potential Biomarkers for Rhegmatogenous Retinal Detachment Associated with Choroidal Detachment by Vitreous iTRAQ-Based Proteomic Profiling. AB - Rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD) is a complicated and serious type of rhegmatogenous retinal detachment (RRD). In this study, we identified differentially expressed proteins in the vitreous humors of RRDCD and RRD using isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano-liquid chromatography-electrospray ion trap-mass spectrometry-mass spectrometry (nano-LC-ESI-MS/MS) and bioinformatic analysis. Our result shows that 103 differentially expressed proteins, including 54 up-regulated and 49 down-regulated proteins were identified in RRDCD. Gene ontology (GO) analysis suggested that most of the differentially expressed proteins were extracellular.The Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis suggested that proteins related to complement and coagulation cascades were significantly enriched. iTRAQ-based proteomic profiling reveals that complement and coagulation cascades and inflammation may play important roles in the pathogenesis of RRDCD. This study may provide novel insights into the pathogenesis of RRDCD and offer potential opportunities for the diagnosis and treatment of RRDCD. PMID- 27941625 TI - A Novel Two-Step Liquid-Liquid Extraction Procedure Combined with Stationary Phase Immobilized Human Serum Albumin for the Chiral Separation of Cetirizine Enantiomers along with M and P Parabens. AB - The research into the separation of drug enantiomers is closely related to the safety and efficiency of the drugs. The aim of this study was to develop a simple and validated HPLC method to analyze cetirizine enantiomers. In the case of liquid dosage forms, besides the active substance in large amounts there are usually also inactive ingredients such as methyl- and propylparaben. Unfortunately, these compounds can interfere with the analyte, inter alia during chiral separation of the analyte enantiomers. The proposed innovative two-step liquid-liquid extraction procedure allowed for the determination of cetirizine enantiomers (along with M and P parabens) also in liquid dosage forms. The main focus of this study was the chromatographic activity of cetirizine dihydrochloride on the proteinate-based chiral stationary phase. The chromatographic separation of cetirizine enantiomers was performed on an immobilized human serum albumin (HSA) column for the first time. Measurements were performed at a wavelength of 227 nm. Under optimal conditions, baseline separation of two enantiomers was obtained with 1.43 enantioseparation factor (alpha) and 1.82 resolution (Rs). Finally, the proposed method was successfully applied to the selected pharmaceutical formulations. PMID- 27941624 TI - An Ionic 1,4-Bis(styryl)benzene-Based Fluorescent Probe for Mercury(II) Detection in Water via Deprotection of the Thioacetal Group. AB - Highly sensitive and selective mercury detection in aqueous media is urgently needed because mercury poisoning usually results from exposure to water-soluble forms of mercury by inhalation and/or ingesting. An ionic conjugated oligoelectrolye (M1Q) based on 1,4-bis(styryl)benzene was synthesized as a fluorescent mercury(II) probe. The thioacetal moiety and quaternized ammonium group were incorporated for Hg2+ recognition and water solubility. A neutral Hg2+ probe (M1) was also prepared based on the same molecular backbone, and their sensor characteristics were investigated in a mixture of acetonitrile/water and in water. In the presence of Hg2+, the thioacetal group was converted to aldehyde functionality, and the resulting photoluminescence intensity decreased. In water, M1Q successfully demonstrated highly sensitive detection, showing a binding toward Hg2+ that was ~15 times stronger and a signal on/off ratio twice as high, compared to M1 in acetonitrile/water. The thioacetal deprotection by Hg2+ ions was substantially facilitated in water without an organic cosolvent. The limit of detection was measured to be 7 nM with a detection range of 10-180 nM in 100% aqueous medium. PMID- 27941626 TI - The Protective Effect of Selenium on Chronic Zearalenone-Induced Reproductive System Damage in Male Mice. AB - This study aims to explore the protective effect of selenium (Se) on chronic zearalenone (ZEN)-induced reproductive system damage in male mice and the possible protective molecular mechanism against this. The chronic ZEN-induced injury mouse model was established with the continuous intragastric administration of 40 mg/kg body mass (B.M.) ZEN for 28 days. Then, interventions with different doses (0.1, 0.2, and 0.4 mg/kg B.M.) of Se were conducted on mice to analyse the changes in organ indexes of epididymis and testis, antioxidant capability of testis, serum level of testosterone, sperm concentration and motility parameters, and the expression levels of apoptosis-associated genes and blood testis barrier- (BTB) related genes. Our results showed that Se could greatly improve the ZEN-induced decrease of epididymis indexes and testis indexes. Results also showed that the decrease in sperm concentration, sperm normality rate, and sperm motility parameters, including percentage of motile sperm (motile), tropism percentage (progressive) and sperm average path velocity (VAP), caused by ZEN were elevated upon administration of the higher dose (0.4 mg/kg) and intermediate dose (0.2 mg/kg) of Se. Selenium also significantly reduced the content of malondialdehyde (MDA) but enhanced the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the testis tissue. Further research demonstrated that ZEN increased the level of mRNA expression of BCL2-associated X protein (Bax) and caspase 3 (Casp3), decreased the level of mRNA expression of B cell leukemia/lymphoma 2 (Bcl2), vimentin (Vim) and cadherin 2 (Cdh2), whereas the co-administration of Se reversed these gene expression levels. Our results indicated that high levels of Se could protect against reproductive system damage in male mice caused by ZEN and the mechanism might such be that Se improved mice antioxidant ability, inhibited reproductive cell apoptosis, and increased the decrease of BTB integrity-related genes caused by ZEN. PMID- 27941628 TI - Ground Level PM2.5 Estimates over China Using Satellite-Based Geographically Weighted Regression (GWR) Models Are Improved by Including NO2 and Enhanced Vegetation Index (EVI). AB - Highly accurate data on the spatial distribution of ambient fine particulate matter (<2.5 MUm: PM2.5) is currently quite limited in China. By introducing NO2 and Enhanced Vegetation Index (EVI) into the Geographically Weighted Regression (GWR) model, a newly developed GWR model combined with a fused Aerosol Optical Depth (AOD) product and meteorological parameters could explain approximately 87% of the variability in the corresponding PM2.5 mass concentrations. There existed obvious increase in the estimation accuracy against the original GWR model without NO2 and EVI, where cross-validation R2 increased from 0.77 to 0.87. Both models tended to overestimate when measurement is low and underestimate when high, where the exact boundary value depended greatly on the dependent variable. There was still severe PM2.5 pollution in many residential areas until 2015; however, policy-driven energy conservation and emission reduction not only reduced the severity of PM2.5 pollution but also its spatial range, to a certain extent, from 2014 to 2015. The accuracy of satellite-derived PM2.5 still has limitations for regions with insufficient ground monitoring stations and desert areas. Generally, the use of NO2 and EVI in GWR models could more effectively estimate PM2.5 at the national scale than previous GWR models. The results in this study could provide a reasonable reference for assessing health impacts, and could be used to examine the effectiveness of emission control strategies under implementation in China. PMID- 27941627 TI - Hepatoprotective Effect of Cuscuta campestris Yunck. Whole Plant on Carbon Tetrachloride Induced Chronic Liver Injury in Mice. AB - Cuscuta seeds and whole plant have been used to nourish the liver and kidney. This study was aimed to investigate the hepatoprotective activity of the ethanol extract of Cuscuta campestris Yunck. whole plant (CCEtOH). The hepatoprotective effect of CCEtOH (20, 100 and 500 mg/kg) was evaluated on carbon tetrachloride (CCl4)-induced chronic liver injury. Serum alanine aminotransferase, aspartate aminotransferase, triglyceride and cholesterol were measured and the fibrosis was histologically examined. CCEtOH exhibited a significant inhibition of the increase of serum alanine aminotransferase, aspartate aminotransferase, triglyceride and cholesterol. Histological analyses showed that fibrosis of liver induced by CCl4 were significantly reduced by CCEtOH. In addition, 20, 100 and 500 mg/kg of the extract decreased the level of malondialdehyde (MDA) and enhanced the activities of anti-oxidative enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRd) in the liver. We demonstrate that the hepatoprotective mechanisms of CCEtOH were likely to be associated to the decrease in MDA level by increasing the activities of antioxidant enzymes such as SOD, GPx and GRd. In addition, our findings provide evidence that C. campestris Yunck. whole plant possesses a hepatoprotective activity to ameliorate chronic liver injury. PMID- 27941630 TI - Geometry Constrained N-(5,6,7-Trihydroquinolin-8-ylidene)arylaminopalladium Dichloride Complexes: Catalytic Behavior toward Methyl Acrylate (MA), Methyl Acrylate-co-Norbornene (MA-co-NB) Polymerization and Heck Coupling. AB - A new pair of plladium complexes (Pd4 and Pd5) ligated with constrained N-(5,6,7 trihydroquinolin-8-ylidene)arylamine ligands have been prepared and well characterized by 1H-, 13C-NMR and FTIR spectroscopies as well as elemental analysis. The molecular structure of Pd4 and Pd5 in solid state have also been determined by X-ray diffraction, showing slightly distorted square planar geometry around the palladium metal center. All complexes Pd1-Pd5 are revealed highly efficient catalyst in methyl acrylate (MA) polymerization as well as methyl acrylate/norbornene (MA/NB) copolymerization. In the case of MA polymerization, as high as 98.4% conversion with high molecular weight up to 6282 kg.mol-1 was achieved. Likewise, Pd3 complex has good capability to incorporate about 18% NB content into MA polymer chains. Furthermore, low catalyst loadings (0.002 mol %) of Pd4 or Pd5 are able to efficiently mediate the coupling of haloarenes with styrene affording up to 98% conversion. PMID- 27941629 TI - The Telomerase-Derived Anticancer Peptide Vaccine GV1001 as an Extracellular Heat Shock Protein-Mediated Cell-Penetrating Peptide. AB - Cell-penetrating peptides (CPPs), which can facilitate the transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular delivery of macromolecules. GV1001, a peptide derived from a reverse transcriptase subunit of telomerase (hTERT) and developed as a vaccine against various cancers, reportedly has unexpected CPP properties. Unlike typical CPPs, such as the HIV-1 TAT peptide, GV1001 enabled the cytosolic delivery of macromolecules such as proteins, DNA and siRNA via extracellular heat shock protein 90 (eHSP90) and 70 (eHSP70) complexes. The eHSP-GV1001 interaction may have biological effects in addition to its cytosolic delivery function. GV1001 was originally designed as a major histocompatibility complex (MHC) class II binding cancer epitope, but its CPP properties may contribute to its strong anti cancer immune response relative to other telomerase peptide-based vaccines. Cell signaling via eHSP-GV1001 binding may lead to unexpected biological effects, such as direct anticancer or antiviral effects. In this review, we focus on the CPP effects of GV1001 bound to eHSP90 and eHSP70. PMID- 27941631 TI - A Low Cost VLSI Architecture for Spike Sorting Based on Feature Extraction with Peak Search. AB - The goal of this paper is to present a novel VLSI architecture for spike sorting with high classification accuracy, low area costs and low power consumption. A novel feature extraction algorithm with low computational complexities is proposed for the design of the architecture. In the feature extraction algorithm, a spike is separated into two portions based on its peak value. The area of each portion is then used as a feature. The algorithm is simple to implement and less susceptible to noise interference. Based on the algorithm, a novel architecture capable of identifying peak values and computing spike areas concurrently is proposed. To further accelerate the computation, a spike can be divided into a number of segments for the local feature computation. The local features are subsequently merged with the global ones by a simple hardware circuit. The architecture can also be easily operated in conjunction with the circuits for commonly-used spike detection algorithms, such as the Non-linear Energy Operator (NEO). The architecture has been implemented by an Application-Specific Integrated Circuit (ASIC) with 90-nm technology. Comparisons to the existing works show that the proposed architecture is well suited for real-time multi channel spike detection and feature extraction requiring low hardware area costs, low power consumption and high classification accuracy. PMID- 27941633 TI - A Prospective Study on Serum Methylmalonic Acid and Homocysteine in Pregnant Women. AB - This study aimed to investigate serum methylmalonic acid (MMA) and homocysteine levels and to assess their effects on pregnancy and neonatal outcomes. Serum MMA and homocysteine levels in 278 pregnant Korean women, determined by liquid chromatography-tandem mass spectrometry in each trimester, were compared with those of previous studies in other ethnic groups. We investigated the association between MMA and homocysteine status with pregnancy and neonatal events: gestational diabetes, preeclampsia, gestational age at delivery, preterm birth, small for gestational age, neonatal birth weight, and congenital abnormalities. The median (range) MMA level was 0.142 (0.063-0.446) umol/L and homocysteine level was 10.6 (4.4-38.0) umol/L in pregnant women. MMA levels were significantly higher in the third trimester than during other trimesters (p < 0.05), while homocysteine levels were not. No significant association was observed between MMA or homocysteine levels and any of the maternal or neonatal outcomes examined. Future studies are needed to assess the associations among maternal serum concentrations of MMA and homocysteine, and maternal and neonatal outcomes. PMID- 27941635 TI - A Target-Less Vision-Based Displacement Sensor Based on Image Convex Hull Optimization for Measuring the Dynamic Response of Building Structures. AB - Existing vision-based displacement sensors (VDSs) extract displacement data through changes in the movement of a target that is identified within the image using natural or artificial structure markers. A target-less vision-based displacement sensor (hereafter called "TVDS") is proposed. It can extract displacement data without targets, which then serve as feature points in the image of the structure. The TVDS can extract and track the feature points without the target in the image through image convex hull optimization, which is done to adjust the threshold values and to optimize them so that they can have the same convex hull in every image frame and so that the center of the convex hull is the feature point. In addition, the pixel coordinates of the feature point can be converted to physical coordinates through a scaling factor map calculated based on the distance, angle, and focal length between the camera and target. The accuracy of the proposed scaling factor map was verified through an experiment in which the diameter of a circular marker was estimated. A white-noise excitation test was conducted, and the reliability of the displacement data obtained from the TVDS was analyzed by comparing the displacement data of the structure measured with a laser displacement sensor (LDS). The dynamic characteristics of the structure, such as the mode shape and natural frequency, were extracted using the obtained displacement data, and were compared with the numerical analysis results. TVDS yielded highly reliable displacement data and highly accurate dynamic characteristics, such as the natural frequency and mode shape of the structure. As the proposed TVDS can easily extract the displacement data even without artificial or natural markers, it has the advantage of extracting displacement data from any portion of the structure in the image. PMID- 27941632 TI - Dietary Keratan Sulfate from Shark Cartilage Modulates Gut Microbiota and Increases the Abundance of Lactobacillus spp. AB - Keratan sulfate (KS) represents an important family of glycosaminoglycans that are critical in diverse physiological processes. Recently, accumulating evidence has provided a wealth of information on the bioactivity of KS, which established it as an attractive candidate for drug development. However, although KS has been widely explored, less attention has been given to its effect on gut microbiota. Therefore, given that gut microbiota plays a pivotal role in health homeostasis and disease pathogenesis, we investigated here in detail the effect of KS on gut microbiota by high-throughput sequencing. As revealed by heatmap and principal component analysis, the mice gut microbiota was readily altered at different taxonomic levels by intake of low (8 mg/kg) and high dosage (40 mg/kg) of KS. Interestingly, KS exerted a differing effect on male and female microbiota. Specifically, KS induced a much more drastic increase in the abundance of Lactobacillus spp. in female (sixteen-fold) versus male mice (two-fold). In addition, combined with alterations in gut microbiota, KS also significantly reduced body weight while maintaining normal gut homeostasis. Altogether, we first demonstrated a sex-dependent effect of KS on gut microbiota and highlighted that it may be used as a novel prebiotic for disease management. PMID- 27941634 TI - A Review on Microfluidic Paper-Based Analytical Devices for Glucose Detection. AB - Glucose, as an essential substance directly involved in metabolic processes, is closely related to the occurrence of various diseases such as glucose metabolism disorders and islet cell carcinoma. Therefore, it is crucial to develop sensitive, accurate, rapid, and cost effective methods for frequent and convenient detections of glucose. Microfluidic Paper-based Analytical Devices (MUPADs) not only satisfying the above requirements but also occupying the advantages of portability and minimal sample consumption, have exhibited great potential in the field of glucose detection. This article reviews and summarizes the most recent improvements in glucose detection in two aspects of colorimetric and electrochemical MUPADs. The progressive techniques for fabricating channels on MUPADs are also emphasized in this article. With the growth of diabetes and other glucose indication diseases in the underdeveloped and developing countries, low-cost and reliably commercial MUPADs for glucose detection will be in unprecedentedly demand. PMID- 27941636 TI - A Portable Array-Type Optical Fiber Sensing Instrument for Real-Time Gas Detection. AB - A novel optical fiber array-type of sensing instrument with temperature compensation for real-time detection was developed to measure oxygen, carbon dioxide, and ammonia simultaneously. The proposed instrument is multi-sensing array integrated with real-time measurement module for portable applications. The sensing optical fibers were etched and polished before coating to increase sensitivities. The ammonia and temperature sensors were each composed of a dye coated single-mode fiber with constructing a fiber Bragg grating and a long period filter grating for detecting light intensity. Both carbon dioxide and oxygen sensing structures use multimode fibers where 1-hydroxy-3,6,8-pyrene trisulfonic acid trisodium salt is coated for carbon dioxide sensing and Tris(2,2'-bipyridyl) dichlororuthenium(II) hexahydrate and Tris(bipyridine)ruthenium(II) chloride are coated for oxygen sensing. Gas-induced fluorescent light intensity variation was applied to detect gas concentration. The portable gas sensing array was set up by integrating with photo-electronic measurement modules and a human-machine interface to detect gases in real time. The measured data have been processed using piecewise-linear method. The sensitivity of the oxygen sensor were 1.54%/V and 9.62%/V for concentrations less than 1.5% and for concentrations between 1.5% and 6%, respectively. The sensitivity of the carbon dioxide sensor were 8.33%/V and 9.62%/V for concentrations less than 2% and for concentrations between 2% and 5%, respectively. For the ammonia sensor, the sensitivity was 27.78%/V, while ammonia concentration was less than 2%. PMID- 27941637 TI - Investigating Sterol and Redox Regulation of the Ion Channel Activity of CLIC1 Using Tethered Bilayer Membranes. AB - The Chloride Intracellular Ion Channel (CLIC) family consists of six conserved proteins in humans. These are a group of enigmatic proteins, which adopt both a soluble and membrane bound form. CLIC1 was found to be a metamorphic protein, where under specific environmental triggers it adopts more than one stable reversible soluble structural conformation. CLIC1 was found to spontaneously insert into cell membranes and form chloride ion channels. However, factors that control the structural transition of CLIC1 from being an aqueous soluble protein into a membrane bound protein have yet to be adequately described. Using tethered bilayer lipid membranes and electrical impedance spectroscopy system, herein we demonstrate that CLIC1 ion channel activity is dependent on the type and concentration of sterols in bilayer membranes. These findings suggest that membrane sterols play an essential role in CLIC1's acrobatic switching from a globular soluble form to an integral membrane form, promoting greater ion channel conductance in membranes. What remains unclear is the precise nature of this regulation involving membrane sterols and ultimately determining CLIC1's membrane structure and function as an ion channel. Furthermore, our impedance spectroscopy results obtained using CLIC1 mutants, suggest that the residue Cys24 is not essential for CLIC1's ion channel function. However Cys24 does appear important for optimal ion channel activity. We also observe differences in conductance between CLIC1 reduced and oxidized forms when added to our tethered membranes. Therefore, we conclude that both membrane sterols and redox play a role in the ion channel activity of CLIC1. PMID- 27941638 TI - Bronchiectasis in the Last Five Years: New Developments. AB - Bronchiectasis, a chronic lung disease characterised by cough and purulent sputum, recurrent infections, and airway damage, is associated with considerable morbidity and mortality. To date, treatment options have been limited to physiotherapy to clear sputum and antibiotics to treat acute infections. Over the last decade, there has been significant progress in understanding the epidemiology, pathophysiology, and microbiology of this disorder. Over the last five years, methods of assessing severity have been developed, the role of macrolide antibiotic therapy in reducing exacerbations cemented, and inhaled antibiotic therapies show promise in the treatment of chronic Pseudomonas aeruginosa infection. Novel therapies are currently undergoing Phase 1 and 2 trials. This review aims to address the major developments within the field of bronchiectasis over this time. PMID- 27941639 TI - Evolution of the Cytolytic Pore-Forming Proteins (Actinoporins) in Sea Anemones. AB - Sea anemones (Cnidaria, Anthozoa, and Actiniaria) use toxic peptides to incapacitate and immobilize prey and to deter potential predators. Their toxin arsenal is complex, targeting a variety of functionally important protein complexes and macromolecules involved in cellular homeostasis. Among these, actinoporins are one of the better characterized toxins; these venom proteins form a pore in cellular membranes containing sphingomyelin. We used a combined bioinformatic and phylogenetic approach to investigate how actinoporins have evolved across three superfamilies of sea anemones (Actinioidea, Metridioidea, and Actinostoloidea). Our analysis identified 90 candidate actinoporins across 20 species. We also found clusters of six actinoporin-like genes in five species of sea anemone (Nematostella vectensis, Stomphia coccinea, Epiactis japonica, Heteractis crispa, and Diadumene leucolena); these actinoporin-like sequences resembled actinoporins but have a higher sequence similarity with toxins from fungi, cone snails, and Hydra. Comparative analysis of the candidate actinoporins highlighted variable and conserved regions within actinoporins that may pertain to functional variation. Although multiple residues are involved in initiating sphingomyelin recognition and membrane binding, there is a high rate of replacement for a specific tryptophan with leucine (W112L) and other hydrophobic residues. Residues thought to be involved with oligomerization were variable, while those forming the phosphocholine (POC) binding site and the N-terminal region involved with cell membrane penetration were highly conserved. PMID- 27941640 TI - Fibroblast Growth Factor-23-A Potential Uremic Toxin. AB - Fibroblast growth factor-23 (FGF23) is a circulating member of the FGF family produced mainly by the osteocytes and osteoblasts that can act as a hormone. The main action of FGF23 is to lower phosphatemia via the reduction of urinary phosphate reabsorption and the decrease of 1,25(OH)2-D generation in the kidney. In the course of chronic kidney disease (CKD), plasma FGF23 concentration rises early, most probably to compensate the inability of the deteriorating kidneys to excrete an adequate amount of phosphate. However, this comes at the cost of FGF23 related target organ toxicity. Results of clinical studies suggest that elevated plasma FGF23 concentration is independently associated with the increased risk of CKD progression, occurrence of cardio-vascular complications, and mortality in different stages of CKD. FGF23 also contributes to cardiomyocyte hypertrophy, vascular calcification, and endothelial dysfunction. The impact of FGF23 on heart muscle is not dependent on Klotho, but rather on the PLCgamma-calcineurin-NFAT (nuclear factor of activated T-cells) pathway. Among the factors increasing plasma FGF23 concentration, active vitamin D analogues play a significant role. Additionally, inflammation and iron deficiency can contribute to the increase of plasma FGF23. Among the factors decreasing plasma FGF23, dietary phosphate restriction, some intestinal phosphate binders, cinacalcet (and other calcimimetics), and nicotinamide can be enumerated. Anti-FGF23 antibodies have also recently been developed to inhibit the action of FGF23 in target organs. Still, the best way to normalize plasma FGF23 in maintenance hemodialysis patients is restoring kidney function by successful kidney transplantation. PMID- 27941643 TI - The BASE-Program-A Multidimensional Approach for Health Promotion in Companies. AB - Multidimensional assessments for conducting interventions are needed to achieve positive health effects within companies. BASE is an acronym, consisting of B = "Bedarfsbestimmung" (requirements); A = "Arbeitsplatzorganisation" (organisation of work); S = "Schulung des belastungsvertraglichen Alltagshandelns" (coaching preventive behaviour at work); E = "Eigenverantwortung und Selbstwirksamkeit" (self-responsibility and self-efficacy). It is a prevention program designed to avoid and reduce work-related musculoskeletal diseases. It was developed to support prevention strategies within companies. It comprises aspects of health protection, ergonomics, exercise and self-efficacy. A comprehensive assessment will identify strain e.g., musculoskeletal discomforts due to body positions or psychological stress. Moreover, the general health status, preferences and barriers for participating in health promotion programs are evaluated. This analysis leads to practical and goal-oriented recommendations and interventions which suit the needs of companies and employees. These are executed onsite in real workplace situations and involve the introduction of first-hand experience in behavioural change. Therefore, this practical approach enhances the employees' acceptance and self-efficacy for health promotion. This can result in long-term health promoting behaviour. This article presents the outcome and sustainability effects of BASE in three different application fields (logistic, industrial and office workers). PMID- 27941642 TI - The Virulence Regulator Rns Activates the Expression of CS14 Pili. AB - Although many viral and bacterial pathogens cause diarrhea, enterotoxigenic E. coli (ETEC) is one of the most frequently encountered in impoverished regions where it is estimated to kill between 300,000 and 700,000 children and infants annually. Critical ETEC virulence factors include pili which mediate the attachment of the pathogen to receptors in the intestinal lumen. In this study we show that the ETEC virulence regulator Rns positively regulates the expression of CS14 pili. Three Rns binding sites were identified upstream of the CS14 pilus promoter centered at -34.5, -80.5, and -155.5 relative to the Rns-dependent transcription start site. Mutagenesis of the promoter proximal site significantly decreased expression from the CS14 promoter. In contrast, the contribution of Rns bound at the promoter distal site was negligible and largely masked by occupancy of the promoter proximal site. Unexpectedly, Rns bound at the site centered at 80.5 had a slight but statistically significant inhibitory effect upon the pilin promoter. Nevertheless, this weak inhibitory effect was not sufficient to overcome the substantial promoter activation from Rns bound to the promoter proximal site. Thus, CS14 pili belong to a group of pili that depend upon Rns for their expression. PMID- 27941641 TI - Potential of Induced Pluripotent Stem Cells (iPSCs) for Treating Age-Related Macular Degeneration (AMD). AB - The field of stem cell biology has rapidly evolved in the last few decades. In the area of regenerative medicine, clinical applications using stem cells hold the potential to be a powerful tool in the treatment of a wide variety of diseases, in particular, disorders of the eye. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are promising technologies that can potentially provide an unlimited source of cells for cell replacement therapy in the treatment of retinal degenerative disorders such as age-related macular degeneration (AMD), Stargardt disease, and other disorders. ESCs and iPSCs have been used to generate retinal pigment epithelium (RPE) cells and their functional behavior has been tested in vitro and in vivo in animal models. Additionally, iPSC-derived RPE cells provide an autologous source of cells for therapeutic use, as well as allow for novel approaches in disease modeling and drug development platforms. Clinical trials are currently testing the safety and efficacy of these cells in patients with AMD. In this review, the current status of iPSC disease modeling of AMD is discussed, as well as the challenges and potential of this technology as a viable option for cell replacement therapy in retinal degeneration. PMID- 27941644 TI - Host-Derived Artificial MicroRNA as an Alternative Method to Improve Soybean Resistance to Soybean Cyst Nematode. AB - The soybean cyst nematode (SCN), Heterodera glycines, is one of the most important pests limiting soybean production worldwide. Novel approaches to managing this pest have focused on gene silencing of target nematode sequences using RNA interference (RNAi). With the discovery of endogenous microRNAs as a mode of gene regulation in plants, artificial microRNA (amiRNA) methods have become an alternative method for gene silencing, with the advantage that they can lead to more specific silencing of target genes than traditional RNAi vectors. To explore the application of amiRNAs for improving soybean resistance to SCN, three nematode genes (designated as J15, J20, and J23) were targeted using amiRNA vectors. The transgenic soybean hairy roots, transformed independently with these three amiRNA vectors, showed significant reductions in SCN population densities in bioassays. Expression of the targeted genes within SCN eggs were downregulated in populations feeding on transgenic hairy roots. Our results provide evidence that host-derived amiRNA methods have great potential to improve soybean resistance to SCN. This approach should also limit undesirable phenotypes associated with off-target effects, which is an important consideration for commercialization of transgenic crops. PMID- 27941649 TI - Extract of Monascus purpureus CWT715 Fermented from Sorghum Liquor Biowaste Inhibits Migration and Invasion of SK-Hep-1 Human Hepatocarcinoma Cells. AB - Liver cancer is the most endemic cancer in a large region of the world. This study investigated the anti-metastatic effects of an extract of Monascus purpureus CWT715 (MP) fermented from sorghum liquor biowaste and its mechanisms of action in highly metastatic human hepatocarcinoma SK-Hep-1 cells. Kinmen sorghum liquor waste was used as the primary nutrient source to produce metabolites (including pigments) of MP. In the presence of 10 ug/mL MP-fermented broth (MFB), the anti-invasive activity increased with increasing fermentation time reaching a maximum at six days of fermentation. Interestingly, MFB also produced maximal pigment content at six days. Treatment for 24 h with MFB (10-100 ug/mL) obtained from fermentation for six days significantly inhibited cell migration and invasion, and these effects were concentration-dependent. MFB also significantly enhanced nm23-H1 protein expression in a concentration-dependent manner, which was highly correlated with migration and invasion. These results suggest that MFB has significant anti-migration and anti-invasion activities and that these effects are associated with the induction of nm23-H1 protein expression. PMID- 27941646 TI - Low Concentration of Exogenous Carbon Monoxide Modulates Radiation-Induced Bystander Effect in Mammalian Cell Cluster Model. AB - During radiotherapy procedures, radiation-induced bystander effect (RIBE) can potentially lead to genetic hazards to normal tissues surrounding the targeted regions. Previous studies showed that RIBE intensities in cell cluster models were much higher than those in monolayer cultured cell models. On the other hand, low-concentration carbon monoxide (CO) was previously shown to exert biological functions via binding to the heme domain of proteins and then modulating various signaling pathways. In relation, our previous studies showed that exogenous CO generated by the CO releasing molecule, tricarbonyldichlororuthenium (CORM-2), at a relatively low concentration (20 uM), effectively attenuated the formation of RIBE-induced DNA double-strand breaks (DSB) and micronucleus (MN). In the present work, we further investigated the capability of a low concentration of exogenous CO (CORM-2) of attenuating or inhibiting RIBE in a mixed-cell cluster model. Our results showed that CO (CORM-2) with a low concentration of 30 uM could effectively suppress RIBE-induced DSB (p53 binding protein 1, p53BP1), MN formation and cell proliferation in bystander cells but not irradiated cells via modulating the inducible nitric oxide synthase (iNOS) andcyclooxygenase-2 (COX 2). The results can help mitigate RIBE-induced hazards during radiotherapy procedures. PMID- 27941647 TI - The Role of ERK1/2 in the Development of Diabetic Cardiomyopathy. AB - Diabetes mellitus is a chronic metabolic condition that affects carbohydrate, lipid and protein metabolism and may impair numerous organs and functions of the organism. Cardiac dysfunction afflicts many patients who experience the oxidative stress of the heart. Diabetic cardiomyopathy (DCM) is one of the major complications that accounts for more than half of diabetes-related morbidity and mortality cases. Chronic hyperglycemia and hyperlipidemia from diabetes mellitus cause cardiac oxidative stress, endothelial dysfunction, impaired cellular calcium handling, mitochondrial dysfunction, metabolic disturbances, and remodeling of the extracellular matrix, which ultimately lead to DCM. Although many studies have explored the mechanisms leading to DCM, the pathophysiology of DCM has not yet been fully clarified. In fact, as a potential mechanism, the associations between DCM development and mitogen-activated protein kinase (MAPK) activation have been the subjects of tremendous interest. Nonetheless, much remains to be investigated, such as tissue- and cell-specific processes of selection of MAPK activation between pro-apoptotic vs. pro-survival fate, as well as their relation with the pathogenesis of diabetes and associated complications. In general, it turns out that MAPK signaling pathways, such as extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase, are demonstrated to be actively involved in myocardial dysfunction, hypertrophy, fibrosis and heart failure. As one of MAPK family members, the activation of ERK1/2 has also been known to be involved in cardiac hypertrophy and dysfunction. However, many recent studies have demonstrated that ERK1/2 signaling activation also plays a crucial role in FGF21 signaling and exerts a protective environment of glucose and lipid metabolism, therefore preventing abnormal healing and cardiac dysfunction. The duration, extent, and subcellular compartment of ERK1/2 activation are vital to differential biological effects of ERK1/2. Moreover, many intracellular events, including mitochondrial signaling and protein kinases, manipulate signaling upstream and downstream of MAPK, to influence myocardial survival or death. In this review, we will summarize the roles of ERK1/2 pathways in DCM development by the evidence from current studies and will present novel opinions on "differential influence of ERK1/2 action in cardiac dysfunction, and protection against myocardial ischemia reperfusion injury". PMID- 27941645 TI - Pathophysiological Significance of Store-Operated Calcium Entry in Megakaryocyte Function: Opening New Paths for Understanding the Role of Calcium in Thrombopoiesis. AB - Store-Operated Calcium Entry (SOCE) is a universal calcium (Ca2+) influx mechanism expressed by several different cell types. It is now known that Stromal Interaction Molecule (STIM), the Ca2+ sensor of the intracellular compartments, together with Orai and Transient Receptor Potential Canonical (TRPC), the subunits of Ca2+ permeable channels on the plasma membrane, cooperate in regulating multiple cellular functions as diverse as proliferation, differentiation, migration, gene expression, and many others, depending on the cell type. In particular, a growing body of evidences suggests that a tight control of SOCE expression and function is achieved by megakaryocytes along their route from hematopoietic stem cells to platelet production. This review attempts to provide an overview about the SOCE dynamics in megakaryocyte development, with a focus on most recent findings related to its involvement in physiological and pathological thrombopoiesis. PMID- 27941650 TI - Roles of Erythroid Differentiation Regulator 1 (Erdr1) on Inflammatory Skin Diseases. AB - Erythroid Differentiation Regulator 1 (Erdr1) is known as a hemoglobin synthesis factor which also regulates cell survival under conditions of stress. In addition, previous studies have revealed the effects of Erdr1 on cancer progression and its negative correlation with interleukin (IL)-18, a pro inflammatory cytokine. Based on this evidence, the therapeutic effects of Erdr1 have been demonstrated in several inflammatory skin diseases such as malignant skin cancer, psoriasis, and rosacea. This article reviews the roles of Erdr1 in skin inflammation, suggesting that Erdr1 is a potential therapeutic molecule on inflammatory disorders. PMID- 27941648 TI - Anaphase B. AB - Anaphase B spindle elongation is characterized by the sliding apart of overlapping antiparallel interpolar (ip) microtubules (MTs) as the two opposite spindle poles separate, pulling along disjoined sister chromatids, thereby contributing to chromosome segregation and the propagation of all cellular life. The major biochemical "modules" that cooperate to mediate pole-pole separation include: (i) midzone pushing or (ii) braking by MT crosslinkers, such as kinesin 5 motors, which facilitate or restrict the outward sliding of antiparallel interpolar MTs (ipMTs); (iii) cortical pulling by disassembling astral MTs (aMTs) and/or dynein motors that pull aMTs outwards; (iv) ipMT plus end dynamics, notably net polymerization; and (v) ipMT minus end depolymerization manifest as poleward flux. The differential combination of these modules in different cell types produces diversity in the anaphase B mechanism. Combinations of antagonist modules can create a force balance that maintains the dynamic pre-anaphase B spindle at constant length. Tipping such a force balance at anaphase B onset can initiate and control the rate of spindle elongation. The activities of the basic motor filament components of the anaphase B machinery are controlled by a network of non-motor MT-associated proteins (MAPs), for example the key MT cross-linker, Ase1p/PRC1, and various cell-cycle kinases, phosphatases, and proteases. This review focuses on the molecular mechanisms of anaphase B spindle elongation in eukaryotic cells and briefly mentions bacterial DNA segregation systems that operate by spindle elongation. PMID- 27941651 TI - Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer. AB - Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer. PMID- 27941653 TI - Bioassay-Guided Isolation of Cytotoxic Isocryptoporic Acids from Cryptoporus volvatus. AB - The present work constitutes a contribution to the phytochemical investigation of Cryptoporus volvatus aiming to search for effective cytotoxic constituents against tumor cell lines in vivo. Bioassay-guided separation of the ethylacetate extract of C. volvatus afforded four new isocryptoporic acid (ICA) derivatives, ICA-B trimethyl ester (1), ICA-E (2), ICA-E pentamethyl ester (3), and ICA-G (4), together with nine known cryptoporic acids. These isocryptoporic acids are isomers of the cryptoporic acids with drimenol instead of albicanol as the terpenoid fragment; their structures were elucidated on the basis of spectroscopic evidences (UV, IR, HRMS, and NMR) and comparison with literature values. All isolates show certain cytotoxic activities against five tumor cell lines. Among them, compound 4 showed an comparable activity to that of the positive control cis-platin, while other compounds exhibited weak cytotoxic activities. PMID- 27941652 TI - Functional Divergence of Poplar Histidine-Aspartate Kinase HK1 Paralogs in Response to Osmotic Stress. AB - Previous works have shown the existence of protein partnerships belonging to a MultiStep Phosphorelay (MSP) in Populus putatively involved in osmosensing. This study is focused on the identification of a histidine-aspartate kinase, HK1b, paralog of HK1a. The characterization of HK1b showed its ability to homo- and hetero-dimerize and to interact with a few Histidine-containing Phosphotransfer (HPt) proteins, suggesting a preferential partnership in poplar MSP linked to drought perception. Furthermore, determinants for interaction specificity between HK1a/1b and HPts were studied by mutagenesis analysis, identifying amino acids involved in this specificity. The HK1b expression analysis in different poplar organs revealed its co-expression with three HPts, reinforcing the hypothesis of partnership participation in the MSP in planta. Moreover, HK1b was shown to act as an osmosensor with kinase activity in a functional complementation assay of an osmosensor deficient yeast strain. These results revealed that HK1b showed a different behaviour for canonical phosphorylation of histidine and aspartate residues. These phosphorylation modularities of canonical amino acids could explain the improved osmosensor performances observed in yeast. As conserved duplicates reflect the selective pressures imposed by the environmental requirements on the species, our results emphasize the importance of HK1 gene duplication in poplar adaptation to drought stress. PMID- 27941655 TI - Methotrexate and Cytarabine-Loaded Nanocarriers for Multidrug Cancer Therapy. Spectroscopic Study. AB - Determining the properties of nanoparticles obtained by novel methods and defining the scope of their application as drug carriers has important practical significance. This article presents the pioneering studies concerning high degree incorporation of cytarabine (AraC) and methotrexate (MTX) into liposome vesicles. The main focus of this study were cytarabine-methotrexate dipalmitoylphosphatidylcholine (DPPC) interactions observed in the gel and fluid phases of DPPC bilayers. The proposed new method of use the Transmittance2919/2850 ratio presented in our research is sensitive to subtle changes in conformational order resulting from rotations, kinks and bends of the lipid chains. The transition temperatures characterized by Fourier Transform Infrared Spectroscopy (FT-IR) were consistent with the results obtained by Differential Scanning Calorimetry (DSC). Transmission Electron Microscopy (TEM) was used in order to determine the size and shape of the liposomes obtained. The mutual interactions occurring between the drugs studied and the phospholipids were analyzed using the Nuclear Magnetic Resonance (NMR). PMID- 27941654 TI - Metal-Free Photoredox Catalyzed Cyclization of O-(2,4-Dinitrophenyl)oximes to Phenanthridines. AB - A metal-free visible-light photoredox-catalyzed intermolecular cyclization reaction of O-2,4-dinitrophenyl oximes to phenanthridines was developed. In this study, the organic dye eosin Y and i-Pr2NEt were used as photocatalyst and terminal reductant, respectively. The oxime substrates were transformed into iminyl radical intermediates by single-electron reduction, which then underwent intermolecular homolytic aromatic substitution (HAS) reactions to give phenanthridine derivatives. PMID- 27941656 TI - An Open Platform for Seamless Sensor Support in Healthcare for the Internet of Things. AB - Population aging and increasing pressure on health systems are two issues that demand solutions. Involving and empowering citizens as active managers of their health represents a desirable shift from the current culture mainly focused on treatment of disease, to one also focused on continuous health management and well-being. Current developments in technological areas such as the Internet of Things (IoT), lead to new technological solutions that can aid this shift in the healthcare sector. This study presents the design, development, implementation and evaluation of a platform called Common Recognition and Identification Platform (CRIP), a part of the CareStore project, which aims at supporting caregivers and citizens to manage health routines in a seamless way. Specifically, the CRIP offers sensor-based support for seamless identification of users and health devices. A set of initial requirements was defined with a focus on usability limitations and current sensor technologies. The CRIP was designed and implemented using several technologies that enable seamless integration and interaction of sensors and people, namely Near Field Communication and fingerprint biometrics for identification and authentication, Bluetooth for communication with health devices and web services for wider integration with other platforms. Two CRIP prototypes were implemented and evaluated in laboratory during a period of eight months. The evaluations consisted of identifying users and devices, as well as seamlessly configure and acquire vital data from the last. Also, the entire Carestore platform was deployed in a nursing home where its usability was evaluated with caregivers. The evaluations helped assess that seamless identification of users and seamless configuration and communication with health devices is feasible and can help enable the IoT on healthcare applications. Therefore, the CRIP and similar platforms could be transformed into a valuable enabling technology for secure and reliable IoT deployments on the healthcare sector. PMID- 27941657 TI - Australian Food Safety Policy Changes from a "Command and Control" to an "Outcomes-Based" Approach: Reflection on the Effectiveness of Its Implementation. AB - Foodborne illness is a global public health burden. Over the past decade in Australia, despite advances in microbiological detection and control methods, there has been an increase in the incidence of foodborne illness. Therefore improvements in the regulation and implementation of food safety policy are crucial for protecting public health. In 2000, Australia established a national food safety regulatory system, which included the adoption of a mandatory set of food safety standards. These were in line with international standards and moved away from a "command and control" regulatory approach to an "outcomes-based" approach using risk assessment. The aim was to achieve national consistency and reduce foodborne illness without unnecessarily burdening businesses. Evidence demonstrates that a risk based approach provides better protection for consumers; however, sixteen years after the adoption of the new approach, the rates of food borne illness are still increasing. Currently, food businesses are responsible for producing safe food and regulatory bodies are responsible for ensuring legislative controls are met. Therefore there is co-regulatory responsibility and liability and implementation strategies need to reflect this. This analysis explores the challenges facing food regulation in Australia and explores the rationale and evidence in support of this new regulatory approach. PMID- 27941659 TI - The Impact of Greenspace on Thermal Comfort in a Residential Quarter of Beijing, China. AB - With the process of urbanization, a large number of residential quarters, which is the main dwelling form in the urban area of Beijing, have been developed in last three decades to accommodate the rising population. In the context of intensification of urban heat island (UHI), the potential degradation of the thermal environment of residential quarters can give rise to a variety of problems affecting inhabitants' health. This paper reports the results of a numerical study of the thermal conditions of a residential quarter on a typical summertime day under four greening modification scenarios, characterized by different leaf area density (LAD) profiles. The modelling results demonstrated that vegetation could evidently reduce near-surface air temperature, with the combination of grass and mature trees achieving as much as 1.5 degrees C of air temperature decrease compared with the non-green scenario. Vegetation can also lead to smaller air temperature fluctuations, which contribute to a more stable microclimate. The Universal Thermal Climate Index (UTCI) was then calculated to represent the variation of thermal environment of the study area. While grass is helpful in improving outdoor thermal comfort, trees are more effective in reducing the duration and expansion of suffering from severe heat stress. The results of this study showed that proper maintenance of vegetation, especially trees, is significant to improving the outdoor thermal environment in the summer season. In consideration of the deficiency of the current code in the management of greenspace in residential areas, we hope the results reported here will help promote the improvement of the code and related regulations for greenspace management. PMID- 27941658 TI - Estimation of Saliva Cotinine Cut-Off Points for Active and Passive Smoking during Pregnancy-Polish Mother and Child Cohort (REPRO_PL). AB - A reliable assessment of smoking status has significant public health implications and is essential for research purposes. The aim of this study was to determine optimal saliva cotinine cut-off values for smoking during pregnancy. The analyses were based on data from 1771 women from the Polish Mother and Child Cohort. Saliva cotinine concentrations were assessed by high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-ESI + MS/MS). The saliva cotinine cut-off value for active smoking was established at 10 ng/mL (sensitivity 96%, specificity 95%) and for passive smoking at 1.5 ng/mL (sensitivity 63%, specificity 71%). About 5% of the self-reported non-smoking women were classified as smokers based on the cotinine cut-off value. Significantly more younger, single, and less educated self-reported non-smokers had a cotinine concentration higher than 10 ng/mL compared to those who were older, married, and who had a university degree. Close to 30% of the non-smokers who indicated that smoking was not allowed in their home could be classified as exposed to passive smoking based on the cut-off value. The study suggests that self-reported smoking status is a valid measure of active smoking, whereas in the case of passive smoking, a combination of questionnaire data and biomarker verification may be required. PMID- 27941662 TI - Adjustable Trajectory Design Based on Node Density for Mobile Sink in WSNs. AB - The design of movement trajectories for mobile sink plays an important role in data gathering for Wireless Sensor Networks (WSNs), as it affects the network coverage, and packet delivery ratio, as well as the network lifetime. In some scenarios, the whole network can be divided into subareas where the nodes are randomly deployed. The node densities of these subareas are quite different, which may result in a decreased packet delivery ratio and network lifetime if the movement trajectory of the mobile sink cannot adapt to these differences. To address these problems, we propose an adjustable trajectory design method based on node density for mobile sink in WSNs. The movement trajectory of the mobile sink in each subarea follows the Hilbert space-filling curve. Firstly, the trajectory is constructed based on network size. Secondly, the adjustable trajectory is established based on node density in specific subareas. Finally, the trajectories in each subarea are combined to acquire the whole network's movement trajectory for the mobile sink. In addition, an adaptable power control scheme is designed to adjust nodes' transmitting range dynamically according to the movement trajectory of the mobile sink in each subarea. The simulation results demonstrate that the proposed trajectories can adapt to network changes flexibly, thus outperform both in packet delivery ratio and in energy consumption the trajectories designed only based on the network size and the whole network node density. PMID- 27941660 TI - Metformin Treatment and Homocysteine: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - The aim of this systematic review is to assess whether metformin could change the concentration of serum homocysteine (Hcy) with and without simultaneous supplementation of B-group vitamins or folic acid. A literature search was conducted in PubMed, EmBase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) reporting the concentration of serum Hcy in metformin-treated adults. Meta-analysis was applied to assess the association between metformin and the changes of Hcy concentration. Twelve publications were included in this study. In the overall analysis, metformin administration was not statistically associated with the change of Hcy when compared with the control treatment (mean difference (MD), 0.40 MUmol/L; 95% confidence interval (CI), -0.07~0.87 MUmol/L, p = 0.10). In the subgroup analysis, metformin was significantly associated with an increased concentration of Hcy in the absence of exogenous supplementation of folic acid or B-group vitamins (MD, 2.02 MUmol/L; 95% CI, 1.37~2.67 MUmol/L, p < 0.00001), but with a decreased concentration of serum Hcy in the presence of these exogenous supplementations (MD, -0.74 MUmol/L; 95% CI, -1.19~-0.30 MUmol/L, p = 0.001). Therefore, although the overall effect of metformin on the concentration of serum Hcy was neutral, our results suggested that metformin could increase the concentration of Hcy when exogenous B-group vitamins or folic acid supplementation was not given. PMID- 27941661 TI - Phosphorus Supplementation Recovers the Blunted Diet-Induced Thermogenesis of Overweight and Obese Adults: A Pilot Study. AB - Diet-induced thermogenesis (DIT) is believed to be largely related to ATP production, which is dependent on phosphorus (P) availability. We aimed to test the effect of P addition on DIT of lean and overweight/obese healthy subjects. DIT was measured with or without P in 10 lean and 13 overweight/obese adults in a double-blind randomized cross-over pilot study with one week washout period. After 10 h overnight fast, resting metabolic rate, respiratory quotient, and substrate utilization were measured at fasting and every 30 min for 3 h after subjects drank a standardized glucose solution, with P (500 mg) or placebo pills. Subjective ratings of hunger and satiety were assessed before and after the end of each experiment using validated visual analogue scale (VAS) questionnaires. Overweight/obese subjects had a blunted DIT with placebo, while P supplementation induced a 23% increase in their DIT area under the curve (p < 0.05), which was associated with a significant increase in carbohydrate oxidation. Subjects had lower appetite following P supplementation, which was expressed as a significantly (p = 0.02) lower desire to eat a meal (4.0 +/- 0.7 cm) compared with placebo (5.8 +/- 0.9 cm). P supplementation recovers the blunted diet induced thermogenesis in overweight and obese subjects and enhances their postprandial satiety. PMID- 27941663 TI - Continuous Glucose Monitoring Sensors: Past, Present and Future Algorithmic Challenges. AB - Continuous glucose monitoring (CGM) sensors are portable devices that allow measuring and visualizing the glucose concentration in real time almost continuously for several days and are provided with hypo/hyperglycemic alerts and glucose trend information. CGM sensors have revolutionized Type 1 diabetes (T1D) management, improving glucose control when used adjunctively to self-monitoring blood glucose systems. Furthermore, CGM devices have stimulated the development of applications that were impossible to create without a continuous-time glucose signal, e.g., real-time predictive alerts of hypo/hyperglycemic episodes based on the prediction of future glucose concentration, automatic basal insulin attenuation methods for hypoglycemia prevention, and the artificial pancreas. However, CGM sensors' lack of accuracy and reliability limited their usability in the clinical practice, calling upon the academic community for the development of suitable signal processing methods to improve CGM performance. The aim of this paper is to review the past and present algorithmic challenges of CGM sensors, to show how they have been tackled by our research group, and to identify the possible future ones. PMID- 27941664 TI - Evidence of Tolerance to Silica-Based Desiccant Dusts in a Pyrethroid-Resistant Strain of Cimex lectularius (Hemiptera: Cimicidae). AB - Insecticide resistance in bed bugs (Cimex lectularius and Cimex hemipterus) has become widespread, which has necessitated the development of new IPM (Integrated Pest Management) strategies and products for the eradication of infestations. Two promising options are the diatomaceous earth and silica gel-based desiccant dusts, both of which induce dehydration and eventual death upon bed bugs exposed to these products. However, the impact of underlying mechanisms that confer resistance to insecticides, such as cuticle thickening, on the performance of these dusts has yet to be determined. In the present study, two desiccant dusts, CimeXa Insecticide Dust (silica gel) and Bed Bug Killer Powder (diatomaceous earth) were evaluated against two strains of C. lectularius; one highly pyrethroid-resistant and one insecticide-susceptible. Label-rate doses of both products produced 100% mortality in both strains, albeit over dissimilar time frames (3-4 days with CimeXa vs. 14 days with Bed Bug Killer). Sub-label rate exposure to CimeXa indicated that the pyrethroid-resistant strain possessed a degree of tolerance to this product, surviving 50% longer than the susceptible strain. This is the first study to suggest that mechanisms conferring resistance to pyrethroids, such as cuticular thickening, may have potential secondary impacts on non-synthetic insecticides, including desiccant dusts, which target the bed bug's cuticle. PMID- 27941665 TI - Air Pollution Control Policies in China: A Retrospective and Prospects. AB - With China's significant role on pollution emissions and related health damage, deep and up-to-date understanding of China's air pollution policies is of worldwide relevance. Based on scientific evidence for the evolution of air pollution and the institutional background of environmental governance in China, we examine the development of air pollution control policies from the 1980s and onwards. We show that: (1) The early policies, until 2005, were ineffective at reducing emissions; (2) During 2006-2012, new instruments which interact with political incentives were introduced in the 11th Five-Year Plan, and the national goal of reducing total sulfur dioxide (SO2) emissions by 10% was achieved. However, regional compound air pollution problems dominated by fine particulate matter (PM2.5) and ground level ozone (O3) emerged and worsened; (3) After the winter-long PM2.5 episode in eastern China in 2013, air pollution control policies have been experiencing significant changes on multiple fronts. In this work we analyze the different policy changes, the drivers of changes and key factors influencing the effectiveness of policies in these three stages. Lessons derived from the policy evolution have implications for future studies, as well as further reforming the management scheme towards air quality and health risk oriented directions. PMID- 27941666 TI - Subjective Mood in Young Unmedicated Depressed Women under High and Low Sleep Pressure Conditions. AB - Diurnal mood variations are one of the core symptoms in depression, and total sleep deprivation (SD) can induce rapid, short-lasting clinical improvement in depressed patients. Here, we investigated if differential sleep pressure conditions impact on subjective mood levels in young women with major depressive disorder (MDD) without sleep disturbances, and in healthy controls. Eight healthy and eight MDD women underwent 40-h SD (high sleep pressure) and 40-h multiple NAP (low sleep pressure) protocols under constant routine conditions during which subjective mood was assessed every 30-min. MDD women rated overall significantly worse mood than controls, with minimal values for both groups during the biological night (ca. 4 a.m.), under high and low sleep pressure conditions. During SD, nighttime mood ratings in MDD women were lower than in controls and partially recovered during the second day of SD, but never attained control levels. The degree of this diurnal time-course in mood under SD correlated positively with sleep quality in MDD women. Our data indicate that MDD women without sleep disturbances did not exhibit a SD-induced antidepressant response, suggesting that the mood enhancement response to sleep deprivation might be related to the co-existence of sleep disturbances, which is an association that remains to be fully established. PMID- 27941667 TI - Hypoglycemic Effect of Opuntia ficus-indica var. saboten Is Due to Enhanced Peripheral Glucose Uptake through Activation of AMPK/p38 MAPK Pathway. AB - Opuntia ficus-indica var. saboten (OFS) has been used in traditional medicine for centuries to treat several illnesses, including diabetes. However, detailed mechanisms underlying hypoglycemic effects remain unclear. In this study, the mechanism underlying the hypoglycemic activity of OFS was evaluated using in vitro and in vivo systems. OFS treatment inhibited alpha-glucosidase activity and intestinal glucose absorption assessed by Na+-dependent glucose uptake using brush border membrane vesicles. AMP-activated protein kinase (AMPK) is widely recognized as an important regulator of glucose transport in skeletal muscle, and p38 mitogen-activated protein kinase (MAPK) has been proposed to be a component of AMPK-mediated signaling. In the present study, OFS dose-dependently increased glucose uptake in L6 muscle cells. The AMPK and p38 MAPK phosphorylations were stimulated by OFS, and inhibitors of AMPK (compound C) and p38 MAPK (SB203580) abolished the effects of OFS. Furthermore, OFS increased glucose transporter 4 (GLUT4) translocation to the plasma membrane. OFS administration (1 g/kg and 2 g/kg body weight) in db/db mice dose-dependently ameliorated hyperglycemia, hyperinsulinemia, and glucose tolerance. Insulin resistance assessed by homeostasis model assessment of insulin resistance and quantitative insulin sensitivity check index were also dose-dependently improved with OFS treatment. OFS administration improved pancreatic function through increased beta-cell mass in db/db mice. These findings suggest that OFS acts by inhibiting glucose absorption from the intestine and enhancing glucose uptake from insulin-sensitive muscle cells through the AMPK/p38 MAPK signaling pathway. PMID- 27941668 TI - Droplet Microarray Based on Superhydrophobic-Superhydrophilic Patterns for Single Cell Analysis. AB - Single-cell analysis provides fundamental information on individual cell response to different environmental cues and is a growing interest in cancer and stem cell research. However, current existing methods are still facing challenges in performing such analysis in a high-throughput manner whilst being cost-effective. Here we established the Droplet Microarray (DMA) as a miniaturized screening platform for high-throughput single-cell analysis. Using the method of limited dilution and varying cell density and seeding time, we optimized the distribution of single cells on the DMA. We established culturing conditions for single cells in individual droplets on DMA obtaining the survival of nearly 100% of single cells and doubling time of single cells comparable with that of cells cultured in bulk cell population using conventional methods. Our results demonstrate that the DMA is a suitable platform for single-cell analysis, which carries a number of advantages compared with existing technologies allowing for treatment, staining and spot-to-spot analysis of single cells over time using conventional analysis methods such as microscopy. PMID- 27941669 TI - Responses of Vascular Endothelial Cells to Photoembossed Topographies on Poly(Methyl Methacrylate) Films. AB - Failures of vascular grafts are normally caused by the lack of a durable and adherent endothelium covering the graft which leads to thrombus and neointima formation. A promising approach to overcome these issues is to create a functional, quiescent monolayer of endothelial cells on the surface of implants. The present study reports for the first time on the use of photoembossing as a technique to create polymer films with different topographical features for improved cell interaction in biomedical applications. For this, a photopolymer is created by mixing poly(methyl methacrylate) (PMMA) and trimethylolpropane ethoxylate triacrylate (TPETA) at a 1:1 ratio. This photopolymer demonstrated an improvement in biocompatibility over PMMA which is already known to be biocompatible and has been extensively used in the biomedical field. Additionally, photoembossed films showed significantly improved cell attachment and proliferation compared to their non-embossed counterparts. Surface texturing consisted of grooves of different pitches (6, 10, and 20 um) and heights (1 um and 2.5 um). The 20 um pitch photoembossed films significantly accelerated cell migration in a wound-healing assay, while films with a 6 um pitch inhibited cells from detaching. Additionally, the relief structure obtained by photoembossing also changed the surface wettability of the substrates. Photoembossed PMMA-TPETA systems benefited from this change as it improved their water contact angle to around 70 degrees , making it well suited for cell adhesion. PMID- 27941670 TI - Chromosomal Microarray Analysis of Consecutive Individuals with Autism Spectrum Disorders Using an Ultra-High Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders. AB - Copy number variants (CNVs) detected by chromosomal microarray analysis (CMA) significantly contribute to understanding the etiology of autism spectrum disorder (ASD) and other related conditions. In recognition of the value of CMA testing and its impact on medical management, CMA is in medical guidelines as a first-tier test in the evaluation of children with these disorders. As CMA becomes adopted into routine care for these patients, it becomes increasingly important to report these clinical findings. This study summarizes the results of over 4 years of CMA testing by a CLIA-certified clinical testing laboratory. Using a 2.8 million probe microarray optimized for the detection of CNVs associated with neurodevelopmental disorders, we report an overall CNV detection rate of 28.1% in 10,351 consecutive patients, which rises to nearly 33% in cases without ASD, with only developmental delay/intellectual disability (DD/ID) and/or multiple congenital anomalies (MCA). The overall detection rate for individuals with ASD is also significant at 24.4%. The detection rate and pathogenic yield of CMA vary significantly with the indications for testing, age, and gender, as well as the specialty of the ordering doctor. We note discrete differences in the most common recurrent CNVs found in individuals with or without a diagnosis of ASD. PMID- 27941673 TI - Could a Proto-Ribosome Emerge Spontaneously in the Prebiotic World? AB - An indispensable prerequisite for establishing a scenario of life emerging by natural processes is the requirement that the first simple proto-molecules could have had a realistic probability of self-assembly from random molecular polymers in the prebiotic world. The vestige of the proto-ribosome, which is believed to be still embedded in the contemporary ribosome, is used to assess the feasibility of such spontaneous emergence. Three concentric structural elements of different magnitudes, having a dimeric nature derived from the symmetrical region of the ribosomal large subunit, were suggested to constitute the vestige of the proto ribosome. It is assumed to have materialized spontaneously in the prebiotic world, catalyzing non-coded peptide bond formation and simple elongation. Probabilistic and energetic considerations are applied in order to evaluate the suitability of the three contenders for being the initial proto-ribosome. The analysis points to the simplest proto-ribosome, comprised of a dimer of tRNA-like molecules presently embedded in the core of the symmetrical region, as the only one having a realistic statistical likelihood of spontaneous emergence from random RNA chains. Hence it offers a feasible starting point for a continuous evolutionary path from the prebiotic matter, through natural processes, into the intricate modern translation system. PMID- 27941672 TI - Detection and Quantification of the Fragile X Mental Retardation Protein 1 (FMRP). AB - The final product of FMR1 gene transcription, Fragile X Mental Retardation Protein 1 (FMRP), is an RNA binding protein that acts as a repressor of translation. FMRP is expressed in several tissues and plays important roles in neurogenesis, synaptic plasticity, and ovarian functions and has been implicated in a number of neuropsychological disorders. The loss of FMRP causes Fragile X Syndrome (FXS). In most cases, FXS is due to large expansions of a CGG repeat in FMR1-normally containing 6-54 repeats-to over 200 CGGs and identified as full mutation (FM). Hypermethylation of the repeat induces FMR1 silencing and lack of FMRP expression in FM male. Mosaic FM males express low levels of FMRP and present a less severe phenotype that inversely correlates with FMRP levels. Carriers of pre-mutations (55-200 CGG) show increased mRNA, and normal to reduced FMRP levels. Alternative splicing of FMR1 mRNA results in 24 FMRP predicted isoforms whose expression are tissues and developmentally regulated. Here, we summarize the approaches used by several laboratories including our own to (a) detect and estimate the amount of FMRP in different tissues, developmental stages and various pathologies; and (b) to accurately quantifying FMRP for a direct diagnosis of FXS in adults and newborns. PMID- 27941671 TI - Non-Canonical Cell Death Induced by p53. AB - Programmed cell death is a vital biological process for multicellular organisms to maintain cellular homeostasis, which is regulated in a complex manner. Over the past several years, apart from apoptosis, which is the principal mechanism of caspase-dependent cell death, research on non-apoptotic forms of programmed cell death has gained momentum. p53 is a well characterized tumor suppressor that controls cell proliferation and apoptosis and has also been linked to non apoptotic, non-canonical cell death mechanisms. p53 impacts these non-canonical forms of cell death through transcriptional regulation of its downstream targets, as well as direct interactions with key players involved in these mechanisms, in a cell type- or tissue context-dependent manner. In this review article, we summarize and discuss the involvement of p53 in several non-canonical modes of cell death, including caspase-independent apoptosis (CIA), ferroptosis, necroptosis, autophagic cell death, mitotic catastrophe, paraptosis, and pyroptosis, as well as its role in efferocytosis which is the process of clearing dead or dying cells. PMID- 27941675 TI - Photostability and Performance of Polystyrene Films Containing 1,2,4-Triazole-3 thiol Ring System Schiff Bases. AB - Series of 4-(4-substituted benzylideneamino)-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4 triazole-3-thiols were synthesized and their structures were confirmed. The synthesized Schiff bases were used as photostabilizers for polystyrene against photodegradation. Polystyrene polymeric films containing synthesized Schiff bases (0.5% by weight) were irradiated (lambdamax = 365 nm and light intensity = 6.43 * 10-9 ein.dm-3.s-1) at room temperature. The photostabilization effect of 1,2,4 triazole-3-thiols Schiff bases was determined using various methods. All the additives used enhanced the photostability of polystyrene films against irradiation compared with the result obtained in the absence of Schiff base. The Schiff bases can act as photostabilizers for polystyrene through the direct absorption of UV radiation and/or radical scavengers. PMID- 27941674 TI - Biology, Therapy and Implications of Tumor Exosomes in the Progression of Melanoma. AB - Cancer is the second leading cause of death in the United States, and about 6% of the estimated cancer diagnoses this year will be melanoma cases. Melanomas are derived from transformation of the pigment producing cells of the skin, melanocytes. Early stage melanoma is usually curable by surgical resection, but late stage or subsequent secondary metastatic tumors are treated with some success with chemotherapies, radiation and/or immunotherapies. Most cancer patients die from metastatic disease, which is especially the case in melanoma. A better understanding of tumor metastasis will provide insights and guide rational therapeutic designs. Recently, the importance of melanoma-derived exosomes in the progression of that cancer has become more apparent, namely, their role in various stages of metastasis, including the induction of migration, invasion, primary niche manipulation, immune modulation and pre-metastatic niche formation. This review focuses on the critical roles that melanoma exosomes play in the progression of this deadly disease. PMID- 27941676 TI - Optimized and Automated Radiosynthesis of [18F]DHMT for Translational Imaging of Reactive Oxygen Species with Positron Emission Tomography. AB - Reactive oxygen species (ROS) play important roles in cell signaling and homeostasis. However, an abnormally high level of ROS is toxic, and is implicated in a number of diseases. Positron emission tomography (PET) imaging of ROS can assist in the detection of these diseases. For the purpose of clinical translation of [18F]6-(4-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4 yl)methoxy)phenyl)-5-methyl-5,6-dihydrophenanthridine-3,8-diamine ([18F]DHMT), a promising ROS PET radiotracer, we first manually optimized the large-scale radiosynthesis conditions and then implemented them in an automated synthesis module. Our manual synthesis procedure afforded [18F]DHMT in 120 min with overall radiochemical yield (RCY) of 31.6% +/- 9.3% (n = 2, decay-uncorrected) and specific activity of 426 +/- 272 GBq/umol (n = 2). Fully automated radiosynthesis of [18F]DHMT was achieved within 77 min with overall isolated RCY of 6.9% +/- 2.8% (n = 7, decay-uncorrected) and specific activity of 155 +/- 153 GBq/umol (n = 7) at the end of synthesis. This study is the first demonstration of producing 2-[18F]fluoroethyl azide by an automated module, which can be used for a variety of PET tracers through click chemistry. It is also the first time that [18F]DHMT was successfully tested for PET imaging in a healthy beagle dog. PMID- 27941677 TI - The Enrichment of Survivin in Exosomes from Breast Cancer Cells Treated with Paclitaxel Promotes Cell Survival and Chemoresistance. AB - The generation and release of membrane-enclosed packets from cancer cells, called extracellular vesicles (EVs), play important roles in propagating transformed phenotypes, including promoting cell survival. EVs mediate their effects by transferring their contents, which include specific proteins and nucleic acids, to target cells. However, how the cargo and function of EVs change in response to different stimuli remains unclear. Here, we discovered that treating highly aggressive MDAMB231 breast cancer cells with paclitaxel (PTX), a chemotherapy that stabilizes microtubules, causes them to generate a specific class of EV, namely exosomes, that are highly enriched with the cell survival protein and cancer marker, Survivin. Treating MDAMB231 cells with a variety of other chemotherapeutic agents, and inhibitors that block cell growth and survival, did not have the same effect as PTX, with the exception of nocodazole, another inhibitor of microtubule dynamics. Exosomes isolated from PTX-treated MDAMB231 cells strongly promoted the survival of serum-starved and PTX-treated fibroblasts and SKBR3 breast cancer cells, an effect that was ablated when Survivin was knocked-down from these vesicles using siRNA. These findings underscore how the enrichment of a specific cargo in exosomes promotes cell survival, as well as can potentially serve as a marker of PTX resistance. PMID- 27941678 TI - Polyphenols Isolated from Xanthoceras sorbifolia Husks and Their Anti-Tumor and Radical-Scavenging Activities. AB - Xanthoceras sorbifolia Bunge. is used in traditional medicine in North China. To evaluate the anti-tumor and radical-scavenging activities of X. sorbifolia husks polyphenols and determine their structure-activity relationships, 37 polyphenols 1-37 were obtained by bioassay-guided fractionation. Two new compounds 1-2, and compounds 5, 6, 8, 9, 11, 14-17, 21-25, 27-29, 31, 33, 34, 36, and 37 were isolated from the genus Xanthoceras for the first time. Compounds 1-37 did not show strong cytotoxicity against the four tested tumor cell lines (A549, HepG2, MGC-803, and MFC) compared to paclitaxel and under the conditions tested in the anti-tumor assay, but compounds 3, 4, 7, 8, 10, 18-20, 25, 26, 29, 30, 32, and 35 exhibited stronger radical-scavenging activity than ascorbic acid in a 2,2'-azino bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt assay. This was the first report on the anti-tumor and radical-scavenging activities of the polyphenols isolated from X. sorbifolia husks. Overall, the present study contributed valuable information concerning X. sorbifolia husks use in medicine and pharmacology. PMID- 27941679 TI - Correction: Zhao, J., et al. Podophyllotoxin-Loaded Nanostructured Lipid Carriers for Skin Targeting: In Vitro and In Vivo Studies. Molecules 2016, 21, 1549. AB - The authors wish to make the following correction to their paper [1]. PMID- 27941680 TI - Design, Synthesis, and Biological Evaluation of Novel Benzofuran Derivatives Bearing N-Aryl Piperazine Moiety. AB - A series of novel hybrid compounds between benzofuran and N-aryl piperazine have been synthesized and screened in vitro for anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages and for anticancer activity against three human tumor cell lines. The results demonstrated that derivative 16 not only had inhibitory effect on the generation of NO (IC50 = 5.28 MUM), but also showed satisfactory and selective cytotoxic activity against human lung cancer line (A549) and gastric cancer cell (SGC7901) (IC50 = 0.12 MUM and 2.75 MUM, respectively), which was identified as the most potent anti inflammatory and anti-tumor agent in this study. PMID- 27941682 TI - Cancer Preventive Activities of Tea Catechins. AB - Catechins are widely occurring in our diet and beverages. The cancer-preventive activities of catechins have been extensively studied. Of these, (-) epigallocatechin-3-gallate (EGCG), the principal catechin in green tea, has received the most attention. The inhibitory activities of tea catechins against carcinogenesis and cancer cell growth have been demonstrated in a large number of laboratory studies. Many mechanisms for modulating cancer signaling and metabolic pathways have been proposed based on numerous studies in cell lines with EGCG, the most active tea catechin. Nevertheless, it is not known whether many of these mechanisms indeed contribute to the anti-cancer activities in animals and in humans. Human studies have provided some results for the cancer preventive activities of tea catechins; however, the activities are not strong. This article reviews the cancer preventive activities and mechanisms of action of tea catechins involving their redox activities, biochemical properties and binding to key enzymes or signal transduction proteins. These mechanisms lead to suppression of cell proliferation, increased apoptosis and inhibition of angiogenesis. The relevance of the proposed mechanisms for cancer prevention are assessed in the light of the situation in vivo. The potential and possible problems in the application of tea and tea-derived products for cancer prevention are discussed. PMID- 27941684 TI - Structural Determinants of Alkyne Reactivity in Copper-Catalyzed Azide-Alkyne Cycloadditions. AB - This work represents our initial effort in identifying azide/alkyne pairs for optimal reactivity in copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. In previous works, we have identified chelating azides, in particular 2-picolyl azide, as "privileged" azide substrates with high CuAAC reactivity. In the current work, two types of alkynes are shown to undergo rapid CuAAC reactions under both copper(II)- (via an induction period) and copper(I)-catalyzed conditions. The first type of the alkynes bears relatively acidic ethynyl C-H bonds, while the second type contains an N-(triazolylmethyl)propargylic moiety that produces a self-accelerating effect. The rankings of reactivity under both copper(II)- and copper(I)-catalyzed conditions are provided. The observations on how other reaction parameters such as accelerating ligand, reducing agent, or identity of azide alter the relative reactivity of alkynes are described and, to the best of our ability, explained. PMID- 27941681 TI - Tools for Sequence-Based miRNA Target Prediction: What to Choose? AB - MicroRNAs (miRNAs) are defined as small non-coding RNAs ~22 nt in length. They regulate gene expression at a post-transcriptional level through complementary base pairing with the target mRNA, leading to mRNA degradation and therefore blocking translation. In the last decade, the dysfunction of miRNAs has been related to the development and progression of many diseases. Currently, researchers need a method to identify precisely the miRNA targets, prior to applying experimental approaches that allow a better functional characterization of miRNAs in biological processes and can thus predict their effects. Computational prediction tools provide a rapid method to identify putative miRNA targets. However, since a large number of tools for the prediction of miRNA:mRNA interactions have been developed, all with different algorithms, the biological researcher sometimes does not know which is the best choice for his study and many times does not understand the bioinformatic basis of these tools. This review describes the biological fundamentals of these prediction tools, characterizes the main sequence-based algorithms, and offers some insights into their uses by biologists. PMID- 27941683 TI - The Roles of Autophagy and the Inflammasome during Environmental Stress-Triggered Skin Inflammation. AB - Inflammatory skin diseases are the most common problem in dermatology. The induction of skin inflammation by environmental stressors such as ultraviolet radiation (UVR), hexavalent chromium (Cr(VI)) and TiO2/ZnO/Ag nanoparticles (NPs) has been demonstrated previously. Recent studies have indicated that the inflammasome is often wrongly activated by these environmental irritants, thus inducing massive inflammation and resulting in the development of inflammatory diseases. The regulation of the inflammasome with respect to skin inflammation is complex and is still not completely understood. Autophagy, an intracellular degradation system that is associated with the maintenance of cellular homeostasis, plays a key role in inflammasome inactivation. As a housekeeping pathway, cells utilize autophagy to maintain the homeostasis of the organ structure and function when exposed to environmental stressors. However, only a few studies have examined the effect of autophagy and/or the inflammasome on skin pathogenesis. Here we review recent findings regarding the involvement of autophagy and inflammasome activation during skin inflammation. We posit that autophagy induction is a novel mechanism inter-modulating environmental stressor induced skin inflammation. We also attempt to highlight the role of the inflammasome and the possible underlying mechanisms and pathways reflecting the pathogenesis of skin inflammation induced by UVR, Cr(VI) and TiO2/ZnO/Ag NPs. A more profound understanding about the crosstalk between autophagy and the inflammasome will contribute to the development of prevention and intervention strategies against human skin disease. PMID- 27941685 TI - Association of Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms with Osteoporotic Vertebral Compression Fractures (OVCFs) in Postmenopausal Women. AB - Osteoporosis and osteoporotic fractures are strongly associated with mortality and morbidity, both in developing and developed countries. Menopause accelerates bone loss due to estrogen deficiency and age-related linear bone loss. We investigated plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms in postmenopausal women with osteoporotic vertebral compression fractures (OVCFs). In this case-control study, 355 postmenopausal women were genotyped for the presence of PAI-1 gene polymorphisms -844A > G, -675 4G > 5G, 43G > A, 9785A > G, and 11053T > G. Genetic polymorphisms of PAI-1 were analyzed by the polymerization chain reaction restriction fragment length polymorphism assay, and their association with disease status and folate and homocysteine levels was determined in 158 OVCF patients and 197 control subjects. The PAI-1 -675 5G5G (adjusted odds ratio (AOR), 3.302; p = 0.017) and 43GA + AA (AOR, 2.087; p = 0.042) genotype frequencies showed significant association with the increased prevalence of OVCFs in postmenopausal women. In addition, we performed gene environment interaction studies and demonstrated an association between PAI-1 gene polymorphisms and OVCF prevalence. Our novel finding is the identification of several PAI-1 genetic variants that increase susceptibility to OVCF. Our findings suggest that polymorphisms in PAI-1 may contribute to OVCF, and that they can be developed as biomarkers for evaluating OVCF risk. PMID- 27941688 TI - Virtual-Wall Model for Molecular Dynamics Simulation. AB - A large number of molecules are usually required to model atomic walls in molecular dynamics simulations. A virtual-wall model is proposed in this study to describe fluid-wall molecular interactions, for reducing the computational time. The infinite repetition of unit cell structures within the atomic wall causes the periodicity of the force acting on a fluid molecule from the wall molecules. This force is first calculated and then stored in the memory. A fluid molecule appearing in the wall force field is subjected to the force from the wall molecules. The force can then be determined by the position of the molecule relative to the wall. This model avoids excessive calculations of fluid-wall interactions and reduces the computational time drastically. The time reduction is significant for small fluid density and channel height. The virtual-wall model is applied to Poiseuille and Couette flows, and to a flow in a channel with a rough surface. Results of the virtual and atomic wall simulations agree well with each other, thereby indicating the usefulness of the virtual-wall model. The appropriate bin size and cut-off radius in the virtual-wall model are also discussed. PMID- 27941686 TI - Venom Gland Transcriptomic and Proteomic Analyses of the Enigmatic Scorpion Superstitionia donensis (Scorpiones: Superstitioniidae), with Insights on the Evolution of Its Venom Components. AB - Venom gland transcriptomic and proteomic analyses have improved our knowledge on the diversity of the heterogeneous components present in scorpion venoms. However, most of these studies have focused on species from the family Buthidae. To gain insights into the molecular diversity of the venom components of scorpions belonging to the family Superstitioniidae, one of the neglected scorpion families, we performed a transcriptomic and proteomic analyses for the species Superstitionia donensis. The total mRNA extracted from the venom glands of two specimens was subjected to massive sequencing by the Illumina protocol, and a total of 219,073 transcripts were generated. We annotated 135 transcripts putatively coding for peptides with identity to known venom components available from different protein databases. Fresh venom collected by electrostimulation was analyzed by LC-MS/MS allowing the identification of 26 distinct components with sequences matching counterparts from the transcriptomic analysis. In addition, the phylogenetic affinities of the found putative calcins, scorpines, La1-like peptides and potassium channel kappa toxins were analyzed. The first three components are often reported as ubiquitous in the venom of different families of scorpions. Our results suggest that, at least calcins and scorpines, could be used as molecular markers in phylogenetic studies of scorpion venoms. PMID- 27941687 TI - Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic Neural Progenitor Cells. AB - Mitochondria are essential organelles and important targets for environmental pollutants. The detection of mitochondrial biogenesis and generation of reactive oxygen species (ROS) and p53 levels following low-dose methylmercury (MeHg) exposure could expand our understanding of underlying mechanisms. Here, the sensitivity of immortalized human neural progenitor cells (ihNPCs) upon exposure to MeHg was investigated. We found that MeHg altered cell viability and the number of 5-ethynyl-2'-deoxyuridine (EdU)-positive cells. We also observed that low-dose MeHg exposure increased the mRNA expression of cell cycle regulators. We observed that MeHg induced ROS production in a dose-dependent manner. In addition, mRNA levels of peroxisome-proliferator-activated receptor gammacoactivator-1alpha (PGC-1alpha), mitochondrial transcription factor A (TFAM) and p53-controlled ribonucleotide reductase (p53R2) were significantly elevated, which were correlated with the increase of mitochondrial DNA (mtDNA) copy number at a concentration as low as 10 nM. Moreover, we examined the expression of microRNAs (miRNAs) known as regulatory miRNAs of p53 (i.e., miR-30d, miR-1285, miR-25). We found that the expression of these miRNAs was significantly downregulated upon MeHg treatment. Furthermore, the overexpression of miR-25 resulted in significantly reducted p53 protein levels and decreased mRNA expression of genes involved in mitochondrial biogenesis regulation. Taken together, these results demonstrated that MeHg could induce developmental neurotoxicity in ihNPCs through altering mitochondrial functions and the expression of miRNA. PMID- 27941689 TI - Six New Triterpene Derivatives from Aralia chinensis Var. dasyphylloides. AB - Aralia chinensis var. dasyphylloides is widely distributed in China and used as a traditional herbal medicine for the treatment of digestive and immune system diseases. The present study aimed to search for novel oleanolic-type triterpenoids in low-polarity fractions. Six new triterpene derivatives (1-6), together with two known compounds were isolated from the barks of A. chinensis var. dasyphylloides. Their structures were elucidated by 1D- and 2D-NMR spectroscopic analysis and chemical methods. They were identified as 3-oxo-oleana 11,13(18)-dien-28,30-dioic acid (1), 30-hydroxy-3-oxo-oleana-11,13(18)-dien-28 oic acid (2), 3beta-hydroxy-oleana-11,13(18)-dien-28-oic acid-28-O-beta-d glucopyranoside (3), 3beta,30-dihydroxy-oleana-11,13(18)-dien-28-oic acid-28-O beta-d-glucopyranoside (4), 3beta-hydroxy-oleana-11,13(18)-dien-28-oic acid-3-O beta-d-xylopyranosyl-(1 -> 2)-beta-d-glucopyranoside (5), 3beta,29-dihydroxy oleana-9(11),12-dien-28-oic acid-28-O-beta-d-glucopyranoside (6), namely, araliachinolic acids I and II and araliachinosides I-IV. The cytotoxicity of the isolated compounds was tested against HepG2, A549, SGC7901, and MCF7 cell lines, but no apparent activity was observed at a concentration of 50 MUM. PMID- 27941690 TI - Procyanidins Mitigate Osteoarthritis Pathogenesis by, at Least in Part, Suppressing Vascular Endothelial Growth Factor Signaling. AB - Procyanidins are a family of plant metabolites that have been suggested to mitigate osteoarthritis pathogenesis in mice. However, the underlying mechanism is largely unknown. This study aimed to determine whether procyanidins mitigate traumatic injury-induced osteoarthritis (OA) disease progression, and whether procyanidins exert a chondroprotective effect by, at least in part, suppressing vascular endothelial growth factor signaling. Procyanidins (extracts from pine bark), orally administered to mice subjected to surgery for destabilization of the medial meniscus, significantly slowed OA disease progression. Real-time polymerase chain reaction revealed that procyanidin treatment reduced expression of vascular endothelial growth factor and effectors in OA pathogenesis that are regulated by vascular endothelial growth factor. Procyanidin-suppressed vascular endothelial growth factor expression was correlated with reduced phosphorylation of vascular endothelial growth factor receptor 2 in human OA primary chondrocytes. Moreover, components of procyanidins, procyanidin B2 and procyanidin B3 exerted effects similar to those of total procyanidins in mitigating the OA-related gene expression profile in the primary culture of human OA chondrocytes in the presence of vascular endothelial growth factor. Together, these findings suggest procyanidins mitigate OA pathogenesis, which is mediated, at least in part, by suppressing vascular endothelial growth factor signaling. PMID- 27941691 TI - Glucose-6-Phosphate Dehydrogenase: Update and Analysis of New Mutations around the World. AB - Glucose-6-phosphate dehydrogenase (G6PD) is a key regulatory enzyme in the pentose phosphate pathway which produces nicotinamide adenine dinucleotide phosphate (NADPH) to maintain an adequate reducing environment in the cells and is especially important in red blood cells (RBC). Given its central role in the regulation of redox state, it is understandable that mutations in the gene encoding G6PD can cause deficiency of the protein activity leading to clinical manifestations such as neonatal jaundice and acute hemolytic anemia. Recently, an extensive review has been published about variants in the g6pd gene; recognizing 186 mutations. In this work, we review the state of the art in G6PD deficiency, describing 217 mutations in the g6pd gene; we also compile information about 31 new mutations, 16 that were not recognized and 15 more that have recently been reported. In order to get a better picture of the effects of new described mutations in g6pd gene, we locate the point mutations in the solved three dimensional structure of the human G6PD protein. We found that class I mutations have the most deleterious effects on the structure and stability of the protein. PMID- 27941692 TI - Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich's Ataxia Transgenic Mice. AB - Friedreich's ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that includes neurological and non neurological damage. Recent studies have proven the effectiveness of neurotrophic factors in a number of neurodegenerative diseases. Therefore, we intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 MUg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA. PMID- 27941693 TI - The Relationship between Serum Bilirubin and Elevated Fibrotic Indices among HBV Carriers: A Cross-Sectional Study of a Chinese Population. AB - The study probed the association between bilirubin and hepatitis B virus (HBV) infection and progression. A cross-sectional analysis of 28,500 middle aged and elderly Chinese participants was performed to analyze the differences of bilirubin in terms of hepatitis B surface antigen (HBsAg) positive or negative and the correlation between bilirubin and severity of hepatic fibrosis estimated by non-invasive indices. Bilirubin was significantly higher in the HBsAg (+) group than the HBsAg (-) group. Higher bilirubin levels were consistently associated with elevated liver fibrosis indices among HBsAg carriers. Compared with quartile 1 of total bilirubin (TBil), the multivariable-adjusted ORs (95% CIs) for elevated fibrosis indices of quartile 4 were 2.24 (95% CIs, 1.57-3.21) estimated by fibrosis 4 score (FIB-4) and 2.22 (95% CIs, 1.60-3.08) estimated by aspartate transaminase to platelet ratio index (APRI). In addition, direct bilirubin (DBil) had a stronger association with elevated liver fibrosis indices than did indirect bilirubin (IBil). Furthermore, the relationship between DBil and elevated fibrosis indices was more robust among participants who were female, overweight or had central fat distribution. These findings suggested that bilirubin levels, especially DBil, were independently associated with an increased risk of increased fibrosis indices. PMID- 27941695 TI - How Do Households Respond to Unreliable Water Supplies? A Systematic Review. AB - Although the Millennium Development Goal (MDG) target for drinking water was met, in many developing countries water supplies are unreliable. This paper reviews how households in developing countries cope with unreliable water supplies, including coping costs, the distribution of coping costs across socio-economic groups, and effectiveness of coping strategies in meeting household water needs. Structured searches were conducted in peer-reviewed and grey literature in electronic databases and search engines, and 28 studies were selected for review, out of 1643 potentially relevant references. Studies were included if they reported on strategies to cope with unreliable household water supplies and were based on empirical research in developing countries. Common coping strategies include drilling wells, storing water, and collecting water from alternative sources. The choice of coping strategies is influenced by income, level of education, land tenure and extent of unreliability. The findings of this review highlight that low-income households bear a disproportionate coping burden, as they often engage in coping strategies such as collecting water from alternative sources, which is labour and time-intensive, and yields smaller quantities of water. Such alternative sources may be of lower water quality, and pose health risks. In the absence of dramatic improvements in the reliability of water supplies, a point of critical avenue of enquiry should be what coping strategies are effective and can be readily adopted by low income households. PMID- 27941694 TI - Quantification of Microbial Phenotypes. AB - Metabolite profiling technologies have improved to generate close to quantitative metabolomics data, which can be employed to quantitatively describe the metabolic phenotype of an organism. Here, we review the current technologies available for quantitative metabolomics, present their advantages and drawbacks, and the current challenges to generate fully quantitative metabolomics data. Metabolomics data can be integrated into metabolic networks using thermodynamic principles to constrain the directionality of reactions. Here we explain how to estimate Gibbs energy under physiological conditions, including examples of the estimations, and the different methods for thermodynamics-based network analysis. The fundamentals of the methods and how to perform the analyses are described. Finally, an example applying quantitative metabolomics to a yeast model by 13C fluxomics and thermodynamics-based network analysis is presented. The example shows that (1) these two methods are complementary to each other; and (2) there is a need to take into account Gibbs energy errors. Better estimations of metabolic phenotypes will be obtained when further constraints are included in the analysis. PMID- 27941696 TI - Effects of Indoor Air Pollutants on Atopic Dermatitis. AB - The increasing prevalence of atopic dermatitis (AD) is associated with variations in indoor environments. In Korea, many inner walls of homes are covered with wallpaper: such walls emit indoor air pollutants, including volatile organic compounds (VOCs) and formaldehyde. This randomized, double-blind study investigated the effects of wallpaper on indoor air quality and AD. Thirty-one children (aged three to eight years) with moderate AD were assigned to environmentally-friendly (EF) and polyvinyl chloride (PVC) wallpaper groups. Indoor air concentrations of VOCs, natural VOCs (NVOCs), formaldehyde, and total suspended bacteria were measured before and two (W2) and eight weeks (W8) after wallpapering. Scoring Atopic Dermatitis (SCORAD) evaluations and blood tests were performed during the same period. The EF wallpaper and PVC wallpaper groups showed similar trends in the changes in total VOCs (TVOC) and formaldehyde content in the indoor air. However, the EF wallpaper group showed more improvement on the SCORAD at W2 and W8 than the PVC wallpaper group. The SCORAD index was positively correlated with several indoor air pollutants. Further, the SCORAD index and NVOC % were negatively correlated. Improved SCORAD index and effects of wallpapering on indoor air quality improvements occurred within a short period of time in both groups. We believe that NVOCs in indoor air after EF wallpapering have a beneficial effect on health. PMID- 27941698 TI - Spatial Characteristics and Driving Factors of Provincial Wastewater Discharge in China. AB - Based on the increasing pressure on the water environment, this study aims to clarify the overall status of wastewater discharge in China, including the spatio temporal distribution characteristics of wastewater discharge and its driving factors, so as to provide reference for developing "emission reduction" strategies in China and discuss regional sustainable development and resources environment policies. We utilized the Exploratory Spatial Data Analysis (ESDA) method to analyze the characteristics of the spatio-temporal distribution of the total wastewater discharge among 31 provinces in China from 2002 to 2013. Then, we discussed about the driving factors, affected the wastewater discharge through the Logarithmic Mean Divisia Index (LMDI) method and classified those driving factors. Results indicate that: (1) the total wastewater discharge steadily increased, based on the social economic development, with an average growth rate of 5.3% per year; the domestic wastewater discharge is the main source of total wastewater discharge, and the amount of domestic wastewater discharge is larger than the industrial wastewater discharge. There are many spatial differences of wastewater discharge among provinces via the ESDA method. For example, provinces with high wastewater discharge are mainly the developed coastal provinces such as Jiangsu Province and Guangdong Province. Provinces and their surrounding areas with low wastewater discharge are mainly the undeveloped ones in Northwest China; (2) The dominant factors affecting wastewater discharge are the economy and technological advance; The secondary one is the efficiency of resource utilization, which brings about the unstable effect; population plays a less important role in wastewater discharge. The dominant driving factors affecting wastewater discharge among 31 provinces are divided into three types, including two-factor dominant type, three-factor leading type and four-factor antagonistic type. In addition, the proposals aimed at reducing the wastewater discharge are provided on the basis of these three types. PMID- 27941697 TI - Crystal Structure of a Putative Cytochrome P450 Alkane Hydroxylase (CYP153D17) from Sphingomonas sp. PAMC 26605 and Its Conformational Substrate Binding. AB - Enzymatic alkane hydroxylation reactions are useful for producing pharmaceutical and agricultural chemical intermediates from hydrocarbons. Several cytochrome P450 enzymes catalyze the regio- and stereo-specific hydroxylation of alkanes. We evaluated the substrate binding of a putative CYP alkane hydroxylase (CYP153D17) from the bacterium Sphingomonas sp. PAMC 26605. Substrate affinities to C10-C12 n alkanes and C10-C14 fatty acids with Kd values varied from 0.42 to 0.59 MUM. A longer alkane (C12) bound more strongly than a shorter alkane (C10), while shorter fatty acids (C10, capric acid; C12, lauric acid) bound more strongly than a longer fatty acid (C14, myristic acid). These data displayed a broad substrate specificity of CYP153D17, hence it was named as a putative CYP alkane hydroxylase. Moreover, the crystal structure of CYP153D17 was determined at 3.1 A resolution. This is the first study to provide structural information for the CYP153D family. Structural analysis showed that a co-purified alkane-like compound bound near the active-site heme group. The alkane-like substrate is in the hydrophobic pocket containing Thr74, Met90, Ala175, Ile240, Leu241, Val244, Leu292, Met295, and Phe393. Comparison with other CYP structures suggested that conformational changes in the beta1-beta2, alpha3-alpha4, and alpha6-alpha7 connecting loop are important for incorporating the long hydrophobic alkane-like substrate. These results improve the understanding of the catalytic mechanism of CYP153D17 and provide valuable information for future protein engineering studies. PMID- 27941699 TI - Nutrimetabolomics: An Update on Analytical Approaches to Investigate the Role of Plant-Based Foods and Their Bioactive Compounds in Non-Communicable Chronic Diseases. AB - Metabolomics is the study of low-weight molecules present in biological samples such as biofluids, tissue/cellular extracts, and culture media. Metabolomics research is increasing, and at the moment, it has several applications in the food science and nutrition fields. In the present review, we provide an update about the most frequently used methodologies and metabolomic platforms in these areas. Also, we discuss different metabolomic strategies regarding the discovery of new bioactive compounds (BACs) in plant-based foods. Furthermore, we review the existing literature related to the use of metabolomics to investigate the potential protective role of BACs in the prevention and treatment of non communicable chronic diseases, namely cardiovascular disease, diabetes, and cancer. PMID- 27941702 TI - Resonance-Based Reflector and Its Application in Unidirectional Antenna with Low Profile and Broadband Characteristics for Wireless Applications. AB - In this research, the novel concept of a resonance-based reflector (RBR) was proposed, and a ring-shaped RBR was utilized to design a unidirectional antenna with low-profile and broadband characteristics. Research found the ring operates as two half-wavelength (lambda/2) resonators. Then, the resonance effect transforms the reflection phase of the ring RBR, and achieves a reflection phase of 0 degrees < phi < 180 degrees in a wide frequency range above the resonance. Then, the in-phase reflection characteristic (-90 degrees < phi < 90 degrees ) can be obtained in the wide frequency band by placing an antenna above the RBR with a distance smaller than lambda/4. Two unidirectional antennas, named Case 1 and Case 2, were designed with the ring-shaped RBRs and bowtie antennas (RBR BAs). The impedance bandwidths of Case 1 and the Case 2 are 2.04-5.12 GHz (86.3%) and 1.97-5.01 GHz (87.1%), respectively. The front-to-back ratio (FBR, an important parameter to measure the unidirectional radiation) of Case 1 ranges from 5-9.9 dB for frequencies 2.04-2.42 GHz, and the FBR of Case 2 ranges from 5 16 dB for frequencies 2.16-3.15 GHz. The proposed concept of RBR is desirable in wideband unidirectional antenna design, and the designing antennas can be used at the front end of wireless systems-such as indoors communication, remote sensing, and wireless sensor systems-for signal receiving or transmitting. PMID- 27941700 TI - The Adverse Effects of Heavy Metals with and without Noise Exposure on the Human Peripheral and Central Auditory System: A Literature Review. AB - Exposure to some chemicals in the workplace can lead to occupational chemical induced hearing loss. Attention has mainly focused on the adverse auditory effects of solvents. However, other chemicals such as heavy metals have been also identified as ototoxic agents. The aim of this work was to review the current scientific knowledge about the adverse auditory effects of heavy metal exposure with and without co-exposure to noise in humans. PubMed and Medline were accessed to find suitable articles. A total of 49 articles met the inclusion criteria. Results from the review showed that no evidence about the ototoxic effects in humans of manganese is available. Contradictory results have been found for arsenic, lead and mercury as well as for the possible interaction between heavy metals and noise. All studies found in this review have found that exposure to cadmium and mixtures of heavy metals induce auditory dysfunction. Most of the studies investigating the adverse auditory effects of heavy metals in humans have investigated human populations exposed to lead. Some of these studies suggest peripheral and central auditory dysfunction induced by lead exposure. It is concluded that further evidence from human studies about the adverse auditory effects of heavy metal exposure is still required. Despite this issue, audiologists and other hearing health care professionals should be aware of the possible auditory effects of heavy metals. PMID- 27941703 TI - Bent Fiber Sensor for Preservative Detection in Milk. AB - A fiber optic sensor sensitive to refractive index changes of the outer region of the fiber cladding is presented. The sensor uses bent plastic optical fibers in different bending lengths to increase sensitivity. Measurements were made for low fat milk, the refractive index of which is altered by some preservatives such as formaldehyde, hydrogen peroxide, and sodium carbonate. Concentrations of the preservatives in the milk were changed between 0% and 14.3% while the refractive indices occurred between 1.34550 and 1.35093 for the minimum (0%) and maximum (14.286%) concentrations of sodium carbonate, respectively. Due to bending induced sensitivity, the sensor is able to detect refractive index changes less of than 0.4%. The results show that there is excellent linearity between the concentration and normalized response of the sensor. PMID- 27941704 TI - Node Deployment with k-Connectivity in Sensor Networks for Crop Information Full Coverage Monitoring. AB - Wireless sensor networks (WSNs) are suitable for the continuous monitoring of crop information in large-scale farmland. The information obtained is great for regulation of crop growth and achieving high yields in precision agriculture (PA). In order to realize full coverage and k-connectivity WSN deployment for monitoring crop growth information of farmland on a large scale and to ensure the accuracy of the monitored data, a new WSN deployment method using a genetic algorithm (GA) is here proposed. The fitness function of GA was constructed based on the following WSN deployment criteria: (1) nodes must be located in the corresponding plots; (2) WSN must have k-connectivity; (3) WSN must have no communication silos; (4) the minimum distance between node and plot boundary must be greater than a specific value to prevent each node from being affected by the farmland edge effect. The deployment experiments were performed on natural farmland and on irregular farmland divided based on spatial differences of soil nutrients. Results showed that both WSNs gave full coverage, there were no communication silos, and the minimum connectivity of nodes was equal to k. The deployment was tested for different values of k and transmission distance (d) to the node. The results showed that, when d was set to 200 m, as k increased from 2 to 4 the minimum connectivity of nodes increases and is equal to k. When k was set to 2, the average connectivity of all nodes increased in a linear manner with the increase of d from 140 m to 250 m, and the minimum connectivity does not change. PMID- 27941701 TI - Influence of Tyrosine Kinase Inhibitors on Hypertension and Nephrotoxicity in Metastatic Renal Cell Cancer Patients. AB - Renal cell carcinoma (RCC) is one of the most common kidney malignancies. An upgraded comprehension of the molecular biology implicated in the development of cancer has stimulated an increase in research and development of innovative antitumor therapies. The aim of the study was to analyze the medical literature for hypertension and renal toxicities as the adverse events of the vascular endothelial growth factor (VEGF) signaling pathway inhibitor (anti-VEGF) therapy. Relevant studies were identified in PubMed and ClinicalTrials.gov databases. Eligible studies were phase III and IV prospective clinical trials, meta-analyses and retrospective studies that had described events of hypertension or nephrotoxicity for patients who received anti-VEGF therapy. A total of 48 studies were included in the systematic review. The incidence of any grade hypertension ranged from 17% to 49.6%. Proteinuria and increased creatinine levels were ascertained in 8% to 73% and 5% to 65.6% of patients, respectively. These adverse events are most often mild in severity but may sometimes lead to treatment discontinuation. Nephrotoxicity and hypertension are related to multiple mechanisms; however, one of the main disturbances in those patients is VEGF inhibition. There is a significant risk of developing hypertension and renal dysfunction among patients receiving anti-VEGF treatment; however, there is also some evidence that these side effects may be used as biomarkers of response to antiangiogenic agents. PMID- 27941705 TI - An Accurate Non-Cooperative Method for Measuring Textureless Spherical Target Based on Calibrated Lasers. AB - Strong demands for accurate non-cooperative target measurement have been arising recently for the tasks of assembling and capturing. Spherical objects are one of the most common targets in these applications. However, the performance of the traditional vision-based reconstruction method was limited for practical use when handling poorly-textured targets. In this paper, we propose a novel multi-sensor fusion system for measuring and reconstructing textureless non-cooperative spherical targets. Our system consists of four simple lasers and a visual camera. This paper presents a complete framework of estimating the geometric parameters of textureless spherical targets: (1) an approach to calibrate the extrinsic parameters between a camera and simple lasers; and (2) a method to reconstruct the 3D position of the laser spots on the target surface and achieve the refined results via an optimized scheme. The experiment results show that our proposed calibration method can obtain a fine calibration result, which is comparable to the state-of-the-art LRF-based methods, and our calibrated system can estimate the geometric parameters with high accuracy in real time. PMID- 27941706 TI - A Wide-Swath Spaceborne TOPS SAR Image Formation Algorithm Based on Chirp Scaling and Chirp-Z Transform. AB - Based on the terrain observation by progressive scans (TOPS) mode, an efficient full-aperture image formation algorithm for focusing wide-swath spaceborne TOPS data is proposed. First, to overcome the Doppler frequency spectrum aliasing caused by azimuth antenna steering, the range-independent derotation operation is adopted, and the signal properties after derotation are derived in detail. Then, the azimuth deramp operation is performed to resolve image folding in azimuth. The traditional dermap function will introduce a time shift, resulting in appearance of ghost targets and azimuth resolution reduction at the scene edge, especially in the wide-swath coverage case. To avoid this, a novel solution is provided using a modified range-dependent deramp function combined with the chirp z transform. Moreover, range scaling and azimuth scaling are performed to provide the same azimuth and range sampling interval for all sub-swaths, instead of the interpolation operation for the sub-swath image mosaic. Simulation results are provided to validate the proposed algorithm. PMID- 27941709 TI - Reference Intervals of Alpha-Fetoprotein and Carcinoembryonic Antigen in the Apparently Healthy Population. AB - BACKGROUND The aim of this study was to calculate 95% reference intervals and double-sided limits of serum alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) according to the CLSI EP28-A3 guideline. MATERIAL AND METHODS Serum AFP and CEA values were measured in samples from 26 000 healthy subjects in the Shuyang area receiving general health checkups. The 95% reference intervals and upper limits were calculated by using MedCalc. RESULTS We provided continuous reference intervals from 20 years old to 90 years old for AFP and CEA. The reference intervals were: AFP, 1.31-7.89 ng/ml (males) and 1.01-7.10 ng/ml (females); CEA, 0.51-4.86 ng/ml (males) and 0.35-3.45ng/ml (females). AFP and CEA were significantly positively correlated with age in both males (r=0.196 and r=0.198) and females (r=0.121 and r=0.197). CONCLUSIONS Different races or populations and different detection systems may result in different reference intervals for AFP and CEA. Continuous reference intervals of age changes are more accurate than age groups. PMID- 27941707 TI - Biological Characteristics of H9N2 Avian Influenza Viruses from Healthy Chickens in Shanghai, China. AB - BACKGROUND H9N2 avian influenza viruses that circulate in domestic poultry in eastern China pose challenges to human health. However, few studies have compared the biological characteristics of H9N2 viruses isolated from healthy chickens in Shanghai. MATERIAL AND METHODS Three H9N2 viruses - CK/SH/Y1/07, CK/SH/Y1/02, and CK/SH/23/13 - isolated from healthy chickens in Shanghai between 2002 and 2013, were selected and their biological characteristics were determined. RESULTS All 3 H9N2 viruses showed a preference for both the avian- and human-like receptors, and they replicated well in MDCK and A549 cells. All H9N2 viruses were non pathogenic to mini-pigs and were detected in the trachea and lung tissues. The CK/SH/Y1/07 and CK/SH/Y1/02 viruses were transmitted to mini-pigs through direct contact or respiratory droplet exposure, but CK/SH/23/13 virus was not. CONCLUSIONS These results suggest that H9N2 viruses isolated from healthy chickens in Shanghai efficiently replicate and transmit among pigs and other mammals. PMID- 27941708 TI - Chloral Hydrate Treatment Induced Apoptosis of Macrophages via Fas Signaling Pathway. AB - BACKGROUND There are recent reports on several anesthetics that have anti inflammatory and anti-infective effects apart from their uses for pain relief and muscle relaxation. Chloral hydrate is a clinical anesthetic drug and sedative that has also been reported to attenuate inflammatory response, but the mechanisms are not clearly understood. MATERIAL AND METHODS This study investigated the effect of chloral hydrate treatment on the apoptosis of macrophages and explored the underlying mechanisms. RAW264.7 macrophages were treated with various concentrations of chloral hydrate for various lengths of time. Morphological changes were observed under a light microscope and apoptosis was detected with annexin-V-FITC/PI double-staining assay, Hochest 33258 and DNA ladder assay, the expression of Fas/FasL was detected with a flow cytometer, and the Fas signaling pathway was assessed by Western blotting. RESULTS The results showed that chloral hydrate treatment induced the morphology of RAW264.7 macrophages to change shape from typical fusiform to round in a concentration- and time-dependent manner, and was finally suspended in the supernatant. For the induction of apoptosis, chloral hydrate treatment induced the apoptosis of RAW264.7 macrophages from early-to-late stage apoptosis in a concentration- and time-dependent manner. For the mechanism, chloral hydrate treatment induced higher expression of Fas on RAW264.7 macrophages, and was also associated with changes in the expression of proteins involved in Fas signaling pathways. CONCLUSIONS Chloral hydrate treatment can induce the apoptosis of RAW264.7 macrophages through the Fas signaling pathway, which may provide new options for adjunctive treatment of acute inflammation. PMID- 27941710 TI - Could Heterozygous Beta Thalassemia Provide Protection Against Multiple Sclerosis? AB - BACKGROUND Heterozygous beta thalassemia (HBT) has been proposed to increase the risk of developing autoimmune disease. Our aim in this study was to examine the prevalence of HBT among multiple sclerosis (MS) patients. MATERIAL AND METHODS HBT frequency was investigated in our MS group (243 patients with MS). Hemoglobin electrophoresis (HE) was carried out if MS patients had a mean corpuscular volume of (MCV) <80 fL and a mean corpuscular hemoglobin level of (MCH) <27 pg/L according to a complete blood count (CBC). If MCV was lower than 80 fL, MCH was lower than 27 pg/L, and Hemoglobin A2 equal to or higher than 3.5%, a diagnosis of HBT was established. The frequency of patients with HBT in our MS patient group was statistically compared with the prevalence of HBT in the city of Istanbul, where our MS patients lived. RESULTS The HBT prevalence was 0.823% (2 patients) in the MS patient group. The prevalence of HBT in Istanbul has been reported to be 4.5%. According to the z-test, the HBT prevalence in our MS patient group was significantly lower than that in Istanbul (Z=6.3611, two-sided p value <0.0001, 95% confidence interval of prevalence of HBT in our MS patient group: 0.000998-0.029413). CONCLUSIONS Contrary to our hypothesis at the outset of study, the reduced HBT prevalence in the MS group compared to HBT frequency in the city of Istanbul might indicate that HBT is protective against MS. PMID- 27941711 TI - Recurrent Acute Myocardial Infarction in a Patient with Severe Coronary Artery Ectasia: Implication of Antithrombotic Therapy. AB - BACKGROUND Acute myocardial infarction (AMI) can be caused not only by plaque rupture/erosion, but also by many other mechanisms. Thromboembolism due to atrial fibrillation and coronary thrombosis due to coronary artery ectasia are among the causes. Here we report on a case of recurrent myocardial infarction with coronary artery ectasia. CASE REPORT Our case was a 78-year-old woman with hypertension. Within a one-month interval, she developed AMI twice at the distal portion of her right coronary artery along with coronary artery ectasia. On both events, emergent coronary angiography showed no obvious organic stenosis or trace of plaque rupture at the culprit segment after thrombus aspiration. After the second acute event, we started anticoagulation therapy with warfarin to prevent thrombus formation. In the chronic phase, we confirmed, by using coronary angiography, optimal coherence tomography and intravascular ultrasound, that there was no plaque rupture and no obvious thrombus formation along the coronary artery ectasia segment of the distal right coronary artery, which suggested effectiveness of anticoagulant. Furthermore, by Doppler velocimetry we found sluggish blood flow only in the coronary artery ectasia lesion but not in the left atrium which is generally the main site of systemic thromboembolism revealed by transesophageal echocardiography. CONCLUSIONS These results suggest that the two AMI events at the same coronary artery ectasia segment were caused by local thrombus formation due to local stagnant blood flow. Although it has not yet been generally established, anticoagulation therapy may be effective to prevent thrombus formation in patients with coronary artery ectasia regardless of the prevalence of atrial fibrillation. PMID- 27941712 TI - Changes in Gait Symmetry After Training on a Treadmill with Biofeedback in Chronic Stroke Patients: A 6-Month Follow-Up From a Randomized Controlled Trial. AB - BACKGROUND One of the most significant challenges for patients who survive a stroke is relearning basic motor tasks such as walking. The goal of this study was to evaluate whether training on a treadmill with visual biofeedback improves gait symmetry, as well as spatiotemporal and kinematic gait parameters, in stroke patients. MATERIAL AND METHODS Thirty patients in the chronic phase after a stroke were randomly allocated into groups with a rehabilitation program of treadmill training with or without visual biofeedback. The training program lasted 10 days. Spatiotemporal and kinematic gait parameters were evaluated. For all parameters analyzed, a symmetrical index was calculated. Follow-up studies were performed 6 months after completion of the program. RESULTS The symmetrical index had significantly normalized in terms of the step length (p=0.006), stance phase time, and inter-limb ratio in the intervention group. After 6 months, the improvement in the symmetry of the step length had been maintained. In the control group, no statistically significant change was observed in any of the parameters tested. There was no significant difference between the intervention group and the control group on completion of the program or at 6 months following the completion of the program. CONCLUSIONS Training on a treadmill has a significant effect on the improvement of spatiotemporal parameters and symmetry of gait in patients with chronic stroke. In the group with the treadmill training using visual biofeedback, no significantly greater improvement was observed. PMID- 27941715 TI - Peak Expiratory Flow Rate (PEFR) in First and Third Trimester of Pregnancy. AB - In this cross sectional study peak expiratory flow rate (PEFR) were estimated in pregnant women during the first trimester of pregnancy and in third trimester of pregnancy, to observe the alteration in airflow rate during pregnancy. This cross sectional study carried out in the Department of Physiology of Mymensingh Medical College, Mymensingh, Bangladesh from July 2014 to June 2015. For this purpose, total 300 women with age ranged from 18 to 35 years without any recent history of respiratory diseases were selected and divided into 100 healthy non pregnant women as control group and 200 normal pregnant women as study group. Study group was further subdivided into 100 pregnant women in first trimester and 100 pregnant women in third trimester of pregnancy. The PEFR was estimated by using mini version of Wrights peak flow meter. PEFR was measured during 1st and 3rd trimester of pregnant women and in non pregnant women. In this study, the PEFR significantly decreased both in first and third trimester of pregnancy than that of non pregnant women. Again the PEFR was significantly decreased in 3rd trimester of pregnancy than that of 1st trimester of pregnant women. It may be concluded that PEFR were significantly decreased in pregnancy, most likely due to the mechanical effects of progressively increased size of uterus that progressively decreases lung volumes and capacities. PMID- 27941714 TI - Inhibition of Cervical Cancer by Promoting IGFBP7 Expression Using Ellagic Acid from Pomegranate Peel. AB - BACKGROUND The aim of this study was to explore the mechanism by which cervical cancer is inhibited by promoting IGFBP7 expression using ellagic acid from pomegranate peel extract. MATERIAL AND METHODS HeLa cells were divided into 6 groups: control group (NC), blank control group (BL), and IGFBP7 overexpression group (IGFBP7), and 2.5 uM, 5. 0 uM, and 10.0 uM ellagic acid-treated groups. The cell proliferation ability was detected and the degree of invasion in the 6 groups was measured by Transwell assay. The expression levels of IGFBP7 and AKT/mTOR in the 6 groups of cells were detected by RT-PCR technique. RESULTS Compared with NC and BL groups, The IGFBP7 gene expressions of the IGFPB7 and ellagic acid-treated groups were significantly increased (P<0.05). There was a dose-effect dependence in the ellagic acid-treated groups. The invasion ability of the IGFBP7 group and ellagic acid-treated groups was significantly lower than that of NC and BL groups in HeLa cells (P<0.05). The apoptosis rate of the IGFBP7 group and ellagic acid-treated groups was significantly higher than that of the NC and BL groups in HeLa cells (P<0.05). AKT and mTOR mRNA and protein expressions of the IGFBP7 group and ellagic acid-treated groups were significantly lower than that of the NC and BL groups (P<0.05). There was a dose effect dependence in the ellagic acid-treated groups. CONCLUSIONS The ellagic acid in pomegranate peel extract can inhibit the AKT/mTOR signaling pathway by enhancing the expression level of IGFBP7, which can inhibit the HeLa cells in cervical cancer. PMID- 27941713 TI - Pathogenic Effects of Biofilm on Pseudomonas Aeruginosa Pulmonary Infection and Its Relationship to Cytokines. AB - BACKGROUND An animal (Sprague-Dawley rat) model of Pseudomonas aeruginosa biofilm associated with chronic pulmonary infection in vivo was established and the effects of the biofilm on P. aeruginosa and its relationship to cytokines were investigated. MATERIAL AND METHODS Biofilm of P. aeruginosa in alginate beads and planktonic PA0725 were purified by anion-exchange chromatograph. Sprague-Dawley (SD) rats were immunized with the biofilm and then inhaled the same strain of P. aeruginosa. Anti-biofilm antibody titer was detected using the enzyme linked immunosorbent assay (ELISA) method. The cell count and differential count in the bronchoalveolar lavage fluid (BALF) were measured. The levels of cytokines (IL 17, IL-1beta, MIP-2, and G-CSF) and tumor necrosis factor (TNF)-alpha in sera were also measured using an ELISA kit. RESULTS The sera anti-biofilm IgG antibody titer of immunized SD rats was increased significantly on the 5th and 8th days after inhalation. The IL-17 concentration was significantly higher on the 8th day after inhalation. The results indicated that when biofilm-pre-immunized rats were challenged with inhalation of PA0725 of P. aeruginosa, the biofilm acted as an antigen substance and mediated the antibody reaction of the antigen, which might cause serious airway inflammatory response and lung tissue injury. This effect may be related to IL-17. CONCLUSIONS P. aeruginosa biofilm protected the bacterium from antibiotics and might induce host immune damage in lung tissue and facilitate bacterium evading the host barrier. PMID- 27941716 TI - Relationship of Hemoglobin Concentration in Adult Asthmatic Patients. AB - Asthma is a chronic inflammatory disorder of the airways, in which many cells and cellular elements play a role. Asthma is one of the most common diseases globally and currently affects 300 million people. The epidemic rise in anemia, asthma, and related allergic disease is a common major public health problem worldwide. Asthma and anemia associated with acute infections occur both in children and adults. This descriptive type of cross sectional study was done to find out the levels of hemoglobin concentration in adult asthmatic patients and carried out in the Department of Physiology, Mymensingh Medical College, Mymensingh, Bangladesh from July 2014 to January 2016. Fifty (50) male and 50 (fifty) female adult asthmatic patients aged 18-60 years were included in the study group. They are enrolled from the Department of Medicine, Mymensingh Medical College, Mymensingh, Bangladesh and also from locality. For comparison age matched 50 male and 50 female apparently healthy persons were also studied as control. Hemoglobin concentration was estimated by Cyanmethemoglobin method. For statistical analysis unpaired student's 't' test was used. Mean hemoglobin concentration was significantly decreased in study group in comparison to control group and the result was statistically significant (p<0.001). The study findings showed a high prevalence of anemia among asthmatic patients than non asthmatic healthy persons. PMID- 27941718 TI - Serum Copper Status among Acute Myocardial Infarction Male Patients in Bangladesh. AB - This case control study was carried out in the Department of Biochemistry, Mymensingh Medical College in collaboration with the Department of Cardiology, Mymensingh Medical College Hospital, Mymensingh, Bangladesh from January 2015 to December 2015. The aim of the study was to explore the serum copper status among acute myocardial infarction (AMI) patients as a means to monitor the possibility of management of these patients. A total of 120 subjects were included in this study. Among them 60 were diagnosed AMI patients denoted as case group and 60 were normal healthy individuals denoted as control group. Serum copper determined by colorimetric method from each sample. Statistical analysis was performed by SPSS windows package, version 20. Among the study groups the mean serum copper levels were 150.30+/-26.16 and 103.65+/-9.38 in case and control group respectively. Analysis showed that the mean serum copper level was significantly (p<0.01) increased in AMI patients in comparison to that of control group. PMID- 27941717 TI - Variation of Length of Trachea in Different Age & Sex Group of Bangladeshi Cadaver. AB - A cross sectional descriptive study was performed on 70 post mortem human trachea (44 of male and 35 of female) to find out the difference in length of the trachea of Bangladeshi people in relation to age and sex. The specimens were collected from the morgue in the department of Forensic Medicine, Mymensingh Medical College, Mymensingh, Bangladesh by purposive sampling technique. All specimens were grouped into three categories, Group A (upto 20 years), Group B (21-40 years) and Group C (41-60 years) according to age. Dissection was performed according to standard autopsy techniques. The length of the trachea was measured with the help of a metallic tape and data was analyzed by using one way ANOVA test. A general trend of increasing tracheal length was observed as age advanced. The mean+/-SD length of the trachea was 7.88+/-1.01cm in Group A, 8.81+/-0.81cm in Group B and 8.94+/-1.04cm in Group C. The mean length of the trachea in male were 8.1+/-0.81cm, 8.95+/-0.69cm and 8.92+/-1.1cm in Group A, Group B and in Group C respectively and in female the length were 7.57+/-1.24cm, 8.61+/-0.96cm and 9+/-1cm in Group A, Group B and Group C respectively. Variance analysis shows significant difference in mean length of the trachea between the age Group A & B and Group A & C but no significant difference was shown between Group B & C. No significant difference of length of trachea between male and female was observed. The study would help to increase the information pool on the length of the trachea of Bangladeshi people. PMID- 27941719 TI - Study of Prostatic Volume and its Variations in Different Age Groups of Bangladeshi Cadaver. AB - Benign prostatic hyperplasia and carcinoma of the prostate are the most common disorders of Bangladeshi male in recent years. Volume of the prostate is necessary to estimate the amount of BPH adenoma to determine the appropriate therapy or to select the surgical approach. Transurethral resection of prostate (TURP) is preferred for small glands and open prostatectomy for larger ones. Decrease in prostatic mass after hormonal manipulation or radiation therapy can be used as an indicator of therapeutic efficacy. The effect of prostate volume on biopsy outcome was assessed and was noted that there was an inverse relationship in between size of the gland and prostate cancer. A cross sectional descriptive study was conducted in Department of Anatomy, Mymensingh Medical College, Mymensingh, Bangladesh to find out the difference in volume of the prostate gland of Bangladeshi people in relation to age. The present study was performed on 67 postmortem human prostate gland collected from the morgue in the Department of Forensic Medicine, Mymensingh Medical College by non random purposive sampling technique. The specimens were collected from Bangladeshi cadaver of age ranging from 10 to 80 years. All the specimens were grouped into three categories: Group A (upto 18 years), Group B (19 to 45 years) and Group C (above 45 years) according to age. Dissection was performed according to standard autopsy techniques. The volume of the prostate gland were measured and recorded. The mean volume of the prostate gland was 13.75ml in Group A, 24.44ml in Group B and 29.72ml in Group C. Variance analysis shows that mean differences of volume of the prostate were highly significant among all age groups. The volume of prostate gland was found to be increased with increasing age. For statistical analysis, differences between age groups were analyzed by using students unpaired 't' test. The present study will help to increase the information pool on the volume of prostate gland of Bangladeshi people. PMID- 27941721 TI - Association between Metabolic Syndrome and Acute Myocardial Infarction (AMI). AB - To evaluate the biochemical parameters of metabolic syndrome in case of acute myocardial infarction (AMI) patients this case control study was carried out in the department of Biochemistry, Mymensingh Medical College in collaboration with Department of Cardiology, Mymensingh Medical College Hospital, Mymensingh, Bangladesh from July 2012 to June 2013. To assess of serum total cholesterol, triacylglycerol, HDL-cholesterol, LDL-cholesterol, to estimate of serum glucose and to establish the association of age, sex, BMI, waist circumference, waist hip ratio and blood pressure of myocardial infarction patients. A total of 120 subjects were included in the study. Among them 60 were subjects of AMI cases and another 60 subjects of non AMI patients as controls. Serum total cholesterol, serum triacylglycerol, serum LDL-Cholesterol & serum HDL-Cholesterol were estimated in each sample. All values were expressed as Mean+/-SD. Statistical significance of difference between case and control were evaluated by using student's unpaired 't' test. All statistical analysis was done by using SPSS windows package. Past history of diabetes Mellitus and hypertension were more common in cases compared to those in control (p<0.001) which was statistically highly significant. There was no significant difference in the history of smoking between case and control. Statistical mean values of serum triacylglycerol, serum FBS, serum total cholesterol were highly significant in AMI patients in comparison to control (p<0.001). Statistical mean value of HDL-C was significantly decreased in AMI patients in contrast to control (p<0.001). In this study systolic blood pressure and diastolic blood pressure were significantly increased in AMI patients in comparison to control (p<0.05). Waist circumference was highly significant in AMI patients in comparison to control (p<0.001). Analyzing the findings of the present study there were significant alteration in lipid profile, blood pressure, fasting blood sugar & WC. These findings reaffirm the clinical importance of the metabolic syndrome as a significant risk factor for AMI. So it may be recommended that estimation of these parameters may help pivotal for better management of AMI. PMID- 27941720 TI - Effectiveness of Topical Corticosteroid, Topical Calcineurin Inhibitors and Combination of Them in the Treatment of Vitiligo. AB - Vitiligo is an acquired pigmentary skin disorder which is disfiguring and difficult to treat. Cure and response rates for vitiligo are significantly lower. This study was conducted to evaluate the effectiveness of topical corticosteroid, topical calcineurin inhibitors (tacrolimus) and combination of them in the treatment of vitilligo in two tertiary care Hospital, in the Department of Dermatology and Venereology OPD (out patient department) in Mymensingh Medical College Hospital and Jahurul Islam Medical College Hospital, Bajitpur, Kishoregonj from January 2015 to December 2015. Newly diagnosed 112 vitiligo patients, aged more than 1 year to 70 years were assigned for therapy and to observe the response. This study indicates that, in case of vitiligo treatment topical tacrolimus was the most effective drug. Topical tacrolimus, topical corticosteroid and combination of them are to be effective in the treatment of vitiligo with reduction in the number of vitiliginous spots by increased repigmentation. But topical tacrolimus was the most effective drug, as it caused highest percentage of repigmentation of vitiliginous spot. PMID- 27941723 TI - Doppler Assessment of Hepatic Venous Waves for Evaluation of Large Varices in Cirrhotic Patient. AB - This cross sectional study was conducted to evaluate the role of doppler ultrasonography of hepatic venous waves for evaluation of large varices in cirrhotic patients from July 2013 to June 2015 in Mymensingh Medical College Hospital, Mymensingh, Bangladesh. Patients getting admitted in the ward with a diagnosis of cirrhosis were enrolled in the study and purposive sampling technique was adopted. The sample size was 43. Data were collected by face to face interview and some data were gathered by records review and analyzed with the help of SPSS windows version - 12 software programs. Statistical significance was set at P<0.05 and confidence interval set at 95%. The research protocol was approved by the local ethical committee. Esophagogastroduodenoscopy is the gold standard for the diagnosis of esophageal varices. If the gold standard is not available, other possible diagnostic steps would be Doppler ultrasonography of the blood circulation (not endoscopic ultrasonography). Although and it can certainly demonstrate the presence of varices. In 60.47% of patient's monophasic wave pattern was seen and in 39.53% of cases biphasic & triphasic wave pattern were detected. Endoscopic examination was performed in all selected patients. In this study, 67.44% is large varices, 32.66% is small varices. Chi Square test was done for hypothesis testing and it was found significant (<0.05) and it indicates monophasic wave in Doppler USG signifies large varices. This test was also done to find out whether any significant difference of hepatic venous waveform in between male and female but it was not significant (>0.05). Diagnostic performance of USG for evaluation of varices showed, Sensitivity: 86.2%, Specificity: 92.85%, PPV: 96%, NPV: 76.47%, Accuracy 88%. Correlation co efficient was 0.0064 which indicates moderately positive correlation in between monophasic hepatic venous waveform pattern by Doppler USG and large varices in oesophagogastroduodenoscopic findings Normal hepatic wave form shows triphasic pattern. Loss of this pattern in cirrhosis is mainly due to loss of compliance of liver. In conclusion, the loss of triphasic pattern of hepatic wave form is highly sensitive in predicting the presence of large varices in cirrhotic patients and this doppler parameter may be used as a non-invasive test for cirrhotic patients, who wish to avoid upper GI endoscopy. Further studies using a combination of various doppler parameters are needed to create indices with a better predictive value. PMID- 27941722 TI - Serum Zinc, Copper, Magnesium & Phosphorus Level in Children with Severe Acute Malnutrition (SAM). AB - Malnutrition is widely prevalent among hospitalized children in most developing countries including Bangladesh. Though malnutrition accounts for the high rate of under 5 mortality sometimes it is overlooked. Keeping in this in mind A comparative cross sectional study was done in Mymensingh Medical College Hospital from 1st October 2009 to 31st May 2011. Children aged 1-5 years with presence of one or more criteria WHM <70%, WHZ-score <-3SD, Bipedal edema & Mid upper arm circumference <110mm were taken as study group and children aged 1-5 years with normal growth allowable normal range of variation is between 3rd and 97th centile curve or median (50th centile) +/-2SD of weight for age growth chart (CDC growth chart, USA, 2000) were taken as reference group. Persistent diarrhea, Patients taking medications containing zinc, copper, magnesium, phosphorus & calcium, PEM with shock were excluded from study group. Nutritional assessment was done according to WHO criteria of SAM. Serum Zinc, Copper Magnesium and Phosphorus level were determined by Atomic Absorption Spectrometry using UNICAM - AA Spectrometer, model no. 969, Spain. Total 120 study populations were taken. Ninety Out of 120 were taken as a study group (SAM) & 30 were reference group. In reference group serum Zn, Cu, Mg, P value was 103.80+/-8.86MUg/dl, 135.92+/ 13.57MUg/dl, 2.31+/-0.18mg/dl, 3.96+/-0.22mg/dl respectively. In study group serum Zn, Cu, Mg, P value was 60.33+/-11.08MUg/dl, 80.60+/-15.46MUg/dl, 1.47+/ 0.22mg/dl, 2.00+/-0.52mg/dl respectively. All these results show that there is significant difference between study group & reference group. Considering the decreased level of these parameters, close biochemical monitoring and follow up should be emphasized for the children with SAM. PMID- 27941724 TI - Status of Low Birth Weight Babies in Mymensingh Medical College Hospital. AB - Low birth weight (LBW) is the major neonatal health problem in Bangladesh like other developing countries with limited resource. But only a few studies had done about status of LBW at hospital setting in this country. The objective of the study that to evaluate the status and immediate outcome of the LBW This cross sectional retrospective study was done in neonatal ward of Mymensingh medical college hospital. In this 1000 bedded tertiary care level teaching hospital only 40 cots and 10 open incubators are sanctioned but daily average admission in neonatal ward more than 30. On an average about 100 patients are remaining in the ward. Three or four patients are nursed in each cot. It covers the vast catchment's area of Bangladesh having more than two cores of population. With limited resources and manpower, this neonatal ward has to bear the burden of 100 neonates and daily admission of 30 neonates. Study period was one year (October 2013 to September 2014). Total admitted neonates were 8359. All admitted neonates were considered as study population and all LBW babies were considered as sample. Among total population 41% (3423) were LBW. Among total LBW babies maximum (80.7%) had birth weight 1500-2499gm followed by Very Low birth weight (VLBW) 1000 - 1499gm 14.7%, Extreme Low birth weight (ELBW) 1000-750gm 1.6% and Incredible low birth weight <750gm 1.7%. Term LBW (IUGR) babies were 52% and preterm LBW were 48%. Death rate among LBW babies group were higher (18.5%) than death rate (15.8%) among all admitted neonate. By comparison of mortality rate among different subgroup of LBW shows highest mortality (65.5%) was in incredible low birth weight babies group followed by ELBW group (58.8%) and among VLBW group 26.4% and lowest mortality (15.3%) was among birth weight 1500-2499gm group babies. Death rate was inversely related to birth weight. Death rate among preterm LBW babies (21.5%) was higher than Term LBW (IUGR) babies (15.7%). So, death rate was also inversely related to the maturity. Death rate among LBW babies is still higher in our institute than other developed institute of home and abroad. Death rate specially higher among incredible birth weight group and ELBW group in our institute. Further improvement in neonatal care is needed to decrease the mortality among LBW babies. PMID- 27941725 TI - Anthropometric Study of Carrying Angle on Bangladeshi Garo People. AB - The present study was designed to construct an anthropometric data of 20-40 years aged 104 Bangladeshi Garo people (60 male and 44 female) regarding carrying angle and an attempt has been made out to grow interest among the researchers for future study and also to compare the data with the data of the people of other races. Participants were selected through purposive sampling for this cross sectional, observational, descriptive and analytic type study which was carried out in different areas of Mymensingh district (Haluaghat, Mymensingh Sadar), Bangladesh from July 2015 to June 2016. The carrying angles of both side were measured by goniometer. Data were tabulated and statistically analyzed using Microsoft excel and SPSS software. Carrying angle was found to be higher in males but angle of inclination was higher in females. Comparison of differences of means between male and female was statistically significant. The results of present study would be useful for Anthropologist and Forensic Medicine experts. PMID- 27941726 TI - Current Trends of Using Antimicrobial Drugs in the ICU at a Tertiary Level Teaching Hospital in Mymensingh. AB - The aim of the present study was to investigate the current trends of using antimicrobial drugs in the ICU at a tertiary level teaching hospital in Mymensingh. The study of prescribing patterns seeks to monitor, evaluate and suggest modifications in clinicians prescribing habits so as to make medical care rational. It was an observational type of descriptive study, conducted in the Mymensingh medical college hospital, Mymensingh, during the study period of June 2016 to September 2016.The study was approved by the institutional ethical committee. Most patients in the ICU belonged to the older age group >60 years. Male patients were more than the female patients in ICU. Average duration of stay in ICU was 4.35 days. Admissions in ICU were common due to respiratory system related diseases and the present study showed that 31.68% of the reported cases belong to the respiratory system. Average number of drugs per prescription was 6.46. Average number of anti-microbial drugs per prescription was 1.38. Cephalosporin group and individually ceftriaxone was the most frequently prescribed antimicrobial group and agent respectively in the ICU. Most commonly used antimicrobial combination was Cephalosporin and Metronidazole (43.33%) followed by Carbapenem (Meropenem) and Metronidazole (13.33%). Most antimicrobial agents were prescribed without bacteriological culture and sensivity testing evidence. There is a need for motivating the physicians to prescribe antimicrobial agents with supportive bacteriological evidences. PMID- 27941727 TI - Risk of Acute Coronary Syndrome is Better Predicted by Apolipoprotein B in Young People than Dyslipidemic Parameter of Conventional Lipid Profile. AB - The traditional lipidic parameters when present and clusters within reference range, often fails to predict the risk of acute coronary syndrome in young population in this region. Measurement of Apolipoprotein B (Apo B), a parameter of the lipoprotein-lipid profile, provides a method of quantifying the concentration of lipoproteins, rather than their cholesterol content. Present study aimed to quantify the risk of acute coronary syndrome (ACS) in young people with having none to less number of traditional lipidic parameters for dyslipidemia. This is a case control study among 50 cases of first attack of ACS among 18-45 years of age of both sexes, admitted in coronary care unit of Mymensingh Medical College Hospital, Mymensingh, Bangladesh from June 2009 to May 2010. Data was recently reanalyzed. Out of five sub-sets of lipid profile, namely TC, TG, HDL-C, LDL-C and non-HDL-C, 16(32%) cases were dyslipidemic by 0 (none) parameter, 13(26%) cases by one parameter, 7(14%) cases by two parameters, 4(8%) cases by three cases, 7(14%) cases by four parameters and 3(6%) cases by all five parameters. It was found that none to lesser the number of dyslipidemic parameters, greater the percentage of ACS cases and they are having hyper ApoB with statistically significant association (p<0.05). PMID- 27941728 TI - Prevalence of Psychiatric Disorders among Female Juvenile Offenders. AB - Inmates of Juvenile Developmental Centers are the special group of youth population who are in conflict with law. They are vulnerable to psychiatric illness. The objective of this study was to see the prevalence and type of psychiatric disorders in institutionalized female juvenile offenders and non offenders of same age, sex and socioeconomic group in the community. The association of mental disorders was examined in 43 female inmates of Juvenile Development Centers and 43 randomly selected comparison subjects in community. One stage-structured assessment of psychopathology was carried out by using a structured and valid Bangla version of the Development and Well-Being Assessment (DAWBA). Development and Well-Being Assessment generated psychiatric diagnosis was assigned based on ICD-10 diagnostic criteria for research. The result revealed that, of those who were in conflict with law, 93% had mental disorder, whereas 14% of non-offenders had psychiatric disorder. Among the offenders with psychiatric disorders, most of them (32.6%) suffered from Major Depressive Disorder (MDD), followed by combined MDD & Post Traumatic Stress Disorder (PTSD). On the other hand, among the non-offenders with psychiatric disorder 9.3% suffered from MDD. It can be concluded that considerable psychiatric disorders are prevalent among the female juvenile offenders with comparison to non offenders. Broad-based replication study could confirm these findings. PMID- 27941729 TI - Histological and Cytological Correlation of Cervical Cancer and Precancerous Lesions in a Tertiary Hospital in Bangladesh. AB - Over 500,000 new cases of cervical cancer are diagnosed each year in the world, resulting in 250000 deaths. Prevalence of HPV-related cervical carcinoma in Bangladesh is highest among SAARC countries. In Bangladesh very few studies have been published on establishing the correlation between histological and cytological findings on cervical cancer and precancerous lesions. This descriptive cross-sectional study was performed to find out the correlation between histological & cytological findings of cervical cancer and precancerous lesions. In the present study, cervical smears were collected from the selected patients attending the colposcopy clinic of BSMMU from July 2011 to April 2013. Biopsy was done on colposcopically positive cases and histopathological reports were obtained. Thus 99 histologically proven cases of cervical cancer and precancerous lesion were selected. Pap smear was carried out on these 99 samples after histopathological examination. Among the 60 CIN-1 cases in histology, 18(30%) cases were diagnosed positive by Pap smear; out of 20 histologically diagnosed cases of CIN-II, only 12(60%) cases were correctly diagnosed by cytology. But in case of invasive squamous cell carcinoma 18 out of 19 were correctly diagnosed by Pap smear reaching a concordance rate of 94.74%. Overall the relation reached statistical significance (p<0.05). Larger community based studies are required in this respect to find a consistent correlation between hr HPV load and cervical cancer and precancerous lesions. PMID- 27941730 TI - Efficacy of Vitamin C in Lowering Serum Uric Acid. AB - The objective of the study was to determine the efficacy of vitamin C in reducing serum uric acid (UA). This study was a double-blind placebo-controlled randomized trial conducted in the Department of Rheumatology, Bangabandhu Sheikh Mujib Medical University (BSMMU) Dhaka, Bangladesh from July 2007 and August 2008. Study participants were included from out patient department (OPD) of Rheumatology of BSMMU suffering from various Rheumatological problems other than gouty arthritis. All of the participants were non-smokers, non-alcoholics, and randomized to take either placebo or vitamin C (500 mg/day) for 12 weeks. A total of 98 subjects were enrolled in the study; 71 completed the trial, with 34 in the placebo group and 37 receiving vitamin C. Serum uric acid levels were not significantly reduced in the experimental group and they increased in the placebo group. In the vitamin C group, the mean change was -0.32mg/dl [95% confidence interval -0.73, 0.77], whereas in the placebo group, the mean change was +0.12mg/dl [95% confidence interval was -0.22, 0.47]. Subgroups were defined by sex, body mass index, and quartiles of baseline serum uric acid levels. In a subgroup analysis, vitamin C lowered serum uric acid significantly in those who had comparatively higher baseline uric acid levels. Although vitamin C did not lower serum uric acid significantly, participants with higher baseline serum uric acid levels experienced a significant uric acid lowering effect, but as the sample size was very small, it is difficult to draw any definitive conclusion. PMID- 27941731 TI - Structural Variations of Nose and Paranasal Sinuses in Various Sinonasal Pathologies: Tomographic Study of 50 Cases in Bangladeshi People. AB - The aim of this study was to determine the frequency of structural variations in nose & paranasal sinuses in computed tomography in Bangladeshi people. This retrospective study was done at the Sir Salimullah Medical College Mitford Hospital and Apollo Hospitals, Dhaka, Bangladesh. Fifty (50) CT scan of Nose and Para nasal sinuses were collected from the patients presented with different sinonasal pathologies in OPD, IPD of both hospitals from July 2013 to June 2014. The scans were reviewed for the presence of different structural variations of nose and paranasal sinuses. The age range of the patients was 25 to 65 years. The most common anatomical variation in this study was hypertrophied inferior turbinate (82%) followed by ethmoidal bulla (70%), deviated nasal septum (64%), agar nasi cell (40%), concha bullosa (38%). In most of the patients we found more than one variation. There is wide range of anatomical variations in nose and paranasal sinuses which might be regarded as the aetiological factors of different sinonasal pathologies. To maximize patients' benefit and to avoid unexpected situations during surgeries as well as dreadful complications, individualized pre-planning through tomographic study should be considered. PMID- 27941732 TI - Glycosylated Hemoglobin in Different Levels of BMI. AB - Body mass index is an inexpensive and easy method of screening for weight categories that may lead to health problems. Increased BMI in overweight and obese persons is directly associated with an increase in metabolic disease, such as type 2 diabetes mellitus. This Analytical cross sectional study was undertaken to assess the relation between increasing BMI and glycemic control of body through measuring glycosylated hemoglobin. This study was carried out in the Department of Physiology, Mymensingh Medical College, Mymensingh, Bangladesh from July 2011 to June 2012 on 180 equally divided male and female persons between the age of 25 to 55 years. Age more than 55 years and less than 25 years and diagnosed case of hypothyroidism, cushing's syndrome, polycystic ovary, antipsychotic drug user and regular steroid users were excluded. Non probability purposive type of sampling technique was used for selecting the study subjects. Measurement of body mass index was done as per procedure. Glycosylated hemoglobin was estimated by Boronate Affinity method. Statistical analysis was done by SPSS (version 17.0). Data were expressed as Mean (+/-SE) and statistical significance of difference among the groups were calculated by unpaired student's 't' test and Pearson's correlation coefficient tests were done as applicable. There was no significant difference of glycosylated hemoglobin level between control and study groups. But there was positive correlation within each group (r=0.255, 0.37 and 0.39 in control, overweight and obese respectively). The observed positive correlation between BMI and glycosylated hemoglobin emphasizes the maintenance of normal BMI to prevent early onset of type 2 diabetes mellitus. Health education activities highlighting the danger of becoming overweight and obese should be undertaken. PMID- 27941733 TI - Evaluation of Body Mass Index Before and After Prosthetic Rehabilitation with Complete Denture Therapy. AB - The objective of this study was to compare body mass index (BMI) of the edentulous patients before and after complete denture therapy. Forty five (45) patients who had been edentulous for six months to one year and required complete dentures were selected for this study; of them 25(55.56%) were males and 20(44.44%) were females and age range was between 40 to 70 years. Every patient was provided with complete dentures fabricated with ethical standard procedures. Analysis of the body mass index (BMI) was done at base line; and at three and six months follow up. The mean BMI values were found 19.58+/-1.93; 20.63+/-1.89 and 22.02+/-1.80 at base line, at three months follow up and at six months follow up respectively. The differences of the BMI values were found to be statistically significant (p<0.05) both at 3 months and 6 months follow up compared to the base line value. PMID- 27941734 TI - Health Related Quality of Life in Children with Nephrotic Syndrome in Bangladesh. AB - Outcome of children with nephrotic syndrome has continued to improve over time. However minimal data exist to describe health-related quality of life in children with nephrotic syndrome. This cross sectional study was conducted over a period of six months to assess the health related quality of life in children with nephrotic syndrome in the Department of Pediatric Nephrology, Dhaka Medical College Hospital, Bangladesh. Fifty children (age ranged 2-12 years) with nephrotic syndrome who had three or more relapses diagnosed at least one year back receiving treatment and on follow up were included in this study. Quality of Life scores were collected using Bengali translated instruments- the Pediatric Quality of Life InventoryTM (PedsQLTM) version 4.0 Generic Scale and the Pediatric Quality of Life Questionnaire for Nephrotic Syndrome proxy-report from parents. Medical data and Demographic data were collected from medical records, and from parents in outpatient department or hospital ward. Interviews of eligible guardians were performed individually to collect quality of life (QoL) scores. Among 50 children, mean+/-SD age of the children was 7+/-2.92 years. Most children were male (58%). Female parents respondent during interview were 62%, most parents (48%) were very poor in socioeconomic condition. Most children had frequent relapses (60%). Median time since diagnosis was 2 years. Regarding PedsQL scores, child age with physical summary score (p value <0.001), child age with social summary score (p value 0.003), frequent relapse with kidney disease summary score (p value 0.04) and time since diagnosis (p value <0.001) were statistically significant. In conclusion physical and social summary score were worst. Frequent relapse found to be an important factor in impaired QoL. Prolonged duration of the disease activity was associated with significant impairment of QoL. PMID- 27941735 TI - Isolation of Extended Spectrum beta-Lactamase Producing Gram Negative Bacilli from Wound Swab with Their Antimicrobial Susceptibility Pattern. AB - Extended Spectrum beta-lactamases (ESBLs) producing organisms have become the major clinical concern worldwide. The present study was undertaken to see the frequency of ESBLs producing gram-negative bacilli with their antibiogram in post surgical wound swab collected over a period of 12 months from July 2011 to June 2012 at Dhaka Medical College Hospital. Among 200 samples 121(60.5%) gram negative bacilli and 52(26%) gram-positive bacteria were isolated. Escherichia coli (36.42%) was the most predominant gram-negative bacilli followed by Klebsiella species (9.83%) and Pseudomonas aeruginosa (8.67%). Thirty four (28.1%) isolates were detected as ESBLs producers by double-disc synergy test (DDST) and the prevalence among Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa were 33.33%, 35.29% and 26.67% respectively. All the ESBL producing strains were sensitive to imipenem but they were significantly more resistant to ciprofloxacin, doxycycline, amoxiclav, co-trimoxazole, azithromycin and gentamycin than non-ESBLs producers (p<0.01). The finding suggests more effective strategies are needed to control the spread of these resistant organisms. PMID- 27941736 TI - Comparison of Low Density Lipoprotein Cholesterol Level in Second and Third Trimester of Pregnancy in Mymensingh Region of Bangladesh. AB - Altered metabolic and hormonal status of the body in pregnancy leads to changes in lipid profile. High Lipid profile, a major factor behind atherosclerosis may leads to unconsciousness. To avoid such problems during pregnancy this longitudinal study was carried out in the Department of Biochemistry, Mymensingh Medical College in co-operation with the Department of Obstetrics and Gynaecology, Mymensingh Medical College Hospital and Community Based Medical College Hospital, Bangladesh during the period from July 2011 to December 2012 to compare the changes in low density lipoprotein cholesterol level during 2nd and 3rd trimester of pregnancy. A total of one hundred subjects were participated in this study comprising of second and third trimester of pregnancy. All subjects were made to fast overnight at least for a minimum of 8 hrs. Blood samples were taken and analyzed by enzymatic colorimetric kit method. Pregnancy has being found to be associated with changes in lipid profile and this differs with each trimester. The average results were analyzed with respect to each pregnancy for the whole group. The study proves that serum Low Density Lipoprotein (LDL) cholesterol increases in third trimester (174.83+/-13.78 mg/dl) than second trimester (156.77+/-7.96 mg/dl) of pregnancy. Therefore, lipid profile estimation and monitoring should be made as a part of routine investigation during antenatal period. PMID- 27941737 TI - Challenges in HbA1C Level as a Diagnostic Tool of Diabetes and Pre-Diabetes in Middle-Aged Population: The Bangladesh Study. AB - Worldwide prevalence of diabetes is found to be the human health at an alarming rate. However, large numbers of patient remain undiagnosed. Oral glucose tolerance test (OGTT) still is regarded as gold standard in diagnosis of blood glucose abnormality. Although the less number of bodies are considering measurement of HbA1C as an alternate tool to identify risk group. This study was undertaken to evaluate the role of measurement of HbA1C in the diagnosis of diabetes and pre-diabetes in middle-aged Bangladeshi subjects and carried out in the department of Biochemistry, BIRDEM from July 2013 to June 2014. A total 177 subjects of age within the range of 30-45 years were selected for the purpose and classified into healthy control (n=62) pre-diabetes (n=69) and diabetes (n=46) groups based on the values of OGTT. Middle aged Bangladeshi subjects attending Bangladesh Institute of Research & Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM) hospital, the HbA1C values were 5.0-5.6% in control group, 5.6-6.2% in pre-diabetes and 8.1-9.7% in diabetes group (95% CI). The optimal cut-off value of HbA1C related to pre-diabetes diagnosed by OGTT was 5.6%, which showed the sensitivity 47.8%, specificity 74.2%, positive predictive value 67.3% and negative predictive value 58.5%. Variants of hemoglobin especially Hemoglobin E (HbE) is prevalent in South East Asia including Bangladesh. The presence of genetic variants of hemoglobin can profoundly affect the accuracy of HbA1C measurements. So measurement of HbA1C may not be used as an alternate tool of OGTT to identify people of diabetes and pre-diabetes in certain situation. PMID- 27941738 TI - Pattern of Changes in the Findings among the Patients Undergoing Diagnostic Esophagogastroduodenoscopy in Bangladesh. AB - This cross-sectional observational study was conducted in the Department of Gastroenterology, Bangabandhu Sheikh Mujib Medical University, Sir Salimullah Medical College and Mitford Hospital, Holy family Red Crescent Medical College and Hospital and Popular Diagnostic Centre, Shantinagar branch, Dhaka, Bangladesh from January 2012 to July 2013. Study subjects were included in the study irrespective of age and sex having different upper GI tract. Complaints like dysphagia, heart burn, abdominal pain/dyspepsia, nausea, vomiting, haematemesis and/or malena, anorexia, unexplained anemia, weight loss etc. All the findings of oesophagus, stomach and duodenal lesions were observed and data were recorded. The results were considered positive based on the macroscopic appearance using standard diagnostic criteria. During the study period endoscopy was performed in 5608 subjects. Among which 2968(52.92%) were male and 2640(47.07%) were female. The patients age range from 7 years to 108 years. The majority of the patients were from 40-50 years. Normal findings were observed among 3321(59.21%) cases. Gastroduodenal erosions were present among 684(12.19%) cases, Oesophageal varices in 444(7.91%) cases, duodenal ulcer diseases in 415(7.40%) cases and gastric ulcer in 184(3.28%) cases. Ca stomach was found among 165(2.94%) cases. A number of diseases were identified through this procedure. Current study observed a large proportion of patients (40.79%) had positive upper GI endoscopy. PMID- 27941739 TI - Incidence of Hyperglycemia during Induction of Remission Phase of Pediatric Acute Lymphoblastic Leukemia. AB - Hyperglycemia is frequently associated with acute lymphoblastic leukemia (ALL) therapy. It has long been recognized as a consequence of corticosteroids and asparaginase. These medications are usually administrated concurrently in high doses during the initial induction phase of chemotherapy. As a result, hyperglycemia frequently develops during this phase, with resolution after the steroids and asparaginase have been discontinued or reduced in dose. Various recent studies have evaluated the incidence of hyperglycemia in this particular group of patients and its relationship with chemotherapy. However the incidence of hyperglycemia during induction of remission therapy in children with ALL is not known, and is the subject of this study. To determine the incidence as well as identification of day of onset and duration of hyperglycemia and other complications during induction of remission therapy. This prospective cross sectional study included 50 newly diagnosed patients aged 1-15 years and was done from December 2010 to May 2011 in the department of Pediatric Haemato Oncology, Bangabandhu Sheikh Mujib Medical University, Bangladesh. Hyperglycemia was defined as >=2 random glucose determinations of >=200mg/dl during the first 28 days of induction chemotherapy. Out of 50 patients, 4(8%) patients developed hyperglycemia during remission induction therapy. No significant difference was found between two groups regarding age distribution (p>0.05) and body weight (p>0.05). Among patients who developed hyperglycemia 3 patients (75%) and 1 patient (25%) experienced hyperglycemia during second week and third week of induction therapy respectively. Hyperglycemia persists <7 days in case of 3(75%) patients and >7 days in case of 1(25%) patients. The incidence of chemotherapy induced hyperglycemia in this present study is 8%. Most patients who develop therapy induced hyperglycemia recover when L-asparaginase and corticosteroids are discontinued and they suffer no long term adverse effects. PMID- 27941740 TI - Assessing the Rehabilitation of Achilles Tendon Ruptures using Modified Teuffer and Lindholm Technique. AB - The aim of this study is to assess the optimum rehabilitation and the functional outcome of open repaired Achilles tendon ruptures. This study was conducted for the 18 consecutive patients of complete ruptures at Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from 2012 to 2013. Two groups were considered during 6 to 18 months post-operative observation and each group consist 9 patients. In the Group I, modified Teuffer's and in Group II, Lindholm operative methods were employed for the open repair of Achille tendon. The post operative outcomes were assessed for both of the groups through the modified Thermann's scores. In this study the patients median age was seen 39 years with 72.2% male and 27.8% female. The Thompson test was found positive in pre operative and negative in post-operative outcome. The results shown that Achilles tendon ruptures occurred in 4 to 6cm rupture site, where the rupture side was 61.1% left and 38.9% right. The subjective overall assessment of total Thermann's scores were found very good (91 to 96) in 4 cases and (90 to 98) in 3 cases for Group I and Group II, respectively. Both of the operative techniques were found accountable results for rehabilitation. Therefore, based on the further statistical evidence of higher correlations and errors it may be concluded that Achilles tendon ruptures can be treated by modified Teuffer's or Lindholm technique. PMID- 27941741 TI - Neurodevelopmental Outcomes in Children Born to Climate Refugee Mothers in Bangladesh: Experiences from Cyclone Aila. AB - Cyclone Aila hit the South-West coast of Bangladesh in May 2009, when in Dacope Upazilla over 50,000 people were left homeless as climate refugees (CRs) for over two years. We determined neurodevelopmental status of children born as CRs compared to their non-Climate Refugee (NCR) counterparts. Pregnant mothers were enrolled from May 2009 to April 2010 in entire Dacope in a study which profiled their health conditions. From among these mothers, 12 months post-Aila 267 CR mother-child dyads, and 552 NCR mother-child dyads were enrolled to assess their children's neurodevelopmental outcomes. There were significantly more landless families among CRs compared to NCRs (p value = 0.0001; OR = 1.86, 95% CI: 1.37 - 2.51). The mean+/-SD age at assessment of CR children was 8.52+/-4.57 months compared to a mean age 9.09+/-4.13 months of the NCR children (p=0.610). Neurodevelopmental Impairments (NDIs) were three times higher in the former (21.3%), compared to the latter (7.4%) group (p=0.0001; OR 3.83, 95% CI: 2.16 - 5.21). Specifically, expressive language (p value 0.002; OR 2.86, 95% CI: 1.46 - 5.57) and gross motor functions (p=0.007; OR 2.27, 95% CI 1.22 - 4.20) were the most significantly affected areas of impairment. Children born to CR mothers had a three times higher proportion of NDIs. The findings are of concern as in Bangladesh large populations are forced to leave their homes and become CRs annually. Optimum antenatal care of pregnant women as well as their offsprings within refugee situations needs to be ensured to prevent NDIs and poor quality of survival. PMID- 27941742 TI - Experience of Percutaneous Versus Surgically Placed Catheter for Continuous Ambulatory Peritoneal Dialysis in Children with Chronic Kidney Disease Stage-V. AB - The lifespan and outcome of end stage renal disease (ESRD) children have dramatically improved since the development of continuous ambulatory peritoneal dialysis (CAPD), it offers several advantages over hemodialysis. Percutaneous placement of CAPD catheters in children is minimally invasive, reliable, safe and cost-effective method. Percutaneous method of CAPD catheter insertion can be used in children to avoid the complications of general anesthesia and surgery. This study was done to evaluate the efficacy of CAPD in children, to find out the complication profile of CAPD & to compare the advantages of surgical versus percutaneously placed CAPD catheters in children. This prospective longitudinal comparative study was carried out in the department of Pediatric Nephrology, Dhaka Medical College Hospital (DMCH), Bangladesh from July 2011 to June 2014. A total of 8 children with ESRD were included (Age 5-14 year, M: F=1: 1). All underwent CAPD, Group I = surgically placed CAPD catheter (N=5), Group II = percutaneously placed CAPD catheter (N=3). Average duration of CAPD in Group I and Group II were 31.6 vs. 9 (months) with a total of 158 vs. 27 patient months of CAPD respectively. The rate of complications of the 2 groups and their outcome were compared. Common complications being observed were peritonitis 1 episode per 12.1 vs. 1.8 patient months (p<0.001), catheter obstruction by omental capture 1 vs. 3 in Group I and Group II respectively. Catheter tip dislocation was commonly found in all Group II children (p<0.01) and all needed laparotomy and omentectomy. Three out of 5 in Group I is still on CAPD, 1 transferred to HD and another 1 expired due to uncontrolled hypertension with congestive heart failure. Among 3 of Group II, 2 died of repeated peritonitis and hypertensive complications and rest 1 is transferred to HD after 1year due to exit site fluid leaking. Satisfactory level of improvement of mean weight, mean serum albumin and declining of serum creatinine in both groups has been found after CAPD. Although CAPD is an effective modality of renal replacement therapy for children, but percutaneous method of catheter insertion is associated with higher rate of complications. Placement of catheter by surgical method with elective omentectomy will reduce catheter related complications. Early detection of peritonitis and prompt therapy is essential for a favourable outcome. PMID- 27941743 TI - Response of Dapsone in Refractory Chronic Immune Thrombocytopenia. AB - This was a prospective study. A total number of 19 patients with chronic ITP with platelet count <50*108/L, treated with dapsone at a dose of 100 mg/day for nine months and followed up to 12 months were included in this study. Among them 13 patients (76.5%) were responded well shortly to dapsone which persisted during Dapsone therapy. Response rate of Dapsone was declining after Dapsone therapy. Response persisted in 6 patients (35.3%) after stoppage of dapsone up to last follow up at 1 year. Mean platelets count during Dapsone therapy was 168.35*108/L. Shorter duration of thrombocypenic patients were responded well. Except one all patients experienced mild to moderate anaemia. Mean fall of Haemoglobin was 1.4gm/dl during dapsone therapy observed which come back to normal shortly after stoppage of dapsone. Only 2 patients were suffered from moderate anaemia. Dapsone syndrome and methemoglobinamia caused permanent discontinuation of therapy in 2 patients (10.5%) which was revert back to normal shortly after stoppage of drug. This study demonstrates that dapsone is an effective, inexpensive and well tolerated treatment for chronic, refractory ITP. PMID- 27941744 TI - Assessing Attitudes and Perceptions of Obstructive Pulmonary Disease Patients towards Inhaler Therapy in a Low Income Country: A Cross Sectional Study. AB - Chronic respiratory diseases (CRD) like asthma and chronic obstructive pulmonary disease (COPD) are one of the leading causes of morbidity and mortality worldwide. A patient's perception, about his or her medicine, may have an impact on adherence to medications. The purpose was to assess the attitudes and perceptions, regarding inhaler therapy use, among patients with obstructive pulmonary disease in Pakistan, a developing country. With a questionnaire developing this cross-sectional study was conducted at the Department of Medicine's outpatient clinic at Civil Hospital, Karachi from October 2013 to January 2014. We used SPSS version 19 for data entry. The number of patients included in the study was 202. Fifty eight percent (58%) of the patients concurred that they were not compliant with the usage of inhalers and frequently missed their doses. Thirty three percent (33%) patients had the misconception that inhalers are prescribed for severe diseases only. Almost forty percent (40%) patients said that they would prefer oral medicines over inhalers for the management of their lung diseases. Sixteen percent (16%) of the patients had problems using their inhalers. Twenty six percent (26%) of the patients believed that inhalers have side effects. Thirty eight percent (38%) of the patients believed inhalers are addictive. Misconceptions regarding inhalers and its usage in asthma and COPD patients are common in Pakistan. These misconceptions not only lead to poor compliance with medications prescribed but also to frequent visits to hospitals. There is a need to educate patients in the country regarding inhalers in order to improve not only their symptoms, but also to improve their quality of life. PMID- 27941745 TI - Cystic Lymph Node: Caution of Safety in Calot's Triangle Dissection. AB - Different landmarks are described in laparoscopic cholecystectomy for correct identification and orientation of structures to make the procedure as safe as possible. Among these one of the important landmarks is cystic lymphnode which always lies lateral to the biliary tree and forms the medial end point of dissection. This study was done to determine frequency of identification of cystic lymph node in our population. This retrospective descriptive study was conducted on 217 patients who underwent laparoscopic cholecystectomy for cholelithiasis from January 2012 to December 2013 over a period of two years in Jamal Noor Hospital and Hamdard University Hospital Karachi. All procedures were recorded and reviewed. Frequency of identification of cystic lymph node was documented in different levels of difficulty and whether it was possible to keep the dissection lateral to lymph node. Difficulty was assessed per-operatively by Cuschieri's scale. During dissection cystic lymph node was identified in 170(78.34%) cases. In majority of patients i.e. 165(97.05%), it was related to cystic artery. In 78(45.88%) patient dissection was possible lateral to lymph node. Cystic lymph node can be identified in majority of patients undergoing laparoscopic cholecystectomy and this identification helps in safe dissection of Calot's triangle. Efforts should be made to remain lateral to lymph node to avoid injuries to hepatic pedicle. PMID- 27941746 TI - Klippel Trenaunay Syndrome: A Case Report. AB - Klippel Trenaunay syndrome refers to a rare congenital anomaly which is characterized by capillary malformation, venous malformation and sometimes lymphatic malformation associated with overgrowth of a limb, with soft tissue hypertrophy and/or bony hypertrophy. The anomaly, if present, is present at birth and usually involves the lower limbs as well as portion of trunk, face, uppper limb or head. Our reporting case is a preterm male neonate having port wine stain, varicose veins and excessive growth of soft tissue of left lower limb clinically consistent with Klippel Trenaunay Syndrome. PMID- 27941748 TI - Congenital Complete Heart Block Presenting in Pregnancy: A Case Report. AB - Congenital complete heart block presenting for the first time in pregnancy is a rare occurrence posing a therapeutic challenge. We present a case of unpaced preexisting congenital complete heart block in pregnancy diagnosed for the first time during routine prenatal care at her early weeks of gestation. Our patient was asymptomatic and haemodynamically stable and was managed conservatively with a multidisciplinary term approach. Intrauterine growth retardation (IUGR) was present and she was delivered by ceasarean section at term for foetal distress with IUGR. Prophylactic temporary pacing was done before surgery and was weaned off in the early postpartum period. When a multidisciplinary approach is used both maternal and neonatal outcome are favorable. We review the literature in an attempt to discuss the therapeutic policy for such patients. PMID- 27941747 TI - A Case Report on Percutaneous Coronary Intervention in Chronic Total Occlusion by Retrograde Visualization. AB - As bilateral approach is paramount in chronic total occlusions with retrograde flow, the use of two radial arteries, two femoral arteries or combination technique using one radial and one femoral artery will probably be increasingly reported in the near future. After puncture of opposite groin, a diagnostic 6 Fr catheter is used to intubate the ostium of the contralateral artery. By visualizing the distal vessel in multiple projections, contralateral injections help to direct the progression of the wire in the occluded segment towards the distal true lumen and confirm the intraluminal position of the wire after the occluded segment. We are reporting a case with chronic total occlusion where we used bilateral femoral access and simultaneous contrast injection to visualize retrograde flow in LAD while opening CTO through ante-grade pathway. PMID- 27941749 TI - Central Precocious Puberty: A Case Report. AB - Precocious puberty in a male child is uncommon. Moreover, a predominantly luteinising hormone secreting pituitary tumor is rare. We report a case of predominantly luteinising hormone secreting pituitary adenoma causing precocious puberty in a three year old boy. A thorough systematic investigation including serum gonadotropins and imaging should be done to search for an underlying cause, even in the absence of pressure symptoms. Surgery with long term follow up is the recommended treatment for functioning gonadotrophin tumors. PMID- 27941750 TI - Role of syn-eruptive plagioclase disequilibrium crystallization in basaltic magma ascent dynamics. AB - Timescales of magma ascent in conduit models are typically assumed to be much longer than crystallization and gas exsolution for basaltic eruptions. However, it is now recognized that basaltic magmas may rise fast enough for disequilibrium processes to play a key role on the ascent dynamics. The quantification of the characteristic times for crystallization and exsolution processes are fundamental to our understanding of such disequilibria and ascent dynamics. Here we use observations from Mount Etna's 2001 eruption and a magma ascent model to constrain timescales for crystallization and exsolution processes. Our results show that plagioclase reaches equilibrium in 1-2 h, whereas ascent times were <1 h. Using these new constraints on disequilibrium plagioclase crystallization we also reproduce observed crystal abundances for different basaltic eruptions. The strong relation between magma ascent rate and disequilibrium crystallization and exsolution plays a key role in controlling eruption dynamics in basaltic volcanism. PMID- 27941751 TI - A programmable DNA origami nanospring that reveals force-induced adjacent binding of myosin VI heads. AB - Mechanosensitive biological nanomachines such as motor proteins and ion channels regulate diverse cellular behaviour. Combined optical trapping with single molecule fluorescence imaging provides a powerful methodology to clearly characterize the mechanoresponse, structural dynamics and stability of such nanomachines. However, this system requires complicated experimental geometry, preparation and optics, and is limited by low data-acquisition efficiency. Here we develop a programmable DNA origami nanospring that overcomes these issues. We apply our nanospring to human myosin VI, a mechanosensory motor protein, and demonstrate nanometre-precision single-molecule fluorescence imaging of the individual motor domains (heads) under force. We observe force-induced transitions of myosin VI heads from non-adjacent to adjacent binding, which correspond to adapted roles for low-load and high-load transport, respectively. Our technique extends single-molecule studies under force and clarifies the effect of force on biological processes. PMID- 27941752 TI - Co-axial heterostructures integrating palladium/titanium dioxide with carbon nanotubes for efficient electrocatalytic hydrogen evolution. AB - Considering the depletion of fossil-fuel reserves and their negative environmental impact, new energy schemes must point towards alternative ecological processes. Efficient hydrogen evolution from water is one promising route towards a renewable energy economy and sustainable development. Here we show a tridimensional electrocatalytic interface, featuring a hierarchical, co axial arrangement of a palladium/titanium dioxide layer on functionalized multi walled carbon nanotubes. The resulting morphology leads to a merging of the conductive nanocarbon core with the active inorganic phase. A mechanistic synergy is envisioned by a cascade of catalytic events promoting water dissociation, hydride formation and hydrogen evolution. The nanohybrid exhibits a performance exceeding that of state-of-the-art electrocatalysts (turnover frequency of 15000 H2 per hour at 50 mV overpotential). The Tafel slope of ~130 mV per decade points to a rate-determining step comprised of water dissociation and formation of hydride. Comparative activities of the isolated components or their physical mixtures demonstrate that the good performance evolves from the synergistic hierarchical structure. PMID- 27941754 TI - Suppressing photochemical reactions with quantized light fields. AB - Photoisomerization, that is, a photochemical reaction leading to a change of molecular structure after absorption of a photon, can have detrimental effects such as leading to DNA damage under solar irradiation, or as a limiting factor for the efficiency of solar cells. Here, we show that strong coupling of organic molecules to a confined light mode can be used to strongly suppress photoisomerization, as well as other photochemical reactions, and thus convert molecules that normally show fast photodegradation into photostable forms. We find this to be especially efficient in the case of collective strong coupling, where the distribution of a single excitation over many molecules and the light mode leads to a collective protection effect that almost completely suppresses the photochemical reaction. PMID- 27941753 TI - Emergent Weyl excitations in systems of polar particles. AB - Weyl fermions are massless chiral particles first predicted in 1929 and once thought to describe neutrinos. Although never observed as elementary particles, quasiparticles with Weyl dispersion have recently been experimentally discovered in solid-state systems causing a furore in the research community. Systems with Weyl excitations can display a plethora of fascinating phenomena and offer great potential for improved quantum technologies. Here, we show that Weyl excitations generically exist in three-dimensional systems of dipolar particles with weakly broken time-reversal symmetry (by for example a magnetic field). They emerge as a result of dipolar-interaction-induced transfer of angular momentum between the J=0 and J=1 internal particle levels. We also discuss momentum-resolved Ramsey spectroscopy methods for observing Weyl quasiparticles in cold alkaline-earth atom systems. Our results provide a pathway for a feasible experimental realization of Weyl quasiparticles and related phenomena in clean and controllable atomic systems. PMID- 27941756 TI - H2S inhibits pulmonary arterial endothelial cell inflammation in rats with monocrotaline-induced pulmonary hypertension. AB - This study aimed to determine whether hydrogen sulfide (H2S) inhibits pulmonary arterial endothelial inflammation in rats with monocrotaline (MCT)-induced pulmonary hypertension and its possible mechanisms. Twenty-four male Wistar rats were divided randomly into control, MCT, and MCT+H2S treatment groups. Human pulmonary arterial endothelial cells (HPAEC) were cultured and divided into four groups: control, MCT, MCT+H2S, and H2S. Pulmonary artery pressure was determined using a right cardiac catheterization procedure 3 weeks after MCT administration. Pulmonary vascular morphological changes and inflammatory infiltration were measured. Endogenous H2S levels, cystathionine-gamma-lyase (CSE) expression, and inflammatory cytokines were determined both in vivo and in vitro. In addition, phosphorylation of NF-kappaB p65 and IkappaBalpha was detected by western blotting, and NF-kappaB p65 nuclear translocation, as well as its DNA-binding activity, was determined. Pulmonary hypertension and vascular remolding developed 3 wks after MCT administration, with elevated lung tissue inflammatory infiltration and cytokine level associated with activation of the NF-kappaB pathway, both in vivo and in vitro. However, the endogenous H2S/CSE pathway was downregulated in MCT rats. By contrast, an H2S donor markedly reduced pulmonary artery pressure, pulmonary vascular structural remolding, and increased lung inflammatory infiltration and cytokine levels of MCT-treated rats. Meanwhile, H2S reversed the activation of the NF-kappaB pathway successfully. The downregulated pulmonary arterial endothelial H2S/CSE pathway is involved in the pulmonary inflammatory response in MCT-treated pulmonary hypertensive rats. H2S attenuated endothelial inflammation by inhibiting the NF-kappaB pathway. PMID- 27941757 TI - Characterization of histone-related chemical modifications in formalin-fixed paraffin-embedded and fresh-frozen human pancreatic cancer xenografts using LC MS/MS. AB - Post-translational modifications (PTMs) of histones including acetylation, methylation, and ubiquitination are known to be involved in the epigenetic regulation of gene expression and thus can have an important role in tumorigenesis. A number of PTMs have been linked to pancreatic cancer and are frequently studied as potential targets for cancer therapy or diagnosis. The availability of biobank-stored, formalin-fixed, paraffin-embedded (FFPE) materials and advanced proteomic analytical tools make it possible to detect histone-related PTMs using predicted mass shifts caused by specific modification. It is, however, important to take into account the fact that formaldehyde (FA) present in the FFPE material is chemically reactive and may undergo condensation reactions, for example, with terminal amino groups and active CH functionalities of the studied proteins. As supported by the results of this study, the possibility to misinterpret such protein condensation product as endogenous PTMs should be taken into consideration in all proteomic analytical work involving FFPE materials. In this study, we used liquid chromatography-tandem mass spectrometry to assess preassumed modification of the lysine residues of histone proteins in FFPE or fresh-frozen (FF) tumor xenografts, derived from the human pancreatic cancer cell line, Capan-1. Here we report modifications with a defined mass shift of +14.016, +28.031, +42.011, or +114.043 Da, corresponding to apparent methylation, dimethylation, acetylation, or ubiquitination that were differentially distributed between the groups. The identified modifications were significantly more frequent in FFPE samples as compared with FF samples. Our results indicate that FFPE tissue processing may result in persistent chemical modifications of histones, which correspond in mass shift of important PTMs. Herein, we highlight the importance to investigate and report FA-formed modifications in FFPE-treated tissues, as well as the necessity of careful manual examination of observed modifications to eliminate false-positive PTMs. PMID- 27941755 TI - Fibroblastic foci, covered with alveolar epithelia exhibiting epithelial mesenchymal transition, destroy alveolar septa by disrupting blood flow in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause. IPF has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci (FF) represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: (1) from resident fibroblasts, (2) from bone marrow derived progenitors of fibroblasts, and (3) from alveolar epithelial cells that have undergone epithelial-mesenchymal transition (EMT). We found that FF dissociated capillary vessels from the alveolar epithelia, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100 MUm below the alveolar epithelia. Furthermore, the alveolar epithelial cells covering the FF exhibited a partial EMT phenotype. In addition, normal human alveolar epithelial cells in vitro underwent dynamic EMT in response to transforming growth factor-beta signaling within 72 h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the alveolar epithelia and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to mesenchymal transitioned alveolar epithelia located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the alveolar septa, thus destroying them. Consequently, collapse of the alveolar septa is likely to be the first step toward honeycombing in the lung during late stage IPF. On the basis of these findings, inhibition of transforming growth factor-beta signaling, which can suppress EMT of the alveolar epithelial cells in vitro, is a potential strategy for treating IPF. PMID- 27941758 TI - Single-molecule analysis reveals multi-state folding of a guanine riboswitch. AB - Guanine-responsive riboswitches undergo ligand-dependent structural rearrangements to control gene expression by transcription termination. While the molecular basis for ligand recognition is well established, the associated structural rearrangements and the kinetics involved in the formation of the aptamer domain are less well understood. Using high-resolution optical tweezers, we followed the folding trajectories of a single molecule of the xpt-pbuX guanine aptamer from Bacillus subtilis. We report a rapid six-state conformational rearrangement, in which three of the states are guanine dependent, during the transition from the linear to the native receptor conformation. The folding completes in <1 s. The force-dependent equilibrium kinetics and the mutational data indicated that the flexible J2-J3 junction undergoes a ligand-dependent conformational switching, which triggers the formation of the long-range tertiary interactions and the P1 helix. In the absence of the right ligand, the junction failed to initiate the series of conformational rearrangements required for the riboswitch activities. PMID- 27941759 TI - Rewiring human cellular input-output using modular extracellular sensors. AB - Engineered cell-based therapies comprise a promising emerging strategy for treating diverse diseases. Realizing this promise requires new tools for engineering cells to sense and respond to soluble extracellular factors, which provide information about both physiological state and the local environment. Here, we report such a biosensor engineering strategy, leveraging a self contained receptor-signal transduction system termed modular extracellular sensor architecture (MESA). We developed MESA receptors that enable cells to sense vascular endothelial growth factor (VEGF) and, in response, secrete interleukin 2 (IL-2). By implementing these receptors in human T cells, we created a customized function not observed in nature-an immune cell that responds to a normally immunosuppressive cue (VEGF) by producing an immunostimulatory factor (IL-2). Because this platform utilizes modular, engineerable domains for ligand binding (antibodies) and output (programmable transcription factors based upon Cas9), this approach may be readily extended to novel inputs and outputs. This generalizable approach for rewiring cellular functions could enable both translational applications and fundamental biological research. PMID- 27941760 TI - Precise small-molecule recognition of a toxic CUG RNA repeat expansion. AB - Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, the toxic noncoding repeat expansion (r(CUG)exp) that causes myotonic dystrophy type 1 (DM1). We developed several strategies to generate allele selective small molecules, including non-covalent binding, covalent binding, cleavage and on-site probe synthesis. Covalent binding and cleavage enabled target profiling in cells derived from individuals with DM1, showing precise recognition of r(CUG)exp. In the on-site probe synthesis approach, small molecules bound adjacent sites in r(CUG)exp and reacted to afford picomolar inhibitors via a proximity-based click reaction only in DM1-affected cells. We expanded this approach to image r(CUG)exp in its natural context. PMID- 27941761 TI - Atomic-scale observation of structural and electronic orders in the layered compound alpha-RuCl3. AB - A pseudospin-1/2 Mott phase on a honeycomb lattice is proposed to host the celebrated two-dimensional Kitaev model which has an elusive quantum spin liquid ground state, and fascinating physics relevant to the development of future templates towards topological quantum bits. Here we report a comprehensive, atomically resolved real-space study by scanning transmission electron and scanning tunnelling microscopies on a novel layered material displaying Kitaev physics, alpha-RuCl3. Our local crystallography analysis reveals considerable variations in the geometry of the ligand sublattice in thin films of alpha-RuCl3 that opens a way to realization of a spatially inhomogeneous magnetic ground state at the nanometre length scale. Using scanning tunnelling techniques, we observe the electronic energy gap of ~0.25 eV and intra-unit cell symmetry breaking of charge distribution in individual alpha-RuCl3 surface layer. The corresponding charge-ordered pattern has a fine structure associated with two different types of charge disproportionation at Cl-terminated surface. PMID- 27941762 TI - Achieving ZT=2.2 with Bi-doped n-type SnSe single crystals. AB - Recently SnSe, a layered chalcogenide material, has attracted a great deal of attention for its excellent p-type thermoelectric property showing a remarkable ZT value of 2.6 at 923 K. For thermoelectric device applications, it is necessary to have n-type materials with comparable ZT value. Here, we report that n-type SnSe single crystals were successfully synthesized by substituting Bi at Sn sites. In addition, it was found that the carrier concentration increases with Bi content, which has a great influence on the thermoelectric properties of n-type SnSe single crystals. Indeed, we achieved the maximum ZT value of 2.2 along b axis at 733 K in the most highly doped n-type SnSe with a carrier density of -2.1 * 1019 cm-3 at 773 K. PMID- 27941763 TI - Long-term survival of patients with CLL after allogeneic transplantation: a report from the European Society for Blood and Marrow Transplantation. AB - Even with the availability of targeted drugs, allogeneic hematopoietic cell transplantation (allo-HCT) is the only therapy with curative potential for patients with CLL. Cure can be assessed by comparing long-term survival of patients to the matched general population. Using data from 2589 patients who received allo-HCT between 2000 and 2010, we used landmark analyses and methods from relative survival analysis to calculate excess mortality compared with an age-, sex- and calendar year-matched general population. Estimated event-free survival, overall survival and non-relapse mortality (NRM) 10 years after allo HCT were 28% (95% confidence interval (CI), 25-31), 35% (95% CI, 32-38) and 40% (95% CI, 37-42), respectively. Patients who passed the 5-year landmark event-free survival (N=394) had a 79% probability (95% CI, 73-85) of surviving the subsequent 5 years without an event. Relapse and NRM contributed equally to treatment failure. Five-year mortality for 45- and 65-year-old reference patients who were event-free at the 5-year landmark was 8% and 47% compared with 3% and 14% in the matched general population, respectively. The prospect of long-term disease-free survival remains an argument to consider allo-HCT for young patients with high-risk CLL, and programs to understand and prevent late causes of failure for long-term survivors are warranted, especially for older patients. PMID- 27941765 TI - Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation for high-risk AML. PMID- 27941766 TI - Exploratory research for optimal GvHD prophylaxis after single unit CBT in adults: short-term methotrexate reduced the incidence of severe GvHD more than mycophenolate mofetil. AB - In order to examine GvHD prophylaxis in umbilical cord blood transplantation (UCBT) in more detail, we compared transplant outcomes after UCBT for acute leukemia among GvHD prophylaxes using registry data. We selected patients transplanted with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 1516 first myeloablative UCBT between 2000 and 2012 (Cyclosporine A (CyA) plus MTX, 824, Tacrolimus (Tac) plus MTX, 554, Tac plus MMF, 138) were included. With adjusted analyses, Tac plus MMF showed a significantly higher risk for grade II-IV and III-IV acute GvHD than CyA or Tac plus MTX. Although NRM was similar, Tac plus MMF showed a significantly lower risk of relapse than CyA or Tac plus MTX. A significant difference was observed in the risk of overall mortality (OM) between the MTX-containing group and MMF containing group. In patients with standard-risk disease, there was no significant difference in the risk of OM in any GvHD prophylaxis. However, in patients with advanced-risk disease, Tac plus MMF showed a significantly lower risk of OM. Therefore, MTX-containing prophylaxis is preferred in UCBT for standard-risk disease, whereas MMF-containing prophylaxis is preferred for advanced-risk disease. A prospective study to identify optimal GvHD prophylaxis for UCBT is warranted. PMID- 27941764 TI - GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes. AB - Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (?18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22 29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD. PMID- 27941767 TI - MDS disease characteristics, not donor source, predict hematopoietic stem cell transplant outcomes. AB - Myelodysplastic syndrome (MDS) is a heterogeneous group of hematological malignancies with considerably variable prognoses and curable only with hematopoietic cell transplantation (HCT). Few studies comparing MDS HCT outcomes between sibling and umbilical cord blood (UCB) donors exist. Using the University of Minnesota Blood and Marrow Transplant (BMT) database, we retrospectively analyzed HCT outcomes among 89 MDS patients undergoing either sibling or double UCB HCT in 2000-2013. We observed similar survival, relapse and non-relapse mortality between sibling and UCB donor sources. Relapse was increased in those with monosomal karyotype (P=0.04) and with reduced intensity conditioning (P<0.01). In summary, our data highlight similar MDS HCT outcomes regardless of donor source and support the use of UCB as an alternative donor when a sibling is unavailable. PMID- 27941768 TI - Androgens in women after allogeneic hematopoietic cell transplantation: impact of chronic GvHD and glucocorticoid therapy. AB - Low androgen levels may contribute to sexual dysfunction in women after allogeneic hematopoietic cell transplantation (alloHCT). However, data on serum androgens in women after alloHCT are limited. The aim of this study was to assess androgen levels and their association with chronic GvHD (cGvHD) and glucocorticoid (GC) therapy. Included were 65 allografted women, 33 with cGvHD, and 23 of these were on GC therapy. Controls were 94 healthy, age-matched women. Supportive study groups were women after autologous HCT (autoHCT; n=20) and non transplanted women on GC therapy (n=26). Compared with controls, free testosterone (free T) and dehydroepiandrosterone sulfate (DHEAS) levels were lower in both the alloHCT group and GC groups; P<0.0001 and P<0.05, respectively. Androgens in the autoHCT group were similar or higher than controls. In the subgroup of alloHCT patients without cGvHD, free T was similar to controls (7.2 vs 8.6 pmol/L; P=0.42), whereas DHEAS levels was lower than controls (1.7 vs 2.5 MUmol/L; P=0.008). Compared with controls, cGvHD without GC (n=10) was associated with lower free T and DHEAS; P=0.004 and P=0.0004, respectively). The lowest androgen levels were seen in women with both cGvHD and GC therapy. In conclusion, low serum androgens were associated with cGvHD and GC therapy, prompting for studies assessing a possible association between low androgens and sexual dysfunction and quality of life in allografted women. PMID- 27941770 TI - Polyvalent immunoglobulins, platelet lysate and lenalidomide: cocktail for polyfunctional NK cells expansion for multiple myeloma. PMID- 27941771 TI - Hyperglycemia as a possible risk factor for mold infections-the potential preventative role of intensified glucose control in allogeneic hematopoietic stem cell transplantation. AB - Diabetes mellitus (DM) is well-known as a disorder that increases the risk of infectious diseases. Various reports have shown that innate immunity is impaired in patients with DM, which is considered to be a major cause of increased risk of infectious diseases. However, there is a paucity of data about the actual risk of mold infections in patients with DM. Several treatment procedures, such as solid organ transplantation and hematopoietic stem cell transplantation (HSCT), are intrinsically associated with a high risk of mold infections and also correlated with an increased risk of post-transplant DM. Therefore, we could assume that organ transplant recipients or HSCT recipients with DM are at quite high risk of mold infections. Here, we aim to summarize the information about the increased risk of mold infections in patients with DM, and propose possible interventions such as intensive glucose control to reduce this risk in patients with DM. PMID- 27941769 TI - Sensing danger: toll-like receptors and outcome in allogeneic hematopoietic stem cell transplantation. AB - Pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) play key roles in initiating innate and adaptive immune responses. Based mainly on animal studies there is growing evidence to suggest that TLRs are involved in the development of chemotherapy-induced mucositis and in the propagation of graft versus host reactions as well as graft versus tumor effects in allogeneic hematopoietic stem cell transplantation (HSCT). In this review we discuss these findings along with the emerging, although still preliminary, clinical evidence, that points to a role of PRRs in determining the outcome of HSCT and new therapeutic perspectives that may be related to this development. PMID- 27941772 TI - Pretransplant chest computed tomography screening in asymptomatic patients with leukemia and myelodysplastic syndrome. PMID- 27941773 TI - Haploidentical transplantation for pediatric patients with acquired severe aplastic anemia. AB - Techniques for haploidentical hematopoietic stem cell transplantation (haplo HSCT) to treat severe aplastic anemia (SAA) have recently improved, but no protocol has been evaluated in a large number of pediatric patients. Fifty-two children with SAA received haplo-HSCT in our center. The treatment protocol used G-CSF-primed bone marrow with G-CSF-mobilized PBSCs without in vitro T-cell depletion. The conditioning regimen included busulfan/cyclophosphamide and antithymocyte globulin. Fifty-one patients achieved primary engraftment; one child died of regimen-related toxicity on the day +1. Secondary graft failure occurred in three patients. The cumulative incidences of aGVHD grade II-IV and grade III-IV were 39.2+/-0.5 and 13.7+/-0.2%, respectively. The cumulative incidence of cGVHD was 34.2+/-0.5%. The 3-year overall and failure-free survival rates were 84.5+/-5.0 and 82.7+/-5.2%, respectively, with a median follow-up time of 744.5 days (100-3294) for surviving patients. The Eastern Cooperative Oncology Group score was the only predictor of overall and failure-free survival rates. Clinical outcomes were similar between the upfront and salvage group. This result suggests that both newly diagnosed and refractory pediatric SAA patients benefit from haplo-HSCT, especially when patients are in good general condition. Therefore, haplo-HSCT might be an alternative therapy for pediatric SAA patients without HLA-matched sibling donors. PMID- 27941774 TI - Usefulness of liver stiffness measurement in predicting hepatic veno-occlusive disease development in patients who undergo HSCT. PMID- 27941776 TI - Low-dose alemtuzumab for GvHD prevention followed by prophylactic donor lymphocyte infusions in high-risk leukemia. AB - We analyzed the use of low-dose alemtuzumab in a cohort of 158 consecutive patients who underwent allogeneic PBSC transplantation. Patients with high-risk acute leukemia were prospectively screened for prophylactic donor lymphocyte infusion (pDLI). Lymphocytes were administered repeatedly at low and non escalating doses (0.5-1 * 106/kg). Low-dose alemtuzumab was effective in prevention of acute GvHD after sibling or well-matched unrelated transplantation, whereas a more intensified approach was needed after mismatched transplantation. The cumulative incidence of chronic moderate/severe chronic-GvHD (cGvHD) was 15.6%. In total, 63 high-risk leukemia patients were eligible for pDLI. Only 1 out of the 39 pDLI recipients relapsed as compared with 7 out of the 24 recipients, who did not receive pDLI due to logistical hurdles. In multivariate analysis, the use of adjuvant lymphocyte therapy was significantly associated with reduced incidence of relapse and improved disease-free survival. In summary, low-dose alemtuzumab confers to a low cGvHD incidence and the administration of pDLIs in this context is very likely to reduce relapse risk in high risk leukemia patients. This is translated in an estimated 5-year probability of GvHD-free and relapse-free survival of 43.3% for the 136 leukemia patients. PMID- 27941775 TI - Cognitive problems following hematopoietic stem cell transplant: relationships with sleep, depression and fatigue. AB - Cognitive problems are a significant, persistent concern for patients undergoing hematopoietic stem cell transplant (HSCT). Sleep is important for many cognitive tasks; however, the relationship between sleep and cognitive problems for HSCT patients is unknown. This study examined the relationship between sleep and cognitive problems for HSCT patients from pre to post transplant. Patients undergoing HSCT (N=138) completed questionnaires at pre-transplant and during the 12 months following transplant. Questionnaires assessed sleep and cognitive problems as well as commonly co-occurring symptoms: depressive symptoms, fatigue and pain. Post hoc analyses examined the relationship of specific sleep problems with cognitive problems. Sleep problems covaried with cognitive problems even after controlling for depressive symptoms, fatigue and pain. Depressive symptoms and fatigue were also uniquely related to cognitive problems. Post hoc analyses suggest that sleep somnolence, shortness of breath, snoring and perceptions of inadequate sleep may contribute to the association found between sleep and cognitive problems. Findings suggest that sleep problems are associated with and may contribute to cognitive problems for HSCT patients. However, sleep problems are rarely screened for or discussed during clinic visits. Assessing and treating specific sleep problems in addition to depressive symptoms and fatigue may have implications for improving cognitive problems for HSCT patients. PMID- 27941779 TI - Publish or perish: can a 'Write Club' help junior faculty be more productive? PMID- 27941777 TI - GvL effects in T-prolymphocytic leukemia: evidence from MRD kinetics and TCR repertoire analyses. AB - Allogeneic stem cell transplantation (alloSCT) is used for treating patients with T-prolymphocytic leukemia (T-PLL). However, direct evidence of GvL activity in T PLL is lacking. We correlated minimal residual disease (MRD) kinetics with immune interventions and T-cell receptor (TCR) repertoire diversity alterations in patients after alloSCT for T-PLL. Longitudinal quantitative MRD monitoring was performed by clone-specific real-time PCR of TCR rearrangements (n=7), and TCR repertoire diversity assessment by next-generation sequencing (NGS; n=3) Although post-transplant immunomodulation (immunosuppression tapering or donor lymphocyte infusions) resulted in significant reduction (>1 log) of MRD levels in 7 of 10 occasions, durable MRD clearance was observed in only two patients. In all three patients analyzed by TCR-NGS, MRD responses were reproducibly associated with a shift from a clonal, T-PLL-driven profile to a polyclonal signature. Novel clonotypes that could explain a clonal GvL effect did not emerge. In conclusion, TCR-based MRD quantification appears to be a suitable tool for monitoring and guiding treatment interventions in T-PLL. The MRD responses to immune modulation observed here provide first molecular evidence for GvL activity in T-PLL which, however, may be often only transient and reliant on a poly-/oligoclonal rather than a monoclonal T-cell response. PMID- 27941778 TI - Cytogenetics and outcome of allogeneic transplantation in first remission of acute myeloid leukemia: the French pediatric experience. AB - We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved. PMID- 27941781 TI - If the gut works, use it! But does the gut work in gastrointestinal GvHD? PMID- 27941780 TI - Good responses but high TRM in adult patients after MSC therapy for GvHD. PMID- 27941782 TI - Pre-transplant persistence of minimal residual disease does not contraindicate allogeneic stem cell transplantation for adult patients with acute myeloid leukemia. PMID- 27941783 TI - Simulation-based comprehensive benchmarking of RNA-seq aligners. AB - Alignment is the first step in most RNA-seq analysis pipelines, and the accuracy of downstream analyses depends heavily on it. Unlike most steps in the pipeline, alignment is particularly amenable to benchmarking with simulated data. We performed a comprehensive benchmarking of 14 common splice-aware aligners for base, read, and exon junction-level accuracy and compared default with optimized parameters. We found that performance varied by genome complexity, and accuracy and popularity were poorly correlated. The most widely cited tool underperforms for most metrics, particularly when using default settings. PMID- 27941784 TI - Control of cerebral ischemia with magnetic nanoparticles. AB - The precise manipulation of microcirculation in mice can facilitate mechanistic studies of brain injury and repair after ischemia, but this manipulation remains a technical challenge, particularly in conscious mice. We developed a technology that uses micromagnets to induce aggregation of magnetic nanoparticles to reversibly occlude blood flow in microvessels. This allowed induction of ischemia in a specific cortical region of conscious mice of any postnatal age, including perinatal and neonatal stages, with precise spatiotemporal control but without surgical intervention of the skull or artery. When combined with longitudinal live-imaging approaches, this technology facilitated the discovery of a feature of the ischemic cascade: selective loss of smooth muscle cells in juveniles but not adults shortly after onset of ischemia and during blood reperfusion. PMID- 27941785 TI - Nontargeted in vitro metabolomics for high-throughput identification of novel enzymes in Escherichia coli. AB - Our understanding of metabolism is limited by a lack of knowledge about the functions of many enzymes. Here, we develop a high-throughput mass spectrometry approach to comprehensively profile proteins for in vitro enzymatic activity. Overexpressed or purified proteins are incubated in a supplemented metabolome extract containing hundreds of biologically relevant candidate substrates, and accumulating and depleting metabolites are determined by nontargeted mass spectrometry. By combining chemometrics and database approaches, we established an automated pipeline for unbiased annotation of the functions of novel enzymes. In screening all 1,275 functionally uncharacterized Escherichia coli proteins, we discovered 241 potential novel enzymes, 12 of which we experimentally validated. Our high-throughput in vitro metabolomics method is generally applicable to any purified protein or crude cell lysate of its overexpression host and enables performing up to 1,200 nontargeted enzyme assays per working day. PMID- 27941786 TI - Transcriptional programs that control expression of the autoimmune regulator gene Aire. AB - Aire is a transcriptional regulator that induces promiscuous expression of thousands of genes encoding tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs that regulate its own expression have remained elusive. Here we comprehensively analyzed both cis-acting and trans-acting regulatory mechanisms and found that the Aire locus was insulated by the global chromatin organizer CTCF and was hypermethylated in cells and tissues that did not express Aire. In mTECs, however, Aire expression was facilitated by concurrent eviction of CTCF, specific demethylation of exon 2 and the proximal promoter, and the coordinated action of several transcription activators, including Irf4, Irf8, Tbx21, Tcf7 and Ctcfl, which acted on mTEC-specific accessible regions in the Aire locus. PMID- 27941787 TI - Recruitment of calcineurin to the TCR positively regulates T cell activation. AB - Calcineurin is a phosphatase whose primary targets in T cells are NFAT transcription factors, and inhibition of calcineurin activity by treatment with cyclosporin A (CsA) or FK506 is a cornerstone of immunosuppressive therapies. Here we found that calcineurin was recruited to the T cell antigen receptor (TCR) signaling complex, where it reversed inhibitory phosphorylation of the tyrosine kinase Lck on Ser59 (LckS59). Loss of calcineurin activity impaired phosphorylation of Tyr493 of the tyrosine kinase ZAP-70 (ZAP-70Y493), as well as some downstream pathways in a manner consistent with signaling in cells expressing LckS59A (Lck that cannot be phosphorylated) or LckS59E (a phosphomimetic mutant). Notably, CsA inhibited integrin-LFA-1-dependent and NFAT independent adhesion of T cells to the intercellular adhesion molecule ICAM-1, with little effect on cells expressing mutant Lck. These results provide new understanding of how widely used immunosuppressive drugs interfere with essential processes in the immune response. PMID- 27941788 TI - Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity. AB - The skin is equipped with specialized mechanoreceptors that allow the perception of the slightest brush. Indeed, some mechanoreceptors can detect even nanometer scale movements. Movement is transformed into electrical signals via the gating of mechanically activated ion channels at sensory endings in the skin. The sensitivity of Piezo mechanically gated ion channels is controlled by stomatin like protein-3 (STOML3), which is required for normal mechanoreceptor function. Here we identify small-molecule inhibitors of STOML3 oligomerization that reversibly reduce the sensitivity of mechanically gated currents in sensory neurons and silence mechanoreceptors in vivo. STOML3 inhibitors in the skin also reversibly attenuate fine touch perception in normal mice. Under pathophysiological conditions following nerve injury or diabetic neuropathy, the slightest touch can produce pain, and here STOML3 inhibitors can reverse mechanical hypersensitivity. Thus, small molecules applied locally to the skin can be used to modulate touch and may represent peripherally available drugs to treat tactile-driven pain following neuropathy. PMID- 27941789 TI - Manipulating stored phonological input during verbal working memory. AB - Verbal working memory (vWM) involves storing and manipulating information in phonological sensory input. An influential theory of vWM proposes that manipulation is carried out by a central executive while storage is performed by two interacting systems: a phonological input buffer that captures sound-based information and an articulatory rehearsal system that controls speech motor output. Whether, when and how neural activity in the brain encodes these components remains unknown. Here we read out the contents of vWM from neural activity in human subjects as they manipulated stored speech sounds. As predicted, we identified storage systems that contained both phonological sensory and articulatory motor representations. Unexpectedly, however, we found that manipulation did not involve a single central executive but rather involved two systems with distinct contributions to successful manipulation. We propose, therefore, that multiple subsystems comprise the central executive needed to manipulate stored phonological input for articulatory motor output in vWM. PMID- 27941790 TI - A cortical-hippocampal-cortical loop of information processing during memory consolidation. AB - Hippocampal replay during sharp-wave ripple events (SWRs) is thought to drive memory consolidation in hippocampal and cortical circuits. Changes in neocortical activity can precede SWR events, but whether and how these changes influence the content of replay remains unknown. Here we show that during sleep there is a rapid cortical-hippocampal-cortical loop of information flow around the times of SWRs. We recorded neural activity in auditory cortex (AC) and hippocampus of rats as they learned a sound-guided task and during sleep. We found that patterned activation in AC precedes and predicts the subsequent content of hippocampal activity during SWRs, while hippocampal patterns during SWRs predict subsequent AC activity. Delivering sounds during sleep biased AC activity patterns, and sound-biased AC patterns predicted subsequent hippocampal activity. These findings suggest that activation of specific cortical representations during sleep influences the identity of the memories that are consolidated into long term stores. PMID- 27941791 TI - Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. AB - Excess levels of protein in urine (proteinuria) is a hallmark of kidney disease that typically occurs in conjunction with diabetes, hypertension, gene mutations, toxins or infections but may also be of unknown cause (idiopathic). Systemic soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor implicated in the onset and progression of chronic kidney disease (CKD), such as focal segmental glomerulosclerosis (FSGS). The cellular source(s) of elevated suPAR associated with future and progressing kidney disease is unclear, but is likely extra-renal, as the pathological uPAR is circulating and FSGS can recur even after a damaged kidney is replaced with a healthy donor organ. Here we report that bone marrow (BM) Gr-1lo immature myeloid cells are responsible for the elevated, pathological levels of suPAR, as evidenced by BM chimera and BM ablation and cell transfer studies. A marked increase of Gr-1lo myeloid cells was commonly found in the BM of proteinuric animals having high suPAR, and these cells efficiently transmit proteinuria when transferred to healthy mice. In accordance with the results seen in suPAR-associated proteinuric animal models, in which kidney damage is caused not by local podocyte-selective injury but more likely by systemic insults, a humanized xenograft model of FSGS resulted in an expansion of Gr-1lo cells in the BM, leading to high plasma suPAR and proteinuric kidney disease. Together, these results identify suPAR as a functional connection between the BM and the kidney, and they implicate BM immature myeloid cells as a key contributor to glomerular dysfunction. PMID- 27941793 TI - Fasting selectively blocks development of acute lymphoblastic leukemia via leptin receptor upregulation. AB - New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia. PMID- 27941792 TI - Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. AB - In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction of histone H3K27 trimethylation as a novel pathway of acquired resistance to tyrosine kinase inhibitors (TKIs) and cytotoxic drugs in AML. Low EZH2 protein levels correlated with poor prognosis in AML patients. Suppression of EZH2 protein expression induced chemoresistance of AML cell lines and primary cells in vitro and in vivo. Low EZH2 levels resulted in derepression of HOX genes, and knockdown of HOXB7 and HOXA9 in the resistant cells was sufficient to improve sensitivity to TKIs and cytotoxic drugs. The endogenous loss of EZH2 expression in resistant cells and primary blasts from a subset of relapsed AML patients resulted from enhanced CDK1 dependent phosphorylation of EZH2 at Thr487. This interaction was stabilized by heat shock protein 90 (HSP90) and followed by proteasomal degradation of EZH2 in drug-resistant cells. Accordingly, inhibitors of HSP90, CDK1 and the proteasome prevented EZH2 degradation, decreased HOX gene expression and restored drug sensitivity. Finally, patients with reduced EZH2 levels at progression to standard therapy responded to the combination of bortezomib and cytarabine, concomitant with the re-establishment of EZH2 expression and blast clearance. These data suggest restoration of EZH2 protein as a viable approach to overcome treatment resistance in this AML patient population. PMID- 27941794 TI - Hall effect in charged conducting ferroelectric domain walls. AB - Enhanced conductivity at specific domain walls in ferroelectrics is now an established phenomenon. Surprisingly, however, little is known about the most fundamental aspects of conduction. Carrier types, densities and mobilities have not been determined and transport mechanisms are still a matter of guesswork. Here we demonstrate that intermittent-contact atomic force microscopy (AFM) can detect the Hall effect in conducting domain walls. Studying YbMnO3 single crystals, we have confirmed that p-type conduction occurs in tail-to-tail charged domain walls. By calibration of the AFM signal, an upper estimate of ~1 * 1016 cm 3 is calculated for the mobile carrier density in the wall, around four orders of magnitude below that required for complete screening of the polar discontinuity. A carrier mobility of~50 cm2V-1s-1 is calculated, about an order of magnitude below equivalent carrier mobilities in p-type silicon, but sufficiently high to preclude carrier-lattice coupling associated with small polarons. PMID- 27941795 TI - Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin. AB - Trithorax-group proteins and their mammalian homologs, including those in BAF (mSWI/SNF) complexes, are known to oppose the activity of Polycomb repressive complexes (PRCs). This opposition underlies the tumor-suppressive role of BAF subunits and is expected to contribute to neurodevelopmental disorders. However, the mechanisms underlying opposition to Polycomb silencing are poorly understood. Here we report that recurrent disease-associated mutations in BAF subunits induce genome-wide increases in PRC deposition and activity. We show that point mutations in SMARCA4 (also known as BRG1) mapping to the ATPase domain cause loss of direct binding between BAF and PRC1 that occurs independently of chromatin. Release of this direct interaction is ATP dependent, consistent with a transient eviction mechanism. Using a new chemical-induced proximity assay, we find that BAF directly evicts Polycomb factors within minutes of its occupancy, thereby establishing a new mechanism for the widespread BAF-PRC opposition underlying development and disease. PMID- 27941796 TI - Dynamics of BAF-Polycomb complex opposition on heterochromatin in normal and oncogenic states. AB - The opposition between Polycomb repressive complexes (PRCs) and BAF (mSWI/SNF) complexes has a critical role in both development and disease. Mutations in the genes encoding BAF subunits contribute to more than 20% of human malignancies, yet the underlying mechanisms remain unclear, owing largely to a lack of assays to assess BAF function in living cells. To address this, we have developed a widely applicable recruitment assay system through which we find that BAF opposes PRC by rapid, ATP-dependent eviction, leading to the formation of accessible chromatin. The reversal of this process results in reassembly of facultative heterochromatin. Surprisingly, BAF-mediated PRC eviction occurs in the absence of RNA polymerase II (Pol II) occupancy, transcription, and replication. Further, we find that tumor-suppressor and oncogenic mutant BAF complexes have different effects on PRC eviction. The results of these studies define a mechanistic sequence underlying the resolution and formation of facultative heterochromatin, and they demonstrate that BAF opposes PRC on a minute-by-minute basis to provide epigenetic plasticity. PMID- 27941797 TI - SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. AB - SMARCB1 (also known as SNF5, INI1, and BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here we show that, despite having indistinguishable mutational landscapes, human rhabdoid tumors exhibit distinct enhancer H3K27ac signatures, which identify remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared by all subtypes, such as SPRY1, and other lineage-specific super-enhancers, such as SOX2 in brain-derived rhabdoid tumors. Taken together, our findings identify a new chromatin-based epigenetic mechanism underlying the tumor-suppressive activity of SMARCB1. PMID- 27941800 TI - Modulation of membrane phosphoinositide dynamics by the phosphatidylinositide 4 kinase activity of the Legionella LepB effector. AB - Legionella pneumophila, the causative bacterium for Legionnaires' disease, hijacks host membrane trafficking for the maturation of the Legionella-containing vacuole (LCV). The LCV membrane mainly contains PtdIns4P, which is important for anchoring many secreted Legionella effectors onto the LCV. Here, we identify a cryptic functional domain (LepB_NTD) preceding the well-characterized RabGAP domain in the Legionella Dot/Icm type IV secretion system effector LepB. LepB_NTD alone is toxic to yeast and can disrupt the Golgi in mammalian cells. The crystal structure reveals an unexpected kinase fold and catalytic motif important for LepB_NTD function in eukaryotes. Cell biology-guided biochemical analyses uncovered a lipid kinase activity in LepB_NTD that specifically converts PtdIns3P into PtdIns(3,4)P2. PtdIns(3,4)P2 is efficiently hydrolysed into PtdIns4P by another Dot/Icm effector SidF that is known to possess phosphoinositide phosphatase activity. Consistently, SidF is capable of counteracting the cellular functions of LepB_NTD. Genetic analyses show a requirement for LepB kinase activity as well as lipid phosphatase activity of SidF for PtdIns4P biosynthesis on the LCV membrane. Our study identifies an unprecedented phosphatidylinositide 4-kinase activity from bacteria and highlights a sophisticated manipulation of host phosphoinositide metabolism by a bacterial pathogen. PMID- 27941798 TI - ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. AB - Genes encoding subunits of SWI/SNF (BAF) chromatin-remodeling complexes are collectively mutated in ~20% of all human cancers. Although ARID1A is the most frequent target of mutations, the mechanism by which its inactivation promotes tumorigenesis is unclear. Here we demonstrate that Arid1a functions as a tumor suppressor in the mouse colon, but not the small intestine, and that invasive ARID1A-deficient adenocarcinomas resemble human colorectal cancer (CRC). These tumors lack deregulation of APC/beta-catenin signaling components, which are crucial gatekeepers in common forms of intestinal cancer. We find that ARID1A normally targets SWI/SNF complexes to enhancers, where they function in coordination with transcription factors to facilitate gene activation. ARID1B preserves SWI/SNF function in ARID1A-deficient cells, but defects in SWI/SNF targeting and control of enhancer activity cause extensive dysregulation of gene expression. These findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as a principal tumor-suppressor function of ARID1A. PMID- 27941799 TI - Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence. AB - Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of gamma-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of gamma-secretase inhibitors in advanced prostate cancer patients. PMID- 27941801 TI - Sinoatrial node cardiomyocytes derived from human pluripotent cells function as a biological pacemaker. AB - The sinoatrial node (SAN) is the primary pacemaker of the heart and controls heart rate throughout life. Failure of SAN function due to congenital disease or aging results in slowing of the heart rate and inefficient blood circulation, a condition treated by implantation of an electronic pacemaker. The ability to produce pacemaker cells in vitro could lead to an alternative, biological pacemaker therapy in which the failing SAN is replaced through cell transplantation. Here we describe a transgene-independent method for the generation of SAN-like pacemaker cells (SANLPCs) from human pluripotent stem cells by stage-specific manipulation of developmental signaling pathways. SANLPCs are identified as NKX2-5- cardiomyocytes that express markers of the SAN lineage and display typical pacemaker action potentials, ion current profiles and chronotropic responses. When transplanted into the apex of rat hearts, SANLPCs are able to pace the host tissue, demonstrating their capacity to function as a biological pacemaker. PMID- 27941803 TI - Genome-wide mapping of mutations at single-nucleotide resolution for protein, metabolic and genome engineering. AB - Improvements in DNA synthesis and sequencing have underpinned comprehensive assessment of gene function in bacteria and eukaryotes. Genome-wide analyses require high-throughput methods to generate mutations and analyze their phenotypes, but approaches to date have been unable to efficiently link the effects of mutations in coding regions or promoter elements in a highly parallel fashion. We report that CRISPR-Cas9 gene editing in combination with massively parallel oligomer synthesis can enable trackable editing on a genome-wide scale. Our method, CRISPR-enabled trackable genome engineering (CREATE), links each guide RNA to homologous repair cassettes that both edit loci and function as barcodes to track genotype-phenotype relationships. We apply CREATE to site saturation mutagenesis for protein engineering, reconstruction of adaptive laboratory evolution experiments, and identification of stress tolerance and antibiotic resistance genes in bacteria. We provide preliminary evidence that CREATE will work in yeast. We also provide a webtool to design multiplex CREATE libraries. PMID- 27941802 TI - Influence of donor age on induced pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) are being pursued as a source of cells for autologous therapies, many of which will be aimed at aged patients. To explore the impact of age on iPSC quality, we produced iPSCs from blood cells of 16 donors aged 21-100. We find that iPSCs from older donors retain an epigenetic signature of age, which can be reduced through passaging. Clonal expansion via reprogramming also enables the discovery of somatic mutations present in individual donor cells, which are missed by bulk sequencing methods. We show that exomic mutations in iPSCs increase linearly with age, and all iPSC lines analyzed carry at least one gene-disrupting mutation, several of which have been associated with cancer or dysfunction. Unexpectedly, elderly donors (>90 yrs) harbor fewer mutations than predicted, likely due to a contracted blood progenitor pool. These studies establish that donor age is associated with an increased risk of abnormalities in iPSCs and will inform clinical development of reprogramming technology. PMID- 27941805 TI - Superconductivity in the antiperovskite Dirac-metal oxide Sr3-xSnO. AB - Investigations of perovskite oxides triggered by the discovery of high temperature and unconventional superconductors have had crucial roles in stimulating and guiding the development of modern condensed-matter physics. Antiperovskite oxides are charge-inverted counterpart materials to perovskite oxides, with unusual negative ionic states of a constituent metal. No superconductivity was reported among the antiperovskite oxides so far. Here we present the first superconducting antiperovskite oxide Sr3-xSnO with the transition temperature of around 5 K. Sr3SnO possesses Dirac points in its electronic structure, and we propose from theoretical analysis a possibility of a topological odd-parity superconductivity analogous to the superfluid 3He-B in moderately hole-doped Sr3-xSnO. We envision that this discovery of a new class of oxide superconductors will lead to a rapid progress in physics and chemistry of antiperovskite oxides consisting of unusual metallic anions. PMID- 27941804 TI - Resveratrol rescues hyperglycemia-induced endothelial dysfunction via activation of Akt. AB - Resveratrol (RSV), a phytoalexin, has shown to prevent endothelial dysfunction and reduce diabetic vascular complications and the risk of cardiovascular diseases. The aim of this study was to investigate the signaling mechanisms underlying the protecting effects of RSV against endothelial dysfunction during hyperglycemia in vitro and in vivo. Human umbilical vein endothelial cells (HUVECs) were treated with RSV, and then exposed to high glucose (HG, 30 mmol/L). Akt-Ser473 phosphorylation, eNOS-Ser1177 phosphorylation, and PTEN protein levels in the cells were detected using Western blot. For in vivo studies, WT and Akt-/- mice were fed a normal diet containing RSV (400 mg.kg-1.d-1) for 2 weeks, then followed by injection of STZ to induce hyperglycemia (300 mg/dL). Endothelial function was evaluated using aortic rings by assessing ACh-induced vasorelaxation. RSV (5-20 MUmol/L) dose-dependently increased Akt-Ser473 phosphorylation, accompanied by increased eNOS-Ser1177 phosphorylation in HUVECs; these effects were more prominent under HG stimulation. Transfection with Akt siRNA abolished RSV-enhanced eNOS phosphorylation and NO release. Furthermore, RSV (5-20 MUmol/L) dose-dependently decreased the levels of PTEN, which was significantly increased under HG stimulation, and PTEN overexpression abolished RSV-stimulated Akt phosphorylation in HG-treated HUVECs. Moreover, RSV dramatically increased 26S proteasome activity, which induced degradation of PTEN. In in vivo studies, pretreatment with RSV significantly increased Akt and eNOS phosphorylation in aortic tissues and ACh-induced vasorelaxation, and improved diabetes-induced endothelial dysfunction in wild-type mice but not in Akt-/- mice. RSV attenuates endothelial function during hyperglycemia via activating proteasome-dependent degradation of PTEN, which increases Akt phosphorylation, and consequentially upregulation of eNOS-derived NO production. PMID- 27941806 TI - High operational and environmental stability of high-mobility conjugated polymer field-effect transistors through the use of molecular additives. AB - Due to their low-temperature processing properties and inherent mechanical flexibility, conjugated polymer field-effect transistors (FETs) are promising candidates for enabling flexible electronic circuits and displays. Much progress has been made on materials performance; however, there remain significant concerns about operational and environmental stability, particularly in the context of applications that require a very high level of threshold voltage stability, such as active-matrix addressing of organic light-emitting diode displays. Here, we investigate the physical mechanisms behind operational and environmental degradation of high-mobility, p-type polymer FETs and demonstrate an effective route to improve device stability. We show that water incorporated in nanometre-sized voids within the polymer microstructure is the key factor in charge trapping and device degradation. By inserting molecular additives that displace water from these voids, it is possible to increase the stability as well as uniformity to a high level sufficient for demanding industrial applications. PMID- 27941808 TI - Temporal mapping of photochemical reactions and molecular excited states with carbon specificity. AB - Photochemical reactions are essential to a large number of important industrial and biological processes. A method for monitoring photochemical reaction kinetics and the dynamics of molecular excitations with spatial resolution within the active molecule would allow a rigorous exploration of the pathway and mechanism of photophysical and photochemical processes. Here we demonstrate that laser excited muon pump-probe spin spectroscopy (photo-MUSR) can temporally and spatially map these processes with a spatial resolution at the single-carbon level in a molecule with a pentacene backbone. The observed time-dependent light induced changes of an avoided level crossing resonance demonstrate that the photochemical reactivity of a specific carbon atom is modified as a result of the presence of the excited state wavefunction. This demonstrates the sensitivity and potential of this technique in probing molecular excitations and photochemistry. PMID- 27941807 TI - Self-organized amniogenesis by human pluripotent stem cells in a biomimetic implantation-like niche. AB - Amniogenesis-the development of amnion-is a critical developmental milestone for early human embryogenesis and successful pregnancy. However, human amniogenesis is poorly understood due to limited accessibility to peri-implantation embryos and a lack of in vitro models. Here we report an efficient biomaterial system to generate human amnion-like tissue in vitro through self-organized development of human pluripotent stem cells (hPSCs) in a bioengineered niche mimicking the in vivo implantation environment. We show that biophysical niche factors act as a switch to toggle hPSC self-renewal versus amniogenesis under self-renewal permissive biochemical conditions. We identify a unique molecular signature of hPSC-derived amnion-like cells and show that endogenously activated BMP-SMAD signalling is required for the amnion-like tissue development by hPSCs. This study unveils the self-organizing and mechanosensitive nature of human amniogenesis and establishes the first hPSC-based model for investigating peri implantation human amnion development, thereby helping advance human embryology and reproductive medicine. PMID- 27941809 TI - Engineering dissipation with phononic spectral hole burning. AB - Optomechanics, nano-electromechanics, and integrated photonics have brought about a renaissance in phononic device physics and technology. Central to this advance are devices and materials supporting ultra-long-lived photonic and phononic excitations that enable novel regimes of classical and quantum dynamics based on tailorable photon-phonon coupling. Silica-based devices have been at the forefront of such innovations for their ability to support optical excitations persisting for nearly 1 billion cycles, and for their low optical nonlinearity. While acoustic phonon modes can persist for a similar number of cycles in crystalline solids at cryogenic temperatures, it has not been possible to achieve such performance in silica, as silica becomes acoustically opaque at low temperatures. We demonstrate that these intrinsic forms of phonon dissipation are greatly reduced (by >90%) by nonlinear saturation using continuous drive fields of disparate frequencies. The result is a form of steady-state phononic spectral hole burning that produces a wideband transparency window with optically generated phonon fields of modest (nW) powers. We developed a simple model that explains both dissipative and dispersive changes produced by phononic saturation. Our studies, conducted in a microscale device, represent an important step towards engineerable phonon dynamics on demand and the use of glasses as low-loss phononic media. PMID- 27941810 TI - Spin doping using transition metal phthalocyanine molecules. AB - Molecular spins have become key enablers for exploring magnetic interactions, quantum information processes and many-body effects in metals. Metal-organic molecules, in particular, let the spin state of the core metal ion to be modified according to its organic environment, allowing localized magnetic moments to emerge as functional entities with radically different properties from its simple atomic counterparts. Here, using and preserving the integrity of transition metal phthalocyanine high-spin complexes, we demonstrate the magnetic doping of gold thin films, effectively creating a new ground state. We demonstrate it by electrical transport measurements that are sensitive to the scattering of itinerant electrons with magnetic impurities, such as Kondo effect and weak antilocalization. Our work expands in a simple and powerful way the classes of materials that can be used as magnetic dopants, opening a new channel to couple the wide range of molecular properties with spin phenomena at a functional scale. PMID- 27941811 TI - Inferring time derivatives including cell growth rates using Gaussian processes. AB - Often the time derivative of a measured variable is of as much interest as the variable itself. For a growing population of biological cells, for example, the population's growth rate is typically more important than its size. Here we introduce a non-parametric method to infer first and second time derivatives as a function of time from time-series data. Our approach is based on Gaussian processes and applies to a wide range of data. In tests, the method is at least as accurate as others, but has several advantages: it estimates errors both in the inference and in any summary statistics, such as lag times, and allows interpolation with the corresponding error estimation. As illustrations, we infer growth rates of microbial cells, the rate of assembly of an amyloid fibril and both the speed and acceleration of two separating spindle pole bodies. Our algorithm should thus be broadly applicable. PMID- 27941812 TI - VRK3-mediated nuclear localization of HSP70 prevents glutamate excitotoxicity induced apoptosis and Abeta accumulation via enhancement of ERK phosphatase VHR activity. AB - Most of neurodegenerative disorders are associated with protein aggregation. Glutamate-induced excitotoxicity and persistent extracellular signal-regulated kinase (ERK) activation are also implicated in neurodegenerative diseases. Here, we found that vaccinia-related kinase 3 (VRK3) facilitates nuclear localization of glutamate-induced heat shock protein 70 (HSP70). Nuclear HSP70 leads to enhancement of vaccinia H1-related phosphatase (VHR) activity via protein-protein interaction rather than its molecular chaperone activity, thereby suppressing excessive ERK activation. Moreover, glutamate-induced ERK activation stimulates the expression of HSP70 and VRK3 at the transcriptional level. Downregulation of either VRK3 or HSP70 rendered cells vulnerable to glutamate-induced apoptosis. Overexpression of HSP70 fused to a nuclear localization signal attenuated apoptosis more than HSP70 alone. The importance of nuclear localization of HSP70 in the negative regulation of glutamate-induced ERK activation was further confirmed in VRK3-deficient neurons. Importantly, we showed a positive correlation between levels of VRK3 and HSP70 in the progression of Alzheimer's and Parkinson's diseases in humans, and neurons with HSP70 nuclear localization exhibited less Abeta accumulation in brains from patients with Alzheimer's disease. Therefore, HSP70 and VRK3 could potentially serve as diagnostic and therapeutic targets in neurodegenerative diseases. PMID- 27941814 TI - Development of an oxide-dispersion-strengthened steel by introducing oxygen carrier compound into the melt aided by a general thermodynamic model. AB - In general, melting process is not a common method for the production of oxide dispersion strengthened (ODS) alloys due to agglomeration and coarsening of oxide particles. However, vacuum casting process has recently been employed as a promising process to produce micro-scale oxide dispersed alloys. In this paper, we report the process and characterization of in situ formation and uniform dispersion of nano-scale Y-Ti oxide particles in Fe-10Ni-7Mn (wt.%) alloy. The processing route involves a solid-liquid reaction between the added TiO2 as an oxygen carrier and dissolved yttrium in liquid metal leading to an optimal microstructure with nano-sized dispersed oxide particles. The developed thermodynamic model shows the independence of the final phase constituents from experimental conditions such as melting temperature or vacuum system pressure which offers a general pathway for the manufacture of oxide dispersion strengthened materials. PMID- 27941813 TI - MHC-dependent mate choice is linked to a trace-amine-associated receptor gene in a mammal. AB - Major histocompatibility complex (MHC) genes play a pivotal role in vertebrate self/nonself recognition, parasite resistance and life history decisions. In evolutionary terms, the MHC's exceptional diversity is likely maintained by sexual and pathogen-driven selection. Even though MHC-dependent mating preferences have been confirmed for many species, the sensory and genetic mechanisms underlying mate recognition remain cryptic. Since olfaction is crucial for social communication in vertebrates, variation in chemosensory receptor genes could explain MHC-dependent mating patterns. Here, we investigated whether female mate choice is based on MHC alleles and linked to variation in chemosensory trace amine-associated receptors (TAARs) in the greater sac-winged bat (Saccopteryx bilineata). We sequenced several MHC and TAAR genes and related their variation to mating and paternity data. We found strong evidence for MHC class I-dependent female choice for genetically diverse and dissimilar males. We also detected a significant interaction between mate choice and the female TAAR3 genotype, with TAAR3-heterozygous females being more likely to choose MHC-diverse males. These results suggest that TAARs and olfactory cues may be key mediators in mammalian MHC-dependent mate choice. Our study may help identify the ligands involved in the chemical communication between potential mates. PMID- 27941815 TI - Association between neutrophil-to-lymphocyte ratio and differentiated thyroid cancer: a meta-analysis. AB - The association between neutrophil-to-lymphocyte ratio (NLR) and differentiated thyroid cancer (DTC) is undecided. To rectify this question, we conducted a systematic meta-analysis based on 7 prospective cohort studies published between 2013 and 2015, comprising 7349 patients. Six of these cohorts included pretreatment (baseline) NLR data for patients with thyroid nodules. The meta analysis of these 6 cohorts showed that the NLR of patients with DTC (4617 cases) was statistically similar to patients with benign nodules only (1666 cases), with a mean difference (MD) of 0.19 (95% CI: -0.09 to 0.46; I2 = 93%; P < 0.001). No significant difference in NLR was found between patients with DTC and patients with benign nodules. Two studies addressed an association between NLR and papillary thyroid carcinoma in patients stratified by age <45 and >=45 years (496 and 891 cases, respectively); the pooled MD was 0.09 (95% CI: -0.37 to 0.55; I2 = 92.2%, P < 0.001). An elevated NLR seems not a reliable indicator of progressing DTC in patients with goiters, and there was no difference in NLR between patients aged <45 years and those aged >=45 years. Well-designed and large-scale investigations are warranted to understand the value of NLR in the prognosis of DTC. PMID- 27941818 TI - Simulating US agriculture in a modern Dust Bowl drought. AB - Drought-induced agricultural loss is one of the most costly impacts of extreme weather1-3, and without mitigation, climate change is likely to increase the severity and frequency of future droughts4,5. The Dust Bowl of the 1930s was the driest and hottest for agriculture in modern US history. Improvements in farming practices have increased productivity, but yields today are still tightly linked to climate variation6 and the impacts of a 1930s-type drought on current and future agricultural systems remain unclear. Simulations of biophysical process and empirical models suggest that Dust-Bowl-type droughts today would have unprecedented consequences, with yield losses ~50% larger than the severe drought of 2012. Damages at these extremes are highly sensitive to temperature, worsening by ~25% with each degree centigrade of warming. We find that high temperatures can be more damaging than rainfall deficit, and, without adaptation, warmer mid century temperatures with even average precipitation could lead to maize losses equivalent to the Dust Bowl drought. Warmer temperatures alongside consecutive droughts could make up to 85% of rain-fed maize at risk of changes that may persist for decades. Understanding the interactions of weather extremes and a changing agricultural system is therefore critical to effectively respond to, and minimize, the impacts of the next extreme drought event. PMID- 27941819 TI - Corrigendum: Non-canonical RNA-directed DNA methylation. PMID- 27941816 TI - Cellulosomes: bacterial nanomachines for dismantling plant polysaccharides. AB - Cellulosomes are multienzyme complexes that are produced by anaerobic cellulolytic bacteria for the degradation of lignocellulosic biomass. They comprise a complex of scaffoldin, which is the structural subunit, and various enzymatic subunits. The intersubunit interactions in these multienzyme complexes are mediated by cohesin and dockerin modules. Cellulosome-producing bacteria have been isolated from a large variety of environments, which reflects their prevalence and the importance of this microbial enzymatic strategy. In a given species, cellulosomes exhibit intrinsic heterogeneity, and between species there is a broad diversity in the composition and configuration of cellulosomes. With the development of modern technologies, such as genomics and proteomics, the full protein content of cellulosomes and their expression levels can now be assessed and the regulatory mechanisms identified. Owing to their highly efficient organization and hydrolytic activity, cellulosomes hold immense potential for application in the degradation of biomass and are the focus of much effort to engineer an ideal microorganism for the conversion of lignocellulose to valuable products, such as biofuels. PMID- 27941821 TI - Elevated Type II Secretory Phospholipase A2 Increases the Risk of Early Atherosclerosis in Patients with Newly Diagnosed Metabolic Syndrome. AB - A critical association between type II secretory phospholipase A2 (sPLA2-IIa) and established atherosclerotic cardiovascular disease has been demonstrated. However, the contribution of sPLA2-IIa to early atherosclerosis remains unknown. This study investigated the association between early-stage atherosclerosis and sPLA2-IIa in metabolic syndrome (MetS) patients. One hundred and thirty-six MetS patients and 120 age- and gender-matched subjects without MetS were included. Serum sPLA2-IIa protein levels and activity were measured using commercial kits. Circulating endothelial activation molecules (vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and P selectin), and carotid intima-media thickness (cIMT), were measured as parameters of vascular endothelial dysfunction and early atherosclerosis. MetS patients exhibited significantly higher sPLA2-IIa protein and activity levels than the controls. Both correlated positively with fasting blood glucose and waist circumference in MetS patients. Additionally, MetS patients exhibited strikingly higher levels of endothelial activation molecules and increased cIMT than controls. These levels correlated positively with serum sPLA2-IIa protein levels and activity. Moreover, multivariate analysis showed that high sPLA2-IIa protein and activity levels were independent risk factors of early atherosclerosis in MetS patients. This study demonstrates an independent association between early stage atherosclerosis and increased levels of sPLA2-IIa, implying that increased sPLA2-IIa may predict early-stage atherosclerosis in MetS patients. PMID- 27941820 TI - Isolated pores dissected from human two-pore channel 2 are functional. AB - Multi-domain voltage-gated ion channels appear to have evolved through sequential rounds of intragenic duplication from a primordial one-domain precursor. Whereas modularity within one-domain symmetrical channels is established, little is known about the roles of individual regions within more complex asymmetrical channels where the domains have undergone substantial divergence. Here we isolated and characterised both of the divergent pore regions from human TPC2, a two-domain channel that holds a key intermediate position in the evolution of voltage-gated ion channels. In HeLa cells, each pore localised to the ER and caused Ca2+ depletion, whereas an ER-targeted pore mutated at a residue that inactivates full length TPC2 did not. Additionally, one of the pores expressed at high levels in E. coli. When purified, it formed a stable, folded tetramer. Liposomes reconstituted with the pore supported Ca2+ and Na+ uptake that was inhibited by known blockers of full-length channels. Computational modelling of the pore corroborated cationic permeability and drug interaction. Therefore, despite divergence, both pores are constitutively active in the absence of their partners and retain several properties of the wild-type pore. Such symmetrical 'pore-only' proteins derived from divergent channel domains may therefore provide tractable tools for probing the functional architecture of complex ion channels. PMID- 27941822 TI - Unique visible-light-assisted field emission of tetrapod-shaped ZnO/reduced graphene-oxide core/coating nanocomposites. AB - The electronic and the optoelectronic properties of graphene-based nanocomposites are controllable, making them promising for applications in diverse electronic devices. In this work, tetrapod-shaped zinc oxide (T-ZnO)/reduced graphene oxide (rGO) core/coating nanocomposites were synthesized by using a hydrothermal assisted self-assemble method, and their optical, photoelectric, and field emission properties were investigated. The ZnO, an ideal ultraviolet-light sensitive semiconductor, was observed to have high sensitivity to visible light due to the rGO coating, and the mechanism of that sensitivity was investigated. We demonstrated for the first time that the field-emission properties of the T ZnO/rGO core/coating nanocomposites could be dramatically enhanced under visible light by decreasing the turn-on field from 1.54 to 1.41 V/MUm and by increasing the current density from 5 to 12 mA/cm2 at an electric field of 3.5 V/MUm. The visible-light excitation induces an electron jump from oxygen vacancies on the surface of ZnO to the rGO layer, resulting in a decrease in the work function of the rGO and an increase in the emission current. Furthermore, a field-emission light-emitting diode with a self-enhanced effect was fabricated making full use of the photo-assisted field-emission process. PMID- 27941817 TI - Nuclear landscape of HIV-1 infection and integration. AB - To complete its life cycle, HIV-1 enters the nucleus of the host cell as reverse transcribed viral DNA. The nucleus is a complex environment, in which chromatin is organized to support different structural and functional aspects of cell physiology. As such, it represents a challenge for an incoming viral genome, which needs to be integrated into cellular DNA to ensure productive infection. Integration of the viral genome into host DNA depends on the enzymatic activity of HIV-1 integrase and involves different cellular factors that influence the selection of integration sites. The selection of integration site has functional consequences for viral transcription, which usually follows the integration event. However, in resting CD4+ T cells, the viral genome can be silenced for long periods of time, which leads to the generation of a latent reservoir of quiescent integrated HIV-1 DNA. Integration represents the only nuclear event in the viral life cycle that can be pharmacologically targeted with current therapies, and the aspects that connect HIV-1 nuclear entry to HIV-1 integration and viral transcription are only beginning to be elucidated. PMID- 27941823 TI - Meandering instability of air flow in a granular bed: self-similarity and fluid solid duality. AB - Meandering instability is familiar to everyone through river meandering or small rivulets of rain flowing down a windshield. However, its physical understanding is still premature, although it could inspire researchers in various fields, such as nonlinear science, fluid mechanics and geophysics, to resolve their long standing problems. Here, we perform a small-scale experiment in which air flow is created in a thin granular bed to successfully find a meandering regime, together with other remarkable fluidized regimes, such as a turbulent regime. We discover that phase diagrams of the flow regimes for different types of grains can be universally presented as functions of the flow rate and the granular-bed thickness when the two quantities are properly renormalized. We further reveal that the meandering shapes are self-similar as was shown for meandering rivers. The experimental findings are explained by theory, with elucidating the physics. The theory is based on force balance, a minimum-dissipation principle, and a linear-instability analysis of a continuum equation that takes into account the fluid-solid duality, i.e., the existence of fluidized and solidified regions of grains along the meandering path. The present results provide fruitful links to related issues in various fields, including fluidized bed reactors in industry. PMID- 27941825 TI - Defect-free high Sn-content GeSn on insulator grown by rapid melting growth. AB - GeSn is an attractive semiconductor material for Si-based photonics. However, large lattice mismatch between GeSn and Si and the low solubility of Sn in Ge limit its development. In order to obtain high Sn-content GeSn on Si, it is normally grown at low temperature, which would lead to inevitable dislocations. Here, we reported a single-crystal defect-free graded GeSn on insulator (GSOI) stripes laterally grown by rapid melting growth (RMG). The Sn-content reaches to 14.2% at the end of the GSOI stripe. Transmission electron microscopy observation shows the GSOI stripe without stacking fault and dislocations. P-channel pseudo metal-oxide-semiconductor field effect transistors (MOSFETs) and metal semiconductor-metal (MSM) Schottky junction photodetectors were fabricated on these GSOIs. Good transistor performance with a low field peak hole mobility of 402 cm2/Vs is obtained, which indicates a high-quality of this GSOI structure. Strong near-infrared and short-wave infrared optical absorption of the MSM photodetectors at 1550 nm and 2000 nm were observed. Owing to high Sn-content and defect-free, responsivity of 236 mA/W@-1.5 V is achieved at 1550 nm wavelength. In addition, responsivity reaches 154 mA/W@-1.5 V at 2000 nm with the optical absorption layer only 200 nm-thick, which is the highest value reported for GeSn junction photodetectors until now. PMID- 27941824 TI - Reactivity of disulfide bonds is markedly affected by structure and environment: implications for protein modification and stability. AB - Disulfide bonds play a key role in stabilizing protein structures, with disruption strongly associated with loss of protein function and activity. Previous data have suggested that disulfides show only modest reactivity with oxidants. In the current study, we report kinetic data indicating that selected disulfides react extremely rapidly, with a variation of 104 in rate constants. Five-membered ring disulfides are particularly reactive compared with acyclic (linear) disulfides or six-membered rings. Particular disulfides in proteins also show enhanced reactivity. This variation occurs with multiple oxidants and is shown to arise from favorable electrostatic stabilization of the incipient positive charge on the sulfur reaction center by remote groups, or by the neighboring sulfur for conformations in which the orbitals are suitably aligned. Controlling these factors should allow the design of efficient scavengers and high-stability proteins. These data are consistent with selective oxidative damage to particular disulfides, including those in some proteins. PMID- 27941829 TI - TiO2 nanotubes and mesoporous silica as containers in self-healing epoxy coatings. AB - The potential of inorganic nanomaterials as reservoirs for healing agents is presented here. Mesoporous silica (SBA-15) and TiO2 nanotubes (TNTs) were synthesized. Both epoxy-encapsulated TiO2 nanotubes and amine-immobilized mesoporous silica were incorporated into epoxy and subsequently coated on a carbon steel substrate. The encapsulated TiO2 nanotubes was quantitatively estimated using a 'dead pore ratio' calculation. The morphology of the composite coating was studied in detail using transmission electron microscopic (TEM) analysis. The self-healing ability of the coating was monitored using electrochemical impedance spectroscopy (EIS); the coating recovered 57% of its anticorrosive property in 5 days. The self-healing of the scratch on the coating was monitored using Scanning Electron Microscopy (SEM). The results confirmed that the epoxy pre-polymer was slowly released into the crack. The released epoxy pre-polymer came into contact with the amine immobilized in mesoporous silica and cross-linked to heal the scratch. PMID- 27941826 TI - G-rich DNA-induced stress response blocks type-I-IFN but not CXCL10 secretion in monocytes. AB - Excessive inflammation can cause damage to host cells and tissues. Thus, the secretion of inflammatory cytokines is tightly regulated at transcriptional, post transcriptional and post-translational levels and influenced by cellular stress responses, such as endoplasmic reticulum (ER) stress or apoptosis. Here, we describe a novel type of post-transcriptional regulation of the type-I-IFN response that was induced in monocytes by cytosolic transfection of a short immunomodulatory DNA (imDNA), a G-tetrad forming CpG-free derivative of the TLR9 agonist ODN2216. When co-transfected with cytosolic nucleic acid stimuli (DNA or 3P-dsRNA), imDNA induced caspase-3 activation, translational shutdown and upregulation of stress-induced genes. This stress response inhibited the type-I IFN induction at the translational level. By contrast, the induction of most type I-IFN-associated chemokines, including Chemokine (C-X-C Motif) Ligand (CXCL)10 was not affected, suggesting a differential translational regulation of chemokines and type-I-IFN. Pan-caspase inhibitors could restore IFN-beta secretion, yet, strikingly, caspase inhibition did not restore global translation but instead induced a compensatory increase in the transcription of IFN-beta but not CXCL10. Altogether, our data provide evidence for a differential regulation of cytokine release at both transcriptional and post-transcriptional levels which suppresses type-I-IFN induction yet allows for CXCL10 secretion during imDNA induced cellular stress. PMID- 27941830 TI - Coexistence of Write Once Read Many Memory and Memristor in blend of Poly(3,4 ethylenedioxythiophene): polystyrene sulfonate and Polyvinyl Alcohol. AB - In this work, the coexistence of Write Once Read Many Memory (WORM) and memristor can be achieved in a single device of Poly(3,4-ethylenedioxythiophene): polystyrene sulfonate (PEDOT: PSS) and Polyvinyl Alcohol (PVA) blend organic memory system. In memristor mode, the bistable resistance states of the device can be cycled for more than 1000 times. Once a large negative bias of -8V was applied to the device, it was switched to permanent high resistance state that cannot be restored back to lower resistance states. The mechanism of the memristor effect can be attributed to the charge trapping behaviour in PVA while the WORM effect can be explained as the electrochemical characteristic of PEDOT: PSS which harnesses the percolative conduction pathways. The results may facilitate multipurpose memory device with active tunability. PMID- 27941827 TI - Reduction of translating ribosomes enables Escherichia coli to maintain elongation rates during slow growth. AB - Bacteria growing under different conditions experience a broad range of demand on the rate of protein synthesis, which profoundly affects cellular resource allocation. During fast growth, protein synthesis has long been known to be modulated by adjusting the ribosome content, with the vast majority of ribosomes engaged at a near-maximal rate of elongation. Here, we systematically characterize protein synthesis by Escherichia coli, focusing on slow-growth conditions. We establish that the translational elongation rate decreases as growth slows, exhibiting a Michaelis-Menten dependence on the abundance of the cellular translational apparatus. However, an appreciable elongation rate is maintained even towards zero growth, including the stationary phase. This maintenance, critical for timely protein synthesis in harsh environments, is accompanied by a drastic reduction in the fraction of active ribosomes. Interestingly, well-known antibiotics such as chloramphenicol also cause a substantial reduction in the pool of active ribosomes, instead of slowing down translational elongation as commonly thought. PMID- 27941828 TI - Metastatic lymph node ratio demonstrates better prognostic stratification than pN staging in patients with esophageal squamous cell carcinoma after esophagectomy. AB - This study aimed to evaluate the prognostic significance of lymph node ratio (LNR) by establishing a hypothetical tumor-ratio-metastasis (TRM) staging system in patients with esophageal squamous cell carcinoma (ESCC). The records of 387 ESCC patients receiving curative esophagectomy were retrospectively investigated. The optimal cut-point for LNR was assessed via the best cut-off approach. Potential prognostic parameters were identified through univariate and multivariate analyses. A novel LNR-based TRM stage was proposed. The prognostic discriminatory ability and prediction accuracy of each system were determined using hazard ratio (HR), Akaike information criterion (AIC), concordance index (C index), and area under the receiver operating characteristic curve (AUC). The optimal cut-points of LNR were set at 0, 0~0.2, 0.2~0.4, and 0.4~1.0. Multivariate Cox analysis indicated that the LNR category was an independent risk factor of overall survival (P < 0.001). The calibration curves for the probability of 3- and 5-year survival showed good consistency between nomogram prediction and actual observation. The LNR category and TRM stage yielded a larger HR, a smaller AIC, a larger C-index, and a larger AUC than the N category and TNM stage did. In summary, the proposed LNR category was superior to the conventional N category in predicting the prognosis of ESCC patients. PMID- 27941832 TI - Breakthrough in 4pi ion emission mechanism understanding in plasma focus devices. AB - Ion emission angular distribution mechanisms in plasma focus devices (PFD) have not yet been well developed and understood being due to the lack of an efficient wide-angle ion distribution image detection system to characterize a PFD space in detail. Present belief is that the acceleration of ions points from "anode top" upwards in forward direction within a small solid angle. A breakthrough is reported in this study, by mega-size position-sensitive polycarbonate ion image detection systems invented, on discovery of 4pi ion emission from the "anode top" in a PFD space after plasma pinch instability and radial run-away of ions from the "anode cathodes array" during axial acceleration of plasma sheaths before the radial phase. These two ion emission source mechanisms behave respectively as a "Point Ion Source" and a "Line Ion Source" forming "Ion Cathode Shadows" on mega size detectors. We believe that the inventions and discoveries made here will open new horizons for advanced ion emission studies towards better mechanisms understanding and in particular will promote efficient applications of PFDs in medicine, science and technology. PMID- 27941831 TI - Molecular mechanism for sphingosine-induced Pseudomonas ceramidase expression through the transcriptional regulator SphR. AB - Pseudomonas aeruginosa, an opportunistic, but serious multidrug-resistant pathogen, secretes a ceramidase capable of cleaving the N-acyl linkage of ceramide to generate fatty acids and sphingosine. We previously reported that the secretion of P. aeruginosa ceramidase was induced by host-derived sphingolipids, through which phospholipase C-induced hemolysis was significantly enhanced. We herein investigated the gene(s) regulating sphingolipid-induced ceramidase expression and identified SphR, which encodes a putative AraC family transcriptional regulator. Disruption of the sphR gene in P. aeruginosa markedly decreased the sphingomyelin-induced secretion of ceramidase, reduced hemolytic activity, and resulted in the loss of sphingomyelin-induced ceramidase expression. A microarray analysis confirmed that sphingomyelin significantly induced ceramidase expression in P. aeruginosa. Furthermore, an electrophoretic mobility shift assay revealed that SphR specifically bound free sphingoid bases such as sphingosine, dihydrosphingosine, and phytosphingosine, but not sphingomyelin or ceramide. A beta-galactosidase-assisted promoter assay showed that sphingosine activated ceramidase expression through SphR at a concentration of 100 nM. Collectively, these results demonstrated that sphingosine induces the secretion of ceramidase by promoting the mRNA expression of ceramidase through SphR, thereby enhancing hemolytic phospholipase C-induced cytotoxicity. These results facilitate understanding of the physiological role of bacterial ceramidase in host cells. PMID- 27941833 TI - Tunable reflecting terahertz filter based on chirped metamaterial structure. AB - Tunable reflecting terahertz bandstop filter based on chirped metamaterial structure is demonstrated by numerical simulation. In the metamaterial, the metal bars are concatenated to silicon bars with different lengths. By varying the conductivity of the silicon bars, the reflectivity, central frequency and bandwidth of the metamaterial could be tuned. Light illumination could be introduced to change the conductivity of the silicon bars. Numerical simulations also show that the chirped metamaterial structure is insensitive to the incident angle and polarization-dependent. The proposed chirped metamaterial structure can be operated as a tunable bandstop filter whose modulation depth, bandwidth, shape factor and center frequency can be controlled by light pumping. PMID- 27941834 TI - Lin28a promotes self-renewal and proliferation of dairy goat spermatogonial stem cells (SSCs) through regulation of mTOR and PI3K/AKT. AB - Lin28a is a conserved RNA-binding protein that plays an important role in development, pluripotency, stemness maintenance, proliferation and self-renewal. Early studies showed that Lin28a serves as a marker of spermatogonial stem cells (SSCs) and promotes the proliferation capacity of mouse SSCs. However, there is little information about Lin28a in livestock SSCs. In this study, we cloned Capra hircus Lin28a CDS and found that it is evolutionarily conserved. Lin28a is widely expressed in different tissues of Capra hircus, but is expressed at a high level in the testis. Lin28a is specifically located in the cytoplasm of Capra hircus spermatogonial stem cells and may also be a marker of dairy goat spermatogonial stem cells. Lin28a promoted proliferation and maintained the self-renewal of GmGSCs-I-SB in vivo and in vitro. Lin28a-overexpressing GmGSCs-I-SB showed an enhanced proliferation rate, which might be due to increased PCNA expression. Moreover, Lin28a maintained the self-renewal of GmGSCs-I-SB by up-regulating the expression of OCT4, SOX2, GFRA1, PLZF and ETV5. Furthermore, we found that Lin28a may activate the AKT, ERK, and mTOR signaling pathways to promote the proliferation and maintain the self-renewal of GmGSCs-I-SB. PMID- 27941835 TI - Nutrient availability shapes the microbial community structure in sugarcane bagasse compost-derived consortia. AB - Microbial communities (MCs) create complex metabolic networks in natural habitats and respond to environmental changes by shifts in the community structure. Although members of MCs are often not amenable for cultivation in pure culture, it is possible to obtain a greater diversity of species in the laboratory setting when microorganisms are grown as mixed cultures. In order to mimic the environmental conditions, an appropriate growth medium must be applied. Here, we examined the hypothesis that a greater diversity of microorganisms can be sustained under nutrient-limited conditions. Using a 16 S rRNA amplicon metagenomic approach, we explored the structure of a compost-derived MC. During a five-week time course the MC grown in minimal medium with sugarcane bagasse (SCB) as a sole carbon source showed greater diversity and enrichment in lignocellulose degrading microorganisms. In contrast, a MC grown in nutrient rich medium with addition of SCB had a lower microbial diversity and limited number of lignocellulolytic species. Our approach provides evidence that factors such as nutrient availability has a significant selective pressure on the biodiversity of microorganisms in MCs. Consequently, nutrient-limited medium may displace bacterial generalist species, leading to an enriched source for mining novel enzymes for biotechnology applications. PMID- 27941836 TI - RNA interference: a promising biopesticide strategy against the African Sweetpotato Weevil Cylas brunneus. AB - The African sweetpotato weevil Cylas brunneus is one of the most devastating pests affecting the production of sweetpotatoes, an important staple food in Sub Saharan Africa. Current available control methods against this coleopteran pest are limited. In this study, we analyzed the potential of RNA interference as a novel crop protection strategy against this insect pest. First, the C. brunneus transcriptome was sequenced and RNAi functionality was confirmed by successfully silencing the laccase2 gene. Next, 24 potential target genes were chosen, based on their critical role in vital biological processes. A first screening via injection of gene-specific dsRNAs showed that the dsRNAs were highly toxic for C. brunneus. Injected doses of 200ng/mg body weight led to mortality rates of 90% or higher for 14 of the 24 tested genes after 14 days. The three best performing dsRNAs, targeting prosalpha2, rps13 and the homolog of Diabrotica virgifera snf7, were then used in further feeding trials to investigate RNAi by oral delivery. Different concentrations of dsRNAs mixed with artificial diet were tested and concentrations as low as 1 MUg dsRNA/ mL diet led to significant mortality rates higher than 50%.These results proved that dsRNAs targeting essential genes show great potential to control C. brunneus. PMID- 27941838 TI - The high osmotic response and cell wall integrity pathways cooperate to regulate morphology, microsclerotia development, and virulence in Metarhizium rileyi. AB - Microsclerotia (MS) formation was successfully induced in Metarhizium rileyi under changing liquid culture conditions. Mitogen-activated protein kinases (MAPKs) play important roles in fungal development and in coordinating many stress responses. To investigate how M. rileyi transduces growth stress and regulates MS differentiation, we characterized the roles of two MAPKs, Hog1- and Slt2-type orthologues, in M. rileyi. Compared with the wild-type strain, the deletion mutants of Mrhog1 (DeltaMrhog1) and Mrslt2 (DeltaMrslt2) delayed germination and vegetative growth, displayed sensitivities to various stress, and produced morphologically abnormal clones. The DeltaMrhog1 and DeltaMrslt2 mutants significantly reduced conidial (42-99%) and MS (96-99%) yields. A transcriptional analysis showed that the two MAPKs regulate MS development in a cooperative manner. Insect bioassays revealed that DeltaMrhog1 and DeltaMrslt2 had decreased virulence levels in topical (36-56%) and injection (78-93%) bioassays. Our results confirmed the roles of MrHog1 and MrSlt2 in sensing growth-related stress and in regulating MS differentiation. PMID- 27941837 TI - Nuclear Factor Erythroid 2-related Factor 2 Deficiency Exacerbates Lupus Nephritis in B6/lpr mice by Regulating Th17 Cell Function. AB - Lupus nephritis (LN) is the major clinical manifestation of systemic lupus erythematosus. LN is promoted by T helper 17 (Th17) cells, which are the major pro-inflammatory T cell subset contributing to autoimmunity regulation. Nuclear factor erythroid 2-related factor 2 (NRF2) is critical for suppressing reactive oxygen species (ROS) and relieving oxidant stress by regulating antioxidant gene expression. Previous studies have demonstrated that Nrf2 deficiency promotes drug induced or spontaneous LN. However, whether NRF2 regulates Th17 function during LN development is still unclear. In this study, we introduced Nrf2 deficiency into a well-known LN model, the B6/lpr mouse strain, and found that it promoted early-stage LN with altered Th17 activation. Th17 cells and their relevant cytokines were dramatically increased in these double-mutant mice. We also demonstrated that naive T cells from the double-mutant mice showed significantly increased differentiation into Th17 cells in vitro, with decreased expression of the Th17 differentiation suppressor Socs3 and increased phosphorylation of STAT3. Our results demonstrated that Nrf2 deficiency promoted Th17 differentiation and function during LN development. Moreover, our results suggested that the regulation of Th17 differentiation via NRF2 could be a therapeutic target for the treatment of subclinical LN patients. PMID- 27941839 TI - Graphene nanoplatelets induced heterogeneous bimodal structural magnesium matrix composites with enhanced mechanical properties. AB - In this work, graphene nanoplatelets (GNPs) reinforced magnesium (Mg) matrix composites were synthesised using the multi-step dispersion route. Well-dispersed but inhomogeneously distributed GNPs were obtained in the matrix. Compared with the monolithic alloy, the nanocomposites exhibited dramatically enhanced Young's modulus, yield strength and ultimate tensile strength and relatively high plasticity, which mainly attributed to the significant heterogeneous laminated microstructure induced by the addition of GNPs. With increasing of the concentration of GNPs, mechanical properties of the composites were gradually improved. Especially, the strengthening efficiency of all the composites exceeded 100%, which was significantly higher than that of carbon nanotubes reinforced Mg matrix composites. The grain refinement and load transfer provided by the two dimensional and wrinkled surface structure of GNPs were the dominated strengthening mechanisms of the composites. This investigation develops a new method for incorporating GNPs in metals for fabricating high-performance composites. PMID- 27941841 TI - Predicting the growth situation of Pseudomonas aeruginosa on agar plates and meat stuffs using gas sensors. AB - A rapid method of predicting the growing situation of Pseudomonas aeruginosa is presented. Gas sensors were used to acquire volatile compounds generated by P. aeruginosa on agar plates and meat stuffs. Then, optimal sensors were selected to simulate P. aeruginosa growth using modified Logistic and Gompertz equations by odor changes. The results showed that the responses of S8 or S10 yielded high coefficients of determination (R2) of 0.89-0.99 and low root mean square errors (RMSE) of 0.06-0.17 for P. aeruginosa growth, fitting the models on the agar plate. The responses of S9, S4 and the first principal component of 10 sensors fit well with the growth of P. aeruginosa inoculated in meat stored at 4 degrees C and 20 degrees C, with R2 of 0.73-0.96 and RMSE of 0.25-1.38. The correlation coefficients between the fitting models, as measured by electronic nose responses, and the colony counts of P. aeruginosa were high, ranging from 0.882 to 0.996 for both plate and meat samples. Also, gas chromatography-mass spectrometry results indicated the presence of specific volatiles of P. aeruginosa on agar plates. This work demonstrated an acceptable feasibility of using gas sensors-a rapid, easy and nondestructive method for predicting P. aeruginosa growth. PMID- 27941842 TI - Extreme ultraviolet resonant inelastic X-ray scattering (RIXS) at a seeded free electron laser. AB - In the past few years, we have been witnessing an increased interest for studying materials properties under non-equilibrium conditions. Several well established spectroscopies for experiments in the energy domain have been successfully adapted to the time domain with sub-picosecond time resolution. Here we show the realization of high resolution resonant inelastic X-ray scattering (RIXS) with a stable ultrashort X-ray source such as an externally seeded free electron laser (FEL). We have designed and constructed a RIXS experimental endstation that allowed us to successfully measure the d-d excitations in KCoF3 single crystals at the cobalt M2,3-edge at FERMI FEL (Elettra-Sincrotrone Trieste, Italy). The FEL-RIXS spectra show an excellent agreement with the ones obtained from the same samples at the MERIXS endstation of the MERLIN beamline at the Advanced Light Source storage ring (Berkeley, USA). We established experimental protocols for performing time resolved RIXS experiments at a FEL source to avoid X ray-induced sample damage, while retaining comparable acquisition time to the synchrotron based measurements. Finally, we measured and modelled the influence of the FEL mixed electromagnetic modes, also present in externally seeded FELs, and the beam transport with ~120 meV experimental resolution achieved in the presented RIXS setup. PMID- 27941840 TI - Enhancing radiosensitization in EphB4 receptor-expressing Head and Neck Squamous Cell Carcinomas. AB - Members of the Eph family of receptor tyrosine kinases have been implicated in a wide array of human cancers. The EphB4 receptor is ubiquitously expressed in head and neck squamous cell carcinoma (HNSCC) and has been shown to impart tumorigenic and invasive characteristics to these cancers. In this study, we investigated whether EphB4 receptor targeting can enhance the radiosensitization of HNSCC. Our data show that EphB4 is expressed at high to moderate levels in HNSCC cell lines and patient-derived xenograft (PDX) tumors. We observed decreased survival fractions in HNSCC cells following EphB4 knockdown in clonogenic assays. An enhanced G2 cell cycle arrest with activation of DNA damage response pathway and increased apoptosis was evident in HNSCC cells following combined EphB4 downregulation and radiation compared to EphB4 knockdown and radiation alone. Data using HNSCC PDX models showed significant reduction in tumor volume and enhanced delay in tumor regrowth following sEphB4-HSA administration with radiation compared to single agent treatment. sEphB4-HSA is a protein known to block the interaction between the EphB4 receptor and its ephrin-B2 ligand. Overall, our findings emphasize the therapeutic relevance of EphB4 targeting as a radiosensitizer that can be exploited for the treatment of human head and neck carcinomas. PMID- 27941844 TI - Direct-written polymer field-effect transistors operating at 20 MHz. AB - Printed polymer electronics has held for long the promise of revolutionizing technology by delivering distributed, flexible, lightweight and cost-effective applications for wearables, healthcare, diagnostic, automation and portable devices. While impressive progresses have been registered in terms of organic semiconductors mobility, field-effect transistors (FETs), the basic building block of any circuit, are still showing limited speed of operation, thus limiting their real applicability. So far, attempts with organic FETs to achieve the tens of MHz regime, a threshold for many applications comprising the driving of high resolution displays, have relied on the adoption of sophisticated lithographic techniques and/or complex architectures, undermining the whole concept. In this work we demonstrate polymer FETs which can operate up to 20 MHz and are fabricated by means only of scalable printing techniques and direct-writing methods with a completely mask-less procedure. This is achieved by combining a fs laser process for the sintering of high resolution metal electrodes, thus easily achieving micron-scale channels with reduced parasitism down to 0.19 pF mm-1, and a large area coating technique of a high mobility polymer semiconductor, according to a simple and scalable process flow. PMID- 27941843 TI - Whole-genome sequencing of eight goat populations for the detection of selection signatures underlying production and adaptive traits. AB - The goat (Capra hircus) is one of the first farm animals that have undergone domestication and extensive natural and artificial selection by adapting to various environments, which in turn has resulted in its high level of phenotypic diversity. Here, we generated medium-coverage (9-13*) sequences from eight domesticated goat breeds, representing morphologically or geographically specific populations, to identify genomic regions representing selection signatures. We discovered ~10 million single nucleotide polymorphisms (SNPs) for each breed. By combining two approaches, ZHp and di values, we identified 22 genomic regions that may have contributed to the phenotypes in coat color patterns, body size, cashmere traits, as well as high altitude adaptation in goat populations. Candidate genes underlying strong selection signatures including coloration (ASIP, KITLG, HTT, GNA11, and OSTM1), body size (TBX15, DGCR8, CDC25A, and RDH16), cashmere traits (LHX2, FGF9, and WNT2), and hypoxia adaptation (CDK2, SOCS2, NOXA1, and ENPEP) were identified. We also identified candidate functional SNPs within selected genes that may be important for each trait. Our results demonstrated the potential of using sequence data in identifying genomic regions that are responsible for agriculturally significant phenotypes in goats, which in turn can be used in the selection of goat breeds for environmental adaptation and domestication. PMID- 27941845 TI - Generation of radially-polarized terahertz pulses for coupling into coaxial waveguides. AB - Coaxial waveguides exhibit no dispersion and therefore can serve as an ideal channel for transmission of broadband THz pulses. Implementation of THz coaxial waveguide systems however requires THz beams with radially-polarized distribution. We demonstrate the launching of THz pulses into coaxial waveguides using the effect of THz pulse generation at semiconductor surfaces. We find that the radial transient photo-currents produced upon optical excitation of the surface at normal incidence radiate a THz pulse with the field distribution matching the mode of the coaxial waveguide. In this simple scheme, the optical excitation beam diameter controls the spatial profile of the generated radially polarized THz pulse and allows us to achieve efficient coupling into the TEM waveguide mode in a hollow coaxial THz waveguide. The TEM quasi-single mode THz waveguide excitation and non-dispersive propagation of a short THz pulse is verified experimentally by time-resolved near-field mapping of the THz field at the waveguide output. PMID- 27941846 TI - Fast Quantum Rabi Model with Trapped Ions. AB - We show how to produce a fast quantum Rabi model with trapped ions. Its importance resides not only in the acceleration of the phenomena that may be achieved with these systems, from quantum gates to the generation of nonclassical states of the vibrational motion of the ion, but also in reducing unwanted effects such as the decay of coherences that may appear in such systems. PMID- 27941847 TI - Association between vitamin A, retinol and carotenoid intake and pancreatic cancer risk: Evidence from epidemiologic studies. AB - Pancreatic cancer is a devastating disease with poor prognosis. The association between vitamin A, retinol and carotenoid intake and the risk of pancreatic cancer occurrence remains controversial, and therefore it is necessary to make a meta-analysis to clarify the association between vitamin A, retinol and carotenoid intake and pancreatic cancer risk. In the present study, PubMed and EMBASE databases were used to identify qualified studies. The association between dietary vitamin A, retinol and carotenoids was estimated by pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). It was found that there was an inverse correlation between vitamin A, beta-carotene and lycopene intake and the risk of pancreatic cancer (for vitamin A, pooled OR = 0.85, 95%CI = 0.74 0.97, P = 0.015; for beta-carotene, pooled OR = 0.78, 95%CI = 0.66-0.92, P = 0.003; for lycopene, pooled OR = 0.84, 95%CI = 0.73-0.97, P = 0.020), which was more prominent in case-control study subgroup. In conclusion, dietary vitamin A, beta-carotene and lycopene might inversely correlate with pancreatic cancer. PMID- 27941848 TI - In vitro and in vivo comparison of the immunotoxicity of single- and multi layered graphene oxides with or without pluronic F-127. AB - Graphene oxide (GO) has been a focus of research in the fields of electronics, energy, and biomedicine, including drug delivery. Thus, single- and multi-layered GO (SLGO and MLGO) have been produced and investigated. However, little information on their toxicity and biocompatibility is available. In the present study, we performed a comprehensive study of the size- and dose-dependent toxicity of GOs in the presence or absence of Pluronic F-127 on THP-1 cells by examining their viability, membrane integrity, levels of cytokine and ROS production, phagocytosis, and cytometric apoptosis. Moreover, as an extended study, a toxicity evaluation in the acute and chronic phases was performed in mice via intravenous injection of the materials. GOs exhibited dose- and size dependent toxicity. Interestingly, SLGO induced ROS production to a lesser extent than MLGO. Cytometric analysis indicated that SLGO induced necrosis and apoptosis to a lesser degree than MLGO. In addition, cell damage and IL-1beta production were influenced by phagocytosis. A histological animal study revealed that GOs of various sizes induced acute and chronic damage to the lung and kidney in the presence or absence of Pluronic F-127. These results will facilitate studies of GO prior to its biomedical application. PMID- 27941849 TI - Interleukin-37 Enhances the Suppressive Activity of Naturally Occurring CD4+CD25+ Regulatory T Cells. AB - Naturally occurring CD4+CD25+ regulatory T cells (Tregs) are essential for the suppression of autoimmunity and can control the immune-mediated pathology during the early phase of sepsis. Our previous data showed that silencing interleukin-37 (IL-37) in human CD4+CD25+ Tregs obviously reduced the suppressive activity of CD4+CD25+ Tregs. Here, we found that rhIL-37 stimulation markedly enhanced the suppressive activity of CD4+CD25+ Tregs isolated from naive C57BL/6 J mice in the absence or presence of lipopolysaccharide (LPS). Treatment with rhIL-37 could significantly upregulate the expression of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3) on CD4+CD25+ Tregs. Also, rhIL-37 stimulation promoted the production of transforming growth factor-beta1 (TGF-beta1) but not IL-10 in the supernatants of cultured CD4+CD25+ Tregs. Pretreated CD4+CD25+ Tregs with rhIL-37 in the presence or absence of LPS were cocultured with CD4+CD25- T cells, ratio of IL 4/interferon-gamma in the supernatants obviously increased in IL-37-stimulated groups. In addition, early administration of IL-37 significantly improved the survival rate of septic mice induced by cecal ligation and puncture. Taken together, we concluded that rhIL-37 enhances the suppressive activity of CD4+CD25+ Tregs and might be a potential immunomodulator for the treatment of septic complications. PMID- 27941851 TI - Unconscious processing of invisible visual stimuli. AB - Unconscious processing of subliminal visual information, as illustrated by the above-chance accuracy in discriminating invisible visual stimuli, is evident in both blindsight patients and healthy human observers. However, the dependence of such unconscious processing on stimulus properties remains unclear. Here we studied the impact of stimulus luminance and stimulus complexity on the extent of unconscious processing. A testing stimulus presented to one eye was rendered invisible by a masking stimulus presented to the other eye, and healthy human participants made a forced-choice discrimination of the stimulus identity followed by a report of the perceptual awareness. Without awareness of the stimulus existence, participants could nevertheless reach above-chance accuracy in discriminating the stimulus identity. Importantly, the discrimination accuracy for invisible stimuli increased with the stimulus luminance and decreased with the stimulus complexity. These findings suggested that the input signal strength and the input signal complexity can affect the extent of unconscious processing without altering the subjective awareness. PMID- 27941852 TI - Creation of Sub-diffraction Longitudinally Polarized Spot by Focusing Radially Polarized Light with Binary Phase Lens. AB - The generation of a sub-diffraction longitudinally polarized spot is of great interest in various applications, such as optical tweezers, super-resolution microscopy, high-resolution Raman spectroscopy, and high-density optical data storage. Many theoretical investigations have been conducted into the tight focusing of a longitudinally polarized spot with high-numerical-aperture aplanatic lenses in combination with optical filters. Optical super-oscillation provides a new approach to focusing light beyond the diffraction limit. Here, we propose a planar binary phase lens and experimentally demonstrate the generation of a longitudinally polarized sub-diffraction focal spot by focusing radially polarized light. The lens has a numerical aperture of 0.93 and a long focal length of 200lambda for wavelength lambda = 632.8 nm, and the generated focal spot has a full-width-at-half-maximum of about 0.456lambda, which is smaller than the diffraction limit, 0.54lambda. A 5lambda-long longitudinally polarized optical needle with sub-diffraction size is also observed near the designed focal point. PMID- 27941850 TI - BLR1 and FCGR1A transcripts in peripheral blood associate with the extent of intrathoracic tuberculosis in children and predict treatment outcome. AB - Biomarkers reflecting the extent of Mycobacterium tuberculosis-induced pathology and normalization during anti-tuberculosis treatment (ATT) would considerably facilitate trials of new treatment regimens and the identification of patients with treatment failure. Therefore, in a cohort of 99 Indian children with intrathoracic tuberculosis (TB), we performed blood transcriptome kinetic analysis during ATT to explore 1) the association between transcriptional biomarkers in whole blood (WB) and the extent of TB disease at diagnosis and treatment outcomes at 2 and 6 months, and 2) the potential of the biomarkers to predict treatment response at 2 and 6 months. We present the first data on the association between transcriptional biomarkers and the extent of TB disease as well as outcome of ATT in children: Expression of three genes down-regulated on ATT (FCGR1A, FPR1 and MMP9) exhibited a positive correlation with the extent of TB disease, whereas expression of eight up-regulated genes (BCL, BLR1, CASP8, CD3E, CD4, CD19, IL7R and TGFBR2) exhibited a negative correlation with the extent of disease. Baseline levels of these transcripts displayed an individual capacity >70% to predict the six-month treatment outcome. In particular, BLR1 and FCGR1A seem to have a potential in monitoring and perhaps tailoring future antituberculosis therapy. PMID- 27941854 TI - Effects of iron and boron combinations on the suppression of Fusarium wilt in banana. AB - The effects of mineral nutrient on banana wilt disease, which are the result of a competitive relationship between host plants and pathogens, can affect the interactions of plants with microorganisms. To investigate the mineral nutrient effect, hydroponic experiments were conducted in glasshouse containing combinations of low, medium, and high iron (Fe) and boron (B) concentrations, followed by pathogen inoculation. High Fe and B treatment significantly reduced the disease index and facilitated plants growth. With increasing Fe and B concentrations, more Fe and B accumulated in plants. High Fe and B treatment dramatically reduced the Fusarium oxysporum conidial germination rate and fungal growth compared with the other two treatments, contributing to decreased numbers of the pathogen on infected plants. Furthermore, High Fe and B treatment decreased the fusaric acid production of F. oxysporum in vitro and also increased the mannitol content of the plants, which in turn decreased the phytotoxin production of infected plants and finally reduced the disease index due to the virulence factor of phytotoxin. Taken together, these results indicate that Fe and B play a multifunctional role in reducing the severity of diseases by affecting the growth of F. oxysporum and the responses between plants and pathogens. PMID- 27941853 TI - Antimicrobial mechanism of theaflavins: They target 1-deoxy-D-xylulose 5 phosphate reductoisomerase, the key enzyme of the MEP terpenoid biosynthetic pathway. AB - 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is the first committed enzyme in the 2-methyl-D-erythritol 4-phosphate (MEP) terpenoid biosynthetic pathway and is also a validated antimicrobial target. Theaflavins, which are polyphenolic compounds isolated from fermented tea, possess a wide range of pharmacological activities, especially an antibacterial effect, but little has been reported on their modes of antimicrobial action. To uncover the antibacterial mechanism of theaflavins and to seek new DXR inhibitors from natural sources, the DXR inhibitory activity of theaflavins were investigated in this study. The results show that all four theaflavin compounds could specifically suppress the activity of DXR, with theaflavin displaying the lowest effect against DXR (IC50 162.1 MUM) and theaflavin-3,3'-digallate exhibiting the highest (IC50 14.9 MUM). Moreover, determination of inhibition kinetics of the theaflavins demonstrates that they are non-competitive inhibitors of DXR against 1-deoxy-D-xylulose 5-phosphate (DXP) and un-competitive inhibitors with respect to NADPH. The possible interactions between DXR and the theaflavins were simulated via docking experiments. PMID- 27941856 TI - Nonlinear coupling in graphene-coated nanowires. AB - We propose and analyze nonlinear coupler based on a pair of single mode graphene coated nanowires. Nonlinear wave interactions in such structure are analyzed by the coupled mode equations derived from the unconjugated Lorentz reciprocity theorem. We show that the routing of plasmons in the proposed structure can be controlled by the input power due to the third order nonlinear response of graphene layer. Our findings show that graphene nonlinearity can be exploited in tunable nanoplasmonic circuits based on low-loss, edgeless cylindrical graphene waveguides. PMID- 27941855 TI - Clinical Predictors of Neurological Outcome within 72 h after Traumatic Cervical Spinal Cord Injury. AB - To investigate the prognostic values of clinical factors 72 h within traumatic cervical spinal cord injury (TCSCI). Data were extracted from the medical materials of 57 TCSCI cases. AIS was used as the outcome measure and divided into dichotomous variables by two methods, i.e. "complete(AIS = A)/incomplete(AIS ? A) SCI" and "motor complete(AIS = A or B)/incomplete(AIS ? A and B) SCI". Relationships between evaluated factors and outcomes were investigated by univariate and multivariate methods. MRI Cord transection (MCT) cases, most significantly related to complete SCIs by univariate analysis (P = 0.006), all showed complete SCIs when discharged, which makes it unsuitable for logistic regression. With MCT cases removed, univariate analysis was conducted again, then logistic regression. At last, only C5 spine injury (P = 0.024, OR = 0.241) was related to complete SCI. Cases with compression flexion injury mechanism (CFIM), most significantly related to motor complete SCIs by univariate analysis (P = 0.001), was also unsuitable for logistic regression for the same reason. At last, C3 spine injury (P = 0.033, OR = 0.068) and high energy injury (P = 0.033, OR = 14.763) were related to motor complete SCIs with CFIM cases removed. The results show that MCT and C5 spine injury are good predictors for complete/incomplete SCIs. CFIM, C3 spine injury and high energy injury are good predictors for motor complete/incomplete SCIs. PMID- 27941858 TI - Basic research: Suffocating the heart to stimulate regeneration. PMID- 27941857 TI - Self-preservation and structural transition of gas hydrates during dissociation below the ice point: an in situ study using Raman spectroscopy. AB - The hydrate structure type and dissociation behavior for pure methane and methane ethane hydrates at temperatures below the ice point and atmospheric pressure were investigated using in situ Raman spectroscopic analysis. The self-preservation effect of sI methane hydrate is significant at lower temperatures (268.15 to 270.15 K), as determined by the stable C-H region Raman peaks and AL/AS value (Ratio of total peak area corresponding to occupancies of guest molecules in large cavities to small cavities) being around 3.0. However, it was reduced at higher temperatures (271.15 K and 272.15 K), as shown from the dramatic change in Raman spectra and fluctuations in AL/AS values. The self-preservation effect for methane-ethane double hydrate is observed at temperatures lower than 271.15 K. The structure transition from sI to sII occurred during the methane-ethane hydrate decomposition process, which was clearly identified by the shift in peak positions and the change in relative peak intensities at temperatures from 269.15 K to 271.15 K. Further investigation shows that the selectivity for self preservation of methane over ethane leads to the structure transition; this kind of selectivity increases with decreasing temperature. This work provides new insight into the kinetic behavior of hydrate dissociation below the ice point. PMID- 27941859 TI - Basic research: Killing the old: cell senescence in atherosclerosis. PMID- 27941860 TI - Lactate signalling regulates fungal beta-glucan masking and immune evasion. AB - As they proliferate, fungi expose antigens at their cell surface that are potent stimulators of the innate immune response, and yet the commensal fungus Candida albicans is able to colonize immuno competent individuals. We show that C. albicans may evade immune detection by presenting a moving immunological target. We report that the exposure of beta-glucan, a key pathogen-associated molecular pattern (PAMP) located at the cell surface of C. albicans and other pathogenic Candida species, is modulated in response to changes in the carbon source. Exposure to lactate induces beta-glucan masking in C. albicans via a signalling pathway that has recruited an evolutionarily conserved receptor (Gpr1) and transcriptional factor (Crz1) from other well-characterized pathways. In response to lactate, these regulators control the expression of cell-wall-related genes that contribute to beta-glucan masking. This represents the first description of active PAMP masking by a Candida species, a process that reduces the visibility of the fungus to the immune system. PMID- 27941862 TI - Cryo-EM structures of human RAD51 recombinase filaments during catalysis of DNA strand exchange. AB - The central step in eukaryotic homologous recombination (HR) is ATP-dependent DNA strand exchange mediated by the Rad51 recombinase. In this process, Rad51 assembles on single-stranded DNA (ssDNA) and generates a helical filament that is able to search for and invade homologous double-stranded DNA (dsDNA), thus leading to strand separation and formation of new base pairs between the initiating ssDNA and the complementary strand within the duplex. Here, we used cryo-EM to solve the structures of human RAD51 in complex with DNA molecules, in presynaptic and postsynaptic states, at near-atomic resolution. Our structures reveal both conserved and distinct structural features of the human RAD51-DNA complexes compared with their prokaryotic counterpart. Notably, we also captured the structure of an arrested synaptic complex. Our results provide new insight into the molecular mechanisms of the DNA homology search and strand-exchange processes. PMID- 27941861 TI - Warfarin and vitamin K compete for binding to Phe55 in human VKOR. AB - Vitamin K epoxide reductase (VKOR) catalyzes the reduction of vitamin K quinone and vitamin K 2,3-epoxide, a process essential to sustain gamma-carboxylation of vitamin K-dependent proteins. VKOR is also a therapeutic target of warfarin, a treatment for thrombotic disorders. However, the structural and functional basis of vitamin K reduction and the antagonism of warfarin inhibition remain elusive. Here, we identified putative binding sites of both K vitamers and warfarin on human VKOR. The predicted warfarin-binding site was verified by shifted dose response curves of specified mutated residues. We used CRISPR-Cas9-engineered HEK 293T cells to assess the vitamin K quinone and vitamin K 2,3-epoxide reductase activities of VKOR variants to characterize the vitamin K naphthoquinone head- and isoprenoid side chain-binding regions. Our results challenge the prevailing concept of noncompetitive warfarin inhibition because K vitamers and warfarin share binding sites on VKOR that include Phe55, a key residue binding either the substrate or inhibitor. PMID- 27941864 TI - Sulfur Geochemistry of a Lacustrine Record from Taiwan Reveals Enhanced Marine Aerosol Input during the Early Holocene. AB - Lacustrine record of marine aerosol input has rarely been documented. Here, we present the sulfur geochemistry during the last deglaciation and early Holocene of a sediment core retrieved from the Dongyuan Lake in southern Taiwan. An unusually high sulfur peak accompanying pyrite presence is observed at 10.5 ka BP. Such high sulfur content in lacustrine record is unusual. The delta34S of sulfur varied from +9.5 to + 17.10/00 with two significant positive shifts at 10.5 and 9.4 ka BP. The sources of sulfur and potential processes involving the sulfur isotope variation including bacterial sulfate reduction, volcanic emissions, in-catchment sulfide oxidation and marine aerosol input are discussed. Enhanced marine aerosol input is the most likely explanation for such sulfur peaks and delta34S shifts. The positive delta34S shifts appeared concurrently with the maximum landslide events over Taiwan resulted from enhanced typhoon activities. The synchronicity among records suggests that increased typhoon activities promoted sea spray, and consequently enhanced the marine aerosol input with 34S-enriched sulfate. Our sulfur geochemistry data revealed sea spray history and marine influence onto terrestrial environment at coastal regions. Wider coverage of spatial-temporal lacustrine sulfur geochemistry record is needed to validate the applicability of sulfur proxy in paleoenvironmental research. PMID- 27941863 TI - CozE is a member of the MreCD complex that directs cell elongation in Streptococcus pneumoniae. AB - Most bacterial cells are surrounded by a peptidoglycan cell wall that is essential for their integrity. The major synthases of this exoskeleton are called penicillin-binding proteins (PBPs)1,2. Surprisingly little is known about how cells control these enzymes, given their importance as drug targets. In the model Gram-negative bacterium Escherichia coli, outer membrane lipoproteins are critical activators of the class A PBPs (aPBPs)3,4, bifunctional synthases capable of polymerizing and crosslinking peptidoglycan to build the exoskeletal matrix1. Regulators of PBP activity in Gram-positive bacteria have yet to be discovered but are likely to be distinct due to the absence of an outer membrane. To uncover Gram-positive PBP regulatory factors, we used transposon-sequencing (Tn-Seq)5 to screen for mutations affecting the growth of Streptococcus pneumoniae cells when the aPBP synthase PBP1a was inactivated. Our analysis revealed a set of genes that were essential for growth in wild-type cells yet dispensable when pbp1a was deleted. The proteins encoded by these genes include the conserved cell wall elongation factors MreC and MreD2,6,7, as well as a membrane protein of unknown function (SPD_0768) that we have named CozE (coordinator of zonal elongation). Our results indicate that CozE is a member of the MreCD complex of S. pneumoniae that directs the activity of PBP1a to the midcell plane where it promotes zonal cell elongation and normal morphology. CozE homologues are broadly distributed among bacteria, suggesting that they represent a widespread family of morphogenic proteins controlling cell wall biogenesis by the PBPs. PMID- 27941865 TI - Unusual dimeric tetrahydroxanthone derivatives from Aspergillus lentulus and the determination of their axial chiralities. AB - The research on secondary metabolites of Aspergillus lentulus afforded eight unusual heterodimeric tetrahydroxanthone derivatives, lentulins A-H (2-9), along with the known compound neosartorin (1). Compounds 1-6 exhibited potent antimicrobial activities especially against methicillin-resistant Staphylococci. Their absolute configurations, particularly the axial chiralities, were unambiguously demonstrated by a combination of electronic circular dichroism (ECD), Rh2(OCOCF3)4-induced ECD experiments, modified Mosher methods, and chemical conversions. Interestingly, compounds 1-4 were the first samples of atropisomers within the dimeric tetrahydroxanthone class. Further investigation of the relationships between their axial chiralities and ECD Cotton effects led to the proposal of a specific CD Exciton Chirality rule to determine the axial chiralities in dimeric tetrahydroxanthones and their derivatives. PMID- 27941866 TI - Size-dependent bending modulus of nanotubes induced by the imperfect boundary conditions. AB - The size-dependent bending modulus of nanotubes, which was widely observed in most existing three-point bending experiments [e.g., J. Phys. Chem. B 117, 4618 4625 (2013)], has been tacitly assumed to originate from the shear effect. In this paper, taking boron nitride nanotubes as an example, we directly measured the shear effect by molecular dynamics (MD) simulations and found that the shear effect is not the major factor responsible for the observed size-dependent bending modulus of nanotubes. To further explain the size-dependence phenomenon, we abandoned the assumption of perfect boundary conditions (BCs) utilized in the aforementioned experiments and studied the influence of the BCs on the bending modulus of nanotubes based on MD simulations. The results show that the imperfect BCs also make the bending modulus of nanotubes size-dependent. Moreover, the size dependence phenomenon induced by the imperfect BCs is much more significant than that induced by the shear effect, which suggests that the imperfect BC is a possible physical origin that leads to the strong size-dependence of the bending modulus found in the aforementioned experiments. To capture the physics behind the MD simulation results, a beam model with the general BCs is proposed and found to fit the experimental data very well. PMID- 27941867 TI - Antibacterial and anticancer PDMS surface for mammalian cell growth using the Chinese herb extract paeonol(4-methoxy-2-hydroxyacetophenone). AB - Polydimethylsiloxane (PDMS) is widely used as a cell culture platform to produce micro- and nano-technology based microdevices. However, the native PDMS surface is not suitable for cell adhesion and is always subject to bacterial pollution and cancer cell invasion. Coating the PDMS surface with antibacterial or anticancer materials often causes considerable harm to the non-cancer mammalian cells on it. We have developed a method to fabricate a biocompatible PDMS surface which not only promotes non-cancer mammalian cell growth but also has antibacterial and anticancer activities, by coating the PDMS surface with a Chinese herb extract, paeonol. Coating changes the wettability and the elemental composition of the PDMS surface. Molecular dynamic simulation indicates that the absorption of paeonol onto the PDMS surface is an energy favourable process. The paeonol-coated PDMS surface exhibits good antibacterial activity against both Gram-positive and Gram-negative bacteria. Moreover considerable antibacterial activity is maintained after the coated surface is rinsed or incubated in water. The coated PDMS surface inhibits bacterial growth on the contact surface and promotes non-cancer mammalian cell growth with low cell toxicity; meanwhile the growth of cancer cells is significantly inhibited. Our study will potentially guide PDMS surface modification approaches to produce biomedical devices. PMID- 27941869 TI - Deterministic composite nanophotonic lattices in large area for broadband applications. AB - Exotic manipulation of the flow of photons in nanoengineered materials with an aperiodic distribution of nanostructures plays a key role in efficiency-enhanced broadband photonic and plasmonic technologies for spectrally tailorable integrated biosensing, nanostructured thin film solarcells, white light emitting diodes, novel plasmonic ensembles etc. Through a generic deterministic nanotechnological route here we show subwavelength-scale silicon (Si) nanostructures on nanoimprinted glass substrate in large area (4 cm2) with advanced functional features of aperiodic composite nanophotonic lattices. These nanophotonic aperiodic lattices have easily tailorable supercell tiles with well defined and discrete lattice basis elements and they show rich Fourier spectra. The presented nanophotonic lattices are designed functionally akin to two dimensional aperiodic composite lattices with unconventional flexibility- comprising periodic photonic crystals and/or in-plane photonic quasicrystals as pattern design subsystems. The fabricated composite lattice-structured Si nanostructures are comparatively analyzed with a range of nanophotonic structures with conventional lattice geometries of periodic, disordered random as well as in plane quasicrystalline photonic lattices with comparable lattice parameters. As a proof of concept of compatibility with advanced bottom-up liquid phase crystallized (LPC) Si thin film fabrication, the experimental structural analysis is further extended to double-side-textured deterministic aperiodic lattice structured 10 MUm thick large area LPC Si film on nanoimprinted substrates. PMID- 27941868 TI - Mosaicism in health and disease - clones picking up speed. AB - Post-zygotic variation refers to genetic changes that arise in the soma of an individual and that are not usually inherited by the next generation. Although there is a paucity of research on such variation, emerging studies show that it is common: individuals are complex mosaics of genetically distinct cells, to such an extent that no two somatic cells are likely to have the exact same genome. Although most types of mutation can be involved in post-zygotic variation, structural genetic variants are likely to leave the largest genomic footprint. Somatic variation has diverse physiological roles and pathological consequences, particularly when acquired variants influence the clonal trajectories of the affected cells. Post-zygotic variation is an important confounder in medical genetic testing and a promising avenue for research: future studies could involve analyses of sorted and single cells from multiple tissue types to fully explore its potential. PMID- 27941870 TI - Chemical ordering in substituted fluorite oxides: a computational investigation of Ho2Zr2O7 and RE2Th2O7 (RE=Ho, Y, Gd, Nd, La). AB - Fluorite-structured oxides find widespread use for applications spanning nuclear energy and waste containment, energy conversion, and sensing. In such applications the host tetravalent cation is often partially substituted by trivalent cations, with an associated formation of charge-compensating oxygen vacancies. The stability and properties of such materials are known to be influenced strongly by chemical ordering of the cations and vacancies, and the nature of such ordering and associated energetics are thus of considerable interest. Here we employ density-functional theory (DFT) calculations to study the structure and energetics of cation and oxygen-vacancy ordering in Ho2Zr2O7. In a recent neutron total scattering study, solid solutions in this system were reported to feature local chemical ordering based on the fluorite-derivative weberite structure. The calculations show a preferred chemical ordering qualitatively consistent with these findings, and yield values for the ordering energy of 9.5 kJ/mol-cation. Similar DFT calculations are applied to additional RE2Th2O7 fluorite compounds, spanning a range of values for the ratio of the tetravalent and trivalent (RE) cation radii. The results demonstrate that weberite-type order becomes destabilized with increasing values of this size ratio, consistent with an increasing energetic preference for the tetravalent cations to have higher oxygen coordination. PMID- 27941874 TI - HRG/HER2/HER3 signaling promotes AhR-mediated Memo-1 expression and migration in colorectal cancer. AB - Colorectal cancer (CRC) is a complex disease with still unsatisfactory prognosis even in western societies, although substantial progress has been made in pre screening programs, surgical techniques and targeted therapy options. Mediator of motility-1 (Memo-1) was previously recognized as an important effector of cell migration downstream of receptor tyrosine kinase signaling in breast cancer. This study identified Memo-1 as frequently overexpressed in CRC and established a close link between extracellular HER2 activation, AhR/ARNT transcriptional activity and Memo-1 expression. Dissection of the hMemo-1 gene promoter using reporter assays and chromatin IP techniques revealed recruitment of Aryl hydrocarbon receptor (AhR)/Aryl hydrocarbon receptor nuclear-translocator (ARNT) complex, which positively influenced Memo-1 expression in cancer cells. We found that Memo-1 depletion negatively influenced the cellular actin network and that its expression is required for HER2-mediated cell migration and invasion. Moreover, analyses of Memo-1 expression in primary CRC revealed correlation with clinical parameters that point to Memo-1 as a new prognostic factor of aggressive disease in CRC patients. Altogether, these observations demonstrate that Memo-1 is an important downstream regulator of HER2-driven CRC cell migration and invasion through connecting extracellular signals from membrane to the cytoskeletal actin network. PMID- 27941871 TI - Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells. AB - Successful chemotherapeutic intervention for management of lung cancer requires an efficient drug delivery system. Gold nanoparticles (GNPs) can incorporate various therapeutics; however, GNPs have limitations as drug carriers. Nano-sized cellular vesicles like exosomes (Exo) can ferry GNP-therapeutic complexes without causing any particle aggregation or immune response. In the present study, we describe the development and testing of a novel Exo-GNP-based therapeutic delivery system -'nanosomes'- for lung cancer therapy. This system consists of GNPs conjugated to anticancer drug doxorubicin (Dox) by a pH-cleavable bond that is physically loaded onto the exosomes (Exo-GNP-Dox). The therapeutic efficacy of Dox in nanosomes was assessed in H1299 and A549 non-small cell lung cancer cells, normal MRC9 lung fibroblasts, and Dox-sensitive human coronary artery smooth muscle cells (HCASM). The enhanced rate of drug release under acidic conditions, successful uptake of the nanosomes by the recipient cells and the cell viability assays demonstrated that nanosomes exhibit preferential cytotoxicity towards cancer cells and have minimal activity on non-cancerous cells. Finally, the underlying mechanism of cytotoxicity involved ROS-mediated DNA damage. Results from this study mark the establishment of an amenable drug delivery vehicle and highlight the advantages of a natural drug carrier that demonstrates reduced cellular toxicity and efficient delivery of therapeutics to cancer cells. PMID- 27941873 TI - SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway. AB - SIRT4 is well-known for its deacetylase activity in energy metabolism, but little is known about its roles in carcinogenesis. We demonstrated that SIRT4 was decreased in 70 out of 133 non-small cell lung cancer (NSCLC) cases by immunohistochemical staining and localized in the mitochondria using confocal microscopy. Low levels of SIRT4 expression was correlated with tumor node metastasis (TNM) stage, histological type of tumor (adenocarcinoma), lymph nodal status, Ki-67 (proliferation index) and poor overall survival. We also studied the biological role of SIRT4 in lung cancer cell lines transfected with SIRT4 plasmid or SIRT4-siRNA. SIRT4 inhibited lung cancer cell proliferation, blocked the cell cycle and repressed cell invasion and migration. Mitochondrial dynamics has been implicated in malignant properties of cells, particularly metastasis that is the major cause of death in patients diagnosed with cancer including lung cancer. This is the first study to identify an association between SIRT4 expression and decreased mitochondrial fission, which was driven by Drp1. SIRT4 inhibited Drp1 phosphorylation and weakened Drp1 recruitment to the mitochondrial membrane via an interaction with Fis-1. SIRT4 expression was lower in nodal metastatic tumor samples than their corresponding primary tumors, and cases with low expression of SIRT4 tended to have high p-Drp1 labeling. Also, MEK/ERK activity appeared to be hampered by SIRT4 expression, which may have implications for cells' invasive capacities. In conclusion, our findings suggest that SIRT4 functions as an important antitumor protein in NSCLC, and should be investigated further with respect to future anticancer strategies. PMID- 27941872 TI - ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation. AB - The mechanisms of initiation of pancreatic ductal adenocarcinoma (PDAC) are still largely unknown. In the present study, we analysed the role of anterior gradient 2 (AGR2) in the earliest stages of pancreatic neoplasia. Immunohistochemical analysis of chronic pancreatitis (CP) and peritumoral areas in PDAC tissues showed that AGR2 was present in tubular complexes (TC) and early pancreatic intraepithelial neoplasia (PanINs). Moreover, AGR2 was also found in discrete subpopulations of non-transformed cells neighbouring these pre-neoplastic lesions. In primary cells derived from human patient-derived xenograft (PDX) model, flow-cytometry revealed that AGR2 was overexpressed in pancreatic cancer stem cells (CSC) compared with non-stem cancer cells. In LSL-KrasG12D;Pdx1-Cre (KC) mouse model Agr2 induction preceded the formation of pre-neoplastic lesions and their development was largely inhibited by Agr2 deletion in engineered LSL KrasG12D;Pdx1-Cre; Agr2-/- mice. In vitro, AGR2 expression was stimulated by tunicamycin-induced endoplasmic reticulum (ER) stress in both KRAS wild-type normal pancreas cells, as well as in KRAS mutated pancreatic cancer cells and was essential for ER homoeostasis. The unfolded protein response proteins GRP78, ATF6 and XBP1s were found expressed in CP and PDAC peritumoral tissues, but in contrast to AGR2, their expression was switched off during TC and PanIN formation. Real-time PCR and ELISA analyses showed that ER stress induced a pro inflammatory phenotype in pancreatic normal, cancer and stellate cells. Moreover, AGR2 expression was inducible by paracrine transfer of ER stress and pro inflammation between different pancreatic cell types. Our findings demonstrate that AGR2 induced in ER-stressed and inflammatory pre-neoplastic pancreas is a potential marker of cancer progenitor cells with an important functional role in PDAC initiation. PMID- 27941875 TI - Transamidase site-targeted agents alter the conformation of the transglutaminase cancer stem cell survival protein to reduce GTP binding activity and cancer stem cell survival. AB - Type 2 transglutaminase (TG2) is an important cancer stem cell survival protein that exists in open and closed conformations. The major intracellular form is the closed conformation that functions as a GTP-binding GTPase and is required for cancer stem cell survival. However, at a finite rate, TG2 transitions to an open conformation that exposes the transamidase catalytic site involved in protein protein crosslinking. The activities are mutually exclusive, as the closed conformation has GTP binding/GTPase activity, and the open conformation transamidase activity. We recently showed that GTP binding, but not transamidase activity, is required for TG2-dependent cancer stem cell invasion, migration and tumour formation. However, we were surprised that transamidase site-specific inhibitors reduce cancer stem cell survival. We now show that compounds NC9, VA4 and VA5, which react exclusively at the TG2 transamidase site, inhibit both transamidase and GTP-binding activities. Transamidase activity is inhibited by direct inhibitor binding at the transamidase site, and GTP binding is blocked because inhibitor interaction at the transamidase site locks the protein in the extended/open conformation to disorganize/inactivate the GTP binding/GTPase site. These findings suggest that transamidase site-specific inhibitors can inhibit GTP binding/signalling by driving a conformation change that disorganizes the TG2 GTP binding to reduce TG2-dependent signalling, and that drugs designed to target this site may be potent anti-cancer agents. PMID- 27941876 TI - Inhibition of KPNA4 attenuates prostate cancer metastasis. AB - Prostate cancer (PCa) is a common cancer in men. Although current treatments effectively palliate symptoms and prolong life, the metastatic PCa remains incurable. It is important to find biomarkers and targets to improve metastatic PCa diagnosis and treatment. Here we report a novel correlation between karyopherin alpha4 (KPNA4) and PCa pathological stages. KPNA4 mediates the cytoplasm-to-nucleus translocation of transcription factors, including nuclear factor kappa B, although its role in PCa was largely unknown. We find that knockdown of KPNA4 reduces cell migration in multiple PCa cell lines, suggesting a role of KPNA4 in PCa progression. Indeed, stable knockdown of KPNA4 significantly reduces PCa invasion and distant metastasis in mouse models. Functionally, KPNA4 alters tumor microenvironment in terms of macrophage polarization and osteoclastogenesis by modulating tumor necrosis factor (TNF) alpha and -beta. Further, KPNA4 is proved as a direct target of miR-708, a tumor suppressive microRNA. We disclose the role of miR-708-KPNA4-TNF axes in PCa metastasis and KPNA4's potential as a novel biomarker for PCa metastasis. PMID- 27941879 TI - Neutrophil extracellular traps: protagonists of cancer progression? AB - Neutrophil extracellular traps (NETs) are a defense mechanism first described to trap and kill bacteria and other pathogens. Increasingly, however, their involvement in the pathogenesis of inflammatory and malignant diseases is being recognized. Several recent studies have suggested important roles of NETs in tumor progression, metastasis and tumor-associated thrombosis. Although systematic studies to address the role of NETs in tumor development are still scarce, we will explore the emerging evidence for NETs as potential protagonists in malignant disease and highlight the mechanisms through which these effects may be exerted. Future questions arising from our current knowledge of direct and indirect interactions between NETs and cancer cells will be outlined and we will explore NETs as candidate pharmaceutical targets in cancer patients. PMID- 27941878 TI - The molecular mechanisms underlying the ERalpha-36-mediated signaling in breast cancer. AB - Alterations in estrogen-mediated cellular signaling have largely been implicated in the pathogenesis of breast cancer. Here, we investigated the signaling regulation of a splice variant of the estrogen receptor, namely estrogen receptor (ERalpha-36), associated with a poor prognosis in breast cancers. Coupling in vitro and in vivo approaches we determined the precise sequential molecular events of a new estrogen signaling network in an ERalpha-negative cell line and in an original patient-derived xenograft. After estrogen treatment, ERalpha-36 rapidly associates with Src at the level of the plasma membrane, initiating downstream cascades, including MEK1/ERK activation and paxillin phosphorylation on S126, which in turn triggers a higher expression of cyclin D1. Of note, the direct binding of ERalpha-36 to ERK2 prevents its dephosphorylation by MKP3 and enhances the downstream signaling. These findings improve our understanding of the regulation of non-genomic estrogen signaling and open new avenues for personalized therapeutic approaches targeting Src or MEK in ERalpha-36-positive patients. PMID- 27941877 TI - Repression of caspase-3 and RNA-binding protein HuR cleavage by cyclooxygenase-2 promotes drug resistance in oral squamous cell carcinoma. AB - A well-studied RNA-binding protein Hu Antigen-R (HuR), controls post transcriptional gene regulation and undergoes stress-activated caspase-3 dependent cleavage in cancer cells. The cleavage products of HuR are known to promote cell death; however, the underlying molecular mechanisms facilitating caspase-3 activation and HuR cleavage remains unknown. Here, we show that HuR cleavage associated with active caspase-3 in oral cancer cells treated with ionizing radiation and chemotherapeutic drug, paclitaxel. We determined that oral cancer cells overexpressing cyclooxygenase-2 (COX-2) limited the cleavage of caspase-3 and HuR, which reduced the rate of cell death in paclitaxel resistant oral cancer cells. Specific inhibition of COX-2 by celecoxib, promoted apoptosis through activation of caspase-3 and cleavage of HuR in paclitaxel-resistant oral cancer cells, both in vitro and in vivo. In addition, oral cancer cells overexpressing cellular HuR increased the half-life of COX-2 mRNA, promoted COX-2 protein expression and exhibited enhanced tumor growth in vivo in comparison with cells expressing a cleavable form of HuR. Finally, our ribonucleoprotein immunoprecipitation and sequencing (RIP-seq) analyses of HuR in oral cancer cells treated with ionizing radiation (IR), determined that HuR cleavage product-1 (HuR CP1) bound and promoted the expression of mRNAs encoding proteins involved in apoptosis. Our results indicated that, cellular non-cleavable HuR controls COX-2 mRNA expression and enzymatic activity. In addition, overexpressed COX-2 protein repressed the cleavage of caspase-3 and HuR to promote drug resistance and tumor growth. Altogether, our observations support the use of the COX-2 inhibitor celecoxib, in combination with paclitaxel, for the management of paclitaxel resistant oral cancer cells. PMID- 27941880 TI - Different in vivo and in vitro transformation of intestinal stem cells in mismatch repair deficiency. AB - Mutations in mismatch repair (MMR) genes result in microsatellite instability (MSI) and early onset of colorectal cancer. To get mechanistic insights into the time scale, sequence and frequency of intestinal stem cell (ISC) transformation, we quantified MSI and growth characteristics of organoids of Msh2-deficient and control mice from birth until tumor formation and related them to tissue gene expression. Although in Msh2-deficient organoids MSI continuously increased from birth, growth characteristics remained stable at first. Months before tumor onset, normal Msh2-deficient tissue contained tumor precursor cells forming organoids with higher MSI, cystic growth and growth rates resembling temporarily those of tumor organoids. Consistently, Msh2-deficient tissue exhibited a tumor like gene signature. Normal Msh2-deficient organoids showed increased inheritable transient cyst-like growth, which became independent of R-spondin. ISC transformation proceeded faster in vitro than in vivo independent of the underlying genotype but more under MMR deficiency. Transient cyst-like growth but not MSI was suppressed by aspirin. In summary, as highlighted by organoids, molecular alterations continuously proceeded long before tumor onset in MMR deficient intestine, thus increasing its susceptibility for ISC transformation. PMID- 27941881 TI - The NADPH oxidase NOX4 represses epithelial to amoeboid transition and efficient tumour dissemination. AB - Epithelial to mesenchymal transition is a common event during tumour dissemination. However, direct epithelial to amoeboid transition has not been characterized to date. Here we provide evidence that cells from hepatocellular carcinoma (HCC), a highly metastatic cancer, undergo epithelial to amoeboid transition in physiological environments, such as organoids or three-dimensional complex matrices. Furthermore, the NADPH oxidase NOX4 inhibits this transition and therefore suppresses efficient amoeboid bleb-based invasion. Moreover, NOX4 expression is associated with E-cadherin levels and inversely correlated with invasive features. NOX4 is necessary to maintain parenchymal structures, increase cell-cell and cell-to-matrix adhesion, and impair actomyosin contractility and amoeboid invasion. Importantly, NOX4 gene deletions are frequent in HCC patients, correlating with higher tumour grade. Contrary to that observed in mesenchymal cell types, here NOX4 suppresses Rho and Cdc42 GTPase expression and downstream actomyosin contractility. In HCC patients, NOX4 expression inversely correlates with RhoC and Cdc42 levels. Moreover, low expression of NOX4 combined with high expression of either RhoC or Cdc42 is associated with worse prognosis. Therefore, loss of NOX4 increases actomyosin levels and favours an epithelial to amoeboid transition contributing to tumour aggressiveness. PMID- 27941882 TI - Use of an anti-viral drug, Ribavirin, as an anti-glioblastoma therapeutic. AB - The median survival for glioblastoma patients is ~15 months despite aggressive surgery and radio-chemotherapy approaches. Thus, developing new therapeutics is necessary to improve the treatment of these invasive brain tumors, which are known to show high levels of the eukaryotic initiation factor, eIF4E, a potent oncogene. Ribavirin, the only clinically approved drug known to target eIF4E, is an anti-viral molecule currently used in hepatitis C treatment. Here, we report the effect of ribavirin on proliferation, cell cycle, cell death and migration of several human and murine glioma cell lines, as well as human glioblastoma stem like cells, in vitro. In addition, we tested ribavirin efficacy in vivo, alone and in combination with temozolomide and radiation. Our work showed that ribavirin inhibits glioma cell growth and migration, and increases cell cycle arrest and cell death, potentially through modulation of the eIF4E, EZH2 and ERK pathways. We also demonstrate that ribavirin treatment in combination with temozolomide or irradiation increases cell death in glioma cells. Finally and most importantly, ribavirin treatment in vivo significantly enhances chemo radiotherapy efficacy and improves survival of rats and mice orthotopically implanted with gliosarcoma tumors or glioma stem-like cells, respectively. On the basis of these results, we propose that ribavirin represents a new therapeutic option for glioblastoma patients as an enhancer of the cytotoxic effects of temozolomide and radiotherapy. PMID- 27941883 TI - The DEAD box protein p68: a novel coactivator of Stat3 in mediating oncogenesis. AB - DEAD box RNA helicase p68 acts as a transcriptional coactivator of several oncogenic transcription factors apart from being a vital player of RNA metabolism. Signal transducer and activator of transcription 3 (Stat3) is a major oncogenic contributor of diverse cancers, including that of colon. Deciphering the mechanistic insights of coactivation of Stat3 transcriptional activity may aid in improved therapeutic strategies. Here we report for the first time a novel mechanism of alliance between p68 and Stat3 in stimulating transcriptional activity of Stat3. Interestingly, we observed that the expression of p68 and Stat3 bears strong positive correlation and significant colocalization in normal and colon carcinoma patient samples. We demonstrated that p68 directly interacts with Stat3 in HEK293 cells as well as multiple colon cancer cell lines. Additionally, p68 positively modulated both mRNA and protein expression levels of Stat3 target genes; promoter activity of Stat3 target gene Mcl-1 in multiple colon cancer cell lines. Also, p68 occupied the promoters of multiple Stat3 target genes in enhancing Stat3-dependent transcription. Moreover, the strong positive correlation between the abundance of p68 and Stat3 target genes in the same set of colon carcinoma samples further supported our observations. Enhanced expression levels of Stat3 target genes observed in primary tumors and metastatic lung nodules, generated in mice colorectal allograft model using syngeneic cells stably expressing p68, further reinforced our in vitro findings. Hence, this study unravels novel modes of p68-mediated oncogenesis through coactivation of Stat3 and enhancing Stat3 signaling. PMID- 27941885 TI - DBC2/RhoBTB2 functions as a tumor suppressor protein via Musashi-2 ubiquitination in breast cancer. AB - The gene encoding 'deleted in breast cancer 2' (DBC2), also referred to as RHOBTB2 (Rho-related BTB domain-containing protein 2), is classified as a tumor suppressor gene. DBC2 is a substrate-specific adaptor protein for a novel class of Cullin-3 (CUL3)-based E3 ubiquitin ligases; however, it is unclear if the substrate adaptor function of DBC2 is required for its tumor suppressor activity. Furthermore, the key substrates of DBC2-mediated ubiquitination have yet to be identified. In the present study, we established a genome-wide human cDNA library based in vitro ubiquitination target screening assay and identified Musashi-2 (MSI2) as a novel ubiquitination target protein of DBC2. MSI2 directly interacted with DBC2, and this interaction promoted MSI2 polyubiquitination and proteasomal degradation in breast cancer cells. Overexpression and knockdown experiments demonstrated that DBC2 suppressed MSI2-associated oncogenic functions and induced apoptosis. Immunohistochemistry analysis of a breast cancer tissue microarray revealed that DBC2 and MSI2 protein levels are inversely correlated in both normal breast tissues and breast cancer tissues. Taken together, these findings provide evidence that DBC2 suppresses tumorigenesis in breast cancer by ubiquitinating MSI2. PMID- 27941884 TI - Emergent role of the fractalkine axis in dissemination of peritoneal metastasis from epithelial ovarian carcinoma. AB - Epithelial ovarian carcinoma is the most common cause of death from gynecologic cancers largely due to advanced, relapsed and chemotherapy-resistant peritoneal metastasis, which is refractory to the currently used treatment approaches. Mechanisms supporting advanced and relapsed peritoneal metastasis are largely unknown, precluding development of more effective targeted therapies. In this study, we investigated the function of a potentially targetable fractalkine axis in the formation and the development of advanced and relapsed peritoneal metastasis and its impact on patients' outcomes. Our mouse model studies support a role for the fractalkine receptor (CX3CR1) in the initiation of peritoneal adhesion important for recolonization of relapsed peritoneal metastasis. We show that downregulation of CX3CR1 results in reduction of metastatic burden at several peritoneal sites commonly colonized by advanced and relapsed metastatic ovarian carcinoma. We show that the chemokine fractalkine (CX3CL1), an activating ligand of CX3CR1, regulates organ-specific peritoneal colonization. High expression of CX3CR1 correlates with significantly shorter survival, specifically in post-menopausal patients with advanced and terminal stages of the disease. Taken together, our studies support a key regulatory role for the fractalkine axis in advanced and relapsed peritoneal metastasis in epithelial ovarian carcinoma. PMID- 27941889 TI - Stochastic quantum Zeno-based detection of noise correlations. AB - A system under constant observation is practically freezed to the measurement subspace. If the system driving is a random classical field, the survival probability of the system in the subspace becomes a random variable described by the Stochastic Quantum Zeno Dynamics (SQZD) formalism. Here, we study the time and ensemble average of this random survival probability and demonstrate how time correlations in the noisy environment determine whether the two averages do coincide or not. These environment time correlations can potentially generate non Markovian dynamics of the quantum system depending on the structure and energy scale of the system Hamiltonian. We thus propose a way to detect time correlations of the environment by coupling a quantum probe system to it and observing the survival probability of the quantum probe in a measurement subspace. This will further contribute to the development of new schemes for quantum sensing technologies, where nanodevices may be exploited to image external structures or biological molecules via the surface field they generate. PMID- 27941886 TI - c-Jun N-terminal kinase promotes stem cell phenotype in triple-negative breast cancer through upregulation of Notch1 via activation of c-Jun. AB - c-Jun N-terminal kinase (JNK) plays a vital role in malignant transformation of different cancers, and JNK is highly activated in basal-like triple-negative breast cancer (TNBC). However, the roles of JNK in regulating cancer stem-like cell (CSC) phenotype and tumorigenesis in TNBC are not well defined. JNK is known to mediate many cellular events via activating c-Jun. Here, we found that JNK regulated c-Jun activation in TNBC cells and that JNK activation correlated with c-Jun activation in TNBC tumors. Furthermore, the expression level of c-Jun was significantly higher in TNBC tumors than in non-TNBC tumors, and high c-Jun mRNA level was associated with shorter disease-free survival of patients with TNBC. Thus, we hypothesized that the JNK/c-Jun signaling pathway contributes to TNBC tumorigenesis. We found that knockdown of JNK1 or JNK2 or treatment with JNK-IN 8, an adenosine triphosphate-competitive irreversible pan-JNK inhibitor, significantly reduced cell proliferation, the ALDH1+ and CD44+/CD24- CSC subpopulations, and mammosphere formation, indicating that JNK promotes CSC self renewal and maintenance in TNBC. We further demonstrated that both JNK1 and JNK2 regulated Notch1 transcription via activation of c-Jun and that the JNK/c-Jun signaling pathway promoted CSC phenotype through Notch1 signaling in TNBC. In a TNBC xenograft mouse model, JNK-IN-8 significantly suppressed tumor growth in a dose-dependent manner by inhibiting acquisition of the CSC phenotype. Taken together, our data demonstrate that JNK regulates TNBC tumorigenesis by promoting CSC phenotype through Notch1 signaling via activation of c-Jun and indicate that JNK/c-Jun/Notch1 signaling is a potential therapeutic target for TNBC. PMID- 27941890 TI - Infection: TSLP complements neutrophil killing of bacteria. PMID- 27941887 TI - Evolution and heterogeneity of non-hereditary colorectal cancer revealed by single-cell exome sequencing. AB - Recently single-cell whole-exome sequencing (scWES) has deeply expanded and sharpened our knowledge of cancer evolution and subclonality. Herein, with scWES and matched bulk whole-exome sequencing (bulk WES) on two colorectal cancer (CRC) patients with normal or adenomatous polyps, we found that both the adenoma and cancer were of monoclonal origin, and both shared partial mutations in the same signaling pathways, but each showed a specific spectrum of heterogeneous somatic mutations. In addition, the adenoma and cancer further developed intratumor heterogeneity with the accumulation of nonrandom somatic mutations specifically in GPCR, PI3K-Akt and FGFR signaling pathways. We identified novel driver mutations that developed during adenoma and cancer evolution, particularly in OR1B1 (GPCR signaling pathway) for adenoma evolution, and LAMA1 (PI3K-Akt signaling pathway) and ADCY3 (FGFR signaling pathway) for CRC evolution. In summary, we demonstrated that both colorectal adenoma and CRC are monoclonal in origin, and the CRCs further diversified into different subclones with heterogeneous mutation profiles accumulating in GPCR, PI3K-Akt and FGFR signaling pathways. ScWES provides evidence for the importance of mutations in certain pathways that would not be as apparent from bulk sequencing of tumors, and can potentially establish whether specific mutations are mutually exclusive or occur sequentially in the same subclone of cells. PMID- 27941888 TI - CIB1 contributes to oncogenic signalling by Ras via modulating the subcellular localisation of sphingosine kinase 1. AB - CIB1 (calcium and integrin binding protein 1) is a small intracellular protein with numerous interacting partners, and hence has been implicated in various cellular functions. Recent studies have revealed emerging roles of CIB1 in regulating cancer cell survival and angiogenesis, although the mechanisms involved have remained largely undefined. In investigating the oncogenic function of CIB1, we initially found that CIB1 is widely up-regulated across a diverse range of cancers, with this upregulation frequently correlating with oncogenic mutations of KRas. Consistent with this, we found that ectopic expression of oncogenic KRas and HRas in cells resulted in elevated CIB1 expression. We previously described the Ca2+-myristoyl switch function of CIB1, and its ability to facilitate agonist-induced plasma membrane localisation of sphingosine kinase 1 (SK1), a location where SK1 is known to elicit oncogenic signalling. Thus, we examined the role this may play in oncogenesis. Consistent with these findings, we demonstrated here that over-expression of CIB1 by itself is sufficient to drive localisation of SK1 to the plasma membrane and enhance the membrane associated enzymatic activity of SK1, as well as its oncogenic signalling. We subsequently demonstrated that elevated levels of CIB1 resulted in full neoplastic transformation, in a manner dependent on SK1. In agreement with our previous findings that SK1 is a downstream mediator of oncogenic signalling by Ras, we found that targeting CIB1 also inhibited neoplastic growth of cells induced by oncogenic Ras, suggesting an important pro-tumorigenic role for CIB1. Thus, we have demonstrated for the first time a role for CIB1 in neoplastic transformation, and revealed a novel mechanism facilitating oncogenic signalling by Ras and SK1. PMID- 27941891 TI - Haematopoiesis: HSC function determined by epigenetic memory. PMID- 27941892 TI - Allergy: Pollutants drive atopic dermatitis. PMID- 27941893 TI - EnhancerPred: a predictor for discovering enhancers based on the combination and selection of multiple features. AB - Enhancers are cis elements that play an important role in regulating gene expression by enhancing it. Recent study of modifications revealed that enhancers are a large group of functional elements with many different subgroups, which have different biological activities and regulatory effects on target genes. As powerful auxiliary tools, several computational methods have been proposed to distinguish enhancers from other regulatory elements, but only one method has been considered to clustering them into subgroups. In this study, we developed a predictor (called EnhancerPred) to distinguish between enhancers and nonenhancers and to determine enhancers' strength. A two-step wrapper-based feature selection method was applied in high dimension feature vector from bi-profile Bayes and pseudo-nucleotide composition. Finally, the combination of 104 features from bi profile Bayes, 1 feature from nucleotide composition and 9 features from pseudo nucleotide composition yielded the best performance for identifying enhancers and nonenhancers, with overall Acc of 77.39%. The combination of 89 features from bi profile Bayes and 10 features from pseudo-nucleotide composition yielded the best performance for identifying strong and weak enhancers, with overall Acc of 68.19%. The process and steps of feature optimization illustrated that it is necessary to construct a particular model for identifying strong enhancers and weak enhancers. PMID- 27941894 TI - Klein tunneling in Weyl semimetals under the influence of magnetic field. AB - Klein tunneling refers to the absence of normal backscattering of electrons even under the case of high potential barriers. At the barrier interface, the perfect matching of electron and hole wavefunctions enables a unit transmission probability for normally incident electrons. It is theoretically and experimentally well understood in two-dimensional relativistic materials such as graphene. Here we investigate the Klein tunneling effect in Weyl semimetals under the influence of magnetic field induced by ferromagnetic stripes placed at barrier boundaries. Our results show that the resonance of Fermi wave vector at specific barrier lengths gives rise to perfect transmission rings, i.e., three dimensional analogue of the so-called magic transmission angles in two dimensional Dirac semimetals. Besides, the transmission profile can be shifted by application of magnetic field in the central region, a property which may be utilized in electro-optic applications. When the applied potential is close to the Fermi level, a particular incident vector can be selected by tuning the magnetic field, thus enabling highly selective transmission of electrons in the bulk of Weyl semimetals. Our analytical and numerical calculations obtained by considering Dirac electrons in three regions and using experimentally feasible parameters can pave the way for relativistic tunneling applications in Weyl semimetals. PMID- 27941895 TI - Tunable optical analog to electromagnetically induced transparency in graphene ring resonators system. AB - The analogue of electromagnetically induced transparency in optical ways has shown great potential in optical delay and quantum-information technology due to its flexible design and easy implementation. The chief drawback for these devices is the bad tunability. Here we demonstrate a tunable optical transparency system formed by graphene-silicon microrings which could control the transparent window by electro-optical means. The device consists of cascaded coupled ring resonators and a graphene/graphene capacitor which integrated on one of the rings. By tuning the Fermi level of the graphene sheets, we can modulate the round-trip ring loss so that the transparency window can be dynamically tuned. The results provide a new method for the manipulation and transmission of light in highly integrated optical circuits and quantum information storage devices. PMID- 27941897 TI - Theoretical analyses of resonant frequency shift in anomalous dispersion enhanced resonant optical gyroscopes. AB - Rigorous expressions of resonant frequency shift (RFS) in anomalous dispersion enhanced resonant optical gyroscopes (ADEROGs) are deduced without making approximation, which provides a precise theoretical guidance to achieve ultra sensitive ADEROGs. A refractive index related modification factor is introduced when considering special theory of relativity (STR). We demonstrate that the RFS will not be "infinitely large" by using critical anomalous dispersion (CAD) and negative modification does not exist, which make the mechanism of anomalous dispersion enhancement clear and coherent. Although step change of RFS will happen when the anomalous dispersion condition varies, the amplification of RFS is limited by attainable variation of refractive index in practice. Moreover, it is shown that the properties of anomalous dispersion will influence not only the amplification of RFS, but also the detection range of ADEROGs. PMID- 27941896 TI - Tissue-engineered 3-dimensional (3D) microenvironment enhances the direct reprogramming of fibroblasts into cardiomyocytes by microRNAs. AB - We have recently shown that a combination of microRNAs, miR combo, can directly reprogram cardiac fibroblasts into functional cardiomyocytes in vitro and in vivo. Reprogramming of cardiac fibroblasts by miR combo in vivo is associated with improved cardiac function following myocardial infarction. However, the efficiency of direct reprogramming in vitro is relatively modest and new strategies beyond the traditional two-dimensional (2D) culture should be identified to improve reprogramming process. Here, we report that a tissue engineered three-dimensional (3D) hydrogel environment enhanced miR combo reprogramming of neonatal cardiac and tail-tip fibroblasts. This was associated with significantly increased MMPs expression in 3D vs. 2D cultured cells, while pharmacological inhibition of MMPs blocked the effect of the 3D culture on enhanced miR combo mediated reprogramming. We conclude that 3D tissue-engineered environment can enhance the direct reprogramming of fibroblasts to cardiomyocytes via a MMP-dependent mechanism. PMID- 27941899 TI - Quantum materials: The quest for ultrafast plasmonics. PMID- 27941900 TI - Femtosecond photo-switching of interface polaritons in black phosphorus heterostructures. AB - The possibility of hybridizing collective electronic motion with mid-infrared light to form surface polaritons has made van der Waals layered materials a versatile platform for extreme light confinement and tailored nanophotonics. Graphene and its heterostructures have attracted particular attention because the absence of an energy gap allows plasmon polaritons to be tuned continuously. Here, we introduce black phosphorus as a promising new material in surface polaritonics that features key advantages for ultrafast switching. Unlike graphene, black phosphorus is a van der Waals bonded semiconductor, which enables high-contrast interband excitation of electron-hole pairs by ultrashort near infrared pulses. Here, we design a SiO2/black phosphorus/SiO2 heterostructure in which the surface phonon modes of the SiO2 layers hybridize with surface plasmon modes in black phosphorus that can be activated by photo-induced interband excitation. Within the Reststrahlen band of SiO2, the hybrid interface polariton assumes surface-phonon-like properties, with a well-defined frequency and momentum and excellent coherence. During the lifetime of the photogenerated electron-hole plasma, coherent hybrid polariton waves can be launched by a broadband mid-infrared pulse coupled to the tip of a scattering-type scanning near-field optical microscopy set-up. The scattered radiation allows us to trace the new hybrid mode in time, energy and space. We find that the surface mode can be activated within ~50 fs and disappears within 5 ps, as the electron-hole pairs in black phosphorus recombine. The excellent switching contrast and switching speed, the coherence properties and the constant wavelength of this transient mode make it a promising candidate for ultrafast nanophotonic devices. PMID- 27941898 TI - Targeted intracellular voltage recordings from dendritic spines using quantum-dot coated nanopipettes. AB - Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot coated nanopipette electrodes (tip diameters ~15-30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5-1 mV) and that the estimated neck resistance (mean 420 MOmega) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures. PMID- 27941901 TI - A Novel Bioreactor System for the Assessment of Endothelialization on Deformable Surfaces. AB - The generation of a living protective layer at the luminal surface of cardiovascular devices, composed of an autologous functional endothelium, represents the ideal solution to life-threatening, implant-related complications in cardiovascular patients. The initial evaluation of engineering strategies fostering endothelial cell adhesion and proliferation as well as the long-term tissue homeostasis requires in vitro testing in environmental model systems able to recapitulate the hemodynamic conditions experienced at the blood-to-device interface of implants as well as the substrate deformation. Here, we introduce the design and validation of a novel bioreactor system which enables the long term conditioning of human endothelial cells interacting with artificial materials under dynamic combinations of flow-generated wall shear stress and wall deformation. The wall shear stress and wall deformation values obtained encompass both the physiological and supraphysiological range. They are determined through separate actuation systems which are controlled based on validated computational models. In addition, we demonstrate the good optical conductivity of the system permitting online monitoring of cell activities through live-cell imaging as well as standard biochemical post-processing. Altogether, the bioreactor system defines an unprecedented testing hub for potential strategies toward the endothelialization or re-endothelialization of target substrates. PMID- 27941902 TI - Protective role for lipid modifications of Src-family kinases against chromosome missegregation. AB - Src-family tyrosine kinases, which are expressed in various cell types, play critical roles in cell signalling at the cytoplasmic side of the plasma membrane through their lipid modifications. Src-family kinases are cotranslationally myristoylated and posttranslationally palmitoylated in the amino-terminal region. The Src-family member Lyn contains a myristoylation site at glycine-2 and a palmitoylation site at cysteine-3, whereas c-Src has a myristoylation site at glycine-2 but not any palmitoylation sites. However, little is known about the role for lipid modifications of Src-family kinases in cell division. Here, we show that non-lipid-modified Lyn and c-Src, Lyn(G2A/C3A) and c-Src(G2A), are delocalized from membranes to the cytoplasm and the nucleus, which gives rise to a significant increase in the rate of chromosome missegregation, such as chromosome lagging and anaphase chromosome bridging, in a tyrosine kinase activity-dependent manner. Treatment with the Src inhibitor PP2 shows that the kinase activity of non-lipid-modified, non-membrane-bound Src during M phase is critical for giving rise to chromosome missegregation. Given that only a fraction of Src-family kinases fails in lipid modifications during biosynthesis, these results suggest that Src's membrane anchorage through their lipid modifications from prophase to anaphase plays a protective role against induction of chromosome missegregation. PMID- 27941903 TI - A Novel Method for Estimating Myocardial Strain: Assessment of Deformation Tracking Against Reference Magnetic Resonance Methods in Healthy Volunteers. AB - We developed a novel method for tracking myocardial deformation using cardiac magnetic resonance (CMR) cine imaging. We hypothesised that circumferential strain using deformation-tracking has comparable diagnostic performance to a validated method (Displacement Encoding with Stimulated Echoes- DENSE) and potentially diagnostically superior to an established cine-strain method (feature tracking). 81 healthy adults (44.6 +/- 17.7 years old, 47% male), without any history of cardiovascular disease, underwent CMR at 1.5 T including cine, DENSE, and late gadolinium enhancement in subjects >45 years. Acquisitions were divided into 6 segments, and global and segmental peak circumferential strain were derived and analysed by age and sex. Peak circumferential strain differed between the 3 groups (DENSE: -19.4 +/- 4.8%; deformation-tracking: -16.8 +/- 2.4%; feature-tracking: -28.7 +/- 4.8%) (ANOVA with Tukey post-hoc, F-value 279.93, p < 0.01). DENSE and deformation-tracking had better reproducibility than feature tracking. Intra-class correlation co-efficient was >0.90. Larger magnitudes of strain were detected in women using deformation-tracking and DENSE, but not feature-tracking. Compared with a reference method (DENSE), deformation-tracking using cine imaging has similar diagnostic performance for circumferential strain assessment in healthy individuals. Deformation-tracking could potentially obviate the need for bespoke strain sequences, reducing scanning time and is more reproducible than feature-tracking. PMID- 27941904 TI - The role of GRIP1 and ephrin B3 in blood pressure control and vascular smooth muscle cell contractility. AB - Several erythropoietin-producing hepatocellular receptor B family (EPHB) and their ligands, ephrinBs (EFNBs), are involved in blood pressure regulation in animal models. We selected 528 single nucleotide polymorphisms (SNPs) within the genes of EPHB6, EFNB2, EFNB3 and GRIP1 in the EPH/EFN signalling system to query the International Blood Pressure Consortium dataset. A SNP within the glutamate receptor interacting protein 1 (GRIP1) gene presented a p-value of 0.000389, approaching the critical p-value of 0.000302, for association with diastolic blood pressure of 60,396 individuals. According to echocardiography, we found that Efnb3 gene knockout mice showed enhanced constriction in the carotid arteries. In vitro studies revealed that in mouse vascular smooth muscle cells, siRNA knockdown of GRIP1, which is in the EFNB3 reverse signalling pathway, resulted in increased contractility of these cells. These data suggest that molecules in the EPHB/EFNB signalling pathways, specifically EFNB3 and GRIP1, are involved blood pressure regulation. PMID- 27941905 TI - A nomogram improves AJCC stages for colorectal cancers by introducing CEA, modified lymph node ratio and negative lymph node count. AB - Lymph node stages (pN stages) are primary contributors to survival heterogeneity of the 7th AJCC staging system for colorectal cancer (CRC), indicating spaces for modifications. To implement the modifications, we selected eligible CRC patients from the Surveillance Epidemiology and End Results (SEER) database as participants in a training (n = 6675) and a test cohort (n = 6760), and verified tumor deposits to be metastatic lymph nodes to derive modified lymph node count (mLNC), lymph node ratio (mLNR), and positive lymph node count (mPLNC). After multivariate Cox regression analyses with forward stepwise elimination of the mLNC and mPLNC for the training cohort, a nomogram was constructed to predict overall survival (OS) via incorporating preoperative carcinoembryonic antigen, pT stages, negative lymph node count, mLNR and metastasis. Internal validations of the nomogram showed concordance indexes (c-index) of 0.750 (95% CI, 0.736-0.764) and 0.749 before and after corrections for overfitting. Serial performance evaluations indicated that the nomogram outperformed the AJCC stages (c-index = 0.725) with increased accuracy, net benefits, risk assessment ability, but comparable complexity and clinical validity. All the results were reproducible in the test cohort. In summary, the proposed nomogram may serve as an alternative to the AJCC stages. However, validations with longer follow-up periods are required. PMID- 27941906 TI - Exploration of the Optimal Minimum Lymph Node Count after Colon Cancer Resection for Patients Aged 80 Years and Older. AB - The elderly colon cancer (CC) patients are increasing and represent a heterogeneous patient group. The objectives of this study were to identify the features of lymph node examination and to explore the optimal minimum lymph node count after CC resection for patients aged >=80. Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 65719 CC patients in stage I-III between 2004 and 2012, 26.0% of patients were aged >=80. The median node count decreased with increasing age, which were 25.5, 20.2, 17.8 and 16.9 for patients aged 20-39, 40-59, 60-79, and >=80. The rate of >=12 nodes and the rate of node positivity for patients aged >=80 were obviously lower than younger patients. Using X-tile analysis, we determined 9 nodes as the optimal node count for patients aged >=80. Then, we compared the 5-year cancer specific survival (CSS) between patients with >=9 nodes and <9 nodes. The results showed the 5-year CSSs were improved for patients with >=9 nodes. Furthermore, the rate of node positivity and survival under the 9-node measure were equal to 12-node measure. Therefore, the lymph node examination should be discriminately evaluated for elder patients, and 9-node measure was available for patients aged >=80. PMID- 27941907 TI - Identification of specific biomarkers for gastric adenocarcinoma by ITRAQ proteomic approach. AB - The aim of this study was to identify biomarkers for gastric cancer (GC) by iTRAQ. Using proteins extracted from a panel of 4 pairs of gastric adenocarcinoma samples (stage III-IV, Her-2 negative), we identified 10 up regulated and 9 down regulated proteins in all four pairs of GC samples compared to adjacent normal gastric tissue. The up regulated proteins are mainly involved in cell motility, while the down regulated proteins are mitochondrial enzymes involved in energy metabolism. The expression of three up regulated proteins (ANXA1, NNMT, fibulin 5) and one of the down regulated proteins (UQCRC1) was validated by Western Blot in 97 GC samples. ANXA1 was up regulated in 61.36% of stage I/II GC samples compared to matched adjacent normal gastric tissue, and its expression increased further in stage III/IV samples. Knockdown of ANXA1 by siRNA significantly inhibited GC cell migration and invasion, whereas over expression of ANXA1 promoted migration and invasion. We found decreased expression of UQCRC1 in all stages of GC samples. Our data suggest that increased cell motility and decreased mitochondrial energy metabolism are important hallmarks during the development of GC. PMID- 27941908 TI - Association of Bicipital Peritendinous Effusion with Subacromial Impingement: A Dynamic Ultrasonographic Study of 337 Shoulders. AB - Bicipital peritendinous effusion (BPE) is the most common biceps tendon abnormality and can be related to various shoulder ultrasonographic findings. Since the association of BPE with subacromial impingement is unclear, our study aimed to explore its association with the dynamic subacromial impingement test during ultrasound (US) imaging. We included 337 shoulders referred for US examinations and quantified the amount of BPE. Effusion more than 1 mm in thickness was considered a positive finding. A comparison of three grades of subacromial impingement, adjusted by patient demographics, static sonographic shoulder pathology, and physical findings, by using multivariate regression models revealed that the odds ratio of subacromial impingement (with 95% confidence intervals) in the presence of BPE was 6.54 (3.21-13.32) in grade 1, 6.93 (3.05-15.76) in grade 2 and 3.18 (1.48-6.80) in grade 3. An increase in age, subdeltoid bursitis, full-thickness supraspinatus tendon tear, and shoulder stiffness were also associated with BPE. Since our study demonstrated a positive association of BPE with all grades of impingement, a US dynamic subacromial impingement test is suggested when BPE is present. Future prospective studies are needed to identify changes in BPE after treatment. PMID- 27941909 TI - Chaos and Hyperchaos in a Model of Ribosome Autocatalytic Synthesis. AB - Any vital activities of the cell are based on the ribosomes, which not only provide the basic machinery for the synthesis of all proteins necessary for cell functioning during growth and division, but for biogenesis itself. From this point of view, ribosomes are self-replicating and autocatalytic structures. In current work we present an elementary model in which the autocatalytic synthesis of ribosomal RNA and proteins, as well as enzymes ensuring their degradation are described with two monotonically increasing functions. For certain parameter values, the model, consisting of one differential equation with delayed argument, demonstrates both stationary and oscillatory dynamics of the ribosomal protein synthesis, which can be chaotic and hyperchaotic dependent on the value of the delayed argument. The biological interpretation of the modeling results and parameter estimation suggest the feasibility of chaotic dynamics in molecular genetic systems of eukaryotes, which depends only on the internal characteristics of functioning of the translation system. PMID- 27941911 TI - Adiporedoxin suppresses endothelial activation via inhibiting MAPK and NF-kappaB signaling. AB - Adiporedoxin (Adrx) is a recently discovered redox regulatory protein that is preferentially expressed in adipose tissue and plays a critical role in the regulation of metabolism via its modulation of adipocyte protein secretion. We here report that Adrx suppresses endothelial cell activation via inhibiting MAPK and NF-kB signaling pathways. Adrx is constitutively expressed in human vascular endothelial cells, and significantly induced by a variety of stimuli such as TNFalpha, IL-1beta, H2O2 and OxLDL. Overexpression of Adrx significantly attenuated TNFalpha-induced expression of VCAM-1 and ICAM-1, and thus reduced monocyte adherence to human umbilical vein endothelial cells (HUVECs). Conversely, siRNA-mediated knockdown of Adrx increased TNFalpha-induced expression of adhesion molecules and monocyte adherence to HUVECs. Furthermore, forced expression of Adrx decreased TNFalpha-induced activation of ERK1/2, JNK, p38 and IKKs in HUVECs. Adrx mutant in the CXXC motif that lost its anti-redox activity is less efficient than the wild-type Adrx, suggesting that Adrx-mediated inhibition of endothelial activation is partially dependent on its antioxidant activity. Finally, Adrx expression was markedly increased in human atheroma compared with normal tissue from the same carotid arteries. These results suggest that Adrx is an endogenous inhibitor of endothelial activation, and might be a therapeutic target for vascular inflammatory diseases. PMID- 27941910 TI - Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT. AB - 3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [123I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [123I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [123I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA induced serotonergic toxicity in the brains of the non-human primate. PMID- 27941912 TI - Quantitative determination and toxicity evaluation of 2,4-dichlorophenol using poly(eosin Y)/hydroxylated multi-walled carbon nanotubes modified electrode. AB - This study aimed at developing simple, sensitive and rapid electrochemical approach to quantitatively determine and assess the toxicity of 2,4 dichlorophenol (2,4-DCP), a priority pollutant and has potential risk to public health through a novel poly(eosin Y, EY)/hydroxylated multi-walled carbon nanotubes composite modified electrode (PEY/MWNTs-OH/GCE). The distinct feature of this easy-fabricated electrode was the synergistic coupling effect between EY and MWNTs-OH that enabled a high electrocatalytic activity to 2,4-DCP. Under optimum conditions, the oxidation peak current enhanced linearly with concentration increasing from 0.005 to 0.1 MUM and 0.2 to 40.0 MUM, and revealed the detection limit of 1.5 nM. Moreover, the PEY/MWNTs-OH/GCE exhibited excellent electrocatalytic activity toward intracellular electroactive species. Two sensitive electrochemical signals ascribed to guanine/xanthine and adenine/hypoxanthine in human hepatoma (HepG2) cells were detected simultaneously. The sensor was successfully applied to evaluate the toxicity of 2,4-DCP to HepG2 cells. The IC50 values based on the two electrochemical signals are 201.07 and 252.83 MUM, respectively. This study established a sensitive platform for the comprehensive evaluation of 2,4-DCP and posed a great potential to simplify environmental toxicity monitoring. PMID- 27941913 TI - Choroidal fissure acts as an overflow device in cerebrospinal fluid drainage: morphological comparison between idiopathic and secondary normal-pressure hydrocephalus. AB - To clarify the pathogenesis of two different types of adult-onset normal-pressure hydrocephalus (NPH), we investigated cerebrospinal fluid distribution on the high field three-dimensional MRI. The subarachnoid spaces in secondary NPH were smaller than those in the controls, whereas those in idiopathic NPH were of similar size to the controls. In idiopathic NPH, however, the basal cistern and Sylvian fissure were enlarged in concurrence with ventricular enlargement towards the z-direction, but the convexity subarachnoid space was severely diminished. In this article, we provide evidence that the key cause of the disproportionate cerebrospinal fluid distribution in idiopathic NPH is the compensatory direct CSF communication between the inferior horn of the lateral ventricles and the ambient cistern at the choroidal fissure. In contrast, all parts of the subarachnoid spaces were equally and severely decreased in secondary NPH. Blockage of CSF drainage from the subarachnoid spaces could cause the omnidirectional ventricular enlargement in secondary NPH. PMID- 27941915 TI - Fully transparent flexible tin-doped zinc oxide thin film transistors fabricated on plastic substrate. AB - In this work, we have successfully fabricated bottom gate fully transparent tin doped zinc oxide thin film transistors (TZO TFTs) fabricated on flexible plastic substrate at low temperature by RF magnetron sputtering. The effect of O2/Ar gas flow ratio during channel deposition on the electrical properties of TZO TFTs was investigated, and we found that the O2/Ar gas flow ratio have a great influence on the electrical properties. TZO TFTs on flexible substrate has very nice electrical characteristics with a low off-state current (Ioff) of 3 pA, a high on/off current ratio of 2 * 107, a high saturation mobility (MUsat) of 66.7 cm2/V*s, a steep subthreshold slope (SS) of 333 mV/decade and a threshold voltage (Vth) of 1.2 V. Root-Mean-Square (RMS) roughness of TZO thin film is about 0.52 nm. The transmittance of TZO thin film is about 98%. These results highlight that the excellent device performance can be realized in TZO film and TZO TFT can be a promising candidate for flexible displays. PMID- 27941914 TI - High fidelity visualization of cell-to-cell variation and temporal dynamics in nascent extracellular matrix formation. AB - Extracellular matrix dynamics are key to tissue morphogenesis, homeostasis, injury, and repair. The spatiotemporal organization of this matrix has profound biological implications, but is challenging to monitor using standard techniques. Here, we address these challenges by using noncanonical amino acid tagging to fluorescently label extracellular matrix synthesized in the presence of bio orthogonal methionine analogs. This strategy labels matrix proteins with high resolution, without compromising their distribution or mechanical function. We demonstrate that the organization and temporal dynamics of the proteinaceous matrix depend on the biophysical features of the microenvironment, including the biomaterial scaffold and the niche constructed by cells themselves. Pulse labeling experiments reveal that, in immature constructs, nascent matrix is highly fibrous and interdigitates with pre-existing matrix, while in more developed constructs, nascent matrix lacks fibrous organization and is retained in the immediate pericellular space. Inhibition of collagen crosslinking increases matrix synthesis, but compromises matrix organization. Finally, these data demonstrate marked cell-to-cell heterogeneity amongst both chondrocytes and mesenchymal stem cells undergoing chondrogenesis. Collectively, these results introduce fluorescent noncanonical amino acid tagging as a strategy to investigate spatiotemporal matrix organization, and demonstrate its ability to identify differences in phenotype, microenvironment, and matrix assembly at the single cell level. PMID- 27941916 TI - LncRNAs expression profiling in normal ovary, benign ovarian cyst and malignant epithelial ovarian cancer. AB - Long noncoding RNA (lncRNA) has been recognized as a regulator of gene expression, and the dysregulation of lncRNAs is involved in the progression of many types of cancer, including epithelial ovarian cancer (EOC). To explore the potential roles of lncRNAs in EOC, we performed lncRNA and mRNA microarray profiling in malignant EOC, benign ovarian cyst and healthy control tissues. In this study, 663 transcripts of lncRNAs were found to be differentially expressed in malignant EOC compared with benign and normal control tissues. We also selected 18 altered lncRNAs to confirm the validity of the microarray analysis using quantitative real-time PCR (qPCR). Pathway and Gene Ontology (GO) analyses demonstrated that these altered transcripts were involved in multiple biological processes, especially the cell cycle. Furthermore, Series Test of Cluster (STC) and lncRNA-mRNA co-expression network analyses were conducted to predict lncRNA expression trends and the potential target genes of lncRNAs. We also determined that two antisense lncRNAs (RP11-597D13.9 and ADAMTS9-AS1) were associated with their nearby coding genes (FAM198B, ADAMTS9), which participated in cancer progression. This study offers helpful information to understand the initiation and development mechanisms of EOC. PMID- 27941918 TI - Profiling bacterial communities associated with sediment-based aquaculture bioremediation systems under contrasting redox regimes. AB - Deposit-feeding invertebrates are proposed bioremediators in microbial-driven sediment-based aquaculture effluent treatment systems. We elucidate the role of the sediment reduction-oxidation (redox) regime in structuring benthic bacterial communities, having direct implications for bioremediation potential and deposit feeder nutrition. The sea cucumber Holothuria scabra was cultured on sediments under contrasting redox regimes; fully oxygenated (oxic) and redox stratified (oxic-anoxic). Taxonomically, metabolically and functionally distinct bacterial communities developed between the redox treatments with the oxic treatment supporting the greater diversity; redox regime and dissolved oxygen levels were the main environmental drivers. Oxic sediments were colonised by nitrifying bacteria with the potential to remediate nitrogenous wastes. Percolation of oxygenated water prevented the proliferation of anaerobic sulphate-reducing bacteria, which were prevalent in the oxic-anoxic sediments. At the predictive functional level, bacteria within the oxic treatment were enriched with genes associated with xenobiotics metabolism. Oxic sediments showed the greater bioremediation potential; however, the oxic-anoxic sediments supported a greater sea cucumber biomass. Overall, the results indicate that bacterial communities present in fully oxic sediments may enhance the metabolic capacity and bioremediation potential of deposit-feeder microbial systems. This study highlights the benefits of incorporating deposit-feeding invertebrates into effluent treatment systems, particularly when the sediment is oxygenated. PMID- 27941919 TI - Multiplex CRISPR/Cas9-based genome engineering enhanced by Drosha-mediated sgRNA shRNA structure. AB - The clustered regularly interspaced short palindromic repeats (CRISPR) system has recently been developed into a powerful genome-editing technology, as it requires only two key components (Cas9 protein and sgRNA) to function and further enables multiplex genome targeting and homology-directed repair (HDR) based precise genome editing in a wide variety of organisms. Here, we report a novel and interesting strategy by using the Drosha-mediated sgRNA-shRNA structure to direct Cas9 for multiplex genome targeting and precise genome editing. For multiplex genome targeting assay, we achieved more than 9% simultaneous mutant efficiency for 3 genomic loci among the puromycin-selected cell clones. By introducing the shRNA against DNA ligase IV gene (LIG4) into the sgRNA-shRNA construct, the HDR based precise genome editing efficiency was improved as more than 2-fold. Our works provide a useful tool for multiplex and precise genome modifying in mammalian cells. PMID- 27941917 TI - Oxidative stress and carbon metabolism influence Aspergillus flavus transcriptome composition and secondary metabolite production. AB - Contamination of crops with aflatoxin is a serious global threat to food safety. Aflatoxin production by Aspergillus flavus is exacerbated by drought stress in the field and by oxidative stress in vitro. We examined transcriptomes of three toxigenic and three atoxigenic isolates of A. flavus in aflatoxin conducive and non-conducive media with varying levels of H2O2 to investigate the relationship of secondary metabolite production, carbon source, and oxidative stress. We found that toxigenic and atoxigenic isolates employ distinct mechanisms to remediate oxidative damage, and that carbon source affected the isolates' expression profiles. Iron metabolism, monooxygenases, and secondary metabolism appeared to participate in isolate oxidative responses. The results suggest that aflatoxin and aflatrem biosynthesis may remediate oxidative stress by consuming excess oxygen and that kojic acid production may limit iron-mediated, non-enzymatic generation of reactive oxygen species. Together, secondary metabolite production may enhance A. flavus stress tolerance, and may be reduced by enhancing host plant tissue antioxidant capacity though genetic improvement by breeding selection. PMID- 27941920 TI - Adaptive use of interaction torque during arm reaching movement from the optimal control viewpoint. AB - The study aimed at investigating the extent to which the brain adaptively exploits or compensates interaction torque (IT) during movement control in various velocity and load conditions. Participants performed arm pointing movements toward a horizontal plane without a prescribed reach endpoint at slow, neutral and rapid speeds and with/without load attached to the forearm. Experimental results indicated that IT overall contributed to net torque (NT) to assist the movement, and that such contribution increased with limb inertia and instructed speed and led to hand trajectory variations. We interpreted these results within the (inverse) optimal control framework, assuming that the empirical arm trajectories derive from the minimization of a certain, possibly composite, cost function. Results indicated that mixing kinematic, energetic and dynamic costs was necessary to replicate the participants' adaptive behavior at both kinematic and dynamic levels. Furthermore, the larger contribution of IT to NT was associated with an overall decrease of the kinematic cost contribution and an increase of its dynamic/energetic counterparts. Altogether, these results suggest that the adaptive use of IT might be tightly linked to the optimization of a composite cost which implicitly favors more the kinematic or kinetic aspects of movement depending on load and speed. PMID- 27941922 TI - Universal structural parameter to quantitatively predict metallic glass properties. AB - Quantitatively correlating the amorphous structure in metallic glasses (MGs) with their physical properties has been a long-sought goal. Here we introduce 'flexibility volume' as a universal indicator, to bridge the structural state the MG is in with its properties, on both atomic and macroscopic levels. The flexibility volume combines static atomic volume with dynamics information via atomic vibrations that probe local configurational space and interaction between neighbouring atoms. We demonstrate that flexibility volume is a physically appropriate parameter that can quantitatively predict the shear modulus, which is at the heart of many key properties of MGs. Moreover, the new parameter correlates strongly with atomic packing topology, and also with the activation energy for thermally activated relaxation and the propensity for stress-driven shear transformations. These correlations are expected to be robust across a very wide range of MG compositions, processing conditions and length scales. PMID- 27941921 TI - p53 activates miR-192-5p to mediate vancomycin induced AKI. AB - Pathogenic role of p53 in AKI remains controversial and the underlying mechanism is unclear. Here, we tested whether the inhibition of p53 may ameliorate vancomycin (VAN) induced acute kidney injury (AKI). Mice with p53 knock out (p53 KO) were resistant to VAN induced AKI, indicated by the analysis of renal function, histology, and apoptosis. Mechanistically, AKI was associated with the upregulation of several known p53 target genes, including Bax and p21, and this association was attenuated in p53-KO mice. Furthermore, the expression of miR-192 5p was significantly decreased in the p53-KO kidney tissues. In human renal tubular epithelial cell line (HK-2), VAN induced p53 accumulation and miR-192-5p expression. Both apoptosis of HK-2 cells and expression of miR-192-5p were also suppressed by pifithrin-alpha. Anti-miR-192-5p significantly blocked VAN-induced apoptosis and caspase activity in HK-2 cells. Consistently, in vivo inhibition of miR-192-5p also suppressed VAN induced AKI. Thus, we provided clinical and genetic evidence that p53 was associated with the development of VAN induced AKI through upregulation of miR-192-5p. PMID- 27941923 TI - Variability of outcome reporting in Hirschsprung's Disease and gastroschisis: a systematic review. AB - Heterogeneity in outcome reporting limits identification of gold-standard treatments for Hirschsprung's Disease(HD) and gastroschisis. This review aimed to identify which outcomes are currently investigated in HD and gastroschisis research so as to counter this heterogeneity through informing development of a core outcome set(COS). Two systematic reviews were conducted. Studies were eligible for inclusion if they compared surgical interventions for primary treatment of HD in review one, and gastroschisis in review two. Studies available only as abstracts were excluded from analysis of reporting transparency. Thirty five HD studies were eligible for inclusion in the review, and 74 unique outcomes were investigated. The most commonly investigated was faecal incontinence (32 studies, 91%). Seven of the 28 assessed studies (25%) met all criteria for transparent outcome reporting. Thirty gastroschisis studies were eligible for inclusion in the review, and 62 unique outcomes were investigated. The most commonly investigated was length of stay (24 studies, 80%). None of the assessed studies met all criteria for transparent outcome reporting. This review demonstrates that heterogeneity in outcome reporting and a significant risk of reporting bias exist in HD and gastroschisis research. Development of a COS could counter these problems, and the outcome lists developed from this review could be used in that process. PMID- 27941925 TI - The concept of entropic rectifier facing experiments. AB - The transport of molecules in confined media is subject to entropic barriers. So theoretically, asymmetry of the confinement length may lead to molecular ratchets with entropy as the only driving force for the biased transport. We address experimentally this question by performing alternative ionic current measurements on electrolytes confined in neutral conical nanopores. In case anions and cations widely differ in size, we show that rectification of ionic current can be obtained that depends on ions size and cycle frequency, consistently with the entropic ratchet mechanism. PMID- 27941924 TI - Conditional repair by locally switching the thermal healing capability of dynamic covalent polymers with light. AB - Healable materials could play an important role in reducing the environmental footprint of our modern technological society through extending the life cycles of consumer products and constructions. However, as most healing processes are carried out by heat alone, the ability to heal damage generally kills the parent material's thermal and mechanical properties. Here we present a dynamic covalent polymer network whose thermal healing ability can be switched 'on' and 'off' on demand by light, thereby providing local control over repair while retaining the advantageous macroscopic properties of static polymer networks. We employ a photoswitchable furan-based crosslinker, which reacts with short and mobile maleimide-substituted poly(lauryl methacrylate) chains forming strong covalent bonds while simultaneously allowing the reversible, spatiotemporally resolved control over thermally induced de- and re-crosslinking. We reason that our system can be adapted to more complex materials and has the potential to impact applications in responsive coatings, photolithography and microfabrication. PMID- 27941926 TI - Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-kappaB pathway. AB - Osteoarthritis is a disease with inflammatory and catabolic imbalance in cartilage. Dihydroartemisinin (DHA), a natural and safe anti-malarial agent, has been reported to inhibit inflammation, but its effects on chondrocytes have yet to be elucidated. We investigated the effects of DHA on catabolism in chondrocytes. Viability of SD rats chondrocytes was analyzed. Autophagy levels were determined via expression of autophagic markers LC3 and ATG5, GFP-LC3 analysis, acridine orange staining, and electron microscopy. ATG5 siRNA induced autophagic inhibition. Catabolic gene and chemokine expression was evaluated using qPCR. The NF-kappaB inhibitor SM7368 and p65 over-expression were used to analyze the role of NF-kappaB pathway in autophagic activation. A concentration of 1 MUM DHA without cytotoxicity increased LC3-II and ATG5 levels as well as autophagosomal numbers in chondrocytes. DHA inhibited TNF-alpha-induced expression of MMP-3 and -9, ADAMTS5, CCL-2 and -5, and CXCL1, which was reversed by autophagic inhibition. TNF-alpha-stimulated nuclear translocation and degradation of the p65 and IkappaBalpha proteins, respectively, were attenuated in DHA-treated chondrocytes. NF-kappaB inhibition activated autophagy in TNF alpha-treated chondrocytes, but p65 over-expression reduced the autophagic response to DHA. These results indicate that DHA might suppress the levels of catabolic and inflammatory factors in chondrocytes by promoting autophagy via NF kappaB pathway inhibition. PMID- 27941927 TI - Observation of spin Seebeck contribution to the transverse thermopower in Ni-Pt and MnBi-Au bulk nanocomposites. AB - Transverse thermoelectric devices produce electric fields perpendicular to an incident heat flux. Classically, this process is driven by the Nernst effect in bulk solids, wherein a magnetic field generates a Lorentz force on thermally excited electrons. The spin Seebeck effect also produces magnetization-dependent transverse electric fields. It is traditionally observed in thin metallic films deposited on electrically insulating ferromagnets, but the films' high resistance limits thermoelectric conversion efficiency. Combining Nernst and spin Seebeck effect in bulk materials would enable devices with simultaneously large transverse thermopower and low electrical resistance. Here we demonstrate experimentally that this is possible in composites of conducting ferromagnets (Ni or MnBi) containing metallic nanoparticles with strong spin-orbit interactions (Pt or Au). These materials display positive shifts in transverse thermopower attributable to inverse spin Hall electric fields in the nanoparticles. This more than doubles the power output of the Ni-Pt materials, establishing proof of principle that the spin Seebeck effect persists in bulk nanocomposites. PMID- 27941928 TI - Dual matter-wave inertial sensors in weightlessness. AB - Quantum technology based on cold-atom interferometers is showing great promise for fields such as inertial sensing and fundamental physics. However, the finite free-fall time of the atoms limits the precision achievable on Earth, while in space interrogation times of many seconds will lead to unprecedented sensitivity. Here we realize simultaneous 87Rb-39K interferometers capable of operating in the weightless environment produced during parabolic flight. Large vibration levels (10-2 g Hz-1/2), variations in acceleration (0-1.8 g) and rotation rates (5 degrees s-1) onboard the aircraft present significant challenges. We demonstrate the capability of our correlated quantum system by measuring the Eotvos parameter with systematic-limited uncertainties of 1.1 * 10-3 and 3.0 * 10-4 during standard- and microgravity, respectively. This constitutes a fundamental test of the equivalence principle using quantum sensors in a free-falling vehicle. Our results are applicable to inertial navigation, and can be extended to the trajectory of a satellite for future space missions. PMID- 27941929 TI - Characterization of enterovirus 71 infection and associated outbreak of Hand, Foot, and Mouth Disease in Shawo of China in 2012. AB - Infection of enterovirus 71 (EV71) and associated hand, foot, and mouth disease (HFMD) are recognized as emerging public health issues worldwide. Hundreds of thousands of children are annually infected with EV71 and develop HFMD in China alone. Studies of EV71 infection are critical to the treatment and prevention of the associated HFMD outbreaks. In this report, we studied an outbreak of 105 HFMD cases in Shawo Township of China between September to October 2012. More than 90% of cases were children younger than 9 years old, with over 50% of cases aged 3-6 years old. Laboratory studies detected a high prevalence of EV71 and suggested EV71 as the most common enterovirus causing HFMD in Shawo. Sequencing analysis showed that the EV71 strains from Shawo belong to the C4 subgenotype, and are phylogenetically more related to those from the distant city of Nanchang than those from the nearby city of Wuhan with distinct variations. More girls were found to be associated with EV71 in Shawo whereas more boys were associated with EV71 in Wuhan and Nanchang. Our studies further the understanding of the molecular epidemiological features of HFMD and infection by enteroviruses in China. PMID- 27941930 TI - ERK-mediated NF-kappaB activation through ASIC1 in response to acidosis. AB - Acidic microenvironment is a common feature of solid tumors. We have previously shown that neuron specific acid-sensing ion channel 1 (ASIC1) is expressed in breast cancer, and it is responsible for acidosis-induced cellular signaling through AKT, leading to nuclear factor-kappaB (NF-kappaB) activation, and cell invasion and metastasis. However, AKT is frequently activated in cancer. Thus, a key question is whether ASIC1-mediated cell signaling still takes place in the cancer cells carrying constitutively active AKT. In the present study, we show that among four prostate cancer cell lines tested, 22Rv1 cells express the highest level of phosphorylated AKT that is not impacted by acidosis. However, acidosis can still induce NF-kappaB activation during which extracellular signal regulated kinase (ERK) serves as an alternative pathway for ASIC-mediated cell signaling. Inhibition of ERK by chemical inhibitors or small interfering RNAs suppresses the acidosis-induced NF-kappaB activity through regulation of the inhibitory subunit IkappaBalpha phosphorylation. Furthermore, suppression of ASIC1-mediated generation of reactive oxygen species (ROS) by ROS scavengers, such as glutathione or N-acetyl-cysteine causes a decrease in ERK phosphorylation and degradation of IkappaBalpha. Finally, ASIC1 is upregulated in a subset of prostate cancer cases and ASIC1 knockout by CRISPR/Cas9 significantly suppresses cell invasion, and castration resistance both in vitro and in vivo. Together, these results support the significance of ASIC1-ROS-ERK-IkappaBalpha-NF-kappaB axis in prostate tumorigenesis, especially in the constitutively active AKT background. PMID- 27941931 TI - In vivo functional dissection of a context-dependent role for Hif1alpha in pancreatic tumorigenesis. AB - Hypoxia-inducible factor 1alpha (Hif1alpha) is a key regulator of cellular adaptation and survival under hypoxic conditions. In pancreatic ductal adenocarcinoma (PDAC), it has been recently shown that genetic ablation of Hif1alpha accelerates tumour development by promoting tumour-supportive inflammation in mice, questioning its role as the key downstream target of many oncogenic signals of PDAC. Likely, Hif1alpha has a context-dependent role in pancreatic tumorigenesis. To further analyse this, murine PDAC cell lines with reduced Hif1alpha expression were generated using shRNA transfection. Cells were transplanted into wild-type mice through orthotopic or portal vein injection in order to test the in vivo function of Hif1alpha in two major tumour-associated biological scenarios: primary tumour growth and remote colonization/metastasis. Although Hif1alpha protects PDAC cells from stress-induced cell deaths in both scenarios-in line with the general function Hif1alpha-its depletion leads to different oncogenic consequences. Hif1alpha depletion results in rapid tumour growth with marked hypoxia-induced cell death, which potentially leads to a persistent tumour-sustaining inflammatory response. However, it simultaneously reduces tumour colonization and hepatic metastases by increasing the susceptibility to anoikis induced by anchorage-independent conditions. Taken together, the role of Hif1alpha in pancreatic tumorigenesis is context-dependent. Clinical trials of Hif1alpha inhibitors need to take this into account, targeting the appropriate scenario, for example palliative vs adjuvant therapy. PMID- 27941933 TI - Transplantation: Efficacy of rapid steroid withdrawal after induction therapy. PMID- 27941932 TI - Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression. AB - Sharpin (Shank-associated RH domain-interacting protein, also known as SIPL1) is a multifunctional molecule that participates in various biological settings, including nuclear factor-kappaB signaling activation and tumor suppressor gene inhibition. Sharpin is upregulated in various types of cancers, including hepatocellular carcinoma (HCC), and is implicated in tumor progression. However, the exact roles of Sharpin in tumorigenesis and tumor progression remain largely unknown. Here we report novel mechanisms of HCC progression through Sharpin overexpression. In our study, Sharpin was upregulated in human HCC tissues. Increased Sharpin expression enhanced hepatoma cell invasion, whereas decrease in Sharpin expression by RNA interference inhibited invasion. Microarray analysis identified that Versican, a chondroitin sulfate proteoglycan that plays crucial roles in tumor progression and invasion, was also upregulated in Sharpin expressing stable cells. Versican expression increased in the majority of HCC tissues and knocking down of Versican greatly attenuated hepatoma cell invasion. Sharpin expression resulted in a significant induction of Versican transcription synergistically with Wnt/beta-catenin pathway activation. Furthermore, Sharpin overexpressing cells had high tumorigenic properties in vivo. These results demonstrate that Sharpin promotes Versican expression synergistically with the Wnt/beta-catenin pathway, potentially contributing to HCC development. A Sharpin/Versican axis could be an attractive therapeutic target for this currently untreatable cancer. PMID- 27941934 TI - The global burden of chronic kidney disease: estimates, variability and pitfalls. AB - Chronic kidney disease (CKD) is currently defined by abnormalities of kidney structure or function assessed using a matrix of variables - including glomerular filtration rate (GFR), thresholds of albuminuria and duration of injury - and is considered by many to be a common disorder globally. However, estimates of CKD prevalence vary widely, both within and between countries. The reasons for these variations are manifold, and include true regional differences in CKD prevalence, vagaries of using estimated GFR (eGFR) for identifying CKD, issues relating to the use of set GFR thresholds to define CKD in elderly populations, and concerns regarding the use of one-off testing for assessment of eGFR or albuminuria to define the prevalence of CKD in large-scale epidemiological studies. Although CKD is common, the suggestion that its prevalence is increasing in many countries might not be correct. Here, we discuss the possible origins of differences in estimates of CKD prevalence, and present possible solutions for tackling the factors responsible for the reported variations in GFR measurements. The strategies we discuss include approaches to improve testing methodologies for more accurate assessment of GFR, to improve awareness of factors that can alter GFR readouts, and to more accurately stage CKD in certain populations, including the elderly. PMID- 27941936 TI - Neural Pathway of Renovative and Innovative Products Appreciation. AB - According to the level of change an invention makes on existing things and how it overrides people's mental schemas on established categories, new inventions can be classified into two groups: incremental inventions (i.e., renovations), which make minor improvements on existing designs, and radical inventions (i.e., innovations), which make major developments that enable people to do things they have never been able to do before. Although innovation and renovation are two fundamentally different types of creation that feature new changes ranging from those in product development to those in large scale social changes, and people tend to report higher subjective preferences for incremental inventions compared to radical inventions, the cognitive brain mechanisms underlying the mental representation of these two types of inventions remains unknown. Through the use of innovative and renovative designs as materials, we found that relative to non creative designs, creative (renovative &innovative) designs enhanced memory or association-related activation in the right parahippocampus. In particular, innovations evoked more activation in the conceptual pathway for representing objects than did renovations, whereas renovations evoked more activation in the motor pathway than innovations. These results suggest that operating experiences may provide advantages for understanding and appreciating creative designs. PMID- 27941937 TI - NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha 2b therapy of chronic hepatitis B. AB - A pressing need exists for improved therapeutic options for chronic hepatitis B (CHB). Pegylated-interferon-alpha (Peg-IFN-alpha) achieves sustained off treatment responses in many cases because of its direct anti-viral effects and regulation of the immune response. However, non-responsiveness to Peg-IFN-alpha is frequent, and the mechanism is poorly understood. In this study, we found that the frequency and absolute number of NKp30+ natural killer (NK) cells increased markedly, accompanied by enhanced CD107a and IFN-gamma production, during Peg-IFN alpha-2b monotherapy or combination therapy with adefovir dipivoxil in patients with CHB, especially in responders. The responders and non-responders differed in the frequency of polyfunctional IFN-gamma+ CD107+ NK cells. In addition, the increase in NKp30+ NK cells was negatively correlated with the HBV viral load and plasma HBeAg. Moreover, it was found that IL-15 may contribute to the up regulation of NKp30 on the NK cells, and this up-regulation was not induced in vitro by Peg-IFN-alpha-2b alone. However, in the non-responders, these NKp30+ NK cells were dysfunctional because of increased NKG2A expression, which partly explains the inactivation of NKp30+ NK cells and the reduced capacity of these cells to produce antiviral cytokines. These findings may provide a new mechanism to explain the variable efficacy of Peg-IFN-alpha-2b therapy. PMID- 27941935 TI - Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. AB - The kidney has a pivotal role in maintaining glucose homeostasis by using glucose as a metabolic fuel, by producing glucose through gluconeogenesis, and by reabsorbing all filtered glucose through the sodium-glucose cotransporters SGLT1 and SGLT2 located in the proximal tubule. In patients with diabetes, the maximum glucose reabsorptive capacity (TmG) of the kidney, as well as the threshold for glucose spillage into the urine, are elevated, contributing to the pathogenesis of hyperglycaemia. By reducing the TmG and, more importantly, the threshold of glucosuria, SGLT2 inhibitors enhance glucose excretion, leading to a reduction in fasting and postprandial plasma glucose levels and improvements in both insulin secretion and insulin sensitivity. The beneficial effects of SGLT2 inhibition extend beyond glycaemic control, however, with new studies demonstrating that inhibition of renal glucose reabsorption reduces blood pressure, ameliorates glucotoxicity and induces haemodynamic effects that lead to improved cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. In this Review we examine the role of SGLT2 and SGLT1 in the regulation of renal glucose reabsorption in health and disease and the effect of SGLT2 inhibition on renal function, glucose homeostasis, and cardiovascular disease. PMID- 27941938 TI - Effects of Exendin-4 on human adipose tissue inflammation and ECM remodelling. AB - BACKGROUND/OBJECTIVES: Subjects with type-2 diabetes are typically obese with dysfunctional adipose tissue (AT). Glucagon-like peptide-1 (GLP-1) analogues are routinely used to improve glycaemia. Although, they also aid weight loss that improves AT function, their direct effect on AT function is unclear. To explore GLP-1 analogues' influence on human AT's cytokine and extracellular matrix (ECM) regulation, we therefore obtained and treated omental (OMAT) and subcutaneous (SCAT) AT samples with Exendin-4, an agonist of the GLP-1 receptor (GLP-1R). SUBJECTS/METHODS: OMAT and abdominal SCAT samples obtained from women during elective surgery at the Royal Devon & Exeter Hospital (UK) were treated with increasing doses of Exendin-4. Changes in RNA expression of adipokines, inflammatory cytokines, ECM components and their regulators were assessed and protein secretion analysed by ELISA. GLP-1R protein accumulation was compared in paired AT depot samples. RESULTS: Exendin-4 induced an increase in OMAT adiponectin (P=0.02) and decrease in elastin expression (P=0.03) in parallel with reduced elastin secretion (P=0.04). In contrast to OMAT, we did not observe an effect on SCAT. There was no change in the expression of inflammatory markers (CD14, TNFA, MCP-1), collagens, TGFB1 or CTGF. GLP-1R accumulation was higher in SCAT. CONCLUSIONS: Independently of weight loss, which may bias findings of in vivo studies, GLP-1 analogues modify human OMAT physiology favourably by increasing the insulin-sensitising cytokine adiponectin. However, the reduction of elastin and no apparent effect on AT's inflammatory cytokines suggest that GLP 1 analogues may be less beneficial to AT function, especially if there is no associated weight loss. PMID- 27941939 TI - Testosterone supplementation improves glucose homeostasis despite increasing hepatic insulin resistance in male mouse model of type 2 diabetes mellitus. AB - Clinical studies have revealed that testosterone supplementation had a positive effect on glucose homeostasis in type 2 diabetes mellitus (T2DM), but did not address how testosterone supplementation affected insulin responsiveness in the liver, a key glucose homeostatic organ. In this study, we aimed to study the effect of testosterone supplementation on hepatic insulin responsiveness and glucose homeostasis through liver in male high-fat diet-induced T2DM mice. Testosterone treatment to T2DM animals showed reduced hepatic glucose output. Testosterone inhibited the insulin signaling in liver, thus increased insulin resistance. However, testosterone treatment inactivated GSK3alpha independent of PI3K/AKT pathway and inhibited FOXO1 By interaction of androgen receptor to FOXO1 and downregulated PEPCK, causing repression of gluconeogenic pathway, which is otherwise upregulated in T2DM, resulted in better glucose homeostasis. PMID- 27941940 TI - Kefir peptides prevent high-fructose corn syrup-induced non-alcoholic fatty liver disease in a murine model by modulation of inflammation and the JAK2 signaling pathway. AB - OBJECTIVE: In recent years, people have changed their eating habits, and high fructose-containing bubble tea has become very popular. High-fructose intake has been suggested to be a key factor that induces non-alcoholic fatty liver disease (NAFLD). Kefir, a fermented milk product composed of microbial symbionts, has demonstrated numerous biological activities, including antibacterial, antioxidant and immunostimulating effects. The present study aims to evaluate the effects of kefir peptides on high-fructose-induced hepatic steatosis and the possible molecular mechanism. RESULTS: An animal model of 30% high-fructose-induced NAFLD in C57BL/6J mice was established. The experiment is divided into the following six groups: (1) normal: H2O drinking water; (2) mock: H2O+30% fructose; (3) KL: low-dose kefir peptides (50 mg kg-1)+30% fructose; (4) KM: medium-dose kefir peptides (100 mg kg-1)+30% fructose; (5) KH: high-dose kefir peptides (150 mg kg 1)+30% fructose; and (6) CFM: commercial fermented milk (100 mg kg-1)+30% fructose. The results show that kefir peptides improve fatty liver syndrome by decreasing body weight, serum alanine aminotransferase, triglycerides, insulin and hepatic triglycerides, cholesterol, and free fatty acids as well as the inflammatory cytokines (TNF-alpha, IL-6 and IL-1beta) that had been elevated in fructose-induced NAFLD mice. In addition, kefir peptides markedly increased phosphorylation of AMPK to downregulate its targeted enzymes, ACC (acetyl-CoA carboxylase) and SREBP-1c (sterol regulatory element-binding protein 1), and inhibited de novo lipogenesis. Furthermore, kefir peptides activated JAK2 to stimulate STAT3 phosphorylation, which can translocate to the nucleus, and upregulated several genes, including the CPT1 (carnitine palmitoyltransferase-1) involved in fatty acid oxidation. CONCLUSION: Our data have demonstrated that kefir peptides can improve the symptoms of NAFLD, including body weight, energy intake, inflammatory reaction and the formation of fatty liver by activating JAK2 signal transduction through the JAK2/STAT3 and JAK2/AMPK pathways in the high fructose-induced fatty liver animal model. Therefore, kefir peptides may have the potential for clinical application for the prevention or treatment of clinical metabolic syndrome. PMID- 27941942 TI - Construction of A Triple-Stimuli-Responsive System Based on Cerium Oxide Coated Mesoporous Silica Nanoparticles. AB - In this work, a triple-stimuli (GSH, pH and light irradiation) responsive system were designed based on CeO2 nanoparticles (CeO2 NPs) coated doxorubicin (DOX) and photosensitizer hematoporphyrin (HP) dual-loaded mesoporous silica nanoparticles (MSN). Upon entering into cancer cells, both high concentration of intracellular GSH and low pH environment would reduce CeO2 NPs to cerium ions, accompanied with the degradation of CeO2 NPs and the conformational change of HP under light irradiation, the preloaded DOX are thus released from the nanocarrier, resulting in a contrast fluorescence enhancement. Meanwhile, 1O2 generated from HP for potential photodynamic therapy (PDT) upon light irradiation. In comparison, not much influence can be observed for normal cells. This nanosystem not only has a significantly enhanced efficacy for cancer cells but also broad the scope for the future design and applications of multifunctional platforms for synergetic chemotherapy and PDT. PMID- 27941941 TI - Potentiation of Amitriptyline Anti-Hyperalgesic-Like Action By Astroglial Connexin 43 Inhibition in Neuropathic Rats. AB - Antidepressants, prescribed as first line treatment of neuropathic pain, have a limited efficacy and poorly tolerated side effects. Because recent studies pointed out the implication of astroglial connexins (Cx) in both neuropathic pain and antidepressive treatment, we investigated whether their blockade by mefloquine could modulate the action of the tricyclic antidepressant amitriptyline. Using primary cultures, we found that both mefloquine and amitriptyline inhibited Cx43-containing gap junctions, and that the drug combination acted synergically. We then investigated whether mefloquine could enhance amitriptyline efficacy in a preclinical model of neuropathic pain. Sprague-Dawley rats that underwent chronic unilateral constriction injury (CCI) to the sciatic nerve (SN) were treated with either amitriptyline, mefloquine or the combination of both drugs. Whereas acute treatments were ineffective, chronic administration of amitriptyline reduced CCI-SN-induced hyperalgesia-like behavior, and this effect was markedly enhanced by co-administration of mefloquine, which was inactive on its own. No pharmacokinetic interactions between both drugs were observed and CCI-SN-induced neuroinflammatory and glial activation markers remained unaffected by these treatments in dorsal root ganglia and spinal cord. Mechanisms downstream of CCI-SN-induced neuroinflammation and glial activation might therefore be targeted. Connexin inhibition in astroglia could represent a promising approach towards improving neuropathic pain therapy by antidepressants. PMID- 27941943 TI - Transcriptomic insights into the allelopathic effects of the garlic allelochemical diallyl disulfide on tomato roots. AB - Garlic is an allelopathic crop that can alleviate the obstacles to continuous cropping of vegetable crops. Diallyl disulfide (DADS), one of the most important allelochemicals in garlic, promotes tomato root growth. Therefore, the global transcriptome profiles of DADS-treated tomato roots over time were investigated to reveal the potential growth-promoting mechanisms. We detected 1828, 1296 and 1190 differentially expressed genes (DEGs) in the 4, 24 and 48 h samples, respectively. Most DEGs involved in assimilatory sulfate reduction and glutathione metabolism were up-regulated after short-term (4 h) DADS treatment. In addition, increased activity of defensive enzymes and up-regulation of six peroxidase genes were observed, suggesting that DADS could induce tomato resistance. In plant-pathogen interactions, DEGs related to calcium signaling were primarily inhibited, while those encoding pathogenesis-related proteins were primarily up-regulated. Although plant hormone synthesis and signal transduction were both significantly affected by DADS, the expression trends of the genes in these two pathways were conflicting. This research provides comprehensive information concerning the changes in the tomato root transcriptome affected by DADS and may help direct further studies on DADS-responsive genes to enhance the current understanding of the mechanisms by which DADS alleviates the obstacles to continuous cropping. PMID- 27941944 TI - N-tert-butylmethanimine N-oxide is an efficient spin-trapping probe for EPR analysis of glutathione thiyl radical. AB - The electron spin resonance (EPR) spin-trapping technique allows detection of radical species with nanosecond half-lives. This technique is based on the high rates of addition of radicals to nitrones or nitroso compounds (spin traps; STs). The paramagnetic nitroxides (spin-adducts) formed as a result of reactions between STs and radical species are relatively stable compounds whose EPR spectra represent "structural fingerprints" of the parent radical species. Herein we report a novel protocol for the synthesis of N-tert-butylmethanimine N-oxide (EBN), which is the simplest nitrone containing an alpha-H and a tertiary alpha' C atom. We present EPR spin-trapping proof that: (i) EBN is an efficient probe for the analysis of glutathione thiyl radical (GS*); (ii) beta-cyclodextrins increase the kinetic stability of the spin-adduct EBN/*SG; and (iii) in aqueous solutions, EBN does not react with superoxide anion radical (O2-*) to form EBN/*OOH to any significant extent. The data presented complement previous studies within the context of synthetic accessibility to EBN and efficient spin trapping analysis of GS*. PMID- 27941945 TI - High-resolution transcript profiling reveals shoot abscission process of spruce dwarf mistletoe Arceuthobium sichuanense in response to ethephon. AB - Arceuthobium (dwarf mistletoes) are hemiparasites that may cause great damage to infected trees belonging to Pinaceae and Cupressaceae. Currently, dwarf mistletoe control involves the use of the ethylene-producing product ethephon (ETH), which acts by inducing dwarf mistletoe shoot abscission. However, the process by which ETH functions is mostly unknown. Therefore, the transcriptome of the ETH-exposed plants was compared to non-exposed controls to identify genes associated with the response to ethephon. In this study, the reference transcriptome was contained 120,316 annotated unigenes, with a total of 21,764 ETH-responsive differentially expressed unigenes were identified. These ETH-associated genes clustered into 20 distinctly expressed pattern groups, providing a view of molecular events with good spatial and temporal resolution. As expected, the greatest number of unigenes with changed expression were observed at the onset of abscission, suggesting induction by ethylene. ETH also affected genes associated with shoot abscission processes including hormone biosynthesis and signaling, cell wall hydrolysis and modification, lipid transference, and more. The comprehensive transcriptome data set provides a wealth of genomic resources for dwarf mistletoe communities and contributes to a better understanding of the molecular regulatory mechanism of ethylene-caused shoots abscission. PMID- 27941946 TI - Using deep belief network modelling to characterize differences in brain morphometry in schizophrenia. AB - Neuroimaging-based models contribute to increasing our understanding of schizophrenia pathophysiology and can reveal the underlying characteristics of this and other clinical conditions. However, the considerable variability in reported neuroimaging results mirrors the heterogeneity of the disorder. Machine learning methods capable of representing invariant features could circumvent this problem. In this structural MRI study, we trained a deep learning model known as deep belief network (DBN) to extract features from brain morphometry data and investigated its performance in discriminating between healthy controls (N = 83) and patients with schizophrenia (N = 143). We further analysed performance in classifying patients with a first-episode psychosis (N = 32). The DBN highlighted differences between classes, especially in the frontal, temporal, parietal, and insular cortices, and in some subcortical regions, including the corpus callosum, putamen, and cerebellum. The DBN was slightly more accurate as a classifier (accuracy = 73.6%) than the support vector machine (accuracy = 68.1%). Finally, the error rate of the DBN in classifying first-episode patients was 56.3%, indicating that the representations learned from patients with schizophrenia and healthy controls were not suitable to define these patients. Our data suggest that deep learning could improve our understanding of psychiatric disorders such as schizophrenia by improving neuromorphometric analyses. PMID- 27941947 TI - Bursaphelenchus xylophilus and B. mucronatus secretomes: a comparative proteomic analysis. AB - The pinewood nematode, Bursaphelenchus xylophilus, recognized as a worldwide major forest pest, is a migratory endoparasitic nematode with capacity to feed on pine tissues and also on fungi colonizing the trees. Bursaphelenchus mucronatus, the closest related species, differs from B. xylophilus on its pathogenicity, making this nematode a good candidate for comparative analyses. Secretome profiles of B. xylophilus and B. mucronatus were obtained and proteomic differences were evaluated by quantitative SWATH-MS. From the 681 proteins initially identified, 422 were quantified and compared between B. xylophilus and B. mucronatus secretomes and from these, 243 proteins were found differentially regulated: 158 and 85 proteins were increased in B. xylophilus and B. mucronatus secretomes, respectively. While increased proteins in B. xylophilus secretome revealed a strong enrichment in proteins with peptidase activity, the increased proteins in B. mucronatus secretome were mainly related to oxidative stress responses. The changes in peptidases were evaluated at the transcription level by RT-qPCR, revealing a correlation between the mRNA levels of four cysteine peptidases with secretion levels. The analysis presented expands our knowledge about molecular basis of B. xylophilus and B. mucronatus hosts interaction and supports the hypothesis of a key role of secreted peptidases in B. xylophilus pathogenicity. PMID- 27941948 TI - Additional energy scale in SmB6 at low-temperature. AB - Topological insulators give rise to exquisite electronic properties because of their spin-momentum locked Dirac-cone-like band structure. Recently, it has been suggested that the required opposite parities between valence and conduction band along with strong spin-orbit coupling can be realized in correlated materials. Particularly, SmB6 has been proposed as candidate material for a topological Kondo insulator. Here we observe, by utilizing scanning tunnelling microscopy and spectroscopy down to 0.35 K, several states within the hybridization gap of about +/-20 meV on well characterized (001) surfaces of SmB6. The spectroscopic response to impurities and magnetic fields allows to distinguish between dominating bulk and surface contributions to these states. The surface contributions develop particularly strongly below about 7 K, which can be understood in terms of a suppressed Kondo effect at the surface. Our high resolution data provide insight into the electronic structure of SmB6, which reconciles many current discrepancies on this compound. PMID- 27941949 TI - In vitro effects of the small-molecule protein kinase C agonists on HIV latency reactivation. AB - The persistence of latently HIV-infected cellular reservoirs represents the major obstacle to virus eradication in patients under antiretroviral therapy (ART). Cure strategies to eliminate these reservoirs are thus needed to reactivate proviral gene expression in latently infected cells. In this study, we tested optimal concentrations of PKC agonist candidates (PEP005/Ingenol-3-angelate, prostratin, bryostatin-1, and JQ1) to reactivate HIV latency in vitro, and examined their effects on cell survival, activation and epigenetic histone methylation after treatment alone or in combination in cell line and isolated CD4 T cells from SIV-infected macaques. The results showed that PKC agonists increased cell activation with different degrees of latency reactivation, concomitant with reduced levels of histone methylation. With increasing concentrations, prostratin and byrostain-1 treatment rapidly reduced cell survival and cell activation. The PKC agonist combinations, or in combination with JQ1, led to modest levels of synergistic reactivation of HIV. Remarkably, PEP005 treatment alone caused marked reactivation of HIV latency, similar to PMA stimulation. These findings suggested that PEP005 alone, as indicated its lower cytotoxicity and lower effective dose inducing maximal reactivation, might be a candidate for effectively reactivating HIV latency as part of a therapeutic strategy for HIV infection. PMID- 27941950 TI - Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice. AB - The present study aimed to determine the effect of thyroid hormone dysfunction on brown adipose tissue activity and white adipose tissue browning in mice. Twenty randomized female C57BL/6NTac mice per treatment group housed at room temperature were rendered hypothyroid or hyperthyroid. In-vivo small animal 18F-FDG PET/MRI was performed to determine the effects of hypo- and hyperthyroidism on BAT mass and BAT activity. Ex-vivo14C-acetate loading assay and assessment of thermogenic gene and protein expression permitted analysis of oxidative and thermogenic capacities of WAT and BAT of eu-, hyper and hypothyroid mice. 18F-FDG PET/MRI revealed a lack of brown adipose tissue activity in hypothyroid mice, whereas hyperthyroid mice displayed increased BAT mass alongside enhanced 18F-FDG uptake. In white adipose tissue of both, hyper- and hypothyroid mice, we found a significant induction of thermogenic genes together with multilocular adipocytes expressing UCP1. Taken together, these results suggest that both the hyperthyroid and hypothyroid state stimulate WAT thermogenesis most likely as a consequence of enhanced adrenergic signaling or compensation for impaired BAT function, respectively. PMID- 27941953 TI - Thermal imaging of spin Peltier effect. AB - The Peltier effect modulates the temperature of a junction comprising two different conductors in response to charge currents across the junction, which is used in solid-state heat pumps and temperature controllers in electronics. Recently, in spintronics, a spin counterpart of the Peltier effect was observed. The 'spin Peltier effect' modulates the temperature of a magnetic junction in response to spin currents. Here we report thermal imaging of the spin Peltier effect; using active thermography technique, we visualize the temperature modulation induced by spin currents injected into a magnetic insulator from an adjacent metal. The thermal images reveal characteristic distribution of spin current-induced heat sources, resulting in the temperature change confined only in the vicinity of the metal/insulator interface. This finding allows us to estimate the actual magnitude of the temperature modulation induced by the spin Peltier effect, which is more than one order of magnitude greater than previously believed. PMID- 27941951 TI - Inhibition of the processing of miR-25 by HIPK2-Phosphorylated-MeCP2 induces NOX4 in early diabetic nephropathy. AB - Phosphorylated methyl-CpG binding protein2 (p-MeCP2) suppresses the processing of several microRNAs (miRNAs). Homeo-domain interacting protein kinase2 (HIPK2) phosphorylates MeCP2, a known transcriptional repressor. However, it is not known if MeCP2 and HIPK2 are involved in processing of miRNAs implicated in diabetic nephropathy. p-MeCP2 and HIPK2 levels were significantly increased, but Seven in Absentia Homolog1 (SIAH1), which mediates proteasomal degradation of HIPK2, was decreased in the glomeruli of streptozotocin injected diabetic mice. Among several miRNAs, miR-25 and its precursor were significantly decreased in diabetic mice, whereas primary miR-25 levels were significantly increased. NADPH oxidase4 (NOX4), a target of miR-25, was significantly increased in diabetic mice. Protein levels of p-MeCP2, HIPK2, and NOX4 were increased in high glucose (HG)- or TGF beta-treated mouse glomerular mesangial cells (MMCs). miR-25 (primary, precursor, and mature) and mRNA levels of genes indicated in the in vivo study showed similar trends of regulation in MMCs treated with HG or TGF-beta. The HG- or TGF beta-induced upregulation of p-MeCP2, NOX4 and primary miR-25, but downregulation of precursor and mature miR-25, were attenuated by Hipk2 siRNA. These results demonstrate a novel role for the SIAH1/HIPK2/MeCP2 axis in suppressing miR-25 processing and thereby upregulating NOX4 in early diabetic nephropathy. PMID- 27941954 TI - Boron doped graphene wrapped silver nanowires as an efficient electrocatalyst for molecular oxygen reduction. AB - Metal nanowires exhibit unusually high catalytic activity towards oxygen reduction reaction (ORR) due to their inherent electronic structures. However, controllable synthesis of stable nanowires still remains as a daunting challenge. Herein, we report the in situ synthesis of silver nanowires (AgNWs) over boron doped graphene sheets (BG) and demonstrated its efficient electrocatalytic activity towards ORR for the first time. The electrocatalytic ORR efficacy of BG AgNW is studied using various voltammetric techniques. The BG wrapped AgNWs shows excellent ORR activity, with very high onset potential and current density and it followed four electron transfer mechanism with high methanol tolerance and stability towards ORR. The results are comparable to the commercially available 20% Pt/C in terms of performance. PMID- 27941952 TI - A novel approach to quantify different iron forms in ex-vivo human brain tissue. AB - We propose a novel combination of methods to study the physical properties of ferric ions and iron-oxide nanoparticles in post-mortem human brain, based on the combination of Electron Paramagnetic Resonance (EPR) and SQUID magnetometry. By means of EPR, we derive the concentration of the low molecular weight iron pool, as well as the product of its electron spin relaxation times. Additionally, by SQUID magnetometry we identify iron mineralization products ascribable to a magnetite/maghemite phase and a ferrihydrite (ferritin) phase. We further derive the concentration of magnetite/maghemite and of ferritin nanoparticles. To test out the new combined methodology, we studied brain tissue of an Alzheimer's patient and a healthy control. Finally, we estimate that the size of the magnetite/maghemite nanoparticles, whose magnetic moments are blocked at room temperature, exceeds 40-50 nm, which is not compatible with the ferritin protein, the core of which is typically 6-8 nm. We believe that this methodology could be beneficial in the study of neurodegenerative diseases such as Alzheimer's Disease which are characterized by abnormal iron accumulation in the brain. PMID- 27941958 TI - Adherence to a Gluten-Free Diet in Mexican Subjects with Gluten-Related Disorders: A High Prevalence of Inadvertent Gluten Intake. AB - BACKGROUND: The rate of compliance with a gluten-free diet in patients with gluten-related disorders is unknown in most Latin American countries. OBJECTIVE: To study the adherence to a gluten-free diet of Mexican individuals with celiac disease and nonceliac gluten sensitivity at the time of their first medical and nutritional consultation at a tertiary referral center. METHODS: A cross sectional study was performed. A specific questionnaire was used to gather information on demographics, clinical condition, and self-reported adherence to a gluten-free diet, and to determine strict compliance and intentional or inadvertent gluten consumption. All questionnaires were applied by a nutritionist with expertise in gluten-related disorders. RESULTS: Fifty-six patients with celiac disease and 24 with non-celiac gluten sensitivity were included. Overall, 46 (57.5%) subjects perceived themselves as strictly adherent; however, inadvertent gluten intake was frequent in both celiac disease and non-celiac gluten sensitivity patients (39.2 vs. 33.3%; p = 0.2). Intentional consumption was more prevalent in subjects with celiac disease (48.8 vs. 29.1%; p = 0.048) and individuals with non-celiac gluten sensitivity showed better adherence (37.5 vs. 12.5%; p = 0.035). CONCLUSIONS: The importance of a gluten-free diet is underestimated by Mexican patients with celiac disease. The role of a team with expertise in gluten-related disorders is essential to identify inadvertent gluten intake. PMID- 27941955 TI - Diversity, abundance and activity of ammonia-oxidizing microorganisms in fine particulate matter. AB - Increasing ammonia emissions could exacerbate air pollution caused by fine particulate matter (PM2.5). Therefore, it is of great importance to investigate ammonia oxidation in PM2.5. This study investigated the diversity, abundance and activity of ammonia oxidizing archaea (AOA), ammonia oxidizing bacteria (AOB) and complete ammonia oxidizers (Comammox) in PM2.5 collected in Beijing-Tianjin-Hebei megalopolis, China. Nitrosopumilus subcluster 5.2 was the most dominant AOA. Nitrosospira multiformis and Nitrosomonas aestuarii were the most dominant AOB. Comammox were present in the atmosphere, as revealed by the occurrence of Candidatus Nitrospira inopinata in PM2.5. The average cell numbers of AOA, AOB and Ca. N. inopinata were 2.82 * 104, 4.65 * 103 and 1.15 * 103 cell m-3 air, respectively. The average maximum nitrification rate of PM2.5 was 0.14 MUg (NH4+ N) [m3 air.h]-1. AOA might account for most of the ammonia oxidation, followed by Comammox, while AOB were responsible for a small part of ammonia oxidation. Statistical analyses showed that Nitrososphaera subcluster 4.1 was positively correlated with organic carbon concentration, and Nitrosomonas eutropha showed positive correlation with ammonia concentration. Overall, this study expanded our knowledge concerning AOA, AOB and Comammox in PM2.5 and pointed towards an important role of AOA and Comammox in ammonia oxidation in PM2.5. PMID- 27941957 TI - Invasive and Complicated Pneumococcal Infection in Patients with Cancer. AB - BACKGROUND: In susceptible patients, Streptococcus pneumoniae can cause complicated pneumonia and invasive pneumococcal disease. The aim of this study was to assess the clinical and antimicrobial features of complicated and invasive pneumococcal disease in patients with cancer. METHODS: We conducted a retrospective study including all S. pneumoniae isolates between January 1, 2007 and December 31, 2015 in an oncology center. Capsular serotyping was done in isolates from sterile sites. RESULTS: There were 103 episodes: 69 with invasive pneumococcal disease and 34 with complicated pneumonia. Sixty-two patients were male (60%); mean age was 50 years. Eighty-four isolates were susceptible to penicillin (81.6%), 11 (10%) were intermediate, and eight (8.3%) were resistant. Serotyping was performed in 64 isolates; the main serotypes identified were 3 (n = 13) and 19A (n = 11). No patient had a record of vaccination. Mortality at seven days attributed to pneumococcal infection was different in invasive pneumococcal disease (n = 18, 28.6%) vs. pneumonia (n = 3, 8.9%; p = 0.04). Thirty-day mortality related with the infectious process was statistically different between both groups: 21 patients with invasive pneumococcal disease (30.4%) and six with pneumonia (17.6%; p = 0.04). By logistic analysis, the risk factor associated with mortality was not having received appropriate antimicrobial treatment in the first 48 hours. CONCLUSIONS: S. pneumoniae is a pathogen related with high mortality in patients with cancer. Pneumococcal immunization needs to be reinforced in this population. PMID- 27941956 TI - Microbial community structure and dynamics in thermophilic composting viewed through metagenomics and metatranscriptomics. AB - Composting is a promising source of new organisms and thermostable enzymes that may be helpful in environmental management and industrial processes. Here we present results of metagenomic- and metatranscriptomic-based analyses of a large composting operation in the Sao Paulo Zoo Park. This composting exhibits a sustained thermophilic profile (50 degrees C to 75 degrees C), which seems to preclude fungal activity. The main novelty of our study is the combination of time-series sampling with shotgun DNA, 16S rRNA gene amplicon, and metatranscriptome high-throughput sequencing, enabling an unprecedented detailed view of microbial community structure, dynamics, and function in this ecosystem. The time-series data showed that the turning procedure has a strong impact on the compost microbiota, restoring to a certain extent the population profile seen at the beginning of the process; and that lignocellulosic biomass deconstruction occurs synergistically and sequentially, with hemicellulose being degraded preferentially to cellulose and lignin. Moreover, our sequencing data allowed near-complete genome reconstruction of five bacterial species previously found in biomass-degrading environments and of a novel biodegrading bacterial species, likely a new genus in the order Bacillales. The data and analyses provided are a rich source for additional investigations of thermophilic composting microbiology. PMID- 27941959 TI - Acute Respiratory Distress Syndrome Secondary to Influenza A(H1N1)pdm09: Clinical Characteristics and Mortality Predictors. AB - BACKGROUND: Acute respiratory distress syndrome secondary to influenza A(H1N1)pdm09 virus is the leading cause of death among this patient population. Expanding the knowledge of its course and predictors of mortality is relevant to decision making. We aimed to describe the clinical characteristics and identify factors associated with mortality in patients with acute respiratory distress syndrome secondary to influenza A(H1N1)pdm09 during the 2013-2014 influenza season. METHODS: This is an observational study of a prospective cohort of 70 patients with acute respiratory distress syndrome and influenza A(H1N1) pdm09 seen in an academic medical center. Multivariate logistic regression was used to identify the independent mortality predictors. Bootstrap was used for internal model validation. RESULTS: This cohort was represented by young adults (43 +/- 11 years old). Obesity was present in 62.5% and was not associated with mortality. Mortality at 28 days and at discharge from the respiratory intensive care unit was 14 and 20%, respectively. All patients met the criteria for acute respiratory distress syndrome, 73% had vasodilatory shock, and 27.1% had acute kidney injury on respiratory intensive care unit admission. We observed a high incidence of intensive care unit-acquired weakness (81.4%). Ventilator-associated pneumonia developed in 47.1% and was not associated with mortality. In multivariate analysis, independent risk factors for intensive care unit mortality were age (odds ratio [OR] = 1.102), white blood cell count (OR = 1.22), and lactate dehydrogenase levels (OR = 1.004) on admission to the intensive care unit. CONCLUSIONS: We described the clinical characteristics and course of a cohort of patients with acute respiratory distress syndrome secondary to influenza A(H1N1)pdm09, and developed a predictive model of mortality based on the covariates age, levels of lactate dehydrogenase, and white cell count on admission to the respiratory intensive care unit. PMID- 27941960 TI - Gender Differences in Quantitative Electroencephalogram During a Simple Hand Movement Task in Young Adults. AB - BACKGROUND: No consensus has been reached regarding the existence of gender differences during motor tasks in electroencephalography. This could lead to misinterpretation of electroencephalography clinical diagnosis and affect the calibration of brain-computer interfaces. OBJECTIVE: To assess whether there are statistically significant gender differences in electroencephalography recorded during hand movements. METHODS: Electroencephalography data were recorded from 18 women and 18 men while performing hand movements and rest. Electroencephalography power was computed for alpha (8-13 Hz), beta (14-30 Hz), and a broader band including alpha and beta (8-30 Hz) using wavelet transform. Statistical analysis was done using a General Linear Model for repeated measurements (alpha = 0.05). Additionally, topographic maps were computed for each gender. RESULTS: Significant gender differences were found for the rest condition in all analyzed bands. For the hand movement tasks, gender differences were mainly found in the beta band and located in temporoparietal areas. Power decrease observed in topographic maps was located in the centro-parietal areas for females and the centro-frontal areas for males. Additionally, greater power decreases were observed for women in all analyzed frequency bands. CONCLUSION: Electroencephalography parameters used for the diagnosis of neuromotor diseases, as well as for brain-computer interface calibration, must take gender into account. PMID- 27941961 TI - Therapeutic Effects of Bipolar Coagulation Forceps on Open Thyroid Surgery. AB - BACKGROUND: The aim was to compare the therapeutic effects of bipolar coagulation forceps, harmonic scalpel, and conventional thyroidectomy on open thyroid surgery. METHODS: A total of 527 patients who received open thyroid surgery in the Affiliated Drum Tower Hospital of Nanjing University Medical School between February 2013 and February 2016 were randomly divided into three groups: bipolar coagulation forceps, harmonic scalpel, and conventional thyroidectomy. There were no statistically significant differences in gender, age, disease constituents or mass diameter between the three groups. All surgeries were performed by the same surgeon. The surgical time, intraoperative blood loss, postoperative volume of drainage, postoperative hospital stay, and postoperative complications of the three surgical methods were compared. RESULTS: The bipolar coagulation forceps and harmonic scalpel groups were significantly superior to the conventional thyroidectomy group (p < 0.05) in terms of surgical time, intraoperative blood loss, postoperative volume of drainage, and postoperative hospital stay, but the first two groups had similar outcomes (p > 0.05). There were significant differences between the three groups in temporary recurrent laryngeal nerve palsy and temporary hypoparathyroidism, and the results of the bipolar coagulation forceps group were significantly better than those of the other two groups (p < 0.05). No significant differences were found in airway depression due to postoperative bleeding or irritating cough induced by superior laryngeal nerve palsy between the three groups (p > 0.05). None of the patients in the three groups suffered from permanent recurrent laryngeal nerve palsy or permanent hypoparathyroidism. CONCLUSIONS: The effects of bipolar coagulation forceps on open thyroid surgery exceeded those of the harmonic scalpel and conventional thyroidectomy. This method is worthy of promotion in clinical practice. PMID- 27941962 TI - Microalbuminuria and its Association with Subclinical Atherosclerosis in the Mexican Mestizo population: the GEA study. AB - BACKGROUND: Microalbuminuria is an early marker of atherosclerosis. Ethnic differences for both conditions have been reported. We studied microalbuminuria prevalence and its association with coronary artery calcification as an early atherosclerosis marker in a Mexican-Mestizo population free of diabetes and hypertension (healthy), as well as in hypertensive and diabetic subjects. METHODS: In 1,472 adults (53.3 +/- 9.4 years old, 50.3% women), anthropometric measurements, fasting blood glucose, and lipid profile were determined. A spot urine sample was used to quantify the albumin-to-creatinine ratio and to define microalbuminuria (20-200 mg/g in men, and 30-300 mg/g in women). A coronary artery calcification score was obtained by electron-beam computed tomography and subclinical atherosclerosis was defined as a score > 0. RESULTS: Overall microalbuminuria prevalence was 9.3% (5.4% in healthy, 11.6% in obese, 12% in hypertensive, and 25% in diabetic subjects). Compared to "healthy" subjects without microalbuminuria, those with microalbuminuria had a ~3-fold higher prevalence of coronary artery calcification > 0, while normal-high albumin-to creatinine ratio (OR: 1.8; p < 0.05) and microalbuminuria (OR: 2.6; p < 0.001) was independently associated with coronary artery calcification > 0 only among diabetic subjects. CONCLUSIONS: Microalbuminuria and high-normal albumin-to creatinine ratio were independently associated with subclinical atherosclerosis, suggesting that they may confer a higher risk of future cardiovascular events. PMID- 27941963 TI - Clinical and Genetic Findings in Mexican Patients with Duane Anomaly and Radial Ray Malformations/Okihiro Syndrome. AB - BACKGROUND: Okihiro syndrome is an autosomal-dominant condition characterized by radial ray malformations associated with Duane anomaly and other clinical characteristics. SALL4 mutations have been identified in 80-90% of patients with Duane- Radial ray defects/Okihiro syndrome. We report the clinical findings and results of SALL4 sequencing from a group of Mexican patients with this disorder. OBJECTIVE: Clinical description and identification of SALL4 mutations in Mexican subjects with radial defects and Duane anomaly. MATERIALS AND METHODS: Five unrelated index cases were studied. Complete ophthalmologic and general physical examination was performed in all patients. Polymerase chain reaction amplification and automated nucleotide sequencing of coding exons and intron-exon junctions of SALL4 gene were carried out in genomic DNA. RESULTS: A novel heterozygous deletion was identified in one patient. Intragenic heterozygous single nucleotide polymorphisms on SALL4 gene ruled out deletions of some exons in other affected patients in whom non-pathogenic variants were identified by Sanger sequencing. Likewise, multiplex ligation-dependent probe amplification analysis ruled out large deletions in this gene. CONCLUSION: We observed a low frequency of SALL4 mutations in Mexican patients with clinical criteria of Okihiro syndrome. PMID- 27941964 TI - Study Break: Bacterial Cancer. PMID- 27941967 TI - Biompha-LAMP: A New Rapid Loop-Mediated Isothermal Amplification Assay for Detecting Schistosoma mansoni in Biomphalaria glabrata Snail Host. AB - BACKGROUND: Schistosomiasis remains one of the most common endemic parasitic diseases affecting over 230 million people worlwide. Schistosoma mansoni is the main species causing intestinal and hepatic schistosomiasis and the fresh water pulmonate snails of the genus Biomphalaria are best known for their role as intermediate hosts of the parasite. The development of new molecular monitoring assays for large-scale screening of snails from transmission sites to detect the presence of schistosomes is an important point to consider for snail control interventions related to schistosomiasis elimination. Our work was focussed on developing and evaluating a new LAMP assay combined with a simple DNA extraction method to detect S. mansoni in experimentally infected snails as a diagnostic tool for field conditions. METHODOLOGY/PRINCIPAL FINDINGS: A LAMP assay using a set of six primers targeting a sequence of S. mansoni ribosomal intergenic spacer 28S-18S rRNA was designed. The detection limit of the LAMP assay was 0.1 fg of S. mansoni DNA at 63 degrees C for 50 minutes. LAMP was evaluated by examining S. mansoni DNA in B. glabrata snails experimentally exposed to miracidia at different times post-exposure: early prepatent period (before cercarial shedding), light infections (snails exposed to a low number of miracidia) and detection of infected snails in pooled samples (within a group of uninfected snails). DNA for LAMP assays was obtained by using a commercial DNA extraction kit or a simple heat NaOH extraction method. We detected S. mansoni DNA in all groups of snails by using no complicated requirement procedure for DNA obtaining. CONCLUSIONS/SIGNIFICANCE: Our LAMP assay, named Biompha-LAMP, is specific, sensitive, rapid and potentially adaptable as a cost-effective method for screening of intermediate hosts infected with S. mansoni in both individual snails and pooled samples. The assay could be suitable for large-scale field surveys for schistosomes control campaigns in endemic areas. PMID- 27941965 TI - CD4/CD8 Ratio and KT Ratio Predict Yellow Fever Vaccine Immunogenicity in HIV Infected Patients. AB - BACKGROUND: HIV-infected individuals have deficient responses to Yellow Fever vaccine (YFV) and may be at higher risk for adverse events (AE). Chronic immune activation-characterized by low CD4/CD8 ratio or high indoleamine 2,3-dioxygenase 1 (IDO) activity-may influence vaccine response in this population. METHODS: We prospectively assessed AE, viremia by the YFV virus and YF-specific neutralizing antibodies (NAb) in HIV-infected (CD4>350) and -uninfected adults through 1 year after vaccination. The effect of HIV status on initial antibody response to YFV was measured during the first 3 months following vaccination, while the effect on persistence of antibody response was measured one year following vaccination. We explored CD4/CD8 ratio, IDO activity (plasma kynurenine/tryptophan [KT] ratio) and viremia by Human Pegivirus as potential predictors of NAb response to YFV among HIV-infected participants with linear mixed models. RESULTS: 12 HIV infected and 45-uninfected participants were included in the final analysis. HIV was not significantly associated with AE, YFV viremia or NAb titers through the first 3 months following vaccination. However, HIV-infected participants had 0.32 times the NAb titers observed for HIV-uninfected participants at 1 year following YFV (95% CI 0.13 to 0.83, p = 0.021), independent of sex, age and prior vaccination. In HIV-infected participants, each 10% increase in CD4/CD8 ratio predicted a mean 21% higher post-baseline YFV Nab titer (p = 0.024). Similarly, each 10% increase in KT ratio predicted a mean 21% lower post-baseline YFV Nab titer (p = 0.009). Viremia by Human Pegivirus was not significantly associated with NAb titers. CONCLUSIONS: HIV infection appears to decrease the durability of NAb responses to YFV, an effect that may be predicted by lower CD4/CD8 ratio or higher KT ratio. PMID- 27941966 TI - Metabolomics Identifies Multiple Candidate Biomarkers to Diagnose and Stage Human African Trypanosomiasis. AB - Treatment for human African trypanosomiasis is dependent on the species of trypanosome causing the disease and the stage of the disease (stage 1 defined by parasites being present in blood and lymphatics whilst for stage 2, parasites are found beyond the blood-brain barrier in the cerebrospinal fluid (CSF)). Currently, staging relies upon detecting the very low number of parasites or elevated white blood cell numbers in CSF. Improved staging is desirable, as is the elimination of the need for lumbar puncture. Here we use metabolomics to probe samples of CSF, plasma and urine from 40 Angolan patients infected with Trypanosoma brucei gambiense, at different disease stages. Urine samples provided no robust markers indicative of infection or stage of infection due to inherent variability in urine concentrations. Biomarkers in CSF were able to distinguish patients at stage 1 or advanced stage 2 with absolute specificity. Eleven metabolites clearly distinguished the stage in most patients and two of these (neopterin and 5-hydroxytryptophan) showed 100% specificity and sensitivity between our stage 1 and advanced stage 2 samples. Neopterin is an inflammatory biomarker previously shown in CSF of stage 2 but not stage 1 patients. 5 hydroxytryptophan is an important metabolite in the serotonin synthetic pathway, the key pathway in determining somnolence, thus offering a possible link to the eponymous symptoms of "sleeping sickness". Plasma also yielded several biomarkers clearly indicative of the presence (87% sensitivity and 95% specificity) and stage of disease (92% sensitivity and 81% specificity). A logistic regression model including these metabolites showed clear separation of patients being either at stage 1 or advanced stage 2 or indeed diseased (both stages) versus control. PMID- 27941968 TI - Reactive Case Detection for Plasmodium vivax Malaria Elimination in Rural Amazonia. AB - BACKGROUND: Malaria burden in Brazil has reached its lowest levels in 35 years and Plasmodium vivax now accounts for 84% of cases countrywide. Targeting residual malaria transmission entrenched in the Amazon is the next major challenge for ongoing elimination efforts. Better strategies are urgently needed to address the vast reservoir of asymptomatic P. vivax carriers in this and other areas approaching malaria elimination. METHODS: We evaluated a reactive case detection (RCD) strategy tailored for P. vivax transmission in farming settlements in the Amazon Basin of Brazil. Over six months, 41 cases detected by passive surveillance triggered four rounds of RCD (0, 30, 60, and 180 days after index case enrollment), using microscopy- and quantitative real-time polymerase chain reaction (qPCR)-based diagnosis, comprising subjects sharing the household (HH) with the index case (n = 163), those living in the 5 nearest HHs within 3 km (n = 878), and individuals from 5 randomly chosen control HHs located > 5 km away from index cases (n = 841). Correlates of infection were identified with mixed effects logistic regression models. Molecular genotyping was used to infer local parasite transmission networks. PRINCIPAL FINDINGS/CONCLUSIONS: Subjects in index and neighbor HHs were significantly more likely to be parasitemic than control HH members, after adjusting for potential confounders, and together harbored > 90% of the P. vivax biomass in study subjects. Clustering patterns were temporally stable. Four rounds of microscopy-based RCD would identify only 49.5% of the infections diagnosed by qPCR, but 76.8% of the total parasite biomass circulating in the proximity of index HHs. However, control HHs accounted for 27.6% of qPCR positive samples, 92.6% of them from asymptomatic carriers beyond the reach of RCD. Molecular genotyping revealed high P. vivax diversity, consistent with complex transmission networks and multiple sources of infection within clusters, potentially complicating malaria elimination efforts. PMID- 27941969 TI - Biomonitoring along the Tropical Southern Indian Coast with Multiple Biomarkers. AB - We assessed the spatial and temporal variations of pollution indicators and geochemical and trace metal parameters (23 in total) from water and sediment (144 samples) of three different eco-niches (beach, fishing harbor, and estuary) in larger coastal cities of southern India (Cuddalore and Pondicherry) for one year. A total of 120 marine Pseudomonas isolates were challenged against different concentrations of copper solutions and 10 different antibiotics in heavy metal and antibiotic resistance approaches, respectively. The study shows that 4.16% of the isolates could survive in 250 mM of copper; 70% were resistant to minimum concentrations. Strains were resistant (98.4%) to at least one antibiotic in Cuddalore compared to the Pondicherry (78.4%) region. Pollution index (PI) (0 14.55) and antibiotic resistance index (ARI) (0.05-0.10) ratio indicated that high bacterial and antibiotic loads were released into the coastal environment. The degree of trace metal contamination in sediments were calculated by enrichment factor (EF), contamination factor (CF), pollution load index (PLI), and geo-accumulation index (Igeo). Statistical parameters like two-way analysis of variance (ANOVA), correlation, factor analysis and scatter matrix tools were employed between the 23 parameters in order to find sources, pathways, disparities and interactions of environmental pollutants. It indicates that geochemical and biological parameters were not strongly associated with each other (except a few) and were affected by different sources. Factor analysis elucidated, 'microbe-metal' interaction (Factor 1-48.86%), 'anthropogenic' factor (Factor 2-13.23%) and 'Pseudomonas-Cadmium' factor (Factor 3-11.74%), respectively. PMID- 27941970 TI - Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids. AB - Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafish glucocorticoid deficiency model by RNA-Seq, NMR spectroscopy and liquid chromatography-based methods. We observed dysregulation of metabolic pathways including glutaminolysis, the citrate and urea cycles and glyoxylate detoxification. Constant, non-rhythmic glucocorticoid treatment rescued many of these changes, with some notable exceptions among the amino acid related pathways. Surprisingly, the non-rhythmic glucocorticoid treatment rescued almost half of the entire dysregulated diurnal transcriptome patterns. A combination of E-box and glucocorticoid response elements is enriched in the rescued genes. This simple enhancer element combination is sufficient to drive rhythmic circadian reporter gene expression under non-rhythmic glucocorticoid exposure, revealing a permissive function for the hormones in glucocorticoid-dependent circadian transcription. Our work highlights metabolic pathways potentially contributing to morbidity in patients with glucocorticoid deficiency, even under glucocorticoid replacement therapy. Moreover, we provide mechanistic insight into the interaction between the circadian clock and glucocorticoids in the transcriptional regulation of metabolism. PMID- 27941971 TI - Plasma Metabolomics Biosignature According to HIV Stage of Infection, Pace of Disease Progression, Viremia Level and Immunological Response to Treatment. AB - BACKGROUND: We evaluated plasma samples HIV-infected individuals with different phenotypic profile among five HIV-infected elite controllers and five rapid progressors after recent HIV infection and one year later and from 10 individuals subjected to antiretroviral therapy, five of whom were immunological non responders (INR), before and after one year of antiretroviral treatment compared to 175 samples from HIV-negative patients. A targeted quantitative tandem mass spectrometry metabolomics approach was used in order to determine plasma metabolomics biosignature that may relate to HIV infection, pace of HIV disease progression, and immunological response to treatment. RESULTS: Twenty-five unique metabolites were identified, including five metabolites that could distinguish rapid progressors and INRs at baseline. Severe deregulation in acylcarnitine and sphingomyelin metabolism compatible with mitochondrial deficiencies was observed. beta-oxidation and sphingosine-1-phosphate-phosphatase-1 activity were down regulated, whereas acyl-alkyl-containing phosphatidylcholines and alkylglyceronephosphate synthase levels were elevated in INRs. Evidence that elite controllers harbor an inborn error of metabolism (late-onset multiple acyl coenzyme A dehydrogenase deficiency [MADD]) was detected. CONCLUSIONS: Blood based markers from metabolomics show a very high accuracy of discriminating HIV infection between varieties of controls and have the ability to predict rapid disease progression or poor antiretroviral immunological response. These metabolites can be used as biomarkers of HIV natural evolution or treatment response and provide insight into the mechanisms of the disease. PMID- 27941972 TI - A Kinase-Phosphatase Switch Transduces Environmental Information into a Bacterial Cell Cycle Circuit. AB - The bacterial cell cycle has been extensively studied under standard growth conditions. How it is modulated in response to environmental changes remains poorly understood. Here, we demonstrate that the freshwater bacterium Caulobacter crescentus blocks cell division and grows to filamentous cells in response to stress conditions affecting the cell membrane. Our data suggest that stress switches the membrane-bound cell cycle kinase CckA to its phosphatase mode, leading to the rapid dephosphorylation, inactivation and proteolysis of the master cell cycle regulator CtrA. The clearance of CtrA results in downregulation of division and morphogenesis genes and consequently a cell division block. Upon shift to non-stress conditions, cells quickly restart cell division and return to normal cell size. Our data indicate that the temporary inhibition of cell division through the regulated inactivation of CtrA constitutes a growth advantage under stress. Taken together, our work reveals a new mechanism that allows bacteria to alter their mode of proliferation in response to environmental cues by controlling the activity of a master cell cycle transcription factor. Furthermore, our results highlight the role of a bifunctional kinase in this process that integrates the cell cycle with environmental information. PMID- 27941973 TI - Immune-Inflammatory and Metabolic Effects of High Dose Furosemide plus Hypertonic Saline Solution (HSS) Treatment in Cirrhotic Subjects with Refractory Ascites. AB - INTRODUCTION: Patients with chronic liver diseases are usually thin as a result of hypermetabolism and malnutrition expressed by reduced levels of leptin and impairment of other adyponectins such as visfatin. AIMS: We evaluated the metabolic and inflammatory effects of intravenous high-dose furosemide plus hypertonic saline solutions (HSS) compared with repeated paracentesis and a standard oral diuretic schedule, in patients with cirrhosis and refractory ascites. METHODS: 59 consecutive cirrhotic patients with refractory ascites unresponsive to outpatient treatment. Enrolled subjects were randomized to treatment with intravenous infusion of furosemide (125-250mg/bid) plus small volumes of HSS from the first day after admission until 3 days before discharge (Group A, n:38), or repeated paracentesis from the first day after admission until 3 days before discharge (Group B, n: 21). Plasma levels of ANP, BNP, Leptin, visfatin, IL-1beta, TNF-a, IL-6 were measured before and after the two type of treatment. RESULTS: Subjects in group A were observed to have a significant reduction of serum levels of TNF-alpha, IL-1beta, IL-6, ANP, BNP, and visfatin, thus regarding primary efficacy endpoints, in Group A vs. Group B we observed higher Delta-TNF-alpha, Delta-IL-1beta, Delta-IL-6, Delta-ANP, Delta BNP, Delta-visfatin, Delta-Leptin at discharge. DISCUSSION: Our findings underline the possible inflammatory and metabolic effect of saline overload correction in treatment of cirrhosis complications such as refractory ascites, suggesting a possible role of inflammatory and metabolic-nutritional variables as severity markers in these patients. PMID- 27941974 TI - Cost Evaluation of Dried Blood Spot Home Sampling as Compared to Conventional Sampling for Therapeutic Drug Monitoring in Children. AB - Dried blood spot (DBS) sampling for the purpose of therapeutic drug monitoring can be an attractive alternative for conventional blood sampling, especially in children. This study aimed to compare all costs involved in conventional sampling versus DBS home sampling in two pediatric populations: renal transplant patients and hemato-oncology patients. Total costs were computed from a societal perspective by adding up healthcare cost, patient related costs and costs related to loss of productivity of the caregiver. Switching to DBS home sampling was associated with a cost reduction of 43% for hemato-oncology patients (?277 to ?158) and 61% for nephrology patients (?259 to ?102) from a societal perspective (total costs) per blood draw. From a healthcare perspective, costs reduced with 7% for hemato-oncology patients and with 21% for nephrology patients. Total savings depend on the number of hospital visits that can be avoided by using home sampling instead of conventional sampling. PMID- 27941975 TI - Novel and De Novo Mutations Extend Association of POU3F4 with Distinct Clinical and Radiological Phenotype of Hearing Loss. AB - POU3F4 mutations (DFNX2) are the most prevalent among non-syndromic X-linked hearing loss (HL) identified to date. Clinical manifestations of DFNX2 usually comprise congenital HL either sensorineural or mixed, a tendency towards perilymphatic gusher during otologic surgery and temporal bone malformations. The aim of the present study was to screen for POU3F4 mutations in a group of 30 subjects with a suggestive clinical phenotype as well as a group (N = 1671-2018) of unselected hearing loss patients. We also planned to analyze audiological and radiological features in patients with HL caused by POU3F4 defects. The molecular techniques used to detect POU3F4 mutations included whole exome sequencing (WES), Sanger sequencing and real-time polymerase chain reaction. Hearing status was assessed with pure-tone audiometry and auditory brainstem response. Computer tomography scans were evaluated to define the pattern of structural changes in the temporal bones. Six novel (p.Gln27*, p.Glu187*, p.Leu217*, p.Gln275*, p.Gln306*, p.Val324Asp) and two known (p.Ala116fs141*, p.Leu208*) POU3F4 mutations were detected in the studied cohort. All probands with POU3F4 defects suffered from bilateral, prelingual, severe to profound HL. Morphological changes of the temporal bone in these patients presented a similar pattern, including malformations of the internal auditory canal, vestibular aqueduct, modiolus and vestibule. Despite different localization in the POU3F4 gene all mutations severely impair the protein structure affecting at least one functional POU3F4 domain, and results in similar and severe clinical manifestations. Sequencing of the entire POU3F4 gene is recommended in patients with characteristic temporal bone malformations. Results of POU3F4 mutation testing are important not only for a proper genetic counseling, but also for adequate preparation and conduction of a surgical procedure. PMID- 27941977 TI - Conflict Adaptation and Cue Competition during Learning in an Eriksen Flanker Task. AB - Two experiments investigated competition between cues that predicted the correct target response to a target stimulus in a response conflict procedure using a flanker task. Subjects received trials with five-character arrays with a central target character and distractor flanker characters that matched (compatible) or did not match (incompatible) the central target. Subjects' expectancies for compatible and incompatible trials were manipulated by presenting pre-trial cues that signaled the occurrence of compatible or incompatible trials. On some trials, a single cue predicted the target stimulus and the required target response. On other trials, a second redundant, predictive cue was also present on such trials. The results showed an effect of competition between cues for control over strategic responding to the target stimuli, a finding that is predicted by associative learning theories. The finding of competition between pre-trial cues that predict incompatible trials, but not cues that predict compatible trials, suggests that different strategic processes may occur during adaptation to conflict when different kinds of trials are expected. PMID- 27941978 TI - The Sex Ratio at Birth for 5,338,853 Deliveries in China from 2012 to 2015: A Facility-Based Study. AB - OBJECTIVE: The accuracy of a population-based sex ratio at birth (SRB) in China has long been questioned. To depict a more accurate profile, the present study used data from a national surveillance system for health facility births to explore the characteristics of SRB in China. METHODS: Data from China's National Maternal Near Miss Surveillance System between 2012 and 2015 were used. We restricted the analysis to live births of >=28 completed gestational weeks or >=1000 g birth weight. The strength of association between obstetric characteristics and SRB was examined using logistic regression, taking into account the sampling strategy and clustering of births within health facilities. RESULTS: There were 2,785,513 boys and 2,549,269 girls born alive between 2012 and 2015 in 441 health facilities. The SRB was 111.04 in 2012, 110.16 in 2013, 108.79 in 2014, and 109.53 in 2015. The SRB was high in the eastern region, especially in rural areas. The SRBs increased with mother's age and decreased with mother's education. The SRB in women who were pregnant for the first time was 104.30. The SRB in primipara was normal (104.35), but it was extremely high in non-primipara, especially for women with three or more parities (141.76); only 5.26% of live births fell within this group. The SRBs increased significantly by the number of parities, especially in the rural areas of the central region. After adjustment for sociodemographic factors, women with three or more parities were 1.39 (95% CI 1.34, 1.43) times more likely to give birth to a boy compared with primiparae who were pregnant for the first time. CONCLUSION: Our analysis suggests that the SRB was lower than what was reported officially but higher than normal. The government should keep strengthening supervision to prevent sex selection, especially in the wake of the two-child policy implemented in 2015. PMID- 27941976 TI - The Effect of Contact Investigations and Public Health Interventions in the Control and Prevention of Measles Transmission: A Simulation Study. AB - BACKGROUND: Measles cases continue to occur despite its elimination status in the United States. To control transmission, public health officials confirm the measles diagnosis, identify close contacts of infectious cases, deliver public health interventions (i.e., post-exposure prophylaxis) among those who are eligible, and follow-up with the close contacts to determine overall health outcomes. A stochastic network simulation of measles contact tracing was conducted using existing agent-based modeling software and a synthetic population with high levels of immunity in order to estimate the impact of different interventions in controlling measles transmission. METHODS AND FINDINGS: The synthetic population was created to simulate California's population in terms of population demographics, household, workplace, school, and neighborhood characteristics using California Department of Finance 2010 census data. Parameters for the model were obtained from a review of the literature, California measles case surveillance data, and expert opinion. Eight different scenarios defined by the use of three different public health interventions were evaluated: (a) post-exposure measles, mumps, and rubella (MMR) vaccine, (b) post exposure immune globulin (IG), and (c) voluntary isolation and home quarantine in the presence or absence of public health response delays. Voluntary isolation and home quarantine coupled with one or two other interventions had the greatest reduction in the number of secondary cases infected by the index case and the probability of escape situations (i.e., the outbreak continues after 90 days). CONCLUSIONS: Interrupting contact patterns via voluntary isolation and home quarantine are particularly important in reducing the number of secondary cases infected by the index case and the probability of uncontrolled outbreaks. PMID- 27941979 TI - Impact and Effectiveness of 10 and 13-Valent Pneumococcal Conjugate Vaccines on Hospitalization and Mortality in Children Aged Less than 5 Years in Latin American Countries: A Systematic Review. AB - BACKGROUND: Several Latin American and Caribbean (LAC) countries have introduced pneumococcal conjugate vaccine (PCV-10 or PCV-13) in their routine national immunization programs. OBJECTIVES: We aimed to summarize the evidence of PCV impact and effectiveness in children under 5 years old in the LAC Region. METHODS: We conducted a systematic review of the literature on impact or effectiveness of PCVs on deaths or hospitalizations due to invasive pneumococcal disease (IPD), pneumonia, meningitis and sepsis. We searched Medline, WoS, Lilacs, Scopus, Central and gray literature published in any language from 2009 to January 2016. We included studies addressing the outcomes of interest in children in the target age group, and with the following designs: randomized trials, cohort or case-control, interrupted time series with at least three data points before and after the intervention, and before-after studies. Screening of citations, data extraction, and risk of bias assessment were conducted in duplicate by independent reviewers, according to the study protocol registered on PROSPERO. Descriptive analysis of the effectiveness measurements and sensitivity analysis were conducted. Effectiveness is reported as 1-OR or 1-RR for case control or cohort/clinical trials, and as percent change of disease incidence rates for before-after studies. RESULTS: We identified 1,085 citations, 892 from databases and 193 from other sources. Of these, 22 were further analyzed. Studies were from Brazil, Chile, Uruguay, Argentina, Peru and Nicaragua. Effectiveness ranged from 8.8-37.8% for hospitalizations due to X-ray confirmed pneumonia, 7.4 20.6% for clinical pneumonia, and 13.3-87.7% for meningitis hospitalizations, and 56-83.3% for IPD hospitalization, varying by age, outcome definition, type of vaccine and study design. CONCLUSIONS: Available evidence to date indicates significant impact of both PCV-10 and PCV-13 in the outcomes studied, with no evidence of the superiority of one vaccine over the other on pneumonia, IPD or meningitis hospitalization reduction in children under 5 years old. PMID- 27941981 TI - "A More Equitable Society": The Politics of Global Fairness in Paralympic Sport. AB - The Paralympic Movement explicitly sets out to create a more equitable society and promote participation for all and fairness in disability sport. This is primarily achieved through the use of a range of interventions with less attention given to how economic factors may hinder access and achievement in Paralympic sport. We investigated how country-level economic variables influence the level of participation and achievement in the 2015 International Paralympic Committee (IPC) Athletics Championships held in Doha. We used multiple regression analysis to show how levels of participation and achievement in the Championships were significantly determined by economic factors independent of population size. Our data show that in spite of the ideals of inclusion and fairness within the Paralympic Movement and the considerable effort expended on the use of technologies to achieve this, economic factors continue to exert a statistically significant influence on both the level of participation and achievement of Paralympic athletes. LMICs participate at lower levels and achieve fewer medals when compared to HICs. These differences are particularly marked in events that have a high cost of participation. Our findings raise questions regarding the use of current technologies and the level to which they are able to truly disrupt the politics of global inequality in sport. PMID- 27941980 TI - Cytokine Attenuation and Free Radical Scavenging Activity of a New Flavanone7,4' Dihydroxy-3",3"-Dimethyl -(5,6-Pyrano-2"-One)- 8- (3''',3'''-Dimethyl Allyl)- Isolated from Mallotus philippensis: Possible Mechanism for Its Anti-Inflammatory Activity. AB - Mallotus philippensis L.(MP) commonly known as Kamala tree in Hindi,is a small to medium-sized monoecious tree.The objective of the study was to evaluate the anti inflammatory activity of MPand a new flavanoneisolated from it by using in vivo models of inflammation.Albino wistar rats of either sex weighing 150-200g were used. Seven groups were made (n = 6), namely normal control group (normal saline, 1 ml/kg), standard control group (acetylsalicylic acid, 100 mg/kg), methanol crude extract (300 and 500 mg/kg), ethylacetate fraction (300 and 500 mg/kg) and active compound 4 (new flavanone, 50 mg/kg). The anti-inflammatory activity was studied using carrageenan induced paw edema method and cotton pellet granuloma method. Levels of cytokines (TNF-alpha, IL-1and IL-6) and activity of antioxidant enzymeslike catalase and glutathione peroxidase were estimated. It was found that the methanol extract, ethylacetate fraction and Flavanonedemonstrated significant reduction in paw edema in carrageenan induced paw edema method as compared to control. They also diminished the serum TNF-alpha, IL-6 and IL-1 levels. Significantly attenuated the malondialdehyde levels and increased the activities of catalase and glutathione peroxidase in paw tissue. Similarly there was asignificant decrease in granuloma formation in cotton pellet induced granuloma method. In conclusion, MP extracts and the newflavanonepossess anti-inflammatory activity and this might be due to the inhibition of various cytokines and increased free radical scavenging activity. PMID- 27941983 TI - Underreporting of Congenital Syphilis as a Cause of Fetal and Infant Deaths in Northeastern Brazil. AB - INTRODUCTION: Of all syphilis-related pregnancy outcomes, fetal death is certainly the most common one, being directly related to the availability, accessibility and quality of prenatal care. The present study aimed to analyze the underreporting of fetal and infant deaths and other maternal factors associated with congenital syphilis (CS) death. METHODS: This cross-sectional study integrated data of infants that were diagnosed and/or died of CS from the Sistema de Informacao de Agravos de Notificacao-Sinan (Notifiable Diseases Information System) and the Sistema de Informacao de Mortalidade-SIM (Mortality Information System) in Fortaleza, Northeastern Brasil to identify unreported cases of congenital syphilis. We assessed data during the period from 2007 to 2013. RESULTS: The underreporting of CS as a cause of fetal or infant death increased from 41 to 415 cases (90.1%) during 2007-2013. Exactly 3,209 cases of CS were identified in Sinan and 6,578 deaths in SIM. After database linkage, we identified 382 cases that were reported in the SIM and SINAN databases consisting of 309 fetal deaths and 73 infant deaths related to CS. From the children notified at Sinan that born alive, 3.0% (78/2,542) died; Out of these, 39 (50.0%) were early and 25 (32.1%) were late neonatal deaths. The proportion of death by CS increased from 0.62 to 5.8 from 2007 to 2013. At logistic regression, the variable that maintained statistical significance with fetal and infant death outcomes was the presence of CS signs and/or symptoms at birth (OR = 3.20; IC 95% 1.54-6.62; p = 0.002). CONCLUSIONS: Neonatal and Infant deaths following CS associated live births are underreported in Northeastern Brazil. Data base linkage identified unreported fetal and neonatal deaths due to CS leading to an increased awareness of fetal/infant mortality due to this infection. PMID- 27941982 TI - Overexpression of a Mycobacterium ulcerans Ag85B-EsxH Fusion Protein in Recombinant BCG Improves Experimental Buruli Ulcer Vaccine Efficacy. AB - Buruli ulcer (BU) vaccine design faces similar challenges to those observed during development of prophylactic tuberculosis treatments. Multiple BU vaccine candidates, based upon Mycobacterium bovis BCG, altered Mycobacterium ulcerans (MU) cells, recombinant MU DNA, or MU protein prime-boosts, have shown promise by conferring transient protection to mice against the pathology of MU challenge. Recently, we have shown that a recombinant BCG vaccine expressing MU-Ag85A (BCG MU-Ag85A) displayed the highest level of protection to date, by significantly extending the survival time of MU challenged mice compared to BCG vaccination alone. Here we describe the generation, immunogenicity testing, and evaluation of protection conferred by a recombinant BCG strain which overexpresses a fusion of two alternative MU antigens, Ag85B and the MU ortholog of tuberculosis TB10.4, EsxH. Vaccination with BCG MU-Ag85B-EsxH induces proliferation of Ag85 specific CD4+ T cells in greater numbers than BCG or BCG MU-Ag85A and produces IFNgamma+ splenocytes responsive to whole MU and recombinant antigens. In addition, anti Ag85A and Ag85B IgG humoral responses are significantly enhanced after administration of the fusion vaccine compared to BCG or BCG MU-Ag85A. Finally, mice challenged with MU following a single subcutaneous vaccination with BCG MU Ag85B-EsxH display significantly less bacterial burden at 6 and 12 weeks post infection, reduced histopathological tissue damage, and significantly longer survival times compared to vaccination with either BCG or BCG MU-Ag85A. These results further support the potential of BCG as a foundation for BU vaccine design, whereby discovery and recombinant expression of novel immunogenic antigens could lead to greater anti-MU efficacy using this highly safe and ubiquitous vaccine. PMID- 27941984 TI - Tropical Forest Fragmentation Limits Movements, but Not Occurrence of a Generalist Pollinator Species. AB - Habitat loss and fragmentation influence species distributions and therefore ecological processes that depend upon them. Pollination may be particularly susceptible to fragmentation, as it depends on frequent pollinator movement. Unfortunately, most pollinators are too small to track efficiently which has precluded testing the hypothesis that habitat fragmentation reduces or eliminates pollen flow by disrupting pollinator movement. We used radio-telemetry to examine space use of the green hermit hummingbird (Phaethornis guy), an important 'hub' pollinator of understory flowering plants across substantial portions of the neotropics and the primary pollinator of a keystone plant which shows reduced pollination success in fragmented landscapes. We found that green hermits strongly avoided crossing large stretches of non-forested matrix and preferred to move along stream corridors. Forest gaps as small as 50 m diminished the odds of movement by 50%. Green hermits occurred almost exclusively inside the forest, with the odds of occurrence being 8 times higher at points with >95% canopy cover compared with points having <5% canopy cover. Nevertheless, surprisingly. the species occurred in fragmented landscapes with low amounts of forest (~30% within a 2 km radius). Our results indicate that although green hermits are present even in landscapes with low amounts of tropical forest, movement within these landscapes ends up strongly constrained by forest gaps. Restricted movement of pollinators may be an underappreciated mechanism for widespread declines in pollination and plant fitness in fragmented landscapes, even when in the presence of appropriate pollinators. PMID- 27941985 TI - Diversity of Cultivable Midgut Microbiota at Different Stages of the Asian Tiger Mosquito, Aedes albopictus from Tezpur, India. AB - Aedes aegypti and Ae. albopictus are among the most important vectors of arboviral diseases, worldwide. Recent studies indicate that diverse midgut microbiota of mosquitoes significantly affect development, digestion, metabolism, and immunity of their hosts. Midgut microbiota has also been suggested to modulate the competency of mosquitoes to transmit arboviruses, malaria parasites etc. Interestingly, the midgut microbial flora is dynamic and the diversity changes with the development of vectors, in addition to other factors such as species, sex, life-stage, feeding behavior and geographical origin. The aim of the present study was to investigate the midgut bacterial diversity among larva, adult male, sugar fed female and blood fed female Ae. albopictus collected from Tezpur, Northeastern India. Based on colony morphological characteristics, we selected 113 cultivable bacterial isolates for 16S rRNA gene sequence based molecular identification. Of the 113 isolates, we could identify 35 bacterial species belonging to 18 distinct genera under four major phyla, namely Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes. Phyla Proteobacteria and Firmicutes accounted for majority (80%) of the species, while phylum Actinobacteria constituted 17% of the species. Bacteroidetes was the least represented phylum, characterized by a single species- Chryseobacterium rhizoplanae, isolated from blood fed individuals. Dissection of midgut microbiota diversity at different developmental stages of Ae. albopictus will be helpful in better understanding mosquito-borne diseases, and for designing effective strategies to manage mosquito-borne diseases. PMID- 27941986 TI - Numerical Investigation of Oxygenated and Deoxygenated Blood Flow through a Tapered Stenosed Arteries in Magnetic Field. AB - Current paper is focused on transient modeling of blood flow through a tapered stenosed arteries surrounded a by solenoid under the presence of heat transfer. The oxygenated and deoxygenated blood are considered here by the Newtonian and Non-Newtonian fluid (power law and Carreau-Yasuda) models. The governing equations of bio magnetic fluid flow for an incompressible, laminar, homogeneous, non-Newtonian are solved by finite volume method with SIMPLE algorithm for structured grid. Both magnetization and electric current source terms are well thought-out in momentum and energy equations. The effects of fluid viscosity model, Hartmann number, and magnetic number on wall shear stress, shearing stress at the stenosis throat and maximum temperature of the system are investigated and are optimized. The current study results are in agreement with some of the existing findings in the literature and are useful in thermal and mechanical design of spatially varying magnets to control the drug delivery and biomagnetic fluid flows through tapered arteries. PMID- 27941988 TI - Genetic and Morphological Variation of the Forkbeard, Phycis phycis (Pisces, Phycidae): Evidence of Panmixia and Recent Population Expansion along Its Distribution Area. AB - The knowledge of population structure of a species is essential to effectively assess and manage fisheries. In the present study, genetics, by mitochondrial DNA cytochrome b sequence analysis, and body geometric morphometrics were used to evaluate the existence of distinct populations of the forkbeard (Phycis phycis), an important commercial species in several European countries, especially Portugal and Spain. For geometric morphometric analysis, specimens were collected in the Northeast Atlantic Ocean-Azores, Madeira and mainland Portugal, and for genetic analysis, these samples were complemented with samples collected in the Mediterranean Sea-Spain, Italy and Croatia, in order to cover the entire distribution area of the species. Body shape of the forkbeard from the Northeast Atlantic was found to be highly variable. This variation was probably associated with different environmental factors between the study areas. Despite morphological variation, a low genetic differentiation between samples from different areas was found, most likely due to gene flow that occurred in the past or with the demographic history of the species. Moreover, the presence of unique haplotypes in the Northeast Atlantic and in the Mediterranean suggests that recent gene flow between populations from these areas should be limited. Altogether, a high haplotype diversity, a low nucleotide diversity, a "star-like" network and the results of the mismatch distribution, indicate a possible signature of recent population expansions, which probably started during the end of the Last Glacial Maximum and led to the colonization of the Northeast Atlantic and the Mediterranean. PMID- 27941987 TI - Mutant PIK3CA Induces EMT in a Cell Type Specific Manner. AB - Breast cancer is characterized into different molecular subtypes, and each subtype is characterized by differential gene expression that are associated with distinct survival outcomes in patients. PIK3CA mutations are commonly associated with most breast cancer subtypes. More recently PIK3CA mutations have been shown to induce tumor heterogeneity and are associated with activation of EGFR signaling and reduced relapse free survival in basal subtype of breast cancer. Thus, understanding what determines PIK3CA induced heterogeneity and oncogenesis, is an important area of investigation. In this study, we assessed the effect of mutant PIK3CA together with mutant Ras plus mutant p53 on oncogenic behavior of two distinct stem/progenitor breast cell lines, designated as K5+/K19- and K5+/K19+. Constructs were ectopically overexpressed in K5+/K19- and K5+/K19+ stem/progenitor cells, followed by various in-vitro and in-vivo analyses. Oncogene combination m-Ras/m-p53/m-PIK3CA efficiently transformed both K5+/K19- and K5+/K19+ cell lines in-vitro, as assessed by anchorage-independent soft agar colony formation assay. Significantly, while this oncogene combination induced a complete epithelial-to-mesenchymal transition (EMT) in K5+/K19- cell line, mostly epithelial phenotype with minor EMT component was seen in K5+/K19+ cell line. However, both K5+/K19- and K5+/K19+ transformed cells exhibited increased invasion and migration abilities. Analyses of CD44 and CD24 expression showed both cell lines had tumor-initiating CD44+/CD24low cell population, however transformed K5+/K19- cells had more proportion of these cells. Significantly, both cell types exhibited in-vivo tumorigenesis, and maintained their EMT and epithelial nature in-vivo in mice tumors. Notably, while both cell types exhibited increase in tumor-initiating cell population, differential EMT phenotype was observed in these cell lines. These results suggest that EMT is a cell type dependent phenomenon and does not dictate oncogenesis. PMID- 27941989 TI - Real-World Assessment of Renal and Bone Safety among Patients with HIV Infection Exposed to Tenofovir Disoproxil Fumarate-Containing Single-Tablet Regimens. AB - OBJECTIVES: Tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimens have been associated with an increased incidence of renal and bone adverse outcomes. Here, we estimated the real-world incidence of renal and bone adverse outcomes among patients with HIV infection receiving different TDF containing single-tablet regimens (STRs). METHODS: This cohort study used US health insurance data spanning the years 2008-2014. We identified HIV-infected patients aged >=18 years (all HIV patients) and those with >=6 months of continuous enrollment prior to initiating efavirenz/emtricitabine/TDF (EFV/FTC/TDF), rilpivirine/FTC/TDF (RPV/FTC/TDF) or elvitegravir/cobicistat/FTC/TDF (EVG/COBI/FTC/TDF). Renal adverse outcomes were identified using renal International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Bone adverse outcomes were identified using ICD-9-CM diagnosis codes for fracture. Incidence rates (IRs) and associated 95% confidence intervals (CIs) were estimated assuming a Poisson distribution, and outcomes between STRs were compared using IR ratios (IRRs) and IR differences (IRDs). RESULTS: We identified 9876 and 10,383 eligible patients for the renal and fracture analyses, respectively. Observed IRs for renal adverse outcomes were 9.7, 10.5, 13.6, and 18.0 per 1000 person-years among those receiving EFV/FTC/TDF, RPV/FTC/TDF, or EVG/COBI/FTC/TDF, or all HIV patients, respectively. Corresponding values for IRs of fracture were 3.4, 3.6, 7.2, and 4.4 per 1000 person-years, respectively. Renal adverse outcomes with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRD -3.96; 95% CI: 7.31, -1.06). No IRR differences were identified for the renal analysis. Fractures with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRR 0.47; 95% CI: 0.27, 0.81 and IRD -3.85; 95% CI: -5.02, 2.78). CONCLUSIONS: In this large real-world database, observed IRs for renal adverse outcomes with TDF-containing STRs were lower or similar to those for all HIV patients, with the lowest IRs observed among patients receiving EFV/FTC/TDF. Compared with all HIV patients, the observed IR for fracture was higher with EVG/COBI/FTC/TDF, comparable with RPV/FTC/TDF, and lower with EFV/FTC/TDF. PMID- 27941990 TI - Non-Sinusoidal Activity Can Produce Cross-Frequency Coupling in Cortical Signals in the Absence of Functional Interaction between Neural Sources. AB - The analysis of cross-frequency coupling (CFC) has become popular in studies involving intracranial and scalp EEG recordings in humans. It has been argued that some cases where CFC is mathematically present may not reflect an interaction of two distinct yet functionally coupled neural sources with different frequencies. Here we provide two empirical examples from intracranial recordings where CFC can be shown to be driven by the shape of a periodic waveform rather than by a functional interaction between distinct sources. Using simulations, we also present a generalized and realistic scenario where such coupling may arise. This scenario, which we term waveform-dependent CFC, arises when sharp waveforms (e.g., cortical potentials) occur throughout parts of the data, in particular if they occur rhythmically. Since the waveforms contain both low- and high-frequency components, these components can be inherently phase aligned as long as the waveforms are spaced with appropriate intervals. We submit that such behavior of the data, which seems to be present in various cortical signals, cannot be interpreted as reflecting functional modulation between distinct neural sources without additional evidence. In addition, we show that even low amplitude periodic potentials that cannot be readily observed or controlled for, are sufficient for significant CFC to occur. PMID- 27941991 TI - In vivo Distribution and Clearance of Purified Capsular Polysaccharide from Burkholderia pseudomallei in a Murine Model. AB - Burkholderia pseudomallei is the causative agent of melioidosis, a severe infection prominent in northern Australia and Southeast Asia. The "gold standard" for melioidosis diagnosis is bacterial isolation, which takes several days to complete. The resulting delay in diagnosis leads to delayed treatments, which could result in death. In an attempt to develop better methods for early diagnosis of melioidosis, B. pseudomallei capsular polysaccharide (CPS) was identified as an important diagnostic biomarker. A rapid lateral flow immunoassay utilizing CPS-specific monoclonal antibody was developed and tested in endemic regions worldwide. However, the in vivo fate and clearance of CPS has never been thoroughly investigated. Here, we injected mice with purified CPS intravenously and determined CPS concentrations in serum, urine, and major organs at various intervals. The results indicate that CPS is predominantly eliminated through urine and no CPS accumulation occurs in the major organs. Immunoblot analysis demonstrated that intact CPS was excreted through urine. To understand how a large molecule like CPS was eliminated without degradation, a 3-dimenational structure of CPS was modeled. The predicted CPS structure has a rod-like shape with a small diameter that could allow it to flow through the glomerulus of the kidney. CPS clearance was determined using exponential decay models and the corrected Akaike Information Criterion. The results show that CPS has a relatively short serum half-life of 2.9 to 4.4 hours. Therefore, the presence of CPS in the serum and/or urine suggests active melioidosis infection and provides a marker to monitor treatment of melioidosis. PMID- 27941993 TI - Socioeconomic Determinants of Antibiotic Consumption in the State of Sao Paulo, Brazil: The Effect of Restricting Over-The-Counter Sales. AB - BACKGROUND: Improper antibiotic use is one of the main drivers of bacterial resistance to antibiotics, increasing infectious diseases morbidity and mortality and raising costs of healthcare. The level of antibiotic consumption has been shown to vary according to socioeconomic determinants (SED) such as income and access to education. In many Latin American countries, antibiotics could be easily purchased without a medical prescription in private pharmacies before enforcement of restrictions on over-the-counter (OTC) sales in recent years. Brazil issued a law abolishing OTC sales in October 2010. This study seeks to find SED of antibiotic consumption in the Brazilian state of Sao Paulo (SSP) and to estimate the impact of the 2010 law. METHODS: Data on all oral antibiotic sales having occurred in the private sector in SSP from 2008 to 2012 were pooled into the 645 municipalities of SSP. Linear regression was performed to estimate consumption levels that would have occurred in 2011 and 2012 if no law regulating OTC sales had been issued in 2010. These values were compared to actual observed levels, estimating the effect of this law. Linear regression was performed to find association of antibiotic consumption levels and of a greater effect of the law with municipality level data on SED obtained from a nationwide census. RESULTS: Oral antibiotic consumption in SSP rose from 8.44 defined daily doses per 1,000 inhabitants per day (DID) in 2008 to 9.95 in 2010, and fell to 8.06 DID in 2012. Determinants of a higher consumption were higher human development index, percentage of urban population, density of private health establishments, life expectancy and percentage of females; lower illiteracy levels and lower percentage of population between 5 and 15 years old. A higher percentage of females was associated with a stronger effect of the law. CONCLUSIONS: SSP had similar antibiotic consumption levels as the whole country of Brazil, and they were effectively reduced by the policy. PMID- 27941992 TI - High Expression of KIF20A Is Associated with Poor Overall Survival and Tumor Progression in Early-Stage Cervical Squamous Cell Carcinoma. AB - BACKGROUND: The kinesin family member 20a (KIF20A) protein has been implicated in the development and progression of many human cancers; however, its precise function and role in cervical cancer remain largely unclear. This study aimed to investigate the expression profile and prognostic value of KIF20A in patients with early-stage cervical squamous cell carcinoma. METHODS: We examined the mRNA and protein levels of KIF20A in eight cervical cancer cell lines and eight paired cervical cancer samples, compared with normal cervical epithelial cells and adjacent normal cervical tissues, respectively. Immunohistochemistry was performed to detect the expression of KIF20A in paraffin-embedded specimens from 169 early-stage cervical squamous cell carcinoma patients. Statistical analyses were applied to analyze the association between KIF20A expression and clinical variables, as well with patient survival. RESULTS: The mRNA and protein expression levels of KIF20A were significantly elevated in cervical cancer cell lines and lesions compared with normal cells and corresponding normal tissues (P < 0.05). Immunohistochemistry analysis in 169 cervical cancer cases revealed that increased KIF20A expression was strongly associated with human papillomavirus (HPV) infection (P = 0.008), clinical stage (P = 0.001), tumor recurrence (P = 0.016), vital status (P < 0.001), the property of the surgical margin (P = 0.032), the lymphovascular space involvement (P = 0.014), and pelvic lymph node metastasis (P = 0.001). The overall survival and disease-free survival of patients with high levels of KIF20A expression were significantly poorer than those with low KIF20A expression. KIF20A was an independent survival prognostic factor, as evidenced by univariate and multivariate analysis. CONCLUSIONS: Our results illustrate that elevated KIF20A expression correlates with HPV infection, clinical stage, tumor recurrence, lymphovascular space involvement, pelvic lymph node metastasis, and poor outcome in early-stage cervical squamous cell carcinoma patients. KIF20A aberrant expression is a novel independent unfavorable prognostic factor and may present a potential therapeutic target for cervical cancer. PMID- 27941994 TI - Deletion of Gpr55 Results in Subtle Effects on Energy Metabolism, Motor Activity and Thermal Pain Sensation. AB - The G-protein coupled receptor 55 (GPR55) is activated by cannabinoids and non cannabinoid molecules and has been speculated to play a modulatory role in a large variety of physiological and pathological processes, including in metabolically perturbed states. We therefore generated male mice deficient in the gene coding for the cannabinoid/lysophosphatidylinositol (LPI) receptor Gpr55 and characterized them under normal dietary conditions as well as during high energy dense diet feeding followed by challenge with the CB1 receptor antagonist/GPR55 agonist rimonabant. Gpr55 deficient male mice (Gpr55 KO) were phenotypically indistinguishable from their wild type (WT) siblings for the most part. However, Gpr55 KO animals displayed an intriguing nocturnal pattern of motor activity and energy expenditure (EE). During the initial 6 hours of the night, motor activity was significantly elevated without any significant effect observed in EE. Interestingly, during the last 6 hours of the night motor activity was similar but EE was significantly decreased in the Gpr55 KO mice. No significant difference in motor activity was detected during daytime, but EE was lower in the Gpr55 KO compared to WT mice. The aforementioned patterns were not associated with alterations in energy intake, daytime core body temperature, body weight (BW) or composition, although a non-significant tendency to increased adiposity was seen in Gpr55 KO compared to WT mice. Detailed analyses of daytime activity in the Open Field paradigm unveiled lower horizontal activity and rearing time for the Gpr55 KO mice. Moreover, the Gpr55 KO mice displayed significantly faster reaction time in the tail flick test, indicative of thermal hyperalgesia. The BW decreasing effect of rimonabant in mice on long-term cafeteria diet did not differ between Gpr55 KO and WT mice. In conclusion, Gpr55 deficiency is associated with subtle effects on diurnal/nocturnal EE and motor activity behaviours but does not appear per se critically required for overall metabolism or behaviours. PMID- 27941995 TI - Characteristics of the Motor Units during Sternocleidomastoid Isometric Flexion among Patients with Mechanical Neck Disorder and Asymptomatic Individuals. AB - Mechanical neck disorder is a widespread and non-neurological musculoskeletal condition resulting from modern lifestyles. Presently, the fundamental electrophysiological properties of the motor units of the sternocleidomastoid muscles and the characteristics of the short-term synchronization of the motor unit in patients with neck pain are ambiguous. This study therefore aims to clarify the fundamental electrophysiological properties of the motor units of the sternocleidomastoid muscles in patients with mechanical neck disorder and in asymptomatic individuals. We further investigated whether alterations in the degree of motor unit short-term synchronization occur. The surface electrophysiological signals of the bilateral sternal heads of the sternocleidomastoid muscles of twelve patients with mechanical neck disorder and asymptomatic individuals were detected at 25% of the maximum voluntary contraction during cervical isometric flexion and then decomposed into individual motor unit action potential trains. We found that the patients with mechanical neck disorder showed significantly higher initial and mean firing rates of the sternocleidomastoid muscles and displayed substantially lower motor unit short term synchronization values compared with the asymptomatic subjects. Consequently, these convincing findings support the assertion that patients with mechanical neck disorder display altered neuromuscular control strategies, such as the reinforcement of motor unit recruitment firing rates in the sternocleidomastoid muscles. The motor units of these patients also revealed neural recruitment strategies with relatively poor efficiency when executing the required motor tasks. PMID- 27941996 TI - Biomolecular Evidence of Silk from 8,500 Years Ago. AB - Pottery, bone implements, and stone tools are routinely found at Neolithic sites. However, the integrity of textiles or silk is susceptible to degradation, and it is therefore very difficult for such materials to be preserved for 8,000 years. Although previous studies have provided important evidence of the emergence of weaving skills and tools, such as figuline spinning wheels and osseous lamellas with traces of filament winding, there is a lack of direct evidence proving the existence of silk. In this paper, we explored evidence of prehistoric silk fibroin through the analysis of soil samples collected from three tombs at the Neolithic site of Jiahu. Mass spectrometry was employed and integrated with proteomics to characterize the key peptides of silk fibroin. The direct biomolecular evidence reported here showed the existence of prehistoric silk fibroin, which was found in 8,500-year-old tombs. Rough weaving tools and bone needles were also excavated, indicating the possibility that the Jiahu residents may possess the basic weaving and sewing skills in making textile. This finding may advance the study of the history of silk, and the civilization of the Neolithic Age. PMID- 27941997 TI - Primary Cilia Negatively Regulate Melanogenesis in Melanocytes and Pigmentation in a Human Skin Model. AB - The primary cilium is an organelle protruding from the cell body that senses external stimuli including chemical, mechanical, light, osmotic, fluid flow, and gravitational signals. Skin is always exposed to the external environment and responds to external stimuli. Therefore, it is possible that primary cilia have an important role in skin. Ciliogenesis was reported to be involved in developmental processes in skin, such as keratinocyte differentiation and hair formation. However, the relation between skin pigmentation and primary cilia is largely unknown. Here, we observed that increased melanogenesis in melanocytes treated with a melanogenic inducer was inhibited by a ciliogenesis inducer, cytochalasin D, and serum-free culture. However, these inhibitory effects disappeared in GLI2 knockdown cells. In addition, activation of sonic hedgehog (SHH)-smoothened (Smo) signaling pathway by a Smo agonist, SAG inhibited melanin synthesis in melanocytes and pigmentation in a human skin model. On the contrary, an inhibitor of primary cilium formation, ciliobrevin A1, activated melanogenesis in melanocytes. These results suggest that skin pigmentation may be regulated partly by the induction of ciliogenesis through Smo-GLI2 signaling. PMID- 27941998 TI - Voltage-Dependent Anion Channel 1(VDAC1) Participates the Apoptosis of the Mitochondrial Dysfunction in Desminopathy. AB - Desminopathies caused by the mutation in the gene coding for desmin are genetically protein aggregation myopathies. Mitochondrial dysfunction is one of pathological changes in the desminopathies at the earliest stage. The molecular mechanisms of mitochondria dysfunction in desminopathies remain exclusive. VDAC1 regulates mitochondrial uptake across the outer membrane and mitochondrial outer membrane permeabilization (MOMP). Relationships between desminopathies and Voltage-dependent anion channel 1 (VDAC1) remain unclear. Here we successfully constructed the desminopathy rat model, evaluated with conventional stains, containing hematoxylin and eosin (HE), Gomori Trichrome (MGT), (PAS), red oil (ORO), NADH-TR, SDH staining and immunohistochemistry. Immunofluorescence results showed that VDAC1 was accumulated in the desmin highly stained area of muscle fibers of desminopathy patients or desminopathy rat model compared to the normal ones. Meanwhile apoptosis related proteins bax and ATF2 were involved in desminopathy patients and desminopathy rat model, but not bcl-2, bcl-xl or HK2.VDAC1 and desmin are closely relevant in the tissue splices of deminopathies patients and rats with desminopathy at protein lever. Moreover, apoptotic proteins are also involved in the desminopathies, like bax, ATF2, but not bcl-2, bcl-xl or HK2. This pathological analysis presents the correlation between VDAC1 and desmin, and apoptosis related proteins are correlated in the desminopathy. Furthermore, we provide a rat model of desminopathy for the investigation of desmin related myopathy. PMID- 27941999 TI - Plasmid Complement of Lactococcus lactis NCDO712 Reveals a Novel Pilus Gene Cluster. AB - Lactococcus lactis MG1363 is an important gram-positive model organism. It is a plasmid-free and phage-cured derivative of strain NCDO712. Plasmid-cured strains facilitate studies on molecular biological aspects, but many properties which make L. lactis an important organism in the dairy industry are plasmid encoded. We sequenced the total DNA of strain NCDO712 and, contrary to earlier reports, revealed that the strain carries 6 rather than 5 plasmids. A new 50-kb plasmid, designated pNZ712, encodes functional nisin immunity (nisCIP) and copper resistance (lcoRSABC). The copper resistance could be used as a marker for the conjugation of pNZ712 to L. lactis MG1614. A genome comparison with the plasmid cured daughter strain MG1363 showed that the number of single nucleotide polymorphisms that accumulated in the laboratory since the strains diverted more than 30 years ago is limited to 11 of which only 5 lead to amino acid changes. The 16-kb plasmid pSH74 was found to contain a novel 8-kb pilus gene cluster spaCB-spaA-srtC1-srtC2, which is predicted to encode a pilin tip protein SpaC, a pilus basal subunit SpaB, and a pilus backbone protein SpaA. The sortases SrtC1/SrtC2 are most likely involved in pilus polymerization while the chromosomally encoded SrtA could act to anchor the pilus to peptidoglycan in the cell wall. Overexpression of the pilus gene cluster from a multi-copy plasmid in L. lactis MG1363 resulted in cell chaining, aggregation, rapid sedimentation and increased conjugation efficiency of the cells. Electron microscopy showed that the over-expression of the pilus gene cluster leads to appendices on the cell surfaces. A deletion of the gene encoding the putative basal protein spaB, by truncating spaCB, led to more pilus-like structures on the cell surface, but cell aggregation and cell chaining were no longer observed. This is consistent with the prediction that spaB is involved in the anchoring of the pili to the cell. PMID- 27942000 TI - Free Fatty Acids Modulate Thrombin Mediated Fibrin Generation Resulting in Less Stable Clots. AB - Upon platelet activation, free fatty acids are released at the stage of thrombus formation, but their effects on fibrin formation are largely unexplored. Our objective was to characterize the kinetic effects of fatty acids on thrombin activity, as well as the structural and mechanical properties of the resultant fibrin clots. Thrombin activity on fibrinogen was followed by turbidimetry and detailed kinetic characterization was performed using a fluorogenic short peptide substrate. The viscoelastic properties of fibrin were measured with rotatory oscillation rheometer, whereas its structure was analyzed with scanning electron microscopy (SEM). In turbidimetric assays of fibrin generation, oleate and stearate at physiologically relevant concentrations (60-600 MUM) produced a bell shaped inhibitory dose response, increasing 10- to 30-fold the time to half maximal clotting. Oleate inhibited thrombin activity on a short peptide substrate according to a mixed-type inhibitor pattern (a 9-fold increase of the Michaelis constant, Km and a 20% decrease of the catalytic constant), whereas stearate resulted in only a minor (15%) drop in the catalytic constant without any change in the Km. Morphometric analysis of SEM images showed a 73% increase in the median fiber diameter in the presence of stearate and a 20% decrease in the presence of oleate. Concerning the viscoelastic parameters of the clots, storage and loss moduli, maximal viscosity and critical shear stress decreased by 32-65% in the presence of oleate or stearate, but loss tangent did not change indicating decreased rigidity, higher deformability and decreased internal resistance to shear stress. Our study provides evidence that free fatty acids (at concentrations comparable to those reported in thrombi) reduce the mechanical stability of fibrin through modulation of thrombin activity and the pattern of fibrin assembly. PMID- 27942002 TI - The Impact of Adding a Physician Assistant to a Critical Care Outreach Team. AB - RATIONALE: Hospitals are increasingly using critical care outreach teams (CCOTs) to respond to patients deteriorating outside intensive care units (ICUs). CCOT staffing is variable across hospitals and optimal team composition is unknown. OBJECTIVES: To assess whether adding a critical care medicine trained physician assistant (CCM-PA) to a critical care outreach team (CCOT) impacts clinical and process outcomes. METHODS: We performed a retrospective study of two cohorts-one with a CCM-PA added to the CCOT (intervention hospital) and one with no staffing change (control hospital)-at two facilities in the same system. All adults in the emergency department and hospital for whom CCOT consultation was requested from October 1, 2012-March 16, 2013 (pre-intervention) and January 5-March 31, 2014 (post-intervention) were included. We performed difference-in-differences analyses comparing pre- to post-intervention periods in the intervention versus control hospitals to assess the impact of adding the CCM-PA to the CCOT. MEASUREMENTS AND MAIN RESULTS: Our cohort consisted of 3,099 patients (control hospital: 792 pre- and 595 post-intervention; intervention hospital: 1114 pre- and 839 post-intervention). Intervention hospital patients tended to be younger, with fewer comorbidities, but with similar severity of acute illness. Across both periods, hospital mortality (p = 0.26) and hospital length of stay (p = 0.64) for the intervention vs control hospitals were similar, but time-to-transfer to the ICU was longer for the intervention hospital (13.3-17.0 vs 11.5-11.6 hours, p = 0.006). Using the difference-in-differences approach, we found a 19.2% reduction (95 confidence interval: 6.7%-31.6%, p = 0.002) in the time-to-transfer to the ICU associated with adding the CCM-PA to the CCOT; we found no difference in hospital mortality (p = 0.20) or length of stay (p = 0.52). CONCLUSIONS: Adding a CCM-PA to the CCOT was associated with a notable reduction in time-to-transfer to the ICU; hospital mortality and length of stay were not impacted. PMID- 27942001 TI - Biophysical Studies of the Induced Dimerization of Human VEGF Receptor 1 Binding Domain by Divalent Metals Competing with VEGF-A. AB - Angiogenesis is tightly regulated through the binding of vascular endothelial growth factors (VEGFs) to their receptors (VEGFRs). In this context, we showed that human VEGFR1 domain 2 crystallizes in the presence of Zn2+, Co2+ or Cu2+ as a dimer that forms via metal-ion interactions and interlocked hydrophobic surfaces. SAXS, NMR and size exclusion chromatography analyses confirm the formation of this dimer in solution in the presence of Co2+, Cd2+ or Cu2+. Since the metal-induced dimerization masks the VEGFs binding surface, we investigated the ability of metal ions to displace the VEGF-A binding to hVEGFR1: using a competition assay, we evidenced that the metals displaced the VEGF-A binding to hVEGFR1 extracellular domain binding at micromolar level. PMID- 27942004 TI - STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor of Treatment Response in Rheumatoid Arthritis. AB - OBJECTIVE: To find novel predictors of treatment response to disease-modifying antirheumatic drugs (DMARDs), we studied activation of STAT (signal transducers and activators of transcription) 6 and 1 in circulating leukocytes of patients with rheumatoid arthritis (RA). METHODS: 19 patients with untreated recent-onset RA, 16 patients with chronic RA irresponsive to synthetic DMARDs and 37 healthy volunteers provided blood samples for whole blood flow cytometric determination of intracellular STAT6 and STAT1 phosphorylation, expressed as relative fluorescence units, in response to IL-4 and IFN-gamma, respectively. Phosphorylation was restudied and treatment response (according to European League Against Rheumatism) determined after 1-year treatment with synthetic DMARDs in recent-onset RA and with biological DMARD in synthetic DMARD irresponsive RA. Estimation-based exact logistic regression was used to investigate relation of baseline variables to treatment response. 95% confidence intervals of means were estimated by bias-corrected bootstrapping and the significance between baseline and follow-up values was calculated by permutation test. RESULTS: At baseline, levels of phosphorylated STAT6 (pSTAT6) induced by IL 4 in monocytes were higher in those who achieved good treatment response to synthetic DMARDs than in those who did not among patients with untreated RA (OR 2.74, 95% CI 1.05 to 9.47), and IFN-gamma -stimulated lymphocyte pSTAT1 levels were higher in those who achieved good treatment response to a biological drug than in those who did not among patients with chronic RA (OR 3.91, 95% CI 1.12 to 20.68). During follow-up, in recent-onset RA patients with good treatment response to synthetic DMARDS, the lymphocyte pSTAT6 levels decreased (p = 0.011), and, consequently, the ratio of pSTAT1/pSTAT6 in lymphocytes increased (p = 0.042). CONCLUSION: Cytokine-stimulated STAT6 and STAT1 phosphorylation in circulating leukocytes was associated with treatment response to DMARDs in this pilot study. The result, if confirmed in larger studies, may aid in developing personalized medicine in RA. PMID- 27942003 TI - Biochemical and Cellular Determinants of Renal Glomerular Elasticity. AB - The elastic properties of renal glomeruli and their capillaries permit them to maintain structural integrity in the presence of variable hemodynamic forces. Measured by micro-indentation, glomeruli have an elastic modulus (E, Young's modulus) of 2.1 kPa, and estimates from glomerular perfusion studies suggest that the E of glomeruli is between 2 and 4 kPa. F-actin depolymerization by latrunculin, inhibition of acto-myosin contractility by blebbistatin, reduction in ATP synthesis, and reduction of the affinity of adhesion proteins by EDTA reduced the glomerular E to 1.26, 1.7, 1.5, and 1.43 kPa, respectively. Actin filament stabilization with jasplakinolide and increasing integrin affinity with Mg2+ increased E to 2.65 and 2.87 kPa, respectively. Alterations in glomerular E are reflected in commensurate changes in F/G actin ratios. Disruption of vimentin intermediate filaments by withaferin A reduced E to 0.92 kPa. The E of decellularized glomeruli was 0.74 kPa, indicating that cellular components of glomeruli have dominant effects on their elasticity. The E of glomerular basement membranes measured by magnetic bead displacement was 2.4 kPa. Podocytes and mesangial cells grown on substrates with E values between 3 and 5 kPa had actin fibers and focal adhesions resembling those of podocytes in vivo. Renal ischemia and ischemia-reperfusion reduced the E of glomeruli to 1.58 kPa. These results show that the E of glomeruli is between 2 and 4 kPa. E of the GBM, 2.4 kPa, is consistent with this value, and is supported by the behavior of podocytes and mesangial cells grown on variable stiffness matrices. The podocyte cytoskeleton contributes the major component to the overall E of glomeruli, and a normal E requires ATP synthesis. The reduction in glomerular E following ischemia and in other diseases indicates that reduced glomerular E is a common feature of many forms of glomerular injury and indicative of an abnormal podocyte cytoskeleton. PMID- 27942005 TI - Treatment Outcomes and Costs of Providing Antiretroviral Therapy at a Primary Health Clinic versus a Hospital-Based HIV Clinic in South Africa. AB - BACKGROUND: In 2010 South Africa revised its HIV treatment guidelines to allow the initiation and management of patients on antiretroviral therapy (ART) by nurses, rather than solely doctors, under a program called NIMART (Nurse Initiated and Managed Antiretroviral Therapy). We compared the outcomes and costs of NIMART between the two major public sector HIV treatment delivery models in use in South Africa today, primary health clinics and hospital-based HIV clinics. METHODS AND FINDINGS: The study was conducted at one hospital-based outpatient HIV clinic and one primary health clinic (PHC) in Gauteng Province. A retrospective cohort of adult patients initiated on ART at the PHC was propensity score matched to patients initiated at the hospital outpatient clinic. Each patient was assigned a 12-month outcome of alive and in care or died/lost to follow up. Costs were estimated from the provider perspective for the 12 months after ART initiation. The proportion of patients alive and in care at 12 months did not differ between the PHC (76.5%) and the hospital-based site (74.2%). The average annual cost per patient alive and in care at 12 months after ART initiation was significantly lower at the PHC (US$238) than at the hospital outpatient clinic (US$428). CONCLUSIONS: Initiating and managing ART patients at PHCs under NIMART is producing equally good outcomes as hospital-based HIV clinic care at much lower cost. Evolution of hospital-based clinics into referral facilities that serve complicated patients, while investing most program expansion resources into PHCs, may be a preferred strategy for achieving treatment coverage targets. PMID- 27942006 TI - Ground Squirrel Shooting and Potential Lead Exposure in Breeding Avian Scavengers. AB - Recreational ground squirrel shooting is a popular activity throughout the western United States and serves as a tool for managing ground squirrel populations in agricultural regions. Belding's ground squirrels (Spermophilus beldingi) are routinely shot in California, Nevada, and Oregon across habitats that overlap with breeding avian scavengers. Ground squirrels shot with lead (Pb) based bullets may pose a risk to avian scavengers if they consume carcasses containing Pb fragments. To assess the potential risk to breeding avian scavengers we developed a model to estimate the number, mass, and distribution of Pb fragments in shot ground squirrels using radiographic images. Eighty percent of shot carcasses contained detectible Pb fragments with an average of 38.6 mg of Pb fragments. Seven percent of all carcasses contained Pb fragment masses exceeding a lethal dose for a model raptor nestling (e.g. American kestrel Falco sparverius). Bullet type did not influence the number of fragments in shot ground squirrels, but did influence the mass of fragments retained. Belding's ground squirrels shot with .17 Super Mag and unknown ammunition types contained over 28 and 17 times more mass of Pb fragments than those shot with .22 solid and .22 hollow point bullets, respectively. Ground squirrel body mass was positively correlated with both the number and mass of Pb fragments in carcasses, increasing on average by 76% and 56% respectively across the range of carcass masses. Although the mass of Pb retained in ground squirrel carcasses was small relative to the original bullet mass, avian scavenger nestlings that frequently consume shot ground squirrels may be at risk for Pb-induced effects (e.g., physiology, growth, or survival). Using modeling efforts we found that if nestling golden eagles (Aquila chrysaetos), red-tailed hawks (Buteo jamaicensis), and Swainson's hawks (B. swainsoni) consumed shot ground squirrels proportionately to the nestling's mass, energy needs, and diet, 100% of the nestling period would exceed a 50% reduction in delta-aminolevulinic acid dehydratase production threshold, the last 13-27% of the nestling stage would exceed a reduced growth rate threshold, but no nestlings would be expected to exceed a level of Pb ingestion that would be lethal. PMID- 27942007 TI - Validation of Reference Genes for Real-Time Quantitative PCR (qPCR) Analysis of Avibacterium paragallinarum. AB - Real-time quantitative reverse transcription PCR (qRT-PCR) offers a robust method for measurement of gene expression levels. Selection of reliable reference gene(s) for gene expression study is conducive to reduce variations derived from different amounts of RNA and cDNA, the efficiency of the reverse transcriptase or polymerase enzymes. Until now reference genes identified for other members of the family Pasteurellaceae have not been validated for Avibacterium paragallinarum. The aim of this study was to validate nine reference genes of serovars A, B, and C strains of A. paragallinarum in different growth phase by qRT-PCR. Three of the most widely used statistical algorithms, geNorm, NormFinder and DeltaCT method were used to evaluate the expression stability of reference genes. Data analyzed by overall rankings showed that in exponential and stationary phase of serovar A, the most stable reference genes were gyrA and atpD respectively; in exponential and stationary phase of serovar B, the most stable reference genes were atpD and recN respectively; in exponential and stationary phase of serovar C, the most stable reference genes were rpoB and recN respectively. This study provides recommendations for stable endogenous control genes for use in further studies involving measurement of gene expression levels. PMID- 27942008 TI - The DPP4 Inhibitor Linagliptin Protects from Experimental Diabetic Retinopathy. AB - BACKGROUND/AIMS: Dipeptidyl peptidase 4 (DPP4) inhibitors improve glycemic control in type 2 diabetes, however, their influence on the retinal neurovascular unit remains unclear. METHODS: Vasculo- and neuroprotective effects were assessed in experimental diabetic retinopathy and high glucose-cultivated C. elegans, respectively. In STZ-diabetic Wistar rats (diabetes duration of 24 weeks), DPP4 activity (fluorometric assay), GLP-1 (ELISA), methylglyoxal (LC-MS/MS), acellular capillaries and pericytes (quantitative retinal morphometry), SDF-1a and heme oxygenase-1 (ELISA), HMGB-1, Iba1 and Thy1.1 (immunohistochemistry), nuclei in the ganglion cell layer, GFAP (western blot), and IL-1beta, Icam1, Cxcr4, catalase and beta-actin (quantitative RT-PCR) were determined. In C. elegans, neuronal function was determined using worm tracking software. RESULTS: Linagliptin decreased DPP4 activity by 77% and resulted in an 11.5-fold increase in active GLP-1. Blood glucose and HbA1c were reduced by 13% and 14% and retinal methylglyoxal by 66%. The increase in acellular capillaries was diminished by 70% and linagliptin prevented the loss of pericytes and retinal ganglion cells. The rise in Iba-1 positive microglia was reduced by 73% with linagliptin. In addition, the increase in retinal Il1b expression was decreased by 65%. As a functional correlate, impairment of motility (body bending frequency) was significantly prevented in C. elegans. CONCLUSION: Our data suggest that linagliptin has a protective effect on the microvasculature of the diabetic retina, most likely due to a combination of neuroprotective and antioxidative effects of linagliptin on the neurovascular unit. PMID- 27942009 TI - Hydroxycholesterol Levels in the Serum and Cerebrospinal Fluid of Patients with Neuromyelitis Optica Revealed by LC-Ag+CIS/MS/MS and LC-ESI/MS/MS with Picolinic Derivatization: Increased Levels and Association with Disability during Acute Attack. AB - Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS). Hydroxycholesterols (OHCs), metabolites of CNS cholesterol, are involved in diverse cellular responses to inflammation and demyelination, and may also be involved in the pathogenesis of NMO. We aimed to develop a sensitive and reliable method for the quantitative analysis of three major OHCs (24S-, 25-, and 27-OHCs), and to evaluate their concentration in the cerebrospinal fluid (CSF) and serum of patients with NMO. The levels of the three OHCs in the serum and CSF were measured using liquid chromatography-silver ion coordination ionspray tandem mass spectrometry and liquid chromatography electrospray ionization tandem mass spectrometry with picolinyl ester derivatization, respectively. The linear range was 5-250 ng/mL for 24S- and 27 OHC, and 0.5-25 ng/mL for 25-OHC in serum, and was 0.1-5 ng/mL for 24S- and 27 OHC, and 0.03-1 ng/mL for 25-OHC in CSF. Precision and accuracy were 0.5%-14.7% and 92.5%-109.7%, respectively, in serum, and were 0.8%-7.7% and 94.5%-119.2%, respectively, in CSF. Extraction recovery was 82.7%-90.7% in serum and 68.4% 105.0% in CSF. When analyzed in 26 NMO patients and 23 control patients, the 25 OHC (0.54 +/- 0.96 ng/mL vs. 0.09 +/- 0.04 ng/mL, p = 0.032) and 27-OHC (2.68 +/- 3.18 ng/mL vs. 0.68 +/- 0.25 ng/mL, p = 0.005) were increased in the CSF from NMO patients. When we measured the OHCCSF index that controls the effects of blood brain barrier disruption on the level of OHC in the CSF, the 27-OHCCSF index was associated with disability (0.723; 95% confidence interval (CI)- 0.181, 0.620; p = 0.002), while the 24-OHCCSF index (0.518; 95% CI- 1.070, 38.121; p = 0.040) and 25-OHCCSF index (0.677; 95% CI- 4.313, 18.532; p = 0.004) were associated with the number of white blood cells in the CSF of NMO patients. Our results imply that OHCs in the CNS could play a role in the pathogenesis of NMO. PMID- 27942011 TI - GlycCompSoft: Software for Automated Comparison of Low Molecular Weight Heparins Using Top-Down LC/MS Data. AB - Low molecular weight heparins are complex polycomponent drugs that have recently become amenable to top-down analysis using liquid chromatography-mass spectrometry. Even using open source deconvolution software, DeconTools, and automatic structural assignment software, GlycReSoft, the comparison of two or more low molecular weight heparins is extremely time-consuming, taking about a week for an expert analyst and provides no guarantee of accuracy. Efficient data processing tools are required to improve analysis. This study uses the programming language of Microsoft ExcelTM Visual Basic for Applications to extend its standard functionality for macro functions and specific mathematical modules for mass spectrometric data processing. The program developed enables the comparison of top-down analytical glycomics data on two or more low molecular weight heparins. The current study describes a new program, GlycCompSoft, which has a low error rate with good time efficiency in the automatic processing of large data sets. The experimental results based on three lots of Lovenox(r), Clexane(r) and three generic enoxaparin samples show that the run time of GlycCompSoft decreases from 11 to 2 seconds when the data processed decreases from 18000 to 1500 rows. PMID- 27942010 TI - Limited Impact of Imatinib in a Murine Model of Sclerodermatous Chronic Graft versus-Host Disease. AB - BACKGROUND: Sclerodermatous chronic Graft-versus-Host Disease (scl-cGVHD) is one of the most severe form of cGVHD. The Platelet-derived Grotwth Factor (PDGF) and the Transforming Growth Factor-beta (TGF-beta) play a significant role in the fibrosing process occurring in scl-cGVHD. This prompted us to assess the impact of the PDGF-r and c-Abl tyrosine kinase inhibitor imatinib on scl-cGVHD. METHODS: To assess the impact of imatinib on T cell subset proliferation in vivo, Balb/cJ recipient mice were lethally (7 Gy) irradiated and then injected with 10x106 bone marrow cells from B10.D2 mice on day 0. Fourteen days later, 70x106 carboxyfluorescein succinimidyl ester (CFSE)-labeled splenocytes from B10.D2 mice were infused and imatinib or sterile water was administered for 5 days. To induce severe scl-cGVHD, Balb/cJ mice were injected i.v. with 10.106 bone marrow cells and 70.106 splenocytes from B10.D2 donor mice after 7 Gy irradiation. Mice were then given sterile water or imatinib from day +7 after transplantation to the end of the experiment (day +52). RESULTS: Imatinib decreased the proliferation of total T cells (P = 0.02), CD8+ T cells (P = 0.01), and of regulatory T cells (Tregs) (P = 0.02) in the spleen. In the severe scl-cGVHD model, imatinib-treated mice had significantly lower levels of PDGF-r phosphorylation than control mice on day 29 after transplantation (P = 0.008). However, scl-cGVHD scores were similar between vehicle- and imatinib-treated mice during the whole experiment, while there was a suggestion for less weight loss in imatinib-treated mice that reached statistical significance at day +52 following transplantation (P = 0.02). CONCLUSIONS: Imatinib had a limited impact in murine scl-cGVHD despite significant inhibition of PDGF-r. PMID- 27942012 TI - Still Bay Point-Production Strategies at Hollow Rock Shelter and Umhlatuzana Rock Shelter and Knowledge-Transfer Systems in Southern Africa at about 80-70 Thousand Years Ago. AB - It has been suggested that technological variations associated with Still Bay assemblages of southern Africa have not been addressed adequately. Here we present a study developed to explore regional and temporal variations in Still Bay point-production strategies. We applied our approach in a regional context to compare the Still Bay point assemblages from Hollow Rock Shelter (Western Cape) and Umhlatuzana Rock Shelter (KwaZulu-Natal). Our interpretation of the point production strategies implies inter-regional point-production conventions, but also highlights variability and intra-regional knapping strategies used for the production of Still Bay points. These strategies probably reflect flexibility in the organisation of knowledge-transfer systems at work during the later stages of the Middle Stone Age between about 80 ka and 70 ka in South Africa. PMID- 27942013 TI - Scheduling Independent Partitions in Integrated Modular Avionics Systems. AB - Recently the integrated modular avionics (IMA) architecture has been widely adopted by the avionics industry due to its strong partition mechanism. Although the IMA architecture can achieve effective cost reduction and reliability enhancement in the development of avionics systems, it results in a complex allocation and scheduling problem. All partitions in an IMA system should be integrated together according to a proper schedule such that their deadlines will be met even under the worst case situations. In order to help provide a proper scheduling table for all partitions in IMA systems, we study the schedulability of independent partitions on a multiprocessor platform in this paper. We firstly present an exact formulation to calculate the maximum scaling factor and determine whether all partitions are schedulable on a limited number of processors. Then with a Game Theory analogy, we design an approximation algorithm to solve the scheduling problem of partitions, by allowing each partition to optimize its own schedule according to the allocations of the others. Finally, simulation experiments are conducted to show the efficiency and reliability of the approach proposed in terms of time consumption and acceptance ratio. PMID- 27942015 TI - Varroa destructor Mites Can Nimbly Climb from Flowers onto Foraging Honey Bees. AB - Varroa destructor, the introduced parasite of European honey bees associated with massive colony deaths, spreads readily through populations of honey bee colonies, both managed colonies living crowded together in apiaries and wild colonies living widely dispersed in natural settings. Mites are hypothesized to spread between most managed colonies via phoretically riding forager bees when they engage in robbing colonies or they drift between hives. However, widely spaced wild colonies show Varroa infestation despite limited opportunities for robbing and little or no drifting of bees between colonies. Both wild and managed colonies may also exchange mites via another mechanism that has received remarkably little attention or study: floral transmission. The present study tested the ability of mites to infest foragers at feeders or flowers. We show that Varroa destructor mites are highly capable of phoretically infesting foraging honey bees, detail the mechanisms and maneuvers by which they do so, and describe mite behaviors post-infestation. PMID- 27942014 TI - Structural and Behavioral Correlates of HIV Infection among Pregnant Women in a Country with a Highly Generalized HIV Epidemic: A Cross-Sectional Study with a Probability Sample of Antenatal Care Facilities in Swaziland. AB - INTRODUCTION: HIV disproportionately affects women in Sub-Saharan Africa. Swaziland bears the highest HIV prevalence of 41% among pregnant women in this region. This heightened HIV-epidemic reflects the importance of context-specific interventions. Apart from routine HIV surveillance, studies that examine structural and behavioral factors associated with HIV infection among women may facilitate the revitalization of existing programs and provide insights to inform context-specific HIV prevention interventions. METHODS AND FINDINGS: This cross sectional study employed a two-stage random cluster sampling in ten antenatal health care facilities in the Hhohho region of Swaziland in August and September 2015. Participants were eligible for the study if they were 18 years or older and had tested for HIV. Self-administered tablet-based questionnaires were used to assess HIV risk factors. Of all eligible pregnant women, 827 (92.4%) participated, out of which 297 (35.9%) were self-reportedly HIV positive. Among structural factors, family function was not significantly associated with self reported HIV positive status, while lower than high school educational attainment (AOR, 1.65; CI, 1.14-3.38; P = 0.008), and income below minimum wage (AOR, 1.81; CI, 1.09-3.01; P = 0.021) were significantly associated with self-reported HIV positive status. Behavioral factors significantly associated with reporting a positive HIV status included; >=2 lifetime sexual partners (AOR, 3.16; CI, 2.00 5.00; P<0.001), and ever cohabited (AOR, 2.39; CI, 1.66-3.43; P = 0.00). The most cited reason for having multiple sexual partners was financial gain. HIV/AIDS related knowledge level was high but not associated to self-reported HIV status (P = 0.319). CONCLUSIONS: Structural and behavioral factors showed significant association with self-reported HIV infection among pregnant women in Swaziland while HIV/AIDS-related knowledge and family function did not. This suggests that HIV interventions should be reinforced taking into consideration these findings. The findings also suggest the importance of future research sensitive to the Swazi and African sociocultural contexts, especially research for family function. PMID- 27942016 TI - Dengue and Chikungunya Virus Infections among Young Febrile Adults Evaluated for Acute HIV-1 Infection in Coastal Kenya. AB - BACKGROUND: Fever is common among patients seeking care in sub-Saharan Africa (sSA), but causes other than malaria are rarely diagnosed. We assessed dengue and chikungunya virus infections among young febrile adults evaluated for acute HIV infection (AHI) and malaria in coastal Kenya. METHODS: We tested plasma samples obtained in a cross-sectional study from febrile adult patients aged 18-35 years evaluated for AHI and malaria at urgent care seeking at seven health facilities in coastal Kenya in 2014-2015. Dengue virus (DENV) and chikungunya virus (CHIKV) were amplified using quantitative real-time reverse-transcription polymerase chain reaction. We conducted logistic regression analyses to determine independent predictors of dengue virus infection. RESULTS: 489 samples that were negative for both AHI and malaria were tested, of which 43 (8.8%, 95% confidence interval [CI]: 6.4-11.7) were positive for DENV infection. No participant was positive for CHIKV infection. DENV infections were associated with clinic visits in the rainy season (adjusted odds ratio (AOR) = 3.0, 95% CI: 1.3-6.5) and evaluation at a private health facility (AOR 5.2, 95% CI: 2.0-13.1) or research health facility (AOR = 25.6, 95% CI: 8.9-73.2) instead of a public health facility. CONCLUSION: A high prevalence of DENV infections was found in febrile young adult patients evaluated for AHI. Our data suggests that DENV, along with AHI and malaria, should be considered in the differential diagnosis of the adult patient seeking care for fever in coastal Kenya. PMID- 27942017 TI - Characterisation of Neutropenia-Associated Neutrophil Elastase Mutations in a Murine Differentiation Model In Vitro and In Vivo. AB - Severe congenital neutropenia (SCN) is characterised by a differentiation block in the bone marrow and low neutrophil numbers in the peripheral blood, which correlates with increased risk of bacterial infections. Several underlying gene defects have been identified in SCN patients. Mutations in the neutrophil elastase (ELANE) gene are frequently found in SCN and cyclic neutropenia. Both mislocalization and misfolding of mutant neutrophil elastase protein resulting in ER stress and subsequent induction of the unfolded protein response (UPR) have been proposed to be responsible for neutrophil survival and maturation defects. However, the detailed molecular mechanisms still remain unclear, in part due to the lack of appropriate in vitro and in vivo models. Here we used a system of neutrophil differentiation from immortalised progenitor lines by conditional expression of Hoxb8, permitting the generation of mature near-primary neutrophils in vitro and in vivo. NE-deficient Hoxb8 progenitors were reconstituted with murine and human forms of typical NE mutants representative of SCN and cyclic neutropenia, and differentiation of the cells was analysed in vitro and in vivo. ER stress induction by NE mutations could be recapitulated during neutrophil differentiation in all NE mutant-reconstituted Hoxb8 cells. Despite ER stress induction, no change in survival, maturation or function of differentiating cells expressing either murine or human NE mutants was observed. Further analysis of in vivo differentiation of Hoxb8 cells in a murine model of adoptive transfer did not reveal any defects in survival or differentiation in the mouse. Although the Hoxb8 system has been found to be useful for dissection of defects in neutrophil development, our findings indicate that the use of murine systems for analysis of NE-mutation-associated pathogenesis is complicated by differences between humans and mice in the physiology of granulopoiesis, which may go beyond possible differences in expression and activity of neutrophil elastase itself. PMID- 27942019 TI - Correction: Context-Aware Image Compression. AB - [This corrects the article DOI: 10.1371/journal.pone.0158201.]. PMID- 27942018 TI - Caspase-8 and Caspase-9 Functioned Differently at Different Stages of the Cyclic Stretch-Induced Apoptosis in Human Periodontal Ligament Cells. AB - BACKGROUND: Human periodontal ligament (PDL) cells underwent apoptosis after mechanical stretch loading. However, the exact signalling pathway remains unknown. This study aimed to elucidate how the apoptotic caspases functioned in the cyclic stretch-induced apoptosis in human PDL cells. MATERIALS AND METHODS: In the present study, 20% cyclic stretch was selected to load the cells for 6 or 24 h. The following parameters were analyzed: apoptotic rates, the protein levels of caspase-3, -7, -8 and -9 and the activities of caspase-8 and -9. Subsequently, the influences of caspase-8 and caspase-9 inhibitors on the apoptotic rate and the protein level of the activated caspase-3 were assessed as well. RESULTS: The apoptotic rates increased in response to cyclic stretch, but the cells entered different apoptotic stages after 6 and 24 h stretches. Caspase-3, -7, -8 and -9 were all activated after stretch loading. The stretch-induced apoptosis and the protein level of the activated caspase-3 were inhibited after inhibiting both caspase-8 and caspase-9 in both 6 and 24 h stretched cells and after inhibiting caspase-9 in 24 h stretched cells. CONCLUSION: Caspase-8 and -9 functioned differently at different apoptotic stages in human PDL cells after cyclic stretch. PMID- 27942020 TI - Evolutionary and Functional Diversification of the Vitamin D Receptor-Lithocholic Acid Partnership. AB - The evolution, molecular behavior, and physiological function of nuclear receptors are of particular interest given their diverse roles in regulating essential biological processes. The vitamin D receptor (VDR) is well known for its canonical roles in calcium homeostasis and skeletal maintenance. Additionally, VDR has received an increased amount of attention due to the discovery of numerous non-calcemic functions, including the detoxification of lithocholic acid. Lithocholic acid is a toxic metabolite of chenodeoxycholic acid, a primary bile acid. The partnership between the VDR and lithocholic acid has been hypothesized to be a recent adaptation that evolved to mediate the detoxification and elimination of lithocholic acid from the gut. This partnership is speculated to be limited to higher vertebrates (birds and mammals), as lower vertebrates do not synthesize the parent compound of lithocholic acid. However, the molecular functions associated with the observed insensitivity of basal VDRs to lithocholic acid have not been explored. Here we characterize canonical nuclear receptor functions of VDRs from select species representing key nodes in vertebrate evolution and span a range of bile salt phenotypes. Competitive ligand binding assays revealed that the receptor's affinity for lithocholic acid is highly conserved across species, suggesting that lithocholic acid affinity is an ancient and non-adaptive trait. However, transient transactivation assays revealed that lithocholic acid-mediated VDR activation might have evolved more recently, as the non-mammalian receptors did not respond to lithocholic acid unless exogenous coactivator proteins were co-expressed. Subsequent functional assays indicated that differential lithocholic acid-mediated receptor activation is potentially driven by differential protein-protein interactions between VDR and nuclear receptor coregulator proteins. We hypothesize that the vitamin D receptor-lithocholic acid partnership evolved as a by-product of natural selection on the ligand-receptor partnership between the vitamin D receptor and the native VDR ligand: 1alpha,25-dihydroxyvitamin D3, the biologically active metabolite of vitamin D3. PMID- 27942022 TI - A Large Collection of Novel Nematode-Infecting Microsporidia and Their Diverse Interactions with Caenorhabditis elegans and Other Related Nematodes. AB - Microsporidia are fungi-related intracellular pathogens that may infect virtually all animals, but are poorly understood. The nematode Caenorhabditis elegans has recently become a model host for studying microsporidia through the identification of its natural microsporidian pathogen Nematocida parisii. However, it was unclear how widespread and diverse microsporidia infections are in C. elegans or other related nematodes in the wild. Here we describe the isolation and culture of 47 nematodes with microsporidian infections. N. parisii is found to be the most common microsporidia infecting C. elegans in the wild. In addition, we further describe and name six new species in the Nematocida genus. Our sampling and phylogenetic analysis further identify two subclades that are genetically distinct from Nematocida, and we name them Enteropsectra and Pancytospora. Interestingly, unlike Nematocida, these two genera belong to the main clade of microsporidia that includes human pathogens. All of these microsporidia are horizontally transmitted and most specifically infect intestinal cells, except Pancytospora epiphaga that replicates mostly in the epidermis of its Caenorhabditis host. At the subcellular level in the infected host cell, spores of the novel genus Enteropsectra show a characteristic apical distribution and exit via budding off of the plasma membrane, instead of exiting via exocytosis as spores of Nematocida. Host specificity is broad for some microsporidia, narrow for others: indeed, some microsporidia can infect Oscheius tipulae but not its sister species Oscheius sp. 3, and conversely some microsporidia found infecting Oscheius sp. 3 do not infect O. tipulae. We also show that N. ausubeli fails to strongly induce in C. elegans the transcription of genes that are induced by other Nematocida species, suggesting it has evolved mechanisms to prevent induction of this host response. Altogether, these newly isolated species illustrate the diversity and ubiquity of microsporidian infections in nematodes, and provide a rich resource to investigate host-parasite coevolution in tractable nematode hosts. PMID- 27942024 TI - Correction: Linear Quantitative Profiling Method Fast Monitors Alkaloids of Sophora Flavescens that was Verified by Tri-marker Analyses. AB - [This corrects the article DOI: 10.1371/journal.pone.0161146.]. PMID- 27942021 TI - MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis. AB - Vacuolar bacterial pathogens are sheltered within unique membrane-bound organelles that expand over time to support bacterial replication. These compartments sequester bacterial molecules away from host cytosolic immunosurveillance pathways that induce antimicrobial responses. The mechanisms by which the human pulmonary pathogen Legionella pneumophila maintains niche homeostasis are poorly understood. We uncovered that the Legionella-containing vacuole (LCV) required a sustained supply of host lipids during expansion. Lipids shortage resulted in LCV rupture and initiation of a host cell death response, whereas excess of host lipids increased LCVs size and housing capacity. We found that lipids uptake from serum and de novo lipogenesis are distinct redundant supply mechanisms for membrane biogenesis in Legionella-infected macrophages. During infection, the metabolic checkpoint kinase Mechanistic Target of Rapamycin (MTOR) controlled lipogenesis through the Serum Response Element Binding Protein 1 and 2 (SREBP1/2) transcription factors. In Legionella-infected macrophages a host-driven response that required the Toll-like receptors (TLRs) adaptor protein Myeloid differentiation primary response gene 88 (Myd88) dampened MTOR signaling which in turn destabilized LCVs under serum starvation. Inactivation of the host MTOR-suppression pathway revealed that L. pneumophila sustained MTOR signaling throughout its intracellular infection cycle by a process that required the upstream regulator Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and one or more Dot/Icm effector proteins. Legionella-sustained MTOR signaling facilitated LCV expansion and inhibition of the PI3K-MTOR-SREPB1/2 axis through pharmacological or genetic interference or by activation of the host MTOR suppression response destabilized expanding LCVs, which in turn triggered cell death of infected macrophages. Our work identified a host metabolic requirement for LCV homeostasis and demonstrated that L. pneumophila has evolved to manipulate MTOR-dependent lipogenesis for optimal intracellular replication. PMID- 27942023 TI - Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema. AB - INTRODUCTION: Secondary lymphedema is a common complication of cancer treatment and recent studies have demonstrated that lymph node transplantation (LNT) can decrease swelling, as well as the incidence of infections. However, although these results are exciting, the mechanisms by which LNT improves these pathologic findings of lymphedema remain unknown. Using a transgenic mouse model of lymphedema, this study sought to analyze the effect of LNT on lymphatic regeneration and T cell-mediated immune responses. METHODS: We used a mouse model in which the expression of the human diphtheria toxin receptor is driven by the FLT4 promoter to enable the local ablation of the lymphatic system through subdermal hindlimb diphtheria toxin injections. Popliteal lymph node dissection was subsequently performed after a two-week recovery period, followed by either orthotopic LNT or sham surgery after an additional two weeks. Hindlimb swelling, lymphatic vessel regeneration, immune cell trafficking, and T cell-mediated immune responses were analyzed 10 weeks later. RESULTS: LNT resulted in a marked decrease in hindlimb swelling, fibroadipose tissue deposition, and decreased accumulation of perilymphatic inflammatory cells, as compared to controls. In addition, LNT induced a marked lymphangiogenic response in both capillary and collecting lymphatic vessels. Interestingly, the resultant regenerated lymphatics were abnormal in appearance on lymphangiography, but LNT also led to a notable increase in dendritic cell trafficking from the periphery to the inguinal lymph nodes and improved adaptive immune responses. CONCLUSIONS: LNT decreases pathological changes of lymphedema and was shown to potently induce lymphangiogenesis. Lymphatic vessels induced by LNT were abnormal in appearance, but were functional and able to transport antigen-presenting cells. Animals treated with LNT have an increased ability to mount T cell-mediated immune responses when sensitized to antigens in the affected hindlimb. PMID- 27942027 TI - Correction: Elevating CLIC4 in Multiple Cell Types Reveals a TGF-beta Dependent Induction of a Dominant Negative Smad7 Splice Variant. AB - [This corrects the article DOI: 10.1371/journal.pone.0161410.]. PMID- 27942026 TI - Characterisation of the Immunophenotype of Dogs with Primary Immune-Mediated Haemolytic Anaemia. AB - BACKGROUND: Immune-mediated haemolytic anaemia (IMHA) is reported to be the most common autoimmune disease of dogs, resulting in significant morbidity and mortality in affected animals. Haemolysis is caused by the action of autoantibodies, but the immunological changes that result in their production have not been elucidated. AIMS: To investigate the frequency of regulatory T cells (Tregs) and other lymphocyte subsets and to measure serum concentrations of cytokines and peripheral blood mononuclear cell expression of cytokine genes in dogs with IMHA, healthy dogs and dogs with inflammatory diseases. ANIMALS: 19 dogs with primary IMHA, 22 dogs with inflammatory diseases and 32 healthy control dogs. METHODS: Residual EDTA-anti-coagulated blood samples were stained with fluorophore-conjugated monoclonal antibodies and analysed by flow cytometry to identify Tregs and other lymphocyte subsets. Total RNA was also extracted from peripheral blood mononuclear cells to investigate cytokine gene expression, and concentrations of serum cytokines (interleukins 2, 6 10, CXCL-8 and tumour necrosis factor alpha) were measured using enhanced chemiluminescent assays. Principal component analysis was used to investigate latent variables that might explain variability in the entire dataset. RESULTS: There was no difference in the frequency or absolute numbers of Tregs among groups, nor in the proportions of other lymphocyte subsets. The concentrations of pro-inflammatory cytokines were greater in dogs with IMHA compared to healthy controls, but the concentration of IL-10 and the expression of cytokine genes did not differ between groups. Principal component analysis identified four components that explained the majority of the variability in the dataset, which seemed to correspond to different aspects of the immune response. CONCLUSIONS: The immunophenotype of dogs with IMHA differed from that of dogs with inflammatory diseases and from healthy control dogs; some of these changes could suggest abnormalities in peripheral tolerance that permit development of autoimmune disease. The frequency of Tregs did not differ between groups, suggesting that deficiency in the number of these cells is not responsible for development of IMHA. PMID- 27942028 TI - Recovery of Coastal Fauna after the 2011 Tsunami in Japan as Determined by Bimonthly Underwater Visual Censuses Conducted over Five Years. AB - Massive tsunamis induce catastrophic disturbance in marine ecosystems, yet they can provide unique opportunities to observe the process of regeneration. Here, we report the recovery of fauna after the 2011 tsunami in northeast Japan based on underwater visual censuses performed every two months over five years. Both total fish abundance and species richness increased from the first to the second year after the tsunami followed by stabilization in the following years. Short-lived fish, such as the banded goby Pterogobius elapoides, were relatively abundant in the first two years, whereas long-lived species, such as the black rockfish Sebastes cheni, increased in the latter half of the survey period. Tropical fish species were recorded only in the second and third years after the tsunami. The body size of long-lived fish increased during the survey period resulting in a gradual increase of total fish biomass. The recovery of fish assemblages was slow at one site located in the inner bay, where the impact of the tsunami was the strongest. Apart from fish, blooms of the moon jellyfish Aurelia sp. occurred only in the first two years after the tsunami, whereas the abundances of sea cucumber Apostichopus japonicus and abalone Haliotis discus hannai increased after the second year. Although we lack quantitative data prior to the tsunami, we conclude that it takes approximately three years for coastal reef fish assemblages to recover from a heavy disturbance such as a tsunami and that the recovery is dependent on species-specific life span and habitat. PMID- 27942025 TI - Clostridium difficile Toxin A Undergoes Clathrin-Independent, PACSIN2-Dependent Endocytosis. AB - Clostridium difficile infection affects a significant number of hospitalized patients in the United States. Two homologous exotoxins, TcdA and TcdB, are the major virulence factors in C. difficile pathogenesis. The toxins are glucosyltransferases that inactivate Rho family-GTPases to disrupt host cellular function and cause fluid secretion, inflammation, and cell death. Toxicity depends on receptor binding and subsequent endocytosis. TcdB has been shown to enter cells by clathrin-dependent endocytosis, but the mechanism of TcdA uptake is still unclear. Here, we utilize a combination of RNAi-based knockdown, pharmacological inhibition, and cell imaging approaches to investigate the endocytic mechanism(s) that contribute to TcdA uptake and subsequent cytopathic and cytotoxic effects. We show that TcdA uptake and cellular intoxication is dynamin-dependent but does not involve clathrin- or caveolae-mediated endocytosis. Confocal microscopy using fluorescently labeled TcdA shows significant colocalization of the toxin with PACSIN2-positive structures in cells during entry. Disruption of PACSIN2 function by RNAi-based knockdown approaches inhibits TcdA uptake and toxin-induced downstream effects in cells indicating that TcdA entry is PACSIN2-dependent. We conclude that TcdA and TcdB utilize distinct endocytic mechanisms to intoxicate host cells. PMID- 27942029 TI - Predictors of Participation of Sophomore Medical Students in a Health-Promoting Intervention: An Observational Study. AB - Medical students and doctors have to be particularly stress-resilient, as both medical education and practice are considered very stressful. Specific stressors can lead to increased risks of developing, for example, depression, anxiety and burnout. Relaxation techniques have proven to be effective for the prevention of these outcomes in student populations. However, only a very few medical students practice relaxation techniques regularly early on in their studies. Furthermore, it is unclear which students make use of stress-management offers and hence whether vulnerable students are generally reachable. Therefore, the aim of our study was to explore predictors of participating in a voluntary stress management course for sophomore medical students. One cohort of freshmen at a German medical school was surveyed at the end of the freshman year [t1] and at the end of the sophomore year [t2]. In addition to sociodemographic information, we captured perceived study stress, self-rated general health and mental health and dimensions of study-related behaviour and experience as potential predictors of participation at t1. During the sophomore year, we offered the participants a progressive muscle relaxation (PMR) beginners' course. At t2, we registered participation status. We used binary logistic regression analyses in order to assess correlations between potential predictors and participation. About one third of the whole class took part in the course. The main reason for non participation was "no time". Being female and higher levels of anxiety were the strongest predictors of course participation. Career ambition (the higher, the less likely to participate) and emotional distancing (the higher, the more likely to participate) were further significant predictors. Future interventions should be attractive to both male and female medical students. Ideally, for every hour of stress management teaching, the curriculum should be cut by at least the same amount of time. PMID- 27942032 TI - The Productivity Costs of Premature Mortality Due to Cancer in Australia: Evidence from a Microsimulation Model. AB - AIM: To estimate the productivity costs of premature mortality due to cancer in Australia, in aggregate and for the 26 most prevalent cancer sites. METHODS: A human capital approach was adopted to estimate the long term impacts of Australian cancer deaths in 2003. Using population mortality data, the labour force participation and the present value of lifetime income (PVLI) forgone due to premature mortality was estimated based on individual characteristics at the time of death including age, sex and socioeconomic status. Outcomes were modelled to the year 2030 using economic data from a national microsimulation model. A discount rate of 3% was applied and costs were reported in 2016 Australian dollars. RESULTS: Premature deaths from cancer in 2003 resulted in 88,000 working years lost and a cost of $4.2 billion in the PVLI forgone. Costs were close to three times higher in males than females due to the higher number of premature deaths in men, combined with higher levels of workforce participation and income. Lung, colorectal and brain cancers accounted for the highest proportion of costs, while testicular cancer was the most costly cancer site per death. CONCLUSIONS: The productivity costs of premature mortality due to cancer are significant. These results provide an economic measure of the cancer burden which may assist decision makers in allocating scare resources amongst competing priorities. PMID- 27942030 TI - Identification of Emotional Facial Expressions: Effects of Expression, Intensity, and Sex on Eye Gaze. AB - The identification of emotional expressions is vital for social interaction, and can be affected by various factors, including the expressed emotion, the intensity of the expression, the sex of the face, and the gender of the observer. This study investigates how these factors affect the speed and accuracy of expression recognition, as well as dwell time on the two most significant areas of the face: the eyes and the mouth. Participants were asked to identify expressions from female and male faces displaying six expressions (anger, disgust, fear, happiness, sadness, and surprise), each with three levels of intensity (low, moderate, and normal). Overall, responses were fastest and most accurate for happy expressions, but slowest and least accurate for fearful expressions. More intense expressions were also classified most accurately. Reaction time showed a different pattern, with slowest response times recorded for expressions of moderate intensity. Overall, responses were slowest, but also most accurate, for female faces. Relative to male observers, women showed greater accuracy and speed when recognizing female expressions. Dwell time analyses revealed that attention to the eyes was about three times greater than on the mouth, with fearful eyes in particular attracting longer dwell times. The mouth region was attended to the most for fearful, angry, and disgusted expressions and least for surprise. These results extend upon previous findings to show important effects of expression, emotion intensity, and sex on expression recognition and gaze behaviour, and may have implications for understanding the ways in which emotion recognition abilities break down. PMID- 27942031 TI - Evaluation of 19,460 Wheat Accessions Conserved in the Indian National Genebank to Identify New Sources of Resistance to Rust and Spot Blotch Diseases. AB - A comprehensive germplasm evaluation study of wheat accessions conserved in the Indian National Genebank was conducted to identify sources of rust and spot blotch resistance. Genebank accessions comprising three species of wheat-Triticum aestivum, T. durum and T. dicoccum were screened sequentially at multiple disease hotspots, during the 2011-14 crop seasons, carrying only resistant accessions to the next step of evaluation. Wheat accessions which were found to be resistant in the field were then assayed for seedling resistance and profiled using molecular markers. In the primary evaluation, 19,460 accessions were screened at Wellington (Tamil Nadu), a hotspot for wheat rusts. We identified 4925 accessions to be resistant and these were further evaluated at Gurdaspur (Punjab), a hotspot for stripe rust and at Cooch Behar (West Bengal), a hotspot for spot blotch. The second round evaluation identified 498 accessions potentially resistant to multiple rusts and 868 accessions potentially resistant to spot blotch. Evaluation of rust resistant accessions for seedling resistance against seven virulent pathotypes of three rusts under artificial epiphytotic conditions identified 137 accessions potentially resistant to multiple rusts. Molecular analysis to identify different combinations of genetic loci imparting resistance to leaf rust, stem rust, stripe rust and spot blotch using linked molecular markers, identified 45 wheat accessions containing known resistance genes against all three rusts as well as a QTL for spot blotch resistance. The resistant germplasm accessions, particularly against stripe rust, identified in this study can be excellent potential candidates to be employed for breeding resistance into the background of high yielding wheat cultivars through conventional or molecular breeding approaches, and are expected to contribute toward food security at national and global levels. PMID- 27942034 TI - Synthesis, Characterization, and Biological Evaluation of Anti-HER2 Indocyanine Green-Encapsulated PEG-Coated PLGA Nanoparticles for Targeted Phototherapy of Breast Cancer Cells. AB - Human epidermal growth factor receptor 2 (HER2)-overexpressed breast cancer is known to be more aggressive and resistant to medicinal treatment and therefore to whom an alternative therapeutics is needed. Indocyanine green (ICG) has been widely exploited in breast cancer phototherapy. However, drawbacks of accelerated degradation and short half-life (2-4 min) in blood seriously hamper its use in the clinic. To overcome these challenges, an anti-HER2 ICG-encapsulated polyethylene glycol-coated poly(lactic-co-glycolic acid) nanoparticles (HIPPNPs) were developed in this study. Through the analyses of degradation rate coefficients of ICG with and without polymeric encapsulation, the photostability of HIPPNP-entrapped ICG significantly enhanced 4 folds (P < 0.05) while its thermal stabilities at 4 and 37 degrees C significantly enhanced 5 and 3 (P < 0.05 for each) folds, respectively, under equal lighting and/or heating treatment for 48 h. The target specificity of HIPPNPs to HER2-positive cells was demonstrated based on a 6-fold (P < 0.05) enhancement of uptake efficiency of HIPPNPs in MDA-MB-453/HER2(+) cells within 4 h as compared with that in MCF7/HER2(-) cells. Moreover, the HIPPNPs with <= 25 MUM ICG equivalent were nontoxic to cells in the absence of light illumination, and enabled to generate similar amount of singlet oxygen and hyperthermia effect as compared with that used by free ICG upon NIR irradiation. After 808 nm-laser irradiation with intensity of 6 W/cm2 for 5 min, the viability of MDA-MB-453 cells pre-treated by HIPPNPs with >= 5 MUM ICG equivalent for 4 h significantly reduced as compared with that treated by equal concentration of free ICG (P < 0.05) and > 90% of the cells were eradicated while the dose of HIPPNPs was increased to 25 MUM ICG equivalent. In summary, the developed HIPPNPs are anticipated as a feasible tool for use in phototherapy of breast cancer cells with HER2 expression. PMID- 27942033 TI - Feedback Loops of the Mammalian Circadian Clock Constitute Repressilator. AB - Mammals evolved an endogenous timing system to coordinate their physiology and behaviour to the 24h period of the solar day. While it is well accepted that circadian rhythms are generated by intracellular transcriptional feedback loops, it is still debated which network motifs are necessary and sufficient for generating self-sustained oscillations. Here, we systematically explore a data based circadian oscillator model with multiple negative and positive feedback loops and identify a series of three subsequent inhibitions known as "repressilator" as a core element of the mammalian circadian oscillator. The central role of the repressilator motif is consistent with time-resolved ChIP-seq experiments of circadian clock transcription factors and loss of rhythmicity in core clock gene knockouts. PMID- 27942035 TI - Thyroid Hormone Signaling in the Mouse Retina. AB - Thyroid hormone is a crucial regulator of gene expression in the developing and adult retina. Here we sought to map sites of thyroid hormone signaling at the cellular level using the transgenic FINDT3 reporter mouse model in which neurons express beta-galactosidase (beta-gal) under the control of a hybrid Gal4-TRalpha receptor when triiodothyronine (T3) and cofactors of thyroid receptor signaling are present. In the adult retina, nearly all neurons of the ganglion cell layer (GCL, ganglion cells and displaced amacrine cells) showed strong beta-gal labeling. In the inner nuclear layer (INL), a minority of glycineric and GABAergic amacrine cells showed beta-gal labeling, whereas the majority of amacrine cells were unlabeled. At the level of amacrine types, beta-gal labeling was found in a large proportion of the glycinergic AII amacrines, but only in a small proportion of the cholinergic/GABAergic 'starburst' amacrines. At postnatal day 10, there also was a high density of strongly beta-gal-labeled neurons in the GCL, but only few amacrine cells were labeled in the INL. There was no labeling of bipolar cells, horizontal cells and Muller glia cells at both stages. Most surprisingly, the photoreceptor somata in the outer nuclear layer also showed no beta-gal label, although thyroid hormone is known to control cone opsin expression. This is the first record of thyroid hormone signaling in the inner retina of an adult mammal. We hypothesize that T3 levels in photoreceptors are below the detection threshold of the reporter system. The topographical distribution of beta-gal-positive cells in the GCL follows the overall neuron distribution in that layer, with more T3-signaling cells in the ventral than the dorsal half-retina. PMID- 27942036 TI - Determinants of Three-Year Change in Children's Objectively Measured Sedentary Time. AB - BACKGROUND: Sedentary behaviours (SB) are highly prevalent in young people and may be adversely associated with physical and mental health. Understanding of the modifiable determinants of SB is necessary to inform the design of behaviour change interventions but much of the existing research is cross-sectional and focussed upon screen-based behaviours. PURPOSE: To examine the social, psychological and environmental determinants of change in children's objectively measured sedentary time from age 11 to 14 years. METHODS: Data are from the second (2008) and third (2011) waves of assessment in the Sport, Physical Activity, and Eating Behaviour: Environmental Determinants in Young People (SPEEDY) study, conducted in the county of Norfolk, United Kingdom. Longitudinal data on accelerometer assessed sedentary time were available for 316 (53.5% female, 11.2+/-0.3 years at baseline) and 264 children after-school and at the weekend respectively. Information on 14 candidate determinants, including school travel mode and electronic media ownership, was self-reported. Change in the proportion of registered time spent sedentary was used as the outcome variable in cross-classified linear regression models, adjusted for age, sex, body mass index and baseline sedentary time. Simple and multiple models were run and interactions with sex explored. RESULTS: Daily sedentary time increased by 30-40 minutes after school and at the weekend from baseline to follow-up. Participants who travelled to school by cycle exhibited smaller increases in after-school sedentary time (beta; 95%CI for change in % time spent sedentary: -3.3;-6.7,-0.07). No significant determinants of change in weekend sedentary time were identified. CONCLUSIONS: Time spent sedentary increased during the three-year duration of follow-up but few of the variables examined were significantly associated with changes in sedentary time. Children's mode of school travel may influence changes in their sedentary time over this period and should be examined further, alongside broader efforts to identify modifiable determinants of SB during childhood. PMID- 27942038 TI - Who Cares about Forests and Why? Individual Values Attributed to Forests in a Post-Frontier Region in Amazonia. AB - Understanding the multiple ways people value forests is important, as individual values regarding nature have been shown to partly determine willingness to participate in conservation initiatives. As individual values are influenced by past experiences, the way people value forests may be related to the ecosystem services they use and receive. We here aim to investigate if people value forests because of material and non-material benefits forest provide (material and non material values), and if these values are defined by previous experiences associated with using forest resources and having frequent contact with forests. By interviewing 363 residents across 20 landscapes varying in forest cover in a post-frontier region in Amazonia, we evaluated: (1) if the use of forest resources-especially bushmeat, important for sustenance and cash income in virtually all tropical forests-is associated with attributing higher material value to forests; (2) whether the contact with forest (estimated by local forest cover and visits to forests) is associated with attributing higher non-material value to forests. As expected, respondents from households where hunting occurs and bushmeat consumption is more frequent attributed higher material value to forests, and those living in more deforested landscapes and that visited forests less often attributed lower non-material value to forests. The importance of bushmeat in shaping the way people value forests suggests that encouraging the sustainable use of this product will encourage forest conservation. Results also point to a potential dangerous reinforcing cycle: low forest cover and the loss of contact with forests may erode forest values and facilitate further deforestation. Engaging rural communities in forest conservation initiatives is challenging yet urgent in degraded landscapes, although harnessing appreciation for bushmeat could offer a starting point. PMID- 27942037 TI - Time of Initiating Enzyme Replacement Therapy Affects Immune Abnormalities and Disease Severity in Patients with Gaucher Disease. AB - Gaucher disease (GD) patients often present with abnormalities in immune response that may be the result of alterations in cellular and/or humoral immunity. However, how the treatment and clinical features of patients impact the perturbation of their immunological status remains unclear. To address this, we assessed the immune profile of 26 GD patients who were part of an enzyme replacement therapy (ERT) study. Patients were evaluated clinically for onset of GD symptoms, duration of therapy and validated outcome measures for ERT. According to DS3 disease severity scoring system criteria, they were assigned to have mild, moderate or severe GD. Flow cytometry based immunophenotyping was performed to analyze subsets of T, B, NK, NKT and dendritic cells. GD patients showed multiple types of immune abnormalities associated to T and B lymphocytes with respect to their subpopulations as well as memory and activation markers. Skewing of CD4 and CD8 T cell numbers resulting in lower CD4/CD8 ratio and an increase in overall T cell activation were observed. A decrease in the overall B cells and an increase in NK and NKT cells were noted in the GD patients compared to controls. These immune alterations do not correlate with GD clinical type or level of biomarkers. However, subjects with persistent immune alterations, especially in B cells and DCs correlate with longer delay in initiation of ERT (DeltaTX). Thus, while ERT may reverse some of these immune abnormalities, the immune cell alterations become persistent if therapy is further delayed. These findings have important implications in understanding the immune disruptions before and after treatment of GD patients. PMID- 27942039 TI - Child Schooling in Ethiopia: The Role of Maternal Autonomy. AB - This paper examines the effects of maternal autonomy on child schooling outcomes in Ethiopia using a nationally representative Ethiopian Demographic and Health survey for 2011. The empirical strategy uses a Hurdle Negative Binomial Regression model to estimate years of schooling. An ordered probit model is also estimated to examine age grade distortion using a trichotomous dependent variable that captures three states of child schooling. The large sample size and the range of questions available in this dataset allow us to explore the influence of individual and household level social, economic and cultural factors on child schooling. The analysis finds statistically significant effects of maternal autonomy variables on child schooling in Ethiopia. The roles of maternal autonomy and other household-level factors on child schooling are important issues in Ethiopia, where health and education outcomes are poor for large segments of the population. PMID- 27942040 TI - Effects of Poor Maternal Nutrition during Gestation on Bone Development and Mesenchymal Stem Cell Activity in Offspring. AB - Poor maternal nutrition impairs overall growth and development of offspring. These changes can significantly impact the general health and production efficiency of offspring. Specifically, poor maternal nutrition is known to reduce growth of bone and muscle, and increase adipose tissue. Mesenchymal stem cells (MSC) are multipotent stem cells which contribute to development of these tissues and are responsive to changes in the maternal environment. The main objective was to evaluate the effects of poor maternal nutirtion during gestation on bone and MSC function in offspring. Thirty-six ewes were fed 100%, 60%, or 140% of energy requirements [NRC, 1985] beginning at day 31 +/- 1.3 of gestation. Lambs from ewes fed 100% (CON), 60% (RES) and 140% (OVER) were euthanized within 24 hours of birth (1 day; n = 18) or at 3 months of age (n = 15) and bone and MSC samples were collected. Dual X-ray absorptiometry was performed on bones obtained from day 1 and 3 months. Proliferation, differentiation, and metabolic activity were determined in the MSC isolated from lambs at day 1. Data were analyzed using mixed procedure in SAS. Maternal diet negatively affected offspring MSC by reducing proliferation 50% and reducing mitochondrial metabolic activity. Maternal diet did not alter MSC glycolytic activity or differentiation in culture. Maternal diet tended to decrease expression of P2Y purinoreceptor 1, but did not alter expression of other genes involved in MSC proliferation and differentiation. Maternal diet did not alter bone parameters in offspring. In conclusion, poor maternal diet may alter offspring growth through reduced MSC proliferation and metabolism. Further studies evaluating the potential molecular changes associated with altered proliferation and metabolism in MSC due to poor maternal nutrition are warranted. PMID- 27942041 TI - Improving Physical Task Performance with Counterfactual and Prefactual Thinking. AB - Counterfactual thinking (reflecting on "what might have been") has been shown to enhance future performance by translating information about past mistakes into plans for future action. Prefactual thinking (imagining "what might be if...") may serve a greater preparative function than counterfactual thinking as it is future-orientated and focuses on more controllable features, thus providing a practical script to prime future behaviour. However, whether or not this difference in hypothetical thought content may translate into a difference in actual task performance has been largely unexamined. In Experiment 1 (n = 42), participants performed trials of a computer-simulated physical task, in between which they engaged in either task-related hypothetical thinking (counterfactual or prefactual) or an unrelated filler task (control). As hypothesised, prefactuals contained more controllable features than counterfactuals. Moreover, participants who engaged in either form of hypothetical thinking improved significantly in task performance over trials compared to participants in the control group. The difference in thought content between counterfactuals and prefactuals, however, did not yield a significant difference in performance improvement. Experiment 2 (n = 42) replicated these findings in a dynamic balance task environment. Together, these findings provide further evidence for the preparatory function of counterfactuals, and demonstrate that prefactuals share this same functional characteristic. PMID- 27942044 TI - Clinical Characteristics and Outcomes of Gastric Cancer Patients Aged over 80 Years: A Retrospective Case-Control Study. AB - BACKGROUND AND AIMS: The average human life expectancy is increasing worldwide, thus the proportion of elderly gastric cancer patients is also increasing. In this case-control study, we investigated the clinical and oncologic outcomes of gastric cancer in patients over 80 years old. METHODS: From January 2004 to December 2010, 291 patients aged over 80 years old (case group) were diagnosed and treated with gastric cancer at Asan Medical Center, Seoul, Korea. From the same period, 291 patients aged 18 to 80 years old were selected as the control group. The clinical findings and clinical outcomes of gastric cancer were retrospectively reviewed and compared between the two groups. RESULTS: There were significant differences in the overall 5-year survival rate between the case and control groups (30.9% vs. 73.8%, respectively; P<0.001). In patients who received the curative treatment, overall 3- and 5-year survival rates showed 74.3% and 57.9% in case group and 91.6% and 86.5% in the control group. When analysis was confined to resectable elderly patients with a favorable performance, the curative resection group showed significantly better overall 3- and 5-year survival rates than the conservative treatment group (73.7% and 58.8% vs. 29.8% and 0%, respectively). CONCLUSIONS: Although elderly gastric cancer patients show an advanced stage at diagnosis and poor prognosis compared with non-elderly patients, elderly patients with good performance could benefit from curative resection. Thus, the clinical decision whether to undergo curative resection or conservative management should be made on an individualized basis. PMID- 27942042 TI - Faecal Carriage of Gram-Negative Multidrug-Resistant Bacteria among Patients Hospitalized in Two Centres in Ulaanbaatar, Mongolia. AB - Gram-negative multidrug-resistant organisms (GN-MDRO) producing beta-lactamases (ESBL, plasmid-mediated AmpC beta-lactamases and carbapenemases) are increasingly reported throughout Asia. The aim of this surveillance study was to determine the rate of bacterial colonization in patients from two hospitals in the Mongolian capital Ulaanbaatar. Rectal swabs were obtained from patients referred to the National Traumatology and Orthopaedics Research Centre (NTORC) or the Burn Treatment Centre (BTC) between July and September 2014, on admission and again after 14 days. Bacteria growing on selective chromogenic media (CHROMagar ESBL/KPC) were identified by MALDI-ToF MS. We performed susceptibility testing by disk diffusion and PCR (blaIMP-1, blaVIM, blaGES, blaNDM, blaKPC, blaOXA-48, blaGIM-1, blaOXA-23, blaOXA-24/40, blaOXA-51, blaOXA-58, blaOXA-143, blaOXA-235, blaCTX-M, blaSHV blaTEM and plasmid-mediated blaAmpC). Carbapenemase-producing isolates were additionally genotyped by PFGE and MLST. During the study period 985 patients in the NTORC and 65 patients in the BTC were screened on admission. The prevalence of GN-MDRO-carriage was 42.4% and 69.2% respectively (p<0.001). Due to the different medical specialities the two study populations differed significantly in age (p<0.029) and gender (p<0.001) with younger and more female patients in the burn centre (BTC). We did not observe a significant difference in colonization rate in the respective age groups in the total study population. In both centres most carriers were colonized with CTX-M-producing E. coli, followed by CTX-M-producing K. pneumoniae and CTX-M-producing E. cloacae. 158 patients from the NTORC were re-screened after 14 days of whom 99 had acquired a new GN MDRO (p<0.001). Carbapenemases were detected in both centres in four OXA-58 producing A. baumannii isolates (ST642) and six VIM-2-producing P. aeruginosa isolates (ST235). This study shows a high overall prevalence of GN-MDRO in the study population and highlights the importance of routine surveillance, appropriate infection control practice and antibiotic prescribing policies to prevent further spread especially of carbapenemases. PMID- 27942043 TI - Precision of Readout at the hunchback Gene: Analyzing Short Transcription Time Traces in Living Fly Embryos. AB - The simultaneous expression of the hunchback gene in the numerous nuclei of the developing fly embryo gives us a unique opportunity to study how transcription is regulated in living organisms. A recently developed MS2-MCP technique for imaging nascent messenger RNA in living Drosophila embryos allows us to quantify the dynamics of the developmental transcription process. The initial measurement of the morphogens by the hunchback promoter takes place during very short cell cycles, not only giving each nucleus little time for a precise readout, but also resulting in short time traces of transcription. Additionally, the relationship between the measured signal and the promoter state depends on the molecular design of the reporting probe. We develop an analysis approach based on tailor made autocorrelation functions that overcomes the short trace problems and quantifies the dynamics of transcription initiation. Based on live imaging data, we identify signatures of bursty transcription initiation from the hunchback promoter. We show that the precision of the expression of the hunchback gene to measure its position along the anterior-posterior axis is low both at the boundary and in the anterior even at cycle 13, suggesting additional post transcriptional averaging mechanisms to provide the precision observed in fixed embryos. PMID- 27942046 TI - Measuring and reporting disease progression in subclinical rheumatic heart disease. PMID- 27942045 TI - Metabolic Profiling Reveals Effects of Age, Sexual Development and Neutering in Plasma of Young Male Cats. AB - Neutering is a significant risk factor for obesity in cats. The mechanisms that promote neuter-associated weight gain are not well understood but following neutering, acute changes in energy expenditure and energy consumption have been observed. Metabolic profiling (GC-MS and UHPLC-MS-MS) was used in a longitudinal study to identify changes associated with age, sexual development and neutering in male cats fed a nutritionally-complete dry diet to maintain an ideal body condition score. At eight time points, between 19 and 52 weeks of age, fasted blood samples were taken from kittens neutered at either 19 weeks of age (Early Neuter (EN), n = 8) or at 31 weeks of age (Conventional Neuter (CN), n = 7). Univariate and multivariate analyses were used to compare plasma metabolites (n = 370) from EN and CN cats. Age was the primary driver of variance in the plasma metabolome, including a developmental change independent of neuter group between 19 and 21 weeks in lysolipids and fatty acid amides. Changes associated with sexual development and its subsequent loss were also observed, with differences at some time points observed between EN and CN cats for 45 metabolites (FDR p<0.05). Pathway Enrichment Analysis also identified significant effects in 20 pathways, dominated by amino acid, sterol and fatty acid metabolism. Most changes were interpretable within the context of male sexual development, and changed following neutering in the CN group. Felinine metabolism in CN cats was the most significantly altered pathway, increasing during sexual development and decreasing acutely following neutering. Felinine is a testosterone-regulated, felid-specific glutathione derivative secreted in urine. Alterations in tryptophan, histidine and tocopherol metabolism observed in peripubertal cats may be to support physiological functions of glutathione following diversion of S amino acids for urinary felinine secretion. PMID- 27942047 TI - Are drug-eluting stents any better than bare metal? New evidence in non-ST elevation acute coronary syndrome. PMID- 27942048 TI - Early maltreatment effects on adolescent attention control to non-emotional and emotional distractors. AB - OBJECTIVE: Early maltreatment increases lifetime risk of psychopathology. Emerging models suggest that exposure to maltreatment leads to changes in cognitive processes associated with the processing of threat, including processes of selective attention. Existing data may be interpreted to suggest that maltreatment is associated with an automatic attentional engagement with threatening cues, or that maltreatment is associated with generally poorer attention control. Using a pair of attention tasks, this study sought to examine whether maltreatment was associated with threat-related interference on attention processing and if this could be explained by poorer attentional control capacity. METHOD: Fifty-one maltreated adolescents from an out-of-home care sample in New South Wales, Australia were recruited to complete two attention tasks. Data from 24 of these participants were compared with that of a sample of non-maltreated peers matched on gender, age, cognitive ability, and household income to identify maltreatment-associated group differences. Data from all participants were then used to explore the degree to which attention variables correlated with continuous measures of internalising symptoms, subtypes, and severity of maltreatment. RESULTS: On the first task, maltreated adolescents showed significant interference from an irrelevant but non-emotional distractor on reaction times when completing a central letter identification task under low perceptual task conditions. On the second task, maltreated adolescents also showed similar interference on a probe-identification task that involved ignoring threatening (angry face) distractors, again under low perceptual load. CONCLUSIONS: These data may suggest difficulties exercising attention control following early maltreatment. These may contribute to the emergence of psychiatric disorders and other difficulties for those exposed to maltreatment. PMID- 27942050 TI - The mandatory regulations from the Medical Council of India: Facts, opinions and prejudices. PMID- 27942051 TI - Faculty promotions in medical institutions in India: Can we improve the criteria? AB - Research publications are desirable for academic promotion in medical colleges as per the current rules of the Medical Council of India (MCI). These rules reflect an endeavour to improve the academic standards. We strongly believe that every medical college teacher should conduct true research and contribute to good peer reviewed publications. However, it is felt that the MCI rule has the potential to lead to undesirable consequences, and the quality of teaching and learning could take a back-seat. There is an urgent need to adopt more objective criteria and better guidelines as followed by well-known global institutes. In our own country, the University Grants Commission has formulated specific guidelines for this purpose in the form of Academic Performance Indicators which, it appears, are not taken into consideration by the MCI. This article discusses the adverse impact of the rule and suggests ways for the adoption of a more scientific assessment system for faculty appointment and promotion. PMID- 27942049 TI - Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3. AB - Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase complex that regulates blood pressure by targeting With-No-Lysine (WNK) kinases for degradation. Mutations in KLHL3 cause constitutively increased renal salt reabsorption and impaired K+ secretion, resulting in hypertension and hyperkalemia. Although clinical studies have shown that dietary K+ intake affects blood pressure, the mechanisms have been obscure. In this study, we demonstrate that the KLHL3 ubiquitin ligase complex is involved in the low-K+-mediated activation of Na-Cl cotransporter (NCC) in the kidney. In the distal convoluted tubules of mice eating a low-K+ diet, we found increased KLHL3 phosphorylation at S433 (KLHL3S433-P), a modification that impairs WNK binding, and also reduced total KLHL3 levels. These changes are accompanied by the accumulation of the target substrate WNK4, and activation of the downstream kinases SPAK (STE20/SPS1 related proline-alanine-rich protein kinase) and OSR1 (oxidative stress responsive 1), resulting in NCC phosphorylation and its accumulation at the plasma membrane. Increased phosphorylation of S433 was explained by increased levels of active, phosphorylated protein kinase C (but not protein kinase A), which directly phosphorylates S433. Moreover, in HEK cells expressing KLHL3 and WNK4, we showed that the activation of protein kinase C by phorbol 12-myristate 13-acetate induces KLHL3S433-P and increases WNK4 levels by abrogating its ubiquitination. These data demonstrate the role of KLHL3 in low-K+-mediated induction of NCC; this physiologic adaptation reduces distal electrogenic Na+ reabsorption, preventing further renal K+ loss but promoting increased blood pressure. PMID- 27942053 TI - Ultrasonography - A viable tool for airway assessment. AB - BACKGROUND AND AIMS: Accurate prediction of the Cormack-Lehane (CL) grade preoperatively can help in better airway management of the patient during induction of anaesthesia. Our aim was to determine the utility of ultrasonography in predicting CL grade. METHODS: We studied 100 patients undergoing general endotracheal anaesthesia. Mallampati (MP) class, thyromental distance (TMD) and sternomental distance (SMD) were noted. Ultrasound measurements of the anterior neck soft tissue thickness at the level of the hyoid (ANS-Hyoid), anterior neck soft tissue thickness at the level of the vocal cords (ANS-VC) and ratio of the depth of the pre-epiglottic space (Pre-E) to the distance from the epiglottis to the mid-point of the distance between the vocal cords (E-VC) were obtained. CL grade was noted during intubation. Chi-square test was employed to determine if there was any statistical difference in the measurements of patients with different CL grades. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated for the various parameters. RESULTS: The incidence of difficult intubation was 14%. An ANS-VC >0.23 cm had a sensitivity of 85.7% in predicting a CL Grade of 3 or 4, which was higher than that of MP class, TMD and SMD. However, the specificity, PPV and accuracy were lower than the physical parameters. The NPV was comparable. CONCLUSION: Ultrasound is a useful tool in airway assessment. ANS-VC >0.23 cm is a potential predictor of difficult intubation. ANS-Hyoid is not indicative of difficult intubation. The ratio Pre-E/E-VC has a low to moderate predictive value. PMID- 27942052 TI - Critical incidents in paediatric anaesthesia: A prospective analysis over a 1 year period. AB - BACKGROUND AND AIMS: Critical incident reporting helps to identify errors and formulate preventive strategies. Many countries have existing national reporting systems. Such a system is yet to be established in India. We aimed to study the incidence of critical events in the paediatric operation theatre (OT) of our institute. METHODS: We conducted a prospective observational study of all children receiving anaesthesia in paediatric OT over a period of 1 year. They were monitored intraoperatively as well as postoperatively, and critical incidents were noted in terms of date and time of incident, location (OT/post anaesthesia care unit, clinical category, age of patient, degree of patient harm resulting from the incident, description of what happened and duration of surgery. Percentage incidence of critical events was calculated. RESULTS: A total of 1206 children received an anaesthetic during the study. Incidence of critical events was 8.9% (108). Airway and respiratory events were the maximum recorded accounting for 60 (55%) incidents. There were 43 cases of oxygen desaturation out of which 21 were attributable to laryngospasm. Cardiovascular events were 12 (11.1%). Medication-related incidents were 4 (3.8%). Severe harm was reported in ten incidents, and 1 death was reported. A few uncommon incidents like change in voice following use of a cuffed endotracheal tube and post-operative acute renal failure requiring haemodialysis were noted. CONCLUSION: Incidence of critical incidents was almost one for every ten patients, and the audit helped us establish policy guidelines in our institution. PMID- 27942054 TI - Effect of melatonin on duration of delirium in organophosphorus compound poisoning patients: A double-blind randomised placebo controlled trial. AB - BACKGROUND AND AIMS: Organophosphate compound poisoning (OPCP) is associated with high incidence of delirium. Melatonin has been tried in the treatment of delirium and has shown a beneficial effect in OPCP. This study was conducted to know the effect of melatonin on duration of delirium and recovery profile in OPCP patients. METHODS: Double-blind randomised placebo control trial in which 56 patients of OPCP confirmed by history and syndrome of OPCP with low plasma pseudocholinesterase, aged >18 years and weighing between 50 and 100 kg, and Acute Physiology and Chronic Health Evaluation II score of <20 were studied. Group M (n = 26) received tablet melatonin 3 mg and Group C (n = 30) received placebo tablet at 9 PM, every night throughout the Intensive Care Unit (ICU) stay. Delirium was assessed using the Confusion Assessment Method for ICU, thrice a day. Sedation was provided with injection midazolam, fentanyl and lorazepam. Duration of mechanical ventilation, vital parameters, ICU stay, sedative and atropine requirement, were recorded. RESULTS: The time taken to be delirium free was significantly lower in Group M (6 +/- 2.92 days) compared to Group C (9.05 +/ 2.75 days) (P = 0.001) and prevalence of delirium was significantly decreased in Group M compared to Group C from day 3 onwards. The requirement of midazolam (Group M - 2.98 +/- 4.99 mg/day, Group C - 9.68 +/- 9.17 mg/day, P < 0.001) and fentanyl (Group M - 94.09 +/- 170.05 MUg/day, Group C - 189.33 +/- 156.38 MUg/day, P = 0.03) decreased significantly in Group M. There was no significant difference in the average atropine consumption (P = 0.27), duration of mechanical ventilation (P = 0.26), ICU stay (P = 0.21) and the number of patients requiring mechanical ventilation (P = 0.50). CONCLUSION: Orally given melatonin in organophosphate compound poisoning patients reduces the duration of delirium and the requirement of sedation and analgesia. PMID- 27942055 TI - Students' satisfaction to hybrid problem-based learning format for basic life support/advanced cardiac life support teaching. AB - BACKGROUND AND AIMS: Students are exposed to basic life support (BLS) and advanced cardiac life support (ACLS) training in the first semester in some medical colleges. The aim of this study was to compare students' satisfaction between lecture-based traditional method and hybrid problem-based learning (PBL) in BLS/ACLS teaching to undergraduate medical students. METHODS: We conducted a questionnaire-based, cross-sectional survey among 118 1st-year medical students from a university medical college in the city of New Delhi, India. We aimed to assess the students' satisfaction between lecture-based and hybrid-PBL method in BLS/ACLS teaching. Likert 5-point scale was used to assess students' satisfaction levels between the two teaching methods. Data were collected and scores regarding the students' satisfaction levels between these two teaching methods were analysed using a two-sided paired t-test. RESULTS: Most students preferred hybrid PBL format over traditional lecture-based method in the following four aspects; learning and understanding, interest and motivation, training of personal abilities and being confident and satisfied with the teaching method (P < 0.05). CONCLUSION: Implementation of hybrid-PBL format along with the lecture-based method in BLS/ACLS teaching provided high satisfaction among undergraduate medical students. PMID- 27942057 TI - A nested case-control study to determine the incidence and factors associated with unanticipated admissions following day care surgery. AB - BACKGROUND AND AIMS: Day care surgery offers respite from hospitalisation for specific surgical procedures and has many advantages. However, occasionally patients who undergo such surgery require hospitalisation for unanticipated complications. We aimed to determine their incidence and to identify factors associated with unanticipated admissions in a tertiary care hospital in South India. METHODS: During the 3-month study, 63 cases requiring admission and 126 randomly selected controls were taken from the 776 procedures that were performed were compared. The variables studied were patients' demographic characteristics, pre-operative medical illness, personal habits, American Society of Anesthesiologists status, the diagnosis and surgical procedures, time since last meal, duration of anaesthesia and surgery, experience of the surgeon and anaesthetist, and intraoperative management (techniques, drugs, monitoring, etc.). Univariate and bivariate statistics were used to determine factors associated with unanticipated admissions. RESULTS: The incidence of unanticipated admissions following day care surgery was 8.11%. The reasons for admission were anaesthetic (33.33%), surgical (15.87%), medical (6.34%) and social (44.44%). The factors significantly associated with unanticipated admissions included duration of anaesthesia more than 50 min (odds ratio [OR]: 3.179; 95% confidence interval [CI]: 1.503-6.722), and starting the last case after 3 pm (OR: 10.095; 95% CI: 2.418-42.148). CONCLUSION: Unanticipated admissions following day care surgery occur mainly due to anaesthetic, surgical, medical and social reasons. PMID- 27942056 TI - A comparison of ropivacaine, ropivacaine with tramadol and ropivacaine with midazolam for post-operative caudal epidural analgesia. AB - BACKGROUND AND AIMS: Caudal epidural analgesia is the most commonly used method of post-operative analgesia in children undergoing subumbilical surgeries. Many additive drugs have been used to prolong the post-operative analgesia. The aim of this study was to compare the efficacy of tramadol or midazolam addition to caudal ropivacaine for post-operative analgesia in children undergoing subumbilical surgeries. METHODS: In this prospective, randomised, double-blinded comparative study, sixty children of either gender, in the age group of 1-5 years and scheduled for elective subumbilical surgeries were randomly divided into three groups of twenty each. Children in Group R received an epidural injection of 1 mL/kg of 0.2% plain ropivacaine whereas children in Group RT received an epidural injection of 2 mg/kg of tramadol plus 1 mL/kg of 0.2% ropivacaine and Group RM received an epidural injection of 50 MUg/kg midazolam plus 1 mL/kg of 0.2% ropivacaine. The primary outcome variable was the duration of time to rescue analgesia. The secondary outcome variables were motor block, sedation score and urinary retention. Statistical comparison among the three groups was performed using one-way ANOVA with post hoc analysis using Bonferroni. For qualitative variables, Chi-square test was used. Statistical significance was defined as P < 0.05. RESULTS: The mean duration of time to rescue analgesia was significantly longer (P < 0.001) in Group RT (913 +/- 315.5 min) and Group RM (769.2 +/- 331.9 min) compared to Group R (437.75 +/- 75.68 min). However, there was no significant difference in the duration of time to rescue analgesia between RT and RM groups. Motor block and sedation scores were comparable between groups. CONCLUSIONS: The addition of tramadol or midazolam to caudal epidural ropivacaine prolongs the duration of analgesia without causing significant side effects. PMID- 27942058 TI - Pre-operative laboratory testing: A prospective study on comparison and cost analysis. AB - BACKGROUND AND AIMS: Pre-operative investigations are performed before any surgical intervention under anaesthesia. Many are considered as routine. However, there are no clear guidelines regarding these in India. We aim to look at the relevance of the laboratory investigations ordered routinely and their cost implications compared with the National Institute of Clinical Excellence (NICE) guidelines. METHODS: This prospective study was carried out at a tertiary care hospital. A total of 163 patients scheduled for elective surgical procedures were included in this study. Neither the surgeons nor anaesthesiologists involved in the case were aware of the study. The laboratory investigations of the patients who underwent surgery were noted. All values were categorised as normal or abnormal and they were assessed as indicated or unindicated based on NICE guidelines. RESULTS: One hundred and sixty-three patients were subjected to a total of 984 tests. Forty three patients (26%) were subjected to tests as per NICE guidelines. Of the 984 tests, 515 tests were unindicated (52%). Out of the 515 unindicated tests, 7 (1.3%) were abnormal. None of these seven tests required any intervention or change of anaesthetic plan. The most common unindicated tests done were cardiac echocardiography and chest X-ray (92.5% and 93% respectively). The additional cost incurred towards unindicated tests was 63% of the total cost for the tests. CONCLUSION: Pre-operative laboratory investigations add to cost significantly. Patient premorbid conditions and surgical grade should guide the clinician to request for the relevant laboratory tests. PMID- 27942059 TI - Role of pre-operative multimedia video information in allaying anxiety related to spinal anaesthesia: A randomised controlled trial. AB - BACKGROUND AND AIMS: A high incidence of anxiety has been reported in patients in the operation theatre set up. We developed a short visual clip of 206 s duration depicting the procedure of spinal anaesthesia (SAB) and aimed to compare the effect of this video on perioperative anxiety in patients undergoing procedures under SAB. METHODS: A prospective randomised study of 200 patients undergoing surgery under SAB was conducted. Patients were allotted to either the nonvideo group (Group NV - those who were not shown the video) or the video group (Group V - those who were shown the video). Anxiety was assessed using the Spielberger State-Trait Anxiety Inventory during the pre-anaesthetic check-up and before surgery. Haemodynamic parameters such as heart rate (HR) and mean arterial pressure (MAP) were also noted. Student's t-test was used for normally distributed and Mann-Whitney U-test for nonnormally distributed quantitative data. Chi-square test was used for categorical data. RESULTS: Both groups were comparable with respect to baseline anxiety scores and haemodynamic parameters. The nonvideo group showed a significant increase in state anxiety scores before administration of SAB (P < 0.001). Patients in the video group had significantly lower HR and MAP preoperatively (P < 0.001). The prevalence of 'high anxiety' for SAB was 81% in our study which decreased to 66% in the video group before surgery. CONCLUSION: Multimedia information in the form of a short audiovisual clip is an effective and feasible method to reduce perioperative anxiety related to SAB. PMID- 27942060 TI - Efficacy of methylprednisolone and lignocaine on propofol injection pain: A randomised, double-blind, prospective study in adult cardiac surgical patients. AB - BACKGROUND AND AIMS: Propofol (2, 6-di-isopropylphenol) used for the induction of anaesthesia often causes mild to severe pain or discomfort on injection. We designed this double-blind study to compare the efficacy of methylprednisolone and lignocaine in reducing the pain of propofol injection in patients scheduled for cardiac surgery. METHODS: A total of 165 adult patients, scheduled for elective cardiac surgery, were divided into three groups: saline (group S, n = 55), lignocaine 20 mg (Group L, n = 55) and methylprednisolone 125 mg diluted into 2 ml of distilled water (Group MP, n = 55). Drugs were administered after tourniquet application and occlusion was released after 1 min and 1/4th of the total dose of propofol (2 mg/kg) was administered at the rate of 0.5 ml/s. Pain on propofol injection was evaluated by four-point verbal rating scale. Statistical methods used included Student's t-test and Chi-square test/Fisher's exact test. RESULTS: The overall incidence of pain was 70.9% in the saline group, 30.9% in the lignocaine group and 36.4% in the methylprednisolone group. The intensity of pain was significantly less in patients receiving methylprednisolone and lignocaine than those receiving saline (P < 0.012). CONCLUSION: Pre-treatment with intravenous methylprednisolone was found to be as effective as lignocaine in reducing propofol injection-induced pain. PMID- 27942061 TI - Anaesthetic challenges in conjoined twins' separation surgery. AB - Conjoined twins are a rare congenital anomaly of unknown aetiology. We report the successful anaesthetic management of separation of ischiopagus tetrapus conjoined twins. The importance of a multidisciplinary approach, thorough pre-operative evaluation and planning, vigilant monitoring and anticipation of complications such as massive blood and fluid loss, haemodynamic instability, hypothermia and intensive, post-operative care are emphasised. PMID- 27942062 TI - Role of dexmedetomidine for sedation in a patient with schizophrenia for strabismus surgery. PMID- 27942063 TI - Management of chronic shoulder pain with restricted mobility - a case series. PMID- 27942064 TI - The isolation of morphine by Serturner. PMID- 27942065 TI - A failure of pre-anaesthetic check-up leading to unsuspected difficult intubation. PMID- 27942066 TI - The significance (or the insignificance) of wide pulse pressure. PMID- 27942067 TI - Anaesthetic management of a patient with Huntington's chorea undergoing robot assisted nephron-sparing surgery. PMID- 27942069 TI - Acquired tracheoesophageal fistula with undiagnosed tracheal stenosis: A simple innovation to avoid tracheostomy! PMID- 27942068 TI - Overcoming airway challenges with the C-MAC(r) video laryngoscope in a child with Goldenhar syndrome. PMID- 27942070 TI - A peculiar manufacturing defect in catheter mount. PMID- 27942071 TI - Successful Airtraq(r) use for emergency off-centre glottic intubation in a patient with post-dialysis neck haematoma. PMID- 27942072 TI - Pectus carinatum repair in an adolescent with hyperhomocysteinaemia: Anaesthetic implications. PMID- 27942073 TI - Incremental epidural anaesthesia for emergency caesarean section in a patient with ostium secundum atrial septal defect and severe pulmonary stenosis with right to left shunt. PMID- 27942074 TI - Modelling and the Nation: Institutionalising Climate Prediction in the UK, 1988 92. AB - How climate models came to gain and exercise epistemic authority has been a key concern of recent climate change historiography. Using newly released archival materials and recently conducted interviews with key actors, we reconstruct negotiations between UK climate scientists and policymakers which led to the opening of the Hadley Centre for Climate Prediction and Research in 1990. We historicize earlier arguments about the unique institutional culture of the Hadley Centre, and link this culture to broader characteristics of UK regulatory practice and environmental politics. A product of a particular time and place, the Hadley Centre was shaped not just by scientific ambition, but by a Conservative governmental preference for 'sound science' and high evidential standards in environmental policymaking. Civil servants sought a prediction programme which would appeal to such sensibilities, with transient and regional climate simulation techniques seemingly offering both scientific prestige and persuasive power. Beyond the national level, we also offer new insights into the early role of the Intergovernmental Panel on Climate Change and an evolving international political context in the shaping of scientific practices and institutions. PMID- 27942075 TI - Hidden in the Middle: Culture, Value and Reward in Bioinformatics. AB - Bioinformatics - the so-called shotgun marriage between biology and computer science - is an interdiscipline. Despite interdisciplinarity being seen as a virtue, for having the capacity to solve complex problems and foster innovation, it has the potential to place projects and people in anomalous categories. For example, valorised 'outputs' in academia are often defined and rewarded by discipline. Bioinformatics, as an interdisciplinary bricolage, incorporates experts from various disciplinary cultures with their own distinct ways of working. Perceived problems of interdisciplinarity include difficulties of making explicit knowledge that is practical, theoretical, or cognitive. But successful interdisciplinary research also depends on an understanding of disciplinary cultures and value systems, often only tacitly understood by members of the communities in question. In bioinformatics, the 'parent' disciplines have different value systems; for example, what is considered worthwhile research by computer scientists can be thought of as trivial by biologists, and vice versa. This paper concentrates on the problems of reward and recognition described by scientists working in academic bioinformatics in the United Kingdom. We highlight problems that are a consequence of its cross-cultural make-up, recognising that the mismatches in knowledge in this borderland take place not just at the level of the practical, theoretical, or epistemological, but also at the cultural level too. The trend in big, interdisciplinary science is towards multiple authors on a single paper; in bioinformatics this has created hybrid or fractional scientists who find they are being positioned not just in-between established disciplines but also in-between as middle authors or, worse still, left off papers altogether. PMID- 27942076 TI - Validation of temperature and humidity thermal model of 23-person tent-type refuge alternative. AB - U.S. Mine Safety and Health Administration (MSHA) regulations require underground coal mines to use refuge alternatives (RAs) to provide a breathable air environment for 96 hours. One of the main concerns with the use of mobile RAs is heat and humidity buildup inside the RA. The accumulation of heat and humidity can result in miners suffering heat stress or even death. MSHA regulations require that the apparent temperature in an occupied RA not exceed 95 degrees F. To investigate this, the U.S. National Institute for Occupational Safety and Health (NIOSH) conducted testing on a 23-person tent-type RA in its Experimental Mine in a test area that was isolated from the mine ventilation system. The test results showed that the average measured air temperature within the RA increased by 9.4 degrees C (17 degrees F) and the relative humidity approached 94 percent at the end of a 96-hour test. The test results were used to benchmark a thermal simulation model of the tested RA. The validated thermal simulation model predicted the volume-weighted average air temperature inside the RA tent at the end of 96 hours to within 0.06 degrees C (0.1 degrees F) of the average measured air temperature. PMID- 27942077 TI - Robust multi-atlas label propagation by deep sparse representation. AB - Recently, multi-atlas patch-based label fusion has achieved many successes in medical imaging area. The basic assumption in the current state-of-the-art approaches is that the image patch at the target image point can be represented by a patch dictionary consisting of atlas patches from registered atlas images. Therefore, the label at the target image point can be determined by fusing labels of atlas image patches with similar anatomical structures. However, such assumption on image patch representation does not always hold in label fusion since (1) the image content within the patch may be corrupted due to noise and artifact; and (2) the distribution of morphometric patterns among atlas patches might be unbalanced such that the majority patterns can dominate label fusion result over other minority patterns. The violation of the above basic assumptions could significantly undermine the label fusion accuracy. To overcome these issues, we first consider forming label-specific group for the atlas patches with the same label. Then, we alter the conventional flat and shallow dictionary to a deep multi-layer structure, where the top layer (label-specific dictionaries) consists of groups of representative atlas patches and the subsequent layers (residual dictionaries) hierarchically encode the patchwise residual information in different scales. Thus, the label fusion follows the representation consensus across representative dictionaries. However, the representation of target patch in each group is iteratively optimized by using the representative atlas patches in each label-specific dictionary exclusively to match the principal patterns and also using all residual patterns across groups collaboratively to overcome the issue that some groups might be absent of certain variation patterns presented in the target image patch. Promising segmentation results have been achieved in labeling hippocampus on ADNI dataset, as well as basal ganglia and brainstem structures, compared to other counterpart label fusion methods. PMID- 27942079 TI - Heavy Metals in Water Percolating Through Soil Fertilized with Biodegradable Waste Materials. AB - The influence of manure and composts on the leaching of heavy metals from soil was evaluated in a model lysimeter experiment under controlled conditions. Soil samples were collected from experimental fields, from 0- to 90-cm layers retaining the layout of the soil profile layers, after the second crop rotation cycle with the following plant species: potatoes, spring barley, winter rapeseed, and winter wheat. During the field experiment, 20 t DM/ha of manure, municipal sewage sludge composted with straw (SSCS), composted sewage sludge (SSC), dried granular sewage sludge (DGSS), "Dano" compost made from non-segregated municipal waste (CMMW), and compost made from municipal green waste (CUGW) was applied, i.e., 10 t DM/ha per crop rotation cycle. The concentrations (MUg/dm3) of heavy metals in the leachate were as follows: Cd (3.6-11.5) < Mn (4.8-15.4) < Cu (13.4 35.5) < Zn (27.5-48.0) < Cr (36.7-96.5) < Ni (24.4-165.8) < Pb (113.8-187.7). Soil fertilization with organic waste materials did not contaminate the percolating water with manganese or zinc, whereas the concentrations of the other metals increased to the levels characteristic of unsatisfactory water quality and poor water quality classes. The copper and nickel content of percolating water depended on the concentration of those metals introduced into the soil with organic waste materials. The concentrations of Cd in the leachate increased, whereas the concentrations of Cu and Ni decreased with increasing organic C content of organic fertilizers. The widening of the C/N ratio contributed to Mn leaching. The concentrations of Pb, Cr, and Mn in the percolating water were positively correlated with the organic C content of soil. PMID- 27942078 TI - Church-Based Social Support Among Caribbean Blacks in the United States. AB - An emerging body of research notes the importance of church-based social support networks in the daily lives of Americans. However, few studies examine church based support, and especially among ethnic subgroups within the U.S. Black population, such as Caribbean Blacks. This study uses data from the National Survey of American Life (NSAL) to examine demographic and religious participation (e.g., attendance, interaction) correlates of church-based social support (e.g., receipt of emotional support, receipt of general support, provision of support to others, and negative interaction) among Caribbean Blacks residing in the U.S. Multiple regression analyses indicated that religious participation was associated with all four dependent variables. Church attendance was positively associated with receiving emotional support, general social support, and providing support to others, but was not associated with negative interaction. Frequency of interaction with fellow congregants was positively associated with receiving emotional support, receiving general support, providing support to others and negative interaction. Demographic findings indicated that women provided more support to church members and experienced more negative interactions with members than did men. Education was positively associated with frequency of support; household income was negatively associated with receiving emotional support and providing social support to others. Findings are discussed in relation to the role of church-based support networks in the lives of Caribbean Black immigrants and communities. PMID- 27942080 TI - Policy documents as sources for measuring societal impact: how often is climate change research mentioned in policy-related documents? AB - In the current UK Research Excellence Framework (REF) and the Excellence in Research for Australia (ERA), societal impact measurements are inherent parts of the national evaluation systems. In this study, we deal with a relatively new form of societal impact measurements. Recently, Altmetric-a start-up providing publication level metrics-started to make data for publications available which have been mentioned in policy documents. We regard this data source as an interesting possibility to specifically measure the (societal) impact of research. Using a comprehensive dataset with publications on climate change as an example, we study the usefulness of the new data source for impact measurement. Only 1.2 % (n = 2341) out of 191,276 publications on climate change in the dataset have at least one policy mention. We further reveal that papers published in Nature and Science as well as from the areas "Earth and related environmental sciences" and "Social and economic geography" are especially relevant in the policy context. Given the low coverage of the climate change literature in policy documents, this study can be only a first attempt to study this new source of altmetrics data. Further empirical studies are necessary, because mentions in policy documents are of special interest in the use of altmetrics data for measuring target-oriented the broader impact of research. PMID- 27942081 TI - Unbalanced international collaboration affects adversely the usefulness of countries' scientific output as well as their technological and social impact. AB - The unbalanced international scientific collaboration as cause of misleading information on the country's contribution to the scientific world output was analyzed. ESI Data Base (Thomson Reuters' InCites), covering the scientific production of 217 active countries in the period 2010-2014 was used. International collaboration implicates in a high percentage (33.1 %) of double counted world articles, thus impacting qualitative data as citations, impact and impact relative to word. The countries were divided into three groups, according to their individual contribution to the world publications: Group I (24 countries, at least 1 %) representing 83.9 % of the total double-counted world articles. Group II (40 countries, 0.1-0.99 % each). Group III, 153 countries (70.5 %) with <0.1 % and altogether 1.9 % of the world. Qualitative characteristics of each group were also analyzed: percentage of the country's GNP applied in R&D, proportion of Scientists and Engineers per million inhabitants and Human Development Index. Average international collaboration were: Group I, 43.0 %; Group II, 55.8 % and Group III, 85.2 %. We concluded that very high and unbalanced international collaboration, as presented by many countries, misrepresent the importance of their scientific production, technological and social outputs. Furthermore, it jeopardizes qualitative outputs of the countries themselves, artificially increasing their scientific impact, affecting all fields and therefore, the whole world. The data confirm that when dealing with the qualitative contribution of countries, it is necessary to take in consideration the level of international cooperation because, as seen here, it can and in fact it does create false impression of the real contribution of countries. PMID- 27942082 TI - Revisiting an open access monograph experiment: measuring citations and tweets 5 years later. AB - An experiment run in 2009 could not assess whether making monographs available in open access enhanced scholarly impact. This paper revisits the experiment, drawing on additional citation data and tweets. It attempts to answer the following research question: does open access have a positive influence on the number of citations and tweets a monograph receives, taking into account the influence of scholarly field and language? The correlation between monograph citations and tweets is also investigated. The number of citations and tweets measured in 2014 reveal a slight open access advantage, but the influence of language or subject should also be taken into account. However, Twitter usage and citation behaviour hardly overlap. PMID- 27942083 TI - The contribution of ethnic groups to Malaysian scientific output, 1982-2014, and the effects of the new economic policy. AB - Malaysia has three main ethnic communities: Chinese, Indians and Malays. At independence in 1957, the Chinese dominated commercial life, and this led to ethnic tensions and finally riots. As a result in 1969 Malaysia introduced a "New Economic Policy" (NEP) to promote Malays in all areas of activity, and in particular to assist them to obtain basic and higher education. We examined the scientific outputs from Malaysia between 1982 and 2014 and classified the names of Malaysian researchers into one of these three groups and two others. There was a major increase in Malay participation in research, which has risen from 20 % of researchers in 1982-1984 to 65 % in 2012-2014, with corresponding declines in the percentages of Chinese and Indian authors, although their absolute numbers have increased because Malaysian scientific output has increased so rapidly in the last 10 years. The huge increase in Malay researchers contrasts with their presence in the Malaysian population which has remained stable at about 50 % since 1969. PMID- 27942084 TI - Measuring efficiency of university-industry Ph.D. projects using best worst method. AB - : A collaborative Ph.D. project, carried out by a doctoral candidate, is a type of collaboration between university and industry. Due to the importance of such projects, researchers have considered different ways to evaluate the success, with a focus on the outputs of these projects. However, what has been neglected is the other side of the coin-the inputs. The main aim of this study is to incorporate both the inputs and outputs of these projects into a more meaningful measure called efficiency. A ratio of the weighted sum of outputs over the weighted sum of inputs identifies the efficiency of a Ph.D. PROJECT: The weights of the inputs and outputs can be identified using a multi-criteria decision making (MCDM) method. Data on inputs and outputs are collected from 51 Ph.D. candidates who graduated from Eindhoven University of Technology. The weights are identified using a new MCDM method called Best Worst Method (BWM). Because there may be differences in the opinion of Ph.D. candidates and supervisors on weighing the inputs and outputs, data for BWM are collected from both groups. It is interesting to see that there are differences in the level of efficiency from the two perspectives, because of the weight differences. Moreover, a comparison between the efficiency scores of these projects and their success scores reveals differences that may have significant implications. A sensitivity analysis divulges the most contributing inputs and outputs. PMID- 27942085 TI - Cited references and Medical Subject Headings (MeSH) as two different knowledge representations: clustering and mappings at the paper level. AB - For the biomedical sciences, the Medical Subject Headings (MeSH) make available a rich feature which cannot currently be merged properly with widely used citing/cited data. Here, we provide methods and routines that make MeSH terms amenable to broader usage in the study of science indicators: using Web-of Science (WoS) data, one can generate the matrix of citing versus cited documents; using PubMed/MEDLINE data, a matrix of the citing documents versus MeSH terms can be generated analogously. The two matrices can also be reorganized into a 2-mode matrix of MeSH terms versus cited references. Using the abbreviated journal names in the references, one can, for example, address the question whether MeSH terms can be used as an alternative to WoS Subject Categories for the purpose of normalizing citation data. We explore the applicability of the routines in the case of a research program about the amyloid cascade hypothesis in Alzheimer's disease. One conclusion is that referenced journals provide archival structures, whereas MeSH terms indicate mainly variation (including novelty) at the research front. Furthermore, we explore the option of using the citing/cited matrix for main-path analysis as a by-product of the software. PMID- 27942086 TI - Professional and citizen bibliometrics: complementarities and ambivalences in the development and use of indicators-a state-of-the-art report. AB - Bibliometric indicators such as journal impact factors, h-indices, and total citation counts are algorithmic artifacts that can be used in research evaluation and management. These artifacts have no meaning by themselves, but receive their meaning from attributions in institutional practices. We distinguish four main stakeholders in these practices: (1) producers of bibliometric data and indicators; (2) bibliometricians who develop and test indicators; (3) research managers who apply the indicators; and (4) the scientists being evaluated with potentially competing career interests. These different positions may lead to different and sometimes conflicting perspectives on the meaning and value of the indicators. The indicators can thus be considered as boundary objects which are socially constructed in translations among these perspectives. This paper proposes an analytical clarification by listing an informed set of (sometimes unsolved) problems in bibliometrics which can also shed light on the tension between simple but invalid indicators that are widely used (e.g., the h-index) and more sophisticated indicators that are not used or cannot be used in evaluation practices because they are not transparent for users, cannot be calculated, or are difficult to interpret. PMID- 27942087 TI - Twenty-first century macro-trends in the institutional fabric of science: bibliometric monitoring and analysis. AB - Some say that world science has become more 'applied', or at least more 'application-oriented', in recent years. Replacing the ill-defined distinction between 'basic research' and 'applied research', we introduce 'research application orientation' domains as an alternative conceptual and analytical framework for examining research output growth patterns. To distinguish possible developmental trajectories we define three institutional domains: 'university', 'industry', 'hospitals'. Our macro-level bibliometric analysis takes a closer look at general trends within and across some 750 of the world's largest research intensive universities. To correct for database changes, our time-series analysis was applied to both a fixed journal set (same research journals and conference proceedings over time) and a dynamic journal set (changing set of publication outlets). We find that output growth in the 'hospital research orientation' has significantly outpaced the other two application domains, especially since 2006/2007. This happened mainly because of the introduction of new publication outlets in the WoS, but also partially because some universities-especially in China-seem to have become more visible in this domain. Our analytical approach needs further broadening and deepening to provide a more definitive answer whether hospitals and the medical sector are becoming increasingly dominant as a domain of scientific knowledge production and an environment for research applications. PMID- 27942088 TI - The information value of early career productivity in mathematics: a ROC analysis of prediction errors in bibliometricly informed decision making. AB - The aim of this study was to provide a framework to evaluate bibliometric indicators as decision support tools from a decision making perspective and to examine the information value of early career publication rate as a predictor of future productivity. We used ROC analysis to evaluate a bibliometric indicator as a tool for binary decision making. The dataset consisted of 451 early career researchers in the mathematical sub-field of number theory. We investigated the effect of three different definitions of top performance groups-top 10, top 25, and top 50 %; the consequences of using different thresholds in the prediction models; and the added prediction value of information on early career research collaboration and publications in prestige journals. We conclude that early career performance productivity has an information value in all tested decision scenarios, but future performance is more predictable if the definition of a high performance group is more exclusive. Estimated optimal decision thresholds using the Youden index indicated that the top 10 % decision scenario should use 7 articles, the top 25 % scenario should use 7 articles, and the top 50 % should use 5 articles to minimize prediction errors. A comparative analysis between the decision thresholds provided by the Youden index which take consequences into consideration and a method commonly used in evaluative bibliometrics which do not take consequences into consideration when determining decision thresholds, indicated that differences are trivial for the top 25 and the 50 % groups. However, a statistically significant difference between the methods was found for the top 10 % group. Information on early career collaboration and publication strategies did not add any prediction value to the bibliometric indicator publication rate in any of the models. The key contributions of this research is the focus on consequences in terms of prediction errors and the notion of transforming uncertainty into risk when we are choosing decision thresholds in bibliometricly informed decision making. The significance of our results are discussed from the point of view of a science policy and management. PMID- 27942089 TI - StratomeX: Visual Analysis of Large-Scale Heterogeneous Genomics Data for Cancer Subtype Characterization. AB - Identification and characterization of cancer subtypes are important areas of research that are based on the integrated analysis of multiple heterogeneous genomics datasets. Since there are no tools supporting this process, much of this work is done using ad-hoc scripts and static plots, which is inefficient and limits visual exploration of the data. To address this, we have developed StratomeX, an integrative visualization tool that allows investigators to explore the relationships of candidate subtypes across multiple genomic data types such as gene expression, DNA methylation, or copy number data. StratomeX represents datasets as columns and subtypes as bricks in these columns. Ribbons between the columns connect bricks to show subtype relationships across datasets. Drill-down features enable detailed exploration. StratomeX provides insights into the functional and clinical implications of candidate subtypes by employing small multiples, which allow investigators to assess the effect of subtypes on molecular pathways or outcomes such as patient survival. As the configuration of viewing parameters in such a multi-dataset, multi-view scenario is complex, we propose a meta visualization and configuration interface for dataset dependencies and data-view relationships. StratomeX is developed in close collaboration with domain experts. We describe case studies that illustrate how investigators used the tool to explore subtypes in large datasets and demonstrate how they efficiently replicated findings from the literature and gained new insights into the data. PMID- 27942090 TI - Pathfinder: Visual Analysis of Paths in Graphs. AB - The analysis of paths in graphs is highly relevant in many domains. Typically, path-related tasks are performed in node-link layouts. Unfortunately, graph layouts often do not scale to the size of many real world networks. Also, many networks are multivariate, i.e., contain rich attribute sets associated with the nodes and edges. These attributes are often critical in judging paths, but directly visualizing attributes in a graph layout exacerbates the scalability problem. In this paper, we present visual analysis solutions dedicated to path related tasks in large and highly multivariate graphs. We show that by focusing on paths, we can address the scalability problem of multivariate graph visualization, equipping analysts with a powerful tool to explore large graphs. We introduce Pathfinder (Figure 1), a technique that provides visual methods to query paths, while considering various constraints. The resulting set of paths is visualized in both a ranked list and as a node-link diagram. For the paths in the list, we display rich attribute data associated with nodes and edges, and the node-link diagram provides topological context. The paths can be ranked based on topological properties, such as path length or average node degree, and scores derived from attribute data. Pathfinder is designed to scale to graphs with tens of thousands of nodes and edges by employing strategies such as incremental query results. We demonstrate Pathfinder's fitness for use in scenarios with data from a coauthor network and biological pathways. PMID- 27942091 TI - From Visual Exploration to Storytelling and Back Again. AB - The primary goal of visual data exploration tools is to enable the discovery of new insights. To justify and reproduce insights, the discovery process needs to be documented and communicated. A common approach to documenting and presenting findings is to capture visualizations as images or videos. Images, however, are insufficient for telling the story of a visual discovery, as they lack full provenance information and context. Videos are difficult to produce and edit, particularly due to the non-linear nature of the exploratory process. Most importantly, however, neither approach provides the opportunity to return to any point in the exploration in order to review the state of the visualization in detail or to conduct additional analyses. In this paper we present CLUE (Capture, Label, Understand, Explain), a model that tightly integrates data exploration and presentation of discoveries. Based on provenance data captured during the exploration process, users can extract key steps, add annotations, and author "Vistories", visual stories based on the history of the exploration. These Vistories can be shared for others to view, but also to retrace and extend the original analysis. We discuss how the CLUE approach can be integrated into visualization tools and provide a prototype implementation. Finally, we demonstrate the general applicability of the model in two usage scenarios: a Gapminder-inspired visualization to explore public health data and an example from molecular biology that illustrates how Vistories could be used in scientific journals. (see Figure 1 for visual abstract). PMID- 27942092 TI - TOY SAFETY SURVEILLANCE FROM ONLINE REVIEWS. AB - Toy-related injuries account for a significant number of childhood injuries and the prevention of these injuries remains a goal for regulatory agencies and manufacturers. Text-mining is an increasingly prevalent method for uncovering the significance of words using big data. This research sets out to determine the effectiveness of text-mining in uncovering potentially dangerous children's toys. We develop a danger word list, also known as a 'smoke word' list, from injury and recall text narratives. We then use the smoke word lists to score over one million Amazon reviews, with the top scores denoting potential safety concerns. We compare the smoke word list to conventional sentiment analysis techniques, in terms of both word overlap and effectiveness. We find that smoke word lists are highly distinct from conventional sentiment dictionaries and provide a statistically significant method for identifying safety concerns in children's toy reviews. Our findings indicate that text-mining is, in fact, an effective method for the surveillance of safety concerns in children's toys and could be a gateway to effective prevention of toy-product-related injuries. PMID- 27942093 TI - Measurement Invariance Conventions and Reporting: The State of the Art and Future Directions for Psychological Research. AB - Measurement invariance assesses the psychometric equivalence of a construct across groups or across time. Measurement noninvariance suggests that a construct has a different structure or meaning to different groups or on different measurement occasions in the same group, and so the construct cannot be meaningfully tested or construed across groups or across time. Hence, prior to testing mean differences across groups or measurement occasions (e.g., boys and girls, pretest and posttest), or differential relations of the construct across groups, it is essential to assess the invariance of the construct. Conventions and reporting on measurement invariance are still in flux, and researchers are often left with limited understanding and inconsistent advice. Measurement invariance is tested and established in different steps. This report surveys the state of measurement invariance testing and reporting, and details the results of a literature review of studies that tested invariance. Most tests of measurement invariance include configural, metric, and scalar steps; a residual invariance step is reported for fewer tests. Alternative fit indices (AFIs) are reported as model fit criteria for the vast majority of tests; chi2 is reported as the single index in a minority of invariance tests. Reporting AFIs is associated with higher levels of achieved invariance. Partial invariance is reported for about one-third of tests. In general, sample size, number of groups compared, and model size are unrelated to the level of invariance achieved. Implications for the future of measurement invariance testing, reporting, and best practices are discussed. PMID- 27942094 TI - Glioma Grading Using Cell Nuclei Morphologic Features in Digital Pathology Images. AB - This work proposes a computationally efficient cell nuclei morphologic feature analysis technique to characterize the brain gliomas in tissue slide images. In this work, our contributions are two-fold: 1) obtain an optimized cell nuclei segmentation method based on the pros and cons of the existing techniques in literature, 2) extract representative features by k-mean clustering of nuclei morphologic features to include area, perimeter, eccentricity, and major axis length. This clustering based representative feature extraction avoids shortcomings of extensive tile [1] [2] and nuclear score [3] based methods for brain glioma grading in pathology images. Multilayer perceptron (MLP) is used to classify extracted features into two tumor types: glioblastoma multiforme (GBM) and low grade glioma (LGG). Quantitative scores such as precision, recall, and accuracy are obtained using 66 clinical patients' images from The Cancer Genome Atlas (TCGA) [4] dataset. On an average ~94% accuracy from 10 fold cross validation confirms the efficacy of the proposed method. PMID- 27942095 TI - Bridging the Gap between Sample Collection and Laboratory Analysis: Using Dried Blood Spots to Identify Human Exposure to Chemical Agents. AB - Public health response to large scale chemical emergencies presents logistical challenges for sample collection, transport, and analysis. Diagnostic methods used to identify and determine exposure to chemical warfare agents, toxins, and poisons traditionally involve blood collection by phlebotomists, cold transport of biomedical samples, and costly sample preparation techniques. Use of dried blood spots, which consist of dried blood on an FDA-approved substrate, can increase analyte stability, decrease infection hazard for those handling samples, greatly reduce the cost of shipping/storing samples by removing the need for refrigeration and cold chain transportation, and be self-prepared by potentially exposed individuals using a simple finger prick and blood spot compatible paper. Our laboratory has developed clinical assays to detect human exposures to nerve agents through the analysis of specific protein adducts and metabolites, for which a simple extraction from a dried blood spot is sufficient for removing matrix interferents and attaining sensitivities on par with traditional sampling methods. The use of dried blood spots can bridge the gap between the laboratory and the field allowing for large scale sample collection with minimal impact on hospital resources while maintaining sensitivity, specificity, traceability, and quality requirements for both clinical and forensic applications. PMID- 27942096 TI - Dietary practices and nutritional status of under-five children in rural and urban communities of Lagos State, Nigeria. AB - BACKGROUND: Evidence shows that urban children generally have a better nutritional status than their rural counterparts. However, data establishing whether this difference in prevalence of undernutrition could be ascribed to difference in dietary practices are few. OBJECTIVE: The aim of this study was to compare dietary practices and nutritional status of children in rural and urban communities of Lagos State, Nigeria. METHODS: This was a comparative-analytical study conducted using the multistage sampling technique to select the study cases. A total of 300 mother-child pairs were studied, including 150 each from rural and urban communities. Data collected include demographics, socioeconomic characteristics, feeding practices and anthropometric measurements of the participants. Food intake data were collected using 24-h dietary recall. Malnutrition in children was determined by calculating the prevalence of low height-for-age (stunting), low weight-for-age (underweight), and low weight-for height (wasting) using the World Health Organization cutoff points. RESULTS: The prevalence of exclusive breastfeeding for 6 months (25.3% vs. 28.7%; P = 0.516), use of formula feeds (48.7% vs. 44%; P = 0.077), and mean age of child at introduction of semisolid foods (7.54 +/- 4.0 months vs. 8.51 +/- 7.3 months; P = 0.117) were not significantly different between urban and rural communities. The diversity of food choices and frequencies of consumption were similar between urban and rural communities. However, prevalence levels of underweight and stunted children were significantly higher in rural than that of urban communities (19.4% vs. 9.3%, P < 0.001 and 43.3% vs. 12.6%, P < 0.001, respectively). CONCLUSIONS: Other risk factors besides inappropriate feeding practices need to be considered for higher prevalence of undernutrition among children in rural communities. PMID- 27942097 TI - Sociodemographic profiles and use-dynamics of Jadelle (levonorgestrel) implants in Jos, Nigeria. AB - BACKGROUND: Contraceptive implants (including Jadelle) are highly effective, safe, and easy to use and have a long duration of action. They do not interfere with intercourse with immediate return to fertility after removal. However, disruption of the menstrual bleeding pattern is almost inevitable and coercive prescription may be a problem because insertion and removal of implants are provider dependent. The objective of this study was to determine the sociodemographic profiles of acceptors of Jadelle and the reasons for discontinuation in Jos, Nigeria. MATERIALS AND METHODS: This was a 6-year retrospective chart review carried out at the Jos University Teaching Hospital. RESULTS: About 1401 women accepted Jadelle with a mean (+/-standard deviation) of 33.4 +/- 5.9 years. About 88% of the women were Christians and almost three quarters (73.5%) had at least secondary school education. The means of parity and number of children still alive at the time of accepting Jadelle were 4.1 and 3.8, respectively. Half of the women (49.5%) were breastfeeding and over half (55.9%) had future fertility desires at the time of commencing Jadelle. About 82% had previously used other contraceptives (mostly short-acting methods such as injectables, pills, and condoms), with only 18% starting Jadelle as the first ever contraceptive method. About 90% of the women had regular menstrual cycles. The major reason for discontinuation of Jadelle was desire for pregnancy although menstrual pattern disruption was the most common reason for removal in the first 6 months of use. CONCLUSION: The main reason for discontinuation of Jadelle was to have more children although menstrual pattern disruptions accounted for earlier discontinuation. PMID- 27942098 TI - Obstetric predictors of hypertension: A cross-sectional study of women attending the postnatal clinic of Jos University Teaching Hospital. AB - BACKGROUND: Hypertensive disease in pregnancy (HDP) accounts for high mother and child morbi-mortality and predict future cardiometabolic diseases. This study aimed to identify obstetric predictors of HDP needing preventive action to reduce its consequences; when women present to antenatal clinic (ANC). MATERIALS AND METHODS: Cross-sectional descriptive this was an Interviewer-administered semi structured questionnaire-based study of the anthropometric, and blood pressure measurementsin attendees at the postnatal clinic (PNC) of Jos University with ANC records. SETTING: Six weeks postnatal clinic (PNC) of Jos University Teaching Hospital (JUTH). RESULTS: The following indices proved predictive of HDP and subsequent hypertension: weight (P = 0.009), hip circumference (P = 0.018), parity (P = 0.043), waist circumference (P = 0.00), abdominal height (P = 0.040), waist/height (P = 0.020), history of developing hypertension in previous pregnancy (P = 0.000), birth weight of baby (P = 0.02), and mode of delivery (P = 0.05). CONCLUSION: To initiate preventive action on ANC registration in mitigating effects of or outrightly preventing HDP, careful check on anthropometry as well as history of hypertension or operative/preterm delivery in a previous pregnancy is necessary. PMID- 27942099 TI - Study of pentoxifylline effects on motility and viability of spermatozoa from infertile asthenozoospermic males. AB - BACKGROUND: The quality of semen is one of the major parameters in male infertility. Pentoxifylline, a methylxanthine derivative, is an agent primarily used in the treatment of intermittent claudication and other vascular disorders. Studies have shown that pentoxifylline enhances the quality and quantity of sperms. In this study, we have investigated the in vitro effects of pentoxifylline on viability and motility of spermatozoa in samples of infertile oligoasthenozoospermic males. MATERIALS AND METHODS: In this observer-blinded clinical trial, semen samples of 25 infertile oligoasthenozoospermic males were collected in Alzahra Educational Medical Center of Tabriz University of Medical Sciences from August 2010 to August 2012. After the isolation of spermatozoa by the swim-up method, they were randomized into four groups in ISM1 environment: The controls treated normally: Group 1 treated by pentoxifylline at a dose of 50 MUg/ml, Group 2 treated by pentoxifylline at a dose of 100 MUg/ml, and Group 3 treated by pentoxifylline at a dose of 200 MUg/ml. Sperm viability and motility were compared among the groups on 45 min, 24 h, 36 h, and 48 h intervals. RESULTS: Mean percentages of live sperms were 98.40%, 51.40%, 20.60%, and 6.00% in control group and 98.40%, 69.20%, 38.60%, and 14.60% in Group 3 on the mentioned intervals, respectively. This mean percentage decrease of live sperms was significantly lower in Group 3 comparing with that of other groups (P = 0.01). Mean percentages of motile sperms were 54%, 8.40%, 2.80%, and 0% in control group; and 54%, 16%, 4.80%, and 1.40% in Group 3 on the mentioned intervals, respectively. There was not a significant difference between the four groups in this regard (P = 0.19). CONCLUSION: Pentoxifylline can enhance the viability of sperm of infertile oligoasthenozoospermic males with no significant effect on its motility. PMID- 27942100 TI - Abdominal wall endometrioma: Our experience in Vladimir, Russia. AB - BACKGROUND: Endometriosis is defined as an estrogen-dependent, benign inflammatory disease characterized by the presence of ectopic endometrial implants. Abdominal wall endometrioma (AWE) being a rare entity is a benign tumor defined as ectopic functional, endometrial tissue located in the abdominal wall. SUBJECTS AND METHODS: A retrospective study of 23 female patients treated with AWE in four departments of three centers in Vladimir city, Russia, from January 2010 to December 2014 was performed. RESULTS: In twenty patients (87%), AWE was symptomatic, and in three patients (13%), AWE was asymptomatic. Esquivel triad presented in 17 patients (74%), and modified Esquivel triad existed in 20 patients (87%). All 23 patients were operated, and AWE excision was performed. Recurrence occurred in 4 cases (17.4%) and was associated with postoperative pain and seroma. CONCLUSION: Postoperative pain for more than 7 days and seroma (on ultrasonography) seem to be associated with recurrence of AWE. PMID- 27942101 TI - Unintended pregnancy among antenatal women in a tertiary hospital in North Central Nigeria. AB - BACKGROUND: Unintended pregnancy is a pregnancy that is either unwanted or mistimed. The objectives of this study were to determine the prevalence of unintended pregnancy as well as to document the determinant factors among pregnant women attending antenatal clinic at the University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria. MATERIALS AND METHODS: This was a descriptive, cross-sectional study of 300 women attending the antenatal clinic of the Teaching Hospital. Information on sociodemographic characteristics, desirability of the current pregnancy at the time of conception, and knowledge and practice of contraceptive methods were collected using a pretested questionnaire. The data obtained were analyzed using SPSS version 20. Chi-square test was used for tests of associations with the level of significance set at P < 0.05. RESULTS: The average age of the respondents was 30.0 +/- 4.7 years. Overall, 33.3% and 58.3% of the respondents attained secondary and tertiary levels of education, respectively. The prevalence rate of unintended pregnancy was 16%. Contraceptive awareness was quite high (259, 86.3%). However, contraceptive usage was low as 192 (61.9%) had never used any form of contraceptives. Univariate analysis using Chi-square test showed a statistically significant association between age and unwanted pregnancy (chi2 = 68.56, P < 0.001), as well as between parity and unwanted pregnancy (chi2 = 39.92, P < 0.001). CONCLUSION: The prevalence of unintended pregnancy among women attending antenatal clinic is high, possibly due to low contraceptive usage. Adequate information, education, and communication materials should be provided during antenatal health talks. Advocacy visits for community sensitization should also be increased. PMID- 27942102 TI - Quality of acute asthma care in two tertiary hospitals in a state in South Western Nigeria: A report of clinical audit. AB - BACKGROUND: To audit the quality of acute asthma care in two tertiary hospitals in a state in the southwestern region of Nigeria and to compare the clinical practice against the recommendations of the Global Initiative for Asthma (GINA) guideline. PATIENTS AND METHODS: We carried out a retrospective analysis of 101 patients who presented with acute exacerbation of asthma to the hospital between November 2010 and October 2015. RESULTS: Majority of the cases were females (66.3%), <45 years of age (60.4%), and admitted in the wet season (64.4%). The median duration of hospital stay was 2 days (interquartile range; 1-3 days) and the mortality was 1.0%. At admission, 73 (72.3%) patients had their triggering factors documented and 33 (32.7%) had their severity assessed. Smoking status, medication adherence, serial oxygen saturation, and peak expiratory flow rate measurement were documented in less than half of the cases, respectively. Seventy six (75.2%) patients had nebulized salbutamol, 89 (88.1%) had systemic corticosteroid, and 78 (77.2%) had within 1 h. On discharge, 68 (67.3%) patients were given follow-up appointment and 32 (31.7%) were reviewed within 30 days after discharge. Less than half were prescribed an inhaled corticosteroid (ICS), a self-management plan, or had their inhaler technique reviewed or controller medications adjusted. Overall, adherence to the GINA guideline was not satisfactory and was very poor among the medical officers. CONCLUSION: The quality of acute asthma care in our setting is not satisfactory, and there is a low level of compliance with most recommendations of asthma guidelines. This audit has implicated the need to address the non-performing areas and organizational issues to improve the quality of care. PMID- 27942104 TI - Serum thyroid-stimulating hormone level and relation with size of hippocampus in patients with mild cognitive disorders. AB - BACKGROUND: Cognitive disorders and dementia are common problems, and Alzheimer's disease is one of the major leading causes of death worldwide. Thyroid hormone disorders as a common problem effect on hippocampus size which as a prognostic factor in dementia. The aim of the present study was to investigate the relationship between serum thyroid-stimulating hormone (TSH) level and the size of hippocampus in patients with mild cognitive disorders. MATERIALS AND METHODS: In a descriptive-analytical study, 41 patients with symptoms of mild cognitive disorders whom referred to take the brain magnetic resonance image (MRI) in a radiology center under the direction of Tabriz University of Medical Sciences (Tabriz, Iran) were evaluated. The right and left hippocampal and brain volume was calculated by MRI at coronal T1-weighted. Serum TSH level was also measured in these patients. Correlation between serum TSH level and hippocampal volume size was evaluated. RESULTS: Male to female ratio was 1.05:1 with mean age of 54.09 +/- 3.11 years. Mean serum TSH level of patients was 1.55 +/- 1.45 uU/ml. The right and left hippocampal volumes were 1.61 +/- 0.42 and 1.62 +/- 0.39 ml, respectively. There were slight negative correlations between the right and left hippocampal volumes with TSH level (r = -0.133 and r = -0.092, respectively). Correlations between the right and left hippocampal volumes with TSH level were not statistically significant (P = 0.406, P = 0.566, respectively). CONCLUSION: Based on findings of the present study, there was a weak negative correlation between serum level of TSH with the right and left hippocampal and brain volume ratio, but the correlation was not statistically significant. It seems that controlling of clinical or subclinical hypothyroidism may have a role in slowing of dementia progression and also have a preventive role. PMID- 27942103 TI - Gentamicin-mediated ototoxicity and nephrotoxicity: A clinical trial study. AB - BACKGROUND: Aminoglycosides and mainly gentamicin are the most important antimicrobial agents. Two different methods of administration exist: Single and multiple doses. There has always been a controversy about the less harmful administration method, to minimize adverse effects of gentamicin - deafness and renal insufficiency. In this study, it was aimed to compare two different methods of administration to figure out the least harmful treatment method. MATERIALS AND METHODS: In a clinical study, eighty patients aged 12-55 years who were admitted with sepsis syndrome were included in the study; they were divided into two groups: The first group received single-dose treatment (5 mg/kg) whereas the second group was treated with multiple doses (1.7 mg/kg three times a day) of gentamicin. RESULTS: The results show that blood urea nitrogen (BUN) and creatinine (CR) levels were decreased in the first group. Both blood urea nitrogen and creatinine and also mean glomerular filtration rate was increased in the same group. In the second group, mean BUN and CR levels were increased while the GFR was decreased in the same group. There was also a gradual increase in GFR in the first group. GFR <80 was decreased from 20% to 5.1% in the first group while increased from 5% to 27.5% in the second group. Results of audiometric studies show 6.1% hearing problem in the first group and 12.8% in the second one. CONCLUSIONS: Results of the present study showed that nephrotoxicity and ototoxicity are minimized in single-dose administration compared to multiples doses. PMID- 27942105 TI - Measuring Wealth and Wealth Inequality: Comparing Two U.S. Surveys. AB - Household wealth and its distribution are topics of broad public debate and increasing scholarly interest. We compare the relative strength of two of the main data sources used in research on the wealth holdings of U.S. households, the Survey of Consumer Finances (SCF) and the Panel Study of Income Dynamics (PSID), by providing a description and explanation of differences in the level and distribution of wealth captured in these two surveys. We identify the factors that account for differences in average net worth but also show that estimates of net worth are similar throughout most of the distribution. Median net worth in the SCF is 6% higher than in the PSID and the largest differences between the two surveys are concentrated in the 1-2 percent wealthiest households, leading to a different view of wealth concentration at the very top but similar results for wealth inequality across most of the distribution. PMID- 27942106 TI - Enhanced Model Predictive Control (eMPC) Strategy for Automated Glucose Control. AB - Development of an effective artificial pancreas (AP) controller to deliver insulin autonomously to people with type 1 diabetes mellitus is a difficult task. In this paper, three enhancements to a clinically validated AP model predictive controller (MPC) are proposed that address major challenges facing automated blood glucose control, and are then evaluated by both in silico tests and clinical trials. First, the core model of insulin-blood glucose dynamics utilized in the MPC is expanded with a medically inspired personalization scheme to improve controller responses in the face of inter- and intra-individual variations in insulin sensitivity. Next, the asymmetric nature of the short-term consequences of hypoglycemia versus hyperglycemia is incorporated in an asymmetric weighting of the MPC cost function. Finally, an enhanced dynamic insulin-on-board algorithm is proposed to minimize the likelihood of controller induced hypoglycemia following a rapid rise of blood glucose due to rescue carbohydrate load with accompanying insulin suspension. Each advancement is evaluated separately and in unison through in silico trials based on a new clinical protocol, which incorporates induced hyper- and hypoglycemia to test robustness. The advancements are also evaluated in an advisory mode (simulated) testing of clinical data. The combination of the three proposed advancements show statistically significantly improved performance over the nonpersonalized controller without any enhancements across all metrics, displaying increased time in the 70-180 mg/dL safe glycemic range (76.9 versus 68.8%) and the 80-140 mg/dL euglycemic range (48.1 versus 44.5%), without a statistically significant increase in instances of hypoglycemia. The proposed advancements provide safe control action for AP applications, personalizing and improving controller performance without the need for extensive model identification processes. PMID- 27942107 TI - Relationship between atherosclerosis and knee osteoarthritis as graded by radiography and ultrasonography in females. AB - [Purpose] The aim of this study was to assess the relationship between atherosclerosis and knee osteoarthritis grade in women as assessed by both ultrasonography and radiography. [Subjects and Methods] Seventy women diagnosed with knee osteoarthritis were classified into two groups according to cartilage grading/radiographic grading. Patients with Kellgren-Lawrence grades 1 and 2 were included in group 1, while those with Kellgren-Lawrence grades 3 and 4 were included in group 2. Patients with cartilage grades 1-3 were included in group 1, while those with cartilage grades 4-6 were included in group 2. Patients were clinically assessed using a visual analog scale and the Western Ontario and McMaster Universities Arthritis Index. Radiographic osteoarthritis grade was scored using the Kellgren and Lawrence grading system. Using ultrasonography, symptomatic knees were graded and evaluated for distal femoral cartilage thickness. Carotid intima-media thickness and serum lipid levels were measured to assess atherosclerosis. [Results] Carotid intima-media thickness measurements were higher in group 2 than in group 1 as determined by the Kellgren-Lawrence and cartilage grading systems. Carotid intima-media thickness measurements were positively correlated with both the ultrasonographic cartilage grade and Kellgren Lawrence. [Conclusion] The results of this study suggest that osteoarthritis as assessed by ultrasonography was successful and comparable to assessment with radiography. We showed a correlation between atherosclerosis and ultrasonographic knee osteoarthritis grade. PMID- 27942108 TI - Effects of scapular stability exercise on shoulder stability and rehabilitative ultrasound images in office workers. AB - [Purpose] To examine the clinical effectiveness of scapular stability exercise on shoulder stability and rehabilitative ultrasound images in office workers. [Subjects and Methods] Thirty-eight subjects were randomly divided into a scapular stability exercise group (n=19) and a manual therapy group (n=19). Subjects in the scapular stability exercise group performed a scapular stability exercise designed to correct the abnormal location of the scapula, at 40 minutes per session, two times per week, for 6 weeks. Forward head horizontal distance, rounded shoulder posture, stability of the upper limb for the shoulder, and rehabilitative ultrasound images were evaluated before and after 6 weeks. [Results] After the intervention, both groups showed significantly decreased forward head horizontal distance and rounded shoulder posture, with significantly improved stability of the upper limb and rehabilitative ultrasound images. Forward head horizontal distance, rounded shoulder posture, stability of the upper limb, and rehabilitative ultrasound images showed greater improvements in the shoulder stability exercise group than in the manual therapy group. [Conclusion] Scapular stability exercise can improve shoulder stability and the thickness of the lower trapezius in rehabilitative ultrasound images of office workers, and could be useful in clinical rehabilitation. PMID- 27942109 TI - Effects of treadmill speed on the knee angle and stance time of white rats with knee osteoarthritis according to the treadmill speed. AB - [Purpose] The purpose of this study was to identify whether walking on a treadmill at an adjusted speed is suitable for humans by examining the effects of exercise on the joint functions of white rats with induced knee osteoarthritis. [Subjects and Methods] The subjects were 20 Sprague-Dawley white rats, aged eight weeks, weighing 250 to 300 g. The moderate-speed exercise group performed their exercise at a gradient of 0% and a speed of 15 m/min, and the high-speed exercise group performed their exercise at a gradient of 0% and a speed of 26 m/min. [Results] Statistically significant changes were elicited by the moderate-speed and high-speed exercises. [Conclusion] In conclusion, the results of the present study present the importance of walking exercise. In particular, they demonstrate that changes in knee ROM and stance time are elicited by changes in walking speed. PMID- 27942110 TI - Comparison of maximum voluntary isometric contraction of the biceps on various posture and respiration conditions for normalization of electromyography data. AB - [Purpose] Maximum voluntary isometric contraction can increase the reliability of electromyography data by controlling respiration; however, many studies that use normalization of electromyography data fail to account for this. This study aims to check changes in maximum voluntary isometric contraction based on changes in posture and respiration conditions. [Subjects and Methods] Twenty-two healthy volunteers were included in this study. Using 22 healthy subjects, MVIC of the biceps brachii muscle was measured in three respiration conditions: (1) Maximum voluntary isometric contraction during inspiration after maximal expiration, (2) Maximum voluntary isometric contraction during expiration after maximal inspiration and (3) Maximum voluntary isometric contraction during the Valsalva maneuver. The subjects were in tested in standing and supine postures under all three respiration conditions. [Results] A significant difference was observed in the standing and supine postures based on the respiration condition. A significant difference was observed in the maximum voluntary isometric contraction during inspiration after maximal expiration and maximum voluntary isometric contraction during the Valsalva maneuver conditions when the subjects were in the supine posture. [Conclusion] It is necessary to apply the same respiration condition and the same posture to each subject when measuring Maximum voluntary isometric contraction for the normalization of electromyography data. PMID- 27942111 TI - Influence of biofeedback weight bearing training in sit to stand to sit and the limits of stability on stroke patients. AB - [Purpose] The purpose of this study is to observe the influence of biofeedback weight bearing training in sit to stand to sit and limits of stability on stroke patients. [Subjects and Methods] For subjects of this study, 30 stroke patients were randomly divided into two groups of 15, a biofeedback weight bearing training group and a functional weight bearing training group. Biofeedback weight bearing training was conducted for 30 minutes, five times a week for eight weeks, using Biorescue. Analysis of sit to stand to sit was done with LUKOtronic while the analysis of limits of stability was done with Biorescue. [Results] In a comparison of sit to stand to sit and limits of stability between the two groups before and after intervention, Group I showed significant difference in sit to stand to sit and limits of stability when compared to Group II. [Conclusion] This study concludes that biofeedback weight bearing training is more effective in improving sit to stand to sit and limits of stability in stroke patients. PMID- 27942112 TI - Impact of the difference in the plantar flexor strength of the ankle joint in the affected side among hemiplegic patients on the plantar pressure and walking asymmetry. AB - [Purpose] This study was to examine the changes in the gait lines and plantar pressures in static and dynamic circumstances, according to the differences in the strengths of the plantar flexors in the ankle joints on the affected sides of hemiplegic patients, and to determine their impacts on walking symmetry. [Subjects and Methods] A total of thirty hospitalized stroke patients suffering from hemiplegia were selected in this study. The subjects had ankylosing patterns in the ankle joints of the affected sides. Fifteen of the patients had plantar flexor manual muscle testing scores between poor and fair, while fifteen of the patients had zero and trace. [Results] The contact pattern of the plantar surface with the ground is a reliable method for walking analysis, which is an important index for understanding the ankle mechanism and the relationship between the plantar surface and the ground. [Conclusion] The functional improvement of patients with stroke could be supported through a verification of the analysis methods of the therapy strategy and walking pattern. PMID- 27942113 TI - Knowledge of the pelvic floor in menopausal women and in peripartum women. AB - [Purpose] Pelvic floor dysfunction is an important health-care issue, with pregnancy, childbirth, and menopause as the most important risk factors. Insufficient knowledge about pelvic floor dysfunction is the largest barrier to seeking care. The aim of this study was to investigate the level of knowledge and information on pelvic floor dysfunction in peripartum and menopausal women. [Subjects and Methods] The present study was a cross-sectional survey. A valid and reliable questionnaire of 48 items was distributed to 402 women who were pregnant or had recently given birth and to 165 postmenopausal women. All answers were analyzed and interpreted. The study was approved by an ethics committee (B300201318334). [Results] On a VAS scale of 0 to 10, the mean ratings of the peripartum and postmenopausal women concerning their knowledge were 4.38 (SD 2.71) and 4.92 (SD 2.72). Peripartum women held significantly more pessimistic perceptions about the occurrence of postpartum pelvic floor dysfunction. The results showed that 75% of the peripartum women and 68% of the postmenopausal women felt insufficiently informed or want to get better informed. [Conclusion] The results reveal sparse knowledge about the pelvic floor among women of all ages and that a major proportion of them would be interested in more information. Amelioration of common knowledge could improve help-seeking behavior in women. PMID- 27942114 TI - Pilot study of effective methods for measuring and stretching for pectoral muscle tightness in breast cancer patients. AB - [Purpose] To evaluate differences in pectoral muscle tightness according to arm abduction angle and to determine the best arm abduction angle for stretching of pectoral muscle tightness in breast cancer patients. [Subjects and Methods] Horizontal abduction differences of shoulders were measured bilaterally by arm abduction to 45 degrees , 90 degrees , and 135 degrees to determine the best arm abduction angle for measuring pectoral muscle tightness. Thirty-two patients were divided into three pectoral muscle stretching groups (A: 45 degrees , B: 90 degrees , and C: 135 degrees ). We measured the shoulder range of motion, scores of the Disabilities of the Arm, Shoulder, and Hand, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and the Breast Module, and pain levels (using a visual analog scale) before and after therapy. [Results] The differences in degree of horizontal abduction between shoulders were significantly larger for arm abduction to 90 degrees and 135 degrees than that to 45 degrees . Groups B and C showed greater improvements in horizontal abduction limitations than group A. [Conclusion] Horizontal abduction differences between shoulders are prominent when arms are abducted to 90 degrees and 135 degrees . The appropriate arm abduction angle for measuring horizontal abduction and effective stretching of pectoral muscle tightness may be >90 degrees . PMID- 27942115 TI - Efficacy of single-dose hyaluronic acid products with two different structures in patients with early-stage knee osteoarthritis. AB - [Purpose] There are many types of hyaluronic acid preparations, but no clear data are available about which preparations is more effective. The aim of this trial was to investigate the effectiveness of different types of hyaluronic acid preparations on pain and function of inpatients with knee osteoarthritis. [Subjects and Methods] All patients were diagnosed by clinical examination and x ray. Ostenil PLUS(r) was injected into 28 patients (group 1, 1.6 million daltons), and MONOVISC(r) (group 2, 2.5 million daltons) was injected into 46 patients. Demographic data and Western Ontario and McMaster Universities Osteoarthritis Index and Visual Analog Scale scores were used for clinical evaluation at 1, 3, and 6 months post injection. [Results] In both groups, baseline Ontario and McMaster Universities Osteoarthritis Index and Visual Analog Scale scores were higher compared with those in subsequent evaluations. Based on the pre- and post-injection data, a significant reduction in all scores was observed after the injections for in both groups. According to intergroup comparisons, there was no significant difference in any of the scores between the two groups. [Conclusion] There were no difference in Ontario and McMaster Universities Osteoarthritis Index and Visual Analog Scale scores in patients with knee osteoarthritis injected with two different hyaluronic acid structures in short-term preparations. PMID- 27942116 TI - The relationship between physical activity levels and metabolic syndrome in male white-collar workers. AB - [Purpose] Physical activity is important for preventing and managing metabolic syndrome. White-collar workers can be inherently predisposed to chronic diseases, as their jobs are primarily sedentary. The purpose of this study was to examine the relationship between physical activity and metabolic syndrome in male white collar workers. [Subjects and Methods] Physical activity and metabolic syndrome factors were measured in 331 male public office workers. Physical activity was classified as high (N=101), moderate (N=115), or low (N=111) using the International Physical Activity Questionnaire. To diagnose metabolic syndrome, the U.S. National Cholesterol Education Program's standard was used. [Results] Waist circumference and triglyceride levels, factors of metabolic syndrome, were significantly higher in the low physical activity group than in the moderate or high activity group. High-density lipoprotein cholesterol was significantly lower in the low physical activity group than in the moderate or high activity group. Waist circumference and fasting glucose were negatively correlated with physical activity level, and HDL cholesterol showed a positive correlation with waist circumference. The odds ratios for metabolic syndrome were 2.03 times higher (95% confidence interval, 1.01-4.09) in the low physical activity group than in the high physical activity group. [Conclusion] Low physical activity was a risk factor for metabolic syndrome in white-collar workers. Therefore, increasing physical activity in daily life may prevent metabolic syndrome in white-collar workers. PMID- 27942117 TI - Analysis of stress, musculoskeletal disorders, and fatigue among broadcasting actors. AB - [Purpose] The purpose of the study was to assess the health effects of broadcasting actors through a comprehensive research on their job stress, psychosocial stress, and fatigue and to investigate those factors having an impact on their health condition to present a basis for comparative studies and effective human resource management in the future. [Subjects and Methods] A survey was performed to analyze the relevance of the general features, job stress, psychosocial stress, and fatigue. [Results] Analysis of job stress, one of the characteristics of individuals, revealed that 32.4% of the subjects with less than 5 years of service, 55.5% of those with 6 to 10 years of service, and 52.4% of those with more than 10 years of service showed a high level of stress. Analysis of psychosocial stress, another characteristic of individuals, revealed that 13.4% of the nonsmokers had a high level of psychosocial stress, while 37.7% of smokers had a high level of psychosocial stress based on analysis of chronic disease and psychosocial health. [Conclusion] Based on this study of the stress and fatigue of broadcasting actors, it is expected that improvements can be made to promote their mental health conditions and, organizational safety and to promote effective human resource management. PMID- 27942119 TI - Effects of proprioceptive sense-based Kinesio taping on walking imbalance. AB - [Purpose] The aim of this study was to determine how application of Kinesio tape to the upper and lower limbs affects walking through stimulation of the proprioceptive sense. [Subjects and Methods] Twelve patients diagnosed with hemiplegia due to stroke were selected as the subjects of the study. To ascertain the effects of Kinesio taping on walking, all subjects performed a straight line walking test three times while barefoot. In terms of the actual taping application, elastic Kinesio tape was used on the hemiplegic side in all subjects. [Results] The results of testing showed a significant difference in the values between before and after taping. In terms of left and right deviation according to the site of the taping application, there were statistically significant differences among the groups. [Conclusion] In conclusion, application of Kinesio taping for central nerve injury was confirmed to be effective in reducing walking deviation. PMID- 27942118 TI - Intra- and inter-rater reliability of isometric shoulder extensor and internal rotator strength measurements performed using a hand-held dynamometer. AB - [Purpose] The purpose of the present study was to establish the intra- and inter rater reliability of measurement of extensor strength in the maximum shoulder abducted position and internal rotator strength in the 90 degrees abducted and the 90 degrees external rotated position using a hand-held dynamometer. [Subjects and Methods] Twelve healthy volunteers (12 male; mean +/- SD: age 19.0 +/- 1.1 years) participated in the study. The examiners were two students who had nonclinical experience with a hand-held dynamometer measurement. The examiners and participants were blinded to measurement results by the recorder. Participants in the prone position were instructed to hold the contraction against the ground reaction force, and peak isometric force was recorded using the hand-held dynamometer on the floor. Reliability was determined using intraclass correlation coefficients. [Results] The intra- and inter-rater reliability data were found to be "almost perfect". [Conclusion] This study investigated intra- and inter-rater reliability and reveald high reliability. Thus, the measurement method used in the present study can evaluate muscle strength by a simple measurement technique. PMID- 27942120 TI - An analysis of pulmonary function in different lying positions in the 20's normal adults. AB - [Purpose] The purpose of this study was to study the changes in pulmonary functions in relation to lying positions of experimental participants. [Subjects and Methods] Twenty participants participated in this experiment. Measurements were taken in the supine position, the left side-lying position, the right side lying position, and the prone position. Vital capacity (VC) was evaluated using a Fit mate. [Results] A comparison of four lying position showed significant differences in participants' VC. In comparison of four position, supine and left sidelying, and between supine and right sidelying, and between supine and prone, between left sidelying and prone. [Conclusion] In conclusion, changing the participants lying position produce changes in pulmonary functions. The greatest change occurred with a supine lying position. We presume that ventilation is affected by body structures. The results provide objective data for establishing the most suitable positions for stroke patients performing respiratory exercises. PMID- 27942121 TI - The impact of exercise training on basal BDNF in athletic adolescents. AB - [Purpose] The purpose of this study was to investigate the impact of exercise training on basal brain-derived neurotrophic factor in athletic adolescents. [Subjects and Methods] Twenty-two male adolescents participated in this study. The subjects were divided into a control group (n=9) and trained group (n=13). The trained group comprised table tennis athletes with more than 3 years of training who regularly exercised 18 hours per week. [Results] The results of this study show the trained group had significantly lower basal brain-derived neurotrophic factor levels than the control group. Further, platelet levels were significantly higher in the trained group than in the control group. However, no significant differences were observed between the groups in serum nerve growth factor level or physical characteristics (body weight, body mass index, fasting blood glucose). [Conclusion] This study showed that the basal brain-derived neurotrophic factor level of well-trained athletic adolescents was lower than that of the control group. Further research with a larger sample size is required to confirm the finding that lower basal brain-derived neurotrophic factor levels are associated with long-term habitual exercise in athletic adolescents. PMID- 27942122 TI - The effect of the shoulder stability exercise using resistant vibration stimulus on forward head posture and muscle activity. AB - [Purpose] The purpose of this study was to analyze shoulder stabilization using resistant vibration stimulus during bodyblade exercise followed by forward head posture improvement. [Subjects and Methods] Craniovertebral angle and cranial rotation angle were measured with 24 patients who were diagnosed with forward head posture. The experimental group conducted bodyblade exercise for 6 weeks and all patients received conventional physical therapy. The craniovertebral angle and cranial rotation angle were measured using a diagnostic imaging device to measure the change in forward head posture. Sternocleidomastoid, upper trapezius and serratus anterior muscle activity were measured using surface electromyography, voluntary contraction was converting into a percentage and mean value was calculated. [Results] The experimental group showed a significant increase in the comparison of the results of both groups before and after the intervention. The comparing group showed no significant difference. The experimental group showed the significant difference in mean value after the intervention in the comparison between the groups. [Conclusion] Resistant vibration stimulus by bodyblade controlled shoulder muscle activity causing scapular stabilization followed by neck position stability improvement. Rehabilitation program that activates whole kinetic chain of proximal and distal muscles such as bodyblade will show more effective improvement when choosing rehabilitation program for neck and shoulder disease clinically. PMID- 27942123 TI - The effects on postural control and low back pain according to the types of orthoses in chronic low back pain patients. AB - [Purpose] This study investigated how types of lumbosacral orthoses applied to patients with chronic lumbar pain affect postural control and low back pain. [Subjects and Methods] Ten subjects were randomly selected and allocated to each a group wearing soft lumbosacral orthoses and a group wearing rigid lumbosacral orthoses. They wore the lumbosacral orthoses for 4 weeks. Pain index and postural control were measured on the first day of wearing lumbosacral orthoses and 4 weeks later. Pain index was evaluated using a visual analogue scale, and postural control was measured using a Balance measurement system. The measurements examined included the overall balance index, anteroposterior balance index, and mediolateral balance index. [Results] There were statistically meaningful within group differences in all variables, the visual analogue scale, overall balance index, anteroposterior balance index, and mediolateral balance index, in the group wearing soft lumbosacral orthoses. There were meaningful differences in visual analogue scale, overall balance index, and mediolateral balance index in the group wearing rigid lumbosacral orthoses. Furthermore, there was a meaningful difference in anteroposterior balance index between the group wearing soft lumbosacral orthoses and the group wearing rigid lumbosacral orthoses. [Conclusion] The results of the present study showed that wearing soft lumbosacral orthoses was more effective than wearing rigid lumbosacral orthoses. PMID- 27942124 TI - Effects of orthotic insoles on adults with flexible flatfoot under different walking conditions. AB - [Purpose] This study was to evaluate the effects of orthotics on adults with flexible flatfoot when wearing orthotic insoles while walking on horizontal ground, walking up and down stairs and to determine if flexible flatfoot needs treatment. [Subjects and Methods] Fifteen college students with flexible flatfoot and fifteen college students with normal feet were recruited. First, load rate and contact area were measured by RSscan force plate when the subjects were walking on horizontal ground, walking up and down 10 cm and 20 cm stairs. Then the subjects with flexible flatfoot were instructed to wear orthotic insoles for 3 months, and plantar pressure was measured again. Finally, the data were subjected to repeated measures ANOVA. [Results] After treatment for 3 months, the plantar pressure of flatfoot was significantly improved. In addition, the data of the subjects with normal feet and flatfoot were significantly influenced by walking down 10 cm or 20 cm stairs. [Conclusion] Orthotic insoles could significantly improve the plantar pressure of flatfoot. Additionally, the arches of subjects with normal feet and flatfoot can be significantly deformed when walking down stairs. Therefore, it is essential for subjects with flexible flatfoot to wear orthotic insoles to avoid needless injury. PMID- 27942125 TI - Edema and pain reduction using transcutaneous electrical nerve stimulation treatment. AB - [Purpose] The purpose of this study was to investigate the impact on the edema and pain when applying transcutaneous electrical nerve stimulation. [Subjects and Methods] Eleven patients who were diagnosed with lymphedema were selected as the subjects of the study. The experimental group received transcutaneous electrical nerve stimulation treatment on edema regions three times per week for four weeks. Surface tape measurement was used to measure changes in lower extremity edema. Pain intensity was measured using the visual analog scale. [Results] The edema decrements in the experimental group were significantly larger than those in the control group. The pain decrements in the experimental group were significantly larger than those in the control group. [Conclusion] In conclusion, application of transcutaneous electrical nerve stimulation was confirmed to be effective in reducing edema and pain. PMID- 27942126 TI - Availability, usage, and factors affecting usage of electrophysical agents by physical therapists: a regional cross-sectional survey. AB - [Purpose] The aim of this study was to investigate the availability, usage, and factors affecting usage of electrophysical agents by physical therapists in Nagano Prefecture, Japan. [Subjects and Methods] Questionnaires were sent to all 1,571 physical therapists working in 245 institutions within Nagano Prefecture. A total of 1,110 questionnaires were returned, out of which 1,099 (70%) questionnaires containing valid responses were analyzed. Frequencies and percentages were calculated for 22 modalities with regards to availability, usage, rate of usage, and confidence level in usage. Factors affecting usage and the relationship between rate of usage and confidence level (Spearman's rho) were also determined. [Results] The top three responses for the various outcome measures were as follows: (1) hot packs (88%), low frequency stimulators (76%), and ultrasound (68%) for availability; (2) hot packs (72%), ultrasound (61%), and cold packs (59%) for usage; (3) hot packs (75%), cold spray (49%), and ultrasound (44%) for confidence in usage; and (4) equipment availability (80%), past experience (79%), and research evidence (78%) for factors affecting usage. There was a significant positive relationship between confidence and usage for all modalities, except for ultraviolet radiation, iontophoresis, and magnetic field. [Conclusion] Usage was strongly correlated with confidence, with the top three used modalities also being the ones with the highest confidence in usage. PMID- 27942127 TI - Effects of body mass index on plantar pressure and balance. AB - [Purpose] To suggest physiotherapy programs and to determine foot stability based on the results of plantar pressure and spontaneity balance in the normal group and in the obesity group according to the body mass index (BMI). [Subjects and Methods] The plantar pressure and balance of 20 females college students in their 20s were measured according to their BMI. BMI was measured by using BMS 330. The peak plantar pressure was measured in a static position in the forefoot and hind foot areas. To study balance, the spontaneity balance of each foot was measured on both stable and unstable surfaces. [Results] In terms of plantar pressure, no significant change was observed in the forefoot and hind-foot peak pressure. In terms of spontaneity balance, no significant difference in foot position interaction was observed on both stable and unstable surfaces, while a significant difference was observed in the foot position between the groups. [Conclusion] The index of hind-foot spontaneity balance was low, particularly in the obesity group. This meant significant hind-foot swaying. The forefoot body weight support percentage increased to reinforce the reduced spontaneity balance index. PMID- 27942128 TI - Effects of complex rehabilitation training on low back strength in chronic low back pain. AB - [Purpose] The purpose of this study was to assess the effects of complex rehabilitation training on chronic low back pain. [Subjects and Methods] Complex rehabilitation training for lumbar isometric muscle strength was conducted for 12 weeks for males (n=10) and females (n=10) with chronic low back pain, who were aged in their 30s. [Results] Isometric strength of lumbar extension was increased post-test, and significant differences were found between males and females, at MedX angle of 0, 48, and 60. [Conclusion] This study showed that complex rehabilitation training had a beneficial effect on the muscle strength of lumbar extension in patients with chronic low back pain. PMID- 27942129 TI - Muscle activation patterns in acceleration-based phases during reach-to-grasp movement. AB - [Purpose] An earlier study divided reaching activity into characteristic phases based on hand velocity profiles. By synchronizing muscle activities and the acceleration profile, a phasing approach for reaching movement, based on hand acceleration profiles, was attempted in order to elucidate the roles of individual muscle activities in the different phases of the acceleration profile in reaching movements. [Subjects and Methods] Ten healthy volunteer subjects participated in this study. The aim was to electromyographically evaluate muscles around the shoulder, the upper trapezius, the anterior deltoid, the biceps brachii, and the triceps brachii, most of which have been used to evaluate arm motion, as well as the acceleration of the upper limb during simple reaching movement in the reach-to-grasp task. [Results] Analysis showed the kinematic trajectories of the acceleration during a simple biphasic profile of the reaching movement could be divided into four phases: increasing acceleration (IA), decreasing acceleration (DA), increasing deceleration (ID), and decreasing deceleration (DD). Muscles around the shoulder showed different activity patterns, which were closely associated with these acceleration phases. [Conclusion] These results suggest the important role of the four phases, derived from the acceleration trajectory, in the elucidation of the muscular mechanisms which regulate and coordinate the muscles around the shoulder in reaching movements. PMID- 27942130 TI - Effects of virtual reality training using Nintendo Wii and treadmill walking exercise on balance and walking for stroke patients. AB - [Purpose] The purpose of this study is to investigate the effects of virtual reality training using Nintendo Wii on balance and walking for stroke patients. [Subjects and Methods] Forty stroke patients with stroke were randomly divided into two exercise program groups: virtual reality training (n=20) and treadmill (n=20). The subjects underwent their 40-minute exercise program three times a week for eight weeks. Their balance and walking were measured before and after the complete program. We measured the left/right weight-bearing and the anterior/posterior weight-bearing for balance, as well as stance phase, swing phase, and cadence for walking. [Results] For balance, both groups showed significant differences in the left/right and anterior/posterior weight-bearing, with significant post-program differences between the groups. For walking, there were significant differences in the stance phase, swing phase, and cadence of the virtual reality training group. [Conclusion] The results of this study suggest that virtual reality training providing visual feedback may enable stroke patients to directly adjust their incorrect weight center and shift visually. Virtual reality training may be appropriate for patients who need improved balance and walking ability by inducing their interest for them to perform planned exercises on a consistent basis. PMID- 27942131 TI - Assessment of lower urinary tract symptoms in different stages of menopause. AB - [Purpose] To assess lower urinary tract symptoms in different stages of menopause and the quality of life of females with incontinence. [Subjects and Methods] The sample consisted of 302 females, aged between 40 and 56 years, divided into three groups: PRE (n= 81), PERI (n= 108) and POST (n= 113). This was a cross-sectional, analytical, observational study. Data were collected by assessment chart and conducting the International Consultation on Incontinence Questionnaire-Short Form. [Results] Most of the women had less than 10 years of schooling and were married. In PERI and POST menopause, the most frequent lower urinary tract symptoms were urinary urgency and stress incontinence. The PRE group did not exhibit nocturia, urge incontinence or urinary urgency, and had the lowest symptoms frequency. In the three stages, stress incontinence was the most prevalent symptom. Of the three menopause stages, PERI had a greater impact on urinary incontinence according to the International Consultation on Incontinence Questionnaire. [Conclusion] The presence of lower urinary tract symptoms can vary across the different stages of menopause and the urinary incontinence was the most frequent complaint. Moreover, it was observed that quality of life was more affected in the perimenopause stage. PMID- 27942132 TI - Knee joint angle of intracerebral hemorrhage-induced rats after extracorporeal shock wave therapy. AB - [Purpose] The purpose of this study was to investigate the impact on rat knee joints of extracorporeal shock wave therapy after experimentally induced intracerebral hemorrhage. [Subjects and Methods] Sprague-Dawley (SD) rats were divided into an experimental group that received extracorporeal shock wave therapy after central nervous system injury (n=10) and a control group that did not receive any therapeutic intervention after central nervous system injury (n=10). The Dartfish program was used to evaluate the SD rats' locomotion. [Results] There was a significant difference between the control group and the experimental group in the change of knee joint angle during midstance after the intervention. [Conclusion] In conclusion, at extracorporeal shock wave therapy for central nervous system injury was confirmed to be effective at reducing knee joint angle, confirming it is a good physical therapy intervention, based on its efficacy. PMID- 27942133 TI - Effect of spinal decompression on the lumbar muscle activity and disk height in patients with herniated intervertebral disk. AB - [Purpose] This study was conducted to clarify the difference in therapeutic effects between traction and decompression therapies, and their clinical therapeutic significance. [Subjects and Methods] The subjects were 31 patients aged 35 to 50 years who had unilateral or bilateral lumbar and radicular leg pain. An intervention program was implemented in 31 patients with lumbar herniated intervertebral disks. For the experimental group, 15 subjects were randomly selected to receive decompression therapy and trunk stabilization exercise. For the control group, 16 subjects were randomly selected to receive traction therapy and trunk stabilization exercise. [Results] Activities of the rectus abdominis, transverse abdominis, and external oblique muscles increased significantly in both groups. However, the activity of the erector spine muscle decreased, which was the only significant change in muscle activity among those of the other muscles in both groups. The disk herniation index in the experimental group decreased significantly in comparison with that in the control group, and the difference in the change in disk herniation index between the groups was significant. [Conclusion] Decompression therapy was demonstrated to be more effective clinically than conventional traction therapy as an intervention method for disk disease. PMID- 27942135 TI - The effects of short foot exercises and arch support insoles on improvement in the medial longitudinal arch and dynamic balance of flexible flatfoot patients. AB - [Purpose] The purpose of the present study is to apply short foot exercises and arch support insoles in order to improve the medial longitudinal arch of flatfoot and compare the results to identify the effects of the foregoing exercises on the dynamic balance of the feet and the lower limbs. [Subjects and Methods] Fourteen university students with flexible flatfoot were selected by conducting navicular drop tests and randomly assigned to a short foot exercise group of seven subjects and an arch support insoles group of seven subjects. The intervention in the experiment was implemented for 30 minutes per time, three times per week for five weeks in total. [Results] In inter-group comparison conducted through navicular drop tests and Y-balance tests, the short foot exercise group showed significant differences. Among intra-group comparisons, in navicular drop tests, the short foot exercise group showed significant decreases. In Y-balance tests, both the short foot exercise group and the arch support insoles group showed significant increases. [Conclusion] In the present study, it could be seen that to improve flatfoot, applying short foot exercises was more effective than applying arch support insoles in terms of medial longitudinal arch improvement and dynamic balance ability. PMID- 27942134 TI - Examinations of factors influencing toe grip strength. AB - [Purpose] This study examined the relationship between toe grip strength and its associated factors by focusing on factors that were suggested to have a relationship with toe grip strength in previous studies, aiming to clarify the factors influencing the toe grip strength of healthy women. [Subjects and Methods] Twelve healthy young women were selected for this study. Their toe grip strength, angular changes in their ankle joint during toe grip, maximum voluntary contraction activities of the rectus femoris, biceps femoris, and tibialis anterior muscles, and the medial head of the gastrocnemius muscles were measured using electromyography. Their toe curl ability, foot-arch height ratio, and weight were also measured. [Results] Multiple regression analysis demonstrated that the predictors of toe grip strength in the resulting model were foot-arch height ratio and the percentage of integrated electromyography (%IEMG) of the tibialis anterior muscle, as the dependent variables. This reveals that women whose tibialis anterior muscle %IEMG values and foot-arch height ratio are high have greater %IEMG values have greater toe grip strength. [Conclusion] These findings suggest a significant relationship between foot-arch height ratio and toe grip strength, with a reciprocal interaction. These findings further indicate that the risk of falls by the elderly could be decreased if toe grip strength were enhanced, by increasing the height of a low foot-arch with the help of an inserted insole. PMID- 27942136 TI - Comparison of whole-body vibration exercise and plyometric exercise to improve isokinetic muscular strength, jumping performance and balance of female volleyball players. AB - [Purpose] The purpose of this study was to assess the effect of whole-body vibration exercise and plyometric exercise on female volleyball players. [Subjects and Methods] Subjects were randomly allocated to two exercise groups (whole-body vibration exercise group and plyometric exercise group). The exercise was conducted three times each week for 8 weeks. Isokinetic muscular strength, jumping performance, and balance were measured before starting the exercise and after finishing the 8 weeks of exercise. [Results] Measurements of isokinetic muscular strength revealed that the whole-body vibration exercise group showed significant increase after the exercise. However, the plyometric exercise group had no significant increase in lumbar flexion, extension, and knee flexion. Measurements of vertical jumping revealed that, the whole-body vibration exercise group had no significant increase after the exercise. However, the plyometric exercise group showed significant increase. Measurements of balance revealed that, the whole-body vibration exercise group showed significant increase. However, the plyometric exercise group showed no significant increase. [Conclusion] Although both whole-body vibration and plyometric exercises are effective intervention methods, the two methods have different effects on the improvement of isokinetic muscular strength, jumping performance, and balance of female volleyball players. PMID- 27942137 TI - Study on the quality of life of children with cerebral palsy. AB - [Purpose] This study aims to analyze the factors that affect the quality of life of children with cerebral palsy. [Subjects and Methods] The study subjects were 138 children, aged 7-12, who suffer from cerebral palsy. Factors affecting subjects' quality of life were evaluated using the ICF-CY; quality of life was evaluated using the KIDSCREEN 52 - Health-Related Quality of Life questionnaire. Multiple regression analysis was conducted. [Results] The factors related to physical functions that affect subjects' quality of life were mental function, sensory function and pain, genitourinary and reproductive function, as well as neuromusculoskeletal and movement-related functions. Factors related to activities and participation were learning and applying knowledge, self-care, interpersonal interactions and relationships, major life areas, and community, social and civic life. Lastly, factors related to the environment were products and technology, natural environment and human made changes to environment, and attitude. [Conclusion] In order to improve the quality of life of children with cerebral palsy, the compound effects of several factors should be comprehensively considered without being limited to a specific variable from physical function. And children should be provided with ample opportunities to participate in diverse activities and their physical functions, as well as the environmental factors, should improve. PMID- 27942138 TI - The effects of visual control whole body vibration exercise on balance and gait function of stroke patients. AB - [Purpose] This study aims to verify the effects of visual control whole body vibration exercise on balance and gait function of stroke patients. [Subjects and Methods] A total of 22 stroke patients were randomly assigned to two groups; 11 to the experimental group and 11 to the control group. Both groups received 30 minutes of Neuro-developmental treatment 5 times per week for 4 weeks. The experimental group additionally performed 10 minutes of visual control whole body vibration exercise 5 times per week during the 4 weeks. Balance was measured using the Functional Reach Test. Gait was measured using the Timed Up and Go Test. [Results] An in-group comparison in the experimental group showed significant differences in the Functional Reach Test and Timed Up and Go Test. In comparing the groups, the Functional Reach Test and Timed Up and Go Test of the experimental group were more significantly different compared to the control group. [Conclusion] These results suggest that visual control whole body vibration exercise has a positive effect on the balance and gait function of stroke patients. PMID- 27942139 TI - Comparison of older adults' visual perceptual skills, cognitive function, and fall efficacy according to fall risk in the elderly. AB - [Purpose] This research aims to identify the relationships among visual perceptual skills, cognitive functioning, and fall efficacy of older adults based on whether they are at risk for falls. [Subjects and Methods] Subjects included 116 older adults over 65 years of age who use D Seniors Welfare Center and Y Senior Citizen Center in Busan Metropolitan City. All research subjects were classified based on balance maintenance ability evaluation and whether or not they had experienced falls more than once. Those with scores below the cut-off standard were selected as a group of older adults at risk for falls. An MVPT-3 test was used to assess visual perceptual skill, MMSE-KC, and MoCA-K tests to assess cognitive function, and the FES-K falls efficacy test to classify subjects as either at risk for falls or not. [Results] After comparing scores for visual perceptual skills, cognitive functioning, and fall efficacy, subjects at risk for falls showed significantly lower scores than did those not at risk. [Conclusion] The study found that there are significant differences in balance ability, visual perceptual skill, cognitive functioning, and fall efficacy between older adults at risk for falls and those not at risk. PMID- 27942140 TI - Reliability and validity of standing balance assessment index using a hand-held dynamometer in stroke patients. AB - [Purpose] This study aimed to determine the reliability and validity of our standing balance assessment index using a hand-held dynamometer (the hand-held dynamometer assessment index) in stroke patients. [Subjects and Methods] The participants were 60 stroke patients with impaired standing balance. Intrarater and interrater reliabilities were evaluated employing the intraclass correlation coefficient. Criterion-related validity was evaluated by Spearman's rank correlation coefficient between the HHD assessment index and the functional balance scale. [Results] The intraclass correlation coefficient values obtained ranged from 0.91 to 0.98, and the correlation coefficient with the FBS was 0.83. [Conclusion] Our findings confirmed the reliability and validity of the hand-held dynamometer assessment index in stroke patients. PMID- 27942141 TI - The effects of sitting with the right leg crossed on the trunk length and pelvic torsion of healthy individuals. AB - [Purpose] The purpose of this study was to determine the effects on the trunk length and pelvic torsion of healthy individuals that arise from crossing the right leg while sitting. [Subjects and Methods] The subjects in this study were 30 healthy individuals consisting of 18 males and 12 females. The subjects were instructed to sit on a chair, the height of which was adjustable, so that their knee and hip joints were bent at 90 degrees . For the study, they sat stripped to the waist, with the back and hips bare. They were then instructed to perform a one-leg-crossed sitting posture by placing the right leg on the top of the left knee. A spinal posture test was performed to measure the subjects' trunk length and pelvic torsion by using a three-dimensional image-based spinal diagnostic system. [Results] The results of the three-dimensional spine examination showed statistically significant decreases in trunk length and pelvic torsion after the one-leg-crossed sitting posture. [Conclusion] In this study, the right leg crossed sitting posture led to a decrease in the right trunk length with time and, in terms of pelvic torsion, increased the posterior rotation of the right pelvis when compared with the left pelvis. PMID- 27942142 TI - The effects of horse riding simulation exercise with blindfolding on healthy subjects' balance and gait. AB - [Purpose] The study was conducted to determine the effect of horse riding simulation combined with blindfolding on healthy individuals' balance and gait. [Subjects and Methods] Thirty subjects were randomly divided into an experimental group (n=15) and a control group (n=15). The subjects in the experimental group covered their eyes using a blindfold, climbed onto a horse riding simulator, and performed the horse riding simulation exercise. The control group took part in the horse riding exercises without a blindfold. All of the subjects performed the 20 minutes long exercise once a day, five times a week, over a four-week period. [Results] The experimental group showed significant improvement in static balance, dynamic balance, velocity, and cadence compared to pre-intervention measurements. In addition, the control group showed significant improvement in static balance, dynamic balance, single support, and cadence compared to pre intervention measurements. Significant differences in post-training gains in static balance, dynamic balance, and cadence were observed between the experimental group and the control group. [Conclusion] Subjects that performed horse riding simulation exercise after blindfolding showed significant improvements in balance and cadence compared to the control group. PMID- 27942143 TI - Effects of virtual reality training with modified constraint-induced movement therapy on upper extremity function in acute stage stroke: a preliminary study. AB - [Purpose] The purpose of this study was to investigate the effects of virtual reality training combined with modified constraint-induced movement therapy on upper extremity motor function recovery in acute stage stroke patients. [Subjects and Methods] Four acute stage stroke patients participated in the study. A multiple baseline single subject experimental design was utilized. Modified constraint-induced movement therapy was used according to the EXplaining PLastICITy after stroke protocol during baseline sessions. Virtual reality training with modified constraint-induced movement therapy was applied during treatment sessions. The Manual Function Test and the Box and Block Test were used to measure upper extremity function before every session. [Results] The subjects' upper extremity function improved during the intervention period. [Conclusion] Virtual reality training combined with modified constraint-induced movement is effective for upper extremity function recovery in acute stroke patients. PMID- 27942145 TI - Effect of proprioception cross training on repositioning accuracy and balance among healthy individuals. AB - [Purpose] To investigate possible cross effects of proprioception training on proprioception repositioning accuracy of the knee joint and on balance in healthy subjects. [Subjects and Methods] Sixty healthy college students and faculty members from faculty of physical therapy, Cairo University were recruited to participate. Participants were randomly assigned to training group (n=30) and control group (n=30). The training group received proprioceptive training program only for the dominant leg while the control group did not receive any kind of training. Outcome measures were twofold: (1) proprioception repositioning accuracy quantified through the active repositioning test for the non-dominant knee; and (2) balance stability indices determined through using Biodex balance system. Measurements were recorded before and after 8 weeks of proprioception training. [Results] There were significant decrease in the error of repositioning accuracy and the stability indices including anterposterior stability index, mediolateral stability index, and overall stability index of training group, measured post training, compared with control group. [Conclusion] Proprioception training has significant cross training effects on proprioception repositioning accuracy of the knee joint and on balance among healthy subjects. PMID- 27942144 TI - Changes of oxidative/antioxidative parameters and DNA damage in firefighters wearing personal protective equipment during treadmill walking training. AB - [Purpose] The purpose of this study was to investigate the influence of personal protective equipment on the oxidant/antioxidant parameters and DNA damage in firefighters during training and recovery. [Subjects and Methods] Twelve male nonsmoking volunteer firefighters (35.1 +/- 7.2 years) underwent two maximal treadmill training (9 METs, 6 km/h), within 2 weeks, one in regular clothes and one in personal protective equipment weighing 22.1 kg. Blood samples were obtained before, right after, and 40 min after training. Plasma conjugated dienes, total radical trapping antioxidant potential, erythrocytes antioxidant enzymes activities, and leukocyte DNA damage were measured. [Results] Wearing personal protective equipment during treadmill walking training resulted in increases of plasma conjugated dienes, total radical trapping antioxidant potential, and leukocyte DNA resistance to oxidative stress, which were recovered after in 40 min of rest. Erythrocyte antioxidant enzymes activities remained unchanged during the training either with regular clothes or personal protective equipment. [Conclusion] These results suggest that wearing personal protective equipment during firefighting work could induce oxidative stress, which was enough to produce DNA damage in leukocytes. PMID- 27942146 TI - Effect of a simple and adherent home exercise program on the physical function of community dwelling adults sixty years of age and older with pre-sarcopenia or sarcopenia. AB - [Purpose] To evaluate the effect of a home exercise program on physical function in community dwelling elderly with pre-sarcopenia or sarcopenia. [Subjects and Methods] Fifty-two community-dwelling individuals, over 60 years and meeting the diagnostic criteria for pre-sarcopenia or sarcopenia, were randomly assigned to intervention group (n=34) and control group (n=18). The intervention group completed 6-months home exercise programs, combining walking with lower limb resistance exercises. Body mass index, skeletal mass index, body fat percentage, handgrip strength, single-leg standing, walking speed (comfortable and maximal), and knee extension strength were evaluated at baseline and post-intervention. Activity was assessed using the 25-question Geriatric Locomotive Functional Scale (GLFS-25) and quality of life using the Euro QOL questionnaire. [Results] Pre- and post-training assessments were completed by 76.5% and 77.8% of participants in the intervention and control groups, respectively. The intervention improved single-leg standing (60.5 s to 77.2 s) and knee extension strength (1.38 Nm/kg to 1.69 Nm/kg). In the control group, maximum walking speed (2.02 m/s to 1.86 m/s) and GLFS-25 score (2.9 to 5.1) worsened. Change of pre-sarcopenia/sarcopenia status was comparable for the intervention (15.4%) and control (14.3%) groups. [Conclusion] A 6-month home exercise program improved physical function in community-dwelling individuals with pre-sarcopenia or sarcopenia. PMID- 27942147 TI - Effects of elastic-band resistance exercise on balance, mobility and gait function, flexibility and fall efficacy in elderly people. AB - [Purpose] The purpose of this study was to analyze the effects of elastic-band resistance exercise on balance, gait function, flexibility and fall efficacy in the elderly people of rural community. [Subjects and Methods] It is selected by 45 outpatients. They have come into the clinic continually to treat of physical therapy at least 1-2 times for a week. A group treated with both general physical therapy and elastic-band resistance exercise (23 patients), and the other group treated with only general physical therapy (22 patients). Elastic-band resistance exercise is composed of 8 movements of lower extremity joints. It is performed for 30 minutes during 8 weeks by 3 times for a week. It is measured and recorded at the pre and post test that sit and reach test (SRT), functional reach test (FRT), timed up and go test (TUG) for every subjects by measurement equipments. And, subjects performed for the form of performance and question as its rated scale by Berg's balance scale (BBS), dynamic gait index (DGI), activities specific balance confidence scale (ABC). [Results] In the study, both the elastic band exercise group and the general physical therapy group showed a significant improvement in balance, gait function, flexibility and fall efficacy. And the group with elastic-band resistance exercise showed more effectiveness than the contrast group in value of variation. [Conclusion] From this study, it was confirmed that elastic-band resistance exercise has influence on balance, gait function, flexibility and fall efficacy are working for agriculture of elderly people of rural community. Based on this result, elastic-band resistance exercise can be better instrument and easier to elderly people of rural community for the improvement in balance, gait function, flexibility and fall efficacy as it performing along with and reciprocal physical therapy. PMID- 27942148 TI - The effects of high intensity laser therapy on pain and function in patients with knee osteoarthritis. AB - [Purpose] The purpose of this study was to examine the effects of high intensity laser therapy (HILT) on pain and function in patients with knee osteoarthritis. [Subjects and Methods] In this study, an experiment was conducted on 20 subjects who were divided into the control group (n=10), which would receive conservative physical therapy (CPT), and the experimental group (n=10), which would receive effects of high intensity laser therapy after conservative physical therapy. All patients received their respective therapies three times each week over a four week period. In terms of the intensity of the high intensity laser therapy, it was applied to each patient in the tibia and femoral epicondyle for five minutes while the patient's knee joint was bent at around 30 degrees and the separation distance between the handpiece and the skin was maintained at around 1 cm. The visual analogue scale was used to measure pain, and the Korean Western Ontario and McMaster Universities Osteoarthritis Index was used for functional evaluations. [Results] The comparison of differences in the measurements taken before and after the experiment within each group showed a statistically significant decline in both the VAS and the K-WOMAC. The comparison of the two groups showed that the high intensity laser therapy group had statistically significant lower scores in both the visual analogue scale and the Korean Western Ontario and McMaster Universities Osteoarthritis Index than the conservative physical therapy group. [Conclusion] High intensity laser therapy is considered an effective non-surgical intervention for reducing pain in patients with knee osteoarthritis and helping them to perform daily activities. PMID- 27942149 TI - The effects of the intake of an isotonic sports drink before orienteering competitions on skeletal muscle damage. AB - [Purpose] The purpose of this study was to investigate the effects of the intake of an isotonic sports drink (500 ml water, 32 gr carbonhydrate, 120 mg calcium, 248 mg chloride, 230 mg sodium) the level of the skeletal muscle damage of orienteering athletes. [Subjects and Methods] The study was carried out on 21 male elite orienteering athletes. The athletes were divided into two groups by randomized double-blind selection. The experimental group (n=11) was given the isotonic sports drink, while the placebo group (n=10) was given 500 ml pure water. Blood samples were taken pre-competition, post-competition, 2 hours post competition and 24 hours post-competition. [Results] The pre-c troponin, myoglobin and creatinine kinase serum levels of the placebo group were significantly lower than the post-competition and 2 hours post-competition values. The 24 hours post-competition levels of the same analyses were also significantly lower than the post-c and 2 hours post-competition. The pre competition troponin, myoglobin and creatinine kinase levels of the experimental group were found to be significantly lower than the post-competition, 2 hours post-competition 24 hours post-competition values. In conclusion, the present results suggest that the intake of supportive sports drinks before exercising significantly prevents the observed muscle damage. The study showed that serum myoglobin levels between the experimental and the placebo group is significantly different during the 2 hours post-competition period. [Conclusion] The level of serum creatinine kinase and myoglobin accurately shows the extent of the muscle damage. However, further studies on the effect of isotonic sports drink in different training programs on the cell membrane and the muscle damage are needed. PMID- 27942150 TI - The relationship between thoracic configuration and changes in volumes of hemithoraces in upright sitting. AB - [Purpose] Some patients with respiratory disease exhibit asymmetrical movement of the thorax. The purpose of this study was to investigate the relationship of thoracic configuration with changes in thoracic volume in 13 sedentary healthy men. [Subjects and Methods] In upright sitting, 84 reflective markers were placed on the anterior and posterior aspects of the trunk to record thoracic volume during quiet and volitional deep breathing. Using a three-dimensional motion analyzer, the difference in volume within the upper and lower hemithoraces was measured. For calculation of the thoracic volume six imaginary hexahedra were visualized for the upper and lower thorax using four reflective markers for each on the anterior and posterior aspects of the thorax. Each hexahedron was then divided into three imaginary triangular pyramids to calculate positional vectors. Finally, the volume for both the hexahedra and triangular pyramids was calculated. Four thoracic volumes were obtained. [Results] The findings showed that the left upper and right lower hemithorax yielded significantly larger thoracic volumes. [Conclusion] In conclusion the left upper and right lower hemithoraces were found to expand more than their corresponding sides. Understanding the characteristics of thoracic excursion during quiet and volitional deep breathing could be of value in assessment and instruction of breathing techniques to patients. PMID- 27942151 TI - Effects of compound music program on cognitive function and QOL in community dwelling elderly. AB - [Purpose] Interventions using music, physical exercise, and reminiscence therapy are widely used both for rehabilitation and care of the elderly. This study aimed to investigate the effect of structured interventions comprising music, physical exercise, and reminiscence therapy on cognitive function and quality of life of the community-dwelling elderly. [Subjects and Methods] The study included 15 community-dwelling elderly people who used a day-care center. Participants underwent sessions comprising the following three factors: 1) singing songs familiar to the elderly; 2) physical exercise to music; and 3) observation of historical pictures. Sessions were conducted once or twice per week, 30 to 40 min per day, for 10 weeks. Pre and post interventions of the Mini Mental State Examination, the Behavioral Rating Scale for the Elderly, and the SF-8 were compared. [Results] No significant difference was observed between pre- and post intervention scores on the Mini Mental State Examination and the Behavioral Rating Scale for the Elderly. However, the post intervention physical component summary of SF-8 was significantly higher than the pre intervention summary. [Conclusion] This study suggests that interventions comprising music, physical exercise, and reminiscence therapy may contribute toward the improvement of elderly individuals' health-related quality of life, especially physical health. PMID- 27942152 TI - The temporal relationship of thresholds between muscle activity and ventilation during bicycle ramp exercise in community dwelling elderly males. AB - [Purpose] To compare the appearance time of the ventilatory threshold point and the electromyographic threshold in the activity of the vastus lateralis, rectus femoris, biceps femoris long head and gastrocnemius lateral head muscles during ramp cycling exercise in elderly males. [Subjects and Methods] Eleven community dwelling elderly males participated in this study. Subjects performed exercise testing with an expiratory gas analyzer and surface electromyography to evaluate the tested muscle activities during ramp exercise. [Results] The electromyographic threshold for rectus femoris was not valid because the slope after electromyographic threshold was not significant as compared to that before electromyographic threshold. The slope of the regression line for vastus lateralis was significantly decreased after electromyographic threshold while biceps femoris and gastrocnemius were increased. The electromyographic threshold appearance times for vastus lateralis and gastrocnemius were significantly earlier than ventilatory threshold point. There were no difference in electromyographic threshold appearance times among three muscles. [Conclusion] These results suggest that the increase in the slope of the regression line after electromyographic threshold for vastus lateralis was decreased, possibly indicating to postpone muscular fatigue resulting from the activation of biceps femoris and gastrocnemius as biarticular antagonists. This recruitment pattern might be an elderly-specific strategy. PMID- 27942153 TI - Preoperative physical performance predictors of self-reported physical function and quality of life in patients scheduled for total knee arthroplasty. AB - [Purpose] To determine the preoperative self-reported and performance-based physical function of patients with end-stage knee osteoarthritis who awaited total knee arthroplasty. The preoperative physical performance factors that predicted self-reported physical function and quality of life were also identified. [Subjects and Methods] All adults with end-stage knee osteoarthritis awaiting surgery were enrolled. Before surgery, self-reported disease-specific physical function and self-reported pain were measured using the Western Ontario McMaster Universities Osteoarthritis Index, self-reported quality of life was measured using the EuroQOL five dimensions questionnaire, and physical performance tests were performed, the 6 minute walk test, the timed up-and-go test, instrumental gait analysis, and measurement of isometric knee flexor and extensor strength of the surgical and nonsurgical knees. [Results] In total, 55 adults (49 females; 73.3 +/- 6.1 years) were included. This study showed that several preoperative self-reported and physical performance factors were predictive of self-reported physical function and quality of life. [Conclusion] In patients with end-stage knee osteoarthritis, preoperative pain and dynamic balance ability were the most powerful predictors of self-reported physical function. Preoperative pain and exercise tolerance were the most powerful predictors of quality of life. Preoperative rehabilitation strategies that focus on dynamic balance, aerobic, and resistance exercises may improve surgical outcomes. PMID- 27942154 TI - Systematic review of the effects of mirror therapy in children with cerebral palsy. AB - [Purpose] To provide data for systematic intervention plans in occupational therapy practice by objectivity showing the value of mirror therapy interventions in children with cerebral palsy. [Subjects and Methods] Medline and EMBASE databases were searched for the key words "cerebral palsy," "mirror movement," "mirror therapy," and "mirror visual feedback." Nine studies that met the inclusion and exclusion criteria were identified. The qualitatively determined level of evidence, period of research, comparisons and interventions, tools used to measure the intervention, and the effects were analyzed. [Results] According to the results analyzed, one (1/9, 11.1%) study showed the same result as the control group, one (1/9, 11.1%) showed a negative effect, and seven (7/9, 77.8%) showed positive effects of mirror-mediated therapy, with meaningful improvement in function, such as hand strength, movement speed, muscle activity, and accuracy of hand matching. [Conclusion] Through this study, the value of mirror-mediated therapeutic interventions in occupational therapy practice targeting cerebral palsy was confirmed. It is expected that this result will be useful in establishing mirror therapy as an interventional program. PMID- 27942155 TI - The effects of neck and trunk stabilization exercises on upper limb and visuoperceptual function in children with cerebral palsy. AB - [Purpose] The present study aimed to investigate the effects of neck and trunk stabilization exercises on upper limb and visuoperceptual function in children with cerebral palsy. The Jebson-Taylor hand function test and the Korean Developmental Test of Visual Perception-2 (K-DTVP-2) test were utilised. [Subjects and Methods] The study subjects were 11 schoolchildren who had paraplegia caused by premature birth, and who had been diagnosed with periventricular leukomalacia. Kinesitherapy was implemented in individual children for eight weeks, twice a week, for 45 minutes at a time. After a preliminary evaluation, kinesitherapy, including neck and trunk stabilization exercises common to all the children, was implemented for eight weeks according to the functioning and level of each child. A post evaluation was performed after the eight weeks of kinesitherapy. [Results] The intervention showed a significant effect in five subcategories of the Jebson-Taylor hand function test, as well as according to the K-DTVP-2 test. [Conclusion] Because neck and trunk stabilization exercises requiring positive participation by the children included fundamental elements of daily living motion, the exercises might have had a positive effect on upper limb and visuoperceptual function. PMID- 27942156 TI - The effect of a powered ankle foot orthosis on walking in a stroke subject: a case study. AB - [Purpose] Standing and walking are impaired in stroke patients. Therefore, assisted devices are required to restore their walking abilities. The ankle foot orthosis with an external powered source is a new type of orthosis. The aim of this study was to evaluate the performance of a powered ankle foot orthosis compared with unpowered orthoses in a stroke patient. [Subjects and Methods] A single stroke subject participated in this study. The subject was fitted with three types of ankle foot orthosis (powered, posterior leg spring, and carbon ankle foot orthoses). He was asked to walk with and without the three types of orthoses, and kinetic and kinematic parameters were measured. [Results] The results of the study showed that the moments applied on the ankle, knee, and hip joints increased while walking with the powered ankle foot orthosis. [Conclusion] As the powered ankle foot orthosis influences the moments of the ankle, knee, and hip joints, it can increase the standing and walking abilities of stroke patients more than other available orthoses. Therefore, it is recommended to be used in rehabilitation programs for stroke patients. PMID- 27942157 TI - Effect of the push-up plus guide and resistance device (PPGRD) on the serratus anterior during push-up plus. AB - [Purpose] This study developed a push-up plus guide and resistance device and investigated the effectiveness of the device. [Subject and Methods] A 39-year-old man presented with moderate pain with left scapular dyskinesis. A newly designed assistance device was used as a push-up plus guide and resistance device (PPGRD). The subject performed the push-up plus exercise without and then with the PPGRD for 2 weeks each. [Results] After performing the push-up plus exercise with the PPGRD for 2 weeks, the serratus anterior muscle power was increased, the pain score was decreased, and the absence of scapular dyskinesis was confirmed. [Conclusion] The PPGRD provided appropriate guidance and prevented excessive trunk flexion during the push-up plus exercise. PMID- 27942158 TI - Changes of heart rate variability and prefrontal oxygenation during Tai Chi practice versus arm ergometer cycling. AB - [Purpose] Exercise has been shown to improve cardiovascular fitness and cognitive function. Whether the inclusion of mind over exercise would increase parasympathetic control of the heart and brain activities more than general exercise at a similar intensity is not known. The aim of this study was to compare the effects of Tai Chi (mind-body exercise) versus arm ergometer cycling (body-focused exercise) on the heart rate variability and prefrontal oxygenation level. [Subjects and Methods] A Tai Chi master was invited to perform Tai Chi and arm ergometer cycling with similar exercise intensity on two separate days. Heart rate variability and prefrontal oxyhemoglobin levels were measured continuously by a RR recorder and near-infrared spectroscopy, respectively. [Results] During Tai Chi exercise, spectral analysis of heart rate variability demonstrated a higher high-frequency power as well as a lower low-frequency/high-frequency ratio than during ergometer cycling, suggesting increased parasympathetic and decreased sympathetic control of the heart. Also, prefrontal oxyhemoglobin and total hemoglobin levels were higher than those during arm ergometer exercise. [Conclusion] These findings suggest that increased parasympathetic control of the heart and prefrontal activities may be associated with Tai Chi practice. Having a "mind" component in Tai Chi could be more beneficial for older adults' cardiac health and cognitive function than body-focused ergometer cycling. PMID- 27942159 TI - Usefulness of continuous actigraph monitoring in the assessment of the effect of corticosteroid treatment for Duchenne muscular dystrophy: a case report. AB - [Purpose] This study evaluated the effect of corticosteroid treatment on the daily activity of a patient with Duchenne muscular dystrophy using an actigraph and examined whether this method produces the same results as the conventional motor-function evaluation methods. [Subject and Methods] A patient with 5 year old Duchenne muscular dystrophy was recruited. An actigraph was attached to his waist to measure the energy expenditure and the number of steps taken by him during a period of two weeks, 14 days before and 14 days after corticosteroid administration. The outcomes of these measurements were compared with the results of conventional motor-function evaluation methods-the 10-m run test, 6-minute walk test, and North Star Ambulatory Assessment-on his next visit. [Results] The actigraph data for energy expenditure and the number of steps taken correlated well with the results of the above-mentioned conventional motor-function tests, and the value of each data point improved after corticosteroid administration. [Conclusion] An actigraph was effectively used to non-invasively measure consecutive daily activity for four weeks. It was easily done and the results were consistent with conventional motor-function evaluation methods. PMID- 27942160 TI - Accelerometer based analysis of gait initiation failure in advanced juvenile parkinsonism: a single subject study. AB - [Purpose] This study used an accelerometer placed close to the center of gravity to quantitatively investigate whether unexpected gait initiation aggravates start hesitation (freezing of gait in gait initiation). [Subject and Methods] The subject was a 53-year-old female who had been suffering from juvenile parkinsonism since she was aged 21 years. An alternating-treatment design was used to compare acceleration characteristics under two gait initiation conditions, which were 1) deliberate gait initiation and 2) gait initiation on a sudden "go" verbal command (sudden gait initiation), in the "on" state of the medication cycle. [Results] In six out of eight sessions, a combination of reduced peak positive anterior accelerations and large power percentage in the high frequency band was consistently observed in the sudden gait initiation compared with deliberate gait initiation. In the other two sessions, although a large acceleration just after the "go" signal was observed, subsequent acceleration signals were blocked by sudden gait initiation. [Conclusion] The results suggest that, even in the "on" state, start hesitation is apparent without increased reliance on frontal cortical attentional mechanisms to compensate for impaired automaticity. In advanced juvenile parkinsonism, sudden gait initiation may be an effective paradigm as a provoking test for start hesitation. PMID- 27942161 TI - Effect of unilateral exercises on low back pain in an urban driver. AB - [Purpose] This study aimed to develop unilateral exercises for urban drivers and investigate the effect of these exercises on low back pain (LBP). [Subject and Methods] A 40-year-old male driver, who complained of LBP on the left side at L3 5 levels, participated in this study. A two-session program was conducted, and LBP, pelvic tilt angle, and trunk range of motion were measured after each session. [Results] After the unilateral exercises, the anterior pelvic tilt angle was improved and the visual analog scale score of back pain decreased. [Conclusion] Analyzing car features and performing individual approaches are necessary in providing treatment for urban drivers with LBP. PMID- 27942162 TI - Upward pulling plus exercise improves scapulocostal pain and scapular position. AB - [Purpose] To investigate the effect of upward pulling combined with shoulder retraction (upward pulling plus exercise) on scapulocostal pain and scapular position. [Subject and Methods] A 22-year-old woman with severe pain in the right and left scapulocostal areas. The horizontal distance from the inferior angle to the spinal process was measured. The tester assessed scapulocostal pain after stretching and massage. The tester assessed pain after upward pulling plus exercise. [Results] Left and right scapulocostal pain reduced to 2/10 after the upward pulling plus exercise. The horizontal distance from the inferior angle to the spinal process also decreased. [Conclusion] Upward pulling plus exercise might be recommended as a primary therapeutic approach to treat scapulocostal pain or scapulocostal syndrome. PMID- 27942163 TI - Effect of physical therapy scoliosis specific exercises using breathing pattern on adolescent idiopathic scoliosis. AB - [Purpose] This study was performed to confirm physical therapy scoliosis specific exercises on adolescent idiopathic scoliosis patients. [Subject and Methods] A 15 year-old male middle school student with scoliosis. Cobb's angle, angle of rotation of the spine, and breathing pattern were measured before and after 8 weeks training. [Results] After 8 weeks training, Cobb's angle, angle of rotation of the spine, and breathing pattern were improved better. [Conclusion] These results indicate that physical therapy scoliosis specific exercises improves scoliosis curves and could provide an effective intervention and management of scoliosis. PMID- 27942164 TI - Effects of community-based rehabilitation program on activities of daily living and cognition in elderly chronic stroke survivors. AB - [Purpose] The aim of this study was to examine the effects of community-based rehabilitation program in chronic stroke patients. [Subjects and Methods] Eleven subjects received community-based rehabilitation program ten times for ten months. The main outcome measures were the Modified Barthel Index score for activities of daily living and the Korean Mini-Mental State Examination score for cognition. [Results] The results of the study demonstrated that the community based rehabilitation program improved activities of daily living performance and cognition significantly. [Conclusion] Based on the study results, the community based rehabilitation program is an effective method for improving activities of daily living performance and cognitive function in elderly patients with chronic stroke. PMID- 27942165 TI - Between China and South Asia: A Middle Asian corridor of crop dispersal and agricultural innovation in the Bronze Age. AB - The period from the late third millennium BC to the start of the first millennium AD witnesses the first steps towards food globalization in which a significant number of important crops and animals, independently domesticated within China, India, Africa and West Asia, traversed Central Asia greatly increasing Eurasian agricultural diversity. This paper utilizes an archaeobotanical database (AsCAD), to explore evidence for these crop translocations along southern and northern routes of interaction between east and west. To begin, crop translocations from the Near East across India and Central Asia are examined for wheat (Triticum aestivum) and barley (Hordeum vulgare) from the eighth to the second millennia BC when they reach China. The case of pulses and flax (Linum usitatissimum) that only complete this journey in Han times (206 BC-AD 220), often never fully adopted, is also addressed. The discussion then turns to the Chinese millets, Panicum miliaceum and Setaria italica, peaches (Amygdalus persica) and apricots (Armeniaca vulgaris), tracing their movement from the fifth millennium to the second millennium BC when the Panicum miliaceum reaches Europe and Setaria italica Northern India, with peaches and apricots present in Kashmir and Swat. Finally, the translocation of japonica rice from China to India that gave rise to indica rice is considered, possibly dating to the second millennium BC. The routes these crops travelled include those to the north via the Inner Asia Mountain Corridor, across Middle Asia, where there is good evidence for wheat, barley and the Chinese millets. The case for japonica rice, apricots and peaches is less clear, and the northern route is contrasted with that through northeast India, Tibet and west China. Not all these journeys were synchronous, and this paper highlights the selective long-distance transport of crops as an alternative to demic-diffusion of farmers with a defined crop package. PMID- 27942166 TI - 'It's better if someone can see me for who I am': Stories of (In)visibility for Students with a visual impairment within South African Universities. AB - Issues of visibility, invisibility and the nondisabled gaze are very relevant to the lives of many disabled persons. With this paper we tentatively show that, despite the physical 'over'visibility of disabled bodies, many intricate parts of their personhood remain obscured and invisible. Interviews with 23 students with a visual impairment revealed that they sometimes experienced stares and averted gazes from their sighted counterparts. In response, they often hid their entire impairment, or parts thereof, in an effort to conform and gain acceptance and to earn membership to a nondisabled peer group. Acceptance was often found in companionship with fellow disabled peers. Since these stories told of continuing exclusion for disabled students on tertiary grounds, further participatory research is recommended. PMID- 27942167 TI - Kidney donation: Clinical practice and ethical dilemmas. PMID- 27942168 TI - Attitude of medical professionals regarding controversial issues in kidney donation/transplantation. AB - There is a dire need to evaluate new strategies to bridge the wide kidney demand supply gap. The current study examined the attitude of medical professionals regarding controversial issues pertaining to transplantation. A questionnaire, presenting controversial issues related to kidney transplantation, in an agree disagree format with supporting reasons, was employed. The research was exploratory. Data were analyzed quantitatively and qualitatively. The sample comprised 140 doctors from Mumbai (mean = 38.1 years, standard deviation = 17.95; Males = 44.3%, Females = 55.7%). Whereas 47.1% of the participants felt that live donors should be given incentives for kidney donation, others (52.9%) disagreed, fearing commercialization and illegal activities. The eligibility of patients with HIV/hepatitis for a transplant was denied by 52.9% because of poor outcomes, with the others (47.1%) maintaining that these individuals too had a right to live. A substantial majority (90.7%) of the participants maintained that organ donors should be given priority in the event of a future need for an organ because their previous humane act should be rewarded (47.1%). Most of the participants (91.4%) felt that individuals from the higher socioeconomic strata should not receive preference for kidney transplantation. A majority (77.1%) of them were also against kidney selling getting legalized. Compulsory possession of a donor card elicited mixed responses, with some accepting (56.4%), but others rejecting (43.6%) this idea as donation was perceived to be a voluntary act (33.6%). While compulsory kidney donation found favor with 44.3%, it found disfavor with others (55.7%). This study will benefit transplant healthcare personnel to formulate new policies in relation to kidney donation/transplantation. PMID- 27942170 TI - End-stage renal disease in Tunisian infants: Etiology and outcome. AB - End stage renal disease (ESRD) in infants has particular features in terms of etiologies and therapeutic modalities. The aim of our study is to describe the etiologies and the ESRD outcomes among Tunisian infants. This retrospective study was conducted over 15 years (from January 1998 to December 31, 2013) in the Pediatric Department at Charles Nicolle Hospital. In total, 157 pediatric patients had ESRD. The mean incidence was 4.25 million children. The study involved 24 infants; the sex ratio was equal to 2. The mean age at diagnosis of ESRD was 8 months (range, 1-21 months). Growth retardation was noticed in 14 patients. The main causes were Congenital Anomalies of the Kidneys and Urinary Tract (9 infants) and hereditary renal disease (9 infants). All patients were treated with peritoneal dialysis; 16 infants presented peritonitis. Mortality rate was about 28%. The leading causes of death were cardiovascular diseases and infections. PMID- 27942169 TI - Assessment of hemodialysis adequacy in patients with chronic kidney disease in the hemodialysis unit at Tanta University Hospital in Egypt. AB - Worldwide, hemodialysis (HD) constitutes the most common form of renal replacement therapy. Many studies have shown strong correlation between HD dose and clinical outcome. The cross-sectional study was conducted on 100 patients in Hemodialysis Unit at Tanta University Hospital, Egypt. Data were collected using a reliable questionnaire (including clinical, demographic, dialysis, laboratory, and radiological data). SpKt/V was used to assess the adequacy of HD. The results revealed inadequate HD dose among 60% of the study population. The results also showed that increasing time and frequency of dialysis, blood flow rates, low recirculation percentages, reduction of intradialytic complaints, and well functioning vascular access are associated with better HD adequacy. Our findings showed a positive correlation between dialysis dose and hemoglobin, serum albumin, normalized protein catabolic rate, and physical health. A great percentage of patients had inadequate HD. HD adequacy was influenced by several factors such as duration and frequency of dialysis session, patients' complaints, and well-functioning vascular access. PMID- 27942171 TI - Development and validation of limited sampling strategy equation for mycophenolate mofetil in children with systemic lupus erythematosus. AB - The aim of this study was to establish a limited sample strategy (LSS) to predict the mycophenolic acid (MPA) area under the curve (AUC)(0-12) in children with systemic lupus erythematosus (SLE). Three months after initiation of mycophenolate mofetil (MMF) 26 children with SLE presented for therapeutic drug monitoring of MPA. On the day of the test, 10 specimens were collected, analyzed, and MPA AUC(0-12) was calculated. Using step-wise regression analysis, LSS equations were developed. Using bootstrap validation, the predictive performance was calculated. The measured mean (standard deviation) for the trough concentration and AUC(0-12) were 2.55 (1.57) MUg/ml and 62.6 (21.67) mg.h/L, respectively. The range of trough concentrations and AUC(0-12) were 0.7-5.54 MUg/ml and 22.1-104.8 mg.h/L, respectively. The interindividual variability (%CV) for dose normalized AUC(0-12) and dose normalized Ctrough was 46.5% and 61.1%, respectively. The correlation between the concentrations at the different time points and MPA AUC(0-12) ranged from 0.05 (1.5 h) to 0.56 (4 h). Two LSS equations that included 4 or 5 time points up to 3 h were developed and validated. The 4 point LSS had a correlation (R2) of 0.88 and the 5 point LSS an R2 of 0.87. With respect to the 4 point and 5 point MPA LSS AUC(0-12), the bias was 1.92% and 1.96%, respectively, and the imprecision was 11.24% and 11.28%, respectively. A 4 point LSS which concludes within 3 h after the administration of the MMF dose was developed and validated, to determine the MPA AUC(0-12) in children with SLE. PMID- 27942172 TI - Prevalence of obesity and risk of chronic kidney disease among young adults in Egypt. AB - Increasing body mass index (BMI) has reached epidemic proportions globally and recently emerged as strong, independent risk factors for chronic kidney disease (CKD). We conducted this study to verify the prevalence of obesity and the associated risk of developing CKD among 3000 Egyptian students. The World Health Organization classification of BMI categorized study population into 1-5 groups, 1146 subjects with normal BMI (20-25), 951 subjects with BMI 25-29.9, 540 subjects with BMI 30-34.9, 225 with BMI 35-39.9, and 138 with BMI above 40. The participants were subjected to clinical examination, anthropometric measurements, laboratory investigation, including urinary albumin/creatinine ratio (ACR) and estimation of glomerular filtration rate (eGFR). The prevalence of overweight, obesity, and metabolic syndrome (MS) was 31.7%, 30.1%, and 16%, respectively. The prevalence of CKD among subjects with BMI >25 was 6.5%, almost all of them had BMI >35. ACR and eGFR rose progressively with increasing BMI. Elevated mean arterial pressure (MAP), high sensitivity C-reactive protein, and MS increased the risk of development of CKD. Moreover, MAP, waist to height ratio, and triglycerides to high-density lipoprotein ratios at levels of >95 mm Hg, >0.6, and >3 had sensitivity 91.7%, 88.4%, and 86.7%; and specificity 92.3%, 96.4%, and 96.5%, respectively to predict CKD. The prevalence of obesity among Egyptian young adults was high (30.1%) and was associated with increased the risk of CKD (6.5%). PMID- 27942173 TI - Effect of Ferula assa-foetida oleo-gum-resin on renal function in normal Wistar rats. AB - In traditional Iranian medicine, asafoetida, an oleo-gum-resin obtained from the roots of Ferula assa-foetida, has been prescribed as a diuretic. This study was undertaken to investigate the diuretic effect of asafoetida in normal rats. Asafoetida was administered orally at the doses of 25 and 50 mg/kg and furosemide (10 mg/kg, intraperitoneal) was used as positive control. The diuretic effect was evaluated by measuring urine volume and sodium, potassium, urea, and creatinine content in urine and serum. Urine volume, excretion of sodium, and potassium were significantly increased by asafoetida as compared to the control group. A significant increase in creatinine clearance was observed in the groups treated with asafoetida at the doses of 25 and 50 mg/kg (P < 0.05). We conclude that asafoetida induced a diuretic effect comparable to that produced by the reference diuretic furosemide. This study provides a quantitative basis for explaining the folkloric use of asafoetida as a diuretic agent. PMID- 27942174 TI - Follow-up rates of living kidney donor in Japan: A single center study. AB - Long-term follow-up of kidney donors is needed not only for the individual donor's benefit but also to establish analyzable databases to improve the selection criteria for future donors. We collected data including the date of transplantation, the date of the last follow-up, donor's age, sex, their relationship to the recipient, renal function, proteinuria, and the prevalence of hypertension. Of 124 donors, 52 donors were not being followed up. The mean duration of follow-up was 4.3 +/- 3.6 years. Follow-up rates were 83.9%, 74.6%, and 59.2% at 1 year, 2 years, and 5 years postdonation, respectively. Of those not being followed up, 75% dropped out. Follow-up rates did not differ between parent and spouse donors 5 years (57.1% vs. 71.4%; P = 0.4) postdonation. Similarly, follow-up rates at 5 years did not differ between donors aged 60 years or older and those younger than 60 (57.5% vs. 61.3%; P = 0.6). Of 72 donors being followed up, 75.0% had estimated glomerular filtration rate of <60 mL/min/1.73 m2, 8.3% had proteinuria, and 41.7% had hypertension requiring medication. There is a limitation to the endeavor of each transplant center to follow-up all their donors. Long-term donor follow-up in Japan requires a national registration system and mandates transplant center participation. PMID- 27942175 TI - Snakebite mediated acute kidney injury, prognostic predictors, oxidative and carbonyl stress: A prospective study. AB - Snake bite is an occupational hazard in India and important preventable cause of acute kidney injury (AKI). This study was done to estimate the magnitude of snakebite-induced AKI (SAKI) who required renal replacement therapy, prognostic predictors, and final outcome, and to measure the oxidative and carbonyl stress (CS) level in SAKI patient who underwent hemodialysis (HD). All SAKI patients dialyzed between April 2010 and July 2011 in NRS Medical College were included. Demographical, clinical, and biochemical data were analyzed, and patients are followed to discharge or death. Oxidative and CS markers (advanced oxidation protein product [AOPP], advanced glycation end product, pentosidine, dityrosine, thioberbituric acid reactive substance, and methylglyoxal [MG]) were measured in 48 SAKI patient requiring HD. About 155 SAKI patients (M: F 2.2:1) received HD. Of them. The age was 36.2 (range 4-74) years. The most common site of the bite was lower limb (88.7%). Oliguria and bleeding manifestation were the common presentation. Hypotension was found in 52 (33.5%) cases, cellulitis and inflammation were found in about 63%. Mean creatinine was 4.56 +/- 0.24 mg/dl. About 42 (27.1%) had disseminated intravascular coagulation (DIC). 36 (78.2%) had cellulites, 24 (52.2%) had hypotension or shock at initial presentation (P < 0.05), bleeding manifestation was found in 37 (80.4%), and 22 (47.8%) had DIC (P < 0.05). Forty-six (29.7%) patient died. DIC and hypotension/shock at initial presentation came out as an independent predictor of death. Among all markers measured for oxidative and CS (n = 48) AOPP and MG came out as an independent predictor (P < 0.05) of adverse outcome. Hypotension, DIC, AOPP, and MG were a poor prognostic marker in SAKI patients requiring dialysis. PMID- 27942178 TI - White collar rhabdomyolysis with acute kidney injury. AB - Rhabdomyolysis is a clinical syndrome resulting from the disintegration of muscle cell and spillage of toxic intracellular contents into circulation. Strenuous, unaccustomed exercise leads to exertional rhabdomyolysis and cause AKI. We report a 26-year-old female who developed white collar rhabdomyolysis with AKI after performing sit-ups (Super Yoga Brain) for 108 times in temple. She was managed with hemodialysis and supporting therapy. She made a full recovery after 4 weeks. Awareness of this condition and early diagnosis is highlighted. PMID- 27942177 TI - Acute kidney injury associated with ingestion of star fruit: Acute oxalate nephropathy. AB - Starfruit (Averrhoa carambola) and its juice are popular in the Indian subcontinent as an indigenous medicine. Oxalate concentration in this fruit and it's freshly prepared juice is very high. We present a report of patients presenting with acute kidney injury due to oxalate nephropathy admitted in a single center. All patients had history of ingesting star fruit. Patients became symptomatic after 10-12 h of eating and main symptoms were pain abdomen and decrease in urine output. Three patients needed hemodialysis. All improved with complete renal recovery. Taking star fruit in large amount on an empty stomach and in a dehydrated state is a risk factor for nephrotoxicity. PMID- 27942176 TI - Identification of urinary proteins potentially associated with diabetic kidney disease. AB - Diabetic nephropathy (DN) is the most common cause of chronic kidney disease. Although several parameters are used to evaluate renal damage, in many instances, there is no pathological change until damage is already advanced. Mass spectrometry-based proteomics is a novel tool to identify newer diagnostic markers. To identify urinary proteins associated with renal complications in diabetes, we collected urine samples from 10 type 2 diabetes patients each with normoalbuminuria, micro- and macro-albuminuria and compared their urinary proteome with that of 10 healthy individuals. Urinary proteins were concentrated, depleted of albumin and five other abundant plasma proteins and in-gel trypsin digested after prefractionation on sodium dodecyl sulfate polyacrylamide gel electrophoresis. The peptides were analyzed using a nanoflow reverse phase liquid chromatography system coupled to linear trap quadrupole-Orbitrap mass spectrometer. We identified large number of proteins in each group, of which many were exclusively present in individual patient groups. A total of 53 proteins were common in all patients but were absent in the controls. The majority of the proteins were functionally binding, biologically involved in metabolic processes, and showed enrichment of alternative complement and blood coagulation pathways. In addition to identifying reported proteins such as alpha2-HS-glycoprotein and Vitamin D binding protein, we detected novel proteins such as CD59, extracellular matrix protein 1 (ECM1), factor H, and myoglobin in the urine of macroalbuminuria patients. ECM1 and factor H are known to influence mesangial cell proliferation, and CD59 causes microvascular damage by influencing membrane attack complex deposition, suggestive their biological relevance to DN. Thus, we have developed a proteome database where various proteins exclusively present in the patients may be further investigated for their role as stage-specific markers and possible therapeutic targets. PMID- 27942179 TI - Mixed acid-base disorder secondary to topiramate use in traumatic brain injury. AB - We report a case of a man with traumatic brain injury. He was started on to prophylactic topiramate which led to a mixed acid-base disorder. He had severe metabolic acidosis secondary to renal tubular acidification defect and respiratory alkalosis secondary to hyperventilation. Withdrawal of the offending drug led to the prompt resolution of the acid-base disturbance. PMID- 27942180 TI - Imerslund-Grasbeck syndrome in a 5-year-old Iranian boy. AB - Imerslund-Grasbeck syndrome (IGS) is a rare syndrome characterized by clinical symptoms and signs of Vitamin B12 deficiency and proteinuria. Our patient was a 5 year-old boy with pallor, lack of appetite, and low weight gain. Laboratory studies showed severe macrocytic anemia, normal reticulocyte count, negative direct coombs test, normal osmotic fragility, and autohemolysis test. He has had intermittent proteinuria since 3 years ago despite normal creatinine level and absence of hematuria or hypertension. Finally, based on low level of serum B12 vitamin and normal folate level accompanied by asymptomatic proteinuria, the diagnosis of IGS was made. Furthermore, his sister has had laboratory abnormalities without any symptoms. IGS responded to B12 replacement therapy dramatically but intermittent proteinuria persisted even after appropriate therapy. PMID- 27942181 TI - Combined surgical and immunosupressive therapy for encapsulating peritoneal sclerosis. AB - Encapsulating peritoneal sclerosis (EPS) is an infrequent but serious complication of long-term peritoneal dialysis with 50% mortality and lack consensus on treatment. The pathogenesis of EPS is ill understood, and diagnosis lacks specificity and relies on clinical, radiographic and microscopic evaluation. Since there is no general agreement on managing EPS, we report a case treated successfully with surgery followed by immunosuppressive therapy with tamoxifen and steroids. He later successfully underwent deceased donor renal transplantation. PMID- 27942182 TI - Acquired Bartter syndrome following gentamicin therapy. AB - Aminoglycoside nephrotoxicity may manifest as nonoliguric renal failure or tubular dysfunction, such as Fanconi-like syndrome, Bartter-like syndrome (BS), or distal renal tubular acidosis. We report a case who developed severe renal tubular dysfunction on the the 7th day of gentamicin therapy, resulting in metabolic alkalosis, refractory hypokalemia, hypocalcemia, hypomagnesemia, and polyuria. The patient was diagnosed as a case of transient BS associated with gentamicin exposure. The patient recovered with conservative management. PMID- 27942183 TI - Saprochaete capitata fungal infection in renal transplant recipient. AB - Saprochaete capitata is a fungus that rarely causes human infections; majority of infections were reported in patients with hematological malignancies. Here, we report a case of Saprochaete capitata infection in a renal transplant recipient. To the best of our knowledge, this is the first case report of infection with this unusual organism in renal transplant recipients. In our patient, this organism was isolated from broncho alveolar lavage, and it responded dramatically to the combination of amphotericin and voriconazole. PMID- 27942184 TI - An interesting case of renal amyloidosis. AB - In amyloidosis, there is an extracellular deposition of beta-sheet fibrils. Over 25 proteins have been demonstrated to form amyloid. One of them is Ig amyloid light (AL) chains. We are presenting a 40-year-old female who presented with progressive kyphoscoliosis for last 2 years following a minor trauma and bilateral pedal edema for last 3 months. On further investigation, we found that she had a biclonal variety of MM with amyloidosis of kidney leading to massive proteinuria. Very few case reports are available where patient with biclonal variety of MM develop renal amyloidosis. PMID- 27942185 TI - Magnetic resonance imaging as problem-solving tool in renal pseudotumor in chronic kidney disease: A case of nodular compensatory hypertrophy. PMID- 27942186 TI - Spontaneous callosal hemorrhage in a child on continuous ambulatory peritoneal dialysis. PMID- 27942187 TI - Urban and rural population comparison of hepatic profile and associated etiology among children with end-stage renal disease. PMID- 27942188 TI - Secretary's Message. PMID- 27942189 TI - From The Chair, Scientific Committee. PMID- 27942190 TI - Ang-2 but not Ang-1 expression in perivascular soft tissue tumors. AB - Perivascular soft tissue tumors are relatively uncommon neoplasms of unclear line of differentiation, although most are presumed to originate from pericytes. Previously, we reported a shared immunophenotype across these related tumor types. Here, we extend these findings to examine the expression of the pericyte markers angiopoietin-1 and -2 (Ang-1 and -2) among perivascular soft tissue tumors. Results showed consistent Ang-2 but not Ang-1 expression across tumor types. In summary, the absence of Ang-1 expression distinguishes perivascular from vascular soft tissue tumors. Ang-2 expression is present across perivascular soft tissue tumors, with some variation between histologic subtypes. PMID- 27942191 TI - State of the Globe: Acute Febrile Encephalopathy. PMID- 27942192 TI - Consensus Recommendation for India and Bangladesh for the Use of Pneumococcal Vaccine in Mass Gatherings with Special Reference to Hajj Pilgrims. AB - Respiratory tract infections are prevalent among Hajj pilgrims with pneumonia being a leading cause of hospitalization. Streptococcus pneumoniae is a common pathogen isolated from patients with pneumonia and respiratory tract infections during Hajj. There is a significant burden of pneumococcal disease in India, which can be prevented. Guidelines for preventive measures and adult immunization have been published in India, but the implementation of the guidelines is low. Data from Bangladesh are available about significant mortality due to respiratory infections; however, literature regarding guidelines for adult immunization is limited. There is a need for extensive awareness programs across India and Bangladesh. Hence, there was a general consensus about the necessity for a rapid and urgent implementation of measures to prevent respiratory infections in pilgrims traveling to Hajj. About ten countries have developed recommendations for pneumococcal vaccination in Hajj pilgrims: France, the USA, Kuwait, Qatar, Bahrain, the UAE (Dubai Health Authority), Singapore, Malaysia, Egypt, and Indonesia. At any given point whether it is Hajj or Umrah, more than a million people are present in the holy places of Mecca and Madina. Therefore, the preventive measures taken for Hajj apply for Umrah as well. This document puts forward the consensus recommendations by a group of twenty doctors following a closed-door discussion based on the scientific evidence available for India and Bangladesh regarding the prevention of respiratory tract infections in Hajj pilgrims. PMID- 27942193 TI - Identification and Antifungal Susceptibility Testing of Candida Species: A Comparison of Vitek-2 System with Conventional and Molecular Methods. AB - BACKGROUND: Candida infection is a major cause of morbidity and mortality in immunocompromised patients; an accurate and early identification is a prerequisite need to be taken as an effective measure for the management of patients. The purpose of this study was to compare the conventional identification of Candida species with identification by Vitek-2 system and the antifungal susceptibility testing (AST) by broth microdilution method with Vitek 2 AST system. MATERIALS AND METHODS: A total of 172 Candida isolates were subjected for identification by the conventional methods, Vitek-2 system, restriction fragment length polymorphism, and random amplified polymorphic DNA analysis. AST was carried out as per the Clinical and Laboratory Standards Institute M27-A3 document and by Vitek-2 system. RESULTS: Candida albicans (82.51%) was the most common Candida species followed by Candida tropicalis (6.29%), Candida krusei (4.89%), Candida parapsilosis (3.49%), and Candida glabrata (2.79%). With Vitek-2 system, of the 172 isolates, 155 Candida isolates were correctly identified, 13 were misidentified, and four were with low discrimination. Whereas with conventional methods, 171 Candida isolates were correctly identified and only a single isolate of C. albicans was misidentified as C. tropicalis. The average measurement of agreement between the Vitek-2 system and conventional methods was >94%. Most of the isolates were susceptible to fluconazole (88.95%) and amphotericin B (97.67%). The measurement of agreement between the methods of AST was >94% for fluconazole and >99% for amphotericin B, which was statistically significant (P < 0.01). CONCLUSION: The study confirmed the importance and reliability of conventional and molecular methods, and the acceptable agreements suggest Vitek-2 system an alternative method for speciation and sensitivity testing of Candida species infections. PMID- 27942194 TI - Acute Undifferentiated Febrile Illness in Patients Presenting to a Tertiary Care Hospital in South India: Clinical Spectrum and Outcome. AB - BACKGROUND: Acute undifferentiated febrile illness (AUFI) may have similar clinical presentation, and the etiology is varied and region specific. MATERIALS AND METHODS: This prospective observational study was conducted in a tertiary hospital in South India. All adult patients presenting with AUFI of 3-14 days duration were evaluated for etiology, and the differences in presentation and outcome were analyzed. RESULTS: The study cohort included 1258 patients. A microbiological cause was identified in 82.5% of our patients. Scrub typhus was the most common cause of AUFI (35.9%) followed by dengue (30.6%), malaria (10.4%), enteric fever (3.7%), and leptospirosis (0.6%). Both scrub typhus and dengue fever peaked during the monsoon season and the cooler months, whereas no seasonality was observed with enteric fever and malaria. The mean time to presentation was longer in enteric fever (9.9 [4.7] days) and scrub typhus (8.2 [3.2] days). Bleeding manifestations were seen in 7.7% of patients, mostly associated with dengue (14%), scrub typhus (4.2%), and malaria (4.6%). The requirement of supplemental oxygen, invasive ventilation, and inotropes was higher in scrub typhus, leptospirosis, and malaria. The overall mortality rate was 3.3% and was highest with scrub typhus (4.6%) followed by dengue fever (2.3%). Significant clinical predictors of scrub typhus were breathlessness (odds ratio [OR]: 4.96; 95% confidence interval [CI]: 3.38-7.3), total whole blood cell count >10,000 cells/mm3 (OR: 2.31; 95% CI: 1.64-3.24), serum albumin <3.5 g % (OR: 2.32; 95% CI: 1.68-3.2). Overt bleeding manifestations (OR: 2.98; 95% CI: 1.84-4.84), and a platelet count of <150,000 cells/mm3 (OR: 2.09; 95% CI: 1.47 2.98) were independent predictors of dengue fever. CONCLUSION: The similarity in clinical presentation and diversity of etiological agents demonstrates the complexity of diagnosis and treatment of AUFI in South India. The etiological profile will be of use in the development of rational guidelines for control and treatment of AUFI. PMID- 27942195 TI - Prevalence of Multidrug-resistant, Extensively Drug-resistant, and Pandrug resistant Pseudomonas aeruginosa from a Tertiary Level Intensive Care Unit. AB - BACKGROUND: Infection by Pseudomonas aeruginosa is common in the Intensive Care Unit (ICU), leading to increased morbidity and mortality. The organism is classified into various phenotypes based on the drug resistance pattern, namely, drug-resistant (DR), multi-DR (MDR), extensively DR (XDR), and pan-DR (PDR). We aim to study the incidence of P. aeruginosa phenotypes in a tertiary level ICU. MATERIALS AND METHODS: We conducted this prospective, observational study for 2 years (January 2014-December 2015) and collected appropriate clinical samples (blood, urine, wound discharge, etc.,) from all the patients admitted to ICU. We excluded patients with known septicemia and P. aeruginosa infection. Group 1 comprised a total 1915 patient samples and Group 2 comprised 100 active surveillance samples, collected from the medical staff and the hospital environment. The data were analyzed using appropriate statistical methods, and a P < 0.05 was considered statistically significant. RESULTS: We isolated 597 pathogenic bacteria out of 1915 specimens, giving a culture positivity rate of 31.2%. Klebsiella (43%), Acinetobacter (22%), and P. aeruginosa (15%) were the top three isolated bacteria. None of the surveillance samples grew P. aeruginosa. Antibiotic resistance studies revealed that 47.7% of P. aeruginosa isolates were DR, 50% were MDR, and 2.3% were XDR phenotype. None of the strains showed PDR phenotype. CONCLUSION: Our data revealed a high prevalence of DR phenotypes of P. aeruginosa in the ICU. Judicious use of antibiotics and strict infection control measures are essential to reduce the prevalence of drug resistance. PMID- 27942196 TI - Comment on: A Case of Aerococcus urinae Vertebral Osteomyelitis. PMID- 27942197 TI - Hepatitis A Vaccine Response in Human Immunodeficiency Virus-infected Patients: The Interchangeability of Single Dose versus Double: A Prospective Look. PMID- 27942198 TI - Social Isolation from Extended Family Members and Friends among African Americans: Findings from a National Survey. PMID- 27942199 TI - Parental Resources, Sibship Size, and Educational Performance in 20 Countries: Evidence for the Compensation Model. AB - We study whether having several siblings decreases the level of educational performance of adolescents and whether this phenomenon can be compensated by other factors such as the economic or cultural resources of the parents. Based on this compensation model, parental resources should be associated with children's educational attainments more strongly in families with a higher rather than a lower number of children. We analyzed the Program for International Student Assessment (PISA) data from 20 Western countries and found that better family wealth, an increased level of parental education, and a higher parental occupational status were associated with increased educational attainments more strongly among 15-year-old children who have siblings than among children without siblings. The same effect was not found in the case of family cultural possessions. Although parental resources may matter more in larger families than in smaller families, some types of resources are more important than others regarding compensation. PMID- 27942200 TI - Quantifying Conceptual Novelty in the Biomedical Literature. AB - We introduce several measures of novelty for a scientific article in MEDLINE based on the temporal profiles of its assigned Medical Subject Headings (MeSH). First, temporal profiles for all MeSH terms (and pairs of MeSH terms) were characterized empirically and modelled as logistic growth curves. Second, a paper's novelty is captured by its youngest MeSH (and pairs of MeSH) as measured in years and volume of prior work. Across all papers in MEDLINE published since 1985, we find that individual concept novelty is rare (2.7% of papers have a MeSH <= 3 years old; 1.0% have a MeSH <= 20 papers old), while combinatorial novelty is the norm (68% have a pair of MeSH <= 3 years old; 90% have a pair of MeSH <= 10 papers old). Furthermore, these novelty measures exhibit complex correlations with article impact (as measured by citations received) and authors' professional age. PMID- 27942201 TI - Vulvar Intraepithelial Neoplasia 3 in Women Less Than 35 Years. AB - OBJECTIVE: To examine the outcome of women diagnosed with vulvar intraepithelial neoplasia (VIN) 3 at less than 35 years. MATERIALS AND METHODS: All cases of VIN 3 treated in women less than 35 years treated at Roswell Park Cancer Institute between January 1973 and January 2008 were reviewed. Medical records were reviewed for year of diagnosis, treatment modality, recurrence and/or progression, associated medical conditions, history of genital condyloma, smoking status, history of cervical pathology, and treatment. RESULTS: Thirty-one women were identified. The mean age at diagnosis was 29 years. Smoking status was available in 28 patients, of which 82% (23/28) were current or former smokers. Eighty-one percent (25/31) of the women had cervical disease. Fifty-two percent (16/31) had a history of genital condyloma. Ten of the 31 women (32%) were diagnosed with persistence or recurrence of VIN 3. Three women (9.7%) progressed to invasive carcinoma. CONCLUSIONS: Women diagnosed with VIN 3 at less than 35 years are at risk for persistence and/or recurrence of their disease as well as progression to carcinoma, warranting frequent and prolonged follow-up with liberal utilization of directed biopsies of suspicious lesions. PMID- 27942202 TI - The measurement repeatability using different partition methods of intraretinal tomographic thickness maps in healthy human subjects. AB - PURPOSE: To determine the repeatability and profiles with different partition methods in intraretinal thickness layers in healthy human subjects, using optical coherence tomography (OCT). METHODS: A custom-built ultrahigh-resolution OCT was used to acquire three-dimensional volume of the macula in 20 healthy subjects. The dataset was acquired twice using the macular cube 512*128 protocol in an area of 6*6 mm2 centered on the fovea. Commercially available segmentation software (OrionTM) was used to segment the dataset into thickness maps of six intraretinal layers. The coefficient of repeatability and intraclass coefficient of correlation (ICC) were analyzed using hemispheric zoning and sectors defined by the Early Treatment Diabetic Retinopathy Study (ETDRS). RESULTS: All datasets were successfully segmented to create six thickness maps of individual intraretinal layers. Coefficients of repeatabilities of these layers in hemispheric zones ranged from 0.9 to 6.6 um, with an average of 3.6 um (standard deviation [SD] 1.4), which was not significantly different compared to ETDRS sectors (P>0.05). ICCs of these layers in hemispheric zones ranged from 0.68 to 0.99, with an average of 0.91 (SD 0.07). There were no significant differences in ICCs between two zoning methods (P>0.05). Significant variations of tomographic intraretinal thicknesses were found between the inner and outer annuli and among the quadrantal sectors within the inner and outer annuli (P<0.05). Significant variations of the quadrantal sectors including both inner and outer annuli were evident in intraretinal layers (P<0.05) except for the outer plexiform layer. CONCLUSION: The measurement repeatabilities of tomographic thicknesses of intraretinal layers are comparable using both hemispheric and ETDRS partitions in volumetric data combined with the commercially available segmentation software. In keeping with known, normal anatomical variation, significant differences in tomographic thickness in various intraretinal layers were apparent in both hemispheric and ETDRS sectors. PMID- 27942203 TI - Pharmacoutilization of epoetins in naive patients with hematological malignancies in an unselected Italian population under clinical practice setting: a comparative analysis between originator and biosimilars. AB - AIM: The purpose of this study was to assess the prescription of epoetins and consumption of health care resources (in terms of drug treatments) in naive patients with hematological malignancies in a real-world setting; in particular, we compared the results between reference product and biosimilar products. METHODS: An observational retrospective study based on administrative and laboratory databases of three local health units was conducted. All adults diagnosed with hematological malignancies and who had received at least one epoetin (either reference product or biosimilars) prescription for the first time between 1 January 2010 and 30 April 2012 (enrollment period) were included. The date of the first prescription of epoetin within the enrollment period was defined as index date (ID). Patients were followed up for 4 weeks after ID (follow-up period) and were investigated for the 1-year period before the ID. The difference between the last hemoglobin (Hb) measurement after ID and the one prior to ID (DeltaHb) was evaluated. The drug cost analysis was conducted from the perspective of the Italian National Health System. RESULTS: Overall, 69 patients were included in the study; 48 of them received reference epoetin product and 21 received biosimilars as first prescription. Among reference product users, the mean +/- standard deviation (SD) age was 62.5+/-14.7 years; this cohort of patients was slightly significantly younger than the biosimilar users (71.8+/-11.8 years). The mean +/- SD overall Hb level prior to treatment was lower among patients who started with biosimilar products (9.6+/-1.1 g/dL) compared to those who started with a reference product (10.1+/-2.1 g/dL). No significant differences in DeltaHb were observed between biosimilar and originator groups during the followup period. The mean +/- SD cost per patient was ?667.98+/-573.93 and ?340.85+/-235.73 for the reference product and biosimilar users, respectively (p=0.065). CONCLUSION: Our study showed that the use of biosimilar products might contribute to controlling health care costs (in terms of drug treatments) for patients with hematological malignancies being maintained by high-quality anemia therapy. Our findings also showed some discordances regarding the most appropriate therapeutic approach in daily clinical practice. PMID- 27942204 TI - Loading cisplatin onto 6-mercaptopurine covalently modified MSNS: a nanomedicine strategy to improve the outcome of cisplatin therapy. AB - In the treatment of cancer patients, cisplatin (CDDP) exhibits serious cardiac and renal toxicities, while classical combinations related to CDDP are unable to solve these problems and may result in worse prognosis. Alternately, this study covalently conjugated 6-mercaptopurine (6MP) onto the surface of mercapto modified mesoporous silica nanoparticles (MSNS) to form MSNS-6MP and loaded CDDP into the holes on the surface of MSNS-6MP to form MSNS-6MP/CDDP, a tumor targeting nano-releasing regime for CDDP and 6MP specifically. In the S180 mouse model, the anti-tumor activity and overall survival of MSNS-6MP/CDDP (50 mg.kg 1.day-1, corresponding to 1 mg.kg-1.day-1 of 6MP and 5 mg.kg-1.day-1 of CDDP) were significantly higher than those of CDDP alone (5 mg.kg-1.day-1) or CDDP (5 mg.kg-1.day-1) plus 6MP (1 mg.kg-1.day-1). The assays of serum alanine aminotransferase, aspartate aminotransferase and creatinine, as well as the images of myocardium and kidney histology, support that MSNS-6MP/CDDP is able to completely eliminate liver, kidney and heart toxicities induced by CDDP alone or CDDP plus 6MP. PMID- 27942205 TI - The design, rationale, and baseline characteristics of a nationwide cohort registry in China: blood pressure and clinical outcome in TIA or ischemic stroke. AB - BACKGROUND: The relationship between poststroke blood pressure (BP) and clinical outcomes in ischemic stroke (IS) is still controversial. However, there is no large BP database for IS or transient ischemic attack (TIA) in China. This study aims to describe the rationale, study design, and baseline characteristics of a nationwide BP database in IS or TIA patients in China. MATERIALS AND METHODS: The BOSS (blood pressure and clinical outcome in TIA or ischemic stroke) study was a hospital-based, prospective cohort study aiming to assess BP parameters and clinical outcome in IS/TIA patients. BP parameters were based on office BP, ambulatory BP, and home BP. Clinical outcomes included stroke recurrence, combined vascular events, and disability. Electronic case-report forms were used to record baseline and follow-up data. The patients were followed up for clinical outcomes at 3 months through face-to-face interview and at 12 months by telephone. RESULTS: Between October 2012 and February 2014, the BOSS registry recruited 2,608 patients from 61 hospitals, with a mean age of 62.5 years, 32.4% of whom were female, 88.9% with an entry diagnosis of IS, and 86% diagnosed with hypertension. The rates of patients lost-to-follow-up were 3.1% at 3 months and 5.1% at 1 year; 93% of patients completed ambulatory BP monitoring during hospitalization and 94.7% finished a 3-month BP diary. CONCLUSION: The BOSS registry will provide important evidence about BP management in the acute phase and secondary prevention for IS/TIA patients. PMID- 27942206 TI - Carers' education improves oral health of older people suffering from dementia - results of an intervention study. AB - AIM: The aim of this study was to evaluate the effectiveness of carers' education on improvements in oral health and denture hygiene of care-dependent and cognitively impaired older people in nursing homes compared to those without intervention. METHODS: A total of 219 seniors living in 14 nursing homes in southwest Germany (intervention: n=144; control: n=75) were enrolled in this study. For each participant, Plaque Control Record (PCR), Gingival Bleeding Index (GBI), Denture Hygiene Index (DHI) and Community Periodontal Index of Treatment Needs (CPITN) were assessed at baseline and six months following the interventions. In addition, demographic parameters such as age, sex, chronic diseases, permanent medications, level of dependency and cognitive state were recorded. In the intervention homes, education for caregivers was provided and ultrasound baths for denture cleaning were implemented. Changes in the dental target variables PCR, GBI, CPITN and DHI during the six-month study period were compared between subjects in the intervention and the control groups as well as between subjects with and without dementia. Additionally, multivariate models were compiled for each dental index to evaluate possible confounders. RESULTS: In the intervention group, PCR and DHI significantly improved during the study period (P<0.001). Oral health and denture hygiene improved likewise in subjects with and without dementia. In the control group, no significant improvements were observed (P>0.05). CONCLUSION: Carers' education improves oral health of people in nursing homes over a clinically relevant period of time. Implementation of ultrasound baths is a simple and effective measure to improve denture hygiene of both institutionalized elderly people and seniors with dementia and in severe need of care. From a clinical standpoint, it is noteworthy that the respective interventions can be easily implemented in everyday care routine. PMID- 27942207 TI - Effects of short-term Nordic walking training on sarcopenia-related parameters in women with low bone mass: a preliminary study. AB - BACKGROUND: Several studies have demonstrated the positive effects of physical activity on skeletal muscle mass and muscle strength in women with osteoporosis. However, the impact of Nordic walking training on sarcopenia-related parameters in women with low bone mass remains unknown. Therefore, the purpose of this study was to evaluate the impact of 12 weeks of Nordic walking training on skeletal muscle index, muscle strength, functional mobility, and functional performance in women with low bone mass. MATERIALS AND METHODS: The participants were 45 women, aged 63-79 years, with osteopenia or osteoporosis. The subjects were randomly assigned either to an experimental group (12 weeks of Nordic walking training, three times a week) or to a control group. Skeletal muscle mass and other body composition factors were measured with octapolar bioimpedance InBody 720 analyser. Knee extensor and flexor isometric muscle strength were measured using Biodex System 4 ProTM dynamometers. This study also used a SAEHAN Digital Hand Dynamometer to measure handgrip muscle strength. The timed up-and-go test was used to measure functional mobility, and the 6-minute walk test was used to measure functional performance. RESULTS: Short-term Nordic walking training induced a significant increase in skeletal muscle mass (P=0.007), skeletal muscle index (P=0.007), strength index of the knee extensor (P=0.016), flexor (P<0.001), functional mobility (P<0.001), and functional performance (P<0.001) and a significant decrease in body mass (P=0<006), body mass index (P<0.001), and percent body fat (P<0.001) in participants. Regarding handgrip muscle strength, no improvement was registered (P=0.315). No significant changes in any of the analyzed parameters were observed in the control group. CONCLUSION: Overall, short-term Nordic walking training induces positive changes in knee muscle strength and functional performance in women with low bone mass. This finding could be applied in clinical practice for intervention programs in women with osteopenia and osteoporosis. PMID- 27942208 TI - Three-minute constant rate step test for detecting exertional dyspnea relief after bronchodilation in COPD. AB - BACKGROUND: The aim of this study was to evaluate the responsiveness of the 3 minute constant rate step test (3-MST) to detect the relief of exertional dyspnea (respiratory discomfort) after acute bronchodilation in COPD patients. PATIENTS AND METHODS: A total of 40 patients with moderate-to-severe COPD (mean forced expiratory volume in 1 second: 45.7 (+/-14.7), % predicted) performed four 3-MSTs at randomly assigned stepping rates of 14, 16, 20 and 24 steps/min after inhalation of nebulized ipratropium bromide (500 ug)/salbutamol (2.5 mg) and saline placebo, which were randomized to order. Patients rated their intensity of perceived dyspnea at the end of each 3-MST using Borg 0-10 category ratio scale. RESULTS: A total of 37 (92.5%), 36 (90%), 34 (85%) and 27 (67.5%) patients completed all 3 minutes of exercise at 14, 16, 20 and 24 steps/min under both treatment conditions, respectively. Compared with placebo, ipratropium bromide/salbutamol significantly decreased dyspnea at the end of the third minute of exercise at 14 steps/min (by 0.6+/-1.0 Borg 0-10 scale units, P<0.01) and 16 steps/min (by 0.7+/-1.3 Borg 0-10 scale units, P<0.01); however, no statically significant differences were observed between treatments at 20 and 24 steps/min (both P>0.05). CONCLUSION: The 3-MST, when performed at 14 and 16 steps/min, was responsive to detect the relief of exertional dyspnea after acute bronchodilation in patients with moderate-to-severe COPD. PMID- 27942209 TI - Association of serum ferritin levels with smoking and lung function in the Korean adult population: analysis of the fourth and fifth Korean National Health and Nutrition Examination Survey. AB - BACKGROUND: Iron-catalyzed oxidative stress contributes to lung injury after exposure to various toxins, including cigarette smoke. An oxidant/antioxidant imbalance is considered to play a critical role in the pathogenesis of COPD. Ferritin is a key protein in iron homeostasis, and its capacity to oxidize and sequester the metal preventing iron prooxidant activity implicates its possible role in the alteration of antioxidant imbalance. We investigated the relationship among cigarette smoking, lung function, and serum ferritin concentration in a large cohort representative of the Korean adult population. MATERIALS AND METHODS: Among 50,405 participants of the Korean National Health and Nutrition Examination Survey from 2010 to 2014, 15,239 adult subjects older than 40 years with serum ferritin levels and spirometric data were selected for this study. RESULTS: The mean age was 56.5 years for men (43%) and 56.9 years for women (57%). The prevalence of airway obstruction was 13.4%, which was significantly higher in men than in women, and increased in former or current smokers. The median levels of serum ferritin were highest in the airway obstruction group, followed by the restrictive pattern group, and lowest in the normal lung function group. The median ferritin levels were increased by smoking status and amounts in each spirometric subgroup. In multivariable regression analysis, serum ferritin was positively associated with forced expiratory volume in 1 second and forced expiratory volume in 1 second/forced vital capacity, whereas the smoking amount was negatively associated with the adjustment with age, sex, height, and weight. CONCLUSION: Serum ferritin levels were increased in former or current smokers and were increased with smoking amount in all subgroups of participants categorized according to spirometric results. The result was also evident in the subgroups divided by obstructive severity. While smoking amount was inversely related to lung function, higher levels of serum ferritin were associated with enhanced spirometric results in a representative sample of the general Korean adult population. Future prospective studies will be needed to clarify the causality between serum ferritin and lung functions and their role in COPD morbidity. PMID- 27942211 TI - Computer quantification of "angle of collapse" on maximum expiratory flow volume curve for diagnosing asthma-COPD overlap syndrome. AB - BACKGROUND: In a previous study, we demonstrated that asthma patients with signs of emphysema on quantitative computed tomography (CT) fulfill the diagnosis of asthma-COPD overlap syndrome (ACOS). However, quantitative CT measurements of emphysema are not routinely available for patients with chronic airway disease, which limits their application. Spirometry was a widely used examination tool in clinical settings and shows emphysema as a sharp angle in the maximum expiratory flow volume (MEFV) curve, called the "angle of collapse (AC)". The aim of this study was to investigate the value of the AC in the diagnosis of emphysema and ACOS. METHODS: This study included 716 participants: 151 asthma patients, 173 COPD patients, and 392 normal control subjects. All the participants underwent pulmonary function tests. COPD and asthma patients also underwent quantitative CT measurements of emphysema. The AC was measured using computer models based on Matlab software. The value of the AC in the diagnosis of emphysema and ACOS was evaluated using receiver-operating characteristic (ROC) curve analysis. RESULTS: The AC of COPD patients was significantly lower than that of asthma patients and control subjects. The AC was significantly negatively correlated with emphysema index (EI; r=-0.666, P<0.001), and patients with high EI had a lower AC than those with low EI. The ROC curve analysis showed that the AC had higher diagnostic efficiency for high EI (area under the curve =0.876) than did other spirometry parameters. In asthma patients, using the AC <=137 degrees as a surrogate criterion for the diagnosis of ACOS, the sensitivity and specificity were 62.5% and 89.1%, respectively. CONCLUSION: The AC on the MEFV curve quantified by computer models correlates with the extent of emphysema. The AC may become a surrogate marker for the diagnosis of emphysema and help to diagnose ACOS. PMID- 27942210 TI - Airflow obstruction: is it asthma or is it COPD? AB - Despite the availability of guideline recommendations, diagnostic confusion between COPD and asthma appears common, and often it is very difficult to decide whether the obstruction is caused by asthma or COPD in a patient with airway obstruction. However, there are well-defined features that help in differentiating asthma from COPD in the presence of fixed airflow obstruction. Nonetheless, the presentations of asthma and COPD can converge and mimic each other, making it difficult to give these patients a diagnosis of either condition. The association of asthma and COPD in the same patient has been designated mixed asthma-COPD phenotype or overlap syndrome. However, since the absence of a clear definition and the inclusion of patients with different characteristics under this umbrella term, it may not facilitate treatment decisions, especially in the absence of clinical trials addressing this heterogeneous population. We are realizing that neither asthma nor COPD are single diseases, but rather syndromes consisting of several endotypes and phenotypes, consequently comprising a spectrum of diseases that must be recognized and adequately treated with targeted therapy. Therefore, we must treat patients by personalizing therapy on the basis of those treatable traits present in each subject. PMID- 27942212 TI - Multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation. AB - Oxaliplatin (OXA) is a third-generation cisplatin analog that has been approved as first-line chemotherapy in combination with 5-fluorouracil (5-FU) for the treatment of resectable and advanced colorectal cancer. However, the therapeutic efficacy of oral OXA and 5-FU is limited by their low bioavailability due to poor membrane permeability. The aim of the present study was to develop an oral delivery system for OXA and 5-FU. We constructed an ion-pairing complex of OXA with a deoxycholic acid derivative (Nalpha-deoxycholyl-l-lysyl-methylester, DCK) (OXA/DCK) as a permeation enhancer. Next, we prepared multiple water-in-oil-in water nanoemulsions incorporating OXA/DCK and 5-FU to enhance their oral absorption. To evaluate their membrane permeability, we assessed in vitro permeabilities of OXA/DCK and 5-FU through an artificial intestinal membrane and Caco-2 cell monolayer. Finally, oral bioavailability in rats and tumor growth inhibition in the colorectal adenocarcinoma cell (CT26)-bearing mouse model were investigated after oral administration of nanoemulsion containing OXA/DCK and 5 FU. The droplet size of the optimized nanoemulsion was 20.3+/-0.22 nm with a zeta potential of -4.65+/-1.68 mV. In vitro permeabilities of OXA/DCK and 5-FU from the nanoemulsion through a Caco-2 cell monolayer were 4.80- and 4.30-fold greater than those of OXA and 5-FU, respectively. The oral absorption of OXA/DCK and 5-FU from the nanoemulsion also increased significantly, and the resulting oral bioavailability values of OXA/DCK and 5-FU in the nanoemulsive system were 9.19- and 1.39-fold higher than those of free OXA and 5-FU, respectively. Furthermore, tumor growth in CT26 tumor-bearing mice given the oral OXA/DCK- and 5-FU-loaded nanoemulsion was maximally inhibited by 73.9%, 48.5%, and 38.1%, compared with tumor volumes in the control group and the oral OXA and 5-FU groups, respectively. These findings demonstrate the therapeutic potential of a nanoemulsion incorporating OXA/DCK and 5-FU as an oral combination therapy for colorectal cancer. PMID- 27942213 TI - Upregulation of Akt/NF-kappaB-regulated inflammation and Akt/Bad-related apoptosis signaling pathway involved in hepatic carcinoma process: suppression by carnosic acid nanoparticle. AB - Primary liver cancer is globally the sixth most frequent cancer, and the second leading cause of cancer death and its incidence is increasing in many countries, becoming a serious threat to human health. Many researches focused on the treatment and prevention of liver cancer. However, due to the underlying molecular mechanism of liver cancer still not fully understood, the studies and development of treatments were forced to be delayed. Akt has been suggested to play an essential role in the progression of inflammation response and apoptosis. Hence, in this study, Akt-knockout mice and cells of liver cancer were used as a model to investigate the molecular mechanism of Akt-associated inflammatory and apoptotic signaling pathway linked with NF-kappaB and Bcl-2-associated death promoter (Bad) for the progression of liver cancer. Carnosic acid (CA), as a phenolic diterpene with anticancer, antibacterial, antidiabetic, as well as neuroprotective properties, is produced by many species from Lamiaceae family. Administration of CA nanoparticles was sufficient to lead to considerable inhibition of liver cancer progression. The results indicated that, compared to the normal liver cells, the expression of Akt was significantly higher in liver cancer cell lines. Also, we found that Akt-knockout cancer cell lines modulated inflammation response and apoptosis via inhibiting NF-kappaB activation and inducing apoptotic reaction. Our results indicated that the downstream signals, including cytokines regulated by NF-kappaB and caspase-3-activated apoptosis affected by Bad, were re-modulated for knockout of Akt. And CA nanoparticles, acting as Akt-knockout, could inhibit inflammation and accelerate apoptosis in liver cancer by altering NF-kappaB activation and activating caspase-3 through Bad pathway. These findings demonstrated that the nanoparticulate drug CA performed its effective role owing to its ability to reduce inflammatory action and enhance apoptosis for the overexpression of NF-kappaB and Bad via Akt signaling pathway, playing a direct role in liver cancer progression. Thus, nanoparticle CA might be an important and potential choice for the clinical treatment in the future. PMID- 27942216 TI - A novel herbal treatment reduces depressive-like behaviors and increases brain derived neurotrophic factor levels in the brain of type 2 diabetic rats. AB - BACKGROUND: Radix Puerariae and hawthorn fruit have been demonstrated to treat diabetes. They offer potential benefits for preventing depression in diabetes. OBJECTIVE: The aim of this study was to investigate whether the combination of Radix Puerariae and hawthorn fruit (CRPHF) could prevent depression in a diabetic rat model generated by feeding the rats with a high-fat diet and a low-dose streptozotocin (STZ). METHODS: The CRPHF was provided by the Shanghai Chinese Traditional Medical University. Twenty-four rats were randomly divided into four groups: normal control, normal-given-CRPHF (NC), diabetic control, and diabetic given-CRPHF (DC) groups. The type 2 diabetic model was created by feeding the rats with a high-fat diet for 4 weeks followed by injection of 25 mg/kg STZ. CRPHF was given at 2 g/kg/d to the rats of NC and DC groups by intragastric gavage daily for 4 weeks after the type 2 diabetic model was successfully created. Body weight, random blood glucose (RBG), oral glucose tolerance test, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured during the study. Depressive-like behavior was evaluated at the end of the treatment by using the open field test (OFT), the elevated plus-maze test (EPMT), locomotor activity test (LAT), and forced swimming test (FST). Levels of extracellular signal-regulated protein kinase (ERK) and brain-derived neurotrophic factor (BDNF) in the prefrontal cortex were evaluated by using Western blot. RESULTS: 1) CRPHF reduced RBG and improved glucose tolerance in diabetic rats; 2) CRPHF reduced TC and TG but did not significantly change HDL-C or LDL-C in diabetic rats; 3) CRPHF reversed the loss in body weights observed in diabetic rats; 4) CRPHF reduced depressive-like behavior as measured by OFT, EPMT, LAT, and FST; 5) BDNF was upregulated, and ERK was activated in the prefrontal cortex of diabetic rats treated with CRPHF. CONCLUSION: CRPHF has the potential of preventing depression in patients with diabetes. PMID- 27942215 TI - Synergistic locoregional chemoradiotherapy using a composite liposome-in-gel system as an injectable drug depot. AB - The use of radiosensitizers in clinical radiotherapy is limited by systemic toxicity. The biopolymeric, biodegradable, injectable liposome-in-gel-paclitaxel (LG-PTX) system was developed for regional delivery of the radiosensitizer paclitaxel (PTX), and its efficacy was evaluated with concurrent fractionated radiation. LG-PTX is composed of nano-sized drug-loaded fluidizing liposomes, which are incorporated into a porous biodegradable gellan hydrogel. This allows enhanced drug permeation while maintaining a localization of the drug depot. LG PTX had an IC50 of 325+/-117 nM in B16F10 melanoma cells, and cytotoxicity with concurrent doses of fractionated radiation showed significant increase in apoptotic cells (75%) compared to radiation (39%) or LG-PTX (43%) alone. Peri tumoral injection in tumor-bearing mice showed PTX localization in the tumor 2 hours after administration, with no drug detected in plasma or other organs. LG PTX administration with doses of focal radiation (5*3 Gy) significantly reduced tumor volumes compared to control (6.4 times) and radiation alone (1.6 times) and improved animal survival. LG-PTX thus efficiently localizes the drug at the tumor site and synergistically enhances the effect of concurrent radiotherapy. This novel liposome-in-gel system can potentially be used as a platform technology for the delivery of radiosensitizing drugs to enhance the efficacy of chemoradiotherapy. PMID- 27942214 TI - Nanotoxicity: emerging concerns regarding nanomaterial safety and occupational hard metal (WC-Co) nanoparticle exposure. AB - As the number of commercial and consumer products containing engineered nanomaterials (ENMs) continually rises, the increased use and production of these ENMs presents an important toxicological concern. Although ENMs offer a number of advantages over traditional materials, their extremely small size and associated characteristics may also greatly enhance their toxic potentials. ENM exposure can occur in various consumer and industrial settings through inhalation, ingestion, or dermal routes. Although the importance of accurate ENM characterization, effective dosage metrics, and selection of appropriate cell or animal-based models are universally agreed upon as important factors in ENM research, at present, there is no "standardized" approach used to assess ENM toxicity in the research community. Of particular interest is occupational exposure to tungsten carbide cobalt (WC-Co) "dusts," composed of nano- and micro-sized particles, in hard metal manufacturing facilities and mining and drilling industries. Inhalation of WC-Co dust is known to cause "hard metal lung disease" and an increased risk of lung cancer; however, the mechanisms underlying WC-Co toxicity, the inflammatory disease state and progression to cancer are poorly understood. Herein, a discussion of ENM toxicity is followed by a review of the known literature regarding the effects of WC-Co particle exposure. The risk of WC-Co exposure in occupational settings and the updates of in vitro and in vivo studies of both micro- and nano-WC-Co particles are discussed. PMID- 27942217 TI - Association between serotonin transporter gene polymorphisms and heroin dependence: a meta-analytic study. AB - BACKGROUND: Studies have examined the association between heroin dependence and serotonin transporter gene polymorphisms but yielded inconsistent results. The purpose of current study is to determine the overall effect of these polymorphisms on the risk for heroin dependence through a meta-analytic method. METHODS: A meta-analysis was conducted to examine the association of heroin dependence with two common polymorphisms of serotonin transporter gene, in the promoter (5-hydroxytryptamine transporter-linked promotor region [5-httlpr]) and intron 2 (a various number tandem repeat in serotonin transporter intron 2 [STin2]). Data from studies with 5-httlpr (6 studies) and STin2 (8 studies) were synthesized by random effects model. RESULTS: In the analysis, heroin dependence was found to be significantly associated with the S allele of 5-httlpr (odds ratio [OR] =1.22, 95% confidence interval [CI] =1.08-1.41, P=0.002). The association between the S allele of 5-httlpr and heroin dependence was significant in Caucasian subjects (OR =1.37, 95% CI =1.12-1.68, P=0.003), but not in non-Caucasian subjects. On the other hand, no association with STin2 polymorphism was found (OR =1.14, 95% CI =0.91-1.42, P=0.242). CONCLUSION: The results suggest an ethnic-specific effect of the 5-httlpr polymorphism on the risk for heroin dependence, but the influence of the genetic variance in the patients with comorbidities or intermediate phenotypes of heroin dependence needs to be further examined. PMID- 27942219 TI - Efficacy of three-dimensional conformal radiotherapy combined with transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus. AB - OBJECTIVE: The current study aimed to evaluate the efficacy and outcomes of three dimensional conformal radiotherapy (3DCRT) combined with transarterial chemoembolization (TACE) for treating patients with hepatocellular carcinoma involving portal vein tumor thrombus. METHODS: Between January 2000 and December 2013, a total of 182 hepatocellular carcinoma patients with portal vein tumor thrombus were retrospectively analyzed: 68 patients were treated by 3DCRT alone (group A), 74 by TACE alone (group B), and 40 by a combination of 3DCRT + TACE (group C). The overall survival (OS) of the three groups was compared using the Kaplan-Meier method. The independent predictors of survival were identified using multivariate analysis. RESULTS: The total effective rate (complete response + partial response) among all patients was 44% (80/182). The objective response rate (complete response + partial response) was higher in group C than in group A or B, but the differences were not significant. OS rates at 1, 2, and 3 years were significantly higher in group C than in group A or B (P<0.05), while OS rates were similar between groups A and B. Multivariate analysis identified serum levels of alpha-fetoprotein <400 ng/mL and the use of 3DCRT + TACE as independent predictors of better OS. CONCLUSION: These results suggest that combining 3DCRT with TACE may provide better OS than either technique alone in hepatocellular carcinoma patients with portal vein tumor thrombus. PMID- 27942218 TI - Ceftolozane/tazobactam and ceftazidime/avibactam for the treatment of complicated intra-abdominal infections. AB - Complicated intra-abdominal infections (cIAI) represent a large proportion of all hospital admissions and are a major cause of morbidity and mortality in the intensive care unit. Rising rates of multidrug resistant organisms (MDRO), including extended-spectrum beta-lactamase producing Enterobacteriaceae and carbapenem-nonsusceptible Pseudomonas spp., for which there are few remaining active antimicrobial agents, pose an increased challenge to clinicians. Patients with frequent exposures to the health care system or multiple recurrent IAIs are at increased risk for MDRO; however, treatment options have traditionally been limited, in some cases necessitating the utilization of last-line agents with unfavorable side-effect profiles. Ceftolozane/tazobactam and ceftazidime/avibactam are two new cephalosporin and beta-lactamase inhibitor combinations with recent US Food and Drug Administration approvals for the treatment of cIAI in combination with metronidazole. Ceftolozane/tazobactam has demonstrated excellent in vitro activity against MDR and extensively drug resistant Pseudomonas spp., including carbapenem-nonsusceptible strains, while ceftazidime/avibactam effectively inhibits a broad range of beta-lactamases, making it an excellent option for the treatment of carbapenem-resistant Enterobacteriaceae. Both agents were shown to be noninferior to meropenem for treatment of cIAI in Phase III trials; however, reduced responses in patients with renal impairment at baseline highlight the importance of routine serum creatinine monitoring and ongoing dose adjustments. This review highlights in vitro and in vivo data of these two agents and suggests their proper place in cIAI treatment to ensure adequate therapy in our most at-risk patients while sparing unnecessary use in patients without MDRO risk factors. PMID- 27942221 TI - A randomized Phase II trial of the tumor vascular disrupting agent CA4P (fosbretabulin tromethamine) with carboplatin, paclitaxel, and bevacizumab in advanced nonsquamous non-small-cell lung cancer. AB - INTRODUCTION: Combretastatin A4-phosphate, fosbretabulin tromethamine (CA4P) is a vascular disrupting agent that targets tumor vasculature. This study evaluated the safety of CA4P when combined with carboplatin, paclitaxel, and bevacizumab in chemotherapy-naive subjects with advanced nonsquamous, non-small-cell lung cancer. METHODS: Adult subjects with confirmed American Joint Committee on Cancer six stage IIIB/IV non-small-cell lung cancer and an Eastern Cooperative Oncology Group performance score of 0 or 1 were randomized to receive six cycles (treatment phase) of paclitaxel (200 mg/m2), carboplatin (area under the concentration versus time curve 6), and bevacizumab (15 mg/kg) on day 1 and repeated every 21 days, or this regimen plus CA4P (60 mg/m2) on days 7, 14, and 21 of each cycle. Subjects could then receive additional maintenance treatment (excluding carboplatin and paclitaxel) for up to 1 year. RESULTS: Sixty-three subjects were randomized, 31 to control and 32 to CA4P, and 19 (61.3%) and 17 (53.1%), respectively, completed the treatment phase. Exposure to study treatment and dose modifications were comparable between the randomized groups. The overall incidence of treatment-emergent adverse events was similar between groups, with increased neutropenia, leukopenia, and hypertension in the CA4P group. Deaths, serious adverse events, and early discontinuations from treatment were comparable between the randomized treatment groups. The overall tumor response rate with CA4P was 50% versus 32% in controls. Overall and progression-free survival rates were comparable between the groups. CONCLUSION: CA4P plus carboplatin, paclitaxel, and bevacizumab appears to be a tolerable regimen with an acceptable toxicity profile in subjects with advanced non-small-cell lung cancer. PMID- 27942220 TI - Androgen deprivation therapy as backbone therapy in the management of prostate cancer. AB - Androgen deprivation therapy (ADT) is well established as a backbone therapy for metastatic prostate cancer (mPCa), and both European and American guidelines emphasize the importance of maintaining ADT after progression to metastatic castration-resistant prostate cancer (CRPC). However, the use of ADT varies widely in clinical practice despite these recommendations. Both research and development of increasingly precise assay technologies have improved our understanding of androgen production and signaling, and the recent data have suggested that a new serum testosterone cutoff value of <0.7 nmol/L should be employed. Most clinical trials to date have used the historical 1.7 nmol/L cutoff, but the <0.7 nmol/L cutoff has been associated with improved patient outcomes. Combining agents with different mechanisms of action to achieve intense androgen blockade may improve survival both before and after progression to CRPC. Data suggest that this intensive approach to androgen deprivation could delay the transition to CPRC and hence improve survival dramatically. Various combinations of backbone ADT with chemotherapy or radiotherapy are under investigation. Administration of ADT is established in patients with intermediate or high-risk localized prostate cancer (PCa) receiving radiotherapy with curative intent. This article reviews the current and potential role of ADT as backbone therapy in both hormone-sensitive PCa and CRPC with a focus on mPCa. PMID- 27942222 TI - CTGF enhances resistance to 5-FU-mediating cell apoptosis through FAK/MEK/ERK signal pathway in colorectal cancer. AB - Colorectal cancer (CRC) is one of the most commonly diagnosed cancers among both males and females; the chemotherapy drug 5-fluorouracil (5-FU) is one of a doctors' first lines of defense against CRC. However, therapeutic failures are common because of the emergence of drug resistance. Connective tissue growth factor (CTGF) is a secreted protein that binds to integrins, and regulates the invasiveness and metastasis of certain carcinoma cells. Here, we found that CTGF was upregulated in drug-resistant phenotype of human CRC cells. Overexpression of CTGF enhanced the resistance to 5-FU-induced cell apoptosis. Moreover, downregulating the expression of CTGF promoted the curative effect of chemotherapy and blocked the cell cycle in the G1 phase. We also found that CTGF facilitated resistance to 5-FU-induced apoptosis by increasing the expression of B-cell lymphoma-extra large (Bcl-xL) and survivin. Then we pharmacologically blocked MEK/ERK signal pathway and assessed 5-FU response by MTT assays. Our current results indicate that the expression of phosphorylated forms of MEK/ERK increased in high CTGF expression cells and MEK inhibited increases in 5-FU mediated apoptosis of resistant CRC cells. Therefore, our data suggest that MEK/ERK signaling contributes to 5-FU resistance through upstream of CTGF, and supports CRC cell growth. Comprehending the molecular mechanism underlying 5-FU resistance may ultimately aid the fight against CRC. PMID- 27942223 TI - Silencing of miR-1247 by DNA methylation promoted non-small-cell lung cancer cell invasion and migration by effects of STMN1. AB - MicroRNAs (miRNAs) play an important role in cancer development and progression, altering several biological functions by affecting targets through either degradation of mRNAs or suppression of protein translation. One such miRNA, miR 1247, is downregulated in various cancers, but its biological role in non-small cell lung cancer (NSCLC) is unknown. This study found that the expression of miR 1247 was significantly reduced in NSCLC cell lines and tumor tissues compared with matched normal lung tissues and cell lines as a result of DNA hypermethylation. Overexpression of miR-1247 or demethylation by 5-azacytidine (5 Aza) treatment dramatically inhibited cell growth, migration, invasion, and cell cycle progression. Furthermore, Stathmin 1 (STMN1) was found to be an immediate and functional target of miR-1247. The expression of STMN1 was significantly increased in NSCLC cell lines but was decreased by 5-Aza treatment. In addition, miR-1247 upregulation partially inhibited STMN1-induced promotion of migration and invasion of A549 and H1299 cells. The results suggest that miR-1247 was silenced by DNA methylation. MiR-1247 and its downstream target gene STMN1 may therefore be a future target for the treatment of NSCLC. PMID- 27942224 TI - Long-term benefit of sunitinib in patients with metastatic renal cell carcinoma in Latin America: retrospective analysis of patient clinical characteristics. AB - OBJECTIVE: To describe the clinical characteristics of Latin American patients with metastatic renal cell carcinoma (mRCC) who experienced a progression-free survival (PFS) for at least 15 months following treatment with sunitinib. PATIENTS AND METHODS: In this retrospective analysis, mRCC patients in two institutions in Latin America received sunitinib at a starting dose of either 50 mg/day for 4 weeks followed by 2 weeks off treatment (Schedule 4/2) in repeated 6 week cycles or sunitinib 37.5 mg on a continuous daily dosing schedule. Clinical characteristics, tolerability, and PFS data were collected. RESULTS: Twenty-nine patients with long-term clinical benefit from sunitinib were identified between September 2005 and August 2009. Median PFS was 23 months (range: 15-54 months). Two of the 29 patients with prolonged PFS achieved a complete response and additional eleven had a partial response. Most patients were aged <60 years, had good performance status, favorable or intermediate Memorial Sloan Kettering Cancer Center prognostic risk, and disease limited to one or two sites. Dose reduction was necessary in all patients who started sunitinib at 50 mg/day administered on Schedule 4/2. Adverse events leading to dose reduction included grade 3 hand-foot syndrome, mucositis, fatigue, and hypertension. At the time of data cutoff, four patients were still receiving sunitinib treatment. CONCLUSION: Extended PFS can be achieved in Latin American patients with mRCC treated with sunitinib. Although the small sample size and retrospective nature of this evaluation preclude the identification of pretreatment predictive factors contributing to this benefit, the current analysis warrants further investigation using a larger data set in this population. PMID- 27942225 TI - Postoperative adjuvant chemotherapy combined with intracavitary brachytherapy in early-stage cervical cancer patients with intermediate risk factors. AB - OBJECTIVE: To investigate the impact of postoperative adjuvant therapy on survival of patients with intermediate risk early-stage cervical squamous cell carcinoma. METHODS: A total of 133 consecutive patients with intermediate risk early-stage cervical squamous cell carcinoma treated at Shandong Cancer Hospital and Institute from February 2010 to March 2014 were enrolled in our study. All patients received adjuvant therapy and were subdivided into three groups: pelvic radiotherapy (RT; N=42), adjuvant chemotherapy + intracavitary radiotherapy (CT+ICRT; N=47), or concurrent chemoradiation (CCRT; N=44). Disease-free survival (DFS) and therapeutic complications were evaluated. RESULTS: There were no significant differences in DFS for patients treated with RT, CT+ICRT, and CCRT (P>0.05) with 3-year rates of 94.0%, 93.4%, and 97.6%, respectively. Frequencies of grade III-IV acute toxicities were higher in patients treated with CCRT (34.1%) than those treated with RT (9.5%) or CT+ICRT (16.7%; P<0.05), with no significant differences observed between RT and CT+ICRT groups (P>0.05). Grade I II late toxicities were higher in CCRT (25%), followed by RT (19.0%), and finally, the CT+ICRT group (4.3%; P<0.05); with no significant differences observed between CCRT and RT groups (P>0.05). CONCLUSION: Treatment with CT+ICRT or RT resulted in the equivalent of 3-year DFS compared to CCRT, but fewer therapeutic complications were observed with CT for patients with intermediate risk early-stage cervical squamous cell carcinoma. PMID- 27942227 TI - Aquagenic urticaria: diagnostic and management challenges. AB - Aquagenic urticaria (AU) is a rare inducible form of physical urticaria, which occurs in response to cutaneous exposure to water, including sweat and tears. Patients present with characteristic 1-3 mm folliculocentric wheals with surrounding 1-3 cm erythematous flares within 20-30 minutes following skin contact with water. In rare cases, there are concomitant systemic symptoms, such as wheezing or shortness of breath. The pathogenesis of AU is poorly understood at this time, and it appears to be mediated in both a histamine-dependent and independent manner. Diagnosis is based on eliciting a thorough clinical history combined with a water challenge test. Some patients may need to undergo further testing to exclude other physical urticarias. Rarely, multiple physical urticarias can be present in one patient, which can complicate diagnosis and treatment. Currently, the first-line therapy for AU is an oral administration of nonsedating, second-generation H1 antihistamines, but many patients may require further interventions to have adequate symptomatic control. In this review, we discuss the diagnostic and management challenges of AU. We review the key diagnostic features that differentiate AU from other physical urticarias. We additionally describe a therapeutic ladder for the treatment of AU and the rationale supporting these treatments. PMID- 27942226 TI - History and progression of Fat cadherins in health and disease. AB - Intercellular adhesions are vital hubs for signaling pathways during multicellular development and animal morphogenesis. In eukaryotes, under aberrant intracellular conditions, cadherins are abnormally regulated, which can result in cellular pathologies such as carcinoma, kidney disease, and autoimmune diseases. As a member of the Ca2+-dependent adhesion super-family, Fat proteins were first described in the 1920s as an inheritable lethal mutant phenotype in Drosophila, consisting of four member proteins, FAT1, FAT2, FAT3, and FAT4, all of which are highly conserved in structure. Functionally, FAT1 was found to regulate cell migration and growth control through specific protein-protein interactions of its cytoplasmic tail. FAT2 and FAT3 are relatively less studied and are thought to participate in the development of human cancer through a pathway similar to that of the Ena/VASP proteins. In contrast, FAT4 has been widely studied in the context of biological functions and tumor mechanisms and has been shown to regulate the planar cell polarity pathway, the Hippo signaling pathway, the canonical Wnt signaling cascade, and the expression of YAP1. Overall, Fat cadherins may be useful as emerging disease biomarkers and as novel therapeutic targets. PMID- 27942228 TI - Reactivating the extracellular matrix synthesis of sulfated glycosaminoglycans and proteoglycans to improve the human skin aspect and its mechanical properties. AB - BACKGROUND: The aim of this study was to demonstrate that a defined cosmetic composition is able to induce an increase in the production of sulfated glycosaminoglycans (sGAGs) and/or proteoglycans and finally to demonstrate that the composition, through its combined action of enzyme production and synthesis of macromolecules, modulates organization and skin surface aspect with a benefit in antiaging applications. MATERIALS AND METHODS: Gene expression was studied by quantitative reverse transcription polymerase chain reaction using normal human dermal fibroblasts isolated from a 45-year-old donor skin dermis. De novo synthesis of sGAGs and proteoglycans was determined using BlyscanTM assay and/or immunohistochemical techniques. These studies were performed on normal human dermal fibroblasts (41- and 62-year-old donors) and on human skin explants. Dermis organization was studied either ex vivo on skin explants using bi-photon microscopy and transmission electron microscopy or directly in vivo on human volunteers by ultrasound technique. Skin surface modification was investigated in vivo using silicone replicas coupled with macrophotography, and the mechanical properties of the skin were studied using Cutometer. RESULTS: It was first shown that mRNA expression of several genes involved in the synthesis pathway of sGAG was stimulated. An increase in the de novo synthesis of sGAGs was shown at the cellular level despite the age of cells, and this phenomenon was clearly related to the previously observed stimulation of mRNA expression of genes. An increase in the expression of the corresponding core protein of decorin, perlecan, and versican and a stimulation of their respective sGAGs, such as chondroitin sulfate and heparan sulfate, were found on skin explants. The biosynthesis of macromolecules seems to be correlated at the microscopic level to a better organization and quality of the dermis, with collagen fibrils having homogenous diameters. The dermis seems to be compacted as observed on images obtained by two photon microscopy and ultrasound imaging. At the macroscopic level, this dermis organization shows a smoothed profile similar to a younger skin, with improved mechanical properties such as firmess. CONCLUSION: The obtained results demonstrate that the defined cosmetic composition induces the synthesis of sGAGs and proteoglycans, which contributes to the overall dermal reorganization. This activity in the dermis in turn impacts the surface and mechanical properties of the skin. PMID- 27942229 TI - Analysis of binary responses with outcome-specific misclassification probability in genome-wide association studies. AB - Errors in the binary status of some response traits are frequent in human, animal, and plant applications. These error rates tend to differ between cases and controls because diagnostic and screening tests have different sensitivity and specificity. This increases the inaccuracies of classifying individuals into correct groups, giving rise to both false-positive and false-negative cases. The analysis of these noisy binary responses due to misclassification will undoubtedly reduce the statistical power of genome-wide association studies (GWAS). A threshold model that accommodates varying diagnostic errors between cases and controls was investigated. A simulation study was carried out where several binary data sets (case-control) were generated with varying effects for the most influential single nucleotide polymorphisms (SNPs) and different diagnostic error rate for cases and controls. Each simulated data set consisted of 2000 individuals. Ignoring misclassification resulted in biased estimates of true influential SNP effects and inflated estimates for true noninfluential markers. A substantial reduction in bias and increase in accuracy ranging from 12% to 32% was observed when the misclassification procedure was invoked. In fact, the majority of influential SNPs that were not identified using the noisy data were captured using the proposed method. Additionally, truly misclassified binary records were identified with high probability using the proposed method. The superiority of the proposed method was maintained across different simulation parameters (misclassification rates and odds ratios) attesting to its robustness. PMID- 27942230 TI - IgA1 dominant subclass of latent IgA mesangial deposition in donated kidney. AB - BACKGROUND: In the pathogenesis of immunoglobulin A nephropathy (IgAN), the IgA1 subclass is more important than the IgA2 subclass. In healthy men, the prevalence of mesangial IgA deposition has been previously investigated. However, it remains unknown whether the presence of urinary abnormalities depends on the subclass of IgA deposition. MATERIALS AND METHODS: We researched the subclasses of IgA (IgA1 and IgA2) by the direct immunofluorescence (IF) staining method using specimens in which we identified the deposition of IgA through zero-hour renal transplant biopsies from donors without urinary abnormalities. The samples of the zero-hour biopsies were collected from 46 cases of living renal transplant patients at Nishinomiya Hospital, Hyogo Prefecture, from January 2011 to December 2013. RESULTS: In seven of the 46 cases (15%), IgA deposition and C3 in mesangium were confirmed. All seven cases showed IgA1 predominant mesangial deposition on IF. The results of the histological evaluations for all seven cases were Oxford Classification M0.S0.E0.T0. CONCLUSION: This study showed similar patterns of latent mesangial IgA deposition according to IgA subclass and frequency of C3 deposition as IgAN. Latent mesangial IgA deposition may require some, as yet undefined factors, to become clinically apparent as IgAN. PMID- 27942232 TI - Prevalence of different pain categories based on pain spreading on the bodies of older adults in Sweden: a descriptive-level and multilevel association with demographics, comorbidities, medications, and certain lifestyle factors (PainS65+). AB - BACKGROUND AND OBJECTIVE: There is limited knowledge about the prevalence of pain and its relation to comorbidities, medication, and certain lifestyle factors in older adults. To address this limitation, this cross-sectional study examined the spreading of pain on the body in a sample of 6611 subjects >=65 years old (mean age = 75.0 years; standard deviation [SD] = 7.7) living in southeastern Sweden. METHODS: Sex, age, comorbidities, medication, nicotine, alcohol intake, and physical activity were analyzed in relation to the following pain categories: local pain (LP) (24.1%), regional pain medium (RP-Medium) (20.3%), regional pain heavy (RP-Heavy) (5.2%), and widespread pain (WSP) (1.7%). RESULTS: RP-Medium, RP Heavy, and WSP were associated more strongly with women than with men (all p<0.01). RP-Heavy was less likely in the 80-84 and >85 age groups compared to the 65-69 age group (both p<0.01). Traumatic injuries, rheumatoid arthritis/osteoarthritis, and analgesics were associated with all pain categories (all p<0.001). An association with gastrointestinal disorders was found in LP, RP Medium, and RP-Heavy (all p<0.01). Depressive disorders were associated with all pain categories, except for LP (all p<0.05). Disorders of the central nervous system were associated with both RP-Heavy and WSP (all p<0.05). Medication for peripheral vascular disorders was associated with RP-Medium (p<0.05), and hypnotics were associated with RP-Heavy (p<0.01). CONCLUSION: More than 50% of older adults suffered from different pain spread categories. Women were more likely to experience greater spreading of pain than men. A noteworthy number of common comorbidities and medications were associated with increased likelihood of pain spread from LP to RP-Medium, RP-Heavy, and WSP. Effective management plans should consider these observed associations to improve functional deficiency and decrease spreading of pain-related disability in older adults. PMID- 27942233 TI - Risks associated with borrowing and sharing of prescription analgesics among patients observed by pain management physicians in Croatia: a qualitative study. AB - BACKGROUND: Understanding and improving patient safety is a key issue in medicine. One of the potential threats to patient safety is the sharing of medication among patients, which is a form of self-medication. This study analyzed experiences and attitudes of pain management physicians (PMPs) about sharing prescription analgesics among patients. METHODS: This qualitative study was conducted by semi-structured interviews among PMPs employed in Croatian pain clinics. The study involved two researchers and 15 PMPs. RESULTS: Among PMPs, 80% have seen patients who share their prescription analgesics with other patients for whom prescription is not intended. Most PMPs consider prescription analgesics sharing a risky and negative behavior. Some of them, however, found certain positive aspects associated to it, such as being a benevolent behavior, helping patients to get medications when they need them, and helping them cope with pain. CONCLUSION: The majority of physicians specialized in pain management encountered patients sharing prescription analgesics. Most of them considered this as risky behavior with a number of potential consequences. It has been noted that this problem is neglected and that physicians should inquire about medication sharing. Direct-to-consumers advertising was perceived as a factor contributing to such behavior. Patient education and more involvement of physicians in identifying this behavior were cited as potential remedies for preventing sharing of prescription analgesics. PMID- 27942234 TI - Long-term follow-up of anatomical and functional macular changes after a single intravitreal implant of dexamethasone 0.7 mg for radiation macular edema secondary to proton beam therapy for choroidal melanoma. AB - PURPOSE: To describe the efficacy and safety of a single intravitreal implant of dexamethasone in a patient affected by radiation maculopathy due to proton beam radiotherapy for choroidal melanoma. PATIENT AND METHODS: Retrospective data of a 46-year-old woman treated with a single intravitreal injection of dexamethasone for radiation maculopathy due to proton beam radiotherapy were collected. The main outcome measures were best-corrected visual acuity and central retinal thickness. Intraocular pressure, anterior segment evaluation with slit lamp, macular changes depicted with spectral domain optical coherence tomography, retinal perfusion studied with fundus fluorescein angiography, and grade of macular edema using the Horgan classification were also evaluated during a 16 month follow-up. RESULTS: Macular edema occurred 25 months after radiation treatment in the left eye. The patient underwent a single intravitreal implant of dexamethasone. Preinjection visual acuity and central retinal thickness were 6/12 and 502 um, respectively. After 8 months, visual acuity was 6/6 and remained stable until 16 months. Central retinal thickness was 269 um at 16 months. CONCLUSION: A single intravitreal implant of dexamethasone could effectively and stably improve visual acuity and central retinal thickness in some patients with radiation macular edema for 16 months after injection. PMID- 27942235 TI - Investigating the effects of strap tension during non-invasive ventilation mask application: a combined biomechanical and biomarker approach. AB - Non-invasive ventilation is commonly used for respiratory support. However, in some cases, mask application can cause pressure ulcers to specific features of the face, resulting in pain and reduced quality of life for the individual. This study investigated the effects of mask strap tension on the biomechanical and biomarker responses at the skin interface. Healthy participants (n = 13) were recruited and assigned two different masks in a random order, which were fitted with three strap conditions representing increments of 5 mm to increase tension. Masks were worn for 10 minutes at each tension followed by a 10-minute refractory period. Assessment at the device-skin interface included measurements of pressures at the nose and cheeks, temperature and humidity, a selection of inflammatory cytokine concentrations collected from sebum and scores of comfort. The results indicated significantly higher interface pressures at the bridge of the nose compared to the cheeks for both masks (p < 0.05), with nasal interface pressures significantly increasing with elevated strap tension (p < 0.05). One inflammatory cytokine, IL-1alpha, increased following mask application at the highest tension, with median increases from baselines ranging from 21 to 33%. The other cytokines revealed a less consistent trend with strap tension. The participants reported statistically greater discomfort during elevated strap tension. Temperature and humidity values under the mask were elevated from ambient conditions, although no differences were observed between mask type or strap tension. The bony prominence on the bridge of the nose represented a vulnerable area of skin during respiratory mask application. This study has shown that mask strap tension has a significant effect on the pressure exerted on the nose. This can result in discomfort and an inflammatory response at the skin surface. Further studies are required to investigate respiratory mask application for appropriate individuals with comorbidities. PMID- 27942236 TI - Letter to the editor regarding "Clinical effectiveness and safety of powered exoskeleton-assisted walking in patients with spinal cord injury: systematic review with meta-analysis". PMID- 27942231 TI - CYP2D6 polymorphisms and their influence on risperidone treatment. AB - Cytochrome P450 enzyme especially CYP2D6 plays a major role in biotransformation. The interindividual variations of treatment response and toxicity are influenced by the polymorphisms of this enzyme. This review emphasizes the effect of CYP2D6 polymorphisms in risperidone treatment in terms of basic knowledge, pharmacogenetics, effectiveness, adverse events, and clinical practice. Although the previous studies showed different results, the effective responses in risperidone treatment depend on the CYP2D6 polymorphisms. Several studies suggested that CYP2D6 polymorphisms were associated with plasma concentration of risperidone, 9-hydroxyrisperidone, and active moiety but did not impact on clinical outcomes. In addition, CYP2D6 poor metabolizer showed more serious adverse events such as weight gain and prolactin than other predicted phenotype groups. The knowledge of pharmacogenomics of CYP2D6 in risperidone treatment is increasing, and it can be used for the development of personalized medication in term of genetic-based dose recommendation. Moreover, the effects of many factors in risperidone treatment are still being investigated. Both the CYP2D6 genotyping and therapeutic drug monitoring are the important steps to complement the genetic based risperidone treatment. PMID- 27942237 TI - Design evolution enhances patient compliance for low-intensity pulsed ultrasound device usage. AB - Poor patient compliance or nonadherence with prescribed treatments can have a significant unfavorable impact on medical costs and clinical outcomes. In the current study, voice-of-the-customer research was conducted to aid in the development of a next-generation low-intensity pulsed ultrasound (LIPUS) bone healing product. An opportunity to improve patient compliance reporting was identified, resulting in the incorporation into the next-generation device of a visual calendar that provides direct feedback to the patient, indicating days for which they successfully completed treatment. Further investigation was done on whether inclusion of the visual calendar improved patient adherence to the prescribed therapy (20 minutes of daily treatment) over a 6-month period. Thus, 12,984 data files were analyzed from patients prescribed either the earlier- or the next-generation LIPUS device. Over the 6-month period, overall patient compliance was 83.8% with the next-generation LIPUS device, compared with 74.2% for the previous version (p<0.0001). Incorporation of the calendar feature resulted in compliance never decreasing below 76% over the analysis period, whereas compliance with the earlier-generation product fell to 51%. A literature review on the LIPUS device shows a correlation between clinical effectiveness and compliance rates more than 70%. Incorporation of stakeholder feedback throughout the design and innovation process of a next-generation LIPUS device resulted in a measurable improvement in patient adherence, which may help to optimize clinical outcomes. PMID- 27942238 TI - Targeted transplantation of mitochondria to hepatocytes. AB - BACKGROUND: Mitochondrial defects in hepatocytes can result in liver dysfunction and death. Hepatocytes have cell-surface asialoglycoprotein receptors (AsGRs) which internalize AsGs within endosomes. The aim of this study was to determine whether mitochondria could be targeted to hepatocytes by AsGR-mediated endocytosis. MATERIALS AND METHODS: An AsG, AsOR, was linked to polylysine to create a conjugate, AsOR-PL, and complexed with healthy and functional mitochondria (defined by normal morphology, cytochrome c assays, and oxygen consumption rates). Huh7 (AsGR+) and SK Hep1 (AsGR-) cells were treated with a mitochondrial toxin to form Huh7-Mito- and SK Hep1-Mito- cells, lacking detectable mitochondrial DNA. An endosomolytic peptide, LLO, was coupled to AsOR to form AsOR-LLO. A lysosomal inhibitor, amantadine, was used in mitochondria uptake studies as a control for nonspecific endosomal release. RESULTS: Coincubation of complexed mitochondria and AsOR-LLO with Huh7-Mito- cells increased mitochondrial DNA to >9,700-fold over control at 7 days (P<0.001), and increased mitochondrial oxygen-consumption rates to >90% of control by 10 days. CONCLUSION: Rescue of mitochondria-damaged hepatocytes can be achieved by targeted uptake of normal mitochondria through receptor-mediated endocytosis. PMID- 27942240 TI - Impact of the health insurance scheme for stateless people on inpatient utilization in Kraburi Hospital, Thailand. AB - OBJECTIVES: This study sought to investigate the impact of the Thai "Health Insurance for People with Citizenship Problems" (HI-PCP) on access to care for stateless patients, compared to Universal Coverage Scheme patients and the uninsured, using inpatient utilization as a proxy for impact. METHODS: Secondary data analysis of inpatient records of Kraburi Hospital, Ranong province, between 2009 (pre-policy) and 2012 (post-policy) was employed. Descriptive statistics and multivariate analysis by difference-in-difference model were performed. RESULTS: The volume of inpatient service utilization by stateless patients expanded after the introduction of the HI-PCP. However, this increase did not appear to stem from the HI-PCP per se. After controlling for key covariates, including patients' characteristics, disease condition, and domicile, there was only a weak positive association between the HI-PCP and utilization. Critical factors contributing significantly to increased utilization were older age, proximity to the hospital, and presence of catastrophic illness. CONCLUSION: A potential explanation for the insignificant impact of the HI-PCP on access to inpatient care of stateless patients is likely to be a lack of awareness of the existence of the scheme among the stateless population and local health staff. This problem is likely to have been accentuated by operational constraints in policy implementation, including the poor performance of local offices in registering stateless people. A key limitation of this study is a lack of data on patients who did not visit the health facility at the first opportunity. Further study of health-seeking behavior of stateless people at the household level is recommended. PMID- 27942239 TI - Seasonal affective disorder, winter type: current insights and treatment options. AB - Seasonal affective disorder (SAD), winter type, is a seasonal pattern of recurrent major depressive episodes most commonly occurring in autumn or winter and remitting in spring/summer. The syndrome has been well-known for more than three decades, with light treatment being the treatment of first choice. In this paper, an overview is presented of the present insights in SAD. Description of the syndrome, etiology, and treatment options are mentioned. Apart from light treatment, medication and psychotherapy are other treatment options. The predictable, repetitive nature of the syndrome makes it possible to discuss preventive treatment options. Furthermore, critical views on the concept of SAD as a distinct diagnosis are discussed. PMID- 27942242 TI - Tips for using mobile audience response systems in medical education. AB - BACKGROUND: With growing evidence on the benefits of active learning, audience response systems (ARSs) have been increasingly used in conferences, business, and education. With the introduction of mobile ARS as an alternative to physical clickers, there are increasing opportunities to use this tool to improve interactivity in medical education. AIM: The aim of this study is to provide strategies on using mobile ARS in medical education by discussing steps for implementation and pitfalls to avoid. METHOD: The tips presented reflect our commentary of the literature and our experiences using mobile ARS in medical education. RESULTS: This article offers specific strategies for the preparation, implementation, and assessment of medical education teaching sessions using mobile ARS. CONCLUSION: We hope these tips will help instructors use mobile ARS as a tool to improve student interaction, teaching effectiveness, and participant enjoyment in medical education. PMID- 27942241 TI - Once-weekly prophylactic dosing of recombinant factor IX improves adherence in hemophilia B. AB - Regular prophylactic treatment in severe hemophilia should be considered an optimal treatment. There is no general agreement on the optimal prophylaxis regimen, and adherence to prophylaxis is a main challenge due to medical, psychosocial, and cost controversies. Improved approaches in prophylaxis regimen of hemophilia B are needed to make patients' lives easier. There is some evidence to support the efficacy of once-weekly prophylaxis. Longer sampling schedules are required for the determination of pharmacokinetic (PK) properties of factor IX (FIX). The half-life of FIX seems to be longer than previously described and is expected to be 34 hours. The clinical significance of maintaining a 1% trough level is widely debated in hemophilia B. The overall relationship between factor concentrate levels and incidence of joint bleeding was found to be very weak. Data also indicate that the distribution of FIX into an extravascular FIX compartment may contribute to hemostasis independently of circulating plasma FIX levels. Clinical assessment of the frequency and severity of bleeds remain an important measure of the efficacy of treatment. Role of PK-guided therapy remains to be established. Two prospective randomized studies had evaluated the efficacy and safety of 100 IU/kg once-weekly prophylaxis with nonacog alfa, and this prophylaxis regimen was found to be associated with lower annual bleeding rate compared with on-demand treatment in adolescents and adults with moderately severe-to-severe hemophilia B. Secondary prophylaxis therapy with 100 IU/kg nonacog alfa once weekly reduced annual bleeding rate by 89.4% relative to on demand treatment. Residual FIX may be supportive of effectiveness. Once-weekly prophylaxis was well tolerated in the two studies, with a safety profile similar to that reported during the on-demand treatment period. To individually tailor treatment to clinical response and to minimize costs of factor concentrate, it would be of interest to investigate the efficacy of lower doses of the drug administered once a week. PMID- 27942243 TI - Prevalence, seasonal variation, and antibiotic resistance pattern of enteric bacterial pathogens among hospitalized diarrheic children in suburban regions of central Kenya. AB - BACKGROUND: The epidemiology of enteric pathogens has not been well studied in Kenya because of wide disparities in health status across the country. Therefore, the present study describes the prevalence of enteropathogenic bacteria, their seasonal variation, and antibiotic resistance profiles among hospitalized diarrheic children in a suburban region of central Kenya. METHODS: Fecal samples were collected between July 2009 and December 2013 from a total of 1410 children younger than 5 years, hospitalized with acute diarrhea in Kiambu County Hospital, Kenya. Conventional culture, biochemical, and molecular methods were conducted to identify causative bacterial pathogens and their virulence factors. Antimicrobial susceptibility tests were performed using E-test strips and VITEK-2 advanced expert system (AES) to evaluate the drug-resistance pattern of the isolates. RESULTS: Of the 1410 isolates, bacterial infections were identified in 474 cases. Diarrheagenic Escherichia coli (DEC) was the most frequently isolated pathogen (86.5%). Other pathogens such as Aeromonas (5.5%), Shigella (4%), Salmonella (3.4%), Providencia (3.2%), Vibrio spp. (1.1%), Yersinia enterocolitica (1.1%), and Plesiomonas shigelloides (0.2%) were also identified. Mixed bacterial infection was observed among 11.1% of the cases. The highest infection rate was found during the dry season (59.3%, p = 0.04). Most of the DEC was found to be multidrug resistant to trimethoprim/sulfamethoxazole 97.6%, amoxicillin 97.6%, erythromycin 96.9%, ampicillin 96.6%, and streptomycin 89%. CONCLUSIONS: This study suggests that DEC is the leading diarrhea-causing bacterial pathogen circulating in central Kenya, and seasonality has a significant effect on its transmission. Proper antibiotic prescription and susceptibility testing is important to guide appropriate antimicrobial therapy. PMID- 27942244 TI - Characterization of Tamyb10 allelic variants and development of STS marker for pre-harvest sprouting resistance in Chinese bread wheat. AB - Wheat grain color does not only affect the brightness of flour but also seed dormancy and pre-harvest sprouting (PHS) tolerance. The transcription factor Tamyb10 is an important candidate for R-1 gene, and the expression of its homologs determines wheat seed coat color. In the present study, the allelic variations of Tamyb10 were explored in a set of Chinese bread wheat varieties and advanced lines with different PHS tolerance, and a sequenced-tagged site (STS) marker for Tamyb10-D1 gene was developed, designated as Tamyb10D, which could be used as an efficient and reliable marker to evaluate the depth dormancy of wheat seeds. Using the marker Tamyb10D, 1629- and 1178-bp PCR fragments were amplified from the tolerant varieties, whereas a 1178-bp fragment was from the susceptible ones. Of the Chinese bread wheat varieties and advanced lines, 103 were used to validate the relationship between the polymorphic fragments of Tamyb10D and PHS tolerance. Statistical analysis indicated that Tamyb10D was significantly (P < 0.001) associated with depth of seed dormancy in these germplasms. To further confirm the association between allelic variants of Tamyb10-D1 and PHS tolerance, 200 recombinant inbred lines (RILs) from the cross between Zhongyou 9507 (1178-bp fragment) and Yangxiaomai (1178- and 1629-bp fragments) were genotyped using the marker Tamyb10D. General linear model analysis indicated that variation in Tamyb10-D1 had a significant (P < 0.001) association with the germination index (GI) values, explaining 13.7, 4.7, and 9.8 % of the phenotypic variation in GI in Shijiazhuang, Beijing, and the averaged data from those environments, respectively. In addition, among the 103 wheat varieties, 8 Tamyb10 genotypes (Tamybl0-A1, Tamybl0-B1, and Tamyb10-D1 loci) were detected, namely, aaa, aab, aba, abb, baa, bab, bba, and bbb, and these were significantly associated with GI value. PMID- 27942246 TI - Effects of methylation-sensitive enzymes on the enrichment of genic SNPs and the degree of genome complexity reduction in a two-enzyme genotyping-by-sequencing (GBS) approach: a case study in oil palm (Elaeis guineensis). AB - Advances in next generation sequencing have facilitated a large-scale single nucleotide polymorphism (SNP) discovery in many crop species. Genotyping-by sequencing (GBS) approach couples next generation sequencing with genome complexity reduction techniques to simultaneously identify and genotype SNPs. Choice of enzymes used in GBS library preparation depends on several factors including the number of markers required, the desired level of multiplexing, and whether the enrichment of genic SNP is preferred. We evaluated various combinations of methylation-sensitive (AatII, PstI, MspI) and methylation insensitive (SphI, MseI) enzymes for their effectiveness in genome complexity reduction and enrichment of genic SNPs. We discovered that the use of two methylation-sensitive enzymes effectively reduced genome complexity and did not require a size selection step. On the contrary, the genome coverage of libraries constructed with methylation-insensitive enzymes was quite high, and the additional size selection step may be required to increase the overall read depth. We also demonstrated the effectiveness of methylation-sensitive enzymes in enriching for SNPs located in genic regions. When two methylation-insensitive enzymes were used, only 16% of SNPs identified were located in genes and 18% in the vicinity (+/- 5 kb) of the genic regions, while most SNPs resided in the intergenic regions. In contrast, a remarkable degree of enrichment was observed when two methylation-sensitive enzymes were employed. Almost two thirds of the SNPs were located either inside (32-36%) or in the vicinity (28-31%) of the genic regions. These results provide useful information to help researchers choose appropriate GBS enzymes in oil palm and other crop species. PMID- 27942245 TI - Molecular diversity of alpha-gliadin expressed genes in genetically contrasted spelt (Triticum aestivum ssp. spelta) accessions and comparison with bread wheat (T. aestivum ssp. aestivum) and related diploid Triticum and Aegilops species. AB - The gluten proteins of cereals such as bread wheat (Triticum aestivum ssp. aestivum) and spelt (T. aestivum ssp. spelta) are responsible for celiac disease (CD). The alpha-gliadins constitute the most immunogenic class of gluten proteins as they include four main T-cell stimulatory epitopes that affect CD patients. Spelt has been less studied than bread wheat and could constitute a source of valuable diversity. The objective of this work was to study the genetic diversity of spelt alpha-gliadin transcripts and to compare it with those of bread wheat. Genotyping data from 85 spelt accessions obtained with 19 simple sequence repeat (SSR) markers were used to select 11 contrasted accessions, from which 446 full open reading frame alpha-gliadin genes were cloned and sequenced, which revealed a high allelic diversity. High variations among the accessions were highlighted, in terms of the proportion of alpha-gliadin sequences from each of the three genomes (A, B and D), and their composition in the four T-cell stimulatory epitopes. An accession from Tajikistan stood out, having a particularly high proportion of alpha-gliadins from the B genome and a low immunogenic content. Even if no clear separation between spelt and bread wheat sequences was shown, spelt alpha-gliadins displayed specific features concerning e.g. the frequencies of some amino acid substitutions. Given this observation and the variations in toxicity revealed in the spelt accessions in this study, the high genetic diversity held in spelt germplasm collections could be a valuable resource in the development of safer varieties for CD patients. PMID- 27942247 TI - Characterization of Brassica napus L. genotypes utilizing sequence-related amplified polymorphism and genotyping by sequencing in association with cluster analysis. AB - Identifying parental combinations that exhibit high heterosis is a constant target for commercial Brassica napus L. hybrid development programs. Finding high heterotic parental combinations can require hundreds of test crosses and years of yield evaluation. Heterotic pool development could be used to divide breeding material into specific breeding pools and focus the number of parental combinations created. Here, we report the genotypic characterization of 79 B. napus genotypes by calculating genetic distance based on sequence-related amplified polymorphism (SRAP) and genotyping by sequencing (GBS) in association with a neighbour-joining clustering algorithm. Despite the different genotypic analyses, neighbour-joining cluster analysis based on genetic distance of SRAP and GBS produced similar clusters. Homology between SRAP and GBS clusters was approximately 77 % when manually comparing clusters and 68 % when comparing clusters using Compare2Trees. This research demonstrates that SRAP can have similar efficacy when compared to next-generation sequencing technology for heterotic pool classification. This information may provide an important breeding scaffold for the development of hybrid cultivars based upon genetic distance and cluster analysis. PMID- 27942248 TI - Foundations of reusable and interoperable facet models using category theory. AB - Faceted browsing has become ubiquitous with modern digital libraries and online search engines, yet the process is still difficult to abstractly model in a manner that supports the development of interoperable and reusable interfaces. We propose category theory as a theoretical foundation for faceted browsing and demonstrate how the interactive process can be mathematically abstracted. Existing efforts in facet modeling are based upon set theory, formal concept analysis, and light-weight ontologies, but in many regards, they are implementations of faceted browsing rather than a specification of the basic, underlying structures and interactions. We will demonstrate that category theory allows us to specify faceted objects and study the relationships and interactions within a faceted browsing system. Resulting implementations can then be constructed through a category-theoretic lens using these models, allowing abstract comparison and communication that naturally support interoperability and reuse. PMID- 27942249 TI - Odorant Receptor Gene Choice. PMID- 27942250 TI - Working Face-to-Face for Pediatric CT Dose Reduction: A Community Toolkit. AB - Although children are especially vulnerable to the health risks of ionizing radiation, approximately 8 million CTs are performed on children in the USA. Widespread dose variation is common, particularly in non-pediatric focused facilities. In this article we present our rationale and hands-on approach in developing and refining a toolkit aimed at helping a community hospital with pediatric CT dose reduction. PMID- 27942251 TI - The Effects of Radical Prostatectomy on Gay and Bisexual Men's Mental Health, Sexual Identity and Relationships: Qualitative Results from the Restore Study. AB - The effect of prostate cancer treatment in gay and bisexual men is an under researched area. In 2015, we conducted in-depth telephone interviews with 19 gay and bisexual men who had undergone radical prostatectomies. Across the respondents' five emotional themes emerged: (1) shock at the diagnosis, (2) a reactive, self-reported "depression", (3) sex-specific situational anxiety, (4) a sense of grief, and, (5) an enduring loss of sexual confidence. Identity challenges included loss of a sense of maleness and manhood, changes in strength of sexual orientation, role-in-sex identity, and immersion into sexual sub cultures. Relationship challenges identified included disclosing the sexual effects of treatment to partners, loss of partners, and re-negotiation of sexual exclusivity. Most to all of these effects stem from sexual changes. To mitigate these negative effects of radical prostatectomy, and to address health disparities n outcomes observed in gay and bisexual men, all these challenges need to be considered in any tailored rehabilitation program for gay and bisexual men. PMID- 27942253 TI - Lived Time Disturbances of Drug Addiction Therapy Newcomers. A Qualitative, Field Phenomenology Case Study at Monar-Markot Center in Poland. AB - The aim of this study was to qualitatively assess the disturbances of lived time in individuals with multiple drug dependencies. The research was conducted at Monar-Markot Center for Humanitarian Aid in Roznowice (Poland) in 2014 through direct, non-disguised observational study in a therapeutic community setting. Overall, 10 clients with multiple drug dependencies forming a newcomers group participated in. They previously abstained from usage for negligible periods of time. The measurements included participant observation of collective time regimes at the center; group discussions; written accounts by clients; Zimbardo Time Perspective Inventory; semi-structured interviews. It was found that the clients experienced difficulties in following a strict therapeutic temporal regime, and they also showed a concomitant need to accelerate time as it passed. They also suffered an unpleasant domination by traumatic past within lived time. Their time horizons appeared significantly shortened and their planning capacity impaired, while a distant (dissociated) future was fantasized about in a realistic manner. Altogether, their disturbances of lived time consisted of the propensity to overemphasize their past dimensions at the expense of their future, while a gap between a close and a distant future appeared. PMID- 27942252 TI - Special Considerations for the Treatment of Pain from Torture and War. AB - Pain care for survivors of torture and of war shows similarities and marked differences. For both, pain can be complex with unfamiliar presentations and the pains hard to assign to known disorders. For many survivors, pain and associated disability are overshadowed by psychological distress, often by post-traumatic stress symptoms that can be frightening and isolating. Pain medicine in war can exemplify best techniques and organisation, reducing suffering, but many military veterans have persistent pain that undermines their readjustment. By contrast, survivors of torture rarely have any acute health care; their risk for developing chronic pain is high. Even when settled as refugees in a well-resourced country, their access to healthcare may be restricted. Recent evidence is reviewed that informs assessment and treatment of pain in both groups, with the broader context of psychological distress addressed at the end. Clinical and research implications are briefly outlined. PMID- 27942254 TI - Group Treatment for Women Gamblers Using Web, Teleconference and Workbook: Effectiveness Pilot. AB - While the past decades have seen a dramatic increase in the number of women who gamble and develop consequent problems, treatment services are being underutilized in Ontario. This pilot study explores the feasibility of using web- and phone-based group interventions to expand services available for women who might not otherwise seek or be able to access treatment. Distinct treatment considerations for working with women, such as the value of a women's group, advantages of phone counselling, and the implementation of modern web-based services, were reviewed. The study involved a clinician-facilitated group that used teleconferencing and webinar technology (Adobe Connect) for support and discussion, and a Tutorial Workbook (TW) developed specifically to address the issues and treatment needs of women who gamble at a problematic level. A mixed method analysis used to evaluate the results suggested that the group-based teleconference/webinar approach provided a much-needed means of treatment support for women. Participants reported that the program helped them to understand their gambling triggers, to improve their awareness, to feel better about themselves, to modify their mood and anxiety levels, to feel less isolated, to address their relationships, and to feel more hopeful for the future. The Tutorial Workbook, which was used to supplement the educational component of the group interaction, was highly rated. PMID- 27942255 TI - Validation of the Portuguese DSM-IV-MR-J. AB - Youth problem gambling is viewed as an emergent public health issue in many countries, and is also an emerging area of public concern in Portugal. However, there is currently no Portuguese instrument that focuses specifically on the measurement of problem gambling among young people. Consequently, the present study aimed to validate the DSM-IV-MR-J for use among Portuguese adolescents and to examine its' psychometric properties. A cross-cultural adaption of this instrument to the Portuguese language was performed using the translation and back translation method. The final version of the instrument was administered to 753 Portuguese high school and first year college students. The findings revealed an acceptable internal reliability and replicated the one-factor structure of this scale. Based on these findings, the Portuguese DSM-IV-MR-J appears to be a valid and reliable instrument, and provides a much needed psychometric tool for the development of more research on youth gambling in Portugal. PMID- 27942256 TI - When Is a New Scale not a New Scale? The Case of the Bergen Shopping Addiction Scale and the Compulsive Online Shopping Scale. AB - Manchiraju et al. (International Journal of Mental Health and Addiction, 1-15, 2016) published the Compulsive Online Shopping Scale (COSS) in the International Journal of Mental Health and Addiction (IJMHA). To develop their measure of compulsive online shopping, Manchiraju and colleagues adapted items from the seven-item Bergen Shopping Addiction Scale (BSAS) and its' original 28-item item pool. Manchiraju et al. did not add or remove any of the original seven items, and did not substantially change the content of any of the 28 items on which the BSAS was based. They simply added the word "online" to each existing item. Given that the BSAS was specifically developed to take into account the different ways in which people now shop and to include both online and offline shopping, there does not seem to be a good rationale for developing an online version of the BSAS. It is argued that the COSS is not really an adaptation of the BSAS but an almost identical instrument based on the original 28-item pool. PMID- 27942258 TI - Measuring Mean Cup Depth in the Optic Nerve Head. AB - Since the deformation of structures in the optic nerve head (ONH) is associated with glaucoma and other diseases of the optic nerve, measurement of this deformation is of current research interest. This paper considers the computation of cup depth, a measurement of the depth of the internal limiting membrane (ILM). The computation of cup depth requires a reference structure against which to measure the ILM, and the construction of two reference structures is discussed, one based on Bruch's membrane opening (BMO) and the other based on the anterior surface of the peripapillary sclera (AS). A main focus of the paper is the robust computation of mean cup depth, which requires a good sampling of a reconstruction of the ILM surface. To evaluate our algorithm, the construction of synthetic datasets is considered. PMID- 27942257 TI - Multi-Material Tissue Engineering Scaffold with Hierarchical Pore Architecture. AB - Multi-material polymer scaffolds with multiscale pore architectures were characterized and tested with vascular and heart cells as part of a platform for replacing damaged heart muscle. Vascular and muscle scaffolds were constructed from a new material, poly(limonene thioether) (PLT32i), which met the design criteria of slow biodegradability, elastomeric mechanical properties, and facile processing. The vascular-parenchymal interface was a poly(glycerol sebacate) (PGS) porous membrane that met different criteria of rapid biodegradability, high oxygen permeance, and high porosity. A hierarchical architecture of primary (macroscale) and secondary (microscale) pores was created by casting the PLT32i prepolymer onto sintered spheres of poly(methyl methacrylate) (PMMA) within precisely patterned molds followed by photocuring, de-molding, and leaching out the PMMA. Pre-fabricated polymer templates were cellularized, assembled, and perfused in order to engineer spatially organized, contractile heart tissue. Structural and functional analyses showed that the primary pores guided heart cell alignment and enabled robust perfusion while the secondary pores increased heart cell retention and reduced polymer volume fraction. PMID- 27942259 TI - Graph reconstruction using covariance-based methods. AB - Methods based on correlation and partial correlation are today employed in the reconstruction of a statistical interaction graph from high-throughput omics data. These dedicated methods work well even for the case when the number of variables exceeds the number of samples. In this study, we investigate how the graphs extracted from covariance and concentration matrix estimates are related by using Neumann series and transitive closure and through discussing concrete small examples. Considering the ideal case where the true graph is available, we also compare correlation and partial correlation methods for large realistic graphs. In particular, we perform the comparisons with optimally selected parameters based on the true underlying graph and with data-driven approaches where the parameters are directly estimated from the data. PMID- 27942260 TI - Effect of Infrared Radiation on the Healing of Diabetic Foot Ulcer. AB - BACKGROUND: Diabetic foot ulcer is a worldwide health care concern affecting tens of thousands of patients. If these ulcers left untreated, they can create severe complications. OBJECTIVES: This study was designed to examine the effect of infrared radiation on the healing of diabetic foot ulcer. PATIENTS AND METHODS: This clinical trial was performed on 50 patients referred to Dr. Ganjavian hospital in Dezful city, Iran, with diabetic foot ulcer degree 1 and 2 (based on Wegener Scale). Sample size was determined based on relevant studies of the recent decade. Patients were classified into the intervention and control groups (n = 25 in each group) in terms of age, gender, degree of ulcer, ulcer site and body mass index. In this study, work progress was evaluated according to the checklist of diabetic foot ulcer healing evaluation. RESULTS: The results of the current study showed that there was a statistically significant difference in healing ulcers (P < 0.05) and mean healing time (P < 0.05) between the two groups. CONCLUSIONS: Using the infrared plus routine dressing is more effective than using merely routine dressing. PMID- 27942262 TI - Association Between Obstructive Sleep Apnea and Osteoporosis: A Systematic Review and Meta-Analysis. AB - CONTEXT: Hypoxia reduces osteoblast growth resulting in bone thinning and osteoporosis. Although obstructive sleep apnea (OSA) with recurrent hypoxia might be a contributing factor for osteoporosis development, whether OSA is a risk or protective factor for osteoporosis has not been demonstrated. OBJECTIVES: This systematic review and meta-analysis evaluated the association between OSA and osteoporosis using published observational studies. DATA SOURCES: PubMed/MEDLINE and EMBASE databases. STUDY SELECTION: We completed a systematic review and meta analysis of published observational studies that evaluated incidence or prevalence of osteoporosis or bone mineral density in obstructive sleep apnea compared with controls. Severity of OSA was characterized using the apnea hypopnea index (AHI). DATA EXTRACTION: Primary outcomes were incidence, prevalence, or odds ratio of having osteoporosis, defined as bone mineral density T-score < -2.5 SD. RESULTS: Of 353 articles, 344 articles were excluded, 9 underwent full-length review and data were extracted from 7 studies consisting of 113,558 patients. Finally, 3 extracted studies were included in the meta-analysis of osteoporosis. Among cohort studies, the pooled odds ratio of osteoporosis in patients with OSA was 1.92 (95% confidence interval [CI]: 1.24 - 2.97) compared with controls. Among cross-sectional studies, odds of osteoporosis was higher in controls compared with patients with OSA (OR = 0.60, 95% CI: 0.42 - 0.87). In subgroup analysis by gender and study design, in both sexes, only cohort studies had higher odds of osteoporosis compared with controls. CONCLUSIONS: There was significant association between OSA and osteoporosis in studies with cohort design. Further prospective studies with large numbers of patients adjusted for the effects of age, sex, or BMI are required to comprehensively determine whether OSA is a risk factor for osteoporosis. PMID- 27942261 TI - Congenital Hypothyroidism: Optimal Initial Dosage and Time of Initiation of Treatment: A Systematic Review. AB - CONTEXT: Appropriate management of neonates, tested positive for congenital hypothyroidism (CH), in particular, the initial dosage of levothyroxine and the time of initiation of treatment is a critical issue. The aim of this study was to assess all current evidence available on the subject to ascertain the optimal initial dose and optimal initiation time of treatment for children with CH. EVIDENCE ACQUISITION: In this study, all published research related to the initiation treatment dose and the onset time of treatment in congenital hypothyroidism were reviewed. The searched electronic databases included Medline, Science direct, Scopus EMBASE, PsycINFO, Cochrane, BIOSIS and ISI Web of Knowledge. Additional searches included websites of relevant organizations, reference lists of included studies, and issues of major thyroid and pediatrics journals published within the past 35 years. Studies were included if they were written in English and investigated levothyroxine dose or timing of treatment or both, used for the treatment of children with congenital hypothyroidism. RESULTS: Two thousand three hundred and seventy-four articles (excluding duplicates) were retrieved from the primary search. After reviewing the titles, abstracts and full texts of studies, eventually, 22 studies were found that met our inclusion criteria. Amongst these, 17 and 12 evaluated outcomes of different treatment doses and treatment timing, respectively. Overall, the majority of these studies emphasized the initial high dose of levothyroxine and early treatment of newborns with hypothyroidism. There were, however, some studies that disagreed with increasing levothyroxine dose at initiation of treatment. CONCLUSIONS: Considering the results of this review, apparently there is no difference in opinion regarding the early initiation of treatment, whereas determining the optimal dose of levothyroxine for start of treatment in CH patients still remains a controversial issue, demonstrating the need for further studies, despite the fact that use of high doses can lead to rapid normalization of biochemical indices, although this may cause complications. PMID- 27942263 TI - The Association Between Physical Activity During Pregnancy and Gestational Diabetes Mellitus: A Case-Control Study. AB - BACKGROUND: Gestational diabetes mellitus is one of the most common complications of pregnancy. Physical activity is associated with a lower risk of type 2 diabetes mellitus. A recent meta-analysis study suggested that more research is needed to investigate the type, duration and intensity of physical activity that can help to reduce the risk of gestational diabetes mellitus. OBJECTIVES: The present study aimed to understand the association between physical activity and gestational diabetes mellitus through comparing the type and intensity of physical activity performed by pregnant females with gestational diabetes and healthy pregnant females in the first 20 weeks of their pregnancy. PATIENTS AND METHODS: In the current case-control study, 100 pregnant females with gestational diabetes mellitus as the case group and 100 pregnant females as the non-diabetic control group were recruited. The age range of the participants was 18 - 40 years with the gestation of 20 - 28 weeks. To diagnose gestational diabetes mellitus using the criteria introduced by carpenter and coustan females with abnormal glucose challenge test (> 140 mg/dL) were asked to perform the three-hour 100 g oral glucose tolerance test. The details of physical activity were collected by a modified version of the pregnancy physical activity questionnaire. Anthropometric and relevant data were recorded for all of the participants. Data were analyzed by SPSS version 21. Risk estimates were obtained by logistic regression and adjusted for confounders. RESULTS: Females who had low total physical activity according to the pregnancy physical activity questionnaire during early pregnancy were at a significantly higher risk of developing gestational diabetes mellitus (OR = 4.12, 95% CI (2.28 - 7.43), P = 0.001) compared to the ones who reported higher levels of physical activity. Moreover, after adjusting for age, body mass index (BMI), gravidity and a family history of diabetes, females with low physical activity in the domain of transportation activity during 20 weeks of pregnancy were at a significantly higher risk of developing gestational diabetes mellitus. The statistical findings indicate that females with the low intensity of sedentary, light and moderate physical activity are at a higher risk of developing gestational diabetes mellitus (OR 2.32; 95% CI 1.21-4.43, P = 0.010, OR 6.26; 95% CI 2.95 - 13.30, P = 0.001 and OR 6.73; 95% CI 3.15 - 14.38, P = 0.001) compared to females with a higher intensity of sedentary, light and moderate physical activity. CONCLUSIONS: The amount and intensity of physical activity during pregnancy is associated with a lower risk of gestational diabetes mellitus. As a result, the pregnant Iranian females have to be encouraged to do regular daily physical activity during pregnancy, if there is no specific contraindication to it. PMID- 27942264 TI - The Relationship Between Increased Epicardial Fat Thickness and Left Ventricular Hypertrophy and Carotid Intima-Media Thickness in Patients With Nonfunctional Adrenal Incidentaloma. AB - BACKGROUND: Emerging evidences indicate that patients diagnosed with Adrenal Incidentaloma (AI) may present cardiovascular complications. Epicardial fat thickness (EFT) has recently been described as a new risk factor and an active player in metabolic syndrome and cardiovascular disease. OBJECTIVES: We aimed to evaluate the relationship between EFT and left ventricular hypertrophy and carotid intima-media thickness, which are both strong predictors of cardiovascular morbity and mortality, in patients with nonfunctioning AI. PATIENTS AND METHODS: We evaluated 51 patients (36 females and 15 males) diagnosed with AI and 35 (29 females, 6 males) age, gender and body mass index (BMI) matched healthy controls in terms of cardiovascular risk parameters. Epicardial fat was identified as the echo-free space between the outer wall of the myocardium and the visceral layer of the pericardium. RESULTS: Epicardial fat thickness was significantly higher in patients with AI when compared to the control group (0.89 +/- 0.32 cm vs. 0.74 +/- 0.26 cm; P = 0.023). left ventricular (LV) mass index and median carotid intima-media thickness (CIMT) were also higher in subjects with AI than in controls (99.8 g/m2 vs. 86.9 g/m2; P = 0.024 and 7.5 mm (5.5 - 11.5) vs. 6.5 mm (4.5 - 9.5); P = 0.017). There was a positive correlation between EFT, LV mass index, EFT and CIMT (r = 0.315, P = 0.004; r = 0.363, P < 0.001; respectively). CONCLUSIONS: In this study we showed that EFT, measured by echocardiography is higher in subjects with AI when compared to healthy controls. epicardial fat thickness had the best independent correlation with AI in multiple logistic regression analysis. Incidentaloma is also associated with increased left ventricular mass index and CIMT. Adrenal incidentaloma patients may show early cardiac changes, such as increased left ventricular mass and increased CIMT. PMID- 27942265 TI - Correlations Between Changes in Undercarboxylated Osteocalcin and Muscle Function in Hypoparathyroidism. AB - BACKGROUND: Muscles and bones are interconnected. Recent studies suggest that undercarboxylated osteocalcin from bone may affect muscle mass and strength. There are, however, no prospective human data on this relationship. METHODS: We previously treated patients with hypoparathyroidism with intact Parathyroid Hormone (PTH) or placebo in a six-month randomized, placebo-controlled trial and demonstrated a marked increase in undercarboxylated osteocalcin (ucOC) in the PTH treated group. We therefore investigated if this increase correlated with changes in muscle mass, strength or function. Primarily, the muscle mass using Dual energy X-ray Absorptiometry (DXA) was measured and the maximal voluntary isometric muscle strength at the upper and lower extremities, using dynamometry, was assessed. Furthermore, repeated chair stands test, Timed Up and Go test were performed and postural stability using a stadiometer was assessed. Finally, the relationship between change in ucOC or the ratio of the changes in ucOC and total OC (ucOC%/OC%) and different measures of muscle function were analyzed, using regression analyses. RESULTS: The findings indicated that ucOC%/OC% was positively and significantly associated with percentage change in max force production during elbow extension (beta = 0.28, P = 0.034), however, all other associations were non-significant. CONCLUSIONS: Given the number of statistical tests that were carried out, our one significant finding may represent a false positive. Thus the results do not support the role of ucOC in muscle function in humans with hypoparathyroidism. Our results are inconsistent with previous data from a human cross-sectional study; however, cross-sectional studies, do not allow for inference of causality. The analyses should be repeated in larger, randomized trials including healthy individuals. PMID- 27942266 TI - Modeling the transition state structure to probe a reaction mechanism on the oxidation of quinoline by quinoline 2-oxidoreductase. AB - BACKGROUND: Quinoline 2-oxidoreductase (Qor) is a member of molybdenum hydroxylase which catalyzes the oxidation of quinoline (2, 3 benzopyridine) to 1 hydro-2-oxoquinoline. Qor has biological and medicinal significances. Qor is known to metabolize drugs produced from quinoline for the treatment of malaria, arthritis, and lupus for many years. However, the mechanistic action by which Qor oxidizes quinoline has not been investigated either experimentally or theoretically. PURPOSE OF THE STUDY: The present study was intended to determine the interaction site of quinoline, predict the transition state structure, and probe a plausible mechanistic route for the oxidative hydroxylation of quinoline in the reductive half-reaction active site of Qor. RESULTS: Density functional theory calculations have been carried out in order to understand the events taking place during the oxidative hydroxylation of quinoline in the reductive half-reaction active site of Qor. The most electropositivity and the lowest percentage contribution to the HOMO are shown at C2 of quinoline compared to the other carbon atoms. The transition state structure of quinoline bound to the active site has been confirmed by one imaginary negative frequency of -104.500/s and -1.2365899E+06 transition state energies. The Muliken atomic charges, the bond distances, and the bond order profiles were determined to characterize the transition state structure and the reaction mechanism. CONCLUSION: The results have shown that C2 is the preferred locus of interaction of quinoline to interact with the active site of Qor. The transition state structure of quinoline bound to the active site has been confirmed by one imaginary negative frequency. Moreover, the presence of partial negative charges on hydrogen at the transitions state suggested hydride transfer. Similarly, results obtained from total energy, iconicity and molecular orbital analyses supported a concerted reaction mechanism. PMID- 27942267 TI - Synthesis and characterization of novel rhenium(I) complexes towards potential biological imaging applications. AB - BACKGROUND: Re(I) tricarbonyl complexes exhibit immense potential as fluorescence imaging agents. However, only a handful of rhenium complexes have been utilized in biological imaging. The present study describes the synthesis of four novel rhenium complexes, their characterization and preliminary biological studies to assess their potential as biological imaging agents. RESULTS: Four facial rhenium tricarbonyl complexes containing a pyridyl triazine core, (L1 = 5,5'(3-(2 pyridyl)-1,2,4-triazine-5,6-diyl)-bis-2-furansulfonic acid disodium salt and L2 = (3-(2- pyridyl)-5,6-diphenyl-1,2,4-triazine-4',4''-disulfonic acid sodium salt) have been synthesized by utililzing two different Re metal precursors, Re(CO)5Br and [Re(CO)3(H2O)3]OTf in an organic solvent mixture and water, respectively. The rhenium complexes [Re(CO)3(H2O)L1]+ (1), Re(CO)3L1Br (2), [Re(CO)3(H2O)L2]+ (3), and Re(CO)3L2Br (4), were obtained in 70-85% yield and characterized by 1H NMR, IR, UV, and luminescence spectroscopy. In both H2O and acetonitrile, complexes display a weak absorption band in the visible region which can be assigned to a metal to ligand charge transfer excitation and fluorescent emission lying in the 650-710 nm range. Cytotoxicity assays of complexes 1, 3, and 4 were carried out for rat peritoneal cells. Both plant cells (Allium cepa bulb cells) and rat peritoneal cells were stained using the maximum non-toxic concentration levels of the compounds, 20.00 mg ml-1 for 1 and 3 and 5.00 mg ml-1 for 4 to observe under the epifluorescence microscope. In both cell lines, compound concentrated specifically in the nuclei region. Hence, nuclei showed red fluorescence upon excitation at 550 nm. CONCLUSIONS: Four novel rhenium complexes have been synthesized and characterized. Remarkable enhancement of fluorescence upon binding with cells and visible range excitability demonstrates the possibility of using the new complexes in biological applications.Graphical abstractMicrograph of rat peritoneal cells incubated with novel rhenium complex under epifluorescence microscope. PMID- 27942268 TI - Towards agile large-scale predictive modelling in drug discovery with flow-based programming design principles. AB - Predictive modelling in drug discovery is challenging to automate as it often contains multiple analysis steps and might involve cross-validation and parameter tuning that create complex dependencies between tasks. With large-scale data or when using computationally demanding modelling methods, e-infrastructures such as high-performance or cloud computing are required, adding to the existing challenges of fault-tolerant automation. Workflow management systems can aid in many of these challenges, but the currently available systems are lacking in the functionality needed to enable agile and flexible predictive modelling. We here present an approach inspired by elements of the flow-based programming paradigm, implemented as an extension of the Luigi system which we name SciLuigi. We also discuss the experiences from using the approach when modelling a large set of biochemical interactions using a shared computer cluster.Graphical abstract. PMID- 27942269 TI - Reciprocal Family, Friendship and Church Support Networks of African Americans: Findings from the National Survey of American Life. AB - This study examined reciprocal support networks involving extended family, friends and church members among African Americans. Our analysis examined specific patterns of reciprocal support (i.e., received only, gave only, both gave and received, neither gave or received), as well as network characteristics (i.e., contact and subjective closeness) as correlates of reciprocal support. The analysis is based on the African American sub-sample of the National Survey of American Life (NSAL). Overall, our findings indicate that African Americans are very involved in reciprocal support networks with their extended family, friends and church members. Respondents were most extensively involved in reciprocal supports with extended family members, followed closely by friends and church networks. Network characteristics (i.e., contact and subjective closeness) were significantly and consistently associated with involvement with reciprocal support exchanges for all three networks. These and other findings are discussed in detail. This study complements previous work on the complementary roles of family, friend and congregational support networks, as well as studies of racial differences in informal support networks. PMID- 27942271 TI - Recent developments in near-infrared spectroscopy (NIRS) for the assessment of local skeletal muscle microvascular function and capacity to utilise oxygen. AB - PURPOSE OF REVIEW: Continuous wave near infrared spectroscopy (CW NIRS) provides non-invasive technology to measure relative changes in oxy- and deoxy-haemoglobin in a dynamic environment. This allows determination of local skeletal muscle O2 saturation, muscle oxygen consumption ([Formula: see text]) and blood flow. This article provides a brief overview of the use of CW NIRS to measure exercise limiting factors in skeletal muscle. RECENT FINDINGS: NIRS parameters that measure O2 delivery and capacity to utilise O2 in the muscle have been developed based on response to physiological interventions and exercise. NIRS has good reproducibility and agreement with gold standard techniques and can be used in clinical populations where muscle oxidative capacity or oxygen delivery (or both) are impaired. CW NIRS has limitations including: the unknown contribution of myoglobin to the overall signals, the impact of adipose tissue thickness, skin perfusion during exercise, and variations in skin pigmentation. These, in the main, can be circumvented through appropriate study design or measurement of absolute tissue saturation. SUMMARY: CW NIRS can assess skeletal muscle O2 delivery and utilisation without the use of expensive or invasive procedures and is useable in large population-based samples, including older adults. PMID- 27942270 TI - The Dynamic Interplay Between DNA Topoisomerases and DNA Topology. AB - Topological properties of DNA influence its structure and biochemical interactions. Within the cell DNA topology is constantly in flux. Transcription and other essential processes including DNA replication and repair, alter the topology of the genome, while introducing additional complications associated with DNA knotting and catenation. These topological perturbations are counteracted by the action of topoisomerases, a specialized class of highly conserved and essential enzymes that actively regulate the topological state of the genome. This dynamic interplay among DNA topology, DNA processing enzymes, and DNA topoisomerases, is a pervasive factor that influences DNA metabolism in vivo. Building on the extensive structural and biochemical characterization over the past four decades that established the fundamental mechanistic basis of topoisomerase activity, the unique roles played by DNA topology in modulating and influencing the activity of topoisomerases have begun to be explored. In this review we survey established and emerging DNA topology dependent protein-DNA interactions with a focus on in vitro measurements of the dynamic interplay between DNA topology and topoisomerase activity. PMID- 27942272 TI - The Organization of Behavior Over Time: Insights from Mid-Session Reversal. AB - What are the mechanisms by which behavior is organized sequentially over time? The recently developed mid-session reversal (MSR) task offers new insights into this fundamental question. The typical MSR task is arranged to have a single reversed discrimination occurring in a consistent location within each session and across sessions. In this task, we examine the relevance of time, reinforcement, and other factors as the switching cue in the sequential modulation of control in MSR. New analyses also highlight some of the potential mechanisms underlying this serially organized behavior. MSR provides new evidence and we offer some ideas about how cues interact to compete for the control of behavior within and across sessions. We suggest that MSR is an excellent preparation for studying the competition among psychological states and their resolution toward action. PMID- 27942273 TI - A clinical perspective on electronically collecting patient-reported outcomes at the point-of-care for overactive bladder. AB - INTRODUCTION: Collecting patient-reported outcomes (PROs) can inform the treatment and management of overactive bladder (OAB). However, collecting these data at the point-of-care can be time-consuming and have a negative impact on a clinic's workflow. The purpose of this study was to pilot a digital system for collecting PROs at the point-of-care and qualitatively assess clinicians' perspectives in terms of the system's impact on the delivery of care for OAB. METHODS: Patients visiting a urology clinic for OAB completed several PRO instruments using a tablet while awaiting assessment. Clinicians reviewed their responses using a digital dashboard during clinical encounters. Qualitative interviews were conducted with the clinicians, to assess the collection system's impact in terms of: 1) logistics, 2) workflow; 3) patient communication; 4) influence on clinical decisions; 5) user experiences; and 6) the care model. RESULTS: Six interviews were conducted and thematic saturation was met, with several themes emerging. All participants were generally positive regarding the use of the digital collecting system. Participants felt that the dashboard improved workflow and enhanced communication with patients, but it was not thought to be any more influential on clinical decision-making than conventional collection methods. Several aspects of the digital PRO collection system were identified as needing improvement. CONCLUSIONS: The digital PRO collection system used at the point-of-care had a positive impact on the delivery of care for OAB. The results from this study could provide insight to other urologists who are interested in collecting PROs in their clinic. PMID- 27942274 TI - Hepatocellular Carcinoma: Tumorigenesis and Prediction Markers. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies. Although many advances have been made in the clinical study of HCC, the prognosis remains poor. Despite the discoveries in cancer biology in respect with physiological and pathological factors in relation to prognosis, HCC remains still a fatal disease due to late diagnosis. For improving the outcomes of patients with HCC, it is important to identify the factors predisposing to patient death. In recent years, based on cellular and molecular biology techniques, many tumor markers related to invasion, metastasis, recurrence and survival have been explored. However, routine biomarkers for the prediction of HCC evolution and prognosis are available in small number and less specific. These reviews focus on the recent advances in HCC tumorigenesis, revealing those biomarkers with prognosis significance or can be used for early detection. PMID- 27942275 TI - Common Pitfalls in Management of Inflammatory Bowel Disease. AB - Our understanding of inflammatory bowel disease (IBD), treatment options, complications and their management has expanded significantly over the past few decades. When caring for patients it is important to remember the complexities of pathogenesis and pharmacology. This review is to identify errors in diagnosis, treatment, complications and preventive care issues that arise while caring for patients with IBD and to provide recommendations and information that can be shared with patients and their health care providers. A review of the literature was undertaken using MEDLINE from 1981 to present. We included randomized controlled studies, case-control studies, and review articles. There are many associated conditions and complications recognized in patients with IBD and current treatment strategies do result in many side effects, some are serious and some are not widely recognized. With the advent of anti-TNF therapies and the newer 5-amino salicylate derivatives, options available have increased significantly. It is also important to remember that these patients are followed by more than one health care provider and it is important for all involved to communicate the plan of action. PMID- 27942276 TI - Colonoscopy with Polypectomy in Patients Taking Clopidogrel. AB - BACKGROUND AND AIMS: To investigate the bleeding risk of colonoscopy with polypectomy in patients taking clopidogrel. METHODS: Retrospective review of patients undergoing colonoscopy with polypectomy without interruption of clopidogrel. Patients with lesions larger than 1cm were generally rescheduled for polypectomy off clopidogrel. Most of the polyps were removed using cold snare technique. Endoscopic clips were routinely applied prophylactically. RESULTS: A total of 125 polypectomies were performed in 60 patients. The average polyp size was 5.4 +/- 2.1 mm. One patient (1.7%, CI 0.3-8.9%) developed post-polypectomy bleeding that resolved without treatment. Three patients (5%, CI 1.7-14%) had immediate bleeding during the procedure and all resolved with prompt clip application. CONCLUSIONS: Polypectomy of lesions up to 1cm in size can be performed without interruption of clopidogrel. PMID- 27942277 TI - Plasma Actin-free Gc-globulin in Patients with Chronic or Acute-on-chronic Liver Failure Caused by Hepatitis B Virus. AB - BACKGROUND: Previous studies have confirmed that serum concentrations of actin free Gc globulin (Af-Gc globulin) may provide prognostic information in patients withacute liver failure (ALF). However, until now the relation between plasma Af Gc globulin levels and chronic or acute-on-chronic liver failure (CLF or ACLF) caused by HBV is unknown. METHODS: Plasma Af-Gc globulin in 56 patients with liver failure, in 23 patients with compensated liver cirrhosis (CR), and in 25 healthy controls were measured using enzyme-linked immunosorbent assay (ELISA). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), choline esterase (CHE), Albumin (ALB), total bilirubin (TBIL), palsma international normalized ratio of prothrombin time (INR), and platelet (PLT) were also detected. The Child-Pugh score was calculated for each patient on admission. RESULTS: Plasma Af-Gc globulin levels in CLF, ACLF and CR were significantly lower than that of healthy controls (P < 0.001, respectively). The median (range) Af-Gc globulin level at admission for the liver failure (CLF or ACLF) was significantly reduced compared with that of CR group (P <= 0.001); additionally, there was significant difference between CLF and ACLF patients (P < 0.001). In liver failure cohort, plasma Af-Gc globulin was significantly positive correlated with ALB, ALT, AST and CHE (P was 0.001, 0.001, 0.001, < 0.001, respectively). Meanwhile, there was significantly negative correlation between plasma Af-Gc globulin and Child-Pugh score (P = 0.02). The level of Af-Gc globulin in ascites or hydrothorax-infected liver failure patients were markedly lower than that of non-infected (P = 0.015), the levels of Af-Gc in encephalopathy presence were lower than in encephalopathy absence. No significant difference of Af-Gc was noted between non-survivors and survivors during the follow-up period in liver failure patients. CONCLUSIONS: Plasma Af-Gc globulin levels in liver failure patients are significantly reduced compared with compensated liver cirrhosis patients and healthy controls, however, it might not be used in the prognosis of liver failure. PMID- 27942278 TI - Clinical Characteristics of Torsion of the Omentum. AB - BACKGROUND: The aim of this paper is to describe clinical aspects of the torsion of the omentum. METHODS: In this observational, retrospective study, the study group consisted of patients surgically managed for torsion of the omentum, between 1998 and 2008, in a second level medical facility in Mexico. Variables in the study included age, sex, signs and symptoms, body mass index (BMI), treatment and evolution time. Descriptive statistical analysis was employed. RESULTS: Eleven patients were confirmed torsion of omentum, 7 (63.63%) women and 4 (36.36%) men, median age 33 (20 to 58) years, BMI > 25.0 in 9 (81.81%), average evolution 6.54, SD 3.47 days. All presented with abdominal pain, 6 (54.54%) with abdominal distension, 4 (36.36%) with ambulatory difficulty, 3 (27.27%) with malaise, and 5 (45.45%) with previous surgery. In all cases diagnosis was made by means of laparotomy, treatment was the resection of the affected segment, and there were no further complications. CONCLUSIONS: Torsion of the omentum resembles acute appendicitis; abdominal pain and abdominal distension are the most common symptoms. It is often discovered during surgery and it is treated surgically by removal of the affected segment of the omentum. PMID- 27942279 TI - Total Enteral Nutrition Facilitates Wound Healing Through Preventing Intestinal Atrophy, Keeping Protein Anabolism and Suppressing Inflammation. AB - BACKGROUND: In clinical settings, early total enteral nutrition (TEN) is known to reduce the postoperative complication and infection rate as well as duration of postoperative stay compared with total parenteral nutrition (TPN) in a variety of critical conditions. We aimed to compare effects TEN and TPN on wound healing and explore its possible mechanisms using rat model. METHODS: Seven days after operation for inserting enteral tube into gastric space for TEN, Sprague-Dawley rats were made burn (15 mm) in the back. Rats were administrated with either TEN (N = 17) or TPN (N = 15) and evaluated condition of wound healing as well as serum/urine immunological and biochemical parameters at 28 days. RESULTS: Burned area was significantly reduced in TEN than in TPN group. Although body weight, serum levels of total protein, albumin and transferrin were the same levels between the two groups, urine nitrogen and intestinal atrophy were significant in TPN group. Conversely, weight of small bowel showed positive linear relationship with levels of parameters calculated as follows: [medication nitrogen quantity - (urine nitrogen + feces nitrogen)]/[medication nitrogen - feces nitrogen quantity]. Weights of spleen and tumor necrotizing factor-a levels in serum were higher in TPN than in TEN. CONCLUSIONS: These results suggest that TEN may facilitate wound healing compared with TPN through preventing intestinal atrophy, keeping protein anabolism and suppressing inflammation. PMID- 27942280 TI - A Novel Approach with Supra- and Retro-hepatic Cavocaval Bypass for Short Segmental Occlusion of Inferior Vena Cava in Budd-Chiari Syndrome. AB - BACKGROUND: Budd-Chiari syndrome (BCS) is defined as chronic, progressive and congestive liver dysfunction resulting from obstruction of the outflow of inferior vena cava (IVC) and/or hepatic veins. One of the common types of BCS is short segmental occlusion of retrohepatic IVC (SSOR-IVC) accompanied by varied extent of obstruction of intrahepatic veins. The mainstay of surgical treatment at present for SSOR-IVC is cavoartrial bypass via thoracolaparotomic approach, in which thoracic and pulmonary complications intra- and/or post-operation are common. We have developed an abdominal approach using suprahepatic and retrohepatic inferior vena cavocaval bypass to treat SSOR-IVC, herein we compared it with the conventional thoracolaparotomic approach. METHODS: From 2005 to 2008, we performed suprahepatic and retrohepatic inferior vena cavocaval bypass using artificial vessel in 16 BCS patients with SSOR-IVC (group A), we compared the results of this new modality with that using traditional thoracolaparotomic approach in 18 patients (group B) from 2001 to 2004. RESULTS: In group A, one patient had intraoperative acute cardiac failure due to rapid opening of the bypassed vessel, and the symptom was resolved immediately through prompt management, while the others were not eventful during or post-operation. The length of artificial vessel required was 6 to 8 cm, and all patients had no graft vessel thrombosis after 10 to 55 months follow-up. In group B, one patient had intraoperative acute pericardial tamponment due to anastomotic leakage. The total occurrence rate of postoperative complication was 27.8%, including three pleural effusions, one pulmonary infection and one acute pericarditis. The length of the artificial vessel required was 12 to 14 cm. Three patients had graft vessel thrombosis at 37, 42 and 58 months post-operation, respectively. CONCLUSIONS: The abdominal approach for suprahepatic and retrohepatic cavocaval bypass have advantages as follows over the traditional thoracolaparotomic approach for cavoartrial bypass: 1) Less traumatic with fewer postoperative thoracic and pulmonary complications; 2) A shorter artificial vessel required to facilitate endothelial seeding for improved long term patency; 3) Void of risk of fatal pericardial tamponment; 4) Prevention of acute pericarditis due to pericardial irritation by the artificial vessel in the thoracolaparotomic approach. We concluded that this novel abdominal approach is a safe and effective technique for treatment of SSOR-IVC. PMID- 27942281 TI - Massive Small Bowel Infaction: A Comparison of Two Cases. AB - We present two similar cases of massive small bowel infarction in which two different surgical approaches were employed, illustrating the advantages of the staged approach of damage control surgery. This comprises an initial operation, limited to bowel resection and temporary closure of the bowel ends, and a second performed after 48 to 72 hours where the bowel continuity is re-established. We strongly advocate such an approach as it appears to offer a quicker recovery with fewer complications. PMID- 27942282 TI - Non-invasive Adenocarcinoma of the Vermiform Appendix: Incidence and Report of Four Cases among 512 Appendectomies. AB - Tumors of the vermiform appendix are relatively rare. More than 50% of appendiceal tumors are carcinoid tumors. The author reviewed 512 consecutive pathological specimens of appendectomies in last ten years in our pathology laboratory in search for appendiceal tumors. As the results, 4 cases (incidence: 0.8%) of non-invasive adenocarcinoma were found. No other tumors including carcinoid tumors were recognized. The age of the 4 patients with adenocarcinoma was 48, 39, 84 and 86 years, respectively. Male to female ratio was 3:1. The clinical diagnoses were acute appendicitis in 2 cases and suspected malignancy in 2 cases. The post-operative outcome was good without metastasis, recurrence, and pseudomyxoma peritonei. Pathologically, all the 4 tumors were non-invasive adenocarcinomas: 2 cases were flat type adenocarcinoma, 1 case was papillary adenocarcinoma, and 1 case was mucinous adenocarcinoma. Immunohistochemically, expression of p53 protein was observed in all the 4 cases, and Ki-67 labeling ranged from 40% to 90%. The results suggest that incidence of appendiceal adenocarcinoma was 0.8% of all appendectomies, and that non-invasive adenocarcinoma of the appendix shows variable morphologies, and that postoperative clinical outcome of non-invasive appendiceal tumor is good. PMID- 27942283 TI - Partial Splenectomy for Splenic Cyst using a Bipolar Radiofrequency Device. AB - The main goals of spleen preserving surgery are control of peroperative bleeding and maintaining the spleen's function postoperatively. Several techniques of spleen preserving surgery have been described. This report presents a new technique to perform partial splenectomy. We performed this partial splenectomy with a bipolar radiofrequency (RF) device in a 21 years old woman with a splenic cyst, with almost no peroperative blood loss. PMID- 27942285 TI - Diffrential Diagnosis of Hepatic Hydrothorax by 99mTc Sulfur Colloid Peritoneal Scintigraphy: Two Cases. AB - Large symptomatic pleural effusions can be seen in cirrhotic patients with ascites. In this report, two cirrhotic patients with ascites and large pleural effusions were evaluated. To determine the cause of pleural effusion and to understand whether there was a communication of fluid between peritoneal and pleural cavities, 99mTc sulfur colloid peritoneal scintigraphy was used. According to the scintigraphic results, the diagnosis of hepatic hydrothorax and tuberculosis was confirmed easily and the treatments of the patients were managed rapidly. PMID- 27942284 TI - Successful Management of Pancreatic Ascites with both Conservative Management and Pancreatic Duct Stenting. AB - Pancreatic ascites is a rare complication and should be suspected in patients with chronic alcoholism and pancreatitis presenting with ascites. The etiology is likely from a pancreatic pseudocyst leakage or due to ductal disruption. Treatment is controversial but includes conservative medical therapy or endoscopic transpapillary pancreatic duct stenting or surgery. We present a case of pancreatic ascites in a patient with alcohol use and chronic pancreatitis. Patient received conservative therapy including octreotide. An endoscopic retrograde cholangiopancreatography was performed, which confirmed a pancreatic duct dehiscence with extravasation of the injected contrast. This was treated with placement of a stent. Patient improved clinically and symptomatically. This case report augments the existing data from two prior reported case series, and this modality of management should be actively pursued in such cases. PMID- 27942286 TI - A RecQ Protein-like 5 Haplotype is Associated With Colon Cancer. AB - BACKGROUND: Emerging murine model data suggests RecQ protein-like 5 (RECQL5) is a tumor suppressor gene. The goal of our study was to test whether RECQL5 gene variants are associated with colon cancer susceptibility. METHODS: We examined the association of two haplotype-tagging SNPs in RECQL5 and colon cancer in a population-based study of 390 colon cancer cases and 464 population controls. RESULTS: While both crude and covariate-adjusted single SNP analyses were only suggestive for an association with borderline significance (p = 0.07), haplotype analysis shows that individuals carrying the T-G haplotype (rs820196 common allele and rs4789223 minor allele) were at significantly increased risk for colon cancer (OR = 1.34, 95% CI = 1.02-1.76, p = 0.05). Adjustment for age, sex, body mass index, non-steroidal anti-inflammatory use and family history of colon cancer did not alter the results. CONCLUSIONS: These results suggest that a haplotype harboring the minor allele of rs4789223 is associated with colon cancer risk. Further study of RECQL5 as a colon cancer susceptibility gene is warranted, particularly with respect to variants in linkage disequilibrium with rs4789223. PMID- 27942287 TI - Effects of Gelatinization of Enteral Nutrients on Human Gastric Emptying. AB - BACKGROUND: Gastrointestinal side effects, particularly diarrhea, are still the main reasons for discontinuation of enteral nutrition. Gelatinization of liquid meal for the prevention of diarrhea has been reported as effective. The purpose of this study was to investigate the effects of gelatinization of liquid meal on gastric emptying. METHODS: Ten healthy volunteers were studied two times, with 2 week interval between tests. The total calorific value was set at 225 kcal, and 3 test meals were prepared: liquid meal and 2 types of gelatinized meals. These 2 types of gelatinized meals are different viscosity. 13C-sodium acetate (100 mg) was thoroughly mixed, and exhaled air was sampled. The results of gastric emptying were expressed as the time of peak excretion (Tmax), and absorption was expressed as the area under the 13CO2 curve up to Tmax (AUC-Tmax). At the same time, blood samples were collected to measure levels of blood glucose, insulin and gastrin. RESULTS: The mean value of Tmax were 52.0, 77.3 and 85.6 min. Compared to liquid meal, gastric emptying for gelatinized meals was significantly delayed. The mean value of AUC-Tmax were 22.7, 28.7 and 33.7%dose, respectively, and no significant differences in absorption were seen. No significant differences existed in blood glucose, gastrin and insulin. CONCLUSIONS: Gelatinization of liquid meal delays gastric emptying. Gelatinized liquid meal may be useful for the management of diarrhea accompanied with enteral nutrition without influencing gastrointestinal hormone and blood glucose. PMID- 27942289 TI - Increased Expression of Matrix Metalloproteinase-1 and 3 in Remission Patients of Steroid-Dependent Ulcerative Colitis. AB - BACKGROUND: This study was to investigate the pathological significance of protein expression of matrix metalloproteinase-1 (MMP1) and matrix metalloproteinase-3 (MMP3) in colon tissues of remission patients of steroid dependent uncreative colitis (SDUC). METHODS: To test the possible involvement of MMP-1 and MMP-3 in SDUC, Western- blot and immunohistochemistry were applied to examine the protein expression of MMP-1 and MMP-3 in the colonic healing region from 10 remission patients with SDUC as well as from 10 remission patients with non-SDUC. Ten specimens from normal colon tissues were used as controls. RESULTS: Compared with the control group, the protein expression of MMP-1 and MMP-3 from non-SDUC remission patients slightly increased (p > 0.05), in contrast, those from SDUC patients significantly increased (p < 0.01). CONCLUSIONS: Over expression of MMP-1 and MMP-3 play a critical role in the pathogenesis of SDUC. PMID- 27942288 TI - Thrombophilic Risk Factors in Patients With Inflammatory Bowel Disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) patients have an increased risk for thromboembolism. The aim of this study was to assess the presence of thrombophilic risk factors in IBD patients and to assess the associations of these factors with disease activity. METHODS: Forty-eight patients with IBD (24 ulcerative colitis, 24 Crohn's disease) and 40 matched healthy control individuals were enrolled. In addition to routine biochemical analysis, fasting blood samples were studied for prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, protein-C, protein-S, antithrombin III, factor VII, factor VIII, D-dimer, vitamin B12, folic acid and homocysteine. RESULTS: Levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, D-dimer and the number of platelets were significantly higher in patients with IBD. When compared to control group, in patients with Crohn's disease serum homocystein levels were significantly higher (p = 0.025) while serum folic acid levels were significantly lower (p < 0.019). Levels of fibrinogen, D-dimer, protein C, factor VIII, total homocystein and the number of platelets were found to be significantly higher in Crohn's disease patients who were in active period of the disease. CONCLUSIONS: Thrombophilic defects are multifactorial and might be frequently seen in IBD patients. They might contribute to thrombotic complications of this disease. PMID- 27942290 TI - Recombinant Human Epidermal Growth Factor Alleviates Gastric Antral Ulcer Induced by Naproxen: A Non-steroidal Anti Inflammatory Drug. AB - BACKGROUND: To study the effect (s) of recombinant human Epidermal Growth Factor (rhEGF) on naproxen induced gastric ulcer in Wistar NIN rats. METHODS: Male Wistar NIN rats were randomly divided into six experimental groups: Group I - Control, Group II - Naproxen treated, Group III - Naproxen with rhEGF/7 days, Group IV - Naproxen without rhEGF/7 days, Group V - Naproxen with rhEGF/14 days, and Group VI - Naproxen without rhEGF/14 days. Gastric ulcer was induced with naproxen at a concentration of 80 mg/kg by oral administration. After 24 hours of induction of ulcer, rhEGF treatment was started at a concentration of 100 ug/kg. Ulcer presence and healing were confirmed by histopathology study and molecular markers. RESULTS: Naproxen per se induced gastric antral ulcers in Wistar NIN rats. Compared with control rats, naproxen induced rats had increased lipid peroxide content in serum. Subsequent decrease in lipid peroxide was observed in rhEGF treated groups. Treatment with rhEGF significantly resulted in healing of the ulcers, which was evident by 7 days of rhEGF treatment with total healing seen by 14 days. Significant increase in immunoreactivity for Cox-2 was observed when compared to control groups, whereas less immunoreactivity of Cox-2 was observed in rhEGF treated group. Compared with control group, naproxen induced group exhibited more gene expression of both Cox-2 and TGF beta while gene expression of Cox-2 and TGF beta in rhEGF group was comparable to control group. CONCLUSIONS: The beneficial effects of rhEGF in the management of ulcer healing can be understood. Oral rhEGF can promote healing of the rats with gastric ulcer by stimulating Cox-2 and TGF-beta expression. PMID- 27942291 TI - Actinomycosis of the Pancreas: A Case Report and Review. AB - Actinomyces is a normal commensal of the upper aerodigestive tract, colon and female reproductive tract. It can give rise to invasive disease in case of any breach in mucosal integrity, as well as, in patients with immunosuppression. Rarely, actinomycosis can involve the pancreas especially after episodes of pancreatitis or in post operative patients. We observed a case of actinomycosis affecting recurrent intraductal papillary mucinous neoplasm (IPMN) of pancreatic remnant, 5 years after a Whipple's procedure. Our patient, a 66 years old male with a history of Whipple's procedure for IPMN of pancreatic uncinate process, presented with repeated episodes of acute pancreatitis. Repeated radiological investigations (CT, MRI and EUS) revealed resolving pancreatitis with recurrent IPMN of the pancreatic tail. The patient underwent laparobotic assisted resection of the remnant pancreas and spleen 3 months later. Intraoperatively, in addition to the recurrent IPMN of pancreatic tail, we found a dense peripancreatic desmoplastic reaction with areas of thick yellow pus pockets in the remnant pancreatic body. Bacteriology and histopathology revealed it as a recurrent IPMN associated with actinomycosis of pancreas with chronic xanthogranulomatous changes. We conclude that actinomycosis of the pancreas is a rare entity with only 5 cases reported in English literature to the best of our knowledge. If diagnosed preoperatively, early institution of antibiotics can improve the surgical outcome. Fortunately, after diagnosis, we were able to start antibiotics in early postoperative period with successful outcome. PMID- 27942292 TI - Follicular Dendritic Cell Tumor in Liver: A Case Report and Collective Review. AB - Follicular dendritic cells (FDC) are a subset of the immune system and present in the germinal centers of lymphoid follicles in the spleen and lymph nodes. They are functionally as antigen-presenting cells and thus improving the quality of the humoral immune response. Follicular dendritic cell tumor is rare but considered low-grade sarcoma. Including our case, there were totally 17 cases with FDC tumor involved the liver from Medline. In these cases, the mean age was 47 years old, ranged from 19 to 82. It was much more common in females than in males (13:4). The clinical manifestations of these patients included abdominal discomfort, palpable mass, weight loss and malaise. The average size of the tumor was 11 cm. Most of the FDC tumors were associated with Epstein-Barr virus expression, 13/17 (76.5%). Surgical resection remains the mainstay of the treatment. PMID- 27942293 TI - Subcapsular Liver Hematoma in HELLP Syndrome: Case Report. AB - Subcapsular liver hematoma, as a rare complication of HELLP syndrome, must be managed in a tertiary center for prompt recognition and treatment with close monitoring of hemodynamic and coagulation parameters, treatment of underlying disorders, and assessment by the imaging techniques. These patients underwent different therapeutic options varying from conservative therapy to operative management, including liver transplantation. As a choice of treatment, patients with HELLP syndrome can be followed up conservatively in stable hemodynamic conditions. In this report, we presented a 32-year-old woman with subcapsular liver hematoma secondary to HELLP syndrome managed conservatively. PMID- 27942294 TI - Spontaneous Perforation of the Colon and Hypothyroidism: Report of a Case and Review of Literature. AB - Spontaneous perforation of the colon is a well documented but rare clinical entity commonly found to occur in the elderly and associated with chronic constipation. Hypothyroidism is known to be associated with intestinal motility disorders ranging from chronic constipation to more serious conditions like mega colon and pseudo obstruction. The case described here is that of a 35 years old hypothyroid male who presented with perforation peritonitis due to spontaneous perforation of the rectosigmoid. A thorough search of literature shows only one report of spontaneous perforation of the colon associated with hypothyroidism, to date. This case gives an opportunity to review the literature and discuss such unusual and dangerous presentations of hypothyroidism associated colonic motility disorders. PMID- 27942295 TI - Effect of Traditional Japanese Medicine, Daikenchuto (TJ-100) in Patients With Chronic Constipation. AB - BACKGROUND: This study was to compare the effect of a stimulant laxative alone and in combination with traditional Japanese medicine Daikenchuto (TJ-100) in improving stool frequency and in alleviating bloating and abdominal pain in patients with chronic constipation. METHODS: Twenty-two patients with chronic constipation who required sennoside (24 - 60 mg daily) were allocated to two groups for treatment with 7.5 g /day (N = 14) or with 15 g/day (N = 8) of TJ-100. The study period was 12 weeks and consisted of 4 weeks (pretreatment phase) before the administration of TJ-100, 6 weeks (treatment phase) for the administration of TJ-100, and 2 weeks (washout period) after cessation of TJ-100. The bowel movement frequency and the dose of sennoside required were recorded during the study period. Bloating and abdominal pain and gastrointestinal symptoms rating scale were evaluated at 0, 4, 6, and 8 weeks. The gas volume score was measured at 0 week and 6 weeks. RESULTS: The addition of TJ-100 to sennoside resulted in significant improvement in bloating (P < 0.01) and abdominal pain (P < 0.05). Its effects for abdominal pain were dose-dependent. There was no significant change in frequency of bowel movements or the dose of sennoside used. The gas volume score was significantly decreased after the addition of TJ-100 (P < 0.05). CONCLUSIONS: The addition of a traditional Japanese medicine, TJ-100, reduced bloating and abdominal pain in patients with chronic constipation receiving stimulant laxatives, possibly by decreasing the bowel gas volume. PMID- 27942296 TI - Esophageal Contractions After Wet and Dry Swallows in Patients With Esophagitis, Chagas' Disease and Idiopathic Achalasia. AB - BACKGROUND: In normal subjects the distal esophageal response to dry swallows differs from that of wet swallows. Our aim in this investigation was to compare the esophageal contractions of the proximal and distal esophageal body to wet and dry swallows. METHODS: We studied the esophageal contractions of eight patients with idiopathic achalasia, 37 patients with Chagas' disease, 28 patients with esophagitis, and 31 normal volunteers using manometric examination with continuous perfusion. The esophageal contractions were measured at 2 cm (proximal) and 22 cm (distal) from the upper esophageal sphincter. Five swallows of a 5 ml bolus of water alternated with 5 dry swallows were performed. RESULTS: In the proximal esophagus there was no difference between wet and dry swallows. In patients with esophagitis and volunteers the contractions in the distal esophagus had greater amplitude with wet swallows than with dry swallows. Contraction amplitude was lower than the amplitude of the other groups, in both the proximal and distal esophageal body in achalasia, and in distal esophageal body in Chagas' disease. The interval between the upstroke of contractions in the proximal and distal esophageal body was longer in volunteers and patients with esophagitis than in patients with Chagas' disease and achalasia. CONCLUSIONS: Wet swallows cause higher amplitude of contraction in distal esophagus than dry swallows, which is not seen in diseases with impairment of esophageal innervation (achalasia and Chagas' disease). In the proximal esophagus there is no difference in contractions caused by wet or dry swallows. PMID- 27942297 TI - Quality of Life and Symptomatology Before and After Nissen Fundoplication. AB - BACKGROUND: Post surgical quality of life (QOL) plays an important role in the decision making process for patients. This study evaluated the subjective opinion of those that underwent Nissen fundoplication to correct their symptoms of hiatus hernia. This study was to evaluate the quality of life and symptomatology before and after in those patients that underwent Nissen fundoplication over an 8-year period. METHODS: A questionnaire that graded the severity of symptoms and quality of life pre- and post-operatively was sent out to those patients that had undergone Nissen fundoplication. RESULTS: After the operation the symptoms of heartburn, regurgitation, burping and difficulty lying down were markedly decreased (P < 0.0001). There was however an increased incidence of flatulence associated with the procedure (P < 0.0001). Despite this the quality of life was significantly increased in those that underwent Nissen fundoplication (P < 0.0001). CONCLUSIONS: Nissen Fundoplication has a positive impact on quality of life and is effective in reducing symptoms of heartburn, regurgitation, burping and difficulty lying down associated with a hiatus hernia. There is however an increase in the incidence of flatulence associated with the procedure. In spite of this, 94% of patients would recommend the procedure to someone else. PMID- 27942298 TI - Platelet Function and Other Indices of Hemostasis in Chronic Liver Disease. AB - BACKGROUND: Bleeding time has been used for a long time as a global test of platelet function. Due to a number of pitfalls the test has been losing popularity. This study was designed to determine the prevalence of prolonged bleeding time in Nigerians with chronic liver disease in relation to other indices of hemostasis. METHODS: Bleeding time, platelet count, prothrombin time (PT) and activated partial thromboplastin time (aPTT) were determined in patients with chronic liver disease seen over a twenty-eight-month period. Liver disease severity was graded using Child's score. RESULTS: Only 14 of 164 (8.5%) patients with chronic liver disease had prolonged bleeding time while 60 patients (36.6%) had significantly prolonged PT. Thirty seven patients (22.6%) had prolonged aPTT. Bleeding time showed positive correlation with PT and aPTT but negative correlation with platelet count. CONCLUSIONS: Bleeding time is not sensitive in detecting disorders of hemostasis in patients with chronic liver disease although it correlates significantly with other indices of hemostasis. PMID- 27942299 TI - Uncommon Cause of Acute Drug-induced Liver Injury Following Mammoplasty. AB - Cephalexin is a well tolerated antimicrobial and hepatic injury is an infrequent occurrence with its use. We here describe a 21-year-old female who presented with jaundice and elevated liver enzymes after 4 weeks completion of 10 day course of cephalexin, prescribed prophylactically after mammoplasty. Extensive work up including all causes of hepatitis was within normal limits and she improved with conservative management. This case highlights the need to suspect drug induced liver injury in cases of jaundice and cephalexin use. PMID- 27942300 TI - Dermatophilus Congolensis Infection of the Esophagus. AB - We report the first case of Dermatophilus congolensis infection of the human esophagus. We demonstrate initial endoscopic diagnosis, progression and then spontaneous resolution of D. congolensis infection, once the patient's occupational exposure had ceased. PMID- 27942301 TI - Concomitant Rupture of Hydatid Cyst of Liver in Hepatic Duct and Gallbladder: Case Report. AB - Hydatid cyst liver rupture into the biliary tree may involve the common hepatic duct, lobar biliary branches, the small intrahepatic bile ducts or rarely the gallbladder. Rupture can be occult or frank. A frank intrabiliary rupture of hepatic hydatid cyst is a rare but serious event. The authors are reporting a case of concomitant rupture of hydatid cyst of liver into right hepatic duct and the gallbladder. A 50-year-old female patient who presented with acute cholangitis was confirmed as a case of intrabilary rupture on ultrasonography, endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography. Rupture of hydatid cyst of liver in right hepatic and the gallbladder was confirmed on surgery. Suture repair of cystobiliary fistula, choledochoduodenostomy with cholecystectomy was done. PMID- 27942302 TI - Primary Small Cell Carcinoma of Liver: A Rare Tumor. AB - Primary small cell carcinoma of the liver is very rare tumor. Till date only 12 cases have been reported in the English literature. We are reporting a case of primary small cell carcinoma of the liver in a female patient. She had 13 cm x 7 cm tumor in the right lobe of liver and fine needle aspiration cytology revealed features of small cell carcinoma. After ruling primary from elsewhere, patient underwent central bisectionectomy of the liver and histopathology confirmed the diagnosis of primary small cell carcinoma of the liver. On immunohistochemistry examination, the tumor was positive for Neuron-specific enolase and synaptophysin but negative for Thyroid transcription factor 1 and Hep-Par 1. Here we discuss the clinical course and treatment of primary small cell carcinoma of the liver in our case and review the literature. PMID- 27942304 TI - Swallowing Evaluation in Patients With Unilateral Vocal Fold Immobility. AB - BACKGROUND: Unilateral vocal fold immobility is the neurological disorder most frequently seen in the larynx that may cause swallowing dysfunction. The objective of this investigation was to evaluate the oral and pharyngeal phases of swallowing in patients with unilateral vocal fold immobility. METHODS: It was evaluated by videofluoroscopy of the swallowing of 14 patients with unilateral vocal fold immobility and 11 control subjects. The examination was performed with swallows of 5 mL and 10 mL of liquid and paste boluses. The oral transit, pharyngeal transit and clearance, the duration of upper esophageal sphincter (UES) transit, the duration of the hyoid movement, and the timing of the events were measured. RESULTS: With swallows of 10 mL of liquid bolus (controls: 0.23 +/ 0.04s, patients: 0.27 +/- 0.05s, p = 0.03) and 5 mL of paste bolus (controls: 0.18 +/- 0.04s, patients: 0.22 +/- 0.04s, p = 0.01) there was a longer duration of UES transit in patients compared with controls. The UES opened earlier in the control subjects with the increase in bolus volume from 5 mL to 10 mL (p < 0.05), an effect that was not seen in patients with vocal fold immobility. CONCLUSIONS: We conclude that patients with unilateral vocal fold immobility may have alteration of bolus transit through the UES and have no adaptation in the swallowing timing related to the increase in bolus volume. PMID- 27942303 TI - Management of Esophageal Perforation in Adults. AB - Perforation of esophagus in the adult is a very morbid condition with high morbidity and mortality. The ideal treatment is controversial. The main causes for esophageal perforation in adults are iatrogenic, traumatic, spontaneous and foreign bodies. The morbidity and mortality rate is directly related to the delay in diagnosis and initiation of optimum treatment. The reported mortality from treated esophageal perforation is 10% to 25%, when therapy is initiated within 24 hours of perforation, but it could rise up to 40% to 60% when the treatment is delayed beyond 48 hours. Primary closure of the perforation site and wide drainage of the mediastinum is recommended if perforation is detected in less than 24 hours. Treatment option for delayed or missed rupture of esophagus is not very clear and is controversial. Recently a substantial number of patients with esophageal perforation are being managed by nonoperative measures. Patients with small perforations and minimal extraesophageal involvement may be better managed by nonoperative treatment Major prognostic factors determining mortality are the etiology and site of the injury, the presence of underlying esophageal pathology, the delay in diagnosis and the method of treatment. For optimum outcome for management of esophageal perforations in adults a multidisciplinary approach is needed. PMID- 27942305 TI - Compound Pollen Protein Nutrient Increases Serum Albumin in Cirrhotic Rats. AB - BACKGROUND: Malnutrition, especially protein-calorie malnutrition, is common in patients with liver cirrhosis. When in the status of malnutrition, the complications increase, liver function deteriorates, and the prognosis of patients with liver cirrhosis worsens. Hence, nutritional support and treatment is essential in patients with liver cirrhosis. Previous studies suggested that compound nutrition based on pollen can improve liver function, and can be a basic nutrient for patients with liver cirrhosis. However, the nutritional support based on pollen for malnutrition of cirrhotic patients needs to be further evaluated. In this study, we investigated the nutritional support of Noveliver, a new compound pollen protein nutrient, in the cirrhotic rats induced by carbon tetrachloride (CCl4). METHODS: The cirrhotic rats induced by CCl4 were treated with Noveliver in different doses, and treated with a regular compound pollen nutrient, untreated cirrhotic rats and normal rats were used as controls. Serum albumin were measured before and after the nutritional treatment in each group. At the same time, liver function, cytokines and pathological changes were also determined. RESULTS: In the second week of nutritional treatment, the levels of serum albumin in normal control group, low dose noveliver group, high dose noveliver group, compound protein pollen group and spontaneous recovery group were 35.67 +/- 1.42, 33.07 +/- 1.27, 32.27 +/- 1.50, 30.53 +/- 0.25, 24.53 +/- 3.56 (g/L), respectively, the differences among the groups were significant (F = 14.007, P = 0.000); The levels of serum albumin in low dose Noveliver group, high dose Noveliver group and the compound protein pollen group were higher than that in the spontaneous recovery group (P = 0.000, 0.001, 0.003, respectively). In the second week of nutritional treatment, the serum levels of HGF in normal control group, low dose Noveliver group, high dose Noveliver group, compound protein pollen group and spontaneous recovery group were 101.55 +/- 0.87, 94.62 +/- 8.80, 98.94 +/- 3.68, 78.77 +/- 21.79, 39.52 +/- 14.03 (pg/ml), respectively, the differences among the groups were significant (F = 11.12, P = 0.002); the levels of HGF in low dose Noveliver group, high dose Noveliver group and the compound protein pollen group were higher than that in spontaneous recovery group (P = 0.001, 0.000, 0.005). Histological results showed that the fibrosis in spontaneous recovery group was severer than those in low dose Noveliver group, high dose Noveliver group and compound protein pollen group. CONCLUSIONS: Our data show that the both the Noveliver and the compound pollen protein nutrient increase the serum albumin and ameliorate malnutrition in cirrhotic rats; the recovery of serum albumin might be related to the hepatic damage repair and liver regeneration. PMID- 27942307 TI - Small Bowel Obstruction Caused by Carcinoid Tumor and Incidental Capsule Retention. AB - Capsule endoscopy (CE) is a sensitive modality for examining the small bowel and is commonly employed to identify a variety of small bowel pathologies. We report a case of capsule retention leading to diagnosis of a chronic condition. A 60 year-old female presented with abdominal pain, nausea, and weight loss for 3 years. Physical exam revealed a mildly tender abdomen with hypoactive bowel sounds. Laboratory was normal. Abdominal radiographs showed a partial small bowel obstruction with retained capsule. Abdominal computed tomography (CT) demonstrated a retained capsule in the mid-portion of the jejunum, dilated small bowel, and terminal ileal mass. She underwent exploratory laparotomy showing an ileal mass with hepatic metastasis. A right hemicolectomy, reanastomosis, and removal of the retained capsule were performed. Pathology showed well differentiated carcinoid tumor. She was discharged home for further treatment with oncology. Carcinoid tumors of the small bowel usually present with abdominal pain or small bowel obstruction. Our patient had intermittent small bowel obstruction due to a carcinoid tumor and retained capsule causing her symptoms. CE is a valuable tool but requires extensive consideration and possible patency capsule prior to use in patients presenting with symptoms consistent with Crohn's disease or small bowel tumor. PMID- 27942308 TI - Gastric Schwannoma Presenting as an Incidentaloma on CT-Scan and MRI. AB - A 67 year old female was referred because of an incidentaloma on CT-scan and MRI which showed a 5.0 cm large mass in the wall of the distal stomach. After an initial work-up which suggested a gastrointestinal stromal tumor (GIST), a partial gastrectomy with a Billroth II gastrojejunostomy was performed. The histological diagnosis was a schwannoma. Gastric schwannomas are rare tumors which comprise 0.2% of all gastric tumors and 4% of all benign gastric neoplasms with a peak of incidence in the 4th and 5th decade of life. Gastric schwannomas are usually asymptomatic, but can present with ulceration and/or gastrointestinal bleeding. Clinical, endoscopical, surgical, radiological and histological features of this case are described and the relevant literature is reviewed. PMID- 27942306 TI - Clinical Benefits of Biochemical Markers of Fibrosis in Egyptian Children With Chronic Liver Diseases. AB - BACKGROUND: The need for repetition of liver biopsy, especially in assessing the degree of fibrosis and follow-up of treatment protocols, justifies an intensive search for non-invasive alternatives. We attempted to investigate the clinical usefulness of serum fibrogenesis markers in pediatric chronic liver diseases. METHODS: We measured serum levels of TGF-beta1, collagen IV, laminin, MMP-2 and EGF-R, in 50 children with chronic liver disease (HBV, HCV and Bilharziasis) and 30 healthy controls, and determined their relationship to frequently used liver function tests and liver biopsy findings in patients. RESULTS: TGF-beta1, collagen IV, laminin and MMP-2, but not EGF-R, were significantly higher in patients than in controls (P < 0.01). None of these markers correlated with the histological fibrosis stage, whereas laminin correlated with necroinflammatory activity (P < 0.01). TGF-beta1, collagen IV, laminin and MMP-2 had the ability to discriminate patients with significant fibrosis, while only collagen IV and laminin were able to discriminate those with cirrhosis. Among these markers, collagen IV had the best predictive accuracy for significant fibrosis (AUROC 0.94; PPV 91.5%) and cirrhosis (AUROC 0.85; PPV 80%). CONCLUSIONS: In conclusion, these markers may be useful in reducing but not replacing the need for liver biopsy in the monitoring of disease progression and treatment effectiveness and might be an inseparable part of assessment of chronic hepatopathies. PMID- 27942310 TI - Wilson's Disease and Ulcerative Colitis in the Same Patient: Just A Coincidence? A Case Report and Literature Review. AB - Ulcerative Colitis (UC) is a chronic relapsing inflammatory bowel disease (IBD). Wilson's disease (WD) is a disorder of copper (Cu) metabolism due to inherited mutations in a gene encoding a putative Cu-transporting P-type ATPase, with a heterogeneous clinical presentation that includes hepatic, neurological, or psychiatric symptoms. The case of a 17-year-old female that presented with severe liver failure, three years after UC onset, and in which diagnosis of WD was established is reported. We review the literature and discuss the possible association between the two rare diseases. Although evidence of a common genetic background between UC and WD has not been described, high Cu serum level is present in both diseases. Cu is one of the trace elements necessary for antioxidant defenses during inflammatory processes, affecting the production of free radicals of oxygen and the levels of cellular antioxidants. The presence of both entities in the same patient may suggest abnormal metabolism of Cu or be just a coincidence. PMID- 27942309 TI - A Case of Isolated Duodenal Varices Secondary to Chronic Pancreatitis with Review of Literature. AB - An unusual case of upper gastrointestinal hemorrhage due to an isolated varix involving the 2nd part of the duodenum is presented here. The varix was the result of Chronic Pancreatitis induced the superior mesenteric vein obstruction. The diagnosis was made preoperatively by upper gastrointestinal endoscopy and selective mesenteric angiogram. Patient was treated successfully with Mesocaval shunt surgery between the superior mesenteric vein and the inferior vena cava using a 10 mm Dacron graft. This is the unique case showing hemorrhagic complication of Chronic Pancreatitis due to the superior mesenteric vein obstruction. PMID- 27942311 TI - Duodenal Lipoma as a Rare Cause of Upper Gastrointestinal Bleeding. AB - A 52-year-old female was referred because of melaena. After initital work-up, including gastroduodenoscopy, endosonography and CT scan, a duodenotomy was performed. Definite diagnosis was a duodenal lipoma based on histological findings. Lipomas of the gastrointestinal tract are rare. Only 4% occur in the duodenum. The peak incidence is around the 5th and 7th decade of life, with a slight female preponderance. Gastrointestinal lipomas are usually asymptomatic, but can present with mild to severe gastrointestinal bleeding, intussusceptions, abdominal pain, constipation and diarrhea. Clinical, endoscopical, surgical, and radiological features are described in this case of duodenal lipoma. PMID- 27942312 TI - Hepatic Epithelioid Angiomyolipoma: Case Series. AB - Hepatic epithelioid angiomyolipoma (AML) is a rare, benign, mesenchymal neoplasm found in both males and females, and most commonly encountered in adult females. These lesions are difficult to diagnose by imaging, especially when fatty component is scant or absent. Histomorphologically, they resemble hepatocellular carcinoma. The tumor cells are strongly positive for homatropine methylbromide-45 (HMB-45) and smooth muscle actin by immunohistochemistry, which are the key markers for accurate pathological diagnosis. Hepatic AML should be considered in the differential diagnosis of a well circumscribed hepatic mass, even in the absence of an adipose tissue component. PMID- 27942313 TI - Implications of Serum 25-Hydroxyvitamin D on the Prevalence of Neoplastic Polyps: A Cross-Sectional Study. AB - BACKGROUND: Vitamin D is believed to help in the suppression of malignant cells. Epidemiologic studies suggest that there is an association between vitamin D deficiency and an increased risk of colorectal cancer. The primary aim of this study is to determine if the prevalence of neoplastic polyps is inversely related to serum 25-hydroxyvitamin D levels 25(OH)D. METHODS: A prevalence study conducted between April 2009 and October 2009 evaluated 651 patients undergoing colonoscopy in order to determine if an association existed between low 25(OH)D levels and the prevalence of neoplastic colon polyps. Multivariate logistic and linear regression analyses were used to establish an association between 25(OH)D levels and histology of colon polyp with gender, race, age and BMI. RESULTS: The presence of tubular adenoma, villous adenoma, tubulo-villous adenoma, or malignancies did not differ (P = 0.5) among the stratified 25(OH)D groups (10 ng, 10.1 - 30 ng, > 30 ng). In addition, despite having more African-Americans than Caucasians in the lowest 25(OH)D category (22.7% versus 7.7%), the presence of neoplastic polyps did not differ significantly (P = 0.8) between the categorized racial groups (Caucasian and African-Americans). CONCLUSIONS: Low plasma 25(OH)D levels are not associated with an increased prevalence of neoplastic polyps. PMID- 27942314 TI - Esophageal Dysmotility in Chronic Hemodialysis Patients After Ingestion of Liquids With Different Viscosities. AB - BACKGROUND: Previous studies assessing esophageal motility in chronic renal failure (CRF) patients had no consistency in their findings. These studies evaluated esophageal contractility in response to dry/water swallows. Our aim was to reassess esophageal motility in CRF patients to better define its abnormalities. To unmask minor defects not seen in conventional dry/water manometry we also evaluated esophageal contractility in response to a highly viscous substance. METHODS: Fifteen controls and nine asymptomatic CRF patients underwent esophageal manometry with dry swallows, swallows of 5 mL of water (1 centipoise) and 5 mL of sugar cane syrup (24500 centipoise). CRF patients were compared with controls for esophageal motility parameters, considering each type of swallow (dry/water/syrup). RESULTS: CRF patients had: tendency for higher lower esophageal sphincter (LES) resting pressure (P = 0.09); shorter LES relaxation duration after dry/water/syrup swallows (P = 0.0001, P < 0.0001, P = 0.0001, respectively); higher amplitude of proximal contractions after dry/water/syrup swallows (P = 0.008, P = 0.01, P = 0.04); tendency for longer duration of distal contractions after dry/water/syrup swallows (P = 0.07, P = 0.04, P = 0.09); lower velocity of distal contractions after dry/water/syrup swallows (P = 0.006, P = 0.09, P = 0.02); and higher incidence of multi-peaked contractions after dry/water/syrup swallows (P = 0.03, P = 0.0001, P < 0.0001). CONCLUSIONS: Esophageal motility dysfunction can be a sub-clinical manifestation in CRF patients. Data also showed that swallows of a highly viscous liquid did not help to detect minor esophageal dysmotility in these patients. PMID- 27942315 TI - Clinical Significance of Isolated Peri-Appendiceal Lesions in Patients With Left Sided Ulcerative Colitis. AB - BACKGROUND: Ulcerative colitis is classically described as a condition originating in the rectum and extending proximally towards the cecum. In recent years, a discontinuous peri-appendiceal lesion has been described. Our aim was to evaluate the risk of progression to pancolitis in patients presenting with an isolated peri-appendiceal lesion on ileocolonoscopy. METHODS: Endoscopy databases at three tertiary care centers were searched for patients undergoing ileocolonoscopy for diagnosis or surveillance of ulcerative colitis. Patients with isolated periappendiceal lesions as well as histologically confirmed left sided colitis were enrolled. Controls were defined as patients with left-sided ulcerative colitis without evidence of peri-appendiceal inflammation. The main outcome was the need for escalation of therapy to systemic corticosteroids, immunomodulators or biologic agents. Secondary outcomes were progression to pancolitis or requirement for colectomy. A secondary analysis of other risk factors for proximal extension/progression of colitis was also performed. RESULTS: We identified 228 patients with ulcerative colitis, 123 were included in the analysis. Four point eight percent of patients had isolated peri-appendiceal lesions. In the group with peri-appendiceal lesions, 47.4% required escalation of therapy vs. 70% in the control group (P = 0.53). There was no difference in progression to pan-colitis or colectomy rates between the two groups. Progression was not predicted by inflammatory markers, age, gender, initial Mayo UC score or IBD therapy utilization. CONCLUSIONS: The presence of isolated peri-appendiceal lesions is not a risk factor for future escalation of therapy for ulcerative colitis and is not correlated with proximal extension of disease. PMID- 27942316 TI - Invaginated Pancreaticojejunostomy via the Space Behind the Root of Superior Mesenteric Vessels. AB - BACKGROUND: This study was to explore a safe and effective procedure to prevent pancreatic fistula (PF) after pancreaticoduodenectomy (PD). METHODS: Forty-three modified PD with pancreaticojejunostomy by direct invagination of the pancreas to the jejunum that was brought up via the space behind the root of superior mesenteric vessel were performed between January 2003 and June 2006, and were compared to the fifty-six conventional PD (Child' method). RESULTS: There was no pancreatic fistula after PD in the modified group. Two cases developed biliary fistula that were successfully treated with complete drainage for 2 to 3 weeks; 2 cases abdominal infection managed with anti-infection and completely drainage; 4 cases stress ulcer cured with Losec and coagulant. Three cases in the Child group developed PF of different severities, with amylase level > 9000 U/L in the abdominal drainage fluid. Two of the PF were treated with Stilamin, parenteral nutrition, fasting and completely drainage and cured after 21 to 32 days. The other 82-year-old patient died. Other complications had no significant difference between the two groups (P > 0.05). CONCLUSIONS: The modified PD can effectively prevent PF and is a safe and effective procedure for periampullary neoplasm. Further studies of its clinical use are warranted. PMID- 27942317 TI - Alterations of Mast Cells in the Esophageal Mucosa of the Patients With Non Erosive Reflux Disease. AB - BACKGROUND: Mast cells (MCs) are widely distributed in the gastrointestinal tract, which could be involved in visceral hypersensitivity and gut dysmotility. Whether esophageal MCs play a role in non-erosive reflux disease (NERD) has yet to be determined. The aim of this study was to characterize esophageal MCs distribution, degranulation, and ultrastructure. METHODS: The esophageal mucosa at 5 cm above the end of esophagus was obtained from 26 NERD and 14 healthy volunteers (control) by gastroscopy. Immunohistochemistry was performed and average MC counts per high-power field (HPF) and the percentage of degranulated MCs were obtained. The ultrastructure of MCs was observed by transmission electron microscope (TEM). RESULTS: More MCs were observed in NERD (7.23 +/- 2.41 cells/HPF) as compared with controls (3.79 +/- 1.67 cells/HPF) (P < 0.01) and the percentage of degranulated MCs in NERD was also significantly higher than controls (26.85 +/- 8.79% vs 11.5 +/- 4.18%, P < 0.01). Under TEM, more Golgi apparatus, mitochondria and endoplasmic reticulum were found in MCs in patients with NERD. Special secreting particles were also found in cytoplasm, more vacuoles were left after MCs degranulation in patients with NERD. CONCLUSIONS: Our results indicate that increased numbers of MCs and MCs activation may be involved in the pathogenesis of NERD. PMID- 27942318 TI - Emphysematous Pyelonephritis Associated With Emphysematous Gastritis and Air in the Portal Vein. AB - Emphysematous gastritis with portal venous air is a rare condition usually caused by gas forming organisms. This may be secondary to local spread of an infection through the mucosa or rarely hematogenous dissemination from a distant focus. We present a young diabetic woman with uncontrolled diabetes mellitus who was admitted with sepsis and severe abdominal symptoms. Investigation revealed emphysematous pyelonephritis due to E. coli infection associated with emphysematous gastritis and air in the portal tract. She improved with broad spectrum antibiotics, fluid resuscitation and electrolyte and diabetic management. To our knowledge this is the first report showing the association between emphysematous pyelonephritis and gastritis with air in the portal system. PMID- 27942319 TI - Diagnosis and Treatment of Multiple Intestinal Angioectasias: A Case Report. AB - The diagnostic course and management of a severe anemia due to recurrent bleeding from colonic angioectasias have been described. A 63-year-old man with chronic heart and renal failure, hypertension and diabetes presented severe anemia requiring transfusion. Anemia recurred and did not recover despite intravenous iron, folate and B12 vitamin supplementation, associated with eritropoietin administration. A bleeding angiodysplasia was finally diagnosed and long-acting octreotide prescribed, obtaining increased hemoglobin levels in the time. PMID- 27942320 TI - Synchronous Esophageal Squamous Cell Carcinoma and Esophageal Variceal Bleeding due to Idiopathic Portal Hypertension: A Case Report. AB - Squamous cell carcinomas of esophagus are responsible for more than 80% of esophageal malignancies in Turkey. Idiopathic portal hypertension is a rare underlying cause of esophageal variceal bleeding. In such cases, detection of concomitant esophageal squamous cell cancer is also a rare occurrence. We report an unusual case of bleeding esophageal varices secondary to idiopathic portal hypertension associated with esophageal squamous cell cancer. To our knowledge, until now, there have been no reported cases of esophageal variceal bleeding due to idiopathic portal hypertension associated with esophageal squamous cell cancer. This case report demonstrates the two different conditions which may cause esophageal bleeding and there may be an association between idiopathic portal hypertension and esophageal squamous cell cancer. PMID- 27942321 TI - Hypertriglyceridemia Induced Pancreatitis in a Non-Diabetic Pregnant Patient Requiring the Use of Total Parenteral Nutrition. AB - Hypertriglyceridemia induced pancreatitis in pregnancy is established and has been widely reported. However there are very scanty reports of cases involving the use of total parenteral nutrition. We report the case of a 37-year-old gravida 3, para 2 woman at 34 weeks of gestation who presented with one day of severe epigastric pain radiating to the back, nausea and bilious vomiting caused by pancreatitis induced by hypertriglyceridemia. Her initial serum triglyceride, amylase and lipase concentration were 6,552 mg/dl, 314 U/L and 537 U/L respectively. She initially received intravenous fluids and insulin with reduction of serum triglyceride levels to 583 mg/dl on the fifth day of admission. However attempts to refeed the patient with solid food resulted in induction of hypertriglyceridemia and relapse of pancreatitis. Lipid free total parenteral nutrition was commenced in the third week of admission and lead to a better control of triglyciderides and resolution of pancreatitis until delivery of a full term healthy neonate. PMID- 27942322 TI - Fidaxomicin for the Treatment of Clostridium Difficile Infection in the Pediatric Population - Not Quite So Soon Yet. AB - Fidaxomicin is a new narrow spectrum macrocyclic antibiotic. It inhibits bacterial RNA polymerase and eradicates C difficile with minimal effect on normal intestinal flora. The US FDA granted orphan drug designation for all formulations of fidaxomicin for the treatment of C difficile infections in pediatric patients on January 10, 2011. Fidaxomicin has bactericidal activity against C difficile with a prolonged post-antibiotic effect. Even though this medication has an orphan designation for pediatrics, all the available pharmacokinetic and pharmacodynamic data were in subjects >= 18 years old. The MIC90 for fidaxomicin against C. difficile varies from 0.0078 to 0.25 mcg/ml. Fidaxomicin is poorly absorbed. The highest peak plasma concentration in patients treated with fidaxomicin was 0.191 mcg/ml. Fecal levels of fidaxomicin after oral administration are extremely high. The average fecal concentrations in C difficile patients were 255.6 mcg/g, 441.7 mcg/g, and 1443.3 mcg/g in the 100, 200, and 400 mg/day groups, respectively. At a dose of 400 mg/day the average fecal concentration was 5700 times higher than the highest MIC90 of fidaxomicin against C difficile. In a phase III clinical trial fidaxomicin 200 mg twice daily was compared with vancomycin 125 mg four times per day orally for 10 days. Only two patients were 18 years old, and no patients younger than 18 years old participated in the study. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin. Patients who were infected with non-North American Pulsed Field type 1 strains had fewer recurrences in the fidaxomicin group than patients in the vancomycin group. Side effects were similar between both therapies. Most patients experienced mild gastro-intestinal symptoms. Fidaxomicin is a good therapeutic alternative to vancomycin and metronidazole, especially in patients with recurrence of C difficile infection. Patients rarely experience systemic side effects which improves compliance. The dose of fidaxomicin is expected to be 200 mg given orally twice a day for patients 16 years and older. At this point, Optimer Pharmaceuticals Inc has conducted clinical trials in adults only. Additional clinical trials in pediatric patients are needed before therapeutic recommendations can be made in this population. PMID- 27942323 TI - Povidone-Iodine Irrigation of Subcutaneous Tissues May Decrease Surgical Site Infections in Elective Colorectal Operations: A Systematic Review. AB - BACKGROUND: Postoperative wound infection is the most common complication following abdominal surgery and leads to delayed wound healing, prolonged hospital length of stay (LOS), and causes morbidity. Povidone-Iodine (PVI) is a broad-spectrum anti-septic and disinfectant solution, and can be used intra operatively to irrigate subcutaneous tissues prior to abdominal skin closure. We systematically reviewed the literature regarding the efficacy of intra-operative PVI irrigation of subcutaneous tissues following elective colorectal surgery. METHODS: A comprehensive search of electronic databases and various grey literature sources was completed. Unpublished and non-English-language results were included. All clinical controlled trials involving PVI solution in adult colorectal surgery were included. Two independent reviewers assessed the studies for relevance, inclusion, methodological quality and extracted data from the full versions of the manuscripts. Disagreements were resolved by re-extraction or third party adjudication. Data for dichotomous outcomes are reported as relative risks (RR) with 95% confidence intervals (CI). For continuous data, mean differences (MD) are reported with 95% CIs. RESULTS: Five randomized controlled trials (RCTs) involving 205 patients comparing PVI solution or spray to a control group following abdominal fascial closure in elective colorectal or clean contaminated operations were identified. Pooled results demonstrated a reduction in surgical site infection for patients treated with PVI (RR = 1.97; 95% CI: 1.22 to 3.17) compared to controls. CONCLUSIONS: Irrigation of subcutaneous tissues with PVI following abdominal fascial closure is associated with a reduced incidence of surgical site infection. Due to the small number of included trials and patients, additional robust randomized trials are needed. PMID- 27942325 TI - Electron Microscopic Radioautographic Study on the Protein Synthesis in the Pancreas of Aging Mice With Special Reference to Mitochondria. AB - BACKGROUND: The purpose of this study was to investigate the aging changes of macromolecular synthesis in animal cells. METHODS: We studied 10 groups of mice during development aged from fetal day 19 to postnatal month 24. They were injected with 3H-leucine, a precursor for protein synthesis, sacrificed and the pancreatic tissues were taken out, fixed and processed for light and electron microscopic radioautography. On many radioautograms the localization of silver grains demonstrating protein synthesis in pancreatic acinar cells in respective aging groups were first analyzed qualitatively. Then the number of silver grains and the number of cell organelles in each cell in respective aging groups were analyzed quantitatively in relation to the aging of animals. The number of mitochondria, the number of labeled mitochondria and the mitochondrial labeling index labeled with silver grains were counted in each pancreatic acinar cell. RESULTS AND CONCLUSIONS: The number of silver grains in cell nuclei and cell organelles changed with the aging of animals. The number of mitochondria, the number of labeled mitochondria and the labeling indices showing protein synthesis at various ages increased from embryonic day 19 to postnatal newborn day 1, 3, 7, 14, to young adult month 1, and 2, reaching the maxima, then decreased at old adult month 6 and senile year 1 to 2, indicating the aging changes. PMID- 27942324 TI - Low Risk of Thromboembolic Complications After Fast-Track Abdominal Surgery With Thrombosis-Prophylaxis Only During Hospital Stay. AB - BACKGROUND: Subcutaneous low molecular weight heparin (LMWH) reduces the risk of thromboembolic complications after abdominal surgery. With enhanced recovery after surgery (ERAS), median hospital stay after abdominal surgery may be as short as 3 - 4 days. The aim of our study was to investigate whether thrombosis prophylaxis during the short hospital stay was sufficient to maintain a low frequency of thromboembolic complications. METHODS: Ninety-eight patients, median age 67 years, were enrolled in a prospective two-center observational study of colorectal resections following the ERAS principles. Seventy-seven patients (78.6%) were resected for colonic cancer, the rest for benign colonic diseases. Fifty percent of the patients were discharged from hospital within three days after surgery. Follow-up examinations took place at 8 and 30 days after surgery with clinical examination for thromboembolism. The patients enrolled at one of the centers were also scheduled for a routine venography at day 8. Seventeen of these were evaluated. RESULTS: Clinical follow-up at day 8 of 72 patients (73.5%) revealed no venous thromboembolism (VTE), and the 17 venograms did not show any thromboses. Clinical follow-up at day 30 of 74 patients (75.5%) showed no deep venous thrombosis (DVT), whereas pulmonary embolus (PE) was suspected and verified in one patient (1.3%) with pulmonary metastases and pneumonia. CONCLUSIONS: Prophylaxis until full mobilization seems to be sufficient following major surgery in patients treated with the principles of ERAS who remain in hospital for 3 - 4 days. PMID- 27942326 TI - Treatment of Liver Metastases From Colorectal Cancer: Medico-Surgical Strategies. AB - BACKGROUND: The management of hepatic metastases from colorectal cancer can be understood only as part of a multidisciplinary strategy. Progress experienced by medical treatment, surgical techniques and ways of imaging, has improved the prognosis of patients with liver metastases of colorectal cancers. This work displays the experience of Medical Oncology unit at the Military training hospital in Rabat. METHODS: From January 2007 to December 2009, 60 patients with liver metastases from colorectal cancer, synchronous or metachronous were supported in the Medical Oncology unit at the Military training hospital in Rabat. RESULTS: Liver metastases were synchronous in 41 (68%) patients and metachronous in 19 (32%). Patients were classified into 3 categories according to their resectability: 14 (22%) were resectable at the outset, 28 (47%) were unresectable and 18 (31%) were considered uncertain resectability. Thirty-five patients (58%) received neoadjuvant chemotherapy before surgical gesture, 25 (42%) received chemotherapy after resection of primary tumor. This chemotherapy enabled the resection of liver metastases in 5 patients initially deemed uncertain resectability. The average objective responses to chemotherapy were in the range of 59% with 4 complete responses and one confirmed histologically. Twenty-three patients (38%) underwent surgery including 15 liver resections with R0 (25%). The median progression-free survival in this series was 15.5 months. Some minor side effects were noted, which have not entered the prognosis of patients. CONCLUSIONS: Hepatic resection remains the only potentially curative treatment of liver metastases of colorectal cancers. Perioperative chemotherapy is a promising standard, which has improved the prognosis of patients historically associated with a poor prognosis. PMID- 27942327 TI - Multifocal Carcinoid Tumor of Small Intestine: A Rare Cause of Chronic Obscure Gastrointestinal Bleeding, Suspected on Capsule Endoscopy and Diagnosed on Double Balloon Enteroscopy. AB - We reported a case of multifocal carcinoid tumor of small intestine causing chronic obscure gastrointestinal bleeding, suspected on capsule endoscopy and diagnosed on double balloon enteroscopy. PMID- 27942328 TI - Hepatic Encephalopathy in Connection With Budd-Chiari Syndrome due to Infection With Echinococcus Multilocularis: A Case Report. AB - Budd-Chiari syndrome (BCS) is a hepatic venous outflow block generally resulting from disorders affecting hepatic venous system. Elevated hepatic venous pressure results in portal hypertension. BCS may also cause hepatic encephalopathy. Echinococcus multilocularis is a tapeworm parasite and the natural course of the disease may affect liver parenchyma as well as hepatic venous tree. It is the most terrible parasitic disease of the liver and is easily confused with hepatic malignancies. Albendazole therapy may suppress disease progression. Alveolar echinococcosis of the liver rarely causes Budd-Chiari syndrome-related hepatic encephalopathy (HE). We report a rare case of alveolar echinococcosis-related BCS with HE, who was successfully managed by rifaximin and albendazole. PMID- 27942329 TI - Small, Depressed-Type Early Colon Cancer Invading Shallow Submucosal Layer With Extensive Lymph Node Metastasis: A Case Report. AB - Early colorectal cancers are defined as invasive tumors that are limited to the mucosal layer or submucosal layer (SM), regardless of the presence or absence of lymph node (LN) metastasis. The reported incidence of LN metastasis of SM1 colon cancers is 0 - 5.9%, but the incidence in SM2 and SM3 colon cancers could be as high as 11.3 - 25.0%, and risk factors for LN metastasis include depth of SM invasion, growth patterns (polypoid or non-polypoid), histological sub classification (moderate or poor differentiation) and regional lymphatic and vascular invasion. Among colorectal cancers with non-polypoid growth, the malignant potential is higher for depressed, than polypoid types, even for small tumors. Herein, we describe a patient with small, depressed-type early colon cancer with extensive LN metastasis and superficial SM invasion (pSM 450 um). Six courses of chemotherapy with mFOLFOX6 and bevacizumab reduced the size of the LN metastases, thus eliciting a partial response (PR) according to the response evaluation criteria in solid tumors (RECIST). PMID- 27942330 TI - Diagnostic Yield of Microscopic Colitis in Open Access Endoscopy Center. AB - BACKGROUND: The diagnostic yield in open access endoscopy has been evaluated which generally support the effectiveness and efficiency of open access endoscopy. With a few exceptions, diagnostic yield studies have not been performed in open access endoscopy for more specific conditions. Therefore, we conducted a study to determine the efficiency of open access endoscopy in the detection of microscopic colitis as compared to traditional referral via a gastroenterologist. METHODS: A retrospective search of the pathology database at the University of Missouri for specimens from a local open access endoscopy center was conducted via SNOMED code using the terms: "microscopic", "lymphocytic", "collagenous", "spirochetosis", "focal active colitis", "melanosis coli" and "histopathologic" in the diagnosis line for the time period between January 1, 2004 and May 25, 2006. Specimens and colonoscopy reports were reviewed by a single pathologist. RESULTS: Of 266 consecutive patients with chronic diarrhea and normal colonoscopies, the number of patients with microscopic disease are as follows: Lymphocytic colitis (n = 12, 4.5%), collagenous colitis (n = 17, 6.4%), focal active colitis (n = 15, 5.6%), and spirochetosis (n = 2, 0.4%). CONCLUSIONS: The diagnostic yield of microscopic colitis in this study of an open access endoscopy center does not differ significantly from that seen in major medical centers. In terms of diagnostic yield, open access endoscopy appears to be as effective in diagnosing microscopic colitis. PMID- 27942331 TI - The Utility of Lighted Ureteral Stents in Laparoscopic Colorectal Resection: A Survey of Canadian Surgeons. AB - BACKGROUND: Establishing the exact location of the ureters is critical in preventing ureteric injury during colorectal surgery. In laparoscopic colorectal resections this identification can be facilitated by the pre-operative insertion of lighted ureteral stents (LUS). LUS may also serve as an invaluable educational aid during the teaching of colorectal surgery. However, the available evidence does not support the routine use of stents as an injury prevention measure. Furthermore, stent insertion carries inherent risks of ureteric injury. The objective of this study was to determine the frequency of use and indications for LUS in laparoscopic colorectal resections among Canadian surgeons. METHODS: A seven-question survey was administered to Canadian surgeons through the monthly Canadian Association of General Surgeons (CAGS) e-news over a period of three months. The questions focused on surgeon demographics, experience with laparoscopic colon resections and the use of stents. RESULTS: Seventy-five surgeons completed the survey. There was a wide range of experience among the surgeons in terms of years in practice. The majority (84%) reported performing laparoscopic colorectal resections and of those 65% reported performing less than 25 resections a year. Only 26% of surgeons used LUS during laparoscopic resections. Furthermore, 75% of LUS users did not have sub-specialty training, 69% performed less than 25 resections per year and 50% were in practice for less than five years. When used, LUS were inserted for diverticular disease (100%), left colon resection (88%) and low anterior resections (75%). CONCLUSION: The majority of surgeons across Canada do not use LUS for laparoscopic colorectal resections. Of those performing laparoscopic colorectal resections, there may be a preference to use LUS for complex cases and by novice operators. This data suggests that proponents of LUS deem that it may have a role in diverticular disease. PMID- 27942333 TI - Improving the Yield of Histological Sampling in Patients With Suspected Colorectal Cancer During Colonoscopy by Introducing a Colonoscopy Quality Assurance Program. AB - BACKGROUND: Masses discovered by clinical examination, imaging or endoscopic studies that are suspicious for malignancy typically require biopsy confirmation before treatment is initiated. Biopsy specimens may fail to yield a definitive diagnosis if the lesion is extensively ulcerated or otherwise necrotic and viable tumor tissue is not obtained on sampling. The diagnostic yield is improved when multiple biopsy samples (BSs) are taken. A colonoscopy quality-assurance program (CQAP) was instituted in 2003 in our institution. The aim of this study was to determine the effect of instituting a CQAP on the yield of histological sampling in patients with suspected colorectal cancer (CRC) during colonoscopy. METHOD: Initial assessment of colonoscopy practice was performed in 2003. A total of five patients with suspected CRC during colonoscopy were documented in 2003. BSs confirmed CRC in three (60%) patients and were nondiagnostic in two (40%). A quality-improvement process was instituted which required a minimum six BSs with adequate size of the samples from any suspected CRC during colonoscopy. A total of 37 patients for the period 2004-2010 were prospectively assessed. RESULTS: The diagnosis of CRC was confirmed with histological examination of BSs obtained during colonoscopy in 63% of patients in 2004, 60% in 2005, 50% in 2006, 67% in 2007, 100% in 2008, 67% in 2009 and 100% in 2010. The yield of histological sampling increased significantly (p<0.02) from 61% in 2004-2007 to 92% in 2008 2010. CONCLUSION: The implementation of a quality assurance and improvement program increased the yield of histological sampling in patients with suspected CRC during colonoscopy. PMID- 27942332 TI - Dietary Phytosterols Protective Against Peptic Ulceration. AB - BACKGROUND: In developing countries the prevalence of duodenal ulceration is related to the staple diet and not to the prevalence of Helicobacter pylori. Experiments using animal peptic ulcer models show that the lipid fraction in foods from the staple diets of low prevalence areas gives protection against ulceration, including ulceration due to non-steroidal anti-inflammatory drugs (NSAIDs), and also promotes healing of ulceration. The lipid from the pulse Dolichos biflorus (Horse gram) was highly active and used for further investigations. Further experiments showed the phospholipids, sterol esters and sterols present in Horse gram lipid were gastroprotective. Dietary phospholipids are known to be protective, but the nature of protective sterols in staple diets is not known. The present research investigates the nature of the protective phytosterols. METHODS: Sterol fractions were extracted from the lipid in Dolichos biflorus and tested for gastroprotection using the rat ethanol model. The fractions showing protective activity were isolated and identification of the components was investigated by Gas Chromatography-Mass Spectrometry (GC-MS). RESULTS: The protective phytosterol fraction was shown to consist of stigmasterol, beta-sitosterol and a third as yet unidentified sterol, isomeric with beta-sitosterol. CONCLUSIONS: Dietary changes, affecting the intake of protective phospholipids and phytosterols, may reduce the prevalence of duodenal ulceration in areas of high prevalence and may reduce the incidence of recurrent duodenal ulceration after healing and elimination of Helicobacter pylori infection. A combination of phospholipids and phytosterols, such as found in the lipid fraction of ulceroprotecive foods, may be of value in giving protection against the ulcerogenic effect of NSAIDs. PMID- 27942334 TI - Biotherapy in the Adjuvant Treatment of Colorectal Cancer. AB - The use of adjuvant chemotherapy has improved survival in early-stage colon cancer. Ongoing adjuvant clinical trials are evaluating the addition of targeted therapies to standard chemotherapy regimen. Preliminary results with bevacizumab were disappointing. Also, cetuximab added to chemotherapy does not seem to be better than chemotherapy alone, even in selected wild-type KRAS populations. A better understanding of mechanisms of action of drugs, tumor biology, and predictive biomarkers are needed to design future adjuvant trials. PMID- 27942335 TI - A Case of Hypereosinophilia-Associated Multiple Mass Lesions of Liver Showing Non Granulomatous Eosinophilic Hepatic Necrosis. AB - Hypereosinophilic syndrome (HES) is defined by elevation more than 1.5*109/L of presence of a peripheral blood count, evidence of organ involvement, and exclusion of secondary eosinophilia such as allergic, vasculitis, drugs, or parasite infection and also clonal eosinophilia. We present the HES case with hepatic involvement. The patient is 70-year-old male. He complained fever and back pain. Blood examination showed marked peripheral eosinophilia, elevation of transaminase and biliary enzymes. Multiple irregular mass lesions of the liver were pointed out by CT and MRI. The liver biopsy was done for differentiation from malignancy. In parenchyma, hepatic necrotic lesion was observed accompanying severe eosinophilic infiltration with Charcot-Leyden's crystals. There was granulomatous reaction. He was diagnosed as HES and got recovery due to steroid therapy. From the review of HES article, the hepatic histology is categorized into four types as below: 1) cholangitis type; 2) chronic active hepatitis type; 3) vasculopathic type, 4) hepatic necrosis type. Our case is classified in hepatic necrosis type. This type seems to be important to distinguish malignant tumor and also visceral larva migrans by liver biopsy. PMID- 27942336 TI - A Unique Case of Eosinophilic Pancreatitis and Anencephaly in the Fetus of a Type I Diabetic Mother. AB - Pancreatic infiltration with eosinophils is an uncommon finding with numerous etiologies. While two rare cases of eosinophilic pancreatitis in infants born to Type I diabetic mothers have been reported once in the English literature and once in the French literature, we present the additional finding of anencephaly in a 34 week old fetus. Although the pancreas was grossly unremarkable, histological inspection demonstrated an eosinophilic infiltrate in the fibrous septae and islets of Langerhans along with hypertrophy and hyperplasia of the pancreatic islets. PMID- 27942337 TI - Rectal Involvement of Recurrent Buschke-Lowenstein Tumor Causing Subileus: a Case Report. AB - We present a 48-year-old caucasian woman presenting with anal pain, discharge and difficulty in defecation due to recurrent Buschke-Lowenstein tumor with rectal involvement discuss it in the light of literature. A 48-year old caucasian woman was referred to our institute with anal mass causing pain, discharge and difficulty in defecation. She initially had simple excision and electrocoterisation 3 and 15 years before at different centers. At physical examination, multiple vegetative mass lesions presented as a cauliflower-like tumor were seen at perianal region. Colonoscopy showed an inflamated, vegetative mass covering all mucosa annularly and starting from 2 cm away from anal verge and reaching until 20 cm was seen. Due to the large extent of tumor invasion in this case, curative surgery would have been achieved only by wide local surgical excision and abdominoperineal resection due to rectal involvement. This severe mutilation was refused by the patient. Thus, patient was referred to medical oncology for radiochemotherapy. Wide radical excision of Buschke-Lowenstein tumor (BLT) is the preferred treatment for achieving local control, but excision alone often is ineffective treatment. Abdominoperineal resection is necessary in cases with infiltration involving the sphincter muscles or rectum, especialy for recurrent cases. PMID- 27942338 TI - Risk of Confusion: Detection of a Circular Thickness of the Wall in the Lower Part of the Esophagus. AB - We report a case of a woman with a gastrointestinal bleeding. An esophageal ulcer was detected in the endoscopy, however a histological malignancy could not be found. A computer tomography (CT) scan showed a thickness in the distal esophagus and enlarged lymph nodes, so a malignancy was highly suspected. However, the patient refused to follow the recommended clinical procedure of a surgical intervention. Four years later a carcinoma could be ruled out because of follow up examinations. PMID- 27942339 TI - The state and future of emergency medicine in Macedonia. AB - BACKGROUND: Macedonia has universal public health care coverage. Acute and emergency patient care is provided in different care environments based on the medical complaint and resource proximity. While emergency medicine and well organized emergency departments (EDs) are an essential component of any developed health care system, emergency medicine as a specialty is relatively non-existent in Macedonia. DATA RESOURCES: A system assessment regarding presence, availability and capacity of EDs was completed from 2013-2015, based upon assessments of 21 institutions providing emergency care and information provided by the Ministry of Health. This assessment establishes a benchmark from which to strategically identify, plan and implement the future of emergency medicine in Macedonia. RESULTS: In general, emergency departments - defined by offering acute care 24 hours per day, 7 days per week - were available at all general and university hospitals. However, care resources, emergency and acute care training, and patient care capacity vary greatly within the country. There is limited uniformity in acute care approach and methodology. Hospital EDs are not organized as separate divisions run by a head medical doctor, nor are they staffed by specialists trained in emergency medicine. The diagnostic and treatment capacities are insufficient or outdated by current international emergency medicine standards and frequently require patient transfer or admission prior to initiation. CONCLUSION: Most of the surveyed hospitals are capable of providing essential diagnostic tests, but very few are able to do so at the point or time of presentation. While emergency medical services (EMS) have improved system wide, emergent care interventions by EMS and within all hospitals remain limited. Further system-wide acute and emergency care improvements are forthcoming. PMID- 27942340 TI - Amiodaron in atrial fibrillation: post coronary artery bypass graft. AB - BACKGROUND: Atrial fibrilation (AF) is the most common complication following heart surgeries; it often occurs in patients after coronary artery bypass graft (CABG). The purpose of this review is to categorize prophylaxes or treatment by administration of Amiodaron in patients with CABG. DATA RESOURCES: We searched google scholar, pubmed, and Cochrane Library databases (the period 1970-2010) for articles on Amiodaron in CABG and cardiac surgery. A total of 1 561 articles were identified, and 30 articles met the criteria and were enrolled in this review. RESULTS: Most studies supported Amiodarone for prophylaxi purpose in patients who were performed with CABG; few papers supported Amiodaron as a drug for treating CABG. The prophylaxis can decrease the incidence rate of AF in CABG, but if it uses as a treatment, the side effect of Amiodaron will decrease because all of the patients will not get Amiodarone. In the other hand use of Amiodarone as a treatment does not influence the length of hospital stay significantly but these kinds of study are so few. CONCLUSION: No appropriate therapeutic method has been defined for AF. At present, the common way of treating AF following cardiac surgery is mainly based on prophylaxis in medical books and references. PMID- 27942341 TI - Short lessons in basic life support improve self-assurance in performing cardiopulmonary resuscitation. AB - BACKGROUND: There are several reasons why resuscitation measures may lead to inferior results: difficulties in team building, delayed realization of the emergency and interruption of chest compression. This study investigated the outcome of a new form of in-hospital cardiopulmonary resuscitation (CPR) training with special focus on changes in self-assurance of potential helpers when faced with emergency situations. METHODS: Following a 12-month period of CPR training, questionnaires were distributed to participants and non-participants. Those non participants who intended to undergo the training at a later date served as control group. RESULTS: The study showed that participants experienced a significant improvement in self-assurance, compared with their remembered self assurance before the training. Their self-assurance also was significantly greater than that of the control group of non-participants. CONCLUSION: Short lessons in CPR have an impact on the self-assurance of medical and non-medical personnel. PMID- 27942342 TI - Is current training in basic and advanced cardiac life support (BLS & ACLS) effective? A study of BLS & ACLS knowledge amongst healthcare professionals of North-Kerala. AB - BACKGROUND: Healthcare professionals are expected to have knowledge of current basic and advanced cardiac life support (BLS/ACLS) guidelines to revive unresponsive patients. METHODS: A cross-sectional study was conducted to evaluate the current practices and knowledge of BLS/ACLS principles among healthcare professionals of North-Kerala using pretested self-administered structured questionnaire. Answers were validated in accordance with American Heart Association's BLS/ACLS teaching manual and the results were analysed. RESULTS: Among 461 healthcare professionals, 141 (30.6%) were practicing physicians, 268 (58.1%) were nurses and 52 (11.3%) supporting staff. The maximum achievable score was 20 (BLS 15/ACLS 5). The mean score amongst all healthcare professionals was 8.9+/-4.7. The mean score among physicians, nurses and support staff were 8.6+/ 3.4, 9+/-3.6 and 9+/-3.3 respectively. The majority of healthcare professionals scored <=50% (237, 51.4%); 204 (44.3%) scored 51%-80% and 20 (4.34%) scored >80%. Mean scores decreased with age, male sex and across occupation. Nurses who underwent BLS/ACLS training previously had significantly higher mean scores (10.2+/-3.4) than untrained (8.2+/-3.6, P=0.001). Physicians with <5 years experience (P=0.002) and nurses in the private sector (P=0.003) had significantly higher scores. One hundred and sixty three (35.3%) healthcare professionals knew the correct airway opening manoeuvres like head tilt, chin lift and jaw thrust. Only 54 (11.7%) respondents were aware that atropine is not used in ACLS for cardiac arrest resuscitation and 79 (17.1%) correctly opted ventricular fibrillation and pulseless ventricular tachycardia as shockable rhythms. The majority of healthcare professionals (356, 77.2%) suggested that BLS/ACLS be included in academic curriculum. CONCLUSION: Inadequate knowledge of BLS/ACLS principles amongst healthcare professionals, especially physicians, illuminate lacunae in existing training systems and merit urgent redressal. PMID- 27942343 TI - Effects of a general practitioner cooperative co-located with an emergency department on patient throughput. AB - BACKGROUND: In 2013 a General Practitioner Cooperative (GPC) was introduced at the Emergency Department (ED) of our hospital. One of the aims of this co-located GPC was to improve throughput of the remaining patients at the ED. To determine the change in patient flow, we assessed the number of self-referrals, redirection of self-referrals to the GPC and back to the ED, as well as ward and ICU admission rates and length of stay of the remaining ED population. METHODS: We conducted a four months' pre-post comparison before and after the implementation of a co-located GPC with an urban ED in the Netherlands. RESULTS: More than half of our ED patients were self-referrals. At triage, 54.5% of these self-referrals were redirected to the GPC. After assessment at the GPC, 8.5% of them were referred back to the ED. The number of patients treated at the ED declined with 20.3% after the introduction of the GPC. In the remaining ED population, there was a significant increase of highly urgent patients (P<0.001), regular admissions (P<0.001), and ICU admissions (P<0.001). Despite the decline of the number of patients at the ED, the total length of stay of patients treated at the ED increased from 14 682 hours in the two months' control period to 14 962 hours in the two months' intervention period, a total increase of 270 hours in two months (P<0.001). CONCLUSION: Introduction of a GPC led to efficient redirection of self-referrals but failed to improve throughput of the remaining patients at the ED. PMID- 27942344 TI - Acute Care/Trauma Surgeon's role in obstetrical/gynecologic emergencies (The OBCAT Alert). AB - BACKGROUND: Overwhelming hemorrhage or other intra-abdominal complications may be associated with obstetrical or gynecologic (OB/GYN) procedures and may require the surgical training of an Acute Care/Trauma Surgeon. The OB Critical Assessment Team (OBCAT Alert) was developed at our institution to facilitate a multidisciplinary response to complex OB/GYN cases. We sought to review and characterize the Acute Care/Trauma Surgeon's role in these cases. METHODS: We conducted a retrospective review of all emergency consults during an OB/GYN case at our institution from 2008 to 2015. An OBCAT is a hospital based alert system designed to immediately notify OB/GYN, anesthesiology, Acute Care/Trauma, the intensive care unit (ICU), and the blood bank of a potential emergency during an OB/GYN case. RESULTS: There were 7+/-3 OBCAT alerts/year. Seventeen patients required Acute Care/Trauma surgery intervention for hemorrhage. Thirteen patients required damage control packing during their hospitalization. Blood loss averaged 6.8+/-5.5 L and patients received a total of 21+/-14 units during deliveries with hemorrhage. There were 17 other surgical interventions not related to hemorrhage; seven of these cases were related to adhesions or intestinal injury. Seven additional cases required evaluation post routine OB/GYN procedure; the most common reason was for severe wound complications. There were three deaths during this study period. CONCLUSION: Emergency OB/GYN cases are associated with high morbidity and may require damage control or other surgical techniques in cases of overwhelming hemorrhage. Acute Care/Trauma Surgeons have a key role in the treatment of these complex cases. PMID- 27942346 TI - Prevention of aspiration of gastric contents during attempt in tracheal intubation in the semi-lateral and lateral positions. AB - BACKGROUND: Pulmonary aspiration of gastric contents during tracheal intubation is a life-threatening complication in emergency patients. Rapid sequence intubation is commonly performed to prevent aspiration but is not associated with low risk of intubation related complications. Although it has been considered that aspiration can be prevented in the lateral position, few studies have evaluated the ability to prevent aspiration. Moreover, this position is not always a favorable position for tracheal intubation. If aspiration can be prevented in a clinically relevant semi-lateral position, it may be advantageous. We assessed the ability to prevent aspiration in the lateral position and various degrees of the semi-lateral position using a vomiting-regurgitation manikin model. METHODS: A manikin's head was placed in the neutral, simple extension, or sniffing position. The amount of aspirated saline into the bronchi during simulated vomiting was measured at semi-lateral position angles of 0o to 90o in 10o increments. The difference in the vertical height between the mouth corner and the inferior border of the vocal cord was measured radiologically at each semi-lateral position in the three head-neck positions. RESULTS: Pulmonary aspiration was prevented at the >=70o, >=80o, and 90o semi-lateral positions in the neutral, simple extension, and sniffing positions, respectively. The mouth was lower than the vocal cord in the semi-lateral position in which aspiration was prevented. CONCLUSION: The lateral or excessive semi-lateral position was necessary to protect the lung from aspiration in the head-neck positions commonly used for tracheal intubation. Prevention of aspiration was difficult within clinically relevant semi-lateral positions. PMID- 27942345 TI - The Buffering analysis to identify common geographical factors within the vicinity of severe injury related to motor vehicle crash in Malaysia. AB - BACKGROUND: The main objective was to identify common geographical buildup within the 100-meter buffer of severely injured based on injury severity score (ISS) among the motor vehicle crash (MVC) victims in Malaysia. METHODS: This was a prospective cohort study from July 2011 until June 2013 and involved all MVC patients attending emergency departments (ED) of two tertiary centers in a district in Malaysia. A set of digital maps was obtained from the Town Planning Unit of the district Municipal Office (local district map). Vector spaces were spanned over these maps using GIS software (ARCGIS 10.1 licensed to the study center), and data from the identified severe injured cases based on ISS of 16 or more were added. Buffer analysis was performed and included all events occurring within a 100 -meter perimeter around a reference point. RESULTS: A total of 439 cases were recruited over the ten-month data collection period. Fifty two (11%) of the cases were categorized as severe cased based on ISS scoring of 16 and more. Further buffer analysis looking at the buildup areas within the vicinity of the severely injured locations showed that most of the severe injuries occurred at locations on municipal roads (15, 29%), straight roads (16, 30%) and within villages buildup (suburban) areas (18, 35%). CONCLUSION: This study has successfully achieved its objective in identifying common geographical factors and buildup areas within the vicinity of severely injured road traffic cases. PMID- 27942347 TI - Pattern of acute poisoning in Jimma University Specialized Hospital, South West Ethiopia. AB - BACKGROUND: Poisoning is a common cause of morbidity and mortality worldwide. People can be exposed to poisons either intentionally or accidentally. Designing appropriate treatment or prevention approaches depends on understanding of the nature and pattern of poisoning in a specific place. Information on the patterns of acute poisoning in Ethiopian hospitals is limited. This study was, therefore, conducted to evaluate the patterns of acute poisoning in Jimma University Specialized Hospital (JUSH), South West Ethiopia. METHODS: A record based retrospective analysis of acute poisoning cases presented to JUSH from January 1, 2012 to December 31, 2013 was conducted. The collected data was analyzed using SPSS version 16. RESULTS: Of the 103 patients, 49 (47.6%) were male and 54 (52.4%) were female. The highest prevalence of poisoning was observed in persons aged 12-20 years (70, 67.96%). Majority of the cases were intentional poisoning (52, 50.5%), and 28 (27.2%) of the cases were accidental. The common causes of poisoning were house hold cleansing agents (43, 41.7%), organophosphates (28, 27.2%) and drugs (13, 12.6%). Diarrhea and vomiting (49.5%), altered consciousness (16.5%) and epigastric pain (13.6%) were the common presenting symptoms. CONCLUSION: Majority of the victims of the acute poisoning in this study were aged 12-20 years. The most common mode of poisoning was intentional poisoning resulting from temporary quarrel. The common poisons used by the victims were found to be household cleansing agents. PMID- 27942348 TI - Estimated economic benefit of increasing 25-hydroxyvitamin D concentrations of Canadians to or above 100 nmol/L. AB - Mounting evidence from observational and clinical trials indicates that optimal vitamin D reduces the risk of many diseases. We used observational studies and recent data on 25-hydroxyvitamin D [25(OH)D] concentrations of Canadians from Cycle 3 of the Canadian Health Measures Survey to estimate the reduction in disease incidence, mortality rates, and the total economic burden (direct plus indirect) of disease if 25(OH)D concentrations of all Canadians were raised to or above 100 nmol/L. Recently, the mean 25(OH)D concentration of Canadians varied depending on age and season (51-69 nmol/L), with an overall mean of 61 nmol/L. The diseases affected by 25(OH)D concentration included cancer, cardiovascular disease, dementia, diabetes mellitus, multiple sclerosis, respiratory infections, and musculoskeletal disorders. We used 25(OH)D concentration-health outcome relations for breast cancer and cardiovascular disease and results of clinical trials with vitamin D for respiratory infections and musculoskeletal disorders to estimate the reductions in disease burden for increased 25(OH)D concentrations. If all Canadians attained 25(OH)D concentrations>100 nmol/L, the calculated reduction in annual economic burden of disease was $12.5 +/- 6 billion on the basis of economic burdens for 2016 and a reduction in annual premature deaths by 23,000 (11,000-34,000) on the basis of rates for 2011. However, the effects on disease incidence, economic burden, and mortality rate would be phased in gradually over several years primarily because once a chronic disease is established, vitamin D affects its progression only modestly. Nevertheless, national policy changes are justified to improve vitamin D status of Canadians through promotion of safe sun exposure messages, vitamin D supplement use, and/or facilitation of food fortification. PMID- 27942350 TI - Omalizumab for chronic urticaria in Latin America. AB - BACKGROUND: Chronic urticaria (CU) is defined as the spontaneous appearance of wheals, with or without angioedema, persisting for >=6 weeks. Chronic Spontaneous Urticaria (CSU) is a type of CU which affects 0.5-1 % of the global population, but it represents a high burden to patients. In recent years, omalizumab is available as treatment of disease. Our aim is to extend previous findings, analyzing effects of omalizumab on symptoms in Latin American patients with CSU. METHODS: Retrospective analysis of patients treated with omalizumab in Cuenca Ecuador. 150 mg omalizumab was administered every 4 weeks, and its effects were measured by Urticaria Activity Score (UAS) at baseline and each month in follow up. Complete response was defined as a UAS of 0 or 1, and partial response was classified as a UAS of 2 or more. Also, demographic and clinical variables were collected. Descriptive analyses were employed. Response rates were summarized as counts and percentages after 3 and 5 months. Related Samples Wilcoxon signed rank tests were used to compare UAS at baseline and after 3 months. P values <0.05 indicated statistical significance. RESULTS: 26 subjects were enrolled, almost half were female individuals (57.7 %), with mean age 47.8 years (range, 18-81 years). Mean duration of CU after diagnosis was 23.3 months (range, 2-180 months). Mean UAS at baseline was 5.7 points (range, 4-6 points). Nine patients (34.6 %) completed 3 months of treatment (33 % reported a complete response), with a mean difference in UAS of 3.33 (p = 0.01). Four patients completed 5 months of treatment (75.0 % showed a complete response). All patients previously treated with first-generation antihistamines plus corticosteroids showed no responses at neither 3 nor 5 months of treatment. CONCLUSION: Omalizumab is an effective treatment for patients with CU. It is necessary to conduct some future investigations where we can establish if 150 mg could be an option in developing countries. PMID- 27942349 TI - The risks and benefits of sun exposure 2016. AB - Public health authorities in the United States are recommending that men, women and children reduce their exposure to sunlight, based on concerns that this exposure will promote skin cancer. On the other hand, data show that increasing numbers of Americans suffer from vitamin D deficiencies and serious health problems caused by insufficient sun exposure. The body of science concerning the benefits of moderate sun exposure is growing rapidly, and is causing a different perception of sun/UV as it relates to human health. Melanoma and its relationship to sun exposure and sunburn is not adequately addressed in most of the scientific literature. Reports of favorable health outcomes related to adequate serum 25(OH)D concentration or vitamin D supplementation have been inappropriately merged, so that benefits of sun exposure other than production of vitamin D are not adequately described. This review of recent studies and their analyses consider the risks and benefits of sun exposure which indicate that insufficient sun exposure is an emerging public health problem. This review considers the studies that have shown a wide range health benefits from sun/UV exposure. These benefits include among others various types of cancer, cardiovascular disease, Alzheimer disease/dementia, myopia and macular degeneration, diabetes and multiple sclerosis. The message of sun avoidance must be changed to acceptance of non-burning sun exposure sufficient to achieve serum 25(OH)D concentration of 30 ng/mL or higher in the sunny season and the general benefits of UV exposure beyond those of vitamin D. PMID- 27942352 TI - Complete genome anatomy of the emerging potato pathogen Dickeya solani type strain IPO 2222T. AB - Several species of the genus Dickeya provoke soft rot and blackleg diseases on a wide range of plants and crops. Dickeya solani has been identified as the causative agent of diseases outbreaks on potato culture in Europe for the last decade. Here, we report the complete genome of the D. solani IPO 2222T. Using PacBio and Illumina technologies, a unique circular chromosome of 4,919,833 bp was assembled. The G + C content reaches 56% and the genomic sequence contains 4,059 predicted proteins. The ANI values calculated for D. solani IPO 2222T vs. other available D. solani genomes was over 99.9% indicating a high genetic homogeneity within D. solani species. PMID- 27942353 TI - Capacity and Utilization in Health Care: The Effect of Empty Beds on Neonatal Intensive Care Admission. AB - Because geographic variation in medical care utilization is jointly determined by both supply and demand, it is difficult to empirically estimate whether capacity itself has a causal impact on utilization in health care. In this paper, I exploit short-term variation in Neonatal Intensive Care Unit (NICU) capacity that is unlikely to be correlated with unobserved demand determinants. I find that available NICU beds have little to no effect on NICU utilization for the sickest infants, but do increase utilization for those in the range of birth weights where admission decisions are likely to be more discretionary. PMID- 27942351 TI - Therapeutic interventions in severe asthma. AB - The present paper addresses severe asthma which is limited to 5-10% of the overall population of asthmatics. However, it accounts for 50% or more of socials costs of the disease, as it is responsible for hospitalizations and Emergency Department accesses as well as expensive treatments. The recent identification of different endotypes of asthma, based on the inflammatory pattern, has led to the development of tailored treatments that target different inflammatory mediators. These are major achievements in the perspective of Precision Medicine: a leading approach to the modern treatment strategy. Omalizumab, an anti-IgE antibody, has been the only biologic treatment available on the market for severe asthma during the last decade. It prevents the linkage of the IgE and the receptors, thereby inhibiting mast cell degranulation. In clinical practice omalizumab significantly reduced the asthma exacerbations as well as the concomitant use of oral glucocorticoids. In the "Th2-high asthma" phenotype, the hallmarks are increased levels of eosinophils and other markers (such as periostin). Because anti-IL-5 in this condition plays a crucial role in driving eosinophil inflammation, this cytokine or its receptors on the eosinophil surface has been studied as a potential target for therapy. Two different anti-IL-5 humanized monoclonal antibodies, mepolizumab and reslizumab, have been proven effective in this phenotype of asthma (recently they both came on the market in the United States), as well as an anti-IL-5 receptor alpha (IL5Ralpha), benralizumab. Other monoclonal antibodies, targeting different cytokines (IL-13, IL-4, IL-17 and TSLP) are still under evaluation, though the preliminary results are encouraging. Finally, AIT, Allergen Immunotherapy, a prototype of Precision Medicine, is considered, also in light of the recent evidences of Sublingual Immunotherapy (SLIT) tablet efficacy and safety in mite allergic asthma patients. Given the high costs of these therapies, however, there is an urgent need to identify biomarkers that can predict the clinical responders. PMID- 27942354 TI - Heart Failure: Diagnosis, Severity Estimation and Prediction of Adverse Events Through Machine Learning Techniques. AB - Heart failure is a serious condition with high prevalence (about 2% in the adult population in developed countries, and more than 8% in patients older than 75 years). About 3-5% of hospital admissions are linked with heart failure incidents. Heart failure is the first cause of admission by healthcare professionals in their clinical practice. The costs are very high, reaching up to 2% of the total health costs in the developed countries. Building an effective disease management strategy requires analysis of large amount of data, early detection of the disease, assessment of the severity and early prediction of adverse events. This will inhibit the progression of the disease, will improve the quality of life of the patients and will reduce the associated medical costs. Toward this direction machine learning techniques have been employed. The aim of this paper is to present the state-of-the-art of the machine learning methodologies applied for the assessment of heart failure. More specifically, models predicting the presence, estimating the subtype, assessing the severity of heart failure and predicting the presence of adverse events, such as destabilizations, re-hospitalizations, and mortality are presented. According to the authors' knowledge, it is the first time that such a comprehensive review, focusing on all aspects of the management of heart failure, is presented. PMID- 27942355 TI - Role of Toll-Like Receptors in Tuberculosis Infection. AB - BACKGROUND: One-third of the world's population is infected with Mycobacterium tuberculosis. Investigation of Toll-like receptors (TLRs) has revealed new information regarding the immunopathogenesis of this disease. Toll-like receptors can recognize various ligands with a lipoprotein structure in the bacilli. Toll like receptor 2 and TLR-4 have been identified in association with tuberculosis infection. OBJECTIVES: The aim of our study was to investigate the relationship between TLR polymorphism and infection progress. METHODS: Twenty-nine patients with a radiologically, microbiologically, and clinically proven active tuberculosis diagnosis were included in this 25-month study. Toll-like receptor 2 and TLR-4 polymorphisms and allele distributions were compared between these 29 patients and 100 healthy control subjects. Peripheral blood samples were taken from all patients. Genotyping of TLR-2, TLR-4, and macrophage migration inhibitory factor was performed. The extraction step was completed with a Qiagen mini blood purification system kit (Qiagen, Ontario, Canada) using a peripheral blood sample. The genotyping was performed using polymerase chain reaction restriction fragment length polymorphism. RESULTS: In total, 19 of the 29 patients with tuberculosis infection had a TLR-2 polymorphism, and 20 of the 100 healthy subjects had a TLR-2 polymorphism (P < 0.001). The TLR-4 polymorphism and interferon-gamma allele distributions were not statistically correlated. CONCLUSIONS: Toll-like receptor 2 polymorphism is a risk factor for tuberculosis infection. The limiting factor in this study was the lack of investigation of the interferon-gamma and tumor necrosis factor-alpha levels, which are important in the development of infection. Detection of lower levels of these cytokines in bronchoalveolar lavage specimens, especially among patients with TLR-2 defects, will provide new data that may support the results of this study. PMID- 27942356 TI - Rapid Detection of Rifampicin- and Isoniazid-Resistant Mycobacterium tuberculosis Using Real-Time PCR. AB - BACKGROUND: Accurate and rapid detection of drug-resistant Mycobacterium tuberculosis is fundamental for the successful treatment of tuberculosis (TB). OBJECTIVES: The aim of this study was to determine the frequency of common mutations leading to isoniazid (INH) and rifampicin (RMP) resistance. PATIENTS AND METHODS: In a cross-sectional study carried out in 2014, 90 patients with M. tuberculosis from five border provinces of Iran were selected. After a full clinical history and physical evaluation, real-time polymerase chain reaction (PCR) technique was performed for the detection of mutations in the patients' katG and rpoB genes. The results were compared with results of a standard proportion method as well as a multiplex allele-specific PCR (MAS-PCR). RESULTS: A total of 23 mutations were found in isolates among which, codon katG 315, rpoB P1 (511 - 519 sequence) and rpoB P2 (524-533 sequence) were responsible for seven, nine and seven cases, respectively. The mean (standard deviation (SD)) of melting temperature (Tm) in katG 315 codon, rpoB P1 and P2 sequences in susceptible and mutant isolates was as follows: katG 85.4 degrees C (0.18) and 87.54 degrees C (0.62); rpoBeta P1 84.6 degrees C (0.61) and 82.9 degrees C (0.38); rpoBeta P2 83.4 degrees C (0.18) and 85.3 degrees C (0.19), respectively. In comparison to the standard proportion test, the sensitivity of real-time PCR in detecting INH- and RMP-resistant mutations was 75% and 83.3%, respectively. In comparison to the MAS-PCR test, 100% of katG 315 mutations and 80% of rpoB mutations were determined. Overall, 10% of the patients were diagnosed with a recurrence of TB. Age and previous history of TB treatment increased mutation odds in rpoB sequences (P = 0.046, P = 0.036, respectively). CONCLUSIONS: Detection of drug resistance associated with mutations through real-time PCR by melting analysis technique showed a high differentiating power. This technique had high concordance with the standard proportion test and MAS-PCR results. PMID- 27942358 TI - NDM-1 and rmtC-Producing Klebsiella pneumoniae Isolates in Turkey. AB - BACKGROUND: The resistance of aminoglycosides in strains that produce beta lactamase can be developed through the multidrug resistant encoding genes carried by common plasmids. Recently, the association between 16S rRNA methyltransferase resistance and beta-lactamase enzymes carried by the same plasmids has drawn increased attention from researchers, particularly the association in aminoglycoside-resistant strains with a minimum inhibitory concentration (MIC) of >= 256 ug/mL. OBJECTIVES: We aimed to investigate the co-existence of 16S rRNA methyltransferase and beta-lactamase genes in multidrug resistant (MDR) Klebsiella pneumoniae strains isolated from clinical samples. METHODS: We determined the molecular mechanisms of aminoglycoside resistance and its relationship with resistance to carbapenem and beta-lactam group antibiotics in 40 extended-spectrum beta-lactamase (ESBL)-positive carbapenem- and aminoglycoside-resistant K. pneumoniae strains. Multidrug resistant K. pneumoniae was isolated from various clinical samples in the faculty of medicine of Cukurova University, Turkey. First, the resistance of aminoglycoside and beta-lactam antibiotics was phenotypically investigated using the Kirby-Bauer disk diffusion test, double disk synergy test, and modified Hodge test. The MIC values of aminoglycoside were determined using the agar dilution method. Polymerase chain reaction was performed to detect the carbapenemases, ESBL, and 16S rRNA methyltransferase genes. The results were confirmed by a sequence analysis. RESULTS: Twenty K. pneumoniae strains showed resistance to amikacin, and 40 were resistant to gentamicin. The MIC value was found to be > 512 ug/mL in five amikacin-resistant strains and > 128 ug/mL in 10 gentamicin-resistant isolates. The rmtC gene, a type of 16S rRNA methyltransferase, was amplified in four isolates (MIC amikacin: > 512 ug/mL, gentamicin: > 128 ug/mL). Of these four isolates, three had the blaNDM-1 gene and all contained at least one ESBL gene. CONCLUSIONS: This study demonstrated the co-existence of rmtC and blaNDM-1 genes for the first time in Turkey. The spread of this resistant type should be monitored and limited through molecular surveillance. PMID- 27942357 TI - The Effect of Ferula assa-foetida L and Carum copticum Hydroalcoholic Extract on the Expression Levels of Staphylococcus aureus Genes Involved in Quorum Sensing. AB - BACKGROUND: Quorum sensing is a microbial cell-to-cell communication process. Quorum sensing bacteria produce and release extracellular messenger molecules called autoinducers. Gram-positive and Gram-negative, homoserine lactones, and oligopeptides are autoinducers used to communicate and regulate gene expression. OBJECTIVES: The goal of this study was to assess the impact of subinhibitory concentrations of Ferula assa-foetida l oleo-gum resin and Carum copticum fruit on the expression of tst and hld genes of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) strains. METHODS: This analytical study was performed using standard strains of MRSA (ATCC 33591) and MSSA (ATCC 29213). Suspensions of MRSA and MSSA bacteria were incubated at 37 degrees C for 7 and 16 hours in the presence of ethanol extracts from F. assa foetida and C. copticum. The expression of the hld and tst genes was then assessed using the real-time PCR protocol and SYBR Green Master Mix. The data analysis was carried out using the 2-DeltaDeltaCT method. RESULTS: The hld gene expression (RNAIII) of MRSA after 7 and 16 hours of exposure to the sMIC of the F. assa-foetida extract showed a fold change of -1 and 0.08, respectively, in comparison with controls. After 7 and 16 hours of exposure to the sMIC of the C. copticum extract, the fold change was -0.23 and -0.27, respectively. After exposure to the sMIC of the C. copticum extract for 16 hours, the fold change in the expression of the tst (TSST-1) MSSA gene was 0.37 lower than that of the control sample. CONCLUSIONS: The results indicate that sMICs of ethanol extracts from F. assa-foetida and C. copticum can be used to control the expression of virulence genes in pathogenic bacteria, such as MRSA and MSSA. PMID- 27942359 TI - Cytolethal Distending Toxin From Campylobacter jejuni Requires the Cytoskeleton for Toxic Activity. AB - BACKGROUND: Campylobacter jejuni is one of the major causes of infectious diarrhea worldwide. The distending cytolethal toxin (CDT) of Campylobacter spp. interferes with normal cell cycle progression. This toxic effect is considered a result of DNase activity that produces chromosomal DNA damage. To perform this event, the toxin must be endocytosed and translocated to the nucleus. OBJECTIVES: The aim of this study was to evaluate the role of the cytoskeleton in the translocation of CDT to the nucleus. METHODS: Campylobacter jejuni ATCC 33291 and seven isolates donated from Instituto de Biotecnologia were used in this study. The presence of CDT genes in C. jejuni strains was determined by PCR. To evaluate the effect of CDT, HeLa cells were treated with bacterial lysate, and the damage and morphological changes were analyzed by microscopy, immunofluorescence staining, and flow cytometry. To evaluate the role of the cytoskeleton, HeLa cells were treated with either latrunculin A or by nocodazole and analyzed by microscopy, flow cytometry, and immunoquantification (ELISA). RESULTS: The results obtained showed that the eight strains of C. jejuni, including the reference strain, had the ability to produce the toxin. Usage of latrunculin A and nocodazole, two cytoskeletal inhibitors, blocked the toxic effect in cells treated with the toxin. This phenomenon was evident in flow cytometry analysis and immunoquantification of Cdc2-phosphorylated. CONCLUSIONS: This work showed that the cytotoxic activity of the C. jejuni CDT is dependent on its endocytosis. The alteration in the microtubules and actin filaments caused a blockage transit of the toxin, preventing it from reaching the nucleus of the cell, as well as preventing DNA fragmentation and alteration of the cell cycle. The CDT toxin appears to be an important element for the pathogenesis of campylobacteriosis, since all clinical isolates showed the presence of cdtA, cdtB and cdtC genes. PMID- 27942360 TI - Antibacterial Activity of Silver Nanoparticles and Their Combination with Zataria multiflora Essential Oil and Methanol Extract. AB - BACKGROUND: Against a variety of antimicrobial resistant pathogens, the scientists attempted substitution of antimicrobial medicine with various nanoparticles and plant-based antibacterial substances. OBJECTIVES: The aim of this study was to assess the antibacterial effects of silver nanoparticles solely and in combination with Zataria multiflora essential oil and methanolic extract on some photogenic bacteria. METHODS: Minimum inhibitory concentrations (MICs) and fractional inhibitory concentrations (FICs) of plant essential oil, methanolic extract, and silver nanoparticles against bacteria were evaluated using the broth microdilution method and check board microtiter assays. RESULTS: The results of the experiment showed that the MIC and minimal bacterial concentration (MBC) values of Ag-NPs against all strains were in the range of 15.625 - 500 ug/mL, and values for the essential oil and plant extract were in the range of 1.56 - 100 mg/mL. CONCLUSIONS: Silver nanoparticles were observed to have additive effects with essential oil against Staphylococcus epidermidis and S. aureus. The obtained results suggest the need for further investigations of the antibacterial effects of the combination of silver nanoparticles with other plant extracts and essential oils. PMID- 27942361 TI - Isolation, Characterization, and Antibacterial Activity of Bacteriophages Against Methicillin-Resistant Staphylococcus aureus in Pakistan. AB - BACKGROUND: In recent years, antibiotic resistance has been indicated as a paramount threat to public health. The use of bacteriophages appears to be a safer alternative for the control of bacterial infections. OBJECTIVES: The present study aims to explore sewage water for the presence of indigenous bacteriophages, and to investigate their antibacterial potential against Methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Bacterial isolates were first collected and identified from pus samples taken from the surgical and burn units using standard microbiological procedures. A cefoxitin disk screen test was then used and interpreted according to the clinical laboratory standards institute (CLSI) guidelines for the detection of MRSA. The sewage samples were processed and the phages enriched using S. aureus as a host organism. Turbid and clear plaques of different sizes were isolated using an overlay method, purified, and then enumerated by means of a dilution method. RESULTS: The phages exhibited good lytic activity against MRSA when tested in-vitro, and the highest activity was attained within three to six hours of phage infection. The isolated phage pq/48 was also found efficient in decreasing the bacterial count during an in vivo trial in rabbits. A protein analysis using SDS-PAGE revealed 10 proteins of between 20 kDa and 155 kDa in size. CONCLUSIONS: The overall results indicated that bacteriophages isolated from sewage exhibited excellent lytic activity against MRSA strains. In conclusion, bacteriophages can be further characterized and appear to be a promising candidate for phage therapy against MRSA in the future. PMID- 27942363 TI - Design of Indigenous ELISA Using Tachyzoites from the RH Strain of Toxoplasma gondii and Comparison with Commercial Kits in Ahvaz, Southwest of Iran, 2015. AB - BACKGROUND: Toxoplasma gondii is one of the most common causes of latent infections in humans worldwide. Detecting anti-Toxoplasma antibodies in serum using serological tests is a common method to diagnose toxoplasmosis. OBJECTIVES: In the present study, an indigenous ELISA kit was prepared using tachyzoites from the RH strain of T. gondii, and its sensitivity and specificity were compared with those of commercial kits. METHODS: To produce antigens, 0.02 mL of locally isolated T. gondii RH strain parasites along with 109 tachyzoites were injected into the peritoneal cavities of 50 laboratory mice (BALB/C). Parasites were collected after 4 days. After filtering and washing, the concentration of protein in sonicated tachyzoites was calculated using the Lowry protein assay. The dilution of antigen, serum and alkaline phosphatase conjugate was assessed in designing an indigenous ELISA method; then ELISA was performed based on these dilutions, and its sensitivity was determined using 200 serum samples. In addition, the specificity of the assay was evaluated using 40 serum samples from patients with tuberculosis, leukemia or hydatid cyst. RESULTS: Indigenous ELISA was used to examine 100 serum samples containing anti-T. gondii IgG, with a sensitivity of 98% (commercial kits: 100%). Another 100 serum samples containing anti-T. gondii IgM were also tested, with a sensitivity of 99% (commercial kits: 100%). When 40 serum samples from patients with leukemia, hydatid cyst or tuberculosis were examined using anti-T. gondii IgG, the specificity was 100%, identical to commercial kits. However, the specificity of a similar test with anti-T. gondii IgM was just 28.6% for serum samples from leukemia patients, 21.4% for hydatid cyst and 16.7% for tuberculosis. CONCLUSIONS: We found that purified locally isolated soluble crude antigens of the RH strain of T. gondii from the peritoneal cavity of mice may be one of the most promising antigens for detection of human toxoplasmosis in routine screening. PMID- 27942362 TI - Immunization with Protein D from Non-Typeable Haemophilus influenzae (NTHi) Induced Cytokine Responses and Bioactive Antibody Production. AB - BACKGROUND: Outer membrane protein D (PD) is a highly conserved and stable protein in the outer membrane of both encapsulated (typeable) and non-capsulated (non-typeable) strains of Haemophilus influenzae. As an immunogen, PD is a potential candidate vaccine against non-typeable H. influenzae (NTHi) strains. OBJECTIVES: The aim of this study was to determine the cytokine pattern and the opsonic antibody response in a BALB/c mouse model versus PD from NTHi as a vaccine candidate. METHODS: Protein D was formulated with Freund's and outer membrane vesicle (OMV) adjuvants and injected into experimental mice. Sera from all groups were collected. The bioactivity of the anti-PD antibody was determined by opsonophagocytic killing test. To evaluate the cytokine responses, the spleens were assembled, suspension of splenocytes was recalled with antigen, and culture supernatants were analyzed by ELISA for IL-4, IL-10, and IFN-gamma cytokines. RESULTS: Anti-PD antibodies promoted phagocytosis of NTHi in both immunized mice groups (those administered PD + Freund's and those administered PD + OMV adjuvants, 92.8% and 83.5%, respectively, compared to the control group). In addition, the concentrations of three cytokines were increased markedly in immunized mice. CONCLUSIONS: We conclude that immunization with PD protects mice against NTHi. It is associated with improvements in both cellular and humoral immune responses and opsonic antibody activity. PMID- 27942364 TI - A Low Prevalence of Inducible Macrolide, Lincosamide, and Streptogramin B Resistance Phenotype among Methicillin-Susceptible Staphylococcus aureus Isolated from Malaysian Patients and Healthy Individuals. AB - BACKGROUND: Antibiotic resistance among Staphylococcus aureus is of great concern worldwide. This resistance is further complicated by the ability of S. aureus to confer cross-resistance to other antibiotics due to the presence of resistance genes, such as erythromycin resistance methylase (erm) genes, which render the bacterium resistant to macrolide-lincosamide-streptogramin B (MLSB) antibiotics. Resistance to these antibiotics can lead to therapeutic failure, resulting in significant morbidity and mortality in patients with S. aureus infections. OBJECTIVES: This study was performed to examine the distribution of MLSB resistant strains of methicillin-susceptible S. aureus (MSSA), which were obtained from hospitalized patients and normal healthy individuals (carriers) using phenotypic methods, such as the double-disk diffusion (D-test) and the genotypic method by polymerase chain reaction (PCR). METHODS: A total of 183 nonduplicative MSSA isolates obtained from hospitalized patients (133) and carriers (50) in our previous studies were randomly selected for the D-test. The guidelines of the Clinical and Laboratory Standards Institute (CLSI) were used for the interpretation of the results of this test. The detection of ermA, ermB, ermC and msrA genes by PCR was performed for isolates that had positive D-test results and that were resistant to erythromycin. RESULTS: Of the 183 MSSA isolates, 97.2% and 98.4% were highly susceptible to erythromycin and clindamycin, respectively. MSLB resistance was detected in four isolates (2.2%). Of the 133 MSSA isolated from hospitalized patients, only 3.0% (4/133) and 2.3% (3/133) exhibited resistance to erythromycin and clindamycin, respectively. With regard to the MLSB resistance phenotypes, only 1.6% and 0.6% exhibited inducible MLSB (iMLSB) and MS phenotypes, respectively. The ermC gene was detected in all three iMLSB phenotypes, and the msrA gene was detected in the MS phenotype. Surprisingly, all MSSA isolates (100%) from carriers exhibited extremely high susceptibility to both antibiotics. CONCLUSIONS: The prevalence rates of iMLSB MSSA isolates vary according to geographical locations and the local antibiotic policy. The low prevalence rate of iMLSB MSSA isolates could probably be related to the judicious use of antibiotics for treating S. aureus infections in our studied population. Nonetheless, continuous antibiotic surveillance is still necessary to control any emergence of resistance isolates so that targeted therapy and effective control can be implemented accordingly. PMID- 27942365 TI - Isolation, Antimicrobial Susceptibility Profile and Detection of Sul1, blaTEM, and blaSHV in Amoxicillin-Clavulanate-Resistant Bacteria Isolated From Retail Sausages in Kampar, Malaysia. AB - BACKGROUND: Due to the overuse of antibiotics in livestock as a growth-promoting agent, the emergence of multi-antibiotic resistant bacteria is becoming a concern. OBJECTIVES: In this study, we aimed to detect the presence and discover the molecular determinants of foodborne bacteria in retail sausages resistant towards the antibacterial agent amoxicillin-clavulanate. METHODS: Two grams of sausages were chopped into small pieces and transferred into sterile Luria Bertani (LB) enrichment broths overnight before they were plated on MacConkey agar petri dishes. The bacteria isolated were then screened for amoxicillin clavulanate resistance, and an antimicrobial susceptibility test of each isolate was performed by using the disc diffusion method. Double synergy and phenotypic tests were carried out to detect the presence of extended spectrum beta-lactamase (ESBL). API 20E kit was used to identify the Enterobacteriaceae. All isolates were further examined by polymerase chain reaction (PCR) for resistant genes blaOXA-1, blaOXA-10, plasmid-mediated AmpC (blaCMY and blaDHA), and the chromosome-mediated AmpC, Sul1, blaTEM, and blaSHV genes. RESULTS: A total of 18 amoxicillin-clavulanate resistant isolates were obtained from seven different types of retail sausages. Only half of them were identified as Enterobacteriaceae, but none were ESBL-producers. All the 18 isolated strains demonstrated resistance towards amoxicillin-clavulanate, penicillin and oxacillin (100%), cefotaxime (71.4%), cefpodoxime (66.7%), and ampicillin (83.3%). blaTEM was the most frequently detected beta-lactamase gene. Both plasmid- and chromosomal-bound blaTEM genes were detected in all of the isolated Enterobacteriaceae. blaSHV and Sul1 accounted for 22.2% and 11.1% of the amoxicillin-clavulanate resistant isolates, respectively, whereas blaAMPC, blaCMY, blaDHA, blaOXA-1, and blaOXA-10 were not found in any of the isolates. The only one ESBL-producing bacteria detected in this study was Chryseobacterium meningosepticum, which harbored the blaTEM gene. CONCLUSIONS: The multidrug resistant bacteria that carry antibiotic resistant genes from retail sausages may increase the risk of transmission to humans via the consumption of contaminated sausages. Stricter measures must be taken to address the use of antibiotics in animal agriculture and to consider their potential impact on human health. PMID- 27942366 TI - Surveillance of Antibiotic-Resistant Bacteria in King Khalid Hospital, Hafr Al Batin, Saudi Arabia, During 2013. AB - BACKGROUND: Research to understand and control the emergence and spread of antimicrobial resistance has become a public health priority. OBJECTIVES: This study was conducted to study epidemiology and resistant pattern of bacteria causing infection in different King Khalid hospital units. PATIENTS AND METHODS: All samples were sent to the lab and routinely processed according to the standard microbiological procedures. Then, the cultures yielding growth were selected for the study. Identification and antibiotic susceptibility test for all clinical isolates were processed by using MicroScan instrumentation. A total of 428 clinical samples were collected within 8 months; out of them, 300 clinical isolates were subjected to validation test. RESULTS: Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa were the commonly identified Gram-negative bacteria. Staphylococcus aureus was the only identified Gram-positive bacterium. The most common infections were taken from the wounds (39.0%), urinary tract (32.3%), and bloodstream (17.8%). The most common antibiotic-resistant bacteria were found on female surgical ward (100%) followed by ICU (90.2%), and male surgical ward (88.2%). The overall results of antibiotic resistance were 100% for S. aureus, 93.3% K. pneumonia, 75.7 % E. coli, and 100% for P. aeruginosa. Staphylococcus aureus showed high resistance to ampicillin and linezolid (94.1%). High (86.95%) and full resistance (100%) against ampicillin were observed from E. coli and K. pneumonia, respectively. P. aeruginosa was fully resistant to 4 antibiotics of cefazoline, cefoxitin, tetracycline, and trimethoprim sulfamethoxazole. CONCLUSIONS: The study was useful in determining the risk factors and defining different hospital units which should be targeted for measures to prevent infection. PMID- 27942367 TI - Digit-Length Ratios (2D:4D) as a Phenotypic Indicator of in Utero Androgen Exposure is Not Prognostic for Androgenic Alopecia: a Descriptive-Analytic Study of 1200 Iranian Men. AB - The etiology of androgenic alopecia (AGA) involves several factors, including genetics, androgens, age and nutrition. Digit-length ratio of the index and ring finger (2D:4D) is an indicator of prenatal exposure to sex hormones. There is a paucity of studies that systemically review the possible positive predictive value of 2D:4D in the development of AGA. We performed a single-site, descriptive analytical study among a racially homogeneous population. Our results revealed that no significant association was determined between right 2D:4D and AGA severity within our entire population (P=0.384, r=0.025), however a positive correlation coefficient was identified in subjects above the age of 40. Based on the receiver operating characteristic curve analysis, 2D:4D does not predict the development of AGA. AGA is truly a multifactorial disease. Further, our findings suggest that increased in utero exposure to androgens as a fetus does not predispose men to develop AGA. PMID- 27942368 TI - Rosacea: a Clinical Review. AB - Rosacea is a field within dermatology with new insight within immunological research and new treatment-algorithm. Patient education on rosacea and appropriate treatments is an important aspect in helping patients succeed with therapy. Treatment should be tailored to each individual patient, taking into account: symptoms, trigger factors, patients' wishes, most bothersome symptoms, psychological aspect, individual needs. A combination of clinical therapies to treat different symptoms concomitantly may offer the best possible outcomes for the patient. In this review article we describe these aspects. PMID- 27942369 TI - Erythrodermic Psoriasis Treated with Apremilast. AB - Erythroderma is a rare potentially deadly exfoliative dermatitis characterized by diffuse cutaneous erythema which may be associated with multi-organ dysfunction. Therefore, it is imperative to recognize and treat it promptly. Erythrodermic psoriasis is the most common form of erythroderma. Management of this condition is largely based on aggressive supportive care and the use of anti-inflammatory immunosuppressive and biologic agents. We describe a case of psoriatic erythroderma which was triggered by withdrawal from systemic steroids and successfully treated with apremilast and cyclosporine. Apremilast induced atrial fibrillation limited its continued use after the initial response period. PMID- 27942370 TI - Surgical Pearl on Reconstructing Surgical Defects of the Nasal Tip. AB - Repairing surgical defects of the nasal tip is challenging, mainly because of the lack of freely mobile skin available peripherally. The Peng flap is a one-stage cutaneous flap that circumvents this difficulty by recruiting skin from the nasal dorsum and sidewall regions. The design produces a tridimensional shape perfectly adapted to the configuration of the nasal tip and allows for an inconspicuous closure of the defect. We present three examples of full-thickness skin defects involving the nasal tip, reconstructed using a modified version of the Peng flap, and present the experience at our department with this surgical technique. PMID- 27942371 TI - An Exploratory Study Identifying a Possible Response Shift Phenomena of the Glasgow Hearing Aid Benefit Profile. AB - A then-test technique was used to investigate the possibility of a response shift in the Glasgow hearing aid benefit profile (GHABP). Following completion of part 1 of the GHABP, 16 adults were invited for hearing-aid follow up appointments. In accordance with then-test technique, participants were asked to think back to before they had their hearing-aids fitted and the GHABP part 1 was completed again to re-establish the disability and handicap scores. These scores were then compared with the initial GHABP part I scores. Paired T testing and Wilcoxon Rank tests were carried out to investigate the statistical significance of the response shift effect. Statistically significant differences were seen between initial and retrospective GHABP (disability) scores using t test. No significant differences could be seen between the initial and retrospective handicap scores. Results suggest participants may have demonstrated a possible response shift phenomenon with the disability construct of the GHABP questionnaire, related to a possible re-calibration effect or a denial of disability effect. This exploratory study suggests that the GHABP questionnaire may be subject to a response shift phenomena. We suggest that further more robust studies are completed to verify this and recommend that this could have psychological impact on participants when explaining the results of the outcome measure and may affect hearing aid use. There is also potential for this phenomenon to affect global GHABP scores specifically when demonstrating to stakeholders the overall success of an audiology service. PMID- 27942372 TI - Transient Noise Reduction in Cochlear Implant Users: a Multi-Band Approach. AB - A previously-tested transient noise reduction (TNR) algorithm for cochlear implant (CI) users was modified to detect and attenuate transients independently across multiple frequency-bands. Since speech and transient noise are often spectrally distinct, we hypothesized that benefits in speech intelligibility can be achieved over the earlier single-band design. Fifteen experienced CI users (49 to 72 years) were tested unilaterally using pre-processed stimuli delivered directly to a speech processor. Speech intelligibility in transient and soft stationary noise, subjective sound quality and the recognition of warning signals was investigated in three processing conditions: no TNR (TNRoff), single-band TNR (TNRsgl) and multi-band TNR (TNRmult). Notably, TNRmult improved speech reception thresholds (SRTs) in cafeteria noise and office noise by up to 3 dB over both TNRoff and TNRsgl, and yielded higher comfort and clarity ratings in cafeteria noise. Our results indicate that multi-band transient noise reduction may be advantageous compared to a single-band approach, and reveal a substantial overall potential for TNR to improve speech perception and listening comfort in CI users. PMID- 27942373 TI - Impact of Different Cutoff Criteria on Rate of (Central) Auditory Processing Disorders Diagnosis Using the Central Test Battery. AB - The purpose of this study was to quantify how the use of two different cutoff criteria affects the test failure rate and potential diagnosis of central auditory processing disorder ([C]APD) in a sample of children subjected to central auditory processing ([C]AP) assessment. Test failure rates for the central test battery (CTB) using two different cutoff criteria (1 and 2 SDs below the mean) were measured retrospectively for 98 children who completed (C)AP assessment. The rates of potential (C)APD diagnosis ranged from 86.8% [when a 1 standard deviation (SD) cutoff was used] to 66.2% (when a 2 SD cutoff was used). The current use of two different cutoffs for the CTB has a large impact on the diagnostic rate for (C)APD. These findings have clinical implications for the diagnosis of (C)APD due to the widespread use of the CTB in the United States for the assessment of (C)APD in children. Thus, it is important to create awareness among audiologists that use of the 2 SDs cutoff criterion is recommended for reducing false positives (error). PMID- 27942374 TI - New Treatment Strategy for Apogeotropic Horizontal Canal Benign Paroxysmal Positional Vertigo. AB - The apogeotropic variant of horizontal semicircular canal benign paroxysmal positional vertigo (HC-BPPV) is attributed to canalithiasis of the anterior arm or cupulolithiasis. Despite some therapeutic maneuvers, I propose a new treatment strategy for apogeotropic HC-BPPV that is designed to detach both the otoconial debris from the anterior arm of the semicircular canal and the debris that is attached to the utricular side of the cupula using inertia and gravity and based on simulations with a 3D biomechanical model. PMID- 27942375 TI - Coping with potential bi-parental inbreeding: limited pollen and seed dispersal and large genets in the dioecious marine angiosperm Thalassia testudinum. AB - The high prevalence of dioecy in marine angiosperms or seagrasses (>50% of all species) is thought to enforce cross-fertilization. However, seagrasses are clonal plants, and they may still be subject to sibling-mating or bi-parental inbreeding if the genetic neighborhood is smaller than the size of the genets. We tested this by determining the genetic neighborhoods of the dioecious seagrass Thalassia testudinum at two sites (Back-Reef and Mid-Lagoon) in Puerto Morelos Reef Lagoon, Mexico, by measuring dispersal of pollen and seeds in situ, and by fine-scale spatial autocorrelation analysis with eight polymorphic microsatellite DNA markers. Prevalence of inbreeding was verified by estimating pairwise kinship coefficients; and by analysing the genotypes of seedlings grown from seeds in mesocosms. Average dispersal of pollen was 0.3-1.6 m (max. 4.8 m) and of seeds was 0.3-0.4 m (max. 1.8 m), resulting in a neighborhood area of 7.4 m2 (range 3.4 11.4 m2) at Back-Reef and 1.9 (range 1.87-1.92 m2) at Mid-Lagoon. Neighborhood area (Na) derived from spatial autocorrelation was 0.1-20.5 m2 at Back-Reef and 0.1-16.9 m2 at Mid-Lagoon. Maximal extensions of the genets, in 19 * 30 m plots, were 19.2 m (median 7.5 m) and 10.8 m (median 4.8 m) at Back-Reef and Mid-Lagoon. There was no indication of deficit or excess of heterozygotes nor were coefficients of inbreeding (FIS) significant. The seedlings did not show statistically significant deficit of heterozygotes (except for 1 locus at Back Reef). Contrary to our expectations, we did not find evidence of bi-parental inbreeding in this dioecious seagrass with large genets but small genetic neighborhoods. Proposed mechanisms to avoid bi-parental inbreeding are possible selection against homozygotes during fecundation or ovule development. Additionally, the genets grew highly dispersed (aggregation index Ac was 0.09 and 0.10 for Back-Reef and Mid-Lagoon, respectively); such highly dispersed guerrilla like clonal growth form likely increases the probability of crossing between different potentially unrelated genets. PMID- 27942376 TI - Improved nutrition cues switch from efficiency to luxury phenotypes for a long lived ungulate. AB - Cervid phenotype can be categorized as efficiency, which promotes survival but not extravagant growth, or luxury which promotes growth of large weaponry and body size. Although nutritional variation greatly influences these phenotypic forms, the potential for subspecies-linked genetic or founder effects from restocking efforts of harvested species has not been eliminated. We measured intergenerational phenotypic change of males in response to improved nutrition in three captive-reared populations of white-tailed deer. Study animals were offspring of females captured from three regions displaying variation in antler and body size as well as nutritional variation. We fed all animals a high-quality diet and measured antler and body size for two generations. We predicted that improved long-term nutrition would cue a switch from efficiency to luxury phenotype for all populations and that regional compensation of antler and body size would occur. Improved nutrition positively influenced all measures of antler and body size; however, changes varied in magnitude. Antler size was more responsive than body size. Improved nutrition also facilitated regional compensation of antler size and partial compensation of body size. Our results show that improved long-term nutrition cues a shift from efficiency to luxury phenotype in a long-lived cervid with weaponry being more responsive than body size. Compensation of antler size suggests that weaponry is greatly influenced by nutrition and is not restricted by subspecies-linked genetic or founder effects from restocking efforts related to our regional populations. Therefore, strategies to improve cervid antler and body size should include habitat management that elevates long-term diet quality. PMID- 27928497 TI - The invariances of power law size distributions. AB - Size varies. Small things are typically more frequent than large things. The logarithm of frequency often declines linearly with the logarithm of size. That power law relation forms one of the common patterns of nature. Why does the complexity of nature reduce to such a simple pattern? Why do things as different as tree size and enzyme rate follow similarly simple patterns? Here I analyze such patterns by their invariant properties. For example, a common pattern should not change when adding a constant value to all observations. That shift is essentially the renumbering of the points on a ruler without changing the metric information provided by the ruler. A ruler is shift invariant only when its scale is properly calibrated to the pattern being measured. Stretch invariance corresponds to the conservation of the total amount of something, such as the total biomass and consequently the average size. Rotational invariance corresponds to pattern that does not depend on the order in which underlying processes occur, for example, a scale that additively combines the component processes leading to observed values. I use tree size as an example to illustrate how the key invariances shape pattern. A simple interpretation of common pattern follows. That simple interpretation connects the normal distribution to a wide variety of other common patterns through the transformations of scale set by the fundamental invariances. PMID- 27942379 TI - Are all after-hours diagnostic imaging appropriate? An Australian Emergency Department pilot study. AB - BACKGROUND: This study was aimed at determining the extent to which after-hours diagnostic imaging is appropriate within the case hospital's Emergency Department. This was amid growing concerns of the inappropriateness of some medical investigations within the Australian health-care system. METHODS: After hours referral data and patient notes were used in reviewing the clinical case. Diagnostic imaging was deemed appropriate if reflective of clinical guidelines, and if not reflective, whether the investigation changed the patient's ongoing management. RESULTS: Results indicated that 96.37% of after-hours diagnostic imaging adhered to clinical guidelines and was appropriately requested, with 95.85% changing the ongoing management of the patient. The most sought after diagnostic imaging procedures were Chest X-Ray (30.83%), and CT Brain (16.58%), with 99.16% and 98.44 appropriateness respectively. Chest pain (14.49%) and motor vehicle accidents (8.12%) were the leading reason for ordering after-hours imaging. CONCLUSION: This study provided an Emergency Department example as it relates to after-hours diagnostic imaging appropriateness. This study found that most after-hours referrals were appropriate. PMID- 27942381 TI - Problem-based learning in medical school: A student's perspective. AB - Problem-based learning (PBL) has been a concept in existence for decades yet its implementation in medical student education is limited. Considering the nature of a physician's work, PBL is a logical step towards developing students' abilities to synthesize and integrate foundational concepts into clinical medicine. Harvard's recently redesigned Pathways curriculum has shifted almost exclusively towards PBL in its one-year preclinical curriculum. This piece provides my thoughts, both derived from my own reflections as well as conversations and observations of my peers, on the effectiveness, advantages, and disadvantages of a PBL curriculum. All in all, the feelings of my peers and I regarding PBL has been overwhelmingly positive despite potential areas of improvement and continued fine-tuning. PMID- 27942382 TI - A case report: Giant intra-abdominal liposarcoma presenting acute renal failure. AB - INTRODUCTION: Liposarcomas represent 20-30% of adult soft tissue tumors and its abdominal localization occurs only in 5% of cases. Most are asymptomatic, but few present with abdominal mass and pain, fatigue, nausea, vomiting. They infiltrate adjacent organs and cause intestinal obstruction, intestinal ischemia perforation, hydronephrosis, ureteric fistula and even aortic rupture. Here we aimed to report a rare case of a giant liposarcoma which originated from mesentery. PRESENTATION OF CASE: A 45-year-old male presented with slightly abdomen distention, urinary retention, oliguria since fifteen days. There was no concomitant nausea, vomiting and lower extremity edema. We found renal function tests abnormal. Contrast-enhanced computed tomography (CT) demonstrated a 20 * 18 cm, well-circumscribed, lobulated, heterogeneous mass. Both ureters were compressed by the mass. The entire mass was totally excised. After the operation, the patient's renal function returned to normal levels dramatically. The tumor was diagnosed as dedifferentiated liposarcoma. DISCUSSION: In cases of intra abdominal mass is detected, surely abdominal compartment syndrome (ACS) should be considered. If vital signs, pulmonary function tests (PFT) and value of the CVP are abnormal, intra-abdominal pressure should be measured. Our findings mentioned above were not observed. CONCLUSION: A detailed history should be obtained other abdominal solid organs should also be considered while performing a careful physical examination, the amount of urinary output in particular should be questioned and this sytemic questioning should be supported by specific laboratory tests. PMID- 27942377 TI - Unique aspects of the developing lung circulation: structural development and regulation of vasomotor tone. AB - This review summarizes our current knowledge on lung vasculogenesis and angiogenesis during normal lung development and the regulation of fetal and postnatal pulmonary vascular tone. In comparison to that of the adult, the pulmonary circulation of the fetus and newborn displays many unique characteristics. Moreover, altered development of pulmonary vasculature plays a more prominent role in compromised pulmonary vasoreactivity than in the adult. Clinically, a better understanding of the developmental changes in pulmonary vasculature and vasomotor tone and the mechanisms that are disrupted in disease states can lead to the development of new therapies for lung diseases characterized by impaired alveolar structure and pulmonary hypertension. PMID- 27942380 TI - The place of nasolabial flap in orofacial reconstruction: A review. AB - BACKGROUND: The use of Nasolabial flap (NLF) to reconstruct orofacial soft tissue defects is one of the oldest methods for reconstruction in the medical literature. Despite widespread use of this invaluable flap, there are still controversies over the terms used for the description of this flap. MATERIALS AND METHODS: A search was run in PubMed for articles in English language on nasolabial flap in oral cavity/facial reconstruction, between 1960 and 2016. Inclusion criteria was case series that focused on the anatomy, flap design, blood supply, composition, flap motion, and the reconstructed area and donor site complications. RESULTS: 560 articles were found in PubMed search for nasolabial flap (between 1960 and 2016). 84 articles with case series structure and available full text were included. The results of the search in this topic for anatomy, flap design, blood supply,NLF composition, flap motion, reconstructed area and donor site morbidity are presented. CONCLUSION: Nasolabial flap is an old flap for reconstructive purposes. Over time different modifications have been introduced to expand its usage. Clear definition of the terms used with this flap is given. PMID- 27942384 TI - Efficacy of computed tomography for the prediction of colectomy and mortality in patients with clostridium difficile infection. AB - AIM: To develop a CT predictor scale for the need for colectomy and to evaluate predictors of all-cause mortality within 30 days after diagnosis ofC. difficile infection (CDI). METHODS: We conducted a retrospective study of adult hospitalized patients whounderwent abdominal CT within 72 h of diagnosis of CDI. RESULTS: Presence of abnormal wall thickening in caecum (OR 8.0; CI 1.37-46.81; p = 0.021), transverse colon (OR 6.7; CI 1.15-35.60; p = 0.034), sigmoid colon (OR 12.6; CI 1.37-115.97; p = 0.025), pancolitis (OR 7.0; CI 1.36-36.01; p = 0.02) and bowel dilation (OR 16.5; CI 2.41-112.83; p = 0.004) predicted colectomy. With these values, a five parameter radiological scale from 0 to 24 was developed (sensitivity and NPV of 100%, cut-off of 6). Furthermore, wall thickening of caecum (OR 6.2; CI 1.06-35.57; p = 0.043), ascending colon (OR 12.0; CI 1.29 111.32; p = 0.029), descending colon (OR 17.0; CI 1.81-160.05; p = 0.013) and sigmoid (OR 10.2; CI 1.10-94.10; p = 0.041) independently predicted mortality within 30 days of CDI diagnosis. CONCLUSION: We designed a CT scale to predict colectomy, able to rule out the development of fulminant colitis and the need for surgical procedure. Patients with wall thickening of the caecum, ascending, descending or sigmoid colon were more likely to die within 30 days of CDI diagnosis. PMID- 27942383 TI - Autologous fat transplantation for breast reconstruction: A literature review. AB - INTRODUCTION: The use of autologous fat transplantation to correct volume and contour defects, scars, and asymmetry after breast cancer surgery has increased over the past 20 years. Many developments and refinements in this technique have taken place in recent years, and several studies of the safety of lipofilling in the breast have been published. PRESENTATION OF CASE: We performed a literature review of this technique, highlighting the crucial role of lipofilling in breast cancer reconstruction. DISCUSSION: The efficacy of the fat graft transplantation depends on the experience and the technique used by the surgeon. The ASCs (adipose-derived stem cells) contained in the fat graft has proven to be crucial for breast reconstruction by mean the regeneration of tissue, through the chemotactic, paracrine, and immunomodulatory activities and their in situ differentiation. CONCLUSION: The role of lipofilling for breast reconstruction could be more significant with the application of the findings of experimental research on tissue engineering and ASCs. PMID- 27942385 TI - Walking the Talk: Adopting and Adapting Sustainable Scientific Software Development processes in a Small Biology Lab. AB - The khmer software project provides both research and production functionality for largescale nucleic-acid sequence analysis. The software implements several novel data structures and algorithms that perform data pre-fltering for common bioinformatics tasks, including sequence mapping and de novo assembly. Development is driven by a small lab with one full-time developer (MRC), as well as several graduate students and a professor (CTB) who contribute regularly to research features. Here we describe our efforts to bring better design, testing, and more open development to the khmer software project as of version 1.1. The khmer software is developed openly at http://github.com/dib-lab/khmer/. PMID- 27942386 TI - Are patients with pulmonary tuberculosis who are identified through active case finding in the community different than those identified in healthcare facilities? AB - The lack of healthcare access contributes to large numbers of tuberculosis (TB) cases being missed and has led to renewed interest in outreach approaches to increase detection. It is however unclear whether outreach activities increase case detection or merely identify patients before they attend health facilities. We compared adults with cough of >2 weeks' duration recruited in health facilities (1202 participants) or in urban slums (2828 participants) in Nigeria. Participants provided demographic and clinical information and were screened using smear microscopy. The characteristics of smear-positive and smear-negative individuals were compared stratified by place of enrolment. Two hundred nine health facility participants (17.4%) and 485 community-based participants (16.9%) were smear positive for pulmonary TB. Community-based smear-positive cases were older (mean age, 36.3 vs. 31.8 years), had longer cough duration (10.3 vs. 6.8 weeks) and longer duration of weight loss (4.6 vs. 3.6 weeks) than facility-based cases; and they complained more of fever (87.4% vs. 74.6%), chest pain (89.0% vs. 67.0%) and anorexia (79.5% vs. 55.5%). Community smear-negative participants were older (mean, 39.4 vs. 34.0 years), were more likely to have symptoms and were more likely to have symptoms of longer duration than smear-negative facility based participants. Patients with pulmonary TB identified in the community had more symptoms and longer duration of illness than facility-based patients, which appeared to be due to factors differentially affecting access to healthcare. Community-based activities targeted at urban slum populations may identify a different TB case population than that accessing stationary services. PMID- 27942387 TI - "Libanicoccus massiliensis" gen. nov., sp. nov., a new bacterium isolated from a stool sample from a pygmy woman. AB - This study supports the main characteristics of a new genus "Libanicoccus massiliensis" strain Marseille-P3237 (CSURP3237); a new member of the order Coribacteriaceae that was isolated from a stool sample from a healthy 35-year-old pygmy woman. PMID- 27942388 TI - Aligning provider incentives to improve primary healthcare delivery in the United States. AB - BACKGROUND: The United States (US) is reforming primary care delivery systems, including the implementation of 'patient-centered medical homes.' Alignment of provider incentives with desired outcomes will likely be important to the success of these delivery system reforms. METHODS: This critical review uses a theoretical framework from game-theory models to discuss some of the dominant primary care provider payment models and how they create 'prisoner's dilemmas' that have stalled past reform efforts. It then uses this framework to illustrate, hypothetically, how advantages from different models could be blended together to encourage cooperation and improve the quality of primary care services delivered, thus providing an escape from current prisoner's dilemmas faced by providers. FINDINGS: Improvements in primary care delivery will largely hinge on blended payment mechanisms that can effectively combine the advantageous elements of fee for-service, capitation, and incentive payments into a balanced equation that enables providers to escape the perverse financial incentives of current payment mechanisms and overcome collective action problems. CONCLUSIONS: If balanced appropriately, a blend of guaranteed payment and selective incentives designed to encourage primary care providers to deliver high quality care, efficient and equitable care and to eliminate incentives towards over-servicing could reach outcomes leading to shared benefits for everyone involved. PMID- 27942389 TI - Feasibility study of emergency intervention for vascular injury outside the hospital. AB - BACKGROUND: Minimally invasive surgery in the field of traumatic vascular injury diagnosis and treatment has achieved good results. This study was designed to determine whether pre-hospital emergency intervention is feasible for vascular injury in a field intervention cabin under the condition of war or a disaster site. METHODS: Different types of animal experiments of vascular injury intervention were performed in a field intervention cabin. Treatment capacity was evaluated by data collection, including duration of surgery, clinical evaluation, image clarity, and equipment handling. Environmental adaptability and mobility were evaluated by maneuverability and long-distance mobility. RESULTS: A total of 56 surgeries (7 types) were performed in the field intervention cabin. Digital subtraction angiography (DSA) had good imaging performance. A total of 4800 km of long-distance mobility was performed, and all the equipment operated normally without any equipment failure. We participated in the medical service maneuver twice. The cabin unfolded and worked properly. There was no equipment damage during the medical service maneuver. CONCLUSIONS: Use of a field intervention cabin under the conditions of war or disaster is feasible for pre-hospital emergency intervention of vascular injury. PMID- 27942390 TI - Whip spiders (Amblypygi) become water-repellent by a colloidal secretion that self-assembles into hierarchical microstructures. AB - BACKGROUND: Among both plants and arthropods, super-hydrophobic surfaces have evolved that enable self-cleaning, locomotion on water surfaces, or plastron respiration. Super-hydrophobicity is achieved by a combination of non-polar substances and complex micro- and nano-structures, usually acquired by growing processes or the deposition of powder-like materials. RESULTS: Here we report on a multi-phasic secretion in whip spiders (Arachnida, Amblypygi), which externally forms durable, hierarchical microstructures on the basically smooth cuticle. The solidified secretion crust makes the previously highly wettable cuticle super hydrophobic. We describe the ultrastructure of secretory cells, and the maturation and secretion of the different products involved. CONCLUSION: Whip spiders represent intriguing objects of study for revealing the mechanisms of the formation of complex microstructures in non-living systems. Understanding the physical and chemical processes involved may, further, be of interest for bio inspired design of functional surface coatings. PMID- 27942391 TI - Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy. AB - Metastatic basal cell carcinomas are rare malignancies harbouring Hedgehog pathway alterations targetable by SMO antagonists (vismodegib/sonidegib). We describe, for the first time, the molecular genetics and response of a patient with Hedgehog inhibitor-resistant metastatic basal cell carcinoma who achieved rapid tumour regression (ongoing near complete remission at 4 months) with nivolumab (anti-PD1 antibody). He had multiple hallmarks of anti-PD1 responsiveness including high mutational burden (> 50 mutations per megabase; 19 functional alterations in tissue next-generation sequencing (NGS; 315 genes)) as well as PDL1/PDL2/JAK2 amplification (as determined by both tissue NGS and by analysis of plasma-derived cell-free DNA). The latter was performed using technology originally developed for the genome-wide detection of sub-chromosomal copy-number alterations (CNAs) in noninvasive prenatal testing and showed numerous CNAs including amplification of the 9p24.3-9p22.2 region containing PD L1, PD-L2 and JAK2. Of interest, PD-L1, PD-L2 and JAK2 amplification is a characteristic of Hodgkin lymphoma, which is exquisitely sensitive to nivolumab. In conclusion, selected SMO antagonist-resistant metastatic basal cell carcinomas may respond to nivolumab based on underlying molecular genetic mechanisms that include PD-L1 amplification and high tumour mutational burden. PMID- 27942392 TI - Disruption of type 3 adenylyl cyclase expression in the hypothalamus leads to obesity. AB - Evidence from human studies and transgenic mice lacking the type 3 adenylyl cyclase (AC3) indicates that AC3 plays a role in the regulation of body weight. It is unknown in which brain region AC3 exerts such an effect. We examined the role of AC3 in the hypothalamus for body weight control using a floxed AC3 mouse strain. Here, we report that AC3 flox/flox mice became obese after the administration of AAV-CRE-GFP into the hypothalamus. Both male and female AC3 floxed mice showed heavier body weight than AAV-GFP injected control mice. Furthermore, mice with selective ablation of AC3 expression in the ventromedial hypothalamus also showed increased body weight and food consumption. Our results indicated that AC3 in the hypothalamus regulates energy balance. PMID- 27942393 TI - Off-pump coronary artery bypass grafting: where are we now? PMID- 27942394 TI - Current outcomes of off-pump versus on-pump coronary artery bypass grafting: evidence from randomized controlled trials. AB - Coronary artery bypass grafting remains the standard treatment for patients with extensive coronary artery disease. Coronary surgery without use of cardiopulmonary bypass avoids the deleterious systemic inflammatory effects of the extracorporeal circuit. However there is an ongoing debate surrounding the clinical outcomes after on-pump versus off-pump coronary artery bypass (ONCAB versus OPCAB) surgery. The current review is based on evidence from randomized controlled trials (RCTs) and meta-analyses of randomized studies. It focuses on operative mortality, mid- and long-term survival, graft patency, completeness of revascularisation, neurologic and neurophysiologic outcomes, perioperative complications and outcomes in the high risk groups. Early and late survival rates for both OPCAB and ONCAB grafting are similar. Some studies suggest early poorer vein graft patency with off-pump when compared with on-pump, comparable midterm arterial conduit patency with no difference in long term venous and arterial graft patency. A recent, pooled analysis of randomised trials shows a reduction in stroke rates with use off-pump techniques. Furthermore, OPCAB grafting seems to reduce postoperative renal dysfunction, bleeding, transfusion requirement and respiratory complications while perioperative myocardial infarction rates are similar to ONCAB grafting. The high risk patient groups seem to benefit from off pump coronary surgery. PMID- 27942396 TI - Off-pump coronary artery bypass grafting in left main stem stenosis: outcomes, concerns and controversies. AB - Left main stem (LMS) disease is known to be a poor prognostic factor in terms of morbidity or mortality. Traditionally, it has been treated with constitution of bypass to provide required haemodynamic stability. We searched the literature for evidence on off-pump (OFP) surgery for treating this high-risk group of patients focusing in our review on postoperative outcomes, concerns and controversies. The majority of the studies identified showed favourable or equal outcomes of OFP when compared to conventional approach. All of the studies, apart from two, which showed lower incidence of postoperative deaths, demonstrated equal mortality rates. Stroke rates were found less in three studies. Less blood transfusions, inotropic use and length of study has been also demonstrated. The main concerns of OFP surgery are: haemodynamic instability and less complete revascularization. Main controversies are: same or favourable outcomes despite lower number of grafts with OFP surgery and less stroke rates despite manipulation of aorta with side-clamping. Despite these concerns and controversies OFP surgery has been proven to be feasible and safe as demonstrated by results from numerous studies. PMID- 27942395 TI - Current outcomes of off-pump coronary artery bypass grafting: evidence from real world practice. AB - Coronary artery bypass grafting (CABG) can be performed conventionally using cardiopulmonary bypass (CPB) and aortic clamping or on a beating heart (BH) without the use of CPB, the so-called off-pump CABG. Some surgeons, who are proponents of off-pump CABG, preferentially use this technique for the majority of operations, whereas others use it only in certain situations which warrant avoidance of CPB. Ever since the conception of off-pump CABG, the never-ending debate about which technique of CABG is safe and efficacious continues to date. Several randomized controlled trials (RCTs) have been conducted that have either favored on-pump CABG or have failed to show a significant difference in outcomes between the two techniques. However, these RCTs have been fraught with claims that they do not represent the majority of patients undergoing CABG in real world practice. Therefore, assessment of the benefits and drawbacks of each technique through observational and registry studies would be more representative of patients encountered in daily practice. The present review examines various retrospective studies and meta-analyses of observational studies that compare the early and long-term outcomes of off- and on-pump CABG, which assesses their safety and efficacy. Additionally, their outcomes in older patients, females, and those with diabetes mellitus, renal dysfunction, presence of ascending aortic disease, and/or acute coronary syndrome (ACS) have also been discussed separately. The general consensus is that early results of off-pump CABG are comparable to or in some cases better than on-pump CABG. However, on-pump CABG provides a survival benefit in the long term according to a majority of publications in literature. PMID- 27942397 TI - Off-pump coronary artery bypass grafting in high-risk patients: a review. AB - The role of off-pump coronary artery bypass (OPCAB) grafting in high risk patients remains controversial. While there have been studies showing the potential benefits of it, there is still a lot to be learned from the application of this technique in this sub-group of patients. The results of the different trials and papers that we reviewed seem to indicate a benefit in the OPCAB group. Despite of the fact that trials were significantly different in methodology, especially when choosing the risk score stratification tool or the cut-off to define high risk the literature seems to suggest a benefit from the use of OPCAB surgery. Here, we present a review which focussed on early and late outcome in high risk patients undergoing on- and off-pump coronary revascularization. PMID- 27942398 TI - Off-pump coronary artery bypass grafting in octogenarians. AB - Enhanced life expectancy has confronted cardiac surgery with a rapidly growing population of octogenarians needing coronary artery bypass grafting (CABG). Octogenarians are deemed a high-risk patient population with increased postoperative morbidity and mortality following conventional CABG using cardiopulmonary bypass (CPB). In such patients reducing the invasiveness of the surgical procedure by avoiding CPB may be tried in an attempt to improve outcomes. The increasing performance of off-pump coronary artery bypass (OPCAB) grafting within certain centers reflects surgeon preference to avoid the inherent risks of CPB and cardioplegic arrest including hemodilution, nonpulsatile arterial flow, global myocardial ischemia, atherosclerotic embolization from aortic manipulation, and systemic inflammatory response. Although OPCAB grafting is a well-established surgical myocardial revascularization strategy, its actual benefits in terms of morbidity and mortality remain questionable in the general population. In the higher risk octogenarian patients, however, there is a potential for more tangible clinical benefits when CPB is avoided. This review article provides an overview of the impact of OPCAB grafting on postoperative mortality and morbidity in octogenarians. PMID- 27942400 TI - We should ban the OPCAB approach in CABG, just as we should ban jetliners and bicycles, or maybe not! AB - Implementing a new technical process demands a complex preparation. In cardiac surgery this complex preparation is often reduced to visiting a surgeon who is familiar with a technique. The science of learning has identified that several steps are needed towards a successful implementation. The first step is the creation of a complete conceptual approach; this demands the deposit in writing of the actions and reactions of every involved party in this new approach. By definition a successful implementation starts with the creation of a group of involved individuals willing to collaborate towards a new goal. Then every teachable component, described in this concept, needs to be worked out in simulation training, from the smallest manual step to complete scenario training for complex situations. Finally, optimal organisational learning needs to have an existing database of the previous situation, a clear goal and objective and a new database where every new approach is restudied versus the previous one, using appropriate methods of corrections for variability. A complete implementation will always be more successful versus a partial one, due to the habit in partial implementation to return to the previous routines. PMID- 27942399 TI - Impact of off-pump coronary artery bypass grafting on survival: current best available evidence. AB - The superiority of either off-pump (OPCAB) or on-pump (ONCAB) coronary artery bypass grafting (CABG) remains unclear despite a large body of literature evidence comparing the two approaches. The potential advantages of avoiding cardiopulmonary bypass (CPB), minimizing aortic manipulation and maintaining pulsatile flow may be associated with reduced inflammatory responses and embolic events. Numerous studies compared OPCAB with ONCAB and the cumulative data have been presented in meta-analyses of both randomized and observational studies. Although there is an abundance of data with respect to the operative morbidity and mortality and the short-term outcomes associated with these two strategies, not much is known about how they impact long-term survival and recurrence of myocardial ischaemic events. Recent studies and meta-analyses have focused on long-term survival and major secondary outcomes in OPCAB vs. ONCAB within the general population. Significant limitations in methodology, however, have raised concerns about the strength of several randomized trials with restrictive inclusion criteria that reduced the populations to those at low risk only, thus creating result bias. Here, we present a review of the best available evidence with a focus on long-term outcomes. PMID- 27942401 TI - Two decades of off-pump coronary artery bypass surgery: Harefield experience. AB - The morbidity and mortality associated with conventional coronary artery bypass grafting (CABG) attributed to invasiveness of cardiopulmonary bypass (CPB) has been well documented. Recognition of this invasiveness with a focus centered on abolishing, or at least reducing the CPB associated morbidity and mortality led to the resurgence of off-pump coronary artery bypass (OPCAB) surgery nearly two decades ago. At about the same time, OPCAB was adopted at Harefield hospital partly as an institutional drive to promote innovation and partly as a strategy to improve outcomes. What was deemed as a challenging technique initially and practiced by a single surgeon has now become a valid substitute to conventional CABG for achieving complete myocardial revascularization. This strategy now accounts for more than 50% of all coronary artery surgery operations at Harefield hospital and is systematically used to treat all coronary anatomies; achieve complete revascularization by accessing all territories subtended by main coronary arteries; and accomplish equivalent quality grafts without restriction in vascular conduit usage. This review article provides an overview of the evolution of OPCAB surgery at an institution with a well-established OPCAB program confirming that as surgeons' experience matures, OPCAB surgery permits safe and effective total myocardial revascularization in virtually all patients with multivessel coronary artery disease. PMID- 27942402 TI - Off-pump coronary artery bypass grafting (OPCABG)-a 'personal' European perspective. AB - Although popularised over two decades ago off-pump coronary artery bypass grafting (OPCABG) has seen a decrease in utilisation especially over the last decade. This has been due to publication of a number of trials which suggested inferior outcomes with OPCABG. However, the validity of the findings in these trials has been questioned on the basis of doubts over operator experience as witnessed by large numbers of cross-overs. Two more recent large randomised trials have shown very similar outcomes between on and off-pump surgery up to 1- and 5-year outcomes are imminently due. Furthermore several meta-analyses have reported that OPCABG reduces mortality, myocardial infarction and major morbidity in higher risk patients. Consequently there is a clear rationale for OPCABG in certain cohorts of patients and especially when combined with a no touch aortic technique in those with significant disease of the ascending aorta. The article discusses the importance of routine performance of OPCABG if it is to produce high quality results and especially in higher risk patients. PMID- 27942404 TI - What's new in advanced lung cancers? PMID- 27942403 TI - The future of off-pump coronary artery bypass grafting: a North American perspective. AB - Off-pump coronary artery bypass graft (OPCAB) is currently performed routinely in a minority of specialized centers and in many more centers, utilized only when a porcelain aorta mandates a no-touch aortic technique. The OPCAB literature can be summarized as follows: (I) large-scale randomized trials in relatively low risk patients that include surgeons with a range of experience demonstrating no consistent beneficial differences in major cardiovascular and cerebrovascular outcomes but lower transfusion rates and shorter length of stay, tempered by some reports of higher rates of incomplete revascularization and lower rates of long term graft patency; (II) smaller randomized controlled trials (RCTs) from highly specialized programs demonstrating equivalent or superior outcomes with OPCAB and similar completeness of revascularization and graft patency; and (III) observational data from large databases demonstrating a consistent benefit of OPCAB, especially in higher-risk patient subsets. Our rationale for OPCAB remains that if complete and precise revascularization can be safely and routinely accomplished, then the patient should benefit by avoiding the morbidities that can be attributed to aortic cannulation/clamping, cardiopulmonary bypass (CPB), hemodilution, hypothermia and global myocardial ischemia/cardioplegia. We further believe that OPCAB procedures should emphasize the use of arterial grafts to optimize long term patency and minimize aortic manipulation to limit the risk of stroke. Moving forward, the off-pump surgical community and specialty societies must address the challenge of training surgeons and their teams to master this technically demanding procedure. Furthermore, OPCAB opens the door to minimally invasive surgical revascularization via hybrid coronary revascularization (HCR). A large NIH-funded RCT is currently underway to determine whether hybrid revascularization can offer a superior alternative to multi-vessel percutaneous coronary intervention for patients with low SYNTAX score and proximal LAD disease. PMID- 27942405 TI - Preoperative functional workup for patients with advanced lung cancer. AB - Locally advanced lung cancer remains a surgical indication in selected patients. This condition often demands larger resections. As a consequence preoperative functional workup is of paramount importance to stratify the risk and choose the most appropriate treatment. We reviewed the current evidence on functional evaluation with a special focus on specific aspects related to locally advanced lung cancer stages (i.e., risk after neoadjuvant treatment, pneumonectomy). Evidence is discussed to provide information that could assist clinicians in their preoperative workup of these challenging patients. PMID- 27942406 TI - N2-IIIA non-small cell lung cancer: a plea for surgery! AB - Management of stage IIIA-N2 non-small cell lung cancer is still matter of ongoing controversy. The debate is flawed by the heterogeneity of this group of patients, lack of strong evidence from controlled trials, diverging treatment strategies, and hesitating estimation of prognosis. Surgery is credited a survival advantage in a trimodality setting. For many teams, N2 is by principle managed with induction chemotherapy, followed by surgery if the patient is down-staged. However, surgery remains a suitable option even in case of persistent N2. On the other hand, outcomes are comparable, regardless whether chemotherapy has been given as induction or adjuvant treatment. Hence, upfront surgery without invasive staging, followed by adjuvant therapies, appears reasonable in resectable single station N2 disease, simplifying patient care and reducing cost. We expect that molecular biomarkers will improve estimation of prognosis and patient selection in the future. PMID- 27942407 TI - Primary lung tumors invading the chest wall. AB - Chest wall (CW) involvement occurs in approximately 5% of all primary lung neoplasms. According to the most recent TNM classification, lung tumors invading CW are classified as T3, and they represent approximately 45% of all T3 lung cancers. The most common clinical symptom at presentation is chest pain (>60%), which is highly specific of CW infiltration (>90%). Dyspnoea and hemoptysis are also described, especially in case of large lesions. A realistic chance to cure locally advanced tumors invading CW is a surgical resection, consisting in the excision of the primary lung cancer along with the involved CW (sometimes an "en bloc" resection) and an appropriate lymph-nodal dissection. However, such patients are at high-risk of facing postoperative complications; prognosis mainly depends on: (I) the completeness of resection; and (II) the lymph-nodal involvement. Hence, due to these reasons (incidence, symptoms, prognosis, post operative complications), such category of patients are to be carefully assessed preoperatively and if deemed practicable, surgery should be taken into consideration. In this view, the aim of this paper is to critically review the most recent series of lung tumors invading the CW, with a particular focus on patients' preoperative evaluation, surgical techniques, postoperative complications and overall outcome. PMID- 27942408 TI - Chest wall reconstruction after extended resection. AB - Extensive chest wall resection and reconstruction is a challenging procedure that requires a multidisciplinary approach, including input from thoracic surgeons, plastic surgeons, neurosurgeons, and radiation oncologists. The primary goals of any chest wall reconstruction is to obliterate dead space, restore chest wall rigidity, preserve pulmonary mechanics, protect intrathoracic organs, provide soft tissue coverage, minimize deformity, and allow patients to receive adjuvant radiotherapy. Successful chest wall reconstruction requires the re-establishment of skeletal stability to prevent chest wall hernias, avoids thoracoplasty-like contraction of the operated side, protects underlying viscera, and maintain a cosmetically-acceptable appearance. After skeletal stability is established, full tissue coverage can be achieved using direct closure, skin grafts, local advancement flaps, pedicled myocutaneous flaps, or free flaps. This review examines the indications for chest wall reconstruction and describes techniques for establishment of chest wall rigidity and soft tissue coverage. PMID- 27942409 TI - Bronchial and arterial sleeve resection for centrally-located lung cancers. AB - The use of bronchial and arterial sleeve resections for the treatment of centrally-located lung cancers, when available, has become the option of choice in comparison with pneumonectomy (PN). Technical expertise, in particular in vascular reconstruction, and perioperative management improved over time allowing excellent short-term and long-term results. This is even truer if considering literature data from the main experiences published in the last years. These evidences have given to such lung sparing reconstructive procedures more and more acceptance among the surgical community. This article focuses on the main technical aspects and literature data regarding bronchovascular sleeve resections. PMID- 27942410 TI - Carinal resection and sleeve pneumonectomy. AB - Carinal resection (CR) and sleeve pneumonectomy (SP) are one of the challenging issues in thoracic surgery and performed rarely. In spite of the knowledge of the technique, the incidence of postoperative complications is higher compared to standard resections. Adequate patient selection, improved anesthetic management, surgical technique and better postoperative management might reduce the rate of postoperative morbidity and mortality. PMID- 27942411 TI - Surgery for lung cancer invading the mediastinum. AB - Lung cancer infiltrating the mediastinum is a subset of locally advanced lung tumors for which surgery is not routinely offered. Radical operations that involve removal of adjacent mediastinal structures to obtain free margins may provide a realistic cure. Such extended resections are typically reserved to highly motivated patients seeking more aggressive management, and are only offered following complete evaluation on a case-by-case basis. Positive prognosis depends on complete R0 resection and lack of mediastinal nodal metastases. Careful and exhaustive preoperative planning as well as surgical expertise cannot be overemphasized for successful surgical outcomes. Here we provide a brief summary of the literature as well as our own experience managing these rare and sometimes challenging surgeries. PMID- 27942412 TI - Surgical management of oligometastatic non-small cell lung cancer. AB - The oligometastatic stage IV non-small cell lung cancer (NSCLC) offers a new surgical opportunity. New reported data is showing that surgery can offer a reasonable benefit, in terms of long-term survival, to some patients. The advantages of surgical treatment rely on a more adequate patient selection and a better understanding of the biology of these tumors. Currently, mediastinal involvement of the primary tumor can be identified as the most important prognostic variable after curative-intent of synchronous or metachronous metastasis. It seems clear that the routine use of combined FDG-PET and CT will help to detect the more favorable cohort of oligometastatic patients. As expected, pathological T staging of the primary tumor and the completeness of its resection are also crucial factors influencing final results. The real benefit of the local treatment over synchronous or metachronous metastasis is controversial with series showing better outcomes for metachronous lesions than for synchronous and others offering equal results. Also non conclusive results appear when analyzing different sites of metastasis. Retrospective series tend to show different outcomes depending on the affected organ while usually no differences are found in prospective ones. Most of the current evidence is based on retrospective studies on patients collected along extended periods of time. That represents a great limitation to the knowledge on this topic. Some prospective analyses have added some insight, but still the quality of the evidence is too low to allow drawing robust conclusions. As frequently concluded, prospective well designed investigation is requested to ascertain the value of surgery in this specific population of patients with extended NSCLC. PMID- 27942413 TI - The role of surgical intervention in lung cancer with carcinomatous pleuritis. AB - Patients with non-small cell lung cancer (NSCLC) associated with carcinomatous pleuritis are currently classified as having stage IV disease per the 7th edition of the tumor-node-metastasis (TNM) system, which means that the disease is deemed incurable. In fact, the 5-year survival rate of these patients was only 2% in a large global cohort collected by the International Association for the Study of Lung Cancer. However, patients with carcinomatous pleuritis have heterogeneous conditions. Some have minimal pleural effusion, which is first detected at thoracotomy; some have numerous pleural nodules without any effusion; and others have massive effusion and nodules with symptoms. Several investigators have reported the contribution of surgical intervention to favorable outcomes of patients with carcinomatous pleuritis first detected at thoracotomy. These reports show a relatively higher 5-year survival rate of 15% to 37%. The extrapleural pneumonectomy (EPP) is a radical surgical procedure that is commonly employed in the treatment of malignant pleural mesothelioma. Two authors reported that they have successfully performed EPPs for the treatment of patients with carcinomatous pleuritis. Their 5-year survival rates were estimated to be 22% and 61%, a significantly improved outcome. Although the development of chemotherapeutic agents, including molecular targeted drugs, might have the potential to prolong the survival of patients with advanced lung cancer, surgical interventions including EPP might have a role in improving the survival of patients with carcinomatous pleuritis of minimal disease and those without massive effusion or numerous pleural nodules. PMID- 27942414 TI - Lung cancer in elderly patients. AB - There is a worldwide-accepted evidence of a population shift toward older ages. This shift favors an increased risk of developing lung cancer that is primarily a disease of older populations. Decision making is extremely difficult in elderly patients, since this group is under-represented in clinical trials with only 25% of them historically opening to patients older than 65 years. For all these reasons, a "customized" preoperative assessment to identify physiological or pathological frailty should be encouraged since standard tools may be less reliable. The work already done to improve patient selection for lung surgery in the elderly population clearly shows that surgical resection seems the treatment of choice for early stage lung cancer. Further studies are required to improve outcome by reducing postoperative morbidity and mortality. PMID- 27942416 TI - Ckmeans.1d.dp: Optimal k-means Clustering in One Dimension by Dynamic Programming. AB - The heuristic k-means algorithm, widely used for cluster analysis, does not guarantee optimality. We developed a dynamic programming algorithm for optimal one-dimensional clustering. The algorithm is implemented as an R package called Ckmeans.1d.dp. We demonstrate its advantage in optimality and runtime over the standard iterative k-means algorithm. PMID- 27942415 TI - Lung cancer: a rare indication for, but frequent complication after lung transplantation. AB - Lung transplantation is an effective and safe therapy for carefully selected patients suffering from a variety of end-stage pulmonary diseases. Lung cancer negatively affects prognosis, particularly in patients who are no longer candidates for complete resection. Lung transplantation can be considered for carefully selected and well staged lung cancer patients with proven, lung limited, multifocal, (minimally invasive) adenocarcinoma in situ (AIS) (previously called bronchioloalveolar cell carcinoma) causing respiratory failure. Despite a substantial risk of tumour recurrence (33-75%), lung transplantation may offer a survival benefit (50% at 5 years) with best palliation of their disease. Reports on lung transplantation for other low-grade malignancies are rare. Lung transplant candidates at higher risk for developing lung cancer [mainly previous smokers with chronic obstructive lung disease (COPD) and idiopathic pulmonary fibrosis (IPF) or older patients] should be thoroughly and repeatedly screened for lung cancer prior to listing, and preferably also during waiting list time if longer than 1 year, including the use of PET-CT scan and EBUS-assisted bronchoscopy in case of undefined, but suspicious pulmonary abnormalities. Double-lung transplantation should now replace single-lung transplantation in these high-risk patients because of a 6-9% prevalence of lung cancer developing in the remaining native lung. Patients with unexpected, early stage bronchial carcinoma in the explanted lung may have favourable survival without recurrence. Early PET-CT (at 3-6 months) following lung transplantation is advisable to detect early, subclinical disease progression. Donor lungs from (former) smokers should be well examined at retrieval. Suspicious nodules should be biopsied to avoid grafting cancer in the recipient. Close follow-up with regular visits and screening test in all recipients is needed because of the increased risk of developing a primary or secondary cancer in the allograft from either donor or recipient origin. PMID- 27942417 TI - Quantitative structure-activity relationship and molecular docking studies of a series of quinazolinonyl analogues as inhibitors of gamma amino butyric acid aminotransferase. AB - Quantitative structure-activity relationship and molecular docking studies were carried out on a series of quinazolinonyl analogues as anticonvulsant inhibitors. Density Functional Theory (DFT) quantum chemical calculation method was used to find the optimized geometry of the anticonvulsants inhibitors. Four types of molecular descriptors were used to derive a quantitative relation between anticonvulsant activity and structural properties. The relevant molecular descriptors were selected by Genetic Function Algorithm (GFA). The best model was validated and found to be statistically significant with squared correlation coefficient (R2) of 0.934, adjusted squared correlation coefficient (R2adj) value of 0.912, Leave one out (LOO) cross validation coefficient (Q2) value of 0.8695 and the external validation (R2pred) of 0.72. Docking analysis revealed that the best compound with the docking scores of -9.5 kcal/mol formed hydrophobic interaction and H-bonding with amino acid residues of gamma aminobutyric acid aminotransferase (GABAAT). This research has shown that the binding affinity generated was found to be better than the commercially sold anti-epilepsy drug, vigabatrin. Also, it was found to be better than the one reported by other researcher. Our QSAR model and molecular docking results corroborate with each other and propose the directions for the design of new inhibitors with better activity against GABAAT. The present study will help in rational drug design and synthesis of new selective GABAAT inhibitors with predetermined affinity and activity and provides valuable information for the understanding of interactions between GABAAT and the anticonvulsants inhibitors. PMID- 27942418 TI - Mid-career faculty development in academic medicine: How does it impact faculty and institutional vitality? AB - PURPOSE: Faculty vitality is integral to the advancement of higher education. Strengthening vitality is particularly important for mid-career faculty, who represent the largest and most dissatisfied segment. The demands of academic medicine appear to be another factor that may put faculty at risk of attrition. To address these issues, we initiated a ten-month mid-career faculty development program. METHODS: A mixed-methods quasi-experimental design was used to evaluate the program's impact on faculty and institutional vitality. Pre/post surveys compared participants with a matched reference group. Quantitative data were augmented by interviews and focus groups with multiple stakeholders. RESULTS: At the program's conclusion, participants showed statistically significant gains in knowledge, skills, attitudes, and connectivity when compared to the referents. CONCLUSION: Given that mid-career faculty development in academic medicine has not been extensively studied, our evaluation provides a useful perspective to guide future initiatives aimed at enhancing the vitality and leadership capacity of mid-career faculty. PMID- 27942420 TI - ER Stress-induced Inflammasome Activation Contributes to Hepatic Inflammation and Steatosis. AB - Endoplasmic reticulum (ER) stress functions as a protein folding and quality control mechanism to maintain cell homeostasis. Emerging evidence indicates that ER stress is also involved in metabolic and inflammatory diseases. However, the link between ER stress and inflammation remains not well characterized. In this study, we have demonstrated that ER stress-induced inflammasome activation plays a critical role in the pathogenesis of hepatic steatosis. By utilizing genetic and pharmacological agent-induced hepatic steatosis animal models, we found that hepatic steatosis was associated with inflammasome activation and ER stress. Our results show that caspase-1 ablation alleviated liver inflammation and injury. Liver tissues from caspase-1 KO mice had significantly reduced production of IL 1beta under ER stress conditions. We also found that ER stress promoted inflammasome activation and IL-1beta processing in both hepatocytes and Kupffer cells/macrophages. Moreover, lack of caspase-1 ameliorated cell death or pyropoptosis of hepatocytes induced by ER stress. Taken together, our findings suggest that ER stress-induced inflammasome activation and IL-1beta production generate a positive feedback loop to amplify inflammatory response, eventually leading to liver steatosis and injury. PMID- 27942419 TI - Immune Suppression Mediated by Myeloid and Lymphoid Derived Immune Cells in the Tumor Microenvironment Facilitates Progression of Thyroid Cancers Driven by HrasG12V and Pten Loss. AB - Thyroid cancer is the most common endocrine malignancy and is predicted to be the 4th most commonly diagnosed cancer by 2030. Approximately one-half of follicular thyroid carcinomas (FTC) contain genetic alterations in RAS family members. Furthermore, Cowden's disease, which is characterized by loss of PTEN, predisposes for the development of FTC in humans. We have shown that thyroid specific expression of HrasG12V at endogenous levels and Pten inactivation (HrasG12V/Pten-/-/TPO-cre mice) leads to the development of FTCs that closely recapitulate human disease, with complete penetrance at one year. In patients, FTCs metastasize via the bloodstream to distant sites, frequently the lungs, bones and brain. The first objective of the study was to determine if these mice developed de novo metastasis to relevant sites. Indeed, spontaneous metastasis to the lungs was observed in 56% of HrasG12V/Pten-/-/TPO-cre mice. We next sought to identify the cellular components within the tumor microenvironment (TME) of FTC that contribute to tumor progression and metastasis via FACS analysis. Surprisingly, a large amount of immune infiltrate was observed. HrasG12V/Pten-/ /TPO-Cre thyroid tumors were comprised of 68.5 +/- 11.79% CD45+ cells, in stark contrast to wild-type (WT) thyroids which were comprised of 17.6% CD45+ cells. Further, 53.1 +/- 10.9% of the CD45+ cells from HrasG12V/Pten-/-/TPO-Cre thyroid tumors were of myeloid-lineage (CD11b+), consisting of macrophages (F4/80+Gr-1-) and myeloid-derived suppressor cells (F4/80-Gr-1+). Further, HrasG12V/Pten-/-/TPO cre tumors contained Arginase-1 positive cells as determined by immunohistochemical analysis, supporting an immunosuppressive TME in HrasG12V/Pten-/-/TPO-Cre thyroid tumors. We next evaluated whether or not cytotoxic (CD8+) or helper T cells (CD4+) were recruited to HrasG12V/Pten-/-/TPO Cre tumors. The majority of T cells in these tumors were double positive for CD4 and CD25, markers of immune suppressive regulatory T cells (Treg). Additionally, we identified Foxp3 positive cells by immunohistochemical analysis of tumor sections, indicating a functional suppressive Treg phenotype in vivo. HrasG12V/Pten-/-/TPO-Cre tumor cell lines displayed increased secretion of SDF-1, I-TAC, CCL9/10, and MCP5, cytokines that have been reported to play a direct role in the chemotaxis of immune cells and thus could contribute to the increased recruitment of myeloid and lymphoid derived cells in HrasG12V/Pten-/-/TPO-Cre tumors. These studies are the first to identify and implicate the interaction between tumor cells and immune cells in Ras-driven thyroid cancer progression, which we hope will lead to the development of more effective therapeutic approaches for aggressive forms of thyroid cancer that target the TME. PMID- 27942421 TI - Economic Hardship, Parents' Depression, and Relationship Distress among Couples With Young Children. AB - Using data from the Fragile Families and Child Well-being Study (N = 1,492 couples), we assessed stress, health selection, and couple-crossover hypotheses by examining (1) the bidirectional association between economic hardship and depressive symptoms one, three, and five years after the birth of a child; (2) the association between economic hardship and depressive symptoms on relationship distress for both parents; and (3) whether the associations vary by marital status. The results suggest a pernicious cycle for mothers after the birth of the child. Economic hardship increases depression, but maternal depression also increases economic hardship. These reinforcing mechanisms increase both mothers' and fathers' relationship distress. Taken together, policies aimed at strengthening couples' relationships should work in tandem with economic and mental health policies to reach optimal outcomes for couples with a young child. Effect patterns were generally consistent between married and cohabiting couples, with some variation in levels of statistical significance. PMID- 27942423 TI - Evaluating the Use of Stretchers in Two Mobile Refuge Alternatives. AB - In a mine emergency where refuge is necessary, miners may sustain injuries that will render them unable to walk or crawl. In this situation, a miner may have to rely on others for transportation into the mobile refuge alternative (RA) while on a stretcher. Since requirements for mine first-aid stations were developed before RAs, stretchers should be evaluated to determine whether they are usable in an RA and within the physical capabilities of miners in a refuge. The size of the RA airlock is a concern, as it has not been determined if current airlocks will accommodate a miner on a stretcher. This study evaluated the time required to move three types of stretchers into two commercially available RAs. The splint stretcher had the longest average time to move into each RA as compared to the backboard and soft stretcher. This increase was mostly due to the increased time requirements for getting the splint stretcher into the airlock. For all stretchers, it took approximately two to three times longer to enter the inflatable tent-type RA compared to the rigid steel RA. Mining companies should consider how well their current first-aid implements work with their RAs and manufacturers of inflatable RAs should maximize the size of the outer doors leading into the airlock to allow an easier entry for stretchers. PMID- 27942422 TI - Expansion of the RASopathies. AB - The Ras/mitogen activated protein kinase (MAPK) pathway is essential in the regulation of cell cycle, differentiation, growth, cell senescence and apoptosis, all of which are critical to normal development. A class of neurodevelopmental disorders, RASopathies, is caused by germline mutations in genes of the Ras/MAPK pathway. Through the use of whole exome sequencing and targeted sequencing of selected genes in cohorts of panel-negative RASopathy patients, several new genes have been identified. These include: RIT1, SOS2, RASA2, RRAS and SYNGAP1, that likely represent new, albeit rare, causative RASopathy genes. In addition, A2ML1, LZTR1, MYST4, SPRY1 and MAP3K8 may represent new rare genes for RASopathies, but, additional functional studies regarding the mutations are warranted. In addition, recent reports have demonstrated that chromosomal copy number variation in regions encompassing Ras/MAPK pathway genes may be a novel pathogenetic mechanism expanding the RASopathies. PMID- 27942425 TI - Learning stochastic finite-state transducer to predict individual patient outcomes. AB - The high frequency data in intensive care unit is flashed on a screen for a few seconds and never used again. However, this data can be used by machine learning and data mining techniques to predict patient outcomes. Learning finite-state transducers (FSTs) have been widely used in problems where sequences need to be manipulated and insertions, deletions and substitutions need to be modeled. In this paper, we learned the edit distance costs of a symbolic univariate time series representation through a stochastic finite-state transducer to predict patient outcomes in intensive care units. The Nearest-Neighbor method with these learned costs was used to classify the patient status within an hour after 10 h of data. Several experiments were developed to estimate the parameters that better fit the model regarding the prediction metrics. Our best results are compared with published works, where most of the metrics (i.e., Accuracy, Precision and F-measure) were improved. PMID- 27942426 TI - Urdu Nasta'liq text recognition using implicit segmentation based on multi dimensional long short term memory neural networks. AB - The recognition of Arabic script and its derivatives such as Urdu, Persian, Pashto etc. is a difficult task due to complexity of this script. Particularly, Urdu text recognition is more difficult due to its Nasta'liq writing style. Nasta'liq writing style inherits complex calligraphic nature, which presents major issues to recognition of Urdu text owing to diagonality in writing, high cursiveness, context sensitivity and overlapping of characters. Therefore, the work done for recognition of Arabic script cannot be directly applied to Urdu recognition. We present Multi-dimensional Long Short Term Memory (MDLSTM) Recurrent Neural Networks with an output layer designed for sequence labeling for recognition of printed Urdu text-lines written in the Nasta'liq writing style. Experiments show that MDLSTM attained a recognition accuracy of 98% for the unconstrained Urdu Nasta'liq printed text, which significantly outperforms the state-of-the-art techniques. PMID- 27942424 TI - Levels of DNA methylation and transcript accumulation in leaves of transgenic maize varieties. AB - BACKGROUND: Prior to their release in the environment, transgenic crops are examined for their health and environmental safety. In addition, transgene expression needs to be consistent in order to express the introduced trait (e.g. insecticidal and/or herbicide tolerance). Moreover, data on expression levels for GM events are usually required for approval, but these are rarely disclosed or they are considered insufficient. On the other hand, biosafety regulators do not consider epigenetic regulation (e.g. DNA methylation, ncRNAs and histone modifications), which are broadly known to affect gene expression, within their risk assessment analyses. Here we report the results of a DNA methylation (bisulfite sequencing) and transgene transcript accumulation (RT-qPCR) analysis of four Bt-expressing single transgenic maize hybrids, under different genetic backgrounds, and a stacked transgenic hybrid expressing both insecticidal and herbicide tolerance traits. RESULTS: Our results showed differences in cytosine methylation levels in the FMV promoter and cry2Ab2 transgene of the four Bt expressing hybrid varieties. The comparison between single and stacked hybrids under the same genetic background showed differences in the 35S promoter sequence. The results of transgene transcript accumulation levels showed differences in both cry1A.105 and cry2Ab2 transgenes among the four Bt-expressing hybrid varieties. The comparison between single and stacked hybrids showed difference for the cry2Ab2 transgene only. CONCLUSIONS: Overall, our results show differences in DNA methylation patterns in all varieties, as well as in transgene transcript accumulation levels. Although the detection of changes in DNA methylation and transgenic accumulation levels does not present a safety issue per se, it demonstrates the need for additional studies that focus on detecting possible safety implications of such changes. PMID- 27942428 TI - Empirical mode decomposition with missing values. AB - This paper considers an improvement of empirical mode decomposition (EMD) in the presence of missing data. EMD has been widely used to decompose nonlinear and nonstationary signals into some components according to intrinsic frequency called intrinsic mode functions. However, the conventional EMD may not be efficient when missing values are present. This paper proposes a modified EMD procedure based on a novel combination of empirical mode decomposition and self consistency concept. The self-consistency provides an effective imputation method of missing data, and hence, the proposed EMD procedure produces stable decomposition results. Simulation studies and the image analysis demonstrate that the proposed method produces substantially effective results. PMID- 27942427 TI - Molecular linkage tracing of HIV-1 transmission events in seroconcordant couples in Guangxi Province, Southeastern China. AB - BACKGROUND: Guangxi Province in Southeastern China has one of the highest HIV-1 infection and transmission rates in stable couples. However, the mode of transmission at the molecular level has seldom been reported amongst this group. It is important to investigate this issue to support the treatment-as-prevention approach and for efficient interventions. METHODS: HIV-1 subgenomic regions (1.2 kb of pol and a 660-bp env C2V5 fragment) were sequenced in 42 couples. A couple linkage assessment was performed by phylogenetic analysis of sequences and Bayesian analysis of genetic distances. A subset of pairs was selected for single genome amplification. RESULTS: Thirty-five pairs (83.3 %, 35/42) were identified as linked, 3 pairs (7.1 %, 3/42) were identified as indeterminate, and 4 pairs (9.5 %) were identified as unlinked. The predominant intra-couple-transmitted HIV 1 subtype was CRF01_AE (80 %, 28/35). The median genetic distance of linked couples was 0.5 %. CONCLUSION: The majority of HIV-1 transmission events in this study occurred within the partnership, and the predominant HIV-1 subtype was CRF01_AE. Further research on the mode of HIV transmission in other locations is needed. PMID- 27942429 TI - Agreement between self-reported healthcare service use and administrative records in a longitudinal study of adults recently released from prison. AB - BACKGROUND: Studies of healthcare service use often rely on self-reported data, especially in disadvantaged populations. Despite this, the reliability of self reported healthcare service use is often questioned and routinely-collected, administrative data are usually considered preferable. In this paper we examine the agreement between self-reported healthcare service use and administrative records, in a large cohort of adults recently released from prison in Australia. METHODS: Baseline interviews within 6 weeks of expected release from prison and follow-up interviews at 1, 3 and 6 months post-release were linked to routinely collected, administrative health records over the same time period. Outcomes of interest included use of primary care, emergency department presentation, hospitalisation and dispensing of subsidised pharmaceuticals. Kappa statistics and positive and negative predictive values were calculated for each service type and time point, and a modified Poisson regression was used to identify participant characteristics associated with better agreement. RESULTS: 864 participants completed interviews and were successfully linked to administrative records. There was good agreement between self-report and administrative health records. Agreement between data sources at 1 month was best for psychotropic medications (kappa = 0.79) and primary care visits (kappa = 0.69). CONCLUSION: Despite a common perception that studies using self-reported data are subject to bias, particularly among the disadvantaged, our findings suggest that self reported healthcare may be valid in vulnerable populations. PMID- 27942430 TI - Prevalence and risk factors of problematic internet use and the associated psychological distress among graduate students of Bangladesh. AB - A growing body of epidemiological literature suggests that problematic Internet use (PIU) is associated with a range of psychological health problems in adolescents and young adults. This study aimed to explore socio-demographic and behavioural correlates of PIU and examine its association with psychological distress. A total of 573 graduate students from Dhaka University of Bangladesh responded to a self-administered questionnaire that included internet addiction test (IAT), 12-items General Health Questionnaire and a set of socio-demographic and behavioural factors. The study found that nearly 24% of the participants displayed PIU on the IAT scale. The prevalence of PIU significantly varied depending on gender, socioeconomic status, smoking habit and physical activity (p < 0.05). The multiple regression analyses suggested that PIU is strongly associated with psychological distress regardless of all other explanatory variables (adjusted OR 2.37, 95% CI 1.57, 3.58). Further research is warranted to confirm this association by employing prospective study designs. PMID- 27942432 TI - Mast Cell Clonal Disorders: Classification, Diagnosis and Management. AB - Mast cell clonal disorders are characterized by the clonal proliferation of pathological mast cells as a result of somatic mutations in the KIT gene, most commonly the D816V mutation. Accumulation and degranulation of these cells causes a wide variety of symptoms. Mast cell clonal disorders can be divided into mastocytosis and monoclonal mast cell activation syndrome, depending of the level of clonality. The severity of mastocytosis varies from an indolent variant with a good prognosis, to an aggressive condition with short life expectancy. Diagnosis is based on demonstration of clonality and accumulation in the skin and in extracutaneous tissues. Treatment is highly individualized, and is based on the severity of the condition. Treatment of patients with indolent systemic mastocytosis is aimed at reducing symptoms, using histamine H1 and H2 receptor antagonists as a starting point. In addition, associated conditions such as osteoporosis must be treated. Treatment of advanced systemic mastocytosis is aimed at reducing mast cell load through cytoreductive therapy. The choice of such therapy depends on the KIT mutational status. Though currently there is no curative treatment available, promising new therapies such as midostaurin are emerging that have demonstrated success in reducing symptoms and improving quality of life. PMID- 27942433 TI - Probabilistic double guarantee kidnapping detection in SLAM. AB - For determining whether kidnapping has happened and which type of kidnapping it is while a robot performs autonomous tasks in an unknown environment, a double guarantee kidnapping detection (DGKD) method has been proposed. The good performance of DGKD in a relative small environment is shown. However, a limitation of DGKD is found in a large-scale environment by our recent work. In order to increase the adaptability of DGKD in a large-scale environment, an improved method called probabilistic double guarantee kidnapping detection is proposed in this paper to combine probability of features' positions and the robot's posture. Simulation results demonstrate the validity and accuracy of the proposed method. PMID- 27942431 TI - Biomarkers for the Phenotyping and Monitoring of Asthma in Children. AB - An important issue in relation to the utility and reliability of biomarkers for asthma monitoring is how asthma is defined and characterized. What kind of asthma, or at what stage of the disease is a particular biomarker supposed to add information? Often, the purpose, or usefulness of a biomarker is not made clear. Diagnosis, severity evaluation, and monitoring are all different clinical uses for a biomarker, and confusion may arise when a biomarker is suitable for one of these but not another. When the utility of available biomarkers are discussed, these different roles need to be clarified. Our opinion is that there are four aspects of relevance to asthma, for which biomarkers are required: to diagnose allergies, to evaluate inflammation in the airways, to evaluate hyper responsiveness, and for certain measures of lung function, such as lung clearance index. These types of biomarkers are needed for the phenotyping and monitoring of asthma. Another important role for biomarkers is, as mentioned above, to monitor asthma in order to follow treatment effects on inflammation and hyper responsiveness as objective adjuncts to the patients' own symptom reports and lung function. This review will mainly focus on biomarkers that reflect airway inflammation. In spite of the numerous studies that have been conducted, we still have to remember that the value of biomarkers available for routine use, such as eosinophil counts in blood and sputum and exhaled nitric oxide, have to be interpreted in relation to reported symptoms and lung function. Measures of bronchial hyper-responsiveness, performed either by direct (methacholine challenge) or indirect (exercise or mannitol challenge) methods, could be considered biomarkers but will not be included in this review. On the other hand, diagnosing allergy is not usually useful for monitoring asthma although it is of fundamental importance for the interpretation of most biomarkers that are suitable for monitoring. We have therefore included the different approaches for diagnosing and evaluating allergic sensitization in this review. PMID- 27942434 TI - micROS: a morphable, intelligent and collective robot operating system. AB - Robots are developing in much the same way that personal computers did 40 years ago, and robot operating system is the critical basis. Current robot software is mainly designed for individual robots. We present in this paper the design of micROS, a morphable, intelligent and collective robot operating system for future collective and collaborative robots. We first present the architecture of micROS, including the distributed architecture for collective robot system as a whole and the layered architecture for every single node. We then present the design of autonomous behavior management based on the observe-orient-decide-act cognitive behavior model and the design of collective intelligence including collective perception, collective cognition, collective game and collective dynamics. We also give the design of morphable resource management, which first categorizes robot resources into physical, information, cognitive and social domains, and then achieve morphability based on self-adaptive software technology. We finally deploy micROS on NuBot football robots and achieve significant improvement in real-time performance. PMID- 27942435 TI - Electricity generation from rice bran in microbial fuel cells. AB - BACKGROUND: Rice bran is a by-product of the rice milling process and mostly discarded in Japan. Although many studies have shown that microbial fuel cells (MFCs) are able to generate electricity from organic wastes, limited studies have examined MFCs for generating electricity from rice bran. FINDINGS: Laboratory scale single-chamber MFCs were inoculated with paddy field soil and supplied with rice bran for examining electricity generation. Power outputs and microbiome compositions were compared between MFCs containing pure water as the liquid phase (MFC-W) and those containing mineral solution (MFC-M). Polarization analyses showed that both MFCs successfully generated electricity with the maximum power densities of 360 and 520 mW m-2 (based on the projected area of anode) for MFC-W and MFC-M, respectively. Amplicon-sequencing analyses revealed that Trichococcus and Geobacter specifically occurred in anode biofilms in MFC-W and MFC-M, respectively. CONCLUSIONS: The results suggest that rice bran is a feasible fuel by itself for generating electricity in MFCs. PMID- 27942437 TI - Metabolic engineering of Serratia marcescens MG1 for enhanced production of (3R) acetoin. AB - BACKGROUND: Optically pure acetoin (AC) is an important platform chemical which has been widely used to synthesize novel optically active alpha-hydroxyketone derivatives and liquid crystal composites. RESULTS: In this study, slaC and gldA encoding meso-2,3-butanediol dehydrogenase (meso-2,3-BDH) and glycerol dehydrogenase (GDH), respectively, in S. marcescens MG1 were knocked out to block the conversion from AC to 2,3-butanediol (2,3-BD). The resulting strain MG14 was found to produce a large amount of optically pure (3R)-AC with a little 2,3-BD, indicating that another enzyme responsible for 2,3-BD formation except meso-2,3 BDH and GDH existed in the strain MG1. Furthermore, SlaR protein, a transcriptional activator of AC cluster, was overexpressed using PC promoter in the strain MG14, leading to enhancement of the (3R)-AC yield by 29.91%. The recombinant strain with overexpression of SlaR, designated as S. marcescens MG15, was used to perform medium optimization for improving (3R)-AC production. CONCLUSION: Under the optimized conditions, 39.91 +/- 1.35 g/l (3R)-AC was produced by strain MG15 with the productivity of 1.11 g/l h and the conversion rate of 80.13%. PMID- 27942436 TI - Engineering a wild-type diploid Saccharomyces cerevisiae strain for second generation bioethanol production. AB - BACKGROUND: The cost-effective production of second-generation bioethanol, which is made from lignocellulosic materials, has to face the following two problems: co-fermenting xylose with glucose and enhancing the strain's tolerance to lignocellulosic inhibitors. Based on our previous study, the wild-type diploid Saccharomyces cerevisiae strain BSIF with robustness and good xylose metabolism genetic background was used as a chassis for constructing efficient xylose fermenting industrial strains. The performance of the resulting strains in the fermentation of media with sugars and hydrolysates was investigated. RESULTS: The following two novel heterologous genes were integrated into the genome of the chassis cell: the mutant MGT05196N360F, which encodes a xylose-specific, glucose insensitive transporter and is derived from the Meyerozyma guilliermondii transporter gene MGT05196, and Ru-xylA (where Ru represents the rumen), which encodes a xylose isomerase (XI) with higher activity in S. cerevisiae. Additionally, endogenous modifications were also performed, including the overproduction of the xylulokinase Xks1p and the non-oxidative PPP (pentose phosphate pathway), and the inactivation of the aldose reductase Gre3p and the alkaline phosphatase Pho13p. These rationally designed genetic modifications, combined with alternating adaptive evolutions in xylose and SECS liquor (the leach liquor of steam-exploding corn stover), resulted in a final strain, LF1, with excellent xylose fermentation and enhanced inhibitor resistance. The specific xylose consumption rate of LF1 reached as high as 1.089 g g-1 h-1 with xylose as the sole carbon source. Moreover, its highly synchronized utilization of xylose and glucose was particularly significant; 77.6% of xylose was consumed along with glucose within 12 h, and the ethanol yield was 0.475 g g-1, which is more than 93% of the theoretical yield. Additionally, LF1 performed well in fermentations with two different lignocellulosic hydrolysates. CONCLUSION: The strain LF1 co-ferments glucose and xylose efficiently and synchronously. This result highlights the great potential of LF1 for the practical production of second-generation bioethanol. PMID- 27942438 TI - Best-classifier feedback in diagnostic classification training. AB - Diagnostic classification training requires viewing many examples along with category membership feedback. "Objective" feedback based on category membership suggests that perfect accuracy is attainable when it may not be (e.g., with confusable categories). Previous work shows that feedback based on an "optimal" responder (that sometimes makes classification errors) leads to higher long-run reward, especially in unequal category payoff conditions. In the current study, participants learned to classify normal or cancerous mammography images, earning more points for correct "cancer" than "normal" responses. Feedback was either objective or based on performance of an empirically determined "best" classifier. This approach is necessary because theoretically optimal responses cannot be determined with complex real-world stimuli with unknown perceptual distributions. Replicating earlier work that used simple artificial stimuli, we found that best classifier performance led to decision-criterion values (beta) closer to the reward-maximizing criterion, along with higher point totals and a slight reduction (as predicted) in overall accuracy. PMID- 27942439 TI - Special Issue - Pharmacogenomics & personalized medicine, Journal of Applied and Translational Genomics. PMID- 27942441 TI - Pharmacogenomics, Theranostics and Personalized Medicine - the complexities of clinical trials: challenges in the developing world. AB - While the potential for the application of pharmacogenomics and theranostics to develop personalized healthcare solutions is enormous, multiple challenges will need to be addressed to get there. Understanding the complex interactions and detailed characterization of the functional variants of individual ADME (Absorption Distribution Metabolism Excretion) genes and drug target genes is needed to demonstrate clinical utility, using both a bottoms-up as well as a top down approach. Clinical trials need to be designed appropriately so as to identify not only individual but also population variations. The impact of non genetic and environmental factors, epigenetic variations and circadian rhythms on an individual's response need to be assessed to make pharmacogenomics clinically indicated. More advanced algorithms and appropriate study designs need to be developed to allow this pipeline to grow and to be used effectively in the clinical setting. Another challenge lies in the value proposition to the pharmaceutical industry. Fearing the impact of the slice and dice approach on revenues, companies are going slow on developing pharmacogenomic solutions; yet many are hedging their bets, amassing huge amounts of single nucleotide polymorphisms (SNP) data. They are being used as predictors of drug efficacy and safety to zero in on subpopulations that are at risk for either a bad response or no response in clinical trials, supporting the Fail fast, Fail cheap approach. In addition, the growth of theranostics is impeded by the fear that the approval of both the diagnostic and the drug would get delayed. Education of the health care provider, payor, regulator and the patient is also required and an exercise of change management needs to occur. Countries such as India should exploit the joint benefit of the reduced cost of tests today, complemented by a large and a highly genetically diverse population. PMID- 27942442 TI - Curbing stem cell tourism in South Africa. AB - Stem cells have received much attention globally due in part to the immense therapeutic potential they harbor. Unfortunately, malpractice and exploitation (financial and emotional) of vulnerable patients have also drawn attention to this field as a result of the detrimental consequences experienced by some individuals that have undergone unproven stem cell therapies. South Africa has had limited exposure to stem cells and their applications and, while any exploitation is detrimental to the field of stem cells, South Africa is particularly vulnerable in this regard. The current absence of adequate legislation and the inability to enforce existing legislation, coupled to the sea of misinformation available on the Internet could lead to an increase in illegitimate stem cell practices in South Africa. Circumstances are already precarious because of a lack of understanding of concepts involved in stem cell applications. What is more, credible and easily accessible information is not available to the public. This in turn cultivates fears born out of existing superstitions, cultural beliefs, rituals and practices. Certain cultural or religious concerns could potentially hinder the effective application of stem cell therapies in South Africa and novel ways of addressing these concerns are necessary. Understanding how scientific progress and its implementation will affect each individual and, consequently, the community, will be of cardinal importance to the success of the fields of stem cell therapy and regenerative medicine in South Africa. A failure to understand the ethical, cultural or moral ramifications when new scientific concepts are introduced could hinder the efficacy and speed of bringing discoveries to the patient. Neglecting proper procedure for establishing the field would lead to long delays in gaining public support in South Africa. Understanding the dangers of stem cell tourism - where vulnerable patients are subjected to unproven stem cell therapies that have not undergone peer review or been registered with the relevant local authorities - becomes imperative so that strategies to overcome this threat can be implemented. PMID- 27942440 TI - C-C chemokine receptor type five (CCR5): An emerging target for the control of HIV infection. AB - When HIV was initially discovered as the causative agent of AIDS, many expected to find a vaccine within a few years. This has however proven to be elusive; it has been approximately 30 years since HIV was first discovered, and a suitable vaccine is still not in effect. In 2009, a paper published by Hutter et al. reported on a bone marrow transplant performed on an HIV positive individual using stem cells that were derived from a donor who was homozygous for a mutation in the CCR5 gene known as CCR5 delta-32 (Delta32) (Hutter et al., 2009). The HIV positive individual became HIV negative and remained free of viral detection after transplantation despite having halted anti-retroviral (ARV) treatment. This review will focus on CCR5 as a key component in HIV immunity and will discuss the role of CCR5 in the control of HIV infection. PMID- 27942443 TI - Incorporate gene signature profiling into routine molecular testing. AB - The success of gene and gene expression profiling, such as the Oncotype DX(r) test for breast cancer patients, demonstrates that as technology becomes more sophisticated molecular diagnostics will continue to play a more important role in disease management in the future. Such promises have been and continue to be enabled by advances in real-time PCR, microarray detection platforms and next generation sequencing technologies. Practical adoption of new technologies into routine clinical care, however, has not always been a smooth ride. Challenges lie on several fronts: establishment of clinical validity in large scale patient population, mechanisms of incorporating molecular tests into standard care, and keeping up with the pace of ever changing technologies in regulated clinical laboratories, just to name a few. This review's goals are to educate, to stimulate discussion and to provoke efforts to build consensus, share resources, and establish standards in order to realize the promises of genomic technologies for routine patient care. PMID- 27942444 TI - Practical, ethical and regulatory considerations for the evolving medical and research genomics landscape. AB - Recent advances in sequencing technology are making possible the application of large-scale genomic analyses to individualized care, both in wellness and disease. However, a number of obstacles remain before genomic sequencing can become a routine part of clinical practice. One of the more significant and underappreciated is the lack of consensus regarding the proper environment and regulatory structure under which clinical genome sequencing and interpretation should be performed. The continued reliance on pure research vs. pure clinical models leads to problems for both research participants and patients in an era in which the lines between research and clinical practice are becoming increasingly blurred. Here, we discuss some of the ethical, regulatory and practical considerations that are emerging in the field of genomic medicine. We also propose that many of the cost and safety issues we are facing can be mitigated through expanded reliance on existing clinical regulatory frameworks and the implementation of distributive work-sharing strategies designed to leverage the strengths of our genomics centers and clinical interpretive teams. PMID- 27942445 TI - Combination therapy with riociquat and inhaled treprostinil in inoperable and progressive chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by formation of chronic, organized thrombus in pulmonary arteries resulting in development of pulmonary hypertension. We describe the favorable recovery of a patient with inoperable CTEPH treated with combination riociguat and inhaled treprostinil. The patient is a 77 year old female who presented with bilateral pulmonary emboli and was anticoagulated with warfarin for six months. One year later the patient developed recurrent dyspnea and multiple bilateral pulmonary emboli were again noted. Pulmonary arterial pressure (PAP) was estimated at 91 mmHg by echocardiography. The patient was treated with warfarin and sildenafil. Eighteen months later the PAP was estimated at 106 mmHg with significant right ventricular enlargement. The patient was referred to our center for pulmonary hypertension consultation. Right heart catheterization confirmed severe pulmonary hypertension with preserved cardiac output. The patient was not a candidate for thromboendarterectomy due to the peripheral location of chronic obstructing thrombi. Systemic prostacyclin therapy was declined by the patient. Inhaled treprostinil was added to sildenafil and warfarin. The patient maintained good performance status for 2 years, but then developed progressive activity limitation with depressed cardiac output on right heart catheterization. Systemic prostacyclin therapy was declined again. Sildenafil was replaced with riociguat, and 1 year later the patient demonstrated significant recovery of functional capacity and improved hemodynamic profile. We describe significant recovery in a patient with inoperable, progressive CTEPH treated with riociguat and inhaled treprostinil after failing sequential addition of sildenafil and inhaled treprostinil to warfarin. The reported benefits may relate to riociguat's ability to directly stimulate production of cyclic GMP independent of nitric oxide levels in pulmonary artery smooth muscle. There may also be a unique interaction between riocguat and treprostinil that enhanced treatment outcome. Further investigation of this combination of agents may be warranted. PMID- 27942446 TI - Voxel-based lesion symptom mapping analysis of depressive mood in patients with isolated cerebellar stroke: A pilot study. AB - Post-stroke depression (PSD) is the most common neuropsychological sequela of stroke and occurs in approximately one-third of all stroke survivors. However, there are no well-established predictors of PSD. Depression in stroke patients is correlated with unfavorable outcomes. Meta-analyses of the relationship between PSD and lesion location have yielded contradictory results and have not adequately addressed the impact of cerebellar lesions. Furthermore, other brain regions associated with depression in patients with cerebellar stroke remain a matter of debate. For these reasons, this cross-sectional study investigated the relationship between PSD and lesion location in patients with isolated cerebellar stroke. Twenty-four patients in the subacute rehabilitative period following a first-ever isolated cerebellar stroke were enrolled in the study. Depressive mood were evaluated using the Geriatric Depression Scale. Regions of interest were drawn manually on T1-weighted magnetic resonance images using MRIcron software, and data were normalized to a standard brain template in order to examine the neural correlates of depression using voxel-based lesion-symptom mapping analysis. Voxel-wise subtraction and chi (Ayerbe et al., 2014) analyses indicated that damage to the left posterior cerebellar hemisphere was associated with depression. Significant correlations were also found between the severity of depressive symptoms and lesions in lobules VI, VIIb, VIII, Crus I, and Crus II of the left cerebellar hemisphere (Pcorrected = 0.045). Our results suggest that damage to the left posterior cerebellum is associated with increased depressive mood severity in patients with isolated cerebellar stroke. PMID- 27942447 TI - Altered structural and functional thalamocortical networks in secondarily generalized extratemporal lobe seizures. AB - Structural and functional abnormalities in the thalamocortical network in primary generalized epilepsies or mesial temporal lobe epilepsy have recently been identified by voxel-wise analyses of neuroimaging. However, evidence is needed regarding the profiles of the thalamocortical network in patients with secondarily generalized seizures from focal neocortical sources. We used high resolution T1-weighted, diffusion-tensor and resting-state functional MR imaging (rs-fMRI) to examine 16 patients with secondarily generalized extratemporal lobe seizures and 16 healthy controls. All the patients were medically effective and MRI-negative. Using whole brain voxel-based morphometry (VBM) to compare the patients with the normal controls, we observed significantly decreased gray matter (GM) density in the thalamus and 3 frontal gyri and significantly reduced white matter (WM) fractional anisotropy (FA) in the bilateral anterior corona radiata of the patients. Alterations in the thalamocortical functional connectivity with different cortices were identified by the rs-fMRI analysis seeding of the whole thalamus. The prefrontal gyri with the greatest functional connectivity were also traced by seeding a sub-thalamic region that is demarcated in an atlas, in which the thalamic parcellation is based on the WM connectivity to the cortices. This sub-thalamic region anatomically contains the mediodorsal thalamic nucleus where, concordantly, there was a significant decrease in thalamic GM density in the VBM study. In contrast to the negative correlation between the disease duration and reduced thalamic densities and subcortical FA values, the strength of the functional thalamocortical connectivity had a paradoxical correlation. Our results conclusively indicate that generalized seizures with a focal cortical source are associated with structural and functional alterations in the thalamocortical network. PMID- 27942448 TI - Brain connectivity aberrations in anabolic-androgenic steroid users. AB - Sustained anabolic-androgenic steroid (AAS) use has adverse behavioral consequences, including aggression, violence and impulsivity. Candidate mechanisms include disruptions of brain networks with high concentrations of androgen receptors and critically involved in emotional and cognitive regulation. Here, we tested the effects of AAS on resting-state functional brain connectivity in the largest sample of AAS-users to date. We collected resting-state functional magnetic resonance imaging (fMRI) data from 151 males engaged in heavy resistance strength training. 50 users tested positive for AAS based on the testosterone to epitestosterone (T/E) ratio and doping substances in urine. 16 previous users and 59 controls tested negative. We estimated brain network nodes and their time series using ICA and dual regression and defined connectivity matrices as the between-node partial correlations. In line with the emotional and behavioral consequences of AAS, current users exhibited reduced functional connectivity between key nodes involved in emotional and cognitive regulation, in particular reduced connectivity between the amygdala and default-mode network (DMN) and between the dorsal attention network (DAN) and a frontal node encompassing the superior and inferior frontal gyri (SFG/IFG) and the anterior cingulate cortex (ACC), with further reductions as a function of dependency, lifetime exposure, and cycle state (on/off). PMID- 27942449 TI - Resting state functional network disruptions in a kainic acid model of temporal lobe epilepsy. AB - We studied the graph topological properties of brain networks derived from resting-state functional magnetic resonance imaging in a kainic acid induced model of temporal lobe epilepsy (TLE) in rats. Functional connectivity was determined by temporal correlation of the resting-state Blood Oxygen Level Dependent (BOLD) signals between two brain regions during 1.5% and 2% isoflurane, and analyzed as networks in epileptic and control rats. Graph theoretical analysis revealed a significant increase in functional connectivity between brain areas in epileptic than control rats, and the connected brain areas could be categorized as a limbic network and a default mode network (DMN). The limbic network includes the hippocampus, amygdala, piriform cortex, nucleus accumbens, and mediodorsal thalamus, whereas DMN involves the medial prefrontal cortex, anterior and posterior cingulate cortex, auditory and temporal association cortex, and posterior parietal cortex. The TLE model manifested a higher clustering coefficient, increased global and local efficiency, and increased small-worldness as compared to controls, despite having a similar characteristic path length. These results suggest extensive disruptions in the functional brain networks, which may be the basis of altered cognitive, emotional and psychiatric symptoms in TLE. PMID- 27942450 TI - Impact of schizophrenia on anterior and posterior hippocampus during memory for complex scenes. AB - OBJECTIVES: Hippocampal dysfunction has been proposed as a mechanism for memory deficits in schizophrenia. Available evidence suggests that the anterior and posterior hippocampus could be differentially affected. Accordingly, we used fMRI to test the hypothesis that activity in posterior hippocampus is disproportionately reduced in schizophrenia, particularly during spatial memory retrieval. METHODS: 26 healthy participants and 24 patients with schizophrenia from the UC Davis Early Psychosis Program were studied while fMRI was acquired on a 3 Tesla Siemens scanner. During encoding, participants were oriented to critical items through questions about item features (e.g., "Does the lamp have a square shade?") or spatial location (e.g., "Is the lamp on the table next to the couch?"). At test, participants determined whether scenes were changed or unchanged. fMRI analyses contrasted activation in a priori regions of interest (ROI) in anterior and posterior hippocampus during correct recognition of item changes and spatial changes. RESULTS: As predicted, patients with schizophrenia exhibited reduced activation in the posterior hippocampus during detection of spatial changes but not during detection of item changes. Unexpectedly, patients exhibited increased activation of anterior hippocampus during detection of item changes. Whole brain analyses revealed reduced fronto-parietal and striatal activation in patients for spatial but not for item change trials. CONCLUSIONS: Results suggest a gradient of hippocampal dysfunction in which posterior hippocampus - which is necessary for processing fine-grained spatial relationships - is underactive, and anterior hippocampus - which may process context more globally - is overactive. PMID- 27942451 TI - Neuroanatomical correlates of prion disease progression - a 3T longitudinal voxel based morphometry study. AB - PURPOSE: MRI has become an essential tool for prion disease diagnosis. However there exist only a few serial MRI studies of prion patients, and these mostly used whole brain summary measures or region of interest based approaches. We present here the first longitudinal voxel-based morphometry (VBM) study in prion disease. The aim of this study was to systematically characterise progressive atrophy in patients with prion disease and identify whether atrophy in specific brain structures correlates with clinical assessment. METHODS: Twenty-four prion disease patients with early stage disease (3 sporadic, 2 iatrogenic, 1 variant and 18 inherited CJD) and 25 controls were examined at 3T with a T1-weighted 3D MPRAGE sequence at multiple time-points (2-6 examinations per subject, interval range 0.1-3.2 years). Longitudinal VBM provided intra-subject and inter-subject image alignment, allowing voxel-wise comparison of progressive structural change. Clinical disease progression was assessed using the MRC Prion Disease Rating Scale. Firstly, in patients, we determined the brain regions where grey and white matter volume change between baseline and final examination correlated with the corresponding change in MRC Scale score. Secondly, in the 21/24 patients with interscan interval longer than 3 months, we identified regions where annualised rates of regional volume change in patients were different from rates in age matched controls. Given the heterogeneity of the cohort, the regions identified reflect the common features of the different prion sub-types studied. RESULTS: In the patients there were multiple regions where volume loss significantly correlated with decreased MRC scale, partially overlapping with anatomical regions where yearly rates of volume loss were significantly greater than controls. The key anatomical areas involved included: the basal ganglia and thalamus, pons and medulla, the hippocampal formation and the superior parietal lobules. There were no areas demonstrating volume loss significantly higher in controls than patients or negative correlation between volume and MRC Scale score. CONCLUSIONS: Using 3T MRI and longitudinal VBM we have identified key anatomical regions of progressive volume loss which correlate with an established clinical disease severity index and are relevant to clinical deterioration. Localisation of the regions of progressive brain atrophy correlating most strongly with clinical decline may help to provide more targeted imaging endpoints for future clinical trials. PMID- 27942452 TI - CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3. AB - This cross-sectional study investigated the correlation between the CAG repeat length and the degeneration of cerebellum in spinocerebellar ataxia type 3 (SCA3) patients based on neuroimaging approaches. Forty SCA3 patients were recruited and classified into two subgroups according to their CAG repeat lengths (>= 74 and < 74). We measured each patient's Scale for the Assessment and Rating of Ataxia (SARA) score, N-acetylaspartate (NAA)/creatine (Cr) ratios based on magnetic resonance spectroscopy (MRS), and 3-dimensional fractal dimension (3D-FD) values derived from magnetic resonance imaging (MRI) results. Furthermore, the 3D-FD values were used to construct structural covariance networks based on graph theoretical analysis. The results revealed that SCA3 patients with a longer CAG repeat length demonstrated earlier disease onset. However, the CAG repeat length did not significantly correlate with their SARA scores, cerebellar NAA/Cr ratios or cerebellar 3D-FD values. Network dissociation between cerebellar regions and parietal-occipital regions was found in SCA3 patients with CAG >= 74, but not in those with CAG < 74. In conclusion, the CAG repeat length is uncorrelated with the change of SARA score, cerebellar function and cerebellar structure in SCA3. Nevertheless, a longer CAG repeat length may indicate early structural covariance network dissociation. PMID- 27942454 TI - Acetazolamide-augmented dynamic BOLD (aczBOLD) imaging for assessing cerebrovascular reactivity in chronic steno-occlusive disease of the anterior circulation: An initial experience. AB - The purpose of this study was to measure cerebrovascular reactivity (CVR) in chronic steno-occlusive disease using a novel approach that couples BOLD imaging with acetazolamide (ACZ) vasoreactivity (aczBOLD), to evaluate dynamic effects of ACZ on BOLD and to establish the relationship between aczBOLD and dynamic susceptibility contrast (DSC) perfusion MRI. Eighteen patients with unilateral chronic steno-occlusive disease of the anterior circulation underwent a 20-min aczBOLD imaging protocol, with ACZ infusion starting at 5 min of scan initiation. AczBOLD reactivity was calculated on a voxel-by-voxel basis to generate CVR maps for subsequent quantitative analyses. Reduced CVR was observed in the diseased vs. the normal hemisphere both by qualitative and quantitative assessment (gray matter (GM): 4.13% +/- 1.16% vs. 4.90% +/- 0.98%, P = 0.002; white matter (WM): 2.83% +/- 1.23% vs. 3.50% +/- 0.94%, P = 0.005). In all cases BOLD signal began increasing immediately following ACZ infusion, approaching a plateau at ~ 8.5 min after infusion, with the tissue volume of reduced augmentation increasing progressively with time, peaking at 2.60 min (time range above 95% of the maximum value: 0-4.43 min) for the GM and 1.80 min (time range above 95% of the maximum value: 1.40-3.53 min) for the WM. In the diseased hemisphere, aczBOLD CVR significantly correlated with baseline DSC time-to-maximum of the residue function (Tmax) (P = 0.008 for the WM) and normalized cerebral blood flow (P = 0.003 for the GM, and P = 0.001 for the WM). AczBOLD provides a novel, safe, easily implementable approach to CVR measurement in the routine clinical environments. Further studies can establish quantitative thresholds from aczBOLD towards identification of patients at heightened risk of recurrent ischemia and cognitive decline. PMID- 27942453 TI - Development, validation and application of a new fornix template for studies of aging and preclinical Alzheimer's disease. AB - We developed a merged younger-older adult template of the fornix and demonstrated its utility for studies of aging and preclinical Alzheimer's disease (AD). In Experiment 1, probabilistic tractography was used to reconstruct the fornix in younger and older adults and successful streamlines were then averaged to create a merged template in standard space. The new template includes the majority of the fornix from the hippocampal formation to the subcallosal region and the thalamus/hypothalamus. In Experiment 2, the merged template was validated as an appropriate measure for studies of aging, with comparisons against manual tracing measures indicating identical spatial coverage in younger and older adult groups. In Experiment 3, the merged template was found to outperform age-specific templates in measures of sensitivity and specificity computed on diffusion tensor imaging data of an independent participant cohort. In Experiment 4, relevance to preclinical AD was demonstrated via associations between fractional anisotropy within the new fornix template and cerebrospinal fluid markers of AD pathology (Abeta42 and the t-tau/Abeta42 ratio) in a third independent cohort of cognitively normal older adults. Our new template provides an appropriate measure for use in future studies seeking to characterize microstructural alterations in the fornix associated with aging and preclinical AD. PMID- 27942456 TI - Fecal parasite identification by microscopy and PCR in scimitar-horned oryx, Oryx dammah, managed at two sites. AB - The scimitar-horned oryx, Oryx dammah, an endangered species extinct in the wild, is managed in various captive management programs and is the focus of reintroduction efforts. Management variability can contribute to substantial parasite load differences, which can affect deworming programs and potentially transfer parasites to different regions with translocations. Parasite studies in O. dammah are lacking. In this study, we determined fecal egg/oocyst counts of O. dammah in two captive herds, Fossil Rim Wildlife Center (FRWC) and Kansas City Zoo (KCZ). Fecal egg counts (FEC) were performed on O. dammah feces collected seasonally using the modified McMaster method, and microscopy provided additional identification of parasite genera ova and oocysts. To identify parasites to species level, homogenized fecals provided DNA subjected to the polymerase chain reaction (PCR) using genus specific primers. Microscopy and sequencing results indicated the presence of Strongylus (Strongylus vulgaris, Angiostrongylus cantonensis), Trichostrongylus (Haemonchus contortus, Camelostrongylus mentulatus), Trichuris (T. leporis, T. ovis, and T. discolor), Isospora (Isospora gryphoni) and Eimeria (E. zuernii and E. bovis), with Strongylus being the most common. Nematodirus was identified through microscopy at FRWC. Fecal egg counts were significantly higher in (FRWC) than in (KCZ) in all samplings (P = <0.001). No significant difference was seen between parasite load and seasons (P = 0.103), nor site and season (P = 0.51). Both study sites maintained most animals within commonly accepted FEC levels found in domestic livestock. Individuals with high numbers of EPG or OPG were subordinate males, pregnant females, or neonates. Several significant interactions were found between genera of parasites, age, sex, season, and pregnancy status in the FRWC herd. Sampling limitations prevented further analysis of the KCZ herd. Understanding interactions between parasite loads and physiological, environmental, and regional differences can help determine inter-specific transfer of parasites, and establish appropriate anthelmintic programs for O. dammah herds. PMID- 27942457 TI - Insights into bacterioplankton community structure from Sundarbans mangrove ecoregion using Sanger and Illumina MiSeq sequencing approaches: A comparative analysis. AB - Next generation sequencing using platforms such as Illumina MiSeq provides a deeper insight into the structure and function of bacterioplankton communities in coastal ecosystems compared to traditional molecular techniques such as clone library approach which incorporates Sanger sequencing. In this study, structure of bacterioplankton communities was investigated from two stations of Sundarbans mangrove ecoregion using both Sanger and Illumina MiSeq sequencing approaches. The Illumina MiSeq data is available under the BioProject ID PRJNA35180 and Sanger sequencing data under accession numbers KX014101-KX014140 (Stn1) and KX014372-KX014410 (Stn3). Proteobacteria-, Firmicutes- and Bacteroidetes-like sequences retrieved from both approaches appeared to be abundant in the studied ecosystem. The Illumina MiSeq data (2.1 GB) provided a deeper insight into the structure of bacterioplankton communities and revealed the presence of bacterial phyla such as Actinobacteria, Cyanobacteria, Tenericutes, Verrucomicrobia which were not recovered based on Sanger sequencing. A comparative analysis of bacterioplankton communities from both stations highlighted the presence of genera that appear in both stations and genera that occur exclusively in either station. However, both the Sanger sequencing and Illumina MiSeq data were coherent at broader taxonomic levels. Pseudomonas, Devosia, Hyphomonas and Erythrobacter-like sequences were the abundant bacterial genera found in the studied ecosystem. Both the sequencing methods showed broad coherence although as expected the Illumina MiSeq data helped identify rarer bacterioplankton groups and also showed the presence of unassigned OTUs indicating possible presence of novel bacterioplankton from the studied mangrove ecosystem. PMID- 27942458 TI - Single nucleotide-level mapping of DNA double-strand breaks in human HEK293T cells. AB - Constitutional biological processes involve the generation of DNA double-strand breaks (DSBs). The production of such breaks and their subsequent resolution are also highly relevant to neurodegenerative diseases and cancer, in which extensive DNA fragmentation has been described Stephens et al. (2011), Blondet et al. (2001). Tchurikov et al. Tchurikov et al. (2011, 2013) have reported previously that frequent sites of DSBs occur in chromosomal domains involved in the co ordinated expression of genes. This group report that hot spots of DSBs in human HEK293T cells often coincide with H3K4me3 marks, associated with active transcription Kravatsky et al. (2015) and that frequent sites of DNA double strand breakage are likely to be relevant to cancer genomics Tchurikov et al. (2013, 2016) . Recently, they applied a RAFT (rapid amplification of forum termini) protocol that selects for blunt-ended DSB sites and mapped these to the human genome within defined co-ordinate 'windows'. In this paper, we re-analyse public RAFT data to derive sites of DSBs at the single-nucleotide level across the built genome for human HEK293T cells (https://figshare.com/s/35220b2b79eaaaf64ed8). This refined mapping, combined with accessory ENCODE data tracks and ribosomal DNA-related sequence annotations, will likely be of value for the design of clinically relevant targeted assays such as those for cancer susceptibility, diagnosis, treatment-matching and prognostication. PMID- 27942455 TI - The age-dependent effects of a single-dose methylphenidate challenge on cerebral perfusion in patients with attention-deficit/hyperactivity disorder. AB - Methylphenidate (MPH) is a stimulant drug and an effective treatment for attention-deficit/hyperactivity disorder (ADHD) in both children and adults. Pre clinical studies suggest that the response to stimulants is dependent on age, which may reflect the ontogeny of the dopamine (DA) system, which continues to develop throughout childhood and adolescence. Therefore, the aim of this study was to investigate the modulating effect of age on the cerebral blood flow (CBF) response to MPH in stimulant treatment-naive children and adults with ADHD. Ninety-eight stimulant treatment-naive male pediatric (10-12 years) and adult (23 40 years) patients with ADHD were included in this study. The CBF response to an acute challenge with MPH (0.5 mg/kg) was measured using arterial spin labeling (ASL) pharmacological magnetic resonance imaging, as a proxy for DA function. Region-of-interest (ROI) analyses were carried out for the striatum, thalamus and medial prefrontal cortex and in addition voxel-wise analyses were conducted. An acute challenge with MPH decreased CBF in both children and adults in cortical areas, although to a greater extent in adults. In contrast, ROI analyses showed that MPH decreased thalamic CBF only in children, but not adults. Our findings highlight the importance of taking the developmental perspective into account when studying the effects of stimulants in ADHD patients. PMID- 27942459 TI - Genome sequencing and annotation of Aeromonas veronii strain Ae52, a multidrug resistant isolate from septicaemic gold fish (Carassius auratus) in Sri Lanka. AB - Here we report the draft genome sequence and annotation of A. veronii strain Ae52 isolated from the kidney of a morbund, septicaemic gold fish (Carassius auratus) in Sri Lanka. This clinical isolate showed resistance to multiple antimicrobials; amoxicillin, neomycin, trimethoprim-sulphonamide, chloramphenicol, tetracycline, enrofloxacin, erythromycin and nitrofurantoin. The size of the draft genome is 4.56 Mbp with 58.66% of G + C content consisting 4328 coding sequences. It harbors a repertoire of putative antibiotic resistant determinants that explains the genetic basis of its resistance to various classes of antibiotics. The genome sequence has been deposited in DDBJ/EMBL/GenBank under the accession numbers BDGY01000001-BDGY01000080. PMID- 27942460 TI - Transcription profiling data set of different states of Mycoplasma gallisepticum. AB - Mycoplasma gallisepticum belongs to class Mollicutes and causes chronic respiratory disease in birds. It has a reduced genome, lack of cell wall and many metabolic pathways, and also easy to culture and non-pathogenic to humans. Aforementioned made it is a convenient model for studying of systems biology of minimal cell. Studying the transcriptomic level of M. gallisepticum is interesting for both understanding of common principles of transcription regulation of minimal cell and response to definite influence for pathogen bacteria. For rapid investigation of gene expression we developed microarray design including 3366 probes for 678 genes. They included 665 protein coding sequences and 13 antisense RNAs from 816 genes and 17 ncRNAs present in Mycoplasma gallisepticum. The study was performed on Agilent one-color microarray with custom design and random-T7 polymerase primer for cDNA synthesis. Here we present the data for transcription profiling of M. gallisepticum under different types of exposures: genetic knock-out mutants, cell culture exposed to sublethal concentrations of antibiotics and well-characterized heat stress effect. Mutants have transposon insertion to hypothetical membrane protein, lactate dehydrogenase, helicase with unknown function, 1-deoxy-d-xylulose 5-phosphate reductoisomerase or potential sigma factor. For inhibition of important cell systems, treatment with carbonyl cyanide m-chlorophenylhydrazone (CCCP), novobiocin or tetracycline were chosen. Data are available via NCBI Gene Expression Omnibus (GEO) with the accession number GSE85777 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE85777). PMID- 27942461 TI - Prosthetic vascular graft infection and prosthetic joint infection caused by Pseudomonas stutzeri. AB - Pseudomonas stutzeri is infrequently isolated from clinical specimens, and if isolated, more likely represents colonization or contamination rather than infection. Despite this, there are dozens of case reports which describe clinically significant P. stutzeri infections at variable sites. A 69-year-old man had a P. stutzeri infection of a prosthetic vascular graft infection, which he received in Panama City. He was successfully treated with a single antipseudomonal agent for 6 weeks and the removal of the infected vascular graft. A 70-year-old man had a P. stutzeri infection of a prosthetic joint, which was successfully treated with a single anti-pseudomonal agent for 6 weeks. There is only one other documented case of a prosthetic vascular graft infection secondary to P. stutzeri. There are 5 documented cases of P. stutzeri prosthetic joint infections. The previous cases were treated with antibiotics and variably, source control with the removal of prosthetic material. Most cases of P. stutzeri infection are due to exposure in health care settings. Immunocompromised states such as HIV or hematological and solid tumor malignancies are risk factors for P. stutzeri infection. Infections caused by P. stutzeri are far less frequent and less fatal than those caused by P. aeruginosa. The etiology of a P. stutzeri infection could be exposure to soil and water, but also contaminated material in the health care setting or an immunocompromised state. Iatrogenic infections that are secondary to health care tourism are a potential cause of fever in the returned traveler. PMID- 27942462 TI - Successful treatment of Candida tropicalis osteomyelitis with Micafungin in a leukemia patient. PMID- 27942463 TI - Multigene panel next generation sequencing in a patient with cherry red macular spot: Identification of two novel mutations in NEU1 gene causing sialidosis type I associated with mild to unspecific biochemical and enzymatic findings. AB - BACKGROUND: Lysosomal storage diseases (LSD) often manifest with cherry red macular spots. Diagnosis is based on clinical features and specific biochemical and enzymatic patterns. In uncertain cases, genetic testing with next generation sequencing can establish a diagnosis, especially in milder or atypical phenotypes. We report on the diagnostic work-up in a boy with sialidosis type I, presenting initially with marked cherry red macular spots but non-specific urinary oligosaccharide patterns and unusually mild excretion of bound sialic acid. METHODS: Biochemical, enzymatic and genetic tests were performed in the patient. The clinical and electrophysiological data was reviewed and a genotype phenotype analysis was performed. In addition a systematic literature review was carried out. CASE REPORT AND RESULTS: Cherry red macular spots were first noted at 6 years of age after routine screening myopia. Physical examination, psychometric testing, laboratory investigations as well as cerebral MRI were unremarkable at 9 years of age. So far no clinical myoclonic seizures occurred, but EEG displays generalized epileptic discharges and visual evoked potentials are prolonged bilaterally. Urine thin layer chromatography showed an oligosaccharide pattern compatible with different LSD including sialidosis, galactosialidosis, GM1 gangliosidosis or mucopolysaccharidosis type IV B. Urinary bound sialic acid excretion was mildly elevated in spontaneous and 24 h urine samples. In cultured fibroblasts, alpha-sialidase activity was markedly decreased to < 1%; however, bound and free sialic acid were within normal range. Diagnosis was eventually established by multigene panel next generation sequencing of genes associated to LSD, identifying two novel, compound heterozygous variants in NEU1 gene (c.699C > A, p.S233R in exon 4 and c.803A > G; p.Y268C in Exon 5 in NEU1 transcript NM_000434.3), leading to amino acid changes predicted to impair protein function. DISCUSSION: Sialidosis should be suspected in patients with cherry red macular spots, even with non-significant urinary sialic acid excretion. Multigene panel next generation sequencing can establish a definite diagnosis, allowing for counseling of the patient and family. PMID- 27942464 TI - Short-term caloric restriction in db/db mice improves myocardial function and increases high molecular weight (HMW) adiponectin. AB - BACKGROUND: Obesity and metabolic syndrome lead to the development of metabolic heart disease (MHD) that is characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and increased mitochondrial ROS. Caloric restriction (CR) is a nutritional intervention that protects against obesity, diabetes, and cardiovascular disease. Healthy adipose tissue is cardioprotective via releasing adipokines such as adiponectin. We tested the hypothesis that CR can ameliorate MHD and it is associated with improved adipose tissue function as reflected by increased circulating levels of high molecular weight (HMW) adiponectin and AMP activated protein kinase (AMPK) in db/db mice. METHODS: Genetically obese db/db and lean db/+ male mice were fed either ad libitum or subjected to 30% CR for 5 weeks. At the end of the study period, echocardiography was carried out to assess diastolic function. Blood, heart, and epididymal fat pads were harvested for mitochondrial study, ELISA, and Western blot analyses. RESULTS: CR reversed the development of LVH, prevented diastolic dysfunction, and decreased cardiac mitochondrial H2O2 in db/db (vs. ad lib) mice. These beneficial effects on the heart were associated with increased circulating level of HMW adiponectin. Furthermore, CR increased AMPK and eNOS activation in white adipose tissue of db/db mice, but not in the heart. CONCLUSIONS: These findings indicate that even short-term CR protects the heart from MHD. Whether the beneficial effects of CR on the heart could be related to the improved adipose tissue function warrants future investigation. PMID- 27942465 TI - LongQt: A cardiac electrophysiology simulation platform. AB - Mathematical modeling has been used for over half a century to advance our understanding of cardiac electrophysiology and arrhythmia mechanisms. Notably, computational studies using mathematical models of the cardiac action potential (AP) have provided important insight into the fundamental nature of cell excitability, mechanisms underlying both acquired and inherited arrhythmia, and potential therapies. Ultimately, an approach that tightly integrates mathematical modeling and experimental techniques has great potential to accelerate discovery. Despite the increasing acceptance of mathematical modeling as a powerful tool in cardiac electrophysiology research, there remain significant barriers to its more widespread use in the field, due in part to the increasing complexity of models and growing need for specialization. To help bridge the gap between experimental and theoretical worlds that stands as a barrier to transformational breakthroughs, we present LongQt, which has the following key features: *Cross platform, threaded application with accessible graphical user interface.*Facilitates advanced computational cardiac electrophysiology and arrhythmia studies.*Does not require advanced programming skills. PMID- 27942466 TI - The 2016 World Health Organization Classification of tumours of the Central Nervous System: what the paediatric neuroradiologist needs to know. AB - The recently published 2016 World Health Organization (WHO) classification of tumours of the Central Nervous System (CNS) introduces a number of significant changes from the previous edition. Based on an improved understanding of the genetic and molecular basis of tumorigenesis there has been a shift towards defining tumours by means of these characteristics in addition to their histological features, thus providing an integrated diagnosis. In this article, we will provide a concise overview of the salient changes in the 2016 WHO classification of tumours of the CNS that are of relevance to the paediatric neuroradiologist when it comes to day-to-day reporting. PMID- 27942467 TI - Can pontine trigeminal T2-hyperintensity suggest herpetic etiology of trigeminal neuralgia? AB - BACKGROUND: Trigeminal neuralgia (TN) is usually classified into two different categories: idiopathic and secondary. We have investigated the frequency of brainstem pontine lesions in patients with idiopathic TN without multiple sclerosis (MS) or stroke, and their association with herpes zoster (HZ) infection. METHODS: Brain magnetic resonance imaging (MRI) studies of 28 patients with TN were retrospectively reviewed. RESULTS: We found seven patients with clinical suspicion of HZ infection and pontine T2 hyperintense lesions, associated with nerve atrophy in one case. Fifteen patients had a neurovascular conflict (NVC) without brainstem involvement, two of them associated with trigeminal atrophy, while four patients had only volumetric reduction of the nerve. In all patients MRI findings were ipsilateral to the side of TN. CONCLUSIONS: Pontine T2 hyperintensities could be considered as a MRI sign of TN in patients without NVCs. This "trigeminal pontine sign" (TPS) is frequently found in association with herpetic infections. PMID- 27942468 TI - Isolated macrocerebellum: description of six cases and literature review. AB - BACKGROUND: Macrocerebellum is a rare entity described as an isolated and abnormal increase of the cerebellum (CB) size without morphological or signal abnormalities. There have been only eleven patients with macrocerebellum reported in the literature so far. METHODS: From December 2011 to March 2014, among 950 paediatric patients that underwent a magnetic resonance scan of the brain in our department, in six subjects an abnormal increase of the cerebellar volume was suspected. A volumetric analysis was performed in all patients on T1- weighted 3D imaging to confirm the diagnosis of macrocerebellum. The ratios between (I) volume of the CB and volume of the supratentorial structures (STB) and (II) volume of the CB and the sum of CB and STB (WB) were calculated in order to normalize the absolute values obtained and compared with the normal values present in literature. RESULTS AND DISCUSSION: Quantitative analysis confirmed an increased cerebellar volume relatively to the STB volume ("t": 6.9518; P<0.001) and to the WB ("t": 7.1415; P<0.001) volume in comparison to the normal controls available in literature. Clinical characteristics and other neuroradiological findings of the patients are described. We also describe the differential features between isolated macrocerebellum and other pathological conditions that are characterized by cerebellar enlargement such as Lhermitte-Duclos, Sotos syndrome, Costello syndrome, Williams syndrome, Alexander disease and fucosidosis. Furthermore a detailed literature review is provided. Macrocerebellum is always associated with an abnormal mental and motor development. CONCLUSION: Macrocerebellum is a neuroradiological entity that can be identified qualitatively and confirmed quantitatively through volumetric analysis. This is the largest cohort of patients with macrocerebellum described so far. The data available in literature on this entity show that macrocerebellum is not a specific disease but an epiphenomenon found in heterogeneous brain disorders. PMID- 27942469 TI - Intraventricular hemorrhage in term neonates with hypoxic-ischemic encephalopathy: a comparison study between neonates treated with and without hypothermia. AB - BACKGROUND: To retrospectively determine the prevalence of intraventricular hemorrhage (IVH) in term neonates with hypoxic-ischemic encephalopathy (HIE) using head ultrasound (HUS) and MRI, and to compare the incidence of IVH in term babies with HIE treated by therapeutic hypothermia versus those managed conventionally. METHODS: A total of 61 term neonates from two institutions were diagnosed with HIE shortly after birth. Thirty infants from one institution were treated with whole body hypothermia. These infants had to satisfy the entry criteria for the neonatal hypothermia protocol of the institution. Thirty-one neonates underwent conventional treatment at the second institution. At that time, hypothermia was not yet a standard of care at that institution. All the neonates underwent HUS in their first 23 days of life. The 54 survivors also underwent MRI. The imaging studies were all reviewed for IVH. RESULTS: Amongst the 30 babies, who received whole body hypothermia, there were 18 males and 12 females, the mean birth weight was 3.5 kg (2.5 to 5.2 kg), and the HUS study was performed within 14.8 to 41 hours of life. The group of 31 infants treated conventionally was comprised of 12 boys and 19 girls, the infants had an average birth weight of 3.3 kg (2.3 to 4.2 kg), and they underwent HUS 1 to 23 days after birth, with only five children being older than 1 week at the time of the imaging studies. Four of the 61 infants (7%) were diagnosed with IVH on HUS. Three were confirmed with MRI. The fourth case showed a bilateral enlarged choroid plexus on HUS, but IVH could not be confirmed with MRI, as the infant did not survive. In the group of neonates treated with hypothermia, there were three cases (10%) of IVH, whereas in the group managed conventionally, IVH occurred in one infant (3%). CONCLUSIONS: Our study shows that IVH remains uncommon in term infants with HIE. IVH was more prevalent in the group treated with hypothermia. PMID- 27942470 TI - Basal ganglia perfusion using dynamic color Doppler sonography in infants with hypoxic ischemic encephalopathy receiving therapeutic hypothermia: a pilot study. AB - BACKGROUND: The objective of this study was to evaluate the cerebral perfusion of the basal ganglia in infants with hypoxic-ischemic encephalopathy (HIE) receiving hypothermia using dynamic color Doppler sonography (CDS) and investigate for any correlation between these measurements and survival. METHODS: Head ultrasound (HUS) was performed with a 9S4 MHz sector transducer in HIE infants submitted to hypothermia as part of their routine care. Measurements of cerebral perfusion intensity (CPI) with an 11LW4 MHz linear array transducer were performed to obtain static images and DICOM color Doppler videos of the blood flow in the basal ganglia area. Clinical and radiological data were evaluated retrospectively. The video images were analyzed by two radiologists using dedicated software, which allows automatic quantification of color Doppler data from a region of interest (ROI) by dynamically assessing color pixels and flow velocity during the heart cycle. CPI is expressed in cm/sec and is calculated by multiplying the mean velocity of all pixels divided by the area of the ROI. Three videos of 3 seconds each were obtained of the ROI, in the coronal plane, and used to calculate the CPI. Data are presented as mean +/- SEM or median (quartiles). RESULTS: A total of 28 infants were included in this study: 16 male, 12 female. HUS was performed within the first 48 hours of therapeutic hypothermia treatment. CPI values were significantly higher in the seven non-survivors when compared to survivors (0.226+/-0.221 vs. 0.111+/-0.082 cm/sec; P=0.02). CONCLUSIONS: Increased perfusion intensity of the basal ganglia area within the first 48 of therapeutic hypothermia treatment was associated with poor outcome in neonates with HIE. PMID- 27942471 TI - Mixed vascular nevus syndrome: a report of four new cases and a literature review. AB - BACKGROUND: Mixed vascular nevus (or nevus vascularis mixtus) represents an admixture of cutaneous vascular malformations of the telangiectatic type and angiospastic spots of nevus anemicus. It can occur as an purely cutaneous trait or as a hallmark of a neurocutaneous phenotype (mixed vascular nevus syndrome) characterised by the combination of: (I) paired vascular (telangiectatic and anemic) twin nevi and brain abnormalities of the Dyke-Davidoff-Masson type (i.e., crossed cerebral/cerebellar hemiatrophy with hypoplasia of the ipsilateral cerebral vessels and homolateral hypertrophy of the skull and sinuses (hyperpneumatisation) with contralateral hemispheric hypertrophy); or (II) paired vascular twin nevi and brain malformations of the Dyke-Davidoff-Masson type in association with systemic abnormalities consisting in facial asymmetry, skeletal anomalies (i.e., Legg-Calve-Perthes-like disease) and disorders of autoimmunity (i.e., diabetes, thyroiditis). In 2014, Happle proposed to name the syndrome with the eponym Ruggieri-Leech syndrome. METHODS: Review of the existing literature on nevus vascularis mixtus and information on our personal experience on new cases and follow-up of previously reported cases by some of us. RESULTS: The existing literature revealed 4 previous studies including 33 cases with an inferred purely cutaneous trait and 3 cases with a combination of paired vascular twin nevi and brain malformation of the Dyke-Davidoff-Masson type. Our personal experience includes 4 unpublished patients (1 female and 3 males; currently aged 2 to 34 years) seen and followed-up at our Institutions in Italy who had: paired vascular nevi involving either the face (n=2) or the face and parts of the body (n=2); facial asymmetry (n=4); mild to moderate facial dysmorphic features (n=2); developmental delay (n=3); seizures/stroke-like episodes and associated hemiplegia (n=4); muscular hypotrophy (n=2); mild to moderate hemispheric atrophy (n=4); skull osseous hypertrophy (n=4); hyperpneumatisation of the sinuses (n=2); hypoplastic brain vessels (n=4); colpocephaly and malformation of cortical development (n=2). Follow-up data on our previous 2 cases revealed that the vascular abnormalities in the skin and nervous system were stable over years without neurological progression or deterioration. CONCLUSIONS: Pathogenically, this complex phenotype suggests that embryonic pairing and somatic recombination of recessive (didymotic) alleles controlling the balance between constriction (i.e., nevus anemicus) and dilatation (i.e., nevus telangiectaticus) of blood vessels could be the primary event causing the phenomena of cutaneous and brain vascular twin spotting and the paired phenomena of skull hyperpneumatisation vs. hypertrophy and brain megalencephaly/colpocephaly vs. cortical dysplasia. This association is likely more frequent than previously thought and should be investigated by means of: (I) brain and spinal cord imaging (combination of CT and MRI studies); (II) skeletal X-ray studies (when dictated by clinical findings); (III) systemic ultrasound studies; (IV) neurophysiologic studies (EEG); (V) psychomotor testing; (VI) and laboratory investigation (including immune-mediated dysfunction). PMID- 27942473 TI - Post-operative pediatric cerebellar mutism syndrome and its association with hypertrophic olivary degeneration. AB - BACKGROUND: The dentato-thalamo-cortical (DTC) pathway is recognized as the anatomical substrate for postoperative pediatric cerebellar mutism (POPCMS), a well-recognized complication affecting up to 31% of children undergoing posterior fossa brain tumour resection. The proximal structures of the DTC pathway also form a segment of the Guillain and Mollaret triangle, a neural network which when disrupted causes hypertrophic olivary degeneration (HOD) of the inferior olivary nucleus (ION). We hypothesize that there is an association between the occurrence of POPCMS and HOD and aim to evaluate this on MR imaging using qualitative and quantitative analysis of the ION in children with and without POPCMS. METHODS: In this retrospective study we qualitatively analysed the follow up MR imaging in 48 children who underwent posterior fossa tumour resection for presence of HOD. Quantitative analysis of the ION was possible in 28 children and was performed using semi-automated segmentation followed by feature extraction and feature selection techniques and relevance of the features to POPCMS were evaluated. The diagnosis of POPCMS was made independently based on clinical and nursing assessment notes. RESULTS: There was significant association between POPCMS and bilateral HOD (P=0.002) but not unilateral HOD. Quantitative analysis showed that hyperintensity in the left ION was the most relevant feature in children with POPCMS. CONCLUSIONS: Bilateral HOD can serve as a reliable radiological indicator in establishing the diagnosis of POPCMS particularly in equivocal cases. The strong association of signal change due to HOD in the left ION suggests that injury to the right proximal efferent cerebellar pathway plays an important role in the causation of POPCMS. PMID- 27942472 TI - Cutis tricolor: a literature review and report of five new cases. AB - BACKGROUND: Cutis tricolor is a skin abnormality consisting in a combination of congenital hyper- and hypopigmented skin lesions (in the form of paired macules, patches or streaks) in close proximity to each other in a background of normal skin. It is currently regarded as a twin-spotting (mosaic) phenomenon and today is clear that not all cases of cutis tricolor represent one single entity. This phenomenon has been reported so far either: (I) as an purely cutaneous trait; (II) as a part of a complex malformation phenotype (Ruggieri-Happle syndrome, RHS) including distinct facial features, eye (cataract), skeletal (skull and vertebral defects, and long bones dysplasia), nervous system (corpus callosum, cerebellar and white matter anomalies, cavum vergae and holoprosencephaly) and systemic abnormalities; (III) as a distinct type with multiple, disseminated smaller skin macules (cutis tricolor parvimaculata); and (IV) in association with other skin disturbances [e.g., cutis marmorata telangectasica congenita (phacomatosis achromico-melano-marmorata)] or in the context of other skin (e.g., ataxia-telangiectasia and phacomatosis pigmentovascularis, PPV) or complex malformation phenotypes (e.g., microcephaly and dwarfism). METHODS: (I) Review of the existing literature; and (II) information on our personal experience (clinical, laboratory and imaging data) on new cases with cutis tricolor seen and followed-up at our institutions during years 2010-2016. RESULTS: The existing literature revealed 19 previous studies (35 cases) with pure cutaneous or syndromic cutis tricolor phenomena. Our personal experience included 5 unpublished patients (3 boys; 2 girls; currently aged 2 to 14 years) seen and followed-up at our Institutions in Italy who had: (I) skin manifestations of the cutis tricolor type (N=5); (II) skeletal abnormalities including small skull (n=2), obtuse angle of mandible (n=3), mild to moderate scoliosis (n=3), vertebral defects (n=3), and long bones bowing (n=3); mild psychomotor delay (n=3); epilepsy (n=2); anomalies of the corpus callosum (n=3); and cavum vergae (n =2). CONCLUSIONS: This study further confirms and expands the overall phenotype of cutis tricolor. By literature review and personal experience we conclude that the skin abnormalities of the cutis tricolor type are stable over time; the skeletal defects are mild to moderate and do not progress or cause relevant orthopaedic complications; the neurological/behavioural phenotype does not progress and the paroxysmal events (when present) tend to decrease over time; there is a typical facial phenotype in some patients (long, elongated face, thick and brushy eyebrows, hypertelorism, deep nasal bridge with large bulbous nose and anteverted nostrils), which characterizes a somewhat distinct syndromic phenotype; some patients may develop early onset cataracts. The allelic dydymotic hypothesis of post-zygotic mutations likely involving the same gene loci could well explain the overall skin, bone, lens and nervous system phenomena of migration of different streaks of clones in the different tissues. PMID- 27942474 TI - Ultrasonographic clues for diagnosis of spina bifida occulta in children. AB - BACKGROUND: The aim of the current study was to find out if spinal ultrasonography might have a predictive potential for detection of spina bifida occulta (SBO) in pediatric nocturnal enuresis patients. METHODS: A total of 108 children (58 females, 50 males) with a mean age of 8 (range, 6-15) years diagnosed for nocturnal enuresis in our tertiary care center were included in this cross-sectional analysis. Half of the cases (n=54, 50%) were found to have SBO, while the other half did not have SBO. After obtaining radiographs and computed tomography examinations of L5-S1 vertebra, patients were examined by spinal ultrasound regarding radiologic clues which may aid in the detection of SBO. RESULTS: The clues of "single and double echogeneous cap signs and the V shaped tip of spine" were found useful for diagnosing SBO at levels of L5 and S1 in pediatric patients suspected for SBO. Receiver operating curve (ROC) curve analysis of CT and ultrasonographic clues for diagnosis of SBO on S1 level revealed that these clues yielded a comparable diagnostic accuracy to CT. Areas under curve for CT and studied ultrasonographic clues were are 0.667+/-0.053 and 0.907+/-0.032 (P<0.001) respectively. CONCLUSIONS: Ultrasonography seems to be a useful and practical diagnostic tool for diagnosing spina bifida. However, to implement our ultrasonographic criteria in routine radiological practice, further studies in larger series are warranted. PMID- 27942475 TI - Sinogram-based coil selection for streak artifact reduction in undersampled radial real-time magnetic resonance imaging. AB - BACKGROUND: Streak artifacts are a common problem in radial magnetic resonance imaging (MRI). We therefore developed a method for automatically excluding receiver coil elements which lead to these artifacts. METHODS: The proposed coil selection relates to real-time MRI data based on highly undersampled radial acquisitions. It exploits differences between high- and low-resolution sinograms reconstructed from datasets acquired during preparatory scans. Apart from phantom validations, the performance was assessed for real-time MRI studies of different human organ systems in vivo. RESULTS: The algorithm greatly reduces streak artifact strength without compromising image quality in other parts of the image. It is robust with respect to different experimental settings and fast to be included in the online reconstruction pipeline for real-time MRI. CONCLUSIONS: The proposed method enables a fast reduction of streak artifacts in radial real time MRI. PMID- 27942476 TI - Highly efficient eigen decomposition based statistical optical microangiography. AB - BACKGROUND: To overcome the drawbacks of the voxel-based eigen-decomposition (vED) approach to achieve the purpose of imaging blood flow in living tissue in real time. METHODS: A highly efficient and practical method for contrasting in vivo blood flow by applying eigen-decomposition (ED) filter on repeated complex valued optical coherence tomography (OCT) B-scans eigen-decomposition (bED) is proposed. We first present basic mathematics for bED. We then validate the bED through imaging cerebral blood flow in a mouse model. RESULTS: Through evaluating signal to noise ratio, contrast and vessel connectivity, it is found that the proposed method can better contrast blood flow with drastic saving on computational power when compared with traditional ED approach where the filtering is applied on the basis of pixel by pixel or voxel by voxel. CONCLUSIONS: The bED is practically feasible to realize real time OCT angiography. In addition, the proposed ED approach is equally applicable to the operations on repeated A-scans or volumetric scans. PMID- 27942477 TI - The effect of reducing spatial resolution by in-plane partial volume averaging on peak velocity measurements in phase contrast magnetic resonance angiography. AB - BACKGROUND: The aim of this study was to quantify the degree of the effect of in plane partial volume averaging on recorded peak velocity in phase contrast magnetic resonance angiography (PCMRA). METHODS: Using cardiac optimized 1.5 Tesla MRI scanners (Siemens Symphony and Avanto), 145 flow measurements (14 anatomical locations; ventricular outlets, aortic valve (AorV), aorta (5 sites), pulmonary arteries (3 sites), pulmonary veins, superior and inferior vena cava)- in 37 subjects (consisting of healthy volunteers, congenital and acquired heart disease patients) were analyzed by Siemens Argus default voxel averaging technique (where peak velocity = mean of highest velocity voxel and four neighbouring voxels) and by single voxel technique (1.3*1.3*5 or 1.7*1.7*5.5 mm3) (where peak velocity = highest velocity voxel only). The effect of scan protocol (breath hold versus free breathing) and scanner type (Siemens Symphony versus Siemens Avanto) were also assessed. Statistical significance was defined as P<0.05. RESULTS: There was a significant mean increase in peak velocity of 7.1% when single voxel technique was used compared to voxel averaging (P<0.0001). Significant increases in peak velocity were observed by single voxel technique compared to voxel averaging regardless of subject type, anatomical flow location, scanner type and breathing command. Disabling voxel averaging did not affect the volume of flow recorded. CONCLUSIONS: Reducing spatial resolution by the use of voxel averaging produces a significant underestimation of peak velocity. While this is of itself not surprising this is the first report to quantify the size of the effect. When PCMRA is used to assess peak velocity recording pixel averaging should be disabled. PMID- 27942478 TI - Arterial spin labeling perfusion magnetic resonance imaging of non-human primates. AB - Non-human primates (NHPs) resemble most aspects of humans in brain physiology and anatomy and are excellent animal models for translational research in neuroscience, biomedical research and pharmaceutical development. Cerebral blood flow (CBF) offers essential physiological information of the brain to examine the abnormal functionality in NHP models with cerebral vascular diseases and neurological disorders or dementia. Arterial spin labeling (ASL) perfusion MRI techniques allow for high temporal and spatial CBF measurement and are intensively used in studies of animals and humans. In this article, current high resolution ASL perfusion MRI techniques for quantitative evaluation of brain physiology and function in NHPs are described and their applications and limitation are discussed as well. PMID- 27942479 TI - Posterior fossa syndrome-a narrative review. AB - Posterior fossa syndrome (PFS), or cerebellar mutism syndrome (CMS), is a collection of neurological symptoms that occur following surgical resection of a posterior fossa tumour, and is characterised by either a reduction or an absence of speech. Some authors suggest that CM is only one symptom of the CMS complex that also includes ataxia, hypotonia and irritability as well as cranial nerve deficits, neurobehavioral changes and urinary retention or incontinence. It is seen almost exclusively in children. In 1985 Rekate et al. published the first work describing CM as a clinical entity, occurring as a consequence of bilateral cerebellar injury. Other associated symptoms include visual impairment, altered mood, impaired swallowing and significant gross and fine motor deficits. The effects of this can have a devastating impact on both the patient and their carers, posing a significant clinical challenge to neurorehabilitation services. The reported incidence was between 8% and 31% of children undergoing surgery for posterior fossa tumour. The underlying pathologies include vasospasm, oedema, and axonal/neuronal injury. Neuroimaging has contributed to a better understanding of the anatomical location of postoperative injury. There have been a number of suggestions for treatment interventions for PFS. However, apart from some individual reports, there have been no clinical trials indicating possible benefit. Occupational therapy, speech and language therapy, as well as neurocognitive support, contribute to the recovery of these patients. PMID- 27942480 TI - Diagnostic imaging of benign and malignant neck masses in children-a pictorial review. AB - Neck masses are frequently encountered in pediatric medicine, and can present a diagnostic dilemma for the clinicians involved. There are several means by which neck masses in children can be subdivided, for example by age at presentation, anatomical location including compartments and fascia of the neck, their classical appearance when imaged, or by etiology. When imaging children the clinicians must be mindful of radiation exposure and as such ultrasound (US) is often attempted first. Cross sectional imaging can be helpful for problem solving with CT being particularly useful for assessing the patient in more acute scenarios, for example when there is airway compromise. Nuclear medicine scintigraphy has a role in specific circumstances and can aid in staging in the presence of malignancy. If required, additional acquisition by means of magnetic resonance imaging (MRI) and computed tomography (CT) can be considered. This pictorial review describe the diagnostic imaging of (I) congenital and Developmental Pathologies, including thyroglossal duct cyst, branchial cleft cyst, cystic hygroma, dermoid cyst, thymic cyst and ectopic thymus; (II) neoplastic lesions, including hemangiomas and vascular malformations, pilomatrixoma, neurofibroma, neuroblastoma, rhabdomyosarcoma, papillary thyroid cancer, lymphoma & leukemia; (III) neck masses of Infective causes, including lymphadenitis, retropharyngeal and peritonsilar abscess, salivary gland inflammation; and (IV) other miscellaneous lesions, including ranula, sternocleidomastoid fibromatosis coli, and goiter. Neck masses are common in the pediatric population with a broad and varied differential; malignant etiologies are less frequently encountered when compared with adults but an awareness of its potential is important when reviewing imaging. PMID- 27942481 TI - Posterior reversible encephalopathy syndrome after intrathecal methotrexate infusion: a case report and literature update. AB - Posterior reversible encephalopathy syndrome (PRES) is a rare clinical radiological entity characterised by seizures, severe headache, mental status instability and visual disturbances. Hypertension is typically present. We report a case of a 13-year old boy with Burkitt lymphoma/leukaemia, who presented with posterior leukoencephalopathy 24 hours after intrathecal methotrexate (MTX) infusion. The child presented with headache, seizures, elevated blood pressure and gradual deterioration of his neurological status. Midazolam, dexamethazone and furosemide were initiated leading to reduction of cerebral oedema and clinical improvement. A thorough literature review is discussed in this report. Pathophysiology of leukoencephalopathy remains unclear. It develops within 5-14 days after intrathecal MTX and resolves within a week usually without permanent neurological sequelae. Broad use of MRI has led to an increasing number of identified cases of PRES. Treatment approach is mainly to manage the underlying cause of PRES. Prognosis is generally benign; however delayed diagnosis and improper management may result in permanent brain insult. PMID- 27942482 TI - A pre-tracer approach for improving the accuracy of metabolic measurements by hyperpolarized nuclear magnetic resonance. PMID- 27942483 TI - Systemic review and meta-analysis of diagnostic imaging technologies. PMID- 27942484 TI - Erratum to preoperative portal vein embolization in liver cancer: indications, techniques and outcomes. AB - [This corrects the article on p. 730 in vol. 5, PMID: 26682142.]. PMID- 27942485 TI - A systematic review on robotic coronary artery bypass graft surgery. AB - BACKGROUND: Robotic-assisted coronary artery bypass graft surgery (CABG) has been performed over the past decade. Despite encouraging results from selected centres, there is a paucity of robust clinical data to establish its clinical safety and efficacy. The present systematic review aimed to identify all relevant clinical data on robotic CABG. The primary endpoint was perioperative mortality, and secondary endpoints included perioperative morbidities, anastomotic complications, and long-term survival. METHODS: Electronic searches were performed using three online databases from their dates of inception to 2016. Relevant studies fulfilling the predefined search criteria were categorized according to surgical techniques as (I) totally endoscopic coronary artery bypass without cardiopulmonary bypass (TECAB off-pump); (II) TECAB on-pump; and robotic assisted mammary artery harvesting followed by minimally invasive direct coronary artery bypass (robotic MIDCAB). RESULTS: The present systematic review identified 44 studies that fulfilled the study selection criteria, including nine studies in the TECAB off-pump group and 16 studies in the robotic MIDCAB group. Statistical analysis reported a pooled mortality of 1.7% for the TECAB off-pump group and 1.0% for the robotic MIDCAB group. Intraoperative details such as the number and location of grafts performed, operative times and conversion rates, as well as postoperative secondary endpoints such as morbidities, anastomotic complications and long-term outcomes were also summarized for both techniques. CONCLUSIONS: A number of technical, logistic and cost-related issues continue to hinder the popularization of the robotic CABG procedure. Current clinical evidence is limited by a lack of randomized controlled trials, heterogeneous definition of techniques and complications, as well as a lack of robust clinical follow-up with routine angiography. Nonetheless, the present systematic review reported acceptable perioperative mortality rates for selected patients at specialized centres. These results should be considered as a useful benchmark for future studies, until further data is reported in the form of randomized trials. PMID- 27942486 TI - Robotic mitral valve surgery: overview, methodology, results, and perspective. AB - Robotic mitral valve repair began in 1998 and has advanced remarkably. It arose from an interest in reducing patient trauma by operating through smaller incisions with videoscopic assistance. In the United States, following two clinical trials, the FDA approved the daVinci Surgical System in 2002 for intra cardiac surgery. This device has undergone three iterations, eventuating in the current daVinci XI. At present it is the only robotic device approved for mitral valve surgery. Many larger centers have adopted its use as part of their routine mitral valve repair armamentarium. Although these operations have longer perfusion and arrest times, complications have been either similar or less than other traditional methods. Preoperative screening is paramount and leads to optimal patient selection and outcomes. There are clear contraindications, both relative and absolute, that must be considered. Three-dimensional (3D) echocardiographic studies optimally guide surgeons in operative planning. Herein, we describe the selection criteria as well as our operative management during a robotic mitral valve repair. Major complications are detailed with tips to avoid their occurrence. Operative outcomes from the author's series as well as those from the largest experiences in the United States are described. They show that robotic mitral valve repair is safe and effective, as well as economically reasonable due to lower costs of hospitalization. Thus, the future of this operative technique is bright for centers adopting the "heart team" approach, adequate clinical volume and a dedicated and experienced mitral repair surgeon. PMID- 27942487 TI - Long-term results after robotically assisted coronary bypass surgery. AB - BACKGROUND: Robotically-assisted coronary bypass grafting (CABG) was introduced in 1998 and dedicated centers have continuously applied and developed this minimally invasive method of coronary bypass surgery. While short-term results are relatively well published, data on long-term outcome are limited. In this literature review, we assessed the outcomes after robotic CABG following the first postoperative year. METHODS: We searched PubMed for articles containing the terms "robotic" or "robotically assisted" and "coronary bypass". A total of 11 papers contained long-term results. We specifically investigated survival, graft patency, freedom from angina and re-intervention, as well as freedom from major adverse cardiac and cerebrovascular events (MACCE). RESULTS: Five-year survival after robotic CABG was consistently consistently greater than 90% and graft patency between 3 and 5 years was reported to be above 90%. Fifteen percent to 26% of patients re-experienced angina at 3 to 5 years postoperatively. Long-term freedom from re-intervention reached the range and the 5-year freedom from MACCE rate was approximately 75%. CONCLUSIONS: According to data in the literature, long-term results after CABG carried out with the assistance of a surgical robot appear to be in line with results achieved after conventional CABG. PMID- 27942488 TI - Robotic surgery is the optimal approach for mitral surgery. AB - This report presented an overview of the patient selection, technical considerations and clinical evidence for robotic mitral valve surgery. A review of comparative outcomes to medical therapy, sternotomy approach, and the MitraClip device suggested that robotic mitral valve surgery is safe and effective in specialized centres. Potential benefits include a reliable and durable repair, with reduced perioperative morbidity and improved quality of life. Future studies should aim to delineate mid- and long-term clinical and echocardiographic outcomes following robotic mitral valve repair compared to the conventional sternotomy approach. PMID- 27942489 TI - Is minimally invasive thoracoscopic surgery the new benchmark for treating mitral valve disease? AB - The treatment of mitral valve disease remains dynamic; surgeons and patients must now choose between many different surgical options when addressing mitral regurgitation and mitral stenosis. Notably, advances in imaging and surgical instrumentation allow surgeons to perform less invasive mitral valve surgery that spares the sternum. With favorable long-term data now emerging, we compare the benefits and risks of thoracoscopic mitral valve surgery with that through conventional sternotomy or surgery that is robot-assisted. PMID- 27942490 TI - Robotic mitral valve surgery: current limitations and future directions. AB - Use of the surgical robot facilitates less invasive mitral valve surgery. Although multiple single center studies confirmed excellent results with robotically-assisted mitral valve surgery, both real and perceived limitations have slowed adoption of this technology. Some still question the safety and efficacy of robotically-assisted mitral valve surgery. However, present data suggests that robotic operations can be performed by specialized surgeons in appropriately selected patients without compromising results. That said, the robot does introduce additional procedural complexity related to management of cardiopulmonary bypass and myocardial protection. A direct approach to these challenges combined with careful patient selection enables the surgeon to obtain excellent results with robotically-assisted mitral valve surgery. PMID- 27942491 TI - Technical aspects of robotic posterior mitral valve leaflet repair. AB - Posterior mitral valve leaflet repair is safe, effective and durable and can be performed through conventional sternotomy or by using minimally invasive thoracoscopic or robotic-assisted approaches. Triangular resection with ventricularization, quadrangular resection with sliding or folding leaflet reconstruction, neochordae implantation and edge-to-edge leaflet repair are different techniques for eliminating the prolapsing mitral leaflet segment and restoring normal leaflet coaptation. Recent studies have demonstrated that minimally invasive approaches are associated with a reduced risk of postoperative complications, shorter hospital stay and improved cosmetic outcomes when compared to conventional sternotomy. In this review, we sought to describe technical aspects of robotic posterior mitral valve repair. PMID- 27942492 TI - Hybrid robotic coronary artery bypass grafting: how do we do it. PMID- 27942493 TI - Robotic mitral valve repair: algorithmic approach in degenerative mitral valve disease. PMID- 27942495 TI - Erratum to ravitch versus Nuss procedure for pectus excavatum: systematic review and meta-analysis. AB - [This corrects the article DOI: 10.21037/acs.2016.08.06.]. PMID- 27942494 TI - Robotic totally endoscopic coronary artery bypass grafting (TECAB)-placement of bilateral internal mammary arteries to the left ventricle. PMID- 27942496 TI - Robotic coronary artery bypass graft surgery. PMID- 27942497 TI - Classification of biosensor time series using dynamic time warping: applications in screening cancer cells with characteristic biomarkers. AB - The development of biosensors that produce time series data will facilitate improvements in biomedical diagnostics and in personalized medicine. The time series produced by these devices often contains characteristic features arising from biochemical interactions between the sample and the sensor. To use such characteristic features for determining sample class, similarity-based classifiers can be utilized. However, the construction of such classifiers is complicated by the variability in the time domains of such series that renders the traditional distance metrics such as Euclidean distance ineffective in distinguishing between biological variance and time domain variance. The dynamic time warping (DTW) algorithm is a sequence alignment algorithm that can be used to align two or more series to facilitate quantifying similarity. In this article, we evaluated the performance of DTW distance-based similarity classifiers for classifying time series that mimics electrical signals produced by nanotube biosensors. Simulation studies demonstrated the positive performance of such classifiers in discriminating between time series containing characteristic features that are obscured by noise in the intensity and time domains. We then applied a DTW distance-based k-nearest neighbors classifier to distinguish the presence/absence of mesenchymal biomarker in cancer cells in buffy coats in a blinded test. Using a train-test approach, we find that the classifier had high sensitivity (90.9%) and specificity (81.8%) in differentiating between EpCAM-positive MCF7 cells spiked in buffy coats and those in plain buffy coats. PMID- 27942498 TI - Down Syndrome: Current Status, Challenges and Future Perspectives. AB - Down syndrome (DS) is a birth defect with huge medical and social costs, caused by trisomy of whole or part of chromosome 21. It is the most prevalent genetic disease worldwide and the common genetic cause of intellectual disabilities appearing in about 1 in 400-1500 newborns. Although the syndrome had been described thousands of years before, it was named after John Langdon Down who described its clinical description in 1866. Scientists have identified candidate genes that are involved in the formation of specific DS features. These advances in turn may help to develop targeted therapy for persons with trisomy 21. Screening for DS is an important part of routine prenatal care. Until recently, noninvasive screening for aneuploidy depends on the measurement of maternal serum analytes and ultrasonography. More recent progress has resulted in the development of noninvasive prenatal screening (NIPS) test using cell-free fetal DNA sequences isolated from a maternal blood sample. A review on those achievements is discussed. PMID- 27942499 TI - MAP3K1 May be a Promising Susceptibility Gene for Type 2 Diabetes Mellitus in an Iranian Population. AB - Considering that MAPK (mitogen- activated protein kinase) signaling pathway has an important role in the progression of inflammatory cytokine secretion in type 2 diabetes mellitus (T2DM), we have recently investigated the reported genetic polymorphism from genome wide association study in MAP3K1 (mitogen-activated protein kinase kinase kinase 1) in diabetes as an important member of MAPK signaling. This study aimed to investigate the possible association of rs10461617 at the upstream of MAP3K1 gene in an Iranian case-control study with the risk of T2DM. The study population was comprised of 342 unrelated Iranian individuals including 177 patients with T2DM and 165 unrelated healthy control subjects. Genotyping was performed using PCR-RFLP and confirmed with sequencing. In a logistic regression analysis, the rs10461617A allele was associated with a significantly higher risk of T2DM assuming the log- additive model (OR: 1.44, 95% CI: 1.01-2.05, P = 0.039). In conclusion, we provided the first evidence for the association of rs10461617 at the upstream of MAP3K1 with the risk of T2DM in an Iranian population. PMID- 27942500 TI - Salvia officinalis (Sage) Leaf Extract as Add-on to Statin Therapy in Hypercholesterolemic Type 2 Diabetic Patients: a Randomized Clinical Trial. AB - The efficacy and safety of Salvia officinalis combined with statin have not been evaluated in dyslipidemic diabetes mellitus type 2 (DDMT2) so far. The plant extract antioxidant activity was determined by the DPPH radical scavenging assay. The total flavonoid, total phenolic and quercetin contents of the capsules containing the plant extract were also measured. Moreover, the effects of 2-month extract intake (500 mg capsule three times a day) as add-on to daily use of 15 mg glyburide, 2000 mg metformin and 10 mg atorvastatin on the blood levels of fasting glucose (FG), 2 h postprandial glucose (2hPPG), glycosylated hemoglobin (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride, high-density lipoprotein cholesterol (HDL-C), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), creatinine and body mass index were studied in 50 patients and compared with the placebo group (n=50).The extract IC50 in the DPPH assay was 87.26+/-0.003 ug/mL (mean+/-SD), whereas the ascorbic acid IC50 was 5.626+/- 0.001 ug/mL (mean+/-SD). The total flavonoid, total phenolic and quercetin contents of the capsule containing the plant extract were 39.76+/-3.58 mg of rutin equivalents (mean+/-SD), 30.33+/-1.23 mg of gallic acid (mean+/-SD) and 0.13 mg, respectively. The extract lowered FG, 2hPPG, HbA1c, TC, LDL-C and triglyceride levels, but increased HDL-C level compared to the placebo at the endpoint (P<0.05). The extract did not affect the other parameters significantly and no adverse effect was reported. The extract has substantial antioxidant activity which may be beneficial for the prevention of the cardiovascular complications of DDMT2. Moreover, addition of the extract to statin therapy is apparently safe and further improves lipid profile. PMID- 27942501 TI - Beneficial Effects of a Protein Rich Diet on Coping Neurotrans-mitter Levels During Ampicillin-Induced Neurotoxicity Compared to Propionic-Acid Induced Autistic Biochemical Features. AB - This study examined the effects of a protein rich diet on coping neurotransmitter levels in orally administered ampicillin-induced neurotoxic rats compared with propionic acid (PA) models of autism. 40 young male western albino rats were divided into four groups. The first group served as control and received phosphate buffered saline orally; the second group serving as autistic model was treated with oral dose of PA (250 mg/kg body weight/day for 3 days); the third group was treated with the neurotoxic dose of ampicillin (50 mg/kg for three weeks); the fourth group received the same dose of ampicillin and was fed with special protein rich diets. Noradrenaline, dopamine, serotonin glutamate, glutamine and interleukin 6 (IL-6) were measured in the brain homogenate of all tested groups. Specified doses of PA and ampicillin significantly (P<0.001) decreased noradrenaline, dopamine, and serotonin levels when compared to control. Also glutamate, IL-6 levels were significantly (P<0.001) increased in PA treated group while non-significant increase was found in ampicillin treated group. Non significant increase of glutamine was found in PA treated group with a significant increase in ampicillin treated group. The effects of ampicillin on these parameters were found to be potentiated when the rats were fed on a protein rich diet. Our results end with the conclusion that dietary protein level may be a useful tool to find out a path to restrict neurotransmitter alterations in neurodevelopmental disorders like autism. PMID- 27942502 TI - Utility of Specific IgE to Ara h 2 in Italian Allergic and Tolerant Children Sensitized to Peanut. AB - Emerging data suggest that measurement of serum IgE to peanut components can be clinically helpful and more accurate than IgE to whole peanut to predict peanut allergy. Not all studies have used prospective samples, multiple components and oral challenges. Currently, there are no data on this topic involving Italian children. 32 patients (23 males; median age 9 years) with reported history for peanut allergy and evidence of peanut sensitization (skin prick test to peanut extract >= 3mm) have been analyzed for serum IgE to whole peanut and recombinant allergen components Ara h 1, 2, 3, 8, and 9 with Immuno CAP and completed an open oral food challenge with peanut. 12 (37.5%) children had a positive challenge to peanut and were considered allergic. No differences were seen between the median values of IgE to peanut, Ara h 1, 3, 8 and 9 in allergic and tolerant children to peanut challenge. Noteworthy, 5 of 20 tolerant children had IgE to peanut> 15 kUA/l which is commonly considered a predictive value of peanut allergy. Conversely, a significant difference was seen when comparing the median value of IgE to Ara h 2 in the two groups: 0.75 kUA/l (IQR: 0.22-4.34 kUA/l) in allergic children versus 0.1 kUA/l (IQR: 0.1-0.12 kUA/l) in tolerant ones (P< 0.001). IgE levels to Ara h 2 are significantly higher in children that react to oral peanut challenge. Our findings in Italian children have been in line with recent reports in various populations of Northern Europe, the US and Australia and add confirmatory evidence that analysis of IgE to Ara h 2 could reduce the need for peanut challenge in suspected allergic patients. PMID- 27942503 TI - Rapid Induction of Neural Differentiation in Human Umbilical Cord Matrix Mesenchymal Stem Cells by cAMP-elevating Agents. AB - Human umbilical cord matrix (hUCM) is considered as a promising source of mesenchymal stem cells (MSCs) due to several advantages over other tissues. The potential of neural differentiation of hUCM-MSCs is of great interest in the context of treating neurodegenerative diseases. In recent years, considerable efforts have been made to establish in vitro conditions for improving the differentiation of hUCM-MSCs toward neuronal cells. In the present study, we evaluated the neural differentiation potential of hUCM-MSCs in the presence of cAMP-elevating agents forskolin and 3-isobutyl-1-methylxanthine (IBMX). hUCM-MSCs were isolated from fetal umbilical cord and characterized by flow cytometry analysis for mesenchymal specific markers. Mesodermal differentiation potential was assessed through selective media with lineage-specific induction factors. For assessment of neural differentiation, cells were cultured in the presence of cAMP elevating agents for 8 and 24 h. The neuronal differentiated MSCs were characterized for neuronal specific markers by immunocytochemistry and western blotting. Isolated hUCM-MSCs were found positive for mesenchymal markers (CD73, CD90, and CD105) while negative for hematopoietic markers (CD34 and CD45) .Following neural induction, most cells represented neural-like cells morphology. Neural markers including beta-tubulin III (Tuj-1), neuron-specific enolase (NSE), microtubule-associated protein-2 (MAP-2) and nestin were expressed in treated cells with respect to control group. The astrocyte specific marker, glial fibrillary acidic protein (GFAP) was also shown by immunofluorescence in treated cells. (These findings demonstrate that hUCM-MSCs have the ability to rapidly differentiate into neural cell types of neuron-like cells and astrocytes by cAMP elevating agents without the presence of growth factors. PMID- 27942504 TI - Genistein Induces Apoptosis and Inhibits Proliferation of HT29 Colon Cancer Cells. AB - Soybean isoflavone genistein has multiple anticancer properties and its pro apoptotic and anti-proliferative effects have been studied in different cancer cells. However, the mechanisms of action of genistein and its molecular targets on human colon cells have not been fully elucidated. Therefore, caspase-3 and p38 mitogen-activated protein kinase (p38 MAPK) as the main therapeutic targets were investigated in this study at both gene expression and protein levels in HT29 colon cancer cells. The caspase-3 and p38 MAPK gene expression levels were examined by real time PCR whereas flow cytometry technique was performed to determine their intracellular protein levels. The caspase-3 enzyme activity was obtained by colorimetric method while the gelatinase activity of matrix metalloproteinase-2 (MMP2) was determined by zymography. In addition, MTT test, wound healing assay and clonogenic assay were carried out to determine the effect of genistein on HT29 cell viability, migration, and proliferation, respectively. Genistein induced apoptotic death in HT29 cells through activation of caspase-3 pathway at the transcriptional, protein, and enzymatic levels. Moreover, genistein inhibited the proliferation of HT29 cells by reducing of both p38 MAPK gene expression and its active phosphorylated protein level. Also, we showed that genistein strongly suppressed the metastatic potency of HT29 colon cancer cells via the reduction of MMP2 activity. Based on the results of this study, we conclude that genistein may exhibit its anticancer properties on HT29 colon cancer cells by modulating caspase-3 and p38 MAPK pathway at different transcriptional and protein levels. PMID- 27942505 TI - A Novel Splice Site Mutation in HPS1 Gene is Associated with Hermansky-Pudlak Syndrome-1 (HPS1) in an Iranian Family. PMID- 27942506 TI - Emery-Dreifuss Muscular Dystrophy: a Report of a Large Family with 11 Affected Individuals. PMID- 27942507 TI - Impact of enzalutamide on patient-related outcomes in metastatic castration resistant prostate cancer: current perspectives. AB - Prostate cancer claims the lives of more than 25,000 men in the United States yearly, most from metastatic disease. In the past decade, several new medications have been approved for the treatment of metastatic prostate cancer including the antiandrogen enzalutamide. In addition, there has been mounting interest in evaluating health-related quality of life (QoL) in patients with cancer including new more detailed recommendations released by the Prostate Cancer Working Group 3 on how to evaluate patient-related outcomes in clinical trials. A total of four randomized double-blind placebo-controlled trials have evaluated patients with metastatic castration-resistant prostate cancer (mCRPC) randomized to receive enzalutamide vs control or bicalutamide. Each study used validated health-related QoL and pain surveys to evaluate patient-related outcomes. The studies suggest that patients with mCRPC, including those aged 75 years and older, have favorable overall QoL scores taking enzalutamide compared to standard of care. There was short-term improved pain control in patients taking enzalutamide compared to those in the placebo group. Some commonly reported adverse effects included fatigue, back pain, and hot flashes. These studies were limited in their patient attrition in filling out surveys as well as difficulty in comparing them to each other. Future studies examining patients with mCRPC taking enzalutamide will have to rigorously standardize ways patient-reported outcomes are collected and evaluate patients in a more diversified real-world population. PMID- 27942508 TI - Urinary gas chromatography mass spectrometry metabolomics in asphyxiated newborns undergoing hypothermia: from the birth to the first month of life. AB - BACKGROUND: Perinatal asphyxia is a severe clinical condition affecting around four million newborns worldwide. It consists of an impaired gas exchange leading to three biochemical components: hypoxemia, hypercapnia and metabolic acidosis. METHODS: The aim of this longitudinal experimental study was to identify the urine metabolome of newborns with perinatal asphyxia and to follow changes in urine metabolic profile over time. Twelve babies with perinatal asphyxia were included in this study; three babies died on the eighth day of life. Total-body cooling for 72 hours was carried out in all the newborns. Urine samples were collected in each baby at birth, after 48 hours during hypothermia, after the end of the therapeutic treatment (72 hours), after 1 week of life, and finally after 1 month of life. Urine metabolome at birth was considered the reference against which to compare metabolic profiles in subsequent samples. Quantitative metabolic profiling in urine samples was measured by gas chromatography mass spectrometry (GC-MS). The statistical approach was conducted by using the multivariate analysis by means of principal component analysis (PCA) and orthogonal partial least square discriminant analysis (OPLS-DA). Pathway analysis was also performed. RESULTS: The most important metabolites depicting each time collection point were identified and compared each other. At birth before starting therapeutic hypothermia (TH), urine metabolic profiles of the three babies died after 7 days of life were closely comparable each other and significantly different from those in survivors. CONCLUSIONS: In conclusion, a plethora of data have been extracted by comparing the urine metabolome at birth with those observed at each time point collection. The modifications over time in metabolites composition and concentration, mainly originated from the depletion of cellular energy and homeostasis, seems to constitute a fingerprint of perinatal asphyxia. PMID- 27942509 TI - Clinical significance of cell population data (CPD) on Sysmex XN-9000 in septic patients with our without liver impairment. AB - BACKGROUND: This study evaluated the clinical significance of cell population data (CPD) parameters obtained on Sysmex XN-9000 in septic patients admitted to intensive care unit (ICU) and stratified according to liver function. METHODS: The study population consisted in 84 patients, 44 of whom did not develop sepsis (NS), whereas the remaining 40 developed sepsis (SE) (n=24) or septic shock (SS) (n=16). Two hundred ostensibly healthy blood donors [healthy subjects (HS)], undergoing routine blood testing before a regular blood donation, were studied. RESULTS: Except for neutrophils and lymphocytes cell size (NE-FCS and LY-Z), all other CPD values were significantly different in ICU patients compared to HS. Neutrophils and monocytes fluorescence intensity (NE-SFL and MO-X) values were significantly higher in SS compared to sepsis and not develop sepsis patients. The value of many parameters was also different according to liver function. Overall, MO-X and neutrophils fluorescence intensity (NE-SFL) exhibited the best performance for diagnosing sepsis in all patients (AUC, 0.75 and 0.72), as well as in those with (AUC, 0.95 and 0.89) or without (AUC, 0.72 for both) liver impairment. These parameters were also significantly correlated with Sequential Organ Failure Assessment (SOFA) score. CONCLUSIONS: This study suggested that some novel CPD parameters (namely NE-SFL and MO-X) may provide useful information for diagnosis and management of sepsis. PMID- 27942510 TI - Is clinical evaluation alone sufficient for the diagnosis of a Bankart lesion without the use of magnetic resonance imaging? AB - BACKGROUND: Imaging modalities such as magnetic resonance arthrogram (MRA) offer great utility in diagnosing Bankart lesions but they are associated with a high degree of intra and interobserver variability. This study aims to evaluate the diagnostic accuracy of clinical evaluation and imaging modalities in Bankart lesions such as magnetic resonance imaging (MRI) and MRA of the shoulder. METHODS: Between February 2004 to January 2015, a retrospectively review of the surgical records at a tertiary hospital identified a total of 250 patients treated with a shoulder arthroscopy for Bankart repair. All patients were thoroughly investigated preoperatively in which a detailed history were obtained, relevant physical examinations were performed (Load and Shift/Anterior Apprehension test) and pre-operative radiographs taken. Some patients subsequently underwent either an MRI or an MRA scan if the initial clinical evaluation was equivocal. RESULTS: Anterior Shoulder Apprehension test and the Load and Shift test identified 214 of 227 Bankart tears, with a sensitivity of 94% [95% confidence interval (CI), 90-97%]. MRI correctly identified 23 of 26 Bankart tears, with a sensitivity of 89% (95% CI, 70-98%). Out of the five superior labrum anterior-posterior (SLAP) tears identified on MRI, only three were confirmed during arthroscopic surgery. MRA correctly identified 84 of 89 Bankart tears, for a sensitivity of 94% (95% CI, 87-98%). CONCLUSIONS: In our study, we report that clinical evaluation with focused history-taking and anterior apprehension, load and shift clinical examination can diagnose anterior shoulder instability as reliably as MR imaging. For patients with equivocal clinical findings, MR imaging can aid in the diagnosis. PMID- 27942511 TI - Local lung deposition of ultrafine particles in healthy adults: experimental results and theoretical predictions. AB - BACKGROUND: Ultrafine particles (UFP) of biogenic and anthropogenic origin occur in high numbers in the ambient atmosphere. In addition, aerosols containing ultrafine powders are used for the inhalation therapy of various diseases. All these facts make it necessary to obtain comprehensive knowledge regarding the exact behavior of UFP in the respiratory tract. METHODS: Theoretical simulations of local UFP deposition are based on previously conducted inhalation experiments, where particles with various sizes (0.04, 0.06, 0.08, and 0.10 um) were administered to the respiratory tract by application of the aerosol bolus technique. By the sequential change of the lung penetration depth of the inspired bolus, different volumetric lung regions could be generated and particle deposition in these regions could be evaluated. The model presented in this contribution adopted all parameters used in the experiments. Besides the obligatory comparison between practical and theoretical data, also advanced modeling predictions including the effect of varying functional residual capacity (FRC) and respiratory flow rate were conducted. RESULTS: Validation of the UFP deposition model shows that highest deposition fractions occur in those volumetric lung regions corresponding to the small and partly alveolated airways of the tracheobronchial tree. Particle deposition proximal to the trachea is increased in female probands with respect to male subjects. Decrease of both the FRC and the respiratory flow rate results in an enhancement of UFP deposition. CONCLUSIONS: The study comes to the conclusion that deposition of UFP taken up via bolus inhalation is influenced by a multitude of factors, among which lung morphometry and breathing conditions play a superior role. PMID- 27942513 TI - Oscillating blood pressure therapeutic target in type 2 diabetes patients with hypertension. AB - There is controversy regarding the J-shaped curve associating low blood pressure (BP) with increased cardiovascular events and mortality in hypertensive treated patients. This has partially motivated the revision of several hypertension treatment guidelines to raise the threshold for the definition and initiation of pharmacological treatment of hypertension in diabetes patients from 130/80 to 140/90 mmHg. However, there are increasing evidence that the increase cardiovascular risk caused by lower BP is not due to hypertensive treatment itself, rather to co-morbidities, especially in patients with diabetes. Much more, lower BP than currently recommended might be associated with significantly lower risk of cardiovascular events in diabetes patients. In this paper, we revisit the issue of ideal therapeutic BP target in diabetes patients with hypertension. PMID- 27942514 TI - Hepatitis B virus infection and risk of coronary artery disease: a meta-analysis. AB - BACKGROUND: Hepatitis B virus (HBV)-infected patients might be associated with coronary artery disease (CAD) from process of chronic inflammation. However, available studies yield conflicting results. This meta-analysis was performed to assess risk of CAD in HBV-infected patients. METHODS: We searched MEDLINE and EMBASE for relevant literatures from database inception to June 2016. Studies comparing the risk of CAD among HBV-infected patients versus subjects without HBV infection using hazard ratio (HR), odd ratios, or relative risk (RR) were included. Random-effect model and generic inverse variance method were used to combine odds ratio (OR) and 95% confidence interval (CI). RESULTS: A total of five studies, including three cross-sectional studies, one case-control study, and one cohort study, were subjected to analysis. The result demonstrates no significant risk of CAD among chronic HBV-infected patients and subjects without HBV infection (OR, 0.68; 95% CI, 0.40-1.13). CONCLUSIONS: This meta-analysis did not demonstrate a significantly increased risk of CAD among HBV-infected patients. PMID- 27942515 TI - Streamlining laboratory expenditures through direct to consumer testing and reference prices: first do not harm. PMID- 27942512 TI - Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. AB - There is an ongoing threat of epidemic or pandemic diseases that could be caused by influenza, Ebola or other emerging viruses. It will be difficult and costly to develop new drugs that target each of these viruses. Statins and angiotensin receptor blockers (ARBs) have been effective in treating patients with sepsis, pneumonia and influenza, and a statin/ARB combination appeared to dramatically reduce mortality during the recent Ebola outbreak. These drugs target (among other things) the endothelial dysfunction found in all of these diseases. Most scientists work on new drugs that target viruses, and few accept the idea of treating the host response with generic drugs. A great deal of research will be needed to show conclusively that these drugs work, and this will require the support of public agencies and foundations. Investigators in developing countries should take an active role in this research. If the next Public Health Emergency of International Concern is caused by an emerging virus, a "top down" approach to developing specific new drug treatments is unlikely to be effective. However, a "bottom up" approach to treatment that targets the host response to these viruses by using widely available and inexpensive generic drugs could reduce mortality in any country with a basic health care system. In doing so, it would make an immeasurable contribution to global equity and global security. PMID- 27942516 TI - Causal mediation analysis in the context of clinical research. AB - Clinical researches usually collected numerous intermediate variables besides treatment and outcome. These variables are often incorrectly treated as confounding factors and are thus controlled using a variety of multivariable regression models depending on the types of outcome variable. However, these methods fail to disentangle underlying mediating processes. Causal mediation analysis (CMA) is a method to dissect total effect of a treatment into direct and indirect effect. The indirect effect is transmitted via mediator to the outcome. The mediation package is designed to perform CMA under the assumption of sequential ignorability. It reports average causal mediation effect (ACME), average direct effect (ADE) and total effect. Also, the package provides visualization tool for these estimated effects. Sensitivity analysis is designed to examine whether the results are robust to the violation of the sequential ignorability assumption since the assumption has been criticized to be too strong to be satisfied in research practice. PMID- 27942517 TI - Troubleshooting an isolate prolongation of activated partial thromboplastin time in a patient with acute myocardial infarction-a paradigmatic case report. AB - We describe here the case of a 46-year-old man admitted to the emergency department (ED) and diagnosed with a non-ST elevation myocardial infarction. Before referring the patient to the coronary care unit and initiating antiplatelet and anticoagulant therapy, a highly prolonged activated partial thromboplastin time (APTT) was observed among results of laboratory testing. Results of mixing test showed complete correction of APTT, thus ruling out the presence of inhibitors of blood coagulation. On the following day, second line coagulation testing revealed normal activity of all clotting factors except factor XII, the concentration of which was found to be 1.5%. This result was suggestive for a diagnosis of inherited factor XII deficiency, thus highlighting the importance of combining clinical history, symptoms and results of first-line coagulation tests in similar emergency conditions. PMID- 27942518 TI - Lost wire? Ultrasound can find it for you! AB - The use of ultrasound (US) in clinical practice is becoming increasingly popular. This unique case highlights the importance of this technology in management of a complication arising from a central line placement in an intensive care unit (ICU). PMID- 27942519 TI - Isolated idiopathic aortitis with an unusually thickened aortic wall: case report. AB - Aortitis includes a broad range of disorders involving inflammation of the aorta. While most forms of aortitis can be linked to a specific cause, patients with idiopathic aortitis (IDA), are asymptomatic and usually diagnosed after surgical removal. The specific pathophysiology is not well understood, but can be strongly associated with tobacco smoking, young age at presentation, and family history of aortic aneurysm. Wall thickening is the most common physical characteristic of aortitis, and the inflammation can affect any layer of the aorta. The normal wall thickness of the aorta is less than 4 mm and can be as thick as 9 mm. Few studies document a correlation between wall thickness and the severity of aortitis. This paper presents a unique case of severe aortic aneurysm associated with an abnormal thickening of the ascending aorta. PMID- 27942520 TI - Reference pricing may have limited use but is not a blanket solution for laboratory testing. PMID- 27942521 TI - Is it time to break the fast?-a paradigm shift in clinical lipidology. PMID- 27942522 TI - Re-assessing the role of non-fasting lipids; a change in perspective. PMID- 27942523 TI - CONCERT-1, an additional piece in the puzzle of (bio)-(chemo)-radiation. PMID- 27942524 TI - CK1delta: a pharmacologically tractable Achilles' heel of Wnt-driven cancers? AB - Aberrant Wnt signaling has been widely accepted to be a key driver of a subset of human cancers and a heavily scrutinized molecular pathway for the development of personalized medicine. In a recently published issue of Science Translational Medicine, Rosenberg and coworkers reported that the delta isoform of the CK1 family of serine/threonine kinases (CK1delta), an important mediator of intracellular Wnt signaling, is amplified and overexpressed in human breast tumors. They further demonstrated that pharmacological inhibition of CK1delta is efficacious for these cancers and implicate beta-catenin signaling as a key target of CK1delta. In this perspective, we will discuss the salient features of this novel anti-cancer therapeutic approach and the challenges that lie ahead to translate it into a viable treatment option for cancer patients. PMID- 27942525 TI - Are long stimulus pulse durations the answer to improving spatial resolution in retinal prostheses? AB - Retinal prostheses can provide artificial vision to patients with degenerate retinae by electrically stimulating the remaining inner retinal neurons. The evoked perception is generally adequate for light localization, but of limited spatial resolution owing to the indiscriminate activation of multiple retinal cell types, leading to distortions in the perceived image. Here we present a perspective on a recent work by Weitz and colleagues who demonstrate a focal confinement of retinal ganglion cell (RGC) activation when using extended pulse durations in the stimulation waveform. Using real-time calcium imaging, they provide evidence that long pulse durations selectively stimulate inner retinal neurons, whilst avoiding unwanted axonal activations. The application of this stimulation technique may provide enhanced spatial resolution for retinal prosthesis users. These experiments provide a robust analysis of the effects of increasing pulse duration and introduce the potential for alternative stimulation paradigms in retinal prostheses. PMID- 27942526 TI - Patellar resurfacing after endoprosthetic replacement for primary or secondary bone tumors. PMID- 27942527 TI - Epigenetic therapy in a new era of medicine: creating and integrating molecular profiles of patients. PMID- 27942528 TI - One-size-fits-all management of hypertension: a key to poor control of hypertension in low income settings in sub-Saharan Africa? PMID- 27942529 TI - THP-1 cells as a model for human monocytes. PMID- 27942530 TI - Drugs targeting dynamin can restore cytoskeleton and focal contact alterations of urinary podocytes derived from patients with nephrotic syndrome. PMID- 27942532 TI - Annals of Translational Medicine is endorsed by the Hellenic Cooperative Oncology Group (HeCOG): new horizons for strong academic collaboration in medical oncology boost the academic development. PMID- 27942531 TI - Which future for circulating microRNAs as biomarkers of acute myocardial infarction? PMID- 27942533 TI - Retraction: CYP1A2 rs2069514 polymorphism and lung cancer susceptibility: a meta analysis. AB - [This retracts the article on p. 93 in vol. 3, PMID: 26015935.]. PMID- 27942534 TI - Information and communication technology use by female residents of public housing. AB - BACKGROUND: Evidence suggests that Internet, mobile, or social media based interventions may promote obesity-lowering behavior change, which has implications for cancer prevention and control interventions. However, the uptake of communication technologies among low socioeconomic status individuals, who need obesity management strategies most, is unclear. METHODS: Using the baseline data from a cluster-randomized behavioral intervention trial, we examined the cross-sectional associations of frequency of information and communication technologies (ICT) use among female public housing residents, as well as the variation of ICT use across demographic and health-related variables. RESULTS: ICT use was common among female public housing residents, with mobile use for calls and texts most prevalent (97% and 84%, respectively). Internet, social media, and health information users tended to be younger compared to non-users. Email, Internet, multimodal, and health information users were more likely to be born in the U.S. and be more highly educated than non-users. Social media and health information users were more likely to be Spanish speakers and people of Hispanic ethnicity compared to non-users, although this was not statistically significant. There were few differences according to obesity or physical activity level. CONCLUSIONS: Our findings of differential socio-demographics between users vs. non-users suggests that future cancer prevention and control interventions among public housing residents should consider selecting ICT that are aligned with the usage patterns of different groups making up the intended audience. PMID- 27942536 TI - Clinical Profi le and Predictors of Outcomes of Patients with Peripartum Cardiomyopathy: The Philippine Heart Center Experience. AB - BACKGROUND: Peripartum cardiomyopathy is a rare form of dilated cardiomyopathy characterized by heart failure and left ventricular dysfunction associated with pregnancy. While clinical characteristics of these patients have been previously described in literature, there is limited data regarding the natural history and predictors of outcomes of these patients in Asia, most specifi cally in Filipino patients. METHODS: Clinical and echocardiographic data of 39 patients diagnosed with peripartum cardiomyopathy were analyzed. Patients were followed up for the occurrence of death and major adverse events (MAE) and outcomes were correlated with patient variables. RESULTS: The mean age of the patients was 28.4 +/- 6.9 and the mean ejection fraction (EF) was 27.8 +/- 8.4%. Heart failure was the most common symptom (98%) while arrhythmia was the initial presentation in 5 patients (12.8%). 14 patients had recovery of ejection fraction in 6 months (39%) with a mean EF of 55.5 +/- 6.3. 16 patients had an initial EF of <25% (41%) and only 2 patients in this subgroup experienced improvement in EF. 29 patients experienced death and/or MAEs (74.4%). Multivariate analysis showed that an EF of <25% (HR 12.0,p=0.019), recovery of LV function (HR 0.23,p=0.05) and improvement of EF in 6 months (HR 0.32,p=0.024) were signifi cant predictors of MAEs. Kaplan Meier curves showed that patients whose ejection fraction was <25% had a 50% incidence of MAEs in 1 year with an increasing trend. Patients whose EF recovered in 6 months experienced a 60% freedom from MAE for almost 6 years. Patients with an EF of <25% had a mortality rate of 50% in two years. Patients with an EF of >25% had a 90% likelihood of survival for 8 years with a higher trend of mortality for patients whose EF did not recover in 6 months. CONCLUSION: Peripartum cardiomyopathy is associated with signifi cant morbidity and mortality. The degree of left ventricular dysfunction on presentation as well as improvement of EF within 6 months were predictive for the occurrence of death and major adverse events. This study emphasizes the need for aggressive treatment as well as clinical and echocardiographic follow up early in the course of disease in order to improve outcomes. PMID- 27942535 TI - Xenobiotic Receptor-Mediated Regulation of Intestinal Barrier Function and Innate Immunity. AB - The molecular basis for the regulation of the intestinal barrier is a very fertile research area. A growing body of knowledge supports the targeting of various components of intestinal barrier function as means to treat a variety of diseases, including the inflammatory bowel diseases. Herein, we will summarize the current state of knowledge of key xenobiotic receptor regulators of barrier function, highlighting recent advances, such that the field and its future are succinctly reviewed. We posit that these receptors confer an additional dimension of host-microbe interaction in the gut, by sensing and responding to metabolites released from the symbiotic microbiota, in innate immunity and also in host drug metabolism. The scientific evidence for involvement of the receptors and its molecular basis for the control of barrier function and innate immunity regulation would serve as a rationale towards development of non-toxic probes and ligands as drugs. PMID- 27942538 TI - Sepsis Incidence: A Population-Based Study. AB - BACKGROUND: Although sepsis is a major health problem, data on sepsis epidemiology are scarce. The aim of this study was to assess the incidence of sepsis, based on clinical findings in all adult patients treated with intravenous antibiotic in all parts of all hospitals in an entire population. METHODS: This is a retrospective chart review of patients >=18 years, living in 2 regions in Sweden, who were started on an intravenous antibiotic therapy on 4 dates, evenly distributed over the year of 2015. The main outcome was the incidence of sepsis with organ dysfunction. The mean population >=18 years at 2015 in the regions was 1275753. Five hundred sixty-three patients living in the regions were started on intravenous antibiotic treatment on the dates of the survey. Patients who had ongoing intravenous antibiotic therapy preceding the inclusion dates were excluded, if sepsis was already present. RESULTS: Four hundred eighty-two patients were included in the study; 339 had a diagnosed infection, of those, 96 had severe sepsis according to the 1991/2001 sepsis definitions, and 109 had sepsis according to the sepsis-3. This is equivalent to an annual incidence of traditional severe sepsis of 687/100000 persons (95% confidence interval [CI], 549-824) or according to the sepsis-3 definition of 780/100000 persons (95% CI, 633-926). Seventy-four patients had sepsis according to both definitions. CONCLUSIONS: The incidence of sepsis with organ dysfunction is higher than most previous estimates independent of definition. The inclusion of all inpatients started on intravenous antibiotic treatment of sepsis in a population makes an accurate assessment of sepsis incidence possible. PMID- 27942537 TI - Risk of Herpes Zoster in Individuals on Biologics, Disease-Modifying Antirheumatic Drugs, and/or Corticosteroids for Autoimmune Diseases: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Studies examining the risk of herpes zoster (HZ) associated with immunosuppressants, such as biologics, nonbiological disease-modifying antirheumatic drugs (nbDMARDs), or corticosteroids, have generated conflicting results. METHODS: We conducted a systematic literature search from January 1946 to February 2016. Search terms related to HZ, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematous, or inflammatory bowel disease, biologics, nbDMARDS, and corticosteroids were used. We included randomized controlled trials (RCTs) and observational studies reporting associations between immunosuppressants and HZ outcomes in adults. For RCTs, we used the Mantel Haenszel fixed-effects model to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for HZ risk. For observational studies, adjusted ORs were pooled separately using random-effects inverse variance models. RESULTS: Data were pooled from 40 eligible RCTs (20136 patients) and 19 observational studies (810939 patients). Biologics were associated with a greater risk of HZ than control (RCTs: OR = 1.71, 95% CI = 1.11-2.64; observational studies: OR = 1.58, 95% CI = 1.39-1.81). In RCTs, the OR of non-tumor necrosis factor (TNF) blockers was 2.19 (95% CI 1.20-4.02), but that of TNF blockers was not significantly different from control. Increased risks of HZ with nbDMARDs (OR = 1.21; 95% CI = 1.15-1.28) and corticosteroids (OR = 1.73; 95% CI = 1.57-1.89) were observed in observational studies, but few RCTs examined these comparisons. CONCLUSIONS: Immunocompromised patients receiving biologics were associated with an increased risk of HZ. The risk is also increased with corticosteroids and nbDMARDs. These findings raise the issue of prophylaxis with zoster vaccine in patients initiating immunosuppressive therapy for autoimmune diseases. PMID- 27942540 TI - A Potential Explanation of a Positive Serum beta-Glucan Assay in Mucormycosis. PMID- 27942539 TI - Nocardiosis in the Tropical Northern Territory of Australia, 1997-2014. AB - BACKGROUND: Nocardia is an opportunistic pathogen that can cause life-threatening disease. We aimed to characterize the epidemiological, microbiological, and clinical features of nocardiosis in the tropical north of Australia. METHODS: We conducted a retrospective cohort study of nocardiosis diagnosed between 1997 and 2014. Population-based incidences were calculated using district population data. RESULTS: Clinically significant nocardiosis was identified in 61 patients. The unadjusted population-based annual incidence of nocardiosis was 2.02 (95% confidence interval [CI], 1.55-2.60) per 100000 people and was 1.7 (95% CI, .96 2.90) fold higher in Indigenous compared with non-Indigenous persons (P = .027). Of 61 patients, 47 (77%) had chronic lung disease, diabetes, and/or hazardous alcohol consumption; 22 (36%) were immunocompromised; and 8 (13%) had no identified comorbidities. Disease presentations included pulmonary (69%; 42 of 61), cutaneous (13%; 8 of 61), and disseminated nocardiosis (15%; 9 of 61). The most commonly identified species were Nocardia asteroides and Nocardia cyriacigeorgica (each 11%). Linezolid was the only antimicrobial to which isolates were universally susceptible; 89% (48 of 54), 60% (32 of 53), and 48% (26 of 54) of isolates were susceptible to trimethoprim-sulfamethoxazole, ceftriaxone, and imipenem, respectively. Eighteen patients (30%) required intensive care unit (ICU) admission, and 1-year mortality was 31%. CONCLUSIONS: The incidence of nocardiosis in tropical Australia is amongst the highest reported globally. Nocardiosis occurs in both immunocompromised and immunocompetent hosts, and it is associated with high rates of ICU admission, 1 year mortality, and resistance to commonly recommended antimicrobials. Diagnosis should be considered in patients with consistent clinical features, particularly if they are Indigenous or have chronic lung disease. PMID- 27942541 TI - Early Antiretroviral Therapy at High CD4 Counts Does Not Improve Arterial Elasticity: A Substudy of the Strategic Timing of AntiRetroviral Treatment (START) Trial. AB - BACKGROUND: Both human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) risk. Vascular function assessments can be used to study CVD pathogenesis. We compared the effect of immediate versus deferred ART initiation at CD4 counts >500 cells/mm3 on small arterial elasticity (SAE) and large artery elasticity (LAE). METHODS: Radial artery blood pressure waveforms were recorded noninvasively. Small arterial elasticity and LAE were derived from analysis of the diastolic pulse waveform. Randomized treatment groups were compared with linear models at each visit and longitudinal mixed models. RESULTS: Study visits involved 332 participants in 8 countries: mean (standard deviation [SD]) age 35 (10), 70% male, 66% nonwhite, 30% smokers, and median CD4 count 625 cells/mm3 and 10-year Framingham risk score for CVD 1.7%. Mean (SD) SAE and LAE values at baseline were 7.3 (2.9) mL/mmHg * 100 and 16.6 (4.1) mL/mmHg * 10, respectively. Median time on ART was 47 and 12 months in the immediate and deferred ART groups, respectively. The treatment groups did not demonstrate significant within-person changes in SAE or LAE during the follow-up period, and there was no difference in mean change from baseline between treatment groups. The lack of significant differences persisted after adjustment, when restricted to early or late changes, after censoring participants in deferred group who started ART, and among subgroups defined by CVD and HIV risk factors. CONCLUSIONS: Among a diverse global population of HIV positive persons with high CD4 counts, these randomized data suggest that ART treatment does not have a substantial influence on vascular function among younger HIV-positive individuals with preserved immunity. PMID- 27942542 TI - Carbapenem-Resistant Klebsiella pneumoniae Infection in Three New York City Hospitals Trended Downwards From 2006 to 2014. AB - BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection is a rising public health threat since its first outbreaks in New York City (NYC) in the early 2000s. We investigated annual trends of CRKP infection in hospital acquired infections (HAIs) and community-onset infections (COIs) treated in 3 NYC hospitals from 2006 to 2014. METHODS: We extracted K pneumoniae infection data including carbapenem susceptibility and anatomical sites, compared clinical characteristics between CRKP and carbapenem-susceptible K pneumoniae infections, and determined CRKP infection proportions in total K pneumoniae infections in HAI and COI to identify statistically significant trends from 2006 to 2014 using the Cochran-Armitage trend test. RESULTS: Carbapenem-resistant K pneumoniae contributed 17.3% (601 of 3477) of hospital-acquired K pneumoniae infection compared with 7.7% (149 of 1926) in COI from 2006 to 2014. Carbapenem-resistant K pneumoniae proportions in HAI and COI were positively correlated over time (r = 0.83, P < .01), and there were downward annual trends of CRKP proportions from 2006 to 2014 in both HAI and COI (25.8% to 10.5% in HAI, P < .001; 13.6% to 3.1% in COI, P < .001). By anatomical site, significant downward annual trends were present only in urinary tract infection (P < .001 for both HAI and COI) from 2006 to 2014. CONCLUSIONS: Annual trends of CRKP proportions from 2006 to 2014 were downward in both HAI and COI, and HAI and COI were positively correlated. Efforts to reduce and prevent CRKP infections in both hospital and community settings were successful and warrant continuation. PMID- 27942543 TI - Nicotine Replacement, Topography, and Smoking Phenotypes of E-cigarettes. AB - OBJECTIVES: Little is known about the degree of nicotine replacement across first generation e-cigarette brands, how e-cigarettes are used, and if there is variation across brands in relevant smoking phenotypes. The objective of this project was to collect data that are critical to better understanding, use, and exposure when using e-cigarettes, which may then inform clinical trials and tobacco regulatory policy. METHODS: Twenty-eight cigarette smokers were randomized to use one of 5 popular brands of e-cigarettes for a 10-day study. Day 1 (own cigarette brand) data established baseline levels for cotinine, carbon monoxide (CO), topography, cigarette liking, withdrawal, and craving. Participants returned on Days 5 and 10 to reassess these measures while exclusively using e-cigarettes. RESULTS: Compared to cigarette smoking, e cigarettes provided significantly lower nicotine levels (25%-50%), reduced CO exposure, and lower ratings of liking (p < .05). Topography significantly differed between cigarette and e-cigarette sessions (p < .05). All brands significantly reduced withdrawal and craving (p < .05). There were no significant brand differences in outcome measures associated with exposure or use. CONCLUSIONS: E-cigarettes are not liked as much as cigarettes, provide significantly lower nicotine replacement, reduce CO exposure, and mitigate withdrawal and craving. The patterns of use significantly differ compared to cigarette smoking. PMID- 27942544 TI - Oral Health Knowledge and Attitudes of Community Health Workers in East Azerbaijan, Iran. AB - STATEMENT OF THE PROBLEM: Prevention is the key factor in acquiring dental and oral health. Community health workers, as a part of health care networks in Iran, play an important role in delivering primary care and their knowledge and attitude directly affect the population whom they interact with in their service scope. PURPOSE: The aim of this research was to evaluate the knowledge and attitude level of community health workers regarding oral health. MATERIALS AND METHOD: This descriptive analytical study was carried out on 1170 community health workers who were employed in health offices in East Azerbaijan to evaluate their knowledge and attitude level about oral health. Data were acquired through filled out questionnaires and were analyzed by SPSS software. RESULTS: There was no significant statistical relationship between knowledge and gender (p= 0.063), level of education (p= 0.08) and the period spent from the last continuing education course (p= 0.148).However, by increasing age (p= 0.016), work experience (p=0.083) and number of attended continuing education courses (p= 0.023), the knowledge scores were reduced. No statistically significant relationships were found between attitude and any of research variables. CONCLUSION: The level of knowledge and attitude of community health workers in East Azerbaijan regarding oral health was good. There was a reverse relationship between age, work experience, and frequency of participation in continuing education courses and knowledge scores which emphasizes the necessity of continuous training and revising the method of training in education of community health workers and other staffs of health care system. PMID- 27942545 TI - A Comparison of the Marginal and Internal Fit of Cobalt- Chromium Copings Fabricated by Two Different CAD/CAM Systems (CAD/ Milling, CAD/ Ceramill Sintron). AB - STATEMENT OF THE PROBLEM: Marginal fitness is the most important criteria for evaluation of the clinical acceptability of a cast restoration. Marginal gap which is due to cement solubility and plaque retention is potentially detrimental to both tooth and periodontal tissues. PURPOSE: This in vitro study aimed to evaluate the marginal and internal fit of cobalt- chromium (Co-Cr) copings fabricated by two different CAD/CAM systems: (CAD/ milling and CAD/ Ceramill Sintron). MATERIALS AND METHOD: We prepared one machined standard stainless steel master model with following dimensions: 7 mm height, 5mm diameter, 90 shoulder marginal finish line with 1 mm width, 10 convergence angle and anti-rotational surface on the buccal aspect of the die. There were 10 copings produced from hard presintered Co-Cr blocks according to CAD/ Milling technique and ten copings from soft non- presintered Co-Cr blocks according to CAD/ Ceramill Sintron technique. Marginal and internal accuracies of copings were documented by the replica technique. Replicas were examined at ten reference points under a digital microscope (230X). The Student's t-test was used for statistical analysis. p< 0.001 was considered significant. RESULTS: Statistically significant differences existed between the groups (p< 0.001). The CAD/milling group (hard copings) had a mean marginal discrepancy (MD) of 104 um, axial discrepancy (AD) of 23 um and occlusal discrepancy of 130 um. For CAD/ Ceramill Sintron group, these values were 195 um (MD), 46 um (AD), and 232 um (OD). Internal total discrepancy (ITD) for the CAD/milling group was 77 um, whereas for the CAD/Ceramill Sintron group was 143 um. CONCLUSION: Hard presintered Co-Cr copings had significantly higher marginal and internal accuracies compared to the soft non-presintered copings. PMID- 27942546 TI - The Effect of Lucite Glass Reinforcement on the Properties of Conventional Glass Ionomer Filling Materials. AB - STATEMENT OF THE PROBLEM: The usage of glass ionomer cements (GICs) restorative materials are very limited due to lack of flexural strength and toughness. PURPOSE: The aim of this study was to investigate the effect of using a leucite glass on a range of mechanical and optical properties of commercially available conventional glass ionomer cement. MATERIALS AND METHOD: Ball milled 45MUm leucite glass particles were incorporated into commercial conventional GIC, Ketac Molar Easymix (KMEm). The characteristics of the powder particles were observed under scanning electron microscopy. The samples were made for each experimental group; KMEm and lucite- modified Ketac-Molar easy Mix (LMKMEm) according to manufacturer's instruction then were collected in damp tissue and stored in incubator for 1 hour. The samples were divided into two groups, one stored in distilled water for 24 hours and the others for 1 week.10 samples were made for testing biaxial flexural strength after 1 day and 1 week, with a crosshead speed of 1mm/min, calculated in MPa. The hardness (Vickers hardness tester) of each experimental group was also tested. To evaluate optical properties, 3 samples were made for each experimental group and evaluated with a spectrophotometer. The setting time of modified GIC was measured with Gillmore machine. RESULT: The setting time in LMKMEm was 8 minutes. The mean biaxial flexural strength was LMKMEm/ 1day: 24.13+/-4.14 MPa, LMKMEm/ 1 week: 24.22+/-4.87 MPa KMEm/1day:28.87+/-6.31 MPa and KMEm/1 week: 26.65+/-5.82 MPa which were not statistically different from each other. The mean Vickers hardness was LMKMEm: 403+/-66 Mpa and KMEm: 358+/-22 MPa; though not statistically different from each other. The mean total transmittance (Tt) was LMKMEm: 15.9+/-0.7, KMEm: 22.3+/ 1.2, the mean diffuse transmittance (Td) was LMKMEm: 12.2+/-0.5, KMEm: 18.0+/-0.5 which were statistically different from each other. CONCLUSION: Leucite glass can be incorporated with a conventional GIC without interfering with setting time. Yet, it did not improve the mechanical and optical properties of the GIC. PMID- 27942547 TI - Evaluation of Condylar Position after Orthognathic Surgery for Treatment of Class II Vertical Maxillary Excess and Mandibular Deficiency by Using Cone-Beam Computed Tomography. AB - STATEMENT OF THE PROBLEM: In orthognathic surgeries, proper condylar position is one of the most important factors in postoperative stability. Knowing the condylar movement after orthognathic surgery can help preventing postoperative instabilities. PURPOSE: The aim of this study was to evaluate the condylar positional changes after Le Fort I maxillary superior repositioning along with mandibular advancement by using cone beam computed tomography (CBCT). MATERIALS AND METHOD: This cross-sectional study was conducted on 22 subjects who had class II skeletal malocclusion along with vertical maxillary excess. Subjects underwent maxillary superior repositioning (Le Fort I osteotomy) along with mandibular advancement. The CBCT images were taken a couple of days before the surgery (T0), and one month (T1) and 9 months (T2) after the surgery. The condyles positions were determined from the most superior point of the condyle to three distances including the deepest point of the glenoid fossa, the most anterior-inferior point of the articular eminence, and the most superior point of the external auditory meatus in the sagittal plane. RESULTS: The mean mandibular advancement was 4.33+/-2.1 mm and the mean maxillary superior repositioning was 4.66+/-0.3 mm. The condyles displaced inferiorly, anteriorly, and laterally between T0 and T1. They were repositioned approximately in the initial position in T2. No correlation was observed between the mandibular and maxillary movement and the condylar positions. CONCLUSION: The condyles displaced in the inferior-anterior lateral position one month after the bilateral sagittal split osteotomy for mandibular advancement in combination with the maxillary Le Fort I superior repositioning. It seems that the condyles adapted approximately in their initial position nine months after the surgeries. PMID- 27942548 TI - Effect of Self-etch Adhesives on Self-sealing Ability of High-Copper Amalgams. AB - STATEMENT OF THE PROBLEM: Similar to conventional amalgam, high-copper amalgam alloy may also undergo corrosion, but it takes longer time for the resulting products to reduce microleakage by sealing the micro-gap at the tooth/amalgam interface. PURPOSE: The aim of this study was to evaluate the effect of self-etch adhesives with different pH levels on the interfacial corrosion behavior of high copper amalgam restoration and its induction potential for self-sealing ability of the micro-gap in the early hours after setting by means of Electro-Chemical Tests (ECTs). MATERIALS AND METHOD: Thirty cylindrical cavities of 4.5mm x 4.7mm were prepared on intact bicuspids. The samples were divided into five main groups of application of Adhesive Resin (AR)/ liner/ None (No), on the cavity floor. The first main group was left without an AR/ liner (No). In the other main groups, the types of AR/ liner used were I-Bond (IB), Clearfil S3 (S3), Single Bond (SB) and Varnish (V). Each main group (n=6) was divided into two subgroups (n=3) according to the types of the amalgams used, either admixed ANA 2000 (ANA) or spherical Tytin (Tyt). The ECTs, Open Circuit Potential (OCP), and the Linear Polarization Resistance (LPR) for each sample were performed and measured 48 hours after the completion of the samples. RESULTS: The Tyt-No and Tyt-IB samples showed the highest and lowest OCP values respectively. In LPR tests, the Rp values of ANA-V and Tyt-V were the highest (lowest corrosion rate) and contrarily, the ANA-IB and Tyt-IB samples, with the lowest pH levels, represented the lowest Rp values (highest corrosion rates). CONCLUSION: Some self-etch adhesives may increase interfacial corrosion potential and self-sealing ability of high-copper amalgams. PMID- 27942549 TI - Topical Olive Leaf Extract Improves Healing of Oral Mucositis in Golden Hamsters. AB - STATEMENT OF THE PROBLEM: Oral mucositis (OM) is a common side effect of anti cancer drugs and needs significant attention for its prevention. PURPOSE: This study aimed to evaluate the healing effects of olive leaf extract on 5 fluorouracil-induced OM in golden hamster. MATERIALS AND METHOD: OM was induced in 63 male golden hamsters by the combination of 5-fluorouracil injections (days 0, 5 and 10) and the abrasion of the cheek pouch (days 3 and 4). On day 12, hamsters were received topical olive leaf extract ointment, base of ointment, or no treatment (control) for 5 days. Histopathology evaluations, blood examinations, and tissue malondialdehyde level measurement were performed 1, 3 and 5 days after treatments. RESULTS: Histopathology score and tissue malondialdehyde level were significantly lower in olive leaf extract treated group in comparison with control and base groups (p= 0.000). Significant decreases in white blood cell, hemoglobin, hematocrit , and mean corpuscular volume and an increase in mean corpuscular hemoglobin concentration were observed in olive leaf extract treated group in comparison with control and base groups (p< 0.05). CONCLUSION: Our findings demonstrated that daily application of olive leaf extract ointment had healing effect on 5-fluorouracil induced OM in hamsters. Moreover, the beneficial effect of olive leaf extract on OM might be due to its antioxidant and anti-inflammatory properties. PMID- 27942550 TI - Palifermin and Chlorhexidine Mouthwashes in Prevention of Chemotherapy-Induced Mucositis in Children with Acute Lymphocytic Leukemia: a Randomized Controlled Trial. AB - STATEMENT OF THE PROBLEM: Over the past three decades, significant improvements have been achieved in the survival of children with cancer. However, the considerable morbidity which occurs as a result of chemotherapy often restricts the treatment intensity. One of the important dose-limiting and costly adverse effects of cancer therapy is mucositis. Children with hematological malignancies are greatly at risk of developing mucositis. PURPOSE: This study aimed to assess the effectiveness of palifermin in preventing mucositis in children with acute lymphocytic leukemia (ALL) who undergo chemotherapy. MATERIALS AND METHOD: In this clinical trial, 90 children with ALL were randomized to receive chlorhexidine (n=45) or palifermin (n=45). One group received 60 MUg/ kg/ day palifermin as an intravenous bolus once daily for 3 days before and 3 days after the chemotherapy. Chlorhexidine mouthwash was administered once daily for 3 days before and 3 days after the chemotherapy. The world health organization (WHO) oral toxicity scale was employed for grading the mucositis. The data were analyzed by using two-way ANOVA. RESULTS: The two groups were matched for age and gender. The study groups were significantly different in terms of mucositis grading (P values after 1 and 2 week therapy were 0.00). Palifermin decreased the incidence and severity of chemotherapy-induced mucositis. CONCLUSION: Palifermin reduces the oral mucositis in children with ALL. Several mechanisms of action are suggested for keratinocyte growth factor (such as palifermin) including promotion of cell proliferation and cytoprotection, restraining the apoptosis, and changing the cytokine profile. PMID- 27942551 TI - The Effect of 1alpha,25(OH)2D3 on Osteogenic Differentiation of Stem Cells from Dental Pulp of Exfoliated Deciduous Teeth. AB - STATEMENT OF THE PROBLEM: Stem cells from human exfoliated deciduous teeth (SHEDs) are a population of highly proliferative cells, being capable of differentiating into osteogenic, odontogenic, adipocytes, and neural cells. Vitamin D3 metabolites such as 1alpha, 25-dihydroxyvitamin D3 are key factors in the regulation of bone metabolism. PURPOSE: The aim of this study was to investigate the effect of 1alpha, 25-dihydroxyvitamin D3 on osteogenic differentiation (alkaline phosphatase activity and alizarin red staining) of stem cells of exfoliated deciduous teeth. MATERIALS AND METHOD: Dental pulp was removed from freshly extracted primary teeth and immersed in a digestive solution. Then, the dental pulp cells were immersed in alpha-MEM (minimum essential medium) to which 10% fetal bovine serum was added. After the third passage, the cells were isolated from the culture plate and were used for osteogenic differentiation. As a control group, the cells were cultured in osteogenic cell culture medium. As the case group, the cells were cultured in osteogenic culture medium supplemented with 100 nM 1alpha,25 (OH)2D3. The alkaline phosphatase (ALP) activity and alizarin red staining were analyzed to evaluate the osteogenic differentiation at day 21. The results were analyzed by using t-test. RESULTS: Compared with the control group, significant increase was observed in ALP activity of SHEDs after being treated with 1alpha,25(OH)2D3 (p= 0.002). Alizarin red staining demonstrated that the cells exposed to 1alpha,25(OH)2D3 induced higher mineralized nodules (p< 0.001). CONCLUSION: Osteoblast differentiation in SHEDs was stimulated by 1alpha,25(OH) 2D3. It can be concluded that 1alpha,25(OH)2D3 can improve osteoblastic differentiation. PMID- 27942552 TI - Susceptibility of Candida albicans and Candida dubliniensis to Photodynamic Therapy Using Four Dyes as the Photosensitizer. AB - STATEMENT OF THE PROBLEM: Oral candidiasis is the most common opportunistic infection affecting the human oral cavity. Photodynamic therapy, as one of its proposed treatment modalities, needs a distinct dye for achieving the best effect. PURPOSE: The purpose of this study was to evaluate photosensitization effects of four distinct dyes on standard suspension of Candida albicans (C. albicans) and Candida dubliniensis (C. dubliniensis) and biofilm of C. albicans considering the obtained optimum dye concentration and duration of laser irradiation. MATERIALS AND METHOD: In this in vitro study, colony forming units (CFU) of two sets of four groups of Laser plus Dye (L+D+), Dye (L-D+), Laser (L+D ) and No Laser, No Dye (L-D-) were assessed individually with different methylene blue concentrations and laser irradiation period. The photodynamic therapy effect on standard suspension of Candida species (using methylene blue, aniline blue, malachite green and crystal violet) were studied based on the obtained results. Similar investigation was performed on biofilm of C. albicans using the spectral absorbance. Data were imported to SPSS and assessed by statistical tests of analysis of variance (ANOVA) and Tukey test (alpha= 0.05). RESULTS: CFU among the different dye concentration and irradiation time decrease in dose- and time dependent manner (p> 0.05), all of which were significantly lower than the control groups (p< 0.05). Among the examined photosensitizers, there was no statistically significant difference, (p> 0.05) though all of them were significantly decrease CFU compared with the control groups (p< 0.05). In L+D- and L+D+ groups, biofilm was significantly destroyed more than that of L-D- (p< 0.05). CONCLUSION: Photodynamic therapy might be used as an effective procedure to treat Candida associated mucocutaneous diseases and killing biofilm in the infected surfaces such as dentures. PMID- 27942553 TI - Evaluation of Internal Echogenic Pattern of Masseter in Subjects with Myofascial Pain/ Myositis, Oral Submucous Fibrosis, Chewers, Bruxers and Healthy Individuals A Preliminary Ultrasonographic Study. AB - STATEMENT OF THE PROBLEM: The masseter is generally involved in myofascial pain, myositis, oral submucous fibrosis (OSMF), bruxism, and in subjects with habitual tobacco/arecanut chewing. In all the above conditions, changes in the internal echogenic pattern on ultrasonography of the muscle may be observed. PURPOSE: The present study aimed at evaluating the internal echogenic pattern of masseter by ultrasonography in subjects with various conditions affecting masster muscle. MATERIALS AND METHOD: The study subjects were categorized into 5 groups consisting of 20 subjects each with the following conditions; Group 1: myofascial pain or myositis, Group 2: oral submucous fibrosis (OSMF), Group 3: habitual chewing of tobacco/arecanut without OSMF, Group 4: bruxism. Group 5 consisted of 20 healthy subjects. An ultrasonographic examination of masseter was performed in all subjects and the echogenic pattern was classified into Types I, II and III. The images were examined by two observers and inter-observer variability was assessed. Differences in internal echogenic pattern between study groups and control group was evaluated using Chi- square test. RESULTS: A good inter observer agreement was noted (k value= 0.8). An equal distribution of Types II and III echogenic pattern was noted in myofascial pain/myositis group. Type II was predominant in subjects with OSMF, habitual tobacco/arecanut chewing and bruxism. Type I was predominant in controls. The echogenic pattern differed significantly from controls in subjects with myofascial pain/myositis and OSMF (p=0.00001*, 0.0237* respectively), whereas in subjects with habitual tobacco/ arecanut chewing and bruxism, it did not differ significantly from controls (p=0.2482, 0.1223 respectively). CONCLUSION: Ultrasonographic examination of the echogenic pattern may help in understanding the nature of the disease process affecting the masseter muscle in various conditions. PMID- 27942554 TI - Peripheral Ameloblastic Fibroma: Report of a Rare Case. AB - Ameloblastic fibroma is a rare mixed odontogenic tumor mostly occurring in the posterior region of the mandible. The peripheral variant is very rare and to the best of our knowledge, only three cases have been reported in the English literature. In this report, we describe a case of peripheral ameloblastic fibroma in a 54-year-old woman with two years of follow-up. PMID- 27942555 TI - Extrafollicular Adenomatoid Odontogenic Tumor: An Unusual Case Presentation. AB - Adenomatoid odontogenic tumor (AOT) is an uncommon tumor of odontogenic origin and often misdiagnosed as an odontogenic cyst. It is predominantly found in young female patients, located more often in maxilla, and in most cases associated with an unerupted permanent tooth. There are three variants of AOT namely follicular, extra follicular, and peripheral. We report an unusual case of extrafollicular AOT in maxilla of a 50-year old male patient. PMID- 27942556 TI - Data on metal levels in the inlet and outlet wastewater treatment plant of hospitals in Bushehr province, Iran. AB - In this paper, we measured the levels of metals including Pb, Cr, Cd, Ni, Hg, Fe, and Cu in the inlet and outlet wastewater of hospitals. The samples were taken from wastewater in Bushehr's province hospitals, Iran. After the collection of samples, the concentration levels of metals were determined by using graphite furnace absorption spectrometer (AAS) method (Varian, SpectrAA 240, Australia). Statistical analysis of the data was carried out using Special Package for Social Sciences (SPSS 16). PMID- 27942557 TI - Data on the quantitative assessment pulmonary ground-glass opacification from coronary computed tomography angiography datasets. AB - We assessed the CT attenuation density of the pulmonary tissue adjacent to the heart in patients with acute non-ST segment elevation myocardial infarction (J.T. Kuhl, T.S. Kristensen, A.F. Thomsen et al., 2016) [1]. This data was related to the level of ground-glass opacification evaluated by a radiologist, and data on the interobserver variability of semi-automated assessment of pulmonary attenuation density was provided. PMID- 27942558 TI - Data on polymorphism of XRCC1 and cervical cancer risk from South India. AB - X-ray repair cross-complementing group 1 (XRCC1) is a major DNA repair gene involved in BER mutation. Polymorphisms in DNA repair genes associated with repair efficiency against DNA damage may predispose an individual's cancer susceptibility. Data from cervical cancer patients was collected from South Indian Women. Genotyping of XRCC1 polymorphisms (194C/T, 280G/A and 399G/A) was done by polymerase-chain-reaction with the confronting-two-pair primer (PCR-CTPP) method. PMID- 27942559 TI - Dataset of tear film cytokine levels in dry eye disease (DED) patients with and without HIV infection. AB - The tear film cytokine profiling data in this article was obtained from a prospective case-control study with a sample size of 34 dry eye disease (DED) patients with HIV infection and 32 DED patients without HIV infection, see "A distinct cytokines profile in tear film of dry eye disease (DED) patients with HIV infection" (R. Agrawal, P.K. Balne, A. Veerappan, V.B. Au, B. Lee, E. Loo, A. Ghosh, L. Tong, S.C. Teoh, J. Connolly, P. Tan, 2016) [1]. Tear samples were collected from all the subjects using Schirmer's strips and cytokine profiling was done using the Luminex bead based multiplex assay with a panel of 41 analytes. The cytokine level differences in each group of subjects were analyzed using logistic regression models. PMID- 27942560 TI - Dataset for analysing the relationships among economic growth, fossil fuel and non-fossil fuel consumption. AB - The data presented in this article are related to the research article entitled 'Economic Growth, Fossil Fuel and Non-Fossil Consumption: A Pooled Mean Group Analysis using Proxies for Capital' (J. Asafu-Adjaye, D. Byrne, M. Alvarez, 2016) [1]. This article describes data modified from three publicly available data sources: the World Bank's World Development Indicators (http://databank.worldbank.org/data/reports.aspx?source=world-development indicators), the U.S. Energy Information Administration's International Energy Statistics (http://www.eia.gov/cfapps/ipdbproject/IEDIndex3.cfm?tid=44&pid=44&aid=2) and the Barro-Lee Educational Attainment Dataset (http://www.barrolee.com). These data can be used to examine the relationships between economic growth and different forms of energy consumption. The dataset is made publicly available to promote further analyses. PMID- 27942561 TI - Effect of chemical mechanical polishing on surface nature of titanium implants FT IR and wettability data of titanium implants surface after chemical mechanical polishing implementation. AB - Bioactivity of titanium depends on the quality and characteristics of its surface oxide film. Through implementation of chemical mechanical polishing (CMP) process on titanium plates, a protective oxide (titania) film grows on the titanium based implant surface. In this article, surface properties of the titanium oxide are investigated as a function of the CMP process conditions. Surface responses were evaluated in terms of wettability, nano-scale surface roughness and material removal rates (MRR). Surface chemical compositions were also evaluated through Fourier transform infrared spectroscopy (FT-IR). PMID- 27942562 TI - Survey data on factors influencing participation in towel reuse programs. AB - This data article provides a data description on all subsamples related to the research article entitled "Don't change my towels please: Factors influencing participation in towel reuse programs" (E. Dimara, E. Manganari, D. Skuras, 2017) [1]. The dataset was compiled from a field questionnaire survey of 1304 tourists in Greece that captured key demographic, behavioral and psychographic characteristics. The dataset is split into distinct sub-samples that differ depending on whether tourists chose to respond to certain parts of the questionnaire or not. We provide descriptive statistics for the entire sample and all sub-samples as well the questionnaire's version in English and the econometric procedures to analyze this complex dataset. This dataset will allow researchers to include the study's results in future elaborated meta-analyses and/or gain a better insight to the study's major conclusions. PMID- 27942563 TI - Datasets used to discover the microbial signatures of oral dysbiosis, periodontitis and edentulism in humans. AB - This article provides supporting data for the research article 'Microbial Signatures of Oral Dysbiosis, Periodontitis and Edentulism Revealed by Gene Meter Methodology' (M.C. Hunter, A.E. Pozhitkov, P.A. Noble, 2016) [1]. In that article, we determined the microbial abundance signatures for patient with periodontics, edentulism, or health using Gene Meter Technology. Here we provide the data used to make the DNA microarray and the resulting microbial abundance data that was determined using the calibrated probes and the 16S rRNA genes harvested from patients. The first data matrix contains two columns: one is the GenInfo Identifier (GI) numbers of the 16S rRNA gene sequences and the other is the corresponding oral bacterial taxonomy. The probes were then screened for redundancy and if they were found to be unique, they were synthesized onto the surface of the DNA microarrays. The second data matrix consists of the abundances of the 576 16S rRNA genes that was determined using the median value of all individual calibrated probes targeting each gene. The data matrix consists of 16 columns and 576 rows, with the columns representing the 16 patients and the rows representing 576 different oral microorganisms. The third data matrix consists of the abundances of 567 16S rRNA genes determined using the calibrated abundance of all aggregated probes targeting the same 16S rRNA gene. The data matrix of the aggregated probes consists of 16 samples and 567 rows. PMID- 27942564 TI - Data on inflammasome gene polymorphisms of patients with sporadic malignant melanoma in a Brazilian cohort. AB - This article presents data related to our another article entitled, Genotyping and differential expression analysis of inflammasome genes in sporadic malignant melanoma reveal novel contribution of CARD8, IL1B and IL18 in melanoma susceptibility and progression (W.C. Silva, T.M. Oshiro, D.C. Sa, D.D.G.S. Franco, C. Festa Neto, A. Pontillo, 2016) [2]. Data presented here refers to the distribution of selected inflammasome SNPs in a Brazilian case/control cohort. We have identified 4 inflammasome related Single Nucleotide Polymorphisms (SNPs) for CARD8 (rs6509365); IL1B (rs1143643) and IL18 (rs5744256 and rs1834481) related to melanoma susceptibility/protection. This data can serve as a potential prognostic marker in sporadic malignant melanoma. PMID- 27942565 TI - Microarray dataset on the genome-wide expression profile of an M. smegmatis amtR mutant (JR258) compared to M. smegmatis mc2155. AB - The dataset presented here describes a microarray experiment to identify the AmtR regulon of Mycobacterium smegmatis comparing the transcription profile of a M. smegmatis amtR mutant to M. smegmatis wild-type. The raw and processed microarray data are available in the ArrayExpress database under Accession Number E-MTAB 4857 and interpretation of this data is found in the research article "Structure and function of AmtR in Mycobacterium smegmatis: implications for post transcriptional regulation of urea metabolism through a small antisense RNA" (Petridis et al., in press) [1]. PMID- 27942566 TI - Data demonstrating the Finnish wood pellet industry and future perspectives. AB - This article contains data related to the research article entitled "A survey analysis of the wood pellet industry in Finland: Future perspectives" (S. Proskurina, E. Alakangas, J. Heinimo, M. Mikkila, E. Vakkilainen, 2016) [1]. The dataset include information about the importance of wood pellets on the global bioenergy development and role of wood pellets on the Finnish bioenergy development. Data leads to an expansion of knowledge and discoveries of new possibility for wood pellets industry analysis. PMID- 27942567 TI - Data on fossil fuel availability for Shared Socioeconomic Pathways. AB - The data files contain the assumptions and results for the construction of cumulative availability curves for coal, oil and gas for the five Shared Socioeconomic Pathways. The files include the maximum availability (also known as cumulative extraction cost curves) and the assumptions that are applied to construct the SSPs. The data is differentiated into twenty regions. The resulting cumulative availability curves are plotted and the aggregate data as well as cumulative availability curves are compared across SSPs. The methodology, the data sources and the assumptions are documented in a related article (N. Bauer, J. Hilaire, R.J. Brecha, J. Edmonds, K. Jiang, E. Kriegler, H.-H. Rogner, F. Sferra, 2016) [1] under DOI: http://dx.doi.org/10.1016/j.energy.2016.05.088. PMID- 27942568 TI - Data on the role of accessible surface area on osmolytes-induced protein stabilization. AB - This paper describes data related to the research article "Testing the dependence of stabilizing effect of osmolytes on the fractional increase in the accessible surface area on thermal and chemical denaturations of proteins" [1]. Heat- and guanidinium chloride (GdmCl)-induced denaturation of three disulfide free proteins (bovine cytochrome c (b-cyt-c), myoglobin (Mb) and barstar) in the presence of different concentrations of methylamines (sarcosine, glycine-betaine (GB) and trimethylamine-N-oxide (TMAO)) was monitored by [Theta]222, the mean residue ellipticity at 222 nm at pH 7.0. Methylamines belong to a class of osmolytes known to protect proteins from deleterious effect of urea. This paper includes comprehensive thermodynamic data obtained from the heat- and GdmCl induced denaturations of barstar, b-cyt-c and Mb. PMID- 27942569 TI - Data for outcomes of acute hospital administration of amiodarone and/or lidocaine in shockable patients presenting with out-of-hospital cardiac arrest. AB - The data presented in this article are related to the research article entitled "Acute Hospital Administration of Amiodarone and/or Lidocaine in Shockable Patients Presenting with Out-of-hospital Cardiac Arrest: A Nationwide Cohort Study" (C.H. Huang, P.H. Yu, M.S. Tsai et al., 2016) [1]. The data contains the information of co-morbidities coding from ICD-9 CM codes and specific difference in requirement between medical centers and non-medical centers in resuscitation. Univariate and multivariate logistic regression analysis for factors related to the outcome of survival to ICU admission and survival to hospital discharge are included in the data set. The data also contains bootstrap sensitivity analysis of the logistic regression model for survival to ICU admission and hospital discharge outcomes in out-of-hospital cardiac arrest. Subgroup analysis of epinephrine dosage related to outcome of one-year survival is shown. PMID- 27942570 TI - A systematic databasing of diatoms from different geographical localities and sites of Haryana for advancing validation of forensic diatomology. AB - Verdict on tracing exact place of drowning is a part of medico-legal investigation. This question often stands when circumstances remain unclear about true drowning place. Usually, when a dead body rises from the bottom of drowning site, it will appear near to the point where it had actually disappeared but rapid current may carry a body to real distance from the exact place of death before any major obstruction. Forensic methodology has suggested qualitative as well as quantitative comparison of diatoms recovered in dead body and reference water samples to corroborate drowning as cause of death and locating precise place of drowning. Collection of wrong reference water samples from drowning site can also hamper the investigation process. Since, the distributions of different genera in certain extents relate particular water where the death due to drowning might have taken place; therefore, the present attempt was made to understand diatom distribution in five water bodies of Haryana with reference to diatom growth factors. This research data represents diatomological profiles of selected sites for possible application of forensic diatomology. Both, the light and scanning electron microscopy identified diatoms. It is envisioned that this data report is informative enough for the experts to plan future strategy for investigating mysteries associating place of drowning. PMID- 27942571 TI - Multiferroic La0.2Pb0.7Fe12O19 ceramics: Ferroelectricity, ferromagnetism and colossal magneto-capacitance effect. AB - The mutual control of the electric and magnetic properties of a multiferroic solid is of fundamental and great technological importance. In this article, the synthesis procedure of La0.2Pb0.7Fe12O19 ceramics was briefly described and the data acquired for the materials characterization is presented. This data article is related to the research article-Acta Mater. 2016, 121, 144 (j.actamat.2016.08.083). Electric polarization hysteresis loop and I-V curve, which help to confirm the ferroelectricity of La0.2Pb0.7Fe12O19 ceramics, were presented. Strong magnetic polarization data was also presented. The great variation of the dielectric constants along with the magnetic field has been presented which helped to demonstrat the giant magnetocapacitance of La0.2Pb0.7Fe12O19. All the datasets were collected at room temperature. Large ferroelectricity, strong magnetism and colossal magneto-capacitance effect have been all realized in one single phase La0.2Pb0.7Fe12O19 at room temperature. PMID- 27942572 TI - Data describing the association between rs266729 polymorphism inadiponectin promoter gene and Type 2 Diabetes Mellitus. AB - This article investigates whether there is an association between the rs266729 polymorphism in adiponectin promoter gene with metabolic parameters and disease status in 300 type 2 diabetes patients and 300 healthy adults from Jahrom city, Iran. The variants (G/C) were tested by polymerase chain reaction-restriction fragment length polymorphism method (RFLP) and metabolic parameters (glucose, cholesterol, HDL and LDL cholesterol) were measured using biochemical methods. However, no differences were detected between the haplotypes investigated, and the data obtained from our lab shown association of the ADIPOQ promoter polymorphism neither with biochemical parameters, nor with disease status. PMID- 27942573 TI - The testes transcriptome of the New World Screwworm, Cochliomyia hominivorax. AB - The New World Screwworm (NWS), Cochliomyia hominivorax, is a pest insect that is endemic to subtropical and tropical regions of the Western Hemisphere. The female lays eggs in open wounds or orifices of warm-blooded animals. Upon hatching, the resulting larvae feed upon the host's living tissues, which can become infected and death can occur. The sterile insect technique was developed to eradicate this pest from North America and new female conditional-lethal strains that generate only male individuals are being developed for use in the eradication program. To facilitate the identification of useful transcripts and gene promoters for these new strains, we used an Illumina Hi-Seq protocol to sequence the testes transcriptome of NWS. We report the assembly of 4149 transcripts (>=200 nt) from testes dissected from NWS males obtained from the J06 strain used in the screwworm production plant in Pacora, Panama. Functional annotation resulted in 2060, 2031, 558, and 325 transcripts with assigned BlastX, Gene Ontology, Enzyme Codes, and KEGG pathway information, respectively. In the Gene Ontology annotations, 6% and 3% of the transcripts in the Biological Process Ontology were noted as Developmental Process and Reproduction, respectively. This data set will serve as a resource to facilitate studies of sex determination in the NWS and the development of recombinant vectors that can be used to create new male-only strains of NWS. PMID- 27942574 TI - Nonphoto-exposed initial cutaneous manifestation of lupus after zoster: A case of Wolf's isotopic reaction. PMID- 27942575 TI - In vitro maturation and cryopreservation of oocytes retrieved from intra operative aspiration during second enucleation for ovarian tumor: A case report. AB - *We reported oocyte collection from an ovarian tumor with a single ovary.*Intra operative retrieval of oocytes may be useful for preserving fertility.*We have done in vitro maturation for immature oocytes with ovarian enucleation. PMID- 27942576 TI - A daughter's frustration with the dearth of patient- and family-centered care. AB - Patient involvement in decision-making is an increasingly recognized ethical imperative, one that requires attention to health literacy. Health care that is truly patient- and family-centered, however, is the exception rather than the rule. This first person account of a hospitalization describes the lack of patient and family inclusion in decision-making, failure to use plain language and other health literacy strategies, and disregard for patient and family preferences. The author concludes that if the health care system is going to shift from paternalistic to patient- and family-centered, providers must be trained how to communicate and partner with patients and families. Even the most skilled health professionals, however, will not be able to deliver patient- and family-centered care if the system they work in is not designed to foster or support such care. Committed hospitals will integrate patient- and family centered care throughout their organizations. This includes their mission statements, quality improvement activities, personnel policies, decision and self management support, and patient portals. Payment policies can encourage, but are a blunt instrument to drive, health care toward patient and family-centered care. The author references resources to help hospitals make systematic changes to hard wire health literate and patient- and family-centered care. PMID- 27942577 TI - Laboratory Notes From Behavioral Pharmacologists and Trainees: Considerations for the Discipline. AB - In several laboratory meetings, we discussed the challenges that face trainees in behavioral pharmacology. Major concerns, such as a difficult funding climate and limited academic job prospects were discussed at first. However, we decided to concentrate on ways to meet these challenges; versus focusing on negatives and listing gripes. Within this more constructive framework, we identified the importance of broadening training to aligned areas to enhance the capacity of behavioral pharmacologists to collaborate in multidisciplinary teams. With increased breadth of training comes the concern for a balance that does not cheat trainees out of the depth of training also needed for success. We believe that behavioral pharmacologists trained in this manner will be ideally positioned to be leaders of these translational research teams. Related to the breadth and depth of training is the recent concerns over replicability and reproducibility of published research. Behavioral pharmacologists, with the rigors of training in behavioral analysis and experimental design, can be at the forefront of this conversation. This will be especially true if current training is reinforced with additional experience in the use of cutting-edge statistical tools that address the complex experimental designs and large data sets that emerge from modern multidisciplinary collaborations. Finally, communicating the import and potential societal impact of our research to legislators, other scientists, educators, school children, neighbors, and acquaintances is needed to ensure that our field thrives. In closing, the process of explicitly discussing the challenges and potential solutions with current trainees will enhance their mentoring and training. PMID- 27942578 TI - Three-Dimensional Printing of Bone Extracellular Matrix for Craniofacial Regeneration. AB - Tissue-engineered approaches to regenerate bone in the craniomaxillofacial region utilize biomaterial scaffolds to provide structural and biological cues to stem cells to stimulate osteogenic differentiation. Bioactive scaffolds are typically comprised of natural components but often lack the manufacturability of synthetic materials. To circumvent this trade-off, we 3D printed materials comprised of decellularized bone (DCB) matrix particles combined with polycaprolactone (PCL) to create novel hybrid DCB:PCL scaffolds for bone regeneration. Hybrid scaffolds were readily printable at compositions of up to 70% bone by mass and displayed robust mechanical properties. Assessments of surface features revealed both collagenous and mineral components of bone were present. Qualitative and quantitative assessments showed increased surface roughness relative to that of pure PCL scaffolds. These findings correlated with enhanced cell adhesion on hybrid surfaces relative to that on pure surfaces. Human adipose-derived stem cells (hASCs) cultured in DCB:PCL scaffolds without soluble osteogenic cues exhibited significant upregulation of osteogenic genes in hybrid scaffolds relative to pure PCL scaffolds. In the presence of soluble phosphate, hybrid scaffolds resulted in increased calcification. The hASC-seeded scaffolds were implanted into critical-sized murine calvarial defects and yielded greater bone regeneration in DCB:PCL scaffolds compared to that in PCL-only at 1 and 3 months post-transplantation. Taken together, these results demonstrate that 3D printed DCB:PCL scaffolds might be effective for stimulating bone regeneration. PMID- 27942579 TI - Nitinol-Based Nanotubular Arrays with Controlled Diameters Upregulate Human Vascular Cell ECM Production. AB - Current approaches to reducing restenosis do not balance the reduction of vascular smooth muscle cell proliferation with the increase in the healing of the endothelium. Building on our previous work, we present our study on the effects of Nitinol-based nanotubular coatings with different nanotube diameters on the reduction of restenosis. Here, we demonstrate that the nanotubular coatings reduced primary human aortic smooth muscle cell (HASMC) proliferation and increased the migration (by more than 4 times), collagen (by 2-3 times per cell) and elastin (by 5-8 times per cell) production of primary human aortic endothelial cells (HAEC). Furthermore, a significant increase in elastin and soluble collagen production of HAEC was observed with an increase in nanotube diameter. Our findings suggest that nanotubes-coated Nitinol may provide a surface conducive for HAEC reendothelialization while reducing the proliferation of HASMC. PMID- 27942580 TI - Genetic variation in the insulin, insulin-like growth factor, growth hormone, and leptin pathways in relation to breast cancer in African-American women: the AMBER consortium. AB - The insulin/insulin-like growth factor (IGF) system and related pathways such as growth hormone, and leptin signaling have a key role in cancer development. It is unclear how germline variation in these pathways affects breast cancer risk. We conducted gene-based analyses of 184 genes in the insulin/IGF, growth hormone, and leptin pathways to identify genetic variation associated with risk of breast cancer overall, and for estrogen receptor (ER) subtypes. Tag single-nucleotide polymorphisms (SNPs) for each gene were selected and genotyped on a customized Illumina SNP array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 91,627 SNPs genotyped or imputed in 3,663 breast cancer cases, (1,983 ER-positive and 1,098 ER-negative) and 4,687 controls from the African American Breast Cancer Epidemiology and Risk consortium, a collaborative project of four large studies of breast cancer in African-American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multiethnic Cohort). We used a multi-locus adaptive joint test to determine the association of each gene with overall breast cancer and ER subtypes. The most significant gene associations (P <= 0.01) were BAIAP2 and CALM2 for overall breast cancer; BAIAP2 and CSNK2A1 for ER+ breast cancer; and BRAF, BAD, and MAPK3 for ER- breast cancer. The association of BAD with ER- breast cancer was explained by a two-SNP risk model; all other associations were best explained by one-SNP risk models. In total, six genes and seven SNPs had suggestive associations with overall breast cancer or ER subtypes in African-American women. PMID- 27942581 TI - B cell repertoire expansion occurs in meningeal ectopic lymphoid tissue. AB - Ectopic lymphoid tissues (ELT) can be found in multiple sclerosis (MS) and other organ-specific inflammatory conditions. Whether ELT in the meninges of central nervous system (CNS) autoimmune disease exhibit local germinal center (GC) activity remains unknown. In an experimental autoimmune encephalomyelitis model of CNS autoimmunity, we found activation-induced cytidine deaminase, a GC defining enzyme, in meningeal ELT (mELT) densely populated by B and T cells. To determine GC activity in mELT, we excised meningeal lymphoid aggregates using laser capture microscopy and evaluated B cell repertoires in mELT and secondary lymphoid organs by next-generation immune repertoire sequencing. We found immunoglobulin heavy chain variable region sequences that were unique to mELT and had accumulated functionally relevant somatic mutations, together indicating localized antigen-driven affinity maturation. Our results suggest that B cells in mELT actively participate in CNS autoimmunity, which may be relevant to mELT in MS and ELT in other chronic inflammatory conditions. PMID- 27942582 TI - Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease. AB - Pentraxin-2 (PTX-2), also known as serum amyloid P component (SAP/APCS), is a constitutive, antiinflammatory, innate immune plasma protein whose circulating level is decreased in chronic human fibrotic diseases. Here we show that recombinant human PTX-2 (rhPTX-2) retards progression of chronic kidney disease in Col4a3 mutant mice with Alport syndrome, reducing blood markers of kidney failure, enhancing lifespan by 20%, and improving histological signs of disease. Exogenously delivered rhPTX-2 was detected in macrophages but also in tubular epithelial cells, where it counteracted macrophage activation and was cytoprotective for the epithelium. Computational analysis of genes regulated by rhPTX-2 identified the transcriptional regulator c-Jun along with its activator protein-1 (AP-1) binding partners as a central target for the function of rhPTX 2. Accordingly, PTX-2 attenuates c-Jun and AP-1 activity, and reduces expression of AP-1-dependent inflammatory genes in both monocytes and epithelium. Our studies therefore identify rhPTX-2 as a potential therapy for chronic fibrotic disease of the kidney and an important inhibitor of pathological c-Jun signaling in this setting. PMID- 27942583 TI - Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes. AB - The adaptive immune repertoire plays a critical role in type 1 diabetes (T1D) pathogenesis. However, efforts to characterize B cell and T cell receptor (TCR) profiles in T1D subjects have been largely limited to peripheral blood sampling and restricted to known antigens. To address this, we collected pancreatic draining lymph nodes (pLN), "irrelevant" nonpancreatic draining lymph nodes, peripheral blood mononuclear cells (PBMC), and splenocytes from T1D subjects (n = 18) and control donors (n = 9) as well as pancreatic islets from 1 T1D patient; from these tissues, we collected purified CD4+ conventional T cells (Tconv), CD4+ Treg, CD8+ T cells, and B cells. By conducting high-throughput immunosequencing of the TCR beta chain (TRB) and B cell receptor (BCR) immunoglobulin heavy chain (IGH) on these samples, we sought to analyze the molecular signature of the lymphocyte populations within these tissues and of T1D. Ultimately, we observed a highly tissue-restricted CD4+ repertoire, while up to 24% of CD8+ clones were shared among tissues. We surveyed our data set for previously described proinsulin- and glutamic acid decarboxylase 65-reactive (GAD65-reactive) receptors, and interestingly, we observed a TRB with homology to a known GAD65 reactive TCR (clone GAD4.13) present in 7 T1D donors (38.9%), representing >25% of all productive TRB within Tconv isolated from the pLN of 1 T1D subject. These data demonstrate diverse receptor signatures at the nucleotide level and enriched autoreactive clones at the amino acid level, supporting the utility of coupling immunosequencing data with knowledge of characterized autoreactive receptors. PMID- 27942584 TI - IFN-epsilon protects primary macrophages against HIV infection. AB - IFN-epsilon is a unique type I IFN that is not induced by pattern recognition response elements. IFN-epsilon is constitutively expressed in mucosal tissues, including the female genital mucosa. Although the direct antiviral activity of IFN-epsilon was thought to be weak compared with IFN-alpha, IFN-epsilon controls Chlamydia muridarum and herpes simplex virus 2 in mice, possibly through modulation of immune response. We show here that IFN-epsilon induces an antiviral state in human macrophages that blocks HIV-1 replication. IFN-epsilon had little or no protective effect in activated CD4+ T cells or transformed cell lines unless activated CD4+ T cells were infected with replication-competent HIV-1 at a low MOI. The block to HIV infection of macrophages was maximal after 24 hours of treatment and was reversible. IFN-epsilon acted on early stages of the HIV life cycle, including viral entry, reverse transcription, and nuclear import. The protection did not appear to operate through known type I IFN-induced HIV host restriction factors, such as APOBEC3A and SAMHD1. IFN-epsilon-stimulated immune mediators and pathways had the signature of type I IFNs but were distinct from IFN-alpha in macrophages. IFN-epsilon induced significant phagocytosis and ROS, which contributed to the block to HIV replication. These findings indicate that IFN-epsilon induces an antiviral state in macrophages that is mediated by different factors than those induced by IFN-alpha. Understanding the mechanism of IFN-epsilon-mediated HIV inhibition through immune modulation has implications for prevention. PMID- 27942585 TI - Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaques. AB - The ALVAC prime/ALVAC + AIDSVAX B/E boost RV144 vaccine trial induced an estimated 31% efficacy in a low-risk cohort where HIV-1 exposures were likely at mucosal surfaces. An immune correlates study demonstrated that antibodies targeting the V2 region and in a secondary analysis antibody-dependent cellular cytotoxicity (ADCC), in the presence of low envelope-specific (Env-specific) IgA, correlated with decreased risk of infection. Thus, understanding the B cell repertoires induced by this vaccine in systemic and mucosal compartments are key to understanding the potential protective mechanisms of this vaccine regimen. We immunized rhesus macaques with the ALVAC/AIDSVAX B/E gp120 vaccine regimen given in RV144, and then gave a boost 6 months later, after which the animals were necropsied. We isolated systemic and intestinal vaccine Env-specific memory B cells. Whereas Env-specific B cell clonal lineages were shared between spleen, draining inguinal, anterior pelvic, posterior pelvic, and periaortic lymph nodes, members of Env-specific B cell clonal lineages were absent in the terminal ileum. Env-specific antibodies were detectable in rectal fluids, suggesting that IgG antibodies present at mucosal sites were likely systemically produced and transported to intestinal mucosal sites. PMID- 27942586 TI - IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans. AB - Hepatic fibrosis arises from inflammation in the liver initiated by resident macrophage activation and massive leukocyte accumulation. Hepatic macrophages hold a central position in maintaining homeostasis in the liver and in the pathogenesis of acute and chronic liver injury linked to fibrogenesis. Interferon regulatory factor 5 (IRF5) has recently emerged as an important proinflammatory transcription factor involved in macrophage activation under acute and chronic inflammation. Here, we revealed that IRF5 is significantly induced in liver macrophages from human subjects developing liver fibrosis from nonalcoholic fatty liver disease or hepatitis C virus infection. Furthermore, IRF5 expression positively correlated with clinical markers of liver damage, such as plasma transaminase and bilirubin levels. Interestingly, mice lacking IRF5 in myeloid cells (MKO) were protected from hepatic fibrosis induced by metabolic or toxic stresses. Transcriptional reprogramming of macrophages lacking IRF5 was characterized by immunosuppressive and antiapoptotic properties. Consequently, IRF5 MKO mice respond to hepatocellular stress by promoting hepatocyte survival, leading to complete protection from hepatic fibrogenesis. Our findings reveal a regulatory network, governed by IRF5, that mediates hepatocyte death and liver fibrosis in mice and humans. Therefore, modulating IRF5 function may be an attractive approach to experimental therapeutics in fibroinflammatory liver disease. PMID- 27942587 TI - Chorioretinal thinning in chronic kidney disease links to inflammation and endothelial dysfunction. AB - BACKGROUND. Chronic kidney disease (CKD) is strongly associated with cardiovascular disease and there is an established association between vasculopathy affecting the kidney and eye. Optical coherence tomography (OCT) is a novel, rapid method for high-definition imaging of the retina and choroid. Its use in patients at high cardiovascular disease risk remains unexplored. METHODS. We used the new SPECTRALIS OCT machine to examine retinal and retinal nerve fiber layer (RNFL) thickness, macular volume, and choroidal thickness in a prospective cross-sectional study in 150 subjects: 50 patients with hypertension (defined as a documented clinic BP greater than or equal to 140/90 mmHg (prior to starting any treatment) with no underlying cause identified); 50 with CKD (estimated glomerular filtration rate (eGFR) 8-125 ml/min/1.73 m2); and 50 matched healthy controls. We excluded those with diabetes. The same, masked ophthalmologist carried out each study. Plasma IL-6, TNF-alpha , asymmetric dimethylarginine (ADMA), and endothelin-1 (ET-1), as measures of inflammation and endothelial function, were also assessed. RESULTS. Retinal thickness, macular volume, and choroidal thickness were all reduced in CKD compared with hypertensive and healthy subjects (for retinal thickness and macular volume P < 0.0001 for CKD vs. healthy and for CKD vs. hypertensive subjects; for choroidal thickness P < 0.001 for CKD vs. healthy and for CKD vs. hypertensive subjects). RNFL thickness did not differ between groups. Interestingly, a thinner choroid was associated with a lower eGFR (r = 0.35, P <0.0001) and, in CKD, with proteinuria (r = -0.58, P < 0.001) as well as increased circulating C-reactive protein (r = -0.57, P = 0.0002), IL-6 (r = -0.40, P < 0.01), ADMA (r = -0.37, P = 0.02), and ET-1 (r = 0.44, P < 0.01). Finally, choroidal thinning was associated with renal histological inflammation and arterial stiffness. In a model of hypertension, choroidal thinning was seen only in the presence of renal injury. CONCLUSIONS. Chorioretinal thinning in CKD is associated with lower eGFR and greater proteinuria, but not BP. Larger studies, in more targeted groups of patients, are now needed to clarify whether these eye changes reflect the natural history of CKD. Similarly, the associations with arterial stiffness, inflammation, and endothelial dysfunction warrant further examination. TRIAL REGISTRATION. Registration number at www.clinicalTrials.gov: NCT02132741. SOURCE OF FUNDING. TR was supported by a bursary from the Erasmus Medical Centre, Rotterdam. JJMHvB was supported by a bursary from the Utrecht University. JRC is supported by a Rowling Scholarship. SB was supported by a Wellcome Trust funded clinical research fellowship from the Scottish Translational Medicine and Therapeutics Initiative, and by a Rowling Scholarship, at the time of this work. ND is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/13/30/29994). PMID- 27942588 TI - Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokine. AB - T cells that enter tumors are largely tolerized, but how that process is choreographed and how the ensuing "dysfunctional" tumor-infiltrating lymphocytes (TILs) are maintained are poorly understood and are difficult to assess in spontaneous disease. We exploited an autochthonous model of breast cancer for high-resolution imaging of the early and later stages of tumor residence to understand the relationships between cellular behaviors and cellular phenotypes. "Dysfunctional" differentiation began within the first days of tumor residence with an initial phase in which T cells arrest, largely on tumor-associated macrophages. Within 10 days, cellular motility increased and resembled a random walk, suggesting a relative absence of TCR signaling. We then studied the concurrent and apparently contradictory phenomenon that many of these cells express molecular markers of activation and were visualized undergoing active cell division. We found that whereas proliferation did not require ongoing TCR/ZAP70 signaling, instead this is driven in part by intratumoral IL-15 cytokine. Thus, TILs undergo sequential reprogramming by the tumor microenvironment and are actively retained, even while being antigen insensitive. We conclude that this program effectively fills the niche with ineffective yet cytokine-dependent TILs, and we propose that these might compete with new clones, when they arise. PMID- 27942589 TI - Interleukin 6 regulates psoriasiform inflammation-associated thrombosis. AB - Psoriasis patients are at increased risk of heart attack and stroke and have elevated MRP8/14 levels that predict heart attack. The KC-Tie2 psoriasiform mouse model exhibits elevated MRP8/14 and is prothrombotic. Mrp14-/- mice, in contrast, are protected from thrombosis, but, surprisingly, KC-Tie2xMrp14-/- mice remain prothrombotic. Treating KC-Tie2xMrp14-/- mice with anti-IL-23p19 antibodies reversed the skin inflammation, improved thrombosis, and decreased IL-6. In comparison, IL-6 deletion from KC-Tie2 animals improved thrombosis despite sustained skin inflammation, suggesting that thrombosis improvements following IL 23 inhibition occur secondary to IL-6 decreases. Psoriasis patient skin has elevated IL-6 and IL-6 receptor is present in human coronary atheroma, supporting a link between skin and distant vessel disease in patient tissue. Together, these results identify a critical role for skin-derived IL-6 linking skin inflammation with thrombosis, and shows that in the absence of IL-6 the connection between skin inflammation and thrombosis comorbidities is severed. PMID- 27942590 TI - Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation. AB - BACKGROUND. Orthotopic liver transplant (OLT) is the primary therapy for end stage liver disease and acute liver failure. However, ischemia/reperfusion injury (IRI) can severely compromise allograft survival. To understand the evolution of immune responses underlying OLT-IRI, we evaluated longitudinal cytokine expression profiles from adult OLT recipients before transplant through 1 month after transplant. METHODS. We measured the expression of 38 cytokines, chemokines, and growth factors in preoperative and postoperative recipient circulating systemic blood (before transplant and 1 day, 1 week, and 1 month after transplant) and intraoperative portal blood (before and after reperfusion) of 53 OLT patients and analyzed this expression in relation to biopsy-proven IRI (n = 26 IRI+; 27 IRI-), clinical liver function tests early (days 1-7) after transplant, and expression of genes encoding cytokine receptors in biopsies of donor allograft taken before and after reperfusion. RESULTS. Bilirubin and arginine transaminase levels early after transplant correlated with IRI. Fourteen cytokines were significantly increased in the systemic and/or portal blood of IRI+ recipients that shifted from innate to adaptive-immune responses over time. Additionally, expression of cognate receptors for 10 of these cytokines was detected in donor organ biopsies by RNAseq. CONCLUSION. These results provide a mechanistic roadmap of the early immunological events both before and after IRI and suggest several candidates for patient stratification, monitoring, and treatment. FUNDING. Ruth L. Kirschstein National Research Service Award T32CA009120, Keck Foundation award 986722, and a Quantitative & Computational Biosciences Collaboratory Postdoctoral Fellowship. PMID- 27942591 TI - mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regeneration. AB - Muscle trauma is highly morbid due to intramuscular scarring, or fibrosis, and muscle atrophy. Studies have shown that bone morphogenetic proteins (BMPs) reduce muscle atrophy. However, increased BMP signaling at muscle injury sites causes heterotopic ossification, as seen in patients with fibrodysplasia ossificans progressiva (FOP), or patients with surgically placed BMP implants for bone healing. We use a genetic mouse model of hyperactive BMP signaling to show the development of intramuscular fibrosis surrounding areas of ectopic bone following muscle injury. Rapamycin, which we have previously shown to eliminate ectopic ossification in this model, also eliminates fibrosis without reducing osteogenic differentiation, suggesting clinical value for patients with FOP and with BMP implants. Finally, we use reporter mice to show that BMP signaling is positively associated with myofiber cross-sectional area. These findings underscore an approach in which 2 therapeutics (rapamycin and BMP ligand) can offset each other, leading to an improved outcome. PMID- 27942592 TI - DNA methylation in lung cells is associated with asthma endotypes and genetic risk. AB - The epigenome provides a substrate through which environmental exposures can exert their effects on gene expression and disease risk, but the relative importance of epigenetic variation on human disease onset and progression is poorly characterized. Asthma is a heterogeneous disease of the airways, for which both onset and clinical course result from interactions between host genotype and environmental exposures, yet little is known about the molecular mechanisms for these interactions. We assessed genome-wide DNA methylation using the Infinium Human Methylation 450K Bead Chip and characterized the transcriptome by RNA sequencing in primary airway epithelial cells from 74 asthmatic and 41 nonasthmatic adults. Asthma status was based on doctor's diagnosis and current medication use. Genotyping was performed using various Illumina platforms. Our study revealed a regulatory locus on chromosome 17q12-21 associated with asthma risk and epigenetic signatures of specific asthma endotypes and molecular networks. Overall, these data support a central role for DNA methylation in lung cells, which promotes distinct molecular pathways of asthma pathogenesis and modulates the effects of genetic variation on disease risk and clinical heterogeneity. PMID- 27942593 TI - Low-dose dasatinib rescues cardiac function in Noonan syndrome. AB - Noonan syndrome (NS) is a common autosomal dominant disorder that presents with short stature, craniofacial dysmorphism, and cardiac abnormalities. Activating mutations in the PTPN11 gene encoding for the Src homology 2 (SH2) domain containing protein tyrosine phosphatase-2 (SHP2) causes approximately 50% of NS cases. In contrast, NS with multiple lentigines (NSML) is caused by mutations that inactivate SHP2, but it exhibits some overlapping abnormalities with NS. Protein zero-related (PZR) is a SHP2-binding protein that is hyper-tyrosyl phosphorylated in the hearts of mice from NS and NSML, suggesting that PZR and the tyrosine kinase that catalyzes its phosphorylation represent common targets for these diseases. We show that the tyrosine kinase inhibitor, dasatinib, at doses orders of magnitude lower than that used for its anticancer activities inhibited PZR tyrosyl phosphorylation in the hearts of NS mice. Low-dose dasatinib treatment of NS mice markedly improved cardiomyocyte contractility and functionality. Remarkably, a low dose of dasatinib reversed the expression levels of molecular markers of cardiomyopathy and reduced cardiac fibrosis in NS and NSML mice. These results suggest that PZR/SHP2 signaling is a common target of both NS and NSML and that low-dose dasatinib may represent a unifying therapy for the treatment of PTPN11-related cardiomyopathies. PMID- 27942594 TI - miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways. AB - Maladaptive epithelial repair from chronic injury is a common feature in fibrotic diseases, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs (miRs) can regulate expression of multiple genes and fundamentally alter cellular phenotypes during fibrosis. Although several miRs have been shown to be associated with lung fibrosis, the mechanisms by which miRs modulate epithelial behavior in lung fibrosis are lacking. Here, we identified miR-323a-3p to be downregulated in the epithelium of lungs with bronchiolitis obliterans syndrome (BOS) after lung transplantation, idiopathic pulmonary fibrosis (IPF), and murine bleomycin induced fibrosis. Antagomirs for miR-323a-3p augment, and mimics suppress, murine lung fibrosis after bleomycin injury, indicating that this miR may govern profibrotic signals. We demonstrate that miR-323a-3p attenuates TGF-alpha and TGF beta signaling by directly targeting key adaptors in these important fibrogenic pathways. Moreover, miR-323a-3p lowers caspase-3 expression, thereby limiting programmed cell death from inducers of apoptosis and ER stress. Finally, we find that epithelial expression of miR-323a-3p modulates inhibitory crosstalk with fibroblasts. These studies demonstrate that miR-323a-3p has a central role in lung fibrosis that spans across murine and human disease, and downregulated expression by the lung epithelium releases inhibition of various profibrotic pathways to promote fibroproliferation. PMID- 27942595 TI - Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease characterized by airway remodeling, inflammation, alveolar destruction, and fibrosis. We utilized single-cell RNA sequencing (scRNA-seq) to identify epithelial cell types and associated biological processes involved in the pathogenesis of IPF. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 (AT2) cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of IPF cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in IPF. Individual IPF cells frequently coexpressed alveolar type 1 (AT1), AT2, and conducting airway selective markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-beta, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of IPF. The present study provides a rich data source to further explore lung health and disease. PMID- 27942596 TI - Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis. AB - A barrier to drug development for nonalcoholic steatohepatitis (NASH) is the absence of translational preclinical human-relevant systems. An in vitro liver model was engineered to incorporate hepatic sinusoidal flow, transport, and lipotoxic stress risk factors (glucose, insulin, free fatty acids) with cocultured primary human hepatocytes, hepatic stellate cells (HSCs), and macrophages. Transcriptomic, lipidomic, and functional endpoints were evaluated and compared with clinical data from NASH patient biopsies. The lipotoxic milieu promoted hepatocyte lipid accumulation (4-fold increase, P < 0.01) and a lipidomics signature similar to NASH biopsies. Hepatocyte glucose output increased with decreased insulin sensitivity. These changes were accompanied by increased inflammatory analyte secretion (e.g., IL-6, IL-8, alanine aminotransferase). Fibrogenic activation markers increased with lipotoxic conditions, including secreted TGF-beta (>5-fold increase, P < 0.05), extracellular matrix gene expression, and HSC activation. Significant pathway correlation existed between this in vitro model and human biopsies. Consistent with clinical trial data, 0.5 MUM obeticholic acid in this model promoted a healthy lipidomic signature, reduced inflammatory and fibrotic secreted factors, but also increased ApoB secretion, suggesting a potential adverse effect on lipoprotein metabolism. Lipotoxic stress activates similar biological signatures observed in NASH patients in this system, which may be relevant for interrogating novel therapeutic approaches to treat NASH. PMID- 27942597 TI - How do You Select an Anesthesia Method Prior to Tympanostomy Tube Insertion for a Child? AB - The use of general (face-mask inhalation and intravenous) anesthesia has been the method of choice for tympanostomy tube insertion in children. However, there is no exact guideline for the choice of anesthesia method and there is no evidence to support the use of one anesthesia method over another. Clinically, the anesthesia method used to be decided by old customs and the surgeon's blind faith that children cannot bear tympanostomy tube insertion under local anesthesia. Clinicians should keep in mind that pediatric anesthesia has a potential risk. Despite infrequent serious complications, their seriousness necessitates that sedation or general anesthesia should be done by an anesthesiologist and thus children requiring tympanostomy tube insertion should be referred to secondary or tertiary hospitals, even if they have been followed by a primary care physician for a long time. Previous evidence showed that local anesthesia is appropriate for tympanostomy tube insertion in selected children, especially in children older than 5 years are older. Proper choice of anesthesia method is helpful for both patient and medical service provider. Local anesthesia can give psychological relief to children and their parent. It is easier for the medical service providers to schedule the operation and allocate the medical resources in their hospital. Local anesthesia can reduce individual, social, and national burdens for the health care services. PMID- 27942598 TI - MicroRNA-183 Family in Inner Ear: Hair Cell Development and Deafness. AB - miRNAs are essential factors of an extensively conserved post-transcriptional process controlling gene expression at mRNA level. Varoius biological processes such as growth and differentiation are regulated by miRNAs. Web of Science and PubMed databases were searched using the Endnote software for the publications about the role miRNA-183 family in inner ear: hair cell development and deafness published from 2000 to 2016. A triplet of these miRNAs particularly the miR-183 family is highly expressed in vertebrate hair cells, as with some of the peripheral neurosensory cells. Point mutations in one member of this family, miR 96, underlie DFNA50 autosomal deafness in humans and lead to abnormal hair cell development and survival in mice. In zebrafish, overexpression of the miR-183 family induces extra and ectopic hair cells, while knockdown decreases the number of hair cell. The miR-183 family (miR-183, miR-96 and miR-182) is expressed abundantly in some types of sensory cell in the eye, nose and inner ear. In the inner ear, mechanosensory hair cells have a robust expression level. Despite much similarity of these miRs sequences, small differences lead to distinct targeting of messenger RNAs targets. In the near future, miRNAs are likely to be explored as potential therapeutic agents to repair or regenerate hair cells, cell reprogramming and regenerative medicine applications in animal models because they can simultaneously down-regulate dozens or even hundreds of transcripts. PMID- 27942599 TI - Fibrinogen-Based Collagen Fleece Graft Myringoplasty for Traumatic Tympanic Membrane Perforation. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to investigate how fibrinogen-based collagen fleece (Tachocomb(r)) graft myringoplasty (FCGM), performed under microscopic guidance, improves both hearing and tympanic membrane tissue repair in patients with traumatic tympanic membrane perforation (TMP). SUBJECTS AND METHODS: Between August 2009 and March 2015, a total of 52 patients with traumatic TMP visited the department of otorhinolaryngology at a secondary medical center. Twenty-nine of these underwent FCGM under microscopic guidance in our outpatient clinic. For each patient, we recorded the location and size of the perforation, the time elapsed from the onset of TMP until the myringoplasty, and the hearing level both before and after myringoplasty. RESULTS: The TMP closed completely in all cases (29 of 29 patients). After myringoplasty, the postoperative air-bone gap (ABG) differed significantly from the preoperative ABG. Three of the 29 patients (10.3%) experienced complications. Specifically, 2 presented with otorrhea after FCGM, but conservative management led to improvement without recurrence of perforation. One patient showed delayed facial palsy 1 week after the procedure. The condition of this patient also improved and the palsy was not permanent. CONCLUSIONS: FCGM may be an effective treatment option in case of traumatic TMP. The procedure requires no hospitalization, and can be used to avoid traditional tympanoplasty. PMID- 27942600 TI - Characteristics of Patients with Hearing Aids according to the Degree and Pattern of Hearing Loss. AB - BACKGROUND AND OBJECTIVES: This study was designed to assess the characteristics of patients according to the degree and audiogram shape of hearing loss and the association of these characteristics with hearing aids (HA) choice, return rate, and cause of return. SUBJECTS AND METHODS: This study included 460 individuals who received HAs from 2011 to 2015. The relationships between type of HA and age, primary and accompanying symptoms, HA choice and return and cause of return were evaluated according to the degree and pattern of hearing loss. RESULTS: HA type did not differ significantly according to the degree and pattern of hearing loss. Intensity of hearing loss was greater in male than in female (p<0.05). Open and completely-in-canal types of HA decreased with age (p<0.05). As degree of hearing loss intensified, behind-the-ear and in-the-ear types increased and Open type decreased (p<0.05). The HA return rate was 9.7%, but was not associated with degree or pattern of hearing loss. The main causes of HA return were costs, psychological fears and adaptive failure. CONCLUSIONS: Choice of HA is affected by age, sex, and degree and pattern of hearing loss. HA for hearing rehabilitation in patients with hearing loss can be personalized according to each patient's characteristics and tendencies. PMID- 27942601 TI - High Frequency Tympanometry (1,000 Hz) for Neonates with Normal and Abnormal Transient Evoked Otoacoustic Emissions. AB - BACKGROUND AND OBJECTIVES: This paper aimed at evaluating the characteristics of high-frequency (1,000 Hz) acoustic admittance (ya) for the neonates with transient evoked otoacoustic emissions (TEOAE) as either pass or refer group. SUBJECTS AND METHODS: Using a 1,000 Hz probe tone, 297neonates (152 male, 145 female aged 0-104 days old) were evaluated. Tympanometric parameters admittance value at +200 dapa, middle ear admittance, and tympanometric peak pressure were calculated for each tympanogram. RESULTS: The mean of ya was 0.9678 mmho in the TEOAE for the pass group and 0.7229 mmho in the refer group. The mean of acoustic admittance at +200 (y200) was 2.0657 in the TEOAE for the pass group and 1.7191 for the refer group. The mean of Tpp was 23/8591 in the TEOAE for the pass group and 59/7619 for the refer group. CONCLUSIONS: There were significant differences in the distribution of different types of tympanograms, the mean of ya, tympanic peak pressure, and y200 between the TEOAEs for the pass and the refer groups. PMID- 27942602 TI - Audiological Profile of Adult Persons with Auditory Neuropathy Spectrum Disorders. AB - BACKGROUND AND OBJECTIVES: The auditory profile of a large number of persons with late onset auditory neuropathy spectrum disorder (ANSD) is recently described in the Indian context. The purpose of study was 1) to profile data on routine audiological parameters, cortical evoked potentials, and temporal processing, 2) to analyze the benefit from hearing aids for persons with ANSD, and 3) to understand the association between benefit from hearing aids and auditory profile. SUBJECTS AND METHODS: Thirty-eight adults with late onset ANSD and a matched group of 40 normally hearing adults participated in the study. Basic audiological tests, recording of cortical evoked potentials, and temporal processing tests were carried out on both groups of participant while only persons with ANSD were fitted with hearing aid. RESULTS: Subjects in the two groups were significantly different on all the audiological parameters. ANSD group seemed to benefit from hearing aids variably. The mean amplitude of N2 was significantly different between normally-hearing participants and patients with ANSD. CONCLUSIONS: Residual temporal processing, particularly amplitude modulation detection seems to be associated with benefit from hearing aids in patients with ANSD. PMID- 27942603 TI - Clinical Aspects and Surgical Outcomes of Congenital Cholesteatoma in 93 Children: Increasing Trends of Congenital Cholesteatoma from 1997 through 2012. AB - BACKGROUND AND OBJECTIVES: The recent increase in the reported incidence of congenital cholesteatoma (CC) may be secondary to the widespread use of otoendoscopy as well as an increased awareness of these lesions among primary care physicians. However, little research about CC has been conducted in a large group of patients. This study aimed to analyze the clinical characteristics of CC including the annual number of patients, symptoms, age at diagnosis, stage and type of disease, surgical techniques, recurrence, and postoperative complications. SUBJECTS AND METHODS: Retrospective chart review was performed for patients who met the inclusion criteria between January 1997 and June 2012. RESULTS: Ninety-three patients underwent surgery for CC. The age at operation ranged from 12 months to 17 years (mean age, 6.1 years). The number of patients was less than 4 per year until 2005, but increased to more than 10 per year since 2008. CC was most commonly reported as an incidental finding (58.1%). The operative procedures included the transcanal myringotomy approach (46.2%), canal wall up mastoidectomy (37.6%), tympanoplasty (8.6%), and canal wall down mastoidectomy (7.5%). The recurrence rate was 20.4% and the complication rate was 12.9%. No patients with stage I CC had complications. CONCLUSIONS: This study showed that the incidence of CC has recently increased notably. Most patients with stage I and II CC were completely cured by transtympanic surgery, and complication and recurrence rates increased according to the extent of disease. Early detection of CC is important to facilitate minimally invasive surgery and to reduce complication and recurrence rates. PMID- 27942604 TI - Clinical Analysis of Dizzy Patients with High Levels of Depression and Anxiety. AB - BACKGROUND AND OBJECTIVES: Some patients experiencing dizziness also report psychological distress. However, the association between vestibular deficits and psychological symptoms remains controversial. Thus, the aim of this paper is to report the proportion of patients who complained of dizziness who also had high depression and anxiety indices. Also we investigated the severity of their dizziness and the distribution of the diseases underlying this symptom. SUBJECTS AND METHODS: We assessed the dizziness and psychological distress of 544 patients experiencing dizziness using the Korean versions of the Dizziness Handicap Inventory (DHI), the Beck Depression Inventory (BDI), and the Spielberger State Trait Anxiety Inventory (STAI). We also reviewed the audio-vestibular symtoms of patients with high levels of depression and anxiety. RESULTS: The incidences of high depression and anxiety scores were 11% (60/544) and 18% (98/544), respectively. Patients with vestibular migraine were most likely to have high depression and anxiety indices. Patients in the high-BDI or high-STAI groups (117/544) obtained significantly higher DHI scores than those in neither the high BDI nor the high-STAI group (427/544). We noticed that about 20% of the patients experiencing dizziness had high levels of psychological distress in this study; this group also suffered from various vestibular diseases and more symptoms of dizziness. CONCLUSIONS: The results of the study suggest that psychological evaluation should be considered when assessing patients with vertigo. PMID- 27942605 TI - Neuroglial Choristoma of the Middle Ear with Massive Tympanosclerosis: A Case Report and Literature Review. AB - Neuroglialchoristoma is a rare cerebral heterotopia typically involving extracranial midline structures of the head and neck, including the nose, nasopharynx and oral cavity. It rarely involves non-midline structures, such as the middle ear, mastoid and orbit. We report the case of a 63-year-old woman with right-sided hearing loss and aural fullness who was diagnosed with neuroglialchoristoma of the middle ear and mastoid. To our knowledge, this is the first report on neuroglialchoristomawith massive tympanosclerosis. The presence of combination supported the inhalation theory of neuroglialchoristoma, given that tympanosclerosis is typically caused by Eustachian tube dysfunction. PMID- 27942606 TI - A Case of Squamous Cell Carcinoma in the External Auditory Canal Previously Treated for Verrucous Carcinoma. AB - Carcinoma in the external auditory canal (EAC) is a rare malignancy with an annual incidence of one per one million people, accounting for less than 0.2% of all head and neck cancers. The most common histopathological type of EAC cancer is squamous cell carcinoma. Verrucous carcinoma is a well-differentiated, low grade variant of squamous cell carcinoma. It is a locally destructive, invasive, and slow growing tumor that rarely metastasizes. Verrucous carcinoma occurs predominantly in the oral cavity and larynx, and its occurrence in the EAC is extremely rare. In this report, we present a histologically confirmed case of verrucous carcinoma in the EAC and temporal bone, which for several years had been classified as epithelial hyperplasia. Two-and-a-half years after diagnosis of verrucous carcinoma, a recurrent mass was found and the lesion was then confirmed to be squamous cell carcinoma. PMID- 27942607 TI - Should We Leave Patients with an Only Hearing Ear to Their Fate? PMID- 27942608 TI - Formulation development and optimization of Lamivudine 300 mg and Tenofovir Disoproxil Fumarate (TDF) 300 mg FDC tablets by D-optimal mixture design. AB - The usage of fixed dose combination (FDC) tablets of Lamivudine and Tenofovir Disoproxil Fumarate (TDF) is increasing due to increased incidences of HIV/Hepatitis B and HIV/TB co-infections. This is likely to increase the financial crisis due to limited resources for funding procurement of ready-made products from the pharmaceuticals manufacturing leading countries. Therefore, production of local oral tablets containing Lamivudine and TDF FDC is inevitable. Lamivudine 300 mg/TDF 300 mg tablets were developed and optimized by D-optimal mixture design and produced by direct compression technique. Twenty trial formulations with independent variables, including PVP-CL 1-12.00%, PVP-K30 1 10.00%, starch-1500 2.5-12.5% and Avicel-PH102 2-19.25% were prepared by direct compression technique. The formulations were assessed on assay, dissolution, friability, weight variation and disintegration time. It was found that assay ranged from 98.13-101.95% for Lamivudine, 98.25-102.84 for TDF, both were within the in-house assay specification of 95 to 105%. Dissolution at single point was above 80% for Lamivudine 93.96-100.55% and 95.85-103.15% for TDF, disintegration time was between 1.92-66.33 min and friability 0.06-12.56%. Out of twenty formulation trials, eight formulations had all parameters in proven acceptable range. On optimization, one formulation with independent variables, PVP-CL 5.67%, PVP-K30 1.00%, Starch-1500 5.76% was selected. The optimized formulation was comparable to the reference product on the market with similarity factor (f2) and difference factor (f1) within the acceptable range for both Lamivudine and TDF. PMID- 27942609 TI - Membranous nephropathy: Pilot study of a novel regimen combining cyclosporine and Rituximab. AB - INTRODUCTION: There is broad consensus that high grade basal proteinuria and failure to achieve remission of proteinuria are key determinants of adverse renal prognosis in patients with primary membranous nephropathy. Based on the fact that current regimens are not ideal due to short and long-term toxicity and propensity to relapse after treatment withdrawal, we developed a treatment protocol based on a novel combination of rituximab and cyclosporine which targets both the B and T cell limbs of the immune system. Herein, we report pilot study data on proteinuria, changes in autoantibody levels and renal function that offer a potentially effective new approach to treatment of severe membranous nephropathy. METHODS: Thirteen high-risk patients defined by sustained high-grade proteinuria (mean 10.8 g/d) received combination induction therapy with rituximab plus cyclosporine for 6 months, followed by a second cycle of rituximab and tapering of cyclosporine during an 18 month maintenance phase. RESULTS: Mean proteinuria decreased by 65% at 3 months and by 80% at 6 months. Combined complete or partial remission was achieved in 92% of patients by 9 months; 54% achieved complete remission at 12 months. Two patients relapsed during the trial. All patients with autoantibodies to PLA2R achieved antibody depletion. Renal function stabilized. The regimen was well tolerated. DISCUSSION: We report these encouraging preliminary results for their potential value to other investigators needing prospectively collected data to inform the design and power calculations of future randomized clinical trials. Such trials will be needed to formally compare this novel regimen to current therapies for membranous nephropathy. PMID- 27942610 TI - SIMULTANEOUS LIVER KIDNEY TRANSPLANTATION IN LIVER TRANSPLANT CANDIDATES WITH RENAL DYSFUNCTION: IMPORTANCE OF CREATININE LEVELS, DIALYSIS, AND ORGAN QUALITY IN SURVIVAL. AB - BACKGROUND: The survival benefit from simultaneous liver-kidney transplantation (SLK) over liver transplant alone (LTA) in recipients with moderate renal dysfunction is not well understood. Moreover, the impact of deceased donor organ quality in SLK transplant survival has not been well described in the literature. METHODS: The Scientific Registry of Transplant Recipients was studied for adult recipients receiving LTA (N=2,700) or SLK (N=1,361) transplantation with moderate renal insufficiency between 2003 and 2013. The study cohort was stratified into four groups based on serum creatinine (Scr< 2 mg/dL versus Scr>= 2 mg/dL) and dialysis status at listing and at transplant. The patients with end-stage renal disease and requiring acute dialysis more than three months before transplantation were excluded. A propensity score (PS)-matching was performed in each stratified groups to factor out imbalances between the SLK and LTA regarding covariates distribution and to reduce measured confounding. Donor quality was assessed with liver-donor risk index (L-DRI). The primary outcome of interest was post-transplant mortality. RESULTS: On multivariable PS-matched Cox proportional hazard models, SLK led to decrease in post-transplant mortality compared to LTA across all four groups, but only reached statistical significance (HR 0.77; 95% CI, 0.62-0.96) in the recipients not exposed to dialysis and Scr>= 2 mg/dL at transplant (mortality incidence rate per patient-year 5.7% in SLK vs. 7.6% in LTA, p=0.005). The decrease in mortality was observed among SLK recipients with better quality donors (L-DRI<1.5). CONCLUSIONS: Exposure to pre-transplantation dialysis and donor quality affected overall survival among SLK recipients. PMID- 27942611 TI - Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation. AB - Transplantation of allogeneic organs and tissues represents a lifesaving procedure for a variety of patients affected with end-stage diseases. Although current immunosuppressive therapy prevents early acute rejection, it is associated with nephrotoxicity and increased risks for infection and neoplasia. This stresses the need for selective immune-based therapies relying on manipulation of lymphocyte recognition of donor antigens. The passenger leukocyte theory states that allograft rejection is initiated by recipient T cells recognizing donor major histocompatibility complex (MHC) molecules displayed on graft leukocytes migrating to the host's lymphoid organs. We revisited this concept in mice transplanted with allogeneic skin, heart, or islet grafts using imaging flow cytometry. We observed no donor cells in the lymph nodes and spleen of skin-grafted mice, but we found high numbers of recipient cells displaying allogeneic MHC molecules (cross-dressed) acquired from donor microvesicles (exosomes). After heart or islet transplantation, we observed few donor leukocytes (100 per million) but large numbers of recipient cells cross-dressed with donor MHC (>90,000 per million). Last, we showed that purified allogeneic exosomes induced proinflammatory alloimmune responses by T cells in vitro and in vivo. Collectively, these results suggest that recipient antigen-presenting cells cross-dressed with donor MHC rather than passenger leukocytes trigger T cell responses after allotransplantation. PMID- 27942612 TI - Statistical Analysis of Discrete Dynamical System Models for Biological Networks. AB - Very few data-driven methods for dynamic biological networks reconstruction from gene expression data evaluate the statistical significance of a model. A hypothesis testing procedure examining the goodness of fit of trajectory-based modeling is designed, in contrast to transition-based model fitting. The former has substantially reduced the modeling error. Simulation studies on the residual between noisy observations and true system dynamics suggest the use of the statistical hypothesis testing, so that one can evaluate how significantly a model is supported by the observed data under certain noise distribution. This method can also evaluate the dynamic model for each individual gene. Through a biochemical reaction model in the yeast pheromone pathway the effectiveness of the proposed evaluation procedure is demonstrated. PMID- 27942613 TI - Characterization of mAb6-9-1 monoclonal antibody against hemagglutinin of avian influenza virus H5N1 and its engineered derivative, single-chain variable fragment antibody. AB - Hemagglutinin (HA), as a major surface antigen of influenza virus, is widely used as a target for production of neutralizing antibodies. Monoclonal antibody, mAb6 9-1, directed against HA of highly pathogenic avian influenza virus A/swan/Poland/305-135V08/2006(H5N1) was purified from mouse hybridoma cells culture and characterized. The antigenic specificity of mAb6-9-1 was verified by testing its cross-reactivity with several variants of HA. The mimotopes recognized by mAb6-9-1 were selected from two types of phage display peptide libraries. The comparative structural model of the HA variant used for antibody generation was developed to further facilitate epitope mapping. Based on the sequences of the affinity- selected polypeptides and the structural model of HA the epitope was located to the region near the receptor binding site (RBS). Such localization of the epitope recognized by mAb6-9-1 is in concordance with its moderate hemagglutination inhibiting activity and its antigenic specificity. Additionally, total RNA isolated from the hybridoma cell line secreting mAb6-9-1 was used for obtaining two variants of cDNA encoding recombinant single-chain variable fragment (scFv) antibody. To ensure high production level and solubility in bacterial expression system, the scFv fragments were produced as chimeric proteins in fusion with thioredoxin or displayed on a phage surface after cloning into the phagemid vector. Specificity and affinity of the recombinant soluble and phage-bound scFv were assayed by suitable variants of ELISA test. The observed differences in specificity were discussed. PMID- 27942614 TI - The mechanism and application of the protein-stabilized gold nanocluster sensing system. AB - Protein-stabilized gold nanoclusters (protein-Au NCs) have been an attractive frontier of nanoparticle research. Due to their unique fluorescence properties, high stability, environmentally friendly synthetic routes and nontoxicity, protein-Au NCs could find applications in highly sensitive and selective detection of metal ions, inorganic ions and biomolecules in food, soil, water and biological samples. The past few years have witnessed the development of many successful strategies for the preparation of numerous protein-Au NC-based sensing systems. In this review, we focus on a number of sensing systems based on protein Au NCs for the detection of various analytes of interest with a special emphasis on their corresponding sensing mechanisms. PMID- 27942615 TI - Purification technologies for colloidal nanocrystals. AB - Almost all applications of colloidal nanocrystals require some type of purification or surface modification process following nanocrystal growth. Nanocrystal purification - the separation of nanocrystals from undesired solution components - can perturb the surface chemistry and thereby the physical properties of colloidal nanocrystals due to changes in solvent, solute concentrations, and exposure of the nanocrystal surface to oxidation or hydrolysis. For example, nanocrystal quantum dots frequently exhibit decreased photoluminescence brightness after precipitation from the growth solvent and subsequent redissolution. Consequently, purification is an integral part of the synthetic chemistry of colloidal nanocrystals, and the effect of purification methods must be considered in order to accurately compare and predict the behavior of otherwise similar nanocrystal samples. In this Feature Article we examine established and emerging approaches to the purification of colloidal nanoparticles from a nanocrystal surface chemistry viewpoint. Purification is generally achieved by exploiting differences in properties between the impurities and the nanoparticles. Three distinct properties are typically manipulated: polarity (relative solubility), electrophoretic mobility, and size. We discuss precipitation, extraction, electrophoretic methods, and size-based methods including ultracentrifugation, ultrafiltration, diafiltration, and size-exclusion chromatography. The susceptibility of quantum dots to changes in surface chemistry, with changes in photoluminescence decay associated with surface chemical changes, extends even into the case of core/shell structures. Accordingly, the goal of a more complete description of quantum dot surface chemistry has been a driver of innovation in colloidal nanocrystal purification methods. We specifically examine the effect of purification on surface chemistry and photoluminescence in quantum dots as an example of the challenges associated with nanocrystal purification and how improved understanding can result from increasingly precise techniques, and associated surface-sensitive analytical methods. PMID- 27942616 TI - Metal oxide semiconductor SERS-active substrates by defect engineering. AB - A general route to transform metal oxide semiconductors from non-SERS active to SERS-active substrates based on defect engineering is reported. The SERS enhancement factor (EF) of metal oxide semiconductors like alpha-MoO3 and V2O5 can be greatly enhanced and the SERS performance can be optimized according to the detecting analyte and activating laser wavelength by introducing oxygen vacancy defects. The EF of R6G on alpha-MoO3-x nanobelts can be as high as 1.8 * 107 with a detection limit of 10-8 M, which is the best among metal oxide semiconductors and comparable to noble metals without a "hot spot". A model, named "effective electric current model", was proposed to describe the photo induced charge transfer process between the absorbed molecules and semiconductor substrates. The EF of 4-MBA, R6G and MB on alpha-MoO3-x nanobelts with different oxygen vacancy concentrations calculated based on the model matches very well with experimental results. As an extension, some potential metal oxide semiconductor SERS-active substrates were predicted based on the model. Our results clearly demonstrate that, through defect engineering, the metal oxide semiconductors can be made SERS-active substrates with high stability and high biocompatibility. PMID- 27942617 TI - Surface modification and endothelialization of polyurethane for vascular tissue engineering applications: a review. AB - Cardiovascular implants, especially vascular grafts made of synthetic polymers, find wide clinical applications in the treatment of cardiovascular diseases. However, cases of failure still exist, notably caused by restenosis and thrombus formation. Aiming to solve these problems, various approaches to surface modification of synthetic vascular grafts have been used to improve both the hemocompatibility and long-term patency of artificial vascular grafts. Surface modification using hydrophilic molecules can enhance hemocompatibility, but this may limit the initial vascular endothelial cell adhesion. Therefore, the improvement of endothelialization on these grafts with specific peptides and biomolecules is now an exciting field of research. In this review, several techniques to improve surface modification and endothelialization on vascular grafts, mainly polyurethane (PU) grafts, are summarized, together with the recent development and evolution of the different strategies: from the use of PEG, zwitterions, and polysaccharides to peptides and other biomolecules and genes; from in vitro endothelialization to in vivo endothelialization; and from bio inert and bio-active to bio-mimetic approaches. PMID- 27942618 TI - Intracellular GSH-activated galactoside photosensitizers for targeted photodynamic therapy and chemotherapy. AB - Ligand-targeted cancer therapeutics has been developed to minimize non-specific cytotoxicity via ligand-drug conjugates during the past few decades. We present here the design and synthesis of a GSH-activated amphiphilic photosensitizer conjugated with galactose (TPP-S-S-Gal) for targeted photodynamic therapy. Furthermore, the galactoside photosensitizer as supramolecular amphiphiles can self-assemble into micelles, which can be applied in integrative cancer treatment with chemotherapy drugs such as camptothecin (CPT) encapsulated in the hydrophobic core of micelles. Upon reaction with free thiol GSH that is relatively abundant in tumor cells, disulfide bond cleavage occurs as well as the active photosensitizer TPP and chemotherapy drug CPT release, which can cause cell apoptosis. The in vitro biological assessment of TPP-S-S-Gal micelles against the A549 cell line was evaluated by MTT assay, flow cytometry and confocal scanning laser microscopy, respectively. According to the MTT assay, TPP S-S-Gal micelles exhibited low dark toxicity and efficient integrative efficacy of PDT and chemotherapy towards A549 cells after light irradiation. PMID- 27942619 TI - Effect of Co co-doping on the optical properties of ZnTe:Mn nanocrystals. AB - We study the effect of Co co-doping on the optical properties of Mn-doped ZnTe nanocrystals (NCs) embedded in a glass matrix. Optical absorption (OA) and crystal field theory strongly indicated the substitutional incorporation of Co2+ ions into these semiconducting NCs as well as the characteristic transitions of these ions in the visible and near infrared spectral region. Transmission electron microscopy (TEM) images revealed an invariant NC lattice parameter with the incorporation of Mn2+ and Co2+ ions. The same was confirmed by X-ray diffraction (XRD). The photoluminescence (PL) spectra showed that the characteristic emission bands of Co2+ ions (E1Co2+ and E2Co2+) are intense and evident at low temperatures. Indeed, Raman spectra showed that the dependence of luminescence intensity on temperature is due to the electron-phonon interaction that arises from multiphonon relaxation processes. The redshifts in the PL spectra from green to orange with the incorporation of Mn2+ ions into ZnTe NCs, and in the near infrared with increasing Co-concentration, result from sp-d exchange interactions associated with the increase in Mn2+ and Co2+ ions in tetrahedral sites of ZnTe NCs, which may be very interesting for applications in luminescent devices. These observations provide strong evidence that higher Co concentrations inhibit the incorporation of Mn2+ into ZnTe NCs, suggesting that there may be competition between Co2+ and Mn2+ ions substituting Zn2+ ions and, furthermore, that these ions replace zinc vacancies (VZn) in these NCs. PMID- 27942620 TI - Correction: A binary catalyst system of a cationic Ru-CNC pincer complex with an alkali metal salt for selective hydroboration of carbon dioxide. AB - Correction for 'A binary catalyst system of a cationic Ru-CNC pincer complex with an alkali metal salt for selective hydroboration of carbon dioxide' by Chee Koon Ng et al., Chem. Commun., 2016, 52, 11842-11845. PMID- 27942621 TI - Unravelling the early photochemical behavior of (8-substituted-7 hydroxyquinolinyl)methyl acetates through electronic structure theory and ultrafast transient absorption spectroscopy. AB - The photophysical processes and photochemical reactions in the ultrafast time region of (8-bromo-7-hydroxyquinolin-2-yl)methyl acetate (BHQ-OAc) in acetonitrile and neutral aqueous solutions were investigated using quantum chemical calculations and femtosecond transient absorption spectroscopy. After initial excitation into the pi,pi* excited state, BHQ-OAc undergoes an ultrafast intersystem crossing (ISC) into a pi,pi* excited triplet state on a timescale of 16 ps. The n,pi* and pi,pi* excited singlet and triplet states involved in the photochemistry were identified by means of their characteristic excited state absorption (ESA) bands and from second order coupled-cluster (CC2) calculations. The high ISC rate of BHQ-OAc and related compounds is traced back to involvement of almost energetically degenerate n,pi* excited states that enable efficient ISC that obeys El-Sayed's rules. PMID- 27942622 TI - A self-assembled white-light-emitting system in aqueous medium based on a macrocyclic amphiphile. AB - A novel FRET platform was fabricated based on a macrocyclic amphiphile, reliant on the self-sorting complexation of a donor on the periphery of the assemblies and entrapment of an acceptor within the inner hydrophobic phase. By tuning subtly the donor/acceptor ratio, white light emission was successfully achieved with high quantum yield. PMID- 27942623 TI - Effects of nilotinib on leukaemia cells using vibrational microspectroscopy and cell cloning. AB - Over the last few years, both synchrotron-based FTIR (S-FTIR) and Raman microspectroscopies have helped to better understand the effects of drugs on cancer cells. However, cancer is a mixture of cells with different sensitivity/resistance to drugs. Furthermore, the effects of drugs on cells produce both chemical and morphological changes, the latter could affect the spectra of cells incubated with drugs. Here, we successfully cloned sensitive and resistant leukaemia cells to nilotinib, a drug used in the management of leukaemia. This allowed both the study of a more uniform population and the study of sensitive and resistant cells prior to the addition of the drug with both S FTIR and Raman microspectroscopies. The incubation with nilotinib produced changes in the S-FTIR and Raman spectra of both sensitive and resistant clones to nilotinib. Principal component analysis was able to distinguish between cells incubated in the absence or presence of the drug, even in the case of resistant clones. The latter would confirm that the spectral differences between the so called resistant clonal cells prior to and after adding a drug might reside on those more or less sensitive cells that have been able to remain alive when they were collected to be studied with S-FTIR or Raman microspectroscopies. The data presented here indicate that the methodology of cell cloning can be applied to different types of malignant cells. This should facilitate the identification of spectral biomarkers of sensitivity/resistance to drugs. The next step would be a better assessment of sensitivity/resistance of leukaemia cells from patients which could guide clinicians to better tailor treatments to each individual patient. PMID- 27942624 TI - Atomic models for anionic ligand passivation of cation-rich surfaces of IV-VI, II VI, and III-V colloidal quantum dots. AB - We formulated atomic models of cation-rich surfaces passivated with anionic ligands for IV-VI, II-VI, and III-V colloidal quantum dots, employing electron counting models and quantum mechanical calculations. We found that the fractional dangling bonds of cation-rich (100) and (111) surfaces could be greatly stabilized by dimerization-anion passivation and amine-anion co-passivation. PMID- 27942625 TI - Interfacial gas nanobubbles or oil nanodroplets? AB - The existence of nanobubbles at a solid-liquid interface with high stability has been confirmed by myriad experimental studies, and their gaseous nature has also been extensively verified. However, nanodroplets of polydimethylsiloxane (PDMS) recently observed in the atomic force microscopy (AFM) measurement of nanobubbles plague the nanobubble community. It may easily lead to wrong interpretations of the AFM results and thus hinders further application of the already widely used AFM in nanobubble studies. Therefore, finding a direct experimental solution to distinguish nanobubbles from nanodroplets in AFM measurements is a matter of great urgency. Herein, we first developed an effective and reproducible method to produce PDMS nanodroplets at the highly ordered pyrolytic graphite (HOPG)/water interface. From their size, contact angle, and stiffness, the formed PDMS nanodroplets are not distinguishable from nanobubbles. However, the force curves on these two objects are strikingly different from each other, i.e., a peculiar plateau in both the approach and retraction curves was found on nanobubbles whereas they changed linearly between the jump-in and jump-off point on PDMS nanodroplets. Thus, the present study not only provided a simple and effective procedure to generate PDMS nanodroplets but also paved a simple practical and in situ way to discriminate nanobubbles from the PDMS nanodroplets by direct AFM force measurements. PMID- 27942626 TI - Biological and related applications of pillar[n]arenes. AB - Pillar[n]arenes are a new class of synthetic supramolecular macrocycles streamlined by their particular pillar-shaped architecture which consists of an electron-rich cavity and two fine-tuneable rims. The ease and diversity of the functionalization of the two rims open possibilities for the design of new architectures, topological isomers, and scaffolds. Significantly, this emerging class of macrocyclic receptors offers a unique platform for biological purposes. This review article covers the most recent contributions from the pillar[n]arene field in terms of artificial membrane transport systems, controlled drug delivery systems, biomedical imaging, biosensors, cell adhesion, fluorescent sensing, and pesticide detection based on host-guest interactions. The review also uniquely describes the properties of sub-units that make pillar[n]arenes suitable for biological applications and it provides a detailed outline for the design of new innovative pillar-like structures with specific properties to open up a new avenue for pillar[n]arene chemistry. PMID- 27942627 TI - Rh(0)/Rh(iii) core-shell nanoparticles as heterogeneous catalysts for cyclic carbonate synthesis. AB - Rh(0)/Rh(iii) core-shell nanoparticles were prepared by surface oxidation of Rh nanoparticles with N-bromosuccinimide. They were employed as heterogeneous catalysts for cyclic carbonate synthesis from propylene oxide and CO2, and exhibited high activity and excellent recyclability due to Lewis acidic Rh(iii) species on the shells. PMID- 27942628 TI - Large-scale fabrication of a flexible, highly conductive composite paper based on molybdenum disulfide-Pt nanoparticle-single-walled carbon nanotubes for efficient hydrogen production. AB - Creating efficient hydrogen production properties from the macroscopic assembly of two-dimensional materials is still an unaccomplished goal. Here we report a facile route to fabricate a flexible MoS2/PtNPs/SWCNT paper with an ultralow onset potential of -35 mV, a Tafel slope of 39.6 mV per decade and over 60 h of electrochemical durability. PMID- 27942629 TI - Hydrogen divacancy diffusion: a new perspective on H migration in MgH2 materials for energy storage. AB - The formation and diffusion of pairs of hydrogen vacancies (divacancies) in magnesium hydride is modeled using density functional theory. Compared to the commonly studied case of single hydrogen vacancies, it is found that divacancies are energetically favored over two isolated vacancies. Also, as a function of the diffusion axis considered, the calculated diffusion barriers of divacancies are either smaller or of comparable magnitude with respect to the diffusion barriers of a single vacancy. These findings shed new light on hydrogen transport in MgH2, which is of crucial importance to understand the kinetics of hydrogen take-up and release in this storage material. PMID- 27942630 TI - Seeing the invisible plasma with transient phonons in cuprous oxide. AB - The emission of phonons from electron-hole plasma is the primary limit on the efficiency of photovoltaic devices operating above the bandgap. In cuprous oxide (Cu2O) there is no luminescence from electron-hole plasma. Therefore, we searched for optical phonons emitted by energetic charge carriers using phonon-to-exciton upconversion transitions. We found 14 meV phonons with a lifetime of 0.916 +/- 0.008 ps and 79 meV phonons that are longer lived and overrepresented. It is surprising that the higher energy phonon has a longer lifetime. PMID- 27942631 TI - Morphology, structure, and metal binding mechanisms of biogenic manganese oxides in a superfund site treatment system. AB - Manganese oxides, which may be biogenically produced in both pristine and contaminated environments, have a large affinity for many trace metals. In this study, water and Mn oxide-bearing biofilm samples were collected from the components of a pump and treat remediation system at a superfund site. To better understand the factors leading to their formation and their effects on potentially toxic metal fate, we conducted a chemical, microscopic, and spectroscopic characterization of these biofilm samples. Scanning electron microscopy revealed the presence of Mn oxides in close association with biological structures with morphologies consistent with fungi. X-ray absorption spectroscopy (XAS) and X-ray diffraction (XRD) revealed the oxides to be a mixture of layer and tunnel structure Mn(iv) oxides. In addition, XAS suggested that Ba, Co, and Zn all primarily bind to oxides in the biofilm in a manner that is analogous to synthetic or laboratory grown bacteriogenic Mn oxides. The results indicate that Mn oxides produced by organisms in the system may effectively scavenge metals, thus highlighting the potential utility of these organisms in designed remediation systems. PMID- 27942632 TI - Temperature- and vapor-induced reversible single-crystal-to-single-crystal transformations of three 2D/3D GdIII-organic frameworks exhibiting significant magnetocaloric effects. AB - By using Gd2O3, propanedioic acid (H2pda) and oxalic acid (H2ox), a new Gd-based metal-organic framework (MOF) [Gd(pda)(ox)0.5(H2O)2]n (1) has been successfully constructed and structurally characterized. Interestingly, temperature- and vapor induced reversible single-crystal-to-single-crystal transformations occurred and two new MOFs, namely [Gd(pda)(ox)0.5(H2O)]n (1a) and [Gd(pda)(ox)0.5]n (1b), have been obtained. Complex 1 displays a two-dimensional (2D) layer structure composed of zigzag [Gd(pda)]n chains and it could also be made up of numerous Gd6 macrocycles. Thermal dehydration leads to more complicated three-dimensional (3D) 'pillar-layer' structures (1a and 1b) with the same coordination mode of pda2- anions. Magnetic studies suggest the presence of ferromagnetic couplings between the intrachain or intralayer GdIII ions and large magnetocaloric effects (MCEs) with -DeltaS = 45.0 J kg-1 K-1 (1), 46.1 J kg-1 K-1 (1a) and 46.8 J kg-1 K-1 (1b) under a 7 T applied field. Therefore, the interest of 'robust magnetocaloric MOFs' is now extended to compounds showing weak ferromagnetic couplings and hence having better magnetocaloric performances for small field changes. PMID- 27942633 TI - Synthesis, crystal structure and phase transition of a Xe-N2 compound at high pressure: experimental indication of orbital interaction between xenon and nitrogen. AB - The van der Waals compound Xe(N2)2 with a C15 Laves structure was successfully synthesised at pressures greater than 4.4 GPa. We found that, at 10 GPa, the structure reversibly transforms from a cubic to a tetragonal phase. Further compression results in changes of Xe-N compound, which could result in the enhancement of orbital interactions between the xenon and nitrogen atoms. PMID- 27942634 TI - The effect of gme topology on multicomponent adsorption in zeolitic imidazolate frameworks. AB - We employ a simulation approach to study the adsorption of single, binary and ternary mixtures on eight gme Zeolitic Imidazolate Frameworks (ZIFs) at 298 K. Four adsorbate fluids were considered; carbon dioxide, methane, nitrogen and water. We compute the high pressure adsorption density profiles inside the micropore channels of each crystal. The profiles are compared directly for the different structures and adsorbate components and used to highlight the influence of the imidazolate ligands on pure and competitive adsorption. ZIFs with long ligands reveal an additional, accessible to the fluid space detected for the first time. This is a wedged volume on one direction of the pore walls, shaped thus because the long ligands tilt in order to be connected. We estimate the pressure required for water to become the dominating competing adsorbate within different crystal cavities. The simulated data for CO2 adsorption in ZIF69 strongly correlate with a set of Raman spectroscopy intensity values that correspond to the same adsorbate-adsorbent system. PMID- 27942635 TI - Theranostic TEMPO-functionalized Ru(ii) complexes as photosensitizers and oxidative stress indicators. AB - New TEMPO-functionalized Ru(ii) polypyridyl complexes were synthesized as efficient theranostic photosensitizers for cancer treatment. Interestingly, due to the presence of a redox sensitive TEMPO moiety, an enhancement in the intracellular fluorescence of TEMPO-functionalized Ru(ii) complexes was observed during photodynamic treatment in both confocal microscopy and flow cytometry. This can be explained by the conversion of the TEMPO radical moiety to diamagnetic non-radical species in cells upon PDT-induced oxidative stress. To the best of our knowledge this is the first ruthenium complex capable of simultaneously inducing and monitoring the oxidative stress. The tethered TEMPO moiety decreased the inherent dark-cytotoxicity and increased the photo-toxicity simultaneously, both of which contributed to the greatly improved photodynamic therapy (PDT) efficacy, ultimately resulting in cancer cell apoptosis. The phototoxicity index value for TEMPO-functionalized Ru(ii) complexes was selective towards cancer cell lines (280.5 for HeLa cells vs. 30.2 for LO2 cells) and ca. 40-fold higher than that for TEMPO-free Ru(ii) analogues (6.7 for HeLa cells). The main contributor for such a greatly enhanced PDT efficacy was the effect of the TEMPO moiety on the cellular uptake and intracellular ROS levels. We therefore demonstrate that the combination of TEMPO with the photosensitizers may be an emerging strategy to develop novel photosensitizer-based theranostic platforms, which can induce and monitor the PDT response simultaneously. PMID- 27942636 TI - Integrating recognition elements with nanomaterials for bacteria sensing. AB - Pathogenic bacterial contamination is a major threat to human health and safety. In this review, we summarize recent strategies for the integration of recognition elements with nanomaterials for the detection and sensing of pathogenic bacteria. Nanoprobes can provide sensitive and specific detection of bacterial cells, which can be applied across multiple applications and industries. PMID- 27942637 TI - Synthesis of vanadium-alkylidene complexes and their use as catalysts for ring opening metathesis polymerization. AB - Reported examples for synthesis of vanadium-alkylidene complexes and some selected reactions have been summarized. (Imido)vanadium(v)-alkylidene complexes exhibit catalytic activities for ring-opening metathesis polymerization (ROMP) of cyclic olefins; V(CHSiMe3)(N-2,6-Cl2C6H3)(OC6F5)(PMe3)2 exhibited remarkable catalytic activities for ROMPs of norbornene derivatives, polymerized cyclopentene and cis-cyclooctene. Highly cis-specific (living) ROMPs of norbornene have been achieved by V(CHSiMe3)(N-2,6-X2C6H3)[OC(CF3)3](PMe3)2 (X = H, Cl), and the activity increased at high temperature (50 and 80 degrees C) without a decrease in cis specificity (98%) in the presence of PMe3. PMID- 27942638 TI - Diamond nanostructures for drug delivery, bioimaging, and biosensing. AB - Diamond features an attractive combination of outstanding mechanical, optical, thermal and electrical properties; tunable surface characteristics; and unprecedented biocompatibility. Additionally, diamond can possess unique nitrogen vacancy emission centers that are highly photostable and extremely sensitive to magnetic fields, temperatures, ion concentrations, and spin densities. With these inherent merits, diamond in various nanoscale configurations has demonstrated a variety of distinctive applications in a broad range of fields. In particular, research on diamond nanoparticles (0-dimensional structures) and arrays of diamond nanoneedles/nanowires (1-dimensional structures) has witnessed important and exciting progress in recent years. Here, we systematically review the superior properties of diamond nanomaterials and the nitrogen-vacancy centers they contain as well as their uses in biomedical applications, including biosensing, bioimaging and drug delivery. Moreover, systematic studies of the biocompatibility and toxicity of diamond nanostructures, which constitute an important issue for the biomedical applications of diamond that has not yet been thoroughly addressed in previous reviews, are also discussed. Finally, we present our insights into the key issues concerning these diamond nanomaterials and their future development for applications. PMID- 27942639 TI - Unravelling the dissociation pathways of acetic acid upon electron transfer in potassium collisions: experimental and theoretical studies. AB - Electron transfer in alkali-molecule collisions with gas phase acetic acid and its deuterated analogues resulting in OH- formation requires considerable internal rearrangement in the temporary negative ion. At a collision energy well above the threshold of negative ion formation, electron transfer from potassium to CH3COOH/CH3COOD and CD3COOH results not only in H transfer from CH3 to COOH/COOD, but also in H release from COOH and subsequent rearrangement to eliminate OH-. These processes are also investigated by theoretical post-Hartree Fock and DFT calculations. The combination of both studies reveals that the most favourable intermediate mechanism occurs via diol formation. Such intramolecular H transfer is reported here for the first time in the context of electron transfer induced dissociation experiments in alkali-molecule collisions. A comprehensive fragmentation study is presented and dissociation mechanisms are suggested. PMID- 27942640 TI - Basis set convergence of the binding energies of strongly hydrogen-bonded atmospheric clusters. AB - We investigate the basis set convergence of second order Moller Plesset perturbation theory for the binding energies of 11 strongly hydrogen-bonded clusters relevant to the atmosphere. The binding energies are calculated both as the uncorrected (UC) value, as well as by employing the counterpoise (CP) and the Same Number Of Optimized Parameters (SNOOP) correction schemes, with and without explicit correlation (F12). We find that the use of the F12 corrections is of utter importance for obtaining converged binding energies. Without F12 corrections at least a quadruple-zeta basis set is generally required to yield errors below 1 kcal mol-1 compared to the complete basis set (CBS) limit. Using coupled cluster methods we obtain a best estimate of the CCSD(T) CBS limit of the binding energies of the considered clusters and compare it with approximate DLPNO CCSD(T) and DFT methods. We identify a pragmatic approach, relying solely on a series of double-zeta basis set calculations, for obtaining results in remarkably good agreement with our CBS estimate. PMID- 27942641 TI - Electrochemical polypyrrole formation from pyrrole 'adlayer'. AB - In this research study, we investigated the morphology of polypyrrole nanostructures, which were formed during the electrochemical deposition of conducting polymer. An electrochemical quartz crystal microbalance (EQCM) cell equipped with a flow-through system was employed to exchange solutions of different compositions within the EQCM cell. When bare PBS buffer in the EQCM cell was exchanged with PBS buffer with pyrrole we observed a distinct increase in the resonance frequency Deltaf. This change in the resonance frequency and electrical capacitance, which was calculated from electrochemical impedance spectroscopy (EIS) data, illustrate that pyrrole on the surface of the gold electrode formed an adsorbed layer (adlayer). The formation of a pyrrole adlayer before the potential pulse that induced polymerization was investigated by QCM based measurements. The electrochemical polymerization of this adlayer was induced by a single potential pulse and a nanostructured layer, which consisted of adsorbed polypyrrole (Ppy) nanoparticles with a diameter of 50 nm, was formed. QCM and EIS data revealed that by the next cycle of the electrochemical formation of Ppy, which was investigated after flow-through-based exchange of solutions, the initially formed Ppy surface was covered by the adlayer of pyrrole. This adlayer was desorbed when pyrrole was removed from the solution. When electrochemical polymerization was performed using 50 potential pulses, a Ppy layer, which had more complex morphology, was formed on the EQCM crystal. Scanning electron microscopy showed that the conductivity of this layer was unequally distributed. We observed that the polypyrrole layer formed by electrochemical deposition, which was performed using potential pulses, was formed out of aggregated spherical Ppy particles with a diameter of 50 nm. PMID- 27942642 TI - Polar solvent fluctuations drive proton transfer in hydrogen bonded complexes of carboxylic acid with pyridines: NMR, IR and ab initio MD study. AB - We study a series of intermolecular hydrogen-bonded 1 : 1 complexes formed by chloroacetic acid with 19 substituted pyridines and one aliphatic amine dissolved in CD2Cl2 at low temperature by 1H and 13C NMR and FTIR spectroscopy. The hydrogen bond geometries in these complexes vary from molecular (O-HN) to zwitterionic (O-H-N+) ones, while NMR spectra show the formation of short strong hydrogen bonds in intermediate cases. Analysis of C[double bond, length as m dash]O stretching and asymmetric CO2- stretching bands in FTIR spectra reveal the presence of proton tautomerism. On the basis of these data, we construct the overall proton transfer pathway. In addition to that, we also study by use of ab initio molecular dynamics the complex formed by chloroacetic acid with 2 methylpyridine, surrounded by 71 CD2Cl2 molecules, revealing a dual-maximum distribution of hydrogen bond geometries in solution. The analysis of the calculated trajectory shows that the proton jumps between molecular and zwitterionic forms are indeed driven by dipole-dipole solvent-solute interactions, but the primary cause of the jumps is the formation/breaking of weak CHO bonds from solvent molecules to oxygen atoms of the carboxylate group. PMID- 27942643 TI - "Energy Relay Center" for doped mechanoluminescence materials: a case study on Cu doped and Mn-doped CaZnOS. AB - We unraveled the mechanisms of transition metal-doped mechanoluminescent materials through a case study of CaZnOS. We found that the native point defect levels in Cu or Mn-doped CaZnOS system acted as energy relay centers for luminescence energy transfer. In combination with native point defect levels, discussed in a previous study [Phys. Chem. Chem. Phys., 2016, 18, 25946], we found that phosphor luminescence belongs to two different mechanisms. For Cu doping, it occurs by the path via the conduction band minimum to the Cu-t2g level of the 3d orbital localized in the band gap. The hole-drifting effect was found to support the reported red-shifting of the emission. Both reversible and irreversible mechanical quenching were attributed to the spatially separated electrons recombining with the hole localized on the Cu-t2g level within the gap at levels below or above respectively. For Mn-doping, this occurs by a collaborative luminescence assisted by native point defects, and the excited states of Mn2+ overlap with the conduction band edge. The coexistence of MnZn and MnCa was confirmed, but was relatively low in MnCa. The concentration quenching effect, as well as the red-shift of absorption, shows a strong correlation with native point defect levels and the relative position of the 4T1(4G) state for both MnZn and MnCa. Further simplified approximations were used for modeling such concentration quenching effects. PMID- 27942644 TI - Chiral organocatalysts based on lipopeptide micelles for aldol reactions in water. AB - A comprehensive study of the self-assembly in water of a lipopeptide consisting of a sequence of l-proline, l-arginine and l-tryptophan with a hydrocarbon chain has been performed. Fluorescence assays were used to determine the critical aggregation concentration. In situ small-angle X-ray scattering (SAXS) and molecular dynamics simulations showed the presence of spherical micelles with diameters around 6 nm. In agreement with these results, cryo-TEM images showed globular aggregates with diameters ranging from ~4 nm up to ~9 nm. Furthermore, the lipopeptide catalytic activity has been tested for the direct aldol reaction between cyclohexanone and p-nitrobenzaldehyde, and we have observed that the self association of the organocatalyst played a critical role in the enhanced activity. Water affects the selectivity, and poor results are obtained under neat reaction conditions. The location of the catalytic groups at the lipopetide/water solvent interface also endowed unusual selectivity in the catalyzed aldol reactions. Under optimized reaction conditions, high yields (up to >99%), good enantioselectivity (ee up to 85%) and high diastereoselectivity (ds up to 92 : 8) were obtained. PMID- 27942645 TI - An absorption mechanism and polarity-induced viscosity model for CO2 capture using hydroxypyridine-based ionic liquids. AB - A series of new hydroxypyridine-based ionic liquids (ILs) are synthesized and applied in CO2 capture through chemical absorption, in which one IL, i.e., tetrabutylphosphonium 2-hydroxypyridine ([P4444][2-Op]), shows a viscosity as low as 193 cP with an absorption capacity as high as 1.20 mol CO2 per mol IL. Because the traditional anion-CO2 absorption mechanism cannot provide an explanation for the influences of cations and temperature on CO2 absorption capacity, herein, a novel cation-participating absorption mechanism based on the proton transfer is proposed to explain the high absorption capacity and the existence of a turning point of absorption capacity with the increase of temperature for the capture of CO2 using [P4444][n-Op] (n = 2, 3, 4) ILs. Also, the relationship between the viscosity of ILs and the linear interaction energy is proposed for the first time, which can guide how to design and synthesize ILs with low viscosity. Quantum chemistry calculations, which are based on the comprehensive analysis of dipole moment, cation-anion interaction energy and surface electrostatic potential, indicate that the different viscosities of hydroxypyridine-based ILs and the changes after CO2 absorption mainly resulted from the different distribution of negative charges in the anion. PMID- 27942646 TI - Adsorption and dehydrogenation of ethane, propane and butane on Rh13 clusters supported on unzipped graphene oxide and TiO2(110) - a DFT study. AB - The catalytic activity for the adsorption and dehydrogenation of alkanes (CnH2n+2, n = 2, 3, 4) on a low-symmetry Rh13 cluster (Rh13-Ls) is compared with a system consisting of the same cluster (Rh13-Ls) supported on either an unzipped graphene-oxide (UGO) sheet (Rh13-Ls/UGO) or a TiO2(110) surface (Rh13-Ls/TiO2). The adsorption energies of these alkanes, calculated using density-functional theory, follow the order Rh13-Ls/TiO2 ~ Rh13-Ls/UGO > Rh13-Ls. Our proposed reaction path for the dehydrogenation of ethane, propane and butane on Rh13 Ls/UGO has first barrier heights of 0.21, 0.22 and 0.16 eV for the dissociation of a terminal C-H bond to form -C2H5, -C3H7 and -C4H9, respectively. Compared with the barriers on Rh13-Ls and Rh13-Ls/TiO2, the barrier on Rh13-Ls/UGO is the lowest for all alkanes. The calculated data, including the electronic distribution and the density of states of alkanes adsorbed on Rh13-Ls/UGO, Rh13 Ls and Rh13-Ls/TiO2, to support our results are presented. PMID- 27942647 TI - Probing helical transitions in a DNA duplex. AB - The complex conformational change from B-DNA to Z-DNA requires inversion of helix handedness. Multiple degrees of freedom are intricately coupled during this transition, and formulating an appropriate reaction coordinate that captures the underlying complexity would be problematic. In this contribution, we adopt an alternative approach, based on the potential energy landscape perspective, to construct a kinetic transition network. Microscopic insight into the B -> Z transition is provided in terms of geometrically defined discrete paths consisting of local minima and the transition states that connect them. We find that the inversion of handedness can occur via two competing mechanisms, either involving stretched intermediates, or a B-Z junction, in agreement with previous predictions. The organisation of the free energy landscape further suggests that this process is likely to be slow under physiological conditions. Our results represent a key step towards decoding the more intriguing features of the B -> Z transition, such as the role of ionic strength and negative supercoiling in reshaping the landscape. PMID- 27942648 TI - Effect of doping and chemical ordering on the optoelectronic properties of complex oxides: Fe2O3-V2O3 solid solutions and hetero-structures. AB - The electronic and optical properties of alpha-(Fe1-xVx)2O3 at low (x = 0.04) and high (x = 0.5) doping levels are investigated using a combination of periodic and embedded cluster approaches, and time-dependent density functional theory. At low V concentrations the onset of the optical absorption is ~0.5 eV (i.e., nearly 1.6 eV lower than that in pure alpha-Fe2O3) and corresponds to the electron transitions from V 3d to Fe 3d* orbitals. At high V concentrations, optical absorption energies and intensities are sensitive to specific arrangements of Fe and V atoms and their spin configuration that determine Fe-V hybridization. The onset of the lowest inter-vanadium absorption band in the case of Fe2O3/V2O3 hetero-structures is as low as ~0.3 eV and the corresponding peak is at ~0.7 eV. In contrast, in the case of solid solutions this peak has lower intensity and is shifted to higher energy (~1.2 eV). Analysis of the orbital character of electronic excitation suggests that Fe2O3/V2O3 hetero-structures absorb light much more effectively than random alloys, thus promoting efficient photo-induced carrier generation. These predictions can be tested in alpha-(Fe1-xVx)2O3 thin films synthesized with well-controlled spatial distribution of Fe and V species. PMID- 27942649 TI - Influence of chemical speciation and biofilm composition on mercury accumulation by freshwater biofilms. AB - Mercury (Hg) is a pollutant of high concern for aquatic systems due to the biomagnification of its methylated form along the food chain. However, in contrast to other metals, gaining knowledge of its bioavailable forms for aquatic microorganisms remains challenging, making Hg risk assessment difficult. Ubiquitous and sessile freshwater biofilms are well known to accumulate and to transform Hg present in their ambient environment. The present study thus aims to evaluate whether non-extractable (proxy of intracellular) Hg accumulated by biofilms could be a good indicator of Hg bioavailability for microorganisms in freshwater. To that end, the link between Hg concentration and speciation, as well as biofilm composition (percentage of abiotic, biotic, chlorophyll and phycocyanin-fractions and abundance of dsrA, gcs, merA and hgcA bacterial genes) and biofilm Hg accumulation was examined. The studied biofilms were grown on artificial substrata in four reservoirs along the Olt River (Romania), which was contaminated by Hg coming from chlor-alkali plant effluents. The 0.45 MUm filterable Hg concentrations in ambient waters were measured and inorganic IHg speciation was modelled. Biofilms were analyzed for their non-extractable IHg and methylmercury (MeHg) contents as well as for their composition. The non extractable IHg content was related, but not significantly, to the concentration of total IHg (r2 = 0.88, p = 0.061) whereas a significant correlation was found with the predicted IHg concentration that is not bound to dissolved organic matter (r2 = 0.95, p = 0.027), despite its extremely low concentrations (10-25 M), showing a limitation of the thermodynamic Hg modelling to predict Hg bioavailability. The studied biofilms were different in biomass and composition and a principal component analysis showed that the non-extractable IHg content correlated with the abundance of the merA and hgcA genes, while MeHg accumulation was only linked with the abundance of the rRNA 16S gene. The present study suggests that non-extractable IHg concentrations in biofilms are a useful proxy of IHg bioavailable forms in waters whereas the hgcA and merA genes are good biomarkers of both biofilm IHg exposure and bioavailability. PMID- 27942650 TI - QSARs for phenols and phenolates: oxidation potential as a predictor of reaction rate constants with photochemically produced oxidants. AB - Quantitative structure-activity relationships (QSARs) for prediction of the reaction rate constants of phenols and phenolates with three photochemically produced oxidants, singlet oxygen, carbonate radical, and triplet excited state sensitizers/organic matter, are developed. The predictive variable is the one electron oxidation potential (E1), which is calculated for each species using density functional theory. The reaction rate constants are obtained from the literature, and for singlet oxygen, are augmented with new experimental data. Calculated E1 values have a mean unsigned error compared to literature values of 0.04-0.06 V. For singlet oxygen, a single linear QSAR that includes both phenols and phenolates is developed that predicts experimental rate constants, on average, to within a factor of three. Predictions for only 6 out of 87 compounds are off by more than a factor of 10. A more limited data set for carbonate radical reactions with phenols and phenolates also gives a single linear QSAR with prediction of rate constant being accurate to within a factor of three. The data for the reactions of phenols with triplet state sensitizers demonstrate that two sensitizers, 2-acetonaphthone and methylene blue, most closely predict the reactivity trend of triplet excited state organic matter with phenols. Using sensitizers with stronger reduction potentials could lead to overestimation of rate constants and thus underestimation of phenolic pollutant persistence. PMID- 27942651 TI - Ternary solvent for CH3NH3PbI3 perovskite films with uniform domain size. AB - A ternary solvent system consisting of dimethyl sulfoxide (DMSO), gamma butyrolactone (GBL) and N-methyl-2-pyrrolidone (NMP) has been developed to improve the uniformity of CH3NH3PbI3 (MAPbI3) perovskite domains. Compared to MAPbI3 perovskite films prepared using a binary solvent consisting of DMSO and GBL, the surface roughness and uniformity of MAPbI3 films fabricated by using the ternary solvent system are greatly improved. The thermogravimetric analysis reveals that a NMP-PbI2-MAI intermediate, a DMSO-PbI2-MAI intermediate and MAPbI3 crystals co-existed in the as-cast MAPbI3 films. Furthermore, it is found that the thermal stability of intermediate phases and the solvent evaporation rate are critical for the nucleation of the perovskite crystals during the thermal annealing treatment. The thermally stable intermediates prepared with the ternary solvent are converted to MAPbI3 films with a highly uniform and smooth surface. The film forms an intimate contact with the charge transporting layer when the layer is applied as a photoactive layer in the solar cell. As a result, the power conversion efficiency of ternary solvent processed solar cells is enhanced by 38.2% compared to that of the binary solvent processed one. Furthermore, the stability of the ternary processed perovskite solar cells is greatly improved, as well. This investigation provides a better understanding about the role of different processing solvents or additives in effecting the perovskite film quality. PMID- 27942652 TI - Ferrate(vi) initiated oxidative degradation mechanisms clarified by DFT calculations: a case for sulfamethoxazole. AB - Ferrate(vi) is an efficient and environmentally friendly oxidant for the degradation of organic micropollutants. However, the related mechanism for the degradation is ambiguous and can hardly be elucidated empirically due to the rapid oxidation process and unstable intermediates for experimental trapping. Herein we performed density function theory (DFT) calculations to unveil the mechanism of ferrate(vi)-mediated degradation, taking sulfamethoxazole as a model compound. The results show that nucleophilic attack (rather than electrophilic attack) of HFeO4- on the isoxazole moiety of sulfamethoxazole initiates the subsequent degradations, and ferrate(vi) rather than the water molecule provides O atoms for the oxidation of the nitroso group and isoxazole moiety. Electron delocalization from the Fe atom to the isoxazole moiety is crucial for the ring opening of isoxazole, and organometallic intermediates suggested previously are not the necessary ones in the oxidation of sulfamethoxazole by HFeO4-. Thus, this study has theoretically clarified the ferrate(vi) oxidation mechanisms for a representative sulfonamide, which were also partially corroborated by the intermediates and products observed in the previous experimental studies for phosphite and tryptophan. This study provides an exemplification on the application of quantum chemical calculations to clarify the degradation pathways of organic micropollutants, which is important for the prediction of degradation products needed in their engineering design. PMID- 27942653 TI - Aggregation induced enhanced and exclusively highly Stokes shifted emission from an excited state intramolecular proton transfer exhibiting molecule. AB - The inner filter effect due to self-quenching dominates the normal emission of dyes at higher concentrations, which would limit their applications. Since normal emission was also observed with aggregation induced emission enhancement (AIEE) active excited state intramolecular proton transfer (ESIPT) exhibiting molecules, two new molecules are synthesized and studied to obtain normal emission free AIEE. The molecules are 4-(3-(benzo[d]thiazol-2-yl)-5-tert-butyl-4-hydroxybenzyl) 2-(benzo[d]thiazol-2-yl)-6-tert-butyl phenol (bis-HPBT) and its oxazole analogue (bis-HPBO). Of these molecules, bis-HPBT, which is weakly fluorescent in tetrahydrofuran solution, shows a sudden high enhancement in fluorescence upon addition of 70% water due to the formation of aggregates. Though the normal emission is also observed in tetrahydrofuran, it is completely eliminated in the aggregates, and the aggregates display exclusive tautomer emission. However, bis HPBO does not emit such an exclusive tautomer emission in the water/tetrahydrofuran mixture. The enhancement in the fluorescence quantum yield of bis-HPBT in 70% water is ~300 times higher than that in tetrahydrofuran. The modulated molecular structure of bis-HPBT is the cause of this outstanding AIEE. The observation of almost exclusive tautomer emission is a new additional advantage of AIEE from bis-HPBT over other ESIPT molecules. Since the tautomer emission is highly Stokes shifted, no overlap with the absorption spectrum occurs and therefore, the inner filter effect is averted. The aggregated structure acts as a good fluorescence chemosensor for metal ions as well as anions. The aggregated structure is cell permeable and can be used for cell imaging. PMID- 27942654 TI - Fundamentals: general discussion. PMID- 27942655 TI - Steering air bubbles with an add-on vacuum layer for biopolymer membrane biofabrication in PDMS microfluidics. AB - Membrane functionality is crucial in microfluidics for realizing operations such as filtration, separation, concentration, signaling among cells and gradient generation. Currently, common methods often sandwich commercially available membranes in multi-layer devices, or use photopolymerization or temperature induced gelation to fabricate membrane structures in one-layer devices. Biofabrication offers an alternative to forming membrane structures with biomimetic materials and mechanisms in mild conditions. We have recently developed a biofabrication strategy to form parallel biopolymer membranes in gas permeable polydimethylsiloxane (PDMS) microfluidic devices, which used positive pressure to dissipate air bubbles through PDMS to initiate membrane formation but required careful pressure balancing between two flows. Here, we report a technical innovation by simply placing as needed an add-on PDMS vacuum layer on PDMS microfluidic devices to dissipate air bubbles and guide the biofabrication of biopolymer membranes. Vacuuming through PDMS was simply achieved by either withdrawing a syringe or releasing a squeezed nasal aspirator. Upon vacuuming, air bubbles dissipated within minutes, membranes were effortlessly formed, and the add-on vacuum layer can be removed. Subsequent membrane growth could be robustly controlled with the flows and pH of solutions. This new process is user friendly and has achieved a 100% success rate in more than 200 trials in membrane biofabrication. PMID- 27942656 TI - Highly thermal-stable paramagnetism by rolling up MoS2 nanosheets. AB - Controlling phase transitions through local strain engineering is an exciting avenue for tailoring the electronic and magnetic properties of materials at the nanoscale. Herein, we demonstrate a tunable semiconducting to metallic phase transition of two-dimensional transition metal dichalcogenides using strain engineering through rolled up MoS2 sheets (named as MoS2 scrolls). A phase incorporated structure for MoS2 nanoscrolls containing the maximum concentration of 1T phase (~58%) with high thermal stability up to 473 K can be produced by a gliding-rolling process for the S plane. These phase transitions are irreversible by virtue of the van der Waals interaction between the layers of the nanoscrolls, which is relatively stronger than the bending strain. A high concentration of the 1T phase can tune the bandgap through temperature, and also the magnetic property from nonmagnetic to paramagnetic MoS2. This study, which is able to control phase transitions by strain engineering in the field of 2D materials, proves an exciting avenue for tailoring the novel functional properties of low-dimensional materials. PMID- 27942657 TI - beta-Amyrin synthase from Euphorbia tirucalli L. functional analyses of the highly conserved aromatic residues Phe413, Tyr259 and Trp257 disclose the importance of the appropriate steric bulk, and cation-pi and CH-pi interactions for the efficient catalytic action of the polyolefin cyclization cascade. AB - Many of the functions of the active site residues in beta-amyrin synthase and its catalytic mechanism remain unclear. Herein, we examined the functions of the highly conserved Phe413, Tyr259, and Trp257 residues in the beta-amyrin synthase of Euphorbia tirucalli. The site-specific mutants F416V and F416M showed nearly the same enzymatic activities as the wild type, indicating that pi-electrons are not needed for the catalytic reaction. However, the F416A mutant yielded a large amount of the tetracyclic dammarane skeleton, with decreased production of beta amyrin. This indicates that the Phe416 residue is located near the D-ring formation site and works to position the oxidosqualene substrate correctly within the reaction cavity. On the other hand, the major catalysis-related function of the Tyr259 and Trp257 residues is to yield their pi-electrons to the cationic intermediates. The Y259F variant showed nearly equivalent activity to that of the wild type, but aliphatic mutants such as the Ala, Val, and Leu variants showed significantly decreased the activity and yielded the tetracyclic dammarane scaffold, strongly demonstrating that the Tyr259 residue stabilizes the baccharenyl secondary cation via cation-pi interaction. The aliphatic variants of Trp257 exhibited remarkably decreased enzymatic activity, and lupeol was produced in a high production ratio, indicating that Trp257 stabilizes the oleanyl cation via cation-pi interaction. The aromatic Phe and Tyr mutants exhibited high activities owing to their more increased pi-electron density relative to that of the aliphatic mutants, but lupeol was produced in a significantly high yield besides beta-amyrin. The Trp residue is likely to be responsible for the robust binding of Me-30 through CH-pi interaction. The decreased pi-electron density of the Phe and Tyr mutants compared to that of Trp would have resulted in the high production of lupeol. PMID- 27942658 TI - Defining the human copper proteome and analysis of its expression variation in cancers. AB - Copper (Cu) is essential for living organisms, and acts as a cofactor in many metabolic enzymes. To avoid the toxicity of free Cu, organisms have specific transport systems that 'chaperone' the metal to targets. Cancer progression is associated with increased cellular Cu concentrations, whereby proliferative immortality, angiogenesis and metastasis are cancer hallmarks with defined requirements for Cu. The aim of this study is to gather all known Cu-binding proteins and reveal their putative involvement in cancers using the available database resources of RNA transcript levels. Using the database along with manual curation, we identified a total of 54 Cu-binding proteins (named the human Cu proteome). Next, we retrieved RNA expression levels in cancer versus normal tissues from the TCGA database for the human Cu proteome in 18 cancer types, and noted an intricate pattern of up- and downregulation of the genes in different cancers. Hierarchical clustering in combination with bioinformatics and functional genomics analyses allowed for the prediction of cancer-related Cu binding proteins; these were specifically inspected for the breast cancer data. Finally, for the Cu chaperone ATOX1, which is the only Cu-binding protein proposed to have transcription factor activities, we validated its predicted over expression in patient breast cancer tissue at the protein level. This collection of Cu-binding proteins, with RNA expression patterns in different cancers, will serve as an excellent resource for mechanistic-molecular studies of Cu-dependent processes in cancer. PMID- 27942659 TI - Stereoselective preparation of conjugated (Z)-1,3-enynes by dehydration reactions of allenic bromohydrins and the use of the enynes in base-mediated tandem allylation ene-carbocyclization reactions with beta-ketoesters. AB - A procedure has been developed for the concise, stereoselective synthesis of (Z) 5-bromo-4-aryl-pent-3-en-1-ynes through Sc(OTf)3 catalyzed dehydration reactions of allenic bromohydrins. (Z)-1,3-Enynes are transformed to methylenecyclopentenes when subjected to a sequential, one-pot process involving base mediated allylation reactions with ethyl acetoacetate followed by ene-carbocyclization reactions. An unprecedented rearrangement reaction involving 1,5-acyl migration takes place when the methylenecyclopentenes are treated with acid to form highly substituted cyclopentadienes. PMID- 27942660 TI - Interface-induced terahertz persistent photoconductance in rGO-gelatin flexible films. AB - Light-induced difference terahertz (THz) spectroscopy is used to investigate the dielectric characteristics of reduced graphene oxide-gelatin (rGO-Gel) flexible films. RGO-Gel films are observed to exhibit positive photoconductance under 800 nm laser illumination, resulting in the modulation depth of the THz transmission up to 33.5%. Moreover, persistent photoconductance (PPC), which is a prolonged light-induced conducting behavior, has been observed to last as long as tens of seconds in rGO-Gel films. The PPC phenomenon is due to the electrons trapped in the defects of rGO and in the interface between rGO and gelatin, and is enhanced by the strong interaction between rGO (a p-type semiconductor) and gelatin (electron donors). This work holds potential for creating optoelectronic devices based on rGO-Gel films, such as optical modulators, switches, photodetectors, photosensors, and persistent photonic memory devices in the THz region. PMID- 27942661 TI - Biomarkerless targeting and photothermal cancer cell killing by surface electrically-charged superparamagnetic Fe3O4 composite nanoparticles. AB - A major challenge in cancer therapy is localized targeting of cancer cells for maximum therapeutic effectiveness. However, due to cancer heterogeneities, the biomarkers are either not readily available or specific for effective targeting of cancer cells. The key, therefore, is to develop a new targeting strategy that does not rely on biomarkers. A general hallmark of cancer cells is the much increased level of glycolysis. The loss of highly mobile lactate from the cytoplasm inevitably removes labile inorganic cations to form lactate salts and acids as part of the lactate cycle, creating a net of negative surface charges. This net of negative charges on cancer cell surfaces biophysically distinguishes themselves from normal cells. In this study, cancer cells are targeted by using positively-charged, fluorescent, superparamagnetic Fe3O4-composite nanoparticles. The positively-charged Fe3O4 composite nanoparticles bind predominantly to cancer cells due to their negatively-charged surfaces. Upon electrical-charge-mediated Fe3O4 nanoparticle binding onto cancer cells, irradiation by using an 808 nm laser is subsequently applied to induce photothermal hyperthermia that kills the cancer cells directly. The negatively-charged composite nanoparticles are found, however, not to target and bind the cancer cells due to the electrostatic repulsive force between them. This unique strategy paves a new path for effective targeting and direct cancer cell killing without relying on any biomarkers and anticancer drugs. PMID- 27942662 TI - Finding reaction mechanisms, intuitive or otherwise. AB - Chemical reaction mechanisms have been frequently studied using computational simulations, but these tools have been primarily effective at examining reaction paths within the scope of chemical intuition. To determine reaction mechanisms that were not already preconceived by chemists, nonstandard simulation tools are required. This perspective introduces new methods developed by the Zimmerman group that are designed to uncover sequences of elementary steps, from first principles and without substantial human guidance. Results from the areas of organo catalysis and transition metal catalysis indicate that new frontiers of knowledge will be gained through continued development and application of reaction discovery simulation techniques. PMID- 27942663 TI - NIR upconversion fluorescence glucose sensing and glucose-responsive insulin release of carbon dot-immobilized hybrid microgels at physiological pH. AB - This work reports the preparation of multifunctional hybrid microgels based on the one-pot free radical dispersion polymerization of hydrogen-bonding complexes in water, formed from hydroxyl/carboxyl bearing carbon dots with 4 vinylphenylboronic acid and acrylamide comonomers, which can realize the simultaneous optical detection of glucose using near infrared light and glucose responsive insulin delivery. PMID- 27942664 TI - Phenolics extracted from tartary (Fagopyrum tartaricum L. Gaerth) buckwheat bran exhibit antioxidant activity, and an antiproliferative effect on human breast cancer MDA-MB-231 cells through the p38/MAP kinase pathway. AB - Phenolics extracted from tartary buckwheat (Fagopyrum tartaricum L. Gaerth) bran were analyzed quantitatively and qualitatively. The bioactivity of the phenolic extracts was evaluated, such as the antioxidant activity, and the inhibition capacity on the growth of cancer cells. The molecular mechanism for the inhibitive effect on cancer cells was explored. Results indicated that tartary buckwheat bran phenolics mainly exist in a free form, and free phenolics were twice as abundant as bound phenolics. Free caffeic acid (119.75 MUg per 100 mg DW) and bound rutin (51.66 MUg per 100 mg DW) represented the main free and bound phenolic compounds, respectively. The free phenolic extract contributed to the major (>90%) antioxidant activities including the oxygen radical antioxidant capacity (ORAC) and cellular antioxidant activity (CAA). The free phenolic extract exhibited anticancer activity for human breast cancer MDA-MB-231 cells in a dose-dependent manner. This significant inhibition effect was achieved through the p38/MAP kinase pathway by inducing cell apoptosis (up-regulating p-p38 and p ASK1 expressions and down-regulating TRAF2 and p-p53 expressions), and negatively regulating the progression of the cell cycle from the G1 to S phase (increased expression of p21 and suppressed expressions of PCNA, cyclin D1 and CDK4). All these results indicated that tartary buckwheat bran could be a rich resource of natural antioxidants and inhibitors for the growth of MDA-MB-231 cells. PMID- 27942665 TI - Unusual reversal of enantioselectivity in the asymmetric autocatalysis of pyrimidyl alkanol triggered by chiral aromatic alkanols and amines. AB - Temperature dependent inversion of enantioselectivity in asymmetric catalysis is an interesting and somewhat unusual phenomenon. We have observed temperature dependent inversion of enantioselectivity in the asymmetric autocatalysis reaction when triggered by a wide scope of enantioenriched alcohols and amines. The addition reaction of diisopropylzinc to pyrimidine-5-carbaldehyde in the presence of enantiopure alcohols or amines affords the pyrimidyl alkanol product at 0 degrees C with high ee. However, lowering the reaction temperature to -44 degrees C affords the opposite enantioselectivity. PMID- 27942666 TI - Two-dimensional hexagonal CrN with promising magnetic and optical properties: A theoretical prediction. AB - Half-metallic ferromagnetic materials with planar forms are promising for spintronics applications. A wide range of 2D lattices like graphene, h-BN, transition metal dichalcogenides, etc. are non-magnetic or weakly magnetic. Using first principles calculations, the existence of graphene-like hexagonal chromium nitride (h-CrN) with an almost flat atomically thin structure is predicted. We find that freestanding h-CrN has a 100% spin-polarized half-metallic nature with possible ferromagnetic ordering and a high rate of optical transparency. As a possible method for stabilization and synthesis, deposition of h-CrN on 2D MoSe2 or on MoS2 is proposed. The formation of composites retains the half-metallic properties and leads to the reduction of spin-down band gaps to 1.43 and 1.71 eV for energetically favorable h-CrN/MoSe2 and h-CrN/MoS2 configurations, respectively. Calculation of the dielectric functions of h-CrN, h-CrN/MoSe2 and h CrN/MoS2 exhibit the high transparency of all three low-dimensional nanomaterials. The honeycomb CrN may be considered as a promising fundamental 2D material for a variety of potential applications of critical importance. PMID- 27942667 TI - The biphasic dose effect of lychee (Litchi chinensis Sonn.) pulp phenolic extract on alcoholic liver disease in mice. AB - Lychee (Litchi chinensis Sonn.), a subtropical fruit grown widely in Southeast Asia, has been used as a traditional Chinese medicine for liver protection. Our previous study showed that phenolics from lychee pulp had hepatoprotective activity against restraint stress-induced liver injury. The present study investigated the protective effects of lychee pulp phenolic extract (LPPE) on ethanol-induced liver injury and the mechanism responsible for these effects. Mice were divided into four groups and subjected to either a control liquid diet (control group, CON), a 4% (w/v) ethanol-containing liquid diet (ethanol group, EtOH), a 4% (w/v) ethanol-containing liquid diet supplemented with 0.4 g L-1 LPPE (low dose LPPE-supplemented group, EtOH + L-LPPE), or a 4% (w/v) ethanol containing liquid diet supplemented with 0.8 g L-1 LPPE (high dose LPPE supplemented group, EtOH + H-LPPE) for 8 weeks. The ethanol-induced hepatic steatosis and increases of triglyceride levels in the serum and liver were ameliorated by L-LPPE supplementation but aggravated by H-LPPE supplementation. Moreover, L-LPPE supplementation improved the antioxidant status, reduced the nuclear translocation of nuclear erythroid 2-related factor 2 (Nrf2), and reduced the expression of Nrf2 target genes in the liver. H-LPPE supplementation resulted in the improved antioxidant status and reduced the expression of Nrf2 target genes. Furthermore, L-LPPE suppressed the expression of lipid synthesis genes and increased the expression of fatty acid beta-oxidation genes. However, H-LPPE increased the expression of genes responsible for lipid synthesis and uptake and reduced the expression of fatty acid beta-oxidation genes. Additionally, L-LPPE supplementation effectively decreased the serum endotoxin level and reversed ethanol-induced alterations in the intestinal microbiota composition. Collectively, LPPE showed biphasic effects on ethanol-induced liver injury in mice, indicating that a moderate intake of LPPE or Litchi pulp could be useful for the prevention and control of alcoholic liver disease. PMID- 27942668 TI - Enhancement of the luminescence properties of high-nuclearity Cd-Ln (Ln = Eu and Nd) nanoclusters by the introduction of more energy transfer donors. AB - Two Cd-Ln clusters [Ln8Cd24L12(1,4-BDC)4(OAc)38(OH)2] (Ln = Eu (1) and Nd (2)) were constructed using a flexible Schiff base and rigid 1,4-BDC ligands. The Cd Ln clusters exhibit interesting nano-drum-like structures which allow direct visualization by TEM. The introduced 1,4-BDC units act as efficient energy transfer donors for lanthanide luminescence, resulting in superior luminescence properties of 1 and 2. PMID- 27942669 TI - A linear hydroxymethyl tetramate undergoes an acetylation-elimination process for exocyclic methylene formation in the biosynthetic pathway of pyrroindomycins. AB - We herein report the isolation and characterization of a key linear intermediate in the biosynthetic pathway of pyrroindomycins, the potent spirotetramate natural products produced by Streptomyces rugosporus. This polyene intermediate bears a gamma-hydroxymethyl group that is exocyclic to the tetramate moiety, indicating that a serine residue serves as the three-carbon unit for tetramate formation and chain-elongation termination. The further conversion involves an acetylation elimination of the exocyclic gamma-hydroxymethyl group to generate a gamma methylene group, which is indispensable for intramolecular [4 + 2] cross-bridging to construct the characteristic pentacyclic core. The findings presented in this study provide new insights into the biosynthesis of pyrroindomycins, and thus suggest a common paradigm for both spirotetramates and spirotetronates in processing the exocyclic gamma-hydroxymethyl group of the five-membered heterocycle. PMID- 27942670 TI - Fast quantitative ROS detection based on dual-color single rare-earth nanoparticle imaging reveals signaling pathway kinetics in living cells. AB - Reactive oxygen species (ROS), and notably hydrogen peroxide H2O2, are cellular second messengers that are known to control a variety of signaling processes. They can finely regulate the dynamics of signal transduction, cell response and ultimately tissue function. However, there are very few local, quantitative and time-resolved descriptions of their cellular organization at the scale of molecular reactions, due to the lack of efficient sensors. We thus developed a novel nanoprobe-based ROS detection system using the simultaneous imaging of single lanthanide nanoparticles (YAG:Ce and chemically reduced Gd0.6Eu0.4VO4). We reveal that both particle luminescence signals are controlled by their H2O2 local environment. By simultaneously tracking their luminescence, we devised a new approach providing a quantitative (0.5 MUM accuracy in the 1-10 MUM range) H2O2 measurement with a 500 ms time resolution, surpassing all existing methods by two orders of magnitude, and revealing previously inaccessible molecular events controlling ROS concentration. We used this nanoprobe in living cells to track fast signaling pathways, by measuring the dynamics of H2O2 intracellular concentrations, induced by endothelin-1 (ET-1) stimulation. We thus revealed the mechanisms controlling ROS production, notably the activity modulation of the ROS producing enzyme NADPH oxidase by fast (<10 s) EGFR transactivation, and measured quantitatively their kinetic parameters through a minimal analytical model. Altogether, these results illustrate how lanthanide nanoparticle-based sensors are a powerful tool to dynamically probe molecular mechanisms shaping the oxidative cell response. PMID- 27942671 TI - Systematic study of constraints imposed by modified nucleoside triphosphates with protein-like side chains for use in in vitro selection. AB - Successful selection of modified DNAzymes depends on the potential for modified nucleoside triphosphates (dNTPs) to replace their unmodified counterparts in enzyme catalyzed primer extension reactions and, once incorporated, to serve as template bases for information transfer prior to PCR amplification. To date, the most densely modified DNAzymes have been selected from three modified dNTPs: 8 histaminyl-deoxyadenosine (dAimTP), 5-guanidinoallyl-deoxyuridine (dUgaTP), and 5 aminoallyl-deoxycytidine (dCaaTP) to provide several RNA-cleaving DNAzymes with greatly enhanced rate constants compared to unmodified counterparts. Here we report biophysical and enzymatic properties of these three modified nucleosides in the context of specific oligonucleotide sequences to understand how these three modified nucleobases function in combinatorial selection. The base-pairing abilities of oligonucleotides bearing one or three modified nucleosides were investigated by thermal denaturation studies and as templates for enzymatic polymerization with both modified and unmodified dNTPs. While we address certain shortcomings in the use of modified dNTPs, we also provide key evidence of faithful incorporation and enzymatic read-out, which strongly supports their continued use in in vitro selection. PMID- 27942672 TI - FRET enhancement close to gold nanoparticles positioned in DNA origami constructs. AB - Here we investigate the energy transfer rates of a Forster resonance energy transfer (FRET) pair positioned in close proximity to a 5 nm gold nanoparticle (AuNP) on a DNA origami construct. We study the distance dependence of the FRET rate by varying the location of the donor molecule, D, relative to the AuNP while maintaining a fixed location of the acceptor molecule, A. The presence of the AuNP induces an alteration in the spontaneous emission of the donor (including radiative and non-radiative rates) which is strongly dependent on the distance between the donor and AuNP surface. Simultaneously, the energy transfer rates are enhanced at shorter D-A (and D-AuNP) distances. Overall, in addition to the direct influence of the acceptor and AuNP on the donor decay there is also a significant increase in decay rate not explained by the sum of the two interactions. This leads to enhanced energy transfer between donor and acceptor in the presence of a 5 nm AuNP. We also demonstrate that the transfer rate in the three "particle" geometry (D + A + AuNP) depends approximately linearly on the transfer rate in the donor-AuNP system, suggesting the possibility to control FRET process with electric field induced by 5 nm AuNPs close to the donor fluorophore. It is concluded that DNA origami is a very versatile platform for studying interactions between molecules and plasmonic nanoparticles in general and FRET enhancement in particular. PMID- 27942673 TI - Correction: A-site-deficiency facilitated in situ growth of bimetallic Ni-Fe nano alloys: a novel coking-tolerant fuel cell anode catalyst. AB - Correction for 'A-site-deficiency facilitated in situ growth of bimetallic Ni-Fe nano-alloys: a novel coking-tolerant fuel cell anode catalyst' by Yi-Fei Sun et al., Nanoscale, 2015, 7, 11173-11181. PMID- 27942674 TI - Conformationally superarmed S-ethyl glycosyl donors as effective building blocks for chemoselective oligosaccharide synthesis in one pot. AB - A new series of superarmed glycosyl donors has been investigated. It was demonstrated that the S-ethyl leaving group allows for high reactivity, which is much higher than that of equally equipped S-phenyl glycosyl donors that were previously investigated by our groups. The superarmed S-ethyl glycosyl donors equipped with a 2-O-benzoyl group gave complete beta-stereoselectivity. Utility of the new glycosyl donors has been demonstrated in a one-pot one-addition oligosaccharide synthesis with all of the reaction components present from the beginning. PMID- 27942675 TI - Bright and photostable nitrogen-vacancy fluorescence from unprocessed detonation nanodiamond. AB - Bright and photostable fluorescence from nitrogen-vacancy (NV) centers is demonstrated in unprocessed detonation nanodiamond particle aggregates. The optical properties of these particles is analyzed using confocal fluorescence microscopy and spectroscopy, time resolved fluorescence decay measurements, and optically detected magnetic resonance experiments. Two particle populations with distinct optical properties are identified and compared to high-pressure high temperature (HPHT) fluorescent nanodiamonds. We find that the brightness of one detonation nanodiamond particle population is on the same order as that of highly processed fluorescent 100 nm HPHT nanodiamonds. Our results may open the path to a simple and up-scalable route for the production of fluorescent NV nanodiamonds for use in bioimaging applications. PMID- 27942676 TI - Singlet oxygen feedback delayed fluorescence of protoporphyrin IX in organic solutions. AB - Delayed fluorescence (DF) of protoporphyrin IX (PpIX) has been recently proposed as a tool for monitoring of mitochondrial oxygen tension in vivo as well as for observation of the effectiveness of photodynamic therapy (PDT) [E. G. Mik, Anesth. Analg., 2013, 117, 834-346; F. Piffaretti et al., J. Biomed. Opt., 2012, 17, 115007]. However, the efficiency of the mechanism of thermal activation (E type DF), which was considered in the papers, is limited due to a large energy gap between the first excited singlet and the first triplet state of PpIX at room or body temperatures. Moreover, the energy gap is roughly equal to other porphyrinoid photosensitizers that generate DF mostly through the Singlet Oxygen Feedback-Induced mechanism (SOFDF) under certain conditions [M. Scholz and R. Dedic, Singlet Oxygen: Applications in Biosciences and Nanosciences, 2016, vol. 2, pp. 63-81]. The mechanisms of delayed fluorescence of PpIX dissolved either in dimethylformamide (DMF) or in the mixture of DMF with ethylene glycol (EG) were investigated at atmospheric partial pressure of oxygen by means of a simultaneous time-resolved detection of 1O2 phosphorescence and PpIX DF which makes a direct comparison of the kinetics and lifetimes of both the luminescence channels possible. Samples of PpIX (100 MUM) exhibit concave DF kinetics, which is a typical footprint of the SOFDF mechanism. The dramatic decrease in the DF intensity after adding a selective 1O2 quencher sodium azide (NaN3, 10 mM) proves that >90% of DF is indeed generated through SOFDF. Moreover, the analysis of the DF kinetics in the presence of NaN3 implies that the second significant mechanism of DF generation is the triplet-triplet annihilation (P-type DF). The bimolecular mechanism of DF was further confirmed by the decrease of the DF intensity in the more viscous mixture DMF/EG and by the increase of the ratio of DF to the prompt fluorescence (PF) intensity with the increasing excitation intensity. These results show the significant role of the SOFDF mechanism in the DF of PpIX at high concentrations and at atmospheric partial pressure of oxygen and should be considered when developing diagnostic tools for clinical applications. PMID- 27942677 TI - Fluorescence lifetime-based sensing of polymersome leakage. AB - Assays to analyze the degradation, lysis and leakage of vesicles are commonly utilized in biology and physical chemistry. Here we show the fluorescence lifetime-based sensing of the leakage of stimuli responsive PEG114-b-PLA167 block copolymer vesicles. The time-resolved technique differentiates between the fluorophore molecules in the solvated state at high concentrations, and in the wall material and in the solvated state at low concentrations. The vesicle leakage occurs after an incubation period, which was detected by the change of the time correlated single photon counting decays. PMID- 27942678 TI - A closed form large deformation solution of plate bending with surface effects. AB - We study the effect of surface stress on the pure bending of a finite thickness plate under large deformation. The surface is assumed to be isotropic and its stress consists of a part that can be interpreted as a residual stress and a part that stiffens as the surface increases its area. Our results show that residual surface stress and surface stiffness can both increase the overall bending stiffness but through different mechanisms. For sufficiently large residual surface tension, we discover a new type of instability - the bending moment reaches a maximum at a critical curvature. Effects of surface stress on different stress components in the bulk of the plate are discussed and the possibility of self-bending due to asymmetry of the surface properties is also explored. The results of our calculations provide insights into surface stress effects in the large deformation regime and can be used as a test for implementation of finite element methods for surface elasticity. PMID- 27942679 TI - Humanized archaeal ferritin as a tool for cell targeted delivery. AB - Human ferritins have been extensively studied to be used as nanocarriers for diverse applications and could represent a convenient alternative for targeted delivery of anticancer drugs and imaging agents. However, the most relevant limitation to their applications is the need for highly acidic experimental conditions during the initial steps of particle/cargo assembly, a process that could affect both drug stability and the complete reassembly of the ferritin cage. To overcome this issue the unique assembly of Archaeoglobus fulgidus ferritin was genetically engineered by changing a surface exposed loop of 12 amino acids connecting B and C helices to mimic the sequence of the analogous human H-chain ferritin loop. This new chimeric protein was shown to maintain the unique, cation linked, association-dissociation properties of Archaeoglobus fulgidus ferritin occurring at neutral pH values, while exhibiting the typical human H-homopolymer recognition by the transferrin receptor TfR1. The chimeric protein was confirmed to be actively and specifically internalized by HeLa cells, thus representing a unique nanotechnological tool for cell-targeted delivery of possible payloads for diagnostic or therapeutic purposes. Moreover, it was demonstrated that the 12 amino acids' loop is necessary and sufficient for binding to the transferrin receptor. The three-dimensional structure of the humanized Archaeoglobus ferritin has been obtained both as crystals by X-ray diffraction and in solution by cryo-EM. PMID- 27942680 TI - Microscale flow dynamics of ribbons and sheets. AB - Numerical study of the hydrodynamics of thin sheets and ribbons presents difficulties associated with resolving multiple length scales. To circumvent these difficulties, asymptotic methods have been developed to describe the dynamics of slender fibres and ribbons. However, such theories entail restrictions on the shapes that can be studied, and often break down in regions where standard boundary element methods are still impractical. In this paper we develop a regularised stokeslet method for ribbons and sheets in order to bridge the gap between asymptotic and boundary element methods. The method is validated against the analytical solution for plate ellipsoids, as well as the dynamics of ribbon helices and an experimental microswimmer. We then demonstrate the versatility of this method by calculating the flow around a double helix, and the swimming dynamics of a microscale "magic carpet". PMID- 27942681 TI - BN-schwarzite: novel boron nitride spongy crystals. AB - Novel three-dimensional (3-D) structures based on sp2 boron nitride schwarzite (BN-schwarzite) with octagon rings are proposed for the first time by first principles study. The structural stability, and mechanical and electronic properties of three typical BN-schwarzites, that is BN-192P, BN-6.82P and BN 6.82D, are investigated. It is found that the unique cavity structure of BN schwarzite gives rise to a specific surface area (SSA) as high as 2800 m2 g-1 and intrinsic large pores of 5-13 A. All BN-schwarzites studied are good ductile materials with Poisson's ratio as high as 0.35, and dynamically stable. An unusually wide band gap higher than 4 eV is observed which cannot be achieved by the existing carbon schwarzite (C-schwarzite). Furthermore, a high lithium diffusion coefficient is obtained in BN-schwarzite, which is estimated to be 30 times more than that of graphene at room temperature. Our theoretical results would motivate further experimental work related to the synthesis and characterization of BN-schwarzite. Such boron nitride structures with porosity and large surface areas may hold great promise in the fields of lithium ion batteries, molecular sieving, and environmental remediation. PMID- 27942682 TI - Mathematical description of pH-stat kinetic traces measured during photochemical quinone decomposition. AB - Substituted 1,4-benzoquinone (QR) derivatives are photosensitive in aqueous solution and form hydroquinones (QR-H2) and hydroxy-quinones (QR-OH), two weak acids in their photoreaction. For this reason, the kinetics of the photoreaction can be conveniently followed by the pH-stat titration technique. The mathematical description of the kinetic traces measured provides the two main parameters of the photoreaction: the differential quantum yield of the reaction (Phi) and the ratio of the two photo-products, i.e. the fraction of QR that is converted to QR OH (alpha). These values are described in this paper for 2,5-dichloro-1,4 benzoquinone at different pH values, together with the detailed mathematical evaluation of the application limits of the pH-stat method for such reactions. PMID- 27942683 TI - Transition-metal-free B-B and B-interelement reactions with organic molecules. AB - This review is a guided tour along the activation modes and reactivity of B-B, B Si, B-N, B-S, B-Se and B-P reagents, in the absence of any transition metal complex. Here are disclosed the general concepts related to the homolytic and heterolytic cleavage of B-B and B-interelement bonds, as well as the generation of new C-B and C-interelement bonds, in a selective way. The greener consequences of these novel routes facilitate the gram scale preparations of target functionalised organic compounds. Intrinsic data about the suggested mechanisms and spectroscopic evidence that supports the innovative theories are provided along the review. Since this is a stimulating area of work that has emerged within the last decade, this overview serves as the basis to understand the new trends and hopefully to generate inspiration for future discoveries in the field. PMID- 27942684 TI - Rapid dynamics of cell-shape recovery in response to local deformations. AB - It is vital that cells respond rapidly to mechanical cues within their microenvironment through changes in cell shape and volume, which rely upon the mechanical properties of cells' highly interconnected cytoskeletal networks and intracellular fluid redistributions. While previous research has largely investigated deformation mechanics, we now focus on the immediate cell-shape recovery response following mechanical perturbation by inducing large, local, and reproducible cellular deformations using AFM. By continuous imaging within the plane of deformation, we characterize the membrane and cortical response of HeLa cells to unloading, and model the recovery via overdamped viscoelastic dynamics. Importantly, the majority (90%) of HeLa cells recover their cell shape in <1 s. Despite actin remodelling on this time scale, we show that cell-shape recovery time is not affected by load duration, nor magnitude for untreated cells. To further explore this rapid recovery response, we expose cells to cytoskeletal destabilizers and osmotic shock conditions, which uncovers the interplay between actin and osmotic pressure. We show that the rapid dynamics of recovery depend crucially on intracellular pressure, and provide strong evidence that cortical actin is the key regulator in the cell-shape recovery processes, in both cancerous and non-cancerous epithelial cells. PMID- 27942685 TI - Control and formation mechanism of extended nanochannel geometry in colloidal mesoporous silica particles. AB - A large class of colloidal multi-micron mesoporous silica particles have well defined cylindrical nanopores, nanochannels which self-assembled in the templated sol-gel process. These particles are of broad interest in photonics, for timed drug release, enzyme stabilization, separation and filtration technologies, catalysis, etc. Although the pore geometry and mechanism of pore formation of such particles has been widely investigated at the nanoscale, their pore geometry and its formation mechanism at a larger (extended) scale is still under debate. The extended geometry of nanochannels is paramount for all aforementioned applications because it defines accessibility of nanochannels, and subsequently, kinetics of interaction of the nanochannel content with the particle surrounding. Here we present both experimental and theoretical investigation of the extended geometry and its formation mechanism in colloidal multi-micron mesoporous silica particles. We demonstrate that disordered (and consequently, well accessible) nanochannels in the initially formed colloidal particles gradually align and form extended self-sealed channels. This knowledge allows to control the percentage of disordered versus self-sealed nanochannels, which defines accessibility of nanochannels in such particles. We further show that the observed aligning the channels is in agreement with theory; it is thermodynamically favored as it decreases the Gibbs free energy of the particles. Besides the practical use of the obtained results, developing a fundamental understanding of the mechanisms of morphogenesis of complex geometry of nanopores will open doors to efficient and controllable synthesis that will, in turn, further fuel the practical utilization of these particles. PMID- 27942686 TI - Patterns in Saccharomyces cerevisiae yeast colonies via magnetic resonance imaging. AB - We report the use of high-resolution magnetic resonance imaging methods to observe pattern formation in colonies of Saccharomyces cerevisiae. Our results indicate substantial signal loss localized in specific regions of the colony rendering useful imaging contrast. This imaging contrast is recognizable as being due to discontinuities in magnetic susceptibility (chi) between different spatial regions. At the microscopic pixel level, the local variations in the magnetic susceptibility (Deltachi) induce a loss in the NMR signal, which was quantified via T2 and T2* maps, permitting estimation of Deltachi values for different regions of the colony. Interestingly the typical petal/wrinkling patterns present in the colony have a high degree of correlation with the estimated susceptibility distribution. We conclude that the presence of magnetic susceptibility inclusions, together with their spatial arrangement within the colony, may be a potential cause of the susceptibility distribution and therefore the contrast observed on the images. PMID- 27942687 TI - Color-stable water-dispersed cesium lead halide perovskite nanocrystals. AB - Cesium lead halide perovskite nanocrystals are being lately explored for optoelectronic applications due to their emission tunability, high photoluminescence quantum yields, and narrow emission bands. Nevertheless, their incompatibility with polar solvents and composition homogenization driven by a fast anion-exchange are still important drawbacks to overcome. Herein we report on a successful encapsulation of colloidal perovskite nanocrystals within solid lipid structures mainly consisting of stearic acid. The product is water-stable for a period longer than 2 months and anion-exchange is fully arrested when mixing nanocrystals of different halide compositions. This strategy boosts the potential applications of all-inorganic perovskite nanocrystals for ink-printing. PMID- 27942688 TI - Synthesis and characterization of photoaffinity labelling reagents towards the Hsp90 C-terminal domain. AB - Glucosyl-novobiocin-based diazirine photoaffinity labelling reagents (PALs) were designed and synthesized to probe the Hsp90 C-terminal domain unknown binding pocket and the structure-activity relationship. Five PALs were successfully synthesized from novobiocin in six consecutive steps employing phase transfer catalytic glycosylation. Reactions were monitored and guided by analytical LC/MS which led to different strategies of adding either a PAL precursor or a sugar moiety first. The structures and bonding linkages of these compounds were characterised by various 2D-NMR spectroscopy and MS techniques. Synthetic techniques provide powerful probes for unknown protein binding pockets. PMID- 27942689 TI - Deformable and wearable carbon nanotube microwire-based sensors for ultrasensitive monitoring of strain, pressure and torsion. AB - Human joints have the ability to recover their mechanical functions after moderate dislocation. This remarkable capability inspired us to develop a "bone skin-like" mechanosensor that can detect multiple mechanical deformations after recovery from electrical disconnection. To create this sensor, we embedded a low strength, wet-spun single-walled carbon nanotube wire in polydimethylsiloxane. When various mechanical stimuli are applied, the wire gets fragmented and its resistance increases dramatically (from 360 Omega to practically infinity) in a reversible, recoverable manner even after the electrical failure/disconnection. The sensor is sensitive enough (a gauge factor of 105 at 15% uniaxial strain, a pressure sensitivity of 105 MPa-1 at 0.9 MPa pressure and a torsion sensitivity of 860 at a twisting angle of 60 degrees ) to be used for accurate sensing of a variety of deformation modes, suggesting a wide range of applications in wearable and deformable mechanical sensors. PMID- 27942690 TI - Equation of state for random sphere packings with arbitrary adhesion and friction. AB - We systematically generate a large set of random micro-particle packings over a wide range of adhesion and friction by means of adhesive contact dynamics simulation. The ensemble of generated packings covers a range of volume fractions phi from 0.135 +/- 0.007 to 0.639 +/- 0.004, and of coordination numbers Z from 2.11 +/- 0.03 to 6.40 +/- 0.06. We determine phi and Z at four limits (random close packing, random loose packing, adhesive close packing, and adhesive loose packing), and find a universal equation of state phi(Z) to describe packings with arbitrary adhesion and friction. From a mechanical equilibrium analysis, we determine the critical friction coefficient MUf,c: when the friction coefficient MUf is below MUf,c, particles' rearrangements are dominated by sliding, otherwise they are dominated by rolling. Because of this reason, both phi(MUf) and Z(MUf) change sharply across MUf,c. Finally, we generalize the Maxwell counting argument to micro-particle packings, and show that the loosest packing, i.e., adhesive loose packing, satisfies the isostatic condition at Z = 2. PMID- 27942691 TI - Single-electron tunneling through an individual arsenic dopant in silicon. AB - We report the single-electron tunneling behaviour of a silicon nanobridge where the effective island is a single As dopant atom. The device is a gated silicon nanobridge with a thickness and width of ~20 nm, fabricated from a commercially available silicon-on-insulator wafer, which was first doped with As atoms and then patterned using a unique CMOS-compatible technique. Transport measurements reveal characteristic Coulomb diamonds whose size decreases with gate voltage. Such a dependence indicates that the island of the single-electron transistor created is an individual arsenic dopant atom embedded in the silicon lattice between the source and drain electrodes, and furthermore, can be explained by the increase of the localisation region of the electron wavefunction when the higher energy levels of the dopant As atom become occupied. The charge stability diagram of the device shows features which can be attributed to adjacent dopants, localised in the nanobridge, acting as charge traps. From the measured device transport, we have evaluated the tunnel barrier properties and obtained characteristic device capacitances. The fabrication, control and understanding of such "single-atom" devices marks a further step towards the implementation of single-atom electronics. PMID- 27942692 TI - Probing the effect of the Pt-Ni-Pt(111) bimetallic surface electronic structures on the ammonia decomposition reaction. AB - We report a detailed investigation of elementary catalytic decomposition of ammonia on the Pt-Ni-Pt(111) bimetallic surface using in situ near ambient pressure X-ray photoelectron spectroscopy. Under the near ambient pressure (0.6 mbar) reaction conditions, a different dehydrogenation pathway with a reduced activation energy barrier for recombinative nitrogen desorption on the Pt-Ni Pt(111) bimetallic surface is observed. The unique surface catalytic activity is correlated with the downward shift of the Pt 5d band states induced by the Ni subsurface atoms via charge redistribution of the topmost Pt layer. Our results provide a practical understanding of the unique chemistry of bimetallic catalysts for facile ammonia decomposition under realistic reaction conditions. PMID- 27942693 TI - The integrated effect of moderate exercise on coronary heart disease. AB - BACKGROUND: Moderate exercise is associated with a lower risk for coronary heart disease (CHD). A suitable integrated model of the CHD pathogenetic pathways relevant to moderate exercise may help to elucidate this association. Such a model is currently not available in the literature. METHODS: An integrated model of CHD was developed and used to investigate pathogenetic pathways of importance between exercise and CHD. Using biomarker relative-risk data, the pathogenetic effects are representable as measurable effects based on changes in biomarkers. RESULTS: The integrated model provides insight into higherorder interactions underlying the associations between CHD and moderate exercise. A novel 'connection graph' was developed, which simplifies these interactions. It quantitatively illustrates the relationship between moderate exercise and various serological biomarkers of CHD. The connection graph of moderate exercise elucidates all the possible integrated actions through which risk reduction may occur. CONCLUSION: An integrated model of CHD provides a summary of the effects of moderate exercise on CHD. It also shows the importance of each CHD pathway that moderate exercise influences. The CHD risk-reducing effects of exercise appear to be primarily driven by decreased inflammation and altered metabolism. PMID- 27942695 TI - From Stats to Stage-Translational Research in Performing Arts Medicine. AB - Medical Problems of Performing Artists, since its inception under the legendary Alice Brandfonbrener's guidance and vision, has always recognized the need for voices to be heard from the clinic, stage, and experimental research. This has been important in a relatively young field like performing arts medicine, where there is not yet a robust base of evidence to draw from for the complex range of physical, psychological, and institutional challenges that can affect performer health. Evidence-based medicine has long been described as using the best available research in conjunction with clinical expertise, while considering patient beliefs, characteristics, and circumstances. PMID- 27942694 TI - Atrial myxoma: a rare cause of hemiplegia in children. AB - BACKGROUND: Atrial myxoma is an uncommon cause of hemiplegia in children. However hemiplegia is the commonest manifestation of atrial myxoma in the paediatric age group. CASE REPORT: An 11-year-old girl presented with left hemiplegia and palpitations. Three months later she had a deepvein thrombosis of the right common iliac vein. MRI of the brain showed a subacute right thalamic infarct, and an ECG showed left atrial and left ventricular hypertrophy. Transthoracic echocardiography revealed a left atrial myxoma impinging on the mitral valve. A diagnosis of left atrial myxoma with multiple thromboembolic events was made. She was placed on anticoagulants until she died while awaiting surgical tumour resection. CONCLUSION: Echocardiography should be done early in children presenting with ischaemic thromboembolic diseases in order to reduce morbidity and mortality rates resulting from cardiac pathology. PMID- 27942696 TI - Pain and Posture of Children and Adolescents Who Learn the Accordion as Compared with Non-Musician Students. AB - OBJECTIVES: This study assessed the effect of practicing the accordion on pain and posture of children and adolescent students. METHODS: Pain and posture (forward head posture, scapular posture, and lumbar lordosis) were compared between two groups of preparatory and secondary school students, matched for age and sex: those who took accordion lessons (accordionists, n=16) and those who never studied a musical instrument (non-musicians, n=16). RESULTS: Students taking accordion lessons reported significantly more pain in the shoulder, wrist/hand, and thoracic regions (p<0.05), showed significantly more forward head posture (accordionists, median +/- interquartile distance [IQ] distance = 35.6 degrees +/- 7.8 degrees ; non-musicians = 45.3 degrees +/- 10.8 degrees ; p<0.05), and significantly increased lumbar lordosis (accordionists, median +/- IQ distance = 55.5 degrees +/- 30.6 degrees ; nonmusicians = 39.0 degrees +/- 3.9 degrees ; p<0.05). No significant differences were found for scapular posture between groups. CONCLUSIONS: This study suggests that children and adolescents who play the accordion have an increased forward head posture and lumbar lordosis and a tendency to report more pain than children and adolescents who do not play a musical instrument. Results corroborate the need for including healthy preventive teaching-learning strategies at music conservatoires. PMID- 27942697 TI - Prevalence and Associated Factors for Musculoskeletal Pain and Disability Among Spanish Music Conservatory Students. AB - OBJECTIVES: To assess the prevalence of and factors associated with musculoskeletal pain (MSP) and neck and upper limb disability among music conservatory students. METHODS: An observational study in two Spanish conservatories, investigating a total of 206 students, administered the Nordic Musculoskeletal Questionnaire, visual analog scale for pain intensity, Neck Disability Index, DASH, and SF-36. Demographic and lifestyle characteristics and musical performance variables were recorded. Regression models were performed to identify variables associated with MSP for the four most affected anatomical regions and with neck and upper limb disability. RESULTS: The locations with the highest prevalence of MSP were the neck, upper back, shoulders, and lower back. Mild disability affected 47% of participants in the neck and 31% in the upper limbs. Mental health (SF-36) was below the average for the general population (45.5+/-10.2). Women were more likely to suffer neck pain (odds ratio [OR] 1.1 5.2), lower back pain (OR 1.7-8.7), and neck disability (B 0.6-7.8). The risk for shoulder pain was higher in those who played for more hours (OR 1.7-24.7) and lower among those who performed physical activity (OR 0.23-1.00). Disability in the neck (B -0.3) and upper limbs (B -0.4) was associated with poorer mental health (SF-36). CONCLUSION: MSP is highly prevalent in music students. Neck and upper limb disability were slight to moderate and both were associated with poorer mental health. The main factors associated with MSP were being female, hours spent practicing, and physical activity. Physical and psychological factors should be taken into account in the prevention of MSP in student-musicians. PMID- 27942698 TI - Knowledge of Playing-Related Musculoskeletal Disorders Among Classical Piano Students at Tertiary Institutions in Malaysia. AB - Performance injuries among musicians have been widely discussed for decades. However, despite the growing number of classical pianists, this is still a new issue in Malaysia. Therefore, this study aimed to investigate the level of knowledge of playing-related musculoskeletal disorders (PRMDs) among tertiary music students in Malaysia. A survey was conducted among classical piano students at tertiary institutions of Kuala Lumpur and Selangor. Out of 192 respondents, 76% knew that piano playing can cause PRMDs. Slightly over three-quarters of respondents (77.1%) learned about PRMDs from music educators. The survey revealed that the belief in "no pain, no gain" was still ingrained in their minds, as 50.5% respondents believed that pain experienced while playing the piano was normal and 51.6% of them considered that pain must be experienced to improve their piano skill. The respondents were also scored on questions on terminologies of pianist injury and specific PRMD examples: 7.8% of respondents scored high in the questions on the general terminology, while 99.5% of them scored low in the questions on the specific examples of PRMDs. This finding indicated a lack of knowledge of specific musicians' injuries among classical piano students. The attitudes to pain and the level of understanding of the significance of potential injuries indicate that increasing PRMD awareness and introducing courses on PRMD prevention at tertiary institutions are warranted. PMID- 27942699 TI - Relationships Among Performance Anxiety, Agari Experience, and Depressive Tendencies in Japanese Music Students. AB - The purpose of this study was to investigate the relationships among anxiety prior to actual performance (music performance anxiety, MPA), mental and physical negative responses during performance (agari), and depressive tendencies in Japanese college students majoring in music. Participants were 171 music majors (33 males, 138 females, 20.6+/-1.7 yrs). They rated the degree of self-perceived MPA before their performance on a scale ranging from 0-100%. The Features of Agari Experience Questionnaire was used to assess agari response levels during standard performances, and the Japanese version of the Center for Epidemiologic Studies Depression Scale (CESD) was used to measure depressive tendencies. Path analysis showed that MPA levels were positively related to agari scores, which were positively related to CES-D scores. Mediation analysis found a significant indirect effect of MPA scores on CES-D scores via the agari scores. These results suggest that MPA first occurs before an actual music performance and evokes agari, which in turn may cause an increase in depressive tendencies. PMID- 27942700 TI - Lower Extremity Biomechanical Demands During Saut de Chat Leaps. AB - : In dance, high demands are placed on the lower extremity joints during jumping tasks. The purpose of this study was to compare biomechanical demands placed on the lower extremity joints during the takeoff and landing phases of saut de chat leaps. METHODS: Thirty healthy, experienced dancers with 20.8+/-4.9 yrs of dance training performed 5 saut de chat leaps. A three-dimensional motion analysis system and force plates were used to collect kinematic and kinetic data. Ground reaction force (GRF) peaks and impulse and sagittal plane kinematics and kinetics of the hip, knee, ankle, and metatarsophalangeal (MTP) joints were calculated for the takeoff and landing phases of each leap. RESULTS: Saut de chat takeoffs demonstrated greater braking GRF impulse (p<0.001), while landings demonstrated greater peak vertical GRF (p<0.001). During takeoff, greater kinetic demands were placed on the MTP (p<0.001) and ankle (p<0.001) joints, while during landing greater kinetic demands were placed on the hip (p=0.037) joint. CONCLUSIONS: Both the takeoff and landing phases of saut de chat leaps place significant demands on a dancer's body. Takeoff involves greater demands on the more distal joints and requires more braking forces, while the landing phase involves greater demands on the more proximal joints of the lower extremity and requires the dancer to absorb more vertical force. These demands, combined with extensive repetition of movements during training, may contribute to the high number of chronic injuries seen in dance. PMID- 27942701 TI - Is Alcohol Consumption Associated with Job Strain Among Professional Musicians? AB - OBJECTIVE: To assess the strength of the relationship between alcohol consumption and job strain experienced by professional musicians. METHODS: Cross-sectional survey among professional orchestra musicians (n=1,550, response rate 41%, data available for 590 respondents). The difference between groups with and without job strain was assessed by two-way analysis of variance. RESULTS: The median alcohol consumption was 48 g/wk (range 1-648, IQR 12-96). There were only 25 (4%) heavy drinkers, defined as people who consume >210 g of pure alcohol a week. The average frequency of drinking was 2.1 times/wk (SD 2.0, range 0-7). Of the respondents, 125 (21%) reported an elevated level of job strain as defined by the responses to Job Content Questionnaire. There was no significant interaction between the effects of gender and job strain on alcohol consumption: F(1, 586) = 0.82, p=0.365. Simple main effects analysis showed that males were consuming alcohol significantly more than females were (p=0.0005), but there were no differences between participants with elevated level of job strain compared with the rest of the sample (p=0.546). CONCLUSIONS: The amount of alcohol consumed was not associated with the presence or absence of perceived occupational strain among professional orchestra musicians. PMID- 27942702 TI - Imagery-Based Interventions for Music Performance Anxiety: An Integrative Review. AB - Many musicians experience debilitating music performance anxiety (MPA). Outside music performance, imagery-based interventions have been incorporated into treatment protocols to help individuals, including athletes and those with social anxiety, manage heightened levels of anxiety in order to excel in performance based domains. Despite the frequent use of mental imagery in MPA interventions and its importance as a mental rehearsal technique for musicians, no existing reviews have examined the literature on imagery-based interventions for MPA. The primary aim of this review was to analyze the existing MPA literature in order to summarize what is known about the efficacy and mechanisms of pre-performance mental imagery exercises. A literature search yielded eight studies that used imagery-based interventions for MPA, in both student and professional musicians, which included three dissertations and five peer-reviewed journal articles. In extant MPA treatment research, pre-performance imagery is often used in conjunction with other techniques in order to alleviate anxiety. Arousal imagery refers to imagining one's state of arousal during performance and has been incorporated into MPA interventions in various ways that guide musicians to anticipate the heightened arousal that accompanies performance, predominantly through imagery-based relaxation techniques. However, methodological limitations make it impossible to determine whether imagery is itself an active ingredient of treatment that underlies symptom changes, or whether relaxation imagery is the most effective use of pre-performance imagery for all musicians. There is much need for future well-controlled studies to examine whether and how imagery affects MPA independent of the other therapy components and techniques with which it is commonly combined. PMID- 27942703 TI - Fundamentals of Embouchure in Brass Players: Towards a Definition and Clinical Assessment. AB - : Brass players may experience problems producing an optimal sound (or range of sounds) in their instrument. Assessing and treating dysfunctional embouchure requires knowledge of functional embouchure, but peer-reviewed literature on dysfunctional and functional embouchure is scarce. OBJECTIVE: This study aimed to provide a narrative overview of embouchure based on information from different scientific and clinical fields. This should be regarded as a first step in constructing a reliable, valid, and practical multi-item method to assess embouchure for brass players. METHODS: Literature reviews were conducted concerning: 1) the definition of embouchure, 2) physics and acoustics of embouchure, 3) functioning of embouchure-related structures, and 4) instruments to assess embouchure. Also, embouchure experts (clinicians, scientists, and elite wind players) were consulted for information and discussion. RESULTS: A proposal for a new definition of embouchure, an overview of the relevant physics and acoustics, functions of embouchure-related body structures, and the main methods to measure embouchure in brass playing are presented. CONCLUSION: Peer-reviewed information about the fundamentals of dysfunctional embouchure is scarce and sometimes contradictory. A new definition for embouchure is proposed: embouchure is the process needed to adjust the amount, pressure, and direction of the air flow (generated by the breath support) as it travels through the mouth cavity and between the lips, by the position and/or movements of the tongue, teeth, jaws, cheeks, and lips, to produce a tone in a wind instrument. An integrative overview is presented which can serve as a transparent foundation for the present understanding of functional and dysfunctional embouchure and for developing an evidence-based multi-item assessment instrument. PMID- 27942704 TI - A Significant Upper Arm Injury Sustained While Learning Simon Preston's Alleluyas: A Proposal for Avoiding this Malady. AB - Simon Preston's Alleluyas is an organ solo of moderate difficulty written partly in the tonal language of Olivier Messiaen. While learning this piece, I experienced a slight discomfort in my right upper arm. A more severe pain developed later, over several weeks, and my right hand became partially paralyzed. Full recovery took almost 2 months. ... My reversible injury was caused by playing just six bars, and it may owe something to the way I "handled" this brief section, or more likely, "footed" it. PMID- 27942705 TI - Association of a Clinical Practice Guideline With Blood Culture Use in Critically Ill Children. AB - Importance: Sepsis and septic shock are common and, at times, fatal in pediatrics. Blood cultures are often obtained when clinicians suspect sepsis, yet are low-yield with a false-positive rate up to 50%. Objectives: To determine whether a novel, 2-part, clinical practice guideline could decrease the rates of total blood cultures and cultures collected from central venous catheters in critically ill children and to examine the effect of the guideline on patient outcomes. Design, Setting, and Participants: A retrospective cohort study was performed to determine the effect of a new clinical practice guideline on blood culture practices in a 36-bed, combined medical/surgical pediatric intensive care unit of an urban, academic, tertiary care center from April 1, 2013, to March 31, 2015. All patients admitted to the pediatric intensive care unit with length of stay of 4 hours or more were evaluated (4560 patient visits: 2204 preintervention, 2356 postintervention visits). Interventions: Two documents were developed: (1) fever/sepsis screening checklist and (2) blood culture decision algorithm. Clinicians consulted these documents when considering ordering blood cultures and for guidance about the culture source. Main Outcomes and Measures: Primary outcome was the total number of blood cultures collected per 100 patient days. Results: Of the 2204 children evaluated before the intervention, 1215 were male (55.1%); median (interquartile range) age was 5 (1-13) years. Postintervention analysis included 2356 children; 1262 were male (53.6%) and median (interquartile range) age was 6 (1-13) years. A total of 1807 blood cultures were drawn before the intervention during 11 196 patient-days; 984 cultures were drawn after the intervention during 11 204 patient-days (incidence rate, 16.1 vs 8.8 cultures per 100 patient-days). There was a 46.0% reduction after the intervention in the blood culture collection rate (incidence rate ratio, 0.54; 95% CI, 0.50-0.59). After the intervention, there was an immediate 25.0% reduction in the rate of cultures per 100 patient-days (95% CI, 4.2%-39.7%; P = .02) and a sustained 6.6% (95% CI, 4.7%-8.4%; P < .001) monthly decrease in the rate of cultures per 100 patient-days. Significantly fewer cultures were collected from central venous catheters after vs before the intervention (389 [39.5%] vs 1321 [73.1%]; P < .001). Rates of episodes defined as suspected infection and suspected septic shock decreased significantly after the intervention, but patients meeting these criteria underwent cultures at unchanged frequencies before vs after the intervention (52.1% vs 47.0%, P = .09, compared with 56.7% vs 55.0%, P = .75). In-hospital mortality (45 [2.0] vs 37 [1.6]; P = .23) and hospital readmissions (107 [4.9] vs 103 [4.4]; P = .42) were unchanged after the intervention. Conclusions and Relevance: A systematic approach to blood cultures decreased the total number of cultures and central venous catheter cultures, without an increase in rates of mortality, readmission, or episodes of suspected infection and suspected septic shock. PMID- 27942706 TI - The Role of Categorical Speech Perception and Phonological Processing in Familial Risk Children With and Without Dyslexia. AB - Purpose: This study assessed whether a categorical speech perception (CP) deficit is associated with dyslexia or familial risk for dyslexia, by exploring a possible cascading relation from speech perception to phonology to reading and by identifying whether speech perception distinguishes familial risk (FR) children with dyslexia (FRD) from those without dyslexia (FRND). Method: Data were collected from 9-year-old FRD (n = 37) and FRND (n = 41) children and age-matched controls (n = 49) on CP identification and discrimination and on the phonological processing measures rapid automatized naming, phoneme awareness, and nonword repetition. Results: The FRD group performed more poorly on CP than the FRND and control groups. Findings on phonological processing align with the literature in that (a) phonological processing related to reading and (b) the FRD group showed the lowest phonological processing outcomes. Furthermore, CP correlated weakly with reading, but this relationship was fully mediated by rapid automatized naming. Conclusion: Although CP phonological skills are related to dyslexia, there was no strong evidence for a cascade from CP to phonology to reading. Deficits in CP at the behavioral level are not directly associated with dyslexia. PMID- 27942707 TI - Language Change. PMID- 27942708 TI - Dementia Research-A Roadmap for the Next Decade. PMID- 27942709 TI - Addressing Unmet Basic Resource Needs as Part of Chronic Cardiometabolic Disease Management. AB - Importance: It is unclear if helping patients meet resource needs, such as difficulty affording food, housing, or medications, improves clinical outcomes. Objective: To determine the effectiveness of the Health Leads program on improvement in systolic and diastolic blood pressure (SBP and DBP, respectively), low-density lipoprotein cholesterol (LDL-C) level, and hemoglobin A1c (HbA1c) level. Design, Setting, and Participants: A difference-in-difference evaluation of the Health Leads program was conducted from October 1, 2012, through September 30, 2015, at 3 academic primary care practices. Health Leads consists of screening for unmet needs at clinic visits, and offering those who screen positive to meet with an advocate to help obtain resources, or receive brief information provision. Main Outcomes and Measures: Changes in SBP, DBP, LDL-C level, and HbA1c level. We compared those who screened positive for unmet basic needs (Health Leads group) with those who screened negative, using intention-to treat, and, secondarily, between those who did and did not enroll in Health Leads, using linear mixed modeling, examining the period before and after screening. Results: A total of 5125 people were screened, using a standardized form, for unmet basic resource needs; 3351 screened negative and 1774 screened positive. For those who screened positive, the mean age was 57.6 years and 1811 (56%) were women. For those who screened negative, the mean age was 56.7 years and 909 (57%) were women. Of 5125 people screened, 1774 (35%) reported at least 1 unmet need, and 1021 (58%) of those enrolled in Health Leads. Median follow-up for those who screened positive and negative was 34 and 32 months, respectively. In unadjusted intention-to-treat analyses of 1998 participants with hypertension, the Health Leads group experienced greater reduction in SBP (differential change, -1.2; 95% CI, -2.1 to -0.4) and DBP (differential change, -1.0; 95% CI, -1.5 to 0.5). For 2281 individuals with an indication for LDL-C level lowering, results also favored the Health Leads group (differential change, -3.7; 95% CI -6.7 to 0.6). For 774 individuals with diabetes, the Health Leads group did not show HbA1c level improvement (differential change, -0.04%; 95% CI, -0.17% to 0.10%). Results adjusted for baseline demographic and clinical differences were not qualitatively different. Among those who enrolled in Health Leads program, there were greater BP and LDL-C level improvements than for those who declined (SBP differential change -2.6; 95% CI,-3.5 to -1.7; SBP differential change, -1.4; 95% CI, -1.9 to -0.9; LDL-C level differential change, -6.3; 95% CI, -9.7 to -2.8). Conclusions and Relevance: Screening for and attempting to address unmet basic resource needs in primary care was associated with modest improvements in blood pressure and lipid, but not blood glucose, levels. PMID- 27942710 TI - Orthography and Modality Influence Speech Production in Adults and Children. AB - Purpose: The acquisition of literacy skills influences the perception and production of spoken language. We examined if orthography influences implicit processing in speech production in child readers and in adult readers with low and high reading proficiency. Method: Children (n = 17), adults with typical reading skills (n = 17), and adults demonstrating low reading proficiency (n = 18) repeated or read aloud nonwords varying in orthographic transparency. Analyses of implicit linguistic processing (segmental accuracy and speech movement stability) were conducted. The accuracy and articulatory stability of productions of the nonwords were assessed before and after repetition or reading. Results: Segmental accuracy results indicate that all 3 groups demonstrated greater learning when they were able to read, rather than just hear, the nonwords. Speech movement results indicate that, for adults with poor reading skills, exposure to the nonwords in a transparent spelling reduces the articulatory variability of speech production. Reading skill was correlated with speech movement stability in the groups of adults. Conclusions: In children and adults, orthography interacts with speech production; all participants integrate orthography into their lexical representations. Adults with poor reading skills do not use the same reading or speaking strategies as children with typical reading skills. PMID- 27942711 TI - Rural and Urban Differences in Neonatal Abstinence Syndrome and Maternal Opioid Use, 2004 to 2013. PMID- 27942712 TI - A New Standard for the Laboratory Diagnosis of Sporadic Creutzfeldt-Jakob Disease. PMID- 27942714 TI - Guideline-Based Prescribing in Frail Elderly Patients. PMID- 27942715 TI - Osteoporosis and Fracture Risk Evaluation and Management: Shared Decision Making in Clinical Practice. PMID- 27942713 TI - Association of beta-Blockers With Functional Outcomes, Death, and Rehospitalization in Older Nursing Home Residents After Acute Myocardial Infarction. AB - Importance: Although beta-blockers are a mainstay of treatment after acute myocardial infarction (AMI), these medications are commonly not prescribed for older nursing home residents after AMI, in part owing to concerns about potential functional harms and uncertainty of benefit. Objective: To study the association of beta-blockers after AMI with functional decline, mortality, and rehospitalization among long-stay nursing home residents 65 years or older. Design, Setting, and Participants: This cohort study of nursing home residents with AMI from May 1, 2007, to March 31, 2010, used national data from the Minimum Data Set, version 2.0, and Medicare Parts A and D. Individuals with beta-blocker use before AMI were excluded. Propensity score-based methods were used to compare outcomes in people who did vs did not initiate beta-blocker therapy after AMI hospitalization. Main Outcomes and Measures: Functional decline, death, and rehospitalization in the first 90 days after AMI. Functional status was measured using the Morris scale of independence in activities of daily living. Results: The initial cohort of 15 720 patients (11 140 women [70.9%] and 4580 men [29.1%]; mean [SD] age, 83 [8] years) included 8953 new beta-blocker users and 6767 nonusers. The propensity-matched cohort included 5496 new users of beta-blockers and an equal number of nonusers for a total cohort of 10 992 participants (7788 women [70.9%]; 3204 men [29.1%]; mean [SD] age, 84 [8] years). Users of beta blockers were more likely than nonusers to experience functional decline (odds ratio [OR], 1.14; 95% CI, 1.02-1.28), with a number needed to harm of 52 (95% CI, 32-141). Conversely, beta-blocker users were less likely than nonusers to die (hazard ratio [HR], 0.74; 95% CI, 0.67-0.83) and had similar rates of rehospitalization (HR, 1.06; 95% CI, 0.98-1.14). Nursing home residents with moderate or severe cognitive impairment or severe functional dependency were particularly likely to experience functional decline from beta-blockers (OR, 1.34; 95% CI, 1.11-1.61 and OR, 1.32; 95% CI, 1.10-1.59, respectively). In contrast, little evidence of functional decline due to beta-blockers was found in participants with intact cognition or mild dementia (OR, 1.03; 95% CI, 0.89-1.20; P = .03 for effect modification) or in those in the best (OR, 0.99; 95% CI, 0.77 1.26) and intermediate (OR, 1.05; 95% CI, 0.86-1.27) tertiles of functional independence (P = .06 for effect modification). Mortality benefits of beta blockers were similar across all subgroups. Conclusions and Relevance: Use of beta-blockers after AMI is associated with functional decline in older nursing home residents with substantial cognitive or functional impairment, but not in those with relatively preserved mental and functional abilities. Use of beta blockers yielded a considerable mortality benefit in all groups. PMID- 27942716 TI - Prioritizing Pediatric Surgical Conditions-A Call to Go Beyond Operations, Cost, and Comparative Effectiveness Research. PMID- 27942717 TI - Chest Pain and Supplemental Oxygen: Too Much of a Good Thing? PMID- 27942719 TI - Feasibility study: protein denaturation and coagulation monitoring with speckle variance optical coherence tomography. AB - We performed the feasibility study using speckle variance optical coherence tomography (SvOCT) to monitor the thermally induced protein denaturation and coagulation process as a function of temperature and depth. SvOCT provided the depth-resolved image of protein denaturation and coagulation with microscale resolution. This study was conducted using egg white. During the heating process, as the temperature increased, increases in the speckle variance signal was observed as the egg white proteins coagulated. Additionally, by calculating the cross-correlation coefficient in specific areas, denaturized egg white conditions were successfully estimated. These results indicate that SvOCT could be used to monitor the denaturation process of various proteins. PMID- 27942718 TI - Diagnosis of Human Prion Disease Using Real-Time Quaking-Induced Conversion Testing of Olfactory Mucosa and Cerebrospinal Fluid Samples. AB - Importance: Early and accurate in vivo diagnosis of Creutzfeldt-Jakob disease (CJD) is necessary for quickly distinguishing treatable from untreatable rapidly progressive dementias and for future therapeutic trials. This early diagnosis is becoming possible using the real-time quaking-induced conversion (RT-QuIC) seeding assay, which detects minute amounts of the disease-specific pathologic prion protein in cerebrospinal fluid (CSF) or olfactory mucosa (OM) samples. Objective: To develop an algorithm for accurate and early diagnosis of CJD by using the RT-QuIC assay on CSF samples, OM samples, or both. Design, Setting, and Participants: In this case-control study, samples of CSF and OM were collected from 86 patients with a clinical diagnosis of probable (n = 51), possible (n = 24), or suspected (n = 11) CJD and 104 negative control samples (54 CSF and 50 OM). The CSF and OM samples were analyzed using conventional RT-QuIC. The CSF samples underwent further testing using improved RT-QuIC conditions. In addition, the diagnostic performance of a novel, easy-to-use, gentle flocked swab for sampling of OM was evaluated. Data were collected from January 1 to June 30, 2015. Main Outcome and Measures: Correlations between RT-QuIC results and the final diagnosis of recruited patients. Results: Among the 86 patients (37 men [43%] and 49 women [57%]; mean [SD] age, 65.7 [11.5] years) included for analysis, all 61 patients with sporadic CJD had positive RT-QuIC findings using OM or CSF samples or both for an overall RT-QuIC diagnostic sensitivity of 100% (95% CI, 93%-100%). All patients with a final diagnosis of non-prion disease (71 CSF and 67 OM samples) had negative RT-QuIC findings for 100% specificity (95% CI, 94%-100%). Of 8 symptomatic patients with various mutations causing CJD or Gerstmann-Straussler-Scheinker syndrome, 6 had positive and 2 had negative RT QuIC findings for a sensitivity of 75% (95% CI, 36%-96%). Conclusions and Relevance: A proposed diagnostic algorithm for sporadic CJD combines CSF and OM RT-QuIC testing to provide virtually 100% diagnostic sensitivity and specificity in the clinical phase of the disease. PMID- 27942720 TI - Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. AB - Importance: Although levodopa remains the most effective oral pharmacotherapy for Parkinson disease (PD), its use is often limited by wearing off effect and dyskinesias. Management of such complications continues to be a significant challenge. Objective: To investigate the efficacy and safety of safinamide (an oral aminoamide derivative with dopaminergic and nondopaminergic actions) in levodopa-treated patients with motor fluctuations. Design, Setting, and Participants: From March 5, 2009, through February 23, 2012, patients from academic PD care centers were randomized (1:1 ratio) to receive double-blind adjunctive safinamide or placebo for 24 weeks. All patients had idiopathic PD with "off" time (time when medication effect has worn off and parkinsonian features, including bradykinesia and rigidity, return) of greater than 1.5 hours per day (excluding morning akinesia). Their pharmacotherapy included oral levodopa plus benserazide or carbidopa in a regimen that had been stable for 4 weeks or longer. During screening, each patient's regimen was optimized to minimize motor fluctuations. Study eligibility required that after 4 weeks of optimized treatment, the patients still have more than 1.5 hours per day of off time. Adverse events caused the premature study discontinuation of 12 individuals (4.4%) in the safinamide group and 10 individuals (3.6%) in the placebo group. Interventions: Patients took safinamide or placebo as 1 tablet daily with breakfast. If no tolerability issues arose by day 14, the starting dose, 50 mg, was increased to 100 mg. Main Outcomes and Measures: The prespecified primary outcome was each treatment group's mean change from baseline to week 24 (or last "on" treatment value) in daily "on" time (relief of parkinsonian motor features) without troublesome dyskinesia, as assessed from diary data. Results: At 119 centers, 549 patients were randomized (mean [SD] age, 61.9 [9.0] years; 334 male [60.8%] and 371 white [67.6%]): 274 to safinamide and 275 to placebo. Among them, 245 (89.4%) receiving safinamide and 241 (87.6%) receiving placebo completed the study. Mean (SD) change in daily on time without troublesome dyskinesia was +1.42 (2.80) hours for safinamide, from a baseline of 9.30 (2.41) hours, vs +0.57 (2.47) hours for placebo, from a baseline of 9.06 (2.50) hours (least-squares mean difference, 0.96 hour; 95% CI, 0.56-1.37 hours; P < .001, analysis of covariance). The most frequently reported adverse event was dyskinesia (in 40 [14.6%] vs 15 [5.5%] and as a severe event in 5 [1.8%] vs 1 [0.4%]). Conclusions and Relevance: The outcomes of this trial support safinamide as an effective adjunct to levodopa in patients with PD and motor fluctuations to improve on time without troublesome dyskinesia and reduce wearing off. Trial Registration: clinicaltrials.gov Identifier NCT00627640. PMID- 27942721 TI - Gradually Progressive Spastic Ataxia in a Young Man: Steadily Unsteady. AB - A 26-year-old right-handed man presented with progressive gait imbalance over 6 years. His examination was consistent with cerebellar and upper motor neuronal dysfunction. He had no significant family history. Most of the serum and cerebrospinal fluid studies were unremarkable. Neuroimaging was remarkable for mild cerebellar and noticeable thoracic spinal cord atrophy. The initial differential diagnosis for the patient's presentation was broad, but because of certain clinical characteristics, it was later focused on hereditary ataxias. Detailed analysis of the clinical features in the history, neurologic examination, and neuroimaging studies led to the diagnosis. PMID- 27942723 TI - Erratum. PMID- 27942724 TI - Macular Vascular Flow Area and Vascular Density in Healthy Population Using Optical Coherence Tomography Angiography. PMID- 27942722 TI - A Period of Controlled Elevation of IOP (CEI) Produces the Specific Gene Expression Responses and Focal Injury Pattern of Experimental Rat Glaucoma. AB - Purpose: We determine if several hours of controlled elevation of IOP (CEI) will produce the optic nerve head (ONH) gene expression changes and optic nerve (ON) damage pattern associated with early experimental glaucoma in rats. Methods: The anterior chambers of anesthetized rats were cannulated and connected to a reservoir to elevate IOP. Physiologic parameters were monitored. Following CEI at various recovery times, ON cross-sections were graded for axonal injury. Anterior ONHs were collected at 0 hours to 10 days following CEI and RNA extracted for quantitative PCR measurement of selected messages. The functional impact of CEI was assessed by electroretinography (ERG). Results: During CEI, mean arterial pressure (99 +/- 6 mm Hg) and other physiologic parameters remained stable. An 8 hour CEI at 60 mm Hg produced significant focal axonal degeneration 10 days after exposure, with superior lesions in 83% of ON. Message analysis in CEI ONH demonstrated expression responses previously identified in minimally injured ONH following chronic IOP elevation, as well as their sequential patterns. Anesthesia with cannulation at 20 mm Hg did not alter these message levels. Electroretinographic A- and B-waves, following a significant reduction at 2 days after CEI, were fully recovered at 2 weeks, while peak scotopic threshold response (pSTR) remained mildly but significantly depressed. Conclusions: A single CEI reproduces ONH message changes and patterns of ON injury previously observed with chronic IOP elevation. Controlled elevation of IOP can allow detailed determination of ONH cellular and functional responses to an injurious IOP insult and provide a platform for developing future therapeutic interventions. PMID- 27942725 TI - Targeting Unmet Social Needs-Next Steps Toward Improving Chronic Disease Management. PMID- 27942726 TI - Adult Utilization of Psychiatric Drugs and Differences by Sex, Age, and Race. PMID- 27942727 TI - Quantifying the Burden of Interhospital Cost Variation in Pediatric Surgery: Implications for the Prioritization of Comparative Effectiveness Research. AB - Importance: Practice variation is believed to be a driver of excess health care spending, although few objective data exist to guide the prioritization of comparative effectiveness research (CER) in pediatric surgery. Objective: To identify high-priority general pediatric surgical procedures for CER on the basis of the following 2 complementary measures: the magnitude of interhospital cost variation as a surrogate for the need for and potential effect of CER at the patient level and the cumulative fiscal burden of this cost variation when considering the case volume from all hospitals as a surrogate for public health relevance. Design, Setting, and Participants: This was a cohort study of patients undergoing 1 of the 30 most costly pediatric surgical operations at 45 children's hospitals between January 1, 2014, and September 30, 2015. Cost data were extracted from the Pediatric Health Information System database and adjusted for differences in unit-based costing at the hospital level and for differences in case mix and disease severity at the patient level. Main Outcomes and Measures: First, the width of the interquartile range (WIQR) of the adjusted procedure specific median cost across hospitals. Second, the procedure-specific cost variation burden, which was calculated as the aggregate sum of absolute cost differences between the overall adjusted median cost derived from all patients treated at all hospitals and the adjusted cost of each individual patient treated at all hospitals. Results: A total of 92 535 encounters were analyzed. The median number of encounters per hospital was 2011 (interquartile range [IQR], 1224 2619), and the median number of encounters per procedure was 610 (IQR, 442-2610). In the final cohort, 66.9% (n = 61 933) of the patients were male, and the median age was 7 years (IQR, 1.9-12.3 years). Cost variation at the hospital level was greatest for gastroschisis (WIQR, $48 471; median, $111 566 [IQR, $91 195-$139 936]), congenital diaphragmatic hernia (WIQR, $43 948; median, $154 730 [IQR, $129 764-$173 712]), tracheoesophageal fistula/esophageal atresia (WIQR, $39 206; median, $105 259 [IQR, $87 335-$126 541]), and total colectomy for ulcerative colitis (WIQR, $24 497; median, $34 910 [IQR, $28 815-$53 312]). The following 5 diagnoses accounted for 52.5% of the cumulative cost variation burden from all 30 conditions: uncomplicated appendicitis (18.0% [$66 205 117]), complicated appendicitis (14.1% [$51 702 402]), gastroschisis (9.5% [$34 940 331]), gastrostomy (5.8% [$21 227 436]), and small-intestinal atresia (5.1% [$18 840 546]). Neonatal cases contributed 3.6% of the case volume and accounted for 26.8% of the cumulative cost variation burden from all 30 conditions. Conclusions and Relevance: A small number of procedures account for most of the cost variation burden in pediatric surgery, with some demonstrating wide cost variation among hospitals. Gastroschisis and small-intestinal atresia may be particularly high yield targets for multidisciplinary CER efforts, while the management of appendicitis and gastrostomy should be considered high-priority conditions among pediatric surgeons. PMID- 27942729 TI - Why Oxygen Is Not Necessary for All STEMIs. PMID- 27942728 TI - Sex and Race Differences in the Association Between Statin Use and the Incidence of Alzheimer Disease. AB - Importance: To our knowledge, no effective treatments exist for Alzheimer disease, and new molecules are years away. However, several drugs prescribed for other conditions have been associated with reducing its risk. Objective: To analyze the association between statin exposure and Alzheimer disease incidence among Medicare beneficiaries. Design, Setting, and Participants: We examined the medical and pharmacy claims of a 20% sample of Medicare beneficiaries from 2006 to 2013 and compared rates of Alzheimer disease diagnosis for 399 979 statin users 65 years of age or older with high or low exposure to statins and with drug molecules for black, Hispanic, and non-Hispanic white people, and men and women of Asian, Native American, or unkown race/ethnicity who are referred to as "other." Main Outcomes and Measures: The main outcome was incident diagnosis of Alzheimer disease based on the International Classification of Diseases, Ninth Revision, Clinical Modification. We used Cox proportional hazard models to analyze the association between statin exposure and Alzheimer disease diagnosis for different sexes, races and ethnicities, and statin molecules. Results: The 399 979 study participants included 7794 (1.95%) black men, 24 484 (6.12%) black women, 11 200 (2.80%) Hispanic men, 21 458 (5.36%) Hispanic women, 115 059 (28.77%) white men, and 195 181 (48.80%) white women. High exposure to statins was associated with a lower risk of Alzheimer disease diagnosis for women (hazard ratio [HR], 0.85; 95% CI, 0.82-0.89; P<.001) and men (HR, 0.88; 95% CI, 0.83 0.93; P<.001). Simvastatin was associated with lower Alzheimer disease risk for white women (HR, 0.86; 95% CI, 0.81-0.92; P<.001), white men (HR, 0.90; 95% CI, 0.82-0.99; P=.02), Hispanic women (HR, 0.82; 95% CI, 0.68-0.99; P=.04), Hispanic men (HR, 0.67; 95% CI, 0.50-0.91; P=.01), and black women (HR, 0.78; 95% CI, 0.66 0.93; P=.005). Atorvastatin was associated with a reduced risk of incident Alzheimer disease diagnosis for white women (HR, 0.84, 95% CI, 0.78-0.89), black women (HR, 0.81, 95% CI, 0.67-0.98), and Hispanic men (HR, 0.61, 95% CI, 0.42 0.89) and women (HR, 0.76, 95% CI, 0.60-0.97). Pravastatin and rosuvastatin were associated with reduced Alzheimer disease risk for white women only (HR, 0.82, 95% CI, 0.70-0.95 and HR, 0.81, 95% CI, 0.67-0.98, respectively). High statin exposure was not associated with a statistically significant lower Alzheimer disease risk among black men. Conclusions and Relevance: The reduction in Alzheimer disease risk varied across statin molecules, sex, and race/ethnicity. Clinical trials that include racial and ethnic groups need to confirm these findings. Because statins may affect Alzheimer disease risk, physicians should consider which statin is prescribed to each patient. PMID- 27942733 TI - Obscured by administrative data? Racial disparities in occupational injury. AB - Objectives Underreporting of occupational injuries is well documented, but underreporting patterns may vary by worker characteristics, obscuring disparities. We tested for racial and ethnic differences in injury reporting patterns by comparing injuries reported via research survey and administrative injury database in the same group of healthcare workers in the US. Methods We used data from a cohort of 1568 hospital patient-care workers who were asked via survey whether they had been injured at work during the year prior (self-reported injury; N=244). Using the hospital's injury database, we determined whether the same workers had reported injuries to the hospital's occupational health service during that year (administratively reported injury; N=126). We compared data sources to test for racial and ethnic differences in injury reporting practices. Results In logistic regression models adjusted for demographic and occupational characteristics, black workers' odds of injury as measured by self-report data were 1.91 [95% confidence interval (95% CI) 1.04-3.49] compared with white workers. The same black workers' odds of injury as measured by administrative data were 1.22 (95% CI 0.54-2.77) compared with white workers. Conclusions The undercount of occupational injuries in administrative versus self-report data may be greater among black compared to white workers, leading to underestimates of racial disparities in workplace injury. PMID- 27942735 TI - Total Humeral Endoprosthesis Replacement to Salvage Periprosthetic Fractures in Rheumatoid Arthritis. AB - The authors report their experience in the management of a 53-year-old woman with rheumatoid arthritis who presented with bilateral asynchronous traumatic periprosthetic fractures of the humerus after bilateral elbow replacements. One side was treated with a long-stem revision and internal fixation with bone graft, while the other side was treated with a long-stem distal humeral replacement. She sustained pathological periprosthetic fractures on top of the long-stemmed implants. Total humeral endoprosthesis replacements were performed bilaterally as salvage procedures to provide a stable platform for her elbow and hand function. At manuscript submission, the patient was 24 months and 36 months postoperatively on the left and right sides, respectively. Her Oxford Shoulder Scores were 21 (left side) and 24 (right side). There is little information about the management of periprosthetic fractures of the humerus after long-stem revisions with severe bone loss. To the best of the authors' knowledge, this is the first case report describing the use of bilateral total humeral endoprosthesis replacements in the management of complex unstable periprosthetic fractures. This is a valuable treatment option for patients with poor bone quality, bone loss, and loose components. [Orthopedics. 2017; 40(2):e363-e366.]. PMID- 27942734 TI - The impact of reduced worktime on sleep and perceived stress - a group randomized intervention study using diary data. AB - Objective Insufficient time for recovery between workdays may cause fatigue and disturbed sleep. This study evaluated the impact of an intervention that reduced weekly working hours by 25% on sleep, sleepiness and perceived stress for employees within the public sector. Method Participating workplaces (N=33) were randomized into intervention and control groups. Participants (N=580, 76% women) worked full-time at baseline. The intervention group (N=354) reduced worktime to 75% with preserved salary during 18 months. Data were collected at baseline and after 9 and 18 months follow-up. Sleep quality, sleep duration, sleepiness, perceived stress,and worries and stress at bedtime were measured with diary during one week per data collection. Result A multilevel mixed model showed that compared with the control group, at the 18-month follow-up, the intervention group had improved sleep quality and sleep duration (+23 minutes) and displayed reduced levels of sleepiness, perceived stress, and worries and stress at bedtime on workdays (P<0.002). The same effects were shown for days off (P<0.006), except for sleep length. Effect sizes were small (Cohen's f2<0.08). Adding gender, age, having children living at home, and baseline values of sleep quality and worries and stress at bedtime as additional between-group factors did not influence the results. Conclusion A 25% reduction of weekly work hours with retained salary resulted in beneficial effects on sleep, sleepiness and perceived stress both on workdays and days off. These effects were maintained over an 18-month period. This randomized intervention thus indicates that reduced worktime may improve recovery and perceived stress. PMID- 27942736 TI - The Doubled-Suture Nice Knot. AB - The authors describe a novel suture fixation technique that combines a doubled suture with a sliding knot. The knot can be tied in both open and arthroscopic surgery to fix torn tendons/ligaments and fractured/osteotomized bones. The advantages of the doubled-suture Nice knot include strength, adjustability, simplicity, and versatility. This technique, which has proven useful in the authors' practice for the past 10 years, has replaced metallic wires and cables for bone fixation. The doubled-suture Nice knot can also be tied over a double button and has been used for ankle syndesmosis, acromioclavicular joint separation repair, and coracoid bone block fixation. [Orthopedics. 2017; 40(2):e382-e386.]. PMID- 27942737 TI - Prothrombin Complex Concentrates: An Alternative to Fresh Frozen Plasma. AB - Insufficiency fractures are a common cause of morbidity among geriatric patients worldwide. Improved outcomes are known to result from decreased delay to definitive operative fixation and mobilization. Use of warfarin is an important potential cause of delay. The ideal mode of warfarin reversal is currently unknown. Prothrombin complex concentrates (PCCs) offer rapid correction with small infusion volume, both of which are important for elderly patients with multiple comorbidities. The authors present 2 cases of insufficiency fractures occurring in geriatric patients receiving warfarin therapy reversed with a 3 factor PCC. Both patients were independent, community ambulators without significant functional disability and returned to their prior level of functioning. There were no significant bleeding or venous thromboembolic complications. To the authors' knowledge, no previous reports have described the use of PCC in geriatric patients with fractures. Nonetheless, its potential is well documented in emergency and trauma surgery literature. The use of PCC could potentially allow surgeons and hospitals to avoid complications related to immobility and the associated costs of treatment, extended hospital stay, and readmission. The authors' limited experience suggests 3-factor PCC preparations may provide adequate correction to allow expeditious surgical treatment. [Orthopedics. 2017; 40(2):e367-e369.]. PMID- 27942738 TI - Anterior Approach in Total Hip Replacement. AB - In total hip replacement, the anterior approach is intermuscular and internervous and allows the surgeon to reach the capsule without muscle detachment. Advantages include faster recovery and excellent functional outcome as well as reduced postoperative pain and hospital stay. Experienced surgeons currently performing total hip replacement should be aware of all of the difficulties associated with this procedure as well as all of the tricks to overcome the most challenging steps in order to reduce complications during the learning curve. The authors present the most crucial steps in total hip replacement through the anterior approach and describe the potential pitfalls and solutions. [Orthopedics. 2017; 40(3):e553-e556.]. PMID- 27942739 TI - Predictors of Inpatient Mortality and Systemic Complications in Acetabular Fractures Requiring Operative Treatment. AB - Patient demographics, physiologic variables, and injury characteristics predictive of mortality and major systemic complications following operative fixation of acetabulum fractures were identified using the National Sample Program of the National Trauma Data Bank. Age older than 60 years, obesity, and Injury Severity Score greater than 15 portended a statistically significant increase in mortality and major systemic complications (P<=.05). Systolic blood pressure less than 90 mm Hg and Glasgow Coma Scale score less than 8 were also significant predictors of mortality and major systemic complications (P<.0001). Time to surgery and hospital length of stay did not affect mortality. The most common potentially modifiable risk factors were smoking (22.3%) and obesity (body mass index >=30 kg/m2) (9.1%). Increasing age, Injury Severity Score, and obesity independently predicted a statistically significant increase in both mortality and major systemic complications. A better understanding of the associated risk factors and unique complication profile will provide orthopedic surgeons with a basis on which to effectively counsel and care for patients. [Orthopedics. 2017; 40(2):e223-e228.]. PMID- 27942740 TI - Primary Ankle Arthrodesis for Severely Comminuted Tibial Pilon Fractures. AB - Management of severely comminuted, complete articular tibial pilon fractures (Ruedi and Allgower type III) remains a challenge, with few treatment options providing good clinical outcomes. Twenty patients with severely comminuted tibial pilon fractures underwent primary ankle arthrodesis with a retrograde calcaneal nail and autogenous fibular bone graft. The fusion rate was 100% and the varus malunion rate was 10%. Fracture union occurred at a mean of 16 weeks (range, 13 18 weeks) postoperatively. Primary ankle arthrodesis is a successful method for treating highly comminuted tibial pilon fractures, having a low complication rate and a high satisfaction score. [Orthopedics. 2017; 40(2):e378-e381.]. PMID- 27942741 TI - Interpretation of amperometric kinetics of content release during contacts of vesicles with a lipid membrane. AB - The exocytotic pathway of secretion of molecules from cells includes transport by vesicles, tether-mediated fusion of vesicles with the plasma membrane accompanied by pore formation, and diffusion-mediated release of their contents via a pore to the outside. In related basic biophysical studies, vesicle-content release is tracked by measuring corresponding amperometric spikes. Although experiments of this type have a long history, the understanding of the underlying physics is still elusive. The present study elucidates the likely contribution of line energy, membrane tension and bending, osmotic pressure, hydration forces, and tethers to the potential energy for fusion-related pore formation and evolution. The overdamped Langevin equation is used to describe the pore dynamics, which are in turn employed to calculate the kinetics of content release and to interpret the shape of amperometric spikes. PMID- 27942742 TI - Health and social determinants of health in Vietnam: local evidence and international implications. PMID- 27942743 TI - Reduction of antimicrobial use and resistance needs sectoral-collaborations with a One Health approach: perspectives from Asia. PMID- 27942744 TI - Which long-term illnesses do patients find most limiting? A census-based cross sectional study of 340,000 people. AB - OBJECTIVES: To investigate associations between a widely used measure of self assessed health (limiting long-term illness, LLTI) and 11 long-term health conditions. METHODS: Information on LLTI and health conditions was obtained from 2011 Census returns for a 28% representative sample of the Northern Ireland population (n = 342,868). Logistic regression was used to predict LLTI by sex and age group for each condition found in isolation, adjusting for marital status, social class, household car access, housing tenure, and educational attainment. The relationship between limitation and multimorbidity was also assessed. RESULTS: Prevalence of LLTI varied considerably among conditions when found in isolation; those with mobility problems were over 50 times more likely to report limitation than those with hearing loss. Women were less likely to report limitation than men [OR = 0.93 (0.90, 0.96)], but the pattern of associations with health conditions was similar for both sexes. Prevalence of LLTI increased with age and number of health conditions. CONCLUSIONS: LLTI was most closely associated with mobility problems. Limitation increased slightly with age, but patterns of LLTI across conditions were not sex dependent. PMID- 27942745 TI - Long-term trends of inequalities in mortality in 6 European countries. AB - OBJECTIVES: We aimed to assess whether trends in inequalities in mortality during the period 1970-2010 differed between Finland, Norway, England and Wales, France, Italy (Turin) and Hungary. METHODS: Total and cause-specific mortality data by educational level and, if available, occupational class were collected and harmonized. Both relative and absolute measures of inequality in mortality were calculated. RESULTS: In all countries except Hungary, all-cause mortality declined strongly over time in all socioeconomic groups. Relative inequalities in all-cause mortality generally increased, but more so in Hungary and Norway than elsewhere. Absolute inequalities often narrowed, but went up in Hungary and Norway. As a result of these trends, Hungary (where inequalities in mortality where almost absent in the 1970s) and Norway (where inequalities in the 1970s were among the smallest of the six countries in this study) now have larger inequalities in mortality than the other four countries. CONCLUSIONS: While some countries have experienced dramatic setbacks, others have made substantial progress in reducing inequalities in mortality. PMID- 27942746 TI - Building leadership capacity to prevent and control noncommunicable diseases: evaluation of an international short-term training program for program managers from low- and middle-income countries. AB - OBJECTIVES: To assess the impact of a 1-week training seminar jointly developed and conducted by the World Health Organization and the University Institute of Social and Preventive Medicine of Lausanne targeting senior policy-makers in low- and middle-income countries on public health aspects of noncommunicable diseases (NCDs). METHODS: A short qualitative questionnaire was emailed to all participants to one of the nine seminars organized between 2010 and 2015. RESULTS: From the 195 participants from 96 different countries, 122 (63%) completed the questionnaire. Among them, 87% reported that the seminar made a positive contribution to their professional development and 48% said it helped strengthening their national NCD program. All respondents remained directly or indirectly involved in NCD work. A frequent suggestion was that similar seminars are developed in their region or country. CONCLUSIONS: The evaluation strongly suggests that this short-term seminar had positive impact on both participants' personal development and the organization they worked for. There is a demand for organizing similar seminars at regional/country levels to support NCD prevention and control programs. PMID- 27942747 TI - Evictions and short-term all-cause mortality: a 3-year follow-up study of a middle-aged Swedish population. AB - OBJECTIVES: This study sets out to explore whether being forcibly removed from one's home is related to all-cause mortality. METHODS: With the help of unique register data covering all middle-aged persons registered at the Swedish Enforcement Authority with a case closed by an eviction during the period 2009 2011 (n = 2092), evictees' deaths from any cause that occurred within 3 years of the date of the eviction are compared with the all-cause mortality of a random sample of the Swedish population (n = 426,117). The analysis is based on penalized maximum likelihood logistic regressions. RESULTS: Those who had been evicted from their homes were found to be approximately one and a half times more likely to die from any cause than those who had not been exposed to this experience (OR = 1.59), controlling for several demographic, socio-economic and health conditions prior to the date of the eviction. CONCLUSIONS: The results provide support for the notion that the experience of losing one's dwelling place should be treated as a major life event in its own right, just like other well established social stressors. PMID- 27942749 TI - The role of dietary carbohydrates in organismal aging. AB - Carbohydrates are essential nutrients that are used as a primary source of energy. Carbohydrate utilization should be properly controlled, as abnormal regulation of carbohydrate metabolism is associated with diseases, such as diabetes, cardiovascular diseases, and stroke. These metabolic syndromes have become a serious problem in developed countries, and there is an increased need for research examining the influence of carbohydrates on animal physiology. Diets enriched in glucose, a major carbohydrate, are also associated with accelerated aging in several model organisms, including yeast and Caenorhabditis elegans (C. elegans). Genetic factors that mediate the effects of high glucose diets on aging have been identified during the last decade, mostly through the use of C. elegans. In this review, we describe studies that determine the effects of carbohydrate-enriched diets on aging by focusing on the mechanisms through which evolutionarily conserved pathways mediate the lifespan-altering effects of glucose in C. elegans. These include the insulin/insulin-like growth factor-1, sterol-regulatory element-binding protein, and AMP-activated protein kinase signaling pathways. We also discuss the effects of various carbohydrates and carbohydrate-derived metabolites on aging in model organisms and cultured mammalian cells. Finally, we discuss how dietary carbohydrates influence health and aging in humans. PMID- 27942751 TI - A sphingosine 1-phosphate receptor agonist ameliorates animal model of vasculitis. AB - OBJECTIVES: Sphingosine 1-phosphate (S1P) is a bioactive lipid that binds to cell surface receptors (S1P1-5). In this study, we examined the effect of S1P1 agonist, ONO-W061, on murine Candida albicans water-soluble fraction (CAWS) induced vasculitis. METHODS: Mice were administered ONO-W061, and the number of peripheral blood cells was counted. Vasculitis was induced by an intraperitoneal injection of CAWS. Expression of S1P receptors and CXCL1 was analyzed by quantitative RT-PCR. ONO-W061 was orally administered, and vasculitis was evaluated histologically. Number of neutrophils, macrophages and T cells in the vasculitis tissue was counted using flow cytometry. Production of chemokines from S1P-stimulated human umbilical vein endothelial cells (HUVECs) was measured by ELISA. RESULTS: Number of peripheral blood lymphocytes was decreased by ONO-W061. Expression of CXCL1 and S1P1 was enhanced in CAWS-induced vasculitis tissue. Vasculitis score, CXCL1 and number of neutrophils in the vasculitis tissue were lower in ONO-W061-treated mice. Treatment of HUVECs with S1P upregulated the production of CXCL1 and IL-8 in vitro, and this was inhibited by ONO-W061. CONCLUSIONS: ONO-W061 significantly improved CAWS-induced vasculitis. This effect may be partly exerted through the inhibited production of chemokines by endothelial cells, which in turn could induce neutrophil recruitment into inflamed vessels. PMID- 27942752 TI - Participation in organized leisure-time activities and risk behaviors in Czech adolescents. AB - OBJECTIVES: The study aimed to assess the associations between participation in organized leisure-time activities (OLTA) and risk behaviors, and whether the associations differed by gender, age, and pattern of OLTA involvement. METHODS: Data from the 2013/2014 Health Behaviour in School-Aged Children study on 10,279 11-, 13-, and 15-year-old Czech adolescents (49.2% boys) were used. We assessed the associations between OLTA participation and risk behaviors, and modification by age and gender. RESULTS: OLTA participants were less likely to smoke, get drunk repeatedly, or skip school and, in contrast, more likely to get injured and fight repeatedly. The associations with lower occurrence of risk behaviors were the strongest for artists, while none was significant for adolescents participating only in team sports. Girls participating in OLTA had lower odds to smoke, get drunk, or skip school than boys, and these boys had higher odds to get injured or fight. CONCLUSIONS: OLTA participation is associated with lower occurrence of repeated substance use and truancy and inversely with higher odds for physical fights and injuries. Girls, in general, are at lower risk when participating in OLTA than boys. PMID- 27942750 TI - The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome. AB - Sterile inflammation is a cornerstone of immune activation in obesity and type 2 Diabetes Mellitus. The molecular underpinnings of this inflammation include nutrient excess-mediated activation of the innate immune NLRP3 inflammasome. At the same time, disruption of mitochondrial integrity is emerging as an integral control node in NLRP3 inflammasome activation and is also associated with caloric overload conditions including obesity and diabetes. Conversely, caloric restriction and fasting mimetic interventions alleviate these caloric excess linked diseases and reduce inflammation and the NLRP3 inflammasome. The objective of this review is to integrate the findings linking mitochondrial integrity to the activation of the NLRP3 inflammasome and to evaluate how caloric restriction or caloric restriction mimetic compounds may play a role in attenuating the NLRP3 inflammasome and sterile inflammation. PMID- 27942748 TI - Complement factor H in host defense and immune evasion. AB - Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune response in coordination with innate and adaptive immunity. When activated, the complement system unleashes powerful cytotoxic and inflammatory mechanisms, and thus its tight control is crucial to prevent damage to host tissues and allow restoration of immune homeostasis. Factor H is the major soluble inhibitor of complement, where its binding to self markers (i.e., particular glycan structures) prevents complement activation and amplification on host surfaces. Not surprisingly, mutations and polymorphisms that affect recognition of self by factor H are associated with diseases of complement dysregulation, such as age-related macular degeneration and atypical haemolytic uremic syndrome. In addition, pathogens (i.e., non-self) and cancer cells (i.e., altered-self) can hijack factor H to evade the immune response. Here we review recent (and not so recent) literature on the structure and function of factor H, including the emerging roles of this protein in the pathophysiology of infectious diseases and cancer. PMID- 27942753 TI - Cyanophycinase CphE from P. alcaligenes produced in different compartments of N. benthamiana degrades high amounts of cyanophycin in plant extracts. AB - One of the major constraints in pig and poultry farming is the supply of protein rich forage, containing sufficient amounts of key amino acids such as arginine (Ufaz and Galili 2008). Since these are underrepresented in plant proteins, the usage of plants as feed is limited. The heterologous production of the cyanobacterial storage polymer cyanophycin granule polypeptide (CGP) in plastids increases the amount of arginine substantially (Huhns et al. 2008; Huhns et al. 2009; Nausch et al. 2016a). CGP degradation releases arginine-aspartate dipeptides. CGP is stable in plants because its degradation is exclusively restricted to bacterial cyanophycinases (CGPases; Law et al. 2009). Since animals are also unable to digest CGP, CGPases need to be co-delivered with CGP containing plant feed in order to release the dipeptides in the gastrointestinal tract of animals during digestion. Therefore, an extracellular CGPase, CphE from Pseudomonas alcaligenes DIP-1, was targeted to the cytosol, ER, and apoplasm of Nicotiana benthamiana. Translocation to the chloroplast was not successful. Although CphE accumulated in high amounts in the cytosol, only moderate levels were present in the ER, while the enzyme was nearly undetectable in the apoplasm. This correlates with the higher instability of post-translationally modified CphE in crude plant extracts. In addition, the production in the ER led to an increased number and size of necroses compared with cytosolic expression and might therefore interfere with the endogenous metabolism in the ER. Due to the high and robust enzyme activity, even moderate CphE concentrations were sufficient to degrade CGP in plant extracts. PMID- 27942754 TI - A copper-responsive promoter replacement system to investigate gene functions in Trichoderma reesei: a case study in characterizing SAGA genes. AB - Trichoderma reesei represents an important workhorse for industrial production of cellulases as well as other proteins. The molecular mechanism underlying the regulation of cellulase production as well as other physiological processes in T. reesei is still insufficiently understood. We constructed a P tcu1 -based promoter substitution cassette that allowed one-step replacement of the endogenous promoter for controlling the target gene expression with copper. We then showed that copper repression of the histone acetyltransferase gene gcn5 phenocopied the gcn5 deletion strain. Using the same strategy, we further characterized the function of another putative Spt-Ada-Gcn5 acetyltransferase (SAGA) complex subunit encoding gene, ada2, in T. reesei. Similar to the repression of gcn5, the addition of copper to the P tcu1 -ada2 strain not only drastically reduced the vegetative growth and conidiation in T. reesei but also severely compromised the induced cellulase gene expression. The developed strategy will thus be potentially useful to probe the biological function of the large fraction of T. reesei genes with unknown functions including those essential genes in the genome to expand its extraordinary biotechnological potential. PMID- 27942755 TI - Tyramine-modified pectins via periodate oxidation for soybean hull peroxidase induced hydrogel formation and immobilization. AB - Pectin was modified by oxidation with sodium periodate at molar ratios of 2.5, 5, 10, 15 and 20 mol% and reductive amination with tyramine and sodium cyanoborohydride afterwards. Concentration of tyramine groups within modified pectin ranged from 54.5 to 538 MUmol/g of dry pectin while concentration of ionizable groups ranged from 3.0 to 4.0 mmol/g of dry polymer compared to 1.5 mmol/g before modification due to the introduction of amino group. All tyramine pectins showed exceptional gelling properties and could form hydrogel both by cross-linking of carboxyl groups with calcium or by cross-linking phenol groups with peroxidase in the presence of hydrogen peroxide. These hydrogels were tested as carriers for soybean hull peroxidase (SHP) immobilization within microbeads formed in an emulsion based enzymatic polymerization reaction. SHP immobilized within tyramine-pectin microbeads had an increased thermal and organic solvent stability compared to the soluble enzyme. Immobilized SHP was more active in acidic pH region and had slightly decreased K m value of 2.61 mM compared to the soluble enzyme. After 7 cycles of repeated use in batch reactor for pyrogallol oxidation microbeads, immobilized SHP retained half of the initial activity. PMID- 27942756 TI - Quorum sensing-disrupting coumarin suppressing virulence phenotypes in Vibrio splendidus. AB - In the present study, the effects of an environmental friendly natural reagent coumarin, on the growth and potential virulence factors, as well as its ability to interfere the infection of Vibrio splendidus (Vs), were determined. Coumarin showed no effects on the maximal growth of Vs, and biofilm formation of Vs, while it significantly decreased protease activity and hemolytic activity by 43 and 80%, respectively. Correspondingly, coumarin exhibited an obviously protective effect, with a relative percent survival of 60% upon Apostichopus japonicus from infection by Vs. To preliminarily investigate the mechanism underlining the inhibitory effects, regulation of genes Vsm and Vsh respectively related to protease activity and hemolytic activity by supernatant and supernatant extract containing acyl-homoserine lactones (AHLs) and coumarin was determined. Cell-free supernatant from higher density and its ethyl acetate extract containing AHL signal molecules could respectively upregulate the mRNA level of Vsm by 17.4- and 2.3-fold and Vsh by 7.2- and 5.0-fold, when Vs was at lower cell density. However, coumarin could reduce the stimulatory effects of both the supernatant and its ethyl acetate extract. Combining all the results in our study, it was suggested that coumarin could be considered as an alternative to be used for controlling infection of Vs, downregulating the expression of potential virulence factors through interfering the AHL-mediated pathways. PMID- 27942757 TI - Functional dissection of the N-terminal sequence of Clostridium sp. G0005 glucoamylase: identification of components critical for folding the catalytic domain and for constructing the active site structure. AB - Clostridium sp. G0005 glucoamylase (CGA) is composed of a beta-sandwich domain (BD), a linker, and a catalytic domain (CD). In the present study, CGA was expressed in Escherichia coli as inclusion bodies when the N-terminal region (39 amino acid residues) of the BD was truncated. To further elucidate the role of the N-terminal region of the BD, we constructed N-terminally truncated proteins (Delta19, Delta24, Delta29, and Delta34) and assessed their solubility and activity. Although all evaluated proteins were soluble, their hydrolytic activities toward maltotriose as a substrate varied: Delta19 and Delta24 were almost as active as CGA, but the activity of Delta29 was substantially lower, and Delta34 exhibited little hydrolytic activity. Subsequent truncation analysis of the N-terminal region sequence between residues 25 and 28 revealed that truncation of less than 26 residues did not affect CGA activity, whereas truncation of 26 or more residues resulted in a substantial loss of activity. Based on further site-directed mutagenesis and N-terminal sequence analysis, we concluded that the 26XaaXaaTrp28 sequence of CGA is important in exhibiting CGA activity. These results suggest that the N-terminal region of the BD in bacterial GAs may function not only in folding the protein into the correct structure but also in constructing a competent active site for catalyzing the hydrolytic reaction. PMID- 27942758 TI - Translation-dependent bioassay for amino acid quantification using auxotrophic microbes as biocatalysts of protein synthesis. AB - Bioassay for amino acid quantification is an important technology for a variety of fields, which allows for easy, inexpensive, and high-throughput analyses. Here, we describe a novel translation-dependent bioassay for the quantification of amino acids. For this, the gene encoding firefly luciferase was introduced into Lactococcus lactis auxotrophic to Glu, His, Ile, Leu, Pro, Val, and Arg. After a preculture where luciferase expression was repressed, the cells were mixed with analytes, synthetic medium, and an inducer for luciferase expression. Luminescence response to the target amino acid appeared just after mixing, and linear standard curves for these amino acids were obtained during 15-60-min incubation periods. The rapid quantification of amino acids has neither been reported in previous works on bioassays nor is it theoretically feasible with conventional methods, which require incubation times of more than 4 h to allow for the growth of the microbe used. In contrast, our assay was shown to depend on protein translation, rather than on cell growth. Furthermore, replacement of the luciferase gene with that of the green fluorescent protein (GFP) or beta galactosidase allowed for fluorescent and colorimetric detection of the amino acids, respectively. Significantly, when a Gln-auxotrophic Escherichia coli mutant was created and transformed by a luciferase expression plasmid, a linear standard curve for Gln was observed in 15 min. These results demonstrate that this methodology can provide versatile bioassays by adopting various combinations of marker genes and host strains according to the analytes and experimental circumstances. PMID- 27942759 TI - Integrating health technology assessment requirements in the clinical development of medicines: the experience from NICE scientific advice. AB - PURPOSE: The primary objective of the study was to analyse the proposed clinical development and economic evaluation plans for investigational medicinal products for which pharmaceutical companies have sought health technology assessment (HTA) scientific advice (SA). METHODS: We have selected and analysed all the scientific advice procedures undertaken by National Institute for Health and Care Excellence (NICE) SA between 1 January 2009 and 3 December 2015 for investigational medicinal products. We have mapped the questions asked by the companies and the areas of advice highlighted in the advice reports to the sections of the NICE methods guide to the technology appraisals (2013). RESULTS: An overwhelming proportion of SA procedures have addressed questions related to the clinical development and specifically the main pivotal efficacy studies. Approximately a quarter of the questions relate to the approaches to economic evaluation. Questions raised in European Medicines Agency-HTA procedures generally focus on clinical efficacy issues whereas cost-effectiveness ones tend to dominate in NICE only procedures. Our analysis shows that the issues mostly discussed in the HTA SA are the choice of comparator, the generalisability of the clinical trial evidence to the NHS practice and the impact of the clinical trial outcomes on quality of life and survival. Less disagreement with the developers' plans was seen in the choice of clinical endpoints, population definition, position of the technology in the treatment pathway and study design. CONCLUSIONS: Scientific advice is designed to improve the quality of evidence and approaches to evidence generation for future regulatory approval and HTA evaluation. Our experience to date suggests that payer requirements are inconsistently integrated in the clinical development programmes. More efforts should be dedicated to demonstrating the clinical value of new medicinal products to patients and key decision-makers. PMID- 27942760 TI - Multivariate Analyses of Heavy Metals in Surface Soil Around an Organized Industrial Area in Eskisehir, Turkey. AB - A total of 50 surface industrial area soil in Eskisehir, Turkey were collected and the concentrations of As, Cr, Cd, Co, Cu, Ni, Pb, Zn, Fe and Mg, at 11.34, 95.8, 1.37, 15.28, 33.06, 143.65, 14.34, 78.79 mg/kg, 188.80% and 78.70%, respectively. The EF values for As, Cu, Pb and Zn at a number of sampling sites were found to be the highest among metals. Igeo-index results show that the study area is moderately polluted with respect to As, Cd, Ni. According to guideline values of Turkey Environmental Quality Standard for Soils, there is no problem for Pb, but the Cd values are fairly high. However, Cr, Cu, Ni and Zn values mostly exceed the limits. Cluster analyses suggested that soil the contaminator values are homogenous in those sub classes. The prevention and remediation of the heavy metal soil pollution should focus on these high-risk areas in the future. PMID- 27942761 TI - HAND1 Loss-of-Function Mutation Causes Tetralogy of Fallot. AB - As the most prevalent form of birth defect in humans worldwide, congenital heart disease (CHD) is responsible for substantial morbidity and is still the leading cause of birth defect-related demises. Increasing evidence demonstrates that genetic defects play an important role in the pathogenesis of CHD, and mutations in multiple genes, especially in those coding for cardiac core transcription factors, have been causally linked to various CHDs. Nevertheless, CHD is a genetically heterogeneous disease and the genetic determinants underpinning CHD in an overwhelming majority of patients remain elusive. In the current study, genomic DNA was extracted from venous blood samples of 165 unrelated patients with CHD, and the coding exons and splicing junction sites of the HAND1 gene, which encodes a basic helix-loop-helix transcription factor essential for cardiovascular development, were sequenced. As a result, a novel heterozygous mutation, p.R118C, was identified in a patient with tetralogy of Fallot (TOF). The missense mutation, which was absent in 600 referential chromosomes, altered the amino acid that was completely conserved evolutionarily. Biological assays with a dual-luciferase reporter assay system revealed that the R118C-mutant HAND1 protein had significantly reduced transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation significantly decreased the synergistic activation of a downstream target gene between HAND1 and GATA4, another cardiac core transcription factor associated with TOF. To our knowledge, this is the first report on the association of a HAND1 loss-of-function mutation with enhanced susceptibility to TOF in humans. The findings provide novel insight into the molecular etiology underlying TOF, suggesting potential implications for the improved prophylactic and therapeutic strategies for TOF. PMID- 27942762 TI - Tricuspid Atresia with Non-compaction: An Early Experience with Implications for Surgical Palliation. AB - Left ventricle non-compaction (LVNC) has worse outcomes when associated with congenital heart defects (CHD). The co-occurrence and outcomes of LVNC with tricuspid atresia (TA) are not well described. Our study aims to determine the prevalence of LVNC with functionally single ventricle due to TA, and to describe the early outcomes of surgical palliation. A retrospective database search for patients (n = 167,566) and echocardiograms (n = 44,053) was performed in order to collect clinical, echocardiographic, and hemodynamic data of pediatric patients with TA and LVNC at St. Louis Children's Hospital, Missouri, USA, from January 1, 2008, to August 31, 2013. The prevalence of TA and LVNC was 0.015 and 0.08%, respectively. Eight patients with TA had LVNC (32%, group 1). Seventeen patients had only TA (68%, group 2). Five patients from group 1 and 8 patients from group 2 were surgically palliated with the Fontan procedure. They exhibited similar remodeling indices, and hemodynamics (median LV end-diastolic pressure <=10 mmHg; median mean pulmonary artery pressure <=15 mmHg) that allowed for completion of the Fontan procedure. All Fontan patients were in New York Heart Association class I after a 3-year (median) follow-up period. Our data show that TA with LVNC patients, who have acceptable cardiac remodeling indices, LV systolic function, and hemodynamics (LVEDP <= 10 mmHg, mean pulmonary artery pressure <= 15 mmHg) can have successful completion of the Fontan procedure and positive early outcomes. PMID- 27942763 TI - Changes in movement organization and control strategies when learning a biomechanically constrained gait pattern, racewalking: a PCA study. AB - Combining advances from gait analysis and motor learning fields, this study aims to examine invariant characteristics and practice-related changes in the control of walking gait when learning a biomechanically constrained pattern, racewalking (RW). RW's regulation imposes a straightened knee at the stance phase which differentiates it qualitatively from normal walking. Using 3D motion analysis, we computed key kinematic variables from a whole-body model. Principal component analysis was then used as a tool to evaluate the evolution of normal walking synergies (S0) immediately at the first practice session (S1) and further with practice (S1-S4). Before the start of practice, normal walking was characterized by two predominant control dimensions explaining an upper-extremities/antero posterior component (PC1) and a lower-extremities/vertical component (PC2). Compared to normal walking, the immediate increase at S1 in the number of PCs needed to explain a significant portion of movement variance could be suggestive of a recruitment of a task-specific component. With practice, the significant decrease in the variance accounted for by PC1 and in the correlations between many variables could indicate a destabilization of spontaneous tendencies to facilitate the adoption of more task-specific coordinative pattern. PC2 seemed to be reinforced with practice where a significant increase in its explained variance was observed. In sum, this study shows that common features in the gait control are preserved with practice, and the movement reorganization, however, seems rather defined by shifts in the relative contribution of some variables within each PC. PMID- 27942765 TI - Stochastic phenotypic interconversion in tumors can generate heterogeneity. AB - Phenotype variations define heterogeneity in biological and molecular systems, and play a crucial mechanistic role, and heterogeneity has been demonstrated in tumor cells. In this work, cells from blood of patients affected by colon cancer were analyzed and sorted using a microfluidic assay based on galactose-active moieties and incubated for culturing in severe combined immunodeficiency (SCID) mice. Based on the results of these experiments, a model based on Markov theory is implemented and discussed to explain the equilibrium existing between phenotypes of cell subpopulations sorted using the microfluidic assay. In combination with the experimental results, the model has many implications for tumor heterogeneity; For example, it displays interconversion of phenotypes, confirming the experiments. Such interconversion generates metastatic cells and implies that targeting circulating tumor cells (CTC) will not be an efficient method for prevention of tumor recurrence. Most importantly, understanding the transitions between cell phenotypes in the cell population can improve understanding of tumor generation and growth. PMID- 27942764 TI - Increased inter-hemispheric resting-state functional connectivity in acute lacunar stroke patients with aphasia. AB - Aphasia is a devastating neurological condition affecting a person's ability to communicate and reintegrate into the society. It may occur in 20% or more of patients after stroke. The recovery of language function is accompanied by brain reorganization, and identifying the inter-hemispheric interaction post-stroke will conduce to more targeted treatments. Previous studies suggested that robust homotopic resting-state functional connectivity is a key characteristic of the brain's intrinsic functional architecture, and communication between the left and right cerebral hemispheres is important for language processing. In this study, voxel-mirrored homotopic connectivity (VMHC) was used to examine the inter hemispheric resting-state functional connectivity (RSFC) differences between 37 patients with acute lacunar stroke in the left hemisphere and 28 healthy controls. Besides, correlation analyses were carried out to investigate the relationship between VMHC values of brain regions showing abnormal inter hemispheric RSFC and clinical variables [i.e., aphasia quotient (AQ) scores, National Institutes of Health Stroke Scale (NIHSS) and Mini-Mental State Examination of patients]. Compared with healthy controls, patients showed significantly increased VMHC in the pars orbitalis of the inferior frontal gyrus, anterior part of the superior temporal gyrus (STG) and lingual gyrus. No brain region showed decreased VMHC in the patient group than in the healthy control group. The AQ scores were negatively correlated with VMHC values in the STG. NIHSS scores were positively correlated with VMHC values in the lingual gyrus. We hope these results could shed new insights into the pathology of aphasia in patients with acute lacunar stroke. PMID- 27942766 TI - Intensive Care Medicine in 2050: cost-effectiveness analysis. PMID- 27942767 TI - Erratum to: Bacterial Diversity Patterns Differ in Soils Developing in Sub tropical and Cool-Temperate Ecosystems. PMID- 27942769 TI - Sublethal Toxicity of Crude Oil Exposure in The Blue Crab, Callinectes sapidus, at Two Life History Stages. AB - The 2010 Deepwater Horizon oil spill occurred during peak spawning season for many Gulf of Mexico fish and invertebrates. Early life stages of important fishery species were at risk to encounter crude oil. In this study, we investigated the effect of crude oil exposure on two life stages of the blue crab (Callinectes sapidus). We tested the effects of oil exposure on the survival and growth of larval (pelagic) and juvenile (estuarine) blue crabs as well as the effects of oil on the molt frequency of juveniles. Larval crabs exposed to crude oil showed no discernable growth or mortality differences when compared to non exposed controls. Juvenile crabs exposed to oil also showed no differences in size but exhibited increased intermolt duration (time between molts). Our study suggests that different life-stages may respond differently when exposed to crude oil and that oil exposure negatively affects growth rate of juvenile blue crabs. PMID- 27942768 TI - Mechanical properties of different esthetic and conventional orthodontic wires in bending tests : An in vitro study. AB - AIMS: The goal of this study was to determine the mechanical properties of different esthetic and conventional orthodontic wires in three-point and four point bending tests, and in a biomechanical test employing three bracket systems. METHODS: The behavior of round wires with a diameter of 0.46 mm (0.018") were investigated: uncoated nickel titanium (NiTi) wires, surface modified NiTi wires; FLI(r) Orthonol Wire(r) and glass fiber reinforced plastic wires. The biomechanical bending test was performed using the following bracket types: metal brackets (Discovery(r), Dentaurum), ceramic brackets (Fascination(r), Dentaurum), and plastic brackets (Elegance(r), Dentaurum). All bending tests were performed in the orthodontic measurement and simulation system (OMSS) at a temperature of 37 degrees C. The classical three-point bending test was performed according to an ISO standard (DIN EN ISO 15841:2007) using the appropriate thrust die and supports with a predefined span of 10 mm. In the other tests the supports or interbracket distances were chosen such that the free wire length was also 10 mm (5 mm between adjacent brackets). All wires were loaded centrally to a maximum of 3.1 and 3.3 mm in the biomechanical test, respectively. The force was measured upon unloading with a loading velocity of 1 mm/min. Each specimen was loaded twice and a total of 10 specimens tested for each product. Weighted means and the error of the weighted mean were calculated for each product. RESULTS: Fiber reinforced wires displayed lowest forces in three-point bending with values of 0.4 N at a displacement of 1 mm and 0.7 N at a 2 mm displacement. In four-point bending the forces were 0.9 N and 1.4 N, respectively, at the same displacements. Almost all of the translucent wires showed fracture upon bending at displacements greater than 3 mm, independent of the bending test and bracket type. The different investigated NiTi wires, surface modified or conventional, only showed minor variation, e.g., 2.2 N for rematitan(r) Lite White and 2.0 N for rematitan(r), 2.1 N for FLI(r) Coated Orthonol(r) and 1.7 N for Orthonol(r) in four-point bending. The rhodinized wire generated forces between these values (2.1 N). CONCLUSION: The translucent wires had the lowest forces in all three bending tests; however, displacements above 3 mm resulted in increased risk of fracture. Forces of investigated NiTi wires were very high and in part above clinically recommended values. PMID- 27942770 TI - Management of Unruptured Saccular Aneurysms of the M1 Segment with Flow Diversion : A Single Centre Experience. AB - PURPOSE: The optimal strategy for the treatment of M1 segment aneurysms has not yet been determined as both standard microneurosurgical and endovascular techniques can pose challenges. We sought to determine the efficacy of flow diverting stents to treat small, unruptured aneurysms of the M1 segment. METHODS: We retrospectively reviewed our database of prospectively collected information for all patients treated with flow diversion for an unruptured saccular aneurysm of the middle cerebral artery (MCA) between February 2009 and February 2016. The relationship to early cortical branches, aneurysm fundus size, number and type of flow diverting stent (FDS), complications and follow-up data were recorded. RESULTS: In total 15 patients were identified that matched our inclusion criteria (11 female and 4 male). The average age of the patients was 58.3 years (range 14 76 years). All patients had a single aneurysm affecting the M1 segment of the MCA, 10 (66.6%) of which were related to early cortical branches and 10 aneurysms were located on the left (66.6%). The average aneurysm fundus size was 3 mm (range 2-9 mm) and 13 patients had follow-up angiographic studies. In total, 8 aneurysms were completely excluded, and 6 remained incompletely occluded (3 modified Raymond-Roy classification [mRRC] II and 3 mRRC IIIa). One patient suffered a stroke and another patient had an iatrogenic vessel dissection that was not flow limiting. CONCLUSION: Flow diversion can be used to treat small, unruptured aneurysms of the M1 segment of the MCA and even though side vessel occlusion can occur clinically relevant infarction occurs infrequently. PMID- 27942771 TI - Evaluation of Cerebral Hyperperfusion After Carotid Artery Stenting Using C-Arm CT Measurements of Cerebral Blood Volume. AB - PURPOSE: Hyperperfusion syndrome (HPS) after carotid artery stenting (CAS) causes serious symptoms; therefore, early evaluation after CAS is considered to be important. Measurement of cerebral blood volume using C-arm computed tomography (C-arm CBV) has recently become possible. Here, the usefulness of C-arm CBV for the evaluation of hyperperfusion was investigated. METHODS: C-arm CBV was measured before and immediately after CAS in 30 patients. The regions of interest (ROI) were set in the bilateral middle cerebral artery perfused regions, and the affected/healthy side ratio of measured C-arm CBV (CBV ratios) was determined to evaluate cerebral perfusion. For comparing values before and after CAS, the CBV ratio increase rate (postoperative CBV ratios/preoperative CBV ratios) was also determined. RESULTS: C-arm CBV was successfully measured in 30 patients. Intracerebral hemorrhage (ICH) was detected in 3 patients, and no other patient had hyperperfusion syndrome. In the patients who developed ICH, postoperative C arm CBV on the affected side was high, and a marked increase was confirmed in the postoperative CBV ratios. Postoperative CBV ratios were 1.03 +/- 0.40 and 1.45 +/ 0.68 in the non-ICH and ICH groups, and CBV ratio increase rates were 2.7 +/- 24.0% and 28.5 +/- 26.7% in the non-ICH and ICH groups, respectively; these differences were statistically significant (P < 0.01). CONCLUSION: C-arm CT allows CBV measurements immediately after CAS without requiring transport of the patient out of the angiography room, and it may enable the evaluation of hyperperfusion before and after CAS. PMID- 27942773 TI - Vegetation type and layer depth influence nitrite-dependent methane-oxidizing bacteria in constructed wetland. AB - Nitrite-dependent anaerobic methane oxidation (n-damo) process might be an important methane sink in wetland system. However, information on n-damo microorganisms in constructed wetland (CW) system for water treatment is still lacking. The present study investigated the n-damo communities in five full-scale vertical-flow CW systems with different plants. N-damo bacterial abundance did not show a considerable shift in CW planted with Cyperus papyrus, but varied greatly in other CW systems. However, the evident vertical change of n-damo community diversity occurred in each CW system. These CW systems displayed the different vertical change trends for either n-damo community abundance or diversity. In addition, CW n-damo community structure could change with wetland layer depth. At a given wetland layer depth, the evident difference of n-damo community abundance, diversity and structure could be observed in the five different CW systems. Both wetland layer depth and vegetation type could contribute to the shift of n-damo bacterial abundance and community structure in CWs. PMID- 27942772 TI - Interleukin-19 contributes as a protective factor in experimental Th2-mediated colitis. AB - Inflammatory bowel disease results from chronic dysregulation of the mucosal immune system and aberrant activation of both the innate and adaptive immune responses. IL-19 is a member of the IL-10 family, and IL-10 plays an important role in inflammatory bowel disease. We have previously shown that IL-19 knockout mice are more susceptible to innate-mediated colitis. Next, we ask whether IL-19 contributes to T cells-mediated colitis. Here, we investigated the role of IL-19 in a mouse model of Th2 cell-mediated colitis. Inflammatory responses in IL-19 deficient mice were assessed using a Th2-mediated colitis induced by oxazolone. The colitis was evaluated by analyzing the body weight loss and histology of the colon. Lymph node cells were cultured in vitro to determine cytokine production. IL-19 knockout mice exacerbated oxazolone-induced colitis by stimulating the transport of inflammatory cells into the colon, and by increasing IgE production and the number of circulating eosinophil. The exacerbation of oxazolone-induced colonic inflammation following IL-19 knockout mice was accompanied by an increased production of IL-4 and IL-9, but no changes in the expression of IL-5 and IL-13 in lymph node cells. IL-19 plays an anti-inflammatory role in the Th2 mediated colitis model, suggesting that IL-19 may represent a potential therapeutic target for reducing colonic inflammation. PMID- 27942774 TI - Mapping and expression of genes associated with raspberry fruit ripening and softening. AB - KEY MESSAGE: QTL mapping identifies a range of underlying and unrelated genes with apparent roles in raspberry fruit ripening and softening that show characteristic developing fruit expression profiles. Fruit softening is an important agronomical trait that involves a complex interaction of plant cell processes. We have used both qualitative and quantitative scoring of fruit firmness, length, mass, and resistance to applied force to identify QTL in a raspberry mapping population. QTLs were located primarily on linkage group (LG) 3 with other significant loci on LG 1 and LG 5 and showed mostly additive effects between the two parents. The expression of key genes that underlie these QTLs with roles in cell-wall solubility, water uptake, polyamine synthesis, transcription, and cell respiration was tested across five stages of fruit development, from immature green to red ripe fruit, using real-time RT-qPCR. Gene expression patterns showed variable expression patterns across fruit development with a highly significant positive and negative correlation between genes, supporting precise regulation of expression of different cell processes throughout raspberry fruit development. Variable timing in expression was also found in some genes at different fruit development stages between soft and firm cultivars. Multiple processes have a role to play in fruit softening and this will require development of multiple marker combinations to genes that characterise raspberry fruit softening. PMID- 27942775 TI - An innovative SNP genotyping method adapting to multiple platforms and throughputs. AB - KEY MESSAGE: An innovative genotyping method designated as semi-thermal asymmetric reverse PCR (STARP) was developed for genotyping individual SNPs with improved accuracy, flexible throughputs, low operational costs, and high platform compatibility. Multiplex chip-based technology for genome-scale genotyping of single nucleotide polymorphisms (SNPs) has made great progress in the past two decades. However, PCR-based genotyping of individual SNPs still remains problematic in accuracy, throughput, simplicity, and/or operational costs as well as the compatibility with multiple platforms. Here, we report a novel SNP genotyping method designated semi-thermal asymmetric reverse PCR (STARP). In this method, genotyping assay was performed under unique PCR conditions using two universal priming element-adjustable primers (PEA-primers) and one group of three locus-specific primers: two asymmetrically modified allele-specific primers (AMAS primers) and their common reverse primer. The two AMAS-primers each were substituted one base in different positions at their 3' regions to significantly increase the amplification specificity of the two alleles and tailed at 5' ends to provide priming sites for PEA-primers. The two PEA-primers were developed for common use in all genotyping assays to stringently target the PCR fragments generated by the two AMAS-primers with similar PCR efficiencies and for flexible detection using either gel-free fluorescence signals or gel-based size separation. The state-of-the-art primer design and unique PCR conditions endowed STARP with all the major advantages of high accuracy, flexible throughputs, simple assay design, low operational costs, and platform compatibility. In addition to SNPs, STARP can also be employed in genotyping of indels (insertion deletion polymorphisms). As vast variations in DNA sequences are being unearthed by many genome sequencing projects and genotyping by sequencing, STARP will have wide applications across all biological organisms in agriculture, medicine, and forensics. PMID- 27942776 TI - Percutaneous guided biopsy for diagnosing suspected primary malignant bone tumors in pediatric patients: a safe, accurate, and cost-saving procedure. AB - BACKGROUND: Percutaneous biopsy is the reference diagnostic procedure for adult musculoskeletal tumors. Its place in pediatrics is controversial and open biopsy remains recommended. OBJECTIVE: To assess diagnostic performance and feasibility of percutaneous biopsy performed on children and young adults for suspected malignant bone tumors. MATERIALS AND METHODS: We conducted a 5-year retrospective study including patients <=21 years who underwent a bone biopsy for a suspected malignant bone tumor. We assessed diagnostic yield (percentage of analyzable biopsies), accuracy (percentage of accurate diagnoses among all analyzable biopsies) and efficacy (percentage of accurate diagnoses among all biopsies), costs, anesthetic requirements and sample availability for biomedical research. Patients diagnosed with an open biopsy were used to compare diagnostic performances, anesthetic requirements and costs. RESULTS: We included 90 percutaneous and 27 open biopsies in 117 patients. For percutaneous biopsy, diagnostic yield was 95.5% (95% confidence interval [CI] 88.8-98.7%), accuracy was 96.2% (95% CI 86.8-99.5%) and efficacy was 89.3% (95% CI 78.1-96.0%). There was no statistical difference with open biopsy (Fisher exact test, P > 0.05). Mean costs were reduced with percutaneous biopsy: ?1,937 (standard deviation [SD] ?2,408) versus ?6,362 (SD ?5,033; Mann-Whitney, P < 0.0001). Thirty-two of the 48 (67%) patients included in clinical trials and diagnosed with percutaneous biopsy had suitable samples for ancillary analyses. CONCLUSION: Percutaneous biopsy is a valid alternative to open biopsy for diagnosing pediatric and young adult primary malignant bone tumors. PMID- 27942777 TI - Comparison of peripheral quantitative computed tomography forearm bone density versus DXA in rheumatoid arthritis patients and controls. AB - : Rheumatoid arthritis (RA) has been associated with osteoporosis. Quantitative computed tomography (QCT) is capable of assessing bone density and composition. We found lower bone density in RA compared to controls. Age and RA duration influenced bone density. QCT may be useful to assess bone metabolism in RA. INTRODUCTION: RA is associated with generalized and periarticular osteoporosis. In addition to DXA that determines areal bone mineral density (BMD), peripheral QCT also detects volumetric BMD. QCT differentiates between total, trabecular, and cortical BMD. Here, we compared DXA and QCT in RA patients and healthy controls. METHODS: BMD of 57 female RA patients and 32 age-matched healthy female controls were assessed by DXA. QCT of the forearm ultradistal region was also performed. Densitometry data were correlated with age, disease duration, disease activity, serum CRP, and anti-CCP levels. RESULTS: Total bone density (310.4 +/- 79.7 versus 354.0 +/- 54.1 mg/cm3; p = 0.007) and attenuation (0.37 +/- 0.05 versus 0.40 +/- 0.03 1/cm; p = 0.001), trabecular density (157.6 +/- 57.0 versus 193.8 +/- 48.7 mg/cm3; p = 0.005) and attenuation (0.28 +/- 0.03 versus 0.32 +/- 0.04 1/cm; p < 0.0001), and cortical density (434.3 +/- 115.8 versus 492.5 +/- 64.0 mg/cm3; p = 0.006) and attenuation (0.44 +/- 0.07 versus 0.47 +/- 0.04 1/cm; p = 0.004) were significantly lower in RA. Both lumbar and femoral neck BMD, as well as T-scores, were significantly lower in RA versus controls (p < 0.001 in all cases). In RA, total and cortical QCT attenuation and density were associated with age, the presence of RA, and their combination. In contrast, trabecular density and attenuation were only affected by the presence of the disease but not by age. Also in RA, total trabecular and cortical density as determined by QCT significantly correlated with lumbar and/or femoral neck BMD as measured by DXA. Finally, anti-CCP seropositivity was associated with lower trabecular density and attenuation. CONCLUSIONS: Both DXA and QCT may be suitable to study bone metabolism in RA. Areal BMD determined by DXA may correlate with volumetric bone density measured by QCT. Moreover, trabecular osteoporosis may be associated by the underlying autoimmune-inflammatory disease, while cortical osteoporosis may rather be age-related. PMID- 27942778 TI - Novel mutations in the SEC24D gene in Chinese families with autosomal recessive osteogenesis imperfecta. AB - : We sought to characterize the phenotypes and identify the SEC24D gene mutations associated with Chinese families of osteogenesis imperfecta (OI). Using whole exome sequencing, we discovered two novel compound SEC24D mutations of OI patients. Our study extended both the phenotypic and the genotype of the OI patients with SEC24D mutations. INTRODUCTION: To date, only three compound heterozygous mutations in the SEC24D gene have been found to cause recessively inherited forms of OI. We sought to characterize the phenotypes and to identify the SEC24D gene mutations associated with Chinese families with OI. METHODS: Using whole-exome sequencing in two probands, we identified two novel compound heterozygous mutations in SEC24D. In family 1, the proband was a 23-year-old male; he had recurrent fractures and dentinogenesis imperfecta. His anterior fontanel was not closed, and he showed facial dysmorphism. A computed tomography three-dimensional imaging of the cranium showed skull deformities associated with a broad ossification defect in the frontoapical area, a widened sagittal suture, and Wormian bones. In family 2, the proband was a 7-year-old boy, who also had recurrent fractures and dentinogenesis imperfecta. His anterior fontanel was not closed, and he did not have obvious facial dysmorphism. RESULTS: We identified one novel compound heterozygous missense substitution in the proband in family 1, including c.2723G>A (p. Cys908Tyr) and c.2842T>C (p. Ser948Pro). In the proband in family 2, we identified another novel compound heterozygous missense substitution, including c.938G>A (p. Arg313His) and c.875C>T (p. Pro292Leu). CONCLUSIONS: We discovered two novel compound SEC24D mutations of autosomal recessive OI patients. Our study extended both the phenotypic and the genotypic spectrum of the autosomal recessive OI patients with SEC24D mutations. PMID- 27942779 TI - Assessing the impact of complications on the costs of Type II diabetes. AB - AIMS/HYPOTHESIS: 'The Cost of Diabetes in Europe-Type II (CODE-2) study' provides the first coordinated attempt to assess the total costs of managing people with Type II (non-insulin-dependent) diabetes mellitus in Europe. Type II diabetes is associated with a number of serious long-term complications, which are a major cause of morbidity, hospitalisation and mortality in diabetic patients. METHODS: Patients were divided into four broad categories defining their complication status in terms of no complications, one or more microvascular complications, one or more macrovascular complications or one or more of each microvascular and macrovascular complication. The prevalence of complications and associated costs were assessed retrospectively for 6 months. RESULTS: In total, 72% of patients in the CODE-2 study had at least one complication, with 19% having microvascular only, 10% having macrovascular only and 24% of the total having both microvascular and macrovascular complications. Of patients with microvascular complications, 28% had neuropathy, 20% renal damage, 20% retinopathy and 6.5% required treatment for eye complications. Among the patients with macrovascular complications, 18% had peripheral vascular disease, 17% angina, 12% heart failure and 9% had myocardial infarction. Percutaneous transluminal coronary angioplasty, coronary artery bypass graft or stroke occurred in 3%, 4% and 5% of the patients, respectively. In patients with both microvascular and macrovascular complications, the total cost of management was increased by up to 250% compared to those without complications. CONCLUSION/INTERPRETATION: Complications have a substantial impact on the costs of managing Type II diabetes. This study has confirmed that the prevention of diabetic complications will not only benefit patients, but potentially reduce overall healthcare expenditure. PMID- 27942780 TI - Coping with Type II diabetes: the patient's perspective. AB - AIMS/HYPOTHESIS: The Cost of Diabetes in Europe-Type II study is the first coordinated attempt to assess the total costs of Type II (non-insulin-dependent) diabetes mellitus in Europe. Although gaining a clearer understanding of the economics of diabetes was the goal of the study, a secondary objective was to consider the impact of Type II diabetes from the patient's perspective. METHODS: The protocol included a health status questionnaire completed by the patient, the EQ-5D instrument, which assessed health-related quality of life by asking the patient to consider five dimensions: mobility, self-care, usual activities, pain and discomfort, as well as anxiety and depression. RESULTS: A total of 4189 patients in five of the eight countries completed the EQ-5D questionnaire for assessing the quality of life. Overall, patients with Type II diabetes reported scores between good and fair states of health, although the average score (0.69) was lower than that of the similarly aged, healthy population in the United Kingdom. However, these values were higher (0.76) in Type II diabetic patients without complications. The onset of either microvascular or macrovascular complications adversely affected quality of life (0.69 and 0.69, respectively), and the presence of both types of complications further reduced the quality of life score to 0.59. Treatment with insulin was also associated with a reduced quality of life (0.62). Multivariate analysis showed that the following factors, in order of importance, independently pre-dict a poorer quality of life: gender, complications, treatment type, age, obesity and hyperglycaemia. CONCLUSION/INTERPRETATION: The results showed that health-related quality of life is an important issue in Type II diabetes and this decreases with disease progression. The implication for policy-makers is that reducing or preventing the complications of diabetes is the key to improving patient quality of life. PMID- 27942782 TI - Revealing the cost of Type II diabetes in Europe. AB - AIMS/HYPOTHESIS: 'The Cost of Diabetes in Europe-Type II study' is the first coordinated attempt to measure total healthcare costs of Type II (non-insulin dependent) diabetes mellitus in Europe. The study evaluated more than 7000 patients with Type II diabetes in eight countries - Belgium, France, Germany, Italy, the Netherlands, Spain, Sweden and the United Kingdom. METHODS: A bottom up, prevalence-based design was used, which optimised the collection of data at the national level while maintaining maximum international comparability. Effort was made to ensure consistency in terms of data specification, data collection tools and methods, sampling design, and the analysis and reporting of results. Results are reported for individual countries and in aggregate for the total study population. RESULTS: The total direct medical costs of Type II diabetes in the eight European countries was estimated at EUR 29 billion a year (1999 values). The estimated average yearly cost per patient was EUR 2834 a year. Of these costs, hospitalisations accounted for the greatest proportion (55%, range 30-65%) totalling EUR 15.9 billion for the eight countries. During the 6-month evaluation period, 13% of the Type II diabetic patients were hospitalised, with an average of 23 days in hospital projected annually. In contrast, drug costs for managing Type II diabetes were relatively low, with antidiabetic drugs and insulin accounting for only 7% of the total healthcare costs for Type II diabetes. CONCLUSION/INTERPRETATION: Type II diabetes mellitus is a common disease and the prevalence is expected to increase considerably in the future, especially in developing countries. Current comprehensive economic data on the costs of diabetes are required for policy decisions to optimise resource allocation and to evaluate different approaches for disease management. PMID- 27942781 TI - Evaluation of risk factors for development of complications in Type II diabetes in Europe. AB - AIMS/HYPOTHESIS: The Cost of Diabetes in Europe-Type II study is the first large coordinated attempt to measure the current standard of care and determine the costs of managing patients with Type II (non-insulin-dependent) diabetes mellitus. METHODS: The study evaluated glycaemic control, blood lipid levels and blood pressure, all of which are risk factors for complications. Records of these clinical characteristics were collected from over 7000 patients during the 6 month study period. RESULTS: The mean HbAlc value for the entire study population was 7.5%, ranging from 7.0% in Sweden to 7.8% in the United Kingdom. Only 31% of individuals achieved good glycaemic control (HbAlc<==6.5%) according to current European guidelines. Only 64% of the total study population were tested for HbAlc values at least once within the 6-month study period (ranging from 49% in Spain to 71% in the UK), although HbAlc testing every 3 months is recommended for all patients, by European Diabetes Policy Group guidelines. The majority of patients had borderline total cholesterol values, with a mean value of 5.7 mmol/1. Overall, 21% of patients were classified as having low risk cholesterol levels (<4.8 mmol/1). Good triglyceride levels (<1.7 mmol/1) were achieved by 47% of the total study population. During the study period, 81 % of patients had their blood pressure measured, with 35% and 53.3% of the patients reaching the recommended targets for systolic and diastolic blood pressure, respectively. CONCLUSION/INTERPRETATION: This study showed that a high proportion of patients with risk factors for diabetes-related complications are not adequately controlled. Improvements in disease management and monitoring are therefore required to ensure that guideline targets are met, thus reducing the long-term complications of Type II diabetes. PMID- 27942783 TI - [Practical training for paramedics : Transformation at the Leipzig University teaching hospital]. AB - BACKGROUND: The "Notfallsanitatergesetz" (the law pertaining to paramedics), which came into effect in January 2014, has fundamentally changed the training of health personnel in German prehospital emergency medicine. The apprenticeship now takes 3 years including 720 h of practical training in eligible hospitals. To date, however, there has been little experience of how the contents of the guidelines for practical training ("Ausbildungs- und Prufungsverordnung") can be reasonably applied in the teaching hospitals. METHODS: In a total of nine interdisciplinary working group meetings between October 2014 and June 2016, we developed a curriculum concerning the practical training of paramedics to implement the contents of the guidelines for practical training in a didactically and an organizationally meaningful way. RESULTS: The implementation of the practical training of paramedics is an excellent chance for the teaching hospitals to contribute to higher quality prehospital emergency medicine. Otherwise, the teaching hospitals face an organizational and personal effort that is not to be underestimated. Thus, a modular curriculum constitutes the possibility of standardizing practical training and simultaneously reducing the time and expenditure for the participating hospitals. CONCLUSION: The development of a unique curriculum for the practical training of paramedics may contribute to standardized, high-quality, and cost-efficient training. PMID- 27942784 TI - [Introduction of Prehospital Emergency Ultrasound into an Emergency Medical Service Area]. AB - BACKGROUND: Emergency ultrasound as part of the provision of emergency medical services using mobile devices offers great benefits regarding to some important questions related to the management of critically ill and injured patients in the prehospital situation where diagnostic resources are limited. The aim of this study is to determine whether the comprehensive introduction of prehospital emergency ultrasound examinations into a German Emergency Medical Services ("rescue services") area is both feasible and beneficial for patients. METHODS: All emergency physicians at a rural emergency physician base were trained in emergency ultrasound scanning techniques (FAST, FEEL, 14 h of instruction), followed by regular weekly training sessions of approximately 30 min. Over a period of 12 months, prehospital ultrasound examinations performed during emergency physician callouts at this base were documented and analysed. RESULTS: A total of 87 emergency ultrasound examinations were performed during 1343 callouts. Among these, focussed assessment with sonography for trauma (FAST) was performed in 35 patients (40.2%) and focused echocardiography in emergency life support (FEEL) in 41 patients (47.1%). In 11 patients (12.6%), ultrasound scans were performed for other indications (e. g. to rule out urinary tract obstruction in a case of flank pain). One trauma patient's life was saved by the decision to transport him to the nearest hospital and once there directly to the operating room, based on the ultrasound finding of significant free intra-abdominal fluid (ruptured spleen and liver). CONCLUSION: Prehospital emergency ultrasound can be introduced into an emergency medical service area as a diagnostic modality that provides benefits to patients. Emergency physicians have to be specifically trained and to participate in continuous education activities. Especially in rural areas with longer transport routes and journey times, the early diagnosis of for example massive intra-abdominal bleeding is critical for the patient's prognosis. PMID- 27942786 TI - [Ventilator-associated pneumonia (VAP) : A risk already at the time of anesthetic induction]. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is one of the most common and preventable infections in mechanically ventilated patients. It is associated with a high mortality rate. To prevent VAP, various strategies address this issue using "VAP-bundles", which are implemented in many intensive care units. The risk of acquiring VAP starts with the induction of anesthesia, strictly speaking at the time of intubation. This article considers measures to prevent VAP during general anesthesia in adult patients (>18 years). Procedures beyond standard hygienic precautions for VAP prevention are reviewed. METHODS: A literature search in different databases (PubMed, Cochrane, Ovid und CINAHL) over the last five years. RESULTS: Beyond standard hygienic precautions, microaspiration should be avoided to prevent VAP. During mechanical ventilation at least 5 cm H2O PEEP is advised. Continuous monitoring and adjustment of cuff pressure is necessary. All patients mechanically ventilated after general anesthesia for more than 24 h should be intubated with an ETT with a port for subglottic suctioning. PMID- 27942785 TI - [Factor XIII : Pharmacodynamic and pharmacokinetic characteristics]. AB - Factor XIII (FXIII) plays an important role in the field of blood coagulation. In the last decade, both congenital and acquired deficiencies have been investigated in clinical studies. FXIII is a versatile enzyme that leads to a covalent cross linking of fibrin fibrils at the end of the clotting cascade and supports platelet adhesion to the damaged sub-endothelium with the result of a mechanically stable clot.Symptoms of FXIII deficiencies vary within a broad spectrum from superficial skin bleeding episodes to severe, sometimes life threatening hemorrhage, requiring prophylactic or therapeutic replacement therapy.Since 1993 purified plasma-derived FXIII concentrate has been available in Germany, large parts of Europe and in the USA and Canada. The administration is conducted intravenously, and FXIII is immediately available in the plasma. The dosage should be determined by measuring actual plasma FXIII-activity. Repetitive application is possible, especially with regard to the mean half-time of 7.9 days.Administration is considered to be safe and effective, but there are some case reports, as with other coagulation factors, describing the appearance of inhibitory antibodies.This summary seeks to provide an insight into the principle pharmacokinetic and pharmacodynamic characteristics of plasma-derived FXIII concentrate, reviewing the current literature. For detailed use in clinical settings, the application of FXIII concentrate or substitution therapy with fresh frozen plasma, we therefore refer to current guidelines and significant studies that have been recently published. PMID- 27942787 TI - [Full-scale simulation in German medical schools and anesthesia residency programs : Status quo]. AB - BACKGROUND: Simulation has been increasingly used in medicine. In 2003 German university departments of anesthesiology were provided with a full-scale patient simulator, designated for use with medical students. Meanwhile simulation courses are also offered to physicians and nurses. Currently, the national model curriculum for residency programs in anesthesiology is being revised, possibly to include mandatory simulation training. OBJECTIVES: To assess the status quo of full-scale simulation training for medical school, residency and continuing medical education in German anesthesiology. METHODS: All 38 German university chairs for anesthesiology as well as five arbitrarily chosen non-university facilities were invited to complete an online questionnaire regarding their centers' infrastructure and courses held between 2010 and 2012. RESULTS: The overall return rate was 86 %. In university simulation centers seven non-student staff members, mainly physicians, were involved, adding up to a full-time equivalent of 1.2. All hours of work were paid by 61 % of the centers. The median center size was 100 m2 (range 20-500 m2), equipped with three patient simulators (1-32). Simulators of high or very high fidelity are available at 80 % of the centers. Scripted scenarios were used by 91 %, video debriefing by 69 %. Of the participating university centers, 97 % offered courses for medical students, 81 % for the department's employees, 43 % for other departments of their hospital, and 61 % for external participants. In 2012 the median center reached 46 % of eligible students (0-100), 39 % of the department's physicians (8-96) and 16 % of its nurses (0-56) once. For physicians and nurses from these departments that equals one simulation-based training every 2.6 and 6 years, respectively. 31 % made simulation training mandatory for their residents, 29 % for their nurses and 24 % for their attending physicians. The overall rates of staff ever exposed to simulation were 45 % of residents (8-90), and 30 % each of nurses (10-80) and attendings (0-100). Including external courses the average center trained 59 (4 271) professionals overall in 2012. No clear trend could be observed over the three years polled. The results for the non-university centers were comparable. CONCLUSIONS: Important first steps have been taken to implement full-scale simulation in Germany. In addition to programs for medical students courses for physicians and nurses are available today. To reach everyone clinically involved in German anesthesiology on a regular basis the current capacities need to be dramatically increased. The basis for that to happen will be new concepts for funding, possibly supported by external requirements such as the national model curriculum for residency in anesthesiology. PMID- 27942788 TI - Pan-European inter-laboratory studies on a panel of in vitro cytotoxicity and pro inflammation assays for nanoparticles. AB - The rapid development of nanotechnologies and increased production and use of nanomaterials raise concerns about their potential toxic effects for human health and environment. To evaluate the biological effects of nanomaterials, a set of reliable and reproducible methods and development of standard operating procedures (SOPs) is required. In the framework of the European FP7 NanoValid project, three different cell viability assays (MTS, ATP content, and caspase-3/7 activity) with different readouts (absorbance, luminescence and fluorescence) and two immune assays (ELISA of pro-inflammatory cytokines IL1-beta and TNF-alpha) were evaluated by inter-laboratory comparison. The aim was to determine the suitability and reliability of these assays for nanosafety assessment. Studies on silver and copper oxide nanoparticles (NPs) were performed, and SOPs for particle handling, cell culture, and in vitro assays were established or adapted. These SOPs give precise descriptions of assay procedures, cell culture/seeding conditions, NPs/positive control preparation and dilutions, experimental well plate preparation, and evaluation of NPs interference. The following conclusions can be highlighted from the pan-European inter-laboratory studies: Testing of NPs interference with the toxicity assays should always be conducted. Interference tests should be designed as close as possible to the cell exposure conditions. ATP and MTS assays gave consistent toxicity results with low inter-laboratory variability using Ag and CuO NPs and different cell lines and therefore, could be recommended for further validation and standardization. High inter-laboratory variability was observed for Caspase 3/7 assay and ELISA for IL1-beta and TNF alpha measurements. PMID- 27942789 TI - Evaluation of the automated MicroFlow(r) and MetaferTM platforms for high throughput micronucleus scoring and dose response analysis in human lymphoblastoid TK6 cells. AB - The use of manual microscopy for the scoring of chromosome damage in the in vitro micronucleus assay is often associated with user subjectivity. This level of subjectivity can be reduced by using automated platforms, which have added value of faster with high-throughput and multi-endpoint capabilities. However, there is a need to assess the reproducibility and sensitivity of these automated platforms compared with the gold standard of the manual scoring. The automated flow cytometry-based MicroFlow(r) and image analysis-based MetaferTM were used for dose response analyses in human lymphoblastoid TK6 cells exposed to the model clastogen, methyl methanesulfonate (MMS), aneugen, carbendazim, and the weak genotoxic carcinogen, ochratoxin A (OTA). Cells were treated for 4 or 30 h, with a 26- or 0-h recovery. Flow cytometry scoring parameters and the MetaferTM image classifier were investigated, to assess any potential differences in the micronucleus (MN) dose responses. Dose response data were assessed using the benchmark dose approach with chemical and scoring system set as covariate to assess reproducibility between endpoints. A clear increase in MN frequency was observed using the MicroFlow(r) approach on TK6 cells treated for 30 h with MMS, carbendazim and OTA. The MicroFlow(r)-based MN frequencies were comparable to those derived by using the MetaferTM and manual scoring platforms. However, there was a potential overscoring of MN with the MicroFlow(r) due to the cell lysis step and an underscoring with the MetaferTM system based on current image classifier settings. The findings clearly demonstrate that the MicroFlow(r) and MetaferTM MN scoring platforms are powerful tools for automated high-throughput MN scoring and dose response analysis. PMID- 27942790 TI - Is mirabegron equally as effective when used as first- or second-line therapy in women with overactive bladder? AB - INTRODUCTION AND HYPOTHESIS: No previous studies have investigated the efficacy of mirabegron 50 mg as the first-line therapy in OAB patients. Hence, the primary objective of this study was to evaluate the efficacy of mirabegron in treatment naive patients in comparison with those who had discontinued antimuscarinic therapy because of insufficient efficacy. METHODS: All consecutive women who had pure OAB symptoms (including urgency with or without urgency incontinence and frequency) for at least 3 months were considered for this study. Women were divided into two groups: women without any previous pharmacological treatment for OAB (group 1) and women with a previous history of failed antimuscarinics therapy (group 2). RESULTS: At 3-month follow-up, the objective results on the basis of the frequency-volume chart showed a significant improvement in both groups. Furthermore, a significant reduction in the Overactive Bladder Questionnaire Short Form (OABq-SF) score and in the Indevus Urgency Severity Scale (IUSS) questionnaire were reported in both groups. However, the improvement in objective and subjective outcomes was superior in group 1 to that in group 2. CONCLUSIONS: Mirabegron is efficacious in improving OAB symptoms in both naive patients and those who discontinued primary antimuscarinic therapy; however, its efficacy is superior when prescribed as first-line therapy. PMID- 27942791 TI - Accuracy and precision of a new portable ultrasound scanner, the Biocon-700, in residual urine volume measurement. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to examine the accuracy of a new portable abdominal ultrasound (US) machine (Biocon-700, Mcube Technology, Seoul, Korea) for measuring postvoid residual (PVR) urine. METHOD: One-hundred and twenty-five patients with voiding problems underwent PVR measurements, which were compared with the postvoid bladder volume measurements obtained by catheterization within 5 min in the same patients. Accuracy was assessed by comparing the two methods, and correlation coefficients were obtained. RESULT: The Pearson's correlation coefficient between PVR volume as measured by US and by catheterization was 0.872 (R 2 = 0.76). The mean difference was 23.59 +/- 37.32 ml (95% confidence interval, 17.5-30.65 ml), and the absolute scan error tended to increase with a greater amount of catheterized residual urine volume (R 2 = 0.49). CONCLUSIONS: Accuracy of the Biocon-700 scanner is as good as catheter assessments of residual volume and is therefore a sufficient alternative to catheterization for determining residual urine volume. PMID- 27942792 TI - Transvaginal uterosacral ligament hysteropexy: a video tutorial. AB - INTRODUCTION AND HYPOTHESIS: Uterine-sparing procedures could be attractive in patients concerned about fertility preservation and corporeal image changes. Transvaginal uterosacral ligaments (USLs) hysteropexy can provide a mesh-free technique for uterine suspension. This video is intended to serve as a tutorial for surgical steps. METHODS: A 38-year-old woman with symptomatic stage III POP desired preserving fertility. After proper counseling, the patient was admitted for vaginal hysteropexy through bilateral high USL suspension according to the featured technique. RESULTS: Prolapse repair was successfully achieved without complications. We had already published a series of 20 cases that confirmed that transvaginal USLs hysteropexy is a promising technique for correcting genital prolapse with uterus preservation. CONCLUSION: Transvaginal USLs hysteropexy provides a feasible technique for apical support without the use of prosthetic material. This procedure could be attractive to women who desire a uterine sparing surgical option. PMID- 27942794 TI - [IgG4-associated autoimmune diseases - radiological manifestation]. PMID- 27942793 TI - Pessary types and discontinuation rates in patients with advanced pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to investigate factors associated with long-term pessary use in patients with advanced pelvic organ prolapse (POP). METHODS: This was a retrospective chart review of patients with POP of stage >=2 managed with a pessary. Patients were excluded if the date of fitting or follow-up was unavailable. Long-term use was defined as more than 1 year. Patient demographics, pessary fitting, and follow-up visit dates were collected. The primary end point was the duration of use and the prognostic impact of pessary type. Secondary objectives addressed other influencing factors including age, estrogen use, and prolapse stage. The data were analyzed using SPSS version 21. RESULTS: The final analysis included 311 patients. The mean (+/- standard deviation, SD) duration of pessary use was 7.0 +/- 0.72 years (median 5.7 years). Long-term use was found in 76 % (164) of these patients. Factors associated with longer use were age >65 years (p = 0.004) and estrogen use (p = 0.048). The estimated mean (+/- SD) durations of use of the Gellhorn, open ring, ring with support, cube and donut pessaries were 10.5 +/- 0.7 years, 3.4 +/- 0.6 years, 1.8 +/- 0.2 years, 1.8 +/- 0.3 years and 1.7 +/- 0.5 years, respectively. The Gellhorn pessary was associated with significantly longer use than other pessary types (10.5 +/- 0.7, p < 0.0000001); this finding was independent of age, prolapse stage, hysterectomy, and vaginal estrogen use. CONCLUSIONS: In this retrospective analysis, the duration of use was longest with the Gellhorn pessary. Older age and vaginal estrogen use were associated with longer pessary use. PMID- 27942795 TI - ? PMID- 27942797 TI - Bone histology sheds light on the nature of the "dermal armor" of the enigmatic sauropod dinosaur Agustinia ligabuei Bonaparte, 1999. AB - Agustinia ligabuei is an Early Cretaceous sauropod dinosaur from the northwest of Patagonia that is currently the topic of debate with respect to its phylogenetic position and atypical dermal armor. The presence of four morphotypes of laminar and transversely elongated putative osteoderms was used to consider Agustinia as an armored sauropod. Regarding the different hypotheses about the identity of the bony structures of Agustinia (e.g., osteoderms, cervical or dorsal ribs, hypertrophied elements), a comparative histological analysis has been carried out. Histological evidence is presented herein and reveals that none of the morphotypes of Agustinia shows a primary bone tissue formed by structural fiber bundles as in other sauropod dinosaur osteoderms. Furthermore, on the basis of their gross morphology and microstructure, the bony structures originally classified as types 1 + 4 and 3 are more comparable respectively with dorsal and cervical ribs than any other kind of dermal or bony element. Due to poor preservation, the nature of the type 2 cannot be assessed but is here tentatively assigned to a pelvic girdle element. Although a phylogenetic reassessment of Agustinia is not the purpose of this paper, our paleohistological analyses have broader implications: by not supporting the dermal armor hypothesis for Agustinia, its inclusion in Lithostrotia is not justified in the absence of other diagnostic features. PMID- 27942796 TI - Calcium urolithiasis course in young stone formers is influenced by the strength of family history: results from a retrospective study. AB - The role of the strength of family history of stones (FHS), i.e., degree of relatives with the disease, on the course of calcium urolithiasis (CU) is not fully understood, particularly in young patients where genetic background has the greatest influence on disease expression. Thus, with a retrospective cross sectional design, we examined baseline clinical parameters and urinary chemistries of 369 subjects (196 M) with CU and 96 controls (41 M) aged between 15 and 25 at the time of the first visit at our stone clinic. Subjects with metabolic syndrome traits, known causes of CU or CU onset before the age of 15 were excluded. Clinical and metabolic parameters were compared among stone formers (SF) and controls, stratified by gender, the presence and type of FHS determined through the kinship coefficient of relatives with stones. No significant differences in clinical course were found between SF with and without FHS, except for the presence of bilateral stones (OR 2.01, 95% CI 1.20-3.39, p < 0.01). A significant age-, sex- and disease duration-adjusted trend for a higher number of colics (p for trend = 0.001), number of stones (p for trend = 0.002), stone rate (p for trend = 0.003) and the presence of retained stones (OR 1.60, 95% CI 1.14-2.21, p = 0.006) was detected with increasing FHS strength. Urinary chemistries were unaffected by FHS in both SF and controls, except for a higher calcium excretion in females with FHS (p < 0.05). The type of FHS, thus, significantly influences the clinical course of CU in young SF, mainly irrespective of urinary factors. PMID- 27942798 TI - Are the Institute of Medicine weight gain targets applicable in women with gestational diabetes mellitus? AB - AIMS/HYPOTHESIS: Our aim was to study the relationship between excessive gestational weight gain (GWG) according to Institute of Medicine (IOM) targets and perinatal outcomes, and examine whether modifying targets may improve outcomes in women with gestational diabetes mellitus (GDM). METHODS: This was a retrospective cohort study of all GDM pregnancies from 1992 to 2013. ORs were calculated for associations between excessive GWG (EGWG) using IOM targets and adverse pregnancy outcomes. ORs were then adjusted for maternal age, gestational age at diagnosis, prepregnancy BMI, gravidity, parity, ethnicity, antenatal fasting blood glucose level (BGL), 2 h BGL and HbA1c. BMI was categorised into underweight (<18.5 kg/m2), healthy weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2) and obese (>=30 kg/m2). Large for gestational age (LGA) was defined as birthweight above the 90th percentile, small for gestational age (SGA) was birthweight below the 10th percentile, macrosomia was birthweight >4000 g, and preterm delivery was delivery prior to 37 weeks' gestation. Modified GWG targets were derived by: (1) subtracting 2 kg from the upper IOM target only; (2) subtracting 2 kg from both upper and lower targets; (3) using the interquartile range of maternal GWG of women with infants who were appropriate for gestational age per BMI category; and (4) restricting GWG to 0-4 kg in women with BMI >=35 kg/m2. RESULTS: Among 3095 GDM pregnancies, only 31.7% had GWG within IOM guidelines. Adjusted ORs for women who exceeded GWG were Caesarean section (1.5; 95% CI 1.2, 1.9), LGA (1.8; 95% CI 1.4, 2.4) and macrosomia (2.3; 95% CI 1.6, 3.3); there was a lower risk of SGA (adjusted OR 0.5; 95% CI 0.3, 0.7). CONCLUSIONS/INTERPRETATION: EGWG according to IOM targets was associated with Caesarean section, LGA and macrosomia. Modification of IOM criteria, including more restrictive targets, did not improve perinatal outcomes. PMID- 27942801 TI - Differentiating Pseudomonas sp. strain ADP cells in suspensions and biofilms using Raman spectroscopy and scanning electron microscopy. AB - High quality spectra of Pseudomonas sp. strain ADP in the planktonic and biofilm state were obtained using Raman microspectroscopy. These spectra enabled the identification of key differences between free and biofilm cells in the fingerprint region of Raman spectra in the nucleic acid, carbohydrate, and protein regions. Scanning electron microscopy (SEM) enabled detailed visualization of ADP biofilm with confirmation of associated extracellular matrix structure. Following extraction and Raman analysis of extracellular polymeric substances, Raman spectral differences between free and biofilm cells were largely attributed to the contribution of extracellular matrix components produced in mature biofilms. Raman spectroscopy complemented with SEM proves to be useful in distinguishing physiological properties among cells of the same species. Graphical Abstract Raman spectroscopy complemented with SEM proves to be useful in distinguishing physiological properties among cells of the same species. PMID- 27942802 TI - Challenges and successes in implementing active learning laboratory experiments for an undergraduate analytical chemistry course. PMID- 27942799 TI - Interrupting prolonged sitting in type 2 diabetes: nocturnal persistence of improved glycaemic control. AB - AIMS/HYPOTHESIS: We aimed to examine the effect of interrupting 7 h prolonged sitting with brief bouts of walking or resistance activities on 22 h glucose homeostasis (including nocturnal-to-following morning hyperglycaemia) in adults with type 2 diabetes. METHODS: This study is an extension of a previously published randomised crossover trial, which included 24 inactive overweight/obese adults with type 2 diabetes (14 men; 62 +/- 6 years) who completed three 7 h laboratory conditions, separated by 6-14 day washout periods: SIT: (1) prolonged sitting (control); (2) light-intensity walking (LW): sitting plus 3 min bouts of light-intensity walking at 3.2 km/h every 30 min; (3) simple resistance activities (SRA): sitting plus 3 min bouts of simple resistance activities (alternating half-squats, calf raises, brief gluteal contractions and knee raises) every 30 min. In the present study, continuous glucose monitoring was performed for 22 h, encompassing the 7 h laboratory trial, the evening free living period after leaving the laboratory and sleeping periods. Meals and meal times were standardised across conditions for all participants. RESULTS: Compared with SIT, both LW and SRA reduced 22 h glucose [SIT: 11.6 +/- 0.3 mmol/l, LW: 8.9 +/- 0.3 mmol/l, SRA: 8.7 +/- 0.3 mmol/l; p < 0.001] and nocturnal mean glucose concentrations [SIT: 10.6 +/- 0.4 mmol/l, LW: 8.1 +/- 0.4 mmol/l, SRA: 8.3 +/- 0.4 mmol/l; p < 0.001]. Furthermore, mean glucose concentrations were sustained nocturnally at a lower level until the morning following the intervention for both LW and SRA (waking glucose both -2.7 +/- 0.4 mmol/l compared with SIT; p < 0.001). CONCLUSIONS/INTERPRETATION: Interrupting 7 h prolonged sitting time with either LW or SRA reduced 22 h hyperglycaemia. The glycaemic improvements persisted after these laboratory conditions and nocturnally, until waking the following morning. These findings may have implications for adults with relatively well-controlled type 2 diabetes who engage in prolonged periods of sitting, for example, highly desk-bound workers. TRIAL REGISTRATION: anzctr.org.au ACTRN12613000576729 FUNDING: : This research was supported by a National Health and Medical Research Council (NHMRC) project grant (no. 1081734) and the Victorian Government Operational Infrastructure Support scheme. PMID- 27942800 TI - The effects of 2 weeks of interval vs continuous walking training on glycaemic control and whole-body oxidative stress in individuals with type 2 diabetes: a controlled, randomised, crossover trial. AB - AIMS/HYPOTHESIS: The aim of this study was to evaluate the effects of oxygen consumption-matched short-term interval walking training (IWT) vs continuous walking training (CWT) on glycaemic control, including glycaemic variability, in individuals with type 2 diabetes. We also assessed whether any training-induced improvements in glycaemic control were associated with systemic oxidative stress levels. METHODS: Participants (n = 14) with type 2 diabetes completed a crossover trial using three interventions (control intervention [CON], CWT and IWT), each lasting 2 weeks. These were performed in a randomised order (computerised generated randomisation) and separated by washout periods of 4 or 8 weeks after CON or training interventions, respectively. Training included ten supervised treadmill sessions, lasting 60 min/session, and was performed at the research facility. CWT was performed at moderate walking speed (75.6% +/- 2.5% of walking peak oxygen consumption [[Formula: see text]]), while IWT was performed as alternating 3 min repetitions at slow (58.9% +/- 2.0% [Formula: see text]) and fast (90.0% +/- 3.6% [Formula: see text]) walking speed. Before and after each intervention, the following was assessed: 24 h continuous glucose monitoring (CGM) and urinary free 8-iso prostaglandin F2alpha (8-iso PGF2alpha; a marker for oxidative stress), physical fitness and body composition. Neither participants nor assessors were blinded to the interventions. RESULTS: No intervention-induced changes were seen in physical fitness or body composition. Compared with baseline, IWT reduced mean glucose levels non-significantly (-0.7 +/- 0.3 mmol/l, p = 0.08) and significantly reduced maximum glucose levels (-1.8 +/- 0.5 mmol/l, p = 0.04) and mean amplitude of glycaemic excursions (MAGE; -1.7 +/- 0.4 mmol/l, p = 0.02), whereas no significant within-group changes were seen with CON or CWT. Although 8-iso PGF2alpha was associated with minimum glucose levels at baseline, no change in 8-iso PGF2alpha was seen with any intervention, nor were there any associations between changes in 8-iso PGF2alpha and changes in glycaemic control (p > 0.05 for all). No adverse effects were observed with any of the interventions. CONCLUSIONS/INTERPRETATION: Short-term IWT, but not CWT, improves CGM-derived measures of glycaemic control independent of changes in physical fitness and body composition in individuals with type 2 diabetes. Systemic oxidative stress levels are unaffected by short-term walking and changes in oxidative stress levels are not associated with changes in glycaemic control. TRIAL REGISTRATION: ClinicalTrials.gov NCT02320526 FUNDING : The Centre for Physical Activity Research (CFAS) is supported by a grant from TrygFonden. During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). The study was further supported by grants from Diabetesforeningen, Augustinusfonden and Krista og Viggo Petersens Fond. CIM/CFAS is a member of the Danish Center for Strategic Research in Type 2 Diabetes (DD2; the Danish Council for Strategic Research, grant no. 09-067009 and 09-075724). MR-L was supported by a post-doctoral grant from the Danish Diabetes Academy supported by the Novo Nordisk Foundation. PMID- 27942804 TI - Selective improvement of peptides imaging on tissue by supercritical fluid wash of lipids for matrix-assisted laser desorption/ionization mass spectrometry. AB - There is a high analytical demand for improving the detection sensitivity for various peptides in matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) because exhaustive distribution analyses of various peptides could help to reveal the function of peptides in vivo. To improve the sensitivity of peptide detection, we used supercritical fluid of CO2 (scCO2) as washing solvent for a pretreatment to remove lipids. We evaluated whether our wash method using scCO2 with an entrainer improved the detection of peptides and suppressed lipid detection in MALDI-IMS. Our analysis revealed that the signal intensities of peptides such as m/z 3339.8, 3530.9, 4233.3, 4936.7, and 4963.7 were increased in scCO2-washed samples. The greatest improvement in the signal-to noise ratio (S/N) was found at m/z 4963.7, which was identified as thymosin beta4, with the S/N reaching almost 190-fold higher than the control. Additionally, all of the improved signals were associated with the morphologic structure. Our method allows us to analyze the distribution of molecules, especially in the region of m/z 3000-5200. For these improvements, the polarity difference between scCO2 and the matrix solution used was considered as a key. A wider variety of molecules can be analyzed in the future due to this improvement of the detection sensitivity by optimizing the polarity of scCO2 with various entrainers. Graphical Abstract Mass spectra of m/z 4900-5000 obtained from a scCO2-washed tissue (upper, blue) and a control tissue (lower, red). Ion distribution of the signals at m/z 4936.7 and m/z 4963.7 specifically ditected from scCO2-washed samples. PMID- 27942805 TI - Low circulating coenzyme Q10 during acute phase is associated with inflammation, malnutrition, and in-hospital mortality in patients admitted to the coronary care unit. AB - Coenzyme Q10 (CoQ10) has a potential role in the prevention and treatment of heart failure through improved cellular bioenergetics. In addition, it has antioxidant, free radical scavenging, and vasodilatory effects that may be beneficial. Although critical illness in intensive care unit is associated with decreased circulating CoQ10 levels, the clinical significance of CoQ10 levels during acute phase in the patients of cardiovascular disease remains unclear. We enrolled 257 consecutive cardiovascular patients admitted to the coronary care unit (CCU). Serum CoQ10 levels were measured after an overnight fast within 24 h of admission. We examined the comparison of serum CoQ10 levels between survivors and in-hospital mortalities in patients with cardiovascular disease. Serum CoQ10 levels during the acute phase in patients admitted to the CCU had similar independent of the diagnosis. CoQ10 levels were significantly lower in patients with in-hospital mortalities than in survivors (0.43 +/- 0.19 vs. 0.55 +/- 0.35 mg/L, P = 0.04). In patients admitted to the CCU, CoQ10 levels were negatively associated with age and C-reactive protein levels, and positively associated with body mass index, total cholesterol, and high-density lipoprotein cholesterol levels. Low CoQ10 levels correlated with low diastolic blood pressure. Multivariate logistic regression analysis demonstrated that low CoQ10 levels were an independent predictor of in-hospital mortality. Low serum CoQ10 levels during acute phase are significantly associated with cardiovascular risk and in-hospital mortality in patients admitted to the CCU. PMID- 27942806 TI - Laparoscopic versus open pyloromyotomy in infants: a systematic review and meta analysis. AB - PURPOSE: To determine whether open or laparoscopic pyloromyotomy is superior for the treatment of hypertrophic pyloric stenosis in infants. METHODS: We searched MEDLINE, EMBASE, and CENTRAL for articles comparing laparoscopic and open procedures. We conducted meta-analyses when possible and described other results narratively. RESULTS: Our meta-analyses revealed no significant difference in our primary outcome of major complications [risk difference (RD) 0.03, 95% confidence interval (CI) -0.03 to 0.08, P = 0.35, I 2 = 55%], or in our secondary outcomes of all perioperative complications (RD -0.01, 95% CI -0.06 to 0.04, P = 0.74, I 2 = 0%), operative time [mean difference (MD) 0.68, 95% CI -3.60 to 4.79, P = 0.76, I 2 = 86%], and length of stay (MD -2.60, 95% CI -6.05 to 0.86, P = 0.14, I 2 = 0%). Laparoscopy was associated with a shorter time to full feeds (standardized mean difference -0.25, 95% CI -0.43 to -0.06, P = 0.009, I 2 = 8%) and a slightly higher rate of inadequate pyloromyotomy (RD 0.04, 95% CI 0.00-0.08, P = 0.03, I 2 = 0%). Results from one randomized controlled trial indicate a better cosmetic outcome after laparoscopy compared to open procedure. CONCLUSION: There is no strong evidence to support a recommendation of one procedure over the other; therefore, the choice of laparoscopic or open procedure should be left to the discretion of the surgeon. PMID- 27942808 TI - Diabetes and the nervous system. PMID- 27942807 TI - Neural control and precision of flight muscle activation in Drosophila. AB - Precision of motor commands is highly relevant in a large context of various locomotor behaviors, including stabilization of body posture, heading control and directed escape responses. While posture stability and heading control in walking and swimming animals benefit from high friction via ground reaction forces and elevated viscosity of water, respectively, flying animals have to cope with comparatively little aerodynamic friction on body and wings. Although low frictional damping in flight is the key to the extraordinary aerial performance and agility of flying birds, bats and insects, it challenges these animals with extraordinary demands on sensory integration and motor precision. Our review focuses on the dynamic precision with which Drosophila activates its flight muscular system during maneuvering flight, considering relevant studies on neural and muscular mechanisms of thoracic propulsion. In particular, we tackle the precision with which flies adjust power output of asynchronous power muscles and synchronous flight control muscles by monitoring muscle calcium and spike timing within the stroke cycle. A substantial proportion of the review is engaged in the significance of visual and proprioceptive feedback loops for wing motion control including sensory integration at the cellular level. We highlight that sensory feedback is the basis for precise heading control and body stability in flies. PMID- 27942809 TI - Transport of nutrients and hormones through the blood-brain barrier. AB - An understanding of the mechanisms of transport of circulating nutrients and hormones through the brain capillary wall, i. e., the blood-brain barrier, is important because the availability in brain of these substances influences a number of cerebral metabolic pathways. For example, the utilization by brain of glucose, ketone bodies and branched chain amino acids or the production of monoamines, acetylcholine, carnosine, and nucleosides may under certain conditions be influenced by BBB transport of circulating precursor nutrients. Steroid and thyroid hormones readily traverse the BBB via lipid-mediation and carrier-mediation, respectively. Although the steroid and thyroid hormones are tightly bound by plasma proteins, protein-bound hormone, not the free (dialyzable) moiety, is the major plasma fraction transported through the BBB. With regard to circulating peptides, the available evidence indicates peptides rapidly distribute into brain interstitial space of the circumventricular organs of brain, i. e., about six small regions around the ventricles which lack a BBB. Conversely, the absence of peptide carriers in the BBB prevents the rapid distribution of peptides into the vast majority of brain interstitial or synaptic spaces. However, recent studies indicate that some peptides, e. g., insulin, may bind specific receptors on the blood side of the BBB and thereby transmit messages to cells on the brain side of the BBB, without the peptide traversing the capillary wall. PMID- 27942810 TI - Cellular basis of direct insulin action in the central nervous system. AB - The in vivo radioautographic method has been applied to elucidate the mechanism of direct peptide hormone "feedback" action in the CNS. Using this method we have identified the circumventricular organs of the brain as general endocrine target tissues for a variety of blood-borne polypeptide hormones, including insulin. In the arcuatemedian eminence region of the hypothalamus blood-borne insulin directly interacts with receptive nerve terminals, suggesting that insulin acts to influence the electrical activity of select hypothalamic nerve circuits at the level of synaptic transmission. Recent results obtained from preliminary surgical and chemical lesion studies of brain indicate that insulin-receptive nerve terminals in the arcuate-median eminence region arise from neurons intrinsic to the medial basal hypothalamus. This has lead us to propose the concept of the hypothalamic tuberoinfundibular insulin-receptive neuron and its axon collaterals as a pathway for the centripetal flow of insulin "signals" in the form of electrical impulses. We envisige that the neuroanatomic pathway, provided by the hypothalamic tuberoinfundibular neuron, functions to link changes in body metabolic activity, as reflected in changing levels of circulating insulin, to the neuronal process of elaborating specific central metabolic-regulatory programs. This pathway could be of key importance in understanding and combating metabolic disease. PMID- 27942811 TI - Insulin and insulin receptors in rodent brain. AB - While insulin effects on the central nervous system (CNS) mediated through hypoglycaemia are well known, direct insulin effects on the CNS remain controversial. Recently, we found insulin receptors in all areas of the rat brain, with highest concentrations in the olfactory bulb, cerebral cortex and hypothalamus; all areas involved in feeding. Insulin receptors in brain were, by multiple criteria, similar to insulin receptors on classical target tissues for insulin, such as liver and fat. Insulin itself has been identified in the rat brain at concentrations on average ten times higher than in plasma. Highest concentrations were found in the olfactory bulb and hypothalamus. Brain insulin was indistinguishable from purified insulin by its behaviour in the radioimmunoassay, radioreceptor assay, bioassay and gel chromatography. In two experimental models representing extremes of plasma insulin concentrations (obese hyperinsulinaemic mice and diabetic insulinopenic rats) there were no significant changes in the concentration of insulin receptors in brain while liver receptors were modified in the expected way. This may reflect the protective influence of the blood-brain barrier or some special quality of brain insulin receptors. Insulin concentrations in brain were also unchanged in both models, which is probably indicative of the local synthesis of insulin. The role of insulin in the CNS is unknown. Besides well known metabolic actions of insulin, new roles can be postulated such as neurotransmission, neuromodulation and paracrine signalling. PMID- 27942812 TI - Regulation of food intake and body weight by insulin. AB - A feedback system for the regulation of food intake and body weight, consisting of two elements is proposed. One is related to the quantitiy and quality of the food ingested. It consists of neural afferents, psychosocial conditioning factors, and peptide signals from the gastrointestinal tract released by specific nutrient intake. The other is also sensitive to nutrient intake, but importantly modulated by relative adiposity. We present evidence to suggest that insulin serves as the key feedback signal to the central nervous system to serve this second function (body adiposity signal). Insulin has been found in cerebrospinal fluid where its concentration is increased by systemic infusions of glucose or insulin and is proportional to its concentration in plasma. When insulin (10 and 100 MUU/kg/day) is infused into the lateral cerebral ventricles of free feeding baboons a dose dependent suppression of food intake and body weight is found. Intravenous infusion of 25% and 50% of total calories as glucose elevates endogenous insulin concentrations and suppresses food intake. These findings suggest that the amount of insulin secreted per day and more modulates food intake to maintain a constant body weight. PMID- 27942813 TI - Effects of precursors on brain neurotransmitter synthesis and brain functions. AB - This paper reviews factors which influence the levels of aminergic transmitters in the brain. In particular precursor availability to the brain influences the rates of synthesis of serotonin, the catecholamines, and acetylcholine by brain neurons. The diet readily influences brain neurotransmitter formation via this mechanism. At present, the importance of this relationship to body regulation is not well understood. Nonetheless, precursors (tryptophan, tyrosine, choline, and lecithin) have begun to find uses as therapeutic agents in the treatment of disease states involving diminished transmitter formation and release. Hopefully, these compounds will find a wide range of uses, as they lack many of the side effects that accompany the use of drugs. PMID- 27942814 TI - Insulin acting as a modulator of feeding through the hypothalamus. AB - To understand the functional role of insulin in the control of feeding, biochemical and physiological studies were performed in the rat. 1) Insulin content in the brain was much higher than that in the blood, and was extremely variable from animal to animal. 2) Specific binding sites of insulin in the brain were most abundant in the hypothalamus and olfactory bulb. 3) Neither insulin content nor binding sites in the brain was significantly affected by peripheral insulin concentration. 4) Activity of glucoreceptor neurons in the ventromedial hypothalamus (VMH) was facilitated by simultaneous application of insulin and glucose, but inhibited by insulin alone. 5) Activity of the glucose-sensitive neurons in the lateral hypothalamus (LHA) was facilitated by insulin in a dose dependent manner. 6) Stimulation of the ventral part of the LHA accelerated pancreatic vagal nerve activity. Stimulation of the dorsal part of the LHA and the VMH was inhibitory. 7) Pancreatic splanchnic nerve activity during LHA stimulation tended to show inhibition, but sometimes was modulated by the stimulus frequency. Both inhibition and facilitation were observed in the activity in response to VMH stimulation. PMID- 27942815 TI - Neuropeptides: Central nervous system effects on nutrient metabolism. AB - Several neural peptides have been demonstrated to influence central nervous system control of nutrient metabolism. The principal mechanism by which these peptides influence peripheral nutrient metabolism is by altering the secretion of adrenal epinephrine. Bombesin or its mammalian counterpart, gastrin releasing peptide, and TRF act within the brain to stimulate the secretion of epinephrine from the adrenal gland. Associated with these changes in epinephrine secretion is a reduction of plasma insulin and elevation of plasma glucagon and glucose. Somatostatin and various somatostatin analogs act in the brain to inhibit adrenal epinephrine secretion stimulation by a variety of stimuli. PMID- 27942818 TI - Visceral afferents and metabolic function. AB - The effect of glucose, 2 DG, CCK and serotonin on the firing rate of the vagal hepatic afferents and vagal pancreatic afferents was studied in rabbits, guinea pigs and rats. The hepatic and pancreatic afferents showed a decrease in activity following administration of glucose and an increase in activity after the injection of 2 DG. These afferent elements may have a mechanism to respond to blood glucose similar to that of lateral hypothalamic neurons. The results also indicate that CCK and serotonin showed the opposite effects in the vagal hepatic afferents and in the pancreatic efferents. Decrease in the discharge rate in the vagal hepatic afferents due to CCK or serotonin may cause a suppression of food intake behavior. Increase in the discharge rate in the vagal pancreatic afferents resulting from CCK or serotonin or insulin suggests the existence of a nervous information system for these substances in the circulating blood in the pancreas. PMID- 27942816 TI - Peptides and the control of meal size. AB - There are now a large number of experiments demonstrating that peripheral administration of exogenous cholecystokinin or its synthetic analogue, CCK-8, reduces meal size in a number of species. The peptide interacts with other factors which influence satiety, and treatments thought to be effective in eliciting secretion of cholecystokinin have predictable effects on meal size. Cholecystokinin is effective in the genetically obese Zucker rat, obese rats with lesions of the ventromedial hypothalamus, and subdiaphragmatically vagotomized rats. Somatostatin and bombesin are also reasonable candidates for satiety factors. Intraperitoneal naloxone reduces meal size in rats, and beta-endorphin injected intraventricularly causes an increase in meal size of 50% over 30 minutes. We conclude that cholecystokinin and bombesin may interact in weight regulation and control of meal time food intake. PMID- 27942819 TI - Visceral afferent and efferent connections in the brain. AB - Behavioral and physiological studies have revealed increasing evidence in thirst, hunger, energy and water metabolism for the importance of visceral input to the brain as well as central modulation of visceral events. Recent work in our laboratory has now revealed some new information about the central course of these afferent and efferent systems. From our work and others there is now good evidence that the bed of the hepatic-portal system contains sodium and osmoreceptors. Our electrophysiological and histochemical studies show that one branch overlaps the gustatory pathway. That is, involves the vagus nerve, nucleus tractus solitarius, parabrachial nucleus and ventro-basal thalamus (VBC). Another branch goes not to VBC but to the supra-optic nucleus. At the one level so far investigated clear evidence was obtained for convergence on single cells of visceral and gustatory inputs. It may well occur at other levels. A parallel and perhaps interacting efferent system more related to energy regulation has also been explored. The major parasympathetic output to the viscera are the axons of the brain stem dorsal-motor nucleus (DMV) forming the vagus nerves. We have shown that the paraventricular nucleus, which was known to project to DMV, is the only structure above the brain stem that has a direct input to DMV. However, since the nucleus of the solitary tract and reticular formation send fibers to the DMV the neural substrate exists for considerable indirect input. The significance of these results is that it provides a central neural substrate of the 2-way pathways linking brain and viscera. Thus, we now know more about neural control mechanisms involved in several motivational and metabolic systems. The close contiguity and even convergence of gustatory and visceral afferents may help to explain taste-aversion learning and alterations in the hedonics of taste under different nutritional states. The unique place of the paraventricular nucleus in relation to parasympathetic efferents will doubtless lead to new knowledge of the role of the brain in control of energy metabolism. PMID- 27942817 TI - Interactions between autonomic nerves and endocrine cells of the gastroenteropancreatic system. AB - Autonomic nerves and endocrine cells of both the gastrointestinal tract and the pancreatic islets participate in the control of several processes related to the digestion and metabolism of nutrients. While it was once thought that they acted separately to regulate these processes, it is now appreciated that numerous interactions exist between the functions of autonomic nerves and GEP endocrine cells. Recent studies show that autonomic signals play a role in the secretory activity of various GEP cells, thus providing a mechanism by which the central nervous system can integrate digestive and metabolic functions. It also has been shown that nerves and endocrine cells frequently share certain common peptides and/or amines. Therefore, in functional terms, it is often difficult to determine whether a specific peptide or amine should be considered a neurotransmitter or a hormone. Within the next few years, one can reasonably expect that new techniques and methods of investigation will clarify the roles of putative chemical messengers such as the peptides found within autonomic nerves and the amines found within endocrine cells. It also seems likely that future studies will demonstrate that the specific chemical messenger and the mechanism by which it reaches its target cells are far more important factors in the understanding of gastrointestinal and endocrine pancreatic function, than whether or not these signals are neural or endocrine in origin. PMID- 27942820 TI - Peptides in metabolic autonomic nerves. AB - Most polypeptides originally assigned to a specific organ and a specific effect seem to occur in many different parts of the body, in neurons as well as in endocrine cells. Thus gastrin and insulin, or very similar peptides can be demonstrated in extracts of the vagal nerves and of peripheral somatic nerves. Electrical stimulation of the sciatic nerve of a perfused cat leg causes appearance of gastrin and insulin like immunoreactivity in the perfusates. This gastrin and insulin like immunoreactivity might originate from nervous depots. If so it might be assumed that insulin and other peptides are released in response to activation of autonomic or somatic nerves and that they might exert local metabolic effects in response to the acute needs of energy in eg. striated or smooth muscles. PMID- 27942822 TI - Effects of ventromedial hypothalamic lesions on adipose tissue of weanling male rats. AB - In weanling male rats, destruction of the ventromedial hypothalamus causes increased carcass lipid deposition and decreased linear growth without changes in food intake or blood glucose levels. These changes are not dependent on altered pituitary function. Lipogenesis and glucose utilization are increased in vivo and in vitro, while gluconeogenesis is accelerated in vivo. The enhanced lipogenesis occurs before increased gluconeogenesis. PMID- 27942821 TI - Central nervous system regulation of liver and adipose tissue metabolism. AB - Hypothalamic and autonomic nervous regulation of carbohydrate and amino acid metabolism in the liver and of lipid metabolism in adipose tissues is described. The direct neural mechanism underlying this regulation has been evaluated. Electrical stimulation of the ventromedial hypothalamic nucleus (VMH)-splanchnic nerve system causes glycogenolysis in the liver by rapid activation of glycogen phosphorylase, whereas electrical stimulation of the lateral hypothalamic nucleus (LH)-vagus nerve system promotes glycogenesis in the liver by activation of glycogen synthetase, through direct neural and neural-hormonal mechanisms. Studies on chemical coding of the hypothalamic neurones have revealed that norepinephrine-sensitive neurones in the VMH and acetylcholine-sensitive neurones in the LH are specifically involved in the regulation of liver phosphorylase and glycogen synthetase, respectively. Acetylcholine-sensitive neurones of the LH were also found to be concerned in regulation of hepatic tyrosine aminotransferase activity, through intermediation of the cholinergic system in the LH-vagal pathway. Finally, it has been shown that the VMH acts as a regulatory centre for lipolysis in adipose tissues by modulating activation of the sympathetic nervous system. In addition, stimulation of the VMH enhanced lipogenesis in brown adipose tissue preferentially, probably through a mechanism mediated by sympathetic innervation of this tissue. The latter finding suggests that both the breakdown and resynthesis of triglycerides in brown adipose tissue, but not in white adipose tissue, are accelerated by stimulation of the VMH. PMID- 27942823 TI - Is there a sympathetic regulation of the efficiency of energy utilization? AB - Brown adipose tissue, a well known effector of regulatory thermogenesis found in mammals, is unique in its ability to steadily increase its heat production several fold for very long periods of time. It constitutes a shunt of energy flow between food intake and heat dissipation, it is activated through its sympathetic nerve supply. There are evidence in the rat, that brown adipose tissue is activated following overfeading, thus decreasing food efficiency and determining resistance to obesity. Genetically obese (ob/ob) mice fed and kept at 22 degrees C lack the possibility of activating their brown fat energy shunt; they are known to be poorly resistant to cold stress despite their large insulation. This is taken as a further circumstantial evidence of an overlap in thermal and food efficiency regulatory systems in rodents through sympathetically controlled brown fat as a common effector. PMID- 27942824 TI - Hypothalamic obesity : The autonomic hypothesis and the lateral hypothalamus. AB - Several lines of evidence support the hypothesis that derangements in the function of the autonomic nervous system play an important role in the development of hypothalamic obesity. Vagotomy below the diaphragm reverses the syndrome. In diabetic rats cured of their diabetes with transplants of fetal pancreatic tissue beneath the renal capsule, ventromedial hypothalamic (VMH) lesions do not produce the characteristic rise in food intake nor do they significantly increase serum insulin. These observations indicate that the hyperinsulinaemia following VMH lesions is the result of neural connections rather than from a circulating humoral factor released following VMH injury. The smaller salivary glands, reduced level of glucagon and impaired mobilization of fatty acids during stress in VMH lesioned rats point to reduced activity of the sympathetic nervous system. The impaired mobilization of fat from retroperitoneal depots in VMH lesioned rats during fasting is similar to the effect of sympathetic denervation of the retroperitoneal fat pad. Similarly, unilateral sympathectomy caused an increased weight gain in rats almost as much as unilateral VMH lesions but significantly less than in bilaterally lesioned rats. These studies with fasting and feeding implicate the VMH in the control of the sympathetic nervous system. When atropine and epinephrine were given to VMH lesioned rats, there was a significant depression in basal and glucose-stimulated levels of insulin. Finally when VMH lesions were placed after lateral hypothalamic lesions, the effect of the VMH lesions did not seem to be reduced, suggesting that the two effects are independent. A model dealing with the effects of VMH lesions is presented in an attempt to integrate these findings. PMID- 27942825 TI - Neural pathways involved in the hypothalamic integration of autonomic responses. AB - Recent mapping studies of hypothalamic and autonomic mechanisms have considerably extended our understanding of the anatomy of this system. The pattern of connections emerging from physiological, anatomical, and histochemical experiments suggests several conclusions about the functional organization of the system as well. Recent evidence supports the idea that the hypothalamic (and other limbic) areas involved in the control of ingestion and metabolism form the rostral pole of a longitudinally and hierarchically organized system that elaborates autonomic responses that influence the energy economy of the animal. Substantially the same pathways are apparently responsible for the modulation of ingestive behavior as well. This circuitry, the "visceromotor system" in Nauta's terminology, seems to weld afferent inputs, particularly those of the gustatory and visceral receptors, into a coordinated integrative control strategy influencing autonomic responses. In addition, the system seems to have unique tissue properties, at least at its two periventricularly located sites of integration with special access to both humorally and ventricularly circulated substrates. These nodes, the basomedial hypothalamus and the vagal complex of the medulla, seem to share similar biochemical specializations reflected in susceptibility to goldthioglucose toxicity, specific insulin binding, and susceptibility to alloxan diabetes. PMID- 27942826 TI - Autonomic function and control of pancreatic somatostatin. AB - In the canine pancreas alpha and beta adrenergic receptors exist on D cells with alpha stimulation inhibiting and beta stimulation increasing somatostatin release. There are no dopaminergic receptors on D cells. Stimulation of muscarinic receptors causes mild inhibition of somatostatin secretion. Autonomic receptors on the D cell may be physiologically stimulated in vivo via local ganglionic and/or central autonomic drivers. PMID- 27942828 TI - The role of hyperinsulinema and the vagus nerve in hypothalamic hyperphagia reexamined. AB - Three series of experiments investigated the role of hyperinsulinemia and the vagus nerve in the hyperphagia and obesity syndrome produced in female rats by knife cuts in the ventromedial hypothalamus (VMH). The findings of the first series revealed that VMH cuts do not produce hyperinsulinemia when the rats are prevented from overeating, but insulin levels are elevated in rats allowed to overeat. The second series of experiments demonstrated that VMH-cut rats overconsume sweet sugar solutions during daily short-term tests, and that pharmacological blockade of vagal efferent activity with atropine methyl nitrate fails to inhibit this overconsumption. The third study revealed that subdiaphragmatic vagotomy completely blocks VMH hyperphagia and obesity on a chow diet, but does not prevent overeating and rapid weight gain in rats fed an assortment of highly palatable foods. These findings indicate that vagally mediated insulin release is not an essential component to the VMH knife cut syndrome. PMID- 27942827 TI - Cephalic phase, reflex insulin secretion neuroanatomical and physiological characterization. AB - Using chronically catheterized, freely moving male Wistar rats, we have shown that the sweet taste of a saccharin solution reliably triggers a rapid cephalic phase insulin response (CPIR), in the absence of any significant change of glycemia. To establish the neural mediation of this reflex response we used rats that were cured from streptozotocin diabetes by intrahepatic islet transplantation as a denervated B-cell preparation. The complete lack of any saccharin-induced CPIR in these rats suggests that it is indeed mediated by the peripheral autonomic nervous system, and that the insulin-stimulating gastrointestinal hormones are not involved in this response. It was further found that this reflex insulin secretion is not easily extinguishable and thus might have an unconditioned component. To investigate the central neural pathways involved in this reflex response we used both electrophysiological methods in anesthetized and semi-micro CNS manipulations in freely moving rats. On the basis of our preliminary results, and several reports, using the decerebrate rat preparation for measuring behavioral or saliva secretory oral taste reactivity, it appears that CPIR might be organized at the brain stem/midbrain level, receiving strong modulatory influences from the diencephalon. But much further work has to be done to establish the central nervous circuitry. Finally, in two experiments, aiming at the question of how important and physiologically relevant the CPIR might be, we found that, on one hand, its lack can result in pathological oral glucose tolerance and on the other hand its exaggeration might contribute to the behavioral reaction to highly palatable sweet food and the resulting development of dietary obesity. PMID- 27942829 TI - The modulatory effect of the hypothalamus on glucagon and insulin secretion in the rat. AB - Rats were provided both with brain cannulas, to permit infusion of fluids in the ventromedial and lateral hypothalamic areas (resp. VMH and LH), and with two heart catheters. In this way infusions of fluids and withdrawal of blood could be done in unanesthetized free moving animals. Infusion of norepinephrine (NE) in the VMH elicited glucagon release during the whole period of NE infusion whereas insulin levels did not change. This glucagon release could not be suppressed by alpha- and beta-receptor blockade but it was suppressed by hexamethonium, a blocking agent of signal transmission in peripheral ganglia of the autonomic nervous system. On the other hand, infusion of NE in the LH elicited insulin release during the whole period of NE infusion whereas glucagon levels remained unchanged. It is argued that [1] the sympathetic nervous system is involved in glucagon release, [2] no alpha- and beta-receptor mechanisms are involved during this glucagon release, [3] the parasympathetic nervous system is involved in insulin release during noradrenergic LH stimulation. PMID- 27942830 TI - CNS modulation of pancreatic endocrine function : Multiple modes of expression. AB - The involvement of the CNS in pancreatic hormone release has been studied. 1.) It has been shown that one source of vagal efferent fibers capable of facilitating insulin secretion originated in the rostral half of the nucleus ambiguus. 2.) Acute lesions of the ventromedial hypothalamus resulted in hyperinsulinaemia that could be abolished by acute vagotomy. 3.) Chronic lesions of the ventromedial hypothalamus increased secretion of insulin and glucagon, and decreased secretion of somatostatin when the pancreas was subsequently isolated and perfused. These changes were attributed to altered cholinergic activity related to previous ventromedial hypothalamic lesions as they could be reversed toward normal by atropine infusion or mimicked by the cholinergic agonist, methacholine. 4.) Electrical stimulation of the lateral hypothalamus in anaesthetized rats produced both an inhibitory component of insulin secretion, probably related to adrenergic stimulation, and a stimulatory component, probably due to the release into the blood of factor(s) that promote insulin secretion. 5.) The anatomical organization of brain of the genetically obese (ob/ob) mice is abnormal. These abnormalities could be involved in the endocrinological disturbances of these animals. PMID- 27942831 TI - Lateral hypothalamic control of metabolic factors related to feeding. AB - States of hunger and satiety are under ischymetric (i. e., rate of cellular energy production) control which depends on both substrate availability and hormonal composition. The latter varies in response to external (olfactory, gustatory and gastrointestinal) stimuli sensed by specific receptors and projected on lateral hypothalamic (LH) units from which departs the descendant control pathway of metabolic glands. This neurohormonal loop is responsible for the anticipatory glycemic and other changes observed during a meal and the preabsorptive "satiation" ending the meal long before the post-absorptive cellular repletion will induce the state of more permanent "satiety". New data on LH "sweet" taste projection and hypothalamo-pancreatic control are shown and strengthen the above view. PMID- 27942833 TI - Radionuclide therapy of malignant bone lesions. PMID- 27942832 TI - Control of bacterial chromosome replication by non-coding regions outside the origin. AB - Chromosome replication in Eubacteria is initiated by initiator protein(s) binding to specific sites within the replication origin, oriC. Recently, initiator protein binding to chromosomal regions outside the origin has attracted renewed attention; as such binding sites contribute to control the frequency of initiations. These outside-oriC binding sites function in several different ways: by steric hindrances of replication fork assembly, by titration of initiator proteins away from the origin, by performing a chaperone-like activity for inactivation- or activation of initiator proteins or by mediating crosstalk between chromosomes. Here, we discuss initiator binding to outside-oriC sites in a broad range of different taxonomic groups, to highlight the significance of such regions for regulation of bacterial chromosome replication. For Escherichia coli, it was recently shown that the genomic positions of regulatory elements are important for bacterial fitness, which, as we discuss, could be true for several other organisms. PMID- 27942834 TI - European Network of Trainees in Obstetrics and Gynaecology: experiences from the 2016 exchange programme in Turin, Italy. AB - INTRODUCTION: The European Network of Trainees in Obstetrics and Gynaecology (ENTOG) is an organization representing trainees from 30 European member countries. Together with the European Board and College of Obstetrics and Gynaecology (EBCOG), it seeks to achieve the highest possible standards of training and consequently to improve the quality of medical care in the field of gynaecology and obstetrics. Every year, the ENTOG council meets and holds a scientific meeting in a different European country. To coincide with this, the host country arranges an exchange, to which each member country can send two trainees. This exchange allows trainees to gain insight into both daily clinical work and the structure of the health care system. METHODS: This article reports the experiences of participants in the May 2016 ENTOG exchange to Turin, Italy. The aim is to outline differences in training between Germany and Italy as well as some striking differences with other European countries. PERSPECTIVE: The participants' personal benefit from this unique experience was not only to get familiar with the Italian trainee programme and health care system, but also to exchange experiences among representatives from other European countries and build up a young gynaecological network within Europe. PMID- 27942835 TI - Pregnancy outcome among partners of male patients receiving imatinib, dasatinib or nilotinib in chronic myeloid leukemia: reports collected by the French network pharmacovigilance centers. PMID- 27942836 TI - Comparison of three different application routes of butyrate to improve colonic anastomotic strength in rats. AB - INTRODUCTION: Despite extensive research, anastomotic leakage (AL) remains one of the most dreaded complications after colorectal surgery. Since butyrate enemas are known to enhance anastomotic healing, several administration routes have been explored in this study. METHODS: Three intraluminal approaches involving butyrate were investigated: (1) butyrin-elucidating patch, (2) a single injection of hyaluronan-butyrate (HA-But) prior to construction of the proximal anastomosis and (3) rectal hyaluronan-butyrate (HA-But) enemas designed for distal anastomoses. The main outcome was AL and secondary outcomes were bursting pressure, histological analysis of the anastomosis, zymography to detect MMP activity and qPCR for gene expression of MMP2, MMP9, MUC2 and TFF3. RESULTS: Neither the patches nor the injections led to a reduction of AL in experiments 1 and 2. In experiment 3, a significant reduction of AL was accomplished with the (HA-But) enema compared to the control group together with a higher bursting pressure. Histological analysis detected only an increased inflammation in experiment 2 in the hyaluronan injection group compared to the control group. No other differences were found regarding wound healing. Zymography identified a decreased proenzyme of MMP9 when HA-But was administered as a rectal enema. qPCR did not show any significant differences between groups in any experiment. CONCLUSION: Butyrate enemas are effective in the enhancement of colonic anastomosis. Enhanced butyrate-based approaches designed to reduce AL in animal models for both proximal and distal anastomoses were not more effective than were butyrate enemas alone. Further research should focus on how exogenous butyrate can improve anastomotic healing after gastrointestinal surgery. PMID- 27942837 TI - Refining prognosis in patients with hepatocellular carcinoma through incorporation of metabolic imaging biomarkers. AB - PURPOSE: 18F-fluorodeoxyglucose positron emission tomopraphy/computed tomography (FDGPET/CT) has been proven to be useful for imaging many types of cancer; however, its role is not well defined in hepatocellular carcinoma (HCC). We assessed the prognostic value of metabolic imaging biomarkers as established by baseline pretreatment FDG PET/CT in patients with HCC. METHODS: We retrospectively analyzed the records of patients with HCC who underwent FDG PET/CT before initial treatment from May 2013 through May 2014. Four PET/CT parameters were measured: maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and tumor-to-normal-liver SUV ratio (TNR). Optimal cut-off values for the PET/CT parameters to stratify patients in terms of overall survival (OS) were determined. Multivariate analysis was performed to determine whether the PET/CT parameters could add to the prognostic value of the Cancer of the Liver Italian Program (CLIP) scoring system and the Barcelona-Clinic Liver Cancer (BCLC) staging system. RESULTS: The analysis included 56 patients. Univariate analysis of the association between OS and continuous variables, including the PET/CT parameters SUVmax, TLG, tumor size, total bilirubin level, and alkaline phosphatase level were significant predictors of OS. SUVmax >= 11.7, TLG >= 1,341, MTV >= 230 mL, and TNR >= 4.8 were identified as cut-off values. Multivariate analysis revealed that SUVmax >= 11.7 and TNR >= 4.8 were independent factors predicting a poor prognosis in both the CLIP scoring system and the BCLC staging system, as was TLG in the BCLC staging system. CONCLUSION: Pretreatment FDG PET/CT in patients with HCC can add to the prognostic value of standard clinical measures. Incorporation of imaging biomarkers derived from FDG PET/CT into HCC staging systems should be considered. PMID- 27942838 TI - Deciphering the regulation of porcine genes influencing growth, fatness and yield related traits through genetical genomics. AB - Genetical genomics approaches aim at identifying quantitative trait loci for molecular traits, also known as intermediate phenotypes, such as gene expression, that could link variation in genetic information to physiological traits. In the current study, an expression GWAS has been carried out on an experimental Iberian * Landrace backcross in order to identify the genomic regions regulating the gene expression of those genes whose expression is correlated with growth, fat deposition, and premium cut yield measures in pig. The analyses were conducted exploiting Porcine 60K SNP BeadChip genotypes and Porcine Expression Microarray data hybridized on mRNA from Longissimus dorsi muscle. In order to focus the analysis on productive traits and reduce the number of analyses, only those probesets whose expression showed significant correlation with at least one of the seven phenotypes of interest were selected for the eGWAS. A total of 63 eQTL regions were identified with effects on 36 different transcripts. Those eQTLs overlapping with phenotypic QTLs on SSC4, SSC9, SSC13, and SSC17 chromosomes previously detected in the same animal material were further analyzed. Moreover, candidate genes and SNPs were analyzed. Among the most promising results, a long non-coding RNA, ALDBSSCG0000001928, was identified, whose expression is correlated with premium cut yield. Association analysis and in silico sequence domain annotation support TXNRD3 polymorphisms as candidate to regulate ALDBSSCG0000001928 expression, which can be involved in the transcriptional regulation of surrounding genes, affecting productive and meat quality traits. PMID- 27942839 TI - Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma. AB - BACKGROUND: Vascular endothelial growth factor (VEGF), in addition to being pro angiogenic, is an immunomodulatory cytokine systemically and in the tumor microenvironment. We previously reported the immunomodulatory effects of radiation and temozolomide (TMZ) in newly diagnosed glioblastoma. This study aimed to assess changes in peripheral blood mononuclear cell (PBMC) populations, plasma cytokines, and growth factor concentrations following treatment with radiation, TMZ, and bevacizumab (BEV). METHODS: Eleven patients with newly diagnosed glioblastoma were treated with radiation, TMZ, and BEV, following surgery. We measured immune-related PBMC subsets using multi-parameter flow cytometry and plasma cytokine and growth factor concentrations using electrochemiluminescence-based multiplex analysis at baseline and after 6 weeks of treatment. RESULTS: The absolute number of peripheral blood regulatory T cells (Tregs) decreased significantly following treatment. The lower number of peripheral Tregs was associated with a CD4+ lymphopenia, and thus, the ratio of Tregs to PBMCs was unchanged. The addition of bevacizumab to standard radiation and temozolomide led to the decrease in the number of circulating Tregs when compared with our prior study. There was a significant decrease in CD8+ cytotoxic and CD4+ recent thymic emigrant T cells, but no change in the number of myeloid derived suppressor cells. Significant increases in plasma VEGF and placental growth factor (PlGF) concentrations were observed. CONCLUSIONS: Treatment with radiation, TMZ, and BEV decreased the number but not the proportion of peripheral Tregs and increased the concentration of circulating VEGF. This shift in the peripheral immune cell profile may modulate the tumor environment and have implications for combining immunotherapy with anti-angiogenic therapy. PMID- 27942840 TI - Expression of an immunogenic LTB-based chimeric protein targeting Zaire ebolavirus epitopes from GP1 in plant cells. AB - KEY MESSAGE: An antigenic protein targeting two epitopes from the Zaire ebolavirus GP1 protein was expressed in plant cells rendering an antigen capable of inducing humoral responses in mouse when administered subcutaneously or orally. The 2014 Ebola outbreak made clear that new treatments and prophylactic strategies to fight this disease are needed. Since vaccination is an intervention that could achieve the control of this epidemic disease, exploring the production of new low-cost vaccines is a key path to consider; especially in developing countries. In this context, plants are attractive organisms for the synthesis and delivery of subunit vaccines. This study aimed at producing a chimeric protein named LTB-EBOV, based on the B subunit of the Escherichia coli heat-labile enterotoxin as an immunogenic carrier and two epitopes from the Zaire ebolavirus GP1 protein recognized by neutralizing antibodies. The LTB-EBOV protein was expressed in plant tissues at levels up to 14.7 ug/g fresh leaf tissue and proven to be immunogenic in BALB/c mice when administered by either subcutaneous or oral routes. Importantly, IgA and IgG responses were induced following the oral immunization. The potential use of the plant-made LTB-EBOV protein against EBOV is discussed. PMID- 27942841 TI - Membrane-related hallmarks of kinetin-induced PCD of root cortex cells. AB - KEY MESSAGE: Changes in cellular membrane potential and their fluidisation are the hallmarks of cell death induction with kinetin in root cortex. Programmed cell death (PCD), one of the essential processes in plant development, is still poorly understood. In this paper, the scientific plant model, V. faba ssp. minor seedling roots after kinetin application which triggers off programmed death of cortex cells, was used to recognise membrane-related aspects of plant cell death. Spectrophotometric, reflectometric and microscopic studies showed that the PCD induced by kinetin is accompanied by higher potassium ions leakage from roots, loss of plasma and ER membrane potentials (expressed by their lower amounts and higher index of fatty acid unsaturation), malformation of nuclear envelope, lower total lipid amount and formation of their peroxides, lower amount of phospholipids and changes in their composition. The results showed that potassium ions leakage, expressed in percentage of their amounts, and loss of plasma and ER membrane potential, expressed in percentage of their fluorescence intensity, together with the nuclear chromatin double staining with ethidium bromide and acridine orange, might be direct and universal methods for detecting specific plant PCD hallmarks and estimation of PCD intensity (percentage of dying and dead cells). PMID- 27942842 TI - Isolation and Genome Sequencing of a Novel Pseudoalteromonas Phage PH1. AB - The family Pseudoalteromonas is highly adaptable to dissimilar ecological habitats and plays an important ecological role in the marine environment. In this study, a new Pseudoalteromonas phage PH1 was isolated from the Yellow Sea. To better understand the bacteriophage, its biological properties, including morphology, host range, growth phenotype, thermal and pH stability, and nucleic acid composition, were investigated in detail. The result showed that the phage PH1 is a Podoviridae-phage with an icosahedral head (60 nm of diameter) and a short tail (26 nm in length). The phage PH1 genome consists of 42,685 bp length double-stranded DNA with a G+C content of 42.24% and is predicted to have 55 open reading frames (ORFs) with an average length of 740 bp nucleotides each. The phage PH1 genome adds a new Podoviridae-phage genome to marine bacteriophage dataset, which will provide useful basic information for further molecular research on interaction mechanisms between bacteriophages and their hosts. PMID- 27942844 TI - Referees 2016. PMID- 27942843 TI - Common findings of bla CTX-M-55-encoding 104-139 kbp plasmids harbored by extended-spectrum beta-lactamase-producing Escherichia coli in pork meat, wholesale market workers, and patients with urinary tract infection in Vietnam. AB - Extended-spectrum, beta-lactamase-producing Escherichia coli (ESBL-E) harboring the bla CTX-M-55-encoding plasmid (ESBL-E55) has been reported to be associated with urinary tract infection (UTI). The aims of this study were to clarify the prevalence of ESBL-E55 in pork meats and workers from the same wholesale market, as well as patients with UTI from a nearby hospital in Vietnam; we also investigated the plasmids encoding bla CTX-M-55. Sequencing analysis showed that 66.6% of the ESBL-E isolated from pork meats contained bla CTX-M-55, whereas the gene was present in 25.0% of workers and 12.5% of patients with UTI. Plasmid analysis showed that several sizes of plasmid encoded bla CTX-M-55 in ESBL-E55 isolated from pork meats, whereas ESBL-E55 isolated from workers and patients with UTI contained only 104-139 kbp of bla CTX-M-55-encoding plasmids. This indicates that the 104-139 kbp sizes of bla CTX-M-55-encoding plasmids were commonly disseminated in pork meats, wholesale market workers, and patients with UTI. PMID- 27942845 TI - In vitro assessment of iron availability from commercial Young Child Formulae supplemented with prebiotics. AB - PURPOSE: Iron is essential for development and growth in young children; unfortunately, iron deficiency (ID) is a significant public health problem in this population. Young Child Formulae (YCF), milk-derived products fortified with iron and ascorbic acid (AA, an enhancer of iron absorption) may be good sources of iron to help prevent ID. Furthermore, some YCF are supplemented with prebiotics, non-digestible carbohydrates suggested to enhance iron bioavailability. The aim of our study was to evaluate iron bioavailability of YCF relative to prebiotic and AA concentrations. We hypothesised that YCF with the highest levels of prebiotics and AA would have the most bioavailable iron. METHODS: We used the in vitro digestion/Caco-2 cell model to measure iron bioavailability from 4 commercially available YCF with approximately equal amounts of iron, but varying amounts of: AA and the prebiotics fructo- and galacto-oligosaccharides. Caco-2 cell ferritin formation was used as a surrogate marker for iron bioavailability. RESULTS: The YCF with the highest concentration of prebiotics and AA had the highest iron bioavailability; conversely, the YCF with the lowest concentration of prebiotics and AA had the lowest. After the addition of exogenous prebiotics, so that all tested YCF had equivalent amounts, there was no longer a significant difference between YCF iron bioavailability. CONCLUSION: Our results suggest that ascorbic acid and prebiotics in YCF improve iron bioavailability. Ensuring that iron is delivered in a bioavailable form would improve the nutritional benefits of YCF in relation to ID/IDA amongst young children; therefore, further exploration of our findings in vivo is warranted. PMID- 27942846 TI - Concurrent iron and zinc deficiencies in lactating mothers and their children 6 23 months of age in two agro-ecological zones of rural Ethiopia. AB - PURPOSE: The aim of this study is to examine the co-occurrences of low serum ferritin and zinc and anaemia among mothers and their children in two agro ecological zones of rural Ethiopia. METHODS: Data were collected from 162 lactating mothers and their breast fed children aged 6-23 months. The data were collected via a structured interview, anthropometric measurements, and blood tests for zinc, ferritin and anaemia. Correlation, Chi-square and multivariable analysis were used to determine the association between nutritional status of mothers and children, and agro-ecological zones. RESULTS: Low serum levels of iron and zinc, anaemia and iron deficiency anaemia were found in 44.4, 72.2, 52.5 and 29.6% of children and 19.8, 67.3, 21.8, 10.5% of mothers, respectively. There was a strong correlation between the micronutrient status of the mothers and the children for ferritin, zinc and anaemia (p < 0.005). Deficiency in both zinc and ferritin and one of the two was observed in 19.1, and 53.7% of the mothers and 32.7 and 46.3%, of their children, respectively. In the 24 h before the survey, 82.1% of mothers and 91.9% of their infants consumed foods that can decrease zinc bioavailability while only 2.5% of mothers and 3.7% of their infants consumed flesh foods. CONCLUSION: This study shows that micronutrient deficiencies were prevalent among lactating mothers and their children, with variation in prevalence across the agro-ecological zones. This finding calls for a need to design effective preventive public health nutrition programs to address both the mothers' and their children's needs. PMID- 27942847 TI - Neuroendocrine neoplasms of the genitourinary tract in adults: cross-sectional imaging spectrum. AB - Neuroendocrine (NE) neoplasms of the genitourinary (GU) tract in adults are rare tumors with distinct histopathology and variable biological behavior and imaging findings. They may be primary or metastatic in origin. The spectrum of primary GU tract NE neoplasms includes carcinoid, small cell carcinoma, large cell NE carcinoma, and paraganglioma. The tumors commonly show positivity to specific immunohistochemical markers and characteristic dense-core granules at the ultra structural level. Although imaging findings are nonspecific and accurate differentiation from the more common malignancies of the individual organs is not possible, cross-sectional imaging modalities play an important role in the diagnosis, staging, and surveillance of these tumors. Somatostatin receptor scintigraphy (octreotide scan) may be useful in the detection and treatment of metastatic disease in select patients. Knowledge of the various NE tumors of the adult GU tract and familiarity with their pathological and imaging findings permit optimal patient management. PMID- 27942849 TI - Chylous Ascites Management After Pancreatic Surgery. PMID- 27942848 TI - Thromboembolic Prophylaxis with Heparin in Patients with Blunt Solid Organ Injuries Undergoing Non-operative Treatment. AB - BACKGROUND: Patients with blunt solid organ injuries (SOI) are at risk for venous thromboembolism (VTE), and VTE prophylaxis is crucial. However, little is known about the safety of early prophylactic administration of heparin in these patients. METHODS: This is a retrospective study including adult trauma patients with SOI (liver, spleen, kidney) undergoing non-operative management (NOM) from 01/01/2009 to 31/12/2014. Three groups were distinguished: prophylactic heparin (low molecular weight heparin or low-dose unfractionated heparin) <=72 h after admission ('early heparin group'), >72 h after admission ('late heparin group'), and no heparin ('no heparin group'). Patient and injury characteristics, transfusion requirements, and outcomes (failed NOM, VTE, and mortality) were compared between the three groups. RESULTS: Overall, 179 patients were included; 44.7% in the 'early heparin group,' 34.6% in the 'late heparin group,' and 20.8% in the 'no heparin group.' In the 'late heparin group,' the ISS was significantly higher than in the 'early' and 'no heparin groups' (median 29.0 vs. 17.0 vs. 19.0; p < 0.001). The overall NOM failure rate was 3.9%. Failed NOM was significantly more frequent in the 'no heparin group' compared to the 'early' and 'late heparin groups' (10.8 vs. 3.2 vs. 1.3%; p = 0.043). In the 'early heparin group' 27.5% patients suffered from a high-grade SOI; none of these patients failed NOM. Mortality did not differ significantly. Although not statistically significant, VTE were more frequent in the 'no heparin group' compared to the 'early' and 'late heparin groups' (10.8 vs. 4.8 vs. 1.3%; p = 0.066). CONCLUSION: In patients with SOI, heparin was administered early in a high percentage of patients and was not associated with an increased NOM failure rate or higher in hospital mortality. PMID- 27942851 TI - Erratum to: Corrective osteotomy assisted by computer simulation for a malunited intra-articular fracture of the distal humerus: two case reports. PMID- 27942850 TI - Blood loss and transfusion rate in short stem hip arthroplasty. A comparative study. AB - PURPOSE: Little scientific evidence on blood loss and transfusion rates after short-stem hip arthroplasty exists. The hypothesis of this study was that the blood loss and transfusion rate is lower in short stems compared to straight stems. METHODS: We compared 124 patients who underwent total hip arthroplasty (THA) using a short-stem design (group 1) and 141 patients using a straight-stem design (group 2). All patients were operated on by the same surgeon, and both groups were similar in age, gender, affected side, body mass index, and ASA score. RESULTS: The calculated blood loss was 1139 ml in group 1 and 1358 ml in group 2 (p < 0.001). The transfusion rate was 8% in group 1 and 15.6% in group 2 (p < 0.001). There was no significant difference between groups 1 and 2 regarding complications and operation time (p > 0.05). CONCLUSION: Compared to patients after straight stem THA, both blood loss and blood transfusion rates were lower in patients after short stem THA. PMID- 27942852 TI - Salidroside accelerates fracture healing through cell-autonomous and non autonomous effects on osteoblasts. AB - Salidroside (SAL), a major active component of Rhodiola rosea L., exhibits diverse pharmacological effects. However, the direct roles of SAL in fracture healing remain largely unknown. Here, we demonstrate that SAL significantly promotes proliferation by altering the cell-cycle distribution of osteoblastic cells. SAL also greatly stimulates osteoblast differentiation and mineralization by inducing the expression of Runx2 and Osterix. In addition to its osteoblast autonomous effects, SAL can activate the HIF-1alpha pathway coupling of angiogenesis and osteogenesis through cell-non-autonomous effects. Our in vitro results suggest that SAL significantly up-regulates HIF-1alpha expression at the mRNA and protein levels. Furthermore, the nuclear translocation and transcriptional activity of HIF-1alpha and the HIF-responsive gene VEGF increase following SAL treatment. Our mechanistic study revealed that the regulation of osteoblastic proliferation and HIF-1alpha expression partly involves MAPK/ERK and PI3K/Akt signaling. Our in vivo analysis also demonstrated that SAL can promote angiogenesis within the callus and accelerate fracture healing. Thus, SAL promotes skeletal regeneration in cell-autonomous and cell-non-autonomous ways and might be a potential therapy for accelerating fracture healing. PMID- 27942853 TI - Notch signaling-mediated cell-to-cell interaction is dependent on E-cadherin adhesion in adult rat anterior pituitary. AB - The rat anterior pituitary is composed of hormone-producing cells, non-hormone producing cells (referred to as folliculostellate cells) and marginal layer cells. In the adult rat, progenitor cells of hormone-producing cells have recently been reported to be maintained within this non-hormone-producing cell population. In tissue, non-hormone-producing cells construct homophilic cell aggregates by the differential expression of the cell adhesion molecule E cadherin. We have previously shown that Notch signaling, a known regulator of progenitor cells in a number of organs, is activated in the cell aggregates. We now investigate the relationship between Notch signaling and E-cadherin-mediated cell adhesion in the pituitary gland. Immunohistochemically, Notch signaling receptor Notch2 and the ligand Jagged1 were localized within E-cadherin-positive cells in the marginal cell layer and in the main part of the anterior lobe, whereas Notch1 was localized in E-cadherin-positive and -negative cells. Activation of Notch signaling within E-cadherin-positive cells was confirmed by immunostaining of the Notch target HES1. Notch2 and Jagged1 were always co localized within the same cells suggesting that homologous cells have reciprocal effects in activating Notch signaling. When the E-cadherin function was inhibited by exposure to a monoclonal antibody (DECMA-1) in primary monolayer cell culture, the percentage of HES1-positive cells among Notch2-positive cells was less than half that of the control. The present results suggest that E-cadherin-mediated cell attachment is necessary for the activation of Notch signaling in the anterior pituitary gland but not for the expression of the Notch2 molecule. PMID- 27942854 TI - Altered expression of Crb2 in podocytes expands a variation of CRB2 mutations in steroid-resistant nephrotic syndrome. AB - BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a genetically heterogeneous disorder for which more than 25 single-gene hereditary causes have been identified. METHODS: Whole exome sequencing was performed in a 3-year-old girl with SRNS. We analyzed the expression of Crb2 and slit diaphragm molecules in the patient's glomeruli, and compared it with that of controls or other nephrotic patients. RESULTS: Whole-exome analysis identified novel compound heterozygous mutations in exons 10 and 12 of CRB2 (p.Trp1086ArgfsX64 and p.Asn1184Thr, each from different parents; Asn1184 within extracellular 15th EGF repeat domain). Renal pathology showed focal segmental glomerulosclerosis with effaced podocyte foot processes in a small area, with significantly decreased Crb2 expression. Molecules critical for slit diaphragm were well-expressed in this patient's podocytes. Crb2 expression was not altered in the other patients with congenital nephrotic syndrome with NPHS1 mutations. CONCLUSIONS: These findings demonstrate that Crb2 abnormalities caused by these mutations are the mechanism of steroid-resistant NS. Although CRB2 mutations previously found in SRNS patients have been clustered within the extracellular tenth EGF-like domain of this protein, the present results expand the variation of CRB2 mutations that cause SRNS. PMID- 27942855 TI - Functional neuroimaging of visuo-vestibular interaction. AB - The brain combines visual, vestibular and proprioceptive information to distinguish between self- and world motion. Often these signals are complementary and indicate that the individual is moving or stationary with respect to the surroundings. However, conflicting visual motion and vestibular cues can lead to ambiguous or false sensations of motion. In this study, we used functional magnetic resonance imaging to explore human brain activation when visual and vestibular cues were either complementary or in conflict. We combined a horizontally moving optokinetic stimulus with caloric irrigation of the right ear to produce conditions where the vestibular activation and visual motion indicated the same (congruent) or opposite directions of self-motion (incongruent). Visuo vestibular conflict was associated with increased activation in a network of brain regions including posterior insular and transverse temporal areas, cerebellar tonsil, cingulate and medial frontal gyri. In the congruent condition, there was increased activation in primary and secondary visual cortex. These findings suggest that when sensory information regarding self-motion is contradictory, there is preferential activation of multisensory vestibular areas to resolve this ambiguity. When cues are congruent, there is a bias towards visual cortical activation. The data support the view that a network of brain areas including the posterior insular cortex may play an important role in integrating and disambiguating visual and vestibular cues. PMID- 27942856 TI - Prevalence and risk factors of adhesive capsulitis of the shoulder after breast cancer treatment. AB - PURPOSE: The present study investigated the prevalence and risk factors of adhesive capsulitis of the shoulder in breast cancer patients between 13 and 18 months after surgery. METHODS: This study included 271 women who underwent surgery for breast cancer with a postoperative period of 13-18 months. Current adhesive capsulitis was defined as restriction of external rotation and one or more additional directional restrictions with history of shoulder pain. Cumulative adhesive capsulitis was defined as current adhesive capsulitis or a previous history of adhesive capsulitis after breast cancer surgery. Multivariate logistic regression analysis was performed to examine associations between current or cumulative adhesive capsulitis and potential risk factors. RESULTS: Among the 271 study patients, 28 (10.3%) and 21 (7.7%) had cumulative or current adhesive capsulitis, respectively. The incidences of cumulative and current adhesive capsulitis were higher in those aged 50-59 years (odds ratio [OR], 9.912; 95% confidence interval [CI], 1.790-54.880; and OR, 12.395; 95% CI, 1.187 129.444, respectively) and those who underwent mastectomy (OR, 6.805; 95% CI, 1.800-25.733; and OR, 9.645; 95% CI, 2.075-44.829, respectively) or mastectomy with reconstruction (OR, 13.122; 95% CI, 2.488-69.218; and OR, 20.075; 95% CI, 2.873-140.261, respectively). CONCLUSIONS: Adhesive capsulitis of the shoulder is a common problem after breast cancer treatment. An age of 50-59 years and mastectomy are major risk factors for adhesive capsulitis, and breast reconstruction additionally increases the risk. Patients with these risk factors require greater attention for early diagnosis and proper treatment. PMID- 27942857 TI - Sustainable impact of an individualized exercise program on physical activity level and fatigue syndrome on breast cancer patients in two German rehabilitation centers. AB - PURPOSE: Although physical activity has been demonstrated to increase cancer survival in epidemiological studies, breast cancer patients tend toward inactivity after treatment. METHODS: Breast cancer patients were quasi-randomly allocated to two different groups, intervention (IG) and control (CG) groups. The intervention group (n = 111) received an individual 3-week exercise program with two additional 1-week inpatient stays after 4 and 8 months. At the end of the rehabilitation, a home-based exercise program was designed. The control group (n = 83) received a 3-week rehabilitation program and did not obtain any follow-up care. Patients from both groups were measured using questionnaires on physical activity, fatigue, and quality of life (QoL) at five time points, 4 months (t1), 8 months (t2), 12 months (t3), 18 months (t4), and 24 months (t5) after the beginning of the rehabilitation. RESULTS: After 2 years, the level of physical activity (total metabolic rate) increased significantly from 2733.16 +/- 2547.95 (t0) to 4169.71 +/- 3492.27 (t5) metabolic equivalent (MET)-min/week in the intervention group, but just slightly changed from 2858.38 +/- 2393.79 (t0) to 2875.74 +/- 2590.15 (t5) MET-min/week in the control group (means +/- standard deviation). Furthermore, the internal group comparison showed significant differences after 2 years as well. These results came along with a significantly reduced fatigue syndrome and an increased health-related quality of life. CONCLUSIONS: The data indicate that an individual, according to their preferences, and physical-resource-adapted exercise program has a more sustainable impact on the physical activity level in breast cancer patients than the usual care. It is suggested that the rehabilitation program should be personalized for all breast cancer patients. PMID- 27942859 TI - Cellulase immobilization on magnetic nanoparticles encapsulated in polymer nanospheres. AB - Immobilization of cellulases on magnetic nanoparticles, especially magnetite nanoparticles, has been the main approach studied to make this enzyme, economically and industrially, more attractive. However, magnetite nanoparticles tend to agglomerate, are very reactive and easily oxidized in air, which has strong impact on their useful life. Thus, it is very important to provide proper surface coating to avoid the mentioned problems. This study aimed to investigate the immobilization of cellulase on magnetic nanoparticles encapsulated in polymeric nanospheres. The support was characterized in terms of morphology, average diameter, magnetic behavior and thermal decomposition analyses. The polymer nanospheres containing encapsulated magnetic nanoparticles showed superparamagnetic behavior and intensity average diameter about 150 nm. Immobilized cellulase exhibited broader temperature stability than in the free form and great reusability capacity, 69% of the initial enzyme activity was maintained after eight cycles of use. The magnetic support showed potential for cellulase immobilization and allowed fast and easy biocatalyst recovery through a single magnet. PMID- 27942858 TI - Genetic polymorphisms of 17 Y-chromosomal STRs in the Chengdu Han population of China. AB - Chengdu is located at the center of Sichuan Province in southwestern China, and its primary demographic group is the Han population. The aim of this study was to contribute data detailing 17 Y-short tandem repeat (Y-STR) loci from 3291 Chengdu Han male samples analyzed with the AmpFLSTR(r) Yfiler(r) PCR Amplification Kit. We observed 2228 different haplotypes, and haplotype diversity (HD) was 0.9992. Gene diversity (GD) values for the 17 Y-STR loci of the Chengdu Han population ranged from 0.4156 to 0.9529. Haplotype match probability (HMC) was 0.0011. Compared with 13 reference populations of six provinces surrounding Chengdu, we observed that the Chengdu Han population was significantly different from each of these populations. PMID- 27942860 TI - Comprehensive gene and microRNA expression profiling reveals a role for miRNAs in the oncogenic roles of SphK1 in papillary thyroid cancer. AB - PURPOSE: The oncogenic roles of sphingosine kinase 1 (SphK1) in various cancers, including thyroid cancer, have been well demonstrated. However, the microRNAs (miRNAs) associated with the oncogenic roles of SphK1 remain largely unknown. METHODS: Global gene and miRNA expression in TPC1-Vector and TPC1-SphK1 cells was analyzed using digital gene expression (DGE) analysis and small RNA-seq, respectively. miRNA-mRNA interactions were explored by microT-CDS, and the predicted networks were visualized using CytoScape(r). Cell invasion and migration were assessed by performing Transwell invasion and wound-healing assays. Luciferase reporter and immunoblot assays were used to evaluate the targeting of fibronectin 1 (FN1) by miR-144-3p. RESULTS: In this study, we found that overexpression of SphK1 differentially regulates the expression of 46 miRNAs and 506 mRNAs in papillary thyroid cancer (PTC) TPC1 cells. Combining bioinformatics predictions of mRNA targets with DGE data on mRNA expression allowed us to identify the mRNA targets of deregulated miRNAs. The direct interaction between miR-144-3p and FN1, which mediates the pro-invasive role of SphK1 in PTC cells, was experimentally validated. CONCLUSIONS: Our results demonstrated that SphK1 overexpression drives a regulatory network governing miRNA and mRNA expression in PTC cells. We also demonstrated the roles played by miR-144-3p and FN1 in mediating the oncogenic function of SphK1, which enhanced the understanding of the etiology of PTC. PMID- 27942862 TI - Altered immune reconstitution of B and T cells precedes the onset of clinical symptoms of chronic graft-versus-host disease and is influenced by the type of onset. AB - We analyzed lymphocyte subpopulations and cytokines 3 months after allogeneic hematopoietic stem cell transplantation aiming to identify predictive cellular and serum markers for chronic graft-versus-host disease (cGVHD). Samples of 49 patients (pts) (no cGVHD (n = 14), subsequent quiescent onset (n = 16), de novo onset of cGVHD (n = 19)) were analyzed in the absence of active GVHD by flow cytometry and enzyme-linked immunosorbent assay. All mean absolute cell counts are presented as cells per microliter; relative cell counts are presented as percentage of lymphocytes. Pts with subsequent de novo cGVHD had significantly higher relative and absolute counts of CD4+ T cells including higher absolute counts of CD4+ memory T cells (22.36%; 206.55/MUl; 136/MUl, respectively) compared to pts with subsequent quiescent onset of cGVHD (12.41%; 83.42/MUl; 54.3/MUl) and pts without cGVHD (10.55%) with regard to relative counts of CD4+ T cells. Similarly, significantly more relative and absolute regulatory T cell numbers (CD4+FOXP3+) were detected in pts with de novo onset of cGVHD (3.08% and 24.63/MUl) compared to those in pts without (1.25% and 9.06/MUl) or with quiescent onset of cGVHD (1.15% and 6.91/MUl). Finally, relative B cell counts, including naive and memory B cells, were also significantly decreased in pts developing quiescent cGVHD (0.85, 0.73, 0.12% resp.) when compared to pts with de novo onset (5.61, 5.24, 0.38%). The results demonstrate that alterations in immune reconstitution are already present before onset of clinical symptoms and differ between de novo and quiescent onset of disease. PMID- 27942861 TI - Decreased white matter FA values in the left inferior frontal gyrus is a possible intermediate phenotype of schizophrenia: evidences from a novel group strategy. AB - Intermediate phenotype could be used to investigate genetic susceptibility. However, genetic and environmental heterogeneity may interfere with identification of intermediate phenotypes. In this study, we minimized these interferences by using a novel group strategy. A total of 22 drug-naive and first episode schizophrenia (FES) patients, along with 22 of their kin healthy siblings (HS), 22 non-kin healthy siblings (nHS) of other schizophrenia patients and 22 healthy controls (HC), were recruited. Brain imaging was acquired from the participants. Voxel-based analysis was used to investigate differences in white matter integrity derived from diffusion tensor imaging among the four groups. Two cognitive tests related to our findings were selected to confirm the related phenotypic changes. All of the FES, HS, and nHS groups showed decreased fractional anisotropy (FA) values in the left inferior frontal gyrus (IFG) compared with the HC group (p < 0.05, FDR corrected). The scores of Hopkins Verbal learning Test-Revised and Animal Naming in FES patients were significantly lower than in participants belonging to the other three groups (p < 0.05). Significant correlation between Animal Naming scores and FA values in the left IFG was found in FES patients (r = 0.53, p = 0.01). Moreover, FES patients also showed decreased FA values in the left medial frontal gyrus, left inferior temporal gyrus, left parahippocampal gyrus, left posterior cingulate, and right middle temporal gyrus compared with HC (p < 0.05, FDR corrected). Decreased FA values in the left IFG is a possible intermediate phenotype of schizophrenia, and this finding supports the hypothesis that disrupted connectivity of white matter may be the key substrate of schizophrenia. PMID- 27942863 TI - Non-native parasite enhances susceptibility of host to native predators. AB - Parasites often alter host physiology and behavior, which can enhance predation risk for infected hosts. Higher consumption of parasitized prey can in turn lead to a less parasitized prey population (the healthy herd hypothesis). Loxothylacus panopaei is a non-native castrating barnacle parasite on the mud crab Eurypanopeus depressus along the Atlantic coast. Through prey choice mesocosm experiments and a field tethering experiment, we investigated whether the predatory crab Callinectes sapidus and other predators preferentially feed on E. depressus infected with L. panopaei. We found that C. sapidus preferentially consumed infected E. depressus 3 to 1 over visibly uninfected E. depressus in the mesocosm experiments. Similarly, infected E. depressus were consumed 1.2 to 1 over uninfected conspecifics in field tethering trials. We evaluated a mechanism behind this skewed prey choice, specifically whether L. panopaei affects E. depressus movement, making infected prey more vulnerable to predator attack. Counter to our expectations, infected E. depressus ran faster during laboratory trials than uninfected E. depressus, suggesting that quick movement may not decrease predation risk and seems instead to make the prey more vulnerable. Ultimately, the preferential consumption of L. panopaei-infected prey by C. sapidus highlights how interactions between organisms could affect where novel parasites are able to thrive. PMID- 27942864 TI - Seasonal survival estimation for a long-distance migratory bird and the influence of winter precipitation. AB - Conservation of migratory animals requires information about seasonal survival rates. Identifying factors that limit populations, and the portions of the annual cycle in which they occur, are critical for recognizing and reducing potential threats. However, such data are lacking for virtually all migratory taxa. We investigated patterns and environmental correlates of annual, oversummer, overwinter, and migratory survival for adult male Kirtland's warblers (Setophaga kirtlandii), an endangered, long-distance migratory songbird. We used Cormack Jolly-Seber models to analyze two mark-recapture datasets: 2006-2011 on Michigan breeding grounds, and 2003-2010 on Bahamian wintering grounds. The mean annual survival probability was 0.58 +/- 0.12 SE. Monthly survival probabilities during the summer and winter stationary periods were relatively high (0.963 +/- 0.005 SE and 0.977 +/- 0.002 SE, respectively). Monthly survival probability during migratory periods was substantially lower (0.879 +/- 0.05 SE), accounting for ~44% of all annual mortality. March rainfall in the Bahamas was the best supported predictor of annual survival probability and was positively correlated with apparent annual survival in the subsequent year, suggesting that the effects of winter precipitation carried over to influence survival probability of individuals in later seasons. Projection modeling revealed that a decrease in Bahamas March rainfall >12.4% from its current mean could result in negative population growth in this species. Collectively, our results suggest that increased drought during the non-breeding season, which is predicted to occur under multiple climate change scenarios, could have important consequences on the annual survival and population growth rate of Kirtland's warbler and other Neotropical-Nearctic migratory bird species. PMID- 27942865 TI - European perspective on less invasive surfactant administration-a survey. AB - : Less invasive surfactant administration or minimally invasive surfactant therapy (LISA/MIST) has been proposed for the administration of surfactant in preterm infants without intubation. The aim of our survey was to assess the rate of utilization, premedication as well as technique and equipment used for LISA/MIST. Furthermore, attitudes and experiences in regard to indications, side effects, and efficacy should be assessed. An online-based survey was sent to 324 neonatologists from different centers within 37 European countries between December 2015 and March 2016. Of those 165 who responded (response rate 51%), 86 (52%) were using LISA/MIST. It is regarded the standard procedure for surfactant administration by 41%, with a wide variation in personal views on patient selection in terms of indication, appropriate gestational and postnatal age. Policies concerning premedication, devices, and technique of LISA/MIST differed widely. Side effects like surfactant reflux, bradycardia, and hypoxia were observed by 77% of neonatologists. Of neonatologists inexperienced in LISA/MIST, 89% would consider utilizing it in the future. Perceived efficacy of LISA/MIST was high (52%) to medium (33%). CONCLUSION: The use of LISA/MIST within Europe is widespread. There is a wide variation concerning all aspects of LISA in daily clinical routine and different views on when and how LISA should be performed. What is Known: * Noninvasive surfactant administration has been the subject of randomized controlled trials and has found its way into clinical routine. What is New: * Noninvasive surfactant administration techniques are widely applied in European neonatal units. * There is a wide variety of equipment used and techniques applied for less invasive surfactant delivery as well as different views on the indications and perceived efficacy of this intervention. PMID- 27942868 TI - Music therapy improves the mood of patients undergoing hematopoietic stem cells transplantation (controlled randomized study). AB - PURPOSE: The allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a therapeutic medical treatment for various neoplastic hematologic, congenital, genetic, or acquired disorders. In this procedure which combines high-dose chemotherapy and/or radiotherapy and has a high degree of cytotoxicity, the patient experiences solitary confinement, which causes psychological distress, pain, anxiety, mood disorders and can lead him/her to depression. Music therapy was applied with the purpose of decreasing this social confinement. This is a randomized controlled trial. METHOD: Patients (n = 100) were selected randomly. Patients (n = 50) were selected for the Experimental Music Therapy Group (EMG) and n = 50 for the control group (CG) who received the standard treatment. The intervention of live music was applied using music therapy techniques. Assessment and quantification were made using the visual analog scale (VAS). The dependent variables were pain, anxiety, and mood of patients. RESULTS: The Mann-Whitney test (p < 0.05) applied was considered statistically significant when comparing the groups, improving mood significantly (EMG). CONCLUSION: Music therapy proved to be a strong ally in the treatment of patients undergoing allo-HSCT, providing bio-psychosocial welfare. PMID- 27942866 TI - Protective effects of levamisole, acetylsalicylic acid, and alpha-tocopherol against dioxin toxicity measured as the expression of AhR and COX-2 in a chicken embryo model. AB - Polychlorinated dibenzo-p-dioxins and dibenzofurans (dioxins) are classed as persistent organic pollutants and have adverse effects on multiple functions within the body. Dioxins are known carcinogens, immunotoxins, and teratogens. Dioxins are transformed in vivo, and interactions between the products and the aryl hydrocarbon receptor (AhR) lead to the formation of proinflammatory and toxic metabolites. The aim of this study was to determine whether alpha tocopherol (vitamin E), acetylsalicylic acid (ASA), and levamisole can decrease the amount of damage caused by dioxins. Fertile Hubbard Flex commercial line chicken eggs were injected with solutions containing 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) or containing TCDD and the test compounds. The chicken embryos and organs were analyzed after 7 and 13 days. The levels at which AhR and cyclooxygenase-2 (COX-2) proteins (which are induced during inflammation) were expressed were evaluated by performing immunohistochemical analyses on embryos treated with TCDD alone or with TCDD and the test compounds. TCDD caused developmental disorders and increased AhR and COX-2 expression in the chicken embryo tissues. Vitamin E, levamisole, ASA, and ASA plus vitamin E inhibited AhR and COX-2 expression in embryos after 7 days and decreased AhR and COX-2 expression in embryos after 13 days. ASA, levamisole, and ASA plus vitamin E weakened the immune response and prevented multiple organ changes. Vitamin E was not fully protective against developmental changes in the embryos. PMID- 27942867 TI - Thymosin beta4 overexpression regulates neuron production and spatial distribution in the developing avian optic tectum. AB - Thymosin beta4 (Tbeta4), the principal G-actin regulating entity in eukaryotic cells, has also multiple intra- and extracellular functions related to tissue regeneration and healing. While its effect in adult organs is being widely investigated, currently, little is known about its influence on embryonic tissues, i.e., in the developing nervous system. The importance of Tbeta4 for neural stem cell proliferation in the embryonic chicken optic tectum (OT) has previously been shown by us for the first time. In the present study, using in ovo electroporation, we carried out a quantification of the effects of the Tbeta4 overexpression on the developing chicken OT between E4 and E6 at the hemisphere as well as cellular level. We precisely examined tissue growth and characterized cells arising from the elevated mitotic activity of progenitor cells. By using spinning-disk confocal laser scanning microscopy, we were able to visualize these effects across whole OT sections. Our experiments now demonstrate more clearly that the overexpression of Tbeta4 leads to a tangential expansion of the treated OT-hemisphere and that, under these circumstances, overall density of tectal and in particular of postmitotic neuronal cells is increased. Thanks to this new quantitative approach, the present results extend our previous findings that Tbeta4 is important for the proliferation of progenitor cells, neurogenesis, tangential expansion, and tissue growth in the young embryonic chicken optic tectum. Taken together, our results further illustrate and support the current idea that Tbeta4 is widely implicated in shaping and maintenance of the nervous system. PMID- 27942869 TI - Xenopus laevis neuronal cell adhesion molecule (nrcam): plasticity of a CAM in the developing nervous system. AB - Neuron-glial-related cell adhesion molecule (NRCAM) is a neuronal cell adhesion molecule of the L1 immunoglobulin superfamily, which plays diverse roles during nervous system development including axon growth and guidance, synapse formation, and formation of the myelinated nerve. Perturbations in NRCAM function cause a wide variety of disorders, which can affect wiring and targeting of neurons, or cause psychiatric disorders as well as cancers through abnormal modulation of signaling events. In the present study, we characterize the Xenopus laevis homolog of nrcam. Expression of Xenopus nrcam is most abundant along the dorsal midline throughout the developing brain and in the outer nuclear layer of the retina. PMID- 27942870 TI - New insights in the analysis of blunt force trauma in human bones. Preliminary results. AB - Determining the time of injury is an important but still a challenging task in forensic anthropology. In literature, many descriptions can be found to make a distinction between perimortem and postmortem fractures. Characteristics that are more related to fractures in fresh conditions, however, are not extensively investigated. This study compared 28 perimortem fractures from autopsies and 21 both fresh and dry experimentally reproduced human bone fractures. Preliminary results showed the following five distinct traits that might be related to perimortem conditions: layered breakage, bone scales, crushed margins, wave lines and flakes with matching flake defect. These distinct traits might not only be good estimators of perimortem trauma but also may be an indicator of trauma in intra vitam conditions, especially related with muscular reaction to injury. Furthermore, layered breakage seems to be a good trait to infer the biomechanics of trauma. PMID- 27942873 TI - Identification of a novel SPG4 tandem base substitution in a Chinese hereditary spastic paraplegia family. PMID- 27942872 TI - Erratum to: Incidence of neuroepithelial primary brain tumors among adult population of Emilia-Romagna Region, Italy. PMID- 27942875 TI - Comparison of long-term survival and immediate postoperative liver function after laparoscopic and open distal gastrectomy for early gastric cancer patients with liver cirrhosis. AB - BACKGROUND: Several studies have suggested no difference in the liver function of early gastric cancer (EGC) patients with liver cirrhosis (LC) between laparoscopic and open distal gastrectomy. However, the number of patients and comparison of long-term survival rates between the two groups are limited. The purpose of this study was to compare the long-term survival and immediate postoperative liver function of EGC patients with LC after laparoscopic and open distal gastrectomy. MATERIALS AND METHODS: The clinical data of EGC patients with LC who had no other malignancy and underwent distal gastrectomy at Asan Medical Center between January 2005 and April 2013 were investigated retrospectively. All patients were divided into two groups: the open group (OG) and laparoscopic group (LG). The clinicopathologic data of the two groups were compared. RESULTS: The number of patients in each group was 48 and 27 in the OG and LG, respectively. There were no significant differences in the age, sex ratio, ASA score, cause of liver cirrhosis, preoperative Child-Pugh classification, tumor location, TNM stage, total postoperative drain amount, albumin, total bilirubin, alkaline phosphatase, alanine aminotransferase, prothrombin time, morbidity and recurrence rate. Shorter hospital stay, longer operative time and more retrieved lymph nodes were observed in LG. The long-term overall survival rate was not different between the two groups (P = 0.356). CONCLUSIONS: For EGC patients with liver cirrhosis, especially Child A cirrhosis, laparoscopic or laparoscopy-assisted distal gastrectomy can be a safe surgical procedure in comparison to open distal gastrectomy in terms of the long-term survival rate and immediate postoperative liver function. PMID- 27942874 TI - Side overlap esophagogastrostomy to prevent reflux after proximal gastrectomy. AB - BACKGROUND: No optimal method of reconstruction for proximal gastrectomy has been established because of problems associated with postoperative reflux and anastomotic stenosis. It is also important that the reconstruction is easily performed laparoscopically because laparoscopic gastrectomy has become widely accepted in recent years. METHODS: We have developed a new method of esophagogastrostomy, side overlap with fundoplication by Yamashita (SOFY). The remnant stomach is fixated to the diaphragmatic crus on the dorsal side of the esophagus. The esophagus and the remnant stomach are overlapped by a length of 5 cm. A linear stapler is inserted in two holes on the left side of the esophageal stump and the anterior gastric wall. The stapler is rotated counterclockwise on its axis and fired. The entry hole is closed, and the right side of the esophagus is fixated to the stomach so that the esophagus sticks flat to the gastric wall. The surgical outcomes of the SOFY method were compared with those of esophagogastrectomy different from SOFY. RESULTS: Thirteen of the 14 patients in the SOFY group were asymptomatic without a proton pump inhibitor, but reflux esophagitis was observed in 5 of the 16 patients in the non-SOFY group and anastomotic stenosis was observed in 3 patients. Contrast enhancement findings in the SOFY group showed inflow of Gastrografin to the remnant stomach was extremely good, and no reflux into the esophagus was observed even with patients in the head-down tilt position. CONCLUSIONS: SOFY can be easily performed laparoscopically and may overcome the problems of postoperative reflux and stenosis. PMID- 27942876 TI - Quantitative assessment of the impacts of stoppa repair and total extraperitoneal repair on the lower extremity muscular functions in cases of unilateral inguinal hernia: a randomized controlled study. AB - PURPOSE: Choosing the best operative technique for unilateral inguinal hernia is a challenge for surgeons. Therefore, anticipating loss of strength in the lower extremity muscles could be the initial step to make the right decision. To this end, this prospective randomized controlled study compared the physical activity parameters of the lower extremity muscles in patients who underwent total extraperitoneal repair (TEP) and Stoppa repair. METHODS: Fifty patients with unilateral inguinal hernia who were 18-65 years of age were admitted to a single institution in a metropolitan city in Turkey. Patients were randomized in a 1:1 ratio to parallel study arms of TEP and STOPPA repair. They were evaluated in the preoperative period and on the postoperative day 3 for an objective isometric and isokinetic assessment of the pain-related functional changes in the lower extremity muscles. RESULTS: The measurement results obtained with the Cybex device on the postoperative day 3 were presented as numeric parameters in the digital setting, where the Stoppa repair resulted in a higher loss of strength in the lower extremities compared to the TEP repair. With respect to the total workforce loss in isokinetic muscular measurements at 90 degrees C/s extension, 90 degrees C/s flexion, 180 degrees C/s extension and 180 degrees C/s flexion, the difference between the TEP repair and Stoppa repair was statistically significant in favor of TEP repair (p < 0.05). CONCLUSION: This study is the first comparative study in the literature to demonstrate the favorable impact of the laparoscopic hernia repair on the physical activity on the same anatomic site compared to the open surgical procedure by using quantitative values. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT02813057. PMID- 27942871 TI - Evidence-based clinical practice guidelines for cholelithiasis 2016. AB - Cholelithiasis is one of the commonest diseases in gastroenterology. Remarkable improvements in therapeutic modalities for cholelithiasis and its complications are evident. The Japanese Society of Gastroenterology has revised the evidence based clinical practice guidelines for cholelithiasis. Forty-three clinical questions, for four categories-epidemiology and pathogenesis, diagnosis, treatments, and prognosis and complications-were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases for the period between 1983 and June 2012. The guidelines were developed with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. This article preferentially describes the clinical management of cholelithiasis and its complications. Following description of the diagnosis performed stepwise through imaging modalities, treatments of cholecystolithiasis, choledocholithiasis, and hepatolithiasis are introduced along with a flowchart. Since there have been remarkable improvements in endoscopic treatments and surgical techniques, the guidelines ensure flexibility in choices according to the actual clinical environment. The revised clinical practice guidelines are appropriate for use by clinicians in their daily practice. PMID- 27942877 TI - Spontaneous temporomandibular joint herniation: a rare case. AB - Spontaneous herniation of temporomandibular joint into the external auditory canal through the foramen of Huschke is a very rare condition. We describe a case of spontaneous temporomandibular joint herniation in a 35-year-old male, who presented with otorrhea and aural fullness. The herniation was repaired using collagen mesh. A literature review of all the previous reported cases of spontaneous temporomandibular joint was done to study the presenting clinical features and the method of surgical repair. PMID- 27942878 TI - Community-acquired Pseudomonas aeruginosa bloodstream infection: a classification that should not falsely reassure the clinician. AB - Pseudomonas aeruginosa bloodstream infection (BSI) is predominantly acquired in the hospital setting. Community-onset infection is less common. Differences in epidemiology, clinical features, microbiological factors and BSI outcomes led to the separation of bacterial community-onset BSI into the categories of healthcare associated infection (HCAI) and community-acquired infection (CAI). Community acquired P. aeruginosa BSI epidemiology is not well defined in the literature. In addition, it is also not clear if the same factors separate CAI and HCAI BSI caused by P. aeruginosa alone. A retrospective multicentre cohort study was performed looking at P. aeruginosa BSI from January 2008 to January 2011. Strict definitions for HCAI and CAI were applied. Extensive epidemiological, clinical and outcome data were obtained. Thirty-four CAI episodes and 156 HCAI episodes were analysed. The CAI group could be characterised into seven distinct categories based on comorbidities and clinically suspected source of infection. A pre-morbidly healthy group could not be identified. On multivariate analysis, the presence of a rheumatological or a gastrointestinal comorbidity were significantly associated with CAI. There was no significant difference in length of stay or rates of mortality between HCAI or CAI. The clinician should not be falsely reassured regarding outcome by the diagnosis of a community-acquired P. aeruginosa BSI. PMID- 27942880 TI - Erratum to: Spontaneous regression of a parafalcine meningioma in a multiple sclerosis patient being treated with interferon beta-1a. PMID- 27942879 TI - The sesquiterpene alpha-bisabolol in the adipocyte-cancer desmoplastic crosstalk: does it have an action on epithelial-mesenchymal transition mechanisms? AB - Alpha-bisabolol is a plant-derived sesquiterpene alcohol recently associated with a supposed anti-cancer action due to its ability to induce BID-related apoptosis. The molecule, which enters the cell through lipid rafts, may also interact with kisspeptin receptor 1, which has recently been associated with tumor mobility and invasiveness. This evidence suggests the possibility that alpha-bisabolol might act on the epithelial-mesenchymal transition mechanism, closely associated with the desmoplastic reaction of adipose tissue surrounding a pancreatic ductal adenocarcinoma. This review addresses the issue on the basis of the most recent reported literature in the field. PMID- 27942881 TI - Predictors of early in-hospital death after decompressive craniectomy in swollen middle cerebral artery infarction. AB - BACKGROUND: Swollen middle cerebral artery infarction is a life-threatening disease and decompressive craniectomy is improving survival significantly. Despite decompressive surgery, however, many patients are not discharged from the hospital alive. We therefore wanted to search for predictors of early in-hospital death after craniectomy in swollen middle cerebral artery infarction. METHODS: All patients operated with decompressive craniectomy due to swollen middle cerebral artery infarction at the Department of Neurosurgery, Oslo University Hospital Rikshospitalet, Oslo, Norway, between May 1998 and October 2010, were included. Binary logistic regression analyses were performed and candidate variables were age, sex, time from stroke onset to decompressive craniectomy, NIHSS on admission, infarction territory, pineal gland displacement, reduction of pineal gland displacement after surgery, and craniectomy size. RESULTS: Fourteen out of 45 patients (31%) died during the primary hospitalization (range, 3-44 days). In the multivariate logistic regression model, middle cerebral artery infarction with additional anterior and/or posterior cerebral artery territory involvement was found as the only significant predictor of early in-hospital death (OR, 12.7; 95% CI, 0.01-0.77; p = 0.029). CONCLUSIONS: The present study identified additional territory infarction as a significant predictor of early in hospital death. The relatively small sample size precludes firm conclusions. PMID- 27942883 TI - Mutation screening of PLA2G6 in Japanese patients with early onset dystonia parkinsonism. AB - A recessive mutation in PLA2G6, which is known to cause infantile neuroaxonal dystrophy (INAD) and neurodegeneration associated with brain iron accumulation (NBIA), has recently been shown to be responsible for PARK14-linked dystonia parkinsonism. To study the frequency of PLA2G6 mutations, including those caused by gene rearrangement in patients with parkinsonism, we performed direct sequencing and investigated copy number variations (CNVs) of this gene in 109 Japanese patients with parkinsonism. Direct sequencing revealed a homozygous mutation (c.1495G>A; p.A499T), which is likely to be pathogenic and is already registered as rs141045127, and two compound-heterozygous mutations we have previously reported. No CNVs in PLA2G6 were detected in our subjects. Our results suggest that CNV in PLA2G6 is rare in parkinsonism, at least in the Japanese population, in contrast to the reports of its frequency in INAD. Further large studies in various populations are warranted to elucidate what causes the difference in frequencies of PLA2G6 rearrangement mutations between INAD and dystonia-parkinsonism. PMID- 27942882 TI - Clinical features of CKD-MBD in Japan: cohort studies and registry. AB - Randomized controlled trials (RCTs) are essential for evidence-based medicine; however, cohort studies and registries provide an important information about risk factors and, hence, shed light on the target of laboratory parameters. The uniqueness of the current Japanese CKD-MBD guidelines lies in the lower target range of intact parathyroid hormone levels than those used in other countries, which is based on analyses of the nationwide Japan Renal Data Registry. Cohort studies were also useful in exploring risk factors of renal outcome in predialysis patients. It was revealed that low vitamin D status (very prevalent in Japan) and high fibroblast growth factor 23 (FGF23) levels predict poor renal outcome. The reported association of FGF23 levels with left ventricular hypertrophy (LVH) and heart failure observed in cohort studies may support the idea of adding the 4th component of CKD-MBD, namely, "LVH" to the three original components. When it is not feasible to conduct RCTs regarding intervention, we have no choice but to rely on observational studies with sophisticated analysis methods, such as facility-level analysis and marginal structural model minimizing indication bias. Observational studies conducted in Japan revealed that the side effects of medications for CKD-MBD, resultant compliance, and effective doses in terms of hard outcome in Japanese patients were found to be different from those in other countries. For example, the MBD-5D study confirmed the benefit of cinacalcet in terms of mortality despite its median dose of only 25 mg/day. These data are very helpful for future guidelines specific to Japanese patients with CKD. PMID- 27942884 TI - An exploratory cohort study of sensory extinction in acute stroke: prevalence, risk factors, and time course. AB - Most studies on sensory extinction have focused on selected patients with subacute and chronic right hemisphere lesions. In studies conducted on acute stroke patients, risk factors and time course were not evaluated. Our aim was to determine the prevalence, risk factors, and time course of sensory extinction in the acute stroke setting. Consecutive patients with acute stroke were tested for tactile, visual, auditory, and auditory-tactile cross-modal extinction, as well as for peripersonal visuospatial neglect (PVN). Tests were repeated at 2, 7, 15, 30, and 90 days after initial examination. A multivariable logistic regression analysis was performed to test the association between sensory extinction and demographic and clinical risk factors. Seventy-three patients (38.4% women) were recruited: 64 with ischemic stroke and nine with haemorrhagic stroke. Mean age was 62.3 years (95% CI 58.8-65.7), mean NIHSS score was 1.6 (95% CI 1.2-2.1), and mean time to first examination was 4.1 days (95% CI 3.5-4.8). The overall prevalence of all subtypes of sensory extinction was 13.7% (95% CI 6.8-23.8). Tactile extinction was the most frequent subtype with a prevalence of 8.2% (95% CI 3.1-17.0). No extinction was found beyond 15 days after the first examination. After adjustment for age, sex, lesion side, type of stroke, time to first examination and stroke severity, a lesion volume >=2 mL (adjusted OR = 38.88, p = 0.04), and presence of PVN (adjusted OR = 24.27, p = 0.04) were independent predictors of sensory extinction. The insula, the putamen, and the pallidum were the brain regions most frequently involved in patients with sensory extinction. Extinction is a rare and transient phenomenon in patients with minor stroke. The presence of PVN and lesion volume >=2 mL are independent predictors of sensory extinction in acute stroke. PMID- 27942885 TI - Toxoplasma infection in individuals in central Italy: does a gender-linked risk exist? AB - An accurate estimate of the impact of toxoplasmosis on the population in Italy is not available. We performed a cross-sectional study on individuals living in Italy to assess: (1) differences in access to Toxo testing and in the prevalence of recent and past Toxoplasma gondii infection according to gender and age, and (2) the clinical impact of disease burden on the male patient subset. Reason for testing, condition of in- or outpatient and clinical data were analysed. Between gender differences were observed in access to the test. Immunoglobulin M (IgM) prevalence was increased in males in the age range 5-34 years [odds ratio (OR) = 2.03, 95% confidence interval (CI) 1.18-3.49, p = 0.01), with a peak at 25-34 years. In females, it decreased in the age range 20-39 years (OR = 0.49, 95% CI 0.32-0.74, p = 0.0008). The attack rate of recent infection was twice as high for males than for females. Estimates pointed out 3.3 and 1.7 events in 1000 at-risk person-years in the male and female cohorts, respectively. Most IgM-positive subjects did not experience severe forms of toxoplasmosis, with 35% having lymphadenopathy. Chorioretinitis, systemic and neurological manifestations were also observed. Our findings suggest that the acute phase of toxoplasmosis is largely unapparent or clinically mild in this area. It is also possible that the disease burden for Toxoplasma infection in Italy is underestimated. Further study should focus on information acquisition and Toxo test access in hospital units for a better estimation of the real burden of mild and severe forms of the disease. PMID- 27942886 TI - Modified technique for endoscopic endonasal reduction of medial orbital wall fracture using an absorbable packing. AB - PURPOSE: The purpose of this study was to describe a modified technique using only biological dura substitute (Lyoplant(r)) associated or not to a sheet of Medpore(r) (porous polyethylene plate) avoiding the use of Silastic(r) or Merocel(r) packing for endoscopic endonasal reduction of medial orbital wall fracture. METHODS: An interventional case report was used involving two patients with medial orbital wall fracture that were treated with the modified technique. Postoperatively, the patients were evaluated for visual acuity, enophthalmos, extraocular motility, and diplopia. RESULT: Twelve months after surgery, patients recovered completely without any residual eye symptoms or complications, and postoperative CT showed a completely corrected medial orbital wall fractures. CONCLUSION: The reported technique proved itself to be safe and effective, and it may be expected to have advantages over the conventional endoscopic approach using a non-absorbable packing, avoiding the need for long-term nasal packing and a secondary removal procedure. PMID- 27942887 TI - Predictions of the Contribution of HCN Half-Maximal Activation Potential Heterogeneity to Variability in Intrinsic Adaptation of Spiral Ganglion Neurons. AB - Spiral ganglion neurons (SGNs) exhibit a wide range in their strength of intrinsic adaptation on a timescale of 10s to 100s of milliseconds in response to electrical stimulation from a cochlear implant (CI). The purpose of this study was to determine how much of that variability could be caused by the heterogeneity in half-maximal activation potentials of hyperpolarization activated cyclic nucleotide-gated cation (HCN) channels, which are known to produce intrinsic adaptation. In this study, a computational membrane model of cat type I SGN was developed based on the Hodgkin-Huxley model plus HCN and low threshold potassium (KLT) conductances in which the half-maximal activation potential of the HCN channel was varied and the response of the SGN to pulse train and paired-pulse stimulation was simulated. Physiologically plausible variation of HCN half-maximal activation potentials could indeed determine the range of adaptation on the timescale of 10s to 100s of milliseconds and recovery from adaptation seen in the physiological data while maintaining refractoriness within physiological bounds. This computational model demonstrates that HCN channels may play an important role in regulating the degree of adaptation in response to pulse train stimulation and therefore contribute to variable constraints on acoustic information coding by CIs. This finding has broad implications for CI stimulation paradigms in that cell-to-cell variation of HCN channel properties are likely to significantly alter SGN excitability and therefore auditory perception. PMID- 27942888 TI - Wear of dual-mobility cups: a review article. AB - Dual-mobility (DM) cups have been clinically used in hip surgery in Europe for more than 35 years and continue to gain popularity worldwide due to promising results at reducing instability. Concerns related to polyethylene wear apply as in conventional standard bearings but are accentuated by the larger-diameter articulations with multiple surfaces. We critically reviewed the reported literature regarding the in vivo and in vitro wear occurring on all surfaces involved. We looked for patterns to create a rational classification of sites of wear and to identify areas for future research. Wear was a significant problem for first-generation designs and appeared to be design related. Improved polyethylene, thinner and smoother trunnions, chamfered rims and eccentric configuration of insert and shell seem to enhance outcome performance; however, long-term clinical evidence and retrieval studies are needed to better understand the balance of benefit and risk when opting for DM bearings. PMID- 27942889 TI - Off-loading strategies in diabetic foot syndrome-evaluation of different devices. AB - INTRODUCTION: Diabetic foot syndrome is one of the most dreaded complications in diabetes mellitus. The purpose of this study was to assess the value of different offloading devices compared to walking in barefoot condition and in normal shoes both in healthy subjects and in patients with diabetes and neuropathy. METHODS: Twenty patients with diabetes and polyneuropathy and ten healthy probands were included. Pedobarographic examination was performed in barefoot condition, with sneakers, postoperative shoes, Aircast(r) Diabetic Pneumatic WalkerTM and VACO(r)diaped. In the diabetic group, a total contact cast was additionally tested. RESULTS: The most effective reduction of force was achieved by TCC (75%) and VACOdiaped (64.3%) with the VACO(r)diaped resulting in the most homogeneous distribution of forces all over the foot. DISCUSSION/CONCLUSION: A customized device like the TCC is still the most proven offloading device. However, a removable cast walker being based on vacuum pads and a cushioning sole, provides better results concerning force distribution. PMID- 27942890 TI - The removal of an implant beneath the optic canal by modified endoscopic-assisted sinus surgery. AB - Displacement of dental implants into the maxillary sinus is one of the rare complications during the implant surgery. However, it is always possible that clinicians confront with this unexpected result and patients should be informed ahead of maxillary implant surgery. For clinicians, it is important to be aware of how to deal with the complication, because the migrated implant must be removed as early as possible. There have been several classical ways to approach the maxillary sinus, such as the Caldwell-Luc procedure and endoscopic sinus surgery and these methods still have been chosen by many surgeons although quite a lot of complications exist. In this study, the author introduced a new sinus approach technique, modified endoscopic-assisted sinus surgery (MESS) as an efficient, easy and less complication-inducing sinus approach. A clinical case was described where a displaced dental implant beneath the optic nerve was successfully removed by MESS. Furthermore, essential considerations to avoid medical litigation and maintain close rapport with the patients were discussed when dealing with the case of displaced implant in the maxillary sinus. PMID- 27942892 TI - Erratum to: Laryngeal transplantation in minipigs: vascular, myologic and functional outcomes. PMID- 27942891 TI - Recurrent oropharyngeal cancer after organ preserving treatment: pattern of failure and survival. AB - The objectives is to thoroughly analyze the pattern of failure and oncologic outcome in recurrent oropharyngeal cancer (OPC) after (chemo)radiotherapy and correlate the site of failure to the planned radiation dose. Between January 2010 and April 2014, 57 patients with recurrent OPC after (chemo)radiotherapy were analyzed. Endpoints were pattern of failure and overall survival (OS). Local (LF) and regional failure (RF) were classified as in-field [>50% within gross tumor volume (GTV)], marginal [<50% within GTV but >50% within clinical target volume (CTV)], or out-of-field (>50% outside CTV) recurrences. In the whole group, 70 recurrences were reported. Of the 31 LF, 29 (93.5%) were in-field and 2 (6.5%) were marginal. No out-field LF was reported. Of the 21 RF, 13 RF (62%) were in field, 6 (28.5%) marginal, and 2 (9.5%) out-of-field recurrences. Forty-three percent of RF was developed in an electively treated neck level, and 2 of them were contralateral. OS at 2 years in recurrent HPV positive, compared to HPV negative OPC, were 66 and 18%, respectively (p = 0.011). OS was also significantly better in patients that were salvage treatment which was possible (70 vs. 6%, p < 0.001). Median survival after distant failure was 3.6 months. The great majority of LFs were located within the GTV and 43% of RFs developed in an electively treated neck level. The currently used margins and dose recipe and the indication for bilateral nodal irradiation need to be reevaluated. OS was significantly better in recurrent HPV-positive OPC and in patients, where salvage treatment was possible. PMID- 27942893 TI - Remarks on the Rotterdam experience. PMID- 27942894 TI - Personality traits inventory in patients with vocal nodules. AB - The objective of the study was to analyze temperament and character in females with vocal nodules (VN) compared to a vocally healthy control population. 61 females were examined over a 17-month period for dysphonia with VN (mean age 46 years, duration of vocal complaints from 2 months to 6 years). 71 control females were recruited in their environment (mean age 34 years). The validated French Version of the Temperament and Character Inventory (TCI) was used. Patients with VN had significantly (p < 0,05) greater scores for Persistence and Novelty Seeking, particularly for the subscales exploratory excitability and extravagance. They had lower scores for Harm Avoidance, in particular fear of uncertainty, shyness and fatigability. Scores on Reward Dependence were not significantly different except for the subscale dependence, which were significantly lower in patients. No significant difference was found with regard to scores on Self-directedness, except for scores on the subscale self acceptance, which were significantly lower in patients. Scores on Cooperativeness were not significantly different, except for the subscale helpfulness, which were significantly higher in patients. Patients had significant greater scores for Self-transcendence overall and specifically on the subscales self-forgetfulness and spiritual acceptance. Our findings suggested that women with VN are likely to have a passionate temperament, which might constitute an indirect predisposition to elevated vocal loading and greater risk for phonotrauma. The risk for developing or maintaining VN could be decreased by attending to those personality specific maladaptive behaviors. A possible personalized approach to voice therapy could be organized on the basis of the TCI findings. PMID- 27942896 TI - An evaluation on novel application of cone-beam CT imaging with multi-volume technique in carotid body tumor. AB - Due to the high risk of vascular and nerve damage during surgery, precise pre operative evaluation of carotid body tumor (CBT) is important. We aim to apply intra-operative contrast-enhanced cone-beam CT (CBCT) with multi-volume technique in CBT evaluation, where the tumor, patent carotid arteries, and skull are demonstrated in three different colors, and to compare this novel technique with traditional computed tomography angiography (CTA). Seven CBT patients scheduled for traditional surgical removal were enrolled in this study between October 2013 and March 2016. For each patient, two CBCT scans were performed on the carotid region both pre- and post-operatively, with contrast injected into the common carotid artery directly. CT-like cross-sectional slices were then reconstructed with a dedicated workstation, and a novel multi-volume technique was further applied for advanced image post-processing. For all seven patients, the anatomic relationship between tumor and surrounding vessels was clearly demonstrated by reconstructed CBCT images with multiple fused volumes. Carotid was either completely or partially incarcerated by tumors. Interestingly, two sets of draining vein systems of CBT were found feeding into the internal jugular vein and the anterior vertebral venous plexus, respectively, which have not been revealed in pre-operative CTA. Post-operative CBCT confirmed the thorough removal of the tumor with an intact preservation of the internal carotid artery. CBCT with multi-volume technique outperforms CTA in discovering fine structures and revealing tumor-vessel relationship for CBT. This emerging imaging technique would offer more accurate diagnosis of CBT and assist in the decision of surgical plan. PMID- 27942895 TI - Predictive and prognostic factors for patients with locoregionally advanced laryngeal carcinoma treated with surgical multimodality protocol. AB - The prognosis is suboptimal in patients with locoregionally advanced laryngeal carcinoma even after multimodality protocols. The purpose of this study was to determine the potential influential factors that have an impact on the development of locoregional recurrence, distant metastasis, and oncological outcomes in patients with locoregionally advanced laryngeal carcinoma who had surgical multimodality protocols. A sample size of 85 cases was determined based on a power of 90% and an effect size of alpha 2 = 0.05. A retrospective analysis of 357 patients with a diagnosis of laryngeal cancer between 2002 and 2015 was performed. Eighteen variables based on sociodemographic, clinical, histopathological and treatment data were analyzed. Medical records of 85 consecutive patients with locoregionally advanced laryngeal carcinoma who underwent surgical multimodality protocols were reviewed. Five-year overall, disease-specific, disease-free, locoregional recurrence-free and distant metastasis-free survival were 68.7, 78.0, 69.6, 68.9 and 69.2%, respectively. Extracapsular extension was an independent predictive factor for locoregional recurrence. Pathologic tumor volume was an independent predictive factor for distant metastasis. pT-stage was an independent prognostic factor for 5-year overall survival, disease-free survival, locoregional recurrence-free survival and distant metastasis-free survival. High volume, pT4a laryngeal tumors with extracapsular extension are associated with a high risk of locoregional recurrence and distant metastasis; and have poor oncological outcomes in patients with locoregionally advanced laryngeal carcinoma treated with surgical multimodality protocols. PMID- 27942897 TI - Voice feminization in male-to-female transgendered clients after Wendler's glottoplasty with vs. without voice therapy support. AB - The objective of this study was to evaluate the medium-term results of Wendler's glottoplasty surgery (WG) and the effects of post-operative voice therapy in a group of male-to-female transsexuals. This is a retrospective study of 18 transsexuals who voluntarily underwent WG between 2010 and 2014 at a single hospital. Ten of the subjects underwent an additional voice therapy training. The group was assessed pre- vs. post-treatments with a limited battery of measures consisting of fundamental frequency (Fo), maximum phonation time, the TSEQ transgender self-assessment questionnaire, and perceptual assessment of the voice (Visual Analog Scale and a simplified version of the classical Hirano-GRBAS scale) by inter-rater agreement. The surgical procedure consisted of a de epithelialization of the anterior third of both vocal folds; this area was sutured, and the surface of both vocal folds was vaporized with a laser diode. The results showed a significant increase in vocal tone and feminization of voice in all participants, including a significant increase in Fo 12 months after treatment. Significant improvements were also shown in other evaluated measures, such as self-reported satisfaction and the degree of feminization of the voice. However, no improvements in maximum phonation time were observed. The use of voice therapy appears decisive for optimal improvement of this class of patients. WG applied appropriately by well-trained hands is thus a very effective and less traumatic procedure than other techniques that aim for an acceptable feminization of the voice in MtoF transgendered clients. PMID- 27942899 TI - Screening of molecular cell targets for carcinogenic heterocyclic aromatic amines by using CALUX(r) reporter gene assays. AB - Heterocyclic aromatic amines (HCAs) are compounds formed when meat or fish are cooked at high temperatures for a long time or over an open fire. To determine which pathways of toxicity are activated by HCAs, nine out of the ten HCAs known to be carcinogenic in rodents (2-amino-9H-pyrido[2,3-b]indole (AalphaC), 2 aminodipyrido[1,2-a:3',2-d]imidazole (Glu-P-2), 2-amino-3-methylimidazo[4,5 f]quinoline (IQ), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC), 2-amino 3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo[4,5 f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 3 amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), and 3-amino-1-methyl-5H pyrido[4,3-b]indole (Trp-P-2)) were tested in the estrogen receptor alpha (ERalpha), androgen receptor (AR), glucocorticoid receptor (GR), peroxisome proliferator-activated receptor gamma2 (PPARgamma2), polycyclic aromatic hydrocarbons (PAH), Nrf2, and p53 CALUX(r) reporter gene assays. Trp-P-1 was the only HCA that led to a positive response in the ERalpha, PPARgamma2, and Nrf2 CALUX(r) assays. In the PAH CALUX(r) assay, Trp-P-2, MeAalphaC, and AalphaC induced luciferase activity to a greater extent than MeIQ and PhIP. In the p53 CALUX(r) assay without a coupled metabolic activation, only Trp-P-1 and Trp-P-2 enhanced luciferase expression; when a metabolic activation step was coupled to the p53 CALUX(r) assay, Trp-P-1, Glu-P-2, MeIQ, MeIQx, and PhIP induced a positive response. No HCA was positive in the AR and GR CALUX(r) assays. Taken together, the results obtained show that the battery of CALUX(r) assays performed in the present study can successfully be used to screen for molecular cell targets of carcinogenic compounds such as HCAs. PMID- 27942898 TI - Assessment of endolymphatic hydrops and otolith function in patients with Meniere's disease. AB - Meniere's disease is associated with hydrops of the inner ear endolymphatic space, and histopathologically, the cochlea and vestibule are usually involved. We used gadolinium-enhanced magnetic resonance imaging and measured cervical and ocular vestibular evoked myogenic potentials and the gain in the utricular induced linear vestibulo-ocular reflex to test the hypothesis that vestibular hydrops in Meniere's disease patients is associated with otolith organ dysfunction. We evaluated 21 patients diagnosed with unilateral definitive Meniere's disease using gadolinium magnetic resonance imaging to detect endolymphatic hydrops in the cochlea and vestibule. Cervical and ocular vestibular evoked myogenic potentials and the gain in utricular induced linear vestibulo-ocular reflex during eccentric rotation were measured to assess otolith organ function. For eccentric rotation, patients were rotated while displaced from the axis of rotation, while linear acceleration stimulated the utricle and induced the vestibulo-ocular reflex. Magnetic resonance imaging revealed vestibular hydrops in 14 of 20 patients (70%). Among the 14 patients, ten (71%) had abnormal cervical and three (21%) had abnormal ocular vestibular evoked myogenic potentials. Four patients (4/21, 19%) had abnormal linear vestibulo ocular reflexes, three of whom also had abnormal ocular vestibular evoked myogenic potentials. Overall, 16 of 17 patients had normal linear vestibulo ocular reflexes and normal ocular vestibular evoked myogenic potentials. Vestibular endolymphatic hydrops in Meniere's disease patients caused otolith organ dysfunction, mainly in the saccule. The number of Meniere's disease patients with abnormal ocular vestibular evoked myogenic potentials was low (19%), and they also had abnormal utricular induced linear vestibulo-ocular reflexes. PMID- 27942900 TI - Developmental changes in digestive enzyme activity in American shad, Alosa sapidissima, during early ontogeny. AB - In order to assess the digestive physiological capacity of the American shad Alosa sapidissima and to establish feeding protocols that match larval nutritional requirements, we investigated the ontogenesis of digestive enzymes (trypsin, amylase, lipase, pepsin, alkaline phosphatase, and leucine aminopeptidase) in larvae, from hatching to 45 days after hatching (DAH). We found that all of the target enzymes were present at hatching, except pepsin, which indicated an initial ability to digest nutrients and precocious digestive system development. Trypsin rapidly increased to a maximum at 14 DAH. Amylase sharply increased until 10 DAH and exhibited a second increase at 33 DAH, which coincided with the introduction of microdiet at 30 DAH, thereby suggesting that the increase was associated with the microdiet carbohydrate content. Lipase increased until 14 DAH, decreased until 27 DAH, and then increased until 45 DAH. Pepsin was first detected at 27 DAH and then sharply increased until 45 DAH, which suggested the formation of a functional stomach. Both alkaline phosphatase and leucine aminopeptidase markedly increased until 18 DAH, which indicated intestinal maturation. According to our results, we conclude that American shad larvae possess the functional digestive system before mouth opening, and the significant increases in lipase, amylase, pepsin, and intestinal enzyme activities between 27 and 33 DAH suggest that larvae can be successfully weaned onto microdiets around this age. PMID- 27942901 TI - Laparoscopic Partial Splenectomy for Unknown Primary Cancer: A Stepwise Approach. AB - BACKGROUND: Laparoscopic partial splenectomy (LPS) for focal splenic lesions is technically demanding and carries risk of hemorrhage. Nevertheless, it can be a valuable option, particularly for children and adults in whom attempt at preservation of splenic immunologic function outweighs risk associated with organ preservation. PATIENT: A 58-year-old man was diagnosed with a focal splenic lesion at the upper splenic pole on surveillance imaging following axillary lymph node metastasis for cancer of unknown primary origin (CUP). After an interval of 8 months, repeat FDG-PET showed increase in size and PET-avidity without any evidence of new lesions. Due to isolated site and history of CUP, the patient was considered for a LPS. TECHNIQUE: With the patient in reversed modified French position, the upper pole splenic vessels were controlled and a well-defined area of ischemia encompassing the lesion identified. Under intermittent inflow occlusion and ultrasonography guidance, the parenchymal transection was performed. Total operative time was 180 min, estimated blood loss was 175 cc, the patient was discharged on postoperative day 2, and final pathology confirmed an Epstein-Barr virus associated inflammatory pseudotumor.1 , 2 CONCLUSION: Safe LPS requires systematic pre-operative assessment of hilar vascular anatomy and a stepwise approach to controlling the vessels intra-operatively. Anatomic parenchymal transection and intermitted vascular isolation for lesions close to the demarcation zone minimizes blood loss. Risk/benefit stratification of LPS may be beneficial in select patients only. Whether in patients with CUP LPS may aid in preserving innate and adaptive immunity with potential clinical, including oncologic, benefits will require further investigations.3 - 5. PMID- 27942902 TI - Impact of Proximal Vascular Ligation on Survival of Patients with Colon Cancer. AB - In an effort to optimize further the surgical management of colon cancer, many groups have advocated extended lymphadenectomy as a strategy to improve completeness of resection and lymph node harvest. This review evaluates lymphadenectomy according to the definitions for extent of lymph node dissection based on the guidelines provided by the Japanese Society of Cancer of the Colon and Rectum and the contemporary concepts of complete mesocolic excision and central vascular ligation. The proposed benefits of a D3 or central nodal dissection along root vessels in colon cancer is improving accuracy of lymph node evaluation and ensuring complete removal of lymph nodes that may harbor undetected tumor cells or other undefined immunologic processes important for metastases. Metastasis to central lymph nodes occurs in 1 to 8% of patients with colon cancer and is most commonly seen in T3 and T4 tumors. Although central lymph node metastasis is associated with decreased survival after resection, resection of the nodes, when present, may confer a survival benefit analogous to resection of metastasis at distant sites. Current data support a standardized anatomic approach to colonic resection with complete resection of the mesocolic envelope and ligation at least to the D2 level. PMID- 27942904 TI - Whole-genome sequencing reveals a potential causal mutation for dwarfism in the Miniature Shetland pony. AB - The Miniature Shetland pony represents a horse breed with an extremely small body size. Clinical examination of a dwarf Miniature Shetland pony revealed a lowered size at the withers, malformed skull and brachygnathia superior. Computed tomography (CT) showed a shortened maxilla and a cleft of the hard and soft palate which protruded into the nasal passage leading to breathing difficulties. Pathological examination confirmed these findings but did not reveal histopathological signs of premature ossification in limbs or cranial sutures. Whole-genome sequencing of this dwarf Miniature Shetland pony and comparative sequence analysis using 26 reference equids from NCBI Sequence Read Archive revealed three probably damaging missense variants which could be exclusively found in the affected foal. Validation of these three missense mutations in 159 control horses from different horse breeds and five donkeys revealed only the aggrecan (ACAN)-associated g.94370258G>C variant as homozygous wild-type in all control samples. The dwarf Miniature Shetland pony had the homozygous mutant genotype C/C of the ACAN:g.94370258G>C variant and the normal parents were heterozygous G/C. An unaffected full sib and 3/5 unaffected half-sibs were heterozygous G/C for the ACAN:g.94370258G>C variant. In summary, we could demonstrate a dwarf phenotype in a miniature pony breed perfectly associated with a missense mutation within the ACAN gene. PMID- 27942903 TI - Downregulation of CX3CR1 ameliorates experimental colitis: evidence for CX3CL1 CX3CR1-mediated immune cell recruitment. AB - PURPOSE: Inflammatory conditions like inflammatory bowel diseases (IBD) are characterized by increased immune cell infiltration. The chemokine ligand CX3CL1 and its receptor CX3CR1 have been shown to be involved in leukocyte adhesion, transendothelial recruitment, and chemotaxis. Therefore, the objective of this study was to describe CX3CL1-CX3CR1-mediated signaling in the induction of immune cell recruitment during experimental murine colitis. METHODS: Acute colitis was induced by dextran sodium sulfate (DSS), and sepsis was induced by injection of lipopolysaccharide (LPS). Serum concentrations of CX3CR1 and CX3CL1 were measured by ELISA. Wild-type and CX3CR1-/- mice were challenged with DSS, and on day 6, intravital microscopy was performed to monitor colonic leukocyte and platelet recruitment. Intestinal inflammation was assessed by disease activity, histopathology, and neutrophil infiltration. RESULTS: CX3CR1 was upregulated in DSS colitis and LPS-induced sepsis. CX3CR1-/- mice were protected from disease severity and intestinal injury in DSS colitis, and CX3CR1 deficiency resulted in reduced rolling of leukocytes and platelets. CONCLUSIONS: In the present study, we provide evidence for a crucial role of CX3CL1-CX3CR1 in experimental colitis, in particular for intestinal leukocyte recruitment during murine colitis. Our findings suggest that CX3CR1 blockade represents a potential therapeutic strategy for treatment of IBD. PMID- 27942905 TI - Spatiotemporal variation of bacterial and archaeal communities in sediments of a drinking reservoir, Beijing, China. AB - Bacterial and archaeal assemblages are one of the most important contributors to the recycling of nutrients and the decomposition of organic matter in aquatic sediments. However, their spatiotemporal variation and its driving factors remain unclear, especially for drinking reservoirs, which are strongly affected by human consumption. Using quantitative PCR and Illumina MiSeq sequencing, we investigated the bacterial and archaeal communities in the sediments of a drinking reservoir, the Miyun Reservoir, one of the most important drinking sources for Beijing City. The abundance of bacteria and archaea presented no spatiotemporal variation. With respect to community diversity, visible spatial and temporal differences were observed in archaea, whereas the bacterial community showed minor variation. The bacterial communities in the reservoir sediment mainly included Proteobacteria, Bacteroidetes, Nitrospirae, Acidobacteria, and Verrucomicrobia. The bacterial community structure showed obvious spatial variation. The composition of the bacterial operational taxonomic units (OTUs) and main phyla were dam-specific; the composition of samples in front of the dam were significantly different from the composition of the other samples. The archaeal communities were mainly represented by Woesearchaeota and Euryarchaeota. Distinctly spatial and seasonal variation was observed in the archaeal community structure. The sediment NH4+-N, pH, and water depth were identified as the key driving factors of changes in the composition of the bacterial and archaeal communities. Water depth might have the greatest influence on the microbial community structure. The dam-specific community structure may be related to the greater water depth in front of the dam. This finding indicates that water depth might be the greatest contributor to the microbial community structure in the Miyun Reservoir. PMID- 27942906 TI - Microbial community changes in methanogenic granules during the transition from mesophilic to thermophilic conditions. AB - Upflow anaerobic sludge blanket (UASB) reactor is one of the most applied technologies for various high-strength wastewater treatments. The present study analysed the microbial community changes in UASB granules during the transition from mesophilic to thermophilic conditions. Dynamicity of microbial community in granules was analysed using high-throughput sequencing of 16S ribosomal RNA gene amplicons, and the results showed that the temperature strictly determines the diversity of the microbial consortium. It was demonstrated that most of the microbes which were present in the initial mesophilic community were not found in the granules after the transition to thermophilic conditions. More specifically, only members from family Anaerolinaceae managed to tolerate the temperature change and contributed in maintaining the physical integrity of granular structure. On the contrary, new hydrolytic and fermentative bacteria were quickly replacing the old members in the community. A direct result from this abrupt change in the microbial diversity was the accumulation of volatile fatty acids and the concomitant pH drop in the reactor inhibiting the overall anaerobic digestion process. Nevertheless, by maintaining deliberately the pH levels at values higher than 6.5, a methanogen belonging to Methanoculleus genus emerged in the community enhancing the methane production. PMID- 27942907 TI - Who contributes more to N2O emission during sludge bio-drying with two different aeration strategies, nitrifiers or denitrifiers? AB - Global warming effects have drawn more and more attention to studying all sources and sinks of nitrous oxide (N2O). Sludge bio-drying, as an effective sludge treatment technology, is being adopted worldwide. In this study, two aeration strategies (piles I and II) were compared to investigate the primary contributors to N2O emission during sludge bio-drying through studying the evolution of functional genes involved in nitrification (amoA, hao, and nxrA) and denitrification (narG, nirS, nirK, norB, and nosZ) by quantitative PCR (qPCR). Results showed that the profile of N2O emission can be divided into three stages, traditional denitrification contributed largely to N2O emission at stage I (days 1-5), but N2O emission mainly happened at stage II (days 5-14) due to nitrifier denitrification and NH2OH accumulation by ammonia-oxidizing bacteria (AOB), accounting for 51.4% and 58.2% of total N2O emission for piles I and II, respectively. At stage III (days 14-21), nitrifier denitrification was inhibited because sludge bio-drying proceeded mainly by the physical aeration, thus N2O emission decreased and changed little. The improved aeration strategy availed pile I to reduce N2O emission much especially at stages II and III, respectively. These results indicated that nitrifier denitrification by AOB and biological NH2OH oxidation due to AOB made more contribution to N2O emission, and aeration strategy was crucial to mitigate N2O emission during sludge bio-drying. PMID- 27942909 TI - Garland Allen: An Appreciation. PMID- 27942910 TI - Reflections on the History of Biology as a Field: 1966-2014. PMID- 27942908 TI - Could Sirtuin Activities Modify ALS Onset and Progression? AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a complex etiology. Sirtuins have been implicated as disease-modifying factors in several neurological disorders, and in the past decade, attempts have been made to check if manipulating Sirtuin activities and levels could confer benefit in terms of neuroprotection and survival in ALS models. The efforts have largely focused on mutant SOD1, and while limited in scope, the results were largely positive. Here, the body of work linking Sirtuins with ALS is reviewed, with discussions on how Sirtuins and their activities may impact on the major etiological mechanisms of ALS. Moving forward, it is important that the potentially beneficial effect of Sirtuins in ALS disease onset and progression are assessed in ALS models with TDP-43, FUS, and C9orf72 mutations. PMID- 27942912 TI - Distinguishing features of psychogenic (functional) versus organic hemifacial spasm. AB - Hemifacial spasm (HFS) is one of the most common presentations in patients with cranial psychogenic (functional) movement disorders (PMD). Medical records and videos of patients with PMD and HFS were reviewed to identify those with psychogenic HFS and to compare the phenomenology of psychogenic HFS with organic HFS. We identified 18 (9.8%) patients with psychogenic HFS from a cohort of 184 patients with PMDs. There were 14 (78%) women and 4 men, with a mean age at onset of 33 +/- 13.5 years. These were compared with 37 consecutive patients with organic (primary) HFS. Patients with psychogenic HFS were significantly younger and had more frequently tonic muscle contractions, bilateral asynchronous hemifacial involvement, isolated lower facial involvement, downward deviation of the mouth's angle, and lack of the "other Babinski sign" compared to those with organic HFS. Other features such as ipsilateral downward movements of the eyebrow; associated tremor, dystonia and hemi-masticatory spasms were more frequently observed in patients with psychogenic HFS but these differences did not reach statistical significance. Lack of other Babinski sign and tonic muscle contractions showed the highest sensitivity (1.00 and 0.87, respectively), whereas downward mouth's angle deviation showed the highest specificity (1.00) for the diagnosis of psychogenic HFS. Besides other features such as suggestibility, distractibility, periods of unexplained improvements observed in most patients with PMDs, several clinical features, such as tonic muscle contractions, downward mouth's angle deviation, predominant lower facial and bilateral involvement, may be helpful in distinguishing psychogenic from organic HFS. PMID- 27942914 TI - Are Youth Psychopathic Traits Related to Bullying? Meta-analyses on Callous Unemotional Traits, Narcissism, and Impulsivity. AB - In the current manuscript meta-analyses are performed to analyze the relations between three aspects of psychopathy in youth, Callous-Unemotional (CU) traits, Narcissism, and Impulsivity, and bullying behaviors. The databases PsycINFO, MEDLINE, ERIC, Web of Science and Proquest were searched for relevant articles on bullying and CU traits, Narcissism, or Impulsivity in youth under 20 years of age. Two authors each independently screened 842 studies that were found in the literature search. Two authors independently coded ten studies on bullying and CU (N = 4115) traits, six studies on bullying and Narcissism (N = 3376) and 14 studies on bullying and Impulsivity (N = 33,574) that met the inclusion criteria. Significant correlations were found between bullying and CU traits, Narcissism, and Impulsivity. These results were not affected by publication bias. Anti bullying interventions could potentially benefit from including elements that have been found effective in the treatment of youth psychopathy. PMID- 27942915 TI - Treatment of hand enchondroma with injectable calcium phosphate cement: a series of eight cases. AB - The gold standard treatment for enchondroma in the hand is curettage and filling of the defect. The goal of this study was to evaluate the results when injectable calcium phosphate cement is used to fill the bone defect. Eight patients having a mean age of 44 years were operated through a minimally invasive skin incision. After a small bone window was made, curettage of the lesion was performed and verified by intraosseous endoscopy. The defect was filled with injectable calcium phosphate cement (JectOS/AREX(r)BONE, Kasios, L'Union France). The mean pain score (out of 10) decreased from 4.1 preoperatively to 1.6 postoperatively. The mean QuickDASH (out of 100) improved from 37.66 to 24.14. At the last follow-up (mean of 16 months), the range of motion in the operated hand had reached 89.3% of the contralateral hand. Based on radiographs, a mean of 69.3% calcium phosphate cement remained in the bone. There were two cases of extraosseous cement leakage, one of which required revision and resulted in a poor outcome. Overall, these results show that curettage of a hand enchondroma followed by filling of the defect with injectable calcium phosphate cement is a simple, reliable technique with no donor site morbidity, as long as cement does not leak out. PMID- 27942916 TI - Synergistic disruption of ERalpha/HER2 crosstalk by endoxifen and lapatinib in breast cancer cells. AB - BACKGROUND: Despite decades of clinical success, tamoxifen therapy is complicated by inter-individual variability due to CYP450 polymorphism and resistance attributed to ERalpha/HER2 crosstalk. Direct administration of endoxifen shows promise in circumventing obligatory CYP450 bioactivation while maintaining efficacy. Separately, disruption of the crosstalk using probe antagonists against ERalpha (tamoxifen) and HER2 (e.g., lapatinib) has been explored clinically. However, the efficacy of this combination may be confounded by lapatinib, a potent inactivator of CYP3A4/5 which could negate the bioactivation of tamoxifen to the active metabolite endoxifen. Additionally, in a manner analogous to tamoxifen, endoxifen is similarly not immune to the development of ERalpha/HER2 crosstalk that could result in resistance. Simultaneous antagonism of ERalpha and HER2 using endoxifen and lapatinib could overcome these problems. METHODS: Metabolism studies were performed in human liver microsomes to determine the extent of inhibition of tamoxifen bioactivation by lapatinib. Synergism of endoxifen and lapatinib was assessed using the combination index design in a panel of cell models exhibiting either a priori ERalpha/HER2 crosstalk (BT474) or acquired ERalpha/HER2 crosstalk (TAM-R and MCF-7/HER2). RESULTS: Lapatinib inhibited tamoxifen bioactivation by up to 1.8-fold. Synergistic activity was uncovered for lapatinib and endoxifen against BT474, TAM-R and MCF-7/HER2 models of ERalpha/HER2 crosstalk. Western blot confirmed that endoxifen and lapatinib disrupted this crosstalk. CONCLUSION: This forward-looking study extends the success of tamoxifen by exploring the effectiveness of combining the next generation tamoxifen derivative, endoxifen with an anti-HER2 agent to combat ERalpha/HER2 crosstalk, and at the same time provides a solution to the predicted pharmacokinetic antagonism between lapatinib and tamoxifen. PMID- 27942917 TI - LJM716 in Japanese patients with head and neck squamous cell carcinoma or HER2 overexpressing breast or gastric cancer. AB - PURPOSE: Human epidermal growth factor receptor 3 (HER3) has been identified as an important component of many receptor tyrosine kinase-driven cancers. LJM716 is a human IgG monoclonal antibody that binds HER3, trapping it in an inactive conformation. In this study, a phase I dose escalation was performed with a primary objective to establish the maximum tolerated dose and/or the recommended dose of LJM716 in Japanese patients with selected advanced solid tumors. Secondary objectives included the evaluation of the safety and tolerability, preliminary antitumor activity, and pharmacokinetics of LJM716 in Japanese patients. METHODS: LJM716 was administered intravenously at doses of 10, 20, or 40 mg/kg once weekly, in 28-day cycles, to 12 patients with HER2-amplified breast cancer or gastric cancer, or with esophageal squamous cell carcinoma or squamous cell carcinoma of the head and neck, regardless of HER2 status. RESULTS: The maximum tolerated dose was not reached, and the recommended dose was established at 40 mg/kg. No dose-limiting toxicities were observed in the first cycle. The most frequently reported adverse events were diarrhea, fatigue, stomatitis, pyrexia, and paronychia. One unconfirmed partial response was observed in a patient with breast cancer, and 50% of the patients achieved stable disease as the best overall response. Exposure increased with ascending dose, and half-life was estimated to be 11-14 days. No anti-LJM716 antibodies were detected. CONCLUSIONS: LJM716 was well tolerated in Japanese patients, and a degree of tumor shrinkage was observed. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov NCT01911936. PMID- 27942913 TI - Genomic and rapid effects of aldosterone: what we know and do not know thus far. AB - Aldosterone is the most known mineralocorticoid hormone synthesized by the adrenal cortex. The genomic pathway displayed by aldosterone is attributed to the mineralocorticoid receptor (MR) signaling. Even though the rapid effects displayed by aldosterone are long known, our knowledge regarding the receptor responsible for such event is still poor. It is intense that the debate whether the MR or another receptor-the "unknown receptor"-is the receptor responsible for the rapid effects of aldosterone. Recently, G protein-coupled estrogen receptor-1 (GPER-1) was elegantly shown to mediate some aldosterone-induced rapid effects in several tissues, a fact that strongly places GPER-1 as the unknown receptor. It has also been suggested that angiotensin receptor type 1 (AT1) also participates in the aldosterone-induced rapid effects. Despite this open question, the relevance of the beneficial effects of aldosterone is clear in the kidneys, colon, and CNS as aldosterone controls the important water reabsorption process; on the other hand, detrimental effects displayed by aldosterone have been reported in the cardiovascular system and in the kidneys. In this line, the MR antagonists are well-known drugs that display beneficial effects in patients with heart failure and hypertension; it has been proposed that MR antagonists could also play an important role in vascular disease, obesity, obesity-related hypertension, and metabolic syndrome. Taken altogether, our goal here was to (1) bring a historical perspective of both genomic and rapid effects of aldosterone in several tissues, and the receptors and signaling pathways involved in such processes; and (2) critically address the controversial points within the literature as regarding which receptor participates in the rapid pathway display by aldosterone. PMID- 27942918 TI - Immunological low-dose radiation modulates the pediatric medulloblastoma antigens and enhances antibody-dependent cellular cytotoxicity. AB - BACKGROUND: Immunotherapy can be an effective treatment for pediatric medulloblastoma (MB) patients. However, major subpopulations do not respond to immunotherapy, due to the lack of antigenic mutations or the immune-evasive properties of MB cells. Clinical observations suggest that radiation therapy (RT) may expand the therapeutic reach of immunotherapy. The aim of the present investigation is to study the effect of low-dose X-ray radiation (LDXR, 1 Gy) on the functional immunological responses of MB cells (DAOY, D283, and D341). METHODS: Induction of MB cell death was examined using the 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Production of reactive oxygen species (ROS) was measured by fluorescent probes. Changes in the expression of human leukocyte antigen (HLA) molecules and caspase-3 activities during treatment were analyzed using Western blotting and caspase-3 assay. RESULTS: Western blot analysis demonstrated that LDXR upregulated the expression of HLA class I and HLA II molecules by more than 20% compared with control and high-dose (12 Gy) groups in vitro. Several of these HLA subtypes, such as MAGE C1, CD137, and ICAM-1, have demonstrated upregulation. In addition, LDXR increases ROS production in association with phosphorylation of NF-kappaB and cell surface expression of mAb target molecules (HER2 and VEGF). These data suggest that a combined LDXR and mAb therapy can create a synergistic effect in vitro. CONCLUSION: These results suggest that LDXR modulates HLA molecules, leading to alterations in T-cell/tumor cell interaction and enhancement of T-cell-mediated MB cell death. Also, low-dose radiotherapy combined with monoclonal antibody therapy may one day augment the standard treatment for MB, but more investigation is needed to prove its utility as a new therapeutic combination for MB patients. PMID- 27942919 TI - Giant posterior fossa dural cavernoma in a child. AB - PURPOSE: Extra-axial (dural) cavernomas are rare and constitutes 5% of all cavernomas. They are thought to arise from the venous plexus of the dura. They can reach large sizes before diagnosis and can have an aggressive presentation. METHODS: The authors report a rare case of giant cavernoma based on the posterior fossa dura adjacent to the sigmoid sinus (sino-dural angle) in an 8-year-old boy which was excised with good outcome. The authors describe its clinico radiological profile and outcome characteristics along with a comprehensive review of relevant literature. RESULTS: This child underwent retromastiod craniectomy and complete excision of the dural cavernoma. The dural attachment was coagulated. Histopathological examination confirmed the diagnosis. CONCLUSION: We report cavernoma needs to be considered in the differential diagnosis of a dural-based posterior fossa lesion in paediatric population as complete excision is possible. PMID- 27942920 TI - Traumatic elevated vertex fracture with delayed increase in intracranial pressure: a rare case. AB - INTRODUCTION: Skull fractures are traditionally classified into linear, comminuted or depressed which can either be simple or compound. A skull fracture where the bone fragment is elevated above the intact skull known as elevated skull fracture has been reported infrequently in literature. CASE PRESENTATION: We report a unique case of simple elevated vertex fracture in a 3-month-old child where the vertex had separated from the calvarium and was elevated above the level of outer table in a patient with delayed neurological deterioration. Cerebrospinal fluid leak into tight subgaleal space and gradual thrombosis of superior sagittal sinus could have led to late clinical deterioration. CONCLUSION: Prolonged monitoring, probably early repair of dural tear and aggressive management of raised ICP, is required. Reduction of fracture with careful manipulation of SSS should weigh the risk of exsanguination. No such case of an elevated vertex fracture has been reported so far in the literature. PMID- 27942921 TI - Multiple neural tube defects: a rare combination of limited dorsal myeloschisis, diplomyelia with dorsal bony spur, sacral meningocoele, syringohydromyelia, and tethered cord. AB - Multiple neural tube defects are relatively rare. They account for less than 1% reported neural tube defects. Cases of limited dorsal myeloschisis (LDM) and diplomyelia (two cords in single sac without intervening bony or fibrous septae) with dorsal bony spur are also a rare event. Here, the authors report a rare case of neonate with thoracic LDM, diplomyelia with dorsal bony spur, sacral meningocoele with syringohydromyelia, and low-lying tethered cord. The child also had a ventricular septal defect (VSD) and bilateral rocker bottom feet. Various environmental factors and genetic mutations in transmembrane proteins have been studied in animal models explaining the origin of neural tube defects. To the best of author's knowledge, this is the first case of varied multiple neural tube defects with diplomyelia reported in world literature. PMID- 27942922 TI - Pediatric central nervous system tumors in the first 3 years of life: pre operative mean platelet volume, neutrophil/lymphocyte count ratio, and white blood cell count correlate with the presence of a central nervous system tumor. AB - PURPOSE: The aim of this study is to describe the relationship of pre-operative complete blood count parameters [mean platelet volume (MPV), neutrophil/lymphocyte count ratio (NLCR), and white blood cell count (WBC)], with the clinical, radiological, and histopathological features and the management options for patients under 3 years of age with a newly diagnosed central nervous system tumors. METHODS: Children with central nervous system (CNS) tumors in the first 3 years of life admitted in the Erciyes University Hospital between April 2004 and April 2014 were enrolled in this study. The CBC parameters were compared with those of an age- and sex-matched normal control group. RESULTS: In the study group, the means of MPV and WBC were 8.00 +/- 1.24 fl, and 10,855 +/- 3642/mm3 respectively; the median (25-75%) of NLCR was 0.98 (0.66-1.46). For the control group, the means of MPV and WBC were 6.8 +/- 0.73 fl and 8565 +/- 2522/mm3; the median (25-75%) of NLCR was 0.52 (0.36-0.70). The MPV, WBC, and NLCR were higher in the study group. The median overall survival (OS) of the patients was 60 months (range 0-81.6 months); and median event free survival (EFS) was 24 months (range 0-70.1 months). The formulation of MPV, NLCR, and WBC was found to be predictive for the diagnosis of CNS tumor in children with nonspecific symptoms. The univariate and multiple binary regression analyses showed a positive association of MPV, NLCR, and WBC and the risk of a diagnosis of CNS tumor. There was no relationship between MPV, WBC, NLCR, and histological subgroups. However, there were no associations between CBC parameters and OS or EFS of the patients. CONCLUSIONS: By causing suspicion, MPV, NLCR, and WBC may provide both an earlier radiological investigation decision and thereby an early diagnosis of CNS tumor in children with nonspecific symptoms in the first 3 years of life. PMID- 27942923 TI - Paraplegia after posterior fossa surgery in prone position: can we prevent it? PMID- 27942924 TI - Pediatric traumatic brain injury: discussion about hyperosmolar therapy. PMID- 27942925 TI - Low Cerebral Blood Volume Identifies Poor Outcome in Stent Retriever Thrombectomy. AB - BACKGROUND: Mechanical thrombectomy (MT) is an efficient treatment of acute stroke caused by large-vessel occlusion. We evaluated the factors predicting poor clinical outcome (3-month modified Rankin Scale, mRS >2) although MT performed with modern stent retrievers. METHODS: We prospectively collected the clinical and imaging data of 105 consecutive anterior circulation stroke patients who underwent MT after multimodal CT imaging. Patients with occlusion of the internal carotid artery and/or middle cerebral artery up to the M2 segment were included. We recorded baseline clinical, procedural and imaging variables, technical outcome, 24-h imaging outcome and the clinical outcome. Differences between the groups were studied with appropriate statistical tests and binary logistic regression analysis. RESULTS: Low cerebral blood volume Alberta stroke program early CT score (CBV-ASPECTS) was associated with poor clinical outcome (median 7 vs. 9, p = 0.01). Lower collateral score (CS) significantly predicted poor outcome in regression modelling with CS = 0 increasing the odds of poor outcome 4.4-fold compared to CS = 3 (95% CI 1.27-15.5, p = 0.02). Lower CBV-ASPECTS significantly predicted poor clinical outcome among those with moderate or severe stroke (OR 0.82, 95% CI 0.68-1, p = 0.05) or poor collateral circulation (CS 0-1, OR 0.66, 95% CI 0.48-0.90, p = 0.009) but not among those with mild strokes or good collaterals. CONCLUSIONS: CBV-ASPECTS estimating infarct core is a significant predictor of poor clinical outcome among anterior circulation stroke patients treated with MT, especially in the setting of poor collateral circulation and/or moderate or severe stroke. PMID- 27942926 TI - Laser Guidance in C-Arm Cone-Beam CT-Guided Radiofrequency Ablation of Osteoid Osteoma Reduces Fluoroscopy Time. AB - PURPOSE: To assess whether laser guidance can reduce fluoroscopy and procedure time of cone-beam computed tomography (CBCT)-guided radiofrequency (RF) ablations of osteoid osteoma compared to freehand CBCT guidance. MATERIALS AND METHODS: 32 RF ablations were retrospectively analyzed, 17 laser-guided and 15 procedures using the freehand technique. Subgroup selection of 18 ablations in the hip pelvic region with a similar degree of difficulty was used for a direct comparison. Data are presented as median (ranges). RESULTS: Comparison of all 32 ablations resulted in fluoroscopy times of 365 s (193-878 s) for freehand and 186 s (75-587 s) for laser-guided procedures (p = 0.004). Corresponding procedure times were 56 min (35-97 min) and 52 min (30-85 min) (p = 0.355). The subgroup showed comparable target sizes, needle path lengths, and number of scans between groups. Fluoroscopy times were lower for laser-guided procedures, 215 s (75-413 s), compared to 384 s (193-878 s) for freehand (p = 0.012). Procedure times were comparable between groups, 51 min (30-72 min) for laser guidance and 58 min (35 79 min) for freehand (p = 0.172). CONCLUSION: Adding laser guidance to CBCT guided osteoid osteoma RF ablations significantly reduced fluoroscopy time without increasing procedure time. LEVEL OF EVIDENCE: Level 4, case series. PMID- 27942927 TI - Real-Time Patient and Staff Radiation Dose Monitoring in IR Practice. AB - PURPOSE: Knowledge of medical radiation exposure permits application of radiation protection principles. In our center, the first dedicated real-time, automated patient and staff dose monitoring system (DoseWise Portal, Philips Healthcare) was installed. Aim of this study was to obtain insight in the procedural and occupational doses. MATERIALS AND METHODS: All interventional radiologists, vascular surgeons, and technicians wore personal dose meters (PDMs, DoseAware, Philips Healthcare). The dose monitoring system simultaneously registered for each procedure dose-related data as the dose area product (DAP) and effective staff dose (E) from PDMs. Use and type of shielding were recorded separately. All procedures were analyzed according to procedure type; these included among others cerebral interventions (n = 112), iliac and/or caval venous recanalization procedures (n = 68), endovascular aortic repair procedures (n = 63), biliary duct interventions (n = 58), and percutaneous gastrostomy procedure (n = 28). RESULTS: Median (+/-IQR) DAP doses ranged from 2.0 (0.8-3.1) (percutaneous gastrostomy) to 84 (53-147) Gy cm2 (aortic repair procedures). Median (+/-IQR) first operator doses ranged from 1.6 (1.1-5.0) MUSv to 33.4 (12.1-125.0) for these procedures, respectively. The relative exposure, determined as first operator dose normalized to procedural DAP, ranged from 1.9 in biliary interventions to 0.1 MUSv/Gy cm2 in cerebral interventions, indicating large variation in staff dose per unit DAP among the procedure types. CONCLUSION: Real-time dose monitoring was able to identify the types of interventions with either an absolute or relatively high staff dose, and may allow for specific optimization of radiation protection. PMID- 27942928 TI - Efficacy and safety of everolimus and sunitinib in patients with gastroenteropancreatic neuroendocrine tumor. AB - PURPOSE: Efficacy of targeted agents, such as everolimus and sunitinib, has been demonstrated in prospective trials on patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Considering the heterogeneous clinicopathological characteristics of neuroendocrine tumors (NETs), evaluation of treatment outcomes in a real-world setting is necessary. METHODS: Clinical records of 44 patients with GEP-NET who were treated with everolimus or sunitinib between March 2007 and October 2014 were retrospectively reviewed. Considering the distinct characteristics of pancreatic NETs (pNETs) and non-pancreatic gastrointestinal NETs (GI-NETs), efficacy analysis was performed separately. RESULTS: Pancreas was the most common primary site (n = 28, 64%), followed by rectum (n = 10, 23%) and stomach (n = 3, 7%). Sunitinib and everolimus were administered in 27 (61%) and 17 (39%) patients, respectively. In patients with pNET, median progression-free survival (PFS) with everolimus and sunitinib was 16.6 months (95% CI 8.0-25.1) and 8.0 months (95% CI 0.0-17.4), respectively (p = 0.51). Among non-pancreatic GI-NET patients, median PFS with everolimus and sunitinib was 14.7 months (95% CI 2.4-27.0) and 1.7 months (95% CI 0.5-3.0), respectively (p = 0.001). Compared to patients treated with everolimus, tumor grade 3 (30 vs. 0%) and history of prior cytotoxic chemotherapy (70 vs. 50%) were more common in patients treated with sunitinib. CONCLUSIONS: Both everolimus and sunitinib were effective in GEP-NET patients. Outcomes of everolimus therapy in GEP-NETs were consistent with those reported elsewhere. Poor efficacy of sunitinib in non-pancreatic GI-NETs may be attributable to the baseline characteristics associated with poor clinical outcomes. PMID- 27942929 TI - Use of retinoic acid/aldehyde dehydrogenase pathway as potential targeted therapy against cancer stem cells. AB - A large number of studies have investigated possible drug resistance mechanisms of cancer cells and suggested strategies to overcome it. In this review, we outline the role and function of aldehyde dehydrogenase (ALDH) activity in multiple cellular functions and in cancer stem cells (CSCs) and focus on the role of retinoic acid (RA), one of the products of ALDH isozymes. We discuss our observation that ATRA and other RAs can suppress ALDH activity and decrease different ALDH isozyme proteins and result in detrimental effects on cell proliferation, invasion and chemotherapy sensitivity. We review the known uses of different RAs in the treatment of cancers. We review the use of RAs in combination with chemo-/radiotherapy and the major signaling pathways affected in different tumor types. We provide follow-up on studies that may have used our prior observation with the aim of targeting the CSCs. We conclude with summary of the findings and potential impact of published studies on future use of RAs in the targeting of CSCs and drug resistance. PMID- 27942930 TI - Phase II trial of capecitabine plus modified cisplatin (mXP) as first-line therapy in Japanese patients with metastatic gastric cancer (KSCC1104). AB - PURPOSE: Capecitabine plus cisplatin (XP) is a standard therapy for metastatic gastric cancer (mGC). However, while results from previous phase III trials suggested that the cisplatin dosage should be reduced in Japanese patients, no clinical data exist to support this. Here, we conducted a multicenter study to evaluate the efficacy and safety of modified XP (mXP) in Japanese patients with mGC. METHODS: Patients with previously untreated mGC received mXP (cisplatin 60 mg/m2 on day 1 plus capecitabine 1000 mg/m2 twice daily on days 1-14) every 3 weeks. The primary endpoint was the Response Evaluation Criteria in Solid Tumors confirmed overall response rate (ORR). A sample size of 40 was planned for a threshold ORR of 30% and an expected value of 50%, with a one-sided alpha of 0.05 and a beta of approximately 0.2. RESULTS: Forty-two patients were enrolled. One patient did not fulfill the eligibility criteria; therefore, a total of 41 patients were assessed. The results were as follows: complete response in 2 patients, partial response in 16, stable disease in 14, progressive disease in 8, and no evaluation in 1. The confirmed ORR was 43.9% (95% confidence interval 28.7 59.1%). The median progression-free survival and median overall survival were 4.6 and 11.3 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (37.5%), anemia (24.4%), anorexia (24.4%), and nausea (12.2%). CONCLUSIONS: First-line chemotherapy with mXP in Japanese patients with mGC did not reach its primary objective. However, it did show a promising response rate and an acceptable tolerability profile. PMID- 27942931 TI - 3D modeling of keloid scars in vitro by cell and tissue engineering. AB - Keloids are pathologic scars defined as dermal fibrotic tumors resulting from a disturbance of skin wound healing process. Treatments against keloids are multiple, sometimes empirical and none of them really provides an effective tool for physicians. The lack of effective treatments is correlated with the poor understanding of keloid pathogenesis. To fill this gap, researchers need strong models mimicking keloids as closely as possible. The objective of this study was to establish in vitro a new reconstructed keloid model (RKM), by combining fibroblasts extracted from the three major area of a keloid (center, periphery, non-lesional) in a three-dimensional biomaterial. To this aim, fibroblasts of three keloid locations were extracted and characterized, and then integrated in a hydrated collagen gel matrix during a three-step procedure. The heterogeneity of fibroblasts was assessed according to their proliferative and remodeling capacities. RKMs were further visualized and characterized by both light and scanning electron microscopy. This reconstructed keloid model should be very useful for investigating keloid fibroblasts function in conditions mimicking in vivo situation. Moreover, RKM should also be a suitable model for either drug study and discovery or innovative approaches using medical devices both during cancer and cancer-like disease investigation. PMID- 27942932 TI - Transactional Relations between Motivational Beliefs and Help Seeking from Teachers and Peers across Adolescence. AB - Adolescents often avoid seeking academic help when needed, making it important to understand the motivational processes that support help seeking behavior. Using expectancy-value theory as a framework, this study examined transactional relations between motivational beliefs (i.e., academic self-concept or academic importance) and seeking help from teachers and peers across adolescence (i.e., from approximately age 12 to 17 years). Data were collected from 1479 adolescents (49% female; 61.9% African American, 31.2% European American, 6.9% other race). Analyses were conducted with cross-lagged panel models using three waves of data from seventh, ninth, and eleventh grade. Results indicated that both academic self-concept and academic importance were associated with increases in teacher help seeking in earlier adolescence, but were associated only with increases in peer help seeking in later adolescence. Help-seeking behavior positively influenced motivational beliefs, with teacher help seeking increasing academic self-concept earlier in adolescence and peer help seeking increasing academic importance later in adolescence. These transactional relations differed by adolescents' prior achievement and racial background, but not by adolescents' gender. PMID- 27942933 TI - Cadaveric assessment of a 3D-printed aiming device for implantation of a hinged elbow external fixator. AB - INTRODUCTION: Proper implantation of a hinged external elbow fixator (HEEF) is demanding since it requires precise alignment between the flexion-extension's and HEEF's axis. In order to optimize this alignment, we have developed a 3D-printed aiming device. The primary goal of the study was to compare the aiming device based technique with the conventional pin technique. The secondary goal was to determine whether it is possible to share the aiming device with the surgical community. MATERIALS AND METHODS: A HEEF was implanted in cadavers with either the aiming device (n = 6) or the conventional pin technique (n = 6). For both techniques the duration of the procedure, the radiation exposure as well as the offset and angular divergence between the HEEF's and flexion-extension's axis were compared. To achieve the secondary goal, two surgeons used aiming devices 3D printed from files sent by email in order to implant HEEF on cadaveric specimens (n = 6). RESULTS: Duration of the procedure was not significantly different between both techniques. However, the aiming device allowed for reduction of the number of image intensifier shots (p = 0.005), angular divergence (p = 0.02) and offset between both axes (p = 0.05). The aiming devices have been delivered less than 15 days after ordering, and they have allowed proper implantation of six HEEF. CONCLUSION: The 3D-printed aiming device allowed less irradiant and more accurate implantation of HEEF. It is possible to share it with other surgeons. PMID- 27942934 TI - Socio-economic disparities in long-term cancer survival-10 year follow-up with individual patient data. AB - PURPOSE: Reasons for the social gradient in cancer survival are not fully understood yet. Previous studies were often only able to determine the socio economic status of the patients from the area they live in, not from their individual socio-economic characteristics. METHODS: In a multi-centre cohort study with 1633 cancer patients and 10-year follow-up, individual socio-economic position was measured using the indicators: education, job grade, job type, and equivalence income. The effect on survival was measured for each indicator individually, adjusting for age, gender, and medical characteristics. The mediating effect of health behaviour (alcohol and tobacco consumption) was analysed in separate models. RESULTS: Patients without vocational training were at increased risk of dying (rate ratio (RR) 1.5, 95% confidence interval (CI) 1.1 2.2) compared to patients with the highest vocational training; patients with blue collar jobs were at increased risk (RR 1.2; 95% CI 1.0-1.5) compared to patients with white collar jobs; income had a gradual effect (RR for the lowest income compared to highest was 2.7, 95% CI 1.9-3.8). Adding health behaviour to the models did not change the effect estimates considerably. There was no evidence for an effect of school education and job grade on cancer survival. CONCLUSIONS: Patients with higher income, better vocational training, and white collar jobs survived longer, regardless of disease stage at baseline and of tobacco and alcohol consumption. PMID- 27942936 TI - Differences in Subjective Well-being Between Older Migrants and Natives in Europe. AB - This study examines disparities in subjective well-being (SWB) among older migrants and natives across several European countries using data from the Survey of Health, Aging and Retirement in Europe (SHARE). Our results show a significant SWB gap between migrants and non-migrants that diminishes with increasing age. While migrants from Northern and Central Europe have similar SWB levels as natives, Southern European, Eastern European, and Non-European migrants have significantly lower levels of SWB than the native population. The immigrant native gap becomes smaller but remains significant after controlling for sociodemographic characteristics and health, the financial situation, citizenship, age at migration, and length of residence. Additionally, we find that the size of the SWB gap varies largely across countries. Current family reunion policies as measured by the Migrant Integration Policy Index (MIPEX) correlate with these country differences. The immigrant-native gap is bigger in countries with restrictive and smaller in countries with open policies. PMID- 27942935 TI - Propagation and synchronization of reverberatory bursts in developing cultured networks. AB - Developing networks of neural systems can exhibit spontaneous, synchronous activities called neural bursts, which can be important in the organization of functional neural circuits. Before the network matures, the activity level of a burst can reverberate in repeated rise-and-falls in periods of hundreds of milliseconds following an initial wave-like propagation of spiking activity, while the burst itself lasts for seconds. To investigate the spatiotemporal structure of the reverberatory bursts, we culture dissociated, rat cortical neurons on a high-density multi-electrode array to record the dynamics of neural activity over the growth and maturation of the network. We find the synchrony of the spiking significantly reduced following the initial wave and the activities become broadly distributed spatially. The synchrony recovers as the system reverberates until the end of the burst. Using a propagation model we infer the spreading speed of the spiking activity, which increases as the culture ages. We perform computer simulations of the system using a physiological model of spiking networks in two spatial dimensions and find the parameters that reproduce the observed resynchronization of spiking in the bursts. An analysis of the simulated dynamics suggests that the depletion of synaptic resources causes the resynchronization. The spatial propagation dynamics of the simulations match well with observations over the course of a burst and point to an interplay of the synaptic efficacy and the noisy neural self-activation in producing the morphology of the bursts. PMID- 27942937 TI - Factors affecting the outcome in appearance of AIS surgery in terms of the minimal clinically important difference. AB - PURPOSE: The minimal clinically important difference (MCID) of the Appearance domain of the SRS-22 questionnaire is an increase >=1.0 in surgically treated patients with adolescent idiopathic scoliosis (AIS). However, no study has sought to identify the factors associated with an SRS-22 Appearance score increase greater than the MCID at 2 years. METHODS: A retrospective analysis was performed on a prospectively collected multicenter database of 1020 surgically treated AIS patients with a minimum 2-year follow-up. Patients were divided into two cohorts: "I" = Improved after surgery (Delta Appearance >=1.0) and "NI" = Not improved after surgery (Delta Appearance <1.0). Univariate regression was used to find a significant difference between the cohorts for individual measures. Multivariate logistic regression was used to find continuous predictors. RESULTS: 663 (65%) patients were improved greater than the MCID, and 357 were not improved (35%). The improved cohort trended toward a greater percentage of underweight patients (p = 0.074) with lower preoperative SRS Appearance scores (p < 0.001) and larger preoperative trunk shifts (p = 0.033). Postoperatively, those patients with greater percent correction of thoracic (p = 0.021) and lumbar (p = 0.003) Cobb angles, smaller apical lumbar translation (p = 0.006), and a greater correction in trunk shift (p = 0.003) were most likely to attain the MCID. CONCLUSION: Several factors influence which patients are most likely to attain the MCID following surgery for AIS. Factors such as preoperative appearance scores and body weight are patient specific; other factors such as percent correction of the thoracic and lumbar Cobb angles, trunk shift, and lumbar apical translation may be influenced by the surgeon. LEVEL OF EVIDENCE: II. PMID- 27942938 TI - Recurrence and survival factors analysis of 171 cases of sacral chordoma in a single institute. AB - PURPOSE: To evaluate postoperative recurrence, survival and metastasis results and related factors of sacral chordoma. METHODS: Between 1978 and 2013, a total of 171 patients with sacral chordoma were diagnosed at our institution and 162 cases underwent operation. The clinical characteristics, treatment and outcomes of all these patients were reviewed. RESULTS: The 3-year recurrence free survival rate was 83.1%. The median recurrence free survival time was 73 +/- 7.8 months. Tumor level in sacrum and surgical margin were significant factors influencing recurrence. Recurrence was significant factor influencing metastasis. One hundred and fifty-seven cases were followed up for an average of 55.6 months. 135 cases (86%) survived, 37 cases (23.6%) developed recurrence, and 17 cases (10.8%) developed metastasis. The overall 5- and 10-year survival rate was 88.3% and 59.6%, respectively. Age (p = 0.037) and metastasis (p = 0.001) were significant factors influencing survival. The 3-year recurrence free survival rate was 80.1%. The median recurrence free survival time was 69 +/- 12.7 months. Tumor level in sacrum (p = 0.035) and surgical margin (p = 0.009) were significant factors influencing recurrence. Seventeen cases (10.8%) had metastasis. Recurrence (p = 0.016) was significant factors influencing metastasis. CONCLUSIONS: Sacral chordoma tended to occur in elderly male patients and locate below sacral 3 level. The recurrence rate was high, especially for tumor above sacral 3 level. Wide surgical margin is very important for good local control. The patients with metastasis had poor prognosis. PMID- 27942939 TI - Modification of PMMA vertebroplasty cement for reduced stiffness by addition of normal saline: a material properties evaluation. AB - PURPOSE: Vertebral augmentation is an established treatment for patients with pathological vertebral compression fractures. These procedures typically employ a PMMA-based bone cement, which possesses a high compressive stiffness. Because of the increased risk of subsequent fractures after vertebral augmentations, there is a desire for reducing this stiffness. The goal of our study was to examine the influence of adding isotonic saline on the biomechanical properties of PMMA vertebroplasty cement. METHODS: A PMMA-based vertebroplasty cement was prepared according to the manufacturer's recommendations after which isotonic saline was mixed into the cement at 10, 20, and 30% (volume:volume). Testing bodies were cast, and compression and bending tests were performed. Fracture surfaces were studied using SEM. Measurements of injectability, setting temperature, and radioopacity were also performed. RESULTS: The addition of saline solution (of up to vol-30%) led to a pronounced reduction in the compression modulus of the cement from 3409 +/- 312 to 1131 +/- 127 MPa. In parallel, maximal compression strength was reduced from 86 +/- 4 to 33 +/- 3 MPa and bending strength from 40 +/- 4 to 24 +/- 3 MPa. The differences regarding injectability, setting temperature, and radioopacity were small and probably of no clinical relevance. CONCLUSIONS: The compressive stiffness of PMMA-based vertebroplasty cement can be reduced to almost a third by the addition of saline. The probable explanation is an increase in microporosity. Future simulator experiments will show whether the achieved reduction in stiffness is large enough to reduce the rate of subsequent vertebral fractures. PMID- 27942940 TI - Growth modulation and remodeling by means of posterior tethering technique for correction of early-onset scoliosis with thoracolumbar kyphosis. AB - PURPOSE: The aim of this study is to evaluate the role of the non-fusion instrumented procedure with compression adjunct to lengthening by distraction in facilitating spinal modulation of the wedged peak vertebra, in patients with congenital thoracolumbar kyphosis/kyphoscoliosis according to the Hueter-Volkmann law. The authors seek to address the progressive modulation of the most wedged vertebra by analyzing the subjects' pre-operative and latest follow-up sagittal radiograph. METHODS: Ongoing data collection of 14 peak wedged vertebra modulation during surgical management of 13 patients with Type I congenital thoracolumbar kyphosis (5 patients) or kyphoscoliosis (8 patients). Age at initial surgery averaged 58.6 months, with mean follow-up of 55.6 months (24-78). All were done with hybrid rib construct with clawing fashion through a single posterior approach with at least 4 lengthenings. RESULTS: Two vertebral bodies were selected, the peaked deformed vertebrae within the instrumentation compression level (WICL) and the vertebrae nearest but outside the instrumentation compression process (OICL). Anterior vertebral body height (AVBH) and posterior vertebral body height (PVBH) were measured in both vertebral bodies. Regarding measured vertebrae (WICL), average preoperative AVBH/PVBH ratio significantly increased from 0.54 to 0.77 in the final follow-up. Regarding measured vertebrae (OICL), the average preoperative AVBH/PVBH ratio increased from 0.76 to 0.79 in the final follow-up. Modulation can be confirmed in the most deformed vertebrae (WICL) as the difference between the change in AVBH/PVBH ratio between vertebrae (OICL) and (WICL) was statistically significant (P < 0.001). CONCLUSIONS: Through the compression model adjunct to lengthening through distraction implemented in the surgical management of early-onset scoliosis, wedging improves through vertebral modulation (WICL) in comparison with the (OICL). This calls for further studies on the impact of surgical correction of EOS on modulation of the vertebrae. PMID- 27942941 TI - Migratory low velocity intradural lumbosacral spinal bullet causing cauda equina syndrome: report of a case and review of literature. AB - BACKGROUND: Migration of the bullet within the spinal subarachnoid space has long been recognized as unusual complication of spinal gunshot injury. OBJECTIVE: We report a case of migratory low velocity intradural lumbosacral spinal bullet causing cauda equina syndrome. The relevant literature is reviewed and all cases of migratory spinal bullet are summarised, and management strategies are discussed. STUDY DESIGN: Literature review. METHODS: A 32-year-old male suffered abdominal gunshot injury for which emergency laparotomy and repair of colonic perforation were performed. The bullet was seen lodged within the sacral spinal canal behind the S1 vertebral body. The probable entry point was at L2-L3 level. Caudal migration of the bullet within the spinal subarachnoid space leads to the appearance of cauda equina syndrome. RESULTS: Bullet was retrieved following upper sacral and lower lumbar laminectomy. Prone positioning of the patient had lead to cranial migration of the bullet at L4 level which was confirmed on fluoroscopy. Laminectomy had to be extended upwards with the patient in reverse Trendelenburg position for bullet removal. CONCLUSIONS: Caudal migration of the bullet within the lumbosacral subarachnoid space results in cauda equina syndrome. Surgical retrieval of the bullet ensures the early recovery of neurological symptoms. Prone patient positioning can influence bullet location. Intraoperative fluoroscopy prior to skin incision is essential in addition to preoperative imaging to locate the bullet and thus avoid incorrect lower level laminectomy. Trapping the bullet after durotomy using suction and dissector in reverse Trendelenburg position is a useful aid in bullet removal. PMID- 27942942 TI - Phylogenetic analysis of HSP70 and cyt b gene sequences for Chinese Leishmania isolates and ultrastructural characteristics of Chinese Leishmania sp. AB - Leishmaniasis is a worldwide epidemic disease caused by the genus Leishmania, which is still endemic in the west and northwest areas of China. Some viewpoints of the traditional taxonomy of Chinese Leishmania have been challenged by recent phylogenetic researches based on different molecular markers. However, the taxonomic positions and phylogenetic relationships of Chinese Leishmania isolates remain controversial, which need for more data and further analysis. In this study, the heat shock protein 70 (HSP70) gene and cytochrome b (cyt b) gene were used for phylogenetic analysis of Chinese Leishmania isolates from patients, dogs, gerbils, and sand flies in different geographic origins. Besides, for the interesting Leishmania sp. in China, the ultrastructure of three Chinese Leishmania sp. strains (MHOM/CN/90/SC10H2, SD, GL) were observed by transmission electron microscopy. Bayesian trees from HSP70 and cyt b congruently indicated that the 14 Chinese Leishmania isolates belong to three Leishmania species including L. donovani complex, L. gerbilli, and L. (Sauroleishmania) sp. Their identity further confirmed that the undescribed Leishmania species causing visceral Leishmaniasis (VL) in China is closely related to L. tarentolae. The phylogenetic results from HSP70 also suggested the classification of subspecies within L. donovani complex: KXG-918, KXG-927, KXG-Liu, KXG-Xu, 9044, SC6, and KXG 65 belong to L. donovani; Cy, WenChuan, and 801 were proposed to be L. infantum. Through transmission electron microscopy, unexpectedly, the Golgi apparatus were not observed in SC10H2, SD, and GL, which was similar to previous reports of reptilian Leishmania. The statistical analysis of microtubule counts separated SC10H2, SD, and GL as one group from any other reference strain (L. donovani MHOM/IN/80/DD8; L. tropica MHOM/SU/74/K27; L. gerbilli MRHO/CN/60/GERBILLI). The ultrastructural characteristics of Leishmania sp. partly lend support to the phylogenetic inference that Chinese Leishmania sp. is in close relationship with reptilian Leishmania. PMID- 27942943 TI - A High School-Based Evaluation of TakeCARE, a Video Bystander Program to Prevent Adolescent Relationship Violence. AB - Although bystander programs to prevent relationship and sexual violence have been evaluated with college students, few evaluations have been conducted with high school students. This study evaluated the effectiveness of TakeCARE, a brief video bystander program designed to promote helpful bystander behavior in situations involving relationship violence among high school students. Students (N = 1295; 52.5% female; 72.3% Hispanic) reported their bystander behavior at a baseline assessment. Classrooms (N = 66) were randomized to view TakeCARE or to a control condition, and high school counselors administered the video in the classrooms assigned to view TakeCARE. Students again reported their bystander behavior at a follow-up assessment approximately 3 months afterward. Results indicate that students who viewed TakeCARE reported more helpful bystander behavior at the follow-up assessment than students in the control condition. Results of exploratory analyses of the likelihood of encountering and intervening upon specific situations calling for bystander behavior are also reported. TakeCARE is efficacious when implemented in an urban high school by high school counselors. PMID- 27942945 TI - Anatomy of the falcine sinus during the prenatal period. AB - BACKGROUND: The falcine sinus in the falx cerebri is rarely encountered in adults, appearings in approximately 2.1% of CT examinations of adult patients. Some authors have studied the plexus rather than the sinus, a rare form of the venous pathway between the layers of the cerebral falx, which connects the superior sagittal sinus with the inferior sagittal sinus and the straight sinus. The aim of this study was to analyse the anatomy of the falcine sinus in the prenatal period, which will fill a gap in the literature. MATERIALS AND METHODS: This study consisted of 50 foetuses with a v-tube length of 89-229 mm and the equivalent of 15-28 weeks of intrauterine development on the Scammon and Calkins scale. METHOD: Blood vessels were filled with latex LBS 3022, and analysis was performed using the Scion Image for Windows 4.0.3.2 and Image J. We used various linear and nonlinear transformations. RESULTS: In 20 cases, intraventricular and periventricular haemorrhages were detected. The other cases showed sinuses in the cerebral falx, specifically in the back parts of the falx, and were described as oblique, straight, wavy, or network. A very rich venous network is located around the superior sagittal sinus; the middle section grew twice its length and the back section grew three times its width, reaching the lowest areas of the cerebral falx, the inferior sagittal sinus, and the straight sinus. Anastomotic intersinual loops appeared. There were three forms of venous weave crescents: isolated limited to the area adjacent to the superior sagittal sinus, partly merging with the straight sinus and a fully developed falcine sinus, which appeared in the older age groups with the most primitive forms being plexiform. Their remains a plurality of channels within the same superior sagittal sinus that show a predominance in the posterior segment. CONCLUSION: The location of the falcine sinus has been mostly associated with the rear one-third of the cerebral falx and should be considered during neurosurgery, because the front two thirds of the cerebral falx are called the "safe zone". Knowledge of the falcine sinus anatomy is important for descriptions in neuroimaging examinations. PMID- 27942944 TI - The suprapineal recess of the third ventricle: an anatomic study with magnetic resonance imaging. AB - PURPOSE: The suprapineal recess (SPR) is a small, backward extension of the third ventricle. Few radiological studies have investigated the morphology of the SPR. Here, we explore the SPR with magnetic resonance (MR) imaging. METHODS: A total of 124 patients underwent thin-slice MR imaging examinations with T2-weighted imaging and the constructive interference steady-state (CISS) sequence. Imaging data were transferred to a workstation for analysis. RESULTS: The pineal gland (P) was delineated in 99% of the patients on T2-weighted imaging and 100% of the patients on the CISS sequence. In contrast, the SPR was identified in 27% of the patients on T2-weighted imaging and 82% of the patients on the CISS sequence. The location of the P relative to the lowest point of the splenium was roughly classified into two types. Of them, the anterior P location was the more frequent type and observed in 73% of the patients. The angle formed by the roof and floor of the SPR showed remarkable interindividual diversity. A membranous posterior extension with variable length, spanning between the posterosuperior margin of the P and Galenic complex was found in 55% of the identified SPRs on T2-weighted imaging and 45% on the CISS sequence. CONCLUSIONS: The SPR is a distinct structure with diversity in appearance among individuals but commonly extends posterior to the P. High-resolution MR imaging is useful for delineating the SPR in vivo. PMID- 27942946 TI - A lateral costal artery complicating video-assisted thorascopic surgery (VATS) pleurectomy. AB - The lateral costal artery is a rare variant arising from the internal thoracic artery (ITA). It has been associated with steel syndrome after coronary artery bypass using the ITA as a conduit. Clinically, it is under-reported in the literature. We report the presence of a prominent lateral costal artery, coursing below the diaphragm, discovered during video-assisted thorascopic surgery pneumothorax surgery and preventing parietal pleurectomy. PMID- 27942947 TI - Identification landmark for right anterior portal pedicle: "the zone of 2 cm". AB - PURPOSE/BACKGROUND: Cystic plate is easily visible while right anterior portal pedicle (RAPP) is a difficult to identify due to its intrahepatic location. This study aims to determine the relation between these two structures so as to facilitate rapid identification of RAPP during the operation. METHODS: Thirty seven cadaveric liver dissections were carried in the Forensic Department at the Charles Nicolle Hospital, Tunisia. RESULTS: The cystic plate was thin (<=1 mm), medium (1-3 mm), and thick (>=3 mm) in 14 (37.8%), 17 (46%), and 6 cases (16.2%), respectively. RAPP was found to be originating from right, main, and left portal trunk in 29 (78.3%), 6 (16.3%), and 2 (5.4%) livers, respectively. The origin of RAPP was extrahepatic in nine cases (24.3%). RAPP was located underneath the cystic plate in 21 livers (56.8%). Thirteen RAPPs (35.1%) were located to its right at the mean distance of 1.4 cm (range 0.4-2.5). Three RAPPs were present to the left of cystic plate (8.1%) at the mean distance of 0.9 cm (range 0.7-1.3). CONCLUSION: Rapid identification of RAPP is possible by knowing its anatomic variations and its relation with cystic plate. PMID- 27942948 TI - Potentially inappropriate prescribing in a population of frail elderly people. AB - Background Frailty is a clinical syndrome highly predictive of functional decline after a stress or a medical event, such as adverse drug events. Objective To describe the prevalence of potentially inappropriate prescribing in a population of frail elderly patients. Setting Geriatric day hospital for assessment of frailty and prevention of disability, Toulouse, France. Method A cross-sectional study performed from January to April 2014. Two pharmacists retrospectively analyzed the prescriptions of elderly patients who were sent to the day hospital to assess their frailty and to be given a personalized plan of care and prevention. Potentially inappropriate prescribing was defined by combining explicit criteria: Laroche list, screening tool of older people's prescriptions, and screening tool to alert to right treatment with an implicit method (drug utilization review for each medication). Prescriptions' optimizations were then suggested to the geriatricians of the day hospital and classified according to criteria defined by the French Society of Clinical Pharmacy. Main outcome measure Prevalence of potentially inappropriate prescribing. Results Among the 229 patients included, 71.2% had potentially inappropriate prescribing. 76 patients (33.2%) had at least one drug without any valid indication. 51 (22.3%) had at least one drug with an unfavorable benefit-to-risk ratio according to their clinical and biological data, 42 (18.3%) according to the Laroche list and 38 (16.6%) had at least one drug with questionable efficacy. Conclusion Our work shows that the incidence of PIP is high in the frail elderly and that, in most cases, it could be avoided with an adequate and regular reassessment of the prescriptions. In future, prescription optimization will be integrated into the personalized medical care plan to further prevent drug-related disability. PMID- 27942949 TI - Assessment of the elderly's functional ability to manage their medication: a systematic literature review. AB - Background The evaluation of the elderly's ability to manage medication through the use of a validated tool can be a significant step in identifying inabilities and needs, with the objective of increasing their self-care skills, and promoting successful aging. Aim of the review To identify studies assessing the elderly's functional ability to manage their own medication. Method For the search strategy, the PICO method was used: P-Population (elderly), I-Instruments (tools for assessing medication management ability), C-Context (community) and O Outcomes (functional ability to manage medication). The final search query was run in MEDLINE/PubMed, CINAHL Plus, ISI Web of Science and Scopus. The whole process was developed according to the PRISMA statement. Results The search retrieved 8051 records. In each screening stage, the selection criteria were applied to eliminate records where at least one of the exclusion criteria was verified. At the end of this selection, we obtained a total of 18 papers (17 studies). The results allow the conclusion to be drawn that studies use several different instruments, most of them not validated. The authors agree that medication management abilities decrease as cognitive impairment increases, even if a lot of studies assess only the physical dimension. DRUGS was the instrument most often used. Conclusion Older adults' ability to manage their medication should be assessed using tools specifically built and validate for the purpose. DRUGS (which uses the real regimen taken by the elderly) was the most widely used assessment instrument in the screened studies. PMID- 27942950 TI - Morphological differences between optic disc collaterals and neovascularization on optical coherence tomography angiography. AB - BACKGROUND: To study morphological features of optic disc venous collaterals (OVCs) and neovascularization of optic disc (NVD) on optical coherence tomography angiography (OCTA). METHODS: Patients with OVCs and NVDs secondary to ischemic retinal diseases were prospectively enrolled. Multimodal imaging was performed using color fundus photography, fluorescein angiography (FA), and OCTA. Morphological evaluation of en-face structural OCT, cross-sectional and en-face OCTA was performed. RESULTS: Twenty eyes (20 patients; OVCs: n = 10 and NVD: n = 10) were included. OVCs appeared as small, loopy vessels distinct from surrounding peripapillary capillaries on OCTA in the radial peripapillary capillary frame. NVDs appeared as a mesh of fine caliber, raised vessels best seen in the vitreous slab of OCTA. Flow signals in these vascular alterations correlated well with hyperfluorescence on FA. CONCLUSIONS: OCTA provides improved visualization of NVDs and OVCs in ischemic retinal diseases such as diabetic retinopathy and retinal vein occlusions compared to conventional FA. PMID- 27942951 TI - Effects of face cooling on pulse waveform and sympathetic activity in hypertensive subjects. AB - Adverse cardiovascular events occur more frequently during cold weather. To test the hypothesis that cold exposure would lead to increased sympathetic activity and impaired hemodynamic control, we measured muscle sympathetic nerve activity and hemodynamic parameters in nine men with hypertension before and during trigeminal stimulation and facial cooling. The procedure increased blood pressure (p < 0.01), aortic hemodynamic parameters (p < 0.01), and muscle sympathetic nerve activity (p < 0.05). These results suggest that sympathetic activation during cold exposure in hypertensive subjects may increase the risk of cardiovascular events during cold weather. PMID- 27942952 TI - One gene, two paracellular ion channels-claudin-10 in the kidney. AB - Claudins are tight junction membrane proteins and regulate the paracellular passage of ions and water. They can seal the paracellular cleft against solute passage but also form paracellular channels. They are tetraspan proteins with two extracellular segments. Claudin-10 exists in at least two functional isoforms, claudin-10a and claudin-10b, that differ in their first transmembrane segment and first extracellular segment. Both isoforms act as selective paracellular ion channels, either for anions (claudin-10a) or for cations (claudin-10b). Their diverse functions are reflected in completely different expression patterns in the body, especially in the kidney. Their structural and functional similarities and differences make them ideal subjects to study determinants of claudin charge selectivity and pore formation. This review aims to summarise research on permeability properties of the claudin-10 channels and their role in physiology and pathophysiology of the kidney. PMID- 27942953 TI - Relatedness support enhances motor learning. AB - The present experiment was designed to test the effects of practice with relatedness support on motor learning. Forty-five young adults practiced a task in which they were required to learn to swim the front crawl stroke for one length in an indoor swimming pool (25 m) using 50% of the maximal speed. In the relatedness support condition (RS group), the instructions emphasized acknowledgement, caring, and interest in the participants' experiences, while in the relatedness thwart condition (RTh group), instructions emphasized disinterest in the participant as a person. A third, neutral condition (Control group) did not receive specific relatedness instructions. One day after practice, participants completed retention and transfer tests. The RS group demonstrated greater improvement in performance during practice and enhanced learning relative to the RTh and Control groups, while the RTh group showed decreased learning compared with the Control group. Furthermore, RS participants reported higher motivation and greater positive affect than the RTh and Control groups. The present findings demonstrate that relatedness support enhances the learning of motor skills. They also highlight motivational and affective effects that are observed when learners are provided with relatedness support. PMID- 27942955 TI - Management dilemmas in pediatric nephrology: time-limited trials of dialysis therapy. AB - BACKGROUND: Time-limited trials of dialysis have been proposed as a third option in addition to initiation of treatment and comfort-care only in the setting of high uncertainty or discordance between the treating team and child/family or among the treating team. CASE-DIAGNOSIS/TREATMENT: The index case was noted antenatally to have severe kidney disease and pulmonary hypoplasia. In light of the guarded, but uncertain prognosis and a lack of consensus among the treating team, as well as between the treating team and the family, a time-limited trial of dialysis was initiated. Six days later the child developed bacteremia due to infection of the dialysis catheter. The treating team felt this was a failure of the trial and that future dialysis should be withheld, the family disagreed. CONCLUSION: A time-limited trial is a problematic option. Providers may be better suited by returning to the dichotomous choice of withholding or initiating treatment. KEY MANAGEMENT POINTS: * Time-limited trials offer potential benefits in terms of alleviating the burden of decision-making in the setting of uncertainty, offering an opportunity to forecast a poor prognosis, help avoid interprofessional conflict, and providing support for patients, their families, and staff. * Time-limited trials have important limitations, including the use of time limits, difficulty in determining clear, meaningful endpoints, and different interpretations of a trial of therapy between parents and providers. * Decisions regarding the initiation, withholding, and withdrawal of dialysis should be made based on regular assessments of the benefits and burdens of the intervention for the child. * Pediatric nephrologists are better served to abandon the concept of time-limited trials. PMID- 27942956 TI - Building on evidence to improve patient care. AB - Evidence-based medicine (EBM) is gaining importance in the current paediatric healthcare landscape. Improvement of paediatric health status is its major aim. However, for EBM to be successful, all stakeholders involved should understand what EBM really is, why and how EBM should or should not be practiced, and have the necessary skills to distinguish methodologically sound papers from biased opinion papers, and understand how and why guidelines are different from systematic reviews. Improving patient outcome requires attention to high-quality evidence and understanding of the processes of medical decision-making. Rigorous methodology is the cornerstone of guideline production, but in cases where quality evidence cannot be produced, as is often the case in paediatric nephrology because of low patient numbers, consensus-based guidance may be suitable to assist the practitioner at the bedside, as long as the underlying process is transparent. Most importantly, EBM should support patient involvement in a shared decision-making process. The more consistent and accurately predictable the effect of certain interventions is, clinically relevant to patients rather than affecting surrogate outcomes, and a priority for patients and other stakeholders, the more likely it is that adherence to the guidance provided will improve the outcome of patients. PMID- 27942954 TI - Assessment of gas compression and lung volume during air stacking maneuver. AB - PURPOSE: We reasoned that the application of positive pressure through air stacking (AS) technique could cause gas compression and the absolute lung volumes could be estimated. The aim of this study was to estimate the amount of gas compression (DeltaV comp) during AS in healthy subjects positioned at 45 degrees trunk inclination and verify if the simultaneous measurements of chest wall volume changes (DeltaV CW), by optoelectronic plethysmography, and changes in lung volume (DeltaV ao), by pneumotachograph, combined with pressure variation at the airways opening (DeltaP ao) during AS are able to provide reliable data on absolute lung volumes. METHODS: Twenty healthy subjects (mean age 23.5 +/- 3.8 years) were studied during a protocol that included slow vital capacity and AS maneuvers. V comp was calculated by subtracting DeltaV ao and DeltaV CW occurring during AS and total lung capacity (TLC) was estimated by applying Boyle-Mariote's law using V comp and DeltaP ao. RESULTS: During AS, 0.140 +/- 0.050 L of gas was compressed with an average DeltaP ao of 21.78 +/- 6.18 cmH2O. No significant differences between the estimated TLC (-0.03 +/- 3.0% difference, p = 0.6020), estimated FRC (-2.0 +/- 12.4% difference, p = 0.5172), measured IC (1.2 +/- 11.2% difference, p = 0.7627) and predicted values were found. CONCLUSION: During AS, a significant gas compression occurs and absolute lung volumes can be estimated by simultaneous measurements of DeltaV CW, DeltaV ao and DeltaP ao. PMID- 27942957 TI - Arbuscular mycorrhizal fungal community differences among European long-term observatories. AB - Arbuscular mycorrhizal fungal (AMF) communities have been demonstrated to respond to a variety of biotic and abiotic factors, including various aspects of land management. Numerous studies have specifically addressed the impact of land use on AMF communities, but usually have been confined to one or a few sites. In this study, soil AMF assemblages were described in four different long-term observatories (LTOs) across Europe, each of which included a site-specific high intensity and a low-intensity land use. AMF communities were characterized on the basis of 454 sequencing of the internal transcribed spacer 2 (ITS2) rDNA region. The primary goals of this study were (i) to determine the main factors that shape AMF communities in differentially managed sites in Europe and (ii) to identify individual AMF taxa or combinations of taxa suitable for use as biomarkers of land use intensification. AMF communities were distinct among LTOs, and we detected significant effects of management type and soil properties within the sites, but not across all sites. Similarly, indicator species were identified for specific LTOs and land use types but not universally for high- or low-intensity land uses. Different subsets of soil properties, including several chemical and physical variables, were found to be able to explain an important fraction of AMF community variation alone or together with other examined factors in most sites. The important factors were different from those for other microorganisms studied in the same sites, highlighting particularities of AMF biology. PMID- 27942958 TI - ABI5-binding proteins (AFPs) alter transcription of ABA-induced genes via a variety of interactions with chromatin modifiers. AB - KEY MESSAGE: Overexpression of ABI5/ABF binding proteins (AFPs) results in extreme ABA resistance of seeds via multiple mechanisms repressing ABA response, including interactions with histone deacetylases and the co-repressor TOPLESS. Several ABI5/ABF binding proteins (AFPs) inhibit ABA response, resulting in extreme ABA resistance in transgenic Arabidopsis overexpression lines, but their mechanism of action has remained obscure. By analogy to the related Novel Interactor of JAZ (NINJA) protein, it was suggested that the AFPs interact with the co-repressor TOPLESS to inhibit ABA-regulated gene expression. This study shows that the AFPs that inhibit ABA response have intrinsic repressor activity in a heterologous system, which does not depend on the domain involved in the interaction with TOPLESS. This domain is also not essential for repressing ABA response in transgenic plants, but does contribute to stronger ABA resistance. Additional interactions between some AFPs and histone deacetylase subunits were observed in yeast two-hybrid and bimolecular fluorescence assays, consistent with a more direct mechanism of AFP-mediated repression of gene expression. Chemical inhibition of histone deacetylase activity by trichostatin A suppressed AFP effects on a small fraction of the ABI5-regulated genes tested. Collectively, these results suggest that the AFPs participate in multiple mechanisms modulating ABA response, including both TOPLESS-dependent and -independent chromatin modification. PMID- 27942959 TI - The PPR protein SLOW GROWTH 4 is involved in editing of nad4 and affects the splicing of nad2 intron 1. AB - KEY MESSAGE: SLO4 is a mitochondrial PPR protein that is involved in editing nad4, possibly required for the efficient splicing of nad2 intron1. Pentatricopeptide repeat (PPR) proteins constitute a large protein family in flowering plants and are thought to be mostly involved in organellar RNA metabolism. The subgroup of PLS-type PPR proteins were found to be the main specificity factors of cytidine to uridine RNA editing. Identifying the targets of PLS-type PPR proteins can help in elucidating the molecular function of proteins encoded in the organellar genomes. In this study, plants lacking the SLOW GROWTH 4 PPR protein were characterized. Slo4 mutants were characterized as having restricted root growth, being late flowering and displaying an overall delayed growth phenotype. Protein levels and activity of mitochondrial complex I were decreased and putative complex I assembly intermediates accumulated in the mutant plants. An editing defect, leading to an amino acid change, in the mitochondrial nad4 transcript, encoding for a complex I subunit, was identified. Furthermore, the splicing efficiency of the first intron of nad2, encoding for another complex I subunit, was also decreased. The change in splicing efficiency could however not be linked to any editing defects in the nad2 transcript. PMID- 27942960 TI - Comparison of elementary steps of the cross-bridge cycle in rat papillary muscle fibers expressing alpha- and beta-myosin heavy chain with sinusoidal analysis. AB - In mammalian ventricles, two myosin heavy chain (MHC) isoforms have been identified. Small animals express alpha-MHC, whereas large animals express beta MHC, which contribute to a large difference in the heart rate. Sprague-Dawley rats possessing ~99% alpha-MHC were treated with propylthiouracil to result in 100% beta-MHC. Papillary muscles were skinned, dissected into small fibers, and used for experiments. To understand the functional difference between alpha-MHC and beta-MHC, skinned-fibers were activated under the intracellular ionic conditions: 5 mM MgATP, 1 mM Mg2+, 8 mM Pi, 200 mM ionic strength, pH 7.00 at 25 degrees C. Small amplitude sinusoidal length oscillations were applied in the frequency range 0.13-100 Hz (corresponding time domain: 1.6-1200 ms), and effects of Ca2+, Pi, and ATP were studied. The results show that Ca2+ sensitivity was slightly less (10-15%) in beta-MHC than alpha-MHC containing fibers. Sinusoidal analysis at pCa 4.66 (full Ca2+ activation) demonstrated that, the apparent rate constants were 2-4* faster in alpha-MHC containing fibers. The ATP study demonstrated that, in beta-MHC containing fibers, K 1 (ATP association constant) was greater (1.7*), k 2 and k -2 (cross-bridge detachment and its reversal rate constants) were smaller (*0.6). The Pi study demonstrated that, in beta-MHC containing fibers, k 4 (rate constant of the force-generation step) and k -4 were smaller (0.75* and 0.25*, respectively), resulting in greater K 4 (3*). There were no differences in active tension, rigor stiffness, or K 2 (equilibrium constant of the cross-bridge detachment step). Our study further demonstrated that there were no differences in parameters between fibers obtained from left and right ventricles, but with an exception in K 5 (Pi association constant). PMID- 27942961 TI - Long-lasting permethrin-impregnated clothing: protective efficacy against malaria in hyperendemic foci, and laundering, wearing, and weathering effects on residual bioactivity after worst-case use in the rain forests of French Guiana. AB - Personal protective measures against hematophagous vectors constitute the first line of defense against arthropod-borne diseases. However, guidelines for the standardized testing and licensing of insecticide-treated clothing are still lacking. The aim of this study was to analyze the preventive effect of long lasting polymer-coated permethrin-impregnated clothing (PTBDU) against malaria after exposure to high-level disease transmission sites as well as the corresponding loss of permethrin and bioactivity during worst-case field use. Between August 2011 and June 2012, 25 personnel wearing PTBDUs and exposed for 9.5 person-months in hyperendemic malaria foci in the rain forest of French Guiana contracted no cases of malaria, whereas 125 persons wearing untreated uniforms only, exposed for 30.5 person-months, contracted 11 cases of malaria, indicating that PTBDU use significantly (p = 0.0139) protected against malaria infection. In the field, PTBDUs were laundered between 1 and 218 times (mean 25.2 +/- 44.8). After field use, the mean remaining permethrin concentration in PTBDU fabric was 732.1 +/- 321.1 min varying between 130 and 1270 mg/m2 (mean 743.9 +/- 304.2 mg/m2) in blouses, and between 95 and 1290 mg/m2 (mean 720.2 +/- 336.9 mg/m2) in trousers. Corresponding bioactivity, measured according to internal licensing conditions as KD99 times against Aedes aegypti mosquitoes, varied between 27.5 and 142.5 min (mean 47.7 +/- 22.1 min) for blouses, and between 25.0 and 360 min (mean 60.2 +/- 66.1 min) for trousers. We strongly recommend the use of long-lasting permethrin-impregnated clothing for the prevention of mosquito borne diseases, including chikungunya, dengue, and zika fevers, which are currently resurging globally. PMID- 27942963 TI - Rhomboid-shaped advancement flap anoplasty to treat anal stenosis. PMID- 27942962 TI - Evaluating an indirect rMPSP enzyme-linked immunosorbent assay for the detection of bovine Theileria infection in China. AB - Bovine theileriosis, a tick-borne protozoan disease caused by Theileria annulata, Theileria orientalis and Theileria sinensis, is widespread in China and is a serious economic problem for the Chinese livestock industry. In this study, recombinant major piroplasma surface proteins (MPSP) of T. annulata, T. orientalis and T. sinensis based on MPSP genes were expressed in Escherichia coli BL21(DE3). The immunogenicity and specificity of the three purified recombinant MPSP proteins were evaluated with the reference positive sera of T. annulata, T. orientalis, T. sinensis, Babesia bovis, B abesia bigemina, Babesia major, Babesia motasi, Theileria luwenshuni, Theileria uilenbergi and Anaplasma ovis using an enzyme-linked immunosorbent assay (ELISA) or western blotting. The results showed that all three of the rMPSP proteins had a strong reaction with the sera from cattle infected with T. annulata, T. orientalis and T. sinensis via western blotting but not with other piroplasma and Anaplasma species. Then, the rMPSP protein of T. sinensis was used to develop an iELISA for detecting the three Theileria species infections. The specificity and sensitivity were 95.7 and 95.5 %, respectively, with a threshold of 28.8 % of the specific mean antibody rate (AbR). Finally, 2473 field-collected bovine sera, from 42 prefectures of 17 provinces in China, were tested using the ELISA to evaluate the prevalence of bovine theileriosis, and the average positive rate was 43.6 %. The developed iELISA could be a suitable tool to detect the three bovine Theileria species, and the data also provided important information regarding the current prevalence of bovine theileriosis in China. PMID- 27942964 TI - Meta-analysis of botulinum toxin injection for chronic anal fissure: healing rates controversies. PMID- 27942965 TI - Prophylactic mesh to prevent parastomal hernia: a meta-analysis of randomized controlled studies. AB - The aim of the present meta-analysis was to determine whether prophylactic mesh decreases the odds of parastomal hernia formation. Randomized controlled trials referenced in MEDLINE or EMBASE between 1946 and 2016 comparing prophylactic mesh to standard stoma formation were included. The primary outcome was occurrence of parastomal hernia. Secondary outcomes were parastomal hernia requiring surgical intervention and complications. Odds ratios were calculated for the primary and secondary outcomes. Subgroup analyses were conducted based on mesh type, mesh location, laparoscopic versus open, and method of hernia diagnosis. Nine randomized controlled trials with 569 participants were included. There was a significant decrease in the odds of developing a parastomal hernia in the prophylactic mesh group [odds ratio (OR) 0.21, 95% confidence interval (CI) 0.11 0.38, p < 0.00001, I 2 = 36%], as well as decreased odds of requiring surgical repair (OR 0.36, 95% CI 0.15-0.87, p = 0.02, I 2 = 0%). There was no evidence that prophylactic mesh increased the odds of surgical complications (seven studies, OR 1.34, 95% CI 0.73-2.46, p = 0.34, I 2 = 34%) or stoma-specific complications (eight studies, OR 0.65, 95% CI 0.40-1.05, p = 0.08, I 2 = 0%). There was a subgroup effect with synthetic mesh associated with a lower incidence of parastomal hernias which was not appreciated in the biologic mesh group (test of subgroup effect p = 0.01). Five studies had a high risk of bias. The Grades of Recommendation, Assessment, Development and Evaluation quality of evidence was moderate. Prophylactic mesh is associated with decreased odds of parastomal hernia formation and the need for surgical repair. There is no evidence that mesh placement increases the odds of complications. PMID- 27942966 TI - Improving risk equalization with constrained regression. AB - State-of-the-art risk equalization models undercompensate some risk groups and overcompensate others, leaving systematic incentives for risk selection. A natural approach to reducing the under- or overcompensation for a particular group is enriching the risk equalization model with risk adjustor variables that indicate membership in that group. For some groups, however, appropriate risk adjustor variables may not (yet) be available. For these situations, this paper proposes an alternative approach to reducing under- or overcompensation: constraining the estimated coefficients of the risk equalization model such that the under- or overcompensation for a group of interest equals a fixed amount. We show that, compared to ordinary least-squares, constrained regressions can reduce under/overcompensation for some groups but increase under/overcompensation for others. In order to quantify this trade-off two fundamental questions need to be answered: "Which groups are relevant in terms of risk selection actions?" and "What is the relative importance of under- and overcompensation for these groups?" By making assumptions on these aspects we empirically evaluate a particular set of constraints using individual-level data from the Netherlands (N = 16.5 million). We find that the benefits of introducing constraints in terms of reduced under/overcompensations for some groups can be worth the costs in terms of increased under/overcompensations for others. Constrained regressions add a tool for developing risk equalization models that can improve the overall economic performance of health plan payment schemes. PMID- 27942967 TI - Preferences for public involvement in health service decisions: a comparison between best-worst scaling and trio-wise stated preference elicitation techniques. AB - Stated preference elicitation techniques, such as discrete choice experiments and best-worst scaling, are now widely used in health research to explore the public's choices and preferences. In this paper, we propose an alternative stated preference elicitation technique, which we refer to as 'trio-wise'. We explain this new technique, its relative advantages, modeling framework, and how it compares to the best-worst scaling method. To better illustrate the differences and similarities, we utilize best-worst scaling Case 2, where individuals make best and worst (most and least) choices for the attribute levels that describe a single profile. We demonstrate this new preference elicitation technique using an empirical case study that explores preferences among the general public for ways to involve them in decisions concerning the health care system. Our findings show that the best-worst scaling and trio-wise preference elicitation techniques both retrieve similar preferences. However, the capability of our trio-wise method to provide additional information on the strength of rank preferences and its ability to accommodate indifferent preferences lead us to prefer it over the standard best-worst scaling technique. PMID- 27942968 TI - False-positive Cultures After Native Knee Aspiration: True or False. AB - BACKGROUND: Synovial fluid aspiration is a routine practice used by most orthopaedic surgeons to aid in the diagnosis of joint infection. In patients for whom there is a low pretest probability of infection, a positive culture particularly if it is a broth-only culture-may be considered a contaminant, especially if the bacterial species are skin pathogens. To our knowledge no study has evaluated the incidence of contamination of aspirations from the native knee. QUESTIONS/PURPOSES: What is the frequency of false-positive cultures among knee aspirations of the native knee? METHODS: Two hundred patients, with a total of 200 knees, with the diagnosis of degenerative osteoarthritis undergoing a total knee arthroplasty (TKA) were identified for this study. None of these patients had symptoms, signs, or laboratory studies to suggest the presence of joint infection; a positive culture in this population therefore would be considered contaminated. Thirty-two (16%) patients were excluded secondary to a dry aspiration. One patient was enrolled in the study but did not have the knee aspirated and another patient's specimen was accidentally discarded. Each knee was aspirated under sterile conditions before performing the TKA. The fluid was sent for cell count and culture. If insufficient fluid was obtained for both cell count and culture, culture was performed rather than cell count. RESULTS: There were no false-positive cultures (zero of 166 [0%]) in aspirations of native knees. CONCLUSIONS: Our study would indicate that when done properly under sterile technique, cultures taken from knee arthrocentesis in patients without prosthetic joints should not be affected by perceived contaminant species. A positive specimen finding on culture should raise a strong suspicion of bacterial septic arthritis. Future studies should include more specimens as well as knees with prior TKA to help further identify the rate of false-positive cultures in knee arthrocentesis in both populations. LEVEL OF EVIDENCE: Level I, diagnostic study. PMID- 27942969 TI - Not the Last Word: Safety Alert: One in 200 Knee Replacement Patients Die Within 90 Days of Surgery. PMID- 27942971 TI - In memoriam: Frederick Griffith Pearson, a legend in thoracic surgery and a great teacher (1926-2016). PMID- 27942970 TI - Do HDL and LDL subfractions play a role in atherosclerosis in end-stage renal disease (ESRD) patients? AB - BACKGROUND: Significantly increased cardiovascular mortality in patients with chronic kidney (CKD) disease cannot be explained by traditional risk factors. Recent studies revealed that the quality of HDL and LDL cholesterol may be more important than their serum levels. The aim of this study was to assess which LDL and HDL subfractions were more abundant in end-stage renal disease (ESRD) patients and to analyse whether subfraction distribution could be associated with accelerated atherosclerotic processes. METHODS: This study included 50 ESRD patients undergoing dialysis and 20 healthy volunteers. LDL and HDL subfractions were analysed in serum with the use of Lipoprint system. All patients had intima media thickness (IMT) measured. RESULTS: Statistically significant differences in subfractions between control and study group were observed in case of: HDL1 (p < 0.0001), HDL2 (p = 0.009), HDL3 (p < 0.0001), HDL4 (p = 0.003), HDL5 (p = 0.01), HDL7 (p < 0.0001), HDL8 (p < 0.0001), HDL9 (p < 0.0001), HDL10 (p < 0.0001), large HDL (p < 0.0001), HDL Small (p < 0.0001) as well as IDL-B (p = 0.014), IDLA (p = 0.011), LDL2 (p = 0.007). Significant differences were also observed in HDL and LDL subfraction distribution between haemodialysis patients with normal and increased IMT: HDL6 (p = 0.020), HDL Large (HDL1-3) (p = 0.017), HDL Intermediate (HDL4-7) (p = 0.017). CONCLUSIONS: This study revealed that ESRD influenced HDL subfractions. In HD patients, large HDL subfractions are more abundant while small HDL fraction is more frequent in healthy persons. It failed to show the influence of end-stage disease on LDL subfraction levels. Shift in HDL subfractions might be responsible for the increased risk of atherosclerosis in CKD patients. PMID- 27942972 TI - The influenza A virus matrix protein 2 undergoes retrograde transport from the endoplasmic reticulum into the cytoplasm and bypasses cytoplasmic proteasomal degradation. AB - The matrix protein 2 (M2) is a spliced product of segment 7 genome of influenza A virus. Previous studies indicate its role in uncoating of the viral ribonucleoprotein complex during viral entry and in membrane scission while budding. Despite its crucial role in the viral life cycle, little is known about its subcellular distribution and dynamics. In this study, we have shown that the M2 protein is translocated from the membrane to the cytoplasm by a retrograde route via endosomes and the Golgi network. It utilizes retromer cargo while moving from the endosome to the trans-Golgi network and prevents endosome fusion with the lysosome. Further, M2 interacts with the endoplasmic-reticulum-resident AAA-ATPase p97 for its release into the cytoplasm. Our study also revealed that the M2 protein in the cellular milieu does not undergo ubiquitin-mediated proteasomal degradation. The migration of M2 through this pathway inside the infected cell suggests possible new roles that the M2 protein may have in the host cytoplasm, apart from its previously described functions. PMID- 27942973 TI - High-throughput sequencing analysis reveals the genetic diversity of different regions of the murine norovirus genome during in vitro replication. AB - In this study, we report the genetic diversity and nucleotide mutation rates of five representative regions of the murine norovirus genome during in vitro passages. The mutation rates were similar in genomic regions encompassing partial coding sequences for non-structural (NS) 1-2, NS5, NS6, NS7 proteins within open reading frame (ORF) 1. In a region encoding a portion of the major capsid protein (VP1) within ORF2 (also including the ORF4 region) and a portion of the minor structural protein (VP2), the mutation rates were estimated to be at least one order of magnitude higher. The VP2 coding region was found to have the highest mutation rate. PMID- 27942974 TI - Turkey herpesvirus with an insertion in the UL3-4 region displays an appropriate balance between growth activity and antibody-eliciting capacity and is suitable for the establishment of a recombinant vaccine. AB - We constructed turkey herpesvirus (HVT) vector vaccines in which the VP2 gene of infectious bursal disease virus (IBDV) was inserted into the HVT genome in the following regions: UL3-4, UL22-23, UL45-46, and US10-SORF3. We then evaluated the relationship between the gene insertion site and the capacity of the virus to elicit antibodies. rHVT/IBD (US10) showed good growth activity in vitro, with growth comparable to that of the parent HVT. On the other hand, rHVT/IBD (UL3-4), rHVT/IBD (UL22-23), and rHVT/IBD (UL45-46) exhibited decreased growth activity in chicken embryo fibroblast (CEF) cells compared to the parent HVT. However, the rHVT/IBD (US10) elicited lower levels of virus-neutralizing (VN) antibodies compared to the other constructs. rHVT/IBD (UL3-4) and rHVT/IBD (UL45-46) appeared to be similar in their ability to elicit VN antibodies. Based on the results of in vitro and in vivo assays, rHVT/IBD (UL3-4) was selected for further testing. In a challenge assay, rHVT/IBD (UL3-4) protected chickens from challenge with virulent Marek's disease virus serotype 1 and IBDV. In conclusion, the site of gene insertion may have a strong effect on the growth of the vector virus in vitro and its antibody-eliciting capacity. Insertions in the UL3-4 region permitted a balance between growth activity and VN-antibody-eliciting capacity, and this region might therefore be an appropriate insertion site for IBDV VP2. PMID- 27942975 TI - Association between vitamin D and sperm parameters: Clinical evidence. PMID- 27942976 TI - Loss in photosynthesis during senescence is accompanied by an increase in the activity of beta-galactosidase in leaves of Arabidopsis thaliana: modulation of the enzyme activity by water stress. AB - The precise nature of the developmental modulation of the activity of cell wall hydrolases that breakdown the wall polysaccharides to maintain cellular sugar homeostasis under sugar starvation environment still remains unclear. In this work, the activity of beta-galactosidase (EC 3.2.1.23), a cell-wall-bound enzyme known to degrade the wall polysaccharides, has been demonstrated to remarkably enhance during senescence-induced loss in photosynthesis in Arabidopsis thaliana. The enhancement in the enzyme activity reaches a peak at the terminal phase of senescence when the rate of photosynthesis is at its minimum. Although the precise nature of chemistry of the interface between the decline in photosynthesis and enhancement in the activity of the enzyme could not be fully resolved, the enhancement in its activity in dark and its suppression in light or with exogenous sugars may indicate the involvement of loss of photosynthetic production of sugars as a key factor that initiates and stimulates the activity of the enzyme. The hydrolase possibly participates in the catabolic network of cell wall polysaccharides to produce sugars for execution of energy-dependant senescence program in the background of loss of photosynthesis. Drought stress experienced by the senescing leaves accelerates the decline in photosynthesis with further stimulation in the activity of the enzyme. The stress recovery of photosynthesis and suppression of the enzyme activity on withdrawal of stress support the proposition of photosynthetic modulation of the cell-wall-bound enzyme activity. PMID- 27942977 TI - Maintenance of efficacy and safety with subcutaneous golimumab in rheumatoid arthritis patients with low disease activity who previously received TNF inhibitors. AB - The study was conducted to evaluate continued maintenance of the efficacy and safety of therapy by switching to subcutaneous golimumab (GLM-SC) in rheumatoid arthritis patients with low disease activity or remission who previously received a tumor necrosis factor (TNF) inhibitor. Thirty patients who had been treated with etanercept or infliximab were switched to GLM-SC in maintaining disease activity at a low level. The patients were divided into two groups through discussion with each patient, considering general condition and convenience: the low disease activity (LDA) group and the LDAq8w group, which included patients with low disease activity or remission who switched to 50 mg GLM therapy at 4- and 8-week intervals, respectively. The effects of the TNF inhibitors to GLM-SC switch were evaluated at 12, 24, and 52 weeks after switching. The mean DAS28-ESR and DAS-CRP values in the LDA groups (16 patients) and LDAq8w groups (14 patients) were maintained from baseline throughout the 52-week treatment period. DAS28-ESR remission (93.8 and 92.3%) rates were also maintained through week 52 from the baseline remission rate (75.0 and 78.6%) in the LDA and LDAq8w groups, respectively. Thus, both GLM-SC treatment regimens were effective in maintaining the clinical response achieved with LDA secondary to TNF inhibitors. No serious adverse events occurred, and the continuation rate at 52 weeks was 100% in both groups. Therapeutic efficacy is adequately maintained in most patients switching from TNF inhibitor to GLM-SC (50 mg/4-8 weeks). Patients receiving TNF inhibitor can seamlessly switch to GLM-SC without serious safety concerns. PMID- 27942978 TI - Dietary factors and fibroblast growth factor-23 levels in young adults with African ancestry. AB - Fibroblast growth factor-23 (FGF23), a phosphaturic hormone secreted mainly by osteocytes, maintains serum phosphate levels within a tight range by promoting phosphaturia. Previous studies have mainly focused on the link between FGF23 levels and dietary intake of phosphate, but other dietary factors may also influence FGF23 levels. This cross-sectional study pooled three populations of young adults with African ancestry (452 in Chicago, IL, USA; 477 in Victoria, Seychelles; and 482 in Kumasi, Ghana) with estimated glomerular filtration rate >80 ml/min/1.73 m2 to examine the association of dietary factors based on two 24 h recalls with FGF23 levels measured using a C-terminal assay. Linear regression was used to examine the association between log-transformed FGF23 levels and quartiles of calorie-adjusted dietary factors with adjustment for covariates. In the pooled sample of 1411 study participants, the mean age was 35.2 (6.2) years and 45.3% were male. Median plasma C-terminal FGF23 values in relative units (RU)/ml were 59.5 [interquartile range (IQR) 44.1, 85.3] in the USA, 43.2 (IQR 33.1, 57.9) in Seychelles, and 34.0 (IQR 25.2, 50.4) in Ghana. With adjustment for covariates, increasing quartiles of calcium and animal protein and decreasing quartiles of vegetable protein, fiber, and magnesium intake were associated with significantly higher FGF23 levels compared to the lowest quartile. After further adjustment for dietary factors, significant trends in FGF23 levels were noted only for quartiles of calcium, fiber, and magnesium intake (P < 0.001). Dietary factors other than phosphate are associated with FGF23 levels in young adults. PMID- 27942980 TI - Age differences in physiological responses to self-paced and incremental [Formula: see text] testing. AB - PURPOSE: A self-paced maximal exercise protocol has demonstrated higher [Formula: see text] values when compared against traditional tests. The aim was to compare physiological responses to this self-paced [Formula: see text] protocol (SPV) in comparison to a traditional ramp [Formula: see text] (RAMP) protocol in young (18 30 years) and old (50-75 years) participants. METHODS: Forty-four participants (22 young; 22 old) completed both protocols in a randomised, counter-balanced, crossover design. The SPV included 5 * 2 min stages, participants were able to self-regulate their power output (PO) by using incremental 'clamps' in ratings of perceived exertion. The RAMP consisted of either 15 or 20 W min-1. RESULTS: Expired gases, cardiac output (Q), stroke volume (SV), muscular deoxyhaemoglobin (deoxyHb) and electromyography (EMG) at the vastus lateralis were recorded throughout. Results demonstrated significantly higher [Formula: see text] in the SPV (49.68 +/- 10.26 ml kg-1 min-1) vs. the RAMP (47.70 +/- 9.98 ml kg-1 min-1) in the young, but not in the old group (>0.05). Q and SV were significantly higher in the SPV vs. the RAMP in the young (<0.05) but not in the old group (>0.05). No differences seen in deoxyHb and EMG for either age groups (>0.05). Peak PO was significantly higher in the SPV vs. the RAMP in both age groups (<0.05). CONCLUSION: Findings demonstrate that the SPV produces higher [Formula: see text], peak Q and SV values in the young group. However, older participants achieved similar [Formula: see text] values in both protocols, mostly likely due to age-related differences in cardiovascular responses to incremental exercise, despite them achieving a higher physiological workload in the SPV. PMID- 27942979 TI - Use of dual-energy computed tomography to measure skeletal-wide marrow composition and cancellous bone mineral density. AB - Temporal and spatial variations in bone marrow adipose tissue (MAT) can be indicative of several pathologies and confound current methods of assessing immediate changes in bone mineral remodeling. We present a novel dual-energy computed tomography (DECT) method to monitor MAT and marrow-corrected volumetric BMD (mcvBMD) throughout the body. Twenty-three cancellous skeletal sites in 20 adult female cadavers aged 40-80 years old were measured using DECT (80 and 140 kVp). vBMD was simultaneous recorded using QCT. MAT was further sampled using MRI. Thirteen lumbar vertebrae were then excised from the MRI-imaged donors and examined by microCT. After MAT correction throughout the skeleton, significant differences (p < 0.05) were found between QCT-derived vBMD and DECT-derived mcvBMD results. McvBMD was highly heterogeneous with a maximum at the posterior skull and minimum in the proximal humerus (574 and 0.7 mg/cc, respectively). BV/TV and BMC have a nearly significant correlation with mcvBMD (r = 0.545, p = 0.057 and r = 0.539, p = 0.061, respectively). MAT assessed by DECT showed a significant correlation with MRI MAT results (r = 0.881, p < 0.0001). Both DECT- and MRI-derived MAT had a significant influence on uncorrected vBMD (r = -0.86 and r = -0.818, p <= 0.0001, respectively). Conversely, mcvBMD had no correlation with DECT- or MRI-derived MAT (r = 0.261 and r = 0.067). DECT can be used to assess MAT while simultaneously collecting mcvBMD values at each skeletal site. MAT is heterogeneous throughout the skeleton, highly variable, and should be accounted for in longitudinal mcvBMD studies. McvBMD accurately reflects the calcified tissue in cancellous bone. PMID- 27942982 TI - Primates Social Impact Award 2016. PMID- 27942981 TI - Influence of aqueous humor convection current on IOL opacification. AB - BACKGROUND AND PURPOSE: The opacification of Akreos Adapt (Bausch & Lomb, Rochester; NY) intraocular lens (IOL) has been previously reported in Literature. A metabolic change in aqueous humour was considered as the main trigger factor to IOL opacification. We report our case and discuss the association with Ex-PRESS, highlighting the particular pattern of IOL opacification and its possible relation with the intraocular convective motions of the aqueous. MATERIAL AND METHODS: We analyzed our case using both digital slit lamp acquisition and OCT Visante (Zeiss, Germany) images. A literature review was conducted to evaluate our results with that previously reported. CONCLUSION: The role of a relative stationary flow was reported as suggested concurrent mechanism in IOL opacification phenomenon. PMID- 27942983 TI - Coccomyxa: a dominant planktic alga in two acid lakes of different origin. AB - The aim of this study was to reveal the taxonomic position and phylogenetic relationships of the dominant planktic algae in two acid metal-rich lakes of different origin (Hromnice Lake and Plesne Lake, Czech Republic) and to investigate their morphology and ultrastructure under natural and laboratory conditions. Phylogenetic analyses (18S rRNA and ITS-2) revealed that the strain isolated from Hromnice Lake belongs to the species Coccomyxa elongata, while Coccomyxa from Plesne Lake was described as a new species C. silvae-gabretae. It is the first evidence that representatives of this genus are capable of becoming the dominant primary producers in the extreme environment of acid lakes with an increased supply of phosphorus. There were clear differences in cell morphology under different growth conditions, revealing the high phenotypic plasticity of the strains. The ability to change the morphology may help the cells of Coccomyxa to survive harsh conditions in the aforementioned acid lakes. PMID- 27942985 TI - Assessing pulp stones by cone-beam computed tomography. AB - OBJECTIVES: The aim of this study was to evaluate the occurrence of pulp stones by cone-beam computed tomography (CBCT) and to correlate their prevalence with patient's gender, location of tooth (right or left of maxillary or mandibular arch), group of teeth, and restorations. MATERIALS AND METHODS: CBCT images of 382 patients randomly selected from the database of the University Oral Radiology Department were retrospectively examined. A total of 2833 tooth images obtained using the i-CAT 3D Imaging System were evaluated. Image analysis was performed with the i-CAT software, and all teeth were evaluated in sagittal, axial, and coronal views. All the measurements were subjected to chi square test, odds ratio, and Fisher's exact tests (p < 0.05). RESULTS: The prevalence of pulp stones was similar between patient's genders and tooth locations. Pulp stones were detected in 31.9% of patients and 9.5% of teeth. Maxillary and mandibular molars were the groups of teeth with the highest frequency of pulp stones. The presence of restorations increased the chance of occurrence of pulp stones by 2.1 times in all teeth examined (p < 0.0001) and by 4.7 times in maxillary teeth (p < 0.0001). CONCLUSIONS: Pulp stones had a high prevalence with molar teeth showing the highest prevalence. The presence of restorations increased the chance of occurrence of these calcifications, specifically in maxillary teeth. CLINICAL RELEVANCE: CBCT provides accurate anatomical details in three dimensions, offering the possibility to view an individual tooth in axial, sagittal, and coronal views. This study performed an investigation of the occurrence of pulp stones by CBCT. PMID- 27942986 TI - Determinants of utilisation differences for cancer medicines in Belgium, Scotland and Sweden. AB - BACKGROUND: Little comparative evidence is available on utilisation of cancer medicines in different countries and its determinants. The aim of this study was to develop a statistical model to test the correlation between utilisation and possible determinants in selected European countries. METHODS: A sample of 31 medicines for cancer treatment that obtained EU-wide marketing authorisation between 2000 and 2012 was selected. Annual data on medicines' utilisation covering the in- and out-patient public sectors were obtained from national authorities between 2008 and 2013. Possible determinants of utilisation were extracted from HTA reports and complemented by contacts with key informants. A longitudinal mixed effect model was fitted to test possible determinants of medicines utilisation in Belgium, Scotland and Sweden. RESULTS: In the all country model, the number of indications reimbursed positively correlated with increased consumption of medicines [one indication 2.6, 95% CI (1.8-3.6); two indications 2.4, 95% CI (1.4-4.3); three indications 4.9, 95% CI (2.2-10.9); all P < 0.01], years since EU-wide marketing authorisation [1.2, 95% CI (1.02-1.4); p < 0.05], price per DDD [0.9, 95% CI (0.998-0.999), P < 0.01], and Prescrire rating [0.5, 95% CI (0.3-0.9), P < 0.05] after adjusting for time and other covariates. CONCLUSIONS: In this study, the most important correlates of increased utilisation in a sample of cancer medicines introduced in the past 15 years were: medicines coverage and time since marketing authorisation. Prices had a negative effect on consumption in Belgium and Sweden. The positive impact of financial MEAs in Scotland suggests that the latter may remove the regressive effect of list prices on consumption. PMID- 27942984 TI - LPS-treated bone marrow-derived dendritic cells induce immune tolerance through modulating differentiation of CD4+ regulatory T cell subpopulations mediated by 3G11 and CD127. AB - Intravenous transfer of LPS-treated bone marrow-derived dendritic cells blocks development of autoimmunity induced by CD4+ T cells in vivo. However, cellular mechanisms of dendritic cell-mediated immune tolerance have not yet been fully elucidated. Here, we report that there are two new subpopulations of CD4+CD25+FoxP3+GITR+ regulatory T cells (CD127+3G11+ and CD127+3G11- cells). LPS treated dendritic cells facilitate development of CD4+CD127+3G11- regulatory T cells but inhibit that of CD4+CD127+3G11+ regulatory T cells. LPS-induced tolerogenic dendritic cells may cause immune tolerance through modulating balance of different subsets of CD4+ regulatory T cells mediated by CD127 and 3G11. Our results imply a new potential cellular mechanism of dendritic cell-mediated immune tolerance. PMID- 27942987 TI - Research Translation and Emerging Health Technologies: Synthetic Biology and Beyond. AB - New health technologies are rapidly emerging from various areas of bioscience research, such as gene editing, regenerative medicine and synthetic biology. These technologies raise promising medical possibilities but also a range of ethical considerations. Apart from the issues involved in considering whether novel health technologies can or should become part of mainstream medical treatment once established, the process of research translation to develop such therapies itself entails particular ethical concerns. In this paper I use synthetic biology as an example of a new and largely unexplored area of health technology to consider the ways in which novel health technologies are likely to emerge and the ethical challenges these will present. I argue that such developments require us to rethink conventional attitudes towards clinical research, the roles of doctors/researchers and patients/participants with respect to research, and the relationship between science and society; and that a broader framework is required to address the plurality of stakeholder roles and interests involved in the development of treatments based on novel technologies. PMID- 27942988 TI - Investigation of malignant transformation of sporadic adenomas of colon by fluorimetry. AB - In this work, biochemical changes in sporadic adenoma during progression to colon cancer have been detected by spectral techniques. It is shown that spectra of all types of adenomas as well as adenocarcinoma have two maxima at 265 / 270 nm and at 330 / 340 nm. The first maximum is primarily defined by tryptophan containing peptides. The second maximum of the spectra is in the main defined by collagen presence in stroma of tumors and normal mucosa. Progression of precancer lesions to advanced cancer leads to increase of NADH concentration impacting on the second maximum of spectra. At the time, the spectra of both AC differ from each other by widths of the second maximum. For well-differentiated AC, the second maximum is wider. It gives reason to suggest that two fluorophores impact on its intensity. These fluorophores can be NADH and vitamin B6. Correlation between microscopical and spectral results can allow to use fluorimetry for detail diagnostics and investigation of colon cancer development. PMID- 27942989 TI - Efficacy of femtosecond lasers for application of acupuncture therapy. AB - Acupuncture treatment utilizes the stimulation of metal acupuncture needles that are manually inserted into a living body. In the last decades, laser light has been used as an alternative to needles to stimulate acupuncture points. We previously reported suppression of myostatin (Mstn) gene expression in skeletal muscle by means of femtosecond laser (FL) irradiation, after electroacupuncture, in which acupuncture needles are stimulated with a low-frequency microcurrent. The purpose of the study here was to investigate the efficacy of FL irradiation in mouse skeletal muscle with regard to protein synthesis. After irradiation of the hindlimbs, we first analyzed Mstn gene expression and Mstn protein level in the skeletal muscle. We then evaluated phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream target 70-kDa ribosomal protein S6 kinase (p70S6K). The results showed that FL irradiation significantly reduced the amount of Mstn protein and enhanced the phosphorylation of p70S6K in of the mTOR/S6K signaling pathway. We suggest that FL irradiation activated the protein synthetic pathway in the skeletal muscle. In conclusion, we determined that FL irradiation can serve as an alternative for acupuncture needles and has the potential of being a new non-invasive acupuncture treatment of skeletal muscle. PMID- 27942990 TI - Extratarsal presentation of chalazion. AB - PURPOSE: We report a case of atypical, extratarsal chalazion referred with a history of a chronic inflammatory mass found on the edge of the lower eyelid. METHODS: A 3-year-old female developed a small mass on the medial side of the right lower lid in 4-month duration. She was seen by her ophthalmologist and the diagnosis of a chalazion was made. Over the ensuing one month with warm compression, the lesion subsided and the new lesion appeared away from the edge on the lateral eyelid 3 months ago. RESULTS: She underwent surgery and drainage was performed. We found a track, a proof of migration, on the lower tarsal conjunctiva in the medial side of the right eyelid during surgery. CONCLUSIONS: Long-term observation in chalazion may induce migration with tract and express as an atypical chalazion. PMID- 27942991 TI - [Effectiveness of three biological larvicides and of an insect growth regulator against Anopheles arabiensis in Senegal]. AB - Urban malaria is a major public health problem in Africa. In Senegal, the environmental changes seem to favor the persistence of malaria transmission in Dakar suburbs by creating, throughout the year, potential breeding sites of malaria vectors. In such a situation and in a context of a growing threat of insecticide resistance in anopheline vectors, the larval control making use of products from biological origin or growth regulators could represent an additional tool to the current strategies developed against anophelines. In this study conducted in 2012, the efficiency and residual effect of three biological larvicides (VectoBac(r) WG, Vecto-Max(r) CG, and VectoBac(r) GR) and an insect growth regulator (MetaLarvTM) were evaluated on Anopheles gambiae s.l. larvae in seminatural conditions (experimental station) and natural breeding sites in the suburbs of Dakar. The formulations were tested according to the manufacturer recommendations, namely 0.03 g/m2 for VectoBac(r) WG, 0.5 g/m2 for VectoBac(r) GR, 0.75 g/m2 for VectoMax(r) CG, and 0.5 g/m2 for MetaLarvTM. In experimental station, the treatment with larvicides was effective over a period of 14 days with a mortality ranging between 92% and 100%. The insect growth regulator remained effective up to 55 days with a single emergence recorded in the 27th day after treatment. In natural conditions, a total effectiveness (100% mortality) of larvicides was obtained 48 hours after treatment, then a gradual recolonization of breeding sites was noted. However, the insect growth regulator has reduced adult emergence higher than 80% until the end of follow-up (J28). This study showed a good efficiency of the larvicides and of the growth regulator tested. These works provide current data on potential candidates for the implementation of larval control interventions in addition to that of chemical adulticide for control of urban malaria. PMID- 27942993 TI - Diadenosine pentaphosphate affects electrical activity in guinea pig atrium via activation of potassium acetylcholine-dependent inward rectifier. AB - Diadenosine pentaphosphate (Ap5A) belongs to the family of diadenosine polyphosphates, endogenously produced compounds that affect vascular tone and cardiac performance when released from platelets. The previous findings indicate that Ap5A shortens action potentials (APs) in rat myocardium via activation of purine P2 receptors. The present study demonstrates alternative mechanism of Ap5A electrophysiological effects found in guinea pig myocardium. Ap5A (10-4 M) shortens APs in guinea pig working atrial myocardium and slows down pacemaker activity in the sinoatrial node. P1 receptors antagonist DPCPX (10-7 M) or selective GIRK channels blocker tertiapin (10-6 M) completely abolished all Ap5A effects, while P2 blocker PPADS (10-4 M) was ineffective. Patch-clamp experiments revealed potassium inward rectifier current activated by Ap5A in guinea pig atrial myocytes. The current was abolished by DPCPX or tertiapin and therefore was considered as potassium acetylcholine-dependent inward rectifier (I KACh). Thus, unlike rat, in guinea pig atrium Ap5A produces activation of P1 receptors and subsequent opening of KACh channels leading to negative effects on cardiac electrical activity. PMID- 27942992 TI - Increased bone resorption by osteoclast-specific deletion of the sodium/calcium exchanger isoform 1 (NCX1). AB - Calcium is a key component of the bone mineral hydroxyapatite. During osteoclast mediated bone resorption, hydroxyapatite is dissolved and significant quantities of calcium are released. Several calcium transport systems have previously been identified in osteoclasts, including members of the sodium/calcium exchanger (NCX) family. Expression pattern and physiological role of NCX isoforms in osteoclasts, however, remain largely unknown at the moment. Our data indicate that all three NCX isoforms (NCX1, NCX2, and NCX3) are present in murine osteoclasts. RANKL-induced differentiation of murine osteoclast precursors into mature osteoclasts significantly attenuated the expression of NCX1, while NCX2 and NCX3 expressions were largely unaffected. To study the role of NCX1 during osteoclast differentiation and bone resorption, we crossed mice with exon 11 of the NCX1 gene flanked by loxP sites with cathepsin K-Cre transgenic mice. Mature osteoclasts derived from transgenic mice exhibited an 80-90% reduction of NCX1 protein. In vitro studies indicate that NCX1 is dispensable for osteoclast differentiation, but NCX1-deficient osteoclasts exhibited increased resorptive activity. In line with these in vitro findings, mice with an osteoclast-targeted deletion of the NCX1 gene locus displayed an age-dependent loss of bone mass. Thus, in summary, our data reveal NCX1 as a regulator of osteoclast-mediated bone resorption. PMID- 27942994 TI - A new algorithm for a better characterization and timing of the anti-VEGF vascular effect named "normalization". AB - Antiangiogenics are widely used in cancer treatment in combination with chemotherapy and radiotherapy for their vascular effects. Antiangiogenics are supposed to induce morphological and functional changes in the chaotic tumor vasculature that would help enhance the therapeutic efficacy of chemotherapy and radiotherapy through the amelioration of the drug delivery or the oxygenation in the tumor, respectively. However, finding the best treatment sequence is not an easy task to achieve and no consensus has yet been established because of the lack of knowledge regarding when and for how long the vascular network is ameliorated. The aim of this work was to develop a dedicated image processing algorithm able to analyze the vascular structures on optical microscopy images of the vascular network and to follow its fine modifications in vivo, over time. We applied this algorithm to follow the evolution of the vascular parameters (vascularized tissue surface, branches, sprouts and length), in response or not to anti-VEGF therapy (10 mg/kg/day) and determine precisely whether there is really a vascular "normalization" with anti-VEGF therapy in comparison with the parameters extracted from healthy vascular networks. We found that for this determination, the choice of region of interest to analyze is critical as it is important to compare only microcirculation areas and avoid areas with arteriole venule-capillary hierarchy. The algorithm analysis allowed us to define a vascular "normalization" in treated tumors, between 8 and 12 days of bevacizumab treatment that was confirmed by standard immunohistochemical analysis, microvascular permeability assessment and immunohistological blood perfusion assessment. PMID- 27942996 TI - A theoretical study of the diastereoselective allylation of aldehydes with new chiral allylsilanes. AB - In this paper, we investigate the reaction mechanism for the synthesis of new functionalized chiral hydroxyamides theoretically, using a concerted density functional theory (DFT)-conceptual DFT-quantum theory of atoms-in-molecules (QTAIM) approach, which casts light on the main physicochemical properties responsible for the observed selectivity. We use a particular nucleophilic addition step to illustrate the strengths of this general strategy, which could, in principle, be applied to unravel the main features of any chemical synthesis. PMID- 27942995 TI - Unique Associations between Childhood Temperament Characteristics and Subsequent Psychopathology Symptom Trajectories from Childhood to Early Adolescence. AB - Existing research suggests that temperamental traits that emerge early in childhood may have utility for early detection and intervention for common mental disorders. The present study examined the unique relationships between the temperament characteristics of reactivity, approach-sociability, and persistence in early childhood and subsequent symptom trajectories of psychopathology (depression, anxiety, conduct disorder, and attention-deficit hyperactivity disorder; ADHD) from childhood to early adolescence. Data were from the first five waves of the older cohort from the Longitudinal Study of Australian Children (n = 4983; 51.2% male), which spanned ages 4-5 to 12-13. Multivariate ordinal and logistic regressions examined whether parent-reported child temperament characteristics at age 4-5 predicted the study child's subsequent symptom trajectories for each domain of psychopathology (derived using latent class growth analyses), after controlling for other presenting symptoms. Temperament characteristics differentially predicted the symptom trajectories for depression, anxiety, conduct disorder, and ADHD: Higher levels of reactivity uniquely predicted higher symptom trajectories for all 4 domains; higher levels of approach-sociability predicted higher trajectories of conduct disorder and ADHD, but lower trajectories of anxiety; and higher levels of persistence were related to lower trajectories of conduct disorder and ADHD. These findings suggest that temperament is an early identifiable risk factor for the development of psychopathology, and that identification and timely interventions for children with highly reactive temperaments in particular could prevent later mental health problems. PMID- 27942997 TI - The need for evidence-based intake, progress, and outcomes assessment. PMID- 27943000 TI - Low Uptake of Voluntary Medical Male Circumcision Among High Risk Men in Malawi. AB - Malawi is one of 14 priority countries for voluntary medical male circumcision (VMMC) initiatives with the lowest VMMC uptake. Using data from a study of 269 men accessing VMMC in southern Malawi and latent class analysis, men were classified based on four risk factors: ever tested for HIV, condom use at last sex, having casual/concurrent sexual partners, and using alcohol before sex. Two distinct classes were identified: 8% of men were classified as high risk, while 92% were classified as low/medium risk. Poisson regression modeling indicated that men who had lower education (risk ratio [RR] 1.07, p < 0.05) and were ages 19-26 (RR 1.07, p < 0.05) were more likely to be in the high risk group. The low numbers of men in the high risk category seeking services suggests the need to implement targeted strategies to increase VMMC uptake among such high risk men. PMID- 27942998 TI - Health-related quality of life, anxiety and depression in parents of adolescents with Gilles de la Tourette syndrome: a controlled study. AB - Our objectives were to assess health-related quality of life (HRQoL), anxiety, depression of Gilles de la Tourette syndrome (GTS) adolescents' parents compared to controls; to assess GTS adolescents' HRQoL compared to controls; to investigate which parental and adolescent variables are associated with poorer parental HRQoL. The controlled study involved GTS outpatients and their parents, adolescent healthy controls matched for gender and age and their parents. Parents' HRQoL was assessed using SF-36 and WHOQOL-BREF; anxiety, depression using HADS. Adolescents' HRQoL was assessed by adolescents using VSP-A instrument and by their parents using VSP-P. A total of 75 GTS adolescents, 75 mothers, 63 fathers were compared to 75 control adolescents, 75 mothers, 62 fathers. GTS mothers had worse HRQoL than controls on 5 of the 8 SF-36 dimensions and 1 of the 4 WHOQOL-BREF dimensions, while GTS fathers had worse HRQoL on 2 of the WHOQOL BREF dimensions. GTS mothers had poorer HRQoL than fathers. GTS mothers had more depression than control mothers and GTS fathers had more anxiety than control fathers. GTS adolescents had worse HRQoL than controls on 5 of the 9 VSP-A dimensions. Factors significantly related to parental HRQoL were anxiety, depression, GTS adolescents' HRQoL and, concerning mothers, behavioural and emotional adolescents' problems; concerning fathers, severity of vocal tics, duration since first symptoms. This study provides a better understanding of poorer HRQoL and psychiatric morbidity of GTS adolescents' parents. Clinicians should pay attention to their emotional well-being and HRQoL and be aware that mothers and fathers are differently affected. PMID- 27942999 TI - A Pilot Trial Examining African American and White Responses to Algorithm-Guided Smoking Cessation Medication Selection in Persons Living with HIV. AB - Algorithm-based treatments (AT) may be an effective clinical tool to aid HIV clinicians in prescribing pharmacotherapy to increase smoking cessation among people living with HIV (PLWH). Initial results from AT indicated significant increases in abstinence self-efficacy and medication utilization and declines in cigarettes smoked per day across time. Given historical racial disparities, it is unclear if both African Americans and White smokers would benefit equally from this type of intervention. Thus, the aim of this study was to examine racial differences in response to AT guided smoking cessation for African American and White smokers living with HIV. One hundred PLWH smokers (n = 100) were randomized to receive either AT guided smoking cessation or Treatment as Usual (TAU) which consisted of instructing participants to talk to a provider about smoking cessation assistance when ready to make a quit attempt. Participants were African American (75%) and White (25%) and majority men (71%) who had never been married (56%). African Americans smoked fewer cigarettes and were more likely to smoke mentholated cigarettes compared to White smokers at baseline. African Americans increased their use of other tobacco products (cigars/cigarillos) over time relative to White smokers. A significant interaction between race and quit goal was observed, with White smokers who reported complete abstinence as their goal having higher quit rates, while African Americans who reported a goal other than complete abstinence demonstrating higher quit rates. The increased use of cigars/cigarillos during quit attempts as well as having a goal other than complete abstinence should be considered when applying algorithm based interventions for PLWH African American smokers. PMID- 27943001 TI - 1H, 13C and 15N resonance assignments of the new lysostaphin family endopeptidase catalytic domain from Staphylococcus aureus. AB - Lysostaphin family endopeptidases, produced by Staphylococcus genus, are zinc dependent enzymes that cleave pentaglycine bridges of cell wall peptidoglycan. They act as autolysins to maintain cell wall metabolism or as toxins and weapons against competing strains. Consequently, these enzymes are compelling targets for new drugs as well as are potential antimicrobial agents themselves against Staphylococcus pathogens, which depend on cell wall to retain their immunity against antibiotics. The rapid spread of methicillin and vancomycin-resistant Staphylococcus aureus strains draws demand for new therapeutic approaches. S. aureus gene sa0205 was found to be implicated in resistance to vancomycin and synthesis of the bacteria cell wall. The gene encodes for a catalytic domain of a lysostaphin-type endopeptidase. We aim to obtain the structure of the Sa0205 catalytic domain, the first solution structure of the catalytic domain of the lysostaphin family enzymes. In addition, we are to investigate the apparent binding of the second zinc ion, which has not been previously reported for the enzyme group. Herein, we present the backbone and side chain resonance assignments of Sa0205 endopeptidase catalytic domain in its one and two zinc bound forms. PMID- 27943002 TI - Early Prediction of Sepsis Incidence in Critically Ill Patients Using Specific Genetic Polymorphisms. AB - Several diagnostic methods for the evaluation and monitoring were used to find out the pro-inflammatory status, as well as incidence of sepsis in critically ill patients. One such recent method is based on investigating the genetic polymorphisms and determining the molecular and genetic links between them, as well as other sepsis-associated pathophysiologies. Identification of genetic polymorphisms in critical patients with sepsis can become a revolutionary method for evaluating and monitoring these patients. Similarly, the complications, as well as the high costs associated with the management of patients with sepsis, can be significantly reduced by early initiation of intensive care. PMID- 27943003 TI - Maskless wafer-level microfabrication of optical penetrating neural arrays out of soda-lime glass: Utah Optrode Array. AB - Borrowing from the wafer-level fabrication techniques of the Utah Electrode Array, an optical array capable of delivering light for neural optogenetic studies is presented in this paper: the Utah Optrode Array. Utah Optrode Arrays are micromachined out of sheet soda-lime-silica glass using standard backend processes of the semiconductor and microelectronics packaging industries such as precision diamond grinding and wet etching. 9 * 9 arrays with 1100MU m * 100MU m optrodes and a 500MU m back-plane are repeatably reproduced on 2i n wafers 169 arrays at a time. This paper describes the steps and some of the common errors of optrode fabrication. PMID- 27943004 TI - Carney complex: A familial lentiginosis predisposing to a variety of tumors. AB - Carney complex is a familial lentiginosis syndrome; these disorders cover a wide phenotypic spectrum ranging from a benign inherited predisposition to develop cutaneous spots not associated with systemic disease to associations with several syndromes. Carney complex is caused by PRKAR1A mutations and perturbations of the cyclic AMP-dependent protein kinase (PKA) signaling pathway. In addition to the cutaneous findings, the main tumors associated with Carney complex are endocrine: 1) primary pigmented nodular adrenocortical disease, a bilateral adrenal hyperplasia leading to Cushing syndrome; 2) growth-hormone secreting pituitary adenoma or pituitary somatotropic hyperplasia leading to acromegaly; 3) thyroid and gonadal tumors, including a predisposition to thyroid cancer. Other tumors associated with Carney complex include: 1) myxomas of the heart, breast and other sites; 2) psamommatous melanotic schwannomas which can become malignant; 4) a predisposition to a variety of cancers. PMID- 27943005 TI - Skin manifestations of Cushing's syndrome. AB - Among the most common diagnostic manifestations of Cushing's syndrome (CS) are those involving the skin; they include violaceous striae, facial acne, hirsutism, acanthosis nigricans (AN), fungal infections, hyperpigmentation (Hp) and easy bruisability. Fortunately, most resolve within a year or two after cure of CS, although light-colored striae can persist for years depending on the age of the patients. AN, Hp, and bruisability usually resolve within months after cure in almost all ages. Facial plethora (along with acne and other facial skin changes) is a typical sign of CS that is due to increased perfusion. It resolves immediately after curative therapy of CS. Typically, the severity of the manifestations does not correlate with the biochemical indices of the disease, pointing to age, gender, genetic and skin-type differences that determine the cutaneous manifestations of CS. PMID- 27943006 TI - Hereditary syndromes predisposing to endocrine tumors and their skin manifestations. AB - We often think of the lentiginoses, phacomatoses and other neurocutaneous syndromes as conditions that affect the skin and also predispose to a variety of tumors. However, we rarely think of Peutz-Jeghers syndrome (PJS), Carney complex (CNC), Cowden disease (CD), neurofibromatosis type-1 (NF-1) or tuberous sclerosis (TSC) as conditions that are multiple endocrine neoplasias (MEN). Indeed, all of these conditions predispose to a variety of endocrine tumors, in addition to many other neoplasms. On the other hand, the classic MENs, type 1 and 2 (MEN-1 and MEN 2, respectively) are almost never thought in terms of their skin manifestations. In this review, we present extensively the MEN-1, MEN-2 and PJS syndromes, and briefly refer to CD, NF-1, and TSC. CNC is discussed in another article in this journal issue. PMID- 27943008 TI - Effects of exemestane and letrozole therapy on plasma concentrations of estrogens in a randomized trial of postmenopausal women with breast cancer. AB - PURPOSE: Inter-individual differences in estrogen concentrations during treatment with aromatase inhibitors (AIs) may contribute to therapeutic response and toxicity. The aim of this study was to determine plasma concentrations of estradiol (E2), estrone (E1), and estrone sulfate (E1S) in a large cohort of AI treated breast cancer patients. METHODS: In a randomized, multicenter trial of postmenopausal women with early-stage breast cancer starting treatment with letrozole (n = 241) or exemestane (n = 228), plasma estrogen concentrations at baseline and after 3 months were quantitated using a sensitive mass spectrometry based assay. Concentrations and suppression below the lower limit of quantification (LLOQ) were compared between estrogens and between drugs. RESULTS: The ranges of baseline estrogen concentrations were =0.52 mm was deemed necessary in order to achieve sufficient core protection in the acid medium. The technology proved viable for incorporating different drug candidates; theophylline, budesonide and diclofenac sodium. XRPD indicated the presence of theophylline crystals whilst budesonide and diclofenac sodium remained amorphous in the PVP matrix of the filaments and 3D printed tablets. Fabricated tablets demonstrated gastric resistant properties and a pH responsive drug release pattern in both phosphate and bicarbonate buffers. CONCLUSIONS: Despite its relatively limited resolution, FDM 3D printing proved to be a suitable platform for a single-process fabrication of delayed release tablets. This work reveals the potential of dual FDM 3D printing as a unique platform for personalising delayed release tablets to suit an individual patient's needs. PMID- 27943016 TI - Identifying Drug-Induced Liver Illness (DILI) with Computerized Information Extraction: No More Dilly-Dallying. PMID- 27943015 TI - Personalized Drug Dosage - Closing the Loop. AB - A brief account is given of various approaches to the individualization of drug dosage, including the use of pharmacodynamic markers, therapeutic monitoring of plasma drug concentrations, genotyping, computer-guided dosage using 'dashboards', and automatic closed-loop control of pharmacological action. The potential for linking the real patient to his or her 'virtual twin' through the application of physiologically-based pharmacokinetic modeling is also discussed. PMID- 27943017 TI - Carcinoembryonic Antigen Level in Primary Sclerosing Cholangitis Is Not Influenced by Dominant Strictures or Bacterial Cholangitis. AB - BACKGROUND: Carcinoembryonic antigen (CEA) can be used to screen for biliary tract cancer in patients with primary sclerosing cholangitis (PSC). AIM: To study the influence of benign dominant strictures (DS), superimposed bacterial cholangitis (SBC), smoking status, and inflammatory bowel disease on CEA serum levels. METHODS: A retrospective analysis of CEA values in cancer-free PSC patients was performed. We included the maximal CEA value obtained during follow up and information on the presence of DS and SBC at that time, and we analyzed the CEA values in the presence and absence of DS and SBC. Results are reported as medians with the interquartile range (IQR). RESULTS: The median maximal CEA level, which was 1.8 ng/mL (IQR 1.2-2.9) in the final 270 PSC patients included in the study, was not influenced by the presence of either DS or SBC (P = 0.320). Moreover, in 49 patients, the first CEA value available at the time of DS (1.5 ng/mL; IQR 1.2-2.1) and that at a time without DS (1.6 ng/mL; IQR 1.1-2.3) did not differ significantly (P = 0.397). Lastly, in 24 patients, the median CEA values at a time without SBC (1.8 ng/mL; IQR 1.2-2.5) and at the time of SBC (1.8 ng/mL; IQR 1.0-3.0) were comparable (P = 0.305). Smoking did not influence CEA based cancer screening. CONCLUSIONS: Serum CEA level is not influenced by the presence of DS or SBC and might therefore serve as a favorable parameter for improving cancer screening in PSC patients. PMID- 27943018 TI - Item bias detection in the Hospital Anxiety and Depression Scale using structural equation modeling: comparison with other item bias detection methods. AB - PURPOSE: Comparison of patient-reported outcomes may be invalidated by the occurrence of item bias, also known as differential item functioning. We show two ways of using structural equation modeling (SEM) to detect item bias: (1) multigroup SEM, which enables the detection of both uniform and nonuniform bias, and (2) multidimensional SEM, which enables the investigation of item bias with respect to several variables simultaneously. METHOD: Gender- and age-related bias in the items of the Hospital Anxiety and Depression Scale (HADS; Zigmond and Snaith in Acta Psychiatr Scand 67:361-370, 1983) from a sample of 1068 patients was investigated using the multigroup SEM approach and the multidimensional SEM approach. Results were compared to the results of the ordinal logistic regression, item response theory, and contingency tables methods reported by Cameron et al. (Qual Life Res 23:2883-2888, 2014). RESULTS: Both SEM approaches identified two items with gender-related bias and two items with age-related bias in the Anxiety subscale, and four items with age-related bias in the Depression subscale. Results from the SEM approaches generally agreed with the results of Cameron et al., although the SEM approaches identified more items as biased. CONCLUSION: SEM provides a flexible tool for the investigation of item bias in health-related questionnaires. Multidimensional SEM has practical and statistical advantages over multigroup SEM, and over other item bias detection methods, as it enables item bias detection with respect to multiple variables, of various measurement levels, and with more statistical power, ultimately providing more valid comparisons of patients' well-being in both research and clinical practice. PMID- 27943019 TI - The influence of acculturation strategies in quality of life by immigrants in Northern Chile. AB - PURPOSE: To establish the influence of acculturation strategies on quality of life, henceforth QoL. METHODS: Using a cross-sectional design, two questionnaires were applied, the WHOQoL-BREF from the World Health Organization and Basabe's acculturation strategies. The questionnaires were applied to 853 Colombian and Peruvian immigrants living in Northern Chilean cities of Arica, Antofagasta and Santiago de Chile. RESULTS: In the psychological and social domains, as well as in the overall assessment of QoL, the most beneficial strategies are those where customs are maintained from the homeland, where "integration" then "separation" are the most beneficial. On the contrary, when the strategy for maintaining homeland customs is low, the QoL tends to be lower. The strategy of "marginalized" is associated with a lower QoL. CONCLUSIONS: Acculturation strategies mildly or moderately affect the psychological and social domains of quality of life as well as the overall assessment of QoL. PMID- 27943020 TI - Chloroplast differentiation in the growing leaves of Arabidopsis thaliana. AB - Here, we describe the development of chloroplasts and the buildup of the thylakoid membranes in growing Arabidopsis leaves. Organelles were analyzed from three distinct positions, namely, at the tip, the upper leaf margin, and the base from leaves 1, 3, 5, and 7 of 14-day-old plants. Clear developmental gradients are described within a given leaf and between leaves of different age. Chloroplasts at the tip of every leaf are always the most matured within a given leaf, while already at the upper leaf margin a differentiation gradient can be observed from the edge of the leaf toward the midrib. The data presented here can serve as a standard for a subcellular phenotypic analysis in chloroplast biogenesis mutants. PMID- 27943021 TI - Novel mutations involving betaI-, betaIIA-, or betaIVB-tubulin isotypes with functional resemblance to betaIII-tubulin in breast cancer. AB - Tubulin is the target for very widely used anti-tumor drugs, including Vinca alkaloids, taxanes, and epothilones, which are an important component of chemotherapy in breast cancer and other malignancies. Paclitaxel and other tubulin-targeting drugs bind to the beta subunit of tubulin, which is a heterodimer of alpha and beta subunits. beta-Tubulin exists in the form of multiple isotypes, which are differentially expressed in normal and neoplastic cells and differ in their ability to bind to drugs. Among them, the betaIII isotype is overexpressed in many aggressive and metastatic cancers and may serve as a prognostic marker in certain types of cancer. The underpinning mechanisms accounting for the overexpression of this isotype in cancer cells are unclear. To better understand the role of beta-tubulin isotypes in cancer, we analyzed over 1000 clones from 90 breast cancer patients, sequencing their beta-tubulin isotypes, in search of novel mutations. We have elucidated two putative emerging molecular subgroups of invasive breast cancer, each of which involve mutations in the betaI-, betaIIA-, or betaIVB isotypes of tubulin that increase their structural, and possibly functional, resemblance to the betaIII isotype. A unifying feature of the first of the two subgroups is the mutation of the highly reactive C239 residue of betaI- or betaIVB-tubulin to L239, R239, Y239, or P239, culminating in probable conversion of these isotypes from ROS-sensitive to ROS resistant species. In the second subgroup, betaI, betaIIA, and betaIVB have up to seven mutations to the corresponding residues in betaIII-tubulin. Given that betaIII-tubulin has emerged as a pro-survival factor, overexpression of this isotype may confer survival advantages to certain cancer cell types. In this mini review, we bring attention to a novel mechanism by which cancer cells may undergo adaptive mutational changes involving alternate beta-tubulin isotypes to make them acquire some of the pro-survival properties of betaIII-tubulin. These "hybrid" tubulins, combining the sequences and/or properties of two wild-type tubulins (betaIII and either betaI, betaIIA, or betaIVB), are novel isotypes expressed solely in cancer cells and may contribute to the molecular understanding and stratification of invasive breast cancer and provide novel molecular targets for rational drug development. PMID- 27943023 TI - Copulation duration, sperm transfer and reproduction of the two closely related phytoseiid mites, Neoseiulus womersleyi and Neoseiulus longispinosus (Acari: Phytoseiidae). AB - The effects of copulation duration on reproduction were studied in two important biological control agents, Neoseiulus womersleyi (Schicha) and Neoseiulus longispinosus (Evans), to better understand their reproductive potential. The number of eggs produced was significantly and positively related to the copulation duration in both species. Egg production was observed even in females which experienced only 15 min of copulation and increased as copulation period increased in both species. Both pre- and post-oviposition periods of N. womersleyi and N. longispinosus decreased with the increase of copulation durations, and they were significantly different between the two species. Copulation duration had no effect on the female adult longevity of N. womersleyi and N. longispinosus, but N. womersleyi showed higher adult longevity than N. longispinosus. Fecundity remarkably increased in both species when the copulation period exceeded 90 min. The size of the spermatophore inside the spermathecae increased in proportion to the copulation duration in both species. Fecundity was consistent with the sizes of the spermathecae and spermatophores. When copulation was extended, males first filled one spermatheca and then filled the other. The results obtained in this study suggest that copulation duration had similar effects on egg production in N. womersleyi and N. longispinosus. Egg production depended on the quantity of sperm transferred during copulation. The two species have similar reproductive potentials and mating properties under laboratory conditions. PMID- 27943024 TI - Photoactive platinum diimine complexes showing induced cancer cell death by apoptosis. AB - Photoinduced cytotoxicity mediated by a triphenylenamine-modified platinum diimine complex in human breast adenocarcinoma cells has been studied by cell viability assay. The triphenylenamine-modified platinum diimine complex showed more potent cytotoxicity in light than its carboxylate-modified analogue. To gain insights into the mechanism of photodynamic activity of this class of platinum diimine complexes, flow cytometric analyses were performed. The results suggest that upon irradiation the two platinum diimine complexes studied could induce cell cycle arrest in G2/M or S phase, and both of them could induce cancer cell death by apoptosis. PMID- 27943025 TI - A Theoretical Approach to Analyze the Parametric Influence on Spatial Patterns of Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) Populations. AB - Studies of the influence of biological parameters on the spatial distribution of lepidopteran insects can provide useful information for managing agricultural pests, since the larvae of many species cause serious impacts on crops. Computational models to simulate the spatial dynamics of insect populations are increasingly used, because of their efficiency in representing insect movement. In this study, we used a cellular automata model to explore different patterns of population distribution of Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), when the values of two biological parameters that are able to influence the spatial pattern (larval viability and adult longevity) are varied. We mapped the spatial patterns observed as the parameters varied. Additionally, by using population data for S. frugiperda obtained in different hosts under laboratory conditions, we were able to describe the expected spatial patterns occurring in corn, cotton, millet, and soybean crops based on the parameters varied. The results are discussed from the perspective of insect ecology and pest management. We concluded that computational approaches can be important tools to study the relationship between the biological parameters and spatial distributions of lepidopteran insect pests. PMID- 27943026 TI - Evaluating the safety and effectiveness of venous thromboembolism prophylaxis in patients with sickle cell disease. AB - Nearly every component of hemostasis is altered in sickle cell disease (SCD), yet little evidence exists to guide utilization of venous thromboembolism prophylaxis (VTEP) in this population. This retrospective cohort study included 135 adult patients admitted with a diagnosis of SCD vaso-occlusive crisis to the general medicine service at a tertiary care academic medical center from August 1, 2011 to August 1, 2013. If VTEP was discontinued, the medical record was reviewed for suspicion of VTE, hemorrhage, heparin-induced thrombocytopenia (HIT), or other adverse events. The primary objective was to characterize the safety and effectiveness of VTEP in SCD. The secondary objective was to assess the correlation of VTE with risk factors documented in the general medical population. Most patients (116/135, 85.9%) were prescribed VTEP upon admission, with early discontinuation in 23 patients (19.8%). Reasons for discontinuation included suspicion of VTE (10/116, 8.6%), hemorrhage (5/116, 4.3%), and/or HIT (4/116, 3.4%). Since patients with SCD receiving standard VTEP regimens appear to have similar outcomes compared to medically ill patients in prospective studies, using these regimens appears to be safe when indicated in the opinion of the provider. Once daily injections may be preferred in order to optimize adherence. PMID- 27943022 TI - A journey through the microscopic ages of DNA replication. AB - Scientific discoveries and technological advancements are inseparable but not always take place in a coherent chronological manner. In the next, we will provide a seemingly unconnected and serendipitous series of scientific facts that, in the whole, converged to unveil DNA and its duplication. We will not cover here the many and fundamental contributions from microbial genetics and in vitro biochemistry. Rather, in this journey, we will emphasize the interplay between microscopy development culminating on super resolution fluorescence microscopy (i.e., nanoscopy) and digital image analysis and its impact on our understanding of DNA duplication. We will interlace the journey with landmark concepts and experiments that have brought the cellular DNA replication field to its present state. PMID- 27943027 TI - FTY720 Attenuates 6-OHDA-Associated Dopaminergic Degeneration in Cellular and Mouse Parkinsonian Models. AB - FTY720 (fingolimod) is the first oral drug approved for treating relapsing remitting forms of multiple sclerosis. It is also protective in other neurological models including ischemia, Alzheimer's disease, Huntington disease and Rett syndrome. However, whether it might protect in a 6-hydroxydopamine (6 OHDA) mouse model associated with the dopaminergic pathology of Parkinson's disease (PD), has not been explored. Therefore, in the present study, we investigated the effects of FTY720 on 6-OHDA-induced neurotoxicity in cell cultures and mice. Here we show that FTY720 protected against 6-OHDA cytotoxicity and apoptosis in SH-SY5Y cells. We also show that prior administration of FTY720 to 6-OHDA lesioned mice ameliorated both motor deficits and nigral dopaminergic neurotoxicity, while also reducing 6-OHDA-associated inflammation. The protective effects of FTY720 were associated with activation of AKT and ERK1/2 pro-survival pathways and an increase in brain derived neurotrophic factor (BDNF) expression in vitro and in vivo. These findings suggest that FTY720 holds promise as a PD therapeutic acting, at least in part, through AKT/ERK1/2/P-CREB-associated BDNF expression. PMID- 27943028 TI - The Protective Effects of Polysaccharides from Agaricus blazei Murill Against Cadmium-Induced Oxidant Stress and Inflammatory Damage in Chicken Livers. AB - This study aimed to assess the protective roles of polysaccharides from Agaricus blazei Murill (ABP) against cadmium (Cd)-induced damage in chicken livers. A total of 80 Hy-Line laying chickens (7 days old) were randomly divided into four groups (n = 20). Group I (control) was fed with a basic diet and 0.2 ml saline per day, group II (Cd-treated group) was fed with a basic diet containing 140 mg/kg cadmium chloride (CdCl2) and 0.2 ml saline per day, group III (Cd + ABP treated group) was fed with a basic diet containing 140 mg/kg CdCl2 and 0.2-ml ABP solution (30 mg/ml) per day via oral gavage, and group IV (ABP-treated group) was fed with 0.2-ml ABP solution (30 mg/ml) per day via oral gavage. The contents of Cd and malondialdehyde (MDA), the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), the messenger RNA (mRNA) levels of inflammatory cytokines and heat shock proteins (HSPs), the protein levels of HSPs, and the histopathological changes of livers were evaluated on days 20, 40, and 60. The results showed that Cd exposure resulted in Cd accumulating in livers and inhibiting the activities of antioxidant enzymes (SOD and GSH-PX). Cd exposure caused histopathological damage and increased the MDA content, the mRNA levels of inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) and HSPs (HSP27, HSP40, HSP60, HSP70, and HSP90) and the protein levels of HSPs (HSP60, HSP70, and HSP90). ABP supplementation during dietary exposure to Cd reduced the histopathological damage and decreased the contents of Cd and MDA and the expression of inflammatory cytokines and HSPs and improved the activities of antioxidant enzymes. The results indicated that ABP could partly ameliorate the toxic effects of Cd on chicken livers. PMID- 27943029 TI - Erratum to: Familial Chronic Granulomatous Disease Affecting Three Siblings and Causing Recurrent Tuberculosis. PMID- 27943030 TI - The role of endoglin in post-ischemic revascularization. AB - Following arterial occlusion, blood vessels respond by forming a new network of functional capillaries (angiogenesis), by reorganizing preexisting capillaries through the recruitment of smooth muscle cells to generate new arteries (arteriogenesis) and by growing and remodeling preexisting collateral arterioles into physiologically relevant arteries (collateral development). All these processes result in the recovery of organ perfusion. The importance of endoglin in post-occlusion reperfusion is sustained by several observations: (1) endoglin expression is increased in vessels showing active angiogenesis/remodeling; (2) genetic endoglin haploinsufficiency in humans causes deficient angiogenesis; and (3) the reduction of endoglin expression by gene disruption or the administration of endoglin-neutralizing antibodies reduces angiogenesis and revascularization. However, the precise role of endoglin in the several processes associated with revascularization has not been completely elucidated and, in some cases, the function ascribed to endoglin by different authors is controversial. The purpose of this review is to organize in a critical way the information available for the role of endoglin in several phenomena (angiogenesis, arteriogenesis and collateral development) associated with post-ischemic revascularization. PMID- 27943032 TI - Subtyping Non-treatment-seeking Problem Gamblers Using the Pathways Model. AB - This study examined whether distinct subgroups could be identified among a sample of non-treatment-seeking problem and pathological/disordered gamblers (PG) using Blaszczynski and Nower's (Addiction 97:487-499, 2002) pathways model (N = 150, 50% female). We examined coping motives for gambling, childhood trauma, boredom proneness, risk-taking, impulsivity, attention-deficit/hyperactivity disorder (ADHD), and antisocial personality disorder as defining variables in a hierarchical cluster analysis to identify subgroups. Subgroup differences in gambling, psychiatric, and demographic variables were also assessed to establish concurrent validity. Consistent with the pathways model, our analyses identified three gambling subgroups: (1) behaviorally conditioned (BC), (2) emotionally vulnerable (EV), and (3) antisocial-impulsivist (AI) gamblers. BC gamblers (n = 47) reported the lowest levels of lifetime depression, anxiety, gambling severity, and interest in problem gambling treatment. EV gamblers (n = 53) reported the highest levels of childhood trauma, motivation to gamble to cope with negative emotions, gambling-related suicidal ideation, and family history of gambling problems. AI gamblers (n = 50) reported the highest levels of antisocial personality disorder and ADHD symptoms, as well as higher rates of impulsivity and risk-taking than EV gamblers. The findings provide evidence for the validity of the pathways model as a framework for conceptualizing PG subtypes in a non treatment-seeking sample, and underscore the importance of tailoring treatment approaches to meet the respective clinical needs of these subtypes. PMID- 27943031 TI - Substance Use Prevention for Urban American Indian Youth: A Efficacy Trial of the Culturally Adapted Living in 2 Worlds Program. AB - This article describes a small efficacy trial of the Living in 2 Worlds (L2W) substance use prevention curriculum, a culturally adapted version of keepin' it REAL (kiR) redesigned for urban American Indian (AI) middle school students. Focused on strengthening resiliency and AI cultural engagement, L2W teaches drug resistance skills, decision making, and culturally grounded prevention messages. Using cluster random assignment, the research team randomized three urban middle schools with enrichment classes for AI students. AI teachers of these classes delivered the L2W curriculum in two schools; the remaining school implemented kiR, unadapted, and became the comparison group. AI students (N = 107) completed a pretest questionnaire before they received the manualized curriculum lessons, and a posttest (85% completion) 1 month after the final lesson. We assessed the adapted L2W intervention, compared to kiR, with paired t tests, baseline adjusted general linear models, and effect size estimates (Cohen's d). Differences between the L2W and kiR groups reached statistically significant thresholds for four outcomes. Youth receiving L2W, compared to kiR, reported less growth in cigarette use from pretest to posttest, less frequent use of the Leave drug resistance strategy, and less loss of connections to AI spirituality and cultural traditions. For other substance use behaviors and antecedents, the direction of the non-significant effects in small sample tests was toward more positive outcomes in L2W and small to medium effect sizes. Results suggest that evidence based substance use prevention programs that are culturally adapted for urban AI adolescents, like L2W, can be a foundation for prevention approaches to help delay initiation and slow increases in substance use. In addition to study limitations, we discuss implementation challenges in delivering school-based interventions for urban AI populations. PMID- 27943033 TI - Evaluation of an Educational Initiative to Promote Shopping at Farmers' Markets Among the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) Participants in New York City. AB - Public Health Solutions' (PHS) Neighborhood WIC (The Special Supplemental Nutrition Program for Women, Infants, and Children) serves approximately 43,000 women and families at eight locations in high-need communities in New York City. Farmers' markets (FMs) exist in many low-income areas, and, coupled with incentives and benefits, are viable venues for WIC participants to purchase affordable produce. During the 2015 FM season (July-November), PHS launched a campaign to change participants' knowledge, attitudes, and shopping habits at FMs. WIC center staff were provided with educational materials, were trained to educate participants on FM locations and how to use their benefits at FMs, and provided tours for participants at nearby markets. To assess changes in knowledge, attitudes, and behaviors, staff administered surveys to 404 matched participants before and after the initiative. For all variables below, McNemar's test was conducted and demonstrated statistically significant increases from pre season to post-season (p < 0.001 for all variables). After the initiative compared to before, a higher percentage of participants had heard of FM Nutrition Program (FMNP) checks (51% pre-74% post) and of Health Bucks (13-24%). Additionally, a higher percentage knew that WIC checks can be used at FMs (38 53%), knew that Supplemental Nutrition Assistance Program (SNAP/EBT) can be used at FMs (20-32%), had shopped at a FM (58-75%), and had used their FMNP checks at a FM (48-66%). These results suggest that promoting the use of WIC and SNAP benefits at FMs resulted in positive change. PMID- 27943034 TI - Hedgehog: the key to maintaining adult lung repair and regeneration. PMID- 27943035 TI - Research on the Solid State Fermentation of Jerusalem Artichoke Pomace for Producing R,R-2,3-Butanediol by Paenibacillus polymyxa ZJ-9. AB - R,R-2,3-butanediol (R,R-2,3-BD) was produced by Paenibacillus polymyxa ZJ-9, which was capable of utilizing inulin without previous hydrolysis. The Jerusalem artichoke pomace (JAP) derived from the conversion of Jerusalem artichoke powder into inulin extract, which was usually used for biorefinery by submerged fermentation (SMF), was utilized in solid state fermentation (SSF) to produce R,R 2,3-BD. In this study, the fermentation parameters of SSF were optimized and determined in flasks. A novel bioreactor was designed and assembled for the laboratory scale-up of SSF, with a maximum yield of R,R-2,3-BD (67.90 g/kg (JAP)). This result is a 36.3% improvement compared with the flasks. Based on the same bath of Jerusalem artichoke powder, the total output of R,R-2,3-BD increased by 38.8% for the SSF of JAP combined with the SMF of inulin extraction. Overall, the utilization of JAP for R,R-2,3-BD production was beneficial to the comprehensive utilization of Jerusalem artichoke tuber. PMID- 27943037 TI - Carrying My Father. PMID- 27943036 TI - Omitting perioperative urinary catheterization in laparoscopic cholecystectomy: a single-institution experience. AB - PURPOSE: In 2009, the Centers for Disease Control and Prevention published Guidelines for the Prevention of Catheter-Associated Urinary Tract Infections, which limited the indications for perioperative urinary catheter use. We conducted this study to evaluate the safety of elective laparoscopic cholecystectomy (LC) without urinary catheter placement and to investigate whether it reduces the incidence of urinary complications. METHODS: Of 244 patients who underwent elective LC between March, 2010 and April 2011, 192 patients fulfilled the eligibility criteria and underwent surgery without urinary catheterization (non-catheterized group). We compared the clinical features and surgical outcomes of the non-catheterized group with those of an historical control of 90 patients who underwent LC with routine urinary catheterization. RESULTS: The operating times were similar in the two groups and there was no case of conversion to open surgery. The postoperative hospital stay was slightly shorter and the incidence of urinary complications was significantly lower in the non-catheterized group. Three patients in the non-catheterized group suffered urinary retention, which resolved after temporary catheterization. CONCLUSION: Our study demonstrated that elective LC without urinary catheter placement is feasible for most patients and might reduce the incidence of perioperative urinary complications. PMID- 27943038 TI - Primary Health Care as a Foundation for Strengthening Health Systems in Low- and Middle-Income Countries. AB - Primary health care (PHC) has been recognized as a core component of effective health systems since the early part of the twentieth century. However, despite notable progress, there remains a large gap between what individuals and communities need, and the quality and effectiveness of care delivered. The Primary Health Care Performance Initiative (PHCPI) was established by an international consortium to catalyze improvements in PHC delivery and outcomes in low- and middle-income countries through better measurement and sharing of effective models and practices. PHCPI has developed a framework to illustrate the relationship between key financing, workforce, and supply inputs, and core primary health care functions of first-contact accessibility, comprehensiveness, coordination, continuity, and person-centeredness. The framework provides guidance for more effective assessment of current strengths and gaps in PHC delivery through a core set of 25 key indicators ("Vital Signs"). Emerging best practices that foster high-performing PHC system development are being codified and shared around low- and high-income countries. These measurement and improvement approaches provide countries and implementers with tools to assess the current state of their PHC delivery system and to identify where cross country learning can accelerate improvements in PHC quality and effectiveness. PMID- 27943039 TI - Follow-Up Consultation Through a Healthcare Kiosk for Patients with Stable Chronic Disease in a Primary Care Setting: A Prospective Study. AB - INTRODUCTION: The global healthcare kiosk market is growing, and kiosks are projected to be a larger part of healthcare delivery in the coming decades. We developed an unmanned healthcare kiosk that automates the management of stable patients with chronic conditions to complement face-to-face primary care physician (PCP) visits. AIM: The aim of our study was to show that the kiosk could be a feasible means of delivering care for stable patients with chronic conditions and could generate cost savings for the management of patients with stable chronic disease. METHODS: We conducted a prospective single-arm study of 95 participants with well-controlled chronic cardiovascular diseases who visited our clinic in Singapore every 3 months for review and medication refill. During their subsequent appointments for chronic disease management at 3 and 6 months, participants used the kiosk instead of consulting a physician. All participants who used the kiosk were also evaluated by a nurse clinician (NC). The kiosk assessment of whether the patient was well controlled was then compared to the NC's assessment to determine rates of agreement. Patient satisfaction was evaluated through a questionnaire, and any adverse outcomes were documented. RESULTS: Cohen's kappa for agreement between the kiosk and the NC assessment of patients' chronic care control was 0.575 (95% CI, 0.437-0.713). The modest agreement was due to differences in systolic blood pressure measurements between the kiosk and the NC. The 96% of participants who completed two kiosk visits were all satisfied with the kiosk as a care delivery alternative. None of the participants managed through the kiosk suffered any adverse outcomes. Use of the kiosk resulted in a reduction of 128 face-to-face PCP visits. CONCLUSIONS: Healthcare kiosks can potentially be used to complement primary care clinician visits for managing patients with stable chronic diseases and can generate cost savings. PMID- 27943040 TI - Knowledge and Health Belief Attitudes of Oral Cancer and Its Screening Among At Risk Southern Thai Muslims. AB - Oral cancer is one of the leading cancers in Thailand; southern Thai Muslims seem to have a longer delay in attending treatment for oral cancer than Buddhists in the same area. Visual screenings of high-risk populations have been suggested to be an effective prevention method. This study assessed oral cancer knowledge and belief attitudes influencing oral cancer screening in Thai Muslim high-risk groups. Twelve semi-structured in-depth interviews and the focus group discussion were conducted based on the health belief model. Stratified purposeful sampling was used to recruit the participants. Inclusion criteria were those who practiced the risk habits for oral cancer and were 40 years of age or older, smokers (20+ cigarettes per day for at least 20 years) and/or betel quid chewers (10+ times per day for at least 10 years). Participants lacked knowledge about oral cancer in terms of signs and symptoms and predisposing factors. This influenced misleading belief attitudes concerning susceptibility of oral cancer, barriers, and their self-efficacy to have oral cancer screening examinations. Betel quid chewing was not regarded as a risk habit but as having a protective role against the disease. Perceived susceptibility was also seen by some to be dependent upon Allah's will. Traditional medication was mentioned as a preferred alternative to modern treatment. The latter was believed by some to be the cause of death for cancer patients. Interventions to promote oral cancer knowledge and right belief attitudes for oral cancer screening are clearly indicated. PMID- 27943041 TI - Gestational di-n-butyl phthalate exposure induced developmental and teratogenic anomalies in rats: a multigenerational assessment. AB - With the limited but ongoing usage of di-n-butyl phthalate (DBP) as plasticizer, the health effects of both phthalate and its alternatives are far from being understood. Multigenerational effects of phthalates were evaluated in rats upon exposure to DBP, aiming to provide some evidences about its potential in causing developmental teratogenicity. Gestational rats were exposed to DBP (500 mg/kg bw/day) and control groups with olive oil. On the 18th day of gestation, fetuses (F1) isolated from a few dams were subjected to prenatal screening, and the other rats were allowed to litter, and later postnatal screening was made. DBP toxicated (F1) rats were crossed and reared up to three generations (F2 and F3) by adopting the same experimental design. A considerable decrease in the weight of placenta, low number of corpora lutea and increased resorptions, and pre- and postimplantation loss were observed in F1, F2, and F3 generations. Further, there was a decrease in the number of live births and fetal body weight with high mortality, the developmental indices showed reduction in litter size and sex ratio, and a considerable incidence of skeletal and malformation complex involving face and eye was observed in later generations compared to the first. The pre-weaning indices in neonates showed a considerable delay in physical growth milestones and poor scores in sensory motor development. Alterations noticed in the levels of thyroid profile and testosterone found to have a role in sensory motor, craniofacial development, and eye formation. In brief, results confirm multigenerational and fetotoxic effects of DBP; thereby, findings imply that developing tissues are the targets and endocrine disruption appears to be the underlying mechanism of phthalate action. PMID- 27943043 TI - Handling topological changes during elastic registration : Application to augmented reality in laparoscopic surgery. AB - PURPOSE: Locating the internal structures of an organ is a critical aspect of many surgical procedures. Minimally invasive surgery, associated with augmented reality techniques, offers the potential to visualize inner structures, allowing for improved analysis, depth perception or for supporting planning and decision systems. METHODS: Most of the current methods dealing with rigid or non-rigid augmented reality make the assumption that the topology of the organ is not modified. As surgery relies essentially on cutting and dissection of anatomical structures, such methods are limited to the early stages of the surgery. We solve this shortcoming with the introduction of a method for physics-based elastic registration using a single view from a monocular camera. Singularities caused by topological changes are detected and propagated to the preoperative model. This significantly improves the coherence between the actual laparoscopic view and the model and provides added value in terms of navigation and decision-making, e.g., by overlaying the internal structures of an organ on the laparoscopic view. RESULTS: Our real-time augmentation method is assessed on several scenarios, using synthetic objects and real organs. In all cases, the impact of our approach is demonstrated, both qualitatively and quantitatively ( http://www.open cas.org/?q=PaulusIJCARS16 ). CONCLUSION: The presented approach tackles the challenge of localizing internal structures throughout a complete surgical procedure, even after surgical cuts. This information is crucial for surgeons to improve the outcome for their surgical procedure and avoid complications. PMID- 27943042 TI - Association between left atrial appendage emptying velocity, N-terminal plasma brain natriuretic peptide levels, and recurrence of atrial fibrillation after catheter ablation. AB - PURPOSE: Multiple studies have shown the efficacy and potentially curative effect of catheter ablation (CA). However, CA is always accompanied by a considerable recurrence rate for atrial fibrillation (AF). We hypothesized that pre-procedure assessments of baseline left atrial appendage emptying flow velocity (LAAFV) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels would help identify abnormal atrial substrate and offer preliminary evidence regarding susceptibility to AF recurrence in patients with paroxysmal or persistent AF, respectively. METHODS: In 120 patients with AF (paroxysmal, 55; persistent, 65), transesophageal echocardiography was performed with assessment of LAAFV and NT proBNP was measured before the first AF ablation. RESULTS: After 12 months of follow-up, 16 patients (29.1%) in the paroxysmal AF and 23 patients (35.4%) in the persistent AF experienced recurrence of AF. In ROC analysis, a NT-proBNP value of >=291 pg/ml in the paroxysmal AF and >=368 pg/ml in the persistent AF discriminated AFR and non-AFR with the greatest sensitivity and specificity. In multivariate regression analysis, LAAFV (OR 0.88, 95% CI 0.79-0.98, p = 0.023) was identified as an independent predictor of AFR in the paroxysmal AF population post-CA after adjustment for other risk factors; however, in the persistent AF population, LAAFV (OR 0.81, 95% CI 0.68-0.94, p = 0.007) and a NT-proBNP value >=368 pg/ml (OR 18.29, 95% CI 1.32-252.84, p = 0.030) were identified as independent predictors for rhythm outcome compared to other parameters. CONCLUSIONS: In patients with persistent AF, elevated plasma NT-proBNP concentrations combined with low LAAFV were associated with rhythm outcome after AF ablation; however, LAAFV was the only independent predictor of CA efficacy in patients with paroxysmal AF. PMID- 27943044 TI - Anti-MCV antibodies predict radiographic progression in Greek patients with very early (<3 months duration) rheumatoid arthritis. AB - This study aimed to assess the diagnostic and prognostic value of anti-mutated citrullinated vimentin (MCV) antibodies in very early rheumatoid arthritis (VERA) and in established rheumatoid arthritis (RA). Seventy-one patients with undifferentiated arthritis (UA) of <3 months duration, 141 with established RA, 53 with other rheumatic diseases, and 40 healthy individuals were included in the study. Anti-MCV, anti-cyclic citrullinated peptide (CCP) antibodies, and rheumatoid factor (RF) were determined and hand radiographs were recorded. Patients were assessed prospectively for 2 years, and hand radiographs were repeated. Diagnostic performance of anti-MCV was studied with receiver operating characteristic (ROC) curves and evaluation of sensitivity, specificity, and likelihood ratios. Forty-six percent of UA patients progressed to RA at 2 years. In VERA patients, sensitivity of anti-MCV was 52 %, compared to 44 % of anti-CCP and 37 % of RF, while specificity was 91 %, compared to 91 % of RF and 84 % of anti-CCP. Anti-MCV were detected in 25 % of VERA patients negative for both anti CCP and RF. In established RA, anti-MCV did not sustain its diagnostic performance. By multivariable analysis, anti-MCV, but not anti-CCP or RF, showed significant correlation with radiographic progression in VERA patients. In established RA, anti-MCV, anti-CCP, and RF were associated with active disease (p <= 0.03) and joint damage (p <= 0.004). By multivariate analysis, the strongest factors for radiographic damage were disease duration (p = 0.000), HAQ score (p = 0.000), and RF (p = 0.002). In conclusion, in patients with very early UA, anti MCV predict both progression to RA and radiological damage, and therefore, anti MCV antibody testing may be useful in every day practice. PMID- 27943045 TI - The association of sociodemographic and objectively-assessed disease variables with fatigue in systemic sclerosis: an analysis of 785 Canadian Scleroderma Research Group Registry patients. AB - Fatigue is prevalent among patients with systemic sclerosis (SSc). To date, studies investigating fatigue in SSc have been hampered by the instruments used to measure fatigue in SSc and have included patient-reported rather than objectively-rated measures of disease. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale is a validated measure for assessing fatigue in SSc that, compared to other instruments, provides good coverage of the full range of the fatigue spectrum. The objective of this study was to assess sociodemographic and objectively-rated disease-related associates of fatigue, as measured by the FACIT-F, in a large sample of patients with SSc. Fatigue was assessed using the FACIT-F scale. Disease severity was assessed using Medsger's severity scale. Multivariable linear regression was performed to assess the independent associations between sociodemographic and medical variables and fatigue. Among 785 patients, the mean FACIT-F score was 32.2 (SD = 12.1). Being age 40-49 (reference = 60+; standardized regression coefficient (beta) = -0.11), less than post-secondary education (beta = 0.07), having more medical comorbidities (beta = -0.11) and more severe muscle (beta = -0.10), gastrointestinal (beta = -0.15), lung (beta = -0.13), and general system disease severity (beta = -0.13) were independently associated with more fatigue (p < 0.05). Fatigue in SSc was independently associated with more severe disease. These data contribute to a better understanding of fatigue in SSc and help inform patient-centered research in SSc. PMID- 27943046 TI - Fungal Exposure and Asthma: IgE and Non-IgE-Mediated Mechanisms. AB - Fungi are ubiquitous in indoor and outdoor environments and have been associated with respiratory disease including childhood and adult asthma. A growing body of evidence from human and animal studies has revealed a link between fungal exposure, especially indoor fungal exposure, with asthma initiation, persistence, and exacerbation. Despite the overwhelming evidence linking mold exposure and asthma, the mechanistic basis for the association has remained elusive. It is now clear that fungi need not be intact to impart negative health effects. Fungal components and fungal fragments are biologically active and contribute to asthma development and severity. Recent mechanistic studies have demonstrated that fungi are potent immunomodulators and have powerful effects on asthma independent of their potential to act as antigens. This paper will review the connection between fungal exposure and asthma with a focus on the immunological mechanisms underlying this relationship. PMID- 27943047 TI - Epigenetic Changes During Food-Specific Immunotherapy. AB - PURPOSE OF REVIEW: The prevalence and severity of IgE-mediated food allergy has increased dramatically over the last 15 years and is becoming a global health problem. Multiple lines of evidence suggest that epigenetic modifications of the genome resulting from gene-environment interactions have a key role in the increased prevalence of atopic disease. In this review, we describe the recent evidence suggesting how epigenetic changes mediate susceptibility to food allergies, and discuss how immunotherapy (IT) may reverse these effects. We discuss the areas of the epigenome as yet unexplored in terms of food allergy and IT such as histone modification and chromatin accessibility, and new techniques that may be utilized in future studies. RECENT FINDINGS: Recent findings provide strong evidence that DNA methylation of certain promoter regions such as Forkhead box protein 3 is associated with clinical reactivity, and further, can be changed during IT treatment. Reports on other epigenetic changes are limited but also show evidence of significant change based on both disease status and treatment. In comparison to epigenetic studies focusing on asthma and allergic rhinitis, food allergy remains understudied. However, within the next decade, it is likely that epigenetic modifications may be used as biomarkers to aid in diagnosis and treatment of food-allergic patients. DNA methylation at specific loci has shown associations between food challenge outcomes, successful desensitization treatment, and overall phenotype compared to healthy controls. PMID- 27943049 TI - Functional Properties of Lactobacillus mucosae Strains Isolated from Brazilian Goat Milk. AB - The search for probiotic candidates among lactic acid bacteria (LAB) isolated from food may uncover new strains with promising health and technological properties. Lactobacillus mucosae strains attracted recent research attention due to their ability to adhere to intestinal mucus and to inhibit pathogens in the gastrointestinal tract, both related to a probiotic potential. Properties of interest and safety aspects of three Lb. mucosae strains (CNPC006, CNPC007, and CNPC009) isolated from goat milk were investigated employing in vitro tests. The presence of genetic factors related to bile salt hydrolase production (bsh), intestinal adhesion properties (msa, map, mub, and ef-tu), virulence, and biogenic amine production were also verified. All strains exhibited the target map, mub, and ef-tu sequences; the msa gene was detected in CNPC006 and CNPC007 strains. Some of the searched sequences for virulence factors were detected, especially in the CNPC009 strain; all strains carried the hyl gene, related to the production of hyaluronidase. Lb. mucosae CNPC007 exhibited a high survival rate in simulated gastric and enteric conditions. Besides, all strains exhibited the bsh sequence, and CNPC006 and CNPC007 were able to deconjugate salts of glycodeoxycholic acid (GDC). Regarding technological properties for dairy product applications, a relatively higher milk acidification and clotting capacity, diacetyl production, and proteolytic activity were registered for CNPC007 in comparison to the other strains. Collectively, the results aim at Lb. mucosae CNPC007 as a promising probiotic candidate for application in dairy products, deserving further studies to confirm and explore its potential. PMID- 27943048 TI - Vocal emotion processing deficits in HIV-infected individuals. AB - We aimed to explore the brain imaging correlates of vocal emotion processing in a group of HIV+ individuals and to compare the vocal emotion processing of HIV+ individuals with a group of healthy adults. We conducted multiple linear regressions to determine the cerebral correlates of a newly designed vocal emotion processing test in a sub-group of HIV+ individuals who completed the cerebral magnetic resonance scan (n = 36). Separately, we test whether the association between our test scores and each cerebral measure persisted regardless of the presence of neurocognitive impairment. We also calculated differences in average test scores between the total HIV+ group (n = 100) and a healthy adult group (n = 46). We found a positive association between the test scores and several brain area volumes: right frontal, temporal and parietal lobes, bilateral thalamus, and left hippocampus. We found a negative association between inflammatory markers in frontal white matter and the test scores. After controlling by neurocognitive impairment, several brain area volumes remained positively associated to the prosody test scores. Moreover, the whole HIV+ sample had significantly poorer test scores than healthy adults, but only in the subset of HIV+ individuals with neurocognitive impairment. For the first time, our results suggest that cerebral dysfunctions in particular brain areas involved in the processing of emotional auditory stimuli may occur in HIV+ individuals. These results highlight the need for broad characterization of the neuropsychological consequence of HIV brain damages. PMID- 27943050 TI - In Vitro Evaluation of Beneficial Properties of Bacteriocinogenic Lactobacillus plantarum ST8Sh. AB - Lactobacillus plantarum ST8Sh, isolated from Bulgarian salami "shpek" and previously characterized as bacteriocin producer, was evaluated for its beneficial properties. Based on the PCR analysis, Lb. plantarum ST8Sh was shown to host a gene related to the production of adhesion proteins such as Mab, Mub, EF, and PrgB. Genetic and physiological tests suggest Lb. plantarum ST8Sh to represent a potential probiotic candidate, including survival in the presence of low levels of pH and high levels of ox bile, production of beta-galactosidase, bile salt deconjugation, high level of hydrophobicity, functional auto- and co aggregation properties, and adhesion to cell lines. Application of semi-purified bacteriocin produced by Lb. plantarum ST8Sh in combination with ciprofloxacin presented synergistic effect on inhibition of Listeria monocytogenes Scott A. Based on observed properties, Lb. plantarum ST8Sh can be considered as a potential probiotic candidate with additional bacteriocinogenic properties. PMID- 27943052 TI - Cardiovascular disease in the literature: A selection of recent original research papers. PMID- 27943051 TI - Effect of Lactobacillus plantarum Tennozu-SU2 on Salmonella Typhimurium Infection in Human Enterocyte-Like HT-29-Luc Cells and BALB/c Mice. AB - The probiotic properties and inhibitory effect on Salmonella Typhimurium adhesion on human enterocyte-like HT-29-Luc cells of three Lactobacillus plantarum strains isolated from fermented fish, beach sand and a coastal plant were determined. Compared with the type strain L. plantarum NBRC 15891T, which was isolated from pickled cabbage, L. plantarum Tennozu-SU2 isolated from the acorn of a coastal tree showed high autoaggregation in de Man, Rogosa and Sharpe (MRS) broth and an antagonistic effect against S. Typhimurium in brain heart infusion (BHI) broth. Furthermore, heat-killed L. plantarum Tennozu-SU2 cells inhibited S. Typhimurium adhesion on HT-29-Luc cells. Both live and heat-killed L. plantarum Tennozu-SU2 cells showed an inhibitory effect on gut colonisation in BALB/c mice, as assessed by viable Salmonella count in faecal samples and by invasion into liver and spleen tissues. The properties shown in this study suggest that L. plantarum Tennozu-SU2 is useful as a starter and probiotic bacteria in functional food material. PMID- 27943053 TI - Technical consideration for dual ECG/respiratory-gated cardiac PET imaging. PMID- 27943054 TI - Reporting nuclear cardiology studies: Is the cup half-full or half-empty? PMID- 27943055 TI - Reproducible segmentation of white matter hyperintensities using a new statistical definition. AB - OBJECTIVES: We present a method based on a proposed statistical definition of white matter hyperintensities (WMH), which can work with any combination of conventional magnetic resonance (MR) sequences without depending on manually delineated samples. MATERIALS AND METHODS: T1-weighted, T2-weighted, FLAIR, and PD sequences acquired at 1.5 Tesla from 119 subjects from the Kings Health Partners-Dementia Case Register (healthy controls, mild cognitive impairment, Alzheimer's disease) were used. The segmentation was performed using a proposed definition for WMH based on the one-tailed Kolmogorov-Smirnov test. RESULTS: The presented method was verified, given all possible combinations of input sequences, against manual segmentations and a high similarity (Dice 0.85-0.91) was observed. Comparing segmentations with different input sequences to one another also yielded a high similarity (Dice 0.83-0.94) that exceeded intra-rater similarity (Dice 0.75-0.91). We compared the results with those of other available methods and showed that the segmentation based on the proposed definition has better accuracy and reproducibility in the test dataset used. CONCLUSION: Overall, the presented definition is shown to produce accurate results with higher reproducibility than manual delineation. This approach can be an alternative to other manual or automatic methods not only because of its accuracy, but also due to its good reproducibility. PMID- 27943056 TI - Knowledge and Awareness of Colorectal Cancer Early Warning Signs and Risk Factors among University Students in Jordan. AB - In the present study, we aimed to assess the level of awareness regarding CRC warning signs and risk factors among undergraduate students. A cross-sectional survey using standardized questionnaire developed by the Cancer Research Center in the UK was carried out in three different public universities in Jordan including Jordan University of Science and Technology, Yarmouk University, and AL al-Bayt University over a 5-month period. Volunteers were asked about their knowledge regarding CRC symptoms, risk factors, and their behaviors regarding seeking medical advice. Findings revealed that response rate was 80.1%. Vast majority of responders were female (70.9%) and 18.2% of them were studying medical-related specialties. Regarding CRC symptoms, 14.3% of responders experienced poor knowledge, 52.9% have fair knowledge, and 32.8% have good knowledge. Abdominal pain was the most recognized warning signs where 70.8% of responders could recall it. In addition, risk factors awareness was lower than warning signs awareness. About 36.1% of responders have poor knowledge, 47.4% had fair knowledge, and 16.5% had good knowledge. Unhealthy diet was the most recognized risk factor where 32.3% of responders could recall it. Moreover, females were more aware regarding CRC symptoms. Similar findings were obtained for participants who were aged 20 years or more and for those who had previous experience of cancer. Students who were studying medical-related specialties were more aware of both CRC symptoms and risk factors than those who studying other specialties. Furthermore, regarding time to seek medical attention we found that 60.6% of volunteers would seek medical advice within 1 week of noticing CRC symptoms and 12% would seek it within 2 weeks. The mean duration for seeking medical advice was found to be 1.9 weeks. University students' awareness level of CRC is poor, and therefore, extended attention should be attempted to enhance the awareness of CRC via continuous education programs, lectures, or campaigns to encourage the early detection CRC. PMID- 27943057 TI - Effects of urinary incontinence on psychosocial outcomes in adolescence. AB - To examine whether daytime wetting and bedwetting urinary incontinence (UI) in childhood and adolescence are associated with psychosocial problems in adolescence. We used data from the Avon Longitudinal Study of Parents and Children to examine the association between trajectories of UI from 4 to 9 years and self-reported psychosocial problems in adolescence (13-14 years) including depressive symptoms, peer victimisation, poor self-image and school experiences (negative perception of school and teachers, problems with peer relationships). Sample sizes ranged from 5162 (perception of teachers) to 5887 (self-image). We also examined associations between self-reported UI at 14 years and psychosocial problems. Relative to normative development, adolescents who experienced delayed development of bladder control had poorer self-image [standardised mean difference = 0.18 (95% CI 0.04, 0.32)], more negative perceptions of school [0.18 (0.02, 0.34)] and more problems with peer relationships at school [0.25 (0.10, 0.40)]. Persistent wetting (bedwetting with daytime wetting) in childhood was associated with increased problems with peer relationships in adolescence [0.19 (0.03, 0.34)]. The strongest associations between adolescent UI and psychosocial problems were found for daytime wetting (reference = no UI at 14 years): depressive symptoms [OR = 3.04 (95% CI 1.91-4.84)], peer victimisation [2.14 (1.48-3.10)], poor self-image (t = -8.49, p < 0.001) and problems with peer relationships (t = -4.69, p < 0.001). Children with delayed development of bladder control and persistent wetting have increased psychosocial problems in adolescence. Adolescents with UI reported a range of psychosocial problems and clinicians should be aware that they might require support from psychological services. PMID- 27943058 TI - Association Between Statin Medications and COPD-Specific Outcomes: A Real-World Observational Study. AB - BACKGROUND: Disease-modifying drugs are not yet available for the management of chronic obstructive pulmonary disease (COPD). HMG-CoA reductase inhibitors (statins) have anti-inflammatory properties and are therefore being considered for use in the management of COPD. OBJECTIVE: Our objective was to examine the association between statin use and COPD-specific outcomes in a real-world setting. METHODS: This was a retrospective longitudinal dynamic cohort study that used Medicaid claims data from multiple years (2005-2008) to identify patients with newly diagnosed COPD. Statin therapy was determined from the prescription drug file using National Drug Codes (NDCs). COPD-specific outcomes such as hospitalizations and emergency room and outpatient visits were identified based on a primary diagnosis of COPD. Multivariable logistic regressions with inverse probability treatment weights (IPTWs) were used to examine the relationship between statin therapy and COPD-specific outcomes. RESULTS: The study included 19,060 Medicaid beneficiaries with newly diagnosed COPD, 30.3% of whom received statins during the baseline period. Adults who received statins had significantly lower rates of COPD-specific hospitalizations (4.7 vs. 5.2%; p < 0.05), emergency room visits (13.4 vs. 15.4%; p < 0.001), and outpatient visits (41.4 vs. 44.7%; p < 0.001) than those who did not receive statin therapy. Even after adjusting for observed selection bias with IPTWs, adults receiving statins were less likely to have COPD-specific hospitalizations [adjusted odds ratio (AOR) 0.76; 95% confidence interval (CI) 0.66-0.87], emergency room visits (AOR 0.81; 95% CI 0.75 0.89), and outpatient visits (AOR 0.86; 95% CI 0.80-0.91) than those not receiving statins. CONCLUSIONS: Findings from this study suggest statins have beneficial effects in patients with newly diagnosed COPD and warrant further clinical trial investigation. PMID- 27943059 TI - Intimate partner violence and women's cancer quality of life. AB - PURPOSE: Because intimate partner violence (IPV) may disproportionately impact women's quality of life (QOL) when undergoing cancer treatment, women experiencing IPV were hypothesized to have (a) more symptoms of depression or stress and (b) lower QOL as measured with the Functional Assessment of Cancer Therapy (FACT-B) and Functional Assessment of Chronic Illness Therapy-Spiritual Well-being (FACIT-SP) Scales relative to those never experiencing IPV. METHODS: Women, aged 18-79, who were included in one of two state cancer registries from 2009 to 2015 with a recent incident, primary, invasive biopsy-confirmed cancer diagnosis were recruited and asked to complete a phone interview, within 12 months of diagnosis. This interview measured IPV by timing (current and past) and type (physical, sexual, psychological), socio-demographics, and health status. Cancer registries provided consenting women's cancer stage, site, date of diagnosis, and age. RESULTS: In this large cohort of 3,278 women who completed a phone interview, 1,221 (37.3%) disclosed lifetime IPV (10.6% sexual, 24.5% physical, and 33.6% psychological IPV). Experiencing IPV (particularly current IPV) was associated with poorer cancer-related QOL defined as having more symptoms of depression and stress after cancer diagnosis and lower FACIT-SP and FACT scores than women not experiencing IPV and controlling for confounders including demographic factors, cancer stage, site, and number of comorbid conditions. Current IPV was more strongly associated with poorer QOL. When compared with those experiencing past IPV (and no IPV), women with cancer who experienced current IPV had significantly higher depression and stress symptoms scores and lower FACIT-SP and FACT-G scores indicating poorer QOL for all domains. While IPV was not associated with being diagnosed at a later cancer stage, current IPV was significantly associated with having more than one comorbid physical conditions at interview (adjusted rate ratio = 1.35; 95% confidence interval 1.19-1.54) and particularly for women diagnosed with cancer when <55 years of age. CONCLUSIONS: Current and past IPV were associated with poorer mental and physical health functioning among women recently diagnosed with cancer. Including clinical IPV screening may improve women's cancer-related QOL. PMID- 27943060 TI - Massive ascites caused by intra-pancreatic arterioportal fistula: a rare complication of chronic pancreatitis. AB - An 86-year-old man with a long-term habit of ethanol consumption was admitted due to massive transudate ascites and leg edema. Abdominal computed tomography revealed a dilated main pancreatic duct and atrophied pancreatic parenchyma, leading to the diagnosis of chronic pancreatitis. Moreover, the portal vein was enhanced in the early arterial phase, which indicated the presence of an arterioportal fistula. The fistula was located between the posterior superior pancreaticoduodenal artery and the portal vein near a pancreatic retention cyst. Transarterial coil embolization dramatically improved the ascites. Arterioportal fistula and ensuing ascites should be recognized as a complication of chronic pancreatitis. PMID- 27943061 TI - Identification and characterization of host cell proteins interacting with Scylla serrata reovirus non-structural protein p35. AB - We have previously shown that non-structural protein p35, encoded by Scylla serrata reovirus (SsRV) S10, may act as a viroporin. To characterize the role of p35 protein in the modulation of cellular function, a yeast two-hybrid system was used to screen a cDNA library derived from S. serrata to find its interacting partner. Protein interactions were confirmed in vitro by GST pull-down. Full cDNAs of p35 interactors were cloned by the rapid amplification of cDNA ends. After two-hybrid library screening, we isolated partial cDNAs encoding hemocyanin, cryptocyanin, and TAX1BP1. Interaction of p35 with each of hemocyanin, cryptocyanin, and TAX1BP1 was confirmed by GST pull-down. The full length cDNA fragments of hemocyanin, cryptocyanin, and TAX1BP1 were 2287, 2422, and 3437 bp, respectively, and they encoded three putative proteins with molecular masses of ~76.9, ~79.2, and ~107.2 kDa, respectively. This study casts new light on the function and physiological significance of p35 during the SsRV replication cycle. PMID- 27943062 TI - Longitudinal function and ventricular dyssynchrony are restored in children with pulmonary stenosis after percutaneous balloon pulmonary valvuloplasty. AB - The aim of this study was to evaluate the impact of balloon pulmonary valvuloplasty on longitudinal ventricular dysfunction and cardiac dyssynchrony in children with congenital moderately severe pulmonary stenosis (PS). Forty-eight children with congenital moderately severe valvular pulmonary stenosis and 36 age matched normal children were included. Successful percutaneous balloon pulmonary valvuloplasty was performed for children with PS. Longitudinal Cardiac function and myocardial synchrony was assessed by echocardiography with tissue Doppler imaging (TDI). Mitral annular plane excursion (MAPSE), tricuspid annular plane excursion (TAPSE), left ventricular systolic wave (LVs), right ventricular systolic wave (RVs) and myocardial synchrony was assessed by echocardiography with TDI. TAPSE, RVs, TAPSE/MAPSE ratio and RVs/LVs ratio were significantly lower in children with PS compared to control subjects: (P < 0.001, P < 0.001, P < 0.001 and P < 0.001). All these parameters were significantly improved after balloon valvuloplasty in children with PS. Intra& inter-ventricular dyssynchrony were significantly increased in PS patients than in control group, (P < 0.03, <0.001 and 0.02 respectively). All these variables were significantly reduced after pulmonary valvuloplasty. In children with valvular PS, balloon valvuloplasty restored longitudinal function and cardiac Synchrony. This gives good insights for the importance of early intervention in children with PS to prevent the progression for cardiac deformation. PMID- 27943063 TI - Association of PDCD1 gene markers with susceptibility to thyroid cancer. AB - PURPOSE: PD-1 receptor is a co-signaling molecule with an important role in regulation of T-lymphocyte activity. Correlation between PD-1 gene (PDCD1) polymorphisms and some immune-related diseases has been reported before. In current study, we aimed to investigate the association of PD-1 polymorphisms at positions +7146 G/A (PD-1.3) and +7785 C/T (PD-1.5), as well as the emerged haplotypes with susceptibility to thyroid carcinoma. METHODS: One hundred five patients with confirmed thyroid cancer and 160 healthy individuals as control group were enrolled. Genotypes were identified using PCR-RFLP and nested PCR-RFLP methods. Results were analyzed by Arlequin and SPSS software packages. RESULTS: Analysis revealed a significant increase in the frequency of PD-1.5 mutant T allele and heterozygous CT genotype in patients with thyroid cancer in comparison with controls [79 (37.7%) vs. 71 (22.2%), and 51 (48.6%) vs. 51 (31.9%), p = 0.0001 and p = 0.009, receptively]. CC genotype at this position observed to be significantly higher among controls than the patients [99 (61.9%) vs. 40 (38.1%), p = 0.0002]. There were no significant differences in the frequencies of genotypes and alleles at locus PD-1.3 between patients and control group. Despite this, GT haplotype emerged from both positions (PD-1.3 G and PD-1.5 T) has also been observed with significant increased frequency between patients and controls [70 (36.8%) vs. 71 (22.2%), p = 0.0005]. CONCLUSION: As the first study to investigate two mentioned polymorphisms in thyroid cancer, current study confirmed the association of PD-1.5 C/T polymorphism and a haplotype resulted from both loci, PD-1.3 and PD-1.5, with susceptibility of Iranians to thyroid cancer. PMID- 27943064 TI - Investigating the Impact of Cognitive Load and Motivation on Response Control in Relation to Delay Discounting in Children with ADHD. AB - Attention-deficit/hyperactivity disorder (ADHD) is characterized by deficits in impulse control across a range of behaviors, from simple actions to those involving complex decision-making (e.g., preference for smaller-sooner versus larger later rewards). This study investigated whether changes in motor response control with increased cognitive load and motivational contingencies are associated with decision-making in the form of delay discounting among 8-12 year old children with and without ADHD. Children with ADHD (n = 26; 8 girls) and typically developing controls (n = 40; 11 girls) completed a standard go/no-go (GNG) task, a GNG task with motivational contingencies, a GNG task with increased cognitive load, and two measures of delay discounting: a real-time task in which the delays and immediately consumable rewards are experienced in real-time, and a classic task involving choices about money at longer delays. Children with ADHD, particularly girls, exhibited greater delay discounting than controls during the real-time discounting task, whereas diagnostic groups did not significantly differ on the classic discounting task. The effect of cognitive load on response control was uniquely associated with greater discounting on the real-time task for children with ADHD, but not for control children. The effect of motivational contingencies on response control was not significantly associated with delay discounting for either diagnostic group. The findings from this study help to inform our understanding of the factors that influence deficient self-control in ADHD, suggesting that impairments in cognitive control may contribute to greater delay discounting in ADHD. PMID- 27943065 TI - A Mutual Hostility Explanation for the Co-Occurrence of Delinquency and Depressive Mood in Adolescence. AB - Different interpersonal experiences are related to delinquency and depressive mood. In many studies, delinquency has been associated with exposing others to hostility, while depressive mood has been associated with being a victim of others' hostility. In this study, we proposed that adolescents with a co occurrence of high delinquency and depressive mood may be both perpetrators and victims in their relations with parents at home, peers and teachers at school, and other people encountered in leisure time. We studied a normative sample of 1452 mid-adolescents (50.61% boys and 49.38% girls). Cluster analyses found a group with a co-occurrence of high delinquency and high depressive mood. Adolescents in this cluster group were highest on being exposed to hostility, exposing others to hostility, and being involved in mutually hostile interactions with others in different everyday contexts. The findings were especially strong when we examined being a victim and a perpetrator across contexts. The results were similar for boys and girls. We conclude that the co-occurrence of high delinquency and depressive mood among some adolescents is intimately linked to the mutually hostile interactions that these adolescents experience in their everyday interpersonal contexts. PMID- 27943066 TI - Antibacterial and anticancerous drug loading kinetics for (10-x)CuO-xZnO-20CaO 60SiO2-10P2O5 (2 <= x <= 8) mesoporous bioactive glasses. AB - In the present study, antibacterial and anticancerous drug loading kinetics for the (10-x)CuO-xZnO-20CaO-60SiO2-10P2O5 (2<=x<=8, varying in steps of 2) mesoporous bioactive glasses (MBGs) have been studied. XRD analysis of the as prepared glass samples proved its amorphous nature. Scanning electron microscopy (SEM) revealed the apatite layer formation on the surface of the MBGs after soaking for 15 days in SBF. Ion dissolution studies of calcium, phosphorous and silicon have been performed using inductively coupled plasma (ICP). FTIR and Raman analysis depicted about the presence of various bonds and groups present in the glasses. The pore size of MBGs lies in the range of 4.2-9.7 nm. Apart from this, specific surface area of the MBGs varied from 263 to 402 cm2/g. The MBGs were loaded with Doxorubicin (DOX), Vancomycin (VANCO) and Tetracycline (TETRA) drugs among which, the decreasing copper content influenced the loading properties of doxorubicin and tetracycline drugs. Vancomycin was fully loaded almost in all the MBGs, whereas other drugs depicted varying loading with respect to the copper content. PMID- 27943068 TI - Further considerations on competence by design: when opportunity stops knocking. PMID- 27943067 TI - Two coffins and a funeral: early or late caspase activation determines two types of apoptosis induced by DNA damaging agents. AB - Cell cytoskeleton makes profound changes during apoptosis including the organization of an Apoptotic Microtubule Network (AMN). AMN forms a cortical structure which plays an important role in preserving plasma membrane integrity during apoptosis. Here, we examined the cytoskeleton rearrangements during apoptosis induced by camptothecin (CPT), a topoisomerase I inhibitor, in human H460 and porcine LLCPK-1alpha cells. Using fixed and living cell imaging, we showed that CPT induced two dose- and cell cycle-dependent types of apoptosis characterized by different cytoskeleton reorganizations, time-dependent caspase activation and final apoptotic cell morphology. In the one referred as "slow" (~h) or round-shaped, apoptosis was characterized by a slow contraction of the actinomyosin ring and late caspase activation. In "slow" apoptosis the gamma tubulin complexes were not disorganized and microtubules were not depolymerized at early stages. In contrast, "fast" (~min) or irregular-shaped apoptosis was characterized by early caspase activation followed by full contraction of the actinomyosin ring. In fast apoptosis gamma-tubulin complexes were disorganized and microtubules were initially depolymerized. However, after actinomyosin contraction, microtubules were reformed adopting a cortical but irregular disposition near plasma membrane. In addition to distinctive cytoskeleton reorganization kinetics, round and irregular-shaped apoptosis showed different biological properties with respect to AMN maintenance, plasma membrane integrity and phagocytes response. Our results suggest that the knowledge and modulation of the type of apoptosis promoted by genotoxic agents may be important for deciding a better therapeutic option and predicting the immune response in cancer treatment. PMID- 27943069 TI - In reply: Further considerations on competence by design: when opportunity stops knocking. PMID- 27943071 TI - Analysis of Melanin-like Pigment Synthesized from Homogentisic Acid, with or without Tyrosine, and Its Implications in Alkaptonuria. AB - Alkaptonuria is an iconic disease used by Archibald Garrod to demonstrate the theory of "inborn errors of metabolism". AKU knowledge has advanced in recent years: development of an in vitro model, discovery of murine models and advances in understanding bone and cartilage phenotypes and arthropathy in AKU. These discoveries have aided in a new clinical trial into nitisinone. However, there are still knowledge gaps surrounding the pigment in AKU and the pigmentation process. We demonstrate an advance in the understanding in the kinetics and chemistry of the polymerisation of homogentisic acid (HGA) into its pigment using size-exclusion chromatography and IR spectroscopy. We compared the properties of HGA-based pigments that were freshly prepared to those stored in solution for 2 years. Our results demonstrate the importance of pH in the polymerisation process and that colour change seen in solution (analogous to AKU patient urine) is not initially due to presence of ochronotic pigment but the quinone intermediary. In addition, we observed that pigment formation from HGA can occur in the presence of tyrosine, without the inclusion of this tyrosine into the pigment. These observations have positive implications for patients with alkaptonuria; an increased understanding of the pigment polymer chemistry, the presence of an intermediary and their kinetics present more therapeutic opportunities for treating the condition, including preventing the pigment from forming, binding or reversing established pigmentation. AKU patients treated with nitisinone show elevated tyrosine levels causing side effects such as corneal opacities; our data demonstrates that elevated tyrosine levels should not contribute or add to the ochronotic pigment burden in these patients. PMID- 27943070 TI - Development of a Tandem Mass Spectrometry Method for Rapid Measurement of Medium- and Very-Long-Chain Acyl-CoA Dehydrogenase Activity in Fibroblasts. AB - Mitochondrial fatty acid oxidation is a vital biochemical process for energy metabolism. Among the known fatty-acid metabolism disorders, very-long-chain acyl CoA dehydrogenase (VLCAD) deficiency and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency count among the most frequent. Both are potentially very serious diseases as they carry a risk of severe neurological post-crisis sequelae, and even sudden death. Diagnosis relies on plasma acylcarnitine profile analysis and urine organic acid analysis, followed by genetic testing to confirm diagnosis. However, in some cases, it is crucial to run a specific diagnostic assay for enzyme activity, which is generally performed in leukocytes or fibroblasts. The aim of this study was to address this need, first by developing a MCAD and VLCAD enzyme activity-specific diagnostic assay in fibroblasts (by measuring the reaction products, i.e. enoyl-CoA) via a rapid LC-MS/MS-based technique, and then by testing MCAD-deficient patients (n = 6), VLCAD-deficient patients (n = 10), and control patients (n = 12). MCAD activity was significantly different in the MCAD-deficiency (MCADD) group (mean = 0.07 nmol C8:1 formed/min/mg protein) compared to the control group (mean = 0.36 nmol C8:1 formed/min/mg protein). All MCADD patients showed less than 35% residual MCAD activity. VLCAD activity was significantly decreased in the VLCADD group (mean = 0.06 nmol C16:1 formed/min/mg protein) compared to the control group (mean = 0.86 nmol C16:1 formed/min/mg protein, respectively). All VLCADD patients showed less than 35% residual VLCAD activity. This technique allowed also to confirm that a novel ACADVL gene mutation (c.1400T>C) is responsible for a defective VLCAD activity (residual activity at 10%). PMID- 27943072 TI - Fields of Tension in a Boundary-Crossing World: Towards a Democratic Organization of the Self. AB - In their study of the relationship between self and society, scientists have proposed taking society as a metaphor for understanding the dynamics of the self, such as the analogy between the self and the functioning of a totalitarian state or the analogy between the self and the functioning of a bureaucratic organization. In addition to these models, the present article proposes a democratic society as a metaphor for understanding the workings of a dialogical self in a globalizing, boundary-crossing world. The article follows four steps. In the first step the self is depicted as extended to the social and societal environment and made up of fields of tension in which a multiplicity of self positions are involved in processes of positioning and counter-positioning and in relationships of social power. In the second step, the fertility of the democratic metaphor is demonstrated by referring to theory and research from three identity perspectives: multicultural, multiracial, and transgender. In the fields of tension emerging between the multiplicity of self-positions, new, hybrid, and mixed identities have a chance to emerge as adaptive responses to the limitations of existing societal structures. In the third step, we place the democratic self in a broader societal context by linking three levels of inclusiveness, proposed by Self-Categorization Theory (personal, social, and human) to recent conceptions of a cosmopolitan democracy. In the fourth and final step, a model is presented which allows the formulation of a series of specific research questions for future studies of a democratically organized self. PMID- 27943073 TI - The Semantic Processing of Motion Verbs: Coercion or Underspecification? AB - Underspecification and coercion are two prominent interpretive mechanisms to account for meaning variability beyond compositionality. While there is plentiful evidence that natural language meaning constitution exploits both mechanisms, it is an open issue whether a concrete phenomenon of meaning variability is an instance of underspecification or coercion. This paper argues that this theoretical dispute can be settled experimentally. The test case are standard motion verbs (e.g. walk, ride) in combination with +/-telic directional phrases, for which both underspecifaction and coercion analyses have been proposed in the literature. A self-paced reading study which incorporates motion verbs, directional phrases and durative/completive temporal adverbials (1) aims at determining the aspectual value of such verbs, and (2) compares the hypotheses of the Underspecification and Coercion Accounts. The results of the reading time experiment (flanked by a corpus study and a completion study) indicate that motion verbs are aspectually underspecified. They combine with +/-telic directional phrases with equal ease. The combination with a mismatching temporal adverbial is an instance of coercion, causing additional processing costs. PMID- 27943074 TI - Eliciting 10E8-like antibodies by the membrane proximal external region peptide of HIV-1 in guinea pigs. AB - OBJECTIVE: To develop an immunotherapy for HIV that can elicit 10E8-like broadly neutralizing antibodies in guinea pigs, using a multiple antigen peptide (MAP) system as the platform and 10E8 peptide as the epitope. RESULTS: The immunogen, 10E8-MAP4, was synthetized using the MAP system. The synthetic 10E8-MAP4 was stable, and the epitopes could be exposed for recognition. In addition, the 10E8 epitope was present in an alpha-helical structure, which was hypothesized to aid in the generation of neutralizing antibodies. In vivo analysis showed that 10E8 MAP4 could efficiently elicit HIV binding antibodies in guinea pigs, although only weak neutralizing activities were observed. CONCLUSIONS: Multiple antigen peptide is an excellent vaccine platform for generating binding antibodies, but may elicit weak neutralizing antibodies for HIV. PMID- 27943076 TI - Progressive hemorrhagic injury in patients with traumatic intracerebral hemorrhage: characteristics, risk factors and impact on management. AB - BACKGROUND: Progressive hemorrhagic injury (PHI) is a common occurrence in clinical practice; however, how PHI affects clinical management remains unclear. We attempt to evaluate the characteristics and risk factors of PHI and also investigate how PHI influences clinical management in traumatic intracerebral hemorrhage (TICH) patients. METHODS: This retrospective study included a cohort of 181 patients with TICH who initially underwent conservative treatment and they were dichotomized into a PHI group and a non-PHI group. Clinical data were reviewed for comparison. Multivariate logistic regression analysis was applied to identify predictors of PHI and delayed operation. RESULTS: Overall, 68 patients (37.6%) experienced PHI and 27 (14.9%) patients required delayed surgery. In the PHI group, 17 patients needed late operation; in the non-PHI group, 10 patients received decompressive craniectomy. Compared to patients with non-PHI, the PHI group was more likely to require late operation (P = 0.005, 25.0 vs 8.8%), which took place within 48 h (P = 0.01, 70.6 vs 30%). Multivariate logistic regression identified past medical history of hypertension (odds ratio [OR] = 4.56; 95% confidence interval [CI] = 2.04-10.45), elevated international normalized ratio (INR) (OR = 20.93; 95% CI 7.72-71.73) and linear bone fracture (OR = 2.11; 95% CI = 1.15-3.91) as independent risk factors for PHI. Hematoma volume of initial CT scan >5 mL (OR = 3.80; 95% CI = 1.79-8.44), linear bone fracture (OR = 3.21; 95% CI = 1.47-7.53) and PHI (OR = 3.49; 95% CI = 1.63-7.77) were found to be independently associated with delayed operation. CONCLUSIONS: Past medical history of hypertension, elevated INR and linear bone fracture were predictors for PHI. Additionally, the latter was strongly predictive of delayed operation in the studied cohort. PMID- 27943075 TI - Informing Prevention and Intervention Policy Using Genetic Studies of Resistance. AB - The common paradigm for conceptualizing the influence of genetic and environmental factors on a particular disease relies on the concept of risk. Consequently, the bulk of etiologic, including genetic, work focuses on "risk" factors. These factors are aggregated at the high end of the distribution of liability to disease, the latent variable underlying the distribution of probability and severity of a disorder. However, liability has a symmetric but distinct aspect to risk, resistance to disorder. Resistance factors, aggregated at the low end of the liability distribution and supporting health and recovery, appear to be more promising for effective prevention and intervention. Herein, we discuss existing work on resistance factors, highlighting those with known genetic influences. We examine the utility of incorporating resistance genetics in prevention and intervention trials and compare the statistical power of a series of ascertainment schemes to develop a general framework for examining resistance outcomes in genetically informative designs. We find that an approach that samples individuals discordant on measured liability, a low-risk design, is the most feasible design and yields power equivalent to or higher than commonly used designs for detecting resistance genetic and environmental effects. PMID- 27943077 TI - Outcome and prognostic factors after delayed second subarachnoid haemorrhage. AB - BACKGROUND: Data of patients suffering from delayed second subarachnoid haemorrhage (SAH) after aneurysm treatment are still missing. Patients become clearly older than before. Thus, the risk suffering from a second delayed SAH rises. The aim of this study was to analyse clinical outcome and prognostic factors in patients after delayed second SAH. METHOD: From 1999 to 2013, 18 of 1,493 patients (1.2%) suffered from a second SAH. Clinical and radiological characteristics were entered into a prospective conducted database. Outcome was assessed according to modified Rankin Scale 6 months after second SAH. P < 0.05 was considered statistically significant. RESULTS: Eighteen patients were admitted to our department with a second SAH. The second SAH occurred at a mean interval of 144 months after surgical treatment and 78 months after endovascular treatment (P < 0.05), with an overall mean interval of 125 months. The earliest event of second SAH was after 35 months. In 11 (61%) patients, a de novo aneurysm was detected; in one patient (6%), no cause of second SAH was detected. In six (33%) cases, re-rupture of the formerly secured aneurysm was found. Half of the rebleedings occurred from a basilar aneurysm, 33% from an aneurysm of anterior communicating artery and in one patient from a median cerebral artery aneurysm. At second SAH, 8 of 18 patients presented WFNS grade I-III at time of admission (44%). Overall, favourable outcome was achieved in seven patients (39%). Four patients died (22%), one of them before treatment. Favourable outcome seems to be associated with younger age. In our patients, 39% achieved a favourable outcome after second SAH. CONCLUSIONS: A delayed second SAH is a rare entity. After delayed second SAH, age seems to be a prognostic factor for patients' outcome and patients seem to have a worse prognosis. Nonetheless, up to 40% of patients can achieve a favourable outcome. PMID- 27943078 TI - The Fluoropen: a simple low-cost device to detect intraoperative fluorescein fluorescence in stereotactic needle biopsy of brain tumors. AB - BACKGROUND: The use of fluorescein fluorescence-guided stereotactic needle biopsy has been shown to improve diagnostic accuracy and to expedite operative procedure in the stereotactic needle biopsy of high-grade gliomas. We developed a device (Fluoropen) for detecting fluorescence in brain tumor tissues obtained by fluorescein fluorescence-guided stereotactic needle biopsy. METHODS: The Fluoropen is a device consisting of a light source fitted with color filters to create the required emission and visualization wavelengths. The proof-of-concept study consisted of four consecutive patients who underwent fluorescein fluorescence-guided frameless stereotactic biopsy of brain tumor. Each sample was examined for the presence of fluorescence using the Fluoropen and compared with a microscope with fluorescence visualization capability. RESULTS: A total of six samples were obtained from four stereotactic needle biopsy procedures. Four out of five samples (80%) taken from the contrast-enhancing part of the tumors were shown to be fluorescent under the microscope fitted with fluorescence module and the Fluoropen. One non-contrast enhancing lesion was non-fluorescent using both the microscope fitted with fluorescence module and the Fluoropen. The Fluoropen was shown to have 100% concordance with the microscope fitted with fluorescence module. CONCLUSIONS: The Fluoropen is a low-cost and simple standalone device for the detection of fluorescein fluorescence that can expedite stereotactic needle biopsy by providing instant confirmation of the diagnostic sample and therefore avoid the need for an intraoperative frozen section. In patients with non contrast enhancing tumors and those who were pre-treated with dexamethasone prior to surgery, fluorescein fluorescence-guided stereotactic needle biopsy will need to be used with caution. PMID- 27943079 TI - Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease. AB - PURPOSE: Increased type I interferon is considered relevant to the pathology of a number of monogenic and complex disorders spanning pediatric rheumatology, neurology, and dermatology. However, no test exists in routine clinical practice to identify enhanced interferon signaling, thus limiting the ability to diagnose and monitor treatment of these diseases. Here, we set out to investigate the use of an assay measuring the expression of a panel of interferon-stimulated genes (ISGs) in children affected by a range of inflammatory diseases. DESIGN, SETTING, AND PARTICIPANTS: A cohort study was conducted between 2011 and 2016 at the University of Manchester, UK, and the Institut Imagine, Paris, France. RNA PAXgene blood samples and clinical data were collected from controls and symptomatic patients with a genetically confirmed or clinically well-defined inflammatory phenotype. The expression of six ISGs was measured by quantitative polymerase chain reaction, and the median fold change was used to calculate an interferon score (IS) for each subject compared to a previously derived panel of 29 controls (where +2 SD of the control data, an IS of >2.466, is considered as abnormal). Results were correlated with genetic and clinical data. RESULTS: Nine hundred ninety-two samples were analyzed from 630 individuals comprising symptomatic patients across 24 inflammatory genotypes/phenotypes, unaffected heterozygous carriers, and controls. A consistent upregulation of ISG expression was seen in 13 monogenic conditions (455 samples, 265 patients; median IS 10.73, interquartile range (IQR) 5.90-18.41), juvenile systemic lupus erythematosus (78 samples, 55 patients; median IS 10.60, IQR 3.99-17.27), and juvenile dermatomyositis (101 samples, 59 patients; median IS 9.02, IQR 2.51-21.73) compared to controls (78 samples, 65 subjects; median IS 0.688, IQR 0.427-1.196), heterozygous mutation carriers (89 samples, 76 subjects; median IS 0.862, IQR 0.493-1.942), and individuals with non-molecularly defined autoinflammation (89 samples, 69 patients; median IS 1.07, IQR 0.491-3.74). CONCLUSIONS AND RELEVANCE: An assessment of six ISGs can be used to define a spectrum of inflammatory diseases related to enhanced type I interferon signaling. If future studies demonstrate that the IS is a reactive biomarker, this measure may prove useful both in the diagnosis and the assessment of treatment efficacy. PMID- 27943081 TI - Disambiguation and Integration in Korean Relative Clause Processing. AB - Previous studies on Korean relative clauses (RC) show that, with respect to processing, object-extracted relative clauses (ORC) are more difficult to process at the head noun than subject-extracted relative clauses within temporarily ambiguous contexts. ORCs, however, are predicted by experience-based processing models to incur a greater processing cost during early processing stages at the RC verb, since it is a likely locus of disambiguation for RCs in Korean, and because ORCs are a less frequent structure. Consequently, the current study investigates whether processing difficulty for ORCs manifests itself at the RC verb using eye-tracking methods, a simple sentence structure and a sentential decision task. The results revealed significantly increased go-past reading times for ORCs at the RC verb. We believe this is a result of a less frequent structure being more difficult to parse during disambiguation. Accordingly, experience based models of processing can accurately predict difficulty for ORCs in Korean. PMID- 27943080 TI - Kostmann's Disease and HCLS1-Associated Protein X-1 (HAX1). AB - Severe congenital neutropenia (SCN), originally described by the Swedish pediatrician Rolf Kostmann, constitutes a heterogeneous disorder associated with a dramatic decrease of peripheral neutrophil granulocytes. Patients suffer from life-threatening bacterial infections unless treated by recombinant human granulocyte colony stimulating factor (G-CSF) or allogeneic hematopoietic stem cells. This review is focused on the SCN variant caused by mutations in HCLS1 Associated Protein X-1 (HAX1) (SCN3, "Kostmann Disease"). HAX1 is a ubiquitously expressed protein with pleotropic functions, including control of cellular viability, migration, and cancer progression. Even though scientific evidence on the molecular mechanisms regarding HAX1 accumulates, no unified picture has emerged. This review highlights historical milestones and our current understanding of SCN related to mutations in HAX1. PMID- 27943084 TI - Need For Improved Skin Cancer Surveillance in Pediatric Cancer Survivors. AB - Survivors of pediatric cancer are at increased risk of developing secondary malignancies, with non-melanoma skin cancer being the most common. These patients are also at increased risk of melanoma. Currently, guidelines provided by the National Cancer Institute and Children's Oncology Group emphasize the importance of annual clinical examination for skin cancer screening; however, the literature reports that less than one-third of survivors of pediatric cancer have ever had a clinical skin exam by a physician. In this article, we review the risk factors for skin cancer in survivors of pediatric cancer as well as the current evidence and recommendations for their care. We suggest that dermatologists collectively establish guidelines for skin cancer surveillance in survivors of pediatric cancer. PMID- 27943083 TI - Effects of Elevated Atmospheric Carbon Dioxide and Tropospheric Ozone on Phytochemical Composition of Trembling Aspen ( Populus tremuloides ) and Paper Birch ( Betula papyrifera ). AB - Anthropogenic activities are altering levels of atmospheric carbon dioxide (CO2) and tropospheric ozone (O3). These changes can alter phytochemistry, and in turn, influence ecosystem processes. We assessed the individual and combined effects of elevated CO2 and O3 on the phytochemical composition of two tree species common to early successional, northern temperate forests. Trembling aspen (Populus tremuloides) and paper birch (Betula papyrifera) were grown at the Aspen FACE (Free-Air Carbon dioxide and ozone Enrichment) facility under four combinations of ambient and elevated CO2 and O3. We measured, over three years (2006-08), the effects of CO2 and O3 on a suite of foliar traits known to influence forest functioning. Elevated CO2 had minimal effect on foliar nitrogen and carbohydrate levels in either tree species, and increased synthesis of condensed tannins and fiber in aspen, but not birch. Elevated O3 decreased nitrogen levels in both tree species and increased production of sugar, condensed tannins, fiber, and lignin in aspen, but not birch. The magnitude of responses to elevated CO2 and O3 varied seasonally for both tree species. When co-occurring, CO2 offset most of the changes in foliar chemistry expressed under elevated O3 alone. Our results suggest that levels of CO2 and O3 predicted for the mid-twenty-first century will alter the foliar chemistry of northern temperate forests with likely consequences for forest community and ecosystem dynamics. PMID- 27943082 TI - Direct introduction of gene constructs into the pronucleus-like structure of cloned embryos: a new strategy for the generation of genetically modified pigs. AB - Due to a rising demand of porcine models with complex genetic modifications for biomedical research, the approaches for their generation need to be adapted. In this study we describe the direct introduction of a gene construct into the pronucleus (PN)-like structure of cloned embryos as a novel strategy for the generation of genetically modified pigs, termed "nuclear injection". To evaluate the reliability of this new strategy, the developmental ability of embryos in vitro and in vivo as well as the integration and expression efficiency of a transgene carrying green fluorescence protein (GFP) were examined. Eighty percent of the cloned pig embryos (633/787) exhibited a PN-like structure, which met the prerequisite to technically perform the new method. GFP fluorescence was observed in about half of the total blastocysts (21/40, 52.5%), which was comparable to classical zygote PN injection (28/41, 68.3%). In total, 478 cloned embryos injected with the GFP construct were transferred into 4 recipients and from one recipient 4 fetuses (day 68) were collected. In one of the fetuses which showed normal development, the integration of the transgene was confirmed by PCR in different tissues and organs from all three primary germ layers and placenta. The integration pattern of the transgene was mosaic (48 out of 84 single-cell colonies established from a kidney were positive for GFP DNA by PCR). Direct GFP fluorescence was observed macro- and microscopically in the fetus. Our novel strategy could be useful particularly for the generation of pigs with complex genetic modifications. PMID- 27943085 TI - Facial Hyperpigmentation in Skin of Color: Special Considerations and Treatment. AB - Differences in cutaneous diseases in people of color call for nuanced evaluation and management. One of the most common dermatological complaints from patients with skin of color is dyspigmentation, particularly hyperpigmentation. The challenge for clinicians is to establish correct diagnoses along with consistently successful treatments to meet the needs of the increasingly diverse population served. This review focuses on facial hyperpigmentation and outlines the most common skin disorders and treatment options. PMID- 27943086 TI - A data-driven soft sensor for needle deflection in heterogeneous tissue using just-in-time modelling. AB - Global modelling has traditionally been the approach taken to estimate needle deflection in soft tissue. In this paper, we propose a new method based on local data-driven modelling of needle deflection. External measurement of needle-tissue interactions is collected from several insertions in ex vivo tissue to form a cloud of data. Inputs to the system are the needle insertion depth, axial rotations, and the forces and torques measured at the needle base by a force sensor. When a new insertion is performed, the just-in-time learning method estimates the model outputs given the current inputs to the needle-tissue system and the historical database. The query is compared to every observation in the database and is given weights according to some similarity criteria. Only a subset of historical data that is most relevant to the query is selected and a local linear model is fit to the selected points to estimate the query output. The model outputs the 3D deflection of the needle tip and the needle insertion force. The proposed approach is validated in ex vivo multilayered biological tissue in different needle insertion scenarios. Experimental results in five different case studies indicate an accuracy in predicting needle deflection of 0.81 and 1.24 mm in the horizontal and vertical lanes, respectively, and an accuracy of 0.5 N in predicting the needle insertion force over 216 needle insertions. PMID- 27943087 TI - Accurate lumen diameter measurement in curved vessels in carotid ultrasound: an iterative scale-space and spatial transformation approach. AB - Monitoring of cerebrovascular diseases via carotid ultrasound has started to become a routine. The measurement of image-based lumen diameter (LD) or inter adventitial diameter (IAD) is a promising approach for quantification of the degree of stenosis. The manual measurements of LD/IAD are not reliable, subjective and slow. The curvature associated with the vessels along with non uniformity in the plaque growth poses further challenges. This study uses a novel and generalized approach for automated LD and IAD measurement based on a combination of spatial transformation and scale-space. In this iterative procedure, the scale-space is first used to get the lumen axis which is then used with spatial image transformation paradigm to get a transformed image. The scale space is then reapplied to retrieve the lumen region and boundary in the transformed framework. Then, inverse transformation is applied to display the results in original image framework. Two hundred and two patients' left and right common carotid artery (404 carotid images) B-mode ultrasound images were retrospectively analyzed. The validation of our algorithm has done against the two manual expert tracings. The coefficient of correlation between the two manual tracings for LD was 0.98 (p < 0.0001) and 0.99 (p < 0.0001), respectively. The precision of merit between the manual expert tracings and the automated system was 97.7 and 98.7%, respectively. The experimental analysis demonstrated superior performance of the proposed method over conventional approaches. Several statistical tests demonstrated the stability and reliability of the automated system. PMID- 27943088 TI - Patient Perspectives on Intimate Partner Violence Discussion during Genetic Counseling Sessions. AB - Intimate partner violence (IPV) is a major health concern in the United States (ACOG 2013). The World Health Organization (WHO) describes IPV as any physical, sexual, psychological harm by a current or former intimate partner (WHO 2016). Due to the psychosocial depth and nature of discussions within genetic counseling sessions, patients may disclose and/or discuss IPV as it relates to sexual well being, reproductive and overall health. This study aims to assess the role for IPV screening, counseling and intervention in genetic counseling practice by investigating the incidence, experiences and attitudes about IPV among genetic counseling patients. Patients receiving genetic counseling at an urban metropolitan hospital were anonymously surveyed about experiences and perspectives on IPV as a topic of discussion during genetic counseling sessions. Among 60 eligible patients, 50 completed the survey (49 females, 1 male, of which, 5 identified as LGBT) ages 20 to 66. The incidence of IPV in this group was 16.0 % (n = 8). Majority of participants had never been asked about IPV by a healthcare provider (n = 32; 64.0%), would have felt comfortable answering questions about IPV by their healthcare provider (n = 34; 68.0%), and would have felt comfortable answering questions about IPV by their genetic counselor (n = 39; 78.0%). Perspectives from all participants, notably those with IPV history, provided insights to the role of genetic counselors in areas for IPV screening and counseling training. PMID- 27943091 TI - James Kenneth (Ken) Champion, MD, FACS 15 Aug 1951-25 Sep 2016. PMID- 27943089 TI - Diltiazem co treatment with cyclosporine for induction of disease remission in sight-threatening non-infectious intraocular inflammation. AB - PURPOSE: To investigate the effects of diltiazem co-treatment with microemulsified cyclosporine-A (CsA) on dosage, blood concentrations of CsA, as well as therapeutic and side effects in patients with sight-threatening non infectious intraocular inflammation. METHODS: A prospective, randomized, placebo controlled, open-label trial of 39 patients with sight-threatening non-infectious intraocular inflammation. The change in visual acuity (LogMAR), the grade of inflammatory activity, therapeutic concentration of CsA in the blood and systemic and renal toxicity were determined after comparing two groups, one treated with CsA and diltiazem (treatment group), and the other without diltiazem (control group). RESULTS: Compared with the control group, the concentration of CsA in the blood of the treatment group significantly increased (P < 0.05) requiring a reduction in dosage of CsA (P < 0.05). CONCLUSION: In patients with severe intraocular inflammation treated with CsA and diltiazem, blood concentrations of CsA increased as the dosage decreased. This efficient combination therapy reduced patient's economic burden, at the same time decreasing systemic and renal toxicity which in turn may promote the use of CsA for longer periods. PMID- 27943090 TI - Evaluation of factors affecting visual acuity after Descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To elucidate the factors affecting visual acuity after Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: We reviewed consecutive patients who underwent primary DSAEK for corneal endothelial dysfunction at Inouye Eye Hospital from January 2010 through January 2015 and who had a follow-up of at least 6 months. Fifty-four eyes of 49 patients (24 men and 25 women) were enrolled; the mean age was 72.5 +/- 8.7 years. Medical charts were retrospectively examined for best spectacle-corrected visual acuity (BSCVA), intraocular pressure, keratometric value, keratometric cylinder, grade of preoperative corneal edema, preoperative graft thickness, and endothelial cell density (ECD) before and at 1, 3, 6, 12, and 24 months after surgery. A multiple regression analysis was used to evaluate the factors associated with BSCVA at 3, 6 months, and 1 year after surgery. Explanatory variables included age, sex, preoperative factors (BSCVA, degree of corneal edema, donor ECD, and graft thickness), and factors at each time point (keratometric value, keratometric cylinder, and intraocular pressure). RESULTS: The mean logarithms of the minimum angle of resolution (logMAR) BSCVA preoperatively and at 1, 3, 6, and 12 months after surgery were 1.03 +/- 0.49, 0.42 +/- 0.26, 0.29 +/- 0.21, 0.24 +/- 0.20, and 0.22 +/- 0.20, respectively. Multiple regression analysis showed that preoperative BSCVA alone was significantly associated with BSCVA at 3, 6, and 12 months. CONCLUSION: A better preoperative BSCVA was associated with a better BSCVA after DSAEK, which suggests that DSAEK should be considered earlier than stromal changes such as subepithelial fibrosis occurrence. PMID- 27943092 TI - Robotic Kidney Transplantation for Morbidly Obese Patients Excluded from Traditional Transplantation. PMID- 27943093 TI - Relevance of Self-reported Behavioral Changes Before Bariatric Surgery to Predict Success After Surgery. AB - BACKGROUND: International guidelines emphasize the need for multidisciplinary preparation to improve the safety and effectiveness of bariatric surgery (BS), but whether the patient is ready for surgery is difficult to assess. The objective of this study was to explore whether inquiries on dietary habits and physical activity before surgery are predictive of postoperative weight loss. METHODS: We prospectively assessed in 78 candidates for BS (age, 43 +/- 12 years; M/F, 15/63; weight, 122 +/- 17 kg; IMC, 44 +/- 5 kg/m2) anthropometric parameters, food intake, and physical activity (Baecke questionnaire) at the beginning and the end of a systematized preoperative preparation (7 +/- 2 months) including consultations (mean number 7 +/- 2) with a nutritionist, dietician, psychologist, and sports coach. RESULTS: During the preparation, weight change was zero (+/-5 kg). In contrast, self-reported caloric intake decreased from 2143 +/- 640 to 1906 +/- 564 kcal/24 h (p < 0.001) and snacking from 68 to 13% during the preparation. Self-reported physical activity increased (p < 0.05). The decrease in reported caloric intake was positively correlated with the mean number of preoperative consultations attended (R = 0.2885, p < 0.05) but not with the changes in preoperative weight. Postsurgical weight loss (recorded at 6 and 12 months) was correlated with preoperative changes in weight and physical activity but not with preoperative dietary changes. CONCLUSIONS: Self-reported improvement of dietary habits is not a good reflection of actual changes in dietary behavior among candidates for bariatric surgery, as illustrated by the absence of weight changes on average during the preoperative preparation. In contrast to dietary inquiry, self-reported changes in physical activity are predictive of postoperative weight loss after bariatric surgery. PMID- 27943094 TI - Primary Brain Calcification Causal PiT2 Transport-Knockout Variants can Exert Dominant Negative Effects on Wild-Type PiT2 Transport Function in Mammalian Cells. AB - Primary brain calcification (PBC) is a neurodegenerative disorder characterized by calcium-phosphate deposits in the basal ganglia and often also other areas of the brain. The prevalent clinical manifestations are cognitive impairment, neuropsychiatric symptoms, and movement disorders. In recent years, monoallelic variants in SLC20A2, which encodes the type III sodium-dependent inorganic phosphate (Pi) transporter 2 (PiT2), have been linked to the familial form of PBC in 40-50% of the families reported worldwide as well as to sporadic cases of PBC. Further insight into the disease mechanism is, however, needed. Based on co expression studies of wild-type and variant PiT2 in Xenopus laevis oocytes, the molecular disease mechanism associated with SLC20A2 missense variants has formerly been suggested to be haploinsufficiency. We have here used mammalian cells isolated from a Slc20a2 -/- mouse and co-expression of human wild-type and variant PiT2. Two of the variants studied have both been reported twice in unrelated PBC cases: PiT2D28N in two sporadic cases and PiT2E575K in a familial and a sporadic case. We find that in mammalian cells, the analyzed SLC20A2 missense variants can exert their effect in a dominant negative manner resulting in decreased wild-type PiT2 Pi transport. Thus, compared to monoallelic lack of functional PiT2 protein expression, which reasonably points towards haploinsufficiency, certain SLC20A2 missense variants may be more detrimental for cellular Pi uptake and potentially contribute to an earlier disease onset and/or a more severe phenotype as observed for Slc20a2 -/- mice compared to Slc20a2 +/- mice. PMID- 27943095 TI - Predictors of Inadequate Weight Loss After Laparoscopic Gastric Bypass for Morbid Obesity. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is an effective treatment for morbid obesity resulting in approx. 70% excess weight loss (EWL) at 1-2 years. The aim of this study was to identify factors predictive of inadequate EWL following primary LRYGB. METHODS: Data on consecutive patients who underwent primary LRYGB between September 2009 and March 2013 were collected prospectively. The effects of age, gender, baseline body mass index (BMI), preoperative EWL, length of time between initial consultation and surgery (TtS), presence of diabetes mellitus (DM), arthritis, obstructive sleep apnea (OSA) and postoperative length of hospital stay (LOS) on EWL at 12 months were studied. General linear regression models were used to evaluate group differences in EWL and to assess independent associations between baseline variables and EWL at 12 months. Stepwise regression analyses were used to estimate individual contributions of independent variables to the variance in EWL at 12 months. In this study, inadequate EWL was defined as <50% EWL at 12 months. RESULTS: LRYGB was performed in 227 patients with a mean +/- SD age and BMI of 48.6 +/- 11 years and 53.6 +/- 7.1 kg/m2, respectively. Female to male ratio was 3:1. EWL at 12 months had an inverse correlation with age (p = 0.01), baseline BMI (p < 0.001), TtS (p = 0.001), OSA (p = 0.039) and DM (p = 0.039). Conversely, there was a significant positive association between preoperative EWL and that at 12 months (p = 0.009). There was no effect of gender, arthritis or LOS on EWL at 12 months. Multiple regression analysis demonstrated inadequate EWL at 12 months to be predicted by older age (>60 years), patients with diabetes, higher baseline BMI (>60), those who gained weight preoperatively and in patients who waited longer than 18 months for surgery (p = 0.027). CONCLUSIONS: Preoperative factors that predict inadequate EWL at 12 months following primary LRYGB include higher initial BMI, older age, presence of DM and preoperative weight gain. Identification of these factors preoperatively should aid in providing intensive support to these at-risk patient groups. PMID- 27943097 TI - COLLABORADI: a rule-based diagnostic imaging prescription system to help the general practitioner to choose the most appropriate radiological imaging procedures. AB - Significant advances in medical imaging have been made in the past decades, enabling physicians to reach high precision in diagnosing patients' diseases by means of sophisticated imaging tools. However, the use of sophisticated tools is limited by the high costs and, in some cases, by the utilization of ionizing radiation, which have both great impact on the economy of a nation and on citizens' health, respectively. Guidelines have been published among countries to provide physicians with structured rules to be followed to suggest the correct imaging technique, suiting better the diagnostic question and avoiding inappropriate imaging requests. The COLLABORADI is a research project that addressed the phenomenon of inappropriate imaging prescriptions in Sicily (Italy) and proposed the design and implementation of a clinical decision support system to help physicians to set up the most appropriate diagnostic route for their patients. The aim of this paper is to describe the characteristics of the COLLABORADI software and its potential impact in diminishing inappropriate imaging. PMID- 27943096 TI - Gastrointestinal stromal tumors (GISTs): SEAP-SEOM consensus on pathologic and molecular diagnosis. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, with an incidence of 1.1 cases/100,000 inhabitants/year. A group of experts from the Spanish Society of Pathology and the Spanish Society of Oncology met to discuss a brief update on GISTs and agree on aspects relating to the pathological and molecular diagnosis of these tumors. GISTs are generally solitary, well-circumscribed lesions of variable size (<10 mm-35 cm) that may present with intra- or extra-luminal parietal growth or a mixed-type (hourglass) growth pattern. Histologically, they are unencapsulated neoplasms displaying expansive growth and spindle-shaped (70%), epithelioid (20%), or mixed cellularity (10%). Mitotic activity is generally moderate or low and should be evaluated only in areas with high cellularity or higher mitotic frequency. The great majority of GISTs harbour mutually exclusive activating mutations in genes coding for the type III receptor tyrosine kinases KIT and PDGFRA; less commonly, GISTs have also been reported to display mutations elsewhere, including BRAF and NF1 and SDH-complex genes. The method most widely used to detect KIT and PDGFRA mutations is amplification of the exons involved by polymerase chain reaction followed by direct sequencing (Sanger method) of these amplification products. Molecular analyses should always specify the type of analysis performed, the region or mutations evaluated, and the sensitivity of the detection method employed. PMID- 27943098 TI - Incidence of greater trochanteric pain syndrome in patients suspected for femoroacetabular impingement evaluated using magnetic resonance arthrography of the hip. AB - OBJECTIVES: We evaluated the incidence of greater trochanter pain syndrome (GTPS) in patients who underwent magnetic resonance arthrography (MRA) of the hip for a suspected femoroacetabular impingement (FAI) syndrome. METHODS: Hip MRA performed at our institution (3/2012-1/2014) were reviewed. The absence/presence of FAI (cam, pincer, and mixed) was noted. GTPS diagnosis was based on gluteus medius/minimus tendinopathy/tears, trochanteric bursitis, fascia lata thickening, and trochanter bone oedema/erosion. Subgroup analysis for age (under/over 40 years) and FAI type (cam, pincer, and mixed) was also performed. RESULTS: N = 189 patients were included (n = 125 males; age 39 +/- 12 years). FAI was diagnosed in n = 133 (70, 4%): cam type, n = 85 (63, 9%); pincer type, n = 22 (16, 6%); and mixed type, n = 26 (19, 5%). N = 72 patients (38.1%) had tendinopathy, n = 14 (7.4%) had trochanter erosion, n = 31 (16.4%) had bursitis, n = 4 had bone oedema (2.1%), and n = 3 (1.6%) had fascia lata thickening, resulting in GTPS diagnosis in n = 74 patients (39.2%). The association of normal hip morphology/GTPS was significantly higher (P = 0.023) than that of FAI/GTPS. Under 40 years, GTPS incidence was higher in patients with normal hip and pincer-type FAI (P = 0.028). Over 40 years, no difference between patients with/without FAI (P = 0.119) was seen. CONCLUSIONS: GTPS was more frequently observed in patients with normal hip morphology than in patients with FAI, particularly in patients under 40. PMID- 27943099 TI - Incremental value of high b value diffusion-weighted magnetic resonance imaging at 3-T for prediction of extracapsular extension in patients with prostate cancer: preliminary experience. AB - PURPOSE: To investigate whether high b value diffusion-weighted imaging (DWI) contributes to the improvement of diagnostic ability of extracapsular extension (ECE) in prostate cancer (PC). MATERIALS AND METHODS: Forty-three patients with PC underwent multiparametric MRI including DWI (b values: 0, 2000 s/mm2) at 3-T. Two radiologists assessed the presence of ECE and the diagnostic certainty degree using conventional diagnostic method by consensus. Tumor apparent diffusion coefficient (ADC, *10-3 mm2/s) was also measured. Independent predictors of ECE were identified among PSA, tumor ADC, Gleason score, and conventional MRI. ECE in patients with low diagnostic certainty by conventional MRI was further reevaluated using ADC cutoff value, and the results were combined with those of patients with high diagnostic certainty by conventional MRI (MRI + ADC method). RESULTS: Tumor ADC was an independent predictor of ECE, and the ADC cutoff value was 0.72. The sensitivity, specificity, and accuracy of conventional MRI and MRI + ADC method in the diagnosis of ECE were 44, 92, and 72%, and 78, 96, and 88%, respectively. Among MRI findings leading to the judgement of low diagnostic certainty, broad tumor contact was most common (72% of the patients). CONCLUSIONS: The addition of ADC obtained with high b value DWI at 3-T to conventional MRI improved the diagnostic ability of ECE. PMID- 27943100 TI - K-Ras, H-Ras, N-Ras and B-Raf mutation and expression analysis in Wilms tumors: association with tumor growth. AB - Nephroblastoma (Wilms tumor) is a kidney neoplasia, predominately occurring at very young age, resulting from the malignant transformation of renal stem cells. The Ras proto-oncogenes and B-Raf are members of an intracellular cascade pathway, which regulates cell growth and differentiation, and ultimately cancer development. Our objective was to determine the mutation rate and to measure the mRNA levels of the three Ras genes and of B-Raf in formalin-fixed paraffin embedded tissue samples from 32 patients with nephroblastoma and 10 controls. No mutations were detected in the four studied genes among our Wilms tumors cases, while Ras and B-Raf expression was higher in malignant samples versus controls. Statistical analysis revealed a positive correlation of K-Ras (p < 0.001) and B Raf (p = 0.006) with tumor size, a negative correlation of K-Ras (p = 0.041) and H-Ras (p = 0.033) with the percentage of tissue necrosis, and an association of N Ras (p = 0.047) and B-Raf (p = 0.044) with tissue histology. From the above, we deduce that although Ras and B-Raf mutations are rare events in Wilms tumors, their expression pattern suggests that they play an important role in the development and progression of this malignancy. PMID- 27943101 TI - Salivary biomarkers in cancer detection. AB - Cancer is the second most common cause of death in the USA. Its symptoms are often not specific and absent, until the tumors have already metastasized. Therefore, there is an urgent demand for developing rapid, highly accurate and noninvasive tools for cancer screening, early detection, diagnostics, staging and prognostics. Saliva as a multi-constituent oral fluid comprises secretions from the major and minor salivary glands, extensively supplied by blood. Molecules such as DNAs, RNAs, proteins, metabolites, and microbiota, present in blood, could be also found in saliva. Recently, salivary diagnostics has drawn significant attention for the detection of specific biomarkers, since the sample collection and processing are simple, cost-effective, and precise and do not cause patient discomfort. Here, we review recent salivary candidate biomarkers for systemic cancers by dividing them according to their origin into: genomic, transcriptomic, proteomic, metabolomic and microbial types. PMID- 27943102 TI - Clinicopathological evaluation of Sox10 expression in diffuse-type gastric adenocarcinoma. AB - Sox10, one of the transcription factors, regulates Wnt/beta-catenin signaling in diverse developmental processes in normal tissues. Sox10 is also expressed in variable solid tumors such as breast cancer, salivary tumor, hepatocellular carcinoma, ovarian tumor, nasopharyngeal carcinoma, prostate cancer, and digestive cancer. The role of Sox10 during tumorigenesis is still controversial, especially in digestive cancers; thus, we performed clinicopathological evaluation of Sox10 expression in 41 cases of diffuse-type gastric adenocarcinoma (DGA). We examined the expression of Sox10 by immunohistochemical staining and real-time quantitative reverse transcriptase PCR and evaluated the correlation between Sox10 expression and clinicopathological factors. A low-level expression of Sox10 was significantly associated with high-level venous invasion by immunohistochemical evaluation, while it was significantly associated with high level lymphatic permeation when analyzed by real-time PCR assay. Survival analysis of 41 cases indicated that high level of vascular permeation was a statistically poor prognostic factor, suggesting that derogation of Sox10 would lead to unfavorable patients' outcome through the acceleration of vascular invasion. In this study, we revealed the clinical benefit of evaluation of Sox10 expression to predict the risk of vascular permeation which yields patients' poor prognosis in DGA. PMID- 27943103 TI - Numerical study to indicate the vulnerability of plaques using an idealized 2D plaque model based on plaque classification in the human coronary artery. AB - Atherosclerosis is one of the leading causes of death in the world. In this study, an idealized 2D plaque model based on plaque classification in the coronary artery is developed. When creating the idealized 2D model for each plaque type (fibrocalcic, FC; fibrofatty, FT; calcified fibroatheroma, CaFA; fibroatheroma, FA; calcified thin-cap fibroatheroma, CaTCFA; thin-cap fibroatheroma, TCFA), the cap thickness and stenosis by diameter were set as variables. In order to establish the correlation between each plaque type and plaque rupture, a numerical simulation was performed and the stress and stress gradient were reviewed to analyze the mechanical behavior. Results show that both the TCFA and CaTCFA plaque types, which have the smallest cap thicknesses of the different types of plaque, showed relatively high stress values in the thin membrane when compared with the FT type. The FT type is considered to be relatively stable since it does not have necrotic core or a thin membrane. With a stenosis rate of 50% and a cap thickness of 60 MUm, the TCFA and CaTCFA types showed approximately 11 and 110% higher stress values, respectively, and 679 and 1568% higher negative stress gradient values, respectively. In other words, the plaque types with thin caps, which have weak load-bearing capacities, showed high stress values and high negative stress gradients in the radial direction. It is understood that this result could indicate the possibility of plaque rupture. PMID- 27943104 TI - Stress analysis of fracture of atherosclerotic plaques: crack propagation modeling. AB - Traditionally, the degree of luminal obstruction has been used to assess the vulnerability of atherosclerotic plaques. However, recent studies have revealed that other factors such as plaque morphology, material properties of lesion components and blood pressure may contribute to the fracture of atherosclerotic plaques. The aim of this study was to investigate the mechanism of fracture of atherosclerotic plaques based on the mechanical stress distribution and fatigue analysis by means of numerical simulation. Realistic models of type V plaques were reconstructed based on histological images. Finite element method was used to determine mechanical stress distribution within the plaque. Assuming that crack propagation initiated at the sites of stress concentration, crack propagation due to pulsatile blood pressure was modeled. Results showed that crack propagation considerably changed the stress field within the plaque and in some cases led to initiation of secondary cracks. The lipid pool stiffness affected the location of crack formation and the rate and direction of crack propagation. Moreover, increasing the mean or pulse pressure decreased the number of cycles to rupture. It is suggested that crack propagation analysis can lead to a better recognition of factors involved in plaque rupture and more accurate determination of vulnerable plaques. PMID- 27943105 TI - Hypolipidemic and hypoglycemic activities of a oleanolic acid derivative from Malva parviflora on streptozotocin-induced diabetic mice. AB - One new oleanolic acid derivative, 2alpha,3beta,23alpha,29alpha tetrahydroxyolean 12(13)-en-28-oic acid (1) was isolated from the aerial parts of Malva parviflora. Their structure was characterized by spectroscopic methods. The hypolipidemic and hypoglycemic activities of 1 was analyzed in in streptozotocin (STZ)-nicotinamide induced type 2 diabetes in mice (MD) and type 1 diabetes in streptozotocin induced diabetic mice (SD). Triterpene was administered orally at doses of 20 mg/kg for 4 weeks. Organ weight, body weight, glucose, fasting insulin, cholesterol-related lipid profile parameters, glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT), serum alkaline phosphatase (SALP), glucokinase, hexokinase, glucose-6-phosphatase activities and glycogen in liver were measured after 4 weeks of treatment. The results indicated that 1 regulate glucose metabolism, lipid profile, lipid peroxidation, increased body weight, glucokinase and hexokinase activities inhibited triglycerides, total cholesterol, low density lipoproteins level, SGOT, SGPT, SALP, glycogen in liver and glucose-6-phosphatase. In addition, improvement of insulin resistance and protective effect for pancreatic beta-cells, also 1 may changes the expression of pro-inflammatory cytokine (IL-6 and TNF-alpha levels) and enzymes (PAL2, COX-2, and LOX). The results suggest that 1 has hypolipidemic and hypoglycemic, anti inflammatory, activities, improve insulin resistance and hepatic enzymes in streptozotocin-induced diabetic mice. PMID- 27943106 TI - The Association Between Weight Status, Weight History, Physical Activity, and Cognitive Task Performance. AB - PURPOSE: Physical activity has been shown to attenuate the association between overweight/obesity and deleterious cardiovascular health-related outcomes, with emerging work also taking the duration of overweight/obesity into consideration. No previous work, however, has explored the interrelationships between physical activity, obesity, and obesity duration in the context of cognitive task performance, which was the purpose of this study. METHOD: Data from the 1999-2002 National Health and Nutrition Examination Survey were used (N = 2322 adults 60-85 yrs). Physical activity was assessed via self-report, with body mass index (BMI) directly measured. Participants were classified into one of eight mutually exclusive groups: (0) normal weight now and 10 years ago and active now (n = 195), (1) normal weight and 10 years ago and inactive now (n = 265), (2) normal weight now but not 10 years ago and active now (n = 46), (3) normal weight now but not 10 years ago and inactive now (n = 123), (4) overweight/obese now but not 10 years ago and active now (n = 117), (5) overweight/obese now but not 10 years ago and inactive now (n = 168), (6) overweight/obese now and 10 years ago and active now (n = 435), and (7) overweight/obese now and 10 years ago and inactive now (n = 973). The digit symbol substitution test (DSST) was employed to assess cognitive task performance. RESULTS: After adjustments, only individuals who were inactive (groups 1, 3, 5, and 7) had significantly lower cognitive task performance. CONCLUSION: Being inactive, regardless of weight classification and duration of overweight/obesity, was inversely associated with cognitive task performance in this national sample of older adults. PMID- 27943107 TI - The Efficacy of IDegLira (Insulin Degludec/Liraglutide Combination) in Adults with Type 2 Diabetes Inadequately Controlled with a GLP-1 Receptor Agonist and Oral Therapy: DUAL III Randomized Clinical Trial. AB - INTRODUCTION: The progressive nature of type 2 diabetes necessitates treatment intensification. This often involves intensification with oral antidiabetic drugs (OADs) initially, followed by other agents, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), with the majority of patients eventually requiring insulin therapy. Therefore, this trial aimed to investigate the efficacy of IDegLira (combination of insulin degludec and liraglutide) in controlling glycemia in adults with type 2 diabetes who were inadequately controlled on a GLP 1RA and OADs. METHODS: In this 26-week open-label phase 3b trial, patients on maximum-dose GLP-1RA therapy (liraglutide once daily or exenatide twice daily) with metformin alone or with pioglitazone and/or sulfonylurea were randomized 2:1 to IDegLira once daily (n = 292) or to unchanged GLP-1RA therapy (n = 146), continuing OADs at the pre-trial dose. RESULTS: After 26 weeks, HbA1c reductions were superior with IDegLira versus unchanged GLP-1RA; estimated treatment difference -0.94% (-10.3 mmol/mol), p < 0.001. Mean HbA1c reduced from 7.8% to 6.4% (61.5 to 46.9 mmol/mol) with IDegLira and from 7.7 to 7.4% (60.8 to 57.1 mmol/mol) with unchanged GLP-1RA. With IDegLira, 75% and 63% of patients achieved HbA1c <7% and <=6.5%, compared with 36% and 23% on unchanged GLP-1RA, respectively. Fasting plasma glucose and 9-point self-monitored blood glucose profiles improved significantly more with IDegLira versus unchanged GLP-1RA. The mean change in weight was +2.0 kg with IDegLira, versus -0.8 kg with unchanged GLP-1RA. Rates of confirmed hypoglycemia were low, but higher with IDegLira versus unchanged GLP-1RA. The safety profile of IDegLira was consistent with previous findings; both treatments were well tolerated and the rate of nausea was low in both groups. IDegLira improved patient-reported outcomes versus unchanged GLP-1RA. CONCLUSIONS: IDegLira provided superior glycemic control versus unchanged GLP-1RA and represents an efficacious intensification approach in patients inadequately controlled on GLP-1RAs. TRIAL REGISTRATION: ClinicalTrials.gov #NCT01676116. FUNDING: Novo Nordisk. PMID- 27943108 TI - Associations between IVF outcomes and essential trace elements measured in follicular fluid and urine: a pilot study. AB - PURPOSE: A hypothesis-generating pilot study exploring associations between essential trace elements measured in follicular fluid (FF) and urine and in vitro fertilization (IVF) endpoints. METHODS: We recruited 58 women undergoing IVF between 2007 and 2008, and measured cobalt, chromium, copper, manganese, molybdenum, and zinc in FF (n = 46) and urine (n = 45) by inductively coupled plasma mass spectrometry (ICP-MS). We used multivariable regression models to assess the impact of FF and urine trace elements on IVF outcomes, adjusted for age, body mass index, race, and cigarette smoking. RESULTS: Trace elements were mostly present at lower concentrations in FF than in urine. The average number of oocytes retrieved was positively associated with higher urine cobalt, chromium, copper, and molybdenum concentrations. FF chromium and manganese were negatively associated with the proportion of mature oocytes, yet urine manganese had a positive association. FF zinc was inversely associated with average oocyte fertilization. Urine trace elements were significant positive predictors for the total number of embryos generated. FF copper predicted lower embryo fragmentation while urine copper was associated with higher embryo cell number and urine manganese with higher embryo fragmentation. No associations were detected for implantation, pregnancy, or live birth. CONCLUSIONS: Our results suggest the importance of trace elements in both FF and urine for intermediate, although not necessarily clinical, IVF endpoints. The results differed using FF or urine biomarkers of exposure, which may have implications for the design of clinical and epidemiologic investigations. These initial findings will form the basis of a more definitive future study. PMID- 27943109 TI - Morphokinetics of vitrified and warmed blastocysts predicts implantation potential. AB - PURPOSE: It was studied whether morphokinetics of blastocoele re-expansion and hatching in vitrified-warmed blastocysts is predictive of implantation, clinical pregnancy, and live birth. METHODS: In 144 patients aiming for single warmed blastocyst transfer, blastocysts were cultured in a new time-lapse system (Miri(r) TL) immediately after warming. Video sequences with an image interval of 5 min were annotated and the corresponding morphokinetic variables were correlated with pregnancy outcome. In detail, tRE (start of re-expansion), tCRE (completion of re-expansion), tAH (hatching from the manipulated zona pellucida), and presence of collapses were recorded. RESULTS: In the pregnant group, tRE and tCRE were significantly lower (0.69 +/- 0.45 h and 2.16 +/- 0.94 h) as compared to the non-pregnant group (1.23 +/- 1.08 h and 2.70 +/- 1.20 h). Both variables and the duration of re-expansion (tCRE-tRE) allowed for distinction between "non pregnant," "loss of pregnancy," and live birth/ongoing pregnancy. Presence and number of collapses showed no correlation with outcome. CONCLUSIONS: Time-lapse imaging of vitrified-warmed blastocysts offers additional selection criteria allowing for prediction of implantation potential. As a consequence, cumulative pregnancy rate could be increased and time-to-pregnancy reduced. PMID- 27943111 TI - From theory to bench confirmation or from bench to theory. AB - In this commentary, the authors discuss two possible approaches in experimental studies. The first approach is to replicate an experimentation in order to confirm or not previously published results. The second one is more theoretical and consists in estimating the expected effect of all the components of the problem. When theoretical calculations suggest a theoretical failure that contradicts previous published results, investigators are between a rock and a hard place. Indeed, how can already published data and theoretical likelihood of failure be reconciled? PMID- 27943110 TI - Food-Borne Viruses in Shellfish: Investigation on Norovirus and HAV Presence in Apulia (SE Italy). AB - Shellfish are an important vehicle for transmission of food-borne pathogens including norovirus (NoV) and hepatitis A virus (HAV). The risks related with consumption of shellfish are greater if these products are eaten raw or slightly cooked. As molluscs are filter-feeding organisms, they are able to concentrate pathogens dispersed in the water. Data on shellfish viral contamination are therefore useful to obtain a background information on the presence of contamination in the environment, chiefly in shellfish production areas and to generate a picture of the epidemiology of viral pathogens in local populations. From January 2013 to July 2015, 253 samples of bivalve molluscs collected in harvesting areas from a large coastal tract (860 km) of Southern Italy were screened for HAV and NoV of genogroups GI and GII, using real-time reverse transcription qualitative PCR. The RNA of HAV was not detected in any of the analyzed samples. In contrast, the RNA of NoV was identified in 14.2% of the samples with a higher prevalence of NoVs of genogroup GII (12.2%) than genogroup GI (1.6%). Upon sequence analysis of a short diagnostic region located in capsid region, the NoV strains were characterized as GII.2, GII.4 Sydney 2012, GII.6, GII.13, GI.4, and GI.6, all which were circulating in local populations in the same time span. These data confirm that consumption of mussels can expose consumers to relevant risks of infection. Also, matching between the NoV genotypes circulating in local population and detected in molluscs confirms the diffusion in the environment of NoVs. PMID- 27943113 TI - Significance and clinical characteristics of atrial fibrillation post epicardial access. AB - INTRODUCTION: Epicardial access (EpiAcc) has become an important adjunct for ventricular tachycardia (VT) or premature ventricular complex (PVC) ablation. We hypothesized that post-procedural pericarditis may lead to an increased risk of atrial fibrillation (AF), and therefore assessed the incidence and clinical impact of post-procedural AF in patients undergoing EpiAcc. METHODS: We reviewed the records of all patients who underwent EpiAcc as part of an ablation procedure between January 1, 2004 and July 31, 2014 at Mayo Clinic Rochester. AF occurrence was determined by clinical documentation or electrocardiographic recordings post procedure. RESULTS: Epicardial access was obtained in 170 pts (indication 110 VT and 60 PVC). The mean age was 53 +/- 16 years and 122 (72%) were male. Seven (4.1%) patients developed AF within 7 days of the procedure, at a mean of 49 +/- 18 h post procedure; it was paroxysmal in all patients with an average duration 6.0 +/- 5.5 h (range 2-18). All patients spontaneously converted to sinus rhythm; but 3 needed rate control with AV nodal blockade (calcium channel blockers [n = 2] or beta blockers [n = 1]). One patient out of 60 who received intrapericardial steroids developed AF (2%), while of the 110 who did not receive steroids, 6 developed AF (5%) (p = 0.42). During average follow-up 2.3 years, there were no documented recurrences of atrial fibrillation in these patients. CONCLUSION: Atrial fibrillation following epicardial access is infrequent. When it occurs, it tends to be paroxysmal in nature and without severe symptoms. Administration of intrapericardial steroids did not affect the rate of AF post procedure; further studies however are needed to define their role. PMID- 27943112 TI - Efficacy and safety of uninterrupted rivaroxaban taken preoperatively for radiofrequency catheter ablation of atrial fibrillation compared to uninterrupted warfarin. AB - PURPOSE: Data on uninterrupted rivaroxaban taken preoperatively for radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) is limited. The aim was to evaluate safety and efficacy of rivaroxaban taken in the morning for AF ablation, especially with regard to asymptomatic cerebral emboli (ACE) and anticoagulation parameters. METHODS: We prospectively evaluated 147 consecutive patients who underwent RFCA (mean age 66, 110 patients with paroxysmal AF), 76 of whom were on rivaroxaban, 71 on warfarin. The drugs were continued throughout the periprocedural period, including the morning of RFCA. Heparin infusion was maintained during RFCA to achieve an activated clotting time (ACT) of >300 s. RESULTS: There were no significant differences in basic patient characteristics and ablation procedure between the two groups. ACT during the procedure correlated significantly with prothrombin time and international normalized ratio in each group (correlation coefficient 0.799 in rivaroxaban, 0.705 in warfarin, p < 0.01). D-dimer level was more elevated after RFCA in the warfarin group than in the rivaroxaban group (warfarin 0.37 +/- 0.28 to 0.67 +/- 0.81, rivaroxaban 0.41 +/- 0.33 to 0.51 +/- 0.25, p = 0.02). One major bleeding event (1.3%), a cardiac tamponade, was observed in the warfarin group. No symptomatic thromboembolic complications were observed in either group. Two patients (3%) in each group had minor bleeding, specifically, groin hematoma. Postprocedural MRI indicated ACE in 5/46 (11%) patients in the rivaroxaban group and 4/39 (10%) in the warfarin group (p = 0.99). CONCLUSIONS: Uninterrupted rivaroxaban taken preoperatively for AF ablation is clinically effective and safe. Its ACE profile is similar to warfarin. ACT is sufficient for monitoring anticoagulation. PMID- 27943114 TI - Predictors of serious arrhythmic events in patients with nonischemic heart failure. AB - PURPOSE: Risk stratification of serious arrhythmic events in patients with nonischemic heart failure (HF), beyond estimates of left ventricular ejection fraction (LVEF), remains an important clinical challenge. This study aims to determine the clinical value of different noninvasive and invasive tests as predictors of serious arrhythmic events in patients with nonischemic HF. METHODS: A prospective observational study was conducted including 106 nonischemic HF patients who underwent a comprehensive clinical and laboratory evaluation including two-dimensional echocardiography, 24-h Holter monitoring, cardiopulmonary exercise testing (CPX), and an invasive electrophysiological study. The study's primary end-point was either syncope, appropriate therapy by implantable cardioverter-defibrillators, or sudden cardiac death. RESULTS: During a mean follow-up of 704 +/- 320 days, the primary end-point occurred in 15 patients (14.2%). In multivariable analysis, LV end-diastolic diameter >73 mm (hazard ratio [HR] 3.7; p = 0.016), exercise periodic breathing (EPB) on CPX (HR 2.88; p = 0.045), and non-sustained ventricular tachycardia (NSVT) >=10 beats (HR 8.2; p < 0.01) remained independently associated with serious arrhythmic events. The positive predictive value of the presence of two of these predictors ranged from 44 to 100%. The absence of all three factors (n = 65, 61% of the sample) identified a subset of patients with low risk of future arrhythmic events, with a negative predictive value of 96.9%. CONCLUSIONS: In this cohort study of nonischemic HF patients, LV dimension, EPB, and NSVT >=10 beats were independent predictors of serious arrhythmic events. The presence or absence of these characteristics identified sub-groups of high and low risk of serious arrhythmic events, respectively. PMID- 27943115 TI - Harnessing bone marrow resident regulatory T cells to improve allogeneic stem cell transplant outcomes. AB - Regulatory T cells (Treg) are a suppressive T cell population which play a crucial role in the establishment of tolerance after stem cell transplantation (SCT) by controlling the effector T cell responses that drive acute and chronic GVHD. The BM compartment is enriched in a highly suppressive, activated/memory autophagy-dependent Treg population, which contributes to the HSC engraftment and the control of GVHD. G-CSF administration releases Treg from the BM through disruption of the CXCR4/SDF-1 axis and further improves Treg survival following SCT through the induction of autophagy. However, AMD3100 is more efficacious in mobilizing these Treg highlighting the potential for optimized mobilization regimes to produce more tolerogenic grafts. Notably, the disruption of adhesive interaction between integrins and their ligands contributes to HSC mobilization and may be relevant for BM Treg. Importantly, the Tregs in the BM niche contribute to maintenance of the HSC niche and appear required for optimal control of GVHD post-transplant. Although poorly studied, the BM Treg appear phenotypically and functionally unique to Treg in the periphery. Understanding the requirements for maintaining the enrichment, function and survival of BM Treg needs to be further investigated to improve therapeutic strategies and promote tolerance after SCT. PMID- 27943117 TI - Serum IgM levels independently predict immune response to influenza vaccine in long-term survivors vaccinated at >1 year after undergoing allogeneic hematopoietic stem cell transplantation. AB - Influenza virus infection can cause fatal complications (e.g., pneumonia) in immunodeficient long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The immune response to the vaccine improves if it is administered at >1 year after allo-HSCT, although the response may vary according to the patient's immune status. We sought to identify predictors of immune response to trivalent inactivated influenza vaccine (TIV) among patients vaccinated at >1 year after allo-HSCT. We included 27 allo-HSCT recipients, with a median interval of 4.3 years (range 1.0-10.1 years) from transplantation to vaccination. Nineteen patients achieved a response to TIV, although a low immune response to TIV was significantly associated with calcineurin inhibitor treatment, and moderate chronic graft-versus-host disease and IgM levels of <0.5 g/L at the time of vaccination. Multivariate analysis revealed that IgM levels of <0.5 g/L at the vaccination were an independent predictor of a low immune response to TIV. These results indicate that a more effective approach is needed to induce a vaccine-specific immune response among long-term survivors of allo HSCT who have low serum IgM levels. PMID- 27943116 TI - Cellular players of hematopoietic stem cell mobilization in the bone marrow niche. AB - Hematopoietic stem cells (HSC) reside in perivascular regions of the bone marrow (BM) embedded within a complex regulatory unit called the niche. Cellular components of HSC niches include vascular endothelial cells, mesenchymal stromal progenitor cells and a variety of mature hematopoietic cells such as macrophages, neutrophils, and megakaryocytes-further regulated by sympathetic nerves and complement components as described in this review. Three decades ago the discovery that cytokines induce a large number of HSC to mobilize from the BM into the blood where they are easily harvested, revolutionised the field of HSC transplantation-curative for immune-deficiencies and some malignancies. However, despite now routine use of granulocyte-colony stimulating factor (G-CSF) to mobilise HSC for transplant, only in last 15 years has research on the mechanisms behind why and how HSC can be induced to move into the blood began. These studies have revealed the complexity of the niche that retains HSC in the BM. This review describes how BM niches and HSC themselves change during administration of G-CSF or in the recovery phase of chemotherapy-to facilitate movement of HSC into the blood, and research now leading to development of novel therapeutics to further boost HSC mobilization and transplant success. PMID- 27943118 TI - Hospitalization Costs for Patients Undergoing Orthopedic Surgery Treated With Intravenous Acetaminophen (IV-APAP) Plus Other IV Analgesics or IV Opioid Monotherapy for Postoperative Pain. AB - INTRODUCTION: To assess the impact on hospitalization costs of multimodal analgesia (MMA), including intravenous acetaminophen (IV-APAP), versus IV opioid monotherapy for postoperative pain management in patients undergoing orthopedic surgery. METHODS: Utilizing the Truven Health MarketScan(r) Hospital Drug Database (HDD), patients undergoing total knee arthroplasty (TKA), total hip arthroplasty (THA), or surgical repair of hip fracture between 1/1/2011 and 8/31/2014 were separated into postoperative pain management groups: MMA with IV APAP plus other IV analgesics (IV-APAP group) or an IV opioid monotherapy group. All patients could have received oral analgesics. Baseline characteristics and total hospitalization costs were compared. Additionally, an inverse probability treatment weighting [IPTW] with propensity scores analysis further assessed hospitalization cost differences. RESULTS: The IV-APAP group (n = 33,954) and IV opioid monotherapy group (n = 110,300) differed significantly (P < 0.0001) across baseline characteristics, though the differences may not have been clinically meaningful. Total hospitalization costs (mean +/- standard deviation) were significantly lower for the IV-APAP group than the IV opioid monotherapy group (US$12,540 +/- $9564 vs. $13,242 +/- $35,825; P < 0.0001). Medical costs accounted for $701 of the $702 between-group difference. Pharmacy costs were similar between groups. Results of the IPTW-adjusted analysis further supported the statistically significant cost difference. CONCLUSIONS: Patients undergoing orthopedic surgery who received MMA for postoperative pain management, including IV-APAP, had significantly lower total costs than patients who received IV opioid monotherapy. This difference was driven by medical costs; importantly, there was no difference in pharmacy costs. Generalizability of the results may be limited to patients admitted to hospitals similar to those included in HDD. Dosing could not be determined, so it was not possible to quantify utilization of IV-APAP or ascertain differences in opioid consumption between the 2 groups. This study did not account for healthcare utilization post-discharge. PMID- 27943119 TI - Reconsidering alternative transportation systems to reach academic conferences and to convey an example to reduce greenhouse gas emissions. AB - Scientists are typically responsible for greater greenhouse gas emissions than the general population. These 'extra' emissions are largely due to frequent travel, often by airplane, to professional and academic meetings. In the following commentary, we explore how employing mixed modes of transportation, particularly by prioritizing train travel, can significantly reduce the environmental costs associated with attending conferences. Estimating travel distances for attendants to recent meetings, we demonstrate that the proposed strategy has the potential to decrease emissions, even when considering exotic, remote (and potentially enticing) locations. Our suggestions are easy to implement, can be combined with previous proposals for reducing emissions, and provide an opportunity for scientists to convey an important message to the general public. This message is not confined to our particular example and we hope that it will encourage ecologists, sociologists and other scientists, historians and philosophers to pursue additional creative behavioural solutions in order to reduce our impact on an increasingly stressed ecosphere. PMID- 27943121 TI - The effects of the binocular disparity differences between targets and maskers on visual search. AB - A visual search for targets is facilitated when the target objects are on a different depth plane than other masking objects cluttering the scene. The ability of observers to determine whether one of four letters presented stereoscopically at four symmetrically located positions on the fixation plane differed from the other three was assessed when the target letters were masked by other randomly positioned and oriented letters appearing on the same depth plane as the target letters, or in front, or behind it. Three additional control maskers, derived from the letter maskers, were also presented on the same three depth planes: (1) random-phase maskers (same spectral amplitude composition as the letter masker but with the phase spectrum randomized); (2) random-pixel maskers (the locations of the letter maskers' pixel amplitudes were randomized); (3) letter-fragment maskers (the same letters as in the letter masker but broken up into fragments). Performance improved with target duration when the target letter plane was in front of the letter-masker plane, but not when the target letters were on the same plane as the masker, or behind it. A comparison of the results for the four different kinds of maskers indicated that maskers consisting of recognizable objects (letters or letter fragments) interfere more with search and comparison judgments than do visual noise maskers having the same spatial frequency profile and contrast. In addition, performance was poorer for letter maskers than for letter-masker fragments, suggesting that the letter maskers interfered more with performance than the letter-fragment maskers because of the lexical activity they elicit. PMID- 27943120 TI - Polycyclic aromatic hydrocarbons and PAH-related DNA adducts. AB - Investigations on the impact of chemicals on the environment and human health have led to the development of an exposome concept. The exposome refers to the totality of exposures received by a person during life, including exposures to life-style factors, from the prenatal period to death. The exposure to genotoxic chemicals and their reactive metabolites can induce chemical modifications of DNA, such as, for example, DNA adducts, which have been extensively studied and which play a key role in chemically induced carcinogenesis. Development of different methods for the identification of DNA adducts has led to adopting DNA adductomic approaches. The ability to simultaneously detect multiple PAH-derived DNA adducts may allow for the improved assessment of exposure, and offer a mechanistic insight into the carcinogenic process following exposure to PAH mixtures. The major advantage of measuring chemical-specific DNA adducts is the assessment of a biologically effective dose. This review provides information about the occurrence of the polycyclic aromatic hydrocarbons (PAHs) and their influence on human exposure and biological effects, including PAH-derived DNA adduct formation and repair processes. Selected methods used for determination of DNA adducts have been presented. PMID- 27943123 TI - Formulation and Delivery of Macromolecules. PMID- 27943122 TI - Shikonin inhibits TNF-alpha production through suppressing PKC-NF-kappaB dependent decrease of IL-10 in rheumatoid arthritis-like cell model. AB - Shikonin, a major effective component in the Chinese herbal medicine Lithospermum erythrorhizon Sieb., exhibits an anti-inflammatory property towards rheumatoid arthritis (RA), but the potential mechanism is unclear. Our aim was to investigate the mechanism of shikonin on the lipopolysaccharide (LPS)-induced fibroblast-like synoviocyte (LiFLS) inflammation model. Fibroblast-like synoviocytes (FLSs) were treated with 200 MUg/ml of LPS for 24 h to establish the RA-like model, LiFLS. FLSs were pretreated with shikonin (0.1-1 MUM) for 30 min in the treatment groups. Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays were used to detect mRNA and protein levels of interleukin (IL)-10 and tumor necrosis factor (TNF)-alpha. Signal proteins involved in IL-10 production were analyzed by Western blotting. Shikonin significantly reversed the inhibitory effects of LPS on IL-10 expression in FLSs by inactivating the PKC-NF-kappaB pathway. In addition, shikonin inhibited LPS induced TNF-alpha expression in FLSs, and this effect was markedly diminished by IL-10-neutralizing antibody. The IL-10-mediated suppression of TNF-alpha transcription was demonstrated by no response to the protein synthesis inhibitor cyclohexamide and no mRNA decay. Shikonin inhibits LPS-induced TNF-alpha production in FLSs through suppressing the PKC-NF-kappaB-dependent decrease in IL 10, and this study also highlights the potential application of shikonin in the treatment of RA. PMID- 27943124 TI - Probing the Gaseous Structure of a beta-Hairpin Peptide with H/D Exchange and Electron Capture Dissociation. AB - An improved understanding of the extent to which native protein structure is retained upon transfer to the gas phase promises to enhance biological mass spectrometry, potentially streamlining workflows and providing fundamental insights into hydration effects. Here, we investigate the gaseous conformation of a model beta-hairpin peptide using gas-phase hydrogen-deuterium (H/D) exchange with subsequent electron capture dissociation (ECD). Global gas-phase H/D exchange levels, and residue-specific exchange levels derived from ECD data, are compared among the wild type 16-residue peptide GB1p and several variants. High protection from H/D exchange observed for GB1p, but not for a truncated version, is consistent with the retention of secondary structure of GB1p in the gas phase or its refolding into some other compact structure. Four alanine mutants that destabilize the hairpin in solution show levels of protection similar to that of GB1p, suggesting collapse or (re)folding of these peptides upon transfer to the gas phase. These results offer a starting point from which to understand how a key secondary structural element, the beta-hairpin, is affected by transfer to the gas phase. This work also demonstrates the utility of a much-needed addition to the tool set that is currently available for the investigation of the gaseous conformation of biomolecules, which can be employed in the future to better characterize gaseous proteins and protein complexes. Graphical Abstract ?. PMID- 27943125 TI - Identifying High-Risk Medications Associated with Acute Kidney Injury in Critically Ill Patients: A Pharmacoepidemiologic Evaluation. AB - BACKGROUND: Nephrotoxic medications are a common cause of acute kidney injury (AKI). Critically ill children receive more medication than other inpatients; however, the risk of nephrotoxic medication-induced AKI in these children is not well understood. OBJECTIVE: The aim of this study was to determine the association between exposure to nephrotoxic medications in the intensive care unit (ICU) and the development of AKI amongst critically ill children, adjusting for differences in underlying risk. METHODS: We conducted a nested case-control study among a cohort of patients admitted to a paediatric intensive care unit between January 2006 and June 2009. Cases were identified according to the RIFLE criteria. Using incidence density sampling, controls were matched 1:1 according to pre-ICU nephrotoxic drug exposure. Administration of nephrotoxic medications and other known risk factors of AKI were evaluated during the ICU stay prior to the diagnosis of AKI. RESULTS: A total of 914 patients in the cohort developed AKI and had an identifiable matched control. Eighty-seven percent of cases and 74% of controls were exposed to one or more nephrotoxic medications in the ICU during the study period. Furosemide (administered to 67.8% of patients), vancomycin (28.7%), and gentamicin (21.4%) were the most frequently administered nephrotoxic drugs. Patients who developed AKI were more likely to be exposed to at least one nephrotoxic medication and risk increased with increasing number of nephrotoxic medications. Ganciclovir (adjusted odds ratio [AOR] 4.7; 95% CI 1.7 13.0), furosemide (AOR 1.9; 95% CI 1.4-2.4), and gentamicin (AOR 1.8; 95% CI 1.4 2.4) significantly increased the odds of developing AKI after adjusting for underlying differences in risk factors of AKI. CONCLUSION: This is the first study to assess the association between risk-adjusted nephrotoxic medication exposure and the development of AKI in critically ill children. Nephrotoxic medication exposure was common amongst children in the ICU and we found AKI was associated with the administration of specific drugs after adjustment for important risk factors. PMID- 27943126 TI - Effects of temperature-humidity index on health and growth performance in Japanese black calves. AB - We evaluated the relationship between the temperature-humidity index (THI) and health and growth performance in Japanese black calves in Japan. Data were collected from medical records of 19,313 Japanese black calves aged up to 3 months for correlation analysis with THI from July 2008 to June 2011. Data were also collected on the market weights of 57,144 Japanese black calves, and we calculated the body weight gain (BWG) of each calf based on body weight and age in days at the calf market. Analysis for the relationship between disease incidence and THI demonstrated a negative correlation (r = -0.54, p < 0.01). In addition, the mean disease incidence at THI of <=50 was significantly higher than that at THI of >=71. Analysis for the relationship between growth performance in calves and THI revealed that a lower THI during the month of birth was associated with a lower BWG at the calf market and that BWG with THI of <=70 was significantly lower than that with THI of >=71 (p < 0.05). In contrast, a higher mean THI during the third month after birth was associated with a lower BWG at the calf market, and BWG with THI of >75 was significantly lower than that with THI of <=50 or THI ranging from 56 to 60 (p < 0.05). These results indicate that Japanese black calves are susceptible to a cold environment immediately after birth, whereas they are susceptible to a heat environment 3 months after birth. PMID- 27943127 TI - Prescription of anti-osteoporosis medications after hospitalization for hip fracture: a multicentre Italian survey. AB - PURPOSE: Literature data indicate that the proportion of patients with recent hip fracture who receive a prescription for anti-osteoporotic drugs is low and does not seem to increase over time. This study aimed to obtain data on the prescription for anti-osteoporotic drugs in Italian patients discharged after a recent hip fracture and to assess which variables could have influenced the decision for prescribing osteoporosis medication. METHODS: A total of four Italian centres located in four different geographical areas (Siena, Verona, Naples and Palermo) participated in this retrospective study. In each centre, experienced clinicians gathered the data of up to 200 consecutive patients discharged after a recent low-trauma hip fracture. The analysis was carried out on 697 patients (540 women and 157 men; mean age 81.9 +/- 8.6 years). RESULTS: The percentage of patients who were receiving any type of treatment for osteoporosis before the hip fracture was 8.8% (ranging from 2.4% in Naples to 17.4% in Verona). After the index hip fracture, only 23.2% of patients (namely 10.5% of men and 27.2% of women) received prescription for any pharmacological treatments for osteoporosis. Both female gender and previous use of medications for osteoporosis were positively associated with the likelihood of receiving prescription for anti-osteoporotic treatment at discharge. CONCLUSIONS: This study showed that less than 25% of the elderly Italian patients discharged after a hip fracture received a prescription for any type of treatment for osteoporosis and highlights the urgent need for implementing new strategies in the management of hip fracture patients. PMID- 27943128 TI - Psychotherapy by Psychiatrists: Why Choose a Bugle When You Can Play the Trumpet? PMID- 27943129 TI - Improving Health Equity Through Minority Psychiatry Trainees: One Journey to Becoming an Academic Psychiatrist of Indigenous Ancestry. PMID- 27943130 TI - Altmetrics for Medical Educators. PMID- 27943131 TI - Knowledge and Attitude Towards Pharmacological Management of Acute Agitation: A Survey of Psychiatrists, Psychiatry Residents, and Psychiatric Nurses. AB - OBJECTIVE: The authors compared the current knowledge and attitude of psychiatrists, psychiatry residents, and psychiatric nurses towards the pharmacological management of acute agitation. METHODS: Questionnaires were electronically distributed to all attending psychiatrists, psychiatry residents, and psychiatric nurses who were either employed by the University Department of Psychiatry and Behavioral Sciences or were staff at a 250-bed affiliated Psychiatric Hospital. Where possible, Fisher's exact test was used to compare responses to questions based on designation. RESULTS: Of the 250 questionnaires distributed, 112 were returned (response rate of 44.8%), of which 64 (57.1%) were psychiatric nurses, 27 (24.1%) were attending psychiatrists, and 21 (18.8%) were psychiatry residents. A significantly higher percentage of attending psychiatrists and psychiatric nurses compared to psychiatry residents thought that newer second- generation antipsychotics (SGAs) are not as effective as older first-generation antipsychotics (FGAs) for managing acute agitation (55.6, 48.4, and 9.5% respectively, p = 0.008). The combination of intramuscular haloperidol, lorazepam, and diphenhydramine was the most preferred option chosen by all designations for the psychopharmacological management of severe agitation. Furthermore, a larger percentage of the psychiatric nurses, in comparison to attending psychiatrists, also chose the combination of intramuscular chlorpromazine, lorazepam, and diphenhydramine as an option for managing severe agitation; no psychiatry resident chose this option. CONCLUSION: Knowledge of evidence-based psychopharmacological management of agitation differs among attending psychiatrists, psychiatry residents and psychiatric nurses. Although the management of agitation should be individualized and context specific, monotherapy should be considered first where applicable. PMID- 27943132 TI - New Non-Intravenous Routes for Benzodiazepines in Epilepsy: A Clinician Perspective. AB - Benzodiazepines represent the first-line treatment for the acute management of epileptic seizures and status epilepticus. The emergency use of benzodiazepines must be timely, and because most seizures occur outside of the hospital environment, there is a significant need for delivery methods that are easy for nonclinical caregivers to use and administer quickly and safely. In addition, the ideal route of administration should be reliable in terms of absorption. Rectal diazepam is the only licensed formulation in the USA, whereas rectal diazepam and buccal midazolam are currently licensed in the EU. However, the sometimes unpredictable absorption with rectal and buccal administration means they are not ideal routes. Several alternative routes are currently being explored. This is a narrative review of data about delivery methods for benzodiazepines alternative to the intravenous and oral routes for the acute treatment of seizures. Unconventional delivery options such as direct delivery to the central nervous system or inhalers are reported. Data show that intranasal diazepam or midazolam and the intramuscular auto-injector for midazolam are as effective as rectal or intravenous diazepam. Head-to-head comparisons with buccal midazolam are urgently needed. In addition, the majority of trials focused on children and adolescents, and further trials in adults are warranted. PMID- 27943133 TI - Targeting Functional Impairments in the Treatment of Children and Adolescents with ADHD. AB - The diagnostic criteria for attention-deficit hyperactivity disorder (ADHD) require both symptoms and impairment to be present. Impairment in functioning is commonly the primary reason for referral, and is also a better predictor of long term outcomes than ADHD symptoms. And yet, only recently has research begun to examine the impact of ADHD treatments on functional impairment using efficient and psychometrically sound outcome measures. In this article, we identify several noteworthy multidimensional measures of functional impairment (ADHD FX, Barkley Functional Impairment Scale [BFIS], Impairment Rating Scale [IRS], Weiss Functional Impairment Rating Scale [WFIRS]) utilized in recent clinical trials for ADHD, and describe their psychometric properties and clinical utility. We also review existing evidence on the impact of pharmacological and behavioral treatments on different domains of functional impairment in ADHD youth as measured by these specific measures. Further research is needed to evaluate longitudinal effects of ADHD treatments on functional impairment, and the use of these measures in adaptive treatment designs. PMID- 27943134 TI - Cooling dynamics: a new predictor of long-term efficacy of atrioventricular nodal reentrant tachycardia cryoablation. AB - PURPOSE: Catheter ablation of the slow pathway is the most effective treatment for atrioventricular nodal reentrant tachycardia (AVNRT). Cryoenergy, compared to radiofrequency, relates to lower heart block risk but higher incidence of AVNRT recurrences. The aims of this study are to confirm the safety and efficacy of AVNRT cryoablation and to identify predictors of long-term recurrences. METHODS: Among 241 patients undergoing AVNRT cryoablation, 239 (99.2%) experienced acute effective cryoablation of the slow pathway, and no procedure-related complications were reported. RESULTS: After a follow-up of 44.9 +/- 31.7 months, 28 (11.7%) patients presented AVNRT recurrences. A shorter preablation (p = 0.05) and postablation anterograde Wenckebach cycle length (p < 0.01), a shorter postablation atrioventricular node refractory period (p = 0.04), and persistence of the crossover sign (p = 0.03) were associated with higher incidence of long term recurrences. Considering cooling dynamics, a longer time to reach temperature <=-70 degrees C (p = 0.03) and a higher minimal temperature during ablation (p = 0.04) were related to recurrences. Patients without residual markers of dual AV node physiology (AH jump, single atrial echo beat, crossover) reported a lower recurrence rate (p = 0.05) compared to those without. At multivariate analysis, a longer time to -70 degrees C was the strongest independent predictor of long-term recurrence (OR 1.75, 95% CI 1.01-3.03, p = 0.04). CONCLUSIONS: AVNRT cryoablation is safe and effective. Long-term recurrence rate was 11.7%. An ablation approach directed to the complete elimination of dual AV node physiology, along with assessment of the tissue's cooling dynamics, holds the potential to improve long-term AVNRT cryoablation efficacy. PMID- 27943135 TI - Degarelix for Treating Advanced Hormone-Dependent Prostate Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - As part of its Single Technology Appraisal Process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of degarelix (Ferring Pharmaceuticals) to submit evidence for the clinical and cost effectiveness of degarelix for the treatment of advanced hormone-dependent prostate cancer. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence contained within the company's submission to NICE. The evidence, which included a randomised controlled trial (RCT) of degarelix versus leuprorelin, found that degarelix was non-inferior to leuprorelin for reduction of testosterone levels and that degarelix achieved a more rapid suppression of prostate-specific antigen levels and subsequently decreased incidences of testosterone flare associated with luteinising hormone releasing-hormone (LHRH) agonists. However, protection against testosterone flare for the comparators in the clinical trials was not employed in line with UK clinical practice. Further claims surrounding overall survival, cardiovascular adverse events and clinical equivalence of the comparator drugs from six RCTs of degarelix should be regarded with caution because of flaws and inconsistencies in the pooling of trial data to draw conclusions. The cost-effectiveness evidence included a de novo economic model. Based on the ERG's preferred base case, the deterministic incremental cost effectiveness analysis (ICER) for degarelix versus 3-monthly triptorelin was L14,798 per quality-adjusted life-year (QALY) gained. Additional scenario analyses undertaken by the ERG resulted in ICERs for degarelix versus 3-monthly triptorelin ranging from L17,067 to L35,589 per QALY gained. Subgroup analyses undertaken using the Appraisal Committee's preferred assumptions suggested that degarelix was not cost effective for the subgroup with metastatic disease but could be cost effective for the subgroup with spinal metastases. The company submitted further evidence to NICE following an initial negative Appraisal Committee decision. Further analyses from the Decision Support Unit found that that, whilst some evidence indicated that degarelix could be cost effective for a small subgroup of people with spinal cord compression (SCC), data on the potential size of this subgroup and the rate of SCC were insufficient to estimate an ICER based on the evidence submitted by the company and a separately commissioned systematic review. NICE recommended degarelix as an option for treating advanced hormone-dependent prostate cancer in people with spinal metastases, only if the commissioner can achieve at least the same discounted drug cost as that available to the UK NHS in June 2016. PMID- 27943136 TI - g-C3N4-promoted degradation of ofloxacin antibiotic in natural waters under simulated sunlight. AB - This is the first report on the photodegradation of ofloxacin under simulated solar light and in actual environmental matrices in the presence of a g-C3N4 suspension. The catalyst, prepared from the polymerization of dicyandiamide (650 degrees C, reaction yield 60%), was characterized by means of powder X-ray diffraction (PXRD), UV-vis diffuse reflectance spectroscopy (DRS), scanning electron microscopy (SEM), and BET surface area measurements. The experiments were carried out in a lab-scale batch reactor at concentrations in the range of micrograms/milligrams per liter. The course of the reaction was monitored by high pressure liquid chromatography with UV-vis and fluorescence detectors. The g-C3N4 promoted photodegradation occurred at a rate 10 times faster than the direct photolysis and obeyed a first-order kinetics; in addition, the photodegradation kinetics of sonicated g-C3N4 resulted to be of the same order of that caused by P25 TiO2. Finally, the photochemical paths and the photoproducts have been identified and compared to those obtained by using P25 TiO2. From the results of this study, it can be concluded that g-C3N4 is a very attractive photocatalyst compared to P25 TiO2 in view of its ease of preparation, low cost, excellent oxidizing properties, large fraction of solar radiation absorbed, and intrinsically layered structure. PMID- 27943137 TI - The characteristics of BTEX concentration in various types of environment in the Baltic Sea Region, Lithuania. AB - Benzene, toluene, ethylbenzene and xylene (BTEX) form an important group of volatile organic compounds (VOCs) affecting troposphere and posing risk to human health. The article examines the Mazeikiai area in the northern part of Lithuania where one of the largest Central European companies and the only oil refinery in the Baltic region (200,000 barrels/day) are close to the Baltic Sea. The research carried out mainly focuses on the following objectives: quantitative assessment of the amounts of BTEX occurring in the impact zone of the oil refinery and transport; estimation of background BTEX concentrations in the region; establishing the main sources of BTEX in the region researched and evaluation of impact of meteorological parameters on BTEX concentrations in different seasons. The passive measurement method was used for analysing VOCs (benzene (C6H6), toluene (C7H8), ethylbenzene (C8H10) and ortho-, meta- para-xylene (C8H10)). The research was carried out in 2010-2012. Its results showed that the average annual concentration of benzene was below the threshold value of 5 MUg/m3. Within the measurement period, the average concentration of benzene fluctuated from 1.2 to 2.4 MUg/m3, that of toluene varied from 1.3 to 3.5 MUg/m3, that of ethylbenzene varied from 0.3 to 0.7 MUg/m3 and that of xylene (calculated as para-, meta- and ortho-xylene) varied from 1.0 to 2.4 MUg/m3. Compared to the established BTEX concentration, the actual background BTEX concentration in the urban area is two times higher. The seasonal analysis suggests that the highest values of benzene concentration are observed in the winter season. PMID- 27943138 TI - Assessment of trace metal concentrations and human health risk in clam (Tapes decussatus) and mussel (Mytilus galloprovincialis) from the Homa Lagoon (Eastern Aegean Sea). AB - Seasonal variations of trace metal concentrations (Hg, Cd, Pb, Cr, Zn, and Cu) were investigated in the hepatopancreas and soft tissues (remaining parts of bivalves such as gill, mantle, foot, and muscle) of Tapes decussatus and Mytilus galloprovincialis from the Homa Lagoon. The highest metal concentrations were recorded frequently in February and July in M. galloprovincialis and T. decussatus, respectively. Trace metal levels (except Zn) in the hepatopancreas were higher than those in soft tissue for both bivalves. The results showed that the mean concentrations of Hg, Cd, and Zn for M. galloprovincialis were higher compared to T. decussatus in both tissues. The metal concentrations in both bivalves from the Homa Lagoon were generally below the values of provisional tolerable weekly intake (PTWI) estimates, in terms of human health risk. According to hazard quotient (HQ), Cr values for both species and Cd values for only M. galloprovincialis were found greater than one. Also, total hazard index (THI) values were greater than one in both bivalves, having a potential risk for consumers. PMID- 27943139 TI - Analytical transport modelling of metabolites formed in dual-porosity media. AB - Contaminants like nitroaromatic compounds can be degraded in the subsurface to similar or even more toxic metabolites. Degradation or transformation rates are dependent on physical, chemical and biological properties which can be different in sedimentological layers or other heterogeneous structures of aquifers. Sediments with low hydraulic conductivity can even consist of immobile water. These regions are only accessible by diffusion. Most modelling approaches accounting for immobile water regions focused on the mathematical description of the transport and decay of the parent compound. The objective of this study was to develop an analytical model to quantify the transport and formation of a metabolite in dual-porosity media describing the exchange between mobile and immobile water regions based on the metabolite's diffusion coefficient. Column experiments with a well-defined immobile water region were performed under anoxic conditions at three different water flow velocities. The model compound 4-Cl nitrobenzene was reduced to 4-Cl-aniline (4-Cl-An) by surface-bound Fe (II) species within the immobile water region. Transport and formation of the metabolite were quantified with a modified solution of the single fissure dispersion model assuming additionally for the region with immobile water first order metabolite production, irreversible sorption and an instantaneous equilibrium sorption. The number of unknown fitting parameters was reduced to two (sorption rate and retardation factor) by stepwise parameter estimation using tracer and parent compound data. Experimental results of the metabolite for each water flow velocity were successfully described with a first-order production term (lambda prod = 1.51 +/- 0.08 h-1), retardation factor (R im = 2.94 +/- 0.45) and first-order irreversible sorption rate (K im = 0.39 +/- 0.16 h-1) within the immobile water region. Model results supported that 4-Cl-An was formed within the immobile water region. 4-Cl-An sorbed instantaneously onto the clay matrix while a fraction was irreversibly sorbed. Experimental results and the provided analytical solution help to improve the understanding about reactive transport and the formation of metabolites in dual-porosity media. PMID- 27943140 TI - Ignored fungal community in activated sludge wastewater treatment plants: diversity and altitudinal characteristics. AB - Fungi are important contributors to the various functions of activated sludge wastewater treatment plants (WWTPs); however, the diversity and geographic characteristics of fungal populations have remained vastly unexplored. Here, quantitative polymerase chain reaction and 454 pyrosequencing were combined to investigate the abundance and diversity of the activated sludge fungal communities from 18 full-scale municipal WWTPs in China. Phylogenetic taxonomy revealed that the members of the fungal communities were assigned to 7 phyla and 195 genera. Ascomycota and Basidiomycota were the most abundant phyla, dominated by Pluteus, Wickerhamiella, and Penicillium. Twenty-three fungal genera, accounting for 50.1 % of the total reads, were shared by 18 WWTPs and constituted a core fungal community. The fungal communities presented similar community diversity but different community structures across the WWTPs. Significant distance decay relationships were observed for the dissimilarity in fungal community structure and altitudinal distance between WWTPs. Additionally, the community evenness increased from 0.25 to 0.7 as the altitude increased. Dissolved oxygen and the C/N ratio were determined to be the most dominant contributors to the variation in fungal community structure via redundancy analysis. The observed data demonstrated the diverse occurrence of fungal species and gave a marked view of fungal community characteristics based on the previously unexplored fungal communities in activated sludge WWTPs. PMID- 27943141 TI - Spatial variation of air quality index and urban driving factors linkages: evidence from Chinese cities. AB - Daily air quality index (AQI) of 161 Chinese cities obtained from the Ministry of Environmental Protection of China in 2015 is conducted. In this study, to better explore spatial distribution and regional characteristic of AQI, global and local spatial autocorrelation is utilized. Pearson's correlation is introduced to determine the influence of single urban indicator on AQI value. Meanwhile, multiple linear stepwise regression is chosen to estimate quantitatively the most influential urban indicators on AQI. The spatial autocorrelation analysis indicates that the AQI value of Chinese 161 cities shows a spatial dependency. Higher AQI is mainly located in north and northwest regions, whereas low AQI is concentrated in the south and the Qinghai-Tibet regions. The low AQI and high AQI values in China both exhibit relative immobility through seasonal variation. The influence degree of three adverse urban driving factors on AQI value is ranked from high to low: coal consumption of manufacturing > building area > coal consumption of the power industry. It is worth noting that the risk of exposed population to poor quality is greater in the northern region than in other regions. The results of the study provide a reference for the formulation of urban policy and improvement of air quality in China. PMID- 27943142 TI - Research on the influencing factors of reverse logistics carbon footprint under sustainable development. AB - With the concerns of ecological and circular economy along with sustainable development, reverse logistics has attracted the attention of enterprise. How to achieve sustainable development of reverse logistics has important practical significance of enhancing low carbon competitiveness. In this paper, the system boundary of reverse logistics carbon footprint is presented. Following the measurement of reverse logistics carbon footprint and reverse logistics carbon capacity is provided. The influencing factors of reverse logistics carbon footprint are classified into five parts such as intensity of reverse logistics, energy structure, energy efficiency, reverse logistics output, and product remanufacturing rate. The quantitative research methodology using ADF test, Johansen co-integration test, and impulse response is utilized to interpret the relationship between reverse logistics carbon footprint and the influencing factors more accurately. This research finds that energy efficiency, energy structure, and product remanufacturing rate are more capable of inhibiting reverse logistics carbon footprint. The statistical approaches will help practitioners in this field to structure their reverse logistics activities and also help academics in developing better decision models to reduce reverse logistics carbon footprint. PMID- 27943143 TI - Heterogeneous nano-Fe/Ca/CaO catalytic ozonation for selective surface hydrophilization of plastics containing brominated and chlorinated flame retardants (B/CFRs): separation from automobile shredder residue by froth flotation. AB - One method of weakening the inherently hydrophobic surface of plastics relevant to flotation separation is heterogeneous nano-Fe/Ca/CaO catalytic ozonation. Nano Fe/Ca/CaO-catalyzed ozonation for 15 min efficiently decreases the surface hydrophobicity of brominated and chlorinated flame retardant (B/CFR)-containing plastics (such as acrylonitrile-butadienestyrene (ABS), high-impact polystyrene (HIPS), and polyvinyl chloride (PVC)) in automobile shredder residue (ASR) to such an extent that their flotation ability is entirely depressed. Such a hydrophilization treatment also stimulates the ABS, HIPS, and PVC surface roughness, wetting of the surface, and the thermodynamic equilibrium conditions at the surface and ultimately changes surface polarity. SEM-EDS, AFM, and XPS analyses of the PVC and ABS surfaces demonstrated a marked decrease in [Cl/Br] and a significant increase in the number of hydrophilic groups, such as C-O, C=O, and (C=O)-O. Under froth flotation conditions at 50 rpm, about 99.5 % of ABS and 99.5 % of HIPS in ASR samples settled out, resulting in a purity of 98 and 98.5 % for ABS and HIPS in ASR samples, respectively. Furthermore, at 150 rpm, we also obtained 100 % PVC separation in the settled fraction, with 98 % purity in ASR. Total recovery of non-B/CFR-containing plastics reached nearly 100 % in the floating fraction. The amount of nano-Fe/Ca/CaO reagent employed during ozonation is very small, and additional removal of surface contaminants from the recycled ASR plastic surfaces by ozonation makes the developed process simpler, greener, and more effective. PMID- 27943144 TI - Tropospheric ozone pollution in India: effects on crop yield and product quality. AB - Ozone (O3) in troposphere is the most critical secondary air pollutant, and being phytotoxic causes substantial losses to agricultural productivity. Its increasing concentration in India particularly in Indo-Gangetic plains is an issue of major concern as it is posing a threat to agriculture. In view of the issue of rising surface level of O3 in India, the aim of this compilation is to present the past and the prevailing concentrations of O3 and its important precursor (oxides of nitrogen) over the Indian region. The resulting magnitude of reductions in crop productivity as well as alteration in the quality of the product attributable to tropospheric O3 has also been taken up. Studies in relation to yield measurements have been conducted predominantly in open top chambers (OTCs) and also assessed by using antiozonant ethylene diurea (EDU). There is a substantial spatial difference in O3 distribution at different places displaying variable O3 concentrations due to seasonal and geographical variations. This review further recognizes the major information lacuna and also highlights future perspectives to get the grips with rising trend of ground level O3 pollution and also to formulate the policies to check the emissions of O3 precursors in India. PMID- 27943145 TI - Novel aerosol analysis approach for characterization of nanoparticulate matter in snow. AB - Tropospheric aerosols are involved in several key atmospheric processes: from ice nucleation, cloud formation, and precipitation to weather and climate. The impact of aerosols on these atmospheric processes depends on the chemical and physical characteristics of aerosol particles, and these characteristics are still largely uncertain. In this study, we developed a system for processing and aerosolization of melted snow in particle-free air, coupled with a real-time measurement of aerosol size distributions. The newly developed technique involves bringing snow borne particles into an airborne state, which enables application of high resolution aerosol analysis and sampling techniques. This novel analytical approach was compared to a variety of complementary existing analytical methods as applied for characterization of snow samples from remote sites in Alert (Canada) and Barrow (USA), as well as urban Montreal (Canada). The dry aerosol measurements indicated a higher abundance of particles of all sizes, and the 30 nm size dominated in aerosol size distributions for the Montreal samples, closely followed by Barrow, with about 30% fewer 30 nm particles, and about four times lower 30 nm particle abundance in Alert samples, where 15 nm particles were most abundant instead. The aerosolization technique, used together with nanoparticle tracking analysis and electron microscopy, allowed measurement of a wide size range of snow-borne particles in various environmental snow samples. Here, we discuss the application of the new technique to achieve better physicochemical understanding of atmospheric and snow processes. The results showed high sensitivity and reduction of particle aggregation, as well as the ability to measure a high-resolution snow-borne particle size distribution, including nanoparticulate matter in the range of 10 to 100 nm. PMID- 27943146 TI - Retrospective Study of Patients Switched from Tablet Formulations to a Gel Cap Formulation of Levothyroxine: Results of the CONTROL Switch Study. AB - INTRODUCTION: Medication changes involving levothyroxine-either dose titrations or switching formulations-occur frequently in patients with erratic thyroid stimulating hormone (TSH) levels and persistent hypothyroid symptoms. We investigated whether switching patients from levothyroxine tablets to a gel cap formulation of levothyroxine might reduce dose adjustments and improve tolerability and efficacy outcomes. OBJECTIVES: Primary study objectives included quantifying the percentage of patients achieving TSH levels within a pre specified range, median dose changes experienced, and the percentage of patients with improved hypothyroid symptom control after switching from levothyroxine tablets to levothyroxine gel caps. METHODS: A retrospective medical chart review was conducted among 99 randomly selected hypothyroid patients who were switched from a tablet to a gel cap formulation of levothyroxine. Patients were required to have been on levothyroxine monotherapy for >=1 year prior to the medication switch. Data was collected for 6 months pre-switch and up to 6 months post switch. RESULTS: Of the 99 patients studied, the majority (51.5%) experienced no documented change in TSH status after the switch (P < 0.0001). However, there was a decrease in the mean number of dose changes experienced (1.61 +/- 0.96 vs. 0.73 +/- 0.96; P < 0.0001). Improved hypothyroid symptom control was reported among 61.6% of patients (61 of 99; P < 0.0001). CONCLUSION: The results of CONTROL Switch support a strategy of switching patients who may experience tolerability or efficacy problems with standard levothyroxine tablets to the levothyroxine gel cap formulation. PMID- 27943147 TI - Sedentary Time and Physical Activity Surveillance Through Accelerometer Pooling in Four European Countries. AB - OBJECTIVE: The objective of this study was to pool, harmonise and re-analyse national accelerometer data from adults in four European countries in order to describe population levels of sedentary time and physical inactivity. METHODS: Five cross-sectional studies were included from England, Portugal, Norway and Sweden. ActiGraph accelerometer count data were centrally processed using the same algorithms. Multivariable logistic regression analyses were conducted to study the associations of sedentary time and physical inactivity with sex, age, weight status and educational level, in both the pooled sample and the separate study samples. RESULTS: Data from 9509 participants were used. On average, participants were sedentary for 530 min/day, and accumulated 36 min/day of moderate to vigorous intensity physical activity. Twenty-three percent accumulated more than 10 h of sedentary time/day, and 72% did not meet the physical activity recommendations. Nine percent of all participants were classified as high sedentary and low active. Participants from Norway showed the highest levels of sedentary time, while participants from England were the least physically active. Age and weight status were positively associated with sedentary time and not meeting the physical activity recommendations. Men and higher-educated people were more likely to be highly sedentary, while women and lower-educated people were more likely to be inactive. CONCLUSIONS: We found high levels of sedentary time and physical inactivity in four European countries. Older people and obese people were most likely to display these behaviours and thus deserve special attention in interventions and policy planning. In order to monitor these behaviours, accelerometer-based cross-European surveillance is recommended. PMID- 27943148 TI - Association Between Exercise-Induced Hyperthermia and Intestinal Permeability: A Systematic Review. AB - BACKGROUND: Prolonged and strenuous physical exercise increases intestinal permeability, allowing luminal endotoxins to translocate through the intestinal barrier and reach the bloodstream. When recognized by the immune system, these endotoxins trigger a systemic inflammatory response that may affect physical performance and, in severe cases, induce heat stroke. However, it remains to be elucidated whether there is a relationship between the magnitude of exercise induced hyperthermia and changes in intestinal permeability. OBJECTIVE: In this systematic review, we evaluated whether an exercise-induced increase in core body temperature (T Core) is associated with an exercise-induced increase in intestinal permeability. METHODS: The present systematic review screened the MEDLINE/PubMed and Web of Science databases in September 2016, without any date restrictions. Sixteen studies that were performed in healthy participants, presented original data, and measured both the exercise-induced changes in T Core and intestinal permeability were selected. These studies assessed intestinal permeability through the measurement of sugar levels in the urine and measurement of intestinal fatty acid binding protein or lipopolysaccharide levels in the blood. RESULTS: Exercise increased both T Core and intestinal permeability in most of the 16 studies. In addition, a positive and strong correlation was observed between the two parameters (r = 0.793; p < 0.001), and a T Core exceeding 39 degrees C was always associated with augmented permeability. CONCLUSION: The magnitude of exercise-induced hyperthermia is directly associated with the increase in intestinal permeability. PMID- 27943150 TI - Hand Foot and Mouth Disease Like Illness in Office Practice. AB - OBJECTIVE: To describe the clinical profile of Hand Foot and Mouth Disease (HFMD) like illness in a cluster of cases. METHODS: Children presenting with papulovesicular skin lesions with or without oral lesions were clinically examined, treated and followed up. RESULTS: Out of 21 cases, 18 (85.7%) were less than 3y and 15 (71.4%) were males. Skin lesions were seen in 100% with predominant involvement of dorsum of hands, feet, palms and soles. Oral lesions were noticed in 20 (95.2%), fever in 14 (66.6%) and upper respiratory infection in 6 (28.6%). Irritability was the presenting feature in infants. Only clinical diagnosis was made. All the children recovered completely. On follow up of 16 (76.2%) cases for 3 mo, no nail changes or any other sequelae were noticed. CONCLUSIONS: Early clinical diagnosis of HFMD is needed for monitoring and prevention of its spread. PMID- 27943151 TI - L-carnitine significantly decreased aging of rat adipose tissue-derived mesenchymal stem cells. AB - Mesenchymal stem cells are undifferentiated cells that have the ability to divide continuously and tissue regeneration potential during the transplantation. Aging and loss of cell survival, is one of the main problems in cell therapy. Since the production of free radicals in the aging process is effective, the use of antioxidant compounds can help in scavenging free radicals and prevent the aging of cells. The aim of this study is evaluate the effects of L-carnitine (LC) on proliferation and aging of rat adipose tissue-derived mesenchymal stem cells (rADSC). rADSCs were isolated from inguinal region of 5 male Rattus rats. Oil red O, alizarin red-S and toluidine blue staining were performed to evaluate the adipogenic, osteogenic and chondrogenic differentiation of rADSCs, respectively. Flow cytometric analysis was done for investigating the cell surface markers. The methyl thiazol tetrazolium (MTT) method was used to determine the cell proliferation of rADSCs following exposure to different concentrations of LC. rADSCs aging was evaluated by beta-galactosidase staining. The results showed significant proliferation of rADSCs 48 h after treatment with concentrations of 0.2 mM LC. In addition, in the presence of 0.2 mM LC, rADSCs appeared to be growing faster than control group and 0.2 mM LC supplementation could significantly decrease the population doubling time and aging of rADSCs. It seems that LC would be a good antioxidant to improve lifespan of rADSCs due to the decrease in aging. PMID- 27943149 TI - Utility of Microdialysis in Infectious Disease Drug Development and Dose Optimization. AB - Adequate drug penetration to a site of infection is absolutely imperative to ensure sufficient antimicrobial treatment. Microdialysis is a minimally invasive, versatile technique, which can be used to study the penetration of an antiinfective agent in virtually any tissue of interest. It has been used to investigate drug distribution and pharmacokinetics in variable patient populations, as a tool in dose optimization, a potential utility in therapeutic drug management, and in the study of biomarkers of disease progression. While all of these applications have not been fully explored in the field of antiinfectives, this review provides an overview of how microdialysis has been applied in various phases of drug development, a focus on the specific applications in the subspecialties of infectious disease (treatment of bacterial, fungal, viral, parasitic, and mycobacterial infections), and developing applications (biomarkers and therapeutic drug management). PMID- 27943152 TI - Oocyte maturation, embryo development and gene expression following two different methods of bovine cumulus-oocyte complexes vitrification. AB - OBJECTIVE: To examine the maturational competence, embryo development and expression of genes involved in oocyte maturation and cumulus expansion (GDF9, BMP15, HAS2, TNFAIP6, FGF17 and FSHr) following two standard methods of bovine COCs vitrification. METHODS: Bovine cumulus-oocyte complexes (COCs) were aspirated from slaughtered ovaries and then distributed into three groups: non vitrified COCs (control), vitrification 1 group (V1); vitrification was performed by 15% ethylene glycol (EG) and 15% DMSO in holding media (TCM-199 with 20% FCS); and vitrification 2 group (V2); vitrification was performed by 40% EG in holding media. After vitrification, COCs were warmed in two steps and cultured and then evaluated for nuclear maturation, embryo development and gene expressions. RESULTS: The mean (+/-SD) percentages of nuclear maturation and blastocyst/cleaved were higher in control group (79.5 +/- 8.0 and 31.0 +/- 5.1%) than the V1 (34.8 +/- 9.1 and 4.4 +/- 5.1%) and V2 (47.8 +/- 11.7 and 7.1 +/- 5.8%) groups (P < 0.05), respectively. Further, COCs in V2 group showed higher mean (+/-SD) percentages of cleavage compared to V1 group (31.8 +/- 1.0 vs 21.7 +/- 2.8%; P < 0.05). GDF9 and BMP15 expression levels were higher in COCs in the control than of the vitrification groups (P < 0.05). In addition, expression level of GDF9 and BMP15 was higher in V2 group than in V1group (P < 0.05). The expression of HAS2 and FGF17 in V1 group was lower (P < 0.05) than that of the V2 groups. CONCLUSIONS: Expression of oocyte maturation genes was affected by vitrification procedure and conditions. Using EG alone for vitrification of bovine immature COCs, resulted in higher expression of GDF9, BMP15 and production of more in vitro matured and cleaved oocytes. PMID- 27943153 TI - Phase I/II Randomized Trial of Sorafenib and Bevacizumab as First-Line Therapy in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma: North Central Cancer Treatment Group Trial N0745 (Alliance). AB - BACKGROUND: Angiogenesis has been a major target of novel drug development in hepatocellular carcinoma (HCC). It is hypothesized that the combination of two antiangiogenic agents, sorafenib and bevacizumab, will provide greater blockade of angiogenesis. OBJECTIVE: To determine the optimal dose, safety, and effectiveness of dual anti-angiogenic therapy with sorafenib and bevacizumab in patients with advanced HCC. PATIENTS AND METHODS: Patients with locally advanced or metastatic HCC not amenable for surgery or liver transplant were eligible. The phase I starting dose level was bevacizumab 1.25 mg/kg day 1 and 15 plus sorafenib 400 mg twice daily (BID) days 1-28. In the phase II portion, patients were randomized to receive bevacizumab and sorafenib at the maximum tolerated dose (MTD) or sorafenib 400 mg BID. RESULTS: Seventen patients were enrolled in the phase I component. Dose-limiting toxicities included grade 3 hand/foot skin reaction, fatigue, hypertension, alanine/aspartate aminotransferase increase, dehydration, hypophosphatemia, creatinine increase, hypoglycemia, nausea/vomiting, and grade 4 hyponatremia. Seven patients were enrolled in the phase II component at the MTD: sorafenib 200 mg BID days 1-28 and bevacizumab 2.5 mg/kg every other week; 57% (4/7) had grade 3 AEs at least possibly related to treatment. No responses were observed in the phase II portion. Estimated median time to progression and survival were 8.6 months (95% CI: 0.4-16.3) and 13.3 months (95% CI 4.4 - not estimable), respectively. CONCLUSIONS: The MTD of the combination is sorafenib 200 mg twice daily on days 1-28 plus bevacizumab 2.5 mg/kg on days 1 and 15 of a 28-day cycle. In the phase II portion of the trial, concerns regarding excessive toxicity, low efficacy, and slow enrollment led to discontinuation of the trial. (Clinical Trials ID: NCT00867321.). PMID- 27943154 TI - Development of Metaphorical Thought before Language: the Pragmatic Construction of Metaphors in Action. AB - In this article, we set out, first, a general overview of metaphor and metaphorical thought research within cognitive psychology and developmental psychology. We claim that, although research efforts broadened perspectives that considered metaphors to be ornaments of poetic language, certain predominance of a linguistic point of view within investigations led to relatively little attention paid to (i) non-verbal and non-written metaphorical instantiations, and (ii) the pre-linguistic and cultural origins of metaphorical thought. Next, we attempt to delve into, and model, the ontogenetic origins of metaphor, taking into consideration social and cultural elements. To that end, we consider the Vygotskian perspective and contemporary research from the pragmatics of the object. We propose that metaphorical thought is an emerging result of a complex web of dynamic relationships between pre-linguistic and socioculturally regulated semiotic systems. The analysis undertaken shows the need for a research programme with a developmental orientation that considers metaphor to be a product of the intertwining between the individual and social dimensions of cognitive development. We suggest this programme should find its roots in the analysis of the semiotic skills that precede the acquisition of metaphorical language. PMID- 27943156 TI - A geochemical approach to the restoration plans for the Odiel River basin (SW Spain), a watershed deeply polluted by acid mine drainage. AB - The Odiel River Basin (SW Spain) drains the central part of the Iberian Pyrite Belt (IPB), a world-class example of sulfide mining district and concomitantly of acid mine drainage (AMD) pollution. The severe AMD pollution and the incipient state of remediation strategies implemented in this region, coupled with the proximity of the deadline for compliance with the European Water Framework Directive (WFD), urge to develop a restoration and water resources management strategy. Furthermore, despite the presence of some reservoirs with acid waters in the Odiel basin, the construction of the Alcolea water reservoir has already started. On the basis of the positive results obtained after more than 10 years of developing a specific passive remediation technology (dispersed alkaline substrate (DAS)) for the highly polluted AMD of this region, a restoration strategy is proposed. The implementation of 13 DAS treatment plants in selected acid discharges along the Odiel and Oraque sub-basins and other restoration measurements of two acidic creeks is proposed as essential to obtain a good water quality in the future Alcolea reservoir. This restoration strategy is also suggested as an economically and environmentally sustainable approach to the extreme metal pollution affecting the waters of the region and could be considered the starting point for the future compliance with the WFD in the Odiel River Basin. PMID- 27943155 TI - Effects of different ratios of glucose to acetate on phosphorus removal and microbial community of enhanced biological phosphorus removal (EBPR) system. AB - In this study, the effects of different ratios of glucose to acetate on enhanced biological phosphorus removal (EBPR) were investigated with regard to the changes of intercellular polyhydroxyalkanoates (PHAs) and glycogen, as well as microbial community. The experiments were carried out in five sequencing batch reactors (SBRs) fed with glucose and/or acetate as carbon sources at the ratios of 0:100 %, 25:75 %, 50:50 %, 75:25 %, and 100:0 %. The experimental results showed that a highest phosphorus removal efficiency of 96.3 % was obtained with a mixture of glucose and acetate at the ratio of 50:50 %, which should be attributed to more glycogen and polyhydroxyvalerate (PHV) transformation in this reactor during the anaerobic condition. PCR-denaturing gradient gel electrophoresis (DGGE) analysis of sludge samples taken from different anaerobic/aerobic (A/O) SBRs revealed that microbial community structures were distinctively different with a low similarity between each other. PMID- 27943157 TI - Trace elements and nitrogen content in naturally growing moss Hypnum cupressiforme in urban and peri-urban forests of the Municipality of Ljubljana (Slovenia). AB - We monitored trace metals and nitrogen using naturally growing moss Hypnum cupressiforme Hedw. in urban and peri-urban forests of the City Municipality of Ljubljana. The aim of this study was to explore the differences in atmospheric deposition of trace metals and nitrogen between urban and peri-urban forests. Samples were collected at a total of 44 sites in urban forests (forests within the motorway ring road) and peri-urban forests (forests outside the motorway ring road). Mosses collected in urban forests showed increased trace metal concentrations compared to samples collected from peri-urban forests. Higher values were significant for As, Cr, Cu, Hg, Mo, Ni, Pb, Sb, Tl and V. Within the motorway ring road, the notable differences in element concentrations between the two urban forests were significant for Cr, Ni and Mo. Factor analysis showed three groups of elements, highlighting the contribution of traffic emissions, individual heating appliances and the resuspension of contaminated soils and dust as the main sources of trace elements in urban forests. PMID- 27943158 TI - Individual and mixture effects of five agricultural pesticides on zebrafish (Danio rerio) larvae. AB - In the present study, we evaluated the individual and mixture toxicities of imidacloprid and other four pesticides (atrazine, chlorpyrifos, butachlor, and lambda-cyhalothrin) to the zebrafish (Danio rerio) larvae in order to clarify the interactive effects of pesticides on aquatic organisms. Results from the 96-h semi-static toxicity test indicated that chlorpyrifos, lambda-cyhalothrin, and butachlor had the highest toxicities to D. rerio with an LC50 value ranging from 0.28 (0.13~0.38) to 0.45 (0.31~0.59) mg AI L-1, followed by atrazine with an LC50 value of 15.63 (10.71~25.76) mg AI L-1, while imidacloprid exhibited the least toxicity to the organisms with an LC50 value of 143.7 (99.98~221.6) mg AI L-1. Seven pesticide mixtures (two binary mixtures of imidacloprid + atrazine and imidacloprid + lambda-cyhalothrin, two ternary mixtures of imidacloprid + atrazine + lambda-cyhalothrin and imidacloprid + butachlor + lambda-cyhalothrin, two quaternary mixtures of imidacloprid + atrazine + chlorpyrifos + lambda cyhalothrin and imidacloprid + chlorpyrifos + butachlor + lambda-cyhalothrin, and one quinquenary mixture of imidacloprid + atrazine + chlorpyrifos + butachlor + lambda-cyhalothrin) exhibited synergistic effects with equitoxic ratio and equivalent concentration on the zebrafish. Our results highlighted that the simultaneous presence of several pesticides in the aquatic environment might lead to increased toxicity, causing serious damage to the aquatic ecosystems compared with their individual toxicities. Therefore, the toxic effects of both individual pesticides and their mixtures should be incorporated into the environmental risk evaluation of pesticides. PMID- 27943160 TI - Melanoma and Non-Melanoma Skin Cancer Associated with Angiotensin-Converting Enzyme Inhibitors, Angiotensin-Receptor Blockers and Thiazides: A Matched Cohort Study. AB - INTRODUCTION: Controversy exists about an association between angiotensin converting-enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), and thiazides (TZs) and the risk of malignant melanoma (MM), and non-melanoma skin cancer-basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). OBJECTIVE: The aim of this study was to determine if an association exists for ACEI, ARB, or TZ exposure and skin cancers. METHODS: This was a matched cohort study using a large electronic medical records repository, the Northwestern Medicine Enterprise Data Warehouse (NMEDW). The exposed population consisted of patients with a documented order for an ACEI, ARB, or TZ with no prior history of skin cancer. The control population consisted of matched patients without documented exposure to ACEI, ARB, or TZ and no previous skin cancer. Incident MM, BCC, or SCC diagnosis by ICD-9 codes was recorded. Odds ratios (ORs) were obtained by using logistic regression analyses. RESULTS: Among the 27,134 patients exposed to an ACEI, 87 MM, 533 BCC, and 182 SCC were detected. Among the 13,818 patients exposed to an ARB, 96 MM, 283 BCC, and 106 SCC were detected. Among the 15,166 patients exposed to a TZ, 99 MM, 262 BCC, and 130 SCC were detected. Significant associations using ORs from logistic regression were found for MM and TZs (OR 1.82; 95% confidence interval [CI] 1.01-3.82); BCC and ARBs (OR 2.86; 95% CI 2.13 3.83), ACEIs (OR 2.23; 95% CI 1.78-2.81) and TZs (OR 2.11; 95% CI 1.60-2.79); SCC and ARBs (OR 2.22; 95% CI 1.37-3.61), ACEIs (OR 1.94; 95% CI 1.37-2.76), and TZs (OR 4.11; 95% CI 2.66-6.35). CONCLUSIONS: A safety signal for ACEIs, ARBs, and TZs and BCC and SCC, as well as for TZs and MM, was detected. An increased awareness and education, especially for those who are at high risk for skin cancer, are warranted for patients and healthcare providers. Further exploration of such associations for these commonly used drug classes is warranted. PMID- 27943161 TI - The effects of roadway characteristics on farm equipment crashes: a geographic information systems approach. AB - BACKGROUND: Tractors and other slow-moving self-propelled farm equipment are often used on public roadway to transfer goods from the farm to a market or distributer. Increased roadway exposure has led to a growing concern on the occurrence of farm equipment crashes. This study aims to compare characteristics of road segments with farm equipment crashes to road segments without farm equipment crashes in the state of Iowa. METHODS: Data were obtained from the Iowa Department of Transportation from 2005 to 2011 on all crashes involving farm equipment, and features of all Iowa roadways. Geographic Information Systems (GIS) was used to identify geospatial features, such as road type, speed limit, traffic volume surface type, road and shoulder width of where a crash occurred. Logistic regression models were used to measure the associations between road characteristics and the occurrence of farm equipment crashes. Crude and adjusted odds ratios and 95% confidence intervals were reported. RESULTS: A total of 1371 farm equipment crashes were reported in Iowa over the 6-year period and geocoded onto a street location. As traffic volume increased, the odds of a crash occurring also increased. Roadways with posted speed limits between 50 and 60 mph were associated with a higher odds of having crashes on them compared to roadways with speeds less than 35 mph (OR = 8.05, 95% CI: 6.59-9.84). Iowa routes (OR = 5.98, 95% CI: 4.97-7.20) had the highest odds of having crashes compared to local routes. Increased road width (OR = 0.90, 95% CI: 0.86-0.94) was associated with a 10% decrease in the odds of a crash. CONCLUSIONS: Higher traffic volume, higher posted speed limits, road type, and smaller road widths were associated with the occurrence of farm equipment crashes. Findings from this study can be used to guide policy to improve roadway design and conditions for all road users. PMID- 27943162 TI - Tubulopapillary Hidradenoma-like Tumour of the Mandible: A Case Report and Literature Review. AB - Tubulopapillary hidradenoma is an uncommon benign sweat gland tumour which appears as a well-defined superficially located dermal nodule, most commonly occurring in the head or of the extremities. Its occurrence is extremely rare in the mandible, as there are only two cases of tubulopapillary hidradenoma-like tumour of the mandiblereported in the literature. Microscopically, the lesion appears as a well circumscribed but unencapsulated neoplasm composed of numerous irregularly shaped tubular structures that have a double to several layered epithelial lining. The outer layer consists of flat to cuboidal myoepithelial cells and inner layer contains cuboidal to columnar cells that demonstrate decapitation secretions. We report an unusual case of tubulopapillary hidradenoma like tumour presented as a nodular growth in the right retromolar region of the mandible in a 67-year-old man. The light microscopic features along with immunohistochemical findings of this unusual neoplasm are discussed. PMID- 27943159 TI - Conditioned task-set competition: Neural mechanisms of emotional interference in depression. AB - Depression has been associated with increased response times at the incongruent-, neutral-, and negative-word trials of the classical and emotional Stroop tasks (Epp et al., Clinical Psychology Review, 32, 316-328, 2012). Response-time slowdown effects at incongruent- and negative-word trials of the Stroop tasks were reported to correlate with depressive severity, indicating strong relevance of the effects to the symptomatology. This study proposes a novel integrative computational model of neural mechanisms of both the classical and emotional Stroop effects, drawing on the previous prominent theoretical explanations of performance at the classical Stroop task (Cohen, Dunbar, & McClelland, Psychological Review, 97, 332-361, 1990; Herd, Banich, & O'Reilly, Journal of Cognitive Neuroscience, 18, 22-32, 2006), and in addition suggesting that negative emotional words represent conditioned stimuli for future negative outcomes. The model is shown to explain the classical Stroop effect and the slow (between-trial) emotional Stroop effect with biologically plausible mechanisms, providing an advantage over the previous theoretical accounts (Matthews & Harley, Cognition & Emotion, 10, 561-600, 1996; Wyble, Sharma, & Bowman, Cognition & Emotion, 22, 1019-1051, 2008). Simulation results suggested a candidate mechanism responsible for the pattern of depressive performance at the classical and the emotional Stroop tasks. Hyperactivity of the amygdala, together with increased inhibitory influence of the amygdala over dopaminergic neurotransmission, could be at the origin of the performance deficits. PMID- 27943164 TI - Sustaining Gains in Health Programs: Technical Efficiency and its Determinants in Malaria Programs in Sub-Saharan Africa. AB - BACKGROUND: Since the year 2000, Africa has made significant progress in the fight against malaria. Between 2000 and 2015, the incidence and death from malaria fell by 42 and 66%, respectively. However, the African region still accounts for most global cases of malaria. In 2015, the region was home to 89% of malaria cases and 91% of malaria death. OBJECTIVE: This study aimed to evaluate efficiency of policies against malaria in 30 malaria-endemic Sub-Saharan African (SSA) countries, from the perspective of sustaining gains. METHODS: The data came from World Malaria Report 2013. Data were analyzed using the double bootstrap method. We first estimated bootstrapped efficiency scores. Then, bootstrapped truncated regression was used to determine factors associated with malaria program efficiency. RESULTS: This study showed that most malaria programs in SSA are technically inefficient. We also found that aid from international institutions and public expenditures on malaria programs do not significantly affect the efficiency of malaria programs. However, in an enhanced governance context, international aid and public expenditure impact positively on the efficiency of malaria programs. Moreover, intermittent preventive treatment for pregnant women is associated with a positive effect on the efficiency. Surprisingly, the free care policies-artemisinin-based combinations for under five-year-old children in the public facilities, rapid diagnostic tests, and distribution of insecticide-treated bed nets and long-lasting insecticide impregnated nets-does not significantly affect the efficiency of malaria programs. CONCLUSION: Financing alone does not ensure efficiency of malaria programs. Good governance and the targeting of the most vulnerable segments of the population are necessary to reduce malaria deaths and improve efficiency of malaria programs in SSA. PMID- 27943163 TI - Atypical femoral fracture after receiving antiresorptive drugs in breast cancer patients with bone metastasis. AB - BACKGROUND: Atypical femoral fracture (AFF) occurs with minor trauma in patients receiving antiresorptive drugs such as bisphosphonate and denosumab. We hypothesized that patients with bone metastasis who receive higher doses of antiresorptive drugs tend to experience AFF more frequently. This study aimed to investigate the prevalence rate of AFF in patients receiving antiresorptive drugs for bone metastasis of breast cancer. METHODS: Based on the database from our hospital, patients with breast cancer between March and September 2014 were investigated. Thirty-two patients with bone metastasis who received higher doses of antiresorptive drugs were included for analysis and defined as the metastasis (M) group. For the control (C) group, 32 patients in the same period with breast cancer without bone metastasis who did not undergo antiresorptive drug therapy were included. We evaluated the localized periosteal thickening of the lateral cortex (beaking) and femoral neck-shaft angle in CT scout view, the periods from induction of antiresorptive drugs to the appearance of beaking, and the occurrence rate of complete fracture. The 2 groups were compared. RESULTS: Of the 64 limbs in 32 patients of the M group, 8 limbs in 6 patients showed beaking at the subtrochanteric area (12.5%). After the occurrence of beaking, 5 limbs in 3 patients eventually had a complete fracture with minor trauma (7.8%). On the other hand, no beaking was observed in the C group. CONCLUSIONS: The frequency of AFF in patients with breast cancer receiving bisphosphonate and/or denosumab for bone metastasis was high. More attention should be paid to the occurrence of AFF in these patients than osteoporotic patients. PMID- 27943165 TI - Assessment of Public Health and Economic Impact of Intranasal Live-Attenuated Influenza Vaccination of Children in France Using a Dynamic Transmission Model. AB - OBJECTIVES: We estimated the epidemiological and economic impact of extending the French influenza vaccination programme from at-risk/elderly (>=65 years) only to healthy children (2-17 years). METHODS: A deterministic, age-structured, dynamic transmission model was used to simulate the transmission of influenza in the French population, using the current vaccination coverage with trivalent inactivated vaccine (TIV) in at-risk/elderly individuals (current strategy) or gradually extending the vaccination to healthy children (aged 2-17 years) with intranasal, quadrivalent live-attenuated influenza vaccine (QLAIV) from current uptake up to 50% (evaluated strategy). Epidemiological, medical resource use and cost data were taken from international literature and country-specific information. The model was calibrated to the observed numbers of influenza-like illness visits/year. The 10-year number of symptomatic cases of confirmed influenza and direct medical costs ('all-payer') were calculated for the 0-17- (direct and indirect effects) and >=18-year-old (indirect effect). The incremental cost-effectiveness ratio (ICER) was calculated for the total population, using a 4% discount rate/year. RESULTS: Assuming 2.3 million visits/year and 1960 deaths/year, the model calibration yielded an all-year average basic reproduction number (R 0) of 1.27. In the population aged 0-17 years, QLAIV prevented 865,000 influenza cases/year (58.4%), preventing 10-year direct medical expenses of ?374 million. In those aged >=18 years with unchanged TIV coverage, 1.2 million cases/year were averted (27.6%) via indirect effects (additionally prevented expenses, ?457 million). On average, 613 influenza related deaths were averted annually overall. The ICER was ?18,001/life-year gained. The evaluated strategy had a 98% probability of being cost-effective at a ?31,000/life-year gained threshold. CONCLUSIONS: The model demonstrated strong direct and indirect benefits of protecting healthy children against influenza with QLAIV on public health and economic outcomes in France. PMID- 27943167 TI - Erratum to: Bioinformatics Pipeline for Transcriptome Sequencing Analysis. PMID- 27943166 TI - Use of mycophenolate mofetil and a calcineurin inhibitor in allogeneic hematopoietic stem-cell transplantation from HLA-matched siblings or unrelated volunteer donors: Japanese multicenter phase II trials. AB - To test the feasibility of mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis in Japanese patients, we conducted two multicenter prospective phase II trials of allogeneic hematopoietic stem-cell transplantation (HSCT) from HLA-matched related donors (MRD group) with MMF and cyclosporine or HLA 7-8/8 allele-matched unrelated bone-marrow donors (URD group) with MMF and tacrolimus. The cumulative incidences of grade II-IV acute GVHD on day 100, which was the primary endpoint in these trials, were 45.0% (90% CI 25.8-62.5) and 25.8% (90% CI 13.9-39.5) in the MRD (n = 20) and URD (n = 31) groups, respectively. The rates of 3-year overall survival and non-relapse mortality were 80.0 and 15.0% in the MRD group and 74.2 and 6.5% in the URD group, respectively. GVHD prophylaxis with MMF may lead to a lower incidence of severe mucositis and faster neutrophil engraftment compared to that with methotrexate. A pharmacokinetics study of mycophenolic acid (MPA) showed that a relatively higher plasma concentration of MPA was associated with a lower incidence of acute GVHD. In conclusion, the results of these studies suggest that GVHD prophylaxis with MMF may be useful as an alternative in Japanese patients who may benefit from faster engraftment or less severe mucositis after allogeneic HSCT. PMID- 27943168 TI - Hemodialysis-induced repolarization abnormalities on ECG are influenced by serum calcium levels and ultrafiltration volumes. AB - PURPOSE: Hemodialysis (HD) patients are known to have high cardiovascular mortality rate. Sudden cardiac death (SCD) due to arrhythmias causes most of the cardiac deaths. HD per se may lead to ECG abnormalities and ventricular arrhythmias. Monitoring ECG parameters such as corrected QT interval, QT dispersion (QTd), Tpe interval may be useful to stratify the patients with high risk of arrhythmia and SCD. Herein we aimed to investigate the effects of changes in serum electrolyte levels and pH on ECG parameters before and after the HD. METHODS: A total of 50 chronic HD patients (mean age 58 +/- 19; male 27) were enrolled. Patients with unmeasurable T waves; atrial fibrillation; bundle branch block; use of class I or class III antiarrhythmic drugs were excluded. Serum potassium, magnesium, calcium, urea, creatinine and pH were measured before and after HD treatment. Standard surface 12-lead ECGs were recorded before and after HD. QTc, QTd, Tpe, JT interval, P-wave-duration, P-wave dispersion were determined. RESULTS: Serum potassium and magnesium decreased, and calcium, pH and bicarbonate levels increased; QRS and Tpe interval were increased after HD. Basal Tpe was correlated with urea (r = 0.31, p = 0.02). Tpe interval was higher in hypocalcemic compared to normocalcemic patients (77 +/- 11 vs 70 +/- 9 ms, p = 0.02). ?Tpe was correlated with ?calcium (r = -0.32, p = 0.02). Basal QTc was correlated with calcium (r = -0.62, p < 0.001). ?QTc was correlated with basal calcium (r = 0.39, p = 0.005) and ?calcium (r = -0.46, p < 0.001). Basal JT was correlated with calcium (r = -0.55, p < 0.001). ?JT was correlated with pH (r = 0.35, p = 0.01), ?calcium (r = -0.53, p < 0.001) and ?magnesium (r = -0.30, p = 0.03). Before HD, 12 patients (12%) were hypermagnesemic of whom JT intervals were lower (314 +/- 20 vs 332 +/- 23 ms, p = 0.02). Ultrafiltration per body weight was associated with ?QTc (r = -0.40, p = 0.007) and ?JT (r = -0.36, p = 0.01). CONCLUSION: QRS and Tpe intervals were increased after HD. Tpe interval was longer in hypocalcemic patients. Change in Tpe was negatively associated with the change in calcium. Ultrafiltration was associated with ?QTc and ?JT. Calcium and ultrafiltration seem to be the most important determinants of ECG parameters of HD-induced repolarization abnormalities. PMID- 27943169 TI - The metabolic hormone FGF21 is associated with endothelial dysfunction in hemodialysis patients. AB - PURPOSE: Finding new, reliable biomarkers of cardiovascular risk in hemodialysis (HD) patients is of utmost importance. Fibroblast growth factor 21 (FGF21) has been recently associated with atherosclerosis in the general population. The relationship between markedly elevated FGF21 levels in HD patients and endothelial dysfunction is unknown. The aim of the study was to assess the determinants of FGF21, the correlation between FGF21 and tumor necrosis factor TNF-like weak inducer of apoptosis (sTWEAK) and the correlation between FGF21 and endothelial dysfunction in HD patients. METHODS: A cross-sectional observational study was conducted in 70 HD patients (mean age 59.9 +/- 12.5 years, 14.3% diabetes mellitus, 57.1% male) from Nefromed Dialysis Center Cluj. We registered clinical and biological data, and serum FGF21 levels were measured by ELISA. Endothelial function was evaluated by brachial flow-mediated dilation (FMD). An analysis based on stratification of FGF21 values into quartiles was performed. RESULTS: FGF21 levels were directly correlated with sTWEAK, tricipital skinfold thickness (TST), systolic blood pressure (SBP), total cholesterol and triglycerides. In multivariate linear analysis, only sTWEAK and SBP remained significantly associated with FGF21. FGF21 values in the inferior quartile were directly correlated with HDL-cholesterol, while FGF21 values in the superior quartile were directly correlated with SBP, pulse pressure and sTWEAK. FMD was significantly higher in the inferior quartile as compared to the superior quartile. CONCLUSIONS: High FGF21 values in our patients are correlated with atherosclerosis risk factors: hypercholesterolemia, hypertriglyceridemia, hypertension, increased TST and increased levels of sTWEAK. Endothelial dysfunction is associated with high FGF21 in HD patients. PMID- 27943171 TI - Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53-MDM2 Interaction Useful in Targeted Cancer Therapy. AB - As a result of the toxicity of currently available anticancer drugs and the inefficiency of chemotherapeutic treatments, the design and discovery of effective and selective antitumor agents continues to be a hot topic in organic medicinal chemistry. Targeted therapy is a newer type of cancer treatment that uses drugs designed to interfere with specific molecules necessary for tumor growth and progression. This review explains the mechanism of regulation of p53 (tumor suppressor protein) by MDM2 and illustrates the role of targeting p53-MDM2 protein-protein interaction using small molecules as a new cancer therapeutic strategy. Spirocyclic oxindoles or spiro-oxindoles, with a rigid heterocyclic ring fused at the 3-position of the oxindole core with varied substitution around it, are the most efficacious class of small molecules which inhibit cell proliferation and induce apoptosis in cancer cells, leading to complete tumor growth regression without affecting activities of normal cells. In this review, we present a comprehensive account of the systematic development of and recent progress in diverse spiro-oxindole derivatives active as potent selective inhibitors of p53-MDM2 interaction with special emphasis on spiro-pyrrolidinyl oxindoles (the MI series), their mechanism of action, and structure-activity relationship. This review will help in understanding the molecular mechanism of p53 reactivation by spiro-oxindoles in tumor tissues and also facilitates the design and exploration of more potent analogues with high efficacy and low side effects for the treatment of cancer. Recent progress in spiro-oxindole derivatives as potent small molecule inhibitors of p53-MDM2 interaction, useful as anticancer agents, is described with reference to their mechanism of action and structure-activity relationship. PMID- 27943170 TI - Comparison of multiple fluid status assessment methods in patients on chronic hemodialysis. AB - PURPOSE: Control of hydration status is an important constituent of adequate and efficient hemodialysis (HD) treatment. Nevertheless, there are no precise clinical indices for early recognition of small changes in fluid status of patients undergoing chronic hemodialysis therapy. This study aimed to evaluate and compare the widely used and reliable method of indexed inferior vena cava diameter (IVCDi) with established and more recently available techniques (bioelectrical impedance analysis [BIA], continuous blood volume monitoring [Crit line], and the B-line score [BLS] with lung ultrasonography) for estimating the hydration status of patients on HD. METHODS: Fifty-three patients undergoing chronic HD thrice weekly were included in the study. Evaluation of hydration status methods (IVCDi, BLS, BIA, and Crit-line) was performed thrice weekly before and after HD. Receiver operating characteristic curve analysis was performed to evaluate the discriminative power of (methods) the BLS, BIA, and Crit-line for predicting over- and underhydration of patients, as determined by the reference method, IVCDi. RESULTS: BLS showed the most promising results in predicting overhydration, as determined by IVCDi, compared with BIA and Crit-line and presented a sensitivity of 77% and specificity of 74%. The accuracy of the BLS was higher than that of BIA (0.81 vs. 0.71, p = 0.032) and Crit-line (0.61, p = 0.001). BLS also showed more promising results in predicting underhydration, as determined by IVCDi, than BIA and Crit-line and presented a sensitivity of 78% and a specificity of 73%. The accuracy of the BLS was higher than that of BIA (0.83 vs. 0.76, p = 0.035) and Crit-line (0.50, p < 0.001). CONCLUSIONS: The BLS is a useful and easily performed technique that has recently become available for accurate evaluation of dry weight and fluid status in patients with end-stage renal disease undergoing chronic HD. This method might help recognize asymptomatic lung congestion in these patients. PMID- 27943173 TI - Discounting the Recommendations of the Second Panel on Cost-Effectiveness in Health and Medicine. AB - Twenty years ago, the "Panel on Cost-effectiveness in Health and Medicine" published a landmark text setting out appropriate methods for conducting cost effectiveness analyses of health technologies. In the two decades since, the methods used for economic evaluations have advanced substantially. Recently, a "second panel" (hereafter "the panel") was convened to update the text and its recommendations were published in November 2016. The purpose of this paper is to critique the panel's updated guidance regarding the discounting of costs and health effects. The advances in discounting methodology since the first panel include greater theoretical clarity regarding the specification of discount rates, how these rates vary with the analytical perspective chosen, and whether the healthcare budget is constrained. More specifically, there has been an important resolution of the debate regarding the conditions under which differential discounting of costs and health effects is appropriate. We show that the panel's recommendations are inconsistent with this recent literature. Importantly, the panel's departures from previously published findings do not arise from an alternative interpretation of theory; rather, we demonstrate that this is due to fundamental errors in methodology and logic. The panel also failed to conduct a formal review of relevant empirical evidence. We provide a number of suggestions for how the panel's recommendations could be improved in future. PMID- 27943172 TI - Defining the Place of Ezetimibe/Atorvastatin in the Management of Hyperlipidemia. AB - Statin-ezetimibe combinations are a potentially advantageous therapeutic option for high-risk patients who need additional lowering of low-density lipoprotein cholesterol (LDL-C). These combinations may overcome some of the limitations of statin monotherapy by blocking both sources of cholesterol. Recently, a fixed dose combination with atorvastatin, one of the most extensively studied statins, was approved and launched in several countries, including the USA. Depending on atorvastatin dose, this combination provides LDL-C reductions of 50-60%, triglyceride reductions of 30-40%, and high-density lipoprotein cholesterol (HDL C) increases of 5-9%. Studies comparing the lipid-lowering efficacy of the atorvastatin-ezetimibe combination with the alternatives of statin dose titration or switching to a more potent statin consistently showed that combination therapy provided greater LDL-C reduction, translating into a greater proportion of patients achieving lipid goals. Simvastatin-ezetimibe combinations have been shown to reduce the incidence of major atherosclerotic events in several clinical settings to a magnitude that seems similar to that observed with statins for the same degree of absolute LDL-C lowering. The atorvastatin-ezetimibe combination has also been shown to induce the regression of coronary atherosclerosis measured by intravascular ultrasound in a significantly greater proportion of patients than atorvastatin alone. Atorvastatin-ezetimibe combinations are generally well tolerated. Previous concerns of a possible increase in the incidence of cancer with ezetimibe were dismissed in large trials with long follow-up periods. In this paper, we examine the rationale for an atorvastatin-ezetimibe combination, review the evidence supporting it, and discuss its potential role in the management of dyslipidemia. PMID- 27943174 TI - The Dutch SCORE-based risk charts seriously underestimate the risk of cardiovascular disease. AB - INTRODUCTION: Dutch cardiovascular disease (CVD) prevention guidelines recommend the use of modified SCORE risk charts to estimate 10-year risk of fatal and nonfatal CVD (myocardial infarction, cerebrovascular disease and congestive heart failure). This combined risk is derived from the SCORE mortality risk using multipliers. These multipliers have been shown to underestimate overall CVD risk. We aimed to compare the current Dutch risk charts with charts that estimate a broader range of clinically relevant CVD using updated multipliers. METHODS: We constructed new risk charts for 10-year CVD using updated, recently published multipliers from the EPIC-Norfolk study, based on ratios of fatal CVD to clinically relevant CVD (fatal plus nonfatal CVD requiring hospitalisation for ischaemic heart disease, cardiac failure, cerebrovascular disease, peripheral artery disease, and aortic aneurysm). Our primary outcome was the proportion of the three risk categories, i. e. 'high risk' (>20% 10-year risk), 'intermediate risk' (10-19%) and 'low risk' (<10%) in the new risk charts as compared with the current risk charts. RESULTS: Applying the updated fatal CVD/clinical CVD multipliers led to a marked increase in the high-risk categories (109 (27%) vs. 244 (61%), (p < 0.001)), an absolute increase of 229%. Similarly, the number of low-risk categories decreased (190 (48%) vs. 81 (20%) (p < 0.001)). CONCLUSION: The current Dutch risk charts seriously underestimate the risk of clinical CVD, even in the first 10 years. Even when analyses are restricted to CVD events that required hospitalisation, true 10-year risks are more than double the currently estimated risks. Future guidelines may be revised to reflect these findings. PMID- 27943175 TI - Left atrial appendage closure: outcomes and challenges. AB - Whereas the left atrial appendage plays a rather minor role under physiological circumstances, it gains an importance in patients with atrial fibrillation. Compelling evidence has revealed that the left atrial appendage is implicated as the source of thrombus in the vast majority of strokes in atrial fibrillation. Oral anticoagulation remains the standard of care for stroke prevention in atrial fibrillation; nevertheless, this treatment has several limitations and is often contraindicated, particularly in the elderly population in whom the risk of stroke is high. Therefore, occluding the left atrial appendage is a logical approach to prevent thrombus formation and subsequent cardioembolic events in these patients. We present a review of clinical outcomes of patients with atrial fibrillation undergoing left atrial appendage closure and the challenges faced in this field. PMID- 27943176 TI - Rationale and design of the Edwards SAPIEN-3 periprosthetic leakage evaluation versus Medtronic CoreValve in transfemoral aortic valve implantation (ELECT) trial : A randomised comparison of balloon-expandable versus self-expanding transcatheter aortic valve prostheses. AB - BACKGROUND AND OBJECTIVES: Periprosthetic aortic regurgitation (PPR) after transcatheter aortic valve implantation (TAVI) remains an important issue associated with impaired long-term outcomes. The current randomised study aims to evaluate potential differences between the balloon-expandable Edwards SAPIEN-3 and the self-expanding Medtronic CoreValve system with the main focus on post TAVI PPR by means of novel imaging endpoints, and an additional focus on other clinical endpoints. ENDPOINTS: The primary endpoint of this study is quantitative assessment of the severity of post-procedural PPR using cardiac magnetic resonance imaging. Several other novel imaging modalities (X-ray contrast angiography, echocardiography) are used as secondary imaging modalities for the assessment of PPR following TAVI. Secondary objectives of the study include clinical outcomes such as cerebral and kidney injury related to TAVI, and quality of life. METHODS AND DESIGN: The ELECT study is a single-centre, prospective, two armed randomised controlled trial. For the purpose of this study, 108 consecutive adult patients suitable for transfemoral TAVI will be randomly allocated to receive the SAPIEN-3 (n = 54) or the CoreValve system (n = 54). DISCUSSION: The ELECT trial is the first randomised controlled trial to quantitatively compare the extent of post-TAVI PPR between the SAPIEN-3 and CoreValve. Furthermore, it will evaluate potential differences between the two prostheses with regard to mid term clinical outcome and quality of life. PMID- 27943178 TI - Early experience with the Venus p-valve for percutaneous pulmonary valve implantation in native outflow tract. AB - INTRODUCTION: The Venus p-valve (MedTech, Shanghai, China) is a self-expanding percutaneous heart valve designed to be implanted in a native patched right ventricle outflow tract. The worldwide clinical experience with this valve is just beginning and the results have so far been encouraging. We present our initial early experience implanting the Venus p-valve in the native right ventricle outflow tract of patients with Tetralogy of Fallot repaired with a transannular patch. METHODS: In 10 selected patients a procedure for percutaneous pulmonary valve implantation was performed using the Venus p-valve. The patients mean age was 32 years (13-57), mean weight 59.6 kg (40-80). All patients had Tetralogy of Fallot with moderate to severe pulmonary regurgitation and an indication for pulmonary valve replacement. RESULTS: The implantation procedure was successful in all the patients resulting in an immediately functional valve. No procedure-related complications were observed. Follow-up after 12 months (4 21) resulted in an improvement in NYHA class. There was a reduction of the mean right ventricle diastolic volume from 139 ml/m2 (105-179) to 78 ml/m2 (65-100) and improvement in the regurgitation fraction from 42% (29-58) to 1% (0-5), as seen on routine cardiac magnetic resonance 6 months after the implantation. No stent fractures have been observed so far. CONCLUSION: Percutaneous pulmonary valve implantation with the Venus p-valve resulted in a safe and effective procedure. The valve has predictable and sustained functional competence, resulting in clinical improvement in the patients. PMID- 27943177 TI - NT-proBNP during and after primary PCI for improved scheduling of early hospital discharge. AB - BACKGROUND: The Zwolle Risk Score (ZRS) identifies primary percutaneous coronary intervention (PPCI) patients at low mortality risk, eligible for early discharge. Recently, this score was improved by adding baseline NT-proBNP. However, the optimal timepoint for NT-proBNP measurement is unknown. METHODS: PPCI patients in the On-Time 2 study were candidates. The ZRS and NT-proBNP levels on admission, at 18-24 h, at 72-96 h, and the change in NT-proBNP from baseline to 18-24 h (delta NT-proBNP) were determined. We investigated whether addition of the different NT-proBNP measurements to the ZRS improves the prediction of 30-day mortality. Based on cut-off values reflecting zero mortality at 30 d, patients who potentially could be discharged early were identified and occurrence of major adverse cardiac events (MACE) and major bleeding until 10 d was registered. RESULTS: 845 patients were included. On multivariate analyses, NT-proBNP at baseline (HR 2.09, 95% CI 1.59-2.74, p < 0.001), at 18-24 h (HR 6.83, 95% CI 2.94 15.84), and at 72-96 h (HR 3.32, 95% CI 1.22-9.06) independently predicted death at 30 d. Addition of NT-proBNP to the ZRS improved prediction of mortality, particularly at 18-24 h (net reclassification index 29%, p < 0.0001, integrated discrimination improvement 17%, p < 0.0001). Based on ZRS (<2) or NT-proBNP at 18 24 h (<2500 pg/ml) 75% of patients could be targeted for early discharge at 48 h, with expected re-admission rates of 1.2% due to MACE and/or major bleeding. CONCLUSIONS: NT-proBNP at different timepoints improves prognostication of the ZRS. Particularly at 18-24 h post PPCI, the largest group of patients that potentially could be discharged early was identified. PMID- 27943179 TI - A Cell Culture System to Investigate the Presynaptic Control of Subsynaptic Membrane Differentiation at the Neuromuscular Junction. AB - For decades the neuromuscular junction (NMJ) has been a favorite preparation to investigate basic mechanisms of synaptic function and development. As its function is to transmit action potentials in a 1:1 ratio from motor neurons to muscle fibers, the NMJ shows little or no functional plasticity, a property that makes it poorly suited to investigate mechanisms of use-dependent adaptations of synaptic function, which are thought to underlie learning and memory formation in the brain. On the other hand, the NMJ is unique in that the differentiation of the subsynaptic membrane is regulated by one major factor secreted from motor neurons, agrin. As a consequence, myotubes grown on a laminin substrate that is focally impregnated with recombinant neural agrin closely resemble the situation in vivo, where agrin secreted from motor neurons binds to the basal lamina of the NMJ's synaptic cleft to induce and maintain the subsynaptic muscle membrane. We provide here a detailed protocol through which acetylcholine receptor clusters are induced in cultured myotubes contacting laminin-attached agrin, enabling molecular, biochemical and cell biological analyses including high resolution microscopy in 4D. This preparation is ideally suited to investigate the mechanisms involved in the assembly of the postsynaptic muscle membrane, providing distinct advantages over inducing AChR clusters using soluble agrin. PMID- 27943180 TI - Co-culture Synaptogenic Assay: A New Look at Fluorescence Reporters and Technological Devices. AB - The mechanism underlying the differentiation of pre- and postsynaptic specifications involves the sequential and dynamic recruitment of specific molecules coordinated by bidirectional signaling across the synaptic cleft. In this chapter, we describe the co-culture assay, a useful method to evaluate cell surface molecules through its ability to promote the recruitment of proteins required for synapse structure and function. The versatility of this simple and reliable method is illustrated by the wide variety of applications ranging from analysis of synaptogenic activity to evaluation of soluble compounds with therapeutic potential. In addition, we provide a framework to enable the co culture assay as a tool for high-throughput studies, thereby improving the efficiency and sensitivity of this classic method in neuroscience. PMID- 27943181 TI - Synaptogenic Assays Using Neurons Cultured on Micropatterned Substrates. AB - One of the difficulties for studying the mechanisms of synaptogenesis stems from the spatial unpredictability of contact formation between neurons, and the involvement of many parallel adhesive pathways mediating axon/dendrite recognition. To circumvent these limitations, we describe here a method allowing the investigation of synaptic contacts at controlled locations with high precision and statistics. Specifically, primary neurons are cultured on micropatterned substrates comprising arrays of micron-scale dots coated with purified synaptogenic adhesion molecules. Coating the substrates with the homophilic adhesion molecule SynCAM triggers the formation of functional presynaptic structures in axons, while neurexin elicits postsynapses in dendrites from neurons expressing the counter receptor neuroligin. This assay can be combined with various imaging techniques including immunocytochemistry to screen the accumulation of synaptic components, long-term live cell recordings to probe the kinetics of neurite growth and synapse differentiation, as well as high resolution single molecule tracking. PMID- 27943182 TI - Monitoring Synapses Via Trans-Synaptic GFP Complementation. AB - Over the last years, the analysis of synaptic connectivity in the mammalian brain has been accelerated by the use of techniques combining electrophysiology, light microscopy, viral tracing, and genetic manipulations in animal models. Of particular interest are methods that aim to label synapses by tethering complementary split GFP fragments in opposing sites of the synaptic cleft. Here, I describe SynView, a method for monitoring synapse formation based on GFP complementation, and provide a detailed protocol for use in neuronal cultures from mouse hippocampus. PMID- 27943183 TI - Generation of Spinal Motor Neurons from Human Pluripotent Stem Cells. AB - Human embryonic stem cells (ESCs) are characterized by their unique ability to self-renew indefinitely, as well as to differentiate into any cell type of the human body. Induced pluripotent stem cells (iPSCs) share these salient characteristics with ESCs and can easily be generated from any given individual by reprogramming somatic cell types such as fibroblasts or blood cells. The spinal motor neuron (MN) is a specialized neuronal subtype that synapses with muscle to control movement. Here, we present a method to generate functional, postmitotic, spinal motor neurons through the directed differentiation of ESCs and iPSCs by the use of small molecules. These cells can be utilized to study the development and function of human motor neurons in healthy and disease states. PMID- 27943184 TI - Biochemical Purification of Binding Partners of Synaptic Scaffold Proteins. AB - The chemical synapse displays specialized intercellular adhesion between pre- and potsynaptic plasma membranes mediated by synaptic cell adhesion proteins. In this asymmetric cell adhesion, pre- and postsynapses have their own unique functions; the presynaptic terminal releases neurotransmitter, which diffuses through the synaptic cleft and is received by receptors accumulated at the postsynapse. Such distinct modes of actions of pre- and postsynapses in synaptic neurotransmission are the rate-limiting factors in signal processing in the brain, and thus protein protein interactions within the pre- and postsynaptic scaffold are of particular importance for brain function by regulating the pre- and postsynaptic function. In the present paper, we outline a method to screen for binding partners of synaptic scaffold proteins biochemically. PMID- 27943185 TI - In Situ Protein Binding Assay Using Fc-Fusion Proteins. AB - This protocol describes an in situ protein-protein interaction assay between tagged recombinant proteins and cell-surface expressed synaptic proteins. The assay is arguably more sensitive than other traditional protein binding assays such as co-immunoprecipitation and pull-downs and provides a visual readout for binding. This assay has been widely used to determine the dissociation constant of binding of trans-synaptic adhesion proteins. The step-wise description in the protocol should facilitate the adoption of this method in other laboratories. PMID- 27943186 TI - Reconstitution of Synaptic SNAREs into Large Liposomes with Reduced Curvature Stress. AB - Liposomes constitute a convenient biochemical model system to investigate mechanistic aspects of the membrane fusion of synaptic vesicles. The proteins responsible for mediating fusion are the SNAREs that belong to a highly conserved family of transmembrane proteins. Reconstituting SNAREs into liposomes using detergents has become a common approach not only to understand how SNAREs work, but also how fusion is regulated by the vast array of accessory proteins present at the presynapse. However, a concern has been that the high curvature stress of the small liposomes (diameters of ~40 nm) frequently used in many studies renders them prone to spontaneous fusion, bringing into question whether the measurements obtained faithfully represent SNARE-mediated fusion. By systematically varying the detergent concentration and characterizing the SNARE-liposome size distributions by light scattering, we describe a detailed procedure to reconstitute SNAREs into large liposomes with considerably reduced curvature stress. PMID- 27943187 TI - Isolation of Synaptosomes, Synaptic Plasma Membranes, and Synaptic Junctional Complexes. AB - Isolation of synaptic nerve terminals or synaptosomes provides an opportunity to study the process of neurotransmission at many levels and with a variety of approaches. For example, structural features of the synaptic terminals and the organelles within them, such as synaptic vesicles and mitochondria, have been elucidated with electron microscopy. The postsynaptic membranes are joined to the presynaptic "active zone" of transmitter release through cell adhesion molecules and remain attached throughout the isolation of synaptosomes. These "post synaptic densities" or "PSDs" contain the receptors for the transmitters released from the nerve terminals and can easily be seen with electron microscopy. Biochemical and cell biological studies with synaptosomes have revealed which proteins and lipids are most actively involved in synaptic release of neurotransmitters. The functional properties of the nerve terminals, such as responses to depolarization and the uptake or release of signaling molecules, have also been characterized through the use of fluorescent dyes, tagged transmitters, and transporter substrates. In addition, isolated synaptosomes can serve as the starting material for the isolation of relatively pure synaptic plasma membranes (SPMs) that are devoid of organelles from the internal environment of the nerve terminal, such as mitochondria and synaptic vesicles. The isolated SPMs can reseal and form vesicular structures in which transport of ions such as sodium and calcium, as well as solutes such as neurotransmitters can be studied. The PSDs also remain associated with the presynaptic membranes during isolation of SPM fractions, making it possible to isolate the synaptic junctional complexes (SJCs) devoid of the rest of the plasma membranes of the nerve terminals and postsynaptic membrane components. Isolated SJCs can be used to identify the proteins that constitute this highly specialized region of neurons. In this chapter, we describe the steps involved in isolating synaptosomes, SPMs, and SJCs from brain so that these preparations can be used with new technological advances to address many as yet unanswered questions about the synapse and its remarkable activities in neuronal cell communication. PMID- 27943188 TI - Purification of Synaptosome Populations Using Fluorescence-Activated Synaptosome Sorting. AB - For several decades, neurobiologists have used subcellular fractionation methods to analyze the molecular structure and some functional features of the cells in the central nervous system. Indeed, brain tissue contains a complex intermingled network of neuronal, glial, and vascular cells. To reduce this complexity biochemists have optimized fractionation protocols that enrich in specific compartments such as synapses (called "synaptosomes") and synaptic vesicles, for example. However, recently, these approaches suffered from a lack of specificity and purity. In a recent effort, we extended the conventional synaptosome preparation to purify fluorescent synaptosomes on a cell sorter. We could prove that our method allows for the steep enrichment in fluorescent excitatory VGLUT1venus synaptosomes containing the presynaptic element and the tip of the post-synaptic element and a strong depletion in neuronal and glial contaminants. Here, we propose a detailed procedure for the implementation of Fluorescence Activated Synaptosome Sorting. PMID- 27943189 TI - Optimized Protocol for Imaging Cleared Neural Tissues Using Light Microscopy. AB - Understanding physical and chemical processes at an organismal scale is a fundamental goal in biology. While science is adept at explaining biological phenomena at both molecular and cellular levels, understanding how these processes translate to organismal functions remains a challenging problem. This issue is particularly significant for the nervous system where cell signaling and synaptic activities function in the context of broad neural networks. Recent progress in tissue clearing technologies lessens the barriers that previously prevented the study of large tissue samples while maintaining molecular and cellular resolution. While these new methods open vast opportunities and exciting new questions, the logistics of analyzing cellular processes in intact tissue have to be carefully considered. In this protocol, we outline a procedure to rapidly image intact brain tissue up to thousands of cubic millimeters. This experimental pipeline involves three steps: tissue clearing, tissue imaging, and data analysis. In an attempt to streamline the process for researchers entering this field, we address important considerations for each of these stages and describe an integrated solution to image intact biological tissues. Hopefully, this optimized protocol will lower the barrier of implementing high-resolution tissue imaging and facilitate the investigations of mesoscale questions at molecular and cellular resolution. PMID- 27943190 TI - Structured Illumination Microscopy for the Investigation of Synaptic Structure and Function. AB - The neuronal synapse is a primary building block of the nervous system to which alterations in structure or function can result in numerous pathologies. Studying its formation and elimination is the key to understanding how brains are wired during development, maintained throughout adulthood plasticity, and disrupted during disease. However, due to its diffraction-limited size, investigations of the synaptic junction at the structural level have primarily relied on labor intensive electron microscopy or ultra-thin section array tomography. Recent advances in the field of super-resolution light microscopy now allow researchers to image synapses and associated molecules with high-spatial resolution, while taking advantage of the key characteristics of light microscopy, such as easy sample preparation and the ability to detect multiple targets with molecular specificity. One such super-resolution technique, Structured Illumination Microscopy (SIM), has emerged as an attractive method to examine synapse structure and function. SIM requires little change in standard light microscopy sample preparation steps, but results in a twofold improvement in both lateral and axial resolutions compared to widefield microscopy. The following protocol outlines a method for imaging synaptic structures at resolutions capable of resolving the intricacies of these neuronal connections. PMID- 27943191 TI - 3D d STORM Imaging of Fixed Brain Tissue. AB - Central nervous system tissue contains a high density of synapses each composed of an intricate molecular machinery mediating precise transmission of information. Deciphering the molecular nanostructure of pre- and postsynaptic specializations within such a complex tissue architecture poses a particular challenge for light microscopy. Here, we describe two approaches suitable to examine the molecular nanostructure of synapses at 20-30 nm lateral and 50-70 nm axial resolution within an area of 500 MUm * 500 MUm and a depth of 0.6 MUm to several micrometers. We employ single-molecule localization microscopy (SMLM) on immunolabeled fixed brain tissue slices. tomoSTORM utilizes array tomography to achieve SMLM in 40 nm thick resin-embedded sections. dSTORM of cryo-sectioned slices uses optical sectioning in 0.1-4 MUm thick hydrated sections. Both approaches deliver 3D nanolocalization of two or more labeled proteins within a defined tissue volume. We review sample preparation, data acquisition, analysis, and interpretation. PMID- 27943192 TI - Photomarking Relocalization Technique for Correlated Two-Photon and Electron Microcopy Imaging of Single Stimulated Synapses. AB - Synapses learn and remember by persistent modifications of their internal structures and composition but, due to their small size, it is difficult to observe these changes at the ultrastructural level in real time. Two-photon fluorescence microscopy (2PM) allows time-course live imaging of individual synapses but lacks ultrastructural resolution. Electron microscopy (EM) allows the ultrastructural imaging of subcellular components but cannot detect fluorescence and lacks temporal resolution. Here, we describe a combination of procedures designed to achieve the correlated imaging of the same individual synapse under both 2PM and EM. This technique permits the selective stimulation and live imaging of a single dendritic spine and the subsequent localization of the same spine in EM ultrathin serial sections. Landmarks created through a photomarking method based on the 2-photon-induced precipitation of an electrodense compound are used to unequivocally localize the stimulated synapse. This technique was developed to image, for the first time, the ultrastructure of the postsynaptic density in which long-term potentiation was selectively induced just seconds or minutes before, but it can be applied for the study of any biological process that requires the precise relocalization of micron-wide structures for their correlated imaging with 2PM and EM. PMID- 27943193 TI - 3D Analysis of Synaptic Ultrastructure in Organotypic Hippocampal Slice Culture by High-Pressure Freezing and Electron Tomography. AB - Transmission electron microscopy serves as a valuable tool for synaptic structure function analyses aimed at identifying morphological features or modifications associated with specific developmental stages or dysfunctional synaptic states. By utilizing cryo-preparation techniques to minimize the introduction of structural artifacts during sample preparation, and electron tomography to reconstruct the 3D ultrastructural architecture of a synapse, the spatial organization and morphological properties of synaptic organelles and subcompartments can be quantified with unparalleled precision. In this chapter, we present an experimental approach combining organotypic slice culture, high pressure freezing, automated freeze-substitution, and electron tomography to investigate spatial relationships between synaptic vesicles and active zone release sites in synapses from lethal mouse mutants. PMID- 27943194 TI - Analyzing Endosomal Docking, Fusion, Sorting, and Budding Mechanisms in Isolated Organelles. AB - Due to their central role in the reception and sorting of newly internalized material, early endosomes undergo extensive membrane remodeling. They dock and fuse with endocytic carrier vesicles originating from the plasma membrane, sort the internalized material in internal microdomains, and allow the budding of new carrier vesicles from their membrane, destined to fuse with the plasma membrane (recycling) or other organelles. Early endosomal compartments might also be involved in the recycling of synaptic vesicles in nerve terminals. The present protocol describes a technique allowing to assess the mechanistic and molecular aspects of the membrane remodeling processes of docking, fusion, sorting, and budding in early endosomes of neuron-like (and other) cells. It involves the fluorescent labeling and isolation of endosomal organelles, the setup of assays allowing for docking/fusion or sorting/budding in vitro, and finally the assessment and quantification of the membrane remodeling events by fluorescent microscopy. The technique can be easily manipulated by the addition of inhibitors or activators, and can be combined with other techniques, such as immunostaining and high-resolution microscopy, expanding the experimental possibilities in the investigation of early endosomal characteristics. PMID- 27943195 TI - Concurrent Imaging of Receptor Trafficking and Calcium Dynamics by Spinning Disk Confocal Microscopy. AB - Synaptic activity is modulated by the activation of neuromodulator receptors present in dendrites of neurons. The majority of neuromodulator receptors are G protein coupled receptors (GPCRs), in which membrane trafficking regulates their activities. Membrane trafficking of neuromodulator receptors and their signaling occurs on a rapid time scale and emerging studies indicate that neuromodulator receptors function not just from the plasma membrane but also from the endocytic compartments. Here, we describe a live cell imaging approach using spinning disk confocal microscopy to investigate the effect of neuromodulator receptor activation on synaptic activity by measuring calcium dynamics in primary rat striatal neurons. The advantages of spinning disk confocal microscopy and recent improvements in the genetically encoded calcium sensor, GCaMP6, provide an imaging approach to image both the receptor membrane trafficking to endocytic compartments, and calcium dynamics at a high spatial and temporal resolution. We believe this approach of imaging both the neuromodulator receptor membrane trafficking and synaptic activity using GCaMP6 is a powerful tool to address many questions regarding possible roles of membrane trafficking of neuromodulator receptors in synaptic activity. PMID- 27943196 TI - Imaging Activity-Dependent Signaling Dynamics at the Neuronal Synapse Using FRET Based Biosensors. AB - In this chapter, we introduce the combined use of FRET-based biosensors and synaptic markers as an effective tool for studying intracellular signaling pathways in small synaptic terminals of neuronal cells. The approach is based on the unmixing of excitation/emission spectral fingerprints of a FRET donor and acceptor pair, as well as a lipophilic styryl dye, FM1-43, loaded into presynaptic terminals. The destaining of FM1-43 during evoked release provides a map to guide the sampling of fluorescence for FRET analysis. In the example presented here, we measure the temporal dynamics of cAMP at the presynaptic terminal using an intramolecular CFP/YFP-based FRET sensor. However, this methodology can be applied to investigate the spatial and temporal regulation of a variety of signaling processes, as well as dynamic changes in protein-protein interaction. PMID- 27943197 TI - Analyzing Structural Plasticity of Dendritic Spines in Organotypic Slice Culture. AB - Understanding the rules of synapse dynamics in the context of development, learning, and nervous system disorders is an important part of several fields of neuroscience. Despite significant methodological advances, observations of structural dynamics of synapses still present a significant experimental challenge. In this chapter we describe a set of techniques that allow repetitive observations of synaptic structures in vitro in organotypic cultures of rodent hippocampus. We describe culturing of slices, transfection with reporter-carrying plasmids, repetitive imaging of dendritic spines with confocal laser scanning microscopy and analysis of spine morphology dynamics. PMID- 27943198 TI - Using Fluorescent Markers to Estimate Synaptic Connectivity In Situ. AB - Labeling fixed brain tissue with fluorescent synaptic and cellular markers can help assess circuit connectivity. Despite the diffraction-limited resolution of light microscopy there are several approaches to identify synaptic contacts onto a cell-of-interest. Understanding which image quantification methods can be applied to estimate cellular and synaptic connectivity at the light microscope level is beneficial to answer a range of questions, from mapping appositions between cellular structures or synaptic proteins to assessing synaptic contact density onto a cell-of-interest. This chapter provides the reader with details of the image analysis methods that can be applied to quantify in situ connectivity patterns at the level of cellular contacts and synaptic appositions. PMID- 27943199 TI - Dual Anterograde and Retrograde Viral Tracing of Reciprocal Connectivity. AB - Current large-scale approaches in neuroscience aim to unravel the complete connectivity map of specific neuronal circuits, or even the entire brain. This emerging research discipline has been termed connectomics. Recombinant glycoprotein-deleted rabies virus (RABV ?G) has become an important tool for the investigation of neuronal connectivity in the brains of a variety of species. Neuronal infection with even a single RABV ?G particle results in high-level transgene expression, revealing the fine-detailed morphology of all neuronal features-including dendritic spines, axonal processes, and boutons-on a brain wide scale. This labeling is eminently suitable for subsequent post-hoc morphological analysis, such as semiautomated reconstruction in 3D. Here we describe the use of a recently developed anterograde RABV ?G variant together with a retrograde RABV ?G for the investigation of projections both to, and from, a particular brain region. In addition to the automated reconstruction of a dendritic tree, we also give as an example the volume measurements of axonal boutons following RABV ?G-mediated fluorescent marker expression. In conclusion RABV ?G variants expressing a combination of markers and/or tools for stimulating/monitoring neuronal activity, used together with genetic or behavioral animal models, promise important insights in the structure-function relationship of neural circuits. PMID- 27943200 TI - Mapping Synaptic Inputs of Developing Neurons Using Calcium Imaging. AB - Studying changing synaptic activity patterns during development provides a wealth of information on how activity-dependent processes shape synaptic connectivity. In this chapter we introduce a method that combines whole-cell electrophysiology with calcium imaging to map functional synaptic sites on the dendritic tree and follow their activity over time. The key strength of this method lies in its ability to distinguish between synaptic and non-synaptic calcium signaling by their coincidence with synaptic currents measured at the soma. Next to the required materials and protocols that are necessary to perform these experiments, we thoroughly discuss how the acquired data can be analyzed. Since this method can be employed in many neuronal systems we believe that it can be a valuable tool to study developmental changes in synaptic connectivity. PMID- 27943201 TI - Monosynaptic Tracing in Developing Circuits Using Modified Rabies Virus. AB - An attenuated rabies virus that expresses fluorescent protein has made it possible to analyze retrograde (presynaptic) monosynaptic connections in vivo. By combining attenuated rabies virus with a Cre-loxP based system to target cells in a subtype-specific fashion, it is possible to examine neuronal input in vivo onto any class of neuron, in development and in the mature brain. We describe here the methods to amplify deletion mutant, pseudotyped rabies virus, selectively target cells of interest using genetic and viral approaches, as well as the stereotaxic procedures required to target neuronal subtypes of interest in vivo. PMID- 27943203 TI - Methods to Analyze EVs. AB - Research in the field of extracellular vesicles (EVs) is challenged by the small size of the nano-sized particles. Apart from the use of transmission and scanning electron microscopy, established technical platforms to visualize, quantify, and characterize nano-sized EVs were lacking. Recently, methodologies to characterize nano-sized EVs have been developed. This chapter aims to summarize physical principles of novel and conventional technologies to be used in the EV field and to discuss advantages and limitations. PMID- 27943202 TI - Incorporating food addiction into disordered eating: the disordered eating food addiction nutrition guide (DEFANG). AB - Although not formally recognized by the DSM-5, food addiction (FA) has been well described in the scientific literature. FA has emerged as a clinical entity that is recognized within the spectrum of disordered eating, particularly in patients with bulimia nervosa, binge-eating disorder and/or co-occurring addictive disorders and obesity. Integrating the concept of FA into the scope of disordered eating has been challenging for ED treatment professionals, since there is no well-accepted treatment model. The confusion surrounding the implications of FA, as well as the impact of the contemporary Westernized diet, may contribute to poor treatment outcomes. The purpose of this review is twofold. The first is to briefly explore the relationships between EDs and addictions, and the second is to propose a new model of conceptualizing and treating EDs that incorporates recent data on FA. Since treatment for EDs should vary based on individual assessment and diagnosis, the Disordered Eating Food Addiction Nutrition Guide (DEFANG) is presented as a tool for framing treatment goals and helping patients achieve sustainable recovery. PMID- 27943204 TI - Tunable Resistive Pulse Sensing for the Characterization of Extracellular Vesicles. AB - Accurate characterization of extracellular vesicles (EVs), including exosomes and microvesicles, is essential to obtain further knowledge on the biological relevance of EVs. Tunable resistive pulse sensing (tRPS) has shown promise as a method for single particle-based quantification and size profiling of EVs. Here, we describe the technical background of tRPS and its applications for EV characterization. Besides the standard protocol, we describe an alternative protocol, in which samples are spiked with polystyrene beads of known size and concentration. This alternative protocol can be used to overcome some of the challenges of direct EV characterization in biological fluids. PMID- 27943205 TI - Immuno-characterization of Exosomes Using Nanoparticle Tracking Analysis. AB - Due to their size, small extracellular vesicles such as exosomes have been difficult to identify and to quantify. As the roles that exosomes play in intercellular signalling become clearer, so does their potential utility as both diagnostic biomarkers for disease and as therapeutic vectors. Accurate assessment of exosomes, both their number and their cargo, is important for continued advancement in the field of vesicle research. To that end, several technologies, including nanoparticle tracking analysis, have been developed to define the physical characteristics of vesicle preparations and determine their concentration. This chapter describes a method for identifying the size and concentration of a subpopulation of vesicles in biological samples, using nanoparticle tracking analysis. Characterization of distinct exosomes is enabled by specific marker antibodies, coupled to fluorescent quantum dots. PMID- 27943206 TI - Imaging and Quantification of Extracellular Vesicles by Transmission Electron Microscopy. AB - Extracellular vesicles (EVs) are cell-derived vesicles that are present in blood and other body fluids. EVs raise major interest for their diverse physiopathological roles and their potential biomedical applications. However, the characterization and quantification of EVs constitute major challenges, mainly due to their small size and the lack of methods adapted for their study. Electron microscopy has made significant contributions to the EV field since their initial discovery. Here, we describe the use of two transmission electron microscopy (TEM) techniques for imaging and quantifying EVs. Cryo-TEM combined with receptor-specific gold labeling is applied to reveal the morphology, size, and phenotype of EVs, while their enumeration is achieved after high-speed sedimentation on EM grids. PMID- 27943207 TI - Quantitative Analysis of Exosomal miRNA via qPCR and Digital PCR. AB - Extracellular vesicles, such as exosomes and microvesicles, have been shown to contain potential microRNA (miRNA) biomarkers that may be utilized in the diagnosis of various diseases from cancer to neurological disorders. The unique nature of the extracellular vesicle bilayer allows miRNA to be protected from degradation making it an ideal source of material for biomarkers discovery from both fresh and archived samples. Here we describe the quantitative analysis of miRNA isolated from exosomes by quantitative PCR and digital PCR. PMID- 27943208 TI - Small RNA Library Construction for Exosomal RNA from Biological Samples for the Ion Torrent PGMTM and Ion S5TM System. AB - Next-generation deep sequencing (NGS) technology represents a powerful and innovative approach to profile small RNA. Currently, there are a number of large scale and benchtop sequencing platforms available on the market. Although each platform is relatively straightforward to operate, constructing cDNA libraries can be the most difficult part of the NGS workflow. Constructing quality libraries is essential to obtaining a successful sequencing run of high-quality reads and coverage. The quality and yield of RNA affect hybridization and ligation of sequencing adapters. In the field of biomarker discovery, there has been an interest in profiling exosomal RNA from biological fluids. However, very little RNA yield is obtained when extracting RNA from exosomes, thus making library construction difficult. Here, this protocol describes an optimized protocol for constructing small RNA libraries from low yields of RNA, in particular, extracted from exosomes isolated from biological fluids. PMID- 27943209 TI - A Protocol for Isolation and Proteomic Characterization of Distinct Extracellular Vesicle Subtypes by Sequential Centrifugal Ultrafiltration. AB - Scientific and clinical interest in extracellular vesicles (EVs) has increased rapidly as evidence mounts that they may constitute a new signaling paradigm. Recent studies have highlighted EVs carry preassembled complex biological information that elicit pleiotropic responses in target cells. It is well recognized that cells secrete essentially two EV subtypes that can be partially separated by differential centrifugation (DC): the larger size class (referred to as "microvesicles" or "shed microvesicles," sMVs) is heterogeneous (100-1500 nm), while the smaller size class (referred to as "exosomes") is relatively homogeneous in size (50-150 nm). A key issue hindering progress in understanding underlying mechanisms of EV subtype biogenesis and cargo selectivity has been the technical challenge of isolating homogeneous EV subpopulations suitable for molecular analysis. In this protocol we reveal a novel method for the isolation, purification, and characterization of distinct EV subtypes: exosomes and sMVs. This method, based on sequential centrifugal ultrafiltration (SCUF), affords unbiased isolation of EVs from conditioned medium from a human colon cancer cell model. For both EV subtypes, this protocol details extensive purification and characterization based on dynamic light scattering, cryoelectron microscopy, quantitation, immunoblotting, and comparative label-free proteome profiling. This analytical SCUF method developed is potentially scalable using tangential flow filtration and provides a solid foundation for future in-depth functional studies of EV subtypes from diverse cell types. PMID- 27943210 TI - Multiplexed Phenotyping of Small Extracellular Vesicles Using Protein Microarray (EV Array). AB - The Extracellular Vesicle (EV) Array is based on the technology of protein microarray and provides the opportunity to detect and phenotype small EVs from unpurified starting material in a high-throughput manner (Jorgensen et al., J Extracell vesicles 2:1-9, 2013). The technology was established to perform multiplexed phenotyping of EVs in an open platform. This protocol outlines the microarray printing procedure followed by the steps of capture and detection of small extracellular vesicles from plasma/serum or cell culture supernatants. The principles of data treatment and analysis are thoroughly described as well. PMID- 27943211 TI - Purification and Analysis of Exosomes Released by Mature Cortical Neurons Following Synaptic Activation. AB - Exosomes are vesicles released by most cells into their environment upon fusion of multivesicular endosomes with the plasma membrane. Exosomes are vesicles of 60 100 nm in diameter, floating in sucrose at a density of ~1.15 g/mL and carrying a number of marker proteins such as Alix, Tsg101, and Flotillin-1. We use dissociated cortical neurons cultured for around two weeks as exosome-releasing cells. In these conditions, neurons make mature synapses and form networks that can be activated by physiological stimuli. Here, we describe methods to culture differentiated cortical neurons, induce exosome release by increasing glutamatergic synapse activity, and purify exosomes by differential centrifugations followed by density separation using sucrose gradients. These protocols allow purification of neuronal exosomes released within minutes of activation of glutamatergic synapses. PMID- 27943212 TI - A Method for Isolation of Extracellular Vesicles and Characterization of Exosomes from Brain Extracellular Space. AB - Extracellular vesicles (EV), including exosomes, secreted vesicles of endocytic origin, and microvesicles derived from the plasma membrane, have been widely isolated and characterized from conditioned culture media and bodily fluids. The difficulty in isolating EV from tissues, however, has hindered their study in vivo. Here, we describe a novel method designed to isolate EV and characterize exosomes from the extracellular space of brain tissues. The purification of EV is achieved by gentle dissociation of the tissue to free the brain extracellular space, followed by sequential low-speed centrifugations, filtration, and ultracentrifugations. To further purify EV from other extracellular components, they are separated on a sucrose step gradient. Characterization of the sucrose step gradient fractions by electron microscopy demonstrates that this method yields pure EV preparations free of large vesicles, subcellular organelles, or debris. The level of EV secretion and content are determined by assays for acetylcholinesterase activity and total protein estimation, and exosomal identification and protein content are analyzed by Western blot and immuno electron microscopy. Additionally, we present here a method to delipidate EV in order to improve the resolution of downstream electrophoretic analysis of EV proteins. PMID- 27943213 TI - Isolation of Exosomes and Microvesicles from Cell Culture Systems to Study Prion Transmission. AB - Extracellular vesicles (EVs) are composed of microvesicles and exosomes. Exosomes are small membrane vesicles (40-120 nm sized) of endosomal origin released in the extracellular medium from cells when multivesicular bodies fuse with the plasma membrane, whereas microvesicles (i.e., shedding vesicles, 100 nm to 1 MUm sized) bud from the plasma membrane. Exosomes and microvesicles carry functional proteins and nucleic acids (especially mRNAs and microRNAs) that can be transferred to surrounding cells and tissues and can impact multiple dimensions of the cellular life. Most of the cells, if not all, from neuronal to immune cells, release exosomes and microvesicles in the extracellular medium, and all biological fluids including blood (serum/plasma), urine, cerebrospinal fluid, and saliva contain EVs.Prion-infected cultured cells are known to secrete infectivity into their environment. We characterized this cell-free form of prions and showed that infectivity was associated with exosomes. Since exosomes are produced by a variety of cells, including cells that actively accumulate prions, they could be a vehicle for infectivity in body fluids and could participate to the dissemination of prions in the organism. In addition, such infectious exosomes also represent a natural, simple, biological material to get key information on the abnormal PrP forms associated with infectivity.In this chapter, we describe first a method that allows exosomes and microvesicles isolation from prion infected cell cultures and in a second time the strategies to characterize the prions containing exosomes and their ability to disseminate the prion agent. PMID- 27943214 TI - Isolation of Platelet-Derived Extracellular Vesicles. AB - Platelets participate in several physiological functions, including hemostasis, immunity, and development. Additionally, platelets play key roles in arterial thrombosis and cancer progression. Given this plethora of functions, there is a strong interest of the role of platelet-derived (extracellular) vesicles (PDEVs) as functional mediators and biomarkers. Moreover, the majority of the blood-borne EVs are thought to originate from either platelets or directly from the platelet precursor cells, the megakaryocytes, which reside in the bone marrow. To circumvent confusion, we use the term PDEVs for both platelet-derived and/or megakaryocyte-derived EVs. PDEVs can be isolated from blood or from isolated platelets after activation. In this chapter, we describe all commonly used PDEV isolation methods from blood and prepurified platelets. PMID- 27943215 TI - Bioinformatics Tools for Extracellular Vesicles Research. AB - Extracellular vesicles (EVs) are a class of membranous vesicles that are released by multiple cell types into the extracellular environment. This unique class of extracellular organelles which play pivotal role in intercellular communication are conserved across prokaryotes and eukaryotes. Depending upon the cell origin and the functional state, the molecular cargo including proteins, lipids, and RNA within the EVs are modulated. Owing to this, EVs are considered as a subrepertoire of the host cell and are rich reservoirs of disease biomarkers. In addition, the availability of EVs in multiple bodily fluids including blood has created significant interest in biomarker and signaling research. With the advancement in high-throughput techniques, multiple EV studies have embarked on profiling the molecular cargo. To benefit the scientific community, existing free Web-based resources including ExoCarta, EVpedia, and Vesiclepedia catalog multiple datasets. These resources aid in elucidating molecular mechanism and pathophysiology underlying different disease conditions from which EVs are isolated. Here, the existing bioinformatics tools to perform integrated analysis to identify key functional components in the EV datasets are discussed. PMID- 27943216 TI - Preparation and Isolation of siRNA-Loaded Extracellular Vesicles. AB - RNA interference (RNAi) has tremendous potential for specific silencing of disease-causing genes. Its clinical usage however critically depends on the development of carrier systems that can transport the RNAi-mediating small interfering RNA (siRNA) molecules to the cytosol of target cells. Recent reports have suggested that extracellular vesicles (EVs) form a natural transport system through which biomolecules, including RNA, is exchanged between cells. Therefore, EVs are increasingly being considered as potential therapeutic siRNA delivery systems.In this chapter we describe a method for preparing siRNA-loaded EVs, including a robust, scalable method to isolate them from cell culture supernatants. PMID- 27943217 TI - Interaction of Extracellular Vesicles with Endothelial Cells Under Physiological Flow Conditions. AB - In the last few years it has become clear that, in addition to soluble molecules such as growth factors and cytokines, cells use extracellular vesicles (EVs) for intercellular communication. For example, EVs derived from cancer cells interact with endothelial cells, thereby affecting angiogenesis and metastasis, two essential processes in tumor progression. In most experiments, the interaction of EVs with target cells is investigated under static conditions. However the use of dynamic flow conditions is considered more relevant, especially when studying EV uptake by endothelial cells. Here, we describe the use of a perfusion system to investigate the interaction of (tumor) EVs with endothelial cells under dynamic flow conditions. PMID- 27943218 TI - Flow Cytometric Analysis of Extracellular Vesicles. AB - To analyze EVs with conventional flow cytometers, most researchers will find it necessary to bind EVs to beads that are large enough to be individually resolved on the flow cytometer available in their lab or facility. Although high resolution flow cytometers are available and are being used for EV analysis, the use of these instruments for studying EVs requires careful use and validation by experienced small-particle flow cytometrists, beyond the scope of this chapter. Shown here is a method for using streptavidin-coated beads to capture biotinylated antibodies, and stain the bead-bound EVs with directly conjugated antibodies. We find that this method is a useful tool not only on its own, without further high resolution flow cytometric analysis, but also as a means for optimizing staining methods and testing new labels for later use in high resolution, single EV flow cytometric studies. The end of the chapter includes sphere-packing calculations to quantify aspects of EV- and bead-surface geometry, as a reference for use as readers of this chapter optimize their own flow cytometry assays with EVs. PMID- 27943219 TI - Visualization of the improvement of myocardial perfusion after coronary intervention using motorized fractional flow reserve pullback curve. AB - This study aimed to evaluate the feasibility and utility of using motorized pullback of the pressure guidewire to provide a graphic assessment and prediction of the benefits of coronary intervention. Fractional flow reserve (FFR) measurements were performed with motorized pullback imaging in 20 patients who underwent successful percutaneous coronary intervention (PCI) of the left anterior descending artery. Physiological lesion length (PLL) was calculated using frame counts to determine stent length. FFR area was calculated by integrating the FFR values recorded during pullback tracing (FFRarea). The percentage increase in FFR area (%FFRarea) was defined as the ratio of the difference between the pre- and post-intervention FFRarea to the total frame count. The average FFR values were enhanced following PCI, from 0.64 to 0.82, and the median value of the difference between pre- and post-interventional FFR values (D-FFR) and %FFRarea were 0.13 and 10.6%, respectively. The %FFRarea demonstrated a significant positive correlation with D-FFR (R 2, 0.61; p < 0.01). PLL tended to be longer and the %FFRarea was smaller in lesions with a gradual pressure-drop pattern than those with an abrupt pressure-drop pattern (35.37 vs. 20.40 mm, p = 0.07; 5.78 vs. 16.21%, p < 0.05, respectively). Motorized pullback tracing was able to identify the extent and location of stenosis and help in appropriate stent implantation, in addition to visualizing and quantifying the improvement in FFR following PCI. PMID- 27943221 TI - A Population Pharmacokinetic Model for 51Cr EDTA to Estimate Renal Function. AB - BACKGROUND AND OBJECTIVES: 51Cr EDTA clearance (CL) from plasma is used to estimate glomerular filtration rate (GFR). We propose that current methods for analysing the raw 51Cr EDTA measurements over-simplifies the disposition of 51Cr EDTA and therefore could produce biased GFR estimates. The aim of this study was to develop a population pharmacokinetic model for 51Cr EDTA disposition and to compare model-predicted GFR to other methods of estimating renal function. PATIENTS AND METHODS: Data from 40 individuals who received ~7.4 MBq of 51Cr EDTA, as an intravenous bolus, were available for analysis. Plasma radioactivity (counts/min) was measured from timed collection points at 2, 4, 6 and 24 h after the dose. A population analysis was conducted using NONMEM(r) version 7.2. Model predicted GFR was compared with other methods for estimating renal function using mean prediction error (MPE). RESULTS: A two-compartment pharmacokinetic model with first-order elimination best fit the data. Compared with the model predictions, creatinine CL from 24 h urine data was unbiased. The commonly used 'slope-intercept' method for estimating isotopic GFR was positively biased compared with the model (MPE 15.5 mL/min/1.73 m2 [95% confidence interval {CI} 8.9-22.2]. The Cockcroft Gault, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equations led to negatively biased GFR estimates (MPE -19.0 [95% CI -25.4 to -12.7], -20.1 [95% CI -27.2 to -13.1] and -16.5 [95% CI -22.2 to -10.1] mL/min/1.73 m2, respectively). CONCLUSIONS: The biased GFR estimates were most obvious in patients with relatively normal renal function. This may lead to inaccurate dosing in patients who are receiving drugs with a narrow therapeutic range where dosing is adjusted according to GFR estimates (e.g. carboplatin). STUDY REGISTRATION: The study is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number: ACTRN 12611000035921. PMID- 27943220 TI - Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus. AB - BACKGROUND: Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE. METHODS: We developed a population pharmacokinetic model for lorazepam using the NONMEM software. We then assessed exploratory exposure response relationships using the overall efficacy and safety study endpoints, and performed dosing simulations. RESULTS: A total of 145 patients contributed 439 pharmacokinetic samples. The median (range) age and dose were 5.4 years (0.3 17.8) and 0.10 mg/kg (0.02-0.18), respectively. A two-compartment pharmacokinetic model with allometric scaling described the data well. In addition to total body weight (WT), younger age was associated with slightly higher weight-normalized clearance (CL). The following relationships characterized the typical values for the central compartment volume (V1), CL, peripheral compartment volume (V2), and intercompartmental CL (Q), using individual subject WT (kg) and age (years): V1 (L) = 0.879*WT; CL (L/h) = 0.115*(Age/4.7)0.133*WT0.75; V2 (L) = 0.542*V1; Q (L/h) = 1.45*WT0.75. No pharmacokinetic parameters were associated with clinical outcomes. Simulations suggest uniform pediatric dosing (0.1 mg/kg, to a maximum of 4 mg) can be used to achieve concentrations of 50-100 ng/mL in children with SE, which have been previously associated with effective seizure control. CONCLUSIONS: The population pharmacokinetics of lorazepam were successfully described using a sparse sampling approach and a two-compartment model in pediatric patients with active SE. PMID- 27943223 TI - In vitro Activity of Ceftolozane/Tazobactam Alone or with an Aminoglycoside Against Multi-Drug-Resistant Pseudomonas aeruginosa from Pediatric Cystic Fibrosis Patients. AB - INTRODUCTION: Gram-negative multi-drug resistance is an emerging threat among pediatric patients with cystic fibrosis (CF). Ceftolozane/tazobactam (C/T) is an extended-spectrum cephalosporin/beta-lactamase inhibitor combination that has been shown to maintain activity against MDR P. aeruginosa isolates. The understanding of C/T effectiveness in pediatric patients is extremely limited. Minimum inhibitory concentration (MIC) testing and time-kill analyses were performed to better understand the antimicrobial susceptibility and potential role of C/T. METHODS: Non-duplicate clinical respiratory MDR P. aeruginosa isolates (n = 5) from four pediatric CF patients were identified. MICs were determined for these isolates using CLSI broth microdilution methods. Time-kill analyses were performed using multiples of C/T alone, and combinations of C/T 2* and 8* the MIC with 30 mg/L tobramycin or 80 mg/L amikacin for all isolates. Cell counts were determined by serial dilution plating. RESULTS: Isolates had variable susceptibilities to C/T (range 0.5-8 mg/L), tobramycin (range 2 to >64 mg/L) and amikacin (range 8 to >256 mg/L). Time-kill analyses revealed an average of 0.71 (range -0.6 to 4.4), 1.50 (range 0.8-2.0) and 2.1 (range 1.2-3.4) log-kill at 4*, 8* and 16* the C/T MIC, respectively. At a tobramycin MIC of 32 mg/L, combination therapy showed synergistic benefit when the isolate was C/T susceptible. C/T and amikacin combination therapy showed synergistic activity at an amikacin MIC >256 mg/L when C/T MIC was 2 mg/L (4.7 log-kill at 2* C/T MIC and 4.0 log-kill at 8* C/T MIC). CONCLUSION: C/T appears to be a promising treatment option for treatment of MDR P. aeruginosa in pediatric CF patients, both alone and in combination with tobramycin or amikacin. Interestingly, the benefit of C/T combination therapy with amikacin may be more pronounced than with the addition of tobramycin. Further evaluation of such combination regimens in pediatric CF patients is warranted. PMID- 27943222 TI - Clinical Pharmacokinetics and Pharmacodynamics of Cediranib. AB - Cediranib potently and selectively inhibits all three vascular endothelial growth factor receptors (VEGFR-1, -2 and -3), and clinical studies have shown that it is effective in patients with ovarian cancer at a dose of 20 mg/day. Cediranib is absorbed moderately slowly; a high-fat meal reduced the cediranib area under the plasma concentration-time curve (AUC) by 24% and maximum plasma concentration (C max) by 33%. Cediranib binds to serum albumin and alpha1-acid glycoprotein; protein binding in human plasma is approximately 95%. The cediranib AUC and C max increase proportionally with dose from 0.5 to 60 mg, and cediranib has linear pharmacokinetics (PK) over time. Cediranib is metabolized via flavin-containing monooxygenase 1 and 3 (FMO1, FMO3) and uridine 5'-diphospho glucuronosyltransferase (UGT) 1A4. Cediranib and its metabolites are mainly excreted in faeces (59%), with <1% of unchanged drug being excreted in urine. The apparent oral clearance is moderate and the mean terminal half-life is 22 h. Cediranib is a substrate of multidrug resistance-1 (MDR1) protein (also known as P-glycoprotein [P-gp]). Coadministration with ketoconazole, a potent P-gp inhibitor, increases cediranib AUC at steady-state (AUCss) in patients by 21%, while coadministration with rifampicin, a potent inducer of P-gp, decreases cediranib AUCss by 39%. Administration of cediranib with chemotherapies demonstrated minimal PK impact on each other. No dose adjustment is recommended for patients with mild or moderate hepatic or renal impairment, and no dose adjustment is needed on the basis of age and body weight. A pooled analysis at doses of 0.5-60 mg showed no significant increase in QTc intervals. Increases in blood pressure and the incidence of diarrhoea were associated with increased cediranib dose and systemic exposure. PMID- 27943225 TI - Polymorphisms in the Matrix Metalloproteinase-9 Promoters and Susceptibility to Glial Tumors in Turkey. AB - AIM: Evidence suggests an association between MMP-9 functional gene polymorphisms and several tumors. The aim of this study was to investigate the possible role of single-nucleotide polymorphisms (SNP) at MMP-9 R279Q A/G, P574R G/C and R668Q G/A and R668Q (rs17577) genotypes with glial tumors in Turkey. MATERIAL AND METHODS: The present series consisted of tissue samples obtained from 100 cancer-free controls and 100 patients who had undergone glial tumor resection from 2007 to 2011 at the Cerrahpasa Medical Faculty of Istanbul University. Blood samples were collected to extract the genomic deoxyribonucleic acid (DNA) of each subject by polymerase chain reaction (PCR) and DNA sequencing. The genotypes of MMP-9 P574R, R279Q and R668Q SNPs were determined by using the PCR-RFLP assay. Genotypic distributions between patient and control groups were compared for correlations with glial tumor occurrence. RESULTS: SNPs in MMP-9 were not found to be significantly associated with glial tumor risk among participants except R279Q (G G) which showed high risk only in multivariate analysis (OR adjusted, 3.15 95% CI, 1.10-9.01). The comparisons between the grade of tumor and the genotypic polymorphisms also showed no significant associations in the case group (all p values > 0.05). CONCLUSION: The current study showed a significant association between the R279Q G/G polymorphism and formation of glial tumor in advanced age. Changed protein features may cause triggering of some subcellular mechanisms that may have a role in activating oncogenic processes over the years. These data add to the growing epidemiological and experimental evidence that MMP-9 may play a role in glial tumors. PMID- 27943226 TI - Effects of Two Types of Human Cells on Outgrowth of Human Glioma in Rats. AB - AIM: Glioblastoma multiforme (GBM) is one of the malignant brain tumors that occur most frequently. Despite advances in therapy techniques, the cure of GBM is a major concern. Accordingly, there is a lot of interest in devising novel approaches, such as stem cell therapy, to treat patients with GBM. The aim of this study was to investigate the effects of human bone marrow stem (BMS) cells as well as human olfactory ensheathing cells (OECs) on the outgrowth of U87 glioma in rats. MATERIAL AND METHODS: OECs and BMS cells were obtained from volunteers. After verification of the stem cell type by flow cytometry and immunocytochemistry (ICC), cells were labeled and injected into human glioma bearing rats. Magnetic resonance imaging (MRI), Hematoxylin and Eosin (H&E), and Immunohistochemistry (IHC) were utilized to assess the properties of the groups. RESULTS: We found extensive migration and homing of the OECs and BMS cells towards the tumor area. H&E and IHC staining indicated that the grafted OECs survived and prevented the development of glioma. BMS cells supported proliferation and new vessel formation, and metastasis in glioma tissue. CONCLUSION: OECs and BMS cells can pass the blood brain barrier and reach the glioma mass. Therefore, this approach can be a potentially powerful method for the delivery of therapeutic agents to malignant brain tumors. In addition, these cells may be genetically modified in order to specifically express tumor suppressive factors. PMID- 27943224 TI - Quantitative Computed Tomography (QCT) derived Bone Mineral Density (BMD) in finite element studies: a review of the literature. AB - BACKGROUND: Finite element modeling of human bone provides a powerful tool to evaluate a wide variety of outcomes in a highly repeatable and parametric manner. These models are most often derived from computed tomography data, with mechanical properties related to bone mineral density (BMD) from the x-ray energy attenuation provided from this data. To increase accuracy, many researchers report the use of quantitative computed tomography (QCT), in which a calibration phantom is used during image acquisition to improve the estimation of BMD. Since model accuracy is dependent on the methods used in the calculation of BMD and density-mechanical property relationships, it is important to use relationships developed for the same anatomical location and using the same scanner settings, as these may impact model accuracy. The purpose of this literature review is to report the relationships used in the conversion of QCT equivalent density measures to ash, apparent, and/or tissue densities in recent finite element (FE) studies used in common density-modulus relationships. For studies reporting experimental validation, the validation metrics and results are presented. RESULTS: Of the studies reviewed, 29% reported the use of a dipotassium phosphate (K2HPO4) phantom, 47% a hydroxyapatite (HA) phantom, 13% did not report phantom type, 7% reported use of both K2HPO4 and HA phantoms, and 4% alternate phantom types. Scanner type and/or settings were omitted or partially reported in 31% of studies. The majority of studies used densitometric and/or density-modulus relationships derived from different anatomical locations scanned in different scanners with different scanner settings. The methods used to derive various densitometric relationships are reported and recommendations are provided toward the standardization of reporting metrics. CONCLUSIONS: This review assessed the current state of QCT-based FE modeling with use of clinical scanners. It was found that previously developed densitometric relationships vary by anatomical location, scanner type and settings. Reporting of all parameters used when referring to previously developed relationships, or in the development of new relationships, may increase the accuracy and repeatability of future FE models. PMID- 27943227 TI - Practical Aspects of Neuroendoscopic Techniques and Complication Avoidance: A Systematic Review. AB - Although endoscopic techniques have many advantages including improved visualization and magnification, they are also associated with limitations. The objective of this review is to discuss the practical aspects that can reduce complications after endoscopic procedures, and their management. The review is based on the personal experience of more than 2000 neuroendoscopic procedures performed by the senior author. Topic search was made on PubMed using Neuroendoscopy, complications and neuroendoscopy, complication avoidance and neuroendoscopy, endoscopic neurosurgery, and minimally invasive neurosurgery. Relevant articles were selected after analyzing abstracts and/or topics. Endoscopic procedures are also associated with limitations such as obstruction in instruments manipulation, steep learning curve, blind area, difficulty in visualization, disorientation, loss of stereoscopic image and others. Neuroendoscopy is distinct from microsurgery and the surgeon has to learn endoscopic skills in addition to microsurgical techniques. Difficulties in controlling bleeding, working in a limited area, higher complication rate during the initial learning curve and longer operative time are some of the limitations. Attending live workshops, practicing on models, and hands on cadaveric workshops can reduce the learning curve. Proper case selection, multidisciplinary team approach, watching operative video, visiting other departments, observing a skillful endoscopic surgeon, lab training, and simulators can improve results and shorten the learning curve. Limitations of this review are that the search is limited to the English literature and personal experience of a single surgeon that may create some bias. Although neuroendoscopic techniques are associated with improved results in some indications, they have many limitations. Neuroendoscopic skills need to be learned to improve results. PMID- 27943228 TI - History of Spine Deformity in Turkey. AB - Spine deformities are among the most important spinal disorders, affecting health related life quality. Although there are some studies in past centuries, most spine deformity-related studies and research has started in the last century. Many surgical techniques, performed between 1960 and 1990, made scoliosis a touchable pathology. These techniques started with Harrington"s system, wiring techniques, pedicle screw techniques, and all other universal techniques. Anterior and 360 degree techniques contributed to this process. The use of spinal osteotomies, and recent technologies such as magnetic rods, intraoperative neuromonitoring added much to the body of knowledge of literature and improved the outcome. Advancement has not been limited to surgery only and diagnostic advancements had also impact to this process. Surgical techniques performed in the west have been performed soon in our countries. Currently almost all surgical techniques for treatment of spine deformities can be performed in our country. This article reviews historical aspects related to the diagnosis and treatment of spine deformities in Turkey. PMID- 27943229 TI - 2-Methoxyestradiol Inhibits Intracerebral Hemorrhage- Induced Angiogenesis in Rats. AB - AIM: Angiogenesis occurs after intracerebral hemorrhage (ICH). Hypoxia-inducible factor-1? (HIF-1?) is a critical regulator of angiogenesis. However, its role in the central nervous system remains controversial. 2-Methoxyestradiol (2ME2), a natural metabolite of estrogen, is known to inhibit HIF-1?. In the present study, we investigated the effect of 2ME2 in a rat model of ICH-induced angiogenesis. MATERIAL AND METHODS: Sprague-Dawley male rats (n=50) were randomly divided into 5 groups: Sham operated group; ICH; ICH+2ME2; and ICH+Vehicle groups. ICH model was induced by stereotactic injection of collagenase type VII into the right globus pallidus. 2ME2 or vehicle (10% dimethyl sulfoxide) was administered intraperitoneally 10 min after ICH. Angiogenesis and expression of HIF-1? was evaluated by immunohistochemistry, quantitative real time-reverse transcription polymerase chain reaction and western blot, respectively. RESULTS: Proliferating cell nuclear antigen (PCNA)-labeled nuclei were detected in cerebral endothelial cells (ECs) around the hematoma. The labeling peaked at 14 days post-ICH. HIF-1? immunoreactive microvessels with dilated outline were detected in the perihematomal tissues. The vessels extended into the clot from the surrounding tissues from day 7 onwards. HIF-1? protein levels increased, while no change was observed in HIF-1? mRNA expression after ICH. 2ME2 decreased the PCNA-labeled nuclei in cerebral ECs and down-regulated the expression of HIF-1? protein as well, while it had little effect on the mRNA expression of HIF-1?. CONCLUSION: HIF-1? inhibitor, 2ME2, inhibited post-ICH angiogenesis by suppressing HIF-1? expression, thus exerting detrimental effects in ICH. PMID- 27943230 TI - Is the Thoracolumbar Injury Classification and Severity Score (TLICS) Superior to the AO Thoracolumbar Injury Classification System for Guiding the Surgical Management of Unstable Thoracolumbar Burst Fractures without Neurological Deficit? AB - AIM: To determine whether the Thoracolumbar Injury Classification and Severity Score (TLICS) and the Arbeitsgemeinschaft fur Osteosynthesefragen (AO) Spine Thoracolumbar Injury Classification System have any superiority to each other regarding the reliability of their recommendations in the surgical management of unstable thoracolumbar burst fractures. MATERIAL AND METHODS: Fifty-five consecutive patients with thoracolumbar burst fractures undergoing instrumentation between 2010 and 2015 were analyzed retrospectively. TLICS and AO systems were compared based on patients" American Spinal Injury Association (ASIA) scores and they were analyzed for their safety and reliability. RESULTS: A total of 55 patients were studied. Neurological deficits were detected in 18 patients and the remaining 37 patients had normal neurological functions. All the patients with neurological deficits received > 4 points according to TLICS. There were 14 patients with incomplete spinal cord injury and all of them received > 4 points according to TLICS (p < 0.01). On the other hand; 8 of these 14 patients received 4 points according to the AO system. None of the 37 patients without neurological deficit received < 4 points of TLICS whereas 18 of these 37 patients received 3 AO points, to whom AO recommends conservative treatment despite the fact that they had unstable burst fractures (p < 0.01). CONCLUSION: Recommendations of TLICS might be more reliable than those of AO particularly for guiding the surgical management of unstable thoracolumbar burst fractures without neurological deficit. However, this conclusion needs to be verified with further multicenter prospective studies. PMID- 27943231 TI - Morphometric Characteristics of C1-C2 Vertebrae to Perform Anterior Transarticular Crossing Screw Fixation. AB - AIM: In unique clinical situations where C1-C2 posterior fixation is not available or has previously failed, an anterior transarticular screw (ATAS) may be a viable alternative. However, there are no previous reports that investigate possible screw angles, screw entry points, and screw length based on computed tomography (CT) multiplanar reconstruction images in Turkish patients. The aim of this study was to determine the morphometric characteristics C1-C2 vertebrae in order to perform anterior transarticular crossing screw fixation. MATERIAL AND METHODS: Patients who underwent a complete CT scan of the cervical spine for causes other than an investigation of cervical spine malformation or congenital anomaly between the years 2013 and 2015 were included in this study. The anterior transarticular C1-C2 screw angles, screw entry point, and screw length were measured on coronal and sagittal CT multiplanar reconstruction images. RESULTS: Twenty-five male and 14 female patients were included in the study. The mean maximum screw angle for ATAS was found to be 41.18 degrees +/-4.49 degrees . The minimum and maximum screw lengths were 27.46+/-3.39 mm and 28.46+/-3.60 mm, respectively. CONCLUSION: Preoperatively, performing a calculation of the possible screw angles, screw entry point, and screw length based on CT multiplanar reconstruction images for ATAS is a safe and applicable method. In cases in which ATAS fixation across the atlantoaxial joint procedure should be performed without performing a measurement, a screw angle not more than 41.18 degrees +/-4.49 degrees on the coronal plane does not damage the vertebral artery. Furthermore, using screws shorter than 28.46+/-3.60 mm doesn"t purchase the atlantoaxial joint. PMID- 27943232 TI - Distinct presence of the tight junction protein claudin-3 in olfactory bulb and fila olfactoria of the mouse. AB - The tight junction protein claudin-3 is overexpressed in diverse epithelial tumours and is associated with increased survival, progression and motility of tumour cells. Claudin-3 expression profiles are being increasingly used for diagnostic and prognostic tumour classification. Claudin-3 has been identified as a receptor for Clostridium perfringens enterotoxin, which is under consideration for selective lysis of claudin-3-expressing tumours, particularly brain metastases, and other translational medicine uses. However, the localization of claudin-3 in the brain has not been completely elucidated. While claudin-3 in brain tissue adjacent to claudin-3-expressing metastases had been excluded and low or undetectable levels proposed in the CNS, under physiological conditions, in adult human, rat and mouse brains, claudin-3 was exclusively found in choroid plexus epithelium where it is considered an integral component of the blood cerebrospinal-fluid barrier. We report here the pronounced presence of claudin-3 not only in the nasal region (as described for rat), but also in the mouse olfactory bulb and nerve using immunohistochemistry and Western blot. Claudin-3 was present in the fila olfactoria from the epithelium to the olfactory nerve and in the main and accessory olfactory bulb. We propose that the abundant presence of claudin-3 in the olfactory system, particularly in nerve fibres and the olfactory bulb cone, which we present here, may play a role at the interface of the central and peripheral nervous system, both as barrier and for axonal growth and communication. Thus, claudin-3 should be considered and further explored with regards to treatment approaches addressing the olfactory bulb and nasal region. PMID- 27943233 TI - Enhancing functional expression of codon-optimized heterologous enzymes in Escherichia coli BL21(DE3) by selective introduction of synonymous rare codons. AB - Rare codon in a heterologous gene may cause premature termination of protein synthesis, misincorporation of amino acids, and/or slow translation of mRNA, decreasing the heterologous protein expression. However, its hypothetical function pertaining to functional protein folding has been barely reported. Here, we investigated the effects of selective introduction of synonymous rare codons (SRCs) to two codon-optimized (i.e., rare codon-free) genes sucrose phosphorylase (SP) gene from Thermoanaerobacterium thermosaccharolyticum and amidohydrolase gene from Streptomyces caatingaensis on their expression levels in Escherichia coli BL21(DE3). We investigated the introduction of a single SRC to the coding regions of alpha-helix, beta-strand, or linker in the first half of rare codon free sp and ah gene. The introduction of a single SRC in the beginning of the coding regions of beta-strand greatly enhanced their soluble expression levels as compared to the other regions. Also, we applied directed evolution to test multi SRC-containing sp gene mutants for enhanced soluble SP expression levels. To easily identify the soluble SP expression level of colonies growing on Petri dishes, mCherry fluorescent protein was used as a SP-folding reporter when it was fused to the 3' end of the sp gene mutant libraries. After three rounds of screening, the best sp gene mutant containing nine SRCs exhibited an approximately six-fold enhancement in soluble protein expression level as compared to the wild-type and rare codon-free sp control. This study suggests that the selective introduction of SRCs can attenuate translation at specific points and such discontinuous attenuation can temporally separate the translation of segments of the peptide chains and actively coordinates their co-translational folding, resulting in enhanced functional protein expression. Biotechnol. Bioeng. 2017;114: 1054-1064. (c) 2016 Wiley Periodicals, Inc. PMID- 27943234 TI - Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors. AB - Cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein and programmed cell death protein ligand 1 monoclonal antibodies (immune checkpoint inhibitors), are used to treat various malignancies. Their mechanism of action involves the inhibition of negative regulators of immune activation, resulting in immune-related adverse events (irAEs) including endocrinopathies, pneumonitis, colitis, hepatitis and dermatological events. Dermatological irAEs include maculopapular rash, pruritus, vitiligo, blistering disorders, mucocutaneous lichenoid eruptions, rosacea and the exacerbation of psoriasis. Alopecia secondary to immune checkpoint inhibitors has been reported in 1.0-2.0% of treated patients. Our objective is to characterize for the first time the clinicopathology of patients with alopecia areata (AA) secondary to immune checkpoint inhibitors, including the first report of anti-PD-L1 therapy-induced AA, and review of the literature. Four cases of patients who developed partial or complete alopecia during treatment with immune checkpoint inhibitors for underlying cancer were identified from our clinics. Methods include the review of the history and clinicopathologic features. Three patients (75%) had AA and one had universalis. Two patients had a resolution after topical, oral or intralesional therapies and one had a resolution after immunotherapy was discontinued; all regrown hair exhibited poliosis. One of the four patients had coincident onychodystrophy. This report describes a series of four patients who developed partial or complete alopecia (i.e. areata and universalis) during treatment with immune checkpoint inhibitor therapies for cancer. The recognition and management of hair-related irAEs are important for pretherapy counselling and interventions that contribute to maintaining optimal health-related quality of life in patients. PMID- 27943235 TI - The relationship between disease severity and quality of life in discoid lupus erythematosus. PMID- 27943236 TI - The treatment of hidradenitis suppurativa with the glucagon-like peptide-1 agonist liraglutide. AB - Hidradenitis suppurativa (HS) is a cutaneous disease associated with systemic inflammation, obesity and metabolic syndrome. Effective treatment options are limited. The antidiabetic agents, incretins, have been used successfully to treat psoriasis - a disease also associated with metabolic syndrome. We report the use of liraglutide, a glucagon-like peptide-1 agonist, in a patient with HS, leading to subsequent weight loss and improvement in disease control. To our knowledge, this is the first report of liraglutide used in the treatment of HS. PMID- 27943237 TI - Patient- and parent-initiated oral steroids for asthma exacerbations. AB - BACKGROUND: Asthma is a chronic inflammatory disease of the airways affecting an estimated 334 million people worldwide. During severe exacerbations, patients may need to attend a medical centre or hospital emergency department for treatment with systemic corticosteroids, which can be administered intravenously or orally. Some people with asthma are prescribed oral corticosteroids (OCS) for self administration (i.e. patient-initiated) or to administer to their child with asthma (i.e. parent-initiated), in the event of an exacerbation. This approach to treatment is becoming increasingly common. OBJECTIVES: To evaluate the effectiveness and safety of patient- or parent-initiated oral steroids for adults and children with asthma exacerbations. SEARCH METHODS: We identified trials from Cochrane Airways' Specialised Register (CASR) and also conducted a search of the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch). We searched CASR from its inception to 18 May 2016 and trial registries from their inception to 24 August 2016; we imposed no restriction on language of publication. SELECTION CRITERIA: We looked for randomised controlled trials (RCTs), reported as full-text, those published as abstract only, and unpublished data; we excluded cross-over trials.We looked for studies where adults (aged 18 years or older) or children of school age (aged 5 years or older) with asthma were randomised to receive: (a) any patient-/parent-initiated OCS or (b) placebo, normal care, alternative active treatment, or an identical personalised asthma action plan without the patient- or parent-initiated OCS component. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results to identify any studies that met the prespecified inclusion criteria.The prespecified primary outcomes were hospital admissions for asthma, asthma symptoms at follow-up and serious adverse events. MAIN RESULTS: Despite comprehensive searches of electronic databases and clinical trial registries, we did not identify any studies meeting the inclusion criteria for this review. Five potentially relevant studies were excluded for two reasons: the intervention did not meet the inclusion criteria for this review (three studies) and studies had a cross-over design (two studies). Two of the excluded studies asked the relevant clinical question. However, these studies were excluded due to their cross-over design, as per the protocol. We contacted the authors of the cross-over trials who were unable to provide data for the first treatment period (i.e. prior to cross-over). AUTHORS' CONCLUSIONS: There is currently no evidence from randomised trials (non-cross-over design) to inform the use of patient- or parent-initiated oral corticosteroids in people with asthma. PMID- 27943238 TI - Combination therapy of infliximab and ciclosporin in the treatment of recalcitrant psoriasis: a case series. PMID- 27943239 TI - An 18-year retrospective study on the outcomes of keratoacanthomas with different treatment modalities at a single academic centre. PMID- 27943240 TI - Autoinflammation in pyoderma gangrenosum and its syndromic form (pyoderma gangrenosum, acne and suppurative hidradenitis). AB - BACKGROUND: Pyoderma gangrenosum (PG) is a rare skin disease characterized clinically by ulcers with undermined borders, and histologically by neutrophil rich infiltrates. PG may occur alone, in syndromic forms or associated with systemic diseases, such as inflammatory bowel disease and haematological or rheumatological disorders. OBJECTIVES: To determine a specific genetic background related to autoinflammation for PG. METHODS: We assessed autoinflammation by evaluating the cytokine profile and genes involved in classic autoinflammatory diseases in 13 patients with PG and in seven patients with the syndromic form, known as PASH (pyoderma gangrenosum, acne and suppurative hidradenitis). RESULTS: In skin samples, the expression of interleukin (IL)-1beta and its receptors, IL 17 and its receptor, and tumour necrosis factor-alpha and its receptors were significantly higher in both PG (P = 0.001) and in PASH (P < 0.001) than in controls. The chemokines IL-8; chemokine (C-X-C motif) ligand 1/2/3; chemokine (C X-C motif) ligand 16; and RANTES (regulated on activation, normal T-cell expressed and secreted) were also overexpressed. Cases of PG and PASH showed mutations in the autoinflammatory genes MEFV, NLRP3, NLRP12, NOD2, LPIN2 and PSTPIP1. CONCLUSIONS: Overexpression of cytokines/chemokines, along with genetic changes, supports the hypothesis that PG and its syndromic form, PASH, are a spectrum of polygenic autoinflammatory conditions. PMID- 27943241 TI - QSAR models for prediction of chromatographic behavior of homologous Fab variants. AB - While quantitative structure activity relationship (QSAR) models have been employed successfully for the prediction of small model protein chromatographic behavior, there have been few reports to date on the use of this methodology for larger, more complex proteins. Recently our group generated focused libraries of antibody Fab fragment variants with different combinations of surface hydrophobicities and electrostatic potentials, and demonstrated that the unique selectivities of multimodal resins can be exploited to separate these Fab variants. In this work, results from linear salt gradient experiments with these Fabs were employed to develop QSAR models for six chromatographic systems, including multimodal (Capto MMC, Nuvia cPrime, and two novel ligand prototypes), hydrophobic interaction chromatography (HIC; Capto Phenyl), and cation exchange (CEX; CM Sepharose FF) resins. The models utilized newly developed "local descriptors" to quantify changes around point mutations in the Fab libraries as well as novel cluster descriptors recently introduced by our group. Subsequent rounds of feature selection and linearized machine learning algorithms were used to generate robust, well-validated models with high training set correlations (R2 > 0.70) that were well suited for predicting elution salt concentrations in the various systems. The developed models then were used to predict the retention of a deamidated Fab and isotype variants, with varying success. The results represent the first successful utilization of QSAR for the prediction of chromatographic behavior of complex proteins such as Fab fragments in multimodal chromatographic systems. The framework presented here can be employed to facilitate process development for the purification of biological products from product-related impurities by in silico screening of resin alternatives. Biotechnol. Bioeng. 2017;114: 1231-1240. (c) 2016 Wiley Periodicals, Inc. PMID- 27943243 TI - Objective Longitudinal Measures of Physical Activity and Bone Health in Older Japanese: the Nakanojo Study. AB - OBJECTIVES: To examine dose/response relationships between habitual physical activity and bone health in the elderly. DESIGN: Longitudinal. SETTING: Community of Nakanojo. PARTICIPANTS: Community-living Japanese aged 65 to 84 (212 men, 284 women). MEASUREMENTS: Daily 24-h pedometer/accelerometer data were collected continuously for 5 years. A quantitative calcaneal osteosonic index (OSI) was determined annually. RESULTS: Year-end OSI values were higher in those with greater daily step counts and especially a greater duration of activity >3 metabolic equivalents (METs). However, after controlling for baseline OSI, age and body mass, final OSI values were not significantly greater in the fourth than in the third activity quartile, where men and women, respectively, took means of 7,700 and 7,500 steps/day and/or exercised at an intensity >3 METs for means of 19 and 17 min/day. A multivariate-adjusted proportional hazards model predicted that the OSI values of men and women were, respectively, 2.6 (1.4-4.4) and 3.3 (2.1-5.2) and/or 2.8 (1.5-5.6) and 3.9 (2.4-6.7) times more likely to drop below the OSI fracture threshold over 5 years in the two lowest activity quartiles (<7,000 and <6,900 steps/day and/or <18 and <17 min/day at >3 METs) than in the highest quartile (>9,100 and >8,800 steps/day and/or >30 and >25 min/day at >3 METs). CONCLUSION: After adjustment for potential confounders, the calcaneal health of seniors is associated with both the daily step count and the duration of activity at an intensity >3 METs. The bone health is optimal in elderly people who take at least 7,000-8,000 steps/day and/or spend at least 15-20 min/day at an intensity >3 METs. PMID- 27943242 TI - Knockout of a difficult-to-remove CHO host cell protein, lipoprotein lipase, for improved polysorbate stability in monoclonal antibody formulations. AB - While the majority of host cell protein (HCP) impurities are effectively removed in typical downstream purification processes, a small population of HCPs are particularly challenging. Previous studies have identified HCPs that are challenging for a variety of reasons. Lipoprotein lipase (LPL)-a Chinese hamster ovary (CHO) HCP that functions to hydrolyze esters in triglycerides-was one of ten HCPs identified in previous studies as being susceptible to retention in downstream processing. LPL may degrade polysorbate 80 (PS-80) and polysorbate 20 (PS-20) in final product formulations due to the structural similarity between polysorbates and triglycerides. In this work, recombinant LPL was found to have enzymatic activity against PS-80 and PS-20 in a range of solution conditions that are typical of mAb formulations. LPL knockout CHO cells were created with CRISPR and TALEN technologies and resulting cell culture harvest fluid demonstrated significantly reduced polysorbate degradation without significant impact on cell viability when compared to wild-type samples. Biotechnol. Bioeng. 2017;114: 1006 1015. (c) 2016 Wiley Periodicals, Inc. PMID- 27943244 TI - Genetic Variations in Bilirubin Metabolism Genes and Their Association with Unconjugated Hyperbilirubinemia in Adults. AB - OBJECTIVE: The present study was undertaken to investigate the genotype and allele frequencies of the variants in the four bilirubin metabolism genes (UGT1A1, OATP2, HMOX1, and BLVRA) and their association with hyperbilirubinemia. MATERIAL AND METHODS: Genotyping of 17 genetic variants was performed in 115 adults with hyperbilirubinemia and 150 controls by PCR-RFLP, GeneScan analysis, and direct DNA sequencing. RESULTS: Genetic polymorphisms of the UGT1A1 promoter, specifically the T-3279G phenobarbital-responsive enhancer module and (TA)7 dinucleotide repeat, as well as the intron and coding region variants of the OATP2, HMOX1, and BLVRA genes, were significantly higher among the cases than the controls. Further, nearly 82% of the cases showed the presence of significantly four or more variants as compared to 37% of the controls (P < 0.0001) and the mean total serum bilirubin levels also increased according to the number of variants co-expressed. CONCLUSIONS: This study demonstrates that polymorphisms in the bilirubin metabolism genes had a significant effect on bilirubin levels and could be genetic risk factors for hyperbilirubinemia. PMID- 27943245 TI - Variability of Delirium Motor Subtype Scale-Defined Delirium Motor Subtypes in Elderly Adults with Hip Fracture: A Longitudinal Study. AB - OBJECTIVES: To examine changes in motor subtype profile in individuals with delirium. DESIGN: Observational, longitudinal study; substudy of a multicenter, randomized controlled trial. SETTING: Departments of surgery and orthopedics, Academic Medical Center and Tergooi Hospital, the Netherlands. PARTICIPANTS: Elderly adults acutely admitted for hip fracture surgery who developed delirium according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for 2 days or longer (n = 76, aged 86.4 +/- 6.1, 68.4% female). MEASUREMENTS: Delirium Motor Subtype Scale (DMSS), Delirium Rating Scale R98 (DRS R98), comorbidity, and function. RESULTS: Median delirium duration was 3 days (interquartile range 2.0 days). At first assessment, the hyperactive motor subtype was most common (44.7%), followed by hypoactive motor subtype (28.9%), mixed motor subtype (19.7%), and no motor subtype (6.6%). Participants with no motor subtype had lower DRS-R98 scores than those with the other subtypes (P < .001). The DMSS-defined motor subtype of 47 (61.8%) participants changed over time. Katz Index of Activities of Daily Living, Charlson Comorbidity Index, cognitive impairment, age, sex, and delirium duration or severity were not associated with change in motor subtype. CONCLUSION: Motor subtype profile was variable in the majority of participants, although changes that occurred were often related to changes from or to no motor subtype, suggesting evolving or resolving delirium. Changes appeared not be associated with demographic or clinical characteristics, suggesting that evidence from cross-sectional studies of motor subtypes could be applied to many individuals with delirium. Further longitudinal studies should be performed to clarify the stability of motor subtypes in different clinical populations. PMID- 27943246 TI - Producing desulfurized biogas through removal of sulfate in the first-stage of a two-stage anaerobic digestion. AB - In the present work, a two-stage anaerobic digestion system (TSADS) was newly designed to produce biogas with a greatly reduced H2 S content. The role of first (sulfidogenic)-stage digester was not only acidogenesis but also sulfidogenesis (sulfate reduction to H2 S), which would minimize the input of H2 S-producing source in the followed second (methanogenic)-stage digester. For the coexistence of acidogens and sulfate reducing bacteria (SRB) in the sulfidogenic-stage digester, it was found that pH played a crucial role. The acidogenic activity was not affected within a pH range of 4.5-6.0, while it was important to maintain a pH at 5.5 to achieve a sulfate removal efficiency over 70%. The highest sulfate removal attained was 78% at a hydraulic retention time (HRT) of 5 h at pH 5.5 +/- 0.1. The H2 S content in the biogas produced in the conventional single-stage digester (SSAD), used as a control, reached 1,650 +/- 25 ppmv . In contrast, the biogas produced in the methanogenic-stage digester of the developed process had an H2 S content of 200 +/- 15 ppmv . Microbial analysis, done by the next generation sequencing technique, clearly showed the changes in community under different operating conditions. Desulfovibrio bastinii (4.9%) played a key role in sulfate removal in the sulfidogenic-stage of the TSADS owing to its characteristics of a short doubling time and growth in an acidic environment. Biotechnol. Bioeng. 2017;114: 970-979. (c) 2016 Wiley Periodicals, Inc. PMID- 27943247 TI - Long-Term Outcomes of Medication Intervention Using the Screening Tool of Older Persons Potentially Inappropriate Prescriptions Screening Tool to Alert Doctors to Right Treatment Criteria. AB - OBJECTIVES: To compare 24-month outcomes of participants of a prospective randomized controlled trial (RCT) assigned to undergo a medication intervention of orally communicated recommendations based on Screening Tool of Older Persons potentially inappropriate Prescriptions (STOPP) and Screening Tool to Alert Doctors to Right Treatment (START) (intervention group) with outcomes of those assigned to undergo written medication review (control group). DESIGN: Retrospective cohort study. SETTING: Chronic care geriatric facility. PARTICIPANTS: Of 359 participants from a prospective RCT conducted between April 2012 and September 2013, 306 were evaluable for another 12-month follow-up. MEASUREMENTS: Outcomes at 24-month follow-up included quality of prescribing (assessed according to STOPP/START), hospitalizations, falls, costs of medications, and all-cause mortality. Outcomes were compared with those reported at the beginning (baseline) and end (12-month follow-up) of the RCT. RESULTS: There was a significant rise in potentially inappropriate prescriptions (PIPs) (P = .01) and potentially prescriptions omissions (PPOs) (P < .001) in the intervention group between 12 and 24 months, although the prevalence of PIPs was significantly lower in the intervention group (33.3%) than the control group (48.4%) at 24-month follow-up (P = .02). Costs of medications were significantly lower in the intervention group than the control group (P < .001) at 24-month follow-up. The average number of falls in both groups dropped significantly between baseline and study closure (P = .04 and P = .008, respectively). There was no significant difference in hospitalizations and mortality between the two groups at 24-month follow-up. CONCLUSION: The effect of an orally communicated medication intervention with the STOPP/START criteria on falls was maintained over time. Direct communication between pharmacists and prescribing physicians is more efficient than written medication review and is recommended every 6 months in geriatric facilities. PMID- 27943248 TI - Treatment of moderate-to-severe atopic eczema in adults within the U.K.: results of a national survey of dermatologists. AB - BACKGROUND: Little is known about U.K. dermatologists' treatment approaches towards adult patients with recalcitrant moderate-to-severe atopic eczema. OBJECTIVES: We wanted to learn about (i) treatment approaches used for this disease in the U.K.; (ii) factors that influence treatment decisions and (iii) perceived gaps in evidence on treatment safety and efficacy, and priorities for future trials. METHODS: We conducted an online survey of consultant-level dermatologists in the U.K. RESULTS: Sixty-one respondents from over 30 centres reported on management of moderate-to-severe atopic eczema in adults, outwith the context of an acute flare. Phototherapy or psoralen-ultraviolet A was the most common therapeutic modality chosen first line (46%), and this was usually narrowband ultraviolet B. Systemic therapy was chosen as a first-line approach by 36% of dermatologists. Azathioprine was the commonest drug reported being used as first line followed by oral corticosteroids, ciclosporin and methotrexate. Methotrexate was the most common second-line treatment of respondents. The key factors that influenced decision making on the use of phototherapy and systemic agents were the respondent's clinical experience, results of baseline tests (systemic agents) and knowledge of both efficacy and acute and chronic side effect profiles. The most important evidence gaps identified were the relative effectiveness of treatments, the alternatives to current approaches and the safety of long-term maintenance treatment. With regard to future trials, respondents suggested that priority should be given to studies involving methotrexate. CONCLUSIONS: While survey study designs have limitations, we found that phototherapy, in particular narrowband ultraviolet B, was respondents' preferred first-line treatment for adults with recalcitrant moderate-to-severe atopic eczema, perhaps reflecting access to, and clinical experience of, this approach. Azathioprine is widely used as a longer-term maintenance treatment. PMID- 27943249 TI - Metabolic engineering of fatty alcohol production in transgenic hairy roots of Crambe abyssinica. AB - Biotechnological production of fatty alcohols, important raw materials in the chemical industry, has been receiving considerable attention in recent years. Fatty alcohols are formed by the reduction of fatty acyl-CoAs or fatty acyl-ACPs catalyzed by a fatty acyl reductase (FAR). In this study, we introduced genes encoding FARs from Arabidopsis thaliana (AtFAR5) and Simmondsia chinensis (ScFAR) into Crambe abyssinica hairy roots via Agrobacterium rhizogenes-mediated transformation. The efficiency of the transformation ranged between 30 and 45%. The fatty alcohols were only detected in the transgenic hairy root lines expressing ScFAR gene. In all tested lines stearyl alcohol (18:0-OH), arachidyl alcohol (20:0-OH), and behenyl alcohol (22:0-OH) were produced. The content of 18:0-OH varied from 1 to 3% of total fatty acids and fatty alcohols, while the amount of either 20:0-OH and 22:0-OH did not exceed 2%. The transgenic hairy root lines produced from 0.98 to 2.59 nmol of fatty alcohols per mg of dry weight. Very low activity of ScFAR was detected in the microsomal fractions isolated from the selected hairy root lines. To our knowledge, this is the first report on the fatty alcohol production in the hairy root cultures. Biotechnol. Bioeng. 2017;114: 1275-1282. (c) 2016 Wiley Periodicals, Inc. PMID- 27943251 TI - Frequency of squamous cell carcinoma in situ (SCCIS) and SCC in re-excisions of biopsy-proven cutaneous SCCIS. PMID- 27943250 TI - Multifocal versus monofocal intraocular lenses after cataract extraction. AB - BACKGROUND: Good unaided distance visual acuity (VA) is now a realistic expectation following cataract surgery and intraocular lens (IOL) implantation. Near vision, however, still requires additional refractive power, usually in the form of reading glasses. Multiple optic (multifocal) IOLs are available which claim to allow good vision at a range of distances. It is unclear whether this benefit outweighs the optical compromises inherent in multifocal IOLs. OBJECTIVES: To assess the visual effects of multifocal IOLs in comparison with the current standard treatment of monofocal lens implantation. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2016), Embase (January 1980 to June 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 June 2016. SELECTION CRITERIA: All randomised controlled trials comparing a multifocal IOL of any type with a monofocal IOL as control were included. Both unilateral and bilateral implantation trials were included. We also considered trials comparing multifocal IOLs with "monovision" whereby one eye is corrected for distance vision and one eye corrected for near vision. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We assessed the 'certainty' of the evidence using GRADE. MAIN RESULTS: We found 20 eligible trials that enrolled 2230 people with data available on 2061 people (3194 eyes). These trials were conducted in Europe (13), China (three), USA (one), Middle East (one), India (one) and one multicentre study in Europe and the USA. Most of these trials compared multifocal with monofocal lenses; two trials compared multifocal lenses with monovision. There was considerable variety in the make and model of lenses implanted. Overall we considered the trials at risk of performance and detection bias because it was difficult to mask participants and outcome assessors. It was also difficult to assess the role of reporting bias.There was moderate-certainty evidence that the distance acuity achieved with multifocal lenses was not different to that achieved with monofocal lenses (unaided VA worse than 6/6: pooled RR 0.96, 95% confidence interval (CI) 0.89 to 1.03; eyes = 682; studies = 8). People receiving multifocal lenses may achieve better near vision (RR for unaided near VA worse than J3/J4 was 0.20, 95% CI 0.07 to 0.58; eyes = 782; studies = 8). We judged this to be low-certainty evidence because of risk of bias in the included studies and high heterogeneity (I2 = 93%) although all included studies favoured multifocal lenses with respect to this outcome.People receiving multifocal lenses may be less spectacle dependent (RR 0.63, 95% CI 0.55 to 0.73; eyes = 1000; studies = 10). We judged this to be low-certainty evidence because of risk of bias and evidence of publication bias (skewed funnel plot). There was also high heterogeneity (I2 = 67%) but all studies favoured multifocal lenses. We did not additionally downgrade for this.Adverse subjective visual phenomena were more prevalent and more troublesome in participants with a multifocal IOL compared with monofocals (RR for glare 1.41, 95% CI 1.03 to 1.93; eyes = 544; studies = 7, low-certainty evidence and RR for haloes 3.58, 95% CI 1.99 to 6.46; eyes = 662; studies = 7; moderate-certainty evidence).Two studies compared multifocal lenses with monovision. There was no evidence for any important differences in distance VA between the groups (mean difference (MD) 0.02 logMAR, 95% CI -0.02 to 0.06; eyes = 186; studies = 1), unaided intermediate VA (MD 0.07 logMAR, 95% CI 0.04 to 0.10; eyes = 181; studies = 1) and unaided near VA (MD -0.04, 95% CI -0.08 to 0.00; eyes = 186; studies = 1) compared with people receiving monovision. People receiving multifocal lenses were less likely to be spectacle dependent (RR 0.40, 95% CI 0.30 to 0.53; eyes = 262; studies = 2) but more likely to report problems with glare (RR 1.41, 95% CI 1.14 to 1.73; eyes = 187; studies = 1) compared with people receiving monovision. In one study, the investigators noted that more people in the multifocal group underwent IOL exchange in the first year after surgery (6 participants with multifocal vs 0 participants with monovision). AUTHORS' CONCLUSIONS: Multifocal IOLs are effective at improving near vision relative to monofocal IOLs although there is uncertainty as to the size of the effect. Whether that improvement outweighs the adverse effects of multifocal IOLs, such as glare and haloes, will vary between people. Motivation to achieve spectacle independence is likely to be the deciding factor. PMID- 27943252 TI - Patients with erythropoietic protoporphyria have reduced erythrocyte protoporphyrin IX from early in pregnancy. PMID- 27943253 TI - Understanding the Journey. PMID- 27943254 TI - Minimally invasive surgery versus radiotherapy/chemoradiotherapy for small-volume primary oropharyngeal carcinoma. AB - BACKGROUND: More than 400,000 cases of oropharyngeal squamous cell carcinoma (OPSCC) are diagnosed each year worldwide and the incidence is rising, partly as a result of human papillomavirus. Human papillomavirus-associated OPSCC affects younger patients and often presents at a higher stage; however, it is associated with a better prognosis.Until recently, first-line management of OPSCC involved chemoradiotherapy, as research had demonstrated comparable survival outcomes when compared with open surgery, with significantly decreased morbidity. However, interventions have now evolved with computerised planning and intensity-modulated radiotherapy, and the advent of endoscopic head and neck surgery, which provide the potential for decreased treatment-associated morbidity.The oropharynx plays an essential role in swallowing, speech and protecting the airway as it is situated at the bifurcation of the respiratory and digestive tracts. Treatment modality recommendations are based on survival outcomes. Given the younger patient demographic, establishing the safety of modalities that potentially have better functional outcome is becoming increasingly important. OBJECTIVES: To assess the efficacy of endoscopic head and neck surgery (transoral robotic surgery or transoral laser microsurgery) for small-volume, primary (T1-2, N0-2) oropharyngeal squamous cell carcinoma (OPSCC) in comparison to radiotherapy/chemoradiotherapy. SEARCH METHODS: The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2016, Issue 10); PubMed; EMBASE; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 8 November 2016. SELECTION CRITERIA: Randomised controlled trials in patients with carcinoma in the oropharynx subsite (as defined by the World Health Organization classification C09, C10). Cancers included were primary squamous cell carcinomas arising from the oropharyngeal mucosa. The tumours were classified as T1-T2 with or without nodal disease and with no evidence of distant metastatic spread. The intervention was transoral, minimally invasive surgery with or without adjuvant radiotherapy or adjuvant chemoradiotherapy. The comparator was primary radiotherapy with or without induction or concurrent chemotherapy for the tumour. The treatments received and compared were of curative intent and patients had not undergone prior intervention, other than diagnostic biopsy. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival (disease-related mortality was to be studied where possible), locoregional control, disease-free survival and progression-free survival or time to recurrence. All outcomes were to be measured at two, three and five years after diagnosis. Our secondary outcomes included quality of life, harms associated with treatment, patient satisfaction and xerostomia score. MAIN RESULTS: No completed studies met the inclusion criteria for the review. Two ongoing trials fulfilled the selection criteria, however neither are complete.'Early-stage squamous cell carcinoma of the oropharynx: radiotherapy versus trans-oral robotic surgery (ORATOR)' is a phase II randomised controlled trial comparing primary radiation therapy with primary transoral robotic surgery for small-volume primary (T1-2, N0-2) OPSCC. It is currently in progress with an estimated completion date of June 2021.'European Organisation for Research and Treatment of Cancer 1420 (EORTC 1420-HNCG-ROG)' is a phase III, randomised study assessing the "best of" radiotherapy compared to transoral robotic surgery/transoral laser microsurgery in patients with T1-T2, N0 squamous cell carcinoma of the oropharynx and base of tongue. It was due to start accrual mid 2016. AUTHORS' CONCLUSIONS: The role of endoscopic head and neck surgery in the management of OPSCC is clearly expanding as evidenced by its more overt incorporation into the current National Comprehensive Cancer Network guidelines. Data are mounting regarding its outcomes both in terms of survival and lower morbidity. As confidence increases, it is being used in the management of more advanced OPSCC.Based on this review, there is currently no high-quality evidence from randomised controlled trials regarding clinical outcomes for patients with oropharyngeal cancer receiving endoscopic head and neck surgery compared with primary chemoradiotherapy. PMID- 27943255 TI - Self-Reported Physical Activity Levels of Older Cancer Survivors: Results from the 2014 National Health Interview Survey. AB - OBJECTIVES: To examine adherence to the American College of Sports Medicine and American Cancer Society guidelines on leisure-time aerobic and muscle strengthening physical activity (PA) of older cancer survivors. DESIGN: Cross sectional study based on the 2014 National Health Interview Survey. SETTING: United States. PARTICIPANTS: Young-old (65-74) (n = 627), old-old (>=75) (n = 656), and middle-aged (45-64) (n = 786) cancer survivors and adults without cancer (n = 18,369), stratified according to the same age groups. MEASUREMENTS: Weighted percentages were used to describe sociodemographic and health-related characteristics of the study population. Unadjusted and adjusted predicted probabilities from generalized ordered and multinomial logistic regressions were estimated to examine levels of aerobic and muscle-strengthening PA in the study population. RESULTS: Cancer survivors and those without a cancer diagnosis had similarly low rates of adherence to PA guidelines according to age group. In unadjusted analyses, the age effect was statistically significant in long-term cancer survivors only. Adjusting for sociodemographic and health-related characteristics, on average, 34.0% of young-old and 35.4% of old-old cancer survivors engaged in sufficient levels of aerobic PA, versus 44.3% of their middle-aged counterparts (P's <.05). Approximately 10% of older cancer survivors met aerobic and muscle-strengthening guidelines, compared with 19.1% of middle aged cancer survivors (P = .001). CONCLUSION: Adherence to the recommended levels of leisure-time aerobic and muscle-strengthening PA is lower in older than middle aged cancer survivors in the United States. Greater efforts must be made to encourage and support PA participation in this population. PMID- 27943256 TI - Specimens processed with an extraction solution of the Dermatophyte Test Strip can be used for direct microscopy. PMID- 27943257 TI - A clinical and serological study of linear IgA bullous dermatosis without linear immunoglobulin deposition other than IgA at the basement membrane zone using direct immunofluorescence. AB - BACKGROUND: Linear IgA bullous dermatosis (LABD) is a heterogeneous disease. Different diagnostic criteria have been used in different reports. OBJECTIVES: To reappraise the characteristic features of LABD with only IgA deposition at the basement membrane zone (BMZ) with direct immunofluorescence (DIF). METHODS: We retrospectively collected data from 101 patients from our archival records from 1 January 1996 to 31 December 2014 who had: (i) blisters on the skin and/or mucous membranes; (ii) subepidermal blisters in a biopsy specimen; and (iii) linear IgA deposition along the BMZ with/without linear C3 deposition at the BMZ with DIF. Most patients were referred for serological evaluation. Patients who showed concurrent linear IgG and/or IgM deposition at the BMZ under DIF were excluded. Clinical manifestations and serological findings were analysed. RESULTS: Heterogeneity of autoantigens in LABD was confirmed. Fifty-four of 101 patients (53%) had IgG antibodies detected either by indirect immunofluorescence, immunoblotting or enzyme-linked immunosorbent assays (ELISA). No statistical difference in clinical manifestations was found between patients in the IgG antibody-possessing group and patients in the other group. CONCLUSIONS: An association of IgG anti-BMZ antibodies with LABD may increase if new IgG immunoblotting or ELISA techniques become available. Consensus for diagnostic criteria for LABD is desired for prospective data storage, although it may be arbitrary. PMID- 27943258 TI - Improving metabolite production in microbial co-cultures using a spatially constrained hydrogel. AB - Microbial co-cultures promise the development of more efficient bioproductions. However, the design of obligate mutualisms is complicated when using organisms that possess differing growth rates or incompatible media requirements. In this work, we investigate sucrose production by cscB Synechococcus elongatus PCC 7942 within a polyacrylate hydrogel matrix. This system secretes sucrose only when the hydrogel is spatially constrained, demonstrating a new utilization of hydrogel swelling pressure to control the osmotic strength of a microbial microenvironment. The sucrose produced via the constrained microbial hydrogel is used to grow the diazotrophic organism, Azotobacter vinelandii, in a mutually dependent fashion. The growth of this hydrogel-based coculture has several advantages over batch cultures, including better growth over a longer period of time and decreased salt stress on A. vinelandii. Biotechnol. Bioeng. 2017;114: 1195-1200. (c) 2016 Wiley Periodicals, Inc. PMID- 27943260 TI - Effects of a Safe Transportation Educational Program for Older Drivers on Driving Exposure and Community Participation: A Randomized Controlled Trial. AB - OBJECTIVES: To ascertain whether a safe-transportation program can change driving exposure while maintaining community participation of older drivers. DESIGN: Randomized controlled trial. SETTING: Northwest Sydney. PARTICIPANTS: Drivers aged 75 and older (mean 80 +/- 4) (n = 380). INTERVENTION: Intervention group participated in an individualized, one-on-one safe-transportation program adapted from the Knowledge Enhances Your Safety curriculum. A registered occupational therapist delivered the intervention in two sessions held approximately 1 month apart. MEASUREMENTS: An in-vehicle monitoring device hardwired into participants' vehicles measured driving exposure. Community participation was measured using the Keele Assessment of Participation. A staging algorithm based on the Precaution Adoption Process Model measured behavior change toward increased and sustained driving self-regulation. Main outcomes were distance driven per week over 12 months and community participation. Secondary outcomes were behavior change, depressive symptoms, and alternate transportation use. Generalized estimating equations were used to model effect on driving exposure, adjusting for weekly measures, and ordinal regression was used to analyze differences in behavior change profiles between groups using an intention-to-treat approach. RESULTS: Participants were randomized after baseline assessment-190 each to the intervention and control groups. One hundred eighty-three of 190 completed the intervention and 366 of 380 completed the study. On average, participants drove 140 +/- 167 km/wk. Although there was no significant difference between the groups in distance driven per week over 12 months (between-group difference -5.5 km, 95% confidence interval (CI) = -24.5-13.5 km, p = .57), intervention group participants showed greater readiness to engage in self-regulatory driving practices, such as reporting avoiding driving at night or at rush hours, than control group participants (odds ratio (OR) = 1.6, 95% CI = 1.1-2.3, P = .02). At 12 months, use of alternate transportation was similar (between-group difference 0.1, 95% CI = -1.4-1.6, P = .90). Although there was no difference in community participation (between-group difference -0.1, 95% CI = -0.6-0.3, P = .59), older drivers with low function in the intervention group were 3.1 times as likely to report depressive symptoms (95% CI = 1.04-9.2, P = .04) than those with low function in the control group. CONCLUSION: An individualized safe-transportation program can promote behavior change but did not translate to significant differences in weekly mileage after 12 months. Longer follow-up may detect changes over time. PMID- 27943259 TI - MicroRNA (miR)-203 and miR-205 expression patterns identify subgroups of prognosis in cutaneous squamous cell carcinoma. AB - BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most widespread cancer in humans and its incidence is rising. These tumours can evolve as diseases of poor prognosis, and therefore it is important to identify new markers to better predict its clinical evolution. OBJECTIVES: We aimed to identify the expression pattern of microRNAs (miRNAs or miRs) at different stages of skin cancer progression in a panel of murine skin cancer cell lines. Owing to the increasing importance of miRNAs in the pathogenesis of cancer, we considered the possibility that miRNAs could help to define the prognosis of CSCC and aimed to evaluate the potential use of miR-203 and miR-205 as biomarkers of prognosis in human tumours. METHODS: Seventy-nine human primary CSCCs were collected at the University Hospital of Salamanca in Spain. We identified differential miRNA expression patterns at different stages of CSCC progression in a well-established panel of murine skin cancer cell lines, and then selected miR-205 and miR-203 to evaluate their association with the clinical prognosis and evolution of human CSCC. RESULTS: miR-205 was expressed in tumours with pathological features recognized as indicators of poor prognosis such as desmoplasia, perineural invasion and infiltrative growth pattern. miR-205 was mainly expressed in undifferentiated areas and in the invasion front, and was associated with both local recurrence and the development of general clinical events of poor evolution. miR-205 expression was an independent variable selected to predict events of poor clinical evolution using the multinomial logistic regression model described in this study. In contrast, miR-203 was mainly expressed in tumours exhibiting the characteristics associated with a good prognosis, was mainly present in well-differentiated zones, and rarely expressed in the invasion front. Therefore, the expression and associations of miR-205 and miR-203 were mostly mutually exclusive. Finally, using a logistic biplot we identified three clusters of patients with differential prognosis based on miR-203 and miR-205 expression, and pathological tumour features. CONCLUSIONS: miR-205 and miR-203 tended to exhibit mutually exclusive expression patterns in human CSCC. This work highlights the utility of miR-205 and miR-203 as prognostic markers in CSCC. PMID- 27943261 TI - Efavirenz or nevirapine in three-drug combination therapy with two nucleoside or nucleotide-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naive individuals. AB - BACKGROUND: The advent of highly active antiretroviral therapy (ART) has reduced the morbidity and mortality due to HIV infection. The World Health Organization (WHO) ART guidelines focus on three classes of antiretroviral drugs, namely nucleoside or nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors. Two of the most common medications given as first-line treatment are the NNRTIs, efavirenz (EFV) and nevirapine (NVP). It is unclear which NNRTI is more efficacious for initial therapy. This systematic review was first published in 2010. OBJECTIVES: To determine which non-nucleoside reverse transcriptase inhibitor, either EFV or NVP, is more effective in suppressing viral load when given in combination with two nucleoside reverse transcriptase inhibitors as part of initial antiretroviral therapy for HIV infection in adults and children. SEARCH METHODS: We attempted to identify all relevant studies, regardless of language or publication status, in electronic databases and conference proceedings up to 12 August 2016. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov to 12 August 2016. We searched LILACS (Latin American and Caribbean Health Sciences Literature) and the Web of Science from 1996 to 12 August 2016. We checked the National Library of Medicine (NLM) Gateway from 1996 to 2009, as it was no longer available after 2009. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) that compared EFV to NVP in people with HIV without prior exposure to ART, irrespective of the dosage or NRTI's given in combination.The primary outcome of interest was virological success. Other primary outcomes included mortality, clinical progression to AIDS, severe adverse events, and discontinuation of therapy for any reason. Secondary outcomes were change in CD4 count, treatment failure, development of ART drug resistance, and prevention of sexual transmission of HIV. DATA COLLECTION AND ANALYSIS: Two review authors assessed each reference for inclusion using exclusion criteria that we had established a priori. Two review authors independently extracted data from each included trial using a standardized data extraction form. We analysed data on an intention-to-treat basis. We performed subgroup analyses for concurrent treatment for tuberculosis and dosage of NVP. We followed standard Cochrane methodological procedures. MAIN RESULTS: Twelve RCTs, which included 3278 participants, met our inclusion criteria. None of these trials included children. The length of follow-up time, study settings, and NRTI combination drugs varied greatly. In five included trials, participants were receiving concurrent treatment for tuberculosis.There was little or no difference between EFV and NVP in virological success (RR 1.04, 95% CI 0.99 to 1.09; 10 trials, 2438 participants; high quality evidence), probably little or no difference in mortality (RR 0.84, 95% CI 0.59 to 1.19; 8 trials, 2317 participants; moderate quality evidence) and progression to AIDS (RR 1.23, 95% CI 0.72 to 2.11; 5 trials, 2005 participants; moderate quality evidence). We are uncertain whether there is a difference in all severe adverse events (RR 0.91, 95% CI 0.71 to 1.18; 8 trials, 2329 participants; very low quality evidence). There is probably little or no difference in discontinuation rate (RR 0.93, 95% CI 0.69 to 1.25; 9 trials, 2384 participants; moderate quality evidence) and change in CD4 count (MD -3.03; 95% CI -17.41 to 11.35; 9 trials, 1829 participants; moderate quality evidence). There may be little or no difference in treatment failure (RR 0.97, 95% CI 0.76 to 1.24; 5 trials, 737 participants; low quality evidence). Development of drug resistance is probably slightly less in the EFV arms (RR 0.76, 95% CI 0.60 to 0.95; 4 trials, 988 participants; moderate quality evidence). No studies were found that looked at sexual transmission of HIV.When we examined the adverse events individually, EFV probably is associated with more people with impaired mental function (7 per 1000) compared to NVP (2 per 1000; RR 4.46, 95% CI 1.65 to 12.03; 6 trials, 2049 participants; moderate quality evidence) but fewer people with elevated transaminases (RR 0.52, 95% CI 0.35 to 0.78; 3 trials, 1299 participants; high quality evidence), fewer people with neutropenia (RR 0.48, 95% CI 0.28 to 0.82; 3 trials, 1799 participants; high quality evidence), and probably fewer people withrash (229 per 100 with NVP versus 133 per 1000 with EFV; RR 0.58, 95% CI 0.34 to 1.00; 7 trials, 2277 participants; moderate quality evidence). We found that there may be little or no difference in gastrointestinal adverse events (RR 0.76, 95% CI 0.48 to 1.21; 6 trials, 2049 participants; low quality evidence), pyrexia (RR 0.65, 95% CI 0.15 to 2.73; 3 trials, 1799 participants; low quality evidence), raised alkaline phosphatase (RR 0.65, 95% CI 0.17 to 2.50; 1 trial, 1007 participants; low quality evidence), raised amylase (RR 1.40, 95% CI 0.72 to 2.73; 2 trials, 1071 participants; low quality evidence) and raised triglycerides (RR 1.10, 95% CI 0.39 to 3.13; 2 trials, 1071 participants; low quality evidence). There was probably little or no difference in serum glutamic oxaloacetic transaminase (SGOT; MD 3.3, 95% CI -2.06 to 8.66; 1 trial, 135 participants; moderate quality evidence), serum glutamic- pyruvic transaminase (SGPT; MD 5.7, 95% CI -4.23 to 15.63; 1 trial, 135 participants; moderate quality evidence) and raised cholesterol (RR 6.03, 95% CI 0.75 to 48.78; 1 trial, 64 participants; moderate quality evidence).Our subgroup analyses revealed that NVP slightly increases mortality when given once daily (RR 0.34, 95% CI 0.13 to 0.90; 3 trials, 678 participants; high quality evidence). There were little or no differences in the primary outcomes for patients who were concurrently receiving treatment for tuberculosis. AUTHORS' CONCLUSIONS: Both drugs have similar benefits in initial treatment of HIV infection when combined with two NRTIs. The adverse events encountered affect different systems, with EFV more likely to cause central nervous system adverse events and NVP more likely to raise transaminases, cause neutropenia and rash. PMID- 27943264 TI - Predicting Water Resource Impacts of Unconventional Gas Using Simple Analytical Equations. AB - The rapid expansion in unconventional gas development over the past two decades has led to concerns over the potential impacts on groundwater resources. Although numerical models are invaluable for assessing likelihood of impacts at particular sites, simpler analytical models are also useful because they help develop hydrological understanding. Analytical approaches are also valuable for preliminary assessments and to determine where more complex models are warranted. In this article, we present simple analytical solutions that can be used to predict: (1) the spatial extent of drawdown from horizontal wells drilled into the gas-bearing formation, and rate of recovery after gas production ceases; (2) the potential for upward transport of contaminants from the gas-bearing formation to shallow aquifers during hydraulic fracturing operations when pressures in the gas-bearing formation are greatly increased; and (3) the potential downward leakage of water from shallow aquifers during depressurization of gas-bearing formations. In particular, we show that the recovery of pressure after production ceases from gas-bearing shale formations may take several hundred years, and we present critical hydraulic conductivity values for intervening aquitards, below which the impact on shallow aquifers will be negligible. The simplifying assumptions inherent in these solutions will limit their predictive accuracy for site-specific assessments, compared to numerical models that incorporate knowledge of spatial variations in formation properties and which may include processes not considered in the simpler solutions. PMID- 27943265 TI - Assessing opportunities for coordinated R&D in early cancer detection and management in Europe. PMID- 27943263 TI - Distinct hepatitis B virus integration patterns in hepatocellular carcinoma and adjacent normal liver tissue. AB - Infection by the hepatitis B virus (HBV) is one of the main etiologies of hepatocellular carcinoma (HCC). During chronic infection, HBV DNA can integrate into the human genome, and this has been postulated as a possible mechanism of HBV-induced HCC. In this study we used 2199 HBV integration sites from Dr.VIS v2.0 and mapped them to the human genome (hg19) to obtain viral integration sites (VIS) related to protein-coding and non-protein-coding genes. In total, we found 1,377 and 767 VIS within close proximity to protein coding genes and noncoding genes, respectively. Genes affected more than two times included 23.1% of protein coding genes and 24.7% of long noncoding RNAs (lncRNA). Only 4.8% of VIS were shared between HCC and non-tumor tissues. HBV integrations were more common in chromosomes 5, 8, 10, and 19 in HCC tissue and chromosomes 1 and 2 in non tumorous tissue. The number of integration sites on each chromosome correlated with the number of fragile sites in non-tumorous tissue but not in HCC tissue. Functional enrichment analysis of the protein-coding genes containing or in close proximity to HBV integration sites in HCC tissue showed an enrichment of cancer related gene ontology terms. Additionally, the most frequently associated lncRNA genes were related to telomere maintenance, protein modification processes, and chromosome localization. Thus, HBV may have preferred integration sites in the human genome that serve a critical role in HCC development. These results show that HCC treatment may benefit from the development of next generation anti-viral therapies. PMID- 27943262 TI - Contribution of upregulated dipeptidyl peptidase 9 (DPP9) in promoting tumoregenicity, metastasis and the prediction of poor prognosis in non-small cell lung cancer (NSCLC). AB - Dipeptidyl peptidase 9 (DPP9) is encoded by DPP9, which belongs to the DPP4 gene family. Proteins encoded by these genes have unique peptidase and extra-enzymatic functions that have been linked to various diseases including cancers. Here, we describe the expression pattern and biological function of DPP9 in non-small-cell lung cancer (NSCLC). The repression of DPP9 expression by small interfering RNA inhibited cell proliferation, migration, and invasion. Moreover, we explored the role of DPP9 in regulating epithelial-mesenchymal transition (EMT). The epithelial markers E-cadherin and MUC1 were significantly increased, while mesenchymal markers vimentin and S100A4 were markedly decreased in DPP9 knockdown cells. The downregulation of DPP9 in the NSCLC cells induced the expression of apoptosis-associated proteins both in vitro and in vivo. We investigated the protein expression levels of DPP9 by tissue microarray immunohistochemical assay (TMA-IHC) (n = 217). Further we found mRNA expression levels of DPP9 in 30 pairs of clinical NSCLC tissues were significantly lower than in the adjacent non cancerous tissues. Survival analysis showed that the overexpression of DPP9 was a significant independent factor for poor 5-year overall survival in patients with NSCLC (p = 0.003). Taken together, DPP9 expression correlates with poor overall survival in NSCLC. PMID- 27943266 TI - Evaluation of the child oral health promotion 'MaliMali' Programme based on schools in the Kingdom of Tonga. AB - INTRODUCTION: The South Pacific Medical Team (SPMT) has supported oral health care for Tongan juveniles since 1998. This voluntary activity, named the MaliMali ('smile' in Tongan) Programme, is evaluated in detail in this paper. METHODS: This evaluation was guided by the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework. The objectives were to explore: (i) whether the programme was accessible to Tongan schoolchildren (Reach); (ii) the impact of the programme on decayed, missing and filled teeth (DMFT) scores and toothbrushing habits (Effectiveness); (iii) factors that affected the adoption of the programme (Adoption); (iv) whether implementation was consistent with the programme model (Implementation); and (v) the long-term sustainability of the programme (Maintenance). RESULTS: The MaliMali Programme has grown into an international project, has spread countrywide as a uniform health promotion and is reaching children in need. Following implementation of this programme, the oral health of Tongan juveniles has improved, with a decrease in the mean DMFT index and an increase in toothbrushing. To provide training that will allow Tongans to assume responsibility for the MaliMali Programme in the future, dental health education literature was prepared and workshops on oral hygiene and the MaliMali Programme were held frequently. At present, the programme is predominantly managed by Tongan staff, rather than by Japanese staff. CONCLUSIONS: This evaluation found the MaliMali Programme to be feasible and acceptable to children and schools in the Kingdom of Tonga. The programme promotes oral health and provides accessible and improved oral health care in the school setting, consistent with the oral health-promoting school framework. PMID- 27943267 TI - Lifetime alcohol intake is associated with an increased risk of KRAS+ and BRAF /KRAS- but not BRAF+ colorectal cancer. AB - Ethanol in alcoholic beverages is a causative agent for colorectal cancer. Colorectal cancer is a biologically heterogeneous disease, and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist. We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal cancer. We calculated usual alcohol intake for 10 year periods from age 20 using recalled frequency and quantity of beverage specific consumption for 38,149 participants aged 40-69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between lifetime alcohol intake and colorectal cancer risk. Heterogeneity in the HRs across subtypes of colorectal cancer was assessed. A positive dose-dependent association between lifetime alcohol intake and overall colorectal cancer risk (mean follow up = 14.6 years; n = 596 colon and n = 326 rectal cancer) was observed (HR = 1.08, 95% CI: 1.04-1.12 per 10 g/day increment). The risk was greater for rectal than colon cancer (phomogeneity = 0.02). Alcohol intake was associated with increased risks of KRAS+ (HR = 1.07, 95% CI: 1.00-1.15) and BRAF-/KRAS- (HR = 1.05, 95% CI: 1.00-1.11) but not BRAF+ tumors (HR = 0.89, 95% CI: 0.78-1.01; phomogeneity = 0.01). Alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- tumors originating via specific molecular pathways including the traditional adenoma-carcinoma pathway but not with BRAF+ tumors originating via the serrated pathway. Therefore, limiting alcohol intake from a young age might reduce colorectal cancer originating via the traditional adenoma carcinoma pathway. PMID- 27943269 TI - Digest: Female squid influence insemination success after mating to show a preference for smaller males. PMID- 27943268 TI - Non-internalizing antibody-drug conjugates display potent anti-cancer activity upon proteolytic release of monomethyl auristatin E in the subendothelial extracellular matrix. AB - Antibody-drug conjugates (ADCs) represent a promising class of biopharmaceuticals with the potential to localize at the tumor site and improve the therapeutic index of cytotoxic drugs. While it is generally believed that ADCs need to be internalized into tumor cells in order to display optimal therapeutic activity, it has recently been shown that non-internalizing antibodies can efficiently liberate disulfide-linked drugs at the extracellular tumor site, leading to potent anti-cancer activity in preclinical animal models. Here, we show that engineered variants of the F16 antibody, specific to a splice isoform of tenascin C, selectively localize to the subendothelial tumor extracellular matrix in three mouse models of human cancer (U87, A431, MDA-MB-231). A site-specific coupling of F16 in IgG format with a monomethyl auristatin E (MMAE) derivative, featuring a valine-citrulline dipeptide linker equipped with a self-immolative spacer, yielded an ADC product, which cured tumor-bearing mice at a dose of 7 mg/Kg. The observation of an efficient extracellular proteolytic cleavage of the valine citrulline linker was surprising, as it has generally been assumed that this peptidic structure would be selectively cleaved by cathepsin B in intracellular compartments. The products described in this article may be useful for the treatment of human malignancies, as their cognate antigen is strongly expressed in the majority of human solid tumors, lymphomas and aggressive leukemias, while being virtually undetectable in most normal adult tissues. PMID- 27943270 TI - A genetic risk score is significantly associated with statin therapy response in the elderly population. AB - The ability of statins to strongly reduce low-density lipoprotein cholesterol (LDL-C) varies interindividually and is partially influenced by genetic variants. Based on a comprehensive analysis of 23 single nucleotide polymorphisms (SNPs) known to be associated with pharmacokinetics and dynamics of statins, we developed a genetic risk score to study its impact on the therapy outcome in elderly individuals under at least 5 years statin therapy. The study was performed in a population-based cohort of 1016 elderly individuals, which comprised 168 statin users investigated at age 75 and 80. Using random forest models, the major variants influencing LDL-C levels were summarized in a weighted GRS (wGRS). The wGRS was tested with lipid and glucose outcomes and validated in an independent population-based cohort including 221 statin users. Four SNPs within the APOE cluster (rs7412, rs4420638), ABCC2 (rs2002042) and CELSR/SORT1/PSRC1 (rs646776), displayed a major impact on statin efficacy. The wGRS was significantly associated with lower LDL-C at age 75 and 80. This association was replicated displaying similar results. GRS analysis is a powerful tool to evaluate the additive effects of genetic variants on statin response and to estimate the magnitude of LDL-C reduction to a considerable extent in the older population. PMID- 27943272 TI - Diagnostic and prognostic role of cell-free DNA testing for colorectal cancer patients. AB - Circulating cell-free DNA (cfDNA) was found in increased amounts in cancer patients and tumor-associated molecular alteration can be detected in cancer patient's samples. For this reason, the cfDNA analysis is actually considered as a new concept of liquid biopsy. We evaluated the presence and integrity of plasma cfDNA by ALU-based qPCR and the methylation profile of OSMR and SFRP1 genes promoter in a large cohort of colorectal cancer (CRC) patients (n = 114) in comparison to healthy subjects (n = 56) and patients with adenomatous lesions (n = 22). Moreover, we studied the prognosis value focusing on histopathological staging and survival. The cfDNA concentration and the integrity index were increased in CRC patients. The ALU83 and ALU244 fragment dosage showed a moderate discriminant capacity between CRC patients and controls and CRC and adenoma patients. Especially, cfDNA was significantly higher in CRC patients at advanced histopathological stage. In addition, the increased cfDNA level was associated with poor prognosis. A comparison of methylation profile in matched tissue and plasma on 25 CRC patients was performed and only three mismatched cases were observed. A lower methylation quantification was observed in cfDNA than tissue DNA. The cfDNA methylation frequency was statistically different in controls, adenoma and CRC patients and this frequency increased with the histopathological stage of tumor. The adenoma and CRC patients methylated cfDNA showed a higher quantity of ALU83 and ALU244. An integrated approach, combining the detection of ALU fragments and cancer type-specific epigenetic alteration, can improve diagnostic efficiency and better define the prognostic value for CRC disease. PMID- 27943271 TI - 18 F-FDG PET/CT vs. human papillomavirus, p16 and Epstein-Barr virus detection in cervical metastatic lymph nodes for identifying primary tumors. AB - Squamous cell carcinoma of unknown primary of the head and neck (SCCUP) is a heterogeneous disease entity that requires careful examination to locate the occult primary. We examined the diagnostic value of expression of biomarkers, such as human papillomavirus (HPV), p16 and Epstein-Barr virus (EBV), in metastatic lymph nodes vs. 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography/computed tomography (PET/CT). We prospectively enrolled 54 consecutive SCCUP patients who received HPV, p16 and EBV analyses of lymph node fine-needle aspirates and 18 F-FDG PET/CT scans and subsequently underwent examinations and biopsies under general anesthesia to detect primary tumors. The diagnostic performance of the biomarkers and 18 F-FDG PET/CT were compared by using receiver operating characteristics (ROC) curve analyses with histopathological results for identification of primary tumors. Primary tumors were identified in 28 (51.9%) of 54 patients: the palatine tonsil in 24, base of the tongue in 1, nasopharynx in 2, and hypopharynx in 1. The sensitivity of p16 (85.7%) and accuracy of HPV (85.2%) were higher than those (42.9% and 68.5%) of 18 F-FDG PET/CT (p < 0.05). The area under the ROC curve of HPV was higher than that of 18 F-FDG PET/CT (0.857 vs. 0.666, p = 0.007). The disease-free survival rates were higher in the patients with primary tumor detection or p16 nodal immunopositivity than in the other patients (p < 0.05). The results showed that HPV and p16 detection in metastatic lymph nodes can help locate hidden primary tumors, guide definitive treatment and predict patient survival. PMID- 27943273 TI - Granulomatosis With Polyangiitis-Associated Hypertrophic Pachymeningitis Mimicking Spontaneous Intracranial Hypotension: A Case Report. AB - BACKGROUND: Dural enhancement is a characteristic finding in both spontaneous intracranial hypotension and hypertrophic pachymeningitis. Positional headache is the most important feature that distinguishes the two diseases. We report a patient with granulomatosis with polyangiitis (formerly Wegener's granulomatosis) who initially manifested like spontaneous intracranial hypotension. CASE PRESENTATION: We report here the case of a 63-year old man who presented with severe positional headache. The patient had typical symptoms, symmetric dural enhancement, and a recent history of nontraumatic subdural hygroma which led to the diagnosis of spontaneous intracranial hypotension, but was finally diagnosed as granulomatosis with polyangiitis-associated secondary hypertrophic pachymeningitis. Cyclophosphamide therapy was effective for the maintenance of remission. CONCLUSIONS: Hypertrophic pachymeningitis associated with granulomatosis with polyangiitis can present with positional headache and subdural hygroma, mimicking spontaneous intracranial hypotension. Granulomatosis with polyangiitis should be suspected when patients with spontaneous intracranial hypotension or hypertrophic pachymeningitis show atypical features. PMID- 27943274 TI - Postdiagnosis social networks and breast cancer mortality in the After Breast Cancer Pooling Project. AB - BACKGROUND: Large social networks have been associated with better overall survival, though not consistently with breast cancer (BC)-specific outcomes. This study evaluated associations of postdiagnosis social networks and BC outcomes in a large cohort. METHODS: Women from the After Breast Cancer Pooling Project (n = 9267) provided data on social networks within approximately 2 years of their diagnosis. A social network index was derived from information about the presence of a spouse/partner, religious ties, community ties, friendship ties, and numbers of living first-degree relatives. Cox models were used to evaluate associations, and a meta-analysis was used to determine whether effect estimates differed by cohort. Stratification by demographic, social, tumor, and treatment factors was performed. RESULTS: There were 1448 recurrences and 1521 deaths (990 due to BC). Associations were similar in 3 of 4 cohorts. After covariate adjustments, socially isolated women (small networks) had higher risks of recurrence (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.15-1.77), BC-specific mortality (HR, 1.64; 95% CI, 1.33-2.03), and total mortality (HR, 1.69; 95% CI, 1.43-1.99) than socially integrated women; associations were stronger in those with stage I/II cancer. In the fourth cohort, there were no significant associations with BC specific outcomes. A lack of a spouse/partner (P = .02) and community ties (P = .04) predicted higher BC-specific mortality in older white women but not in other women. However, a lack of relatives (P = .02) and friendship ties (P = .01) predicted higher BC-specific mortality in nonwhite women only. CONCLUSIONS: In a large pooled cohort, larger social networks were associated with better BC specific and overall survival. Clinicians should assess social network information as a marker of prognosis because critical supports may differ with sociodemographic factors. Cancer 2017;123:1228-1237. (c) 2016 American Cancer Society. PMID- 27943275 TI - Do males pay for sex? Sex-specific selection coefficients suggest not. AB - Selection acting on males can reduce mutation load of sexual relative to asexual populations, thus mitigating the twofold cost of sex, provided that it seeks and destroys the same mutations as selection acting on females, but with higher efficiency. This could happen due to sexual selection-a potent evolutionary force that in most systems predominantly affects males. We used replicate populations of red flour beetles (Tribolium castaneum) to study sex-specific selection against deleterious mutations introduced with ionizing radiation. We found no evidence for selection being stronger in males than in females; in fact, we observed a nonsignificant trend in the opposite direction. This suggests that selection on males does not reduce mutation load below the level expected under the (hypothetical) scenario of asexual reproduction. Additionally, we employed a novel approach, based on a simple model, to quantify the relative contributions of sexual and offspring viability selection to the overall selection observed in males. We found them to be similar in magnitude; however, only the offspring viability component was statistically significant. In summary, we found no support for the hypothesis that selection on males in general, and sexual selection in particular, contributes to the evolutionary maintenance of sex. PMID- 27943276 TI - Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A. AB - A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions. PMID- 27943277 TI - The Mental Health Parity and Addiction Equity Act Evaluation Study: Impact on Mental Health Financial Requirements among Commercial "Carve-In" Plans. AB - OBJECTIVE: Did mental health cost-sharing decrease following implementation of the Mental Health Parity and Addiction Equity Act (MHPAEA)? DATA SOURCE: Specialty mental health copayments, coinsurance, and deductibles, 2008-2013, were obtained from benefits databases for "carve-in" plans from a national commercial managed behavioral health organization. STUDY DESIGN: Bivariate and regression adjusted analyses compare the probability of use and (conditional) level of cost sharing pre- and postparity. An interaction term is added to compare differential levels of pre- and postparity cost-sharing changes for plans that were and were not already at parity pre-MHPAEA. FINDINGS: Controlling for employer/plan characteristics, MHPAEA is associated with higher intermediate care copayments ($15.9) but lower outpatient ($2.6) copayments among in-network-only plans. Among plans with in- and out-of-network benefits, MHPAEA is associated with lower inpatient ($23.2) and outpatient ($2.5) copayments, but increases in inpatient and intermediate in-network and out-of-network coinsurance (about 1 percentage point). Among the few plans not at parity pre-MHPAEA, changes in use and level of cost-sharing associated with MHPAEA were more dramatic. CONCLUSION: Mixed evidence that MHPAEA led to more generous mental health benefits may stem from the finding that many plans were already at parity pre-MHPAEA. Future policy focus in mental health may shift to slowing growth in cost-sharing for all health services. PMID- 27943280 TI - War and disaster in Sri Lanka: Implications for widows' family adjustment and perception of self-efficacy in caring for one's family. AB - The data for this study were collected in 2014 from widows in Eastern Sri Lanka whose spouses died in the civil war, tsunami, or from health-related problems. Conservation of resources (COR) theory was used as a lens to examine the extent to which war and tsunami-related damages and family problems predict variation in social support, family adjustment and a perception of self-efficacy in caring for one's family as reported by widowed women. We also investigated whether social support from the community and social support from family and friends mediated those relationships. Results of a path model fit to the data suggested variation in family adjustment to be negatively predicted by war-related family problems and positively predicted by the social support of friends and family. Additionally, a sense of self-efficacy in caring for one's family was found to be inversely predicted by war-related family problems and tsunami damages. Clinical, social and theoretical implications are discussed as well as directions for further research. PMID- 27943279 TI - Biology and therapeutic implications of VEGF-A splice isoforms and single nucleotide polymorphisms in colorectal cancer. AB - Tumor growth, dissemination and metastasis are dependent on angiogenesis. The predominant vascular endothelial growth factor (VEGF) isoform that plays a major role in angiogenesis is VEGF-A. Indeed, VEGF-A is implicated in promoting angiogenesis of numerous solid malignancies, including colorectal cancer (CRC). A large body of preclinical and clinical evidence indicates that the expression of specific VEGF-A isoforms represents a predominant pro-angiogenic factor, which is associated with formation of metastases and poor prognosis in CRC patients. Different isoforms of human VEGF-A have been identified, all of which arise from alternative splicing of the primary transcript of a single gene. Notably, it has been recently demonstrated that expression of type 3 isoform pattern is significantly correlated with venous involvement in CRC as well as in progression to metastatic colorectal cancer (mCRC), although it remains unclear what proportion of CRC tumors express these isoforms. This review highlights the importance of investigating the genetic and the epigenetic variations in VEGF-A pathways in CRC, the functions of different VEGF-A isoforms and their potential application as prognostic markers and/or therapeutic targets. Better understanding of the mechanisms controlling angiogenesis in liver metastases is necessary to address the limitations of current anti-angiogenic therapies. PMID- 27943281 TI - Latissimus dorsi flap with vascularized lymph node transfer for lymphedema treatment: Technique, outcomes, indications and review of literature. AB - BACKGROUND AND OBJECTIVES: One of the surgical treatment options for lymphedema is vascularized lymph node transfer (VLNT). We present our experience with latissimus dorsi (LD) flap based VLNT for lymphedema treatment. METHODS: We reviewed 14 consecutive patients treated with pedicled or free LD VLNT between 2014 and 2016 for recalcitrant upper or lower extremity lymphedema. Seven patients underwent lymphovenous bypass in addition to LD VLNT. Limb volume and quality of life scores using the Lymphedema Life Impact Scale (LLIS) were analyzed for quantitative and qualitative assessment. RESULTS: Mean duration of lymphedema was 69 months (range 24-124 months). Follow-up ranged from 3 to 12 months (mean 6.7 month). Major complications included one free flap loss and one reoperation for thrombosis. Mean preoperative volume differential between normal and affected limb was 35% (range 3-87%). Volume differential reduction was 48%, 28%, and 46% at 3, 6, and 12 months, respectively. The LLIS score improved from mean of 46.8 before surgery to a mean of 38.6 at 12 month, demonstrating improvement in quality of life. CONCLUSIONS: The LD VLNT provides a viable option for treatment of UE and LE lymphedema in selected patients. J. Surg. Oncol. 2017;115:72-77. (c) 2016 Wiley Periodicals, Inc. PMID- 27943278 TI - Frequency and clinical correlates of elevated plasma Epstein-Barr virus DNA at diagnosis in peripheral T-cell lymphomas. AB - Epstein-Barr virus (EBV)-encoded RNAs (EBER) in tumor tissue and cell-free plasma EBV-DNA (pEBVd) are detected in EBV-associated lymphomas. Studies have suggested that EBER+ peripheral T-cell lymphomas (PTCL) have worse prognosis but the role of EBV in these neoplasms remains unclear. pEBVd is quantitative and more easily amenable to standardization than EBER, but frequency of pEBVd detection, clinical impact and agreement with EBER status in PTCL are unknown. We retrospectively assessed frequency of detectable pre-treatment pEBVd, presence of EBER in tumor tissue, and outcomes in 61 of 135 EBV-assessable PTCL patients. Fifteen of 61 patients (24.5%, 95% CI: 14-37%) were pre-treatment pEBVd+, with no significant differences in baseline characteristics or treatment between pEBVd+ and pEBVd- patients. EBER-ISH was performed on 10 pEBVd+ and 35 pEBVd- tumors. All 10 pEBVd+ patients were EBER+, but 9 pEBVd- patients were also EBER+. With median follow up of 24 months (range 1-96), overall survival (OS) was shorter in pEBVd+ compared to pEBVd- patients (13 vs. 72 months; p = 0.04). In our retrospective study, pre treatment pEBVd was elevated in 25% of PTCL patients, was highly specific for EBER+ tumors, and was associated with shorter survival. pEBVd should be further explored as a prognostic variable and tumor biomarker in PTCL. PMID- 27943282 TI - BRCA1/2-negative hereditary triple-negative breast cancers exhibit BRCAness. AB - BRCA1/2-associated breast cancers are sensitive to poly(ADPribose) polymerase (PARP) inhibitors and platinum compounds mainly due to their deficiency in DNA repair via homologous recombination (HR). However, approximately only 15% of triple-negative breast cancers (TNBCs) are BRCA1/2-associated. TNBCs that exhibit BRCAness (a phenotype reflecting impaired HR in BRCA1/2-negative tumors) are also regarded sensitive to PARP inhibitors and platinum compounds. Thus, we hypothesized that hereditary BRCA1/2-negative TNBCs may exhibit BRCAness. To find a subset of hereditary BRCA1/2-negative TNBCs among 360 TNBCs, we first identified a group of 41 hereditary TNBCs by analyzing the family histories of the patients. Next, we tested this group for the presence of germline BRCA1/2 mutations, and finally, we compared the expression levels of 120 genes involved in HR and five other major mechanisms of DNA damage repair between BRCA1/2 associated and BRCA1/2-negative subgroups of hereditary TNBCs using real-time PCR arrays. Approximately 73% of the hereditary TNBCs were BRCA1/2-associated and 27% were BRCA1/2-negative. The expression levels of the analyzed genes showed no significant differences between these two subgroups indicating the BRCAness of the BRCA1/2-negative hereditary TNBCs and thereby distinguishing a novel subset of TNBCs as a potential target for PARP inhibitors or platinum-based therapy. The results show the significance of family history in selecting patients with TNBC for therapies directed at incompetent DNA repair (e.g., PARP inhibitors and/or platinum-based therapies) and indicate that a relatively simple strategy for broadening the target group for these modes of treatment is to identify patients with hereditary TNBCs. PMID- 27943283 TI - Prophylactic window therapy with the clinical poly(ADP-ribose) polymerase inhibitor olaparib delays BRCA1-deficient mammary tumour formation in mice. AB - Women with heterozygous germline mutations in the BRCA1 tumour suppressor gene are strongly predisposed to developing early-onset breast cancer through loss of the remaining wild-type BRCA1 allele and inactivation of TP53. Although tumour prevention strategies in BRCA1-mutation carriers are still limited to prophylactic surgery, several therapeutic strategies have been developed to target the DNA repair defects (also known as 'BRCAness') of BRCA1-deficient tumours. In particular, DNA-damaging agents such as platinum drugs and poly(ADP ribose) polymerase (PARP) inhibitors show strong activity against BRCA1-mutated tumours. However, it is unclear whether drugs that target BRCAness can also be used to prevent tumour formation in BRCA1-mutation carriers, especially as loss of wild-type BRCA1 may not be the first event in BRCA1-associated tumourigenesis. We performed prophylactic treatments in a genetically engineered mouse model in which de novo development of BRCA1-deficient mammary tumours is induced by stochastic loss of BRCA1 and p53. We found that prophylactic window therapy with nimustine, cisplatin or olaparib reduced the amount and size of mammary gland lesions, and significantly increased the median tumour latency. Similar results were obtained with intermittent prophylactic treatment with olaparib. Importantly, prophylactic window therapy with nimustine and cisplatin resulted in an increased fraction of BRCA1-proficient mammary tumours, suggesting selective survival and malignant transformation of BRCA1-proficient lesions upon prophylactic treatment with DNA-damaging agents. Prophylactic therapy with olaparib significantly prolonged mammary tumour-free survival without any significant increase in the fraction of BRCA1-proficient tumours, warranting the evaluation of this PARP inhibitor in prophylactic trials in BRCA1-mutation carriers. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27943284 TI - Annual Research Review: Breaking cycles of violence - a systematic review and common practice elements analysis of psychosocial interventions for children and youth affected by armed conflict. AB - BACKGROUND: Globally, one in 10 children live in regions affected by armed conflict. Children exposed to armed conflict are vulnerable to social and emotional difficulties, along with disrupted educational and occupational opportunities. Most armed conflicts occur in low- and middle-income countries (LMICs), where mental health systems are limited and can be further weakened by the context of war. Research is needed to determine feasible and cost-effective psychosocial interventions that can be delivered safely by available mental health workforces (including nonspecialists). A vital first step toward achieving this is to examine evidence-based psychosocial interventions and identify the common therapeutic techniques being used across these treatments. METHODS: A systematic review of psychosocial interventions for conflict-affected children and youth living in LMICs was performed. Studies were identified through database searches (PsycINFO, PubMed, Cochrane Central Register of Controlled Trials, PILOTS and Web of Science Core Collection), hand-searching of reference lists, and contacting expert researchers. The PracticeWise coding system was used to distill the practice elements within clinical protocols. RESULTS: Twenty-eight randomized controlled trials and controlled trials conducted in conflict-affected settings, and 25 efficacious treatments were identified. Several practice elements were found across more than 50% of the intervention protocols of these treatments. These were access promotion, psychoeducation for children and parents, insight building, rapport building techniques, cognitive strategies, use of narratives, exposure techniques, and relapse prevention. CONCLUSIONS: Identification of the common practice elements of effective interventions for conflict-affected children and youth can inform essential future treatment development, implementation, and evaluation for this vulnerable population. To further advance the field, research should focus on identifying which of these elements are the active ingredients for clinical change, along with attention to costs of delivery, training, supervision and how to sustain quality implementation over time. PMID- 27943285 TI - Annual Research Review: Digital health interventions for children and young people with mental health problems - a systematic and meta-review. AB - BACKGROUND: Digital health interventions (DHIs), including computer-assisted therapy, smartphone apps and wearable technologies, are heralded as having enormous potential to improve uptake and accessibility, efficiency, clinical effectiveness and personalisation of mental health interventions. It is generally assumed that DHIs will be preferred by children and young people (CYP) given their ubiquitous digital activity. However, it remains uncertain whether: DHIs for CYP are clinically and cost-effective, CYP prefer DHIs to traditional services, DHIs widen access and how they should be evaluated and adopted by mental health services. This review evaluates the evidence-base for DHIs and considers the key research questions and approaches to evaluation and implementation. METHODS: We conducted a meta-review of scoping, narrative, systematic or meta-analytical reviews investigating the effectiveness of DHIs for mental health problems in CYP. We also updated a systematic review of randomised controlled trials (RCTs) of DHIs for CYP published in the last 3 years. RESULTS: Twenty-one reviews were included in the meta-review. The findings provide some support for the clinical benefit of DHIs, particularly computerised cognitive behavioural therapy (cCBT), for depression and anxiety in adolescents and young adults. The systematic review identified 30 new RCTs evaluating DHIs for attention deficit/hyperactivity disorder (ADHD), autism, anxiety, depression, psychosis, eating disorders and PTSD. The benefits of DHIs in managing ADHD, autism, psychosis and eating disorders are uncertain, and evidence is lacking regarding the cost-effectiveness of DHIs. CONCLUSIONS: Key methodological limitations make it difficult to draw definitive conclusions from existing clinical trials of DHIs. Issues include variable uptake and engagement with DHIs, lack of an agreed typology/taxonomy for DHIs, small sample sizes, lack of blinded outcome assessment, combining different comparators, short-term follow-up and poor specification of the level of human support. Research and practice recommendations are presented that address the key research questions and methodological issues for the evaluation and clinical implementation of DHIs for CYP. PMID- 27943286 TI - New and historical records of the ocean sunfish Mola mola in Icelandic waters. AB - The ocean sunfish Mola mola is considered to be globally distributed in both temperate and tropical waters, but there are many gaps in the knowledge of this species' distribution. A total of 31 records of M. mola from Icelandic waters, dating from 1845 to 2014, are presented and georeferenced. An increase in the number of records at the beginning of this century and particularly in 2012, is suggested to be a consequence of both an increase in ocean temperature on the Icelandic shelf and changes in large scale temperature variations in the North Atlantic Ocean. PMID- 27943287 TI - Disentangling the Influence of Socioeconomic Risks on Children's Early Self Control. AB - OBJECTIVE: Previous studies have shown that individual differences in self control emerge early in childhood and predict a range of important outcomes throughout childhood and adulthood. There is, however, less knowledge about the social origins of self-control, including the mechanisms by which early socioeconomic adversity may lead to lower levels of self-control. This study aimed to extend understanding of the link between socioeconomic adversity and self-control by (a) testing which individual aspects of socioeconomic risk uniquely predict lower self-control; (b) testing whether objective socioeconomic risk operates independently of, or via, subjective parental stress; and (c) examining the interplay of socioeconomic risk factors and individual differences in children's temperament as predictors of early self-control. METHOD: Data were from a UK population birth cohort of 18,552 children born in 2000 and 2001. RESULTS: Multiple individual socioeconomic risk factors have independent associations with children's self-control, including low parental education, income, and occupational class; insecure housing tenure; and younger parenthood. Results point to independent additive effects of exposure to objective and subjective risk. There was evidence of mothers' subjective stress partially mediating objective socioeconomic risks but only weak evidence of hypothesized interaction effects between temperament and socioeconomic risk. CONCLUSIONS: Results were consistent with additive risk and bioecological perspectives. PMID- 27943288 TI - Motivational profiles in high school students: Differences in behavioural and emotional homework engagement and academic achievement. AB - This work examined whether combinations of academic and non-academic goals generated different motivational profiles in high school students. Besides, differences in homework behavioural engagement (i.e. amount of homework, time spent in homework, homework time management), homework emotional engagement (i.e. homework anxiety) and academic achievement were analysed. Participants were 714 high school students (43.4% boys and 56.6% girls). The study of potential motivational profiles was conducted by latent profile analysis, and the differences between the motivational profiles regarding homework variables and academic achievement were analysed using multivariate analysis. The results indicate the existence of five groups of motivational profiles: a group of students with multiple goals, a group of unmotivated students, two groups of students with a predominance of learning goals and, finally, a group comprising students with a high fear of failure. Both the group with multiple goals and the learning goals-oriented groups reported to do more homework, spending more time on homework, making better use of that time and having a higher academic achievement than counterparts. The avoidance-failure group and the group with multiple goals showed higher levels of homework anxiety. Globally, these results provide support for a person-centred approach. PMID- 27943289 TI - Roles of Notch1 Signaling in Regulating Satellite Cell Fates Choices and Postnatal Skeletal Myogenesis. AB - Adult skeletal muscle stem cells, also called satellite cells, are indispensable for the growth, maintenance, and regeneration of the postnatal skeletal muscle. Satellite cells, predominantly quiescent in mature resting muscles, are activated after skeletal muscle injury or degeneration. Notch1 signaling is an evolutionarily conserved pathway that plays crucial roles in satellite cells homeostasis and postnatal skeletal myogenesis and regeneration. Activation of Notch1 signaling promotes the muscle satellite cells quiescence and proliferation, but inhibits differentiation of muscle satellite cells. Notably, the new roles of Notch1 signaling during late-stage of skeletal myogenesis including in post-differentiation myocytes and post-fusion myotubes have been recently reported. Here, we mainly review and discuss the regulatory roles of Notch1 in regulating satellite cell fates choices and skeletal myogenesis. J. Cell. Physiol. 232: 2964-2967, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27943291 TI - Distribution and ecology of lampreys Lethenteron spp. in interior Alaskan rivers. AB - This study describes phenetic characteristics and examines the life history of anadromous Arctic lamprey Lethenteron camtschaticum and freshwater-resident Alaskan brook lamprey Lethenteron alaskense in two tributaries of the middle Yukon River, Alaska. Larval lampreys could not be identified to species using pigmentation density patterns or trunk myomere counts, but adults could be identified to species based on colouration, body size and oral-disc dentition. Although larvae were patchily distributed in both rivers, there was a greater proportion of sample locations where Lethenteron spp. were absent in upper reaches than in middle and lower reaches. Relative abundance, density and median and maximum total length (LT ) of larvae were highly variable among sampling locations. Current velocity, substratum type and coarse woody debris were most strongly correlated with larval Lethenteron spp. density; velocity and substratum size was negatively correlated, whereas woody debris was positively correlated. Water depth, dissolved oxygen levels and specific conductance did not influence habitat selection. Length-frequency distributions, diet composition (organic detritus >= 98%), assimilation efficiency (>70%) and gut fullness (<0.2 mg diet ash-free dry mass) were similar for larvae, regardless of river or sampling location. These results increase understanding of Lethenteron spp. biology and ecology in interior Alaska drainages and add to the existing literature on Lethenteron spp. life history. PMID- 27943290 TI - Isolation, Characterization, and Establishment of Spontaneously Immortalized Cell Line HRPE-2S With Stem Cell Properties. AB - The retinal pigment epithelium is a monolayer of highly specialized pigmented cells located between the neural retina and the Bruch's membrane of the choroid. RPE cells play a crucial role in the maintenance and function of the underlying photoreceptors. This study introduces a spontaneously arising human retinal pigment epithelial cell line, HRPE-2S, which was isolated from primary RPE cell culture of 2 days old male donor. We characterized morphology and functional properties of the new cell line. The immortalized cell line was maintained in culture for more than 70 passages and 240 divisions. The average doubling time of the cells was approximately 22 h and got freezed at 26th passage. The cell line expressed RPE-specific markers RPE65 and cell junction protein ZO1 as an epithelial cell marker. It also expressed CHX10, PAX6, Nestin, SOX2 as stem and retinal progenitor cell markers. Ki67 as a marker of cell proliferation was expressed in all HRPE-2S cells. It represented typical epithelial cobblestone morphology and did not phenotypically change through several passages. Stem cell like aggregations (neurospheres) were observed in SEM microscopy. The cells represented high mitotic index. They could be viable under hypoxic conditions and serum deprivation. According to functional studies, the cell line exhibited stem cell-like behaviors with particular emphasis on its self-renewal capacity. LDH isoenzymes expression pattern confirmed the same cellular source for both of the HRPE-2S cells and primary RPE cells. Characteristics of HRPE-2S cells promise it as an in vitro model for RPE stem cell-based researches. J. Cell. Physiol. 232: 2626-2640, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27943293 TI - Foscan and foslip based photodynamic therapy in osteosarcoma in vitro and in intratibial mouse models. AB - Current osteosarcoma therapies cause severe treatment-related side effects and chemoresistance, and have low success rates. Consequently, alternative treatment options are urgently needed. Photodynamic therapy (PDT) is a minimally invasive, local therapy with proven clinical efficacy for a variety of tumor types. PDT is cytotoxic, provokes anti-vascular effects and stimulates tumor cell targeting mechanisms of the immune system and, consequently, has potential as a novel therapy for osteosarcoma patients. This study investigated the uptake and the dark- and phototoxicity and cytotoxic mechanisms of the photosensitizer (PS) 5,10,15,20-tetrakis(meta-hydroxyphenyl) chlorine (mTHPC, Foscan) and a liposomal mTHPC formulation (Foslip) in the human 143B and a mouse K7M2-derived osteosaroma cell line (K7M2L2) in vitro. Second, the tumor- and metastasis-suppressive efficacies of mTHPC formulations based PDT and associated mechanisms in intratibial, metastasizing osteosarcoma mouse models (143B/SCID and syngeneic K7M2L2/BALB/c) were studied. The uptake of Foscan and Foslip in vitro was time- and dose-dependent and resulted in mTHPC and light dose-dependent phototoxicity associated with apoptosis. In vivo, the uptake of both i.v. administered mTHPC formulations was higher in tumor than in healthy control tissue. PDT caused significant (Foscan p < 0.05, Foslip p < 0.001) tumor growth inhibition in both models. A significant (Foscan p < 0.001, Foslip p < 0.001) immune system dependent suppression of lung metastasis was only observed in the K7M2L2/BALB/c model and was associated with a marked infiltration of T-lymphocytes at the primary tumor site. In conclusion, mTHPC-based PDT is effective in clinically relevant experimental osteosarcoma and suppresses lung metastasis in immunocompetent mice with beneficial effects of the liposomal mTHPC formulation Foslip. PMID- 27943292 TI - Characterization and expression of Megalobrama amblycephala toll-like receptor 22 involved in the response to Aeromonas hydrophila. AB - The toll-like receptors (TLR) tlr22 was identified and characterized for the first time in one of the economically most important freshwater fish species in China, Megalobrama amblycephala. The full-length cDNA (4039 bp) of M. amblycephala tlr22 contains an open reading frame of 2706 bp, encoding a 901 amino-acid long polypeptide. The putative polypeptide contains 16 leucine-rich repeat (LRR) motifs, an LRR C-terminal, a transmembrane region and a cytoplasmic toll-interleukin-1 receptor (TIR) domain. Phylogenetic analyses revealed that M. amblycephala Tlr22 shared the closest relationship with a grass carp ortholog. tlr22 was constitutively expressed in nine tissues and during 10 developmental stages studied, albeit with varying expression levels. Along with many pathological changes observed after Aeromonas hydrophila bacterium infection, tlr22 and myd88 mRNA were significantly upregulated in blood, head kidney, spleen and intestine, indicating that tlr22 is involved in the immune response. These results provide an insight into tlr22 regulation mechanisms in the innate immune response to bacterial infection. PMID- 27943294 TI - Laryngeal pacing for bilateral vocal fold paralysis: Voice and respiratory aspects. AB - OBJECTIVE: To evaluate the effects of neurostimulation with the laryngeal pacemaker (LP) system in patients with bilateral vocal fold paralysis (BVFP) in terms of voice quality and respiratory function. STUDY DESIGN: Feasibility study, first-in-human, single-arm, open-label, prospective, multicenter study with group sequential design and 6-month follow-up period, as described in details in our previous publication. METHODS: Nine symptomatic BVFP subjects were unilaterally implanted with the LP system at three study sites in Germany and Austria. Subjective and objective voice function, spirometric parameters other than peak expiratory/inspiratory flow (PEF/PIF), and PEF-meter self-assessment were evaluated pre- and 6 months postimplantation. RESULTS: In general, the LP system did not considerably change the voice quality of the implanted patients. Only the sound pressure level range improved significantly 6 months postimplantation (P = 0.018). The LP system implantation did not affect the glottal closure configuration, the duration of the closed phase, and the mucosal wave of the implanted side. The evaluated spirometric parameters were not significantly affected by laryngeal pacing, whereas PEF meter self-assessment showed a stable and significant (P = 0.028) improvement of the PEF within a week upon activation of the LP system. CONCLUSION: Neurostimulation with the LP system results in an immediate and stable PEF improvement, without negative effects on the voice quality. The PEF meter self-assessment confirmed the spirometry results of the PEF. The stimulated abduction did not affect the glottal closure during phonation. These results should be confirmed in larger and more homogenous patient cohorts. LEVEL OF EVIDENCE: 2b Laryngoscope, 127:1838-1844, 2017. PMID- 27943295 TI - Pharmacokinetic and pharmacodynamic characterization of ceftiofur crystalline free acid following subcutaneous administration in domestic goats. AB - Pharmacokinetic (PK)-pharmacodynamic (PD) integration of crystalline ceftiofur free acid (CCFA) was established in six healthy female goats administered subcutaneously (s.c.) on the left side of the neck at a dosage of 6.6 mg/kg body weight. Serum concentrations of ceftiofur and desfuroylceftiofur (DFC) were determined using high-performance liquid chromatography. Mutant prevention concentration (MPC), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ceftiofur were determined for Pasteurella (P.) multocida. Mean terminal half-life and mean residence time of ceftiofur + DFC were 48.6 h and 104 h, respectively. In vitro plasma protein binding of ceftiofur was 46.6% in goats. The MIC and MBC values of ceftiofur were similar in serum and MHB and a very small difference between these values confirmed bactericidal activity of drug against P. multocida. In vitro and ex vivo time kill curves for P. multocida demonstrated a time-dependent killing action of drug. Considering target serum concentration of 0.20 MUg/mL, PK-PD values for AUC24 h /MIC90 and T > MIC90 , respectively, were 302 h and 192 h against P. multocida. A MPC/MIC ratio of 10-14 indicated that selective pressure for proliferation of resistant mutants of P. multocida is minimal after CCFA single dose administration. Based on MPC = 1.40 MUg/mL for P. multocida, the PK-PD indices, viz. T > MPC and AUC24 /MPC, were 48 h and 43 h, respectively. The data suggested the use of single dose (6.6 mg/kg, s.c.) of CCFA in goats to obtain clinical and bacteriological cure of pneumonia due to P. multocida. PMID- 27943296 TI - Safety of the Wearable Cardioverter Defibrillator (WCD) in Patients with Implanted Pacemakers. AB - BACKGROUND: The wearable cardioverter defibrillator (WCD) is an important approach for better risk stratification, applied to patients considered to be at high risk of sudden arrhythmic death. Patients with implanted pacemakers may also become candidates for use of the WCD. However, there is a potential risk that pacemaker signals may mislead the WCD detection algorithm and cause inappropriate WCD shock delivery. The aim of the study was to test the impact of different types of pacing, various right ventricular (RV) lead positions, and pacing modes for potential misleading of the WCD detection algorithm. METHODS: Sixty patients with implanted pacemakers received the WCD for a short time and each pacing mode (AAI, VVI, and DDD) was tested for at least 30 seconds in unipolar and bipolar pacing configuration. In case of triggering the WCD detection algorithm and starting the sequence of arrhythmia alarms, shock delivery was prevented by pushing of the response buttons. RESULTS: In six of 60 patients (10%), continuous unipolar pacing in DDD mode triggered the WCD detection algorithm. In no patient, triggering occurred with bipolar DDD pacing, unipolar and bipolar AAI, and VVI pacing. Triggering was independent of pacing amplitude, RV pacing lead position, and pulse generator implantation site. CONCLUSION: Unipolar DDD pacing bears a high risk of false triggering of the WCD detection algorithm. Other types of unipolar pacing and all bipolar pacing modes do not seem to mislead the WCD detection algorithm. Therefore, patients with no reprogrammable unipolar DDD pacing should not become candidates for the WCD. PMID- 27943297 TI - First isolation of a new type of human adenovirus (genotype 79), species Human mastadenovirus B (B2) from sewage water in Japan. AB - Human mastadenoviruses (HAdVs) are highly infectious viral pathogens that survive for prolonged periods in environmental waters. We monitored the presence of HAdVs in sewage waters between April 2014 and March 2015. A total of 27 adenoviral strains were detected in 75% (18/24 in occasion-base) of 24 wastewater collected samples. We identified the types of the strains as HAdV-C2 (n = 5), HAdV-A31 (5), HAdV-C1 (4), HAdV-B3 (4), HAdV-C5 (4), HAdV-B11 (2), P11H34F11 (2), and HAdV-D56 (1). The complete genome sequence of one P11H34F11 (strain T150125) was determined by next-generation sequencing and compared to other genome sequences of HAdV-B strains. The comparisons revealed evidence of a recombination event with breaking point in the hexon encoding region, which evidenced high similarity to HAdV-B34, while half of the rest of the genome showed similarity to HAdV-B11, including regions encoding fiber and E3 region proteins. The penton base encoding region seemed to be a recombinant product of HAdV-B14, -34; however, it was evidenced to be divergent to both as a novel type despite showing low bootstrap to support a new clade. We propose T150125 (P11H34F11) is a strain of a novel genotype, HAdV-79. These results support the usefulness of environmental surveillance approaches to monitor circulating HAdVs including novel types. PMID- 27943298 TI - A physiologically based pharmacokinetic model for chickens exposed to feed supplemented with monensin during their lifetime. AB - We developed a flow-limited physiologically based pharmacokinetic model for residues of monensin in chickens and evaluated its predictive ability by comparing it with an external data set describing concentration decays after the end of treatment. One advantage of this model is that the values for most parameters (34 of 38) were taken directly from the literature or from field data (for growth and feed intake). Our model included growth (changes in body weight) to describe exposure throughout the life of the chicken. We carried out a local sensitivity analysis to evaluate the relative importance of model parameters on model outputs and revealed the predominant influence of 19 parameters (including three estimated ones): seven pharmacokinetic parameters, five physiological parameters and seven animal performance parameters. Our model estimated the relative bioavailability of monensin as feed additive at 3.9%, which is even lower than the absolute bioavailability in solution (29.91%). Our model can be used for extrapolations of farming conditions, such as monensin supplementation or building lighting programme (which may have a significant impact for short half-life molecules such as monensin). This validated PBPK model may also be useful for interspecies extrapolations or withdrawal period calculations for modified dosage regimens. PMID- 27943301 TI - Crystal structures of wild-type Trichoderma reesei Cel7A catalytic domain in open and closed states. AB - Trichoderma reesei Cel7A efficiently hydrolyses cellulose. We report here the crystallographic structures of the wild-type TrCel7A catalytic domain (CD) in an open state and, for the first time, in a closed state. Molecular dynamics (MD) simulations indicate that the loops along the CD tunnel move in concerted motions. Together, the crystallographic and MD data suggest that the CD cycles between the tense and relaxed forms that are characteristic of work producing enzymes. Analysis of the interactions formed by R251 provides a structural rationale for the concurrent decrease in product inhibition and catalytic efficiency measured for product-binding site mutants. PMID- 27943299 TI - A Nonfluoroscopic Technique for Coronary Arteries Three-Dimensional Mapping during Epicardial Ventricular Tachycardia Ablation. AB - When performing epicardial ablation of ventricular tachycardia (VT), caution must be taken not to damage the coronary arteries. We report a case in which a new, nonfluoroscopic technique for incorporating an accurate, real-time reconstruction of the main coronary vessels into a three-dimensional electroanatomic map was used for epicardial VT ablation. PMID- 27943300 TI - Glycogen metabolism in the glucose-sensing and supply-driven beta-cell. AB - Glycogen metabolism in beta-cells may affect downstream metabolic pathways controlling insulin release. We examined glycogen metabolism in human islets and in the rodent-derived INS-1 832/13 beta-cells and found them to express the same isoforms of key enzymes required for glycogen metabolism. Our findings indicate that glycogenesis is insulin-independent but influenced by extracellular glucose concentrations. Levels of glycogen synthase decrease with increasing glucose concentrations, paralleling accumulation of glycogen. We did not find cAMP elicited glycogenolysis and insulin secretion to be causally related. In conclusion, our results reveal regulated glycogen metabolism in human islets and insulin-secreting cells. Whether glycogen metabolism affects insulin secretion under physiological conditions remains to be determined. PMID- 27943302 TI - Structure and inhibition of N-acetylneuraminate lyase from methicillin-resistant Staphylococcus aureus. AB - N-Acetylneuraminate lyase is the first committed enzyme in the degradation of sialic acid by bacterial pathogens. In this study, we analyzed the kinetic parameters of N-acetylneuraminate lyase from methicillin-resistant Staphylococcus aureus (MRSA). We determined that the enzyme has a relatively high KM of 3.2 mm, suggesting that flux through the catabolic pathway is likely to be controlled by this enzyme. Our data indicate that sialic acid alditol, a known inhibitor of N acetylneuraminate lyase enzymes, is a stronger inhibitor of MRSA N acetylneuraminate lyase than of Clostridium perfringens N-acetylneuraminate lyase. Our analysis of the crystal structure of ligand-free and 2R-sialic acid alditol-bound MRSA N-acetylneuraminate lyase suggests that subtle dynamic differences in solution and/or altered binding interactions within the active site may account for species-specific inhibition. PMID- 27943304 TI - The role of local temperature and other clinical characteristics of localized scleroderma as markers of disease activity. AB - BACKGROUND: Determining the activity of localized scleroderma (LS) remains crucial for decision making, and reliable clinical indicators of activity are lacking. Our objective in this study was to analyze the utility of infrared thermography (IRT) in assessing the activity of LS according to existing clinical scales. A secondary objective was to study whether clinical characteristics of patients and/or IRT have any role in predicting the activity of LS. METHODS: In this cross-sectional study, the activity of LS was determined using a visual analog scale (VAS), a dyspigmentation-induration-erythema-telangiectasias (DIET) scale, and a localized scleroderma skin severity index (LoSSI). Local temperature was measured by IRT. RESULTS: We studied 56 patients with a median age of 14.2 years. The mean difference in temperature between the affected and unaffected skin was 0.29 degrees C. The comparison of patients with active versus inactive LS (using a 50% composite score cutoff) according to differences in temperature was not significant. An exploratory regression analysis showed an insignificant association of difference in temperature and other clinical characteristics for activity of LS. Our relatively small sample size consisted primarily of patients with low to moderate activity, and the lack of a standard definition of activity of LS was another limitation. CONCLUSIONS: There is a possible role for temperature and other clinical characteristics as predictors of activity of LS. More studies and better definitions of activity in LS are needed. PMID- 27943306 TI - A case-control study on the association of pulse oral poliomyelitis vaccination and Gianotti-Crosti syndrome. AB - BACKGROUND: Since 1995, the Indian government has been launching two National Immunization Days (NIDs) annually to administer oral polio vaccines (OPVs) to children under the age of 5. Our aim was to investigate the association between OPVs and Gianotti-Crosti syndrome (GCS). METHODS: A board-certified dermatologist in solo practice conducted the examinations. The patients consulted without the need of a referral. We retrieved files of all children under the age of 5 who were diagnosed with GCS in 18 months. There were three NIDs during these months. We charted the number of children 1 month before, 1 week before, 1 week after, and 1 month after the three NIDs. RESULTS: A total of 116 children (49 boys and 67 girls) under the age of 5 with GCS were found (average age: 2.9 years) within these 18 months of three NIDs. Eleven (9.5%) and 105 (90.5%) children developed GCS 1 month before and 1 month following OPV administration, respectively (RR: 1.81; 95% CI: 1.40-2.35; P < 0.0001). Three (2.6%) and 58 (50.0%) children developed GCS 1 week before and 1 week after OPV administration, respectively (RR: 1.90; 95% CI: 1.12-3.22; P < 0.0001). CONCLUSIONS: The administration of OPV is significantly associated with the occurrence of GCS in the part of the world that we investigated. As we demonstrated a temporal relationship, this association is likely to be causal. PMID- 27943307 TI - Erratum. PMID- 27943303 TI - Becoming an Air Force Nurse: The Experience of Transition A New Perspective of a Known Phenomenon. AB - PROBLEM: Transitions in nursing have consistently been described as complex and stressful. While the literature is replete with studies investigating role transitions in civilian healthcare settings, there is no known research that explores the role transition of experienced nurses who move from civilian to military nursing practice. Using nurses in the U.S. Air Force as an exemplar, this study serves as a starting point to understand the transition process and challenges likely encountered by nurses new to the military. The outcomes of this study could influence future efforts to recruit and retain qualified nurses. METHODS: A hermeneutic, phenomenologic approach was used to explore and describe the lived experience of transition from civilian staff nurse to Air Force staff nurse. FINDINGS: The results indicated that new Air Force nurses encounter challenges related to a lack of knowledge and role preparedness, which led to feelings of stress and frustration. Support from peers, mentors, and managers helped the new Air Force nurses bridge the gap in knowledge and successfully integrate into the military culture. IMPLICATIONS: Efforts to reduce the perceived lack of knowledge through improvements to the Commissioned Officer Training program and the clinical orientation period are recommended. PMID- 27943305 TI - Use of skin-lightening products among selected urban communities in Accra, Ghana. AB - BACKGROUND: The practice of skin lightening has been reported from North America, Europe, Asia, and Africa. In literature, some prevalence rates exceed 50%, and both sexes are involved. Common agents used include hydroquinone, mercury, corticosteroids, and caustic agents. The agents are easily accessible and affordable with very little regulation. Cutaneous and systemic side effects occur but do not appear to be a deterrent, as the notion of light skin as a surrogate for beauty is strong. In Ghana, anecdotal reports of high bleaching rates among certain urban communities resulted in a study supported by the Food and Drugs Authority to determine various facets of this practice. METHODS: A cross sectional study among adults in selected urban fishing communities of Accra was undertaken. Consecutive cases were enrolled after written informed consent. A questionnaire was administered, followed by physical examination and clinical photographs. Descriptive statistics were used to analyze the data. RESULTS: Of the 555 participants from the three communities, prevalence was 279 (50.3%). Duration of use ranged from 2 months to 17 years. Approximately 212 (76%) used more than one product, and 231 (82%) used agents on their face and body. Dermatological features were hypopigmentation 270 (96.8%), other color changes including ochronosis 241 (86.4%), changes in consistency 141 (50.3%), striae 157 (56.3%), and infections 42 (15.1%). CONCLUSIONS: The prevalence of skin bleaching was 50.3% in these communities, which is high considering the adverse effects from the practice. We recommend regulation of products by enforcing the law, more education, and a population prevalence study. PMID- 27943308 TI - Metabolic injury in a variable rat model of post-status epilepticus. AB - OBJECTIVE: In vivo studies of epilepsy typically use prolonged status epilepticus to generate recurrent seizures. However, reports on variable status duration have found discrete differences in injury after 40-50 min of seizures, suggesting a pathophysiologic sensitivity to seizure duration. In this report we take a multivariate cluster analysis to study a short duration status epilepticus model using in vivo 7T magnetic resonance spectroscopy (MRS) and histologic evaluation. METHODS: The Hellier Dudek model was applied with 45 min of status epilepticus after which the animals were imaged twice, at 3 days and 3 weeks post-status epilepticus. Single voxel point resolved spectroscopy (PRESS) MRS was used to acquire data from the dentate gyrus and CA3 region of the hippocampus, assessing metabolite ratios to total creatine (tCr). In a subset of animals after the second imaging study, brains were analyzed histologically by Nissl staining. RESULTS: A hierarchical cluster analysis performed on the 3-day data from 21 kainate-treated animals (dentate gyrus voxel) segregated into two clusters, denoted by KM (more injured, n = 6) and KL (less injured, n = 15). Although there was no difference in kainate dosing or seizure count between them, the metabolic pattern of injury was different. The KM group displayed the largest significant changes in neuronal and glial parameters; the KL group displayed milder but significant changes. At 3 weeks, the KL group returned to normal compared to controls, whereas the KM group persisted with depressed N-acetyl aspartate (NAA)/tCr, glutamate/tCr, and increased inositol/tCr and glutamine/tCr. The classification was also consistent with subsequent histologic patterns at 3 weeks. SIGNIFICANCE: Although a short status period might be expected to generate a continuous distribution of metabolic injury, these data show that the short Hellier Dudek model appears to generate two levels of injury. The changes seen in segregated groups persisted into 3 weeks, and can be interpreted according to neuronal and glial biomarkers consistent with histology results. PMID- 27943310 TI - Cd-induced Cu deficiency responses in Arabidopsis thaliana: are phytochelatins involved? AB - Cadmium (Cd) exposure can disturb the homeostasis of essential elements. In Arabidopsis thaliana, Cd induces a squamosa promoter binding protein-like 7 (SPL7)-dependent Cu deficiency response. We investigated how Cd induces a Cu deficiency response. The Cu deficiency response consists of the active SPL7 transcription factor binding to GTAC motifs in promoters of among others several Cu transporters, a Cu chaperone, and cupro-miRNAs to regulate Cu homeostasis. We demonstrated that the addition of supplemental Cu to Cd-exposed A. thaliana plants diminished the Cu deficiency response in roots, while it even disappeared in leaves. Exposure of plants to Cd in combination with extra Cu reduced Cd levels in both roots and leaves resulting in an improved cellular oxidative state. Furthermore, we demonstrated a role for phytochelatins (PCs) in the Cd induced Cu deficiency response, because it was reduced in roots of cad1-3 mutant plants exposed to Cd. In conclusion, a working mechanism is provided in which it is suggested that Cd increases PC levels that can complex both Cd and Cu. This results in cellular Cu deficiency and subsequently the activation of SPL7 and hence the induction of the Cu deficiency response. PMID- 27943309 TI - Monoterpene 'thermometer' of tropical forest-atmosphere response to climate warming. AB - Tropical forests absorb large amounts of atmospheric CO2 through photosynthesis but elevated temperatures suppress this absorption and promote monoterpene emissions. Using 13 CO2 labeling, here we show that monoterpene emissions from tropical leaves derive from recent photosynthesis and demonstrate distinct temperature optima for five groups (Groups 1-5), potentially corresponding to different enzymatic temperature-dependent reaction mechanisms within beta-ocimene synthases. As diurnal and seasonal leaf temperatures increased during the Amazonian 2015 El Nino event, leaf and landscape monoterpene emissions showed strong linear enrichments of beta-ocimenes (+4.4% degrees C-1 ) at the expense of other monoterpene isomers. The observed inverse temperature response of alpha pinene (-0.8% degrees C-1 ), typically assumed to be the dominant monoterpene with moderate reactivity, was not accurately simulated by current global emission models. Given that beta-ocimenes are highly reactive with respect to both atmospheric and biological oxidants, the results suggest that highly reactive beta-ocimenes may play important roles in the thermotolerance of photosynthesis by functioning as effective antioxidants within plants and as efficient atmospheric precursors of secondary organic aerosols. Thus, monoterpene composition may represent a new sensitive 'thermometer' of leaf oxidative stress and atmospheric reactivity, and therefore a new tool in future studies of warming impacts on tropical biosphere-atmosphere carbon-cycle feedbacks. PMID- 27943313 TI - Detecting and quantifying influenza virus with self- versus investigator collected mid-turbinate nasal swabs. AB - We compared pairs of self- and investigator-collected mid-turbinate nasal swabs to detect and quantify influenza viral loads. We used RNase P, which reflects presence of human cells to determine adequate sample collection. Sixteen pairs of influenza-positive swabs and 25 pairs of influenza-negative swabs were included in this study. The median influenza A viral loads for self- and investigator collected swabs were 1.68 and 1.67 log10 copies/mL, respectively (P = 0.96). RNase P loads were also similar between self- and investigator-collected swabs (P = 0.51). Self-collected mid-turbinate nasal swabs yield comparable viral loads to investigator-collected swabs, and therefore might be considered for research and clinical management. PMID- 27943311 TI - FV-100 versus valacyclovir for the prevention of post-herpetic neuralgia and the treatment of acute herpes zoster-associated pain: A randomized-controlled trial. AB - This prospective, parallel-group, randomized, double-blind, multicenter study compared the efficacy and safety of FV-100 with valacyclovir for reducing pain associated with acute herpes zoster (HZ). Patients, >=50 years of age, diagnosed with HZ within 72 h of lesion appearance who had HZ-associated pain, were randomized 1:1:1 to a 7-day course of either FV-100 200 mg QD (n = 117), FV-100 400 mg QD (n = 116), or valacyclovir 1000 mg TID (n =117). Efficacy was evaluated on the basis of the burden of illness (BOI; Zoster Brief Pain Inventory scores); incidence and duration of clinically significant pain (CSP); pain scores; incidence and severity of post-herpetic neuralgia (PHN); and times to full lesion crusting and to lesion healing. Safety was evaluated on the basis of adverse event (AE)/SAE profiles, changes in laboratory and vital signs values, and results of electrocardiograms. The burden of illness scores for pain through 30 days were 114.5, 110.3, and 118.0 for FV-100 200 mg, FV-100 400 mg, and valacyclovir 3000 mg, respectively. The incidences of PHN at 90 days for FV-100 200 mg, FV-100 400 mg, and valacyclovir 3000 mg were 17.8%, 12.4%, and 20.2%, respectively. Adverse event and SAE profiles of the two FV-100 and the valacyclovir groups were similar and no untoward signals or trends were evident. These results demonstrate a potential for FV-100 as an antiviral for the treatment of shingles that could both reduce the pain burden of the acute episode and reduce the incidence of PHN compared with available treatments. PMID- 27943314 TI - Caring for Patients of the Millennial Generation: Considerations for Nurses. AB - Much has been written about teaching students of the Millennial Generation (those born between the years 1980 and 2000) and about intergenerational dynamics in the healthcare workforce. However, little can be found in the literature regarding generation-specific nursing care of Millennial patients. This article presents six categories of considerations for nurses caring for patients of the Millennial Generation based on the characteristics, attitudes, and values that have influenced them as well as the healthcare issues confronting this group of young adults. PMID- 27943312 TI - Amino acid transporter mutants of Arabidopsis provides evidence that a non mycorrhizal plant acquires organic nitrogen from agricultural soil. AB - Although organic nitrogen (N) compounds are ubiquitous in soil solutions, their potential role in plant N nutrition has been questioned. We performed a range of experiments on Arabidopsis thaliana genetically modified to enhance or reduce root uptake of amino acids. Plants lacking expression of the Lysine Histidine Transporter 1 (LHT1) displayed significantly lower contents of 13 C and 15 N label and of U-13 C5 ,15 N2 L-glutamine, as determined by liquid chromatography mass spectrometry when growing in pots and supplied with dually labelled L glutamine compared to wild type plants and LHT1-overexpressing plants. Slopes of regressions between accumulation of 13 C-labelled carbon and 15 N-labelled N were higher for LHT1-overexpressing plants than wild type plants, while plants lacking expression of LHT1 did not display a significant regression between the two isotopes. Uptake of labelled organic N from soil tallied with that of labelled ammonium for wild type plants and LHT1-overexpressing plants but was significantly lower for plants lacking expression of LHT1. When grown on agricultural soil plants lacking expression of LHT1 had the lowest, and plants overexpressing LHT1 the highest C/N ratios and natural delta15 N abundance suggesting their dependence on different N pools. Our data show that LHT1 expression is crucial for plant uptake of organic N from soil. PMID- 27943315 TI - Characterization of poplar metabotypes via mass difference enrichment analysis. AB - Instrumentation technology for metabolomics has advanced drastically in recent years in terms of sensitivity and specificity. Despite these technical advances, data analytical strategies are still in their infancy in comparison with other 'omics'. Plants are known to possess an immense diversity of secondary metabolites. Typically, more than 70% of metabolomics data are not amenable to systems biological interpretation because of poor database coverage. Here, we propose a new general strategy for mass-spectrometry-based metabolomics that incorporates all exact mass features with known sum formulas into the evaluation and interpretation of metabolomics studies. We extend the use of mass differences, commonly used for feature annotation, by redefining them as variables that reflect the remaining 'omic' domains. The strategy uses exact mass difference network analyses exemplified for the metabolomic description of two grey poplar (Populus * canescens) genotypes that differ in their capability to emit isoprene. This strategy established a direct connection between the metabotype and the non-isoprene-emitting phenotype, as mass differences pertaining to prenylation reactions were over-represented in non-isoprene emitting poplars. Not only was the analysis of mass differences able to grasp the known chemical biology of poplar, but it also improved the interpretability of yet unknown biochemical relationships. PMID- 27943316 TI - To Give and To Get: How Nurse Faculty Scholars Contribute and Benefit From Participating in Interdisciplinary Research Teams. AB - BACKGROUND: Meeting the demands for career advancement in the faculty tenure track of a university becomes a challenge for new researchers when active nursing research is limited or nonexistent. Nurse faculty transitioning from clinical practice settings may face greater difficulty climbing the ladder of promotion because of the limited opportunity for nursing research. A way to create a research thread that will allow an opportunity to ease into the new role and build an effective research team is to participate in an interdisciplinary research (IDR) team. PURPOSE: This article is written to encourage academic nurse faculty who may find themselves in a nursing research "desert" to collaborate with other disciplines and consider joining an IDR team to get started in career advancement. DESCRIPTION: Three "Gs"-get, give, and generate-have been created to illustrate the benefits and contribution of IDR. Practical ways to help get started and make the best use of the IDR team are suggested. CONCLUSION: The participation in an IDR team offers new nurse faculty a way to jump-start a scholarly career. Collaboration with like-minded colleagues from various disciplines offers an opportunity to expand knowledge, gain professional growth, and contribute to scientific development. PMID- 27943317 TI - VI. EXECUTIVE CONTROL IN PRESCHOOLERS: NEW MODELS, NEW RESULTS, NEW IMPLICATIONS. PMID- 27943318 TI - V. ELUCIDATING NEW PATHWAYS TO DIMENSIONS OF ADHD SYMPTOMS IN PRESCHOOL BY JOINTLY MODELING EXECUTIVE CONTROL AND FOUNDATIONAL COGNITIVE ABILITIES. PMID- 27943319 TI - COMMENTARY ON THE CHANGING NATURE OF EXECUTIVE CONTROL IN PRESCHOOL. AB - In this commentary, I provide a critical evaluation of Espy and colleagues' proposal to use a bifactor modeling approach to characterize children's performance on executive control tasks. I draw attention to an old idea regarding treating items as causal or effect indicators of their latent constructs. I remind readers that factor analytic approaches, including the bifactor model that is proposed here, assume that executive control tasks are effect indicators of the latent construct of executive control. I suggest that executive control tasks may be better conceptualized as causal indicators. I further suggest that these different modeling approaches will result in markedly different conclusions about the nature of executive control-including predictors and outcomes of executive control that were the focus of this monograph. PMID- 27943320 TI - II. THE PRESCHOOL PROBLEM SOLVING STUDY: SAMPLE, DATA, AND STATISTICAL METHODS. PMID- 27943321 TI - IV. A NEW LOOK AT THE IMPLICATIONS OF THE SOCIO-FAMILIAL CONTEXT FOR YOUNG CHILDREN'S EXECUTIVE CONTROL: CLARIFYING THE MECHANISMS OF INDIVIDUAL DIFFERENCES. PMID- 27943323 TI - I. EXECUTIVE CONTROL IN EARLY CHILDHOOD. AB - Executive control (EC) is a central construct in developmental science, although measurement limitations have hindered understanding of its nature and development in young children, relation to social risk, and prediction of important outcomes. Disentangling EC from the foundational cognitive abilities it regulates and that are inherently required for successful executive task completion (e.g., language, visual/spatial perception, and motor abilities) is particularly challenging at preschool age, when these foundational abilities are still developing and consequently differ substantially among children. A novel latent bifactor modeling approach delineated respective EC and foundational cognitive abilities components that undergird executive task performance in a socio demographically stratified sample of 388 preschoolers in a longitudinal, cohort-sequential study. The bifactor model revealed a developmental shift, where both EC and foundational cognitive abilities contributed uniquely to executive task performance at ages 4.5 and 5.25 years, but were not separable at ages 3 and 3.75. Contrary to the view that EC is vulnerable to socio-familial risk, the contributions of household financial and learning resources to executive task performance were not specific to EC but were via their relation to foundational cognitive abilities. EC, though, showed a unique, discriminant relation with hyperactive symptoms late in the preschool period, whereas foundational cognitive abilities did not predict specific dimensions of dysregulated behavior. These findings form the basis for a new, integrated approach to the measurement and conceptualization of EC, which includes dual consideration of the contributions of EC and foundational cognitive abilities to executive task performance, particularly in the developmental context of preschool. PMID- 27943324 TI - III. DISTINGUISHING EXECUTIVE CONTROL FROM OVERLAPPING FOUNDATIONAL COGNITIVE ABILITIES DURING THE PRESCHOOL PERIOD. PMID- 27943326 TI - Technologies for Prolonging Cardiac Implantable Electronic Device Longevity. AB - Prolonged longevity of cardiac implantable electronic devices (CIEDs) is needed not only as a passive response to match the prolonging life expectancy of patient recipients, but will also actively prolong their life expectancy by avoiding/deferring the risks (and costs) associated with device replacement. CIEDs are still exclusively powered by nonrechargeable primary batteries, and energy exhaustion is the dominant and an inevitable cause of device replacement. The longevity of a CIED is thus determined by the attrition rate of its finite energy reserve. The energy available from a battery depends on its capacity (total amount of electric charge), chemistry (anode, cathode, and electrolyte), and internal architecture (stacked plate, folded plate, and spiral wound). The energy uses of a CIED vary and include a background current for running electronic circuitry, periodic radiofrequency telemetry, high-voltage capacitor reformation, constant ventricular pacing, and sporadic shocks for the cardiac resynchronization therapy defibrillators. The energy use by a CIED is primarily determined by the patient recipient's clinical needs, but the energy stored in the device battery is entirely under the manufacturer's control. A larger battery capacity generally results in a longer-lasting device, but improved battery chemistry and architecture may allow more space-efficient designs. Armed with the necessary technical knowledge, healthcare professionals and purchasers will be empowered to make judicious selection on device models and maximize the utilization of all their energy-saving features, to prolong device longevity for the benefits of their patients and healthcare systems. PMID- 27943325 TI - Exploring growth-defence trade-offs in Arabidopsis: phytochrome B inactivation requires JAZ10 to suppress plant immunity but not to trigger shade-avoidance responses. AB - Under conditions that involve a high risk of competition for light among neighbouring plants, shade-intolerant species often display increased shoot elongation and greater susceptibility to pathogens and herbivores. The functional links between morphological and defence responses to crowding are not well understood. In Arabidopsis, the protein JAZ10 is thought to play a key role connecting the inactivation of the photoreceptor phytochrome B (phyB), which takes place under competition for light, with the repression of jasmonate mediated plant defences. Here, we show that a null mutation of the JAZ10 gene in Arabidopsis did not affect plant growth nor did it suppress the shade-avoidance responses elicited by phyB inactivation. However, the jaz10 mutation restored many of the defence traits that are missing in the phyB mutant, including the ability to express robust responses to jasmonate and to accumulate indolic glucosinolates. Furthermore, the jaz10phyB double mutant showed a significantly increased resistance to the pathogenic fungus Botrytis cinerea compared with the phyB parental line. Our results demonstrate that, by inactivating JAZ10, it is possible to partially uncouple shade avoidance from defence suppression in Arabidopsis. These findings may provide clues to improve plant resistance to pathogens in crops that are planted at high density. PMID- 27943327 TI - Videotaping of surgical procedures and outcomes following extraperitoneal laparoscopic radical prostatectomy for clinically localized prostate cancer. AB - BACKGROUND: Video-recording of emerging minimally invasive surgical procedures is likely to become an integral component of patient record-keeping in the future for prostate cancer treatment. No prior work has shown the impact of videotaping of laparoscopic prostatectomy on patient outcomes. Our aim was to determine correlation between independent peer review of videotaping quality scores of extraperitoneal laparoscopic prostatectomy (ELRP) with complications, re admissions, functional, and early oncological outcomes. STUDY DESIGN, SETTING, AND PARTICIPANTS: We conducted a single-institution prospective cohort study comparing videotaping quality scores with the outcomes of ELRP in men with localized prostate cancer. Videotaping of surgical procedures were scored by two experienced laparoscopic surgeons using a validated scoring method. Validated record-linkage methodology and self-reported questionnaires were used to assess surgical complications, re-admissions, functional, and oncological outcomes based on a common identifier called as community health index (CHI) number. Pearson correlation coefficients were calculated between the different covariates with statistical significance considered at P < 0.05. Multivariate analyses assessed oncological outcomes (positive surgical margins/biochemical recurrence), post operative complications, and re-admission into hospital following initial hospital discharge with quality of surgical procedure. RESULTS: 200 men were recruited into the study. 51 (25.5%) participants had post-operative complications. Record-linkage methodology identified 18 (9%) participants had re admissions within 90 days of the procedure. 13 (6.5%) of these men required percutaneous drainage with hospital stay following re-admissions ranged between 3 and 12 days. 10 (5.0%) participants had intra/peri-operative complications. 23 (11.5%) men reported to primary care physicians for various indications. Higher quality surgical technique videotaped scores (assessed by independent peer review) had a significant correlation with early continence recovery at 3 months post-procedure, (P = 0.013), but lost statistical significance with overall continence at 1 year. No statistical correlation was observed between videotaped scores and oncological outcomes (positive surgical margins/biochemical recurrence), post-operative complications, and readmission into hospital. CONCLUSIONS: Quality of surgical procedure assessed by independent third party videotaping score predicted early resumption of continence following extraperitoenal laparoscopic radical prostatectomy, however, it did not predict complications, oncological or functional outcome as assessed using patient reported outcomes at 12 months. J. Surg. Oncol. 2016;114:1016-1023. (c) 2016 Wiley Periodicals, Inc. PMID- 27943328 TI - Distinct physiological and metabolic reprogramming by highbush blueberry (Vaccinium corymbosum) cultivars revealed during long-term UV-B radiation. AB - Despite the Montreal protocol and the eventual recovery of the ozone layer over Antarctica, there are still concerns about increased levels of ultraviolet-B (UV B) radiation in the Southern Hemisphere. UV-B induces physiological, biochemical and morphological stress responses in plants, which are species-specific and different even for closely related cultivars. In woody plant species, understanding of long-term mechanisms to cope with UV-B-induced stress is limited. Therefore, a greenhouse UV-B daily course simulation was performed for 21 days with two blueberry cultivars (Legacy and Bluegold) under UV-BBE irradiance doses of 0, 0.07 and 0.19 W m-2 . Morphological changes, photosynthetic performance, antioxidants, lipid peroxidation and metabolic features were evaluated. We found that both cultivars behaved differently under UV-B exposure, with Legacy being a UV-B-resistant cultivar. Interestingly, Legacy used a combined strategy: initially, in the first week of exposure its photoprotective compounds increased, coping with the intake of UV-B radiation (avoidance strategy), and then, increasing its antioxidant capacity. These strategies proved to be UV-B radiation dose dependent. The avoidance strategy is triggered early under high UV-B radiation in Legacy. Moreover, the rapid metabolic reprogramming capacity of this cultivar, in contrast to Bluegold, seems to be the most relevant contribution to its UV-B stress-coping strategy. PMID- 27943329 TI - Viral pathogens among elderly people with acute respiratory infections in Shanghai, China: Preliminary results from a laboratory-based surveillance, 2012 2015. AB - Acute respiratory infections (ARIs), with viral pathogens as the major contributors, are the most common illnesses worldwide, and increase the morbidity and mortality among the elderly population. The clinical and pathological features of elderly people with ARIs need to be identified for disease intervention. From January 1, 2012 through December 31, 2015, respiratory specimens from patients above 60 years old with ARIs were collected from the outpatient and inpatient settings of six sentinel hospitals in Pudong New Area. Each specimen was tested via multiplex polymerase chain reaction (PCR) for eight target viral etiologies including influenza, human rhinovirus (HRV), human para influenza virus (PIV), adenovirus (ADV), respiratory syncytial virus (RSV), human metapneumovirus (hMPV), human coronavirus (hCoVs), and human bocavirus (hBoV). A total of 967 elderly patients with ARIs were enrolled, including 589 (60.91%) males, and the median age was 73 years old. 306 (31.64%) patients were tested positive for any one of the eight viruses, including 276 single infections and 30 co-infections. Influenza was the predominant virus (14.17%, 137/967), detected from 21.35% (76/356) of the outpatients and 9.98% (61/611) of the inpatients. Influenza infections presented two annual seasonal peaks during winter and summer. Compared with non-influenza patients, those with influenza were more likely to have fever, cough, sore throat, and fatigue. This study identified influenza as the leading viral pathogen among elderly with ARIs, and two seasonal epidemic peaks were observed in Shanghai. An influenza vaccination strategy needs to be advocated for the elderly population. PMID- 27943330 TI - White Paper on Natural Products. AB - The American College of Clinical Pharmacy (ACCP) published an initial white paper on herbal products in 2000. Since then, the global market for natural products has continued to expand, with tens of millions of consumers using such products on an annual basis in the United States alone. However, despite this expansion, natural products remain largely unregulated compared with prescription medications, have moderate- to low-level clinical evidence for efficacy, and continue to have safety concerns, including adulteration and misbranding. As comprehensive medication management experts, clinical pharmacists are uniquely qualified to navigate these concerns and advise patients appropriately. To develop and recommend a suitable care plan involving natural products, clinical pharmacists must establish a strong pharmacist-patient relationship, assess the appropriateness of therapy, educate the patient regarding key issues, and continuously monitor and follow up on the effectiveness of the care plan. This process should not only occur in an individual community or hospital setting, but also whenever a patient transitions from one care setting to another in cooperation with other clinicians. PMID- 27943331 TI - Genomic investigation of piglet resilience following porcine epidemic diarrhea outbreaks. AB - Porcine epidemic diarrhea virus (PEDV) belongs to the Coronaviridae family and causes malabsorptive watery diarrhea, vomiting, dehydration and imbalanced blood electrolytes in pigs. Since the 1970s, PED outbreaks have become a source of problems in pig producing countries all over the world, causing large economic losses for pig producers. Although the infection in adults is not fatal, in naive suckling piglets mortality is close to 100%. In this study, we investigated genome-wide differences between dead and recovered suckling piglets from commercial farms after PED outbreaks. Samples from 262 animals (156 dead and 106 recovered) belonging to several commercial lines were collected from five different farms in three different countries (USA, Canada and Germany) and genotyped with the porcine 80K SNP chip. Mean Fst value was calculated in 1-Mb non-overlapping windows between dead and recovered individuals, and the results were normalized to find differences within the comparison. Seven windows with high divergence between dead and recovered were detected-five on chromosome 2, one on chromosome 4 and one on chromosome 15-in total encompassing 152 genes. Several of these genes are either under- or overexpressed in many virus infections, including Coronaviridae (such as SARS-CoV). A total of 32 genes are included in one or more Gene Ontology terms that can be related to PED development, such as Golgi apparatus, as well as mechanisms generally linked to resilience or diarrhea development (cell proliferation, ion transport, ATPase activity). Taken together this information provides a first genomic picture of PEDV resilience in suckling piglets. PMID- 27943332 TI - Cytokine response to Hantaan virus infection in patients with hemorrhagic fever with renal syndrome. AB - Hantaan virus (HTNV) infection of the human body causes a severe acute infectious disease known as hemorrhagic fever renal syndrome (HFRS). The aim of this study was to correlate patient cytokine profiles to HFRS severity. In this study, we discuss the clinical significance of evaluating HFRS treatment outcomes using cytokine information. The levels of 18 cytokines were quantitatively determined in three groups: 34 HTNV IgM+ cases, 63 HTNV IgM- negative cases, and 78 healthy volunteers. The level of 14 serum cytokines were higher in the patient group than that in the healthy control group. In the 34 HTNV IgM+ patient sera, a set of 27 cytokines was further assessed. The cytokines of TNF-beta, IL-1ra, and IL-6 were detected at higher level in the IgM+ group than that in the IgM- group. The deterioration of HFRS was accompanied with multiple cytokines increased, such as IL-1ra, IL-12p70, IL-10, IP-10, IL-17, IL-2, and IL-6. Our data indicate that serum cytokine levels are associated with the progression of HFRS. PMID- 27943334 TI - Reply. PMID- 27943333 TI - Endocardial Device Leads in Patients with Patent Foramen Ovale: Echocardiographic Correlates of Stroke/TIA and Mortality. AB - BACKGROUND: Echocardiographically detected patent foramen ovale (PFO) has been associated with stroke/transient ischemic attack (TIA) in patients with cardiac implantable electronic devices (CIEDs). We sought to evaluate the relationship between echocardiographic characteristics and risk of stroke/TIA and mortality in CIED patients with PFO. METHODS: In 6,086 device patients, PFO was detected in 319 patients. A baseline echocardiogram was present in 250 patients, with 186 having a follow-up echocardiogram. RESULTS: Of 250 patients with a baseline echocardiogram, 9.6% (n = 24) had a stroke/TIA during mean follow-up of 5.3 +/- 3.1 years; and 42% (n = 105) died over 7.1 +/- 3.7 years. Atrial septal aneurysm, prominent Eustachian valve, visible shunting across PFO, baseline or change in estimated right ventricular systolic pressure (RVSP)/tricuspid regurgitation (TR), or maximum RVSP were not associated with postimplant stroke/TIA (P > 0.05). An exploratory multivariate analysis using time-dependent Cox models showed increased hazard of death in patients with increase in TR >=2 grades (hazard ratio [HR] 1.780, 95% confidence interval [CI] 1.447-2.189, P < 0.0001), or increase in RVSP by >10 mm Hg (HR 2.018, 95% CI 1.593-2.556, P < 0.0001), or maximum RVSP in follow-up (HR 1.432, 95% CI 1.351-1.516, P < 0.0001). A significant increase (P < 0.001) in TR was also noted during follow-up. CONCLUSIONS: In patients with CIED and PFO, structural and hemodynamic echocardiographic markers did not predict future stroke/TIA. However, a significantly higher TR or RVSP was associated with higher mortality. PMID- 27943335 TI - Hepatocellular carcinoma surveillance: The road ahead. PMID- 27943338 TI - Corrigendum. PMID- 27943336 TI - Verification of protein biomarker specificity for the identification of biological stains by quadrupole time-of-flight mass spectrometry. AB - Advances in proteomics technology over the past decade offer forensic serologists a greatly improved opportunity to accurately characterize the tissue source from which a DNA profile has been developed. Such information can provide critical context to evidence and can help to prioritize downstream DNA analyses. Previous proteome studies compiled panels of "candidate biomarkers" specific to each of five body fluids (i.e., peripheral blood, vaginal/menstrual fluid, seminal fluid, urine, and saliva). Here, a multiplex quadrupole time-of-flight mass spectrometry assay has been developed in order to verify the tissue/body fluid specificity the 23 protein biomarkers that comprise these panels and the consistency with which they can be detected across a sample population of 50 humans. Single-source samples of these human body fluids were accurately identified by the detection of one or more high-specificity biomarkers. Recovery of body fluid samples from a variety of substrates did not impede accurate characterization and, of the potential inhibitors assayed, only chewing tobacco juice appeared to preclude the identification of a target body fluid. Using a series of 2-component mixtures of human body fluids, the multiplex assay accurately identified both components in a single-pass. Only in the case of saliva and peripheral blood did matrix effects appear to impede the detection of salivary proteins. PMID- 27943337 TI - Admixture is a driver rather than a passenger in experimental invasions. AB - Genetic admixture propels invasions of Callosobruchus maculatus across experimental landscapes. In Focus: Wagner, N.K., Ochocki, B.M., Crawford, K.M., Compagnoni, A. & Miller, T.E.X. (2017) Genetic mixture of multiple source populations accelerates invasive range expansion. Journal of Animal Ecology, 86, 21-34. In this issue of Journal of Animal Ecology, Wagner et al. (2017) demonstrate that genetic diversity can alter the course of spread of biological invasions. They employ Callosobruchus seed beetles in a clever array of linked habitat patches to compare experimental invasions using individuals from single population sources or from mixes of two, four or six population sources. By taking a model-selection approach, they find that any amount of mixture propels growth rates and spread of introduced populations. This suggests that heterosis alone can alter the course of an invasive range expansion. PMID- 27943339 TI - Corrigendum. PMID- 27943340 TI - Like a rolling stone: the dynamic world of animal ecology publishing. PMID- 27943341 TI - Pittsburgh Compound-B (PiB) binds amyloid beta-protein protofibrils. AB - The neuropathology of Alzheimer's disease (AD) includes amyloid plaque formation by the amyloid beta-protein (Abeta) and intracellular paired helical filament formation by tau protein. These neuropathogenetic features correlate with disease progression and have been revealed in brains of AD patients using positron emission tomography (PET). One of the most useful positron emission tomography imaging agents has been Pittsburgh Compound-B (PiB). However, since its introduction in 2002, substantial evidence has accumulated suggesting that Abeta oligomerization and protofibril formation, rather than fibril formation per se, may be the more important pathogenetic event in AD. Detecting protofibrils and oligomeric forms of Abeta thus may be of value. We report here the results of experiments to determine whether PiB binds to oligomers or protofibrils formed by Abeta40 and Abeta42. We observed strong binding to Abeta42 fibrils, significant binding to protofibrils, and weaker binding to Abeta42 oligomers. PiB also binds Abeta40 fibrils, but its binding to Abeta40 protofibrils and oligomers is substantially lower than for that observed for Abeta42. PMID- 27943343 TI - Highly segregated trophic niche of two congeneric fish species in Neotropical floodplain lakes. AB - The diets of two sympatric, morphologically similar species of Moenkhausia were studied to investigate whether the manner in which they exploit food resources can help to explain their coexistence. Fish diets were evaluated during the low water season in six lakes of the upper Parana River floodplain (Brazil). The results indicate that these two species segregate in relation to food resources and that the differential use of resources is probably a strategy that reduces competition during periods of a potential food shortage (the low-water season). PMID- 27943342 TI - In vivo metabolite identification of acotiamide in rats using ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry. AB - Acotiamide hydrochloride (ACT) is a drug used for the treatment of functional dyspepsia. Understanding which metabolites are likely to be formed in vivo is essential for interpreting pharmacology, pharmacokinetic and toxicology data. The metabolism of ACT has been investigated using a specific and sensitive liquid chromatography positive ion electrospray ionization high-resolution tandem mass spectrometry method. In vivo samples including rat plasma, urine and feces were collected separately after dosing healthy Sprague-Dawley rats at a dose of 20 mg kg -1 ACT at different time points up to 24 h. The metabolites were enriched by optimized sample preparation involving protein precipitation using acetonitrile followed by solid-phase extraction. The mass defect filter technique was used for better detection of both predicted and unexpected drug metabolites with the majority of interference ions removed. The structural elucidation of the metabolites was performed by comparing their [M + H]+ ions and their product ions with those of the parent drug. As a result, a total of seven hitherto unknown metabolites were characterized from the biosamples. The only phase I metabolite detected was N-despropyl acotiamide, whereas six phase II glucuronide conjugate metabolites were identified. PMID- 27943344 TI - Becoming a better swimmer: structural complexity enhances agility in a captive reared fish. AB - To test whether swimming skills can be improved by exposure to structurally complex environments, juvenile rainbow trout Oncorhynchus mykiss were reared in either physically enriched or plain tanks for 2 months and were then screened to test their ability to swim along a channel while avoiding obstructions. The results show that even a relatively short exposure period to enrichment improves O. mykiss swimming agility. PMID- 27943345 TI - Abnormal tuning of the hepatic circadian metabolic rhythms in lung cancer. PMID- 27943346 TI - Acute variceal bleeding in patients on primary prophylaxis with nonselective beta blockers: A poor prognosis factor? PMID- 27943347 TI - Clinical Significance of J Waves in Patients Undergoing Therapeutic Hypothermia for Out-of-Hospital Cardiac Arrest. AB - BACKGROUND: Hypothermia is associated with the development of J waves. However, little is known about the impact of these electrocardiogram (ECG) findings on the development of ventricular arrhythmias and patient outcomes during therapeutic hypothermia (TH) postresuscitation from out-of-hospital cardiac arrest (OHCA). We investigated the prevalence of J waves in OHCA patients prior to and during TH. Additionally, we explored the incidence of atrial and ventricular arrhythmias and in-hospital mortality for patients with and without J waves either at baseline, during TH, or both. METHODS: We conducted a retrospective analysis of patients who suffered OHCA and underwent TH (goal temperature of 32-34 degrees C). Fifty nine patients were stratified dependent upon the presence of or the development of J waves on surface ECGs. Descriptive analysis and logistic regression modeling were used to assess the population differences and mortality, respectively, between patients who developed J waves during TH and those who did not. RESULTS: There was no difference in the development of in-hospital atrial or ventricular arrhythmias between patients with J waves present during TH (16%) and those without (17.6%, P = 0.834). Compared to patients without J waves at baseline and during TH, those with J waves present both at baseline and during TH had significantly worse survival (hazard ratio = 12.42, P = 0.046). CONCLUSIONS: While J waves are common ECG findings during TH in patients resuscitated from OHCA, our study demonstrated an increase in mortality for patients with J waves present both at baseline and during TH. PMID- 27943348 TI - The Design of the Understanding Outcomes with the S-ICD in Primary Prevention Patients with Low EF Study (UNTOUCHED). AB - BACKGROUND: The UNTOUCHED study will assess the safety and efficacy of the subcutaneous implantable cardioverter defibrillator (S-ICD) in the most common cohort of patients receiving ICDs. The primary goal is to evaluate the inappropriate shock (IAS)-free rate in primary prevention patients with a reduced ejection fraction (EF) and compare with a historical control of transvenous ICD patients with similar programming. METHODS AND RESULTS: The UNTOUCHED study is a global, multicenter, prospective, nonrandomized study of patients undergoing de novo S-ICD implantation for primary prevention of sudden cardiac death with a left ventricular EF <=35%. The primary end point of this trial is freedom from IAS at 18 months. The lower 95% confidence bound of the observed incidence will be compared to a performance goal of 91.6%, which was derived from the IAS rate in MADIT-RIT. The secondary end points are all-cause shock-free rate at 18 months, and system- and procedure-related complication-free rate at 1 month and 6 months. Enrollment of a minimum of 1,100 subjects from up to 200 centers worldwide is planned based on power calculations of the primary and principal secondary end points. CONCLUSIONS: This trial will provide important data regarding the rates of inappropriate and appropriate shock therapy in real-world use of the S-ICD in the most common group of patients receiving ICDs. PMID- 27943349 TI - Problems with continuity of care identified by community pharmacists post discharge. AB - WHAT IS KNOWN AND OBJECTIVE: Medication discrepancies are common at hospital discharge, and medication reconciliation is widely endorsed as a preventive strategy. However, implementation is difficult for instance due to the unreliability of patients medication histories. In the Netherlands, community pharmacies are well-informed about their patients' pre-admission medication status which enables thorough post-discharge reconciliation. Our aim was to study the frequency and nature of medication discrepancies, missing patient's knowledge and administrative problems at admission to primary care. METHODS: A cross sectional study was conducted in pharmacies belonging to the Utrecht Pharmacy Practice network for Education and Research in the Netherlands. Structured checklists were used to evaluate all discharge prescriptions presented by adult patients discharged from the hospital to their own home during the study period. The primary outcome was all possible problems with continuity of care, defined as (i) the number and type of medication discrepancies, (ii) administrative problems and (iii) the necessity for patient education. RESULTS AND DISCUSSION: In forty four pharmacies, checklists were completed for 403 patients. Most discharge prescriptions (92%) led to one or more problems with continuity of care (n = 1154, mean 2.9 +/- 2.0), divided into medication discrepancies (31%), administrative problems (34%) and necessity for further education (35%). Medication discrepancies (n = 356) resulted mainly from missing pre-admission medication (n = 106) and dose regimen changes (n = 55) on the discharge prescription. Administrative problems (n = 392) originated mainly from administrative incompleteness (n = 177), for example missing reimbursement authorization forms, or supply issues (n = 150), for example insufficient pharmacy stock. The patients' lack of medication knowledge post-discharge was illustrated by the high need for patient education (n = 406). WHAT IS NEW AND CONCLUSION: Community pharmacists are still confronted with problems due to inadequate documentation at discharge which can inflict harm to patients if not properly addressed. To reduce these problems, a rigorous implementation of the medication reconciliation process at all transition points, standardized electronic transfer of all medication-related information and interdisciplinary collaboration are crucial. PMID- 27943350 TI - Systematic assessment of the performance of illumina's MiSeq FGxTM forensic genomics system. AB - This study assesses the performance of Illumina's MiSeq FGx System for forensic genomics by systematically analyzing single source samples, evaluating concordance, sensitivity and repeatability, as well as describing the quality of the reported outcomes. DNA from 16 individuals (9 males/7 females) in nine separate runs showed consistent STR profiles at DNA input >=400 pg, and two full profiles were obtained with 50 pg DNA input. However, this study revealed that the outcome of a single sample does not merely depend on its DNA input but is also influenced by the total amount of DNA loaded onto the flow cell from all samples. Stutter and sequence or amplification errors can make the identification of true alleles difficult, particularly for heterozygous loci that show allele imbalance. Sequencing of 16 individuals' STRs revealed genetic variations at 14 loci at frequencies suggesting improvement of mixture deconvolution. The STR loci D1S1656 and DXS10103 were most susceptible to drop outs, and D22S1045 and DYS385a b showed heterozygote imbalance. Most stutters were typed at TH01 and DYS385a-b, while amplification or sequencing errors were observed mostly at D7S820 and D19S433. Overall, Illumina's MiSeq FGx System produced reliable and repeatable results. aSTRs showed fewer drop outs than the Y- and X-STRs. PMID- 27943351 TI - Germline mosaicism is a pitfall in PGD for X-linked disorders. Single sperm typing detects very low frequency paternal gonadal mosaicism in a case of recurrent chondrodysplasia punctata misattributed to a maternal origin. AB - This manuscript presents a molecularly demonstrated gonadal mosaicism from paternal origin for X-linked dominant chondrodysplasia punctata by single sperm typing. A couple who had experienced two medical terminations of pregnancy of female fetuses was referred to our pre-implantation genetic diagnosis (PGD) centre with the diagnosis of maternally derived gonadal mosaicism. Indeed, genetic analyses of different DNA samples - including semen - from the healthy parents failed to detect the variant found in the fetuses. Six embryos, all male, were obtained during the PGD cycle. The causative variant was not detected in any embryo, whereas five embryos had inherited the 'at-risk' maternal haplotype. The assumption of a maternal gonadal mosaicism was still possible, but this finding allowed us to consider the possibility of a paternal rather than maternal gonadal mosaicism. It prompted us to perform extensive single sperm analyses, demonstrating a low-frequency paternal germline mosaicism, which led to completely different haplotype phasing and PGD counselling. In conclusion, this case further exemplifies that germline mosaicism is a pitfall in PGD where diagnosis largely relies on linkage analysis and suggests that tracing the parental inheritance through polar body analysis and/or single sperm typing experiments is of major importance for adequate genetic counselling and accurate PGD. (c) 2016 John Wiley & Sons, Ltd. PMID- 27943352 TI - Electrode Contact Force-Controlled Bipolar Radiofrequency Ablation: Different Effects on Lesion Size between Dual- and Single-Bath Preparations. AB - BACKGROUND: During bipolar (BIP) radiofrequency (RF) ablation using two catheters in humans, each catheter is placed in separate cardiac chambers or spaces. We developed a contact force-controlled experimental preparation, and compared measurements made with two catheters placed in a single bath (SB), versus each catheter placed in separate baths, in order to assess the preparation-dependent differences in the results of BIP-RF ablation. METHODS: In the SB experiments, a porcine heart was placed in the center of the bath, while in the dual-bath (DB) experiments, it was placed between two half baths communicating through windows. RESULTS: The initial impedance was greatest (110.5 +/- 7.2 Omega) with the BIP DB, followed by the BIP-SB (92.0 +/- 5.6 Omega) and the unipolar (UNIP) DB (84.9 +/- 4.7 Omega) configurations. During 50-W ablation for 60 seconds at a 20-g contact force, the root mean square voltage was 75.7 +/- 2.5 V in the BIP-DB, 68.0 +/- 2.1 V in the BIP-SB, and 66.8 +/- 2.0 V in the UNIP-DB. The mean surface lesion diameters were similar among the three configurations. However, the endocardial lesion depth was 5.60 +/- 0.56 mm with the BIP-DB, 4.71 +/- 0.64 mm with the BIP-SB, and 4.24 +/- 0.58 mm with the UNIP-DB configuration. On average, the endocardial lesions were significantly deeper than the epicardial ones. CONCLUSIONS: BIP ablation created much deeper lesions as compared to UNIP ablation. Lesion depth could be different depending on experimental preparation, and contact force-controlled DB preparation may be a much more appropriate model for studying the effects of BIP ablation. PMID- 27943353 TI - Two selective HPTLC methods for determination of some angiotensin II receptor antagonists in tablets and biological fluids. AB - Two simple, selective, precise and highly sensitive high-performance thin-layer chromatography (HPTLC) methods have been developed and validated for analysis of five angiotensin II receptor antagonists, namely losartan, irbesartan valsartan, candesartan and olmesartan, which are widely used in clinical practice. HPTLC of the drugs was performed on pre-coated silica gel HPTLC plates 60 F254 by development using a mobile phase composed of chloroform-acetone-glacial acetic acid (7.8:1.5:0.7m v/v/v), which was suitable for all of the studied drugs. The first method depended on utilizing reflectance/fluorescence mode for detection while the second method depended on using 2,3,5,6-tetrachloro-1,4-benzoquinone as spraying reagent for the first time to form orange spots scanned at 460 nm. A good linear relationship was obtained over the concentration ranges of 1.2-60 and 360-3000 ng/band while detection and quantification limits were in the ranges of 0.07-0.43, 45.2-140.49 and 0.21-1.29, 137.05-425.74 ng/band for reflectance/fluorescence and reflectance/absorbance methods respectively. The developed methods were applied successfully for their determination in tablets and spiked human plasma for reflectance/fluorescence method with good accuracy and precision, and so can be applied in the pharmacokinetic and bioavailability studies. PMID- 27943354 TI - Decade-long temporal trends in the utilization of preventive medicines by centenarians. AB - WHAT IS KNOWN AND OBJECTIVE: Centenarians represent a population of individuals with delayed disability and are an ideal representation of ageing well; however, studies related to medicine use in this population are scarce. Our study aimed to explore the temporal trends associated with the utilization of preventive medicines in centenarians. METHODS: A repeated cross-sectional analysis was conducted from 1st January 2006 to 31st December 2015 for all individuals >=100 years old on the date of dispensing, captured in New Zealand's pharmaceutical claims data set. The variable medication possession ratio (VMPR) was used to identify medicines use as preventive, and was calculated by aggregating days' supply from the first to the last prescription divided by time between the last prescription date plus days' supply and the first prescription date. Poisson regression was used to examine the dispensing trends for low-dose aspirin, clopidogrel, warfarin, dabigatran, statins and bisphosphonates with a VMPR >=0.8. RESULTS: Dispensing of aspirin [incident rate ratio (IRR) 0.92, 95% CI: 0.90 0.94], clopidogrel (IRR 0.91, 95% CI: 0.90-0.93) and aspirin with clopidogrel (IRR 0.81, 95% CI: 0.79-0.82) declined significantly over the study period. Similar trends were observed for statins (IRR 0.98, 95% CI: 0.96-1.00) and bisphosphonates (IRR 0.73, 95% CI: 0.71-0.75). Utilization of both the anticoagulants studied increased significantly: warfarin (IRR 1.04, 95% CI: 1.02 1.06) and dabigatran (IRR 1.11, 95% CI: 1.06-1.16). WHAT IS NEW AND CONCLUSION: Over a decade, dispensing of preventive medicines for centenarians decreased marginally for antiplatelets and statins. A substantial decrease in bisphosphonates use and an increase in anticoagulant use were noted for the same period. Temporal trends provide an opportunity to investigate uptake of guideline based prescribing in this age group. PMID- 27943355 TI - Serum level of CXCL10 is associated with inflammatory prognostic biomarkers in patients with diffuse large B-cell lymphoma. AB - Inflammatory biomarkers, such as the neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and Glasgow Prognostic Score (GPS) have been proposed to predict prognosis in diffuse large B-cell lymphoma (DLBCL). C-X-C motif ligand 10 (CXCL10) is a chemokine released from inflammatory cells in the tumor microenvironment and is known to promote tumor cell migration and invasion. In this study, we investigated the clinical impact of pretreatment serum level of CXCL10 on the prognostic value of inflammatory biomarkers in 313 patients with DLBCL who were enrolled into a prospective cohort study. Serum level of CXCL10 was measured in archived pretreatment frozen samples. The high CXCL10 (>median value) group was significantly associated with high tumor burden status, including advanced stage (III-IV), elevated serum lactic dehydrogenase, and a higher risk International Prognostic Index. Progression-free survival of the high CXCL10 group was significantly worse than that of the low CXCL10 group, and secondary central nervous system involvement was more frequent in the high CXCL10 group. High CXCL10 was associated with high C-reactive protein level (r = 0.246), low albumin level (r = -0.289), low absolute lymphocyte count (r = -0.185), and risk stratification according to NLR, LMR, and GPS. C-X-C motif ligand 10 promoted cell migration of patient-derived cells and several DLBCL cell lines. However, the prognostic value of high CXCL10 was lost in the multivariate analyses. Nevertheless, we suggest serum CXCL10 may have clinical value if it can be more easily assessed because of its contribution to the prognostic value of NLR, LMR, and GPS in DLBCL. PMID- 27943356 TI - Metabolomics-based approach for ranking the candidate structures of unidentified peaks in capillary electrophoresis time-of-flight mass spectrometry. AB - One of the technical challenges encountered during metabolomics research is determining the chemical structures of unidentified peaks. We have developed a metabolomics-based chemoinformatics approach for ranking the candidate structures of unidentified peaks. Our approach uses information about the known metabolites detected in samples containing unidentified peaks and involves three discrete steps. The first step involves identifying "precursor/product metabolites" as potential reactants or products derived from the unidentified peaks. In the second step, candidate structures for the unidentified peak are searched against the PubChem database using a molecular formula. These structures are then ranked by structural similarity against precursor/product metabolites and candidate structures. In the third step, the migration time is predicted to refine the candidate structures. Two simulation studies were conducted to highlight the efficacy of our approach, including the use of 20 proteinogenic amino acids as pseudo-unidentified peaks, and leave-one-out experiments for all of the annotated metabolites with and without filtering against the Human Metabolome Database. We also applied our approach to two unidentified peaks in a urine sample, which were identified as glycocyamidine and N-acetylglycine. These results suggest that our approach could be used to identify unidentified peaks during metabolomics analysis. PMID- 27943357 TI - Reply. PMID- 27943358 TI - Intermuscular Two-Incision Technique for Subcutaneous Implantable Cardioverter Defibrillator Implantation: Results from a Multicenter Registry. AB - BACKGROUND: The traditional technique for subcutaneous implantable cardioverter defibrillator (S-ICD) implantation, which involves three incisions and a subcutaneous pocket, is associated with possible complications, including inappropriate interventions. The aim of this prospective multicenter study was to evaluate the efficacy and safety of an alternative intermuscular two-incision technique for S-ICD implantation. METHODS: The study population included 36 consecutive patients (75% male, mean age 44 +/- 12 years [range 20-69]) who underwent S-ICD implantation using the intermuscular two-incision technique. This technique avoids the superior parasternal incision for the lead placement and consists of creating an intermuscular pocket between the anterior surface of the serratus anterior and the posterior surface of the latissimus dorsi muscles instead of a subcutaneous pocket. RESULTS: All patients were successfully implanted in the absence of any procedure-related complications with a successful 65-J standard polarity defibrillation threshold testing, except in one, who received a second successful shock after pocket revision. During a mean follow-up of 10 months (range 3-30), no complications requiring surgical revision were observed. At device interrogation, stable sensing without interferences was observed in all patients. Two patients (5.5%) experienced appropriate and successful shock on ventricular fibrillation and in four patients (11%), a total of seven nonsustained self-terminated ventricular tachycardias were correctly detected. No inappropriate interventions were observed. CONCLUSIONS: Our experience suggests that the two-incision intermuscular technique is a safe and efficacious alternative to the current technique for S-ICD implantation that may help reducing complications including inappropriate interventions and offer a better cosmetic outcome, especially in thin individuals. PMID- 27943359 TI - In response to 'a plea for greater standardization' in intraductal carcinoma of the prostate: greater standardization requires greater evidence. PMID- 27943362 TI - New insights of red light-induced development. AB - The red/far-red light absorbing photoreceptors phytochromes regulate development and growth and thus play an essential role in optimizing adaptation of the sessile plants to the ever-changing environment. Our understanding of how absorption of a red/far-red photon by phytochromes initiates/modifies diverse physiological responses has been steadily improving. Research performed in the last 5 years has been especially productive and led to significant conceptual changes about the mode of action of these photoreceptors. In this review, we focus on the phytochrome B photoreceptor, the major phytochrome species active in light-grown plants. We discuss how its light-independent inactivation (termed dark/thermal reversion), post-translational modification, including ubiquitination, phosphorylation and sumoylation, as well as heterodimerization with other phytochrome species modify red light-controlled physiological responses. Finally, we discuss how photobiological properties of phytochrome B enable this photoreceptor to function also as a thermosensor. PMID- 27943361 TI - Persistent hepatitis C virus-associated cryoglobulinemic vasculitis following virus eradication after direct-acting antiviral therapy. PMID- 27943363 TI - The Rising Cost of Prescription Drugs: Causes and Solutions. PMID- 27943364 TI - The Inflammation Induced by Lipopolysaccharide can be Mitigated by Short-chain Fatty Acid, Butyrate, through Upregulation of IL-10 in Septic Shock. AB - Short-chain fatty acids (SCFAs) with the anti-inflammatory capacity are produced by intestinal bacteria; however, their effect on the acute systematical inflammation remains unclear. This study aimed to investigate the effects of SCFAs, acetate, propionate and butyrate, on septic shock and the underlying mechanism. The LPS-induced septic model was used to evaluate the function of SCFAs by survival rate observation. Only butyrate, but not acetate or propionate, significantly decrease the mortality of septic mice. At 2 h and 6 h of LPS administration, the levels of TNF-alpha, IL-6 and IL-1beta in plasma were measured by ELISA to estimate the effects of butyrate pretreatment on excessive inflammation. And the anti-inflammatory mediators including TGF-beta, IL-10 and LXT4 in plasma were detected for further mechanism study in septic mice. Moreover, the murine macrophage-like RAW 264.7 cells were stimulated by LPS to further confirm the finding in vivo. Pretreatment with butyrate led to significant attenuation of the LPS-induced elevation of TNF-alpha, IL-6 and IL 1beta levels. However, when detecting the anti-inflammatory factors, a significant increase in IL-10, but not TGF-beta or LXT4, was shown in butyrate pretreated group. Pretreatment of RAW 264.7 cells with butyrate led to downregulation of LPS-induced pro-inflammatory mediators, IL-6 and IL-1beta, but did not affect the level of TNF-alpha, and increased IL-10 (P < 0.01). In conclusion, SCFA butyrate significantly attenuated the inflammation against sepsis through upregulation of anti-inflammatory IL-10. PMID- 27943360 TI - Disease drivers of aging. AB - It has long been known that aging, at both the cellular and organismal levels, contributes to the development and progression of the pathology of many chronic diseases. However, much less research has examined the inverse relationship-the contribution of chronic diseases and their treatments to the progression of aging related phenotypes. Here, we discuss the impact of three chronic diseases (cancer, HIV/AIDS, and diabetes) and their treatments on aging, putative mechanisms by which these effects are mediated, and the open questions and future research directions required to understand the relationships between these diseases and aging. PMID- 27943365 TI - Potential role of ectoparasites (Zeuxapta seriolae and Caligus lalandei) in the transmission of pathogenic bacteria in yellowtail kingfish Seriola lalandi, inferred from cultivable microbiota and molecular analyses. PMID- 27943366 TI - Putting the puzzle together: the role of 'problem definition' in complex clinical judgement. AB - CONTEXT: We teach judgement in pieces; that is, we talk about each aspect separately (patient, plan, resources, technique, etc.). We also let trainees figure out how to put the pieces together. In complex situations, this might be problematic. Using data from a drawing-based study on surgeons' experiences with complex situations, we explore the notion of 'problem definition' in real-world clinical judgement using the theoretical lens of systems engineering. METHODS: 'Emergence', the sensitising concept for analysis, is rooted in two key systems premises: that person and context are inseparable and that what emerges is an act of choice. Via a 'gallery walk' we used these premises to perform analysis on individual drawings as well as cross-comparisons of multiple drawings. Our focus was to understand similarities and differences among the vantage points used by multiple surgeons. RESULTS: In this paper we challenge two assumptions from current models of clinical judgement: that experts hold a fixed and static definition of the problem and that consequently the focus of the expert's work is on solving the problem. Each situation described by our participants revealed different but complementary perspectives of what a surgical problem might come to be: from concerns about ensuring standard of care, to balancing personal emotions versus care choices, to coordinating resources, and to maintaining control while in the midst of personality clashes. CONCLUSION: We suggest that it is only at the situation and system level, not at the individual level, that we are able to appreciate the nuances of defining the problem when experts make judgements during real-world complex situations. PMID- 27943367 TI - Analysis of miR-146a and miR-142-3p as Potential Markers of Freshly Isolated or In Vitro-Expanded Human Treg cells. AB - Regulatory CD4+ T cells (Tregs) are pivotal for prevention of autoimmunity. The use of Tregs is therefore of increasing interest in in vitro drug screening assays as well as for a cytotherapy per se against autoimmune disorders. For both purposes, in vitro expansion of peripheral blood Tregs is necessary and there is an increasing need to identify novel markers that can discriminate natural thymic derived Tregs (tTregs) from other T cell subsets, and ideally, such markers should be stably expressed during in vitro expansion procedures. We screened for novel miRNAs differentially expressed in tTregs and identified miR-146a and 142 3p as possible candidates. We analysed freshly isolated naive and activated tTregs and non-Treg subsets after or prior to in vitro expansion. We observed a tTreg-specific profile of these miRNAs together with FOXP3 and Helios in freshly isolated tTregs, but observed a decline in the same markers in activated tTregs as opposed to naive tTregs. In vitro-expanded Tregs could be identified based on FOXP3 expression, but with loss of a discriminate profile for miRNA candidates and a decline in FOXP3 when activated tTregs were expanded. Our data demonstrate miR-146a and 142-3p as potential miRNA markers for discrimination between non Treg cells and tTregs, but these miRNAs are not stable markers for in vitro expanded Treg cells. In addition, the loss of FOXP3 in expansion of activated tTregs has implication for in vitro use of this cell subset in immunopharmacological assays and cytotherapy as FOXP3 is pivotal for suppressive function. PMID- 27943368 TI - Rapid and durable response to intravenous immunoglobulin in delayed heparin induced thrombocytopenia: a case report. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) results in platelet consumption and a virulent thrombotic state, which generally responds to cessation of heparin and initiation of anticoagulation. Rarely, delayed HIT can occur and/or persist after heparin is discontinued. STUDY DESIGN AND METHODS: A 47-year-old male developed delayed HIT with severe thrombocytopenia and thrombosis after cardiac surgery. Thrombocytopenia developed and persisted after heparin cessation and did not improve despite sequential use of argatroban followed by bivalirudin. Treatment with intravenous immunoglobulin (IVIg) was well tolerated and resulted in rapid resolution of thrombocytopenia. RESULTS: There are few case reports on the management of delayed HIT with severe and prolonged thrombocytopenia. The risk for thrombosis and bleeding in the setting of an undefined time course increases uncertainty in management. CONCLUSION: This case, along with others accumulating in the literature, suggest that IVIg may be effective in treating delayed HIT with persistent thrombocytopenia. PMID- 27943369 TI - Biological limits on nitrogen use for plant photosynthesis: a quantitative revision comparing cultivated and wild species. AB - The relationship between leaf photosynthesis and nitrogen is a critical production function for ecosystem functioning. Cultivated species have been studied in terms of this relationship, focusing on improving nitrogen (N) use, while wild species have been studied to evaluate leaf evolutionary patterns. A comprehensive comparison of cultivated vs wild species for this relevant function is currently lacking. We hypothesize that cultivated species show increased carbon assimilation per unit leaf N area compared with wild species as associated with artificial selection for resource-acquisition traits. We compiled published data on light-saturated photosynthesis (Amax ) and leaf nitrogen (LNarea ) for cultivated and wild species. The relationship between Amax and LNarea was evaluated using a frontier analysis (90th percentile) to benchmark the biological limit of nitrogen use for photosynthesis. Carbon assimilation in relation to leaf N was not consistently higher in cultivated species; out of 14 cultivated species, only wheat, rice, maize and sorghum showed higher ability to use N for photosynthesis compared with wild species. Results indicate that cultivated species have not surpassed the biological limit on nitrogen use observed for wild species. Future increases in photosynthesis based on natural variation need to be assisted by bioengineering of key enzymes to increase crop productivity. PMID- 27943370 TI - Relevance of Uterine Subseptations: What Length Should Warrant Hysteroscopic Resection? AB - OBJECTIVES: Existing recommendations warrant correction of uterine subseptations longer than 10 mm. We assessed whether a different subseptation length is indicated for intervention by evaluating the postoperative decrease in cavity width. METHODS: We conducted a prospective controlled cohort study at a university center. Healthy women and women with subseptations were evaluated with three-dimensional ultrasound before and after undergoing surgical resection of uterine subseptations by hysteroscopy. Measurement of the subseptum's length and width, and total cavity width, were obtained in both groups of women. We created a receiver operating characteristic curve using 7-mm cavity postoperative width change as the reference variable, and subseptation length as the outcome variable. Identifying a new subseptation length that warrants surgical intervention. RESULTS: Seventy-six women with subseptations and 77 with healthy uteri were included in the study. In the subseptate group, 50 had a subseptum less than 10 mm, and 26 were greater than 10 mm. Uterine and uterine cavity widths were significantly greater than in healthy women. The postoperative cavity width (28 +/- 0.9 mm) was correlated with the preoperative subseptum length (R = 0.42; P = .016) and width (R = 0.54; P = .001) and was similar to healthy uteri. The receiver operator characteristic curve identified 5.9 mm (sensitivity = 100%, specificity = 41.4%) as a new threshold length of subseptation, which shows a postoperative cavity adjustment comparable to a subseptation greater than 10 mm. CONCLUSIONS: The relevance of subseptations shorter than 10 mm is currently undetermined and underestimated. Our data indicate a new subseptation cutoff length with postoperative remodeling and statistical relevance similar to longer subseptations. We propose a revision of the recommendations for surgical correction to include the objectively obtained subseptation length greater than or equal to 5.9 mm. PMID- 27943371 TI - A large national study of ferritin testing in Canadian blood donors. AB - BACKGROUND: We assessed risk groups for iron deficiency and the feasibility and efficacy of ferritin testing in a large blood center. STUDY DESIGN AND METHODS: Donors were informed of possible testing in the predonation pamphlet. Plasma ferritin was measured on retention samples (n = 12,595) from representative clinics. Low-ferritin donors (<25 ug/L) were sent a letter and information sheet and not called for 6 months. Ferritin testing was repeated on 25% of donors; donor return rate and frequency were monitored. RESULTS: Low-ferritin donors represented 2.9% of first-time and reactivated (no donation in past 12 months) male donors, 32.2% of first-time and reactivated female donors, 41.6% of repeat male donors, and 65.1% of repeat female donors. A mean of 11.7 months after index donation, the return rate was 76% for normal and 58% for low-ferritin donors; returning low-ferritin donors had made approximately one fewer donation. Ferritin increased by 16.3 and 12.1 ug/L in male and female low-ferritin donors and decreased by 17 ug/L in male and female normal-ferritin donors. CONCLUSION: The minimum hemoglobin level will be increased to 130 g/L for male donors and the minimum interdonation interval changed to 84 days (four donations yearly) for female donors based on iron deficiency risk groups. Large-scale ferritin testing was feasible. Donors informed of low-ferritin results had a lower return rate, donated less often, and had an increase in ferritin on return, approximately 1 year after initial testing, compared to donors with normal ferritin results. PMID- 27943372 TI - Imperfect practice makes perfect: error management training improves transfer of learning. AB - CONTEXT: Traditionally, trainees are instructed to practise with as few errors as possible during simulation-based training. However, transfer of learning may improve if trainees are encouraged to commit errors. The aim of this study was to assess the effects of error management instructions compared with error avoidance instructions during simulation-based ultrasound training. METHODS: Medical students (n = 60) with no prior ultrasound experience were randomised to error management training (EMT) (n = 32) or error avoidance training (EAT) (n = 28). The EMT group was instructed to deliberately make errors during training. The EAT group was instructed to follow the simulator instructions and to commit as few errors as possible. Training consisted of 3 hours of simulation-based ultrasound training focusing on fetal weight estimation. Simulation-based tests were administered before and after training. Transfer tests were performed on real patients 7-10 days after the completion of training. Primary outcomes were transfer test performance scores and diagnostic accuracy. Secondary outcomes included performance scores and diagnostic accuracy during the simulation-based pre- and post-tests. RESULTS: A total of 56 participants completed the study. On the transfer test, EMT group participants attained higher performance scores (mean score: 67.7%, 95% confidence interval [CI]: 62.4-72.9%) than EAT group members (mean score: 51.7%, 95% CI: 45.8-57.6%) (p < 0.001; Cohen's d = 1.1, 95% CI: 0.5-1.7). There was a moderate improvement in diagnostic accuracy in the EMT group compared with the EAT group (16.7%, 95% CI: 10.2-23.3% weight deviation versus 26.6%, 95% CI: 16.5-36.7% weight deviation [p = 0.082; Cohen's d = 0.46, 95% CI: -0.06 to 1.0]). No significant interaction effects between group and performance improvements between the pre- and post-tests were found in either performance scores (p = 0.25) or diagnostic accuracy (p = 0.09). CONCLUSIONS: The provision of error management instructions during simulation-based training improves the transfer of learning to the clinical setting compared with error avoidance instructions. Rather than teaching to avoid errors, the use of errors for learning should be explored further in medical education theory and practice. PMID- 27943373 TI - Most Thyroid Cancers Detected by Sonography Lack Intranodular Vascularity on Color Doppler Imaging: Review of the Literature and Sonographic-Pathologic Correlations for 698 Thyroid Neoplasms. AB - OBJECTIVES: This study investigated the controversy of whether hypervascularity on color Doppler sonography correlates with thyroid malignancy by reviewing the literature and sonographic-pathologic correlation. METHODS: Over a 20-year period, 698 thyroid nodules had color Doppler and histopathologic data. Intranodular vascularity was graded 0 to 3+, and histopathologic findings were recorded. RESULTS: The data were collected from 698 patients (557 women and 141 men) with a mean age of 48 years (range, 16-87 years). Of the 698 neoplasms, 425 were malignant (mean size, 1.7 cm; range, 0.4-9 cm; 150 <=1 cm), and 273 were benign. The carcinomas included 391 papillary, 12 Hurthle cell, 9 medullary, 6 follicular, 5 poorly differentiated, and 2 anaplastic. The grading of intranodular vascularity was 0 in 63.3%, 1+ in 12.9%, 2+ in 6.6%, and 3+ in 17.4%. Among thyroid carcinomas, follicular carcinoma and the encapsulated subtype of the follicular variant of papillary carcinoma had significantly higher intranodular vascularity than the rest (P < .0001). Benign neoplasms included 226 follicular adenoma/adenomatoid nodules (mean size, 3.2 cm; range, 1.2-8.0 cm), 42 Hurthle cell adenoma/adenomatoid nodules (mean size, 2.6 cm; range, 0.8-5.5 cm), and 5 hyalinizing trabecular adenomas (mean size, 2.4 cm; range, 0.6-6.0 cm; 4 <=1 cm). The grading of intranodular vascularity was 0 in 6.9%, 1+ in 12.1%, 2+ in 2.6%, and 3+ in 78.4%. Intranodular hypervascularity was associated with adenoma/adenomatoid thyroid nodules, whereas a lack of vascularity was related to thyroid carcinomas (P < .0001). CONCLUSIONS: Most sonographically detected thyroid cancers lack intranodular vascularity, and most hypervascular thyroid nodules are adenoma/adenomatoid nodules, the encapsulated subtype of the follicular variant of papillary carcinoma, or follicular carcinomas. PMID- 27943374 TI - Expression of Toll-Like Receptors in Peripheral Blood Mononuclear Cells of Patients with Primary Sjogren's Syndrome. AB - Toll-like receptors (TLRs) are pattern recognition receptors important for the detection of pathogen-associated molecular patterns. They are localized on cellular membranes, on either the cell surface or the endosomes. Primary Sjogren's syndrome (pSS) is a systemic rheumatic autoimmune disease characterized by lymphocytic infiltrations in exocrine glands resulting in dryness in eyes and mouth. In a majority of patients, autoantibodies against Ro/SSA and/or La/SSB are present. Here we analysed mRNA levels of TLR1-10 and protein expression levels of most of them in human peripheral blood mononuclear cells from 20 patients with pSS and 20 healthy controls. Patients with pSS showed significantly higher mRNA levels of TLR8 than controls, while transcript levels of TLR9 were significantly lower. At the protein level, patients with pSS expressed significantly less TLR5 and significantly more TLR7 compared with healthy controls. TLR7 and 8 are encoded by genes localized on the X chromosome, which is especially interesting regarding the gender imbalance of pSS. The differential expression of various TLR in PBMC of patients with pSS might contribute to an altered recognition of nucleic acids, eventually resulting in the development of autoimmune disease. PMID- 27943375 TI - Bleeding on probing around dental implants: a retrospective study of associated factors. AB - AIM: To (i) identify factors associated with the probability of a peri-implant site to be positive to bleeding on probing (BoP+) and (ii) compare BoP+ probability around dental implants and contra-lateral teeth. METHODS: In 112 patients, data related to 1725 peri-implant sites and 1020 contra-lateral dental sites were retrospectively obtained. To analyse the association between patient-, implant- and site-related factors and BoP+ probability, a logistic, three-level model was built with BoP as the binary outcome variable (+/-). RESULTS: BoP+ probability for a peri-implant site with probing depth (PD) of 4 mm was 27%, and the odds ratio increased by 1.6 for each 1-mm increment in PD (p < 0.001). Also, BoP+ probability was higher in females compared to males (OR = 1.61; p = 0.048), and lower at posterior compared to anterior dental implants (OR = 0.55; p < 0.01). No significant difference in BoP+ probability was observed between peri implant and contra-lateral dental sites when controlling for the difference in PD. CONCLUSIONS: The probability of a peri-implant site to bleed upon probing is (i) associated with PD, implant position and gender, and (ii) similar to that observed at contra-lateral dental sites when controlling for the effect of PD. PMID- 27943376 TI - Oral Contrast-Enhanced Gastric Ultrasonography in the Assessment of Gastric Lesions: A Large-Scale Multicenter Study. AB - OBJECTIVE: To determine the diagnostic efficiency of oral contrast-enhanced gastric ultrasonography in the evaluation of gastric lesions, based on large scale multicenter study. METHODS: The study enrolled 383,945 patients with suspect gastric lesions who underwent complete oral contrast-enhanced gastric ultrasonography and endoscopic evaluation. Two operators, unaware of the results of other diagnostic procedures, performed each examination independently. The accuracies of conventional ultrasonography, oral contrast-enhanced gastric ultrasonography, and upper gastrointestinal endoscopy were determined. RESULTS: After oral contrast, the anatomy of the stomach and morphologic features of gastric lesions were clearly visualized. The sensitivities, specificities, positive predictive values, negative predictive values and accuracies of oral contrast-enhanced ultrasonography in detecting the sites, sizes, numbers, and the extent of gastric lesions,were similar to those of upper gastrointestinal endoscopy (P > .05) and far greater than those of conventional ultrasonography (P < .01). Moreover, oral contrast-enhanced ultrasonography was far better than upper gastrointestinal endoscopy (P < .01) and was better than conventional ultrasonography (P < .05) in detecting the submucosal abnormalities (<5mm) and the adjacent structures abnormalities identified in surgical pathology. However, oral contrast-enhanced ultrasonography was a bit poorer than upper gastrointestinal endoscopy (P < .05) and far better than conventional ultrasonography (P < .01) in detecting the minor mucosal abnormalities (<5mm). CONCLUSION: Oral contrast-enhanced gastric ultrasonography is superior to conventional gastric ultrasonography in defining the anatomic location and extension of gastric lesions. Its diagnostic performance is not worse than upper gastrointestinal endoscopy and it can be used as a useful supplement to upper gastrointestinal endoscopy. PMID- 27943377 TI - Using rapid reviews: an example from a study conducted to inform policy-making. AB - AIM: A discussion of the potential use of rapid review approaches in nursing and midwifery research which presents a worked example from a study conducted to inform policy decision-making. BACKGROUND: Rapid reviews, which can be defined as outputs of a knowledge synthesis approach that involves modifying or omitting elements of a systematic review process due to limited time or resources, are becoming increasingly popular in health research. This paper provides guidance on how a rapid review can be undertaken and discusses the strengths and challenges of the approach. DESIGN: Data from a rapid review of the literature undertaken in 2015 is used as a worked example to highlight one method of undertaking a rapid review. IMPLICATIONS FOR NURSING: Seeking evidence to inform health policy-making or evidence based practice is a process that can be limited by time constraints, making it difficult to conduct comprehensive systematic reviews. Rapid reviews provide a solution as they are a systematic method of synthesizing evidence quickly. CONCLUSIONS: There is no single best way to conduct a rapid review but researchers can ensure they are adhering to best practice by being systematic, having subject and methodological expertise on the review team, reporting the details of the approach they took, highlighting the limitations of the approach, engaging in good evidence synthesis and communicating regularly with end users, other team members and experts. PMID- 27943378 TI - Sonographic Evaluation of Endothelial Function in Brachial Arteries of Adult Stroke Patients. AB - OBJECTIVES: Brachial artery flow-mediated dilatation on sonography is used to evaluate endothelial dysfunction, which is a key event in the development of atherosclerosis and predates structural atherosclerotic lesions by many years. Atherosclerosis has been implicated in the pathophysiologic mechanisms of ischemic stroke. The aim of this study was to determine the association between brachial flow-mediated dilatation, the presence of cardiovascular risk factors, and acute stroke. METHODS: We evaluated right brachial arteries of 150 participants (50 stroke patients, 50 patients with cardiovascular risk factors, and 50 healthy control individuals) with B-mode sonography before and 5 minutes after sphygmomanometer cuff application to their forearms. Analysis of variance for multiple comparisons was used between each group. RESULTS: Mean ages of the stroke, risk factor, and control groups +/- SD were 57.5 +/- 14.8, 52.4 +/- 16.0, and 56.1 +/- 14.9 years, respectively (P = .235). Flow-mediated dilatation rates were 4.37% +/- 1.50%, 5.62% +/- 1.23%, and 10.33% +/- 1.96% in the stroke, risk factor, and control groups (P <= .001). Dilatation was 3.79% +/- 0.92% in ischemic stroke compared with 6.02% +/- 1.62% in intracerebral hemorrhage (P < .001), but there was no significant difference in dilatation between ischemic stroke subtypes according to the Trial of ORG 10172 in Acute Stroke Treatment classification (P = .301). CONCLUSIONS: Brachial flow-mediated dilatation was significantly lower in patients with acute stroke compared with controls matched for vascular risk factors and healthy controls. Decreased vascular endothelial function in stroke patients was particularly related to cerebral infarction compared with intracerebral hemorrhage. Brachial flow-mediated dilatation did not differentiate ischemic stroke subtypes by the Trial of ORG 10172 in Acute Stroke Treatment classification. Flow-mediated dilatation was therefore found to be a marker of cardiovascular risk and a probable reactant in the acute phase of stroke. PMID- 27943379 TI - Speckle Tracking Imaging in Normal Stress Echocardiography. AB - OBJECTIVES: Exercise stress echocardiography is a widely used modality for the diagnosis and follow-up of patients with coronary artery disease. During the last decade, speckle tracking imaging has been used increasingly for accurate evaluation of cardiac function. This work aimed to assess speckle-tracking imaging parameters during nonischemic exercise stress echocardiography. METHODS: During 2011 to 2014 we studied 46 patients without history of coronary artery disease, who completed exercise stress echocardiography protocol, had normal left ventricular function, a nonischemic response, and satisfactory image quality. These exams were analyzed with speckle-tracking imaging software at rest and at peak exercise. Peak strain and time-to-peak strain were measured at rest and after exercise. Clinical follow-up included a telephone contact 1 to 3 years after stress echo exam, confirming freedom from coronary events during this time. RESULTS: Global and regional peak strain increased following exercise. Time-to peak global and regional strain and time-to-peak strain adjusted to the heart rate were significantly shorter in all segments after exercise. Rest-to-stress ratio of time-to-peak strain adjusted to the heart rate was 2.0 to 2.8. CONCLUSIONS: Global and regional peak strain rise during normal exercise echocardiography. Peak global and regional strain occur before or shortly after aortic valve closure at rest and after exercise, and the delay is more apparent at the basal segments. Time-to-peak strain normally shortens significantly during exercise; after adjustment to heart rate it shortens by a ratio of 2.0 to 2.8. These data may be useful for interpretation of future exercise stress speckle tracking echocardiography studies. PMID- 27943380 TI - In vitro Monocyte IL-6 Secretion Levels Following Stimulation with Autologous Spheroids Derived from Tumour or Benign Mucosa Predict Long-term Survival in Head and Neck Squamous Cell Carcinoma Patients. AB - MCP-1/IL-6 in vitro monocyte secretion upon coculture with autologous fragment spheroids was studied in relation to patient 5- and 10-year overall survival rates in head and neck squamous cell carcinoma (HNSCC) patients (n = 65) diagnosed between 1998 and 2005, nine of whom had an human papilloma virus (HPV) tumour infection. The spheroids were harvested from malignant or benign tissue during primary surgery. Two weeks following surgery, freshly isolated autologous monocytes and benign or malignant spheroids were cocultured 24 h in vitro. The IL 6 secretion was expressed as a fraction of the lipopolysaccharide (LPS) response from the same batch of monocytes. HPV status was obtained by employing PCR analyses of primary diagnostic blocks. IL-6/MCP-1 response levels were not found to be dependent on HPV infection status. MCP-1 secretion did not predict prognosis, nor did in vitro IL-6 monocyte background or LPS-stimulated IL-6 secretion. At 5-year observation, dichotomized IL-6 levels following monocyte coculture, with both malignant and benign spheroids, showed a strong trend towards predicting survival, that is a low monocyte malignant coculture response showed a survival of 31 +/- 17 versus 58 +/- 17% with a high such response (P = 0.057). When studying monocyte IL-6 coculture responses evaluating benign and malignant spheroid results statistically together, a prediction of survival up to 10 years was found (hazard ratio = 0.48; confidence interval = 0.24-0.96; P < 0.05) with double low IL-6 responses. This survival prediction was also present after an adjustment for HPV tumour infection status. In conclusion, monocyte IL-6 in vitro secretion in cocultures with autologous spheroids/serum from HNSCCs predicted 5- and 10-year survivals, both with and without tumour HPV tumour adjustment. PMID- 27943381 TI - Body Mass Normalization for Ultrasound Measurements of Adolescent Lateral Abdominal Muscle Thickness. AB - OBJECTIVES: The purpose of this study was to determine the value of the allometric parameter for ultrasound measurements of the thickness of the oblique external (OE), internal (OI), and transversus abdominis (TrA) muscles in the adolescent population. The allometric parameter is the slope of the linear regression line between the log transformed body mass and log transformed muscle size measurement. METHODS: The study included 321 adolescents between the ages of 10 and 17, consisting of 160 boys and 161 girls. The participants were recruited from local schools and attended regular school classes at normal grade levels. All individuals with no signs of scoliosis (screening with use of a scoliometer), and no surgical procedures performed on the trunk area were included. A real-time ultrasound B-scanner with a linear array transducer was used to obtain images of the lateral abdominal muscles from both sides of the body. RESULTS: The correlation between body mass and the OE muscle was r = 0.69; the OI muscle r = 0.68; and the TrA muscle r = 0.53 (in all cases, P < .0001). The allometric parameter for the OE was 0.88296; the OI 0.718756; and the TrA 0.60986. Using these parameters, no significant correlations were found between body mass and the allometric-scaled thickness of the lateral abdominal muscles. CONCLUSIONS: Significant positive correlations exist between body mass and lateral abdominal muscle thickness assessed by ultrasound imaging. Therefore, it is reasonable to advise that the values of the allometric parameters for OE, OI, and TrA obtained in this study should be used in other studies performed on adolescents. PMID- 27943382 TI - Comparison of approaches for incorporating new information into existing risk prediction models. AB - We compare the calibration and variability of risk prediction models that were estimated using various approaches for combining information on new predictors, termed 'markers', with parameter information available for other variables from an earlier model, which was estimated from a large data source. We assess the performance of risk prediction models updated based on likelihood ratio (LR) approaches that incorporate dependence between new and old risk factors as well as approaches that assume independence ('naive Bayes' methods). We study the impact of estimating the LR by (i) fitting a single model to cases and non-cases when the distribution of the new markers is in the exponential family or (ii) fitting separate models to cases and non-cases. We also evaluate a new constrained maximum likelihood method. We study updating the risk prediction model when the new data arise from a cohort and extend available methods to accommodate updating when the new data source is a case-control study. To create realistic correlations between predictors, we also based simulations on real data on response to antiviral therapy for hepatitis C. From these studies, we recommend the LR method fit using a single model or constrained maximum likelihood. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943383 TI - Statin potency and the risk of hospitalization for community-acquired pneumonia. AB - AIM: Previous studies suggest that statins may have beneficial respiratory effects. However, it is unclear if these purported benefits vary with statin potency. Our objective was to determine if higher potency statins, compared with lower potency statins, were associated with a reduced risk of hospitalization for community-acquired pneumonia (HCAP). METHODS: We conducted a nested case-control analysis of a retrospective, population-based cohort of new users of statins using data extracted from the UK's Clinical Practice Research Datalink and Hospital Episode Statistics. For each HCAP case, we used risk set sampling to randomly select up to 10 controls, matched on sex, age, cohort entry date and follow-up duration. We used conditional logistic regression with high-dimensional propensity scores to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for HCAP with current use of higher potency statin vs. lower potency statins. RESULTS: A total of 217 721 patients entered the cohort on a lower potency statin and 130 707 entered on a higher potency statin; these patients resulted in 2251 cases of HCAP during 561 886 person-years of observation (rate: 4.0 HCAP per 1000 persons per year, 95% CI: 3.8-4.2). The analysis included 22 178 matched controls. Compared with lower potency statins, higher potency statins were associated with an increased rate of HCAP (HR: 1.14, 95% CI: 1.03-1.27). Higher potency statins were also associated with an increased rate of fatal HCAP (HR: 1.29, 95% CI: 1.04-1.59). CONCLUSIONS: Higher potency statins were not associated with a decreased risk of HCAP compared with lower potency statins. PMID- 27943384 TI - Determination of adalimumab and etanercept trough levels and drug antibodies in long-term psoriasis treatment: a single-centre cohort study. AB - BACKGROUND: An algorithm based on measurement of a serum tumour necrosis factor antagonists (anti-TNF) and antidrug antibodies (ADA) has been proposed previously to guide dose escalation or therapy switching in the early (i.e. the first months of) treatment of psoriasis by anti-TNF. In long-term treatment of responding patients with psoriasis, it is usual to empirically reduce standard doses of anti TNF to reduce exposure while maintaining clinical response. The relationship between serum anti-TNF, ADA levels and clinical efficacy in long-term treated patients with psoriasis has not yet been determined, so the potential role of these parameters in guiding dose escalation in this scenario is unknown. AIMS: To evaluate the relationship between drug/ADA levels and clinical efficacy in a group of patients with psoriasis undergoing long-term treatment with adalimumab or etanercept. METHODS: This was a single-centre, prospective, cohort study of patients with psoriasis receiving adalimumab or etanercept for a minimum of 48 weeks. All patients were started on the standard dose, but some adalimumab users had a reduced frequency of administration. Clinical efficacy was measured using the Psoriasis Area and Severity Index. Serum concentrations were measured by ELISA. Clinical assessment and blood sample collection were carried out simultaneously within 24 h before the next drug administration. RESULTS: In total, 21 patients were enrolled (67 simultaneous clinical and serum determinations: 38 receiving adalimumab, 29 receiving etanercept). We did not find any association between serum anti-TNF levels and clinical response. None of the patients developed ADA. CONCLUSIONS: ADA and anti-TNF levels are not related to clinical effectiveness in patients with psoriasis undergoing long-term treatment with adalimumab or etanercept. PMID- 27943385 TI - M2000 (beta-D-Mannuronic Acid) as a Novel Antagonist for Blocking the TLR2 and TLR4 Downstream Signalling Pathway. AB - To date, selective blockade of Toll-like receptor (TLR) signalling has been developed as a new approach for treatment for many inflammatory diseases. As beta D-mannuronic acid (M2000) has been known as an anti-inflammatory molecule in several experimental models, we investigated the antagonistic effects of M2000 on TLR2 and TLR4 downstream signalling transduction pathway in human embryonic kidney (HEK) 293 cell lines overexpressing TLR2/CD14 and the TLR4/MD2/CD14 complex, respectively. M2000 effectively inhibited mRNA expression of MyD88 and p65, major subunit of nuclear factor-kappaB, in HEK293 cells stimulated by lipoteichoic acid (LTA, a TLR2 agonist) and lipopolysaccharide (LPS, a TLR4 agonist) with no evidence of cytotoxicity. In addition, M2000 also suppressed LTA and LPS-induced production of TNF-alpha and IL-6 inflammatory cytokines in these cells. Furthermore, the results revealed that M2000 had no significant effect on Tollip mRNA expression as a negative regulator of TLR signalling in aforesaid cells. Overall, these data point to M2000 inhibitory effect on Toll-like receptor (TLR) 2, 4 signalling in HEK293 cells. This information might provide new insights into the possible roles of this small drug in order to introduce it as a TLR signalling pathway inhibitor. However, more studies are needed to confirm beta-D-mannuronic acid antagonistic effects including the effects of M2000 on peritoneal isolated macrophages and also on blood cells in patients with inflammatory diseases such as ankylosing spondylitis. PMID- 27943386 TI - Early-onset Preeclampsia in Lupus Pregnancy. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that occurs during childbearing years and has been associated with preeclampsia. However, little is known about preeclampsia of early onset, which is associated with severe adverse maternal and perinatal outcomes. METHODS: Using national population-based Swedish registers we identified women with SLE (>=2 visits with corresponding ICD codes) and a sample without SLE who gave birth to singleton infants 2001-12. Risk ratios (RR) and 95% confidence intervals (CI) for early-onset preeclampsia (defined by ICD codes corresponding to preeclampsia registered at <34 weeks) in SLE women were calculated based on adjusted modified Poisson models for first, subsequent, and all pregnancies. RESULT: Among 742 births to women with SLE and 10 484 births to non-SLE women, there were 32 (4.3%) and 55 (0.5%) diagnoses of early-onset preeclampsia respectively. SLE was associated with an increased risk of early-onset preeclampsia (RR 7.8, 95% CI 4.8, 12.9, all pregnancies). The association remained similar upon restriction to women without pregestational hypertension. Adjustment for antiphospholipid syndrome (APS)-proxy attenuated the association. RRs for early-onset preeclampsia were smaller for subsequent pregnancies (RR 4.7, 95% CI 2.0, 11.2) compared to first and all (see above). CONCLUSION: Women with SLE are at increased risk of early-onset preeclampsia and this increased risk may be independent of the traditional risk factors such as pregestational hypertension, APS, BMI, or smoking. Women with SLE during pregnancy should be closely monitored for early onset preeclampsia and future research needs to identify the non-traditional preeclampsia factors that might cause this serious outcome. PMID- 27943387 TI - BMI-1 Mediates Estrogen-Deficiency-Induced Bone Loss by Inhibiting Reactive Oxygen Species Accumulation and T Cell Activation. AB - Previous studies have shown that estrogen regulates bone homeostasis through regulatory effects on oxidative stress. However, it is unclear how estrogen deficiency triggers reactive oxygen species (ROS) accumulation. Recent studies provide evidence that the B lymphoma Mo-MLV insertion region 1 (BMI-1) plays a critical role in protection against oxidative stress and that this gene is directly regulated by estrogen via estrogen receptor (ER) at the transcriptional level. In this study, ovariectomized mice were given drinking water with/without antioxidant N-acetyl-cysteine (NAC, 1 mg/mL) supplementation, and compared with each other and with sham mice. Results showed that ovariectomy resulted in bone loss with increased osteoclast surface, increased ROS levels, T cell activation, and increased TNF and RANKL levels in serum and in CD4 T cells; NAC supplementation largely prevented these alterations. BMI-1 expression levels were dramatically downregulated in CD4 T cells from ovariectomized mice. We supplemented drinking water to BMI-1-deficient mice with/without NAC and compared them with each other and with wild-type (WT) mice. We found that BMI-1 deficiency mimicked alterations observed in ovariectomy whereas NAC supplementation reversed all alterations induced by BMI-1 deficiency. Because T cells are critical in mediating ovariectomy-induced bone loss, we further assessed whether BMI-1 overexpression in lymphocytes can protect against estrogen deficiency-induced osteoclastogenesis and bone loss by inhibiting oxidative stress, T cell activation, and RANKL production. When WT and EMU-BMI-1 transgenic mice with BMI 1 specifically overexpressed in lymphocytes were ovariectomized and compared with each other and with WT sham mice, we found that BMI-1 overexpression in lymphocytes clearly reversed all alterations induced by ovariectomy. Results from this study indicate that estrogen deficiency downregulates BMI-1 and subsequently increases ROS, T cell activation, and RANKL production in T cells, thus enhancing osteoclastogenesis and accelerating bone loss. This study clarifies a novel mechanism regulating estrogen deficiency-induced bone loss. (c) 2016 American Society for Bone and Mineral Research. PMID- 27943388 TI - Is the short axis view of the fetal heart useful in improving the diagnostic accuracy of outlet ventricular septal defects? AB - OBJECTIVES: Outlet ventricular septal defects (VSDs) are usually suspected on the five-chamber view of the fetal heart; however, postnatal confirmation occurs only in a small number of cases. The aim of this study was to evaluate if the systematic assessment of the short axis view may improve the prediction of prenatally detected outlet VSDs. METHODS: Cases where isolated outlet VSD was suspected on the five-chamber view were assessed by using the short axis scanning plane for confirmation of the defect. Postnatal assessment was performed within 2 weeks from birth at our Paediatric Cardiology Unit. RESULTS: An outlet VSD was suspected at five-chamber view in 23 fetuses. Postnatal confirmation of the VSD occurred in 14 cases where the defect was prenatally detected both on the five chamber and the short axis views. VSDs were not confirmed at postnatal assessment only in two cases where outlet VSD was suspected on both views, whereas all the seven cases with a suspected VSD on the five-chamber view only turned out to be false positives. CONCLUSION: The short axis view of the fetal heart seems useful in confirming the presence of outlet VSDs. (c) 2016 John Wiley & Sons, Ltd. PMID- 27943389 TI - The impact of human epidermal growth factor receptor 2 neoadjuvant monoclonal antibody (trastuzumab) therapy in ductal carcinoma in situ of the breast. PMID- 27943390 TI - Polyhydramnios in isolated oral cleft pregnancies: incidence and outcome in a retrospective study. AB - OBJECTIVES: Polyhydramnios is suggested to be associated with oral clefts (OCs) due to swallowing problems. This study assessed incidence and outcome of idiopathic polyhydramnios in isolated OC pregnancies. METHODS: This was a retrospective cohort study of prenatally diagnosed OC. The incidence of idiopathic polyhydramnios in isolated OC pregnancies was determined. Pregnancy outcome, neonatal and paediatric follow-up were compared between cases with polyhydramnios and those with normal amniotic fluid. Subgroup analysis was conducted to evaluate whether an association exists between polyhydramnios and presence of associated anomalies diagnosed after birth. RESULTS: In 230 cases of isolated OC, 15 developed polyhydramnios (6.5%). Involvement of the palate was significantly more common in the presence than in the absence of polyhydramnios (13/15 or 87% vs 125/215 or 58%, p = 0.03, odds ratio 4.7, 95% confidence interval 1.0-30.8). No significant differences were seen in pregnancy outcome or neonatal and paediatric follow-up between the two groups. In subgroup analysis, rate of polyhydramnios was not significantly different in associated cases that appeared isolated prenatally (1/27; 3.7%) compared with that in the isolated cases (15/230; 6.5%). CONCLUSIONS: The incidence of idiopathic polyhydramnios in isolated OC pregnancies is 6.5%. Polyhydramnios in isolated OC increases the risk of palate involvement. The presence of polyhydramnios is not associated with adverse perinatal or long-term outcome. If isolated at prenatal assessment, polyhydramnios does not increase the risk of associated anomalies postpartum. (c) 2016 John Wiley & Sons, Ltd. PMID- 27943391 TI - ICD-ON Registry for Perioperative Management of CIEDs: Most Require No Change. AB - BACKGROUND: There is significant variability in the perioperative management of patients with cardiac implanted electronic devices (CIEDs) undergoing procedures requiring electrosurgery. METHODS: We performed a multicenter registry from February 2014 to August 2015 at three suburban Chicago hospitals. Patients with transvenous CIEDs undergoing procedures requiring electrosurgery were assigned to one of three groups: (1) reprogram, (2) magnet, or (3) no change. Subjects with implantable cardioverter defibrillators (ICDs) or those pacemaker dependent having surgical procedures within 6 inches of their CIED were assigned to the reprogram group, whereby ICD therapies were programmed off with asynchronous pacing if pacemaker dependent. Subjects with ICDs >= 6 inches from their surgical site but above the iliac crest were assigned to the magnet group. All others were in the no change group. We evaluated electromagnetic interference (EMI) and postoperative device reset based on surgical location. RESULTS: All patients (n = 331) had pectoral CIEDs with mean age 73 years, 65% male, ejection fraction 56% for pacemaker subjects, 35% for ICD subjects with 22% pacemaker dependent. Assignments were n = 52 (16%) reprogram group, n = 51 (15%) magnet group, and n = 228 (69%) no change. There was EMI in 45% of thoracic cases, 35% of head/neck, 15% of upper extremity, and 3% of abdominal cases above iliac crest. There was no EMI in procedures below the iliac crest. There were no inappropriate therapies or device reset. CONCLUSION: Results of the ICD-ON protocol demonstrate safe and efficient management of patients with CIEDs based on electrosurgery location, with 69% requiring no reprogramming or magnet application. PMID- 27943392 TI - Production and application of high quality stable isotope-labeled human immunoglobulin G1 for mass spectrometry analysis. AB - Here, we describe the production of stable isotope-labeled human immunoglobulin G1 ([13 C]-hIgG1) using [13 C]-L-lysine/arginine-labeled hIgG1. The fermentation process was run in shake flasks containing labeled arginine and lysinethat were incorporated into the produced recombinant hIgG1. The [13 C]-hIgG1 was purified, and label incorporation was determined to be >99% at all lysine and arginine moieties. Sequence coverage was confirmed by peptide mapping. [13 C]-hIgG1 was then used as an internal standard (IS) for the development of a liquid chromatography-tandem mass spectrometry method applicable to the quantitative analysis of all human types of hIgG1 in rat serum. Four conserved peptides, namely, GPSVFPLAPSSK, TTPPVLDSDGSFFLYSK, VVSVLTVLHQDWLNGK, and FNWYVDGVEVHNAK, originating from different parts of the fraction crystallizable region of hIgG1, were used for quantitation of hIgG1 in rat serum. The calibration curves with a coefficient of determination (r2 ) between 0.9950 and 0.9962 resulting from the peak area ratio of each peptide to its respective labeled IS were reproducible. A mean bias within +/-20.0% of the nominal values and a precision of <=20.0 % were obtained for the calibration standards and quality control samples for each peptide. [13 C]-hIgG1 was shown as a suitable IS for quantitative hIgG1 analysis in preclinical species by LC-MS/MS. PMID- 27943393 TI - Area of the fetal heart's four-chamber view: a practical screening tool to improve detection of cardiac abnormalities in a low-risk population. AB - OBJECTIVE: The objective of this article is to evaluate whether the area of the four-chamber view of the fetal heart computed from two orthogonal diameters could be used to screen for cardiac malformations. METHODS: Two hundred control fetuses were examined between 20 and 40 weeks of gestation. The end-diastolic area was computed from the orthogonal basal-apical and transverse diameters obtained from the four-chamber view. Regression analysis of the computed area versus six independent variables was performed between 20 and 40 weeks. Fetuses with major heart defects were identified from a low-risk population of 4352 fetuses undergoing second-trimester or third-trimester screening ultrasound. The end diastolic area was derived and the Z-score and centile computed. An area greater than the 95th centile was considered to be abnormal. RESULTS: From the screening population, the incidence of major heart defects was 2.8/1000. Of the 12 fetuses with major heart defects, 50% (6/12) demonstrated an area greater than the 95th centile. Of the fetuses with an enlarged heart, 66% (4/6) had outflow tract abnormalities. CONCLUSIONS: Measurements of the orthogonal basal-apical and transverse diameters can be used to compute the area of the four-chamber view. Fetuses with major heart defects who have an enlarged heart can be identified using this technique. (c) 2016 John Wiley & Sons, Ltd. PMID- 27943395 TI - Dihedral angle study in Hesperidin using NMR Spectroscopy. AB - Hesperidin is flavonoid molecule found in citrus fruits (Citrus reticulata), especially difficult to extract, classify and characterize. Present work is to study the unresolved relative configuration of Hesperidin through the dihedral angle, coupling constant and different NMR techniques. The Karplus equation and its modifications have been originated from the valence bond theory and associated with dihedral angle and coupling constant. The result data set of calculated dihedral angle can probe significant method to assign the virtual configuration of natural products and also resolved stereochemistry of Hesperidin at C-2 position in. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943394 TI - The Association Between Protein Intake by Source and Osteoporotic Fracture in Older Men: A Prospective Cohort Study. AB - Dietary protein is a potentially modifiable risk factor for fracture. Our objectives were to assess the association of protein intake with incident fracture among older men and whether these associations varied by protein source or by skeletal site. We studied a longitudinal cohort of 5875 men (mean age 73.6 +/- 5.9 years) in the Osteoporotic Fractures in Men (MrOS) study. At baseline, protein intake was assessed as percent of total energy intake (TEI) with mean intake from all sources = 16.1%TEI. Incident clinical fractures were confirmed by physician review of medical records. There were 612 major osteoporotic fractures, 806 low-trauma fractures, 270 hip fractures, 193 spine fractures, and 919 non-hip non-spine fractures during 15 years of follow-up. We used Cox proportional hazards models with age, race, height, clinical site, TEI, physical activity, marital status, osteoporosis, gastrointestinal surgery, smoking, oral corticosteroids use, alcohol consumption, and calcium and vitamin D supplements as covariates to compute hazard ratios (HRs) with 95% confidence intervals (CIs), all expressed per unit (SD = 2.9%TEI) increase. Higher protein intake was associated with a decreased risk of major osteoporotic fracture (HR = 0.92; 95% CI, 0.84 to 1.00) with a similar association found for low-trauma fracture. The association between protein and fracture varied by protein source; eg, increased dairy protein and non-dairy animal protein were associated with a decreased risk of hip fracture (HR = 0.80 [95% CI, 0.65 to 0.98] and HR = 0.84 [95% CI, 0.72 to 0.97], respectively), whereas plant-source protein was not (HR = 0.99 [95% CI, 0.78 to 1.24]). The association between protein and fracture varied by fracture site; total protein was associated with a decreased risk of hip fracture (HR = 0.84 [95% CI, 0.73 to 0.95]), but not clinical spine fracture (HR = 1.06 [95% CI, 0.92 to 1.22]). In conclusion, those with high protein intake (particularly high animal protein intake) as a percentage of TEI have a lower risk of major osteoporotic fracture. (c) 2016 American Society for Bone and Mineral Research. PMID- 27943396 TI - Malignant melanoma with bone marrow involvement diagnosed from hypercalcemia: Development of a neural cell adhesion molecule stain. PMID- 27943399 TI - Development and validation of the pro-environmental behaviour scale for women's health. AB - AIM: This study was aimed to develop and test the Pro-environmental Behavior Scale for Women's Health. BACKGROUND: Women adopt sustainable behaviours and alter their life styles to protect the environment and their health from environmental pollution. The conceptual framework of pro-environmental behaviours was based on Rogers' protection motivation theory and Weinstein's precaution adoption process model. DESIGN: The cross-sectional design was used for instrument development. METHOD: The instrument development process consisted of a literature review, personal depth interviews and focus group interviews. The sample comprised 356 adult women recruited in April-May 2012 in South Korea using quota sampling. For construct validity, exploratory factor analysis was conducted to examine the factor structure, after which convergent and discriminant validity and known-group comparisons were tested. RESULTS: Principal component analysis yielded 17 items with four factors, including 'women's health protection,' 'chemical exposure prevention,' 'alternative consumption,' and 'community oriented behaviour'. The Cronbach's alpha was 0.81. Convergent and discriminant validity were supported by performing correlations with other environmental health and health-behaviour measures. CONCLUSION: Nursing professionals can reliably use the instrument to assess women's behaviours, which protect their health and the environment. PMID- 27943398 TI - Long-term effects of peer victimization on social outcomes through the fourth decade of life in individuals born at normal or extremely low birthweight. AB - Exposure to early adversity is known to have deleterious effects on brain behaviour relations across the lifespan and across a range of domains. Here, we tested a cumulative risk hypothesis of adult social functioning and health outcomes in the fourth decade of life, using the oldest known longitudinally followed cohort of survivors of extremely low birthweight (ELBW; <1,000 g). We investigated the additional impact of peer victimization in youth on social outcomes at age 29-36 years in ELBW survivors and matched normal birthweight (NBW; >2,500 g) participants. In the combined sample, peer victimization was associated with lower likelihood of having children and household income, poorer family functioning and self-esteem, more loneliness and chronic health conditions, less social support, and increased likelihood for contact with police. Moderation analyses indicated that among ELBW survivors, compared to their NBW counterparts, victimization was more strongly associated with being convicted of a crime and with having chronic health conditions. These findings highlight the negative long-term impact of peer victimization on all children and that some outcomes may be differentially affected by prenatal and early post natal environments. Statement of contribution What is already known on this subject Exposure to early adversity has deleterious effects on brain-behaviour relations across the lifespan. Extremely premature children have higher rates of exposure to adversities, including peer victimization. Peer victimization is associated with adverse outcomes in adulthood in those born at term. What does this study add? Victimization negatively impacts the social outcomes of those born extremely premature and at term into adulthood. Associations appear to be affected by individual differences in prenatal and early post-natal environments. Intervention is crucial when peer victimization occurs in children at risk, as well as those typically developing. PMID- 27943400 TI - Involvement of high mobility group box-1 in imiquimod-induced psoriasis-like mice model. AB - In the previous work, we have indicated that HMGB1, a pro-inflammatory cytokine, is closely associated with the pathogenesis of psoriasis. To further clarify the role of HMGB1 in the pathogenesis of psoriasis, we investigated the direct function of HMGB1 application and HMGB1 blockade in imiquimod (IMQ)-induced psoriatic mouse model in this study. Mice were treated with imiquimod (IMQ) to induce psoriasis-like inflammation, and consecutively injected with recombinant HMGB1 or phosphate-buffered saline (PBS) i.d. Abundant cytoplasmic expression of HMGB1 was observed in lesional skin from IMQ-treated skin. The injection of HMGB1 into the IMQ-treated skin further aggravated the psoriasis-like disease, enhanced the infiltration of CD3+ T cells, myeloperoxidase+ neutrophils and CD11c+ dendritic cells, increased the number of gammadelta T cells, and upregulated the mRNA expression of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and IL-17 compared with the PBS injection. Finally, by using anti-HMGB1 monoclonal antibody or HMGB1 inhibitor glycyrrhizin, we indicated that HMGB1 blockade reduced the number of gammadelta T cells, suppressed the mRNA expression of IL-6, TNF-alpha, IFN-gamma and IL-17, and moderated clinical and histological evolvement in the IMQ-treated skin. Our data suggest that HMGB1 may act as a pro-inflammatory cytokine, and contribute to the development of IMQ-induced psoriasis-like inflammation. HMGB1 blockade may represent a new direction in the suppression of psoriasis. PMID- 27943401 TI - Fixism and conservation science. AB - The field of biodiversity conservation has recently been criticized as relying on a fixist view of the living world in which existing species constitute at the same time targets of conservation efforts and static states of reference, which is in apparent disagreement with evolutionary dynamics. We reviewed the prominent role of species as conservation units and the common benchmark approach to conservation that aims to use past biodiversity as a reference to conserve current biodiversity. We found that the species approach is justified by the discrepancy between the time scales of macroevolution and human influence and that biodiversity benchmarks are based on reference processes rather than fixed reference states. Overall, we argue that the ethical and theoretical frameworks underlying conservation research are based on macroevolutionary processes, such as extinction dynamics. Current species, phylogenetic, community, and functional conservation approaches constitute short-term responses to short-term human effects on these reference processes, and these approaches are consistent with evolutionary principles. PMID- 27943397 TI - Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease. AB - BACKGROUND: Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations. AIM: To determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment. METHODS: The cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase >=5. RESULTS: Forty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 * 108 erythrocytes was defined. Analysis of patients on stable thiopurine dose (n = 174) showed that those exceeding the 6 MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8 8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6-MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75-0.91)]. 6-MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4-4.3), and general malaise: OR = 2.0 (95% CI: 1.1-3.7). CONCLUSIONS: In more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure. PMID- 27943402 TI - Autocalibrating motion-corrected wave-encoding for highly accelerated free breathing abdominal MRI. AB - PURPOSE: To develop a motion-robust wave-encoding technique for highly accelerated free-breathing abdominal MRI. METHODS: A comprehensive 3D wave encoding-based method was developed to enable fast free-breathing abdominal imaging: (a) auto-calibration for wave-encoding was designed to avoid extra scan for coil sensitivity measurement; (b) intrinsic butterfly navigators were used to track respiratory motion; (c) variable-density sampling was included to enable compressed sensing; (d) golden-angle radial-Cartesian hybrid view-ordering was incorporated to improve motion robustness; and (e) localized rigid motion correction was combined with parallel imaging compressed sensing reconstruction to reconstruct the highly accelerated wave-encoded datasets. The proposed method was tested on six subjects and image quality was compared with standard accelerated Cartesian acquisition both with and without respiratory triggering. Inverse gradient entropy and normalized gradient squared metrics were calculated, testing whether image quality was improved using paired t-tests. RESULTS: For respiratory-triggered scans, wave-encoding significantly reduced residual aliasing and blurring compared with standard Cartesian acquisition (metrics suggesting P < 0.05). For non-respiratory-triggered scans, the proposed method yielded significantly better motion correction compared with standard motion corrected Cartesian acquisition (metrics suggesting P < 0.01). CONCLUSION: The proposed methods can reduce motion artifacts and improve overall image quality of highly accelerated free-breathing abdominal MRI. Magn Reson Med 78:1757-1766, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27943403 TI - Does Talker-Specific Information Influence Lexical Competition? Evidence From Phonological Priming. AB - In this study, we examined whether the lexical competition process embraced by most models of spoken word recognition is sensitive to talker-specific information. We used a lexical decision task and a long lag priming experiment in which primes and targets sharing all phonemes except the last one (e.g., /bagaR/"fight" vs. /baga3/"luggage") were presented in two separate blocks of stimuli. In Experiment 1, the competitor prime block was presented only once to listeners, and no modulation of the competitor priming effect as a function of a talker change between the primes and targets was observed. However, attenuation in the competitor priming effect in the case of a talker change between the primes and targets was observed in Experiment 2 in which the competitor prime block was presented five times to listeners. We discuss our findings in reference to hybrid models of spoken word recognition in which repetition of words with the same talker could be a key factor in the formation and access to talker-dependent representations. PMID- 27943404 TI - The prevalence of ALK rearrangement in pulmonary adenocarcinomas in an unselected Caucasian population from a defined catchment area: impact of smoking. AB - AIMS: To assess the prevalence of EML4-ALK rearrangement gene measured by immunohistochemistry in an unselected population-based consecutive cohort of patients with adenocarcinoma of the lung (ACL), and the correlation with smoking history, thyroid transcription factor 1 (TTF1), gender and age. METHODS AND RESULTS: All patients diagnosed in the population of the greater Copenhagen area were included, irrespective of gender, age, smoking habits, stage or type of available diagnostic material. Tumours were stained with immunohistochemistry (clone 5A4). Immunohistochemistry-positive tumours were tested by fluorescence in situ hybridization (FISH). During a 16-month period, 760 patients in the population were diagnosed with ACL. In 2.6% there was insufficient material for ALK testing (20 of 760). Eleven per cent of the remaining 740 ACL patients were never smokers, 43% were ex-smokers smokers and 46% were current smokers. Fourteen patients [1.9%, 95% confidence interval (CI) = 1.1-3.2] were ALK-positive by immunohistochemistry. Nine of 82 never-smokers (11%, 95% CI = 5.9-19.6) and five of 652 ex- or current smokers (0.8%, 95% CI = 0.4-2.1) were ALK-positive. Only two ALK-positive patients were found among 586 heavy smokers (> 15 pack-years) (0.3%, 95% CI = 0.09-1.2). Thirteen of the 14 immunohistochemistry-positive patients were FISH-positive. All ALK-positive tumours were TTF1-positive. The number needed to test (NNT) to identify one ALK positive patient was 9, 22 and 293 among never smokers, light and heavy smokers, respectively. CONCLUSIONS: Immunohistochemical analysis of ALK rearrangement was possible in 97.4% of patients. ALK rearrangement was found primarily in never smokers. NNT to identify one ALK-positive patient was 9, 22 and 293 among never smokers, light and heavy smokers, respectively. PMID- 27943405 TI - N-ICE plasmids for generating N-terminal 3 * FLAG tagged genes that allow inducible, constitutive or endogenous expression in Saccharomyces cerevisiae. AB - PCR-mediated homologous recombination is a powerful approach to introduce epitope tags into the chromosomal loci at the N-terminus or the C-terminus of targeted genes. Although strategies of C-terminal epitope tagging of target genes at their loci are simple and widely used in yeast, C-terminal epitope tagging is not practical for all proteins. For example, a C-terminal tag may affect protein function or a protein may get cleaved or processed, resulting in the loss of the epitope tag. Therefore, N-terminal epitope tagging may be necessary to resolve these problems. In some cases, an epitope tagging strategy is used to introduce a heterologous promoter with the epitope tag at the N-terminus of a gene of interest. The potential issue with this strategy is that the tagged gene is not expressed at the endogenous level. Another strategy after integration is to excise the selection marker, using the Cre-LoxP system, leaving the epitope tagged gene expressed from the endogenous promoter. However, N-terminal epitope tagging of essential genes using this strategy requires a diploid strain followed by tetrad dissection. Here we present 14 new plasmids for N-terminal tagging, which combines two previous strategies for epitope tagging in a haploid strain. These 'N-ICE' plasmids were constructed so that non-essential and essential genes can be N-terminally 3 * FLAG tagged and expressed from an inducible promoter (GAL1), constitutive promoters (CYC1 or PYK1) or the endogenous promoter. We have validated the N-ICE plasmid system by N-terminal tagging two non-essential genes (SET1 and SET2) and two essential genes (ERG11 and PKC1). Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943407 TI - A Novel and Generalized Lithium-Ion-Battery Configuration utilizing Al Foil as Both Anode and Current Collector for Enhanced Energy Density. AB - A novel battery configuration based on an aluminum foil anode and a conventional cathode is developed. The aluminum foil plays a dual role as both the active anode material and the current collector, which enhances the energy density of the packaged battery, and reduces the production cost. This generalized battery configuration has high potential for application in next-generation lithium-ion batteries. PMID- 27943408 TI - Type 2 Diabetes Mellitus Is Associated With Better Bone Microarchitecture But Lower Bone Material Strength and Poorer Physical Function in Elderly Women: A Population-Based Study. AB - Type 2 diabetes mellitus (T2DM) is associated with an increased risk of fractures according to several studies. The underlying mechanisms remain unclear, although small case-control studies indicate poor quality of the cortical bone. We have studied a population-based sample of women aged 75 to 80 years in Gothenburg, randomly invited from the population register. Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (Hologic Discovery A), bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT; ExtremeCT from Scanco Medical AG), and reference point indentation was performed with Osteoprobe (Active Life Scientific). Women with T2DM (n = 99) had higher aBMD compared to controls (n = 954). Ultradistal tibial and radial trabecular bone volume fraction (+11% and +15%, respectively), distal cortical volumetric BMD (+1.6% and +1.7%), cortical area (+11.5% and +9.3%), and failure load (+7.7% and +12.9%) were higher in diabetics than in controls. Cortical porosity was lower (mean +/- SD: 1.5% +/- 1.1% versus 2.0% +/- 1.7%, p = 0.001) in T2DM in the distal radius but not in the ultradistal radius or the tibia. Adjustment for covariates (age, body mass index, glucocorticoid treatment, smoking, physical activity, calcium intake, bone-active drugs) eliminated the differences in aBMD but not in HR-pQCT bone variables. However, bone material strength index (BMSi) by reference point indentation was lower in T2DM (74.6 +/- 7.6 versus 78.2 +/- 7.5, p < 0.01), also after adjustment, and women with T2DM performed clearly worse in measures of physical function (one leg standing: -26%, 30-s chair-stand test: -7%, timed up and go: +12%, walking speed: +8%; p < 0.05 0.001) compared to controls. In conclusion, we observed a more favorable bone microarchitecture but no difference in adjusted aBMD in elderly women with T2DM in the population compared to nondiabetics. Reduced BMSi and impaired physical function may explain the increased fracture risk in T2DM. (c) 2016 American Society for Bone and Mineral Research. PMID- 27943406 TI - Fast Genome-Wide QTL Association Mapping on Pedigree and Population Data. AB - Since most analysis software for genome-wide association studies (GWAS) currently exploit only unrelated individuals, there is a need for efficient applications that can handle general pedigree data or mixtures of both population and pedigree data. Even datasets thought to consist of only unrelated individuals may include cryptic relationships that can lead to false positives if not discovered and controlled for. In addition, family designs possess compelling advantages. They are better equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Pedigrees selected for extreme trait values often segregate a single gene with strong effect. Finally, many pedigrees are available as an important legacy from the era of linkage analysis. Unfortunately, pedigree likelihoods are notoriously hard to compute. In this paper, we reexamine the computational bottlenecks and implement ultra-fast pedigree-based GWAS analysis. Kinship coefficients can either be based on explicitly provided pedigrees or automatically estimated from dense markers. Our strategy (a) works for random sample data, pedigree data, or a mix of both; (b) entails no loss of power; (c) allows for any number of covariate adjustments, including correction for population stratification; (d) allows for testing SNPs under additive, dominant, and recessive models; and (e) accommodates both univariate and multivariate quantitative traits. On a typical personal computer (six CPU cores at 2.67 GHz), analyzing a univariate HDL (high-density lipoprotein) trait from the San Antonio Family Heart Study (935,392 SNPs on 1,388 individuals in 124 pedigrees) takes less than 2 min and 1.5 GB of memory. Complete multivariate QTL analysis of the three time-points of the longitudinal HDL multivariate trait takes less than 5 min and 1.5 GB of memory. The algorithm is implemented as the Ped-GWAS Analysis (Option 29) in the Mendel statistical genetics package, which is freely available for Macintosh, Linux, and Windows platforms from http://genetics.ucla.edu/software/mendel. PMID- 27943409 TI - Sonography of the Coracoid Process Region. AB - Sonography is widely known as an accurate imaging tool for assessment of the rotator cuff of the shoulder, the long head of the biceps tendon, and joint disorders, but it is rarely performed to evaluate the coracoid process and the adjacent soft tissues. Nevertheless, sonography can show anatomic details of this region and be used to assess several pathologic conditions. The aims of this pictorial essay are to briefly review the anatomy of the coracoid process region, describe examination technique and normal sonographic appearances, and present the sonographic findings of the main disorders affecting this region. PMID- 27943410 TI - Number of Weeks Rotating in the Emergency Department Has a Greater Effect on Ultrasound Milestone Competency Than a Dedicated Ultrasound Rotation. AB - OBJECTIVES: Ultrasound (US) is vital to modern emergency medicine (EM). Across residencies, there is marked variability in US training. The "goal-directed focused US" part of the Milestones Project states that trainees must correctly acquire and interpret images to achieve a level 3 milestone. Standardized methods by which programs teach these skills have not been established. Our goal was to determine whether residents could achieve level 3 with or without a dedicated US rotation. METHODS: Thirty-three first- and second-year residents were assigned to control (no rotation) and intervention (US rotation) groups. The intervention group underwent a 2-week curriculum in vascular access, the aorta, echocardiography, focused assessment with sonography for trauma, and pregnancy. To test acquisition, US-trained emergency medicine physicians administered an objective structured clinical examination. To test interpretation, residents had to identify normal versus abnormal findings. Mixed-model logistic regression tested the association of a US rotation while controlling for confounders: weeks in the emergency department (ED) as a resident, medical school US rotation, and postgraduate years. RESULTS: For image acquisition, medical school US rotation and weeks in the ED as a resident were significant (P = .03; P = .04) whereas completion of a US rotation and postgraduate years were not significant. For image interpretation, weeks in the ED as a resident was the only significant predictor of performance (P = .002) whereas completion of a US rotation and medical school US rotation were not significant. CONCLUSIONS: To achieve a level 3 milestone, weeks in the ED as a resident were significant for mastering image acquisition and interpretation. A dedicated US rotation did not have a significant effect. A medical school US rotation had a significant effect on image acquisition but not interpretation. Further studies are needed to best assess methods to meet US milestones. PMID- 27943412 TI - Doppler Characteristics of Recurrent Hepatic Artery Stenosis. AB - OBJECTIVES: We sought to assess midterm sonographic findings in patients after stenting for hepatic artery stenosis. METHODS: Thirty-nine hepatic artery stent procedures were performed for hepatic artery stenosis after liver transplantation between September 2009 and December 2013. Thirty cases were technically successful and met the minimum follow-up time (76 days, defined by earliest diagnosed stenosis). Routine ultrasound surveillance was obtained on all patients, and statistical analysis of the findings in the patency and restenosis groups was performed. RESULTS: Of the 30 cases, restenosis occurred 9 times in 6 patients. Mean follow-up was 677 days. Mean time to restenosis was 267 days. Five cases (56%) were identified within the first 6 months after stent placement. Four cases (44%) were recognized in the second year after stent placement. Prior to the sonographic diagnosis of restenosis, the mean resistive indices of the main (.64 versus .57, P < .0001), left (.63 versus .54, P < .0001), right anterior (.60 versus .52, P < .0001), and right posterior (.60 versus .53, P = .001) hepatic artery branches differed among patency and restenosis groups, respectively. The mean peak systolic velocity also differed significantly between the 2 groups: 254 cm/sec in patients with eventual restenosis versus 220 cm/sec in patients without restenosis (P = .02). CONCLUSIONS: The sonographic evaluation of hepatic artery stenosis remains critical during the first 2 years after stent placement. While the vast majority of patients do not restenose, resistive index and peak systolic velocity differed significantly between the 2 groups and may be prognostic surveillance markers for the development of restenosis. PMID- 27943411 TI - Effect of Pulse Shaping on Subharmonic Aided Pressure Estimation In Vitro and In Vivo. AB - OBJECTIVES: Subharmonic imaging (SHI) is a technique that uses the nonlinear oscillations of microbubbles when exposed to ultrasound at high pressures transmitting at the fundamental frequency ie, fo and receiving at half the transmit frequency (ie, fo /2). Subharmonic aided pressure estimation (SHAPE) is based on the inverse relationship between the subharmonic amplitude of the microbubbles and the ambient pressure change. METHODS: Eight waveforms with different envelopes were optimized with respect to acoustic power at which the SHAPE study is most sensitive. The study was run with four input transmit cycles, first in vitro and then in vivo in three canines to select the waveform that achieved the best sensitivity for detecting changes in portal pressures using SHAPE. A Logiq 9 scanner with a 4C curvi-linear array was used to acquire 2.5 MHz radio-frequency data. Scanning was performed in dual imaging mode with B-mode imaging at 4 MHz and a SHI contrast mode transmitting at 2.5 MHz and receiving at 1.25 MHz. Sonazoid, which is a lipid stabilized gas filled bubble of perfluorobutane, was used as the contrast agent in this study. RESULTS: A linear decrease in subharmonic amplitude with increased pressure was observed for all waveforms (r from -0.77 to -0.93; P < .001) in vitro. There was a significantly higher correlation of the SHAPE gradient with changing pressures for the broadband pulses as compared to the narrowband pulses in both in vitro and in vivo results. The highest correlation was achieved with a Gaussian windowed binomial filtered square wave with an r-value of -0.95. One of the three canines was eliminated for technical reasons, while the other two produced very similar results to those obtained in vitro (r from -0.72 to -0.98; P <.01). The most consistent in vivo results were achieved with the Gaussian windowed binomial filtered square wave (r = -0.95 and -0.96). CONCLUSIONS: Using this waveform is an improvement to the existing SHAPE technique (where a square wave was used) and should make SHAPE more sensitive for noninvasively determining portal hypertension. PMID- 27943414 TI - Lung Sliding Identification Is Less Accurate in the Left Hemithorax. AB - OBJECTIVES: The aim of our study was to compare the accuracy of lung sliding identification for the left and right hemithoraxes, using prerecorded short US sequences, in a group of physicians with mixed clinical and US training. METHODS: A total of 140 US sequences of a complete respiratory cycle were recorded in the operating room. Each sequence was divided in two, yielding 140 sequences of present lung sliding and 140 sequences of absent lung sliding. Of these 280 sequences, 40 were randomly repeated to assess intraobserver variability, for a total of 320 sequences. Descriptive data, the mean accuracy of each participant, as well as the rate of correct answers for each of the original 280 sequences were tabulated and compared for different subgroups of clinical and US training. A video with examples of present and absent lung sliding and a lung pulse was shown before testing. RESULTS: Two sessions were planned to facilitate the participation of 75 clinicians. In the first group, the rate of accurate lung sliding identification was lower in the left hemithorax than in the right (67.0% [interquartile range (IQR), 43.0-83.0] versus 80.0% [IQR, 57.0-95.0]; P < .001). In the second group, the rate of accurate lung sliding identification was also lower in the left hemithorax than in the right (76.3% [IQR, 42.9-90.9] versus 88.7% [IQR, 63.1-96.9]; P = .001). Mean accuracy rates were 67.5% (95% confidence interval, 65.7-69.4) in the first group and 73.1% (95% confidence interval, 70.7 75.5) in the second (P < .001). CONCLUSIONS: Lung sliding identification seems less accurate in the left hemithorax when using a short US examination. This study was done on recorded US sequences and should be repeated in a live clinical situation to confirm our results. PMID- 27943413 TI - Aberrant connective tissue differentiation towards cartilage and bone underlies human keloids in African Americans. AB - Keloids are benign fibroproliferative tumors more frequently found among African Americans. Until now, keloid etiopathogenesis is not fully understood. To characterize keloids in African Americans, we performed transcriptional profiling of biopsies from large chronic keloids, adjacent non-lesional (NL) skin (n=3) and a newly formed keloid lesion using Affymetrix HGU133 2.0 plus arrays. Quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC) staining were performed to confirm increased expression of relevant genes. We identified 1202 upregulated and 961 downregulated differentially expressed genes (DEGs) between keloid and NL skin; 1819 up- and 1867 downregulated DEGs between newly formed keloid and NL skin; and 492 up- and 775 downregulated DEGs between chronic and newly formed keloid (fold change >2, false discovery rate <0.05). Many of the top upregulated DEGs between chronic keloid and NL skin and between newly formed keloid and NL skin are involved in bone/cartilage formation including Fibrillin 2 (FBN2), Collagen type X alpha 1, Asporin (ASPN), Cadherin 11 (CDH11), Bone morphogenic protein 1 (BMP1), Secreted phosphoprotein 1 and Runt-related transcription factor 2 (RUNX2). qRT-PCR confirmed significant (P<.05) upregulation of BMP1, RUNX2, CDH11 and FBN2 in chronic keloid compared to NL skin. IHC staining showed increased protein expression of ASPN, CDH11, BMP1 and RUNX2 on chronic and newly formed keloid compared to NL skin. Our study shows that large keloids in African Americans represent a dysplasia of cutaneous connective tissue towards immature cartilage or bone differentiation. The phenotype is potentially regulated by overexpression of RUNX2. This knowledge may give insights to guide the development of better treatment for the disease in the future. PMID- 27943416 TI - Galanin contributes to ultraviolet irradiation-induced inflammation in human skin. AB - Exposure of the skin to ultraviolet (UV) irradiation causes various consequences such as inflammation and photoageing. Galanin is an active neuropeptide expressed widely in the central nervous system and peripheral tissues including the skin. Galanin promotes or inhibits inflammation in a context-dependent manner, but its role in UV irradiation-induced responses in human skin was still unknown. UV irradiation induced a substantial expression of galanin in primary epidermal keratinocytes in vitro and in human epidermis in vivo. Galanin knock-down by siRNA transfection markedly inhibited UV irradiation-induced expression of matrix metalloproteinase (MMP)-1, interleukin (IL)-1beta, IL-6 and cyclooxygenase (COX) 2. Moreover, siRNA-mediated knock-down of GAL2 , a principal galanin receptor in the skin, led to a considerable decrease in these mediators in keratinocytes. Collectively, our findings suggest that galanin is an important messenger between the neuroendocrine system and UV irradiation-damaged skin. PMID- 27943415 TI - Flow cytometry minimal residual disease after allogeneic transplant for chronic lymphocytic leukemia. AB - OBJECTIVES: This study investigates whether achieving complete remission (CR) with undetectable minimal residual disease (MRD) after allogeneic stem cell transplantation (allo-SCT) for chronic lymphocytic leukemia (CLL) affects outcome. METHODS: We retrospectively studied 46 patients transplanted for CLL and evaluated for post-transplant MRD by flow cytometry. RESULTS: At transplant time, 43% of the patients were in CR, including one with undetectable MRD, 46% were in partial response, and 11% had refractory disease. After transplant, 61% of the patients achieved CR with undetectable MRD status. By multivariate analysis, reaching CR with undetectable MRD 12 months after transplant was the only factor associated with better progression-free survival (P = 0.02) and attaining undetectable MRD, independently of the time of negativity, was the only factor that correlated with better overall survival (P = 0.04). CONCLUSION: Thus, achieving undetectable MRD status after allo-SCT for CLL is a major goal to improve post-transplant outcome. PMID- 27943417 TI - Ultrasound-Guided Suprainguinal Fascia Iliaca Technique Provides Benefit as an Analgesic Adjunct for Patients Undergoing Total Hip Arthroplasty. AB - Analgesia after total hip arthroplasty is often accomplished by the fascia iliaca compartment block, traditionally performed below the inguinal ligament, to anesthetize both femoral and lateral femoral cutaneous nerves. The course of the lateral femoral cutaneous nerve below the inguinal ligament is variable as opposed to consistent above the inguinal ligament in the pelvis. In this case series including 5 patients, we demonstrate that an ultrasound-guided suprainguinal fascia iliaca approach would consistently anesthetize the lateral femoral cutaneous nerve along with anterior cutaneous femoral nerve branches and provide cutaneous analgesia after total hip arthroplasty, as shown by decreased opioid consumption. PMID- 27943418 TI - Nanoreactor of Nickel-Containing Carbon-Shells as Oxygen Reduction Catalyst. AB - A Pt-free nanoreactor, consisting of N-doped hollow carbon nanocapsules with encapsulated Ni nanoparticles, is developed for high-performance oxygen reduction reaction (ORR) catalyst. The nanoreactor effect improves its catalytic activity for ORR mainly in a 4e- pathway. The presence of Ni nanoparticles within the nanoreactor significantly enhances the stability with a current retention of 90% after 40 h. PMID- 27943419 TI - Involvement of viperin in prevention of intrauterine transmission of hepatitis B virus. AB - The aim of this study was to explore the role of viperin in the prevention of intrauterine infection of hepatitis B virus (HBV). Placental samples were collected from seven HBV-positive pregnant women with their infants infected via intrauterine transmission (infected group), 30 HBV-positive women with non infected infants (non-infected group), and 30 HBV-negative women (controls). The expression of viperin in placenta was analyzed with immunohistochemistry and Western blotting. The expression of viperin of placental trophoblast cell line Swan71 was determined after exposed to HBV. Viperin was localized to syncytiotrophoblast, and there was a significant difference in placental viperin levels among control, non-infected group and infected group (F = 12.824, p < 0.001). The expression of viperin was significantly higher in non-infected group than in control (p = 0.019) and in infected group (p < 0.001), and viperin expression was significantly lower in infected group than in control (p = 0.001). The exposure to HBV significantly increased the expression of viperin in Swan 71 (p < 0.001). Exposure to HBV up-regulates viperin expression in vivo and in vitro in placental trophoblast, and lack of this up-regulation is associated with intrauterine transmission of HBV. PMID- 27943420 TI - Association Between TNF-alpha Promoter -308 A/G Polymorphism and Systemic Lupus Erythematosus Susceptibility: A Case-Control Study and Meta-Analysis. AB - The tumour necrosis factor-alpha (TNF-alpha) promoter -308 A/G polymorphism plays an important role in the aetiology of systemic lupus erythematosus (SLE). Several studies have estimated the association between TNF-alpha -308 A/G and SLE risk. However, results were inconsistent. A case-control study was carried out to explore the association between TNF-alpha -308 A/G and the SLE risk in a Chinese Han population. Meta-analysis combining present with previous studies was conducted to further explore the association. Our case-control study included 556 patients with SLE along with 570 matched healthy controls. TNF-alpha -308 A allele was significantly increased in patients with SLE compared with controls (OR = 2.184, 95% CI: 1.718-2.778, P < 0.001). Genotypes AA and AG were associated with the susceptibility to SLE as compared with the GG genotype, as well as the dominant model (AA+AG versus GG), respectively. The meta-analysis included 41 comparative studies involving 4799 patients and 6635 controls. An association between SLE and allele A was found in the overall populations (OR = 1.70, 95% CI: 1.46-1.98, P < 0.001). In addition, we discussed the correlation between this polymorphism and lupus nephritis (LN) risk, showing that allele A was significantly related to LN in the overall populations (OR = 1.80, 95% CI: 1.21 2.68, P = 0.004). The results from our case-control study and the meta-analysis indicate that the TNF-alpha -308 A allele is significantly associated with an increased risk of SLE/LN. PMID- 27943421 TI - TRIM21 is important in the early phase of inflammation in the imiquimod-induced psoriasis-like skin inflammation mouse model. AB - Tripartite motif-containing protein 21 (TRIM21) regulates pro-inflammatory cytokines and type I interferons and acts as an autoantigen in certain autoimmune diseases, but TRIM21 has not been investigated in psoriasis. It has been suggested that TRIM21 may have a dual function; in the early phase of inflammation, it may function as a stimulator; but upon immune stimulation, its ubiquitinating mode of action may shift from stabilization to degradation of IRF3 causing inhibition of the immune responses. The imiquimod (IMQ)-induced psoriasis like mouse model displays features similar to those of human psoriasis. However, chronicity is lacking in this model. We investigated whether the role of TRIM21 in psoriasis was pro-inflammatory or anti-inflammatory. We hypothesized that a shift of the TRIM21-ubiquitinating mode of action may explain the lack of chronicity in the IMQ-induced psoriasis-like mouse model. We showed that TRIM21 expression is increased in lesional psoriatic skin and in the early phase of IMQ induced inflammation both in vitro and in vivo. Surprisingly, inflammation was significantly less pronounced in TRIM21 knockout mice than in wild-type mice as shown by ear thickness measured at days 8, 9 and 10 after treatment start, by spleen weight as a marker of systemic effect of IMQ at 10 days after treatment start and by expression of IL-12p40 at days 3 and 10 after treatment start and IL 17A at day 3 after treatment start. Therefore, induction of TRIM21 expression cannot explain the lack of chronicity in the IMQ-induced psoriasis-like skin inflammation mouse model. PMID- 27943422 TI - Pretransplant FDG-PET in aggressive non-Hodgkin lymphoma: systematic review and meta-analysis. AB - This study aimed to systematically review and meta-analyze the value of pretransplant FDG-PET in predicting outcome after autologous stem cell transplantation in aggressive non-Hodgkin lymphoma. MEDLINE was systematically searched; included studies were methodologically assessed and meta-analyzed, when possible. Overall methodological quality of included studies (n = 11) was poor, with moderate risk of bias in the domains of study participation (n = 7) and prognostic factor measurement (n = 7), and high risk of bias in the domains of outcome measurement (n = 10), and study confounding (n = 11). In all aggressive non-Hodgkin lymphomas, pooled sensitivity and specificity were 54.0% and 73.1% in predicting treatment failure, and 54.5% and 68.7% in predicting death. Because of interstudy heterogeneity, additional subgroup analyses were performed. In newly diagnosed aggressive non-Hodgkin lymphoma, pooled sensitivity and specificity were 20.0% and 70.0% in predicting treatment failure, and 8.3% % and 30.5% in predicting death. In refractory/relapsed aggressive non-Hodgkin lymphoma, pooled sensitivity and specificity were 68.1% and 72.1% in predicting treatment failure, and 77.3% and 69.6% in predicting death. At present, pretransplant FDG-PET cannot be recommended in aggressive non-Hodgkin lymphoma, because available studies suffer from major methodological flaws, and reported prognostic estimates are low (i.e., poor in newly diagnosed and moderate in refractory/relapsed aggressive non Hodgkin lymphoma). PMID- 27943423 TI - Experimental investigation on spontaneous counter-current imbibition in water-wet natural reservoir sandstone core using MRI. AB - Counter-current imbibition is a process whereby a wetting phase spontaneously imbibes into a porous media, displacing the non-wetting phase. This process is considered an important oil recovery mechanism during water flooding in fractured oil reservoirs. In this study, the dynamic process of counter-current imbibition for a natural reservoir sandstone core with an all-face-open boundary condition was monitored using magnetic resonance imaging (MRI). A series of images and relaxation time T1 spectra were acquired. The movement of water spontaneously entering the core sample while oil escapes, the spatial distribution of oil and water, and the in situ saturation change of oil and water in porous media can be accurately detected using MRI. MRI assists the direct evaluation of the basic mechanisms of imbibitions. Experimental results suggest the remaining oil was trapped in some large pores because of the capillary pressure, and the oil recovery in some large-pore regions is lower than that in some small-pore regions at the end of imbibition. Experimental findings show a close agreement between conventional material balance and oil recovery determined from MRI. The in situ oil recovery data agree well with the empirical models. The observations from MRI images could provide test cases to enable the development of mathematical models and to facilitate the evaluation of the proposed imbibition mechanisms. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943424 TI - Silver nanoparticles and dissolved silver activate contrasting immune responses and stress-induced heat shock protein expression in sea urchin. AB - Using immune cells of sea urchin Strongylocentrotus droebachiensis in early development as a model, the cellular protective mechanisms against ionic and poly(allylamine)-coated silver nanoparticle (AgNPs; 14 +/- 6 nm) treatments at 100 MUg L-1 were investigated. Oxidative stress, heat shock protein expression, and pigment production by spherulocytes were determined as well as AgNP translocation pathways and their multiple effects on circulating coelomocytes. Sea urchins showed an increasing resilience to Ag over time because ionic Ag is accumulated in a steady way, although nanoAg levels dropped between 48 h and 96 h. A clotting reaction emerged on tissues injured by dissolved Ag (present as chloro-complexes in seawater) between 12 h and 48 h. Silver contamination and nutritional state influenced the production of reactive oxygen species. After passing through coelomic sinuses and gut, AgNPs were found in coelomocytes. Inside blood vessels, apoptosis-like processes appeared in coelomocytes highly contaminated by poly(allylamine)-coated AgNPs. Increasing levels of Ag accumulated by urchins once exposed to AgNPs pointed to a Trojan-horse mechanism operating over 12-d exposure. However, under short-term treatments, physical interactions of poly(allylamine)-coated AgNPs with cell structures might be, at some point, predominant and responsible for the highest levels of stress-related proteins detected. The present study is the first report detailing nano translocation in a marine organism and multiple mechanisms by which sea urchin cells can deal with toxic AgNPs. Environ Toxicol Chem 2017;36:1872-1886. (c) 2016 SETAC. PMID- 27943426 TI - IL-22-induced miR-122-5p promotes keratinocyte proliferation by targeting Sprouty2. AB - Psoriasis is a common inflammatory skin disease, but the exact pathogenesis is largely unknown. Interleukin-22 (IL-22) has demonstrated its vital role in T-cell mediated immune response by interacting with keratinocytes in the pathogenesis of psoriasis. Here, we showed the differentially expressed miRNAs and their potential targets in HaCaT cells stimulated by IL-22 using miRNA and mRNA microarrays. We revealed a total of 20 significantly changed (more than twofold) miRNAs in HaCaT cells and validated the results with quantitative reverse transcriptase PCR (qRT-PCR). We demonstrated that miR-122-5p was up-regulated both in HaCaT cells stimulated by IL-22 and in psoriatic lesions. Then, we aimed to investigate the biological roles and potential mechanism of miR-122-5p in keratinocytes. As a result, CCK-8 assay indicated that overexpression of miR-122 5p in keratinocytes promoted proliferation and conversely inhibition of endogenous miR-122-5p suppressed proliferation. According to the microarray analysis, we assumed that Sprouty2 (Spry2), a negative regulator of extracellular signal regulated kinase/mitogen-activated protein kinase signalling pathway, was a direct target gene of miR-122-5p. We found that the staining of Spry2 in cytoplasm was mainly localized in both basal and suprabasal layers of epidermis and showed a markedly decreased expression in psoriasis than in normal control by immunohistochemistry. Luciferase reporter and Western blot assays in HaCaT cells demonstrated that Spry2 was a direct target gene of miR-122-5p. In conclusion, IL 22-induced miR-122-5p promotes keratinocyte proliferation possibly by downregulating the expression of Spry2 thus playing important roles in the pathogenesis of psoriasis. PMID- 27943425 TI - Efficacy, safety and drug survival of conventional agents in pediatric psoriasis: A multicenter, cohort study. AB - The data on long-term efficacy, safety and drug survival rates of conventional systemic therapeutics in pediatric psoriasis is lacking. The primary aim of this study is to investigate acitretin, methotrexate, cyclosporin efficacy, safety and drug survival rates in pediatric patients as well as predictors of drug survival. This is a multicenter study including 289 pediatric cases being treated with acitretin, methotrexate and cyclosporin in four academic referral centers. Efficacy, adverse events, reasons for discontinuation, 1, 2- and 3-year drug survival rates, and determinants of drug survival were analyzed. A 75% reduction of Psoriasis Area and Severity Index score or better response rate was obtained in 47.5%, 34.1% and 40% of the patients who were treated with acitretin, methotrexate and cyclosporin, respectively. One-year drug survival rates for acitretin, methotrexate and cyclosporin were 36.3%, 21.1% and 15.1%, respectively. The most significant determinant of drug survival, which diminished over time, was treatment response whereas arthritis, body mass index and sex had no influence. Although all three medications are effective and relatively safe in children, drug survival rates are low due to safety concerns at this age group. Effective disease control through their rational use can be expected to improve survival rates. PMID- 27943427 TI - Parotid cyst due to sialolithiasis masquerading as pilomatrixoma on FNA. PMID- 27943429 TI - An Unconventional Acid-Labile Nucleobase Protection Concept for Guanosine Phosphoramidites in RNA Solid-Phase Synthesis. AB - We present an innovative O6 -tert-butyl/N2 -tert-butyloxycarbonyl protection concept for guanosine (G) phosphoramidites. This concept is advantageous for 2' modified G building blocks because of very efficient synthetic access when compared with existing routes that usually employ O6 -(4-nitrophenyl)ethyl/N2 acyl protection or that start from 2-aminoadenosine involving enzymatic transformation into guanosine later on in the synthetic path. The new phosphoramidites are fully compatible with 2'-O-tBDMS or TOM phosphoramidites in standard RNA solid-phase synthesis and deprotection, and provide excellent quality of tailored RNAs for the growing range of applications in RNA biophysics, biochemistry, and biology. PMID- 27943428 TI - Synthesis of (2-mercaptoacetyl)-L-[2-14 C]tryptophan as a selective metallo-beta lactamase inhibitor via [2-14 C]indole based on chiral pool strategy. AB - Metallo-beta-lactamase enzymes make bacteria resistant to a broad range of commonly used beta-lactam antibiotics. Several thiol derivatives of L-amino acids have been shown their inhibitory effects against the metallo-beta-lactamase IMP 1. In this study, (2-mercaptoacetyl)-L-tryptophan as a new inhibitor of metallo beta-lactamases labeled with carbon-14 in the 2-position of the indole ring was prepared from [2-14 C]indole as a key synthetic intermediate based on chiral pool strategy. The overall synthesis was performed in 10 steps with the overall radiochemical yield 3.6% on the basis of the barium [14 C]carbonate as a starting material. PMID- 27943430 TI - Tissue-specific metabolite profiling of benzylisoquinoline alkaloids in the root of Macleaya cordata by combining laser microdissection with ultra-high performance liquid chromatography/tandem mass spectrometry. AB - RATIONALE: Tissue-specific metabolite profiling helps to find trace alkaloids masked during organ analysis, which contributes to understanding the alkaloid biosynthetic pathways in vivo and evaluating the quality of medical plants by morphology. As Macleaya cordata contains diverse types of benzylisoquinoline alkaloids (BIAs), the alkaloid metabolite profiling was carried out on various tissues of the root. METHODS: Laser microdissection with fluorescence detection was used to recognize and dissect different tissues from the root of M. cordata. Ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry was applied to analyze the trace alkaloids in tissues. These detected alkaloids were elucidated using their accurate molecular weights, MS/MS data, MS fragmentation patterns and the known biosynthetic pathways of BIAs. Finally, the distribution of alkaloids in dissected tissues and whole sections was mapped. RESULTS: Forty-nine alkaloids were identified from five microdissected tissues, and 24 of them were detected for the first time in M. cordata. Some types of alkaloids occurred specifically in dissected tissues. More alkaloids were detected in the cork and xylem vascular bundles which emit strong fluorescence under fluorescence microscopy. Some of the screened alkaloids were intermediates in sanguinarine and chelerythrine biosynthetic pathways, and others were speculated to be involved in the new branches of biosynthetic pathways. CONCLUSIONS: The integrated method is sensitive, specific and reliable for determining trace alkaloids, which is also a powerful tool for metabolite profiling of tissue-specific BIAs in situ. The present findings should contribute to a better understanding of the biosynthesis of BIAs in M. cordata root and provide scientific evidence for its quality evaluation based on morphological characteristics. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943431 TI - Organometallic Fe-Fe Interactions: Beyond Common Metal-Metal Bonds and Inverse Mixed-Valent Charge Transfer. AB - The compounds [Fe(CO)3 (dRpf)]n+ , n=0, 1, 2 and dRpf=1,1' bis(dicyclohexylphosphino)ferrocene ([1]n+ ) or 1,1' bis(diisopropylphosphino)ferrocene ([2]n+ ), were obtained as two-step reversible redox systems by photolytic and redox reactions. The iron-iron distance decreases from about 4 A to about 3 A on oxidation, which takes place primarily at the tricarbonyliron moiety. Whereas ferrocene oxidation is calculated to occur only in excited states, the near infrared absorptions of the mixed-valent monocations are due to an unprecedented "inverse" inter-valence charge transfer from the electron-rich iron(II) in the ferrocene backbone to the electron-deficient tricarbonyliron(I). Protonation of complex 1 results in the formation of the structurally characterized hydride [1H]BF4 , which reacts with acetone to form the dication, 12+ , and isopropanol. While the hydride [2H]BF4 was found to be unstable, protonation of 2 in acetone resulted in the clean formation of 22+, formally a hydrogen transfer. PMID- 27943432 TI - Clinical features of Birt-Hogg-Dube syndrome: A Japanese case with pulmonary cysts, fibrofolliculomas and renal cell carcinoma. PMID- 27943434 TI - Measuring superior vena cava flow as part of echocardiography examinations performed by neonatologists. PMID- 27943433 TI - Melanin granules melanophages and a fully-melanized epidermis are common traits of odontocete and mysticete cetaceans. AB - BACKGROUND: The cellular mechanisms used to counteract or limit damage caused by exposure of marine vertebrates to solar ultraviolet (UV) radiation are poorly understood. Cetaceans are vulnerable because they lack protective skin appendages and are obliged to surface continuously to breathe, thus being exposed repeatedly to UV light. Although molecular mechanisms of photoprotection of cetaceans have been studied, there is limited knowledge about their epidermal structure and photoprotective effectors. OBJECTIVE: To describe and compare the epidermis of mysticete and odontocete cetaceans and identify potentially photoprotective traits. ANIMALS: Twenty eight free-living individuals belonging to six cetacean species were sampled in the Mexican Central Pacific and Gulf of California. Species sampled were the bottlenose dolphin, pantropical spotted dolphin, spinner dolphin, Bryde's whale, fin whale and humpback whale. METHODS: Histological and cytological evaluation of skin biopsy tissue collected in the field between 2014 and 2016. RESULTS: All cetaceans had only three epidermal layers, lacking both the stratum granulosum and stratum lucidum. A relatively thick stratum corneum with a parakeratosis-like morphology was noted. Melanin was observed within keratinocytes in all epidermal layers, including the stratum corneum and apical melanin granules obscured the keratinocyte nucleus. Keratinocytes had a perinuclear halo. Keratinocyte diameter differed between cetacean suborders and amongst species. Melanophage clusters were common in most cetacean species. CONCLUSIONS: The widespread presence of melanin and the unexpectedly high number of melanophages may constitute a unique photoprotective trait of cetaceans and could reflect primitive adaptations to their environment and to their obligate marine-bound life. PMID- 27943435 TI - How relevant are fathers who smoke at home to the passive smoking exposure of their children? PMID- 27943437 TI - Data monitoring committees should be used more frequently and appropriately to monitor paediatric clinical trials, particularly those involving neonates. PMID- 27943439 TI - The way that physical education aims to provide the recommended dose of physical activity in school children is multifaceted. PMID- 27943440 TI - Corrigendum. PMID- 27943441 TI - Putting prevalence trends in allergic conditions under the magnifying glass. PMID- 27943443 TI - Divergent Reactivity of In Situ Generated Metal Azides: Reaction with N,N Bis(oxy)enamines as a Case Study. AB - Metal azides generated in situ by ion exchange exhibit divergent reactivity in reaction with cyclic N-alkoxy,N-siloxy-enamines. Depending on the nature of metal and the [M]/N3- ratio, addition of the azide ion to the C,C-double bond proceeds with regioselective cleavage of either exo- or endo-cyclic N-O bond leading to cyclic or open-chain alpha-azidooxime derivatives, respectively. Mechanistic studies in combination with solvent state FTIR spectroscopy and DFT calculations revealed that covalently bound metal azides (Co, Cu, Zn) transfer N3- anion to the C,C-double bond through a Lewis acid-assisted SN ' substitution of trialkylsilyloxy-group. More ionic metal azides (N1, Mg, Al, Sc, Ni, Yb) tend to react by initial nucleophilic attack of N3- anion on the silicon atom generating conjugated nitrosoalkenes. alpha-Azidooxime derivatives prepared by using the designed protocols were stereoselectively reduced to valuable 1,2-diaminoalcohols bearing up to four contiguous stereogenic centers. By reducing the alpha azidooxime fragment in a stepwise manner site-selective protection and reductive amination of each of the emerging primary amino groups was achieved. PMID- 27943444 TI - Frequency and intensity of symptoms and treatment interventions in hospitalized older palliative cancer patients: a multicentre cross-sectional study. AB - AIM: To increase the knowledge of the frequency and intensity of symptoms and the treatment interventions in older palliative cancer patients. BACKGROUND: Research on symptoms and the treatment modalities in older palliative cancer patients is scarce. Insight into these aspects is needed to enable healthcare professionals to alleviate the burden. DESIGN: A cross-sectional study. METHODS: Four hundred hospitalized older palliative cancer patients participated in the study between March 2013 - February 2015. Two validated instruments were used to assess 40 symptoms in multiple domains and collect data on the treatment modalities in older palliative cancer patients. RESULTS: Patients reported on average approximately 14 symptoms. Dry mouth, physical fatigue, lack of energy, lack of appetite and difficulty moving outside were the most prevalent. Psychological pain, psychological fatigue, lack of willpower, lack of energy and physical fatigue were reported as intensive. On average, 5.15 disciplines were consulted per patient. Few patients were referred to a palliative support team, spiritual consultant or psychologist. Patients received a variety of interventions to increase life expectancy and alleviate symptoms and the side effects of treatment. The occurrence of symptoms was associated with different clinical and treatment variables such as having a geriatric risk profile. CONCLUSIONS: Older patients receiving palliative cancer care are confronted with multiple symptoms. Psychological symptoms are more often reported as intensive. Greater attention should be given to the early referral of patients to palliative care teams, assessment and management of multiple symptoms, particularly psychological symptoms. PMID- 27943442 TI - Temporal and spatial behavior of pharmaceuticals in Narragansett Bay, Rhode Island, United States. AB - The behavior and fate of pharmaceutical ingredients in coastal marine ecosystems are not well understood. To address this, the spatial and temporal distribution of 15 high-volume pharmaceuticals were measured over a 1-yr period in Narragansett Bay (RI, USA) to elucidate factors and processes regulating their concentration and distribution. Dissolved concentrations ranged from below detection to 313 ng/L, with 4 pharmaceuticals present at all sites and sampling periods. Eight pharmaceuticals were present in suspended particulate material, ranging in concentration from below detection to 44 ng/g. Partitioning coefficients were determined for some pharmaceuticals, with their range and variability remaining relatively constant throughout the study. Normalization to organic carbon content provided no benefit, indicating other factors played a greater role in regulating partitioning behavior. Within the upper bay, the continuous influx of wastewater treatment plant effluents resulted in sustained, elevated levels of pharmaceuticals. A pharmaceutical concentration gradient was apparent from this zone to the mouth of the bay. For most of the pharmaceuticals, there was a strong relationship with salinity, indicating conservative behavior within the estuary. Short flushing times in Narragansett Bay coupled with pharmaceuticals' presence overwhelmingly in the dissolved phase indicate that most pharmaceuticals will be diluted and transported out of the estuary, with only trace amounts of several compounds sequestered in sediments. The present study identifies factors controlling the temporal and spatial dynamics of dissolved and particulate pharmaceuticals; their partitioning behavior provides an increased understanding of their fate, including bioavailability in an urban estuary. Environ Toxicol Chem 2017;36:1846-1855. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 27943445 TI - Perylene Bisimide Cyclophanes with High Binding Affinity for Large Planar Polycyclic Aromatic Hydrocarbons: Host-Guest Complexation versus Self Encapsulation of Side Arms. AB - Binding of guest molecules with high affinity and selectivity requires well designed hosts to provide optimized interactions in the host-guest complexes. Herein we report the design and synthesis of new cyclophanes 2PBI(2,6-iPr)2 and 2PBI(2,6-Ph)2 based on core-disubstituted perylene bisimide (PBI) chromophores bearing two phenoxy bay-substituents that evoke almost planar PBI scaffolds. This strategy afforded the new cyclophanes with conformationally rigid cavities to ensure strong binding to stiff planar polycyclic aromatic hydrocarbons (PAHs). Our detailed host-guest binding studies with different PAHs by UV/Vis and fluorescence titration experiments revealed record binding strengths for PAHs with binding constants of up to 1.6*106 m-1 in chloroform at room temperature. One- and two-dimensional NMR experiments and solvent-dependent titration studies revealed self-encapsulation of the side arms of PBI bay-substituents into the cavities that attained high fluorescence quantum yields of these cyclophanes close to unity by preventing the interaction of PBI subunits in the excited states. The binding constants and Gibbs free energies of host-guest complexations disclosed significant effects of PBI bay-substituents and core twist on the binding affinity of the cyclophanes. PMID- 27943446 TI - Scalable Self-Propagating High-Temperature Synthesis of Graphene for Supercapacitors with Superior Power Density and Cyclic Stability. AB - An ultrafast self-propagating high-temperature synthesis technique offers scalable routes for the fabrication of mesoporous graphene directly from CO2 . Due to the excellent electrical conductivity and high ion-accessible surface area, supercapacitor electrodes based on the obtained graphene exhibit superior energy and power performance. The capacitance retention is higher than 90% after one million charge/discharge cycles. PMID- 27943447 TI - Thermal Methane Activation by the Metal-Free Cluster Cation [Si2 O4 ]. AB - The thermal reaction of methane with the metal-free cluster cation [Si2 O4 ].+ has been examined by using Fourier transform-ion cyclotron resonance (FT-ICR) mass spectrometry. In addition to generating a methyl radical via hydrogen-atom abstraction, [Si2 O4 ].+ can selectively oxidize methane to formaldehyde. The mechanisms of these rather efficient reactions have been elucidated by high-level quantum-chemical calculations. PMID- 27943448 TI - One-second MRI of a three-dimensional vocal tract to measure dynamic articulator modifications. AB - PURPOSE: To enable three-dimensional (3D) vocal tract imaging of dynamic singing or speech tasks at voxel sizes of 1.6 * 1.6 * 1.3 mm3 at 1.3 s per image. MATERIALS AND METHODS: A Stack-of-Stars method was implemented and enhanced to allow for fast and efficient k-space sampling of the box-shaped vocal tract using a 3 Tesla MRI system. Images were reconstructed using an off-line image reconstruction using compressed sensing theory, leading to the abovementioned spatial and temporal resolutions. To validate spatial resolution, a phantom with holes of defined sizes was measured. The applicability of the imaging method was validated in an eight-subject study of amateur singers that were required to sustain phonation at a constant pitch, past their comfortable expiratory level. A segmentation of the vocal tract over all phonation time steps was done for one subject. Anatomical distances (larynx position and pharynx width) were calculated and compared for all subjects. RESULTS: Analysis of the phantom study revealed that the imaging method could provide at least 1.6 mm isotropic resolution. Visual inspection of the segmented vocal tract during phonation showed modifications of the lips, tongue, and larynx position in all three dimensions. The mean larynx position per subject amounted to 52-85 mm, deviating up to 5% over phonation time. Parameter pharynx width was 32-181 mm2 on average per subject, deviating up to 16% over phonation time. Visual inspection of the parameter course revealed no common compensation strategy for long sustained phonation. CONCLUSION: The results of both phantom and in vivo measurements show the applicability of the fast 3D imaging method for voice research and indicate that modifications in all three dimensions can be observed and quantified. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:94 101. PMID- 27943449 TI - Investigation and comparison of the binding between tolvaptan and pepsin and trypsin: Multi-spectroscopic approaches and molecular docking. AB - Tolvaptan (TF), a selective arginine vasopressin V2 receptor antagonist, was approved by the Food and Drug Administration in 2009. This study mainly investigated the differences between the binding of TF with pepsin and trypsin by using a series of spectroscopy and molecular modeling methods. Thermodynamic parameters and molecular docking results suggested that the binding of TF to pepsin and trypsin were both spontaneous but driven by different forces. For pepsin, the binding was driven by hydrogen bonds and van der Waals forces; but for trypsin, it was driven by electrostatic forces and hydrophobic forces. The quenching mechanism between TF and pepsin and trypsin was investigated by fluorescence experiments and time-resolved fluorescence spectroscopy. Synchronous fluorescence and 3-dimensional fluorescence were used to investigate the micro environmental and conformational changes of pepsin and trypsin after the insertion of TF. In addition, activity-measurement results showed that both the pepsin and trypsin activities increased with increasing TF concentration, which may help to understand the possible effect of TF on the digestion and absorption of nutrients in vivo. PMID- 27943450 TI - Photobiomodulation therapy in breast cancer-related lymphedema: a randomized placebo-controlled trial. AB - BACKGROUND: The aim of our study was to examine the effects of photobiomodulation therapy (PBMT) in the treatment of breast cancer-related lymphedema using a compactly designed treatment regime consisting of eight therapy sessions in combination with a cluster laser device covering a total area size of 78.54 cm2 over the axillary. METHODS: Forty patients with unilateral lymphedema were enrolled in this double-blind, placebo-controlled trial in order to evaluate effects of PBMT on lymphedema-related pain, quality of life, grip strength and limb volume difference. Subjects received irradiation for ten minutes per session using a cluster laser covering a beam area of 78.54 cm2. The applied energy was 384 Joules resulting in an energy density of 4.89 J/cm2. RESULTS: Post-treatment, a 50% reduction in median pain scores and an increase in mean quality of life were observed. Mean grip strength was persistently higher after eight sessions of PBMT compared with pretreatment; however, no statistically significant intergroup differences (P > 0.05) were found over the time course. CONCLUSION: PBMT using a compactly designed treatment regime in combination with a cluster laser device did not significantly improve quality of life, pain scores, grip strength and limb volume over the time course. PMID- 27943451 TI - Chemical kinetics of multiphase reactions between ozone and human skin lipids: Implications for indoor air quality and health effects. AB - Ozone reacts with skin lipids such as squalene, generating an array of organic compounds, some of which can act as respiratory or skin irritants. Thus, it is important to quantify and predict the formation of these products under different conditions in indoor environments. We developed the kinetic multilayer model that explicitly resolves mass transport and chemical reactions at the skin and in the gas phase (KM-SUB-Skin). It can reproduce the concentrations of ozone and organic compounds in previous measurements and new experiments. This enabled the spatial and temporal concentration profiles in the skin oil and underlying skin layers to be resolved. Upon exposure to ~30 ppb ozone, the concentrations of squalene ozonolysis products in the gas phase and in the skin reach up to several ppb and on the order of ~10 mmol m-3 . Depending on various factors including the number of people, room size, and air exchange rates, concentrations of ozone can decrease substantially due to reactions with skin lipids. Ozone and dicarbonyls quickly react away in the upper layers of the skin, preventing them from penetrating deeply into the skin and hence reaching the blood. PMID- 27943453 TI - Harder Roads to Trek? Paradoxical Slowing of an Atrioventricular Reentrant Tachycardia With Contralateral Bundle Branch Block. AB - Slowing of the tachycardia with increase in cycle length and increase in VA time with ipsilateral bundle branch block is a characteristic feature of accessory pathway mediated AVRT. Contralateral bundle branch block has no effect on the tachycardia as it is not a part of the tachycardia circuit. We present an interesting phenomenon in which contralateral bundle branch block resulted in tachycardia slowing in a case of WPW syndrome. PMID- 27943452 TI - Phylogenetic profiling and gene expression studies implicate a primary role of PSORS1C2 in terminal differentiation of keratinocytes. AB - PSORS1C2 is a gene located between coiled-coil alpha-helical rod protein 1 (CCHCR1) and corneodesmosin (CDSN) within the psoriasis susceptibility locus 1 (PSORS1). Here, we performed a comparative genomics analysis of the as-yet incompletely characterized PSORS1C2 gene and determined its expression pattern in human tissues. In contrast to CCHCR1, which is common to all vertebrates investigated, PSORS1C2 and CDSN are present exclusively in mammals, indicating that the latter genes have originated after the evolutionary divergence of mammals and reptiles. CDSN is conserved in aquatic mammals, whereas PSORS1C2 orthologs contain gene-inactivating frame shift mutations in whales and dolphins, in which the epidermal differentiation programme has degenerated. Reverse transcription PCR screening demonstrated that, in human tissues, PSORS1C2 is expressed principally in the epidermis and weakly in the thymus. PSORS1C2 mRNA was strongly upregulated during terminal differentiation of human keratinocytes in vitro. Immunohistochemistry revealed exclusive expression of PSORS1C2 in the granular layer of the epidermis and in cornifying epithelial cells of Hassall's corpuscles of the thymus. In summary, our results identify PSORS1C2 as a keratinocyte cornification-associated protein that has originated in evolutionarily basal mammals and has undergone gene inactivation in association with the loss of the skin barrier function in aquatic mammals. PMID- 27943454 TI - 13 C NMR Spectroscopy of N-Heterocyclic Carbenes Can Selectively Probe sigma Donation in Gold(I) Complexes. AB - The Dewar-Chatt-Duncanson (DCD) model provides a successful theoretical framework to describe the nature of the chemical bond in transition-metal compounds and is especially useful in structural chemistry and catalysis. However, how to actually measure its constituents (substrate-to-metal donation and metal-to-substrate back donation) is yet uncertain. Recently, we demonstrated that the DCD components can be neatly disentangled and the pi back-donation component put in strict correlation with some experimental observables. In the present work we make a further crucial step forward, showing that, in a large set of charged and neutral N-heterocyclic carbene complexes of gold(I), a specific component of the NMR chemical shift tensor of the carbenic carbon provides a selective measure of the sigma donation. This work opens the possibility of 1) to characterize unambiguously the electronic structure of a metal fragment (LAu(I)n+/0 in this case) by actually measuring its sigma-withdrawing ability, 2) to quickly establish a comparative trend for the ligand trans effect, and 3) to achieve a more rigorous control of the ligand electronic effect, which is a key aspect for the design of new catalysts and metal complexes. PMID- 27943455 TI - Parameters of fetal pulmonary vascular health: baseline trends and response to maternal hyperoxia in the second and third trimesters. AB - OBJECTIVES: Several parameters, including branch pulmonary artery (PA) diameter and Doppler-derived PA acceleration-to-ejection time ratio (AT/ET), peak late systolic/early-diastolic reversed flow (PEDRF) and pulsatility index (PI) response to maternal hyperoxia, have been used to investigate fetal pulmonary health. Lower AT/ET, increased PEDRF and lack of PI response to hyperoxia have been observed in fetuses with severe lung hypoplasia and are considered markers of pulmonary vascular resistance. We sought to further define the evolution of PA diameter and Doppler parameters and their response to maternal hyperoxia in healthy fetuses. METHODS: Fifty-four prospectively recruited women with healthy pregnancy underwent fetal echocardiography from 18-36 weeks of gestation. After baseline branch PA diameter and Doppler assessment, oxygen (8-10 L/min) was administered by non-reservoir facemask for 10 min and PA Doppler parameters were reassessed. RESULTS: Branch PA diameters and AT/ET increased linearly with gestational age, while PEDRF increased quadratically (P < 0.001 for all) and PA PI did not change. In response to maternal hyperoxia, although most fetuses demonstrated a significant decrease in PI for both branch PAs (right PA, P = 0.025; left PA, P = 0.040) >= 30 weeks, significant variability was observed in PI response with 31% of cases demonstrating either no response or a slight decrease. No other parameter demonstrated a measurable change in response to maternal hyperoxia. CONCLUSIONS: From the mid-trimester, fetal branch PA diameters and AT/ET increase linearly and PEDRF increases quadratically, whereas PI remains unchanged. Although maternal hyperoxia triggers a significant decrease in PA-PI after 30 weeks, variability in this response may reduce its utility in clinical practice. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27943456 TI - Implementation of a 4-Year Point-of-Care Ultrasound Curriculum in a Liaison Committee on Medical Education-Accredited US Medical School. AB - OBJECTIVES: The established benefits of point-of-care ultrasound have given rise to multiple new and innovative curriculums to incorporate ultrasound teaching into medical education. This study sought to measure the educational success of a comprehensive and integrated 4-year point-of-care ultrasound curriculum. METHODS: We integrated a curriculum consisting of traditional didactics combined with asynchronous learning modules and hands-on practice on live models with skilled sonographers into all 4 years of education at a Liaison Committee on Medical Education-accredited US Medical School. Each graduating student was administered an exit examination with 48 questions that corresponded to ultrasound milestones. RESULTS: Ninety-five percent (n = 84) of fourth-year medical students completed the exit examination. The mean score was 79.5% (SD, 10.2%), with mean scores on the ultrasound physics and anatomy subsections being 77.1% (SD, 11.0%) and 85.9% (SD, 21.0%), respectively. CONCLUSIONS: A comprehensive 4-year point-of-care ultrasound curriculum integrated into medical school may successfully equip graduating medical students with a fundamental understanding of ultrasound physics, anatomy, and disease recognition. PMID- 27943457 TI - The functions of plant small RNAs in development and in stress responses. AB - Like metazoans, plants use small regulatory RNAs (sRNAs) to direct gene expression. Several classes of sRNAs, which are distinguished by their origin and biogenesis, exist in plants. Among them, microRNAs (miRNAs) and trans-acting small interfering RNAs (ta-siRNAs) mainly inhibit gene expression at post transcriptional levels. In the past decades, plant miRNAs and ta-siRNAs have been shown to be essential for numerous developmental processes, including growth and development of shoots, leaves, flowers, roots and seeds, among others. In addition, miRNAs and ta-siRNAs are also involved in the plant responses to abiotic and biotic stresses, such as drought, temperature, salinity, nutrient deprivation, bacteria, virus and others. This review summarizes the roles of miRNAs and ta-siRNAs in plant physiology and development. PMID- 27943458 TI - Noninvasive red and near-infrared wavelength-induced photobiomodulation: promoting impaired cutaneous wound healing. AB - The innumerable intricacies associated with chronic wounds have made the development of new painless, noninvasive, biophysical therapeutic interventions as the focus of current biomedical research. Red and near-infrared light-induced photobiomodulation therapy appears to emerge as a promising drug-free approach for promoting wound healing, reduction in inflammation, pain and restoration of function owing to penetration power in conjunction with their ability to positively modulate the biochemical and molecular responses. This review will describe the physical properties of red and near-infrared light and their interaction with skin and highlight their efficacy of wound repair and regeneration. Near-infrared (800-830 nm) was found to be the most effective and widely studied wavelength range followed by red (630-680 nm) and 904 nm superpulsed light exhibiting beneficial photobiomodulatory effects on impaired dermal wound healing. PMID- 27943459 TI - Protective roles of melatonin in central nervous system diseases by regulation of neural stem cells. AB - Neural stem cells (NSCs) are immature precursors of the central nervous system (CNS), with self-renewal and multipotential differentiation abilities. Their proliferation and differentiation are dynamically regulated by hormonal and local factors. Alteration in neurogenesis is associated with many neurological disorders. Increasing evidence suggests that modulation of NSCs can be a promising therapeutic approach for neural injury and neurodegenerative disorders. Melatonin, a pineal gland-derived hormone, regulates the neuroimmuno-endocrine axis and is functionally important to the circadian rhythm, tumour suppression and immunity. In the CNS, melatonin exerts neuroprotective effects in many diseases, such as Parkinson's disease, Alzheimer's disease and ischaemic brain injury. Emerging evidence suggests that it might also mediate such protective action by influencing proliferation and differentiation of NSCs. In this article, we review the current literature concerned with effects of melatonin on NSCs in different physiological and pathological conditions. PMID- 27943460 TI - A bacterial artificial chromosome (BAC) genomic approach reveals partial clustering of the furanocoumarin pathway genes in parsnip. AB - Furanocoumarins are specialized metabolites that are involved in the defense of plants against phytophagous insects. The molecular and functional characterization of the genes involved in their biosynthetic pathway is only partially complete. Many recent reports have described gene clusters responsible for the biosynthesis of specialized metabolites in plants. To investigate possible co-localization of the genes involved in the furanocoumarin pathway, we sequenced parsnip BAC clones spanning two different gene loci. We found that two genes previously identified in this pathway, CYP71AJ3 and CYP71AJ4, were located on the same BAC, whereas a third gene, PsPT1, belonged to a different BAC clone. Chromosome mapping using fluorescence in situ hybridization (FISH) indicated that PsPT1 and the CYP71AJ3-CYP71AJ4 clusters are located on two different chromosomes. Sequencing the BAC clone harboring PsPT1 led to the identification of a gene encoding an Fe(II) alpha-ketoglutarate-dependent dioxygenase (PsDIOX) situated in the neighborhood of PsPT1 and confirmed the occurrence of a second gene cluster involved in the furanocoumarin pathway. This enzyme metabolizes p coumaroyl CoA, leading exclusively to the synthesis of umbelliferone, an important intermediate compound in furanocoumarin synthesis. This work provides an insight into the genomic organization of genes from the furanocoumarin biosynthesis pathway organized in more than one gene cluster. It also confirms that the screening of a genomic library and the sequencing of BAC clones represent a valuable tool to identify genes involved in biosynthetic pathways dedicated to specialized metabolite synthesis. PMID- 27943462 TI - Mechanistic target of rapamycin complex 1 is involved in psoriasis and regulated by anti-TNF-alpha treatment. PMID- 27943461 TI - High-efficiency gene targeting in hexaploid wheat using DNA replicons and CRISPR/Cas9. AB - The ability to edit plant genomes through gene targeting (GT) requires efficient methods to deliver both sequence-specific nucleases (SSNs) and repair templates to plant cells. This is typically achieved using Agrobacterium T-DNA, biolistics or by stably integrating nuclease-encoding cassettes and repair templates into the plant genome. In dicotyledonous plants, such as Nicotinana tabacum (tobacco) and Solanum lycopersicum (tomato), greater than 10-fold enhancements in GT frequencies have been achieved using DNA virus-based replicons. These replicons transiently amplify to high copy numbers in plant cells to deliver abundant SSNs and repair templates to achieve targeted gene modification. In the present work, we developed a replicon-based system for genome engineering of cereal crops using a deconstructed version of the wheat dwarf virus (WDV). In wheat cells, the replicons achieve a 110-fold increase in expression of a reporter gene relative to non-replicating controls. Furthermore, replicons carrying CRISPR/Cas9 nucleases and repair templates achieved GT at an endogenous ubiquitin locus at frequencies 12-fold greater than non-viral delivery methods. The use of a strong promoter to express Cas9 was critical to attain these high GT frequencies. We also demonstrate gene-targeted integration by homologous recombination (HR) in all three of the homoeoalleles (A, B and D) of the hexaploid wheat genome, and we show that with the WDV replicons, multiplexed GT within the same wheat cell can be achieved at frequencies of ~1%. In conclusion, high frequencies of GT using WDV-based DNA replicons will make it possible to edit complex cereal genomes without the need to integrate GT reagents into the genome. PMID- 27943464 TI - Alcohol-Enhanced Cu-Mediated Radiofluorination. AB - The potential of many 18 F-labeled (hetero)aromatics for applications in positron emission tomography remains underexplored because convenient procedures for their radiosynthesis are lacking. Consequently, simple methods to prepare radiofluorinated (hetero)arenes are highly sought after. Herein, we report the beneficial effect of primary and secondary alcohols on Cu-mediated 18 F-labeling. This observation contradicts the assumption that such alcohols are inappropriate solvents for aromatic fluorination. Therefore, we developed a protocol for rapid radiolabeling of an extraordinarily broad scope of boronic and stannyl substrates under general reaction conditions. Notably, radiofluorinated indoles, phenols, and anilines were synthesized directly from the corresponding unprotected precursors. Furthermore, the novel method enabled the preparation of radiofluorinated tryptophans, [18 F]F-DPA, [18 F]DAA1106, 6-[18 F]FDA, and 6-[18 F]FDOPA. PMID- 27943463 TI - Use of demand for and spatial flow of ecosystem services to identify priority areas. AB - Policies and research increasingly focus on the protection of ecosystem services (ESs) through priority-area conservation. Priority areas for ESs should be identified based on ES capacity and ES demand and account for the connections between areas of ES capacity and demand (flow) resulting in areas of unique demand-supply connections (flow zones). We tested ways to account for ES demand and flow zones to identify priority areas in the European Union. We mapped the capacity and demand of a global (carbon sequestration), a regional (flood regulation), and 3 local ESs (air quality, pollination, and urban leisure). We used Zonation software to identify priority areas for ESs based on 6 tests: with and without accounting for ES demand and 4 tests that accounted for the effect of ES flow zone. There was only 37.1% overlap between the 25% of priority areas that encompassed the most ESs with and without accounting for ES demand. The level of ESs maintained in the priority areas increased from 23.2% to 57.9% after accounting for ES demand, especially for ESs with a small flow zone. Accounting for flow zone had a small effect on the location of priority areas and level of ESs maintained but resulted in fewer flow zones without ES maintained relative to ignoring flow zones. Accounting for demand and flow zones enhanced representation and distribution of ESs with local to regional flow zones without large trade offs relative to the global ES. We found that ignoring ES demand led to the identification of priority areas in remote regions where benefits from ES capacity to society were small. Incorporating ESs in conservation planning should therefore always account for ES demand to identify an effective priority network for ESs. PMID- 27943465 TI - Constructing Implantable SrTiO3 :Yb,Ho Nanofibers for NIR-Triggered and Optically Monitored Chemotherapy. AB - Light-responsive and photoluminescent (PL) drug-delivery platforms have sparked fascinating advancements in personalized tumor chemotherapy due to their unique characteristics in biological imaging and manipulated release kinetics. Herein, implantable Yb3+ and Ho3+ co-doped strontium titanate (SrTiO3 :Yb,Ho) nanofibers were synthesized and decorated on the surface with polyacrylic acid (PAA) molecules. The preliminary in vitro assay confirmed that this implantable fibrous mesh presented sound cytocompatibility. The PAA surface decoration improved the loading capacity of an anticancer drug (doxorubicin (DOX)) and effectively prevented a daunting burst release in a neutral aqueous environment. Owing to the electrostatic bond between PAA and DOX molecules, low-pH microenvironments and NIR (lambda=808 nm) irradiation both induced significantly accelerated DOX release and consequently enhanced the local cancer-cell-killing effect. Additionally, the ratio of green-to-red emission (I545 /I655 ) from the SrTiO3 :Yb,Ho-PAA fibers responded effectively to the DOX release progress and dosage due to a fluorescence resonance energy transfer (FRET) effect. This unique characteristic enabled optical monitoring of the delivery progress in a timely manner. These SrTiO3 :Yb,Ho-PAA nanofibers, with precise dual-triggering and optical monitoring of DOX release, are expected to serve as a new implantable drug delivery platform for personalized chemotherapy in the future. PMID- 27943466 TI - The impact of Arabidopsis thaliana SNF1-related-kinase 1 (SnRK1)-activating kinase 1 (SnAK1) and SnAK2 on SnRK1 phosphorylation status: characterization of a SnAK double mutant. AB - Arabidopsis thaliana SNF1-related-kinase 1 (SnRK1)-activating kinase 1 (AtSnAK1) and AtSnAK2 have been shown to phosphorylate in vitro and activate the energy signalling integrator, SnRK1. To clarify this signalling cascade in planta, a genetic- and molecular-based approach was developed. Homozygous single AtSnAK1 and AtSnAK2 T-DNA insertional mutants did not display an apparent phenotype. Crossing of the single mutants did not allow the isolation of double-mutant plants, whereas self-pollinating the S1-/- S2+/- sesquimutant specifically gave approximatively 22% individuals in their offspring that, when rescued on sugar supplemented media in vitro, were shown to be AtSnAK1 AtSnAK2 double mutants. Interestingly, this was not obtained in the case of the other sesquimutant, S1+/- S2-/-. Although reduced in size, the double mutant had the capacity to produce flowers, but not seeds. Immunological characterization established the T-loop of the SnRK1 catalytic subunit to be non-phosphorylated in the absence of both SnAKs. When the double mutant was complemented with a DNA construct containing an AtSnAK2 open reading frame driven by its own promoter, a normal phenotype was restored. Therefore, wild-type plant growth and development is dependent on the presence of SnAK in vivo, and this is correlated with SnRK1 phosphorylation. These data show that both SnAKs are kinases phosphorylating SnRK1, and thereby they contribute to energy signalling in planta. PMID- 27943467 TI - Low bleeding rates with increase or maintenance of physical activity in patients treated with recombinant factor VIII Fc fusion protein (rFVIIIFc) in the A-LONG and Kids A-LONG Studies. PMID- 27943470 TI - Case of thymoma-associated multi-organ autoimmunity following herpes zoster. PMID- 27943468 TI - Progression of subcortical atrophy in mild Parkinson's disease and its impact on cognition. AB - BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is associated with pronounced grey matter atrophy in various brain regions. However, the association between atrophy patterns and progression from no cognitive impairment (NCI) to Parkinson's disease (PD)-MCI is not clearly known. We investigated the pattern and progression of atrophy in subcortical structures and its impact on cognition in patients with mild PD. METHODS: Sixty-five patients with mild PD with baseline and longitudinal clinical and neuropsychological assessments, and structural magnetic resonance imaging scans were studied. Movement Disorder Society Task Force criteria were used to classify patients with PD into PD-NCI (n = 54) and PD MCI (n = 11). Based on progression over time, those who remained without cognitive impairment were classified as PD-stable (n = 42) and those who converted to MCI over 18 months were classified as PD-converters (n = 12). FreeSurfer was used to measure cortical thickness and subcortical volumes at baseline and follow-up. RESULTS: Parkinson's disease-MCI showed baseline thalamus atrophy and progressive atrophy in the thalamus, caudate, presubiculum, cornu ammonis 1 and 2-3, and significant memory and executive dysfunction compared with PD-NCI. PD-converters had greater accumbens atrophy at baseline and progressive atrophy in the thalamus, caudate and accumbens with dysfunctions in memory and executive domains. CONCLUSIONS: Progression of cognitive impairment in non demented PD is associated with a specific pattern of subcortical atrophy. Findings from this study will allow future studies to investigate in the role of subcortical structures as a biomarker for PD dementia. PMID- 27943469 TI - Metastatic Ovarian Serous Carcinoma of the Breast. PMID- 27943471 TI - A novel RAB39B gene mutation in X-linked juvenile parkinsonism with basal ganglia calcification. AB - OBJECTIVES: Mutations in RAB39B have been reported as a potential cause of X linked Parkinson's disease (PD), a rare form of familial PD. We conducted a genetic analysis on RAB39B to evaluate whether RAB39B mutations are related to PD in the Chinese population. METHODS: In this study, 2 patients from an X-linked juvenile parkinsonism pedigree were clinically characterized and underwent whole exome sequencing. A comprehensive screening for RAB39B mutations in 505 sporadic patients with PD and 510 healthy controls in a Chinese population was also performed. RESULTS: A novel mutation, c. 536dupA (p.E179fsX48), in RAB39B was identified in the juvenile parkinsonism pedigree. Brain MRI and CT scans in the 2 patients revealed calcification within the bilateral globus pallidus. No other potentially disease-causing RAB39B mutations were found in sporadic PD patients and controls. CONCLUSIONS: X-linked juvenile parkinsonism could be caused by a RAB39B mutation, and basal ganglia calcification may be a novel clinical feature of RAB39B-related parkinsonism. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27943472 TI - Hospital care for mental health and substance abuse conditions in Parkinson's disease. AB - OBJECTIVE: The objective of this study was to examine mental health conditions among hospitalized individuals with Parkinson's disease in the United States. METHODS: This was a serial cross-sectional study of hospitalizations of individuals aged >=60 identified in the Nationwide Inpatient Sample dataset from 2000 to 2010. We identified all hospitalizations with a diagnosis of PD, alcohol abuse, anxiety, bipolar disorder, depression, impulse control disorders, mania, psychosis, substance abuse, and attempted suicide/suicidal ideation. National estimates of each mental health condition were compared between hospitalized individuals with and without PD. Hierarchical logistic regression models determined which inpatient mental health diagnoses were associated with PD, adjusting for demographic, payer, geographic, and hospital characteristics. RESULTS: We identified 3,918,703 mental health and substance abuse hospitalizations. Of these, 2.8% (n = 104, 437) involved a person also diagnosed with PD. The majority of mental health and substance abuse patients were white (86.9% of PD vs 83.3% of non-PD). Women were more common than men in both groups (male:female prevalence ratio, PD: 0.78, 0.78-0.79, non-PD: 0.58, 0.57-0.58). Depression (adjusted odds ratio 1.32, 1.31-1.34), psychosis (adjusted odds ratio 1.25, 1.15-1.33), bipolar disorder (adjusted odds ratio 2.74, 2.69-2.79), impulse control disorders (adjusted odds ratio 1.51, 1.31-1.75), and mania (adjusted odds ratio 1.43, 1.18-1.74) were more likely among PD patients, alcohol abuse was less likely (adjusted odds ratio 0.26, 0.25-0.27). We found no PD-associated difference in suicide-related care. CONCLUSIONS: PD patients have unique patterns of acute care for mental health and substance abuse. Research is needed to guide PD treatment in individuals with pre-existing psychiatric illnesses, determine cross provider reliability of psychiatric diagnoses in PD patients, and inform efforts to improve psychiatric outcomes. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27943473 TI - Gender-, age-, and race/ethnicity-based differential item functioning analysis of the movement disorder society-sponsored revision of the Unified Parkinson's disease rating scale. AB - OBJECTIVE: Assess MDS-UPDRS items for gender-, age-, and race/ethnicity-based differential item functioning. BACKGROUND: Assessing differential item functioning is a core rating scale validation step. For the MDS-UPDRS, differential item functioning occurs if item-score probability among people with similar levels of parkinsonism differ according to selected covariates (gender, age, race/ethnicity). If the magnitude of differential item functioning is clinically relevant, item-score interpretation must consider influences by these covariates. Differential item functioning can be nonuniform (covariate variably influences an item-score across different levels of parkinsonism) or uniform (covariate influences an item-score consistently over all levels of parkinsonism). METHODS: Using the MDS-UPDRS translation database of more than 5,000 PD patients from 14 languages, we tested gender-, age-, and race/ethnicity based differential item functioning. To designate an item as having clinically relevant differential item functioning, we required statistical confirmation by 2 independent methods, along with a McFadden pseudo-R2 magnitude statistic greater than "negligible." RESULTS: Most items showed no gender-, age- or race/ethnicity based differential item functioning. When differential item functioning was identified, the magnitude statistic was always in the "negligible" range, and the scale-level impact was minimal. CONCLUSIONS: The absence of clinically relevant differential item functioning across all items and all parts of the MDS-UPDRS is strong evidence that the scale can be used confidently. As studies of Parkinson's disease increasingly involve multinational efforts and the MDS-UPDRS has several validated non-English translations, the findings support the scale's broad applicability in populations with varying gender, age, and race/ethnicity distributions. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27943474 TI - Cholinergic regulation of striatal dopamine release: New light in dark basements. PMID- 27943475 TI - Posttraumatic growth in breast cancer survivors and their husbands based on the actor-partner interdependence model. AB - OBJECTIVE: This study aimed to verify actor and partner effects, by examining the effects of self-esteem, relationship quality, and subjective distress on posttraumatic growth in breast cancer survivors and their spouses, and involved a structural analysis of descriptive cause-and-effect relationships to verify the suitability of the actor-partner interdependence model. METHODS: A structured questionnaire was used to collect data from breast cancer survivors and their spouses at outpatient centers, wards, and patient meetings in 4 general hospitals in Seoul between April 13 and September 20, 2015. Data for 336 individuals (168 couples) were analyzed. The suitability of the hypothetical model was assessed via SPSS Win 21.0 and AMOS 21.0. Actor and partner effects on posttraumatic growth in breast cancer survivors and their spouses were examined. RESULTS: Self esteem, relationship quality, and subjective distress exerted significant actor effects, and subjective distress exerted a significant partner effect on posttraumatic growth in breast cancer survivors. Relationship quality and support exerted significant actor effects, and self-esteem, relationship quality, and subjective distress exerted significant partner effects on posttraumatic growth in spouses. CONCLUSIONS: Posttraumatic growth in breast cancer survivors was influenced by not only relationship quality and spouses' self- esteem but also subjective distress; therefore, solidarity between breast cancer survivors and their spouses was important and should be maintained to provide healthy relationship support and enhance posttraumatic growth. Further, health care providers should include spouses in health-related education and involve them in interventions and family support programs for couples. PMID- 27943476 TI - Effects of decomposition on carbon and nitrogen stable isotope values of muscle tissue of varying lipid content from three aquatic vertebrate species. AB - RATIONALE: Stable isotopes are a prominent tool in animal ecology where data is obtained from analyzing animal tissues, which are typically stored prior to analysis. However, the effect of decomposition on the reliability of stable isotope ratios from animal tissue prior to storage has been seldom studied. Here, we examine the long-term effects of freezing and decomposition of animal tissue on delta13 C and delta15 N values across three different aquatic species of varying lipid content. METHODS: Ringed seal, lake trout and Greenland shark muscle were divided into different treatment groups and analyzed for their delta13 C values, carbon content (%C), delta15 N values, and nitrogen content (%N) at specific time intervals. The intervals included days 0, 128 and 700 for the frozen storage treatment and at days 0, 1, 2, 4, 8, 16, 32, 64, 128 and 256 for the tissue decomposition treatment in open and closed vials at room temperature. RESULTS: The difference in delta13 C and delta15 N values between the control and days 128 and 700 for the frozen treatment was minimal and not significant for any species. Generally, significant decreases in carbon (%C) and nitrogen (%N) content and significant increases (>0.50/00) in delta13 C and delta15 N values occurred for muscle of each species left to decompose for 256 days, probably due to the preferential uptake of lighter isotopes during decomposition by microbes. However, the magnitude of change in the delta13 C and delta15 N values up to 8 days in both treatments was low (generally <=0.10/00) and not significant across most species. CONCLUSIONS: Freezing for extended time periods (up to 700 days) is a viable storage technique for stable isotope analysis of aquatic animal muscle tissue across a range of lipid contents. Muscle tissue left to decompose at room temperature showed no significant change in delta13 C and delta15 N values after 8 days, and such tissues would still be reliable for ecological interpretations. However, caution should be used for decomposed tissue for >8 days as the delta13 C and delta15 N values will probably be artificially high. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943477 TI - A New Kind of Fireproof, Flexible, Inorganic, Nanocomposite Paper and Its Application to the Protection Layer in Flame-Retardant Fiber-Optic Cables. AB - An innovative method for making a new kind of highly flexible, fireproof, inorganic, nanocomposite paper made from glass fibers (GFs) coated with network structured hydroxyapatite ultralong nanowires (NS-HANWs) is reported. The NS HANW/GF paper is fireproof, high-temperature resistant, highly flexible, highly exquisite, and smooth, which is comparable to high-quality advanced coated paper. The most incredible characteristic of the NS-HANW/GF paper is its incombustibility. The as-prepared NS-HANW/GF paper, with the addition of optimized inorganic additives, has high mechanical properties (tensile strength ~16 MPa) and the tensile strength is nearly 15 times that of GF paper. In addition, the NS-HANW/GF paper exhibits a high biocompatibility, owing to the coating effect of NS-HANWs on GFs. Thermal analysis indicates that the NS-HANW/GF paper has high thermal stability at high temperatures up to 1000 degrees C. Competitive to conventional insulation materials, the NS-HANW/GF paper exhibits a low thermal conductivity and excellent heat insulation performance. Experiments show that the NS-HANW/GF paper is promising for application in the protection layer of fire-retardant fiber-optic cable. The NS-HANW/GF paper can also be used as printing, copying, or writing paper; nonflammable China paper; fire-retardant wallpaper; specialty fireproof paper; and so on. PMID- 27943478 TI - Free-Radical Carbo-Alkenylation of Olefins: Scope, Limitations and Mechanistic Insights. AB - The three-component free-radical carbo-alkenylation of electron-rich olefins has been studied, varying the substitution pattern in the alkene, in the radical precursor and in the final acceptor. New vinylsulfones were also prepared and their reactivity investigated. The scope and limitations of the process was established, and the reaction mechanism clarified using selected dienes as radical clocks. It was thus recognised that the reversible addition onto the olefin of the released sulfonyl group is an important event, which should not be overlooked when using such multicomponent carbo-alkenylation reactions. PMID- 27943479 TI - Schwannoma-Like (Palisaded) Myofibroblastoma: A Challenging Diagnosis on Core Biopsy. PMID- 27943480 TI - Porous Tetrametallic PtCuBiMn Nanosheets with a High Catalytic Activity and Methanol Tolerance Limit for Oxygen Reduction Reactions. AB - Porous PtCuBiMn nanosheets are developed with a thickness of ~3-4 nm. The specific and mass activities of these nanosheets are ten and seven times greater than that of commercial Pt/C catalyst, respectively. PtCuBiMn nanosheets demonstrate superior catalytic performance for the oxygen reduction reaction, as well as resistance to methanol cross-over effects, suggesting that it is a promising catalyst for direct methanol fuel cells. PMID- 27943481 TI - Synchronized Chiral Induction between [5]Helicene-Spermine Ligand and B-Z DNA Transition. AB - The 2,13-dimethoxy[5]helicene-spermine ligand 8 b possesses an axial chirality. The racemic 8 b was bound to B-DNA by the accompanying induction of its (P) chirality together with the B-to-Z helicity change of the duplex DNA, [(dC-dG)3 ]2 . The (P)-chirality of the bound 8 b, in turn, transitioned to the (M) chirality according to the Z-helicity of the DNA. These results illustrate the chirality synchronization between the DNA and the ligand. PMID- 27943482 TI - Knowledge about Risk Factors of Breast Cancer and Its Effect on Women's Screening Behaviour in a Community of Rio Grande do Norte, North-eastern Brazil. PMID- 27943483 TI - Rapid realist review of the evidence: achieving lasting change when mental health rehabilitation staff undertake recovery-oriented training. AB - AIM: The aim of this study was to identify the factors contributing to lasting change in practice following a recovery-based training intervention for inpatient mental health rehabilitation staff. BACKGROUND: Staff training may help nurses and other staff groups in inpatient mental health rehabilitative settings to increase their recovery-oriented practice. There are no published reviews on the effectiveness of such training and few long-term evaluations. This review informed a realist evaluation of a specific intervention (GetREAL). DESIGN: Rapid realist review methodology was used to generate and prioritize programme theories. DATA SOURCES: ASSIA, CINAHL, Cochrane Library, Medline, PsycINFO, Scopus, Web of Science and grey literature searches were performed in September 2014-March 2015 with no date restrictions. Stakeholders suggested further documents. GetREAL project documentation was consulted. REVIEW METHODS: Programme theory development took place iteratively with literature identification. Stakeholders validated and prioritized emerging programme theories and the prioritized theories were refined using literature case studies. RESULTS: Fifty one relevant documents fed into 49 programme theories articulating seven mechanisms for lasting change. Prioritized mechanisms were: staff receptiveness to change; and staff feeling encouraged, motivated and supported by colleagues and management to change. Seven programme theories were prioritized and refined using data from four case studies. CONCLUSION: Lasting change can be facilitated by collaborative action planning, regular collaborative meetings, appointing a change agent, explicit management endorsement and prioritization and modifying organizational structures. Conversely, a challenging organizational climate, or a prevalence of 'change fatigue', may block change. Pre-intervention exploration may help identify any potential barriers to embedding recovery in the organizational culture. PMID- 27943484 TI - Utility of MR enterography and ultrasound for the investigation of small bowel Crohn's disease. AB - : Cross sectional Imaging plays an increasingly important role the diagnosis and management of Crohn's disease. Particular emphasis is placed on MRI and Ultrasound as they do not impart ionising radiation. Both modalities have reported high sensitivity for disease detection, activity assessment and evaluation of extra-luminal complications, and have positive effects on clinical decision making. International Guidelines now recommend MRI and Ultrasound in the routine management of Crohn's disease patients. This article reviews the current evidence base supporting both modalities with an emphasis on the key clinical questions. We describe current protocols, basic imaging findings and highlight areas in need of further research. LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 4 J. MAGN. RESON. IMAGING 2017;45:1573-1588. PMID- 27943486 TI - Information Needs and Internet Use of Breast Cancer Survivors in Mexico. PMID- 27943485 TI - Maintaining the factory: the roles of the unfolded protein response in cellular homeostasis in plants. AB - Much like a factory, the endoplasmic reticulum (ER) assembles simple cellular building blocks into complex molecular machines known as proteins. In order to protect the delicate protein folding process and ensure the proper cellular delivery of protein products under environmental stresses, eukaryotes have evolved a set of signaling mechanisms known as the unfolded protein response (UPR) to increase the folding capacity of the ER. This process is particularly important in plants, because their sessile nature commands adaptation for survival rather than escape from stress. As such, plants make special use of the UPR, and evidence indicates that the master regulators and downstream effectors of the UPR have distinct roles in mediating cellular processes that affect organism growth and development as well as stress responses. In this review we outline recent developments in this field that support a strong relevance of the UPR to many areas of plant life. PMID- 27943488 TI - Electrocardiographic Predictors of Long-Term Cardiac Pacing Dependency Following Transcatheter Aortic Valve Implantation. AB - BACKGROUND: Conduction disorders requiring permanent pacemaker (PPM) implantation are a known complication of transcatheter aortic valve implantation (TAVI). Indications for permanent pacing in this setting are still controversial. The study aim was to characterize the natural history of conduction disorders related to TAVI, and to identify predictors for long-term pacing dependency. METHODS: Consecutive patients who underwent TAVI were included in this prospective observational study. The conduction system was investigated by reviewing 12-lead ECGs during hospitalization and up to 1-year follow-up and by analyzing pacemaker interrogation data. Multivariate analysis was performed in order to identify independent predictors for pacemaker dependency. RESULTS: Of 110 patients included in the analysis, 38 (34.5%) underwent PPM implantation. Of those, 26 (68.4%) had a long-term pacing dependency (required PPM), while 12 (31.6%) did not (not-required PPM). Logistic regression revealed that baseline RBBB (P = 0.01, OR = 18.0), baseline PR interval (P = 0.019, OR = 1.14), post-TAVI PR interval and the change in PR interval from baseline (P < 0.001 for both, OR = 1.17 for each 10 milliseconds increment) were independent predictors for long term pacing dependency. A PR interval increment of greater than 28 milliseconds had the best accuracy in predicting pacemaker dependency. CONCLUSIONS: Increased pre- and postprocedural PR intervals and pre-existing RBBB are reliable predictors for long-term PPM dependency, while left bundle branch block or QRS width are misleading factors. Our study suggests that the decision for implanting PPM after TAVI should be based mostly on the prolongation of the PR interval. PMID- 27943487 TI - A comparison of attitudes toward length and quality of life between community dwelling older adults and patients with advanced cancer. AB - OBJECTIVE: Applying prospect theory to end-of-life decision making, we hypothesize that community-dwelling older adults (CDOAs) will be relatively less inclined towards extending length over improving quality of life compared with patients. We also hypothesize that differences in relative inclination for length over quality of life between the 2 groups will decrease with advancing age. METHODS: We tested these hypotheses by administering the quality-quantity questionnaire to 1067 CDOAs and 320 stage IV cancer patients and applying a linear regression model to assess whether relative inclination for length over quality of life, as estimated by the questionnaire, differed between CDOAs and patients after controlling for differences in sociodemographic characteristics. We also assessed the effect of interaction between age and participant status (CDOA compared to patient) on relative inclination for length over quality of life. RESULTS: Consistent with prospect theory, a lower proportion of CDOAs (26%) than patients (42%) were relatively more inclined towards length over quality of life. Results were significant even after adjusting for differences in sociodemographics (P < .01). With increasing age, the difference in relative inclination between CDOAs and patients increased (P = .01). CONCLUSIONS: Findings indicate that attitudes towards length and quality of life differ by life stage. This has implications for end-of-life care decisions made by CDOAs, such as purchasing health or disability insurance and signing advance directives or care plans. PMID- 27943489 TI - Photosynthetically active radiation and carbon gain drives the southern orientation of Myrtillocactus geometrizans fruits. AB - The equatorial orientation of reproductive structures is known in some columnar cacti from extratropical deserts. It has been hypothesised that photosynthetically active radiation (PAR) interception is the main reason for this orientation, because of its key effect on nocturnal CO2 uptake. However, there are no studies addressing both the effect of PAR and its consequence, carbon gain, on fruit orientation. Accordingly, we tested whether PAR and carbon gain could explain the southern fruit orientation of Myrtillocactus geometrizans, an inter-tropical columnar cactus. We studied three populations of M. geometrizans in Mexico. For each population, azimuth of fruits, total daily PAR, nocturnal acid accumulation (NAA) and fruit production were measured. The relationships between rib orientation and number of fruits, as well as total daily PAR, were evaluated using periodic regressions. The effect of total daily PAR and NAA on number of fruits was assessed using generalised linear models. During spring, mean fruit orientation had a south azimuth for three populations. Likewise, rib orientation had a significant effect on fruit production, with the south-facing ribs having the maximum number of fruits. Total daily PAR was highest in the south-facing ribs, at least for those in the northern and central populations. Furthermore, during spring, there was a significant positive effect of total daily PAR and NAA on fruit production. Our results provide strong evidence that the higher carbon gain in equatorial ribs, through a highest interception of PAR, would be the responsible factor for equatorial orientation of fruits in an inter-tropical columnar cactus. PMID- 27943490 TI - Analysis of human plasma metabolites across different liquid chromatography/mass spectrometry platforms: Cross-platform transferable chemical signatures. PMID- 27943491 TI - Methanol adducts leading to the identification of a reactive aldehyde metabolite of CPAQOP in human liver microsomes by ultra-high-performance liquid chromatography/mass spectrometry. AB - RATIONALE: The incubation of CPAQOP (1-[(2R)-2-[[4-[3-chloro-4-(2 pyridyloxy)anilino]quinazolin-5-yl]oxymethyl]-1-piperidyl]-2-hydroxy) with human liver microsomes generated several metabolites that highlighted the hydroxyacetamide side chain was a major site of metabolism for the molecule. The metabolites were derived predominantly from oxidative biotransformations; however, two unexpected products were detected by liquid chromatography/ultraviolet/mass spectrometry (LC/UV/MS) and identified as methanol adducts. This observation prompted further LC/MS investigations into their formation. METHODS: Three separate incubations of CPAQOP were conducted in human liver microsomes; Naive, fortified with methoxyamine and fortified with glutathione. Separation was achieved via ultra-high-performance liquid chromatography with either methanol or acetonitrile gradients containing formic acid. MS analysis was conducted by electrospray ionisation LTQ Orbitrap mass spectrometry acquiring accurate mass full scan, data-dependent MS2 and all ion fragmentation. RESULTS: No methanol adducts were detected by MS when acetonitrile was used in the mobile phase instead of methanol, verifying that a metabolite was reacting with methanol on column. Although this reactive metabolite could not be isolated or structurally characterised by LC/MS directly, product ion spectra of the methanol adducts confirmed addition of methanol on the hydroxyacetamide side chain. Additional experiments using methoxyamine showed the disappearance of the two methanol adducts and appearance of a methoxyamine adduct, confirming the presence of an aldhyde. Product ion spectra of the methoxyamine adduct confirmed addition of methoxyamine to the hydroxyacetamide side chain. CONCLUSIONS: The proposed bioactivation of CPAQOP occurred via the reactive aldehyde intermediate, which readily reacted with methanol in the mobile phase to form a pair of isomeric hemiacetal methanol adducts. In acidified methanol the equilibrium favoured the methanol adduct and in acidified acetonitrile it favoured the hydrate; therefore, the reactive aldehyde metabolite was not detected and could not be structurally characterised directly. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943493 TI - Adolescent drinking-a touch of social class? AB - AIMS: To estimate whether parental socio-economic status (SES) is associated with adolescent drinking, and the degree to which a possible association may be accounted for by various parental factors. DESIGN AND SETTING: Cross-sectional Norwegian school survey from 2006 (response rate: 86%). PARTICIPANTS: Students aged 13-14 years (n = 5797), 15-16 years (n = 6613) and 17-18 years (n = 5351), of whom 51% were girls. MEASUREMENTS: Parents' education was our main SES indicator, and we distinguished between low (7%) and middle/high (93%) educational level. The outcomes comprised past-year drinking and intoxication. We also applied measures on general parenting, parents' alcohol-related permissiveness and parental intoxication. The main analyses were conducted using Poisson regression. FINDINGS: Parents' education had no statistically significant impact on alcohol use among the 17-18-year-olds, while 13-16-year-olds with low educated parents had an elevated relative risk (RR) of both drinking [RR = 1.21, 95% confidence interval (CI) = 1.13-1.29] and intoxication (RR = 1.32, 95% CI = 1.21-1.44). The RRs became statistically insignificant when including all the parental factors as covariates in the regression models. Among adolescents who had consumed alcohol, low parental education was related to more frequent drinking (RR = 1.24, 95% CI = 1.11-1.38) and intoxication episodes (RR = 1.42, 95% CI = 1.22-1.66). Again, the RRs became statistically insignificant when we accounted for all the parental factors. This pattern was replicated when we applied an alternative indicator for low parental SES. CONCLUSIONS: Adolescent drinking in Norway appears to be related inversely to parents' social standing. The elevated risk of low socio-economic status vanishes when general parenting, alcohol-related parental permissiveness and parents' drinking are accounted for. PMID- 27943492 TI - Microscale magnetic microparticle-based immunopurification of cytokinins from Arabidopsis root apex. AB - Cytokinins (CKs) are pivotal plant hormones that have crucial roles in plant growth and development. However, their isolation and quantification are usually challenging because of their extremely low levels in plant tissues (pmol g-1 fresh weight). We have developed a simple microscale magnetic immunoaffinity based method for selective one-step isolation of CKs from very small amounts of plant tissue (less than 0.1 mg fresh weight). The capacity of the immunosorbent and the effect of the complex plant matrix on the yield of the rapid one-step purification were tested using a wide range of CK concentrations. The total recovery range of the new microscale isolation procedure was found to be 30-80% depending on individual CKs. Immunoaffinity extraction using group-specific monoclonal CK antibodies immobilized onto magnetic microparticles was combined with a highly sensitive ultrafast mass spectrometry-based method with a detection limit close to one attomole. This combined approach allowed metabolic profiling of a wide range of naturally occurring CKs (bases, ribosides and N9 -glucosides) in 1.0-mm sections of the Arabidopsis thaliana root meristematic zone. The magnetic immunoaffinity separation method was shown to be a simple and extremely fast procedure requiring minimal amounts of plant tissue. PMID- 27943494 TI - Direct Fabrication of 3D Metallic Networks and Their Performance. AB - Fabrication of macroscopic nanoporous metallic networks is challenging, because it demands fine structures at the nanoscale over a large-scale. A technique to form pure scalable networks is introduced. The networked-metals ("Netals") exhibit a strong interaction with light and indicate a large fraction of hot electrons generation. These hot-electrons are available to derive photocatalytic processes. PMID- 27943495 TI - The mitochondrial complexome of Arabidopsis thaliana. AB - Mitochondria are central to cellular metabolism and energy conversion. In plants they also enable photosynthesis through additional components and functional flexibility. A majority of those processes relies on the assembly of individual proteins to larger protein complexes, some of which operate as large molecular machines. There has been a strong interest in the makeup and function of mitochondrial protein complexes and protein-protein interactions in plants, but the experimental approaches used typically suffer from selectivity or bias. Here, we present a complexome profiling analysis for leaf mitochondria of the model plant Arabidopsis thaliana for the systematic characterization of protein assemblies. Purified organelle extracts were separated by 1D Blue native (BN) PAGE, a resulting gel lane was dissected into 70 slices (complexome fractions) and proteins in each slice were identified by label free quantitative shot-gun proteomics. Overall, 1359 unique proteins were identified, which were, on average, present in 17 complexome fractions each. Quantitative profiles of proteins along the BN gel lane were aligned by similarity, allowing us to visualize protein assemblies. The data allow re-annotating the subunit compositions of OXPHOS complexes, identifying assembly intermediates of OXPHOS complexes and assemblies of alternative respiratory oxidoreductases. Several protein complexes were discovered that have not yet been reported in plants, such as a 530 kDa Tat complex, 460 and 1000 kDa SAM complexes, a calcium ion uniporter complex (150 kDa) and several PPR protein complexes. We have set up a tailored online resource (https://complexomemap.de/at_mito_leaves) to deposit the data and to allow straightforward access and custom data analyses. PMID- 27943497 TI - Novartis Early Career Award: T. J. Maimone and M. K. Brown / Nagoya Gold Medal: S. L. Buchwald / Nagoya Silver Medal: M. Sawamura. PMID- 27943496 TI - Treatment of cervical pregnancy with ultrasound-guided local methotrexate injection. AB - OBJECTIVES: Cervical pregnancy (CP) is a rare type of ectopic pregnancy. While methotrexate (MTX) is generally the first-line method of choice for clinically stable women, there is still no consensus on the most appropriate treatment for this abnormal pregnancy. The aim of this study was to investigate the efficacy of a single local MTX injection under transvaginal ultrasound guidance for the initial treatment of CP and to assess post-treatment fertility. METHODS: We reviewed retrospectively 15 patients with CP treated with local MTX injection under transvaginal ultrasound guidance. In all patients, the serum human chorionic gonadotropin (hCG) levels were monitored and the gestational sac was evaluated using ultrasonography after treatment. Magnetic resonance imaging (MRI) was performed as necessary. We evaluated the patients' clinical characteristics and clinical course after treatment, the efficacy of the treatment and the post treatment fertility in patients desiring subsequent pregnancy. RESULTS: The median estimated gestational age at the time of MTX injection was 6 + 2 (range, 5 + 2 to 11 + 0) weeks. All 15 patients were treated successfully, without the need for blood transfusion or surgical procedures; however, three patients required an additional local MTX injection due to a poor decline in serum hCG level following the initial injection, while one patient required uterine artery embolization due to persistent vaginal bleeding and an enlarging gestational sac with blood vessels visible on contrast-enhanced MRI. The mean time following initial MTX injection for hCG normalization was 43.8 (95% CI, 33.3-54.3) days and for resumption of menses was 68.4 (95% CI, 51.9-84.9) days. Seven of the 10 women desiring subsequent pregnancy following treatment had uneventful pregnancy, one became pregnant but miscarried spontaneously at 8 weeks of gestation, one was treated by laparoscopic surgery after diagnosis of a tubal pregnancy and one did not conceive. CONCLUSIONS: A single, ultrasound-guided, local MTX injection is apparently effective for the treatment of CP without the need for concomitant procedures or surgical intervention. Furthermore, this conservative technique both preserves fertility and allows for the possibility of subsequent uneventful pregnancy. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27943498 TI - Risk factors for the development of Clostridium difficile infection in adult allogeneic hematopoietic stem cell transplant recipients: A single-center study in Quebec, Canada. AB - BACKGROUND: Clostridium difficile infection (CDI) is a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our primary objective was to determine risk factors for the development of CDI during the first year following allo-HSCT. METHODS: A matched case-control study nested in a cohort of allo-HSCT at a single hospital in Montreal, Quebec, Canada, was conducted from 2002 through 2011. RESULTS: Sixty-five of 760 patients who underwent allo-HSCT between 2002 and 2011 developed CDI, representing an incidence of 8.6%. We selected 123 controls matched for year of transplant for risk factor analyses. In the multivariable analysis, receipt of trimethoprim sulfamethoxazole (TMP-SMX) prior to transplantation (adjusted odds ratio [aOR] 0.07, 95% confidence interval [CI] 0.02-0.27), mucositis (aOR 5.90, 95% CI 2.08 16.72), and reactivation of cytomegalovirus (CMV) (aOR 6.17, 95% CI 2.17-17.57) and of other Herpesviridae viruses (aOR 3.04, 95% CI 1.13-8.16) were the variables that remained statistically associated with CDI. High-risk antibiotic use in the late post-transplant period (aOR 7.63, 95% CI 2.14-27.22) was associated with development of late CDI. CONCLUSION: This study revealed reactivation of CMV and other Herpesviridae viruses as novel risk factors for CDI. Administration of TMP-SMX prior to transplantation was independently associated with a decreased risk of CDI. Early and late CDI after HSCT may have distinct risk factors. PMID- 27943499 TI - Prenatal diagnosis and prognosis of accelerated idioventricular rhythm. AB - OBJECTIVES: As postnatal identification of accelerated idioventricular rhythm (AIVR) relies on specific electrocardiographic patterns, prenatal diagnosis of this condition is challenging and its true incidence is unknown. The objectives of this study were to evaluate the performance of prenatal ultrasonography in identifying intrauterine cardiocirculatory events linked to specific electrocardiographic signs of postnatal AIVR, including left or right ventricular origin, and to assess the prenatal prognosis of this arrhythmia. METHODS: We reviewed Doppler tracings from the superior vena cava/ascending aorta (SVC/Ao), ductus venosus (DV), ductus arteriosus (DA) and aortic isthmus (AoI), as well as simultaneous M-mode recordings of septal and left ventricular wall motions of fetuses diagnosed with AIVR from January 2004 to December 2014. RESULTS: Three cases of AIVR were identified among 27 912 fetuses. SVC/Ao Doppler flow recordings revealed atrioventricular dissociation (ventricular rates within 20% of atrial rates) in all three fetuses and episodes of isorhythmic atrioventricular dissociation in one, while M-mode confirmed normal left ventricular shortening fraction in all cases. Fusion beats were observed on AoI tracing in one fetus, while simultaneous recordings of AoI and DA revealed signs of right bundle branch block in one case and left bundle branch block in the other two. On DV Doppler recordings, retrograde a-waves in the presence of simultaneous atrial and ventricular contractions were observed in all three fetuses, leading to an increase in central venous pressure in all and hydrops fetalis in two cases without evidence of ventricular dysfunction. CONCLUSIONS: Echocardiographic criteria required for postnatal diagnosis of AIVR can be documented in utero using specific ultrasonographic approaches. During fetal life, AIVR may not be a benign entity. Hydrops fetalis is frequently associated with AIVR because of increase in central venous pressure related to simultaneous atrioventricular contractions; thus, the ultrasonographic investigation protocol of fetuses with unexplained hydrops fetalis should aim at ruling out AIVR and include Doppler flow recordings in SVC/Ao, DV, AoI, DA and umbilical vein. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27943500 TI - Knowledge of Density and Screening Ultrasound. AB - To determine breast density awareness and attitudes regarding supplemental breast ultrasound screening since implementation of the nation's first breast density notification law, Connecticut Public Act 09-41. A self-administered survey was distributed at a Connecticut academic breast imaging center between February 2013 and February 2014. Women with prior mammography reports describing heterogeneous or extremely dense breast tissue were invited to participate when presenting for screening mammography, screening ultrasound, or both. Data were collected on breast density awareness, history of prior ultrasounds, attitudes toward ultrasound and breast-cancer risk, and demographics. Data were collected from 950 completed surveys. The majority of surveyed women (92%) were aware of their breast density, and 77% had undergone a prior screening ultrasound. Forty-three percent of participants who were aware of their breast density also expressed increased anxiety about developing breast cancer due to having dense breast tissue. Caucasian race and higher education were significantly associated (p < 0.05) with knowledge of personal breast density (93% and 95%, respectively) and having a prior screening breast ultrasound (79% and 80%, respectively). Patients with less than a college degree (82%) were significantly more likely to rely exclusively on their provider's recommendation regarding obtaining screening ultrasound (p < 0.05). Breast density awareness is strongly associated with higher education, higher income, and Caucasian race. Non-Caucasian patients and those with less than a college education rely more heavily on their physicians' recommendations regarding screening ultrasound. Among women aware of their increased breast density, nearly half reported associated increased anxiety regarding the possibility of developing breast cancer. PMID- 27943501 TI - Risk factors and epidemiology of Clostridium difficile infection in hematopoietic stem cell transplant recipients during the peritransplant period. AB - BACKGROUND: Hematopoietic stem cell transplant (HSCT) recipients represent a high risk group for developing Clostridium difficile (CD) infection (CDI). We aimed to identify specific risk factors for CDI in an HSCT patient population during the peritransplant period. METHODS: We performed a case-control study within a cohort of HSCT patients who received a transplant from November 2010 to March 2013. Cases had a clinical presentation compatible with CDI and a positive stool sample Xpert(r) C. difficile test. Controls were CDI negative and matched on age, gender, and transplant type. Peritransplant period was defined as -30 days or time of stem cell mobilization maneuver to 30 days post transplant in autologous SCT or 90 days post transplant in allogeneic SCT. RESULTS: Of 781 HSCTs performed during the study period, 650 (83.2%) had a stool sample submitted for CD testing. Eight-six (13.2%) cases with CDI were identified. Most of the cases were diagnosed within a week after transplantation (median of 5 days). In adjusted analysis, prior hospitalization (odds ratio [OR]: 2.01, 95% confidence interval [CI] 1.2-3.36), prior cephalosporin administration (OR 2.72, 95% CI: 1.54-4.83), and prior chemotherapy (OR: 3.26, 95% CI: 1.92-5.5) were significantly associated with CDI. CONCLUSIONS: Hospitalization, and prior antibiotic and chemotherapy use are risk factors that are not easily modifiable, which emphasizes the need to start investigating preventive or prophylactic strategies in this high-risk population. PMID- 27943502 TI - Pilot randomized, non-inferiority, cross-over trial of once-weekly vs. three times-weekly recombinant factor VIII prophylaxis in adults with severe haemophilia A. PMID- 27943503 TI - Invasive fungal infection after heart transplantation: A 7-year, single-center experience. AB - BACKGROUND: Invasive fungal infections (IFIs) are an infrequent but major complication of heart transplantation (HT). We sought to describe the epidemiology at our institution. METHODS: A prospective cohort study of 159 heart transplant recipients was performed from June 2005 to December 2012. IFIs were defined by European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. RESULTS: By univariate analysis, Hispanic ethnicity was associated with IFI (P=.01, odds ratio [OR] 7.0, 95% confidence interval [CI] 1.7 27.9). Subsequently, a multivariate logistic regression was performed adjusting for Hispanic ethnicity, age, and gender. Seventeen IFIs were identified, occurring at a median 110 days post HT (interquartile range: 32-411 days). Five IFIs (29% of IFIs and 3.1% of all HT) occurred during the HT hospitalization, with 13 IFIs during the first year (incidence 8.2%). CONCLUSIONS: The cumulative incidence was 10.7%. IFIs were associated with pre- and post-HT vancomycin resistant Enterococcus colonization and/or infection, post-HT renal replacement therapy, anti-thymocyte globulin induction, and antibody-mediated rejection. There were no associations with diabetes mellitus, desensitization, 2R/3R cellular rejection, treatments for rejection, re-operation, neutropenia, or cytomegalovirus infection. IFIs were associated with death (P=.02, OR 3.9, 95% CI 1.3-12.1) and 1-year mortality (P<.001, OR 9.0, 95% CI 2.3-35.7), but not 3-year mortality. Associations with Hispanic ethnicity must be validated. Optimal strategies for risk reduction and prophylaxis remain undefined. PMID- 27943504 TI - Phenological mismatch and the effectiveness of assisted gene flow. AB - The persistence of narrowly adapted species under climate change will depend on their ability to migrate apace with their historical climatic envelope or to adapt in place to maintain fitness. This second path to persistence can only occur if there is sufficient genetic variance for response to new selection regimes. Inadequate levels of genetic variation can be remedied through assisted gene flow (AGF), that is the intentional introduction of individuals genetically adapted to localities with historic climates similar to the current or future climate experienced by the resident population. However, the timing of reproduction is frequently adapted to local conditions. Phenological mismatch between residents and migrants can reduce resident * migrant mating frequencies, slowing the introgression of migrant alleles into the resident genetic background and impeding evolutionary rescue efforts. Focusing on plants, we devised a method to estimate the frequency of resident * migrant matings based on flowering schedules and applied it in an experiment that mimicked the first generation of an AGF program with Chamaecrista fasciculata, a prairie annual, under current and expected future temperature regimes. Phenological mismatch reduced the potential for resident * migrant matings by 40-90%, regardless of thermal treatment. The most successful migrant sires were the most resident like in their flowering time, further biasing the genetic admixture between resident and migrant populations. Other loci contributing to local adaptation-heat-tolerance genes, for instance-may be in linkage disequilibrium with phenology when residents and migrants are combined into a single mating pool. Thus, introgression of potentially adaptive migrant alleles into the resident genetic background is slowed when selection acts against migrant phenology. Successful AGF programs may require sustained high immigration rates or preliminary breeding programs when phenologically matched migrant source populations are unavailable. PMID- 27943505 TI - Visualizing and Quantifying Interactions in the Excited State. AB - Determining the location and nature of the electron pairs within a molecule provides an intuitive representation of electronic structures. Yet, most of the available theoretical representations are not suitable for describing excited state phenomena. The density overlap region indicator (DORI) scalar field, which depends only on the density and its derivatives, overcomes previous limitations, while keeping the intuitiveness of popular scalar fields. Here, its usefulness is demonstrated by pinpointing visual and numerical DORI signatures for both intra- and intermolecular excited state situations. PMID- 27943506 TI - Observation of Slow Relaxation and Single-Molecule Toroidal Behavior in a Family of Butterfly-Shaped Ln4 Complexes. AB - A family of five isostructural butterfly complexes with a tetranuclear [Ln4 ] core of the general formula [Ln4 (LH)2 (MU2 -eta1 eta1 Piv)(eta2 -Piv)(MU3 -OH)2 ]?x H2 O?y MeOH?z CHCl3 (1: Ln=DyIII , x=2, y=2, z=0; 2: Ln=TbIII , x=0, y=0, z=6; 3: Ln=ErIII , x=2, y=2, z=0; 4: Ln=HoIII , x=2, y=2, z=0; 5: Ln=YbIII , x=2, y=2, z=0; LH4 =6-{[bis(2-hydroxyethyl)amino]methyl}-N'-(2-hydroxy-3 methoxybenzylidene)picolinohydrazide; PivH=pivalic acid) was isolated and characterized both structurally and magnetically. Complexes 1-5 were probed by direct and alternating current (dc and ac) magnetic susceptibility measurements and, except for 1, they did not display single-molecule magnetism (SMM) behavior. The ac magnetic susceptibility measurements show frequency-dependent out-of-phase signals with one relaxation process for complex 1 and the estimated effective energy barrier for the relaxation process was found to be 49 K. We have carried out extensive ab initio (CASSCF+RASSI-SO+SINGLE_ANISO+POLY_ANISO) calculations on all the five complexes to gain deeper insights into the nature of magnetic anisotropy and the presence and absence of slow relaxation in these complexes. Our calculations yield three different exchange coupling for these Ln4 complexes and all the extracted J values are found to be weakly ferro/antiferromagentic in nature (J1 =+2.35, J2 =-0.58, and J3 =-0.29 cm-1 for 1; J1 =+0.45, J2 =-0.68, and J3 =-0.29 cm-1 for 2; J1 =+0.03, J2 =-0.98, and J3 =-0.19 cm-1 for 3; J1 =+4.15, J2 =-0.23, and J3 =-0.54 cm-1 for 4 and J1 =+0.15, J2 =-0.28, and J3 =-1.18 cm-1 for 5). Our calculations reveal the presence of very large mixed toroidal moment in complex 1 and this is essentially due to the specific exchange topology present in this cluster. Our calculations also suggest presence of single molecule toroics (SMTs) in complex 2. For complexes 3-5 on the other hand, the transverse anisotropy was computed to be large, leading to the absence of slow relaxation of magnetization. As the magnetic field produced by SMTs decays faster than the normal spin moments, the concept of SMTs can be exploited to build qubits in which less interference and dense packing are possible. Our systematic study on these series of Ln4 complexes suggest how the ligand design can help to bring forth such SMT characteristics in lanthanide complexes. PMID- 27943507 TI - Different Products of the Reduction of (N),C,N-Chelated Antimony(III) Compounds: Competitive Formation of Monomeric Stibinidenes versus 1H-2,1-Benzazastiboles. AB - The reduction of N,C,N-chelated antimony(III) chlorides [C6 H3 -2,6-(CH=NR)2 ]SbCl2 (R=Ph (1), tBu (2), Dip (3); Dip=2,6-iPr2 C6 H3 ) with an appropriate amount of KC8 or Li[AlH4 ] resulted in the formation of rare examples of monomeric stibinidenes [C6 H3 -2,6-(CH=NR)2 ]Sb (R=Ph (4), tBu (5), Dip (6)). Similarly, the reduction of compounds 1 or 2 by two equivalents of K[B(sBu)3 H] led to the stibinidenes 4 and 5. In contrast, the analogous reaction of compound 3 resulted in the formation of an unprecedented stibinidene [C6 H3 -2-(CH=NR)-6 (CH2 NHR)]Sb (7) (R=Dip), in which the hydrogen atoms that come from the K[B(sBu)3 H] are incorporated into the ligand backbone. To gain further insight into this intriguing reactivity with K[B(sBu)3 H] and to assess the influence of the substitution at both the antimony atom and pendant substituents, we prepared compounds [C6 H3 -2-(CH=NDip)]Sb(Ph)Cl (8) and [C6 H2 -2-(CH=NDip)-4,6-(tBu)2 ]SbCl2 (9). The treatment of compound 8 with K[B(sBu)3 H] smoothly led to the 1 Ph-2-Dip-1H-2,1-benzazastibole (11), whereas the reaction of compound 9 with K[B(sBu)3 H] resulted in either tBu-substituted 1-Cl-2-Dip-1H-2,1-benzazastibole (13) or the formation of unprecedented Sb-Sb dimer bis(2-Dip-1H-2,1 benzazastibole) (12) depending on the reaction stoichiometry. The miscellaneous reactivity of antimony(III) precursors with reducing agents together with the structure and bonding of the resulting products has also been investigated from a theoretical point of view. PMID- 27943508 TI - Hepatogenous diabetes: Is it time to separate it from type 2 diabetes? AB - By definition, hepatogenous diabetes is directly caused by loss of liver function, implying that it develops after cirrhosis onset. Therefore, it should be distinguished from type 2 diabetes developing before cirrhosis onset, in which specific causes of liver disease play a major role, in addition to traditional risk factors. Currently, although hepatogenous diabetes shows distinct pathophysiological and clinical features, it is not considered as an autonomous entity. Recent evidence suggests that the failing liver exerts an independent "toxic" effect on pancreatic islets resulting in beta-cell dysfunction. Moreover, patients with hepatogenous diabetes usually present with normal fasting glucose and haemoglobin A1c levels and abnormal response to an oral glucose tolerance test, which is therefore required for diagnosis. This article discusses the need to separate hepatogenous diabetes from type 2 diabetes occurring in subjects with chronic liver disease and to identify individuals suffering from this condition for prognostic and therapeutic purposes. PMID- 27943509 TI - Mushroom poisoning: an overlooked cause of acute liver injury in China. PMID- 27943510 TI - Low dose prophylaxis in Tunisian children with haemophilia. AB - INTRODUCTION: Low dose prophylaxis could be recommended in countries with limited resources. AIM: We report our single centre experience in children with haemophilia. PATIENTS: Fifty-five children were included in our study with a weekly median dose of 30 UI kg-1 given once, twice or thrice a week. Age of initiation of prophylaxis is 5.32 years (0.64-11.44). Outcome assessment used were number of bleeding before and after initiating prophylaxis, haemophilia joint health score (HJHS), functional independence score in haemophilia (FISH) and quality of life with the Haemo-QoL. RESULTS: Reduction of number of bleeding was clear in all patients; HJHS, FISH and Haemo-QOL were satisfactory. CONCLUSION: Low dose prophylaxis is effective and better than on-demand therapy. It should be the starting point for prophylaxis in countries with limited resources. PMID- 27943511 TI - How do text-messaging smoking cessation interventions confer benefit? A multiple mediation analysis of Text2Quit. AB - AIMS: To determine the degree to which the observed benefit of Text2Quit was accounted for by psychosocial mechanisms derived from its quit smoking messaging versus from the use of extra-programmatic smoking cessation treatments and services. DESIGN: Prospective, multiple mediation model of a randomized controlled trial (RCT). SETTING: United States nation-wide. PARTICIPANTS: A total of 409 adult daily smokers participated. Participants were, on average, 35 years of age, predominantly female (68%), white (79%), lacked a college degree (70%), had medium nicotine dependence (average Fagerstrom Nicotine Dependence Score score of 5.2) and more than half (62%) had made a previous quit attempt. INTERVENTION: Adult daily smokers browsing the web for smoking cessation support (n = 409; recruited 19 May2011-10 July 2012) were randomized to receive smoking cessation support via Text2Quit versus a smoking cessation material. MEASUREMENTS: Mediators (i.e. changes in psychosocial constructs of health behavior change, use of extra-programmatic treatment) were assessed at 1 month using single-item measures and outcome (i.e. self-reported 7-day point prevalence abstinence) at 6-month follow-up. FINDINGS: Mediators accounted for 35% of the effect of Text2Quit on smoking cessation. Only psychosocial mechanisms had complete mediational paths, with increases in self-efficacy [b = 0.10 (0.06 0.15)], quitting know-how [b = 0.07 (0.03-0.11)] and the sense that someone cared [b = 0.06 (0.01-0.11)], partially explaining the conferred benefit of Text2Quit. Use of outside resources, including treatments promoted explicitly by Text2Quit, i.e. medication [b = 0.001 (-0.01 to 0.01), quitline [b = -0.002 (-0.01 to 0.04)], treatments and resources not promoted by Text2Quit, i.e. online forums [b = 0.01 (-0.01 to 0.04)] and self-help materials [b = -0.01 (-0.04 to 0.02)], did not have complete mediational paths. An interaction effect existed for medication use that suggested that for participants not using medication, Text2Quit conferred substantial benefit, but not for participants using medication. CONCLUSIONS: Text-messaging programs for smoking cessation appear primarily to confer benefit by promoting improvements in the psychosocial processes related to quitting rather than through the use of extra-programmatic smoking cessation treatments and services. PMID- 27943512 TI - Trajectories of quality of life, life satisfaction, and psychological adjustment after prostate cancer. AB - BACKGROUND: To describe trajectories of health-related quality of life (QoL), life satisfaction, and psychological adjustment for men with prostate cancer over the medium to long term and identify predictors of poorer outcomes using growth mixture models. METHODS: One-thousand sixty-four (82.4% response) men diagnosed with prostate cancer were recruited close to diagnosis and assessed over a 72 month (6-year) period with self-report assessment of health-related QoL, life satisfaction, cancer-related distress, and prostate specific antigen anxiety. Urinary, bowel, and sexual function were also assessed using validated questionnaires. RESULTS: Poorer physical QOL was predicted by older age, lower education, lower income, comorbidities, and receiving hormone therapy. Lower life satisfaction was related to younger age, lower income, not being partnered, and comorbidities. Poorer psychological trajectories were predicted by younger age, lower income, comorbidities, and receiving radical prostatectomy or brachytherapy. Better urinary, bowel, and sexual function were related to better global outcomes over time. Anxiety about prostate specific antigen testing was rare. CONCLUSIONS: Distinct trajectories exist for medium- to long-term QoL, life satisfaction, and psychological adjustment after prostate cancer; with age and socioeconomic deprivation playing a differential role in men's survivorship profile and the impact of functional status on outcomes increasing over time. These results reinforce the need for an appraisal of men's life course in addition to treatment side effects when planning survivorship care after cancer. PMID- 27943513 TI - Endoscopic monopolar coagulation of internal haemorrhoids: a surgeon's experience of the first 100 cases. AB - AIM: The purpose of this study was to evaluate one surgeon's initial experience with a novel technique of retroflexed endoscopic coagulation of internal haemorrhoids. METHOD: Patients who presented with symptoms and signs indicating Grade II-III haemorrhoids were counselled before the procedure. Those who were assessed to require an examination of their colon, based on their age and symptoms, underwent a full colonoscopy before treatment of the haemorrhoids. After the procedure, patients were routinely prescribed nonsteroidal anti inflammatory drugs, antibiotics and laxatives. RESULTS: The first 100 patients of median age 52.0 (20.8-78.5) years included 65 (65%) women. Five (5%) patients suffered from postprocedural complications, of which three (3%) were postprocedural bleeding and two (2%) were postprocedural pain, all treated conservatively. The recurrence rate was 6% at a median follow-up time of 36 (6 76) months. The median duration of follow-up was 36.5 (8.5-57.0) months. CONCLUSION: This novel technique appears to be safe and effective for the treatment of Grade II-III internal haemorrhoids, and can be incorporated seamlessly into the end of a colonoscopy for the evaluation of haematochezia. Comparative trials should be performed. PMID- 27943514 TI - Living donor risk model for predicting kidney allograft and patient survival in an emerging economy. AB - AIM: Living donor kidney is the main source of donor organs in low to middle income countries. We aimed to develop a living donor risk model that predicts graft and patient survival in an emerging economy. METHODS: We used data from the Sindh Institute of Urology and Transplantation (SIUT) database (n = 2283 recipients and n = 2283 living kidney donors, transplanted between 1993 and 2009) and conducted Cox proportional hazard analyses to develop a composite score that predicts graft and patient survivals. RESULTS: Donor factors age, creatinine clearance, nephron dose (estimated by donor/recipient body weight ratio) and human leukocyte antigen (HLA) match were included in the living donor risk model. The adjusted hazard ratios (HRs) for graft failures among those who received a kidney with living donor scores (reference to donor score of zero) of 1, 2, 3 and 4 were 1.14 (95%CI: 0.94-1.39), 1.24 (95%CI:1.03-1.49), 1.25 (95%CI:1.03-1.51) and 1.36 (95%CI:1.08-1.72) (P-value for trend =0.05). Similar findings were observed for patient survival. CONCLUSIONS: Similar to findings in high income countries, our study suggests that donor characteristics such as age, nephron dose, creatinine clearance and HLA match are important factors that determine the long-term patient and graft survival in low income countries. However, other crucial but undefined factors may play a role in determining the overall risk of graft failure and mortality in living kidney donor transplant recipients. PMID- 27943515 TI - Agricultural soil denitrifiers possess extensive nitrite reductase gene diversity. AB - Denitrification transforms nitrogen applied as fertilizer and emits N2 O, which is a potent greenhouse gas. Very little is known about the identities of abundant and active denitrifiers in agricultural soils. We coupled DNA stable-isotope probing (DNA-SIP) with flow-through reactors (FTRs) to detect active agricultural soil denitrifiers. The FTRs were incubated with nitrate and 13 C6 -glucose under anoxic conditions and sampled at multiple time points. Labelled DNA from active microorganisms was analyzed by 16S rRNA gene fingerprinting, amplicon and shotgun metagenomic sequencing. Taxonomic representation of heavy fractions was consistent across sites and time points, including Betaproteobacteria (71%; Janthinobacterium, Acidovorax, Azoarcus and Dechloromonas), Alphaproteobacteria (8%; Rhizobium), Gammaproteobacteria (4%; Pseudomonas) and Actinobacteria (4%; Streptomycetaceae). Most nitrite-reductase reads from heavy DNA annotated to the copper-containing form (nirK). Assigned taxonomies of active denitrifiers based on reads matching the nirK gene were comparable to those obtained through nitric oxide (norB) and RNA polymerase (rpoB) annotations but not the nitrous oxide reductase gene (nosZ). Analysis of recovered metagenomes from heavy DNA demonstrated extensive nirK sequence family diversity, including novel taxonomic groups that are not captured by existing primers. PMID- 27943517 TI - Twenty-Five Years of Health Economics: A Tribute to Alan Maynard and Acknowledgement of the Work of the Editorial Board. PMID- 27943516 TI - Adaptive smoothing based on Gaussian processes regression increases the sensitivity and specificity of fMRI data. AB - Temporal and spatial filtering of fMRI data is often used to improve statistical power. However, conventional methods, such as smoothing with fixed-width Gaussian filters, remove fine-scale structure in the data, necessitating a tradeoff between sensitivity and specificity. Specifically, smoothing may increase sensitivity (reduce noise and increase statistical power) but at the cost loss of specificity in that fine-scale structure in neural activity patterns is lost. Here, we propose an alternative smoothing method based on Gaussian processes (GP) regression for single subjects fMRI experiments. This method adapts the level of smoothing on a voxel by voxel basis according to the characteristics of the local neural activity patterns. GP-based fMRI analysis has been heretofore impractical owing to computational demands. Here, we demonstrate a new implementation of GP that makes it possible to handle the massive data dimensionality of the typical fMRI experiment. We demonstrate how GP can be used as a drop-in replacement to conventional preprocessing steps for temporal and spatial smoothing in a standard fMRI pipeline. We present simulated and experimental results that show the increased sensitivity and specificity compared to conventional smoothing strategies. Hum Brain Mapp 38:1438-1459, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27943519 TI - Rare Adnexal Tumor of the Breast: Poroid Hidradenoma. PMID- 27943520 TI - Evaluation of anatomical and functional results of overlapping anal sphincter repair with or without the injection of bone marrow aspirate concentrate: a case control study. AB - AIM: Overlapping anal sphincter repair (OASR) is used for treatment of faecal incontinence due to an external anal sphincter (EAS) defect; however, it is not the optimal treatment as its functional results tend to deteriorate significantly with time. The present study aimed to evaluate the effect of local injection of bone marrow aspirate concentrate (BMAC) on the outcome of OASR. METHOD: We compared a prospective group of 20 patients with EAS defect who were managed with OASR and BMAC injection (group I) with a historical control group of an equal number of patients managed with OASR alone (group II). Patients were assessed preoperatively and during follow-up by the Wexner continence score and endoanal ultrasound. The primary end-points were the improvement of the continence level measured by the Wexner score and the residual EAS defect size measured by endoanal ultrasound. RESULTS: At the end of follow-up, group I had significantly lower mean postoperative Wexner score (5.4 +/- 7.6 vs 10.6 +/- 7.4; P = 0.03) and smaller EAS defect percentage (12.2 +/- 17.5 vs 18.3 +/- 18.9). These findings were statistically significant in patients with a small preoperative EAS defect equal to or less than one-third of the anal circumference. Patients with larger preoperative EAS did not show a significant improvement of the continence level after repair in either group. CONCLUSION: Augmenting OASR with local injection of BMAC in patients with faecal incontinence caused by an EAS defect, particularly a smaller defect, can improve both functional and anatomical outcomes of OASR. PMID- 27943521 TI - Parent-implemented home therapy programmes for speech and language: a systematic review. AB - BACKGROUND: Parent-delivered home programmes are frequently used to remediate speech and language difficulties in young children. However, the evidence base for this service delivery model is limited. AIMS: The aim of this systematic review is to investigate the effectiveness of parent-implemented home programmes in facilitating the development of children's speech and language skills, and to evaluate the cost-effectiveness and feasibility of this service delivery method. METHODS & PROCEDURES: A systematic search of the PsycINFO, CINAHL and ERIC databases was conducted. Quality appraisal of individual studies was conducted. Findings from each of the studies were then integrated to report on outcomes for the child, the parent and the service. OUTCOMES & RESULTS: There is preliminary evidence that home programmes can lead to growth in a child's speech and language skills and are more effective than no intervention, provided the home programmes are used with high dosage rates and direct parent training. CONCLUSIONS & IMPLICATIONS: Home programmes are a potentially useful service delivery model, but caution should be exercised when considering their use to address broader service delivery challenges. Further high-level evidence is needed across all facets of this service delivery model. PMID- 27943522 TI - No benefit of ultrasound-guided transversus abdominis plane blocks over wound infiltration with local anaesthetic in elective laparoscopic colonic surgery: results of a double-blind randomized controlled trial. AB - AIM: Advances in laparoscopic techniques combined with enhanced recovery pathways have led to faster recuperation and discharge after colorectal surgery. Peripheral nerve blockade using transversus abdominis plane (TAP) blocks reduce opioid requirements and provide better analgesia for laparoscopic colectomies than do inactive controls. This double-blind randomized study was performed to compare TAP blocks using bupivacaine with standardized wound infiltration with local anaesthetic (LA). METHOD: Seventy-one patients were randomized to receive either TAP block or wound infiltration. The TAP blocks were performed by experienced anaesthetists who used ultrasound guidance to deliver 40 ml of 0.25% bupivacaine post-induction into the transverse abdominis plane. In the control group, 40 ml of 0.25% bupivacaine was injected around the trocar and the extraction site by the surgeon. Both groups received patient-controlled analgesia (PCA) with intravenous morphine. Patients and nursing staff assessed pain scores 6, 12, 24 and 48 h after surgery. The primary outcome was overall morphine use in the first 48 h. RESULTS: Of the 71 patients, 20 underwent a right hemicolectomy and 51 a high anterior resection. The modified intention-to-treat analysis showed no significant differences in overall morphine use [47.3 (36.2-58.5) mg vs 46.7 (36.2-57.3) mg; mean (95% CI), P = 0.8663] in the first 48 h. Pain scores were similar at 6, 12, 24 and 48 h. No differences were found regarding time to mobilization, resumption of diet and length of hospital stay. CONCLUSION: In elective laparoscopic colectomies, standardized wound infiltration with LA has the same analgesic effect as TAP blocks post-induction using bupivacaine at 48 h. PMID- 27943523 TI - Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus-infected patients with renal impairment. AB - AIM: Hepatitis C virus (HCV) infection is a risk factor for end-stage renal disease, renal graft failure, and hemodialysis patient mortality. However, the efficacy of direct-acting antiviral therapy for HCV-infected patients with renal impairment is unclear. Additionally, the promising NS5B inhibitor sofosbuvir has not been recommended for patients with severe renal impairment. In this prospective, multicenter study, we evaluated the efficacy and safety of daclatasvir and asunaprevir combination therapy, with a focus on patients with renal impairment. METHODS: The study included 322 genotype 1 HCV-infected patients who received daclatasvir and asunaprevir combination therapy. The safety and sustained virological response was examined at 12 weeks after the end of treatment and safety was evaluated according to renal function. RESULTS: Of 322 patients, 5% (16/322) and 2.5% (8/322) had chronic kidney disease stage G3b (estimated glomerular filtration rate [eGFR], 30-44 mL/min/1.73 m2 ) and stage G4/5 (eGFR, 15-29/<15 mL/min/1.73 m2 ), respectively. Baseline presence of the NS5A resistance-associated variant, previous simeprevir treatment, and HCV RNA titers, which were predictors of a sustained viral response, were similar between patients with eGFR <45 mL/min/1.73 m2 and eGFR >45 mL/min/1.73 m2 . Notably, the 12-week sustained viral response rate was comparable in patients with eGFR <45 mL/min/1.73 m2 (100%, 24/24) and those with eGFR >45 mL/min/1.73 m2 (88.9%, 265/298; P = 0.07). Treatment discontinuation rates and adverse events, including alanine aminotransferase elevation, anemia, and renal disorders, were similar between the two groups. CONCLUSION: Daclatasvir and asunaprevir combination therapy for patients with renal dysfunction was highly effective and safe. PMID- 27943524 TI - Hybrid Magnetoelectric Nanowires for Nanorobotic Applications: Fabrication, Magnetoelectric Coupling, and Magnetically Assisted In Vitro Targeted Drug Delivery. AB - An FeGa@P(VDF-TrFE) wire-shaped magnetoelectric nanorobot is designed and fabricated to demonstrate a proof-of-concept integrated device, which features wireless locomotion and on-site triggered therapeutics with a single external power source (i.e., a magnetic field). The device can be precisely steered toward a targeted location wirelessly by rotating magnetic fields and perform on-demand magnetoelectrically assisted drug release to kill cancer cells. PMID- 27943525 TI - The Relationships between HER2 Overexpression and DCIS Characteristics. AB - The aim of this study was to demonstrate the correlation between human epidermal growth factor receptor 2 (HER2) overexpression and some poor prognosis factors in patients affected by ductal carcinoma in situ (DCIS). We evaluated 48 cases of DCIS, divided into two groups according to HER2 amplification status. Nuclear grade and "cancerization of lobules" were determined within primary DCIS and Ki67, estrogen receptor (ER), PR, and HER2 expression was established using immunohistochemistry. The histopathological variables in HER2-positive and in HER2-negative patients were compared to determine the recurrence risk. We also considered the median age at the time of surgery according to HER2 status. There were 11 recurrences (23%), 6 DCIS (55%), and 5 invasive cancer (45%). In an 8 year-long median follow-up, we hypothesized high risk of recurrence in HER2 positive DCIS. Patients with HER2-positive DCIS were younger than HER2-negative ones (p = 0.002). HER2-positive DCIS was also related to histopathological predictors of recurrence such as high nuclear grade (p < 0.001), high Ki67 expression (p = 0.003), low ER and PgR levels (p < 0.001), and the presence of "cancerization of lobules" (p < 0.049). Our trial suggests that HER2 amplification in primary DCIS is identified more frequently in younger patients and hypothesizes high risk of recurrence in HER2-positive DCIS related to histopathological predictors of overall relapse as high nuclear grade, high Ki67 expression, low ER and PgR levels, and the presence of "cancerization of lobules." In HER2-positive DCIS, other variables of recurrence risk are compared to HER2-negative lesions, without statistical significance. Our results show that HER2 testing might suggest clinicians the optimal treatment of patients with DCIS. PMID- 27943526 TI - Kingella kingae microbial keratitis in a human immunodeficiency virus patient with orthokeratology lens wear. PMID- 27943527 TI - Three-dimensional endoanal ultrasound is accurate and reproducible in determining type and height of anal fistulas. AB - AIM: Surgical treatment of high anal fistulas is associated with the potential risk of faecal incontinence and recurrence. The primary aim of this study was to determine the accuracy of three-dimensional endoanal ultrasound (3D-EAUS) in the assessment of height and type of anal fistulas, compared to the intra-operative findings (gold standard). The secondary aim was to evaluate the inter-observer reproducibility of 3D-EAUS. METHOD: The study design was a prospective analysis of retrospective data. 299 patients (202 men), mean age 45.3 years, who underwent surgery for anal fistulas, were included. All patients were preoperatively assessed by 3D-EAUS. Two readers independently reviewed the volumes to determine the type and height of fistulas. Sensitivity, specificity, positive and negative predictive values, proportion of agreements and Cohen's kappa coefficient (kappa) were calculated for both examiners. Ultrasound findings were compared with intra operative data (reference standard), evaluated blindly by the surgeons. RESULTS: At surgery, 201 (67%) were transsphincteric, 49 (16%) suprasphincteric, 47 (16%) intersphincteric and two (1%) extrasphincteric fistulas. Intra-operatively, 177 (59%) were low and 122 (41%) high fistulas. The overall accuracy of 3D-EAUS was 91% for fistula type (271/299 fistulas: 97% transsphincteric, 100% intersphincteric, 57% suprasphincteric, 0% extrasphincteric) and 92% for fistula height (275/299 fistulas: 80% high and 100% low). Both readers reported very good agreement with surgery in the assessment of fistula type (proportion of agreement 0.88, kappa = 0.89) and height (proportion of agreement 0.90, kappa = 0.91). CONCLUSIONS: 3D-EAUS is an accurate and reproducible modality for the assessment of type and height of anal fistulas. PMID- 27943528 TI - Erroneous data on renal hemodynamics derived from DCE-MRI in rats. PMID- 27943529 TI - Tobacco pollen tubes - a fast and easy tool for studying lipid droplet association of plant proteins. AB - In recent years, lipid droplets have emerged as dynamic organelles rather than inactive storage sites for triacylglycerol. The number of proteins known to be associated with lipid droplets has increased, but remains small in comparison with those found with other organelles. Also the mechanisms of how lipid droplets are recognized and bound by proteins need deeper investigation. Here, we present a fast, simple and inexpensive approach to assay proteins for their association with lipid droplets in vivo that can help to screen protein candidates or mutated variants of proteins for their association in an efficient manner. For this, a system to transiently transform Nicotiana tabacum pollen grains was used because these naturally contain lipid droplets. We designed vectors for fast cloning of genes as fusions with either mVenus or mCherry. This allowed us to assay colocalization with lipid droplets stained with Nile Red and Bodipy 505/515, respectively. We successfully tested our system not only for proteins from Arabidopsis thaliana, but also for proteins from the moss Physcomitrella patens and the alga Chlamydomonas reinhardtii. The small size of the vector used allows easy exchange of codons by site-directed mutagenesis. We used this to show that two proline residues in the proline knot of a caleosin are not essential for the binding of lipid droplets. We also demonstrated that peroxisomes are not associated with the lipid droplets in tobacco pollen tubes, which reduces the risk of false interpretation of microscopic data in our system. PMID- 27943530 TI - Reversible Bioconjugation: Biodegradable Poly(phosphate)-Protein Conjugates. AB - Protein-polymer conjugates are widely used to improve the pharmacokinetic properties of therapeutic proteins. Commercially available conjugates employ poly(ethylene glycol) (PEG) as the protective polymer; however, PEG has a number of shortcomings, including non-biodegradability and immunogenicity, that call for the development of alternatives. Here, the synthesis of biodegradable poly(phosphate), that is, poly(ethyl ethylene phosphate) (PEEP), by organo catalyzed anionic ring-opening polymerization exhibiting dispersity values D < 1.3 is reported. Polymers with molecular weights between 2000 and 33 200 g mol-1 are then omega-functionalized with a succinimidyl carbonate group and subsequently conjugated to model proteins. These are the first conjugates based on polyphosphates which degraded upon exposure to phosphodiesterase. As is the case for PEGylated therapeutics, residual in vitro activity of the PPEylated conjugates depends on the extent of protein modification. These results suggest that PEEP exhibits the desired properties of a biopolymer for use in next generation, fully degradable drug delivery systems. PMID- 27943531 TI - Identification of core subunits of photosystem II as action sites of HSP21, which is activated by the GUN5-mediated retrograde pathway in Arabidopsis. AB - Photosystem II (PSII) is the most thermolabile photosynthetic complex. Physiological evidence suggests that the small chloroplast heat-shock protein 21 (HSP21) is involved in plant thermotolerance, but the molecular mechanism of its action remains largely unknown. Here, we have provided genetic and biochemical evidence that HSP21 is activated by the GUN5-dependent retrograde signaling pathway, and stabilizes PSII by directly binding to its core subunits such as D1 and D2 proteins under heat stress. We further demonstrate that the constitutive expression of HSP21 sufficiently rescues the thermosensitive stability of PSII and survival defects of the gun5 mutant with dramatically improving granal stacking under heat stress, indicating that HSP21 is a key chaperone protein in maintaining the integrity of the thylakoid membrane system under heat stress. In line with our interpretation based on several lines of in vitro and in vivo protein-interaction evidence that HSP21 interacts with core subunits of PSII, the kinetics of HSP21 binding to the D1 and D2 proteins was determined by performing an analysis of microscale thermophoresis. Considering the major role of HSP21 in protecting the core subunits of PSII from thermal damage, its heat-responsive activation via the heat-shock transcription factor HsfA2 is critical for the survival of plants under heat stress. Our findings reveal an auto-adaptation loop pathway that plant cells optimize particular needs of chloroplasts in stabilizing photosynthetic complexes by relaying the GUN5-dependent plastid signal(s) to activate the heat-responsive expression of HSP21 in the nucleus during adaptation to heat stress in plants. PMID- 27943532 TI - "...the eyes of Vesalius and of Harvey might be dazzled by the sight of the tree that has grown out of their (Physick and Anatomy) grain of mustard seed." PMID- 27943534 TI - Biased Interpretation of Ambiguous Social Scenarios in Anorexia Nervosa. AB - Patients with anorexia nervosa experience increased sensitivity to the risk of social rejection. The aims of this study were to assess the interpretation of ambiguous social scenarios depicting the risk of rejection and to examine the relationship between interpretation biases and clinical symptoms. Thirty-five women with anorexia nervosa and 30 healthy eaters completed clinical questionnaires, alongside a sentence completion task. This task required participants to generate completions to ambiguous social scenarios and to endorse their best completion. Responses were rated as being negative, neutral or positive. Patients endorsed more negative interpretations and fewer neutral and positive interpretations compared with healthy eaters. The frequency of endorsed negative interpretations correlated with depression, anxiety and fear of weight gain and body disturbance. A negative interpretation bias towards social stimuli is present in women with anorexia nervosa and correlates with clinical symptoms. Interventions aimed at reducing this bias could improve illness prognosis. Copyright (c) 2016 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 27943533 TI - Expressed Emotions and Depressive Symptoms in Caregivers of Adolescents with First-Onset Anorexia Nervosa-A Long-Term Investigation over 2.5 Years. AB - OBJECTIVE: High levels of expressed emotions (EE) and depressive symptoms (DS) are often found in caregivers of patients with anorexia nervosa (AN). Both parameters are considered to influence AN symptoms of the patient. METHODS: One hundred seventy adolescent women with AN and their caregivers were assessed at admission, discharge, at 1-year and 2.5-year follow up to evaluate AN symptoms of the patient and EE and DS of caregivers. RESULTS: The EE and DS were elevated at admission and decreased during treatment, criticism (as part of EE) exhibited again at the 2.5-year follow up. Caregivers of more severely ill patients reported significantly greater levels of EE and DS. Mothers were more affected than fathers. EE and DS were interrelated. CONCLUSION: Caregivers of adolescent AN patients suffer from elevated levels of EE and DS. Further studies are needed to examine whether therapeutic interventions to reduce caregivers' EE and DS might have a positive influence on treatment outcome. Copyright (c) 2016 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 27943536 TI - Characterization of polyaniline-coated stationary phases by using the linear solvation energy relationship in the hydrophilic interaction liquid chromatography mode using capillary liquid chromatography. AB - A polyaniline coating was used to modify the surface of bare silica gel and octadecyl silica stationary phases to characterize the properties of altered materials. It was assumed that the mixed-mode retention was established on the basis of the polyaniline chemical structure and its combination with the original sorbents. Polyaniline was deposited onto the original surfaces during the chemical polymerization of aniline hydrochloride. The prepared materials were slurry packed into capillary columns and systematic chromatographic characterization was performed using the linear solvation energy relationship, also employing descriptors that allow inclusion of ionic interactions in the proposed retention mechanism. The retention times of 80 solutes with various chemical structures were measured in the hydrophilic interaction liquid chromatography mode. The obtained results demonstrated the significant contribution of the polyaniline coating to the retention mechanism under the given conditions; the assumed mixed-mode retention was confirmed. The dominant retention interaction for both modified stationary phases was based on the protonation of nitrogen atoms in the polyaniline structure, leading to suitable retention and selectivity for the hydrophilic analytes, especially anionic and zwitterionic species. Thus, especially, the polyaniline-coated bare silica gel sorbent seems to be promising for potential applications related to the separation of polar compounds. PMID- 27943535 TI - The expression of Longus type 4 pilus of enterotoxigenic Escherichia coli is regulated by LngR and LngS and by H-NS, CpxR and CRP global regulators. AB - Enterotoxigenic Escherichia coli produces a long type 4 pilus called Longus. The regulatory elements and the environmental signals controlling the expression of Longus-encoding genes are unknown. We identified two genes lngR and lngS in the Longus operon, whose predicted products share homology with transcriptional regulators. Isogenic lngR and lngS mutants were considerably affected in transcription of lngA pilin gene. The expression of lngA, lngR and lngS genes was optimally expressed at 37 degrees C at pH 7.5. The presence of glucose and sodium chloride had a positive effect on Longus expression. The presence of divalent ions, particularly calcium, appears to be an important stimulus for Longus production. In addition, we studied H-NS, CpxR and CRP global regulators, on Longus expression. The response regulator CpxR appears to function as a positive regulator of lng genes as the cpxR mutant showed reduced levels of lngRSA expression. In contrast, H-NS and CRP function as negative regulators since expression of lngA was up-regulated in isogenic hns and crp mutants. H-NS and CRP were required for salt- and glucose-mediated regulation of Longus. Our data suggest the existence of a complex regulatory network controlling Longus expression, involving both local and global regulators in response to different environmental signals. PMID- 27943537 TI - Interdisciplinary approach to education: preparing general dentists to manage dental trauma. AB - The traditional dental curriculum presents limited opportunities for students to evaluate and treat patients with acute dental trauma. In an effort to increase student experiences, faculty at a dental school initiated and taught an interdisciplinary trauma course from 2014 to 2016. This course was elective, offered in the final year of dental school, and combined student-led and faculty led case-based discussions of management of traumatic dental injuries with hospital trauma call shadowing. Modifications of the course were made based on student feedback. Preliminary data from student surveys showed a favorable opinion of the course. Attendees were exposed to a higher number of acute traumatic injuries and they expressed greater confidence in their diagnosis and management abilities than their peers. PMID- 27943539 TI - Gene Variant Databases and Sharing: Creating a Global Genomic Variant Database for Personalized Medicine. PMID- 27943538 TI - Catheter Ablation for Atrial Fibrillation in Patients With Watchman Left Atrial Appendage Occlusion Device: Results from a Multicenter Registry. AB - BACKGROUND: There have been an increasing number of atrial fibrillation (AF) patients with Watchman left atrial appendage occlusion (LAAO) device, requiring catheter ablation (CA) for maintenance of normal sinus rhythm. In this study, we describe our experience with the feasibility and safety of CA in patients with a preexisting Watchman LAAO device. METHODS: This was a retrospective multicenter AF registry of 60 patients with Watchman LAAO device who underwent CA for AF. Baseline clinical and procedural characteristics of the included subjects were retrieved from review of medical records and were analyzed. RESULTS: The mean age was 72.7 +/- 4.9 years and the mean CHADS2 score was 2.3 +/- 0.6. All patients had successful pulmonary vein isolation (PVI). The left atrial appendage (LAA) was electrically active in 34 (56%) while reentrant tachycardia and AF triggers were seen in 17 (28%) patients. Electrical isolation was attempted in these 17 patients with only 10 achieving complete LAA isolation. Repeat imaging showed new peri-device leaks in 30% (12/40) patients, while new significant peri-device leaks (>=5 mm) were noted in 10% (10/40) of patients after RFA, respectively, requiring continuation of oral anticoagulation. There were a higher proportion of patients with severe peri-device leaks (>=5 mm) after LAA isolation. However, >50% of those leaks sealed off on follow-up transesophageal echocardiogram. CONCLUSION: AF ablation is a feasible and safe in patients with preexisting Watchman LAAO device. Electrical isolation of the LAA could be difficult and when attempted can result in increased risk of short-term peri-device leak and recurrence of AT/AF in almost all patients. PMID- 27943540 TI - Are Functional Assays for Pathogenicity Assessment of Genetic Variants Overrated? PMID- 27943541 TI - P-selectin can promote thrombus propagation independently of both von Willebrand factor and thrombospondin-1 in mice. AB - : Essentials The main receptor for platelet glycoprotein (GP) Ibalpha is von Willebrand factor (VWF). P-selectin and thrombospondin-1 (TSP1) have been suggested as counter receptors for GPIbalpha. In a laser injury model, P-selectin promotes thrombus propagation independently of VWF and TSP1. In a laser injury model, thrombus persists in interleukin-4 receptor alpha/GPIbalpha-transgenic mice. SUMMARY: Background P-selectin and thrombospondin-1 (TSP1) have been suggested as counter ligands that may mediate GPIbalpha-dependent thrombus growth independently of von Willebrand factor (VWF) in vitro. However, residual thrombus formation still persists in Vwf -/- Tsp1-/- mice, suggesting existence of other mechanisms that modulate thrombus propagation. Objective We determined whether P selectin modulates thrombus propagation in injured arterioles independently of TSP1 and VWF. Methods CD-62P blocking antibody in Vwf -/- Tsp1-/- mice was used to inhibit P-selectin. We determined thrombus growth kinetics in two models of thrombosis: FeCl3 injury-induced and laser injury-induced thrombosis. Results In a 10% FeCl3 injury-induced thrombosis model, the initial platelet adhesion, time to form first thrombus, and non-occlusive residual thrombus growth kinetics were comparable between P-selectin-blocking antibody-treated Vwf -/- Tsp1-/- mice and control IgG-treated Vwf -/- Tsp1-/- mice. On the other hand, in a laser injury induced thrombosis model, residual thrombus growth kinetics were significantly decreased in P-selectin-blocking antibody-treated Vwf -/- Tsp1-/- mice vs. control IgG-treated Vwf -/- Tsp1-/- mice. Because P-selectin has been suggested as a counter ligand for platelet GPIbalpha, we determined the role of GPIbalpha in a laser injury-induced thrombosis model. Surprisingly, in a laser injury model, unlike in a FeCl3 injury model, thrombus formation was not completely inhibited in IL4Ralpha/GPIbalpha-tg mice. Residual thrombus growth kinetics were comparable between P-selectin-blocking antibody-treated IL4Ralpha/GPIbalpha-tg mice and control IgG-treated IL4Ralpha/GPIbalpha-tg mice. Comparison of slopes over time showed that residual thrombus growth kinetics were comparable in P selectin-blocking antibody-treated Vwf -/- Tsp1-/- and control IgG-treated IL4Ralpha/GPIbalpha-tg mice Conclusion In a laser injury-induced thrombosis model, P-selectin modulates thrombus propagation independently of VWF and TSP1. PMID- 27943543 TI - Plasmon-Enhanced Photoelectrical Hydrogen Evolution on Monolayer MoS2 Decorated Cu1.75 S-Au Nanocrystals. AB - Hydrogen production from water splitting through an efficient photoelectrochemical route requires photoinduced electron transfer from light harvesters to efficient electrocatalysts. Here, the plasmon-enhanced photoelectrical nanocatalysts (NCs) have been successfully developed by coating a monolayer MoS2 on the Cu1.75 S-Au hetero-nanoparticle for hydrogen evolution reaction (HER). The plasmonic NCs dramatically improve the HER, leading to 29.5 fold increase of current under 650 nm excitation (1.0 W cm-2 ). These NCs generate an exceptionally high current density of 200 mA cm-2 at overpotential of 182.8 mV with a Tafel slope of 39 mV per decade and excellent stability, which is better than or comparable to the Pt-free catalysts with carbon rod as counter electrode. The enhanced HER performance can be attributed to the significantly improved broad light absorption (400-3000 nm), more efficient charge separation and abundant active edge sites of monolayer MoS2 . The studies may provide a facile strategy for the fabrication of efficient plasmon-enhanced photoelectrical NCs for HER. PMID- 27943542 TI - HBV/HCV co-infection is associated with a high level of HCV spontaneous clearance among drug users and blood donors in China. AB - Understanding the biology of spontaneous clearance of hepatitis C virus (HCV) infection could lead to improved strategies to prevent the sequelae associated with chronic HCV infection. Chronic infections with hepatitis virus are very common in China, but the factors associated with spontaneous clearance of HCV have not been adequately studied. We evaluated the spontaneous clearance of HCV among 1918 drug users and 1526 HCV-seropositive blood donors in Guangzhou, China. Among participants who were co-infected with hepatitis B virus (HBV), 41.38% of drug users and 39.47% of blood donors had cleared their HCV infection without antiviral therapy compared to 9.41% of drug users and 16.73% of blood donors who were mono-infected with a single virus (P<.01). The proportion of subjects who had cleared their HCV infection was significantly greater in the co-infected subjects whose serum HBV DNA was greater than 2000IU/mL than those with lower levels. A multiple logistic regression analysis found female gender, IL28B rs8099917 TT genotype, HBV co-infection and blood donors (vs drug users) associated with increased spontaneous clearance of HCV infection. Although acute HCV infections are common in China, the incidence of chronic HCV may be reduced among the high prevalence of chronic HBV and IL28B genotypes associated with spontaneous clearance of HCV in Chinese populations. PMID- 27943544 TI - Treatment of hepatitis C virus recurrence after transplantation with sofosbuvir/ledipasvir: The role of ribavirin. AB - BACKGROUND: Hepatitis C virus (HCV) recurrence after liver transplantation (LT) used to be a serious problem in the era of interferon-based treatment. Since the introduction of modern directly acting antivirals, treatment has become easier and shorter. According to published data, in the natural course of hepatitis C infection the duration of antiviral treatment with sofosbuvir (SOF) and ledipasvir (LDV) may be shortened to 12 instead of 24 weeks, using ribavirin (RBV) in addition. Furthermore, the question of whether or not RBV is really necessary, in a 12-week SOF/LDV treatment in the post-transplant setting, is still unanswered. PATIENTS AND METHODS: At our institution, 100 liver transplant patients with HCV recurrence underwent interferon-free SOF-based treatment. A total of 51 patients received SOF/LDV with or without RBV. Twenty-nine HCV genotype 1 or 4 patients with histologically proven stage 0-2 fibrosis were treated with SOF/LDV for 12 weeks; another 22 patients with advanced fibrosis (stage 3-4) either received SOF/LDV plus weight-adjusted RBV or prolonged treatment for 24 weeks. RESULTS: End of treatment response and sustained virological response (SVR) were achieved in 100% of the 51 patients, irrespective of the treatment group. Patients with prolonged treatment duration or with RBV developed significantly more adverse events (AEs) compared to the SOF/LDV group: 19 (86.4%) vs 8 (27.6%), P<.001. One of the predominant and most relevant AEs was the development of anemia in 43.1% of 10 patients receiving RBV, which was a significant result (P<.001). RBV co-medication had to be reduced in 11 (55%) patients and then stopped in 8 (40%) patients because of AEs. No significant difference was observed among the groups regarding kidney function. CONCLUSION: The SOF/LDV combination is a reliable therapy of recurrent HCV infection after LT. It is easy to administer and to achieve SVR in immunocompromised patients without interactions with immunosuppressive medications. Considering the high rate of AEs, frequent discontinuation of RBV treatment, and the 100% SVR, the use of RBV as co-medication in a 12-week SOF/LDV regimen does not seem to be justified after LT. PMID- 27943545 TI - Exploratory scoping of the literature on factors that influence oral health workforce planning and management in developing countries. AB - OBJECTIVES: The purpose of this study was to scope the literature that exists about factors influencing oral health workforce planning and management in developing countries (DCs). METHODS: The Arksey and O'Malley method for conducting a scoping review was used. A replicable search strategy was applied, using three databases. Factors influencing oral health workforce planning and management in DCs identified in the eligible articles were charted. FINDINGS: Four thousand citations were identified; 41 papers were included for review. Most included papers were situational analyses. Factors identified were as follows: lack of data, focus on the restorative rather than preventive care in practitioner education, recent increase in number of dental schools (mostly private) and dentistry students, privatization of dental care services which has little impact on care maldistribution, and debates about skill mix and scope of practice. Oral health workforce management in the eligible studies has a bias towards dentist-led systems. Due to a lack of country-specific oral health related data in developing or least developed countries (LDCs), oral health workforce planning often relies on data and modelling from other countries. DISCUSSION AND CONCLUSION: Approaches to oral health workforce management and planning in developing or LDCs are often characterized by approaches to increase numbers of dentists, thus not ameliorating maldistribution of service accessibility. Governments appear to be reducing support for public and preventative oral healthcare, favouring growth in privatized dental services. Changes to professional education are necessary to trigger a paradigm shift to the preventive approach and to improve relationships between different oral healthcare provider roles. This needs to be premised on greater appreciation of preventive care in health systems and funding models. PMID- 27943548 TI - Use of mycophenolate mofetil to treat immune-mediated skin disease in 14 dogs - a retrospective evaluation. AB - BACKGROUND: Mycophenolate mofetil (MMF) is a lymphocytotoxic immunosuppressive agent used in human and companion animal medicine for the treatment of immune mediated disease. Mycophenolate mofetil is reported to have reduced myelotoxicity and hepatotoxicity when compared to azathioprine. OBJECTIVES: It was hypothesized that treatment with MMF as a secondary agent with glucocorticoids would be effective in treating immune-mediated skin disease. In addition, adverse effects associated with the drug are reported. ANIMALS: Fourteen dogs from a hospital population diagnosed with immune-mediated skin disease. METHODS: A retrospective review of medical records from 2010 to 2015 was used to identify dogs with immune mediated skin disease that were treated with MMF. RESULTS: All dogs were treated with MMF (mean dose 14.7 mg/kg twice daily) in conjunction with glucocorticoids. Ten of 14 cases showed positive results, with complete remission in eight cases and partial remission in two cases. Mean time to remission was 5.7 weeks. Therapy was discontinued in one case (perianal fistula) due to lack of response. Adverse events were noted in six cases and included diarrhoea (n = 6), haematochezia (n = 2), vomiting (n = 3) and papilloma formation (n = 1). Therapy was discontinued in two cases with diarrhoea. Mycophenolate mofetil was discontinued in an additional case because of a diagnosis of neoplasia. All other adverse events were self limiting or easily medically managed. No hepatotoxicity or bone marrow suppression was noted. CONCLUSION: This study supports the use of MMF as a second line immunotherapeutic in immune-mediated skin disease in dogs. PMID- 27943546 TI - Effect of race and ethnicity on vildagliptin efficacy: A pooled analysis of phase II and III studies. AB - AIMS: To determine the impact of race and ethnicity on the efficacy, body weight and hypoglycaemia incidence with vildagliptin treatment in patients with type 2 diabetes mellitus using patient-level data from the vildagliptin clinical trial programme. METHODS: Data from 22 randomized, placebo-controlled global and local (Japan, China) registration studies of vildagliptin (50 mg once-daily or twice daily) of >=12-week duration were analysed by race (Caucasian [n = 2764] and Asian [n = 2232]) and by ethnicity (Japanese, Chinese, and Indian). The placebo subtracted differences in the change in glycated haemoglobin (HbA1c) and body weight from baseline to week 12 or week 24 were evaluated by race or ethnicity using repeated measure analysis of unstructured covariance. Hypoglycaemia incidences were summarized using descriptive statistics. RESULTS: The HbA1c reduction from baseline with vildagliptin was similar across the racial/ethnic subgroups (-0.83% +/- 0.02% to -1.01% +/- 0.05%). Placebo-corrected HbA1c reduction was similar between Caucasian (-0.68% +/- 0.03%) and Asian (-0.80% +/- 0.03%) patients ( P value for interaction = .56); analysis by race and ethnicity showed better efficacy ( P < .02) in Japanese patients. Japanese patients were drug-naive and treated with a single oral anti-diabetes drug only; they showed no response to placebo. Weight neutrality of vildagliptin was demonstrated in all groups (0.47 +/- 0.11 kg to -0.29 +/- 0.08 kg). Hypoglycaemic events (>=1) were infrequent in all ethnic subgroups. CONCLUSIONS: The glycaemic efficacy of vildagliptin was similar in Caucasian and Asian patients. The slightly better efficacy observed in Japanese patients was driven by the absence of placebo effect and might be explained by their earlier stage of diabetes compared to other subgroups. PMID- 27943547 TI - Abdominal rectopexy for the treatment of internal rectal prolapse: a systematic review and meta-analysis. AB - AIM: Internal rectal prolapse (IRP) is a unique functional disorder that presents with a wide spectrum of clinical symptoms, including constipation and/or faecal incontinence (FI). The present review aims to analyse the results of trials evaluating the role of abdominal rectopexy in the treatment of IRP with regard to regarding functional and technical outcomes. METHOD: A systematic review of the literature for the role of abdominal rectopexy in patients with IRP was conducted. PubMed/Medline, Embase and the Cochrane Central Register of Controlled Trials were searched for published and unpublished studies from January 2000 to December 2015. RESULTS: We reviewed 14 studies including 1301 patients (1180 women) of a median age of 59 years. The weighted mean rates of improvement of obstructed defaecation (OD) and FI across the studies were 73.9% and 60.2%, respectively. Twelve studies reported clinical recurrence in 84 (6.9%) patients. The weighted mean recurrence rate of IRP among the studies was 5.8% (95% CI: 4.2 7.5). Two hundred and thirty complications were reported with a weighted mean complication rate of 15%. Resection rectopexy had lower recurrence rates than did ventral rectopexy, whereas ventral rectopexy achieved better symptomatic improvement, a shorter operative time and a lower complication rate. CONCLUSION: Abdominal rectopexy for IRP attained satisfactory results with improvement of OD and, to a lesser extent, FI, a low incidence of recurrence and an acceptable morbidity rate. Although ventral rectopexy was associated with higher recurrence rates, lower complication rates and better improvement of bowel symptoms than resection rectopexy, these findings cannot be confirmed owing to the limitations of this review. PMID- 27943550 TI - Chemical Composition, Antimicrobial Activity, and Mode of Action of Essential Oils against Paenibacillus larvae, Etiological Agent of American Foulbrood on Apis mellifera. AB - This study aimed to characterize the chemical composition of Aloysia polystachia, Acantholippia seriphioides, Schinus molle, Solidago chilensis, Lippia turbinata, Minthostachys mollis, Buddleja globosa, and Baccharis latifolia essential oils (EOs), and to evaluate their antibacterial activities and their capacity to provoke membrane disruption in Paenibacillus larvae, the bacteria that causes the American Foulbrood (AFB) disease on honey bee larvae. The relationship between the composition of the EOs and these activities on P. larvae was also analyzed. Monoterpenes were the most abundant compounds in all EOs. All EOs showed antimicrobial activity against P. larvae and disrupted the cell wall and cytoplasmic membrane of P. larvae provoking the leakage of cytoplasmic constituents (with the exception of B. latifolia EO). While, the EOs' antimicrobial activity was correlated most strongly to the content of pulegone, carvone, (Z)-beta-ocimene, delta-cadinene, camphene, terpinen-4-ol, elemol, beta pinene, beta-elemene, gamma-cadinene, alpha-terpineol, and bornyl acetate; the volatiles that better explained the membrane disruption were carvone, limonene, cis-carvone oxide, pentadecane, trans-carvyl acetate, trans-carvone oxide, trans limonene oxide, artemisia ketone, trans-carveol, thymol, and gamma-terpinene (positively correlated) and biciclogermacrene, delta-2-carene, verbenol, alpha pinene, and alpha-thujene (negatively correlated). The studied EOs are proposed as natural alternative means of control for the AFB disease. PMID- 27943549 TI - Direct-acting antivirals combination for elderly patients with chronic hepatitis C: A cost-effectiveness analysis. AB - BACKGROUND: Chronic hepatitis C (CHC) has been undertreated among elderly patients. Interferon-free treatment represents an opportunity for these patients. The aim of this study was to assess the cost-effectiveness of directly acting antivirals (DAAs) in CHC elderly patients. METHODS: A Markov model of CHC natural history was built. This study focuses on CHC patients older than 65 years, stratified according to genotype (1/4, 2 and 3), liver fibrosis (METAVIR F1 to F4), age and frailty phenotype (robust, pre-frail and frail). DAAs combination vs no treatment was simulated for each theoretical population, assessing life years, quality-adjusted life years (QALYs), costs, incremental cost-effectiveness ratios (ICERs) in a lifetime time horizon and by the Healthcare System perspective. RESULTS: Incremental cost-effectiveness ratio increased with age and frailty status in all fibrosis stages. For robust F3 and F4 patients ICERs remained below the willingness-to-pay threshold (WTP) of 40 000?/QALY up to age 75 and 86 years, respectively, depending on drug price and sustained virological response probability (sensitivity analysis). Notably, in F4 and frail subjects older than 75 years, ICER was more sensitive to non-liver-related mortality rate. In elderly F1 and F2 patients, ICERs were below WTP only up to 77 years old, with wide variability among frailty phenotypes. CONCLUSIONS: Cost-effectiveness of DAAs treatment of elderly CHC patients is solid in those with advanced fibrosis, but it depends strongly on frailty status and age, particularly in patients with milder fibrosis stages. Accurate assessment of clinical variables, including frailty, is necessary to allocate limited resources to this special population. PMID- 27943551 TI - A systematic review of dyadic studies examining relationship quality in couples facing colorectal cancer together. AB - BACKGROUND: Despite the adverse effects that treatment for colorectal cancer can have on patients' quality of life and, in particular, their intimate relationships, very little research has been conducted on the psychosocial adjustment for both patients and their partners/spouses. OBJECTIVES: The aim of this systematic review was to examine dyadic studies of adjustment in couples in which one partner has been diagnosed with colorectal cancer. METHODS: Pub Med, PsychINFO, MEDLINE, Social Sciences Abstracts (EBSCO), and the Cochrane Library were systematically searched for studies reporting quality of life outcomes for colorectal cancer patients and their partners/spouses. Only studies that included dyads in the sample were eligible for inclusion. The Quality Assessment Tool for Quantitative Studies was used to evaluate each study. RESULTS: A total of 277 studies were identified, of which 9 studies met the inclusion criteria (N = 388 couples). The methodological quality of the studies was high in that they used standardized instruments validated with their samples, conducted dyadic data analyses (when appropriate), and used longitudinal designs. A synthesis of the studies revealed that (1) relationship factors (eg, support, communication, dyadic coping, and relationship satisfaction) affect adjustment to cancer; (2) cancer-related distress impacts each partner's adjustment or the relationship; and (3) gender, role (patient/caregiver), and clinical characteristics (treatment, mental health) can mediate adjustment to cancer. CONCLUSION: The quality of the relationship can influence patients' and their partners' adjustment to colorectal cancer. Psychosocial interventions that address relationship issues may be beneficial to couples facing the challenges of colorectal cancer. PMID- 27943552 TI - Usefulness of a simple self-administered joint condition assessment sheet to predict the need for orthopaedic intervention in the management of haemophilic arthropathy. AB - INTRODUCTION: Detecting signs of joint deterioration is important for early effective orthopaedic intervention in managing haemophilic arthropathy. AIM: We developed a simple, patient self-administered sheet to evaluate the joint condition, and assessed the predictive ability of this assessment sheet for the need for an orthopaedic intervention. METHODS: This was a single-centre, cross sectional study. The association between the score of each of the four items of the assessment sheet (bleeding, swelling, pain and physical impairment) and the results of radiological findings and physical examinations based on Haemophilia Joint Health Score 2.1 was assessed. An optimal scoring system was explored by the area under the curve (AUC). The cut-off value for the need for surgery or physiotherapy was determined using the receiver operating characteristic curve procedure. RESULTS: Forty-two patients were included. The 'physical impairment' item showed the highest correlation coefficient with the results of radiographic and physical examinations (range: 0.57-0.76). The AUC of finally adjusted scoring indicates good ability to discriminate between patients with and without a need for orthopaedic intervention. The positive predictive value was the highest at a cut-off value of 4 points for knees (63.0%) and ankles (70.0%), at 5 points for elbows (66.7%) and the highest predictive accuracy at the cut-off value of 4 points for all the joints. The linear trend of the need for an orthopaedic intervention was observed with an increasing score. CONCLUSION: The joint condition assessment sheet can help clinicians assess the need for orthopaedic intervention for haemophilic arthropathy in Japanese patients with haemophilia. PMID- 27943554 TI - Does aspirin detract from the benefits of mineralocorticoid receptor antagonists in patients with heart failure and a reduced left ventricular ejection fraction? Probably! PMID- 27943553 TI - Cell Surface Nano-modulation for Non-invasive in vivo Near-IR Stem Cell Monitoring. AB - A stem cell tracking system is in high demand for the determination of cell destinations and for the validation of cell therapeutic efficacy in regenerative transplantation. To date, near-infrared (NIR) imaging technology has received considerable attention in cell behavior monitoring, owing to its patient compatibility, easy accessibility and cost effectiveness. Conventionally, in vivo cell tracking has been visualized by direct in-cell staining with NIR, where it may be achieved by complicated genetic engineering. Such genetic amendment techniques have suffered from serious challenges, which can destroy a cell's metabolism and can accidentally incur unexpected carcinoma. Herein we demonstrate a novel cell nano-modulation method for noninvasive stem cell monitoring. It is simply achieved by conjugating stem cells with lipid-supported, NIR-tagged, polymeric nanoparticles. These engineered cells, which are designated as NIR labeled light-emitting stem cells (LESCs), maintain their biochemical functionality (i.e., differentiation, quantum efficacy, etc.) even after conjugation. LESCs were used for in situ stem cell monitoring at inoculation sites. It is speculated that the LESC technique could provide a new preparative methodology for in vivo cell tracking in advanced diagnostic medicine, where cell behavior is a critical issue. PMID- 27943555 TI - Superparamagnetic iron oxide-enhanced magnetic resonance imaging is useful in predicting malignant potential of vascular transformation of hypointense hypovascular nodules on gadoxetic acid-enhanced magnetic resonance imaging. AB - AIM: To examine whether superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) can be used to assess the malignant potential of hepatic hypovascular nodules showing hypointensity during the hepatobiliary phase (HBP) on gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI. METHODS: The study included 42 patients with chronic liver disease who had small hypovascular nodules (5-15 mm) showing hypointensity during the HBP on Gd-EOB-DTPA-enhanced MRI. The SPIO enhanced T2-weighted MRI analyzed whether the signal intensity of each nodule was high. Nodules were prospectively followed up until hypervascularization by periodic Gd-EOB-DTPA-enhanced MRI. Initial MRI findings and clinical variables were used to analyze predictive factors for hypervascularization. RESULTS: We analyzed 77 nodules, of which 19 (25%) showed hypervascularization during the observation period. The cumulative rates for hypervascularization were 11% and 22% at 1 and 2 years, respectively. Hyperintensity was observed in 12 nodules (16%) on SPIO-enhanced T2-weighted MRI; among these, 7 (58%) showed hypervascularization, whereas 12 (18%) of the remaining 65 nodules without hyperintensity showed hypervascularization (P = 0.007). A Cox model revealed that independent predictors of hypervascularization included hyperintense nodules on SPIO-enhanced MRI (P < 0.001). The cumulative rates for hypervascularization in hyperintense nodules on SPIO-enhanced MRI were 52% at 1 year, whereas these rates were 3% for non-hyperintense nodules. CONCLUSION: Superparamagnetic iron oxide enhanced MRI is useful for predicting the malignant potential of vascular transformation of hypovascular nodules with hypointensity observed in the HBP on Gd-EOB-DTPA-enhanced MRI. PMID- 27943557 TI - Comment on "The Quadruple Bonding in C2 Reproduces the Properties of the Molecule". PMID- 27943556 TI - It is elemental: soil nutrient stoichiometry drives bacterial diversity. AB - It is well established that resource quantity and elemental stoichiometry play major roles in shaping below and aboveground plant biodiversity, but their importance for shaping microbial diversity in soil remains unclear. Here, we used statistical modeling on a regional database covering 179 locations and six ecosystem types across Scotland to evaluate the roles of total carbon (C), nitrogen (N) and phosphorus (P) availabilities and ratios, together with land use, climate and biotic and abiotic factors, in determining regional scale patterns of soil bacterial diversity. We found that bacterial diversity and composition were primarily driven by variation in soil resource stoichiometry (total C:N:P ratios), itself linked to different land uses, and secondarily driven by other important biodiversity drivers such as climate, soil spatial heterogeneity, soil pH, root influence (plant-soil microbe interactions) and microbial biomass (soil microbe-microbe interactions). In aggregate, these findings provide evidence that nutrient stoichiometry is a strong predictor of bacterial diversity and composition at a regional scale. PMID- 27943558 TI - Macroecology for microbiology. PMID- 27943559 TI - Assessing Anaclitic and Introjective Characteristics Using the SWAP-200 Q-Sort: Concurrent Validity with the Inventory of Interpersonal Problems Circumplex Scales. AB - : This investigation's goal was to assess the concurrent validity of the four scales of the Anaclitic and Introjective Depression Assessment (AIDA), a newly developed clinician-rated measure, and the Inventory of Interpersonal Problems Circumplex Scales (IIP-64). The AIDA is composed of Shedler-Westen Assessment Procedure items and is comprised of two primitive and two more mature scales of introjective and anaclitic personality types. Specific predictions of relationships were made and are discussed further in this paper. The participants in this study were 106 outpatients engaged in psychodynamic psychotherapy. Patients completed the IIP-64 upon assessment and were rated by their therapist on the Shedler-Westen Assessment Procedure 200 (SWAP-200). The present findings demonstrated several expected relationships between the SWAP-derived AIDA and the IIP-64. Primitive levels of Anaclitic and Introjective characteristics on the AIDA were related to more difficulties involving Affiliation and Dominance on the IIP. The primitive Introjective-Dismissive (Dismissive Depression) scale was related to difficulties involving high Dominance and low Affiliation. The more adaptive Introjective-Self-Critical (Self-Critical Depression) scale was not related to any interpersonal problem. The more adaptive Anaclitic-Needy (Needy Depression) scale was related to difficulties involving high Affiliation, and the primitive Anaclitic-Submissive (Submissive Depression) scale was associated with difficulties related to high Affiliation, as well as problems related to low Dominance in one of two domains. Our results bolster the concurrent validity of the four AIDA scales and add to current knowledge of the differential interpersonal patterns of individuals with more mature and primitive levels of anaclitic and introjective personality types. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Clinicians can utilize the Anaclitic and Introjective Depression Assessment (AIDA; Rost, Fonagy, & Luyten, 2014), derived from Shedler-Westen Assessment Procedure (SWAP) items, to assess if their patients possess Anaclitic or Introjective characteristics. This measure can also be used to assess if the Anaclitic and Introjective characteristics are of a more primitive or mature nature. Clinicians should be aware that individuals with more primitive levels of Anaclitic and Introjective characteristics experience more difficulties involving Affiliation and Dominance than individuals with more mature levels of personality development. Specifically, the more primitive Introjective individual will likely encounter difficulties involving high Dominance and low Affiliation. The more adaptive Introjective individual will likely not demonstrate difficulties in these areas. The more primitive Anaclitic individual will likely encounter more difficulties related to high Affiliation, as well as problems related to low Dominance. The more adaptive Anaclitic individual also likely will encounter difficulties involving high Affiliation. PMID- 27943560 TI - Recurrence and mortality after first venous thromboembolism in a large population based cohort. AB - : Essentials Reports on recurrence and mortality after a first venous thromboembolism (VTE) vary considerably. We describe rates of recurrence and mortality in patients with a first VTE from the Tromso study. The overall recurrence rate was 3.9 per 100 person-years, but this varied widely with time. Despite advances in VTE management, the rates of adverse events are still fairly high. SUMMARY: Background Previous reports on recurrence and mortality rates after a first episode of venous thromboembolism (VTE) vary considerably. Advances in the management and treatment of VTE during the last 15 years may have influenced the rates of clinical outcomes. Aim To estimate the rates of recurrence and mortality after a first VTE in patients recruited from a large population-based cohort. Method From the Tromso study, patients (n = 710) with a first, symptomatic, objectively confirmed VTE were included and followed in the period 1994-2012. Recurrent episodes of VTE were identified from multiple sources and carefully validated by review of medical records. Incidence rates and cumulative incidence rates with 95% confidence intervals (CIs) of VTE recurrence and mortality were calculated. Results The mean age of the patients was 68 years (range 28-102 years), and 166 (23.4%) had cancer at the time of first VTE. There were 114 VTE recurrences and 333 deaths during a median study period of 7.7 years (range 0.04-18.2 years). The risk of recurrence was highest during the first year. The overall 1-year recurrence rate was 7.8 (95% CI 5.8-10.6) per 100 person years (PY), whereas the recurrence rate in the remaining follow-up period (1-18 years) was 3.0 (95% CI 2.4-3.8) per 100 PY. The overall 1-year all-cause mortality rate was 29.9 (95% CI 25.7-34.8) per 100 PY, and in those without cancer the corresponding rate was 23.6 (95% CI 17.8-31.3) per 100 PY. Conclusion Despite advances in VTE management, the rates of adverse events remained fairly high, particularly in the first year following a first VTE. PMID- 27943561 TI - Transmission of severe haemophilia A by in vitro fertilization with donated eggs. PMID- 27943562 TI - Observational study of the impact of an individualized multidisciplinary chronic care program for hip and knee osteoarthritis treatment on willingness for surgery. AB - AIM: To determine the impact of an osteoarthritis-specific multidisciplinary conservative care program (OACCP) on willingness for surgery (WFS) and to identify changes and factors in our cohort that influence and predict willingness for surgery. METHODS: Consecutive OACCP participants with hip or knee OA, with WFS (willing, unsure or unwilling) data for at least two appointments were included. The proportions of unwilling versus willing/unsure patients at baseline and last appointment were compared using McNemar's test. Logistic regression was used to analyze baseline age, gender, main language, educational status, living situation, number of comorbidities, index joint, non-index joint osteoarthritis, completion of program, baseline and change in pain, function, depression, body mass index and 6-min walk test (6MWT) for association with changing WFS. RESULTS: At baseline 203/409 were unwilling for surgery while by final appointment 234/409 were unwilling (P = 0.002). Of the 206 initially willing/unsure participants, 63/206 (30.6%) became unwilling by final appointment. Index joint, completion of program, baseline and change in pain, self-reported function and 6MWT were independently associated with becoming unwilling. Final model from multivariate logistic regression analysis regarding becoming unwilling included baseline pain (P < 0.001), change in pain (P < 0.001), completion of program (P < 0.001) and age (P = 0.004). CONCLUSION: A conservative OA-specific treatment program that improves pain and function can reduce willingness for surgery among participants with hip or knee OA. The strongest determinants of this reduction in willingness were baseline and change in pain, completion of the program and participant age. PMID- 27943563 TI - Short-duration treatment for chronic hepatitis C virus with daclatasvir, asunaprevir, beclabuvir and sofosbuvir (FOURward study). AB - BACKGROUND & AIMS: The phase 2, FOURward study (NCT02175966) investigated short duration therapy (4/6 weeks) with four direct-acting antivirals (DAAs) with distinct mechanisms of action in patients infected with hepatitis C virus (HCV) genotype-1. METHODS: Non-cirrhotic patients were randomized 1:1 to DCV-TRIO (fixed-dose daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg) twice daily + sofosbuvir 400 mg once-daily for 4 or 6 weeks. The primary endpoint was sustained virological response at post-treatment Week 12 (SVR12). Patients without SVR12 were offered retreatment based on the DAA resistance profile at failure; patients with resistance to <=1 DCV-TRIO component received DCV-TRIO + RBV for 12 weeks. RESULTS: Twenty-eight patients with HCV genotype-1 were enrolled; 79% had genotype-1a infection and median baseline HCV-RNA levels were high (9 * 106 IU/mL). Most patients had undetectable HCV-RNA at end of treatment (96% [n=27/28]); however, relapse occurred in 77% (n=10/13) and 43% (n=6/14) treated for 4 and 6 weeks, leading to SVR12 rates of 29% (n=4/14) and 57% (n=8/14) respectively. SVR12 was higher in patients with lower baseline HCV-RNA (<2 million IU/mL, 71% [n=5/7]; >=2 million IU/mL, 33% [n=7/21]). None of the 16 non-SVR12 patients had NS3 or NS5B resistance-associated substitutions (RAS) detected at failure. All 15 patients retreated with DCV-TRIO + RBV for 12 weeks achieved SVR12. All regimens were well tolerated. CONCLUSIONS: Short-duration treatment with four DAAs with distinct mechanisms of action was insufficient for most patients with genotype-1 infection and high baseline viraemia. Non-SVR12 was not associated with emergence of NS3 or NS5B RAS and retreatment with DCV-TRIO + RBV for 12 weeks led to SVR in all patients. PMID- 27943565 TI - Long-term use of dipeptidyl peptidase-4 inhibitors and risk of fracture: A retrospective population-based cohort study. AB - AIMS: To investigate the association between long-term dipeptidyl peptidase-4 (DPP-4) inhibitor use and risk of fracture among people with type 2 diabetes mellitus (T2DM). METHODS: A retrospective population-based cohort study, using data from the Clinical Practice Research Datalink database (2007-2015), was conducted. All those (N = 328 254) with at least one prescription for a non insulin antidiabetic drug (NIAD), aged >=18 years at the time of data collection, were included. Cox proportional hazards models were used to estimate the hazard ratios of any fracture, osteoporotic fracture and hip fracture in DPP-4 inhibitor users compared with those using other NIADs. Analyses were stratified by continuous duration of DPP-4 inhibitor use. Time-dependent adjustments were made for age, sex, lifestyle, comorbidity and concomitant drug use. RESULTS: Current use of DPP-4 inhibitors was not associated with risk of any fracture (adjusted hazard ratio [HR] 0.99 [95% confidence interval {CI} 0.93-1.06]) as compared with current other NIAD use. Current use of DPP-4 inhibitors was also not associated with risk of osteoporotic or hip fracture. After stratification by continuous duration of DPP-4 inhibitor use the highest category was not associated with any (>4.0-8.5 years of use, adjusted HR 0.99 [95% CI 0.70-1.41]), osteoporotic (>3.0 8.5 years of use, adjusted HR 0.75 [95% CI 0.52-1.09]) or hip (>2.0-8.5 years of use; adjusted HR 1.24 [95% CI 0.85-1.79]) fracture. CONCLUSION: Continuous long term DPP-4 inhibitor use (defined as >4.0-8.5 years of DPP-4 inhibitor use for any fracture, >3.0-8.5 years for osteoporotic fracture and >2.0-8.5 years for hip fracture was not associated with risk of any, osteoporotic or hip fracture. These findings may be of value for clinical decisions regarding treatment of patients with T2DM, especially those at high risk of fracture. PMID- 27943564 TI - Factors affecting the incidence of early endoscopic recurrence after ileocolonic resection for Crohn's disease: a multicentre observational study. AB - AIM: Early endoscopic recurrence is frequently observed in patients following resection for Crohn's disease (CD). However, factors affecting the incidence of an early postoperative endoscopic recurrence (EPER) have not been fully determined. The aim of this study was to evaluate risk factors for EPER after ileocolonic resection for CD. METHOD: This was a retrospective, international multicentre study, in which 127 patients with a first ileocolonoscopy conducted between 6 and 12 months after ileocolonic resection for CD were included. Endoscopic recurrence was defined as a Rutgeerts score of >= i2. The following variables were investigated as potential risk factors for EPER: gender, age at surgery, location and behaviour of CD, smoking, concomitant perianal lesions, preoperative use of steroids, immunomodulators and biologics, previous resection, blood transfusion, surgical procedure (open vs laparoscopic approach), length of resected bowel, type of anastomosis (side-to-side vs end-to-end), postoperative complications, granuloma and postoperative biological therapy. Variables related to the patient, disease and surgical procedure were investigated as potential risk factors for EPER, with univariate and multivariate (logistic regression) analyses. RESULTS: 43/127 (34%) patients had EPER at the time of the first postoperative ileocolonoscopy. In univariate analysis, only preoperative steroid use was significantly associated with a higher rate of EPER [21/45 patients (47%) on steroids and 22/82 patients (27%) without steroids (P = 0.04)]. In multivariate analysis, only preoperative steroid use was a significant independent risk factor for EPER (odds ratio 3.28, 95% confidence interval: 1.30 8.28; P = 0.01). CONCLUSIONS: This study found that only preoperative steroid use was a significant risk factor for EPER after ileocolonic resection for CD. Prospective studies are necessary to evaluate precisely the impact of perioperative medications on EPER rates. PMID- 27943566 TI - Impact of Androgen Deprivation Therapy on Volume Reduction and Lower Urinary Tract Symptoms in Patients with Prostate Cancer. AB - OBJECTIVE: To evaluate the impact of androgen deprivation therapy (ADT) on prostate volume, lower urinary tract symptoms (LUTS), and LUTS-related quality of life (QOL) in patients with prostate cancer. METHODS: Patients with prostate cancer (PCa) were treated with goserelin and bicalutamide for 24 weeks. Changes in the total prostate volume (TPV), International Prostate Symptom Score (IPSS), and QOL score for urinary symptoms were assessed every 12 weeks. Of the 42 patients enrolled, 8 patients withdrew and 2 were excluded, so 32 patients were analyzed. RESULTS: The median age, PSA levels, and TPV were 77.5 years, 22.0 ng/mL, and 29.5 cm3 , respectively. TPV showed a significant decrease from baseline in weeks 12 and 24, with the mean percent decreases being -37.5 +/- 4.25 and -7.5 +/- 3.84%, respectively. The IPSS decreased from baseline to weeks 12 and 24 (from 11.7 +/- 1.6 to 9.3 +/- 1.0 and 9.3 +/- 1.0; P = 0.15 and 0.2, respectively). The IPSS voiding score showed a significant decrease from baseline to weeks 12 and 24 whereas the IPSS storage score did not. In patients with moderate to severe LUTS, the IPSS and the QOL score showed a significant decrease in weeks 12 and 24. In patients with mild LUTS, nocturia increased significantly from baseline and there was approximately one additional episode of nocturia at 24 weeks. CONCLUSIONS: In this study, we observed that ADT significantly reduced TPV and improved LUTS in patients with PCa and moderate to severe LUTS, but increased nocturia in patients with mild LUTS. PMID- 27943568 TI - Laparoscopic total mesorectal excision for rectal cancer - a video vignette. PMID- 27943569 TI - APOE gene and neuropsychiatric disorders and endophenotypes: A comprehensive review. AB - The Apolipoprotein E (APOE) gene is one of the main candidates in neuropsychiatric genetics, with hundreds of studies carried out in order to explore the possible role of polymorphisms in the APOE gene in a large number of neurological diseases, psychiatric disorders, and related endophenotypes. In the current article, we provide a comprehensive review of the structural and functional aspects of the APOE gene and its relationship with brain disorders. Evidence from genome-wide association studies and meta-analyses shows that the APOE gene has been significantly associated with several neurodegenerative disorders. Cellular and animal models show growing evidence of the key role of APOE in mechanisms of brain plasticity and behavior. Future analyses of the APOE gene might find a possible role in other neurological diseases and psychiatric disorders and related endophenotypes. (c) 2016 Wiley Periodicals, Inc. PMID- 27943567 TI - Methyltransferase-Directed Labeling of Biomolecules and its Applications. AB - Methyltransferases (MTases) form a large family of enzymes that methylate a diverse set of targets, ranging from the three major biopolymers to small molecules. Most of these MTases use the cofactor S-adenosyl-l-Methionine (AdoMet) as a methyl source. In recent years, there have been significant efforts toward the development of AdoMet analogues with the aim of transferring moieties other than simple methyl groups. Two major classes of AdoMet analogues currently exist: doubly-activated molecules and aziridine based molecules, each of which employs a different approach to achieve transalkylation rather than transmethylation. In this review, we discuss the various strategies for labelling and functionalizing biomolecules using AdoMet-dependent MTases and AdoMet analogues. We cover the synthetic routes to AdoMet analogues, their stability in biological environments and their application in transalkylation reactions. Finally, some perspectives are presented for the potential use of AdoMet analogues in biology research, (epi)genetics and nanotechnology. PMID- 27943570 TI - Telephone-delivered individual cognitive behavioural therapy for cancer patients: An equivalence randomised trial. AB - OBJECTIVE: To evaluate Telephone-Delivered Cognitive Behavioural Therapy (T-CBT) compared to CBT face to face treatment as usual (TAU-CBT), in cancer patients with high psychological needs, in terms of mental health and coping. METHOD: A prospective randomised equivalence trial with Patient Reported Outcome (PRO's), measured pre- and post-therapy including; Hospital Anxiety and Depression Scale (HADS), Mental Adjustment to Cancer Scale: Helpless/Hopeless subscale only (MAC H/H), Checklist of Cancer Concerns (CLCC) and the Cancer Coping Questionnaire (CCQ). A study-specific Service Evaluation Questionnaire (SEQ) was include. RESULTS: Assessment of change scores, in n = 118 randomised patients referred for psychological care, indicate significant improvements (P < 0.01 or greater) for both therapy groups pre- and post-therapy in HADS anxiety, depression and total scores and cancer concerns (CLCC). Overall, for the groups combined, there is a significant shift towards reduction of CCQ stress (P = 0.028) and worry (P = 0.003) post-therapy when compared to baseline levels. Median number of therapy sessions was four. For cancer coping (CCQ) and for Mental Adjustment to Cancer (MAC) there were significant change scores only for Positive Focus and Helpless/hopeless scores respectively, in the TAU-CBT group. Although equivalence was not observed, the data demonstrate that T-CBT was non-inferior to TAU-CBT. CONCLUSIONS: Delivery of CBT to patients with clinician identified high need can be offered according to patient choice without loss of mental health benefit. Both TAU-CBT and T-CBT are effective at reducing mental health problems on the specific outcome measures. PMID- 27943571 TI - A review of ecological risk assessment methods for amphibians: Comparative assessment of testing methodologies and available data. AB - Historically, ecological risk assessments have rarely included amphibian species, focusing preferentially on other aquatic (fish, invertebrates, algae) and terrestrial wildlife (birds and mammal) species. Often this lack of consideration is due to a paucity of toxicity data, significant variation in study design, uncertainty with regard to exposure, or a combination of all three. Productive risk assessments for amphibians are particularly challenging, given variations in complex life history strategies. Further consideration is needed for the development of useful laboratory animal models and appropriate experimental test procedures that can be effectively applied to the examination of biological response patterns. Using these standardized techniques, risk estimates can be more accurately defined to ensure adequate protection of amphibians from a variety of stress agents. Patterns in toxicity may help to ascertain whether test results from 1 amphibian group (e.g., Urodela) could be sufficiently protective of another (e.g., Anura) and/or whether some nonamphibian aquatic taxonomic groups (e.g., fish or aquatic invertebrates) may be representative of aquatic amphibian life stages. This scope is intended to be a guide in the development of methods that would yield data appropriate for ecological risk decisions applicable to amphibians. Integr Environ Assess Manag 2017;13:601-613. (c) 2016 SETAC. PMID- 27943572 TI - Synthetic Biology-The Synthesis of Biology. AB - Synthetic biology concerns the engineering of man-made living biomachines from standardized components that can perform predefined functions in a (self )controlled manner. Different research strategies and interdisciplinary efforts are pursued to implement engineering principles to biology. The "top-down" strategy exploits nature's incredible diversity of existing, natural parts to construct synthetic compositions of genetic, metabolic, or signaling networks with predictable and controllable properties. This mainly application-driven approach results in living factories that produce drugs, biofuels, biomaterials, and fine chemicals, and results in living pills that are based on engineered cells with the capacity to autonomously detect and treat disease states in vivo. In contrast, the "bottom-up" strategy seeks to be independent of existing living systems by designing biological systems from scratch and synthesizing artificial biological entities not found in nature. This more knowledge-driven approach investigates the reconstruction of minimal biological systems that are capable of performing basic biological phenomena, such as self-organization, self replication, and self-sustainability. Moreover, the syntheses of artificial biological units, such as synthetic nucleotides or amino acids, and their implementation into polymers inside living cells currently set the boundaries between natural and artificial biological systems. In particular, the in vitro design, synthesis, and transfer of complete genomes into host cells point to the future of synthetic biology: the creation of designer cells with tailored desirable properties for biomedicine and biotechnology. PMID- 27943573 TI - Circulating cell free DNA: a marker to predict the therapeutic response for biological DMARDs in rheumatoid arthritis. AB - AIM: To evaluate the correlation between circulating cell-free DNA (ccfDNA) in plasma and clinical disease activities in patients with rheumatoid arthritis (RA). METHOD: The study group included 30 patients with RA who started biological disease-modifying anti-rheumatic drugs (DMARDs) therapy. The concentration of ccfDNA in plasma was measured by quantitative real-time polymerase chain reaction at baseline to 24 weeks in every 4-week period from 30 patients and 21 healthy individuals. We also evaluated the correlation between ccfDNA and the clinical activity or the therapeutic response for biological DMARDs, using the simplified disease activity index (SDAI), Disease Activity Score of 28 joints (erythrocyte sedimentation rate) and the European League Against Rheumatism (EULAR) response criteria. Synovial fluid samples of knee joints were collected from 13 patients with RA and 12 with osteoarthritis (OA) to measure ccfDNA. RESULT: The concentration of ccfDNA in RA patients at baseline was higher than healthy controls (P = 0.016). After introducing biological DMARDs, ccfDNA was increased until 8 weeks from the baseline, and decreased after 12 weeks. The average of SDAI was improved in all patients enrolled. At 12 weeks after treatment, 15 patients were good responders to the EULAR response criteria, nine showed moderate response and six showed no response. ccfDNA in good responders was increased until 8 weeks, while those of moderate or no response were not (P = 0.042). In joint fluid of RA patients, ccfDNA was remarkably increased as compared to those from OA (P = 0.00011). CONCLUSION: After introducing biological DMARDs, increase of ccfDNA at 8 weeks was associated with improvement of disease activities. Compared with biomarkers reported, ccfDNA is able to predict the early therapeutic effects of biological DMARDs in RA patients. PMID- 27943575 TI - Reduced incidence of extra-articular manifestations of RA through effective disease control: Karnataka Rheumatoid Arthritis Comorbidity (KRAC) study. AB - AIM: To estimate the prevalence of extra-articular manifestations (EAM) in rheumatoid arthritis (RA) patients and the impact of demographic, clinical and treatment factors. METHOD: The study was carried out as a part of 'Karnataka Rheumatoid arthritis comorbidity (KRAC) study' conducted at 14 centers across Karnataka, India between September 2014 and July 2015. The data were collected by trained clinical research associates using a structured pro forma, under the supervision of the consulting rheumatologists. Based on the factors evaluated, the study participants were classified as follows: age, < 30 years, 30-39 years, 40-49 years, 50-59 years and >= 60 years; and duration of illness prior to visiting rheumatologist (DOIP), <= 6 months, > 6 months-2 years, 2-10 years and > 10 years. The Disease Activity Score of 28 joints-3 (erythrocyte sedimentation rate) score was calculated for each patient by three variable methods. RESULTS: The total number of patients considered for the study after exclusion was 1716. The subjects had a mean (SD) age of 48.1 (12.71) years, the male-to-female ratio was 1 : 5, and median (range) of duration of RA was 48 (0.5-484) months. The prevalence of EAM noted was around 13%. EAM were more likely during the first 2 years of the disease (odds ratio [OR]: 1.465; P = 0.047) and increased with longer DOIP. The incidence was less in patients with low disease activity (OR: 0.657) and worse with the presence of deformities (OR: 2.1). CONCLUSION: The study corroborates the current concept of effective disease control to reduce the incidence/likelihood of EAM in RA patients. PMID- 27943576 TI - Predicting difficulty in extending the ileal pouch to the anus in restorative proctocolectomy: investigation of a simple predictive method using computed tomography. AB - AIM: This study aimed to assess the ability of preoperative axial computed tomography (CT) to predict surgical difficulty in bringing the ileal pouch to the level of the anus during restorative proctocolectomy (RPC). METHOD: Patients who underwent RPC with an ileal pouch-anal anastomosis (or ileal pouch-anal canal anastomosis) in our institution between January 2008 and April 2014 were enrolled. The patients were divided into two groups, including those in whom CT indicated potential difficulty in extending the pouch downwards (extension difficult (ED) group) and patients with no CT evidence of potential difficulty (normal group). The groups were compared for clinical factors and the thickness of the slices of CT showing the root of the superior mesenteric artery, the point of communication of the ileocaecal artery with the marginal artery (tICA) and the anal verge (AV). Receiver-operating characteristic analysis was performed, and a cut-off value was calculated for predicting the degree of difficulty in bringing the ileal pouch down to the anal canal. RESULTS: Thirty-four patients were entered in the study. The ED group included significantly taller patients and more with familial adenomatous polyposis than the normal group. The distance between tICA and AV was significantly longer in the ED group, with a cut-off of 21 cm giving a sensitivity of 100% and a specificity of 83.3%. CONCLUSION: The distance between tICA and AV measured by axial CT can be a useful predictor for the difficulty in bringing the ileal pouch down to the anus during RPC. PMID- 27943577 TI - Response of life-history traits to artificial and natural selection for virulence and nonvirulence in a Drosophila parastitoid, Asobara tabida. AB - Co-evolution of host-parasitoid interactions is determined by the costs of host resistance, which received empirical evidence, and the costs of parasitoid virulence, which have been mostly hypothesized. Asobara tabida is a parasitoid, which mainly parasitizes Drosophila melanogaster and D. subobscura, the first species being able to resist to the parasitoid development while the second species is not. To parasitize resistant hosts, including D. melanogaster, A. tabida develops sticky eggs, which prevent encapsulation, but this virulence mechanism may be costly. Interindividual and interpopulation variation in the proportion of sticky eggs respectively allowed us to (i) artificially select and compare life-history traits of a virulent and a nonvirulent laboratory strain, and (ii) compare a virulent and a nonvirulent field strain, to investigate the hypothetical costs of virulence. We observed strong differences between the 2 laboratory strains. The nonvirulent strain invested fewer resources in reproduction and walked less than the virulent one but lived longer. Concerning the field strains, we observed that the nonvirulent strain had larger wings while the virulent one walked more and faster. All together, our results suggest that virulence may not always be costly, but rather that different life histories associated with different levels of virulence may coexist at both intra- and interpopulation levels. PMID- 27943578 TI - Robust GLP-1 secretion by basic L-amino acids does not require the GPRC6A receptor. AB - The G protein-coupled receptor GPRC6A (GPCR, Class C, group 6, subtype A) has been proposed to be a sensor for basic L-amino acids that are hypothesized to translate ingestive behaviour to endocrine information. However, the contribution of the GPRC6A receptor to L-amino acid-induced glucagon-like peptide 1 (GLP-1) secretion is unclear. Therefore, to discover whether the GPRC6A receptor is indispensible for amino acid-induced secretion of GLP-1, we treated, with oral gavage, GPRC6A knock-out (KO) and wild-type (WT) littermate mice with GPRC6A ligands (L-arginine and L-ornithine) and assessed GLP-1 levels in circulation. We found that oral administration of both L-arginine and L-ornithine significantly increased total plasma GLP-1 levels to a similar level in GPRC6A KO and WT mice 15 minutes after gavage (both amino acids) and accumulated up to 60 minutes after gavage (L-arginine). Conversely, GLP-1 secretion at the 30- and 60-minute time points in the KO mice was attenuated and did not reach statistical significance. In summary, these data confirm that L-arginine is a potent GLP-1 secretagogue and show that the main effect occurs independently of GPRC6A. In addition, this is the first study to show that also L-ornithine powerfully elicits GLP-1 release in vivo. PMID- 27943574 TI - Factors associated with functional limitations in the daily living activities of Japanese hip osteoarthritis patients. AB - AIM: As society ages, there is a vast number of elderly people with locomotive syndrome. In this study, the factors associated with functional limitations in daily living activities evaluated by female hip osteoarthritis (OA) patients were investigated. METHODS: This study was a cross-sectional study. The subjects were 353 female patients who were newly diagnosed with hip OA at an orthopedic clinic with no history of hip joint surgery. Outcome indices were functional limitations in two daily living activities obtained from a questionnaire completed by the patients: (i) standing up (standing from a crouched position) and (ii) stair climbing (climbing and/or descending stairs). The odds ratios (ORs) and 95% confidence intervals (CIs) were computed for explanatory variables using the proportional odds model in logistic regression to evaluate their associations with functional limitations. RESULTS: Functional limitations in standing up were associated with heavy weight (third tertile vs. first tertile: 1.91, 1.11-3.27), participation in sports at school (0.62, 0.40-0.98), parity (vs. nullipara: 1.96, 1.08-3.56), old age and OA stage. Associations with functional limitations in stair-climbing were seen with short height (< 151.0 cm vs. >= 156.0 cm: 2.05, 1.02-4.12), bilateral involvement (vs. unilateral: 1.71, 1.01-2.88), old age and OA stage. CONCLUSION: Old age, OA stage, heavy weight, parity, shorter height and bilateral OA were associated with functional limitations in standing up and/or stair-climbing, whereas participation in sports such as club activities in school maintained standing up. PMID- 27943579 TI - Pilot of integrated, colocated neurology in a primary care medical home. AB - RATIONALE, AIMS, AND OBJECTIVES: Novel health care delivery models are needed to reduce health care use while delivering effective and safe care. We developed a model of a neurologist integrated and colocated in primary care leveraging "curbside," electronic, and traditional consultations. Our objective was to examine the impact on health care resource use of diagnostic testing and referrals for face-to-face neurological consultation and adverse outcomes associated with electronic and curbside consultations. METHODS: Consecutive patients from December 1, 2014, to March 13, 2015, were included in the analysis about whom contact was made between a primary care clinician and a colocated neurologist. RESULTS: Over 3.5 months of the pilot, 359 unique patients generated 429 consultations (179 curbsides, 68 electronic consultations, and 182 face-to face visits). The integrated model resulted in avoidance of 78 face-to-face tertiary neurology consultations, 39 brain magnetic resonance imaging, 50 electromyograms, and 53 other advanced imaging studies. Earlier curbside consultation may have prevented unnecessary testing or face-to-face tertiary neurology consultations in 40 (22%) patients. Earlier face-to-face consultation may have avoided expensive testing in 31 (17%) patients. No cases met criteria for an adverse outcome. The number of referrals to tertiary neurology declined by 64%, and the total number of face-to-face visits per month declined by 25%. CONCLUSION: Colocated neurology in a primary care medical home offers a promising intervention to deliver high-value care. PMID- 27943581 TI - Reverse Biosynthesis: Generating Combinatorial Pools of Drug Leads from Enzyme Mediated Fragmentation of Natural Products. AB - A combinatorial pool of hydroxamic acid fragments as potential metalloprotein drug leads was generated from the enzymatic hydrolysis of the natural product desferrioxamine B (DFOB). DFOB is a metabolite produced by Streptomyces pilosus for iron acquisition, and can be selectively catabolised by Niveispirillum irakense to access carbon for growth. The supernatant of a DFOB-supplemented culture of N. irakense was analysed by LC-MS at intervals over 168 h. This identified a mixture of endo-hydroxamic acid fragments that contained reactive terminal groups. The supernatants from two cultures (at 48 h and 168 h) were reacted with 1,8-naphthalic anhydride in a microwave synthesiser to generate pools of scriptaid analogues, which were screened against ZnII -containing histone deacetylases (HDACs) and FeIII -containing 5-lipoxygenase (5-LO). Compound S2 showed relative potency against 5-LO (IC50 =59 MUm; BWA4C, 17 MUm); it was 28-fold more selective towards 5-LO than HDAC1. Compound S1 inhibited HDAC1 but not 5-LO. Enzyme-mediated reverse biosynthesis could yield new benefits from structurally complex natural products in drug design. PMID- 27943582 TI - Evaluation of nicotine in tobacco-free-nicotine commercial products. AB - Recently, a variety of new tobacco-free-nicotine, TFN, products have been commercialized as e-liquids. Tobacco-derived nicotine contains predominantly (S) (-)-nicotine, whereas TFN products may not. The TFN products are said to be cleaner, purer substances, devoid of toxic components that come from the tobacco extraction process. A variety of commercial tobacco and TFN products were analyzed to identify the presence and composition of each nicotine enantiomer. A rapid and effective enantiomeric separation of nicotine has been developed using a modified macrocyclic glycopeptide bonded to superficially porous particles. The enantiomeric assay can be completed in <2 min with high resolution and accuracy using high performance liquid chromatography with electrospray ionization mass spectrometry. The results of this study suggest the need for pharmacological studies of (R)-(+)-nicotine, which is present in much greater quantities in commercial TFN products compared to commercial tobacco-derived products. Such studies are required by the FDA for new enantiomeric pharmacological products. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943580 TI - Variation in baseline factor VIII concentration in a retrospective cohort of mild/moderate hemophilia A patients carrying identical F8 mutations. AB - : Essentials Factor VIII levels vary in mild and moderate hemophilia A (MHA) patients with the same mutation. We aimed to estimate the variation and determinants of factor VIII levels among MHA patients. Age and genotype explain 59% of the observed inter-individual variation in factor VIII levels. Intra individual variation accounted for 45% of the variation in the three largest mutation groups. SUMMARY: Background The bleeding phenotype in patients with mild/moderate hemophilia A (MHA) is inversely associated with the residual plasma concentration of factor VIII (FVIII:C). Within a group of patients with the same F8 missense mutation, baseline FVIII:C may vary, because, in healthy individuals, von Willebrand factor (VWF) levels, ABO blood group and age are also known to influence baseline FVIII:C. Our understanding of the pathophysiologic process of the causative genetic event leading to reduced baseline FVIII:C in MHA patients is still limited. Objectives To estimate the variation and determinants of baseline FVIII:C among MHA patients with the same F8 missense mutation. Methods Three hundred and forty-six patients carrying mutations that were present in at least 10 patients in the cohort were selected from the INSIGHT and the RISE studies, which are cohort studies including data of 3534 MHA patients from Europe, Canada, and Australia. Baseline FVIII:C was measured with a one-stage clotting assay. We used Levene's test, univariate and multivariate linear regression, and mixed-model analyses. Results For 59% of patients, the observed variation in baseline FVIII:C was explained by age and genotype. Compared to FVIII:C in patients with Arg612Cys, FVIII:C was significantly different in patients with eight other F8 missense mutations. Intra-individual variation explained 45% of the observed variance in baseline FVIII:C among patients with the same mutation. Conclusion Our results indicate that baseline FVIII:C levels are not exclusively determined by F8 genotype in MHA patients. Insights into other factors may provide potential novel targets for the treatment of MHA. PMID- 27943583 TI - Human dental pulp stem cells expressing STRO-1, c-kit and CD34 markers in peripheral nerve regeneration. AB - Peripheral nerve injuries are a commonly encountered clinical problem and often result in long-term functional defects. The application of stem cells able to differentiate in Schwann cell-like cells in vitro and in vivo, could represent an attractive therapeutic approach for the treatment of nerve injuries. Further, stem cells sources sharing the same embryological origin as Schwann cells might be considered a suitable tool. The aim of this study was to demonstrate the ability of a neuroectodermal subpopulation of human STRO-1+ /c-Kit+ /CD34+ DPSCs, expressing P75NTR , nestin and SOX-10, to differentiate into Schwann cell-like cells in vitro and to promote axonal regeneration in vivo, which led to functional recovery as measured by sustained gait improvement, in animal rat model of peripheral nerve injury. Transplanted human dental pulp stem cells (hDPSCs) engrafted into sciatic nerve defect, as revealed by the positive staining against human nuclei, showed the expression of typical Schwann cells markers, S100b and, noteworthy, a significant number of myelinated axons was detected. Moreover, hDPSCs promoted axonal regeneration from proximal to distal stumps 1 month after transplantation. This study demonstrates that STRO-1+ /c Kit+ /CD34+ hDPSCs, associated with neural crest derivation, represent a promising source of stem cells for the treatment of demyelinating disorders and might provide a valid alternative tool for future clinical applications to achieve functional recovery after injury or peripheral neuropathies besides minimizing ethical issues. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943584 TI - Cytogenetic features of rRNA genes across land plants: analysis of the Plant rDNA database. AB - The online resource http://www.plantrdnadatabase.com/ stores information on the number, chromosomal locations and structure of the 5S and 18S-5.8S-26S (35S) ribosomal DNAs (rDNA) in plants. This resource was exploited to study relationships between rDNA locus number, distribution, the occurrence of linked (L-type) and separated (S-type) 5S and 35S rDNA units, chromosome number, genome size and ploidy level. The analyses presented summarise current knowledge on rDNA locus numbers and distribution in plants. We analysed 2949 karyotypes, from 1791 species and 86 plant families, and performed ancestral character state reconstructions. The ancestral karyotype (2n = 16) has two terminal 35S sites and two interstitial 5S sites, while the median (2n = 24) presents four terminal 35S sites and three interstitial 5S sites. Whilst 86.57% of karyotypes show S-type organisation (ancestral condition), the L-type arrangement has arisen independently several times during plant evolution. A non-terminal position of 35S rDNA was found in about 25% of single-locus karyotypes, suggesting that terminal locations are not essential for functionality and expression. Single locus karyotypes are very common, even in polyploids. In this regard, polyploidy is followed by subsequent locus loss. This results in a decrease in locus number per monoploid genome, forming part of the diploidisation process returning polyploids to a diploid-like state over time. PMID- 27943585 TI - Nurses' attitudes towards enforced measures to increase influenza vaccination: A qualitative study. AB - BACKGROUND: Despite studies demonstrating that the annual influenza vaccination of healthcare workers reduces morbidity and mortality among vulnerable patients, vaccination rates remain very low, particularly in nursing staff. Educational programmes have failed to improve rates, which has led to a diverse range of enforced approaches being advocated and implemented. OBJECTIVES: To examine the attitudes of non-vaccinated nursing staff towards various enforced measures aimed at increasing rates of influenza vaccination. METHODS: Semi-structured qualitative interviews with a purposive sample of 18 non-vaccinated nurses, working in units with high-risk patients at two hospitals in Switzerland. Analysis of interviews was done using conventional content analysis. RESULTS: Nurses were critical of enforced measures. However, measures that include an element of choice were perceived as more acceptable. Declination forms and mandatory vaccinations as part of the employment requirements were found to be the most accepted measures. CONCLUSION: The perception of choice is crucial to the acceptance of a measure. Respect for choice and autonomy has a positive effect on behavioural change. Mandatory influenza vaccination as a condition of new (and perhaps ongoing) employment could be a feasible, effective and ethical measure to increase vaccination rates among nurses who oppose vaccination. PMID- 27943586 TI - Polar Constituents, Essential Oil and Antioxidant Activity of Marsh Woundwort (Stachys palustris L.). AB - Stachys palustris, well-known as marsh woundwort, is a perennial herb growing in wet environments of Europe. Its tubers, leaves and seeds are eaten raw or cooked. Alike other Stachys species, the plant is also used as a traditional remedy. Despite S. palustris has been consumed for centuries, little is known about its chemical constituents. In this work the main secondary metabolites of S. palustris from Hungary and France have been analysed. From the plant ethanolic extracts, ethanoid glucosides, isoscutellarein derivatives, caffeoyl-quinic acids and iridoids have been isolated and structurally characterized by NMR. The essential oils were analysed by GC/MS and showed (E)-phytol, fatty acids and carbonylic compounds as the most abundant compounds. The radical scavenging capacity of plant ethanolic extracts, as evaluated by the DPPH assay, was noteworthy, with IC50 values of 92.08 - 105.42 MUg/ml. PMID- 27943587 TI - Development and implementation of a site-specific water quality limit for uranium in a high conservation value ecosystem. AB - Water quality guideline values (GVs) are a key tool for water quality assessments. Site-specific GVs, which incorporate data relevant to local conditions and organisms, provide a higher level of confidence that the GV will protect the aquatic ecosystem at a site compared to generic GVs. Site-specific GVs are, therefore, considered particularly suitable for sites of high sociopolitical or ecological importance. The present paper provides an example of the refinement of a site-specific GV for high ecological value aquatic ecosystems in Kakadu National Park, Northern Territory, Australia, to improve its site specificity and statistical robustness, thereby increasing confidence in its application. Uranium is a contaminant of concern for Ranger U mine, which releases water into Magela Creek and Gulungul Creek in Kakadu National Park. A site-specific GV for U has been applied, as a statutory limit, to Magela Creek since 2004 and to Gulungul Creek since 2015. The GV of 6 MUg/L U was derived from toxicity data for 5 local species tested under local conditions. The acquisition of additional U data, including new information on the effect of DOC on U toxicity, enabled a revision of the site-specific U GV to 2.8 MUg/L U and an ability to adjust the value on the basis of environmental concentrations of DOC. The revised GV has been adopted as the statutory limit, with the regulatory framework structured so the GV requires adjustment based on DOC concentration only when an exceedance occurs. Monitoring data for Magela Creek (2001-2013) and Gulungul Creek (2003-2013) downstream of the mine show that dissolved U has not exceeded 1 MUg/L. Integr Environ Assess Manag 2017;13:765-777. (c) 2016 SETAC. PMID- 27943588 TI - Separation of phenolic acids from sugarcane rind by online solid-phase extraction with high-speed counter-current chromatography. AB - Sugarcane rind contains some functional phenolic acids. The separation of these compounds from sugarcane rind is able to realize the integrated utilization of the crop and reduce environment pollution. In this paper, a novel protocol based on interfacing online solid-phase extraction with high-speed counter-current chromatography (HSCCC) was established, aiming at improving and simplifying the process of phenolic acids separation from sugarcane rind. The conditions of online solid-phase extraction with HSCCC involving solvent system, flow rate of mobile phase as well as saturated extent of absorption of solid-phase extraction were optimized to improve extraction efficiency and reduce separation time. The separation of phenolic acids was performed with a two-phase solvent system composed of butanol/acetic acid/water at a volume ratio of 4:1:5, and the developed online solid-phase extraction with HSCCC method was validated and successfully applied for sugarcane rind, and three phenolic acids including 6.73 mg of gallic acid, 10.85 mg of p-coumaric acid, and 2.78 mg of ferulic acid with purities of 60.2, 95.4, and 84%, respectively, were obtained from 150 mg sugarcane rind crude extracts. In addition, the three different elution methods of phenolic acids purification including HSCCC, elution-extrusion counter-current chromatography and back-extrusion counter-current chromatography were compared. PMID- 27943589 TI - Paleomicrobiology to investigate copper resistance in bacteria: isolation and description of Cupriavidus necator B9 in the soil of a medieval foundry. AB - Remains of a medieval foundry were excavated by archaeologists in 2013 in Verdun (France). Ancient workshops specialized in brass and copper alloys were found with an activity between 13th to 16th c. Levels of Cu, Zn and Pb reached 20000, 7000 and 6000 mg kg-1 (dw), respectively, in several soil horizons. The objective of the present work was to examine the microbial community in this contaminated site. A total of 8-22 106 reads were obtained by shotgun metagenomics in four soil horizons. Bioinformatic analyses suggest the presence of complex bacterial communities dominated by Proteobacteria. The structure of the community was not affected by metals, contrary to the set of metal-resistance genes. Using selective media, a novel strain of Cupriavidus necator (eutrophus), strain B9, was isolated. Its genome was sequenced and a novel metal resistance gene cluster with Hg resistance genes (merRTPCA) followed by 24 copper-resistance genes (actP, cusCBAF, silP, copK1, copH4QLOFGJH3IDCBARS, copH2H1, copK2) was found. This cluster is partly homologous to the cop genes of Cupriavidus gilardii CR3 and C. metallidurans CH34. Proteomics indicated that the four copH genes were differentially expressed: CopH1 and CopH2 were mostly induced by Cd while CopH4 was highly expressed by Cu. PMID- 27943590 TI - A collagen cardiac patch incorporating alginate microparticles permits the controlled release of hepatocyte growth factor and insulin-like growth factor-1 to enhance cardiac stem cell migration and proliferation. AB - Cardiac stem cells (CSCs) represent a logical cell type to exploit as a regenerative treatment option for tissue damage accrued as a result of a myocardial infarction. However, the isolation and expansion of CSCs prior to cell transplantation is time consuming, costly and invasive, and the reliability of cell expansion may also prove to be a major obstacle in the clinical application of CSC-based transplantation therapy after a myocardial infarction. In order to overcome this, we propose the incorporation of growth factor-eluting alginate microparticles into collagen-based scaffolds as an implantable biomaterial to promote the recruitment and expansion of CSCs in the myocardium. In order to obtain scaffolds able to enhance the motogenic and proliferative potential of CSCs, the aim of this work was to achieve a sustained delivery of both hepatocyte growth factor and insulin-like growth factor-1. Both proteins were initially encapsulated in alginate microparticles by spray drying and subsequently incorporated into a collagen scaffold. Microparticles were seen to homogeneously distribute through the interconnected scaffold pore structure. The resulting scaffolds were capable of extending the release of both proteins up to 15 days, a three-fold increase over non-encapsulated proteins embedded in the scaffolds. In vitro assays with isolated CSCs demonstrated that the sustained release of both bioactive proteins resulted in an increased motogenic and proliferative effect. As presently practiced, the isolation and expansion of CSCs for autologous cell transplantation is slow, expensive and difficult to attain. Thus, there is a need for strategies to specifically activate in situ the intrinsic cardiac regenerative potential represented by the CSCs using combinations of growth factors obviating the need for cell transplantation. By favouring the natural regenerative capability of CSCs, it is hypothesized that the cardiac patch presented here will result in positive therapeutic outcomes in MI and heart failure patients in the future. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943592 TI - Smokers and ex-smokers have shared differences in the neural substrates for potential monetary gains and losses. AB - Despite an increased understanding of nicotine addiction, there is a scarcity of research comparing the neural correlates of non-drug reward between smokers and ex-smokers. Long-term changes in reward-related brain functioning for non-drug incentives may elucidate patterns of functioning that potentially contribute to ongoing smoking behaviour in current smokers. Similarly, examining the effects of previous chronic nicotine exposure during a period of extended abstinence may reveal whether there are neural correlates responsible for non-drug reward processing that are different from current smokers. The current study, therefore, sets out to examine the neural correlates of reward and loss anticipation, and their respective outcomes, in smokers, ex-smokers and matched controls using a monetary incentive delay task during functional magnetic resonance imaging. Here, we report that in the absence of any significant behavioural group differences, both smokers and ex-smokers showed a significantly greater activation change in the lateral orbitofrontal/anterior insular cortex compared with smokers when anticipating both potential monetary gains and losses. We further report that ex smokers showed a significantly greater activation change in the ventral putamen compared with both controls and smokers and in the caudate compared with controls during the anticipation of potential monetary losses only. The results suggest that smoking may sensitize striato-orbitofrontal circuitry subserving motivational processes for loss avoidance and reward gain in nicotine addiction. PMID- 27943591 TI - Effects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic Neurotransmission. AB - INTRODUCTION: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most prevalent cause of familial and sporadic Parkinson's disease (PD). Because most pathogenic LRRK2 mutations result in enhanced kinase activity, it suggests that LRRK2 inhibitors may serve as a potential treatment for PD. To evaluate whether LRRK2 inhibitors are effective therapies for PD, it is crucial to know whether LRRK2 inhibitors will affect dopaminergic (DAergic) neurotransmission. However, to date, there is no study to investigate the impact of LRRK2 inhibitors on DAergic neurotransmission. AIMS: To address this gap in knowledge, we examined the effects of three types of LRRK2 inhibitors (LRRK2-IN-1, GSK2578215A, and GNE 7915) on dopamine (DA) release in the dorsal striatum using fast-scan cyclic voltammetry and DA neuron firing in the substantia nigra pars compacta (SNpc) using patch clamp in mouse brain slices. RESULTS: We found that LRRK2-IN-1 at a concentration higher than 1 MUM causes off-target effects and decreases DA release, whereas GSK2578215A and GNE-7915 do not. All three inhibitors at 1 MUM have no effect on DA release and DA neuron firing rate. We have further assessed the effects of the inhibitors in two preclinical LRRK2 mouse models (i.e., BAC transgenic hG2019S and hR1441G) and demonstrated that GNE-7915 enhances DA release and synaptic vesicle mobilization/recycling. CONCLUSION: GNE-7915 can be validated for further therapeutic development for PD. PMID- 27943593 TI - Coconut milk and probiotic milk as storage media to maintain periodontal ligament cell viability: an in vitro study. AB - BACKGROUND/AIM: The viability of periodontal ligament (PDL) cells is a significant determinant of the long-term prognosis of replanted avulsed teeth. A storage medium is often required to maintain the viability of these cells during the extra-alveolar period. Many studies have been carried out to search for the most suitable storage medium for avulsed teeth, but an ideal solution has not yet been found. The purpose of the study was to compare and analyze the ability of coconut milk and probiotic milk to maintain PDL cell viability. METHODOLOGY: In an in vitro setting, 69 caries free human premolars with normal periodontium that had been extracted for orthodontic purposes were randomly divided into two experimental groups on the basis of storage media used (i.e., coconut milk or probiotic milk) and a Hanks' balanced salt solution (HBSS) control group (23 samples per group). Immediately after extraction, the teeth were stored dry for 20 min and then immersed for 30 min in one of the storage media. The teeth were then subjected to collagenase-dispase assay and labeled with 0.5% trypan blue staining solution for determination of cell viability. The number of viable cells was counted under a light microscope and statistically analyzed using anova and post hoc Tukey test (P <= 0.05). RESULTS: Statistical analysis demonstrated there was a significant difference (P < 0.001) between coconut milk and probiotic milk as well as HBSS in maintaining cell viability. However, there was no significant difference between probiotic milk and HBSS in ability to maintain PDL cell viability (P > 0.05). CONCLUSION: Coconut milk may not be suitable as an interim transport media due to poor maintenance of cell viability. However, probiotic milk was able to maintain PDL cell viability as well as HBSS. PMID- 27943594 TI - Effects of quercetin and surgicel for preventing adhesions after gynecological surgery: A rat uterine horn model. AB - AIM: Postoperative pelvic adhesions are significant health care problems causing chronic pelvic pain, infertility and intestinal obstruction after abdominal or pelvic surgery. We investigated the effects of quercetin and Surgicel for the prevention of adhesions after gynecological surgery. METHODS: A double blind, randomized, controlled experimental study was designed. Forty female Wistar Hannover rats were divided into five groups: control, sham operated, quercetin, Surgicel, and quercetin + Surgicel. The control group received medication used for the surgical procedure only. The sham group received a laparotomy only. The quercetin group received 15 mg/kg quercetin in addition to undergoing the standard surgical procedure, and the injuries in the surgical group were covered with a single, 1 cm2 layer of Surgicel (oxidized regenerated cellulose). The quercetin + Surgicel group received both 15 mg/kg quercetin and a single, 1 cm2 layer of Surgicel. Adhesions were scored 14 days after the first surgical procedure. RESULTS: The extent, severity, degree, total adhesion, inflammation and fibrosis scores of the control group were significantly higher than those of the quercetin, Surgicel, and quercetin + Surgicel groups. There was no significant difference between the Surgicel and quercetin groups in degree, but all other parameters were significantly higher in the Surgicel than in the quercetin group. The quercetin + Surgicel group had lower adhesion scores than the quercetin group. CONCLUSIONS: Quercetin, Surgicel and quercetin + Surgicel treatment may be useful for preventing pelvic adhesions. PMID- 27943595 TI - Fine Control of the Redox Reactivity of a Nonheme Iron(III)-Peroxo Complex by Binding Redox-Inactive Metal Ions. AB - Redox-inactive metal ions are one of the most important co-factors involved in dioxygen activation and formation reactions by metalloenzymes. In this study, we have shown that the logarithm of the rate constants of electron-transfer and C-H bond activation reactions by nonheme iron(III)-peroxo complexes binding redox inactive metal ions, [(TMC)FeIII (O2 )]+ -Mn+ (Mn+ =Sc3+ , Y3+ , Lu3+ , and La3+ ), increases linearly with the increase of the Lewis acidity of the redox inactive metal ions (DeltaE), which is determined from the gzz values of EPR spectra of O2.- -Mn+ complexes. In contrast, the logarithm of the rate constants of the [(TMC)FeIII (O2 )]+ -Mn+ complexes in nucleophilic reactions with aldehydes decreases linearly as the DeltaE value increases. Thus, the Lewis acidity of the redox-inactive metal ions bound to the mononuclear nonheme iron(III)-peroxo complex modulates the reactivity of the [(TMC)FeIII (O2 )]+ -Mn+ complexes in electron-transfer, electrophilic, and nucleophilic reactions. PMID- 27943596 TI - The telomere lengthening conundrum - it could be biology. AB - Longitudinal studies of human leucocyte telomere length often report a percentage of individuals whose telomeres appear to lengthen. However, based on theoretical considerations and empirical data, Steenstrup et al. (Nucleic Acids Research, 2013, vol 41(13): e131) concluded that this lengthening is unlikely to be a real biological phenomenon and is more likely to be an artefact of measurement error. We dispute the logic underlying this claim. We argue that Steenstrup et al.'s analysis is incomplete because it failed to compare predictions derived from assuming a scenario with no true telomere lengthening with alternative scenarios in which true lengthening occurs. To address this deficit, we built a computational model of telomere dynamics that allowed us to compare the predicted percentage of observed telomere length gainers given differing assumptions about measurement error and the true underling dynamics. We modelled a set of scenarios, all assuming measurement error, but both with and without true telomere lengthening. We found a range of scenarios assuming some true telomere lengthening that yielded either similar or better quantitative fits to the empirical data on the percentage of individuals showing apparent telomere lengthening. We conclude that although measurement error contributes to the prevalence of apparent telomere lengthening, Steenstrup et al.'s conclusion was too strong, and current data do not allow us to reject the hypothesis that true telomere lengthening is a real biological phenomenon in epidemiological studies. Our analyses highlight the need for process-level models in the analysis of telomere dynamics. PMID- 27943597 TI - Re-endothelialization of rat lung scaffolds through passive, gravity-driven seeding of segment-specific pulmonary endothelial cells. AB - Effective re-endothelialization is critical for the use of decellularized scaffolds for ex vivo lung engineering. Current approaches yield insufficiently re-endothelialized scaffolds that haemorrhage and become thrombogenic upon implantation. Herein, gravity-driven seeding coupled with bioreactor culture facilitated widespread distribution and engraftment of endothelial cells throughout rat lung scaffolds. Initially, human umbilical vein endothelial cells were seeded into the pulmonary artery by either gravity-driven, variable flow perfusion seeding or pump-driven, pulsatile flow perfusion seeding. Gravity seeding evenly distributed cells and supported cell survival and re-lining of the vascular walls while perfusion pump-driven seeding led to increased cell fragmentation and death. Using gravity seeding, rat pulmonary artery endothelial cells and rat pulmonary vein endothelial cells attached in intermediate and large vessels, while rat pulmonary microvascular endothelial cells deposited mostly in microvessels. Combination seeding of these cells led to positive vascular endothelial cadherin staining. In addition, combination seeding improved barrier function as assessed by serum albumin extravasation; however, leakage was observed in the distal portions of the re-endothelialized tissue suggesting that recellularization of the alveoli is necessary to complete barrier function of the capillary-alveolar network. Overall, these data indicate that vascular recellularization of rat lung scaffolds is achieved through gravity seeding. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943599 TI - Corrigendum: A Stable Heterocyclic Amino(phosphanylidene-sigma4 -phosphorane) Germylene. PMID- 27943600 TI - Generation of clinical-grade functional cardiomyocytes from human embryonic stem cells in chemically defined conditions. AB - A highly efficient cardiac differentiation from human pluripotent stem cells (hPSCs) is achievable using existing methods, especially with the standard B27 induction system. However, bovine serum albumin (BSA), one of the essential ingredients in B27, may pose significant complications for clinical studies owing to its animal origin and potential risks of virus contamination. Furthermore, the high cost of the B27 induction system also limits the applications of hPSCs derived cardiomyocytes. Here, a BSA-free and chemically defined medium has been developed for differentiating hPSCs to clinical-grade cardiomyocytes, which generated over 80% cardiac troponin T (cTNT)-positive cardiomyocytes with high yield. When engrafting the cardiomyocytes into the hearts of myocardial infarction model rats, the rats survived with significantly improved heart functions in Delta ejection fraction and Delta fractional shortening. Importantly, the human embryonic stem cell (hESC) line (Q-CTS-hESC-2) chosen for differentiation was of a clinical-grade maintained in defined xeno-free conditions. Compliant with the biological safety requirements, the Q-CTS-hESC-2 derived cardiomyocytes have passed the sterility and pathogen criteria tests for clinical applications. This study reports, for the first time, the generation of clinical-grade and functional cardiomyocytes from hPSCs where BSA-free and chemically defined conditions were maintained throughout the whole process. This provides the possibility of future therapeutic use of clinical-grade hPSCs derived cardiomyocytes in treating heart diseases. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943601 TI - Surgical repair of annulus defect with biomimetic multilamellar nano/microfibrous scaffold in a porcine model. AB - Annulus defect is associated with reherniation and disc degeneration after discectomy; currently there is no effective treatment that addresses this problem. The annulus is a hierarchical lamellar structure, where each lamella consists of aligned collagen fibres, which are parallel and tilted at 30 degrees to the spinal axis. In this study, a biomimetic biodegradable scaffold consisting of multilamellar nano/microfibres, sharing nanotopography and microporosity similar to the native lamellar structure, was assessed in a porcine model, aided by sealing with fascia and medical glue and subsequent suture fixation. After 6- and 12-week observation, we found that this treatment restored nucleus volume and slowed down disc degeneration, as indicated by magnetic resonance imaging of T1/T2-weighted, T2-mapping, T1-rho imaging. Histological analysis showed aligned collagen fibres organized in the scaffold and integrated with surrounding native annulus tissue. The autologous bone marrow concentrate-seeded scaffolds showed slightly earlier collagen fibre formation at 6 weeks. This novel treatment could efficiently close the annulus defect with newly formed, organized and integrated collagen fibres in a porcine model. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943602 TI - Boron-Functionalized Graphene Oxide-Organic Frameworks for Highly Efficient CO2 Capture. AB - The capture and storage of CO2 have been suggested as an effective strategy to reduce the global emissions of greenhouse gases. Hence, in recent years, many studies have been carried out to develop highly efficient materials for capturing CO2 . Until today, different types of porous materials, such as zeolites, porous carbons, N/B-doped porous carbons or metal-organic frameworks (MOFs), have been studied for CO2 capture. Herein, the CO2 capture performance of new hybrid materials, graphene-organic frameworks (GOFs) is described. The GOFs were synthesized under mild conditions through a solvothermal process using graphene oxide (GO) as a starting material and benzene 1,4-diboronic acid as an organic linker. Interestingly, the obtained GOF shows a high surface area (506 m2 g-1 ) which is around 11 times higher than that of GO (46 m2 g-1 ), indicating that the organic modification on the GO surface is an effective way of preparing a porous structure using GO. Our synthetic approach is quite simple, facile, and fast, compared with many other approaches reported previously. The synthesized GOF exhibits a very large CO2 capacity of 4.95 mmol g-1 at 298 K (1 bar), which is higher those of other porous materials or carbon-based materials, along with an excellent CO2 /N2 selectivity of 48.8. PMID- 27943603 TI - Phenotypic plasticity in freshwater picocyanobacteria. AB - Picocyanobacteria can occur as single-cell (Pcy) or as colonies (CPcy). Published evidence suggests that some Pcy strains have the capability to aggregate under certain culture conditions, however this has not been demonstrated to occur in natural environments. We investigated whether the Pcy and CPcy belong to the same species (i.e. phylotype), and the factors that determine their morphological and genetic variability in a hypertrophic shallow lake dominated by picocyanobacteria. Six main different morphologies and >30 phylotypes were observed. All sequences retrieved belonged to the 'Anathece + Cyanobium' clade (Synechococcales) that are known to have the capability of aggregation/disaggregation. The temporal variation of picocyanobacteria morphotype composition was weakly correlated with the DGGE temporal pattern, and could be explained by the composition of the zooplankton assemblage. Laboratory experiments confirmed that the small cladoceran Bosmina favoured the dominance of CPcy, i.e. Cyanodictyon doubled the size of the colonies when present, most likely through the aggregation of single-cell picocyanobacteria into colonies. Flow cytometry cell sorting and 16S rRNA + ITS sequencing of the Pcy and CPcy cytometrically-defined populations revealed that some phylotypes could be found in both sorted populations, suggesting phenotypic plasticity in which various Synechococcales phylotypes could be found in situ either as single-cells or as colonies. PMID- 27943604 TI - Time-trends in incidence and prognosis of hepatocellular carcinoma in Denmark: A nationwide register-based cohort study. AB - BACKGROUND & AIMS: There are no recent data on incidence or survival of hepatocellular carcinoma (HCC) in Denmark. We examined current HCC epidemiology. METHODS: We used data from nationwide registries to identify all Danish citizens diagnosed with HCC in 1994-2016. We computed annual standardized incidence rates for the entire 1994-2016 period, and we compared survival for patients diagnosed in 2004-2014; data on HCC stage were available for that period alone and coded according to the TNM classification. RESULTS: The incidence rate for 1994-2016 was 3.7 (95% CI 3.6-3.8) per 100 000 population per year. It was stable around 3.0 in 1994-2007, climbed steadily to 5.7 in 2008-2011, and remained high in 2012 2016. The proportion of non-cirrhotic patients with HCC was 21%, with a slightly decreasing time trend. Median survival time rose from 2.7 months in 2004-2006 to 7.7 months in 2013-2014, but only patients with early HCC (stage I or II HCC or a "probably early HCC") saw improvements after 2007 (confounder-adjusted mortality hazard ratio for 2013-2014 vs 2007-2009=0.67, 95% 0.50-0.90). The proportion of patients with early HCC rose from 17% in 2004-2006 to 30% in 2013-2014. CONCLUSIONS: HCC incidence increased between 2007 and 2011. Concurrently, the HCC stage at diagnosis and patient survival improved. The likely reasons for the changes include easier access to HCC workup, changing diagnostic criteria for HCC, increased prevalence of risk factors for HCC, and improved treatment of patients with HCC. PMID- 27943606 TI - Balancing give and take between patients and their spousal caregivers in hematopoietic stem cell transplantation. AB - OBJECTIVE: Hematopoietic stem cell transplantation (HSCT) is a demanding treatment. Spouses of HSCT patients assume caregiving responsibilities that can induce feelings of burden and disrupt relationship equity. On the basis of equity theory, we propose a conceptual framework examining the individual and dyadic experience of HSCT patients and their caregivers. The model includes feelings of inequity, patient self-perceived burden, caregiver burden, and distress. METHODS: The HSCT patients and their spousal caregivers were recruited prior to HSCT between March 2011 and September 2012. Each member of the dyad self-administered a questionnaire package. RESULTS: Seventy-two dyads were included in the path analyses. Our model demonstrated an inadequate statistical fit; however, with one modification, an adequate to good fit was obtained: chi2 (df) = 6.01(5), normed chi2 = 1.20, standardized root mean square residual = 0.048, comparative fit index = 0.99, Tucker-Lewis index = 0.96, and root-mean-square error of approximation = 0.05 (90% CI, 0.00-0.18). As hypothesized, pre-HSCT caregiver burden mediates the relationship between caregiver underbenefit and caregiver distress. However, patient self-perceived burden was not associated with patient distress; rather, patient perception of overbenefit was related to patient distress. In our modified model, the results demonstrate that patient overbenefit influenced caregiver burden; however, there was not a reciprocal influence, because caregiver variables did not affect patient variables. CONCLUSIONS: Our proposed theoretical framework describes patients' and caregivers' individual experience of distress before HSCT but does not as clearly encompass the dyadic experience. Addressing perceived imbalances and providing psycho-education on role changes within HSCT dyads before transplantation may be a useful prehabilitation strategy for preventing distress. PMID- 27943605 TI - Efficacy and safety of direct-acting antivirals-based antiviral therapies for hepatitis C virus patients with stage 4-5 chronic kidney disease: a meta analysis. AB - BACKGROUND & AIMS: The aim of this study was to assess the efficacy and safety of direct-acting antivirals (DAA)-based antiviral therapies for HCV patients with stage 4-5 chronic kidney disease. METHODS: We conducted a systematic literature search in PubMed, EMBASE, Web of Science, and CENTRAL on the Cochrane Library without time and language limitations. The search strategy used was "(End stage renal disease OR chronic kidney failure OR severe renal impairment OR chronic kidney disease OR dialysis) AND (sofosbuvir OR simeprevir OR grazoprevir OR elbasvir OR ombitasvir OR paritaprevir OR ritonavir OR dasabuvir OR daclatasvir OR asuparevir OR direct-acting antiviral OR DAA)". Sustained virologic response at 12 weeks after the end of treatment (SVR12), adverse events (AEs) and/or serious adverse events (SAEs) with 95% confidence intervals (CI) were pooled. RESULTS: Eleven studies, comprising a total of 264 patients were included for our meta-analysis. The pooled SVR12 rate were 93.2% (95% CI 89.9%-95.9%, I2 =0.0%), 89.4% (95% CI 82.0%-95.0%, I2 =0.0%) and 94.7% (95% CI 91.0%-97.5%, I2 =0.0%) in total population, patients with sofosbuvir-based therapies and patients with non sofosbuvir-based therapies respectively. For HCV genotype 1 patients, the pooled SVR12 rate was 93.1% (95% CI 88.3%-96.7%, I2 =20.0%). The pooled incidence of SAEs was 12.1% (95% CI 6.2%-19.7%, I2 =55.0%). The pooled discontinuation rate because of AEs or SAEs in our meta-analysis was 2.2% (95% CI 0.8%-4.4%, I2 =0.0%). CONCLUSIONS: DAA-based antiviral therapies are effective and well tolerated for HCV patients with stage 4-5 chronic kidney disease. PMID- 27943607 TI - Coastal bacterioplankton community response to diatom-derived polysaccharide microgels. AB - Phytoplankton-derived polysaccharide microgels, including transparent exopolymer particles (TEP), are a major component of the marine organic carbon pool. Previous studies have made correlative links between phytoplankton material and bacterioplankton, and performed experiments that assess general responses to phytoplankton, yet there is a lack of direct empirical evidence of specific bacterioplankton responses to natural phytoplankton polysaccharide microgels. In this study, we used diatom produced TEP in controlled incubation experiments to determine the impact of polysaccharide microgels on a coastal bacterioplankton community. Quantification of bacterial 16S rRNA gene transcripts showed that the addition of TEP caused an increase in bacterioplankton activity. Similarly, high throughput sequencing of RT-PCR amplified bacterial 16S rRNA gene transcripts showed that active bacterioplankton community structure and diversity also changed in response to microgels. Alteromonadales and Rhodobacterales increased in abundance in response to TEP, suggesting that both bacterioplankton taxa utilize diatom-derived microgels. However, through assessing 13 C-labelled TEP uptake via RNA Stable Isotope Probing, we show that only the Alteromonadales (genus Alteromonas) assimilated the TEP carbon. This study adds utilization of diatom-derived TEP to the metabolic repertoire of the archetypal copiotrophic bacterioplankton Alteromonas, and indicates that the Rhodobacterales may utilize TEP for other purposes (e.g. attachment sites). PMID- 27943608 TI - Spheroid model for functional osteogenic evaluation of human adipose derived stem cells. AB - 3D culture systems have the ability to mimic the natural microenvironment by allowing better cell-cell interactions. We have prepared an in vitro 3D osteogenic cell culture model using human adipose derived stem cells (hASCs) cultured atop recombinant elastin-like polypeptide (ELP) conjugated to a charged polyelectrolyte, polyethyleneimine (PEI). We demonstrate that hASCs cultured atop the ELP-PEI coated tissue culture polystyrene (TCPS) formed 3D spheroids and exhibited superior differentiation toward osteogenic lineage compared to the traditional two dimensional (2D) monolayer formed atop uncoated TCPS. Live/dead viability assay confirmed >90% live cells at the end of the 3-week culture period. Over the same culture period, higher protein content was observed in 2D monolayer than 3D spheroids, as the 2D environment allowed continued proliferation, while 3D spheroids underwent contact-inhibited growth arrest. The normalized alkaline phosphatase (ALP) activity, which is an indicator for early osteogenic differentiation was higher for 3D spheroids. The normalized osteocalcin (OCN) production, which is an indicator for osteogenic maturation was also higher for 3D spheroids while 2D monolayer had no noticeable OCN production. On day 22, increased Alizarin red uptake by 3D spheroids showed greater mineralization activity than 2D monolayer. Taken together, these results indicate a superior osteogenic differentiation of hASCs in 3D spheroid culture atop ELP PEI coated TCPS surfaces than the 2D monolayer formed on uncoated TCPS surfaces. Such enhanced osteogenesis in 3D spheroid stem cell culture may serve as an alternative to 2D culture by providing a better microenvironment for the enhanced cellular functions and interactions in bone tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1230-1236, 2017. PMID- 27943609 TI - Sulfasalazine might reduce risk of cardiovascular diseases in patients with ankylosing spondylitis: A nationwide population-based retrospective cohort study. AB - AIM: To assess the effects of celecoxib and sulfasalazine on cardiovascular risk in patients with ankylosing spondylitis (AS). METHODS: We performed a 10-year population-based retrospective cohort study. A total of 1208 AS patients and 19 328 non-AS patients were sampled from the Taiwan National Health Insurance (NHI) database. We compared these two groups of patients to identify the differences in the exposure of non-steroidal anti-inflammatory drugs and sulfasalazine and their effects on cardiovascular risk. Univariate analyses were performed using Chi squared tests for dichotomous variables and t-tests for continuous variables. Cox proportional hazard models were conducted to investigate the risk of developing cardiovascular diseases (CVD). RESULTS: AS patients had an adjusted hazard ratio (HR) of 1.72 (CI = 1.46-2.02, P < 0.01) for CVD compared with non-AS controls. The risk increased significantly with the progression of the disease. The use of celecoxib and sulfasalazine provided protective effects against CVD in both groups of patients. Both drugs at high cumulative defined daily doses (DDD) and celecoxib alone at high cumulative DDD showed significant protective effects against CVD in AS patients and the control group, respectively. Sulfasalazine at >= 0.5 DDD (1000 mg/day) reduced CVD risk in patients with AS (HR = 0.65, CI = 0.43-0.998, P < 0.05). CONCLUSIONS: In this population-based retrospective cohort study, sulfasalazine at its optimal dose reduced CVD risk in patients with AS. Celecoxib was neutral regarding CVD risk in AS patients. PMID- 27943610 TI - Covalent Surface Modification of Gallium Arsenide Photocathodes for Water Splitting in Highly Acidic Electrolyte. AB - Efficient water splitting using light as the only energy input requires stable semiconductor electrodes with favorable energetics for the water-oxidation and proton-reduction reactions. Strategies to tune electrode potentials using molecular dipoles adsorbed to the semiconductor surface have been pursued for decades but are often based on weak interactions and quickly react to desorb the molecule under conditions relevant to sustained photoelectrolysis. Here, we show that covalent attachment of fluorinated, aromatic molecules to p-GaAs(1 0 0) surfaces can be employed to tune the photocurrent onset potentials of p-GaAs(1 0 0) photocathodes and reduce the external energy required for water splitting. Results indicate that initial photocurrent onset potentials can be shifted by nearly 150 mV in pH -0.5 electrolyte under 1 Sun (1000 W m-2 ) illumination resulting from the covalently bound surface dipole. Though X-ray photoelectron spectroscopy analysis reveals that the covalent molecular dipole attachment is not robust under extended 50 h photoelectrolysis, the modified surface delays arsenic oxide formation that results in a p-GaAs(1 0 0) photoelectrode operating at a sustained photocurrent density of -20.5 mA cm-2 within -0.5 V of the reversible hydrogen electrode. PMID- 27943611 TI - Femtosecond laser micro-machined polyimide films for cell scaffold applications. AB - Engineering of sophisticated synthetic 3D scaffolds that allow controlling behaviour and location of the cells requires advanced micro/nano-fabrication techniques. Ultrafast laser micro-machining employing a 1030-nm wavelength Yb:KGW femtosecond laser and a micro-fabrication workstation for micro-machining of commercially available 12.7 and 25.4 MUm thickness polyimide (PI) film was applied. Mechanical properties of the fabricated scaffolds, i.e. arrays of differently spaced holes, were examined via custom-built uniaxial micro-tensile testing and finite element method simulations. We demonstrate that experimental micro-tensile testing results could be numerically simulated and explained by two material model, assuming that 2-6 MUm width rings around the holes possessed up to five times higher Young's modulus and yield stress compared with the rest of the laser intacted PI film areas of 'dog-bone'-shaped specimens. That was attributed to material modification around the micro-machined holes in the vicinity of the position of the focused laser beam track during trepanning drilling. We demonstrate that virgin PI films provide a suitable environment for the mobility, proliferation and intercellular communication of human bone marrow mesenchymal stem cells, and discuss how cell behaviour varies on the micro machined PI films with holes of different diameters (3.1, 8.4 and 16.7 MUm) and hole spacing (30, 35, 40 and 45 MUm). We conclude that the holes of 3.1 MUm diameter were sufficient for metabolic and genetic communication through membranous tunneling tubes between cells residing on the opposite sides of PI film, but prevented the trans-migration of cells through the holes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943612 TI - One-Step Microfluidic Synthesis of Nanocomplex with Tunable Rigidity and Acid Switchable Surface Charge for Overcoming Drug Resistance. AB - Multidrug resistance (MDR), is the key reason accounting for the failure of cancer chemotherapy, remains a dramatic challenge for cancer therapy. In this study, the one-step microfluidic fabrication of a rigid pH-sensitive micellar nanocomplex (RPN) with tunable rigidity and acid-switchable surface charge for overcoming MDR by enhancing cellular uptake and lysosome escape is demonstrated. The RPN is composed of a poly(lactic-co-glycolic acid) (PLGA) core and a pH sensitive copolymer shell, which is of neutral surface charge during blood circulation. Upon internalization of RPN by cancer cells, the pH-responsive shell dissociates inside the acidic lysosomes, while the rigid and positively charged PLGA core improves the lysosomal escape. The cellular uptake and nuclear uptake of doxorubicin (Dox) from Dox-loaded RPN are 1.6 and 2.4 times higher than that from Dox-loaded pH-sensitive micelles (PM) using a Dox-resistant cancer model (MCF-7/ADR, re-designated NCI/ADR-RES) in vitro. Dox-loaded RPN significantly enhances the therapeutic efficacy (92% inhibition of tumor growth) against MCF 7/ADR xenograft tumor in mice, while Dox-loaded PM only inhibits the tumor growth by 36%. RPN avoids the use of complicated synthesis procedure of nanoparticle and the necessary to integrate multiple components, which can facilitate the clinical translation of this novel nanostructure. PMID- 27943613 TI - Synergic effects of VEGF-A and SDF-1 on the angiogenic properties of endothelial progenitor cells. AB - Here we investigated the impact of hypoxic environment on the angiogenic properties of early-outgrowth endothelial progenitor cells (EPCs), with particular focus on the role of secreted vascular endothelial growth factor-A (VEGF-A) and stromal derived factor-1 (SDF-1) in mediating these effects. We found that cultured EPCs secreted factors with paracrine effects on chemotaxis, migration, proliferation and tube formation of mature endothelial cells (ECs), and these properties were not affected by hypoxia. Depletion of VEGF-A did not change the ability of EPC-conditioned medium (CM) to promote EC migration and tube formation in vitro, suggesting that the pro-angiogenic paracrine effects of EPCs did not totally rely on the presence of VEGF-A. These findings were confirmed by in vivo experiments, on a mouse model of hind limb ischaemia, which showed that VEGF-depleted EPC-CM sustained tissue perfusion at the same level as complete EPC-CM. However, concomitant deletion of VEGF-A and SDF-1 in EPC-CM impaired the pro-angiogenic properties of EPC-CM, by inhibition of EC spreading in culture, tube-like structure formation on Matrigel support, in vivo neovessels formation and ischaemic hind limb regeneration. Taken together, our data demonstrate that: (i) hypoxia does not affect the capacity of EPCs to support the angiogenic process; (ii) the absence of either VEGF-A or SDF-1 from EPC-CM can be rescued by the presence of the other one, so that the overall angiogenic effects remain unchanged; and (iii) and the concomitant deletion of VEGF-A and SDF-1 from EPC-CM impairs its pro-angiogenic effect, both in vitro and in vivo. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943615 TI - Direct-Writing Multifunctional Perovskite Single Crystal Arrays by Inkjet Printing. AB - Perovskite single-crystalline microplate arrays are directly achieved in large scale by inkjet printing, which present high performance lasing property with quality factors up to 863 and RGB (red-green-blue) emission. This facile, nonlithographic method makes its promising applications on multi-integrated coherent light sources and other high-performance integrated optoelectronic applications. PMID- 27943614 TI - Cardiac tamponade and severe pericardial effusion in systemic sclerosis: report of nine patients and review of the literature. AB - AIM: To describe the clinical characteristics, treatment and outcome of patients with systemic sclerosis (SSc) developing severe pericardial effusion or cardiac tamponade. METHODS: SSc patients with severe pericardial effusion or cardiac tamponade from three Spanish hospitals were collected. In addition, a computer assisted (PubMed, MEDLINE) search of the literature to identify all cases of cardiac tamponade or severe pericardial effusion associated with SSc reported in English, French and Spanish from 1987 through September 2015 was performed. RESULTS: We included 40 patients (nine cases from the Spanish hospitals and 31 cases from the literature review). Most patients (87%) were female with a mean age at pericardial involvement of 49.3 +/- 15.2 years (range: 18-80 years), and 22 (55%) patients had the diffuse cutaneous subtype. Twenty-five (63%) patients presented with cardiac tamponade and the remaining 15 (37%) as severe or massive pericardial effusion. Pericardial involvement was previous or simultaneous to SSc diagnosis in 13 (32.5%) cases. In most cases (88.9%) pericardial fluid analysis disclosed an exudate. Half the patients received steroids and 35% needed surgical treatment. Five (12.5%) patients died due to cardiac tamponade, three of them during the acute phase and the remaining two, 2 and 9 months later, respectively. CONCLUSIONS: Although cardiac tamponade or severe pericardial effusion is an infrequent complication in SSc patients, it can be the first manifestation of disease associated with the diffuse cutaneous subset. No specific treatment for this complication is known. PMID- 27943616 TI - Bis(Cyclic Alkyl Amino Carbene) Ruthenium Complexes: A Versatile, Highly Efficient Tool for Olefin Metathesis. AB - The state-of-the-art in olefin metathesis is application of N-heterocyclic carbene (NHC)-containing ruthenium alkylidenes for the formation of internal C=C bonds and of cyclic alkyl amino carbene (CAAC)-containing ruthenium benzylidenes in the production of terminal olefins. A straightforward synthesis of bis(CAAC)Ru indenylidene complexes, which are highly effective in the formation of both terminal and internal C=C bonds at loadings as low as 1 ppm, is now reported. PMID- 27943617 TI - Relation between postoperative ileus and anastomotic leakage after colorectal resection: a post hoc analysis of a prospective randomized controlled trial. AB - AIM: Anastomotic leakage (AL) following abdominal surgery is a critical determinant of postoperative recovery, of which the aetiology is largely unknown. Interestingly, interventions aimed at reducing the inflammatory response and postoperative ileus (POI) have an unexpected effect on AL. The aim of this study was to investigate the relation of POI with inflammation and AL after colorectal resection. METHOD: A post hoc analysis of a prospective randomized controlled trial in which patients underwent a colorectal resection was performed. Patients undergoing a colorectal resection were stratified into having or not having POI. The incidence of AL and other clinical parameters was registered prospectively. Intestinal fatty acid binding protein (I-FABP, a marker for tissue damage) and the inflammatory response in plasma and colon tissue were determined. RESULTS: AL was present in nine of 43 patients in the POI group, and in one of 65 in the group without POI (P < 0.001). There was a significant association between POI and AL (OR 12.57, 95% CI: 2.73-120.65; P = 0.0005). Patients with POI had significantly higher plasma levels of soluble tumour necrosis factor receptor 1 (TNFRSF1A) at 4 h postoperatively (0.89 ng/l, interquartile range 0.56) than patients without POI (0.80 ng/l, interquartile range 0.37; P = 0.04) and higher plasma levels of C-reactive protein on the second day postoperatively (234 +/- 77 vs 163 +/- 86 mg/l; P = 0.001). Patients who developed AL had significantly higher plasma levels of I-FABP compared with patients without AL at 24 h after onset of surgery. CONCLUSION: POI is associated with a higher prevalence of AL and an increased inflammatory response. PMID- 27943618 TI - Economic analysis of revenue losses and control costs associated with the spotted wing drosophila, Drosophila suzukii (Matsumura), in the California raspberry industry. AB - BACKGROUND: The spotted wing drosophila (SWD), Drosophila suzukii (Matsumura), is an invasive vinegar fly with a preference for infesting commercially viable berries and stone fruits. SWD infestations can reduce yields significantly, necessitating additional management activities. This analysis estimates economic losses in the California raspberry industry that have resulted from the SWD invasion. RESULTS: California raspberry producers experienced considerable revenue losses and management costs in the first years following SWD's invasion of North America. Conventional producers have since developed effective chemical management programs, virtually eliminating revenue losses due to SWD and reducing the cost of management to that of purchasing and applying insecticides more often. Organic raspberry producers, who do not have access to the same chemical controls, continue to confront substantial SWD-related revenue losses. These losses can be mitigated only by applying expensive insecticides registered for organic use and by performing labor-intensive field sanitation. CONCLUSION: SWD's invasion into North America has caused extensive crop losses to berry and cherry crops in California and elsewhere. Agricultural producers and researchers have responded quickly to this pest by developing management programs that significantly reduce revenue losses. Economic losses are expected to continue to fall as producers learn to manage SWD more efficiently and as new control tactics become available. (c) 2016 Society of Chemical Industry. PMID- 27943620 TI - UV reflectance is associated with environmental conditions in Palaearctic Pieris napi (Lepidoptera: Pieridae). AB - The subject of our investigation was the visual features of wing color with special focus on the UV reflectance in the green-veined white butterfly (Pieris napi). Previous studies had concluded that UV reflectance on dorsal wing surfaces is found only in the female P. napi. Based on UV sensitive photography, we analyzed a correlation between 12 geographic and environmental factors and UV reflectance patterns on 3 patches on the forewings of 407 P. napi specimens from the Palaearctic region. Results had shown that females significantly differ from males: they exhibit a 25% higher UV reflectance. To investigate whether and how UV reflectance levels on the forewings and hindwings of both sexes are influenced by the environment, we performed a principal component analysis (PCA) with several environmental variables. For several variables (in particular, latitude and longitude, mean annual temperature and precipitation, and temperature annual range and altitude), the generalized linear model (GLM) model revealed a significant correlation in both sexes. This suggests a link between UV reflectance levels and the environment and distribution of P. napi. We found that stronger UV reflectance is associated with generally more hostile environments and concluded that large-scale environmental factors influence the UV reflectance on the forewings of both male and female green-veined white butterflies. PMID- 27943619 TI - When size matters: differences in demineralized bone matrix particles affect collagen structure, mesenchymal stem cell behavior, and osteogenic potential. AB - Demineralized bone matrix (DBM) is a natural, collagen-based, osteoinductive biomaterial. Nevertheless, there are conflicting reports on the efficacy of this product. The purpose of this study was to evaluate whether DBM collagen structure is affected by particle size and can influence DBM cytocompatibility and osteoinductivity. Sheep cortical bone was ground and particles were divided in three fractions with different sizes, defined as large (L, 1-2 mm), medium (M, 0.5-1 mm), and small (S, <0.5 mm). After demineralization, the chemical-physical analysis clearly showed a particle size-dependent alteration in collagen structure, with DBM-M being altered but not as much as DBM-S. DBM-M displayed a preferable trend in almost all biological characteristics tested, although all DBM particles revealed an optimal cytocompatibility. Subcutaneous implantation of DBM particles into immunocompromised mice resulted in bone induction only for DBM M. When sheep MSC were seeded onto particles before implantation, all DBM particles were able to induce new bone formation with the best incidence for DBM M and DBM-S. In conclusion, the collagen alteration in DBM-M is likely the best condition to promote bone induction in vivo. Furthermore, the choice of 0.5-1 mm particles may enable to obtain more efficient and consistent results among different research groups in bone tissue-engineering applications. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1019-1033, 2017. PMID- 27943621 TI - The protective effect of human platelet lysate in models of neurodegenerative disease: involvement of the Akt and MEK pathways. AB - Neurodegenerative diseases have huge economic and societal impacts, and place an immense emotional burden on patients and caregivers. Given that platelets have an essential physiological role in wound healing and tissue repair, human platelet lysates (HPLs) are being developed as a novel, effective biotherapy for neurodegenerative diseases. HPLs constitute abundant, readily accessible sources of physiological mixtures of many growth factors (GFs), with demonstrable effects on neuron survival and thus the development, maintenance, function and plasticity of the vertebrate nervous system. Here, we found that HPLs had marked neuroprotective abilities in cell-based models of Parkinson's disease and amyotrophic lateral sclerosis (the LUHMES and NSC-34 cell lines, respectively). The HPLs protected against specific cell death pathways (apoptosis and ferroptosis) and specific oxidative stress inducers [1-methyl-4-phenylpyridinium (MPP+) and menadione], and always afforded more protection than commonly used recombinant GFs (rGFs). The mechanism of protection of HPLs involved specific signalling pathways: whereas the Akt pathway was activated by HPLs under all conditions, the MEK pathway appeared to be more specifically involved in protection against MPP+ toxicity in LUHMES and, in a lesser extent, in staurosporine toxicity in NSC-34. Our present results suggest that HPLs-based therapies could be used to prevent neuronal loss in neurodegenerative diseases while overcoming the limitations currently associated with use of rGFs. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943622 TI - Uncertainty quantification of inflow boundary condition and proximal arterial stiffness-coupled effect on pulse wave propagation in a vascular network. AB - This work aims at quantifying the effect of inherent uncertainties from cardiac output on the sensitivity of a human compliant arterial network response based on stochastic simulations of a reduced-order pulse wave propagation model. A simple pulsatile output form is used to reproduce the most relevant cardiac features with a minimum number of parameters associated with left ventricle dynamics. Another source of significant uncertainty is the spatial heterogeneity of the aortic compliance, which plays a key role in the propagation and damping of pulse waves generated at each cardiac cycle. A continuous representation of the aortic stiffness in the form of a generic random field of prescribed spatial correlation is then considered. Making use of a stochastic sparse pseudospectral method, we investigate the sensitivity of the pulse pressure and waves reflection magnitude over the arterial tree with respect to the different model uncertainties. Results indicate that uncertainties related to the shape and magnitude of the prescribed inlet flow in the proximal aorta can lead to potent variation of both the mean value and standard deviation of blood flow velocity and pressure dynamics due to the interaction of different wave propagation and reflection features. Lack of accurate knowledge in the stiffness properties of the aorta, resulting in uncertainty in the pulse wave velocity in that region, strongly modifies the statistical response, with a global increase in the variability of the quantities of interest and a spatial redistribution of the regions of higher sensitivity. These results will provide some guidance in clinical data acquisition and future coupling of arterial pulse wave propagation reduced-order model with more complex beating heart models. PMID- 27943623 TI - Challenges on the road to a multicellular bioartificial liver. AB - Over recent years, the progress in the development of a bioartificial liver (BAL) as an extracorporeal device or as a tissue engineered transplantable organ has been immense. However, many important BAL characteristics that are necessary to meet clinical demands have not been sufficiently addressed. This review describes the existing challenges in the development of a BAL for clinical applications, highlighting multicellularity and sinusoidal microarchitecture as crucial BAL characteristics to fulfil various liver functions. Currently available sources of nonparenchymal liver cells, such as endothelial cells, cholangiocytes and macrophages, used in BAL development are defined. Also, we discuss the recent studies on the reconstruction of the complex liver sinusoid microarchitecture using various liver cell types. Moreover, we highlight some other aspects of a BAL, such as liver zonation and formation of a vascular as well as biliary network for an adequate delivery, biotransformation and removal of substrates and waste products. Finally, the benefits of a multicellular BAL for the pharmaceutical industry are briefly described. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943625 TI - Noise-Corrected Principal Component Analysis of fluorescence lifetime imaging data. AB - Fluorescence Lifetime Imaging (FLIM) is an attractive microscopy method in the life sciences, yielding information on the sample otherwise unavailable through intensity-based techniques. A novel Noise-Corrected Principal Component Analysis (NC-PCA) method for time-domain FLIM data is presented here. The presence and distribution of distinct microenvironments are identified at lower photon counts than previously reported, without requiring prior knowledge of their number or of the dye's decay kinetics. A noise correction based on the Poisson statistics inherent to Time-Correlated Single Photon Counting is incorporated. The approach is validated using simulated data, and further applied to experimental FLIM data of HeLa cells stained with membrane dye di-4-ANEPPDHQ. Two distinct lipid phases were resolved in the cell membranes, and the modification of the order parameters of the plasma membrane during cholesterol depletion was also detected. Noise corrected Principal Component Analysis of FLIM data resolves distinct microenvironments in cell membranes of live HeLa cells. PMID- 27943624 TI - Temporal cross-correlation between influenza-like illnesses and invasive pneumococcal disease in The Netherlands. AB - BACKGROUND: While the burden of community-acquired pneumonia and invasive pneumococcal disease (IPD) is still considerable, there is little insight in the factors contributing to disease. Previous research on the lagged relationship between respiratory viruses and pneumococcal disease incidence is inconclusive, and studies correcting for temporal autocorrelation are lacking. OBJECTIVES: To investigate the temporal relation between influenza-like illnesses (ILI) and IPD, correcting for temporal autocorrelation. METHODS: Weekly counts of ILI were obtained from the Sentinel Practices of NIVEL Primary Care Database. IPD data were collected from the Dutch laboratory-based surveillance system for bacterial meningitis from 2004 to 2014. We analysed the correlation between time series, pre-whitening the dependent time series with the best-fit seasonal autoregressive integrated moving average (SARIMA) model to the independent time series. We performed cross-correlations between ILI and IPD incidences, and the (pre whitened) residuals, in the overall population and in the elderly. RESULTS: We found significant cross-correlations between ILI and IPD incidences peaking at lags -3 overall and at 1 week in the 65+ population. However, after pre whitening, no cross-correlations were apparent in either population group. CONCLUSION: Our study suggests that ILI occurrence does not seem to be the major driver of IPD incidence in The Netherlands. PMID- 27943627 TI - Osteopontin-deficiency disturbs direct osteogenesis in the process of achieving osseointegration following immediate placement of endosseous implants. AB - BACKGROUND: The role of osteopontin (OPN) in the process of achieving osseointegration following implantation remains to be clarified. PURPOSE: This study aimed to analyze the healing patterns of the bone-implant interface after immediate placement of implants in the maxillae of 4-week-old Opn-knockout (KO) and wild-type (WT) mice. MATERIALS AND METHODS: After maxillary first molars were extracted, cavities were prepared with a drill and titanium implants blasted with ceramic abrasives containing hydroxyapatite/beta-tricalcium phosphate were placed. Following fixation at 3, 5, 7, and 28 days after implantation, the samples were analyzed using immunohistochemistry, in situ hybridization, and an electron probe micro analyzer. RESULTS: Two types of bone healing were observed in the process of achieving osseointegration: "direct osteogenesis," where bone formation occurs at the implant surface, and "indirect osteogenesis," where it does at the pre-existing damaged bone surface in the WT mice. Direct osteogenesis occurred after the recruitment of tartrate resistant acid phosphatase-positive cells and the deposition of OPN on the implant surface. In contrast, the rate of osseointegration or direct osteogenesis was significantly low, and cell proliferation was disturbed in the Opn-KO mice. CONCLUSIONS: These results suggest that Opn-deficiency disturbs direct osteogenesis to lead the delayed osseointegration after immediate placement of endosseous implants. PMID- 27943628 TI - Variations in Chemical Composition, Vasorelaxant and Angiotensin I-Converting Enzyme Inhibitory Activities of Essential Oil from Aerial Parts of Seseli pallasii Besser (Apiaceae). AB - The present paper describes environmental and seasonal-related chemical composition variations, vasorelaxant and angiotensin I-converting enzyme (ACE) activities of essential oil from aerial parts of Seseli pallasii Besser. The composition was analyzed by GC and GC/MS. Monoterpenes were found to be the most abundant chemical class with alpha-pinene (42.7 - 48.2%) as the most prevalent component. Seseli pallasi essential oil relaxed isolated endothelium-intact mesenteric arteries rings precontracted with phenylephrine with IC50 = 3.10 nl/ml (IC50 = 2.70 MUg/ml). Also, S. pallasii essential oil was found to exhibit a dose-dependent ACE inhibitory activity with an IC50 value of 0.33 mg/ml. In silico evaluation of ACE inhibitory activity of the individual components showed that spathulenol exhibited the best binding affinity with ACE, and the lowest binding energy of -7.5 kcal/mol. The results suggested that combination of vasorelaxing and ACE inhibitory effects of the analyzed S. pallasii essential oil might have the potential therapeutic significance in hypertension. PMID- 27943629 TI - Predicting rates of in vivo degradation of recombinant spider silk proteins. AB - Developing fundamental tools and insight into biomaterial designs for predictive functional outcomes remains critical for the field. Silk is a promising candidate as a biomaterial for tissue engineering scaffolds, particularly where high mechanical loads or slow rates of degradation are desirable. Although bioinspired synthetic spider silks are feasible biomaterials for this purpose, insight into how well the degradation rate can be programmed by fine tuning the sequence remains to be determined. Here we integrated experimental approaches and computational modelling to investigate the degradation of two bioengineered spider silk block copolymers, H(AB)2 and H(AB)12 , which were designed based on the consensus domains of Nephila clavipes dragline silk. The effect of protein chain length and secondary structure on degradation was analysed in vivo. The degradation rate of H(AB)12 , the silk with longer chain length/higher molecular weight, and higher crystallinity, was slower when compared to H(AB)2 . Using full atomistic modelling, it was determined that the faster degradation of H(AB)2 was due to the lower folded molecular structure of the silk and the greater accessibility to solvent. Comparison of the specific surface areas of proteins via modelling showed that higher exposure of random coil and lower exposure of ordered domains in H(AB)2 led to the more reactive silk with a higher degradation rate when compared with H(AB)12 , as validated by the experimental results. The study, based on two simple silk designs demonstrated that the control of sequence can lead to programmable degradation rates for these biomaterials, providing a suitable model system with which to study variables in protein polymer design to predict degradation rates in vivo. This approach should reduce the use of animal screening, while also accelerating translation of such biomaterials for repair and regenerative systems. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943630 TI - Nitrate addition has minimal short-term impacts on greenland ice sheet supraglacial prokaryotes. AB - Tropospheric nitrate levels are predicted to increase throughout the 21st century, with potential effects on terrestrial ecosystems, including the Greenland ice sheet (GrIS). This study considers the impacts of elevated nitrate concentrations on the abundance and composition of dominant bulk and active prokaryotic communities sampled from in situ nitrate fertilization plots on the GrIS surface. Nitrate concentrations were successfully elevated within sediment filled meltwater pools, known as cryoconite holes; however, nitrate additions applied to surface ice did not persist. Estimated bulk and active cryoconite community cell abundance was unaltered by nitrate additions when compared to control holes using a quantitative PCR approach, and nitrate was found to have a minimal affect on the dominant 16S rRNA gene-based community composition. Together, these results indicate that sampled cryoconite communities were not nitrate limited at the time of sampling. Instead, temporal changes in biomass and community composition were more pronounced. As these in situ incubations were short (6 weeks), and the community composition across GrIS surface ice is highly variable, we suggest that further efforts should be considered to investigate the potential long-term impacts of increased nitrate across the GrIS. PMID- 27943631 TI - Time dilation in simultaneous simulation. PMID- 27943633 TI - Integrated Genome and Protein Editing Swaps alpha-2,6 Sialylation for alpha-2,3 Sialic Acid on Recombinant Antibodies from CHO. AB - Immunoglobin G with alpha-2,6 sialylation has been reported to have an impact on antibody-dependent cellular cytotoxicity and anti-inflammatory efficacy. However, production of antibodies with alpha-2,6 sialylation from Chinese hamster ovary cells is challenging due to the inaccessibility of sialyltransferases for the heavy chain N-glycan site and the presence of exclusively alpha-2,3 sialyltransferases. In this study, combining mutations on the Fc regions to allow sialyltransferase accessibility with overexpression of alpha-2,6 sialyltransferase produced IgG with significant levels of both alpha-2,6 and alpha-2,3 sialylation. Therefore, ST3GAL4 and ST3GAL6 genes were disrupted by CRISPR/Cas9 to minimize the alpha-2,3 sialylation. Sialidase treatment and SNA lectin blot indicated greatly increased alpha-2,6 sialylation level relative to alpha-2,3 sialylation for the alpha-2,3 sialyltransferase knockouts when combined with alpha-2,6 sialyltransferase overexpression. Indeed, alpha-2,3 linked sialic acids were not detected on IgG produced from the alpha-2,3 sialyltransferase knockout-alpha-2,6 sialyltransferase overexpression pools. Finally, glycoprofiling of IgG with four amino acid substitutions expressed from an alpha 2,3 sialyltransferase knockout-alpha-2,6 sialyltransferase stable clone resulted in more than 77% sialylated glycans and more than 62% biantennary disialylated glycans as indicated by both MALDI-TOF and LC-ESI-MS. Engineered antibodies from these modified Chinese hamster ovary cell lines will provide biotechnologists with IgGs containing N-glycans with different structural variations for examining the role of glycosylation on protein performance. PMID- 27943632 TI - Detoxifying symbionts in agriculturally important pest insects. AB - Pest insects lead to excessive agricultural and therefore economical losses on crops worldwide. These insects have to withstand toxic molecules that are inherent to plant defences, as well as those that are produced and introduced by humans in the form of insecticides. In recent years, research on insect-microbe symbioses has recognized that microbial symbionts may play a role protecting against these toxins, leading to a form of defensive symbiosis between the pest insect and different types of microorganisms that we term detoxifying symbioses. In this minireview, we will highlight well-characterized and emerging insect model systems of detoxifying symbioses and assess how the microorganisms influence the host's success. PMID- 27943638 TI - Controlling Heat Release from a Close-Packed Bisazobenzene-Reduced-Graphene-Oxide Assembly Film for High-Energy Solid-State Photothermal Fuels. AB - A closed-cycle system for light-harvesting, storage, and heat release is important for utilizing and managing renewable energy. However, combining a high energy, stable photochromic material with a controllable trigger for solid-state heat release remains a great challenge for developing photothermal fuels (PTFs). This paper presents a uniform PTF film fabricated by the assembly of close-packed bisazobenzene (bisAzo) grafted onto reduced graphene oxide (rGO). The assembled rGO-bisAzo template exhibited a high energy density of 131 Wh kg-1 and a long half-life of 37 days owing to inter- or intramolecular H-bonding and steric hindrance. The rGO-bisAzo PTF film released and accumulated heat to realize a maximum temperature difference (DT) of 15 degrees C and a DT of over 10 degrees C for 30 min when the temperature difference of the environment was greater than100 degrees C. Controlling heat release in the solid-state assembly paves the way to develop highly efficient and high-energy PTFs for a multitude of applications. PMID- 27943637 TI - Quantitative proteomic profiling of paired cancerous and normal colon epithelial cells isolated freshly from colorectal cancer patients. AB - PURPOSE: The heterogeneous structure in tumor tissues from colorectal cancer (CRC) patients excludes an informative comparison between tumors and adjacent normal tissues. Here, we develop and apply a strategy to compare paired cancerous (CEC) versus normal (NEC) epithelial cells enriched from patients and discover potential biomarkers and therapeutic targets for CRC. EXPERIMENTAL DESIGN: CEC and NEC cells are respectively isolated from five different tumor and normal locations in the resected colon tissue from each patient (N = 12 patients) using an optimized epithelial cell adhesion molecule (EpCAM)-based enrichment approach. An ion current-based quantitative method is employed to perform comparative proteomic analysis for each patient. RESULTS: A total of 458 altered proteins that are common among >75% of patients are observed and selected for further investigation. Besides known findings such as deregulation of mitochondrial function, tricarboxylic acid cycle, and RNA post-transcriptional modification, functional analysis further revealed RAN signaling pathway, small nucleolar ribonucleoproteins (snoRNPs), and infection by RNA viruses are altered in CEC cells. A selection of the altered proteins of interest is validated by immunohistochemistry analyses. CONCLUSION AND CLINICAL RELEVANCE: The informative comparison between matched CEC and NEC enhances our understanding of molecular mechanisms of CRC development and provides biomarker candidates and new pathways for therapeutic intervention. PMID- 27943640 TI - The discovery of LRRK2 p.R1441S, a novel mutation for Parkinson's disease, adds to the complexity of a mutational hotspot. PMID- 27943639 TI - Genetic prion disease: Experience of a rapidly progressive dementia center in the United States and a review of the literature. AB - Although prion diseases are generally thought to present as rapidly progressive dementias with survival of only a few months, the phenotypic spectrum for genetic prion diseases (gPrDs) is much broader. The majority have a rapid decline with short survival, but many patients with gPrDs present as slowly progressive ataxic or parkinsonian disorders with progression over a few to several years. A few very rare mutations even present as neuropsychiatric disorders, sometimes with systemic symptoms such as gastrointestinal disorders and neuropathy, progressing over years to decades. gPrDs are caused by mutations in the prion protein gene (PRNP), and have been historically classified based on their clinicopathological features as genetic Jakob-Creutzfeldt disease (gJCD), Gerstmann-Straussler Scheinker (GSS), or Fatal Familial Insomnia (FFI). Mutations in PRNP can be missense, nonsense, and octapeptide repeat insertions or a deletion, and present with diverse clinical features, sensitivities of ancillary testing, and neuropathological findings. We present the UCSF gPrD cohort, including 129 symptomatic patients referred to and/or seen at UCSF between 2001 and 2016, and compare the clinical features of the gPrDs from 22 mutations identified in our cohort with data from the literature, as well as perform a literature review on most other mutations not represented in our cohort. E200K is the most common mutation worldwide, is associated with gJCD, and was the most common in the UCSF cohort. Among the GSS-associated mutations, P102L is the most commonly reported and was also the most common at UCSF. We also had several octapeptide repeat insertions (OPRI), a rare nonsense mutation (Q160X), and three novel mutations (K194E, E200G, and A224V) in our UCSF cohort. (c) 2016 Wiley Periodicals, Inc. PMID- 27943642 TI - Characterization of the first cultured representative of a Bacteroidetes clade specialized on the scavenging of cyanobacteria. AB - The anaerobic, mesophilic and moderately halophilic strain L21-Spi-D4T was recently isolated from the suboxic zone of a hypersaline cyanobacterial mat using protein-rich extracts of Arthrospira (formerly Spirulina) platensis as substrate. Phylogenetic analyses based on 16S rRNA genes indicated an affiliation of the novel strain with the Bacteroidetes clade MgMjR-022, which is widely distributed and abundant in hypersaline microbial mats and heretofore comprised only sequences of uncultured bacteria. Analyses of the complete genome sequence of strain L21-Spi-D4T revealed a possible specialization on the degradation of cyanobacterial biomass. Besides genes for enzymes degrading specific cyanobacterial proteins a conspicuous transport complex for the polypeptide cyanophycin could be identified that is homologous to typical polysaccharide utilization loci of Bacteroidetes. A distinct and reproducible co-occurrence pattern of environmental 16S rRNA gene sequences of the MgMjR-022 clade and cyanobacteria in the suboxic zone of hypersaline mats points to a specific dependence of members of this clade on decaying cyanobacteria. Based on a comparative analysis of phenotypic, genomic and ecological characteristics we propose to establish the novel taxa Salinivirga cyanobacteriivorans gen. nov., sp. nov., represented by the type strain L21-Spi-D4T , and Salinivirgaceae fam. nov., comprising sequences of the MgMjR-022 clade. PMID- 27943643 TI - The development of spatial and memory circuits in the rat. AB - We provide a concise review of recent studies related to the development of neural circuits supporting spatial navigation and memory in the rat. We chart the relative timeline of the emergence of the four main classes of spatially tuned neurons within the hippocampus and related limbic areas: head direction cells emerge earliest (postnatal day 12, P12), before the eyes of the rats are even open, followed by place cells and boundary responsive cells; grid cells emerge last, around the age of weaning (P21). The rate of maturation is unique to each type of neuron, with the head direction and grid cells showing rapid developmental spurts, in contrast to place cells, which show a more gradual trend of maturation. Interestingly, the emergence of allocentric spatial abilities occurs only after the full complement of spatial neurons becomes functional at P20-21, whereas associative processing in the place cell network is evident from as early as P16. We also present evidence supporting the view that the sensory inputs, which are particularly salient to adult spatial networks, may not be essential for the immature spatial system. Crucially, visual information, although more salient than other sensory modalities for anchoring the adult head direction system, does not appear to be essential for setting up the immature head direction network. We conclude by highlighting an urgent need for new theoretical models that can account for the sequential emergence of spatial cells, as well as the lack of primacy of vision in the early organization of the head direction network. WIREs Cogn Sci 2017, 8:e1424. doi: 10.1002/wcs.1424 For further resources related to this article, please visit the WIREs website. PMID- 27943644 TI - Quercetin-Based Modified Porous Silicon Nanoparticles for Enhanced Inhibition of Doxorubicin-Resistant Cancer Cells. AB - One of the most challenging obstacles in nanoparticle's surface modification is to achieve the concept that one ligand can accomplish multiple purposes. Upon such consideration, 3-aminopropoxy-linked quercetin (AmQu), a derivative of a natural flavonoid inspired by the structure of dopamine, is designed and subsequently used to modify the surface of thermally hydrocarbonized porous silicon (PSi) nanoparticles. This nanosystem inherits several advanced properties in a single carrier, including promoted anticancer efficiency, multiple drug resistance (MDR) reversing, stimuli-responsive drug release, drug release monitoring, and enhanced particle-cell interactions. The anticancer drug doxorubicin (DOX) is efficiently loaded into this nanosystem and released in a pH dependent manner. AmQu also effectively quenches the fluorescence of the loaded DOX, thereby allowing the use of the nanosystem for monitoring the intracellular drug release. Furthermore, a synergistic effect with the presence of AmQu is observed in both normal MCF-7 and DOX-resistant MCF-7 breast cancer cells. Due to the similar structure as dopamine, AmQu may facilitate both the interaction and internalization of PSi into the cells. Overall, this PSi-based platform exhibits remarkable superiority in both multifunctionality and anticancer efficiency, making this nanovector a promising system for anti-MDR cancer treatment. PMID- 27943645 TI - Color Processing in Synesthesia: What Synesthesia Can and Cannot Tell Us About Mechanisms of Color Processing. AB - Synesthetic experiences of color have been traditionally conceptualized as a perceptual phenomenon. However, recent evidence suggests a role of higher order cognition in the formation of synesthetic experiences. Here, we discuss how synesthetic experiences of color differ from and influence veridical color processing, and how non-perceptual processes such as imagery and color memory might play a role in eliciting synesthetic color experience. PMID- 27943641 TI - Genomic variants, genes, and pathways of Alzheimer's disease: An overview. AB - Alzheimer's disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia. With the gradual aging of the world's population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets. Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately ~20 genes with common variants contributing to LOAD risk. In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses. Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple low frequency and rare variant contributors to AD, and discuss on-going efforts with next-generation sequencing studies to develop statistically well- powered and comprehensive genomic studies of AD. Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD. (c) 2016 Wiley Periodicals, Inc. PMID- 27943647 TI - A case of cryopyrin-associated periodic fever syndrome due to Q703K mutation in the NLRP3 gene. PMID- 27943648 TI - Production of p-Methylstyrene and p-Divinylbenzene from Furanic Compounds. AB - A four-step catalytic process was developed to produce p-methylstyrene from methylfuran, a biomass-derived species. First, methylfuran was acylated over zeolite H-Beta with acetic anhydride. Second, the acetyl group was reduced to an ethyl group with hydrogen over copper chromite. Third, p-ethyltoluene was formed through Diels-Alder cycloaddition and dehydration of 2-ethyl-5-methyl-furan with ethylene over zeolite H-Beta. Dehydrogenation of p-ethyltoluene to yield p methylstyrene completes the synthesis but was not investigated because it is a known process. The first two steps were accomplished in high yield (>88 %) and the Diels-Alder step resulted in a 67 % yield of p-ethyltoluene with a 99.5 % selectivity to the para isomer (final yield of 53.5 %). The methodology was also used for the preparation of p-divinylbenzene. It is shown that acylation of furans over H-Beta zeolites is a highly selective and high-yield reaction that could be used to produce other valuable molecules from biomass-derived furans. PMID- 27943649 TI - A comprehensive meta-analysis on dietary flavonoid and lignan intake and cancer risk: Level of evidence and limitations. AB - SCOPE: To summarize available evidence on the association between dietary flavonoid as well as lignan intake and cancer risk in observational studies. METHODS AND RESULTS: A systematic search on electronic databases of all English language case-control and prospective studies published up to June 2016 was performed. Risk ratios (RRs) and 95% confidence intervals were calculated by random-effects model separately by study design. Heterogeneity and publication bias were tested. Out of the 143 studies included, meta-analyses of prospective studies showed isoflavones significantly associated with decreased risk of lung and stomach cancers and nearly significant breast and colorectal cancers; total flavonoids showed nonsignificant decreased risk of breast cancer. Meta-analyses of case-control studies showed: total and/or individual classes of flavonoids associated with upper aero-digestive tract, colorectal, breast, and lung cancers; isoflavones with ovarian, breast, and colorectal cancers, endometrial and lung cancers. CONCLUSIONS: Most evidence reported in previous meta-analyses was driven by case-control studies. Overall results may be promising but are inconclusive. Further prospective cohorts assessing dietary polyphenol exposure and studies using other methods to evaluate exposure (i.e. markers of consumption, metabolism, excretion) are needed to confirm and determine consumption levels required to achieve health benefits. PMID- 27943650 TI - Modern trends in biophotonics for clinical diagnosis and therapy to solve unmet clinical needs. AB - This contribution covers recent original research papers in the biophotonics field. The content is organized into main techniques such as multiphoton microscopy, Raman spectroscopy, infrared spectroscopy, optical coherence tomography and photoacoustic tomography, and their applications in the context of fluid, cell, tissue and skin diagnostics. Special attention is paid to vascular and blood flow diagnostics, photothermal and photodynamic therapy, tissue therapy, cell characterization, and biosensors for biomarker detection. PMID- 27943646 TI - Cancer and inflammation. AB - The relationship between inflammation and cancer has been recognized since the 17th century,1 and we now know much about the cells, cytokines and physiological processes that are central to both inflammation and cancer.2-9 Chronic inflammation can induce certain cancers,10-17 and solid tumors, in turn, can initiate and perpetuate local inflammatory processes that foster tumor growth and dissemination.5 ,18-20 Consequently, inflammatory pathways have been targeted in attempts to control cancer.21-23 Inflammation is a central aspect of the innate immune system's response to tissue damage or infection, and also facilitates the recruitment of circulating cells and antibodies of the adaptive immune response to the tissue. Components of the innate immune response carry out a robust, but sometimes overly-conservative response, sacrificing specificity for the sake of preservation. Thus, when innate immunity goes awry, it can have profound implications. How the innate and adaptive immune systems cooperate to neutralize pathogens and repair damaged tissues is still an area of intense investigation. Further, how these systems can respond to cancer, which arises from normal 'self' cells that undergo an oncogenic transformation, has profound implications for cancer therapy. Recently, immunotherapies that activate adaptive immunity have shown unprecedented promise in the clinic, producing durable responses and dramatic increases in survival rate in patients with advanced stage melanoma.24 26 Consequently, the relationship between cancer and inflammation has now returned to the forefront of clinical oncology. WIREs Syst Biol Med 2017, 9:e1370. doi: 10.1002/wsbm.1370 For further resources related to this article, please visit the WIREs website. PMID- 27943651 TI - Controllably Switched Drug Release from Successively Dual-Targeted Nanoreservoirs. AB - The development of a nanocarrier with a capacity of releasing therapeutic agent "on demand" is of great importance for enhancing drug efficacy and reducing its side effect. Here, a multifunctional mesoporous silica nanoparticle is presented for cancer therapy. This nanoparticle can not only successively target tumor tissue and tumor cells but also has a function of controllably switching the drug release. Low molecular weight poly(ethyleneimine) segments, which are decorated on the surface of magnetic mesoporous silica nanoparticle with disulfide bonds, are chemically cross-linked, leading to the mesopores being "closed" in blood circulation but being "open" via taking off the coating in cytoplasm. As a result, the encapsulated drug can be kept in nanoparticles in the normal conditions, while be rapidly released in a reduction condition. In vivo antitumor activity demonstrates that this nanoparticle has the highest safety to body and the best therapeutic efficacy against tumors. Therefore, this work presents a good example of rational design of nanocarriers for highly effective cancer therapy. PMID- 27943653 TI - Cross-resistance to three phenylpyrazole insecticides and A2'N mutation detection of GABA receptor subunit in fipronil-resistant Laodelphax striatellus (Hemiptera: Delphacidae). AB - BACKGROUND: Laodelphax striatellus (Fallen) is an important pest of crops in East Asia. Over the past decade, phenylpyrazole insecticides, which target the insect GABA receptor, have increasingly been used as alternatives against rice planthoppers. RESULTS: Cross-resistance to ethiprole and butene-fipronil was detected in a laboratory-selected fipronil-resistant strain of L. striatellus (LsFR). Compared with a fipronil-susceptible strain (LsFS), LsFR had obtained a high-level resistance to fipronil (112.1-fold) and moderate resistance to ethiprole (24.5-fold) and butene-fipronil (14.7-fold). For the resistance of field populations, LC50 values of ethiprole were remarkably higher than the other two analogues in Gaochun and Yancheng populations in 2016. Significant correlations were demonstrated between the LC50 values of three phenylpyrazole insecticides (R = 0.944-0.998, P = 0.007-0.016). Additionally, an AS-PCR assay was developed to detect the A2'N mutant GABA receptor in L. striatellus strains or populations. It was noteworthy that mutation frequencies of 19.2 and 3.6% appeared in Lujiang and Gaochun populations in 2016, respectively. Furthermore, there was an extremely significant difference in genomic expression of Lsrdl between the LsFS and LsFR individuals (1.85-fold, F = 26.8, P = 0.0008). CONCLUSIONS: This study could help us better understand the cross-resistance mechanisms in L. striatellus, and be beneficial for proposing effective pest management strategies of phenylpyrazole resistance. (c) 2016 Society of Chemical Industry. PMID- 27943652 TI - Gallic acid improves endothelium-dependent vasodilatory response to histamine in the mesenteric vascular bed of diabetic rats. AB - BACKGROUND: Endothelial dysfunction is one of the many complications caused by diabetes mellitus. The aim of the present study was to evaluate the effects of gallic acid (GA) on the mesenteric vascular bed (MVB) response to histamine in diabetic rats. METHODS: Forty male Wistar rats were randomly assigned to a control group, an untreated alloxan-induced diabetic group and three diabetic groups treated with different doses of GA. Six weeks after induction of diabetes and GA treatment, total antioxidant capacity (TAC), malondialdehyde (MDA) concentrations, and the vasodilatory response to histamine of the MVB (measured as changes in perfusion pressure) were determined. RESULTS: The vasodilatory response to histamine and TAC decreased, whereas MDA increased in the plasma from diabetic rats (P < 0.01). However, in the presence of 3 * 10-5 mol/L N G -nitro l-arginine methyl ester (a nitric oxide synthase inhibitor) and 1 * 10-5 mol/L indomethacin (an inhibitor of prostaglandin production), the vasodilatory response of the MVB to histamine was reduced in all groups (P < 0.001). Treatment of diabetic rats with 20 and 40 mg/kg per day GA, but not 10 mg/kg per day GA, increased TAC and decreased MDA concentrations (P < 0.01 and P < 0.001 vs untreated diabetic rats, respectively) and significantly improved the vasodilatory response to histamine (P < 0.05 and P < 0.001, respectively). CONCLUSION: The results show that, in diabetic rats, the endothelium-dependent vasodilatory response of the MVB to histamine is significantly decreased and depends on both nitric oxide- and prostaglandin-producing pathways and may be mediated by oxidative stress. Treatment with the antioxidant GA restored the vasodilatory response of the MVB to histamine. PMID- 27943654 TI - HLA-DRB1 shared epitope alleles in patients with rheumatoid arthritis: relation to autoantibodies and disease severity in a south Indian population. AB - AIM: To investigate the presence of the 'shared epitope' (SE) in the HLA-DRB1 alleles in patients with RA and to ascertain the frequency of the HLA-DRB1 alleles with autoantibodies (anti-cyclic citrullinated peptide [anti-CCP] rheumatoid factor [RF]) and disease severity. METHODS: A total of 200 RA patients and 200 apparently healthy subjects participated in the study. HLA-DRB1 were genotyped using polymerase chain reaction with sequence-specific primer (PCR SSP). Anti-CCP and RF in serum were determined by in vitro quantitative enzyme linked immunosorbent assay (ELISA) method. Erythrocyte sedimentation rate (ESR) was measured by Westergren method. Disease activity was assessed by using the disease activity score-28 (DAS-28). Chi-square test and Student's t-test were used in the statistical analysis. RESULTS: A significant increase in the frequency of HLA-DRB1*01, *04, *10 and *14 were identified in RA patients and showed a strong association with the disease susceptibility. While the frequencies of HLA-DRB1*03, *07, *11 and *13 were significantly lower in RA patients than in controls. The other HLA-DRB1 alleles *08, *09, *12, *15 and *16 showed no significant difference. The frequency of anti-CCP and RF antibodies did not showed significant difference in SE-positive patients compared with SE negative patients. DAS-28 values of RA patients showed no significant difference between SE-positive and SE-negative groups. CONCLUSION: Our results indicate that HLA-DRB1*01, *04, *10 and *14 alleles are related with RA, while HLA-DRB1*03, *07, *11 and *13 protect against RA in our population. On the other hand, we failed to provide evidence for the association of the autoantibodies and DAS-28 with SE-positive RA patients. PMID- 27943655 TI - Mechanistic Insights into the Unique Role of Copper in CO2 Electroreduction Reactions. AB - Cu demonstrates a unique capability towards CO2 electroreduction that can close the anthropogenic carbon cycle; however, its reaction mechanism remains elusive, owing to the obscurity of the solid-liquid interface on Cu surfaces where electrochemical reactions occur. Using a genetic algorithm method in addition to density functional theory, we explicitly identify the configuration of a water bilayer on Cu(2 1 1) and build electrochemical models. These enable us to reveal a mechanistic picture for CO2 electroreduction, finding the key intermediates CCO* for the C2 H4 pathway and CH* for the CH4 pathway, which rationalize a series of experimental observations. Furthermore, we find that the interplay between the Cu surfaces, carbon monomers, and water network (but not the binding of CO*) essentially determine the unique capability of Cu towards CO2 electroreduction, proposing a new and effective descriptor for exploiting optimal catalysts. PMID- 27943657 TI - A drop array culture for patterning adherent mouse embryonic stem cell-derived neurospheres. AB - New therapeutic approaches for repairing an injured or degenerating nervous system have accelerated the development of methods to generate populations of neurons derived from various stem cell sources efficiently. Many of these methods require the generation of neurospheres. Here a simple technique is described for creating an array of adherent mouse embryonic stem cell (mESC)-derived neurospheres using a conventional plastic culture dish and a patterning template. mESC-derived neurospheres are confined to circular (4-mm diameter), gel-coated regions within an array. The adherent neurosphere arrays require 3 days to prepare from an mESC source; they can be maintained in 15 MUl drops of medium, and exhibit extensive neurite elaboration after 8 days of cultivation. Additionally, the potential of treating the adherent neurospheres in selected drops of an array is demonstrated with a variety of differentiation-inducing reagents and subsequently individually analysing such neurospheres for gene expression, protein levels and morphological development. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943656 TI - Decellularization of human donor aortic and pulmonary valved conduits using low concentration sodium dodecyl sulfate. AB - The clinical use of decellularized cardiac valve allografts is increasing. Long term data will be required to determine whether they outperform conventional cryopreserved allografts. Valves decellularized using different processes may show varied long-term outcomes. It is therefore important to understand the effects of specific decellularization technologies on the characteristics of donor heart valves. Human cryopreserved aortic and pulmonary valved conduits were decellularized using hypotonic buffer, 0.1% (w/v) sodium dodecyl sulfate and nuclease digestion. The decellularized tissues were compared to cellular cryopreserved valve tissues using histology, immunohistochemistry, quantitation of total deoxyribose nucleic acid, collagen and glycosaminoglycan content, in vitro cytotoxicity assays, uniaxial tensile testing and subcutaneous implantation in mice. The decellularized tissues showed no histological evidence of cells or cell remnants and >97% deoxyribose nucleic acid removal in all regions (arterial wall, muscle, leaflet and junction). The decellularized tissues retained collagen IV and von Willebrand factor staining with some loss of fibronectin, laminin and chondroitin sulfate staining. There was an absence of major histocompatibility complex Class I staining in decellularized pulmonary valve tissues, with only residual staining in isolated areas of decellularized aortic valve tissues. The collagen content of the tissues was not decreased following decellularization however the glycosaminoglycan content was reduced. Only moderate changes in the maximum load to failure of the tissues were recorded postdecellularization. The decellularized tissues were noncytotoxic in vitro, and were biocompatible in vivo in a mouse subcutaneous implant model. The decellularization process will now be translated into a good manufacturing practices-compatible process for donor cryopreserved valves with a view to future clinical use. Copyright (c) 2016 The Authors Tissue Engineering and Regenerative Medicine published by John Wiley & Sons, Ltd. PMID- 27943658 TI - Objective identification of dental abnormalities with multispectral fluorescence imaging. AB - Sensitive methods that can enable early detection of dental diseases (caries and calculus) are desirable in clinical practice. Optical spectroscopic approaches have emerged as promising alternatives owing to their wealth of molecular information and lack of sample preparation requirements. In the present study, using multispectral fluorescence imaging, we have demonstrated that dental caries and calculus can be objectively identified on extracted tooth. Spectral differences among control, carious and calculus conditions were attributed to the porphyrin pigment content, which is a byproduct of bacterial metabolism. Spectral maps generated using different porphyrin bands offer important clues to the spread of bacterial infection. Statistically significant differences utilizing fluorescence intensity ratios were observed among three groups. In contrast to laser induced fluorescence, these methods can provide information about exact spread of the infection and may aid in long term dental monitoring. Successful adoption of this approach for routine clinical usage can assist dentists in implementing timely remedial measures. PMID- 27943659 TI - The fabrication and characterization of a multi-laminate, angle-ply collagen patch for annulus fibrosus repair. AB - One major limitation of intervertebral disc (IVD) repair is that no ideal biomaterial has been developed that effectively mimics the angle-ply collagen architecture and mechanical properties of the native annulus fibrosus (AF). Furthermore, it would be beneficial to devise a simple, scalable process by which to manufacture a biomimetic biomaterial that could function as a mechanical repair patch to be secured over a large defect in the outer AF that will support AF tissue regeneration. Such a biomaterial would: (1) enable the employment of early-stage interventional strategies to treat IVD degeneration (i.e. nucleus pulposus arthroplasty); (2) prevent IVD re-herniation in patients with large AF defects; and (3) serve as a platform to develop full-thickness AF and whole IVD tissue engineering strategies. Due to the innate collagen fibre alignment and mechanical strength of pericardium, a procedure was developed to assemble multi laminate angle-ply AF patches derived from decellularized pericardial tissue. Patches were subsequently assessed histologically to confirm angle-ply microarchitecture, and mechanically assessed for biaxial burst strength and tensile properties. Additionally, patch cytocompatibility was evaluated following seeding with bovine AF cells. This study demonstrated the effective removal of porcine cell remnants from the pericardium, and the ability to reliably produce multi-laminate patches with angle-ply architecture using a simple assembly technique. Resultant patches demonstrated their inherent ability to resist biaxial burst pressures reminiscent of intradiscal pressures commonly borne by the AF, and exhibited tensile strength and modulus values reported for native human AF. Furthermore, the biomaterial supported AF cell viability, infiltration and proliferation. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943660 TI - Clinical-scale expansion of adipose-derived stromal cells starting from stromal vascular fraction in a single-use bioreactor: proof of concept for autologous applications. AB - Adipose-derived stromal cells (ASCs) are adult multipotent cells increasingly used for cell therapy due to their differentiation potential, their paracrine effect and their convenience. ASCs are currently selected from stromal vascular fractions (SVFs) of adipose tissue and expanded in 2D flasks following good manufacturing practices. This process is limited in surface area, labour intensive and expensive, especially for autologous applications requiring selection and expansion steps for every patient. Closed and automated bioreactors offer an alternative for scalable and cost-effective production of ASCs. This study investigated a single-use stirred-tank bioreactor that can expand ASCs from SVFs on microcarriers. A preliminary microcarrier screening in static and spinner flask conditions was performed to evaluate the best candidate for adhesion, amplification and harvest. The selected microcarrier was used for process development in the bioreactor. The first experiments showed poor selectivity and growth of the ASCs from the SVF (n = 2). The process was then adjusted by two means: (1) decreasing the platelet lysate in the medium for enhancing cell adherence; and (2) adding a shear protectant (Pluronic F68). Following these modifications, we demonstrated that the number of population doublings of ASCs from SVFs was not significantly different between the bioreactor and the 2D controls (n = 3). In addition, the ASC characterization after culture showed that cells maintained their clonogenic potential, phenotype, differentiation potential and immunosuppressive capacities. This study provides the proof of concept that isolation and amplification of functional ASCs from SVFs can be performed in a stirred-tank bioreactor combined with microcarriers. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943661 TI - Peer-assisted learning for foundation doctors. AB - BACKGROUND: Peer-assisted learning (PAL) is a widely accepted learner-led educational model encouraging cooperative active learning. Whereas attention has historically focussed on the use of PAL in undergraduate contexts, less is known about the benefits and challenges of using PAL for postgraduate clinical trainees. This study describes the implementation and evaluation of a PAL scheme for UK foundation-year trainees (newly qualified doctors). METHODS: Following a needs assessment, a peer-led component was introduced into the weekly foundation teaching programme at the hospital. Each week a peer tutor presented a topic relevant to the foundation curriculum, and peer participants provided written feedback. Questionnaire-based evaluation of the scheme was conducted 7 months after implementation. RESULTS: Ninety-eight per cent of trainees completed the evaluation. Eighty-eight per cent were satisfied with the PAL scheme. Crucially, PAL was seen to address historic barriers to effective learning. Educational content seemed to be better matched to the learning needs and experience of learners, with particular value placed on case-based peer discussions. Furthermore, PAL seemed to promote a learning environment in which questions and conjectures could be safely shared. Although some peer tutors found presenting to peers anxiety-provoking, the majority agreed that PAL not only helped develop their teaching ability but also positively impacted on their everyday clinical work. Less is known about the benefits and challenges of using PAL for postgraduate clinical trainees DISCUSSION: The PAL scheme was well received by participants and supports its use outside of its traditional undergraduate focus. Trainees identified a number of pedagogical benefits through serving as both tutor and tutee. Delivering teaching skills and feedback skills training were identified as future developments to further maximise the educational benefits of PAL. PMID- 27943664 TI - Introduction to Volume 8, Issue 4 of topiCS. PMID- 27943662 TI - Development of Polymer Microcapsules Functionalized with Fucoidan to Target P Selectin Overexpressed in Cardiovascular Diseases. AB - New tools for molecular imaging and targeted therapy for cardiovascular diseases are still required. Herein, biodegradable microcapsules (MCs) made of polycyanoacrylate and polysaccharide and functionalized with fucoidan (Fuco-MCs) are designed as new carriers to target arterial thrombi overexpressing P selectin. Physicochemical characterizations demonstrated that microcapsules have a core-shell structure and that fucoidan is present onto the surface of Fuco-MCs. Furthermore, their sizes range from 2 to 6 um and they are stable on storage over 30 d at 4 degrees C. Flow cytometry experiments evidenced the binding of Fuco MCs for human activated platelets as compared to MCs (mean fluorescence intensity: 12 008 vs. 9, p < 0.001) and its absence for nonactivated platelets (432). An in vitro flow adhesion assay showed high specific binding efficiency of Fuco-MCs to P-selectin and to activated platelet aggregates under arterial shear stress conditions. Moreover, both types of microcapsules reveal excellent compatibility with 3T3 cells in cytotoxicity assay. One hour after intravenous injection of microcapsules, histological analysis revealed that Fuco-MCs are localized in the rat abdominal aortic aneurysm thrombotic wall and that the binding in the healthy aorta is low. In conclusion, these microcapsules appear as promising carriers for targeting of tissues characterized by P-selectin overexpression and for their molecular imaging or treatment. PMID- 27943665 TI - Combination therapy of autologous adipose mesenchymal stem cell-enriched, high density lipoaspirate and topical timolol for healing chronic wounds. AB - Chronic venous leg ulcers are profoundly debilitating and result in billions in health care expenditure. Thus, there is a quest for engineered and innovative approaches. Herein we present a 63-year-old patient with a 30 year history of venous stasis and left lower extremity ulcers, which have been refractory to standard of care, anticoagulation and venous stripping. The medial ulcer was treated with transplantation of autologous adipose mesenchymal stem cell (AMSC) enriched, high-density lipoaspirate (HDL) on OASIS wound matrix and compression therapy. The lateral ulcer was treated as a control with standard debridement and compression therapy. Four weeks later, both ulcers received daily topical timolol. Three months later, the test ulcer was completely epithelized and remains healed for over 15 months. However, the control showed minimal signs of improvement. In companion studies in our laboratory, human AMSC were cultured in Minimum Essential Medium Eagle Alpha Modifications (MEMalpha) with fetal bovine serum (FBS). Timolol was administered to AMSC prior to treatment with epinephrine and 104 bacteria/ml heat-killed Staphylococcus aureus. The MEMalpha with FBS devoid of AMSC served as a background control. After 24 h, cell culture supernatants and protein lysates were collected to determine cytokine production. There was a statistical significant decrease in pro-inflammatory interleukin-6 and -8 induced by the bacteria (to model the wound environment) in AMSC in the presence of timolol compared with control (p < 0.5). This is the first case of a successful combination of autologous AMSC-enriched, HDL with topical timolol for the healing of chronic venous leg ulcers. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27943666 TI - Synthesis of TiC Nanoparticles Anchored on Hollow Carbon Nanospheres for Enhanced Polysulfide Adsorption in Li-S Batteries. AB - A novel spatial confinement strategy based on a carbon/TiO2 /carbon sandwich structure is proposed to synthesize TiC nanoparticles anchored on hollow carbon nanospheres (TiC@C) through a carbothermal reduction reaction. During the synthesis process, two carbon layers not only serve as reductant to convert TiO2 into TiC nanoparticles, but also create a spatial confinement to suppress the aggregation of TiO2 , resulting in the formation of well-dispersed TiC nanoparticles. This unique TiC@C structure shows an outstanding long-term cycling stability at high rates owing to the strong physical and chemical adsorption of lithium polysulfides (i.e., a high capacity of 732.6 mA h g-1 at 1600 mA g-1 ) and it retains a capacity of 443.2 mA h g-1 after 1000 cycles, corresponding to a decay rate of only 0.0395 % per cycle. Therefore, this unique TiC@C composite could be considered as an important candidate for the cathode material in Li-S batteries. PMID- 27943667 TI - Intrinsic Phonon Bands in High-Quality Monolayer T' Molybdenum Ditelluride. AB - The topologically nontrivial and chemically functional distorted octahedral (T') transition-metal dichalcogenides (TMDCs) are a type of layered semimetal that has attracted significant recent attention. However, the properties of monolayer (1L) T'-TMDC, a fundamental unit of the system, are still largely unknown due to rapid sample degradation in air. Here we report that well-protected 1L CVD T'-MoTe2 exhibits sharp and robust intrinsic Raman bands, with intensities about 1 order of magnitude stronger than those from bulk T'-MoTe2. The high-quality samples enabled us to reveal the set of all nine even-parity zone-center optical phonons, providing reliable fingerprints for the previously elusive crystal. By performing light polarization and crystal orientation resolved scattering analysis, we can effectively distinguish the intrinsic modes from Te-metalloid-like modes A (~122 cm-1) and B (~141 cm-1), which are related to the sample degradation. Our studies offer a powerful nondestructive method for assessing sample quality and for monitoring sample degradation in situ, representing a solid advance in understanding the fundamental properties of 1L-T'-TMDCs. PMID- 27943668 TI - Electrochemical Charging of CdSe Quantum Dots: Effects of Adsorption versus Intercalation. AB - Effects of electrochemical charging of quantum dots (QDs) have been reported previously, wherein optical and electrical properties could be modulated through cation adsorption and electron injection into the quantum-confined 1Se states. In this work, we report two different modes of electrochemical double-layer charging in CdSe QDs and their effects on the electronic and optical properties. We show that the charging mechanism at the interface involves cation intercalation for smaller ions, such as Li+, Na+, or K+, and cation adsorption for larger bulky ions, such as tetrabutylammonium ions, where steric hindrance precludes intercalation. As a result, while cation adsorption leads to an increase in the absorbance in the mid-infrared spectral range, cation intercalation into the CdSe core results in an absorbance increase from the visible to infrared spectral range, an enhancement in radiative lifetime of e-, an increase of 158% in the intensity of band-edge photoluminescence, and strong emission in the near infrared spectral range as a result of the formation of Se vacancies. The nature of charging mechanisms is discussed using the results of combined photoluminescence, radiative lifetime, and X-ray photoemission studies. The cation-coupled electronic and optical modulation reported here in CdSe QDs have important implications for electrochromic smart windows, photovoltaics, and other devices. PMID- 27943669 TI - Synthesis of 3-Fluoroindoles via Photoredox Catalysis. AB - A method for the synthesis of 3-fluoroindoles from N-arylamines substituted with the CF2I group is described. The reaction is mediated by a ruthenium photocatalyst in the presence of a substoichiometric amount of triphenylphosphine upon irradiation with blue light. The starting N-arylamines are readily obtained by nucleophilic iododifluoromethylation of iminium ions. PMID- 27943670 TI - Effective and Selective Trapping of Volatile Organic Sulfur Derivatives by Montmorillonite Intercalated with a MU-oxo Fe(III)-Phenanthroline Complex. AB - The MU-oxo Fe(III)-phenanthroline complex [(OH2)3(Phen)FeOFe(Phen) (OH2)3]+4 intercalated in montmorillonite provides a stable hybrid material. In this study, the ability and efficiency of this material to immobilize thiols in gas phase, acting as a trap at the solid-gas interface, were investigated. Aliphatic thiols containing both hydrophilic and hydrophobic end groups were chosen to test the selectivity of this gas trap. DR-UV-vis, IR, elemental analysis, thermal analysis and evolved gas mass spectrometry, X-ray powder diffraction, and X-ray absorption spectroscopy techniques were employed to characterize the hybrid material before and after thiol exposure and to provide information on the entrapping process. Thiol immobilization is very large, up to 21% w/w for heptanethiol. In addition, evidence was obtained that immobilization occurs through the formation of a covalent bond between the iron of the complex and the sulfur of the thiol. This provides an immobilization process characterized by a higher stability with respect to the methods based on physi-adsorption. Thiol immobilization resulted thermally reversible at least for 20 adsorption/desorption cycles. Unlike standard desulfurization processes like hydrotreating and catalytic oxidation which work at high temperatures and pressures, the present system is able to efficiently trap thiols at room temperature and pressure, thus saving energy. Furthermore, we found that the selectivity of thiol immobilization can be tuned acting on the amount of complex intercalated in montmorillonite. In particular, montmorillonite semisaturated with the complex captures both hydrophobic and hydrophilic thiols, while the saturated montmorillonite shows a strong selectivity toward the hydrophobic molecules. PMID- 27943671 TI - Smart Optical Composite Materials: Dispersions of Metal-Organic Framework@Superparamagnetic Microrods for Switchable Isotropic-Anisotropic Optical Properties. AB - A smart optical composite material with dynamic isotropic and anisotropic optical properties by combination of luminescence and high reflectivity was developed. This combination enables switching between luminescence and angle-dependent reflectivity by changing the applied wavelength of light. The composite is formed as anisotropic core/shell particles by coating superparamagnetic iron oxide silica microrods with a layer of the luminescent metal-organic framework (MOF) 3infinity[Eu2(BDC)3].2DMF.2H2O (BDC2- = 1,4-benzenedicarboxylate). The composite particles can be rotated by an external magnet. Their anisotropic shape causes changes in the reflectivity and diffraction of light depending on the orientation of the composite particle. These rotation-dependent optical properties are complemented by an isotropic luminescence resulting from the MOF shell. If illuminated by UV light, the particles exhibit isotropic luminescence while the same sample shows anisotropic optical properties when illuminated with visible light. In addition to direct switching, the optical properties can be tailored continuously between isotropic red emission and anisotropic reflection of light if the illuminating light is tuned through fractions of both UV and visible light. The integration and control of light emission modes within a homogeneous particle dispersion marks a smart optical material, addressing fundamental directions for research on switchable multifunctional materials. The material can function as an optic compass or could be used as an optic shutter that can be switched by a magnetic field, e.g., for an intensity control for waveguides in the visible range. PMID- 27943672 TI - Hematite Reduction Buffers Acid Generation and Enhances Nutrient Uptake by a Fermentative Iron Reducing Bacterium, Orenia metallireducens Strain Z6. AB - Fermentative iron-reducing organisms have been identified in a variety of environments. Instead of coupling iron reduction to respiration, they have been consistently observed to use ferric iron minerals as an electron sink for fermentation. In the present study, a fermentative iron reducer, Orenia metallireducens strain Z6, was shown to use iron reduction to enhance fermentation not only by consuming electron equivalents, but also by generating alkalinity that effectively buffers the pH. Fermentation of glucose by this organism in the presence of a ferric oxide mineral, hematite (Fe2O3), resulted in enhanced glucose decomposition compared with fermentation in the absence of an iron source. Parallel evidence (i.e., genomic reconstruction, metabolomics, thermodynamic analyses, and calculation of electron transfer) suggested hematite reduction as a proton-consuming reaction effectively consumed acid produced by fermentation. The buffering effect of hematite was further supported by a greater extent of glucose utilization by strain Z6 in media with increasing buffer capacity. Such maintenance of a stable pH through hematite reduction for enhanced glucose fermentation complements the thermodynamic interpretation of interactions between microbial iron reduction and other biogeochemical processes. This newly discovered feature of iron reducer metabolism also has significant implications for groundwater management and contaminant remediation by providing microbially mediated buffering systems for the associated microbial and/or chemical reactions. PMID- 27943673 TI - Quantification of Greenhouse Gas Emissions from the Predisposal Stage of Municipal Solid Waste Management. AB - Municipal solid waste (MSW) disposal represents one of the largest sources of anthropogenic greenhouse gas (GHG) emissions. However, the biogenic GHG emissions in the predisposal stage of MSW management (i.e., the time from waste being dropped off in community or household garbage bins to being transported to disposal sites) are excluded from the IPCC inventory methodology and rarely discussed in academic literature. Herein, we quantify the effluxes of carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) from garbage bins in five communities along the urban-rural gradient in Beijing in four seasons. We find that the annual average CO2, CH4, and N2O effluxes in the predisposal stage were (1.6 +/- 0.9)103, 0.049 +/- 0.016, and 0.94 +/- 0.54 mg kg-1h-1 (dry matter basis) and had significant seasonal differences (24- to 159-fold) that were strongly correlated with temperature. According to our estimate, the N2O emission in the MSW predisposal stage amounts to 20% of that in the disposal stage in Beijing, making the predisposal stage a nontrivial source of waste-induced N2O emissions. Furthermore, the CO2 and CH4 emissions in the MSW predisposal account for 5% (maximum 10% in summer) of the total carbon contents in a Beijing's household food waste stream, which has significance in the assessment of MSW related renewable energy potential and urban carbon cycles. PMID- 27943674 TI - Net-Zero-Energy Model for Sustainable Wastewater Treatment. AB - A large external energy input prevents wastewater treatment from being environmentally sustainable. A net-zero-energy (NZE) wastewater treatment concept based on biomass energy recycling was proposed to avoid wasting resources and to promote energy recycling in wastewater treatment plants (WWTPs). Simultaneously, a theoretical model and boundary condition based on energy balance were established to evaluate the feasibility of achieving NZE in WWTPs; the model and condition were employed to analyze data from 20 conventional WWTPs in China. A total of six WWTPs can currently export excess energy, eight WWTPs can achieve 100% energy self-sufficiency by adjusting the metabolic material allocation, and six municipal WWTPs cannot achieve net-zero energy consumption based on the evaluation of the theoretical model. The NZE model offset 79.5% of the electricity and sludge disposal cost compared with conventional wastewater treatment. The NZE model provides a theoretical basis for the optimization of material regulation for the effective utilization of organic energy from wastewater and promotes engineering applications of the NZE concept in WWTPs. PMID- 27943676 TI - Development of a Multiplex Real-Time PCR for Determination of Apricot in Marzipan Using the Plexor System. AB - Marzipan is a confectionary which is mostly offered in form of filled chocolate, pralines, or pure. According to the German guidelines for oil seeds only almonds, sugar and water are admitted ingredients of marzipan. A product very similar in taste is persipan which is used in the confectionary industry because of its stronger flavor. For persipan production almonds are replaced by debittered apricot or peach kernels. To guarantee high quality products for consumers, German raw paste producers have agreed a limit of apricot kernels in marzipan raw paste of 0.5%. Different DNA-based methods for quantitation of persipan contaminations in marzipan are already published. To increase the detection specificity compared to published intercalation dye-based assays, the present work demonstrate the utilization of a multiplex real-time PCR based on the Plexor technology. Thus, the present work enables the detection of at least 0.1% apricot DNA in almond DNA or less. By analyzing DNA mixtures, the theoretical limit of quantification of the duplex PCR for the quantitation of persipan raw paste DNA in marzipan raw paste DNA was determined as 0.05%. PMID- 27943675 TI - Mechanism of Shiga Toxin Clustering on Membranes. AB - The bacterial Shiga toxin interacts with its cellular receptor, the glycosphingolipid globotriaosylceramide (Gb3 or CD77), as a first step to entering target cells. Previous studies have shown that toxin molecules cluster on the plasma membrane, despite the apparent lack of direct interactions between them. The precise mechanism by which this clustering occurs remains poorly defined. Here, we used vesicle and cell systems and computer simulations to show that line tension due to curvature, height, or compositional mismatch, and lipid or solvent depletion cannot drive the clustering of Shiga toxin molecules. By contrast, in coarse-grained computer simulations, a correlation was found between clustering and toxin nanoparticle-driven suppression of membrane fluctuations, and experimentally we observed that clustering required the toxin molecules to be tightly bound to the membrane surface. The most likely interpretation of these findings is that a membrane fluctuation-induced force generates an effective attraction between toxin molecules. Such force would be of similar strength to the electrostatic force at separations around 1 nm, remain strong at distances up to the size of toxin molecules (several nanometers), and persist even beyond. This force is predicted to operate between manufactured nanoparticles providing they are sufficiently rigid and tightly bound to the plasma membrane, thereby suggesting a route for the targeting of nanoparticles to cells for biomedical applications. PMID- 27943677 TI - Yolk/Shell Colloidal Crystals Incorporating Movable Cores with Their Motion Controlled by an External Electric Field. AB - Yolk/shell particles composed of a submicrometer-sized movable core and a silica shell are promising building blocks for novel optical colloidal crystals, because the locations of cores in the shell compartment can be reversibly changed by using external stimuli. Two dimensional arrays of yolk/shell particles incorporating movable cores were prepared by a self-assembly method. The movable cores of colloidal crystals in water could be observed with an optical microscope under application of external electric field. The motions of inner silica cores depended on the electric field strength and frequency and were categorized into three cases: (1) Random Brownian motion, (2) anisotropic motion of cores moving in a direction orthogonal to a field, and (3) suppressed motion fixed in the center of shell compartment. Random Brownian motion of cores was scarcely affected by field strength when a high frequency (in the MHz range) electric field was applied. On the other hand, an increase in field strength at low frequency fields (kHz) transiently changed the core motion from (1) to (2) and a further increase in field strength changed it from (2) to (3). When the silica core was incorporated in a large void a stronger electric field was needed to suppress its motion than when it was in a small void. The high responsivity to electric fields in a low-frequency range indicated the importance of electric double layer (EDL) interaction between core and inner shell in controlling the core location in yolk/shell colloidal crystals. It was also shown that movable titania cores in yolk/shell particles required a low-frequency field with a high strength to change from the random to anisotropic motion. The result suggested that the electrostatic interaction between EDLs of the silica core and the inner silica wall could be stronger than that between EDLs of the titania core and the silica shell. PMID- 27943678 TI - Cytotoxicity of Tirapazamine (3-Amino-1,2,4-benzotriazine-1,4-dioxide)-Induced DNA Damage in Chicken DT40 Cells. AB - Tirapazamine (TPZ) is an anticancer drug with highly selective cytotoxicity toward hypoxic cells. TPZ is converted to a radical intermediate under hypoxic conditions, and this intermediate interacts with intracellular macromolecules, including DNA. TPZ has been reported to indirectly induce DNA double-strand breaks (DSBs) through the formation of various intermediate DNA lesions under hypoxic conditions. Although the topoisomerase II-DNA complex has been identified as one of these intermediates, other lesions have not yet been defined. In order to obtain a deeper understanding of the mechanisms responsible for the selective cytotoxicity of TPZ toward hypoxic cells, its cellular sensitivity was systematically examined with genetically isogenic DNA-repair-deficient mutant DT40 cell lines. Our results showed that tdp1-/-, tdp2-/-, parp1-/-, and aptx1-/- cells displayed hypersensitivity to TPZ only under hypoxic conditions. These results strongly suggest that the accumulation of the topoisomerase I-trapped DNA complex, topoisomerase II-trapped DNA complex, and abortive ligation products with 5'-AMP are the potential causes of TPZ-induced hypoxic cell death. Furthermore, our genetic analysis revealed that under normoxic conditions (as well as hypoxic conditions), TPZ exhibited significant cytotoxicity toward cell lines deficient in homologous recombination, nonhomologous end joining, base excision repair, and translesion synthesis. Ascorbic acid, a radical scavenger, suppressed TPZ-induced cytotoxicity toward normoxic cells. These results suggest the involvement of oxidative DNA damage and DSBs produced by reactive oxygen species generated from superoxide, a byproduct of the oxidation of TPZ radical intermediates in normoxic cells. Collectively, our results demonstrate that TPZ induces oxidative DNA damage under normoxic and hypoxic conditions and selectively introduces abortive topoisomerase-DNA complexes and unligatable DNA ends under hypoxic conditions. PMID- 27943679 TI - Alternative Synthesis Route of Biocompatible Polyvinylpyrrolidone Nanoparticles and Their Effect on Pathogenic Microorganisms. AB - Herein we describe a novel alternative synthesis route of polyvinylpyrrolidone nanoparticles using salting-out method at a temperature close to polyvinylpyrrolidone decomposition. At elevated temperatures, the stability of polyvinylpyrrolidone decreases and the opening of pyrrolidone ring fractions occurs. This leads to cross-linking process, where separate units of polyvinylpyrrolidone interact among themselves and rearrange to form nanoparticles. The formation/stability of these nanoparticles was confirmed by transmission electron microscopy, X-ray photoelectron spectroscopy, mass spectrometry, infrared spectroscopy, and spectrophotometry. The obtained nanoparticles possess exceptional biocompatibility. No toxicity and genotoxicity was found in normal human prostate epithelium cells (PNT1A) together with their high hemocompatibility. The antimicrobial effects of polyvinylpyrrolidone nanoparticles were tested on bacterial strains isolated from the wounds of patients suffering from hard-to-heal infections. Molecular analysis (qPCR) confirmed that the treatment can induce the regulation of stress-related survival genes. Our results strongly suggest that the polyvinylpyrrolidone nanoparticles have great potential to be developed into a novel antibacterial compound. PMID- 27943681 TI - Antimicrobial resistance: a global threat with remarkable geographical differences. PMID- 27943680 TI - Progression of Lung Disease in Preschool Patients with Cystic Fibrosis. AB - RATIONALE: Implementation of intervention strategies to prevent lung damage in early cystic fibrosis (CF) requires objective outcome measures that capture and track lung disease. OBJECTIVES: To define the utility of the Lung Clearance Index (LCI), measured by multiple breath washout, as a means to track disease progression in preschool children with CF. METHODS: Children with CF between the ages of 2.5 and 6 years with a confirmed diagnosis of CF and age-matched healthy control subjects were enrolled at three North American CF centers. Multiple breath washout tests were performed at baseline, 1, 3, 6, and 12 months to mimic time points chosen in clinical care and interventional trials; spirometry was also conducted. A generalized linear mixed-effects model was used to distinguish LCI changes associated with normal growth and development (i.e., healthy children) from the progression of CF lung disease. MEASUREMENTS AND MAIN RESULTS: Data were collected on 156 participants with 800 LCI measurements. Although both LCI and spirometry discriminated health from disease, only the LCI identified significant deterioration of lung function in CF over time. The LCI worsened during cough episodes and pulmonary exacerbations, whereas similar symptoms in healthy children were not associated with increased LCI values. CONCLUSIONS: LCI is a useful marker to track early disease progression and may serve as a tool to guide therapies in young patients with CF. PMID- 27943682 TI - Where Does Dynamic Value Assessment Fit Into Our Role as Agents Advising Our Patients With Cancer? PMID- 27943683 TI - Evolution of Low-Grade Glioma Therapy. PMID- 27943684 TI - Treatment Strategies for Low-Grade Glioma in Adults. AB - Diffuse low-grade gliomas include oligodendrogliomas and astrocytomas. The recent 2016 WHO classification has now updated the definition of these tumors to include molecular characterization, including the presence of isocitrate dehydrogenase mutation and 1p/19q codeletion. In this new classification, the histologic subtype of grade II mixed oligoastrocytoma has been eliminated. Treatment recommendations are currently evolving, mainly because of a change in the prognostic factors that are based on molecular and cytogenetic features. Standard of care includes maximal safe surgical resection. Prior randomized clinical trials stratified treatment arms on the basis of extent of resection and age, with patients stratified into low risk (age younger than 40 years and gross total resection) and high risk (age older than 40 years or subtotal resection). Patients who are low risk may undergo routine magnetic resonance imaging surveillance after resection. On the basis of recently published data, it is now recommended that high-risk patients undergo a combination of both radiation and chemotherapy after surgery. These studies, however, do not address the management of patients with low-grade gliomas in the era of genomic medicine. These treatments can also have great impact on quality of life, and therefore treatment recommendations should be done on an individual basis taking into account the current pathology classification, age, extent of resection, quality of life, and patient preference. PMID- 27943685 TI - Front-Line Treatment of Metastatic Colorectal Cancer. PMID- 27943686 TI - Erratum. PMID- 27943687 TI - Role of Biologics in Colon Cancer: Still Not Clear. PMID- 27943688 TI - Redefining Management of Adult Low-Grade Gliomas. PMID- 27943689 TI - Role of Biologics in First-Line Treatment of Colorectal Cancer. AB - In the past decade, significant advances have been made in the treatment of advanced colorectal cancer. Multiple cytotoxic agents and targeted therapies have been approved for management of metastatic colorectal cancer, leading to improvement of median overall survival in clinical trials to more than 30 months. Of note, before the introduction of biologics into treatment algorithms for metastatic colorectal cancer, median survival in phase III trials never exceeded 24 months. In 2016, the most common treatment approach in first line is a combination of chemotherapy with a biologic agent. The choice of therapy is influenced by patient factors (eg, age, comorbidities), tumor characteristics (eg, overall tumor burden, pattern of metastatic spread, mutation signature), potential adverse effects of therapy, and goals of treatment. The choice between irinotecan- or oxaliplatin-based cytotoxic chemotherapy regimen is primarily based on differential toxicity profile because they have similar efficacy. Currently, three biologic agents-bevacizumab, cetuximab, and panitumumab-are approved for first-line treatment of metastatic colorectal cancer. For patients with mutant RAS and likely mutant BRAF V600E tumors, bevacizumab is the only biologic agent that can be used in conjunction with cytotoxic chemotherapy. The choice of anti-epidermal growth factor antibody or anti-vascular endothelial growth factor antibody in RAS wild-type tumors is based on the specific clinical scenario. Recently, some clinical and molecular biomarkers have emerged that may help in decision making. In this review, we discuss the role of biologics in the management of first-line treatment of metastatic colorectal cancer. PMID- 27951402 TI - Editorial Comment. PMID- 27951401 TI - Does the choice of definition for defibrillation and CPR success impact the predictability of ventricular fibrillation waveform analysis? AB - BACKGROUND: Quantitative analysis of ventricular fibrillation (VF), such as amplitude spectral area (AMSA), predicts shock outcomes. However, there is no uniform definition of shock/cardiopulmonary resuscitation (CPR) success in out-of hospital cardiac arrest (OHCA). The objective of this study is to investigate post-shock rhythm variations and the impact of shock/CPR success definition on the predictability of AMSA. METHODS: A total of 554 shocks from 257 OHCA patients with VF as initial rhythm were analyzed. Post-shock rhythms were analyzed every 5s up to 120s and annotated as VF, asystole (AS) and organized rhythm (OR) at serial time intervals. Three shock/CPR success definitions were used to evaluate the predictability of AMSA: (1) termination of VF (ToVF); (2) return of organized electrical activity (ROEA); (3) return of potentially perfusing rhythm (RPPR). RESULTS: Rhythm changes occurred after 54.5% (N=302) of shocks and 85.8% (N=259) of them occurred within 60s after shock delivery. The observed post-shock rhythm changes were (1) from AS to VF (24.9%), (2) from OR to VF (16.1%), and (3) from AS to OR (12.1%). The area under the receiver operating characteristic curve (AUC) for AMSA as a predictor of shock/CPR success reached its maximum 60s post shock. The AUC was 0.646 for ToVF, 0.782 for ROEA, and 0.835 for RPPR (p<0.001) respectively. CONCLUSIONS: Post-shock rhythm is unstable in the first minute after the shock. The predictability of AMSA varies depending on the definition of shock/CPR success and performs best with the return of potentially perfusing rhythm endpoint for OHCA. PMID- 27951404 TI - Reply by Authors. PMID- 27951403 TI - Editorial Comment. PMID- 27951405 TI - Editorial Comment. PMID- 27951406 TI - Editorial Comment. PMID- 27951407 TI - Editorial Comment. PMID- 27951408 TI - Editorial Comment. PMID- 27951409 TI - The contribution of keratinocytes in capecitabine-stimulated hand-foot-syndrome. AB - Capecitabine, as the first-line treatment for multiple tumor types, has a serious drawback of hand-foot-syndrome (HFS) that limits its clinical use. However, the pathophysiology and mechanism of capecitabine-induced HFS is rarely known. Here we built the experimental mouse model of HFS induced by capecitabine at first and it was shown that 3 of 6 mice appeared HFS in the 5th day and 5 mice occurred HFS in the 30th day. The corneous layer was reduced in capecitabine-induced HFS in vivo. Moreover, we found that capecitabine could significantly induce keratinocytes cells death in vitro through activated apoptosis pathway and decreased mitochondrial membrane potential. In conclusion, these results suggested that HFS of capecitabine may be developed from reduction of corneous layer through stimulation of intracellular mitochondrial dysfunction following activation of caspase-dependent apoptosis pathway. PMID- 27951410 TI - Non-syndromic severe hypodontia caused by a novel frameshift insertion mutation in the homeobox of the MSX1 gene. AB - OBJECTIVE: Inherited congenital anomalies in tooth number, particularly hypodontia are relatively common. Although substantial progress has been made that permits a better understanding of the causes of tooth agenesis, overall knowledge of the phenotype:genotype correlations in this anomaly are still lacking. The aim in this study was to identify the causal gene mutation(s) in a family of two sisters with severe hypodontia (oligodontia) including 2nd premolars and 1st and 3rd molars, using whole exome sequencing (WES). METHODS: WES was performed using in-solution hybridization, followed by massively parallel sequencing. RESULTS: A frameshift insertion of 7 basepairs (GCAAGTT) in the homebox of MSX1 gene located in the exon 2 in heterozygous state has been identified in both sisters (NM_002448:exon2:c.572_573ins GCAAGTT: p.F191fs). CONCLUSION: We conclude that this frameshift mutation in the homeodomain (which plays an essential role in DNA binding) of MSX1 gene is responsible for tooth agenesis in this family. This expands the phenotype-genotype correlation associated with MSX1 mutations. PMID- 27951411 TI - Bioavailability enhancement of itraconazole-based solid dispersions produced by hot melt extrusion in the framework of the Three Rs rule. AB - Solid dispersion formulations made of itraconazole (ITZ) and Soluplus(r) (polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer abbreviated SOL) were produced using hot melt extrusion. Since ITZ possesses a water solubility of less than 1ng/mL, the aim of this work was to enhance the aqueous solubility of ITZ, and thereby improve its bioavailability. The three formulations consisted of a simple SOL/ITZ amorphous solid dispersion (ASD), an optimized SOL/ITZ/AcDiSol(r) (super-disintegrant) ASD and an equimolar inclusion complex of ITZ in hydroxypropyl-beta-cyclodextrin (substitution degree=0.63, CD) with SOL. The three formulations were compared in vitro and in vivo to the marketed product Sporanox(r). The in vitro enhancement of dissolution rate was evaluated using a biphasic dissolution test. In vitro dissolution results showed that all three formulations had a higher percentage of ITZ released than Sporanox(r) with the following ranking: SOL/ITZ/CD>SOL/ITZ/AcDiSol(r)>SOL/ITZ>Sporanox(r). The bioavailability of these four formulations was evaluated in rats. The bioanalytical method was optimized so that only 10MUL of blood was withdrawn from the rats using specific volumetric absorptive microsampling devices. This enabled to keep the same rats during the whole study, which was in accordance with the Three Rs rules (reduction, refinement and replacement). Furthermore, this technique allowed the suppression of inter-individual variability. Higher Cmax and AUC were obtained after the administration of all three formulations compared to the levels after the use of Sporanox(r) as follows: SOL/ITZ/AcDiSol(r)>SOL/ITZ/CD>SOL/ITZ>Sporanox(r). The inversion in the ranking between SOL/ITZ/CD and SOL/ITZ/AcDiSol(r) made impossible the establishment of an in vitro-vivo correlation. Indeed, very different release rates were obtained in vitro and in vivo for the two optimized formulations. These results suggest that ITZ would be protected inside the core of the SOL micelles even during the absorption step at the intestine, while some agents present in the intestinal fluids could displace ITZ from the hydrophobic cavity of CD by competition. PMID- 27951412 TI - Increased cortical capillary transit time heterogeneity in Alzheimer's disease: a DSC-MRI perfusion study. AB - Alzheimer's disease (AD) is characterized by the accumulation of hyperphosphorylated tau and neurotoxic Abeta in the brain parenchyma. Hypoxia caused by microvascular changes and disturbed capillary flows could stimulate this build-up of AD-specific proteins in the brain. In this study, we compared cerebral microcirculation in a cohort of AD and mild cognitive impairment (MCI) patients with that of age-matched controls, all without a history of diabetes or of hypertension for more than 2 years, using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI). Vascular flow disturbances were quantified using a parametric model and mapped to the mid-cortical surface for group-wise statistical analysis. We found widespread hypoperfusion in patients compared with controls and identified areas of increased relative capillary transit time heterogeneity (RTH), consistent with low tissue oxygen tension. Notably, RTH was positively correlated with white matter hyperintensities and positively correlated with symptom severity in the patient cohort. These correlations extended over large parts of the temporal, parietal, and frontal cortices. The results support the hypothesis of disturbed capillary flow patterns in AD and suggest that DSC-MRI may provide imaging biomarkers of impaired cerebral microcirculation in AD. PMID- 27951413 TI - Immunometabolic parameters in overweight dogs during weight loss with or without an exercise program. AB - The influence of physical activity on metabolic health in overweight dogs is unknown. This study was conducted to evaluate biomarkers of immunometabolic health in relation to changes in physical activity and adiposity. Client-owned overweight dogs participated in a 12-wk intervention based on caloric restriction combined with a training program (fitness and diet [FD] group, n = 8), or caloric restriction alone (diet-only [DO] group, n = 8). Physical activity was monitored by accelerometry. All dogs were fed the same diet and achieved similar weight loss. Fasting blood samples were collected before and after 6- and 12-wk intervention. Insulin resistance was evaluated from plasma insulin and C-peptide as well as homeostasis model assessment. Inflammation and dyslipidemia were evaluated from circulating leptin, adiponectin, C-reactive protein (CRP), monocyte chemoattractant factor-1 (MCP-1), interleukin-8 (IL-8), and cholesterol. Accelerometer counts in both groups were high compared with previous reports of physical activity in overweight dogs. No difference in blood parameters was evident between groups, evaluated by linear mixed-effects model (P > 0.05). Within the groups, the following changes were significant by t-test (P < 0.05): leptin decreased in both groups. Within the FD group, IL-8, MCP-1, and CRP decreased at 6 wk and IL-8 and cholesterol at 12 wk. Within the DO group, C peptide and HOMA decreased at 6 wk and C-peptide at 12 wk. We conclude that, for both groups, weight loss resulted in minor indications of improved immunometabolic health, whereas this level of physical activity did not add further benefits. PMID- 27951414 TI - Mental time travel to the future might be reduced in sleep. AB - We present a quantitative study of mental time travel to the future in sleep. Three independent, blind judges analysed a total of 563 physiology-monitored mentation reports from sleep onset, REM sleep, non-REM sleep, and waking. The linguistic tool for the mentation report analysis is based on established grammatical and cognitive-semantic theories and has been validated in previous studies. Our data indicate that REM and non-REM sleep must be characterized by a reduction in mental time travel to the future, which would support earlier physiological evidence at the level of brain function. PMID- 27951415 TI - Tetraploidy/near-tetraploidy acute myeloid leukemia. AB - A tetraploid/near tetraploid (T/NT) karyotype is a rare finding in acute myeloid leukemia (AML). Here we report 38 AML patients with a T/NT karyotype, including 26 men and 12 women with a median age of 65 years. T/NT karyotype was detected at initial diagnosis of AML in 16 patients, and acquired during the course of disease in 22 patients. All patients showed large blasts with frequent prominent nucleoli, cytoplasmic vacuoles and/or inclusions, nuclear irregularity and/or budding. Eleven patients had a non-complex and 27 had a complex T/NT karyotype; 21 patients also had pseudodiploid and/or triploid clones. After T/NT karyotype detection, 32 patients received chemotherapy and 10 also received stem cell transplant. After a median of 6.2 months follow-up, 32 patients died of disease or complications, 5 were alive with complete remission, and 1 alive with persistent AML. Median overall survival (OS) was 5 months. Patients with a non complex T/NT karyotype had a significantly superior OS compared to those with a complex T/NT karyotype (10.7 vs. 3.4 months, p=0.0280). We conclude that T/NT karyotype in AML is often associated with distinctive morphologic features and conveys generally poor outcomes. Distinction of complex versus non-complex T/NT karyotype provides further prognostic information. PMID- 27951416 TI - Nicotine versus 6-hydroxy-l-nicotine against chlorisondamine induced memory impairment and oxidative stress in the rat hippocampus. AB - 6-Hydroxy-l-nicotine (6HLN), a nicotine derivative from nicotine degradation by Arthrobacter nicotinovorans pAO1 strain was found to improve behavioral deficits and to reverse oxidative stress in the rat hippocampus. Rats were given CHL (10mg/kg, i.p.) were used as an Alzheimer's disease-like model. The nicotine (0.3mg/kg) and 6HLN (0.3mg/kg) were administered alone or in combination in the CHL-treated rats. Memory-related behaviors were evaluated using Y-maze and radial arm-maze tests. The antioxidant enzymes activity and the levels of the biomarkers of oxidative stress were measured in the hippocampus. Statistical analyses were performed using two-way ANOVA and Tukey's post hoc test. F values for which p<0.05 were regarded as statistically significant. CHL-caused memory deficits and oxidative stress enhancing were observed. Both nicotine and 6HLN administration attenuated the cognitive deficits and recovered the antioxidant capacity in the rat hippocampus of the CHL rat model. Our results suggest that 6HLN versus nicotine confers anti-amnesic properties in the CHL-induced a rat model of memory impairment via reversing cholinergic function and decreasing brain oxidative stress, suggesting the use of this compound as an alternative agent in AD treatment. PMID- 27951417 TI - Synthesis and evaluation of analgesic, behavioral effects and chronic toxicity of the new 3,5-diaminopyrazole and its precursor the thiocyanoacetamide. AB - This study aimed to explore the analgesic, antioxidant, behavioral and toxicological effects of 3,5-diaminopyrazole and thiocyanoacetamide. Caffeine was used as reference drug whose effects are known after oral treatment with an efficient dose (10mg/kg/day) for 30days. The preliminary bioassays indicated that both compounds at this dose have strong antioxidant capacities and present highly analgesic effects. The behavioral study showed an activation of the rat memory by thiocyanoacetamide. This molecule caused a phobia state to open areas in the elevated plus maze and specifically agoraphobia in the open field with a lack in the development of the exploratory capacity. 3,5-Diaminopyrazole caused memory troubles in rats that forgot the pathway to the exit from the maze, and induced an anxiety state revealed by immobility in closed arms of the elevated plus maze. All these observations were compared to the treatment by the known analgesic, caffeine, which increased the state of vigilance of the rats and developed their exploratory capacity. The chronic treatment with the investigated compounds showed no sign of toxicity with the absence of effect on the body and organ weights, blood count, kidney and liver function and histology. 3,5 Diaminopyrazole and thiocyanoacetamide have potent antioxidant and analgesic activities that are higher than caffeine with a safety profile. The chronic treatment by thiocyanoacetamide activated the memory and caused an emotional state of agoraphobia, but 3,5-diaminopyrazole caused a memory impairment and an emotional state of anxiety. Thus, the present study warrants further investigations involving these novel molecules for a possible development of new strong analgesic and antioxidant drugs which have an effect on the memory capacity. PMID- 27951418 TI - Comparison of the DWI and Gd-EOB-DTPA-enhanced MRI on assessing the hepatic ischemia and reperfusion injury after partial hepatectomy. AB - OBJECTIVE: To compare two different imaging media, diffusion weighted imaging (DWI) with apparent diffusion coefficient (ADC) and Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) with perfusion parameters Ktrans, Kep, and relative contrast enhancement index (RCEI), in assessing the liver function via ischemia/perfusion injury (IRI) + partial hepatectomy rat model. METHODS: Rats underwent 0, 30 and 60min of ischemia/reperfusion with 30% of hepatectomy before subjected to Gd-EOB-DTPA-enhanced MRI in addition to 99mTc-GSA scintigraphy. For 99mTc-GSA scintigraphy test, the receptor index LHL15, modified receptor index and the blood clearance index HH15 were recorded. Apparent diffusion coefficient (ADC) was evaluated by using both mono- and bi-exponential models, and perfusion parameters Ktrans, Kep, and RCEI were measured. Liver function is tested by measuring activity of serum ALT, AST and PT. Histological analysis was performed by H&E and Ki-67 staining. RESULTS: 99mTc-GSA dynamic imaging analysis demonstrated that LHL15 was increased and HH15 was decreased as the extension of ischemia/reperfusion time. ADC value estimated by MRI was significantly increased (P<0.05) in 30min IRI group compared with 0min and 60min IRI groups, respectively. Ktrans value was gradually and significantly decreased (P<0.05) as the extension of IRI time, but there was no significant difference (P>0.05) in Kep value between at 30min and 60min IRI, and RCEI value was significantly higher (P<0.05) in 30min IR compared with 0min and 60min IRI group. Serum level of ALT, AST and PT were gradually and significantly (P<0.05) increased as the extension of IRI time. Histological analysis showed that there was a remarkable difference between 30min and 60min IRI, as protein expression of Ki-67 was significantly higher (P<0.05) in 30min IRI group. CONCLUSION: Fast ADC bi-exponential model in DWI and RCEI in Gd-EOB-DTPA-enhanced MRI showed the good correlation in assessment of liver function after partial hepatectomy, showing consistency with our histological findings. The Ktrans in Gd-EOB-DTPA-enhanced MRI could be a potent parameter for assessing the early ischemic injury, but not the severity of the hepatic injury, in accordance with the correlation with our biochemical findings. PMID- 27951419 TI - Lithium induced, oxidative stress and related damages in testes and heart in male rats: The protective effects of Malva sylvestris extract. AB - Malva sylvestris is widely used in Mediterranean and European traditional medicine and ethnoveterinary for the treatment of various diseases. This study, carried out on male Wistar rats, evaluates the beneficial effects of Malva sylvestris extract upon lithium carbonate-induced damages in testes and heart. For this purpose, Malva sylvestris extract at a dose of 0.2g/kg was orally administrated, followed by 25mg/kg lithium carbonate (intraperitoneal injection, twice daily). Lithium carbonate treatment significantly (p<0.01) decreased the weight of testes, accessory sex organ and heart, sperm count and motility, and serum testosterone level. In addition, exposure to lithium carbonate significantly (p<0.01) increased lipid peroxidation level (LPO) and decreased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities in testes and heart. Treatment with M. sylvestris extract affords substantial protection in testes and heart by altering all the parameters to near normal levels that were further confirmed by histological examination. The beneficial effect of M. Sylvestris extract in several organs could be attributed to the interaction of antioxidant components, such as complex polysaccharides, as confirmed by phytochemical analysis. PMID- 27951421 TI - Exogenous salicylic acid alleviates the toxicity of chlorpyrifos in wheat plants (Triticum aestivum). AB - The role of exogenous salicylic acid (SA) in protecting wheat plants (Triticum aestivum) from contamination by the insecticide chlorpyrifos was investigated in this study. The wheat plants were grown in soils with different concentrations (5, 10, 20, and 40mgkg-1) of chlorpyrifos. When the third leaf emerged, the wheat leaves were sprayed with 1, 2, 4, 8, and 16mgL-1 of SA once a day for 6 days. The results showed that wheat exposed to higher concentrations of chlorpyrifos (>=20mgkg-1) caused declines in growth and chlorophyll content and altered the activities of a series of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX). Interestingly, treatments with different concentrations of SA mitigated the stress generated by chlorpyrifos and improved the measured parameters to varying degrees. Furthermore, a reverse transcription and quantitative PCR experiment revealed that the activities of SOD and CAT can be regulated by their target gene in wheat when treated with SA. We also found that SA is able to block the accumulation of chlorpyrifos in wheat. However, the effect of SA was related to its concentration. In this study, the application of 2mgL-1 of SA had the greatest ameliorating effect on chlorpyrifos toxicity in wheat plants. PMID- 27951420 TI - (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime is a potential therapeutic agent for treatment of hyperuricemia through its dual inhibitory effects on XOD and URAT1. AB - Hyperuricemia is a kind of metabolic disease resulted from imbalance between urate production and excretion. Xanthine oxidase (XOD) or renal urate transporter 1 (URAT1) inhibitors have been applied for hyperuricemia treatment in clinic, but available drugs could not simultaneously target XOD and URAT1 and had various adverse effects. (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime (BDEO), as a deoxybenzoins oxime analog, was obtained from a cluster of deoxybenzoins derivatives synthesized by our research group with potent anti hyperuricemic activity, which was expected to be dual inhibitor of XOD and URAT1. This study aimed to investigate effects of BDEO on XOD and URAT1 in vitro, as well as the possible mechanism by which BDEO attenuated hyperuricemia in vivo. In vitro, BDEO obviously inhibited XOD activity with an IC50 value of 3.33MUM, moreover, in Human embryonic kidney (HEK)293 cells expressing URAT1, BDEO and benzbromarone blocked uptake of uric acid with a Ki value of 0.145MUM. On the other hand, mice were orally administrated by oxonate for seven consecutive days to induce hyperuricemia, BDEO at various doses were administered intragastrically to hyperuricemic and normal mice daily. BDEO dose-dependently decreased serum urate level and uric acid excretion in 24h in hyperuricemic mice. More importantly, BDEO significantly suppressed hepatic XOD activity and down regulated renal URAT1 protein level in hyperuricemic mice. Notably, BDEO exhibited no effects on all these detected biochemical indicators in normal mice, predicting its safety. Taken together, the data suggested that BDEO may serve as a dual XOD and URAT1 inhibitor for treatment of hyperuricemia. PMID- 27951422 TI - Phytoremediation of cadmium and lead-polluted watersheds. AB - Abandoned hard rock mines and the resulting acid mine drainage (AMD) are a source of vast, environmental degradation that are toxic threats to plants, animals, and humans. Cadmium (Cd) and lead (Pb) are metal contaminants often found in AMD. In our mine outwash water samples, Cd and Pb concentrations were 300 and 40 times greater than EPA Aquatic Life Use water quality standards, respectively. We tested the phytoremediation characteristics, accumulation and tolerance of Cd and Pb contamination, for annual aboveground biomass harvest of three montane willows native to the Rocky Mountains: Salix drummondiana, S. monticola, and S. planifolia. We found S. monticola best suited for Pb remediation based on greater growth and tolerance in response to the low Pb treatment compared to the high Pb treatment. Salix monticola stems also contained higher Pb concentrations in control treatment compared to S. planifolia. We found S. planifolia and S. drummondiana best suited for Cd remediation. Salix drummondiana accumulated higher concentrations of Cd in stems than both S. monticola and S. planifolia. Salix planifolia accumulated nearly 2.5 times greater concentrations of Cd in stems in control treatment than did S. drummondiana. Salix planifolia also contained more total Cd in stems than did S. monticola in Cd treatments. Based on our results, S. drummondiana and S. planifolia could aid in reduction of Cd in watersheds, and S. monticola is better suited than is S. planifolia for aboveground accumulation and tolerance of Pb pollution. PMID- 27951423 TI - Accumulation, sources and health risks of trace metals in elevated geochemical background soils used for greenhouse vegetable production in southwestern China. AB - Greenhouse vegetable cultivation with substantive manure and fertilizer input on soils with an elevated geochemical background can accumulate trace metals in soils and plants leading to human health risks. Studies on trace metal accumulation over a land use shift duration in an elevated geochemical background scenario are lacking. Accumulation characteristics of seven trace metals in greenhouse soil and edible plants were evaluated along with an assessment of the health risk to the consumers. A total of 118 greenhouse surface soils (0-20cm) and 30 vegetables were collected from Kunming City, Yunnan Province, southwestern China, and analyzed for total Cd, Pb, Cu, Zn, As, Hg, and Cr content by ICP-MS and AFS. The trace metals were ordered Cu>Cd>Hg>Zn>Pb>As>Cr in greenhouse soils accumulation level, and the geo-accumulation index suggested the soil more severely polluted with Cd, Cu, Hg and Zn. The greenhouse and open-field soils had significant difference in Cd, Cr and Zn. The duration of shift from paddy to greenhouse land-use significantly influenced trace metal accumulation with a dramatic change during five to ten year greenhouse land-use, and continuous increase of Cd and Hg. A spatial pattern from north to south for Cd and Hg and a zonal pattern for Cu and Zn were found. An anthropogenic source primarily caused trace metal accumulation, where the principal component analysis/multiple linear regression indicated a contribution 61.2%. While the assessment showed no potential risk for children and adults, the hazard health risks index was greater than one for adolescents. The extended duration of land use as greenhouses caused the trace metal accumulation, rotation in land use should be promoted to reduce the health risks. PMID- 27951425 TI - Quantitative NMR spectroscopy for gas analysis for production of primary reference gas mixtures. AB - Due to its direct correlation to the number of spins within a sample quantitative NMR spectroscopy (qNMR) is a promising method with absolute comparison abilities in complex systems in technical, as well as metrological applications. Most of the samples studied with qNMR are in liquid state in diluted solutions, while gas phase applications represent a rarely applied case. Commercially available NMR equipment was used for purity assessment of liquid and liquefied hydrocarbons serving as raw materials for production of primary reference gas standards. Additionally, gas-phase studies were performed within an online NMR flow probe, as well as in a high-pressure NMR setup to check feasibility as verification method for the composition of gas mixtures. PMID- 27951424 TI - The effects of perceived quality on behavioral economic demand for marijuana: A web-based experiment. AB - BACKGROUND: Given the growing legalization of recreational marijuana use and related increase in its prevalence in the United States, it is important to understand marijuana's appeal. We used a behavioral economic (BE) approach to examine whether the reinforcing properties of marijuana, including "demand" for marijuana, varied as a function of its perceived quality. METHODS: Using an innovative, Web-based marijuana purchase task (MPT), a sample of 683 young-adult recreational marijuana users made hypothetical purchases of marijuana across three qualities (low, mid and high grade) at nine escalating prices per joint, ranging from $0/free to $20. RESULTS: We used nonlinear mixed effects modeling to conduct demand curve analyses, which produced separate demand indices (e.g., Pmax, elasticity) for each grade of marijuana. Consistent with previous research, as the price of marijuana increased, marijuana users reduced their purchasing. Demand also was sensitive to quality, with users willing to pay more for higher quality/grade marijuana. In regression analyses, demand indices accounted for significant variance in typical marijuana use. CONCLUSIONS: This study illustrates the value of applying BE theory to young adult marijuana use. It extends past research by examining how perceived quality affects demand for marijuana and provides support for the validity of a Web-based MPT to examine the appeal of marijuana. Our results have implications for policies to regulate marijuana use, including taxation based on the quality of different marijuana products. PMID- 27951426 TI - Stacked magnetic resonators for MRI RF coils decoupling. AB - Parallel transmission is a very promising method to tackle B1+ field inhomogeneities at ultrahigh field in magnetic resonant imaging (MRI). This technique is however limited by the mutual coupling between the radiating elements. Here we propose to solve this problem by designing a passive magneto electric resonator that we here refer to as stacked magnetic resonator (SMR). By combining numerical and experimental methodologies, we prove that this novelty passive solution allows an efficient decoupling of elements of a phased-array coil. We demonstrate the ability of this technique to significantly reduce by more than 10dB the coupling preserving the quality of images compared to ideally isolated linear resonators on a spherical salty agar gel phantom in a 7T MRI scanner. PMID- 27951428 TI - Improvement in self-reported eating-related psychopathology and physical health related quality of life after laparoscopic sleeve gastrectomy: A pre-post analysis and comparison with conservatively treated patients with obesity. AB - OBJECTIVE: The present study examined the effects of laparoscopic sleeve gastrectomy (LSG) on self-reported eating-related psychopathology and health related quality of life (HRQoL). Outcomes of the LSG group were compared with a group of conservatively treated (CT) patients, who underwent a 1-year multimodal weight reduction group program that included dietary advice, physical exercise, psychoeducation, cognitive-behavioral therapy, training in Jacobson's progressive muscle relaxation, and social group support. The setting was a multidisciplinary obesity center. METHOD: A sample of 103 patients with obesity were investigated using the Eating Disorder Inventory and the Short Form Health Survey before and, on average, 19 (+/-5) months after weight loss intervention. Thereof, 63 patients (age 45.6+/-10.9years, 71.4% females) underwent LSG, and 40 patients (age 50.6+/ 11.3years, 77.5% females) underwent the CT program. Patients were assigned to either the surgical or the nonsurgical intervention group following clinical guidelines and patient preference. RESULTS: In the LSG group, excess weight loss (%EWL) was 53.0+/-24.0%, and body mass index (BMI) decreased from 51.5+/-8.1 to 38.0+/-7.7kg/m2. In the CT group, %EWL was 13.9+/-27.1%, and BMI decreased from 40.3+/-6.7 to 38.0+/-7.2kg/m2. Significant improvements in eating-related psychopathology were observed in both groups. Although both groups had a similar BMI after the respective interventions, LSG patients reported significantly greater body satisfaction and substantial improvement in perceived physical health from a lower baseline level than CT patients. DISCUSSION: In the second follow-up year, LSG was associated with greater weight loss from a higher baseline weight, and greater improvements in self-reported eating-related psychopathology and physical HRQoL compared with conservative treatment. PMID- 27951427 TI - Anisotropic phantom to calibrate high-q diffusion MRI methods. AB - A silicon oil-filled glass capillary array is proposed as an anisotropic diffusion MRI phantom. Together with a computational/theoretical pipeline these provide a gold standard for calibrating and validating high-q diffusion MRI experiments. The phantom was used to test high angular resolution diffusion imaging (HARDI) and double pulsed-field gradient (d-PFG) MRI acquisition schemes. MRI-based predictions of microcapillary diameter using both acquisition schemes were compared with results from optical microscopy. This phantom design can be used for quality control and quality assurance purposes and for testing and validating proposed microstructure imaging experiments and the processing pipelines used to analyze them. PMID- 27951429 TI - Spoken word recognition in young tone language learners: Age-dependent effects of segmental and suprasegmental variation. AB - The majority of the world's languages rely on both segmental (vowels, consonants) and suprasegmental (lexical tones) information to contrast the meanings of individual words. However, research on early language development has mostly focused on the acquisition of vowel-consonant languages. Developmental research comparing sensitivity to segmental and suprasegmental features in young tone learners is extremely rare. This study examined 2- and 3-year-old monolingual tone learners' sensitivity to vowels and tones. Experiment 1a tested the influence of vowel and tone variation on novel word learning. Vowel and tone variation hindered word recognition efficiency in both age groups. However, tone variation hindered word recognition accuracy only in 2-year-olds, while 3-year olds were insensitive to tone variation. Experiment 1b demonstrated that 3-year olds could use tones to learn new words when additional support was provided, and additionally, that Tone 3 words were exceptionally difficult to learn. Experiment 2 confirmed a similar pattern of results when children were presented with familiar words. This study is the first to show that despite the importance of tones in tone languages, vowels maintain primacy over tones in young children's word recognition and that tone sensitivity in word learning and recognition changes between 2 and 3years of age. The findings suggest that early lexical processes are more tightly constrained by variation in vowels than by tones. PMID- 27951431 TI - Developmental validation of a custom panel including 273 SNPs for forensic application using Ion Torrent PGM. AB - Utilizing massively parallel sequencing (MPS) technology for SNP testing in forensic genetics is becoming attractive because of the shortcomings of STR markers, such as their high mutation rates and disadvantages associated with the current PCR-CE method as well as its limitations regarding multiplex capabilities. MPS offers the potential to genotype hundreds to thousands of SNPs from multiple samples in a single experimental run. In this study, we designed a customized SNP panel that includes 273 forensically relevant identity SNPs chosen from SNPforID, IISNP, and the HapMap database as well as previously related studies and evaluated the levels of genotyping precision, sequence coverage, sensitivity and SNP performance using the Ion Torrent PGM. In a concordant study of the custom MPS-SNP panel, only four MPS callings were missing due to coverage reads that were too low (<20), whereas the others were fully concordant with Sanger's sequencing results across the two control samples, that is, 9947A and 9948. The analyses indicated a balanced coverage among the included loci, with the exception of the 16 SNPs that were used to detect an inconsistent allele balance and/or lower coverage reads among 50 tested individuals from the Chinese HAN population and the above controls. With the exception of the 16 poorly performing SNPs, the sequence coverage obtained was extensive for the bulk of the SNPs, and only three Y-SNPs (rs16980601, rs11096432, rs3900) showed a mean coverage below 1000. Analyses of the dilution series of control DNA 9948 yielded reproducible results down to 1ng of DNA input. In addition, we provide an analysis tool for automated data quality control and genotyping checks, and we conclude that the SNP targets are polymorphic and independent in the Chinese HAN population. In summary, the evaluation of the sensitivity, accuracy and genotyping performance provides strong support for the application of MPS technology in forensic SNP analysis, and the assay offers a straightforward sample-to-genotype workflow that could be beneficial in forensic casework with respect to both individual identification and complex kinship issues. PMID- 27951430 TI - Protect this house: cytosolic sensing of viruses. AB - The ability to recognize invading viral pathogens and to distinguish their components from those of the host cell is critical to initiate the innate immune response. The efficiency of this detection is an important factor in determining the susceptibility of the cell to viral infection. Innate sensing of viruses is, therefore, an indispensable step in the line of defense for cells and organisms. Recent discoveries have uncovered novel sensors of viral components and hallmarks of infection, as well as mechanisms by which cells discriminate between self and non-self. This review highlights the mechanisms used by cells to detect viral pathogens in the cytosol, and recent advances in the field of cytosolic sensing of viruses. PMID- 27951432 TI - Traditions of research into interruptions in healthcare: A conceptual review. AB - BACKGROUND: Researchers from diverse theoretical backgrounds have studied workplace interruptions in healthcare, leading to a complex and conflicting body of literature. Understanding pre-existing viewpoints may advance the field more effectively than attempts to remove bias from investigations. OBJECTIVE: To identify research traditions that have motivated and guided interruptions research, and to note research questions posed, gaps in approach, and possible avenues for future research. METHODS: A critical review was conducted of research on interruptions in healthcare. Two researchers identified core research communities based on the community's motivations, philosophical outlook, and methods. Among the characteristics used to categorise papers into research communities were the predominant motivation for studying interruptions, the research questions posed, and key contributions to the body of knowledge on interruptions in healthcare. In cases where a paper approached an equal number of characteristics from two traditions, it was placed in a blended research community. RESULTS: A total of 141 papers were identified and categorised; all papers identified were published from 1994 onwards. Four principal research communities emerged: epidemiology, quality improvement, cognitive systems engineering (CSE), and applied cognitive psychology. Blends and areas of mutual influence between the research communities were identified that combine the benefits of individual traditions, but there was a notable lack of blends incorporating quality improvement initiatives. The question most commonly posed by researchers across multiple communities was: what is the impact of interruptions? Impact was measured as a function of task time or risk in the epidemiology tradition, situation awareness in the CSE tradition, or resumption lag (time to resume an interrupted task) in the applied cognitive psychology tradition. No single question about interruptions in healthcare was shared by all four of the core communities. CONCLUSIONS: Much research on workplace interruptions in healthcare can be described in terms of fundamental values of four distinct research traditions and the communities that bring the values and methods: of those research traditions to their investigations. Blends between communities indicate that mutual influence has occurred as interruptions research has progressed. It is clear from this review that there is no single or privileged perspective to study interruptions. Instead, these findings suggest that researchers investigating interruptions in healthcare would benefit from being more aware of different perspectives from their own, especially when they consider workplace interventions to reduce interruptions. PMID- 27951433 TI - Interventions to improve communication between people with dementia and nursing staff during daily nursing care: A systematic review. AB - BACKGROUND: To provide adequate nursing care it is important for nursing staff to communicate effectively with people with dementia. Due to their limited communication skills, people with dementia have difficulties in understanding communication and expressing themselves verbally. Nursing staff members often report communication difficulties with people with dementia, which emphasises the urgent need for interventions to improve their communication with people in this specific target group. OBJECTIVES: To provide an up-to-date overview of communication interventions that are applicable during daily nursing care activities, irrespective of care setting, and to describe the effects on communication outcomes in people with dementia and nursing staff. DESIGN: Systematic literature review DATA SOURCES: The Cochrane Library, CINAHL, PsycINFO, and Pubmed databases were searched for all articles published until the 23rd of February 2016. REVIEW METHODS: Papers were included, if: (1) interventions focused on communication between nursing staff and people with dementia and were applicable during daily nursing care; (2) studies were (randomised) controlled trials; (3) papers were written in English, Dutch, or German. Data were extracted on content and communication outcomes of interventions, and on methodological quality of the studies. The data extraction form and methodological quality checklist were based on the Method Guidelines for Systematic Reviews for the Cochrane Back Review Group. RESULTS: Six studies on communication interventions were included. All of the studies incorporated a communication skills training for nursing staff with a broad range in frequency, duration and content. In addition, there was wide variation in the communication outcome measures used. Four studies measured non-verbal communication, all found positive effects on at least some of the communication outcomes. Four studies measured verbal communication, of which three found positive effects on at least one of the measured outcomes. Methodological quality assessment demonstrated a high risk of bias in five of the six studies. CONCLUSIONS: Few studies have been identified with wide variation in interventions and outcome measures. In addition, the methodological shortcomings make it difficult, to draw conclusions about the effectiveness. More research is needed to develop and evaluate communication interventions. Additionally, it is useful to reach consensus on defining and measuring communication. PMID- 27951434 TI - Neutrophil migration in inflammation: intercellular signal relay and crosstalk. AB - Neutrophils are innate effector cells armed with a potent machinery to combat damage and infection within tissues. Their ability to rapidly respond to danger signals and mobilise is crucial to their role. After extravasation, neutrophil populations often exhibit swarming behaviour. Swarming occurs in distinct phases and is coordinated via inter-neutrophil signal relay in the form of small molecule mediators. Neutrophils also engage in multi-dimensional crosstalk with tissue-resident cells and incoming leukocytes in the inflammatory milieu. The complexity of neutrophil crosstalk with other innate immune cells mirrors that of the adaptive immune system, with rudimentary features of 'priming' and 'licensing'. We review recent findings relating to the migration and intercellular crosstalks of neutrophils in the initiation and resolution of inflammation. PMID- 27951435 TI - Habit outweighs planning in grasp selection for object manipulation. AB - Object-directed grasping movements are adapted to intended interactions with an object. We address whether adjusting the grasp for object manipulation is controlled habitually, based on past experiences, or by goal-directed planning, based on an evaluation of the expected action outcomes. Therefore, we asked participants to grasp and rotate a dial. In such tasks, participants typically grasp the dial with an excursed, uncomfortable arm posture, which then allows to complete the dial rotation in a comfortable end-state. We extended this task by manipulating the contingency between the orientation of the grasp and the resulting end-state of the arm. A one-step (control) group rotated the dial to a single target. A two-step group rotated the dial to an initial target and then in the opposite direction. A three-step group rotated the dial to the initial target, then in the opposite direction, and then back to the initial target. During practice, the two-step and three-step groups reduced the excursion of their grasps, thus avoiding overly excursed arm postures after the second rotation. When the two-step and three-step groups were asked to execute one-step rotations, their grasps resembled those that were acquired during the two-step and three-step rotations, respectively. However, the carry-over was not complete. This suggests that adjusting grasps for forthcoming object manipulations is controlled by a mixture of habitual and goal-directed processes. In the present experiment, the former contributed approximately twice as much to grasp selection than the latter. PMID- 27951436 TI - Comparative characterization of hepatitis B virus surface antigen derived from different hepatitis B virus genotypes. AB - For human hepatitis B virus eight distinct and two candidate genotypes are described. These genotypes differ with respect to geographic distribution, molecular virology and virus-associated pathogenesis. Comparative analysis of HBV genotypes revealed, with exception of HBV/G that shows impaired HBsAg release, that no fundamental disparities between genotypes exist regarding glycosylation, subcellular distribution, release of HBsAg and formation of subviral particles. However, there are distinctions regarding the proportion of L to M to S HBs proteins detected intra- and extracellularly for different genotypes. 2D electrophoresis revealed different posttranslational modification patterns for LHBs. In light of the relevance of HBsAg as diagnostic marker, detectability of purified recombinant HBsAg of various genotypes by HBsAg-specific detection systems licensed in Europe was investigated, showing similar sensitivities for genotypes included in this analysis. These data indicate that recombinant HBsAg reproducibly purified following a defined protocol might be used as an alternative to reference materials currently established. PMID- 27951437 TI - Engagement of the left extrastriate body area during body-part metaphor comprehension. AB - Grounded cognition explanations of metaphor comprehension predict activation of sensorimotor cortices relevant to the metaphor's source domain. We tested this prediction for body-part metaphors using functional magnetic resonance imaging while participants heard sentences containing metaphorical or literal references to body parts, and comparable control sentences. Localizer scans identified body part-specific motor, somatosensory and visual cortical regions. Both subject- and item-wise analyses showed that, relative to control sentences, metaphorical but not literal sentences evoked limb metaphor-specific activity in the left extrastriate body area (EBA), paralleling the EBA's known visual limb selectivity. The EBA focus exhibited resting-state functional connectivity with ipsilateral semantic processing regions. In some of these regions, the strength of resting-state connectivity correlated with individual preference for verbal processing. Effective connectivity analyses showed that, during metaphor comprehension, activity in some semantic regions drove that in the EBA. These results provide converging evidence for grounding of metaphor processing in domain-specific sensorimotor cortical activity. PMID- 27951439 TI - Removal of pollutants and pathogens by a simplified treatment scheme for municipal wastewater reuse in agriculture. AB - The availability of high quality water has become a constraint in several countries. Agriculture represents the main water user, therefore, wastewater reuse in this area could increase water availability for other needs. This research was aimed to provide a simplified scheme for treatment and reuse of municipal and domestic wastewater based on Sequencing Batch Biofilter Granular Reactors (SBBGRs). The activity was conducted at pilot-scale and particular attention was dedicated to the microbiological quality of treated wastewater to evaluate the risk associated to its reuse. The following microorganisms were monitored: Escherichia coli, Salmonella, Clostridium perfringens, somatic coliphages, adenovirus, enterovirus, Giardia lamblia and Cryptosporidium parvum. The possibility of SBBGR enhancement with sand filtration was also evaluated. The SBBGR removed >90% of suspended solids and chemical oxygen demand, and 80% and 60% of total nitrogen and phosphorous, respectively. SBBGR was also effective in removing microbial indicators, from 1 (for C. perfringens) up to 4 (for E. coli) log units of these microorganisms. In particular, the quality of SBBGR effluent was already compatible with the WHO criteria for reuse (E. coli <=103CFU/100mL). Sand filtration had positive effects on plant effluent quality and the latter could even comply with more restrictive reuse criteria. PMID- 27951438 TI - Peak-to-valley ratios for three different HPGe detectors for the assessment of 137Cs deposition on the ground and the impact of the detector field-of-view. AB - The peak-to-valley (PTV) method was investigated experimentally comparing PTV ratios for three HPGe detectors, with complementary Monte Carlo simulations of scatter in air for larger source-detector distances. The measured PTV ratios for 137Cs in air were similar for three different detectors for incident angles between 0 and 90 degrees . The study indicated that the PTV method can differentiate between surface and shallow depth sources if the detector field of view is limited to a radius of less than 3.5m. PMID- 27951440 TI - A perspective of chronic low exposure of arsenic on non-working women: Risk of hypertension. AB - The relationship between arsenic (As) exposure and hypertension risk are extensively studied. The As content in scalp hair has been used as a reliable indicator of population for long-time exposure from different sources. Therefore, we investigated the association between hair As concentration and hypertension risk, as well as the potential modifying effects of single nucleotide polymorphisms (SNPs) related to phase II metabolism enzyme genes. We recruited 398 non-working women in Shanxi Province, northern China, from Aug 2012 to May 2013, including 163 subjects with hypertension (cases) and 235 healthy controls. Scalp hair and blood samples were collected from each subject. We analyzed the As concentrations of ~24-cm-long strands of hair representing the two most recent years of growth and SNPs of three genes (epoxide hydrolase 1, N-acetyltransferase 2, and glutathione S-transferase P1) in each subject. The results revealed that the hair As concentration of this population was significantly lower than in populations living near high As polluted sources in China and other countries. The median As concentration (inter-quartile range) of hair in the cases (i.e. 0.211 [0.114-0.395] MUg/g hair) was higher than in the controls (i.e. 0.101 [0.048-0.227] MUg/g hair). Higher hair As concentrations were associated with an elevated hypertension risk, with an adjusted odds ratio of 2.55 [95% confidence interval: 1.55-4.20]. No interaction effects between hair As concentration and SNPs related to phase II metabolism enzymes on hypertension risk were observed. It was concluded that chronic low exposure level of As might be associated with hypertension risk among the study subjects. PMID- 27951441 TI - Resistance to PD1/PDL1 checkpoint inhibition. AB - For the first time in decades, patients with difficult-to-treat cancers such as advanced stage metastatic melanoma are being offered a glimpse of hope in the form of immunotherapies. By targeting factors that foster the development and maintenance of an immunosuppressive microenvironment within tumors, these therapies release the brakes on the host's own immune system; allowing cure of disease. Indeed, phase III clinical trials have revealed that therapies such as ipilimumab and pembrolizumab which target the CTLA4 and PD-1 immune checkpoints, respectively, have raised the three-year survival of patients with melanoma to ~70%, and overall survival (>5years) to ~30%. Despite this unprecedented efficacy, many patients fail to respond, and more concerning, some patients who demonstrate encouraging initial responses to immunotherapy, can acquire resistance over time. There is now an urgent need to identify mechanisms of resistance, to predict outcome and to identify targets for combination therapy. Here, with the aim of guiding future combination trials that target specific resistance mechanisms to immunotherapies, we have summarised and discussed the current understanding of mechanisms promoting resistance to anti-PD1/PDL1 therapies, and how combination strategies which target these pathways might yield better outcomes for patients. PMID- 27951442 TI - One-pot Mukaiyama type carbon-Ferrier rearrangement of glycals: Application in the synthesis of chromanone 3-C-glycosides. AB - One-pot carbon-Ferrier rearrangement of glycals with unactivated aryl methyl ketones has been developed under mild Silyl triflate catalysis. Keto methyl group of various aryl methyl ketones without being converted into silyl enol ether could directly attack anomeric position of glycals to form keto functionalized C glycosides in moderate to good yields with high alpha-selectivity. The versatility of this method has been extended to the synthesis of a small library of chromanone 3-C-glycosides. PMID- 27951443 TI - Synthesis and NMR analysis of model compounds related to fucosylated chondroitin sulfates: GalNAc and Fuc(1 -> 6)GalNAc derivatives. AB - Unsubstituted and 6-O-alpha-L-fucosylated propyl 2-acetamido-2-deoxy-beta-D galactopyranosides and their selectively O-sulfated (both in GalNAc and Fuc units) derivatives were synthesized as model compounds representing the fragments of fucosylated chondroitin sulfates (FCS) from sea cucumbers. Per-O-acetylated 2 deoxy-2-N-phthalimido-D-glucopyranose was used as a key precursor for the preparation of all 2-acetamido-2-deoxy-D-galactopyranoside containing products. Attempts at 6-O-glycosylation of propyl 3-O-benzoyl-2-deoxy-2-N-phthalimido-D galactoside by 2-O-benzyl-3,4-di-O-chloracetyl-L-fucosyl trichloracetimidate in the presence of TMSOTf gave a 1:1 mixture of the corresponding alpha- and beta isomeric disaccharides, while the use of structurally related fucosyl bromide donor with promotion by Bu4NBr led to the formation of desired alpha-isomeric disaccharide exclusively. Selective removal of orthogonal O-protections permitted subsequent O-sulfation both at the GalNAc and Fuc units. Further removal of blocking groups yielded the target products which were systematically studied by 1H and 13C NMR spectroscopy in order to determine the spectral effects of O sulfation and alpha-L-fucosylation needed for the development of computer assisted structural analysis of natural FCS. PMID- 27951444 TI - Modified Poisson equations for calculating solvation free energy. AB - The dielectric polarization (P) is the key factor in calculating the solvation free energy. P can be decomposed into the product of the electric dipole per solvent (p) and the relative solvent molecular density (g). p can be calculated from the electric field (E), and g can be calculated from the mean force (F), where the electric component of F is calculated from ?xE. The Poisson equations were modified for E and ?xE. Strategies to estimate the boundary conditions of E and ?xE were proposed. The dependences of P and g on the parameters used for the numerical analysis were explored. For two charged atoms in a water cluster, the values of P and g obtained by these equations were similar to those obtained from molecular dynamics simulations. The electric potential at the solute atoms and the solvation free energy determined using these equations were similar to those obtained from molecular dynamics simulations. PMID- 27951445 TI - Carbonaceous and nitrogenous disinfection by-product formation from algal organic matter. AB - Seasonal algal blooms in drinking water sources release intracellular and extracellular algal organic matter (AOM) in significant concentrations into the water. This organic matter provides precursors for disinfection by-products (DBPs) formed when the water is subsequently chlorinated at the final disinfection stage of the potable water treatment process. This paper presents results of AOM characterisation from five algal species (three cyanobacteria, one diatom and one green) alongside the measurement of the DBP formation potential from the AOM of six algal species (an additional diatom). The character was explored in terms of hydrophilicity, charge and protein and carbohydrate content. 18 DBPs were measured following chlorination of the AOM samples: the four trihalomethanes (THMs), nine haloacetic acids (HAAs), four haloacetonitriles (HANs) and one halonitromethane (HNM). The AOM was found to be mainly hydrophilic (52 and 81%) in nature. Yields of up to 92.4 MUg mg-1 C carbonaceous DBPs were measured, with few consistent trends between DBP formation propensity and either the specific ultraviolet absorbance (SUVA) or the chemical characteristics. The AOM from diatomaceous algae formed significant amounts of nitrogenous DBPs (up to 1.7 MUg mg-1 C). The weak trends in DBPFP may be attributable to the hydrophilic nature of AOM, which also makes it more challenging to remove by conventional water treatment processes. PMID- 27951446 TI - Assessment of three approaches of bioremediation (Natural Attenuation, Landfarming and Bioagumentation - Assistited Landfarming) for a petroleum hydrocarbons contaminated soil. AB - Contamination with total petroleum hydrocarbons (TPH) subsequent to refining activities, is currently one of the major environmental problems. Among the biological remediation approaches, landfarming and in situ bioremediation strategies are of great interest. Purpose of this study was to verify the feasibility of a remediation process wholly based on biological degradation applied to contaminated soils from a decommissioned refinery. This study evaluated through a pot experiment three bioremediation strategies: a) Natural Attenuation (NA), b) Landfarming (L), c) Bioaugmentation-assisted Landfarming (LB) for the treatment of a contaminated soil with petroleum hydrocarbons (TPHs). After a 90-days trial, Bioagumentation - assistited Landfarming approach produced the best results and the greatest evident effect was shown with the most polluted samples reaching a reduction of about 86% of total petroleum hydrocarbons (TPH), followed by Landfarming (70%), and Natural Attenuation (57%). The results of this study demonstrated that the combined use of bioremediation strategies was the most advantageous option for the treatment of contaminated soil with petroleum hydrocarbons, as compared to natural attenuation, bioaugmentation or landfarming applied alone. Besides, our results indicate that incubation with an autochthonous bacterial consortium may be a promising method for bioremediation of TPH-contaminated soils. PMID- 27951448 TI - Computational design of ligand-binding proteins. AB - Custom-designed ligand-binding proteins with novel functions hold the potential for numerous applications. In recent years, the developments of computational methods together with high-throughput experimental screening techniques have led to the generation of novel, high-affinity ligand-binding proteins for given ligands. In addition, naturally occurring ligand-binding proteins have been computationally designed to recognize new ligands while keeping their original biological functions at the same time. Furthermore, metalloproteins have been successfully designed for novel functions and applications. Though much has been learned in these successful design cases, advances in our understanding of protein dynamics and functions related to ligand binding and development of novel computational strategies are necessary to further increase the success rate of computational protein-ligand binding design. PMID- 27951447 TI - Spatial distribution and transport characteristics of heavy metals around an antimony mine area in central China. AB - The spatial distribution and transport characteristics of heavy metals in an antimony mine area (Xikuangshan, China) were systematically studied using a field survey and geostatistical analytical methods. In the study area, 52 soil and sediment samples were collected from bare land, grassland, woodland and river sediments covering a surface area of 20 km2. The soil properties and heavy metal concentrations were measured by wavelength dispersive X-ray fluorescence spectrometry and inductively coupled plasma-mass spectrometry, respectively. Correlation analysis and principal component analysis suggest that Cu, Zn, Cd, As, Pb and Sb can be attributed to anthropogenic inputs, whereas Cr, Mn and Ni are of natural origin. Distribution maps of heavy metals were generated using the Kriging interpolation method to identify their distribution trends. The results show the influence of wind, river, distance and vegetation on the spatial distribution. The results also revealed that windborne transport may play a significant role in the spreading of contaminants. In addition, the environmental risk of heavy metal pollution was evaluated using their geoaccumulation indexes in the whole region. All of the results indicate that the heavy metal distributions in the soils were consistent with the local prevailing wind direction. In addition, the environmental quality could be seriously threatened by heavy metal contaminants from the smelter and tailings. PMID- 27951449 TI - Plant flavonoids in cancer chemoprevention: role in genome stability. AB - Carcinogenesis is a multistage process that involves a series of events comprising of genetic and epigenetic changes leading to the initiation, promotion and progression of cancer. Chemoprevention is referred to as the use of nontoxic natural compounds, synthetic chemicals or their combinations to intervene in multistage carcinogenesis. Chemoprevention through diet modification, i.e., increased consumption of plant-based food, has emerged as a most promising and potentially cost-effective approach to reducing the risk of cancer. Flavonoids are naturally occurring polyphenols that are ubiquitous in plant-based food such as fruits, vegetables and teas as well as in most medicinal plants. Over 10,000 flavonoids have been characterized over the last few decades. Flavonoids comprise of several subclasses including flavonols, flavan-3-ols, anthocyanins, flavanones, flavones, isoflavones and proanthocyanidins. This review describes the most efficacious plant flavonoids, including luteolin, epigallocatechin gallate, quercetin, apigenin and chrysin; their hormetic effects; and the molecular basis of how these flavonoids contribute to the chemoprevention with a focus on protection against DNA damage caused by various carcinogenic factors. The present knowledge on the role of flavonoids in chemoprevention can be used in developing effective dietary strategies and natural health products targeted for cancer chemoprevention. PMID- 27951451 TI - Electroencephalographic study of chlorpromazine alone or combined with alpha lipoic acid in a model of schizophrenia induced by ketamine in rats. AB - Schizophrenia is characterized by behavioral symptoms, brain function impairments and electroencephalographic (EEG) changes. Dysregulation of immune responses and oxidative imbalance underpins this mental disorder. The present study aimed to investigate the effects of the typical antipsychotic chlorpromazine (CP) alone or combined with the natural antioxidant alpha-lipoic acid (ALA) on changes in the hippocampal average spectral power induced by ketamine (KET). Three days after stereotactic implantation of electrodes, male Wistar rats were divided into groups treated for 10 days with saline (control) or KET (10 mg/kg, IP). CP (1 or 5 mg/kg, IP) alone or combined with ALA (100 mg/kg, P.O.) was administered 30 min before KET or saline. Hippocampal EEG recordings were taken on the 1st, 5th and 10th days of treatment immediately after the last drug administration. KET significantly increased average spectral power of delta and gamma-high bands on the 5th and 10th days of treatment when compared to control. Gamma low-band significantly increased on the 1st, 5th and 10th days when compared to control group. This effect of KET was prevented by CP alone or combined with ALA. Indeed, the combination of ALA 100 + CP1 potentiated the inhibitory effects of CP1 on gamma low-band oscillations. In conclusion, our results showed that KET presents excitatory and time-dependent effects on hippocampal EEG bands activity. KET excitatory effects on EEG were prevented by CP alone and in some situations potentiated by its combination with ALA. PMID- 27951450 TI - Dose-dense adjuvant chemotherapy in premenopausal breast cancer patients: A pooled analysis of the MIG1 and GIM2 phase III studies. AB - BACKGROUND: No evidence exists to recommend a specific chemotherapy regimen in young breast cancer patients. We performed a pooled analysis of two randomised clinical trials to evaluate the efficacy of adjuvant dose-dense chemotherapy in premenopausal breast cancer patients and its impact on the risk of treatment induced amenorrhoea. PATIENTS AND METHODS: In the MIG1 study, node-positive or high-risk node-negative patients were randomised to 6 cycles of fluorouracil/epirubicin/cyclophosphamide every 2 (dose-dense) or 3 (standard interval) weeks. In the GIM2 study, node-positive patients were randomised to 4 cycles of dose-dense or standard-interval EC or FEC followed by 4 cycles of dose dense or standard-interval paclitaxel. Using individual patient data, the hazard ratio (HR) for overall survival by means of a Cox proportional hazards model and the odds ratio for treatment-induced amenorrhoea through a logistic regression model were calculated for each study. A meta-analysis of the two studies was performed using the random effect model to compute the parameter estimates. RESULTS: A total of 1,549 patients were included. Dose-dense chemotherapy was associated with a significant improved overall survival as compared to standard interval chemotherapy (HR, 0.71; 95% confidence intervals [CI], 0.54-0.95; p = 0.021). The pooled HRs were 0.78 (95% CI, 0.54-1.12) and 0.65 (95% CI, 0.40-1.06) for patients with hormone receptor-positive and -negative tumours, respectively (interaction p = 0.330). No increased risk of treatment-induced amenorrhoea was observed with dose-dense chemotherapy (odds ratio, 1.00; 95% CI, 0.80-1.25; p = 0.989). CONCLUSION: Dose-dense adjuvant chemotherapy may be considered the preferred treatment option in high-risk premenopausal breast cancer patients. PMID- 27951452 TI - (1->3)-beta-D-glucan aptamers labeled with technetium-99m: Biodistribution and imaging in experimental models of bacterial and fungal infection. AB - INTRODUCTION: Acid nucleic aptamers are RNA or DNA oligonucleotides capable of binding to a target molecule with high affinity and selectivity. These molecules are promising tools in nuclear medicine. Many aptamers have been used as targeting molecule of radiopharmaceuticals in preclinical studies. (1->3)-beta-D glucans are the main structural cell wall components of fungi and some bacteria. In the present study two radiolabeled (1->3)-beta-D-glucan aptamers (seq6 and seq30) were evaluated to identity infectious foci caused by fungal or bacterial cells. METHODS: Aptamer labeling with 99mTc was performed by the direct method and biodistribution studies were accomplished in Swiss mice (n=6) infected in the right thigh muscle with Staphylococcus aureus or Candida albicans. A 99mTc radiolabeled library consisting of oligonucleotides with random sequences was used as control. RESULTS: There was a higher uptake of 99mTc radiolabeled aptamers in the infected thigh than in the left thigh muscle (non-infected) in the S. aureus infected animals. The target/non-target ratios were 3.17+/-0.22 for seq6 and 2.66+/-0.10 for seq30. These ratios were statistically higher than the value (1.54+/-0.05) found for the radiolabeled library (control). With regard to biodistribution, no statistical difference was verified between aptamers and control uptakes in the infection foci in the C. albicans infected animals. The target/non-target ratios were 1.53+/-0.03, 1.64+/-0.12 and 1.08+/-0.02 for radiolabeled library, seq6 and seq30, respectively. Scintigraphic imaging of infected foci using radiolabeled aptamers was possible only for S. aureus infected mice. CONCLUSIONS: Seq6 and seq30 aptamers proved to be inefficient for diagnosis of C. albicans infection. Nevertheless, their applicability for diagnosis of S. aureus and other bacterial infections by scintigraphy should be further explored. PMID- 27951454 TI - Kamikazes and cultural evolution. AB - Is cultural evolution needed to explain altruistic selfsacrifice? Some contend that cultural traits (e.g. beliefs, behaviors, and for some "memes") replicate according to selection processes that have "floated free" from biology. One test case is the example of suicide kamikaze attacks in wartime Japan. Standard biological mechanisms-such as reciprocal altruism and kin selection-might not seem to apply here: The suicide pilots did not act on the expectation that others would reciprocate, and they were supposedly sacrificing themselves for country and emperor, not close relatives. Yet an examination of both the historical record and the demands of evolutionary theory suggest the kamikaze phenomenon does not cry out for explanation in terms of a special non-biological selection process. This weakens the case for cultural evolution, and has interesting implications for our understanding of altruistic self-sacrifice. PMID- 27951453 TI - Screening and functional identification of lncRNAs under beta-diketone antibiotic exposure to zebrafish (Danio rerio) using high-throughput sequencing. AB - Long non-coding RNAs (lncRNAs) have attracted considerable research interest, but so far no data are available on the roles of lncRNAs and their target genes under chronic beta-diketone antibiotic (DKAs) exposure to zebrafish (Danio rerio). Herein, we identified 1.66, 3.07 and 3.36*104 unique lncRNAs from the 0, 6.25 and 12.5mg/L DKA treatment groups, respectively. In comparison with the control group, the 6.25 and 12.5mg/L treatments led to up-regulation of 2064 and 2479 lncRNAs, and down-regulation of 778 and 954 lncRNAs, respectively. Of these, 44 and 39 lncRNAs in the respective 6.25 and 12.5mg/L treatments displayed significant differential expression. Volcano and Venn diagrams of the differentially expressed lncRNAs were constructed on the basis of the differentially expressed lncRNAs. After analyzing 10 lncRNAs and potential target genes, a complex interaction network was constructed between them. The consistency of 7 target genes (tenm3, smarcc1b, myo9ab, ubr4, hoxb3a, mycbp2 and CR388046.3), co-regulated by 3 lncRNAs (TCONS_00129029, TCONS_00027240 and TCONS_00017790), was observed between their qRT-PCR and transcriptomic sequencing. By in situ hybridization (ISH), abnormal expression of 3 lncRNAs was observed in hepatic and spleen tissues, suggesting that they might be target organs for DKAs. A similar abnormal expression of two immune-related target genes (plk3 and syt10), co-regulated by the 3 identified lncRNAs, was observed in liver and spleen by ISH. Histopathological observations demonstrated hepatic parenchyma vacuolar degeneration and clot formation in hepatic tissues, and uneven distribution of brown metachromatic granules and larger nucleus in spleen tissues resulting from DKA exposure. Overall, DKA exposure led to abnormal expression of some lncRNAs and their potential target genes, and these genes might play a role in immune functions of zebrafish. PMID- 27951455 TI - Relationship of inflammatory profile of elderly patients serum and senescence associated secretory phenotype with human breast cancer cells proliferation: Role of IL6/IL8 ratio. AB - Aging is considered a systemic, chronic and low-grade inflammatory state, called "inflammaging", which has been contemplated as a risk factor for cancer development and progression in the elderly population. Cellular senescence is a multifactorial phenomenon of growth arrest and distorted function, which has been recognized as a contributor to aging. Senescent cells have an altered secretion pattern called Senescent Associated Secretory Phenotype (SASP), that comprise a complex mix of factors including cytokines, growth factors, chemokines and matrix metalloproteinases among others. The SASP secreted by accumulated senescent cells during old age has been related to local inflammation that leads to cellular transformation and therefore may be supporting the inflammaging process. Here, we evaluated if the pro-inflammatory profile within the serum obtained from elderly patients (EPS) was able to induce cellular proliferation in the breast cancer transformed cell line (MCF-7), in a similar way to the proliferation stimulated by the SASP obtained from WI-38 primary cells prematurely induced to senescence by oxidative stress (SIPS). At the same time, the participation of IL-6/IL-8 ratio was determined. Our results showed that not all the EPS increased MCF-7 proliferation. However, there was an interesting relationship between IL-6 and IL 8 concentrations, when the IL-6 was higher than IL-8. Similar results were found with SASP from SIPS-WI-38 on the MCF-7 proliferation. Although it is known that those cytokines are fundamental factors to induce proliferation; the occurrence of other components in the cellular microenvironment is necessary to carry out this effect. PMID- 27951456 TI - Unrealistic self-overconfidence in schizophrenia is associated with left presubiculum atrophy and impaired episodic memory. AB - The study aimed at investigating the role of the hippocampal subfields in cognitive insight and the clinical and neuropsychological underpinnings of the related two sub-dimensions, Self-Reflectiveness (SR), i.e., openness to external feedback, and Self-Certainty (SC), i.e., unrealistic overconfidence in one's opinions. In order to do this, 45 patients with a diagnosis of schizophrenia and 45 age- and gender-matched healthy control subjects (HC) were administered the Beck Cognitive Insight Scale (BCIS), along with neuropsychological, clinical and psychopathological assessment, and underwent an MRI investigation. Hippocampal segmentation was carried out. Regression analyses were performed for BCIS indexes, volumetric parameters of hippocampal subfields and clinical and neuropsychological variables. Results highlighted that in the schizophrenia group, higher levels of SC were related to reduced volume of the left presubiculum, and worse episodic memory. No significant relationship emerged for the SR index. There was no significant relationship between any of the BCIS indexes and volumetric data of the hippocampal subfields in the HC group. Our data support the hypothesis that unrealistic self-overconfidence in schizophrenia is related to the hippocampal presubiculum atrophy, which is involved in episodic memory and cognitive control and is supposed to be underpinned by difficulty in integrating new memories and thus in generating new hypotheses about the self. PMID- 27951457 TI - Radiologic assessment of fetal tracheal balloon occlusion. AB - Fetal endoscopic tracheal occlusion (FETO) is a novel technique to treat cases of isolated severe congenital diaphragmatic hernia (CDH). Although there are benefits of MRI over ultrasound in assessing lung volumes, it is unknown whether there are benefits of MRI for localizing the tracheal balloon. This is a retrospective study reviewing the imaging characteristics of FETO in patients who underwent both MRI and ultrasound exams done to localize tracheal balloons. PMID- 27951458 TI - Clinical applicability and relevance of fibroglandular tissue segmentation on routine T1 weighted breast MRI. AB - PURPOSE: To evaluate clinical applicability of fibroglandular tissue (FGT) segmentation on routine T1 weighted breast MRI and compare FGT quantification with radiologist assessment. METHODS: FGT was segmented on 232 breasts and quantified, and was assessed qualitatively by four breast imagers. RESULTS: FGT segmentation was successful in all 232 breasts. Agreement between radiologists and quantified FGT was moderate to substantial (kappa=0.52-0.67); lower quantified FGT was associated with disagreement between radiologists and quantified FGT (P<=0.002). CONCLUSIONS: FGT segmentation was successful using routine T1 weighted breast MRI. Radiologists were less consistent with quantified results in breasts with lower quantified FGT. PMID- 27951459 TI - FDG PET/MR in initial staging of sarcoma: Initial experience and comparison with conventional imaging. AB - OBJECTIVE: To assess the feasibility of positron emission tomography/magnetic resonance imaging (PET/MR) with 18F-fluordeoxyglucose (FDG) for initial staging of sarcoma. MATERIALS AND METHODS: Twenty-nine patients with sarcoma were included in this study. Weighted kappa (kappa) was used to assess the agreement between PET/MR and conventional imaging (CT and MR). The accuracy of PET/MR and conventional imaging for distant metastases was compared using receiver operating characteristic (ROC) analysis. RESULTS: T and M stage were identical for PET/MR and conventional modalities in all patients (kappa=1). N stage was identical for 28/29 patients (kappa=0.65). CONCLUSIONS: FDG PET/MR shows excellent agreement with the currently preferred imaging methods (CT and MR) in initial staging of sarcoma. PMID- 27951460 TI - Towards an improved understanding of modern health information ecology. PMID- 27951461 TI - Neighbourly support of people with chronic illness; is it related to neighbourhood social capital? AB - The neighbourhood may provide resources for health. It is to date unknown whether people who live in neighbourhoods with more social capital have more access to practical and emotional support by neighbours, or whether this is a resource only available to those who are personally connected to people in their neighbourhood. We investigated whether support by neighbours of people with chronic illness was related to neighbourhood social capital and to individual neighbourhood connections. Furthermore, we investigated whether support received from neighbours by people with chronic illness differed according to demographic and disease characteristics. We collected data on support by neighbours and individual connections to neighbours among 2272 people with chronic illness in 2015. Data on neighbourhood social capital were collected among 69,336 people in 3425 neighbourhoods between May 2011 and September 2012. Neighbourhood social capital was estimated with ecometric measurements. We conducted multilevel regression analyses. People with chronic illness were more likely to receive practical and emotional support from neighbours if they had more individual connections to people in their neighbourhood. People with chronic illness were not more likely to receive practical and emotional support from neighbours if they lived in a neighbourhood with more social capital. People with chronic illness with moderate physical disabilities or with comorbidity, and people with chronic illness who lived together with their partner or children, were more likely to receive support from neighbours. To gain more insight into the benefits of neighbourhood social capital, it is necessary to differentiate between the resources only accessible through individual connections to people in the neighbourhood and resources provided through social capital on the neighbourhood level. PMID- 27951462 TI - Evaluation of energy consumption during aerobic sewage sludge treatment in dairy wastewater treatment plant. AB - The subject of the research conducted in an operating dairy wastewater treatment plant (WWTP) was to examine electric energy consumption during sewage sludge treatment. The excess sewage sludge was aerobically stabilized and dewatered with a screw press. Organic matter varied from 48% to 56% in sludge after stabilization and dewatering. It proves that sludge was properly stabilized and it was possible to apply it as a fertilizer. Measurement factors for electric energy consumption for mechanically dewatered sewage sludge were determined, which ranged between 0.94 and 1.5 kWhm-3 with the average value at 1.17 kWhm-3. The shares of devices used for sludge dewatering and aerobic stabilization in the total energy consumption of the plant were also established, which were 3% and 25% respectively. A model of energy consumption during sewage sludge treatment was estimated according to experimental data. Two models were applied: linear regression for dewatering process and segmented linear regression for aerobic stabilization. The segmented linear regression model was also applied to total energy consumption during sewage sludge treatment in the examined dairy WWTP. The research constitutes an introduction for further studies on defining a mathematical model used to optimize electric energy consumption by dairy WWTPs. PMID- 27951463 TI - Polyspermy barriers: a plant perspective. AB - A common denominator of sexual reproduction in many eukaryotic species is the exposure of an egg to excess sperm to maximize the chances of reproductive success. To avoid potential harmful or deleterious consequences of supernumerary sperm fusion to a single female gamete (polyspermy), many eukaryotes, including plants, have evolved barriers preventing polyspermy. Typically, these checkpoints are implemented at different stages in the reproduction process. The virtual absence of unambiguous reports of naturally occurring egg cell polyspermy in flowering plants is likely reflecting the success of this multiphasic strategy and highlights the difficulty to trace this presumably rare event. We here focus on potential polyspermy avoidance mechanisms in plants and discuss them in light of analogous processes in animals. PMID- 27951464 TI - Compensatory growth in crossbred Aberdeen Angus and Belgian Blue steers: Effects on the colour, shear force and sensory characteristics of longissimus muscle. AB - The effect of feed restriction (99days) followed by compensatory growth during a 200day re-alimentation period on the colour and sensory characteristics of meat from Aberdeen Angus*Holstein-Friesian (AN) and Belgian Blue*Holstein-Friesian (BB) steers was examined. Compensatory growth had no effect on muscle pH and temperature decline, chemical composition, drip loss, fat colour, or juiciness, but increased (P=0.009) Warner-Bratzler shear force and decreased tenderness (P=0.08) and overall liking (P=0.09). Compared to meat from BB steers, meat from AN steers had a higher intramuscular fat concentration and was rated similarly for tenderness, but higher for many of the flavour characteristics examined. While adjustment for intramuscular fat concentration removed some of these differences, genotype-specific flavour differences remained. It is concluded that genotype had greater effects on meat quality than the compensatory growth feeding regime imposed in this study. PMID- 27951465 TI - Development of a heterologous enzyme-linked immunosorbent assay for the detection of clindamycin and lincomycin residues in edible animal tissues. AB - In this study, new clindamycin (CLIN) artificial antigens were prepared and used to produce broad-specificity monoclonal antibodies. Based on the as-produced mAbs, a heterologous ELISA was developed to detect CLIN and lincomycin (LIN) residues in edible animal tissues. The IC50 values of the developed assay were 0.3ng/mL (CLIN) and 1.2ng/mL (LIN) in buffer, respectively. The detection limits were estimated to be 1.8MUg/kg (CLIN) and 6.8MUg/kg (LIN) in bovine, chicken, porcine and fish muscles. In the spike and recovery tests, the mean recovery rate ranged from 76% to 112% at different spiked levels, and the intra-/inter-assay coefficients of variation were in the range of 7.1% to 13.2%. This method was verified using LC-MS/MS with a correlation coefficient >0.97. The developed ELISA is therefore well suited for simultaneous determination of CLIN and LIN residues in bovine, chicken, porcine and fish muscles. PMID- 27951467 TI - Cobalamin-independent Methionine Synthase Distribution and Influence on Vitamin B12 Growth Requirements in Marine Diatoms. AB - The requirement for cobalamin (vitamin B12) in microalgae is primarily a function of the type of methionine synthase present within their gene repertoires. Our study validates this concept through analysis of the distribution of B12 independent methionine synthase in ecologically relevant diatom genera, including the closely related bloom-forming genera Pseudo-nitzschia and Fragilariopsis. Growth and gene expression analysis of the vitamin B12-requiring version of the methionine synthase enzyme, METH, and the B12-independent version, METE, demonstrate that it is the presence of the METE gene which allows Fragilariopsis cylindrus to grow in the absence of B12. Pseudo-nitzschia granii's lack of a functional METE gene means that it cannot survive without the vitamin. Through phylogenetic analysis, we further substantiate a lack of obvious grouping in METE presence among diatom clades. In addition, we also show how this trend may have a biogeographical basis, particularly in regions such as the Southern Ocean where B12 concentrations may be consistently low. Our findings demonstrate the important role vitamins can play in diatom community dynamics within areas where vitamin supply may be variable and limiting. PMID- 27951468 TI - Effects of seawater temperature increase on economically relevant native and introduced clam species. AB - As a consequence of climate change, global warming is expected to increase during the 21st century. Taking this into account, the impact of rising temperatures on the native Ruditapes decussatus and introduced R. philippinarum bivalve species was assessed, through biochemical and mRNA transcription analyses. Our findings showed that at 21 degrees C the electron transport system and antioxidant enzyme activity, as well as the expression of Hsp70 gene were induced in R. decussatus when compared with 17 degrees C. On the other hand, at 25 degrees C results suggested that R. decussatus closed their valves during short periods, as a behavioral strategy, down-regulating the expression of genes associated with mitochondrial metabolism (Cox-1 and 16S) and chaperone function (Hsp70) compared with organisms at 17 degrees C. In addition, the introduced species (R. philippinarum) increased the electron transport system and antioxidant activities, as well as gene expression of antioxidant enzymes and molecular chaperone (Hsp70) at 21 degrees C. However, antioxidant mechanisms were not enough to prevent lipid membrane damages at 21 degrees C. At 25 degrees C R. philippinarum presented increased electron transport system and antioxidant activity, as well as the expression of genes associated with apoptosis regulation and molecular chaperone. Overall, the present findings indicate that in a global warming scenario both species are able to induce different mechanisms to mitigate the impacts of temperature increase. PMID- 27951466 TI - Clinical validation of a novel diagnostic HIV-2 total nucleic acid qualitative assay using the Abbott m2000 platform: Implications for complementary HIV-2 nucleic acid testing for the CDC 4th generation HIV diagnostic testing algorithm. AB - BACKGROUND: The 2014 CDC 4th generation HIV screening algorithm includes an orthogonal immunoassay to confirm and discriminate HIV-1 and HIV-2 antibodies. Additional nucleic acid testing (NAT) is recommended to resolve indeterminate or undifferentiated HIV seroreactivity. HIV-2 NAT requires a second-line assay to detect HIV-2 total nucleic acid (TNA) in patients' blood cells, as a third of untreated patients have undetectable plasma HIV-2 RNA. OBJECTIVES: To validate a qualitative HIV-2 TNA assay using peripheral blood mononuclear cells (PBMC) from HIV-2-infected Senegalese study participants. STUDY DESIGN: We evaluated the assay precision, sensitivity, specificity, and diagnostic performance of an HIV-2 TNA assay. Matched plasma and PBMC samples were collected from 25 HIV-1, 30 HIV 2, 8 HIV-1/-2 dual-seropositive and 25 HIV seronegative individuals. Diagnostic performance was evaluated by comparing the outcome of the TNA assay to the results obtained by the 4th generation HIV screening and confirmatory immunoassays. RESULTS: All PBMC from 30 HIV-2 seropositive participants tested positive for HIV-2 TNA including 23 patients with undetectable plasma RNA. Of the 30 matched plasma specimens, one was HIV non-reactive. Samples from 50 non-HIV-2 infected individuals were confirmed as non-reactive for HIV-2 Ab and negative for HIV-2 TNA. The agreement between HIV-2 TNA and the combined immunoassay results was 98.8% (79/80). Furthermore, HIV-2 TNA was detected in 7 of 8 PBMC specimens from HIV-1/HIV-2 dual-seropositive participants. CONCLUSIONS: Our TNA assay detected HIV-2 DNA/RNA in PBMC from serologically HIV-2 reactive, HIV indeterminate or HIV undifferentiated individuals with undetectable plasma RNA, and is suitable for confirming HIV-2 infection in the HIV testing algorithm. PMID- 27951470 TI - Portable near-infrared instruments: Application for quality control of polymorphs in pharmaceutical raw materials and calibration transfer. AB - This work presents an evaluation of the analytical performance of three different portable near-infrared (NIR) instruments (denominated Port.1, Port.2 and Port.3) for quantifying mebendazole polymorphs (A, B and C) in pharmaceutical raw materials using multivariate calibration models. The performance of the portable instruments was compared with a benchtop one (FT-NIR Frontier spectrometer). In addition, calibration transfer between the benchtop and one of the portable instruments was also performed. For polymorph A, the Port.1 presented the lowest RMSEP value (1.01% w/w) even when compared to the FT-NIR instrument. For polymorphs B and C, the same Port.1 instrument presented RMSEP values of 2.09% w/w and 2.41% w/w, respectively, which were statistically similar to those obtained with the benchtop instrument. The LOD ranges (3.9-5.5 for polymorph A, 3.6-5.1 for polymorph B and 5.7-7.7 for polymorph C) obtained with the Port.1 was higher than those achieved with the benchtop NIR instrument, with high spectral resolution, signal-to-noise ratio and better wavelength reproducibility. Calibration transfer was performed between the benchtop NIR and Port.1 instruments. According to the results, the transferability of models is possible. The results obtained for complete recalibration of the portable instrument and those for the benchtop are comparable. The methods developed demonstrated a flexible, easy, cheap and fast way for quality control of MBZ polymorphs in incoming material, mainly in pharmaceutical laboratory chains. PMID- 27951469 TI - "Evaluation of ion mobility spectrometry for the detection of mitragynine in kratom products". AB - An ion mobility spectrometry (IMS) method was developed for the rapid detection of mitragynine, the most abundant alkaloid in Mitragyna speciosa also known as kratom. The peak corresponding to the mitragynine protonated ion exhibited a reduced ion mobility of 0.95+/-0.00014cm2/(Vs), and the mitragynine limit of detection using IMS was 0.5ng. The IMS method was applied to the analysis of 15 commercial samples suspected of containing kratom. IMS results were compared to those obtained from liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of the same samples. Mitragynine was conclusively detected in 14 of 15 samples using LC-MS/MS and 13 of 15 samples using IMS. The discrepancy between methods reflected the fact that one sample contained mitragynine at a concentration below the IMS detection limit. This study demonstrates the utility of IMS for the rapid screening of products containing kratom as well as the scientific reliability of the IMS screening method, which was demonstrated by comparing the IMS results to the confirmatory results obtained using LC-MS/MS. PMID- 27951471 TI - Bioanalysis of antitubercular drugs using liquid chromatography. AB - Tuberculosis is a life threatening disease and second to HIV in terms of deaths due to infectious diseases. Drug resistance development of the first-line drugs is a major concern in the treatment of this disease. There is no comprehensive and critical review in the literature of the bioanalytical methods for the determination of anti-tubercular agents from last two decades. This work offers a detailed account on the liquid chromatographic methods reported in the literature for the estimation of various anti-tubercular drugs. Major emphasis is given to sample preparation process, sensitivity of method, chromatographic separation conditions and detection systems used in their bioanalysis. PMID- 27951472 TI - Soy protein concentrate mitigates markers of colonic inflammation and loss of gut barrier function in vitro and in vivo. AB - Whereas a number of studies have examined the effects of soy isoflavones and tocopherols on colonic inflammation, few have examined soy protein. We determined the radical scavenging and cytoprotective effects of soy protein concentrate (SPC) in vitro and its anti-inflammatory effects in dextran sulfate sodium (DSS) treated mice. Cotreatment with SPC protected Caco-2 human colon cells from H2O2 induced cell death and mitigated intracellular oxidative stress. Treatment of differentiated Caco-2 cells with SPC blunted DSS-induced increases in monolayer permeability. Pepsin/pancreatin-digested SPC had reduced radical scavenging activity, but retained the monolayer protective effects of SPC. In vivo, 1.5% DSS caused body weight loss, colon shortening, and splenomegaly in CF-1 mice. Co treatment with 12% SPC mitigated DSS-induced body weight loss and splenomegaly. DSS increased colonic interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1 expression. The levels of these markers were significantly lower in mice co-treated with SPC. SPC prevented DSS-mediated reductions in colonic glucagon-like peptide 2 levels, suggesting that SPC can prevent loss of gut barrier function, but no significant effect on claudin 1 and occludin mRNA levels of was observed. SPC-treated mice had lower colonic mRNA expression of toll-like receptor 4 and nucleotide-binding oligomerization domain-containing protein-like receptor family, pyrin domain containing protein 3 (NLRP3), and lower caspase-1 enzyme activity than DSS-treated mice. In summary, SPC exerted antioxidant and cytoprotective effects in vitro and moderated the severity of DSS-induced inflammation and loss of gut barrier function in vivo. These effects appear to be mediated in part through reduced NLRP3 expression and caspase 1 activity. PMID- 27951473 TI - Oleuropein aglycone enhances UCP1 expression in brown adipose tissue in high-fat diet-induced obese rats by activating beta-adrenergic signaling. AB - Oleuropein is the pungent principle of raw olives. Oleuropein aglycone (OA) is a major phenolic compound in extra virgin olive oil and the absorbed form of oleuropein. We aimed to determine the mechanism underlying the nutritional effects of oleuropein and OA on interscapular brown adipose tissue (IBAT) in rats with high-fat (HF) diet-induced obesity by examining the agonistic activity of oleuropein and OA toward the transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1). Four-week-old male Sprague-Dawley rats were fed an HF (palm oil 30% wt:wt) diet alone or with oleuropein (HF-O, 1 g/kg diet) for 28 days. In rats fed HF-O compared to HF, urinary noradrenaline, adrenaline and UCP1 levels in IBAT were significantly higher, whereas plasma leptin levels and the total weight of the abdominal cavity adipose tissue were significantly lower. In anaesthetized 7-week-old male Sprague-Dawley rats, the OA (3.8 mg of intravenous injection)-induced increase in plasma noradrenaline secretion was suppressed by TRPA1 or TRPV1 antagonist and by a beta2- or beta3-adrenoceptor antagonist. Furthermore, OA-activated rat and human TRPV1s expressed on HEK293 cells at the same level as zingerone (pungent component in ginger). OA also activated humanTRPA1, and its potency was approximately 10-fold stronger than that for TRPV1. These findings suggest that OA is the agonist of both TRPA1 and TRPV1 and that OA enhances UCP1 expression in IBAT with a concomitant decrease in the visceral fat mass of HF-diet-induced obese rats through enhanced noradrenaline secretion via beta-adrenergic action following TRPA1 and TRPV1 activation. PMID- 27951474 TI - Down-regulation of fibroblast growth factor 2 and its co-receptors heparan sulfate proteoglycans by resveratrol underlies the improvement of cardiac dysfunction in experimental diabetes. AB - Cardiac remodeling in diabetes involves cardiac hypertrophy and fibrosis, and fibroblast growth factor 2 (FGF2) is an important mediator of this process. Resveratrol, a polyphenolic antioxidant, reportedly promotes the improvement of cardiac dysfunction in diabetic rats. However, little information exists linking the amelioration of the cardiac function promoted by resveratrol and the expression of FGF2 and its co-receptors, heparan sulfate proteoglycans (HSPGs: Glypican-1 and Syndecan-4), in cardiac muscle of Type 2 diabetic rats. Diabetes was induced experimentally by the injection of streptozotocin and nicotinamide, and the rats were treated with resveratrol for 6 weeks. According to our results, there is an up-regulation of the expression of genes and/or proteins of Glypican 1, Syndecan-4, FGF2, peroxisome proliferator-activated receptor gamma and AMP activated protein kinase in diabetic rats. On the other hand, resveratrol treatment promoted the attenuation of left ventricular diastolic dysfunction and the down-regulation of the expression of all proteins under study. The trigger for the changes in gene expression and protein synthesis promoted by resveratrol was the presence of diabetes. The negative modulation conducted by resveratrol on FGF2 and HSPGs expression, which are involved in cardiac remodeling, underlies the amelioration of cardiac function. PMID- 27951475 TI - Activation of respiratory muscles during weaning from mechanical ventilation. AB - PURPOSE: Respiratory muscle dysfunction is a key component of weaning failure. Balancing respiratory muscle loading and unloading by applying different ventilation modes along with spontaneous breathing episodes are established weaning strategies. However, the effects of body positioning on the respiratory muscles during weaning remains unclear. MATERIALS AND METHODS: This study aimed at assessing respiratory drive by surface electromyography (EMG) of the diaphragm (EMGdia) and parasternal muscles (EMGpara) in tracheotomized patients during prolonged weaning in 3 randomized body positions-supine, 30 degrees semirecumbent, and 80 degrees sitting-during mechanical ventilation and spontaneous breathing. RESULTS: Nine patients were included for analysis. Cardiorespiratory parameters (heart rate, blood pressure, arterial oxygen saturation, dyspnea) did not change under each condition (all P>.05). EMGpara and EMGdia did not change under mechanical ventilation (both P>.05). EMGdia changed under spontaneous breathing from supine to sitting (0.45+/-0.26 vs 0.32+/-0.19; P=.012) and between semirecumbent to sitting (0.41+/-0.23 vs 0.32+/-0.19; P=.039), whereas EMGpara did not change. CONCLUSIONS: This is the first study to show that body positioning influences respiratory drive to the diaphragm in tracheotomized patients with prolonged weaning from mechanical ventilation during unassisted breathing. Sitting position reduces respiratory drive compared with semirecumbent and supine positioning and might therefore be favored during spontaneous breathing trials. PMID- 27951476 TI - A nitrocefin-based amperometric assay for the rapid quantification of extended spectrum beta-lactamase-producing Escherichia coli in wastewaters. AB - A sensitive and inexpensive amperometric assay based on the electrochemical detection of the beta-lactamase activity using the nitrocefin as substrate was developed for the rapid and quantitative detection of extended spectrum beta lactamase-producing Escherichia coli (ESBL-EC) in urban wastewaters. The specific detection of ESBL-EC was achieved by culturing the filtered sample in a medium containing the cefotaxime supplemented or not with the potassium clavulanate inhibitor. This step was followed by the incubation of each subculture filtrate with the nitrocefin substrate which hydrolysis was monitored by amperometry using disposable carbon screen-printed sensors. Current intensities iCef and iClav correspond to the intensity of the anodic current measured (~+ 0.2 V vs. Ag/AgCl) for the sample incubated with the cefotaxime without and with potassium clavulanate, respectively. The intensity value i = iCef - iClav was chosen as the analytical response. ESBL-EC calibration plots were established with artificially contaminated wastewater samples. This assay allowed the detection of ESBL-EC amounts as low as 10 cfu in treated effluents and 100 cfu in raw wastewaters with short time analysis of 5.5 h and 4.5 h, respectively. The amperometric method was applied to the analysis of 38 wastewater samples and the results were in good agreement with CFU counts on a selective chromogenic medium for 24 h. Owing to its rapidity, convenience, low-cost and portability, this assay is a promising tool to obtain quantitative data on antimicrobial-resistant E. coli in wastewater effluents. Furthermore, this assay might be used to improve wastewater treatment plant processes in order to minimize the release of antibiotic resistant bacteria into the aquatic environment. PMID- 27951477 TI - Impact of inner-wall reflection on UV reactor performance as evaluated by using computational fluid dynamics: The role of diffuse reflection. AB - Making use of the reflected ultraviolet (UV) radiation with a reflective inner wall is a promising way to improve UV reactor performance. In this study, the impact of inner-wall reflection on UV reactor performance was evaluated in annular single-lamp UV reactors by using computational fluid dynamics, with an emphasis on the role of diffuse reflection. The UV radiation inside the reactor chamber was simulated using a calibrated discrete ordinates radiation model, which has been proven to be a reliable tool for modeling fluence rate (FR) distributions in UV reactors with a reflective inner wall. The results show that UV reactors with a highly reflective inner wall (Reflectivity = 0.80) had obviously higher FRs and reduction equivalent fluences (REFs) than those with an ordinary inner wall (Reflectivity = 0.26). The inner-wall diffuse reflection further increased the reactor REF, as a result of the elevated volume-averaged FR. The FR distribution uniformity had conditioned contributions to UV reactor performance. Specifically, in UV reactors with a plug-like flow the FR distribution uniformity contributed to the REF to some extent, while in UV reactors with a mixed flow it had little influence on the REF. This study has evaluated, for the first time, the impact of inner-wall diffuse reflection on UV reactor performance and has renewed the understanding about the contribution of FR distribution uniformity to UV reactor performance. PMID- 27951478 TI - Family history of suicide and interpersonal functioning in suicide attempters. AB - Difficulties in interpersonal relationships are associated with a wide range of psychiatric diagnoses and have been reported as a trigger for suicidal behavior, too. The aim of this study was to examine the relationship between interpersonal problems and family history of suicide in suicide attempters and to describe relevant patterns of interpersonal problems in this patient group. The study involves 181 patients having their clinical follow-up after a suicide attempt. Family history of suicide was assessed by using the Karolinska Self Harm History Interview or retrieved in patient records. The Inventory of Interpersonal Problems was used to assess personal style in an interpersonal context. Suicide attempters with a family history of suicide had significantly more often an intrusive personal style. The results remained significant after adjustment for personality disorder. The specific interpersonal patterns associated with family history of suicide may interfere with the ability to create stable, long-lasting relationships. In regards to treatment, these personal qualities could cause difficulties in the alliance with health care personnel and make it harder for suicide attempters to accept or benefit from treatment. Attention to suicide attempters' interpersonal problems is of importance to lower their distress. PMID- 27951479 TI - Comorbidity between schizophrenia and keratoconus. PMID- 27951481 TI - Relatives' expressed emotion, distress and attributions in clinical high-risk and recent onset of psychosis. AB - It has been well-demonstrated that Expressed Emotion (EE) in caregivers of schizophrenia patients is related to their illness attributions, but little is known about relatives' cognitive and emotional appraisals at early stages of psychosis. This study examined differences on the relationships of EE with distress and illness attributions in 78 relatives of At-Risk Mental States (ARMS) and First-Episode of Psychosis (FEP) patients, and which of those variables better predicted EE. Criticism and Emotional Over-Involvement (EOI) were associated with distress and with several illness attributions in both groups. Anxiety was more strongly associated with criticism in ARMS than in FEP relatives, and it was associated with EOI in the ARMS but not in the FEP-group. No differences on the relationships of EE with depression or attributions were found. Furthermore, distress and attributions of blame toward the patients predicted criticism. Attributions of control by the patient and emotional negative representation about the disorder predicted EOI. Findings highlight the need to focus on early family interventions that provide proper information and psychological support in accordance with the illness stage, to help relatives improve their understanding of the disorder, handle difficult thoughts and emotions, reduce negative appraisals, and prevent high-EE over the psychotic process. PMID- 27951480 TI - Development of the four-item Letter and Shape Drawing test (LSD-4): A brief bedside test of visuospatial function. AB - Conventional bedside tests of visuospatial function such as the Clock Drawing (CDT) and Intersecting Pentagons (IPT) lack consistency in delivery and interpretation. We compared performance on a novel test of visuospatial ability - the LSD - with the IPT, CDT and MMSE in 180 acute elderly medical inpatients [mean age 79.7+/-7.1 (range 62-96); 91 females (50.6%)]. 124 (69%) scored <=23 on the MMSE; 60 with mild (score 18-23) and 64 with severe (score <=17) impairment. 78 (43%) scored >=6 on the CDT, while for the IPT, 87 (47%) scored >=4. The CDT and IPT agreed on the classification of 138 patients (77%) with modest-strong agreement with the MMSE categories. Correlation between the LSD and visuospatial tests was high. A four-item version of the LSD incorporating items 1,10,12,15 had high correlation with the LSD-15 and strong association with MMSE categories. The LSD-4 provides a brief and easily interpreted bedside test of visuospatial function that has high coverage of elderly patients with neurocognitive impairment, good agreement with conventional tests of visuospatial ability and favourable ability to identify significant cognitive impairment. [181 words]. PMID- 27951482 TI - Pain, not structural impairments may explain activity limitations in people with gluteal tendinopathy or hip osteoarthritis: A cross sectional study. AB - QUESTION: What are the functional differences between people with greater trochanteric pain syndrome (GT), hip osteoarthritis (OA) or an asymptomatic population as measured by walking, Time Up and Go, single leg standing and strength? DESIGN: Cross sectional study with blinded measurers. PARTICIPANTS: 38 participants with GT, 20 with end stage hip OA and 21 asymptomatic healthy control (AS) participants. All participants were women. OUTCOME MEASURES: Pain (numeric rating scale), Walking speed (m/s), cadence (steps/min) and step length (m) measured via the 10m walk test and the Timed Up and Go; balance via single leg stance (s) duration; and hip abduction, adduction, medial and lateral rotation strength, standardized to body mass (BM) via the body mass average index (BMavg), measured via a wall mounted dynamometer. RESULTS: The two symptomatic groups reported similar pain levels (p=0.226), more pain then the AS group (p<0.000). Compared to the AS participants, participants with GT or hip OA demonstrated lower walking speed (10mwt and TUG, p<0.001), lower cadence and shorter duration single leg stance on the affected leg (p<0.05). Participants with GT or hip OA also demonstrated bilaterally weaker hip abduction than the AS group (p<=0.005). Compared to AS and GT participants, participants with hip OA demonstrated adduction weakness on the affected side (p=0.008 and p=0.002 respectively). CONCLUSION: There is a significant level of dysfunction and impairments associated with GT and hip OA. As activity limitations do not appear to be differentiated by structural impairments, we suggest that pain, rather than the underlying pathology may be the driving impairment that leads to walking and single leg standing dysfunction. PMID- 27951483 TI - Synthesis and bioactivity investigation of quinone-based dimeric cationic triazolium amphiphiles selective against resistant fungal and bacterial pathogens. AB - A series of synthetic dimeric cationic anthraquinone analogs (CAAs) with potent antimicrobial activities against a broad range of fungi and bacteria were developed. These compounds were prepared in 2-3 steps with high overall yield and possess alkyl chain, azole, quinone, and quaternary ammonium complexes (QACs). In vitro biological evaluations reveal prominent inhibitory activities of lead compounds against several drug-susceptible and drug-resistant fungal and bacterial strains, including MRSA, VRE, Candida albicans and Aspergillus flavus. Mode of action investigation reveals that the synthesized dimeric CAA's can disrupt the membrane integrity of fungi. Computational studies reveal possible designs that can revive the activity of QACs against drug-resistant bacteria. Cytotoxicity assays in SKOV-3, a cancer cell line, show that the lead compounds are selectively toxic to fungi and bacteria over human cells. PMID- 27951484 TI - Therapeutic evolution of benzimidazole derivatives in the last quinquennial period. AB - Benzimidazole, a fused heterocycle bearing benzene and imidazole has gained considerable attention in the field of contemporary medicinal chemistry. The moiety is of substantial importance because of its wide array of pharmacological activities. This nitrogen containing heterocycle is a part of a number of therapeutically used agents. Moreover, a number of patents concerning this moiety in the last few years further highlight its worth. The present review covers the recent work published by scientists across the globe during last five years. PMID- 27951485 TI - Aurone Mannich base derivatives as promising multifunctional agents with acetylcholinesterase inhibition, anti-beta-amyloid aggragation and neuroprotective properties for the treatment of Alzheimer's disease. AB - A series of aurone Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compound 7d exhibited outstanding inhibitory activity for RatAChE, EeAChE and HuAChE (IC50 = 0.00878 +/- 0.0002 MUM, 0.0212 +/- 0.006 MUM and 0.0371 +/- 0.004 MUM, respectively). Moreover, 7d displayed high antioxidant activity and could confer significant neuroprotective effect against H2O2-induced PC-12 cell injury. In addition, 7d also showed biometal chelating abilities, good self- and Cu2+ induced Abeta1-42 aggregation inhibitory potency and high BBB permeability. These multifunctional properties highlight 7d as promising candidate for further studies directed to the development of novel drugs against AD. PMID- 27951486 TI - In vitro activity and mode of action of distamycin analogues against African trypanosomes. AB - Distamycin, a natural polyamide containing three heterocycle rings with a polar end, has inspired several groups to prepare synthetic analogues, which proved to have anti-trypanosomal and anti-tumoral activity. We describe the synthesis of bi and tri thiazoles amides that harbor different substitutions at their ends and the evaluation of their anti-Trypanosoma brucei activity. The most active compound 10b showed better biological activity (EC50 310 nM and selectivity index 16) than the control drug nifurtimox (EC50 15 MUM and selectivity index 10). Studies on the mode of action show that the parasiticidal activity of 10b originates from disruption of lysosomal homeostasis, which is followed by release of redox active iron, an increase in oxidizing species and collapse of cell membrane integrity. In this respect, our study suggests that non-charged lipophylic distamycins destabilize cell membranes. PMID- 27951487 TI - Synthesis and antiproliferative activity of monocationic arylthiophene derivatives. AB - Eleven compounds of substituted 4-(5-arylthiophen-2-yl)benzamidines 4a-k were synthesized from their corresponding mononitriles via treatment with lithium trimethylsilylamide and subsequent de-protection with ethanol/hydrogen chloride. In vitro antiproliferative activities of the new monocationic arylthiophenes were evaluated against 60 human cell lines at NCI, USA. This class of compounds displayed promising submicromolar antiproliferative activities with the most potent compound being 4i (GI50 and TGI of 0.20 and 0.37 MUM, respectively). On the other hand, most of the tested compounds exhibited LC50 at concentrations much higher than those they had GI50 at; ~10* (for 4b) up to 228* (for 4e) which indicates lower lethality and efficient growth inhibition. Cancer cell lines, HCC 2998 colon, SNB-75 CNS, MDA-MB-435 melanoma, and MCF-7 breast cancer were the most responsive, with GI50s of 0.156, 0.165, 0.163, and 0.168 MUM, respectively. The p-chlorophenyl derivatives 4e and 4i discerned themselves with GI50 values at 0.36 and 0.20 MUM, respectively, and LC50 values at ~83 and 36 MUM, respectively, but safe to RBCs at 1000 MUM. The cytotoxic activity data of these compounds in two normal cell lines; WI38 and WISH proved that they are very safe on normal cells. The plausible mechanism of action of the tested monocations was examined by evaluating their antioxidant power, nuclease-like DNA degradation aptitude and tyrosine kinase (TK) inhibition activities. The tested monocations showed potent activity in all assays. Compounds 4e and 4i caused 88 and 98%, respectively, inhibition in TK activity at 1 MUM and the IC50 for 4i was 13 nM. The tested monocations have selective anticancer activity without insulting normal cells most probably due to inhibition of the key enzyme TK at nanomolar concentrations. PMID- 27951488 TI - Novel dabigatran derivatives with a fluorine atom at the C-2 position of the terminal benzene ring: Design, synthesis and anticoagulant activity evaluation. AB - This manuscript describes the preparation of dabigatran derivatives and their inhibitory potentials toward human thrombin. Among the tested compounds, 7c, 7k, 7m and 7o, with IC50 values of 1.54, 0.84, 1.18 and 1.42 nM, exhibited comparable inhibitory activity to dabigatran (IC50 = 1.20 nM). The in vivo anti-thrombotic activity of compounds 7c and 7o in SD rats was studied. Results showed that intravenously administering the two compounds significantly inhibited the growth of thrombus with an inhibition rate of (84.24 +/- 1.53)% and (84.57 +/- 0.45)%, which were comparable to that of dabigatran (85.07 +/- 0.61)%. Furthermore, the docking simulation of active compounds (7k and 7m) provided a potential binding model. Results indicated that these compounds could be further investigated to determine their anticoagulant activities. PMID- 27951490 TI - 2,4-Disubstituted quinazolines as amyloid-beta aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: Development and structure activity relationship (SAR) studies. AB - A library of fifty-seven 2,4-disubstituted quinazoline derivatives were designed, synthesized and evaluated as a novel class of multi-targeting agents to treat Alzheimer's disease (AD). The biological assay results demonstrate the ability of several quinazoline derivatives to inhibit both acetyl and butyrylcholinesterase (AChE and BuChE) enzymes (IC50 range = 1.6-30.5 MUM), prevent beta-amyloid (Abeta) aggregation (IC50 range 270 nM-16.7 MUM) and exhibit antioxidant properties (34-63.4% inhibition at 50 MUM). Compound 9 (N2-(1-benzylpiperidin-4 yl)-N4-(3,4-dimethoxybenzyl)quinazoline-2,4-diamine) was identified as a dual inhibitor of cholinesterases (AChE IC50 = 2.1 MUM; BuChE IC50 = 8.3 MUM) and exhibited good inhibition of Abeta aggregation (Abeta40 IC50 = 2.3 MUM). Compound 15b (4-(benzylamino)quinazolin-2-ol) was the most potent Abeta aggregation inhibitor (Abeta40 IC50 = 270 nM) and was ~4 and 1.4-fold more potent compared to the reference agents curcumin and resveratrol. These comprehensive structure activity-relationship (SAR) studies demonstrate the application of a 2,4 disubstituted quinazoline ring as a suitable template to develop multi-targeting agents to treat AD. PMID- 27951489 TI - Novel ferulic amide derivatives with tertiary amine side chain as acetylcholinesterase and butyrylcholinesterase inhibitors: The influence of carbon spacer length, alkylamine and aromatic group. AB - Based on our recent investigations on chalcone derivatives as AChE inhibitors, a series of ferulic acid (FA) tertiary amine derivatives similar to chalcone compounds were designed and synthesized. The results of bioactivity evaluation revealed that most of new synthesized compounds had comparable or more potent AChE inhibitory activity than the control drug Rivastigmine. The alteration of carbon chain linking tertiary amine groups and ferulic acid scaffold markedly influenced the inhibition activity against AChE. Among them the inhibitory activity of compound 6d (IC50: 0.71 +/- 0.09 MUmol/L) and 6e (IC50: 1.11 +/- 0.17 MUmol/L) was equal to 15-fold and 9-fold than that of Rivastigmine against AChE (IC50: 10.54 +/- 0.86 MUmol/L), respectively. Moreover, compound 6d shows the highest selectivity for AChE over butyrylcholinesterase(BuChE) (ratio: 18.3). The kinetic study suggested that compound 6d revealed a mixed-type inhibition against AChE. The result of molecular docking showed that compound 6d combines to AChE with three amino acid sites(Trp84, Tyr334 and Trp279), while combines to BuChE with two amino acid sites (Tyr67 and Gly66) in enzyme domains, respectively. Compound 6d might act as a potential agent for the treatment of Alzheimer's diseases (AD). PMID- 27951491 TI - Biochemical and physiological changes during fruit development and ripening of two sweet cherry varieties with different levels of cracking tolerance. AB - The aim of this study was to investigate the biochemical and metabolic changes, related to oxidative stress, ethylene and respiration, cell wall modification and primary metabolism, between a high ('Prime Giant') and a low ('Cristalina') cracking susceptible sweet cherry cultivar during growth and ripening. While cherries are referred as a non-climacteric fruit, our results show that an increase of endogenous ethylene production at earlier fruit developmental stages is parallel to colour development and softening during growth. Higher cracking susceptibility was clearly associated to a higher fruit growth rate and accompanied by an increase net CO2 and ethylene production, on a cherry basis, leading to an enhanced accumulation of oxidative stress markers (i.e. H2O2 and MDA). As observed in other fruit species (i.e. tomatoes) higher cracking susceptibility was also related to enhanced activity of cell wall-modifying enzymes which in turn occurred in parallel to the ethylene rise. Overall, these results suggest that cracking development may be a more complex phenomenon than a mere consequence of altered fruit water absorption or turgor and point out the importance of ethylene on sweet cherry ripening and cracking development. PMID- 27951492 TI - Role of the C-terminal extension peptide of plastid located glutamine synthetase from Medicago truncatula: Crucial for enzyme activity and needless for protein import into the plastids. AB - Glutamine synthetase (GS), a key enzyme in plant nitrogen metabolism, is encoded by a small family of highly homologous nuclear genes that produce cytosolic (GS1) and plastidic (GS2) isoforms. Compared to GS1, GS2 proteins have two extension peptides, one at the N- and the other at the C-terminus, which show a high degree of conservation among plant species. It has long been known that the N-terminal peptide acts as a transit peptide, targeting the protein to the plastids however, the function of the C-terminal extension is still unknown. To investigate whether the C-terminal extension influences the activity of the enzyme, we produced a C terminal truncated version of Medicago truncatula GS2a in Escherechia coli and studied its catalytic properties. The activity of the truncated protein was found to be lower than that of MtGS2a and with less affinity for glutamate. The importance of the C-terminal extension for the protein import into the chloroplast was also assessed by transient expression of fluorescently-tagged MtGS2a truncated at the C-terminus, which was correctly detected in the chloroplast. The results obtained in this work demonstrate that the C-terminal extension of M. truncatula GS2a is important for the activity of the enzyme and does not contain crucial information for the import process. PMID- 27951494 TI - The long-term resistance mechanisms, critical irrigation threshold and relief capacity shown by Eugenia myrtifolia plants in response to saline reclaimed water. AB - Salts present in irrigation water are serious problems for commercial horticulture, particularly in semi-arid regions. Reclaimed water (RW) typically contains, among others elements, high levels of salts, boron and heavy metal. Phytotoxic ion accumulation in the substrate has been linked to different electric conductivities of the treatments. Based on these premises, we studied the long-term effect of three reclaimed water treatments with different saline concentrations on Eugenia myrtifolia plants. We also looked at the ability of these plants to recover when no drainage was applied. The RW with the highest electric conductivity (RW3, EC = 6.96 dS m-1) provoked a number of responses to salinity in these plants, including: 1) accumulation and extrusion of phytotoxic ions in roots; 2) a decrease in the shoot/root ratio, leaf area, number of leaves; 3) a decrease in root hydraulic conductivity, leaf water potential, the relative water content of leaves, leaf stomatal conductance, the leaf photosynthetic rate, water-use efficiency and accumulated evapotranspiration in order to limit water loss; and 4) changes in the antioxidant defence mechanisms. These different responses induced oxidative stress, which can explain the damage caused in the membranes, leading to the death of RW3 plants during the relief period. The behaviour observed in RW2 plants was slightly better compared with RW3 plants, although at the end of the experiment about 55% of the RW2 plants also died, however RW containing low salinity level (RW1, EC = 2.97 dS m-1) can be effective for plant irrigation. PMID- 27951493 TI - Proteomic analysis of the compatible interaction of wheat and powdery mildew (Blumeria graminis f. sp. tritici). AB - Proteome characteristics of wheat leaves with the powdery mildew pathogen Blumeria graminis f. sp. tritici (Bgt) infection were investigated by two dimensional electrophoresis and tandem MALDI-TOF/TOF-MS. We identified 46 unique proteins which were differentially expressed at 24, 48, and 72 h post inoculation. The functional classification of these proteins showed that most of them were involved in photosynthesis, carbohydrate and nitrogen metabolism, defense responses, and signal transduction. Upregulated proteins included primary metabolism pathways and defense responses, while proteins related to photosynthesis and signal transduction were mostly downregulated. As expected, more antioxidative proteins were activated at the later infection stage than the earlier stage, suggesting that the antioxidative system of host plays a role in maintaining the compatible interaction between wheat and powdery mildew. A high accumulation of 6-phosphogluconate dehydrogenase and isocitrate dehydrogenase in infected leaves indicated the regulation of the TCA cycle and pentose phosphate pathway in parallel to the activation of host defenses. The downregulation of MAPK5 could be facilitated for the compatible interaction of wheat plants and Bgt. qRT-PCR analysis supported the data of protein expression profiles. Our results reveal the relevance of primary plant metabolism and defense responses during compatible interaction, and provide new insights into the biology of susceptible wheat in response to Bgt infection. PMID- 27951495 TI - Ionomic and physiological responses to low nitrogen stress in Tibetan wild and cultivated barley. AB - In a previous study, we identified the low-nitrogen (LN) tolerant accessions from the Tibetan wild barley (Hordeum vulgare subsp. spontaneum). In this study, two wild barley genotypes (XZ149, LN-tolerant and XZ56, LN-sensitive) and a barley cultivar ZD9 (H. vulgare) were used to determine the LN tolerant mechanism underlying the wild barley in the ionomic and physiological aspects. XZ149 exhibited higher LN tolerance with highest relative dry weight and N accumulation among three barley genotypes under LN stress. When exposed to LN stress, XZ149 had more N transportation from roots to leaves, and remained relatively higher activities of nitrate reductase (NR, EC.1.7.1.1) and glutamine synthetase (GS, EC.6.3.1.2) in leaves than other two genotypes, ensuring its higher capacity of N assimilation and utilization. The ionome analysis showed that LN stress had a significant effect on tissue ionome and the effect was genotypic and tissue specific difference. On the whole, XZ149 maintained more stable Mn and Cu contents in roots, and less reduction of root P, K and Ca contents than XZ56 and ZD9 when exposed to LN stress. It may be assumed that more N movement into shoots, greater N assimilating capacity and specific rearrangement of nutrient element levels in tissues under LN stress are attributed to LN tolerance in XZ149. PMID- 27951497 TI - Sequential multi-nuclide emission rate estimation method based on gamma dose rate measurement for nuclear emergency management. AB - In case of a nuclear accident, the source term is typically not known but extremely important for the assessment of the consequences to the affected population. Therefore the assessment of the potential source term is of uppermost importance for emergency response. A fully sequential method, derived from a regularized weighted least square problem, is proposed to reconstruct the emission and composition of a multiple-nuclide release using gamma dose rate measurement. The a priori nuclide ratios are incorporated into the background error covariance (BEC) matrix, which is dynamically augmented and sequentially updated. The negative estimations in the mathematical algorithm are suppressed by utilizing artificial zero-observations (with large uncertainties) to simultaneously update the state vector and BEC. The method is evaluated by twin experiments based on the JRodos system. The results indicate that the new method successfully reconstructs the emission and its uncertainties. Accurate a priori ratio accelerates the analysis process, which obtains satisfactory results with only limited number of measurements, otherwise it needs more measurements to generate reasonable estimations. The suppression of negative estimation effectively improves the performance, especially for the situation with poor a priori information, where it is more prone to the generation of negative values. PMID- 27951496 TI - The timing of caffeic acid treatment with cisplatin determines sensitization or resistance of ovarian carcinoma cell lines. AB - Cisplatin is a widely used chemotherapeutic drug showing high efficiency in the treatment of primary tumors such as ovarian, testicular and cervical cancers. The major drawback of cisplatin is tumor resistance either acquired or intrinsic. Many mechanisms are involved in the resistance, among them is the Nrf2 pathway which regulates glutathione related enzymes. Caffeic acid, a non-toxic polyphenol which is abundant in many foods modulates glutathione S-transferase (GST) and glutathione reductase (GSR) activity, these enzymes were shown to be involved in resistance of cells towards cisplatin. Caffeic acid induces the Nrf2 pathway and can also inhibit the activity of GST and GSR. Our findings demonstrate that the co-treatment of cancer cells with cisplatin and caffeic acid can enhance cisplatin cytotoxicity and increases the amount of platinum bound to nuclear DNA. However, 6h of pre incubation with caffeic acid prior to cisplatin treatment led to acquired resistance to cisplatin and reduced DNA binding. In conclusion, the enzyme inhibitory action of caffeic acid is dominant when the two agents are co administered leading to increased cytotoxicity, and the Nrf2 induction is dominant when the cells are treated with caffeic acid prior to cisplatin treatment leading to resistance. The use of caffeic acid as adjuvant for cisplatin should be carefully examined due to different pharmacokinetic profiles of caffeic acid and cisplatin. Thus, it is questionable if the two agents can reach the tumors at the right time frame in vivo. PMID- 27951499 TI - Degradation of nitro-aromatic explosives using recyclable magnetic photocatalyst: Catalyst synthesis and process optimization. AB - In this research, degradation of P-Nitrophenol (PNP) as a model nitro-aromatic compound was carried out by photocatalytic process using magnetic Titania nano particles (MTNPs). The recyclable MTNPs were synthesized with average diameter of 22nm and a narrow size distribution. The process was modeled and optimized by a second order reduced polynomial model. Based on the model prediction, the process can be degraded PNP up to 90% under the optimum conditions of the initial pH=4, [PNP]=15mgL-1, [MTNPs]=85mgL-1, and T=25 degrees C. PNP mineralization was obtained 69%, at the optimum condition after 120min of the process. The process kinetic was well fitted by pseudo first order kinetic model and electrical energy consumption of the process was obtained about 177.8kWh/m3. Furthermore, the effect of sodium sulfite, sodium sulfate and sodium nitrite on the photocatalytic degradation process was assessed. The results showed that sulfite or sulfate ions decrease and nitrite ions increase the process efficiency. Also, a sample of redwater as a nitro-aromatic effluent was treated. PMID- 27951498 TI - A prediction model of ammonia emission from a fattening pig room based on the indoor concentration using adaptive neuro fuzzy inference system. AB - Ammonia (NH3) is considered one of the significant pollutions contributor to indoor air quality and odor gas emission from swine house because of the negative impact on the health of pigs, the workers and local environment. Prediction models could provide a reasonable way for pig industries and environment regulatory to determine environment control strategies and give an effective method to evaluate the air quality. The adaptive neuro fuzzy inference system (ANFIS) simulates human's vague thinking manner to solve the ambiguity and nonlinear problems which are difficult to be processed by conventional mathematics. Five kinds of membership functions were used to build a well fitted ANFIS prediction model. It was shown that the prediction model with "Gbell" membership function had the best capabilities among those five kinds of membership functions, and it had the best performances compared with backpropagation (BP) neuro network model and multiple linear regression model (MLRM) both in wintertime and summertime, the smallest value of mean square error (MSE), mean absolute percentage error (MAPE) and standard deviation (SD) are 0.002 and 0.0047, 31.1599 and 23.6816, 0.0564 and 0.0802, respectively, and the largest coefficients of determination (R2) are 0.6351 and 0.6483, repectively. The ANFIS prediction model could be served as a beneficial strategy for the environment control system that has input parameters with highly fluctuating, complexity, and non-linear relationship. PMID- 27951501 TI - Particle Swarm Optimization approach to defect detection in armour ceramics. AB - In this research, various extracted features were used in the development of an automated ultrasonic sensor based inspection system that enables defect classification in each ceramic component prior to despatch to the field. Classification is an important task and large number of irrelevant, redundant features commonly introduced to a dataset reduces the classifiers performance. Feature selection aims to reduce the dimensionality of the dataset while improving the performance of a classification system. In the context of a multi criteria optimization problem (i.e. to minimize classification error rate and reduce number of features) such as one discussed in this research, the literature suggests that evolutionary algorithms offer good results. Besides, it is noted that Particle Swarm Optimization (PSO) has not been explored especially in the field of classification of high frequency ultrasonic signals. Hence, a binary coded Particle Swarm Optimization (BPSO) technique is investigated in the implementation of feature subset selection and to optimize the classification error rate. In the proposed method, the population data is used as input to an Artificial Neural Network (ANN) based classification system to obtain the error rate, as ANN serves as an evaluator of PSO fitness function. PMID- 27951502 TI - Enhancing the bandwidth of piezoelectric composite transducers for air-coupled non-destructive evaluation. AB - This paper details the development of a novel method for increasing the operational bandwidth of piezocomposites without the need for lossy backing material, the aim being to increase fractional bandwith by geometrical design. Removing the need for lossy backing materials, should in turn increase the transmit efficiency in the desired direction of propagation. Finite element analysis has been employed to determine the mode of operation of the new piezocomposite devices and shows good correlation with that derived experimentally. Through a series of practical and analytical methods it has been shown that additional thickness mode resonances can be introduced into the structure by a simple machining process. The shaped composites described in this paper offer increased operational bandwidth. A simple example of a two step thickness design is described to validate and illustrate the principle. A more complex conical design is presented that illustrates a possible tenfold increase in bandwidth from 30kHz to 300kHz, operating in air without backing. An illustration of the applicability of this type of transducer technology for frequency agile guided mode non-destructive evaluation is then presented. PMID- 27951500 TI - Phytoremediation effect of Scirpus triqueter inoculated plant-growth-promoting bacteria (PGPB) on different fractions of pyrene and Ni in co-contaminated soils. AB - At present, few reveal the mechanism of inoculation plants with PGPB to remediate PAH-metal co-contaminated soil by analyzing the chemical speciations of contaminants. This study investigated the influence of inoculation plants with PGPB on different fractions of pyrene and Ni in rhizospheric and non-rhizospheric soil. The results demonstrated that the addition of PGPB brought the extensive increase of FDA activities in pyrene-Ni co-contaminated soil. PGPB increased the resistance of plants in nickel and pyrene-Ni contaminated soil, but decreased the plant biomass in single pyrene contaminated soil. The addition of PGPB efficiently decreased bioaccessible fractions of pyrene and increased the bioavailability of Ni in both rhizospheric and non-rhizospheric soil. Although inoculation plants with PGPB significantly increased the accumulation of Ni in single Ni and pyrene-Ni co-contaminated soil, the poor bioavailability of Ni in rhizospheric soil still restricted the phytoremediation of the heavy metal. The presence of pyrene hindered the inoculated plant from accumulating Ni to some extent. On the contrary, the presence of Ni significantly promoted the degradation of pyrene in both rhizospheric and non-rhizospheric soil after inoculation plants with PGPB. PMID- 27951503 TI - Effect of pressurization on helical guided wave energy velocity in fluid-filled pipes. AB - The effect of pressurization stresses on helical guided waves in a thin-walled fluid-filled pipe is studied by modeling leaky Lamb waves in a stressed plate bordered by fluid. Fluid pressurization produces hoop and longitudinal stresses in a thin-walled pipe, which corresponds to biaxial in-plane stress in a plate waveguide model. The effect of stress on guided wave propagation is accounted for through nonlinear elasticity and finite deformation theory. Emphasis is placed on the stress dependence of the energy velocity of the guided wave modes. For this purpose, an expression for the energy velocity of leaky Lamb waves in a stressed plate is derived. Theoretical results are presented for the mode, frequency, and directional dependent variations in energy velocity with respect to stress. An experimental setup is designed for measuring variations in helical wave energy velocity in a thin-walled water-filled steel pipe at different levels of pressure. Good agreement is achieved between the experimental variations in energy velocity for the helical guided waves and the theoretical leaky Lamb wave solutions. PMID- 27951504 TI - Damage detection in bent plates using shear horizontal guided waves. AB - Study of the interaction of shear horizontal guided mode with defects in the bend region of an isotropic top hat stiffener is presented. Compared with the SH0 wave in a plate, the shear mode in the bend is dispersive and its wavefield characteristics are affected by the curvature of the bend. The scattering studies showed that the sensitivity of the wave to outer surface cracks in the bend increases with increasing frequency compared to inner surface cracks. Further numerical simulations demonstrated that the shear mode is sensitive to the delamination in the bend due to non-zero transverse shear stress. Results of finite element modeling were validated by experiments and reasonably good agreements were obtained. PMID- 27951505 TI - Corrigendum to "Development and validation of a high-throughput online solid phase extraction - Liquid chromatography - Tandem mass spectrometry method for the detection of tetrodotoxin in human urine" [Toxicon 119 (2016) 64-71]. PMID- 27951506 TI - Corrigendum to "Rapid and selective detection of experimental snake envenomation Use of gold nanoparticle based lateral flow assay" [Toxicon 119 (2016) 299-306]. PMID- 27951507 TI - Corrigendum to "Description of histopathological changes induced by the venom of the Persian Gulf Lionfish (Pterois russelli) in a mouse model of multiorgan toxicity" [Toxicon 122 (2016) 94-102]. PMID- 27951508 TI - Enhanced denitrification in Downflow Hanging Sponge reactors for decentralised domestic wastewater treatment. AB - Enhanced aerobic/anoxic Downflow Hanging Sponge (DHS) bioreactors were assessed for carbon (C) and total nitrogen (TN) removal for decentralised domestic wastewater treatment applications. The initial design included upper aerobic and lower anoxic sponge layers, and effluent recirculation, and achieved >80% CODs and >90% NH4-N removal. However, effluent TN was higher. It was concluded the anoxic layer was C-limited for denitrification, therefore an influent bypass was added to the anoxic layer to provide supplemental C. Differed bypass ratios were compared, including 0%, 10%, 20% and 30% (% of total influent), and effluent TN declined with increasing bypass; i.e., 50.1+/-23.3mg-N/L, 49.9+/-27.8mg-N/L, 31.9+/-18.4mg-N/L and 10.7+/-5.8mg-N/L, respectively, and all reactors removed >80% CODs. This design has potential because it uses limited energy, tolerates variable flows, and simultaneously removes C and TN; all key for effective decentralised treatment applications. PMID- 27951509 TI - Techno-economic comparison of centralized versus decentralized biorefineries for two alkaline pretreatment processes. AB - In this work, corn stover subjected to ammonia fiber expansion (AFEXTM)1 pretreatment or alkaline pre-extraction followed by hydrogen peroxide post treatment (AHP pretreatment) were compared for their enzymatic hydrolysis yields over a range of solids loadings, enzymes loadings, and enzyme combinations. Process techno-economic models were compared for cellulosic ethanol production for a biorefinery that handles 2000tons per day of corn stover employing a centralized biorefinery approach with AHP or a de-centralized AFEX pretreatment followed by biomass densification feeding a centralized biorefinery. A techno economic analysis (TEA) of these scenarios shows that the AFEX process resulted in the highest capital investment but also has the lowest minimum ethanol selling price (MESP) at $2.09/gal, primarily due to good energy integration and an efficient ammonia recovery system. The economics of AHP could be made more competitive if oxidant loadings were reduced and the alkali and sugar losses were also decreased. PMID- 27951510 TI - Modeling global changes induced by local perturbations to the HIV-1 capsid. AB - The HIV-1 capsid is a conical protein shell made up of hexamers and pentamers of the capsid protein. The capsid houses the viral genome and replication machinery, and its opening, or uncoating, within the host cell marks a critical step in the HIV-1 lifecycle. Binding of host factors such as TRIM5alpha and cyclophilin A (CypA) can alter the capsid's stability, accelerating or delaying the onset of uncoating and disrupting infectivity. We employ coarse-grained computational modeling to investigate the effects of point mutations and host factor binding on HIV-1 capsid stability. We find that the largest fluctuations occur in the low curvature regions of the capsid, and that its structural dynamics are affected by perturbations at the inter-hexamer interfaces and near the CypA binding loop, suggesting roles for these features in capsid stability. Our models show that linking capsid proteins across hexamers attenuates vibration in the low-curvature regions of the capsid, but that linking within hexamers does not. These results indicate a possible mechanism through which CypA binding alters capsid stability and highlight the utility of coarse-grained network modeling for understanding capsid mechanics. PMID- 27951511 TI - Prefronto-cerebellar tDCS enhances neurocognition in euthymic bipolar patients. Findings from a placebo-controlled neuropsychological and psychophysiological investigation. AB - OBJECTIVES: The present double blind placebo-controlled study aimed at investigating the efficacy of 3-weeks prefronto-cerebellar transcranial direct current stimulation (tDCS) on neurocognitive functioning in euthymic BD patients. METHODS: Forty-two outpatients with BD were randomly assigned to receive either active (n=21) or sham (n=21) prefronto-cerebellar tDCS for 3 consecutive weeks. Neurocognitive abilities were assessed with both neuropsychological testing and psychophysiological evaluation with a P300 novelty task. RESULTS: Our results showed that (i) Trail Making Test-B, a measure of executive functioning, decreased significantly in the active but not in the sham group, (ii) Rey Complex Figure Test Delay Recall, a measure of visuospatial memory, increased significantly in both groups with a greater increase in the active compared to the sham group, and (iii) P3b latency, a measure of brain information processing stream, decreased significantly in the active but not in the sham group. No significant changes were observed in the other explored neuropsychological and psychophysiological measures. CONCLUSIONS: The study suggests that concomitant prefrontal-excitatory and cerebellar-inhibitory tDCS in euthymic BD patients may lead to better neurocognitive performance, quantified through neuropsychological and psychophysiological measures. PMID- 27951512 TI - One-pot mass self-assembly of MnO2 sponge-like hierarchical nanostructures through a limited hydrothermal reaction and their environmental applications. AB - We report an environmentally-responsible limited hydrothermal reaction to construct gram-scale MnO2 sponge-like hierarchical nanostructures composed of ultrathin nanosheets (~5nm) in one pot. This template-free strategy simultaneously avoids the disposal of toxic materials and provides novel metal oxide nanostructures. As a typical application, the MnO2 hierarchical nanostructures prepared can easily remove positively-charged methylene blue in water with much more adsorption capacity than those of commercial carbon grain and MnO2 microparticles, TiO2 and Fe2O3 nanoparticles. Meanwhile, the solid liquid separation is ready due to higher density resulted from their hierarchical nanostructures. Importantly adsorbed methylene blue can be reclaimed after elution with ethanol. Remarkably, the sponge-like hierarchical nanostructures can be recycled for many times with no obvious loss of adsorption capacity, qualifying them as a great potential application in environmental protection and resource reuse. PMID- 27951514 TI - Simple synthesis of cobalt sulfide nanorods for efficient electrocatalytic oxidation of vanillin in food samples. AB - Well-defined CoS nanorods (NR) were synthesized using a simple hydrothermal method, and were tested as an electrode material for electro-oxidation of vanillin. The NR material was characterized with regard to morphology, crystallinity, and electro-activity by use of appropriate analytical techniques. The resulting CoS NR@Nafion modified glassy carbon electrode (GCE) exhibited efficient electro-oxidation of vanillin with a considerable linear range of current-vs-concentration (0.5-56MUM vanillin) and a detection limit of 0.07MUM. Also, food samples containing vanillin were studied to test suitability for commercial applications. PMID- 27951513 TI - Quantification of interfacial interactions between a rough sludge floc and membrane surface in a membrane bioreactor. AB - Interfacial interactions between foulants and membrane directly determine foulant adhesion and membrane fouling. In this study, surface of sludge foulant particles (flocs) was found to be rough, and could be modeled by a sinusoidal sphere function. A novel method, which combined surface element integration (SEI) method, differential geometry and composite Simpson's rule, was developed to quantify the interfacial interactions between the modeled rough floc surface and membrane surface. Application of the novel method in a membrane bioreactor (MBR) provides broad profiles of quantitative interactions with rough floc surface with separation distance. It is also found that increase in the scaled amplitude of floc surface significantly reduced the interaction strength. Derjaguin's approximation (DA) can be regarded as a special case of the novel method, indicating the extensive application prospect of the novel method. The novel method for interaction calculation was verified to be correct and feasible. Finally, roles of the novel method in membrane fouling research were discussed. PMID- 27951515 TI - Polyphenolics from mango (Mangifera indica L.) suppress breast cancer ductal carcinoma in situ proliferation through activation of AMPK pathway and suppression of mTOR in athymic nude mice. AB - The objective of this study was to assess the underlying mechanisms of mango polyphenol decreased cell proliferation and tumor volume in ductal carcinoma in situ breast cancer. We hypothesized that mango polyphenols suppress signaling along the AKT/mTOR axis while up-regulating AMPK. To test this hypothesis, mango polyphenols (0.8 mg gallic acid equivalents per day) and pyrogallol (0.2 mg/day) were administered for 4 weeks to mice xenografted with MCF10DCIS.com cells subcutaneously (n=10 per group). Tumor volumes were significantly decreased, both mango and pyrogallol groups displayed greater than 50% decreased volume compared to control. There was a significant reduction of phosphorylated protein levels of IR, IRS1, IGF-1R, and mTOR by mango; while pyrogallol significantly reduced the phosphorylation levels of IR, IRS1, IGF-1R, p70S6K, and ERK. The protein levels of Sestrin2, which is involved in AMPK-signaling, were significantly elevated in both groups. Also, mango significantly elevated AMPK phosphorylation and pyrogallol significantly elevated LKB1 protein levels. In an in vitro model, mango and pyrogallol increased reactive oxygen species (ROS) generation and arrested cells in S phase. In silico modeling indicates that pyrogallol has the potential to bind directly to the allosteric binding site of AMPK, inducing activation. When AMPK expression was down-regulated using siRNA in vitro, pyrogallol reversed the reduced expression of AMPK. This indicates that pyrogallol not only activates AMPK, but also increases constitutive protein expression. These results suggest that mango polyphenols and their major microbial metabolite, pyrogallol, inhibit proliferation of breast cancer cells through ROS-dependent up-regulation of AMPK and down-regulation of the AKT/mTOR pathway. PMID- 27951516 TI - Salmosan, a beta-galactomannan-rich product, in combination with Lactobacillus plantarum contributes to restore intestinal epithelial barrier function by modulation of cytokine production. AB - Mannan-oligosaccharides (MOSs) are mannose-rich substrates with several intestinal health-promoting properties. The aim of this study was to investigate the potential capacity of Salmosan (S-betaGM), a beta-galactomannan-rich MOS product, to restore epithelial barrier function independently from its capacity to reduce bacterial invasion. In addition, the combination of S-betaGM with the proven probiotic Lactobacillus plantarum (LP) was also tested. Paracellular permeability was assessed by transepithelial electrical resistance (TER) in co cultures of Caco-2 cells and macrophages (differentiated from THP-1 cells) stimulated with LPS of Salmonella Enteritidis and in Caco-2 cell cultures stimulated with TNF-alpha in the absence or presence of 500 MUg/ml S-betaGM, LP (MOI 10) or a combination of both. In both culture models, TER was significantly reduced up to 25% by LPS or TNF-alpha stimulation, and the addition of S-betaGM or LP alone did not modify TER, whereas the combination of both restored TER to values of nonstimulated cells. Under LPS stimulation, TNF-alpha production was significantly increased by 10-fold, whereas IL-10 and IL-6 levels were not modified. The combination of S-betaGM and LP reduced TNF-alpha production to nonstimulated cell values and significantly increased IL-10 and IL-6 levels (5- and 7.5-fold, respectively). Moreover, S-betaGM has the capacity to induce an increase of fivefold in LP growth. In conclusion, we have demonstrated that S betaGM in combination with LP protects epithelial barrier function by modulation of cytokine secretion, thus giving an additional value to this MOS as a potential symbiotic. PMID- 27951518 TI - Interaction of an antiepileptic drug, lamotrigine with human serum albumin (HSA): Application of spectroscopic techniques and molecular modeling methods. AB - Lamotrigine (an epileptic drug) interaction with human serum albumin (HSA) was investigated by fluorescence, UV-Vis, FTIR, CD spectroscopic techniques, and molecular modeling methods. Binding constant (Kb) of 5.74*103 and number of binding site of 0.97 showed that there is a slight interaction between lamotrigine and HSA. Thermodynamic studies was constructed using the flourimetric titrations in three different temperatures and the resulted data used to calculate the parameters using Vant Hoff equation. Decreased Stern Volmer quenching constant by enhanced temperature revealed the static quenching mechanism. Negative standard enthalpy (DeltaH) and standard entropy (DeltaS) changes indicated that van der Waals interactions and hydrogen bonds were dominant forces which facilitate the binding of Lamotrigine to HSA, the results were confirmed by molecular docking studies which showed no hydrogen binding. The FRET studies showed that there is a possibility of energy transfer between Trp214 and lamotrigine. Also the binding of lamotrigine to HSA in the studied concentrations was not as much as many other drugs, but the secondary structure of the HSA was significantly changed following the interaction in a way that alpha-helix percentage was reduced from 67% to 57% after the addition of lamotrigine in the molar ratio of 4:1 to HSA. According to the docking studies, lamotrigine binds to IB site preferably. PMID- 27951517 TI - Modulation of urinary siderophores by the diet, gut microbiota and inflammation in mice. AB - Mammalian siderophores are believed to play a critical role in maintaining iron homeostasis. However, the properties and functions of mammalian siderophores have not been fully clarified. In this study, we have employed Chrome Azurol S (CAS) assay which is a well-established method for bacterial siderophores study, to detect and quantify mammalian siderophores in urine samples. Our study demonstrates that siderophores in urine can be altered by diet, gut microbiota and inflammation. C57BL/6 mice, fed on plant-based chow diets which contain numerous phytochemicals, have more siderophores in the urine compared to those fed on purified diets. Urinary siderophores were up-regulated in iron overload conditions, but not altered by other tested nutrients status. Further, germ-free mice displayed 50% reduced urinary siderophores, in comparison to conventional mice, indicating microbiota biotransformation is critical in generating or stimulating host metabolism to create more siderophores. Altered urinary siderophores levels during inflammation suggest that host health conditions influence systemic siderophores level. This is the first report to measure urinary siderophores as a whole, describing how siderophores levels are modulated under different physiological conditions. We believe that our study opens up a new field in mammalian siderophores research and the technique we used in a novel manner has the potential to be applied to clinical purpose. PMID- 27951520 TI - Corticotropin-releasing hormone and dopamine release in healthy individuals. AB - Corticotropin-releasing hormone (CRH) is a key component of the neuroendocrine response to stress. In animal models, CRH has been shown to modulate dopamine release, and this interaction is believed to contribute to stress-induced relapse in neuropsychiatric disorders. Here we investigated whether CRH administration induces dopamine release in humans, using positron emission tomography (PET). Eight healthy volunteers (5 female, 22-48 years old) completed two PET scans with the dopamine D2/3 receptor radioligand [11C]-(+)-PHNO: once after saline injection, and once after injection of corticorelin (synthetic human CRH). We also assessed subjective reports and measured plasma levels of endocrine hormones (adrenocorticotropic hormone and cortisol). Relative to saline, corticorelin administration decreased binding of the D2/3 PET probe [11C]-(+)-PHNO, suggesting dopamine release. Endocrine stress markers were also elevated, in line with activation of the hypothalamic-pituitary-adrenal axis, but we detected no changes in subjective ratings. Preliminary results from this proof-of-concept study suggests that CRH challenge in combination with [11C]-(+)-PHNO PET may serve as an assay of dopamine release, presenting a potential platform for evaluating CRH/dopamine interactions in neuropsychiatric disorders and CRH antagonists as potential treatment avenues. PMID- 27951519 TI - Differential cytokine levels between early withdrawal and remission states in patients with alcohol dependence. AB - Alcohol dependence (AD) leads to altered innate and adaptive immune responses, and frequently co-occurs with inflammation. Therefore, inflammatory cytokines potentially play a crucial role in the development of alcohol-related illnesses. This study evaluated changes in plasma cytokine concentrations, liver function, cravings, depression severity, and cognitive function in male patients with AD, during the course of an alcohol-detoxification program. A total of 78 male patients with AD were recruited for a conservative detoxification program; and cytokine levels, depressive score, and cognitive impairment applying the Trail Making Test (TMT) were evaluated during early withdrawal (baseline) and after 4 weeks of abstinence from alcohol. Healthy volunteers (86 males) were also recruited as controls. Inflammatory cytokine expression in all participants was assessed by multiplex magnetic bead assay. AD patients during early withdrawal demonstrated higher cytokine levels than the healthy controls (P<=0.001 for all cytokines). However, the levels of cytokine expression were significantly lower after 4 weeks of abstinence from alcohol (P<=0.001, except for IL-1beta and IL 5). Higher liver function marker levels, depressive severity, and TMT times were observed in patients at the beginning of the detoxification program than in healthy controls. Fortunately, these functions significantly ameliorated after 4 weeks of abstinence. (P<=0.001). Levels of circulating cytokines, liver function, and cognitive function may markers of alcohol use disorder. PMID- 27951521 TI - Virulence in Newcastle disease virus: A genotyping and molecular evolution spectrum perspective. AB - In our research, the molecular evolutions of NDV F and HN genes were analyzed. The phylogenetic analyses of NDV sequences indicated that NDV could be divided into two genotypes: Class I (lentogenic strains) and Class II (velogenic or mesogenic strains). Each genotype possesses high gene homology. Furthermore, the selected pressure analysis showed that the dN/dS of velogenic, mesogenic NDV strains F gene was significantly high and the omega(dN/dS) is 1.1725>1. These results imply that mutations in velogenic, mesogenic NDV F gene are favored by positive natural selection and it has acted to diversify NDV virulence at the nucleotide and amino acid level. We estimated that the subsequent rapid adaptation of the Newcastle disease virus to chickens were likely dependent on a high rate of mutation and the positive selection of mutations in the major F gene. PMID- 27951522 TI - Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease. AB - IMPORTANCE: Neuromyelitis optica spectrum disorders (NMOSD) can present with very similar clinical features to multiple sclerosis (MS), but the international diagnostic imaging criteria for MS are not necessarily helpful in distinguishing these two diseases. OBJECTIVE: This multicentre study tested previously reported criteria of '(1) at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or (2) the presence of a subcortical U-fibre lesion or (3) a Dawson's finger-type lesion' in an independent cohort of relapsing-remitting multiple sclerosis (RRMS) and AQP4-ab NMOSD patients and also assessed their value in myelin oligodendrocyte glycoprotein (MOG)-ab positive and ab-negative NMOSD. DESIGN: Brain MRI scans were anonymised and scored on the criteria by 2 of 3 independent raters. In case of disagreement, the final opinion was made by the third rater. PARTICIPANTS: 112 patients with NMOSD (31 AQP4-ab positive, 21 MOG-ab-positive, 16 ab-negative) or MS (44) were selected from 3 centres (Oxford, Strasbourg and Liverpool) for the presence of brain lesions. RESULTS: MRI brain lesion distribution criteria were able to distinguish RRMS with a sensitivity of 90.9% and with a specificity of 87.1% against AQP4-ab NMOSD, 95.2% against MOG-ab NMOSD and 87.5% in the heterogenous ab-negative NMOSD cohort. Over the whole NMOSD group, the specificity was 89.7%. CONCLUSIONS: This study suggests that the brain MRI criteria for differentiating RRMS from NMOSD are sensitive and specific for all phenotypes. PMID- 27951523 TI - Cognitive reserve moderates long-term cognitive and functional outcome in cerebral small vessel disease. AB - BACKGROUND: Cerebral small vessel disease (SVD) is characterised by progressive white matter hyperintensities (WMH), cognitive decline and loss of functional independence. The correspondence between neuroimaging findings and the severity of clinical symptoms has been modest, however, and thus the outcome may be affected by various host factors. We investigated the predictive value of educational and occupational attainments as proxy measures of cognitive reserve on long-term cognitive and functional outcome in patients with different degrees of WMH. METHODS: In the Leukoaraiosis and Disability (LADIS) study, 615 older individuals with WMH were evaluated with brain MRI and detailed clinical and neuropsychological assessments at 3-year follow-up. A prolonged follow-up of functional and cognitive status was administered with a structured telephone interview after up to 7 years. RESULTS: Higher levels of educational and occupational attainment were strongly related to baseline cognitive scores and predicted a slower rate of decline at 3-year follow-up in measures of processing speed, executive functions and memory independently of WMH volume and other confounders. The deleterious effect of WMH on processing speed and memory was moderated by education and occupation. Education mitigated the relation of WMH volume on 7-year cognitive status. Moreover, higher education and occupational attainments were related to favourable outcome at 7-year follow-up as defined by sustained functional independence and lower mortality. CONCLUSIONS: The results support the presumption that cognitive reserve plays a significant role as a buffer against the clinical manifestations of SVD and may in part explain high individual variability in outcome. PMID- 27951525 TI - Estrogen and the brain: does estrogen treatment improve cognitive function? AB - In this paper we describe potential reasons for the discrepancies between data from basic sciences and observational studies and those of large treatment studies investigating the association between brain function and sex steroids. Observational studies which often showed positive associations between hormone use and cognition can be affected by 'recall bias' and 'healthy user bias', while outcomes of treatment studies were hypothesized to be modified by age at treatment, age at or type of menopause, health status, addition of a progestogen or type of estrogen treatment. However, meta-analyses of data from treatment studies negate many of these hypotheses showing at best mainly short-term (up to 6 months) positive effects of estrogen treatment on cognition regardless of age. This positive effect may reverse, particularly in older women with prolonged hormone treatment, which was predominantly seen after addition of progestogen. Medroxyprogesterone acetate seemed to have worse effects on cognition than other types of progestogen in these long-term studies. Estradiol with or without a progestogen was three times more likely to have positive effects on cognition than conjugated equine estrogens. However, two-thirds of studies showed no associations at all which may be an underestimate given the possibility of publication bias. We briefly review alternative treatments, such as testosterone and soy-derived supplements, but currently insufficient data are available for conclusive comments. Women who have undergone surgical menopause or who undergo natural menopause before age 47 may benefit most from hormone treatment and a special case may need to be made for this group. Long-term safety studies for this group are urgently needed. PMID- 27951526 TI - Long-term health outcomes after exposure to repeated concussion in elite level: rugby union players. AB - BACKGROUND: There is continuing concern about effects of concussion in athletes, including risk of the neurodegenerative disease chronic traumatic encephalopathy. However, information on long-term health and wellbeing in former athletes is limited. METHOD: Outcome after exposure to repeated brain injury was investigated in 52 retired male Scottish international rugby players (RIRP) and 29 male controls who were similar in age and social deprivation. Assessment included history of playing rugby and traumatic brain injury, general and mental health, life stress, concussion symptoms, cognitive function, disability and markers of chronic stress (allostatic load). RESULTS: The estimated number of concussions in RIRP averaged 14 (median=7; IQR 5-40). Performance was poorer in RIRP than controls on a test of verbal learning (p=0.022) and of fine co-ordination of the dominant hand (p=0.038) and not significantly different on other cognitive tests (p>0.05). There were no significant associations between number of concussions and performance on cognitive tests. Other than a higher incidence of cardiovascular disease in controls, no group differences were detected in general or mental health or estimates of allostatic load. In RIRP, persisting symptoms attributed to concussion were more common if reporting more than nine concussions (p=0.028), although these symptoms were not perceived to affect social or work functioning. CONCLUSIONS: Despite a high number of concussions in RIRP, differences in mental health, social or work functioning were not found late after injury. Subtle group differences were detected on two cognitive tests, the cause of which is uncertain. Prospective group comparison studies on representative cohorts are required. PMID- 27951528 TI - Quantifying gene expression: the importance of being subtle. PMID- 27951529 TI - Predictor Variables of Developing Anterior Pituitary Deficiencies in a Group of Paediatric Patients with Central Diabetes Insipidus and Langerhans Cell Histiocytosis. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder of unknown etiopathogenesis. Central diabetes insipidus (CDI) is the most frequent endocrine manifestation and is a known risk factor for the development of further anterior pituitary hormone deficiencies (APD). However, not all CDI patients develop APD, as observed during prolonged periods of follow-up. AIM: To find predictors of developing APD in LCH children with CDI followed in our institution. METHODS: We retrospectively analysed 44 patients over a median period (quartiles) of 12.3 years (8.79-14.24). Patients were subdivided into group 1 and group 2, according to absence or presence of APD, respectively. The main variables studied were: (1) chronological age (CA) at LCH diagnosis, (2) the primary site of LCH at diagnosis: low risk (LR) and multisystemic risk organs, and (3) the presence of reactivation. RESULTS: Multivariate Cox regression analysis showed that APD was positively associated with CA at LCH diagnosis [relative risk (RR) 1.14, p < 0.01], the LR clinical form (RR 8.6, p < 0.03), and negatively associated with the presence of reactivations (RR 0.3, p < 0.01). CONCLUSIONS: Patients with older CA at LCH diagnosis, LR clinical forms, and fewer reactivation episodes might represent a subgroup of paediatric LCH CDI patients with a higher risk of developing APD. PMID- 27951527 TI - Gene-specific correlation of RNA and protein levels in human cells and tissues. AB - An important issue for molecular biology is to establish whether transcript levels of a given gene can be used as proxies for the corresponding protein levels. Here, we have developed a targeted proteomics approach for a set of human non-secreted proteins based on parallel reaction monitoring to measure, at steady state conditions, absolute protein copy numbers across human tissues and cell lines and compared these levels with the corresponding mRNA levels using transcriptomics. The study shows that the transcript and protein levels do not correlate well unless a gene-specific RNA-to-protein (RTP) conversion factor independent of the tissue type is introduced, thus significantly enhancing the predictability of protein copy numbers from RNA levels. The results show that the RTP ratio varies significantly with a few hundred copies per mRNA molecule for some genes to several hundred thousands of protein copies per mRNA molecule for others. In conclusion, our data suggest that transcriptome analysis can be used as a tool to predict the protein copy numbers per cell, thus forming an attractive link between the field of genomics and proteomics. PMID- 27951530 TI - The Economic Burden of Obesity in Germany: Results from the Population-Based KORA Studies. AB - OBJECTIVE: To estimate the excess costs of obese compared to normal-weight persons in Germany based on self-reported resource utilisation and work absence. METHODS: Five cross sectional surveys of cohort studies in southern Germany were pooled resulting in 9,070 observations for 6,731 individuals (31-96 years). BMI was measured in the study centre. Self-reported health care utilisation and work absence was used to estimate direct and indirect costs for the year 2011 based on unit costs. Using regression analyses, adjusted costs for different BMI groups were calculated. RESULTS: Overweight and obese people showed significantly higher odds of health care utilisation and productivity losses compared with normal weight people in most categories. Total direct/indirect costs were significantly higher with increasing severity of obesity (pre-obese (1.05 (0.90-1.23) / 1.38 (1.11-1.71)), obesity level I (1.18 (1.00-1.39) / 1.33 (1.02-1.73)), obesity level II (1.46 (1.14-1.87) / 1.77 (1.18-2.65)) or level III (2.04 (1.40-2.97) / 1.99 (1.20-3.30)) compared to normal-weight participants. In particular, higher obesity classes were significantly associated with increased costs for medication, general practitioner utilisation and work absence. CONCLUSION: Our results show that overweight and obesity are associated with enormous societal direct and indirect costs in Germany. This supports the evidence from previous top-down studies, but provides important new information based on a large pooled data set and measured BMI. PMID- 27951532 TI - Brief Review and a Clinical Case of Hemolytic Uremic Syndrome Associated with Interferon beta Treatment. AB - The hemolytic uremic syndrome (HUS) is one of the thrombotic microangiopathies and it consists of the triad of nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The atypical form of HUS (aHUS) is related to causative mutations in complement genes. Some conditions act as a trigger for aHUS in individuals that have a genetic background predisposing to complement activation. Interferon beta is a recombinant-protein therapy approved to treat multiple sclerosis (MS), and can be a causative agent in the occurrence of HUS through anti-angiogenic activity. In this paper, we briefly review aHUS clinical and genetic characteristics. Furthermore, we present a case of a 48-year old woman, diagnosed with MS and treated with INFbeta-1b from 2008. In December 2015, she presented with asthenia and loss of muscular strength in the legs and she quickly developed aHUS. Our case suggests that INFbeta is a possible triggering factor for HUS. PMID- 27951533 TI - Correlations of Plasma Desphosphorylated Uncarboxylated Matrix Gla Protein with Vascular Calcification and Vascular Stiffness in Chronic Kidney Disease. AB - BACKGROUND: Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification and needs vitamin K-dependent carboxylation for its activity. High levels of desphosphorylated uncarboxylated MGP (dp-ucMGP) were significantly associated with vitamin K deficiency and vascular calcification. This study was conducted to explore the correlations of plasma dp-ucMGP with vascular calcification and vascular stiffness in chronic kidney disease (CKD) patients. METHODS: This cross-sectional study enrolled 83 CKD stages 3-5 patients. Vascular calcification score was determined by calcific lesions in the abdominal aorta (AAC) shown by lateral lumbar film; vascular stiffness was assessed by cardio ankle vascular index (CAVI) and pulse wave velocity, while plasma dp-ucMGP levels were measured using ELISA method. Multivariate regression analyses were used to select factors that were independently associated with vascular calcification and vascular stiffness. RESULTS: The mean age was 62.9 +/- 13.9 years. CKD stages 3, 4, and 5 constituted 51.8, 13.3, and 34.9%, respectively. The median of plasma dp ucMGP levels in CKD stages 3, 4, and 5 were 586 (452-888), 870 (594-1,591), and 1,050 (518-1,298) pmol/L, respectively. The prevalence of vascular calcification (AAC score >=1) was 63.4% and that of vascular stiffness (CAVI >=9) was 46.3%. Vascular calcification was correlated with vascular stiffness (r2 = 0.50, p < 0.001). Multivariate logistic regression analysis models to predict vascular calcification showed that age and plasma dp-ucMGP levels were significantly correlated with vascular calcification (OR 1.21; 95% CI 1.09-1.33; p < 0.001 and OR 1.002; 95% CI 1.001-1.004; p = 0.004, respectively). In contrast, there was no association between plasma dp-ucMGP levels and vascular stiffness. CONCLUSIONS: Plasma dp-ucMGP levels increase according to the severity of CKD. Plasma dp-ucMGP was positively associated with vascular calcification and might be utilized as an early marker for vascular calcification in CKD patients. PMID- 27951531 TI - Reversal Learning Deficits Associated with Increased Frontal Cortical Brain Derived Neurotrophic Factor Tyrosine Kinase B Signaling in a Prenatal Cocaine Exposure Mouse Model. AB - Prenatal cocaine exposure remains a major public health concern because of its adverse impact on cognitive function in children and adults. We report that prenatal cocaine exposure produces significant deficits in reversal learning, a key component of cognitive flexibility, in a mouse model. We used an olfactory reversal learning paradigm and found that the prenatally cocaine-exposed mice showed a marked failure to learn the reversed paradigm. Because brain-derived neurotrophic factor (BDNF) is a key regulator of cognitive functions, and because prenatal cocaine exposure increases the expression of BDNF and the phosphorylated form of its receptor, tyrosine kinase B (TrkB), we examined whether BDNF-TrkB signaling is involved in mediating the reversal learning deficit in prenatally cocaine-exposed mice. Systemic administration of a selective TrkB receptor antagonist restored normal reversal learning in prenatally cocaine-exposed mice, suggesting that increased BDNF-TrkB signaling may be an underlying mechanism of reversal learning deficits. Our findings provide novel mechanistic insights into the reversal learning phenomenon and may have significant translational implications because impaired cognitive flexibility is a key symptom in psychiatric conditions of developmental onset. PMID- 27951534 TI - Statins and the Kidney: Friend or Foe? AB - Statins essentially are cholesterol-lowering drugs that are extensively prescribed for primary and secondary prevention of cardiovascular disease. Compelling evidence suggests that the beneficial effects of statins may not only be due to controlling cholesterol levels but also due to a pleiotropic cholesterol-independent anti-inflammatory, antioxidant, endothelial-protective and plaque-stabilizing activity. Along this line, statins may also exert acute and long-term effects on renal function. We present a narrative literature review that summarizes arguments in favour or against the preventive and/or therapeutic use of statins in kidney-related diseases or complications. We also highlight the ongoing controversy regarding statin therapy in chronic and end-stage kidney disease. PMID- 27951535 TI - Insulin Sensitivity and Secretion in Obese Type 2 Diabetic Women after Various Bariatric Operations. AB - OBJECTIVE: To compare the effects of biliopancreatic diversion (BPD) and laparoscopic gastric banding (LAGB) on insulin sensitivity and secretion with the effects of laparoscopic gastric plication (P). METHODS: A total of 52 obese women (age 30-66 years) suffering from type 2 diabetes mellitus (T2DM) were prospectively recruited into three study groups: 16 BPD; 16 LAGB, and 20 P. Euglycemic clamps and mixed meal tolerance tests were performed before, at 1 month and at 6 months after bariatric surgery. Beta cell function derived from the meal test parameters was evaluated using mathematical modeling. RESULTS: Glucose disposal per kilogram of fat free mass (a marker of peripheral insulin sensitivity) increased significantly in all groups, especially after 1 month. Basal insulin secretion decreased significantly after all three types of operations, with the most marked decrease after BPD compared with P and LAGB. Total insulin secretion decreased significantly only following the BPD. Beta cell glucose sensitivity did not change significantly post-surgery in any of the study groups. CONCLUSION: We documented similar improvement in insulin sensitivity in obese T2DM women after all three study operations during the 6-month postoperative follow-up. Notably, only BPD led to decreased demand on beta cells (decreased integrated insulin secretion), but without increasing the beta cell glucose sensitivity. PMID- 27951537 TI - Association between Obstructive Sleep Apnea and Acute Kidney Injury in Critically Ill Patients: A Propensity-Matched Study. AB - BACKGROUND/AIMS: Obstructive sleep apnea (OSA) is a known risk factor for chronic kidney disease (CKD); however, its association with acute kidney injury (AKI) is not well documented. We aimed to study whether OSA is associated with the risk of AKI in the intensive care unit (ICU) setting. METHODS: All consecutive adult Olmsted County, MN residents who were admitted in Mayo Clinic ICUs from January 1, 2010 to December 31, 2010 were screened. Chronic and acute risk factors were collected within the first 48 h of ICU admission. Logistic regression and propensity score matching were used to examine crude and adjusted associations of OSA with AKI. RESULTS: Among 1,259 enrolled ICU patients, 183 patients had a diagnosis of OSA prior to the index ICU admission. Compared with non-OSA patients, the incidence of AKI in OSA patients was more frequent (41 vs. 57%, p < 0.001). In univariate analysis, it was found that CKD, age, gender, Caucasian race, congestive heart failure, cerebrovascular disease, diabetes mellitus, body mass index, and OSA were associated with AKI. In the multivariate model, following adjustment for age, gender, race, and chronic and acute risk factors, OSA was found to have an independent association with AKI (OR 1.53; 95% CI 1.04 2.24; p = 0.031). Among 176 propensity score matched pairs, there was a significant difference in the incidence of AKI between the OSA and non-OSA groups (OR 1.54; 95% CI 1.01-2.35; p = 0.04). CONCLUSIONS: The history of OSA diagnosed by polysomnography is associated with higher risk of AKI in critically ill patients. PMID- 27951536 TI - Glial Fibrillary Acidic Protein for Prehospital Diagnosis of Intracerebral Hemorrhage. AB - BACKGROUND: Both, acute ischemic stroke (AIS) and hemorrhage stroke (intracerebral hemorrhage, ICH) require early attention but different treatment strategies. Plasma glial fibrillary acidic protein (GFAP) levels were found to be elevated in ICH patients after they arrived in the hospital. Because treatment options differed, we sought to determine whether GFAP can be used to accurately differentiate between of AIS and ICH in the prehospital setting. METHODS: We assessed acute stroke patients in the Stroke Emergency Mobile (STEMO). STEMO is a stroke ambulance staffed by a specialized team including a neurologist and equipped with a computed tomography scanner plus a point-of-care laboratory. The STEMO ambulance is integrated in the emergency medical system of Berlin, Germany. Following prehospital stroke diagnosis, blood was drawn and subsequently analysed using research assays from Roche diagnostics. The clinical accuracy of plasma GFAP was tested using a cut-off value of 0.29 ng/ml. RESULTS: Blood samples of 74 patients were analysed. Twenty-five patients had ICH (mean age 69 +/- 11 years, median National Institutes of Health Stroke Scale (NIHSS) 15) and 49 IS (mean age 75 +/- 10 years, median NIHSS 6). Nine ICH (0 IS patients) had GFAP-levels above 0.29 ng/ml. The sensitivity and specificity of GFAP for differentiating between ICH and AIS were 36.0 and 100%. The sensitivity for ICH volume >15 ml was 61.5%. ICH patients without GFAP elevation had significantly smaller hemorrhage volumes (median 4.5 vs. 37.6 ml, p = 0.004) and were less likely to deteriorate (19 vs. 56%, p = 0.087). CONCLUSIONS: GFAP levels >0.29 ng/ml were seen only in ICH, thus confirming the diagnosis of ICH during prehospital care. However, sensitivity is low particularly in smaller hemorrhages. PMID- 27951538 TI - Colchicine in Renal Medicine: New Virtues of an Ancient Friend. AB - Colchicine is a plant-derived alkaloid that disrupts the cell microtubule system and accumulates in neutrophils, inhibiting neutrophil adhesion and recruitment. Colchicine has been used extensively in the prevention and treatment of gouty arthritis attacks, familial Mediterranean fever attacks and resultant AA amyloidosis, and recurrent pericarditis. Colchicine also disrupts the intracellular traffic of additional inflammatory and fibrosis mediators. Renal fibrosis is the final common pathway of chronic renal disease. Colchicine had anti-fibrotic effects in experimental diabetic nephropathy, renal mass reduction, and cyclosporine nephrotoxicity among others and is undergoing clinical trials for non-diabetic metabolic syndrome and diabetic nephropathy. In this review, we summarize the anti-inflammatory and anti-fibrotic properties of colchicine in experimental and clinical studies in renal diseases or other fibrotic disease processes with renal consequences. We also discuss the potential future uses of colchicine in renal medicine and challenges faced with its use in patients with impaired kidney function. PMID- 27951540 TI - Measurement of Pre- or Post-Filter-Ionised Calcium Concentration during Continuous Veno-Venous Haemofiltration. PMID- 27951539 TI - Wellens Syndrome with Syncope but Not Chest Pain. AB - We report the case of a woman in her 70s presenting to the emergency department with syncope, troponemia, and an electrocardiogram with deep symmetric T-wave inversions in V2 and V3 and prolonged QTc. Her presentation was concerning for acute coronary syndrome, Wellens syndrome in particular, given the elevated troponin levels, lack of ST segment changes, and characteristic T-wave findings. The diagnosis was confirmed with angiography that showed a critical left anterior descending (LAD) artery occlusion. Since myocardial infarction does not typically present with syncope, we explored the differential diagnoses for T-wave inversions, which include electrolyte abnormalities, medications, intracranial hemorrhage, pulmonary embolism, and other cardiac diseases that were ruled out in our patient. We also explored the pathophysiology leading to syncope in the setting of acute myocardial infarction including arrhythmias and exaggerated neurally mediated response. Our patient received two drug-eluting stents to the LAD artery and was started on dual antiplatelet therapy, beta-blockers, and an angiotensin-converting enzyme inhibitor. PMID- 27951541 TI - Pubertal Development in?17Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency?. AB - BACKGROUND: 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 3 deficiency is an autosomal recessive disorder with diminished testosterone synthesis and consequently underandrogenisation. 46,XY patients with 17beta-HSD type 3 deficiency are often assigned a female sex at birth but have a high virilisation potential at the time of puberty. METHODS: We studied four 46,XY patients with 17beta-HSD type 3 deficiency at puberty with regard to the underlying mutations, the hormone values, and the clinical findings. RESULTS: Three patients were initially assigned a female sex and 1 was assigned a male sex. All had relevant mutations in the HSD17B3 gene. The 2 patients with deleterious mutations had lower testosterone values at the time of puberty than the patients with possible residual activity of 17beta-HSD type 3. One of the latter patients changed to male gender. CONCLUSION: All 4 patients with 17beta-HSD type 3 deficiency synthesized relevant amounts (>0.7 ug/L) of testosterone at puberty, which lead to variable androgenisation. In patients with presumable residual activity of the mutated enzyme, testosterone values in the male reference range can be achieved, thereby inducing male pubertal development. These patients should possibly be assigned a male sex. Any surgical intervention should be avoided until the patients are old enough to consider their options of medical and surgical intervention.?. PMID- 27951542 TI - Critical Analysis of a Series of Early Inguinal Ureterostomies: Are They Useful and How Well Are They Tolerated? AB - INTRODUCTION: The study aimed to evaluate the advantages of temporary inguinal ureterostomy in the management of neonates with uropathies and early or recurrent pyelonephritis. PATIENTS AND METHODS: We performed a retrospective analysis of all patients who underwent ureterostomies between 1989 and 2012, with specific regards to indications and outcomes. We also performed a survey of parents to evaluate their acceptance of diversion. RESULTS: We included 18 patients (12 primary high-grade vesicoureteral reflux [VUR] and 6 primary obstructive megaureters [MUs]). Indications were recurrent febrile urinary tract infections (UTIs) despite antibiotic prophylaxis, doubtful function of the overlying kidney for the oldest cases, when renal function was only assessed by intravenous urography, or both. Cutaneous diversion was performed between the ages of 2 weeks to 5 months (median: 1.8 months). Renal function was assessed prior to undiversion to choose between reimplantation and nephrectomy. The incidence of febrile UTIs significantly decreased during the period of diversion. Urinary diversion was judged socially acceptable by parents. Ureterostomy did not modify the overlying kidney function. CONCLUSION: Temporary inguinal ureterostomy does not enable better evaluation of renal function by suppressing the pressure of an obstacle or refluxing urines. Its remaining indication seems to be the prevention of recurrent UTIs in neonates and infants with VUR or MU, pending reimplantation. PMID- 27951544 TI - Haemodiafiltration at Higher Volumes and Patient Survival. AB - Patient morbidity and mortality rates are still very high in standard low-flux haemodialysis (lf-HD). On-line haemodiafiltration (OL-HDF) is considered the most efficient dialysis technique, as clearances of small solutes, like urea, may be even higher than in lf-HD and clearances of middle solutes, like beta2 microglobulin, are much higher than in lf-HD. OL-HDF has been suggested to reduce mortality compared to HD, possibly due to more effective removal of larger uraemic retention solutes and/or better fluid removal. Only 1 out of the 3 largest randomized trials was able to demonstrate a positive effect of OL-HDF on patient survival in comparison to those randomized to HD. Post hoc analyses of these studies consistently showed that the patients randomized to OL-HDF who received the highest convection volumes had a lower risk of mortality and cardiovascular events than those randomized to HD. Four meta-analyses showed inconsistent results concerning the effect of convective treatments in improving general and cardiovascular survival, while they showed a significant reduction of the intradialytic symptomatic hypotension. An individual pooled participant analysis of the 4 largest trials confirmed these findings, suggesting a better survival when a convection volume of at least 23 litres/session was delivered, while other studies did not confirm these conclusions. Even after extensive statistical adjustments, residual confounding always remain; therefore, randomized control trials targeting different convection volumes are required to definitively confirm a dose-response effect of OL-HDF convection volume on patient survival. PMID- 27951543 TI - Adverse Influence of Pre-Stroke Dementia on Short-Term Functional Outcomes in Patients with Acute Ischemic Stroke: The Fukuoka Stroke Registry. AB - BACKGROUND: Dementia and stroke are major causes of disability in the elderly. However, the association between pre-stroke dementia and functional outcome after stoke remains unresolved. We aimed to determine this association in patients with acute ischemic stroke. METHODS: Among patients registered in the Fukuoka Stroke Registry from June 2007 to May 2015, 4,237 patients with ischemic stroke within 24 h of onset, who were functionally independent before the onset, were enrolled in this study. Pre-stroke dementia was defined as any type of dementia that was present prior to the index stroke. Primary and secondary study outcomes were poor functional outcome (modified Rankin Scale 3-6) at 3 months after the stroke onset and neurological deterioration (>=2-point increases on the National Institutes of Health Stroke Scale score during hospitalization), respectively. For propensity score (PS)-matched cohort study to control confounding variables for pre-stroke dementia, 318 pairs of patients with and without pre-stroke dementia were also selected on the basis of 1:1 matching. Multivariable logistic regression models and conditional logistic regression analysis were used to quantify associations between pre-stroke dementia and study outcomes. RESULTS: Of all 4,237 participants, 347 (8.2%) had pre-stroke dementia. The frequencies of neurological deterioration and poor functional outcome were significantly higher in patients with pre-stroke dementia than in those without pre-stroke dementia (neurological deterioration, 16.1 vs. 7.1%, p < 0.01; poor functional outcome, 63.7 vs. 27.1%, p < 0.01). Multivariable analysis showed that pre-stroke dementia was significantly associated with neurological deterioration (OR 1.67; 95% CI 1.14 2.41; p < 0.01) and poor functional outcome (OR 2.91; 95% CI 2.17-3.91; p < 0.01). In the PS-matched cohort study, the same trends were observed between the pre-stroke dementia and neurological deterioration (OR 2.60; 95% CI 1.17-5.78; p < 0.01) and between the dementia and poor functional outcome (OR 3.62; 95% CI 1.89-6.95; p < 0.01). CONCLUSIONS: Pre-stroke dementia was significantly associated with higher risks for poor functional outcome at 3 months after stroke onset as well as for neurological deterioration during hospitalization in patients with acute ischemic stroke. PMID- 27951545 TI - What Is the Optimal Target Convective Volume in On-Line Hemodiafiltration Therapy? AB - Conventional diffusion-based dialysis modalities including high-flux hemodialysis are limited in their capacity to effectively remove large uremic toxins and to improve outcomes for end-stage chronic kidney disease (ESKD) patients. By increasing convective solute transport, hemodiafiltration (HDF) enhances solute removal capacity over a broad range of middle- and large-size uremic toxins implicated in the pathophysiology of chronic kidney disease. Furthermore, by offering flexible convection volume, on-line HDF permits customizing the treatment dose to the patient's needs. In addition, convective-based modalities have been shown to improve hemodynamic stability and to reduce patients' inflammation profile - both of which are implicated in CKD morbidity and mortality. Growing clinical evidence indicates that HDF-based modalities provide ESKD patients with a number of clinical and biological benefits, including improved outcomes. Interestingly, it has recently emerged that the clinical benefits associated with HDF are positively associated with the total ultrafiltered volume per session (and per week), namely convective dose. In this chapter, we revisit the concept of convective dose and discuss the threshold value above which an improvement in ESKD patient outcome can be expected. This particular point will be addressed by stratifying the level of efficacy of convective volumes, schematically defined as minimal, optimal, personalized, and maximal. In addition, factors and best clinical practices implicated in the achievement of an optimal convective dose are reviewed. To conclude, we show how HDF differs from standard hemodialysis and why HDF offers a paradigm shift in renal replacement therapy. PMID- 27951546 TI - Clinical Effectiveness of Intermittent Infusion Hemodiafiltration Using Backfiltration of Ultrapure Dialysis Fluid Compared with Predilution On-Line Hemodiafiltration. AB - BACKGROUND: In conventional hemodialysis (HD) treatment, excessive water removal sometimes induces a rapid drop in blood pressure. Intermittent infusion hemodiafiltration (I-HDF) has been developed to improve patients' peripheral circulation by repeated intermittent infusion during HD treatment. SUMMARY: A prospective, multicenter, parallel group comparative trial examined the clinical effectiveness of I-HDF compared with predilution on-line HDF (pre-HDF), the most popular on-line HDF therapy in Japan. Patients were allocated to 2 groups after matching for age (+/- 5 years), dry weight (+/- 5 kg), and presence/absence of diabetes. After informed consent was obtained, 36 patients (18 pairs) participated in the trial. The results showed no difference in clinical condition or quality of life (QOL) scores between the 2 therapy groups. The rate of reduction in systolic blood pressure initially showed no difference between the groups, but decreased slightly as the trial proceeded after changing from HD therapy. There was also no difference in the incidence rate of treatments initially, although this significantly decreased in both groups as the trial proceeded. Rates of beta2-microglobulin removal were significantly higher in the pre-HDF group than in the I-HDF group. At the same time, the amount of albumin leakage during treatment was significantly greater in the pre-HDF group. Key Messages: The clinical condition and QOL of patients receiving I-HDF was not inferior to those receiving pre-HDF. Pre-HDF demonstrated a significantly higher removal rate of middle- and larger-molecular-weight solutes and higher albumin leakage compared with I-HDF. PMID- 27951547 TI - Are There Any Downsides, Barriers, or Challenges in Delivering Hemodiafiltration in Everyday Clinical Practice? AB - There is considerable evidence to suggest that on-line hemodiafiltration (HDF) is superior to standard hemodialysis when comparing effects on clinical end points, especially when a certain minimum convection volume can be achieved. In this chapter we address the question of whether there are any downsides, challenges, or barriers in delivering on-line HDF in everyday clinical practice. We discuss the subject from a medical/practical point of view and briefly from a financial/economic perspective. PMID- 27951548 TI - Selecting Patients for Home Haemodialysis Modality. AB - Home haemodialysis offers many advantages in that patients take active control of their own health care and have the ability to determine when and how they dialyse. However, in order to develop and maintain a viable home haemodialysis program there has to be a balance between overenthusiastic evangelism and being too conservative in offering patients home haemodialysis. Ideally, preparation for home haemodialysis takes place prior to the need to start dialysis, with educational sessions, discussion with current home haemodialysis patients, and creation of an established vascular access. Preferably, training should take place in a small dedicated centre rather than a main in-centre dialysis unit on a 1:1 basis with a motivated educator. Although there are many potential barriers to home haemodialysis, it is not just an option for younger, physically healthy, well-educated patients, and a surprising number of patients with significant comorbidity can become successful home haemodialysis patients with appropriate support from partners or carers where required. Often the main barrier to home haemodialysis remains suitable accommodation, particularly in inner cities. Once established at home, it is important to ensure that patient expectations and the reality of home haemodialysis do not differ substantially. The amount of support required will vary between patients in terms of psychological support, trouble shooting access, and technical problems. As with all dialysis practice, quality assurance systems are required with patient feedback as appropriate. PMID- 27951549 TI - Recent Trends in Home Hemodialysis Therapy in Japan. AB - BACKGROUND: Home hemodialysis (HHD) is rapidly becoming more widespread because HHD programs enable patients to receive a sufficient dialysis dose to improve their quality of life and survival rate without compromising their lifestyle. SUMMARY: Although HHD in Japan has a long history, the 529 dialysis patients being treated with HHD as of the end of 2014 account for only 0.17% of all dialysis patients. HHD is well indicated for patients who are younger, male, and nondiabetic. The major HHD dialysis programs were provided 4-6 times per week for 3-5 h per session, and 79.3% of HDD patients showed treatment adequacy with a hemodialysis product >72. Key Messages: To expand HHD in Japan, several challenges must be overcome. First, the government should clearly state that home medicine is the way forward and incentivize facilities to provide, and patients to receive, HHD. Second, we need to establish a typical business model for HHD to include the supply of medical devices, collection of disposals, and development of a special machine for HHD. PMID- 27951550 TI - Peritoneal Dialysis or Hemodialysis: Present and Future Trends in the United States. AB - In 2013, 88.4% of all incident end-stage renal disease (ESRD) patients began renal replacement therapy with hemodialysis (HD) while 9.0% began with peritoneal dialysis (PD). The remaining 2.6% received a preemptive kidney transplant. In the US, outpatient HD units are widely distributed and economy of scale has resulted in HD being the most common ESRD modality. Use of PD and preemptive kidney transplant were relatively more common in younger groups and relatively less common among Black and Hispanic patients. Of note is that the new Medicare reimbursement system, known as the 'bundle', provides substantial financial incentives to do PD as opposed to in-center HD. By the end of 2013, 63.9% of all prevalent ESRD cases were receiving HD, 6.9% were being treated with PD, and 29.3% had a functioning kidney transplant. Distributions of modality use by patient characteristics generally mirror those for incident patients. PD and kidney transplant were more commonly used among patients who were younger and were more likely to be non-Hispanic Whites. Differences in the use of home dialysis (PD and HD) are largely driven by differences among individual dialysis centers or groups of centers, rather than by large-scale regional effects. Thus, the future use of PD or home HD will be driven by the proclivities of the largest dialysis providers, which, in turn, are driven by financial reimbursement. PMID- 27951551 TI - What Is the Best Dialysis Therapy in Developed and Developing Countries? Peritoneal Dialysis and/or Hemodialysis: The Trend in Korea. AB - In Korea, peritoneal dialysis (PD) penetration peaked around 2005 at 23%, after which it declined and has remained at 10.5%. Two factors possibly explain the decrease: more favorable physician incentives to perform hemodialysis (HD) and disincentives for private clinics to perform PD, even though they account for a large percentage of dialysis centers in Korea. Early referral to nephrologists has been shown to be associated with better survival and lower medical costs than late referral, highlighting a possible role for systemic intervention to encourage early referrals. This benefits patients by allowing adequate time for dialysis modality selection, relevant training, and preparation for dialysis. In cohorts enrolled from 2005 to 2008, HD showed better survival than PD in patients aged 55 and over. However, PD survival increased more sharply than HD survival over the past decade, a phenomenon particularly significant in diabetic patients and/or patients aged 65 and over. In a prospective study of a cohort enrolled since 2009, PD was associated with better survival than HD, particularly in the early period of dialysis. The survival advantage was shown to last about 3.5 years, with a particularly strong benefit in men or patients under 65. Given the average wait time of 5 years for deceased-donor kidney transplantation (KT) in Korea, PD might be preferably considered for young patients on the wait list. Two critical developments to monitor in PD patients are early death from pneumonia and high risk of acute myocardial infarction. Selection of a dialysis modality that delivers the greatest possible benefit to individual patients should consider age, diabetes status, and KT donor availability. PMID- 27951552 TI - What Is the Best Dialysis Therapy for South Asia: HD or PD? AB - BACKGROUND: South Asian countries have a population of 1.7 billion and are classified as low-middle to poor income nations. Their health care systems cannot presently meet the growing need for renal replacement therapy (RRT), provided as haemodialysis or peritoneal dialysis (PD). Most patients cannot afford the treatment and quickly default. Furthermore, most of the population is located in rural areas, where there are few treatment centres; therefore, there is a huge gap between those treated and those in need. SUMMARY: PD can bridge this gap and can serve as a first line of therapy if it becomes more affordable. Government reimbursement schemes, the Once-in-a-Lifetime Payment Scheme, and PD insurance all provide strong impetus to dialysis programmes. Local manufacturing of PD fluid has also reduced the cost of therapy to some extent. PD may be preferable for patients with cardiovascular morbidity and it also obviates the risk of transmission of blood-borne diseases such as HIV, hepatitis B, and hepatitis C. In our own centre, automated PD is being used as initial RRT for acute kidney injury with good results. In prospective transplant recipients, PD has been found to decrease the risk of posttransplant graft dysfunction. Key Messages: Remote PD and home visits by PD clinical coordinators have brought faraway patients and their nephrologists closer with the use of technology. For these reasons, the current pressing need is to bring PD to the forefront of RRT in resource-poor countries in South Asia to enable universal treatment of patients with renal disease. PMID- 27951553 TI - Nephrologist-Initiated Peritoneal Dialysis Catheter Insertion Programme: A New Paradigm Shift. AB - BACKGROUND: The success rate of peritoneal dialysis (PD) catheter insertion is known to vary among different operators and may be influenced by many factors such as patient and various situational factors. Traditionally, surgeons have inserted Tenckhoff catheters by mini-laparotomy or an open technique. However, with recent advances in endoscopic instrumentation and video capabilities, peritoneoscope Tenckhoff catheter insertion has become a viable approach in interventional nephrologist-initiated PD access programmes. SUMMARY: Nephrologist initiated peritoneoscopic PD access programs have had a positive impact on PD penetration. The technique has been associated with a better primary success rate, superior catheter survival, less postoperative pain, shorter hospital stay, and shorter catheter break-in time compared with the conventional surgical technique. The role of interventional nephrologists in peritoneoscope Tenckhoff catheter placement is still perceived to be a relatively new advance, investigational by some, and many nephrologists and surgeons alike remain sceptical of the value of this recent option. Crucial questions often raised are how many procedures one needs to perform before being considered competent and who should be credentialed to perform the procedure or supervise trainees performing it. The evaluation of technical proficiency in a specific operation is difficult and complex. Cumulative summation (CUSUM) analysis is one option for tracking the success and failure of technical skill and examining trends over time. Key Messages: The author's facility has had good outcomes with a nephrologist-initiated peritoneoscopic PD access programme. Quality control of PD catheter insertion can be performed using CUSUM charting to monitor for primary catheter dysfunction, primary leak, and primary peritonitis. PMID- 27951554 TI - The Birth and Development of Continuous Ambulatory Peritoneal Dialysis. AB - Peritoneal dialysis has a long and tortuous history. First done in animals in the late 1800s, it became clinically practical in the early 1960s. Peritoneal access was first achieved by intermittent abdominal puncture, and then through the development of a 'permanent access' when Silastic became available. The early design is appropriately named for Dr. Henry Tenckhoff. Successful peritoneal dialysis was performed intermittently with infusion of 2 liters of balanced fluid followed by a dwell time of 30-45 min, which in turn was followed by drainage and new infusion. The procedure was used almost exclusively in the intensive care setting but failed to achieve success when applied on a long-term basis. The new concept of extending the dwell time of the dialysis fluid to allow equilibration between an acceptable blood level of urea and the level of urea in the dialysis fluid remarkably reduced the fluid volume required to control uremic toxins and symptoms. This change also allowed the patient to be disconnected from all devices and freely move about as dialysis took place. It was concluded that an acceptable blood level of urea nitrogen was 70 mg %. Equilibration with dialysis fluid, five 2-liter exchanges for 10 liters per day, would allow the removal of 7,000 mg of urea, the average quantity generated on a diet of a 70-kg person eating 1 g of protein per kg of body weight per day. The procedure was originally called 'equilibrium peritoneal dialysis', but was later changed to 'continuous ambulatory peritoneal dialysis'. PMID- 27951555 TI - Evidence for Biocompatible Peritoneal Dialysis Solutions. AB - Glucose-based peritoneal dialysis (PD) solutions are the mainstay of therapy for PD patients, yet are accompanied by a number of adverse effects and potential complications. The high glucose content can cause both systemic effects, such as hyperglycaemia, as well as local effects on the peritoneal membrane, which can interfere with its function. In addition, glucose degradation products (GDPs) generated during heat sterilization of the solutions and the acidic pH at which these solutions are kept have been shown to cause peritoneal membrane injury and precipitate inflow pain, respectively. As a result, biocompatible PD solutions, characterized by neutral pH and low GDP concentrations, have been developed. However, the published evidence supporting their use has often been conflicting and of variable methodological quality. This review aims to discuss the relevant literature and up-to-date evidence for the use of biocompatible PD solutions. PMID- 27951557 TI - Prospects for Vascular Access Education in Developing Countries: Current Situation in Cambodia. AB - We report our activities training doctors on vascular access procedures at International University (IU) Hospital in Cambodia through a program facilitated by Ubiquitous Blood Purification International, a nonprofit organization that provides medical support to developing countries in the field of dialysis medicine. Six doctors from Japan have been involved in the education of medical personnel at IU, and we have collectively visited Cambodia about 15 times from 2010 to 2016. In these visits, we have performed many operations, including 42 for arteriovenous fistula, 1 arteriovenous graft, and 1 percutaneous transluminal angioplasty. Stable development and management of vascular access is increasingly required in Cambodia due to increased use of dialysis therapy, and training of doctors in this technique is urgently required. However, we have encountered several difficulties that need to be addressed, including (1) the situation of personnel receiving this training, (2) problems with facilities, including medical equipment and drugs, (3) financial limitations, and (4) problems with management of vascular access. PMID- 27951556 TI - Japan's Support of Hemodialysis in Southeast Asia. AB - BACKGROUND: With continuing economic development in the developing countries of Southeast Asia, the numbers of dialysis facilities and patients are increasing every year. However, dialysis-related devices tend to be provided with financial support from developed countries and/or donations from nonprofit organizations, and some donated devices are disposed of, without attempts at repair, when they break down. Device management and dialysate quality can also be problematic. SUMMARY: To help address these issues, Japan started to provide technical guidance and support for dialysate purification in these countries. As a result, dialysate quality improved and local medical staff can now perform dialysis therapy using purified dialysate. At the same time, education was provided to staff, and their improved knowledge and skills have contributed to appropriate device maintenance, ensuring the dialysate used is of sufficient quality. Currently, approaches for human resource development are being actively provided in these countries through cooperation with local academic societies or other organizations in the field. Key Messages: A review of the current status of management of dialysis-related devices and dialysate quality in developing countries reveals that financial support and donations for medical devices alone are insufficient and the development of local human resources is crucial. Nurturing and training of clinical engineers, who directly operate today's advanced medical devices for patients, as well as device maintenance and management are urgent issues to address. PMID- 27951558 TI - Evolution of Technology for Continuous Renal Replacement Therapy: Forty Years of Improvements. AB - Continuous arteriovenous hemofiltration (CAVH) was proposed in 1977 as an alternative treatment for acute renal failure in patients in whom peritoneal dialysis or hemodialysis was clinically or technically precluded. In the mid 1980s, this technique was extended to infants and children. CAVH presented important advantages in the areas of hemodynamic stability, control of circulating volume, and nutritional support. However, there were serious shortcomings such as the need for arterial cannulation and limited solute clearance. These problems were solved by the introduction of continuous arteriovenous hemodiafiltration (CAVHDF) and continuous arteriovenous hemodialysis (CAVHD) where uremic control could be by increasing countercurrent dialysate flow rates to 1.5 or 2 liters/h as necessary, or by venovenous techniques utilizing a double-lumen central venous catheter for vascular access. Thus, continuous venovenous hemofiltration replaced CAVH because of its improved performance and safety. From the initial adoptive technology, specific machines have been designed to permit safe and reliable performance of the therapy. These new machines have progressively undergone a series of technological steps that have resulted in the highly sophisticated equipment utilized today. A significant number of advances have taken place since the beginning of continuous renal replacement therapy. In particular, there have been successful experiments with high-volume hemofiltration and high-permeability hemofiltration. The additional and combined use of sorbent has also been tested successfully. Progress has been made in the technology as well as the understanding of the pathophysiology of acute kidney injury. Today, new biomaterials and new devices are available and new frontiers are on the horizon. Although improvements have been made, a lot remains to be done. Critical care nephrology is expected to further evolve in the near future, especially in the area of information and communication technology, utilization of big data and large database registries, biofeedback, and assisted prescription and treatment delivery, with high potential for improvement in morbidity and mortality of the most severely ill patients. PMID- 27951559 TI - Automated Electronic Alert Systems for Acute Kidney Injury: Current Status and Future Perspectives. AB - BACKGROUND: Acute kidney injury (AKI) is a common and serious condition, but the process of care for patients with AKI is currently suboptimal. Automated AKI electronic (e)-alert systems are expected to improve the process of care and patient outcomes. SUMMARY: There have been several reports on the implementation of e-alert systems, which have the potential to improve patient outcomes, but evidence of their effectiveness has not been established. There are some challenges to the development of better e-alert systems. Algorithms for detection should be examined, optimal alert outputs should be designed for each situation, and appropriate evaluation of the overall working of the systems is essential for future studies. Key Messages: Improvements to the current features of e-alert systems should include a better AKI detection algorithm and appropriate alert outputs, and overall system performance should be evaluated in future studies. PMID- 27951560 TI - New Dialysis Technology and Biocompatible Materials. AB - Although haemodialysis is an established treatment for patients with end-stage kidney disease, sustaining life for more than 2 million patients world-wide, the mortality of dialysis patients remains high and is greater than that for some of the more common solid organ cancers. As such, the question arises as to whether more efficient clearance of the waste products of metabolism which accumulate would improve outcomes. Recent reports of an association between improved patient survivals with higher-volume on-line haemodiafiltration exchanges would support this hypothesis. This has led to both the development of newer dialyser designs based on microfluidics using convective clearances to increase middle-molecule clearances and also a generation of superflux dialysers designed to remove larger molecular-weight azotaemic toxins which have yet to be studied in large randomised prospective clinical trials. However, haemodiafiltration and superflux dialysers do not affectively clear protein-bound azotaemic toxins, and there is accumulating evidence that some of these toxins increase cardiovascular morbidity and mortality. This has led to resurgence in the interest of developing adsorption devices, using activated carbon technology, and the development of composite dialyser membranes by either adding carbons or other biomaterials to increase adsorption capacity to the standard dialyser. While anaphylactoid reactions used to be a recognised complication of haemodialysis, improvements in dialyser membrane bioincompatibility and changing sterilisation techniques have markedly reduced these reactions. Organic chemicals can leach out from the plastics in the blood lines and dialyser, and attention is required to adequately rinse the extracorporeal circuit to reduce patient exposure. PMID- 27951561 TI - Design Concept of Dialyzer Biomaterials: How to Find Biocompatible Polymers Based on the Biointerfacial Water Structure. AB - BACKGROUND: Although various types of materials have been used widely in dialyzers, most biomaterials lack the desired functional properties to interface with blood and have not been engineered for optimum performance. Therefore, there is increasing demand to develop novel materials to address such problems in the dialysis arena. Numerous parameters of polymeric biomaterials can affect biocompatibility in a controlled manner. The mechanisms responsible for the biocompatibility of polymers at the molecular level have not been clearly demonstrated, although many theoretical and experimental efforts have been made to try and understand them. Moreover, water interactions have been recognized as fundamental for the blood response to contact with polymers. SUMMARY: We have proposed the 'intermediate water' concept and hypothesized that intermediate water, which prevents the proteins and blood cells from directly contacting the polymer surface, or nonfreezing water on the polymer surface, plays an important role in the biocompatibility of polymers. This chapter provides an overview of the recent experimental progress of biocompatible polymers measured by thermal, spectroscopic, and surface force techniques. Additionally, it highlights recent developments in the use of biocompatible polymeric biomaterials for dialyzers and provides an overview of the progress made in the design of multifunctional biomedical polymers by controlling the biointerfacial water structure through precision polymer synthesis. Key Messages: Intermediate water was found only in hydrated biopolymers (proteins, polysaccharides, and nucleic acids, DNA and RNA) and hydrated biocompatible synthetic polymers. Intermediate water could be one of the main screening factors for the design of appropriate dialyzer materials. PMID- 27951562 TI - Newly Developed Biocompatible Material: Dispersible Titanium-Doped Hydroxyapatite Nanoparticles Suitable for Antibacterial Coating on Intravascular Catheters. AB - BACKGROUND: Thirteen patients with chlorhexidine-silver sulfadiazine-impregnated catheters have experienced serious anaphylactic shock in Japan. These adverse reactions highlight the lack of commercially available catheters impregnated with strong antibacterial chemical agents. A system should be developed that can control both biocompatibility and antibacterial activity. SUMMARY: Hydroxyapatite (HAp) is biocompatible with bone and skin tissues. To provide antibacterial activity by using an external physical stimulus, titanium (Ti) ions were doped into the HAp structure. Highly dispersible, Ti-doped HAp (Ti-HAp) nanoparticles suitable as a coating material were developed. In 3 kinds of Ti-HAp [Ti/(Ca + Ti) = 0.05, 0.1, 0.2], the Ti content in the HAp was approximately 70% of that used in the Ti-HAp preparation, as determined by inductively coupled plasma atomic emission spectroscopy (ICP-AES). ICP-AES and X-ray diffraction showed Ti ions were well substituted into the HAp lattice. The nanoparticles were almost uniformly coated on a polyethylene (PE) sheet in a near-monolayer with a surface coverage ratio >95%. The antibacterial activity of the Ti-HAp nanoparticles containing 7.3% Ti ions and coating the sheet was evaluated by calculating the survival ratio of Pseudomonas aeruginosa on the coated sheet after ultraviolet (UV) irradiation. The Ti-HAp-coated sheet showed a 50% decrease in the number of P. aeruginosa compared with that on an uncoated control PE sheet after UV irradiation for 30 s. Key Messages: A system of biocompatibility and antibacterial activity with an on/off switch controlled by external UV stimulation was developed. The system is expected to be applicable in long-term implanted intravascular catheters. PMID- 27951563 TI - Preparation and Quality Management of Fluids for Hemodialysis. AB - BACKGROUND: In 2008, the Japanese Society for Dialysis Therapy (JSDT) proposed a standard for the quality of fluids for hemodialysis. The standard was geared toward Japan, where the central dialysis fluid delivery system is routinely used. After establishment of the standard, dialysis fluid quality was markedly improved in facilities across the country. Moreover, the number of on-line hemodiafiltration patients dramatically increased. SUMMARY: However, the 2008 standard specifies only microbiological qualities and does not cover toxic chemicals. The basis of toxic chemical management depends on the source water and water treatment equipment for hemodialysis, but no standard applies to water treatment equipment as a medical device. Specifications for the equipment were, for the most part, entrusted to individual manufacturers. Key Messages: The JSDT is investigating revision of its standard for dialysis fluid quality for hemodialysis to add control standards for toxic chemicals and water treatment equipment, with the aim of achieving quality of dialysis water superior to that of terminal dialysis fluid. PMID- 27951564 TI - Preventive Strategies for Vascular Calcification in Patients with Chronic Kidney Disease. AB - BACKGROUND: Vascular calcification is significant because of the close association between the degree of vascular calcification and cardiovascular mortality in chronic kidney disease (CKD) patients. SUMMARY: There are 2 types of vascular calcification in CKD patients. One is endothelial vascular calcification, a common type of vascular calcification. Another is medial vascular calcification, a specific type that is common in CKD patients. The former is mainly associated with atherosclerosis due to hyperlipidemia, especially hypercholesterolemia. The latter CKD-specific type is called Moenckeberg's arteriosclerosis. A known risk factor for this type of vascular calcification is hyperphosphatemia. In this review article, we mainly discuss a preventive strategy for Moenckeberg type vascular calcification in CKD, primarily involving the treatment of hyperphosphatemia. Several possible modalities are considered. However, at present, dietary restriction of phosphate is not recommended so as to avoid malnutrition in CKD patients. The first consideration is the enhancement of phosphate removal by renal replacement therapy in dialysis patients. Various phosphate binder therapies can be beneficial and effective. Surgical and pharmacological parathyroidectomies are also useful for treating secondary hyperparathyroidism. Good quality bone provides a good pool of calcium and phosphate. Thus, bone protection is another option for preventing vascular calcification. Several therapeutic agents have been developed to manage osteoporosis. These trial agents may be reasonably effective in impeding the progression of vascular calcification in CKD patients. Key Messages: We should make full use of several modalities so as to completely prevent vascular calcification. PMID- 27951565 TI - Klotho as a Therapeutic Target during the Development of Renal Fibrosis. AB - Systemic symptoms such as the ectopic calcification, atrophy of skin and muscle, and impaired sexual function observed in chronic kidney diseases (CKD) have been reported to coincide with those observed in geriatric symptoms. Regarding the kidney, clinical/pathological characteristics in CKD patients also coincide with those in the aging kidney. These findings suggest common mechanisms in the development of both CKD and aging. Our investigation of aging factors associated with renal fibrosis in IgA nephropathy patients revealed a significant correlation between accumulation of cells with an arrested cell cycle and decreased expression of Klotho protein. Because cell cycle arrest has a protective effect on organs in the acute phase, the proposed therapeutic target against the aging process is to maintain expression of Klotho protein. In addition, it is recognized that TGF-beta1 plays a central role in the development of renal fibrosis. However, TGF-beta1 has also been reported to decrease expression of Klotho protein. In this report, we provide an interpretation of our new treatment strategy which involves controlling histone methylation. PMID- 27951566 TI - New Strategies for Anaemia Management in Chronic Kidney Disease. AB - Erythropoiesis-stimulating agents (ESAs) and iron therapy are the standard of care for normocytic normochromic anaemia, which is a frequent comorbidity of patients with chronic kidney disease. In a large percentage of patients, ESAs and iron increase haemoglobin levels, thus reducing the risk of blood transfusions and improving patient quality of life. However, randomised trials have raised some concerns about higher haemoglobin targets and/or high ESA dose use. These concerns include higher cardiovascular and thrombosis risk, cancer progression, and increased mortality. A more cautious approach was then advised and partial anaemia correction (haemoglobin 10-12 g/dl) is now strongly suggested. The clinical concerns about ESAs and economic constraints have led to larger intravenous iron use. However, severe anaphylactic reactions, although infrequent, can occur and excessive iron use may be dangerous as well, possibly causing iron overload. Several attempts are being made to develop new drugs with theoretically better activity and safety, and/or easier manufacturing processes as compared to available ESAs. These include drugs manipulating the hypoxia inducible transcription factor (HIF) system, which stimulates the endogenous erythropoietin (EPO) production and avoids unphysiological EPO plasma levels. Several phase I and II studies support the beneficial role of augmenting HIFs to stimulate erythropoiesis. Here we give an update on this new investigational strategy. PMID- 27951567 TI - Evidence for Targeting Low-Molecular-Weight Proteins in Hemodialysis and Hemodiafiltration. AB - BACKGROUND: With the identification of beta2-microglobulin (beta2MG) as an active participant in dialysis-related amyloid fibril formation, low-molecular-weight proteins (LMWPs) are now recognized as a distinct class of uremic toxins, and numerous compounds in this category have been identified. The class of LMWPs, although not precisely defined, has a molecular weight range of approximately 1,000-50,000 Da. With this in mind, dialysis prescriptions have been modified to increase the efficiency of uremic solute removal. Many studies have characterized the dialytic removal of beta2MG and it is therefore regarded as a surrogate for LMWPs. SUMMARY: In Japan, dialysis membranes that can efficiently remove beta2MG are recommended. Recently, researchers have reported that beta2MG is not only a uremic toxin that should be removed, but also a predictor of the prognosis of dialysis patients. In Japan, hemodiafiltration (HDF), especially on-line HDF, and protein-permeable hemodialysis (HD) is being actively carried out, and it is often reported that prognosis is improved by decreasing the concentrations of substances larger than beta2MG. It is important, then, that dialysis prescriptions achieve effective clearance of such substances. Key Messages: Over 2,000 uremic substances have been identified that form or accumulate because of renal failure and cause various symptoms and complications. Focusing on these facts, HD or HDF therapy, which is associated with albumin loss, was implemented targeting the LMWPs. Here, we report the effects of albumin-losing blood purification (HD/HDF) for the purpose of removing LMWPs. PMID- 27951568 TI - The Clear Space Index. AB - BACKGROUND: Kt/V for urea (Kt/V) is a dimensionless clinical index of dialysis dose; however, it does not directly reflect the removal capacity of the solute. Since the total amount of solute removal, M, is directly proportional to the initial solute concentration CB(0), it is reasonable to introduce an index by dividing M by CB(0). This index was termed 'clear space' (CS) because it was later found that it reflects the body fluid volume, the concentration of which becomes zero by the treatment. SUMMARY: Although CS originally requires measurement of M, storing all the effluent of dialysis fluid, it may be more easily calculated by measuring concentrations in blood, using a simpler formula without storing any effluent of dialysis fluid. Moreover, this technique is applied not only for urea, but also for much larger solutes. The concept of CS is also applied to peritoneal dialysis, identifying the maximum CS relative to the total effluent volume of the dialysis fluid. It was shown by CS analysis that the 1-compartment model may not work well, even for small solutes like urea, under higher levels of solute removal. It was also shown that divergence from the 1 compartment model was greater in patients with regenerated cellulose membranes than in those with synthetic polymeric membranes. Key Messages:CS is a simple yet useful solute removal index that avoids the effect of CB(0) and may be used for comparison of dose among two or more treatment modalities. Unlike Kt/V, CS can be measured for all kinds of solute, giving the average for two or more compartments in which the concentration of solute of interest becomes zero. PMID- 27951569 TI - Optimal Design of Dialyzers. AB - BACKGROUND: Several types of synthetic dialysis membranes, including polysulfone, polyethersulfone, and polyester polymer alloy membranes, have asymmetrical structures. Dialyzers with these membranes show higher water and solute transport performance because the actual membrane thickness, which is related to the water and solute transfer resistance, is quite small compared with that in membranes with a homogeneous structure. SUMMARY: The performance of a dialyzer depends not only on membrane permeability to water and solutes, but also on flow conditions of the blood and dialysate, which are determined during dialyzer fabrication. Many types of high-flux dialyzers with high-performance membranes have a high internal filtration/backfiltration (IF/BF) flow rate. In the enhanced IF/BF dialyzer, membrane fouling occurs more readily than with the conventional dialyzer because of the high local transmembrane pressure needed to enhance the IF/BF flow rate. To select the optimal enhanced IF/BF dialyzer for individual patients, we need to balance the disadvantage of membrane fouling with the advantage of increased convective transport. Key Messages: The following principles should guide dialyzer development in the near term. (1) Dialyzers should show high performance for the removal of low-molecular-weight proteins related to certain complications under conditions of low albumin and amino acid loss. (2) Dialyzers with biocompatible membranes are required to prevent severe adverse reactions, even though the causal relationship between these reactions and some complications remains to be clarified. PMID- 27951570 TI - Biocompatibility of Hemodiafilters. AB - BACKGROUND: Biocompatibility and the efficiency of solute removal are important considerations in blood purification therapy. Improvement of biocompatibility is expected to lead to the prevention of dialysis-related complications (e.g. amyloidosis, arteriosclerosis, and malnutrition) and to the delay of disease progression by alleviating microinflammation. SUMMARY: The biocompatibility of dialyzers is greatly influenced by the interaction between blood and the treatment materials, in which the chemical and physical characteristics of membrane materials play important roles. In hemodiafiltration (HDF), treatment characteristics such as dilution modes are also considered to greatly affect this interaction between blood and materials. Studies have reported that the levels of C-reactive protein are decreased in patients receiving HDF. Thus, the improvement of biocompatibility is an important factor in HDF. Key Messages: To improve the biocompatibility of HDF, it is essential to improve the biocompatibility of hemodiafilters. This article outlines the importance of biocompatibility and related factors in HDF. PMID- 27951571 TI - Fundamental Characteristics of the Newly Developed ATATM Membrane Dialyzer. AB - BACKGROUND: Dialysis membranes are often made from synthetic polymers, such as polysulfone. However, membranes made from cellulose triacetate have superior biocompatibility and have been used since the 1980s. On-line hemodiafiltration treatment accompanied by massive fluid replacement is increasingly being used in Europe and Japan, but cellulose triacetate is not suitable for this treatment. SUMMARY: Our newly developed asymmetric triacetate membrane, the ATATM membrane, substantially improved the filtration properties and blood compatibility because of the asymmetric structure and smooth surface of this cellulose acetate membrane. Key Message: The ATA membrane maintains its high permeability even after massive filtration and shows less temporal variation in its permeation performance, lower protein adsorption, and superior biocompatibility compared with conventional membranes. PMID- 27951573 TI - A New Poly(Methyl Methacrylate) Membrane Dialyzer, NF, with Adsorptive and Antithrombotic Properties. AB - BACKGROUND: Poly(methyl methacrylate) (PMMA) membranes adsorb several kinds of proteins and can remove high-molecular-weight proteins, including uremic toxins, which are not removed efficiently by hemodialysis or hemodiafiltration. However, the antithrombogenicity of PMMA membranes is insufficient due to their adsorptive properties. SUMMARY: Coagulation during hemodialysis occurs because proteins that are adsorbed to the PMMA membrane undergo structural changes and are recognized by platelets, which are then activated by adhesion to the membrane surface. In developing a new PMMA membrane dialyzer, NF, we intended to inhibit platelet adhesion to the membrane surface by suppressing the structural change in the proteins adsorbed on the membrane. In addition, we give examples of clinical trials of the NF in Japan and describe its advantages. Key Message: PMMA membrane dialyzers have been used for 40 years. The PMMA dialyzer NF can suppress the adhesion of platelets to the membrane while maintaining protein adsorption. PMID- 27951572 TI - A New Polysulfone Membrane Dialyzer, NV, with Low-Fouling and Antithrombotic Properties. AB - BACKGROUND: The biggest problem in routine hemodialysis therapy is possibly the blood pressure fall experienced by patients during dialysis. In contrast, in medium- and long-term hemodialysis therapy, the main problem might be deterioration of arteriosclerosis because of medial calcification associated with dialysis vintage. Both problems are caused by an autonomic imbalance or structural change in the blood vessels. Inflammation due to extracorporeal blood circulation is another possible cause. This inflammation is considered to cause platelets activated by contact and adherence with the membrane surface to aggregate with white blood cells and attack the endothelium of the blood vessels. Therefore, we tried to develop a new membrane with no adsorption and no platelet activation. SUMMARY: Polysulfone (PS) membranes with polyvinylpyrrolidone (PVP) as a hydrophilic agent are widely used in dialysis, but blood components adhere to the membrane surface. We developed a new dialyzer, NV, by localizing a new hydrophilic polymer onto the inner surface of a hollow-fiber membrane composed of PS and PVP. The number of platelets that adhered to the NV membrane surface drastically decreased to 0.9% of that with the conventional PS dialysis membrane. We also confirmed the mechanism by which NV realizes clinical improvements in blood pressure drops and inflammation during dialysis, and verified its clinical appeal. Key Messages: The new membrane NV, which inhibits platelet adhesion and is compatible with blood vessels, is clinically beneficial. PMID- 27951574 TI - Clinical Performance Assessment of CorDiax Filters in Hemodialysis and Hemodiafiltration. AB - In this study, we evaluate the in vivo clinical performances of CorDiax FX 100 and CorDiax FX 1000 filters incorporating a high-flux membrane (Helixone Plus) designed for use in high-flux hemodialysis (HD) as well as in hemodiafiltration (HDF) in 6 stable end-stage kidney disease patients. In the HDF mode, various substitution modalities (post-, pre-, and mixed) were compared. In addition to conventional markers of efficacy of dialysis dose (urea, ionic dialysance, Kt/V), several additional middle- and large-size solute (beta2-microglobulin, myoglobin, serum-free light-chain kappa and lambda, alpha1-microglobulin, and FGF23) compounds were explored in order to cover the spectrum of uremic toxins that are involved in uremia. A precise quantitative assessment of solute removal was performed in this study mimicking solute kinetic complexity during patient/dialysis interaction (hemoconcentration due to volume contraction, postdialysis rebound due to compartmentalization effect) in order to fit better with clinical reality and to provide clinicians more realistic estimates of solute mass transfer. The study confirms that effective solute body clearances achieved in vivo both in HD and in HDF are significantly lower than instantaneous clearances reported by manufacturers. Among dialysis modalities assessed in this study, postdilution HDF offers the most efficient modality both in terms of solute removal capacity and substitution volume used. The predilution HDF mode provides slightly but significantly lower body clearances than the postdilution mode over the spectrum of solutes assessed, a dilution factor that can be compensated for by increasing the substitution rate adequately. The clinical performance of CorDiax FX filters featuring the same highly permeable membrane engineered in 2 different configurations, one facilitating internal convective transport in HD (high internal resistance) and the other favoring high-volume on line HDF (low internal resistance), offers interesting and effective options for enhancing removal of middle- and larger-size uremic compounds. High-volume HDF relying on different fluid substitution modes remains the more efficient modality across a large spectrum of uremic compounds tested. PMID- 27951575 TI - Clearance Gap: Does It Really Matter for the Evaluation of Vascular Access Function? AB - BACKGROUNDS: Vascular access (VA) stenosis increases the risk of VA obstruction due to the gradual progress of intimal thickening. Therefore, we should try to detect VA stenosis early. However, we do not have a cutoff for when a difference between prescribed Kt/V and delivered Kt/V reflects a clinical issue. Thus, we have devised a new index, the 'clearance gap' (CL-Gap), which quantifies the difference between the effective clearance (eCL) of a hemodialysis (HD) patient and the theoretical clearance (tCL) of a dialyzer to detect a decrease in dialysis efficiency due to VA dysfunction. SUMMARY: We propose a qualitative technique of analyzing dialysis (the CL-Gap method) concerning Kt/V by estimating the eCL based on the delivered Kt/V and the difference with the tCL based on the dialyzer. When VA recirculation and blood removal failure occurs, the eCL decreases, and it is expected that the CL-Gap increases. On the contrary, if uniform internal removal occurs, the eCL rises when we overestimate the delivered Kt/V and the CL-Gap is expected to decrease. However, we cannot judge whether a high CL-Gap indicates VA dysfunction immediately because it is necessary to consider not only VA dysfunction, but also the effect of other factors on the CL Gap. Key Messages: We believe that it is important to think about VA function in a qualitative manner when managing the dose using the CL-Gap to achieve better dialysis treatment. PMID- 27951577 TI - The Economic Issues of Hemodialysis Therapy within the Japanese Health Care System. AB - BACKGROUND: Expenditure on hemodialysis therapy is high within the Japanese health care system, and cost reductions are desirable to maintain the system. Under these circumstances, both a macroeconomic analysis and a microeconomic analysis of the country's health care system are needed to elucidate its problems. SUMMARY: A macroeconomic analysis showed that Japan's sluggish GDP growth since the 1990s has been a major problem in the allocation of health care resources, and government policies have been put in place to reduce health care expenditure. In contrast, a microeconomic analysis showed that the Japanese health care system is being run very efficiently. For hemodialysis therapy specifically, the mortality rate is low and medical costs are not high, indicating that treatment is being provided in a highly efficient manner. Key Messages: These results suggest the direction that Japan's health care system, including hemodialysis therapy, should take will increase health care expenditure commensurate with the nation's economic growth. PMID- 27951576 TI - Future Trends in Vascular Access Creation. AB - Delivery of a prescribed dialysis dose, which is critical for longevity on hemodialysis, is directly dependent on vascular access (VA). However, VA is fraught with high failure rates and has room for innovation. Arteriovenous fistula (AVF), considered the 'best choice', has a high 'failure to mature' rate. Arteriovenous grafts (AVGs) are considered when patients are poor candidates for or have failed AVF, but have a high incidence of infections and thrombosis. Due to associated morbidity and mortality from complications, central venous catheters are considered only as 'bridging short-term access' when there is an urgent need for dialysis. The observation from current data that there is a significant center effect in the rate of AVF maturation supports investigation to identify factors that contribute to success in high-performing centers that create AVF and establish 'best practice' approaches to improve outcomes. Biocompatible AVG constructs that promote rapid tissue incorporation withstand needle punctures due to better integrity and can improve current AVG outcomes. Stenosis in the 'access circuit' is a major cause for short- and long-term permanent access failure. While the pathology of stenosis development is well understood, factors responsible for this problem are poorly studied. Increased flow in the access circuit likely plays a major role in the development of such stenosis. Investigation into understanding the hemodynamics of this flow may help identify etiology and stenosis sites perhaps even prior to the event, thus providing potential targets to mitigate the stenotic response. In summary, this chapter reflects on the shortcomings of current access modalities and discusses potential avenues to improve VA outcomes in the future. PMID- 27951579 TI - Evidence for the Clinical Advantages of Predilution On-Line Hemodiafiltration. AB - BACKGROUND: On-line hemodiafiltration (OL-HDF) is a rapidly developing dialysis modality that is expected to ameliorate the quality of life and survival rate of chronic dialysis patients. There are generally 2 types of dilution methods in OL HDF: postdilution and predilution. SUMMARY: Postdilution OL-HDF is widely performed worldwide, whereas predilution OL-HDF accounts for >90% of all OL-HDF sessions performed in Japan. The reasons for the preference for predilution are to increase the substitution volume at a lower blood flow rate and to remove larger low-molecular-weight proteins (LMWPs). It is a unique Japanese concept for chronic dialysis to remove larger LMWPs, in so-called 'protein permeable dialysis', and ameliorate various uremic symptoms. Evidence for the beneficial effects of OL-HDF has not yet been confirmed, especially in the case of the predilution mode. The beneficial effects of predilution OL-HDF have recently been evaluated by 2 Japanese studies. A study by the Japanese Society for Dialysis Therapy (JSDT) found a clear survival benefit for all-cause mortality and cardiovascular mortality of predilution OL-HDF with a substitution volume >40 liters/session. A study by the Japanese Society for Hemodiafiltration (JSHDF) showed the noninferiority of predilution OL-HDF in relation to intradialytic hemodynamic stability compared with the postdilution mode. Key Messages: Further analysis of the JSDT and JSHDF studies may confirm the superiority of predilution OL-HDF over high-flux or super high-flux hemodialysis. PMID- 27951578 TI - Carbohydrate Counting: A Simple Method of Dietary Management for Glycemic Control in Japanese Diabetic Hemodialysis Patients. AB - BACKGROUND: Carbohydrate counting used in dietary therapy for diabetes is based on the concept that the postprandial rise in blood glucose levels is primarily affected by ingested carbohydrates. This method has been widely accepted and used since 1993, when its usefulness was demonstrated in the United States, largely due to the ease with which patients can understand the method. However, in Japan, there is a common misunderstanding that energy intake determines postprandial blood glucose levels. SUMMARY: We examined the effectiveness of using basic carbohydrate counting and advanced carbohydrate counting with Japanese diabetic dialysis patients. With both methods, predialysis blood glucose and HbA1c levels were significantly decreased at the final follow-up compared with preinstruction values. There were no significant changes in other parameters. The carbohydrate counting method was able to be applied independently of, but concurrently with, the control of potassium and phosphorus intake, which is the basis of dietary therapy for dialysis patients. Moreover, those patients who completed the basic carbohydrate counting instruction sessions had a mean relative carbohydrate intake (% of total energy) of 51.0 +/- 4.7% per meal, indicating they did not consume a low-carbohydrate diet. Key Messages: At present, there is no literature on carbohydrate counting performed by dialysis patients. Carbohydrate counting is a useful method of dietary management for glycemic control that can be applied independently of, but concurrently with, the control of potassium and phosphorus intake in dietary therapy for dialysis patients. PMID- 27951580 TI - The Evolution of Home HD - Meeting Modern Patient Needs. AB - Patients with end-stage renal disease undergoing conventional renal replacement therapy face high morbidities and inappropriately high mortality rates globally. Intensive home hemodialysis has emerged as an alternate form of renal replacement therapy with superior clinical outcomes. In order to describe the international trends in conducting home hemodialysis, we performed a cross-sectional survey of 25 centers reporting the global trends and practices of intensive home hemodialysis. While the practice of home hemodialysis has continued to evolve, similar logistical barriers exist around the world. The Global Forum for Home Hemodialysis was created to provide a user-centric manual to facilitate the delivery of this important mode of renal replacement therapy. PMID- 27951581 TI - MicroRNAs Are Associated with Uremic Toxicity, Cardiovascular Calcification, and Disease. AB - BACKGROUND: Vascular calcification has been recognized to be a major risk factor in chronic kidney disease (CKD) and downstream cardiovascular complications. Micro-RNAs (miRNAs) are small noncoding RNAs comprising 20-25 nucleotides that regulate gene expression by inhibiting or degrading the target mRNA, and constitute potential new biomarkers and future therapeutic strategies. SUMMARY: We tested the relevance of several cardiovascular-specific miRNAs as new biomarkers for CKD, cardiovascular disease, and cardiovascular complications. We have shown, in murine models, that miR-126, miR-143, miR-145, and miR-223 levels and the levels of their specific targets are modulated during the crucial stages of CKD and atherosclerosis. In addition, miRNA levels were correlated with classical biomarkers of CKD and atherosclerosis such as cholesterol, urea, and calcium levels. Dysregulation of these same miRNAs was observed in the serum of CKD, hemodialyzed, and kidney transplant recipients. We also demonstrated correlations between serum miRNAs and uremic toxins. We therefore suggest that miR-126, miR-143, miR-145, and miR-223 are potential biomarkers of vascular calcification and cardiovascular disease associated with CKD. Key Messages: The identification of new biomarkers that can improve the diagnosis and monitoring of CKD and cardiovascular disease patients is crucial in modern medicine. Our data could be particularly useful in the management of cardiovascular disease associated with CKD, provide new light in the understanding of the molecular events underlying cardiovascular disease and cardiovascular calcification, and possibly be used as a treatment strategy to prevent these diseases. PMID- 27951582 TI - Oral Low-Dose Ferric Citrate Is a Useful Iron Source for Hyperphosphatemic Hemodialysis Patients: A Case Series. AB - BACKGROUND: Randomized trials have demonstrated that a phosphate binder ferric citrate (FeC) increases iron parameters in comparison with other phosphate binders, but the doses for FeC to improve iron stores safely have not been clarified. METHODS: We examined changes of iron parameters and blood hemoglobin (Hb) in 7 iron-deficient hemodialysis (HD) patients taking FeC 750 mg/day as a phosphate binder. RESULTS: The median serum transferrin saturation and ferritin increased from 13% (interquartile range (IQR) 7-18) to 28% (IQR 22-31; p = 0.010) and from 17 ng/ml (IQR 11-60) to 106 ng/ml (IQR 58-176; p = 0.015) by 2 and 3 months respectively. With the persistence of these levels thereafter, the FeC administration reduced the usage of erythropoiesis-stimulating agents while maintaining adequate blood Hb levels. CONCLUSION: Oral FeC 750 mg/day improves iron stores without inducing iron overload in hyperphosphatemic HD patients. PMID- 27951583 TI - Bronchoscopic Drainage of Lung Abscesses Using a Pigtail Catheter. AB - BACKGROUND: Lung abscesses are commonly treated with antibiotics. However, some patients fail to respond and may require percutaneous catheter drainage or surgical intervention. Bronchoscopic drainage (BD) of lung abscesses emerged as a therapeutic alternative in selected patients. OBJECTIVE: To describe our experience with 15 patients who underwent BD at our center during 2006-2016. METHODS: Patients underwent flexible bronchoscopy. Under fluoroscopic guidance, a pigtail catheter was introduced into the abscess cavity, its correct position being confirmed by the injection of contrast medium. The catheter remained in place for a few days and was flushed repeatedly with antibiotics. RESULTS: Fifteen patients (9 males; median age 59 years) underwent 16 BD procedures. A pigtail catheter was successfully inserted and pus was drained from the abscess cavity in 13 procedures (81%) conducted in 12 patients, leading to rapid clinical improvement in 10 of them; resolution of fever occurred a median of 2 days (range <1-4) following pigtail insertion, and patients were discharged after 8 days (range 4-21). The pigtail catheter was extracted after a median of 4 days (range 2-6). CONCLUSION: BD of lung abscesses was achieved in 13 out of 16 procedures, leading to rapid improvement in the majority of patients. This work adds to the existing literature in establishing this procedure as an acceptable therapeutic alternative in selected patients who fail to respond to antibiotics, especially those with an airway obstruction or a fairly central lung abscess. PMID- 27951584 TI - 90-Day Mortality after Radical Cystectomy for Bladder Cancer: Prognostic Factors in a Multicenter Case Series. AB - OBJECTIVES: To identify preoperative risk factors for 90-day mortality and to validate existing nomograms in a multicenter series of patients undergoing radical cystectomy (RC). MATERIALS AND METHODS: We evaluated 90-day mortality in 475 patients following RC and urinary diversion at 2 Italian institutions and validated Aziz and Isbarn nomogram. Univariable logistic models assessed the predictive ability of operative volume, age at intervention, gender, body mass index, carcinoma in situ at transurethral resection of the bladder, American Society of Anesthesiologist (ASA) score, Charlson Comorbidity Index, clinical stage and pathological stage (TNM). RESULTS: Of the total number of patients, 387 of them (81%) were male. The median age at RC was 71.8. The most frequent ASA score was 2 (53%). Twenty-five deaths occurred within 90 days (5.3%), all among patients who had undergone RC and incontinent urinary diversion. Risk was higher in patients with advanced disease (OR 2.4); moreover, 90-day mortality odd in 70 79-year-old patients was 13 times higher than those of younger patients (<70). Predictive accuracy using Isbarn's and Aziz's nomogram were 67 and 71%, respectively. CONCLUSIONS: Our multicenter study confirmed the moderate predictive value of the Aziz nomogram. Larger studies are needed to improve on existing nomograms with the aim of enhancing preoperative counseling. PMID- 27951585 TI - Centennial-scale Holocene climate variations amplified by Antarctic Ice Sheet discharge. AB - Proxy-based indicators of past climate change show that current global climate models systematically underestimate Holocene-epoch climate variability on centennial to multi-millennial timescales, with the mismatch increasing for longer periods. Proposed explanations for the discrepancy include ocean atmosphere coupling that is too weak in models, insufficient energy cascades from smaller to larger spatial and temporal scales, or that global climate models do not consider slow climate feedbacks related to the carbon cycle or interactions between ice sheets and climate. Such interactions, however, are known to have strongly affected centennial- to orbital-scale climate variability during past glaciations, and are likely to be important in future climate change. Here we show that fluctuations in Antarctic Ice Sheet discharge caused by relatively small changes in subsurface ocean temperature can amplify multi-centennial climate variability regionally and globally, suggesting that a dynamic Antarctic Ice Sheet may have driven climate fluctuations during the Holocene. We analysed high-temporal-resolution records of iceberg-rafted debris derived from the Antarctic Ice Sheet, and performed both high-spatial-resolution ice-sheet modelling of the Antarctic Ice Sheet and multi-millennial global climate model simulations. Ice-sheet responses to decadal-scale ocean forcing appear to be less important, possibly indicating that the future response of the Antarctic Ice Sheet will be governed more by long-term anthropogenic warming combined with multi-centennial natural variability than by annual or decadal climate oscillations. PMID- 27951586 TI - NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer. AB - NLRs (nucleotide-binding domain and leucine-rich repeats) belong to a large family of cytoplasmic sensors that regulate an extraordinarily diverse range of biological functions. One of these functions is to contribute to immunity against infectious diseases, but dysregulation of their functional activity leads to the development of inflammatory and autoimmune diseases. Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis. NLRC3 (also known as CLR16.2 or NOD3) is a poorly characterized member of the NLR family and was identified in a genomic screen for genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains. Expression of NLRC3 is drastically reduced in the tumour tissue of patients with colorectal cancer compared to healthy tissues, highlighting an undefined potential function for this sensor in the development of cancer. Here we show that mice lacking NLRC3 are hyper-susceptible to colitis and colorectal tumorigenesis. The effect of NLRC3 is most dominant in enterocytes, in which it suppresses activation of the mTOR signalling pathways and inhibits cellular proliferation and stem-cell derived organoid formation. NLRC3 associates with PI3Ks and blocks activation of the PI3K-dependent kinase AKT following binding of growth factor receptors or Toll-like receptor 4. These findings reveal a key role for NLRC3 as an inhibitor of the mTOR pathways, mediating protection against colorectal cancer. PMID- 27951588 TI - The Demise of the Affordable Care Act? Not So Fast. PMID- 27951587 TI - mRNA quality control is bypassed for immediate export of stress-responsive transcripts. AB - Cells grow well only in a narrow range of physiological conditions. Surviving extreme conditions requires the instantaneous expression of chaperones that help to overcome stressful situations. To ensure the preferential synthesis of these heat-shock proteins, cells inhibit transcription, pre-mRNA processing and nuclear export of non-heat-shock transcripts, while stress-specific mRNAs are exclusively exported and translated. How cells manage the selective retention of regular transcripts and the simultaneous rapid export of heat-shock mRNAs is largely unknown. In Saccharomyces cerevisiae, the shuttling RNA adaptor proteins Npl3, Gbp2, Hrb1 and Nab2 are loaded co-transcriptionally onto growing pre-mRNAs. For nuclear export, they recruit the export-receptor heterodimer Mex67-Mtr2 (TAP-p15 in humans). Here we show that cellular stress induces the dissociation of Mex67 and its adaptor proteins from regular mRNAs to prevent general mRNA export. At the same time, heat-shock mRNAs are rapidly exported in association with Mex67, without the need for adapters. The immediate co-transcriptional loading of Mex67 onto heat-shock mRNAs involves Hsf1, a heat-shock transcription factor that binds to heat-shock-promoter elements in stress-responsive genes. An important difference between the export modes is that adaptor-protein-bound mRNAs undergo quality control, whereas stress-specific transcripts do not. In fact, regular mRNAs are converted into uncontrolled stress-responsive transcripts if expressed under the control of a heat-shock promoter, suggesting that whether an mRNA undergoes quality control is encrypted therein. Under normal conditions, Mex67 adaptor proteins are recruited for RNA surveillance, with only quality-controlled mRNAs allowed to associate with Mex67 and leave the nucleus. Thus, at the cost of error-free mRNA formation, heat-shock mRNAs are exported and translated without delay, allowing cells to survive extreme situations. PMID- 27951589 TI - Primary Care Physician Volume and Quality of Diabetes Care: A Population-Based Cohort Study. AB - Background: A relationship between higher patient volume and both better quality of care and better outcomes has been shown for many acute care conditions. Whether a volume-quality relationship exists for the outpatient management of chronic diseases is uncertain. Objective: To explore the association between primary care physician volume and quality of diabetes care. Design: Cohort study. Setting: The study was conducted using linked population-based health care administrative data in Ontario, Canada. Patients: 1 018 647 adults with diabetes in 2011 who received care from 9014 primary care physicians. Two measures of volume were ascertained for each physician: overall ambulatory volume (representing time available to devote to chronic disease management during patient encounters) and diabetes-specific volume (representing disease-specific expertise). Measurements: Quality of care was measured over a 2-year period using 6 indicators: disease monitoring (eye examination, hemoglobin A1c testing, and low-density lipoprotein cholesterol testing), prescribing appropriate medications (angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers and statins), and adverse clinical outcomes (emergency department visits for hypoglycemia or hyperglycemia). Results: Higher overall ambulatory volume was associated with lower rates of appropriate disease monitoring and medication prescription. In contrast, higher diabetes-specific volume was associated with better quality of care across all 6 indicators. Limitation: Only a select set of quality indicators and potential confounders could be ascertained from available data. Conclusion: Primary care physicians with busier ambulatory patient practices delivered lower-quality diabetes care, but those with greater diabetes specific experience delivered higher-quality care. These findings show that relationships between physician volume and quality can be extended from acute care to outpatient chronic disease care. Health policies or programs to support physicians with a low volume of patients with diabetes may improve care. Primary Funding Source: Canadian Institutes of Health Research. PMID- 27951590 TI - Balancing Primary Diabetes Care Quality and Services. PMID- 27951591 TI - Scientific Misconduct Hurts. PMID- 27951592 TI - Novel Bruch's Membrane Opening Minimum Rim Area Equalizes Disc Size Dependency and Offers High Diagnostic Power for Glaucoma. AB - Purpose: The purpose of this study was to assess the diagnostic power of the novel two-dimensional parameter Bruch's membrane opening minimal rim area (BMO MRA) in spectral-domain optical coherence tomography (SD-OCT) for detection of glaucoma compared to minimal rim width (BMO-MRW) and retinal nerve fiber layer (RNFL) thickness in large and small optic discs. Methods: In this case-control, cross-sectional study, 207 eyes of 207 participants, including 89 controls and 97 patients with glaucoma and 21 with ocular hypertension (OHT), with a disc size <1.63 mm2 or >2.43 mm2 underwent SD-OCT, confocal laser scanning tomography (CSLT), visual field testing, and clinical examination. Bruch's membrane opening MRA BMO-MRW, RNFL thickness of SD-OCT and disc margin rim area (DM-RA) of CSLT were evaluated and analyzed for diagnostic power to detect glaucoma. Results: In healthy eyes with macrodiscs, mean BMO-MRW of 243.14 +/- 43.12 MUm was significantly smaller than BMO-MRW in microdiscs (338.97 +/- 69.39; P < 0.001). Bruch's membrane opening-MRA was comparable between disc size groups with 1.22 +/ 0.25 mm2 for macrodiscs and 1.26 +/- 0.27 mm2 for microdiscs (P = 0.51), as was RNFL thickness (82.69 +/- 15.76 MUm versus 78.53 +/- 11.01 MUm, respectively; P = 0.28). Perimetric mean deviation was -8.7 +/- 6.3 dB in glaucoma and -0.6 +/- 1.60 dB in OHT patients. Correlation of BMO-MRA and visual field function was rho (rho) = 0.70 (P < 0.001). Diagnostic power to differentiate glaucoma patients was highest for BMO-MRA. Partial area under the curve (pAUC) for BMO-MRA was 0.14 for specificity between 0.8 and 1.0, exceeding pAUCs of BMO-MRW (P < 0.001), RNFL thickness (P = 0.03), and DM-RA (P = 0.01). Conclusions: Bruch's membrane opening based minimum rim area measurements offer advantages compared to one-dimensional parameters assessing neuroretinal rim by SD-OCT. In nonglaucomatous eyes, BMO-MRA values seem comparable for the full range of disc sizes. Bruch's membrane opening MRA surpasses other parameters in diagnostic power for glaucoma. PMID- 27951593 TI - Autofluorescence Lifetimes in Patients With Choroideremia Identify Photoreceptors in Areas With Retinal Pigment Epithelium Atrophy. AB - Purpose: The purpose of this study was to investigate fundus autofluorescence lifetimes in patients with choroideremia and to identify tissue-specific lifetime characteristics and potential prognostic markers. Methods: Autofluorescence lifetimes of the retina were measured in two spectral channels (498-560 nm and 560-720 nm) in patients with choroideremia and age-matched healthy controls. Furthermore, autofluorescence intensities and spectral-domain optical coherence tomography (OCT) data were acquired and compared to fundus autofluorescence lifetime data. Results: Sixteen eyes from 8 patients with advanced choroideremia (mean +/- SD age, 55 +/- 13 years) were included in this study and compared with 10 age-matched healthy participants. Whereas fundus autofluorescence intensity measurement identified areas of remaining retinal pigment epithelium (RPE), autofluorescence lifetime maps identified areas with remaining photoreceptor layers in OCT but RPE atrophy. In these areas, mean (+/-SEM) lifetimes were 567 +/- 59 ps in the short and 603 +/- 49 ps in the long spectral channels (+98% and +88% compared to controls). In areas of combined RPE atrophy and loss of photoreceptors, autofluorescence lifetimes were significantly prolonged by 1116 +/- 63 ps (+364%) in the short and by 915 +/- 52 ps (+270%) in the long spectral channels compared with controls. Conclusions: Because autofluorescence lifetimes identify areas of remaining photoreceptors in the absence of RPE, this imaging modality may be useful to monitor disease progression in the natural course of disease and in context of potential future therapeutic interventions. PMID- 27951594 TI - Beneficial Effects of Combined AT1 Receptor/Neprilysin Inhibition (ARNI) Versus AT1 Receptor Blockade Alone in the Diabetic Eye. AB - Purpose: Dysfunction of the renin-angiotensin system (RAS) contributes to pathogenesis of diabetic retinopathy (DR). Yet RAS blockers have only limited beneficial effects on progression of DR in clinical trials. The natriuretic peptide system offsets RAS, so that enhancing the activity of this system on top of RAS blockade might be beneficial. Neprilysin has an important role in the degradation of natriuretic peptides. Therefore, we hypothesize that dual angiotensin receptor-neprilysin inhibition (ARNI) may outperform angiotensin receptor blocker (ARB) in protection against DR. We tested this hypothesis in streptozotocin-induced diabetic transgenic (mRen2)27 rats. Methods: Adult male diabetic (mRen2)27 rats were followed for 5 or 12 weeks. Treatment with vehicle, irbesartan (ARB), or ARB combined with the neprilysin inhibitor thiorphan (irbesartan+thiorphan [ARNI]) occurred during the final 3 weeks. Retinal cell death, gliosis, and capillary loss were evaluated. Real-time polymerase chain reaction (RT-PCR) analyses were performed to quantify the retinal level of inflammatory cell markers. Results: Both ARB- and ARNI-treated groups showed similarly reduced retinal apoptotic cell death, gliosis, and capillary loss compared to the vehicle-treated group in the 5-week study. Treatment with ARNI reduced the expression of inflammatory markers more than ARB treatment in the 5 week study. In the 12-week study, ARNI treatment showed significantly more reduction in apoptotic cell death (51% vs. 25% reduction), and capillary loss (68% vs. 43% reduction) than ARB treatment. Conclusions: Treatment with ARNI provides better protection against DR in diabetic (mRen2)27 transgenic rats, compared to ARB alone. This approach may be a promising treatment option for patients with DR. PMID- 27951595 TI - Corneal Endothelial Cell Migration and Proliferation Enhanced by Rho Kinase (ROCK) Inhibitors in In Vitro and In Vivo Models. AB - Purpose: To explore the role of Rho-associated kinases (ROCK) in corneal physiology and regeneration, and the effects of suppressing its activity in stimulating corneal endothelial cell proliferation and migration in vitro and in vivo. Methods: Immunohistochemistry was performed to detect RhoA and ROCK-1 and ROCK-2 in human corneal tissue. Adult porcine corneal endothelial cells (CECs) were isolated, grown to confluence, and further characterized. Under the treatment of ROCK inhibitors, changes in the cellular distribution profile of ZO 1 and F-actin were examined by immunofluorescence staining. Corneal endothelial cells migration was evaluated by scratch assay and analyzed with Axiovision software. Cell proliferation was quantified using Click-iT EdU HCS Assay. In vivo, the corneal endothelia of rabbits were surgically injured and H-1152 was topically applied for 10 days. Progress of wound healing was evaluated daily by monitoring corneal edema, inflammation, and thickness using slit-lamp examination, photography, and pachymetry. Rabbits were euthanized and enucleated for further evaluation. Results: H-1152 exhibited significant stimulatory effect on CEC migration and proliferation in vitro compared with both untreated and Y 27632-treated cells. Furthermore, topical administration of H-1152 led to marked reduction in corneal edema and formation of multinucleate CECs in vivo suggestive of proliferation associated with healing. Conclusions: H-1152 exhibited a better stimulatory effect on CEC migration and proliferation in vitro than Y-27632. Our findings suggest that topical administration of H-1152 promotes healing of injured corneal endothelium in vivo. These results demonstrate the efficacy of ROCK inhibitors as a potential topical therapy for patients with corneal endothelial disease. PMID- 27951597 TI - Dear Plagiarist: A Letter to a Peer Reviewer Who Stole and Published Our Manuscript as His Own. PMID- 27951596 TI - Expression Pattern of HIF-1alpha and VEGF Supports Circumferential Application of Scatter Laser for Proliferative Sickle Retinopathy. AB - Purpose: Retinal vascular occlusions in sickle cell anemia patients cause tissue ischemia and the release of angiogenic mediators that promote the development of retinal neovascularization, initiating proliferative sickle retinopathy (PSR). Laser photocoagulation (LPC) has emerged as the most common treatment for PSR. Nonetheless, only two randomized controlled clinical trials have evaluated the use of LPC for PSR, and both failed to definitively demonstrate efficacy of this approach. This may be due to a lack of knowledge regarding the appropriate location for placement of laser coagulations in PSR eyes. To help address this question, we examined the expression of hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF) in PSR eyes. Methods: The expression pattern of HIF-1alpha and VEGF in PSR (n = 5) and control (n = 3) eyes was examined by immunohistochemistry in different retinal regions defined by the presence or absence of retinal vessels. Results: Hypoxia-inducible factor 1alpha and VEGF were expressed in the inner retina of 5/5 untreated PSR eyes adjacent to retinal neovascularization; expression of HIF-1alpha was not detected (and VEGF only lightly detected) in normal retinal and choroidal vasculature of 3/3 control eyes. Hypoxia-inducible factor 1alpha and VEGF were strongly expressed in retinal cells within avascular (nonperfused) retina, anterior to the boundary between perfused and nonperfused retina, as well as in posterior ischemic retina in the presence or absence of neovascular sea fans. Conclusions: If the goal of LPC in PSR is to quench the expression of HIF-1-driven angiogenic mediators, our results support broad application of peripheral laser for its treatment. PMID- 27951598 TI - Outcomes-Based Pricing as a Tool to Ensure Access to Novel but Expensive Biopharmaceuticals. PMID- 27951599 TI - Computed Tomography Angiography for the Chimeric Anterolateral Thigh Flap in the Reconstruction of the Upper Extremity. AB - Background The chimeric anterolateral thigh (ALT) flap has been an ideal option for restoring complex soft tissue defects. However, as the vascular anatomy of the ALT is variable, the positions of its perforators are uncertain, which makes the surgery more challenging. Therefore, our study utilized computed tomographic angiography (CTA) for preoperative perforator mapping. Methods From October 2013 to October 2015, 37 patients suffering upper extremity soft tissue defects underwent CTA before ALT flap reconstruction. Perforators originating from the same source vessel were mapped by CTA, and the donor thigh and preferred perforators were selected accordingly. All preoperative parameters of perforators detected by CTA were checked during operation. Results Thirty-three dual-skin paddles, three tri-skin paddles, and one quad-skin paddles flap were designed and used in this study. Eighty-seven perforators were mapped by CTA preoperatively. Seventy-nine (90.8%) were used; 97.5% of these were musculocutaneous and 2.5% septocutaneous. All perforators used intraoperatively were consistent with preoperative parameters. Post-operatively, 2 patients experienced complications but there was 100% flap survival overall. The donor sites primarily underwent primary closure, apart for 7 cases which underwent skin grafting. There was no donor site morbidity. Conclusion Preoperative mapping by CTA is a useful, fast, and noninvasive method for assessing the source vessels, and can be a significant aid in chimeric ALT flap surgery. PMID- 27951601 TI - Serum bile acids in patients with hepatopulmonary syndrome. AB - Background Hepatopulmonary syndrome (HPS) occurs in 20 - 30 % of patients with cirrhosis and is associated with increased mortality. Cholestasis and accumulation of bile acids (BAs) play a major role in chronic liver disease. Aim We aimed to evaluate the clinical role of serum BAs in patients with HPS. Methods Seventy-four patients with cirrhosis were included in this prospective study. Marker for cholestasis as total and individual serum BAs, bilirubin, alkaline phosphatase (AP), and gamma-glutamyl transpeptidase (GGT) were analyzed in patients screened for HPS. Criteria of HPS were fulfilled in 26 patients (35 %). Results In contrast to AP and GGT, bilirubin and serum BAs were significantly elevated in patients with HPS (median total BAs in HPS 83.5 MUmol/L, IQR 43.1 - 148.9 vs. no HPS 26.9 MUmol/L, 11 - 75.6; p < 0.001). Total BAs correlated with gas exchange by means of PaO2 / AaPO2 (r: -0.28, p < 0.05; r: 0.24, p < 0.05) and portal pressure (r: 0.33, p < 0.05). BAs were associated with HPS independently severity of underlying liver disease (OR: 1.012, 95 % CI: 1.001 - 1.023, p < 0.05). Conclusion BA retention is associated with HPS and gas exchange abnormalities. Future studies should assess whether modulation of BAs signaling may impact the course of HPS. PMID- 27951600 TI - Multimodal and sequential treatment improves survival in patients with hepatocellular carcinoma. AB - Background and aims Therapy of hepatocellular carcinoma (HCC) mainly depends on tumor stage and liver function. The aim of this study was to identify additional predictors of overall survival in HCC patients with a particular attention to multimodal therapies. Methods Six hundred and seven consecutive HCC-patients treated in a tertiary center between 1988 and 2011 were retrospectively analyzed. Multivariate analysis was performed by logistic and Cox-regression, overall survival was analyzed by Kaplan Meier statistics. Results In comparison to unimodal therapies, multimodal treatment increased overall survival in BCLC-A patients from 16 to 26 months (p < 0.001), in patients with BCLC-B stage from 9.5 to 16 months (p < 0.001), in BCLC-C patients from 6 to 18 months (p < 0.001), and in stage BCLC-D from 2 to 8 months (not significant). Survival increased throughout all Child Pugh scores, and patients experienced benefits from multimodal therapy irrespective of alfa-fetoprotein levels. Comparing the time span 1988 - 1999 with 2000 - 2011, the rate of multimodal/sequential treatment increased from 12.3 % to 30 % (p < 0.001), and the overall survival of all (treated and non-treated) patients increased from 7 months (1988 - 1999) to 10 months (2000 - 2011, p < 0.001). In multivariate analysis, multimodal treatment was shown to be an independent predictor for overall survival besides elevated alfa-fetoprotein, Child Pugh score, and BCLC stage. Conclusion Multimodal therapies increase overall survival in HCC patients and should be considered in patients with HCC if practicable. PMID- 27951602 TI - ? PMID- 27951603 TI - [Side Effects of Occupational Group Therapy]. AB - Background: Occupational therapy is an important co-therapy in psychiatric therapy. It is a common belief that no risks are associated with occupational therapy. Negative effects caused by group therapy, especially occupational therapy, have not been in the focus of research yet. In this study we want to illustrate possible types and intensities of group side effects through occupational therapy. Patients and Methods: Patients of an inpatient rehabilitation facility filled out the Adverse Treatment Reaction Group Checklist. The checklist contains 47 items divided in six dimensions: group size, content, group participants, group outcome and global. The self-rating used a 5 point likert scale (0 = not at all; 4 = very much, extremely stressful) and gives information about types and intensities of the side effects. Results: 88.9 % of 45 patients reported negative effects of occupational group therapy. 28.9 % of the patients rated the side effect as at least severe. Discussion: Occupational therapy is associated with side effects as every other group therapy. Possible side effects caused by group therapy should be considered while planning and implementing occupational therapy. PMID- 27951605 TI - [The Brain-Injured Relationship: Neuropsychological Rehabilitation Counselling and Therapy of Couples and Families]. AB - A brain-injured patient's system of relationships is severely disbalanced, and seeks a new equilibrium very much like a kinetic mobile sculpture responding to an impulse. Thus, it is not only the deficits in the patients and their environment and resources that define the success of participation in the process of rehabilitation. Fundamentally, it relies on stable and adjustable relationships as well as trustful communication in the patients' social systems. Negotiating participation is a concerted, interactive adjustment process for everyone involved in dealing with a disruptive life event. Dysfunction in relationships and communication, which frequently is a direct or indirect consequence of brain injuries, puts at risk the sustainability of progress reached during rehabilitation. In this system of relationships often heavily burdened, neuropsychological rehabilitation counseling is needed to secure the long-term success of rehabilitation. PMID- 27951604 TI - [Integration of Palliative and Hospice Care Structures in the Care of Neurological Patients: Opinion of Chief Consultant Neurologists in Germany]. AB - An online survey of chief neurological consultants was conducted to find out how they judged the demand for and access to palliative and hospice care (PHC) structures for their neurological patients (NP) as well as their collaboration with PHC structures. 110 of 881 chief consultants who were contacted participated in the survey. About 10 % of their NP were considered suitable for PHC. They estimated that 9 % of the deceased had died from their underlying neurological disease. The integration of PHC structures into the management of various neurological diseases was considered worthwhile but 51.9 - 78.5 % indicated that there was no or little collaboration with PHC structures. 12 % of the participants were trained in palliative care (PC). To guarantee an adequate PHC also for NP, PHC knowledge should be integrated into the curriculum and training of neurologists and the PC community should further extend its services to NP, adapting their knowledge and structures to these patients' special needs. PMID- 27951606 TI - [The Basic-Symptom Concept and its Influence on Current International Research on the Prediction of Psychoses]. AB - The early detection of psychoses has become increasingly relevant in research and clinic. Next to the ultra-high risk (UHR) approach that targets an immediate risk of developing frank psychosis, the basic symptom approach that targets the earliest possible detection of the developing disorder is being increasingly used worldwide. The present review gives an introduction to the development and basic assumptions of the basic symptom concept, summarizes the results of studies on the specificity of basic symptoms for psychoses in different age groups as well as on studies of their psychosis-predictive value, and gives an outlook on future results. Moreover, a brief introduction to first recent imaging studies is given that supports one of the main assumptions of the basic symptom concept, i. e., that basic symptoms are the most immediate phenomenological expression of the cerebral aberrations underlying the development of psychosis. From this, it is concluded that basic symptoms might be able to provide important information on future neurobiological research on the etiopathology of psychoses. PMID- 27951608 TI - ? PMID- 27951607 TI - [Chronic Inflammatory Demyelinating Polyneuropathy]. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic progressive or relapsing autoimmune neuropathy with heterogeneous clinical presentation. Symptoms typically include symmetrical, proximal and/or distal paresis and sensory loss. Atypical CIDP variants are increasingly recognized, including subtypes with rapid onset as well as variants with pure sensory, focal or marked asymmetrical deficits. Diagnosis is established by compatible symptoms, characteristic electrophysiological features and cerebrospinal fluid analysis. In unequivocal cases, inflammatory infiltrates in sural nerve biopsy support the diagnosis. Recent studies suggest that diagnostic imaging techniques such as MRI and nerve ultrasound may become useful tools for establishing the diagnosis. First-line therapies include immunoglobulines, steroids, and plasmapheresis. Immunosuppressant agents and monoclonal antibodies are used in therapy-refractory cases or as cortison-saving agents. PMID- 27951609 TI - ? PMID- 27951612 TI - Clinical Management of Endometriosis. PMID- 27951611 TI - Clinical implications of low grade dysplasia found during inflammatory bowel disease surveillance: a retrospective study comparing chromoendoscopy and white light endoscopy. AB - Background and study aims Current guidelines recommend the use of pancolonic chromoendoscopy for surveillance of patients with inflammatory bowel disease (IBD). It is currently unknown whether low grade dysplasia (LGD) found using chromoendoscopy carries a similar risk of high grade dysplasia (HGD) or colorectal cancer (CRC) compared with LGD detected using white-light endoscopy (WLE). The aim of this study was to compare the risk of advanced neoplasia, a combined endpoint of HGD and CRC, during follow-up after detection of lesions containing LGD identified with either chromoendoscopy or WLE. Patients and methods A retrospective cohort was established to identify patients who underwent IBD surveillance for ulcerative colitis or colonic Crohn's disease between 2000 and 2014. Subgroups were identified, based on the endoscopic technique (standard definition resolution WLE, high definition resolution WLE or chromoendoscopy). LGD detected in random biopsies was considered invisible LGD. Patients were followed until detection of advanced neoplasia, colectomy, death, or the last known surveillance colonoscopy. Results Of 1065 patients undergoing IBD surveillance, 159 patients underwent follow-up for LGD, which was visible in 133 cases and invisible in 26 cases. On follow-up, five cases of HGD and five cases of CRC were detected. The overall incidence rate of advanced neoplasia was 1.34 per 100 patient-years with a median follow-up of 4.7 years and a median time to advanced neoplasia of 3.3 years. There were no significant differences in the incidence of advanced neoplasia between chromoendoscopy-detected and WLE-detected LGD. Conclusion Advanced neoplasia was found to develop infrequently after detection of LGD in patients undergoing endoscopic surveillance for IBD. LGD lesions detected with either chromoendoscopy or WLE carry similar risks of advanced neoplasia over time. PMID- 27951610 TI - Elipse, the first procedureless gastric balloon for weight loss: a prospective, observational, open-label, multicenter study. AB - Background and study aims Conventional gastric balloons for weight loss require endoscopy for placement and removal. The Elipse device is swallowed, resides in the stomach for 4 months, and is then expelled. The objectives of this study were to assess the safety of Elipse and to measure its effects on weight loss, metabolic parameters, and quality of life. Methods Each participant swallowed one Elipse device, which was filled with 550 mL of filling fluid through a thin delivery catheter that was then removed. Weight was measured every 2 weeks, and metabolic parameters and quality of life were assessed at baseline and at trial exit. Results 34 patients, with a mean body mass index of 34.8 kg/m2, were enrolled. All 34 patients successfully swallowed the Elipse device. All adverse events were either self-limiting or resolved with medication. All balloons were safely excreted. At 4 months, the mean percent total body weight loss was 10 %. Mean waist circumference was reduced by 8.4 cm. Improvements were also seen in hemoglobin A1c, triglycerides, low density lipoprotein, and blood pressure. At trial exit, quality of life measures had improved across all domains. Conclusion These results demonstrate clinically significant weight loss with the Elipse, the first procedureless gastric balloon. The weight loss was similar to that seen in previous studies of endoscopically placed balloons. In addition, Elipse therapy led to improvements in waist circumference, several metabolic parameters, and overall quality of life.ClinicalTrials.gov identifier: NCT 02802007. PMID- 27951613 TI - Strategies for Management of Colorectal Endometriosis. AB - Endometriosis has clearly three distinct clinical presentations and deep endometriosis, especially compromising the rectosigmoid is probably the most concerning one for both patients and surgeons. Currently, with the available tools, it is mandatory to have a precise diagnostic of this type of disease prior to indication of treatment. Strategies to manage this form of endometriosis will take into account several involved aspects, such as age of the patient, reproductive desire or infertility, clinical symptoms, as well as the extension and localization of the disease. Treatment could vary from more conservative to more radical depending on those aspects. As we pointed out in this article, the key to manage colorectal endometriosis is to start with a good diagnosis. Knowing exactly what is the extension and localization of the disease and knowing the patient's wishes as well as the clinical complaints, surgeons are able to define the best option for each patient. Critical points should always be discussed; for example, patients chosen to have clinical treatment should be aware of important issues regarding the follow-up, while patients undergoing surgery must be advised about all surgical possibilities and related complications. PMID- 27951614 TI - Nerve Sparing and Surgery for Deep Infiltrating Endometriosis: Pessimism of the Intellect or Optimism of the Will. AB - Nerve-sparing surgery is an emerging technique for surgery-related dysfunction. Within the past 15 years, an essential progress in recognition and understanding of the anatomy of the pelvic autonomous nervous system has been made. Surgical preservation of vegetative nerves has become well known in many cancer centers. The technique has led to improvement of the quality of life following oncologic radical procedures. Positive results have led to the adoption of such techniques in the surgical treatment of deep infiltrating endometriosis in an aim to prevent urinary, rectal, and sexual dysfunction. Even though nerve-sparing excision of endometriosis is feasible and offers good outcomes in terms of bladder morbidity; digestive and sexual functions seem to be more complex to assess. Moreover, functional impairment in deep infiltrating endometriosis may preexist prior to surgery and function may not be restored despite nerve preservation. In cases where endometriosis lesions are deeply embedded in the parametrium, nerve-sparing techniques may only be feasible in those with a unilateral involvement. The nerve sparing surgical approach is therefore a safer radical surgery in the hands of experienced surgeons that has to be tailored to the unique nature of deep infiltrating endometriosis and balanced between the natural aggressiveness of such a debilitating disease and postoperative morbidity. Good knowledge of pelvic nerve anatomy and function allows understanding of related symptoms to reduce morbidity, whenever this goal is still achievable. PMID- 27951616 TI - ? PMID- 27951615 TI - Endoscopic Management of Spinal Intradural Extramedullary Tumors. AB - Introduction Posterior midline laminectomy is associated with risks of postoperative instability, spinal deformity, extensive bilateral subperiosteal muscle stripping, partial or total facetectomy especially in foraminal tumor extension, increased cerebrospinal fluid leakage, and wound infection. Minimally invasive approaches with the help of a microscope or endoscope using hemilaminectomy have been found to be safe and effective. We report our initial experience of 18 patients using the endoscopic technique. Material and Methods A retrospective study of intradural extramedullary tumors extending up to two vertebral levels was studied. Pre- and postoperative clinical status, magnetic resonance imaging was done in all patients. The Destandau technique was used, and resection of ipsilateral lamina, medial part of the facet joint, base of the spinous process, and undercutting of the opposite lamina was performed. Dura repair was done using an endoscopic technique. Fibrin glue was used to reinforce repair in the later part of the study. Results The sagittal and axial diameter of tumor ranged from 21 to 41 mm and 12 to 18 mm, respectively. There were four cervical, two cervicothoracic, five thoracic, three thoracolumbar, and four lumbar tumors, respectively. All 18 patients improved after total excision of tumor. Average duration of surgery and blood loss was 140 minutes and 60 mL, respectively. Postoperative stay and follow-up ranged from 3 to 7 days and 9 to 24 months, respectively. Conclusion Although the study is limited by the small number of patients with a short follow-up and is a technically demanding procedure, endoscopic management of intradural extramedullary tumors was an effective and safe alternative technique to microsurgery in such patients. PMID- 27951617 TI - ? PMID- 27951618 TI - [Management and Prevention of Complications in HPB Surgery]. PMID- 27951619 TI - ["STeP" ("Students Teaching Patients"): Medical Students Following up on Informed Consent Discussions. Results of a Methodological Change and Further Considerations]. AB - Background: Literature shows an increasing number of reports on the incompleteness of informed consent discussions held by residents. Residents feel insecure and not adequately prepared for this task. This project aimed to integrate supervised informed consent discussions into the medical curriculum, working with "real" patients instead of other students or actors. Method: "STeP" ("Students Teaching Patients") is a teaching format which has been recently introduced at the University of Magdeburg. Initially, a certified physician prepares medical students for taking informed consent. Using standard questionnaires, students interview patients who have given consent, following up on what patients recall from the informed consent discussion. Afterwards the results are reported to the physician, who then checks back with the patient that there are no new or unanswered questions. In this part of the project, the original process was changed in that a group of patients was interviewed twice to evaluate whether students were able to increase patients' knowledge. Results: Although all students taking part in this study had already completed the surgery course, they were not sufficiently aware of the most relevant complications of laparoscopic cholecystectomy. Also it was difficult for informed patients to render the consequences and complications resulting from such a procedure. Randomly chosen patients recalled only one possible complication on average, although they had signed the informed consent form. Most of them could not explain the effects of a lesion of the bile duct. Although those patients who had been interviewed twice recalled more complications than those who had been interviewed only once, patients generally did not like to be interviewed twice, which caused us to discontinue this part of the project. Conclusions: Based on the analysis of the limitations of this method of repeated interviews, we now plan to perform STeP as a "student consultation" before the physician takes informed consent, with students reflecting their own consultation. Increase in knowledge and patient satisfaction will be measured postoperatively by the students. The results of this project are pending. PMID- 27951620 TI - ["SteP" ("Students Teaching Patients"): Medical Students Following up on Informed Consent Discussions. Results of a Methodological Change and Further Considerations]. PMID- 27951621 TI - Qualitative and quantitative results of interferon-gamma release assays for monitoring the response to anti-tuberculosis treatment. AB - BACKGROUND/AIMS: The usefulness of interferon-gamma release assays (IGRAs) in monitoring to responses to anti-tuberculosis (TB) treatment is controversial. We compared the results of two IGRAs before and after anti-TB treatment in same patients with active TB. METHODS: From a retrospective review, we selected patients with active TB who underwent repeated QuantiFERON-TB Gold (QFN-Gold, Cellestis Limited) and T-SPOT.TB (Oxford Immunotec) assays before and after anti TB treatment with first-line drugs. Both tests were performed prior to the start of anti-TB treatment or within 1 week after the start of anti-TB treatment and after completion of treatment. RESULTS: A total of 33 active TB patients were included in the study. On the QFN-Gold test, at baseline, 23 cases (70%) were early secreted antigenic target 6-kDa protein 6 (ESAT-6) or culture filtrate protein 10 (CFP-10) positive. On the T-SPOT. TB test, at baseline, 31 cases (94%) were ESAT-6 or CFP-10 positive. Most of patients remained both test-positive after anti-TB treatment. Although changes in interferon-gamma release responses over time were highly variable in both tests, there was a mean decline of 27 and 24 spot-forming counts for ESAT-6 and CFP-10, respectively on the T-SPOT.TB test (p < 0.05 for all). CONCLUSIONS: Although limited by the small number of patients and a short-term follow-up, there was significant decline in the quantitative result of the T-SPOT. TB test with treatment. However, both commercial IGRAs may not provide evidence regarding the cure of disease in Korea, a country where the prevalence of TB is within the intermediate range. PMID- 27951622 TI - Analysis of computed tomographic findings according to gastroesophageal flap valve grade. AB - BACKGROUND/AIMS: The gastroesophageal junction is an important barrier against gastroesophageal ref lux. Endoscopic grading of gastroesophageal f lap valve is simple, reproducible, and may predict reflux activity. We investigated the correlation between gastroesophageal flap valve grade and the gastroesophageal junction's structural properties using abdominal computed tomography. METHODS: A total of 138 patients with early gastric cancer who underwent both pre-treatment esophagogastroduodenoscopy and water-distended stomach two-phase computed tomography were enrolled. Endoscopic gastroesophageal f lap valve grade and abdominal computed tomography findings were analyzed to assess anatomical factors including the gastroesophageal junction and related organs. RESULTS: The angle of His increased significantly with gastroesophageal flap valve grade (grade I, 65.2 +/- 19.6; grade II, 66.6 +/- 19.8; grade III, 76.7 +/- 11.9; grade IV, 120.0 +/- 30.3; p < 0.001), as did the size of the diaphragmatic hiatus (grade I, 213.0 +/- 53.8 mm2 ; grade II, 232.6 +/- 71.0 mm2 ; grade III, 292.3 +/- 99.2 mm2 ; grade IV, 584.4 +/- 268.3; p < 0.001). The length of the abdominal esophagus decreased as gastroesophageal flap valve grade increased (grade I, 34.6 +/- 5.8 mm; grade II, 32.0 +/- 6.5 mm; grade III, 24.6 +/- 7.8 mm; grade IV, -22.6 +/- 38.2 mm; p < 0.001). There was no significant relationship between gastroesophageal flap valve grade and visceral and subcutaneous fat areas (p = 0.877 and p = 0.508, respectively). CONCLUSIONS: Endoscopic grading of the gastroesophageal flap valve is well correlated with anatomical changes around the gastroesophageal junction on abdominal computed tomography, and it can provide useful information about the anti-reflux barrier. PMID- 27951624 TI - Postoperative radiotherapy appeared to improve the disease free survival rate of patients with extrahepatic bile duct cancer at high risk of loco-regional recurrence. AB - PURPOSE: To investigate the outcomes of postoperative radiotherapy (RT), in patients with extrahepatic bile duct (EHBD) cancer by comparing the survival rate between patients undergoing surgery alone or surgery plus postoperative RT, and to identify the prognostic factors affecting survival. MATERIALS AND METHODS: Between 2000 and 2013, 52 patients with EHBD cancer underwent surgical resection. Of these, 33 patients did not receive postoperative RT (group I), and 19 patients did (group II). R1 resection was significantly more frequent in group II. The median radiation dose was 5,040 cGy. RESULTS: The 3-year overall survival (OS) rate for group I and group II was 38% and 56%, respectively (p = 0.274). The 3 year disease free survival (DFS) rate for group I and group II was 20% and 31%, respectively (p = 0.049), and the 3-year loco-regional recurrence free survival (LRFS) rates were 19% and 58%, respectively (p = 0.002). Multivariate analyses showed that postoperative RT and lymphovascular invasion were independent prognostic factors for DFS and LRFS. Overall, 42 patients (80%) experienced treatment failure. Distant metastasis was the predominant pattern of failure in group II. CONCLUSION: Postoperative RT after surgical resection appeared to improve the loco-regional control and DFS rate. More effort is needed to reduce distant metastasis, the major pattern of failure, in patients who receive postoperative RT. PMID- 27951623 TI - Clinical significance of positive Pneumocystis jirovecii polymerase chain reaction in non-human immunodeficiency virus immunocompromised patients in a real practice. AB - BACKGROUND/AIMS: Pneumocystis jirovecii polymerase chain reaction (PCR) can be helpful in diagnosing Pneumocystis pneumonia (PCP); however it has limitations. We evaluated the prevalence of positive P. jirovecii PCR from non-human immunodeficiency virus (HIV) immunocompromised patients and tried to determine the risk of PCP development. METHODS: Between May 2009 and September 2012, P. jirovecii PCR was performed in bronchoscopic specimens from 1,231 adult non-HIV immunocompromised patients suspected of respiratory infection. Only 169 patients (13.7%) who were tested positive for P. jirovecii PCR were enrolled. Retrospective chart review was performed. PCP was defined in patients with positive P. jirovecii PCR who were treated for PCP based on the clinical decision. RESULTS: From 169 P. jirovecii PCR-positive patients, 90 patients were in the PCP group (53.3%) and 79 patients were in the non-PCP group (46.7%). In the PCP group, 38% of patients expired or aggravated after therapy, whereas the majority of patients (84%) in the non-PCP group recovered without treatment for PCP. Independent risk factors for PCP by binary logistic regression analysis were underlying conditions- hematological malignancies, solid tumors or solid organ transplantation, dyspnea, age < 60 years, and albumin < 2.9 g/dL. CONCLUSIONS: This study suggests that not all P. jirovecii PCR-positive patients need to be treated for PCP. Among P. jirovecii PCR-positive patients, those who are less than 60 years old, with hematological malignancies, solid tumors or solid organ transplantation, low albumin, and with symptoms of dyspnea, the possibility of PCP might be higher. Treatment should also be selected to these patients. PMID- 27951625 TI - Dosimetric comparison of intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) in total scalp irradiation: a single institutional experience. AB - PURPOSE: Total scalp irradiation (TSI) is a rare but challenging indication. We previously reported that non-coplanar intensity-modulated radiotherapy (IMRT) was superior to coplanar IMRT in organ-at-risk (OAR) protection and target dose distribution. This consecutive treatment planning study compared IMRT with volumetric-modulated arc therapy (VMAT). MATERIALS AND METHODS: A retrospective treatment plan databank search was performed and 5 patient cases were randomly selected. Cranial imaging was restored from the initial planning computed tomography (CT) and target volumes and OAR were redelineated. For each patients, three treatment plans were calculated (coplanar/non-coplanar IMRT, VMAT; prescribed dose 50 Gy, single dose 2 Gy). Conformity, homogeneity and dose volume histograms were used for plan. RESULTS: VMAT featured the lowest monitor units and the sharpest dose gradient (1.6 Gy/mm). Planning target volume (PTV) coverage and homogeneity was better in VMAT (coverage, 0.95; homogeneity index [HI], 0.118) compared to IMRT (coverage, 0.94; HI, 0.119) but coplanar IMRT produced the most conformal plans (conformity index [CI], 0.43). Minimum PTV dose range was 66.8% -88.4% in coplanar, 77.5%-88.2% in non-coplanar IMRT and 82.8%-90.3% in VMAT. Mean dose to the brain, brain stem, optic system (maximum dose) and lenses were 18.6, 13.2, 9.1, and 5.2 Gy for VMAT, 21.9, 13.4, 14.5, and 6.3 Gy for non coplanar and 22.8, 16.5, 11.5, and 5.9 Gy for coplanar IMRT. Maximum optic chiasm dose was 7.7, 8.4, and 11.1 Gy (non-coplanar IMRT, VMAT, and coplanar IMRT). CONCLUSION: Target coverage, homogeneity and OAR protection, was slightly superior in VMAT plans which also produced the sharpest dose gradient towards healthy tissue. PMID- 27951626 TI - Diagnostic role of mean platelet volume and neutrophil to lymphocyte ratio in childhood brucellosis. AB - BACKGROUND/AIMS: Brucellosis patients present various non-specific clinical symptoms, such as fever, fatigue, sweating, joint pain, arthritis, myalgia, and headache. Based on the nonspecifity of its clinical signs and symtoms, we decided to evaluate whether mean platelet volume (MPV) , neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) will contribute to the diagnosis. METHODS: In this retrospective study, we reviewed hospital-records of 60 children with a confirmed diagnosis of brucellosis in Kayseri between January 2013 and January 2016, and compared the hematological parameters; white blood cell (WBC) count, hemoglobin (Hb), neutrophil count, lymphocyte count, platelet count, MPV, NLR, and PLR with 55 healthy age and gender matched children. Also, the well known inf lammation markers; erytrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were compared between the patient and control group. RESULTS: We found significant difference among the Hb, platelet count, MPV and NLR values between the patient and control group (p < 0.05). There was no difference between WBC, neutrophil count, lymphocyte count and PLR between the patient and control group (p > 0.05). When the patients were divided into groups as arthritis positive and arthritis negative and compared to the control group; we found that the NLR is more significant in between the arthritis positive and control group (p = 0.013). Also, we found significant difference among the ESR and CRP values between the patient and control group (p < 0.001). CONCLUSIONS: The results of this study indicates that MPV and NLR values can be used as markers of inflammation in childhood brucellosis. Also, NLR is more valuable in children with brucella arthritis. PMID- 27951627 TI - Primary Care Physicians' Action Plans for Responding to Results of Screening Tests Based on the Concept of Quaternary Prevention. AB - Since noncommunicable diseases (NCDs) are generally controllable rather than curable, more emphasis is placed on prevention than on treatment. For the early detection of diseases, primary care physicians (PCPs), as well as general practitioners and family physicians, should interpret screening results accurately and provide screenees with appropriate information about prevention and treatment, including potential harms. The concept of quaternary prevention (QP), which was introduced by Jamoulle and Roland in 1995, has been applied to screening results. This article summarizes situations that PCPs encounter during screening tests according to the concept of QP, and suggests measures to face such situations. It is suggested that screening tests be customized to fit individual characteristics instead of being performed based on general guidelines. Since screening tests should not be carried out in some circumstances, further studies based on the concept of prevention levels proposed by Jamoulle and Roland are required for the development of strategies to prevent NCDs, including cancers. Thus, applying the concept of QP helps PCPs gain better insights into screening tests aimed at preventing NCDs and also helps improve the doctor-patient relationship by helping screenees understand medical uncertainties. PMID- 27951630 TI - The Relationship Between Job Stress, Job Satisfaction, and the Symptom Checklist 90-Revision (SCL-90-R) in Marine Officers on Board. AB - OBJECTIVES: This study was conducted to investigate the relationships among job stress, job satisfaction, and mental health in marine officers. METHODS: The researchers gathered data on marine officers working at a harbor in Chungcheong Province, South Korea, using a self-reported questionnaire. Mental health was measured by the Symptom Checklist-90-Revision (SCL-90-R), and general characteristics including socioeconomic factors, job stress, and job satisfaction were measured by structured questionnaires. Multiple regression analysis was performed to investigate the relationships among job stress, job satisfaction, and mental health status according to the symptom dimensions of the SCL-90-R. RESULTS: Among the marine officers, obsessive-compulsive behavior, depression, and somatization were the most problematic symptoms. Those who reported poor health, low job satisfaction, and high job stress had a higher prevalence of psychoticism, somatization, depression, anxiety, and phobic anxiety. CONCLUSIONS: An occupational health system should be introduced that would regularly check the mental health of marine officers in charge of ships and sailors, in order to help reduce their stress levels, enhance their job satisfaction, and thereby improve their mental health. PMID- 27951628 TI - The Effect of Breastfeeding Duration and Parity on the Risk of Epithelial Ovarian Cancer: A Systematic Review and Meta-analysis. AB - OBJECTIVES: We conducted a systematic review and meta-analysis to summarize current evidence regarding the association of parity and duration of breastfeeding with the risk of epithelial ovarian cancer (EOC). METHODS: A systematic search of relevant studies published by December 31, 2015 was performed in PubMed and EMBASE. A random-effect model was used to obtain the summary relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: Thirty two studies had parity categories of 1, 2, and >=3. The summary RRs for EOC were 0.72 (95% CI, 0.65 to 0.79), 0.57 (95% CI, 0.49 to 0.65), and 0.46 (95% CI, 0.41 to 0.52), respectively. Small to moderate heterogeneity was observed for one birth (p<0.01; Q=59.46; I2=47.9%). Fifteen studies had breastfeeding categories of <6 months, 6-12 months, and >13 months. The summary RRs were 0.79 (95% CI, 0.72 to 0.87), 0.72 (95% CI, 0.64 to 0.81), and 0.67 (95% CI, 0.56 to 0.79), respectively. Only small heterogeneity was observed for <6 months of breastfeeding (p=0.17; Q=18.79, I2=25.5%). Compared to nulliparous women with no history of breastfeeding, the joint effects of two births and <6 months of breastfeeding resulted in a 0.5-fold reduced risk for EOC. CONCLUSIONS: The first birth and breastfeeding for <6 months were associated with significant reductions in EOC risk. PMID- 27951629 TI - Breast Density and Risk of Breast Cancer in Asian Women: A Meta-analysis of Observational Studies. AB - OBJECTIVES: The established theory that breast density is an independent predictor of breast cancer risk is based on studies targeting white women in the West. More Asian women than Western women have dense breasts, but the incidence of breast cancer is lower among Asian women. This meta-analysis investigated the association between breast density in mammography and breast cancer risk in Asian women. METHODS: PubMed and Scopus were searched, and the final date of publication was set as December 31, 2015. The effect size in each article was calculated using the interval-collapse method. Summary effect sizes (sESs) and 95% confidence intervals (CIs) were calculated by conducting a meta-analysis applying a random effect model. To investigate the dose-response relationship, random effect dose-response meta-regression (RE-DRMR) was conducted. RESULTS: Six analytical epidemiology studies in total were selected, including one cohort study and five case-control studies. A total of 17 datasets were constructed by type of breast density index and menopausal status. In analyzing the subgroups of premenopausal vs. postmenopausal women, the percent density (PD) index was confirmed to be associated with a significantly elevated risk for breast cancer (sES, 2.21; 95% CI, 1.52 to 3.21; I2=50.0%). The RE-DRMR results showed that the risk of breast cancer increased 1.73 times for each 25% increase in PD in postmenopausal women (95% CI, 1.20 to 2.47). CONCLUSIONS: In Asian women, breast cancer risk increased with breast density measured using the PD index, regardless of menopausal status. We propose the further development of a breast cancer risk prediction model based on the application of PD in Asian women. PMID- 27951631 TI - A Qualitative Inquiry Into the Challenges of Medical Education for Retention of General Practitioners in Rural and Underserved Areas of Iran. AB - OBJECTIVES: General practitioners (GPs) retention in rural and underserved areas highly effects on accessibility of healthcare facilities across the country. Education seems to be a critical factor that affects GPs retention. Thus, the present study aimed at inquiry into medical education challenges that limit their retention in rural and underserved areas. METHODS: A qualitative approach was applied for the aim of this study. Data were gathered via 28 semi-structured interviews with experts at different levels of Iran's health system as well as GPs who retained and refused to retain working in rural settings. Interviews mainly were performed face-to-face and in some cases via telephone during 2015 and then coded and analyzed using content analysis approach. RESULTS: Iran's medical education is faced with several challenges that were categorized in four main themes including student selection, medical students' perception about their field of study, education setting and approach, curriculum of medical education. According to experts this challenges could results in making GP graduates disinterested for practicing in rural and underserved areas. CONCLUSIONS: Challenges that were found could have negative effects on retention. Modification in student's perception about rural practice could be done via changing education setting and approach and curriculum. These modifications could improve GPs retention in rural and underserved areas. PMID- 27951632 TI - Effects of Antiretroviral Therapy on the Survival of Human Immunodeficiency Virus positive Adult Patients in Andhra Pradesh, India: A Retrospective Cohort Study, 2007-2013. AB - OBJECTIVES: The survival outcomes of antiretroviral treatment (ART) programs have not been systematically evaluated at the state level in India. This retrospective study assessed the survival rates and factors associated with survival among adult human immunodeficiency virus (HIV)-infected patients in Andhra Pradesh, India. METHODS: The present study used data from 139 679 HIV patients aged >=15 years on ART who were registered from 2007 to 2011 and were followed up through December 2013. The primary end point was death of the patient. Mortality densities (per 1000 person-years) were calculated. Kaplan-Meier and Cox regression models were used to estimate survival and explore the factors associated with survival. RESULTS: The overall median follow-up time was 16.0 months (2.0 months for the deceased and 14.0 months for those lost to follow-up). Approximately 13.2% of those newly initiated on ART died during follow-up. Of those deaths, 56% occurred in the first three months. The crude mortality rate was 80.9 per 1000 person-years at risk. The CD4 count (adjusted hazard ratio [aHR],4.88; 95% confidence interval [CI], 4.36 to 5.46 for <100 cells/mm3 vs. >350 cells/mm3), functional status (aHR, 3.05; 95% CI, 2.82 to 3.30 for bedridden vs. normal), and body weight (aHR, 3.69; 95% CI, 3.42 to 3.97 for <45 kg vs. >60 kg) were strongly associated with the survival of HIV patients. CONCLUSIONS: The study findings revealed that high mortality was observed within the first three months of ART initiation. Patients with poor baseline clinical characteristics had a higher risk of mortality. Expanded testing and counseling should be encouraged, with the goal of ensuring early enrollment into the program followed by the initiation of ART in HIV-infected patients. PMID- 27951634 TI - Structure-Kinetic Relationships of Passive Membrane Permeation from Multiscale Modeling. AB - Passive membrane permeation of small molecules is essential to achieve the required absorption, distribution, metabolism, and excretion (ADME) profiles of drug candidates, in particular intestinal absorption and transport across the blood-brain barrier. Computational investigations of this process typically involve either building QSAR models or performing free energy calculations of the permeation event. Although insightful, these methods rarely bridge the gap between computation and experiment in a quantitative manner, and identifying structural insights to apply toward the design of compounds with improved permeability can be difficult. In this work, we combine molecular dynamics simulations capturing the kinetic steps of permeation at the atomistic level with a dynamic mechanistic model describing permeation at the in vitro level, finding a high level of agreement with experimental permeation measurements. Calculation of the kinetic rate constants determining each step in the permeation event allows derivation of structure-kinetic relationships of permeation. We use these relationships to probe the structural determinants of membrane permeation, finding that the desolvation/loss of hydrogen bonding required to leave the membrane partitioned position controls the membrane flip-flop rate, whereas membrane partitioning determines the rate of leaving the membrane. PMID- 27951633 TI - Light Harvesting for Organic Photovoltaics. AB - The field of organic photovoltaics has developed rapidly over the last 2 decades, and small solar cells with power conversion efficiencies of 13% have been demonstrated. Light absorbed in the organic layers forms tightly bound excitons that are split into free electrons and holes using heterojunctions of electron donor and acceptor materials, which are then extracted at electrodes to give useful electrical power. This review gives a concise description of the fundamental processes in photovoltaic devices, with the main emphasis on the characterization of energy transfer and its role in dictating device architecture, including multilayer planar heterojunctions, and on the factors that impact free carrier generation from dissociated excitons. We briefly discuss harvesting of triplet excitons, which now attracts substantial interest when used in conjunction with singlet fission. Finally, we introduce the techniques used by researchers for characterization and engineering of bulk heterojunctions to realize large photocurrents, and examine the formed morphology in three prototypical blends. PMID- 27951636 TI - Adjuvant Activity Enhanced by Cross-Linked CpG-Oligonucleotides in beta-Glucan Nanogel and Its Antitumor Effect. AB - Cancer vaccine has the ability to directly eradicate tumor cells by creating and activating cytotoxic T lymphocytes (CTLs). To achieve efficient CTL activity and to induce Th1 responses, it is essential to administer an appropriate adjuvant as well as an antigen. CpG-ODN is known as a ligand of Toll-like receptor 9 (TLR9) and strongly induces Th1 responses. In our previous study, we developed a CpG-ODN delivery system by use of the formation of complexes between ODN and a beta glucan SPG, denoted as CpG/SPG, and demonstrated that CpG/SPG induces high Th1 responses. In this study, we created a nanogel made from CpG/SPG complexes through DNA-DNA hybridization (cross-linked (CL)-CpG). Immunization with CL-CpG induced much stronger antigen-specific Th1 responses in combination with the antigenic protein ovalbumin (OVA) than that with CpG/SPG. Mice preimmunized with CL-CpG and OVA exhibited a long delay in tumor growth and an improved survival rate after tumor inoculation. These immune inductions can be attributed to the improvement of cellular uptake by the combination of increased size and the cluster effect of the beta-glucan recognition site in the nanogel structure. In other words, the particle nature of CL-CpG, instead of the semiflexible rod conformation of CpG/SPG, enhanced the efficacy of a cancer vaccine. The present results indicate that CL-CpG can be used as a potent vaccine adjuvant for the treatment of cancers and infectious diseases. PMID- 27951635 TI - Mutagenicity of a Model DNA-Peptide Cross-Link in Human Cells: Roles of Translesion Synthesis DNA Polymerases. AB - DNA-protein cross-links are formed upon exposure of cellular DNA to various agents, including antitumor drugs, UV light, transition metals, and reactive oxygen species. They are thought to contribute to cancer, aging, and neurodegenerative diseases. It has been proposed that DNA-protein cross-links formed in cells are subject to proteolytic degradation to the corresponding DNA peptide cross-links (DpCs). To investigate the effects of DpCs on DNA replication, we have constructed plasmid DNA containing a 10-mer Myc peptide covalently linked to C7 of 7-deaza-dG, a hydrolytically stable mimic of N7-dG lesions. Following transfection in human embryonic kidney cells (HEK 293T), progeny plasmids were recovered and sequenced. Translesion synthesis (TLS) past DpC was 76% compared to that of the unmodified control. The DpC induced 20% targeted G -> A and G -> T plus 15% semitargeted mutations, notably at a guanine (G5) five bases 3' to the lesion site. Proteolytic digestion of the DpC reduced the mutation frequency considerably, indicating that the covalently attached 10 mer peptide was responsible for the observed mutations. TLS efficiency and targeted mutations were reduced upon siRNA knockdown of pol eta, pol kappa, or pol zeta, indicating that they participate in error-prone bypass of the DpC lesion. However, the semitargeted mutation at G5 was only reduced upon knockdown of pol zeta, suggesting its critical role in this type of mutations. Our results indicate that DpCs formed at the N7 position of guanine can induce both targeted and semitargeted mutations in human cells and that the TLS polymerases play a critical role in their error-prone bypass. PMID- 27951638 TI - Structure of Chemisorbed CO(2) Species in Amine-Functionalized Mesoporous Silicas Studied by Solid-State NMR and Computer Modeling. AB - Two-dimensional (2D) solid-state nuclear magnetic resonance (SSNMR) experiments on samples loaded with 13C-labeled CO2, "under controlled partial pressures", have been performed in this work, revealing unprecedented structural details about the formation of CO2 adducts from its reaction with various amine functionalized SBA-15 containing amines having distinct steric hindrances (e.g., primary, secondary) and similar loadings. Three chemisorbed CO2 species were identified by NMR from distinct carbonyl environments resonating at deltaC ~ 153, 160, and 164 ppm. The newly reported chemisorbed CO2 species at deltaC ~ 153 ppm was found to be extremely moisture dependent. A comprehensive 1H-based SSNMR study [1D 1H and 2D 1H-X heteronuclear correlation (HETCOR, X = 13C, 29Si) experiments] was performed on samples subjected to different treatments. It was found that all chemisorbed CO2 species are involved in hydrogen bonds (HBs) with either surface silanols or neighboring alkylamines. 1H chemical shifts up to 11.8 ppm revealed that certain chemisorbed CO2 species are engaged in very strong HBs. We effectively demonstrate that NMR may help in discriminating among free and hydrogen-bonded functional groups. 13C{14N} dipolar-recoupling NMR showed that the formation of carbonate or bicarbonate is excluded. Density functional theory calculations on models of alkylamines grafted into the silica surface assisted the 1H/13C assignments and validated various HB arrangements that may occur upon formation of carbamic acid. This work extends the understanding of the chemisorbed CO2 structures that are formed upon bonding of CO2 with surface amines and readily released from the surface by pressure swing. PMID- 27951637 TI - Ligand-Enabled meta-Selective C-H Arylation of Nosyl-Protected Phenethylamines, Benzylamines, and 2-Aryl Anilines. AB - A Pd-catalyzed, meta-selective C-H arylation of nosyl-protected phenethylamines and benzylamines is disclosed using a combination of norbornene and pyridine based ligands. Subjecting nosyl protected 2-aryl anilines to this protocol led to meta-C-H arylation at the remote aryl ring. A diverse range of aryl iodides are tolerated in this reaction, along with select heteroaryl iodides. Select aryl bromides bearing ortho-coordinating groups can also be utilized as effective coupling partners in this reaction. The use of pyridine ligands has allowed the palladium loading to be reduced to 2.5 mol %. Furthermore, a catalytic amount of 2-norbornene (20 mol %) to mediate this meta-C-H activation process is demonstrated for the first time. Utilization of a common protecting group as the directing group for meta-C-H activation of amines is an important feature of this reaction in terms of practical applications. PMID- 27951639 TI - Using Mercury Isotopes To Understand Mercury Accumulation in the Montane Forest Floor of the Eastern Tibetan Plateau. AB - Mercury accumulation in montane forested areas plays an important role in global Hg cycling. In this study, we measured stable Hg isotopes in soil and litter samples to understand Hg accumulation on the forest floor along the eastern fringe of the Tibetan Plateau (TP). The low atmospheric Hg inputs lead to the small Hg pool size (23 +/- 9 mg m-2 in 0-60 cm soil horizon), up to 1 order of magnitude lower than those found at sites in Southwest China, North America, and Europe. The slightly negative Delta199Hg (-0.12 to -0.050/00) in the litter at low elevations (3100 to 3600 m) suggests an influence of local anthropogenic emissions, whereas the more significant negative Delta199Hg (-0.38 to -0.150/00) at high elevations (3700 to 4300 m) indicates impact from long-range transport. Hg input from litter is more important than wet deposition to Hg accumulation on the forest floor, as evidenced by the negative Delta199Hg found in the surface soil samples. Correlation analyses of Delta199Hg versus total carbon and leaf area index suggest that litter biomass production is a predominant factor in atmospheric Hg inputs to the forest floor. Precipitation and temperature show indirect effects on Hg accumulation by influencing litter biomass production in the eastern TP. PMID- 27951640 TI - Metabolomic Profiling as a Possible Reverse Engineering Tool for Estimating Processing Conditions of Dry-Cured Hams. AB - Dry-cured hams are popular among consumers. To increase the attractiveness of the product, objective analytical methods and algorithms to evaluate the relationship between observable properties and consumer acceptability are required. In this study, metabolomics, which is used for quantitative profiling of hundreds of small molecules, was applied to 12 kinds of dry-cured hams from Japan and Europe. In total, 203 charged metabolites, including amino acids, organic acids, nucleotides, and peptides, were successfully identified and quantified. Metabolite profiles were compared for the samples with different countries of origin and processing methods (e.g., smoking or use of a starter culture). Principal component analysis of the metabolite profiles with sensory properties revealed significant correlations for redness, homogeneity, and fat whiteness. This approach could be used to design new ham products by objective evaluation of various features. PMID- 27951642 TI - The Presentation of Olfactory-Trigeminal Mixed Stimuli Increases the Response to Subsequent Olfactory Stimuli. AB - The aim of this study was to evaluate the effect of (1) the addition of trigeminal stimuli to an olfactory stimulus and (2) the congruence in the odorous mixture after repeated odor presentation. Twenty-five normosmic volunteers were enrolled and presented stimulation blocks, consisting of three habituation stimuli (H) (orange odor), one dishabituation (DH) (control condition, orange odor; congruent condition, orange odor + CO2; incongruent condition, orange odor + l-isopulegol), and one dishabituated stimulus (D) (orange odor). Olfactory event-related potentials were analyzed. Response amplitudes differed significantly in the incongruent condition (N1P2 between H3 and D; peak to peak N1P2 at electrode positions Cz, Fz, and Pz; response amplitudes between H3 and DH). The addition of CO2 modified the perception of orange odor, pronouncing a fruity note, whereas the addition of l-isopulegol as a DH pronounced the l isopulegol note. This study provides evidence that incongruent trigeminal olfactory stimulants increase the response to subsequent olfactory stimulus. PMID- 27951641 TI - Aggregation, Sedimentation, Dissolution, and Bioavailability of Quantum Dots in Estuarine Systems. AB - To understand their fate and transport in estuarine systems, the aggregation, sedimentation, and dissolution of CdSe quantum dots (QDs) in seawater were investigated. Hydrodynamic size increased from 40 to 60 nm to >1 mm within 1 h in seawater, and the aggregates were highly polydispersed. Their sedimentation rates in seawater were measured to be 4-10 mm/day. Humic acid (HA), further increased their size and polydispersity, and slowed sedimentation. Light increased their dissolution and release of dissolved Cd. The ZnS shell also slowed release of Cd ions. With sufficient light, HA increased the dissolution of QDs, while with low light, HA alone did not change their dissolution. The benthic zone in estuarine systems is the most probable long-term destination of QDs due to aggregation and sedimentation. The bioavailability of was evaluated using the mysid Americamysis bahia. The 7-day LC50s of particulate and dissolved QDs were 290 and 23 MUg (total Cd)/L, respectively. For mysids, the acute toxicity appears to be from Cd ions; however, research on the effects of QDs should be conducted with other organisms where QDs may be lodged in critical tissues such as gills or filtering apparatus and Cd ions may be released and delivered directly to those tissues. PMID- 27951643 TI - Identification of Second Shell Coordination in Transition Metal Species Using Theoretical XANES: Example of Ti-O-(C, Si, Ge) Complexes. AB - X-ray absorption near-edge structure (XANES) is a common technique for elucidating oxidation state and first shell coordination geometry in transition metal complexes, among many other materials. However, the structural information obtained from XANES is often limited to the first coordination sphere. In this study, we show how XANES can be used to differentiate between C, Si, and Ge in the second coordination shell of Ti-O-(C, Si, Ge) molecular complexes based on differences in their Ti K-edge XANES spectra. Experimental spectra were compared with theoretical spectra calculated using density functional theory structural optimization and ab initio XANES calculations. The unique features for second shell C, Si, and Ge present in the Ti K pre-edge XANES are attributed to the interaction between the Ti center and the O-X (X = C, Si, or Ge) antibonding orbitals. PMID- 27951644 TI - Mechanism of Selective Nickel Transfer from HypB to HypA, Escherichia coli [NiFe] Hydrogenase Accessory Proteins. AB - [NiFe]-hydrogenase enzymes catalyze the reversible reduction of protons to molecular hydrogen and serve as a vital component of the metabolism of many pathogens. The synthesis of the bimetallic catalytic center requires a suite of accessory proteins, and the penultimate step, nickel insertion, is facilitated by the metallochaperones HypA and HypB. In Escherichia coli, nickel moves from a site in the GTPase domain of HypB to HypA in a process accelerated by GDP. To determine how the transfer of nickel is controlled, the impacts of HypA and nucleotides on the properties of HypB were examined. Integral to this work was His2Gln HypA, a mutant with attenuated nickel affinity that does not support hydrogenase production in E. coli. This mutation inhibits the translocation of nickel from HypB. H2Q-HypA does not modulate the apparent metal affinity of HypB, but the stoichiometry and stability of the HypB-nickel complex are modulated by the nucleotide. Furthermore, the HypA-HypB interaction was detected by gel filtration chromatography if HypB was loaded with GDP, but not a GTP analogue, and the protein complex dissociated upon binding of nickel to His2 of HypA. In contrast, a nucleotide does not modulate the binding of zinc to HypB, and loading zinc into the GTPase domain of HypB inhibits formation of the complex with HypA. These results demonstrate that GTP hydrolysis controls both metal binding and protein-protein interactions, conferring selective and directional nickel transfer during [NiFe]-hydrogenase biosynthesis. PMID- 27951645 TI - Observation of a Dynamic G-Tetrad Flip in Intramolecular G-Quadruplexes. AB - A MYC sequence forming an intramolecular G-quadruplex with a parallel topology was modified by the incorporation of 8-bromoguanosine (BrG) analogues in one of its outer G-tetrads. The propensity of the BrG analogues to adopt a syn glycosidic torsion angle results in an exceptional monomolecular quadruplex conformation featuring a complete flip of one tetrad while keeping a parallel orientation of all G-tracts as shown by circular dichroism and nuclear magnetic resonance spectroscopic studies. When substituting three of the four G-tetrad residues with BrG analogues, two coexisting quadruplex conformational isomers with an all-syn and all-anti outer G-quartet are approximately equally populated in solution. A dynamic interconversion of the two quadruplexes with an exchange rate (kex) of 0.2 s-1 is demonstrated through the observation of exchange crosspeaks in rotating frame Overhauser effect spectroscopy and nuclear Overhauser effect spectroscopy experiments at 50 degrees C. The kinetic properties suggest disruption of the corresponding outer G-tetrad but not of the whole quadruplex core during the tetrad flip. Conformational syn-anti isomers with homopolar and heteropolar stacking interactions are nearly isoenergetic with a transition enthalpy of 18.2 kJ/mol in favor of the all-syn isomer. PMID- 27951646 TI - Phe28B10 Induces Channel-Forming Cytotoxic Amyloid Fibrillation in Human Neuroglobin, the Brain-Specific Hemoglobin. AB - Since its discovery, neuroglobin (Ngb), a neuron-specific oxygen binding hemoglobin, distinct from the classical myoglobin and blood hemoglobin, has attracted attention as an endogenous neuroprotectant. Recent reports suggest that Ngb protects neurons from brain stroke, ischemic stress-induced degeneration, and other brain disorders. Proteins with a specific role in neuroprotection are often associated with neurodegeneration, as well, depending on the cellular environment or specific cellular triggers that tilt the balance one way or the other. This investigation explored the potential role of Ngb in amyloid fibril-related neuronal disorder. Ngb was capable of amyloid formation in vitro at neutral pH and ambient temperature, in both apo and holo forms, albeit at a slower rate in the holo form, unlike other hemoglobins that exhibit such behavior exclusively in the apo states. Elevated temperature enhanced the rate of fibril formation significantly. The B-helix, which is known to play a major role in Ngb ligand binding kinetics, was found to be amyloidogenic with the Phe28B10 amino acid side chain as the key inducer of fibrillation. The Ngb amyloid fibril was also significantly cytotoxic to neuroblastoma cell lines, compared to those obtained from reference hemoglobins. The Ngb fibril probably promoted toxicity by inducing channel formation in the cell membrane, as investigated here using synthetic lipid bilayer membranes and the propidium iodide uptake assay. These findings imply that Ngb plays a role in neurodegenerative disorders in vivo, for which there seems to be indirect evidence by association. Ngb thus presents a novel prospect for understanding amyloid-related brain disorders beyond the limited set of proteins currently investigated for such diseases. PMID- 27951648 TI - Insights into the Membrane Interacting Properties of the C-Terminal Domain of the Monotopic Glycosyltransferase DGD2 in Arabidopsis thaliana. AB - Glycosyltransferases (GTs) are responsible for regulating the membrane composition of plants. The synthesis of one of the main lipids in the membrane, the galactolipid digalactosyldiacylglycerol, is regulated by the enzyme digalactosyldiacylglycerol synthase 2 (atDGD2) under starving conditions, such as phosphate shortage. The enzyme belongs to the GT-B fold, characterized by two beta/alpha/beta Rossmann domains that are connected by a flexible linker. atDGD2 has previously been shown to attach to lipid membranes by the N-terminal domain via interactions with negatively charged lipids. The role of the C-terminal domain in the membrane interaction is, however, not known. Here we have used a combination of in silico prediction methods and biophysical experimental techniques to shed light on the membrane interacting properties of the C-terminal domain. Our results demonstrate that there is an amphipathic sequence, corresponding to residues V240-E258, that interacts with lipids in a charge dependent way. A second sequence was identified as being potentially important, with a high charge density, but no amphipathic character. The features of the plant atDGD2 observed here are similar in prokaryotic glycosyltransferases. On the basis of our results, and by analogy to other glycosyltransferases, we propose that atDGD2 interacts with the membrane through the N-terminus and with parts of the C-terminus acting as a switch, allowing for a dynamic interaction with the membrane. PMID- 27951649 TI - Crystal Structure of a Histone Deacetylase Homologue from Pseudomonas aeruginosa. AB - Despite the recently growing interest in the acetylation of lysine residues by prokaryotic enzymes, the underlying biological function is still not well understood. Deacetylation is accomplished by proteins that belong to the histone deacetylase (HDAC) superfamily. In this report, we present the first crystal structure of PA3774, a histone deacetylase homologue from the human pathogen Pseudomonas aeruginosa that shares a high degree of homology with class IIb HDACs. We determined the crystal structure of the ligand-free enzyme and protein ligand complexes with a trifluoromethylketone inhibitor and the reaction product acetate. Moreover, we produced loss of function mutants and determined the structure of the inhibitor-free PA3774H143A mutant, the inhibitor-free PA3774Y313F mutant, and the PA3774Y313F mutant in complex with the highly selective hydroxamate inhibitor PFSAHA. The overall structure reveals that the exceptionally long L1 loop mediates the formation of a tetramer composed of two "head-to-head" dimers. The distinctive dimer interface significantly confines the entrance area of the active site, suggesting a crucial role for substrate recognition and selectivity. PMID- 27951647 TI - The Escherichia coli BolA Protein IbaG Forms a Histidine-Ligated [2Fe-2S]-Bridged Complex with Grx4. AB - Two ubiquitous protein families have emerged as key players in iron metabolism, the CGFS-type monothiol glutaredoxins (Grxs) and the BolA proteins. Monothiol Grxs and BolA proteins form heterocomplexes that have been implicated in Fe-S cluster assembly and trafficking. The Escherichia coli genome encodes members of both of these proteins families, namely, the monothiol glutaredoxin Grx4 and two BolA family proteins, BolA and IbaG. Previous work has demonstrated that E. coli Grx4 and BolA interact as both apo and [2Fe-2S]-bridged heterodimers that are spectroscopically distinct from [2Fe-2S]-bridged Grx4 homodimers. However, the physical and functional interactions between Grx4 and IbaG are uncharacterized. Here we show that co-expression of Grx4 with IbaG yields a [2Fe-2S]-bridged Grx4 IbaG heterodimer. In vitro interaction studies indicate that IbaG binds the [2Fe 2S] Grx4 homodimer to form apo Grx4-IbaG heterodimer as well as the [2Fe-2S] Grx4 IbaG heterodimer, altering the cluster stability and coordination environment. Additionally, spectroscopic and mutagenesis studies provide evidence that IbaG ligates the Fe-S cluster via the conserved histidine that is present in all BolA proteins and by a second conserved histidine that is present in the H/C loop of two of the four classes of BolA proteins. These results suggest that IbaG may function in Fe-S cluster assembly and trafficking in E. coli as demonstrated for other BolA homologues that interact with monothiol Grxs. PMID- 27951650 TI - Incorporation of an Unnatural Amino Acid as a Domain-Specific Fluorescence Probe in a Two-Domain Protein. AB - The biophysical analysis of multidomain proteins often is difficult because of overlapping signals from the individual domains. Previously, the fluorescent unnatural amino acid p-cyanophenylalanine has been used to study the folding of small single-domain proteins. Here we extend its use to a two-domain protein to selectively analyze the folding of a specific domain within a multidomain protein. PMID- 27951651 TI - Kinetic Mechanism and Intrinsic Rate Constants for the Reaction of a Bacterial Phenylalanine Hydroxylase. AB - The pterin-dependent aromatic amino acid hydroxylases are non-heme iron enzymes that catalyze the hydroxylation of the aromatic side chain of their respective substrates using an FeIVO intermediate. While the eukaryotic enzymes are homotetramers with complex regulatory properties, bacterial phenylalanine hydroxylases are monomers that lack regulatory domains. As a result, the bacterial enzymes are more tractable for mechanistic studies. Using single turnover methods, the complete kinetic mechanism and intrinsic rate constants for Chromobacterium violaceum phenylalanine hydroxylase have been determined with both tetrahydrobiopterin and 6-methyltetrahyropterin as substrates. In addition the kinetics of formation of the enzyme-pterin complex have been determined with the unreactive 5-deaza, 6-methyltetrahydropterin. For all three pterins, binding of phenylalanine and pterin occurs in random order with binding of the pterin first the preferred pathway. The reaction of the ternary enzyme-phenylalanine tetrahydropterin complex can be described by a mechanism involving reversible oxygen binding, formation of an early intermediate preceding formation of the FeIVO, and rate-limiting product release. PMID- 27951652 TI - Multivalent Display of Antifreeze Proteins by Fusion to Self-Assembling Protein Cages Enhances Ice-Binding Activities. AB - Antifreeze proteins (AFPs) are small monomeric proteins that adsorb to the surface of ice to inhibit ice crystal growth and impart freeze resistance to the organisms producing them. Previously, monomeric AFPs have been conjugated to the termini of branched polymers to increase their activity through the simultaneous binding of more than one AFP to ice. Here, we describe a superior approach to increasing AFP activity through oligomerization that eliminates the need for conjugation reactions with varying levels of efficiency. A moderately active AFP from a fish and a hyperactive AFP from an Antarctic bacterium were genetically fused to the C-termini of one component of the 24-subunit protein cage T33-21, resulting in protein nanoparticles that multivalently display exactly 12 AFPs. The resulting nanoparticles exhibited freezing point depression >50-fold greater than that seen with the same concentration of monomeric AFP and a similar increase in the level of ice-recrystallization inhibition. These results support the anchored clathrate mechanism of binding of AFP to ice. The enhanced freezing point depression could be due to the difficulty of overgrowing a larger AFP on the ice surface and the improved ice-recrystallization inhibition to the ability of the nanoparticle to simultaneously bind multiple ice grains. Oligomerization of these proteins using self-assembling protein cages will be useful in a variety of biotechnology and cryobiology applications. PMID- 27951653 TI - Binding Properties of the Transforming Growth Factor-beta Coreceptor Betaglycan: Proposed Mechanism for Potentiation of Receptor Complex Assembly and Signaling. AB - Transforming growth factor (TGF) beta1, beta2, and beta3 (TGF-beta1-TGF-beta3, respectively) are small secreted signaling proteins that each signal through the TGF-beta type I and type II receptors (TbetaRI and TbetaRII, respectively). However, TGF-beta2, which is well-known to bind TbetaRII several hundred-fold more weakly than TGF-beta1 and TGF-beta3, has an additional requirement for betaglycan, a membrane-anchored nonsignaling receptor. Betaglycan has two domains that bind TGF-beta2 at independent sites, but how it binds TGF-beta2 to potentiate TbetaRII binding and how the complex with TGF-beta, TbetaRII, and betaglycan undergoes the transition to the signaling complex with TGF-beta, TbetaRII, and TbetaRI are not understood. To investigate the mechanism, the binding of the TGF-betas to the betaglycan extracellular domain, as well as its two independent binding domains, either directly or in combination with the TbetaRI and TbetaRII ectodomains, was studied using surface plasmon resonance, isothermal titration calorimetry, and size-exclusion chromatography. These studies show that betaglycan binds TGF-beta homodimers with a 1:1 stoichiometry in a manner that allows one molecule of TbetaRII to bind. These studies further show that betaglycan modestly potentiates the binding of TbetaRII and must be displaced to allow TbetaRI to bind. These findings suggest that betaglycan functions to bind and concentrate TGF-beta2 on the cell surface and thus promote the binding of TbetaRII by both membrane-localization effects and allostery. These studies further suggest that the transition to the signaling complex is mediated by the recruitment of TbetaRI, which simultaneously displaces betaglycan and stabilizes the bound TbetaRII by direct receptor-receptor contact. PMID- 27951654 TI - Interaction with the DNA Repair Protein Thymine DNA Glycosylase Regulates Histone Acetylation by p300. AB - How protein-protein interactions regulate and alter histone modifications is a major unanswered question in epigenetics. The histone acetyltransferase p300 binds thymine DNA glycosylase (TDG); utilizing mass spectrometry to measure site specific changes in histone acetylation, we found that the absence of TDG in mouse embryonic fibroblasts leads to a reduction in the rate of histone acetylation. We demonstrate that TDG interacts with the CH3 domain of p300 to allosterically promote p300 activity to specific lysines on histone H3 (K18 and K23). However, when TDG concentrations approach those of histones, TDG acts as a competitive inhibitor of p300 histone acetylation. These results suggest a mechanism for how histone acetylation is fine-tuned via interaction with other proteins, while also highlighting a connection between regulators of two important biological processes: histone acetylation and DNA repair/demethylation. PMID- 27951655 TI - A Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Binary Complex of Escherichia coli 6-Hydroxymethyl-7,8 dihydropterin Pyrophosphokinase with MgATP. AB - 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) catalyzes the first reaction in the folate biosynthetic pathway. Comparison of its X-ray and nuclear magnetic resonance structures suggests that the enzyme undergoes significant conformational change upon binding to its substrates, especially in three catalytic loops. Experimental research has shown that, in its binary form, even bound by analogues of MgATP, loops 2 and 3 remain rather flexible; this raises questions about the putative large-scale induced-fit conformational change of the HPPK-MgATP binary complex. In this work, long-time all-atomic molecular dynamics simulations were conducted to investigate the loop dynamics in this complex. Our simulations show that, with loop 3 closed, multiple conformations of loop 2, including the open, semiopen, and closed forms, are all accessible to the binary complex. These results provide valuable structural insights into the details of conformational changes upon 6-hydroxymethyl-7,8-dihydropterin (HP) binding and biological activities of HPPK. Conformational network analysis and principal component analysis related to the loops are also discussed. PMID- 27951656 TI - Amphiphilicity Is a Key Determinant in the Membrane Interactions of Synthetic 14 mer Cationic Peptide Analogues. AB - Cationic antimicrobial peptides are a component of the innate immune system of several organisms and represent an interesting alternative to fight multiresistant bacteria. In this context, we have elaborated a synthetic peptide scaffold allowing the study of the impact of different molecular determinants on the membrane interactions. The aim of the present study was to elucidate the mechanism of action of two cationic peptides that derive from a neutral 14-mer template peptide and where the hydrophilic portion is composed of a crown ether. The R5R10 peptide is active in the presence of both negatively charged and zwitterionic membranes (nonselective) and adopts an alpha-helical conformation, whereas the R4R11 peptide is more active in the presence of negatively charged membranes (selective) and forms intermolecular beta-sheet structures. Both the membrane topology and the location of the peptides have been assessed using solid state NMR and attenuated total reflectance Fourier transform infrared spectroscopy. In addition, fluorescence experiments have been performed on different membrane mixtures to evaluate the ability of the peptides to induce a positive curvature to the membrane. Overall, for both the R5R10 and R4R11 peptides, the results are consistent with a mechanism of action similar to the sinking-raft model in which the peptides are mainly lying flat on the membrane surface and impose a bending stress to the membrane, thus leading to the formation of pores. Furthermore, the difference of membrane selectivity between R5R10 and R4R11 peptides is due to their differing amphipathic properties which modulate the membrane activity on zwitterionic model membranes. PMID- 27951657 TI - 5-Methylcytosine (5mC) and 5-Hydroxymethylcytosine (5hmC) Enhance the DNA Binding of CREB1 to the C/EBP Half-Site Tetranucleotide GCAA. AB - In human and mouse stem cells and brain, 5-methylcytosine (5mC) and 5 hydroxymethylcytosine (5hmC) can occur outside of CG dinucleotides. Using protein binding microarrays (PBMs) containing 60-mer DNA probes, we evaluated the effect of 5mC and 5hmC on one DNA strand on the double-stranded DNA binding of the mouse B-ZIP transcription factors (TFs) CREB1, ATF1, and JUND. 5mC inhibited binding of CREB1 to the canonical CRE half-site |GTCA but enhanced binding to the C/EBP half site |GCAA. 5hmC inhibited binding of CREB1 to all 8-mers except TGAT|GCAA, where binding is enhanced. We observed similar DNA binding patterns with ATF1, a closely related B-ZIP domain. In contrast, both 5mC and 5hmC inhibited binding of JUND. These results identify new DNA sequences that are well-bound by CREB1 and ATF1 only when they contain 5mC or 5hmC. Analysis of two X-ray structures examines the consequences of 5mC and 5hmC on DNA binding by CREB and FOS|JUN. PMID- 27951658 TI - Analysis of Reaction Intermediates in Tryptophan 2,3-Dioxygenase: A Comparison with Indoleamine 2,3-Dioxygenase. AB - Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are heme containing enzymes that catalyze the O2-dependent oxidation of l-tryptophan (l Trp) in biological systems. Although many decades have passed since their discovery, the mechanism of tryptophan oxidation has not been established. It has been widely assumed that IDO and TDO react using the same mechanism, although there is no evidence that they do. For IDO, a Compound II (ferryl) species accumulates in the steady state and is implicated in the mechanism; in TDO, no such species has ever been observed. In this paper, we examine the kinetics of tryptophan oxidation in TDO. We find no evidence for the accumulation of Compound II during TDO catalysis. Instead, a ternary [Fe(II)-O2, l-Trp] complex is detected under steady state conditions. The absence of a Compound II species in the steady state in TDO is not due to an intrinsic inability of the TDO enzyme to form ferryl heme, because Compound II can be formed directly through a different route in which ferrous heme is reacted with peroxide. We interpret the data to mean that the rate-limiting step in the IDO and TDO mechanisms is not the same. PMID- 27951659 TI - Characterization of the Inward- and Outward-Facing Substrate Binding Sites of the Prokaryotic Aspartate Transporter, GltPh. AB - Crystal structures of the prokaryotic aspartate transporter, GltPh, have provided important insights into the mechanism of amino acid transport by GltPh and related eukaryotic members of the glutamate transporter family (SLC1A family). Identification of inhibitors of GltPh can provide valuable tools for understanding the molecular basis for substrate and inhibitor specificity and selectivity of SLC1A members, but at present, few inhibitors of GltPh have been identified. We have screened a collection of commercially available aspartate analogues and identified new transportable and nontransportable GltPh inhibitors. We have explored the inhibition profile of GltPh by utilizing a thiol modification assay that isolates sided populations of the transporters reconstituted in liposomes to determine if any aspartate analogues display a preference for either the inwardly or outwardly directed binding sites. Here, we have characterized several new inhibitors of GltPh and identified three beta carbon-substituted molecules that display a strong preference for the outwardly directed binding site of GltPh. PMID- 27951660 TI - Conformational Dynamics and Protein-Substrate Interaction of ABC Transporter BtuCD at the Occluded State Revealed by Molecular Dynamics Simulations. AB - ATP-binding cassette (ABC) transporters are ubiquitous in all three kingdoms of life and are implicated in many clinically relevant physiological processes. They couple the energy released by ATP hydrolysis to facilitate substrate translocation across cell membranes. The crystal structures of type II ABC importers have revealed their unique transmembrane domain architecture consisting of 10 transmembrane helices and their structurally conserved nucleotide-binding domains among all ABC transporters. However, molecular details of the interactions between the importers and their substrate remain largely elusive. Taking vitamin B12 importer BtuCD as an exemplar of type II importers, we investigated the dynamics of its occluded state and the detailed protein substrate interactions using molecular dynamics simulation. Our trajectories show that the importer accommodates the substrate through a nonspecific binding mode as the substrate undergoes evident vertical and tilt motions inside the translocation cavity. Extensive hydrogen bond and hydrophobic interactions were observed between the substrate and the importer; however, most of these interactions are weak, with <38% occurrence. The presence of substrate leads to enlargement of the translocation cavity, especially at its cytoplasmic end, which may activate cytoplasmic regions and probably facilitate the transportation. The perturbations caused by periplasmic binding protein and nucleotides were also investigated. The study provides deeper insight into the translocation mechanism of BtuCD. PMID- 27951662 TI - Nucleotide Binding in an Engineered Recombinant Ca2+-ATPase N-Domain. AB - A recombinant Ca2+-ATPase nucleotide binding domain (N-domain) harboring the mutations Trp552Leu and Tyr587Trp was expressed and purified. Chemical modification by N-bromosuccinimide and fluorescence quenching by acrylamide showed that the displaced Trp residue was located at the N-domain surface and slightly exposed to solvent. Guanidine hydrochloride-mediated N-domain unfolding showed the low structural stability of the alpha6-loop-alpha7 motif (the new Trp location) located near the nucleotide binding site. The binding of nucleotides (free and in complex with Mg2+) to the engineered N-domain led to significant intrinsic fluorescence quenching (DeltaFmax ~ 30%) displaying a saturable hyperbolic pattern; the calculated affinities decreased in the following order: ATP > ADP = ADP-Mg2+ > ATP-Mg2+. Interestingly, it was found that Ca2+ binds to the N-domain as monitored by intrinsic fluorescence quenching (DeltaFmax ~ 12%) with a dissociation constant (Kd) of 50 MUM. Notably, the presence of Ca2+ (200 MUM) increased the ATP and ADP affinity but favored the binding of ATP over that of ADP. In addition, binding of ATP to the N-domain generated slight changes in secondary structure as evidenced by circular dichroism spectral changes. Molecular docking of ATP to the N-domain provided different binding modes that potentially might be the binding stages prior to gamma-phosphate transfer. Finally, the nucleotide binding site was studied by fluorescein isothiocyanate labeling and molecular docking. The N-domain of Ca2+-ATPase performs structural dynamics upon Ca2+ and nucleotide binding. It is proposed that the increased affinity of the N-domain for ATP mediated by Ca2+ binding may be involved in Ca2+ ATPase activation under normal physiological conditions. PMID- 27951661 TI - Hydrophobic Shielding Drives Catalysis of Hydride Transfer in a Family of F420H2 Dependent Enzymes. AB - A family of flavin/deazaflavin-dependent oxidoreductases (FDORs) from mycobacteria has been recently characterized and found to play a variety of catalytic roles, including the activation of prodrugs such as the candidate anti tuberculosis drug pretomanid (PA-824). However, our understanding of the catalytic mechanism used by these enzymes is relatively limited. To address this, we have used a combination of quantum mechanics and molecular dynamics calculations to study the catalytic mechanism of the activation of pretomanid by the deazaflavin-dependent nitroreductase (Ddn) from Mycobacterium tuberculosis. The preferred pathway involves an initial hydride transfer step from the deprotonated cofactor (i.e., F420H-), with subsequent protonation, before a series of spontaneous intramolecular reactions to form the final reactive nitrogen species. The most likely proton source is a hydroxonium ion within the solvent accessible active site. Intriguingly, catalysis of the rate-determining hydride transfer step is aided by three tyrosine residues that form a hydrophobic barrier around the active site that, upon reaction, is then disrupted to allow increased water accessibility to facilitate the subsequent proton transfer step. The catalytic mechanism we propose is consistent with previous experimental observations of the Ddn enzyme and will inform the design of improved prodrugs in the future. PMID- 27951663 TI - Automatic Generation of Intermolecular Potential Energy Surfaces. AB - A method is developed for automatic generation of intermolecular two-body, rigid monomer potential energy surfaces based on symmetry-adapted perturbation theory (SAPT). It is also possible to substitute SAPT interaction energies by values computed using sufficiently high-level supermolecular methods. The long-range component of the potential is obtained from a rigorous asymptotic expansion with ab initio computed coefficients which seamlessly connects to SAPT interaction energies at large separations. An accompanying software package has been developed and tested successfully on eight systems ranging in size from the Cl- H2O dimer to the cyclotrimethylene trinitramine dimer containing 42 atoms total. The potentials have a typical fit error of about 0.2 kcal/mol in the negative energy region. The accuracy may be further improved by including off-atomic sites or increasing their number. All aspects of potential development were designed to work reliably on a broad range of systems with no human intervention. PMID- 27951664 TI - A Maximum-Caliber Approach to Predicting Perturbed Folding Kinetics Due to Mutations. AB - We present a maximum-caliber method for inferring transition rates of a Markov state model (MSM) with perturbed equilibrium populations given estimates of state populations and rates for an unperturbed MSM. It is similar in spirit to previous approaches, but given the inclusion of prior information, it is more robust and simple to implement. We examine its performance in simple biased diffusion models of kinetics and then apply the method to predicting changes in folding rates for several highly nontrivial protein folding systems for which non-native interactions play a significant role, including (1) tryptophan variants of the GB1 hairpin, (2) salt-bridge mutations of the Fs peptide helix, and (3) MSMs built from ultralong folding trajectories of FiP35 and GTT variants of the WW domain. In all cases, the method correctly predicts changes in folding rates, suggesting the wide applicability of maximum-caliber approaches to efficiently predict how mutations perturb protein conformational dynamics. PMID- 27951665 TI - Where Does the Density Localize? Convergent Behavior for Global Hybrids, Range Separation, and DFT+U. AB - Approximate density functional theory (DFT) suffers from many-electron self interaction error, otherwise known as delocalization error, that may be diagnosed and then corrected through elimination of the deviation from exact piecewise linear behavior between integer electron numbers. Although paths to correction of energetic delocalization error are well-established, the impact of these corrections on the electron density is less well-studied. Here, we compare the effect on density delocalization of DFT+U (i.e., semilocal DFT augmented with a Hubbard U correction), global hybrid tuning, and range-separated hybrid tuning on a diverse test set of 32 transition metal complexes and observe the three methods to have qualitatively equivalent effects on the ground state density. Regardless of valence orbital diffuseness (i.e., from 2p to 5p), ligand electronegativity (i.e., from Al to O), basis set (i.e., plane wave versus localized basis set), metal (i.e., Ti, Fe, Ni), and spin state, or tuning method, we consistently observe substantial charge loss at the metal and gain at ligand atoms (~0.3-0.5 e or more). This charge loss at the metal is preferentially from the minority spin, leading to increasing magnetic moment as well. Using accurate wave function theory references, we observe that a minimum error in partial charges and magnetic moments occurs at higher tuning parameters than typically employed to eliminate energetic delocalization error. These observations motivate the need to develop multifaceted approximate-DFT error correction approaches that separately treat density delocalization and energetic errors to recover both correct density and orbital energy-derived properties. PMID- 27951666 TI - Multiscale Simulations of a Two-Pore Potassium Channel. AB - Two-pore domain channels control cell excitability by modulating background potassium currents in response to several physicochemical stimuli. Thanks to the many crystal structures available, the TRAAK channel is one of the most studied, but little is known about its functional dynamics. Here, we explore TRAAK functionality complementing molecular dynamics with Brownian dynamics in a multiscale-modeling framework. We identify potential states of the channel that can prevent ion conduction, and we demonstrate that the suppression of currents is consistent with the presence of lipids inside the cavity. PMID- 27951667 TI - Ensemble-Average Representation of Pt Clusters in Conditions of Catalysis Accessed through GPU Accelerated Deep Neural Network Fitting Global Optimization. AB - We first report a global optimization approach based on GPU accelerated Deep Neural Network (DNN) fitting, for modeling metal clusters at realistic temperatures. The seven-layer multidimensional and locally connected DNN is combined with limited-step Density Functional Theory (DFT) geometry optimization to reduce the time cost of full DFT local optimization, which is considered to be the most time-consuming step in global optimization. An algorithm based on bond length distribution analysis is used to efficiently sample the configuration space and generate random initial structures. A structure similarity measurement method based on depth-first search is used to identify duplicates. The performance of the new approach is examined by the application to the global minimum searching for Pt9 and Pt13. The ensemble-average representations of the two clusters are constructed based on all geometrically different isomers, on which the structure transition is predicted at low and high temperatures, for Pt9 and Pt13 clusters, respectively. Finally, the ensemble-averaged vertical ionization potential changes when temperature increases, and the property in conditions of catalysis can be different from that evaluated at the global minimum structure. PMID- 27951668 TI - Assessing the Accuracy of Across-the-Scale Methods for Predicting Carbohydrate Conformational Energies for the Examples of Glucose and alpha-Maltose. AB - A big hurdle when entering the field of carbohydrate research stems from the complications in the analytical and computational treatment. In effect, this extremely important class of biomolecules remains underinvestigated when compared, for example, with the maturity of genomics and proteomics research. On the theory side, the commonly used empirical methods suffer from an insufficient amount of high-quality experimental data against which they can be thoroughly validated. In order to provide a pivotal point for an ascent of accurate carbohydrate simulations, we present here a structure/energy benchmark set of diverse glucose (in three isomeric forms) and alpha-maltose conformations at the coupled-cluster level as well as an assessment of commonly used energy functions. We observe that empirical force fields and semiempirical approaches, on average, do not reproduce accurately the reference energy hierarchies. While the force fields maintain accuracy for the low-energy structures, the semiempirical methods perform unsatisfactory for the entire range. On the contrary, density-functional approximations reproduce the reference energy hierarchies with better than chemical accuracy already at the generalized gradient approximation level (GGA). Particularly, the novel meta-GGA functional SCAN provides the accuracy of more expensive hybrid functionals at fraction of their computational cost. In conclusion, we advocate for electronic-structure theory methods to become the routine tool for simulations of carbohydrates. PMID- 27951669 TI - GPU-Accelerated Exploration of Biomolecular Energy Landscapes. AB - We present graphics processing unit (GPU)-acceleration of various computational energy landscape methods for biomolecular systems. Basin-hopping global optimization, the doubly nudged elastic band method (DNEB), hybrid eigenvector following (EF), and a local rigid body framework are described, including details of GPU implementations. We analyze the results for eight different system sizes, and consider the effects of history size for minimization and local rigidification on the overall efficiency. We demonstrate improvement relative to CPU performance of up to 2 orders of magnitude for the largest systems. PMID- 27951670 TI - Amplitude Determinant Coupled Cluster with Pairwise Doubles. AB - Recently developed pair coupled cluster doubles (pCCD) theory successfully reproduces doubly occupied configuration interaction (DOCI) with mean field cost. However, the projective nature of pCCD makes the method nonvariational and thus hard to improve systematically. As a variational alternative, we explore the idea of coupled-cluster-like expansions based on amplitude determinants and develop a specific theory similar to pCCD based on determinants of pairwise doubles. The new ansatz admits a variational treatment through Monte Carlo methods while remaining size-consistent and, crucially, polynomial cost. In the dissociations of LiH, HF, H2O, and N2, the method performs very similarly to pCCD and DOCI, suggesting that coupled-cluster-like ansatzes and variational evaluation may not be mutually exclusive. In an attractive pairing model, the method retains its accuracy even when pCCD suffers a severe variational violation. PMID- 27951671 TI - Nonadiabatic Molecular Dynamics with Tight-Binding Fragment Molecular Orbitals. AB - This work presents a nonadiabatic molecular dynamics methodology that relies on the use of fragment molecular orbitals computed using tight-binding Hamiltonians. The approach aims to model charge and energy transfer in large systems via quantum-classical trajectory-based approaches. The technique relies on a chemically motivated fragmentation of the overall system into arbitrary fragments. Several types of fragment molecular orbitals (FMO) can be constructed and used in nonadiabatic simulations, comprising quasidiabatic, adiabatic, and Lowdin-transformed ones. The adiabatic FMOs are found to be most suitable for modeling nonadiabatic dynamics in complex molecular systems. The overall algorithm shows advantageous scaling properties, making it possible to model long time scale charge transfer processes in large systems with many hundreds of atoms. The approach is applied to study charge transfer in subphtalocyanine(SubPc)/C60 heterojunction. The computational results emphasize the importance of decoherence and details of interfacial structure for obtaining accurate charge transfer time scales in SubPc/C60 herejunctions. PMID- 27951672 TI - Computational Methods for Configurational Entropy Using Internal and Cartesian Coordinates. AB - The configurational entropy of solute molecules is a crucially important quantity to study various biophysical processes. Consequently, it is necessary to establish an efficient quantitative computational method to calculate configurational entropy as accurately as possible. In the present paper, we investigate the quantitative performance of the quasi-harmonic and related computational methods, including widely used methods implemented in popular molecular dynamics (MD) software packages, compared with the Clausius method, which is capable of accurately computing the change of the configurational entropy upon temperature change. Notably, we focused on the choice of the coordinate systems (i.e., internal or Cartesian coordinates). The Boltzmann-quasi harmonic (BQH) method using internal coordinates outperformed all the six methods examined here. The introduction of improper torsions in the BQH method improves its performance, and anharmonicity of proper torsions in proteins is identified to be the origin of the superior performance of the BQH method. In contrast, widely used methods implemented in MD packages show rather poor performance. In addition, the enhanced sampling of replica-exchange MD simulations was found to be efficient for the convergent behavior of entropy calculations. Also in folding/unfolding transitions of a small protein, Chignolin, the BQH method was reasonably accurate. However, the independent term without the correlation term in the BQH method was most accurate for the folding entropy among the methods considered in this study, because the QH approximation of the correlation term in the BQH method was no longer valid for the divergent unfolded structures. PMID- 27951673 TI - A Fractionally Ionic Approach to Polarizability and van der Waals Many-Body Dispersion Calculations. AB - By explicitly including fractionally ionic contributions to the polarizability of a many-component system, we are able to significantly improve on previous atom wise many-body van der Waals approaches with essentially no extra numerical cost. For nonionic systems, our method is comparable in accuracy to existing approaches. However, it offers substantial improvements in ionic solids, e.g., producing better polarizabilities by over 65% in some cases. It has particular benefits for two-dimensional transition metal dichalcogenides and interactions of H2 with modified coronenes, ionic systems of nanotechnological interest. It thus offers an efficient improvement on existing approaches, valid for a wide range of systems. PMID- 27951674 TI - Multiconformation, Density Functional Theory-Based pKa Prediction in Application to Large, Flexible Organic Molecules with Diverse Functional Groups. AB - We consider the conformational flexibility of molecules and its implications for micro- and macro-pKa. The corresponding formulas are derived and discussed against the background of a comprehensive scientific and algorithmic description of the latest version of our computer program Jaguar pKa, a density functional theory-based pKa predictor, which is now capable of acting on multiple conformations explicitly. Jaguar pKa is essentially a complex computational workflow incorporating research and technologies from the fields of cheminformatics, molecular mechanics, quantum mechanics, and implicit solvation models. The workflow also makes use of automatically applied empirical corrections which account for the systematic errors resulting from the neglect of explicit solvent interactions in the algorithm's implicit solvent model. Applications of our program to large, flexible organic molecules representing several classes of functional groups are shown, with a particular emphasis in illustrations laid on drug-like molecules. It is demonstrated that a combination of aggressive conformational search and an explicit consideration of multiple conformations nearly eliminates the dependence of results on the initially chosen conformation. In certain cases this leads to unprecedented accuracy, which is sufficient for distinguishing stereoisomers that have slightly different pKa values. An application of Jaguar pKa to proton sponges, the pKa of which are strongly influenced by steric effects, showcases the advantages that pKa predictors based on quantum mechanical calculations have over similar empirical programs. PMID- 27951675 TI - Two New Methods To Generate Internal Coordinates for Molecular Wave Packet Dynamics in Reduced Dimensions. AB - The curse of dimensionality still remains as the central challenge of molecular quantum dynamical calculations. Either compromises on the accuracy of the potential landscape have to be made or methods must be used that reduce the dimensionality of the configuration space of molecular systems to a low dimensional one. For dynamic approaches such as grid-based wave packet dynamics that are confined to a small number of degrees of freedom this dimensionality reduction can become a major part of the overall problem. A common strategy to reduce the configuration space is by selection of a set of internal coordinates using chemical intuition. We devised two methods that increase the degree of automation of the dimensionality reduction as well as replace chemical intuition by more quantifiable criteria. Both methods reduce the dimensionality linearly and use the intrinsic reaction coordinate as guidance. The first one solely relies on the intrinsic reaction coordinate (IRC), whereas the second one uses semiclassical trajectories to identify the important degrees of freedom. PMID- 27951677 TI - Combining Simulations and Solution Experiments as a Paradigm for RNA Force Field Refinement. AB - Recent computational efforts have shown that the current potential energy models used in molecular dynamics are not accurate enough to describe the conformational ensemble of RNA oligomers and suggest that molecular dynamics should be complemented with experimental data. We here propose a scheme based on the maximum entropy principle to combine simulations with bulk experiments. In the proposed scheme, the noise arising from both the measurements and the forward models used to back-calculate the experimental observables is explicitly taken into account. The method is tested on RNA nucleosides and is then used to construct chemically consistent corrections to the Amber RNA force field that allow a large set of experimental data on nucleosides and dinucleosides to be correctly reproduced. The transferability of these corrections is assessed against independent data on tetranucleotides and displays a previously unreported agreement with experiments. This procedure can be applied to enforce multiple experimental data on multiple systems in a self-consistent framework, thus suggesting a new paradigm for force field refinement. PMID- 27951676 TI - Molecular Basis for Differential Patterns of Drug Resistance in Influenza N1 and N2 Neuraminidase. AB - Neuraminidase (NA) inhibitors are used for the prevention and treatment of influenza A virus infections. Two subtypes of NA, N1 and N2, predominate in viruses that infect humans, but differential patterns of drug resistance have emerged in each subtype despite highly homologous active sites. To understand the molecular basis for the selection of these drug resistance mutations, structural and dynamic analyses on complexes of N1 and N2 NA with substrates and inhibitors were performed. Comparison of dynamic substrate and inhibitor envelopes and interactions at the active site revealed how differential patterns of drug resistance have emerged for specific drug resistance mutations, at residues I222, S246, and H274 in N1 and E119 in N2. Our results show that the differences in intermolecular interactions, especially van der Waals contacts, of the inhibitors versus substrates at the NA active site effectively explain the selection of resistance mutations in the two subtypes. Avoiding such contacts that render inhibitors vulnerable to resistance by better mimicking the dynamics and intermolecular interactions of substrates can lead to the development of novel inhibitors that avoid drug resistance in both subtypes. PMID- 27951678 TI - A Nonorthogonal State-Interaction Approach for Matrix Product State Wave Functions. AB - We present a state-interaction approach for matrix product state (MPS) wave functions in a nonorthogonal molecular orbital basis. Our approach allows us to calculate, for example, transition and spin-orbit coupling matrix elements between arbitrary electronic states, provided that they share the same one electron basis functions and size of the active orbital space, respectively. The key element is the transformation of the MPS wave functions of different states from a nonorthogonal to a biorthonormal molecular orbital basis representation, by exploiting a sequence of nonunitary transformations, following a proposal by Malmqvist [Int. J. Quantum Chem. 1986, 30, 479]. This is well-known for traditional wave function parametrizations but has not yet been exploited for MPS wave functions. PMID- 27951679 TI - When is the Fukui Function Not Normalized? The Danger of Inconsistent Energy Interpolation Models in Density Functional Theory. AB - When one defines the energy of a molecule with a noninteger number of electrons by interpolation of the energy values for integer-charged states, the interpolated electron density, Fukui function, and higher-order derivatives of the density are generally not normalized correctly. The necessary and sufficient condition for consistent energy interpolation models is that the corresponding interpolated electron density is correctly normalized to the number of electrons. A necessary, but not sufficient, condition for correct normalization is that the energy interpolant be a linear function of the reference energies. Consistent with this general rule, polynomial interpolation models and, in particular, the quadratic E vs N model popularized by Parr and Pearson, do give normalized densities and density derivatives. Interestingly, an interpolation model based on the square root of the electron number also satisfies the normalization constraints. We also derive consistent least-norm interpolation models. In contrast to these models, the popular rational and exponential forms for E vs N do not give normalized electron densities and density derivatives. PMID- 27951680 TI - Probing Hydration Patterns in Class-A GPCRs via Biased MD: The A2A Receptor. AB - Herein, we present a new computational approach for analyzing hydration patterns in biomolecular systems. This protocol aims to efficiently identify regions where structural waters may be located and, in the case of protein-ligand binding, where displacing one or more water molecules could be advantageous in terms of affinity and/or residence time. We validated our approach on the adenosine A2A receptor, a target of significant pharmaceutical relevance. The results of the approach are enriched with an extensive analysis of hydration in A2A and other members of the A-family of GPCRs using available crystallographic evidence and reviewing existing literature. As per the protein-ligand complex case, we conducted a more detailed study of a series of triazine analogues inhibiting A2A. The proposed approach provides results in good agreement with existing data and offers interpretability and simple and fast applicability. PMID- 27951681 TI - Two-Component Fluorescent-Semiconducting Hydrogel from Naphthalene Diimide Appended Peptide with Long-Chain Amines: Variation in Thermal and Mechanical Strengths of Gels. AB - Two-component fluorescent hydrogels have been discovered, containing the mixtures of naphthalene diimide (NDI)-conjugated peptide-functionalized bola-amphiphile and primary amines with long alkyl chains at physiological pH 7.46. The aggregation-induced enhanced emission associated with an NDI-appended peptide in aqueous medium is rare, as water is known to be a good quencher of fluorescence. In this study, an NDI-containing gelator peptide forms a highly fluorescent aggregate in aqueous medium. Absorption and emission spectroscopic techniques reveal the formation of J-aggregates among the chromophoric moieties in their aggregated state in aqueous medium. However, this NDI-containing peptide does not form any gel in aqueous medium. In the presence of the primary amines with long alkyl chains in the buffer solution, it forms two-component fluorescent hydrogels exhibiting bright yellow fluorescence under a UV lamp (365 nm). Probably, the acid-amine interaction between the amines and the bola-amphiphile triggers the gel formation, as evident from Fourier transform infrared data, indicating the presence of a carboxylate group (-COO-) and an ammonium species (NH3+) in the coassembled two-component gel system. Low- and wide-angle powder X-ray diffraction and small-angle X-ray scattering further support the fact that the coassembled state in the gel form is produced by the supramolecular interaction between the NDI-based bola-amphiphile and the long-chain amines. Field-emission scanning electron microscopy and high-resolution transmission electron microscopy images reveal that the pi-conjugated coassembled hydrogels exhibit nanofibrillar network morphologies. Interestingly, the coassembled hydrogels exhibit an enhanced fluorescence emission, excited-state lifetime, and quantum yield when compared with those of the NDI-containing amphiphile alone in its self-assembled state in aqueous medium. Moreover, the thermal stability and mechanical strength of these gels have been successfully tuned by varying the alkyl chain length of the corresponding amine. Moreover, these NDI-peptide-conjugated soft materials exhibit semiconducting behavior in their respective coassembled states. This holds future promise to use these peptide-appended NDI-based coassembled soft materials for applications in optoelectronic and other devices. PMID- 27951682 TI - Tuning Oleophobicity of Silicon Oxide Surfaces with Mixed Monolayers of Aliphatic and Fluorinated Alcohols. AB - We demonstrate the formation of mixed monolayers derived from a microwave assisted reaction of alcohols with silicon oxide surfaces in order to tune their surface oleophobicity. This simple, rapid method provides an opportunity to precisely tune the constituents of the monolayers. As a demonstration, we sought fluorinated alcohols and aliphatic alcohols as reagents to form monolayers from two distinct constituents for tuning the surface oleophobicity. The first aspect of this study sought to identify a fluorinated alcohol that formed monolayers with a relatively high surface coverage. It was determined that 1H,1H,2H,2H perfluoro-1-octanol yielded high quality monolayers with a water contact angle (WCA) value of ~110 degrees and contact angle values of ~80 degrees with toluene and hexadecane exhibiting both an excellent hydrophobicity and oleophobicity. Tuning of the oleophobicity of the modified silicon oxide surfaces was achieved by controlling the molar ratio of 1H,1H,2H,2H-perfluoro-1-octanol within the reaction mixtures. Surface oleophobicity progressively decreased with a decrease in the fluorinated alcohol content while the monolayers maintained their hydrophobicity with WCA values of ~110 degrees . The simple and reliable approach to preparing monolayers of a tuned composition that is described in this article can be utilized to control the fluorocarbon content of the hydrophobic monolayers on silicon oxide surfaces. PMID- 27951683 TI - Insulin Aggregation at a Dynamic Solid-Liquid-Air Triple Interface. AB - Therapeutic proteins are privileged in drug development because of their exquisite specificity, which is due to their three-dimensional conformation in solution. During their manufacture, storage, and delivery, interactions with material surfaces and air interfaces are known to affect their stability. The growing use of automated devices for handling and injection of therapeutics increases their exposure to protocols involving intermittent wetting, during which the solid-liquid and liquid-air interfaces meet at a triple contact line, which is often dynamic. Using a microfluidic setup, we analyze the effect of a moving triple interface on insulin aggregation in real time over a hydrophobic surface. We combine thioflavin T fluorescence and reflection interference microscopy to concomitantly monitor insulin aggregation and the morphology of the liquid as it dewets the surface. We demonstrate that insulin aggregates in the region of a moving triple interface and not in regions submitted to hydrodynamic shear stress alone, induced by the moving liquid. During dewetting, liquid droplets form on the surface anchored by adsorbed proteins, and the accumulation of amyloid aggregates is observed exclusively as fluorescent rings growing eccentrically around these droplets. The fluorescent rings expand until the entire channel surface sweeped by the triple interface is covered by amyloid fibers. On the basis of our experimental results, we propose a model describing the growth mechanism of insulin amyloid fibers at a moving triple contact line, where proteins adsorbed at a hydrophobic surface are exposed to the liquid-air interface. PMID- 27951684 TI - Influence of Surface Chemistry on Ibuprofen Adsorption and Confinement in Mesoporous Silicon Microparticles. AB - The effect of adsorption and confinement on ibuprofen was studied by immersion loading the molecules into porous silicon (PSi) microparticles. The PSi microparticles were modified into thermally oxidized PSi (TOPSi) and thermally hydrocarbonized PSi (THCPSi) to evaluate the effects of the loading solvent and the surface chemistry on the obtainable drug payloads. The payloads, location, and the molecular state of the adsorbed drug were evaluated using thermal analysis. The results showed that after the adsorption of ~800 mg/cm3 (wdrug/vpores) of drug into the mesopores, depending on the solvent used in the immersion, the drug began to rapidly recrystallize on the external surface of the particles. Moderate concentrations, however, enabled payloads of 800-850 mg/cm3 without excessive surface crystallization, and thus, there was no need for rinsing the samples to remove the externally crystallized portion. The results showed that the confined ibuprofen forms nanocrystals inside of the mesopores after approximately 200 mg/cm3 payloads were obtained, accounting for half of the adsorbed drug amount. The presence of both crystalline and noncrystalline phases was further characterized using variable temperature solid-state nuclear magnetic resonance (NMR) measurements. The interactions between the drug molecules and the pore walls of TOPSi and THCPSi were observed using Fourier transform infrared and 1H NMR spectroscopies, and the hydrogen bonding between the silanol groups of TOPSi and the adsorbed ibuprofen was confirmed, but having only limited effect on the overall state of the confined drug. In vitro drug permeation studies in Caco 2 and Caco-2/HT29 cocultures showed that the adsorption onto hydrophilic or hydrophobic PSi microparticles had no significant effects on the ibuprofen permeation, whether the drug was partially nanocrystalline or completely in a liquidlike state. PMID- 27951685 TI - Impacts of Surface Site Coordination on Arsenate Adsorption: Macroscopic Uptake and Binding Mechanisms on Aluminum Hydroxide Surfaces. AB - Aluminum hydroxides play important roles in regulating the fate and transport of contaminants and nutrients in soils and aquatic systems. Like many metal oxides, these minerals display surface functional groups in a series of coordination states, each of which may differ in its affinity for adsorbates. The distribution of functional group types varies among distinct surfaces of aluminum hydroxides, and we thus hypothesize that the adsorption behavior and mechanisms will show a dependence on particle morphology. To test this hypothesis, we investigate arsenate adsorption on two aluminum hydroxide polymorphs with distinct particle morphologies, gibbsite [gamma-Al(OH)3] and bayerite [alpha-Al(OH)3], at pH 4 and 7. Synthetic gibbsite platelets expose large (001) basal surfaces predicted to be terminated by doubly coordinated functional groups (>Al2OH). In contrast, synthetic bayerite microrods display mainly edge surfaces (parallel to the c axis) containing abundant singly coordinated functional groups (>AlOH2). Macroscopic adsorption studies show that gibbsite adsorbs less arsenate per unit surface area than bayerite at both pH values and suggest that two surface complexes form on each material. Similar electrokinetic behavior is displayed at the same relative coverages of arsenate, suggesting that similar reactive surface groups (>AlOH2) control the surface charging on both particles. EXAFS spectroscopy shows that there is no variation in arsenate surface speciation on a given mineral with surface coverage or pH. Whereas bidentate binuclear inner sphere species are the dominant complexes present, the EXAFS result suggest that outer-sphere species also occur on both minerals, with a greater abundance on gibbsite. This binding mode likely involves adsorption to >Al2OH sites, which have a slow ligand exchange rate that inhibits inner-sphere binding. These results demonstrate that adsorption mechanisms and capacity, even when normalized for specific surface area, vary with metal oxide particle morphology because of the distribution of distinct functional groups. PMID- 27951686 TI - Deformation of Surface Nanobubbles Induced by Substrate Hydrophobicity. AB - Recent experimental measurements have shown that there exists a population of nanobubbles with different curvature radii, whereas both computer simulations and theoretical analysis indicated that the curvature radii of different nanobubbles should be the same at a given supersaturation. To resolve such inconsistency, we perform molecular dynamics simulations on surface nanobubbles that are stabilized by heterogeneous substrates either in the geometrical heterogeneity model (GHM) or in the chemical heterogeneity model (CHM) and propose that the inconsistency could be ascribed to the substrate-induced nanobubble deformation. We find that, as expected from theory and computer simulation, for either the GHM or the CHM, there exists a universal upper limit of contact angle for the nanobubbles, which is determined by the degree of supersaturation alone. By analyzing the evolution of the shape of nanobubbles as a function of substrate hydrophobicity that is controlled here by the liquid-solid interaction, two different origins of nanobubble deformation are identified. For substrates in the GHM, where the contact line is pinned by surface roughness, variation in the liquid-solid interaction changes only the location of the contact line and the measured contact angle, without causing a change in the nanobubble curvature. For substrates in the CHM, however, the liquid-solid interaction exerted by the bottom substrate can deform the vapor-liquid interface, resulting in variations in both the curvature of the vapor-liquid interface and the contact angle. PMID- 27951687 TI - Thermodynamic Description of Synergy in Solvent Extraction: I. Enthalpy of Mixing at the Origin of Synergistic Aggregation. AB - Revisiting aggregation of extractant molecules into water-poor mixed reverse micelles, we propose in this paper to identify the thermodynamic origins of synergy in solvent extraction. Considering that synergistic extraction properties of a mixture of extractants is related to synergistic aggregation of this mixture, we identify here the elements at the origin of synergy by independently investigating the effect of water, acid, and extracted cations. Thermodynamic equations are proposed to describe synergistic aggregation in the peculiar case of synergistic solvent extraction by evaluating critical aggregation concentration (CAC) as well as specific interactions between extractants due to the presence of water, acid and cations. Distribution of two extractant molecules in the free extractants and in reverse micelles was assessed, leading to an estimation of the in-plane interaction parameter between extractants in the aggregates as introduced by Bergstrom and Eriksson ( Bergstrom, M.; Eriksson, J. C. A Theoretical Analysis of Synergistic Effects in Mixed Surfactant Systems . Langmuir 2000 , 16 , 7173 - 7181 ). Based on this model, we study the N,N' dimethyl-N,N'-dioctylhexylethoxymalonamide (DMDOHEMA) and di(2-ethylexyl) phosphoric acid (HDEHP) mixture and show that adding nitric acid enhances synergistic aggregation at the equimolar ratio of the two extractants and that this configuration can be related to a favored enthalpy of mixing. PMID- 27951688 TI - Energetics of the Mixing of Phospholipids in Bilayers Determined Using Vesicle Solubilization. AB - Here, we report an experimental approach for determining the change in the free energy and the enthalpy that accompanies the mixing of the anionic phosphatidylglycerol and the zwitterionic phosphatidylcholine. The enthalpy change originates in the thermal changes of disrupting lipid bilayer vesicles titrated into a surfactant micelle solution and is monitored using isothermal titration calorimetry. The difference in the solubilization enthalpies between pure and mixed lipid vesicles yields the lipid mixing enthalpy. The Gibbs free energy changes are estimated by determining the thermodynamic equilibrium constants of forming a molecular complex between phospholipids and methyl-beta cyclodextrin. We provide direct experimental evidence that mixing of the anionic lipid and the zwitterionic lipid is explained well by the entropic term of the electrostatic free energy of a charged surface in the Gouy-Chapman model. The present strategy enables us to determine the precise energetics of lipid-lipid interactions in near-native environments such as liposomes without any chemical modification to lipid molecules. PMID- 27951689 TI - Solid-Liquid Interface Structure of Muscovite Mica in CsCl and RbBr Solutions. AB - The solid-liquid interface formed by single terminated muscovite mica in contact with two different ionic solutions is analyzed using surface X-ray diffraction. Specular and nonspecular crystal truncation rods of freshly cleaved mica immersed in CsCl or RbBr aqueous solution were measured. The half monolayer of the surface potassium ions present after the cleavage is completely replaced by the positive ions (Cs+ or Rb+) from the solution. These ions are located in the ditrigonal surface cavities with small outward relaxations with respect to the bulk potassium position. We find evidence for the presence of a partly ordered hydration shell around the surface Cs+ or Rb+ ions and partly ordered negative ions in the solution. The lateral liquid ordering induced by the crystalline surface vanishes at distances larger than 5 A from the surface. PMID- 27951690 TI - Magnetically Oriented Bicelles with Monoalkylphosphocholines: Versatile Membrane Mimetics for Nuclear Magnetic Resonance Applications. AB - Bicelles (bilayered micelles) are model membranes used in the study of peptide structure and membrane interactions. They are traditionally made of long- and short-chain phospholipids, usually dimyristoylphosphatidylcholine (D14PC) and dihexanoyl-PC (D6PC). They are attractive membrane mimetics because their composition and planar surface are similar to the native membrane environment. In this work, to improve the solubilization of membrane proteins and allow their study in bicellar systems, D6PC was replaced by detergents from the monoalkylphosphocholine (MAPCHO) family, of which dodecylphosphocholine (12PC) is known for its ability to solubilize membrane proteins. More specifically 12PC, tetradecyl- (14PC), and hexadecyl-PC (16PC) have been employed. To verify the possibility of making bicelles with different hydrophobic thicknesses to better accommodate membrane proteins, D14PC was also replaced by phospholipids with different alkyl chain lengths: dilauroyl-PC (D12PC), dipalmitoyl-PC (D16PC), distearoyl-PC (D18PC), and diarachidoyl-PC (D20PC). Results obtained by 31P solid state nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC) at several lipid-to-detergent molar ratios (q) and temperatures indicate that these new MAPCHO bicelles can be formed under a variety of conditions. The quality of their alignment is similar to that of classical bicelles, and the low critical micelle concentration (CMC) of the surfactants and their miscibility with phospholipids are likely to be advantageous for the reconstitution of membrane proteins. PMID- 27951691 TI - Visible-Near-Infrared-Light-Driven Oxygen Evolution Reaction with Noble-Metal Free WO2-WO3 Hybrid Nanorods. AB - Understanding and manipulating the one half-reaction of photoinduced hole oxidation to oxygen are of fundamental importance to design and develop an efficient water-splitting process. To date, extensive studies on oxygen evolution from water splitting have focused on visible-light harvesting. However, capturing low-energy photons for oxygen evolution, such as near-infrared (NIR) light, is challenging and not well-understood. This report presents new insights into photocatalytic water oxidation using visible and NIR light. WO2-WO3 hybrid nanorods were in situ fabricated using a wet-chemistry route. The presence of metallic WO2 strengthens light absorption and promotes the charge-carrier separation of WO3. The efficiency of the oxygen evolution reaction over noble metal-free WO2-WO3 hybrids was found to be significantly promoted. More importantly, NIR light (>=700 nm) can be effectively trapped to cause the photocatalytic water oxidation reaction. The oxygen evolution rates are even up to around 220 (lambda = 700 nm) and 200 (lambda = 800 nm) mmol g-1 h-1. These results demonstrate that the WO2-WO3 material is highly active for water oxidation with low-energy photons and opens new opportunities for multichannel solar energy conversion. PMID- 27951692 TI - Hybrid Fibrillar Xerogels with Unusual Magnetic Properties. AB - We report on the preparation of a hybrid nanomaterial made up of 1D filaments of an antiferromagnetic self-assembling bicopper complex encapsulated in polymer nanofibrils. The encapsulation process is achieved through the heterogeneous nucleation of the growth of polymer fibrils obtained by thermoreversible gelation as shown by calorimetry experiments. Neutron scattering experiments confirm that the filaments of a bicopper complex retain their 1D character after encapsulation in the fibrils. Superconducting quantum interference device experiments show that the bicopper complex, originally in the gapped spin state in the 3D bulk mesophase, displays a gapless behavior once encapsulated. Extended absorption fine structure and infrared results further highlight the difference in the molecular arrangement of the bicopper complex between the bulk mesophase and the encapsulated state, which may account for the magnetic behavior. This material, which is largely disordered, differs totally from the usual magnetic systems where this effect is observed only on highly crystalline systems with long-range order. Also, this hybrid material is very easy to prepare from its basic constituents and can be further processed in many ways. PMID- 27951693 TI - Solvent-Induced Luminescence Variation of Upconversion Nanoparticles. AB - Solvent plays a vital role in the syntheses, purifications, and broad applications of upconversion nanoparticles (UCNPs). In this work, the effect of various dispersive solvents, including single solvents and mixed solvents, on the luminescence properties of NaYF4:Yb3+, Er3+ UCNPs was studied systematically. The differences in both upconversion luminescence (UCL) intensities and color outputs of the nanoparticles were observed when dispersing the UCNPs in deuterium oxide, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethanol, or water. The attenuation of the excitation and emission light of the UCNPs caused by absorption of the solvents, as well as the high-frequency vibrational groups of the solvents, such as -OH, -CH2, and -CH3 groups, are responsible for the decrease in UCL intensities and increase in the red to green emission intensity ratios (RGR). The changes in water or OH- ion contents of ethanol/water mixed solvent triggered similar changes in UCL properties. Interestingly, the quenching of the solvents for the UCL cannot be fully eliminated by changing the dispersive solvents once the UCNPs have touched the solvents containing high-frequency vibrational groups. Our work will facilitate the comprehension of the solvent induced luminescence variations of the nanoparticles and provide guidance for their applications. PMID- 27951694 TI - Trends in Hydrophilicity/Lipophilicity of Phosphonium Ionic Liquids As Determined by Ion-Transfer Electrochemistry. AB - Ionic liquids (ILs) have become valuable new materials for a broad spectrum of applications including additives or components for new hydrophobic/hydrophilic polymer coatings. However, fundamental information surrounding IL molecular properties is still lacking. With this in mind, the microinterface between two immiscible electrolytic solutions (micro-ITIES), for example, water|1,2 dichloroethane, has been used to evaluate the hydrophobicity/lipophilicity of 10 alkylphosphonium ILs. By varying the architecture around the phosphonium core, chemical differences were induced, changing the lipophilicity/hydrophilicity of the cations. Ion transfer (IT) within the polarizable potential window (PPW) was measured to establish a structure-property relationship. The Gibbs free energy of IT and the solubility of their ILs were also calculated. For phosphonium cations bearing either three butyl or three hydroxypropyl groups with a tunable fourth arm, the latter displayed a wide variety of easily characterizable IT potentials. The tributylphosphonium ILs, however, were too hydrophobic to undergo IT within the PPW. Utilizing a micro-ITIES (25 MUm diameter) housed at the tip of a capillary in a uniquely designed pipet holder, we were able to probe beyond the traditional potential window and observe ion transfer of these hydrophobic phosphonium ILs for the first time. A similar trend in lipophilicity was determined between the two subsets of ILs by means of derived solubility product constants. The above results serve as evidence of the validation of this technique for the evaluation of hydrophobic cations that appear beyond the conventional PPW and of the lipophilicity of their ILs. PMID- 27951695 TI - Terminal-Specific Interaction between Double-Stranded DNA Layers: Colloidal Dispersion Behavior and Surface Force. AB - Double-stranded DNA-grafted nanoparticles (dsDNA-NPs) exhibit a unique dispersion behavior under high-salt conditions depending on the pairing status of their outermost base pairs (pairing or unpairing). The dsDNA-NPs having complementary (i.e., pairing) outermost base pairs spontaneously aggregate under high-salt conditions, but not when their outermost base pairs are mismatched (unpairing). In this study, we used colloidal probe atomic force microscopy to examine how the outermost base pairs affect the interaction between the dsDNA-grafted layers (dsDNA layers). To precisely assess the subtle structural differences in the dsDNA layers, we developed a method for the formation of a homogenous dsDNA layer on gold surfaces using hairpin-shaped DNAs. Homogenous dsDNA layers having complementary (G-C) or mismatched (C-C) outermost base pairs were grafted onto the surfaces of colloidal probes and gold substrates. Force-distance curves measured in an aqueous medium under high-salt conditions revealed that the surface forces between the dsDNA layers were bilateral in nature and were governed by the outermost base pairs. Between complementary outermost dsDNA layers, the surface force changed from repulsive to attractive with an increase in the NaCl concentration (10-1000 mM). The attraction observed under high-salt conditions was attributed to the site-specific interaction proceeded only between complementary dsDNA terminals, the so-called blunt-end stacking. In fact, between mismatched outermost dsDNA layers, the repulsive force was mostly dominant within the same NaCl concentration range. Our results clearly revealed that the pairing status of the outermost base pairs has significant implications for the surface forces between dsDNA layers, leading to the unique dispersion behavior of dsDNA NPs. PMID- 27951696 TI - Preparation of Well-Defined Poly(styrene-co-acrylonitrile)/ZnO Hybrid Nanoparticles by an Efficient Ligand Exchange Strategy. AB - Poly(styrene-co-acrylonitrile) (PSAN)-capped ZnO nanoparticles (NPs) were synthesized by a "ligand exchange" method. First, octylamine (OA)-capped ZnO NPs were prepared by reaction of OA and zinc 2-ethylhexanoate (Zn(EH)2). Then PSAN polymer ligands were synthesized by activators regenerated by electron transfer (ARGET) atom transfer radical polymerization (ATRP) and were efficiently exchanged with OA ligands on the ZnO particle surface benefiting from the relatively low boiling point of OA (175 degrees C). The morphology, content of ZnO, and grafting density of the nanocomposite were well controlled by altering the ratio between OA and polymer ligands as well as the molecular weight of PSAN NH2 used in the exchange reaction. The resulting ZnO/polymer nanocomposites were stable in THF with narrow size distributions and varying grafting densities from 0.9 to 2.5 nm-2. With excess amount of polymer ligands, individual dispersed ZnO NPs were observed. However, with a limited amount of ligands, NPs clusters were formed, as confirmed by TEM and DLS. PMID- 27951697 TI - Experimental Modeling of Flavonoid-Biomembrane Interactions. AB - Nonspecific interactions of flavonoids with lipids can alter the membrane's features (e.g., thickness and fluctuations) as well as influence their therapeutic potentials. However, relatively little is known about the details of how flavonoids interact with lipid components. Structure-dependent interactions of a variety of flavonoids with phospholipid monolayers on a mercury (Hg) film electrode were established by rapid cyclic voltammetry (RCV). The data revealed that flavonoids adopting a planar configuration altered the membrane properties more significantly than nonplanar flavonoids. Quercetin, rutin, and tiliroside were selected for follow-up experiments with Langmuir monolayers, Brewster angle microscopy (BAM), and small-angle X-ray scattering (SAXS). Relaxation phenomena in DOPC monolayers and visualization of the surface with BAM revealed a pronounced monolayer stabilization effect with both quercetin and tiliroside, whereas rutin disrupted the monolayer structure rendering the surface entirely smooth. SAXS showed a monotonous membrane thinning for all compounds studied associated with an increase in the mean fluctuations of the membrane. Rutin, quercetin, and tiliroside decreased the bilayer thickness of DOPC by ~0.45, 0.8, and 1.1 A at 6 mol %, respectively. In addition to the novelty of using lipid monolayers to systematically characterize the structure-activity relationship (SAR) of a variety of flavonoids, this is the first report investigating the effect of tiliroside with biomimetic membrane models. All the flavonoids studied are believed to be localized in the lipid/water interface region. Both this localization and the membrane perturbations have implications for their therapeutic activity. PMID- 27951699 TI - Crystallization at Nanodroplet Interfaces in Emulsion Systems: A Soft-Template Strategy for Preparing Porous and Hollow Nanoparticles. AB - A heterophase method to prepare hollow and/or porous crystalline nanoparticles of metal oxides at room temperature is presented, taking cerium(IV) oxide and gamma iron(III) oxide (i.e., maghemite) as representative cases. The crystallization begins at the oil-water interface in aqueous nanodroplets of the precursor in inverse (water-in-oil) miniemulsion systems, and it may continue toward the inner part of the droplets. A poly(styrene-b-acrylic acid) block copolymer is used as a structuring agent because the ability of the carboxylic groups to bind metal ions improves the inorganic shell formation. A precipitating base is added from the continuous phase, generating hydroxide species at the interface that begin the crystallization. We analyze the effects of the synthetic parameters in terms of colloidal stability and morphology of the resulting materials. In the case of maghemite samples, the prepared dispersions of hollow particles present a distinct magnetofluidic behavior. PMID- 27951698 TI - Structure and Mobility of Lactose in Lactose/Sodium Montmorillonite Nanocomposites. AB - This study aims at investigating the molecular level organization and molecular mobility in montmorillonite nanocomposites with the uncharged organic low molecular-weight compound lactose commonly used in pharmaceutical drug delivery, food technology, and flavoring. Nanocomposites were prepared under slow and fast drying conditions, attained by drying at ambient conditions and by spray-drying, respectively. A detailed structural investigation was performed with modulated differential scanning calorimetry, powder X-ray diffraction, solid-state nuclear magnetic resonance spectroscopy, scanning electron microscopy, microcalorimetry, and molecular dynamics simulations. The lactose was intercalated in the sodium montmorillonite interlayer space regardless of the clay content, drying rate, or humidity exposure. Although, the spray-drying resulted in higher proportion of intercalated lactose compared with the drying under ambient conditions, nonintercalated lactose was present at 20 wt % lactose content and above. This indicates limitations in maximum loading capacity of nonionic organic substances into the montmorillonite interlayer space. Furthermore, a fraction of the intercalated lactose in the co-spray-dried nanocomposites diffused out from the clay interlayer space upon humidity exposure. Also, the lactose in the nanocomposites demonstrated higher molecular mobility than that of neat amorphous lactose. This study provides a foundation for understanding functional properties of lactose/Na-MMT nanocomposites, such as loading capacity and physical stability. PMID- 27951700 TI - Proton Transfer Pathways of 2,2'-Bipyridine-3,3'-diol in pH Responsive Fatty Acid Self-Assemblies: Multiwavelength Fluorescence Lifetime Imaging in a Single Vesicle. AB - Fatty acids are known to form different supramolecular aggregates in aqueous solutions depending on the pH of the medium. The dynamics of the transformation of oleate micelles into oleic acid/oleate vesicles has been investigated using a pH-sensitive intramolecular proton transfer fluorophore, 2,2'-bipyridine-3,3' diol [BP(OH)2]. Different prototropic forms of BP(OH)2 exist in different pH values of the system, and thus, the ground state and the excited state dynamics of BP(OH)2 have been modulated in these confined media. The formation of different tautomeric forms of BP(OH)2 in oleate micelles (at basic pH) is confirmed using time-resolved emission spectra and fluorescence anisotropy measurements. The hydrophobic environment provided by these assemblies reduces the water-assisted nonradiative decay channels and lengthens the fluorescence lifetime of BP(OH)2. The rotational relaxation time in the micellar assembly is higher than that in the vesicle, which may be due to the higher microviscosity sensed by the fluorophore in the micelle. Besides, we have shown for the first time that BP(OH)2 can be used as a membrane-bound fluorophore, using fluorescence lifetime imaging microscopy (FLIM). A broad distribution in the size of the vesicle is observed from the FLIM image. Further, we have used multiwavelength FLIM to collect the FLIM images of a single vesicle at different emission wavelengths, and the lifetime distribution obtained from the FLIM images at different emission wavelengths in a single vesicle correlates well with the lifetime values obtained from the ensemble average measurements in the bulk solution. PMID- 27951701 TI - Selective Adsorption and Separation through Molecular Filtration by Hyperbranched Poly(ether amine)/Carbon Nanotube Ultrathin Membranes. AB - In response to the increasing public awareness of serious dye-contained wastewater contamination, we herein fabricated a novel anthracene-containing hyperbranched poly(ether amine) (hPEA-AN)/carbon nanotube (CNT) ultrathin membrane (UTM), which combined both the merits of the conventional dye adsorption strategy and membrane filtration process, to implement efficient selective adsorption of dye molecules and also the separation of dye mixtures by molecular filtration. Taking advantage of the pi-pi stacking interactions between anthracene and CNT sidewalls and hydrophobic interactions, CNTs were coated tightly with hPEA-AN to form the hPEA-AN@CNT complex, which can be well-dispersed very stably in water. The formation of the hPEA-AN@CNT complex was confirmed using X-ray photoelectron spectroscopy, Raman spectra, fluorescence spectra, and thermogravimetric analysis. Meanwhile, a simple filtration process was applied to prepare hPEA-AN@CNT UTMs with a thickness of 1.5 MUm, which can be further cross linked through photodimerization of anthracene moieties. The UTMs represented selective adsorption behaviors toward hydrophilic dyes even with similar backbones and the same charge states, namely, they showed high adsorption capacities (Qeq) toward eosin B, erythrosin B (ETB), 4',5'-dibromofluorescein, and Evans blue (EVB) dyes up to 300 MUmol/g while showing low adsorption capacities toward calcein (Cal), methyl red, and Ponceau S dyes. On the basis of this unique selective adsorption, molecular filtration was then realized toward mixed ETB/Cal and EVB/Cal dyes, with a separation efficiency of up to 100% and regeneration without an obvious efficiency decrease. PMID- 27951702 TI - Detachment Force of Particles with Pinning of Contact Line from Fluid Bubbles/Droplets. AB - Deformation of a spherical droplet or bubble containing a pair of particles on its surface is considered when equal but opposite forces are applied to the particles. The particles are placed opposite each other, thus providing a symmetric problem that is more amenable to analytical treatment. We extend our previous calculations concerning such arrangements with constant contact angles to situations where it is the contact line now that is pinned on the surface of the particles. The force-displacement curves are calculated as the particles are pulled apart and are found to be linear for small displacements. However, it is also found that the "Hookean constant" for the pinned contact line problem is different from the one derived for systems with a constant contact angle, the constant being larger if the pinned line is at the equator of the particles. PMID- 27951703 TI - Modeling the Hydrophobicity of Nanoparticles and Their Interaction with Lipids and Proteins. AB - We present a method of modeling nanoparticle (NP) hydrophobicity using coarse grained molecular dynamics (CG MD) simulations, and apply this to the interaction of lipids with nanoparticles. To model at a coarse-grained level the wettability or hydrophobicity of a given material, we choose the MARTINI coarse-grained force field, and determine through simulation the contact angles of MARTINI water droplets residing on flat regular surfaces composed of various MARTINI bead types (C1, C2, etc.). Each surface is composed of a single bead type in each of three crystallographic symmetries (FCC, BCC, and HCP). While this method lumps together several atoms (for example, one cerium and two oxygens of CeO2) into a single CG bead, we can still capture the overall hydrophobicity of the actual material by choosing the MARTINI bead type that gives the best fit of the contact angle to that of the actual material, as determined by either experimental or all-atom simulations. For different MARTINI bead types, the macroscopic contact angle is obtained by extrapolating the microscopic contact angles of droplets of eight different sizes (containing Nw = 3224-22978 water molecules) to infinite droplet size. For each droplet, the contact angle was computed from a best fit of a circular curve to the droplet interface extrapolated to the first layer of the surface. We then examine how small nanoparticles of differing wettability interact with MARTINI dipalmitoylphosphotidylcholine (DPPC) lipids and SP-C peptides (a component of lung surfactant). The DPPC shows a transition from tails coating the nanoparticle to a hemimicelle coating the water-wet NP, as the contact angle of a water droplet on the surface is lowered below ~60 degrees . The results are relevant to developing a taxonomy describing the potential nanotoxicity of nanoparticle interactions with components in the lung. PMID- 27951704 TI - Multilayering of Calcium Aerosol-OT at the Mica/Water Interface Studied with Neutron Reflection: Formation of a Condensed Lamellar Phase at the CMC. AB - Using specular neutron reflection, the adsorption of sodium and calcium salts of the surfactant bis(2-ethylhexyl) sulfosuccinate (Aerosol-OT or AOT) has been studied at the mica/water interface at concentrations between 0.1 and 2 CMC. The pH dependence of the adsorption was also probed. No evidence of the adsorption of Na(AOT) was found even at the critical micelle concentration (CMC) while the calcium salt was found to adsorb significantly at concentrations of 0.5 CMC and above. This interesting and somewhat unexpected finding demonstrates that counterion identity may be used to tune the adsorption of anionic surfactants on anionic surfaces. At the CMC, three condensed bilayers of Ca(AOT)2 were adsorbed at pH 7 and 9 and four bilayers adsorbed at pH 4. Multilayering at the CMC of Ca(AOT)2 on the mica surface is an unusual feature of this surfactant/surface combination. Only single bilayer adsorption has been observed at other surfaces at the CMC. We suggest this arises from the high charge density of mica which must provide an excellent template for the surfactant. PMID- 27951705 TI - Surfactant- and Aqueous-Foam-Driven Oil Extraction from Micropatterned Surfaces. AB - Liquid-infused surfaces are rough or patterned surfaces in which a lubricating fluid, such as oil, is infused, which exhibits various original properties (omniphobicity, biofouling, drag reduction). An outer flow in a confined geometry can entrain the oil trapped between the pattern of the surfaces by shearing the oil-water interface and cause the loss of the omniphobic properties of the interface. Starting from the theoretical analysis of Wexler et al. (Shear-driven failure of liquid-infused surfaces. Phys. Rev. Lett. 2015, 114, 168301), where a pure aqueous solution is the outer phase, we extend the predictions by introducing an extraction efficiency parameter alpha and by accounting for new dynamical effects induced by surfactants and aqueous foams. For surfactant solutions, decreasing the oil-water interfacial tension (gammaow) not only enhances oil extraction as expected but also modifies the dynamics of the receding oil-water interface through the variations of the receding contact angle (theta) with the capillary number (Ca), which is the ratio between the viscous and the capillary forces at the oil-water interface. For aqueous foams, the extraction dynamics are also influenced by the foam flow: oil is sheared by the thin film between the bubbles and the lubricating layer, which imposes a stronger interfacial shear compared to pure aqueous solutions. In both surfactant and foam cases, the experimental observations show the existence of nonuniform extraction dynamics related to the surfactant-induced instability of a two-fluid shear flow. PMID- 27951706 TI - Competitive and Synergistic Interactions between Polymer Micelles, Drugs, and Cyclodextrins: The Importance of Drug Solubilization Locus. AB - Polymeric micelles, in particular PEO-PPO-based Pluronic, have emerged as promising drug carriers, while cyclodextrins (CD), cyclic oligosaccharides with an apolar cavity, have long been used for their capacity to form inclusion complexes with drugs. Dimethylated beta-cyclodextrin (DIMEB) has the capacity to fully breakup F127 Pluronic micelles, while this effect is substantially hindered if drugs are loaded within the micellar aggregates. Four drugs were studied at physiological temperature: lidocaine (LD), pentobarbital sodium salt (PB), sodium naproxen (NP), and sodium salicylate (SAL); higher temperatures shift the equilibrium toward higher drug partitioning and lower drug/CD binding compared to 25 degrees C ( Valero, M.; Dreiss, C. A. Growth, Shrinking, and Breaking of Pluronic Micelles in the Presence of Drugs and/or beta-Cyclodextrin, a Study by Small-Angle Neutron Scattering and Fluorescence Spectroscopy . Langmuir 2010 , 26 , 10561 - 10571 ). The impact of drugs on micellar structure was characterized by small-angle neutron scattering (SANS), while their solubilization locus was revealed by 2D NOESY NMR. UV and fluorescence spectroscopy, Dynamic and Static Light Scattering were employed to measure a range of micellar properties and drug:CD interactions: binding constant, drug partitioning within the micelles, critical micellar concentration of the loaded micelles, aggregation number (Nagg). Critically, time-resolved SANS (TR-SANS) reveal that micellar breakup in the presence of drugs is substantially slower (100s of seconds) than for the free micelles (<100 ms) ( Valero, M.; Grillo, I.; Dreiss, C. A. Rupture of Pluronic Micelles by Di-Methylated beta-Cyclodextrin Is Not Due to Polypseudorotaxane Formation . J. Phys. Chem. B 2012 , 116 , 1273 - 1281 ). These results combined together give new insights into the mechanisms of protection of the drugs against CD-induced micellar breakup. The outcomes are practical guidelines to improve the design of drug delivery systems as well as a better understanding of competitive assembly mechanisms leading to shape and function modulation. PMID- 27951707 TI - Electrophoretic and Electroosmotic Motion of a Charged Spherical Particle within a Cylindrical Pore Filled with Debye-Bueche-Brinkman Polymeric Solution. AB - Electrophoretic and electroosmotic motion of a charged spherical particle within a cylindrical pore filled with a Debye-Bueche-Brinkman (DBB) polymeric solution is investigated theoretically, which is of high relevance in capillary electrophoresis as well as micro- and nanofluidic applications involving polymeric solutions in a micro- or nanopore. The DBB model describes the rheological response of a polymeric solution with a linear polymer dissolved in a homogeneous solvent. It is a well-known non-Newtonian model in liquid physics based on rigorous theoretical derivations. By Debye and Bueche, corresponding governing fundamental electrokinetic equations are solved numerically with a patched pseudo-spectral method based on Chebyshev polynomials. We found that the double-layer polarization effect reduces the particle mobility severely when the Debye parameter, kappaa, is around unity, especially in narrow pores. This is attributed to the extra confinement effect from the nearby wall, which tends to sweep the predominant counterions within the double layer to the wake of the moving particle, resulting in a motion-deterring induced electric field. The electrophoretic mobility in a polymer solution is smaller than that in an aqueous electrolyte solution in general as a result of the much stronger viscous drag effect in a polymer solution. Moreover, electroosmotic flow (EOF) as a result of a charged pore wall is found to exhibit a highly non-Newtonian behavior. Unlike the corresponding plug-like flow for a Newtonian solution, an axisymmetric flow with a large local maximum in the velocity profile in the region near the pore wall is observed. This radial-varying velocity profile offers a potential extra separation mechanism, which favors the elution of smaller particles in general. The results obtained here provide fundamental understandings and insights of the electrophoresis and electroosmosis phenomena in a cylindrical pore filled with polymeric solution. PMID- 27951708 TI - Dynamics of Pickering Emulsions in the Presence of an Interfacial Reaction: A Simulation Study. AB - Pickering emulsions combining surface-active and catalytic properties offer a promising platform for conducting interfacial reactions between immiscible reagents. Despite the significant progress in the design of Pickering interfacial catalysts for a broad panel of reactions, the dynamics of Pickering emulsions under reaction conditions is still poorly understood. Herein, using benzene hydroxylation with aqueous H2O2 as a model system, we explored the dynamics of benzene/water Pickering emulsions during reaction by dissipative particle dynamics. Our study points out that the surface wettability of the silica nanoparticles is affected to a higher extent by the degree of polymer grafting rather than an increase of the chain length of hydrophobic polymer moieties. A remarkable decline of the oil-in-water (O/W) interfacial tension was observed when increasing the yield of the reaction product (phenol), affecting the emulsion stability. However, phenol did not alter to an important extent the distribution of immiscible reagents around the nanoparticles sitting at the benzene/water interface. A synergistic effect between phenol and silica nanoparticles on the O/W interfacial tension of the biphasic system could be ascertained. PMID- 27951709 TI - Amphiphilic Polymer Mediators Promoting Electron Transfer on Bioanodes with PQQ Dependent Glucose Dehydrogenase. AB - Redox-active phenazinium salts bonded to amphiphilic polymer backbones are demonstrated to function as high-performance electron-transfer mediators in enzymatic bioanodes applicable to biofuel cells. The redox-active moieties could be easily tethered to the electrodes by physical adsorption of the hydrophobic regions of the polymer backbones onto the electrode surface. On the other hand, long hydrophilic chains were essential to ensure high mobility of the redox active moieties in aqueous solutions and to enhance their electron-transfer properties. We found that an amphiphilic mediator with a linear polymer backbone exhibited stable adsorption behavior on the electrode surface and generated high bioelectrocatalytic current (>1.8 +/- 0.32 mA/cm2) in the presence of pyrroloquinoline quinone-dependent glucose dehydrogenase and an aqueous solution of glucose fuel. This current was more than two times higher than that of an electrode treated with a low-molecular-weight phenazinium salt. Moreover, the bioelectrode modified with the polymer mediator retained the high electrocatalytic current after 10 exchanges of the glucose fuel. The mediator modified bioelectrodes are expected to be useful for various bio-related energy and electronic devices. PMID- 27951710 TI - Adsorption of Nanoceria by Phosphocholine Liposomes. AB - Nanoceria (CeO2 nanoparticle) possesses a number of enzyme-like activities. In particular, it scavenges reactive oxygen species based on in vitro and in vivo antioxidation studies. An important aspect of fundamental physical understanding is its interaction with lipid membranes that are the main components of the cell membrane. In this work, adsorption of nanoceria onto phosphocholine (PC) liposomes was performed. PC lipids are the main constituents of the cell outer membrane. Using a fluorescence quenching assay, a nanoceria adsorption isotherm was determined at various pH values and ionic strengths. A non-Langmuir isotherm occurred at pH 4 because of lateral electrostatic repulsion among the adsorbed cationic nanoceria. The phosphate group in the PC lipid is mainly responsible for the interaction, and the adsorbed nanoceria can be displaced by free inorganic phosphate. The tendency of the system to form large aggregates is a function of pH and the concentration of nanoceria, attributable to nanoceria being positively charged at pH 4 and neutral at physiological pH. Calcein leakage tests indicate that nanoceria induces liposome leakage because of transient lipid phase transition, and cryo-transmission electron microscopy indicates that the overall shape of the liposome is retained although deformation is still observed. This study provides fundamental biointerfacial information at a molecular level regarding the interaction of nanoceria and model cell membranes. PMID- 27951711 TI - Domed Silica Microcylinders Coated with Oleophilic Polypeptides and Their Behavior in Lyotropic Cholesteric Liquid Crystals of the Same Polypeptide. AB - Liquid crystals can organize dispersed particles into useful and exotic structures. In the case of lyotropic cholesteric polypeptide liquid crystals, polypeptide-coated particles are appealing because the surface chemistry matches that of the polymeric mesogen, which permits a tighter focus on factors such as extended particle shape. The colloidal particles developed here consist of a magnetic and fluorescent cylindrically symmetric silica core with one rounded, almost hemispherical end. Functionalized with helical poly(gamma-stearyl-l glutamate) (PSLG), the particles were dispersed at different concentrations in cholesteric liquid crystals (ChLC) of the same polymer in tetrahydrofuran (THF). Defects introduced by the particles to the director field of the bulk PSLG/THF host led to a variety of phases. In fresh mixtures, the cholesteric mesophase of the PSLG matrix was distorted, as reflected in the absence of the characteristic fingerprint pattern. Over time, the fingerprint pattern returned, more quickly when the concentration of the PSLG-coated particles was low. At low particle concentration the particles were "guided" by the PSLG liquid crystal to organize into patterns similar to that of the re-formed bulk chiral nematic phase. When their concentration increased, the well-dispersed PSLG-coated particles seemed to map onto the distortions in the bulk host's local director field. The particles located near the glass vial-ChLC interfaces were stacked lengthwise into architectures with apparent two-dimensional hexagonal symmetry. The size of these "crystalline" structures increased with particle concentration. They displayed remarkable stability toward an external magnetic field; hydrophobic interactions between the PSLG polymers in the shell and those in the bulk LC matrix may be responsible. The results show that bio-inspired LCs can assemble suitable colloidal particles into soft crystalline structures. PMID- 27951712 TI - Pore Structure of Macroporous Polymers Using Polystyrene/Silica Composite Particles as Pickering Stabilizers. AB - A novel approach for the preparation of interconnected macroporous polymers with a controllable pore structure was reported. The method was based on the polymerization of water-in-oil Pickering high internal phase emulsion (HIPE) stabilized by polystyrene (PS)/silica composite particles. The composite Pickering stabilizers were facilely obtained by mixing positively charged PS microspheres and negatively charged silica nanoparticles, and their amphiphilicity could be delicately tailored by varying the ratio of PS and silica. The droplet size of Pickering HIPEs was characterized using an optical microscope. The pore structure of polymer foams was observed using a scanning electron microscope. The interconnectivity of macroporous polymers was evaluated upon their gas permeability, which was greatly improved after etching PS microspheres included in the Pickering stabilizers with tetrahydrofuran. As a result, fine tailoring of the pore structure of polymer foams could be realized by simply tuning the ratio of PS to silica particles in the composite stabilizer. PMID- 27951713 TI - Two-Dimensional Alignment of Self-Assembled Organic Nanotubes through Langmuir Blodgett Technique. AB - A C3-symmetric molecule was found to form organic nanotubes through supramolecular gel formation in organic solvents. These nanotubes can be dispersed in toluene without destroying the tubular nanostructures. Using the dispersions of these organic nanotubes as "spreading solutions", Langmuir spreading films of these nanotubes were formed. Through repeated compression and expansion cycles, the nanotubes can be aligned to a certain extent. The formed Langmuir films could be subsequently transferred to a solid substrate, and the well-aligned nanotube films were constructed by Langmuir-Blodgett film deposition technique. Interestingly, many guests including polymers, water-soluble or oil soluble organic molecules can be encapsulated into the nanotubes and further spread on a water subphase. Through elaborate control, large-scale parallel alignment of self-assembled organic nanotubes encapsulated by guests was also realized. This study implies that 2D hierarchical alignment of one-dimensional organic nanostructures can be realized using a simple method. PMID- 27951714 TI - Directed Motion of Metallodielectric Particles by Contact Charge Electrophoresis. AB - We investigate the dynamics of metallodielectric Janus particles moving via contact charge electrophoresis (CCEP) between two parallel electrodes. CCEP uses a constant voltage to repeatedly charge and actuate conductive particles within a dielectric fluid, resulting in rapid oscillatory motion between the electrodes. In addition to particle oscillations, we find that micrometer-scale Janus particles move perpendicular to the field at high speeds (up to 600 MUm/s) and over large distances. We characterize particle motions and propose a mechanism based on the rotation-induced translation of the particle following charge transfer at the electrode surface. The propulsion mechanism is supported both by experiments with fluorescent particles that reveal their rotational motions and by simulations of CCEP dynamics that capture the relevant electrostatics and hydrodynamics. We also show that interactions among multiple particles can lead to repulsion, attraction, and/or cooperative motions depending on the position and phase of the respective particle oscillators. Our results demonstrate how particle asymmetries can be used to direct the motions of active colloids powered by CCEP. PMID- 27951715 TI - Incorporation of Soft Particles into Lipid Vesicles: Effects of Particle Size and Elasticity. AB - The interaction between particles and lipid biomembranes plays an essential role in many fields such as endocytosis, drug delivery, and intracellular traffic. Here we conduct a theoretical study on the incorporation of elastic particles of different sizes and rigidities into a lipid vesicle through adhesive wrapping. It is shown that while the incorporation of relatively small particles involves smooth shape evolution, the vesicle wrapping of large particles exhibits a discontinuous shape transition, followed by a protrusion of the vesicle membrane at infinitesimal cost of elastic deformation energy. Moreover, softer particles require stronger adhesion energy to achieve successful internalization and delay the onset of discontinuous shape transition to a higher wrapping degree. Depending on the adhesion energy, particle-vesicle size, and rigidity ratios, and the spontaneous curvature of the vesicle, a rich variety of wrapping phase diagrams consisting of stable and metastable states of no-wrapping, partial wrapping, and full-wrapping are established. The underlying mechanism of the discontinuous shape transformation of the vesicle and the relation between the uptake proneness and uptake efficiency are discussed. These results shed further light on the elasticity effects in cellular uptake of elastic particles and may provide rational design guidelines for controlled endocytosis and diagnostics delivery. PMID- 27951716 TI - Size Dependent Mechanical Properties of Monolayer Densely Arranged Polystyrene Nanospheres. AB - In contrast to macroscopic materials, the mechanical properties of polymer nanospheres show fascinating scientific and application values. However, the experimental measurements of individual nanospheres and quantitative analysis of theoretical mechanisms remain less well performed and understood. We provide a highly efficient and accurate method with monolayer densely arranged honeycomb polystyrene (PS) nanospheres for the quantitatively mechanical characterization of individual nanospheres on the basis of atomic force microscopy (AFM) nanoindentation. The efficiency is improved by 1-2 orders, and the accuracy is also enhanced almost by half-order. The elastic modulus measured in the experiments increases with decreasing radius to the smallest nanospheres (25-35 nm in radius). A core-shell model is introduced to predict the size dependent elasticity of PS nanospheres, and the theoretical prediction agrees reasonably well with the experimental results and also shows a peak modulus value. PMID- 27951717 TI - Wireless Synthesis and Activation of Electrochemiluminescent Thermoresponsive Janus Objects Using Bipolar Electrochemistry. AB - In this work, bipolar electrochemistry (BPE) is used as a dual wireless tool to generate and to activate a thermoresponsive electrochemiluminescent (ECL) Janus object. For the first time, BPE allows regioselective growth of a poly(N isopropylacrylamide) (pNIPAM) hydrogel film on one side of a carbon fiber. It is achieved thanks to the local reduction of persulfate ions, which initiate radical polymerization of NIPAM. By controlling the electric field and the time of the bipolar electrochemical reactions, we are able to control the length and the thickness of the deposit. The resulting pNIPAM film is found to be swollen in water at room temperature and collapsed when heated above 32 degrees C. We further incorporated a covalently attached ruthenium complex luminophore, Ru(bpy)32+, in the hydrogel film. In the second time, BPE is used to activate remotely the electrogenerated chemiluminescence (ECL) of the Ru(bpy)32+ moieties in the film. We take advantage of the film responsiveness to amplify the ECL signal. Upon collapse of the film, the ECL signal, which is sensitive to the distance between adjacent Ru(bpy)32+ centers, is strongly amplified. It is therefore shown that BPE is a versatile tool to generate highly sophisticated materials based on responsive polymers, which could lead to sensitive sensors. PMID- 27951718 TI - [Molecular Pathogenesis of Colorectal Cancer]. AB - BACKGROUND: Colorectal cancer (CRC) remains a major health burden with an incidence of 1.3 million new cases worldwide and a mortality of almost 8.5%. It is the 2nd most common cancer in women (1st breast carcinoma) and 3rd most common in men (1st lung carcinoma, 2nd prostate carcinoma). CRC alongside breast, lung, prostate and stomach cancer is in the top five most common cancers in men and women worldwide. There are still more than 50% of CRC patients diagnosed with advanced disease (stage III and IV) in the Czech Republic. Genetically, CRC is a very heterogeneous disease with many factors playing key roles in pathogenesis. There are two types of CRC, hereditary with an incidence of between 5% and 10% with APC (FAP, aFAP) or MMR (HNPCC) genes affected, and sporadic colorectal cancer with an incidence of 90-95% with a lot of mutations in variable genes that accumulate during pathogenesis (APC, KRAS, MMR, microRNA, CIMP etc.). Knowledge of the molecular pathogenesis of CRC (hereditary, sporadic) is crucial for treatment, assessment of risk, prognosis, and patient follow-up. CONCLUSION: This article summarizes the molecular pathogenesis of sporadic and hereditary CRC. PMID- 27951719 TI - [Molecular Genetic Testing for Acute Myeloid Leukemia]. AB - BACKGROUND: Acute myeloid leukemia (AML) is a clinically complex and very heterogeneous disease at the molecular level. Conventional cytogenetic analysis and FISH (fluorescence in situ hybridization) tests provide important information about the biological and clinical background of the disease and enable the classification of AML patients into three risk groups. However, up to half of patients have normal cytogenetics. Determining prognosis and treatment strategies in this group of patients is challenging. The development of molecular genetic methods, including next generation sequencing in the last decade, has led to the discovery of a number of recurrent mutations that have contributed to increasing the accuracy of prognosis of those patients with cytogenetically normal AML. Besides the prognostic value of these mutations, they may also be used to monitor minimal residual disease during and after treatment of AML and additionally constitute potential targets for the development of new therapeutic agents. The importance of molecular genetic testing of all patients with AML is highlighted by the WHO classification of 2008 in which subgroups of AML are purely defined by molecular genetics markers. AIM: In this article, we provide an overview of the most significant mutations in patients with cytogenetically normal AML. We describe their significance for prognosis, their importance in monitoring minimal residual disease, and their potential for the development of new targeted therapies. Further, we briefly draw attention to the significance of gene mutation accumulation in clonal disease development and how it affects the time of AML relapse. PMID- 27951721 TI - Quality of Life, Anxiety and Depression in Patients with Differentiated Thyroid Cancer under Short Term Hypothyroidism Induced by Levothyroxine Withdrawal. AB - BACKGROUND: We studied quality of life (QOL), anxiety, and depression in patients with differentiated thyroid cancer (DTC) either during treatment with levothyroxine or during withdrawal from levothyroxine when whole-body scanning (WBS) needed to be performed. METHODS: DTC patients projected to undergo WBS were included in the study. They were studied at two time-points - the day before levothyroxine withdrawal, and one month after levothyroxine withdrawal. They were asked to fill WHOQOL-Bref, BDI-II, and HADS questionnaires at both time-points, and blood samples were taken to measure TSH, Tg, and TgAb levels. RESULTS: Twenty nine subjects (11 males) with a mean age of 42.6 +/- 14.1 years entered the study. From the first to second time-point, the mean TSH level increased from 0.73 to 106.9 U/ml and the mean Tg level increased from 20.4 to 63.6 ng/ml. QOL scores decreased in four dimensions (physical health: 67.8 to 25.7; psychological: 58.9 to 38.9; social relationship: 67.5 to 56; and environment: 57.2 to 48.8). Patients also felt more depressed (48.3% to 93.2%) and anxious (65.5% to 89.6%). All changes were statistically significant (p < 0.005). CONCLUSION: We found decreased QOL after short-term hypothyroidism, especially in physical health and psychological dimensions. We also found that patients became significantly depressed and anxious after levothyroxine withdrawal. Our findings suggest that alternative therapies, such as those employing rhTSH, should be considered for these patients. Psycho-oncological support might also be useful in helping them overcome their symptoms during short-term hypothyroidism; however, considering the reversibility of their symptoms, supportive care might be more effective.Key words: quality of life - anxiety - depression - thyroid cancer - hypothyroidism - levothyroxine - whole body scanning. PMID- 27951720 TI - [Involvement of PIWI-interacting RNAs in Cancerogenesis via the Regulation of Gene Expression]. AB - BACKGROUND: In the past few years, a number of studies have suggested that small non-coding RNAs could be promising diagnostic, prognostic and predictive biomarkers in oncology. Recently, small RNAs interacting with PIWI proteins (piRNAs) have been described. These small RNAs regulate gene expression at transcriptional and post-transcriptional levels; however, they appear to be specifically involved in silencing the transposable elements LINE and SINE and are thus considered to contribute to genomic stability. Furthermore, piRNAs participate also in other important biological processes, such as gametogenesis, chromosome segregation, and stem cell self-renewal. Although their expression was first noted in germ line cells, they are now known to be present in all tissue types and their expression is highly tissue-specific. In addition, piRNA expression is dysregulated in tumor tissues. Nevertheless, the exact function of these molecules in cancerogenesis is not known. Recently, free circulating piRNAs were reported to be stably present in body fluids, suggesting that they could serve as promising noninvasive biomarkers to enable early diagnosis, therapy response prediction, and accurate prognosis prediction of cancer patients. AIM: The aim of this review is to summarize current knowledge about piRNA biogenesis and their functions in the regulation of gene expression and transposons silencing. In addition, the review focuses on piRNAs that show dysregulated expression in different types of cancers and that could serve as potential diagnostic biomarkers and/or therapeutic targets.Key words: PIWI-interacting RNAs - piRNA - biogenesis - cancer - transposon silencing - biomarkers - therapeutic targetsThe results of this research have been acquired within CEITEC 2020 (LQ1601) project with financial contribution made by the Ministry of Education, Youths and Sports of the Czech Republic within special support paid from the National Programme for Sustainability II funds.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 23. 11. 2016Accepted: 5. 12. 2016. PMID- 27951722 TI - [Clinical and Functional Importance of Selected CASP8 and CASP9 Polymorphisms in Breast Carcinoma]. AB - BACKGROUND: Caspase-8 and caspase-9 (encoded by CASP8 and CASP9) are executive caspases of programmed cell death (apoptosis). Dysregulation of apoptosis plays an important role in cancer development, progression, and resistance to anticancer therapy. The goal of this work was to evaluate potential associations between polymorphisms in CASP8 and CASP9, previously linked to breast cancer risk, and the transcript levels of these genes (including their alternative anti apoptotic variants) in tumor tissues and the clinical characteristics of the patients. MATERIAL AND METHODS: Sanger sequencing, high resolution melting (HRM) analysis, and allelic discrimination were used to identify polymorphisms in DNA samples isolated from tumor tissues and peripheral blood lymphocytes of 60 breast carcinoma patients. Total transcript levels of CASP8 and CASP9, and levels of alternative splicing variants CASP8L and CASP9B, were quantified by real-time PCR in tumor tissues. Clinically interesting associations were validated in DNA from lymphocytes of 615 breast carcinoma patients. RESULTS: A haplotype in CASP9 composed of three polymorphisms rs4645978-rs2020903-rs4646034 was significantly associated with CASP9 expression in tumors, with the expression of the progesterone receptor and ERBB2, and with the TNBC subtype of breast carcinoma in the validation study. The associations between the rs3834129 polymorphism in CASP8 and stage of disease, rs6435074 with grade, expression of estrogen receptor and ERBB2, and rs6723097 with ERBB2 expression have not yet been validated. However, rs6723097 was associated with disease-free survival in patients treated with hormonal therapy. CONCLUSION: This study reveals a previously unknown and presumably functional (in silico) association between a haplotype in CASP9 and molecular and clinical phenotypes of breast carcinoma. The potential clinical utility of this association for prognostication of breast carcinoma should be evaluated by independent studies.Key words: breast carcinoma - caspases - polymorphisms - functional - clinical - importanceThis work was supported by grant of the CU Grant Agency No. 1444313, and grant of the Internal Grant Agency of the Czech Ministry of Health No. 15-25618A.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 3. 3. 2016Accepted: 26. 10. 2016. PMID- 27951723 TI - [A Patient with Primary Intraventricular Gliosarcoma and Long-term Survival - a Case Report]. AB - BACKGROUND: Gliosarcoma is a rare, malignant CNS tumor with a very poor prognosis. Gliosarcoma is a variant of glioblastoma multiforme, which is characterized by the presence of both glial and mesenchymal components. The treatment strategy for gliosarcomas has not yet been determined clearly. CASE PRESENTATION: This case report presents a 23-year-old female patient who complained of increasing headaches, nausea and vomiting, and slight motor weakness in her left arm. An MRI scan of the brain showed a tumor filling the anterior part of the right lateral ventricle and extending into the right frontal lobe. Tumor extirpation was performed. Histology revealed gliosarcoma. Subsequently, the patient received concomitant chemoradiotherapy with temozolomide in the Stupp regimen. Following the fourth cycle of maintenance temozolomide chemotherapy, at eight months after diagnosis, an MRI scan detected progression of the tumor residue. The patient underwent another surgery and then received 10 cycles of second-line chemotherapy in the ICE (ifosfamide, carboplatin, and etoposide) regimen. She completed oncological therapy with minimal toxicity and follow-up MRI scans showed virtually no residual tumor. Another follow-up MRI scan, performed 28 months after diagnosis, demonstrated progression of the tumor residue again. A third tumor resection was performed 29 months after initial diagnosis. Histology again confirmed gliosarcoma. An early postoperative MRI scan showed subtotal resection with a tumor residue in eloquent areas and also suspected implantation metastasis in the spinal canal at the C2 level. From the neurological perspective, the patient was fully self-sufficient, and had only a very mild motor deficit in her left arm. Currently, at 31 months after initial diagnosis, the patient is in a stable condition and fully self sufficient. CONCLUSION: Our case report shows that long-term survival can be achieved in a gliosarcoma patient exhibiting all the unfavorable features in clinical-pathological terms. The minimal recommended treatment is maximal resection followed by adjuvant radiotherapy. Our patient also underwent chemoradiotherapy with temozolomide in the Stupp regimen. Recurrence at eight months after diagnosis was managed by a repeat operation and high-dose combination chemotherapy, which kept the disease in remission for 20 months after the initial relapse. The lack of unequivocal rules for chemotherapy provides an opportunity to test less common treatment regimens.Key words: gliosarcoma - surgery - chemotherapy - radiotherapy - survivalThis study was supported in part by the grant No. NT13581-4/2012(86-91) of the Internal Grant Agency of the Czech Ministry of Health.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 26. 3. 2016Accepted: 27. 4. 2016. PMID- 27951724 TI - [Intervention Exercise Program for Cancer Patients with Breast Cancer]. AB - BACKGROUND: Movement is a sign of life and regular physical activity has an indisputable influence on each and every person. When applied selectively to patients after cancer therapy, physical activity, including rehabilitation, positively contributes to complete recuperation and improves quality of life. Our interventional exercise program for cancer patients was prepared and implemented on the basis of reports in the medical literature and on the lecturers own experience. The interventional exercise program was divided into two parts - body and mind and body fitness. AIM: Besides increasing self-confidence and improving quality of life, the aim of the exercise program was to improve cardiovascular function, basal metabolism, muscular strength and endurance, and joint flexibility and to strengthen phasic muscles and stretch tonic muscles, both of which are important for balance.Key words: breast cancer - exercise - quality of lifeThe authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 15. 9. 2016Accepted: 5. 10. 2016. PMID- 27951725 TI - Health concerns associated with unconventional gas mining in rural Australia. AB - CONTEXT: Many governments globally are investigating the benefits and risks associated with unconventional gas mining for shale, tight and coal seam gas (coalbed methane) to determine whether the industry should proceed in their jurisdiction. Most locations likely to be developed are in rural areas, with potential impact on farmers and small communities. Despite significant health concerns, public health knowledge and growing evidence are often overlooked in decision-making. It is difficult to gain a broad but accurate understanding of the health concerns for rural communities because the evidence has grown very recently and rapidly, is complex and largely based in the USA, where the industry is advanced. In 2016, a concerned South Australian beef and lamb farmer in an area targeted for potential unconventional gas development organised visits to homes in developed unconventional gas areas of Pennsylvania and forums with leading researchers and lawyers in Pennsylvania and New York. Guided by priorities identified during this trip, this communication concisely distils the research evidence on these key concerns, highlighting the Australian situation where evidence exists. It summarises key information of particular concern to rural regions, using Australia as an example, to assist rural health professionals to be better prepared to engage in decision-making and address the challenges associated with this new industry. ISSUES: Discussions with communities and experts, supported by the expanding research from the USA and Australia, revealed increasing health concerns in six key areas. These are absence of a safe solution to the toxic wastewater management problems, air pollution, land and water competition, mental health and psychosocial wellbeing risks, fugitive methane emissions and lack of proven regulatory regimes. Emerging epidemiological studies suggesting interference with foetal development and birth outcomes, and exacerbation of asthma conditions, are particularly concerning to rural families and livestock. LESSONS LEARNED: Rural residents in potentially affected areas should be supported to access and interpret the best current evidence regarding the multiple health concerns associated with unconventional gas mining. This knowledge should be part of wider discourse and decision-making processes driving local economic development and national and global energy choices. PMID- 27951726 TI - The Global Burden of Disease Study 2015 and Blood Pressure. PMID- 27951727 TI - Analysing use of the Chinese HHIE-S for hearing screening of elderly in a northeastern industrial area of China. AB - OBJECTIVE: The aim of the present study was to investigate the use of Chinese version of HHIE-S as a hearing screening tool for the elderly in an industrial area in northeast China. DESIGN: Prevalence, sensitivity and specificity of Chinese version of HHIE-S were calculated. Factors that had impact on HHIE-S were analysed. STUDY SAMPLE: Five hundred and seventy Mandarin speaking participants, aged from 50 to 85 years were included. They were tested with pure tone audiometry and Chinese version of HHIE-S. RESULTS: The prevalence of hearing handicap was 55.3%. The sensitivity and specificity of HHIE-S were 84.5% and 58.3% respectively when the pass/fail criteria were set at PTA0.5-4kHz >40 dBHL. In general, HHIE-S total and subscale scores were significantly associated with severity of hearing impairment. After stratified by severity of hearing impairment, both the prevalence of reported handicap and the scores of HHIE-S were not significantly associated with age. Male participants had significantly higher HHIE-S scores than female participants did. CONCLUSIONS: The Chinese version of HHIE-S contributes useful information to identifying hearing handicap and addressing the rehabilitative needs in the elderly in an industrial city in Mainland China. PMID- 27951729 TI - The incorporation of comorbidities in the prognostication of patients with lower risk myelodysplastic syndrome. AB - Chronic medical diseases, evaluated by several comorbidities indexes have been reported to influence on overall survival in patients with myelodysplastic syndrome (MDS). However, these studies included patients with lower and higher risk disease by IPSS. This study retrospectively evaluates the role of comorbidities (evaluated by the MDS comorbidity index; MDS-CI) together with clinical parameters in a series of 232 patients with LR-MDS (defined as either an IPSS score of low/intermediate-1 and favorable cytogenetic categories by IPSS-R). In multivariate analysis, together with age >75 years, diabetes requiring therapy and hemoglobin <10 g/dL; the incorporation of comorbidities by the MDS-CI (HR = 2.5; p< 0.0001) were independently associated to the probability of nonleukemic death (NLD). The combination of these variables allowed development of a model, which categorizes patients in three different groups with significantly different probability of NLD overtime (p< 0.001). This integrated score confirms the importance of comorbidities at diagnosis of patients with LR-MDS. PMID- 27951731 TI - Learning to listen and mindful practice. PMID- 27951728 TI - Effects of astaxanthin on blood coagulation, fibrinolysis and platelet aggregation in hyperlipidemic rats. AB - CONTEXT: Astaxanthin (ASTX) is a xanthophyll carotenoid that reduces hemostasis in hyperlipidemic organisms. Its antihemostatic mechanisms remain unclear. OBJECTIVE: The effects of ASTX on coagulation, the fibrinolytic system and platelet aggregation were investigated in hyperlipidemic rats. MATERIALS AND METHODS: Different doses of ASTX (5, 10 and 30 mg/kg/day, p.o.) were administered for four weeks to high-fat diet-induced hyperlipidemic rats. Serum lipid and lipoprotein levels were measured with an automatic biochemical analyzer. The prothrombin time (PT), activated partial thromboplastin time (APTT) and maximum platelet aggregation rate (MAR) were determined by a coagulation analyzer. The activities of the tissue-type plasminogen activator (t-PA), type-1 plasminogen activator inhibitor (PAI-1) and endothelial nitric oxide synthase (eNOS), as well as the levels of thromboxane B(2) [TXB(2)], 6-keto prostaglandin F(1alpha) [6 keto-PGF(1alpha)] and platelet granule membrane protein (GMP-140), were measured with enzyme-linked immunosorbent assay kits. Gene and protein expression levels were analyzed by reverse transcriptase polymerase chain reaction and Western blot, respectively. RESULTS: ASTX (30 mg/kg) treatment in hyperlipidemic rats reduced serum TG (0.58 +/- 0.14 versus 1.12 +/- 0.24 mmol/L), serum TC (1.77 +/- 0.22 versus 2.24 +/- 0.21 mmol/L), serum LDL-C (1.13 +/- 0.32 versus 2.04 +/- 0.48 mmol/L), serum MDA (69%), plasma MAR (55%), serum TXB2/6-keto-PGF1alpha (34%) and serum GMP-140 levels (25%), plasma PAI-1 activity (48%) and downregulated the mRNA (33%) and protein (23%) expression of aorta eNOS, the mRNA (79%) and protein (72%) expression levels of aorta PAI-1. However, ASTX (30 mg/kg/d) treatment increased serum SOD activity (2.1 fold), serum GPx activity (1.8 fold), plasma PT (1.3 fold), plasma APTT (1.7 fold), serum NO (1.4-fold), serum 6-keto-PGF1alpha (1.3 fold). CONCLUSIONS: ASTX reduced blood coagulation and platelet aggregation and promoted fibrinolytic activity in hyperlipidemic rats. These activities were closely correlated with ASTX, maintaining the balance of t-PA/PAI-1, NO/ROS and TXA2/PGI2 in vivo. PMID- 27951732 TI - Educational innovations to foster resilience in the health professions. AB - Stress and burnout of healthcare providers has become a major healthcare issue that has implications for not only workforce projections, but the cost and quality of care and the lives of healthcare providers and their families. Burnout, characterized by loss of enthusiasm for work, feelings of cynicism and a low sense of personal accomplishment is associated with early retirement, alcohol use, and suicidal ideation. Healthcare professional "wellbeing" or "care of the caregiver" is a topic that has not been significantly addressed in the education of healthcare professionals. The culture that has dominated much of education has been one where students have been expected to forego personal needs, endure stressful environments, and emerge from highly competitive and often dysfunctional environments to work in care settings where health and wellbeing is also largely ignored. Three curricular innovations are highlighted that target pre-professional students, students enrolled in health professions education and practicing health care professionals. Strategies are highlighted that both help individuals cultivate resiliency and wellbeing in their personal and professional lives and that address system issues that contribute to unhealthy learning and work environments. PMID- 27951733 TI - A comparison of the heating characteristics of capacitive and radiative superficial hyperthermia. AB - BACKGROUND: Superficial hyperthermia is applied in combination with radiotherapy for e.g. melanoma and recurrent breast cancer, using both capacitive and radiative systems. In this paper, numerical simulations are applied to address the question which technique yields the most favourable heating characteristics. METHODS: A 434 MHz contact flexible microstrip applicator (CFMA type 4H, size 19.6 * 19.6 cm2) and a capacitive system consisting of two circular electrodes with diameter 15 and 25 cm were modelled. The water bolus of the CFMA was filled with deionised water and for capacitive heating both saline and deionised water were modelled. Specific absorption rate (SAR) and temperature simulations were performed for a perfused muscle-equivalent phantom and phantoms with a 1 cm thick superficial fat layer, assuming cylindrical target regions. Subsequently, a real patient model with a chest wall recurrence was studied with the target assumed to have muscle-like properties, fat properties or heterogeneous properties as derived from the CT Hounsfield Units. RESULTS: Phantom simulations showed that high SAR peaks occur around the bolus edges with capacitive heating. Power absorption below the fat layer is substantially higher for radiative heating and unless the target region is limited to the fat layer, radiative heating yields better target coverage in terms of SAR and temperature. Patient simulations showed that the T90 for radiative heating was 0.4-1.1 degrees C higher compared with capacitive heating. CONCLUSIONS: Radiative heating yields more favourable SAR and temperature distributions for superficial tumours, compared with capacitive heating, especially within heterogeneous tissues. Higher tumour temperatures are achieved without occurrence of treatment limiting hot spots. PMID- 27951730 TI - Long non-coding RNA GAS5 polymorphism predicts a poor prognosis of acute myeloid leukemia in Chinese patients via affecting hematopoietic reconstitution. AB - Whether long non-coding RNA (lncRNA) single-nucleotide polymorphisms (SNPs) affect prognosis of acute myeloid leukemia (AML) remains unknown. To search the association between lncRNA SNPs and AML outcomes, thirty tagSNPs in five lncRNAs were genotyped in 313 AML patients. Survival analysis indicated that GAS5 rs55829688 (T > C) was significantly associated with prognosis of AML (p = 0.018). Patients with rs55829688 CC genotype showed higher GAS5 expression in peripheral blood mononuclear cells (PBMCs) (p = 0.025) and harbored a longer platelets recovery (p = 0.040) than carriers of rs55829688T allele. In vitro study indicated that GAS5 promoter harboring the rs55829688C allele showed marginally increased reporter gene activity (p = 0.019), and the promoter activity was increased by TP63 in a dose-dependent manner (P = 0.001). Moreover, GAS5 higher expression predict shorter AML overall survival (OS), which validated in GEO GSE12417 dataset (p = 0.011). In conclusion, rs55829688 polymorphism could increase GAS5 expression by interacting with TP63, which might aggravate the myelosuppression and in turn lead to poor prognosis in AML. Trail registration number: ChiCTR-PPC-14005297. PMID- 27951734 TI - Caregiver mental health and HIV-infected child wellness: perspectives from Ugandan caregivers. AB - Prior studies indicate a substantial link between maternal depression and early child health but give limited consideration to the direction of this relationship or the context in which it occurs. We sought to create a contextually informed conceptual framework of this relationship through semi-structured interviews with women that had lived experience of caring for an HIV-infected child while coping with depression and anxiety symptoms. Caregivers explained their role in raising healthy children as complex and complicated by poverty, stigma, and isolation. Caregivers discussed the effects of their own mental health on child well-being as primarily emotional and behavioral, and explained how looking after a child could bring distress, particularly when unable to provide desired care for sick children. Our findings suggest the need for investigation of the reciprocal effects of child sickness on caregiver wellness and for integrated programs that holistically address the needs of HIV-affected families. PMID- 27951735 TI - Response to: Can gaming turn doctors into better tacticians? PMID- 27951736 TI - Efficacy of antithymocyte globulin for allogeneic hematopoietic cell transplantation: a systematic review and meta-analysis. AB - The efficacy of rabbit antithymocyte globulin (ATG) for the prevention of graft versus-host disease (GVHD) has been evaluated in several randomized control trials, but the results show some discrepancies. Therefore, we performed a systematic review and meta-analysis covering the latest RCTs including six trials (total 845 patients). The incidence of acute and chronic GVHD was significantly lower in the ATG arms (risk ratio, 0.75 and 0.54, respectively). No significant differences were found regarding overall survival, the incidence of relapse, and non-relapse mortality; however, the incidence of cytomegalovirus and Epstein-Barr virus reactivation increased (risk ratio, 1.25 and 1.33), and neutrophil engraftment was significantly delayed (median, 2.66 days). In conclusion, rabbit ATG should be beneficial as a GVHD prophylaxis in addition to conventional regimens, with close monitoring of virus reactivation and enough attention to delayed engraftment. Studies comparing the timing and dosage of ATG are essential to determine the suitable prophylactic regimens. PMID- 27951738 TI - Functionality of hearing aids: state-of-the-art and future model-based solutions. AB - A review about technical and perceptual factors in hearing aid technology, research and development is provided, covering current commercial solutions, underlying models of hearing loss for usage in hearing devices and emerging future technical solutions for hearing aid functionalities. A chain of techniques has provided incremental, but steady increases in user benefit, e.g. in the fields of hearing aid amplification, feedback suppression, dynamic compression, noise reduction and situation adaptation. The models describing the perceptual consequences of sensorineural hearing impairment describe the effects on the acoustical level, the neurosensory level and the cognitive level and provide the framework for compensatory (or even substitutional) functions of hearing aids in terms of the attenuation component, the distortion component and the neural component of the hearing loss. A major factor is the requirement of a strong individualisation of hearing aid solutions calling for an appropriate assessment of the different sensorineural components of a hearing loss, especially with respect to bilateral and binaural hearing aid solutions. PMID- 27951740 TI - Cultural influence on directional tendencies in children's drawing. AB - The present study was aimed at investigating how print experience as a cultural factor influences directional tendencies in children's drawing in the interplay with biomechanical (hand), syntactic (shape orientation) and semantic (shape meaning) factors. Eighty-eight right-handed children from three literacy/age groups (preliterate, first graders and third graders) had to copy a geometrical shape adapted from the Rey-Osterrieth complex figure. The shape was presented alternatively leftward and rightward, while using both dominant (right) and non dominant (left) hands. Directional tendencies were assessed regarding directionality of drawing movements at global, intermediate and local levels and deviation error in centre line bisection. Results show a global improvement of drawing quality and strategies across groups and an advantage for the dominant right hand from 6 years onward. Regarding directional tendencies, a reinforcement of a congruency effect between conditions and writing direction was found from preliterates to third graders. These results are discussed as a cultural embodiment process and have implications for psychological testing. PMID- 27951737 TI - A systematic review of the active saikosaponins and extracts isolated from Radix Bupleuri and their applications. AB - CONTEXT: Radix Bupleuri has been used in traditional Chinese medicine for over 2000 years with functions of relieving exterior syndrome, clearing heat, regulating liver-qi, and lifting yang-qi. More natural active compounds, especially saikosaponins, have been isolated from Radix Bupleuri, which possess various valuable pharmacological activities. OBJECTIVE: To summarize the current knowledge on pharmacological activities, mechanisms and applications of extracts and saikosaponins isolated from Radix Bupleuri, and obtain new insights for further research and development of Radix Bupleuri. METHODS: PubMed, Web of Science, Science Direct, Research Gate, Academic Journals and Google Scholar were used as information sources through the inclusion of the search terms 'Radix Bupleuri', 'Bupleurum', 'saikosaponins', 'Radix Bupleuri preparation', and their combinations, mainly from the year 2008 to 2016 without language restriction. Clinical preparations containing Radix Bupleuri were collected from official website of China Food and Drug Administration (CFDA). RESULTS AND CONCLUSION: 296 papers were searched and 128 papers were reviewed. A broad spectrum of in vitro and in vivo research has proved that Radix Bupleuri extracts, saikosaponin a, saikosaponin d, saikosaponin c, and saikosaponin b2, exhibit evident anti inflammatory, antitumor, antiviral, anti-allergic, immunoregulation, and neuroregulation activities mainly through NF-kappaB, MAPK or other pathways. 15 clinical preparations approved by CFDA remarkably broaden the application of Radix Bupleuri. The main side effect of Radix Bupleuri is liver damage when the dosage is excess, which indicates that the maximum tolerated dose is critical for clinical use of Radix Bupleuri extract and purified compounds. PMID- 27951739 TI - Phytochemical, antioxidant and protective effect of cactus cladodes extract against lithium-induced liver injury in rats. AB - CONTEXT: Opuntia ficus-indica (L.) Mill. (Castaceae) (cactus) is used in Tunisian medicine for the treatment of various diseases. OBJECTIVE: This study determines phytochemical composition of cactus cladode extract (CCE). It also investigates antioxidant activity and hepatoprotective potential of CCE against lithium carbonate (Li2CO3)-induced liver injury in rats. MATERIALS AND METHODS: Twenty four Wistar male rats were divided into four groups of six each: a control group given distilled water (0.5 mL/100 g b.w.; i.p.), a group injected with Li2CO3 (25 mg/kg b.w.; i.p.; corresponding to 30% of the LD50) twice daily for 30 days, a group receiving only CCE at 100 mg/kg of b.w. for 60 days and then injected with distilled water during the last 30 days of CCE treatment, and a group receiving CCE and then injected with Li2CO3 during the last 30 days of CCE treatment. The bioactive components containing the CCE were identified using chemical assays. RESULTS: Treatment with Li2CO3 caused a significant change of some haematological parameters including red blood cells (RBC), white blood cells (WBC), haemoglobin content (Hb), haematocrit (Ht) and mean corpuscular volume (VCM) compared to the control group. Moreover, significant increases in the levels of glucose, cholesterol, triglycerides and of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) activities were observed in the blood of Li2CO3-treated rats. Furthermore, exposure to Li2CO3 significantly increased the LPO level and decreased superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities in the hepatic tissues. CONCLUSION: CCE possesses a significant hepatoprotective effect. PMID- 27951741 TI - Outcomes of reintervention after failed urethroplasty. AB - OBJECTIVE: Urethroplasty is a procedure that has a high success rate. However, there exists a small subgroup of patients who require multiple procedures to achieve an acceptable result. This study analyses the outcomes of a series of patients with failed urethroplasty. MATERIALS AND METHODS: This is a retrospective review of 82 failures out of 407 patients who underwent urethroplasty due to urethral stricture during the period 1999-2013. Failure was defined as the need for an additional surgical procedure. Of the failures, 26 patients had penile strictures and 56 had bulbar strictures. Meatal strictures were not included. RESULTS: The redo procedures included one or multiple direct vision internal urethrotomies, dilatations or new urethroplasties, all with a long follow-up time. The patients underwent one to seven redo surgeries (mean 2.4 procedures per patient). In the present series of patients, endourological procedures cured 34% (28/82) of the patients. Ten patients underwent multiple redo urethroplasties until a satisfactory outcome was achieved; the penile strictures were the most difficult to cure. In patients with bulbar strictures, excision with anastomosis and substitution urethroplasty were equally successful. Nevertheless, 18 patients were defined as treatment failures. Of these patients, nine ended up with clean intermittent self-dilatation as a final solution, five had perineal urethrostomy and four are awaiting a new reintervention. Complicated cases need centralized professional care. CONCLUSION: Despite the possibility of needing multiple reinterventions, the majority of patients undergoing urethroplasty have a good chance of successful treatment. PMID- 27951743 TI - Determination of dihydromyricetin in rat plasma by LC-MS/MS and its application to a pharmacokinetic study. AB - CONTEXT: The pharmacokinetics properties of dihydromyricetin (DHM) are still unknown. OBJECTIVE: This study investigates the pharmacokinetic characteristics of DHM using a sensitive and reliable LC-MS/MS method. MATERIALS AND METHODS: A rapid and sensitive LC-MS/MS method was developed for the determination of DHM in male Sprague-Dawley rat plasma. Twelve rats were equally randomized into two groups, including the intravenous group (2 mg/kg) and the oral group (20 mg/kg). Blood samples (250 MUL) were collected at designated time points and analyzed using this method. The pharmacokinetic parameters were calculated using DAS 3.0 pharmacokinetic software. RESULTS: The calibration curve was linear within the range of 0.5-200 ng/mL (r > 0.998) with the lower limit of quantification at 0.5 ng/mL. After the intravenous injection, DHM reached a maximum concentration of 165.67 +/- 16.35 ng/mL, and t1/2 was 2.05 +/- 0.52 h. However, DHM was not readily absorbed and reached Cmax 21.63 +/- 3.62 ng/mL at approximately 2.67 h following the oral administration of DHM, and t1/2 was 3.70 +/- 0.99 h. The MRT for the intravenous group and the oral group were 2.62 +/- 0.36 and 5.98 +/- 0.58 h, respectively. The AUC(0-t) for the intravenous group and the oral group were 410.73 +/- 78.12 and 164.97 +/- 41.76 ng.L/mL, respectively, so the absolute bioavailability of DHM was 4.02% which was poor. DISCUSSION AND CONCLUSION: The results indicated that the bioavailability was poor. Further work needs to be conducted to investigate the reason for poor bioavailability and improve this situation. PMID- 27951744 TI - [Prevention of eating disorder: a review]. AB - Eating disorders are severe mental illnesses that are challenging to treat and often follow a chronic course. They are associated withimmense impairment on the psychological, physical, interpersonal, and social level as well as signifi cant direct and indirect cost. Therefore,prevention and early intervention are of utmost importance. Based on a qualitative literature review, we summarized the empirical evidence forthe effi cacy of universal and selective prevention of eating disorders. Programs available in German and/or English were included in the review.In addition to research on effi cacy and effectiveness, the areas of implementation, dissemination, and reach were identifi ed as key issues forfuture studies. Furthermore, more research is needed on the relationship of cost, benefi t, and risks of eating disorder prevention. PMID- 27951742 TI - Healing effect of Dillenia indica fruit extracts standardized to betulinic acid on ultraviolet radiation-induced psoriasis-like wounds in rats. AB - CONTEXT: Dillenia indica Linn. (Dilleniaceae) is traditionally used to treat skin inflammation. OBJECTIVE: This study evaluated the healing effect of Dillenia indica fruit extracts on induced psoriasis-like wounds in Wistar rats. MATERIALS AND METHODS: Extracts were standardized to betulinic acid, including an aqueous ethanolic extract (AEE), ethyl acetate extract (EAE) and petroleum ether extract. Effects against lipid peroxidation were assessed in vitro. Wounds were created at rat tails (n = 12). Topical treatments were applied once daily for 7 days (1 mL of AEE or EAE at 5 or 50 mg/mL). Maximal dose was defined by the extract solubility. A 10-fold lower dose was also tested. Positive and negative controls were treated with clobetasol (0.5 mg/mL) or excipient. Half of each group was euthanized for histology. The remaining animals were observed for 20 days for wound measurements. RESULTS: Yields of AEE and EAE were 4.3 and 0.7%, respectively. Betulinic acid concentrations in AEE and EAE were 4.6 and 107.6 mg/g. Extracts neutralized lipid peroxidation in vitro at 0.02 MUg/mL, accelerating healing at 50 mg/mL. Complete healing in mice treated with AEE occurred 16 days after wound induction. This time was 14 and 12 days in mice treated with EAE and clobetasol. Compared to orthokeratosis, parakeratosis was reduced by AEE (25%), EAE (45%) and clobetasol (55%). EAE caused superior protection against biomolecules oxidation of skin compared to AEE. DISCUSSION AND CONCLUSION: EAE exhibited activity closer to that of clobetasol. Betulinic acid may be an active constituent, which should be assessed in future studies. PMID- 27951745 TI - Studies on phytochemical, antioxidant, anti-inflammatory, hypoglycaemic and antiproliferative activities of Echinacea purpurea and Echinacea angustifolia extracts. AB - CONTEXT: Echinacea (Asteraceae) is used because of its pharmacological properties. However, there are few studies that integrate phytochemical analyses with pharmacological effects. OBJECTIVE: Evaluate the chemical profile and biological activity of hydroalcoholic Echinacea extracts. MATERIALS AND METHODS: Density, dry matter, phenols (Folin-Ciocalteu method), flavonoids (AlCl3 method), alkylamides (GC-MS analysis), antioxidant capacity (DPPH and ABTS methods), antiproliferative effect (SRB assay), anti-inflammatory effect (paw oedema assay, 11 days/Wistar rats; 0.4 mL/kg) and hypoglycaemic effect (33 days/Wistar rats; 0.4 mL/kg) were determined in three Echinacea extracts which were labelled as A, B and C (A, roots of Echinacea purpurea L. Moench; B, roots, leaves, flowers and seeds of Echinacea purpurea; C, aerial parts and roots of Echinacea purpurea and roots of Echinacea angustifolia DC). RESULTS: Extract C showed higher density (0.97 g/mL), dry matter (0.23 g/mL), phenols (137.5 +/- 2.3 mEAG/mL), flavonoids (0.62 +/- 0.02 mEQ/mL), and caffeic acid (0.048 mg/L) compared to A and B. A, B presented 11 alkylamides, whereas C presented those 11 and three more. B decreased the oedema (40%) on day 2 similar to indomethacin. A and C showed hypoglycaemic activity similar to glibenclamide. Antiproliferative effect was only detected for C (IC50 270 MUg/mL; 8171 MUg/mL; 9338 MUg/mL in HeLa, MCF-7, HCT-15, respectively). DISCUSSION AND CONCLUSION: The difference in the chemical and pharmacological properties among extracts highlights the need to consider strategies and policies for standardization of commercial herbal extracts in order to guarantee the safety and identity of this type of products. PMID- 27951746 TI - Glutathione sulfotransferase inhibition activity of a self-fermented beverage, Kanji. AB - CONTEXT: Kanji, a liquid preparation of roots of Daucus carota L. ssp. sativus (Hoffm.) Arcang. var. vavilovii Mazk. (Apiaceae), may inhibit glutathione sulfotransferase (GST) activity due to ferulic acid content. OBJECTIVES: GST inhibition activity and characterization of Kanji and methanol extract of D. carota roots, and oral absorption pattern of ferulic acid from Kanji in rats. MATERIALS AND METHODS: GST inhibition activity of Kanji and methanol extract of D. carota roots in concentration range 0.001-100.00 mg/mL was determined using Sprague Dawley rat liver cytosolic fraction. Methanol extract upon column chromatography gave ferulic acid, which was used to characterize Kanji and determine its oral absorption pattern in Wistar rats. RESULTS: The GST inhibition activity of Kanji (100.00 MUg/mL), methanol extract of D. carota roots (100.00 MUg/mL) and tannic acid (10.00 MUg/mL, positive control) was found to be 0.162 +/ 0.016, 0.106 +/- 0.013 and 0.073 +/- 0.004 MUM/min/mg, respectively. Different Kanji samples and methanol extract contained ferulic acid (0.222-0.316 mg/g) and 0.77 mg/g, respectively. Ferulic acid did not appear in plasma after oral administration of Kanji. DISCUSSION: Kanji having solid contents 80.0 MUg/mL, equivalent to 0.0025 MUg/mL ferulic acid, does not inhibit the activity of GST. The oral administration of Kanji, in human equivalent dose (528 mg/kg, 16.67 MUg ferulic acid), to rats indicated poor absorption of ferulic acid. CONCLUSION: Kanji having solid contents 14-36 mg/mL does not inhibit GST activity, hence may not interfere with drugs that are the substrates of GST, if taken concomitantly. PMID- 27951747 TI - Differences between left- and right-sided neglect revisited: A large cohort study across multiple domains. AB - : Unilateral spatial neglect (USN) is a syndrome that can occur after right- and left-hemisphere damage. It is generally accepted that left-sided USN is more severe than right-sided USN. Evidence for such a difference in other domains is lacking. Primary aims were to compare frequency, severity, region specificity, cognition, physical functioning, and physical independence between left and right USN. Secondary aims were to compare lesion characteristics. A total of 335 stroke patients admitted for inpatient rehabilitation were included. The severity of the lateralized attentional deficit was measured with a shape cancellation and line bisection test (in peripersonal and extrapersonal space) and the Catherine Bergego scale. The Mini-Mental State Examination, Stichting Afasie Nederland score, search organization (i.e., best R and intersections rate), Motricity Index, balance, mobility, and self-care were assessed. Measures were statistically compared between left, right, and no USN patients. Lesion overlay plots were compared with lesion subtraction analyses. RESULTS: Left USN (15.82%) was more frequent than right USN (9.25%). Demographic and stroke characteristics were comparable between groups. The lateralized attentional deficit was most severe in left USN. USN in both peripersonal and extrapersonal space was more frequently left-sided in nature. Search efficiency was lower in left USN. Balance was poorer in right USN. No differences between left and right USN were found for cognitive ability, communication, motor strength, mobility, and self-care. Most patients with left USN had right-hemispheric lesions, whereas patients with right USN could have lesions in either the left or the right hemisphere. To conclude, left and right USN are both common after stroke. Although the lateralized attention deficit is worse in left than in right USN, consequences at the level of physical functioning and physical independence are largely comparable. From a clinical perspective, it is important to systematically screen for USN, both after right- and after left-hemisphere damage. PMID- 27951748 TI - Remediation of groundwater contaminated with the lead-phenol binary system by granular dead anaerobic sludge-permeable reactive barrier. AB - Computer solutions (COMSOL) Multiphysics 3.5a software was used for simulating the one-dimensional equilibrium transport of the lead-phenol binary system including the sorption process through saturated sandy soil as the aquifer and granular dead anaerobic sludge (GDAS) as the permeable reactive barrier. Fourier transform infrared spectroscopy analysis proved that the carboxylic and alcohol groups are responsible for the bio-sorption of lead onto GDAS, while phosphines, aromatic and alkane are the functional groups responsible for the bio-sorption of phenol. Batch tests have been performed to characterize the equilibrium sorption properties of the GDAS and sandy soil in lead and/or phenol containing aqueous solutions. Numerical and experimental results proved that the barrier plays a potential role in the restriction of the contaminant plume migration and there is a linear relationship between longevity and thickness of the barrier. A good agreement between these results was recognized with root mean squared error not exceeding 0.04. PMID- 27951749 TI - Confirmation of beta-agonist residues in bovine retina and liver using HPLC-MS/MS and evaluation of matrix-dependent problems. AB - beta-Agonists or beta-adrenergic agonists are synthetic drugs sometimes used for therapeutic purposes in veterinary medicine. However, these compounds also belong to a class of illegal growth promoters that decrease the fat content in farm animals. The purpose of this study was to develop an analytical LC-MS/MS confirmatory method for the detection of nine beta-agonists in bovine retina and liver tissues. The obtained CCalpha values ranged from 0.29 to 1.54 ug kg-1 in retina and from 0.03 to 0.18 ug kg-1 in liver, and CCbeta values from 0.50 to 2.63 ug kg-1 and from 0.05 to 0.30 ug kg-1, respectively. Additionally, the importance of a matrix effect in these two tissues for the achievement of accurate detection of non-compliant samples was studied and discussed. It was concluded that the main characteristic of this phenomena is its considerable variability from one animal to another. Also, the total amount of matrix in the final extract can provide differences in the matrix-matched calibration line. PMID- 27951751 TI - Distancing the present self from the past and the future: Psychological distance in anxiety and depression. AB - Humans show a systematic tendency to perceive the future as psychologically closer than the past. Based on the clinical hypothesis that anxiety would be associated more with future threat life events, whereas depression with past loss events, here we explored whether people with anxiety- and depression-related personality traits perceive differently the psychological distance of temporal events. Results showed that the common tendency to perceive the future as psychologically closer than the past is exaggerated in individuals with anxiety related personality traits, whereas this asymmetry drastically shrinks in individuals with depression-related personality traits. Beyond substantiating the hypothesis that the past and the future are differently faced by people with depression- and anxiety-related personality traits, the present findings suggest that temporal orientation of one's self may be greatly altered in anxiety and depression. PMID- 27951752 TI - The differential recruitment of short-term memory and executive functions during time, number, and length perception: An individual differences approach. AB - Developmental, behavioural, and neurological similarities in the processing of different magnitudes (time, number, space) support the existence of a common magnitude processing system (e.g., a theory of magnitude, ATOM). It is, however, unclear whether the recruitment of wider cognitive resources (short-term memory, STM; and executive function) during magnitude processing is similar across magnitude domains or is domain specific. The current study used an individual differences approach to examine the relationship between STM, executive function, and magnitude processing. In two experiments, participants completed number, length, and duration bisection tasks to assess magnitude processing and tasks that have been shown to assess STM span and executive component processes. The results suggest that the recruitment of STM and executive resources differed for the different magnitude domains. Duration perception was associated with access, inhibition, and STM span. Length processing was associated with updating, and number processing was associated with access to semantic memory. For duration and length, greater difficulty in the magnitude judgement task resulted in more relationships to STM and executive function. It is suggested that duration perception may be more demanding of STM and executive resources because it is represented sequentially, unlike length and number which can be represented nonsequentially. PMID- 27951753 TI - Novel imaging modalities for the comparison of bone microarchitecture among HIV+ patients with and without fractures: a pilot study. AB - BACKGROUND: HIV-infected adults have increased fracture risk. OBJECTIVES: To generate pilot data comparing bone density, structure, and strength between HIV infected adults with and without a prior fracture. METHODS: Adults with and without a prior fracture after their HIV diagnosis were matched 1:1 based on age, sex, race, and smoking history. Participants underwent dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS), hip structural analyses (HSA), vertebral fracture assessment (VFA), high-resolution peripheral quantitative tomography (HR-pQCT) and measurement of bone turnover markers. Results were compared between cases and controls, with differences expressed as percentages of control group values. RESULTS: 23 pairs were included. On DXA, cases had lower areal bone mineral density (aBMD) at the total hip (median difference in T-score 0.25, p = 0.04), but not the lumbar spine (median difference in T-score 0.10, p = 0.68). Cases had greater abnormalities in HSA and most HR-pQCT and HSA measures, by up to 15%. VFA revealed two subclinical fractures among cases but none among controls. TBS, CTX, and P1NP levels were similar between groups, with differences of 1.9% (p = 0.90), 9.7% (p = 0.55), and 10.0% (p = 0.24), respectively. For each parameter, we report the median and interquartile range for the absolute and relative difference between cases and controls, the correlation between cases and controls, and our recruitment rates, to inform the design of future studies. CONCLUSIONS: These pilot data suggest potential differences in bone structure, estimated bone strength, and asymptomatic vertebral fractures among HIV-infected adults with and without fracture, warranting further study as markers of fracture risk in HIV. PMID- 27951754 TI - Immunomodulatory activity of Buchholzia coriacea seed methanol extract on Trypanosoma brucei brucei infected mice. AB - CONTEXT: The seeds of Buchholzia coriacea Engler (Capparaceae) are used in Eastern Nigeria to treat feverish conditions, and to treat malaria and sleeping sickness that cause fever. OBJECTIVE: The current study assesses the immunomodulatory activity of Buchholzia coriacea seed extract on Trypanosoma brucei brucei infected mice. MATERIALS AND METHODS: Delayed hypersensitivity reaction, humoral antibody response and in-vivo leucocyte mobilization tests were assessed in three different experiments to determine the effect of the extract on immune response. Seventy-five (75) mice (25 mice per experiment) were used for the study and were each infected with 1.00 * 106 trypanosomes intra-peritoneally. Groups A, B and C were given 250, 500 and 1000 mg/kg of the extract, respectively, group D received 7.5 mg/kg body weight of levamisole and group E was the control. Sheep RBCs were used as antigen. RESULTS: The acute toxicity tests did not cause clinical signs or death within 24 h post treatment at all the doses tested. The extract inhibited delayed hypersensitivity reaction by 20.9 and 20.8% at 250 and 500 mg/kg, respectively, while at 1000 mg/kg, the paw size increased (-101.9%) when compared with the control. The extract elevated the antibody titre from 1.60 +/- 0.40 for control to 8.00 +/- 3.58 for 500 mg/kg group. The extract increased in total leucocytes counts. DISCUSSION AND CONCLUSION: The extract has a very wide safety margin and was able to improve immune response. The results of the present study showed that Buchholzia coriacea seed methanol extract possesses immunostimulatory activity on trypanosome infected mice. PMID- 27951755 TI - Comparative effectiveness of tenofovir in HIV-infected treatment-experienced patients: systematic review and meta-analysis. AB - BACKGROUND: Antiretroviral therapy (ART) regimens for HIV infection are frequently changed. We conducted a systematic review of randomized trials (RCTs) on the benefits and harms of switching to tenofovir disoproxil fumarate (TDF) based regimens in ART-experienced patients. METHODS: We included RCTs in HIV infected adults comparing switching to a TDF-containing regimen with maintaining or switching to another regimen. We searched MEDLINE, EMBASE, CENTRAL, LILACS, SCI, and the WHO Global Health Library. We assessed bias with the Cochrane tool and synthesized data using random-effects meta-analyses and Peto's approach. For further analyses, we added data from a previous systematic review in treatment naive patients. RESULTS: 17 RCTs with 2210 patients were included. All but one study had a high risk of bias. There was no significant association of switching to TDF-based regimens with mortality, fractures, CD4-cell count, body fat, virological failure, LDL-, and HDL-cholesterol. TDF-based regimens decreased total cholesterol (mean difference -12.05 mg/dL; 95% CI -20.76 to -3.34), trigylcerides (-14.33 mg/dL; -23.73 to -4.93), and bone mineral density (BMD; hip: -2.46%; -3.9 to -1.03; lumbar spine -1.52%; -2.69 to -0.34). Effects on estimated glomerular filtration (eGFR) were inconsistent and depended on the measurement. Adding 22 RCTs from 8297 treatment-naive patients gave consistent results with then significant reductions of LDL (-7.57 mg/dL; -10.37 to -4.78), HDL (-2.38 mg/dL; -3.83 to -0.93), and eGFR (-3.49 ml/min; -5.56 to -1.43). CONCLUSIONS: Switching to TDF-based regimens is associated with reductions of BMD and lipid levels and possibly lowered kidney function. The evidence is limited by the high risk of bias. PMID- 27955615 TI - Erratum to: Functional variants of human papillomavirus type 16 demonstrate host genome integration and transcriptional alterations corresponding to their unique cancer epidemiology. PMID- 27955616 TI - The ability of human nuclear DNA to cause false positive low-abundance heteroplasmy calls varies across the mitochondrial genome. AB - BACKGROUND: Low-abundance mutations in mitochondrial populations (mutations with minor allele frequency <= 1%), are associated with cancer, aging, and neurodegenerative disorders. While recent progress in high-throughput sequencing technology has significantly improved the heteroplasmy identification process, the ability of this technology to detect low-abundance mutations can be affected by the presence of similar sequences originating from nuclear DNA (nDNA). To determine to what extent nDNA can cause false positive low-abundance heteroplasmy calls, we have identified mitochondrial locations of all subsequences that are common or similar (one mismatch allowed) between nDNA and mitochondrial DNA (mtDNA). RESULTS: Performed analysis revealed up to a 25-fold variation in the lengths of longest common and longest similar (one mismatch allowed) subsequences across the mitochondrial genome. The size of the longest subsequences shared between nDNA and mtDNA in several regions of the mitochondrial genome were found to be as low as 11 bases, which not only allows using these regions to design new, very specific PCR primers, but also supports the hypothesis of the non random introduction of mtDNA into the human nuclear DNA. CONCLUSION: Analysis of the mitochondrial locations of the subsequences shared between nDNA and mtDNA suggested that even very short (36 bases) single-end sequencing reads can be used to identify low-abundance variation in 20.4% of the mitochondrial genome. For longer (76 and 150 bases) reads, the proportion of the mitochondrial genome where nDNA presence will not interfere found to be 44.5 and 67.9%, when low-abundance mutations at 100% of locations can be identified using 417 bases long single reads. This observation suggests that the analysis of low-abundance variations in mitochondria population can be extended to a variety of large data collections such as NCBI Sequence Read Archive, European Nucleotide Archive, The Cancer Genome Atlas, and International Cancer Genome Consortium. PMID- 27955617 TI - Planar cell polarity genes Frizzled3a, Vangl2, and Scribble are required for spinal commissural axon guidance. AB - BACKGROUND: A fundamental feature of early nervous system development is the guidance of axonal projections to their targets in order to assemble neural circuits that control behavior. Spinal commissural neurons are an attractive model to investigate the multiple guidance cues that control growth cone navigation both pre- and post-midline crossing, as well as along both the dorsal ventral (D-V) and anterior-posterior (A-P) axes. Accumulating evidence suggests that guidance of spinal commissural axons along the A-P axis is dependent on components of the planar cell polarity (PCP) signaling pathway. In the zebrafish, the earliest born spinal commissural neuron to navigate the midline and turn rostrally is termed commissural primary ascending (CoPA). Unlike mammalian systems, CoPA axons cross the midline as a single axon and allow an analysis of the role of PCP components in anterior pathfinding in single pioneering axons. RESULTS: Here, we establish CoPA cells in the zebrafish spinal cord as a model system for investigating the molecular function of planar cell polarity signaling in axon guidance. Using mutant analysis, we show that the functions of Fzd3a and Vangl2 in the anterior turning of commissural axons are evolutionarily conserved in teleosts. We extend our findings to reveal a role for the PCP gene scribble in the anterior guidance of CoPA axons. Analysis of single CoPA axons reveals that these commissural axons become responsive to PCP-dependent anterior guidance cues even prior to midline crossing. When midline crossing is prevented by dcc gene knockdown, ipsilateral CoPA axons still extend axons anteriorly in response to A P guidance cues. We show that this ipsilateral anterior pathfinding that occurs in the absence of midline crossing is dependent on PCP signaling. CONCLUSION: Our results demonstrate that anterior guidance decisions by CoPA axons are dependent on the function of planar cell polarity genes both prior to and after midline crossing. PMID- 27955618 TI - N-terminal pro-brain natriuretic peptide improves the C-ACS risk score prediction of clinical outcomes in patients with ST-elevation myocardial infarction. AB - BACKGROUND: It remained unclear whether the combination of the Canada Acute Coronary Syndrome Risk Score (CACS-RS) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) could have a better performance in predicting clinical outcomes in acute ST-elevation myocardial infarction (STEMI) patients with primary percutaneous coronary intervention. METHODS: A total of 589 consecutive STEMI patients were enrolled. The potential additional predictive value of NT-pro BNP with the CACS-RS was estimated. Primary endpoint was in-hospital mortality and long-term poor outcomes. RESULTS: The incidence of in-hospital death was 3.1%. Patients with higher NT-pro-BNP and CACS-RS had a greater incidence of in hospital death. After adjustment for the CACS-RS, elevated NT-pro-BNP (defined as the best cutoff point based on the Youden's index) was significantly associated with in hospital death (odd ratio = 4.55, 95%CI = 1.52-13.65, p = 0.007). Elevated NT-pro-BNP added to CACS-RS significantly improved the C-statistics for in-hospital death, as compared with the original score (0.762 vs. 0.683, p = 0.032). Furthermore, the addition of NT-pro-BNP to CACS-RS enhanced net reclassification improvement (0.901, p < 0.001) and integrated discrimination improvement (0.021, p = 0.033), suggesting effective discrimination and reclassification. In addition, the similar result was also demonstrated for in hospital major adverse clinical events (C-statistics: 0.736 vs. 0.695, p = 0.017) or 3-year mortality (0.699 vs. 0.604, p = 0.004). CONCLUSIONS: Both NT-pro-BNP and CACS-RS are risk predictors for in hospital poor outcomes in patients with STEMI. A combination of them could derive a more accurate prediction for clinical outcome s in these patients. PMID- 27955619 TI - Hierarchical imaging: a new concept for targeted imaging of large volumes from cells to tissues. AB - BACKGROUND: Imaging large volumes such as entire cells or small model organisms at nanoscale resolution seemed an unrealistic, rather tedious task so far. Now, technical advances have lead to several electron microscopy (EM) large volume imaging techniques. One is array tomography, where ribbons of ultrathin serial sections are deposited on solid substrates like silicon wafers or glass coverslips. RESULTS: To ensure reliable retrieval of multiple ribbons from the boat of a diamond knife we introduce a substrate holder with 7 axes of translation or rotation specifically designed for that purpose. With this device we are able to deposit hundreds of sections in an ordered way in an area of 22 * 22 mm, the size of a coverslip. Imaging such arrays in a standard wide field fluorescence microscope produces reconstructions with 200 nm lateral resolution and 100 nm (the section thickness) resolution in z. By hierarchical imaging cascades in the scanning electron microscope (SEM), using a new software platform, we can address volumes from single cells to complete organs. In our first example, a cell population isolated from zebrafish spleen, we characterize different cell types according to their organelle inventory by segmenting 3D reconstructions of complete cells imaged with nanoscale resolution. In addition, by screening large numbers of cells at decreased resolution we can define the percentage at which different cell types are present in our preparation. With the second example, the root tip of cress, we illustrate how combining information from intermediate resolution data with high resolution data from selected regions of interest can drastically reduce the amount of data that has to be recorded. By imaging only the interesting parts of a sample considerably less data need to be stored, handled and eventually analysed. CONCLUSIONS: Our custom-designed substrate holder allows reproducible generation of section libraries, which can then be imaged in a hierarchical way. We demonstrate, that EM volume data at different levels of resolution can yield comprehensive information, including statistics, morphology and organization of cells and tissue. We predict, that hierarchical imaging will be a first step in tackling the big data issue inevitably connected with volume EM. PMID- 27955620 TI - Implications of methodological differences in measuring the rates of exclusive breastfeeding in Nepal: findings from literature review and cohort study. AB - BACKGROUND: Correct measurement and continuous monitoring of exclusive breastfeeding are essential to promote exclusive breastfeeding. Measuring exclusive breastfeeding is a complex issue as rates can vary according to the definition, measurement period, questions asked, and infant's age. This article reviewed the methodology of reporting exclusive breastfeeding in Nepal, and compared exclusive breastfeeding rates using data from a cohort study undertaken in western Nepal. METHODS: A literature review was first conducted on studies published during 2000-2014. In our cohort study, 735 mother-infant pairs were recruited within the first month postpartum and followed up during the fourth and sixth months. RESULTS: The majority of studies in Nepal, including national surveys, used the World Health Organization (WHO) recommended definition (only breastmilk with the exception of medicine and vitamin syrup), and the most common measurement period was a 24-h recall. Our data demonstrated that the exclusive breastfeeding rate during the sixth month was 8.9% using the recall-since-birth method but was 18.7% using the 24-h recall method. Substantial differences in rates were also found during the first (66.3% vs 83.9%) and fourth months (39.2% vs 61.1%). CONCLUSION: We found that recent studies reporting exclusive breastfeeding in Nepal varied considerably in methodology. The most commonly used measurement, the 24-h recall, leads to over-estimation of the prevalence of exclusive breastfeeding when compared to the recall-since-birth method. A common standard of reporting exclusive breastfeeding is clearly needed for evidence based decision making. PMID- 27955621 TI - A quantitative model for dermal infection and oedema in BALB/c mice pinna. AB - BACKGROUND: Pharmaceutical industry demands innovation for developing new molecules to improve effectiveness and safety of therapeutic medicines. Preclinical assays are the first tests performed to evaluate new therapeutic molecules using animal models. Currently, there are several models for evaluation of treatments, for dermal oedema or infection. However, the most common or usual way is to induce the inflammation with chemical substances instead of infectious agents. On the other hand, this kind of models require the implementation of histological techniques and the interpretation of pathologies to verify the effectiveness of the therapy under assessment. This work was focused on developing a quantitative model of infection and oedema in mouse pinna. The infection was achieved with a strain of Streptococcus pyogenes that was inoculated in an injury induced at the auricle of BALB/c mice, the induced oedema was recorded by measuring the ear thickness with a digital micrometer and histopathological analysis was performed to verify the damage. The presence of S. pyogenes at the infection site was determined every day by culture. RESULTS: Our results showed that S. pyogenes can infect the mouse pinna and that it can be recovered at least for up to 4 days from the infected site; we also found that S. pyogenes can induce a bigger oedema than the PBS-treated control for at least 7 days; our results were validated with an antibacterial and anti-inflammatory formulation made with ciprofloxacin and hydrocortisone. CONCLUSIONS: The model we developed led us to emulate a dermal infection and allowed us to objectively evaluate the increase or decrease of the oedema by measuring the thickness of the ear pinna, and to determine the presence of the pathogen in the infection site. We consider that the model could be useful for assessment of new anti inflammatory or antibacterial therapies for dermal infections. PMID- 27955622 TI - Are aphid parasitoids locally adapted to the prevalence of defensive symbionts in their hosts? AB - BACKGROUND: Insect parasitoids are under strong selection to overcome their hosts' defences. In aphids, resistance to parasitoids is largely determined by the presence or absence of protective endosymbionts such as Hamiltonella defensa. Hence, parasitoids may become locally adapted to the prevalence of this endosymbiont in their host populations. To address this, we collected isofemale lines of the aphid parasitoid Lysiphlebus fabarum from 17 sites in Switzerland and France, at which we also estimated the frequency of infection with H. defensa as well as other bacterial endosymbionts in five important aphid host species. The parasitoids' ability to overcome H. defensa-mediated resistance was then quantified by estimating their parasitism success on a single aphid clone (Aphis fabae fabae) that was either uninfected or experimentally infected with one of three different isolates of H. defensa. RESULTS: The five aphid species (Aphis fabae fabae, A. f. cirsiiacanthoides, A. hederae, A. ruborum, A. urticata) differed strongly in the relative frequencies of infection with different bacterial endosymbionts, but there was also geographic variation in symbiont prevalence. Specifically, the frequency of infection with H. defensa ranged from 22 to 47 % when averaged across species. Parasitoids from sites with a high prevalence of H. defensa tended to be more infective on aphids possessing H. defensa, but this relationship was not significant, thus providing no conclusive evidence that L. fabarum is locally adapted to the occurrence of H. defensa. On the other hand, we observed a strong interaction between parasitoid line and H. defensa isolate on parasitism success, indicative of a high specificity of symbiont-conferred resistance. CONCLUSIONS: This study is the first, to our knowledge, to test for local adaptation of parasitoids to the frequency of defensive symbionts in their hosts. While it yielded useful information on the occurrence of facultative endosymbionts in several important host species of L. fabarum, it provided no clear evidence that parasitoids from sites with a high prevalence of H. defensa are better able to overcome H. defensa-conferred resistance. The strong genetic specificity in their interaction suggests that it may be more important for parasitoids to adapt to the particular strains of H. defensa in their host populations than to the general prevalence of this symbiont, and it highlights the important role symbionts can play in mediating host-parasitoid coevolution. PMID- 27955624 TI - A case report: Becker muscular dystrophy presenting with epilepsy and dysgnosia induced by duplication mutation of Dystrophin gene. AB - BACKGROUND: Becker muscular dystrophy (BMD), a genetic disorder of X-linked recessive inheritance, typically presents with gradually progressive muscle weakness. The condition is caused by mutations of Dystrophin gene located at Xp21.2. Epilepsy is an infrequent manifestation of BMD, while cases of BMD with dysgnosia are extremely rare. CASE PRESENTATION: We describe a 9-year-old boy with BMD, who presented with epilepsy and dysgnosia. Serum creatine kinase level was markedly elevated (3665 U/L). Wechsler intelligence tests showed a low intelligence quotient (IQ = 65). Electromyogram showed slight myogenic changes and skeletal muscle biopsy revealed muscular dystrophy. Immunohistochemical staining showed partial positivity of sarcolemma for dystrophin-N. Multiplex ligation-dependent probe amplification revealed a duplication mutation in exons 37-44 in the Dystrophin gene. CONCLUSIONS: The present case report helps to better understand the clinical and genetic features of BMD. PMID- 27955623 TI - PROPER: global protein interaction network alignment through percolation matching. AB - BACKGROUND: The alignment of protein-protein interaction (PPI) networks enables us to uncover the relationships between different species, which leads to a deeper understanding of biological systems. Network alignment can be used to transfer biological knowledge between species. Although different PPI-network alignment algorithms were introduced during the last decade, developing an accurate and scalable algorithm that can find alignments with high biological and structural similarities among PPI networks is still challenging. RESULTS: In this paper, we introduce a new global network alignment algorithm for PPI networks called PROPER. Compared to other global network alignment methods, our algorithm shows higher accuracy and speed over real PPI datasets and synthetic networks. We show that the PROPER algorithm can detect large portions of conserved biological pathways between species. Also, using a simple parsimonious evolutionary model, we explain why PROPER performs well based on several different comparison criteria. CONCLUSIONS: We highlight that PROPER has high potential in further applications such as detecting biological pathways, finding protein complexes and PPI prediction. The PROPER algorithm is available at http://proper.epfl.ch . PMID- 27955625 TI - Frequency of empiric antibiotic de-escalation in an acute care hospital with an established Antimicrobial Stewardship Program. AB - BACKGROUND: Expanding antimicrobial resistance patterns in the face of stagnant growth in novel antibiotic production underscores the importance of antibiotic stewardship in which de-escalation remains an integral component. We measured the frequency of antibiotic de-escalation in a tertiary care medical center with an established antimicrobial stewardship program to provide a plausible benchmark for de-escalation. METHODS: A retrospective, observational study was performed by review of randomly selected electronic medical records of 240 patients who received simultaneous piperacillin/tazobactam and vancomycin from January to December 2011 at an 885-bed tertiary care medical center. Patient characteristics including antibiotic regimen, duration and indication, culture results, length of stay, and hospital mortality were evaluated. Antibiotic de-escalation was defined as the use of narrower spectrum antibiotics or the discontinuation of antibiotics after initiation of piperacillin/tazobactam and vancomycin therapy. Subjects dying within 72 h of antibiotic initiation were considered not de-escalated for subsequent analysis and were subtracted from the study population in determining a modified mortality rate. RESULTS: The most commonly documented indications for piperacillin/tazobactam and vancomycin therapy were pneumonia and sepsis. Of the 240 patients studied, 151 (63%) had their antibiotic regimens de-escalated by 72 h. The proportion of patients de-escalated by 96 h with positive vs. negative cultures was similar, 71 and 72%, respectively. Median length of stay was 4 days shorter in de-escalated patients, and the difference in adjusted mortality was not significant (p = 0.82). CONCLUSIONS: The empiric antibiotic regimens of approximately two-thirds of patients were de-escalated by 72 h in an institution with a well-established antimicrobial stewardship program. While this study provides one plausible benchmark for antibiotic de-escalation, further studies, including evaluations of antibiotic appropriateness and patient outcomes, are needed to inform decisions on potential benchmarks for antibiotic de-escalation. PMID- 27955626 TI - Antibiotics and antiseptics for preventing infection in people receiving revision total hip and knee prostheses: a systematic review of randomized controlled trials. AB - BACKGROUND: Infection rates in revision (second and subsequent) major joint arthroplasty continues to be a significant issue with rates 2-3 times those of primary procedures. The effect of antibiotic and antiseptic prophylaxis on outcomes for this type of surgery has not been adequately reviewed. METHODS: A systematic search of the main databases for randomized controlled trials (RCTs) evaluating antibiotics and antiseptics was conducted to evaluate the predetermined endpoints of infection. RESULTS: There were five (5) RCTs identified that examined the effects of antibiotic and antiseptic prophylaxis on infections after revision total hip arthroplasty [THA] (total of 304 participants) and total knee arthroplasty [TKA] (total of 206 participants). For TKA, preoperative systemic intravenous (IV) antibiotic prophylaxis plus antibiotic cement may be effective in reducing the incidence of infection in revision TKA at 8+ years. These results however should be interpreted with caution due to the significant biases. For revision THA, there is no RCT evidence that antibiotics/antiseptics have any effect on the infection rate. CONCLUSIONS: There is a lack of high quality data demonstrating an effect of antibiotics or antiseptics on infection rates in revision THA/TKA. Considering the rate of infections in revisions is 2-3X that of primary procedures and; there is a consensus recommendation to use similar antibiotic and antiseptic regimens in both primary and revision procedures, there is a need for high quality studies in revision THA/TKA. PMID- 27955629 TI - Cerebellar ataxia due to Leptospirosis- a case report. AB - BACKGROUND: Leptospirosis involves nervous system in around 10-15% of the cases, the commonest presentation being aseptic meningitis. Most of the clinical features of neuroleptospirosis are due to capillary endothelial damage and vasculitis. Ataxia is an extremely uncommon manifestation of Leptospirosis occuring in <5% of cases. CASE PRESENTATION: A 28 year old female from North India presented with a short febrile illness followed by an acute onset cerebellar ataxia, anemia, thrombocytopenia and transaminitis. Leptospira serology showed high titres of IgM (ELISA) and MAT (microscopic agglutination test titre >1:800) . She was treated with intravenous ceftriaxone for 14 days following which she showed marked recovery. CONCLUSION: The clinical features of neuroleptospirosis are varied, most of them resulting from endothelial damage and vasculitis. Immune mediated phenomenon with no structural damage is another possible mechanism leading to cerebellar ataxia. Cerebellar ataxia due to common tropical infections should be ruled out in the appropriate setting, as early institution of treatment can abate neurological morbidity. The case report highlights the importance of identifying a reversible cause of cerebellar ataixa due to a tropical infection, possibly due to a immune mediated phenomenon, and would be of interest to both internists and neurologists. PMID- 27955628 TI - Analysis of association between circulating miR-122 and histopathological features of nonalcoholic fatty liver disease in patients free of hepatocellular carcinoma. AB - BACKGROUND: The association between circulating microRNA-122 (miR-122) and histopathological features of nonalcoholic fatty liver disease (NAFLD) remains unclear. METHODS: The association of serum miR-122 levels with histopathological features of NAFLD (steatosis, ballooning, lobular inflammation, and stage, as histological components of nonalcoholic steatohepatitis) was examined in serial liver biopsies from 36 hepatocellular carcinoma (HCC)-free Japanese patients with histopathologically-proven NAFLD. The median interval between first and second liver biopsies was 4.6 years. RESULTS: In patients who showed improvement of histopathological scores (steatosis, ballooning, and stage), serum miR-122 levels were significantly lower at second biopsy than first biopsy. In patients who showed no improvement, the changes at second biopsy were not different from those at first biopsy. There were significant and strong associations between serum miR 122 ratio (ratio of level at second biopsy to that at first biopsy) and changes in histopathological scores (of steatosis, lobular inflammation, and stage). There were also significant and strong associations between serum miR-122 ratio and changes in other clinical parameters, including aspartate aminotransferase and alanine aminotransferase. CONCLUSIONS: Longitudinal examination of serial liver biopsies showed the association of serum miR-122 with histopathological features of HCC-free NAFLD patients. PMID- 27955627 TI - A longitudinal cohort study of HIV 'treatment as prevention' in gay, bisexual and other men who have sex with men: the Treatment with Antiretrovirals and their Impact on Positive And Negative men (TAIPAN) study protocol. AB - BACKGROUND: Australia has increased coverage of antiretroviral treatment (ART) over the past decade, reaching 73% uptake in 2014. While ART reduces AIDS-related deaths, accumulating evidence suggests that it could also bolster prevention efforts by reducing the risk of HIV transmission ('treatment as prevention'). While promising, evidence of community-level impact of treatment as prevention on reducing HIV incidence among gay and bisexual men is limited. We describe a study protocol that aims to determine if scale up of testing and treatment for HIV leads to a reduction in community viraemia and, in turn, if this reduction is temporally associated with a reduction in HIV incidence among gay and bisexual men in Australia's two most populous states. METHODS: Over the period 2009 to 2017, we will establish two cohorts making use of clinical and laboratory data electronically extracted retrospectively and prospectively from 73 health services and laboratories in the states of New South Wales and Victoria. The 'positive cohort' will consist of approximately 13,000 gay and bisexual men (>90% of all people living with HIV). The 'negative cohort' will consist of at least 40,000 HIV-negative gay and bisexual men (approximately half of the total population). Within the negative cohort we will use standard repeat-testing methods to calculate annual HIV incidence. Community prevalence of viraemia will be defined as the proportion of men with a viral load >=200RNA copies/mm3, which will combine viral load data from the positive cohort and viraemia estimates among those with an undiagnosed HIV infection. Using regression analyses and adjusting for behavioural and demographic factors associated with infection, we will assess the temporal association between the community prevalence of viraemia and the incidence of HIV infection. Further analyses will make use of these cohorts to assess incidence and predictors of treatment initiation, repeat HIV testing, and viral suppression. DISCUSSION: This study will provide important information on whether 'treatment as prevention' is associated with a reduction in HIV incidence at a community level among gay and bisexual men. PMID- 27955630 TI - Estimation of Zika virus prevalence by appearance of microcephaly. AB - BACKGROUND: There currently is a severe Zika Virus (ZIKV) epidemic in Brazil and other South American countries. Due to international travel, this poses severe public health risk of ZIKV importation to other countries. We estimate the prevalence of ZIKV in an import region by the time a microcephaly case is detected, since microcephaly is presently the most significant indication of ZIKV presence. METHODS: We establish a mathematical model to describe ZIKV spread from a source region to an import region. This model incorporates both vector transmission (between humans and mosquitoes) and sexual transmission (from males to females). We take account of population structure through a contact network for sexually active individuals. Parameter values of our model are either taken from the literature or estimated from travel data. RESULTS: This model gives us the probability distribution of time until detection of the first microcephaly case. Based on current field observations, our results also indicate that the percentage of infected pregnant women that results in fetal abnormalities is more likely to be on the smaller end of the 1%-30% spectrum that is currently hypothesized. Our model predicts that for import regions with at least 250,000 people, on average 1,000-12,000 will have been infected by the time of the first detection of microcephaly, and on average 200-1,500 will be infectious at this time. Larger population sizes do not significantly change our predictions. CONCLUSIONS: By the first detection of a microcephaly case, a sizable fraction of the population will have been infected by ZIKV. It is thus clear that adequate surveillance, isolation, and quarantine are needed in susceptible import regions to stop the dissemination of a Zika epidemic. PMID- 27955631 TI - The impact of gender difference on operative time in laparoscopic partial nephrectomy for T1 renal tumor and the utility of retroperitoneal fat thickness as a predictor of operative time. AB - BACKGROUND: To investigate the impact of biological gender on operative parameters, especially operative time, in laparoscopic partial nephrectomy (LPN) for T1 renal tumor. METHODS: One hundred and eleven (28 female and 83 male) patients and 64 (20 female and 44 male) patients with renal tumors suspected to be RCC cT1aN0M0 who underwent retroperitoneal and transperitoneal LPN, respectively, were analyzed. The influence of sex on operative factors including retroperitoneal fat tissue thickness, determined on CT, was analyzed. The correlation between operative time and gender was evaluated by unpaired t-test and linear logistic regression model. RESULTS: In both retroperitoneal and transperitoneal LPN, the retroperitoneal fat tissue thickness was greater in men than in women. In retroperitoneal LPN, the operative time was significantly longer in men than in women. In contrast, in transperitoneal LPN, no gender difference was observed in regard to the operative time. In retroperitoneal LPN, linear logistic regression assessment showed that gender, retroperitoneal fat tissue thickness, and tumor size were significantly associated with operative time. Coefficient of determination of the prediction model was 0.317. CONCLUSIONS: The operative time of retroperitoneal LPN is significantly correlated with gender, maximum tumor diameter, and retroperitoneal fat tissue thickness. We have developed a prediction model for the operative time of retroperitoneal LPN based on preoperative parameters. Interestingly, in transperitoneal LPN, a gender difference in operative time was not apparent, and also predicting operative time might be difficult. PMID- 27955632 TI - Paternal involvement and early infant neurodevelopment: the mediation role of maternal parenting stress. AB - BACKGROUND: Father-child interactions are associated with improved developmental outcomes among infants. However, to the best of our knowledge, no study has addressed the effects of paternal involvement on the neurodevelopment of infants who are less than 6 months of age, and no study has reported how maternal parenting stress mediates the relationship between paternal involvement and infant neurodevelopment during early infancy. This study investigates the direct and indirect relationship between paternal involvement and infant neurodevelopment at 3-4 months of age. The indirect relationship was assessed through the mediating factor of maternal parenting stress. METHODS: The participants were recruited through the Sesalmaul Research Center's website from April to June 2014. The final data included 255 mothers and their healthy infants, who were aged 3-4 months. The mothers reported paternal involvement and maternal parenting stress by using Korean Parenting Alliance Inventory (K-PAI) and Parenting Stress Index (PSI), respectively. Experts visited the participants' homes to observe infant neurodevelopment, and completed a developmental examination using Korean version of the Ages and Stages Questionnaire II (K-ASQ II). A hierarchical multiple regression analysis was used for data analysis. RESULTS: Infants' mean ages were 106 days and girls accounted for 46.3%. The mean total scores (reference range) of the K-PAI, PSI, and the K-ASQ II were 55.5 (17 68), 45.8 (25-100), and 243.2 (0-300), respectively. Paternal involvement had a positive relationship with K-ASQ II scores (beta = 0.29, p < 0.001) at 3-4 months of age, whereas maternal parenting stress was negatively related with K-ASQ II scores (beta = -0.32, p < 0.001). Maternal parenting stress mediated the relationship between paternal involvement and early infant neurodevelopment (Z = 3.24, p < 0.001). A hierarchical multiple regression analysis showed that paternal involvement reduced maternal parenting stress (beta = -0.25, p < 0.001), which led to positive infant outcomes (beta = 0.23, p < 0.001). CONCLUSIONS: Paternal involvement is significantly associated with infant neurodevelopment during early infancy, and maternal parenting stress partially mediates that association. This result emphasizes the importance of fathers' involvement and mothers' parenting stress on early infant neurodevelopment. PMID- 27955633 TI - The clinical and economic burden of pneumonia in patients enrolled in Medicare receiving dialysis: a retrospective, observational cohort study. AB - BACKGROUND: End-stage renal disease (ESRD) patients receiving dialysis are at particular risk for infection. We assessed the clinical and economic burden of pneumonia in a population of Medicare-enrolled ESRD patients with respect to incidence and case fatality rates, rates of all-cause and cardiovascular hospitalization, and costs. METHODS: Patients received dialysis between 01 January 2009 and 31 December 2011 and were enrolled in Medicare Parts A and B. Pneumonia episodes were identified from institutional and supplier claims. Patients were considered at-risk from first date of Medicare coverage and were censored upon transplant, withdrawal from dialysis, recovery of renal function, loss of Medicare benefits, or death. Linear mixed-effects models were used to assess hospitalization rates and costs over the 3 months prior to and 12 months following pneumonia episodes. RESULTS: The pneumonia incidence rate for the study period was 21.4 events/100 patient-years; the majority of episodes (90.1%) required inpatient treatment. The 30-day case fatality rate was 10.7%. Compared to month -3 prior to event, rates of all-cause and cardiovascular hospitalization were higher in the month of the pneumonia episode (IRR, 4.61 and 4.30). All-cause admission rates remained elevated through month 12; cardiovascular admission rates remained elevated through month 6. Mean per-patient per-month costs were $10,976 higher in the month of index episode compared to month -3, largely driven by increased inpatient costs, and remained elevated through end of 12-month follow-up. CONCLUSION: Pneumonia episodes are frequent among ESRD patients and result in hospitalizations and greater overall costs to Medicare over the following year. PMID- 27955634 TI - Transdifferentiation of pancreatic stromal tumor into leiomyosarcoma with metastases to liver and peritoneum: a case report. AB - BACKGROUND: Primary pancreatic leiomyosarcoma is a rare pancreatic malignancy; the clinical presentation and treatment is not well-characterized. Further, the molecular mechanisms underlying its pathogenesis are not known. We report a patient with pancreatic stromal tumor that progressed to primary pancreatic leiomyosarcoma with hepatic and peritoneal metastases. CASE PRESENTATION: A 54 year-old woman was found to have pancreatic and hepatic tumor masses on routine health checkup. Owing to the difficulty in performing biopsy, this patient underwent open operation. Histopathological examination of pancreatic and liver biopsy specimen demonstrated spindle cells with nuclear mitoses. Immunohistochemical examination showed positive staining for Cluster of Differentiation117 (+) and negative staining for S-100 (-) and Smooth Muscle Actin (-). Thus, the patient was diagnosed as a case of advanced pancreatic stromal tumor with liver metastases. After surgery, treatment with oral imatinib mesylate combined with thymosin injection therapy was prescribed. Follow-up examination at 13-months revealed multiple nodular masses in liver and right peritoneum. The patient underwent a second surgery. Liver biopsy and the resected peritoneal specimen showed positive staining for Discovered On Gastrointestinal tumor-1(weak +), Actin (+), Smooth Muscle Actin (+) and negative staining for Cluster of Differentiation117 (-) Cluster of Differentiation34 (-) and S-100 (-). Histopathological examination showed spindle cells with nuclear mitoses. The final diagnosis was primary pancreatic leiomyosarcoma, transdifferentiating from pancreatic stromal tumor, with liver and peritoneal metastases. CONCLUSIONS: Surgery is the first line treatment for primary pancreatic leiomyosarcoma and extra-gastrointestinal stromal tumors. In the present case, radical resection was not performed owing to hepatic metastases. Palliative treatment with radioactive 125I ion implantation and microwave coagulation therapy was administered. However, the long-term therapeutic effect needs to be assessed in future. PMID- 27955635 TI - Molecular characterization and evaluation of the emerging antibiotic-resistant Streptococcus pyogenes from eastern India. AB - BACKGROUND: Group A Streptococcus strains causing wide variety of diseases, recently became noticeable in eastern India, are not amenable to standard treatment protocol thus enhancing the possibility of disease morbidity by becoming antibiotic resistance. METHODS: The association of Lancefield group A Streptococcal variation with degree of vir architectural diversity was evaluated using emm typing and restriction fragment length polymorphism analyses. The antibiotic sensitivity patterns were examined by modified Kirby-Bauer method of disk diffusion. Percentage calculations, 95% confidence interval and one-way ANOVA were used to assess differences in proportions. RESULTS: Our observations revealed 20 different emm types and 13 different HaeIII vir typing patterns. A 1.2 kb fragment was found in all HaeIII typing pattern. Fragments of 1.2 kb and 550 bp were conserved in majority of the isolates. HinfI digestion was found proficient in differentiating the strains of same vir typing patterns. Strong predominance of speC (85%) and speF (80%) genes have been observed encoding exotoxins production. 4 isolates were found to be erythromycin resistant and were of genotype emm49. High degree of tetracycline resistance was shown by 53.57% isolates which belonged to 12 different emm genotypes. CONCLUSIONS: These findings suggested that in addition to emm typing, sequential application of HaeIII and HinfI restriction enzymes in vir typing analysis is an effective tool for group A streptococcal molecular characterization associated with antibiotic resistance. PMID- 27955637 TI - Prognostic and predictive significance of long interspersed nucleotide element-1 methylation in advanced-stage colorectal cancer. AB - BACKGROUND: Hypomethylation of Long Interspersed Nucleotide Element-1 (LINE-1) is associated with worse prognosis in colorectal cancer (CRC). However, little is known about the relevance of this marker for the prognosis and response to chemotherapy of metastatic and recurrent (advanced-stage) CRC. Our aim was therefore to investigate whether tumor LINE-1 hypomethylation correlates with patient survival and with response to 5-fluorouracil (5-FU)/ oxaliplatin (FOLFOX) chemotherapy in advanced-stage CRC. METHODS: The study included 40 CRC patients who developed metastasis or local recurrence after surgery and subsequently underwent FOLFOX therapy. Progression-free and overall survival were estimated using the Kaplan-Meier method. LINE-1 methylation levels in formalin-fixed and paraffin-embedded primary tumor tissues were measured by MethyLight assay and correlated with patient survival. In vitro analyses were also conducted with human colon cancer cell lines having different LINE-1 methylation levels to examine the effects of 5-FU and oxaliplatin on LINE-1 activity and DNA double strand-breaks. RESULTS: Patients with LINE-1 hypomethylation showed significantly worse progression-free (median: 6.6 vs 9.4 months; P = 0.02) and overall (median: 16.6 vs 23.2 months; P = 0.01) survival following chemotherapy compared to patients with high methylation. LINE-1 hypomethylation was an independent factor for poor prognosis (P = 0.018) and was associated with a trend for non-response to FOLFOX chemotherapy. In vitro analysis showed that oxaliplatin increased the LINE-1 score in LINE-1-expressing (hypomethylated) cancer cells, thereby enhancing and prolonging the effect of 5-FU against these cells. This finding supports the observed correlation between tumor LINE-1 methylation and response to chemotherapy in CRC patients. CONCLUSIONS: Tumor LINE-1 hypomethylation is an independent marker of poor prognosis in advanced-stage CRC and may also predict non-response to combination FOLFOX chemotherapy. Prospective studies are needed to optimize the measurement of tumor LINE-1 methylation and to confirm its clinical impact, particularly as a predictive marker. PMID- 27955636 TI - Effects of delaying binge drinking on adolescent brain development: a longitudinal neuroimaging study. AB - BACKGROUND: Onset of alcohol use by 14 relative to 21 years of age strongly predicts elevated risk for severe alcohol use problems, with 27% versus 4% of individuals exhibiting alcohol dependence within 10 years of onset. What remains unclear is whether this early alcohol use (i) is a marker for later problems, reflected as a pre-existing developmental predisposition, (ii) causes global neural atrophy or (iii) specifically disturbs neuro-maturational processes implicated in addiction, such as executive functions or reward processing. Since our group has demonstrated that a novel intervention program targeting personality traits associated with adolescent alcohol use can prevent the uptake of drinking and binge drinking by 40 to 60%, a crucial question is whether prevention of early onset alcohol misuse will protect adolescent neurodevelopment and which domains of neurodevelopment can be protected. METHODS: A subsample of 120 youth at high risk for substance misuse and 30 low-risk youth will be recruited from the Co-Venture trial (Montreal, Canada) to take part in this 5 year follow-up neuroimaging study. The Co-Venture trial is a community-based cluster-randomised trial evaluating the effectiveness of school-based personality targeted interventions on substance use and cognitive outcomes involving approximately 3800 Grade 7 youths. Half of the 120 high-risk participants will have received the preventative intervention program. Cognitive tasks and structural and functional neuroimaging scans will be conducted at baseline, and at 24- and 48-month follow-up. Two functional paradigms will be used: the Stop Signal Task to measure motor inhibitory control and a modified version of the Monetary Incentive Delay Task to evaluate reward processing. DISCUSSION: The expected results should help identify biological vulnerability factors, and quantify the consequences of early alcohol abuse as well as the benefits of early intervention using brain metrics. PMID- 27955638 TI - A retrospective paired study: efficacy and toxicity of nimotuzumab versus cisplatin concurrent with radiotherapy in nasopharyngeal carcinoma. AB - BACKGROUND: To compare efficacy and toxicity of nimotuzumab versus cisplatin (CDDP) concurrent with intensity modulated radiation therapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). METHODS: We retrospectively reviewed patients with NPC from September 2008 to November 2013. The synchronous regimens included h-R3/RT (nimotuzumab and radiotherapy) one time per week for 6-8 weeks and CDDP/RT (cisplatin and radiotherapy) every three weeks for 2-3 cycles. All patients in our analysis completed the planned IMRT and received TPF (docetaxel + cisplatin + 5-fluorouracil) neoadjuvant chemotherapy for two cycles. RESULTS: Among the 302 NPC patients who were treated definitively with TPF neoadjuvant chemotherapy followed by IMRT concurrent with nimotuzumab or cisplatin at West China Hospital Sichuan University, 52 patients received h-R3/RT with complete clinical and follow-up data. Based on age, sex and tumor stage, 104 eligible patients were propensity-matched, with 52 patients in each treatment group (h R3/RT and CDDP/RT). With a median follow-up of 50 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates for the h-R3/RT vs. CDDP/RT treatment groups were 63.9% vs. 81.4% (p = 0.024) and 58.0% vs. 80.6% (p = 0.028), respectively. The h-R3/RT patients experienced less leukopenia and milder nausea and vomiting. In our sub-analysis, for stage II patients, no significant differences were found in OS and PFS, whereas milder nausea and vomiting were found in the h-R3/RT group (p = 0.046). Moreover, for patients older than 60 years, there were no statistically significant differences in OS and PFS, whereas milder nausea and vomiting was observed in the h-R3/RT group (p = 0.020). CONCLUSIONS: Although CDDP/RT remains the preferred choice for most patients with NPC, h-R3/RT may be a treatment option for the patients with stage II, older than sixty years old, and who are intolerable to cisplatin. PMID- 27955639 TI - Control of carbapenem-resistant Acinetobacter baumannii outbreak in an intensive care unit of a teaching hospital in Southern Italy. AB - BACKGROUND: Acinetobacter baumannii is an opportunistic pathogen that has become a major cause of concern, since it is a frequent cause of healthcare-associated infections (HAIs). The aim of the study was to describe the occurrence, the management and the control of an outbreak that occurred in an intensive care unit (ICU) of a teaching hospital in Southern Italy caused by multiple strains of extensively drug-resistant A. baumannii (XDRAB). METHODS: Case-patient was defined as a patient with an healthcare-associated infection caused by an XDRAB isolate identified in a clinically significant culture. Environmental samples were collected from different surfaces. The isolates were identified by typical Gram stain morphology, using the Vitek 2 system (bioMerieux, France) and by MALDI TOF MS mass spectrometry (bioMerieux, France). Genotyping was performed through rep-PCR analysis. RESULTS: A patient presented an XDRAB ventilator-associated pneumonia at admission and was managed with strict isolation precautions until discharge. Five patients had a ventilator-associated pneumonia and two had a central line-associated bloodstream infection. Of the environmental samples, 1 sample obtained from the side of the bed of an infected patient yielded growth of XDRAB. Infection control measures were adopted. Rep-PCR analysis identified four patterns. CONCLUSIONS: The integration of epidemiological and microbiological data and the application of infection control measures were crucial to bring such an outbreak to a rapid halt. The distinctive characteristic of this study was the complex molecular pattern of the outbreak, which subsided in a short period of time due to adherence to infection-control measures, confirming the fundamental role of molecular typing in the comprehension of outbreaks dynamics and of integrated control interventions for the interruption of epidemic events. PMID- 27955640 TI - Adolescent's subjective perceptions of chronic disease and related psychosocial factors: highlights from an outpatient context study. AB - BACKGROUND: Adolescents with chronic disease (CD) can be more vulnerable to adverse psychosocial outcomes. This study aims: 1) to identify differences in psychosocial variables (health-related quality of life, psychosomatic complaints, resilience, self-regulation and social support) among adolescents who feel that CD affects or does not affect school/peers connectedness (measured by self reported participation in school and social activities); and 2) to assess the extent to which psychosocial variables are associated with connectedness in school and peer domains. METHODS: A cross-sectional study was conducted in 135 adolescents with CD (51.9% boys), average age of 14 +/- 1.5 years old (SD = 1.5). Socio-demographic, clinical, and psychosocial variables were assessed, using a self-reported questionnaire, which included the Chronic Conditions Short Questionnaire, KIDSCREEN-10 Index, Symptoms Check-List, Healthy Kids Resilience Assessment Module Scale, Adolescent Self-Regulatory Inventory, and Satisfaction with Social Support Scale. Descriptive statistics, GLM-Univariate ANCOVA and Logistic Regression were performed using the IBM Statistical Package for Social Sciences (SPSS), version 22.0. The significance level was set at p < 0.05. RESULTS: Thirteen to eighteen percent of the adolescents felt that CD affected participation at school (PSCH) and participation in leisure time with friends (PLTF). These adolescents presented lower results for all psychosocial study variables, when compared with adolescents who did not feel affected in both areas of participation. From the studied psychosocial variables, the most important ones associated with PSCH (after controlling for age, gender, diagnosis, and education level of father/mother) were self-regulation and psychosomatic health. Concerning the PLTF, social support was the sole variable explaining such association. CONCLUSIONS: The present study pointed out the association between psychosocial variables; and living with a CD and school/peers connectedness. The need to focus on the assessment of the effects of a CD on adolescents' lives and contexts is suggested, as well as on the identification of vulnerable adolescents. Such identification could help to facilitate the maximization of social participation of adolescents with CD, and to plan interventions centered on providing support and opportunities for a healthy youth development. For that purpose, a complex and multifactorial approach that includes clinicians, schools, family, and peers may be proposed. PMID- 27955641 TI - Microbial phenomics information extractor (MicroPIE): a natural language processing tool for the automated acquisition of prokaryotic phenotypic characters from text sources. AB - BACKGROUND: The large-scale analysis of phenomic data (i.e., full phenotypic traits of an organism, such as shape, metabolic substrates, and growth conditions) in microbial bioinformatics has been hampered by the lack of tools to rapidly and accurately extract phenotypic data from existing legacy text in the field of microbiology. To quickly obtain knowledge on the distribution and evolution of microbial traits, an information extraction system needed to be developed to extract phenotypic characters from large numbers of taxonomic descriptions so they can be used as input to existing phylogenetic analysis software packages. RESULTS: We report the development and evaluation of Microbial Phenomics Information Extractor (MicroPIE, version 0.1.0). MicroPIE is a natural language processing application that uses a robust supervised classification algorithm (Support Vector Machine) to identify characters from sentences in prokaryotic taxonomic descriptions, followed by a combination of algorithms applying linguistic rules with groups of known terms to extract characters as well as character states. The input to MicroPIE is a set of taxonomic descriptions (clean text). The output is a taxon-by-character matrix-with taxa in the rows and a set of 42 pre-defined characters (e.g., optimum growth temperature) in the columns. The performance of MicroPIE was evaluated against a gold standard matrix and another student-made matrix. Results show that, compared to the gold standard, MicroPIE extracted 21 characters (50%) with a Relaxed F1 score > 0.80 and 16 characters (38%) with Relaxed F1 scores ranging between 0.50 and 0.80. Inclusion of a character prediction component (SVM) improved the overall performance of MicroPIE, notably the precision. Evaluated against the same gold standard, MicroPIE performed significantly better than the undergraduate students. CONCLUSION: MicroPIE is a promising new tool for the rapid and efficient extraction of phenotypic character information from prokaryotic taxonomic descriptions. However, further development, including incorporation of ontologies, will be necessary to improve the performance of the extraction for some character types. PMID- 27955643 TI - MindSurf: a pilot study to assess the usability and acceptability of a smartphone app designed to promote contentment, wellbeing, and goal achievement. AB - BACKGROUND: The Method of Levels (MOL) is a transdiagnostic cognitive therapy that promotes contentment, wellbeing, and goal achievement through the resolution of internal conflicts underlying psychological distress. MOL, based on Perceptual Control Theory (PCT), was developed in routine clinical practice and has been used effectively across different health services by different practitioners. Access to MOL-style questions through a smartphone app could, potentially, help both the general public maintain robust mental health, and also be a useful adjunct to therapy for clinical populations. The app is called MindSurf because of its focus on helping people explore their thinking. Prior to developing the app and using it with different populations it was necessary to determine whether such an idea would be usable for and acceptable to potential app users. Therefore, a pilot study was conducted with a non-clinical sample to assess the usability and acceptability of the app including monitoring whether the questions delivered in this way were associated with any adverse events. METHODS: A pilot study using quantitative as well as qualitative methods and incorporating a repeated measures, A-B design was conducted. RESULTS: The 23 participants were healthy adult volunteers who were all either undergraduate students, postgraduate students, or staff of the University of Manchester. They received MOL-style questions on their mobile phones over a 1-week period. Qualitative results were encouraging and indicated that the format and style of questioning were acceptable to participants and did not lead to increased worry or concern. A one way, repeated measures ANOVA indicated that there was a nonsignificant decrease in scores on the 21-item Depression, Anxiety, and Stress Scale (DASS21) over a 2 week period. DISCUSSION: The results of the pilot study justified development of MindSurf and further testing once it is available for use. A power analysis indicated that the pilot study was underpowered to detect significant effects but provided important information regarding the appropriate sample size for future research. The pilot study also indicated that future research should investigate the effects of receiving more than three questions per day. CONCLUSION: Results of the pilot study indicate that MindSurf will be a usable and acceptable app. Its benefits should be further explored through longer studies with larger sample of both the general population as well as clinical populations. PMID- 27955642 TI - Short stature, platyspondyly, hip dysplasia, and retinal detachment: an atypical type II collagenopathy caused by a novel mutation in the C-propeptide region of COL2A1: a case report. AB - BACKGROUND: Heterozygous mutations in COL2A1 create a spectrum of clinical entities called type II collagenopathies that range from in utero lethal to relatively mild conditions which become apparent only during adulthood. We aimed to characterize the clinical, radiological, and molecular features of a family with an atypical type II collagenopathy. CASE PRESENTATION: A family with three affected males in three generations was described. Prominent clinical findings included short stature with platyspondyly, flat midface and Pierre Robin sequence, severe dysplasia of the proximal femora, and severe retinopathy that could lead to blindness. By whole exome sequencing, a novel heterozygous deletion, c.4161_4165del, in COL2A1 was identified. The phenotype is atypical for those described for mutations in the C-propeptide region of COL2A1. CONCLUSIONS: We have described an atypical type II collagenopathy caused by a novel out-of frame deletion in the C-propeptide region of COL2A1. Of all the reported truncating mutations in the C-propeptide region that result in short-stature type II collagenopathies, this mutation is the farthest from the C-terminal of COL2A1. PMID- 27955644 TI - A randomized controlled trial on effects of different hemostatic sponges in posterior spinal fusion surgeries. AB - BACKGROUND: Spinal fusion surgery is associated with significant blood loss, which may result in potential clinical complications, it is necessary to take safe and effective measures to reduce blood loss in surgery. We perform this study to assess the impact of three different hemostatic materials on perioperative blood loss. METHODS: We performed a Randomized Controlled Trial research and recruited patients with lumbar disease into the study between November 2013 and March 2015. All the participants were randomly assigned to 3 groups using a simple equal probability randomization scheme: Group A (Stypro hemostatic sponge), Group B (Collagen hemostatic sponge) and Group C (gelatin sponge). We compared postoperative blood loss between these 3 groups. RESULTS: In our study, drainage volume in the first 24 h of patients in Group A and B is significantly smaller, as well as total postoperative volumes of drainage (p < 0.05) during their hospital stay. The drainage volumes in the second 24 h were similar in the 3 groups. We also found that the average drainage Hematocrit (HCT) reduced over time, the average HCT of drainage is 18.04% and 11.72% on the first day and on the second day respectively. CONCLUSIONS: Hemostatic collagen sponge demonstrated better hemostasis effects than gelatin sponge with lower volume of postoperative drainage volume and blood loss in posterior spinal fusion surgery. TRIAL REGISTRATION: The trial registration number (TRN) of the study is ISRCTN29254316 and date of registration is 25/10/2016. Our trial was registered retrospectively. PMID- 27955645 TI - Association between non-compliance with psychiatric treatment and non-psychiatric service utilization and costs in patients with schizophrenia and related disorders. AB - BACKGROUND: The relationship between medication non-compliance in patients with schizophrenia and related disorders, and increased psychiatric service utilization and costs are well documented; however, non-psychiatric service utilization and costs are not. Therefore, we investigated the association of non compliance with psychiatric treatment and the utilization and costs of non psychiatric services. METHODS: Data on South Korean individuals with a lifetime diagnosis of schizophrenia or a related disorder, who were treated in a psychiatric clinic at least twice during 2011, were selected among national data collected for the Health Insurance Review and Assessment Service-National Patients Sample between January 1, 2011 and December 31, 2011. The sample was divided into two overlapping groups with two different classifications of patterns of medication prescription refills: (1) adherent versus non-adherent group, and (2) persistent versus non-persistent group. A matching method was used to remove the effects of different follow-up durations and insurance system on medical service utilization and costs. The final sample for analysis consisted of data from 5,548 individuals in the adherent versus non-adherent group and 3,912 in the persistent versus non-persistent group. Comparisons of the psychiatric and non-psychiatric service utilizations were made between the groups. RESULTS: The number of psychiatric service utilizations were significantly lower in the non adherent than the adherent group. They were also significantly lower in the non persistent group than the persistent group. The number of non-psychiatric service utilizations was significantly higher in the non-adherent group. They were also significantly higher in the non-persistent group than the persistent group. All psychiatric costs per person during the study period were lower in the non adherent than the adherent group, and lower in the non-persistent than the persistent group. All non-psychiatric costs per person were higher in the non adherent than the adherent group, and higher in the non-persistent than the persistent group. CONCLUSION: Non-adherence to psychiatric treatment by patients with schizophrenia and related disorders was associated with higher medical service utilization and increased personal and societal medical costs. PMID- 27955646 TI - Association between homocysteine and non-alcoholic fatty liver disease in Chinese adults: a cross-sectional study. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and its prevalence is likely to rise even further. To help understand the pathogenesis and early prevention of progressive NAFLD, this large scale study was designed to explore the potential association between homocysteine and the prevalence of NAFLD. METHODS: A total of 7203 subjects aged 18 years or older were enrolled in this cross-sectional study. The association of homocysteine with the prevalence of NAFLD, in the total sample and stratified by subgroups, was examined using multiple logistic regression analyses. RESULTS: Subjects in the higher quartiles of homocysteine had a higher prevalence of NAFLD. After multivariate adjustment, the odds ratio (OR) for NAFLD in the highest compared with the lowest quartile of homocysteine was 2.08 (95% confidence interval [CI] 1.61, 2.67). Moreover, in the subgroup analyses, we found an effect modification by gender, body mass index (BMI) and smoking status on the association between homocysteine and the prevalence of NAFLD (P for interaction: 0.001, 0.002 and <0.001, respectively). A stronger association was observed in female, obese and non-smoking adults than in male, normal weight and smoking subjects. CONCLUSION: Homocysteine was significantly associated with the prevalence of NAFLD, particularly in female, obese or non-smoking adults. PMID- 27955647 TI - Comparisons between comorbid conditions and health care consumption in rheumatoid arthritis patients with or without biological disease-modifying anti-rheumatic drugs: a register-based study. AB - BACKGROUND: Symptoms and prognosis of patients with rheumatoid arthritis (RA) have improved with more intensive therapy, including the biological disease modifying anti-rheumatic drugs (bDMARDs). Real life data concerning how comorbidities are distributed among patients treated or not treated with bDMARDs are scarce. Our objective was to investigate differences in comorbidity and health care consumption in RA patients, with and without bDMARDs. METHODS: This cross-sectional study was performed in the Southwestern part of Sweden. Patients, aged >= 18 years and diagnosed with RA in secondary health care during 2009-2010, were identified in the regional health care database. Aggregated data of comorbidity and health care consumption were retrieved between 2006 and 2010. RA patients treated with bDMARDs on 31st December 2010 were identified in the Swedish Rheumatology Quality Register (SRQ), which includes the biologics register Anti-Rheumatic Therapy in Sweden (ARTIS). Descriptive, comparative, univariate and multiple logistic regression analyses were used to identify factors associated with bDMARDs. RESULTS: Seven thousand seven hundred and twelve (7712) RA patients were identified (age 64.8 +/- 14.9 years, women 74.3%), of whom 1137 (14.7%) were treated with bDMARDs. Overall, the most common comorbidities were infections (69.2%), hypertension (41.1%), chronic respiratory disease (15.3%), ischemic heart disease (14.0%) and malignancy (13.7%). Patients without bDMARDs were older and had more comorbidity. In the multiple logistic regression analysis, older age, cerebrovascular and chronic respiratory disease, heart failure, depression and malignancy were all associated with no present bDMARDs. Infections were associated with bDMARDs. Patients treated with bDMARDs consumed more secondary outpatient care but less visits in primary health care compared to patients without bDMARDs. CONCLUSIONS: Patients treated with bDMARDs versus no bDMARDs were younger and had significantly lower period prevalence for most common comorbidities, with the exception of infections. Differences in comorbidities between RA patients with or without bDMARDs should be taken into consideration when evaluating effectiveness and safety of bDMARDs in ordinary care. PMID- 27955648 TI - Effects of statewide health promotion in primary schools on children's sick days, visits to a physician and parental absence from work: a cluster-randomized trial. AB - BACKGROUND: Based on the World Health Organization's global school health initiative we investigate intervention effects of statewide health promotion in schools on the numbers of children's sick days and visits to a physician, and parental days off work due to child illness. METHODS: Cluster-randomized trial with 1-year follow-up in primary schools in the state of Baden-Wurttemberg, Germany. Anthropometric measurements of first and second grade school children were taken by trained staff. Parents filled in questionnaires for information about socio-demographics, health-related variables, numbers of children's sick days, visits to a physician, and days parents had to stay off work to care for a sick child. Longitudinal differences in the outcome variables were calculated between baseline and follow-up. Intraclass correlation coefficients were determined to quantify a possible clustering of data in schools. Accordingly, linear models and linear mixed models were applied to identify relationships and ascertain significances. RESULTS: Data from 1943 children (1st grade n = 1024, 6.6 +/- 0.4 years old; 2nd grade n = 919, 7.6 +/- 0.4 years old) were available at baseline. Unadjusted differences regarding both grades were found between mean longitudinal changes in intervention and control group in children's sick days ( 3.2 +/- 7.1 vs. -2.3 +/- 5.6, p = 0.013), and maternal days off work (-0.9 +/- 2.4 vs. -0.5 +/- 2.8, p = 0.019). The intervention effect on sick days was adjusted in a linear regression for baseline values, gender and migration background and confirmed for first grade children (B = -0.83, p = 0.003). The intervention effect on maternal days off work lost its significance after adjusting for baseline values. No significant differences were detected in the numbers of children's visits to a physician and paternal days off work. CONCLUSIONS: School-based health promotion slightly reduces sick days in first grade children. Subsequently, parents may not need to stay off work themselves. Small individual effects add up to larger benefits in a statewide implementation of health promotion. Additionally, health promotion may also positively contribute to school success. TRIAL REGISTRATION: The study was registered on the German Clinical Trials Register (DRKS), Freiburg University, Germany, under the DRKS-ID: DRKS00000494 . Registered: 25 August 2010. PMID- 27955649 TI - Engineering Aspergillus niger for galactaric acid production: elimination of galactaric acid catabolism by using RNA sequencing and CRISPR/Cas9. AB - BACKGROUND: meso-Galactaric acid is a dicarboxylic acid that can be produced by the oxidation of D-galacturonic acid, the main constituent of pectin. Mould strains can be engineered to perform this oxidation by expressing the bacterial enzyme uronate dehydrogenase. In addition, the endogenous pathway for D galacturonic acid catabolism has to be inactivated. The filamentous fungus Aspergillus niger would be a suitable strain for galactaric acid production since it is efficient in pectin hydrolysis, however, it is catabolizing the resulting galactaric acid via an unknown catabolic pathway. RESULTS: In this study, a transcriptomics approach was used to identify genes involved in galactaric acid catabolism. Several genes were deleted using CRISPR/Cas9 together with in vitro synthesized sgRNA. As a result, galactaric acid catabolism was disrupted. An engineered A. niger strain combining the disrupted galactaric and D-galacturonic acid catabolism with an expression of a heterologous uronate dehydrogenase produced galactaric acid from D-galacturonic acid. The resulting strain was also converting pectin-rich biomass to galactaric acid in a consolidated bioprocess. CONCLUSIONS: In the present study, we demonstrated the use of CRISPR/Cas9 mediated gene deletion technology in A. niger in an metabolic engineering application. As a result, a strain for the efficient production of galactaric acid from D-galacturonic acid was generated. The present study highlights the usefulness of CRISPR/Cas9 technology in the metabolic engineering of filamentous fungi. PMID- 27955650 TI - Development of an ovine efferent mammary lymphatic cannulation model with minimal tissue damage. AB - BACKGROUND: Two mammary lymphatic cannulation models in sheep have been described with minimal use in the past 50 years. The purpose of this study was to investigate a new surgical technique to allow long term monitoring of mammary lymph flow and composition from the mammary glands, with rapid ewe recovery and minimal complications post-surgery. RESULTS: We developed a modified methodology for cannulating the efferent mammary lymphatic from the mammary lymph node with minimum tissue damage. Compared to the previous models, our method required only a small incision on the aponeurosis of the external abdominal oblique muscles and thus reduced the difficulties in suturing the aponeurosis. It allowed for lymph collection and assessment for at least one week post-surgery with concurrent milk collection. CONCLUSION: This method allows for good ewe recovery post-surgery and in vivo sampling of efferent mammary lymph from the mammary lymph nodes in real time and comparison with milk parameters. PMID- 27955651 TI - Learning pathology using collaborative vs. individual annotation of whole slide images: a mixed methods trial. AB - BACKGROUND: Students in biomedical disciplines require understanding of normal and abnormal microscopic appearances of human tissues (histology and histopathology). For this purpose, practical classes in these disciplines typically use virtual microscopy, viewing digitised whole slide images in web browsers. To enhance engagement, tools have been developed to enable individual or collaborative annotation of whole slide images within web browsers. To date, there have been no studies that have critically compared the impact on learning of individual and collaborative annotations on whole slide images. METHODS: Junior and senior students engaged in Pathology practical classes within Medical Science and Medicine programs participated in cross-over trials of individual and collaborative annotation activities. Students' understanding of microscopic morphology was compared using timed online quizzes, while students' perceptions of learning were evaluated using an online questionnaire. RESULTS: For senior medical students, collaborative annotation of whole slide images was superior for understanding key microscopic features when compared to individual annotation; whilst being at least equivalent to individual annotation for junior medical science students. Across cohorts, students agreed that the annotation activities provided a user-friendly learning environment that met their flexible learning needs, improved efficiency, provided useful feedback, and helped them to set learning priorities. Importantly, these activities were also perceived to enhance motivation and improve understanding. CONCLUSION: Collaborative annotation improves understanding of microscopic morphology for students with sufficient background understanding of the discipline. These findings have implications for the deployment of annotation activities in biomedical curricula, and potentially for postgraduate training in Anatomical Pathology. PMID- 27955652 TI - Early skin-to-skin contact or incubator for very preterm infants: study protocol for a randomized controlled trial. AB - BACKGROUND: Skin-to-skin care immediately following delivery is a common practice for term infants and has been shown to improve cardiorespiratory stability, facilitate early bonding, and promote breastfeeding. Since 2007, the use of skin to-skin care has been practiced for preterm infants from 32 weeks of gestation in the delivery room at St. Olav's University Hospital. In the present study we aim to investigate whether skin-to-skin care following delivery is safe, and how it affects early and late outcomes compared to standard care for very preterm infants. METHODS/DESIGN: A randomized controlled trial (RCT) of skin-to-skin care in the delivery room for very preterm infants born at gestational age 280-316 weeks with birth weight >1000 grams. Infants with severe congenital malformations or need of intubation in the delivery room are excluded. A detailed checklist and a flowchart were prepared for the study, and all involved professionals (neonatologists, neonatal nurses, obstetricians, anesthesiologists, midwives) participated in medical simulation training prior to study start on February 1, 2014. A consultant in neonatology and a neonatal nurse are present at all deliveries. Infants with birth weight <1500 grams receive an intravenous line with glucose, amino acids, and caffeine citrate in the delivery room. Infants with gestational age <30 weeks are routinely put on continuous positive airway pressure (CPAP). After initial stabilization, infants are randomized to skin-to skin care or are transferred to the nursery in an incubator. Primary outcome is cognitive development at 2 years measured with the Bayley Scales of Infant Development, Third Edition. Secondary outcomes are safety defined as hypothermia, respiratory failure, and/or cardiopulmonary resuscitation, physiological stability after birth and motor, language and cognitive development at 1 year for the child, and mental health measured with the State-Trait Anxiety Inventory (STAI) at discharge, and at 3 months and 2 years after expected date of delivery for the mothers. DISCUSSION: The study may have important implications for the initial care for very preterm infants after delivery and increase our understanding of how early skin-to-skin care affects preterm infants and their mothers. TRIAL REGISTRATION: ClinicalTrials, NCT02024854 . Registered on 19 December 2013. PMID- 27955653 TI - (How) do medical students regulate their emotions? AB - BACKGROUND: Medical training can be a challenging and emotionally intense period for medical students. However the emotions experienced by medical students in the face of challenging situations and the emotion regulation strategies they use remains relatively unexplored. The aim of the present study was to explore the emotions elicited by memorable incidents reported by medical students and the associated emotion regulation strategies. METHODS: Peer interviewing was used to collect medical students' memorable incidents. Medical students at both preclinical and clinical stage of medical school were eligible to participate. In total 104 medical students provided memorable incidents. Only 54 narratives included references to emotions and emotion regulation and thus were further analyzed. RESULTS: The narratives of 47 clinical and 7 preclinical students were further analyzed for their references to emotions and emotion regulation strategies. Forty seven out of 54 incidents described a negative incident associated with negative emotions. The most frequently mentioned emotion was shock and surprise followed by feelings of embarrassment, sadness, anger and tension or anxiety. The most frequent reaction was inaction often associated with emotion regulation strategies such as distraction, focusing on a task, suppression of emotions and reappraisal. When students witnessed mistreatment or disrespect exhibited towards patients, the regulation strategy used involved focusing and comforting the patient. CONCLUSIONS: The present study sheds light on the strategies medical students use to deal with intense negative emotions. The vast majority reported inaction in the face of a challenging situation and the use of more subtle strategies to deal with the emotional impact of the incident. PMID- 27955654 TI - Depletion of SAG/RBX2 E3 ubiquitin ligase suppresses prostate tumorigenesis via inactivation of the PI3K/AKT/mTOR axis. AB - BACKGROUND: SAG (Sensitive to Apoptosis Gene), also known as RBX2, ROC2 or RNF7, is a RING component of CRL (Cullin-RING ligase), required for its activity. Our recent study showed that SAG/RBX2 co-operated with Kras to promote lung tumorigenesis, but antagonized Kras to inhibit skin tumorigenesis, suggesting a tissue/context dependent function of Sag. However, it is totally unknown whether and how Sag would play in prostate tumorigenesis, triggered by Pten loss. METHODS: Sag and Pten double conditional knockout mice were generated and prostate specific deletion of Sag and Pten was achieved by PB4-Cre, and their effect on prostate tumorigenesis was evaluated by H&E staining. The methods of immunohistochemistry (IHC) staining and Western blotting were utilized to examine expression of various proteins in prostate cancer tissues or cell lines. The effect of SAG knockdown in proliferation, survival and migration was evaluated in two prostate cancer cell lines. The poly-ubiquitylation of PHLPP1 and DEPTOR was evaluated by both in vivo and in vitro ubiquitylation assays. RESULTS: SAG is overexpressed progressively from early-to-late stage of human prostate cancer with the highest expression seen in metastatic lesion. Sag deletion inhibits prostate tumorigenesis triggered by Pten loss in a mouse model as a result of suppressed proliferation. SAG knockdown in human prostate cancer cells inhibits a) proliferation in monolayer and soft agar, b) clonogenic survival, and c) migration. SAG is an E3 ligase that promotes ubiquitylation and degradation of PHLPP1 and DEPTOR, leading to activation of the PI3K/AKT/mTOR axis, whereas SAG knockdown caused their accumulation. Importantly, growth suppression triggered by SAG knockdown was partially rescued by simultaneous knockdown of PHLPP1 or DEPTOR, suggesting their causal role. Accumulation of Phlpp1 and Deptor with corresponding inactivation of Akt/mTOR was also detected in Sag-null prostate cancer tissues. CONCLUSIONS: Sag is an oncogenic cooperator of Pten-loss for prostate tumorigenesis. Targeting SAG E3 ligase may, therefore, have therapeutic value for the treatment of prostate cancer associated with Pten loss. PMID- 27955655 TI - Short- to long-term follow-up of total femoral replacement in non-oncologic patients. AB - BACKGROUND: Compromised bone stock and heavily impaired structural integrity after multiple endoprosthetic revision surgeries can lead to a comparable condition as encountered in musculoskeletal tumor surgery. Total femoral replacement (TFR) can restore femoral integrity and allow patients to resume ambulation. Even though several authors reported their results of TFR, so far many questions are still on debate: Which patients are at risk to experience low functional outcome? Do complications and clinical outcome after TFR depend on the indication for the surgery (e.g. periprosthetic fractures or aseptic loosening) or the age of the patients? The purpose of the present study was to compare complication rates after TFR performed with modular total femur prosthesis MML (Fa. ESKA/Orthodynamics) in patients without malignant disease. METHODS: We conducted a retrospective chart review and functional investigation of patients treated with a TFR for non-oncologic conditions from 1995 to 2015 and a minimum follow-up of 2 years. Complications were recorded according to the Henderson Classification; outcome was evaluated with established clinical scores. The indication for TFR was periprosthetic fracture (Group A, n = 11) or aseptic loosening (Group B, n = 7) with massive bone defect of the femur deemed unsuitable for conventional arthroplastic or biologic reconstruction. RESULTS: Eighteen patients matched the inclusion criteria and could be investigated clinically after a mean follow-up of 80 months (range: 28-132). Before TFA, all patients had previously undergone multiple operations (range: 1-8). The overall failure rate for any reason was 72% (n = 13/18), leading to a total of 37 surgical revisions with total exchange of TFR in 22% (n = 4/18). Most common failure mechanism was Type I (soft tissue), followed by Type IV (infection) and Type III (mechanical failure). According to Enneking's functional evaluation method (MSTS-Score), the function ranged from 1 to 15 with a mean of 10 +/- 4 out of 30. CONCLUSION: TFR is a salvage procedure to restore mechanical integrity and regain functional ability after extensive femoral bone loss. Outcome of the patients in the present study did mainly depend on the age at reconstruction and not on the indication for TFR. PMID- 27955656 TI - Means of enhancing bone fracture healing: optimal cell source, isolation methods and acoustic stimulation. AB - BACKGROUND: The human body has an extensive capacity to regenerate bone tissue after trauma. However large defects such as long bone fractures of the lower limbs cannot be restored without intervention and often lead to nonunion. Therefore, the aim of the present study was to assess the pool and biological functions of human mesenchymal stromal cells (hMSCs) isolated from different bone marrow locations of the lower limbs and to identify novel strategies to prime the cells prior to their use in bone fracture healing. Following, bone marrow from the ilium, proximal femur, distal femur and proximal tibia was aspirated and the hMSCs isolated. Bone marrow type, volume, number of mononuclear cells/hMSCs and their self-renewal, multilineage potential, extracellular matrix (ECM) production and surface marker profiling were analyzed. Additionally, the cells were primed to accelerate bone fracture healing either by using acoustic stimulation or varying the initial hMSCs isolation conditions. RESULTS: We found that the more proximal the bone marrow aspiration location, the larger the bone marrow volume was, the higher the content in mononuclear cells/hMSCs and the higher the self renewal and osteogenic differentiation potential of the isolated hMSCs were. Acoustic stimulation of bone marrow, as well as the isolation of hMSCs in the absence of fetal bovine serum, increased the osteogenic and ECM production potential of the cells, respectively. CONCLUSION: We showed that bone marrow properties change with the aspiration location, potentially explaining the differences in bone fracture healing between the tibia and the femur. Furthermore, we showed two new priming methods capable of enhancing bone fracture healing. PMID- 27955657 TI - Adverse reactions to metal debris occur with all types of hip replacement not just metal-on-metal hips: a retrospective observational study of 3340 revisions for adverse reactions to metal debris from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man. AB - BACKGROUND: Adverse reactions to metal debris (ARMD) have resulted in the high short-term failure rates observed with metal-on-metal hip replacements. ARMD has recently been reported in non-metal-on-metal total hip replacements (non-MoM THRs) in a number of small cohort studies. However the true magnitude of this complication in non-MoM THRs remains unknown. We used a nationwide database to determine the risk of ARMD revision in all non-MoM THRs, and compared patient and surgical factors associated with ARMD revision between non-MoM and MoM hips. METHODS: We performed a retrospective observational study using data from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man. All primary hip replacements undergoing revision surgery for ARMD were included (n = 3,340). ARMD revision risk in non-MoM THRs was compared between different commonly implanted bearing surfaces and femoral head sizes (Chi-squared test). Differences in patient and surgical factors between non-MoM hips and MoM hips revised for ARMD were also analysed (Chi-squared test and unpaired t-test). RESULTS: Of all ARMD revisions, 7.5% (n = 249) had non-MoM bearing surfaces. The relative risk of ARMD revision was 2.35 times (95% CI 1.76-3.11) higher in ceramic-on-ceramic bearings compared with hard-on-soft bearings (0.055 vs. 0.024%; p < 0.001), and 2.80 times (95% CI 1.74-4.36) higher in 36 mm metal-on polyethylene bearings compared to 28 mm and 32 mm metal-on-polyethylene bearings (0.058 vs. 0.021%; p < 0.001). ARMD revisions were performed earlier in non-MoM hips compared to MoM hips (mean 3.6-years vs. 5.6-years; p < 0.0001). Non-MoM hips had more abnormal findings at revision (63.1 vs. 35.7%; p < 0.001), and more intra-operative adverse events (6.4 vs. 1.6%; p < 0.001) compared to MoM hips. CONCLUSIONS: Although the overall risk of ARMD revision surgery in non-MoM THRs appears low, this risk is increasing, and is significantly higher in ceramic-on ceramic THRs and 36 mm metal-on-polyethylene THRs. ARMD may therefore represent a significant clinical problem in non-MoM THRs. PMID- 27955658 TI - Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes. AB - BACKGROUND: Congenital dilatation of the bile-duct (CDD) is a rare, mostly sporadic, disorder that results in bile retention with severe associated complications. CDD affects mainly Asians. To our knowledge, no genetic study has ever been conducted. METHODS: We aim to identify genetic risk factors by a "trio based" exome-sequencing approach, whereby 31 CDD probands and their unaffected parents were exome-sequenced. Seven-hundred controls from the local population were used to detect gene-sets significantly enriched with rare variants in CDD patients. RESULTS: Twenty-one predicted damaging de novo variants (DNVs; 4 protein truncating and 17 missense) were identified in several evolutionarily constrained genes (p < 0.01). Six genes carrying DNVs were associated with human developmental disorders involving epithelial, connective or bone morphologies (PXDN, RTEL1, ANKRD11, MAP2K1, CYLD, ACAN) and four linked with cholangio- and hepatocellular carcinomas (PIK3CA, TLN1 CYLD, MAP2K1). Importantly, CDD patients have an excess of DNVs in cancer-related genes (p < 0.025). Thirteen genes were recurrently mutated at different sites, forming compound heterozygotes or functionally related complexes within patients. CONCLUSIONS: Our data supports a strong genetic basis for CDD and show that CDD is not only genetically heterogeneous but also non-monogenic, requiring mutations in more than one genes for the disease to develop. The data is consistent with the rarity and sporadic presentation of CDD. PMID- 27955659 TI - Magnitude and associated factors of aggressive behaviour among patients with bipolar disorder at Amanual Mental Specialized Hospital, outpatient department, Addis Ababa, Ethiopia: cross-sectional study. AB - BACKGROUND: Aggressive behavior is a challenging behavior among bipolar patients that causes poor social interaction and hospitalization. But, there is no information regards of the magnitude and contributing factors for aggressive behaviour among bipolar patients in Ethiopia. Therefore, this study was designed to assess the prevalence and associated factors of aggressive behaviour among patients with bipolar disorder. METHOD: An institutional based cross sectional study was conducted at Amanual Mental Specialized Hospital from May 1 to June 1, 2015 among 411 participants who were selected by systematic random sampling technique. Data was collected by interview technique by using Modified Overt Aggression Scale, entered and analyzed by using Epi Data 3.1 and Statistical Package for Social Science version 20, respectively. Adjusted Odd Ratio (AOR) with 95% Confidence Interval (CI) were used to show the odd and P-value <0.05 was considered as statistically significant. RESULTS: A total of 411 bipolar patients were included in the study and the prevalence of aggressive behaviour was 29.4%. Significant associated factors for aggression were, having two or more episode [AOR = 2.35 95% CI (1.18, 4.69)], previous history of aggression, [AOR = 3.72, 95% CI (1.54, 8.98)], depressive symptoms [AOR = 3.63, 95% CI (1.89, 6.96)], psychotic symptoms [AOR = 5.41,95% CI (2.88, 10.1)], manic symptoms [AOR = 3.85,95% CI (2.06, 7.19)], poor medication adherence [AOR = 3.73 95% CI (1.71, 8.13)], poor social support [AOR = 2.99 95% CI (1.30, 6.91)] and current use of substance[AOR = 2.17 95% CI (1.16, 4.06)]. CONCLUSION: Prevalence of aggression is high among bipolar patients and associated with many factors. So it needs public health attention to decrease aggression among bipolar patients. PMID- 27955660 TI - The role of community social capital in the relationship between socioeconomic status and adolescent life satisfaction: mediating or moderating? Evidence from Czech data. AB - BACKGROUND: The concept of social capital has been extensively used to explain the relationship between socioeconomic status (SES) and adolescent health and well-being. Much less is known about the specific mechanism through which social capital impacts the relationship. This paper investigates whether an individual's perception of community social capital moderates or mediates the association between SES and life satisfaction. METHODS: This study employs cross-sectional data from the 2009-2010 Czech Health Behaviour in School-Aged Children survey: a WHO Collaborative Cross-National Study (HBSC). A sample of 4425 adolescents from the 5th, 7th and 9th grade (94.5% school response rate, 87% student response) was used to perform multilevel analysis. RESULTS: We found that pupils' life satisfaction was positively related to both family affluence and perceived wealth. Moreover, we found the cognitive component of social capital to be positively associated with life satisfaction. Additionally, a significant interaction was found, such that the social gradient in life satisfaction was flattened when pupils reported high levels of perceived community social capital. CONCLUSIONS: The present findings suggest that community social capital acts as an unequal health resource for adolescents, but could potentially represent opportunities for public health policy to close the gap in socioeconomic disparities. PMID- 27955662 TI - Lipopolysaccharide derived from the digestive tract triggers an inflammatory response in the uterus of mid-lactating dairy cows during SARA. AB - BACKGROUND: The aims of the current study were to evaluate the inflammatory response in cow uterus and to explore the molecular mechanism triggered by high concentrate-induced subacute ruminal acidosis (SARA) in mid-lactating dairy cows. Twelve mid-lactating Holstein cows with an average weight of 455 kg were allocated into two groups subjected to two diets for 18-weeks either a low concentrate (LC) group containing 4:6 (NDF: NFC) and a high-concentrate (HC) group containing 6:4 (non-forage carbohydrates, NFC): (neutral detergent fiber, NDF) ratio based on dry matter. RESULTS: The HC group showed lower ruminal pH and higher lipopolysaccharide (LPS) concentrations in both the rumen and peripheral plasma compared to the LC group. The LPS concentrations in the rumen fluid and the peripheral plasma were found significantly increased in the HC group compared to the LC group. The concentrations of IL-1beta, TNF-alpha and IL-6 were significantly higher in the HC group compared to the LC group. The uterus of SARA cows revealed elevated mRNA concentrations of nuclear transcription factors and pro-inflammatory cytokines, which confirmed the presence of inflammation. The occurrence of uterine inflammation was further validated by the increased protein expression of NF-kappaB-p65 and its active phosphorylated variant in the uterus of SARA cows. Similarly, the inflammatory genes TLR4, LBP, MyD88, TRAF-6, NF kappaB, IL-6, IL-8, TNF-alpha and IL-1beta were significantly upregulated in the uterus of the HC versus the LC group. CONCLUSION: Therefore, the results indicated that LPS derived from the rumen triggered the genes associated with inflammation in the uterus of mid-lactating dairy cows fed a high-concentrate diet, causing endometritis. PMID- 27955661 TI - Association between neutrophilic granulocyte percentage and depression in hospitalized patients with heart failure. AB - BACKGROUND: Previous researches reveal that depression is associated with increased inflammatory markers. As a simple and cheap inflammatory marker, we hypothesize that neutrophilic granulocyte percentage is associated with depression in hospitalized heart failure patients, whose prevalence of depression is at a very high level. METHODS: Three hundred sixty-six cases of hospitalized heart failure patients with left ventricular ejection fraction (LVEF) <=45% and New York Heart Association (NYHA) class II-IV were enrolled. All the enrolled patients received Hamilton Rating Scale for Depression (24-items) (HAM-D24). The demographic, clinical data, blood samples and echocardiography were documented. The Pearson simple linear correlation was performed to evaluate the confounding factors correlated with HAM-D24 depression index. The significantly correlated factors were enrolled as independent variables in Logistic regression to determine the risk or protective factors for depression, which was taken as dependent variable. RESULTS: Two hundred ten cases of hospitalized heart failure patients (57.4%) had depression. Among them, 134 patients (63.8%) had mild depression, 58 patients (27.6%) had moderate depression and 18 patients (8.6%) had severe depression. Pearson simple linear correlation revealed that in hospitalized patients with heart failure, the neutrophils granulocyte percentage was positively correlated with the HAM-D24 depression index (r = .435, p < .001). After the adjustment of age, BMI, number of members of the household, smoking index, New York Heart Association (NYHA) classification, hemoglobin, TC, LDL-C, creatinine, cystatin-C, TBIL and albumin, the neutrophils granulocyte percentage is still significantly associated with depression in hospitalized heart failure patients (OR = 1.046, p < .001). CONCLUSIONS: The neutrophils granulocyte percentage may be used as a new marker for depression in hospitalized heart failure patients. PMID- 27955663 TI - The effect of marine n-3 polyunsaturated fatty acids on cardiac autonomic and hemodynamic function in patients with psoriatic arthritis: a randomised, double blind, placebo-controlled trial. AB - BACKGROUND: The aim of this study was to investigate the effect of marine n-3 polyunsaturated fatty acids (PUFA) on cardiac autonomic function and vascular function in patients with psoriatic arthritis. METHODS: The study was conducted as a randomized, double-blind, placebo-controlled trial, where 145 patients with psoriatic arthritis were supplemented with 3 g of n-3 PUFA or olive oil (control) daily for 24 weeks. Blood pressure, heart rate, heart rate variability (HRV), central blood pressure, pulse wave velocity (PWV) and fatty acid composition of granulocytes, were determined at baseline and after supplementation. RESULTS: At baseline we found a significant difference in the mean of all normal RR intervals (inverse of heart rate, vary from beat to beat) when comparing subjects with the highest vs the lowest fish intake (p = 0.03). After supplementation for 24 weeks there was a trend towards an increase in RR (p = 0.13) and decrease in heart rate (p = 0.12) comparing the n-3 PUFA group with the control group. However, per protocol analysis showed significantly increased RR (p = 0.01) and lowered heart rate (p = 0.01) in the n-3 PUFA supplemented patients compared with controls. Blood pressure, PWV and Central blood pressure did not change after supplementation with n-3 PUFA. Adjustment for disease activity and conventional cardiovascular risk factors did not change the results. CONCLUSIONS: Marine n-3 PUFA increased RR intervals in patients with psoriatic arthritis which may suggest a protective effect of n-3 PUFA against cardiovascular disease in this population. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01818804. PMID- 27955664 TI - The burden of hypertension, diabetes mellitus, and cardiovascular risk factors among adult Malawians in HIV care: consequences for integrated services. AB - BACKGROUND: Hypertension and diabetes prevalence is high in Africans. Data from HIV infected populations are limited, especially from Malawi. Integrating care for chronic non-communicable co-morbidities in well-established HIV services may provide benefit for patients by preventing multiple hospital visits but will increase the burden of care for busy HIV clinics. METHODS: Cross-sectional study of adults (>=18 years) at an urban and a rural HIV clinic in Zomba district, Malawi, during 2014. Hypertension and diabetes were diagnosed according to stringent criteria. Proteinuria, non-fasting lipids and cardio/cerebro-vascular disease (CVD) risk scores (Framingham and World Health Organization/International Society for Hypertension) were determined. The association of patient characteristics with diagnoses of hypertension and diabetes was studied using multivariable analyses. We explored the additional burden of care for integrated drug treatment of hypertension and diabetes in HIV clinics. We defined that burden as patients with diabetes and/or stage II and III hypertension, but not with stage I hypertension unless they had proteinuria, previous stroke or high Framingham CVD risk. RESULTS: Nine hundred fifty-two patients were enrolled, 71.7% female, median age 43.0 years, 95.9% on antiretroviral therapy (ART), median duration 47.7 months. Rural and urban patients' characteristics differed substantially. Hypertension prevalence was 23.7% (95%-confidence interval 21.1 26.6; rural 21.0% vs. urban 26.5%; p = 0.047), of whom 59.9% had stage I (mild) hypertension. Diabetes prevalence was 4.1% (95%-confidence interval 3.0-5.6) without significant difference between rural and urban settings. Prevalence of proteinuria, elevated total/high-density lipoprotein-cholesterol ratio and high CVD risk score was low. Hypertension diagnosis was associated with increasing age, higher body mass index, presence of proteinuria, being on regimen zidovudine/lamivudine/nevirapine and inversely with World Health Organization clinical stage at ART initiation. Diabetes diagnosis was associated with higher age and being on non-standard first-line or second-line ART regimens. CONCLUSION: Among patients in HIV care 26.6% had hypertension and/or diabetes. Close to two thirds of hypertension diagnoses was stage I and of those few had an indication for antihypertensive pharmacotherapy. According to our criteria, 13.0% of HIV patients in care required drug treatment for hypertension and/or diabetes. PMID- 27955665 TI - The economics of malaria control and elimination: a systematic review. AB - BACKGROUND: Declining donor funding and competing health priorities threaten the sustainability of malaria programmes. Elucidating the cost and benefits of continued investments in malaria could encourage sustained political and financial commitments. The evidence, although available, remains disparate. This paper reviews the existing literature on the economic and financial cost and return of malaria control, elimination and eradication. METHODS: A review of articles that were published on or before September 2014 on the cost and benefits of malaria control and elimination was performed. Studies were classified based on their scope and were analysed according to two major categories: cost of malaria control and elimination to a health system, and cost-benefit studies. Only studies involving more than two control or elimination interventions were included. Outcomes of interest were total programmatic cost, cost per capita, and benefit-cost ratios (BCRs). All costs were converted to 2013 US$ for standardization. RESULTS: Of the 6425 articles identified, 54 studies were included in this review. Twenty-two were focused on elimination or eradication while 32 focused on intensive control. Forty-eight per cent of studies included in this review were published on or after 2000. Overall, the annual per capita cost of malaria control to a health system ranged from $0.11 to $39.06 (median: $2.21) while that for malaria elimination ranged from $0.18 to $27 (median: $3.00). BCRs of investing in malaria control and elimination ranged from 2.4 to over 145. CONCLUSION: Overall, investments needed for malaria control and elimination varied greatly amongst the various countries and contexts. In most cases, the cost of elimination was greater than the cost of control. At the same time, the benefits of investing in malaria greatly outweighed the costs. While the cost of elimination in most cases was greater than the cost of control, the benefits greatly outweighed the cost. Information from this review provides guidance to national malaria programmes on the cost and benefits of malaria elimination in the absence of data. Importantly, the review highlights the need for more robust economic analyses using standard inputs and methods to strengthen the evidence needed for sustained financing for malaria elimination. PMID- 27955666 TI - Neutropenia and agranulocytosis during treatment of schizophrenia with clozapine versus other antipsychotics: an observational study in Iceland. AB - BACKGROUND: Data on the haematological outcomes of patients who continue clozapine treatment following neutropenia are very rare as even mild neutropenia results in mandatory discontinuation of clozapine in most countries. However, in Iceland where clozapine monitoring is less stringent allows an observational study to be done on the risk of agranulocytosis and neutropenia during treatment with clozapine compared with other antipsychotics among patients with schizophrenia. METHODS: The present study is a part of a wider ongoing longitudinal study of schizophrenia in Iceland. We identified 201 patients with schizophrenia treated with clozapine and 410 patients with schizophrenia who had never been on clozapine by searching the electronic health records of Landspitali, the National University Hospital. Neutrophil counts were searched in electronic databases to identify patients who developed neutropenia/agranulocytosis and the frequency of neutrophil measurements was examined as well. RESULTS: The median number of days between neutrophil measurements during the first 18 weeks of clozapine treatment was 25 days but after the first 18 weeks on the drug the median became 124 days. Thirty four cases of neutropenia were identified during clozapine treatment with an average follow up time of 9.2 years. The majority, 24 individuals developed mild neutropenia (1500-1900 neutrophils/mm3). None of these progressed to agranulocytosis. The remaining 10 patients developed neutropenia in the range 500 1400 /mm3 of whom one developed agranulocytosis, three stopped clozapine use and 6 patients continued on clozapine for at least a year without developing agranulocytosis. Unexpectedly, schizophrenia patients on other antipsychotics had an equal risk of developing neutropenia as those on clozapine. CONCLUSIONS: Neutropenia is common both in patients with schizophrenia on clozapine treatment and in those never on clozapine. Therefore a large part of neutropenia during clozapine treatment is probably not caused by clozapine. These findings have implications in assessing the balance between the risk of progression from neutropenia to agranulocytosis against the morbidity resulting from the premature discontinuation of clozapine under the current monitoring regulations in the US and in most of Europe. PMID- 27955667 TI - The effect of Chinese herbs and its effective components on coronary heart disease through PPARs-PGC1alpha pathway. AB - BACKGROUND: DanQi pill (DQP) is prescribed widely in China and has definite cardioprotective effect on coronary heart disease. Our previous studies proved that DQP could effectively regulate plasma levels of high density lipoprotein (HDL) and low density lipoprotein (LDL). However, the regulatory mechanisms of DQP and its major components Salvianolic acids and Panax notoginseng saponins (DS) on lipid metabolism disorders haven't been comprehensively studied so far. METHODS: Rat model of coronary heart disease was induced by left anterior descending (LAD) artery ligation operations. Rats were divided into sham, model, DQP treated, DS treated and positive drug (clofibrate) treated groups. At 28 days after surgery, cardiac functions were assessed by echocardiography. Expressions of transcription factors and key molecules in energy metabolism pathway were measured by reverse transcriptase polymerase chain reaction or western blotting. RESULTS: In ischemic heart model, cardiac functions were severely injured but improved by treatments of DQP and DS. Expression of LPL was down-regulated in model group. Both DQP and DS could up-regulate the mRNA expression of LPL. Membrane proteins involved in lipid transport and uptake, such as FABP4 and CPT 1A, were down-regulated in ischemic heart tissues. Treatment with DQP and DS regulated lipid metabolisms by up-regulating expressions of FABP4 and CPT-1A. DQP and DS also suppressed expression of cytochrome P450. Furthermore, transcriptional factors, such as PPARalpha, PPARgamma, RXRA and PGC-1alpha, were down-regulated in ischemic model group. DQP and DS could up-regulate expressions of these factors. However, DS showed a better efficacy than DQP on PGC-1alpha, a coactivator of PPARs. Key molecules in signaling pathways such as AKT1/2, ERK and PI3K were also regulated by DQP and DS simultaneously. CONCLUSIONS: Salvianolic acids and Panax notoginseng are the major effective components of DanQi pill in improving lipid metabolism in ischemic heart model. The effects may be mediated by regulating transcriptional factors such as PPARs, RXRA and PGC-1alpha. PMID- 27955668 TI - Vision-related quality of life and psychological status in Chinese women with Sjogren's syndrome dry eye: a case-control study. AB - BACKGROUND: Sjogren's syndrome dry eye (SSDE) mainly affects middle-aged women and can negatively affect women's psychological and social functioning. However, little is known about the correlation between vision-related quality of life (VR QoL) and psychological status for women with SSDE. We therefore examined VR-QoL and psychological status in two groups of Chinese women: an SSDE group and a non SSDE group. We also explored the associations between VR-QoL scores, sociodemographic measures, ophthalmologic parameters, and psychological status in women with SSDE. METHODS: The case-control study recruited 30 female outpatients with SSDE and 30 without SSDE from the Eye and Ear, Nose, and Throat (ENT) Hospital of Fudan University. Demographic and ophthalmologic data were collected from all participants. Ophthalmologic examinations included best-corrected visual acuity (BCVA), corneal fluorescein staining (CFS), tear break-up time (TBUT) and Schirmer test. Data collected using the National Eye Institute's Visual Function Questionnaire (NEI-VFQ) and Ocular Surface Disease Index (OSDI) survey instruments were analyzed to identify potential differences in VR-QoL between the SSDE group and the non-SSDE group. We also used the Zung Self-Rating Anxiety and Self-Rating Depression Scales (SAS and SDS) to determine psychological status in both groups. RESULTS: The SSDE group scored significantly lower than the non-SSDE group on the NEI-VFQ subscales of general health, general vision, and long distance vision activities (all p < 0.05). The SSDE group achieved a significantly higher ocular symptoms score compared with the control group (p = 0.0256). The SAS and SDS scores of the SSDE group were significantly higher than the non-SSDE group (p = 0.0072 and 0.0162, respectively). The prevalence of anxiety and depression in the SSDE group was significantly higher than the non SSDE group (p = 0.0240 and 0.0200, respectively). Nine of twelve NEI-VFQ subscales were negatively correlated with SAS/SDS scores (all p values were <0.05). The exceptions were social function, color vision and peripheral vision. The composite OSDI score and its three subscale scores for the women in the SSDE group were all positively correlated with overall SAS/SDS scores (all p values were <0.05). CONCLUSIONS: Both VR-QoL and psychological status were significantly worse in SSDE group than in the non-SSDE group. The VR-QoL of women with SSDE had a negative correlation with their anxiety and depression levels. PMID- 27955669 TI - Simulating future supply of and requirements for human resources for health in high-income OECD countries. AB - BACKGROUND: As part of efforts to inform the development of a global human resources for health (HRH) strategy, a comprehensive methodology for estimating HRH supply and requirements was described in a companion paper. The purpose of this paper is to demonstrate the application of that methodology, using data publicly available online, to simulate the supply of and requirements for midwives, nurses, and physicians in the 32 high-income member countries of the Organisation for Economic Co-operation and Development (OECD) up to 2030. METHODS: A model combining a stock-and-flow approach to simulate the future supply of each profession in each country-adjusted according to levels of HRH participation and activity-and a needs-based approach to simulate future HRH requirements was used. Most of the data to populate the model were obtained from the OECD's online indicator database. Other data were obtained from targeted internet searches and documents gathered as part of the companion paper. RESULTS: Relevant recent measures for each model parameter were found for at least one of the included countries. In total, 35% of the desired current data elements were found; assumed values were used for the other current data elements. Multiple scenarios were used to demonstrate the sensitivity of the simulations to different assumed future values of model parameters. Depending on the assumed future values of each model parameter, the simulated HRH gaps across the included countries could range from shortfalls of 74 000 midwives, 3.2 million nurses, and 1.2 million physicians to surpluses of 67 000 midwives, 2.9 million nurses, and 1.0 million physicians by 2030. CONCLUSIONS: Despite important gaps in the data publicly available online and the short time available to implement it, this paper demonstrates the basic feasibility of a more comprehensive, population needs-based approach to estimating HRH supply and requirements than most of those currently being used. HRH planners in individual countries, working with their respective stakeholder groups, would have more direct access to data on the relevant planning parameters and would thus be in an even better position to implement such an approach. PMID- 27955670 TI - "The way the country has been carved up by researchers": ethics and power in north-south public health research. AB - BACKGROUND: Despite the recognition of power as being central to health research collaborations between high income countries and low and middle income countries, there has been insufficient detailed analysis of power within these partnerships. The politics of research in the global south is often considered outside of the remit of research ethics. This article reports on an analysis of power in north south public health research, using Zambia as a case study. METHODS: Primary data were collected in 2011/2012, through 53 in-depth interviews with: Zambian researchers (n = 20), Zambian national stakeholders (n = 8) and northern researchers who had been involved in public health research collaborations involving Zambia and the global north (n = 25). Thematic analysis, utilising a situated ethics perspective, was undertaken using Nvivo 10. RESULTS: Most interviewees perceived roles and relationships to be inequitable with power remaining with the north. Concepts from Bourdieu's theory of Power and Practice highlight new aspects of research ethics: Northern and southern researchers perceive that different habituses exist, north and south - habituses of domination (northern) and subordination (Zambian) in relation to researcher relationships. Bourdieu's hysteresis effect provides a possible explanation for why power differentials continue to exist. In some cases, new opportunities have arisen for Zambian researchers; however, they may not immediately recognise and grasp them. Bourdieu's concept of Capitals offers an explanation of how diverse resources are used to explain these power imbalances, where northern researchers are often in possession of more economic, symbolic and social capital; while Zambian researchers possess more cultural capital. CONCLUSIONS: Inequities and power imbalances need to be recognised and addressed in research partnerships. A situated ethics approach is central in understanding this relationship in north south public health research. PMID- 27955672 TI - An update on the Pauwels classification. AB - BACKGROUND: Femoral neck fractures typically occur as a result of high-energy mechanisms among non-geriatric patients. Complications, including femoral neck shortening, non-union, and avascular necrosis, are relatively common after the internal fixation of this fracture pattern. These complications have serious effects on young patients. The Pauwels classification, which is the first biomechanical classification for femoral neck fractures, is still frequently used to determine and prescribe the appropriate treatment for femoral neck fractures. However, we lack a unified standard for measuring the Pauwels angle, which may make the classification unreliable. Understanding the relationship between the Pauwels classification and the complications arising from the internal fixation of femoral neck fractures is necessary. Meanwhile, a Pauwels type III femoral neck fracture among young adults, which involves a high shear load at the fracture site, is difficult to treat successfully. In addition, the recognized internal fixation for this fracture pattern remains uncertain. MAIN BODY: This review aims to provide an update on the viewpoint on the Pauwels classification including the measurement of the Pauwels angle and to present evidence to prove the aforementioned relationship. Moreover, this article also discusses the optimal internal fixation for femoral neck fractures based on the Pauwels classification. CONCLUSION: A unified standard of measurement should be established for the Pauwels classification, which is still frequently used in the literature and in determining appropriate treatment for femoral neck fractures, to achieve a credible classification. In addition, more randomized, multicentric, and prospective trials should be conducted in the future to clearly understand the relationship between the Pauwels classification and complications arising from the internal fixation of femoral neck fractures and, consequently, to explore ideal fixations for a Pauwels type III femoral neck fracture. PMID- 27955673 TI - Immunohistochemical and in situ hybridization study of urate transporters GLUT9/URATv1, ABCG2, and URAT1 in the murine brain. AB - BACKGROUND: Uric acid (UA) is known to exert neuroprotective effects in the brain. However, the mechanism of UA regulation in the brain is not well characterized. In our previous study, we described that the mouse urate transporter URAT1 is localized to the cilia and apical surface of ventricular ependymal cells. To further strengthen the hypothesis that UA is transported transcellularly at the ependymal cells, we aimed to assess the distribution of other UA transporters in the murine brain. METHODS: Immunostaining and highly sensitive in situ hybridization was used to assess the distribution of UA transporters: GLUT9/URATv1, ABCG2, and URAT1. RESULTS: Immunostaining for GLUT9 was observed in ependymal cells, neurons, and brain capillaries. Immunostaining for ABCG2 was observed in the choroid plexus epithelium and brain capillaries, but not in ependymal cells. These results were validated by in situ hybridization. CONCLUSIONS: We propose that given their specific expression patterns in ependymal, choroid plexus epithelial, and brain capillary endothelial cells in this study, UA may be transported by these UA transporters in the murine brain. This may provide a novel strategy for targeted neuroprotection. PMID- 27955671 TI - Pro-epileptogenic effects of viral-like inflammation in both mature and immature brains. AB - BACKGROUND: Infectious encephalitides are most often associated with acute seizures during the infection period and are risk factors for the development of epilepsy at later times. Mechanisms of viral encephalitis-induced epileptogenesis are poorly understood. Here, we evaluated the contribution of viral encephalitis associated inflammation to ictogenesis and epileptogenesis using a rapid kindling protocol in rats. In addition, we examined whether minocycline can improve outcomes of viral-like brain inflammation. METHODS: To produce viral-like inflammation, polyinosinic-polycytidylic acid (PIC), a toll-like receptor 3 (TLR3) agonist, was applied to microglial/macrophage cell cultures and to the hippocampus of postnatal day 13 (P13) and postnatal day 74 (P74) rats. Cell cultures permit the examination of the inflammation induced by PIC, while the in vivo setting better suits the analysis of cytokine production and the effects of inflammation on epileptogenesis. Minocycline (50 mg/kg) was injected intraperitoneally for 3 consecutive days prior to the kindling procedure to evaluate its effects on inflammation and epileptogenesis. RESULTS: PIC injection facilitated kindling epileptogenesis, which was evident as an increase in the number of full limbic seizures at both ages. Furthermore, in P14 rats, we observed a faster seizure onset and prolonged retention of the kindling state. PIC administration also led to an increase in interleukin 1beta (IL-1beta) levels in the hippocampus in P14 and P75 rats. Treatment with minocycline reversed neither the pro-epileptogenic effects of PIC nor the increase of IL-1beta in the hippocampus in both P14 and P75 rats. CONCLUSIONS: Hippocampal injection of PIC facilitates rapid kindling epileptogenesis at both P14 and P75, suggesting that viral-induced inflammation increases epileptogenesis irrespective of brain maturation. Minocycline, however, was unable to reverse the increase of epileptogenesis, which might be linked to its absence of effect on hippocampal IL 1beta levels at both ages. PMID- 27955674 TI - Attenuation of chemokine receptor function and surface expression as an immunomodulatory strategy employed by human cytomegalovirus is linked to vGPCR US28. AB - BACKGROUND: Some herpesviruses like human cytomegalovirus (HCMV) encode viral G protein-coupled receptors that cause reprogramming of cell signaling to facilitate dissemination of the virus, prevent immune surveillance and establish life-long latency. Human GPCRs are known to function in complex signaling networks involving direct physical interactions as well as indirect crosstalk of orthogonal signaling networks. The human chemokine receptor CXCR4 is expressed on hematopoietic stem cells, leukocytes, endothelial and epithelial cells, which are infected by HCMV or display reservoirs of latency. RESULTS: We investigated the potential heteromerization of US28 with CXCR4 as well as the influence of US28 on CXCR4 signaling. Using Bioluminescence Resonance Energy Transfer and luciferase complementation based methods we show that US28 expression exhibits negative effects on CXCR4 signaling and constitutive surface expression in HEK293T cells. Furthermore, we demonstrate that this effect is not mediated by receptor heteromerization but via signaling crosstalk. Additionally, we show that in HCMV, strain TB40E, infected HUVEC the surface expression of CXCR4 is strongly downregulated, whereas in TB40E-delUS28 infected cells, CXCR4 surface expression is not altered in particular at late time points of infection. CONCLUSIONS: We show that the vGPCR US28 is leading to severely disturbed signaling and surface expression of the chemokine receptor CXCR4 thereby representing an effective mechanism used by vGPCRs to reprogram host cell signaling. In contrast to other studies, we demonstrate that these effects are not mediated via heteromerization. PMID- 27955675 TI - CD24 enrichment protects while its loss increases susceptibility of juvenile chondrocytes towards inflammation. AB - BACKGROUND: Diseases associated with human cartilage, including rheumatoid arthritis (RA) and osteoarthritis (OA) have manifested age, mechanical stresses and inflammation as the leading risk factors. Although inflammatory processes are known to be upregulated upon aging, we sought to gain a molecular understanding of how aging affects the tissue-specific response to inflammation. In this report, we explored the role of cluster of differentiation 24 (CD24) in regulating differential inflammatory responses in juvenile and adult human chondrocytes. METHODS: Differential cell-surface CD24 expression was assessed in juvenile and adult chondrocytes along with human induced pluripotent stem cell (hiPSC)-derived neonatal chondrocytes through gene expression and fluorescence activated cell sorting (FACS) analyses. Loss of function of CD24 was achieved through silencing in chondrocytes and the effects on the response to inflammatory cues were assessed through gene expression and NFkappaB activity. RESULTS: CD24 expression in chondrocytes caused a differential response to cytokine-induced inflammation, with the CD24high juvenile chondrocytes being resistant to IL-1beta treatment as compared to CD24low adult chondrocytes. CD24 protects from inflammatory response by reducing NFkappaB activation, as an acute loss of CD24 via silencing led to an increase in NFkappaB activation. Moreover, the loss of CD24 in chondrocytes subsequently increased inflammatory and catabolic gene expression both in the absence and presence of IL-1beta. CONCLUSIONS: We have identified CD24 as a novel regulator of inflammatory response in cartilage that is altered during development and aging and could potentially be therapeutic in RA and OA. PMID- 27955676 TI - No effect of yeast-like fungi on lipid metabolism and vascular endothelial growth factor level in children and adolescents with type 1 diabetes mellitus. AB - BACKGROUND: The objective of the research was to investigate vascular endothelial growth factor (VEGF) levels in the context of lipid metabolism and amount of yeast-like fungi colonizing the digestive tract in children and adolescents with type 1 diabetes mellitus (T1DM). METHODS: The study included 45 children with T1DM and 27 age- and sex-matched healthy control subjects. In the study sample 33 T1DM patients were administered insulin pump therapy and 12 T1DM patients were administered multiple daily injections with insulin pen devices. All T1DM patients were free of micro- and macrovascular complications. In T1DM patients and healthy controls biochemical tests were performed and measurements of yeast like fungi colonizing the alimentary tract were conducted. Moreover all study subjects had their serum VEGF levels measured with ELISA test. RESULTS: The subgroup of children and adolescents with T1DM and yeast-like fungus colony number 10^3 CFU/g was shown statistically significantly lower HbA1c levels, and lower but not statistically significantly total cholesterol, LDL cholesterol and VEGF levels versus T1DM patients with the amount of yeast-like fungi 10^6 CFU/g. Moreover higher HDL levels were observed in this subgroup versus T1DM patients with the amount of yeast-like fungi 10^6 CFU/g although the difference was not statistically significant. CONCLUSIONS: Our study has shown no influence of yeast like fungi on lipid metabolism and VEGF level in children and adolescents with T1DM. Comprehensive treatment of T1DM patients and intensive insulin therapy with help of personal insulin pumps can reduce or prevent the development of long-term diabetic complications. Further studies in this field are needed. PMID- 27955678 TI - Identification of Ixodes ricinus blood meals using an automated protocol with high resolution melting analysis (HRMA) reveals the importance of domestic dogs as larval tick hosts in Italian alpine forests. AB - BACKGROUND: In Europe, Ixodes ricinus L. is the main vector of a variety of zoonotic pathogens, acquired through blood meals taken once per stage from a vertebrate host. Defining the main tick hosts in a given area is important for planning public health interventions; however, until recently, no robust molecular methods existed for blood meal identification from questing ticks. Here we improved the time- and cost-effectiveness of an HRMA protocol for blood meal analysis and used it to identify blood meal sources of sheep tick larvae from Italian alpine forests. METHODS: Nine hundred questing nymphs were collected using blanket-dragging in 18 extensive forests and 12 forest patches close to rural villages in the Province of Trento. Total DNA was either extracted manually, with the QIAamp DNA Investigator kit, or automatically using the KingFisherTM Flex Magnetic Particle Processors (KingFisher Cell and Tissue DNA Kit). Host DNA was amplified with six independent host group real-time PCR reactions and identified by means of HRMA. Statistical analyses were performed in R to assess the variables important for achieving successful identification and to compare host use in the two types of forest. RESULTS: Automating DNA extraction improved time- and cost-effectiveness of the HRMA protocol, but identification success fell to 22.4% (KingFisherTM) from 55.1% (QIAamp), with larval hosts identified in 215 of 848 questing nymphs; 23 mixed blood meals were noted. However, the list of hosts targeted by our primer sets was extended, improving the potential of the method. Host identification to species or genus level was possible for 137 and 102 blood meals, respectively. The most common hosts were Rodentia (28.9%) and, unexpectedly, Carnivora (28.4%), with domestic dogs accounting for 21.3% of all larval blood meals. Overall, Cetartiodactyla species fed 17.2% of larvae. Passeriformes (14.6%) fed a significantly higher proportion of larvae in forest patches (22.3%) than in extensive forest (9.6%), while Soricomorpha (10.9%) were more important hosts in extensive forest (15.2%) than in forest patches (4.3%). CONCLUSIONS: The HRMA protocol for blood meal analysis is a valuable tool in the study of feeding ecology of sheep ticks, especially with the cost- and time- reductions introduced here. To our knowledge, we show for the first time that domestic dogs are important larval hosts in the Alps, which may have possible implications for tick-borne disease cycles in urbanized areas. PMID- 27955677 TI - Spatio-temporal analysis of malaria vector density from baseline through intervention in a high transmission setting. AB - BACKGROUND: An increase in effective malaria control since 2000 has contributed to a decline in global malaria morbidity and mortality. Knowing when and how existing interventions could be combined to maximise their impact on malaria vectors can provide valuable information for national malaria control programs in different malaria endemic settings. Here, we assess the effect of indoor residual spraying on malaria vector densities in a high malaria endemic setting in eastern Uganda as part of a cohort study where the use of long-lasting insecticidal nets (LLINs) was high. METHODS: Anopheles mosquitoes were sampled monthly using CDC light traps in 107 households selected randomly. Information on the use of malaria interventions in households was also gathered and recorded via a questionnaire. A Bayesian spatio-temporal model was then used to estimate mosquito densities adjusting for climatic and ecological variables and interventions. RESULTS: Anopheles gambiae (sensu lato) were most abundant (89.1%; n = 119,008) compared to An. funestus (sensu lato) (10.1%, n = 13,529). Modelling results suggest that the addition of indoor residual spraying (bendiocarb) in an area with high coverage of permethrin-impregnated LLINs (99%) was associated with a major decrease in mosquito vector densities. The impact on An. funestus (s.l.) (Rate Ratio 0.1508; 97.5% CI: 0.0144-0.8495) was twice as great as for An. gambiae (s.l.) (RR 0.5941; 97.5% CI: 0.1432-0.8577). CONCLUSIONS: High coverage of active ingredients on walls depressed vector populations in intense malaria transmission settings. Sustained use of combined interventions would have a long term impact on mosquito densities, limiting infectious biting. PMID- 27955680 TI - 'Walk This Way' - a pilot of a health coaching intervention to reduce sedentary behaviour and increase low intensity exercise in people with serious mental illness: study protocol for a randomised controlled trial. AB - BACKGROUND: People with serious mental illness (SMI) (psychosis, bipolar disorder and major depressive disorder) experience a considerable risk of premature mortality because of cardiovascular disease. Recent research has demonstrated that this population spends almost 13 h per day being sedentary. Sedentary behaviour is an independent risk factor for cardiovascular disease and mortality. Given the potential for physical activity to improve health and well-being in people with SMI, we developed a pilot randomised controlled trial (RCT) to evaluate a coaching intervention aimed at reducing sedentary behaviour and increasing physical activity in people with SMI. Our primary aim was to assess the acceptability and feasibility of the intervention. Secondary aims were to see if the Walk This Way (WTW) intervention decreased sedentary behaviour and increased activity levels. METHODS/DESIGN: People with SMI who met any of the following criteria were recruited by two community mental health teams in South London: (1) overweight, (2) at risk for or have diabetes, (3) smoke tobacco or (4) have a sedentary lifestyle. Care co-coordinators (clinical case managers) identified potentially eligible participants within their caseload, and these individuals were subsequently invited to participate. All participants' physical activity (self-reported and accelerometer-recorded), health status (including metabolic blood tests) and motivation to exercise were assessed at baseline. Participants were randomised to receive treatment as usual or the WTW intervention. WTW consisted of an educational intervention at baseline on the benefits of an active lifestyle. Participants were then given a pedometer and received fortnightly coaching from a staff member trained in coaching skills to help them to set daily walking targets, and they were invited to a weekly walking group. The WTW intervention lasted 17 weeks in total. DISCUSSION: To our knowledge, WTW is the first RCT to investigate the impact of a health coaching intervention targeting sedentary behaviour in people with SMI. It is hoped that if the intervention is feasible and acceptable, further large scale study can be developed and implemented in routine care. TRIAL REGISTRATION: ISRCTN37724980 . Registered on 4 Aug 2015. PMID- 27955679 TI - Post-mortem histopathology underlying beta-amyloid PET imaging following flutemetamol F 18 injection. AB - In vivo imaging of fibrillar beta-amyloid deposits may assist clinical diagnosis of Alzheimer's disease (AD), aid treatment selection for patients, assist clinical trials of therapeutic drugs through subject selection, and be used as an outcome measure. A recent phase III trial of [18F]flutemetamol positron emission tomography (PET) imaging in 106 end-of-life subjects demonstrated the ability to identify fibrillar beta-amyloid by comparing in vivo PET to post-mortem histopathology. Post-mortem analyses demonstrated a broad and continuous spectrum of beta-amyloid pathology in AD and other dementing and non-dementing disease groups. The GE067-026 trial demonstrated 91% sensitivity and 90% specificity of [18F]flutemetamol PET by majority read for the presence of moderate or frequent plaques. The probability of an abnormal [18F]flutemetamol scan increased with neocortical plaque density and AD diagnosis. All dementia cases with non-AD neurodegenerative diseases and those without histopathological features of beta amyloid deposits were [18F]flutemetamol negative. Majority PET assessments accurately reflected the amyloid plaque burden in 90% of cases. However, ten cases demonstrated a mismatch between PET image interpretations and post-mortem findings. Although tracer retention was best associated with amyloid in neuritic plaques, amyloid in diffuse plaques and cerebral amyloid angiopathy best explain three [18F]flutemetamol positive cases with mismatched (sparse) neuritic plaque burden. Advanced cortical atrophy was associated with the seven false negative [18F]flutemetamol images. The interpretation of images from pathologically equivocal cases was associated with low reader confidence and inter-reader agreement. Our results support that amyloid in neuritic plaque burden is the primary form of beta-amyloid pathology detectable with [18F]flutemetamol PET imaging. ClinicalTrials.gov NCT01165554. Registered June 21, 2010; NCT02090855. Registered March 11, 2014. PMID- 27955681 TI - Prospective evaluation of biodegradable polymeric sealant for intraoperative air leaks. AB - BACKGROUND: A biodegradable polymeric sealant has been previously shown to reduce postoperative air leaks after open pulmonary resection. The aim of this study was to evaluate safety and efficacy during minimally invasive pulmonary resection. METHODS: In a multicenter prospective single-arm trial, 112 patients with a median age of 69 years (range 34-87 years) were treated with sealant for at least one intraoperative air leak after standard methods of repair (sutures, staples or cautery) following minimally invasive pulmonary resection (Video-Assisted Thoracic Surgery (VATS) or Robotic-Assisted). Patients were followed in hospital and 1 month after surgery for procedure-related and device-related complications and presence of air leak. RESULTS: Forty patients had VATS and 72 patients had Robotic-Assisted procedures with the majority (80/112, 71%) undergoing anatomic resection (61 lobectomy, 13 segmentectomy, 6 bilobectomy). There were no device related adverse events. The overall morbidity rate was 41% (46/112), with major complications occurring in 16.1% (18/112). In-hospital mortality and 30-day mortality were 1.9% (2/103). The majority of intraoperative air leaks (107/133, 81%) were sealed after sealant application, and an additional 16% (21/133) were considered reduced. Forty-nine percent of patients (55/112) were free of air leak throughout the entire postoperative study period. Median chest tube duration was 2 days (range 1 - 46 days), and median length of hospitalization was 3 days (range 1 - 20 days). CONCLUSIONS: This study demonstrated that use of a biodegradable polymer for closure of intraoperative air leaks as an adjunct to standard methods is safe and effective following minimally invasive pulmonary resection. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01867658 . Registered 3 May 2013. PMID- 27955682 TI - Health effectiveness and cost-effectiveness of telehealthcare for heart failure: study protocol for a randomized controlled trial. AB - BACKGROUND: Several heart failure studies have shown promising results for implementing telehealthcare. These studies have led to clinical and political interest in telehealthcare as a way to improve heart failure outcomes and lower costs. However, there is a need for large-scale clinical trials with cost effectiveness assessments. METHODS/DESIGN: The present study is known as the TeleCare North Heart Failure Trial in Denmark. We are studying the health effectiveness and cost-effectiveness of a telehealth (Telekit) solution compared with usual care for patients with heart failure. The design is a multicenter, two arm, parallel-group, nonblinded, superiority randomized controlled trial. Outpatient healthcare centers will be responsible for recruiting eligible participants (600 participants are expected) for the trial in the geographic area of the North Denmark Region. Participants are qualified for inclusion if they have been diagnosed according to national guidelines and are categorized in New York Heart Association class 2, 3, or 4. Patients must have a permanent residence and be motivated to use telehealth care. The primary outcomes are changes in health-related quality of life (assessed using the Kansas City Cardiomyopathy Questionnaire, the EuroQol EQ-5D-5L questionnaire, and the Short Form Health Survey [SF-36]) and in the incremental cost-effectiveness ratio measured from baseline to follow-up. The secondary outcomes are changes in mortality and in physiological indicators such as blood pressure, pulse, and weight. DISCUSSION: The TeleCare North Heart Failure Trial is intended to improve the international evidence base for the health effectiveness and cost-effectiveness of telehealthcare for patients with heart failure. The expectation is that the results of the trial can be generalized to all municipalities in Denmark and serve as an inspiration for further international research. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02860013 ). Registered on 28 July 2016. PMID- 27955683 TI - A multidimensional approach to assessing intervention fidelity in a process evaluation of audit and feedback interventions to reduce unnecessary blood transfusions: a study protocol. AB - BACKGROUND: In England, NHS Blood and Transplant conducts national audits of transfusion and provides feedback to hospitals to promote evidence-based practice. Audits demonstrate 20% of transfusions fall outside guidelines. The AFFINITIE programme (Development & Evaluation of Audit and Feedback INterventions to Increase evidence-based Transfusion practIcE) involves two linked, 2*2 factorial, cluster-randomised trials, each evaluating two theoretically-enhanced audit and feedback interventions to reduce unnecessary blood transfusions in UK hospitals. The first intervention concerns the content/format of feedback reports. The second aims to support hospital transfusion staff to plan their response to feedback and includes a web-based toolkit and telephone support. Interpretation of trials is enhanced by comprehensively assessing intervention fidelity. However, reviews demonstrate fidelity evaluations are often limited, typically only assessing whether interventions were delivered as intended. This protocol presents methods for assessing fidelity across five dimensions proposed by the Behaviour Change Consortium fidelity framework, including intervention designer-, provider- and recipient-levels. METHODS: (1) Design: Intervention content will be specified in intervention manuals in terms of component behaviour change techniques (BCTs). Treatment differentiation will be examined by comparing BCTs across intervention/standard practice, noting the proportion of unique/convergent BCTs. (2) Training: draft feedback reports and audio-recorded role-play telephone support scenarios will be content analysed to assess intervention providers' competence to deliver manual-specified BCTs. (3) Delivery: intervention materials (feedback reports, toolkit) and audio-recorded telephone support session transcripts will be content analysed to assess actual delivery of manual-specified BCTs during the intervention period. (4) Receipt and (5) enactment: questionnaires, semi-structured interviews based on the Theoretical Domains Framework, and objective web-analytics data (report downloads, toolkit usage patterns) will be analysed to assess hospital transfusion staff exposure to, understanding and enactment of the interventions, and to identify contextual barriers/enablers to implementation. Associations between observed fidelity and trial outcomes (% unnecessary transfusions) will be examined using mediation analyses. DISCUSSION: If the interventions have acceptable fidelity, then results of the AFFINITIE trials can be attributed to effectiveness, or lack of effectiveness, of the interventions. Hence, this comprehensive assessment of fidelity will be used to interpret trial findings. These methods may inform fidelity assessments in future trials. TRIAL REGISTRATION: ISRCTN 15490813 . Registered 11/03/2015. PMID- 27955684 TI - Safety and efficacy of vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer: VELVET Cohort 1 final results. AB - BACKGROUND: Pertuzumab, trastuzumab, and docetaxel is standard of care for first line treatment of HER2-positive metastatic breast cancer (MBC). However, alternative chemotherapy partners are required to align with patient/physician preferences and to increase treatment flexibility. We report VELVET Cohort 1 results in which the efficacy and safety of pertuzumab and trastuzumab, administered sequentially in separate infusions, followed by vinorelbine, were evaluated. Cohort 2, where pertuzumab and trastuzumab were administered in a single infusion, followed by vinorelbine, recruited after Cohort 1 was fully enrolled, will be reported later. METHODS: In this multicenter, two-cohort, open label, phase II study, patients with HER2-positive locally advanced or MBC who had not received chemotherapy or biological therapy for their advanced disease received 3-weekly pertuzumab (840 mg loading, 420 mg maintenance doses) and trastuzumab (8 mg/kg loading, 6 mg/kg maintenance doses), followed by vinorelbine (25 mg/m2 initial dose, 30-35 mg/m2 maintenance doses) on days 1 and 8 or 2 and 9 of each 3-weekly cycle. Study treatment was given until investigator-assessed disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR) in patients with measurable disease at baseline per RECIST v1.1. Secondary endpoints included progression free survival (PFS) and safety. RESULTS: Cohort 1 enrolled 106 patients. Investigator-assessed ORR was 74.2% (95% CI 63.8-82.9) in intent-to-treat patients with measurable disease (89/106 [84.0%]). Median PFS was 14.3 months (95% CI 11.2-17.5) in the intent-to-treat population. Treatment was reasonably well tolerated, with no unexpected toxicities. Diarrhea (61/106 patients [57.5%]) and neutropenia (54/106 [50.9%]) were the most common adverse events (AEs); neutropenia (33/106 [31.1%]) and leukopenia (14/106 [13.2%]) were the most common grade >=3 AEs. Serious AEs were reported in 32/106 (30.2%) patients. AEs led to study drug discontinuation in 36/106 patients (34.0%). Eighteen of 106 patients (17.0%) had AEs suggestive of congestive heart failure; however, there were no confirmed cases. CONCLUSIONS: The vinorelbine, pertuzumab, and trastuzumab combination is active and reasonably well tolerated. This regimen offers an alternative for patients who cannot receive docetaxel for first-line treatment of HER2-positive locally advanced or MBC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01565083 , registered on 26 March 2012. PMID- 27955685 TI - The magnitude and temporal changes of response in the placebo arm of surgical randomized controlled trials: a systematic review and meta-analysis. AB - BACKGROUND: Understanding changes in the placebo arm is essential for correct design and interpretation of randomized controlled trials (RCTs). It is assumed that placebo response, defined as the total improvement in the placebo arm of surgical trials, is large; however, its precise magnitude and properties remain to be characterized. To the best of our knowledge, the temporal changes in the placebo arm have not been investigated. The aim of this paper was to determine, in surgical RCTs, the magnitude of placebo response and how it is affected by duration of follow-up. METHODS: The databases of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched from their inception to 20 October 2015 for studies comparing the efficacy of a surgical intervention with placebo. Inclusion was not limited to any particular condition, intervention, outcome or patient population. The magnitude of placebo response was estimated using standardized mean differences (SMDs). Study estimates were pooled using random effects meta-analysis. Potential sources of heterogeneity were evaluated using stratification and meta-regression. RESULTS: Database searches returned 88 studies, but for 41 studies SMDs could not be calculated, leaving 47 trials (involving 1744 participants) eligible for inclusion. There were no temporal changes in placebo response within the analysed trials. Meta-regression analysis showed that duration of follow-up did not have a significant effect on the magnitude of the placebo response and that the strongest predictor of placebo response was subjectivity of the outcome. The pooled effect in the placebo arm of studies with subjective outcomes was large (0.64, 95% CI 0.5 to 0.8) and remained significantly different from zero regardless of the duration of follow-up, whereas for objective outcomes, the effect was small (0.11, 95% CI 0.04 to 0.26) or non-significant across all time points. CONCLUSIONS: This is the first study to investigate the temporal changes of placebo response in surgical trials and the first to investigate the sources of heterogeneity of placebo response. Placebo response in surgical trials was large for subjective outcomes, persisting as a time-invariant effect throughout blinded follow-up. Therefore, placebo response cannot be minimized in these types of outcomes through their appraisal at alternative time points. The analyses suggest that objective outcomes may be preferable as trial end-points. Where subjective outcomes are of primary interest, a placebo arm is necessary to control for placebo response. PMID- 27955687 TI - Decline in transmission of schistosomiasis mansoni in Oman. AB - BACKGROUND: Intestinal schistosomiasis due to Schistosoma mansoni was first reported in Oman in 1979. We describe the trend in parasitological and serological prevalence of human infection with S. mansoni in the endemic area over the period 1982-2014, and the compliance of data generated by the national monitoring and evaluation system with schistosomiasis elimination criteria set by the Ministry of Health of Oman. METHODS: Parasitological and serological assessments were carried out on population (mainly children) living in the area at risk for schistosomiasis in Dhofar, the country's only endemic Governorate, for a period of over 30 years. Kato-Katz thick smear and Indirect Haemagglutination Assay were the techniques employed. RESULTS: Data indicate a progressive decline in prevalence of S. mansoni throughout the 1980s and the 1990s, a recrudescence in the early 2000s, and a more marked decrease following the implementation of six rounds of mass treatment with praziquantel from 2007 to 2013. Latest parasitological prevalence (2011) was 0%, while latest serological prevalence (2014) was 0.11%. CONCLUSION: Transmission of schistosomiasis has reached very low levels in Oman. Elimination criteria established by the Ministry of Health of Oman (parasitological prevalence <= 1% and serological prevalence <= 5%) have been met since 2008. Further investigations are required to assess whether interruption of transmission has been achieved in some or all foci, in view of the establishment of a formal verification process under the auspices of WHO. PMID- 27955686 TI - Nutrigenomic effects of glucosinolates on liver, muscle and distal kidney in parasite-free and salmon louse infected Atlantic salmon. AB - BACKGROUND: Reduction of Lepeophtheirus salmonis infection in Atlantic salmon achieved by glucosinolates (GLs) from Brassica plants was recently reported. However, wider application of functional feeds based on GLs requires better knowledge of their positive and adverse effects. METHODS: Liver, distal kidney and muscle transcriptomes of salmon exposed to the extreme dose of GLs were profiled by microarray, while qPCR analysis followed up selected hepatic and renal responses under the extreme and moderate GLs dose during the L. salmonis challenge. Transcriptional analysis were complemented with measurements of organ indices, liver steatosis and plasma profiling, including indicators of cytolysis and bilirubin. Finally, the third trial was performed to quantify the effect of lower GLs doses on growth. RESULTS: The extreme GLs dose caused a decrease in hepatic fat deposition and growth, in line with microarray findings, which suggested tissue remodeling and reduction of cellular proliferation in the skeletal muscle and liver. Lower GLs inclusion levels in a follow-up trial did not show negative effects on growth. Microarray analysis of the distal kidney pointed to activation of anti-fibrotic responses under the overexposure. However, analyses of ALT, CK and AST enzymes in plasma provided no evidence of increased cytolysis and organ damage. Prevalent activation of phase-2 detoxification genes that occurred in all three tissues could be considered part of beneficial effects caused by the extreme dose of GLs. In addition, transcriptomic evidence suggested GLs-mediated iron and heme withdrawal response, including increased heme degradation in muscle (upregulation of heme oxygenase-1), decrease of its synthesis in liver (downregulation of porphobilinogen deaminase) and increased iron sequestration from blood (hepatic induction of hepcidin-1 and renal induction of intracellular storage protein ferritin). This response could be advantageous for salmon upon encountering lice, which depend on the host for the provision of iron carrying heme. Most of the hepatic genes studied by qPCR showed similar expression levels in fish exposed to GLs, lice and their combination, while renal induction of leptin suggested heightened stress by the combination of extreme dose of GLs and lice. High expression of interferon gamma (cytokine considered organ-protective in mammalian kidney) was detected at the moderate GLs level. This fish also showed highest plasma bilirubin levels (degradation product of heme), and had lowest number of attached lice, further supporting hypothesis that making heme unavailable to lice could be part of an effective anti-parasitic strategy. CONCLUSIONS: Modulation of detoxification and iron metabolism in Atlantic salmon tissues could be beneficial prior and during lice infestations. Investigation of anti-lice functional feeds based on low and moderate GLs inclusion levels thus deserves further attention. PMID- 27955688 TI - The RESPITE trial: remifentanil intravenously administered patient-controlled analgesia (PCA) versus pethidine intramuscular injection for pain relief in labour: study protocol for a randomised controlled trial. AB - BACKGROUND: The commonest opioid used for pain relief in labour is pethidine (meperidine); however, its effectiveness has long been challenged and the drug has known side effects including maternal sedation, nausea and potential transfer across the placenta to the foetus. Over a third of women receiving pethidine require an epidural due to inadequate pain relief. Epidural analgesia increases the risk of an instrumental vaginal delivery and its associated effects. Therefore, there is a clear need for a safe, effective, alternative analgesic to pethidine. Evidence suggests that remifentanil patient-controlled analgesia (PCA) reduces epidural conversion rates compared to pethidine; however, no trial has yet investigated this as a primary endpoint. We are, therefore, comparing pethidine intramuscular injection to remifentanil PCA in a randomised controlled trial. METHODS/DESIGN: Women in established labour, requesting systemic opioid pain relief, will be randomised to either intravenously administered remifentanil PCA (intervention) or pethidine intramuscular injection (control) in an unblinded, 1:1 individual randomised trial. Following informed consent, 400 women in established labour, who request systemic opioid pain relief, from NHS Trusts across England will undergo a minimised randomisation by a computer or automated telephone system to either pethidine or remifentanil. In order to balance the groups this minimisation is based on four parameters; parity (nulliparous versus multiparous), maternal age (<20, 20 < 30, 30 < 40, 40+ years), ethnicity (South Asian (Pakistani/Indian/Bangladeshi) versus Other) and induced versus spontaneous labour. The effectiveness of pain relief provided by each technique will be recorded every 30 min after time zero, until epidural placement, delivery or transfer to theatre, quantified by Visual Analogue Scale. Incidence of maternal side effects including sedation, delivery mode, foetal distress requiring delivery, neonatal status at delivery and rate of initiation of breastfeeding within the first hour of birth will also be recorded. Maternal satisfaction with her childbirth experience will be determined by a postpartum questionnaire prior to discharge from the delivery ward. DISCUSSION: The RESPITE trial's primary outcome is the proportion of women who have an epidural placed for pain relief in labour in each arm. TRIAL REGISTRATION: Current Controlled Trials registration number: ISRCTN29654603 . Registered on 23 July 2013. PMID- 27955690 TI - CHD7 promotes proliferation of neural stem cells mediated by MIF. AB - Macrophage migration inhibitory factor (MIF) plays an important role in supporting the proliferation and/or survival of murine neural stem/progenitor cells (NSPCs); however, the downstream effectors of this factor remain unknown. Here, we show that MIF increases the expression of Pax6 and Chd7 in NSPCs in vitro. During neural development, the chromatin remodeling factor Chd7 (chromatin helicase-DNA-binding protein 7) is expressed in the ventricular zone of the telencephalon of mouse brain at embryonic day 14.5, as well as in cultured NSPCs. Retroviral overexpression of Pax6 in NSPCs increased Chd7 gene expression. Lentivirally-expressed Chd7 shRNA suppressed cell proliferation and neurosphere formation, and inhibited neurogenesis in vitro, while decreasing gene expression of Hes5 and N-myc. In addition, CHD7 overexpression increased cell proliferation in human embryonic stem cell-derived NSPCs (ES-NSPCs). In Chd7 mutant fetal mouse brains, there were fewer intermediate progenitor cells (IPCs) compared to wildtype littermates, indicating that Chd7 contributes to neurogenesis in the early developmental mouse brain. Furthermore, in silico database analysis showed that, among members of the CHD family, CHD7 is highly expressed in human gliomas. Interestingly, high levels of CHD7 gene expression in human glioma initiating cells (GICs) compared to normal astrocytes were revealed and gene silencing of CHD7 decreased GIC proliferation. Collectively, our data demonstrate that CHD7 is an important factor in the proliferation and stemness maintenance of NSPCs, and CHD7 is a promising therapeutic target for the treatment of gliomas. PMID- 27955689 TI - The effect of bundling medication-assisted treatment for opioid addiction with mHealth: study protocol for a randomized clinical trial. AB - BACKGROUND: Opioid dependence has devastating and increasingly widespread consequences and costs, and the most common outcome of treatment is early relapse. People who inject opioids are also at disproportionate risk for contracting the human immunodeficiency virus (HIV) and hepatitis C virus (HCV). This study tests an approach that has been shown to improve recovery rates: medication along with other supportive services (medication-assisted treatment, or MAT) against MAT combined with a smartphone innovation called A-CHESS (MAT + A CHESS). METHODS/DESIGN: This unblinded study will randomly assign 440 patients to receive MAT + A-CHESS or MAT alone. Eligible patients will meet criteria for having an opioid use disorder of at least moderate severity and will be taking methadone, injectable naltrexone, or buprenorphine. Patients with A-CHESS will have smartphones for 16 months; all patients will be followed for 24 months. The primary outcome is the difference between patients in the two arms in percentage of days using illicit opioids during the 24-month intervention. Secondary outcomes are differences between patients receiving MAT + A-CHESS versus MAT in other substance use, quality of life, retention in treatment, health service use, and, related to HIV and HCV, screening and testing rates, medication adherence, risk behaviors, and links to care. We will also examine mediators and moderators of the effects of MAT + A-CHESS. We will measure variables at baseline and months 4, 8, 12, 16, 20, and 24. At each point, patients will respond to a 20- to 30-min phone survey; urine screens will be collected at baseline and up to twice a month thereafter. We will use mixed-effects to evaluate the primary and secondary outcomes, with baseline scores functioning as covariates, treatment condition as a between-subject factor, and the outcomes reflecting scores for a given assessment at the six time points. Separate analyses will be conducted for each outcome. DISCUSSION: A-CHESS has been shown to improve recovery for people with alcohol dependence. It offers an adaptive and extensive menu of services and can attend to patients nearly as constantly as addiction does. This suggests the possibility of increasing both the effectiveness of, and access to, treatment for opioid dependence. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02712034 . Registered on 14 March 2016. PMID- 27955691 TI - Early kidney damage induced by subchronic exposure to PM2.5 in rats. AB - BACKGROUND: Particulate matter exposure is associated with respiratory and cardiovascular system dysfunction. Recently, we demonstrated that fine particles, also named PM2.5, modify the expression of some components of the angiotensin and bradykinin systems, which are involved in lung, cardiac and renal regulation. The endocrine kidney function is associated with the regulation of angiotensin and bradykinin, and it can suffer damage even as a consequence of minor alterations of these systems. We hypothesized that exposure to PM2.5 can contribute to early kidney damage as a consequence of an angiotensin/bradykinin system imbalance, oxidative stress and/or inflammation. RESULTS: After acute and subchronic exposure to PM2.5, lung damage was confirmed by increased bronchoalveolar lavage fluid (BALF) differential cell counts and a decrease of surfactant protein-A levels. We observed a statistically significant increment in median blood pressure, urine volume and water consumption after PM2.5 exposure. Moreover, increases in the levels of early kidney damage markers were observed after subchronic PM2.5 exposure: the most sensitive markers, beta-2-microglobulin and cystatin-C, increased during the first, second, sixth and eighth weeks of exposure. In addition, a reduction in the levels of specific cytokines (IL-1beta, IL-6, TNF-alpha, IL-4, IL-10, INF-gamma, IL-17a, MIP-2 and RANTES), and up regulated angiotensin and bradykinin system markers and indicators of a depleted antioxidant response, were also observed. All of these effects are in concurrence with the presence of renal histological lesions and an early pro-fibrotic state. CONCLUSION: Subchronic exposure to PM2.5 induced an early kidney damage response that involved the angiotensin/bradykinin systems as well as antioxidant and immune imbalance. Our study demonstrates that PM2.5 can induce a systemic imbalance that not only affects the cardiovascular system, but also affects the kidney, which may also overall contribute to PM-related diseases. PMID- 27955692 TI - Is the shock index based classification of hypovolemic shock applicable in multiple injured patients with severe traumatic brain injury?-an analysis of the TraumaRegister DGU(r). AB - BACKGROUND: A new classification of hypovolemic shock based on the shock index (SI) was proposed in 2013. This classification contains four classes of shock and shows good correlation with acidosis, blood product need and mortality. Since their applicability was questioned, the aim of this study was to verify the validity of the new classification in multiple injured patients with traumatic brain injury. METHODS: Between 2002 and 2013, data from 40 888 patients from the TraumaRegister DGU(r) were analysed. Patients were classified according to their initial SI at hospital admission (Class I: SI < 0.6, class II: SI >=0.6 to <1.0, class III SI >=1.0 to <1.4, class IV: SI >=1.4). Patients with an additional severe TBI (AIS >= 3) were compared to patients without severe TBI. RESULTS: 16,760 multiple injured patients with TBI (AIShead >=3) were compared to 24,128 patients without severe TBI. With worsening of SI class, mortality rate increased from 20 to 53% in TBI patients. Worsening SI classes were associated with decreased haemoglobin, platelet counts and Quick's values. The number of blood units transfused correlated with worsening of SI. Massive transfusion rates increased from 3% in class I to 46% in class IV. The accuracy for predicting transfusion requirements did not differ between TBI and Non TBI patients. DISCUSSION: The use of the SI based classification enables a quick assessment of patients in hypovolemic shock based on universally available parameters. Although the pathophysiology in TBI and Non TBI patients and early treatment methods such as the use of vasopressors differ, both groups showed an identical probability of recieving blood products within the respective SI class. CONCLUSION: Regardless of the presence of TBI, the classification of hypovolemic shock based on the SI enables a fast and reliable assessment of hypovolemic shock in the emergency department. Therefore, the presented study supports the SI as a feasible tool to assess patients at risk for blood product transfusions, even in the presence of severe TBI. PMID- 27955693 TI - Three-dimensional surface and ultrasound imaging for daily IGRT of prostate cancer. AB - BACKGROUND: Image guided radiotherapy (IGRT) is an essential pre-requisite for delivering high precision radiotherapy. We compared daily variation detected by two non-ionizing imaging modalities (surface imaging and trans-abdominal ultrasound, US) to verify prostate patient setup and internal organ variations. METHODS: Forty patients with organ confined prostate cancer and candidates to curative radiotherapy were enrolled in this prospective study. At each treatment session, after laser alignment, all patients received imaging by a 3D-surface and a 3D-US system. The shifts along the three directions (anterior-posterior AP, cranial-caudal CC, and later-lateral LL) were measured in terms of systematic and random errors. Then, we performed statistical analysis on the differences and the possible correlations between the two modalities. RESULTS: For both IGRT modalities, surface imaging and US, 1318 acquisitions were collected. According with Shapiro Wilk test, the positioning error distributions were not Gaussian for both modalities. The differences between the systematic errors detected by the two modalities were statistically significant only in LL direction (p < 0.05), while the differences between the random errors were not statistically significant in any directions. The 95% confidence interval of the residual errors obtained by subtracting the random errors detected with surface images to those detected with US was included in the range from -7 mm to 7 mm corresponding to the minimum PTV margin adopted in AP direction in our clinical routine. CONCLUSIONS: From our data, it emerges that setup misalignments measured by surface imaging can be predictive of US displacements after the adjustment for systematic errors. Moreover, surface imaging can detect setup errors predictive of registration errors measured by US. This data suggest that the two IGRT modalities could be considered as complementary to each other and could represent a daily "low-cost" and non-invasive IGRT modality in prostate cancer patients. PMID- 27955694 TI - Type I interferon response gene expression in established rheumatoid arthritis is not associated with clinical parameters. AB - BACKGROUND: A peripheral blood interferon (IFN) signature (i.e., elevated type I interferon response gene [IRG] expression) has been described in a subset of patients with rheumatoid arthritis (RA). In the present study, we systematically assessed the association between this IRG expression and clinical parameters. METHODS: Expression of 19 IRGs was determined in peripheral blood from 182 consecutive patients with RA and averaged into an IFN score per individual. Correlation and unpaired analyses were performed on the complete patient group. The analyses were internally validated by using an algorithm to randomize the patient group 1000 times into two equally sized sets, and then analyses were performed on both sets. RESULTS: Associations were assessed between IFN score and disease duration, 28-joint Disease Activity Score and its components, the occurrence of erosions and nodules, autoantibody positivity, and immunosuppressive treatment. This analysis revealed lower IFN scores in patients using hydroxychloroquine, prednisone, and/or sulfasalazine, but it did not show significant associations between the other parameters and the IFN score. Selecting patients who were not treated with hydroxychloroquine, prednisone, and/or sulfasalazine (n = 95) did not reveal any significant associations either. CONCLUSIONS: IRG expression in RA is affected by immunosuppressive treatment with prednisone, hydroxychloroquine, and/or sulfasalazine, but it is not evidently associated with other clinical parameters. Hence, the IFN signature appears to describe a subgroup of patients with RA but does not seem to reflect disease activity. PMID- 27955695 TI - Exon-intron structure and sequence variation of the calreticulin gene among Rhipicephalus sanguineus group ticks. AB - BACKGROUND: Calreticulin proteins (CRTs) are important components of tick saliva, which is involved in the blood meal success, pathogen transmission and host allergic responses. The characterization of the genes encoding for salivary proteins, such as CRTs, is pivotal to understand the mechanisms of tick-host interaction during blood meal and to develop tick control strategies based on their inhibition. In hard ticks, crt genes were shown to have only one intron with conserved position among species. In this study we investigated the exon intron structure and variation of the crt gene in Rhipicephalus spp. ticks in order to assess the crt exon-intron structure and the potential utility of crt gene as a molecular marker. METHODS: We sequenced the exon-intron region of crt gene in ticks belonging to so-called tropical and temperate lineages of Rhipicephalus sanguineus (sensu lato), Rhipicephalus sp. I, Rhipicephalus sp. III, Rhipicephalus sp. IV, R. guilhoni, R. muhsamae and R. turanicus. Genetic divergence and phylogenetic relationships between the sequences obtained were estimated. RESULTS: All individuals belonging to the tropical lineage of R. sanguineus (s.l.), R. guilhoni, R. muhsamae, R. turanicus, Rhipicephalus sp. III and Rhipicephalus sp. IV analysed showed crt intron-present alleles. However, both crt intron-present and intron-absent alleles were found in Rhipicephalus sp. I and the temperate lineage of R. sanguineus (s.l.), showing the occurrence of an intraspecific intron presence-absence polymorphism. Phylogenetic relationships among the crt intron-present sequences showed distinct lineages for all taxa, with the tropical and temperate lineages of R. sanguineus (s.l.) being more closely related to each other. CONCLUSIONS: We expanded previous studies about the characterization of crt gene in hard ticks. Our results highlighted a previously overlooked variation in the crt structure among Rhipicephalus spp., and among hard ticks in general. Notably, the intron presence/absence polymorphism observed herein can be a candidate study-system to investigate the early stages of intron gain/loss before fixation at species level and some debated questions about intron evolution. Finally, the sequence variation observed supports the suitability of the crt gene for molecular recognition of Rhipicephalus spp. and for phylogenetic studies in association with other markers. PMID- 27955696 TI - Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit. AB - BACKGROUND: Understanding blood-brain barrier responses to inflammatory stimulation (such as lipopolysaccharide mimicking a systemic infection or a cytokine cocktail that could be the result of local or systemic inflammation) is essential to understanding the effect of inflammatory stimulation on the brain. It is through the filter of the blood-brain barrier that the brain responds to outside influences, and the blood-brain barrier is a critical point of failure in neuroinflammation. It is important to note that this interaction is not a static response, but one that evolves over time. While current models have provided invaluable information regarding the interaction between cytokine stimulation, the blood-brain barrier, and the brain, these approaches-whether in vivo or in vitro-have often been only snapshots of this complex web of interactions. METHODS: We utilize new advances in microfluidics, organs-on-chips, and metabolomics to examine the complex relationship of inflammation and its effects on blood-brain barrier function ex vivo and the metabolic consequences of these responses and repair mechanisms. In this study, we pair a novel dual-chamber, organ-on-chip microfluidic device, the NeuroVascular Unit, with small-volume cytokine detection and mass spectrometry analysis to investigate how the blood brain barrier responds to two different but overlapping drivers of neuroinflammation, lipopolysaccharide and a cytokine cocktail of IL-1beta, TNF alpha, and MCP1,2. RESULTS: In this study, we show that (1) during initial exposure to lipopolysaccharide, the blood-brain barrier is compromised as expected, with increased diffusion and reduced presence of tight junctions, but that over time, the barrier is capable of at least partial recovery; (2) a cytokine cocktail also contributes to a loss of barrier function; (3) from this time-dependent cytokine activation, metabolic signature profiles can be obtained for both the brain and vascular sides of the blood-brain barrier model; and (4) collectively, we can use metabolite analysis to identify critical pathways in inflammatory response. CONCLUSIONS: Taken together, these findings present new data that allow us to study the initial effects of inflammatory stimulation on blood-brain barrier disruption, cytokine activation, and metabolic pathway changes that drive the response and recovery of the barrier during continued inflammatory exposure. PMID- 27955698 TI - Histologic validation of myocardial fibrosis measured by T1 mapping: a systematic review and meta-analysis. AB - BACKGROUND: Myocardial fibrosis is being increasingly recognised as a common final pathway of a wide range of diseases. Thus, the development of an accurate and convenient method to evaluate myocardial fibrosis is of major importance. Although T1 mapping is a potential alternative for myocardial biopsy, validation studies are limited to small numbers and vary regarding technical facets, and include only a restricted number of disease. A systematic review and meta analysis was conducted to objectively and comprehensively evaluate the performance of T1 mapping on the quantification of myocardial fibrosis using cardiovascular magnetic resonance (CMR). METHODS: PubMed, EMBASE and the Cochrane Library databases were searched for studies applying T1 mapping to measure myocardial fibrosis and that validated the results via histological analysis. A pooled correlation coefficient between the CMR and histology measurements was used to evaluate the performance of the T1 mapping. RESULTS: A total of 15 studies, including 308 patients who had CMR and myocardial biopsy were included and the pooled correlation coefficient between ECV measured by T1 mapping and biopsy for the selected studies was 0.884 (95% CI: 0.854, 0.914) and was not notably heterogeneous chi-squared = 7.44; P = 0.489 for the Q test and I^2 = 0.00%). CONCLUSIONS: The quantitative measurement of myocardial fibrosis via T1 mapping is associated with a favourable overall correlation with the myocardial biopsy measurements. Further studies are required to determine the calibration of the T1 mapping results for the biopsy findings of different cardiomyopathies. PMID- 27955699 TI - Adelmidrol, in combination with hyaluronic acid, displays increased anti inflammatory and analgesic effects against monosodium iodoacetate-induced osteoarthritis in rats. AB - BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease produced by a cascade of events that can ultimately lead to joint damage. The aim of this study was to evaluate the effect of adelmidrol, a synthetic palmitoylethanolamide analogue, combined with hyaluronic acid on pain severity and modulation of the inflammatory response in a rat model of monosodium iodoacetate (MIA)-induced osteoarthritis. METHODS: OA was induced by intra-articular injection of MIA in the knee joint. On day 21 post-MIA administration, the knee joint was analyzed. Rats subjected to OA were treated by intra-articular injection of adelmidrol in combination with sodium hyaluronate at different doses and time points after MIA induction. Limb nociception was assessed by the paw withdrawal latency and threshold measurement. Samples were examined macroscopically, histologically, and by immunohistochemistry. RESULTS: At day 21 post-MIA injection, the MIA + solvent and MIA + 1.0% sodium hyaluronate groups showed irregularities and fibrillation in the surface layer, a decrease in blood cells and multilayering in transition and radial zones, no pannus formation, and modified Mankin scores significantly higher than sham knees. The combination of hyaluronic acid and adelmidrol dose dependently (adelmidrol 0.6% + 1.0% sodium hyaluronate and adelmidrol 2% + 1.0% sodium hyaluronate) reduced the histological alterations induced by MIA. Moreover, degeneration of articular cartilage, mast cell infiltration, and pro inflammatory cytokine and chemokine plasma levels were significantly downregulated by treatment with a combination of hyaluronic acid and adelmidrol at the above doses. CONCLUSIONS: Our results clearly demonstrate that the combination of hyaluronic acid and adelmidrol improves the signs of OA induced by MIA. PMID- 27955701 TI - Lifestyle and geographic insights into the distinct gut microbiota in elderly women from two different geographic locations. AB - BACKGROUND: A large number of microorganisms reside within the gastrointestinal tract, especially in the colon, and play important roles in human health and disease. The composition of the human gut microbiota is determined by intrinsic host factors and environmental factors. While investigating environmental factors to promote human health is of great interest, few studies have focused on their effect on the gut microbiota. This study aimed to investigate differences in gut microbiota composition according to lifestyle and geographical area, even in people with similar genetic background. METHODS: We enrolled ten and nine elderly women in their seventies from island and inland areas, respectively. Fecal samples were obtained from individuals, and bacterial 16S ribosomal RNA genes were analyzed by next-generation sequencing to define the gut microbiota composition. We assessed their diet, which can influence the gut microbial community. We also conducted physical examination and determined the physical activity levels of the subjects. RESULTS: The inland subjects had a significantly higher rectal temperature, systolic blood pressure, and heart rate and a significantly lower physical activity score than the island subjects. Fecal samples from the island group showed a tendency to have greater microbial diversity than those from the inland group. Interestingly, the microbial community composition differed significantly between the two groups. Catenibacterium was enriched in subjects from the island area. Catenibacterium showed a negative correlation with rectal temperature and a positive correlation with the dietary level of animal fat. In contrast, Butyricimonas was enriched in the inland subjects. A positive correlation was found between Butyricimonas and mean arterial pressure. CONCLUSIONS: This study identified differences in the gut microbiota composition between elderly women from different parts of South Korea, and our findings suggest that further studies of the human gut microbiota should evaluate aspects of the living environment. PMID- 27955700 TI - Combined exposure of diesel exhaust particles and respirable Soufriere Hills volcanic ash causes a (pro-)inflammatory response in an in vitro multicellular epithelial tissue barrier model. AB - BACKGROUND: There are justifiable health concerns regarding the potential adverse effects associated with human exposure to volcanic ash (VA) particles, especially when considering communities living in urban areas already exposed to heightened air pollution. The aim of this study was, therefore, to gain an imperative, first understanding of the biological impacts of respirable VA when exposed concomitantly with diesel particles. METHODS: A sophisticated in vitro 3D triple cell co-culture model of the human alveolar epithelial tissue barrier was exposed to either a single or repeated dose of dry respirable VA (deposited dose of 0.26 +/- 0.09 or 0.89 +/- 0.29 MUg/cm2, respectively) from Soufriere Hills volcano, Montserrat for a period of 24 h at the air-liquid interface (ALI). Subsequently, co-cultures were exposed to co-exposures of single or repeated VA and diesel exhaust particles (DEP; NIST SRM 2975; 0.02 mg/mL), a model urban pollutant, at the pseudo-ALI. The biological impact of each individual particle type was also analysed under these precise scenarios. The cytotoxic (LDH release), oxidative stress (depletion of intracellular GSH) and (pro-)inflammatory (TNF-alpha, IL-8 and IL-1beta) responses were assessed after the particulate exposures. The impact of VA exposure upon cell morphology, as well as its interaction with the multicellular model, was visualised via confocal laser scanning microscopy (LSM) and scanning electron microscopy (SEM), respectively. RESULTS: The combination of respirable VA and DEP, in all scenarios, incited an heightened release of TNF alpha and IL-8 as well as significant increases in IL-1beta, when applied at sub lethal doses to the co-culture compared to VA exposure alone. Notably, the augmented (pro-)inflammatory responses observed were not mediated by oxidative stress. LSM supported the quantitative assessment of cytotoxicity, with no changes in cell morphology within the barrier model evident. A direct interaction of the VA with all three cell types of the multicellular system was observed by SEM. CONCLUSIONS: Combined exposure of respirable Soufriere Hills VA with DEP causes a (pro-)inflammatory effect in an advanced in vitro multicellular model of the epithelial airway barrier. This finding suggests that the combined exposure to volcanic and urban particulate matter should be further investigated in order to deduce the potential human health hazard, especially how it may influence the respiratory function of susceptible individuals (i.e. with pre-existing lung diseases) in the population. PMID- 27955697 TI - DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. AB - BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 * 10-7) in the discovery panel of European ancestry and replicated (P < 2.29 * 10-4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 * 10-5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 * 10-3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 * 10-5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation. PMID- 27955702 TI - beta-Amyloid triggers aberrant over-scaling of homeostatic synaptic plasticity. AB - The over-production of beta-amyloid (Abeta) has been strongly correlated to neuronal dysfunction and altered synaptic plasticity in Alzheimer's disease (AD). Accordingly, it has been proposed that disrupted synaptic transmission and neuronal network instability underlie memory failure that is evident in the early phases of AD. Homeostatic synaptic plasticity (HSP) serves to restrain neuronal activity within a physiological range. Therefore a disruption of this mechanism may lead to destabilization in synaptic and neural circuit function. Here, we report that during HSP by neuronal activity deprivation, application of Abeta results in an aberrant over-response of the up-regulation of AMPA receptor (AMPAR)-mediated synaptic currents and cell-surface AMPAR expression. In the visual cortex, in vivo HSP induced by visual deprivation shows a similar over response following an Abeta local injection. Abeta increases the expression of GluA2-lacking, calcium permeable AMPARs (CP-AMPARs), which are required for the initiation, but not maintenance of HSP. Both GluA2-lacking and GluA2-containing AMPARs contribute to the Abeta-mediated over-scaling of HSP. We also find that Abeta induces the dissociation of HDAC1 from the miR124 transcription factor EVI1, leading to an up-regulation of miR124 expression and increased amount of CP AMPARs. Thus, via aberrant stimulation of miR124 expression and biogenesis of CP AMPARs, Abeta is able to induce an over response in HSP. This Abeta-mediated dysregulation in homeostatic plasticity may play an important role in the pathogenesis of altered neural function and memory deficits in the early stages of AD. PMID- 27955703 TI - First microsatellite markers for Paspalum plicatulum (Poaceae) characterization and cross-amplification in different Paspalum species of the Plicatula group. AB - BACKGROUND: Paspalum plicatulum is a perennial rhizomatous grass with natural diploid and polyploid cytotypes. It is a member of Plicatula, which has historically been recognized as a highly complex group containing species of ecological, ornamental and forage importance. The complex nature of the P. plicatulum genome makes it a challenging species for genetic research. This study aimed to develop and characterize microsatellite molecular markers in P. plicatulum and to evaluate their transferability to other Plicatula group species. FINDINGS: Microsatellite sequences were identified from three enriched libraries from P. plicatulum. Specific primers were designed, and 25 displayed polymorphism when screened across 48 polyploid Paspalum spp. genotypes. The number of bands per locus ranged from 2 to 17, with a mean of 8.65. Private bands for each species were identified; the highest number of private bands was observed for P. plicatulum in 52% of the loci analyzed. The mean polymorphism information content of all loci was 0.69, and the mean discriminatory power was 0.82. Microsatellite markers were satisfactorily cross-amplified for the eight tested Plicatula-group Paspalum species, with P. atratum exhibiting the highest transferability rate (89.86%). STRUCTURE and Discriminant Analysis of Principal Components separated accessions into three groups but did not reveal separation of the accessions according to species. CONCLUSIONS: This study describes the first microsatellite markers in P. plicatulum, which are polymorphic, efficient for the detection and quantification of genetic variation, and show high transferability into other species of the Plicatula group. This set of markers can be used in future genetic and molecular studies necessary for the proper development of conservation and breeding programs. Private bands within the markers can be used to assist in species identification. PMID- 27955704 TI - First report on treating spontaneous infectious spondylodiscitis of lumbar spine with posterior debridement, posterior instrumentation and an injectable calcium sulfate/hydroxyapatite composite eluting gentamicin: a case report. AB - BACKGROUND: Spontaneous infectious spondylodiscitis is a rare, but serious disease with the risk of progressive neurological impairment. The surgical approach to spontaneous infectious spondylodiscitis is in most cases an anterior debridement and fusion, often in staged surgeries. Here we report a case of single-stage posterior debridement and posterior instrumented fusion in combination with an injectable calcium sulfate/hydroxyapatite composite eluting gentamicin. CASE PRESENTATION: A 59-year-old Caucasian man presented with a 6 week history of lumbar pain without sensory or motor disorders of his lower extremities. A magnetic resonance imaging scan of his lumbar spine in T2-weighted sequences showed a high signal of the intervertebral disc L4/L5 and in T1 weighted sequences an epidural abscess at the posterior wall of L4. Additional computed tomography imaging revealed osteolytic destruction of the base plate of L4 and the upper plate of L5. Antibiotic therapy was started with intravenous ciprofloxacin and clindamycin. We performed a posterior debridement via a minimally invasive approach, a posterior percutaneous stabilization using transpedicular screw-rod instrumentation and filled the intervertebral space with an injectable calcium sulfate/hydroxyapatite composite which elutes a high concentration of gentamicin. The patient's lower back pain improved quickly after surgery and no recurrence of infection has been noticed during the 1-year follow up. Computed tomography at 11 months shows complete bony fusion of L4 and L5. CONCLUSIONS: An injectable calcium sulfate/hydroxyapatite composite releasing a high level of gentamicin can support the surgical treatment of spondylodiscitis in combination with posterior debridement and transpedicular screw-rod instrumentation. PMID- 27955705 TI - Production of biodegradable plastic by polyhydroxybutyrate (PHB) accumulating bacteria using low cost agricultural waste material. AB - BACKGROUND: Polyhydroxybutyrates (PHBs) are macromolecules synthesized by bacteria. They are inclusion bodies accumulated as reserve materials when the bacteria grow under different stress conditions. Because of their fast degradability under natural environmental conditions, PHBs are selected as alternatives for production of biodegradable plastics. The aim of this work was to isolate potential PHB producing bacteria, evaluate PHB production using agro residues as carbon sources. RESULT: Among fifty bacterial strains isolated from different localities, ten PHB accumulating strains were selected and compared for their ability to accumulate PHB granules inside their cells. Isolate Arba Minch Waste Water (AWW) identified as Bacillus spp was found to be the best producer. The optimum pH, temperature, and incubation period for best PHB production by the isolate were 7, 37 degrees C, and 48 h respectively at 150 rpm. PHB production was best with glucose as carbon source and peptone as nitrogen source. The strain was able to accumulate 55.6, 51.6, 37.4 and 25% PHB when pretreated sugar cane bagasse, corn cob, teff straw (Eragrostis tef) and banana peel were used as carbon sources respectively. Fourier transform-infrared authentication results of the extracted and purified PHB identified its functional units as C-H, CH2, C=O and C-O groups. UV-Vis spectrophotometric analysis and biodegradability test confirmed the similarity of the extract with standard PHB and its suitability for bioplastic production. CONCLUSION: The isolated Bacillus sp can be used for feasible production of PHB using agro-residues especially sugarcane bagasse which can reduce the production cost in addition to reducing the disposal problem of these substrates. The yield of PHB can further be boosted by optimization of production parameters as substrates. PMID- 27955706 TI - Prevalence of Herpes Simplex Virus 2 (HSV-2) infection and associated risk factors in a cohort of HIV negative women in Durban, South Africa. AB - BACKGROUND: Herpes Simplex Virus 2 (HSV-2) is one of the most common sexually transmitted infections (STIs) worldwide and is a risk factor for the acquisition and transmission of other STIs, including HIV. We determined the prevalence and predictors of HSV-2 infection among women screened for a HIV prevention trial in Durban, South Africa. Univariate and multivariate logistic and Cox regression models were used to determine the correlates and predictors of HSV-2 infection at enrolment and seroconversion during the study respectively. RESULTS: Prevalence of HSV-2 at screening was 65% and crude incidence was 22.3 per 100 person-years (PY) (95% CI 20.4-24.3). The HIV seroconversion was significantly higher among those testing positive for HSV-2 at baseline compared to women who were negative [8.7 per 100 person years (PY) versus 5.2 per 100 PY; (p < 0.001)]. In univariate analysis, age was determined to be the most significant predictor for HSV-2 diagnosis, while co-infection with syphilis was also a significant predictor, while age and co-infection with syphilis remained the two most significant predictors of having HSV-2 in multivariate analysis at baseline. Consistent with these results, along with HIV seroconversion, age was also identified as a significant predictor for incidence of HSV-2. CONCLUSION: Given the unacceptably high prevalence and incidence rates of HSV-2 infection reported here, HSV-2 and general STI education needs to be reinforced in these communities, with a focus on condom education for prevention. HSV-2 has emerged as the most prevalent STI which is most often asymptomatic and unrecognized, and which increases women's risk of acquiring other STIs, including HIV. PMID- 27955708 TI - Thematic issue of the Second combined Bio-ontologies and Phenotypes Workshop. AB - This special issue covers selected papers from the 18th Bio-Ontologies Special Interest Group meeting and Phenotype Day, which took place at the Intelligent Systems for Molecular Biology (ISMB) conference in Dublin in 2015. The papers presented in this collection range from descriptions of software tools supporting ontology development and annotation of objects with ontology terms, to applications of text mining for structured relation extraction involving diseases and phenotypes, to detailed proposals for new ontologies and mapping of existing ontologies. Together, the papers consider a range of representational issues in bio-ontology development, and demonstrate the applicability of bio-ontologies to support biological and clinical knowledge-based decision making and analysis.The full set of papers in the Thematic Issue is available at http://www.biomedcentral.com/collections/sig . PMID- 27955707 TI - Desire for predictive testing for Alzheimer's disease and impact on advance care planning: a cross-sectional study. AB - BACKGROUND: It is unknown whether older adults in the United States would be willing to take a test predictive of future Alzheimer's disease, or whether testing would change behavior. Using a nationally representative sample, we explored who would take a free and definitive test predictive of Alzheimer's disease, and examined how using such a test may impact advance care planning. METHODS: A cross-sectional study within the 2012 Health and Retirement Study of adults aged 65 years or older asked questions about a test predictive of Alzheimer's disease (N = 874). Subjects were asked whether they would want to take a hypothetical free and definitive test predictive of future Alzheimer's disease. Then, imagining they knew they would develop Alzheimer's disease, subjects rated the chance of completing advance care planning activities from 0 to 100. We classified a score > 50 as being likely to complete that activity. We evaluated characteristics associated with willingness to take a test for Alzheimer's disease, and how such a test would impact completing an advance directive and discussing health plans with loved ones. RESULTS: Overall, 75% (N = 648) of the sample would take a free and definitive test predictive of Alzheimer's disease. Older adults willing to take the test had similar race and educational levels to those who would not, but were more likely to be <=75 years old (odds ratio 0.71 (95% CI 0.53-0.94)). Imagining they knew they would develop Alzheimer's, 81% would be likely to complete an advance directive, although only 15% had done so already. CONCLUSIONS: In this nationally representative sample, 75% of older adults would take a free and definitive test predictive of Alzheimer's disease. Many participants expressed intent to increase activities of advance care planning with this knowledge. This confirms high public interest in predictive testing for Alzheimer's disease and suggests this may be an opportunity to engage patients in advance care planning discussions. PMID- 27955709 TI - The characteristics of patients with mycobacterium tuberculosis blood stream infections in Beijing, China: a retrospective study. AB - BACKGROUND: Published information regarding the clinical characteristics, laboratory findings, and outcomes of patients with Mycobacterium tuberculosis (MTB) blood stream infection (BSI) is limited. We aimed in this study to evaluate the clinical characteristics, laboratory evaluation, and outcomes of patients with MTB BSI. METHODS: All patients diagnosed with MTB BSI at Peking Union Medical College Hospital between January 2008 and May 2014 were identified by examining the electronic database listing results of all blood cultures. Data on demographics, clinical characteristics, laboratory manifestations, management, and outcomes were abstracted from medical records. RESULTS: Six thousand nine hundred seventy-four patients had mycobacterial blood cultures during the study period. Of 48 patients (0.7%) with MTB BSI, 26 patients (54%) were considered to be immunocompromised (refers to a person who has a significantly impaired immune system). This was due to human immunodeficiency virus (HIV) infection (n = 2 of 48 tested), receiving steroids (n = 17, including 16 with rheumatic diseases and one with myasthenia gravis), malignancy (n = 3), diabetes mellitus (n = 3), and renal transplantation (n = 1). The main clinical manifestations were fever (100%, with a median of 40 degrees C), weight loss (48%) and cough with sputum production (46%). Most patients had one or more organs involved (81%). The median time from onset of fever to diagnosis was 8 weeks (IQR 5 ~ 14). Six patients died within 1 week after diagnosis. Of the 17 patients completing treatment, 14 patients (82%) recovered without major complications and they had a shorter time interval between onsets of symptoms to treatment compared to those died of TB. CONCLUSIONS: In this group of patients with MTB BSI, fever and multiple organs involvement were common, the outcome was poor and timely diagnosis and treatment might favor outcome. PMID- 27955710 TI - Quantitative evaluation of essential medicines lists: the South African case study. AB - BACKGROUND: The South African (SA) health system has employed an Essential Medicines List (EML) with Standard Treatment Guidelines (STGs) since 1996. To date no studies have reported the changes in SA STG/EMLs. This study describes these changes over time (1996-2013) and compares latest SA STG/EMLs with the latest World Health Organization (WHO) Model EMLs to assess alignment of these lists. METHODS: A quantitative evaluation of SA STGs/EMLs at 2 levels of healthcare was performed to assess changes in the number and ratio of molecules, dosage forms, and additions and deletions of medicines. The most recent WHO EMLs (18th list, 4th list for children) and 2012 priority life-saving medicines for women and children (PMWC) list were compared to the most recent available SA STG/EMLs (Primary Health Care (PHC 2008), Adult Hospital 2012, and Paediatric Hospital 2013) at the time of the research. RESULTS: The number of molecules over the years increased for PHC STG/EMLs but decreased slightly for Adult and Paediatric hospital STG/EMLs. The most additions and deletions over time occurred in the Adult hospital level STG/EML (27 in 2006 and 44 in 2012). A comparison between the most recent SA STG/EMLs and WHO Model EML (18th list) showed that a total of 112 medicines were absent on all SA STG/EMLs. A comparison of medicines for children between the 2013 SA Paediatric Hospital level STG/EML and PMWC indicated that these lists were somewhat aligned for most conditions as only 3 of 14 medicines and 11 of 20 vaccines were absent from SA STG/EMLs. CONCLUSION: This is the first study in SA to investigate changes in National EMLs over time in relation to molecules, dosage forms and therapeutic classes. It is also the first to compare the latest SA STG/EMLs to the WHO Model lists. The results therefore provide insight into the trends and SA STG/EML processes over time. PMID- 27955711 TI - HCV co-infection and markers of liver injury and fibrosis among HIV-positive childbearing women in Ukraine: results from a cohort study. AB - BACKGROUND: Ukraine's injecting drug use-driven HIV epidemic is among the most severe in Europe with high burden of HCV co-infection. HIV/HCV co-infected individuals are at elevated risk of HCV-related morbidity, but little is known about burden of liver disease and associated factors in the HIV-positive population in Ukraine, particularly among women. METHODS: Characteristics of 2050 HIV-positive women enrolled into the Ukrainian Study of HIV-infected Childbearing Women were described by HCV serostatus. Aspartate transaminase (AST) to platelet ratio (APRI) and FIB-4 scores were calculated and exact logistic regression models fitted to investigate factors associated with significant fibrosis (APRI >1.5) among 762 women with an APRI score available. RESULTS: Of 2050 HIV-positive women (median age 27.7 years, IQR 24.6-31.3), 33% were HCV co-infected (79% of those with a history of injecting drug use vs 23% without) and 17% HBsAg positive. A quarter were on antiretroviral therapy at postnatal cohort enrolment. 1% of the HIV/HCV co-infected group had ever received treatment for HCV. Overall, 24% had an alanine aminotransferase level >41 U/L and 34% an elevated AST (53% and 61% among HIV/HCV co-infected). Prevalence of significant fibrosis was 4.5%; 2.5% among 445 HIV mono-infected and 12.3% among 171 HIV/HCV co-infected women. 1.2% had a FIB-4 score >3.25 indicating advanced fibrosis. HCV RNA testing in a sub-group of 56 HIV/HCV co-infected women indicated a likely spontaneous clearance rate of 18% and predominance of HCV genotype 1, with one-third having genotype 3 infection. Factors associated with significant fibrosis were HCV co infection (AOR 2.53 95%CI 1.03-6.23), history of injecting drug use (AOR 3.51 95%CI 1.39-8.89), WHO stage 3-4 HIV disease (AOR 3.47 95%CI 1.51-7.99 vs stage 1 2 HIV disease) and not being on combination antiretroviral therapy (AOR 3.08 95%CI 1.23-7.74), adjusted additionally for HBV co-infection, smoking and age. CONCLUSIONS: Most HIV/HCV co-infected women had elevated liver enzymes and 12% had significant fibrosis according to APRI. Risk factors for liver fibrosis in this young HIV-positive population include poorly controlled HIV and high burden of HCV. Results highlight the importance of addressing modifiable risk factors and rolling out HCV treatment to improve the health outcomes of this group. PMID- 27955714 TI - Selection of porcine oocytes in vitro through brilliant cresyl blue staining in distinct incubation media. AB - Staining with brilliant cresyl blue (BCB) may be used for oocyte selection, but BCB staining itself and the most commonly used selection medium (DMPBS) may compromise the development of porcine oocytes in vitro. This study evaluated DNA fragmentation, nuclear maturation, the area of migration of cortical granules (CG) and embryo development for stained (BCB+) and unstained (BCB-) oocytes incubated in DMPBS and in a modified medium (ReproPel) tested for the first time. Unexposed (UN), BCB+ and BCB- oocytes were incubated composing six groups: DMPBS/UN; DMPBS/BCB+; DMPBS/BCB-; ReproPel/UN; ReproPel/BCB+; and ReproPel/BCB-. There were more BCB+ oocytes in ReproPel than in DMPBS (P < 0.05). The DNA fragmentation was evaluated for oocytes in DMPBS/BCB+, DMPBS/BCB-, ReproPel/BCB+, ReproPel/BCB- and in porcine follicular fluid (control). The frequency of oocytes with no DNA fragmentation was greatest (64.6%) in DMPBS/BCB+ and lowest in ReproPel/BCB+ and ReproPel/BCB- (26.8 and 34.1%, respectively) (P < 0.05). Nuclear maturation rates were greater (P < 0.05) for DMPBS/BCB+ (63.1%), ReproPel/UN (55.1%) and ReproPel/BCB+ (50.2%) than for DMPBS/UN (40.8%) and ReproPel/BCB- (35.5%). The area of CG was greater (P < 0.05) for ReproPel/BCB- (80.7%) and DMPBS/UN (77.6%) than for ReproPel/UN (34.7%). Cleavage rates for DMPBS/BCB+ and ReproPel/BCB+ were greater than for DMPBS/UN (P < 0.05). Blastocyst development rates were greatest (P < 0.05) for ReproPel/UN and ReproPel/BCB+. In both media, BCB staining was apparently unable to select competent oocytes, which likely occurred due to toxicity. Despite the similar nuclear maturation and area of CG compared with DMPBS, oocytes selected in ReproPel presented impaired DNA integrity. PMID- 27955712 TI - Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence. AB - BACKGROUND: Pregnancy triggers well-known alterations in maternal glucose and lipid balance but its overall effects on systemic metabolism remain incompletely understood. METHODS: Detailed molecular profiles (87 metabolic measures and 37 cytokines) were measured for up to 4260 women (24-49 years, 322 pregnant) from three population-based cohorts in Finland. Circulating molecular concentrations in pregnant women were compared to those in non-pregnant women. Metabolic profiles were also reassessed for 583 women 6 years later to uncover the longitudinal metabolic changes in response to change in the pregnancy status. RESULTS: Compared to non-pregnant women, all lipoprotein subclasses and lipids were markedly increased in pregnant women. The most pronounced differences were observed for the intermediate-density, low-density and high-density lipoprotein triglyceride concentrations. Large differences were also seen for many fatty acids and amino acids. Pregnant women also had higher concentrations of low-grade inflammatory marker glycoprotein acetyls, higher concentrations of interleukin-18 and lower concentrations of interleukin-12p70. The changes in metabolic concentrations for women who were not pregnant at baseline but pregnant 6 years later (or vice versa) matched (or were mirror-images of) the cross-sectional association pattern. Cross-sectional results were consistent across the three cohorts and similar longitudinal changes were seen for 653 women in 4-year and 497 women in 10-year follow-up. For multiple metabolic measures, the changes increased in magnitude across the three trimesters. CONCLUSIONS: Pregnancy initiates substantial metabolic and inflammatory changes in the mothers. Comprehensive characterisation of normal pregnancy is important for gaining understanding of the key nutrients for fetal growth and development. These findings also provide a valuable molecular reference in relation to studies of adverse pregnancy outcomes. PMID- 27955715 TI - Biases in research: risk factors for non-replicability in psychotherapy and pharmacotherapy research. AB - Replicability of findings is an essential prerequisite of research. For both basic and clinical research, however, low replicability of findings has recently been reported. Replicability may be affected by research biases not sufficiently controlled for by the existing research standards. Several biases such as researcher allegiance or selective reporting are well-known for affecting results. For psychotherapy and pharmacotherapy research, specific additional biases may affect outcome (e.g. therapist allegiance, therapist effects or impairments in treatment implementation). For meta-analyses further specific biases are relevant. In psychotherapy and pharmacotherapy research these biases have not yet been systematically discussed in the context of replicability. Using a list of 13 biases as a starting point, we discuss each bias's impact on replicability. We illustrate each bias by selective findings of recent research, showing that (1) several biases are not yet sufficiently controlled for by the presently applied research standards, (2) these biases have a pernicious effect on replicability of findings. For the sake of research credibility, it is critical to avoid these biases in future research. To control for biases and to improve replicability, we propose to systematically implement several measures in psychotherapy and pharmacotherapy research, such as adversarial collaboration (inviting academic rivals to collaborate), reviewing study design prior to knowing the results, triple-blind data analysis (including subjects, investigators and data managers/statisticians), data analysis by other research teams (crowdsourcing), and, last not least, updating reporting standards such as CONSORT or the Template for Intervention Description and Replication (TIDieR). PMID- 27955716 TI - Development and Feasibility of a Virtual Reality Task for the Cognitive Assessment of Older Adults: The ECO-VR. AB - Cognitive assessment with virtual reality (VR) may have superior ecological validity for older adults compared to traditional pencil-and-paper cognitive assessment. However, few studies have reported the development of VR tasks. The aim of this study was to present the development, feasibility, content validity, and preliminary evidence of construct validity of an ecological task of cognitive assessment for older adults in VR (ECO-VR). The tasks were prepared based on theoretical and clinical backgrounds. We had 29 non-expert judges identify virtual visual stimuli and three-dimensional scenarios, and five expert judges assisted with content analysis and developing instructions. Finally, six older persons participated in three pilot studies and thirty older persons participated in the preliminary study to identify construct validity evidence. Data were analyzed by descriptive statistics and partial correlation. Target stimuli and three-dimensional scenarios were judged adequate and the content analysis demonstrated that ECO-VR evaluates temporo-spatial orientation, memory, language and executive functioning. We made significant changes to the instructions after the pilot studies to increase comprehensibility and reduce the completion time. The total score of ECO-VR was positively correlated mainly with performance in executive function (r = .172, p < .05) and memory tests (r = .488, p <= .01). The ECO-VR demonstrated feasibility for cognitive assessment in older adults, as well as content and construct validity evidences. PMID- 27955717 TI - ENVIRONMENTAL SCAN ON PHARMACEUTICALS REQUIRING COMPANION DIAGNOSTICS. AB - OBJECTIVES: Companion diagnostic tests (CDx) are used to measure an individual's protein or gene expression (biomarkers) to inform choice of therapy. The increasing number of drugs requiring CDx poses challenges for regulatory and reimbursement policies. To better understand this issue, an environmental scan was conducted by the Canadian Agency for Drugs and Technologies in Health (CADTH). METHODS: The environmental scan was based on a focused literature search and feedback solicited from targeted stakeholders. RESULTS: The global market for CDx is expected to grow considerably until the end of this decade, with compound annual growth rate around 20 percent. Several factors may impact the adoption of CDx, including the potential cost-savings associated with reduced treatment failures and adverse reactions. Anticipating an expansion in drugs with CDx, some countries have updated their regulatory frameworks, including the United States where the FDA released new guidance in 2014. With respect to reimbursement, both the United Kingdom and Australia updated their evaluation frameworks to inform reimbursement decisions; however, several countries, including Canada, have not published policies for co-dependent technology. CONCLUSION: The market size for CDx is expected to considerably expand in the future. The drive in uptake may be influenced by many factors including an increased knowledge of biomarkers and molecular drivers of disease and the potential cost-savings associated with fewer treatment failures and adverse reactions. Assessing whether such benefits materialize is important. Health technology assessment will play an important role in informing policies regarding the clinical use and funding of pharmaceuticals with CDx. PMID- 27955713 TI - Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery. AB - BACKGROUND: The relationship between monogenic and polygenic forms of epilepsy is poorly understood and the extent to which the genetic and acquired epilepsies share common pathways is unclear. Here, we use an integrated systems-level analysis of brain gene expression data to identify molecular networks disrupted in epilepsy. RESULTS: We identified a co-expression network of 320 genes (M30), which is significantly enriched for non-synonymous de novo mutations ascertained from patients with monogenic epilepsy and for common variants associated with polygenic epilepsy. The genes in the M30 network are expressed widely in the human brain under tight developmental control and encode physically interacting proteins involved in synaptic processes. The most highly connected proteins within the M30 network were preferentially disrupted by deleterious de novo mutations for monogenic epilepsy, in line with the centrality-lethality hypothesis. Analysis of M30 expression revealed consistent downregulation in the epileptic brain in heterogeneous forms of epilepsy including human temporal lobe epilepsy, a mouse model of acquired temporal lobe epilepsy, and a mouse model of monogenic Dravet (SCN1A) disease. These results suggest functional disruption of M30 via gene mutation or altered expression as a convergent mechanism regulating susceptibility to epilepsy broadly. Using the large collection of drug-induced gene expression data from Connectivity Map, several drugs were predicted to preferentially restore the downregulation of M30 in epilepsy toward health, most notably valproic acid, whose effect on M30 expression was replicated in neurons. CONCLUSIONS: Taken together, our results suggest targeting the expression of M30 as a potential new therapeutic strategy in epilepsy. PMID- 27955719 TI - Promotion of glucose utilization by insulin enhances granulosa cell proliferation and developmental competence of porcine oocyte grown in vitro. AB - In vitro culture of the oocyte granulosa cell complexes (OGCs) from early antral follicles (EAFs) shows granulosa cell (GC) proliferation, but to a lesser extent than that observed in vivo during follicle development. As the number of GCs closely relates to energy sufficiency of the oocytes, enhancement of GC proliferation influences oocyte development. GC proliferation depends on glycolysis and insulin-mediated AKT/mTOR signaling pathway; therefore, addition of culture medium containing insulin and glucose may potentially promote GC proliferation and hence improve oocyte development. In the present study, we assessed the effect of exogenous insulin and glucose concentration on GC proliferation and oocyte energy status as well as developmental abilities of porcine oocytes grown in vitro. In the presence of 5.5 mM of glucose (Low), a comparison of 10 versus 20 MUg/ml insulin showed that high insulin enhanced GC proliferation but exhausted glucose from the medium, which resulted in low energy status including lipid and adenosine triphosphate of the oocyte. Whereas, in the presence of 20 MUg/ml insulin, medium with 11 mM glucose (High) enhanced GC proliferation and oocyte energy status as well as developmental ability up to the blastocyst stage. Considering that there was no difference in OGCs development observed with medium (10 MUg/ml insulin) containing 5.5 versus 11 mM glucose, we concluded that the combination of high insulin and glucose enhanced GC proliferation and energy status of oocytes as well as the developmental ability of the oocytes grown in vitro. PMID- 27955718 TI - Phantom Prescribing: Examining the Frequency of Antimicrobial Prescriptions Without a Patient Visit. AB - OBJECTIVE To investigate the scale of antimicrobial prescribing without a corresponding visit, and to compare the attributes of patients who received antimicrobials with a corresponding visit with those who did not have a visit. DESIGN Retrospective cohort. METHODS We followed up 185,010 Medicare patients for 1 year after an acute myocardial infarction. For each antimicrobial prescribed, we determined whether the patient had an inpatient, outpatient, or provider claim in the 7 days prior to the antimicrobial prescription being filled. We compared the proportions of patient characteristics for those prescriptions associated with a visit and without a visit (ie, phantom prescriptions). We also compared the rates at which different antimicrobials were prescribed without a visit. RESULTS We found that of 356,545 antimicrobial prescriptions, 14.75% had no evidence of a visit in the week prior to the prescription being filled. A higher percentage of patients without a visit were identified as white (P<.001) and female (P<.001). Patients without a visit had a higher likelihood of survival and fewer additional cardiac events (acute myocardial infarction, cardiac arrest, stroke, all P<.001). Among the antimicrobials considered, amoxicillin, penicillin, and agents containing trimethoprim and methenamine were much more likely to be prescribed without a visit. In contrast, levofloxacin, metronidazole, moxifloxacin, vancomycin, and cefdinir were much less likely to be prescribed without a visit. CONCLUSIONS Among this cohort of patients with chronic conditions, phantom prescriptions of antimicrobials are relatively common and occurred more frequently among those patients who were relatively healthy. Infect Control Hosp Epidemiol 2017;38:273-280. PMID- 27955720 TI - Current evidence on the association of the metabolic syndrome and dietary patterns in a global perspective. AB - The metabolic syndrome (MetS) is a key indicator of two main causes of death worldwide: CVD and diabetes. The present paper aimed to perform a review of the population-based research on the association of dietary patterns and the MetS in terms of methodology and findings. For the purpose of the present study, a scoping literature review was conducted using MEDLINE and EMBASE databases and hand searching in Google Scholar. Thirty-nine population-based studies were selected. Most of these studies used the factor analysis method and the a priori dietary approach, which had been initially extracted via a posteriori methods such as using the Mediterranean dietary pattern. The main finding was that following the Mediterranean or similar 'healthy' pattern reduced risk of the MetS, while following a 'Western' pattern increased risk of the MetS. The methodological approach in determining the dietary pattern of a population, whether a priori or a posteriori, should be chosen based on the purpose of the research. Overall, evidence suggests a diet based on the components of the Mediterranean diet and the avoidance of the 'Western' diet can aid in preventing the MetS. PMID- 27955722 TI - HGSA Abstract: Poster Presentation From the 40th Human Genetics Society of Australasia Annual Scientific Meeting. PMID- 27955721 TI - A review of the design and validation of web- and computer-based 24-h dietary recall tools. AB - Technology-based dietary assessment offers solutions to many of the limitations of traditional dietary assessment methodologies including cost, participation rates and the accuracy of data collected. The 24-h dietary recall (24HDR) method is currently the most utilised method for the collection of dietary intake data at a national level. Recently there have been many developments using web-based platforms to collect food intake data using the principles of the 24HDR method. This review identifies web- and computer-based 24HDR tools that have been developed for both children and adult population groups, and examines common design features and the methods used to investigate the performance and validity of these tools. Overall, there is generally good to strong agreement between web based 24HDR and respective reference measures for intakes of macro- and micronutrients. PMID- 27955723 TI - Nutrition: ethical issues and challenges. AB - For nutrition and its associated disciplines, ethical considerations related to research are often complicated by factors that range from the use of experimental research designs that are overly holistic to inextricable links between nutrition research and marketing. As a consequence, there is the need for constant vigilance to assess and deal with apparent conflicts of interest. Also, there are few scientific disciplines that are defined by cultural, religious, or political codifications as is nutrition. Accordingly, examples of historical, cultural, and political events are described that have influenced ethical approaches related to nutrition research. Furthermore, nutrition research questions are often multifaceted and require dealing with complex variables. In this regard, ethical principles and perspectives that have relevance to data acquisition, the publication and translation of nutrition research, and the marketing of nutritional products and concepts are highlighted. PMID- 27955724 TI - Road safety communication campaigns: Theoretical foundations, validity, and empirical case studies. PMID- 27955725 TI - Current status of potential applications of repurposed Cas9 for structural and functional genomics of plants. AB - Redesigned Cas9 has emerged as a tool with various applications like gene editing, gene regulation, epigenetic modification and chromosomal imaging. Target specific single guide RNA (sgRNA) can be used with Cas9 for precise gene editing with high efficiency than previously known methods. Further, nuclease-deactivated Cas9 (dCas9) can be fused with activator or repressor for activation (CRISPRa) and repression (CRISPRi) of gene expression, respectively. dCas9 fused with epigenetic modifier like methylase or acetylase further expand the scope of this technique. Fluorescent probes can be tagged to dCas9 to visualize the chromosome. Due to its wide-spread application, simplicity, accessibility, efficacy and universality, this technique is expanding the structural and functional genomic studies of plant and developing CRISPR crops. The present review focuses on current status of using repurposed Cas9 system in these various areas, with major focus on application in plants. Major challenges, concerns and future directions of using this technique are discussed in brief. PMID- 27955726 TI - Preface. PMID- 27955727 TI - Wilms tumor: "State-of-the-art" update, 2016. AB - Despite an impressive increase in survival rate over the past decades, there is still a need to improve the survival of specific subgroups of Wilms tumor (anaplastic, metastatic, and bilateral) and to decrease the late effects of treatment in terms of renal function and heart toxicity. We aim to explore new areas of improvement, from diagnosis to treatment: in the field of radiology the increased use of MRI and exploration of its diffusion-weighted imaging capabilities to predict WT histology at diagnosis and for preoperative assessment; in biology the emergence of new biomarkers that could be integrated into the decision-making process; and surgical techniques with more accurate indication of nephron-sparing surgery that is no longer reserved for bilateral WT and the minimally invasive approach. The long-term outcome of patients with WT should thus be a strong indicator of the improvement in adapting and personalizing the treatment to each individual. PMID- 27955728 TI - Recent biologic and genetic advances in neuroblastoma: Implications for diagnostic, risk stratification, and treatment strategies. AB - Neuroblastoma is an embryonic cancer of neural crest cell lineage, accounting for up to 10% of all pediatric cancer. The clinical course is heterogeneous ranging from spontaneous regression in neonates to life-threatening metastatic disease in older children. Much of this clinical variance is thought to result from distinct pathologic characteristics that predict patient outcomes. Consequently, many research efforts have been focused on identifying the underlying biologic and genetic features of neuroblastoma tumors in order to more clearly define prognostic subgroups for treatment stratification. Recent technological advances have placed emphasis on the integration of genetic alterations and predictive biologic variables into targeted treatment approaches to improve patient survival outcomes. This review will focus on these recent advances and the implications they have on the diagnostic, staging, and treatment approaches in modern neuroblastoma clinical management. PMID- 27955729 TI - Malignant tumors of the liver in children. AB - This article aims to give an overview of pediatric liver tumors; in particular of the two most frequently occurring groups of hepatoblastomas and hepatocellular carcinomas. Focus lays on achievements gained through worldwide collaboration. We present recent advances in insight, treatment results, and future questions to be asked. Increasing international collaboration between the four major Pediatric Liver Tumor Study Groups (SIOPEL/GPOH, COG, and JPLT) may serve as a paradigm to approach rare tumors. This international effort has been catalyzed by the Children's Hepatic tumor International Collaboration (CHIC) formation of a large collaborative database. Interrogation of this database has led to a new universal risk stratification system for hepatoblastoma using PRETEXT/POSTTEXT staging as a backbone. Pathologists in this international collaboration have established a new histopathological consensus classification for pediatric liver tumors. Concomitantly there have been advances in chemotherapy options, an increased role of liver transplantation for unresectable tumors, and a web portal system developed at www.siopel.org for international education, consultation, and collaboration. These achievements will be further tested and validated in the upcoming Paediatric Hepatic International Tumour Trial (PHITT). PMID- 27955730 TI - Rhabdomyosarcoma. AB - A malignant tumor of striated muscle origin, rhabdomyosarcoma (RMS) is a childhood tumor that has benefited from nearly 30 years of multimodality therapy, culminating in a >70% overall 5-year survival. Prognosis for RMS is dependent on primary tumor site, age, completeness of resection, presence and number of metastatic sites, histology, and biology of the tumor cells. Multimodality treatment is based on risk stratification according to pre-treatment stage, postoperative group, histology, and site. Unique to RMS is the concept of postoperative clinical grouping that assesses the completeness of disease resection and takes into account lymph node evaluation at both the regional and metastatic basins. At all sites, if complete operative resection of disease is accomplished, including microscopic disease, survival is improved. Therefore, the surgeon plays a vital role in determining risk stratification for treatment, local control of the primary tumor and overall outcome for the patient with RMS. PMID- 27955731 TI - Non-rhabdomyosarcoma. AB - Pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a heterogeneous group encompassing more than 50 different histological diagnoses arising from primitive mesenchymal tissue. Together, they comprise about half the soft tissue sarcomas diagnosed in children and young adults. Despite each histologies relative rarity, their management schema is similar among the different NRSTS histologies. Surgical management is an important component of the multimodal treatment strategy of all these tumors. Resection with negative margins, while maintaining function, plays an important role as a primary treatment of these patients as well as diminishing the risks of local and distant recurrence. PMID- 27955732 TI - Pediatric melanoma. AB - Childhood melanoma is a rare pediatric malignancy, with fewer than 500 new diagnoses annually. The incidence is increasing, particularly in the adolescent population. This review highlights the epidemiology, clinical presentation, and histopathologic challenges of pediatric melanoma. Surgical resection remains the cornerstone for localized and regionally advanced disease. Adjuvant therapies, including current options and potential novel therapeutics for this unique population will be discussed. PMID- 27955733 TI - Management of desmoplastic small round cell tumor. AB - Desmoplastic small round cell tumor (DSRCT) is a soft tissue sarcoma of mesenchymal cell origin that typically presents with multiple intra-abdominal tumors and exhibits a multi-phenotypic pattern of immunohistochemical staining. The specific organ or tissue type of origin has yet to be identified. DSRCT rarely arises as a singular tumor in the abdomen; in most cases, there are dozens to hundreds of abdominal peritoneal tumors that are detected on diagnosis. One very large dominant mass is usually present in the omentum, with an additional one or two large conglomerates of tumors in the pelvis and right peritoneum, respectively. Despite an often overwhelmingly large number of abdominal tumors, symptoms of bowel obstruction are rare. Ascites may be present. In late stages, pleural effusions, pleural implants, mediastinal adenopathy, supraclavicular adenopathy, or bone metastasis may be present. With this challenging disease, multidisciplinary therapy, including aggressive surgery, is warranted. This review will address DSRCT biology and treatment options and discuss outcomes. PMID- 27955734 TI - Pediatric/"Wildtype" gastrointestinal stromal tumors. AB - Pediatric/"Wildtype" gastrointestinal stromal tumor (P/WT-GIST) is a rare cancer, distinct and markedly different from the phenotype found predominantly in older patients (adult, non-wildtype GIST). Having a different molecular signature, it is not responsive to standard adjuvant therapies utilized in adult GIST, and surgery remains the only effective cure. However, even with presumed complete resections in patients with localized disease at presentation, recurrence rates are high. Furthermore, it is an indolent cancer that can persist for decades, and treatment strategies must balance the possible morbid risks of intervention with the reality of preserving quality of life in the interim. Effective adjuvant therapies remain elusive, and research is critically needed to identify both targets and drugs for treatment consideration. PMID- 27955736 TI - Fertility considerations and the pediatric oncology patient. AB - Recent years have witnessed marked improvement in cytotoxic treatments with a parallel increase in patient survival. Despite efforts done to minimize long-term side effects of these treatment regimens, it is estimated that 40% of survivors of pediatric cancer will suffer from those. Some will be mild whereas others such as impaired fertility will be a heavy load on parents' expectations and patient's quality of life. Gonadal damage and severe loss of function is not a rare condition among children cured for cancer. Despite the young age of those patients, methods exist to try to reduce gonadal insult or to preserve gonadal function. Some of them are well studied and controlled; others are more experimental with encouraging results so far. This article aims to summarize all the procedures that can be offered to young patients treated for cancer in order to protect, as possible, their fertility potential. PMID- 27955737 TI - Palliative care and pediatric surgical oncology. AB - Survival rate for childhood cancer has increased in recent years, reaching as high as 70% in developed countries compared with 54% for all cancers diagnosed in the 1980s. In the remaining 30%, progression or metastatic disease leads to death and in this framework palliative care has an outstanding role though not well settled in all its facets. In this landscape, surgery has a supportive actor role integrated with other welfare aspects from which are not severable. The definition of surgical palliation has moved from the ancient definition of noncurative surgery to a group of practices performed not to cure but to alleviate an organ dysfunction offering the best quality of life possible in all the aspects of life (pain, dysfunctions, caregivers, psychosocial, etc.). To emphasize this aspect a more modern definition has been introduced: palliative therapy in whose context is comprised not only the care assistance but also the plans of care since the onset of illness, teaching the matter to surgeons in training and share paths. Literature is very poor regarding surgical aspects specifically dedicated and all researches (PubMed, Google Scholar, and Cochrane) with various meshing terms result in a more oncologic and psychosocial effort. PMID- 27955738 TI - Evidence-based paediatric surgical oncology. AB - Surgeons play a pivotal role in the decision-making and multidisciplinary management of childhood solid tumours.1 Evidence-based medicine-"aims to optimise decision making by emphasising on the use of best evidence from well-designed conducted research." This article offers a brief overview in an effort to demonstrate how a selection of well-conducted, recently published studies can help address some topical and controversial themes in paediatric surgical oncology practice. PMID- 27955735 TI - Surgical treatment of pulmonary metastases in pediatric solid tumors. AB - Most children who succumb to solid malignancies do so because of the burden of metastatic disease or due to complications associated with the therapy administered to treat metastatic disease. Approximately one-quarter of children with solid tumors will present with metastatic disease, and an additional 20% ultimately develop metastatic disease, most commonly in the lung. The role of surgery in the treatment of metastatic solid tumors, given its disseminated nature, is not intuitive, yet there are circumstances in which surgical resection of metastatic disease can potentially be curative. However, the utility of surgery is very much dependent on histology, and generally is most appropriate for those malignancies with histologies that are refractory to other adjuvant therapies. PMID- 27955739 TI - Phytochemical overview and medicinal importance of Coffea species from the past until now. AB - Coffea (coffee) species are grown in almost all countries along the Equator. Many members of the genus have a large production history and an important role both in the global market and researches. Seeds (Coffeae semen) are successfully used in food, cosmetic, and pharmaceutical industries due to its caffeine and high polyphenol content. Nowadays, the three best-known coffee species are Arabic (Coffea arabica L.), Robusta (Coffea robusta L. Linden), and Liberian coffees (Coffea liberica Hiern.). Even though, many records are available on coffee in scientific literature, wild coffee species like Bengal coffee (Coffea benghalensis Roxb. Ex Schult.) could offer many new opportunities and challenges for phytochemical and medical studies. In this comprehensive summary, we focused on the ethnomedicinal, phytochemical, and medical significance of coffee species up to the present. PMID- 27955740 TI - Control of animal brucellosis: The Malaysian experience. AB - Brucellosis is a zoonotic disease characterized by reproductive failure in animals and undulent fever in humans. In cattle, it is caused by Brucella abortus while in goats by Brucella melitensis, the main cause of brucellosis in humans. Brucellosis in livestock has been associated with importation of animals from breeder herd of unknown disease status. The prevalence of bovine brucellosis Brucella abortus in 2014 ranged between 1% and 2% in Thailand and Indonesia, and 4%-5% in Malaysia and Myanmar. Prevalence of goat brucellosis Brucella melitensis is approximately 1% in Malaysia and Thailand. 'Test-and-slaughter' is the general policy against brucellosis adopted by most ASEAN countries to eradicate the disease. Under this program, the Rose Bengal Plate Test (RBPT) is used as the screening test to identify infected farm/herd while the complement fixation test (CFT) is the confirmatory test. The test-and-slaughter eradication strategy that was implemented since 1979 had managed to keep the prevalence rate to less than 5%, from 3.3% in 1979, 0.23% in 1988, 1% in 1998 and 5% in 2016. The test-and slaughter program seemed effective in reducing the prevalence of brucellosis but was unable to eradicate the disease due to several factors, which include failure to locate and identify the remaining affected animals and to control their movement, importation of breeder animals from non-brucellosis free countries and lack of participation by the farmers following unreliable test results. To support the eradication policy, research activities since 1980s have suggested combinations of serological tests to improve diagnosis while surveillance should be focused on hotspots areas. The prevalence can be further reduced by strictly sourcing breeder animals from brucella-free areas or countries. PMID- 27955741 TI - Medical plant extracts and natural compounds with a hepatoprotective effect against damage caused by antitubercular drugs: A review. AB - Drug-induced liver injury encompasses a spectrum of diseases ranging from mild biochemical abnormalities to acute liver failure; example of this scenery is hepatotoxicity caused by the first-line antituberculous drugs isoniazid, rifampin and pyrazinamide, which are basic for treatment of drug-sensible and drug resistant tuberculosis. In the search for pharmacological alternatives to prevent liver damage, antitubercular drugs have been the subject of numerous studies and published reviews, a great majority of them carried out by Asian countries. At the same time, hepatoprotectors from plant source are now emerging as a possible alternative to counteract the toxic effects of these therapeutic agents. The present review aims to highlight the most recent studies on the subject, based information published in scientific databases such as Scopus and PubMed. PMID- 27955742 TI - Genetic association study of P2x7 A1513C (rs 3751143) polymorphism and susceptibility to pulmonary tuberculosis: A meta-analysis based on the findings of 11 case-control studies. AB - OBJECTIVE: To summarize the precise association between pulmonary tuberculosis (PTB) and P2x7 A1513C gene polymorphism. METHODS: PubMed and Google Scholar web databases were searched for the studies reporting the association of P2x7 A1513C polymorphism and PTB risk. A meta-analysis was performed for the selected case control studies and pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for all the genetic models. RESULTS: Eleven studies comprising 2678 controls and 2113 PTB cases were included in this meta-analysis. We observed overall no significant risk in all the five genetic models. When stratified population by the ethnicity, Caucasian population failed to show any risk of PTB in all the genetics models. In Asian ethnicity, variant allele (C vs. A: P = 0.001; OR = 1.375, 95% CI = 1.159-1.632) and heterozygous genotype (AC vs. AA: P = 0.001; OR = 1.570, 95% CI = 1.269-1.944) demonstrated significant increased risk of PTB. Likewise, recessive genetic model (CC + AC vs. AA: P = 0.001; OR = 1.540, 95% CI = 1.255-1.890) also demonstrated increased risk of PTB in Asians. CONCLUSIONS: Our meta-analysis did not suggest the association of P2x7 A1513C polymorphism with PTB risk in overall or separately in Caucasian population. However, it plays a significant risk factor for predisposing PTB in Asians. Future larger sample and expression studies are needed to validate this association. PMID- 27955743 TI - Protective effects of a polymethoxy flavonoids-rich Citrus aurantium peel extract on liver fibrosis induced by bile duct ligation in mice. AB - OBJECTIVE: To evaluate the possible protective effect of Citrus aurantium peel extract (CAE) against apoptosis in cholestatic liver fibrosis induced by bile duct ligation in mice. METHODS: Male ICR mice were divided to 5 groups: 1) Control group (Sham-operated mice), 2) Cholestatic liver injury group induced by bile duct ligation (BDL), 3) BDL mice treated with silymarin (200 mg/kg) for 4 weeks, 4) BDL mice treated with 50 mg/kg CAE for 4 weeks, 5) BDL mice treated with 200 mg/kg CAE for 4 weeks. Mice were sacrificed and liver fibrosis was evaluated by serum and hepatic tissue biochemistry tests and liver histopathological examination. Effects of CAE on inflammation and apoptosis gene regulation were investigated through real-time PCR. CAE effect on lipid metabolism related signaling was determined by western blot analysis. RESULTS: In BDL mice, administration of CAE for 4 weeks markedly attenuated liver fibrosis based on histopathological alteration. Serum and hepatic tissue biochemistry results revealed that CAE (50 and 200 mg/kg) decreased the levels of alanine transaminase, aspartate transaminase, gamma-glutamyl transferase, total bilirubin, nitric oxide, and thiobarbituric acid reactive substances. Real-time PCR and western blot analysis showed that CAE regulated inflammation, apoptosis, and lipid metabolism factors increased by BDL. Interleukin family, tumor necrosis factor alpha, and related apoptosis factors mRNA levels were increased by BDL treatment. However, these increases were suppressed by CAE administration. In addition, CAE effectively increased phosphorylation of AMP-activated protein kinase, nuclear factor E2-related factor 2, and related cytoprotective proteins. CONCLUSIONS: CAE can efficiently regulate BDL-induced liver injury with antioxidant, anti-inflammatory, and anti-apoptotic activities. PMID- 27955744 TI - Glycoproteomics analysis of plasma proteins associated with Opisthorchis viverrini infection-induced cholangiocarcinoma in hamster model. AB - OBJECTIVE: To apply lectin affinity chromatography and glycoproteomics-based LC MS/MS to preliminarily investigate the possible potential plasma biomarkers of Opisthorchis viverrini (OV)-associated CCA in OV/dimethylnitrosamine (DMN) induced CCA hamster model. METHODS: Nine Syrian hamsters were divided into 3 groups as follows (n = 3 each): normal (healthy control group); OV group; and OV/DMN group (CCA group). Pooled plasma samples collected from animals in each group at the 6th month post-infection with OV metacercarae were subjected to glycoproteomics analysis. Glycoproteins in the pooled sample from each group were initially isolated by concanavalin A (ConA)-based affinity chromatography. The expression of glycoproteins isolated by both enrichment methods were determined using LC-MS/MS. RESULTS: Among the 24 ConA-binding glycoproteins isolated, two proteins, N-myc downstream regulated gene 1 (NDRG1) and fetuin-B (FETUB) were found up-regulated only in the samples from the OV and control groups, but not in the OV/DMN (CCA) groups. On the other hand, one protein, i.e., NSFL1 cofactor p47 isoform *3 (NSFL1C) was found only in the samples from OV/DMN (CCA) and control groups, but not in the OV group. The remaining 21 proteins were upregulated in the samples from all groups. CONCLUSIONS: NDRG1, FETUB and NSFL1C glycoproteins isolated by ConA-based affinity chromatography could be potential biomarkers for CCA. Plasma samples with negative for NDRG1 and FETUB proteins but positive for NSFL1C are likely to be OV-associated CCA. Nevertheless, this conclusion remains to be confirmed whether this battery test can discriminate OV-associated CCA from other risk factors. PMID- 27955746 TI - Novel neuroprotective and hepatoprotective effects of citric acid in acute malathion intoxication. AB - OBJECTIVE: To study the effect of citric acid given alone or combined with atropine on brain oxidative stress, neuronal injury, liver damage, and DNA damage of peripheral blood lymphocytes induced in the rat by acute malathion exposure. METHODS: Rats were received intraperitoneal (i.p.) injection of malathion 150 mg/kg along with citric acid (200 or 400 mg/kg, orally), atropine (1 mg/kg, i.p.) or citric acid 200 mg/kg + atropine 1 mg/kg and euthanized 4 h later. RESULTS: Malathion resulted in increased lipid peroxidation (malondialdehyde) and nitric oxide concentrations accompanied with a decrease in brain reduced glutathione, glutathione peroxidase (GPx) activity, total antioxidant capacity (TAC) and glucose concentrations. Paraoxonase-1, acetylcholinesterase (AChE) and butyrylcholinesterase activities decreased in brain as well. Liver aspartate aminotransferase and alanine aminotransferase activities were raised. The comet assay showed increased DNA damage of peripheral blood lymphocytes. Histological damage and increased expression of inducible nitric oxide synthase (iNOS) were observed in brain and liver. Citric acid resulted in decreased brain lipid peroxidation and nitric oxide. Meanwhile, glutathione, GPx activity, TAC capacity and brain glucose level increased. Brain AChE increased but PON1 and butyrylcholinesterase activities decreased by citric acid. Liver enzymes, the percentage of damaged blood lymphocytes, histopathological alterations and iNOS expression in brain and liver was decreased by citric acid. Meanwhile, rats treated with atropine showed decreased brain MDA, nitrite but increased GPx activity, TAC, AChE and glucose. The drug also decreased DNA damage of peripheral blood lymphocytes, histopathological alterations and iNOS expression in brain and liver. CONCLUSIONS: The study demonstrates a beneficial effect for citric acid upon brain oxidative stress, neuronal injury, liver and DNA damage due to acute malathion exposure. PMID- 27955745 TI - Asiatic acid-pectin hydrogel matrix patch transdermal delivery system influences parasitaemia suppression and inflammation reduction in P. berghei murine malaria infected Sprague-Dawley rats. AB - OBJECTIVE: To report the influence of transdermal delivery of asiatic acid (AA) in Plasmodium berghei-infected Sprague Dawley rats on physicochemical changes, %parasitaemia and associated pathophysiology. METHODS: A topical once-off AA (5, 10, and 20 mg/kg)- or chloroquine (CHQ)-pectin patch was applied on the shaven dorsal neck region of Plasmodium berghei-infected Sprague Dawley rats (90-120 g) on day 7 after infection. Eating and drinking habits, weight changes, malaria effects and %parasitaemia were compared among animal groups over 21 d. RESULTS: AA-pectin patch application preserved food and water intake together with %weight gain. All animals developed stable parasitaemia (15-20%) by day 7. AA doses suppressed parasitaemia significantly. AA 5 mg/kg patch was most effective. AA and CHQ displayed bimodal time-spaced peaks. CHQ patch had a longer time course to clear parasitaemia. CONCLUSIONS: AA influences bio-physicochemical changes and parasitaemia suppression in dose dependent manner. In comparison by dose administered, AA has much better efficacy than CHQ. AA may be a useful antimalarial. AA and CHQ displays bimodal peaks suggesting possible synergism if used in combination therapy. PMID- 27955747 TI - Recombinant expression and purification of functional vascular endothelial growth factor-121 in the baculovirus expression system. AB - OBJECTIVE: To express human vascular endothelial growth factor121 (VEGF121) in insect cells. METHODS: A gene construct containing VEGF was cloned in the pFastBac-HTA vector, followed by transformation in DH10BAC. The recombinant bacmid was then extracted, and transfected into Sf9 insect cells. The transfected cells were harvested, and then VEGF expression was confirmed by western blotting using specific antibodies. The tube formation assay was used for functional assessment of VEGF. RESULTS: Our results showed that VEGF could be successfully expressed in the baculovirus system. Purified VEGF was able to stimulate in vitro tube formation of human endothelial cells. CONCLUSIONS: Results from this study demonstrated that the recombinantly-produced VEGF can be considered as a promising candidate for therapeutic purposes. PMID- 27955748 TI - Influence of bioactive sulfated polysaccharide-protein complexes on hepatocarcinogenesis, angiogenesis and immunomodulatory activities. AB - OBJECTIVE: To explore the in vivo anticancer, anti-angiogenesis and immunomodulatory efficacies of the bioactive polysaccharide isolated from cold aqueous extract of Jania rubens (JCEM) and Pterocladia capillacea (PCEM) as well as hot aqueous extract of Enteromorpha intestinalis (EHEM) against hepatocellular carcinoma rat model (HCC) and to study their chemical composition. METHODS: The sugars and amino acids composition of the bioactive polysaccharides of JCEM, PCEM and EHEM were determined using gas liquid chromatography and amino acid analyzer, respectively. These polysaccharide extracts (20 mg/kg b.wt. for 5 weeks) were assessed on hepatocarcinogenesis in rats and alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), glypican-3 (GPC-3), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) and Ig G levels were evaluated. RESULTS: The GLC analysis of JCEM, PCEM and EHEM polysaccharide revealed the presence of 10, 9 and 10 sugars, in addition the amino acid analyzer enable identification of 16, 15 and 15 amino acids, respectively. These polysaccharide extracts of JCEM, PCEM and EHEM produced significant decrease in serum AFP, CEA, GPC-3, HGF and VEGF compared with untreated HCC group. JCEM, PCEM and EHEM had an immunostimulatory responses by increasing the IgG levels as compared by naive value (1.23, 1.53 and 1.17 folds), respectively. The bioactive polysaccharides in HCC induced rats improved the humoral immune response. The photomicrographs of liver tissue sections of the groups of HCC treated with polysaccharide extracts of Jania rubens and Enteromorpha intestinalis showed intact histological structure. Moreover, fractions HE1, HE4, HE7 obtained from polysaccharide of EHEM showed moderate cytotoxic activity against HepG2 in vitro with IC50 73.1, 42.6, 76.2 MUg/mL. However, fractions of PCEM and JCEM show no or weak cytotoxicity against HepG2 in vitro where the cytotoxic activity of their crude polysaccharide extract proved synergetic effect. CONCLUSIONS: The pronounced antitumor activity of sulfated polysaccharide-protein complexes of JCEM and EHEM is due to direct cytotoxic activity, anti-hepatocarcinogenesis, and anti-angiogenesis. In addition, JCEM, PCEM and EHEM had an immunostimulatory response and improved the humoral immune response in HCC induced rats. PMID- 27955749 TI - NS1 antigen: A new beam of light in the early diagnosis of dengue infection. AB - OBJECTIVE: To evaluate NS1 antigen detection ELISA for the early laboratory diagnosis of dengue virus infection. METHODS: The present study was conducted to evaluate the overall positivity of NS1 antigen detection ELISA and its comparison with viral RNA detection via real time PCR and IgM antibodies detection by ELISA. RESULTS: A total of 1270 serum samples were tested 86% (1097/1270) were detected positive by one or more than one diagnostic test. Out of 1 270, 64% (807/1270) were positive by NS1 ELISA and 52% (662/1270), 51% (646/1270) were positive by real-time RT-PCR and IgM ELISA respectively. CONCLUSIONS: NS1 antigen detection ELISA is highly suitable diagnostic tools and it also has great value for use in outbreak and epidemic situation. PMID- 27955750 TI - Geohelminths eggs contamination of sandpits in Vladivostok, Russia. AB - OBJECTIVE: To detect nematode eggs in sandpits in urban area in Vladivostok. METHODS: Totally 60 samples were collected from five districts. Sand samples were analysed using combined flotation-sedimentation method. In result, 18 sand samples were positive for at one or two parasites species. RESULTS: Overall, only 3 genera of helminths were recovered. Most samples were positive for Toxocara spp. eggs. Toxocara spp. eggs were found in each district. More samples with Toxocara spp. eggs were found in Pervomaiskii district. Ascaris spp. eggs were also appeared in each district, however Ascaris eggs rate of contamination was less than rate of Toxocara spp. contamination. Toxascaris leonina eggs were the less frequent species in sandpits, it was found only in Sovetskii and Pervomaiskii districts. Ascaris eggs rate of contamination was less than rate of Toxocara spp. contamination. Toxascaris leonina eggs were the less frequent species in sandpits, it was found only in two districts. No correlation between districts and helmiths eggs present in soil samples was found (P > 0.05). CONCLUSIONS: Considering the high sand contamination with parasite infective elements of both human and animal origin, measures to improve environmental and sanitary conditions are indicated, as well as promoting the concept of responsible pet ownership. PMID- 27955751 TI - EUS for pancreatic cystic neoplasms: The roadmap to the future is much more than just a few shades of gray. AB - Pancreatic cystic and neoplasms are being diagnosed with increasing frequency. Accurate diagnosis and determination of benign versus malignant lesions is crucial for determining need for surveillance versus surgery or endoscopic therapy as well as avoiding unnecessary surgery in cysts with no malignant potential. Tumor markers such as KRAS and GNAS hold promise, but which molecular marker or a combination of markers is most useful and cost effective remains to be seen. Advanced imaging with confocal laser endomicroscopy can serve as an optical biopsy and play a part in the diagnostic algorithm. Microforceps aided biopsy of pancreatic cyst wall and tumor contents hold great promise as they allow direct tissue acquisition. Much progress has been made in the role of EUS guided evaluation of pancreatic cystic neoplasms over the last several years, and with the advances enumerated above, the future is more than just a few shades of gray. Future studies should include prospective multi-arm trials of microforceps biopsy versus conventional EUS-FNA and use of biochemical and molecular markers, confocal laser endomicroscopy or a combination thereof to determine best approach to pancreatic cystic neoplasms. In Osler's words, 'Medicine is a science of uncertainty and an art of probability'. Incorporation of advanced imaging and molecular markers into a new diagnostic algorithm with subsequent validation through retrospective and prospective studies has the potential to increase diagnostic accuracy and guide optimal management of patients and improve outcomes. PMID- 27955753 TI - Corrigendum to "A study on reliability and validity of the Turkish version of the Face Anxiety Scale on mechanically-ventilated patients" [Intensive Crit. Care Nurs. 37 (2016) 46-51]. PMID- 27955752 TI - Seronegative disseminated Bartonella spp. infection in an immunocompromised patient. AB - An 11 year old, hispanic girl with a history of B-cell acute lymphoblastic leukemia was admitted to the hospital for symptoms compatible with Bartonella henselae infection. The first molecularly diagnosed case of disseminated Bartonella henselae infection was reported in an immunocompromised patient in Lima, Peru. The analysis was confirmed by Polymerase Chain Reaction and automated sequencing of a liver biopsy sample, even though the serologic tests were negative. In conclusion, Bartonella spp. infection should have a particular diagnostic consideration in immunocompromised patients with fever of unknown origin and further investigation regarding the patient's past exposures with cats should also be elicited. PMID- 27955754 TI - Editorial Overview: The ins and outs of stem cells in differentiation, inflammation & disease. PMID- 27955755 TI - Henry J.M. Barnett, MD, FRCP (C). PMID- 27955756 TI - Corrigendum to "Behavioral activation can normalize neural hypoactivation in subthreshold depression during a monetary incentive delay task" [J. Affect. Disord. 189 (2016) 254-262]. PMID- 27955757 TI - Management of Explosive Incidents: Overview of the Project and Summary of Best Practices Consensus Statements of the Expert Panel. PMID- 27955758 TI - Organization and Operations Management at the Explosive Incident Scene. PMID- 27955759 TI - Medical Management at the Explosive Incident Scene. PMID- 27955760 TI - Organization and Operations Management at the Health Care Facility. PMID- 27955761 TI - Medical Management at the Health Care Facility. PMID- 27955762 TI - Blast Physics and Pathophysiology of Explosive Injuries. PMID- 27955764 TI - Gaps between the Teeth of Cardiovascular Health Strategy. PMID- 27955763 TI - Future Developments in the Management of Explosive Incidents. PMID- 27955765 TI - Festschrift for Professor Stephen Hunyor - Celebrating his Clinical and Scientific Contribution and the Legacy he has Left at Royal North Shore Hospital, and the Broader Cardiovascular Research Community. PMID- 27955766 TI - Adolescence as a Critical Period for Developmental Plasticity. PMID- 27955767 TI - On societal and hemostatic changes. PMID- 27955768 TI - Precision global health: beyond prevention and control. PMID- 27955770 TI - Persistence of Ebola virus RNA in seminal fluid. PMID- 27955771 TI - Uncovering the rising kidney failure deaths in India. PMID- 27955769 TI - 11 years of tracking aid to reproductive, maternal, newborn, and child health: estimates and analysis for 2003-13 from the Countdown to 2015. AB - BACKGROUND: Tracking aid flows helps to hold donors accountable and to compare the allocation of resources in relation to health need. With the use of data reported by donors in 2015, we provided estimates of official development assistance and grants from the Bill & Melinda Gates Foundation (collectively termed ODA+) to reproductive, maternal, newborn, and child health for 2013 and complete trends in reproductive, maternal, newborn, and child health support for the period 2003-13. METHODS: We coded and analysed financial disbursements to reproductive, maternal, newborn, and child health to all recipient countries from all donors reporting to the creditor reporting system database for the year 2013. We also revisited disbursement records for the years 2003-08 and coded disbursements relating to reproductive and sexual health activities resulting in the Countdown dataset for 2003-13. We matched this dataset to the 2015 creditor reporting system dataset and coded any unmatched creditor reporting system records. We analysed trends in ODA+ to reproductive, maternal, newborn, and child health for the period 2003-13, trends in donor contributions, disbursements to recipient countries, and targeting to need. FINDINGS: Total ODA+ to reproductive, maternal, newborn, and child health reached nearly US$14 billion in 2013, of which 48% supported child health ($6.8 billion), 34% supported reproductive and sexual health ($4.7 billion), and 18% maternal and newborn health ($2.5 billion). ODA+ to reproductive, maternal, newborn, and child health increased by 225% in real terms over the period 2003-13. Child health received the most substantial increase in funding since 2003 (286%), followed by reproductive and sexual health (194%), and maternal and newborn health (164%). In 2013, bilateral donors disbursed 59% of all ODA+ to reproductive, maternal, newborn, and child health, followed by global health initiatives (23%), and multilateral agencies (13%). Targeting of ODA+ to reproductive, maternal, newborn, and child health to countries with the greatest health need seems to have improved over time. INTERPRETATION: The increase in reproductive, maternal, newborn, and child health funding over the period 2003-13 is encouraging. Further increases in funding will be needed to accelerate maternal mortality reduction while keeping a high level of investment in sexual and reproductive health and in child health. FUNDING: Subgrant OPP1058954 from the US Fund for UNICEF under their Countdown to 2015 for Maternal, Newborn and Child Survival Grant from the Bill & Melinda Gates Foundation. PMID- 27955772 TI - Tracking aid to reproductive, maternal, newborn, and child health. PMID- 27955773 TI - Campbell replication confirms little or no effect of community deworming. PMID- 27955774 TI - Charity begins at home in global health research funding. PMID- 27955775 TI - Elimination of sleeping sickness in Uganda could be jeopardised by conflict in South Sudan. PMID- 27955776 TI - Abstinence in HIV prevention: science and sophistry. PMID- 27955777 TI - Abstinence in HIV prevention: science and sophistry - Authors' reply. PMID- 27955778 TI - Screening of genital fluid for Ebola virus. PMID- 27955779 TI - Screening of genital fluid for Ebola virus - Authors' reply. PMID- 27955780 TI - Community-based screening and treatment for chronic hepatitis B in sub-Saharan Africa. PMID- 27955781 TI - Community-based screening and treatment for chronic hepatitis B in sub-Saharan Africa - Authors' reply. PMID- 27955782 TI - DeNIS collaboration: setting the future research agenda. PMID- 27955783 TI - Data pooling efforts in Africa and Latin America. PMID- 27955785 TI - Correction to Lancet Glob Health 2017; 5: e22-24. PMID- 27955784 TI - Triumph over adversity: Pakistan's successes against polio. PMID- 27955786 TI - Correction to Lancet Glob Health 2016; 4: e633-41. PMID- 27955787 TI - The benefits of mass deworming on health outcomes: new evidence synthesis, the debate persists. PMID- 27955788 TI - Mass deworming to improve developmental health and wellbeing of children in low income and middle-income countries: a systematic review and network meta analysis. AB - BACKGROUND: Soil-transmitted helminthiasis and schistosomiasis, considered among the neglected tropical diseases by WHO, affect more than a third of the world's population, with varying intensity of infection. We aimed to evaluate the effects of mass deworming for soil-transmitted helminths (with or without deworming for schistosomiasis or co-interventions) on growth, educational achievement, cognition, school attendance, quality of life, and adverse effects in children in endemic helminth areas. METHODS: We searched 11 databases up to Jan 14, 2016, websites and trial registers, contacted authors, and reviewed reference lists. We included studies published in any language of children aged 6 months to 16 years, with mass deworming for soil-transmitted helminths or schistosomiasis (alone or in combination with other interventions) for 4 months or longer, that reported the primary outcomes of interest. We included randomised and quasi-randomised trials, controlled before-after studies, interrupted time series, and quasi experimental studies. We screened in duplicate, then extracted data and appraised risk of bias in duplicate with a pre-tested form. We conducted random-effects meta-analysis and Bayesian network meta-analysis. FINDINGS: We included 52 studies of duration 5 years or less with 1 108 541 children, and four long-term studies 8-10 years after mass deworming programmes with more than 160 000 children. Overall risk of bias was moderate. Mass deworming for soil-transmitted helminths compared with controls led to little to no improvement in weight over a period of about 12 months (0.99 kg, 95% credible interval [CrI] -0.09 to 0.28; moderate certainty evidence) or height (0.07 cm, 95% CrI -0.10 to 0.24; moderate certainty evidence), little to no difference in proportion stunted (eight fewer per 1000 children, 95% CrI -48 to 32; high certainty evidence), cognition measured by short-term attention (-0.23 points on a 100 point scale, 95% CI -0.56 to 0.14; high certainty evidence), school attendance (1% higher, 95% CI -1 to 3; high certainty evidence), or mortality (one fewer per 1000 children, 95% CI -3 to 1; high certainty evidence). We found no data on quality of life and little evidence of adverse effects. Mass deworming for schistosomiasis might slightly increase weight (0.41 kg, 95% CrI -0.20 to 0.91) and has little to no effect on height (low certainty evidence) and cognition (moderate certainty evidence). Our analyses do not suggest indirect benefits for untreated children from being exposed to treated children in the community. We are uncertain about effects on long-term economic productivity (hours worked), cognition, literacy, and school enrolment owing to very low certainty evidence. Results were consistent across sensitivity and subgroup analyses by age, worm prevalence, baseline nutritional status, infection status, impact on worms, infection intensity, types of worms (ascaris, hookworm, or trichuris), risk of bias, cluster versus individual trials, compliance, and attrition. INTERPRETATION: Mass deworming for soil transmitted helminths with or without deworming for schistosomiasis had little effect. For schistosomiasis, mass deworming might be effective for weight but is probably ineffective for height, cognition, and attendance. Future research should assess which subset of children do benefit from mass deworming, if any, using individual participant data meta-analysis. FUNDING: Canadian Institutes of Health Research and WHO. PMID- 27955789 TI - Indirect effects of childhood pneumococcal conjugate vaccination on invasive pneumococcal disease: a systematic review and meta-analysis. AB - BACKGROUND: The full extent to which childhood pneumococcal conjugate vaccines (PCV) can indirectly reduce illness in unvaccinated populations is not known. We aimed to estimate the magnitude and timing of indirect effects of PCVs on invasive pneumococcal disease. METHODS: In this systematic review and meta analysis, we searched bibliographic databases for non-randomised quasi experimental or observational studies reporting invasive pneumococcal disease changes following PCV introduction in unvaccinated populations (studies published Sept 1, 2010, to Jan 6, 2016), updating the previous systematic review of the same topic (studies published Jan 1, 1994, to Sept 30, 2010). Two reviewers extracted summary data by consensus. We used a Bayesian mixed-effects model to account for between-study heterogeneity to estimate temporal indirect effects by pooling of invasive pneumococcal disease changes by serotype and serogroup. FINDINGS: Data were extracted from 70 studies included in the previous review and 172 additional studies, covering 27 high-income and seven middle-income countries. The predicted mean times to attaining a 90% reduction in invasive pneumococcal disease were 8.9 years (95% credible interval [CrI] 7.8-10.3) for grouped serotypes contained in the seven-valent PCV (PCV7), and 9.5 years (6.1 16.6) for the grouped six additional serotypes contained in the 13-valent PCV (PCV13) but not in PCV7. Disease due to grouped serotypes contained in the 23 valent pneumococcal polysaccharide vaccine (PPV23) decreased at similar rates per year in adults aged 19-64 years (relative risk [RR] 0.85, 95% CrI 0.75-0.95) and 65 years and older (0.87, 0.84-0.90). However, we noted no changes in either group in invasive pneumococcal disease caused by the additional 11 serotypes covered by PPV23 but not PCV13. INTERPRETATION: Population childhood PCV programmes will lead, on average, to substantial protection across the whole population within a decade. This large indirect protection should be considered when assessing vaccination of older age groups. FUNDING: Policy Research Programme of the Department of Health, England. PMID- 27955790 TI - The indirect effect of pneumococcal conjugate vaccine. PMID- 27955792 TI - Renal failure deaths and their risk factors in India 2001-13: nationally representative estimates from the Million Death Study. AB - BACKGROUND: Renal failure represents a growing but mostly undocumented cause of premature mortality in low-income and middle-income countries. We investigated changes in adult renal failure mortality and its key risk factors in India using the nationally representative Million Death Study. METHODS: In this cross sectional analysis of population-based data, two trained physicians independently assigned underlying causes to 150 018 deaths at ages 15-69 years from a nationally-representative mortality survey in India for 2001-03 and 2010-13, using the International Classification of Diseases, 10th version (ICD-10). We applied the age-specific proportion of renal failure deaths for the 2010-13 period to the 2015 UN estimates of total deaths in India and calculated age standardised death rates for renal failure by rural or urban residence, state, and age group. We used proportional mortality of renal deaths (cases) to injuries (controls) to calculate the odds of renal death in the presence of different comorbidities and stratified risks by decade of birth. FINDINGS: In 2001-03, 2.1% of total deaths among 15-69 year olds were from renal failure (1266 [2.2%] of 58 871; unweighted). By 2010-13, the proportion of deaths from renal failure had risen to 2.9% (2943 [3.2%] of 91 147; unweighted) of total deaths and corresponding to 136 000 renal failure deaths (range 108 000-150 000) of 4 688 000 total deaths nationally in 2015. Age-standardised renal death rates were highest in the southern and eastern states, particularly among adults aged 45-69 years in 2010-13. Diabetes, hypertension, and cardiovascular disease were all significantly associated with increased renal failure deaths, with diabetes the strongest predictor-odds ratio (OR) vs control 9.2 (95% CI 6.7-12.7) in 2001-03, rising to 15.1 (12.6-18.1) in 2010-13. In the 2010-13 study population, the diabetes to non-diabetes OR was twice as large in adults born in the 1970s (25.5, 95% CI 17.6-37.1) as in those individuals born during or before the 1950s (11.7, 9.1-14.9). INTERPRETATION: Renal failure is a growing cause of premature death in India. Poorly treated diabetes is the most probable reason for this increase. Strategies aimed at diabetes prevention, and early detection and treatment are urgently needed in India, as well as greater access to renal replacement therapy. FUNDING: US National Institutes of Health, International Development Research Centre, Centre for Global Health Research, University of Toronto. PMID- 27955791 TI - Persistence and clearance of Ebola virus RNA from seminal fluid of Ebola virus disease survivors: a longitudinal analysis and modelling study. AB - BACKGROUND: By January, 2016, all known transmission chains of the Ebola virus disease (EVD) outbreak in west Africa had been stopped. However, there is concern about persistence of Ebola virus in the reproductive tract of men who have survived EVD. We aimed to use biostatistical modelling to describe the dynamics of Ebola virus RNA load in seminal fluid, including clearance parameters. METHODS: In this longitudinal study, we recruited men who had been discharged from three Ebola treatment units in Guinea between January and July, 2015. Participants provided samples of seminal fluid at follow-up every 3-6 weeks, which we tested for Ebola virus RNA using quantitative real-time RT-PCR. Representative specimens from eight participants were then inoculated into immunodeficient mice to test for infectivity. We used a linear mixed-effect model to analyse the dynamics of virus persistence in seminal fluid over time. FINDINGS: We enrolled 26 participants and tested 130 seminal fluid specimens; median follow up was 197 days (IQR 187-209 days) after enrolment, which corresponded to 255 days (228-287) after disease onset. Ebola virus RNA was detected in 86 semen specimens from 19 (73%) participants. Median duration of Ebola virus RNA detection was 158 days after onset (73-181; maximum 407 days at end of follow-up). Mathematical modelling of the quantitative time-series data showed a mean clearance rate of Ebola virus RNA from seminal fluid of -0.58 log units per month, although the clearance kinetic varied greatly between participants. Using our biostatistical model, we predict that 50% and 90% of male survivors clear Ebola virus RNA from seminal fluid at 115 days (90% prediction interval 72-160) and 294 days (212-399) after disease onset, respectively. We also predicted that the number of men positive for Ebola virus RNA in affected countries would decrease from about 50 in January 2016, to fewer than 1 person by July, 2016. Infectious virus was detected in 15 of 26 (58%) specimens tested in mice. INTERPRETATION: Time to clearance of Ebola virus RNA from seminal fluid varies greatly between individuals and could be more than 13 months. Our predictions will assist in decision-making about surveillance and preventive measures in EVD outbreaks. FUNDING: This study was funded by European Union's Horizon 2020 research and innovation programme, Directorate-General for International Cooperation and Development of the European Commission, Institut national de la sante et de la recherche medicale (INSERM), German Research Foundation (DFG), and Innovative Medicines Initiative 2 Joint Undertaking. PMID- 27955793 TI - A cross-sectional study of cardiorespiratory fitness and gallbladder disease. AB - PURPOSE: To determine the association of different levels of cardiorespiratory fitness (CRF), an objective indicator of habitual physical activity, with gallbladder disease. METHODS: In the Aerobics Center Longitudinal Study (ACLS) database, 41,528 men and 13,206 women aged 20-90 years, with body mass index of 18.5 or more and without history of cardiovascular disease and cancer, received a preventive examination at the Cooper Clinic in Dallas, Texas, between 1970 and 2003. CRF was quantified as maximal metabolic equivalents and classified as low, moderate, and high based on traditional ACLS cut points. Gallbladder disease was defined as physician-diagnosed gallbladder disease. RESULTS: When compared with low CRF, adjusted odds ratios and 95% confidence intervals for gallbladder disease for those with moderate and high CRF were 0.74 (0.55-0.99) and 0.59 (0.42 0.82), respectively when adjusted for all the potential confounders. Each one metabolic equivalent increment of CRF was associated with 10% lower odds of gallbladder disease in all participants (P for trend <.001), 13% lower in women (P for trend <.001), and 8% lower in men (P for trend = .08). The association was consistent across age, history of diabetes mellitus, and physical inactivity subgroups. CONCLUSIONS: CRF is inversely related to the prevalence of gallbladder disease among relatively healthy men and women in the ACLS cohort. PMID- 27955794 TI - Identifying emerging reproductive vulnerability: an approach to decompose differences in total fertility. AB - PURPOSE: We introduce a method to partition the difference in total fertility between two groups. METHODS: We computed the total fertility rate for Francophones and Anglophones of Quebec, Canada, between 1989-1993 and 2004-2008. We partitioned the difference in excess fertility for one group relative to the other into the number of children contributed by maternal age, origin, material deprivation, education, and offspring birth order. We calculated the change in total fertility over time and the factors that contributed. RESULTS: The total fertility rate was higher by 0.18 children for Francophones in 1989-1993, but the gap reversed in 2004-2008, with total fertility higher for Anglophones by 0.12 children. Francophones had higher fertility in 1989-1993 due mainly to women who were Canadian born, aged 15-29 years, without secondary diploma, or living in socioeconomic deprivation. The reversal in 2004-2008 was caused by a reduction in fertility for Francophones aged 15-29 years and an increase in the contribution of Anglophones who were foreign born, aged 30-49 years or socioeconomically disadvantaged. CONCLUSIONS: Through decomposition of differences in total fertility, we identified populations with emerging reproductive vulnerability in a large Canadian province. Socioeconomically disadvantaged Anglophones in Quebec have increasing fertility, a potential sign of increasing reproductive risk. PMID- 27955795 TI - Akinetic mutism revealing an ischemic stroke. AB - We describe a 44-year-old man who developed akinetic mutism following a cerebrovascular accident involving his left middle cerebral artery. We discuss this rare condition and its unusual clinical picture. PMID- 27955796 TI - Shock index, modified shock index, and age shock index for prediction of mortality in emergency severity index level 3: Methodological issues. PMID- 27955797 TI - Acute esophageal injury and strictures following corrosive ingestions in a 27year cohort. AB - PURPOSE: We aimed to determine the incidence of esophageal strictures in corrosive ingestions and potential predictors of severe injury. BASIC PROCEDURES: This was a retrospective cohort study of corrosive ingestions from a toxicology unit (1987-2013) with telephone follow-up at least 1 y post-ingestion. Clinical data and investigations were obtained from a toxicology admission database. The primary outcome was esophageal stricture. Other outcomes included in-hospital mortality, endoscopy grade and early complications. MAIN FINDINGS: There were 89 corrosive ingestions; median age, 31 y [1-87 y; 46 females], including 13 strong alkalis (pH>12), 8 strong acids (pH<2), 29 domestic bleaches, 30 other domestic products, 6 non-domestic products and three unknown. Three patients died in hospital within 24 h (phenol, sodium azide, HCl). Two developed strictures (both strong alkalis): one had complete esophageal destruction; another developed a stricture after 25 d (inpatient grade 2A endoscopy). 24 patients were asymptomatic and discharged without complication. 65 patients were symptomatic (4 catastrophic injuries). 61 reported sore mouth/throat (50), abdominal pain (21), chest pain (17), dysphagia (13); 28 had an abnormal oropharyngeal examination. 25/61 symptomatic patients underwent inpatient endoscopy: normal (3), grade 1 (5), grade 2 (15) and grade 3 (2). Of 88 patients, 12 died (3 inpatients, 9 unrelated), 28 couldn't be contacted and 48 were contacted after 1.7-24 y, including two with strictures. Five couldn't be interviewed (normal endoscopy (1), no dysphagia (3) and stroke (1). 4/41 interviewed reported dysphagia but no objective evidence of stricture. PRINCIPAL CONCLUSIONS: All inpatient deaths and severe complications were apparent within hours of ingestion, and occurred with highly corrosive substances. One delayed stricture occurred, not predicted by inpatient endoscopy. PMID- 27955798 TI - Automatic detection and classification of regions of FDG uptake in whole-body PET CT lymphoma studies. AB - [18F]-Fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) scans of lymphoma patients usually show disease involvement as foci of increased radiotracer uptake. Existing methods for detecting abnormalities, model the characteristics of these foci; this is challenging due to the inconsistent shape and localization information about the lesions. Thresholding the degree of FDG uptake is the standard method to separate different sites of involvement. But may fragment sites into smaller regions, and may also incorrectly identify sites of normal physiological FDG uptake and normal FDG excretion (sFEPU) such as the kidneys, bladder, brain and heart. These sFEPU can obscure sites of abnormal uptake, which can make image interpretation problematic. Identifying sFEPU is therefore important for improving the sensitivity of lesion detection and image interpretation. Existing methods to identify sFEPU are inaccurate because they fail to account for the low inter-class differences between sFEPU fragments and their inconsistent localization information. In this study, we address this issue by using a multi-scale superpixel-based encoding (MSE) to group the individual sFEPU fragments into larger regions, thereby, enabling the extraction of highly discriminative image features via domain transferred convolutional neural networks. We then classify there regions into one of the sFEPU classes using a class-driven feature selection and classification model (CFSC) method that avoids overfitting to the most frequently occurring classes. Our experiments on 40 whole body lymphoma PET-CT studies show that our method achieved better accuracy (an average F-score of 91.73%) compared to existing methods in the classification of sFEPU. PMID- 27955799 TI - Closed treatment of unilateral mandibular condyle fractures in adults: a systematic review. AB - Of all mandibular fractures, 25-35% are condylar. Many studies have focused on whether to treat such fractures via open or closed modalities. A uniform protocol for closed treatment is lacking, but such a protocol could ensure good clinical practice. The aims of this systematic review were to provide an overview of the published studies exclusively pertaining to closed treatment and to summarize the existing modalities for closed treatment and their clinical outcomes. Sixteen studies were selected for detailed analysis. The treatments given were highly variable, ranging from doing nothing to applying maxillomandibular fixation with stainless steel wires. The results of the different studies and the treatment modalities used were difficult to interpret; however no clear differences in the outcome measures were seen between the treatment modalities applied. Complications encountered after closed treatment included malocclusion, limited mouth opening, reduced range of motion, and persistent pain. Due to the heterogeneity between groups, high loss-to-follow-up, poor descriptions of the treatments given, and variability in outcome measurement methods, no clear associations between adverse outcomes and the treatments applied could be determined. This review suggests that due to the high level of methodological variability in the relevant studies published to date, there are currently no uniform standards for the closed treatment of condylar fractures that can be expected to yield good clinical results. The establishment of such standards could potentially improve treatment outcomes. PMID- 27955800 TI - Can repetitive transcranial magnetic stimulation improve neurocognition in schizophrenia when combined with cognitive remediation? PMID- 27955801 TI - Trigeminal nerve stimulation (TNS) for treating negative symptoms in schizophrenia: A case study. PMID- 27955802 TI - [Transient epileptic amnesia]. AB - Transient epileptic amnesia (TEA) is a sub-type of mesial temporal lobe epilepsy, with amnesic seizures. TEA is characterized by recurrent episodes of amnesia. Diagnostic criteria are available for TEA, and these memory disturbances should not be misdiagnosed with transient global amnesia. The neuropsychological evaluation is normal, however, autobiographical memory impairment is present in 70% of the cases and accelerated long term forgetting in 44%. When a patient complains of memory disturbances, especially autobiographical memory, TEA must be considered especially if there was an amnesic episode and symptoms that suggest temporal epilepsia. Video electroencephalography monitoring of sleep is a precious diagnostic tool, as epileptiform activities are found during sleep in 83% cases. TEA is pharmaco-sensitive, with full treatment response in 73 to 96% of the cases. PMID- 27955803 TI - Oral acute toxicity study as well as tissues oxidative stress and histopathological disorders in edible camphor administered rats. AB - In the South-western part of Nigeria, edible camphor (EC) infusions are used to treat pile, back pain, and erectile dysfunction, especially in preparation for sexual intercourse. We therefore carried out oral acute toxicity study, and then investigated the effects of various doses of EC on the activities of lactate dehydrogenase (LDH), catalase (CAT), and superoxide dismutase (SOD), as well as reduced glutathione (GSH) and malondialdehyde (MDA) levels in wistar rats. Oral LD50 of EC was estimated to be 9487mg/kg body weight. Based on this, thirty animals were divided into six groups of five rats each, and were orally administered various doses of EC (1, 2, 4, and 6g/kg body weight) for seven days. Comparing all results with control, EC significantly increased serum LDH activity (4 and 6g/kg), liver (6g/kg) and kidney (4 and 6g/kg) MDA levels, as well testis GSH levels (1g/kg). CAT activities were significantly decreased in liver, kidney, and testis, and also lung GSH level by all the tested doses. For SOD, activities were significantly increased in liver and lung, but significantly decreased in kidney (2, 4, and 6g/kg). Various pathological disorders were also seen following the various doses of EC administered, especially in liver, kidney and lung. Therefore, from our findings, it is evident that incessant, misuse or overconsumption of EC could lead to oxidative tissue damage in rats. PMID- 27955804 TI - IMPACT FACTOR 1,35Once again; what should and could we do about it? PMID- 27955805 TI - Arthroscopic Treatment of Snapping Scapula Syndrome: Outcomes at Minimum of 2 Years. AB - PURPOSE: To investigate clinical outcomes after primary and revision arthroscopic treatment for snapping scapula syndrome (SSS) and identify predictive factors associated with outcomes. METHODS: Patients who underwent arthroscopic treatment for SSS between October 2005 and December 2013 were identified in a prospectively collected database. The inclusion criteria were patients with a diagnosis of symptomatic SSS, in whom extensive nonoperative modalities failed, who underwent arthroscopic surgery for SSS, and who had undergone surgery a minimum of 2 years earlier. Postoperative clinical outcomes were assessed with the American Shoulder and Elbow Surgeons score; short version of the Disabilities of the Arm, Shoulder and Hand questionnaire; and general health Short Form 12 (SF-12) scores, including both physical component summary and mental component summary. Patient satisfaction was recorded on a 10-point visual analog scale. Scapular bony morphology was determined on preoperative magnetic resonance imaging. RESULTS: Ninety-two scapulae underwent arthroscopic treatment for SSS. There were 74 scapulae that met the inclusion criteria, including having undergone surgery a minimum of 2 years earlier. An outcome questionnaire was completed for 60 of 74 (81%). The mean age was 33 years (range, 12-65 years), and the mean duration of symptoms before surgery was 4 years (range, 90 days to 20.4 years). The mean follow-up period was 3.4 years (range, 2-7 years). Eight scapulae failed initial surgical management (10.9%) because of recurrent pain and underwent revision surgery at a mean of 309 days (range, 120-917 days). After surgery, there was a significant improvement in all outcome scores, including SF-12 physical component summary score, from 39.2 to 45.4 (P = .002); SF-12 mental component summary score, from 45.0 to 49.6 (P = .023); American Shoulder and Elbow Surgeons score, from 52.6 to 75.8 (P < .001); and score on the short version of the Disabilities of the Arm, Shoulder and Hand questionnaire, from 40.2 to 24.2 (P = .001). The median patient satisfaction rating was 7 of 10. Greater age, lower preoperative psychological score, and longer duration of symptoms before surgery correlated with lower postoperative outcome scores. CONCLUSIONS: Arthroscopic surgery is an effective treatment for SSS in both primary and revision cases, showing significant improvements in all postoperative outcome scores at a mean of 3.4 years. Lower preoperative mental status score, longer duration of symptoms, and greater age were associated with poorer outcomes. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 27955807 TI - Efficacy and safety of the use of platelet-rich plasma to manage venous ulcers. AB - OBJECTIVES: The aim of this study was to analyse the efficacy and safety of using platelet rich in growth factor (PRGF) as a local treatment for venous ulcers. METHODS: In a clinical trial 102 venous ulcers (58 patients) were randomly assigned to the study group (application of PRGF) or the control group (standard cure with saline). For both groups the healed area was calculated before and after the follow up period (twenty-four weeks). The Kundin method was used to calculate the healed area (Area = Length * Width * 0.785). Pain was measured at the start and end of treatment as a secondary variable for each group by record obtained by means of self-evaluation visual analogue scale. RESULTS: The average percentage healed area in the platelet rich plasma group was 67.7 +/- 41.54 compared to 11.17 +/- 24.4 in the control group (P = 0.001). Similarly, in the experimental group a significant reduction in pain occurred on the scale (P = 0.001). No adverse effects were observed in either of the two treatment groups. CONCLUSIONS: The study results reveal that application of plasma rich in platelets is an effective and safe method to speed up healing and reduce pain in venous ulcers. PMID- 27955806 TI - Modelling of tetracycline resistance gene transfer by commensal Escherichia coli food isolates that survived in gastric fluid conditions. AB - Antimicrobial resistance (AR) is a major public health concern and a food safety issue worldwide. Escherichia coli strains, indicators of antibiotic resistance, are a source of horizontal gene transfer to other bacteria in the human intestinal system. A probabilistic exposure model was used to estimate the transfer of the AR gene tet(A). The acid resistance and kinetic behaviour of E. coli was analysed as a function of pH to describe the inactivation of E. coli in simulated gastric fluid (SGF), the major host barrier against exogenous micro organisms. The kinetic parameters of microbial inactivation in SGF were estimated using GInaFiT, and log-linear + tail and Weibull models were found to be suitable for commensal and enterohaemorrhagic E. coli (EHEC), respectively. A probabilistic exposure model was developed to estimate E. coli survival in gastric pH conditions as well as gene transfer from resistant to susceptible cells in humans. E. coli-contaminated retail foods for consumption without further cooking and gastric pH data in South Korea were considered as an example. The model predicts that 22-33% of commensal E. coli can survive under gastric pH conditions of Koreans. The estimated total mean tet(A) transfer level by commensal E. coli was 1.68 * 10-4-8.15 * 10-4 log CFU/mL/h. The inactivation kinetic parameters of E. coli in SGF and the quantitative exposure model can provide useful information regarding risk management options to control the spread of AR. PMID- 27955808 TI - Incidence of Hospitalized Stroke in the Czech Republic: The National Registry of Hospitalized Patients. AB - BACKGROUND: Contemporary stroke incidence data are not available in some countries and regions, including in Eastern Europe. Based on previous validation of the accuracy of the National Registry of Hospitalized Patients (NRHOSP), we report the incidence of hospitalized stroke in the Czech Republic (CR) using the NRHOSP. METHODS: The results of the prior validation study assessing the accuracy of coding of stroke diagnoses in the NRHOSP were applied, and we calculated (1) the overall incidence of hospitalized stroke and (2) the incidence rates of hospitalized stroke for the three main stroke types: cerebral infarction (International Classification of Diseases Tenth Revision, CI I63), subarachnoid hemorrhage (SAH I60), and intracerebral hemorrhage (ICH I61). We calculated the average annual age- and sex-standardized incidence. RESULTS: The overall incidence of hospitalized stroke was 241 out of 100,000 individuals. The incidence of hospitalized stroke for the main stroke types was 8.2 cases in SAH, 29.5 in ICH, and 211 in CI per 100,000 individuals. The standardized annual stroke incidence adjusted to the 2000 World Health Organization population for overall stroke incidence of hospitalized stroke was 131 per 100,000 individuals. Standardized stroke incidence for stroke subtypes was 5.7 cases in SAH, 16.7 in ICH, and 113 in CI per 100,000 individuals. CONCLUSIONS: These studies provide an initial assessment of the burden of stroke in this part of the world. The estimates of hospitalized stroke in the CR and Eastern Europe suggest that ICH is about three times more common than SAH, and hemorrhagic stroke makes up about 18% of strokes. PMID- 27955810 TI - Synthesis of 2-methyl-1,4-naphthoquinones with higher gamma-glutamyl carboxylase activity than MK-4 both in vitro and in vivo. AB - Vitamin K is the collective term for compounds that share a 2-methyl-1,4 naphthoquinone ring, but differ in the side-chain at the 3-position. We synthesized novel 2-methyl-1,4-naphthoquinone derivatives with different side chain length at the 3-position. Derivatives with C-14 and C-16 tails showed the highest in vitro bioactivity resulting in 2.5 and 2-fold higher carboxylated osteocalcin synthesis in MG63 cells than menaquinone-4 (MK-4, form of vitamin K2). Longer side chain lengths resulted in lower bioactivity. The in vivo vitamin K activity of the C-14 tail derivative was further tested in WKY rats receiving a vitamin K-deficient diet that resulted in a 40% decrease of prothrombin activity. The C-14 tail derivative was able to counteract the effects on vitamin K deficiency induced by the diet and resulted in the complete restoration of prothrombin activity. Compared to naturally occurring forms of vitamin K, synthetic vitamin K derivatives may have higher bioactivity and different pharmacological characteristics that are more favorable for use as supplements or in clinical settings. PMID- 27955809 TI - Balance Confidence Is Related to Features of Balance and Gait in Individuals with Chronic Stroke. AB - BACKGROUND: Reduced balance confidence is associated with impairments in features of balance and gait in individuals with subacute stroke. However, an understanding of these relationships in individuals at the chronic stage of stroke recovery is lacking. This study aimed to quantify the relationships between balance confidence and specific features of balance and gait in individuals with chronic stroke. METHODS: Participants completed a balance confidence questionnaire and clinical balance assessment (quiet standing, walking, and reactive stepping) at 6 months postdischarge from inpatient stroke rehabilitation. Regression analyses were performed using balance confidence as a predictor variable, and quiet standing, walking, and reactive stepping outcome measures as the dependent variables. RESULTS: Walking velocity was positively correlated with balance confidence, whereas mediolateral center of pressure excursion (quiet standing) and double support time, step width variability, and step time variability (walking) were negatively correlated with balance confidence. CONCLUSIONS: This study provides insight into the relationships between balance confidence and balance and gait measures in individuals with chronic stroke, suggesting that individuals with low balance confidence exhibited impaired control of quiet standing as well as walking characteristics associated with cautious gait strategies. Future work should identify the direction of these relationships to inform community-based stroke rehabilitation programs for individuals with chronic stroke, and determine the potential utility of incorporating interventions to improve balance confidence into these programs. PMID- 27955812 TI - In response to the article published by Fukaya et al., entitled: "Relationships between the center of pressure and the movements of the ankle and knee joints during the stance phase in patients with severe medial knee osteoarthritis". PMID- 27955811 TI - In vivo and in silico anti-inflammatory mechanism of action of the semisynthetic (-)-cubebin derivatives (-)-hinokinin and (-)-O-benzylcubebin. AB - (-)-Cubebin (CUB), isolated from seeds of Piper cubeba, was used as starting material to obtain the derivatives (-)-hinokinin (HK) and (-)-O-benzyl cubebin (OBZ). Using paw edema as the experimental model and different chemical mediators (prostaglandin and dextran), it was observed that both derivatives were active in comparison with both negative (5% Tween(r) 80 in saline) and positive (indomethacin) controls. The highest reduction in the prostaglandin-induced edema was achieved by OBZ (66.0%), while HK caused a 59.2% reduction. Nonetheless, the dextran-induced paw edema was not significantly reduced by either of the derivatives (HK or OBZ), which inhibited edema formation by 18.3% and 3.5%, respectively, in contrast with the positive control, cyproheptadine, which reduced the edema by 56.0%. The docking analysis showed that OBZ presented the most stable ligand-receptor (COX-2 - cyclooxygenase-2) interaction in comparison with CUB and HK. PMID- 27955813 TI - Gap formation following primary repair of the anterior cruciate ligament: A biomechanical evaluation. AB - BACKGROUND: Historically, inconsistent and unpredictable results of open primary anterior cruciate ligament (ACL) repair were reported. Recently, however, good results of arthroscopic primary ACL repair of proximal tears have been reported. Purpose of this study was to assess the direct postoperative gap formation and maximum failure load following simulated knee motion after primary ACL repair. METHODS: Six matched-paired human cadaveric knees (mean age: 52years, range: 48 to 56years) were used. After primary proximal ACL repair with either suture button fixation or suture anchor fixation, knees were cycled five, 50 and 100 times with a simulated active quadriceps force. Gap formation between the femoral wall and ligament was measured using a digital caliper and maximum failure load was tested. RESULTS: Gap formation after five, 50 and 100cycles of the knee were 0.30mm (+/-0.23), 0.75mm (+/-0.55) and 0.97mm (+/-0.70), respectively, with no significant differences between both fixation techniques. The overall maximum failure load was 243N (+/-143) with no difference between both techniques. Most common failure mode was slipping of suture from the fixation. CONCLUSION: Following proximal ACL repair, gap formation of approximately one millimeter was measured after repetitious knee cycling with mean maximum failure load of 243N. These findings are likely to be sufficient for careful early active range of motion (ROM) when extrapolating from other available studies. Future studies with second-look arthroscopy are necessary to assess the gap formation and healing in patients treated with primary repair. PMID- 27955814 TI - Upper Limb Claudication From a Rare Congenital Vascular Anomaly. PMID- 27955815 TI - Salmonella Meningitis Associated with Monocyte Infiltration in Mice. AB - In the current study, we examined the ability of Salmonella enterica serovar Typhimurium to infect the central nervous system and cause meningitis following the natural route of infection in mice. C57BL/6J mice are extremely susceptible to systemic infection by Salmonella Typhimurium because of loss-of-function mutations in Nramp1 (SLC11A1), a phagosomal membrane protein that controls iron export from vacuoles and inhibits Salmonella growth in macrophages. Therefore, we assessed the ability of Salmonella to disseminate to the central nervous system (CNS) after oral infection in C57BL/6J mice expressing either wild-type (resistant) or mutant (susceptible) alleles of Nramp1. In both strains, oral infection resulted in focal meningitis and ventriculitis with recruitment of inflammatory monocytes to the CNS. In susceptible Nramp1-/- mice, there was a direct correlation between bacteremia and the number of bacteria in the brain, which was not observed in resistant Nramp1+/+ mice. A small percentage of Nramp1+/+ mice developed severe ataxia, which was associated with high bacterial loads in the CNS as well as clear histopathology of necrotizing vasculitis and hemorrhage in the brain. Thus, Nramp1 is not essential for Salmonella entry into the CNS or neuroinflammation, but may influence the mechanisms of CNS entry as well as the severity of meningitis. PMID- 27955817 TI - Corrigendum to "Cathepsin L is involved in X-ray-induced invasion and migration of human glioma U251 cells" (Cell. Signal. 29 (2017) 181-191). PMID- 27955816 TI - [Reappraisal role of locoregional radiation therapy in metastatic cancers]. AB - Recent innovations in oncology area helped to improve the prognosis of certain cancers including metastatic ones with a decrease in mortality. Recommendations describe the treatment of metastatic cancer as systemic therapy or complementary care and the role of locoregional treatment in the treatment plan only occurs in a palliative context. Currently, in the clinical practice, out of "the evidence based medicine", an early locoregional therapy (surgery or radiation therapy) can be proposed in several cases of metastatic cancers. The aim of the present review is to describe the role of the primary tumor radiation therapy in metastatic disease. In metastatic breast, prostate, cervix, rectal or nasopharyngeal cancers, locoregional treatment including radiation therapy can, in some cases, be discussed and decided in MDT. Ongoing clinical trials in these locations should soon precise the benefit of this locoregional treatment. It will also be important to define the specific criteria in order to select patients who could benefit from this treatment. PMID- 27955818 TI - Adaptive exponential synchronization of complex-valued Cohen-Grossberg neural networks with known and unknown parameters. AB - The complex-valued Cohen-Grossberg neural network is a special kind of complex valued neural network. In this paper, the synchronization problem of a class of complex-valued Cohen-Grossberg neural networks with known and unknown parameters is investigated. By using Lyapunov functionals and the adaptive control method based on parameter identification, some adaptive feedback schemes are proposed to achieve synchronization exponentially between the drive and response systems. The results obtained in this paper have extended and improved some previous works on adaptive synchronization of Cohen-Grossberg neural networks. Finally, two numerical examples are given to demonstrate the effectiveness of the theoretical results. PMID- 27955819 TI - Decentralized event-triggered synchronization of uncertain Markovian jumping neutral-type neural networks with mixed delays. AB - In this study, we present an approach for the decentralized event-triggered synchronization of Markovian jumping neutral-type neural networks with mixed delays. We present a method for designing decentralized event-triggered synchronization, which only utilizes locally available information, in order to determine the time instants for transmission from sensors to a central controller. By applying a novel Lyapunov-Krasovskii functional, as well as using the reciprocal convex combination method and some inequality techniques such as Jensen's inequality, we obtain several sufficient conditions in terms of a set of linear matrix inequalities (LMIs) under which the delayed neural networks are stochastically stable in terms of the error systems. Finally, we conclude that the drive systems synchronize stochastically with the response systems. We show that the proposed stability criteria can be verified easily using the numerically efficient Matlab LMI toolbox. The effectiveness and feasibility of the results obtained are verified by numerical examples. PMID- 27955820 TI - A Very Late Life-Threatening Complication After Percutaneous Closure of an Atrial Septal Defect. AB - Percutaneous closure is widely recognized as the first therapeutic option in the majority of cases of secundum atrial septal defect (ASD) because of its high effectiveness and safety. Nonetheless, with the progressive increase of implanted devices and follow-up duration, several adverse events, some of them potentially life-threatening, have been reported. We report the case of an asymptomatic aortic erosion that occurred 13 years after the procedure. The main feature of our case is the very late occurrence of a life-threatening asymptomatic complication of ASD percutaneous closure, which should prompt lifelong surveillance in this population. PMID- 27955821 TI - Intravenous sodium thiosulfate for treating tumoral calcinosis associated with systemic disorders: Report of four cases. AB - Intravenous sodium thiosulfate (ivSTS) is a promising new therapeutic option for calciphylaxis related to end-stage renal disease. However, its effect on tumoral calcinosis (TC) complicating autoimmune connective-tissue diseases has been scarcely described. We report here 4 cases (3 adults and 1 child) of TC treated with ivSTS. TC was secondary to CREST syndrome, dermatomyositis (1 adult and 1 child) and systemic erythematous lupus and involved multiple sites in all cases. In all 4 patients, TC was responsible for joint pain, reduced mobility, inflammatory flares and skin fistulations. One patient experienced difficulty sitting due to the pain induced by calcified lesions on the buttock; another patient had major disability, moved only with wheelchair and was under opioid treatment for pain. For all patients, treatment with several medications before STS was unsuccessful. The 3 adults received at least 6 cycles of ivSTS (20g/d, 5 days/month) and the child received a daily infusion of 17g STS during 1 month then a 9-g/d infusion during 3 months. Two adults and the child showed clinical improvement with STS treatment and the third adult felt disappointed and stopped STS treatment after 6 months. The child also stopped STS after 6 months due to vomiting. In one patient, an intensive regimen of ivSTS (20g every 2 days) controlled recurrent flares and fistulations. Unfortunately, TC remained unchanged. Further studies are needed to decipher how STS modulates ectopic calcification, the optimal regimen and posology. PMID- 27955823 TI - Corrigendum to "Exposure reduces negative bias in self-rated performance in public speaking fearful participants" [J. Behav. Ther. Exp. Psychiatry 54 (2017) 101-107]. PMID- 27955822 TI - Febuxostat-associated eosinophilic polymyositis in marginal zone lymphoma. AB - Febuxostat is an orally administered selective inhibitor of xanthine oxidase approved for the treatment of gout and prevention of tumor lysis syndrome. It is a relatively safe medication. Hypersensitivity reactions associated with the use of febuxostat are quite rare with only one reported case of DRESS syndrome. Recently, two case reports of rhabdomyolysis following the initiation of febuxostat were published. We hereby present the first case of rhabdomyolysis with hypereosinophilia following the administration of febuxostat to a 50-year old patient newly diagnosed with marginal zone lymphoma. Three weeks after the initiation of febuxostat for tumor lysis syndrome prophylaxis, the patient presented with generalized weakness, diffuse myalgia and low-grade fever. Initial studies showed creatinine kinase level of 4471, hypereosinophilia of 1900/mm3, and LDH of 2691. All infectious and autoimmune diseases were ruled out. TSH level was normal. Muscle biopsy showed myonecrosis in addition to an eosinophilic inflammatory infiltrate in the endomysium and perimysium. Discontinuation of febuxostat led to prompt symptom resolution and normalization of blood tests eight days later. PMID- 27955824 TI - Assessment of trochanteric osteotomy fragment union after acetabular fracture surgery. AB - BACKGROUND: Trochanteric osteotomies are performed in conjunction with standard approaches to improve surgical exposure during open reduction and internal fixation (ORIF) of acetabular fractures. The literature on total hip arthroplasty reports nonunion rates as high as 30% associated with trochanteric osteotomies; however, few data exist regarding the outcomes of trochanteric osteotomies for acetabular fracture surgery. Our hypotheses were 1) patients receiving trochanteric osteotomies during ORIF of acetabular fractures have a low rate of nonunion of the osteotomy fragment, and 2) hip abduction precautions are not necessary with digastric type osteotomies. PATIENTS AND METHODS: A retrospective review was conducted to identify patients with acetabular fractures between July 2002 and June 2010 (n=734 fractures) who required trochanteric osteotomies (n=64, 9% of fractures). Forty-seven met inclusion criteria of adequate follow-up (>56days). No excluded patient experienced a complication. Fractures were classified using the Letournel-Judet classification system. RESULTS: Only seven (20%) of 35 patients who received digastric osteotomies had hip abduction precautions applied during the postoperative period. All study patients were shown to have radiographic union at the trochanteric osteotomy site (100% union rate, n=47). Hip abduction precautions intended to protect the osteotomy site and reduce the risk of nonunion and fixation failure were infrequently applied to patients with digastric osteotomies (20%) in this cohort. Multiple protective factors against nonunion were present in this study population compared with previous arthroplasty studies from other institutions. CONCLUSIONS: Trochanteric osteotomies are not associated with a significant nonunion rate, and digastric osteotomies might be safely managed without hip abduction precautions. PMID- 27955825 TI - Possession of weapon and school violence among adolescents and their association with history of traumatic brain injury, substance use and mental health issues. AB - PURPOSE: Assessment of the association between illegal possession of weapon and assault on school property among adolescents with and without a history of traumatic brain injury (TBI) while assessing risk factors for these outcomes. METHODS: Data were derived from the Centre for Addiction and Mental Health's 2013 Ontario Student Drug Use and Health Survey completed by students in grades 7-12 (ages 11-20). RESULTS: In this sample of 5478 adolescents, 6.1% (95% CI: 5.0, 7.4) reported carrying a weapon (e.g., gun or knife) on school property, 10.8% (95% CI: 9.5, 12.3) were engaged in a physical fight and 6.4% (95% CI: 5.4, 7.6) reported having beat up or hurt someone on purpose at school, during last year. Youth who reported carrying a weapon, who were engaged in a physical fight and those who assaulted peers on school property during last year had statistically significantly higher odds of reporting a history of TBIs, being male, in first years of high-school, scored positive for elevated psychological distress, and were current regular alcohol (weapon possession only) and cannabis users. CONCLUSION: Previously it was thought that alcohol and drugs were the main contributors to school violence. Here we show that history of TBIs is yet another significant predictor of violence at school among adolescents. The results suggest that school vigilance and combined violence and TBI prevention, treatment and rehabilitation programs in this population are warranted. PMID- 27955826 TI - Can we discontinue disease-modifying treatments in multiple sclerosis patients? Yes. PMID- 27955827 TI - Hydroalcoholic extract of Brazilian red propolis exerts protective effects on acetic acid-induced ulcerative colitis in a rodent model. AB - Ulcerative colitis (UC) is a common intestinal inflammatory disease with an etiology that is not well understood. Although the anti-inflammatory and anti oxidant effects of the hydroalcoholic extract of Brazilian red propolis (HERP) have been reported in various experimental models, its protective effect in models of UC have not been evaluated. The purpose of this study was to investigate the chemopreventive effect of hydroalcoholic extract of Brazilian red propolis (HERP) in acetic acid-induced colitis (AAIC) using a rodent model. The HERP was chemically characterised by HPLC/DAD analyses. Male rats were randomly assigned into four groups: sham, vehicle (with AAIC, treated with vehicle), P10 (with AAIC, treated with 10mg/kg HERP), and P100 (with AAIC, treated with 100mg/kg HERP). Treatments were performed for 7days, and colitis was induced on day seven. Animals were euthanized 24h after colitis induction and body weight, colon length, gross and histological scores, malondialdehyde (MDA) and myeloperoxidase (MPO) concentrations in colon tissue, and the immunohistochemical expression of inducible nitric oxide synthase (iNOS) were assessed. The major compounds found in HERP were liquiritigenin (68.8mg/g), formononetin (54.29mg/g), biochanin A (30.97mg/g), and daidzein (19.90mg/g). Rats treated with 10mg/kg HERP demonstrated significant decreases in MPO concentrations, gross and histological scores of tissue damage, and iNOS expression (p<0.05). Similarly, rats treated with 100mg/kg HERP demonstrated significant decreases in MPO levels (p<0.05) and histological scores of tissue damage (p<0.05). The results of this study indicate that oral administration of HERP attenuates AAIC in rats, which may be due to anti-inflammatory effects related to iNOS inhibition. PMID- 27955828 TI - Enhanced effect of VEGF165 on L-type calcium currents in guinea-pig cardiac ventricular myocytes. AB - The mechanisms of vascular endothelial growth factor 165 (VEGF165) on electrical properties of cardiomyocytes have not been fully elucidated. The aim of this study is to test the hypothesis that VEGF165, an angiogenesis-initiating factor, affects L-type calcium currents (ICa,L) and cell membrane potential in cardiac myocytes by acting on VEGF type-2 receptors (VEGFR2). ICa,L and action potentials (AP) were recorded by the whole-cell patch clamp method in isolated guinea-pig ventricular myocytes treated with different concentrations of VEGF165 proteins. Using a VEGFR2 inhibitor, we also tested the receptor of VEGF165 in cardiomyocytes. We found that VEGF165 increased ICa,L in a concentration dependent manner. SU5416, a VEGFR2 inhibitor, almost completely eliminated VEGF165-induced ICa,L increase. VEGF165 had no significant influence on action potential 90 (APD90) and other properties of AP. We conclude that in guinea-pig ventricular myocytes, ICa,L can be increased by VEGF165 in a concentration dependent manner through binding to VEGFR2 without causing any significant alteration to action potential duration. Results of this study may further expound the safety of VEGF165 when used in the intervention of heart diseases. PMID- 27955829 TI - Open letter on access to the BIA 10-2474 clinical trial data. PMID- 27955830 TI - Inverse agonists - What do they mean for psychiatry? AB - The nomenclature of drugs is a critical aspect of science, since it can direct research and optimize treatment choices. Traditionally drugs acting on CNS receptors have been classified as either agonists or antagonists. Recently a new class of ligand, the inverse agonist, has been identified in some receptor systems. Inverse agonists have opposite actions to those of agonists but the effects of both of these can be blocked by antagonists. Pimavanserin is a new 5 HT2A receptor acting drug that has been given market authorization for psychosis in Parkinson's disease. The FDA have termed it an inverse agonist, but this conclusion is based on in-vitro data. In this paper we discuss the evidence for such a claim being made for pimavanserin in the human brain and conclude that this is not currently sufficient. It is therefore premature to conclude that the actions of pimavanserin in humans are due to inverse agonism, and we are of the opinion that it should be called a 5-HT2A antagonist until better evidence emerges. PMID- 27955832 TI - Transarterial Yttrium-90 Radioembolization Treatment of Patients with Liver Dominant Metastatic Renal Cell Carcinoma. AB - PURPOSE: To evaluate safety and efficacy of transarterial hepatic radioembolization treatment of patients with liver-dominant metastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: From July 2010 to December 2014, 18 patients with liver-dominant metastatic RCC were treated with yttrium-90 glass microsphere radioembolization. Retrospective review of medical records and imaging studies was performed to evaluate toxicities, treatment response, and overall survival. The median follow-up period from radioembolization treatment was 17.8 months (range, 3-54.4 months). RESULTS: Median overall survival from RCC diagnosis was 64 months (95% confidence interval [CI], 0-144.1 months), from diagnosis of liver metastasis was 29 months (95% CI, 7.2-50.8 months), and from radioembolization treatment was 22.8 months (95% CI, 13.2-32.3 months). After treatment, 10 patients reported grade 1 clinical toxicities, and 8 patients had grade 1 or 2 biochemical toxicities. The best radiographic responses of 17 patients who underwent contrast-enhanced cross-sectional imaging showed complete response in 16 patients and partial response in 1 patient evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. The last available imaging of these 17 patients demonstrated complete response in 14 patients, partial response in 1 patient, and progression of disease in 2 patients. Images of a patient who underwent noncontrast CT showed stable disease as best response and stable disease on the last available imaging evaluated by RECIST. CONCLUSIONS: Radioembolization is safe and effective and led to improved hepatic disease control and overall survival in patients with liver-dominant metastatic RCC. PMID- 27955831 TI - Sedative effect of Clozapine is a function of 5-HT2A and environmental novelty. AB - Antipsychotic drugs are the mainstay in the treatment of schizophrenia and bipolar disorder. However, antipsychotics often exhibit sedation or activity suppression among many other side effects, and the factors that influence them remain poorly understood. We now show, using a 5-HT2A knockout (Htr2a-/-) mouse, that environmental circumstances can affect suppression of activity induced by the atypical antipsychotic- Clozapine. We observed that Htr2a-/- mice were more resistant to Clozapine-induced suppression of activity (CISA) and this behaviour was dependent on the environment being 'novel'. In their 'home' environment, at identical doses the mice exhibited CISA. Interestingly, the effect of genotype and environmental novelty on CISA could not be extended to the other antipsychotics that were tested, i.e. Haloperidol and Risperidone. Haloperidol induced activity suppression was independent of context and genotype. Whereas context affected Risperidone-induced activity suppression only in the Htr2a+/+ mice. Furthermore, we observed that caffeine, a stimulant, elicited resistance to CISA similar to that seen in the 'novel' context. Our study establishes a previously unknown interaction between the environmental context, 5-HT2A and CISA and emphasises the role of non-pharmacological factors such as environment on the effects of the drug, which seem antipsychotic-specific. Our findings should advance the understanding of the side effects of individual antipsychotics and the role of environment to overcome side effects such as sedation. PMID- 27955834 TI - A meta-analysis comparing transanal vs. laparoscopic total mesorectal excision for rectal cancer. PMID- 27955833 TI - Outcomes of Esophageal Arterial Embolization for Treatment of Hemoptysis. AB - PURPOSE: To investigate safety and efficacy of esophageal arterial embolization (EAE) in addition to bronchial arterial embolization (BAE) for treatment of hemoptysis as well as the importance and characteristics of esophageal arteries in patients with hemoptysis. MATERIALS AND METHODS: Between January 2013 and December 2014, 20 patients (13 men and 7 women, mean age 58.4 y) underwent EAE in addition to BAE for hemoptysis. Retrospective review of patient records was performed to evaluate major causes of hemoptysis, treatment indications based on CT findings, esophageal angiography findings, and outcomes after embolization including clinical success rate and complications. RESULTS: Hemoptysis was caused by bronchiectasis (12 patients), tuberculosis (7 patients), and lobectomy (1 patient). CT showed lower lobe lung lesions in all (100%) patients. The esophageal arteries originated from the aorta between the carina and diaphragm (18 patients) or from the inferior phrenic arteries (2 patients) and were tortuous with longitudinal off-midline courses. Communications between the esophageal and the bronchial or inferior phrenic arteries were present in 12 patients. One patient who was treated using N-butyl cyanoacrylate developed dysphagia that resolved with medical treatment. Repeat BAE was performed in 2 patients 5 days and 20 days later, and the clinical success rate was 90% (18/20). CONCLUSIONS: EAE in addition to BAE is safe in the treatment of hemoptysis and should be considered for lower lobe lesions. PMID- 27955835 TI - Impact of age on surgical staging and approaches (laparotomy, laparoscopy and robotic surgery) in endometrial cancer management. AB - OBJECTIVE: This study aims to evaluate the different surgical approaches, perioperative morbidity and surgical staging according to age in patients with endometrial cancer. METHODS: Multicentre retrospective study. Cancer characteristics and perioperative data were collected for patients surgically treated for endometrial cancer. The patients were divided into 2 groups according to their age: younger or older than 75 years. RESULTS: Surgery was performed on 270 women <75 years old and on 74 >= 75 years old. Minimally invasive surgery was performed less often in the elderly compared with their younger counterparts (58.2% vs. 74.8%; p = 0.006). Independently of the surgical approach, the rate of pelvic and para-aortic lymphadenectomy was lower in women older than 75 years old than their younger counterparts (52.7% vs. 74.8%; p < 0.001; 8.1% vs. 21.8%; p = 0.007 respectively). According to the guidelines, more frequent surgical understaging was seen in the elderly compared with the younger (37% vs. 15.2%; p = 0.002). In the comparison of complications for each surgical approach, there was no statistical difference in the >=75-year-old age group in terms of intra- or postoperative complications between the laparotomy, laparoscopy or robotic surgery group. We found a shorter length of hospital stay for the women who underwent laparoscopy or robotic surgery compared with laparotomy (p < 0.0001). CONCLUSION: Elderly women with endometrial cancer are often surgically understaged whereas there is no evidence of greater perioperative complications than for their younger counterparts. They should benefit from minimally invasive surgery and optimal surgical staging to the same extent as younger women. PMID- 27955836 TI - Mentored experience of establishing a national peritoneal malignancy programme - Experience of first 50 operative cases. AB - BACKGROUND: Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) are considered standard of care for pseudomyxoma peritonei (PMP) and selected patients with colorectal peritoneal metastases (CPM) or peritoneal mesothelioma. A National Peritoneal Malignancy programme was established in Ireland (population of 4.5 million) in May 2013 with mentoring and support from the Peritoneal Malignancy Institute, Basingstoke UK. This study reviews the operative and oncological outcomes for the first 50 patients who underwent CRS and HIPEC in Ireland. METHODS: This is a retrospective review of all patients referred, and of the subset who underwent CRS and HIPEC, for peritoneal malignancy in Ireland between May 2013 and November 2015. RESULTS: During the study period, 130 patients were referred and 50 patients were selected for CRS and HIPEC. Three patients were found to have unresectable disease at laparotomy. Of the remaining 47 patients, eight had major tumour debulking. In total, 39 underwent complete cytoreduction and 45 received HIPEC. After a median follow-up of 12.7 months, 12 patients had developed further metastatic disease. The rates of complete cytoreduction, major complication (Clavien-Dindo III/IV) and operative mortality were 83%, 0% and 0%, respectively. 32% of patients experienced grade I/II complications. CONCLUSIONS: We report the successful establishment of a national peritoneal malignancy programme. Mentoring from an experienced centre may have shortened the known learning curve evident by our encouraging outcomes. The follow-up period is short, however our early results are comparable with internationally reported figures. PMID- 27955837 TI - Child Neurology Recruitment and Training: Views of Residents and Child Neurologists From the 2015 AAP/CNS Workforce Survey. AB - BACKGROUND: To assess and compare resident and practicing child neurologists' attitudes regarding recruitment and residency training in child neurology. METHODS: A joint task force of the American Academy of Pediatrics and the Child Neurology Society conducted an electronic survey of child neurology residents (n = 305), practicing child neurologists (n = 1290), and neurodevelopmental disabilities specialists (n = 30) in 2015. Descriptive and multivariate analyses were performed. RESULTS: Response rates were 32% for residents (n = 97; 36% male; 65% Caucasian) and 40% for practitioners (n = 523; 63% male; 80% Caucasian; 30% lifetime certification). Regarding recruitment, 70% (n = 372) attributed difficulties recruiting medical students to insufficient early exposure. Although 68% (n = 364) reported that their medical school required a neurology clerkship, just 28% (n = 152) reported a child neurology component. Regarding residency curriculum, respondents supported increased training emphasis for genetics, neurodevelopmental disabilities, and multiple other subspecialty areas. Major changes in board certification requirements were supported, with 73% (n = 363) favoring reduced adult neurology training (strongest predictors: fewer years since medical school P = 0.003; and among practicing child neurologists, working more half-day clinics per week P = 0.005). Furthermore, 58% (n = 289) favored an option to reduce total training to 4 years, with 1 year of general pediatrics. Eighty-two percent (n = 448) would definitely or probably choose child neurology again. CONCLUSIONS: These findings provide support for recruitment efforts emphasizing early exposure of medical students to child neurology. Increased subspecialty exposure and an option for major changes in board certification requirements are favored by a significant number of respondents. PMID- 27955838 TI - Risk Factors for Diagnostic Delay in Psychogenic Nonepileptic Seizures Among Children and Adolescents. AB - BACKGROUND: This study aims to analyze a series of pediatric patients with psychogenic nonepileptic seizures (PNES) to establish the diagnostic gap and possible risk factors for the delayed diagnosis in this age group. METHODS: We evaluated all children with PNES documented by video electroencephalography. None had a previous diagnosis of PNES. In total, we included 53 children (interquartile range: seven to 17 years; mean age 12.81 years [S.D. 3.15]; 60.4% girls) who underwent a protocol consisting of neurological and psychiatric interviews. RESULTS: The average time between seizure onset and referral was 17.76 months (interquartile range: 0.5 to 48 months; S.D. +/- 12.62). Earlier age of onset correlated with a later diagnosis (P < 0.001). The late referral group also presented with a history of psychological abuse (P = 0.018). CONCLUSION: Youth with PNES represent a diagnostic challenge. Identification of children at risk might lead to earlier diagnosis of PNES. PMID- 27955839 TI - Evaluation of an early warning system for airborne radionuclides. AB - An early warning system for detection of increased levels of radioactivity in outdoor air was operative between 2004 and 2011 at the Swedish air sampling stations. The system consisted of a low resolution detector (NaI), positioned directly behind the filter and measurement of the accumulated radioactivity were performed continuously. An evaluation of the data collected during the period is presented with emphasis on natural occurring radionuclides and their influence on the detectability of anthropogenic radionuclides. PMID- 27955840 TI - Persistence and relapse after parathyroidectomy in non family primary hyperparathyroidism. PMID- 27955841 TI - Pulmonary cavity due to Mycobacterium malmoense: Diagnosis with bronchoalveolar lavage following percutaneous instillation of normal saline. PMID- 27955842 TI - Sox10 regulates skin melanocyte proliferation by activating the DNA replication licensing factor MCM5. AB - BACKGROUND: The control of cell proliferation is a fundamental aspect of tissue formation in development and regeneration. A cell type that illustrates this point particularly well is the neural crest-derived melanocyte, the pigment cell of vertebrates, as melanocytes can be followed easily during development and their pigment is directly visible in the integument of the adult. In mammals, melanocytes undergo physiological cycles of loss and proliferative regeneration during the hair cycle, and their proliferation is also critical during wound healing, repigmentation of depigmented lesions, and in melanoma formation and progression. Hence, a thorough analysis of the molecular parameters controlling melanocyte proliferation is crucial for our understanding of the physiology of this cell type both in health and disease. OBJECTIVE: SOX10 is a critical regulator in melanocytes and melanoma cells, but its specific role in their proliferation is far from clear. In this study we analyze the role of SOX10 in regulating mammalian melanocyte proliferation in a mouse model. METHODS: The role of SOX10 in melanoblast proliferation was analyzed in Sox10/+ mice by co-staining for melanocyte-specific markers and cell proliferation. In vitro, the role of SOX10 was studied by manipulating its levels using RNAi and analyzing the effects on DNA synthesis and cell growth and on gene expression at the RNA and protein levels. RESULTS: Reduction of Sox10 gene dose led to a reduction in the number of melanoblasts. Knockdown of Sox10 in melanocytes led to inhibition of cell proliferation and a decrease in the expression of the minichromosome maintenance complex component 5 (MCM5). In fact, SOX10 directly activated MCM5 transcription by binding to conserved SOX10 consensus DNA sequences in the MCM5 promoter. Furthermore, the defect in cell proliferation could be rescued partially by overexpression of MCM5 in Sox10 knockdown melanocytes. CONCLUSION: The results suggest that the SOX10-MCM5 axis plays an important role in controlling melanocyte proliferation. Our findings provide novel insights into the regulatory mechanisms of melanocyte proliferation and may have implications for our understanding of the roles of SOX10 and MCM5 in abnormal melanocyte proliferation disorders such as cutaneous melanoma. PMID- 27955843 TI - Identification of the promoter region of human IL-33 responsive to induction by IFNgamma. PMID- 27955844 TI - Rights and Responsibilities of Nurses Related to Reproductive Health Care. PMID- 27955845 TI - Consensus Bundle on Prevention of Surgical Site Infections After Major Gynecologic Surgery. AB - Surgical site infections are the most common complications of surgery in the United States. Of surgeries in women of reproductive age, hysterectomy is one of the most frequently performed, second only to cesarean birth. Therefore, prevention of surgical site infections in women undergoing gynecologic surgery is an ideal topic for a patient safety bundle. The primary purpose of this safety bundle is to provide recommendations that can be implemented into any surgical environment in an effort to reduce the incidence of surgical site infection. This bundle was developed by a multidisciplinary team convened by the Council on Patient Safety in Women's Health Care. The bundle is organized into four domains: Readiness, Recognition and Prevention, Response, and Reporting and Systems Learning. In addition to recommendations for practice, each of the domains stresses communication and teamwork between all members of the surgical team. Although the bundle components are designed to be adaptable to work in a variety of clinical settings, standardization within institutions is encouraged. PMID- 27955846 TI - Advanced Cardiac Life Support in Obstetric Settings. PMID- 27955847 TI - [Intraoperative neuromonitoring in thyroid surgery]. AB - BACKGROUND: Intraoperative neuromonitoring of the recurrent laryngeal nerve in thyroid surgery facilitates the identification of anatomical structures in cervical endocrine surgery reducing the frequency of vocal cord paralysis. OBJECTIVE: To study the normal electrophysiological values of the vague and recurrent laryngeal nerves before and after thyroid surgery. To compare rates of injury of recurrent nerve before and after the introduction of the intraoperative neuromonitoring in thyroid surgery. MATERIAL AND METHODS: An observational, descriptive and prospective study in which a total of 490 patients were included. Between 2003-2010, surgery was performed on 411 patients (703 nerves at risk) with systematic identification of recurrent laryngeal nerves. Between 2010-2011 neuromonitorization was also systematically performed on 79 patients. RESULTS: Before the introduction of intraoperative neuromonitoring of 704 nerves at risk, there were 14 recurrent laryngeal nerve injuries. Since 2010, after the introduction of the intraoperative neuromonitoring in thyroid surgery, there has been no nerve injury in 135 nerves at risk. CONCLUSIONS: We consider the systematic identification of the recurrent laryngeal nerve is the 'gold standard' in thyroid surgery and the intraoperative neuromonitoring of nerves can never replace surgery but can complement it. PMID- 27955848 TI - [Intrathyroidal location of parathyroid glands. Atypical presentation of multiple endocrine neoplasia type 1 syndrome]. AB - BACKGROUND: The most common manifestation of MEN 1 syndrome is primary hyperparathyroidism (PHPT) with parathyroid multiglandular affectation. The intrathyroidal situation represents 3-4% of all glands, and it is the second most frequent location in the cervical ectopias. CLINICAL CASE: 11 year old patient, with a family history of MEN1 syndrome and carrier of this same mutation. Patient presents HPTP with osteopenia. The cervical ultrasound shows three compatible images with pathological parathyroid glands (bilateral lower and upper left). The Scan and MRI are normal. Bone densitometry displays data on osteopenia. The patient is surgically intervened, only the upper parathyroid glands are located and removed, after this implantation is performed on the forearm, to prevent the possible devascularization in the dissection of the other glands. However, osteopenia persists and an elevated PTH, therefore new diagnostic tests are held which seem to show two lower parathyroid glands with intrathyroidal location. The patient is reoperated. A subtotal parathyroidectomy of the lower right gland and the resection of the left gland is performed, with the use of intraoperative ultrasound and placement of harpoon. The intraoperative pathology study confirms parathyroid tissue in both cases. DISCUSSION: It is necessary to locate the parathyroid glands preoperatively in order to alert us of the existence of topographical and ectopia abnormalities, as well as their intrathyroidal location (0.5-3.6%). CONCLUSION: The intraoperative ultrasound can be a complement to the experience of the endocrine surgeon for the localization of the parathyroid glands and therefore can help determine the best surgical strategy for each clinical case. PMID- 27955849 TI - [Gallbladder volvulus: Diagnostic and surgical challenges]. AB - BACKGROUND: The gallbladder volvulus is defined as the rotation of the gallbladder on its mesentery along the axis of the cystic duct and cystic artery. It is an extremely rare surgical disease and definitive diagnosis is usually made during surgery. CASE REPORT: A 78 year old woman presented with upper right quadrant abdominal pain, with no comorbidities and no other accompanying symptoms. Analysis revealed haemodynamic instability and leukocytosis. Computed tomography of abdomen showed an acute cholecystitis. During emergency right hypochondrium laparotomy, the gallbladder was found to be twisted counterclockwise with huge gangrenous gallbladder distal. Open cholecystectomy was performed and after the surgery, the patient was discharged in a few days. CONCLUSION: Gallbladder volvulus, or gallbladder torsion, is a rare condition and should be considered when clinical and imaging findings of complicated cholecystitis are present. The performance of urgent laparoscopic surgery would be first option to avoid perforation, peritonitis and haemodynamic instability. PMID- 27955850 TI - [A randomized controlled trial of preoperative oral immunonutrition in patients undergoing surgery for colorectal cancer: hospital stay and health care costs]. AB - BACKGROUND: The use of enteral formulas with immunonutrients in patients with gastrointestinal malignancies susceptible to surgery can reduce postoperative morbidity, at the expense of reduced infectious complications, with the consequent reduction in hospital stay and health care costs. MATERIAL AND METHODS: Prospective randomized study. 84 patients operated on a scheduled basis for resectable colorectal cancer were recruited. In the group YES IN Impact (c) Oral was administered for 8 days (3 sachets a day), compared with the NOT IN group who did not receive it. RESULTS: 40.5% (17) patients without immunonutrition suffered infectious complications vs. 33.3% (14) of YES IN. In patients with rectal cancer NOT IN, 50% (8) suffered minor infectious complications (p=.028). In each group (YES IN, NOT IN, colon and rectal cancer) when infectious complications were observed, the variables total hospital stay and costs doubled, with significant differences. These variables showed higher values in the group NOT IN compared with those who received immunonutrition, although these differences were not statistically significant. CONCLUSIONS: NOT IN patients suffered infectious complications more frequently than YES IN, with significant results in the subgroup of patients with rectal cancer. The total hospital stay and costs were slightly higher in the group not supplemented, doubling in each category significantly (YES IN, NOT IN, colon and rectal cancer), when infectious complications were observed. PMID- 27955851 TI - [Maternal metabolic diseases related to pre-pregnancy overweight and obesity in mexican women with high risk pregnancy]. AB - INTRODUCTION: Pre-pregnancy obesity has been proposed as a risk factor related to gestational diabetes and hypertensive disorders during pregnancy. OBJECTIVES: Identify pregnancy related diseases associated with pre-pregnancy obesity as a risk factor ina high risk preganancy patient population. METHODS: 600 patients whose pre-pregnancy obesity had been assessed as a high risk factor were included in the study. The means, standard deviation, median, interquartile intervals, Pearson and Spearman correlation and logistic regression to estimate risk with the odds ratio and 95% confidence intervals were calculated. RESULTS: The mean pre-pregnancy body mass index was 29.59 +/- 6.42 kg/m2. The mean for recommended pregnancy weight gain was 2.31 +/- 1.03 kg, but the mean of real weight gain was 8.91 +/- 6.84 kg. A significant correlation between pre-pregnancy obesity and family history of diabetes mellitus (p=0.000), systemic hypertension (p=0.003), cardiac diseases (p=0.000), dyslipidemia (p=0.000) and obesity (p=0.000) was identified. Pre-pregnancy obesity was identified as a risk factor for the development of gestational diabetes (OR: 1.95; IC95%: 1.39 to 2.76; p=0.000) in this kind of patient. DISCUSSION AND CONCLUSION: 75% of high risk pregnancy women in a high specialty hospital in West Mexico are overweight or obese when they become pregnant. These are risk factors in the development of gestational diabetes. PMID- 27955852 TI - [Chronic appendicitis due to multiple fecaliths. A case report]. AB - BACKGROUND: The appendix inflammatory process is the most common cause of chronic abdominal pain in the right lower quadrant. The frequency of appendiceal lumen obstruction by fecalith ranges from 10 to 20%; few cases of obstruction by multiple fecaliths had been reported. CLINICAL CASE: Sixty-nine years old male, diabetic and hypertensive in control, he underwent bowel resection 30 years previously. He completed 6 months with intermittent, mild pain in the right lower quadrant abdomen; 14 days prior to admission with increasing pain, nausea, vomiting, constipation, abdominal distension and absence of peristalsis; 12,750 leukocytes, neutrophils 90%; plain abdominal radiography without specific bowel pattern, TAC with 3 dense images in right lower quadrant; exploratory laparotomy was performed and perforated appendix with 3 free fecaliths was found. Histopathological report showed fibrosis and lymphocytic infiltrate in the muscle layer of the cecal appendix consistent with chronic appendicitis. CONCLUSIONS: The most common obstruction of the appendix lumen is by a single fecalith. In this case the patient had chronic appendicitis secondary to appendiceal lumen obstruction by multiple fecaliths. Reviewing the international literature any case of chronic appendicitis associated with the presence of multiple fecaliths was found. PMID- 27955853 TI - [Palliativer medicine in surgery]. AB - The concepts and background of palliative medicine, the patient-health team relationship and the right of the patients to receive palliative care, its application in surgery, the criterion defining the terminally ill, proportionate and disproportionate measures, where it is applied and what this consists of, drugs and procedures used, who should administrate them and for how long, the requirements for advanc directives and avoidance of therapeutic obstinacy, were reviewed. It describes and reflects their ethical and legal bases. It describes the main changes to the law in Mexico in 2009 and 2012. It concludes that palliative medicine is not against scientific and technological progress, but promotes its appropriate use with respect to the will and dignity of the patient. It should be applied by a multidisciplinary team, who accompany the patient throughout the progression of their condition, strengthening the doctor's and health team's relationship with the patients and their families. PMID- 27955854 TI - [Transcatheter aortic valve implantation for aortic stenosis. Initial experience]. AB - BACKGROUND: Aortic stenosis is a frequent disease in the elderly, and is associated with other systemic pathologies that may contraindicate the surgical procedure. Another option for these patients is percutaneous aortic valve implantation, which is less invasive. We present our initial experience with this procedure. MATERIAL AND METHODS: Patients with aortic stenosis were included once selection criteria were accomplished. Under general anaesthesia and echocardiographic and fluosocopic control, a transcatheter aortic valve was implanted following s valvuloplasty. Once concluded the procedure, angiographic and pressure control was realized in order to confirm the valve function. RESULTS: Between November 2014 and May 2015, 6 patients were treated (4 males and 2 females), with a mean age of 78.83+/-5.66 years-old. The preoperative transvalvular gradient was 90.16+/-28.53mmHg and posterior to valve implant was 3.33+/-2.92mmHg (P<.05). Two patients had concomitant coronary artery disease which had been treated previously. One patient presented with acute right coronary artery occlusion which was immediately treated. However due to previous renal failure, postoperative sepsis and respiratory failure, the patient died one month later. CONCLUSION: It was concluded that our preliminary results showed that in selected patients percutaneous aortic valve implantation is a safe procedure with clinical improvement for treated patients. PMID- 27955855 TI - [Analysis of population characteristics of infants affected by necrotizing enterocolitis in a tertiary centre in the last 12 years]. AB - BACKGROUND: Necrotizing enterocolitis is the most lethal gastrointestinal emergency in the neonatal period. Incidence and mortality have remained stable in recent years despite advances in neonatal intensive care. The aim of this study is to show the general characteristics of patients diagnosed with necrotizing enterocolitis at Teresa Herrera's Hospital (La Coruna, Spain) in the last 12years. MATERIAL AND METHODS: This study makes a retrospective and prospective descriptive analysis, evaluating the medical records and collecting radiological demographic variables, gestational data, perinatal history, clinical, analytical and perinatal therapeutic management and events in patients diagnosed with and treated for necrotizing enterocolitis between 2003 and 2015. RESULTS: A total of 124 patients met the criteria for inclusion in the study. The mean gestational age of our patients was 33 weeks and remained stable compared with other studies. The average weight of our patients was 1,873g. In our series of cases there was a progressive and significant increase in maternal age and the rate of artificial pregnancies and multiple births. In our series 38.7% of our patients required surgical treatment and the fatality rate was 11.4%. DISCUSSION: Despite advances in pre- and perinatal care necrotizing enterocolitis represents the leading cause of premature mortality. Incidence has remained unchanged in recent decades. More studies are required to identify both, risk and protective factors to reduce the morbidity and mortality of this entity. PMID- 27955856 TI - [Mohs micrographic surgery: 27 year experience in the Northeast of Mexico]. AB - INTRODUCTION: Skin cancer treatment includes surgical and non-surgical techniques. Among surgical techniques, Mohs micrographic surgery permits a complete evaluation of surgical margins with maximal tissue sparing. MATERIAL AND METHODS: Retrospective review of dermatology database of skin cancer cases treated with Mohs surgery at University Hospital Dr. Jose Eleuterio Gonzalez from 1988 to 2015. RESULTS: A total of 546 cases were included, of these 289 (52.93%) corresponded to women and 257 (47.07%) to men. Mean age at presentation was 64.3. Most tumors (63.2%) corresponded to infiltrative basal cell carcinoma and the majority were located on the nose and cheek; 9.7% of cases corresponded to recurrent tumors. A mean of 1 Mohs stages was used in 56%, with a mean of 2 sections in 23.6%. Cutaneous flaps were used in 47.7%, representing the predominant reconstruction technique. CONCLUSION: Mohs surgery has emerged in one of the dermatology reference centres in the North of the country as one of the surgical techniques for the treatment of aggressive carcinomas with high risk of recurrence. PMID- 27955857 TI - [Prognostic value of the presence of pericolic air bubbles detected by computed tomography in acute diverticulitis]. AB - BACKGROUND: Diverticular disease is common in industrialized countries. Computed tomography has been used as the preferred diagnostic method; although different scales haves been described to classify the disease, none of them encompass total disease aspects and behaviour. OBJETIVE: To analyze the patients with acute diverticulitis confirmed by computed tomography at the ABC Medical Center Campus Observatorio from January 1, 2010 to December 31, 2012, in whom pericolic free air in the form of bubbles was identified by computed tomography and if this finding can be considered as a prognostic factor for the disease. METHODS: A series of 124 patients was analyzed who had acute diverticulitis confirmed by computed tomography, in order to identify the presence of pericolic bubbles. RESULTS: Of the 124 patients, 29 presented with pericolic bubbles detected by computed tomography; of these, 62.1% had localized peritoneal signs at the time of the initial assessment, (P<.001); leukocytosis (13.33 vs 11.16, P<.001) and band count (0.97 vs 0.48, P<.001) was higher in this group. Patients with pericolonic bubbles had a longer hospital stay (5.5days vs 4.3days, P<.001) and started and tolerated liquids later (4.24days vs. 3.02days, P<.001) than the group of patients without this finding. CONCLUSIONS: The presence of pericolic bubbles in patients with acute diverticulitis can be related to a more aggressive course of the disease. PMID- 27955858 TI - Comment to "Costs and hospital procedures in an urology department of a tertiary hospital. Analysis of groups related by their diagnosis". PMID- 27955859 TI - Initial experience with the new da Vinci single-port robot-assisted platform. AB - OBJECTIVE: To describe our experience in the first cases of urological surgeries performed with the da Vinci single-port robot-assisted platform. MATERIAL AND METHODS: We performed 5 single-port robot-assisted surgeries (R-LESS) between May and October 2014. We performed 3 ureteral reimplant surgeries, one ureteropyeloplasty in an inverted kidney and 1 partial nephrectomy. The perioperative and postoperative results were collected, as well as a report of the complications according to the Clavien classification system. RESULTS: Of the 5 procedures, 4 were performed completely by LESS, while 1 procedure was reconverted to multiport robot-assisted surgery. There were no intraoperative complications. We observed perioperative complications in 4 patients, all of which were grade 1 or 2. The mean surgical time was 262minutes (range, 230-300). DISCUSSION: In our initial experience with the da Vinci device, R-LESS surgery was feasible and safe. There are still a number of limitations in its use, which require new and improved R-LESS platforms. PMID- 27955860 TI - What Precisely Is Precision Medicine? PMID- 27955861 TI - Genomics of Adverse Drug Reactions. AB - Adverse drug reactions (ADRs) are common, are associated with morbidity and mortality, and are costly to healthcare systems. Genomic factors predispose to ADRs, but these vary depending on the drug, patient, and disease. Genomic testing can not only help to predict and prevent ADRs but can also be used in other ways (diagnosis, closer monitoring of those at risk, pre-emptive genotyping, and understanding of mechanism), all of which will be important in the future to improve the benefit-risk ratio of drugs. In the era of precision medicine, such genomic data will need to be integrated with other forms of data to develop a comprehensive and integrated approach to improve responses to medicines used in patients. PMID- 27955862 TI - Liquid Phase Transition in the Postsynaptic Density? PMID- 27955863 TI - Ultrasound as an alternative technology to extract carotenoids and lipids from Heterochlorella luteoviridis. AB - The present work evaluated the use of ultrasound as a pre-treatment to lipid and carotenoid extraction from the microalgae Heterochlorella luteoviridis. The pre treatment was performed in the presence of ethanol (25%, v/v) with the ultrasound intensity varying from 0 to 100% (435kJkg-1). After the pre-treatment, a diffusive step was performed in order to evaluate different ethanol concentrations (50-75%, v/v). The results regarding carotenoid extraction showed that there is an optimal extraction region: 40-80% of ultrasound intensity and 60 75% of ethanol concentration. The lipid extraction was not influenced by the ultrasound pre-treatment and increased with the increase of ethanol concentration. PMID- 27955864 TI - High-pressure carbon dioxide/water pre-treatment of sugarcane bagasse and elephant grass: Assessment of the effect of biomass composition on process efficiency. AB - The performance of two lignocellulosic biomasses was studied in high-pressure carbon dioxide/water pre-treatment. Sugarcane bagasse and elephant grass were used to produce C5-sugars from hemicellulose and, simultaneously, to promote cellulose digestibility for enzymatic saccharification. Different pre-treatment conditions, with combined severity factor ranging from -1.17 to -0.04, were evaluated and maximal total xylan to xylose yields of 59.2wt.% (34.4wt.% xylooligomers) and 46.4wt.% (34.9wt.% xylooligomers) were attained for sugarcane bagasse and elephant grass, respectively. Furthermore, pre-treated biomasses were highly digestible, with glucan to glucose yields of 77.2mol% and 72.4mol% for sugarcane bagasse and elephant grass, respectively. High-pressure carbon dioxide/water pre-treatment provides high total C5-sugars and glucose recovery from both lignocellulosic biomasses; however it is highly influenced by composition and intrinsic features of each biomass. The obtained results confirm this approach as an effective and greener alternative to conventional pre treatment processes. PMID- 27955865 TI - Economic feasibility of microalgal bacterial floc production for wastewater treatment and biomass valorization: A detailed up-to-date analysis of up-scaled pilot results. AB - The economic potential of outdoor microalgal bacterial floc (MaB-floc) raceway ponds as wastewater treatment technology and bioresource of biomass for fertilizer, shrimp feed, phycobiliproteins and biogas in Northwest Europe is assessed. This assessment is based on cost data provided by industry experts, on experimental data obtained from pilot-scale outdoor MaB-floc ponds treating aquaculture and food-industry effluents, and from different biomass valorization tests. MaB-floc ponds exhibit a cost-performance of EUR 0.25-0.50m-3 wastewater which is similar to conventional wastewater treatment technologies. The production cost of MaB-flocs in aquaculture and food industry effluent is EUR 5.29 and 8.07kg-1TSS, respectively. Capital costs and pond mixing costs are the major expenses. Commercializing MaB-flocs as aquaculture feed generates substantial revenues, but the largest profit potential lies in production of high purity phycobiliproteins from MaB-flocs. These results highlight the large economic potential of MaB-floc technology, and justify its further development. PMID- 27955867 TI - Recovery of phosphorus via harvesting phosphorus-accumulating granular sludge in sequencing batch airlift reactor. AB - A novel approach was developed for phosphorus recovery from wastewater through thermal treatment of matured phosphorus-accumulating granular sludge cultivated in sequencing batch airlift reactor (SBAR) system. Results showed that SBAR system had stable performances, in which COD, total phosphorus (TP) and total nitrogen (TN) removal efficiencies were stabilized at 80%, 89% and 86%, respectively. The matured granules were gathered from SBAR reactor and heated at relatively low temperature (100 degrees C, 200 degrees C, 300 degrees C). The total P content in thermal treated granular sludge was more than half of total nutrient. Furthermore, the phosphorus release rate for treated granules was negatively correlated with thermal treatment temperature. These results demonstrated that the granules harvested from SBAR system followed with thermal pre-treatment could probably be applied as excellent slow-release phosphorus fertilizer. Hence, low temperature treatment of phosphate-accumulating granules is efficient for phosphorus recovery from wastewater, which is likely to promote the application of granulation technology. PMID- 27955866 TI - Oxidative production of xylonic acid using xylose in distillation stillage of cellulosic ethanol fermentation broth by Gluconobacter oxydans. AB - An oxidative production process of xylonic acid using xylose in distillation stillage of cellulosic ethanol fermentation broth was designed, experimentally investigated, and evaluated. Dry dilute acid pretreated and biodetoxified corn stover was simultaneously saccharified and fermented into 59.80g/L of ethanol (no xylose utilization). 65.39g/L of xylose was obtained in the distillation stillage without any concentrating step after ethanol was distillated. Then the xylose was completely converted into 66.42g/L of xylonic acid by Gluconobacter oxydans. The rigorous Aspen Plus modeling shows that the wastewater generation and energy consumption was significantly reduced comparing to the previous xylonic acid production process using xylose in pretreatment liquid. This study provided a practical process option for xylonic acid production from lignocellulose feedstock with significant reduction of wastewater and energy consumption. PMID- 27955868 TI - Engineered Kluyveromyces marxianus for pyruvate production at elevated temperature with simultaneous consumption of xylose and glucose. AB - Xylose and glucose from lignocellulose are sustainable sources for production of pyruvate, which is the starting material for the synthesis of many drugs and agrochemicals. In this study, the pyruvate decarboxylase gene (KmPDC1) and glycerol-3-phosphate dehydrogenase gene (KmGPD1) of Kluyveromyces marxianus YZJ051 were disrupted to prevent ethanol and glycerol accumulation. The deficient growth of PDC disruption was rescued by overexpressing mutant KmMTH1-DeltaT. Then pentose phosphate pathway and xylitol dehydrogenase SsXYL2-ARS genes were overexpressed to obtain strain YZB053 which produced pyruvate with xylose other than glucose. It produced 24.62g/L pyruvate from 80g/L xylose with productivity of 0.51g/L/h at 42 degrees C. Then, xylose-specific transporter ScGAL2-N376F was overexpressed to obtain strain YZB058, which simultaneously consumed 40g/L glucose and 20g/L xylose and produced 29.21g/L pyruvate with productivity of 0.81g/L/h at 42 degrees C. Therefore, a platform for pyruvate production from glucose and xylose at elevated temperature was developed. PMID- 27955869 TI - Outcomes of type I tympanoplasty using a cartilage shield graft in patients with poor prognostic factors. AB - OBJECTIVE: Although fascia is widely used as the grafting material in tympanoplasty (TP), unsatisfactory outcomes can result in patients with poor prognostic factors. Recently, cartilage has emerged as a graft material in TP. This study examined the operative outcomes of type I TP using a cartilage shield graft (CSG) in patients with poor prognostic factors. METHODS: This study reviewed the medical records of patients who underwent type I TP using CSG performed by the same surgeon, with over 24 months of follow-up. RESULTS: There were 94 patients (mean age 46 years). Preoperatively, 39 patients had near-total perforation, 29 had a previous TP or myringoplasty, 14 had adhesive otitis media, and 12 had a marginal perforation covering >=50% of the tympanic membrane area. The mean postoperative air-bone gap was significantly (p<0.0001) reduced compared to preoperative measurements. Postoperatively, tympanic membrane perforation occurred in 2.1% and otorrhea in 6.4%. There were no cases of retraction, adhesion, or lateralization. One subject complained of autophonia and ear fullness. CONCLUSION: Type I TP using CSG has excellent surgical results and minimal complications, even in patients with poor prognostic factors, and should thus be considered in those patients. PMID- 27955870 TI - Evaluation of a pan-serotype point-of-care rapid diagnostic assay for accurate detection of acute dengue infection. AB - The catastrophic rise in dengue infections in India and globally has created a need for an accurate, validated low-cost rapid diagnostic test (RDT) for dengue. We prospectively evaluated the diagnostic performance of NS1/IgM RDT (dengue day 1) using 211 samples from a pediatric dengue cohort representing all 4 serotypes in southern India. The dengue-positive panel consisted of 179 dengue real-time polymerase chain reaction (RT-PCR) positive samples from symptomatic children. The dengue-negative panel consisted of 32 samples from dengue-negative febrile children and asymptomatic individuals that were negative for dengue RT-PCR/NS1 enzyme-linked immunosorbent assay/IgM/IgG. NS1/IgM RDT sensitivity was 89.4% and specificity was 93.8%. The NS1/IgM RDT showed high sensitivity throughout the acute phase of illness, in primary and secondary infections, in different severity groups, and detected all 4 dengue serotypes, including coinfections. This NS1/IgM RDT is a useful point-of-care assay for rapid and reliable diagnosis of acute dengue and an excellent surveillance tool in our battle against dengue. PMID- 27955871 TI - Under-ascertainment from healthcare settings of child abuse events among children of soldiers by the U.S. Army Family Advocacy Program. AB - In cases of maltreatment involving children of U.S. Army service members, the U.S. Army Family Advocacy Program (FAP) is responsible for providing services to families and ensuring child safety. The percentage of cases of maltreatment that are known to FAP, however, is uncertain. Thus, the objective of this retrospective study was to estimate the percentage of U.S. Army dependent children with child maltreatment as diagnosed by a military or civilian medical provider who had a substantiated report with FAP from 2004 to 2007. Medical claims data were used to identify 0-17year old child dependents of soldiers who received a medical diagnosis of child maltreatment. Linkage rates of maltreatment medical diagnoses with corresponding substantiated FAP reports were calculated. Bivariate and multivariable analyses examined the association of child, maltreatment episode, and soldier characteristics with linkage to substantiated FAP reports. Across 5945 medically diagnosed maltreatment episodes, 20.3% had a substantiated FAP report. Adjusting for covariates, the predicted probability of linkage to a substantiated FAP report was higher for physical abuse than for sexual abuse, 25.8%, 95% CI (23.4, 28.3) versus 14.5%, 95% CI (11.2, 17.9). Episodes in which early care was provided at civilian treatment facilities were less likely to have a FAP report than those treated at military facilities, 9.8%, 95% CI (7.3, 12.2) versus 23.6%, 95% CI (20.8, 26.4). The observed low rates of linkage of medically diagnosed child maltreatment to substantiated FAP reports may signal the need for further regulation of FAP reporting requirements, particularly for children treated at civilian facilities. PMID- 27955872 TI - Laparoscopic versus open repair of perforated peptic ulcer: Improving outcomes utilizing a standardized technique. AB - BACKGROUND/OBJECTIVE: The objective of this study was to compare the outcomes of patients who underwent laparoscopic and open repair of perforated peptic ulcers (PPUs) at our institution. METHODS: This is a retrospective review of a prospectively collected database of patients who underwent emergency laparoscopic or open repair for PPU between December 2010 and February 2014. RESULTS: A total of 131 patients underwent emergency repair for PPU (laparoscopic repair, n=63, 48.1% vs. open repair, n=68, 51.9%). There were no significant differences in baseline characteristics between both groups in terms of age (p=0.434), gender (p=0.305), body mass index (p=0.180), and presence of comorbidities (p=0.214). Both groups were also comparable in their American Society of Anesthesiologists (ASA) scores (p=0.769), Boey scores 0/1 (p=0.311), Mannheim Peritonitis Index > 27 (p=0.528), shock on admission (p<0.99), and the duration of symptoms > 24 hours (p=0.857). There was no significant difference in the operating time between the two groups (p=0.618). Overall, the laparoscopic group had fewer complications compared with the open group (14.3% vs. 36.8%, p=0.005). When reviewing specific complications, only the incidence of surgical site infection was statistically significant (laparoscopic 0.0% vs. open 13.2%, p=0.003). The other parameters were not statistically significant. The laparoscopic group did have a significantly shorter mean postoperative stay (p=0.008) and lower pain scores in the immediate postoperative period (p<0.05). Mortality was similar in both groups (open, 1.6% vs. laparoscopic, 2.9%, p < 0.99). CONCLUSION: Laparoscopic repair resulted in reduced wound infection rates, shorter hospitalization, and reduced postoperative pain. Our single institution series and standardized technique demonstrated lower morbidity rates in the laparoscopic group. PMID- 27955873 TI - Long-term outcome of robotic partial nephrectomy for renal angiomyolipoma. AB - BACKGROUND/OBJECTIVE: To present the long-term result and efficacy of robotic partial nephrectomy (RPN) for renal angiomyolipomas (AMLs) with perioperative outcome and renal function preservation. METHODS: From September 2006 to October 2014, the database of a single medical center was reviewed and patients who underwent RPN for AMLs were enrolled. The patient demographics, perioperative complications, and postoperative outcomes were analyzed. RESULTS: We identified 23 patients who were treated with RPN for renal AMLs. The average age was 52.7 (+/- 9.9) years, and 20 (87%) patients were female. The median size of the resected AML was 5.2 [interquartile range (IQR)=3.1-6.8] cm. The median estimated blood loss was 100 (IQR=50-225) mL, and three (13%) patients required blood transfusion. Perioperative complications occurred in six (26%) patients and none of them are higher than Clavien Grade II. The median estimated glomerular filtration rate at 3-month and the latest follow-ups were 103 (IQR=85.5-112) mL/min/1.73m2 and 104 (IQR=90-112) mL/min/1.73m2, respectively, with a median of 89.6% (IQR=84.2-100) and 86.9% (IQR=81.3-97.8) preservation, respectively. The median follow-up period was 40 (IQR=30.5-61.5) months. None of the patients developed complications requiring a second intervention or local recurrence of AML. CONCLUSION: A long-term follow-up of RPN for renal AMLs revealed good preservation of renal function with a low complication rate. It may be considered as a reliable method to manage renal AMLs. PMID- 27955874 TI - Driving After Adolescent Concussion: Advice From Nurse Practitioners in the Absence of Standardized Recommendations. AB - INTRODUCTION: Nurse practitioners (NPs) are authorized to manage concussion recovery. Common adolescent activities, like driving, are omitted from guidelines. We investigated NP driving guidance and its clinical basis for restriction or limitation following adolescent concussion. METHOD: NPs completed a web-based questionnaire after viewing a scripted video scenario of an adolescent describing symptoms of concussion occurring 72 hours prior. Driving recommendations were collected using an open-ended query, then coded and categorized by type, characteristic, and basis. RESULTS: 1,051 (20%) responded to the question of interest. The majority (93.8%) provided driving recommendations: 32.6% based on time, 49.8% based on symptoms, and 28.5% based on health care utilization. 5.3% mentioned fatigue and sleep symptoms. 1% advised use of a standardized assessment tool. DISCUSSION: Symptomatology, examination, and time were key factors in clinical decision-making for post-concussion driving, rather than use of standardized tools. Persistent symptoms that can impact driving, such as sleep and visual disturbances, may warrant consideration. PMID- 27955875 TI - Asthma Home Management in the Inner-City: What can the Children Teach us? AB - OBJECTIVE: Knowledge of asthma home management from the perspective of poor, minority children with asthma is limited. METHOD: Convenience sampling methods were used to recruit families of low-income children who are frequently in the emergency department for uncontrolled asthma. Thirteen youths participated in focus groups designed to elicit reflections on asthma home management. Data were analyzed using grounded theory coding techniques. RESULTS: Participants (Mean age = 9.2 years) were African American (100%), enrolled in Medicaid (92.3%), averaged 1.4 (standard deviation = 0.7) emergency department visits over the prior 3 months, and resided in homes with at least 1 smoker (61.5%). Two themes reflecting multifaceted challenges to the development proper of self-management emerged in the analysis. DISCUSSION: Findings reinforce the need to provide a multipronged approach to improve asthma control in this high-risk population including ongoing child and family education and self-management support, environmental control and housing resources, linkages to smoking cessation programs, and psychosocial support. PMID- 27955876 TI - Rickets: Not Just a Disease Caused by Vitamin D Deficiency. PMID- 27955878 TI - Prevalence and Predictive Value of BI-RADS 3, 4, and 5 Lesions Detected on Breast MRI: Correlation with Study Indication. AB - RATIONALE AND OBJECTIVES: This study aims to determine the prevalence and predictive value of Breast Imaging Reporting and Data System (BI-RADS) 3, 4, and 5 findings on breast magnetic resonance imaging (MRI) and to evaluate the impact of study indication on the predictive value of BI-RADS categories. MATERIALS AND METHODS: This institutional review board approved, Health Insurance Portability and Accountability Act (HIPAA) compliant retrospective review of our breast MRI database from 2009 to 2011, of 5778 contrast-enhanced studies in 3360 patients was performed. At our institution, each breast receives an individual BI-RADS assessment. Breast MRI reports and electronic medical records were reviewed to obtain BI-RADS assessment, patient demographics, and outcomes. Univariate analysis was performed with Fisher exact and chi-square tests. RESULTS: A total of 9216 BI-RADS assessments were assigned during the study period: 7879 (85.5%) BI-RADS 1 and 2, 567 (6.2%) BI-RADS 3, 715 (7.8%) BI-RADS 4, and 55 (0.6%) BI RADS 5 assessments. The frequency of BI-RADS 3, 4, and 5 assessments was higher in studies performed for diagnostic (7.8%, 14.6%, 1.6%, respectively) than screening (5.2%, 4.0%, 0.1%) indications (P < 0.01). A total of 663 BI-RADS 4 and 5 lesions were biopsied with 209 (31.5%) malignant and 454 (68.5%) benign outcomes. The overall cancer rate for BI-RADS 3 findings was 1.9% (11 of 567) with no difference observed by study indication (diagnostic, 1.6%; screening, 2.3%; P = 0.76). The positive predictive value (PPV2) of BI-RADS 4 and 5 was higher for diagnostic (29.1%, 154 of 530) than for screening (22.9%, 55 of 240) indications. CONCLUSIONS: Abnormal interpretation rates and PPV2 for MRIs performed for diagnostic indications are higher than for screening indications. Similar to mammography, breast MRI audits should be separated by study indication. PMID- 27955877 TI - Incremental Cancer Detection of Locoregional Restaging with Diagnostic Mammography Combined with Whole-Breast and Regional Nodal Ultrasound in Women with Newly Diagnosed Breast Cancer. AB - RATIONALE AND OBJECTIVES: This study aims to determine if locoregional restaging with diagnostic mammography and ultrasound (US) of the whole breast and regional nodes performed for quality assurance in women with newly diagnosed breast cancer who were referred to a tertiary care center yields incremental cancer detection. MATERIALS AND METHODS: An institutional review board-approved retrospective, single-institution database review was performed on the first 1000 women referred to our center in 2010 with a provisional breast cancer diagnosis. Locoregional restaging consisted of diagnostic full-field digital mammography combined with US of the whole breast and regional nodal basins. Bilateral whole-breast US was performed in women with contralateral mammographic abnormality or had heterogeneously or extremely dense parenchyma. Demographic, clinical, and pathologic factors were analyzed. RESULTS: Final analyses included 401 women. Of the 401 women, 138 (34%) did not have their outside images available for review upon referral. The median age was 54 years (range 21-92); the median tumor size was 2.9 cm (range 0.6-18.0) for women whose disease was upstaged and 2.2 cm (range 0.4-15.0) for women whose disease was not upstaged. Incremental cancer detection rates were 15.5% (62 of 401) in the ipsilateral breast and 3.9% (6 of 154) in the contralateral breast (P < 0.0001). The total upstage rate was 25% (100 of 401). Surgical management changed from segmentectomy to mastectomy in 12% (50 of 401). The re-excision rate after segmentectomy was 19% (35 of 189). CONCLUSIONS: Locoregional restaging with diagnostic mammography combined with whole-breast and regional nodal US that is performed for standardization of the imaging workup for newly diagnosed breast cancer patients can reduce underestimation of disease burden and impact therapeutic planning. PMID- 27955879 TI - Comparison and Optimization of 3.0 T Breast Images Quality of Diffusion-Weighted Imaging with Multiple B-Values. AB - RATIONALE AND OBJECTIVES: Breast 3.0 T magnetic resonance diffusion-weighted imaging (MR-DWI) of benign and malignant lesions were obtained to measure and calculate the signal-to-noise ratio (SNR), signal intensity ratio (SIR), and contrast-to-noise ratio (CNR) of lesions at different b-values. The variation patterns of SNR and SIR were analyzed with different b-values and the images of DWI were compared at four different b-values with higher image quality. The effect of SIR on the differential diagnostic efficiency of benign and malignant lesions was compared using receiver operating characteristic curves to provide a reference for selecting the optimal b-value. MATERIALS AND METHODS: A total of 96 qualified patients with 112 lesions and 14 patients with their contralateral 14 normal breasts were included in this study. The single-shot echo planar imaging sequence was used to perform the DWI and a total of 13 b-values were used: 0, 50, 100, 200, 400, 600, 800, 1000, 1200, 1500, 1800, 2000, and 2500 s/mm2. On DWI, the suitable regions of interest were selected. The SNRs of normal breasts (SNRnormal), SNRlesions, SIR, and CNR of benign and malignant lesions were measured on DWI with different b-values and calculated. The variation patterns of SNR, SIR, and CNR values on DWI for normal breasts, benign lesions, and malignant lesions with different b-values were analyzed by using Pearson correlation analysis. The SNR and SIR of benign and malignant lesions with the same b-values were compared using t-tests. The diagnostic efficiencies of SIR with different b values for benign and malignant lesions were evaluated using receiver operating characteristic curves. RESULTS: Breast DWI had higher CNR for b-values ranging from 600 to 1200 s/mm2. It had the best CNR at b = 1000 s/mm2 for the benign lesions and at b = 1200 s/mm2 for the malignant lesions. The signal intensity and SNR values of normal breasts decreased with increasing b-values, with a negative correlation (r = -0.945, P < 0.01). The mean SNR values of benign and malignant lesions were negatively correlated (r = -0.982 and -0.947, respectively, and P < 0.01), gradually decreasing with increasing b-values. The mean SIR value of benign lesions gradually decreased with increasing b-values, a negative correlation (r = -0.991, P < 0.01). The mean SIR values of malignant lesions gradually increased with increasing b-values between 0 and 1200 s/mm2, and gradually decreased with increasing b-values >= 1500 s/mm2. For b-values of 600, 800, 1000, and 1200 s/mm2, the sensitivity and specificity of SIR in identifying benign and malignant lesions gradually increased with increasing b-values, peaking at 1200 s/mm2. CONCLUSIONS: Breast DWI had higher image quality for b values ranging from 600 to 1200 s/mm2, and was best for b-values ranging from 1000 to 1200 s/mm2. The SIR had the highest diagnostic efficiency in differentiating benign and malignant lesions for a b-value of 1200 s/mm2. PMID- 27955880 TI - [Encrusted cystitis by Corynebacterium urealyticum]. PMID- 27955881 TI - [Reactive arthritis associated with Chlamydia trachomatis genovar L2b proctitis]. PMID- 27955882 TI - Melanoma long non-coding RNA signature predicts prognostic survival and directs clinical risk-specific treatments. AB - BACKGROUND: Various studies have demonstrated that the Breslow thickness, tumor ulceration and mitotic index could serve as prognostic markers in patients with cutaneous melanoma. Recently, however, as these clinicopathological biomarkers lack efficient interpretation of endogenous mechanism of melanoma, the emphasis on the prognosis of melanoma has transformed to molecular tumor markers. OBJECTIVE: This study was designed to identify survival-related long non-coding RNAs (lncRNAs), and based on the different expressions of these lncRNAs, clinical risk-specific diagnosis and adjuvant therapy could be employed on melanoma patients, especially patients in the early course of disease or patients with a Breslow thickness no more than 2mm. METHODS: The clinical information and corresponding RNA expression data were obtained from The Cancer Genome Atlas dataset and Gene Expression Omnibus dataset (GSE65904). All samples were categorized into one training dataset and two validation datasets. Cox proportional hazard regression analysis was then used to identify survival related lncRNAs and risk assessment signature was constructed in training dataset. Kaplan-Meier method was used to estimate the utility of this signature in predicting the duration of survival of patients both in the training dataset and two validation datasets. Meanwhile receiver operating characteristic analyses were used to evaluate the predictive effectiveness of this signature in two validation datasets. RESULTS: It was found that the signature was effective while used for risk stratification, and Kaplan-Meier analyses indicated that the duration of survival of patients in high-risk groups were significantly shorter than that of low-risk groups. Moreover, areas under the receiver operating characteristic curve were 0.711 (95% confidence interval: 0.618-0.804) and 0.698 (95% confidence interval: 0.614-0.782) when this signature was used to predict the patients' duration of survival in two validation datasets respectively, indicating the superior specificity and sensitivity of this signature. CONCLUSION: We identified a four-lncRNA prognostic signature with the ability of risk stratification for melanoma patients. Risk score acquired from this signature, combining with differential diagnosis and differential adjuvant therapy, could potentially improve the prognosis quality of life for patients, especially patients in the early course of disease or patients with a Breslow thickness no more than 2mm. PMID- 27955883 TI - A needs assessment of education research topics among surgical educators in the United States. AB - BACKGROUND: There are currently no courses that focus specifically on surgical education research. A needs assessment of surgical educators is required to best design these courses. METHODS: A cross-sectional survey-based study on all faculty members of the Association for Surgical Education was done to determine their education research needs. RESULTS: The overall response rate was 15% and the majority of the 78 respondents were physicians (63%) in their mid- to late career stage (65%). Participants thought research topics should be taught at an advanced level in a workshop format. Senior educators were less interested than junior educators in learning to create conceptual frameworks (p = 0.038) and presenting their research at national meetings (p = 0.014). CONCLUSIONS: Surgical educators desire more training in education research techniques that are taught in a workshop format at a national surgical education meeting. These workshops may lay the groundwork for a nationally recognized certificate in surgical education research. PMID- 27955884 TI - Pharmacogenetics-guided analgesics in major abdominal surgery: Further benefits within an enhanced recovery protocol. AB - OBJECTIVE: Effective, narcotic sparing analgesia is a major component of Enhanced Recovery Protocols (ERP), however the risk of poor analgesia and opioid related side effects (ORADE) remains an issue related to poor outcomes and satisfaction, and is strongly related to the risk of narcotic dependence after surgery. A variety of genes can impact narcotic and non-steroidal (NSAID) drug efficacy including: the CYP family (drug metabolism-narcotics and NSAID), or COMT/ABCB1/OPRM1 (functional receptor and transport activity for analgesia vs side effects). The purpose of this study was to perform the first assessment of the impact of a pharmacogenetics (PGx) guided selection of analgesics following major abdominal surgery within an ERP. METHODS: A consecutive series of open and laparoscopic colorectal resections or major ventral hernia repair (PGx group) had a guided analgesic protocol based upon assessment of CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, COMT, OPRM1, and ABCB1 genes. Study patients were compared to a recent historical series of patients (H group) managed using our well validated ERP. The primary outcome measure was the Overall Benefit of Analgesia Score (OBAS). Pain scores were also assessed. RESULTS: The data demonstrated a similar mix of procedures and gender between groups and more than half of the PGx group had revised analgesia from the standard ERP. The PGx group demonstrated significantly lower OBAS scores (p = 0.0.1) from POD1 (3.8 vs 5.4) through POD 5 (3.0 vs 4.5) Analgesia was also superior for the PGx group from POD1 through POD 5 (p = 0.04). CONCLUSION: Pharmacogenetics guidance resulted in frequent modifications of the analgesic program, resulting in excellent analgesia with a 50% reduction in narcotic consumption, and a reduced incidence of analgesic related side effects compared to our standard ERP. These data suggest further improvement in ERP resulting from a patient centric analgesic, reduced narcotic regimen which provides early and durable pain control with fewer narcotic related side effects. PMID- 27955885 TI - The prognostic value of a new left bundle branch block in patients with acute myocardial infarction: A systematic review and meta-analysis. AB - OBJECTIVE: To assess the prognostic value of new left bundle branch block (LBBB) in patients with acute myocardial infarction (AMI). BACKGROUND: LBBB develops in many cardiac conditions, including AMI. The empirical evidence for the contribution of LBBB to mortality in AMI is not consistent. METHODS: Medline, PubMed, CINAHL, and EMBASE were searched. Inverse variance meta-analysis was performed with odds ratios as the effect estimates. The I2 statistic and risk of bias were assessed. RESULTS: Eight studies involving 105,861 participants were eligible. New LBBB was associated with higher mortality at 30 days (OR: 2.10, 95% CI 1.27 to 3.48) and 1-year follow up (OR: 2.81, 95% CI 1.64 to 4.80), and increased heart failure risk (OR: 2.64, 95% CI 1.84 to 3.77). CONCLUSIONS: AMI patients with new LBBB are a high risk group and must be treated accordingly. Yet, more research is needed given the limitations of studies. PMID- 27955886 TI - Generation, characterization and reuse of solid wastes from a biodiesel production plant. AB - The aim of this study was to identify and characterize industrial solid wastes generated by a biodiesel production plant in Brazil, as well as to present strategies for the management of these materials. This plant produces every year around 100,000tons of biodiesel from vegetable oils and animal fats. The methodology of the study included technical visits, interviews with the operational and environmental management staff as well as analysis of documents, reports and computerized data systems. An approach to reduce the generation of hazardous waste was investigated. It was take into account the amount of raw material that was processed, reduction of landfill disposal, and the maximization of the their recycling and reuse. The study also identified the sources of waste generation and accordingly prepared an evaluation matrix to determine the types of waste with the higher potential for minimization. The most important residue of the process was the filter material impregnated with oil and biodiesel, requiring, therefore, measures for its minimization. The use of these residues in the production of ceramic artefacts (light bricks) was considered to be very promising, since no significant effect on the physico-chemical and mechanical properties of the artefacts produced was observed. Phytotoxicity test using seeds of Lactuva sativa (lettuce), Brassica juncea (mustard), Abelmoschus esculentus (okra), Chrysanthemum leucanthemum (daisy), Dendranthema grandiflorum (chrysanthemum) and Allium porrum (leek) were carried out. The results clearly show incorporation of the waste material into bricks did not influence relative germination and relative root elongation in comparison to control tests. PMID- 27955887 TI - Assessment of biogas production in Argentina from co-digestion of sludge and municipal solid waste. AB - In Argentina, there is an important potential to utilize organic waste to generate bioenergy. This work analyzes the environmental impacts and the energetic and economic requirements of the biogas produced by digesting the sewage sludge (SS) produced in a wastewater treatment plant in a medium city in Argentina. The SS is co-digested with the organic fraction of municipal solid waste (OFMSW), and the basis of this study is the life cycle assessment (LCA). The LCA is performed according to ISO 14040-44 using the SimaPro simulator. First, the transport of the raw materials to the biogas plant was defined. Then, the co-digestion and the biogas treatment for final use were evaluated. The co digestion was improved with glycerol, and the generation of biogas was estimated using the GPS-X software. Two alternatives for the end use of biogas were considered: combined heat and power (CHP) and biomethane generation. For the first, H2S and water vapor were removed from the raw biogas stream, and for the second, also CO2 was removed. The H2S removal process was simulated in the SuperPro software by anaerobic biofiltration. The same software was used to simulate the removal of CO2 absorption-desorption with water as solvent. Finally, the environmental impacts related to the end use of biogas (CHP and biomethane) were evaluated. The environmental, energetic and economic analyses showed that the co-digestion of SS and OFMSW has great potential for reducing the environmental impacts and increasing the economic and energetic value of the substances via the production of biomethane, electricity and, potentially, fertilizer. PMID- 27955888 TI - Stereotactic radiotherapy following surgery for brain metastasis: Predictive factors for local control and radionecrosis. AB - PURPOSE: To evaluate local control and adverse effects after postoperative hypofractionated stereotactic radiosurgery in patients with brain metastasis. METHODS: We reviewed patients who had hypofractionated stereotactic radiosurgery (7.7Gy*3 prescribed to the 70% isodose line, with 2mm planning target volume margin) following resection from March 2008 to January 2014. The primary endpoint was local failure defined as recurrence within the surgical cavity. Secondary endpoints were distant failure rates and the occurrence of radionecrosis. RESULTS: Out of 95 patients, 39.2% had metastatic lesions from a non-small cell lung cancer primary tumour. The median Graded Prognostic Assessment score was 3 (48% of patients). One-year local control rates were 84%. Factors associated with improved local control were no cavity enhancement on pre-radiation MRI (P<0.00001), planning target volume less than 12cm3 (P=0.005), Graded Prognostic Assessment score 2 or above (P=0.009). One-year distant cerebral control rates were 56%. Thirty-three percent of patients received whole brain radiation therapy. Histologically proven radionecrosis of brain tissue occurred in 7.2% of cases. The size of the preoperative lesion and the volume of healthy brain tissue receiving 21Gy (V21) were both predictive of the incidence of radionecrosis (P=0.010 and 0.036, respectively). CONCLUSION: Adjuvant hypofractionated stereotactic radiosurgery to the postoperative cavity in patients with brain metastases results in excellent local control in selected patients, helps delay the use of whole brain radiation, and is associated with a relatively low risk of radionecrosis. PMID- 27955891 TI - Association between risk of neonatal pneumothorax and mode of anesthesia for cesarean delivery at term: a nationwide population-based retrospective cohort study. PMID- 27955892 TI - Sampling only ten microliters of whole blood for the quantification of poorly soluble drugs: Itraconazole as case study. AB - Nowadays in animal studies, it is important to comply with the so-called Three Rs rule by replacing or reducing the number of tested animals. Volumetric absorptive microsampling (VAMS) can be used to collect small quantities (10 or 20MUL) of whole blood, thereby limiting the amount of animals needed. In this study, a quantitative method was developed and subsequently validated for the poorly soluble drug itraconazole (ITZ) using VAMS and ultra-high performance liquid chromatography (UHPLC) coupled to tandem mass spectrometry (MS). A proof of concept study showed that the optimized method is applicable to test the bioavailability of drug formulations containing ITZ. Using VAMS, smaller blood volumes can be taken per sampling point (10-20MUL instead of the conventional 0.2 0.5mL) avoiding the sacrifice of animals. Moreover, the same rats can be used to compare different drug formulations which strengthens the validity of the results. In long-term bioavailability studies, it is necessary to guarantee the stability of the tested drugs supported on VAMS devices. In this study, we show that ITZ was only stable for 24h after collection with VAMS, but for at least two weeks by the storage of extracted samples at -80 degrees C. PMID- 27955890 TI - The relation of innate and adaptive immunity with viral-induced acute asthma attacks: Focusing on IP-10 and cathelicidin. AB - BACKGROUND: Despite growing evidence suggesting potential association between innate and adaptive immunity in viral-induced acute asthma, there is paucity of data in this area. OBJECTIVE: This study aimed to investigate the association of innate and adaptive immunity with acute asthma attacks by analysing the role of IFN-gamma-inducible protein 10 (IP-10), TLR2, cathelicidin, vitamin D and cytokines. MATERIAL AND METHODS: This prospective study included 33 patients with viral-induced acute asthma and 30 children with controlled asthma. Nasopharyngeal swab samples were collected for virus identification and asthma attack scores assessed in acute asthma group. Blood sampling for IP-10, TLR2, cathelicidin, vitamin D levels, and spirometric indices were employed. RESULTS: Serum IP-10 and cathelicidin levels of acute asthma group were significantly higher and vitamin D levels were lower than controlled asthma group (IP-10; p=0.006, cathelicidin; p=0.002, vitamin D; p<0.001). Serum IP-10 levels showed a significant negative correlation with age (p=0.009), TLR2 (p=0.05) and spirometric indices (p=0.002) in all asthmatics and a significant positive correlation with parameters of asthma attack severity (p=0.03) in acute asthma group. Higher cathelicidin values showed significant positive relation to IP-10 (beta coefficient: 33, p=0.02). Serum IP-10 levels higher than 38.9pg/ml (sensitivity: 85%, specificity: 47%, p=0.002) were predictive of virus-induced asthma. Serum IP-10 and vitamin D levels were found to be significantly related to viral-asthma attacks (IP-10; aOR: 8.93, p=0.03 and vitamin D; aOR: 0.82, p=0.001). CONCLUSIONS: Innate immunity biomarkers such as serum IP-10 and cathelicidin can be used to predict viral-induced acute asthma. These biomarkers may provide potential new treatment targets for acute asthma. PMID- 27955889 TI - Contributions of Sequence to the Higher-Order Structures of DNA. AB - One of the critical unanswered questions in genome biophysics is how the primary sequence of DNA bases influences the global properties of very-long-chain molecules. The local sequence-dependent features of DNA found in high-resolution structures introduce irregularities in the disposition of adjacent residues that facilitate the specific binding of proteins and modulate the global folding and interactions of double helices with hundreds of basepairs. These features also determine the positions of nucleosomes on DNA and the lengths of the interspersed DNA linkers. Like the patterns of basepair association within DNA, the arrangements of nucleosomes in chromatin modulate the properties of longer polymers. The intrachromosomal loops detected in genomic studies contain hundreds of nucleosomes, and given that the simulated configurations of chromatin depend on the lengths of linker DNA, the formation of these loops may reflect sequence dependent information encoded within the positioning of the nucleosomes. With knowledge of the positions of nucleosomes on a given genome, methods are now at hand to estimate the looping propensities of chromatin in terms of the spacing of nucleosomes and to make a direct connection between the DNA base sequence and larger-scale chromatin folding. PMID- 27955893 TI - Distribution of local anesthetics between aqueous and liposome phases. AB - Liposomes were used as biomimetic models in capillary electrokinetic chromatography (EKC) for the determination of distribution constants (KD) of certain local anesthetics and a commonly used preservative. Synthetic liposomes comprised phosphatidylcholine and phosphatidylglycerol phospholipids with and without cholesterol. In addition, ghost liposomes made from red blood cell (RBC) lipid extracts were used as pseudostationary phase to acquire information on how the liposome composition affects the interactions between anesthetics and liposomes. These results were compared with theoretical distribution coefficients at pH 7.4. In addition to 25 degrees C, the distribution constants were determined at 37 and 42 degrees C to simulate physiological conditions. Moreover, the usability of five electroosmotic flow markers in liposome (LEKC) and micellar EKC (MEKC) was studied. LEKC was proven to be a convenient and fast technique for obtaining data about the distribution constants of local anesthetics between liposome and aqueous phase. RBC liposomes can be utilized for more representative model of cellular membranes, and the results indicate that the distribution constants of the anesthetics are greatly dependent on the used liposome composition and the amount of cholesterol, while the effect of temperature on the distribution constants is less significant. PMID- 27955894 TI - Preparation of three-dimensional mesoporous polymer in situ polymerization solid phase microextraction fiber and its application to the determination of seven chlorophenols. AB - A superior solid-phase microextraction (SPME) fiber-coating material, three dimensional order mesoporous polymers with Ia-3d bicontinuous cubic structure (3D OMPs) was in situ coated on a stainless steel wire by solvent evaporation induced self-assembly (EISA) and thermo-polymerization. Fourier-transform infrared spectrometry (FTIR), transmission electron microscopy (TEM), scanning electron microscopy (SEM), small-angel X-ray diffraction (SAXRD), N2 adsorption-desorption transmission, and thermogravimetry analysis (TGA) were applied to the characterization of the synthesized 3D-OMPs coating. The performance and feasibility of the homemade fiber was evaluated through direct immersion (DI) SPME followed by high-performance liquid chromatography-UV detector (HPLC-UV) for the simultaneous extraction of seven chlorophenols in water samples. Under the optimum conditions, the prepared fiber exhibited excellent extraction properties as compared to three commercial fibers, the DI-SPME-HPLC-UV method showed low limits of detection (0.32-1.85MUgL-1), wide linear ranges (5.0-1000MUgL-1), and acceptable reproducibility (relative standard deviation, RSD<7.6% for one fiber, RSD<8.9% for fiber to fiber). Moreover, the method was further successfully applied to the analysis of seven CPs in real samples with good recoveries (80.5 99.5%) and satisfactory precisions (RSD<9.2%). It was confirmed that the proposed method has high sensitivity, outstanding selectivity and good reproducibility to the determination of trace CPs in the environmental water. PMID- 27955895 TI - Modeling on-column reduction of trisulfide bonds in monoclonal antibodies during protein A chromatography. AB - Trisulfides can be a common post-translational modification in many recombinant monoclonal antibodies. These are a source of product heterogeneity that add to the complexity of product characterization and hence, need to be reduced for consistent product quality. Trisulfide bonds can be converted to the regular disulfide bonds by incorporating a novel cysteine wash step during Protein A affinity chromatography. An empirical model is developed for this on-column reduction reaction to compare the reaction rates as a function of typical operating parameters such as temperature, cysteine concentration, reaction time and starting level of trisulfides. The model presented here is anticipated to assist in the development of optimal wash conditions for the Protein A step to effectively reduce trisulfides to desired levels. PMID- 27955896 TI - Congener specific determination of polychlorinated naphthalenes in sediment and biota by gas chromatography high resolution mass spectrometry. AB - An isotope dilution congener-specific method for the determination of the most abundant and most toxic polychlorinated naphthalenes (PCNs) was developed using gas chromatography with high resolution mass spectrometry (GC-HRMS). The method was used to determine the concentration of 24 target congeners and total PCN concentrations in fish and sediment samples. Tissue samples were extracted using pressurized liquid extraction (PLE) and sediment samples were extracted using Soxhlet extraction. Sample extracts were cleaned up using either a manual two stage open column procedure or an automated FMS Power Prep System with multi analyte and multi-sample capability using a three-column cleanup procedure. Sediment extracts were cleaned up with a dual open column cleanup technique involving the use of both a multi-layered silica (silver nitrate/acid/base/neutral silica) column followed by column containing carbon activated silica. Fish tissue extracts were cleaned up on the automated system involving the use of a high capacity ABN (acid/base/neutral column), carbon celite column, and a basic alumina column. The method is capable of producing instrument detection limits (IDLs) between 0.06 and 0.13pg for each PCN (on column), with method detection limits (MDLs) for the fish extracts ranging from 1.3 to 3.4pg/g (wet weight) and 0.46 to 1.2pg/g (dry weight) for sediments. The average accuracy of 34 spiked fish samples analysed over a period of several months was 100% with a precision (%RSD) of 12%. Similarly, the average accuracy for 28 spiked sediment samples was 104% with a precision (%RSD) of 12%. The application of the method to environmental samples was demonstrated through the analysis of sediment and fish samples obtained from Lake Ontario, Canada. The method is used both for the determination of 24 PCNs and to perform non-targeted screening for the remaining 51 PCN congeners, which are included in the total PCN quantification result. It is currently one of the most comprehensive and accurate congener-specific methods available and was developed from the existing techniques used for the determination of polychlorinated dioxins and furans to produce high quality data with only minor modifications in the clean-up procedure. It can therefore be readily adopted by other laboratories performing dioxin and POP analyses. PMID- 27955898 TI - [Semantical care point]. PMID- 27955897 TI - Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility. AB - BACKGROUND: Women are twice as likely as men to experience stress-related psychiatric disorders. The biological basis of these sex differences is poorly understood. Orexins are altered in anxious and depressed patients. Using a rat model of repeated stress, we examined whether orexins contribute to sex differences in outcomes relevant to stress-related psychiatric diseases. METHODS: Behavioral, neural, and endocrine habituation to repeated restraint stress and subsequent cognitive flexibility was examined in adult male and female rats. In parallel, orexin expression and activation were determined in both sexes, and chromatin immunoprecipitation was used to determine transcription factors acting at the orexin promoter. Designer receptors exclusively activated by designer drugs were used to inhibit orexin activation throughout repeated restraint to determine if the stress-related impairments in female rats could be reduced. RESULTS: Female rats exhibited impaired habituation to repeated restraint with subsequent deficits in cognitive flexibility compared with male rats. Increased orexin expression and activation were observed in female rats compared with male rats. The higher expression of orexin messenger RNA in female rats was due to actions of glucocorticoid receptors on the orexin promoter, as determined by chromatin immunoprecipitation. Inhibition of orexins using designer receptors exclusively activated by designer drugs in female rats throughout repeated restraint abolished their heightened hypothalamic-pituitary-adrenal responsivity and reduced stress-induced cognitive impairments. CONCLUSIONS: Orexins mediate the impairments in adaptations to repeated stress and in subsequent cognitive flexibility exhibited by female rats and provide evidence for a broader role for orexins in mediating functions relevant to stress-related psychiatric diseases. PMID- 27955899 TI - NASA Model of "Threat and Error" in Pediatric Cardiac Surgery: Patterns of Error Chains. AB - BACKGROUND: We introduced the National Aeronautics and Space Association threat and-error model to our surgical unit. All admissions are considered flights, which should pass through stepwise deescalations in risk during surgical recovery. We hypothesized that errors significantly influence risk deescalation and contribute to poor outcomes. METHODS: Patient flights (524) were tracked in real time for threats, errors, and unintended states by full-time performance personnel. Expected risk deescalation was wean from mechanical support, sternal closure, extubation, intensive care unit (ICU) discharge, and discharge home. Data were accrued from clinical charts, bedside data, reporting mechanisms, and staff interviews. Infographics of flights were openly discussed weekly for consensus. RESULTS: In 12% (64 of 524) of flights, the child failed to deescalate sequentially through expected risk levels; unintended increments instead occurred. Failed deescalations were highly associated with errors (426; 257 flights; p < 0.0001). Consequential errors (263; 173 flights) were associated with a 29% rate of failed deescalation versus 4% in flights with no consequential error (p < 0.0001). The most dangerous errors were apical errors typically (84%) occurring in the operating room, which caused chains of propagating unintended states (n = 110): these had a 43% (47 of 110) rate of failed deescalation (versus 4%; p < 0.0001). Chains of unintended state were often (46%) amplified by additional (up to 7) errors in the ICU that would worsen clinical deviation. Overall, failed deescalations in risk were extremely closely linked to brain injury (n = 13; p < 0.0001) or death (n = 7; p < 0.0001). CONCLUSIONS: Deaths and brain injury after pediatric cardiac surgery almost always occur from propagating error chains that originate in the operating room and are often amplified by additional ICU errors. PMID- 27955900 TI - Midterm Durability and Hemodynamic Performance of a Third-Generation Bovine Pericardial Prosthetic Aortic Valve: The Leipzig Experience. AB - BACKGROUND: The Trifecta valve (St. Jude Medical, St. Paul, MN) is a stented bovine pericardial bioprosthesis for aortic valve replacement (AVR). Implantation experience and midterm follow-up of this valve have not yet been reported from a large single-center cohort. METHODS: We retrospectively analyzed data from 918 patients (73.2 +/- 6.5 years; logistic European System for Cardiac Operative Risk Evaluation [EuroSCORE], 13.2 +/- 14.3) who underwent AVR. Analyses addressed implantation safety, short- and long-term survival, and hemodynamic valve performance. RESULTS: Concomitant procedures were performed in 54.9% of the patients. Low cardiac output syndrome, postoperative bleeding requiring transfusion or reoperation, and acute renal failure requiring temporary hemodialysis occurred at rates of 4.3%, 7.0%, and 11.7%, respectively. At discharge, 44 patients (4.8%) were identified with moderate prosthesis-patient mismatch (PPM) and none was identified with severe PPM. Mean follow-up was 2.7 +/ 1.6 years (maximum, 7.4 years). Survival at 30 days was 88.7% and 92.0% for all patients and patients with isolated AVR, respectively; 5-year overall survival for these groups was 73.4% and 82.2%, respectively. Myocardial infarction (odds ratio [OR], 78; 95% confidence interval [CI], 20.8-294) and inotropic medication (OR, 6.8; 95% CI, 3.2-14.5) were the strongest independent predictors for long term mortality. Five-year freedom from structural valve deterioration (SVD) was 97.9% +/- 1.5%. Left ventricular ejection fraction (LVEF) after implantation was similar to baseline and was stable over time (range, 58.9%-62.3%). The mean gradient improved substantially (39.3 mm Hg at baseline versus 9.4 mm Hg at 6 months). CONCLUSIONS: This large single-center cohort shows the easy and safe implantation, adequate hemodynamic performance, and satisfactory durability of the Trifecta valve at midterm follow-up. PMID- 27955901 TI - The Snowballing Literature on Imiquimod-Induced Skin Inflammation in Mice: A Critical Appraisal. AB - Since 2009, the imiquimod- or Aldara-induced (3M Pharmaceuticals, St. Paul, MN) model of acute skin inflammation has become the most widely used mouse model in preclinical psoriasis studies. Although this model offers researchers numerous benefits, there are important limitations and possible confounding variables to consider. The imiquimod model requires careful consideration and warrants scrutiny of the data generated by its use. In this perspective, we provide an overview of the advantages and disadvantages of this mouse model and offer suggestions for its use in psoriasis research. PMID- 27955902 TI - [Prospective evaluation of mouth and eye dryness induced by antimuscarinic drugs used for neurogenic overactive bladder in 35 patients with multiple sclerosis]. AB - INTRODUCTION: Mouth and eye dryness are frequently reported by patients with multiple sclerosis (MS) as side effects of antimuscarinic drugs used for neurogenic overactive bladder. We evaluated the impact of antimuscarinic drugs prescription on these symptoms. METHODS: MS patients consulting for overactive bladder were included. Xerostomia were evaluated at baseline and thirty days after treatment by self-reporting questionnaires (Xerostomia Quality of Life [X Qol] and Xerostomia Questionnaire [XQ]), by salivary flow rate and sugar test. Xerophtalmia were evaluated by a self-reporting questionnaire (Ocular Surface Disease Index [OSDI]) and Schirmer test. Iatrogenic anticholinergic impregnation was evaluated by the Anticholinergic Drug Scale. RESULTS: From January to December 2014, 35 patients were included. Mean age was 50.1+/-10.2 years, mean EDSS=4.9. Mean anticholinergic impregnation was 0.6+/-1.0. Before treatment, none correlation was found between anticholinergic impregnation and other parameters. Twenty-two patients were evaluated after treatment. At baseline and thirty days after treatment, mean scores were respectively: 0.78+/-0.51 and 0.73+/-0.43 (P=0.67) for X-Qol, 9.22+/-11.8 and 7.03+/-11.4 (P=0.32) for XQ, 18.8+/-14.9 and 13.9+/-11.6 (P=0.06) for OSDI. Mean salivary flow rates were respectively 1.54+/ 1.11 and 1.22+/-1.3 (P=0.53), positive sugar tests concerned respectively 68% and 55% of patients (P=0.53), and positive Schirmer test concerned 50% before and after treatment. CONCLUSION: Eye and mouth dryness exist in our MS population, even before prescription of antimuscarinic treatment, and is not getting worse after prescription. Those symptoms should not be the reason to stop an efficient treatment, but should be the reason to find and treat their aetiology. LEVEL OF EVIDENCE: 4. PMID- 27955904 TI - Surgery-based Multimodal Management of High-risk Prostate Cancer Patients: What Is the Functional Price To Pay for Optimal Disease Control? PMID- 27955903 TI - Longitudinal person-centered measurement: A psychometric evaluation of the Preparedness for Colorectal Cancer Surgery Questionnaire (PCSQ). AB - OBJECTIVE: The Preparedness for Colorectal Cancer Surgery Questionnaire (PCSQ) was previously developed in Swedish to assess patients' knowledge seeking and sense making capabilities. Aiming to measure preparedness at different phases during the pre-surgery and recovery period, the objectives were to (a) evaluate psychometric properties of the longitudinal PCSQ, (b) establish measurement invariance over time, and (c) describe change in preparedness. METHODS: Elective colorectal cancer surgery patients completed a questionnaire at five time points from pre-surgery until 6 months post-surgery (n=250). The longitudinal PCSQ consists of 23 items measuring four domains: Searching for and making use of information, Understanding and involvement in care, Making sense of recovery, Support and access to care. Psychometric analyses, including confirmatory factor analysis, were applied to evaluate internal consistency reliability and ascertain invariance over time of the measurement structure and parameters. RESULTS: The psychometric analyses revealed good fit of the measurement models, high internal consistency reliability (>=.94), and support for configural, metric and scalar measurement invariance of the four PCSQ domains. Patients reported lower levels of preparedness after surgery than pre-surgery. CONCLUSION: The adapted version of the PCSQ can be used for longitudinal analyses. PRACTICE IMPLICATIONS: The measurement of preparedness is important for evaluating person-centred outcomes before and during recovery from colorectal cancer surgery. PMID- 27955905 TI - 61-Year-Old Man With Hypercalcemia and Generalized Lymphadenopathy. PMID- 27955907 TI - From waste to sustainable materials management: Three case studies of the transition journey. AB - Waste policy is increasingly moving on from the 'prevention of waste' to a 'sustainable materials policy' focused agenda recognising individual wastes as a resource. In order to comparatively analyse policy developments in enhanced waste management, three case studies were selected; San Francisco's Zero Waste Program, Flanders's Sustainable Materials Management Initiative and Japan's Sound Material Cycle Society Plan. These case studies were chosen as an opportunity to investigate the variety of leading approaches, governance structures, and enhanced waste policy outcomes, emerging globally. This paper concludes that the current transitional state of waste management across the world, is only in the first leg of the journey towards Circular Economy closed loop production models of waste as a resource material. It is suggested that further development in government policy, planning and behaviour change is required. A focus on material policy and incorporating multiple front runners across industry and knowledge institutions are offered as potential directions in the movement away from end pipe land-fill solutions. PMID- 27955908 TI - Expanding the pool of cardiac donors: Is it really possible after cardiac arrest? PMID- 27955906 TI - Overview of manure treatment in France. AB - Manure treatment becomes a focal issue in relation to current EU and national policies on environmental, climate and renewable energy matters. The objective of this desk study was to collect all available data on the treatment of manure from cattle, pig and poultry farms for an overview of manure treatment in France. Specific surveys in 2008 showed that 12% of pig farms, 11% of poultry farms and 7.5% of cattle farms was concerned by manure treatment. Taken together, the treatment of pig, poultry and cattle manure accounted for 13.6milliontons corresponding to 11.3% of the total annual tonnage (120milliontons). The main processes, mostly applied on the farm, were composting (8.5milliontons), aerobic treatment (2.9milliontons of pig slurry) and anaerobic digestion (1milliontons). Other manure treatments, including physical-chemical treatment, were less frequent (0.4million of m3). Treated manure was mainly used to fertilize the soil and crops on the farm concerned. Manure treatment can thus be considered to be underused in France. However, anaerobic digestion is expected to expand to reach the European target of 20% of energy from renewable sources. Nevertheless, this expansion will depend on overcoming the constraint requiring registration or normalization of the use of the digestate as fertilizer. Thus, to avoid penalizing farmers, the further development or creation of collective processing platforms is recommended, combined with an N recovery process that will enable the production of organic amendments and fertilizers in an easy marketable form. PMID- 27955909 TI - Cardiovascular operations for Loeys-Dietz syndrome: Intermediate-term results. AB - OBJECTIVES: Early experience with Loeys-Dietz syndrome (LDS) suggested an aggressive aortopathy with high risk of aneurysm dissection and rupture at young ages and at smaller aortic diameters than in other connective tissue disorders. We reviewed our experience with LDS to re-examine our indications and outcomes of surgical management. METHODS: We reviewed all patients with a diagnosis of LDS who underwent cardiovascular surgery at our institution. The primary endpoint was mortality, and secondary endpoints included postoperative complications and need for reintervention. RESULTS: Seventy-nine operated patients with LDS were identified. Mean age at first operation was 25 years, 39 (49%) were female, and 38 (48%) were children (age <18 years). Six (8%) patients presented with acute dissection. Five (6%) patients had a bicuspid aortic valve, and all presented with an ascending aortic aneurysm with a mean root diameter of 3.5cm. Twenty (25%) patients had a previous sternotomy. Sixty-five (82%) patients underwent aortic root replacement, of whom 52 underwent a valve-sparing operation and 4 had concomitant arch replacement. Mean aortic root diameter in this group was 4.2 cm. Nine (11%) patients underwent aortic arch replacement, 2 (3%) had isolated ascending aorta replacement, and 3 (4%) underwent open thoracoabdominal repair. There were 2 (3%) operative and 8 late deaths. Nineteen patients underwent subsequent operations for late aneurysm and/or dissection. Mean follow-up was 6 years (range 0-24 years). Kaplan-Meier survival was 88% at 10 years. CONCLUSIONS: Growing experience with LDS has confirmed early impressions of its aggressive nature and proclivity toward aortic catastrophe. Surgical outcomes are favorable, but reintervention rates are high. Meticulous follow-up with cardiovascular surveillance imaging remain important for management, particularly as clinical LDS subtypes are characterized and more tailored treatment is developed. PMID- 27955910 TI - A rare triple threat: Rat bite fever, endocarditis of ventricular septal defect patch, and multivalve endocarditis with sinus of Valsalva fistula. PMID- 27955911 TI - Impact of multiple arterial grafts in off-pump and on-pump coronary artery bypass surgery. AB - OBJECTIVES: There is growing concern that off-pump coronary artery bypass (OPCAB) is associated with reduced long-term survival compared with traditional on-pump coronary artery bypass (ONCAB); however, most of available comparisons between OPCAB and ONCAB focus on single-artery (SA) revascularization. We sought to investigate the impact of using multiple arterial (MA) conduits in the comparison between OPCAB versus ONCAB by performing a single-center, long-term propensity score base analysis. METHODS: The study population included 5195 SA-ONCAB, 1208 MA-ONCAB, 4412 SA-OPCAB, and 1818 MA-OPCAB procedures. Late survival was available for all cases (100%). Inverse propensity score weighting and a time segmented Cox model were used for multiple treatments comparison. RESULTS: No significant differences were found between the 4 groups in terms of 30-day mortality, postoperative cerebrovascular accident, and renal replacement therapy. After a mean follow-up time of 8.2 +/- 4.7 years, in the propensity score weighted sample, survival probabilities at 10 years were 74.5 +/- 0.4, 79.7 +/- 0.4, 73.4 +/- 0.5, and 79.0 +/- 0.5 in the SA-ONCAB, MA-ONCAB, SA-OPCAB, and MA OPCAB groups respectively. Propensity-weighted analysis confirmed that MA-OPCAB (hazard ratio, 0.81; 95% confidence interval, 0.69-0.98) and MA-ONCAB (hazard ratio, 0.81; 95% confidence interval, 0.65-0.99) were associated with a lower late mortality compared with standard SA-ONCAB. CONCLUSIONS: OPCAB with multiple arterial grafts is as safe as the conventional ONCAB and achieves excellent long term survival rates which are superior to those observed after standard SA-ONCAB and comparable with MA-ONCAB. PMID- 27955912 TI - Are biventricular assist devices underused as a bridge to heart transplantation in patients with a high risk of postimplant right ventricular failure? AB - OBJECTIVE: Right ventricular failure in patients treated using left ventricular assist devices is associated with poor outcomes. We assessed the strategy of preplanned biventricular assist device implantation in patients with a high risk for right ventricular failure. METHODS: Between 2010 and 2014, we assigned 20 patients to preplanned biventricular assist device and 21 patients to left ventricular assist device as a bridge to heart transplantation on the basis of the estimated risk of postimplant right ventricular failure. Preimplant characteristics and postimplant outcomes were compared between the 2 groups. RESULTS: Patients with a biventricular assist device were younger, more often female, and more frequently had nonischemic heart disease than left ventricular assist device recipients. At preoperative assessment, biventricular assist device recipients had poorer Interagency Registry for Mechanically Assisted Circulatory Support profiles, a lower cardiac index, and more compromised right ventricular function. Survival on device to heart transplantation/weaning/destination for biventricular assist device and left ventricular assist device recipients was 90% versus 86% (not significant), with shorter heart transplantation waiting times for biventricular assist device recipients (median days, 154 vs 302, P < .001). Overall survival at 1 year was 85% (95% confidence interval, 62-95) versus 86% (95% confidence interval, 64-95) (not significant). The majority of both biventricular assist device and left ventricular assist device recipients could be discharged to home during the heart transplantation waiting time (55% vs 71%, not significant), and complication rates on device were comparable between groups (major stroke 10% vs 10%, not significant). CONCLUSIONS: Planned in advance, the biventricular assist device seems to be a feasible option as bridge to heart transplantation for patients with a high risk of postimplant right ventricular failure. The outcomes for these patients were similar to those observed for contemporary left ventricular assist device recipients, despite those receiving biventricular assist devices being more severely ill. PMID- 27955913 TI - Ascending beyond the root of the problem: Aortic root replacement with and without hemiarch repair. PMID- 27955915 TI - Discussion. PMID- 27955916 TI - Skunk's poked: What now? PMID- 27955914 TI - Liver health in adults with Fontan circulation: A multicenter cross-sectional study. AB - OBJECTIVES: Liver disease is an important contributor to morbidity and mortality in patients after Fontan surgery. There has been no large-scale survey of liver health in this population. We sought to explore the prevalence and predictors of liver disease in a multicenter cohort of adults with Fontan physiology. METHODS: Subjects were recruited from 6 adult congenital heart centers. Demographics; clinical history; and laboratory, imaging, and histopathology data were obtained. RESULTS: Of 241 subjects (median age 25.8 years [11.8-59.4], median time since Fontan 20.3 years [5.4-34.5]), more than 94% of those who underwent testing (208 of 221) had at least 1 abnormal liver-related finding. All hepatic imaging (n = 54) and liver histology (n = 68) was abnormal. Subjects with abnormal laboratory values had higher sinusoidal fibrosis stage (2 vs 1, P = .007) and higher portal fibrosis stage (3 vs 1, P = .003) compared with those with all normal values. Low albumin correlated with lower sinusoidal fibrosis stage (1 vs 2; P = .02) and portal fibrosis stage (0 vs 3, P = .002); no other liver studies correlated with fibrosis. Regenerative nodules were seen on 33% of histology specimens. CONCLUSIONS: Regardless of modality, findings of liver disease are common among adults with Fontan circulation, even those appearing clinically well. Cirrhosis is present in up to one-third of subjects. Correlations between hepatic fibrosis stage and clinical history or findings on noninvasive testing are few. Further research is needed to identify patients at risk for more severe liver disease and to determine the best methods for assessing liver health in this population. PMID- 27955917 TI - Silver doped titanium dioxide nanoparticles as antimicrobial additives to dental polymers. AB - OBJECTIVE: The objectives of this in vitro study were to produce a filled resin containing Ag-TiO2 filler particles and to test its antibacterial properties. METHODS: Ag-TiO2 particles were manufactured using the ball milling method and incorporated into an epoxy resin using a high speed centrifugal mixer. Using UV/vis spectrophotometry investigations were performed to assess how the photocatalytic properties of the Ag-TiO2 particles are affected when encased in resin. Adopting the bacteria colony counting technique, the antibacterial properties of Ag-TiO2 particles and Ag-TiO2 containing resins were assessed using Streptococcus mutans under varying lighting conditions. RESULTS: Ag doping of TiO2 results in a band gap shift towards the visible spectrum enabling Ag-TiO2 to exhibit photocatalytic properties when exposed to visible light. Small quantities of Ag-TiO2 were able to produce a bactericidal effect when in contact with S. mutans under visible light conditions. When incorporated into the bulk of an epoxy resin, the photocatalytic properties of the Ag-TiO2 particles were significantly reduced. However, a potent bactericidal effect was still achieved against S. mutans. SIGNIFICANCE: Ag-TiO2 filled resin shows promising antimicrobial properties, which could potentially be used clinically. PMID- 27955918 TI - Dexmedetomidine Added to Local Anesthetic Mixture of Lidocaine and Ropivacaine Enhances Onset and Prolongs Duration of a Popliteal Approach to Sciatic Nerve Blockade. AB - PURPOSE: A literature review of multiple clinical studies on mixing additives to improve pharmacologic limitation of local anesthetics during peripheral nerve blockade revealed inconsistency in success rates and various adverse effects. Animal research on dexmedetomidine as an adjuvant on the other hand has promising results, with evidence of minimum unwanted results. This randomized, double blinded, contrastable observational study examined the efficacy of adding dexmedetomidine to a mixture of lidocaine plus ropivacaine during popliteal sciatic nerve blockade (PSNB). METHODS: Sixty patients undergoing varicose saphenous vein resection using ultrasonography-guided PSNB along with femoral and obturator nerve blocks as surgical anesthesia were enrolled. All received standardized femoral and obturator nerve blocks, and the PSNB group was randomized to receive either 0.5 mL (50 ug) of dexmedetomidine (DL group) or 0.5 mL of saline (SL group) together with 2% lidocaine (9.5 mL) plus 0.75% ropovacaine (10 mL). Sensory onset and duration of lateral sural cutaneous nerve, sural nerve, superficial peroneal nerve, deep peroneal nerve, lateral plantar nerve, and medial plantar nerve were recorded. Motor onset and duration of tibial nerve and common peroneal nerve were also examined. FINDINGS: Sensory onset of sural nerve, superficial peroneal nerve, lateral plantar nerve, and medial plantar nerve was significantly quicker in the DL group than in the SL group (P < 0.05). Sensory onset of lateral sural cutaneous nerve and deep peroneal nerve was not statistically different between the groups (P > 0.05). Motor onset of tibial nerve and common peroneal nerve was faster in the DL group than in in the SL group (P < 0.05). Duration of both sensory and motor blockade was significantly longer in the DL group than in the SL group (P < 0.05). IMPLICATIONS: Perineural dexmedetomidine added to lidocaine and ropivacaine enhanced efficacy of popliteal approach to sciatic nerve blockade with faster onset and longer duration. PMID- 27955920 TI - In vitro susceptibility of cultured human methanogens to lovastatin. AB - Lovastatin is a prodrug that is hydrolysed in vivo to beta-hydroxy acid lovastatin, which inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co-A) reductase (HMGR), thereby lowering cholesterol in humans. A side effect of lovastatin is inhibition of isoprenoid synthesis and cell membrane formation in methanogenic Archaea, which are members of the human digestive tract microbiota and are emerging pathogens. In this study, the in vitro susceptibility of the human-associated methanogens Methanobrevibacter smithii, Methanobrevibacter oralis, Methanobrevibacter massiliense, Methanobrevibacter arboriphilus and Methanomassiliicoccus luminyensis to lovastatin (1-4 ug/mL) was tested in the presence of five gut anaerobes aiming to metabolise lovastatin into beta-hydroxy acid lovastatin as confirmed by ultra-high-performance liquid chromatography. Five days of incubation with lovastatin had no measurable effect on the growth of the five gut anaerobes but significantly reduced CH4 production and methanogen growth as measured by quantitative PCR (P <0.01). Quantitative PCR analyses indicated that compared with controls, beta-hydroxy acid lovastatin significantly increased the expression of the genes mta and mcrA implicated in methanogenesis and significantly decreased the expression of the fno gene implicated in methanogenesis. Expression of the HMGR gene (hmg) implicated in cell wall synthesis was significantly increased by beta-hydroxy acid lovastatin (P <0.01). These results strongly suggest that in the presence of gut anaerobes, lovastatin yields beta-hydroxy acid lovastatin, which inhibits methane production and growth of methanogens by affecting their cell membrane biosynthesis. Lovastatin is the first licensed drug to exclusively affect the growth of methanogens whilst protecting the bacterial microbiota. PMID- 27955919 TI - Long-term Immunogenicity of Elosulfase Alfa in the Treatment of Morquio A Syndrome: Results From MOR-005, a Phase III Extension Study. AB - PURPOSE: Elosulfase alfa is an enzyme replacement therapy for the treatment of Morquio A syndrome (mucopolysaccharidosis IVA), a lysosomal storage disorder caused by a deficiency of the enzyme N-acetylgalactose-amine-6-sulfatase. We previously reported immunogenicity data from our 24-week placebo-controlled Phase III study, MOR-004. Here, we report the long-term immunogenicity profile of elosulfase alfa from MOR-005, the Phase III extension trial to assess potential correlations between antidrug antibodies and efficacy and safety profile outcomes throughout 120 weeks of treatment. METHODS: The long-term immunogenicity of elosulfase alfa was evaluated in patients with Morquio A syndrome in an open label extension study for a total of 120 weeks. All patients received 2.0 mg/kg elosulfase alfa either weekly or every other week before establishment of 2.0 mg/kg/wk as the recommended dose, at which time all patients received weekly treatment. Efficacy measures were compared with those from the MOR-004 baseline, enabling analysis of changes over 120 weeks. The primary efficacy measure was the change from baseline in 6-minute walk test. Secondary measures included changes from baseline in 3-minute stair climb test and normalized urine keratan sulfate, a pharmacodynamic metric. FINDINGS: All patients treated with elosulfase alfa developed antidrug total antibodies (TAb) by week 24 of MOR-004. In the extension study, all patients, including those who had previously received placebo, were TAb positive by study week 36 (MOR-005 week 12). All patients remained TAb positive throughout the study, and TAb titers were similar across treatment groups at week 120. Nearly all patients tested positive for neutralizing antibodies (NAb) at least once, with incidence of NAb positivity peaking at 85.9% at study week 36, then steadily declining to 66.0% at study week 120. In all treatment groups, mean urine keratan sulfate remained below treatment-naive baseline despite the presence of antidrug antibodies. No relationship was observed between TAb titers or NAb positivity and changes in urine keratan sulfate, 6-minute walk test, or 3-minute stair climb test from baseline to week 120. No consistent associations were detected between antidrug antibodies and the occurrence of hypersensitivity adverse events or anaphylaxis over the course of the study. IMPLICATIONS: Immunogenicity results from this long-term study are consistent with previously reported 24-week results. Despite the sustained presence of antidrug antibodies, elosulfase alfa was well tolerated, and patients continued to benefit from treatment through week 120. No associations were detected between higher TAb titers or NAb positivity and reduced treatment effect or worsened safety profile measures. ClinicalTrials.gov identifier: NCT01415427. PMID- 27955921 TI - Clinical and Radiographic Outcomes in Immature Permanent Necrotic Evaginated Teeth Treated with Regenerative Endodontic Procedures. AB - INTRODUCTION: Regenerative endodontics is a promising alternative treatment for immature permanent teeth with necrotic dental pulp. The present study assessed the time to resolution of clinical symptoms and radiographic changes in root dimensions in immature permanent necrotic teeth with dens evaginatus. METHODS: In this prospective study, clinical and radiographic data were collected for 20 teeth with dens evaginatus treated with a revascularization protocol for 1 year. Tooth survival and success rate were analyzed, and radiographic changes in the radiographic root area, apical diameter, and root length were quantified. RESULTS: All 20 treated teeth (100%) survived and met the clinical criteria for success throughout the study period. The within-case percent change in radiographic root area was 28.14% at 3 months and had increased to 97.58% at 12 months. The within-case percent change in apical diameter after 3 months was 21.40% and had increased to 72.90% by 12 months, with 40% (8 of 20) showing complete apical closure at 12 months. The within-case percent change in root length was 2.65% at 3 months and had increased to 23.37% at 12 months. CONCLUSIONS: In this study, revascularization allowed the continued development of roots in teeth with necrotic pulp as well as excellent overall survival and success rates. PMID- 27955922 TI - [Hemovigilance: State 2007-2013 Tunis]. AB - INTRODUCTION: Despite its lifesaving role, blood transfusion still has risks associated with it. Hemovigilance is a set of surveillance procedures of the transfusion chain intended to promote safe and effective use of blood components. This work aims to present a descriptive analysis of adverse reactions, which were notified over a period of 5 years (incidence and etiology); to identify malfunctions and to propose corrections. MATERIALS AND METHODS: All transfusion adverse reactions accidents reported to the blood bank of the hospital La Rabta (n=120) are explored (clinical and laboratory tests). RESULTS: The average age of patients with transfusion reaction was 51.2 years (25 days to 89 years). The transfusion accident rates ranged from 0.59 to 2.19 accidents/1000 labile blood products (LBP) distributed. The investigations were used to classify 71 % of accidents in different categories. The most prevalent reaction is the hemolytic reaction, n=24 (19.8 %), followed by allergic reactions, n=21 (17.5 %) and non hemolytic feverish reaction, n=19 (15.8 %). Transfusion reactions of grade 1 severity were the most frequent (n=94); followed by those of grade 3 severity (n=16), accidents grade 4 (n=4) including two cases of acute pulmonary edema, one case of hyperkalemia, and the last case classified undetermined. CONCLUSION: These data are particularly rich in learning lessons. This study identified several levels failures: under-reporting of certain transfusion accidents, malfunctions at certain stages of the transfusion chain. In order to achieve an accurate statement of each transfusion reaction, it is important to plan in service training. PMID- 27955923 TI - Thymidine esters as substrate analogue inhibitors of angiogenic enzyme thymidine phosphorylase in vitro. AB - Thymidine phosphorylase (TP) catalyzes the cleavage of thymidine into thymine and 2-deoxy-alpha-d-ribose-1-phosphate. Elevated activity of TP prevents apoptosis, and induces angiogenesis which ultimately leads to tumor growth and metastasis. Critical role of TP in cancer progression makes it a valid target in anti-cancer research. Discovery of small molecules as TP inhibitors is vigorously pursued in cancer therapy. In the present study, we functionalized thymidine as benzoyl ester to synthesize compounds 3-16. In vitro evaluation of thymidine esters for their thymidine phosphorylase inhibition activity was subsequently carried out. Compounds 4, 10, 14, and 15 showed good activities with lower IC50 values than the standard, 7-deazaxanthine (IC50=41.0+/-1.63MUM). Among them, compound 14 showed five folds higher activity (IC50=7.5+/-0.8MUM), while 4 (IC50=18.5+/ 1.0MUM) and 10 (IC50=18.8+/-1.2MUM) showed two folds higher activity than the standard. Compound 15 showed slightly better activity (IC50=33.3+/-1.5MUM) to the standard. Potent compounds were further subjected to kinetic and molecular docking studies to identify their mode of inhibition, and to study their interactions with the protein at atomic level, respectively. All active compounds were non-cytotoxic to mouse fibroblast 3T3 cell line. These results identify thymidine esters as substrate analogue (substrate-like) inhibitors of angiogenic enzyme thymidine phosphorylase for further studies. PMID- 27955925 TI - Synthesis and biological evaluation of phosphate isosters of fosmidomycin and analogs as inhibitors of Escherichia coli and Mycobacterium smegmatis 1 deoxyxylulose 5-phosphate reductoisomerases. AB - Hydroxamate analogs of fosfoxacin, the phosphate homolog of fosmidomycin, have been synthesized and their activity tested on Escherichia coli and Mycobacterium smegmatis DXRs. Except for compound 4b, the IC50 values of phosphate derivatives are approximately 10-fold higher than those of the corresponding phosphonates. Although their inhibitory activity on Escherichia coli DXR is less efficient than their phosphonate analogs, we report the ability of phosphate compounds to inhibit the growth of Escherichia coli. This work points out that the uptake of fosfoxacin and its analogs is taking place via the GlpT and UhpT transporters. As expected, these compounds are inefficient to inhibit the growth of M. smegmatis growth inhibition probably due to a lack of uptake. PMID- 27955926 TI - Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies. AB - Fungal infections have became a serious medical problem due to their high incidence and mortality. We describe the discovery and structure-activity relationships studies (SARs) of a series of novel biphenyl imidazole derivatives with excellent antifungal activities against Candida albicans and Cryptococcus neoformans. The most promising compounds 12f-g and 19a-b exhibited excellent activity with minimum inhibitory concentration (MIC) values in the range of 0.03125-2MUg/mL. Preliminary mechanism studies showed that the potent antifungal activity of compound 12g stemed from inhibition of CYP51 in Candida albicans. Furthermore, compounds 12g and 19b exhibited low inhibition profiles for various human cytochrome P450 isoforms. The SARs and binding mode established in this study will be useful for further lead optimization. PMID- 27955928 TI - Plant Endoplasmic Reticulum-Plasma Membrane Contact Sites. AB - The endoplasmic reticulum (ER) acts as a superhighway with multiple sideroads that connects the different membrane compartments including the ER to the plasma membrane (PM). ER-PM contact sites (EPCSs) are a common feature in eukaryotic organisms, but have not been studied well in plants owing to the lack of molecular markers and to the difficulty in resolving the EPCS structure using conventional microscopy. Recently, however, plant protein complexes required for linking the ER and PM have been identified. This is a further step towards understanding the structure and function of plant EPCSs. We highlight some recent studies in this field and suggest several hypotheses that relate to the possible function of EPCSs in plants. PMID- 27955927 TI - Structure-activity relationship of the inhibitory effects of flavonoids on nitric oxide production in RAW264.7 cells. AB - We isolated flavonoids from herbal specimens from the Tibetan region (Sophora yunnanensis and Rhodiola sacra) that suppress nitric oxide (NO) production in macrophages stimulated by lipopolysaccharide and interferon-gamma. The isolated flavonoids carry symmetric substitutions in the B ring (R3'=R5'). We analyzed the quantitative structure-activity relationship of the inhibitory activity by comparative molecular field analysis (CoMFA) using this series of flavonoids. Use of flavonoids with symmetrical substitutions in the B ring made it simpler to align molecules because it was not necessary to consider a huge number of combinations due to the B-ring conformation. The CoMFA model, whose cross validated q2 value was 0.705, suggested the existence of a hydroxy group at the 5 position, the choice of the A/C-ring scaffold (chromane or chromene) and electrostatic field around the B ring are important for NO inhibitory activity. Flavonoids synthesized based on the CoMFA model exhibited significant inhibitory potential against NO production, validating the predictive capability of the CoMFA model. PMID- 27955929 TI - Ten thousand steps: a pedometer study of junior dentists in a major British teaching hospital and a district general hospital. AB - Sedentary behaviour is widely associated with deleterious health outcomes that in modern medicine have similar connotations to smoking tobacco and alcohol misuse. The integration of e-portfolio, e-logbook, British National Formulary (BNF) and encrypted emails has made smartphones a necessity for trainees. Smartphones also have the ability to record the amount of exercise taken, which allows activity at work to be monitored. The aim of this study to compare the activity of the same group of dental core trainees when they worked within a large multisite teaching hospital and a smaller district general hospital, to find out if supplementary activity was needed outside work. Data were collected from smartphones. To ensure continuity, data were collected only from those who had calibrated iPhones (n=10). At the teaching hospital six of the trainees walked over 10 000 steps a day while working (mean (SD) 10 004 (639)). At the district hospital none of the trainees walked 10 000 steps. The mean (SD) number of steps completed by all trainees was 6265 (119). Walking at work provides the full quota of recommended daily exercise most of the time for those working in the teaching hospital, but additional exercise is occasionally required. While working at the district hospital they walk less, meaning that they should try to increase their activity outside work. Trainees working in the teaching hospital walk significantly more steps than in the district hospital. PMID- 27955930 TI - Characteristics of breast cancer patients with brain metastases who live longer than 18 months. PMID- 27955924 TI - Infants Requiring Maintenance Dialysis: Outcomes of Hemodialysis and Peritoneal Dialysis. AB - BACKGROUND: The impact of different dialysis modalities on clinical outcomes has not been explored in young infants with chronic kidney failure. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: Data were extracted from the ESPN/ERA-EDTA Registry. This analysis included 1,063 infants 12 months or younger who initiated dialysis therapy in 1991 to 2013. FACTOR: Type of dialysis modality. OUTCOMES & MEASUREMENTS: Differences between infants treated with peritoneal dialysis (PD) or hemodialysis (HD) in patient survival, technique survival, and access to kidney transplantation were examined using Cox regression analysis while adjusting for age at dialysis therapy initiation, sex, underlying kidney disease, and country of residence. RESULTS: 917 infants initiated dialysis therapy on PD, and 146, on HD. Median age at dialysis therapy initiation was 4.5 (IQR, 0.7-7.9) months, and median body weight was 5.7 (IQR, 3.7-7.5) kg. Although the groups were homogeneous regarding age and sex, infants treated with PD more often had congenital anomalies of the kidney and urinary tract (CAKUT; 48% vs 27%), whereas those on HD therapy more frequently had metabolic disorders (12% vs 4%). Risk factors for death were younger age at dialysis therapy initiation (HR per each 1 month later initiation, 0.95; 95% CI, 0.90-0.97) and non-CAKUT cause of chronic kidney failure (HR, 1.49; 95% CI, 1.08-2.04). Mortality risk and likelihood of transplantation were equal in PD and HD patients, whereas HD patients had a higher risk for changing dialysis treatment (adjusted HR, 1.64; 95% CI, 1.17 2.31). LIMITATIONS: Inability to control for unmeasured confounders not included in the Registry database and missing data (ie, comorbid conditions). Low statistical power because of relatively small number of participants. CONCLUSIONS: Despite a widespread preconception that HD should be reserved for cases in which PD is not feasible, in Europe, we found 1 in 8 infants in need of maintenance dialysis to be initiated on HD therapy. Patient characteristics at dialysis therapy initiation, prospective survival, and time to transplantation were very similar for infants initiated on PD or HD therapy. PMID- 27955931 TI - Comparison of two single-use scrub suits in terms of effect on air-borne bacteria in the operating room. AB - A low level of air-borne bacteria in the operating room air can be achieved if all staff wear clothes made of low-permeability material (i.e. clean air suits). This study investigated if there was a difference in protective efficacy between two single-use scrubs made of polypropylene by testing them during routinely performed orthopaedic surgical procedures. No significant difference in the colony-forming unit count/m3 air was found between the two scrubs, so the choice can be based on which scrub type is more comfortable for staff. PMID- 27955933 TI - Response to "Neuroacanthocytosis: A case with unusual clinical features and novel response to treatment" by Wu et al. PMID- 27955932 TI - Molecular analysis of meticillin-resistant Staphylococcus aureus strains isolated from different types of infections from patients hospitalized in 12 regional, non teaching hospitals in southern Poland. AB - BACKGROUND: Accumulated data indicate that meticillin-resistant Staphylococcus aureus (MRSA) infections are associated with a worse prognosis than methicillin susceptible S. aureus infections. AIM: To assess the epidemiological profile of S. aureus infections and the genetic diversity of clinical strains of MRSA in 12 hospitals in southern Poland. METHODS: Samples from bloodstream infections, pneumonia, and skin and soft tissue infections from adult patients were examined. S. aureus isolates were tested for MRSA and macrolide-lincosamide-streptogramin B (MLSB) phenotypes. Staphylococcal cassette chromosome mec (SCCmec) typing and S. aureus protein A (spa) typing were performed. Analysis of the genetic similarity was performed by pulsed-field gel electrophoresis. RESULTS: This study included 555 patients. An MRSA phenotype was detected in 15.1% of strains. The prevalence of MRSA infection was higher in patients aged >80 years. An MLSB phenotype was detected in 18.2% of strains. Analysis of SmaI profiles did not reveal a dominant clone. Spa typing showed 25 different spa types, and spa type t003 was the most common (49% of strains). Among MRSA strains, SCCmecII (49%) and SCCmecIV (27.4%) were predominant. CONCLUSION: The characteristics of MRSA showed considerable heterogeneity. The results demonstrate the need for caution when drawing conclusions on direct epidemiological relationships between isolates based on a single typing method. As the cases of infection in this study were not associated with the hospital environment and horizontal transfer, a focus on screening at hospital admission, and appropriate infection control, may help to reduce the risk of MRSA infections. PMID- 27955934 TI - Quality of life in adults with facial port-wine stains. AB - BACKGROUND: Facial port-wine stains (PWS) are considered by some an aesthetic skin problem, yet impact on quality of life (QoL) has not been objectively documented. OBJECTIVE: We sought to (1) characterize the effect of PWS on QoL in adults, (2) to identify the clinical and demographic factors that affect QoL, and (3) to compare our results with QoL studies in other skin conditions. METHODS: In total, 244 adults with facial PWS completed an online QoL survey, which included the Skindex-29 instrument. RESULTS: QoL in adults with facial PWS was diminished, especially from an emotional perspective. Variables associated with reduced QoL in all Skindex-29 subdomains included comorbid depression, limited facial mobility, and presence of other skin conditions. Persons with hypertrophy had more emotional and symptomatic impairment. The composite dermatologic-specific QoL scores were similar to those of cutaneous T-cell lymphoma, rosacea, alopecia, and vitiligo. LIMITATIONS: Selection bias was a potential limitation, as participants were primarily recruited from patient support groups. CONCLUSION: Our analysis demonstrates that the presence of a facial PWS has a significant negative impact on QoL. Dermatologists caring for patients with PWS should inquire about QoL, provide appropriate support and resources, and consider QoL when discussing treatment options and obtaining authorization for these procedures. PMID- 27955935 TI - Acute myocardial infarction caused by left atrial myxoma: Role of intracoronary catheter aspiration. AB - Acute ST-segment elevation myocardial infarction (STEMI) caused by left atrial myxoma is very rare. Catheter-based approaches or thrombolytic therapy are mostly the first step in the management of STEMI with less time delay. We report a case of acute anterior/lateral STEMI caused by a left atrial myxoma. The patient was successfully treated by intracoronary aspiration with an Export aspiration catheter, with excellent distal coronary flow. Intracoronary catheter aspiration in acute myocardial infarction caused by a left atrial myxoma may help to salvage the infarcting myocardium with less time delay. PMID- 27955936 TI - Do prices reflect the costs of cardiac surgery in the elderly? AB - INTRODUCTION: Payment for cardiac surgery in Portugal is based on a contract agreement between hospitals and the health ministry. Our aim was to compare the prices paid according to this contract agreement with calculated costs in a population of patients aged >=65 years undergoing cardiac surgery in one hospital department. METHODS: Data on 250 patients operated between September 2011 and September 2012 were prospectively collected. The procedures studied were coronary artery bypass graft surgery (CABG) (n=67), valve surgery (n=156) and combined CABG and valve surgery (n=27). Costs were calculated by two methods: micro costing when feasible and mean length of stay otherwise. Price information was provided by the hospital administration and calculated using the hospital's mean case-mix. RESULTS: Thirty-day mortality was 3.2%. Mean EuroSCORE I was 5.97 (standard deviation [SD] 4.5%), significantly lower for CABG (p<0.01). Mean intensive care unit stay was 3.27 days (SD 4.7) and mean hospital stay was 9.92 days (SD 6.30), both significantly shorter for CABG. Calculated costs for CABG were ?6539.17 (SD 3990.26), for valve surgery ?8289.72 (SD 3319.93) and for combined CABG and valve surgery ?11 498.24 (SD 10 470.57). The payment for each patient was ?4732.38 in 2011 and ?4678.66 in 2012 based on the case-mix index of the hospital group, which was 2.06 in 2011 and 2.21 in 2012; however, the case mix in our sample was 6.48 in 2011 and 6.26 in 2012. CONCLUSION: The price paid for each patient was lower than the calculated costs. Prices would be higher than costs if the case-mix of the sample had been used. Costs were significantly lower for CABG. PMID- 27955937 TI - Subclinical cardiotoxicity in cancer therapy: The impact of early detection. PMID- 27955938 TI - Global and regional patterns of longitudinal strain in screening for chemotherapy induced cardiotoxicity. AB - INTRODUCTION: Serial echocardiographic assessment of left ventricular ejection fraction (LVEF) is the gold standard in screening for chemotherapy-induced cardiotoxicity (CIC). Measurement of myocardial deformation using speckle tracking enables more detailed assessment of myocardial contractility. The aim of this study was to determine the relationship between global and regional longitudinal strain and CIC. METHODS: This was a prospective study of 158 breast cancer patients undergoing chemotherapy with anthracyclines with or without adjuvant trastuzumab who underwent serial monitoring by transthoracic echocardiography with assessment of myocardial deformation. CIC was defined as a decrease in LVEF to <53%. Global longitudinal strain (GLS) was estimated using EchoPAC BT12 software on a GE Vivid E9 cardiac ultrasound system. Patients were classified according to the 2015 ASE/EACVI criteria as having impaired myocardial deformation when GLS was reduced (less negative), with a cutoff of -18%. RESULTS: During a mean follow-up of 5.4 months (1-48 months), the incidence of CIC was 18.9%. A decrease in GLS was observed during follow-up for the entire cohort (baseline GLS -20.1+/-3.5% vs. -18.7+/-3.4% at last follow-up assessment, p=0.001). A total of 97 patients (61.4%) were observed to have impaired myocardial deformation (GLS >=18%) at some point during follow-up. This decrease was more significant in patients who eventually developed CIC (GLS -17.2+/-2.5%, p=0.02). On analysis of regional strain, impaired contractility was observed in the septal (6 out of 6) and anterior (2 out of 3) segments. Multivariate logistic regression showed that patients who developed impaired longitudinal strain had a 4.9-fold increased risk of developing CIC (odds ratio 4.88, confidence interval 1.32-18.0, p=0.017). CONCLUSIONS: Worsening of myocardial deformation as assessed by speckle tracking is common in breast cancer patients undergoing chemotherapy, with predominantly septal and anterior wall involvement. Impaired myocardial deformation was independently associated with increased incidence of CIC. PMID- 27955939 TI - Plasticity of prefrontal cortex connectivity in schizophrenia in response to antisaccade practice. AB - People with schizophrenia exhibit difficulties in cognitive control that are often attributed to deficits in prefrontal cortex (PFC) circuitry. Practice paradigms have been used to improve these PFC-mediated deficits. The neural consequences of practice on task-based PFC activation have been addressed. Effects on task-based PFC connectivity, however, are largely unknown. We recruited people with schizophrenia and controls to practice antisaccades, a measure of PFC-mediated cognitive control that is disrupted in people with schizophrenia. Subjects performed antisaccades during functional magnetic resonance imaging (fMRI) before and after eight days of antisaccade practice. A group (schizophrenia, controls) * time (pre-, post-test) repeated measures ANOVA on the results of a psychophysiological interaction (PPI) analysis was used to evaluate changes in PFC connectivity; a similar model was used to evaluate changes in antisaccade behavior. After practice, antisaccade behavior improved and PFC connectivity with insular/temporal regions (involved in bottom-up orienting processes) increased in the schizophrenia group. The level of connectivity at post-test in the schizophrenia group was similar to that seen at pre-test in controls and positively correlated with antisaccade performance. Increases in connectivity between bottom-up and top-down regions may underlie behavioral improvements in people with schizophrenia after cognitive control practice. PMID- 27955941 TI - Health status and use of partial nephrectomy in older adults with early-stage kidney cancer. AB - INTRODUCTION: The long-term benefits of nephron-sparing surgery for kidney cancer depend on patient health. Accordingly, we examined whether receipt of partial nephrectomy varied with baseline comorbidity or functionality among older adults with stage I kidney cancer. MATERIALS AND METHODS: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2000 to 2009, we identified patients treated with partial or radical nephrectomy for stage I kidney cancer. We examined treatment trends according to baseline comorbidity, function, and relevant health conditions. We then estimated the probability of partial nephrectomy using multivariable, mixed-effects models adjusting for patient, surgeon, and hospital characteristics. RESULTS: Overall, 2,956 of 11,678 patients (25.3%) underwent treatment with partial nephrectomy. Receipt of partial nephrectomy was associated with younger age, male sex, higher socioeconomic position, smaller tumor size, and treatment by a high-volume provider, cancer center, or academic institution (P<0.001). During the study period, utilization increased significantly (P<0.001) but did not differ according to comorbidity or patient function. Adjusting for patient, surgeon, and hospital characteristics, the probability of partial nephrectomy by comorbidity and function categories remained within a narrow range from 19.6% to 22.8%. Only preexisting kidney disease appeared to be linked to partial nephrectomy usage (odds ratio = 1.49, 95% CI: 1.33-1.66). CONCLUSION: With the exception of kidney disease, the increasing use of partial nephrectomy did not vary with respect to health status. As the potential benefits of partial nephrectomy differ according to a patient's underlying health, selection tools and algorithms that match treatment to patient comorbidity or function may be needed to optimize kidney cancer care in the United States. PMID- 27955940 TI - Magnetic resonance imaging-transrectal ultrasound fusion focal cryotherapy of the prostate: A prospective development study. AB - OBJECTIVES: The use of software-based magnetic resonance-transrectal ultrasound fusion to deliver focal therapy may increase the precision of treatment. This is a prospective development study assessing the feasibility of Magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion focal cryotherapy. METHODS AND MATERIALS: Consecutive patients undergoing focal cryotherapy were included in an academic registry (December 2013-June 2014). MRI-TRUS fusion focal cryotherapy was offered to men with visible clinically significant prostate cancer (Galil SeedNet system). Eligibility was determined by multiparametric MRI (mpMRI), and transperineal template mapping or targeted biopsies. A rigid fusion platform (Biojet) was used with the operator ensuring the ice ball covered at least the lesion. Adverse events were scored using the NCICTC V4. Genitourinary toxicity was assessed using patient-reported outcome measures (IPSS, IIEF-15, and UCLA EPIC). Early contrast-enhanced MRI and mpMRI at 6 to 12 months were used to assess extent of lesion ablation. RESULTS: Of 23 patients scheduled, 5 did not have image fusion owing to surgeon preference. Overall, 18 patients undergoing image-fusion cryotherapy had median age of 68 (interquartile range [IQR]: 65-73) years and median preoperative prostate-specific antigen = 9.54 (5.65-16)ng/ml. In all, 13 (72.2%) and 5 (27.8%) patients had intermediate and high-risk cancer, respectively. In total, 10 adverse events were reported with one of these as serious (grade 3) because of admission for hematuria requiring wash out only. There was no difference in the IIEF-15 between baseline and study end (P = 0.24). The IPSS remained stable (P = 0.12), whereas the UCLA-EPIC tended to improve (P = 0.065). The prostate-specific antigen level significantly decreased at 1.8 (1.04 2.93) ng/ml (P<0.001). Both early and late mpMRI showed no residual disease in the treated area. In 2 men, radiological progression of known contralateral disease was observed; both underwent focal high intensity focused ultrasound. CONCLUSION: MRI-TRUS fusion focal cryotherapy is feasible in most patients and seems to accurately guide ablation demonstrated by posttreatment imaging. Additional studies are needed to determine efficacy using postcryotherapy biopsy. PMID- 27955942 TI - The use of midwife-led primary antenatal care by obese women in The Netherlands: An explorative cohort study. AB - OBJECTIVE: to study the effect of body mass index (BMI) on the use of antenatal care by women in midwife-led care. DESIGN: an explorative cohort study. SETTING: 11 Dutch midwife-led practices. PARTICIPANTS: a cohort of 4421 women, registered in the Midwifery Case Registration System (VeCaS), who received antenatal care in midwife-led practices in the Netherlands and gave birth between October 2012 and October 2014. FINDINGS: the mean start of initiation of care was at 9.3 (SD 4.6) weeks of pregnancy. Multiple linear regression showed that with an increasing BMI initiation of care was significantly earlier but BMI only predicted 0.2% (R2) of the variance in initiation of care. The mean number of face-to- face antenatal visits in midwife-led care was 11.8 (SD 3.8) and linear regression showed that with increasing BMI the number of antenatal visits increased. BMI predicted 0.1% of the variance in number of antenatal visits. The mean number of antenatal contacts by phone was 2.2 (SD 2.6). Multiple linear regression showed an increased number of contacts by phone for BMI categories 'underweight' and 'obese class I'. BMI categories predicted 1% of the variance in number of contacts by phone. KEY CONCLUSIONS: BMI was not a relevant predictor of variance in initiation of care and number of antenatal visits. Obese pregnant women in midwife-led practices do not delay or avoid antenatal care. IMPLICATIONS FOR PRACTICE: Taking care of pregnant women with a high BMI does not significantly add to the workload of primary care midwives. Further research is needed to more fully understand the primary maternal health services given to obese women. PMID- 27955943 TI - Endothelium in the pharyngeal arches 3, 4 and 6 is derived from the second heart field. AB - Oxygenated blood from the heart is directed into the systemic circulation through the aortic arch arteries (AAAs). The AAAs arise by remodeling of three symmetrical pairs of pharyngeal arch arteries (PAAs), which connect the heart with the paired dorsal aortae at mid-gestation. Aberrant PAA formation results in defects frequently observed in patients with lethal congenital heart disease. How the PAAs form in mammals is not understood. The work presented in this manuscript shows that the second heart field (SHF) is the major source of progenitors giving rise to the endothelium of the pharyngeal arches 3 - 6, while the endothelium in the pharyngeal arches 1 and 2 is derived from a different source. During the formation of the PAAs 3 - 6, endothelial progenitors in the SHF extend cellular processes toward the pharyngeal endoderm, migrate from the SHF and assemble into a uniform vascular plexus. This plexus then undergoes remodeling, whereby plexus endothelial cells coalesce into a large PAA in each pharyngeal arch. Taken together, our studies establish a platform for investigating cellular and molecular mechanisms regulating PAA formation and alterations that lead to disease. PMID- 27955944 TI - TGF-beta sensu stricto signaling regulates skeletal morphogenesis in the sea urchin embryo. AB - Cell-cell signaling plays a prominent role in the formation of the embryonic skeleton of sea urchins, but the mechanisms are poorly understood. In the present study, we uncover an essential role for TGF-beta sensu stricto signaling in this process. We show that TgfbrtII, a type II receptor dedicated to signaling through TGF-beta sensu stricto, is expressed selectively in skeletogenic primary mesenchyme cells (PMCs) during skeleton formation. Morpholino (MO) knockdowns and studies with a specific TgfbrtII inhibitor (ITD-1) in both S. purpuratus and Lytechinus variegatus embryos show that this receptor is required for biomineral deposition. We provide pharmacological evidence that Alk4/5/7 is the cognate TGF beta type I receptor that pairs with TgfbrtII and show by inhibitor treatments of isolated micromeres cultured in vitro that both Alk4/5/7 and TgfbrtII function cell-autonomously in PMCs. Gene expression and gene knockdown studies suggest that TGF-beta sensu stricto may be the ligand that interacts with TgfbrtII and support the view that this TGF-beta superfamily ligand provides an essential, permissive cue for skeletogenesis, although it is unlikely to provide spatial patterning information. Taken together, our findings reveal that this model morphogenetic process involves an even more diverse suite of cell signaling pathways than previously appreciated and show that PMCs integrate a complex set of both generalized and spatially localized cues in assembling the endoskeleton. PMID- 27955946 TI - Multifaceted plasminogen. PMID- 27955947 TI - Recent Equine Scientific Publications of Interest-"Just in Case You Missed Them". PMID- 27955945 TI - Smartphone text message service to foster hand hygiene compliance in health care workers. AB - BACKGROUND: Health care-associated infections are a major worldwide public health issue. Hand hygiene is a major component in the prevention of pathogen transmission in hospitals, and hand hygiene adherence by health care workers is low in many studies. We report an intervention using text messages as reminders and feedback to improve hand hygiene adherence. MATERIALS AND METHODS: The study is a historical comparison proof-of-concept study. Eighteen health care workers were monitored during 12 months by a radiofrequency identification system. Afterward we sent 2 types of text messages, congratulation or encouragement, and we studied the evolution of hand hygiene adherence. RESULTS: We recorded 15,723 hand hygiene opportunities, 8,973 before intervention and 6,750 during and after the intervention. Using a multilevel logistic regression analysis, we found a significant increase in hand hygiene adherence during the intervention (odds ratio, 1.68) compared with the historical period. DISCUSSION: Despite limitations due to the type of study, a text message encouraging personnel to be more vigilant is effective in increasing hand hygiene adherence in health care workers. CONCLUSIONS: Text message feedback should be incorporated into multimodal approaches for improving hand hygiene compliance. PMID- 27955948 TI - Array Focal Cortical Stimulation Enhances Motor Function Recovery and Brain Remodeling in a Rat Model of Ischemia. AB - OBJECTIVE: Using a new microelectrode array implanted into the cranial window employing a new stimulation protocol, we investigated the effects of the implanted electrode arrays on both motor map plasticity and neural regeneration in a rodent model of stroke. MATERIALS AND METHODS: Rats were pretrained on single-pellet retrieval task, then received focal ischemic infarction and microelectrode arrays implantation. Rats in the cortical stimulation (CS) group received daily electrical stimulation (1 hour each day) for 14 days whereas animals in the no stimulation (NS) group did not receive electrical stimulation and only underwent motor mapping. Behavior data and residual electrophysiological mapping on stimulation days 2, 5, 8, 11, and 14 were statistically compared. Neural reorganization in pathological with glial fibrillary acidic protein and microtubule-associated protein-2 was performed. RESULTS: Rats in CS group showed greater increases in reaching accuracy and significantly decreased in motor threshold than rats in NS group. Immunohistochemical study has shown that array focal CS suppressed inflammatory response, and enhanced dendritic sprouting in the peri-infarction cortex. CONCLUSION: The present findings support the viability of epidural CS with microelectrode arrays for enhancing motor function after stroke and monitoring the neural reorganization of residual electrophysiological mapping after motor cortex injury. PMID- 27955949 TI - Neutrophil-to-Lymphocyte Ratio Is a Prognostic Marker in Acute Ischemic Stroke. AB - BACKGROUND: Neutrophil-to-lymphocyte ratio is an independent predictor of mortality in patients with acute ischemic stroke. However, it is uncertain whether neutrophil-to-lymphocyte ratio is related with functional outcome and recurrent ischemic stroke. In this study, we aimed to investigate the relationship of neutrophil-to-lymphocyte ratio with stroke severity, functional outcome, and recurrent ischemic stroke after acute ischemic stroke. METHODS: A total of 280 patients with acute ischemic stroke were included in the study. Patients were divided into 3 groups according to the neutrophil-to-lymphocyte ratio value (<2, 2-3, >3). Demographic, clinical, and laboratory data were collected for all patients. We evaluated the association between neutrophil-to lymphocyte ratio and (1) stroke severity on admission, (2) functional outcome at 3 months, and (3) recurrent ischemic stroke. Regression analyses were performed, adjusting for confounders. RESULTS: After adjustment for potential confounders, neutrophil-to-lymphocyte ratio was associated with an increased risk of stroke severity on admission (odds ratio [OR] 1.364, 95% confidence interval [CI] 1.101 1.690, P = .005) and primary unfavorable outcome (OR 1.455, 95% CI 1.083-1.956, P = .013). After a median of 1.13 years (interquartile range.91-1.42) of follow-up, neutrophil-to-lymphocyte ratio was associated with recurrent ischemic stroke after adjustment (hazard ratio 1.499, 95% CI 1.161-1.935, P = .002). CONCLUSIONS: Our study suggests that neutrophil-to-lymphocyte ratio is associated with stroke severity on admission, primary unfavorable functional outcome, and recurrent ischemic stroke in patients with acute ischemic stroke. PMID- 27955951 TI - Maternity health care: The experiences of Sub-Saharan African women in Sub Saharan Africa and Australia. AB - BACKGROUND: Increasing global migration is resulting in a culturally diverse population in the receiving countries. In Australia, it is estimated that at least four thousand Sub-Saharan African women give birth each year. To respond appropriately to the needs of these women, it is important to understand their experiences of maternity care. OBJECTIVE: The study aimed to examine the maternity experiences of Sub-Saharan African women who had given birth in both Sub-Saharan Africa and in Australia. DESIGN: Using a qualitative approach, 14 semi-structured interviews with Sub-Saharan African women now living in Australia were conducted. Data was analysed using Braun and Clark's approach to thematic analysis. FINDINGS: Four themes were identified; access to services including health education; birth environment and support; pain management; and perceptions of care. The participants experienced issues with access to maternity care whether they were located in Sub-Saharan Africa or Australia. The study draws on an existing conceptual framework on access to care to discuss the findings on how these women experienced maternity care. CONCLUSION: The study provides an understanding of Sub-Saharan African women's experiences of maternity care across countries. The findings indicate that these women have maternity health needs shaped by their sociocultural norms and beliefs related to pregnancy and childbirth. It is therefore arguable that enhancing maternity care can be achieved by improving women's health literacy through health education, having an affordable health care system, providing respectful and high quality midwifery care, using effective communication, and showing cultural sensitivity including family support for labouring women. PMID- 27955950 TI - Resistive Training and Molecular Regulators of Vascular-Metabolic Risk in Chronic Stroke. AB - BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC-1alpha) gene and Sirtuin-1 (SIRT-1) respond to physiological stimuli and regulate insulin resistance. Inflammatory markers tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), C-reactive protein (CRP), and the soluble forms of intracellular adhesion molecule (sICAM-1) and vascular CAM-1 (sVCAM-1) are associated with increased risk of diabetes and coronary heart disease. Resistive training (RT) reduces hyperinsulinemia and improves insulin action in chronic stroke. Yet, the molecular mechanisms for this are unknown. This study will determine the effects of RT on skeletal muscle PGC-1alpha and SIRT-1 mRNA expression and inflammatory and vascular markers. METHODS: Stroke survivors (50 76 years) underwent a fasting blood draw for measurement of TNF-alpha, IL-6, CRP, serum amyloid A, sICAM-1, sVCAM-1, and bilateral vastus lateralis biopsies before and after RT. Participants were also assessed using bilateral multislice thigh computed tomography scans from the knee to the hip, a total body scan by dual energy X-ray absorptiometry, and 1-repetition maximum strength testing. Subjects performed 2 sets of 3 lower extremity RT exercises 3 times per week for 12 weeks. RESULTS: Bilateral leg press and leg extension strength increased ~30-50% with RT (P < .001). Body weight, total body fat mass, and fat-free mass did not change. Thigh muscle area and volume increased in both legs (P < .05). Nonparetic muscle PGC-1alpha mRNA expression increased 14% (P < .05) after RT and SIRT-1 mRNA decreased 24% (P < .05) and 31% (P < .01) in paretic and nonparetic muscles. There were no significant changes in plasma inflammation with training. DISCUSSION: RT in chronic stroke induces changes in key skeletal muscle regulators of metabolism, without effecting circulating inflammation. PMID- 27955952 TI - Erratum. PMID- 27955953 TI - A 2017 Horizon Scan of Emerging Issues for Global Conservation and Biological Diversity. AB - We present the results of our eighth annual horizon scan of emerging issues likely to affect global biological diversity, the environment, and conservation efforts in the future. The potential effects of these novel issues might not yet be fully recognized or understood by the global conservation community, and the issues can be regarded as both opportunities and risks. A diverse international team with collective expertise in horizon scanning, science communication, and conservation research, practice, and policy reviewed 100 potential issues and identified 15 that qualified as emerging, with potential substantial global effects. These issues include new developments in energy storage and fuel production, sand extraction, potential solutions to combat coral bleaching and invasive marine species, and blockchain technology. PMID- 27955954 TI - Clinical and pathogenic features of SCCmec type II and IV methicillin-resistant Staphylococcus aureus in Japan. AB - Staphylococcal chromosomal cassette mec (SCCmec) type IV methicillin-resistant Staphylococcus aureus (MRSA) has rapidly disseminated in healthcare settings, and its characteristics in the United States and Europe are well known. Because Japanese SCCmec type IV MRSA clones are different and less well documented, this retrospective, single center study was done to determine and compare the characteristics of SCCmec type II and IV MRSA in Japan. For the analysis, 55 SCCmec type II and 101 type IV MRSA samples were collected from lower respiratory tract specimens or from skin or soft tissue. The patients of the SCCmec type IV group were significantly younger than those of the type II group (P < 0.001). The rate of MRSA pneumonia was significantly lower for SCCmec type IV than for type II (7.8% vs 29.0%, P = 0.026). In contrast, the rate of skin and soft tissue infection was not significantly different (66.0% vs 61.9%, P = 0.788). The distribution of MRSA pathogenic genes (sea, seb, sem, seo) was significantly different between SCCmec types II and IV (P < 0.001), which indicates that their clonal complex may be completely different. Interestingly, all SCCmec type II MRSA that caused MRSA pneumonia had seb and egc and lacked tst that belonged to sequence type (ST) 764. This is the first study to reveal and compare the characteristics of Japanese SCCmec type II and type IV MRSA. The information from this study will be helpful for the management of Japanese MRSA infection. PMID- 27955955 TI - What's in this crab? MRI providing high-resolution three-dimensional insights into recent finds and historical collections of Brachyura. AB - Museum collections may be viewed as a unique window onto the diversity and the functional evolution of species on earth. Detailed information about the inner structure of many precious collectors' items is, however, difficult to gain without destruction of the objects of interest. Here we applied magnetic resonance imaging (MRI) to freshly fixed as well as century-old museum specimens and compared the effects of fixative (formalin, ethanol, mercury chloride) on the image quality. Three-dimensional (3D) reconstruction of MRI was exemplarily used to non-invasively visualize anatomical structures of the brachyuran species Ilia nucleus, Ozius guttatus and Austinograea williamsi. Moreover, the potential of combining MRI and micro-computed tomography (MUCT) was exemplarily analyzed for O. guttatus. The best MRI quality was achieved with formalin fixation and this also applied to specimens more than 100 years old. For specimens with a straight carapace width of about 30mm, an isotropic spatial resolution of 100MUm allowed for the delineation of all major organ systems such as the nervous system, the gastrointestinal tract, the reproductive system and the heart. Moreover, combining MRI and MUCT revealed new insights into the interaction of the heart and surrounding skeletal structures. As examples of its potential, MRI of a specimen of O. guttatus showed a very rare double infection with bopyrid isopods and 3D reconstruction of the reproductive tract of A. williamsi revealed a remarkable size of the ovaries as well as a shape and orientation of the seminal receptacles unusual for brachyurans. Thus, MRI may open up extensive possibilities to study evolutionary and ecological questions by utilizing the immense wealth of natural historical collections without any destruction of the items. PMID- 27955956 TI - Maturity-Onset Diabetes of the Young: A Genetic Form of Diabetes in Children. PMID- 27955958 TI - Management of a severely calcified neoatherosclerosis plaque analyzed by intravascular ultrasound. PMID- 27955957 TI - Hospital Magnet(r) Designation and Missed Nursing Care in Neonatal Intensive Care Units. AB - Missed nursing care is an emerging measure of front-line nursing care effectiveness in neonatal intensive care units (NICUs). Given Magnet(r) hospitals' reputations for nursing care quality, missed care comparisons with non Magnet(r) hospitals may yield insights about how Magnet(r) designation influences patient outcomes. The purpose of this secondary analysis was to evaluate the relationship between hospital Magnet(r) designation and 1) the occurrence of nurse-reported missed care and 2) reasons for missed nursing care between NICU nurses employed in Magnet(r) and non-Magnet(r) hospitals. A random sample of certified neonatal intensive care unit nurses was invited to participate in a cross-sectional survey in 2012; data were analyzed from nurses who provided direct patient care (n=230). Logistic regression was used to model relationships between Magnet(r) designation and reports of the occurrence of and reasons for missed care while controlling for nurse and shift characteristics. There was no relationship between Magnet(r) designation and missed care occurrence for 34 of 35 types of care. Nurses in Magnet(r) hospitals were significantly less likely to report tensions and communication breakdowns with other staff, lack of familiarity with policies/procedures, and lack of back-up support from team members as reasons for missed care. Missed nursing care in NICUs occurs regardless of hospital Magnet(r) recognition. However, nurses' reasons for missed care systematically differ in Magnet(r) and non-Magnet(r) hospitals and these differences merit further exploration. PMID- 27955960 TI - The risk environment of anabolic-androgenic steroid users in the UK: Examining motivations, practices and accounts of use. AB - BACKGROUND: The numbers using illicit anabolic-androgenic steroids are a cause of concern for those seeking to reduce health harms. Using the 'risk environment' as a conceptual framework to better comprehend how steroid users' practices and perspectives impact on health risks, this paper examines steroid user motivations, patterns of use, and the ways in which these practices are accounted for. METHODS: As part of a wider mixed-method study into performance and image enhancing drug (PIED) use and supply in one mid-sized city in South West England, qualitative interviews were undertaken with 22 steroid users. Participants were recruited from a local safer injecting service, rather than bodybuilding gyms, in order to access a wider cross-section of steroid users. A limitation of this approach is potential sample bias towards those showing more health optimising behaviours. RESULTS: The research findings highlight that patterns of steroid use varied according to motivation for use, experience and knowledge gained. Most reported having had little or no knowledge on steroids prior to use, with first use being based on information gained from fellow users or suppliers-sometimes inaccurate or incomplete. In accounting for their practices, many users differentiated themselves from other groups of steroid users-for example, older users expressed concern over patterns of use of younger and (what they saw as) inexperienced steroid users. Implicit in these accounts were intimations that the 'other' group engaged in riskier behaviour than they did. CONCLUSION: Examining social contexts of use and user beliefs and motivations is vital to understanding how 'risk' behaviours are experienced so that this, in turn, informs harm reduction strategies. This paper examines the ways in which use of steroids is socially situated and the implications of this for policy and practice. PMID- 27955959 TI - What surgical treatment has the lowest recurrence rate following the management of keratocystic odontogenic tumor?: A large systematic review and meta-analysis. AB - PURPOSE: Among the different surgical treatments for keratocystic odontogenic tumors (KOTs), there is no single method associated with a zero recurrence rate (RR). Thus, this study aimed to seek the best surgical treatment with the least RR using a weighted event rated meta-analysis. MATERIALS AND METHODS: To address our study purpose, a systematic review and meta-analysis based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline was performed. An extensive search of major databases through PubMed, EMBASE, and Cochrane CENTRAL was conducted to identify all relevant articles published without language restrictions from inception to August 2016. Relevant articles were selected based on the following inclusion criteria: prospective, retrospective, and case series studies that assessed various treatments in non syndromic KOTs in which RRs were included. The predictor variable was treatment groups, namely: enucleation alone, enucleation with peripheral ostectomy, enucleation with Carnoy's solution application, enucleation with cryotherapy, marsupialization alone, decompression followed by residual cystectomy, and resection. The outcome variable was RR. A weighted RR using a random effect model (because of variation in follow-up time) with a 95% confidence interval (CI) was performed. Data analysis was performed using a comprehensive meta-analysis software. RESULTS: A total of 2287 KOTs in 35 studies were included in this analysis. The weighted RR for various treatment techniques was as follows: enucleation alone (23.1%), enucleation with curettage (17.4%), enucleation and Carnoy's solution (11.5%), enucleation plus liquid nitrogen cryotherapy (14.5%), marsupialization alone (32.3%), decompression followed by residual cystectomy (14.6%), and resection (8.4%). The pooled weighted overall RR of KOTs for all different treatments was 16.6%. CONCLUSION: Radical resection remains the certain option for obtaining the lowest recurrence with KOTs. However, low recurrence accompanies enucleation with application of Carnoy's solution or cryotherapy as the first-line treatment for primary KOTs. Marsupialization (where indicated) must be followed by secondary cystectomy to minimize recurrence. We believe that to achieve the least possible morbidity, resections should be reserved for multiple recurrent lesions and possibly syndromic cases. PMID- 27955961 TI - Adding Spice to the Porridge: The development of a synthetic cannabinoid market in an English prison. AB - BACKGROUND: In 2014, the annual report of the Her Majesty's Chief Inspector of Prisons (HMIP) for England and Wales raised concerns regarding New Psychoactive Substance (NPS) use in custody, specifically the consumption of synthetic cannabinoids. To date, however, the use of these substances in prison populations, and the markets that have emerged to facilitate it, have been under researched. METHODS: Our research was conducted in an English adult male prison using multi-method techniques. These included: in-depth interviews and focus groups with prison staff and prisoners; observations of prisoner-led focus groups, workshops and restorative justice circles involving discussion of synthetic cannabinoid use and markets; and analysis of routinely collected prison data measuring drug seizures, incidents of violence and incidents of self-harm. RESULTS: The findings highlight: (1) the scale and nature of synthetic cannabinoid markets in a custodial setting and the motivations for establishing them; (2) the nature and motivations for synthetic cannabinoids use in prison; and (3) the impact synthetic cannabinoid markets in this setting have upon prisoners, the prison system and the wider criminal justice system. The policy implications of the stated motivations for use and reported problems are discussed in relation to both prison and community settings, and the recently implemented Psychoactive Substance Act (2016). CONCLUSION: The paper concludes that the rise in synthetic cannabinoid use in custody and the size of the drug market are posing significant challenges to the management of offenders; including healthcare, appropriate detection techniques, license recall and sanctions for both use and supply. We argue that the primary motivation for consumption in this setting is the avoidance of drug use detection, and that this is likely to supersede other motivations for consumption in the future. We propose a revision of the use of mandatory drug tests (MDTs) both in prisons and in the management of offenders in the community. PMID- 27955962 TI - Pneumatic dilation for functional helix stenosis after sleeve gastrectomy: long term follow-up (with videos). AB - BACKGROUND: A large number of patients who undergo laparoscopic sleeve gastrectomy present with surgical complications. Stenosis, in particular, occurs in .7%-4% of cases. OBJECTIVES: To report our experience, results, and long-term follow-up after pneumatic dilation of late functional helix stenosis after laparoscopic sleeve gastrectomy. SETTING: Multicenter study led by an endoscopic tertiary referral center. METHODS: Thirty-five patients were dilated initially at 30 mm. Thirteen out of 35 patients underwent a second dilation up to 35 mm. Only 8 patients underwent a third pneumatic dilation up to 40 mm. The stricture was localized in the mid-body of the sleeve in 32 patients overall; 3 had narrowing adjacent to the cardia. Eleven twists formed an acute angle between the 2 segments of the stomach, whereas 24 angles were obtuse. Seven out of 35 patients presented with persistent dilated pouch above the twist. Two patients were lost to follow-up. Overall outcome at an average follow-up of 15.5 months after primary surgery (range 7-49 mo) was as follows: 12 clinical failures and 1 technical failure (40%) and 60% (20 out of 33) clinical success. CONCLUSION: Pneumatic dilation of late functional helix stricture is an effective technique for treatment of dysphagia in the majority of patients treated. Complete helix stricture, defined in function of the angle within twist, as well as the presence of a persistently dilated gastric pouch above the kinking, seems to be correlated with higher failure rates. PMID- 27955963 TI - Association Between Imaging Characteristics and Different Molecular Subtypes of Breast Cancer. AB - RATIONALE AND OBJECTIVE: Breast cancer can be divided into four major molecular subtypes based on the expression of hormone receptor (estrogen receptor and progesterone receptor), human epidermal growth factor receptor 2, HER2 status, and molecular proliferation rate (Ki67). In this study, we sought to investigate the association between breast cancer subtype and radiological findings in the Chinese population. MATERIALS AND METHODS: Medical records of 300 consecutive invasive breast cancer patients were reviewed from the database: the Breast Imaging Reporting and Data System. The imaging characteristics of the lesions were evaluated. The molecular subtypes of breast cancer were classified into four types: luminal A, luminal B, HER2 overexpressed (HER2), and basal-like breast cancer (BLBC). Univariate and multivariate logistic regression analyses were performed to assess the association between the subtype (dependent variable) and mammography or 15 magnetic resonance imaging (MRI) indicators (independent variables). RESULTS: Luminal A and B subtypes were commonly associated with "clustered calcification distribution," "nipple invasion," or "skin invasion" (P <0.05). The BLBC subtype was more commonly associated with "rim enhancement" and persistent inflow type enhancement in delayed phase (P <0.05). HER2 overexpressed cancers showed association with persistent enhancement in the delayed phase on MRI and "clustered calcification distribution" on mammography (P <0.05). CONCLUSION: Certain radiological features are strongly associated with the molecular subtype and hormone receptor status of breast tumor, which are potentially useful tools in the diagnosis and subtyping of breast cancer. PMID- 27955964 TI - Monitoring Disease Activity in Patients with Aortitis and Chronic Periaortitis Undergoing Immunosuppressive Therapy by Perfusion CT. AB - RATIONALE AND OBJECTIVES: To evaluate the role of perfusion CT for monitoring inflammatory activity in patients with aortitis and chronic periaortitis undergoing immunosuppressive therapy. MATERIALS AND METHODS: Seventeen symptomatic patients (median age 68.5 years) who underwent perfusion-based computed tomography (CT) monitoring after diagnostic contrast-enhanced CT were retrospectively included in this study. Blood flow (BF), blood volume (BV), volume transfer constant (k-trans), time to peak, and mean transit time were determined by setting circular regions of interest in prominently thickened parts of the vessel wall or perfused surrounding tissue at sites where the perfusion CT color maps showed a maximum BF value. Differences in CT perfusion and, morphological parameters, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were tested for significance during therapy. RESULTS: In all patients BF and BV dropped at second perfusion CT (P < 0.05). In aortitis patients, CRP dropped from 3.86 +/- 5.31 mg/dL to 0.9 +/- 1.37 mg/dL and in periaortitis patients from 1.78 +/- 2.25 mg/dL to 0.79 +/- 1.55 mg/dL, whereas ESR dropped from 45.71 +/- 37.59 seconds to 8.57 +/- 3.1 seconds and 36.78 +/- 34.67 seconds to 17.22 +/- 21.82 seconds in aortitis and in periaortitis, respectively. CONCLUSIONS: The course of perfusion CT parameters in aortitis and chronic periaortitis undergoing immunosuppressive therapy dropped at different extent after therapy. PMID- 27955965 TI - Unusual Presentation of Infantile Myofibroma in the Deep Palm of a Child: A Case Report and Discussion of the Differential Diagnosis. AB - Infantile myofibroma or myofibromatosis is a myofibroblastic and fibroblastic proliferation that is most commonly reported in children younger than 2 years of age. It is a benign process composed histologically of a biphasic pattern of spindle-shaped cells surrounding a zone of less differentiated cells in a hemangiopericytoma-like pattern. We report this tumor in a unique presentation in the deep palm of a 2-year-old child without skin ulceration and with an intimate association with the median nerve. The well-circumscribed nature of the tumor facilitated complete excision with neural preservation. Final pathology was consistent with an unusual type of myofibroma or myofibromatosis. Conservative management with partial excision has been advocated for these masses because of potential surgical morbidity and its benign nature. This case report highlights the differential diagnosis of uncommon soft tissue tumors in the pediatric hand as well as the importance of a surgeon's surgical assessment in guiding treatment. PMID- 27955966 TI - Reticular Perineurioma of the Hand: Diagnosis and Treatment of a Rare Case of Hand Mass. AB - Reticular perineurioma is a rare and recently delineated morphologic variant of benign perineurioma of skin and soft tissues. Because of its nonspecific gross appearance, varying histologic patterns, and potential range of cellularity, perineurioma of the hand is likely to be confused with more commonly encountered tumor or tumor-like conditions such as schwannoma, neurofibroma, fibromyxoid tumors, and giant tumor of tendon sheath. We report the case of a 20-year-old woman who presented with a slowly growing mass of the hand, which was eventually identified as a reticular perineurioma. PMID- 27955968 TI - Characterization of ambient-generated exposure to fine particles using sulfate as a tracer in the Chinese megacity of Guangzhou. AB - Total personal exposures can differ from the concentrations measured at stationary ambient monitoring sites. To provide further insight into factors affecting exposure to particles, chemical tracers were used to separate total personal exposure into its ambient and non-ambient components. Simultaneous measurements of ambient and personal exposure to fine particles (PM2.5) were conducted in eight districts of Guangzhou, a megacity in South China, during the winter of 2011. Considerable significant correlations (Spearman's Rho, rs) between personal exposures and ambient concentrations of sulfate (SO42-; rs>0.68) were found in contrast to elemental carbon (EC; rs>0.37). The average fraction of personal SO42- to ambient SO42- resulting in an adjusted ambient exposure factor of alpha=0.72 and a slope of 0.73 was determined from linear regression analysis when there were minimal indoor sources of SO42-. From all data pooled across the districts, the estimated average ambient-generated and non-ambient-generated exposure to PM2.5 were 55.3MUg/m3 (SD=23.4MUg/m3) and 18.1MUg/m3 (SD=29.1MUg/m3), respectively. A significant association was found between ambient-generated exposure and ambient PM2.5 concentrations (Pearson's r=0.51, p<0.001). As expected, the non-ambient generated exposure was not related to the ambient concentrations. This study highlights the importance of both ambient and non ambient components of total personal exposure in the megacity of Guangzhou. Our results support the use of SO42- as a tracer of personal exposure to PM2.5 of ambient origin in environmental and epidemiological studies. PMID- 27955969 TI - Environmental challenges of the chlor-alkali production: Seeking answers from a life cycle approach. AB - Life Cycle Assessment (LCA) has been used to assess the environmental sustainability of the chlor-alkali production in Europe. The three current technologies applied nowadays are mercury, diaphragm, and membrane cell technology. Despite, having achieved higher energy efficiencies since the introduction of membrane technology, energy consumption is still one of the most important issues in this sector. An emerging technology namely oxygen-depolarised cathodes (ODC) is suggested as a promising approach for reducing the electrolysis energy demand. However, its requirement of pure oxygen and the lack of production of hydrogen, which could otherwise be valorised, are controversial features for greener chlorine production. The aim of this work is to evaluate and compare the environmental profiles of the current and emerging technologies for chlorine production and to identify the main hot spots of the process. Salt mining, brine preparation, electrolysis technology and products treatment are included inside the system boundaries. Twelve environmental impact categories grouped into natural resources usage and environmental burdens are assessed from cradle to gate and further normalised and weighted. Furthermore, hydrogen valorisation, current density and allocation procedure are subjected to sensitivity analysis. Results show that the electrolysis stage is the main contributor to the environmental impacts due to energy consumption, causing 99.5-72% of these impacts. Mercury is the less environmentally sustainable technology, closely followed by diaphragm. This difference becomes bigger after normalisation, owing to hazardous waste generated by mercury technique. Conversely, best results are obtained for ODC instead of membrane scenario, although the reduction in energy requirements is lesser than expected (7%). PMID- 27955967 TI - Digital Necrosis After Lidocaine and Epinephrine Injection in the Flexor Tendon Sheath Without Phentolamine Rescue. AB - The literature generally supports the safety of epinephrine injection in the digits, but recent case reports describe ischemic adverse events associated with the use of lidocaine and epinephrine in which phentolamine rescue was not performed. We present a case of finger necrosis and subsequent amputation in a patient after 1% lidocaine with 1:100,000 epinephrine was injected in the fat and flexor sheaths in the palm for a 3-finger trigger release. Phentolamine rescue was not performed. All surgeons who use epinephrine in the finger should be prepared to reverse vasoconstriction with phentolamine rescue if there is persistently inadequate perfusion of the fingertip. PMID- 27955970 TI - The diagnostic value of serum pentraxin 3 levels in pulmonary contusion. AB - PURPOSE: To investigate the difference in pentraxin 3 (PTX 3) levels between patients with pulmonary contusion and healthy volunteers. MATERIALS AND METHODS: This study was conducted with a group of 20 trauma patients diagnosed with pulmonary contusion and 30 healthy individuals enrolled as a control group in a tertiary university hospital. RESULTS: Median PTX 3 levels were 7.05 (3.29-13.1), ng/ml in the contusion group and 1.03 (0.7-1.58) ng/ml in the control group. PTX 3 titers were significantly higher in patients with pulmonary contusion compared to those of the control group (p<0.001). An area under the curve (AUC) value of 0.968 investigated using ROC analysis to determine the diagnostic value of the PTX-3 in pulmonary contusion patients was measured. A PTX-3 cut-off value of 2.06 produced 95.5% sensitivity and 86.7% specificity. CONCLUSION: PTX 3 levels in pulmonary contusion increased significantly compared to the healthy control group. If supported by wider series, PTX 3 may be expected to be capable of use as a marker in pulmonary contusion. PMID- 27955972 TI - The importance of the mesofascial interface in complete mesocolic excision. AB - Complete mesocolic excision (CME) with Central Vascular Ligation (CVL) is progressively gaining acceptance as the most updated surgical treatment in the multimodal management of colonic cancer. The concept is based on excision of the affected organ with its related primitive dorsal mesenterium as an intact package to maximize local clearance, and high tie ligation to boost regional control, translating the original concept of Total Mesorectal Excision proposed by Heald for rectal cancer. Aim of this review is to analyze the modern concept of the mesenteric organ, with particular regard to the interfaces between its single components and the importance of the meso-fascial interface as the correct plane of separation. The integrity of the mesocolon excised along the meso-fascial interface (meso-fascial separation) prevents any breach of its surface and underlying structures, preserving the radial margin and the complex network of the meso-structure, avoiding any spillage of neoplastic cells within the surgical field. Central Vascular ligation allows for the most effective harvesting of lymph nodes, particularly of the apical ones, whose removal appears to be crucial in optimizing regional control. A surgical plane developed along the meso-fascial interface, coupled with high tie ligation, yields higher quality of surgical specimen, with better oncologic outcome in terms of local recurrence rate, disease-free and overall survival. PMID- 27955971 TI - Utility of point of care assessment of platelet reactivity (using the PFA-100(r)) to aid in diagnosis of stroke. AB - BACKGROUND: Rapid and accurate diagnosis of patients presenting with symptoms of stroke is needed to facilitate the timely delivery of proven effective treatment for patients with acute ischemic stroke (AIS). The aim of this study was to determine whether early assessment of platelet reactivity in patients presenting with symptoms of AIS was associated with a diagnosis of AIS, transient ischemic attack (TIA), or stroke mimic. METHODS: This prospective study included patients with symptoms of AIS treated at an inner-city emergency department (ED). Blood samples were obtained and assayed for platelet reactivity (quantified by closure time). Patients were grouped by discharge diagnosis into: AIS, TIA, or stroke mimic. Binary logistic regression model was used to predict the association of closure time with the final diagnosis of 1) either AIS or TIA or, 2) stroke mimic. RESULTS: Of 114 patients enrolled, 32 were diagnosed with AIS, 33 TIA, and 49 were diagnosed as a stroke mimic. There was no significant difference in closure times among patients with a diagnosis of AIS or TIA versus stroke mimic. A history of migraines and history of seizures were independently associated with lower odds of an AIS or TIA diagnosis (OR 0.31, 95% CI 0.10 to 0.94 and OR 0.08, 95% CI 0.01 to 0.88, respectively). CONCLUSION: Closure time was not found to be a clinically reliable differentiator of patients with a diagnosis of AIS, TIA, or stroke mimic in the ED. PMID- 27955973 TI - Value of preoperative biliary drainage on postoperative outcome after pancreaticoduodenectomy: A case-control study. AB - BACKGROUND/OBJECTIVE: The potential benefit of preoperative biliary drainage (PBD) on postoperative outcomes remains controversial. The aim of this study was to elucidate surgical outcomes of pancreaticoduodenectomy (PD) in patients with PBD and to show the impact of bilirubin level. METHODS: We retrospectively studied all patients who underwent PD in our center between January 2003 and June 2015. Patients were divided into: Group A (PBD) and Group B (no PBD). The primary outcome was the rate of postoperative complication. RESULTS: A total of 588 cases underwent PD. Group A included 314 (53.4%) patients while Group B included 274 (46.6%) patients. The overall incidence of complications and its severity were higher in Group A (p = 0.03 and p = 0.02). There was significant difference in the incidence of postoperative pancreatic fistula (p = 0.002), delayed gastric emptying (p = 0.005), biliary leakage (p = 0.04), abdominal collection (p = 0.04), and wound infection (p = 0.04) in Group A. The mean length of hospital stay was significantly longer in Group A than in Group B (12.86 +/- 7.65 days vs. 11.05 +/- 7.98 days, p = 0.01). No significant impact of preoperative bilirubin level on surgical outcome was detected. CONCLUSION: PBD before PD was associated with major postoperative complications and stent-related complications. PMID- 27955974 TI - Increased access to transplantation of highly sensitized patients under the new kidney allocation system. A single center experience. AB - We aimed to investigate the impact of the new kidney allocation system (KAS) on the rate of transplantation of sensitized patients at our center. Pre-KAS and post-KAS intervals were Jan 1st to Dec 3rd 2014 and Jan 1st 2015 to Dec 3rd 2015, respectively. The number of deceased-donor crossmatches performed by flow cytometry increased from 715 pre-KAS to 1188 post-KAS. The percent of crossmatches performed for sensitized patients with calculated panel reactive antibody (cPRA)>0% increased from 19% pre-KAS to 26% post-KAS (p<0.0001). The number of deceased-donor kidney transplants performed at our center increased from 115 pre-KAS to 125 post-KAS (9% increase). There was a significant increase in the percentage of deceased-donor kidney transplants received by sensitized candidates (from 14% to 26% pre- and post-KAS, respectively; p<0.0001). The highest increase was seen in the patients with cPRA>98%, from 0% to 9%, followed by the group with cPRA 50-79%, from 5% to 8%. This increase was balanced by a decrease of 12% in the percentage of non-sensitized recipients, and a modest decrease of 1% in the group with cPRA 1-49%. In conclusion, transplant rate has increased in sensitized patients after KAS. The highest increase was observed among highly sensitized patients (cPRA>98%). PMID- 27955975 TI - Reply to Dr Altundag from the authors of 'Management of breast cancer brain metastases; a practical review'. PMID- 27955976 TI - Latent Class Analysis: An example for reporting results. AB - OBJECTIVE: The purpose of this paper is to provide a brief non-mathematical introduction to Latent Class Analysis (LCA) and a demonstration for researchers new to the analysis technique in pharmacy and pharmacy administration. LCA is a mathematical technique for examining relationships among observed variables when there may be collections of unobserved categorical variables. Traditionally, LCA focused on polytomous observed variables, but recent work has extended the types of data that can be utilized. Included in this introduction are basic guidelines for the information that should be part of a manuscript submitted for review. For the analysis, LatentGold is used, but I also include basic R code for running LCA and LC Regressions with the poLCA package. PMID- 27955977 TI - Healthcare professionals can assist patients with managing post-kidney transplant expectations. AB - Kidney transplantation is the preferred treatment option for end-stage kidney disease. However, transplantation is not a cure and the prospective recipient needs to carefully evaluate the risks and benefits of receiving a transplant before agreeing to have the transplant. The objective of this commentary is to demonstrate that many kidney transplant recipients have unrealistic expectations of what life after transplantation involves. After monitoring participants in a randomised controlled trial through the first 12 months post-transplantation, we question whether patients understood the impact of receiving a transplant. In our study, participants were not prepared for the considerable time and effort involved in adhering to their medications. Participants felt challenged by the constant hospital, pathology and pharmacy visits; they were fearful that their transplant could reject; and they struggled with adapting to their new way of living. This paper offers new insights into understanding the life of patients post transplantation and the challenges of informing patients about the consequences of kidney transplantation. Understanding the challenges faced by new transplant recipients can help health professionals educate patients about life post-transplantation so patients have a genuine understanding of what they are consenting to, which is likely to enhance medication adherence and ultimately, graft success. PMID- 27955978 TI - Role of Thoracic Epidural Analgesia for Thoracic Surgery and Its Perioperative Effects. PMID- 27955980 TI - The metabolism of glucocerebrosides - From 1965 to the present. AB - Gaucher disease is caused by the defective catabolism of the simple glycosphingolipid, glucosylceramide (GlcCer), due to mutations in the GBA1 gene which encodes for acid beta-glucosidase (GCase), the lysosomal enzyme that degrades GlcCer. Today, Gaucher disease patients are routinely treated with recombinant GCase, in a treatment regimen known as enzyme replacement therapy (ERT). We now review the biochemical basis of ERT and discuss how this treatment has advanced since it was first pioneered by Dr. Roscoe Brady in the 1960s. We will place particular emphasis on the three dimensional structure of GCase, and subsequently discuss a relatively new treatment paradigm, substrate reduction therapy (SRT), in which GlcCer synthesis is partially inhibited, thus reducing its accumulation. Both of these approaches are based on studies and concepts developed by Dr. Brady over his remarkable research career spanning six decades. PMID- 27955981 TI - High solids emulsions produced by ultrasound as a function of energy density. AB - The use of emulsifying methods is frequently required before spray drying food ingredients, where using high concentration of solids increases the drying process yield. In this work, we used ultrasound to obtain kinetically stable palm oil-in-water emulsions with 30g solids/100g of emulsion. Sodium caseinate, maltodextrin and dried glucose syrup were used as stabilizing agents. Sonication time of 3, 7 and 11min were evaluated at power of 72, 105 and 148W (which represents 50%, 75% and 100% of power amplitude in relation to the nominal power of the equipment). Energy density required for each assay was calculated. Emulsions were characterized for droplets mean diameter and size distribution, optical microscopy, confocal microscopy, zeta-potential, creaming index (CI) and rheological behavior. Emulsions presented bimodal size distribution, with D[3,2] ranging from 0.7 to 1.4MUm and CI between 5% and 12%, being these parameters inversely proportional to sonication time and power, but with a visual kinetically stabilization after the treatment at 148W at 7min sonication. D[3,2] showed to depend of energy density as a power function. Sonication presented as an effective method to be integrated to spray drying when emulsification is needed before the drying process. PMID- 27955982 TI - Corrigendum to "Sonographic evaluation of inguinal lesions" [Clin Imaging 40 (2016) 949-955]. PMID- 27955983 TI - What Predicts Performance? A Multicenter Study Examining the Association Between Resident Performance, Rank List Position, and United States Medical Licensing Examination Step 1 Scores. AB - BACKGROUND: Each application cycle, emergency medicine (EM) residency programs attempt to predict which applicants will be most successful in residency and rank them accordingly on their program's Rank Order List (ROL). OBJECTIVE: Determine if ROL position, participation in a medical student rotation at their respective program, or United States Medical Licensing Examination (USMLE) Step 1 rank within a class is predictive of residency performance. METHODS: All full-time EM faculty at Los Angeles County + University of Southern California (LAC + USC), Harbor-UCLA (Harbor), Alameda Health System-Highland (Highland), and the University of California-Irvine (UCI) ranked each resident in the classes of 2013 and 2014 at time of graduation. From these anonymous surveys, a graduation ROL was created, and using Spearman's rho, was compared with the program's adjusted ROL, USMLE Step 1 rank, and whether the resident participated in a medical student rotation. RESULTS: A total of 93 residents were evaluated. Graduation ROL position did not correlate with adjusted ROL position (Rho = 0.14, p = 0.19) or USMLE Step 1 rank (Rho = 0.15, p = 0.14). Interestingly, among the subgroup of residents who rotated as medical students, adjusted ROL position demonstrated significant correlation with final ranking on graduation ROL (Rho = 0.31, p = 0.03). CONCLUSIONS: USMLE Step 1 score rank and adjusted ROL position did not predict resident performance at time of graduation. However, adjusted ROL position was predictive of future residency success in the subgroup of residents who had completed a sub-internship at their respective programs. These findings should guide the future selection of EM residents. PMID- 27955984 TI - Lower-Extremity Weakness in a Teenager Due to Thyrotoxic Periodic Paralysis. AB - BACKGROUND: Thyrotoxic hypokalemic paralysis is the hallmark of thyrotoxic periodic paralysis (TPP). TPP is a potentially deadly complication of hyperthyroidism that occurs because of rapid and dramatic intracellular shift of potassium. This transference results in severe hypokalemia and clinically manifests itself as muscle weakness or paralysis. This condition predominantly affects males of Asian descent, and its presentation can range from mild to severe, as seen in our case. CASE REPORT: We present the case of a 15-year-old Asian-American male who presented to a tertiary-care pediatric emergency department complaining of generalized weakness and flaccid paralysis of his lower extremities. The differential for such a complaint is extremely broad, and the symptoms can result from etiologies arising from the cerebral cortex, the spinal cord, peripheral nerves, the neuromuscular junction, or even the muscles themselves. Our patient was found to have an extremely low serum potassium concentration, as well as an electrocardiogram that revealed a prolonged QT interval and right bundle branch block. The etiology of these abnormalities and the patient's symptoms was found to be undiagnosed and uncontrolled hyperthyroidism from Grave's disease, which resulted in this dramatic presentation of thyrotoxic hypokalemic paralysis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This entity is common in Asia but still somewhat rare in the United States and other Western countries. Our case illustrates that careful history taking and a focused diagnostic evaluation, in conjunction with having an awareness of this disease, can help expedite diagnosis and management, as well as avoid unnecessary and potential harmful testing in the emergency department setting. PMID- 27955979 TI - Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation. AB - Cardiomyopathies are a leading cause of heart failure and are often caused by mutations in sarcomeric genes, resulting in contractile dysfunction and cellular damage. This may stimulate the production of a robust proinflammatory response. To determine whether myocardial inflammation is associated with cardiac dysfunction in dilated cardiomyopathy (DCM) caused by MYBPC3 mutation, we used the well-characterized cMyBP-C(t/t) mouse model of DCM at 3months of age. Compared to wild type (WT) mice, DCM mice exhibited significantly decreased fractional shortening (36.4+/-2% vs. 15.5+/-1.0%, p<0.0001) and significantly increased spleen weight (5.3+/-0.3 vs. 7.2+/-0.4mg/mm, p=0.002). Intriguingly, flow cytometry analysis revealed a significant increase in total (CD45+CD11b+Ly6C MHCII+F480+) macrophages (6.5+/-1.4% vs. 14.8+/-1.4%, p=0.002) and classically activated (CD45+CD11b+Ly6C-MHCII+F480+CD206-) proinflammatory (M1) macrophages (3.4+/-0.8% vs. 10.3+/-1.2%, p=0.0009) in DCM hearts as compared with WT hearts. These results were further confirmed by immunofluorescence analysis of heart tissue sections. Splenic red pulp (CD11b+Ly6C+MHCIIlowF480hi) macrophages were significantly elevated (1.3+/-0.1% vs. 2.4+/-0.1%, p=0.0001) in DCM compared to WT animals. Serum cytokine analysis in DCM animals exhibited a significant increase (0.65+/-0.2 vs. 2.175+/-0.5pg/mL, p=0.02) in interleukin (IL)-6 compared to WT animals. Furthermore, RNA-seq analysis revealed the upregulation of inflammatory pathways in the DCM hearts. Together, these data indicate a robust proinflammatory response in DCM hearts, likely in response to cellular damage triggered by MYBPC3 mutation and resultant contractile dysfunction. PMID- 27955985 TI - Quarterly Reporting of Computed Tomography Ordering History Reduces the Use of Imaging in an Emergency Department. AB - BACKGROUND: Computed tomography (CT) is a useful and necessary part of many emergency department (ED) assessments. However, the costs of imaging and the health risks associated with radiation exposure have sparked national efforts to reduce CT ordering in EDs. STUDY OBJECTIVE: We analyzed CT ordering habits prior to and following implementation of a feedback tool at a community hospital. METHODS: In this intervention study, we identified the CT-ordering habits of physicians and mid-level care providers (physician assistants and nurse practitioners) at baseline and after implementation of a system that sent quarterly feedback reports comparing their ordering habits with those of their peers. Variability in ordering and subgroup analyses by body region were included in these reports. RESULTS: We examined the records of 104,454 patients seen between October 1, 2013 and December 31, 2014. There were 5552 or 21.0% of patients seen during the baseline period that underwent CT imaging. We observed an absolute reduction in imaging of 2.3% (95% confidence interval 1.7-2.8%) after implementation, avoiding approximately $400,000 in costs, 22 days of scanning time, and radiation exposure equivalent to 33,000 chest films annually. These changes occurred across physicians and mid-level providers, regardless of the number years of practice or board certification. CONCLUSIONS: Implementation of a feedback mechanism reduced CT use by emergency medicine practitioners, with concomitant reductions in cost and radiation exposure. The change was similar across levels of medical care. Future studies will examine the effect of the feedback reporting system at other institutions in our hospital network. PMID- 27955987 TI - [A pharmacological treatment algorithm for localised neuropathic pain]. PMID- 27955986 TI - Role of angiotensin II and angiotensin type-1 receptor in scorpion venom-induced cardiac and aortic tissue inflammation. AB - Scorpion stings are mainly associated with cardiovascular disturbances that may be the cause of death. In this study, the involvement of angiotensin II (Ang II) in cardiac and aortic inflammatory response was studied. Mice were injected with Androctonus australis hector (Aah) scorpion venom (0.5mg/kg, subcutaneously), in the presence or absence of an angiotensin converting enzyme (ACE) inhibitor, captopril (15mg/kg/day/1day intraperitoneally) or an angiotensin type-1 receptor (AT1R) antagonist, valsartan (15mg/kg/day/15days, orally). In the envenomed group, results revealed severe tissue alterations with a concomitant increase of metabolic enzymes (CK and CK-MB) in sera. An important inflammatory cell (neutrophil and eosinophil) infiltration into the heart and aorta were observed, accompanied by imbalanced redox status (NO, MDA, catalase and GSH) and high cytokine levels (IL-6 and TNF-alpha) in sera with the expression of MMP-2 and MMP 9 metalloproteinases. However, the blockade of the actions of AngII by the ACE inhibitor or by the AT1R antagonist prevented cardiac and aortic tissue alterations, inflammatory cell infiltration, as well as the oxidative stress generation and cytokine and metalloproteinase expression. These results suggest the involvement of AngII, through its AT1R in the inflammation induced by Aah venom, in the heart and the aorta. PMID- 27955988 TI - Electrochemical H2O2 biosensor composed of myoglobin on MoS2 nanoparticle graphene oxide hybrid structure. AB - In this research, the electrochemical biosensor composed of myoglobin (Mb) on molybdenum disulfide nanoparticles (MoS2 NP) encapsulated with graphene oxide (GO) was fabricated for the detection of hydrogen peroxide (H2O2). Hybrid structure composed of MoS2 NP and GO (GO@MoS2) was fabricated for the first time to enhance the electrochemical signal of the biosensor. As a sensing material, Mb was introduced to fabricate the biosensor for H2O2 detection. Formation and immobilization of GO@MoS2 was confirmed by transmission electron microscopy, ultraviolet-visible spectroscopy, scanning electron microscopy, and scanning tunneling microscopy. Immobilization of Mb, and electrochemical property of biosensor were investigated by cyclic voltammetry and amperometric i-t measurements. Fabricated biosensor showed the electrochemical signal enhanced redox current as -1.86MUA at an oxidation potential and 1.95MUA at a reduction potential that were enhanced relative to those of electrode prepared without GO@MoS2. Also, this biosensor showed the reproducibility of electrochemical signal, and retained the property until 9 days from fabrication. Upon addition of H2O2, the biosensor showed enhanced amperometric response current with selectivity relative to that of the biosensor prepared without GO@MoS2. This novel hybrid material-based biosensor can suggest a milestone in the development of a highly sensitive detecting platform for biosensor fabrication with highly sensitive detection of target molecules other than H2O2. PMID- 27955989 TI - Sorption mechanisms of sulfamethazine to soil humin and its subfractions after sequential treatments. AB - Sorption mechanisms of an antibiotic sulfamethazine (SMT) to humin (HM) isolated from a peat soil and its subfractions after sequential treatments were examined. The treatments of HM included removal of ash, O-alkyl carbon, lipid, and lignin components. The HF/HCl de-ashing treatment removed a large amount of minerals (mainly silicates), releasing a fraction of hydrophobic carbon sorption domains that previously were blocked, increasing the sorption of SMT by 33.3%. The de-O alkyl carbon treatment through acid hydrolysis greatly reduced polarity of HM samples, thus weakening the interaction between sorbents with water at the interfaces via H-bonding, leaving more effective sorption sites. Sorption of SMT via mechanisms such as van der Waals forces and pi-pi interactions was enhanced by factors of 2.04-2.50. After removing the lipid/lignin component with the improved Soxhlet extraction/acid hydrolysis, the organic carbon content normalized sorption enhancement index Eoc was calculated. The results demonstrated that the Eoc-lipid for SMT (16.9%) was higher than Eoc-lignin (10.1%), implying that removal of unit organic carbon mass of lipid led to a higher increase in sorption strength than that of lignin. As each component was progressively removed from HM, the sorption strength and isotherm nonlinearity of the residual HM samples for SMT were gradually enhanced. The Koc values of SMT by HM samples were positively correlated with their aromatic carbon contents, implying that pi-pi electron donor-acceptor interactions between the benzene ring of sorbate and the aromatic domains in HM played a significant role in their interactions. PMID- 27955990 TI - Fate of radiolabeled C60 fullerenes in aged soils. AB - Fullerenes (e.g. C60, C70, etc.) present in soil may undergo changes in its retention with aging. In this study, the partitioning behavior of (14C)-C60 aged up to 12 weeks was investigated in biosolids-amended soil. Spiked samples were subjected to sequential partitioning using water, methanol, and toluene followed by total combustion of solids; the distribution of 14C across solvents and matrices were used to provide insights on C60 behavior. In most samples, 14C only partitioned in toluene with the remaining (non-extractable) activity detected in the solid phase. In all biosolids-amended soil samples, an increase in non extractable 14C were observed for those exposed to light (vs dark) with the greatest difference observed in biosolids + sand samples. Possible processes that contribute to the observed 14C distribution, i.e. retention and potential transformation of C60, were discussed. Over-all, results suggest that environmental exposure to C60 and potentially transformed C60 species, as a result of their release from soils, is likely to be low. PMID- 27955991 TI - Antibiotic prescription patterns for upper respiratory tract infections in the outpatient Qatari population in the private sector. AB - BACKGROUND: Antibiotics are often inappropriately prescribed for upper respiratory tract infections (URTIs) in developed countries. Data on the proportion of inappropriate prescriptions are lacking from the Middle East and other developing countries. METHODS: Health insurance claims for all antibiotics prescribed for URTIs in the private sector in the State of Qatar between May 2014 and December 2015 were retrieved. During the study period, health insurance was limited to Qatari nationals. Topical antibiotics were excluded. Data on the prescriber's specialty, as listed with the licensing authority, were also retrieved. Diagnoses were classified as appropriate or inappropriate based on the likelihood of a bacterial etiology that may warrant antibiotic use. RESULTS: A total of 75 733 claims were made during the study period. Of these, 41 556 (55%) were for an appropriate indication, while 34 177 (45%) were for an inappropriate indication. The most common antibiotic classes prescribed were cephalosporins (43% of claims; 44% inappropriate), penicillins (28% of claims; 44% inappropriate), macrolides (19% of claims; 52% inappropriate), and fluoroquinolones (9% of claims; 40% inappropriate). Nearly 5% of antibiotics were prescribed in intravenous formulations. The most common prescribers were General/Family Practice physicians (53% of claims; 50% inappropriate), followed by Pediatrics (18.6% of claims; 36% inappropriate) and Internal Medicine (14.1% of claims; 44% inappropriate). CONCLUSIONS: There is a high rate of inappropriate antibiotic prescription for acute URTIs in the private health care sector in the State of Qatar. Further studies are needed to determine the population-based rates across the country. Interventions to decrease inappropriate use in such settings are urgently needed. PMID- 27955993 TI - Highlights from the 6th International Meeting on Emerging Diseases and Surveillance (IMED 2016) Vienna, Austria from Nov 3 to 7, 2016. PMID- 27955992 TI - Pediatric multidrug-resistant tuberculosis clinical trials: challenges and opportunities. AB - On June 17, 2016, RESIST-TB, IMPAACT, Vital Strategies, and New Ventures jointly hosted the Pediatric Multidrug Resistant Tuberculosis Clinical Trials Landscape Meeting in Arlington, Virginia, USA. The meeting provided updates on current multidrug-resistant tuberculosis (MDR-TB) trials targeting pediatric populations and adult trials that have included pediatric patients. A series of presentations were given that discussed site capacity needs, community engagement, and additional interventions necessary for clinical trials to improve the treatment of pediatric MDR-TB. This article presents a summary of topics discussed, including the following: current trials ongoing and planned; the global burden of MDR-TB in children; current regimens for MDR-TB treatment in children; pharmacokinetics of second-line anti-tuberculosis medications in children; design, sample size, and statistical considerations for MDR-TB trials in children; selection of study population, design, and treatment arms for a trial of novel pediatric MDR-TB regimens; practical aspects of pediatric MDR-TB treatment trials; and strategies for integrating children into adult tuberculosis trials. These discussions elucidated barriers to pediatric MDR-TB clinical trials and provided insight into necessary next steps for progress in this field. Investigators and funding agencies need to respond to these recommendations so that important studies can be implemented, leading to improved treatment for children with MDR-TB. PMID- 27955996 TI - Anti-tau vaccine in Alzheimer's disease: a tentative step. PMID- 27955994 TI - 2016 Annual Report of The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. AB - BACKGROUND: The Society of Thoracic Surgeons (STS)/American College of Cardiology Transcatheter Valve Therapy (TVT) Registry captures all procedures with Food and Drug Administration-approved transcatheter valve devices performed in the United States, and is mandated as a condition of reimbursement by the Centers for Medicaid & Medicare Services. OBJECTIVES: This annual report focuses on patient characteristics, trends, and outcomes of transcatheter aortic and mitral valve catheter-based valve procedures in the United States. METHODS: We reviewed data for all patients receiving commercially approved devices from 2012 through December 31, 2015, that are entered in the TVT Registry. RESULTS: The 54,782 patients with transcatheter aortic valve replacement demonstrated decreases in expected risk of 30-day operative mortality (STS Predicted Risk of Mortality [PROM]) of 7% to 6% and transcatheter aortic valve replacement PROM (TVT PROM) of 4% to 3% (both p < 0.0001) from 2012 to 2015. Observed in-hospital mortality decreased from 5.7% to 2.9%, and 1-year mortality decreased from 25.8% to 21.6%. However, 30-day post-procedure pacemaker insertion increased from 8.8% in 2013 to 12.0% in 2015. The 2,556 patients who underwent transcatheter mitral leaflet clip in 2015 were similar to patients from 2013 to 2014, with hospital mortality of 2% and with mitral regurgitation reduced to grade <=2 in 87% of patients (p < 0.0001). The 349 patients who underwent mitral valve-in-valve and mitral valve-in ring procedures were high risk, with an STS PROM for mitral valve replacement of 11%. The observed hospital mortality was 7.2%, and 30-day post-procedure mortality was 8.5%. CONCLUSIONS: The TVT Registry is an innovative registry that that monitors quality, patient safety and trends for these rapidly evolving new technologies. PMID- 27955995 TI - Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial. AB - BACKGROUND: Neurofibrillary pathology composed of tau protein is a main correlate of cognitive impairment in patients with Alzheimer's disease. Immunotherapy targeting pathological tau proteins is therefore a promising strategy for disease modifying treatment of Alzheimer's disease. We have developed an active vaccine, AADvac1, against pathological tau proteins and assessed it in a phase 1 trial. METHODS: We did a first-in-man, phase 1, 12 week, randomised, double-blind, placebo-controlled study of AADvac1 with a 12 week open-label extension in patients aged 50-85 years with mild-to-moderate Alzheimer's disease at four centres in Austria. We randomly assigned patients with a computer-generated sequence in a 4:1 ratio overall to receive AADvac1 or placebo. They received three subcutaneous doses of AADvac1 or placebo from masked vaccine kits at monthly intervals, and then entered the open-label phase, in which all patients were allocated to AADvac1 treatment and received another three doses at monthly intervals. Patients, carers, and all involved with the trial were masked to treatment allocation. The primary endpoint was all-cause treatment-emergent adverse events, with separate analyses for injection site reactions and other adverse events. We include all patients who received at least one dose of AADvac1 in the safety assessment. Patients who had a positive IgG titre against the tau peptide component of AADvac1 at least once during the study were classified as responders. The first-in-man study is registered with EU Clinical Trials Register, number EudraCT 2012-003916-29, and ClinicalTrials.gov, number NCT01850238; the follow-up study, which is ongoing, is registered with EU Clinical Trials Register, number EudraCT 2013-004499-36, and ClinicalTrials.gov, number NCT02031198. FINDINGS: This study was done between June 9, 2013, and March 26, 2015. 30 patients were randomly assigned in the double-blind phase: 24 patients to the AADvac1 group and six to the placebo group. A total of 30 patients received AADvac1. Two patients withdrew because of serious adverse events. The most common adverse events were injection site reactions after administration (reported in 16 [53%] vaccinated patients [92 individual events]). No cases of meningoencephalitis or vasogenic oedema occurred after administration. One patient with pre-existing microhaemorrhages had newly occurring microhaemorrhages. Of 30 patients given AADvac1, 29 developed an IgG immune response. A geometric mean IgG antibody titre of 1:31415 was achieved. Baseline values of CD3+ CD4+ lymphocytes correlated with achieved antibody titres. INTERPRETATION: AADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study. Further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADvac1. FUNDING: AXON Neuroscience SE. PMID- 27955997 TI - Mobilising Expertise and Resources to Close the Radiotherapy Gap in Cancer Care. AB - Closing the gap in cancer care within low- and middle-income countries and in indigenous and geographically isolated populations in high-income countries requires investment and innovation. This is particularly true for radiotherapy, for which the global disparity is one of the largest in healthcare today. New models and paradigms and non-traditional collaborations have been proposed to improve global equity in cancer control. We describe recent initiatives from within the radiation oncology community to increase access to treatment, build the low- and middle-income countries' radiation oncology workforce, mobilise more professionals from within high-income countries and raise awareness of the global need for equitable cancer care. PMID- 27955998 TI - High level methicillin resistance correlates with reduced Staphylococcus aureus endothelial cell damage. AB - There has been controversy about the intrinsic virulence of methicillin-resistant Staphylococcus aureus (MRSA) as compared to methicillin-susceptible S. aureus (MSSA). To address this discrepancy, the intrinsic virulence of 42 MRSA and 40 MSSA clinical isolates was assessed by testing endothelial cell (EC) damage, a surrogate marker for virulence in blood stream infections. Since these clinical isolates represent a heterogeneous group, well characterized S. aureus laboratory strains with SCCmec loss- and gain-of-function mutations were used in addition. The clinical MRSA isolates carrying typical hospital acquired SCCmec types (I, II or III) induced significantly less damage (47.8%) as compared to isolates with other SCCmec types (62.3%, p=0.03) and MSSA isolates (64.2%, p<0.01). There was a strong inverse correlation between high-level oxacillin resistance and low EC damage induction (R2=0.4464, p<0.001). High-level oxacillin resistant strains (MIC >32MU/ml) grew significantly slower as compared to isolates with low-level resistance (p=0.047). The level of EC damage positively correlated with alpha- and delta-toxin production (p<0.0001 and p<0.05, respectively) but not with beta toxin production. Invasive MRSA isolates (n=21, 56.3%) were significantly less cytotoxic as compared to invasive MSSA isolates (n=20, 68.0%, p<0.05). There was no difference between EC damage induced by superficial versus invasive isolates in either MRSA or MSSA strains. Our data suggest that the intrinsic virulence of MRSA is similar or even reduced as compared to MSSA strains but is linked to the level of methicillin resistance. PMID- 27956000 TI - Bringing Produce to the People: Implementing a Social Marketing Food Access Intervention in Rural Food Deserts. AB - This study describes and evaluates the process of implementing a social marketing food access intervention for food desert communities in rural California. A case study approach used mixed-methods data from nationwide market comparisons, environmental assessment, and community informants. Lessons learned demonstrate room for improvement in implementing such strategies and underscore the importance of involving community in decision making; the strategic importance of operational decisions relating to intervention design, site and product selection, and distribution models; and the need to reconsider the problem of access in rural areas. PMID- 27955999 TI - Neuroprotection for glaucoma: Requirements for clinical translation. AB - Within the field of glaucoma research, neuroprotection is defined as slowing the functional loss in glaucoma by a mechanism independent of lowering of intraocular pressure. There is currently a great potential for research surrounding neuroprotection as it relates to glaucoma. Anatomical targets for neuroprotection should focus on upstream rather than downstream factors, and could include any part of the retinal ganglion cell, the glia, especially astrocytes or Muller cells, and vasculature. The great number of anatomical targets is exceeded only by the number of possible biochemical pathways and potential treatments. Successful treatment may be accomplished through the targeting of one or even a combination of multiple pathways. Once a treatment is shown effective in vitro, it should be evaluated in vivo with carefully chosen animal models and studied in sufficient numbers to detect statistically and clinically significant effects. Such a drug should have few systemic side effects and its delivery should be optimized so as to encourage compliance. There are still a multitude of possible screens available to test the efficacy of a neuroprotective drug and a single gold standard is ideal for the accurate assessment and comparison of new drugs. Future studies in neuroprotection should investigate the genetic component of the disease, novel pharmaceutical agents for new or known pathways, modulations of scleral biomechanics, and relation to research of other complex disorders of the central nervous system. PMID- 27956001 TI - Relation of Functional Status to Risk of Development of Atrial Fibrillation. AB - Identifying patients at risk is now important as there are demonstrable ways to alter disease progression which could potentially prevent atrial fibrillation (AF) and its complications. We sought whether impaired functional capacity was associated with risk of AF, independent of myocardial dysfunction. In this community-based study, asymptomatic participants aged >=65 years were recruited if they had >=1 risk factor (e.g., hypertension, diabetes mellitus, and obesity). Participants underwent baseline echocardiography (including measurement of myocardial mechanics) and six-minute walk test. The CHARGE-AF score was used to calculate 5-year risk of developing AF. Receiver operating characteristic curves were used to assess for independent risk factors for AF. A total of 607 patients (age 71 +/- 5 years, men 47%) were studied at baseline and followed for at least 6 months. Patients in the higher AF risk groups were older and had increased rates of hypertension, diabetes mellitus, and ischemic heart disease (p <0.05). Greater AF risk was associated with lower exercise capacity, independent of lower mean global longitudinal strain, global circumferential strain, greater mean E/e' ratio, indexed left atrial volume and LV mass. Multivariate linear regression confirmed association of LV and functional capacity parameters with AF risk. Although functional capacity is impaired in AF, this association precedes the onset of AF. In conclusion, poor functional status is associated with AF risk, independent of LV function. PMID- 27956002 TI - Comparison of Maximal Wall Thickness in Hypertrophic Cardiomyopathy Differs Between Magnetic Resonance Imaging and Transthoracic Echocardiography. AB - Left ventricular (LV) wall thickness is a prognostic marker in hypertrophic cardiomyopathy (HC). LV wall thickness >=30 mm (massive hypertrophy) is independently associated with sudden cardiac death. Presence of massive hypertrophy is used to guide decision making for cardiac defibrillator implantation. We sought to determine whether measurements of maximal LV wall thickness differ between cardiac magnetic resonance imaging (MRI) and transthoracic echocardiography (TTE). Consecutive patients were studied who had HC without previous septal ablation or myectomy and underwent both cardiac MRI and TTE at a single tertiary referral center. Reported maximal LV wall thickness was compared between the imaging techniques. Patients with >=1 technique reporting massive hypertrophy received subset analysis. In total, 618 patients were evaluated from January 1, 2003, to December 21, 2012 (mean [SD] age, 53 [15] years; 381 men [62%]). In 75 patients (12%), reported maximal LV wall thickness was identical between MRI and TTE. Median difference in reported maximal LV wall thickness between the techniques was 3 mm (maximum difference, 17 mm). Of the 63 patients with >=1 technique measuring maximal LV wall thickness >=30 mm, 44 patients (70%) had discrepant classification regarding massive hypertrophy. MRI identified 52 patients (83%) with massive hypertrophy; TTE, 30 patients (48%). Although guidelines recommend MRI or TTE imaging to assess cardiac anatomy in HC, this study shows discrepancy between the techniques for maximal reported LV wall thickness assessment. In conclusion, because this measure clinically affects prognosis and therapeutic decision making, efforts to resolve these discrepancies are critical. PMID- 27956003 TI - Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients with Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol. AB - To assess the effects of anacetrapib added to statin +/- other lipid-modifying therapies in patients with hypercholesterolemia and not at their low-density lipoprotein cholesterol (LDL-C) goal (as per National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of moderate/high-intensity statin +/- other lipid-modifying therapies with LDL-C >=70, >=100, >=130, or >=160 mg/dl for very high, high, moderate, and low coronary heart disease risk, respectively, or at LDL-C goal with HDL-C <=40 mg/dl, were randomized 1:1:1, stratified by background therapy use, to anacetrapib 100 mg (n = 153), anacetrapib 25 mg (n = 152), or placebo (n = 154) for 24 weeks, followed by a 12-week off-drug reversal phase. The primary end points were percent change from baseline in LDL-C (beta-quantification method) and HDL-C, as well as the safety profile of anacetrapib. Both doses of anacetrapib reduced LDL-C, non-HDL-C, apolipoprotein (Apo) B, and lipoprotein a and increased HDL-C and Apo AI versus placebo (p <0.001 for all). There were no meaningful differences between the anacetrapib 25 mg, 100 mg, and placebo groups in the proportions of discontinuations due to drug-related adverse events (0.7%, 1.3% vs 1.3%) or in abnormalities in liver enzymes (0%, 0% vs 0.7%), creatine kinase elevations overall (0%, 0.7% vs 0%) or with muscle symptoms (none seen), blood pressure, electrolytes, or adjudicated cardiovascular events (0.7%, 0.7% vs 1.3%). In conclusion, treatment with anacetrapib resulted in substantial reductions in LDL-C and increases in HDL-C and was generally well tolerated. PMID- 27956005 TI - Differences Between Access to Follow-Up Care and Inappropriate Shocks Based on Insurance Status of Implantable Cardioverter Defibrillator Recipients. AB - Differences in implantable cardioverter defibrillator (ICD) utilization based on insurance status have been described, but little is known about postimplant follow-up patterns associated with insurance status and outcomes. We collected demographic, clinical, and device data from 119 consecutive patients presenting with ICD shocks. Insurance status was classified as uninsured/Medicaid (uninsured) or private/Health Maintenance Organization /Medicare (insured). Shock frequencies were analyzed before and after a uniform follow-up pattern was implemented regardless of insurance profile. Uninsured patients were more likely to present with an inappropriate shock (63% vs 40%, p = 0.01), and they were more likely to present with atrial fibrillation (AF) as the shock trigger (37% vs 19%, p = 0.04). Uninsured patients had a longer interval between previous physician contact and index ICD shock (147 +/- 167 vs 83 +/- 124 days, p = 0.04). Patients were followed for a mean of 521 +/- 458 days after being enrolled in a uniform follow-up protocol, and there were no differences in the rate of recurrent shocks based on insurance status. In conclusion, among patients presenting with an ICD shock, underinsured/uninsured patients had significantly longer intervals since previous physician contact and were more likely to present with inappropriate shocks and AF, compared to those with private/Medicare coverage. After the index shock, both groups were followed uniformly, and the differences in rates of inappropriate shocks were mitigated. This observation confirms the importance of regular postimplant follow-up as part of the overall ICD management standard. PMID- 27956004 TI - Incidence and Prognostic Impact of Respiratory Support in Patients With ST Segment Elevation Myocardial Infarction. AB - Data addressing the use of respiratory support in acute coronary syndromes are lacking. To address this evidence gap, we characterized prognostic impact and trends in utilization of invasive mechanical ventilation (IMV) and noninvasive ventilation (NIV) in patients hospitalized with ST-segment elevation myocardial infarction (STEMI) from 2002 through 2013 using the National Inpatient Sample. Multivariate logistic regression was performed to identify patient, hospital, and clinical characteristics associated with requiring IMV or NIV within 24 hours of hospitalization. Multivariate Cox proportional hazards regression was used to quantify the magnitude of in-hospital mortality associated with IMV and NIV use. From 2002 to 2013, we identified 1,867,114 patients with STEMI. Age, gender, higher co-morbidity burden, and chronic pulmonary disease were significantly associated with need for respiratory support. The use of IMV and NIV increased at average annual rates of 6.6% and 14.3%, respectively (ptrend <0.001). Age- and gender-adjusted mortality rates are high but declined for patients with STEMI requiring IMV (44.7% in 2002 to 37.6% in 2013, ptrend = 0.002) and NIV (11.6% in 2002 to 6.8% in 2013, ptrend <0.001). Compared to patients with STEMI with no ventilation need, a requirement for IMV or NIV was associated with increased adjusted in-hospital mortality (hazard ratio 2.5, p <0.001 and 1.7, p <0.001, respectively). In conclusion, approximately 1 in 23 patients hospitalized with STEMI will require respiratory support in the form of IMV or NIV. Patients with STEMI who require respiratory support have a high risk of death, although rates of in-hospital mortality have decreased over time. PMID- 27956007 TI - High incidence of clinically significant concomitant prostate cancer in patients undergoing radical cystectomy for bladder cancer: A 10-year single-center experience. AB - AIM: To analyze prostate cancer (PCa) incidence, clinical significance, and recurrence in 213 patients who underwent radical cystectomy (RC) for advanced bladder cancer (BC). PATIENTS AND METHODS: We conducted a 10-year retrospective analysis of a single-center database comprising the effect of PCa in RC specimens. RESULTS: In total, 113/213 male patients (53.1%) had PCa in the RC specimen. Patients' age, prostate-specific antigen (PSA), and also free PSA% were significant predictors for PCa. In addition, adverse bladder histology (>=pT3) was found in 63.7% of patients with PCa. A total of 52.2% (59/113) of patients had at least a Gleason score (GS) 7 in final pathology and 10.6% of RC specimens showed an organ border growth (>=pT3a). It was noted that 28.3% of patients experienced a biochemical recurrence (PSA>=0.2ng/ml), among them 86.7% had GS>=7 in the RC specimen; however, 2 patients were diagnosed with a GS 5. Moreover, we found that 80% of patients with biochemical recurrence had an organ-extended (>=pT3) histology of the bladder and 40% of patients with biochemical recurrence died of PCa rather than from BC. CONCLUSION: Concomitant PCa is occurring in>50% of RC specimens with a significant proportion having characteristics (GS, pathological stage) of clinically relevant disease. Adverse bladder histology is a risk factor for both PCa and biochemical PSA recurrence. Follow-up analyses after RC should include PSA measurements also in low-risk PCa as a considerable number of patients develop biochemical recurrence and metastases from PCa partly ending up with death related to PCa in patients suffering from BC. PMID- 27956008 TI - Effect of bumetanide, a selective NKCC1 inhibitor, on hallucinations of schizophrenic patients; a double-blind randomized clinical trial. PMID- 27956006 TI - Dynamics of three-dimensional telomere profiles of circulating tumor cells in patients with high-risk prostate cancer who are undergoing androgen deprivation and radiation therapies. AB - INTRODUCTION: Accurate assessment and monitoring of the therapeutic efficacy of locally advanced prostate cancer remains a major clinical challenge. Contrary to prostate biopsies, circulating tumor cells (CTCs) are a cellular source repeatedly obtainable by blood sampling and could serve as a surrogate marker for treatment efficacy. In this study, we used size-based filtration to isolate and enumerate CTCs from the blood of 20 patients with high-risk (any one of cT3, Gleason 8-10, or prostate-specific antigen>20ng/ml), nonmetastatic, and treatment naive prostate cancer before and after androgen deprivation therapy (ADT) and radiation therapy (RT). MATERIALS AND METHODS: We performed 3D telomere-specific quantitative fluorescence in situ hybridization on isolated CTCs to determine 3D telomere profiles for each patient before and throughout the course of both ADT and RT. RESULTS: Based on the distinct 3D telomere signatures of CTC before treatment, patients were divided into 3 groups. ADT and RT resulted in distinct changes in 3D telomere signatures of CTCs, which were unique for each of the 3 patient groups. CONCLUSION: The ability of 3D telomere analysis of CTCs to identify disease heterogeneity among a clinically homogeneous group of patients, which reveals differences in therapeutic responses, provides a new opportunity for better treatment monitoring and management of patients with high-risk prostate cancer. PMID- 27956010 TI - Erratum to "Brief interventions to prevent sexually transmitted infections suitable for in-service use: A systematic review" [Prev. Med. 91 (2016) 364-382]. PMID- 27956011 TI - More tilt, less drug: treating severe compression of inferior vena cava during caesarean section. PMID- 27956009 TI - Maintenance pharmacotherapy normalizes the relapse curve in recently abstinent tobacco smokers with schizophrenia and bipolar disorder. AB - OBJECTIVE: To compare the effect of maintenance pharmacotherapy on sustained abstinence rates between recently abstinent smokers with schizophrenia and bipolar disorder (SBD) and general population smokers without psychiatric illness. METHOD: We performed a person-level, pooled analysis of two randomized controlled trials of maintenance varenicline, conducted in adult smokers with SBD and general population smokers, controlling for severity of dependence. Smokers abstinent after 12-weeks of open varenicline treatment were randomly assigned to >=12-weeks maintenance varenicline or identical placebo. RESULTS: In those assigned to maintenance placebo, the abstinence rate at week-24 was lower in those with SBD than for those without psychiatric illness (29.4+/-1.1% vs. 61.8+/ 0.4%, OR:0.26, 95% CI: 0.13, 0.52, p<0.001). In smokers assigned to maintenance pharmacotherapy, however, there was no effect of diagnosis on abstinence rates at week-24 (87.2+/-0.8% vs. 81.9+/-0.2%, OR: 1.68, 95% CI: 0.53, 5.32, p=0.38). Time to first lapse was shortest in those with SBD assigned to maintenance placebo (Q1=12days, 95%CI: 4, 16), longer in those without psychiatric illness assigned to maintenance placebo (Q1=17days, 95%CI: 17, 29), still longer in general population smokers assigned to maintenance varenicline (Q1=88, 95% CI:58,91, and longest in those with SBD who received maintenance varenicline (Q1>95days, 95%CI:non-est), (Chi23df=96.99, p<0.0001; all pairwise comparisons p<0.001). CONCLUSIONS: Following a standard 12-week course of pharmacotherapy, people with schizophrenia and bipolar disorder were more likely to relapse to smoking without maintenance varenicline treatment. Maintenance pharmacotherapy could improve longer-term tobacco abstinence rates and reduce known smoking-related health disparities in those with SMI. PMID- 27956012 TI - A pioneer in marine sediment risk assessment - a tribute to Ed Long (1942-2016). PMID- 27956013 TI - Determination of buildup and dilution of wastewater effluent in shellfish growing waters through a modified application of super-position. AB - Since 1925, dilution analysis has been used to minimize pathogenic impacts to bivalve molluscan shellfish growing areas from treated wastewater effluent in the National Shellfish Sanitation Program (NSSP). For over twenty five years, the U.S. Food and Drug Administration (FDA) has recommended a minimum of 1000:1 dilution of effluent within prohibited closure zones established around wastewater treatment plant (WWTP) discharges. During May 2010, using recent technologies, a hydrographic dye study was conducted in conjunction with a pathogen bioaccumulation study in shellfish adjacent to a WWTP discharge in Yarmouth, ME. For the first time an improved method of the super-position principle was used to determine the buildup of dye tagged sewage effluent and steady state dilution in tidal waters. Results of the improved method of dilution analysis illustrate an economical, reliable and more accurate and manageable approach for estimating the buildup and steady state pollutant conditions in coastal and estuarine waters. PMID- 27956014 TI - Oil permeability variations on lagoon sand beaches in the Patos-Guaiba system in Rio Grande do Sul, Brazil. AB - Permeability is the ability of a sediment deposit to allow fluids to pass through it. It depends on the local types of sediments. When the fluid is oil, high permeability implies greater interaction with the site and more extensive damage, which makes recovery most difficult. Knowledge of permeability oscillations is necessary to understand oil behavior and improve cleanup techniques. The goal is to determine oil permeability variations on lagoon sand beaches. Oil permeability tests were performed at the beach face, using a Modified Phillip Dunne Permeameter and parameters were sampled. Permeability of lagoon beaches is driven by grain diameter and roundness, soil compaction, and depth of the water table. Factors that enhance permeability include: sand sorting, vertical distribution of sediments and gravel percentage. High permeability on lagoon beaches is related to polymodal distribution, to the sediment package, and to the system's low mobility. PMID- 27956016 TI - Low-cost GICs reduce survival rate in occlusal ART restorations in primary molars after one year: A RCT. AB - INTRODUCTION: The high costs of the worldwide recommended GICs might be a barrier for the implementation of ART. To overcome this problem, low cost GIC are used even though there is a lack of evidence for the survival rate of restorations. OBJECTIVES: To evaluate the performance of low-cost GICs used on occlusal ART restorations after one year. METHODS: A total of 150 primary molars in 150 children with occlusal caries lesions were selected in 4-8 year-old children. The patients were randomly allocated in three groups: G1-GC Gold Label 9 (GC Corp); G2-Vitro Molar (DFL) and G3-Maxxion R (FGM). All treatments were performed following the ART premises in school setting. Restorations were evaluated after 2, 6 and 12 months. Restoration survival was evaluated using Kaplan-Meier survival analysis and Log-rank test and Cox regression was used for testing association with clinical factors (alpha=5%). RESULTS: GC Gold Label 9 had better performance compared to the low-cost GICs (HR=1.47, CI=1.04-2.08, p=0.027). The overall SR of restorations was 65.33% and the SR per group was G1=77.55%; G2=61.11% and G3=42.55%. CONCLUSIONS: The low-cost GICs have a poorer performance than GC Gold Label 9 in occlusal ART restoration in primary molars. PMID- 27956015 TI - Bioremediation of polycyclic aromatic hydrocarbon (PAH) compounds: (acenaphthene and fluorene) in water using indigenous bacterial species isolated from the Diep and Plankenburg rivers, Western Cape, South Africa. AB - This study was conducted to investigate the occurrence of PAH degrading microorganisms in two river systems in the Western Cape, South Africa and their ability to degrade two PAH compounds: acenaphthene and fluorene. A total of 19 bacterial isolates were obtained from the Diep and Plankenburg rivers among which four were identified as acenaphthene and fluorene degrading isolates. In simulated batch scale experiments, the optimum temperature for efficient degradation of both compounds was determined in a shaking incubator after 14 days, testing at 25 degrees C, 30 degrees C, 35 degrees C, 37 degrees C, 38 degrees C, 40 degrees C and 45 degrees C followed by experiments in a Stirred Tank Bioreactor using optimum temperature profiles from the batch experiment results. All experiments were run without the addition of supplements, bulking agents, biosurfactants or any other form of biostimulants. Results showed that Raoultella ornithinolytica, Serratia marcescens, Bacillus megaterium and Aeromonas hydrophila efficiently degraded both compounds at 37 degrees C, 37 degrees C, 30 degrees C and 35 degrees C respectively. The degradation of fluorene was more efficient and rapid compared to that of acenaphthene and degradation at Stirred Tank Bioreactor scale was more efficient for all treatments. Raoultella ornithinolytica, Serratia marcescens, Bacillus megaterium and Aeromonas hydrophila degraded a mean total of 98.60%, 95.70%, 90.20% and 99.90% acenaphthene, respectively and 99.90%, 97.90%, 98.40% and 99.50% fluorene, respectively. The PAH degrading microorganisms isolated during this study significantly reduced the concentrations of acenaphthene and fluorene and may be used on a larger, commercial scale to bioremediate PAH contaminated river systems. PMID- 27956017 TI - A pilot study to assess the morphology and progression of non-carious cervical lesions. AB - OBJECTIVE: This longitudinal pilot study aimed to morphologically and quantitatively investigate the progress of non-carious cervical lesions (NCCLs) by using swept-source optical coherence tomography (SS-OCT). METHODS: The samples examined comprised sets of NCCL epoxy resin replicas obtained from 10 lesions in 6 patients who attended annual dental visits over 4 or 5 years. SS-OCT images of the replicas were analyzed in terms of the maximum depth (Dmax) and corresponding vertical width (VW) - using an image analyzer to estimate progression of the NCCLs over time. RESULTS: It was found that differences between wedge- and saucer shaped lesions were morphologically distinguished well by the OCT images. There were significant differences in dimensions among Dmax, VW and horizontal width (HW). HW was the largest and Dmax was the smallest. Although no significant differences in absolute values of annual progression rates were found among Dmax, VW and HW, the percentage increase in Dmax was significantly greater compared to VW and HW. The ratios of Dmax to corresponding VW ranged from 0.49 to 1.01 for the wedge-shaped lesions and from 0.13 to 0.44 for saucer-shaped lesions, respectively. CONCLUSIONS: The dimensional analysis demonstrated notable progression with large variations. The wedge-shaped lesions appeared to show greater Dmax values compared to the saucer-shaped lesions. CLINICAL SIGNIFICANCE: With respect to the depth, the wedge-shaped lesions may progress at a greater rate compared to the saucer-shaped lesions. PMID- 27956018 TI - A Teenager with Sudden Unilateral Breast Enlargement. PMID- 27956019 TI - Recalcitrant Facial Eruption. PMID- 27956020 TI - Characterizing the reduction of stimulation artifact noise in a tripolar nerve cuff electrode by application of a conductive shield layer. AB - Tripolar nerve cuff electrodes have been widely used for measuring peripheral nerve activity. However, despite the high signal-to-noise ratio levels that can be achieved with this recording configuration, the clinical use of cuff electrodes in closed-loop controlled neuroprostheses remains limited. This is largely attributed to artifact noise signals that contaminate the recorded neural activity. In this study, we investigated the use of a conductive shield layer (CSL) as a means of reducing the artifact noise recorded by nerve cuff electrodes. Using both computational simulations and in vivo experiments, we found that the CSL can result in up to an 85% decrease in the recorded artifact signal. Both the electrical conductivity and the surface area of the CSL were identified as important design criteria. Although this study shows that the CSL can significantly reduce artifact noise in tripolar nerve cuff electrodes, long term implant studies are needed to validate our findings. PMID- 27956021 TI - Prediction of the drilling path to surgically pin the femoral neck from the spatial location of pelvic and femoral anatomical landmarks: A cadaver validation study. AB - Several clinical applications rely on accurate guiding information when drilling along the femoral neck (e.g., pin insertion in case of neck fracture). Currently, applications rely on real-time X-ray imaging, which results in irradiation issues for the surgeon conducting the operation. The goal of this paper was to develop an X-ray-free method that would allow for a pathway to be drilled between the lateral aspect of the femoral diaphysis (the so-called piercing point), the femoral neck and the head centres. The method is based on on-the-fly computational predictions relying on a biomechanical database that includes morphological data related to the femoral neck and head and various palpable anatomical landmarks located on the pelvis and the femoral bone. From the spatial location of the anatomical landmarks, scalable multiple regressions allow for the prediction of the most optimal drilling pathway. The method has been entirely validated using in vitro experiments that reproduce surgical conditions. Further, a surgical ancillary prototype that integrates the method of guiding the pin drilling has been developed and used during in vitro and in situ validation using nine hip joints. Pin insertion was controlled after drilling using medical imaging and show successful result for each of the nine trials. The mean accuracy of the estimated hip joint centre and neck orientation was 6.0 +/- 2.8mm and 7.1 +/- 3.8 degrees , respectively. PMID- 27956022 TI - Self-initiated changes in physical activity levels improve cardiometabolic profiles: A longitudinal follow-up study. AB - BACKGROUND AND AIMS: While studies have described the importance of higher physical activity levels (PAL) in weight loss, the impact of self-initiated PAL on health status warrants further study. We aimed to prospectively examine the effects of self-initiated longitudinal PAL changes on body mass index (BMI) and cardiometabolic parameters in normal weight, overweight and obese adults. METHODS AND RESULTS: We included 4840 adults (mean age 41.6 +/- 7.9 years, 79% male) undergoing routine health screening examinations. Self-reported PAL, height, weight, blood pressure and blood samples were collected at baseline and after a mean (95% confidence interval) follow up of 536 (531-541) days. Subjects were stratified according to BMI [39.8% normal weight (<25 kg/m2), 45.1% overweight (25.0-29.9 kg/m2), and 19.1% obese (>=30 kg/m2)]. In normal weight individuals, BMI increased from baseline to follow-up, irrespective of PAL changes. On the other hand, overweight and obese individuals that increased PAL experienced a decrease in BMI by -0.9% and -3.1%, respectively (p < 0.05). Overweight and obese individuals that increased PAL also experienced a decrease in -5.8% -4.6% in non HDL concentrations from baseline to follow-up (p < 0.05). Finally, in overweight individuals, LDL cholesterol concentrations decreased from baseline to follow-up, irrespective of PAL changes whereas in obese individuals, a maintenance or increased PAL were associated with a decrease in -4.7% and -6.1% (p < 0.05), respectively. CONCLUSIONS: In a large cohort of screening patients, longitudinal self-initiated PAL is associated with improved BMI and cardiometabolic profile in overweight and obese individuals. PMID- 27956023 TI - Cardiovascular complications and drug prescriptions in subjects with and without diabetes in a Northern region of Italy, in 2002 and 2012. AB - BACKGROUND AND AIMS: In contrast to the well-documented global prevalence of diabetes, much less is known about the epidemiology of cardiovascular (CV) complications in recent years. We describe the incidence of major CV events, deaths and drug prescribing patterns from 2002 to 2012 in subjects with (DM) or without diabetes mellitus (No DM). METHODS AND RESULTS: Subjects and outcomes were identified using linkable health administrative databases of Lombardy, a region in Northern Italy. A logistic regression model was used to compare myocardial infarction (MI), stroke, major amputation and death between DM and No DM in 2002 and 2012 and between the two index years in each population. The interaction between years and diabetes was introduced in the model. From 2002 to 2012 the incidence of major CV complications and death fell in both groups with a larger reduction among DM only for CV events: OR (95% CI) for the interaction 0.86 (0.79-0.93) for MI, 0.89 (0.82-0.96) for stroke, 0.78 (0.57-1.06) for major amputations. CV prevention drugs rose considerably from 2002 to 2012 particularly in DM and a switch towards safer antihyperglycemic drugs was also observed. CONCLUSIONS: Major CV complications and death declined from 2002 to 2012 in both DM and No DM. This might be due to a larger increase in prescriptions of CV drugs in DM and a relevant change toward recommended antihyperglycemic drugs. PMID- 27956024 TI - Joint position statement on "Nutraceuticals for the treatment of hypercholesterolemia" of the Italian Society of Diabetology (SID) and of the Italian Society for the Study of Arteriosclerosis (SISA). AB - AIM: Evidence showed that LDL-cholesterol lowering is associated with a significant cardiovascular risk reduction. The initial therapeutic approach to hypercholesterolemia includes dietary modifications but the compliance to recommendations is often inadequate. Some dietary components with potential cholesterol-lowering activity are present in small amounts in food. Therefore, in recent years the use of "nutraceuticals" (i.e., nutrients and/or bioactive compounds with potential beneficial effects on human health) has become widespread. Such substances may be added to foods and beverages, or taken as dietary supplements (liquid preparations, tablets, capsules). In the present manuscript, the cholesterol-lowering activity of some nutraceuticals (i.e. fiber, phytosterols, soy, policosanol, red yeast rice and berberine) will be discussed along with: 1) the level of evidence on the cholesterol-lowering efficacy emerging from clinical trial; 2) the possible side effects associated with their use; 3) the categories of patients who could benefit from their use. DATA SYNTHESIS: Based on the current literature, the cholesterol-lowering effect of fiber, phytosterols and red yeast rice is consistent and supported by a good level of evidence. Over berberine, there is sufficient evidence showing significant cholesterol-lowering effects, although the results come from studies carried out almost exclusively in Asian populations. Data on the effects of soy are conflicting and, therefore, the strength of recommendation is quite low. The evidence on policosanol is inconclusive. CONCLUSION: Although health benefits may arise from the use of nutraceuticals with cholesterol-lowering activity, their use might be also associated with possible risks and pitfalls, some of which are common to all nutraceuticals whereas others are related to specific nutraceuticals. PMID- 27956025 TI - Sex differences in the impact of nonalcoholic fatty liver disease on cardiovascular risk factors. AB - BACKGROUND AND AIMS: Information on sex differences in the association of nonalcoholic fatty liver disease (NAFLD) with cardiovascular disease (CVD) risk factors is scarce. We examined whether men exhibit greater differences in established CVD risk factors between NAFLD and non-NAFLD than women. METHODS AND RESULTS: We conducted a cross-sectional analysis using a cohort of 10761 apparently healthy Chinese adults who underwent comprehensive health checkups including abdominal ultrasonography. In the setting of NAFLD and non-NAFLD, although men had significantly higher levels of atherogenic lipids as indicated by higher levels of triglyceride, triglyceride/HDL-cholesterol, and lower levels of HDL-cholesterol and worsen renal function as indicated by higher levels of creatinine and lower levels of estimated glomerular filtration rate (eGFR) than female counterparts, men with NAFLD showed greater relative differences in atherogenic lipids and deteriorated renal function than women with NAFLD when compared with their non-NAFLD counterparts. The interactions between sex and NAFLD on triglyceride, HDL-cholesterol, triglyceride/HDL-cholesterol, creatinine, and eGFR were statistically significant (P < 0.05). In the multivariate Logistic regression analyses, we observed a stronger association of TG with NAFLD and comparable associations of eGFR or HDL-C with NAFLD in men compared with women. CONCLUSION: There was greater adverse influence of NAFLD per se on triglyceride, and triglyceride/HDL-cholesterol in men compared with women. The greater adverse influence of NAFLD per se on HDL-C and eGFR in men compared with women probably related to the gender differences in TG levels. PMID- 27956026 TI - Laparoscopic left lateral sectionectomy: a population-based study. AB - BACKGROUND: Laparoscopic left lateral sectionectomy (LLS) has now become standard practice. However, published series are small and retrospective. The aim was to compare at a national level the use and short-term outcome of laparoscopic and open LLS. METHODS: National hospital discharge databases were screened to identify all adult patients who had undergone elective LLS in France between 2007 and 2012. Outcome measurements included blood transfusion, severe morbidity, mortality and length of hospital stay. The independent influence of the laparoscopic approach on these outcomes was tested overall and after stratifying for the indication (benign condition, primary malignancy, liver metastasis). RESULTS: Over the 6-year study period, 2198 patients underwent LLS, accounting for 6.9% of all elective liver resections. Some 28.5% of LLS procedures were performed laparoscopically. Among hospitals in which LLS was carried out, 33.2% of procedures were done laparoscopically (median 2 laparoscopic LLS resections per year). The laparoscopic approach was independently associated with a shorter length of hospital stay irrespective of the indication, and a lower transfusion rate in patients with benign condition or primary malignancy. CONCLUSION: LLS is seldom performed and the laparoscopic approach has not been adopted widely. The potential benefit of laparoscopic LLS varies according to the indication. PMID- 27956027 TI - Measuring future liver remnant function prior to hepatectomy may guide the indication for portal vein occlusion and avoid posthepatectomy liver failure: a prospective interventional study. AB - BACKGROUND: Estimation of the future liver remnant function (eFLRF) can avoid post-hepatectomy liver failure (PHLF). In a previous study, a cutoff value of 2.3%/min/m2 for eFLRF was a better predictor of PHLF than future liver remnant volume (FLRV%). In this prospective interventional study, investigating a management strategy aimed at avoiding PHLF, this cutoff value was the sole criterion assessing eligibility for hepatectomy, with or without portal vein occlusion (PVO). METHODS: In 100 consecutive patients, eFLRF was determined using the formula: eFLRF = FLRV% * total liver function (TLF). Group 1 (eFLRF >2.3%/min/m2) underwent hepatectomy without preoperative intervention. Group 2 (eFLRF <2.3%/min/m2) underwent PVO and re-evaluation of eFLRF at 4-6 weeks. Hepatectomy was performed if eFLRF had increased to >2.3%/min/m2, but was considered contraindicated if the value remained lower. RESULTS: In group 1 (n = 93), 1 patient developed grade B PHLF. In group 2 (n = 7) no PHLF was recorded. Postoperative recovery of TLF in patients with preoperative eFLRF <2.3%/min/m2 occurred more rapidly when PVO had been performed. CONCLUSION: A predefined cutoff for preoperatively calculated eFLRF can be used as a tool for selecting patients prior to hepatectomy, with or without PVO, thus avoiding PHLF and PHLF related mortality. PMID- 27956029 TI - Molecular mechanisms of deregulation of the thin filament associated with the R167H and K168E substitutions in tropomyosin Tpm1.1. AB - Point mutations R167H and K168E in tropomyosin Tpm1.1 (TM) disturb Ca2+-dependent regulation of the actomyosin ATPase. To understand mechanisms of this defect we studied multistep changes in mobility and spatial arrangement of tropomyosin, actin and myosin heads during the ATPase cycle in reconstituted ghost fibres using the polarized fluorescence microscopy. It was found that both mutations disturbed the mode of troponin operation in the fibres. At high Ca2+, troponin increased the fraction of actin monomers that were in the "switched on" state, but both mutant tropomyosins were shifted toward the outer actin domains, which decreased the fraction of strongly bound myosin heads throughout the ATPase cycle. At low Ca2+, the R167H-TM was located close to the outer actin domains, which reduced the number of strongly-bound myosin heads. However, under these conditions troponin increased the number of actin monomers that were switched on. The K168E-TM was displaced far to the outer actin domains and troponin binding decreased the fraction of switched on actin monomers, but the proportion of the strongly bound myosin heads was abnormally high. Thus, the mutations differently disturbed transmission of conformational changes between troponin, tropomyosin and actin, which is essential for the Sa2+-dependent regulation of the thin filament. PMID- 27956030 TI - Calpain-1 resident in lipid raft/caveolin-1 membrane microdomains plays a protective role in endothelial cells. AB - We are here reporting that calpain-1 is a constitutive component of a distinct lipid raft/caveolin-1 microdomain isolated from bEnd5 cells in association with endothelial nitric oxide synthase (eNOS) and heat shock protein 90 (HSP90). Perturbations in intracellular calcium concentration by Ca2+-ionophore A23187 or prolonged cell exposure to high glucose induce a significant decrease in the level of eNOS accompanied by a recruitment of additional HSP90 molecules at this site. In these conditions the cells are more resistant to cell death by Ca2+ overload. The decrease of eNOS has been due not only to its Ca2+-mediated release from the caveolin-1 aggregates but also to its digestion by calpain-1. The specific involvement of calpain-1 in digestion of eNOS is supported by the preventive effect of a synthetic calpain inhibitor (CI-2) and by the absence of calpain-2 and calpastatin in the caveolin-1 microdomain. These results suggest that the protein adjustments observed in lipid raft/caveolin-1 microdomains could be visualized as a process required to protect the cells against NO overproduction and aberrant calpain activation. Alterations in eNOS, calpain-1 and HSP90 levels have been observed in aorta of Zucker Diabetic Rats (ZDR). The loss of HSP90 occurring in these animals indicates an aberrant activation of calpain and thereby the transition from a physiological to a pathological cell condition. PMID- 27956031 TI - Mesothelial cyst of the pulmonary ligament: An uncommon lesion. PMID- 27956032 TI - Alterations in hypoglossal motor neurons due to GAD67 and VGAT deficiency in mice. AB - There is an emerging body of evidence that glycinergic and GABAergic synaptic inputs onto motor neurons (MNs) help regulate the final number of MNs and axonal muscle innervation patterns. Using mutant glutamate decarboxylase 67 (GAD67) and vesicular inhibitory amino acid transporter (VGAT) deficient mice, we describe the effect that deficiencies of presynaptic GABAergic and/or glycinergic release have on the post-synaptic somato-dendritic structure of motor neurons, and the development of excitatory and inhibitory synaptic inputs to MNs. We use whole cell patch clamp recording of synaptic currents in E18.5 hypoglossal MNs from brainstem slices, combined with dye-filling of these recorded cells with NeurobiotinTM, high-resolution confocal imaging and 3-dimensional reconstructions. Hypoglossal MNs from GAD67- and VGAT-deficient mice display decreased inhibitory neurotransmission and increased excitatory synaptic inputs. These changes are associated with increased dendritic arbor length, increased complexity of dendritic branching, and increased density of spiny processes. Our results show that presynaptic release of inhibitory amino acid neurotransmitters are potent regulators of hypoglossal MN morphology and key regulators of synaptic inputs during this critical developmental time point. PMID- 27956028 TI - Parasite Infection, Carcinogenesis and Human Malignancy. AB - Cancer may be induced by many environmental and physiological conditions. Infections with viruses, bacteria and parasites have been recognized for years to be associated with human carcinogenicity. Here we review current concepts of carcinogenicity and its associations with parasitic infections. The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic while the protozoan Trypanosoma cruzi, the causing agent of Chagas disease, has a dual role in the development of cancer, including both carcinogenic and anticancer properties. Although malaria per se does not appear to be causative in carcinogenesis, it is strongly associated with the occurrence of endemic Burkitt lymphoma in areas holoendemic for malaria. The initiation of Plasmodium falciparum related endemic Burkitt lymphoma requires additional transforming events induced by the Epstein-Barr virus. Observations suggest that Strongyloides stercoralis may be a relevant co-factor in HTLV-1-related T cell lymphomas. This review provides an overview of the mechanisms of parasitic infection-induced carcinogenicity. PMID- 27956033 TI - Effect of cryotherapy on relief of perineal pain after vaginal childbirth with episiotomy: a randomized and controlled clinical trial. AB - OBJECTIVE: Verify the effectiveness of cryotherapy in relieving perineal pain in women after vaginal delivery with episiotomy. DESIGN: Randomized controlled clinical trial. SETTING: Reference Center of Women's Health of Ribeirao Preto (MATER), in the state of Sao Paulo. PARTICIPANTS: The study included 50 women who reported pain in the postpartum period following vaginal delivery with episiotomy. INTERVENTION: The women in the experimental group applied a bag of crushed ice to the perineal region for 20minutes. Both groups were assessed before, immediately after removal of the ice bag, and one hour after cryotherapy treatment. MAIN OUTCOME MEASURES: Complaint of pain was evaluated using a numerical pain assessment scale (0 to 10). Perineal temperature was also measured using an infrared thermometer, and the satisfaction of women undergoing the treatment was assessed using a questionnaire. RESULTS: Pain relief was verified for the experimental group compared to the control group in the second (immediately after use of cryotherapy) and third evaluations (one hour after cryotherapy). The temperature of the perineal region was found to be related to the intensity of pain, e.g. the lower the temperature provided by cryotherapy, the lower the woman's complaint of pain. 88% of women reported being satisfied with the treatment. CONCLUSION: After 20minutes of application, cryotherapy was effective in relieving perineal pain in women in the immediate postpartum period after vaginal birth with episiotomy. TRIAL REGISTRATION NUMBER: ACTRN12613000052730. PMID- 27956034 TI - Classification of patients with chronic obstructive pulmonary disease according to the Latin American Thoracic Association (ALAT) staging systems and the global initiative for chronic obstructive pulmonary disease (GOLD). AB - INTRODUCTION: Several classification systems use different criteria when assessing COPD stages. The objective of this study was to compare the prevalence and distribution of COPD stagesusing Global initiative for chronic Obstructive Lung Disease (GOLD) recommendationsand Latin American Thoracic Association (ALAT) guidelinesin a primary-care population. METHODS: Subjects attending routine primary care visits, >=40 years of age, current or former smokers or exposed to biomass, completed a questionnaire and performed spirometry. COPD was defined as post-bronchodilator FEV1/FVC<0.70 and categorised according to GOLD-2013 criteria and ALAT-2014 guideline. The BODEx index was used to assess the prognostic value of the stratification systems. RESULTS: A total of 1743 subjects completed the interview, 1540 performed acceptable spirometry. COPD prevalence according GOLD 2013 was 20.1% and had a U-shaped stage distribution (group A: 9.3%, B: 4.3%, C: 2.0%, D: 4.6%). According to ALAT, prevalence was 19.7% with a bell-shaped stage distribution (mild: 2.9%, moderate: 9%, severe: 5.4%, very-severe: 2.7%). Approximately 73% of patients were stratified as moderate (45.4%) or severe (27.3%) by ALAT guidelines, whereas using GOLD-2013 criteria the majority of subjects (approximately 69%) were in group A (46.3%) or group B (22.7%). BODE index score increased as COPD worsened according to ALAT stratification. This is not observed with GOLD2013 criteria (similar values for B and C groups). CONCLUSIONS: Disease stages differ under ALAT and GOLD-2013 criteria. ALAT identified a greater proportion of COPD subjects in the moderate and severe categories compared with GOLD-2013, where the majority were categorised in group A. Future evaluation of the ALAT classification should address its predictive ability in terms of hospitalizations and mortality. PMID- 27956035 TI - Synthesis and characterization of novel, conjugated, fluorescent DNJ derivatives for alpha-glucosidase recognition. AB - A series of five new fluorescent deoxynojirimycin (DNJ) conjugates were synthesized and evaluated for their inhibitory effect (IC50) on several alpha- and beta-glucosidases. Three of the conjugates showed enhanced activity. The two synthetic conjugates, DNJ-CF31 and DNJ-Me 2, exhibited improved alpha-glucosidase inhibitory effects compared to DNJ and miglitol. Interestingly, conjugates 1 and 2 showed strong inhibition of almond-derived beta-glucosidase, in contrast to the inhibition tendencies of other inhibitors. Conjugate 5 strongly inhibited rat intestinal maltase, even at 0.10MUM. A docking study indicated that all five conjugates bind to the active site of alpha-glucosidase (PDB: 3L4V, derived from Homo sapiens). The DNJ portion of the conjugate fits into the cavity of the enzyme, and the fluorescent part locates randomly on the outside surface. Thus, it is likely that these conjugates can specifically recognize intestinal cells, specifically the alpha-glucosidase on cell membranes. PMID- 27956036 TI - Effects of new fluorinated analogues of GABA, pregabalin bioisosters, on the ambient level and exocytotic release of [3H]GABA from rat brain nerve terminals. AB - Recently, we have shown that new fluorinated analogues of gamma-aminobutyric acid (GABA), bioisosters of pregabalin (beta-i-Bu-GABA), i.e. beta-polyfluoroalkyl GABAs (FGABAs), with substituents: beta-CF3-beta-OH (1), beta-CF3 (2); beta CF2CF2H (3), are able to increase the initial rate of [3H]GABA uptake by isolated rat brain nerve terminals (synaptosomes), and this effect is higher than that of pregabalin. So, synthesized FGABAs are structural but not functional analogues of GABA. Herein, we assessed the effects of synthesized FGABAs (100MUM) on the ambient level and exocytotic release of [3H]GABA in nerve terminals and compared with those of pregabalin (100MUM). It was shown that FGABAs 1-3 did not influence the ambient level of [3H]GABA in the synaptosomal preparations, and this parameter was also not altered by pregabalin. During blockage of GABA transporters GAT1 by specific inhibitor NO-711, FGABAs and pregabalin also did not change ambient [3H]GABA in synaptosomal preparations. Exocytotic release of [3H]GABA from synaptosomes decreased in the presence of FGABAs 1-3 and pregabalin, and the effects of FGABAs 1 &3 were more significant than those of FGABAs 2 and pregabalin. FGABAs 1-3/pregabalin-induced decrease in exocytotic release of [3H]GABA from synaptosomes was not a result of changes in the potential of the plasma membrane. Therefore, new synthesized FGABAs 1 &3 were able to decrease exocytotic release of [3H]GABA from nerve terminals more effectively in comparison to pregabalin. Absence of unspecific side effects of FGABAs 1 &3 on the membrane potential makes these compounds perspective for medical application. PMID- 27956038 TI - 3-Amino-thieno[2,3-b]pyridines as microtubule-destabilising agents: Molecular modelling and biological evaluation in the sea urchin embryo and human cancer cells. AB - A series of 3-amino-thieno[2,3-b]pyridines was prepared and tested in a phenotypic sea urchin embryo assay to identify potent and specific molecules that affect tubulin dynamics. The most active compounds featured a tricyclic core ring system with a fused cycloheptyl or cyclohexyl substituent and unsubstituted or alkyl-substituted phenyl moiety tethered via a carboxamide. Low nano-molar potency was observed in the sea urchin embryos for the most active compounds (1 5) suggestive of a microtubule-destabilising effect. The molecular modelling studies indicated that the tubulin colchicine site is inhibited, which often leads to microtubule-destabilisation in line with the sea urchin embryo results. Finally, the identified hits displayed a robust growth inhibition (GI50 of 50 250nM) of multidrug-resistant melanoma MDA-MB-435 and breast MDA-MB-468 human cancer cell lines. This work demonstrates that for the thieno[2,3-b]pyridines the most effective mechanism of action is microtubule-destabilisation initiated by binding to the colchicine pocket. PMID- 27956037 TI - Design and synthesis of phosphoryl-substituted diphenylpyrimidines (Pho-DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors: Targeted treatment of B lymphoblastic leukemia cell lines. AB - A family of phosphoryl-substituted diphenylpyrimidine derivatives (Pho-DPPYs) were synthesized and biologically evaluated as potent BTK inhibitors in this study. Compound 7b was found to markedly inhibit BTK activity at concentrations of 0.82nmol/L, as well as to suppress the proliferations of B-cell leukemia cell lines (Ramos and Raji) expressing high levels of BTK at concentrations of 3.17MUM and 6.69MUM. Moreover, flow cytometry analysis results further indicated that 7b promoted cell apoptosis to a substantial degree. In a word, compound 7b is a promising BTK inhibitor for the treatment of B-cell lymphoblastic leukemia. PMID- 27956039 TI - Design, synthesis and pharmacological evaluation of 4-hydroxyphenylglycine and 4 hydroxyphenylglycinol derivatives as GPR88 agonists. AB - The orphan receptor GPR88 is an attractive therapeutic target because of its implications in a number of basal ganglia-associated disorders. To date, pharmacological characterization of GPR88 has been limited due to the lack of potent and selective agonists and antagonists appropriate for CNS investigations. We have previously reported that GPR88 couples to Galphai proteins and modulates cAMP levels upon treatment with a small molecule agonist 2-PCCA. Recently, another chemotype of GPR88 agonist, represented by 2-AMPP [(2S)-N-((1R)-2-amino-1 (4-(2-methylpentyloxy)-phenyl)ethyl)-2-phenylpropanamide], has also been discovered. In this report, a new series of 2-AMPP structurally related 4 hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives have been designed and evaluated for agonist activity at GPR88. The structure-activity relationship (SAR) studies suggest that the amine group in 2-AMPP can be replaced by hydroxyl, ester and amide groups, resulting in analogues with good to moderate potency, whereas the phenyl group on the amide cap is essential for activity and has limited size, shape and electronic tolerance. PMID- 27956040 TI - Shone Complex: An Under-recognized Congenital Heart Disease With Substantial Morbidity in Adulthood. AB - BACKGROUND: Shone complex consists of a constellation of left-sided, usually obstructive, cardiac lesions, including supravalvar mitral ring, parachute mitral valve, subaortic stenosis, and aortic coarctation. Incomplete Shone complex consists of a mitral valve anomaly associated with lesions involving the subaortic region, aortic valve, or thoracic aorta. There is a paucity of data regarding long-term outcomes in adults with Shone complex. METHODS: We reviewed records of adults with complete or incomplete Shone complex followed at the Montreal Heart Institute between 1982 and 2014. RESULTS: Among 4189 adults with congenital heart disease, 28 (0.67%) patients (mean age, 35 +/- 11 years; 50% women) had complete or incomplete Shone complex and were followed for a median of 8 years. Only 39% were previously diagnosed as having Shone complex. The most common defects were congenital mitral stenosis (93%), aortic coarctation (75%), and bicuspid aortic valve (71%). Heart transplantation was required in 2 patients (7.1%) at age 22 and 28 years, respectively. Overall, 48% had cardiovascular hospitalizations during adulthood, predominantly for arrhythmias or heart failure. Freedom from cardiovascular intervention was 55%, 18%, and 8% at 10, 20, and 30 years of age, respectively. Although aortic coarctation was the most common indication for initial intervention (61%), adult interventions occurred predominantly for aortic valve/left ventricular outflow tract (60%) and mitral valve (33%) lesions. CONCLUSIONS: Shone complex is an under-recognized entity associated with relatively low mortality in adulthood but substantial morbidity related to arrhythmias, heart failure, and interventions. Increased awareness of this condition and associated complications may allow for more tailored follow up. PMID- 27956041 TI - Effective Management of Cardiovascular Risk Factors-Are We Doing Enough? PMID- 27956042 TI - Are Existing Risk Scores for Nonvalvular Atrial Fibrillation Useful for Prediction or Risk Adjustment in Patients With Chronic Kidney Disease? AB - BACKGROUND: Comparative effectiveness studies are common in patients with nonvalvular atrial fibrillation (NVAF) and chronic kidney disease (CKD), but the accuracy of current thromboembolic (n = 4) and bleeding (n = 3) prediction scores used for risk adjustment are uncertain in these patients because previous studies have included few CKD patients. METHODS: This was a retrospective cohort study, using Cox models adjusted for time-varying coefficients, of nonanticoagulated adults with incident NVAF and kidney function (defined into Kidney Disease: Improving Global Outcomes [KDIGO] CKD categories) between 2002 and 2013. RESULTS: Of 58,451 patients (mean age 66 years, 31.3% with CKD) followed for a median of 31 months, 21.3% died, 12.6% had a thromboembolic event (4.2 per 100 patient years), and 7.8% had a major bleed (2.6 per 100 patient-years). There were graded associations between kidney function and all-cause mortality (adjusted hazard ratio [aHR], 1.88 [95% confidence interval (CI), 1.79-1.98] for very high vs low risk KDIGO category), major bleeding (aHR, 1.61 [95% CI, 1.47-1.76]), and thromboembolic events (aHR, 1.13 [95% CI, 1.04-1.23]). All 7 prediction scores had significantly poorer c statistics in patients with CKD: 0.50-0.59; all P < 0.0001 compared with those with normal kidney function (c statistics 0.69-0.70 for the 4 thromboembolic risk scores and 0.60-0.68 for the 3 bleeding risk scores). Inclusion of KDIGO category did not improve calibration or discrimination statistics for current prediction scores. CONCLUSIONS: Existing NVAF risk scores exhibit poor discrimination in patients with CKD, limiting their utility for clinical decision-making or for risk adjustment in comparative effectiveness studies. Although CKD is an independent risk factor for adverse events, adding KDIGO class to current risk scores did not improve their performance. PMID- 27956043 TI - Effect of Mobile Health Interventions on the Secondary Prevention of Cardiovascular Disease: Systematic Review and Meta-analysis. AB - BACKGROUND: Despite the strong uptake of mobile health (mhealth) technology targeted at cardiovascular care, it is still unclear if this improves adherence to therapy and patient-related outcomes in those with established cardiovascular disease. METHODS: A systematic search of English and Chinese language studies was conducted to investigate the benefit of mhealth technology for the secondary prevention of cardiovascular disease. RESULTS: Twenty-seven studies with 5165 patients were included in the systematic review. Patients in the mhealth group showed increased adherence to medical therapy (odds ratio [OR], 4.51; P < 0.00001), as well as increased adherence to pharmacologic and nonpharmacologic therapy (OR, 3.86; P < 0.00001). Patients in the mhealth group showed the ability to meet recommended blood pressure targets (OR, 2.80; P < 0.001) with a trend toward the ability to meet exercise goals (OR, 2.55; P = 0.07), however, no significant difference in smoking cessation (OR, 1.42; P = 0.45) and the ability to meet lipid target levels (OR, 1.16; P = 0.29) was found. Patients in the mhealth group did not show a reduction in hospital readmission (OR, 0.93; P = 0.96), with a small number of studies showing a reduction in angina (OR, 0.23; P = 0.005), and a decrease in transient ischemic attack/stroke recurrence in those with cerebrovascular disease (OR, 0.18; P < 0.0001) and a trend toward lower observed mortality rate (OR, 0.19; P = 0.06). CONCLUSIONS: The mhealth group compared with the usual care group had increased adherence to medical therapy, ability to reach blood pressure targets, exercise goals, and showed less anxiety and increased awareness of diet and exercise. There was no difference in smoking cessation, ability to meet low-density lipoprotein cholesterol targets, and hospital readmission. PMID- 27956044 TI - Associations Between Childhood Cognition and Cardiovascular Events in Adulthood: A Systematic Review and Meta-analysis. AB - BACKGROUND: The success of behavioural interventions to optimize cardiovascular health is dependent on adequate cognitive functioning beginning in early life. In this study we aimed to systematically review studies that examined associations between childhood cognition and cardiovascular disease (CVD) events in adulthood. METHODS: This study followed the Meta-analysis Of Observational Studies in Epidemiology guidelines to systematically examine associations between childhood cognition and adult CVD, coronary heart disease, and stroke hospitalization or mortality events. Literature was retrieved from EMBASE, MEDLINE, PsycInfo, and CINAHL. RESULTS: Five longitudinal studies that examined links between childhood cognition and CVD in adulthood were included. Pooled estimates of unadjusted CVD events indicated a relative risk of 1.23 (95% confidence interval, 1.12-1.34) per standard deviation decrease in childhood IQ, whereas the pooled estimate adjusted for biopsychosocial confounding factors indicated an overall relative risk of 1.16 (95% confidence interval, 1.07-1.26). CONCLUSIONS: Lower childhood IQ is associated with an increased risk of cardiovascular events in adulthood, even after adjustment for confounding variables. Future research should examine the behavioural mechanisms by which these risks are mediated to optimize cardiovascular health. PMID- 27956045 TI - Biomechanical properties of early keratoconus: Suppressed deformation signal wave. AB - PURPOSE: To examine the diagnostic validity of different corneal biomechanical parameters for the detection of early keratoconus METHODS: Sixty-one eyes with a diagnosis of early keratoconus and 61 topographically normal eyes were enrolled in the study. All participants underwent testing with the Ocular Response Analyzer (ORA), and 40 indices from each cornea were included in the analysis. RESULTS: The mean (standard deviation: SD) of keratometry and central corneal thickness in keratoconic corneas was 46.9 (2.5) diopter (D) and 473 (31) MUm, respectively. Of the 40 evaluated indices, 32 showed a significant difference between the two groups using t-test (p<0.05). According to the results of logistic regression, the indices of height from the lowest to the highest point in peak 2 (H21) and corneal resistance factor (CRF) with R2=0.79 were the best predictors of early keratoconus (p<0.001). H21 <=190 with a sensitivity and specificity of 87% and 91.8%, respectively, and CRF<=8.6 with sensitivity and specificity of 87% and 85.3%, respectively, yielded an overall diagnostic accuracy of 97.3%. CONCLUSION: This study results point to the important role of novel waveform-derived indices measured by ORA, along with conventional biomechanical indices, for the early diagnosis of keratoconus. The best predictors of keratoconus in its early stages are H21 and CRF which showed very high sensitivity and specificity for the detection of early keratoconus. PMID- 27956046 TI - Erroneus calculation of sample size in a vitamin C and atrial fibrillation trial. PMID- 27956047 TI - Metabolic synthetic lethality in cancer therapy. AB - Our understanding of cancer has recently seen a major paradigm shift resulting in it being viewed as a metabolic disorder, and altered cellular metabolism being recognised as a hallmark of cancer. This concept was spurred by the findings that the oncogenic mutations driving tumorigenesis induce a reprogramming of cancer cell metabolism that is required for unrestrained growth and proliferation. The recent discovery that mutations in key mitochondrial enzymes play a causal role in tumorigenesis suggested that dysregulation of metabolism could also be a driver of tumorigenesis. These mutations induce profound adaptive metabolic alterations that are a prerequisite for the survival of the mutated cells. Because these metabolic events are specific to cancer cells, they offer an opportunity to develop new therapies that specifically target tumour cells without affecting healthy tissue. Here, we will describe recent developments in metabolism-based cancer therapy, in particular focusing on the concept of metabolic synthetic lethality. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux. PMID- 27956049 TI - Parasitological and molecular surveys reveal high rates of infection with vector borne pathogens and clinical anemia signs associated with infection in cattle from two important livestock areas in Colombia. AB - In Colombia, vector-borne diseases are one of the most important problems in the livestock industry. The present study reports parasitological and molecular surveys of vector-borne pathogens in cattle from two high-value livestock areas in Colombia. A total of 464 samples (226 from Antioquia and 238 from Arauca) were analyzed. While the blood smear analysis identified 98 (21.1%), 14 (3.0%) and 30 (6.5%) positive samples for Anaplasma spp., Babesia spp. and Trypanosoma spp., respectively, the molecular methods indicated that 275 (59.3%), 146 (31.5%), 64 (13.8%), 236 (50.9%) and 43 (9.3%) of the samples were positive for Anaplasma marginale, Babesia bigemina, Babesia bovis, Trypanosoma theileri and T. evansi, respectively. Mixed infections were detected in 250 (53.9%) samples. Interestingly, animals aged <=1 year had higher probabilities of being infected with A. marginale and Babesia spp., and lower probabilities of being infected with Trypanosoma spp., while the animals raised under intensive system breeding had higher probabilities of being infected with all pathogens. Additionally, T. theileri infection was found in higher prevalence in anemic animals than animals with normal packed cell volume (PCV). This is the first molecular report that evaluated the infection with three genders of vector-borne pathogens in cattle in Colombia and provides useful information for a better understanding of the epidemiologic aspects, as well as for the management and control, of these diseases. PMID- 27956048 TI - Omental adipocytes enhance the invasiveness of gastric cancer cells by oleic acid induced activation of the PI3K-Akt signaling pathway. AB - A considerable number of patients with advanced gastric cancer have a clear predilection for metastasis to the great omentum, an organ mainly composed of adipose tissue. However, it remains unclear why tumor cells preferentially spread to and progress in the omentum. Here, we used a two-dimensional co-culture system to simulate the crosstalk between adipocytes and gastric cancer cells and showed that after co-culture with isolated omental adipocytes, gastric cancer cells exhibited a significant increase in lipid uptake and enhanced invasiveness. A lipidomic study showed that gastric cancer cells accumulated higher levels of oleic acid during the co-culture. By performing an assay of key enzymes in lipid synthesis, we demonstrated that the increased amount of oleic acid in gastric cancer cells mainly came from the adjacent adipocytes in the co-culture system. Furthermore, our data showed that at a certain concentration range, oleic acid treatment enhanced the invasiveness of gastric cancer cells in vitro and in a CAM assay, through the PI3K/Akt pathway, with the associated increased expression of the key pro-invasion factor MMP-2. Taken together, our results demonstrated that adipocytes may serve as an exogenous source of oleic acid that promotes gastric cancer cell invasion through the PI3K/Akt signaling pathway. PMID- 27956050 TI - The exercise-glucocorticoid paradox: How exercise is beneficial to cognition, mood, and the brain while increasing glucocorticoid levels. AB - Exercise is known to have beneficial effects on cognition, mood, and the brain. However, exercise also activates the hypothalamic-pituitary-adrenal axis and increases levels of the glucocorticoid cortisol (CORT). CORT, also known as the "stress hormone," is considered a mediator between chronic stress and depression and to link various cognitive deficits. Here, we review the evidence that shows that while both chronic stress and exercise elevate basal CORT levels leading to increased secretion of CORT, the former is detrimental to cognition/memory, mood/stress coping, and brain plasticity, while the latter is beneficial. We propose three preliminary answers to the exercise-CORT paradox. Importantly, the elevated CORT, through glucocorticoid receptors, functions to elevate dopamine in the medial prefrontal cortex under chronic exercise but not chronic stress, and the medial prefrontal dopamine is essential for active coping. Future inquiries may provide further insights to promote our understanding of this paradox. PMID- 27956051 TI - Tumor suppressor p53 functions as an essential antiviral molecule against Japanese encephalitis virus. PMID- 27956052 TI - Protocol for culturing low density pure rat hippocampal neurons supported by mature mixed neuron cultures. AB - BACKGROUND: primary hippocampal neuron cultures allow for subcellular morphological dissection, easy access to drug treatment and electrophysiology analysis of individual neurons, and is therefore an ideal model for the study of neuron physiology. While neuron and glia mixed cultures are relatively easy to prepare, pure neurons are particular hard to culture at low densities which are suitable for morphology studies. This may be due to a lack of neurotrophic factors such as brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and Glial cell line-derived neurotrophic factor (GDNF). NEW METHOD: In this study we used a two step protocol in which neuron-glia mixed cultures were initially prepared for maturation to support the growth of young neurons plated at very low densities. COMPARISON WITH EXISTING METHODS: Our protocol showed that neurotrophic support resulted in physiologically functional hippocampal neurons with larger cell body, increased neurite length and decreased branching and complexity compared to cultures prepared using a conventional method. CONCLUSION: Our protocol provides a novel way to culture highly uniformed hippocampal neurons for acquiring high quality, neuron based data. PMID- 27956053 TI - Poststroke glycemic variability increased recurrent cardiovascular events in diabetic patients. AB - BACKGROUND AND PURPOSE: The association between blood glucose fluctuation and poststroke cardiovascular outcome has been largely unknown. This study attempted to evaluate whether initial glycemic variability increases cardiovascular events and mortality in diabetic patients with acute ischemic stroke. METHODS: We recruited consecutive patients with acute ischemic stroke or transient ischemic attack from March 2005 to December 2014. A total of 674 patients with diabetes within 72 hours from stroke onset were included. The serum glucose levels were checked 4 times per day during the initial 3 hospital days. J-index, coefficients of variation and standard deviation were calculated for glycemic variability. Composite outcome (nonfatal stroke, nonfatal myocardial infarction, cardiovascular death) and all-cause mortality at 3 months were prospectively captured. Multivariable logistic regression analyses were done adjusting for covariates which can influence on cardiovascular outcomes. RESULTS: Cardiovascular composite outcomes at 3 months were identified in 71 (10.5%): 11 (6.5%), 15 (8.9%), 18 (10.7%) and 27 (16.0%) in each J-index quartiles (P = .035). The highest quartile of J-index had significantly higher cardiovascular death (4.2%, 3.6%, 6.5% and 11.8%; P = .008). In multivariable logistic regression, age (odds ratio [OR] 1.045; 95% confidence interval [CI] 1.006 1.084), P = .021), NIH stroke scale (OR 1.078; 95% CI 1.024-1.134, P = .004), and the highest J-index (OR 12.058; 95% 1.890-76.912, P = .008) were significantly associated with 3-month cardiovascular composite outcome. Increased cardiovascular outcomes in highest J-index quartile were similar in both euglycemic and hyperglycemic groups. CONCLUSION: The initial glycemic variability might increase cardiovascular events in acute ischemic stroke patients with diabetes. PMID- 27956054 TI - Active vaccination attenuates the psychostimulant effects of alpha-PVP and MDPV in rats. AB - Recreational use of substituted cathinones continues to be an emerging public health problem in the United States; cathinone derivatives alpha pyrrolidinopentiophenone (alpha-PVP) and 3,4-methylenedioxypyrovalerone (MDPV), which have been linked to human fatalities and show high potential for abuse liability in animal models, are of particular concern. The objective of this study was to develop an immunotherapeutic strategy for attenuating the effects of alpha-PVP and MDPV in rats, using drug-conjugate vaccines created to generate antibodies with neutralizing capacity. Immunoconjugates (alpha-PVP-KLH and MDPV KLH) or the control carrier protein, keyhole limpet hemocyanin (KLH), were administered to groups (N = 12) of male Sprague-Dawley rats on Weeks 0, 2 and 4. Groups were administered alpha-PVP or MDPV (0.0, 0.25, 0.5, 1.0, 5.0 mg/kg, i.p.) in acute drug challenges and tested for changes in wheel activity. Increased wheel activity produced by alpha-PVP or MDPV in the controls was attenuated in the alpha-PVP-KLH and MDPV-KLH vaccinated groups, respectively. Rectal temperature decreases produced by MDPV in the controls were reduced in duration in the MDPV-KLH vaccine group. A separate group (N = 19) was trained to intravenously self-administer alpha-PVP (0.05, 0.1 mg/kg/inf) and vaccinated with KLH or alpha-PVP-KLH, post-acquisition. Self-administration in alpha-PVP-KLH rats was initially higher than in the KLH rats but then significantly decreased following a final vaccine booster, unlike the stable intake of KLH rats. The data demonstrate that active vaccination provides functional protection against the effects of alpha-PVP and MDPV, in vivo, and recommend additional development of vaccines as potential therapeutics for mitigating the effects of designer cathinone derivatives. PMID- 27956056 TI - Chemokine neutralization as an innovative therapeutic strategy for atopic dermatitis. AB - Atopic dermatitis is a chronic inflammatory skin disease with no specific treatment, affecting 15-30% of children and 2-10% of adults in developed countries. Current therapies alleviate symptoms and include emollients, glucocorticoids and calcineurin inhibitors. The limited efficiency and side effects of these medicines call for better treatment, and a cure for atopic dermatitis represents an unmet medical need. The chemokine/chemokine-receptor network constitutes an attractive target for drugs in atopic dermatitis. However, the highly intricate nature of the chemokine network makes it difficult to identify a clear receptor to target. After a short description of atopic dermatitis and its current therapies, this review presents the current knowledge of the chemokine/chemokine-receptor system role in the regulation of inflammatory cell recruitment into the skin. We discuss the limitations of classical chemokine receptor blockade and introduce the concept of neutralization of chemokine ligands. This strategy represents a potential breakthrough in developing therapeutic agents to treat atopic diseases. PMID- 27956057 TI - Sedative-analgesic activity of remifentanil and effects of preoperative anxiety on perceived pain in outpatient mandibular third molar surgery. AB - The aim of this study was to assess the sedative-analgesic activity of different doses of remifentanil and effects of preoperative anxiety on intraoperative pain levels in patients attending a dental clinic. The patients (n=60) were divided into two groups according to the remifentanil infusion dose given: group R1: 0.05MUg/kg/min; group R2: 0.1MUg/kg/min. The following were evaluated: haemodynamic parameters, State-Trait Anxiety Inventory (STAI) TX-I score, pain level due to local anaesthesia injection, time to reach a Ramsay Sedation Scale (RSS) score of 3, amount of bolus dose, total drug consumption, recovery period, patient and surgeon satisfaction, and complications. The patient satisfaction score on a visual analogue scale (VAS) was 90 in group R1 and 100 in group R2 (P=0.008); the surgeon satisfaction score was 80 in group R1 and 90 in group R2 (P=0.004). The time to reach an RSS score of 3 and the amount of bolus dose were significantly lower in group R2 than in group R1. High levels of anxiety did not affect intraoperative pain levels. In conclusion, high doses of remifentanil can safely be used for various same-day dental surgery interventions. PMID- 27956055 TI - Diverse arrestin-recruiting and endocytic profiles of tricyclic antipsychotics acting as direct alpha2A adrenergic receptor ligands. AB - The therapeutic mechanism of action underlying many psychopharmacological agents remains poorly understood, due largely to the extreme molecular promiscuity exhibited by these agents with respect to potential central nervous system targets. Agents of the tricyclic chemical class, including both antidepressants and antipsychotics, exhibit a particularly high degree of molecular promiscuity; therefore, any clarification of how these agents interact with specific central nervous system targets is of great potential significance to the field. Here, we present evidence demonstrating that tricyclic antipsychotics appear to segregate into three distinct groups based upon their molecular interactions with the centrally-important alpha2A adrenergic receptor (AR). Specifically, while the alpha2AAR binds all antipsychotics tested with similar affinities, and none of the agents are able to induce classical heterotrimeric G protein-mediated alpha2AAR signaling, significant differences are observed with respect to arrestin3 recruitment and receptor endocytosis. All antipsychotics tested induce arrestin3 recruitment to the alpha2AAR, but with differing strengths. Both chlorpromazine and clozapine drive significant alpha2AAR endocytosis, but via differing clathrin-dependent and lipid raft-dependent pathways, while fluphenazine does not drive a robust response. Intriguingly, in silico molecular modeling suggests that each of the three exhibits unique characteristics in interacting with the alpha2AAR ligand-binding pocket. In addition to establishing these three antipsychotics as novel arrestin-biased ligands at the alpha2AAR, our findings provide key insights into the molecular actions of these clinically important agents. PMID- 27956058 TI - US and Dutch nurse experiences with fall prevention technology within nursing home environment and workflow: A qualitative study. AB - Falls remain a major geriatric problem, and the search for new solutions continues. We investigated how existing fall prevention technology was experienced within nursing home nurses' environment and workflow. Our NIH-funded study in an American nursing home was followed by a cultural learning exchange with a Dutch nursing home. We constructed two case reports from interview and observational data and compared the magnitude of falls, safety cultures, and technology characteristics and effectiveness. Falls were a high-magnitude problem at the US site, with a collectively vigilant safety culture attending to non directional audible alarms; falls were a low-magnitude problem at the NL site which employed customizable, infrared sensors that directed text alerts to assigned staff members' mobile devices in patient-centered care culture. Across cases, 1) a coordinated communication system was essential in facilitating effective fall prevention alert response, and 2) nursing home safety culture is tightly associated with the chosen technological system. PMID- 27956059 TI - Speed Limits for Nonvesicular Intracellular Sterol Transport. AB - Sterol transport between the endoplasmic reticulum (ER) and plasma membrane (PM) occurs by nonvesicular mechanisms requiring sterol transport proteins (STPs). Here we examine the idea that transport is enhanced at membrane contact sites where the ER is closely apposed to the PM. We conclude that sterol desorption from the membrane, rather than STP-mediated diffusion, is rate limiting in the cellular context, so there is no apparent kinetic benefit to having STP-mediated sterol transfer occur at contact sites. Contact sites may instead compartmentalize lipid synthesis or transport machinery, providing opportunities for regulation. PMID- 27956061 TI - Role of LRV1 and RNAi in the Pathogenesis of Leishmania. AB - The recent paper by Brettmann et al. provides insight as to how an RNA virus can persistently coexist in a protozoan with RNAi activity and how these two entities work to maintain balance. The authors were also able to successfully remove the virus and examine the role of the virus in parasitemia and the pathogenesis of leishmaniasis. PMID- 27956062 TI - Interaction between novel oscillation within the ventromedial hypothalamus and the sympathetic nervous system. AB - The ventromedial hypothalamus (VMH) is known to play an important role in feeding behavior and the control of sympathetic nerve activity (SNA). We report the identification of novel neuron groups that showed oscillations on both sides of the VMH in hypothalamus slice preparations from juvenile rats of postnatal days 5 14. We detected spontaneous rhythmic burst activity with a frequency of around 0.06Hz typically in the dorsolateral region of the VMH (i.e., VMH oscillation) using optical recordings (voltage and calcium imaging), field potential recordings and intracellular membrane potential recordings. The oscillation was also confirmed after isolation of the VMH from other hypothalamic structures. The frequency of oscillation was increased by lowering the glucose concentration of the superfusate. To evaluate the relation between VMH oscillation and SNA, we simultaneously recorded VMH oscillation, SNA from the thoracic sympathetic nerve trunk and phrenic nerve discharge (Phr) in the decerebrate and arterially perfused in situ preparation from juvenile rats of postnatal days 5-11. Power spectral analysis in the arterially perfused in situ rat preparation revealed similar peak values to those of slice preparations within the low-frequency range between the VMH oscillation and sympathetic nerve trunk activity. In addition, we analyzed cross-correlations between the VMH, SNA and Phr. The results revealed that a predominant positive correlation of the VMH activity with the SNA existed with an average time lag of 2.4s, suggesting the presence of functional couplings between the VMH and SNA (and respiratory center) in the lower brainstem and spinal cord. We hypothesize that the VMH oscillation might be involved in low frequency modulation of the SNA. PMID- 27956060 TI - Plasmodium vivax Controlled Human Malaria Infection - Progress and Prospects. AB - Modern controlled human malaria infection (CHMI) clinical trials have almost entirely focussed on Plasmodium falciparum, providing a highly informative means to investigate host-pathogen interactions as well as assess potential new prophylactic and therapeutic interventions. However, in recent years, there has been renewed interest in Plasmodium vivax, with CHMI models developed by groups in Colombia, the USA, and Australia. This review summarizes the published experiences, and examines the advantages and disadvantages of the different models that initiate infection either by mosquito bite or using a blood-stage inoculum. As for P. falciparum, CHMI studies with P. vivax will provide a platform for early proof-of-concept testing of drugs and vaccines, accelerating the development of novel interventions. PMID- 27956063 TI - Associations of acute and chronic stress hormones with cognitive functions in autism spectrum disorder. AB - Extensive studies have reported cognitive abnormalities in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Another line of evidence suggests that stress also affects cognitive functions. In this study, we investigated whether there were associations between stress hormones and cognitive functions in ASD and typically developing (TD) children. Cognitive functions in ASD and TD children were evaluated with a battery of psychological tests for working memory, behavioral flexibility, and social cognition for emotional assessments of others. ASD children exhibited higher hair and salivary cortisol, which reflects chronic and acute stress hormone levels of subjects, respectively, than TD children. Autism-spectrum quotient (AQ) was positively correlated with hair cortisol and the scores of Spence Children's Anxiety Scale in ASD children. In addition, a negative correlation was present between spatial working memory performance and hair cortisol in ASD, but not in TD, children. These results suggest that chronic stress hormone elevation may have relationships with some aspects of cognitive dysfunction in ASD subjects. PMID- 27956064 TI - Novel genes in brain tissues of EAE-induced normal and obese mice: Upregulation of metal ion-binding protein genes in obese-EAE mice. AB - Experimental autoimmune encephalomyelitis (EAE) is an inflammatory autoimmune disease of the central nervous system resulting from degeneration of the myelin sheath. This study is aimed to identify differentially expressed genes (DEGs) in the brain of EAE-induced normal diet (ND) mice and high-fat diet (HFD)-induced obese mice, and to identify novel genes responsible for elucidating the mechanism of the disease. Purified mRNA samples from the brain tissue were analyzed for gene microarray and validated by real-time RT-PCR. DEGs were identified if significant changes greater than 1.5-fold or less than 0.66-fold were observed (p<0.05). Pathway construction and functional categorization were performed using the Kyoto encyclopedia of genes and genomes pathways and gene ontology (GO) analysis. HFD-EAE mice showed more severe disease symptoms than ND-EAE mice. From GO study, fold changes of HFD-EAE to ND-EAE genes indicated that the genes were significantly associated to the pathways related with the immune response, antigen presentation, and complement activation. The genes related with metal ion binding proteins were upregulated in HFD-EAE and ND-EAE mice. Upregulation of Cul9, Mast2, and C4b expression is significantly higher in HFD-EAE mice than ND EAE mice. Cul9, Mast2, C4b, Psmb8, Ly86, and Ms4a6d were significantly upregulated in both ND- and HFD-EAE mice. Fcgr4, S3-12, Gca, and Zdhhc4 were upregulated only in ND-EAE, and Xlr4b was upregulated only in HFD-EAE mice. And significant upregulated genes of metal ion-binding proteins (Cul9 and Mast2) were observed in HFD-EAE mice. PMID- 27956065 TI - Effects of deep brain stimulation of the subthalamic nucleus on perceptual decision making. AB - When faced with difficult decisions, people prefer to stay with the default. This status quo bias often leads to suboptimal choice behavior. Neurophysiological evidence suggests a pivot role of the Subthalamic Nucleus (STN) for overcoming such status quo bias in difficult decisions, but causal evidence is lacking. The present study investigated whether subthalamic deep brain stimulation (DBS) in patients with Parkinson's disease (PD) influences the status quo bias. Eighteen PD patients treated with STN-DBS performed a difficult perceptual decision task incorporating intrinsic status quo option. Patients were tested with (ON) and without (OFF) active STN stimulation. Our results show that DBS of the STN affected perceptual decision making in PD patients depending on the difficulty of decision. STN-DBS improved difficult perceptual decisions due to a selective increase in accuracy (hit rate) that was independent of response bias (no effect on false alarm rate). Furthermore, STN-DBS impacted status quo bias as a function of baseline impulsivity. In impulsive patients, STN-DBS increased the default bias, whereas in less impulsive PD patients, DBS of the STN reduced the status quo bias. In line with our hypothesis, STN-DBS selectively affected the tendency to stick with the default option on difficult decisions, and promoted increased decision accuracy. Moreover, we demonstrate the impact of baseline cognitive abilities on DBS-related performance changes in PD patients. PMID- 27956066 TI - The clinical significance of freezing while turning in Parkinson's disease. AB - Freezing of gait (FoG) in people with Parkinson's disease (PD) is an environmentally sensitive, intermittent problem that occurs most often during turning. FoG is difficult for clinicians to evaluate and treat because it can be difficult to elicit during a clinical visit. Here, we aimed to develop a clinically valid objective measure of freezing severity during a 2-min 360-degree turning-in-place. Twenty-eight subjects with PD (16 freezers, FoG+, and 12 nonfreezers, FoG-) in the "off" state and 14 healthy control subjects were tested. Subjects wore three inertial sensors (one on each shin and one on the waist) while (1) turning in place for 2 min (alternating 360 degrees to the right with 360 degrees to the left) and (2) performing an Instrumented 7-m Timed Up and Go test (ITUG). Performance was videotaped, and clinical severity of FoG was independently rated by two movement disorders specialists (co-authors). Turning in place consistently resulted in FoG (13 out of 16 subjects with PD) while FoG was clinically observed in only two subjects with PD during the ITUG test. The Freezing Ratio during the turning test was significantly correlated with the clinical ratings (rho=0.7, p=0.003) and with score on the new FoG questionnaire (rho=0.5, p=0.03). After correcting for symptom severity (UPDRS-III), out of the four objective measures of the turning test (total number of turns, average turn peak speed and average turn smoothness), only the Freezing Ratio was significantly different across groups (p=0.04). Freezing can be well quantified with body-worn inertial sensors during a 2-min turning-in-place protocol. PMID- 27956067 TI - The Action Imitation network and motor imitation in children and adolescents with autism. AB - While deficits in imitation had been reported in children with autism spectrum disorder (ASD), its exact nature remains unclear. A dysfunction in mirroring mechanisms (through action imitation) has been proposed by some studies to explain this, although some recent evidence points against this hypothesis. The current study used behavior and functional MRI to examine the integrated functioning of the regions that are considered part of the Action Imitation network (AIN) in children and adolescents with ASD during a motor imitation task. Fourteen ASD and 15 age-and-IQ-matched typically developing (TD) children were asked to imitate a series of hand gestures in the MRI scanner. Intact performance on imitation (accurate imitation of hand gestures outside the scanner) in both ASD and TD groups was accompanied by significantly lower activity in ASD participants, relative to TD, in right angular gyrus, precentral gyrus, and left middle cingulate. In addition, autism traits were found to be significantly correlated with activation in the right angular gyrus. Overall, the findings of this study support the role of AIN in imitation and a potential difference in the recruitment of this network in ASD children. PMID- 27956069 TI - Cryptorchidism and pesticides: Is there a connection? AB - INTRODUCTION: The aim of our study was to compare the level of the most common organophosphate metabolite, dimethyl phosphate, in urine of women giving birth to both boys with cryptorchidism (study group), and healthy boys (control group), as well as to compare the level of dimethyl phosphate in our population with the results obtained in other populations. MATERIAL AND METHODS: After the ethical approval we included thirty women in both study and control groups. All newborns were born between 38 and 42weeks' gestation. Urine samples were taken on 3rd postpartal day. Gas chromatography with flame photometric detection was used to analyze dimethyl phosphate in urine following the method of Wu et al. Statistical analysis was done using Mann-Whitney test to compare the results in the two groups. RESULTS: Geometric mean of dimethyl phosphate in the study group was 7.18+/-8.26MUg/L and the creatinine-corrected level was 5.63+/-5.95MUg/L, and in the control group, the values are 7.98+/-6.75MUg/L and 6.15+/-7.01MUg/L, respectively. There was not a statistically significant difference in levels of dimethyl phosphate between these two groups (p=0.72786). Dimethyl phosphate levels obtained in similar studies are: 14.4MUg/L in Israel, 3.7MUg/L in Palestine, 10.3MUg/L in Jerusalem, 1.60MUg/L in Caribbean islands and 2.60MUg/L in Canada. CONCLUSIONS: Pregnant women in our country are exposed to organophosphate pesticides, but a correlation between the exposure to organophosphate pesticides and cryptorchidism was not found. LEVEL OF EVIDENCE: I. TYPE OF STUDY: Prognostic study, prospective study. PMID- 27956068 TI - Axial levodopa-induced dyskinesias and neuronal activity in the dorsal striatum. AB - Levodopa-induced dyskinesias are abnormal involuntary movements that limit the effectiveness of treatments for Parkinson's disease. Although dyskinesias involve the striatum, it is unclear how striatal neurons are involved in dyskinetic movements. Here we record from striatal neurons in mice during levodopa-induced axial dyskinesias. We developed an automated 3-dimensional motion tracking system to capture the development of axial dyskinesias at ~10ms resolution, and correlated these movements with neuronal activity of striatal medium spiny neurons and fast-spiking interneurons. The average firing rate of medium spiny neurons increased as axial dyskinesias developed, and both medium spiny neurons and fast-spiking interneurons were modulated around axial dyskinesias. We also found that delta field potential power increased in the striatum with dyskinesia, and that this increased delta power coupled with striatal neurons. Our findings provide insight into how striatal networks change as levodopa-induced dyskinesias develop, and suggest that increased medium spiny neuron firing, increased delta field potential power, and abnormal delta-coupling may be neurophysiological signatures of dyskinesias. These data could be helpful in understanding the role of the striatum in the pathogenesis of dyskinesias in Parkinson's disease. PMID- 27956070 TI - Rates and risk factors of unplanned 30-day readmission following general and thoracic pediatric surgical procedures. AB - BACKGROUND/PURPOSE: Postoperative unplanned readmissions are costly and decrease patient satisfaction; however, little is known about this complication in pediatric surgery. The purpose of this study was to determine rates and predictors of unplanned readmission in a multi-institutional cohort of pediatric surgical patients. METHODS: Unplanned 30-day readmissions following general and thoracic surgical procedures in children <18 were identified from the 2012-2014 National Surgical Quality Improvement Program- Pediatric. Time-dependent rates of readmission per 30 person-days were determined to account for varied postoperative length of stay (pLOS). Patients were randomly divided into 70% derivation and 30% validation cohorts which were used for creation and validation of a risk model for readmission. RESULTS: Readmission occurred in 1948 (3.6%) of 54,870 children for a rate of 4.3% per 30 person-days. Adjusted predictors of readmission included hepatobiliary procedures, increased wound class, operative duration, complications, and pLOS. The predictive model discriminated well in the derivation and validation cohorts (AUROC 0.710 and 0.701) with good calibration between observed and expected readmission events in both cohorts (p>.05). CONCLUSIONS: Unplanned readmission occurs less frequently in pediatric surgery than what is described in adults, calling into question its use as a quality indicator in this population. Factors that predict readmission including type of procedure, complications, and pLOS can be used to identify at-risk children and develop prevention strategies. LEVEL OF EVIDENCE: III. PMID- 27956071 TI - Solution blow spun polymer: A novel preclinical surgical sealant for bowel anastomoses. AB - BACKGROUND: Solution blow spinning is a technique for depositing polymer fibers with promising potential use as a surgical sealant. This study assessed the feasibility and efficacy of solution blow spun polymer (BSP) for sealing bowel perforations in a mouse model of partial cecal transection. We then evaluated its use for reinforcing a surgical anastomosis in a preclinical piglet model. METHODS: Three commercially available surgical sealants (fibrin glue, polyethylene glycol (PEG) hydrogel, and cyanoacrylate) were compared to BSP in the ability to seal partially transected cecum in mice. For anastomosis feasibility testing in a piglet model, piglets were subjected to small bowel transection with sutured anastomosis reinforced with BSP application. Outcome measures included anastomotic burst pressure, anastomotic leak rate, 14-day survival, and complication rate. RESULTS: For the mouse model, the survival rates for the sealants were 30% for fibrin glue, 20% for PEG hydrogel, 78% for cyanoacrylate, and 67% for BSP. Three of 9 mice died after BSP administration because of perforation leak, failure to thrive with partial obstruction at the perforation site, and unknown causes. All other mice died of perforation leak. The mean burst pressure at 24h was significantly higher for BSP (81mm Hg) when compared to fibrin glue (6mm Hg, p=0.047) or PEG hydrogel (10mm Hg, p=0.047), and comparable to cyanoacrylate (64mm Hg, p=0.91). For piglets, 4 of 4 animals survived at 14days. Mean burst pressures at time of surgery were 37+/-5mm Hg for BSP and 11+/-9mm Hg for suture-only controls (p=0.09). CONCLUSIONS: Solution blow spinning may be an effective technique as an adjunct for sealing of gastrointestinal anastomosis. Further preclinical testing is warranted to better understand BSP properties and alternative surgical applications. PMID- 27956072 TI - Older Citizens' Opinions on Long-Term Care Options: A Vignette Survey. AB - BACKGROUND: Older citizens are directly concerned, as potential beneficiaries and informal caregivers, by access to long-term care (LTC) services matching their expectations. The aim of this research was to collect their opinions regarding LTC arrangements for a diversity of disability profiles. DESIGN/SETTING/PARTICIPANTS: Mailed vignette survey in a representative population-based sample of 3133 community-dwelling persons 68 years or older residing in a Swiss region. MEASUREMENTS: All persons received a set of 10 vignettes. For each vignette, they considered 2 social situations successively: a person (1) living with an able-bodied spouse, and (2) living alone or with a spouse unable to help (resulting in 20 vignettes). Subjects selected a care setting (home, sheltered housing, or nursing home) and specified the preferred type of caregivers (spouse, professionals, or both) after community-based care options. Population estimates were based on weighted data accounting for the stratification of the survey sample. RESULTS: A total of 2985 participants (95.3%) expressed opinions on 55,178 vignettes (mean 18.5 vignettes, SD 4.1) Institutionalization was selected by 0.8% (95% confidence interval 0.3-1.4) of the population for the vignette of lowest disability with able-bodied spouse and 78.8% (76.1-81.6) for the vignette of highest disability and no possible help from a spouse. Continence, cognitive, and behavioral difficulties further influenced the preferences expressed for LTC options. Community-based LTC choices involved professionals mostly as a complement to informal help by the spouse, except for vignettes describing isolated moderate cognitive impairment or difficulties in instrumental activities of daily living. In these cases, most favored help provided by spouses only. CONCLUSIONS: This survey had high acceptance. Responses to variations in the disability and social profile displayed in the vignettes suggested the validity of measurements. PMID- 27956073 TI - An Unintended Consequence of Culture Change in VA Community Living Centers. AB - OBJECTIVE: Although a growing body of evidence suggests that culture change and its corollary, person-centered care improves resident outcomes in the nursing home setting, little is known about the effect of culture change in a postacute setting in which patients receive skilled nursing and rehabilitation services for a relatively short period of time before returning home. DESIGN: Data for this study were collected as part of a larger project to understand the impact of Veterans Health Administration (VHA) policies to shift the mission of VHA Community Living Centers (CLCs) from long-stay custodial care to short-stay skilled nursing and rehabilitative care. RESULTS: Although qualitative data collected during interviews from site visits to eight geographically diverse CLCs suggest an increase in the quality of life and care for veterans, interview data also indicate an unintended consequence. Specifically, staff described how aspects of the homelike environment, relationship-based care delivery, and attention to veterans' preferences that characterize culture change can prolong a veteran's length of stay beyond treatment completion. In addition to providing skilled nursing and rehabilitation, VHA CLCs also serve a latent function of providing a comfortable home and a peer community for veterans to connect and socialize with one another. A congregate living environment for persons with the shared symbolic status of being a veteran is unique to VHA CLCs. Strong bonding among peers and staff as well as staff respect for veterans' service to the country may increase their sense of obligation to keep veterans past their expected discharge date. CONCLUSION: Our findings suggest that the complexities of culture change and veteran- centered care in a short-term care setting may be underrecognized. We discuss how findings may also be relevant for the non-VHA sector. PMID- 27956074 TI - AIDE-Acute Illness and Depression in Elderly Patients. Cognitive Behavioral Group Psychotherapy in Geriatric Patients With Comorbid Depression: A Randomized, Controlled Trial. AB - BACKGROUND: Comorbid depression is highly prevalent in geriatric patients and associated with functional loss, frequent hospital re-admissions, and a higher mortality rate. Cognitive behavioral psychotherapy (CBT) has shown to be effective in older depressive patients living in the community. To date, CBT has not been applied to older patients with acute physical illness and comorbid depression. OBJECTIVES: To evaluate the effectiveness of CBT in depressed geriatric patients, hospitalized for acute somatic illness. DESIGN: Randomized controlled trial with waiting list control group. SETTING: Postdischarge intervention in a geriatric day clinic; follow-up evaluations at the patients' homes. PARTICIPANTS: A total of 155 randomized patients, hospitalized for acute somatic illness, aged 82 +/- 6 years and suffering from depression [Hospital Anxiety and Depression Scale (HADS) scores >7]. Exclusion criteria were dementia, delirium, and terminal state of medical illness. INTERVENTION: Fifteen, weekly group sessions based on a CBT manual. Commencement of psychotherapy immediately after discharge in the intervention group and a 4-month waiting list interval with usual care in the control group. MEASUREMENTS: HADS depression total score after 4 months. Secondary endpoints were functional, cognitive, psychosocial and physical status, resource utilization, caregiver burden, and amount of contact with physician. RESULTS: The intervention group improved significantly in depression scores (HADS baseline 18.8; after 4 months 11.4), whereas the control group deteriorated (HADS baseline 18.1; after 4 months 21.6). Significant improvement in the intervention group, but not in the control group, was observed for most secondary outcome parameters such as the Barthel and Karnofsky indexes. Intervention effects were less pronounced in patients with cognitive impairment or acute fractures. CONCLUSIONS: CBT is feasible and highly effective in geriatric patients. The benefits extend beyond effective recovery and include improvement in physical and functional parameters. Early diagnosis, good access to psychotherapy, and early intervention could improve care for depressive older patients. CLINICAL TRIAL REGISTRATION: www.germanctr.de German Trial Register DRKS 00004728. PMID- 27956076 TI - Serum cytokine and chemokine profiles in patients with juvenile muscular atrophy of distal upper extremity (Hirayama disease). AB - Juvenile muscular atrophy of the distal upper extremity (Hirayama disease) is characterized by adolescent-onset muscular weakness of the distal upper limb. Several studies showed the contribution of atopic disposition and hyperIgEaemia to the disease process, but it has not been well clarified. To identify cytokine and chemokine profiles in Hirayama disease, serum samples were analyzed using multiplex magnetic bead-based assay. Eotaxin, MCP-1 and RANTES levels were significantly higher in Hirayama disease (N=11) than in normal controls (N=12). These chemokines are associated with inflammatory cell recruitment. Allergic inflammation may involve in the pathogenesis of Hirayama disease. PMID- 27956075 TI - Natural product HTP screening for attenuation of cytokine-induced neutrophil chemo attractants (CINCs) and NO2- in LPS/IFNgamma activated glioma cells. AB - Chronic and acute central nervous system (CNS) inflammation are contributors toward neurological injury associated with head trauma, stroke, infection, Parkinsons or Alzheimers disease. CNS inflammatory illnesses can also contribute toward risk of developing glioblastoma multiforme (GBM). With growing public interest in complementary and alternative medicines (CAMs), we conduct a high throughput (HTP) screening of >1400 natural herbs, plants and over the counter (OTC) products for anti-inflammatory effects on lipopolysaccharide (LPS)/interferon gamma (IFNgamma) activated C6 glioma cells. Validation studies were performed showing a pro-inflammatory profile of [LPS 3 ug/ml/ IFNgamma 3 ng/ml] consistent with greater release [>8.5 fold] of MCP-1, NO2-, cytokine induced neutrophil chemo-attractants (CINC) 1, CINC 2a and CINC3. The data show no changes to the following, IL-13, TNF-a, fracktaline, leptin, LIX, GM-CSF, ICAM1, L-Selectin, activin A, agrin, IL-1alpha, MIP-3a, B72/CD86, NGF, IL-1b, MMP 8, IL-1 R6, PDGF-AA, IL-2, IL-4, prolactin R, RAGE, IL-6, Thymus Chemokine-1, CNTF,IL-10 or TIMP-1. A HTP screening was conducted, where we employ an in vitro efficacy index (iEI) defined as the ratio of toxicity (LC50)/anti-inflammatory potency (IC50). The iEI was precautionary to ensure biological effects were occurring in fully viable cells (ratio > 3.8) independent of toxicity. Using NO2- as a guideline molecule, the data show that 1.77% (25 of 1410 tested) had anti inflammatory effects with iEI ratios >3.8 and IC50s <250ug/ml. These include reference drugs (hydrocortisone, dexamethasone N6-(1-iminoethyl)-l-lysine and NSAIDS: diclofenac, tolfenamic acid), a histone deacetylase inhibitor (apicidin) and the following natural products; Ashwaganda (Withania somnifera), Elecampagne Root (Inula helenium), Feverfew (Tanacetum parthenium), Green Tea (Camellia sinensis), Turmeric Root (Curcuma longa) Ganthoda (Valeriana wallichii), Tansy (Tanacetum vulgare), Maddar Root (Rubia tinctoria), Red Sandle wood (Pterocarpus santalinus), Bay Leaf (Laurus nobilis, Lauraceae), quercetin, cardamonin, fisetin, EGCG, biochanin A, galangin, apigenin and curcumin. The herb with the largest iEI was Ashwaganda where the IC50/LC50 was 11.1/>1750.0MUg/ml, and the compound with the greatest iEI was quercetin where the IC50/LC50 was 10.0/>363.6MUg/ml. These substances also downregulate the production of iNOS expression and attenuate CINC-3 release. In summary, this HTP screening provides guideline information about the efficacy of natural products that could prevent inflammatory processes associated with neurodegenerative disease and aggressive glioma tumor growth. PMID- 27956077 TI - Modular cementless prosthetic reconstruction after resection of lower extremity malignant tumor. AB - INTRODUCTION: The aim of the study is to report the preliminary clinical and functional outcomes of a modular cementless tumor resection prosthesis system (Megasystem-C(r), Waldemar Link GmbH&Co. KG, Hamburg, Germany) in patients undergoing limb salvage surgery with wide resection in a lower extremity primary or metastatic malignant bone tumor. MATERIAL AND METHODS: Fifty-two consecutive patients (33 male and 19 female; mean age 37.1 years (range, 16 to 79) with primary or metastatic lower extremity malignant bone tumor who underwent wide resection and reconstruction with cementless Megasystem-C(r) system were included in the study. Patients were analyzed for age at diagnosis, gender, type and localization of the tumor, time of follow-up, patient and prosthesis survival, complications, oncological and functional outcomes. RESULTS: Mean follow-up time was 43.2 months (range, 8 to 66). Cumulative patient survival rate was 92.3 percent and cumulative prosthetic survival rate was 65.4 percent. 18 complications were recorded and 9 of them required revision (17.3 percent). Mean overall Musculoskeletal Tumor Society score score was 72.7 percent (range, 52 to 86). Subgroup analyzes demonstrated no difference in complication rates, overall patient or prosthetic survivals. Functional scores according to age, diagnosis and location of the reconstruction also were not significantly different. CONCLUSION: The preliminary short-term follow-up results revealed that, the new generation modular cementless endoprosthetic system offers promising clinical and functional outcomes with reasonable complication rates. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 27956078 TI - Is pin configuration the only factor causing loss of reduction in the management of pediatric type III supracondylar fractures? AB - OBJECTIVE: Closed reduction with percutaneous pinning is the treatment of choice for displaced supracondylar humerus fractures in children. In addition to configuration of pin fixation, many factors have been attributed to loss of reduction (LOR). The aim of the present study was to review potential factors that contribute to loss of reduction in the closed management of type III pediatric supracondylar fractures. METHODS: Treatment of 87 patients with type III supracondylar fractures was reviewed to determine factors associated with loss of reduction; 48 patients were treated with lateral pinning and 39 with crossed-pinning after closed reduction. Outcome parameters included radiographic maintenance of postoperative reduction. RESULTS: Lateral or crossed-pin configuration, pin spread at fracture site, pin-spread ratio (PSR), and direction of coronal displacement of the fracture were not associated with LOR. A significant difference (p = 0.01) was found between LOR rates of patients with medial wall communication and LOR. CONCLUSION: Medial wall communication is a contributing factor to LOR in the management of type III supracondylar fractures. Cross-pinning should be preferred when medial wall communication is present, to provide more stable fixation. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 27956079 TI - Regression of a symptomatic thoracic disc herniation with a calcified intervertebral disc component. AB - There were only a few cases describing spontaneous regression of calcified thoracic disc herniation in the literature. We present a 38-year-old male office worker who had left paramedian-foraminal extruded disc at T7-T8 with calcifications of the T7-T8 and T8-T9 intervertebral discs. This case was unique in that the non-calcified extruded disc material regressed almost completely in 5 months while the calcified intervertebral discs remained the same during the process of regression. This report stresses that regression of the herniated material of the thoracic discs with subsidence of the symptoms is still possible even if the disc material is calcified. PMID- 27956080 TI - A rare case of chondroblastoma of the acromion. AB - We present a 37-year-old patient with a chondroblastoma in his right acromion. The acromion is an unusual site for this type of tumor and the typical surgical treatment involves resection of the involved acromion bone. The patient was surgically treated with resection of the right acromion and autogenous iliac bone grafting. Twenty five months postoperatively, he demonstrated full shoulder function, without evidence of local recurrence or metastasis. PMID- 27956081 TI - Gene markers of fracture healing in early stage and the regulatory mechanism during the process using microarray analysis. AB - BACKGROUND: The aim of this study was to explore crucial markers and uncover the regulatory mechanisms of fracture healing in the early stage. METHODS: Gene expression profile of GSE45156 was downloaded, in which 3 fractured samples and 3 unfractured samples were used in our present study. Based on the threshold value, differentially expressed genes (DEGs) were selected between two kinds of samples using limma package in R. Enrichment analysis of these DEGs was performed by DAVID software. Furthermore, protein-protein interaction (PPI) network was established integrating information in STRING database, and visualized by Cytoscape software. RESULTS: We identified a set of 960 DEGs including 509 up regulated and 451 downregulated genes. Biological processes involving RNA splicing and cell cycle were significantly enriched for the up-regulated genes such as Snrpd2, Eftud2, Plk1 and Bub1b, whereas skeletal system development and bone development processes were predominant for down-regulated genes like Ubc. In the constructed PPI network, all the five genes were the predominant nodes, of which Snrpd2 was linked to Eftud2, while Bub1b was to interact with Plk1. CONCLUSION: Five candidate genes crucial for indicating the process of fracture in early stage were identified. Eftud2, Snrpd2, Bub1b and Plk1 might function through the involvement of cell-cycle-related BP, while Ubc might influence the protein degradation during bone development. However, more experimental validations are needed to confirm these results. PMID- 27956082 TI - Translation, cross-cultural adaptation, reliability and validity of the Turkish version of the Olerud-Molander Ankle Score (OMAS). AB - OBJECTIVE: The aim of this study was to translate and culturally adapt the Olerud Molander Ankle Score (OMAS) into Turkish and to assess its reliability and validity. METHODS: The Turkish version of the OMAS (OMAS-Tr) was developed after the translation and back-translation, which included the stages recommended by Beaton. The OMAS-Tr was administered to one hundred patients (49 females, 51 males; average age: 42.3 +/- 17.7; range 16-81 years) with malleolar fractures. The OMAS-Tr was completed twice by each participant at 7- to 10-days intervals to assess test-retest reliability based on the interrater correlation coefficient, whereas Cronbach's alpha evaluated internal consistency. The external validity was evaluated with correlations between the Turkish version of the Foot and Ankle Ability Measure (FAAM) and the Turkish version of the SF-12 questionnaire. The distribution of floor and ceiling effects was also analyzed. RESULTS: The internal consistency (Cronbach's alpha = 0.84) and the test-retest reliability (ICC = 0.98) were excellent. The mean interval between the two tests was 8.6 +/- 1.4 days. The mean and standard deviation of the first and second assessments of the OMAS-Tr were 74.1 +/- 23.7 and 75.7 +/- 23.9, respectively. There was a strong correlation between the OMAS-Tr and the FAAM subscales on activities of daily living and sports (r = 0.86, r = 0.83; p < 0.001, respectively). The OMAS Tr displayed very good to good correlation with the SF-12 physical component score and the SF-12 mental component score (r = 0.72, r = 0.60, p < 0.001, respectively). CONCLUSION: OMAS-Tr was a valid and reliable tool to assess ankle fracture-related problems. Nonetheless, further studies are needed to assess its responsiveness. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 27956083 TI - [Lung screening]. AB - The NLST study found in more than 53,000 (former-) heavy smokers that annual screening with low-dose CT-scan (LDCT) reduced lung cancer mortality and overall mortality by 20% and 6.7% respectively. However, several potential harms of such screening strategy were underlined: over-diagnosis bias, irradiation risk, and the high rate of false-positive results that could lead to futile invasive (and potentially harmful) exams, to impact quality of life, to increase patient's anxiety and costs. All these concerns were largely debated in several recent publications. Most of them concluded in a risk/benefit ratio favoring screening strategy by LDCT. Conversely, most of American academic societies currently recommend LDCT-based lung cancer screening. In France, a taskforce edited a common statement recommending screening smokers or ex-smokers, from 55 to 75years old who have smoked at least 30packs/year. The taskforce also underlined the need for clinical trials aiming to translate screening strategy to the French setting. However, the French Health Authority recently claimed that lung cancer screening was not relevant in the current setting. PMID- 27956084 TI - [What future for chest x-ray against ultra-low-dose computed tomography?] AB - Technological improvements, with iterative reconstruction at the foreground, have lowered the radiation dose of a chest CT close to that of a PA and lateral chest x-ray. This ultra-low dose chest CT (ULD-CT) has an image quality that is degraded on purpose, yet remains diagnostic in many clinical indications. Thus, its effectiveness is already validated for the detection and the monitoring of solid parenchymal nodules, for the diagnosis and monitoring of infectious lung diseases and for the screening of pleural lesions secondary to asbestos exposure. Its limitations are the analysis of the mediastinal structures, the severe obesity (BMI>35) and the detection of interstitial lesions. If it can replace the standard chest CT in these indications, all the more in situations where radiation dose is a major problem (young patients, repeated exams, screening), it progressively emerges as a first line alternative for chest radiograph, providing more data at a similar radiation cost. PMID- 27956085 TI - Effects of alpha-synuclein on axonal transport. AB - Lewy bodies and Lewy neurites composed primarily of alpha-synuclein characterize synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Despite decades of research on the impact of alpha-synuclein, little is known how abnormal inclusion made of this protein compromise neuronal function. Emerging evidence suggests that defects in axonal transport caused by aggregated alpha-synuclein contribute to neuronal dysfunction. These defects appear to occur well before the onset of neuronal death. Susceptible neurons in PD such as dopamine neurons with long elaborate axons may be particularly sensitive to abnormal axonal transport. Axonal transport is critical for delivery of signaling molecules to the soma responsible for neuronal differentiation and survival. In addition, axonal transport delivers degradative organelles such as endosomes and autophagosomes to lysosomes located in the soma to degrade damaged proteins and organelles. Identifying the molecular mechanisms by which axonal transport is impaired in PD and DLB may help identify novel therapeutic targets to enhance neuron survival and even possibly prevent disease progression. Here, we review the evidence that axonal transport is impaired in synucleinopathies, and describe potential mechanisms by which contribute to these defects. PMID- 27956086 TI - The Caatinga endemic Manilkara rufula possesses remarkable activity against Trichomonas vaginalis and Tritrichomonas foetus. AB - Tritrichomonas foetus infects the bovine urogenital tract, causing bovine trichomoniasis. Significant economic losses may occur due to infertility and abortion among cattle. Trichomonas vaginalis is the causative agent of trichomoniasis; the most common but overlooked non-viral sexually transmitted disease worldwide. Human and bovine trichomoniasis present treatment restrictions and efforts to identify new alternatives are essential. The present study evaluated the anti-trichomonads activities of seven fractions from northwest endemic plant Manilkara rufula. Flavonoids and condensed tannins were identified from these fractions by LC-DAD-MS/MS and MALDI-MS/MS. Altogether, the results demonstrated for the first time the structural description of tannins from leaves of M. rufula and the relation of these compounds with anti-T. vaginalis and anti T. foetus activities. Overall, this report reveals the potential of M. rufula fractions against both parasites and shows new alternatives to treat the infection caused by trichomonads. PMID- 27956087 TI - The biochemical characterization of two phosphate transport systems in Phytomonas serpens. AB - Inorganic phosphate (Pi) is an essential nutrient for all organisms because it is required for a variety of biochemical processes, such as signal transduction and the synthesis of phosphate-containing biomolecules. Assays of 32Pi uptake performed in the absence or in the presence of Na+ indicated the existence of a Na+-dependent and a Na+-independent Pi transporter in Phytomonas serpens. Phylogenetic analysis of two hypothetical protein sequences of Phytomonas (EM1) showed similarities to the high-affinity Pi transporters of Saccharomyces cerevisiae: Pho84, a Na+-independent Pi transporter, and Pho89, a Na+-dependent Pi transporter. Plasma membrane depolarization by FCCP, an H+ ionophore, strongly decreased Pi uptake via both Na+-independent and Na+-dependent carriers, indicating that a membrane potential is essential for Pi influx. In addition, the furosemide-sensitive Na+-pump activity in the cells grown in low Pi conditions was found to be higher than the activity detected in the plasma membrane of cells cultivated at high Pi concentration, suggesting that the up-regulation of the Na+ ATPase pump could be related to the increase of Pi uptake by the Pho89p Na+:Pi symporter. Here we characterize for the first time two inorganic phosphate transporters powered by Na+ and H+ gradients and activated by low Pi availability in the phytopathogen P. serpens. PMID- 27956088 TI - An overview of nonhuman primates in aging research. AB - A graying human population and the rising costs of healthcare have fueled the growing need for a sophisticated translational model of aging. Nonhuman primates (NHPs) experience aging processes similar to humans and, as a result, provide an excellent opportunity to study a closely related species. Rhesus monkeys share >92% homology and are the most commonly studied NHP. However, their substantial size, long lifespan, and the associated expense are prohibitive factors. Marmosets are rapidly becoming the preferred NHP for biomedical testing due to their small size, low zoonotic risk, reproductive efficiency, and relatively low cost. Both species experience age-related pathology similar to humans, such as cancer, diabetes, arthritis, cardiovascular disease, and neurological decline. As a result, their use in aging research is paving the way to improved human health through a better understanding of the mechanisms of aging. PMID- 27956089 TI - Outcome Analysis of First-line Somatostatin Analog Treatment in Metastatic Pulmonary Neuroendocrine Tumors and Prognostic Significance of 18FDG-PET/CT. AB - INTRODUCTION: Pulmonary carcinoids (PCs) are classed according to the World Health Organization 2004 classification as typical or atypical carcinoids. Owing to their rarity, no dedicated clinical trials with somatostatin analogs (SSAs) have been carried out on primary PCs. PATIENTS AND METHODS: From January 2007 to December 2015, 30 patients with metastatic PCs underwent first-line SSA treatment (20 with octreotide long-acting repeatable 30 mg and 10 with lanreotide 120 mg every 28 days). Eight (23.3%) patients had typical carcinoids and 23 (76.7%) had atypical carcinoids. RESULTS: The median age was 65.5 years (range, 47-82 years). All patients (23 males and 7 females) were Gallium-68-DOTA-TOC-positron emission tomography/computed tomography (PET/CT)-positive (29 patients) or octreoscan positive (1 patient). Of the 20 patients who performed fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18FDG PET/CT), 14 (70.0%) were positive and 6 negative (30.0%). The median treatment duration was 10 months (range, 2-59 months). One patient achieved a partial response (3.3%), and 26 (86.6%) showed stable disease. One patient interrupted SSA treatment owing to symptomatic cholelithiasis. Five-year survival was 53.0% (95% confidence interval [CI], 15.0%-80.0%). The median progression-free survival (mPFS) was 11.1 months (95% CI, 7.0-15.0 months). Negative 18FDG-PET/CT patients had an mPFS of 15.2 months (95% CI, 7.6 months to not reached) compared with 7.0 months (95% CI, 4.0-10.1 months) for 18FDG-PET/CT-positive patients. No differences in mPFS were found in relation to TTF1-value, histologic subtype, and presence of extrahepatic metastases. CONCLUSION: SSAs showed antitumor activity in terms of disease control rate and PFS and proved safe, even in patients with poor Eastern Cooperative Oncology Group status. 18FDG-PET/CT would appear to be a prognostic factor. PMID- 27956090 TI - Commentary on "Analysis of the Elective Treatment Process for Critical Limb Ischemia with Tissue Loss: Diabetic Patients Require Rapid Revascularisation". PMID- 27956091 TI - Integrated analysis neurimmiRs of tilapia (Oreochromis niloticus) involved in immune response to Streptococcus agalactiae, a pathogen causing meningoencephalitis in teleosts. AB - MicroRNAs (miRNAs) are a class of noncoding RNA molecules and play important roles in a wide spectrum of biological processes, including in immune response. Recent years have witnessed considerable amount of research interest in studies on miRNA-mediated modulation gene function during neuroinflammation. Here, we evaluated Streptococcus agalactiae infected tilapia (Oreochromis niloticus) brain for the expression profile of miRNAs, potential functions and their correlation with genes involved in inflammatory pathways. A total of 1981 miRNAs were identified, including in 486 miRNAs which have homologues in the currently available databases and 1945 novel miRNAs. The expression levels of 547 miRNAs were significantly altered at 6 h-48 h post-bacterial infection, and these miRNAs were therefore classified as differentially expressed tilapia miRNAs. Real-time PCR were implemented for 14 miRNAs co-expressed in five samples, and agreement was confirmed between the high-throughput sequencing and real-time PCR data. For the 486 differentially expressed miRNAs target 41,820 genes. GO and KEGG enrichment analysis revealed that some target genes of miRNAs were grouped mainly into the categories of apoptotic, signal pathwayand immune response. This is the first report of comprehensive identification of teleost miRNAs being differentially regulated in brain in normal conditions relating to bacterial infection. PMID- 27956092 TI - Ultrasonographic features of hepatobiliary pathology in opisthorchiasis and opisthorchiasis-associated cholangiocarcinoma. AB - Infection with the liver fluke, Opisthorchis viverrini (Ov), is an important public health problem in northeast Thailand where people have a habit of eating raw or inadequately cooked fish. Opisthorchiasis is associated with a number of asymptomatic hepatobiliary abnormalities and cholangiocarcinoma (CCA) that can be observed conveniently by ultrasonography. Based on our accumulated data, characteristic features of ultrasonographic findings of hepatobiliary pathology in Ov infection are reviewed. Also, the ultrasonographic classification of periductal fibrosis in Ov infection of opisthorchiasis will be proposed herein. PMID- 27956094 TI - Gastrointestinal transit scintigraphy in chronic constipation evaluation in pediatric age; an infrequent test. AB - AIM: Chronic constipation is a common pathology in children. The aim of this paper was to show the usefulness of gastrointestinal transit scintigraphy in pediatric patients with chronic constipation, and the advantages with respect to other imaging techniques, despite our limited experience. MATERIAL AND METHODS: We evaluated 5 patients sent to our service with a diagnosis of chronic constipation refractory to treatment. We performed a complete study protocol, including liquid gastric emptying scintigraphy and small and large bowel transit times, using a single dose of 111In-DTPA. Following international guidelines regions of interest were defined in stomach, terminal ileum and in 6 regions of the large intestine. RESULTS: All patients showed altered scintigraphy study, showing 4 of them normal radiological tests. Radioisotopic study changed diagnosis in 2 patients and in other 2 patients contributed to clarify it, since discordance between normal radiological tests and abnormal rectal biopsy. One of the patients showed concordance between each imaging modality. The results of the test changed the therapeutic management in 2 cases. CONCLUSIONS: Our limited experience coincides with published data in which scintigraphy study turns out to be a reproducible and accurate method. It provides physiological, quantitative and useful information in the study of constipation, being the unique exploration that allows both global and regional gastrointestinal transit time determination. PMID- 27956093 TI - Late diagnosis of congenital toxoplasmosis based on serological follow-up: A case report. AB - Toxoplasma gondii is a protozoan parasite infecting up to one third of the world's population. T. gondii infection is usually benign in immunocompetent patients but can be life-threatening when congenitally transmitted. Congenital toxoplasmosis presentation ranges from severe central nervous system and ocular features, to a well appearing newborn with onset of complications late in childhood. The diagnosis of subclinical form remains important since early treatment reduces later complications such as chorioretinitis. We report an atypical case of congenital toxoplasmosis with a delayed diagnosis, based on Toxoplasma-specific serological follow-up. The infant was born to a mother who became infected during pregnancy, thus inducing infant biological and clinical follow-up. Neither biological nor clinical arguments favored a diagnosis of congenital toxoplasmosis until ten months of life. Congenital toxoplasmosis was then suspected because of an unusual increase of specific IgG levels. Diagnosis was confirmed by detection of newly synthesized newborn Ig isotypes using complementary comparative mother-to-child immunological profile techniques and specific treatment therefore administered. This report highlights the importance to follow up newborns at risk of congenital toxoplasmosis with specific and newborn-appropriate techniques until Toxoplasma-IgG titers are completely negative. This allows not only the exclusion of congenital toxoplasmosis when serology becomes negative, but also the diagnosis and treatment of congenital toxoplasmosis when infection is detected later in development. PMID- 27956095 TI - Real-Time Visualization of the Precipitation and Phase Behavior of Octaethylporphyrin in Lipid Microparticles. AB - The material properties of micro- and nanoparticles are fundamental for their bulk properties in suspension, like their stability and encapsulation efficiency. A particularly interesting system with potential biomedical applications is the encapsulation of hydrophobic porphyrins into lipid particles and their use as metal atom chelators, where retention and stability are keys for the design process. The overall goal here was to study the solubility, phase behavior, and mixing of octaethylporphyrin (OEP) and OEP-Cu chelates with 2 core materials, triolein (TO) and cholesteryl acetate, as single microparticles. We employed a real-time, single-particle microscopic technique based on micropipette injection to characterize the behavior of these materials and their mixtures upon solvent loss and precipitation. A clear phase separation was observed between the triolein liquid core and porphyrin microcrystals, and the ternary phase diagram of the droplet compositions and onsets of phase separation over solvent dissolution was built. On the contrary, cholesteryl acetate and OEP-Cu coprecipitated by solvent dissolution, preventing porphyrin crystallization even for very high supersaturations. This type of real-time, single-particle characterization is expected to offer important information about the formulation of other hydrophobic compounds of interest, where finding the proper encapsulation environment is a key step for their retention and stability. PMID- 27956096 TI - Policies towards hospital and GP competition in five European countries. AB - This study provides an overview of policies affecting competition amongst hospitals and GPs in five European countries: France, Germany, Netherlands, Norway and Portugal. Drawing on the policies and empirical evidence described in five case studies, we find both similarities and differences in the approaches adopted. Constraints on patients' choices of provider have been relaxed but countries differ in the amount and type of information that is provided in the public domain. Hospitals are increasingly paid via fixed prices per patient to encourage them to compete on quality but prices are set in different ways across countries. They can be collectively negotiated, determined by the political process, negotiated between insurers and providers or centrally determined by provider costs. Competition amongst GPs varies across countries and is limited in some cases by shortages of providers or restrictions on entry. There are varied and innovative examples of selective contracting for patients with chronic conditions aimed at reducing fragmentation of care. Competition authorities do generally have jurisdiction over mergers of private hospitals but assessing the potential impact of mergers on quality remains a key challenge. Overall, this study highlights a rich diversity of approaches towards competition policy in healthcare. PMID- 27956097 TI - Binding studies and biological evaluation of beta-carotene as a potential inhibitor of human calcium/calmodulin-dependent protein kinase IV. AB - Human calcium/calmodulin-dependent protein kinase IV (CAMKIV), a member of Ser/Thr kinase family, is associated with cancer, cerebral hypoxia and neurodegenerative diseases. beta-carotene is a colored organic compound, abundant in plants and fruits and is used in cancer prevention. Here, we report a strong binding affinity of beta-carotene with CAMKIV using molecular docking, fluorescence binding and isothermal titration calorimetry methods. Furthermore, beta-carotene also reduces the enzyme activity of CAMKIV moderately as observed during ATPase assay. To see the role of beta-carotene on cell proliferation and apoptosis, cancerous cells (HeLa, HuH7and MCF-7) and normal (HEK-293-T) cell lines were used. Admirable anticancer activity of beta-carotene was observed. We further performed propidium iodide and DAPI (4',6-diamidino-2-phenylindole) assays to understand the mechanism of anticancer activity of beta-carotene at molecular level. Our findings provide a newer insight into the use of beta carotene in cancer prevention and protection via inhibition of CAMKIV by regulating the signaling pathways. PMID- 27956098 TI - Identification of natural allosteric inhibitor for Akt1 protein through computational approaches and in vitro evaluation. AB - Akt, a serine/threonine protein kinase, is often hyper activated in breast and prostate cancers, but with poor prognosis. Allosteric inhibitors regulate aberrant kinase activity by stabilizing the protein in inactive conformation. Several natural compounds have been reported as inhibitors for kinases. In this study, to identify potential natural allosteric inhibitor for Akt1, we generated a seven-point pharmacophore model and screened it through natural compound library. Quercetin-7-O-beta-d-glucopyranoside or Q7G was found to be the best among selected molecules based on its hydrogen bond occupancy with key allosteric residues, persistent polar contacts and salt bridges that stabilize Akt1 in inactive conformation and minimum binding free energy during molecular dynamics simulation. Q7G induced dose-dependent inhibition of breast cancer cells (MDA MB 231) and arrested them in G1 and sub-G phase. This was associated with down regulation of anti-apoptotic protein Bcl-2, up-regulation of cleaved caspase-3 and PARP. Expression of p-Akt (Ser473) was also down-regulated which might be due to Akt1 inhibition in inactive conformation. We further confirmed the Akt1 and Q7G interaction which was observed to have a dissociation constant (Kd) of 0.246MUM. With these computational, biological and thermodynamic studies, we suggest Q7G as a lead molecule and propose for its further optimization. PMID- 27956099 TI - Role of two polysaccharide matrices on activity, stability and recycling efficiency of immobilized fungal amyloglucosidase of GH15 family. AB - Current study deals with immobilization of amyloglucosidase using two different strategies (entrapment and covalent binding). Chitosan beads were prepared using neutralization method while alginate beads were synthesized by simple gelation. Results of this study showed that percent recovery of amyloglucosidase after covalent binding was 85% however in case of entrapment it was 66%. Immobilization was optimized by standardizing various conditions including concentrations of polysaccharide (alginate: 4%; chitosan: 3%), divalent ions (0.2M) and glutaraldehyde (5%). Slight shift in catalytic efficiency of soluble amyloglucosidase in terms of reaction time, pH and temperature was also noticed after immobilization. Activation energy decreased after immobilization due to which stability of amyloglucosidase increased for longer time period as compared to soluble enzyme. Results of recycling studies showed that covalently bound amyloglucosidase retained more enzymatic activity even after 15 cycles as compared to the entrapped enzyme that lost its activity within 10 cycles. PMID- 27956100 TI - Sustained release gastroretentive tablet of metformin hydrochloride based on poly (acrylic acid)-grafted-gellan. AB - Development of a gastroretentive sustained release tablet of metformin based on poly (acrylic acid)-grafted-gellan (PAAc-g-GG) is the main purpose of this study. At first, PAAc-g-GG was synthesized by microwave-promoted free radical initiation method using cerric (IV) ammonium nitrate (CAN) as redox initiator and characterized by elemental analysis, FTIR, DSC-TGA, 13C NMR, biodegradation and viscosity study. The synthetic parameters were optimized by 23 full factorial design using Design Expert software. Acute oral toxicity and histological studies were also performed as per OECD guideline. Tablets were then prepared employing wet granulation method using PAAc-g-GG and evaluated for various physical characters, in vitro drug release, ex-vivo mucoadhesion and swelling. Compatibility between drug and excipients was checked by DSC and FTIR analysis. The F3 batch showed excellent mucoadhesion and sustained drug release over a period of 10h with dissolution similarity factor, f2=77.43. Kinetic modeling unveiled Case-1 Fickian diffusion based drug release mechanism. PMID- 27956101 TI - Recent advances in knowledge regarding the head and neck manifestations of IgG4 related disease. AB - IgG4-related disease (IgG4-RD) is a chronic inflammatory disorder, characterized by elevated serum IgG4 levels as well as abundant infiltration of IgG4-positive plasmacytes and fibrosis in various organs, including the head and neck region. In particular, the salivary glands, orbit, and thyroid are common sites of disease involvement. IgG4-RD is diagnosed based on various clinical, serological, and histopathological findings, none of which are pathognomonic. Hence, various differential diagnoses, which exhibit elevated serum IgG4 levels and infiltration of IgG4-postive cells into tissues, need to be excluded, especially malignant diseases and mimicking disorders. Systemic corticosteroids are generally effective in inducing IgG4-RD remission; however, recurrent or refractory cases are common. In addition, although the pathogenic mechanisms of IgG4-RD remain unclear, an antigen-driven inflammatory condition is believed to be involved. Recent studies have indicated the important pathogenic role of B cell/T cell collaboration and innate immunity in this disease. Nevertheless, additional research and discussions are needed to resolve many remaining questions. In this review, we provide an overview of the recent insights on the history, clinical features, diagnosis, and treatment of IgG4-RD in the head and neck region. Furthermore, we have also addressed the pathogenesis of this disease. PMID- 27956102 TI - Pharyngolaryngeal ulcers associated with the improper use of alendronate. AB - Bisphosphonates can cause mucosal irritation. Although esophageal ulceration is a well-recognized adverse effect of bisphosphonates, pharyngolaryngeal ulcers associated with the improper use of oral bisphosphonates have rarely been described. A previously healthy 78-year-old woman presented with refractory pharyngolaryngeal ulcers. Extensive evaluation, including biopsy, bacterial culture, and blood tests did not identify any findings that indicated a specific disease diagnosis. Antibiotics and oral prednisolone were ineffective. Ultimately, it was found that the patient regularly took a tablet of alendronate, a type of bisphosphonate, by dissolving it in the oral cavity. Within 2 weeks after withdrawal of the use of the medication, her symptoms were eliminated, and the lesions were completely healed. This case illustrates the importance of correct administration of bisphosphonates. Given the widespread use of bisphosphonates, physicians need to be aware that their improper use can cause pharyngolaryngeal ulcers. PMID- 27956103 TI - Transoral robotic surgery (TORS) for excision of a retropharyngeal intramuscular lipoma. AB - OBJECTIVE: To describe the feasibility, effectiveness, and improved morbidity profile of transoral robotic surgery (TORS) for the excision of a retropharyngeal intramuscular lipoma. METHODS: Case report of a robot-assisted transoral resection of a retropharyngeal intramuscular lipoma. RESULTS: A 62-year-old woman presented with tongue pain and globus with dysphagia for six months. Transoral exam revealed a pharyngeal submucosal mass, and MRI demonstrated a prevertebral lipomatous lesion with protrusion into the airway. The patient elected for robot assisted transoral surgical treatment. The patient tolerated the procedure well, experienced no complications, and was discharged on post-operative day one. At six months post-operatively, the patient was without dysphagia and was disease free on imaging. CONCLUSIONS: TORS is an effective, safe, feasible, and likely more efficient way to excise a retropharyngeal intramuscular lipoma or other retropharyngeal masses. PMID- 27956104 TI - A Case of Extra-Gastrointestinal Anisakidosis With Incidental Detection of a Live Larva During Laparoscopic Cystectomy. PMID- 27956105 TI - Management of Broad Ligament Defects and Herniation of Colon. PMID- 27956106 TI - Comparison of Laparoscopic Cornual Resection and Cornuotomy for Interstitial Pregnancy. AB - STUDY OBJECTIVE: To compare the clinical efficacy and safety of laparoscopic cornuotomy and cornual resection in the treatment of interstitial pregnancy. DESIGN: Retrospective chart review between 2006 and 2014 (Canadian Task Force classification II-2). SETTING: Two academic tertiary care hospitals. PATIENTS: Seventy-five patients with interstitial pregnancy treated by laparoscopy. MEASUREMENT AND MAIN RESULTS: In the 75 patients, 53 who underwent cornual resection and 22 who underwent cornuotomy, we evaluated operating time, changes in hemoglobin levels after surgery, the rate of major complications, and the incidence of persistent interstitial pregnancy. The mean operating time was significantly shorter for cornuotomy than for cornual resection (59.36 +/- 19.32 minutes vs. 77.11 +/- 23.97 minutes, respectively). Changes in hemoglobin level after the operation, rates of major complications, and the incidence of persistent interstitial pregnancy were not significantly different in the 2 surgery groups. CONCLUSION: Laparoscopic cornuotomy yielded clinical results comparable to those of cornual resection. Laparoscopic cornuotomy may reduce the time of operation, and had the same incidence of persistent interstitial pregnancy as cornual resection. PMID- 27956107 TI - Tips and Tricks for Performing Salpingectomy at the Time of Laparoscopic Hysterectomy. AB - STUDY OBJECTIVE: To demonstrate various techniques to perform salpingectomy efficiently at the time of laparoscopic hysterectomy. DESIGN: Step-by-step explanation of the techniques by video with narration (educational video) (Canadian Task Force Classification III). INTERVENTION: Salpingectomy at the time of laparoscopic hysterectomy. MEASUREMENTS AND MAIN RESULTS: Ovarian cancer is the deadliest gynecologic malignancy and has no effective screening strategies for average-risk women. After recognizing that the origin site for pelvic serous carcinomas may be the fallopian tube, the Society of Gynecologic Oncology published a practice statement in November 2013 addressing the role of salpingectomy at the time of hysterectomy or other pelvic surgery in average-risk women. (https://www.sgo.org/clinical-practice/guidelines/sgo-clinical-practice statement-salpingectomy-for-ovarian-cancer-prevention). They now recommend that these women consider opportunistic salpingectomy to reduce their risk of fallopian tube and ovarian cancers. Various techniques allow the surgeon to complete the salpingectomy in a highly efficient manner. CONCLUSION: Salpingectomy at the time of laparoscopic hysterectomy or other pelvic surgery should be considered in women at average risk of ovarian cancer. Salpingectomy can be performed either before or after control of the uterine blood supply. The surgical approach must also consider the coexisting pelvic pathology. Efficient dissection occurs if the surgeon maximizes exposure to the fallopian tube, optimizes presentation of the tissue to the working instrument, and provides gentle yet constant traction with accompanying countertraction. The fallopian tube specimen should be removed immediately to prevent its loss in the pelvis. PMID- 27956108 TI - Can regional anesthesia have an effect on surgical outcomes in patients undergoing distal hypospadia surgery? AB - BACKGROUND: Caudal and penile blocks are the most popular regional anesthetic techniques used in infants and children undergoing urological surgery. A recent report has suggested that penile venous pooling resulting from caudal blocks could affect surgical outcomes after hypospadias operations. OBJECTIVE: The aim was to report our experience in patients with distal hypospadias undergoing repair with caudal versus penile block. STUDY DESIGN: A retrospective clinical database was constructed for patients who underwent distal hypospadias repair by a single surgeon (M.P.B.) at our sponsoring institutions for the time period 2008 2013 (n = 192). Collected data included hypospadias classification (glanular, coronal, subcoronal), chordee status, perioperative anesthesia (caudal vs. penile), and assessment of postoperative complications (fistula and meatal stenosis). RESULTS: Risk ratio (RR) analysis for all distal hypospadias cases revealed that there is a higher risk of developing complications in patients who underwent caudal anesthesia than in patients who underwent penile block RR for a complication was 3.70 (95% CI 1.05-13.03; p < 0.04) (Figure). DISCUSSION: Similar to other papers in the literature, we found that patients who underwent caudal anesthesia had more complications than those who underwent penile block. The limitations of this study include not adjusting the results according to the severity of hypospadias. CONCLUSION: The main goal of this study was accomplished by demonstrating that, in our series, caudal anesthesia is associated with a higher risk of fistula formation after undergoing distal hypospadias repair than penile block. PMID- 27956109 TI - Practical Steps to Integrate Family Voice in Organization, Policy, Planning, and Decision-Making for Socio-Emotional Trauma-Informed Integrated Pediatric Care. AB - This article explores barriers and strategies to achieving family-driven integrated child health care. Family involvement in health system design and reform has become a guiding principle in national and local efforts to improve children's mental health services. In practice, primary care clinicians, staff, and families continue to describe common barriers to integrating family voice. Drawing from the collective knowledge of the Pediatric Integrated Care Collaborative (PICC) and the National Alliance on Mental Illness (NAMI), we present strategies to overcome these barriers to successfully recruit, sustain, and expand family influence on health systems. Family advocates and clinical leaders from two clinic sites in Albuquerque, New Mexico and Santa Rosa, California share challenges and strategies for building family involvement in system design. PMID- 27956110 TI - DNA methyltransferase inhibitors in cancer: From pharmacology to translational studies. AB - DNA methylation is a mammalian epigenetic mark that participates to define where and when genes are expressed, both in normal cells and in the context of diseases. Like other epigenetic marks, it is reversible and can be modulated by chemical agents. Because it plays an important role in cancer by silencing certain genes, such as tumour suppressor genes, it is a promising therapeutic target. Two compounds are already approved to treat haematological cancers, and many efforts have been carried out to discover new molecules that inhibit DNA methyltransferases, the enzymes responsible for DNA methylation. Here, we analyse the molecular mechanisms and cellular pharmacology of these inhibitors, pointing out the necessity for new pharmacological models and paradigms. The parameters of pharmacological responses need to be redefined: the aim is cellular reprogramming rather than general cytotoxicity. Thus, "epigenetic" rather than cytotoxic dosages are defined. Another issue is the delay of the response: cellular reprogramming can take several generations to produce observable phenotypes. Is this compatible with laboratory scale experiments? Finally, it is important to consider the specificity for cancer cells compared to normal cells and the appearance of resistance. We also discuss different techniques that are used and the selection of pharmacological models. PMID- 27956111 TI - Antibiotic resistance: A current epilogue. AB - The history of the first commercial antibiotics is briefly reviewed, together with data from the US and WHO, showing the decrease in death due to infectious diseases over the 20th century, from just under half of all deaths, to less than 10%. The second half of the 20th century saw the new use of antibiotics as growth promoters for food animals in the human diet, and the end of the 20th century and beginning of the 21st saw the beginning and rapid rise of advanced microbial resistance to antibiotics. PMID- 27956112 TI - Risk factors for complications of laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass. AB - BACKGROUND: Although bariatric procedures are considered safe, yet still they involve a risk of possible perioperative complications. Identification of risk factors for complications would allow for appropriate preoperative optimization of the patient, as well as reasonable postoperative care and early diagnosis and treatment of possible complications. The aim of this study was to determine the risk factors for perioperative complications after laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB). MATERIAL AND METHODS: A retrospective analysis of prospectively collected data of patients operated for morbid obesity. Regarding postoperative complications defined as adverse events occurring within 30 days of the procedure. Factors associated with patient characteristics and those related to the surgical procedure were determined. 408 patients met inclusion criteria and were submitted to surgical treatment. LSG and LRYGB were performed in 233 and 175 patients, respectively. RESULTS: Complications were observed in 30 (7.3%) patients. The maximum preoperative body weight and BMI, as well as body weight and BMI on the day of surgery were associated with increased complication rate. The type of the procedure did not influence perioperative complications (LRYGB vs. LSG; OR: 1.14; CI: 0.53-2.44; p = 0.74). Although operative time statistically significantly increased the risk of complications, it did not seem clinically relevant (OR: 1.01; CI: 1.00-1.02; p = 0.003). An increase in the number of stapler firings used significantly increased complication rate only in LSG group. CONCLUSION: Longer duration of LSG and the increase in the number of stapler firings used during LSG should alert a surgeon to an increased risk of postoperative complications. In patients submitted to LRYGB the risk of possible complications increases with BMI. PMID- 27956113 TI - Efficacy and safety of vitamin C for atrial fibrillation after cardiac surgery: A meta-analysis with trial sequential analysis of randomized controlled trials. AB - OBJECTIVES: Antioxidant supplement is an option in preventing postoperative atrial fibrillation (AF) after cardiac surgery. However, the benefits and adverse effects of vitamin C have not been well assessed. We aimed to systematically evaluate the efficacy and safety of vitamin C in preventing postoperative AF in adult patients after cardiac surgery. METHODS: PubMed, EMBASE, and the Cochrane library databases from inception to September 2016 were searched. Randomized controlled trials (RCTs) that evaluated the efficacy and safety of vitamin C in preventing postoperative AF in adult patients after cardiac surgery were identified. The primary outcome was the incidence of postoperative AF. Secondary outcomes included the length of intensive care unit (ICU) stay, length of hospital stay, and stroke events. RESULTS: Eight RCTs incorporating 1060 patients were included. Compared with placebo group, vitamin C treatment was associated with a substantial reduction in postoperative AF (OR, 0.47; 95% CI, 0.36-0.62; evidence rank: moderate), with no significant heterogeneity (I2 44%; P = 0.09). Trial sequential analysis showed that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit, establishing sufficient and conclusive evidence. In addition, vitamin C administration was not associated with any length of stay, including in the ICU (evidence rank: low) and hospital (evidence rank: low), respectively. CONCLUSIONS: Short-term treatment with vitamin C is safe, and may reduce the incidence of postoperative AF after cardiac surgery. Future studies as well as more high quality RCTs are still warranted to confirm the effects of different durations of vitamin C on cardiac surgery. PMID- 27956115 TI - Future perspectives in adult stem cell turnover: Implications for endocrine physiology and disease. PMID- 27956114 TI - 1,25-Dihydroxy vitamin D3 stimulates system A amino acid transport in primary human trophoblast cells. AB - Vitamin D deficiency during pregnancy is linked to adverse perinatal outcomes such as small for gestational age infants. Recent evidence suggests that changes in placental amino acid transport contribute to altered fetal growth. We tested the hypothesis that 1,25-dihydroxy vitamin D3 increases the gene expression of System A and L amino acid transporter isoforms and stimulates placental amino acid transport activity in cultured primary human trophoblast cells mediated by mTOR signaling. Treatment with 1,25-dihydroxy vitamin D3 significantly increased mRNA expression of the System A isoform SNAT2 and System A activity, but had no effect on System L and did not affect mTOR signaling. siRNA silencing of the vitamin D receptor prevented 1,25-dihydroxy vitamin D3-stimulated System A transport. In conclusion, 1,25-dihydroxy vitamin D3 regulates System A activity through increased mRNA expression of SNAT2 transporters. Effects on placental amino acid transport may be the mechanism underlying the association between maternal vitamin D status and fetal growth. PMID- 27956116 TI - Magnetic Resonance Imaging for Axillary Breast Cancer Metastasis in the Neoadjuvant Setting: A Prospective Study. AB - BACKGROUND: Breast magnetic resonance imaging (MRI) for assessment of regional breast cancer metastasis is controversial owing to the variable specificity. We evaluated breast MRI for axillary metastasis in neoadjuvant chemotherapy patients. MATERIALS AND METHODS: A single-institution, institutional review board approved prospective trial enrolled female breast cancer patients receiving neoadjuvant chemotherapy from 2008 to 2012 and collected the pre- and post treatment MRI, pretreatment axillary ultrasound, axillary biopsy, and surgical pathologic findings. The kappa coefficient was used to evaluate the strength of the agreement between the 2 modalities and Fisher's exact test was used to evaluate the association. RESULTS: A total of 43 patients were included. Of these 45 patients, 35 had stage N1-N2 before treatment. Comparing the abnormal results on the pretreatment MRI scans and axillary biopsy examinations, a consistent diagnosis was found for 92%, with a moderate strength of agreement (kappa coefficient, 0.54). The pretreatment MRI findings were significantly associated with the axillary biopsy results (P = .014). The false-positive rate, false negative rate, sensitivity, and specificity were 50%, 3%, 97%, 50%, respectively. Comparing the post-treatment MRI and surgical pathologic findings revealed a consistent diagnosis rate of, with a slight strength of agreement (kappa, 0.16). The false-positive rate, false-negative rate, sensitivity, and specificity were 38%, 46%, 55%, and 63%, respectively. The post-treatment MRI findings were not associated with the pathologic lymph node results (P = .342). CONCLUSION: Pretreatment breast MRI was more specific for axillary metastasis than was axillary ultrasonography. However, post-treatment breast MRI was not predictive of residual axillary disease and should be used cautiously when altering treatment plans. PMID- 27956117 TI - Binocular vs. monocular hue perception. AB - Hue perception has been shown to differ for the same stimulus when presented to the temporal and the nasal areas of the retina. The present study investigated perceptual differences in stimuli viewed binocularly or monocularly in the peripheral retina to determine how hue information combines across the two retinas for a stimulus falling on the temporal retina of one eye and the nasal retina of the other. A hue-scaling procedure was utilized to ascertain hue perception for three color- and binocular-normal observers viewing monochromatic stimuli (450-670nm, 20nm steps) ranging in size from 1.0 degrees to 3.7 degrees . Peripherally-presented binocular stimuli fell upon the nasal retina of one eye and the temporal retina of the other. Hue-scaling results indicated that peripheral binocular hue and saturation perceptions for smaller stimuli were more similar to those of stimuli falling on the temporal retina in the monocular condition. Hue-scaling data were also used to determine perceptive field sizes for the four elemental hues. Binocular perceptive field sizes were more similar to those obtained for stimuli falling on the temporal retina in the monocular conditions. Eye dominance did not appear to have an effect on hue perception. The results seem to indicate that visual information from the temporal retina is weighted more heavily when information from the two eyes is combined cortically. This finding may relate to differences in V1 cortical activation for stimuli presented to the nasal retina versus the temporal retina. PMID- 27956119 TI - Long-term effects of repeated maternal separation and ethanol intake on HPA axis responsiveness in adult rats. AB - It has been shown that early life manipulations produce behavioral, neural, and hormonal effects. The long term consequences of repeated maternal separation (RMS) plus cold stress and ethanol intake were evaluated during adolescence and adult rats on hypothalamic-pituitary-adrenal (HPA) axis in male adult Wistar rats. RMS+ cold stress was applied from postnatal day (PD) 2 in which the pups were separated from their mothers and exposed to cold stress (4 degrees C) 1h per day for 20days; controls remained with their mothers. Then they were exposed to either voluntary ethanol (6%) or dextrose (1%) intake for 7days: PD22-29 and PD59 66. Half of the animals were sacrificed, while the others were exposed to acute stress (AS) for 2h and then they were killed. RMS+ cold stress: a) increased voluntary ethanol intake in adolescent and adult rats; b) reduced protein expression (Western measurements) in corticotropin-releasing hormone (CRH) in hypothalamus (Hyp) and mineralocorticoid receptor (MR) in hippocampus (Hic) while increased glucocorticoid receptor (GR) in Hic; c) decreased plasmatic levels of adrenocorticotropic hormone (ACTH) and increased corticosterone (COR) levels in HPA axis, d) adult rats exposure a new AS incremented ACTH and COR levels. However, this modification did not alter the HPA axis capacity to respond to a new type of stressor. These results demonstrate the consequences of early life stress on the vulnerability of ethanol consumption and HPA axis responsiveness to a stressor in adult rats. PMID- 27956118 TI - Genetic polymorphisms of phase I metabolizing enzyme genes, their interaction with lifetime grilled and smoked meat intake, and breast cancer incidence. AB - PURPOSE: To examine associations between 22 CYP single nucleotide polymorphisms (SNPs) and breast cancer incidence and their interactions with grilled-smoked meat intake, a source of polycyclic aromatic hydrocarbons. METHODS: White women with first primary in situ or invasive breast cancer (n = 988) and frequency matched controls (n = 1021) from a population-based study were interviewed to assess lifetime grilled-smoked meat intake. SNPs with minor allele frequencies of greater than 0.05 were selected because of their links to carcinogenesis. We used multivariable unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Breast cancer was inversely associated with CYP1A1 rs104C8943 AG + GG genotype (OR = 0.71, 95% CI = 0.50-0.99; vs. AA genotype) and positively associated with CYP1B1 rs10175338 TT genotype (OR = 1.59, 95% CI = 1.12-2.26; vs. GG genotype) and the CYP3A4 rs2242480 CT + TT genotype (OR = 1.25, 95% CI = 1.00-1.56; vs. CC genotype). The sum of the number of "at-risk" alleles for the CYP SNPs was positively associated with breast cancer incidence (4-6 "at-risk" alleles OR = 2.33, 95% CI = 1.37-3.99 vs. 0-1 alleles; PTrend < .01). We observed multiplicative and additive interactions (P < .05) between grilled-smoked meat intake (low vs. high) with CYP1A1 rs1048943 and CYP1B1 rs10175338 SNPs. CONCLUSIONS: Phase I metabolizing enzyme gene SNPs may play a role in breast cancer development and may modify the grilled-smoked meat intake-breast cancer association. PMID- 27956120 TI - Intraperitoneal injection of IL-4/IFN-gamma modulates the proportions of microglial phenotypes and improves epilepsy outcomes in a pilocarpine model of acquired epilepsy. AB - Recent studies have reported microglia that are activated in the central nervous system (CNS) in patients with temporal lobe epilepsy and animal models of epilepsy. However, limited data are available on the dynamic changes of the proportions of various phenotypes of microglia throughout epileptogenesis and whether IL-4/IFN-gamma administration can modulate the proportions of microglial phenotypes to affect the outcome of epilepsy. The current study examined this issue using a mouse model of pilocarpine-induced epilepsy. Flow cytometry showed that classically activated microglia (M1) and alternatively activated microglia (M2) underwent variations throughout the stages of epileptogenesis. The altered trends in the microglia-associated cytokines IL-1beta, IL-4, and IL-10 paralleled the changes in phenotype proportions. We found that intraperitoneal injections of IL-4 and IFN-gamma, which have been reported to modulate the phenotypes of microglia in vitro, also affected the proportion of microglia in vivo. In addition, correctly timing the modulation of the proportion of microglia improved the outcomes of epilepsy based on the reduced frequency, duration, and severity of spontaneous recurrent seizures (SRS) and increased the performances of the mice in the Morris water maze. This study is the first to report altering the proportion of microglial phenotypes in pilocarpine-induced epileptogenesis. Intraperitoneal injection of IL-4/IFN-gamma could be used to modulate the proportions of the types of microglia, and epilepsy outcomes could be improved by correctly timing this modulation of phenotypes. PMID- 27956121 TI - Cardiovascular dysfunction associated with neurodegeneration in an experimental model of Parkinson's disease. AB - Patients with Parkinson's disease (PD) exhibit both motor and non-motor symptoms. Among the non-motor symptoms, cardiovascular autonomic dysfunction is frequently observed. Here, we evaluated baroreflex function, vascular reactivity and neuroanatomical changes in brainstem regions involved in the neural control of circulation in the 6-hydroxydopamine (6-OHDA) model of PD. Male Wistar rats received a bilateral injection of 6-OHDA or vehicle into the striatum. After 61days, baroreflex function and vascular reactivity were assessed. The 6-OHDA and vehicle groups showed similar increases in mean arterial pressure (MAP) in response to phenylephrine (PE). However, the bradycardia observed in the vehicle group was blunted in the 6-OHDA-treated rats. Injection of sodium nitroprusside (SNP) decreased hypotension, tachycardia and vascular relaxation in 6-OHDA treated rats. Bilateral intrastriatal 6-OHDA led to massive degeneration of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and to reductions in the numbers of A1/C1 and A5 catecholaminergic neurons while sparing A2 neurons within the nucleus of the solitary tract (NTS). 6-OHDA-treated rats also showed decreases in Phox2b-expressing neurons in the NTS and in choline acetyltransferase (ChAT) immunoreactivity in the nucleus ambiguus. Altogether, our data suggest that this model of PD includes neuroanatomical and functional changes that lead to cardiovascular impairment. PMID- 27956122 TI - Tactile stimulation partially prevents neurodevelopmental changes in visual tract caused by early iron deficiency. AB - Iron deficiency has a critical impact on maturational mechanisms of the brain and the damage related to neuroanatomical parameters is not satisfactorily reversed after iron replacement. However, emerging evidence suggest that enriched early experience may offer great therapeutic efficacy in cases of nutritional disorders postnatally, since the brain is remarkably responsive to its interaction with the environment. Given the fact that tactile stimulation (TS) treatment has been previously shown to be an effective therapeutic approach and with potential application to humans, here we ask whether exposure to TS treatment, from postnatal day (P) 1 to P32 for 3min/day, could also be employed to prevent neuroanatomical changes in the optic nerve of rats maintained on an iron deficient diet during brain development. We found that iron deficiency changed astrocyte, oligodendrocyte, damaged fiber, and myelinated fiber density, however, TS reversed the iron-deficiency-induced alteration in oligodendrocyte, damaged fiber and myelinated fiber density, but failed to reverse astrocyte density. Our results suggest that early iron deficiency may act by disrupting the timing of key steps in visual system development thereby modifying the normal progression of optic nerve maturation. However, optic nerve development is sensitive to enriching experiences, and in the current study we show that this sensitivity can be used to prevent damage from postnatal iron deficiency during the critical period. PMID- 27956124 TI - Is Physician Quality Reporting System Worth the Cost to Report to Center for Medicare and Medicaid Services? AB - BACKGROUND: The Center for Medicare and Medicaid Services (CMS) has proposed a move to payment based on patient-reported outcomes (PROs), and failure to report on PROs will result in a penalty of 2% in 2016. However, the cost to the physician to collect PROs is not known. METHODS: Using data from the 2013 Medical Group Management Association Compensation and Financial survey and Center for Medicare and Medicaid Services reimbursement, a calculation was performed to determine the cost to the physician to report on PROs for patients undergoing total knee arthroplasty and total hip arthroplasty. Using Medical Group Management Association and Medicare fee for service rates, calculations were performed based on an annual volume of 200 Medicare operative cases (125 total knee arthroplasties, 75 total hip arthroplasties) with 1000 new patients (level 4) and 2000 established patients (level 3) visits. A range of start-up and annual costs necessary to collect PROs including hardware, software, and personnel costs was calculated and then compared with the calculated 2% Medicare penalty for failing to report PROs in 2016. RESULTS: The cost to collect PROs ranged from $47,973 to $56,288 which far outweighed the penalty of $2954 in 2016 for failing to report these measures. CONCLUSION: With the move toward requiring surgeons to report PROs for reimbursement, the current financial model would prove to be cost prohibitive and the incentive to report PROs might be too costly to gain wide acceptance. PMID- 27956125 TI - Open mHealth Architecture: A Primer for Tomorrow's Orthopedic Surgeon and Introduction to Its Use in Lower Extremity Arthroplasty. AB - BACKGROUND: The recent private-public partnership to unlock and utilize all available health data has large-scale implications for public health and personalized medicine, especially within orthopedics. Today, consumer based technologies such as smartphones and "wearables" store tremendous amounts of personal health data (known as "mHealth") that, when processed and contextualized, have the potential to open new windows of insight for the orthopedic surgeon about their patients. METHODS: In the present report, the landscape, role, and future technical considerations of mHealth and open architecture are defined with particular examples in lower extremity arthroplasty. RESULTS: A limitation of the current mHealth landscape is the fragmentation and lack of interconnectivity between the myriad of available apps. The importance behind the currently lacking open mHealth architecture is underscored by the offer of improved research, increased workflow efficiency, and value capture for the orthopedic surgeon. CONCLUSION: There exists an opportunity to leverage existing mobile health data for orthopaedic surgeons, particularly those specializing in lower extremity arthroplasty, by transforming patient small data into insightful big data through the implementation of "open" architecture that affords universal data standards and a global interconnected network. PMID- 27956123 TI - Case-Based Review of Osteonecrosis of the Jaw (ONJ) and Application of the International Recommendations for Management From the International Task Force on ONJ. AB - Osteonecrosis of the jaw (ONJ) has been associated with antiresorptive therapy in both oncology and osteoporosis patients. This debilitating condition is very rare and advances in diagnosis and management may now effectively reduce the risk of its development and offer valuable treatment options for affected patients. This paper provides a case-based review of ONJ and application of the International Task Force on ONJ (referred to as the "Task Force") recommendations for the diagnosis and management of ONJ. The Task Force was supported by 14 international societies and achieved consensus from representatives of these multidisciplinary societies on key issues pertaining to the diagnosis and management of ONJ. The frequency of ONJ in oncology patients receiving oncology doses of bisphosphonate (BP) or denosumab is estimated at 1%-15%, and the frequency in the osteoporosis patient population receiving much lower doses of BP or denosumab is estimated at 0.001%-0.01%. Although the diagnosis of ONJ is primarily clinical, imaging may be helpful in confirming the diagnosis and staging. In those with multiple risk factors for ONJ for whom major invasive oral surgery is being planned, interruption of BP or denosumab therapy (in cancer patients) is advised, if possible, before surgery, until the surgical site heals. Major oral surgery in this context could include multiple extractions if surgical extractions are required, not simple forceps extractions. ONJ development may be reduced by optimizing oral hygiene and postoperatively using topical and systemic antibiotics as appropriate. Periodontal disease should be managed before starting oncology doses of BP or denosumab. Local debridement may be successful in disease unresponsive to conservative therapy. Successful surgical intervention has been reported in those with stage 3 disease; less severe disease is best managed conservatively. Teriparatide may be helpful in healing ONJ lesions and may be considered in osteoporosis patients at a high fracture risk in the absence of contraindications. Resumption of BP or denosumab therapy following healing of ONJ lesions is recommended, and there have not been reports of subsequent local recurrence. PMID- 27956126 TI - A Bundle Protocol to Reduce the Incidence of Periprosthetic Joint Infections After Total Joint Arthroplasty: A Single-Center Experience. AB - BACKGROUND: Periprosthetic joint infection (PJI) represents a devastating complication of total hip arthroplasty (THA) or total knee arthroplasty (TKA). Modifiable patient risk factors as well as various intraoperative and postoperative variables have been associated with risk of PJI. In 2011, our institution formulated a "bundle" to optimize patient outcomes after THA and TKA. The purpose of this report is to describe the "bundle" protocol we implemented for primary THA and TKA patients and to analyze its impact on rates of PJI and readmission. METHODS: Our bundle protocol for primary THA and TKA patients is conceptually organized about 3 chronological periods of patient care: preoperative, intraoperative, and postoperative. The institutional total joint database and electronic medical record were reviewed to identify all primary THAs and TKAs performed in the 2 years before and following implementation of the bundle. Rates of PJI and readmission were then calculated. RESULTS: Thirteen of 908 (1.43%) TKAs performed before the bundle became infected compared to only 1 of 890 (0.11%) TKAs performed after bundle implementation (P = .0016). Ten of 641 (1.56%) THAs performed before the bundle became infected, which was not statistically different from the 4 of 675 (0.59%) THAs performed after the bundle that became infected (P = .09). CONCLUSION: The bundle protocol we describe significantly reduced PJIs at our institution, which we attribute to patient selection, optimization of modifiable risk factors, and our perioperative protocol. We believe the bundle concept represents a systematic way to improve patient outcomes and increase value in total joint arthroplasty. PMID- 27956127 TI - Three-Dimensional Host Bone Coverage in Total Hip Arthroplasty for Crowe Types II and III Developmental Dysplasia of the Hip. AB - BACKGROUND: Recommendations for minimum cup coverage based on anteroposterior radiographs are widely used as an intraoperative guide in total hip arthroplasty for patients with developmental dysplasia of the hip. The purpose of this study was to examine the validity of two-dimensional (2D) measurement of coverage with three-dimensional (3D) coverage and to identify parameters for determining the 3D coverage during surgery. METHODS: We developed a technique to accurately reproduce the intraoperative anatomic geometry of the dysplastic acetabulum and measure the 3D cup coverage postoperatively. With this technique, we retrospectively analyzed the difference and correlation between 2D and 3D measurements of native bone coverage in 35 patients (45 hips) with Crowe II or III DDH. Linear regression analysis was performed to examine the intraoperative parameters related to coverage. The mean follow-up period was 7.64 years (range, 6.1-9.5 years). RESULTS: There was a significant difference and a fair correlation between 2D and 3D measurements. The 2D measurement underestimated the 3D cup coverage by approximately 13%. An excellent linear relationship was noted between the 3D coverage/uncoverage and the height of the uncovered portion (R2 = 0.8440, P < .0001). There was no case of loosening or revision during the follow up. CONCLUSION: Current minimum cup coverage recommendations based on 2D radiograph measurements should not be used as a direct intraoperative guide. The height of the uncovered portion is a useful parameter to determine the 3D coverage during surgery. PMID- 27956128 TI - The HhoA protease from Synechocystis sp. PCC 6803 - Novel insights into structure and activity regulation. AB - Proteases play a vital role in the removal of proteins, which become damaged due to temperature or oxidative stress. Important to this process in the cyanobacterium Synechocystis sp. PCC6803 is the family of Deg/HtrA proteases; HhoA (sll1679), HhoB (sll1427) and HtrA (slr1204). While previous studies have elucidated the structures of Deg/HtrA proteases from Escherichia coli and from the chloroplast of the higher plant Arabidopsis thaliana, no structural data have been available for any Deg/HtrA protease from cyanobacteria, the evolutionary ancestor of the chloroplast. To gain a deeper insight into the molecular mechanisms and regulation of these proteins we have solved the structure of the Synechocystis HhoA protease in complex with a co-purified peptide by X-ray crystallography. HhoA assembles into stable trimers, mediated by its protease domain and further into a cage-like hexamer by a novel interaction between the PDZ domains of opposing trimers. Each PDZ domain contains two loops for PDZ-PDZ formation: interaction clamp one and two (IC1, IC2). IC1 interacts with IC2 on the opposing PDZ domain and vice versa. Our structure shows a peptide bound to a conserved groove on the PDZ domain and the properties of this pocket suggest that it binds substrate proteins as well as the neo C-termini of cleaved substrates. In agreement with previous studies showing the proteolytic activity of HhoA to be activated by Ca2+ or Mg2+, binding of divalent metal ions to the central channel of the trimer by the L1 activation loop was observed. PMID- 27956129 TI - [Epidemiology, risk factors and phenotypes of sleep breathing disorders]. AB - Recent epidemiological studies show that the prevalence of sleep-disordered breathing seems to be higher than previously estimated in the middle to older aged general population with approximatively 49% of men and 23% of women being affected. This higher than expected prevalence of sleep-disordered breathing seems to be due to the high sensitivity of current recording techniques and to the new and more inclusive definition of respiratory events (hypopnea definition in particular). Male sex, age, and truncal obesity (large neck girth, high waist to hip ratio) are the main risk factors for sleep-disordered breathing. Among sleep-disordered breathing patients, different phenotypes can be observed according to the underlying pathophysiologic mechanism of their condition : purely anatomical impairment, central breathing control instability (high "loop gain"), low arousal threshold, or sleep-associated pharyngeal muscles dysfunction. A better phenotyping of the patients could help directing the treatment to the specific cause of their disorder. PMID- 27956130 TI - Lipoprotein-associated phospholipase A2 in coronary heart disease: Review and meta-analysis. AB - BACKGROUND: Risk associations between lipoprotein-associated phospholipase A2 (Lp PLA2) and adverse outcomes in patients with coronary heart disease (CHD) remain unclear. The aim of the meta-analysis was to investigate the association between Lp-PLA2 and prognosis of CHD. METHODS: PubMed and Embase were examined for prospective studies published before June 2016. Multivariate-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of adverse outcomes according to Lp-PLA2 activity or mass were extracted, pooled, and weighted using generic inverse-variance and random-effect modeling. RESULTS: Fifteen studies with 30,857 participants were included. Overall, higher Lp-PLA2 activity or mass was not significantly related to increased risk of long-term all-cause mortality. However, higher Lp-PLA2 activity or mass was independently associated with an increased risk of long-term cardiovascular events, with pooled HR for cardiovascular events of 1.55 (95% CI, 1.08-2.23; P=0.018) and 1.62 (95% CI, 1.09 2.41; P=0.017), respectively. The prognostic value of Lp-PLA2 in predicting cardiovascular events was observed in patients with stable CHD who were not receiving therapies for inhibiting Lp-PLA2. CONCLUSIONS: Greater Lp-PLA2 activity or mass was independently associated with cardiovascular events in patients with CHD, particularly in patients with stable CHD who were not receiving therapies for inhibiting Lp-PLA2. PMID- 27956131 TI - Annexin A2 is involved in Ca2+-dependent plasma membrane repair in primary human endothelial cells. AB - Many cells in an organism are exposed to constant and acute mechanical stress that can induce plasma membrane injuries. These plasma membrane wounds have to be resealed rapidly to guarantee cell survival. Plasma membrane resealing in response to mechanical strain has been studied in some detail in muscle, where it is required for efficient recovery after insult. However, less is known about the capacity of other cell types and tissues to perform membrane repair and the underlying molecular mechanisms. Here we show that vascular endothelial cells, which are subject to profound mechanical burden, can reseal plasma membrane holes inflicted by laser ablation. Resealing in endothelial cells is a Ca2+-dependent process, as it is inhibited when cells are wounded in Ca2+-free medium. We also show that annexin A1 (AnxA1), AnxA2 and AnxA6, Ca2+-regulated membrane binding proteins previously implicated in membrane resealing in other cell types, are rapidly recruited to the site of plasma membrane injury. S100A11, a known protein ligand of AnxA1, is also recruited to endothelial plasma membrane wounds, albeit with a different kinetic. Mutant expression experiments reveal that Ca2+ binding to AnxA2, the most abundant endothelial annexin, is required for translocation of the protein to the wound site. Furthermore, we show by knock-down and rescue experiments that AnxA2 is a positive regulator of plasma membrane resealing. Thus, vascular endothelial cells are capable of active, Ca2+-dependent plasma membrane resealing and this process requires the activity of AnxA2. PMID- 27956132 TI - Characterization of the structure of lipodisq nanoparticles in the presence of KCNE1 by dynamic light scattering and transmission electron microscopy. AB - A recently developed membrane mimetic system called styrene maleic acid lipid particles (SMALPs) or lipodisq nanoparticles has shown to possess significant potential for biophysical studies of membrane proteins. This new nanoparticle system is composed of lipids encircled by SMA copolymers. Previous studies showed that SMA copolymers are capable of extracting membrane proteins directly from their native environments without the assistance of detergents. However, a full structural characterization of this promising membrane mimetic system is still lacking. In this study, the formation of lipodisq nanoparticles was characterized upon addition of the membrane protein KCNE1. Initially, multi-lamellar vesicles (MLVs) containing KCNE1 (KCNE1-MLVs) at a lipid to protein molar ratio of 500/1 were prepared using a standard dialysis method. SMA copolymers were then added to KCNE1-MLVs at a series of lipid to SMA weight ratios to observe the solubilizing property of SMA in the presence of the KCNE1 membrane protein. The solubilizing process of KCNE1-MLVs by SMA copolymers undergoes a transition phase at low SMA concentrations (samples with weight ratios of 1/0.25, 1/0.5, and 1/0.75). More lipodisq nanoparticles were formed at higher SMA concentrations (Samples with weight ratios of 1/1, 1/1.25, and 1/1.5) were directly observed in the corresponding TEM images. A single sharp DLS peak was observed from the sample at the weight ratio of 1/1.5, which indicated the complete solubilization of KCNE1 MLVs. Interestingly, the critical weight ratio for empty MLVs was found to be 1/1.25 previously, which suggested that the presence of KCNE1 makes it more difficult for the solubilizing process of the SMA copolymers. Also, a TEM image of the 1/1.5 sample showed the presence of silky aggregates of excess copolymers. Overall, this study demonstrated the ability of SMA copolymers to form lipodisq nanoparticles in the presence of the membrane protein KCNE1. PMID- 27956135 TI - Effects of ribavirin/sofosbuvir treatment and ITPA phenotype on endogenous purines. AB - Ribavirin (RBV), a purine analog, causes hemolytic anemia in some patients. In vitro, anemia appears to result from depletion of endogenous purines, but there are limited data in vivo. Single nucleotide polymorphisms in the gene encoding the inosine triphosphatase (ITPA) enzyme have been associated with protection against RBV-induced anemia and may mediate the effect of RBV treatment on endogenous purines. The purpose of this work was to determine the effect of RBV treatment on endogenous purine concentrations in individuals being treated for chronic hepatitis C virus (HCV) infection. Adenosine triphosphate (ATP), guanosine triphosphate (GTP), inosine triphosphate (ITP) and ribavirin triphosphate (RTP) were measured in whole blood obtained from 47 HCV-infected individuals at day zero (baseline), day three, day 28 and day 84 of RBV/sofosbuvir (SOF) treatment. ATP decreased -35.1% and -38.6% (p < 0.0001) at day 28 and day 84 of treatment, respectively compared to baseline. The decrease in ATP was greater in patients with <=60% ITPA activity compared to those with 100% ITPA activity (-29.4% vs. -9.6%). GTP did not change during treatment but was 16.5% (p = 0.01) higher per 100 pmol/106 cells RTP in those with 100% ITPA activity. No significant change or effect of RTP or ITPA phenotype was noted for ITP. In summary, only ATP was reduced by RBV/SOF treatment and ITPA variants had larger reductions in ATP suggesting RBV-induced anemia is due to a different mechanism than predicted from in-vitro studies. These data emphasize the importance of characterizing the effect of nucleos(t)ide analog treatment on endogenous purines in-vivo. PMID- 27956136 TI - Prophylactic and therapeutic intranasal administration with an immunomodulator, Hiltonol(r) (Poly IC:LC), in a lethal SARS-CoV-infected BALB/c mouse model. AB - Hiltonol(r), (Poly IC:LC), a potent immunomodulator, is a synthetic, double stranded polyriboinosinic-polyribocytidylic acid (poly IC) stabilized with Poly-L lysine and carboxymethyl cellulose (LC). Hiltonol(r) was tested for efficacy in a lethal SARS-CoV-infected BALB/c mouse model. Hiltonol(r) at 5, 1, 0.5 or 0.25 mg/kg/day by intranasal (i.n.) route resulted in significant survival benefit when administered at selected times 24 h prior to challenge with a lethal dose of mouse-adapted severe acute respiratory syndrome coronavirus (SARS-CoV). The infected BALB/c mice receiving the Hiltonol(r) treatments were also significantly effective in protecting mice against weight loss due to infection (p < 0.001). Groups of 20 mice were dosed with Hiltonol(r) at 2.5 or 0.75 mg/kg by intranasal instillation 7, 14, and 21 days before virus exposure and a second dose was given 24 h later, prophylactic Hiltonol(r) treatments (2.5 mg/kg/day) were completely protective in preventing death, and in causing significant reduction in lung hemorrhage scores, lung weights and lung virus titers. Hiltonol(r) was also effective as a therapeutic when give up to 8 h post virus exposure; 100% of the infected mice were protected against death when Hiltonol(r) was administered at 5 mg/kg/day 8 h after infection. Our data suggest that Hiltonol(r) treatment of SARS-CoV infection in mice leads to substantial prophylactic and therapeutic effects and could be used for treatment of other virus disease such as those caused by MERS-CoV a related coronavirus. These properties might be therapeutically advantageous if Hiltonol(r) is considered for possible clinical use. PMID- 27956134 TI - Identification of compounds with anti-human cytomegalovirus activity that inhibit production of IE2 proteins. AB - Using a high throughput screening methodology we surveyed a collection of largely uncharacterized validated or suspected kinase inhibitors for anti-human cytomegalovirus (HCMV) activity. From this screen we identified three structurally related 5-aminopyrazine compounds (XMD7-1, -2 and -27) that inhibited HCMV replication in virus yield reduction assays at low micromolar concentrations. Kinase selectivity assays indicated that each compound was a kinase inhibitor capable of inhibiting a range of cellular protein kinases. Western blotting and RNA sequencing demonstrated that treatment of infected cells with XMD7 compounds resulted in a defect in the production of the major HCMV transcriptional transactivator IE2 proteins (IE2-86, IE2-60 and IE2-40) and an overall reduction in transcription from the viral genome. However, production of certain viral proteins was not compromised by treatment with XMD7 compounds. Thus, these novel anti-HCMV compounds likely inhibited transcription from the viral genome and suppressed production of a subset of viral proteins by inhibiting IE2 protein production. PMID- 27956133 TI - Post-transcriptional regulation of cytokine and growth factor signaling in cancer. AB - Cytokines and growth factors regulate cell proliferation, differentiation, migration and apoptosis, and play important roles in coordinating growth signal responses during development. The expression of cytokine genes and the signals transmitted through cytokine receptors are tightly regulated at several levels, including transcriptional and post-transcriptional levels. A majority of cytokine mRNAs, including growth factor transcripts, contain AU-rich elements (AREs) in their 3' untranslated regions that control gene expression by regulating mRNA degradation and changing translational rates. In addition, numerous proteins involved in transmitting signals downstream of cytokine receptors are regulated at the level of mRNA degradation by GU-rich elements (GREs) found in their 3' untranslated regions. Abnormal stabilization and overexpression of ARE or GRE containing transcripts had been observed in many malignancies, which is a consequence of the malfunction of RNA-binding proteins. In this review, we briefly summarize the role of AREs and GREs in regulating mRNA turnover to coordinate cytokine and growth factor expression, and we describe how dysregulation of mRNA degradation mechanisms contributes to the development and progression of cancer. PMID- 27956137 TI - Deficiency of glycerol-3-phosphate acyltransferase 1 decreases triacylglycerol storage and induces fatty acid oxidation in insect fat body. AB - Glycerol-3-phosphate acyltransferases (GPAT) catalyze the initial and rate limiting step for the de novo synthesis of triacylglycerol (TAG). Four mammalian GPAT isoforms have been identified: the mitochondria-associated GPAT1 and 2, and the endoplasmic reticulum (ER)-associated GPAT3 and 4. In the insect Rhodnius prolixus, a vector of Chagas' disease, we previously predicted a mitochondrial like isoform (RhoprGPAT1) from genomic data. In the current study, we clone the RhoprGPAT1 coding sequence and identify an ER-associated GPAT (RhoprGPAT4) as the second isoform in the insect. RhoprGPAT1 contributes 15% of the total GPAT activity in anterior midgut, 50% in posterior midgut and fat body, and 70% in the ovary. The RhoprGpat1 gene is the predominant transcript in the midgut and fat body. To evaluate the physiological relevance of RhoprGPAT1, we generate RhoprGPAT1-deficient insects. The knockdown of RhoprGpat1 results in 50% and 65% decrease in TAG content in the posterior midgut and fat body, respectively. RhoprGpat1-deficient insects also exhibits impaired lipid droplet expansion and a 2-fold increase in fatty acid beta-oxidation rates in the fat body. We propose that the RhoprGPAT1 mitochondrial-like isoform is required to channel fatty acyl chains towards TAG synthesis and away from beta-oxidation. Such a process is crucial for the insect lipid homeostasis. PMID- 27956139 TI - Characterization of stem cell-derived liver and intestinal organoids as a model system to study nuclear receptor biology. AB - Nuclear receptors (NRs) are ligand-activated transcription factors regulating a large variety of processes involved in reproduction, development, and metabolism. NRs are ideal drug targets because they are activated by lipophilic ligands that easily pass cell membranes. Immortalized cell lines recapitulate NR biology poorly and generating primary cultures is laborious and requires a constant need for donor material. There is a clear need for development of novel preclinical model systems that better resemble human physiology. Uncertainty due to technical limitations early in drug development is often the cause of preclinical drugs not reaching the clinic. Here, we studied whether organoids, mini-organs derived from the respective mouse tissue's stem cells, can serve as a novel model system to study NR biology and targetability. We characterized mRNA expression profiles of the NR superfamily in mouse liver, ileum, and colon organoids. Tissue-specific expression patterns were largely maintained in the organoids, indicating their suitability for NR research. Metabolic NRs Fxralpha, Lxralpha, Lxrbeta, Pparalpha, and Ppargamma induced expression of and binding to endogenous target genes. Transcriptome analyses of wildtype colon organoids stimulated with Rosiglitazone showed that lipid metabolism was the highest significant changed function, greatly mimicking the PPARs and Rosiglitazone function in vivo. Finally, using organoids we identify Trpm6, Slc26a3, Ang1, and Rnase4, as novel Fxr target genes. Our results demonstrate that organoids represent a framework to study NR biology that can be further expanded to human organoids to improve preclinical testing of novel drugs that target this pharmacologically important class of ligand activated transcription factors. PMID- 27956140 TI - Tired in the Reading Room: The Influence of Fatigue in Radiology. AB - Commonly conflated with sleepiness, fatigue is a distinct multidimensional condition with physical and mental effects. Fatigue in health care providers and any secondary effects on patient care are an important societal concern. As medical image interpretation is highly dependent on visual input, visual fatigue is of particular interest to radiologists. Humans analyze their surroundings with rapid eye movements called saccades, and fatigue decreases saccadic velocity. Oculomotor parameters may, therefore, be an objective and reproducible metric of fatigue and eye movement analysis can provide valuable insight into the etiology of fatigue-related error. PMID- 27956141 TI - Slotplates revisited - A retrospective analysis. AB - CONTEXT: Slotplates were specifically designed to meet the special requirements of corrective surgeries of the facial skeleton. This design enables small readjustments of bone fragments in the midface and chin area during surgery without complete removal of plates and screws. OBJECTIVE, DESIGN, AND SETTING: The aim of this study was to compare morbidity rates of slotplates versus meshplates after Le Fort I osteotomy, genioplasty and/or zygoma 'sandwich' osteotomy performed in a tertiary care centre. RESULTS: The investigators analyzed chart records of 190 patients, including a total of 257 surgeries. Slotplates were used in 109 patients, meshplates in 81 patients. Plate infection rates were 9.2% in the slotplate group and 7.4% in the meshplate group. Twelve patients (11.0%) from the slotplate group underwent plate removal versus four patients (4.9%) from the meshplate group. In total, there were two cases of delayed union, both in the slotplate group, one progressed to non-union. CONCLUSION: Due to the low study power significant differences between the two types of plates could not be detected. However, there is a slight tendency towards higher morbidity associated with the use of slotplates. The probability of mechanical weakness of the configuration being responsible for the fatigue fractures is also discussed in this article. PMID- 27956138 TI - Biogenesis, transport and remodeling of lysophospholipids in Gram-negative bacteria. AB - Lysophospholipids (LPLs) are metabolic intermediates in bacterial phospholipid turnover. Distinct from their diacyl counterparts, these inverted cone-shaped molecules share physical characteristics of detergents, enabling modification of local membrane properties such as curvature. The functions of LPLs as cellular growth factors or potent lipid mediators have been extensively demonstrated in eukaryotic cells but are still undefined in bacteria. In the envelope of Gram negative bacteria, LPLs are derived from multiple endogenous and exogenous sources. Although several flippases that move non-glycerophospholipids across the bacterial inner membrane were characterized, lysophospholipid transporter LplT appears to be the first example of a bacterial protein capable of facilitating rapid retrograde translocation of lyso forms of glycerophospholipids across the cytoplasmic membrane in Gram-negative bacteria. LplT transports lyso forms of the three bacterial membrane phospholipids with comparable efficiency, but excludes other lysolipid species. Once a LPL is flipped by LplT to the cytoplasmic side of the inner membrane, its diacyl form is effectively regenerated by the action of a peripheral enzyme, acyl-ACP synthetase/LPL acyltransferase (Aas). LplT-Aas also mediates a novel cardiolipin remodeling by converting its two lyso derivatives, diacyl or deacylated cardiolipin, to a triacyl form. This coupled remodeling system provides a unique bacterial membrane phospholipid repair mechanism. Strict selectivity of LplT for lyso lipids allows this system to fulfill efficient lipid repair in an environment containing mostly diacyl phospholipids. A rocker-switch model engaged by a pair of symmetric ion-locks may facilitate alternating substrate access to drive LPL flipping into bacterial cells. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. PMID- 27956142 TI - Herpesviruses and Their Host Cells: A Successful Liaison. AB - During a long history of coevolution, herpesviruses have reached a fine-tuned balance with their hosts, allowing them to successfully persist and spread to new hosts without causing too much damage. Only under certain circumstances, as in neonates or immunocompromised individuals, they may cause serious diseases. The delicate balance between herpesviruses and their hosts results from interactions of a great variety of viral and cellular factors which together shape the tropism for a particular host, tissue, or cell. Understanding these interactions will provide insight into the viral life cycle and cell biology in general. Moreover, it will also facilitate comprehension of herpesvirus pathogenesis, enabling the development of new strategies to combat herpesviruses in cases where they cause disease. PMID- 27956143 TI - Transdermal reverse iontophoresis: A novel technique for therapeutic drug monitoring. AB - Application of transdermal reverse iontophoresis for diagnostic purpose is a relatively new concept but its short span of research is full of ups and downs. In early nineties, when the idea was floated, it received a dubious welcome by the scientific community. Yet to the disbelief of many, 2001 saw the launching of GlucoWatch(r) G2 Biographer, the first device that could measure the blood sugar level noninvasively. Unfortunately, the device failed to match the expectation and was withdrawn in 2007. However, the concept stayed on. Research on reverse iontophoresis has diversified in many fields. Numerous in vitro and in vivo experiments confirmed the prospect of reverse iontophoresis as a noninvasive tool in therapeutic drug monitoring and clinical chemistry. This review provides an overview about the recent developments in reverse iontophoresis in the field of therapeutic drug monitoring. PMID- 27956144 TI - Self-aggregating 1.8kDa polyethylenimines with dissolution switch at endosomal acidic pH are delivery carriers for plasmid DNA, mRNA, siRNA and exon-skipping oligonucleotides. AB - Efficiency of polyethylenimine (PEI) for nucleic acid delivery is affected by the size of the carrier and length of the nucleic acids. For instance, PEIs with molecular weights between 10-30kDa provide optimal DNA delivery activity whereas PEIs with molecular weights below 1.8kDa are ineffective. The activity of PEI is also severely diminished by substitution of DNA for shorter nucleic acids such as mRNA or siRNA. Here, through chemical modification of the primary amines to aromatic domains we achieved nucleic acid delivery by the 1.8kDa polyethylenimine (PEI) particles. This modification did not affect the PEI buffering abilities but enhanced its pH-sensitive aggregation, enabling stabilization of the polyplex outside the cell while still allowing nucleic acid release following cellular entry. The aromatic PEIs were then evaluated for their gene, mRNA, siRNA and 2'O methyl phosphorothioate oligonucleotide in vitro transfection abilities. The salicylamide-grafted PEI showed to be a reliable carrier for delivering nucleic acids with cytoplasmic activity such as the mRNA and siRNA or nuclear diffusible oligonucleotide. It was then further equipped with polyethyleneglycol (PEG) and the delivery efficiency of the copolymer was tested in vivo for regeneration of dystrophin in the muscle of mdx mouse through a 2'O-methyl phosphorothioate mediated splicing modulation. Intramuscular administration of polyplexes resulted in dystrophin-positive fibers in a mouse model of Duchenne muscular dystrophy without apparent toxicity. These findings indicate that precise modifications of low molecular weight PEI improve its bio-responsiveness and yield delivery vehicles for nucleic acids of various types in vitro and in vivo. PMID- 27956146 TI - Structural Characterisation Reveals Mechanism of IL-13-Neutralising Monoclonal Antibody Tralokinumab as Inhibition of Binding to IL-13Ralpha1 and IL-13Ralpha2. AB - Interleukin (IL)-13 is a pleiotropic T helper type 2 cytokine frequently associated with asthma and atopic dermatitis. IL-13-mediated signalling is initiated by binding to IL-13Ralpha1, which then recruits IL-4Ralpha to form a heterodimeric receptor complex. IL-13 also binds to IL-13Ralpha2, considered as either a decoy or a key mediator of fibrosis. IL-13-neutralising antibodies act by preventing IL-13 binding to IL-13Ralpha1, IL-4Ralpha and/or IL-13Ralpha2. Tralokinumab (CAT-354) is an IL-13-neutralising human IgG4 monoclonal antibody that has shown clinical benefit in patients with asthma. To decipher how tralokinumab inhibits the effects of IL-13, we determined the structure of tralokinumab Fab in complex with human IL-13 to 2 A resolution. The structure analysis reveals that tralokinumab prevents IL-13 from binding to both IL 13Ralpha1 and IL-13Ralpha2. This is supported by biochemical ligand-receptor interaction assay data. The tralokinumab epitope is mainly composed of residues in helices D and A of IL-13. It is mostly light chain complementarity-determining regions that are driving paratope interactions; the variable light complementarity-determining region 2 plays a key role by providing residue contacts for a network of hydrogen bonds and a salt bridge in the core of binding. The key residues within the paratope contributing to binding were identified as Asp50, Asp51, Ser30 and Lys31. This study demonstrates that tralokinumab prevents the IL-13 pharmacodynamic effect by binding to IL-13 helices A and D, thus preventing IL-13 from interacting with IL-13Ralpha1 and IL 13Ralpha2. PMID- 27956147 TI - Systematic Identification of Oncogenic EGFR Interaction Partners. AB - The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) that-once activated upon ligand binding-leads to receptor dimerization, recruitment of protein complexes, and activation of multiple signaling cascades. The EGFR is frequently overexpressed or mutated in various cancers leading to aberrant signaling and tumor growth. Hence, identification of interaction partners that bind to mutated EGFR can help identify novel targets for drug discovery. Here, we used a systematic approach to identify novel proteins that are involved in cancerous EGFR signaling. Using a combination of high-content imaging and a mammalian membrane two-hybrid protein-protein interaction method, we identified eight novel interaction partners of EGFR, of which half strongly interacted with oncogenic, hyperactive EGFR variants. One of these, transforming acidic coiled-coil proteins (TACC) 3, stabilizes EGFR on the cell surface, which results in an increase in downstream signaling via the mitogen-activated protein kinase and AKT pathway. Depletion of TACC3 from cells using small hairpin RNA (shRNA) knockdown or small-molecule targeting reduced mitogenic signaling in non small cell lung cancer cell lines, suggesting that targeting TACC3 has potential as a new therapeutic approach for non-small cell lung cancer. PMID- 27956148 TI - iFrag: A Protein-Protein Interface Prediction Server Based on Sequence Fragments. AB - Protein-protein interactions (PPIs) are crucial in many biological processes. The first step towards the molecular characterisation of PPIs implies the charting of their interfaces, that is, the surfaces mediating the interaction. To this end, we present here iFrag, a sequence-based computational method that infers possible interacting regions between two proteins by searching minimal common sequence fragments of the interacting protein pairs. By utilising the sequences of two interacting proteins (queries), iFrag derives a two-dimensional matrix computing a score for each pair of residues that relates to the presence of similar regions in interolog protein pairs. The scoring matrix is represented as a heat map reflecting the potential interface regions in both query proteins. Unlike existing approaches, iFrag does not require three-dimensional structural information or multiple sequence alignments and can even predict small interaction sites consisting only of few residues. Thus, predicted interfaces range from short fragments composed of few residues to domains of proteins, depending on available information on PPIs, as we demonstrate in several examples. Moreover, as a proof of concept, we include the experimental validation on the successful prediction of a peptide competing with the aggregation of beta amyloid in Alzheimer's disease. iFrag is freely accessible at http://sbi.imim.es/iFrag. PMID- 27956149 TI - Pain management of trauma patients in the emergency department: a study in a public hospital in Iran. AB - BACKGROUND: Pain is a common problem which the patients in emergency departments (ED) face, especially trauma patients under treatment may suffer from physical, psychological and ethical issues. The purpose of this study was to evaluate traumatic pain management in the emergency department at a public hospital in Iran in 2014. METHODS: This observational prospective study was conducted on 450 trauma patients admitted to a trauma emergency department. The tool used in this study has three parts: demographic data, data of trauma, and VRS (Verbal Rating Scales) score at a 7-point scale-at the arrival time to 4h later. The statistical analysis was conducted by using Mann-Whitney and Kruskal-Wallis tests, repeated measures, survival analysis, and multiple regression analysis. RESULTS: The majority of the samples were male (83.3%) with the mean age of 35.2years. The patients mostly suffered from contusions and strains (42.4%). The majority of the patients [274 patients (60.8%)] received no intervention for pain relief and only 60 patients (13.3%) received analgesics. The mean time period of the first analgesic utilization was 41 (+/-20.4) minutes. Pain in admission, pain assessment, and receiving intervention could explain the 32% of pain reduction. No other variables such as age, sex, education, kind of trauma, and the shift of admission were involved in pain reduction. CONCLUSIONS: This research study demonstrated that comprehensive, adequate pain management remains an obscure goal within the emergency nursing setting. There is a need to undertake further research and develop educational programs on effective analgesic practice in pain management. PMID- 27956145 TI - Recent advances in preclinical model systems for papillomaviruses. AB - Preclinical model systems to study multiple features of the papillomavirus life cycle have greatly aided our understanding of Human Papillomavirus (HPV) biology, disease progression and treatments. The challenge to studying HPV in hosts is that HPV along with most PVs are both species and tissue restricted. Thus, fundamental properties of HPV viral proteins can be assessed in specialized cell culture systems but host responses that involve innate immunity and host restriction factors requires preclinical surrogate models. Fortunately, there are several well-characterized and new animal models of papillomavirus infections that are available to the PV research community. Old models that continue to have value include canine, bovine and rabbit PV models and new rodent models are in place to better assess host-virus interactions. Questions arise as to the strengths and weaknesses of animal PV models for HPV disease and how accurately these preclinical models predict malignant progression, vaccine efficacy and therapeutic control of HPV-associated disease. In this review, we examine current preclinical models and highlight the strengths and weaknesses of the various models as well as provide an update on new opportunities to study the numerous unknowns that persist in the HPV research field. PMID- 27956150 TI - A novel electrochemical biosensor based on Fe3O4 nanoparticles-polyvinyl alcohol composite for sensitive detection of glucose. AB - In this research, a new electrochemical biosensor was constructed for the glucose detection. Iron oxide nanoparticles (Fe3O4) were synthesized through co precipitation method. Polyvinyl alcohol-Fe3O4 nanocomposite was prepared by dispersing synthesized nanoparticles in the polyvinyl alcohol (PVA) solution. Glucose oxidase (GOx) was immobilized on the PVA-Fe3O4 nanocomposite via physical adsorption. The mixture of PVA, Fe3O4 nanoparticles and GOx was drop cast on a tin (Sn) electrode surface (GOx/PVA-Fe3O4/Sn). The Fe3O4 nanoparticles were characterized by X-ray diffraction (XRD). Also, Fourier transform infrared (FTIR) spectroscopy and field emission scanning electron microscopy (FE-SEM) techniques were utilized to evaluate the PVA-Fe3O4 and GOx/PVA-Fe3O4 nanocomposites. The electrochemical performance of the modified biosensor was investigated using electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). Presence of Fe3O4 nanoparticles in the PVA matrix enhanced the electron transfer between enzyme and electrode surface and the immobilized GOx showed excellent catalytic characteristic toward glucose. The GOx/PVA-Fe3O4/Sn bioelectrode could measure glucose in the range from 5 * 10-3 to 30 mM with a sensitivity of 9.36 MUA mM-1 and exhibited a lower detection limit of 8 MUM at a signal-to-noise ratio of 3. The value of Michaelis-Menten constant (KM) was calculated as 1.42 mM. The modified biosensor also has good anti-interfering ability during the glucose detection, fast response (10 s), good reproducibility and satisfactory stability. Finally, the results demonstrated that the GOx/PVA-Fe3O4/Sn bioelectrode is promising in biosensor construction. PMID- 27956151 TI - Enzymatic methods for choline-containing water soluble phospholipids based on fluorescence of choline oxidase: Application to lyso-PAF. AB - In this paper we present methods to determine water soluble phospholipids containing choline (wCh-PL). The analytes were hydrolyzed by the enzyme phospholipase D and the choline formed was oxidized by the enzyme Choline Oxidase (ChOx); the fluorescence changes of the ChOx are followed during the enzymatic reaction, avoiding the necessity of an indicating step. Both reactions (hydrolysis and oxidation) can be combined in two different ways: 1) a two-step process (TSP) in which the hydrolysis reaction takes place during an incubation time and then the oxidation reaction is carried out, the analytical signal being provided by the intrinsic fluorescence of ChOx due to tryptophan; 2) a one-step process (OSP) in which both enzymatic reactions are carried out simultaneously in the same test; in this case the analytical signal is provided by the ChOx extrinsic fluorescence due to a fluorescent probe (Ru (II) chelate) linked to the enzyme (ChOx-RuC). The analytical capabilities of these methods were studied using 1,2-dioctanoyl-sn-glycero-3-phosphocholine (C8PC), a water soluble short alkyl chain Ch-PL as a substrate, and 1-O-hexadecyl-sn-glyceryl-3 phosphorylcholine (lyso-PAF). The analytical features of merit for both analytes using both methods were obtained. The TSP gave a 10-fold sensitivity and lower quantification limit (1.0*10-5 M for lyso-PAF), but OSP reduced the determination time and permitted to use the same enzyme aliquot for several measurements. Both methods gave similar precision (RSD 7%, n = 5). The TSP was applied to the determination of C8PC and lyso-PAF in spiked synthetic serum matrix using the standard addition method. The application of this methodology to PLD activity determination is also discussed. PMID- 27956152 TI - Palliative Care in Heart Failure: Architects Needed. PMID- 27956153 TI - Small benefits in trastuzumab-related cardiotoxicity. PMID- 27956154 TI - Trastuzumab biosimilar shows potential for breast cancer. PMID- 27956156 TI - 58th American Society of Hematology Annual Meeting. PMID- 27956155 TI - Ibrutinib in Waldenstrom's macroglobulinemia: revamping the landscape. PMID- 27956158 TI - Unnecessary thyroid cancer screening in South Korea. PMID- 27956159 TI - 17th World Conference on Lung Cancer. PMID- 27956157 TI - Ibrutinib for patients with rituximab-refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. AB - BACKGROUND: In the era of widespread rituximab use for Waldenstrom's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenstrom's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. METHODS: This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenstrom's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. FINDINGS: Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenstrom Macroglobulinaemia, median number of previous therapies was four (IQR 2-6), and all were rituximab-refractory. At a median follow-up of 18.1 months (IQR 17.5-18.9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66-94), and the estimated 18 month overall survival rate was 97% (95% CI 79-100). Baseline median haemoglobin of 10.3 g/dL (IQR 9.3-11.7) increased to 11.4 g/dL (10.9-12.4) after 4 weeks of ibrutinib treatment and reached 12.7 g/dL (11.8-13.4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. INTERPRETATION: The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenstrom's macroglobulinaemia. FUNDING: Pharmacyclics LLC, an AbbVie Company. PMID- 27956160 TI - MicroRNA-145 Mediates the Formation of Angiotensin II-Induced Murine Abdominal Aortic Aneurysm. AB - BACKGROUND: MicroRNA-145 (miR-145) has been implicated in vascular smooth muscle cell differentiation, but the underlying mechanisms have not been fully understood, especially their role in abdominal aortic aneurysm (AAA) expansion. Here, we sought to explore and define the mechanisms of miR-145 function in the experimental AAA models in AngII-infused ApoE-/- mice. METHODS: miR-145 was overexpressed in ApoE-/- mice via lentivirus infection, and then the incidence of AAA, maximum abdominal aortic diameter, elastin degradation and MMP2 activation were determined in AngII-infused ApoE-/- mice. RESULTS: In vivo overexpression of miR-145 by lentivirus infection greatly decreased the incidence of AAA, maximum abdominal aortic diameter, and elastin degradation, accompanied with downregulation of MMP2 activation in AngII-infused ApoE-/- mice. Cell culture assays indicated that miR-145 inhibited AngII-induced upregulation of MMP2 gene expression. In contrast, deficiency of MMP2 abolished the effects of miR-145 on AngII-induced elastin and collagens degradations in ApoE-/- mice. CONCLUSION: These data suggest that regulation of expression of miR-145 may be a potential therapeutic option for vascular disease progression such as AAA expansion. PMID- 27956161 TI - Prolonged Cardiopulmonary Bypass is a Risk Factor for Intestinal Ischaemic Damage and Endotoxaemia. AB - BACKGROUND: Intestinal ischaemia-reperfusion, a frequent occurrence during cardiac surgery with cardiopulmonary bypass (CPB) induces a systemic inflammatory reaction. We hypothesised that ischaemia-reperfusion following prolonged CPB could increase intestinal permeability and thus, lead to endotoxin translocation from the intestine to the bloodstream. MATERIAL AND METHODS: Patients subjected to coronary artery bypass grafting with CPB were included: Group 1 (CPB >=90minutes) or Group 2 (CPB <90minutes). Intestinal Fatty Acid Binding Protein (I-FABP), TNF alpha, IL6, IL8, and endotoxin levels were measured before the induction of general anaesthesia (T1), at 6 (T2), and 24hours (T3) after surgery. RESULTS: The low level of I-FABP at T1 increased for every patient in Group 1 at T2 (from 1015.5pg/mL to 2608.5pg/mL, p=0.02) and in Group 2 (from 1123.5pg/ml to 2284.0pg/ml, p<0.001). Furthermore, at T3, the I-FABP level was over three times higher in Group 1 than in Group 2 (2178pg/mL vs 615pg/mL; p<0.001). I-FABP correlated with CPB time (R=0.6, p<0.001) at T3. After surgery, endotoxins were elevated in 73% of patients in Group 1 and in 32% in Group 2 and correlated with CPB time (at T2, R=0.5, p=0.002; at T3, R=0.4, p=0.016). CONCLUSIONS: The duration of CPB is linked to the release of biomarkers that indicate ischaemic reperfusion damage to the gastrointestinal mucosa and endotoxaemia. I-FABP assay may help to identify patients presenting with intestinal damage, who are at risk of bacterial translocation. PMID- 27956162 TI - The unchecked pneumococcal reign over Indian children aged younger than 5 years. PMID- 27956163 TI - Invasive pneumococcal disease in children aged younger than 5 years in India: a surveillance study. AB - BACKGROUND: Invasive pneumococcal disease continues to be a major cause of morbidity and mortality among children younger than 5 years of age in India. We aimed to provide nationally representative data for the pattern of disease due to Streptococcus pneumoniae, trends in the serotype of invasive pneumococci, and invasive pneumococci antimicrobial resistance patterns, in India. METHODS: In this prospective hospital-based and retrospective laboratory-based surveillance study, we prospectively enrolled children aged younger than 5 years with suspected or proven invasive pneumococcal disease from 18 hospitals or institutional centres and retrospectively included laboratory-confirmed pneumococcal isolates from ten sentinel laboratories, together representing 11 states in India. Eligibility criteria were fever higher than 38 degrees C without localising symptoms, clinical presentation of suspected meningitis or pneumonia, and evidence of radiographic pneumonia. We cultured blood and other normally sterile body fluids, reconfirmed and serotyped pneumococcal isolates, and established antimicrobial susceptibility using standard study protocols. FINDINGS: Between Jan 1, 2011, and June 30, 2015, we enrolled 4377 patients. Among 361 (8%) patients with culture-proven pneumococcal disease, all clinical data were known for 226 (63%); among these patients, 132 (58%) presented with pneumonia, 78 (35%) presented with meningitis, and 16 (7%) had other clinical conditions. 131 (3%) died overall and 29 (8%) patients with invasive pneumococcal disease died. Serotypes 14 (52 [14%] of 361), 1 (49 [14%]), 5 (37 [10%]), and 19F (33 [9%]) were the most common. Penicillin non-susceptibility occurred in isolates from 29 (8%) patients, co-trimoxazole resistance occurred in 239 (66%), erythromycin resistance occurred in 132 (37%), and chloramphenicol resistance occurred in 33 (9%). We found multidrug resistance in 33 (9%) of 361 patients. INTERPRETATION: The proportion of positive blood cultures, number of isolates, geographical representation, and data generated over the 4.5 years of the study are representative of data for most of India. Continued surveillance is warranted as the decision to introduce protein conjugated vaccine in India is made. FUNDING: GlaxoSmithKline India. PMID- 27956164 TI - The cost-effectiveness of radiofrequency ablation for Barrett's esophagus with low-grade dysplasia: results from a randomized controlled trial (SURF trial). AB - BACKGROUND AND AIMS: The Surveillance versus Radiofrequency Ablation (SURF) trial randomized 136 patients with Barrett's esophagus (BE) containing low-grade dysplasia (LGD), to receive radiofrequency ablation (ablation, n = 68) or endoscopic surveillance (control, n = 68). Ablation reduced the risk of neoplastic progression to high-grade dysplasia and esophageal adenocarcinoma (EAC) by 25% over 3 years (1.5% for ablation vs 26.5% for control). We performed a cost-effectiveness analysis from a provider perspective alongside this trial. METHODS: Patients were followed for 3 years to quantify their use of health care services, including therapeutic and surveillance endoscopies, treatment of adverse events, and medication. Costs for treatment of progression were analyzed separately. Incremental cost-effectiveness ratios (ICER) were calculated by dividing the difference in costs (excluding and including the downstream costs for treatment of progression) by the difference in prevented events of progression. Bootstrap analysis (1000 samples) was used to construct 95% confidence intervals (CIs). RESULTS: Patients who underwent ablation generated mean costs of U.S.$13,503 during the trial versus $2236 for controls (difference $11,267; 95% CI, $9996-$12,378), with an ICER per prevented event of progression of $45,066. Including the costs for treatment of progression, ablation patients generated mean costs of $13,523 versus $4,930 for controls (difference $8593; 95% CI, $6881-$10,153) with an ICER of $34,373. Based on the various ICER estimates derived from the bootstrap analysis, one can be reasonably certain (>75%) that ablation is efficient at a willingness to pay of $51,664 per prevented event of progression or $40,915 including downstream costs of progression. CONCLUSIONS: Ablation for patients with confirmed BE-LGD is more effective and more expensive than endoscopic surveillance in reducing the risk of progression to high-grade dysplasia/EAC. The increase in costs of ablation can be justified to avoid a serious event such as neoplastic progression. At a willingness to pay of $40,915 per prevented event of progression, one can be reasonably certain that ablation is efficient. (www.trialregister.nl number: NTR 1198.). PMID- 27956166 TI - Nutritional status and functional digestive histology of the carnivorous Tasmanian devil (Sarcophilus harrisii). AB - Tasmanian devils (Sarcophilus harrisii) are the largest carnivorous marsupial in Australia. Currently many animals are being held in captivity as a management procedure to combat Devil Facial Tumor Disease. Only one published study thus far has investigated nutrition in Tasmanian devils, determining their maintenance energy requirements and digestibility on a rodent diet. More information is needed on Tasmanian devil nutritional and gastrointestinal function to aid in their management. Our study aimed to investigate the current nutritional status of Tasmanian devils in a captive population and functional morphology and histology of their gastrointestinal tract. Animals were maintained on a diet of kangaroo, rabbit, quail and chicken wings and digestibility of these items by the devils was high (>85% for dry matter, protein and lipid). Kangaroo and rabbit were high protein diet items while the quail and chicken wings provided high lipid to the diet, and carbohydrates were minimal (<=3% energy). Maintenance energy requirements were determined to be 620kJkg-0.75d-1 with no significant difference between males and females. Opportunistic samples for gastrointestinal morphology were obtained from captive specimens. Tasmanian devils have a simple digestive tract similar to other dasyurid species. Both the morphology and histology of the gastrointestinal tract show specialization for a high protein carnivorous diet. PMID- 27956165 TI - Cancer-derived exosomic microRNAs shape the immune system within the tumor microenvironment: State of the art. AB - In recent years there has been an increasing interest of the scientific community on exosome research, with particular emphasis on the mechanisms by which tumor derived exosomes can promote tumor growth. Particularly, exosome-mediated immune escape is under deep investigation and still represents a quite controversial issue. Tumor-derived exosomes are carriers of information able to reprogram functions of immune target cells, influencing their development, maturation, and antitumor activities. They deliver proteins similar to those of the parent cancer cells, but also genetic messages like genomic DNA, mRNA, and microRNAs (miRNAs) that ultimately share the so called "tumor microenvironment" in a pro-tumoral fashion. The content of tumor-derived exosomes could be implicated in several signaling pathways operating in the tumor microenvironment, providing a further modality of dys-regulation of antitumor immunity. The aim of this review is to provide a state-of-the-art highlight of to the most recent discoveries in the field of interaction between tumor-derived exosomic miRNAs and the cells of immune system. PMID- 27956167 TI - Photoperiod and temperature differently affect immune function in striped hamsters (Cricetulus barabensis). AB - Small mammals generally use short day length to elevate immune function to counteract the immunosuppressive effect of low temperature in winter in light of the winter immunoenhancement hypothesis. In the present study, we tested this hypothesis in striped hamsters (Cricetulus barabensis). We expected that immune responses would be increased by short photoperiod but suppressed by low temperature. Thirty-four adult female hamsters were randomly divided into the long day (16L:8D) and short day (8L:16D) groups, which were further assigned into the warm (23+/-1 degrees C) and the cold (5+/-1 degrees C) groups, respectively. We found that body mass was not affected by photoperiod or temperature. Contrary to our expectation, short day reduced phytohaemagglutinin (PHA) response indicative of cellular immunity and the levels of immunoglobin (Ig) M. It had no effect on total body fat mass, thymus and spleen masses, white blood cells (WBC) and Ig G titers. As expected, cold stress decreased total body fat mass, WBC, Ig G and Ig M titers. However, it did not influence the masses of thymus and spleen and PHA responses. The levels of blood glucose, serum leptin and corticosterone were all not affected by temperature or photoperiod except that corticosterone levels were increased by short days. No significant correlations were detected among the levels of blood glucose, serum leptin, corticosterone and all the detected immunological parameters. Taken together, short photoperiod suppressed both cellular and humoral immunity in striped hamsters, which did not support the winter immunoenhancement hypothesis. Cold stress reduced humoral immunity and WBC, which might account for the highest mortality in winter in this species. Blood glucose, leptin and corticosterone could not interpret the changes of immunity in hamsters. PMID- 27956168 TI - Introduction of novel splice variants for CASC18 gene and its relation to the neural differentiation. AB - BACKGROUND: CASC18 along with APPL2, OCC-1 and NUAK1 flanking genes are located in 12q23.3 locus which is known as a potential cancer predisposition locus. Only an uncharacterized EST was initially reported for CASC18 and it was crucial to find its full length sequence and function. METHODS AND RESULTS: In an attempt to search for the CASC18's full-length gene sequence, other related ESTs were bioinformatically collected and four novel splice variants (designated as; CASC18 A, -B, -C and -D) were deduced and some were experimentally validated. Two transcription start sites and two alternative polyadenylation sites were deduced for CASC18 gene, using EST data mining and RACE method. CASC18-A and CASC18-D were exclusively expressed in neural cell lines and CASC18-D expression level was gradually increased during the NT2 differentiation to the neuron-like cells. Consistently, overexpression of CASC18-D variant in NT2 cells resulted in remarkable up-regulation of PAX6 neural differentiation marker, suggesting a crucial role of this variant in neural differentiation. CONCLUSION: Here, we introduced seven novel transcription variants for human CASC18 gene in which CASC18-D has the potential of being used as a neural cell differentiation marker. PMID- 27956169 TI - Differential expression of circadian clock genes in two strains of beetles reveals candidates related to photoperiodic induction of summer diapause. AB - Diapause (also known as dormancy) is a state of arrested development induced by photoperiod or temperature that allows insects to survive adverse environmental conditions. By regulating diapause induction, the circadian clock is involved in short-day-induced winter diapause but whether this is also the case in long-day (LD)-induced summer diapause remains unknown. The cabbage beetle Colaphellus bowringi could enter summer diapause under LD conditions. However, a non photoperiodic-diapause (NPD) strain of this species, which was developed in our laboratory by artificial selection, could not enter diapause under LD photoperiod. Therefore, we identified circadian clock genes in this species and measured differences in their expression between a high diapause (HD) strain and the NPD strain to investigate the potential relationship between circadian clock genes and summer diapause induction in C. bowringi. We successfully cloned eight circadian clock genes and obtained intact ORFs of four; cryptochrome2, double time, shaggy and vrille. Phylogenetic trees and sequence alignment analyses indicated that these circadian clock genes were conserved across insect taxa. The quantitative real-time PCR indicated that clock, cycle, period, timeless, cryptochrome2, and vrille were differentially expressed between HD and NPD strains reared under LD photoperiod during the diapause induction phase. These findings suggest the potential relationship between circadian clock genes and LD regulated summer diapause induction in C. bowringi. PMID- 27956170 TI - In trans promoter activation by enhancers in transient transfection. AB - Earlier, it was reported that the strong cytomegalovirus enhancer can activate the cytomegalovirus promoter in trans, i.e. as a separate plasmid co-transfected with a promoter-reporter gene construct. Here we demonstrate that the ability of enhancers to activate promoters in trans in transient transfection experiments is a property of not only viral regulatory elements but also of various genomic enhancers and promoters. Enhancer-promoter activation in trans is promoter- and cell type-specific, and accompanied by physical interaction between promoter and enhancer as revealed by chromosome conformation capture assays. Thus, promoter activation in transient co-transfection of promoters and enhancers shares a number of important traits with long-distance promoter activation by enhancers in living cells and may therefore serve as a model of this fundamental cellular process. PMID- 27956171 TI - Endovascular parent-artery occlusion of large or giant unruptured internal carotid artery aneurysms. A long-term single-center experience. AB - The development of stent-like devices has increased treatment options for complex internal carotid artery (ICA) aneurysms, but the optimal treatment remains unclear. The purpose of this study was to evaluate the safety and efficacy of endovascular parent-artery occlusion (PAO) for ICA aneurysms. We retrospectively reviewed 28 patients with unruptured ICA aneurysms ?10mm treated with PAO between April 2002 and March 2015 at our institution. Patients who developed neurologic symptoms or with venous-phase delay >2s during balloon test occlusion were not treated by PAO. Patients with venous-phase delays of 1-2s underwent superficial temporal artery to middle cerebral artery (STA-MCA) bypass prior to PAO. The median patient age was 65 (range, 26-84)years. Nineteen aneurysms (68%) were located in the cavernous segment. The median aneurysm size was 25 (range 11 40)mm. Venous-phase delay of 1-2s was observed in five patients. Perioperative ischemic complications (N=9, 32%), which occurred within 30days after treatment, were significantly associated with venous-phase delays of 1-2s (p<0.01) and history of hypertension (p<0.01). Six-month morbidity was observed in one (3.6%) patient. Complete occlusion at final follow-up and delayed (i.e. ?31days after treatment) ischemic events were observed in 100% and 0% of patients, respectively, over a median period of 63 (range, 6-147) months. Despite the high frequency of perioperative ischemic episodes, endovascular PAO with selective use of STA-MCA bypass showed excellent long-term outcomes in patients with unruptured ICA aneurysms ?10mm. PMID- 27956172 TI - Surgical treatment of cavernous malformations involving medulla oblongata. AB - Surgical treatment of cavernous malformations (CMs) involving medulla oblongata is more difficult than the CMs in other sites because of the surrounding vital structures. However, the distinctive features and treatment strategies have not been well illustrated. Therefore, we enrolled a total of 19 patients underwent surgical treatment of CMs involving medulla oblongata in our hospital from August 2008 to August 2014. The clinical features, surgical management and clinical outcome of these patients were retrospectively analyzed, while our institutional surgical indications, approaches and microsurgical techniques were discussed. In our study, gross total resection was achieved in 17 patients and subtotal resection in 2. Two patients underwent emergency surgeries due to severe and progressive neurological deficits. The postoperative new-onset or worsened neurological deficits occurred in 6 patients. After a mean follow-up of 45.8+/ 22.2months, the neurological status was improved in 10 patients and remained stable in 7. The mean modified Rankin Scale (mRS) was 2.58+/-1.26 preoperatively, 3.11+/-0.99 postoperatively and 1.84+/-1.42 at the recent follow-up, respectively. During the follow-up period, no rehemorrhage and recurrence occurred, and the residual lesions remained stable. We recommended surgical resection of symptomatic CMs involving medulla oblongata via optimal approaches, feasible entry zones and meticulous microsurgical techniques in attempting to achieve safe resection and favorable outcome. The clinical features, surgical indications, timing and microsurgical techniques of this special entity should be distinctive from the brainstem cavernous malformations in other sites. PMID- 27956173 TI - Venous infarction mimicking top of basilar syndrome; An uncommon complication of adult influenza infection. AB - Influenza infection increases the risk of ischemic stroke. Here, we represent a case of a 32year-old female who presented with acutely developed altered mental status after influenza A infection. The clinical manifestation and initial lesion on brain DWI mimicked top of basilar syndrome, but without an arterial occlusion or stenosis. Follow-up neuro imaging analysis suggested cerebral venous infarction. It is valuable to report this case of venous infarction in a healthy young adult, as an uncommon complication of adult influenza infection. PMID- 27956174 TI - Soy Isoflavone Intake and Sleep Parameters over 5 Years among Chinese Adults: Longitudinal Analysis from the Jiangsu Nutrition Study. AB - BACKGROUND: Soy isoflavone is beneficial for menopausal/postmenopausal symptoms, including sleep complaints. However, little is known about its longitudinal association with sleep in the general population. OBJECTIVE: Our aim was to investigate the association between soy isoflavone intake and sleep duration and daytime falling asleep among Chinese adults. DESIGN: A longitudinal analysis was performed. Soy isoflavone intake was assessed by food frequency questionnaire. Sleep duration was self-reported at two time points. Occurrence of daytime falling asleep was determined at follow-up. Short and long sleep were defined as sleep <7 h/day or >=9 h/day, respectively. PARTICIPANTS/SETTING: Adults aged 20 years and older from the Jiangsu Nutrition Study (2002-2007) with complete isoflavone intake and sleep duration data at both time points (n=1,474) were analyzed (follow-up, n=1,492). MAIN OUTCOME MEASURES: We measured sleep duration in 2002 and 2007 and daytime falling asleep occurrence in 2007. STATISTICAL ANALYSES PERFORMED: Mixed-effects logistic regression was performed for repeated measures between isoflavone intake and sleep duration. Logistic regression was performed for daytime falling asleep at follow-up. Demographic, anthropometric, and social factors were adjusted in the analyses. RESULTS: The prevalence of long sleep duration was 18.9% in 2002 and 12.6% in 2007, and the prevalence of daytime falling asleep was 5.3%. Compared with the lowest quartile of isoflavone intake, the highest quartile was associated with a lower risk of long sleep duration (odds ratio=0.66; 95% CI 0.48 to 0.90; P for trend=0.018) over 5 years. Compared with persistent low intake of isoflavone (less than median intake of isoflavone at two time points), persistent high intake was associated with a reduced risk of daytime falling asleep in women (odds ratio=0.20; 95% CI 0.06 to 0.68), but not men. No consistent association between soy isoflavone intake and short sleep duration was found. CONCLUSIONS: Soy isoflavone intake was associated with a low risk of long sleep duration in both sexes and a low risk of daytime falling asleep in women but not men. PMID- 27956175 TI - Tumor-promoting effect of IL-23 in mammary cancer mediated by infiltration of M2 macrophages and neutrophils in tumor microenvironment. AB - Interleukin 23 (IL-23) is an inflammatory cytokine which plays a vital role in autoimmune diseases as well as in tumorigenesis. However, the role of IL-23 in tumor procession is still controversial and the underlying mechanism remains unclear. Here we established a stable cell line overexpressing IL-23 to prove that IL-23 promoted tumor growth and pulmonary metastasis through induction of tumor-related inflammation and absence of immune surveillance. IL-23 promotes tumor-associate inflammatory response such as infiltration of M2 macrophages, neutrophils and their elevated secretions of immunosuppressive cytokines transforming growth factor-beta (TGF-beta), IL-10 and vascular endothelial growth factor (VEGF) into tumor tissues, meanwhile the increase of the matrix metalloprotease MMP9. In addition, IL-23 increases the expression of the endothelial marker CD31 and proliferative marker Ki67 in tumors. Moreover, IL23 induces immunosuppression though reducing the infiltration of CD4+and CD8+T cells into tumor tissues. In conclusion, IL-23 is a considerable molecular in tumor progression, which simultaneously facilitates processes of pro-tumor inflammation, such as angiogenesis, immunosuppressive cytokines as well as infiltrations of M2 macrophages and neutrophils, and suppresses antitumor immune responses through reduction of CD4+ T cells and CD8+ T cells. PMID- 27956176 TI - Glucagon-like peptide-1 effects lipotoxic oxidative stress by regulating the expression of microRNAs. AB - Aim to confirm whether the treatment of GLP-1 can modulated body weight, lipid metabolism, insulin content, pancreas oxidative stress, improved T-AOC, MDA levels related to FFA-Induced oxidative stress in C57BL/6 mice and INS-1 cells. In this study, GLP-1 makes the expression of AMPK, PPARalpha, CPT1A and SIRT1 increased, and the expression of SREBP1c, miR-33 and miR-370 decreased. Interestingly, the effects of GLP-1 were less dose dependent as GLP-1 regulated the FFA, which related to gene expression at much lower doses (3 MUg/kg, 10 mM, mice and INS-1 respectively) and effects were relatively maintained at higher dose (30 MUg/kg, 100 mM, mice and INS-1 respectively) as well. Subsequently, the analysis showed that inhibited expression of miR-33 and miR-370 upregulated the expression of CPT1A and SIRT1, reversely mimics. These results demonstrated for the first time that GLP-1 improve lipotoxic oxidative stress of pancreas by regulate expression of microRNAs. PMID- 27956177 TI - Nuclear import of Nkx2-2 is mediated by multiple pathways. AB - Nkx2-2 homeoprotein is essential for the development of the central nervous system and pancreas. Although the nuclear localization signals of Nkx2-2 have been identified, the responsible transport receptor is still unknown. Here, we demonstrate that imp alpha1 not only interacts with Nkx2-2 but also transports it into the nucleus in vitro by acting together with imp beta1. However, the nuclear import of Nkx2-2 in cells was not inhibited in response to knockdown expression of endogenous imp beta1 or over-expression of Bimax2. Furthermore, imp beta1 and imp 13, but not imp 4, directly interact with Nkx2-2 and are capable of transporting Nkx2-2 in an in vitro import assay. By GST pull-down assay, we demonstrate that mutation of NLS1 or NLS2 has no effect on interaction with imp alpha1 or imp 13, but significantly reduced binding to imp beta1. Thus, the nuclear import of Nkx2-2 is mediated not only by the classical import pathway but also directly by imp beta1 or imp 13. PMID- 27956178 TI - Ubiquitin-specific protease 21 regulating the K48-linked polyubiquitination of NANOG. AB - NANOG, one of homeobox proteins, plays a crucial role in regulating self-renewal and pluripotency for embryonic stem cells (ESCs). Since the ubiquitin-mediated degradation of NANOG protein has been implicated in its cellular functions involved in not only maintenance of pluripotency and pluripotent epiblast, but also prevention of primitive endoderm differentiation, the identification of ubiquitin ligases and deubiquitinating enzymes (DUBs) for NANOG is required to elucidate its protein stability and the regulation of cellular functions in these processes. In this study, we have identified a novel deubiquitinating enzyme USP21 which interacts with NANOG by both yeast two hybrid screening for DUBs and immunoprecipitation analyses. These analyses revealed that USP21 specifically regulates the Lys48-linked polyubiquitination and stability of NANOG, providing a new way of maintaining the pluripotency of ESCs and induced pluripotent stem cells (iPSCs). PMID- 27956180 TI - The role of ZmWRKY4 in regulating maize antioxidant defense under cadmium stress. AB - WRKY transcription factors act as positive regulators in abiotic stress responses by activation of the cellular antioxidant systems. However, there are few reports on the response of WRKY genes to cadmium (Cd) stress. In this study, the role of maize ZmWRKY4 in regulating antioxidant enzymes in Cd stress was investigated. The results indicated that Cd induced up-regulation of the expression and the activities of ZmWRKY4 and superoxide dismutase (SOD) and ascorbate peroxidase (APX). Transient expression and RNA interference (RNAi) silencing of ZmWRKY4 in maize mesophyll protoplasts further revealed that ZmWRKY4 was required for the abscisic acid (ABA)-induced increase in expression and activity of SOD and APX. Overexpression of ZmWRKY4 in protoplasts upregulated the expression and the activities of antioxidant enzymes, whereas ABA induced increases in the expression and the activities of antioxidant enzymes were blocked by the RNAi silencing of ZmWRKY4. Bioinformatic analysis indicated that ZmSOD4 and ZmcAPX both harbored two W-boxes, binding motif for WRKY transcription factors, in their promoter region. Intriguingly, ZmWRKY4 belongs to group I WRKYs with two WRKY domains. Moreover, the synchronized expression patterns indicate that ZmWRKY4 might play a critical role in either regulating the ZmSOD4 and ZmcAPX expression or cooperating with them in response to stress and phytohormone. PMID- 27956179 TI - MiR-141-3p promotes prostate cancer cell proliferation through inhibiting kruppel like factor-9 expression. AB - Evidence has revealed that some microRNAs play a critical role in tumor proliferation. We demonstrated that miR-141-3p appears to be a novel oncogene miRNA, which promotes prostate tumorigenesis and facilitates the stemness of prostate cancer cells via suppressing a key transcription factor kruppel-like factor-9 (KLF9). KLF9 is the core effector protein that might suppress tumor growth. MiR-141-3p is upregulated in prostate cancer cells and tissues compared to non-tumorigenic prostate epithelial cells and prostate tissues. MiR-141-3p positively regulated proliferation, spheroid formation, and expression of the stemness factors OCT-4, Nanog, SOX-9, Bmil, CCND1, and CD44 in PC-3 cells. Restoration of miR-141-3p suppresses the expression of the transcription factor KLF9 in PC-3 and accelerates prostate tumorigenesis via targeted binding with its 3'-UTR. Downregulation of KLF9 enhances spheres formation of prostate cancer cells. Our results suggest that miR-141-3p/KLF9 may play an important role in regulating the growth of prostate cancer and is a potential target of prevention and therapy. PMID- 27956181 TI - Latent TGF-beta binding protein-1 deficiency decreases female fertility. AB - The four latent transforming growth factor-beta (TGF-beta) binding proteins LTBP1 4 are extracellular matrix-associated proteins playing a critical role in the activation of TGF-beta. The LTBP1 gene forms two major transcript variants (i.e. Ltbp1S and Ltbp1L) that are derived from different promoters. We have previously shown the importance of LTBP1 in vivo by using three different Ltbp1 null mice that were either deleted for exons 1 and 2 (Ltbp1L knockout), exon 5 (Ltbp1DeltaEx5), or exon 8 (Ltbp1DeltaEx8). While the Ltbp1L knockout and the Ltbp1DeltaEx8 are perinatal lethal and die of cardiovascular abnormalities, the Ltbp1DeltaEx5 is viable because it expresses a short form of Ltbp1L that lacks 55 amino acids (Delta55 variant of Ltbp1) formed by splicing out exon 5, while lacking the Ltbp1S variant. Since only the Ltbp1DeltaEx5 mouse is viable, we have used this model to address aspects of puberty, fertility, age-dependent reproduction, and ovary function. We report for the first time a function of LTBP1 in female reproduction. The Ltbp1DeltaEx5 females showed impaired fertility associated with delayed sexual maturity (p = 0.0074) and ovarian cyst formation in females older than 40 weeks (p = 0.0204). PMID- 27956182 TI - Phosphorylation of proteins during human myometrial contractions: A phosphoproteomic approach. AB - Phasic myometrial contractility is a key component of human parturition and the contractions are driven by reversible phosphorylation of myosin light chains catalyzed by the calcium (Ca2+)-dependent enzyme myosin light chain kinase (MYLK). Other yet unknown phosphorylation or de-phosphorylation events may contribute to myometrial contraction and relaxation. In this study we have performed a global phosphoproteomic analysis of human myometrial tissue using tandem mass tagging to detect changes in the phosphorylation status of individual myometrial proteins during spontaneous and oxytocin-driven phasic contractions. We were able to detect 22 individual phosphopeptides whose relative ratio changed (fold > 2 or < 0.5) in response to spontaneous or oxytocin-stimulated contraction. The most significant changes in phosphorylation were to MYLK on serine 1760, a site associated with reductions in calmodulin binding and subsequent kinase activity. Phosphorylated MYLK (ser1760) increased significantly during spontaneous (9.83 +/- 3.27 fold, P < 0.05) and oxytocin -induced (18.56 +/ 8.18 fold, P < 0.01) contractions and we were able to validate these data using immunoblotting. Pathway analysis suggested additional proteins involved in calcium signalling, cGMP-PRKG signalling, adrenergic signalling and oxytocin signalling were also phosphorylated during contractions. This study demonstrates that a global phosphoproteomic analysis of myometrial tissue is a sensitive approach to detect changes in the phosphorylation of proteins during myometrial contractions, and provides a platform for further validation of these changes and for identification of their functional significance. PMID- 27956183 TI - Untargeted metabolomics analysis reveals dynamic changes in azelaic acid- and salicylic acid derivatives in LPS-treated Nicotiana tabacum cells. AB - To counteract biotic stress factors, plants employ multilayered defense mechanisms responsive to pathogen-derived elicitor molecules, and regulated by different phytohormones and signaling molecules. Here, lipopolysaccharide (LPS), a microbe-associated molecular pattern (MAMP) molecule, was used to induce defense responses in Nicotiana tabacum cell suspensions. Intracellular metabolites were extracted with methanol and analyzed using a liquid chromatography-mass spectrometry (UHPLC-qTOF-MS/MS) platform. The generated data were processed and examined with multivariate and univariate statistical tools. The results show time-dependent dynamic changes and accumulation of glycosylated signaling molecules, specifically those of azelaic acid, salicylic acid and methyl-salicylate as contributors to the altered metabolomic state in LPS-treated cells. PMID- 27956184 TI - New psychoactive substances: Current health-related practices and challenges in responding to use and harms in Europe. AB - BACKGROUND: The availability of new psychoactive substances (NPS) in Europe has rapidly increased over the last decade. Although prevalence levels of NPS use remain low in the general European population, there are serious concerns associated with more problematic forms of use and harms in particular populations and settings. It has thus become a priority to formulate and implement effective public health responses. However, considerable knowledge gaps remain on current practices as well as on the challenges and needs of European health professionals who are responding to use and harms caused by these substances. The aim of this study was to explore current health responses to NPS, and highlight key issues in order to inform planning and implementation of adequate responses. METHODS: This scoping study was based on a targeted multi-source data collection exercise focusing on the provision of health and drug interventions associated with NPS use and harms, in selected intervention settings across Europe. RESULTS: Findings revealed that in the absence of specific evidence, health professionals across most intervention settings rely primarily on acquired expertise with traditional drugs when addressing NPS-related harms. This study also identified a gap in the availability and access to timely and reliable information on NPS to users and health professionals. Health professionals in sexual health settings and custodial settings in contact with certain risk groups reported particular challenges in responding to NPS-related harms. CONCLUSION: Immediate investments are required in expanding substance identification capabilities, competence building among professionals and dissemination of risk information among relevant stakeholders. The risks of neglecting under-served risk populations and failure to address the information needs of health professionals and users on NPS harms in a context of rapid changing drug markets in Europe may have unforeseeable consequences at societal level. PMID- 27956185 TI - Assessing the 'added value' of European policy on new psychoactive substances. AB - BACKGROUND: New psychoactive substances (NPS) are reported to be on the rise throughout Europe, and are often presented as the latest challenge facing drug policy makers. At the European level, legislation on NPS has existed since 1998. Several evaluations, however, have suggested that this legislation is not effective and the European Commission has submitted a new proposal on NPS seeking to extend its powers in this area. METHODS: This article critically evaluates the new proposal against its predecessor's three main criticisms: (i) being unable to tackle the large number of NPS because of lengthy European legislative approaches, (ii) being reactive rather than proactive, and (iii) lacking options for regulatory and control measures. RESULTS AND CONCLUSION: In determining whether or not European interventions can bring added value to what is being done at the national level, it finds that, while the new proposal is more efficient, it is not necessarily more effective, and that there is a disappointing focus on legal frameworks at the expense of research and harm reduction. PMID- 27956186 TI - Life in the time of antiretrovirals in South Africa. PMID- 27956188 TI - Open letter to the candidates for Director-General of WHO: will you support a patient-centred R&D agreement? PMID- 27956187 TI - Trends in the burden of HIV mortality after roll-out of antiretroviral therapy in KwaZulu-Natal, South Africa: an observational community cohort study. AB - BACKGROUND: Antiretroviral therapy (ART) substantially decreases morbidity and mortality in people living with HIV. In this study, we describe population-level trends in the adult life expectancy and trends in the residual burden of HIV mortality after the roll-out of a public sector ART programme in KwaZulu-Natal, South Africa, one of the populations with the most severe HIV epidemics in the world. METHODS: Data come from the Africa Centre Demographic Information System (ACDIS), an observational community cohort study in the uMkhanyakude district in northern KwaZulu-Natal, South Africa. We used non-parametric survival analysis methods to estimate gains in the population-wide life expectancy at age 15 years since the introduction of ART, and the shortfall of the population-wide adult life expectancy compared with that of the HIV-negative population (ie, the life expectancy deficit). Life expectancy gains and deficits were further disaggregated by age and cause of death with demographic decomposition methods. FINDINGS: Covering the calendar years 2001 through to 2014, we obtained information on 93 903 adults who jointly contribute 535 42 8 person-years of observation to the analyses and 9992 deaths. Since the roll-out of ART in 2004, adult life expectancy increased by 15.2 years for men (95% CI 12.4-17.8) and 17.2 years for women (14.5-20.2). Reductions in pulmonary tuberculosis and HIV-related mortality account for 79.7% of the total life expectancy gains in men (8.4 adult life-years), and 90.7% in women (12.8 adult life-years). For men, 9.5% is the result of a decline in external injuries. By 2014, the life expectancy deficit had decreased to 1.2 years for men (-2.9 to 5.8) and to 5.3 years for women (2.6 7.8). In 2011-14, pulmonary tuberculosis and HIV were responsible for 84.9% of the life expectancy deficit in men and 80.8% in women. INTERPRETATION: The burden of HIV on adult mortality in this population is rapidly shrinking, but remains large for women, despite their better engagement with HIV-care services. Gains in adult life-years lived as well as the present life expectancy deficit are almost exclusively due to differences in mortality attributed to HIV and pulmonary tuberculosis. FUNDING: Wellcome Trust, the Bill & Melinda Gates Foundation, and the National Institutes of Health. PMID- 27956190 TI - NaCl strongly modifies the physicochemical properties of aluminum hydroxide vaccine adjuvants. AB - The immunostimulation capacity of most vaccines is enhanced through antigen adsorption on aluminum hydroxide (AH) adjuvants. Varying the adsorption conditions, i.e. pH and ionic strength (I), changes the antigen adsorbed amount and therefore the ability of the vaccine to stimulate the immune system. Vaccine formulations are thus resulting from an empirical screening of the adsorption conditions. This work aims at studying the physicochemical effects of adjusting the ionic strength of commercial AH adjuvant particles suspensions with sodium chloride (NaCl). X-ray photoelectron spectroscopy data show that AH particles surface chemical composition is neither altered by I adjustment with NaCl nor by deposition on gold surfaces. The latter result provides the opportunity to use AH coated gold surfaces as a platform for advanced surface analysis of adjuvant particles, e.g. by atomic force microscopy (AFM). The morphology of adjuvant particles recovered from native and NaCl-treated AH suspensions, as studied by scanning electron microscopy and AFM, reveals that AH particles aggregation state is significantly altered by NaCl addition. This is further confirmed by nitrogen adsorption experiments: I adjustment to 150mM with NaCl strongly promotes AH particles aggregation leading to a strong decrease of the developed specific surface area. This work thus evidences the effect of NaCl on AH adjuvant structure, which may lead to alteration of formulated vaccines and to misinterpretation of data related to antigen adsorption on adjuvant particles. PMID- 27956189 TI - Targeted drug delivery of Sunitinib Malate to tumor blood vessels by cRGD chiotosan-gold nanoparticles. AB - The unique characteristics of tumor vasculature represent an attractive strategy for targeted delivery of antitumor and antiangiogenic agents to the tumor. The purpose of this study was to prepare c(RGDfK) labeled chitosan capped gold nanoparticles [cRGD(CS-Au) NPs] as a carrier for selective intracellular delivery of Sunitinib Malate (STB) to the tumor vasculature. cRGD(CS-Au) NPs was formed by electrostatic interaction between cationic CS and anionic AuNPs. cRGD modified CS Au NPs had a spherical shape with a narrow size distribution. The entrapment efficiency of sunitinib molecule was found to be 45.2%+/-2.05. Confocal microscopy showed enhanced and selective uptake of cRGD(CS-Au) NPs into MCF-7 and HUVEC cells compared with non-targeted CS-Au NPs. Our results suggest that it may be possible to use cRGD(CS-Au) NPs as a carrier for delivery of anticancer drugs, genes and biomolecules for inhibiting tumor vasculature. PMID- 27956191 TI - Effects of excipients and curing process on the abuse deterrent properties of directly compressed tablets. AB - The objective of the present investigation was to understand the effects of excipients and curing process on the abuse deterrent properties (ADP) of PolyoxTM based directly compressible abuse deterrent tablet formulations (ADFs). The excipients investigated were lactose (monohydrate or anhydrous), microcrystalline cellulose and hydroxypropyl methylcellulose. The ADPs studied were tablet crush resistance or hardness, particle size distribution following mechanical manipulation, drug extraction in water and alcohol, syringeability and injectability. Other non-ADPs such as surface morphology and tablet dissolution were also studied. It was found that presence of 50% or more of water soluble or swellable excipient in the ADF tablets significantly affected the tablet hardness, particle size distribution following mechanical manipulation and drug extraction while small amount (5%) of excipients had either minimal or no effect on ADPs of these tablets. Addition of high molecular weight HPMC (K 100M) affected syringeability and injectability of ADF. Curing process was found to affect ADPs (hardness, particle size distribution, drug extraction and syringeability and injectability) when compared with uncured tablet. In conclusion, addition of large amount of excipients, especially water soluble ones in PolyoxTM based ADF tablets increase the risk of abuse by various routes of administration. PMID- 27956192 TI - Quality by Design (QbD)-enabled development of aceclofenac loaded-nano structured lipid carriers (NLCs): An improved dermatokinetic profile for inflammatory disorder(s). AB - Present study was designed to prepare and characterize aceclofenac loaded nanostructured lipid carriers (NLCs) employing Quality by Design (QbD)-oriented approach. The NLCs were evaluated for their transdermal penetration potential and stability. Aceclofenac loaded nanostructured lipid carriers (NLCs) were prepared & characterized, by employing Quality by Design (QbD)-oriented approach and further evaluated for transdermal penetration potential and stability. Different lipids and surfactants were chosen to prepare NLCs using microemulsion method as critical material attributes (CMAs). A 33 factorial design was used for optimization of NLCs, and evaluating them for different critical quality attributes (CQAs), viz. particle size, polydispersity index (PDI), zeta potential, in vitro drug release, entrapment efficiency. The effect of CMAs such as lipids, oil: lipid ratio and concentration of surfactants on CQAs viz. drug entrapment efficiency and particle size were systematically evaluated to optimize NLCs. The optimized NLCs were further incorporated into carbopol gel and characterized for texture and rheology profile followed by in vitro and in vivo evaluations. The optimized ACE-NLCs were found to be spherical, nanometric in size with higher drug loading and entrapment efficiency. Results of the in vitro drug release study showed that the developed formulation followed Korsmeyer Peppas model showing Fickian diffusion. The release was biphasic i.e., initial burst release followed by sustained drug release upto 48h. The optimized NLCs based gel formulation showed superior texture, rheological profile and showed better cell uptake efficiency on hyperkeratinocytic cells (HaCaT cell lines) with higher ex vivo skin permeability efficiency vis-a-vis marketed formulation. In conclusion, dermatokinetic modeling and pharmacodynamic study using carrageenan induced edema mice suggests that aceclofenac loaded NLCs hydrogel may provide a better delivery alternative to target various skin layers. PMID- 27956193 TI - Astaxanthin conjugated polypyrrole nanoparticles as a multimodal agent for photo based therapy and imaging. AB - Polymeric nanoparticles are emerging as promising candidates for photo-based therapy and imaging due to their versatile chemical properties and easy fabrication and functionalization. In the present study we synthesized polypyrrole nanoparticles by stabilization with astaxanthin conjugated bovine serum albumin polymer (PPy@BSA-Astx). The synthesized nanoparticles were biocompatible with MBA-MD-231 and HEK-293 cells. Interestingly, the fabricated nanoparticles produced reactive oxygen species under 808-nm laser exposure and exerted a hyperthermic effect when the power density of the laser was increased. The photodynamic efficiency of PPy@BSA-Astx was measured by DPBF assay, and it was found to generate sufficient amount of reactive radicals to kill the cells at a power density of 0.3W/cm2. In photothermal aspect, the temperature level was reached to 57 degrees C within 5min at 1W/cm2 power density, at the concentration of 50MUg/mL. The in vitro cell toxicity studies showed concentration dependent photothermal and photodynamic toxicity. Fluorescence microscopic investigation explored the cell death and intra-cellular organ destruction by photodynamic treatment. In addition, we observed a strong photoacoustic signal from a tissue mimicking phantom study of nanoparticle treated MBA-MD-231 cells. In conclusion, the fabricated PPy@BSA-Astx nanoparticles can be used as photoacoustic imaging based prognostic agents for photothermal or photodynamic treatment. PMID- 27956194 TI - Enhancement of 8-methoxypsoralen topical delivery via nanosized niosomal vesicles: Formulation development, in vitro and in vivo evaluation of skin deposition. AB - The aim of the present study is to enhance the skin penetration and deposition of 8-methoxypsoraln (8-MOP) via niosomal vesicles to increase its local efficacy and safety. 8-MOP niosomes were prepared by the thin film hydration method using Span 60 or Span 40 along with cholesterol at five different molar ratios. The obtained vesicles revealed high entrapment efficiencies (83.04-89.90%) with nanometric vesicle diameters (111.1-198.8nm) of monodisperse distribution (PDI=0.145-0.216), zeta potential values <-48.3mV and spherical morphology under transmission electron microscopy. Optimized niosomal formulations depicted a biphasic in vitro release pattern in phosphate buffer (pH 5.5)/ethanol (7:3v/v) and displayed good physical stability after storage for 6 months at room (20-25 degrees C) and refrigeration (4-8 degrees C) temperatures. The two optimized formulations were incorporated in 5% sodium carboxy methylcellulose based hydrogel matrix which showed optimum pH values (7.37-7.39), pseudoplastic with thixotropic rheological behavior and more retarded 8-MOP release, by 23.82 and 14.89%, compared to niosomal vesicles after 24h. In vitro drug permeation and deposition studies, using rat skins, revealed promoted penetration and accumulation of 8-MOP after 8h. The skin penetration was further confirmed in vivo by confocal laser scanning microscopy, after 2h application period using rhodamine-loaded niosomal hydrogels compared to plain rhodamine hydrogel, as a florescence marker. Therefore, enhanced permeation and skin deposition of 8-MOP delivered by niosomes may help in improving the efficacy and safety of long-term treatment with 8-MOP. PMID- 27956195 TI - Albumin nanoparticles for glutathione-responsive release of cisplatin: New opportunities for medulloblastoma. AB - Redox-responsive nanoparticles were synthesized by desolvation of bovine serum albumin followed by disulfide-bond crosslinking with N, N'-Bis (acryloyl) cystamine. Dynamic light scattering and transmission electron microscopy studies revealed spherical nanoparticles (mean diameter: 83nm, polydispersity index: 0.3) that were glutathione-responsive. Confocal microscopy revealed rapid, efficient internalization of the nanoparticles by Daoy medulloblastoma cells and healthy controls (HaCaT keratinocytes). Cisplatin-loaded nanoparticles with drug:carrier ratios of 5%, 10%, and 20% were tested in both cell lines. The formulation with the highest drug:carrier ratio reduced Daoy and HaCaT cell viability with IC50 values of 6.19 and 11.17MUgmL-1, respectively. The differential cytotoxicity reflects the cancer cells' higher glutathione content, which triggers more extensive disruption of the disulfide bond-mediated intra-particle cross-links, decreasing particle stability and increasing their cisplatin release. These findings support continuing efforts to improve the safety and efficacy of antineoplastic drug therapy for pediatric brain tumors using selective nanoparticle-based drug delivery systems. PMID- 27956196 TI - Microevolution of bank voles (Myodes glareolus) at neutral and immune-related genes during multiannual dynamic cycles: Consequences for Puumala hantavirus epidemiology. AB - Understanding how host dynamics, including variations of population size and dispersal, may affect the epidemiology of infectious diseases through ecological and evolutionary processes is an active research area. Here we focus on a bank vole (Myodes glareolus) metapopulation surveyed in Finland between 2005 and 2009. Bank vole is the reservoir of Puumala hantavirus (PUUV), the agent of nephropathia epidemica (NE, a mild form of hemorrhagic fever with renal symptom) in humans. M. glareolus populations experience multiannual density fluctuations that may influence the level of genetic diversity maintained in bank voles, PUUV prevalence and NE occurrence. We examine bank vole metapopulation genetics at presumably neutral markers and immune-related genes involved in susceptibility to PUUV (Tnf-promoter, Tlr4, Tlr7 and Mx2 gene) to investigate the links between population dynamics, microevolutionary processes and PUUV epidemiology. We show that genetic drift slightly and transiently affects neutral and adaptive genetic variability within the metapopulation. Gene flow seems to counterbalance its effects during the multiannual density fluctuations. The low abundance phase may therefore be too short to impact genetic variation in the host, and consequently viral genetic diversity. Environmental heterogeneity does not seem to affect vole gene flow, which might explain the absence of spatial structure previously detected in PUUV in this area. Besides, our results suggest the role of vole dispersal on PUUV circulation through sex-specific and density-dependent movements. We find little evidence of selection acting on immune-related genes within this metapopulation. Footprint of positive selection is detected at Tlr-4 gene in 2008 only. We observe marginally significant associations between Mx2 genotype and PUUV genogroups. These results show that neutral processes seem to be the main factors affecting the evolution of these immune-related genes at a contemporary scale, although the relative effects of neutral and adaptive forces could vary temporally with density fluctuations. Immune related gene polymorphism may in turn partly influence PUUV epidemiology in this metapopulation. PMID- 27956197 TI - Acute Pericarditis. AB - Acute pericarditis is an acute inflammatory disease of the pericardium, which may occur in many different disease states (both infectious and non-infectious). Usually the diagnosis is based on symptoms (chest pain, shortness of breath), electrocardiographic changes (ST elevation), physical examination (pericardial friction rub) and elevation of cardiac biomarkers. It may occur in isolation or be associated with an underlying inflammatory disorder. In routine clinical practice, acute pericarditis can be associated with myocarditis due to their overlapping etiologies. PMID- 27956198 TI - Congenital Absence of the Pericardium. AB - Congenital absence of the pericardium (CAP) is one of the rarest cardiac congenital anomalies. It can occur as a complete absence of the entire pericardium, absence of the right or left portion of the pericardium or a partial, foramen-like defect of the right or left pericardium. While the majority of cases are clinically silent, multiple reports associate CAP with symptomatic presentation. The most feared complication of CAP is sudden death due to cardiac strangulation across a partial defect of the left pericardium. Given its rare occurrence, most clinicians and imaging specialists will have little experience with this condition and may fail to recognize it on thoracic or cardiac studies. Thus, the purpose of this review is to highlight the common clinical and multimodality imaging features associated with this anomaly and suggest a management algorithm. PMID- 27956199 TI - The path to successful commercialization of cell and gene therapies: empowering patient advocates. AB - Often, novel gene and cell therapies provide hope for many people living with incurable diseases. To facilitate and accelerate a successful regulatory approval and commercialization path for effective, safe and affordable cell and gene therapies, the involvement of patient advocacy groups (PAGs) should be considered early in the development process. This report provides a thorough overview of the various roles PAGs play in the clinical translation of cell and gene therapies and how they can bring about positive changes in the regulatory process, infrastructure improvements and market stability. PMID- 27956200 TI - Anatomic relationships of the pelvic autonomic nervous system in female cadavers: clinical applications to pelvic surgery. AB - BACKGROUND: The integrity of the pelvic autonomic nervous system is essential for proper bowel, bladder, and sexual function. OBJECTIVE: The purpose of this study was to characterize the anatomic path of the pelvic autonomic system and to examine relationships to clinically useful landmarks. STUDY DESIGN: Detailed dissections were performed in 17 female cadavers. Relationships of the superior hypogastric plexus to aortic bifurcation and midpoint of sacral promontory were examined; the length and width of plexus was documented. Path and width of right and left hypogastric nerves were recorded. The origin and course of the pelvic splanchnic nerves were documented. Individual nerve tissue that contributed to the inferior hypogastric plexus was noted. Relative position of nerves to arteries, viscera, and ligaments was documented. In a subset of specimens, biopsy specimens were obtained to confirm gross findings by histologic analysis. Descriptive statistics were used for data analyses and reporting. RESULTS: In all specimens, the superior hypogastric plexus was embedded in a connective tissue sheet within the presacral space, just below the peritoneum. In 14 of 17 specimens (82.4%), the plexus formed a median distance of 21.3 mm (range, 9-40 mm) below aortic bifurcation; in the remaining specimens, it formed a median distance of 25.3 mm (range, 20.5-30 mm) above bifurcation. In 58.8% of specimens, the superior hypogastric plexus was positioned to the left of midline. The median length and width of the plexus was 39.5 (range, 11.5-68) mm and 9 (range, 2.5-15) mm, respectively. A right and left hypogastric nerve was identified in all specimens and formed a median distance of 23 mm (range, 5-32 mm) below the promontory. The median width of the hypogastric nerve was 3.5 mm (range, 3-4.5 mm) on the right and 3.5 mm (range, 2-6.5 mm) on the left. The median distance from midportion of uterosacral ligament to the closest nerve branch was 0.5 mm (range, 0-4.5 mm) on right and 0 mm (range, 0-27.5 mm) on left. In all specimens, the inferior hypogastric plexus was formed by contributions from the hypogastric nerves and branches from S3 and S4. In 47.1% of hemipelvises, S2 branches contributed to the plexus. The sacral sympathetic trunk contributed to the plexus in 16 of 34 hemipelvises where this structure was identified. The inferior hypogastric plexus formed 1-3 cm lateral to the rectum and upper third of the vagina. From this plexus, 1-3 discrete branches coursed deep to the ureter toward the bladder. A uterine branch that coursed superficial to the ureter followed the ascending branch of the uterine artery. An S4 branch was found directly attaching to lateral walls of the rectum in 53% of specimens. Pelvic splanchnic nerves merged into the inferior hypogastric plexus on the lower and medial surface of the coccygeus muscle. Histologic analysis confirmed neural tissue in all tissues that were sampled. CONCLUSION: Anatomic variability and inability to visualize the small caliber fibers that comprise the inferior hypogastric plexus grossly likely underlines the reasons that some postoperative visceral and sexual dysfunction occur in spite of careful dissection and adequate surgical technique. These findings highlight the importance of a discussion with patients about the risks that are associated with interrupting autonomic fibers during the preoperative consent. PMID- 27956201 TI - Pregnancy in advanced age and the risk of stroke in postmenopausal women: analysis of Women's Health Initiative Study. AB - BACKGROUND: The incidence of pregnancy in advanced age among women is increasing because of the availability of assisted reproduction, although the long-term health consequences are not known. OBJECTIVE: The purpose of this study was to determine the effect of pregnancy in advanced age on the occurrence of cardiovascular events in a large cohort of postmenopausal women. STUDY DESIGN: We analyzed the data for 72,221 women aged 50-79 years who were enrolled in the observational arm of the Women's Health Initiative study. We determined the effect of pregnancy in advanced age (last pregnancy at age >=40 year) on the risk of ischemic stroke, hemorrhagic stroke, myocardial infarction, and cardiovascular death over a mean period (+/-standard deviation) of 12+/-1 years using Cox Proportional Hazards analysis after adjusting for potential confounders. RESULTS: A total of 3306 of the 72,221 participants (4.6%) reported pregnancy in advanced age. Compared with pregnancy in normal age, the rates of ischemic stroke (3.8% vs 2.4%), hemorrhagic stroke (1.0% vs 0.5%), and cardiovascular death (3.9% vs 2.3%) were significantly higher among women with pregnancy in advanced age. In multivariate analysis, women with pregnancy in advanced age were 50% more likely to experience a hemorrhagic stroke (hazard ratio, 1.5; 95% confidence interval, 1.0-2.1) after adjustment for age, race/ethnicity, congestive heart failure, systolic blood pressure, atrial fibrillation, alcohol use, and cigarette smoking. There was no significant difference in the risk of ischemic stroke, myocardial infarction, and cardiovascular death among women with pregnancy in advanced age after adjustment for potential confounders. CONCLUSION: Women with pregnancy at an advanced age have a higher risk for hemorrhagic stroke in the postmenopausal period. PMID- 27956203 TI - Syphilis during pregnancy: a preventable threat to maternal-fetal health. AB - Syphilis remains the most common congenital infection worldwide and has tremendous consequences for the mother and her developing fetus if left untreated. Recently, there has been an increase in the number of congenital syphilis cases in the United States. Thus, recognition and appropriate treatment of reproductive-age women must be a priority. Testing should be performed at initiation of prenatal care and twice during the third trimester in high-risk patients. There are 2 diagnostic algorithms available and physicians should be aware of which algorithm is utilized by their testing laboratory. Women testing positive for syphilis should undergo a history and physical exam as well as testing for other sexually transmitted infections, including HIV. Serofast syphilis can occur in patients with previous adequate treatment but persistent low nontreponemal titers (<1:8). Syphilis can infect the fetus in all stages of the disease regardless of trimester and can sometimes be detected with ultrasound >20 weeks. The most common findings include hepatomegaly and placentomegaly, but also elevated peak systolic velocity in the middle cerebral artery (indicative of fetal anemia), ascites, and hydrops fetalis. Pregnancies with ultrasound abnormalities are at higher risk of compromise during syphilotherapy as well as fetal treatment failure. Thus, we recommend a pretreatment ultrasound in viable pregnancies when feasible. The only recommended treatment during pregnancy is benzathine penicillin G and it should be administered according to maternal stage of infection per Centers for Disease Control and Prevention guidelines. Women with a penicillin allergy should be desensitized and then treated with penicillin appropriate for their stage of syphilis. The Jarisch-Herxheimer reaction occurs in up to 44% of gravidas and can cause contractions, fetal heart rate abnormalities, and even stillbirth in the most severely affected pregnancies. We recommend all viable pregnancies receive the first dose of benzathine penicillin G in a labor and delivery department under continuous fetal monitoring for at least 24 hours. Thereafter, the remaining benzathine penicillin G doses can be given in an outpatient setting. The rate of maternal titer decline is not tied to pregnancy outcomes. Therefore, after adequate syphilotherapy, maternal titers should be checked monthly to ensure they are not increasing four-fold, as this may indicate reinfection or treatment failure. PMID- 27956202 TI - Vaginal birth after cesarean: neonatal outcomes and United States birth setting. AB - BACKGROUND: Women who seek vaginal birth after cesarean delivery may find limited in-hospital options. Increasing numbers of women in the United States are delivering by vaginal birth after cesarean delivery out-of-hospital. Little is known about neonatal outcomes among those who deliver by vaginal birth after cesarean delivery in- vs out-of-hospital. OBJECTIVE: The purpose of this study was to compare neonatal outcomes between women who deliver via vaginal birth after cesarean delivery in-hospital vs out-of-hospital (home and freestanding birth center). STUDY DESIGN: We conducted a retrospective cohort study using 2007 2010 linked United States birth and death records to compare singleton, term, vertex, nonanomolous, and liveborn neonates who delivered by vaginal birth after cesarean delivery in- or out-of-hospital. Descriptive statistics and multivariate regression analyses were conducted to estimate unadjusted, absolute, and relative birth-setting risk differences. Analyses were stratified by parity and history of vaginal birth. Sensitivity analyses that involved 3 transfer status scenarios were conducted. RESULTS: Of women in the United States with a history of cesarean delivery (n=1,138,813), only a small proportion delivered by vaginal birth after cesarean delivery with the subsequent pregnancy (n=109,970; 9.65%). The proportion of home vaginal birth after cesarean delivery births increased from 1.78-2.45%. A pattern of increased neonatal morbidity was noted in unadjusted analysis (neonatal seizures, Apgar score <7 or <4, neonatal seizures), with higher morbidity noted in the out-of-hospital setting (neonatal seizures, 23 [0.02%] vs 6 [0.19%; P<.001]; Apgar score <7, 2859 [2.68%] vs 139 [4.42%; P<.001; Apgar score <4, 431 [0.4%] vs 23 [0.73; P=.01]). A similar, but nonsignificant, pattern of increased risk was observed for neonatal death and ventilator support among those neonates who were born in the out-of-hospital setting. Multivariate regression estimated that neonates who were born in an out-of-hospital setting had higher odds of poor outcomes (neonatal seizures [adjusted odds ratio, 8.53; 95% confidence interval, 2.87-25.4); Apgar score <7 [adjusted odds ratio, 1.62; 95% confidence interval, 1.35-1.96]; Apgar score <4 [adjusted odds ratio, 1.77; 95% confidence interval, 1.12-2.79]). Although the odds of neonatal death (adjusted odds ratio, 2.1; 95% confidence interval, 0.73-6.05; P=.18) and ventilator support (adjusted odds ratio, 1.36; 95% confidence interval, 0.75 2.46) appeared to be increased in out-of-hospital settings, findings did not reach statistical significance. Women birthing their second child by vaginal birth after cesarean delivery in out-of-hospital settings had higher odds of neonatal morbidity and death compared with women of higher parity. Women who had not birthed vaginally prior to out-of-hospital vaginal birth after cesarean delivery had higher odds of neonatal morbidity and mortality compared with women who had birthed vaginally prior to out-of-hospital vaginal birth after cesarean delivery. Sensitivity analyses generated distributions of plausible alternative estimates by outcome. CONCLUSION: Fewer than 1 in 10 women in the United States with a previous cesarean delivery delivered by vaginal birth after cesarean delivery in any setting, and increasing proportions of these women delivered in an out-of-hospital setting. Adverse outcomes were more frequent for neonates who were born in an out-of-hospital setting, with risk concentrated among women birthing their second child and women without a history of vaginal birth. This information urgently signals the need to increase availability of in-hospital vaginal birth after cesarean delivery and suggests that there may be benefit associated with increasing options that support physiologic birth and may prevent primary cesarean delivery safely. Results may inform evidence-based recommendations for birthplace among women who seek vaginal birth after cesarean delivery. PMID- 27956204 TI - A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell derived cardiomyocytes. AB - INTRODUCTION: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC CMs) are anticipated to be a useful tool for conducting proarrhythmia risk assessments of drug candidates. However, a torsadogenic risk prediction paradigm using hiPSC-CMs has not yet been fully established. METHODS: Extracellular field potentials (FPs) were recorded from hiPSC-CMs using the multi-electrode array (MEA) system. The effects on FPs were evaluated with 60 drugs, including 57 with various clinical torsadogenic risks. Actual drug concentrations in medium were measured using the equilibrium dialysis method with a Rapid Equilibrium Dialysis device. Relative torsade de pointes (TdP) scores were determined for each drug according to the degree of FP duration prolongation and early afterdepolarization occurrence. The margins were calculated from the free concentration in medium and free effective therapeutic plasma concentration. Each drug's results were plotted on a two-dimensional map of relative TdP risk scores versus margins. RESULTS: Each drug was categorised as high, intermediate, or low risk based on its location within predefined areas of the two-dimensional map. We categorised 19 drugs as high risk; 18 as intermediate risk; and 17 as low risk. We examined the concordance between our categorisation of high and low risk drugs against the torsadogenic risk categorisation in CredibleMeds(r). Our system demonstrated high concordance, as reflected in a sensitivity of 81%, specificity of 87%, and accuracy of 83%. DISCUSSION: These results indicate that our torsadogenic risk assessment is reliable and has a potential to replace the hERG assay for torsadogenic risk prediction, however, this system needs to be improved for the accurate of prediction of clinical TdP risk. Here, we propose a novel drug induced torsadogenic risk categorising system using hiPSC-CMs and the MEA system. PMID- 27956205 TI - Early echocardiographic predictors of outcomes in the mouse transverse aortic constriction heart failure model. AB - INTRODUCTION: Mouse transverse aortic constriction (TAC) is a widely-used model of pressure overload-induced heart failure. An intrinsic limitation of the model is variability in the response to pressure overload even when employing a standard severity of stenosis. Few literature studies have explicitly reported the use of entry criteria or early predictors to mitigate variability and enrich outcomes in this model. METHODS: Eleven-week-old male C57BL/6J mice underwent TAC or sham surgery. Left ventricular (LV) function and dimensions were assessed by M mode echocardiography at baseline (pre) and 3, 9 and 12weeks post-procedure (end study). At 24h post-procedure, transverse aortic flow velocities were obtained for estimating trans-TAC pressure gradients. Invasive LV hemodynamic assessments were performed and terminal heart and lung weights obtained at end-study. RESULTS: TAC mice displayed early development of LV hypertrophy and wall thickening followed by the later development of LV chamber dilation, and progressive development of LV systolic and diastolic dysfunction. The use of a pre-defined trans-TAC pressure gradient criterion of 45-60mmHg did not affect end study organ weight, echocardiographic and invasive hemodynamic outcomes. A post hoc receiver operator characteristic (ROC) analysis identified early 3week echocardiographic measures of LVmass(echo) and ejection fraction, with threshold changes of ~+30% and -10% normalized to baseline respectively, as good predictors for multiple end-study organ weight, echocardiographic and invasive hemodynamic outcomes. DISCUSSION: This ROC analysis has identified early predictive threshold changes which may serve, alone or in combination, as entry criteria to enrich outcome in this model. PMID- 27956206 TI - Meta-analysis reveals a lack of sexual dimorphism in human amygdala volume. AB - The amygdala plays a key role in many affective behaviors and psychiatric disorders that differ between men and women. To test whether human amygdala volume (AV) differs reliably between the sexes, we performed a systematic review and meta-analysis of AVs reported in MRI studies of age-matched healthy male and female groups. Using four search strategies, we identified 46 total studies (58 matched samples) from which we extracted effect sizes for the sex difference in AV. All data were converted to Hedges g values and pooled effect sizes were calculated using a random-effects model. Each dataset was further meta-regressed against study year and average participant age. We found that uncorrected amygdala volume is about 10% larger in males, with pooled sex difference effect sizes of g=0.581 for right amygdala (kappa=28, n=2022), 0.666 for left amygdala (kappa=28, n=2006), and 0.876 for bilateral amygdala (kappa=16, n=1585) volumes (all p values < 0.001). However, this difference is comparable to the sex differences in intracranial volume (ICV; g=1.186, p<.001, 11.9% larger in males, kappa=11) and total brain volume (TBV; g=1.278, p<0.001, 11.5% larger in males, kappa=15) reported in subsets of the same studies, suggesting the sex difference in AV is a product of larger brain size in males. Among studies reporting AVs normalized for ICV or TBV, sex difference effect sizes were small and not statistically significant: g=0.171 for the right amygdala (p=0.206, kappa=13, n=1560); 0.233 for the left amygdala (p=0.092, kappa=12, n=1512); and 0.257 for bilateral volume (p=0.131, kappa=5, n=1629). These values correspond to less than 0.1% larger corrected right AV and 2.5% larger corrected left AV in males compared to females. In summary, AV is not selectively enhanced in human males, as often claimed. Although we cannot rule out subtle male-female group differences, it is not accurate to refer to the human amygdala as "sexually dimorphic." PMID- 27956207 TI - Modulation of reward-related neural activation on sensation seeking across development. AB - Sensation seeking is a personality construct associated with an increased propensity for engaging in risk-taking. Associations with deleterious outcomes ranging from mental health impairments to increased mortality rates highlight important public health concerns related to this construct. Although some have suggested that increased neural responsivity to reward within the ventral striatum (e.g., nucleus accumbens) may drive sensation seeking behaviors, few studies have examined the neural mechanisms associated with stable individual differences in sensation seeking across development. To address this issue, the current study used functional magnetic resonance imaging to examine the association between neural responding to reward and stable patterns of sensation seeking across a three-year follow-up period among healthy adolescents and young adults (N = 139). Results indicated that during early adolescence (~ages 10-12), increased reactivity to reward within the nucleus accumbens (NAcc) was associated with lower levels of sensation seeking across a three-year follow-up. In middle adolescence (~ages 12-16), there was no evidence of a relationship between NAcc reactivity and sensation seeking. However, during the transition from late adolescence into adulthood (~ages 17-25), heightened reward-related reactivity in the NAcc was linked to increased sensation seeking. Findings suggest that the neural mechanisms underlying individual differences in trait-like levels of sensation seeking change from early to late adolescence. PMID- 27956208 TI - Anatomical evidence for functional diversity in the mesencephalic locomotor region of primates. AB - The mesencephalic locomotor region (MLR) is a highly preserved brainstem structure in vertebrates. The MLR performs a crucial role in locomotion but also controls various other functions such as sleep, attention, and even emotion. The MLR comprises the pedunculopontine (PPN) and cuneiform nuclei (CuN) but their specific roles are still unknown in primates. Here, we sought to characterise the inputs and outputs of the PPN and CuN to and from the basal ganglia, thalamus, amygdala and cortex, with a specific interest in identifying functional anatomical territories. For this purpose, we used tract-tracing techniques in monkeys and diffusion weighted imaging-based tractography in humans to understand structural connectivity. We found that MLR connections are broadly similar between monkeys and humans. The PPN projects to the sensorimotor, associative and limbic territories of the basal ganglia nuclei, the centre median-parafascicular thalamic nuclei and the central nucleus of the amygdala. The PPN receives motor cortical inputs and less abundant connections from the associative and limbic cortices. In monkeys, we found a stronger connection between the anterior PPN and motor cortex suggesting a topographical organisation of this specific projection. The CuN projected to similar cerebral structures to the PPN in both species. However, these projections were much stronger towards the limbic territories of the basal ganglia and thalamus, to the basal forebrain (extended amygdala) and the central nucleus of the amygdala, suggesting that the CuN is not primarily a motor structure. Our findings highlight the fact that the PPN integrates sensorimotor, cognitive and emotional information whereas the CuN participates in a more restricted network integrating predominantly emotional information. PMID- 27956210 TI - Surgical Reconstruction of Giant Penoscrotal Lymphedema in Sub-Saharan Africa. AB - OBJECTIVE: To present management challenges, surgical technique, and outcome associated with penoscrotal reconstruction in patients with giant scrotal lymphedema in sub-Saharan Africa. METHODS: A prospective study of all patients who had penoscrotal reconstruction for giant scrotal lymphedema at our university teaching hospital between January 2003 and December 2012 was carried out. Patients' preoperative clinical evaluation findings, operative technique, and postoperative course were reviewed after obtaining ethical approval and informed consent from the patients. RESULTS: Nineteen patients with giant scrotal lymphedema presented to us during the period of study; out of which, 11 had surgical excision and were studied. Their mean age and median duration of symptoms were 48.5 years and 11.5 years respectively. They all had surgical reconstruction using modified Charles procedure by the same combined team of urologists and plastic surgeons. Scrotal hematoma (27.3%) and superficial surgical site infection (18.2%) were complications encountered postoperatively. One patient (9.1%) had recurrence within 24 months, requiring repeat excision. CONCLUSION: Giant scrotal lymphedema poses severe physical challenge to the sufferer. Surgery remains the only hope to reduce penoscrotal size. Combined effort of urologic and plastic surgeons is essential for reconstruction. PMID- 27956211 TI - Processing of spatial and non-spatial information in rats with lesions of the medial and lateral entorhinal cortex: Environmental complexity matters. AB - The entorhinal-hippocampal circuitry has been suggested to play an important role in episodic memory but the contribution of the entorhinal cortex remains elusive. Predominant theories propose that the medial entorhinal cortex (MEC) processes spatial information whereas the lateral entorhinal cortex (LEC) processes non spatial information. A recent study using an object exploration task has suggested that the involvement of the MEC and LEC spatial and non-spatial information processing could be modulated by the amount of information to be processed, i.e. environmental complexity. To address this hypothesis we used an object exploration task in which rats with excitotoxic lesions of the MEC and LEC had to detect spatial and non-spatial novelty among a set of objects and we varied environmental complexity by decreasing the number of objects or amount of object diversity. Reducing diversity resulted in restored ability to process spatial and non-spatial information in MEC and LEC groups, respectively. Reducing the number of objects yielded restored ability to process non-spatial information in the LEC group but not the ability to process spatial information in the MEC group. The findings indicate that the MEC and LEC are not strictly necessary for spatial and non-spatial processing but that their involvement depends on the complexity of the information to be processed. PMID- 27956213 TI - Sex differences in cough reflex. AB - Majority of patients visiting cough clinics are postmenopausal women, who are affected by intractable cough for years. Why the cough reflex becomes exaggerated in women is not known. Basic research excludes females from the studies contributing to the sex bias which may be responsible for lack of understanding of "hypersensitive" cough in women. Biological and behavioural differences between women and men are the factors affecting cough physiology. Gender also shapes the patterns of behaviour and determines the character of environmental exposures which differs between sexes. The article offers an insight into the physiology of the cough, differences in the maturation of it and biological, social and behavioural factors contributing to the sex differences in cough. PMID- 27956214 TI - GOLD grades are revised in latest strategy update. PMID- 27956212 TI - Voluntary ethanol consumption changes anticipatory ultrasonic vocalizations but not novelty response. AB - Novelty and sensation seeking (NSS) and affective disorders are correlated with earlier ethanol (ETOH) consumption, and sustained drinking into adulthood. Understanding the NSS response and affective response before and after voluntary ETOH consumption could elucidate important individual differences promoting sustained ETOH consumption. This study determined that NSS and affective response to rewarding stimulation-measured by ultrasonic vocalizations (USVs)-change after adolescent ETOH voluntary drinking. Rats were tested for their NSS response using the inescapable novelty test. Then rats were tested for their affective response to a natural reward and USVs were measured. The natural reward was experimenter induced play behavior. Rats were exposed to ETOH for 8 weeks using an intermittent two bottle paradigm. After 8 weeks of voluntary consumption, rats were retested for their response to NSS and affective response to natural reward. Results indicate that voluntary ETOH consumption did not change the response to novelty. Control and ETOH exposed rats decreased their novelty response equally after ETOH consumption, suggesting the decrease was due to age. Importantly, voluntary ETOH consumption changed affective USVs. Compared to water-drinking control rats, ETOH-consuming rats elicited greater anticipatory trill USVs to a natural reward-associated context during a post-drinking probe test. Tickle induced trill USVs did not change differently between ETOH and control rats. These results provide evidence that voluntary intermittent ETOH exposure increases the anticipation of reward and may represent a form of incentive salience. We postulate these diverging effects could be due to differences in incentive salience or reward processing. Together, these results suggest that voluntary ETOH consumption changes the affective response to conditioned and unconditioned natural rewards and offers a behavioral mechanism for studying affective reward processing after ETOH consumption. PMID- 27956215 TI - Multidrug-resistant Mycobacterium abscessus threatens patients with cystic fibrosis. PMID- 27956216 TI - Distribution of CTX-M group I and group III beta-lactamases produced by Escherichia coli and klebsiella pneumoniae in Lahore, Pakistan. AB - Extended-spectrum-lactamases (ESBLs) of the CTX-M type is worrisome issue in many countries of the world from past decade. But little is known about CTX-M beta lactamase producing bacteria in Pakistan. Therefore, this study was carried out to investigate the distribution of CTX-M beta-lactamase producing E. coli and Klebsiella pneumoniae using phenotypic and molecular techniques. A total of 638 E. coli and 338 Klebsiella pneumoniae were isolated from patients attending two hospitals and one diagnostic Centre in Pakistan during 2013-2015. ESBL production was screened by double disc synergism, combination disc (cefotaxime and ceftazidime with clavulanic acid) and E-test. These strains were further characterized by PCR (CTX-M I, CTX-M III) and sequencing. After ribotyping of strains accession numbers were obtained. These isolates were highly resistant to cephalosporins, ceftazidime, cefotaxime, aztreonam, and cefuroxime but susceptible to carbapenems, sulfzone, amikacin and tazocin. Multiple antibiotic resistances index (MAR) revealed that 51% of E. coli strains fell in the range of 0.61-0.7 and 39% of Klebsiella pneumoniae strains fell in the range of 0.71-0.8. 64% Double disc synergism (DDS), 76.4% combination disc (CD), 74% E-test showed ESBL positivity in strains. In E. coli ESBL genes blaCTX-M-I and blaCTX-M-III were detected in 212 (72.1%) and 25 (8.5%) respectively. In Klebsiella pneumoniae ESBL genes blaCTX-M-I and blaCTX-M-III were detected in 89 (82.4%) and 10 (9.2%). Combination of both genes blaCTX-M-I and blaCTX-M-III were found in 16 (5.4%) of E. coli strains and 5 (4.6%) of Klebsiella pneumoniae strains. Sequencing revealed that CTXM-15 was predominately present in the CTX-M-I group. The prevalence of ESBL producing E. coli and Klebsiella pneumoniae isolates was high and the majority of them positive for blaCTX-M-I as compared to blaCTX-M-III. These findings highlight the need to further investigate the epidemiology of other CTX-M beta-lactamases in Pakistan. PMID- 27956217 TI - Janus kinase 3 deficiency caused by a homozygous synonymous exonic mutation that creates a dominant splice site. PMID- 27956209 TI - Methods for cleaning the BOLD fMRI signal. AB - Blood oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI) has rapidly become a popular technique for the investigation of brain function in healthy individuals, patients as well as in animal studies. However, the BOLD signal arises from a complex mixture of neuronal, metabolic and vascular processes, being therefore an indirect measure of neuronal activity, which is further severely corrupted by multiple non-neuronal fluctuations of instrumental, physiological or subject-specific origin. This review aims to provide a comprehensive summary of existing methods for cleaning the BOLD fMRI signal. The description is given from a methodological point of view, focusing on the operation of the different techniques in addition to pointing out the advantages and limitations in their application. Since motion-related and physiological noise fluctuations are two of the main noise components of the signal, techniques targeting their removal are primarily addressed, including both data-driven approaches and using external recordings. Data-driven approaches, which are less specific in the assumed model and can simultaneously reduce multiple noise fluctuations, are mainly based on data decomposition techniques such as principal and independent component analysis. Importantly, the usefulness of strategies that benefit from the information available in the phase component of the signal, or in multiple signal echoes is also highlighted. The use of global signal regression for denoising is also addressed. Finally, practical recommendations regarding the optimization of the preprocessing pipeline for the purpose of denoising and future venues of research are indicated. Through the review, we summarize the importance of signal denoising as an essential step in the analysis pipeline of task-based and resting state fMRI studies. PMID- 27956218 TI - An intensive lifestyle intervention reduces circulating oxidised low-density lipoprotein and increases human paraoxonase activity in obese subjects. AB - OBJECTIVE: Obesity has a great impact on cardiovascular morbidity and mortality, the treatment of this pathological state is important given the significant health consequences. Lifestyle and behaviour changes play a significant role in weight management. The purpose of this study was to investigate the impact of an intensive multidisciplinary lifestyle intervention on well-known atherogenic factors in a group of overweight and obese subjects. METHODS: A total of 44 people with overweight/obesity underwent a lifestyle intervention based on nutritional education, psychological support and a 3-month exercise training program with a frequency of twice a week. Several anthropometric and biochemical parameters were measured before and after the lifestyle intervention. RESULTS: Lifestyle intervention led to a significant reduction in metabolic profile including body mass index (BMI), waist circumference, systolic and diastolic blood pressure, plasma glucose, and plasma triglycerides. These reductions were also accompanied by a significant increase in maximal oxygen consumption and muscle strength. Furthermore, paraoxonase and lactonase activities and the concentration of Apoliproteins A1 (APO A1) were significantly increased and the serum levels of oxLDL reduced without any changes in the circulating levels of LDL and HDL. CONCLUSION: In conclusion, our study suggests that an intensive lifestyle intervention in obese subjects promotes a series of beneficial antiatherogenic changes which included increased enzyme activites of paraoxonase and lactonase, concentration of Apoliproteins A1 and decreased circulating levels of oxLDL. PMID- 27956219 TI - Hoxa1 and Hoxb1 are required for pharyngeal arch artery development. AB - Hox transcription factors play critical roles during early vertebrate development. Previous studies have revealed an overlapping function of Hoxa1 and Hoxb1 during specification of the rhombomeres from which neural crest cells emerge. A recent study on Hoxa1 mutant mice documented its function during cardiovascular development, however, the role of Hoxb1 is still unclear. Here we show using single and compound Hoxa1;Hoxb1 mutant embryos that reduction of Hoxa1 gene dosage in Hoxb1-null genetic background is sufficient to result in abnormal pharyngeal aortic arch (PAA) development and subsequently in great artery defects. Endothelial cells in the 4th PAAs of compound mutant differentiate normally whereas vascular smooth muscle cells of the vessels are absent in the defective PAAs. The importance of Hoxa1 and Hoxb1, and their interaction during specification of cardiac NCCs is demonstrated. Together, our data reveal a critical role for anterior Hox genes during PAA development, providing new mechanistic insights into the etiology of congenital heart defects. PMID- 27956220 TI - Physiologically based pharmacokinetic toolkit to evaluate environmental exposures: Applications of the dioxin model to study real life exposures. AB - Chlorinated dibenzo-p-dioxins (CDDs) are a series of mono- to octa-chlorinated homologous chemicals commonly referred to as polychlorinated dioxins. One of the most potent, well-known, and persistent member of this family is 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). As part of translational research to make computerized models accessible to health risk assessors, we present a Berkeley Madonna recoded version of the human physiologically based pharmacokinetic (PBPK) model used by the U.S. Environmental Protection Agency (EPA) in the recent dioxin assessment. This model incorporates CYP1A2 induction, which is an important metabolic vector that drives dioxin distribution in the human body, and it uses a variable elimination half-life that is body burden dependent. To evaluate the model accuracy, the recoded model predictions were compared with those of the original published model. The simulations performed with the recoded model matched well with those of the original model. The recoded model was then applied to available data sets of real life exposure studies. The recoded model can describe acute and chronic exposures and can be useful for interpreting human biomonitoring data as part of an overall dioxin and/or dioxin-like compounds risk assessment. PMID- 27956221 TI - Ethylene glycol and glycerol loading and unloading in porcine meniscal tissue. AB - The development of a long-term storage method for meniscus, a complex tissue of the knee prone to injury, would improve the procedure and outcomes of meniscus transplantation. Cryopreservation uses cryoprotective agents (CPAs) including ethylene glycol (EG) and glycerol to preserve a variety of live tissues, and understanding of the CPA permeation kinetics will be critical in designing a vitrification protocol for meniscus. The purpose of this preliminary study was to understand the loading and unloading behaviours of EG and glycerol in meniscus by observing their efflux. For the main experiment, lateral and medial porcine menisci were incubated with CPA for 24 h at three temperatures (i.e., 4, 22, and 37 degrees C). Then, the menisci were immersed in 25 ml of X-VIVOTM10 and CPA efflux was recorded by monitoring the molality of two consecutive washout solutions at different time points. In a subsequent experiment, menisci were incubated in the CPA solutions for 48 h at 22 degrees C, and the results were compared to those obtained at 22 degrees C in the main experiment. Results showed a rapid efflux of CPA from meniscus at the beginning of each wash. With increasing temperature, the amount of CPA efflux (and hence loading) increased. Using 24 h incubation, EG loaded the menisci more completely than glycerol. But after 48 h of incubation, both EG and glycerol achieved approximately the same degree of meniscus loading. This study provides preliminary data that will facilitate future design of experiments aimed at development of meniscus permeation studies. PMID- 27956222 TI - Effects of trehalose vitrification and artificial oocyte activation on the development competence of human immature oocytes. AB - Sucrose and trehalose are conventional cryoprotectant additives for oocytes and embryos. Ethanol can artificially enhance activation of inseminated mature oocytes. This study aims to investigate whether artificial oocyte activation (AOA) with ethanol can promote the development competence of in vitro matured oocytes. A total of 810 human immature oocytes, obtained from 325 patients undergoing normal stimulated oocyte retrieval cycles, were in vitro maturated (IVM) either immediately after collection (Fresh group n = 291)) or after being vitrified as immature oocytes (Vitrified group n = 519). These groups were arbitrarily assigned. All fresh and vitrified oocytes which matured after a period of IVM then underwent intra-cytoplasmic sperm injection (ICSI). Half an hour following ICSI, they were either activated by 7% ethanol (AOA group) or left untreated (Non-AOA group). Fertilization, cleavage rate, blastocyst quality and aneuploidy rate were then evaluated. High-quality blastocysts were only obtained in both the fresh and vitrified groups which had undergone AOA after ICSI. Trehalose vitrification slightly, but not significantly, increased the formation rates of high-quality embryos (21.7% VS 15.4%, P > 0.05) and blastocysts (15.7% VS 7.69%, P > 0.05)) when compared with sucrose vitrification. Aneuploidy was observed in 12 of 24 (50%) of the AOA derived high quality blastocysts. High quality blastocysts only developed from fresh or vitrified immature oocytes if the ICSI was followed by AOA. This information may be important for human immature oocytes commonly retrieved in normal stimulation cycles and may be particularly important for certain patient groups, such as cancer patients. AOA with an appropriate concentration of ethanol can enhance the developmental competence of embryos. PMID- 27956223 TI - The effect of cryopreservation on anti-cancer activity of human amniotic membrane. AB - Human amniotic membrane (AM) is an appropriate candidate for treatment of cancer due to special properties, such as inhibition of angiogenesis and secretion of pro-apoptotic factors. This research was designed to evaluate the impact of cryopreservation on cancer cell death induction and anti-angiogenic properties of the AM. Cancer cells were treated with fresh and cryopreserved amniotic condition medium during 24 h and cancer cell viability was determined by MTT assay. To evaluate angiogenesis, the rat aorta ring assay was performed for both fresh and cryopreserved AM within 7 days. In addition, four anti-angiogenic factors Tissue Inhibitor of Matrix Metalloproteinase-1 and 2 (TIMP-1 and TIMP-2), Thrombospondin, and Endostatin were measured by ELISA assay before and after cryopreservation. The results showed that the viability of cultured cancer cells dose-dependently decreased after treatment with condition medium of fresh and cryopreserved tissue and no significant difference was observed between the fresh and cryopreserved AM. The results revealed that the amniotic epithelial stem cells inhibit the penetration of fibroblast-like cells and angiogenesis. Moreover, the penetration of fibroblast-like cells in both epithelial and mesenchymal sides of fresh and cryopreserved AM was observed after removing of epithelial cells. The cryopreservation procedure significantly decreased anti angiogenic factors TIMP-1, TIMP-2, Thrombospondin, and Endostatin which shows that angio-modulatory property is not fully dependent on proteomic and metabolomic profiles of the AM. These promising results demonstrate that cancer cell death induction and anti-angiogenic properties of the AM were maintained within cryopreservation; a procedure which can circumvent limitations of the fresh AM. PMID- 27956224 TI - Impact of a park-based afterschool program replicated over five years on modifiable cardiovascular disease risk factors. AB - Major challenges to the current childhood obesity epidemic include availability of prevention and/or treatment programs that are affordable and acc5essible. We evaluated the change in several modifiable, obesity-related cardiovascular disease risk factors after participation in Fit2PlayTM, a structured afterschool program housed in a large urban county parks system. Children ages 6-14 who participated in Fit2PlayTM in one of 34 parks for one school year during a five year period (2010-2015) had height, weight, 4-site skinfold thicknesses, systolic/diastolic blood pressure (SBP/DBP), fitness tests, and a health/wellness behavior/knowledge test collected at the beginning and end of the school year. Comparison of pre/post outcome measures were assessed via general linear mixed models for normal weight, overweight, and obese participants and both aggregate and cohort/year-specific results were generated. Aggregate (N=1546, 51% Hispanic, 44% NHB) results showed after one year of participation (U.S. Department of Health and Human Services, 2016) both the obese and overweight groups significantly decreased their mean body mass index (BMI) percentile (98th to 95th percentile, p<0.001; 91st percentile to 89th percentile, p<0.001, respectively); (Ogden et al. 2015) the normal weight group maintained a healthy BMI percentile (54.6th); (Ogden et al., 2014) mean SBP and DBP significantly decreased (3.6 percentile and 6 percentile points, respectively, p<0.001 for both). Mean number of sit-ups, push-ups, 400meter run time, and nutrition knowledge scores improved in all participants (p<0.001 for all). These findings suggest that parks-based afterschool health/wellness programs can be a low-cost, high value tool in both preventing and treating the current childhood obesity epidemic and among high risk groups in particular. PMID- 27956226 TI - Sex differences in immune responses: Hormonal effects, antagonistic selection, and evolutionary consequences. AB - Males and females differ in both parasite load and the strength of immune responses and these effects have been verified in humans and other vertebrates. Sex hormones act as important modulators of immune responses; the male sex hormone testosterone is generally immunosuppressive while the female sex hormone estrogen tends to be immunoenhancing. Different sets of T-helper cells (Th) have important roles in adaptive immunity, e.g. Th1 cells trigger type 1 responses which are primarily cell-mediated, and Th2 cells trigger type 2 responses which are primarily humoral responses. In our review of the literature, we find that estrogen and progesterone enhance type 2 and suppress type 1 responses in females, whereas testosterone suppresses type 2 responses and shows an inconsistent pattern for type 1 responses in males. When we combine these patterns of generally immunosuppressive and immunoenhancing effects of the sex hormones, our results imply that the sex differences in immune responses should be particularly strong in immune functions associated with type 2 responses, and less pronounced with type 1 responses. In general the hormone-mediated sex differences in immune responses may lead to genetic sexual conflicts on immunity. Thus, we propose the novel hypothesis that sexually antagonistic selection may act on immune genes shared by the sexes, and that the strength of this sexually antagonistic selection should be stronger for type 2- as compared with type 1 associated immune genes. Finally, we put the consequences of sex hormone-induced effects on immune responses into behavioral and ecological contexts, considering social mating system, sexual selection, geographical distribution of hosts, and parasite abundance. PMID- 27956225 TI - Detecting prediabetes among Hispanics/Latinos from diverse heritage groups: Does the test matter? Findings from the Hispanic Community Health Study/Study of Latinos. AB - The objectives of this analysis were to compare the ability of fasting plasma glucose (FPG), post oral load plasma glucose (2hPG), and hemoglobin A1c (HbA1c) to identify U.S. Hispanic/Latino individuals with prediabetes, and to assess its cardiovascular risk factor correlates. This is a cross-sectional analysis of baseline data from 15,507 adults without self-reported diabetes mellitus from six Hispanic/Latino heritage groups, enrolled in the Hispanic Community Health Study/Study of Latinos, which takes place in four U.S. communities. The prevalence of prediabetes was determined according to individual or combinations of ADA-defined cut points: FPG=5.6-7.0mmol/L, 2hPG=7.8-11.1mmol/L, and HbA1c=5.7% 6.4% (39-46mmol/mol). The sensitivity of these criteria to detect prediabetes was estimated. The prevalence ratios (PRs) for selected cardiovascular risk factors were compared among alternative categories of prediabetes versus normoglycemia [FPG<5.6mmol/L and 2hPG<7.8mmol/L and HbA1c<5.7% (39mmol/mol)]. Approximately 36% of individuals met any of the ADA prediabetes criteria. Using 2hPG as the gold standard, the sensitivity of FPG was 40.1%, HbA1c was 45.6%, and that of HbA1c+FPG was 62.2%. The number of significant PRs for cardiovascular risk factors was higher among individuals with isolated 2hPG=7.8-11.1mmol/L, FPG=5.6 7.0mmol/L+HbA1c=5.7%-6.4%, or those who met the three prediabetes criteria. Assessing FPG, HbA1c, and cardiovascular risk factors in Hispanics/Latinos at risk might enhance the early prevention of diabetes mellitus and cardiovascular complications in this young and growing population, independent of their heritage group. PMID- 27956227 TI - The sexual preference of female rats is influenced by males' adolescent social stress history and social status. AB - Ongoing development of brain systems for social behaviour renders these systems susceptible to the influence of stressors in adolescence. We previously found that adult male rats that underwent social instability stress (SS) in mid adolescence had decreased sexual performance compared with control males (CTL). Here, we test the hypotheses that SS in adolescence decreases the "attractiveness" of male rats as sexual partners compared with CTL rats and that dominance status is a protective factor against the effects of SS. The main prediction was that females would spend more time with CTL males than SS males, and that this bias would be greater for submissive than for dominant rats. Among dominant pairs (n=16), females preferred SS males, spending more time with and visiting more often SS than CTL males (each pair tested 5*), and SS males had shorter latencies to ejaculation, shorter inter-ejaculation intervals, and made more ejaculations compared with CTL males. Among submissive pairs (n=16), females spent more time with, visited more often, and displayed more paracopulatory behaviour with CTL than with SS males, and differences in sexual performance between SS and CTL males were modest and in the opposite direction from that in dominant pairs. The heightened motivation of SS males relative to CTL males for natural rewards may have attenuated differences in sexual performance in a paced mating context. In sum, the experience of stress in adolescence leads to long lasting changes in males that are perceptible to females, are moderated by social status, and influence sexual behaviour. PMID- 27956230 TI - Carotid Reconstruction with Bovine Carotid Heterograft after En Bloc Resection of Squamous Cell Carcinoma with Direct Internal Carotid Invasion. AB - We report a novel use of Artegraft (North Brunswick, NJ) bovine heterograft for carotid reconstruction after resection of a neck squamous cell carcinoma (SCC). A 65-year-old man presented with a large left neck SCC encasing and invading the cervical internal carotid artery (ICA). Computed tomography angiography revealed an incomplete Circle of Willis, and no viable vein conduit on duplex mapping. The patient underwent en bloc resection including portion of the cervical ICA followed by reconstruction with Artegraft which was well tolerated. This represents the first case report of tumor invasion of the ICA reconstructed using Artegraft as conduit. PMID- 27956229 TI - Milk Fat Globule-EGF Factor 8, Secreted by Mesenchymal Stem Cells, Protects Against Liver Fibrosis in Mice. AB - BACKGROUND & AIMS: Mesenchymal stem cells (MSCs) mediate tissue repair and might be used to prevent or reduce liver fibrosis. However, little is known about the anti-fibrotic factors secreted from MSCs or their mechanisms. METHODS: Umbilical cord-derived MSCs (UCMSCs) were differentiated into hepatocyte-like cells (hpUCMSCs), medium was collected, and secretome proteins were identified and quantified using nanochip-liquid chromatography/quadrupole time-of-flight mass spectrometry. Liver fibrosis was induced in mice by intraperitoneal injection of thioacetamide or CCl4; some mice were then given injections of secretomes or proteins. Liver tissues were collected and analyzed by histology or polymerase chain reaction array to analyze changes in gene expression patterns. We analyzed the effects of MSC secretomes and potential anti-fibrotic proteins on transforming growth factor beta 1 (TGFbeta1)-mediated activation of human hepatic stellate cell (HSC) lines (hTert-HSC and LX2) and human primary HSCs. Liver tissues were collected from 16 patients with liver cirrhosis and 16 individuals without cirrhosis (controls) in Korea and analyzed by immunohistochemistry and immunoblots. RESULTS: In mice with fibrosis, accumulation of extracellular matrix proteins was significantly reduced 3 days after injecting secretomes from UCMSCs, and to a greater extent from hpUCMSCs; numbers of activated HSCs that expressed the myogenic marker alpha-smooth muscle actin (alpha-SMA, encoded by ACTA2 [actin, alpha 2, smooth muscle]) were also reduced. Secretomes from UCMSCs, and to a greater extent from hpUCMSCs, reduced liver expression of multiple fibrotic factors, collagens, metalloproteinases, TGFbeta, and Smad proteins in the TGFbeta signaling pathways. In HSC cell lines and primary HSCs, TGFbeta1-stimulated upregulation of alpha-SMA was significantly inhibited (and SMAD2 phosphorylation reduced) by secretomes from UCMSCs, and to a greater extent from hpUCMSCs. We identified 32 proteins in secretomes of UCMSCs that were more highly concentrated in secretomes from hpUCMSCs and inhibited TGFbeta-mediated activation of HSCs. One of these, milk fat globule-EGF factor 8 (MFGE8), was a strong inhibitor of activation of human primary HSCs. We found MFGE8 to down-regulate expression of TGFbeta type I receptor by binding to alphavbeta3 integrin on HSCs and to be secreted by MSCs from umbilical cord, teeth, and bone marrow. In mice, injection of recombinant human MFGE8 had anti-fibrotic effects comparable to those of the hpUCMSC secretome, reducing extracellular matrix deposition and HSC activation. Co-injection of an antibody against MFGE8 reduced the anti-fibrotic effects of the hpUCMSC secretome in mice. Levels of MFGE8 were reduced in cirrhotic liver tissue from patients compared with controls. CONCLUSIONS: MFGE8 is an anti fibrotic protein in MSC secretomes that strongly inhibits TGFbeta signaling and reduces extracellular matrix deposition and liver fibrosis in mice. PMID- 27956231 TI - Viability of Cells From Displaced Fragments of the Elbow Osteochondritis Dissecans: Alternative Source of Autologous Chondrocyte Implantation. AB - PURPOSE: To assess the histological properties of cells from displaced fragments obtained from patients with advanced osteochondritis dissecans (OCD) of the elbow and to examine whether these displaced fragments could be used as cell sources for autologous chondrocyte implantation. METHODS: We harvested 6 displaced fragments from 6 patients who underwent osteochondral mosaicplasty for OCD of the elbow. The displaced fragments were examined histologically and digested to obtain chondrocytes. The cells obtained from young patients and skeletally matured cadaveric donors were examined using quantitative reverse transcription polymerase chain reaction analysis to quantify the expression of chondrocyte marker genes. The cells were cultured in atelocollagen, and the properties of 3 dimensional cultured cartilage were examined. RESULTS: All 6 displaced fragments contained hyaline cartilage tissue. Chondrocyte marker genes were examined using cells from only 4 patients, because we obtained enough cells in only 4 patients. The relative expression levels of aggrecan, type II, Sox 9 were 2.61, 4.03, and 1.71, respectively. Three-dimensional cultured cartilage from all 6 displaced fragments contained 62.0 pg/cell (range, 22.8-91.3 pg/cell) of glycosaminoglycan and expressed type II collagen in the superficial and middle layer. CONCLUSIONS: The chondrocytes obtained from the displaced fragments remained viable and exhibited chondrogenic features. These cells may potentially be a cell source of autologous chondrocytes implantation. CLINICAL RELEVANCE: We have shown that displaced fragments from OCD of the elbow have potential for a cell source for generating 3-dimensional cultured cartilage. PMID- 27956232 TI - Changes in Contact Area in Meniscus Horizontal Cleavage Tears Subjected to Repair and Resection. AB - PURPOSE: To assess the changes in tibiofemoral contact pressure and contact area in human knees with a horizontal cleavage tear before and after treatment. METHODS: Ten human cadaveric knees were tested. Pressure sensors were placed under the medial meniscus and the knees were loaded at twice the body weight for 20 cycles at 0 degrees , 10 degrees , and 20 degrees of flexion. Contact area and pressure were recorded for the intact meniscus, the meniscus with a horizontal cleavage tear, after meniscal repair, after partial meniscectomy (single leaflet), and after subtotal meniscectomy (double leaflet). RESULTS: The presence of a horizontal cleavage tear significantly increased average peak contact pressure and reduced effective average tibiofemoral contact area at all flexion angles tested compared with the intact state (P < .03). There was approximately a 70% increase in contact pressure after creation of the horizontal cleavage tear. Repairing the horizontal cleavage tear restored peak contact pressures and areas to within 15% of baseline, statistically similar to the intact state at all angles tested (P < .05). Partial meniscectomy and subtotal meniscectomy significantly increased average peak contact pressure and reduced average contact area at all degrees of flexion compared with the intact state (P < .05). CONCLUSIONS: The presence of a horizontal cleavage tear in the medial meniscus causes a significant reduction in contact area and a significant elevation in contact pressure. These changes may accelerate joint degeneration. A suture-based repair of these horizontal cleavage tears returns the contact area and contact pressure to nearly normal, whereas both partial and subtotal meniscectomy lead to significant reductions in contact area and significant elevations in contact pressure within the knee. Repairing horizontal cleavage tears may lead to improved clinical outcomes by preserving meniscal tissue and the meniscal function. CLINICAL RELEVANCE: Understanding contact area and peak contact pressure resulting from differing strategies for treating horizontal cleavage tears will allow the surgeon to evaluate the best strategy for treating his or her patients who present with this meniscal pathology. PMID- 27956228 TI - Genome-Wide CRISPR Screen Identifies Regulators of Mitogen-Activated Protein Kinase as Suppressors of Liver Tumors in Mice. AB - BACKGROUND & AIMS: It has been a challenge to identify liver tumor suppressors or oncogenes due to the genetic heterogeneity of these tumors. We performed a genome wide screen to identify suppressors of liver tumor formation in mice, using CRISPR-mediated genome editing. METHODS: We performed a genome-wide CRISPR/Cas9 based knockout screen of P53-null mouse embryonic liver progenitor cells that overexpressed MYC. We infected p53-/-;Myc;Cas9 hepatocytes with the mGeCKOa lentiviral library of 67,000 single-guide RNAs (sgRNAs), targeting 20,611 mouse genes, and transplanted the transduced cells subcutaneously into nude mice. Within 1 month, all the mice that received the sgRNA library developed subcutaneous tumors. We performed high-throughput sequencing of tumor DNA and identified sgRNAs increased at least 8-fold compared to the initial cell pool. To validate the top 10 candidate tumor suppressors from this screen, we collected data from patients with hepatocellular carcinoma (HCC) using the Cancer Genome Atlas and COSMIC databases. We used CRISPR to inactivate candidate tumor suppressor genes in p53-/-;Myc;Cas9 cells and transplanted them subcutaneously into nude mice; tumor formation was monitored and tumors were analyzed by histology and immunohistochemistry. Mice with liver-specific disruption of p53 were given hydrodynamic tail-vein injections of plasmids encoding Myc and sgRNA/Cas9 designed to disrupt candidate tumor suppressors; growth of tumors and metastases was monitored. We compared gene expression profiles of liver cells with vs without tumor suppressor gene disrupted by sgRNA/Cas9. Genes found to be up-regulated after tumor suppressor loss were examined in liver cancer cell lines; their expression was knocked down using small hairpin RNAs, and tumor growth was examined in nude mice. Effects of the MEK inhibitors AZD6244, U0126, and trametinib, or the multi-kinase inhibitor sorafenib, were examined in human and mouse HCC cell lines. RESULTS: We identified 4 candidate liver tumor suppressor genes not previously associated with liver cancer (Nf1, Plxnb1, Flrt2, and B9d1). CRISPR-mediated knockout of Nf1, a negative regulator of RAS, accelerated liver tumor formation in mice. Loss of Nf1 or activation of RAS up regulated the liver progenitor cell markers HMGA2 and SOX9. RAS pathway inhibitors suppressed the activation of the Hmga2 and Sox9 genes that resulted from loss of Nf1 or oncogenic activation of RAS. Knockdown of HMGA2 delayed formation of xenograft tumors from cells that expressed oncogenic RAS. In human HCCs, low levels of NF1 messenger RNA or high levels of HMGA2 messenger RNA were associated with shorter patient survival time. Liver cancer cells with inactivation of Plxnb1, Flrt2, and B9d1 formed more tumors in mice and had increased levels of mitogen-activated protein kinase phosphorylation. CONCLUSIONS: Using a CRISPR-based strategy, we identified Nf1, Plxnb1, Flrt2, and B9d1 as suppressors of liver tumor formation. We validated the observation that RAS signaling, via mitogen-activated protein kinase, contributes to formation of liver tumors in mice. We associated decreased levels of NF1 and increased levels of its downstream protein HMGA2 with survival times of patients with HCC. Strategies to inhibit or reduce HMGA2 might be developed to treat patients with liver cancer. PMID- 27956233 TI - Graft Augmentation Versus Bridging for Large to Massive Rotator Cuff Tears: A Systematic Review. AB - PURPOSE: To systematically review the literature on the healing rates and clinical outcomes of the 2 different graft indications (i.e., augmentation vs bridging) during rotator cuff repair. METHODS: A systematic literature review was performed for clinical studies of rotator cuff repair using grafts for large to massive tears. The primary outcome was tendon healing on either magnetic resonance imaging or ultrasound. The secondary outcomes included visual analog scale for pain, American Shoulder and Elbow Surgeons score, and University of California at Los Angeles score, and forward elevation. Studies were divided into augmentation and bridging groups, and outcomes were compared statistically. RESULTS: Twelve studies with 13 study groups were included: 167 repairs in the augmentation group and 247 repairs in the bridging group. For augmentation and bridging groups, the mean age was 62.2 and 62.8 years and the mean follow-up was 28.5 and 37.7 months, respectively. The estimated healing rates were 64.0% for augmentation and 77.9% for bridging. Although both procedures had improved clinical outcomes, no statistical difference between groups was detected except lower visual analog scale in the bridging group at follow-up. CONCLUSIONS: Bridging grafts had no significant difference in healing or clinical outcomes when compared with a graft used for augmentation. Bridging grafts may be considered for this difficult patient population with large to massive rotator cuff tears. LEVEL OF EVIDENCE: Level IV, systematic review of Level II to IV studies. PMID- 27956235 TI - Valproic acid protects against MPP+-mediated neurotoxicity in SH-SY5Y Cells through autophagy. AB - Autophagy is a common physiological activity in cells. Studies show that dysregulation of autophagy is involved in the pathogenesis of Parkinson's disease (PD). As a commonly used anti-epileptic drug, valproic acid (VPA) has shown neuroprotective effects in PD. The aim of this study was to explore whether the autophagy induced by VPA involved in the neuroprotective effects in PD cell model. We found that VPA treatment counteracted MPP+-caused autophagic flux impairment. Forthermore, VPA could alleviates apoptosis, reduce reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) loss caused by MPP+. And we also observed that VPA up-regulated the active caspase-3 and Bcl 2/Bax ratio and inhibited cytochrome c (Cyt c) release from mitochondria to the cytoplasm. However, 3-Methyladenine (3-MA) or bafilomycin A1 (Baf-A1), blockers for autophagy, partially weakened the neuroprotective effect of VPA. Our findings suggest that the neuroprotective effect of VPA on neuroblastoma cells may partially result from inducing autophagy and related to the inhibition of the mitochondrial apoptosis pathway. PMID- 27956234 TI - Osteochondral Lesions of the Talus and Autologous Matrix-Induced Chondrogenesis: Is Age a Negative Predictor Outcome? AB - PURPOSE: To assess and evaluate healing and functional outcomes after arthroscopic talus autologous matrix-induced chondrogenesis (AT-AMIC) in 2 age groups: patients older than 33 years versus patients 33 years or younger. METHODS: A total of 31 patients, of whom 17 were 33 years or younger (G1) and 14 older than 33 years (G2), were evaluated. All patients were treated with AT-AMIC repair for osteochondral talar lesion. Magnetic resonance imaging (MRI) and computed tomography (CT)-scan evaluations, as well as clinical evaluations measured by the visual analog scale (VAS) score for pain, American Orthopaedic Foot and Ankle Society Ankle and Hindfoot score (AOFAS), and Short Form-12, were performed preoperatively (T0) and at 6 (T1), 12 (T2), and 24 (T3) months postoperatively. RESULTS: G1 consisted of 17 patients (mean age: 25 years, standard deviation: +/-5), whereas G2 consisted of 14 patients (mean age: 47 years, standard deviation: +/-9). In both groups, we found a significant difference for clinical and radiological parameters with the analysis of variance for repeated measures through 4 time points (P < .001). In G1, AOFAS improved significantly between T0 and T1 (P = .025) and T1 and T2 (P = .011); CT showed a significant decrease between T1 and T2 (P = .003) and T2 and T3 (P < .0001), whereas MRI reduced significantly at each follow-up. In G2, AOFAS improved between T0 and T1 (P = .011) and T2 and T3 (P = .018); CT decreased between T1 and T2 (P = .025), whereas MRI showed a reduction between T1 and T2 (P = .029) and T2 and T3 (P = .006). AOFAS in G1 was significantly higher at T0 (P = .017), T2 (P = .036), and T3 (P = .039) compared with G2. A negative linear correlation between AOFAS and VAS at T1 (R = -0.756), T2 (R = -0.637), and T3 (R = -0.728) was found in G1, whereas in G2, AOFAS was negatively correlated with VAS at T1 (R = -0.702). CONCLUSIONS: The study revealed that osteochondral lesions of the talus were characterized by similar sizes and features, both in young and old patients. We conclude that AT-AMIC can be considered a safe and reliable procedure that allows effective healing, regardless of age, with a significant clinical improvement; in particular, clinical results are related to starting conditions of the ankle. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 27956236 TI - New insights into sucking, swallowing and breathing central generators: A complexity analysis of rhythmic motor behaviors. AB - Sucking, swallowing and breathing are dynamic motor behaviors. Breathing displays features of chaos-like dynamics, in particular nonlinearity and complexity, which take their source in the automatic command of breathing. In contrast, buccal/gill ventilation in amphibians is one of the rare motor behaviors that do not display nonlinear complexity. This study aimed at assessing whether sucking and swallowing would also follow nonlinear complex dynamics in the newborn lamb. Breathing movements were recorded before, during and after bottle-feeding. Sucking pressure and the integrated EMG of the thyroartenoid muscle, as an index of swallowing, were recorded during bottle-feeding. Nonlinear complexity of the whole signals was assessed through the calculation of the noise limit value (NL). Breathing and swallowing always exhibited chaos-like dynamics. The NL of breathing did not change significantly before, during or after bottle-feeding. On the other hand, sucking inconsistently and significantly less frequently than breathing exhibited a chaos-like dynamics. Therefore, the central pattern generator (CPG) that drives sucking may be functionally different from the breathing CPG. Furthermore, the analogy between buccal/gill ventilation and sucking suggests that the latter may take its phylogenetic origin in the gill ventilation CPG of the common ancestor of extant amphibians and mammals. PMID- 27956237 TI - The ameliorative effects of exercise on cognitive impairment and white matter injury from blood-brain barrier disruption induced by chronic cerebral hypoperfusion in adolescent rats. AB - Vascular dementia is the progressive change in blood vessels that leads to neuronal injuries in vulnerable areas induced by chronic cerebral hypoperfusion (CCH). CCH induces disruption of blood-brain barrier (BBB), and this BBB disruption can initiate the cognitive impairment and white matter injury. In the present study, we evaluated the effect of treadmill exercise on the cognitive impairment, white matter injury, and BBB disruption induced by CCH. Vascular dementia was induced by permanent bilateral common carotid arteries occlusion (BCCAO) in rats. The rats in the exercise group were made to run on a treadmill for 30min once a day for 14 weeks, starting 4 weeks after birth. Our results revealed that treadmill exercise group was alleviated the cognitive impairment and myelin degradation induced by CCH. The disruption of BBB after CCH indicates degradation of occludin, zonula occluden-1 (ZO-1), and up-regulation of matrix metalloproteinases (MMPs). Treadmill exercise may provide protective effects on BBB disruption from degradation of occludin, ZO-1, and overexpression of MMP-9 after CCH. These findings suggest that treadmill exercise ameliorates cognitive impairment and white matter injury from BBB disruption induced by CCH in rats. The present study will be valuable for means of prophylactic and therapeutic intervention for patients with CCH. PMID- 27956238 TI - Enhanced dopaminergic neurotoxicity mediated by MPTP in IL-32beta transgenic mice. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by prominent loss of the nigral dopaminergic neurons and motor symptoms, such as resting tremor and bradykinesia. Evidence suggests that neuroinflammation may play a critical role in PD pathogenesis. Interleukin (IL)-32 is a newly identified proinflammatory cytokine, which regulates innate and adaptive immune responses by activating p38 MAPK and NF-kappaB signaling pathways. The cytokine has been implicated in cancers and autoimmune, inflammatory, and infectious diseases. In this study, we attempted to identify the effects of IL-32beta on dopaminergic neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), using IL-32beta transgenic mice. Male wild type and IL 32beta transgenic mice received intraperitoneal injections of vehicle or MPTP (15 mg/kg * 4). Immunohistochemistry showed that overexpression of IL-32beta significantly increased MPTP-mediated loss of dopaminergic neurons in the substantia nigra and deletion of tyrosine hydroxylase-positive fibers in the striatum. Dopamine depletion in the striatum and deficit in locomotor activity were enhanced in IL-32beta transgenic mice. These results were accompanied by higher neuroinflammatory responses in the brains of transgenic mice. Finally, we found that IL-32beta exaggerated MPTP-mediated activation of p38 MAPK and JNK pathways, which have been shown to be involved in MPTP neurotoxicity. These results suggest that IL-32beta exacerbates MPTP neurotoxicity through enhanced neuroinflammatory responses. PMID- 27956239 TI - RNAcompete methodology and application to determine sequence preferences of unconventional RNA-binding proteins. AB - RNA-binding proteins (RBPs) participate in diverse cellular processes and have important roles in human development and disease. The human genome, and that of many other eukaryotes, encodes hundreds of RBPs that contain canonical sequence specific RNA-binding domains (RBDs) as well as numerous other unconventional RNA binding proteins (ucRBPs). ucRBPs physically associate with RNA but lack common RBDs. The degree to which these proteins bind RNA, in a sequence specific manner, is unknown. Here, we provide a detailed description of both the laboratory and data processing methods for RNAcompete, a method we have previously used to analyze the RNA binding preferences of hundreds of RBD-containing RBPs, from diverse eukaryotes. We also determine the RNA-binding preferences for two human ucRBPs, NUDT21 and CNBP, and use this analysis to exemplify the RNAcompete pipeline. The results of our RNAcompete experiments are consistent with independent RNA-binding data for these proteins and demonstrate the utility of RNAcompete for analyzing the growing repertoire of ucRBPs. PMID- 27956240 TI - Array-in-well binding assay for multiparameter screening of phage displayed antibodies. AB - Phage display is a well-established and powerful tool for the development of recombinant antibodies. In a standard phage display selection process using a high quality antibody phage library, a large number of unique antibody clones can be generated in short time. However, the pace of the antibody discovery project eventually depends on the methodologies used in the next screening phase to identify the clones with the most promising binding characteristics e.g., in terms of specificity, affinity and epitope. Here, we report an array-in-well binding assay, a miniaturized and multiplexed immunoassay that integrates the epitope mapping to the evaluation of the binding activity of phage displayed antibody fragments in a single well. The array-in-well assay design used here incorporates a set of partially overlapping 15-mer peptides covering the complete primary sequence of the target antigen, the intact antigen itself and appropriate controls printed as an array with 10*10 layout at the bottom of a well of a 96 well microtiter plate. The streptavidin-coated surface of the well facilitates the immobilization of the biotinylated analytes as well-confined spots. Phage displayed antibody fragments bound to the analyte spots are traced using anti phage antibody labelled with horseradish peroxidase for tyramide signal amplification based highly sensitive detection. In this study, we generated scFv antibodies against HIV-1 p24 protein using a synthetic antibody phage library, evaluated the binders with array-in-well binding assay and further classified them into epitopic families based on their capacity to recognize linear epitopes. The array-in-well assay enables the integration of epitope mapping to the screening assay for early classification of antibodies with simplicity and speed of a standard ELISA procedure to advance the antibody development projects. PMID- 27956241 TI - Real-time and quantitative fluorescent live-cell imaging with quadruplex-specific red-edge probe (G4-REP). AB - The development of quadruplex-directed molecular diagnostic and therapy rely on mechanistic insights gained at both cellular and tissue levels by fluorescence imaging. This technique is based on fluorescent reporters that label cellular DNA and RNA quadruplexes to spatiotemporally address their complex cell biology. The photophysical characteristics of quadruplex probes usually dictate the modality of cell imaging by governing the selection of the light source (lamp, LED, laser), the optical light filters and the detection modality. Here, we report the characterizations of prototype from a new generation of quadruplex dye termed G4 REP (for quadruplex-specific red-edge probe) that provides fluorescence responses regardless of the excitation wavelength and modality (owing to the versatility gained through the red-edge effect), thus allowing for diverse applications and most imaging facilities. This is demonstrated by cell images (and associated quantifications) collected through confocal and multiphoton microscopy as well as through real-time live-cell imaging system over extended period, monitoring both non-cancerous and cancerous human cell lines. Our results promote a new way of designing versatile, efficient and convenient quadruplex-reporting dyes for tracking these higher-order nucleic acid structures in living human cells. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. PMID- 27956242 TI - Fusaric acid induces oxidative stress and apoptosis in human cancerous oesophageal SNO cells. AB - Oesophageal cancer (OC) is a global problem incrementally incident among black South African males. The high incidence of OC may be due to the consumption of corn as a staple, often contaminated with mycotoxins. Fusaric acid (FA), a neglected mycotoxin, is known to disrupt mitochondrial energy metabolism, chelates divalent metal cations and induces cell death in plants. This study investigated FA-induced cytotoxicity and apoptotic induction in the SNO OC cell line. Cells were treated with FA (IC50 = 78.81 MUg/mL; 24 h; MTT assay) and assayed for oxidative stress and membrane damage (TBARS, LDH cytotoxicity and glutathione), apoptotic induction (ATP levels, caspase-8, -9, -3/7 activities) (Luminometry), single strand DNA and nuclear fragmentation (Comet and Hoechst assay). Additionally, relative expression of pro- and anti-apoptotic proteins were determined (Western Blotting). Significant antioxidant depletion was consistent with a concomitant increase in ROS-induced lipid peroxidation and extracellular LDH levels. FA induced apoptosis by significantly increasing Bax expression and caspase-8, -9 and -3/7 activities whilst decreasing ATP levels and Bcl-2 expression. Further, FA significantly increased comet tail lengths, PARP-1 expression and late stage apoptotic body formation in SNO cells. This study shows that FA is cytotoxic and induces increased apoptosis in SNO cells. PMID- 27956243 TI - Physicochemical characterization of commercial freeze-dried snake antivenoms. AB - Freeze-drying is a process used to improve the stability of pharmaceutical proteins, including snake antivenoms. This additional step confers these with a higher stability in comparison to liquid formulations, especially in tropical regions where high temperatures could affect the activity of immunoglobulins. Currently, the knowledge about freeze-drying process conditions for snake antivenoms is very limited. Some of the scarce scientific works on this subject reported reconstitution times up to 90 min for these preparations, which could imply a delay in the beginning of the antivenom therapy at the clinical setting. Therefore there is a reasonable concern about whether freeze-dried antivenoms exhibit the desired attributes for solid pharmaceutical proteins. In this work, a physicochemical characterization of seven commercial freeze-dried snake antivenoms was performed based on tests recommended by the World Health Organization (WHO). No significant differences were observed between the products regarding macroscopic appearance of the solid cakes, reconstitution times, residual humidity and monomers content. On the other hand, total protein concentration, turbidity and electrophoretic profile were different among samples. Microscopic analysis by scanning electron microscopy showed no collapsed structure and, instead, most of the samples showed a characteristic protein morphology composed of smooth plates and channels. All the parameters tested in this study were according to literature recommendations and evidenced that, in spite of slight variations found for some products, formulation and freeze-drying conditions chosen by manufacturers are adequate to prevent aggregation and generate, in physicochemical terms, freeze-dried antivenoms of acceptable quality. PMID- 27956244 TI - Sublethal doses of dinophysistoxin-1 and okadaic acid stimulate secretion of inflammatory factors on innate immune cells: Negative health consequences. AB - One of the proposed mechanisms to explain why Diarrhetic Shellfish Poison (DSP) toxins are tumor promoters is founded on the capacity of these toxins to increase TNF-alpha secretion. Although macrophages are the principal cells in the activation of the inflammatory response, the immune profile that Okadaic acid (OA) and Dinophysistoxin-1 (DTX-1) trigger in these cells has not been fully explored. We have therefore investigated the effect of various concentrations of both toxins on the activity of several inflammatory factors. Our results demonstrate that OA and DTX-1, at sublethal doses, stimulate secretion of inflammatory factors. Nevertheless DTX-1 was more potent than OA in increasing TNF-alpha and IL-6 as well as their dependent chemokines KC, MCP-1, LIX, MIP-1 alpha, MIP-1 beta and MIP-2. On the other hand, secretion of IFN-gamma and the anti-inflammatory cytokines, IL-4 and IL-10, was unaffected. In addition, DTX-1 also raises matrix metalloproteinase-9 (MMP-9) activity. In this study, for the first time the effect of OA and DTX-1 over the secretion of pro-inflammatory and carcinogenic signals in macrophages are compared, showing that DTX-1 is ten times more potent that OA. The inflammatory profile produced by DTX-1 is shown for the first time. The safe limit regulation should be changed to DSP toxins zero tolerance in the shellfish to be consumed by humans. PMID- 27956245 TI - Neurotoxins in a water supply reservoir: An alert to environmental and human health. AB - Reservoirs are important source of power generation, recreation, and water supply. Nevertheless, human activities have favored the bloom of toxic cyanobacteria in many reservoirs, which has resulted in environmental, social, and economic problems. This study aims to evaluate the water quality of a reservoir in South Brazil through the analysis of cyanobacteria and cyanotoxins PSTs (Paralytic Shellfish Toxins) and biomarkers of environmental contamination in fish. For this purpose, water samples and fish (Geophagus brasiliensis) (Perciformes: Cichlidae) were collected from September 2013 to May 2014. The fish G. brasiliensis were separated in two groups. The first one "site group" was euthanized after the sampling and their weight and length were measured. The blood, brain, muscle and liver were collected for chemical, biochemical and genetics biomarkers analysis. The second group "depuration group" was submitted to depuration experiment for 40 days in clean water. After that, the same procedures as for the first group were carried out. Cylindrospermopsis raciborskii was the dominant cyanobacteria found in the reservoir, and it showed a density above the recommended limit by Brazilian legislation of 20,000 cells/mL. Results showed that the fish accumulate PSTs in the Reservoir and these were not eliminated after 40 days. The biochemical and genotoxic biomarkers showed a significant difference between "site groups" and "depuration groups", which suggests a recovery of the antioxidant system and a reduction of cellular damage after 40 days in clean water. In conjunction with results reported earlier by others, Alagados Reservoir, in South Brazil, appears to have a persistent contamination of cyanotoxins. Moreover, the mixture of contaminants which may be present in the water body can explain the seasonal differences in fish at the sampled points. PMID- 27956246 TI - Global profiling of viral and cellular non-coding RNAs in Epstein-Barr virus induced lymphoblastoid cell lines and released exosome cargos. AB - The human EBV-transformed lymphoblastoid cell line (LCL), obtained by infecting peripheral blood monocular cells with Epstein-Barr Virus, has been extensively used for human genetic, pharmacogenomic, and immunologic studies. Recently, the role of exosomes has also been indicated as crucial in the crosstalk between EBV and the host microenvironment. Because the role that the LCL and LCL exosomal cargo might play in maintaining persistent infection, and since little is known regarding the non-coding RNAs of LCL, the aim of our work was the comprehensive characterization of this class of RNA, cellular and viral miRNAs, and cellular lncRNAs, in LCL compared with PBMC derived from the same donors. In this study, we have demonstrated, for the first time, that all the viral miRNAs expressed by LCL are also packaged in the exosomes, and we found that two miRNAs, ebv-miR BART3 and ebv-miR-BHRF1-1, are more abundant in the exosomes, suggesting a microvescicular viral microRNA transfer. In addition, lncRNA profiling revealed that LCLs were enriched in lncRNA H19 and H19 antisense, and released these through exosomes, suggesting a leading role in the regulation of the tumor microenvironment. PMID- 27956247 TI - Computerised insulin dosing calculators for the management of continuous insulin infusions after cardiac surgery: A systematic review and meta-analysis. AB - OBJECTIVES: To investigate the effectiveness of computerised insulin dosing calculators for the management of continuous insulin infusions in adult patients who underwent cardiac surgery. METHOD: A systematic review was conducted. The CINAHL, MEDLINE and Cochrane databases were searched for primary studies that compared a computerised insulin dosing calculator to a paper protocol. The main outcome measures were mean Blood Glucose Level (BGL), time to achieve BGL target range, time spent within BGL target range, the incidence of hyperglycaemia and the incidence of hypoglycaemia. RESULTS: Five studies were included in the final review. Pooled data demonstrated significant improvements in mean BGL (MD -14.24, 95% CI -26.93 to -1.55), p=0.03 and significantly lower rates of hypoglycaemia (OR 0.038, 95% CI: 0.16-0.90), p=0.03 amongst the computer calculator groups in comparison to the paper protocol groups. No significant difference in the incidence of severe hypoglycaemia was demonstrated (OR 0.21, 95% CI 0.02-1.79), p=0.15. No difference was found in time (hours) to reach target blood glucose range (MD -1.47, 95% CI -3.75 to 0.81), p=0.21. CONCLUSION: There is some evidence to support the use of computerised insulin dosing calculators for insulin infusion management within critical care environments. PMID- 27956248 TI - Individualized cryoballoon energy pulmonary vein isolation guided by real-time pulmonary vein recordings, the randomized ICE-T trial. AB - BACKGROUND: The ideal energy dosing remains unclear in second-generation cryoballoon (CB) pulmonary vein isolation (PVI). We aimed to investigate the effect of an individualized dosing strategy based on time to PVI (TTI). OBJECTIVE: The purpose of this study was to prospectively investigate the safety and efficacy of individualized PVI using the second-generation CB guided by real time pulmonary vein recordings. METHODS: Two groups were prospectively randomized: ICE-T group: if TTI <75 seconds, then no bonus freeze; and control group: acute PVI followed by 1 empiric bonus freeze. Freeze duration was set to 240 seconds. The primary end point was single procedure sinus rhythm after 12 months (blanking period 3 months). Secondary end points included procedural data, complications, and biomarker release. RESULTS: In total, 100 patients with paroxysmal atrial fibrillation were randomized. The primary end point was not different (88% vs 82%). Procedure and fluoroscopy times were significantly shorter in the ICE-T group (70 +/- 20 minutes vs 89 +/- 21 minutes; P < .001 and 10.6 +/- 3.9 minutes vs 12.7 +/- 5.5 minutes; P = .03). More complications occurred in the control group (n = 9 vs n = 3) (persistent phrenic nerve injury: n = 1 vs n = 0; transient phrenic nerve injury: n = 5 vs n = 2; esophageal lesions: n = 3 vs n = 1). Postablation troponin T levels were not different (ICE T group vs control group: 1035 +/- 402 ng/L vs 1219 +/- 509 ng/L; P = .099), whereas a significantly lower lactic acid dehydrogenase release was observed in the ICE-T group (259 +/- 47 U/L vs 282 +/- 57 U/L; P = .038). Multivariate analysis identified a mean TTI of >43 seconds as the only independent predictor of recurrent atrial tachyarrhythmia. CONCLUSION: The individualized CB PVI strategy allows faster atrial fibrillation ablation without affecting the favorable clinical outcome. A short TTI appears to predict freedom from recurrent atrial tachyarrhythmia. PMID- 27956249 TI - To the Editor- Misuse of null hypothesis testing: Analysis of biophysical model simulations. PMID- 27956250 TI - Maternal di-(2-ethylhexyl) phthalate exposure during pregnancy causes fetal growth restriction in a stage-specific but gender-independent manner. AB - Di (2-ethylhexyl) phthalate (DEHP) is male developmental toxicant that impairs testis development with reduced anogenital distance. The present study aimed to investigate whether maternal DEHP exposure during pregnancy causes intrauterine growth restriction (IUGR) in a gender-specific manner and to identify the critical window of DEHP-induced fetal IUGR. Pregnant mice were administered with DEHP (0, 50 or 200mg/kg) by gavage. Fetal IUGR was observed not only in males but also in females when litters were exposed to DEHP on gestational day (GD)0-GD17. Interestingly, fetal weight and crown-rump length were reduced, markedly in dams with DEHP on GD13-GD17, slightly in dams with on GD7-GD12, but not in dams with on GD0-GD6. Further analysis showed that maternal DEHP exposure on GD7-GD12 inhibited cell proliferation, lowered placental weight, and reduced blood sinusoid area in placental labyrinth layer. These results suggest that maternal DEHP exposure induces IUGR in a stage-specific but gender-independent manner. PMID- 27956252 TI - Clinical Features, Management Considerations and Outcomes in Case Series of Patients with Parasellar Intracranial Aneurysms Undergoing Anterior Skull Base Surgery. AB - BACKGROUND: The coincidence of parasellar aneurysms (IAs) and anterior skull base (ASB) lesions, while rare, presents a management challenge. IAs embedded within, or adjacent to, ASB lesions are at risk in the perioperative period and may have unique presentations, natural histories, and outcomes. The objective of this study was to outline management options and nuances in patients with coexisting IAs and ASB lesions. METHODS: We retrospectively evaluated all patients who presented for management of IAs and ASB lesions from January 2006 to January 2014. Medical charts and imaging were reviewed for patient, tumor and IA characteristics, pathology, operative findings, complications, and outcomes. RESULTS: Of 13 patients included in the study, 11 had histologically proven or presumed pituitary macroadenomas. The majority of cases presented with visual and endocrine deficits, and the median maximal tumor diameter was 3.1 cm. There were 17 IAs, all located in the parasellar area. Endovascular treatment of the IA was performed before tumor resection in 2 cases. Transsphenoidal resection was performed before IA occlusion in 1 case, and intraoperative vascular injury occurred in 2 cases. The median follow-up was 36 months. CONCLUSIONS: Management decisions for patients with coincident IA and ASB lesions require careful, individualized treatment plans. Coil embolization is well tolerated and does not delay surgery, except in cases requiring stent placement. Inadvertent intraoperative rupture of an adjacent IA during anterior skull base surgery may be treated with emergent coil embolization, flow diversion, or carotid sacrifice, but adequate preoperative planning can reduce this risk. PMID- 27956251 TI - The simultaneous detection of trivalent & hexavalent chromium in exhaled breath condensate: A feasibility study comparing workers and controls. AB - The analytical method outlined in this feasibility study has been used to show that trivalent chromium (Cr(III)) and hexavalent chromium (Cr(VI)) can be detected and measured in exhaled breath condensate (EBC) samples. EBC samples and urine samples were collected from a cohort of 58 workers occupationally exposed to hexavalent chromium compounds and 22 unexposed volunteers (control group). Levels of Cr(III) and Cr(VI) were determined in EBC samples and total chromium levels were determined in urine samples. Pre and post working week samples for both EBC and urine were collected in tandem. Total chromium in urine samples was analysed by inductively coupled plasma mass spectrometry (ICP-MS). Analysis of Cr(III) and Cr(VI) in EBC samples used a hyphenated micro liquid chromatography (MULC) system coupled to an ICP-MS. Separation was achieved using an anion exchange micro-sized column. The results showed that the occupationally exposed workers had significantly higher levels of Cr(III) and Cr(VI) in their EBC samples than the control group, as well as higher levels of total chromium in their urine samples. However, for the exposed workers no significant difference was found between pre and post working week EBC samples for either Cr(III) or Cr(VI). This study has established that Cr(III) and Cr(VI) can simultaneously be detected and measured in 'real' EBC samples and will help in understanding inhalation exposure. PMID- 27956253 TI - Surgical Treatment of Skull Base Tumors, Extending to Craniovertebral Junction. AB - OBJECTIVE: To conduct a comparative analysis of 2 groups of patients with skull base chordomas extending onto the craniovertebral junction, who underwent surgical treatment using extracranial approaches with and without craniocervical fusion. METHODS: The study group included 29 patients with skull base chordomas, extending to the craniovertebral junction, who were operated on from 2000 to 2015. The patients underwent the following surgical treatment: posterior craniocervical fusion followed by tumor removal using transoral and combined transoral and transnasal approaches. The reference group included 21 patients with the same disease, who underwent tumor removal surgery using the transoral approach without craniocervical fusion. RESULTS: In the study group, in 27.5% of all cases (8 patients), the tumors were removed radically; in 65.5% of all cases (19 patients), the tumors were removed subtotally; and in 7% of all cases (2 patients), the tumors were removed partially. In the reference group, the extent of surgical radicality was as follows: radical, 0%; subtotal, 19% (4 cases); partial, 81% (17 cases). CONCLUSIONS: Use of the proposed surgical technique in clinical practice may help increase the radicality of tumor excisions, decrease the number of postoperative complications, accelerate the rehabilitation process, and increase the quality of life in patients with skull base tumors extending to the craniovertebral junction. PMID- 27956254 TI - BRAF-Mutated Pleomorphic Xanthoastrocytoma of the Spinal Cord with Eventual Anaplastic Transformation. AB - BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is an uncommon, primary neoplasm of the central nervous system with a relatively favorable prognosis. Most patients are managed with surgery alone and experience significant long-term survival. PXAs occur most commonly along the superficial surfaces of the temporal lobes. Although these tumors may occur in other regions of the brain, their origin within the spinal cord is rare, and it is unclear whether spinal cord PXAs should be managed differently from their intracranial counterparts. CASE DESCRIPTION: We describe a 31-year-old patient with a PXA of spinal cord origin who despite surgery, radiation, and multiple chemotherapy regimens experienced anaplastic transformation of his tumor and died of extensive leptomeningeal progression. CONCLUSIONS: To our knowledge, our patient represents the seventh reported case of PXA of the spinal cord but is the first described to have a BRAF mutation. Specifically, both the initial and recurrent tumors of the patient showed the same BRAF V600E mutation, which refutes previous suggestions that BRAF mutations may be limited to intracranial PXAs and also shows that BRAF mutations may occur earlier in PXA tumorigenesis. PMID- 27956255 TI - Tumor-associated autoantibodies against Fascin as a novel diagnostic biomarker for esophageal squamous cell carcinoma. AB - BACKGROUND AND OBJECTIVE: Autoantibodies against tumor-associated antigens (TAAs) have been found in many kinds of cancers, and might serve as biomarkers for early cancer diagnosis. The present study was carried out to test if there is any relation between autoantibodies against Fascin and esophageal squamous cell carcinoma (ESCC). METHODS: One hundred and forty-nine patients with ESCC and 98 control subjects were recruited in the study. The levels of circulating autoantibodies against Fascin were measured by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) was used to calculate diagnostic accuracy. RESULT: The levels of autoantibodies against Fascin in patients with ESCC were significantly higher than in control subjects (P<0.001). Measurement of autoantibodies against Fascin provided an area under the curve (AUC) of 0.636, [95% confidence interval (CI): 0.568-0.704] 24.8% sensitivity (95% CI: 18.3% 37.2%) and 99.0% specificity (95% CI: 93.6%-99.9%). Moreover, serum level of autoantibodies against Fascin in early-stage ESCC was significantly higher than that of normal controls (P<0.05). The positive rates of autoantibodies against Fascin were correlated with age (P<0.05), but not with gender, tumor size, tumor site, histological grade, T stage, N stage or TNM stage (P>0.05). CONCLUSIONS: Our results suggest that Fascin autoantibody may be a potential biomarker for the early detection of ESCC. PMID- 27956256 TI - Circulating microRNAs: Possible role as non-invasive diagnostic biomarkers in liver disease. AB - Liver is the central organ for metabolism and the hepatocytes metabolize several drugs, hepatotoxins, alcohol, etc. Continuous exposure of the hepatocytes to these toxins result in various chronic diseases, such as alcoholic liver disease, non-alcoholic fatty liver disease, viral hepatitis and hepatocellular carcinoma. Although several diagnostic methods, such as serum markers, liver biopsy or imaging studies are currently available, most of these are either invasive or detect the disease at advanced stages. Hence, there is a need for new molecular markers that can be used for early detection of the disease. MicroRNAs (miRNAs) are naturally occurring, 20-22 nucleotide long, non-coding RNA molecules that regulate the gene expression at post-transcriptional levels, thereby modulating various biological functions. Their expression is deregulated under pathological conditions, and recent studies showed that they are secreted and can be detected in various body fluids. Since the cellular changes occur at earlier stages of the disease, detecting miRNAs in the body fluids could make them as potential novel biomarkers. Albeit, the difficulties in standardization procedures, cost and availability should be addressed before using them in the clinical arena. This review highlights the possible role of secreted miRNAs to use as early non invasive diagnostic markers for liver disease. PMID- 27956258 TI - Extended molecular phylogenetics and revised systematics of Malagasy scincine lizards. AB - Among the endemic biota of Madagascar, skinks are a diverse radiation of lizards that exhibit a striking ecomorphological variation, and could provide an interesting system to study body-form evolution in squamate reptiles. We provide a new phylogenetic hypothesis for Malagasy skinks of the subfamily Scincinae based on an extended molecular dataset comprising 8060bp from three mitochondrial and nine nuclear loci. Our analysis also increases taxon sampling of the genus Amphiglossus by including 16 out of 25 nominal species. Additionally, we examined whether the molecular phylogenetic patterns coincide with morphological differentiation in the species currently assigned to this genus. Various methods of inference recover a mostly strongly supported phylogeny with three main clades of Amphiglossus. However, relationships among these three clades and the limb reduced genera Grandidierina, Voeltzkowia and Pygomeles remain uncertain. Supported by a variety of morphological differences (predominantly related to the degree of body elongation), but considering the remaining phylogenetic uncertainty, we propose a redefinition of Amphiglossus into three different genera (Amphiglossus sensu stricto, Flexiseps new genus, and Brachyseps new genus) to remove the non-monophyly of Amphiglossus sensu lato and to facilitate future studies on this fascinating group of lizards. PMID- 27956257 TI - A report on extensive lateral genetic reciprocation between arsenic resistant Bacillus subtilis and Bacillus pumilus strains analyzed using RAPD-PCR. AB - The study involves isolation of arsenic resistant bacteria from soil samples. The characterization of bacteria isolates was based on 16S rRNA gene sequences. The phylogenetic consanguinity among isolates was studied employing rpoB and gltX gene sequence. RAPD-PCR technique was used to analyze genetic similarity between arsenic resistant isolates. In accordance with the results Bacillus subtilis and Bacillus pumilus strains may exhibit extensive horizontal gene transfer. Arsenic resistant potency in Bacillus sonorensis and high arsenite tolerance in Bacillus pumilus strains was identified. The RAPD-PCR primer OPO-02 amplified a 0.5kb DNA band specific to B. pumilus 3ZZZ strain and 0.75kb DNA band specific to B. subtilis 3PP. These unique DNA bands may have potential use as SCAR (Sequenced Characterized Amplified Region) molecular markers for identification of arsenic resistant B. pumilus and B. subtilis strains. PMID- 27956259 TI - The complete maternal and paternal mitochondrial genomes of Unio crassus: Mitochondrial molecular clock and the overconfidence of molecular dating. AB - The availability of a rapidly growing number of complete mitochondrial genome sequences provokes high confidence dating approaches. However, even if the congruence between mitochondrial and nuclear markers is reasonable, the resulting topologies are frequently questionable. The unique opportunity to study the evolutionary history of two independent mitochondrial genomes in one phylogenetic context exists in the freshwater mussels family Unionidae. The two lineages function under doubly uniparental inheritance since well before the emergence of the family. Despite the relatively high number of available complete sequences of maternally inherited genomes, comparative analyses are limited by the small number of sequences of counterpart paternally inherited genomes. We have sequenced for the first time the representative set of five sequences (two maternal and three paternal) from the species Unio crassus. Comparative analysis of the phylogenies reconstructed using relevant mitogenomic data available in GenBank (13 species in total) reveal that single - genome inferences are congruent only if the relaxed clock is assumed. PMID- 27956260 TI - Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas. AB - The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events that are involved in cell growth and proliferation or the contrary pathway of cell differentiation. Dysregulation of this pathway occurs in more than one-third of all malignancies, a process that has fostered the development of targeted Map kinase pathway inhibitors. Cutaneous melanomas, which arise from skin melanocytes, are the most aggressive form of skin cancer. Mutations that activate the Map kinase pathway occur in more than 90% of these melanomas. This has led to the development of the combination of dabrafenib and trametinib or vemurafenib and cobimetanib for the treatment of BRAF V600E mutant melanomas. Dabrafenib and vemurafenib target V600E/K BRAF mutants while trametinib and cobimetanib target MEK1/2. The latter two agents bind to MEK1/2 at a site that is adjacent to, but separate from, the ATP-binding site and are therefore classified as type III allosteric protein kinase inhibitors. These agents form a hydrogen bond with a conserved beta3 lysine and they make numerous hydrophobic contacts with residues within the alphaC-helix, the beta5 strand, and within the activation segment, regions of the protein kinase domain that exhibit greater diversity than those found within the ATP-binding site. One advantage of such allosteric inhibitors is that they do not have to compete with millimolar concentrations of cellular ATP, which most FDA approved small molecule competitive inhibitors such as imatinib must do. Owing to the wide spread activation of this pathway in numerous neoplasms, trametinib and cobimetinib are being studied in combination with other targeted and cytotoxic drugs in a variety of clinical situations. Except for BRAF and NRAS mutations, there are no other biomarkers correlated with treatment responses following MEK1/2 inhibition and the discovery of such biomarkers would represent an important therapeutic breakthrough. PMID- 27956261 TI - Advances in drug metabolism and pharmacogenetics research in Australia. AB - Metabolism facilitates the elimination, detoxification and excretion in urine or bile (as biotransformation products) of a myriad of structurally diverse drugs and other chemicals. The metabolism of drugs, non-drug xenobiotics and many endogenous compounds is catalyzed by families of drug metabolizing enzymes (DMEs). These include the hemoprotein-containing cytochromes P450, which function predominantly as monooxygenases, and conjugation enzymes that transfer a sugar, sulfate, acetate or glutathione moiety to substrates containing a suitable acceptor functional group. Drug and chemical metabolism, especially the enzymes that catalyse these reactions, has been the research focus of several groups in Australia for over four decades. In this review, we highlight the role of recent and current drug metabolism research in Australia, including elucidation of the structure and function of enzymes from the various DME families, factors that modulate enzyme activity in humans (e.g. drug-drug interactions, gene expression and genetic polymorphism) and the application of in vitro approaches for the prediction of drug metabolism parameters in humans, along with the broader pharmacological/clinical pharmacological and toxicological significance of drug metabolism and DMEs and their relevance to drug discovery and development, and to clinical practice. PMID- 27956262 TI - Advanced technologies charting a new path for traditional Chinese medicine drug discovery. PMID- 27956263 TI - Functional modulation of contralateral bias in early and object-selective areas after stroke of the occipital ventral cortices. AB - Object agnosia is a rare symptom, occurring mainly after bilateral damage of the ventral visual cortex. Most patients suffering from unilateral ventral lesions are clinically non-agnosic. Here, we studied the effect of unilateral occipito temporal lesions on object categorization and its underlying neural correlates in visual areas. Thirteen non-agnosic stroke patients and twelve control subjects performed an event-related rapid object categorization task in the fMRI scanner where images were presented either to the left or to the right of a fixed point. Eight patients had intact central visual fields within at least 10 degrees eccentricity while five patients showed an incomplete hemianopia. Patients made more errors than controls for both contra- and ipsilesional presentation, meaning that object categorization was impaired bilaterally in both patient groups. The activity in cortical visual areas is usually higher when a stimulus is presented contralaterally compared to presented ipsilaterally (contralateral bias). A region of interest analysis of early visual (V1-V4) and object-selective areas (lateral occipital complex, LOC; fusiform face area, FFA; and parahippocampal place area, PPA) revealed that the lesioned-hemisphere of patients showed reduced contralateral bias in early visual areas and LOC. In contrast, literally no contralateral bias in FFA and PPA was found. These findings indicate disturbed processing in the lesioned hemisphere, which might be related to the processing of visually presented objects. Thus, unilateral occipito-temporal damage leads to altered contralateral bias in the lesioned hemisphere, which might be the cause of impaired categorization performance in both visual hemifields in clinically non-agnosic patients. We conclude that both hemispheres need to be functionally intact for unimpaired object processing. PMID- 27956265 TI - Single-reviewer electronic phenotyping validation in operational settings: Comparison of strategies and recommendations. AB - OBJECTIVE: Develop evidence-based recommendations for single-reviewer validation of electronic phenotyping results in operational settings. MATERIAL AND METHODS: We conducted a randomized controlled study to evaluate whether electronic phenotyping results should be used to support manual chart review during single reviewer electronic phenotyping validation (N=3104). We evaluated the accuracy, duration and cost of manual chart review with and without the availability of electronic phenotyping results, including relevant patient-specific details. The cost of identification of an erroneous electronic phenotyping result was calculated based on the personnel time required for the initial chart review and subsequent adjudication of discrepancies between manual chart review results and electronic phenotype determinations. RESULTS: Providing electronic phenotyping results (vs not providing those results) was associated with improved overall accuracy of manual chart review (98.90% vs 92.46%, p<0.001), decreased review duration per test case (62.43 vs 76.78s, p<0.001), and insignificantly reduced estimated marginal costs of identification of an erroneous electronic phenotyping result ($48.54 vs $63.56, p=0.16). The agreement between chart review and electronic phenotyping results was higher when the phenotyping results were provided (Cohen's kappa 0.98 vs 0.88, p<0.001). As a result, while accuracy improved when initial electronic phenotyping results were correct (99.74% vs 92.67%, N=3049, p<0.001), there was a trend towards decreased accuracy when initial electronic phenotyping results were erroneous (56.67% vs 80.00%, N=55, p=0.07). Electronic phenotyping results provided the greatest benefit for the accurate identification of rare exclusion criteria. DISCUSSION: Single-reviewer chart review of electronic phenotyping can be conducted more accurately, quickly, and at lower cost when supported by electronic phenotyping results. However, human reviewers tend to agree with electronic phenotyping results even when those results are wrong. Thus, the value of providing electronic phenotyping results depends on the accuracy of the underlying electronic phenotyping algorithm. CONCLUSION: We recommend using a mix of phenotyping validation strategies, with the balance of strategies based on the anticipated electronic phenotyping error rate, the tolerance for missed electronic phenotyping errors, as well as the expertise, cost, and availability of personnel involved in chart review and discrepancy adjudication. PMID- 27956266 TI - What's Ideal? A case study exploring handoff routines in practice. AB - BACKGROUND: Handoffs of care in the healthcare system between responsible providers have traditionally been conceptualized and studied at the point of patient transfer. Thus, clinical practice and associated information systems are designed with the concept of the handoff as a solitary event. This viewpoint does not consider the routine activities necessary for a successful handoff. We propose expanding the analysis of the handoff beyond the single point of transfer to include a routine of interrelated activities leading up to the transfer of responsibility. We used this expanded definition of handoffs to identify exceptions from standard practice as identified by ideal-type handoff routines. METHOD: We used an ethnographic case method to study handoffs in an interventional cardiology unit in a Midwestern community hospital. This involved examining handoffs and their supporting routines. We conducted thematic analysis of the handoffs using NVivo, a qualitative software analysis program. These analyses include categorization of the types and causes of differences in practice and exceptions from ideal-type handoffs. RESULTS: Observed handoffs that took place within the clinical unit did not consistently align with the ideal type routine, yet this variation did not necessarily lead to exceptions. However, for handoffs between clinical units, although more likely to follow the ideal type routine, differences from the standardized routine more often led to exceptions. We found that problems with performing the routine activities leading up to the handoff and the context in which the handoff occurred affected whether the handoff was successful. CONCLUSIONS: Considering the handoff as a routine rather than simply the point of transition gives broader insight about how care transitions function. Such consideration helps clinicians better understand how variations occur and how differences from ideal-type handoffs can lead to potential exceptions such as missing information. This analysis can be used to develop information systems that better support handoffs. PMID- 27956264 TI - 2016 Annual Report of The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. AB - BACKGROUND: The Society of Thoracic Surgeons (STS)/American College of Cardiology Transcatheter Valve Therapy (TVT) Registry captures all procedures with Food and Drug Administration-approved transcatheter valve devices performed in the United States, and is mandated as a condition of reimbursement by the Centers for Medicaid & Medicare Services. OBJECTIVES: This annual report focuses on patient characteristics, trends, and outcomes of transcatheter aortic and mitral valve catheter-based valve procedures in the United States. METHODS: We reviewed data for all patients receiving commercially approved devices from 2012 through December 31, 2015, that are entered in the TVT Registry. RESULTS: The 54,782 patients with transcatheter aortic valve replacement demonstrated decreases in expected risk of 30-day operative mortality (STS Predicted Risk of Mortality [PROM]) of 7% to 6% and transcatheter aortic valve replacement PROM (TVT PROM) of 4% to 3% (both p < 0.0001) from 2012 to 2015. Observed in-hospital mortality decreased from 5.7% to 2.9%, and 1-year mortality decreased from 25.8% to 21.6%. However, 30-day post-procedure pacemaker insertion increased from 8.8% in 2013 to 12.0% in 2015. The 2,556 patients who underwent transcatheter mitral leaflet clip in 2015 were similar to patients from 2013 to 2014, with hospital mortality of 2% and with mitral regurgitation reduced to grade <=2 in 87% of patients (p < 0.0001). The 349 patients who underwent mitral valve-in-valve and mitral valve-in ring procedures were high risk, with an STS PROM for mitral valve replacement of 11%. The observed hospital mortality was 7.2%, and 30-day post-procedure mortality was 8.5%. CONCLUSIONS: The TVT Registry is an innovative registry that that monitors quality, patient safety and trends for these rapidly evolving new technologies. PMID- 27956267 TI - Intravenous fosfomycin-back to the future. Systematic review and meta-analysis of the clinical literature. AB - OBJECTIVES: We conducted a systematic review and meta-analysis to summarize the clinical evidence and usage patterns of intravenous fosfomycin from its development to the present time. METHODS: PubMed, the Cochrane Library and local journals were searched for relevant studies reporting aggregated data of intravenous fosfomycin use in adults and children, with no restrictions regarding study design. Single case reports were excluded. Data were systematically abstracted for all included studies. Clinical and microbiological efficacy from randomized controlled and comparative observational studies were synthesized using meta-analysis to calculate pooled effect sizes. RESULTS: In all, 128 studies on intravenous fosfomycin in 5527 patients were evaluated. Fosfomycin was predominantly used for sepsis/bacteraemia, urinary tract, respiratory tract, bone and joint, and central nervous system infections. No difference in clinical (OR 1.44, 95% CI 0.96-2.15) or microbiological (OR 1.28, 95% CI 0.82-2.01) efficacy between fosfomycin and other antibiotics was observed in comparative trials. The pooled estimate for resistance development during fosfomycin monotherapy was 3.4% (95% CI 1.8%-5.1%). Fosfomycin showed a favourable safety profile, with generally mild adverse events not requiring discontinuation of treatment. Included studies explored intravenous fosfomycin as an anti-staphylococcal agent in monotherapy and combination therapy, whereas studies from 1990 focused on combination therapy (fosfoymcin + beta-lactams or aminoglycosides) for challenging infections frequently caused by multidrug-resistant organisms. CONCLUSION: Intravenous fosfomycin can play a vital role in the antibiotic armamentarium, given its long history of effective and safe use. However, well-designed randomized controlled trials are still desired. PMID- 27956269 TI - A microbiome assessment of medical marijuana. PMID- 27956270 TI - Awareness Campaign in (bio)Medical Students in Iran: a model for increasing the knowledge regarding hepatitis B and C. PMID- 27956271 TI - 'Old' is not always bad. PMID- 27956272 TI - Vasculogenic mimicry in malignant mesothelioma: an experimental and immunohistochemical analysis. AB - Vasculogenic mimicry, the process in which cancer cells form angiomatoid structures independent of or in addition to host angiogenesis has been recorded in several otherwise non-endothelial malignant neoplasms. This study describes evidence of routine vascular mimicry by human mesothelioma cell lines in vitro, when the cell lines are cultured alone or co-cultured with human umbilical vascular endothelial cells, with the formation of angiomatoid tubular networks. Vasculogenic mimicry is also supported by immunohistochemical demonstration of human-specific anti-mitochondria antibody labelling of tumour-associated vasculature of human mesothelioma cells xenotransplanted into nude mice, and by evidence of vascular mimicry in some biopsy samples of human malignant mesotheliomas. These studies show mosaic interlacing of cells that co-label or label individually for immunohistochemical markers of endothelial and mesothelial differentiation. If vascular mimicry in mesothelioma can be characterised more fully, this may facilitate identification of more specific and targeted therapeutic approaches such as anti-angiogenesis in combination with chemotherapy and immunotherapy or other therapeutic approaches. PMID- 27956273 TI - High endothelial venule-like vessels and lymphocyte recruitment in diffuse sclerosing variant of papillary thyroid carcinoma. AB - Diffuse sclerosing variant of papillary thyroid carcinoma (DSPTC) is a rare subtype of papillary thyroid carcinoma with a high incidence of lymph node metastasis. One of its characteristic histological features is the presence of dense lymphocyte infiltrates; however, how these lymphocytes are recruited in this pathological setting remains unclear. Here, we analysed 17 DSPTC cases immunohistologically for cell adhesion molecules expressed on endothelial cells. We found that venules morphologically similar to high endothelial venules (HEVs) in secondary lymphoid organs were induced in lymphoid aggregates in DSPTC, and such HEV-like vessels expressed 6-sulfo sialyl Lewis X (sLeX) glycans as well as intercellular adhesion molecule 1 (ICAM-1). Triple immunohistochemistry revealed that CD8+ cytotoxic T cells were the major lymphocyte subset attached to the luminal surface of HEV-like vessels. sLeX-type glycans were also expressed on DSPTC carcinoma cells, which in binding assays were decorated with E-selectin*IgM chimaeras calcium-dependently. These findings collectively suggest that 6-sulfo sLeX glycans, together with ICAM-1, on HEV-like vessels may function to recruit CD8+ cytotoxic T cells in DSPTC. Additionally, sLeX-type glycans on carcinoma cells might partly contribute to highly metastatic properties of DSPTC through interaction with E-selectin expressed on endothelial cells. PMID- 27956268 TI - Incidence and progression to cirrhosis of new hepatitis C virus infections in persons living with human immunodeficiency virus. AB - OBJECTIVE: To estimate the incidence of hepatitis C virus (HCV) seroconversion and the risk of severe fibrosis/cirrhosis in HCV seroconverters among persons with human immunodeficiency virus (HIV) infection. METHODS: We analysed data on 4059 persons with HIV enrolled in a cohort study in Italy. RESULTS: Incidence rate of seroconversion was 0.6/100 person-years overall, and drug users and men who-have-sex-with-men were at highest risk. The cumulative risk of progression to severe fibrosis/cirrhosis was 30% by 10 years after seroconversion. CONCLUSIONS: New HCV infections have a rapidly progressive course in this population. Persons with HIV and HCV superinfection should be prioritized for treatment with anti-HCV direct-acting antivirals. PMID- 27956274 TI - Lethal melanoma in children: a clinicopathological study of 12 cases. AB - Melanoma in children is rare, representing 3% of paediatric malignancies and <1% of all melanomas. Very few detailed descriptions of bona fide lethal childhood melanomas exist in the literature. We performed a retrospective clinicopathological review of 12 paediatric (<=16 years) melanoma patients who died of metastatic disease, including detailed assessment of architectural and cytomorphological features. There were nine prepubertal patients (median age 7 years old) and three postpubertal cases (median age 15 years old). The patients died on average 45.7 months after diagnosis with the prepubertal subcohort showing a relatively longer time from diagnosis to death. The tumours were bulky (average tumour thickness=10mm), showed brisk mitotic activity (average mitotic count per mm2=7), and were formed by large expansile nodules with sheet-like growth pattern and infiltrative borders in the majority of cases (83%). Cytologically, large grossly pleomorphic epithelioid cells with massive eosinophilic macronucleoli were present in most cases (75%). In this cohort, we did not identify specific features of melanoma that were unique to children. Although melanomas are extremely rarely encountered in childhood, the above-cited unequivocal malignant features should prompt an outright diagnosis of melanoma even in a paediatric patient. PMID- 27956275 TI - A novel ultrastructural finding in statin-exposed patients with inflammatory myositis. PMID- 27956277 TI - Cytomegalovirus and Burkholderia cepacia complex prostatitis: Hickam's dictum in a post-renal transplant patient. PMID- 27956276 TI - Cytomegalovirus-induced inflammatory pseudotumour. PMID- 27956278 TI - The M694I/M694I genotype: A genetic risk factor of AA-amyloidosis in a group of Algerian patients with familial Mediterranean fever. AB - Familial Mediterranean fever (FMF, OMIM 249100) is the most common hereditary fever, resulting from mutations in MEFV. FMF is characterized by episodic febrile attacks and polyserositis. Renal AA-amyloidosis is a major complication, which often leads to end-stage renal disease in untreated patients. The data about the renal AA-amyloidosis secondary to FMF are scarce in North African countries and non-existent in Algeria. We aimed to investigate the MEFV mutations associated with this complication in an Algerian patient cohort. Molecular analysis included 28 unrelated Algerian FMF patients with ascertained amyloidosis, 23 of them were symptomatic and 5 were asymptomatic. For this study, a group of 20 FMF patients without renal amyloidosis were selected as controls according to their age, disease onset and disease duration. The mutations were detected by sequencing exon 10 of MEFV. A total of 87.5% (49/56) mutant alleles were identified in 27/28 analyzed patients; p.M694I was predominant and appeared with an allele frequency of 62.5%, followed by p.M694V (17.85%), p.M680I (5.35%) and p.I692Del (1.78%). Remarkably, only p.M694I mutation was observed among the asymptomatic patients. The M694I/M694I genotype, identified in 14/27 (52%) patients, was significantly associated with the development of amyloidosis compared to group of controls (p = 0.022). This study did not link the M694V/M694V genotype to the renal complication despite the fact that it has been observed only in the patients with amyloidosis (3/27; 11%) (p = 0.349). The association of other identified genotypes to this complication was statistically insignificant. The progression of amyloidosis led to end-stage renal disease in 14 patients with 6 deaths. This study shows that p.M694I homozygosity is a potential genetic risk factor for the development of renal AA-amyloidosis in Algerian FMF patients. PMID- 27956279 TI - Intraocular antibiotics during cataract surgery: Risks and benefits. PMID- 27956280 TI - New surgical approach in cases of cataract with ocular Stevens-Johnson syndrome. AB - : We describe the intraoperative difficulties encountered in cases of ocular Stevens-Johnson syndrome as a result of a poor ocular surface, the presence of symblepharon, and varying degrees of corneal opacity with secondary poor visibility of anterior segment structures. Modifications to the standard phacoemulsification technique enabled safe and successful completion of the surgery in these cases. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27956281 TI - Retro iris suture fixation of a rigid intraocular lens. AB - : We present an iris suture fixation technique for a rigid poly(methyl methacrylate) (PMMA) intraocular lens (IOL). A 10-0 polypropylene suture on a long curved needle is used to preplace 2 iris suture bites 180 degrees apart. The suture loops below the iris are retracted through the main scleral tunnel using a Kuglen hook and a McPherson forceps. The 2 suture loops are twirled twice around the corresponding haptics of a standard 3-piece PMMA IOL, and the IOL is placed in the sulcus. After it is confirmed that the loop surrounds the haptic, the suture knot is tied to secure the IOL to the iris. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 27956283 TI - Single-step transepithelial photorefractive keratectomy in myopia and astigmatism: 18-month follow-up. AB - PURPOSE: To evaluate the long-term quantitative and qualitative optical outcomes of 1-step transepithelial photorefractive keratectomy (PRK) to correct myopia and astigmatism. SETTING: Bina Eye Hospital, Tehran, Iran. DESIGN: Prospective interventional case series. METHODS: Eyes with myopia with or without astigmatism were evaluated. One-step transepithelial PRK was performed with an aberration free aspheric optimized profile and the Amaris 500 laser. Eighteen-month follow up results for refraction, visual acuities, vector analysis, higher-order aberrations, contrast sensitivity, postoperative pain, and haze grade were assessed. RESULTS: The study enrolled 146 eyes (74 patients). At the end of follow-up, 93.84% of eyes had an uncorrected distance visual acuity of 20/20 or better and 97.94% of eyes were within +/-0.5 diopter of the targeted spherical refraction. On vector analysis, the mean correction index value was close to 1 and the mean index of success and magnitude of error values were close to 0. The achieved correction vector was on an axis counterclockwise to the axis of the intended correction. Photopic and mesopic contrast sensitivities and ocular and corneal spherical, cylindrical, and corneal coma aberrations significantly improved (all P < .001). A slight amount of trefoil aberration was induced (P < .001, ocular aberration; P < .01, corneal aberration). No eye lost more than 1 line of corrected distance visual acuity. No eye had a haze grade of 2+ degrees or higher throughout the follow-up. CONCLUSIONS: Eighteen-month results indicate the efficacy and safety of transepithelial PRK to correct myopia and astigmatism. It improved refraction and quality of vision. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27956282 TI - Dependency of endothelial cell loss on anterior chamber depth within first 4 years after implantation of iris-supported phakic intraocular lenses to treat high myopia. AB - PURPOSE: To evaluate the effect of the anterior chamber depth (ACD) on the central corneal endothelial cell density (ECD) in eyes after implantation of an iris-fixated phakic intraocular lens (pIOL). SETTING: Department of Ophthalmology, Goethe-University, Frankfurt, Germany. DESIGN: Retrospective nonrandomized case series. METHODS: An Artisan pIOL was implanted in eyes of highly myopic patients. Follow-up examinations at 1, 12, 24, 36, and 48 months included evaluation of ECD and adverse events. Three cohorts based on the ACD were established and their ECDs compared. All eyes had 1-year and 4-year postoperative ECD measurements available. Statistical analysis included linear regression analysis to evaluate the influence of ACD on ECD. RESULTS: The study comprised 95 eyes (52 patients). Four years after surgery the mean spherical equivalent changed from -11.06 diopters (D) +/- 4.77 (SD) to -0.42 +/- 0.47 D. Severe adverse events were not detected. There was a significantly higher ECD loss after 4 years in patients with an ACD of less than 3.00 mm than in those with an ACD greater than 3.40 mm (-224 cells/mm2) (P < .01). There was no significant difference in ECD between eyes with an ACD of 3.00 to 3.39 mm and eyes with an ACD less than 3.00 mm (P = .23) or more than 3.40 mm (P = .08). CONCLUSIONS: The iris-claw pIOL precisely and safely corrected high myopia. However, the loss in ECD can be considerable. Establishing stricter exclusion criteria for ACD might reduce this loss. FINANCIAL DISCLOSURE: Proprietary or commercial disclosures are listed after the references. PMID- 27956284 TI - Myopia correction with transepithelial photorefractive keratectomy versus femtosecond-assisted laser in situ keratomileusis: One-year case-matched analysis. AB - PURPOSE: To compare the postoperative clinical outcomes of single-step transepithelial photorefractive keratectomy (PRK) and femtosecond-assisted laser in situ keratomileusis (LASIK). SETTING: Bergman Clinics, Utrecht, the Netherlands. DESIGN: Retrospective case series. METHODS: The eyes of consecutive patients who had transepithelial PRK were retrospectively compared with the same number of case-matched eyes (based on the preoperative refractive components) treated with femtosecond-assisted LASIK. The clinical outcomes evaluated were predictability, refractive outcomes, and visual acuity. The Student t test and chi-square test were used for statistical analysis. RESULTS: The study compared 98 patients (196 eyes) who had transepithelial PRK with the outcomes in 196 case matched eyes that had femtosecond-assisted LASIK. All patients completed the 1 year follow-up. At 1 year, 130 eyes (66%) in the transepithelial PRK group and 91 eyes (46%) in the femtosecond-assisted LASIK group achieved an uncorrected distance visual acuity of -0.1 logMAR or better (P < .005), 4 eyes (2%) in the transepithelial PRK and 2 eyes (1%) in the femtosecond-assisted LASIK group lost 2 lines of corrected distance visual acuity (P = .04), and 163 eyes (83%) in the transepithelial PRK and 167 eyes (85%) in the femtosecond-assisted LASIK group were within +/-0.50 diopter (D) of emmetropia. The postoperative mean spherical equivalent was +0.11 D +/- 0.56 (SD) for transepithelial PRK and -0.09 +/- 0.46 D for femtosecond-assisted LASIK (P < .0001). CONCLUSIONS: Transepithelial PRK outcomes 1 year postoperatively were equivalent to those of femtosecond-assisted LASIK. Transepithelial PRK was efficacious and safe; however, the procedure had a longer recovery time than the femtosecond-assisted LASIK. FINANCIAL DISCLOSURE: Mr. Ewering and Dr. Arba-Mosquera are employees of Schwind eye-tech-solutions GmbH and Co. KG. Dr. Luger has no financial or proprietary interest in any material or method mentioned. PMID- 27956285 TI - Influence on intraocular lens power calculation of corneal radii measurement using an image-guided system. AB - PURPOSE: To analyze the influence on intraocular lens (IOL) power calculation of corneal radii measured by the Verion Image-Guided System in comparison with those measured by partial coherence interferometry (PCI) (IOLMaster) and optical low coherence reflectometry (OLCR) (Lenstar) systems. SETTING: International Vision Correction Research Centre, Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany. DESIGN: Prospective case series. METHODS: One eye of ophthalmologically healthy volunteers was examined with the image-guided, PCI, and OLCR systems. Corneal radii could be measured with all 3 devices; axial length (AL) and anterior chamber depth (ACD) could be measured with PCI and OLCR only. The IOL power calculations for the Acrysof SN60WF IOL using 4 formulas were compared between the image-guided system and both the PCI device and OLCR device. For IOL calculation with the image-guided system, the AL and ACD of the device used for comparison were applied. RESULTS: Of the 150 volunteers, 136 (mean age 39.60 years +/- 17.31 [SD]) had valid measurements with all 3 devices and were included in the analysis. Compared with PCI, the image-guided system measured statistically significant larger values for corneal radii and IOL power calculations for all 4 formulas. There were no statistically significant differences between the image-guided system and the OLCR device. In both groups, the surgeon would have chosen the same IOL power in approximately 60% to 65% of cases and a +/-0.5 diopter different IOL power in approximately 30% to 35% of cases when using the image-guided system. CONCLUSIONS: The IOL power calculation using the image-guided system showed statistically significant differences compared with the PCI device but not when compared with the OLCR device. The clinical relevance of this theoretical approach remains to be evaluated. FINANCIAL DISCLOSURE: Drs. Auffarth and Holzer received travel grants and lecture fees from Alcon Pharma GmbH and Carl Zeiss Meditec AG. PMID- 27956286 TI - Residual astigmatism after toric intraocular lens implantation: Analysis of data from an online toric intraocular lens back-calculator. AB - PURPOSE: To evaluate some possible causes for residual astigmatism after toric intraocular lens (IOL) implantation based on an analysis of data from an online toric IOL back-calculator. DESIGN: Retrospective data review. METHODS: An online toric back-calculator was designed to allow users to input preoperative toric planning information along with postoperative IOL orientation and refractive results. These were then used to determine the optimum orientation of the IOL to reduce refractive astigmatism. The collected aggregate data were extracted from this calculator to investigate the associated reasons for residual astigmatic refractive error with toric IOLs. RESULTS: The study analyzed 12 812 records with a mean postoperative refractive astigmatism of 1.89 diopters (D). Refractive astigmatism was significantly higher with higher IOL cylinder power (P < .01) but was not different by IOL manufacturer. Ninety percent of IOLs were not at the ideal orientation, despite 30% being at the preoperative calculated orientation. Misalignment showed a directional bias for some IOLs but not for others. The mean calculated percentage reduction in residual cylinder after reorientation was 50% +/- 31% (SD), with the magnitude of residual astigmatism after IOL reorientation expected to be 0.50 D or less in 37% of eyes (4835/12 812). Expected outcomes were significantly different by IOL type. CONCLUSIONS: Analysis of data from the online toric back-calculator provided insights into the nature of residual astigmatism after toric IOL implantation. The reasons for residual astigmatism in this data set varied by IOL type. FINANCIAL DISCLOSURE: Proprietary or commercial disclosures are listed after the references. PMID- 27956287 TI - Toxic anterior segment syndrome caused by autoclave reservoir wall biofilms and their residual toxins. AB - PURPOSE: To identify etiology of toxic anterior segment syndrome (TASS) after uneventful phacoemulsification. SETTING: EyeMD Laser and Surgery Center, Oakland, California. DESIGN: Retrospective case series. METHODS: Patient charts with TASS were reviewed. Reservoirs of 2 autoclaves associated with these cases were cultured for bacterial contamination. Cultures were performed on 23 other autoclave reservoirs at surgery centers in the local area. The main outcome measures were the incidence of TASS and prevalence of bacterial biofilm contamination of autoclave reservoirs. RESULTS: From 2010 to 2013, 11 935 consecutive cataract surgeries were performed at 1 center by multiple surgeons with no reported TASS. Between January 1, 2014, and January 15, 2015, 10 cases of TASS occurred out of 3003 cataract surgeries; these patients' charts were reviewed. Cultures of 2 Statim autoclave reservoir walls grew Bacillus species, Williamsia species, Mycobacterium mucogenicum, and Candida parapsilosis. Scanning electron microscopy of reservoir wall sections showed prominent biofilm. The 2 autoclaves were replaced in January 2015. Subsequently, 2875 cataract surgeries were performed with no reported TASS (P < .001, chi2 test). Eighteen of 23 additional regional autoclaves were also contaminated with bacterial biofilms. CONCLUSIONS: Toxic anterior segment syndrome was strongly associated with bacterial biofilm contamination of autoclave reservoirs. An etiological mechanism might involve transport of heat-stable bacterial cell antigens in the steam with deposition on surgical instrumentation. Data suggest widespread prevalence of bacterial biofilms on fluid-reservoir walls, despite adherence to manufacturer guidelines for cleaning and maintenance. Prevention or elimination of autoclave fluid-reservoir biofilms might reduce the risk for postoperative TASS. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27956288 TI - Primary posterior capsulotomy in adults with posterior capsule opacification. AB - PURPOSE: To evaluate the efficacy and safety of primary posterior continuous curvilinear capsulorhexis (PCCC) in adult patients with cataract. SETTING: Zagazig University Hospital, Ash-Sharkya, Egypt. DESIGN: Prospective nonrandomized case series. METHODS: This study comprised patients with senile cataract who had phacoemulsification. All patients had a dense posterior capsule opacification (PCO) discovered intraoperatively. Primary PCCC was performed to remove the residual opacification after posterior capsule polishing. All patients were followed for 3 months postoperatively. The outcome measures were corrected distance visual acuity (CDVA), macular edema detected by optical coherence tomography, and the occurrence of intraoperative or postoperative complications. RESULTS: Twenty-five eyes of 25 cataract patients had phacoemulsification. The mean age was 61.9 years +/- 7.5 (SD). The mean CDVA preoperatively was 0.14 +/- 0.08 and postoperatively it was 0.86 +/- 0.15 at 1 week, 0.93 +/- 0.08 at 1 month, and 0.94 +/- 0.08 at 3 months (P = .001). The mean central macular thickness was 313.16 +/- 8.39 MUm preoperatively and 315.04 +/- 10.6 MUm, 319.88 +/- 26.06 MUm, and 316.4 +/- 13.7 MUm at 1 week, 1 month, and 3 months postoperatively, respectively (P = .35). Posterior capsule opening contracture occurred in 1 eye (4%), although it did not affect the patient's vision. Intraoperative posterior capsule extension occurred in 1 eye (4%). No serious complications, such as retinal detachment or endophthalmitis, were detected in any patient. CONCLUSION: Cataract surgery with primary PCCC was a safe procedure to treat residual PCO in adults and had a low rate of complications. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 27956289 TI - Pterygium size and effect on intraocular lens power calculation. AB - PURPOSE: To evaluate the effects of pterygium on biometry measurements and the relationship between these effects and pterygium size. SETTING: Ulucanlar Eye Hospital, Ankara, Turkey. DESIGN: Prospective comparative study. METHODS: Patients who had unilateral primary pterygium excision were included in the study group. Anterior segment photographed images were taken of eyes with pterygia to calculate the pterygium length and area using the ImageJ program. Preoperative and 3-month postoperative biometry measurements (Lenstar LS900) were obtained for eyes with pterygium and their healthy fellow eyes (control group). RESULTS: Thirty-two patients with pterygium (mean age 63.31 years +/- 7.18 [SD]) were included. The mean pterygium length was 3.07 +/- 0.81 mm, and the mean area was 6.26 +/- 2.07 mm2. The preoperative intraocular lens (IOL) power calculation with all formulas were higher than postoperative and control values (P < .001). The mean changes were 0.47 diopter (D) for the SRK II, 0.59 D for SRK/T, 0.47 D for Hoffer Q, 0.39 D for Haigis, and 0.38 D for Holladay 2 formulas after pterygium surgery. Positive, significant, and moderate correlations were found between the pterygium size and the change in IOL power. Pterygia longer than 2.40 mm and larger than 5.45 mm2 created at least equal to or more than 0.5 D deviation in the IOL power calculations. CONCLUSION: If the pterygium size is larger than 2.40 mm or 5.45 mm2 and simultaneous surgery is planned, the implanted IOL power should be at least 0.50 D smaller than the calculated power. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27956290 TI - Objective evaluation of negative dysphotopsia with Goldmann kinetic perimetry. AB - PURPOSE: To compare the extension of peripheral visual fields in phakic and pseudophakic patients and to evaluate whether Goldmann kinetic perimetry can be used as an objective measure of negative dysphotopsia. SETTING: University Eye Clinic, Maastricht University Medical Centre, Maastricht, the Netherlands. DESIGN: Prospective and case-control study. METHODS: Kinetic perimetry was performed with V4e and I4e stimuli. Visual fields were assessed in the following 4 quadrants: superior temporal, superior nasal, inferior temporal, and inferior nasal. In the control group, patients were evaluated before and 1 month after cataract surgery. Biometric and perimetric data in the control group were compared with data in the patients with negative dysphotopsia (study group). RESULTS: Each group comprised 10 patients. In the control group, the extension of visual field did not change after surgery. Patients in the study group had a significantly shorter axial length and higher intraocular lens powers than those in the control group. The inferior temporal and inferior nasal quadrants were, respectively, 10 degrees and 6 degrees (P < .05) smaller in the study group than in the control group. In 3 patients with negative dysphotopsia, a shadow was drawn in the superior temporal and the inferior temporal quadrants during perimetry and the position of this shadow matched their subjective description of negative dysphotopsia. CONCLUSIONS: The peripheral visual field did not change after cataract surgery in patients without negative dysphotopsia. Kinetic perimetry can be used for objective evaluation of patients with negative dysphotopsia because these patients had constricted peripheral visual fields or a relative temporal scotoma corresponding to the position of the shadow. FINANCIAL DISCLOSURE: Proprietary or commercial disclosures are listed after the references. PMID- 27956291 TI - Modified 360-degree suture trabeculotomy combined with phacoemulsification and intraocular lens implantation for glaucoma and coexisting cataract. AB - PURPOSE: To assess the efficacy and safety of a modified 360-degree suture trabeculotomy combined with a cataract surgery technique in patients with glaucoma and coexisting cataract. SETTING: Hokkaido University Hospital, Sapporo, Japan. DESIGN: Retrospective case series. METHODS: Medical records of patients with glaucoma having a modified 360-degree trabeculotomy combined with cataract surgery (Group 1) were reviewed. Another group of patients who had the modified 360-degree suture trabeculotomy alone served as controls (Group 2). RESULTS: Both groups comprised 46 patients. In each group, eyes were diagnosed with primary angle-closure glaucoma in 2 eyes, primary open-angle glaucoma in 24 eyes, exfoliation glaucoma in 4 eyes, uveitic glaucoma in 15 eyes, and steroid glaucoma in 1 eye. The mean preoperative intraocular pressure (IOP) values were 27.2 mm Hg +/- 7.3 (SD) on 3.0 +/- 0.5 medications in Group 1 and 27.7 +/- 10.7 mm Hg on 2.9 +/- 0.6 medications in Group 2. Twelve months after surgery, the mean IOPs were 13.4 +/- 3.7 mm Hg on 0.8 +/- 1.1 medications in Group 1 and 13.9 +/- 4.1 mm Hg on 0.6 +/- 0.9 medications in Group 2. The success rate (<18 mm Hg) at 12 months was 89.1% and 93.5%, respectively. Major complications included transient IOP spikes (30.4% and 37.0%) and prolonged hyphema (10.9% and 6.5%) in Group 1 and Group 2, respectively. CONCLUSION: The data showed the equivalent effects of suture trabeculotomy combined with cataract surgery and suture trabeculotomy surgery alone on postoperative safety and efficacy. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27956292 TI - Surgical indications, outcomes, and complications with the use of a modified capsular tension ring during cataract surgery. AB - PURPOSE: To determine the surgical indications, outcomes, and complications with the use of modified capsular tension rings (CTRs) during cataract surgery. SETTING: Ivey Eye Institute, Western University, London, Ontario, Canada. DESIGN: Systematic review. METHODS: A systematic review of databases was conducted for studies related to the use of modified CTRs during cataract surgery that were published between 1992 and 2015. Primary research papers on human participants published in English were screened. The surgical indications, outcomes, and complications of modified CTR use during cataract surgery were compiled and analyzed. RESULTS: The search identified 6035 records from published and gray literature. After screening, 10 studies involving 320 eyes were included in the systematic review. The most common surgical indications for modified CTR use were Marfan syndrome (40.3%), idiopathic zonular insufficiency (27.2%), and previous ocular trauma (22.8%). The weighted average of indicated zonular insufficiency was 173 degrees, with 75.4% of eyes achieving visual acuity better than 20/40 postoperatively. The use of modified CTRs resulted in a reduction in intraocular lens (IOL) decentration and tilt. Vitrectomy during surgery was required in 19.8% of eyes. The rate of posterior capsule opacification (PCO) was 41.1%. Intraocular pressure (IOP) elevation, suture breakage, and uveitis were the most common postoperative complications. CONCLUSIONS: The use of modified CTRs during cataract surgery was associated with causes of large and progressive zonular insufficiency. Use of the CTR produced good postoperative visual outcome and reduced IOL decentration and/or tilt. The most common complications were PCO, IOP elevation, and suture breakage. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27956293 TI - Immunohistochemical study of corneal inflammation after femtosecond laser clear corneal incisions or manual surgery. AB - PURPOSE: To use immunohistochemical staining to evaluate corneal inflammation and apoptosis induced after femtosecond laser incisions or manual incisions. SETTING: Ophthalmology Clinic, University G. d'Annunzio, Chieti, Italy. DESIGN: Experimental study. METHODS: Ninety human cadaver corneas were cut manually or with the femtosecond laser at different energies and analyzed by immunohistochemistry after 5 minutes or 4 hours. The corneas were divided into 5 groups: untreated (Group 1), cut manually (Group 2), and treated with the femtosecond laser with increasing energies (Groups 3 to 5; 3.0 MUJ, 6.0 MUJ, and 15.0 MUJ, respectively). RESULTS: At 5 minutes, increased expression of interleukin (IL)-18 was observed in the femtosecond laser groups compared with the manual group (P < .01). Interferon gamma (IFNgamma) positivity was significantly higher in Groups 4 and 5 than in Group 2 and between Groups 3 and 4 (P < .05). The terminal uridine deoxynucleotidyl nick end-labeling (TUNEL) positivity increased with higher energy (Group 2 versus Group 4 and Group 2 versus Group 5; P < .05). After 4 hours, IFNgamma positivity was higher in Group 5 than in Group 2 (P = .0021) and between Group 5 and Groups 3 and 4 (P < .05). No sign of IL-18 positivity was found after 4 hours in any sample. Group 5 showed significant higher TUNEL positivity than all other groups (P < .0001). CONCLUSION: The femtosecond laser technique at high energies induced a higher corneal inflammatory response and a higher corneal cell apoptosis than the manual technique. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27956294 TI - Nonlinear optical corneal collagen crosslinking of ex vivo rabbit eyes. AB - PURPOSE: To determine whether riboflavin-induced collagen crosslinking (CXL) could be precisely achieved in the corneal stroma of ex vivo rabbit eyes using nonlinear optical excitation with a low numerical aperture lens and enlarged focal volume. SETTING: Gavin Herbert Eye Institute, University of California Irvine, Irvine, California, USA. DESIGN: Experimental study. METHODS: The corneal epithelium was removed and the corneas were soaked in 0.5% riboflavin solution. Using a 0.1 numerical aperture objective, a theoretical excitation volume of 150 MUm * 3 MUm was generated using 1 W of 760 nm femtosecond laser light and raster scanned with 4.4 MUm line separation at varying effective speeds over a 4.50 mm * 2.25 mm area. Corneal sections were examined for collagen autofluorescence. RESULTS: Collagen autofluorescence was enhanced 2.9 times compared with ultraviolet-A (UVA) CXL. Also, increasing speed was linearly associated with decreasing autofluorescence intensity. The slowest speed of 2.69 mm/s showed a mean of 182.97 MUm +/- 52.35 (SD) long autofluorescent scan lines axially in the central cornea compared with 147.84 +/- 4.35 MUm for UVA CXL. CONCLUSIONS: Decreasing dwell time was linearly associated with decreasing autofluorescence intensity, approaching that of UVA CXL at a speed of 8.9 mm/s. Using an effective speed of 8.9 mm/s, nonlinear optical CXL could be achieved over a 3.0 mm diameter area in fewer than 4 minutes. Further development of nonlinear optical CXL might result in safer, faster, and more effective CXL treatments. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27956295 TI - Intraoperative complications of phacoemulsification in pseudoexfoliation: Metaanalysis. AB - : This review analyzed the effect of pseudoexfoliation (PXF) syndrome on the risk for surgical complications during phacoemulsification. Peer-reviewed literature in Medline, Embase, Lilacs, Web of Science, and Cochrane databases was systematically searched, along with gray literature in the Teseo and National Institutes of Health clinical trials database. Clinical trial, cohort, case control, and cross-sectional studies comparing phacoemulsification complications in patients with and without PXF were identified, and 22 of 30 studies were selected for analysis. Odds ratios (ORs) for posterior capsule rupture or zonular dialysis were calculated and pooled using random-effects models. A random-effects meta-regression model was also generated. Using the random-effects model, the pooled OR was 2.1363 (95% confidence interval, 1.5394-2.9648), which corresponds to a risk of more than 10%. No significant changes to this risk were observed in the cumulative or stratified analyses. Although advances in surgical technique have been made, PXF syndrome continues to be a risk factor in phacoemulsification. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 27956296 TI - Postoperative hemorrhagic occlusive retinal vasculitis associated with intracameral vancomycin prophylaxis during cataract surgery. AB - : We present the case of a 75-year-old man who had uneventful cataract surgery and administration of intracameral vancomycin for endophthalmitis prophylaxis, followed by the same procedure in the fellow eye 1 week later. The patient subsequently developed bilateral hemorrhagic occlusive retinal vasculitis, resulting in profound vision loss in both eyes. A second case of hemorrhagic occlusive retinal vasculitis previously reported from our institution is summarized. That case was characterized by a far milder course, with rapid resolution of vision loss. The 2 cases illustrate the broad range of toxicity potentially associated with intracameral vancomycin, suggest that bilateral administration results in a worse prognosis, and indicate that this disorder may be underrecognized due to the potential for a mild course. We recommend that intracameral vancomycin not be used for endophthalmitis prophylaxis. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27956298 TI - Intracorneal ring segment breaks following uneventful implantation. PMID- 27956297 TI - Laser in situ keratomileusis flap stability in an aviator following aircraft ejection. AB - : We present the case of a 28-year-old male F/A-18F Super Hornet naval flight officer who ejected from an aircraft at 13 000 feet at a speed in excess of 350 knots 7 years after uneventful laser in situ keratomileusis (LASIK). The patient was evaluated the day after the ejection. No LASIK flap complications or epithelial defects were found, and the corrected distance visual acuity was 20/15 in both eyes. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27956299 TI - November consultation #2. PMID- 27956300 TI - Peripheral iris transillumination defect and recurrent anterior chamber bleeding with bag-fixated intraocular lens: November consultation #1. PMID- 27956301 TI - November consultation #3. PMID- 27956302 TI - November consultation #5. PMID- 27956303 TI - November consultation #4. PMID- 27956304 TI - November consultation #7. PMID- 27956305 TI - November consultation #6. PMID- 27956306 TI - November consultation #8. PMID- 27956307 TI - Femtosecond laser-assisted cataract surgery in complex cases. PMID- 27956308 TI - Reply. PMID- 27956309 TI - Intraocular lens calculations using the Holladay toric calculator. PMID- 27956310 TI - Reply. PMID- 27956311 TI - Corneal asphericity and intraocular lens power in eyes with previous laser in situ keratomileusis. PMID- 27956312 TI - Reply. PMID- 27956313 TI - Risk factors for optic capture after transscleral intraocular lens fixation. PMID- 27956314 TI - [A stereotypical clinical presentation of childhood linear purpura of the arms: Analysis of six cases]. AB - Among causes of childhood purpura, other- or self-induced mechanical purpura, such as factitious purpura, needs to be considered. This cause is unfamiliar to pediatricians, usually compromising early diagnosis. We report on the cases of six children, seen between 1998 and 2014 at the Toulouse and Bordeaux Departments of Dermatology, presenting with a stereotypical linear purpura on the arms. All were females, aged 6-14 years. One patient had a psychiatric history, whereas the others were undergoing a stressful time period. All had several relapses and diagnosis was delayed in all. The patients presented with multiple oval or square purpuric macules, forming a discontinuous linear band. Some patients reported functional discomfort such as pain or pruritus. Lesions were always located on the arms and sometimes on other areas of the body. Biological assessments were normal and there was no vasculitis at skin histology. We retained the diagnosis of induced mechanical purpura. Psychological support was offered to four patients. One of them declared that the lesions were induced by classmates using suction. Another child declared that she caused the lesions herself, without explaining the mechanism. Outcome was favorable in five children (one was lost to follow-up), 1-4 years after diagnosis. In conclusion, induced mechanical purpura in children, although rarely described in the medical literature, must be kept in mind. Investigations should be carried out in cases with uncertain diagnosis. Underlying psychological distress should be sought. PMID- 27956315 TI - Stability of a liquid bridge between nonparallel hydrophilic surfaces. AB - Formation of liquid bridges between two solid surfaces is frequently observed in industry and nature, e.g. in printing applications. When the two solid surfaces are not parallel (with a dihedral angle psi between them), an interesting phenomenon emerges: if psi exceeds a critical angle (denoted as psic) the bridge is no longer stable, and propels itself toward the cusp of the surfaces. In this work we performed, for the first time, a systematic study on the parameters influencing psic by combining experimental, theoretical, and numerical investigations. It was shown that psic is determined by the advancing contact angle (thetaa) and Contact Angle Hysteresis (CAH) of the surfaces: it increases as thetaa or CAH increases, and these two parameters have a nonlinear and interdependent influence on psic. Based on our quantitative results, an empirical equation is presented to predict the critical angle, psic=f(thetaa,CAH) in closed analytical form. This equation can be used to calculate psic for bridges formed by moving down a pre-tilted surface towards a sessile drop on a stationary lower surface, or bridges between initially parallel surfaces which the top surface tilts after bridge formation. PMID- 27956316 TI - Treatment with oxLDL antibody reduces cathepsin S expression in atherosclerosis via down-regulating ADAR1-mediated RNA editing. PMID- 27956317 TI - Response to the letter to editor: Coronary calcium scores: From histology to preventive cardiology. PMID- 27956318 TI - Reply to "delirium in heart failure". PMID- 27956319 TI - Response to the letter to editor: Galectin-3 and atrial fibrillation. PMID- 27956320 TI - Primary tumour resection may improve survival in functional well-differentiated neuroendocrine tumours metastatic to the liver. AB - BACKGROUND: Functional well-differentiated neuroendocrine tumours (NET) with liver metastases represent a therapeutic challenge with few alternative options in guidelines. In these patients, the role of surgical resection of the primary tumour is controversial. PATIENTS AND METHODS: From a regional registry collecting somatostatin analogue (SSA)-treated tumours from 1979 to 2005, a series of 139 patients presenting with symptomatic, liver-metastatic, well differentiated NET (G1-G2, mitoses: <=20, Ki-67: <=20%) was prospectively collected and retrospectively analysed. Surgery on either the primary tumour or liver metastases was chosen: 1) when low perioperative risk was predictable; 2) in presence of an impending risk of obstruction, bleeding, or perforation; or 3) if liver metastases were suitable of curative or subtotal (>90%) tumour removal. Impact of the most relevant clinico-pathological parameters on survival was studied. RESULTS: Median follow-up was 127 months and median survival was 94 months, with 138 vs. 37 months in resected vs. non-resected primary NET (p < 0.001), respectively. In the univariate analysis, prolonged survival was significantly associated with primary tumour resection (p < 0.001), resection of liver metastases (p = 0.002), site of primary (carcinoid vs. pancreatic, p = 0.018), basal chromogranin-A (CgA) <200 ng/mL (p = 0.001), and absence of diarrhea (p = 0.012). Multivariate analysis showed that primary tumour resection was an independent positive prognostic factor (HR = 3.17; 95% CI: 1.77-5.69, p < 0.001), whereas diarrhea, basal CgA >=200 ng/mL, and high tumour load were independent negative prognostic factors. Also, in 103 patients with non resectable liver metastases, primary tumour resection was significantly associated with prolonged survival (median 137 vs. 32 months, p < 0.0001). CONCLUSIONS: Primary tumour resection may improve survival in functional well differentiated NET with liver metastases. PMID- 27956321 TI - Prevalence, incidence, and risk factors for shoulder and neck dysfunction after neck dissection: A systematic review. AB - INTRODUCTION: Shoulder pain and dysfunction may occur following neck dissection among people being treated for head and neck cancer. This systematic review aims to examine the prevalence and incidence of shoulder and neck dysfunction after neck dissection and identify risk factors for these post-operative complications. METHODS: Electronic databases (Pubmed, CINAHL, EMBASE, Cochrane) were searched for articles including adults undergoing neck dissection for head and neck cancer. Studies that reported prevalence, incidence or risk factors for an outcome of the shoulder or neck were eligible and assessed using the Critical Review Form - Quantitative Studies. RESULTS: Seventy-five articles were included in the final review. Prevalence rates for shoulder pain were slightly higher after RND (range, 10-100%) compared with MRND (range, 0-100%) and SND (range, 9 25%). The incidence of reduced shoulder active range of motion depended on surgery type (range, 5-20%). The prevalence of reduced neck active range of motion after neck dissection was 1-13%. Type of neck dissection was a risk factor for shoulder pain, reduced function and health-related quality of life. CONCLUSIONS: The prevalence and incidence of shoulder and neck dysfunction after neck dissection varies by type of surgery performed and measure of dysfunction used. Pre-operative education for patients undergoing neck dissection should acknowledge the potential for post-operative shoulder and neck problems to occur and inform patients that accessory nerve preservation lowers, but does not eliminate, the risk of developing musculoskeletal complications. PMID- 27956322 TI - Fuchs' dystrophy associated with radial keratotomy: Lamellar or perforating keratoplasty? AB - CASE REPORT: A 70 year-old male patient with a history of radial keratotomy suffering from Fuchs' dystrophy and a cataract. The patient received a two-step surgery: lens phacoemulsification and intraocular lens implant, followed by descemet stripping automated endothelial keratoplasty in both eyes, four months later. There were no complications apart from a recurrent cystoid macular oedema in both eyes. The best corrected visual acuity was 20/40 both eyes, and the patient was satisfied. DISCUSSION: Descemet stripping automated endothelial keratoplasty may be considered as an alternative to penetrating keratoplasty in the case of endothelial dysfunction and radial keratotomy in patients with no corneal ectasia or significant stromal opacity. PMID- 27956323 TI - Choroidal metastasis from breast cancer. PMID- 27956324 TI - Perfluorocarbon in anterior chamber. PMID- 27956325 TI - Profile of patients with uveitis referred to a multidisciplinary unit in northern Spain. AB - OBJECTIVE: To describe the main characteristics of a cohort of patients with uveitis referred to a multidisciplinary unit in northern Spain. MATERIAL AND METHODS: Retrospective analysis of clinical records of patients evaluated in the Multidisciplinary Unit of the Navarra Hospital Complex from the period January 2010 until March 2015. An analysis was performed on the demographic characteristics, origin, types of uveitis, laterality, and aetiology. The present series was also compared with 2 previous series from Castilla y Leon and Barcelona. RESULTS: A total of 500 patients were identified, with a mean age of 47.9+/-16.4 years, with 50% women. The most frequent type of uveitis was anterior uveitis (65.4%), followed by posterior uveitis (17.6%), panuveitis (15.2%), and intermediate uveitis (1.8%). The origin was unclassifiable in 31.2%, followed by non-infectious systemic disease in 29.2%. Ankylosing spondylitis was the most frequent cause in 10.8% of patients, followed by herpes infection in 9.2%, and toxoplasmosis in 7.8%, respectively. Compared with the 2other cohorts, the present cohort showed a higher proportion of unilateral anterior uveitis. Furthermore, the patients from the Navarra series had a higher prevalence of unilateral and idiopathic uveitis compared to the series from Barcelona. CONCLUSIONS: The main characteristics of the present cohort of patients with uveitis are similar to those of patients from other regions of our country. Unilateral anterior uveitis and idiopathic uveitis were the most frequent in our series. PMID- 27956326 TI - Syphilitic posterior placoid chorioretinitis as initial presentation of early neurosyphilis. AB - CASE REPORT: A 36 year-old male with a recent HIV diagnosis, presented with loss of vision of his left eye. Ophthalmoscopy revealed a unilateral yellowish placoid lesion in the macula. After fluorescein angiography, optical coherence tomography, optical coherence tomography angiography, syphilis serology, and cerebrospinal fluid results, he was diagnosed with neurosyphilis and syphilitic posterior placoid chorioretinitis. DISCUSSION: Acute syphilitic posterior placoid chorioretinitis is a rare ocular manifestation of syphilis. All patients with characteristic clinical and angiographic findings of acute syphilitic posterior placoid chorioretinitis should be tested for a neurosyphilis and human immunodeficiency virus co-infection. Early treatment with intravenous penicillin is usually effective with good visual results. PMID- 27956328 TI - Synergy of Siam weed (Chromolaena odorata) and poultry manure for energy generation: Effects of pretreatment methods, modeling and process optimization. AB - The co-digestion of Chromolaena odorata with poultry manure was evaluated in this study. Two samples of the weed: (A: which was pre-treated with mechanical, chemical and thermal methods) and (B: which was pretreated using mechanical and chemical methods only) were separately digested with poultry manure. Biogas generation started from the 2nd to 4th and 4th to 7th day for samples 'A' and 'B' respectively. The most desired actual biogas yield from samples 'A' and 'B' were 3884.20 and 2544.70 (10-4m3/kg VS) respectively and the gas composition was 68+/ 2% Methane and 20+/-2% Carbon dioxide for sample A while it was 62+/-3% Methane and 22+/-2% Carbon dioxide for sample B. In all, there was a 38.06% increase in gas generation in 'A' over 'B'. The coefficient of determination (R2) for the Response Surface Methodology (RSM) model (0.9009) was high suggesting high accuracy in the modeling and prediction. The worldwide usage of C. odorata is encouraged. PMID- 27956327 TI - Retrobulbar chlorpromazine in management of painful eye in blind or low vision patients. AB - OBJECTIVE: To evaluate the results of applying retrobulbar chlorpromazine in the management of patients with painful blind eyes or with very poor vision. METHODS: A retrospective, descriptive review was carried out on the medical records of 33 patients who were treated with a retrobulbar injection of chlorpromazine (25mg) for the management of painful blind eyes in Centro Oftalmologico Virgilio Galvis. RESULTS: Pain control was achieved in 90% of cases (with mean follow-up of 2.1 years). The mean intraocular pressure decreased by 37%. In 7 out of 12 eyes that maintained residual vision, loss of some degree of vision was acknowledged. One patient required an additional cyclodestructive procedure, another one required an absolute alcohol injection, and in an additional case evisceration surgery was necessary to achieve pain control. No serious complications were noted with this therapy. CONCLUSIONS: Retrobulbar injection of chlorpromazine is a valid option in painful, blind eye cases (or with very poor vision) with a poor visual prognosis. PMID- 27956329 TI - Valorization of crude glycerol and eggshell biowaste as media components for hydrogen production: A scale-up study using co-culture system. AB - The properties of eggshells (EGS) as neutralizing and immobilizing agent were investigated for hydrogen (H2) production using crude glycerol (CG) by co-culture system. Eggshells of different sizes and concentrations were used during batch and repeated-batch fermentation. For batch and repeated-batch fermentation, the maximum H2 production (36.53+/-0.53 and 41.16+/-0.95mmol/L, respectively) was obtained with the EGS size of 33MUm100MUm) are required for promoting bone ingrowth. Several studies have investigated methods to generate macroporosity within calcium phosphate cements but many of these methods either affect the cement setting or take weeks or months to generate the maximum porosity. This work offers a new method for generating macroporosity within calcium phosphate cements by utilizing glucose microparticles. The microparticles dissolve in less then 72h, thereby generating scaffolds with maximum porosity in short period of time. The results will offer a new method for generating macroporosity within calcium phosphate cements. PMID- 27956364 TI - Proton-sensing transistor systems for detecting ion leakage from plasma membranes under chemical stimuli. AB - : The membrane integrity of live cells is routinely evaluated for cytotoxicity induced by chemical or physical stimuli. Recent progress in bioengineering means that high-quality toxicity validation is required. Here, we report a pH-sensitive transistor system developed for the continuous monitoring of ion leakage from cell membranes upon challenge by toxic compounds. Temporal changes in pH were generated with high reproducibility via periodic flushing of HepG2 cells on a gate insulator of a proton-sensitive field-effect transistor with isotonic buffer solutions with/without NH4Cl. The pH transients at the point of NH4Cl addition/withdrawal originated from the free permeation of NH3 across the semi permeable plasma membranes, and the proton sponge effect produced by the ammonia equilibrium. Irreversible attenuation of the pH transient was observed when the cells were subjected to a membrane-toxic reagent. Experiments and simulations proved that the decrease in the pH transient was proportional to the area of the ion-permeable pores on the damaged plasma membranes. The pH signal was correlated with the degree of hemolysis produced by the model reagents. The pH assay was sensitive to the formation of molecularly sized pores that were otherwise not measurable via detection of the leakage of hemoglobin, because the hydrodynamic radius of hemoglobin was greater than 3.1nm in the hemolysis assay. The pH transient was not disturbed by inherent ion-transporter activity. The ISFET assay was applied to a wide variety of cell types. The system presented here is fast, sensitive, practical and scalable, and will be useful for validating cytotoxins and nanomaterials. STATEMENT OF SIGNIFICANCE: The plasma membrane toxicity and hemolysis are widely and routinely evaluated in biomaterials science and biomedical engineering. Despite the recent development of a variety of methods/materials for efficient gene/drug delivery systems to the cytosol, the methodologies for safety validation remain unchanged in many years while leaving some major issues such as sensitivity, accuracy, and fast response. The paper describes a new way of measuring the plasma membrane leakage in real time upon challenge by toxic reagents using a solid-state transistor that is sensitive to proton as the smallest indicator. Our system was reliable and was correlated to the results from hemolysis assay with advanced features in sensitivity, fast response, and wide applicability to chemical species. The downsizing and integration features of semiconductor fabrication technologies may realize cytotoxicity assays at the single-cell level in multi-parallel. PMID- 27956365 TI - Raman microspectroscopy as a diagnostic tool for the non-invasive analysis of fibrillin-1 deficiency in the skin and in the in vitro skin models. AB - : Fibrillin microfibrils and elastic fibers are critical determinants of elastic tissues where they define as tissue-specific architectures vital mechanical properties such as pliability and elastic recoil. Fibrillin microfibrils also facilitate elastic fiber formation and support the association of epithelial cells with the interstitial matrix. Mutations in fibrillin-1 (FBN1) are causative for the Marfan syndrome, a congenital multisystem disorder characterized by progressive deterioration of the fibrillin microfibril/ elastic fiber architecture in the cardiovascular, musculoskeletal, ocular, and dermal system. In this study, we utilized Raman microspectroscopy in combination with principal component analysis (PCA) to analyze the molecular consequences of fibrillin-1 deficiency in skin of a mouse model (GT8) of Marfan syndrome. In addition, full thickness skin models incorporating murine wild-type and Fbn1GT8/GT8 fibroblasts as well as human HaCaT keratinocytes were generated and analyzed. Skin models containing GT8 fibroblasts showed an altered epidermal morphology when compared to wild-type models indicating a new role for fibrillin-1 in dermal-epidermal crosstalk. Obtained Raman spectra together with PCA allowed to discriminate between healthy and deficient microfibrillar networks in murine dermis and skin models. Interestingly, results obtained from GT8 dermis and skin models showed similar alterations in molecular signatures triggered by fibrillin-1 deficiency such as amide III vibrations and decreased levels of glycan vibrations. Overall, this study indicates that Raman microspectroscopy has the potential to analyze subtle changes in fibrillin-1 microfibrils and elastic fiber networks. Therefore Raman microspectroscopy may be utilized as a non-invasive and sensitive diagnostic tool to identify connective tissue disorders and monitor their disease progression. STATEMENT OF SIGNIFICANCE: Mutations in building blocks of the fibrillin microfibril/ elastic fiber network manifest in disease conditions such as aneurysms, emphysema or lax skin. Understanding how structural changes induced by fibrillin-1 mutation impact the architecture of fibrillin microfibrils, which then translates into an altered activation state of targeted growth factors, represents a huge challenge in elucidating the genotype-phenotype correlations in connective tissue disorders such as Marfan syndrome. This study shows that Raman microspectroscopy is able to reveal structural changes in fibrillin-1 microfibrils and elastic fiber networks and to discriminate between normal and diseased networks in vivo and in vitro. Therefore Raman microspectroscopy may be utilized as a non-invasive and sensitive diagnostic tool to identify connective tissue disorders and monitor their disease progression. PMID- 27956366 TI - Biohybrid cardiac ECM-based hydrogels improve long term cardiac function post myocardial infarction. AB - : Injectable scaffolds for cardiac tissue regeneration are a promising therapeutic approach for progressive heart failure following myocardial infarction (MI). Their major advantage lies in their delivery modality that is considered minimally invasive due to their direct injection into the myocardium. Biomaterials comprising such scaffolds should mimic the cardiac tissue in terms of composition, structure, mechanical support, and most importantly, bioactivity. Nonetheless, natural biomaterial-based gels may suffer from limited mechanical strength, which often fail to provide the long-term support required by the heart for contraction and relaxation. Here we present newly-developed injectable scaffolds, which are based on solubilized decellularized porcine cardiac extracellular matrix (pcECM) cross-linked with genipin alone or engineered with different amounts of chitosan to better control the gel's mechanical properties while still leveraging the ECM biological activity. We demonstrate that these new biohybrid materials are naturally remodeled by mesenchymal stem cells, while supporting high viabilities and affecting cell morphology and organization. They exhibit neither in vitro nor in vivo immunogenicity. Most importantly, their application in treating acute and long term chronic MI in rat models clearly demonstrates the significant therapeutic potential of these gels in the long-term (12weeks post MI). The pcECM-based gels enable not only preservation, but also improvement in cardiac function eight weeks post treatment, as measured using echocardiography as well as hemodynamics. Infiltration of progenitor cells into the gels highlights the possible biological remodeling properties of the ECM based platform. STATEMENT OF SIGNIFICANCE: This work describes the development of new injectable scaffolds for cardiac tissue regeneration that are based on solubilized porcine cardiac extracellular matrix (ECM), combined with natural biomaterials: genipin, and chitosan. The design of such scaffolds aims at leveraging the natural bioactivity and unique structure of cardiac ECM, while overcoming its limited mechanical strength, which may fail to provide the long term support required for heart contraction and relaxation. Here, we present a biocompatible gel-platform with custom-tailored mechanical properties that significantly improve cardiac function when injected into rat hearts following acute and chronic myocardial infarction. We clearly demonstrate the substantial therapeutic potential of these scaffolds, which not only preserved heart functions but also alleviated MI damage, even after the formation of a mature scar tissue. PMID- 27956367 TI - Systematic evaluation of multifunctional paclitaxel-loaded polymeric mixed micelles as a potential anticancer remedy to overcome multidrug resistance. AB - : Multidrug resistance (MDR) of tumor cells is becoming the main reason for the failure of chemotherapy and P-glycoprotein (P-gp) mediated drug efflux has demonstrated to be the key factor for MDR. To address this issue, a novel pH responsive mixed micelles drug delivery system composed of dextran-g-poly(lactide co-glycolide)-g-histidine (HDP) and folate acid-D-alpha-tocopheryl polyethylene glycol 2000 (FA-TPGS2K) copolymers has been designed for the delivery of antitumor agent, paclitaxel (PTX) via FA-receptor mediated cell endocytosis, into PTX-resistant breast cancer MCF-7 cells (MCF-7/PTX). PTX-loaded FA-TPGS2K/HDP mixed micelles were characterized to have a small size distribution, high loading content and excellent pH-responsive drug release profiles. Compared with HDP micelles, FA-TPGS2K/HDP mixed micelles showed a higher cytotoxicity against MCF-7 and MCF-7/PTX cells due to the synergistic effect of FA-receptor mediated cell endocytosis, pH-responsive drug release and TPGS mediated P-gp inhibition. P-gp expression level, ATP content and mitochondrial membrane potential change have been measured, the results indicated blank FA-TPGS2K/HDP mixed micelles could inhibit the P-gp activity by reducing the mitochondrial membrane potential and depleting ATP content but not down-regulating the P-gp expression. In vivo antitumor activities demonstrated FA-TPGS2K/HDP mixed micelles could reach higher antitumor activity compared with HDP micelles for MCF-7/PTX tumor cells. Histological assay also indicated that FA-TPGS2K/HDP mixed micelles showed strongly apoptosis inducing effect, anti-proliferation effect and anti angiogenesis effect. All these evidences demonstrated this pH-sensitive FA TPGS2K/HDP micelle-based drug delivery system is a promising approach for overcoming MDR. STATEMENT OF SIGNIFICANCE: In this work, a novel FA-TPGS2K copolymer has been synthesized and used it to construct mixed micelles with HDP copolymer to overcome MDR effect. Furthermore, a series in vitro and in vivo evaluations have been made, which supported enough evidences for the efficient delivery of antitumor drug to MDR cells. PMID- 27956368 TI - Is the Game Over or Starting Again? The Role of the Transplant Team in Genetic Counseling for Adult Sickle Cell Disease Recipients. PMID- 27956369 TI - Therapeutic International Normalized Ratio Monitoring. PMID- 27956370 TI - Flow Cytometric Aldehyde Dehydrogenase Assay Enables a Fast and Accurate Human Umbilical Cord Blood Hematopoietic Stem Cell Assessment. AB - OBJECTIVE: Colony-forming units of granulocytes/macrophages (CFU-GM) analysis is the most widely used method to determine the hematopoietic stem cell (HSC) content of human umbilical cord blood (CB) for prediction of engraftment potential. The measurement of aldehyde dehydrogenase (ALDH) activity is a more recent method for HSC qualification. Our aim was to correlate phenotypic and functional assays to find the most predictive method. MATERIALS AND METHODS: In this study, flow cytometric quantitation of CD34+ cells and ALDH positivity along with CFU-GM capacity were assessed in fresh and post-thaw CB units. RESULTS: Among 30 post-processing samples, for each CB unit the mean total number of nucleated cells (TNCs) was (93.8+/-30.1)x107, CD34+ cells were (3.85+/-2.55)x106, ALDH+ cells were (3.14+/-2.55)x106, and CFU-GM count was (2.64+/-1.96)x105. Among an additional 19 post-thaw samples the cell counts were as follows: TNCs, (32.79+/-17.27)x107; CD34+, (2.18+/-3.17)x106; ALDH+, (2.01+/-2.81)x106; CFU-GM, (0.74+/-0.92)x105. Our findings showed that in fresh samples TNCs, CD34+ cells, and ALDH correlated highly with counts of CFU-GM, CFU-erythroids/granulocytes macrophages/megakaryocytic cells (GEMM), and burst forming units of erythroids (BFU-E) as follows: TNCs, r=0.47, r=0.35, r=0.41; CD34+, r=0.44, r=0.54, r=0.41; and ALDH, r=0.63, r=0.45, r=0.6, respectively. In terms of post-thaw samples, the correlations were as follows: TNCs, r=0.59, r=0.46, r=0.56; CD34+, r=0.67, r=0.48, r=0.61; and ALDH, r=0.61, r=0.67, r=0.67, for CFU-GM, CFU-GEMM, and BFU E, respectively. All correlations were statistically significant. CONCLUSION: In our experience, HSC assessment by ALDH activity yields the highest correlation with conventional analytical methods, particularly for post-thaw samples. Thus, this fast, inexpensive method has the potential to overcome the weaknesses of other techniques. PMID- 27956371 TI - Discrepancies in Lymphoma Diagnosis Over the Years: A 13-Year Experience in a Tertiary Center. AB - OBJECTIVE: In the past, accurate diagnosis of lymphoma was challenging since there were multiple competing classification systems that caused confusion and debate. After establishment of the World Health Organization lymphoma classification, lymphomas still remain a diagnostic challenge among general pathologists. The purpose of this study was to examine whether the discordance among centers has declined over the years. MATERIALS AND METHODS: All lymphoma or lymphoma-suspected specimens that had been sent to the Cerrahpasa Faculty of Medicine between 2000 and 2013 for a second opinion were deemed eligible. To evaluate the change in the discrepancy rates over time we compared the rates of revision between 2000-2008 and 2009-2013. RESULTS: A total of 1824 patients in two time periods met the inclusion criteria. The overall discordance rate was 45.6%. This rate showed significant variations between different histologic subtypes. Discordance rates also varied significantly over time and decreased from 51.3% in 2000-2008 to 38.7% in 2009-2013 (p<0.0001). CONCLUSION: The high discordance rate, especially in the second period, indicates the need for easily accessible hematopathology consultation centers. PMID- 27956372 TI - Comment: In Response to "Megaloblastic Anemia with Ring Sideroblasts is not Always Myelodysplastic Syndrome". PMID- 27956373 TI - Acute Myocardial Infarction Due to Eltrombopag Therapy in a Patient with Immune Thrombocytopenic Purpura. PMID- 27956376 TI - E-Cigarette Social Media Messages: A Text Mining Analysis of Marketing and Consumer Conversations on Twitter. AB - BACKGROUND: As the use of electronic cigarettes (e-cigarettes) rises, social media likely influences public awareness and perception of this emerging tobacco product. OBJECTIVE: This study examined the public conversation on Twitter to determine overarching themes and insights for trending topics from commercial and consumer users. METHODS: Text mining uncovered key patterns and important topics for e-cigarettes on Twitter. SAS Text Miner 12.1 software (SAS Institute Inc) was used for descriptive text mining to reveal the primary topics from tweets collected from March 24, 2015, to July 3, 2015, using a Python script in conjunction with Twitter's streaming application programming interface. A total of 18 keywords related to e-cigarettes were used and resulted in a total of 872,544 tweets that were sorted into overarching themes through a text topic node for tweets (126,127) and retweets (114,451) that represented more than 1% of the conversation. RESULTS: While some of the final themes were marketing-focused, many topics represented diverse proponent and user conversations that included discussion of policies, personal experiences, and the differentiation of e cigarettes from traditional tobacco, often by pointing to the lack of evidence for the harm or risks of e-cigarettes or taking the position that e-cigarettes should be promoted as smoking cessation devices. CONCLUSIONS: These findings reveal that unique, large-scale public conversations are occurring on Twitter alongside e-cigarette advertising and promotion. Proponents and users are turning to social media to share knowledge, experience, and questions about e-cigarette use. Future research should focus on these unique conversations to understand how they influence attitudes towards and use of e-cigarettes. PMID- 27956374 TI - Current Review of Iron Overload and Related Complications in Hematopoietic Stem Cell Transplantation. AB - Iron overload is an adverse prognostic factor for patients undergoing hematopoietic stem cell transplantation (HSCT). In the HSCT setting, pretransplant and early posttransplant ferritin and transferrin saturation were found to be highly elevated due to high transfusion requirements. In addition to that, post-HSCT iron overload was shown to be related to infections, hepatic sinusoidal obstruction syndrome, mucositis, liver dysfunction, and acute graft versus-host disease. Hyperferritinemia causes decreased survival rates in both pre- and posttransplant settings. Serum ferritin levels, magnetic resonance imaging, and liver biopsy are diagnostic tools for iron overload. Organ dysfunction due to iron overload may cause high mortality rates and therefore sufficient iron chelation therapy is recommended in this setting. In this review the management of iron overload in adult HSCT is discussed. PMID- 27956375 TI - An Ecological Momentary Intervention for Smoking Cessation: Evaluation of Feasibility and Effectiveness. AB - BACKGROUND: Despite substantial public health progress in reducing the prevalence of smoking in the United States overall, smoking among socioeconomically disadvantaged adults remains high. OBJECTIVE: To determine the feasibility and preliminary effectiveness of a novel smartphone-based smoking cessation app designed for socioeconomically disadvantaged smokers. METHODS: Participants were recruited from a safety-net hospital smoking cessation clinic in Dallas, Texas, and were followed for 13 weeks. All participants received standard smoking cessation clinic care (ie, group counseling and cessation pharmacotherapy) and a smartphone with a novel smoking cessation app (ie, Smart-T). The Smart-T app prompted 5 daily ecological momentary assessments (EMAs) for 3 weeks (ie, 1 week before cessation and 2 weeks after cessation). During the precessation period, EMAs were followed by messages that focused on planning and preparing for the quit attempt. During the postcessation period, participant responses to EMAs drove an algorithm that tailored messages to the current level of smoking lapse risk and currently present lapse triggers (eg, urge to smoke, stress). Smart-T offered additional intervention features on demand (eg, one-click access to the tobacco cessation quitline; "Quit Tips" on coping with urges to smoke, mood, and stress). RESULTS: Participants (N=59) were 52.0 (SD 7.0) years old, 54% (32/59) female, and 53% (31/59) African American, and 70% (40/57) had annual household income less than US $16,000. Participants smoked 20.3 (SD 11.6) cigarettes per day and had been smoking for 31.6 (SD 10.9) years. Twelve weeks after the scheduled quit date, 20% (12/59) of all participants were biochemically confirmed abstinent. Participants responded to 87% of all prompted EMAs and received approximately 102 treatment messages over the 3-week EMA period. Most participants (83%, 49/59) used the on-demand app features. Individuals with greater nicotine dependence and minority race used the Quit Tips feature more than their counterparts. Greater use of the Quit Tips feature was linked to nonabstinence at the 2 (P=.02), 4 (P<.01), and 12 (P=.03) week follow-up visits. Most participants reported that they actually used or implemented the tailored app-generated messages and suggestions (83%, 49/59); the app-generated messages were helpful (97%, 57/59); they would like to use the app in the future if they were to lapse (97%, 57/59); and they would like to refer friends who smoke to use the Smart-T app (85%, 50/59). A minority of participants (15%, 9/59) reported that the number of daily assessments (ie, 5) was "too high." CONCLUSIONS: This novel just-in-time adaptive intervention delivered an intensive intervention (ie, 102 messages over a 3-week period), was well-liked, and was perceived as helpful and useful by socioeconomically disadvantaged adults who were seeking smoking cessation treatment. Smartphone apps may be used to increase treatment exposure and may ultimately reduce tobacco-related health disparities among socioeconomically disadvantaged adults. PMID- 27956379 TI - Targets to reduce malaria unlikely to be met, says WHO. PMID- 27956377 TI - Examining Incentives to Promote Physical Activity Maintenance Among Hospital Employees Not Achieving 10,000 Daily Steps: A Web-Based Randomized Controlled Trial Protocol. AB - BACKGROUND: The economic burden of physical inactivity in Canada is estimated at Can $6.8 billion (US $5 billion) per year. Employers bear a substantial proportion of the economic costs, as they pay more for inactive workers in health care and other organizational costs. In response, many Canadian employers offer wellness programs, though these are often underutilized. While financial health incentives have been proposed as one way of increasing participation, their longer term effects (ie postintervention effects) are not clear. OBJECTIVE: The objective of this paper is to outline the methodology for a randomized control trial (RCT) examining the longer term impact of an existing physical activity promotion program that is enhanced by adding guaranteed rewards (Can $1 [US $0.74] per day step goal met) in a lower active hospital employee population (less than 10,000 steps per day). METHODS: A 12-week, parallel-arm RCT (with a 12 week postintervention follow-up) will be employed. Employees using Change4Life (a fully automated, incentive-based wellness program) and accumulating fewer than 10,000 steps per day at baseline (weeks 1 to 2) will be randomly allocated (1:1) to standard care (wellness program, accelerometer) or an intervention group (standard care plus guaranteed incentives). All study participants will be asked to wear the accelerometer and synchronize it to Change4Life daily, although only intervention group participants will receive guaranteed incentives for reaching tailored daily step count goals (Can $1 [US $0.74] per day; weeks 3 to 12). The primary study outcome will be mean proportion of participant-days step goal reached during the postintervention follow-up period (week 24). Mean proportion of participant-days step goal reached during the intervention period (week 12) will be a secondary outcome. RESULTS: Enrollment for the study will be completed in February 2017. Data analysis will commence in September 2017. Study results are to be published in the winter of 2018. CONCLUSIONS: This protocol was designed to examine the impact of guaranteed rewards on physical activity maintenance in lower active hospital employees. CLINICALTRIAL: ClinicalTrials.gov NCT02638675; https://clinicaltrials.gov/ct2/show/NCT0 2638675 (Archived by WebCite at http://www.webcitation.org/6g4pvZvhW). PMID- 27956382 TI - Inconsistent blood pressure phenotype in female Dahl salt-sensitive rats. PMID- 27956383 TI - Comment on osmotically inactive ions. PMID- 27956380 TI - Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade. AB - Immune checkpoint inhibitors are promising treatments for patients with a variety of malignancies. Toward understanding the determinants of response to immune checkpoint inhibitors, it was previously demonstrated that the presence of somatic mutations is associated with benefit from checkpoint inhibition. A hypothesis was posited that neoantigen homology to pathogens may in part explain the link between somatic mutations and response. To further examine this hypothesis, we reanalyzed cancer exome data obtained from our previously published study of 64 melanoma patients treated with CTLA-4 blockade and a new dataset of RNA-Seq data from 24 of these patients. We found that the ability to accurately predict patient benefit did not increase as the analysis narrowed from somatic mutation burden, to inclusion of only those mutations predicted to be MHC class I neoantigens, to only including those neoantigens that were expressed or that had homology to pathogens. The only association between somatic mutation burden and response was found when examining samples obtained prior to treatment. Neoantigen and expressed neoantigen burden were also associated with response, but neither was more predictive than somatic mutation burden. Neither the previously described tetrapeptide signature nor an updated method to evaluate neoepitope homology to pathogens was more predictive than mutation burden. Cancer Immunol Res; 5(1); 84-91. (c)2016 AACR. PMID- 27956381 TI - Hydrogen peroxide suppresses TRPM4 trafficking to the apical membrane in mouse cortical collecting duct principal cells. AB - A Ca2+-activated nonselective cation channel (NSCCa) is found in principal cells of the mouse cortical collecting duct (CCD). However, the molecular identity of this channel remains unclear. We used mpkCCDc14 cells, a mouse CCD principal cell line, to determine whether NSCCa represents the transient receptor potential (TRP) channel, the melastatin subfamily 4 (TRPM4). A Ca2+-sensitive single channel current was observed in inside-out patches excised from the apical membrane of mpkCCDc14 cells. Like TRPM4 channels found in other cell types, this channel has an equal permeability for Na+ and K+ and has a linear current-voltage relationship with a slope conductance of ~23 pS. The channel was inhibited by a specific TRPM4 inhibitor, 9-phenanthrol. Moreover, the frequency of observing this channel was dramatically decreased in TRPM4 knockdown mpkCCDc14 cells. Unlike those previously reported in other cell types, the TRPM4 in mpkCCDc14 cells was unable to be activated by hydrogen peroxide (H2O2). Conversely, after treatment with H2O2, TRPM4 density in the apical membrane of mpkCCDc14 cells was significantly decreased. The channel in intact cell-attached patches was activated by ionomycin (a Ca2+ ionophore), but not by ATP (a purinergic P2 receptor agonist). These data suggest that the NSCCa current previously described in CCD principal cells is actually carried through TRPM4 channels. However, the physiological role of this channel in the CCD remains to be further determined. PMID- 27956384 TI - Among Low-Income Respondents With Diabetes, High-Deductible Versus No-Deductible Insurance Sharply Reduces Medical Service Use. AB - OBJECTIVE: To contrast the effect of private insurance and deductibles (by size) on medical service use, health status, and medical debt for adult respondents with diabetes with low and high incomes. RESEARCH DESIGN AND METHODS: Using the 2011-2013 Medical Expenditure Panel Survey, bivariate and regression analyses were conducted to compare demographic characteristics, medical service use, diabetes care, and health status among privately insured adult respondents with diabetes, aged 18-64 years (N = 1,461) by lower (<200% of the federal poverty level) and higher (>=200% of the federal poverty level) income and deductible vs. no deductible (ND), low deductible ($1,000/$2,400) (LD), and high deductible (>$1,000/$2,400) (HD). The National Health Interview Survey 2012-2014 was used to analyze differences in medical debt and delayed/avoided needed care among adult respondents with diabetes (n = 4,058) by income. RESULTS: Compared with privately insured respondents with diabetes with ND, privately insured lower-income respondents with diabetes with an LD report significant decreases in service use for primary care, checkups, and specialty visits (27%, 39%, and 77% lower, respectively), and respondents with an HD decrease use by 42%, 65%, and 86%, respectively. Higher-income respondents with an LD report significant decreases in specialty (28%) and emergency department (37%) visits. Diabetes care measures are similar by income and insurance; there were no changes in physical health status. Medical debt is similar by income, but deferred service use is two times greater for those indebted and with lower income. CONCLUSIONS: Private insurance with a deductible substantially and problematically reduces medical service use for lower-income insured respondents with diabetes who have an HD; these patients are more likely to report forgoing needed medical services. PMID- 27956385 TI - Evaluating surveillance imaging for diffuse large B-cell lymphoma and Hodgkin lymphoma. AB - Up to 50% of patients with Hodgkin lymphoma and diffuse large B-cell lymphoma will relapse, requiring additional therapy. Although surveillance imaging is commonly performed in clinical practice, its ability to identify asymptomatic relapses and improve survival for patients is not well defined. We evaluated the surveillance imaging role in relapse detection and reviewed its impact on survival for relapsed patients, and found that current imaging approaches do not detect most relapses prior to clinical signs and symptoms or improve survival. PMID- 27956386 TI - Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. PMID- 27956387 TI - Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy and bone marrow transplantation, overall survival remains poor. Sphingosine kinase 1 (SPHK1) generates the bioactive lipid sphingosine 1-phosphate (S1P) and has established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers. The role and targeting of SPHK1 in primary AML, however, has not been previously investigated. Here we show that SPHK1 is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death in AML cell lines, primary AML patient blasts, and isolated AML patient leukemic progenitor/stem cells, with negligible effects on normal bone marrow CD34+ progenitors from healthy donors. Furthermore, administration of SPHK1 inhibitors to orthotopic AML patient-derived xenografts reduced tumor burden and prolonged overall survival without affecting murine hematopoiesis. SPHK1 inhibition was associated with reduced survival signaling from S1P receptor 2, resulting in selective downregulation of the prosurvival protein MCL1. Subsequent analysis showed that the combination of BH3 mimetics with either SPHK1 inhibition or S1P receptor 2 antagonism triggered synergistic AML cell death. These results support the notion that SPHK1 is a bona fide therapeutic target for the treatment of AML. PMID- 27956390 TI - Ludwig angina. PMID- 27956388 TI - Autophagy, a key mechanism of oncogenesis and resistance in leukemia. AB - Autophagy is a lysosomal pathway involved in degradation of intracellular material. It appears as an adaptation mechanism that is essential for cellular homeostasis in response to various stress conditions. Over the past decade, many studies have linked alteration of autophagy with cancer initiation and progression, autoimmune, inflammatory, metabolic, and degenerative diseases. This review highlights recent findings on the impact of autophagy on leukemic transformation of normal hematopoietic stem cells and summarizes its role on leukemic cell response to chemotherapy. PMID- 27956391 TI - Truth in fiction. PMID- 27956392 TI - Oxalate nephropathy from cashew nut intake. PMID- 27956394 TI - The challenges of physician retirement. PMID- 27956395 TI - Fracking tied to cancer-causing chemicals. PMID- 27956396 TI - Standardizing the evaluation and management of neuropathic pain following spinal cord injury. PMID- 27956393 TI - Relative effectiveness of additive pain interventions during vaccination in infants. AB - BACKGROUND: Vaccine injections can cause acute pain and distress in infants, which can contribute to dissatisfaction with the vaccination experience and vaccine hesitancy. We sought to compare the effectiveness of additive pain interventions administered consistently during vaccine injections in the first year of life. METHODS: We conducted a multicentre, longitudinal, double-blind, add-on, randomized controlled trial. Healthy infants were randomly assigned to 1 of 4 levels of pain management for all vaccine injections at 2, 4, 6 and 12 months: (i) placebo control; (ii) parent-directed video education about infant soothing; (iii) the video plus sucrose administered orally or (iv) the video plus sucrose plus liposomal lidocaine applied topically. All infants benefit from injection techniques that minimize pain. We used a double-dummy design; hence all parents watched a video (active psychological intervention or placebo) and all infants received oral solution (sucrose or placebo) and topical cream (lidocaine or placebo). We assessed infant distress during 3 phases - preinjection (baseline), vaccine injection (needle), and 1 minute postinjection (recovery) - using the Modified Behavioural Pain Scale (range 0-10). We compared scores between groups and across infant ages using a mixed-model repeated-measures analysis. RESULTS: A total of 352 infants participated in the study, from Jan. 17, 2012, to Feb. 2, 2016. Demographics did not differ among intervention groups (p > 0.05). Baseline pain scores did not differ among intervention groups (p = 0.4), but did differ across ages (p < 0.001). Needle pain scores differed among groups (p = 0.003) and across ages (p < 0.001). The mean (+/- standard deviation) needle score was 6.3 (+/- 0.8) in the video-sucrose-lidocaine group compared with 6.7 (+/- 0.8) in each of the other groups. There were no other between-group differences. Recovery scores did not differ among groups (p = 0.98), but did differ across ages (p < 0.001). INTERPRETATION: Only liposomal lidocaine provided consistent analgesia within an additive pain intervention regimen during vaccinations in infants. Trial registration: ClinicalTrials.gov, no. NCT01503060. PMID- 27956397 TI - Integration not a solution for frequent ED use. PMID- 27956399 TI - Two urologists conducted research without consent or ethics approval. PMID- 27956398 TI - Neurohormonal Activation After Atrial Fibrillation Initiation in Patients Eligible for Catheter Ablation: A Randomized Controlled Study. AB - BACKGROUND: Biomarker activation in atrial fibrillation (AF) has been widely studied, but the immediate effect of AF initiation remains unclear. We studied the effect of AF initiation on 2 cardiac biomarkers: the N-terminal fragment of the proB-type natriuretic peptide (NT-proBNP), the midregional fragment of the N terminal of pro-atrial natriuretic peptide (MR-proANP), and 2 extracardiac biomarkers-the copeptin and the midregional portion of proadrenomedullin (MR proADM). METHODS AND RESULTS: This was a randomized controlled study, including 45 patients with AF who had been referred for radiofrequency ablation to the University Hospital, Linkoping, Sweden, between February 2012 and April 2014. Freedom from AF during the 4 days prior to radiofrequency ablation was confirmed by transtelephonic ECGs. Biomarkers were collected from the femoral vein (fv), coronary sinus (CS), and left atrium (LA) prior to AF initiation (baseline) and 30 minutes later. The MR-proANP and NT-proBNP concentrations increased in the intervention group compared with the control group 30 minutes after the initiation of AF (MR-proANP: Pfv<0.001, PCS<0.001, PLA<0.001; NT-proBNP: PLA<0.001). Copeptin levels in patients without ischemic heart disease were decreased after the initiation of AF (Pfv=0.003, PCS=0.015, PLA=0.011). CONCLUSIONS: AF is a strong stimulus that results in immediate activation of different biomarkers. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01553045. PMID- 27956402 TI - Looking Beyond Statins: Will the Dollars Make Sense? PMID- 27956400 TI - Complement peptide C3a stimulates neural plasticity after experimental brain ischaemia. AB - Ischaemic stroke induces endogenous repair processes that include proliferation and differentiation of neural stem cells and extensive rewiring of the remaining neural connections, yet about 50% of stroke survivors live with severe long-term disability. There is an unmet need for drug therapies to improve recovery by promoting brain plasticity in the subacute to chronic phase after ischaemic stroke. We previously showed that complement-derived peptide C3a regulates neural progenitor cell migration and differentiation in vitro and that C3a receptor signalling stimulates neurogenesis in unchallenged adult mice. To determine the role of C3a-C3a receptor signalling in ischaemia-induced neural plasticity, we subjected C3a receptor-deficient mice, GFAP-C3a transgenic mice expressing biologically active C3a in the central nervous system, and their respective wild type controls to photothrombotic stroke. We found that C3a overexpression increased, whereas C3a receptor deficiency decreased post-stroke expression of GAP43 (P < 0.01), a marker of axonal sprouting and plasticity, in the peri infarct cortex. To verify the translational potential of these findings, we used a pharmacological approach. Daily intranasal treatment of wild-type mice with C3a beginning 7 days after stroke induction robustly increased synaptic density (P < 0.01) and expression of GAP43 in peri-infarct cortex (P < 0.05). Importantly, the C3a treatment led to faster and more complete recovery of forepaw motor function (P < 0.05). We conclude that C3a-C3a receptor signalling stimulates post ischaemic neural plasticity and intranasal treatment with C3a receptor agonists is an attractive approach to improve functional recovery after ischaemic brain injury. PMID- 27956401 TI - Use of Sodium Glucose Cotransporter 2 Inhibitors in the Hands of Cardiologists: With Great Power Comes Great Responsibility. PMID- 27956403 TI - Vascular Surgeons: Leading the Way in Global Quality Improvement. PMID- 27956404 TI - Percutaneous Therapies for Peripheral Artery Disease. AB - Percutaneous therapies for peripheral artery disease continue to evolve with new techniques and devices. Although guidelines-recommended therapies have impacted cardiovascular morbidity and mortality, endovascular interventions have been shown to reduce limb pain, improve quality of life, and prolong walking distance for those with claudication and to reduce amputation rates among those with critical limb ischemia. Novel devices such as drug-eluting stents and drug-coated balloons have improved patency for moderate-length lesions, whereas others allow treatment of heavily calcified and tortuous segments. New adjunctive devices to cross lesions and reduce or modify associated plaque have also been developed, although level 1 data regarding their efficacy are sparse. There has also been a better mechanistic understanding of lower extremity endovascular treatment using tools such as intravascular ultrasound. This information has highlighted the need for better stent size selection for the femoropopliteal arterial segments and larger balloon diameters for the tibial arteries. Moreover, a wound perfusion approach with direct in-line flow, the so-called angiosome approach, and reconstruction of the pedal loop have been advocated for improved wound healing. Technical advances such as the tibiopedal access and reentry methods have allowed crossing of lesions that were considered no option for the endovascular approach in the past. Collectively, there has been increased awareness, interest, and commitment by various specialty societies and organizations to advance the treatment of peripheral artery disease and critical limb ischemia. This is also evident by the recent coalition of 7 professional societies and organizations that represented >150 000 allied health professionals and millions of patients with peripheral artery disease at the 2015 Centers for Medicaid and Medicare Services Medicare Evidence Development and Coverage Analysis Committee meeting. The percutaneous therapies for peripheral artery disease continue to evolve with longer follow-up with randomized data and larger prospective registries. In the future, it is hopeful that we will treat the lower extremity arteries according to segments, taking into account plaque morphology, luminal versus subintimal crossing, location, and stenotic versus occlusive disease. Until then, we must identify the most cost-effective, efficacious, and safe treatment for each patient. The goal of this article is to aid the practicing vascular specialist consider the optimal choices for the management of patients with vascular disease. PMID- 27956405 TI - Long-Term Outcomes After Percutaneous Transluminal Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension. PMID- 27956406 TI - Letter by Cordero et al Regarding Article, "Regional Systems of Care Demonstration Project: American Heart Association Mission: Lifeline STEMI Systems Accelerator". PMID- 27956407 TI - Coronary Plaque Morphology and the Anti-Inflammatory Impact of Atorvastatin: A Multicenter 18F-Fluorodeoxyglucose Positron Emission Tomographic/Computed Tomographic Study. AB - BACKGROUND: Nonobstructive coronary plaques manifesting high-risk morphology (HRM) associate with an increased risk of adverse clinical cardiovascular events. We sought to test the hypothesis that statins have a greater anti-inflammatory effect within coronary plaques containing HRM. METHODS AND RESULTS: In this prospective multicenter study, 55 subjects with or at high risk for atherosclerosis underwent 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and after 12 weeks of treatment with atorvastatin. Coronary arterial inflammation (18F fluorodeoxyglucose uptake, expressed as target-to-background ratio) was assessed in the left main coronary artery (LMCA). While blinded to the PET findings, contrast-enhanced computed tomographic angiography was performed to characterize the presence of HRM (defined as noncalcified or partially calcified plaques) in the LMCA. Arterial inflammation (target-to-background ratio) was higher in LMCA segments with HRM than those without HRM (mean+/-SEM: 1.95+/-0.43 versus 1.67+/ 0.32 for LMCA with versus without HRM, respectively; P=0.04). Moreover, atorvastatin treatment for 12 weeks reduced target-to-background ratio more in LMCA segments with HRM than those without HRM (12 week-baseline Deltatarget-to background ratio [95% confidence interval]: -0.18 [-0.35 to -0.004] versus 0.09 [ 0.06 to 0.26]; P=0.02). Furthermore, this relationship between coronary plaque morphology and change in LMCA inflammatory activity remained significant after adjusting for baseline low-density lipoprotein and statin dose (beta=-0.27; P=0.038). CONCLUSIONS: In this first study to evaluate the impact of statins on coronary inflammation, we observed that the anti-inflammatory impact of statins is substantially greater within coronary plaques that contain HRM features. These findings suggest an additional mechanism by which statins disproportionately benefit individuals with more advanced atherosclerotic disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00703261. PMID- 27956408 TI - Microvascular Function Contributes to the Relation Between Aortic Stiffness and Cardiovascular Events: The Framingham Heart Study. AB - BACKGROUND: Arterial dysfunction contributes to cardiovascular disease (CVD) progression and clinical events. Inter-relations of aortic stiffness and vasodilator function with incident CVD remain incompletely studied. METHODS AND RESULTS: We used proportional hazards models to relate individual measures of vascular function to incident CVD in 4547 participants (mean age, 51+/-11 years; 54% women) in 2 generations of Framingham Heart Study participants. During follow up (0.02-13.83 years), 232 participants (5%) experienced new-onset CVD events. In multivariable models adjusted for cardiovascular risk factors, both higher carotid-femoral pulse wave velocity (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.07-1.63; P=0.01) and lower hyperemic mean flow velocity (HR, 0.84; 95% CI, 0.71-0.99; P=0.04) were associated significantly with incident CVD, whereas primary pressure wave amplitude (HR, 1.12; 95% CI, 0.99-1.27; P=0.06), baseline brachial diameter (HR, 1.09; 95% CI, 0.90-1.31; P=0.39), and flow mediated vasodilation (HR, 0.85; 95% CI, 0.69-1.04; P=0.12) were not. In mediation analyses, 8% to 13% of the relation between aortic stiffness and CVD events was mediated by hyperemic mean flow velocity. CONCLUSIONS: Our results suggest that associations between aortic stiffness and CVD events are mediated by pathways that include microvascular damage and remodeling. PMID- 27956410 TI - Positron Emission Tomography Assessment of Left Main Coronary Arterial Inflammation With Coronary Computed Tomographic Angiography Validation Before and After Statin Therapy: More Promise for Fluorodeoxyglucose Vascular Uptake? PMID- 27956409 TI - Functional Assessment of Coronary Artery Disease Using Whole-Heart Dynamic Computed Tomographic Perfusion. AB - BACKGROUND: Computed tomographic (CT) angiography is an important tool for the evaluation of coronary artery disease but often correlates poorly with myocardial ischemia. Current dynamic CT perfusion techniques can assess ischemia but have limited accuracy and deliver high radiation dose. Therefore, an accurate, low dose, dynamic CT perfusion technique is needed. METHODS AND RESULTS: A total of 20 contrast-enhanced CT volume scans were acquired in 5 swine (40+/-10 kg) to generate CT angiography and perfusion images. Varying degrees of stenosis were induced using a balloon catheter in the proximal left anterior descending coronary artery, and a pressure wire was used for reference fractional flow reserve (FFR) measurement. Perfusion measurements were made with only 2 volume scans using a new first-pass analysis (FPA) technique and with 20 volume scans using an existing maximum slope model (MSM) technique. Perfusion (P) and FFR measurements were related by PFPA=1.01 FFR-0.03 (R2=0.85) and PMSM=1.03 FFR-0.03 (R2=0.80) for FPA and MSM techniques, respectively. Additionally, the effective radiation doses were calculated to be 2.64 and 26.4 mSv for FPA and MSM techniques, respectively. CONCLUSIONS: A new FPA-based dynamic CT perfusion technique was validated in a swine animal model. The results indicate that the FPA technique can potentially be used for improved anatomical and functional assessment of coronary artery disease at a relatively low radiation dose. PMID- 27956411 TI - Large Artery Stiffness, Microvascular Function, and Cardiovascular Risk. PMID- 27956413 TI - Letter to the editor: Comments on Stuart et al. (2016): "Myosin content of individual human muscle fibers isolated by laser capture microdissection". PMID- 27956412 TI - Expression of renin-angiotensin system (RAS) components in endometrial cancer. AB - A dysfunctional endometrial renin-angiotensin system (RAS) could aid the growth and spread of endometrial cancer. To determine if the RAS is altered in endometrial cancer, we measured RAS gene expression and protein levels in 30 human formalin-fixed, paraffin-embedded (FFPE) endometrioid carcinomas and their adjacent endometrium. All components of the RAS were expressed in most tumours and in adjacent endometrium; mRNA levels of (pro)renin receptor (ATP6AP2), angiotensin II type 1 receptor (AGTR1), angiotensin-converting enzyme (ACE1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were greater in tumour tissue than adjacent non-cancerous endometrium (P = 0.023, 0.008, 0.004 and 0.046, respectively). Prorenin, ATP6AP2, AGTR1, AGTR2 and ACE2 proteins were abundantly expressed in both cancerous and adjacent non-cancerous endometrium. Staining was most intense in cancerous glandular epithelium. One potential target of the endometrial RAS, transforming growth factor beta-1 (TGFB1), which is essential for epithelial-to-mesenchymal transition, was also upregulated in endometrial cancer tissue (P = 0.001). Interestingly, TGFB1 was strongly correlated with RAS expression and was upregulated in tumour tissue. This study is the first to characterise the mRNA and protein expression of all RAS components in cancerous and adjacent non-cancerous endometrium. The greater expression of ATP6AP2, AGTR1 and ACE1, key elements of the pro-angiogenic/proliferative arm of the RAS, suggests that the RAS plays a role in the growth and spread of endometrial cancer. Therefore, existing drugs that inhibit the RAS and which are used to treat hypertension may have potential as treatments for endometrial cancer. PMID- 27956415 TI - Corrigendum. PMID- 27956414 TI - Reply to "Letter to the editor: Comments on Stuart et al. (2016): 'Myosin content of individual human muscle fibers isolated by laser capture microdissection'". PMID- 27956417 TI - Effects of Oritavancin on Coagulation Tests in the Clinical Laboratory. AB - Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid dependent coagulation tests. The effect of oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study after an infusion of a single 1,200-mg intravenous dose of oritavancin in normal healthy volunteers. Pooled plasma with oritavancin added ex vivo showed concentration-dependent prolongation of prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and dilute Russell viper venom time (DRVVT) test results. In contrast, oritavancin had no effect on the activated protein C resistance assay, chromogenic anti-factor Xa assay (anti-FXa), thrombin time, and an immunoassay for the laboratory diagnosis of heparin-induced thrombocytopenia. In participants that received a single dose of oritavancin, elevations in PT/INR result, aPTT, DRVVT, activated clotting time, and silica clotting time occurred, with the maximum times to resolution of test interference determined to be 12, 120, 72, 24, and 18 h, respectively. The anti-FXa assay was unaffected, whereas transient elevations in D dimer levels were observed in 30% of participants, with a maximum time to resolution of 72 h. Although oritavancin has no impact on the coagulation system in vivo, a single dose of oritavancin can produce falsely elevated values of some coagulation tests used to monitor hemostasis. The interference of oritavancin on affected tests is transient, and the test results revert to normal ranges within specified times after dosing. PMID- 27956416 TI - Telomere Shortening, Regenerative Capacity, and Cardiovascular Outcomes. AB - RATIONALE: Leukocyte telomere length (LTL) is a biological marker of aging, and shorter LTL is associated with adverse cardiovascular outcomes. Reduced regenerative capacity has been proposed as a mechanism. Bone marrow-derived circulating progenitor cells are involved in tissue repair and regeneration. OBJECTIVE: Main objective of this study was to examine the relationship between LTL and progenitor cells and their impact on adverse cardiovascular outcomes. METHODS AND RESULTS: We measured LTL by quantitative polymerase chain reaction in 566 outpatients (age: 63+/-9 years; 76% men) with coronary artery disease. Circulating progenitor cells were enumerated by flow cytometry. After adjustment for age, sex, race, body mass index, smoking status, and previous myocardial infarction, a shorter LTL was associated with a lower CD34+ cell count: for each 10% shorter LTL, CD34+ levels were 5.2% lower (P<0.001). After adjustment for the aforementioned factors, both short LTL (=1.5 mg/liter) by Etest and 87 (8.5%) by broth microdilution (BMD). The all-cause 30 day mortality rate was 27.4%. High VAN-MIC by either method was not associated with all-cause 30-day mortality, and this finding was consistent across MIC methodologies and methicillin susceptibilities. We conclude that high VAN-MIC is not associated with increased risk of all-cause 30-day mortality in ISA infections. Our data support the view that VAN-MIC alone is not sufficient evidence to change current clinical practice. PMID- 27956434 TI - Precise Noninvasive ECG Mapping Derived Localization of the Origin of an Epicardial Ventricular Tachycardia. PMID- 27956435 TI - Expecting the Expected: Electrocardiographic Identification for Ablation Targets. PMID- 27956436 TI - Cancer Incidence and Survival Trends by Subtype Using Data from the Surveillance Epidemiology and End Results Program, 1992-2013. AB - Background: Cancers are heterogeneous, comprising distinct tumor subtypes. Therefore, presenting the burden of cancer in the population and trends over time by these tumor subtypes is important to identify patterns and differences in the occurrence of these subtypes, especially to generalize findings to the U.S. general population.Methods: Using SEER Cancer Registry Data, we present incidence rates according to subtypes for diagnosis years (1992-2013) among men and women for five major cancer sites: breast (female only), esophagus, kidney and renal pelvis, lung and bronchus, and thyroid. We also describe estimates of 5-year relative survival according to subtypes and diagnosis year (1992-2008). We used Joinpoint models to identify years when incidence rate trends changed slope. Finally, recent 5-year age-adjusted incidence rates (2009-2013) are presented for each subtype by race and age.Results: Hormone receptor-positive and HER2-negative was the most common subtype (about 74%) of breast cancers. Adenocarcinoma made up about 69% of esophagus cases among men. Adenocarcinoma also is the most common lung subtype (43% in men and 52% in women). Ninety percent of thyroid subtypes were papillary. Distinct incidence and survival patterns emerged by these subtypes over time among men and women.Conclusions: Histologic or molecular subtype revealed different incidence and/or survival trends that are masked when cancer is considered as a single disease on the basis of anatomic site.Impact: Presenting incidence and survival trends by subtype, whenever possible, is critical to provide more detailed and meaningful data to patients, providers, and the public. Cancer Epidemiol Biomarkers Prev; 26(4); 632-41. (c)2016 AACR. PMID- 27956438 TI - No 10 Stationary Hospital and the chapel ward at Saint-Omer, France, 1914-18. PMID- 27956439 TI - Heart failure - what's new and what's changed? AB - Physicians responsible for the care of patients with heart failure due to left ventricular systolic dysfunction have access to a broad range of evidence-based treatments that prolong life and reduce symptoms. In spite of the significant progress made over the last four decades, there is an ongoing need for novel therapies to treat a condition that is associated with stubbornly high morbidity and mortality. In this article, we discuss the findings of SERVE-HF, a randomised controlled trial of adaptive servo-ventilation in patients with left ventricular systolic dysfunction, as well as EMPA-REG, a study of the effects of a novel diabetic agent that may be of greater interest to heart failure specialists than diabetologists. We also examine further analyses of the groundbreaking PARADIGM HF trial, which attempt to answer some of the unresolved questions from the original study of the first combined angiotensin-receptor blocker and neprilysin inhibitor, sacubitril valsartan. The recently published National Institute for Health and Care Excellence guidelines for the management of acute heart failure and plans to introduce best practice tariffs bring into focus the need for well organised, multidisciplinary care. We discuss the challenges involved in developing and delivering a specialist service that meets the needs of a growing population of patients living with heart failure. PMID- 27956437 TI - Transcriptomic Microenvironment of Lung Adenocarcinoma. AB - Background: Tissues surrounding tumors are increasingly studied to understand the biology of cancer development and identify biomarkers.Methods: A unique geographic tissue sampling collection was obtained from patients that underwent curative lobectomy for stage I pulmonary adenocarcinoma. Tumor and nontumor lung samples located at 0, 2, 4, and 6 cm away from the tumor were collected. Whole genome gene expression profiling was performed on all samples (n = 5 specimens * 12 patients = 60). Analyses were carried out to identify genes differentially expressed in the tumor compared with adjacent nontumor lung tissues at different distances from the tumor as well as to identify stable and transient genes in nontumor tissues with respect to tumor proximity.Results: The magnitude of gene expression changes between tumor and nontumor sites was similar with increasing distance from the tumor. A total of 482 up- and 843 downregulated genes were found in tumors, including 312 and 566 that were consistently differentially expressed across nontumor sites. Twenty-nine genes induced and 34 knocked-down in tumors were also identified. Tumor proximity analyses revealed 15,700 stable genes in nontumor lung tissues. Gene expression changes across nontumor sites were subtle and not statistically significant.Conclusions: This study describes the transcriptomic microenvironment of lung adenocarcinoma and adjacent nontumor lung tissues collected at standardized distances relative to the tumor.Impact: This study provides further insights about the molecular transitions that occur from normal tissue to lung adenocarcinoma and is an important step to develop biomarkers in nonmalignant lung tissues. Cancer Epidemiol Biomarkers Prev; 26(3); 389-96. (c)2016 AACR. PMID- 27956440 TI - Acute coronary syndromes. AB - In the UK, there are over 80,000 admissions annually with acute coronary syndromes (ACS). Management of ST-elevation myocardial infarction (STEMI) involves primary percutaneous coronary intervention (PCI), which is delivered via dedicated heart attack centres. Non-ST elevation-ACS (NSTE-ACS) accounts for two thirds of ACS presentations, affecting an older cohort of patients - often with more complex comorbidities. Initial management is with anti-thrombotic therapy with a view to PCI within 24 hours for the most acute cases and within 72 hours for all others. However, varying management pathways and access to specialist cardiology services results in variable times to definitive treatment. Advances in the sensitivity of cardiac biomarkers and the use of risk assessment tools now enable rapid diagnosis within a few hours of symptom onset. Advances in invasive management and drug therapy have resulted in improved clinical outcomes with resultant decline in mortality associated with ACS. PMID- 27956441 TI - Stroke. AB - In this article, we briefly describe some of the challenges in delivering a stroke service in the NHS in England and how we have overcome them. Current issues are considered and research prospects described. We show that providing excellent stroke care is as much about organising services as it is about medical intervention. PMID- 27956442 TI - Multiple sclerosis, a treatable disease. AB - This article reviews our current understanding and modern treatment of multiple sclerosis (MS). MS is a disabling condition resulting in devastating social and economic impacts. As MS can affect any part of the central nervous system, the presentation is often diverse; however, there are key features that can be useful in the clinic. We comment on the diagnostic criteria and review the main subtypes of MS, including clinically isolated syndrome, relapsing remitting MS, secondary progressive MS and primary progressive MS. Although the underlying aetiology of MS is still not known, we summarise those with most evidence of association. Finally, we aim to present treatment strategies for managing the acute relapse, disease-modifying therapies and MS symptoms. This review highlights that progressive MS is an area where there is currently a paucity of available disease modifying treatments and this will be a major focus for future development. PMID- 27956443 TI - Motor neuron disease: biomarker development for an expanding cerebral syndrome. AB - Descriptions of motor neuron disease (MND) documented more than a century ago remain instantly recognisable to the physician. The muscle weakness, typically with signs of upper and lower motor neuron dysfunction, is uniquely relentless. Over the last 30 years, a wider cerebral pathology has emerged, despite the lack of overt cognitive impairment in the majority of patients. From the initial linkage of a small number of cases to mutations in SOD1, diverse cellular pathways have been implicated in pathogenesis. An increasingly complex clinical heterogeneity has emerged around a significant variability in survival. Defining a cellular signature of aggregated TDP-43 common to nearly all MND and a large proportion of frontotemporal dementia (FTD), has placed MND alongside more traditional cerebral neurodegeneration. With new genetic causes, most notably a hexanucleotide expansion in C9orf72 associated with both MND and FTD, the development of biomarkers against which to test therapeutic candidates is a priority. PMID- 27956444 TI - Acute respiratory distress syndrome. AB - Acute respiratory distress syndrome is a common cause of acute respiratory failure that is underdiagnosed both inside and outside of intensive care units. Progression to the most severe forms of the syndrome confers a mortality rate greater than 40% and is associated with often severe functional disability and psychological sequelae in survivors. While there are no disease-modifying pharmacotherapies for the syndrome, this progression may be prevented through the institution of quality improvement measures that minimise iatrogenic injury associated with acute severe illness. PMID- 27956445 TI - Update in diagnosis and management of interstitial lung disease. AB - The field of interstitial lung disease (ILD) has undergone significant evolution in recent years, with an increasing incidence and more complex, ever expanding disease classification. In their most severe forms, these diseases lead to progressive loss of lung function, respiratory failure and eventually death. Despite notable advances, progress has been challenged by a poor understanding of pathological mechanisms and patient heterogeneity, including variable progression. The diagnostic pathway is thus being continually refined, with the introduction of tools such as transbronchial cryo lung biopsy and a move towards genetically aided, precision medicine. In this review, we focus on how to approach a patient with ILD and the diagnostic process. PMID- 27956446 TI - Beyond pills and tests: addressing the social determinants of tuberculosis. AB - Poverty drives tuberculosis (TB) rates but the approach to TB control has been disproportionately biomedical. In 2015, the World Health Organization's End TB Strategy explicitly identified the need to address the social determinants of TB through socio-economic interventions. However, evidence concerning poverty reduction and cost mitigation strategies is limited. The research described in this article, based on the 2016 Royal College of Physicians Linacre Lecture, aimed to address this knowledge gap. The research was divided into two phases: the first phase was an analysis of a cohort study identifying TB-related costs of TB-affected households and creating a clinically relevant threshold above which those costs became catastrophic; the second was the design, implementation and evaluation of a household randomised controlled evaluation of socio-economic support to improve access to preventive therapy, increase TB cure, and mitigate the effects of catastrophic costs. The first phase showed TB remains a disease of people living in poverty - 'free' TB care was unaffordable for impoverished TB affected households and incurring catastrophic costs was associated with as many adverse TB treatment outcomes (including death, failure of treatment, lost to follow-up and TB recurrence) as multidrug resistant (MDR) TB. The second phase showed that, in TB-affected households receiving socio-economic support, household contacts were more likely to start and adhere to TB preventive therapy, TB patients were more likely to be cured and households were less likely to incur catastrophic costs. In impoverished Peruvian shantytowns, poverty remains inextricably linked with TB and incurring catastrophic costs predicted adverse TB treatment outcome. A novel socio-economic support intervention increased TB preventive therapy uptake, improved TB treatment success and reduced catastrophic costs. The impact of the intervention on TB control is currently being evaluated by the Community Randomized Evaluation of a Socio-economic Intervention to Prevent TB (CRESIPT) study. PMID- 27956447 TI - Towards understanding and managing chronic cough. AB - Chronic cough is a common and troublesome condition affecting approximately 12% of the general population. It is associated with poor quality of life with psychological, social and physical consequences. Patients typically complain of a dry irritating cough, driven by a strong urge to cough associated with a sensation or irritation located in the throat. Treatment of potential 'causes', ie asthma, gastro-oesophageal reflux disease and rhino-sinusitis, may produce a complete or partial response, but the response of some patients to opiates and alpha-2-delta ligand antagonists (gabapentin and pregabalin) supports the concept that this is primarily a neurological disorder, characterised by hyper responsiveness of the nerves. Novel and highly effective neuronal treatments are in development and offer hope of better symptom control with fewer side effects within a few years. This review focuses on understanding the mechanism of chronic cough, current management approaches and research that may lead to novel therapies. PMID- 27956448 TI - Delirium: a guide for the general physician. AB - Delirium describes a sudden onset change in mental status of fluctuating course. This is a state of altered consciousness characterised chiefly by inattention or lack of arousal, but can also include new impairment of language, perception and behaviour. Certain predisposing factors can make an individual more susceptible to delirium in the face of a stressor. Stressors include direct insults to the brain, insults peripheral to the brain or external changes in the environment of an individual. Delirium is varied in its presentation, and can be categorised by the psychomotor profile as: hyperactive type (overly vigilant, agitated, often wandersome), hypoactive type (sedate or withdrawn) or mixed types. PMID- 27956449 TI - Drug-induced liver injury. AB - Drug-induced liver injury (DILI) remains the most common cause of acute liver failure (ALF) in the western world. Excluding paracetamol overdose, nearly all DILI encountered in the clinical setting is idiosyncratic in nature because affected individuals represent only a small proportion of those treated with such drugs. In many cases, the mechanism for idiosyncrasy is immune-mediation and is often identified by genetic risk determined by human leukocyte antigen variants. In the absence of diagnostic tests and/or biomarkers, the diagnosis of DILI requires a high index of suspicion after diligently excluding other causes of abnormal liver tests. Antibiotics are the class of drugs most frequently associated with idiosyncratic DILI, although recent studies indicate that herbal and dietary supplements are an increasingly recognised cause. It is imperative that upon development of DILI the culprit drug be discontinued, especially in the presence of elevated transaminases (aspartate aminotransferase/alanine aminotransferase ratio >=5 times the upper limit of normal) and/or jaundice. Risk factors for the development ALF include hepatocellular DILI and female gender, the treatment being supportive with some benefit of N-acetylcysteine in the early stages. In view of the poor transplant-free survival in idiosyncratic DILI, early consideration for liver transplant is mandatory. PMID- 27956450 TI - Medical problems in pregnancy. AB - The prevalence of medical problems in pregnancy is increasing because of a complex interplay between demographic and lifestyle factors, and developments in modern medicine. Maternal mortality and morbidity resulting from treatable medical conditions, such as venous thromboembolism, epilepsy and autoimmune disease, have not decreased in recent years. This is despite a marked decrease in overall maternal mortality. It is vital that all physicians acquire a basic knowledge and understanding of medical problems in pregnancy. This includes prepregnancy measures such as counselling and optimisation of medical therapy, as well as multidisciplinary management throughout pregnancy and the postpartum period. Prompt recognition and treatment of acute and chronic illness is of clear benefit, and most drugs and many radiological investigations may be used in pregnancy. PMID- 27956451 TI - Chronic kidney disease: towards a risk-based approach. AB - Chronic kidney disease (CKD) affects 8-16% of adults worldwide and is associated with multiple adverse outcomes. It includes a heterogeneous group of conditions with widely varied associated risks; risk stratification is therefore vital for clinical management. Use of the CKD Epidemiology Collaboration (CKD-EPI) equation to estimate glomerular filtration rate (GFR) instead of the Modification of Diet in Renal Disease (MDRD) equation will reduce, though not eliminate, over diagnosis of CKD. Cystatin C is recommended as an alternative measure of GFR but is not yet widely used. A new classification system for CKD, which includes GFR and albuminuria, has been endorsed by the National Institute for Health and Care Excellence to aid risk stratification and a recently validated formula, requiring only age, gender, eGFR and albuminuria, is useful to predict risk of end-stage kidney disease (ESKD). A risk-based approach will facilitate appropriate treatment for people at high risk of developing ESKD while sparing the majority, who are at low risk, from unnecessary intervention. PMID- 27956452 TI - Osteoporosis: advances in risk assessment and management. AB - In the past three decades, there have been major advances in our understanding of bone biology and these have been -accompanied by a significant improvement in the management of osteoporosis. Fracture risk prediction algorithms using -clinical risk factors, with or without measurement of bone mineral density, have enabled more accurate targeting of treatment and a range of cost-effective pharmacological interventions is available to reduce fracture risk. Despite these advances, a number of challenges remain. In particular, treatment rates in high risk individuals are low and adherence to treatment is poor. Addressing this treatment gap through measures such as fracture liaison services, which provide a coordinated and cost-effective strategy for secondary fracture prevention, is an important future priority. PMID- 27956453 TI - Lymphoma: turning biology into cures. AB - Diffuse large B-cell lymphoma (DLBCL) is the commonest aggressive non-Hodgkin lymphoma with approximately 5,000 cases annually in the UK. The R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) regimen has become the international standard of care with cure rates of around 75% and despite extensive studies aimed at improving the outcomes, R-CHOP has not been superseded. Those patients that do not respond to R-CHOP have a poor outlook. DLBCL is a disease with marked molecular heterogeneity; advances in gene expression profiling and mutational analysis can be used to increase our understanding of the disease and identify new therapeutic targets. Precision medicine using new agents, including small molecule inhibitors, is now being investigated for DLBCL. Progress in this disease is likely to come by targeting heterogeneous subtypes through novel combinations. Where R-CHOP fails, we hope that these new approaches can succeed by providing personalised medicine using precision diagnostics to guide new treatment paradigms. PMID- 27956459 TI - Recurrent Infections of Emergent Norovirus GII.17 in an Elderly. PMID- 27956455 TI - A Cluster-Randomized Trial to Assess the Efficacy of Targeting Trachoma Treatment to Children. AB - Background: The World Health Organization recommends annual treatment of entire trachoma-endemic communities, although children typically have a higher load, longer duration, and greater likelihood of infection. Methods: Forty-eight communities in Matameye, Niger, were randomized to annual oral azithromycin treatment of the entire community or biannual treatment of children aged 0-12 years only. Both children and adults were monitored for ocular chlamydial infection by polymerase chain reaction. Results: The prevalence of childhood infection was reduced in the annually treated arm from 21.2% (95% confidence interval [CI], 15.2%-28.0%) at baseline to 5.8% (95% CI, 3.2%-9.0%) at 36 months (P < .001) and in the biannual arm from 20.2% (95% CI, 15.5%-25.3%) to 3.8% (95% CI, 2.2%-6.0%; P < .001). Adult infection in the annual arm was reduced from 1.7% (95% CI, .9%-2.7%) to 0.3% (95% CI, .0%-.7%) and in the biannual arm from 1.2% (95% CI, .5%-2.2%) to 0.0% (95% CI, .0%-.7%; P = .005). The effect of biannual treatment of children compared with annual treatment of the entire community in both children (95% CI, -.04% to .02%) and adults (95% CI, .9%-2.7%) excluded the prespecified noninferiority threshold of 6% (P = .003 and P < .001, respectively). Conclusions: Periodic distribution of antibiotics to children in trachoma-endemic communities reduces chlamydial infection in both children and untreated adults, suggesting a form of herd protection. Biannual treatment of children was comparable to (specifically, noninferior to) annual treatment of the entire community, and may offer lower antibiotic use and other logistical advantages. Clinical Trials Registration: NCT00792922. PMID- 27956461 TI - L-DOPA therapy interferes with urine catecholamine analysis in children with suspected neuroblastoma: a case series. AB - Neuroblastoma is the most common solid extracranial malignancy diagnosed in childhood. Clinical presentation is variable, and metastatic disease is common at diagnosis. Analyses of urinary catecholamines and their metabolites are commonly requested as a first-line investigation when clinical suspicion exists. Levodopa (L-Dopa) therapy is utilized as a treatment for a number of disorders in childhood, including Dopa-responsive dystonia. Neuroblastoma may mimic some of the clinical features of this disorder. L-Dopa can interfere with analysis of urinary catecholamines and their metabolites and complicate the interpretation of results. We present the cases of three children who were prescribed L-dopa at the time of analysis of urinary catecholamines and metabolites as a screen for neuroblastoma, but who did not have the disease. Comparison of their results with those from cases with true neuroblastoma reveal that it is impossible to reliably distinguish true neuroblastoma from L-Dopa therapy using these tests. We recommend that patients should be off L-dopa therapy, if possible when these tests are performed. These cases illustrate the importance of providing clinical details and drug history to the laboratory in order to avoid diagnostic confusion. PMID- 27956460 TI - Investment Success in Public Health: An Analysis of the Cost-Effectiveness and Cost-Benefit of the Global Programme to Eliminate Lymphatic Filariasis. AB - Background: It has been estimated that $154 million per year will be required during 2015-2020 to continue the Global Programme to Eliminate Lymphatic Filariasis (GPELF). In light of this, it is important to understand the program's current value. Here, we evaluate the cost-effectiveness and cost-benefit of the preventive chemotherapy that was provided under the GPELF between 2000 and 2014. In addition, we also investigate the potential cost-effectiveness of hydrocele surgery. Methods: Our economic evaluation of preventive chemotherapy was based on previously published health and economic impact estimates (between 2000 and 2014). The delivery costs of treatment were estimated using a model developed by the World Health Organization. We also developed a model to investigate the number of disability-adjusted life years (DALYs) averted by a hydrocelectomy and identified the cost threshold under which it would be considered cost-effective. Results: The projected cost-effectiveness and cost-benefit of preventive chemotherapy were very promising, and this was robust over a wide range of costs and assumptions. When the economic value of the donated drugs was not included, the GPELF would be classed as highly cost-effective. We projected that a typical hydrocelectomy would be classed as highly cost-effective if the surgery cost less than $66 and cost-effective if less than $398 (based on the World Bank's cost effectiveness thresholds for low income countries). Conclusions: Both the preventive chemotherapy and hydrocele surgeries provided under the GPELF are incredibly cost-effective and offer a very good investment in public health. PMID- 27956462 TI - Evaluation of neovascularization patterns in an orthotopic rat glioma model with dynamic contrast-enhanced MRI. AB - Background Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been proved useful in evaluating glioma angiogenesis, but the utility in evaluating neovascularization patterns has not been reported. Purpose To evaluate in vivo real-time glioma neovascularization patterns by measuring glioma perfusion quantitatively using DCE-MRI. Material and Methods Thirty Sprague Dawley rats were used to establish C6 orthotopic glioma model and underwent MRI and pathology detections. As MRI and pathology were performed at six time points (i.e. 4, 8, 12, 16, 20, and 24 days) post transplantation, neovascularization patterns were evaluated via DCE-MRI. Results Four neovascularization patterns were observed in glioma tissues. Sprout angiogenesis and intussusceptive microvascular growth located inside tumor, while vascular co-option and vascular mimicry were found in the tumor margin and necrotic area, respectively. Sprout angiogenesis and intussusceptive microvascular growth increased with Ktrans, Kep, and Vp inside tumor tissue. In addition, Kep and Vp were positively correlated with sprout angiogenesis and intussusceptive microvascular growth. Vascular co option was decreased at 12 and 16 days post transplantation and correlated negatively with Ktrans and Kep detected in the glioma margin, respectively. Changes of vascular mimicry showed no significant statistical difference at the six time points. Conclusion Our results indicate that DCE-MRI can evaluate neovascularization patterns in a glioma model. Furthermore, DCE-MRI could be an imaging biomarker for guidance of antiangiogenic treatments in humans in the future. PMID- 27956463 TI - Internal comparison standard for abdominal diffusion-weighted imaging. AB - Background Standards for abdominal diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) measurements, and analysis are required for reproducibility. Purpose To identify optimal internal comparison standards for DWI to normalize the measured ADC for increased accuracy of differentiating malignant and benign abdominal lesions. Material and Methods We retrospectively studied 97 lesions (89 patients; age, 57 +/- 13 years) with histopathologically confirmed abdominal disease. Seven normal body parts/contents (normal parenchyma, spleen, kidney, gallbladder bile, paraspinal muscle, spinal cord, and cerebrospinal fluid [CSF]) were assessed as internal references for possible use as comparison standards. Three observers performed ADC measurements. Statistical analyses included interclass correlation coefficients (ICCs), Mann-Whitney and Kruskal-Wallis tests, and coefficient of variation (CV). ROC analyses were performed to assess diagnostic accuracy of lesion ADC and normalized ADC for differentiating lesions. Pathology results were the reference standard. Results Mean and normalized ADCs were significantly lower for malignant lesions than for benign lesions ( P < 0.001). ICC was excellent for all internal references. Gallbladder had the lowest CV. Receiver operating characteristic (ROC) analyses showed that normalized ADCs obtained using normal parenchyma were better than lesion ADCs for differentiating malignant and benign abdominal lesions (area under the curve [AUC], 0.808 and 0.756, respectively). The normalized ADCs obtained using CSF shows higher accuracy than lesion ADCs (0.80 and 0.76, respectively) for differentiating between malignant and benign abdominal lesions. Conclusion The normal parenchyma from a lesion-detected organ can be used as an internal comparison standard for DWI. CSF can be used as a generalizable in plane reference standard. PMID- 27956464 TI - Resistance of non-typeable Haemophilus influenzae biofilms is independent of biofilm size. AB - The inflammatory middle ear disease known as otitis media can become chronic or recurrent in some cases due to failure of the antibiotic treatment to clear the bacterial etiological agent. Biofilms are known culprits of antibiotic-resistant infections; however, the mechanisms of resistance for non-typeable Haemophilus influenzae biofilms have not been completely elucidated. In this study, we utilized in vitro static biofilm assays to characterize clinical strain biofilms and addressed the hypothesis that biofilms with greater biomass and/or thickness would be more resistant to antimicrobial-mediated eradication than thinner and/or lower biomass biofilms. Consistent with previous studies, antibiotic concentrations required to eliminate biofilm bacteria tended to be drastically higher than concentrations required to kill planktonic bacteria. The size characterizations of the biofilms formed by the clinical isolates were compared to their minimum biofilm eradication concentrations for four antibiotics. This revealed no correlation between biofilm thickness or biomass and the ability to resist eradication by antibiotics. Therefore, we concluded that biofilm size does not play a role in antibiotic resistance, suggesting that reduction of antibiotic penetration may not be a significant mechanism for antibiotic resistance for this bacterial opportunist. PMID- 27956466 TI - Plasma amino acid levels are elevated in young, healthy low birth weight men exposed to short-term high-fat overfeeding. AB - Low birth weight (LBW) individuals exhibit a disproportionately increased, incomplete fatty acid oxidation and a decreased glucose oxidation, compared with normal birth weight (NBW) individuals, and furthermore have an increased risk of developing insulin resistance and type 2 diabetes. We hypothesized that changes in amino acid metabolism may occur parallel to alterations in fatty acid and glucose oxidation, and could contribute to insulin resistance. Therefore, we measured fasting plasma levels of 15 individual or pools of amino acids in 18 LBW and 25 NBW men after an isocaloric control diet and after a 5-day high-fat, high calorie diet. We demonstrated that LBW and NBW men increased plasma alanine levels and decreased valine and leucine/isoleucine levels in response to overfeeding. Also, LBW men had higher alanine, proline, methionine, citrulline, and total amino acid levels after overfeeding compared with NBW men. Alanine and total amino acid levels tended to be negatively associated with the insulin stimulated glucose uptake after overfeeding. Therefore, the higher amino acid levels in LBW men could be a consequence of their reduction in skeletal muscle insulin sensitivity due to overfeeding with a possible increased skeletal muscle proteolysis and/or could potentially contribute to an impaired insulin sensitivity. Furthermore, the alanine level was negatively associated with the plasma acetylcarnitine level and positively associated with the hepatic glucose production after overfeeding. Thus, the higher alanine level in LBW men could be accompanied by an increased anaplerotic formation of oxaloacetate and thereby an enhanced tricarboxylic acid cycle activity and as well an increased gluconeogenesis. PMID- 27956465 TI - Hfq and three Hfq-dependent small regulatory RNAs-MgrR, RyhB and McaS-coregulate the locus of enterocyte effacement in enteropathogenic Escherichia coli. AB - Enteropathogenic Escherichia coli (EPEC) is a significant cause of infantile diarrhea and death in developing countries. The pathogenicity island locus of enterocyte effacement (LEE) is essential for EPEC to cause diarrhea. Besides EPEC, the LEE is also present in other gastrointestinal pathogens, most notably enterohemorrhagic E. coli (EHEC). Whereas transcriptional control of the LEE has been meticulously examined, posttranscriptional regulation, including the role of Hfq-dependent small RNAs, remains undercharacterized. However, the past few years have witnessed a surge in the identification of riboregulators of the LEE in EHEC. Contrastingly, the posttranscriptional regulatory landscape of EPEC remains cryptic. Here we demonstrate that the RNA-chaperone Hfq represses the LEE of EPEC by targeting the 5' untranslated leader region of grlR in the grlRA mRNA. Three conserved small regulatory RNAs (sRNAs)-MgrR, RyhB and McaS-are involved in the Hfq-dependent regulation of grlRA MgrR and RyhB exert their effects by directly base-pairing to the 5' region of grlR Whereas MgrR selectively represses grlR but activates grlA, RyhB represses gene expression from the entire grlRA transcript. Meanwhile, McaS appears to target the grlRA mRNA indirectly. Thus, our results provide the first definitive evidence that implicates multiple sRNAs in regulating the LEE and the resulting virulence of EPEC. PMID- 27956468 TI - Why proteomics is not the new genomics and the future of mass spectrometry in cell biology. AB - Mass spectrometry (MS) is an essential part of the cell biologist's proteomics toolkit, allowing analyses at molecular and system-wide scales. However, proteomics still lag behind genomics in popularity and ease of use. We discuss key differences between MS-based -omics and other booming -omics technologies and highlight what we view as the future of MS and its role in our increasingly deep understanding of cell biology. PMID- 27956467 TI - LINC complexes promote homologous recombination in part through inhibition of nonhomologous end joining. AB - The Caenorhabditis elegans SUN domain protein, UNC-84, functions in nuclear migration and anchorage in the soma. We discovered a novel role for UNC-84 in DNA damage repair and meiotic recombination. Loss of UNC-84 leads to defects in the loading and disassembly of the recombinase RAD-51. Similar to mutations in Fanconi anemia (FA) genes, unc-84 mutants and human cells depleted of Sun-1 are sensitive to DNA cross-linking agents, and sensitivity is rescued by the inactivation of nonhomologous end joining (NHEJ). UNC-84 also recruits FA nuclease FAN-1 to the nucleoplasm, suggesting that UNC-84 both alters the extent of repair by NHEJ and promotes the processing of cross-links by FAN-1. UNC-84 interacts with the KASH protein ZYG-12 for DNA damage repair. Furthermore, the microtubule network and interaction with the nucleoskeleton are important for repair, suggesting that a functional linker of nucleoskeleton and cytoskeleton (LINC) complex is required. We propose that LINC complexes serve a conserved role in DNA repair through both the inhibition of NHEJ and the promotion of homologous recombination at sites of chromosomal breaks. PMID- 27956470 TI - Epigenetic Regulation of the Sex Determination Gene MeGI in Polyploid Persimmon. AB - Epigenetic regulation can add a flexible layer to genetic variation, potentially enabling long-term but reversible cis-regulatory changes to an allele while maintaining its DNA sequence. Here, we present a case in which alternative epigenetic states lead to reversible sex determination in the hexaploid persimmon Diospyros kaki Previously, we elucidated the molecular mechanism of sex determination in diploid persimmon and demonstrated the action of a Y-encoded sex determinant pseudogene called OGI, which produces small RNAs targeting the autosomal gene MeGI, resulting in separate male and female individuals (dioecy). We contrast these findings with the discovery, in hexaploid persimmon, of an additional layer of regulation in the form of DNA methylation of the MeGI promoter associated with the production of both male and female flowers in genetically male trees. Consistent with this model, developing male buds exhibited higher methylation levels across the MeGI promoter than developing female flowers from either monoecious or female trees. Additionally, a DNA methylation inhibitor induced developing male buds to form feminized flowers. Concurrently, in Y-chromosome-carrying trees, the expression of OGI is silenced by the presence of a SINE (short interspersed nuclear element)-like insertion in the OGI promoter. Our findings provide an example of an adaptive scenario involving epigenetic plasticity. PMID- 27956471 TI - Congenital diaphragmatic hernia with intrathoracic kidney: unusual presentation. PMID- 27956469 TI - The N-Terminal UND Motif of the Arabidopsis U-Box E3 Ligase PUB18 Is Critical for the Negative Regulation of ABA-Mediated Stomatal Movement and Determines Its Ubiquitination Specificity for Exocyst Subunit Exo70B1. AB - The Arabidopsis thaliana U-box E3 ligases PUB18/PUB19 and PUB22/PUB23 are negative regulators of drought stress responses. PUB18/PUB19 regulate the drought stress response in an abscisic acid (ABA)-dependent manner, whereas PUB22/PUB23 regulate this response in an ABA-independent manner. A major structural difference between PUB18/PUB19 and PUB22/PUB23 is the presence of the UND (U-box N-terminal domain). Here, we focused on elucidating the molecular mechanism that mediates the functional difference between PUB18 and PUB22 and found that the UNDPUB18 was critically involved in the negative regulation of ABA-mediated stomatal movements. Exo70B1, a subunit of the exocyst complex, was identified as a target of PUB18, whereas Exo70B2 was a substrate of PUB22. However, the ?UND PUB18 derivative failed to ubiquitinate Exo70B1, but ubiquitinated Exo70B2. By contrast, the UNDPUB18-PUB22 chimeric protein ubiquitinated Exo70B1 instead of Exo70B2, suggesting that the ubiquitination specificities of PUB18 and PUB22 to Exo70B1 and Exo70B2, respectively, are dependent on the presence or absence of the UNDPUB18 motif. The ABA-insensitive phenotypes of the pub18 pub19 exo70b1 triple mutant were reminiscent of those of exo70b1 rather than pub18 pub19, indicating that Exo70B1 functions downstream of PUB18. Overall, our results suggest that the UNDPUB18 motif is crucial for the negative regulation of ABA dependent stomatal movement and for determination of its ubiquitination specificity to Exo70B1. PMID- 27956472 TI - Physician Characteristics Associated With Sugar-Sweetened Beverage Counseling Practices. AB - PURPOSE: Frequent sugar-sweetened beverage (SSB) consumption is associated with chronic disease. Although physician counseling can positively affect patient behavior, physicians' personal characteristics may influence counseling practices. We explored SSB-related topics physicians discuss when counseling overweight/obese patients and examined associations between physicians' SSB related counseling practices and their personal and medical practice characteristics. DESIGN: Cross-sectional survey. SETTING: DocStyles survey, 2014. PARTICIPANTS: A total of 1510 practicing US physicians. MEASURES: Physician's SSB counseling on calories, added sugars, obesity/weight gain, health effects, consumption frequency, water substitution, and referral. ANALYSIS: Adjusted odds ratios (aORs) were calculated with multivariable logistic regression, adjusting for physician's personal and medical practice characteristics. RESULTS: Most physicians (98.5%) reported SSB-related counseling. The most reported topic was obesity/weight gain (81.4%); the least reported were added sugars (53.1%) and referral (35.0%). Physicians in adult-focused specialties had lower odds than pediatricians of counseling on several topics (aOR range: 0.26-0.64). Outpatient physicians had higher odds than inpatient physicians of counseling on consumption frequency and water substitution (aOR range: 1.60-2.01). Physicians consuming SSBs >=1 time/day (15.7%) had lower odds than nonconsumers of counseling on most topics (aOR range: 0.58-0.68). CONCLUSION: Most physicians reported SSB-related counseling; obesity/weight gain was discussed most frequently. Counseling opportunities remain in other topic areas. Opportunities also exist to strengthen SSB counseling practices in adult-focused specialties, inpatient settings, and among physicians who consume SSBs daily. PMID- 27956473 TI - Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel. AB - Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of KATP channels have been identified as the most common cause of human neonatal diabetes mellitus. The critical effect of these mutations is confirmed in mice expressing Kir6.2-GOF mutations in pancreatic beta cells. A second KATP channel pore-forming subunit, Kir6.1, was originally cloned from the pancreas. Although the prominence of this subunit in the vascular system is well documented, a potential role in pancreatic beta cells has not been considered. Here, we show that mice expressing Kir6.1-GOF mutations (Kir6.1[G343D] or Kir6.1[G343D,Q53R]) in pancreatic beta cells (under rat-insulin-promoter [Rip] control) develop glucose intolerance and diabetes caused by reduced insulin secretion. We also generated transgenic mice in which a bacterial artificial chromosome (BAC) containing Kir6.1[G343D] is incorporated such that the transgene is only expressed in tissues where Kir6.1 is normally present. Strikingly, BAC Kir6.1[G343D] mice also show impaired glucose tolerance, as well as reduced glucose- and sulfonylurea-dependent insulin secretion. However, the response to K+ depolarization is intact in Kir6.1-GOF mice compared with control islets. The presence of native Kir6.1 transcripts was demonstrated in both human and wild type mouse islets using quantitative real-time PCR. Together, these results implicate the incorporation of native Kir6.1 subunits into pancreatic KATP channels and a contributory role for these subunits in the control of insulin secretion. PMID- 27956474 TI - On the importance of albumin binding for the flux of 7alpha-hydroxy-3-oxo-4 cholestenoic acid in the brain. AB - We confirmed previous findings by a Japanese group that there is an accumulation of 7alpha-hydroxy-3-oxo-4-cholestenoic acid (7-Hoca) in human subdural hematomas. The accumulation correlated with the time from the bleeding to the sample collection. We present evidence that these accumulations are likely to be caused by the strong affinity of 7-Hoca to albumin and the marked difference between plasma and brain with respect to levels of albumin. In the circulation, 80-90% of 7-Hoca is bound to albumin with a ratio between the steroid acid and albumin of ~1.4 ng/mg. In cerebrospinal fluid (CSF), the ratio between 7-Hoca and albumin is ~30 ng/mg. When albumin or hemolyzed blood in a dialysis bag was exposed to CSF, there was a flux of 7-Hoca from CSF to the albumin. We suggest that the major explanation for accumulation of 7-Hoca in subdural hematoma is a flux from the brain into the hematoma due to the high affinity to albumin and the high capacity of 7-Hoca to pass biomembranes. We discuss the possibility that the markedly different ratios between 7-Hoca and albumin in circulation and brain can explain the flux of 7-Hoca from the brain into circulation against a concentration gradient. PMID- 27956476 TI - Efficacy of homeopathy in livestock according to peer-reviewed publications from 1981 to 2014. AB - Homeopathy is widely used in livestock, especially in order to reduce the use of antibiotics, although it is often seen as controversial. A comprehensive literature review has been conducted to assess the efficacy of homeopathy in cattle, pigs and poultry. Only peer-reviewed publications dealing with homeopathic remedies, which could possibly replace or prevent the use of antibiotics in the case of infective diseases or growth promotion in livestock were included. Search results revealed a total number of 52 trials performed within 48 publications fulfilling the predefined criteria. Twenty-eight trials were in favour of homeopathy, with 26 trials showing a significantly higher efficacy in comparison to a control group, whereas 22 showed no medicinal effect. Cure rates for the treatments with antibiotics, homeopathy or placebo varied to a high degree, while the remedy used did not seem to make a big difference. Looking at all the studies, no study was repeated under comparable conditions. Consequently, the use of homeopathy currently cannot claim to have sufficient prognostic validity where efficacy is concerned. When striving for high therapeutic success in treatment, the potential of homeopathy in replacing or reducing antibiotics can only be validated if evidence of efficacy is confirmed by randomised controlled trials under modified conditions. PMID- 27956477 TI - No calorie comfort: Viewing and drawing "comfort foods" similarly augment positive mood for those with depression. AB - Based on behavioral and neurobiological data, we tested the hypothesis that viewing/drawing visual images of comfort foods in the absence of eating will increase positive mood and that this effect is augmented for those with clinical symptoms of depression. A counterbalanced design was used for 60 participants with and without clinical symptoms in two variations: food image and food art. In each variation, participants viewed/drew foods high or low in fat/sugar; pre-post mood was recorded. Results show a consistent pattern: viewing/drawing comfort foods [food image (95% confidence interval): 2.72-4.85; food art (95% confidence interval): 2.65-4.62] and fruits [food image (95% confidence interval): 1.20 2.23; food art (95% confidence interval): 1.51-2.56] enhanced mood. For comfort foods, mood was augmented for those with clinical symptoms of depression [food image (95% confidence interval): 0.95-3.59; food art (95% confidence interval): 0.97-3.46]. Findings corroborate previous data and reveal a novel finding of augmented mood increases for those with clinical symptoms. PMID- 27956479 TI - Immediate and Long-Term Mental Health Outcomes in Adolescent Female Rape Survivors. AB - Rape is considered a stressful trauma and often has long-lasting health consequences. Compared with adult females, limited data exist on the psychological impact of rape in adolescents. The aim of this study was to assess the prevalence and associated factors of emotional distress in a cohort of adolescent rape survivors in Cape Town. Participants in this prospective longitudinal study were 31 adolescent female rape survivors recruited from a rape clinic in Cape Town and assessed within 2 weeks of the assault. Assessment measures included a sociodemographic questionnaire and initial screening with the Child and Adolescent Trauma Survey (CATS), the patient-rated Children's Depression Inventory (CDI), and the Multidimensional Anxiety Scale for Children (MASC). The CATS, CDI, and MASC were repeated at 1, 3, 6, 9, and 12 months post enrollment. Psychiatric diagnoses were made with the clinician-administered Mini International Neuropsychiatric Interview-Child and Adolescent version (MINI-Kid). At baseline, on the MINI-Kid, a definitive diagnosis of major depressive episode was endorsed in 22.6% of the participants. Stress-related disorders were found in 12.9%, whereas 16.1% had anxiety disorders. There was no diminution of symptoms on self-reported psychopathology measures at follow-up assessment over the five follow-up time points, suggesting persistent psychopathology over a 1-year period despite repeated clinical assessments and supportive counseling. Symptoms of anxiety, depression, and posttraumatic stress disorder in this sample of adolescent female rape survivors were high at enrollment and found to be persistent, underlining the need for long-term support, screening, and evidence based follow-up care. PMID- 27956475 TI - Induction of farnesoid X receptor signaling in germ-free mice colonized with a human microbiota. AB - The gut microbiota influences the development and progression of metabolic diseases partly by metabolism of bile acids (BAs) and modified signaling through the farnesoid X receptor (FXR). In this study, we aimed to determine how the human gut microbiota metabolizes murine BAs and affects FXR signaling in colonized mice. We colonized germ-free mice with cecal content from a mouse donor or feces from a human donor and euthanized the mice after short-term (2 weeks) or long-term (15 weeks) colonization. We analyzed the gut microbiota and BA composition and expression of FXR target genes in ileum and liver. We found that cecal microbiota composition differed between mice colonized with mouse and human microbiota and was stable over time. Human and mouse microbiota reduced total BA levels similarly, but the humanized mice produced less secondary BAs. The human microbiota was able to reduce the levels of tauro-beta-muricholic acid and induce expression of FXR target genes Fgf15 and Shp in ileum after long-term colonization. We show that a human microbiota can change BA composition and induce FXR signaling in colonized mice, but the levels of secondary BAs produced are lower than in mice colonized with a mouse microbiota. PMID- 27956478 TI - Pharmacological treatment of refugees with trauma-related disorders: What do we know today? AB - There is a dearth of evidence on the effectiveness of pharmacological treatment for refugees with trauma-related disorders. The present paper provides an overview of available literature on the subject and discusses the transferability of results from studies on other groups of patients with post traumatic stress disorder (PTSD). We conducted a systematic review of published treatment outcome studies on PTSD and depression among refugees. Fifteen studies were identified and reviewed. Most studies focused on the use of antidepressants. Included studies differed widely in method and quality. The majority were observational studies and case studies. Small sample sizes limited the statistical power. Few studies reported effect sizes, confidence intervals, and statistical significance of findings. No specific pharmacological treatment for PTSD among refugees can be recommended on the basis of the available literature. There is a need for well designed clinical trials, especially with newer antidepressants and antipsychotics. Until such studies are available, clinical practice and design of trials can be guided by results from studies of other groups of PTSD patients, although differences in pharmacogenetics, compliance, and trauma reactions may affect the direct transferability of results from studies on nonrefugee populations. PMID- 27956480 TI - Cultural Distress: An Emerging Paradigm. AB - Although cultural competence in practice is a common goal within the health care professions, little is known about the consequences of a lack of such competence in health and healing. We propose a novel theoretical framework of cultural distress to describe patient experiences of and reactions to care that does not incorporate attention to cultural needs. Use of the cultural distress model to guide research offers an innovative framework by which researchers may identify potential interventions such that patients never reach a level of cultural distress. PMID- 27956481 TI - Exploring the Experience of African Immigrant Mothers Providing Reproductive Health Education to Their Daughters Aged 10 to 14 Years. AB - INTRODUCTION: Adolescents have disproportionate rates of unplanned pregnancies and sexually transmitted infections when compared with all other age groups. Mothers are gatekeepers and providers of reproductive health education, which can prevent teen pregnancy and sexually transmitted infections. Reproductive health education provided by African immigrant mothers is influenced by cultural experiences and cultural contexts that are not well understood and have not been studied. This study sought to describe the experience of African mothers living in the United States providing reproductive health education to their daughters aged 10 to 14 years. METHOD: A qualitative descriptive design was used. Twenty African immigrant mothers were interviewed in a community setting. Qualitative content analysis approach was used for analysis. RESULTS: Three main themes emerged: (1) mothers' reproductive health education in their country of origin, (2) mothers' reproductive health communication with their daughters, and (3) changes due to the move to the United States. DISCUSSION: Mothers believed daughters were too young for reproductive health education, leading to conversations with limited content that were frequently triggered by daughters' exposure to reproductive health education outside the home. IMPLICATIONS: African immigrant mothers may benefit from culturally congruent discussions with health care providers about the reproductive health information they give their daughters. PMID- 27956482 TI - Enhanced fertility and chill tolerance after cold-induced reproductive arrest in females of temperate species of the Drosophila buzzatii complex. AB - Long-term exposure to low temperatures during adult maturation might decrease fertility after cold recovery as a consequence of carry-over effects on reproductive tissues. This pattern should be more pronounced in tropical than in temperate species as protective mechanisms against chilling injuries are expected to be more effective in the latter. We initially determined the lower thermal thresholds to induce ovarian maturation in four closely related Drosophila species, two inhabiting temperate regions and the other two tropical areas of South America. As expected, only temperate species regularly experience cold inducing conditions for reproductive arrest during winter in their natural environment. Subsequently, we exposed reproductively arrested and mature females to cold-inducing conditions for reproductive arrest over a long period. Following cold exposure, tropical species exhibited a dramatic fertility decline, irrespective of reproductive status. In contrast, not only were temperate females fecund and fertile but also fertility was superior in females that underwent cold induced reproductive arrest, suggesting that it might act as a protecting mechanism ensuring fertility after cold recovery. Based on these findings, we decided to evaluate the extent to which reproductive status affects cold tolerance and energy metabolism at low temperature. We found a lower metabolic rate and a higher cold tolerance in reproductively arrested females, although only temperate species attained high levels of chill tolerance. These findings highlight the role of cold-induced reproductive arrest as part of an integrated mechanism of cold adaptation that could potentially contribute to the spread of temperate species into higher latitudes or altitudes. PMID- 27956483 TI - Thermal sensitivity of motor control of muscle-powered versus elastically powered tongue projection in salamanders. AB - Elastic-recoil mechanisms can improve organismal performance and circumvent the thermal limitations of muscle contraction, yet they require the appropriate motor control to operate. We compare muscle activity during tongue projection in salamanders with elastically powered, ballistic projection with activity of those with muscle-powered, non-ballistic projection across a range of temperatures to understand how motor control is integrated with elastically powered movements, and how this integration contributes to reduced thermal sensitivity. Species with ballistic tongue projection activated and deactivated their projector muscles significantly earlier than non-ballistic species, in a pattern consistent with a mechanism in which the muscle strains elastic tissue that subsequently recoils to power projection. Tongue projection was more thermally robust in ballistic species, but in both ballistic and non-ballistic species the projector muscles were activated earlier and for longer as temperature decreased. The retractor muscles showed a pattern similar to that of the projector muscles, but declined in a similar manner in the two groups. Muscle activity intensity also decreased at low temperatures in both groups, revealing that compensatory muscle activation does not account for the improved thermal robustness in ballistic species. Thus, relatively minor shifts in motor patterns accompanying morphological changes such as increased elastic tissue are sufficient to improve performance and decrease its thermal sensitivity without specialization of muscle contractile physiology. PMID- 27956484 TI - Photoperiod but not food restriction modulates innate immunity in an opportunistic breeder, Loxia curvirostra. AB - An organism's investment in immune function often varies seasonally but understanding of how fluctuations in environmental conditions directly modulate investment remains limited. This experiment investigated how changes in photoperiod and food availability affect investment in constitutive innate immunity and the acute phase response induced by lipopolysaccharide (LPS) injections in captive red crossbills (Loxia curvirostra). Crossbills are reproductively flexible songbirds that specialize on an unpredictably available food resource and display temporal variation in immunity in the wild. Birds were separated into four treatments and exposed to long or short day lengths for 6 weeks before continuing on an ad libitum diet or experiencing a 20% food reduction for 10 days. Birds were un-injected or injected with LPS both before and after diet change. Innate immunity was quantified throughout the experiment to assess effects of photoperiod, food availability and their interactions on hemolysis-hemagglutination, haptoglobin, bacterial killing ability and leukocyte counts. Overall, increasing day length significantly increased both bacterial killing ability and leukocyte counts. Surprisingly, food restriction had little effect on the immune parameters, potentially owing to the 'low-cost' environment of captivity and suggesting that investment in innate immunity is prioritized and maintained whenever possible. LPS injections induced stereotypical sickness behaviors and increased bacterial killing ability in short day birds and complement activity (hemolysis) both before and after food restriction. These results demonstrate robust seasonal modulation of immune investment and an ability to maintain innate immunity in the face of limited resources in these temporally flexible songbirds. PMID- 27956485 TI - Ovarian control of growth and sexual size dimorphism in a male-larger gecko. AB - Sexual size dimorphism (SSD) reflects sex-specific solutions to the allocation of energy among growth, reproduction and survival; however, the proximate mechanisms behind these solutions are still poorly known even in vertebrates. In squamates, sexual differences in body size used to be attributed to direct energy allocation to energetically demanding processes, largely to reproduction. In addition, SSD is assumed to be controlled by specific endogenous mechanisms regulating growth in a sex-specific manner, namely masculinization by male gonadal androgens or feminization by ovarian hormones. We performed a manipulative growth experiment in females of the male-larger gecko Paroedura picta in order to test the reproductive cost hypothesis, the male androgen hypothesis and the ovarian hormone hypothesis. Specifically, we investigated the effect of total ovariectomy, prepubertal ovariectomy, unilateral ovariectomy, and total ovariectomy followed by exogenous estradiol, dihydrotestosterone or testosterone treatment, on female growth in comparison to males and reproductively active females. The present results and the results of our previous experiments do not support the hypotheses that SSD reflects direct energy allocation to reproduction and that male gonadal androgens are involved. However, all lines of evidence, particularly the comparable growth of reproducing intact and unilaterally ovariectomized females, were concordant with the control of SSD by ovarian hormones. We suggest that feminization of growth by female gonadal hormones should be taken into consideration as an endogenous pathway responsible for the ontogeny of SSD in squamates. PMID- 27956488 TI - Structural and Biochemical Characterization of Cinnamoyl-CoA Reductases. AB - Cinnamoyl-coenzyme A reductase (CCR) catalyzes the reduction of hydroxycinnamoyl coenzyme A (CoA) esters using NADPH to produce hydroxycinnamyl aldehyde precursors in lignin synthesis. The catalytic mechanism and substrate specificity of cinnamoyl-CoA reductases from sorghum (Sorghum bicolor), a strategic plant for bioenergy production, were deduced from crystal structures, site-directed mutagenesis, and kinetic and thermodynamic analyses. Although SbCCR1 displayed higher affinity for caffeoyl-CoA or p-coumaroyl-CoA than for feruloyl-CoA, the enzyme showed significantly higher activity for the latter substrate. Through molecular docking and comparisons between the crystal structures of the Vitis vinifera dihydroflavonol reductase and SbCCR1, residues threonine-154 and tyrosine-310 were pinpointed as being involved in binding CoA-conjugated phenylpropanoids. Threonine-154 of SbCCR1 and other CCRs likely confers strong substrate specificity for feruloyl-CoA over other cinnamoyl-CoA thioesters, and the T154Y mutation in SbCCR1 led to broader substrate specificity and faster turnover. Through data mining using our structural and biochemical information, four additional putative CCR genes were discovered from sorghum genomic data. One of these, SbCCR2, displayed greater activity toward p-coumaroyl-CoA than did SbCCR1, which could imply a role in the synthesis of defense-related lignin. Taken together, these findings provide knowledge about critical residues and substrate preference among CCRs and provide, to our knowledge, the first three dimensional structure information for a CCR from a monocot species. PMID- 27956489 TI - Physical Mapping of Amplified Copies of the 5-Enolpyruvylshikimate-3-Phosphate Synthase Gene in Glyphosate-Resistant Amaranthus tuberculatus. AB - Recent and rapid evolution of resistance to glyphosate, the most widely used herbicides, in several weed species, including common waterhemp (Amaranthus tuberculatus), poses a serious threat to sustained crop production. We report that glyphosate resistance in A tuberculatus was due to amplification of the 5 enolpyruvylshikimate-3-P synthase (EPSPS) gene, which encodes the molecular target of glyphosate. There was a positive correlation between EPSPS gene copies and its transcript expression. We analyzed the distribution of EPSPS copies in the genome of A tuberculatus using fluorescence in situ hybridization on mitotic metaphase chromosomes and interphase nuclei. Fluorescence in situ hybridization analysis mapped the EPSPS gene to pericentromeric regions of two homologous chromosomes in glyphosate sensitive A tuberculatus In glyphosate-resistant plants, a cluster of EPSPS genes on the pericentromeric region on one pair of homologous chromosomes was detected. Intriguingly, two highly glyphosate resistant plants harbored an additional chromosome with several EPSPS copies besides the native chromosome pair with EPSPS copies. These results suggest that the initial event of EPSPS gene duplication may have occurred because of unequal recombination mediated by repetitive DNA. Subsequently, gene amplification may have resulted via several other mechanisms, such as chromosomal rearrangements, deletion/insertion, transposon-mediated dispersion, or possibly by interspecific hybridization. This report illustrates the physical mapping of amplified EPSPS copies in A tuberculatus. PMID- 27956490 TI - Soluble and Membrane-Bound beta-Glucosidases Are Involved in Trimming the Xyloglucan Backbone. AB - In many flowering plants, xyloglucan is a major component of primary cell walls, where it plays an important role in growth regulation. Xyloglucan can be degraded by a suite of exoglycosidases that remove specific sugars. In this work, we show that the xyloglucan backbone, formed by (1->4)-linked beta-d-glucopyranosyl residues, can be attacked by two different Arabidopsis (Arabidopsis thaliana) beta-glucosidases from glycoside hydrolase family 3. While BGLC1 (At5g20950; for beta-glucosidase active against xyloglucan 1) is responsible for all or most of the soluble activity, BGLC3 (At5g04885) is usually a membrane-anchored protein. Mutations in these two genes, whether on their own or combined with mutations in other exoglycosidase genes, resulted in the accumulation of partially digested xyloglucan subunits, such as GXXG, GXLG, or GXFG. While a mutation in BGLC1 had significant effects on its own, lack of BGLC3 had only minor effects. On the other hand, double bglc1 bglc3 mutants revealed a synergistic interaction that supports a role for membrane-bound BGLC3 in xyloglucan metabolism. In addition, bglc1 bglc3 was complemented by overexpression of either BGLC1 or BGLC3 In overexpression lines, BGLC3 activity was concentrated in a microsome-enriched fraction but also was present in soluble form. Finally, both genes were generally expressed in the same cell types, although, in some cases, BGLC3 was expressed at earlier stages than BGLC1 We propose that functional specialization could explain the separate localization of both enzymes, as a membrane-bound beta-glucosidase could specifically digest soluble xyloglucan without affecting the wall-bound polymer. PMID- 27956492 TI - Screening for novel genes of Saccharomyces cerevisiae involved in recombinant antibody production. AB - Cost-effective manufacturing of biopharmaceuticals in non-mammalian hosts still requires tremendous efforts in strain development. In order to expedite identification of novel leads for strain engineering, we used a transposon mutagenized yeast genomic DNA library to create a collection of Saccharomyces cerevisiae deletion strains expressing a full-length IgG antibody. Using a high throughput screening, transformants with either significantly higher or lower IgG expression were selected. The integration site of the transposon in three of the selected strains was located by DNA sequencing. The inserted DNA lay within the VPS30 and TAR1 open reading frame, and upstream of the HEM13 open reading frame. The complete coding sequence of these genes was deleted in the wild-type strain background to confirm the IgG expression phenotypes. Production of recombinant antibody was increased 2-fold in the Deltavps30 strain, but only mildly affected secretion levels in the Deltatar1 strain. Remarkably, expression of endogenous yeast acid phosphatase was increased 1.7- and 2.4-fold in Deltavps30 and Deltatar1 strains. The study confirmed the power of genome-wide high-throughput screens for strain development and highlights the importance of using the target molecule during the screening process. PMID- 27956491 TI - Fermentation assays reveal differences in sugar and (off-) flavor metabolism across different Brettanomyces bruxellensis strains. AB - Brettanomyces (Dekkera) bruxellensis is an ascomycetous yeast of major importance in the food, beverage and biofuel industry. It has been isolated from various man made ecological niches that are typically characterized by harsh environmental conditions such as wine, beer, soft drink, etc. Recent comparative genomics studies revealed an immense intraspecific diversity, but it is still unclear whether this genetic diversity also leads to systematic differences in fermentation performance and (off-)flavor production, and to what extent strains have evolved to match their ecological niche. Here, we present an evaluation of the fermentation properties of eight genetically diverse B. bruxellensis strains originating from beer, wine and soft drinks. We show that sugar consumption and aroma production during fermentation are determined by both the yeast strain and composition of the medium. Furthermore, our results indicate a strong niche adaptation of B. bruxellensis, most clearly for wine strains. For example, only strains originally isolated from wine were able to thrive well and produce the typical Brettanomyces-related phenolic off-flavors 4-ethylguaiacol and 4 ethylphenol when inoculated in red wine. Sulfite tolerance was found as a key factor explaining the observed differences in fermentation performance and off flavor production. Sequence analysis of genes related to phenolic off-flavor production, however, revealed only marginal differences between the isolates tested, especially at the amino acid level. Altogether, our study provides novel insights in the Brettanomyces metabolism of flavor production, and is highly relevant for both the wine and beer industry. PMID- 27956493 TI - Laura Frontali-my life with yeast. AB - The Author relates her life from University to recent years. It was dominated by the developing importance of yeast, from agent of industrial fermentations to eukaryotic model organism. In this frame she recalls family life , friends, teachers, collaborations. PMID- 27956494 TI - Sch9p kinase and the Gcn4p transcription factor regulate glycerol production during winemaking. AB - Grape juice fermentation is a harsh environment with many stressful conditions, and Saccharomyces cerevisiae adapts its metabolism in response to those environmental challenges. Many nutrient-sensing pathways control this feature. The Tor/Sch9p pathway promotes growth and protein synthesis when nutrients are plenty, while the transcription factor Gcn4p is required for the activation of amino acid biosynthetic pathways. We previously showed that Sch9p impact on longevity depends on the nitrogen/carbon ratio. When nitrogen is limiting, SCH9 deletion shortens chronological life span, which is the case under winemaking conditions. Its deletion also increases glycerol during fermentation, so the impact of this pathway on metabolism under winemaking conditions was studied by transcriptomic and metabolomic approaches. SCH9 deletion causes the upregulation of many amino acid biosynthesis pathways. When Gcn4p was overexpressed during winemaking, increased glycerol production was also observed. Therefore, both pathways are related in terms of glycerol production. SCH9 deletion increased the amount of the limiting enzyme in glycerol biosynthesis, glycerol-3-P dehydrogenase Gpd1p at the protein level. The impact on the metabolome of SCH9 deletion and GCN4 overexpression differed, although both showed a downregulation of glycolysis. SCH9 deletion downregulated the amount of most proteinogenic amino acids and increased the amount of lipids, such as ergosterol. PMID- 27956495 TI - DNA polymerase beta contains a functional nuclear localization signal at its N terminus. AB - DNA polymerase beta (pol beta) requires nuclear localization to fulfil its DNA repair function. Although its small size has been interpreted to imply the absence of a need for active nuclear import, sequence and structural analysis suggests that a monopartite nuclear localization signal (NLS) may reside in the N terminal lyase domain. Binding of this domain to Importin alpha1 (Impalpha1) was confirmed by gel filtration and NMR studies. Affinity was quantified by fluorescence polarization analysis of a fluorescein-tagged peptide corresponding to pol beta residues 2-13. These studies indicate high affinity binding, characterized by a low micromolar Kd, that is selective for the murine Importin alpha1 (mImpalpha1) minor site, with the Kd strengthening to ~140 nM for the full lyase domain (residues 2-87). A further reduction in Kd obtains in binding studies with human Importin alpha5 (hImpalpha5), which in some cases has been demonstrated to bind small domains connected to the NLS. The role of this NLS was confirmed by fluorescent imaging of wild-type and NLS-mutated pol beta(R4S,K5S) in mouse embryonic fibroblasts lacking endogenous pol beta. Together these data demonstrate that pol beta contains a specific NLS sequence in the N-terminal lyase domain that promotes transport of the protein independent of its interaction partners. Active nuclear uptake allows development of a nuclear/cytosolic concentration gradient against a background of passive diffusion. PMID- 27956496 TI - The RNA-binding protein Secisbp2 differentially modulates UGA codon reassignment and RNA decay. AB - Dual-assignment of codons as termination and elongation codons is used to expand the genetic code. In mammals, UGA can be reassigned to selenocysteine during translation of selenoproteins by a mechanism involving a 3? untranslated region (UTR) selenocysteine insertion sequence (SECIS) and the SECIS-binding protein Secisbp2. Here, we present data from ribosome profiling, RNA-Seq and mRNA half life measurements that support distinct roles for Secisbp2 in UGA-redefinition and mRNA stability. Conditional deletions of the Secisbp2 and Trsp (tRNASec) genes in mouse liver were compared to determine if the effects of Secisbp2 loss on selenoprotein synthesis could be attributed entirely to the inability to incorporate Sec. As expected, tRNASec depletion resulted in loss of ribosome density downstream of all UGA-Sec codons. In contrast, the absence of Secisbp2 resulted in variable effects on ribosome density downstream of UGA-Sec codons that demonstrate gene-specific differences in Sec incorporation. For several selenoproteins in which loss of Secisbp2 resulted in greatly diminished mRNA levels, translational activity and Sec incorporation efficiency were shown to be unaffected on the remaining RNA. Collectively, these results demonstrate that Secisbp2 is not strictly required for Sec incorporation and has a distinct role in stabilizing mRNAs that can be separated from its effects on UGA-redefinition. PMID- 27956497 TI - Non-CpG methylation by DNMT3B facilitates REST binding and gene silencing in developing mouse hearts. AB - The dynamic interaction of DNA methylation and transcription factor binding in regulating spatiotemporal gene expression is essential for embryogenesis, but the underlying mechanisms remain understudied. In this study, using mouse models and integration of in vitro and in vivo genetic and epigenetic analyses, we show that the binding of REST (repressor element 1 (RE1) silencing transcription factor; also known as NRSF) to its cognate RE1 sequences is temporally regulated by non CpG methylation. This process is dependent on DNA methyltransferase 3B (DNMT3B) and leads to suppression of adult cardiac genes in developing hearts. We demonstrate that DNMT3B preferentially mediates non-CpG methylation of REST targeted genes in the developing heart. Downregulation of DNMT3B results in decreased non-CpG methylation of RE1 sequences, reduced REST occupancy, and consequently release of the transcription suppression during later cardiac development. Together, these findings reveal a critical gene silencing mechanism in developing mammalian hearts that is regulated by the dynamic interaction of DNMT3B-mediated non-CpG methylation and REST binding. PMID- 27956499 TI - Degradation of Mrc1 promotes recombination-mediated restart of stalled replication forks. AB - The DNA replication or S-phase checkpoint monitors the integrity of DNA synthesis. Replication stress or DNA damage triggers fork stalling and checkpoint signaling to activate repair pathways. Recovery from checkpoint activation is critical for cell survival following DNA damage. Recovery from the S-phase checkpoint includes inactivation of checkpoint signaling and restart of stalled replication forks. Previous studies demonstrated that degradation of Mrc1, the Saccharomyces cerevisiae ortholog of human Claspin, is facilitated by the SCFDia2 ubiquitin ligase and is important for cell cycle re-entry after DNA damage induced S-phase checkpoint activation. Here, we show that degradation of Mrc1 facilitated by the SCFDia2 complex is critical to restart stalled replication forks during checkpoint recovery. Using DNA fiber analysis, we showed that Dia2 functions with the Sgs1 and Mph1 helicases (orthologs of human BLM and FANCM, respectively) in the recombination-mediated fork restart pathway. In addition, Dia2 physically interacts with Sgs1 upon checkpoint activation. Importantly, failure to target Mrc1 for degradation during recovery inhibits Sgs1 chromatin association, but this can be alleviated by induced proteolysis of Mrc1 after checkpoint activation. Together, these studies provide new mechanistic insights into how cells recover from activation of the S-phase checkpoint. PMID- 27956498 TI - H3K27 acetylation activated-long non-coding RNA CCAT1 affects cell proliferation and migration by regulating SPRY4 and HOXB13 expression in esophageal squamous cell carcinoma. AB - Recently, long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in human cancer biology. In our study, we found that lncRNA CCAT1, whose expression is significantly increased and is correlated with outcomes in Esophageal Squamous Cell Carcinoma (ESCC). Consecutive experiments confirmed that H3K27-acetylation could activate expression of colon cancer associated transcript-1 (CCAT1). Further experiments revealed that CCAT1 knockdown significantly repressed the proliferation and migration both in vitro and in vivo. RNA-seq analysis revealed that CCAT1 knockdown preferentially affected genes that are linked to cell proliferation, cell migration and cell adhesion. Mechanistic investigations found that CCAT1 could serve as a scaffold for two distinct epigenetic modification complexes (5? domain of CCAT1 binding Polycomb Repressive Complex 2 (PRC2) while 3? domain of CCAT1 binding SUV39H1) and modulate the histone methylation of promoter of SPRY4 (sprouty RTK signaling antagonist 4) in nucleus. In cytoplasm, CCAT1 regulates HOXB13 as a molecular decoy for miR-7, a microRNA that targets both CCAT1 and HOXB13, thus facilitating cell growth and migration. Together, our data demonstrated the important roles of CCAT1 in ESCC oncogenesis and might serve as targets for ESCC diagnosis and therapy. PMID- 27956503 TI - Application of microtomography and image analysis to the quantification of fragmentation in ceramics after impact loading. AB - Silicon carbide ceramics are widely used in personal body armour and protective solutions. However, during impact, an intense fragmentation develops in the ceramic tile due to high-strain-rate tensile loadings. In this work, microtomography equipment was used to analyse the fragmentation patterns of two silicon carbide grades subjected to edge-on impact (EOI) tests. The EOI experiments were conducted in two configurations. The so-called open configuration relies on the use of an ultra-high-speed camera to visualize the fragmentation process with an interframe time set to 1 us. The so-called sarcophagus configuration consists in confining the target in a metallic casing to avoid any dispersion of fragments. The target is infiltrated after impact so the final damage pattern is entirely scanned using X-ray tomography and a microfocus source. Thereafter, a three-dimensional (3D) segmentation algorithm was tested and applied in order to separate fragments in 3D allowing a particle size distribution to be obtained. Significant differences between the two specimens of different SiC grades were noted. To explain such experimental results, numerical simulations were conducted considering the Denoual-Forquin Hild anisotropic damage model. According to the calculations, the difference of crack pattern in EOI tests is related to the population of defects within the two ceramics.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956504 TI - Strain rate sensitivity of the tensile strength of two silicon carbides: experimental evidence and micromechanical modelling. AB - Ceramic materials are commonly used to design multi-layer armour systems thanks to their favourable physical and mechanical properties. However, during an impact event, fragmentation of the ceramic plate inevitably occurs due to its inherent brittleness under tensile loading. Consequently, an accurate model of the fragmentation process is necessary in order to achieve an optimum design for a desired armour configuration. In this work, shockless spalling tests have been performed on two silicon carbide grades at strain rates ranging from 103 to 104 s 1 using a high-pulsed power generator. These spalling tests characterize the tensile strength strain rate sensitivity of each ceramic grade. The microstructural properties of the ceramics appear to play an important role on the strain rate sensitivity and on the dynamic tensile strength. Moreover, this experimental configuration allows for recovering damaged, but unbroken specimens, giving unique insight on the fragmentation process initiated in the ceramics. All the collected data have been compared with corresponding results of numerical simulations performed using the Denoual-Forquin-Hild anisotropic damage model. Good agreement is observed between numerical simulations and experimental data in terms of free surface velocity, size and location of the damaged zones along with crack density in these damaged zones.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956500 TI - Inhibiting translation elongation can aid genome duplication in Escherichia coli. AB - Conflicts between replication and transcription challenge chromosome duplication. Escherichia coli replisome movement along transcribed DNA is promoted by Rep and UvrD accessory helicases with Deltarep DeltauvrD cells being inviable under rapid growth conditions. We have discovered that mutations in a tRNA gene, aspT, in an aminoacyl tRNA synthetase, AspRS, and in a translation factor needed for efficient proline-proline bond formation, EF-P, suppress Deltarep DeltauvrD lethality. Thus replication-transcription conflicts can be alleviated by the partial sacrifice of a mechanism that reduces replicative barriers, namely translating ribosomes that reduce RNA polymerase backtracking. Suppression depends on RelA-directed synthesis of (p)ppGpp, a signalling molecule that reduces replication-transcription conflicts, with RelA activation requiring ribosomal pausing. Levels of (p)ppGpp in these suppressors also correlate inversely with the need for Rho activity, an RNA translocase that can bind to emerging transcripts and displace transcription complexes. These data illustrate the fine balance between different mechanisms in facilitating gene expression and genome duplication and demonstrate that accessory helicases are a major determinant of this balance. This balance is also critical for other aspects of bacterial survival: the mutations identified here increase persistence indicating that similar mutations could arise in naturally occurring bacterial populations facing antibiotic challenge. PMID- 27956505 TI - Use of simulated experiments for material characterization of brittle materials subjected to high strain rate dynamic tension. AB - Rapid progress in ultra-high-speed imaging has allowed material properties to be studied at high strain rates by applying full-field measurements and inverse identification methods. Nevertheless, the sensitivity of these techniques still requires a better understanding, since various extrinsic factors present during an actual experiment make it difficult to separate different sources of errors that can significantly affect the quality of the identified results. This study presents a methodology using simulated experiments to investigate the accuracy of the so-called spalling technique (used to study tensile properties of concrete subjected to high strain rates) by numerically simulating the entire identification process. The experimental technique uses the virtual fields method and the grid method. The methodology consists of reproducing the recording process of an ultra-high-speed camera by generating sequences of synthetically deformed images of a sample surface, which are then analysed using the standard tools. The investigation of the uncertainty of the identified parameters, such as Young's modulus along with the stress-strain constitutive response, is addressed by introducing the most significant user-dependent parameters (i.e. acquisition speed, camera dynamic range, grid sampling, blurring), proving that the used technique can be an effective tool for error investigation.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956506 TI - Hugoniot equation of state of rock materials under shock compression. AB - Two sets of shock compression tests (i.e. conventional and reverse impact) were conducted to determine the shock response of two rock materials using a plate impact facility. Embedded manganin stress gauges were used for the measurements of longitudinal stress and shock velocity. Photon Doppler velocimetry was used to capture the free surface velocity of the target. Experimental data were obtained on a fine-grained marble and a coarse-grained gabbro over a shock pressure range of approximately 1.5-12 GPa. Gabbro exhibited a linear Hugoniot equation of state (EOS) in the pressure-particle velocity (P-up) plane, while for marble a nonlinear response was observed. The EOS relations between shock velocity (US) and particle velocity (up) are linearly fitted as US = 2.62 + 3.319up and US = 5.4 85 + 1.038up for marble and gabbro, respectively.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956502 TI - A genetically encoded fluorescent tRNA is active in live-cell protein synthesis. AB - Transfer RNAs (tRNAs) perform essential tasks for all living cells. They are major components of the ribosomal machinery for protein synthesis and they also serve in non-ribosomal pathways for regulation and signaling metabolism. We describe the development of a genetically encoded fluorescent tRNA fusion with the potential for imaging in live Escherichia coli cells. This tRNA fusion carries a Spinach aptamer that becomes fluorescent upon binding of a cell permeable and non-toxic fluorophore. We show that, despite having a structural framework significantly larger than any natural tRNA species, this fusion is a viable probe for monitoring tRNA stability in a cellular quality control mechanism that degrades structurally damaged tRNA. Importantly, this fusion is active in E. coli live-cell protein synthesis allowing peptidyl transfer at a rate sufficient to support cell growth, indicating that it is accommodated by translating ribosomes. Imaging analysis shows that this fusion and ribosomes are both excluded from the nucleoid, indicating that the fusion and ribosomes are in the cytosol together possibly engaged in protein synthesis. This fusion methodology has the potential for developing new tools for live-cell imaging of tRNA with the unique advantage of both stoichiometric labeling and broader application to all cells amenable to genetic engineering. PMID- 27956507 TI - Simplified strategies based on damage mechanics for concrete under dynamic loading. AB - Based on previous work, the u damage model has been designed to figure out the various damage effects in concrete correlated with monotonic and cyclic loading, including unilateral effects. Assumptions are formulated to simplify constitutive relationships while still allowing for a correct description of the main nonlinear effects. In this context, the paper presents an enhanced simplified finite-element description including a damage description, based on the use of multifibre beam elements and including strain rate effects. Applications show that such a strategy leads to an efficient tool to simulate dynamic loading at low, medium and high velocities.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956508 TI - Hypervelocity impacts into porous graphite: experiments and simulations. AB - We present experiments and numerical simulations of hypervelocity impacts of 0.5 mm steel spheres into graphite, for velocities ranging between 1100 and 4500 m s 1 Experiments have evidenced that, after a particular striking velocity, depth of penetration no longer increases but decreases. Moreover, the projectile is observed to be trapped below the crater surface. Using numerical simulations, we show how this experimental result can be related to both materials, yield strength. A Johnson-Cook model is developed for the steel projectile, based on the literature data. A simple model is proposed for the graphite yield strength, including a piecewise pressure dependence of the Drucker-Prager form, which coefficients have been chosen to reproduce the projectile penetration depth. Comparisons between experiments and simulations are presented and discussed. The damage properties of both materials are also considered, by using a threshold on the first principal stress as a tensile failure criterion. An additional compressive failure model is also used for graphite when the equivalent strain reaches a maximum value. We show that the experimental crater diameter is directly related to the graphite spall strength. Uncertainties on the target yield stress and failure strength are estimated.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956509 TI - Ultra-high performance fibre-reinforced concrete under impact: experimental analysis of the mechanical response in extreme conditions and modelling using the Pontiroli, Rouquand and Mazars model. AB - To evaluate the vulnerability of ultra-high performance fibre-reinforced concrete (UHPFRC) infrastructure to rigid projectile penetration, over the last few years CEA-Gramat has led an experimental and numerical research programme in collaboration with French universities. During the penetration process, concrete is subjected to extreme conditions of pressure and strain rate. Plasticity mechanisms as well as dynamic tensile and/or shear damage are activated during the tunnelling phase and the cratering of the concrete target. Each mechanism has been investigated independently at the laboratory scale and the role of steel fibres especially has been analysed to understand their influence on the macroscopic behaviour. To extend the experimental results to the structural scale, penetration tests on UHPFRC slabs have been conducted by CEA-Gramat. The analysis of this dataset combined with material characterization experiments allows the role of steel fibres to be identified in the different plasticity and damage mechanisms occurring during penetration. In parallel, some improvements have been introduced into the concrete model developed by Pontiroli, Rouquand and Mazars (PRM model), especially to take into account the contribution made by the fibres in the tensile fracture process. After a primary phase of validation, the capabilities of the PRM model are illustrated by performing numerical simulations of projectile penetration into UHPFRC concrete structures.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956510 TI - Measurement of fracture properties of concrete at high strain rates. AB - An analysis of the spalling technique of concrete bars using the modified Hopkinson bar was carried out. A new experimental configuration is proposed adding some variations to previous works. An increased length for concrete specimens was chosen and finite-element analysis was used for designing a conic projectile to obtain a suitable triangular impulse wave. The aim of this initial work is to establish an experimental framework which allows a simple and direct analysis of concrete subjected to high strain rates. The efforts and configuration of these primary tests, as well as the selected geometry and dimensions for the different elements, have been focused to achieve a simple way of identifying the fracture position and so the tensile strength of tested specimens. This dynamic tensile strength can be easily compared with previous values published in literature giving an idea of the accuracy of the method and technique proposed and the possibility to extend it in a near future to obtain other mechanical properties such as the fracture energy. The tests were instrumented with strain gauges, accelerometers and high-speed camera in order to validate the results by different ways. Results of the dynamic tensile strength of the tested concrete are presented.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956511 TI - Experimental and numerical study of drill bit drop tests on Kuru granite. AB - This paper presents an experimental and numerical study of Kuru grey granite impacted with a seven-buttons drill bit mounted on an instrumented drop test machine. The force versus displacement curves during the impact, so-called bit rock interaction (BRI) curves, were obtained using strain gauge measurements for two levels of impact energy. Moreover, the volume of removed rock after each drop test was evaluated by stereo-lithography (three-dimensional surface reconstruction). A modified version of the Holmquist-Johnson-Cook (MHJC) material model was calibrated using Kuru granite test results available from the literature. Numerical simulations of the single drop tests were carried out using the MHJC model available in the LS-DYNA explicit finite-element solver. The influence of the impact energy and additional confining pressure on the BRI curves and the volume of the removed rock is discussed. In addition, the influence of the rock surface shape before impact was evaluated using two different mesh geometries: a flat surface and a hyperbolic surface. The experimental and numerical results are compared and discussed in terms of drilling efficiency through the mechanical specific energy.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956512 TI - In situ observation of fracture processes in high-strength concretes and limestone using high-speed X-ray phase-contrast imaging. AB - The mechanical properties and fracture mechanisms of geomaterials and construction materials such as concrete are reported to be dependent on the loading rates. However, the in situ cracking inside such specimens cannot be visualized using traditional optical imaging methods since the materials are opaque. In this study, the in situ sub-surface failure/damage mechanisms in Cor Tuf (a reactive powder concrete), a high-strength concrete (HSC) and Indiana limestone under dynamic loading were investigated using high-speed synchrotron X ray phase-contrast imaging. Dynamic compressive loading was applied using a modified Kolsky bar and fracture images were recorded using a synchronized high speed synchrotron X-ray imaging set-up. Three-dimensional synchrotron X-ray tomography was also performed to record the microstructure of the specimens before dynamic loading. In the Cor-Tuf and HSC specimens, two different modes of cracking were observed: straight cracking or angular cracking with respect to the direction of loading. In limestone, cracks followed the grain boundaries and voids, ultimately fracturing the specimen. Cracks in HSC were more tortuous than the cracks in Cor-Tuf specimens. The effects of the microstructure on the observed cracking behaviour are discussed.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956513 TI - Effects of strain rate and surface cracks on the mechanical behaviour of Balmoral Red granite. AB - This work presents a systematic study on the effects of strain rate and surface cracks on the mechanical properties and behaviour of Balmoral Red granite. The tensile behaviour of the rock was studied at low and high strain rates using Brazilian disc samples. Heat shocks were used to produce samples with different amounts of surface cracks. The surface crack patterns were analysed using optical microscopy, and the complexity of the patterns was quantified by calculating the fractal dimensions of the patterns. The strength of the rock clearly drops as a function of increasing fractal dimensions in the studied strain rate range. However, the dynamic strength of the rock drops significantly faster than the quasi-static strength, and, because of this, also the strain rate sensitivity of the rock decreases with increasing fractal dimensions. This can be explained by the fracture behaviour and fragmentation during the dynamic loading, which is more strongly affected by the heat shock than the fragmentation at low strain rates.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956514 TI - High-performance concrete engineered for protective barriers. AB - This paper reviews the effects of high-performance concrete mix ingredients on its resistance to impact of non-deforming projectiles, and on the resistance of layered barriers, engineered based on these findings. First, the reported effects of the aggregate types and sizes and the application of steel fibres, which were observed experimentally, are presented, considering resistance parameters that include the impact energy at the ballistic limit, the extent of the damaged areas at the impacted (front) and rear faces and the overall damage. These findings indicate that a protective barrier may be engineered to have layers that utilize these effects to produce a better performance under impact. Results from reported experiments of double-layered specimens, which examined the effects of the aggregate size and application of fibres, confirm this idea to a certain extent. They lead to conclusions regarding the importance of fibres in mitigating the damage, the use of large aggregates in a thicker front layer and their associated effect on increasing the damage at the front, impacted face. A 'resistance index' is proposed to quantify the resistance in a comprehensive way and the experimental results have been re-evaluated in view of this parameter.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956515 TI - An improved computational constitutive model for glass. AB - In 2011, Holmquist and Johnson presented a model for glass subjected to large strains, high strain rates and high pressures. It was later shown that this model produced solutions that were severely mesh dependent, converging to a solution that was much too strong. This article presents an improved model for glass that uses a new approach to represent the interior and surface strength that is significantly less mesh dependent. This new formulation allows for the laboratory data to be accurately represented (including the high tensile strength observed in plate-impact spall experiments) and produces converged solutions that are in good agreement with ballistic data. The model also includes two new features: one that decouples the damage model from the strength model, providing more flexibility in defining the onset of permanent deformation; the other provides for a variable shear modulus that is dependent on the pressure. This article presents a review of the original model, a description of the improved model and a comparison of computed and experimental results for several sets of ballistic data. Of special interest are computed and experimental results for two impacts onto a single target, and the ability to compute the damage velocity in agreement with experiment data.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956516 TI - A pulse-shaping technique to investigate the behaviour of brittle materials subjected to plate-impact tests. AB - Owing to their significant hardness and compressive strengths, ceramic materials are widely employed for use with protective systems subjected to high-velocity impact loadings. Therefore, their mechanical behaviour along with damage mechanisms need to be significantly investigated as a function of loading rates. However, the classical plate-impact testing procedures produce shock loadings in the brittle sample material which cause unrealistic levels of loading rates. Additionally, high-pulsed power techniques and/or functionally graded materials used as flyer plates to smooth the loading pulse remain costly, and are generally difficult to implement. In this study, a shockless plate-impact technique based on the use of either a wavy-machined flyer plate or buffer plate that can be produced by chip-forming is proposed. A series of numerical simulations using an explicit transient dynamic finite-element code have been performed to design and validate the experimental testing configuration. The calculations, conducted in two-dimensional (2D) plane-strain or in 2D axisymmetric modes, prove that the 'wavy' contact surface will produce a pulse-shaping effect, whereas the buffer plate will produce a homogenizing effect of the stress field along the transverse direction of the sample. In addition, 'wavy-shape' geometries of different sizes provide an easy way to change the level of loading rate and rise time in an experimentally tested ceramic specimen. Finally, when a shockless compression loading method is applied to the sample, a Lagrangian analysis of data is made possible by considering an assemblage of ceramic plates of different thicknesses in the target, so the axial stress-strain response of the brittle sample material can be provided.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956517 TI - Brittle materials at high-loading rates: an open area of research. AB - Brittle materials are extensively used in many civil and military applications involving high-strain-rate loadings such as: blasting or percussive drilling of rocks, ballistic impact against ceramic armour or transparent windshields, plastic explosives used to damage or destroy concrete structures, soft or hard impacts against concrete structures and so on. With all of these applications, brittle materials are subjected to intense loadings characterized by medium to extremely high strain rates (few tens to several tens of thousands per second) leading to extreme and/or specific damage modes such as multiple fragmentation, dynamic cracking, pore collapse, shearing, mode II fracturing and/or microplasticity mechanisms in the material. Additionally, brittle materials exhibit complex features such as a strong strain-rate sensitivity and confining pressure sensitivity that justify expending greater research efforts to understand these complex features. Currently, the most popular dynamic testing techniques used for this are based on the use of split Hopkinson pressure bar methodologies and/or plate-impact testing methods. However, these methods do have some critical limitations and drawbacks when used to investigate the behaviour of brittle materials at high loading rates. The present theme issue of Philosophical Transactions A provides an overview of the latest experimental methods and numerical tools that are currently being developed to investigate the behaviour of brittle materials at high loading rates.This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'. PMID- 27956518 TI - Use of self-expanding stents for better intracranial flow diverter wall apposition. AB - Background Flow diverter (FD) malapposition is associated with stroke-related complications. We document the use of self-expanding nitinol stents to remove/reduce the ledge of a FD deployed for aneurysm treatment. Methods We identified five patients who were treated with the Pipeline embolization device (PED) in conjunction with a Neuroform EZ stent for inadequate wall apposition of the ends of the FD at our institution between May 2014 and July 2015. Among other parameters, angiographic results, cone-beam computed tomography assessment of wall apposition and patient clinical outcome were evaluated. Results Incomplete device end apposition was seen in three cases, and precarious positioning of the distal end of the PED over the aneurysm neck was seen in two cases. In all five cases, successful treatment with good wall apposition and proper pinning of the PED distal edge was achieved using an additional Neuroform EZ stent. Appropriate aneurysm neck coverage and flow stagnation was seen in all cases. The combination of high radial outward force and open-cell design permits the Neuroform EZ stent to jail the malappositioned edges of the FD while maintaining good vessel-wall apposition itself and prevent migration of the PED. Short-term follow-up angiography showed device patency and complete aneurysm obliteration in all cases. Conclusions Preliminary results of this small case series suggest that the Neuroform EZ stent allows for effective treatment of FD malapposition in selected patients amenable for this endovascular approach. Long-term and larger cohort studies are needed to validate these results. PMID- 27956519 TI - Advancing Marksman into contralateral vertebral artery in the treatment of intradural vertebral artery dissecting aneurysm with Pipeline. AB - Unruptured vertebral arteries dissecting aneurysms have a benign clinical course. The most common symptoms compromise headache, neck pain, dizziness and vomiting. The optimal endovascular treatment option remains controversial. Reconstructive techniques have many advantages over deconstructive ones since the advent of flow diverters such as the Pipeline embolization device (PED). Here, we present a case successfully treated with a PED through a combination of the radial access and advancement of the Marksman catheter into the contralateral vertebral artery due to the special angio-architecture of the patient. PMID- 27956520 TI - Dual Inhibition of Key Proliferation Signaling Pathways in Triple-Negative Breast Cancer Cells by a Novel Derivative of Taiwanin A. AB - The treatment of breast cancer cells obtained by blocking the aberrant activation of the proliferation signaling pathways PI3K/Akt/mTOR and MEK/ERK has received considerable attention in recent years. Previous studies showed that Taiwanin A inhibited the proliferation of several types of cancer cells. In this study, we report that 3,4-bis-3,4,5-trimethoxybenzylidene-dihydrofuran (BTMB), a novel derivative of Taiwanin A, significantly inhibited the proliferation of triple negative breast cancer (TNBC) cells both in vitro and in vivo The results show that BTMB inhibited the proliferation of human TNBC cells by the induction of cell-cycle arrest and apoptosis in a dose-dependent fashion. BTMB inhibited the expression of beta-catenin, cdc2 and the cell-cycle regulatory proteins, cyclin A, cyclin D1, and cyclin E. The mechanism of action was associated with the suppression of cell survival signaling through inactivation of the Akt and ERK1/2 signaling pathways. Moreover, BTMB induced cell apoptosis through an increase in the expression of BAX, cleaved caspase-3, and cleaved PARP. Moreover, BTMB inhibited TNBC cell colony formation and sensitized TNBC cells to cisplatin, a chemotherapeutic drug. In a TNBC mouse xenograft model, BTMB significantly inhibited the growth of mammary carcinomas through decreased expression of cyclin D1. BTMB was shown to significantly suppress the growth of mammary carcinoma and therefore to have potential as an anticancer therapeutic agent. Mol Cancer Ther; 16(3); 480-93. (c)2016 AACR. PMID- 27956522 TI - Genetic Characterization of the Galactitol Utilization Pathway of Salmonella enterica Serovar Typhimurium. AB - : Galactitol degradation by salmonellae remains underinvestigated, although this metabolic capability contributes to growth in animals (R. R. Chaudhuri et al., PLoS Genet 9:e1003456, 2013, https://doi.org/10.1371/journal.pgen.1003456). The genes responsible for this metabolic capability are part of a 9.6-kb gene cluster that spans from gatY to gatR (STM3253 to STM3262) and encodes a phosphotransferase system, four enzymes, and a transporter of the major facilitator superfamily. Genome comparison revealed the presence of this genetic determinant in nearly all Salmonella strains. The generation time of Salmonella enterica serovar Typhimurium strain ST4/74 was higher in minimal medium with galactitol than with glucose. Knockout of STM3254 and gatC resulted in a growth deficient phenotype of S Typhimurium, with galactitol as the sole carbon source. Partial deletion of gatR strongly reduced the lag phase of growth with galactitol, whereas strains overproducing GatR exhibited a near-zero growth phenotype. Luciferase reporter assays demonstrated strong induction of the gatY and gatZ promoters, which control all genes of this cluster except gatR, in the presence of galactitol but not glucose. Purified GatR bound to these two main gat gene cluster promoters as well as to its own promoter, demonstrating that this autoregulated repressor controls galactitol degradation. Surface plasmon resonance spectroscopy revealed distinct binding properties of GatR toward the three promoters, resulting in a model of differential gat gene expression. The cyclic AMP receptor protein (CRP) bound these promoters with similarly high affinities, and a mutant lacking crp showed severe growth attenuation, demonstrating that galactitol utilization is subject to catabolite repression. Here, we provide the first genetic characterization of galactitol degradation in Salmonella, revealing novel insights into the regulation of this dissimilatory pathway. IMPORTANCE: The knowledge of how pathogens adapt their metabolism to the compartments encountered in hosts is pivotal to our understanding of bacterial infections. Recent research revealed that enteropathogens have adapted specific metabolic pathways that contribute to their virulence properties, for example, by helping to overcome limitations in nutrient availability in the gut due to colonization resistance. The capability of Salmonella enterica serovar Typhimurium to degrade galactitol has already been demonstrated to play a role in vivo, but it has not been investigated so far on the genetic level. To our knowledge, this is the first molecular description of the galactitol degradation pathway of a pathogen. PMID- 27956521 TI - Dual-Targeting Nanoparticles for In Vivo Delivery of Suicide Genes to Chemotherapy-Resistant Ovarian Cancer Cells. AB - Ovarian cancer is the most lethal gynecologic cancer. Claudin-3 and -4, the receptors for Clostridium perfringens enterotoxin (CPE), are overexpressed in more than 70% of these tumors. Here, we synthesized and characterized poly(lactic co-glycolic-acid) (PLGA) nanoparticles (NPs) modified with the carboxy-terminal binding domain of CPE (c-CPE-NP) for the delivery of suicide gene therapy to chemotherapy-resistant ovarian cancer cells. As a therapeutic payload, we generated a plasmid encoding for the diphtheria toxin subunit-A (DT-A) under the transcriptional control of the p16 promoter, a gene highly differentially expressed in ovarian cancer cells. Flow cytometry and immunofluorescence demonstrated that c-CPE-NPs encapsulating the cytomegalovirus (CMV) GFP plasmid (CMV GFP c-CPE-NP) were significantly more efficient than control NPs modified with a scrambled peptide (CMV GFP scr-NP) in transfecting primary chemotherapy resistant ovarian tumor cell lines in vitro (P = 0.03). Importantly, c-CPE-NPs encapsulating the p16 DT-A vector (p16 DT-A c-CPE-NP) were significantly more effective than control p16 DT-A scr-NP in inducing ovarian cancer cell death in vitro (% cytotoxicity: mean +/- SD = 32.9 +/- 0.15 and 7.45 +/- 7.93, respectively, P = 0.03). In vivo biodistribution studies demonstrated efficient transfection of tumor cells within 12 hours after intraperitoneal injection of CMV GFP c-CPE-NP in mice harboring chemotherapy-resistant ovarian cancer xenografts. Finally, multiple intraperitoneal injections of p16 DT-A c-CPE-NP resulted in a significant inhibition of tumor growth compared with control NP in chemotherapy-resistant tumor-bearing mice (P = 0.041). p16 DT-A c-CPE-NP may represent a novel dual-targeting therapeutic approach for the selective delivery of gene therapy to chemotherapy-resistant ovarian cancer cells. Mol Cancer Ther; 16(2); 323-33. (c)2016 AACR. PMID- 27956523 TI - The Master Regulators of the Fla1 and Fla2 Flagella of Rhodobacter sphaeroides Control the Expression of Their Cognate CheY Proteins. AB - Rhodobacter sphaeroides is an alphaproteobacterium that has two complete sets of flagellar genes. The fla1 set was acquired by horizontal transfer from an ancestral gammaproteobacterium and is the only set of flagellar genes that is expressed during growth under standard laboratory conditions. The products of these genes assemble a single, subpolar flagellum. In the absence of the Fla1 flagellum, a gain-of-function mutation in the histidine kinase CckA turns on the expression of the fla2 flagellar genes through the response regulator CtrA. The rotation of the Fla1 and Fla2 flagella is controlled by different sets of chemotaxis proteins. Here, we show that the expression of the chemotaxis proteins that control Fla2, along with the expression of the fla2 genes, is coordinated by CtrA, whereas the expression of the chemotaxis genes that control Fla1 is mediated by the master regulators of the Fla1 system. The coordinated expression of the chemosensory proteins with their cognate flagellar genes highlights the relevance of integrating the expression of the horizontally acquired fla1 genes with a chemosensory system independently of the regulatory proteins responsible for the expression of fla2 and its cognate chemosensory system. IMPORTANCE Gene acquisition via horizontal transfer represents a challenge to the recipient organism to adjust its metabolic and genetic networks to incorporate the new material in a way that represents an adaptive advantage. In the case of Rhodobacter sphaeroides, a complete set of flagellar genes was acquired and successfully coordinated with the native flagellar system. Here we show that the expression of the chemosensory proteins that control flagellar rotation is dependent on the master regulators of their corresponding flagellar system, minimizing the use of transcription factors required to express the native and horizontally acquired genes along with their chemotaxis proteins. PMID- 27956524 TI - Thermoregulation of Biofilm Formation in Burkholderia pseudomallei Is Disrupted by Mutation of a Putative Diguanylate Cyclase. AB - Burkholderia pseudomallei, a tier 1 select agent and the etiological agent of melioidosis, transitions from soil and aquatic environments to infect a variety of vertebrate and invertebrate hosts. During the transition from an environmental saprophyte to a mammalian pathogen, B. pseudomallei encounters and responds to rapidly changing environmental conditions. Environmental sensing systems that control cellular levels of cyclic di-GMP promote pathogen survival in diverse environments. Cyclic di-GMP controls biofilm production, virulence factors, and motility in many bacteria. This study is an evaluation of cyclic di-GMP associated genes that are predicted to metabolize and interact with cyclic di-GMP as identified from the annotated genome of B. pseudomallei 1026b. Mutants containing transposon disruptions in each of these genes were characterized for biofilm formation and motility at two temperatures that reflect conditions that the bacteria encounter in the environment and during the infection of a mammalian host. Mutants with transposon insertions in a known phosphodiesterase (cdpA) and a predicted hydrolase (Bp1026b_I2285) gene exhibited decreased motility regardless of temperature. In contrast, the phenotypes exhibited by mutants with transposon insertion mutations in a predicted diguanylate cyclase gene (Bp1026b_II2523) were strikingly influenced by temperature and were dependent on a conserved GG(D/E)EF motif. The transposon insertion mutant exhibited enhanced biofilm formation at 37 degrees C but impaired biofilm formation at 30 degrees C. These studies illustrate the importance of studying behaviors regulated by cyclic di-GMP under varied environmental conditions in order to better understand cyclic di-GMP signaling in bacterial pathogens.IMPORTANCE This report evaluates predicted cyclic di-GMP binding and metabolic proteins from Burkholderia pseudomallei 1026b, a tier 1 select agent and the etiologic agent of melioidosis. Transposon insertion mutants with disruptions in each of the genes encoding these predicted proteins were characterized in order to identify key components of the B. pseudomallei cyclic di-GMP-signaling network. A predicted hydrolase and a phosphodiesterase that modulate swimming motility were identified, in addition to a diguanylate cyclase that modulates biofilm formation and motility in response to temperature. These studies warrant further evaluation of the contribution of cyclic di-GMP to melioidosis in the context of pathogen acquisition from environmental reservoirs and subsequent colonization, dissemination, and persistence within the host. PMID- 27956525 TI - IL-17C/IL-17RE Augments T Cell Function in Autoimmune Hepatitis. AB - Autoimmune hepatitis is a worldwide health problem and significant cause of mortality. However, the disease etiology is largely unknown, which accounts for ineffective treatment and uncontrolled disease progression. In this study, we demonstrated the functional importance of the IL-17C/IL-17RE axis in Con A induced hepatitis. Elevated IL-17C expression was detected in liver samples of both human and mouse autoimmune hepatitis. IL-17C, produced by hepatocytes, and its specific receptor IL-17RE on liver-resident T cells were both found to be required in Con A-induced liver damage. Mechanistically, IL-17C augmented the expression of IL-2 by intrahepatic CD4+ T cells to promote NK cell activation and liver damage. To our knowledge, our findings thus for the first time defined the indispensable role of IL-17C/IL-17RE in autoimmune hepatitis; this axis may serve as a novel drug target for the treatment of this disease. PMID- 27956526 TI - TLR10 Is a B Cell Intrinsic Suppressor of Adaptive Immune Responses. AB - Toll-like receptors play a central role in the initiation of adaptive immune responses with several TLR agonists acting as known B cell mitogens. Despite thousands of publications on TLRs, the function of TLR10 remains unknown. We have found that Ab-mediated engagement of TLR10 on primary human B cells suppresses B cell proliferation, cytokine production, and signal transduction. When challenged with either a T independent or T dependent Ag, TLR10 transgenic mice exhibit diminished Ab responses. Adoptive transfer of splenic B cells into B cell deficient mice revealed that the suppressive effects on Ag-specific humoral immune responses are entirely B cell intrinsic. Our results demonstrate that TLR10 has a functional role within the B cell lineage that is distinct from that of other TLR family members and may provide a potential therapeutic target for diseases characterized by dysregulated B cell activity. PMID- 27956527 TI - Role of CCL7 in Type I Hypersensitivity Reactions in Murine Experimental Allergic Conjunctivitis. AB - Molecules that are necessary for ocular hypersensitivity reactions include the receptors CCR1 and CCR3; CCL7 is a ligand for these receptors. Therefore, we explored the role of CCL7 in mast cell activity and motility in vitro and investigated the requirement for CCL7 in a murine model of IgE-mediated allergic conjunctivitis. For mast cells treated with IgE and Ag, the presence of CCL7 synergistically enhanced degranulation and calcium influx. CCL7 also induced chemotaxis in mast cells. CCL7-deficient bone marrow-derived mast cells showed decreased degranulation following IgE and Ag treatment compared with wild-type bone marrow-derived mast cells, but there was no difference in degranulation when cells were activated via an IgE-independent pathway. In vivo, CCL7 was upregulated in conjunctival tissue during an OVA-induced allergic response. Notably, the early-phase clinical symptoms in the conjunctiva after OVA challenge were significantly higher in OVA-sensitized wild-type mice than in control challenged wild-type mice; the increase was suppressed in CCL7-deficient mice. In the OVA-induced allergic response, the numbers of conjunctival mast cells were lower in CCL7-deficient mice than in wild-type mice. Our results demonstrate that CCL7 is required for maximal OVA-induced ocular anaphylaxis, mast cell recruitment in vivo, and maximal FcepsilonRI-mediated mast cell activation in vitro. A better understanding of the role of CCL7 in mediating ocular hypersensitivity reactions will provide insights into mast cell function and novel treatments for allergic ocular diseases. PMID- 27956528 TI - A Novel Function of F-Box Protein FBXO17 in Negative Regulation of Type I IFN Signaling by Recruiting PP2A for IFN Regulatory Factor 3 Deactivation. AB - The F-box proteins were originally identified as the key component of SKP1 Cullin1-F-box E3 ligase complexes that control the stability of their specific downstream substrates essential for cell growth and survival. However, the involvement of these proteins in type I IFN (IFN-I) signaling during innate immunity has not been investigated. In this study we report that the F-box protein FBXO17 negatively regulates IFN-I signaling triggered by double-strand DNA, RNA, or viral infection. We found that FBXO17 specifically interacts with IFN regulatory factor 3 (IRF3) and decreases its dimerization and nuclear translocation. The decrease of IRF3 dimerization and nuclear translocation is due to the recruitment of protein phosphatase 2 (PP2A) mediated by FBXO17, resulting in IRF3 dephosphorylation. Interestingly, PP2A recruitment does not require the F box domain but instead the F-box associated region of the protein; thus, the recruitment is independent of the canonical function of the SKP1-Cullin1-F-box family of E3 ligase. Together, our studies identify a previously unreported role of FBXO17 in regulating IFN-I signaling and further demonstrate a novel mechanism for IRF3 deactivation by F-box protein-mediated recruitment of PP2A. PMID- 27956529 TI - Cutting Edge: Helminth Coinfection Blocks Effector Differentiation of CD8 T Cells through Alternate Host Th2- and IL-10-Mediated Responses. AB - Concurrent helminth infection potently inhibits T cell immunity; however, whether helminthes prevent T cell priming or skew clonal recruitment and effector differentiation is not known. Using coinfection with two natural mouse pathogens, Heligmosomoides polygyrus and Toxoplasma gondii, to investigate the negative impact of helminthes on the CD8 T cell response, we demonstrate helminth-induced suppression of IL-12-dependent differentiation of killer-like receptor G1+ effector CD8 T cells and IFN-gamma production. Nevertheless, reversal of helminth suppression of the innate IL-12 response of CD8alpha+ dendritic cells, which occurred in STAT6-deficient mice, was not sufficient to normalize CD8 T cell differentiation. Instead, a combined deficiency in IL-4 and IL-10 was required to reverse the negative effects of helminth coinfection on the CD8 T cell response. Monoclonal T. gondii-specific CD8 T cells adoptively transferred into coinfected mice recapitulated the spectrum of helminth-induced effects on the polyclonal CD8 T response, indicating the lack of requirement for clonal skewing. PMID- 27956530 TI - Predictive Analysis of Mechanistic Triggers and Mitigation Strategies for Pathological Scarring in Skin Wounds. AB - Wound fibrosis (i.e., excessive scar formation) is a medical problem of increasing prevalence, with poorly understood mechanistic triggers and limited therapeutic options. In this study, we employed an integrated approach that combines computational predictions with new experimental studies in mice to identify plausible mechanistic triggers of pathological scarring in skin wounds. We developed a computational model that predicts the time courses for six essential cell types, 18 essential molecular mediators, and collagen, which are involved in inflammation and proliferation during wound healing. By performing global sensitivity analyses using thousands of model-simulated wound-healing scenarios, we identified five key processes (among the 90 modeled processes) whose dysregulation may lead to pathological scarring in wounds. By modulating a subset of these key processes, we simulated fibrosis in wounds. Moreover, among the 18 modeled molecular mediators, we identified TGF-beta and the matrix metalloproteinases as therapeutic targets whose modulation may reduce fibrosis. The model predicted that simultaneous modulation of TGF-beta and matrix metalloproteinases would be more effective in treating excessive scarring than modulation of either therapeutic target alone. Our model was validated with previously published and newly generated experimental data, and suggested new in vivo experiments. PMID- 27956531 TI - Clr-a: A Novel Immune-Related C-Type Lectin-like Molecule Exclusively Expressed by Mouse Gut Epithelium. AB - The mouse gut epithelium represents a constitutively challenged environment keeping intestinal commensal microbiota at bay and defending against invading enteric pathogens. The complex immunoregulatory network of the epithelial barrier surveillance also involves NK gene complex (NKC)-encoded C-type lectin-like molecules such as NKG2D and Nkrp1 receptors. To our knowledge, in this study, we report the first characterization of the orphan C-type lectin-like molecule Clr-a encoded by the Clec2e gene in the mouse NKC. Screening of a panel of mouse tissues revealed that Clec2e transcripts are restricted to the gastrointestinal tract. Using Clr-a-specific mAb, we characterize Clr-a as a disulfide-linked homodimeric cell surface glycoprotein. Of note, a substantial fraction of Clr-a molecules are retained intracellularly, and analyses of Clr-a/Clr-f hybrids attribute intracellular retention to both the stalk region and parts of the cytoplasmic domain. Combining quantitative PCR analyses with immunofluorescence studies revealed exclusive expression of Clr-a by intestinal epithelial cells and crypt cells throughout the gut. Challenge with polyinosinic-polycytidylic acid results in a rapid and strong downregulation of intestinal Clr-a expression in contrast to the upregulation of Clr-f, a close relative of Clr-a, that also is specifically expressed by the intestinal epithelium and acts as a ligand of the inhibitory Nkrp1g receptor. Collectively, we characterize expression of the mouse NKC-encoded glycoprotein Clr-a as strictly associated with mouse intestinal epithelium. Downregulation upon polyinosinic-polycytidylic acid challenge and expression by crypt cells clearly distinguish Clr-a from the likewise intestinal epithelium-restricted Clr-f, pointing to a nonredundant function of these highly related C-type lectin-like molecules in the context of intestinal immunosurveillance. PMID- 27956533 TI - Palliative Care-The Challenge of Application. PMID- 27956532 TI - An Oncologist's Letter to Santa. PMID- 27956534 TI - A Polycythemia Vera JAK2 Mutation Masquerading as a Duodenal Cancer Mutation. AB - Next-generation sequencing (NGS) is increasingly being used in cancer care to identify both somatic tumor driver mutations that can be targeted for therapy, and heritable mutations in the germline associated with increased cancer risk. This report presents a case of a JAK2 V617F mutation falsely identified as a duodenal cancer mutation via NGS. The patient was found to have a history of polycythemia vera, a disorder with a high incidence of JAK2 somatic mutations. Buccal cell DNA showed heterozygosity for the mutation, suggesting that it was potentially germline. However, subsequent resequencing of tumor, adjacent normal tissue, and fingernail DNA confirmed the mutation was somatic, and its presence in tumor and buccal cells resulted from contaminating blood cells. This report highlights important nuances of NGS that can lead to misinterpretation of results with potential clinical implications. PMID- 27956536 TI - Factors Associated With Delays in Chemotherapy Initiation Among Patients With Breast Cancer at a Comprehensive Cancer Center. AB - BACKGROUND: National guidelines endorse time-dependent quality metrics for breast cancer care. We examined factors associated with delays in chemotherapy initiation at an NCI-Designated Comprehensive Cancer Center. PATIENTS AND METHODS: We identified 523 patients who received postoperative adjuvant chemotherapy between January 2011 and December 2013 at our center. We defined 28 days from last definitive surgery (LDS) to chemotherapy as the target time frame, and an unacceptable delay in chemotherapy initiation (UCD) as greater than 42 days from LDS. Multivariate regression models were used to identify factors associated with UCD and the impact of Oncotype DX testing in patients with hormone receptor (HR)-positive breast cancer. RESULTS: Median days between LDS and chemotherapy initiation was 34 (interquartile range, 15), with 30% of patients starting within 28 days of LDS and 26.9% having UCD. Tumor characteristics such as subtype and stage affected UCD; patients with HR-positive or HER2-positive tumors were more likely to be delayed compared with those with triple-negative breast cancer. Patients with stage I disease, those undergoing mastectomy with or without immediate reconstruction, and those whose pathology sign-out was greater than 10 days postoperatively were more likely to be delayed. A higher proportion of UCD was found in HR-positive patients (31%) for whom Oncotype DX testing was ordered compared with those in whom it was not ordered (20%). CONCLUSIONS: This study provides insight into subpopulations that may be at risk to experience delays in chemotherapy initiation, directing interventions to improve the timeliness of care. PMID- 27956535 TI - NCCN Guidelines Insights: Chronic Myeloid Leukemia, Version 1.2017. AB - The NCCN Guidelines for Chronic Myeloid Leukemia (CML) provide recommendations for the management of chronic-phase and advanced-phase CML in adult patients. The median age of disease onset is 67 years. However, because CML occurs in all age groups, clinical care teams should be prepared to address issues relating to fertility and pregnancy with patients who are of reproductive age at the time of diagnosis. CML is relatively rare in children and there are no evidence-based recommendations for the management of CML in pediatric population. These NCCN Guidelines Insights discuss special considerations for the management of CML during pregnancy and for the management of CML in the pediatric population. PMID- 27956537 TI - Neoadjuvant Therapy for Rectal Cancer Affects Lymph Node Yield and Status Without Clear Implications on Outcome: The Case for Eliminating a Metric and Using Preoperative Staging to Guide Therapy. AB - BACKGROUND: Nodal status has long been considered pivotal to oncologic care, staging, and management. This has resulted in the establishment of rudimentary metrics regarding adequate lymph node yield in colon and rectal cancers for accurate cancer staging. In the era of neoadjuvant treatment, the implications of lymph node yield and status on patient outcomes remains unclear. PATIENT AND METHODS: This study included 1,680 patients with locally advanced rectal cancer from the NCCN prospective oncology database stratified into 3 groups based on preoperative therapy received: no neoadjuvant therapy, neoadjuvant chemoradiation, and neoadjuvant chemotherapy. Clinicopathologic characteristics and survival were compared between the groups, with univariate and multivariate analyses undertaken. RESULTS: The clinicopathologic characteristics demonstrated statistically significant differences and heterogeneity among the 3 groups. The neoadjuvant chemoradiation group demonstrated the statistically lowest median lymph node yield (n=15) compared with 17 and 18 for no-neoadjuvant and neoadjuvant chemotherapy, respectively (P<.0001). Neoadjuvant treatment did impact survival, with chemoradiation demonstrating increased median overall survival of 42.7 compared with 37.3 and 26.6 months for neoadjuvant chemotherapy and no-neoadjuvant therapy, respectively (P<.0001). Patients with a yield of fewer than 12 lymph nodes had improved median overall survival of 43.3 months compared with 36.6 months in patients with 12 or more lymph nodes (P=.009). Multivariate analysis demonstrated that neither node yield nor status were predictors for overall survival. DISCUSSION: This analysis reiterates that nodal yield in rectal cancer is multifactorial, with neoadjuvant therapy being a significant factor. Node yield and status were not significant predictors of overall survival. A nodal metric may not be clinically relevant in the era of neoadjuvant therapy, and guidelines for perioperative therapy may need reconsideration. PMID- 27956538 TI - Differential Radiographic Appearance of BRAF V600E-Mutant Metastatic Colorectal Cancer in Patients Matched by Primary Tumor Location. AB - BACKGROUND: BRAF-mutant metastatic colorectal cancers (mCRCs) share many clinicopathologic features with right-sided colon tumors, including frequent peritoneal involvement. Because of the poorer outcomes associated with BRAF mutations, early enrollment in clinical trials has been encouraged. However, the use of standard eligibility and assessment criteria, such as measurable disease, has anecdotally impeded patient accrual and restricted appraisal of treatment response. We investigated whether the presence of a BRAF V600E mutation is differentially associated with sites and appearance of metastatic disease in patients matched by primary tumor location. METHODS: A total of 40 patients with BRAF-mutant mCRC were matched to 80 patients with BRAF wild-type mCRC by location of primary tumor (right or left colon; rectum), sex, and age. Associations between BRAF mutation status and clinicopathologic characteristics and metastatic sites were analyzed using proportion tests. Survival was summarized with Kaplan Meier and Cox regression methods. RESULTS: The distribution of primary tumor locations was: 60% right colon, 30% left colon, and 10% rectum. Compared with BRAF wild-type tumors, BRAF-mutant tumors more commonly associated with peritoneal metastases (50% vs 31%; P=.045) and ascites (50% vs 24%; P=.0038). In patients with left colon primaries, BRAF mutations were associated with more frequent ascites (58% vs 12%; P=.0038) and less frequent liver metastases (42% vs 79%; P=.024). Among patients with right colon primaries, no significant difference in sites of disease by BRAF mutation status was observed. Disease was not measurable by RECIST 1.1 in 24% of patients with right-sided primary tumors, irrespective of BRAF mutation status. In the BRAF-mutated cohort, ascites correlated unfavorably with survival (hazard ratio, 2.35; 95% CI, 1.14, 4.83; P=.02). CONCLUSIONS: Greater frequency of ascites and peritoneal metastases, which pose challenges for RECIST 1.1 interpretation of therapeutic outcomes, are seen with BRAF-mutant mCRC, even when patients are matched for primary tumor location. PMID- 27956539 TI - Delivery of Adjuvant Oxaliplatin for Colon Cancer: Insights From Routine Clinical Practice. AB - BACKGROUND: Adjuvant oxaliplatin is now a standard treatment option for patients with early-stage colon cancer. However, treatment delivery and outcomes achieved in routine practice are not well described. METHODS: All cases of colon cancer diagnosed in Ontario from 2002 to 2008 were identified using the Ontario Cancer Registry. Pathology reports were obtained for a 25% random sample to identify stage II and III cases; patients treated with adjuvant oxaliplatin were included in this analysis. Treatment records were reviewed to identify oxaliplatin dose reductions or omissions. Modified Poisson regression was used to evaluate factors associated with dose reduction/omission. Cox proportional hazards model was used to explore factors associated with cancer-specific survival (CSS) and overall survival (OS). RESULTS: The study population included 532 patients; 88% (469/532) had stage III disease. The mean/median number of oxaliplatin cycles delivered was 10/12. A dose reduction/omission of oxaliplatin occurred in 54% of cases (288/532), and the dose was subsequently escalated in 34% of these (97/288). Women were more likely than men to have dose reduction/omission (relative risk, 1.29; 95% CI, 1.10-1.51). Dose reduction/omission was not associated with inferior CSS (hazard ratio [HR], 0.76; 95% CI, 0.51-1.14) or OS (HR, 0.81; 95% CI, 0.59-1.13). Five-year CSS and OS of all cases were 77% (95% CI, 72-81) and 72% (95% CI, 68-76), respectively. On-treatment mortality rates were 1% and 3% within 30 and 90 days of oxaliplatin, respectively. CONCLUSIONS: Dose reductions of adjuvant oxaliplatin are common in routine practice but are not associated with inferior survival. Long-term survival achieved in the general population is comparable to the results of clinical trials. PMID- 27956540 TI - Effective Translation of Research to Practice: Hospital-Based Rehabilitation Program Improves Health-Related Physical Fitness and Quality of Life of Cancer Survivors. AB - BACKGROUND: Although exercise has been widely established as an efficacious rehabilitative therapy for cancer survivors in rigorously designed research studies, demonstration of translation of this research into clinical oncology practice is needed. The purpose of this study was to evaluate the effectiveness of a real-world cancer rehabilitation program implemented within a healthcare setting. PATIENTS AND METHODS: This study involved 299 adult cancer survivors enrolled in a hospital-based, supervised, individualized, cancer rehabilitation program. A retrospective review of the 132 participants who completed the follow up assessment was performed. Sixty-minute sessions consisting of aerobic, resistance, flexibility, and relaxation exercises were performed twice weekly. Questionnaires and fitness assessments were administered at enrollment and after 24 sessions by exercise physiologists. Change in a number of health-related physical fitness and patient-reported outcomes and the influence of baseline characteristics on program outcomes were assessed. RESULTS: There were no baseline differences between those who completed the follow-up assessment and those who withdrew. Statistically and/or clinically meaningful improvements occurred in functional capacity, blood pressure, muscular endurance, flexibility, health-related quality of life, and fatigue, but not in body composition. Age, marital status, radiation treatment status, exercise frequency before diagnosis, smoking status, and alcohol consumption frequency influenced functional capacity and/or quality-of-life changes. CONCLUSIONS: Adoption of cancer rehabilitation as a standard part of oncology care may improve cancer survivors' health and well being. PMID- 27956541 TI - Psychological Symptoms Among Patients With BCR-ABL-Negative Myeloproliferative Neoplasms. AB - BACKGROUND: BCR-ABL-negative myeloproliferative neoplasms (MPNs) represent a heterogeneous group of diseases, including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Psychological manifestations among these diseases have not been adequately described. METHODS: Cross-sectional surveys measuring distress, anxiety, and depression were collected from patients with BCR-ABL-negative MPNs from May 2015 to October 2015. Participants provided demographic information and completed the Distress Thermometer and Problem List (DT&PL) to assess distress and the Hospital Anxiety and Depression Scale (HADS) to assess distress, anxiety, and depression. They provided information on how their MPN affected their lives. RESULTS: Of the 117 participants, 31.2% had PV, 28.4% had ET, 28.4% had MF, and 11.9% had another type of MPN. Time with MPN varied from less than 1 year (7.5%), 1 to 3 years (19.8%), 3 to 5 years (23.6%), 5 to 10 years (19.8%), and more than 10 years (29.2%). Distress averaged 3.14 (SD, 2.83; DT&PL), with 40.4% meeting NCCN criteria for distress, and averaged 8.97 (SD, 7.44; HADS), with 38.5% meeting HADS criteria for distress. Anxiety averaged 5.54 (SD, 4.37), with 31.3% meeting HADS criteria for anxiety. Depression averaged 3.4 (SD, 3.4), with 12.5% meeting HADS criteria for depression. Distress was higher for PV (3.86), MF (3.12), and "other" MPN (4.33) than it was for ET (1.81; P=.016). Distress was more common in non-white patients (P=.015) and those with either PV or MF but not ET (DT&PL >=4; P=.038). Patients' comments described coping strategies or symptom burden. CONCLUSIONS: Distress and anxiety are highly prevalent with BCR-ABL-negative MPNs and may correspond to disease-related symptom burden. These findings deserve further study. PMID- 27956542 TI - Myeloproliferative Neoplasms, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. AB - Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The diagnosis and the management of patients with MPNs have evolved since the identification of mutations that activate the JAK pathway (JAK2, CALR, and MPL mutations) and the development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnostic workup of MPN (MF, PV, and ET), risk stratification, treatment, and supportive care strategies for the management of MF. PMID- 27956544 TI - Experience of Myeloproliferative Neoplasms Guidelines in the United Kingdom: Perspective and International Context. PMID- 27956543 TI - Drug Development Pipeline for Myeloproliferative Neoplasms: Potential Future Impact on Guidelines and Management. AB - The unprecedented success of ruxolitinib in myelofibrosis (MF) has paved the way for the development of other Janus kinase (JAK) inhibitors and other agents representing diverse drug classes and mechanisms of action in myeloproliferative neoplasms (MPNs). In particular, the symptomatic benefits afforded by ruxolitinib have led to the recognition of "clinical improvement" in symptoms and the spleen in international consensus response criteria for MF. Ruxolitinib is also approved for the second-line treatment of polycythemia vera and is being developed for essential thrombocythemia. Appreciation of the universal role of activated JAK/signal transducer and activator of transcription (STAT) signaling in MPNs and improved understanding of the canonical and noncanonical actions of JAK2 have yielded a number of drug targets beyond JAK2 in MPNs, which form the basis for a number of ruxolitinib-based rational combinations that are being explored in MF. Other JAK inhibitors with the potential for significantly less myelosuppression or even improvement of anemia continue to be tested. Finally, agents with very distinct mechanisms of action, such as novel interferon formulations, antifibrotic agents, and telomerase inhibitors, are being pursued in polycythemia vera and MF, respectively. This article reviews the current landscape of clinical drug development in MPNs, focusing on the most promising agents and combinations. PMID- 27956546 TI - NCCN News. PMID- 27956547 TI - Antiepileptic drugs in migraine and epilepsy: Who is at increased risk of adverse events? AB - Background The impact of adverse events (AEs) of antiepileptic drugs (AEDs) have an impact on compliance and dropouts. We compared tolerability of AEs of AEDs among patients with migraine, epilepsy, or both. Methods Overall, 335 patients (epilepsy (n = 142), migraine (n = 131), and both (n = 62)), were evaluated with the Liverpool Adverse Events Profile (LAEP) to assess the magnitude, profile and occurrence rate of the AEs of valproate, topiramate, and lamotrigine. Results AEs were significantly more common with topiramate treatment (71.0%) and among migraineurs (69.5%), the latter being more prone to discontinue AEDs (46.6%). The profile of AEs with topiramate and valproate differed among groups. Moreover, treatment with both topiramate and valproate was associated, for all groups, with a worse tolerability profile compared to lamotrigine. Conclusion Our data suggest a specific drug and disease AE profile of AEDs. Specifically, migraineurs are the most affected by AEs, even though they receive very low dosages of AEDs. This finding might be considered a clinical implication of central sensitization mechanisms. Both the profile and tolerability of AEs, highly influencing quality of life, depended on the underlying conditions, and deeply impacted on treatment dropout. Therefore, before starting, switching or stopping AED treatment, all options need to be considered. PMID- 27956548 TI - A Late G1 Lipid Checkpoint That Is Dysregulated in Clear Cell Renal Carcinoma Cells. AB - Lipids are important nutrients that proliferating cells require to maintain energy homeostasis as well as to build plasma membranes for newly synthesized cells. Previously, we identified nutrient-sensing checkpoints that exist in the latter part of the G1 phase of the cell cycle that are dependent upon essential amino acids, Gln, and finally, a checkpoint mediated by mammalian target of rapamycin (mTOR), which integrates signals from both nutrients and growth factors. In this study, we have identified and temporally mapped a lipid-mediated G1 checkpoint. This checkpoint is located after the Gln checkpoint and before the mTOR-mediated cell cycle checkpoint. Intriguingly, clear cell renal cell carcinoma cells (ccRCC) have a dysregulated lipid-mediated checkpoint due in part to defective phosphatase and tensin homologue (PTEN). When deprived of lipids, instead of arresting in G1, these cells continue to cycle and utilize lipid droplets as a source of lipids. Lipid droplets have been known to maintain endoplasmic reticulum homeostasis and prevent cytotoxic endoplasmic reticulum stress in ccRCC. Dysregulation of the lipid-mediated checkpoint forces these cells to utilize lipid droplets, which could potentially lead to therapeutic opportunities that exploit this property of ccRCC. PMID- 27956549 TI - Loss of Glyoxalase 1 Induces Compensatory Mechanism to Achieve Dicarbonyl Detoxification in Mammalian Schwann Cells. AB - The glyoxalase system is a highly specific enzyme system existing in all mammalian cells that is responsible for the detoxification of dicarbonyl species, primarily methylglyoxal (MG). It has been implicated to play an essential role in preventing the increased formation of advanced glycation end products under certain pathological conditions. We have established the first glyoxalase 1 knock out model (GLO1-/-) in mammalian Schwann cells using the CRISPR/Cas9 technique to investigate compensatory mechanisms. Neither elevated concentrations of MG nor associated protein modifications were observed in GLO1-/- cells. Alternative detoxification of MG in GLO1-/- is achieved by increased catalytic efficiency of aldose reductase toward hemithioacetal (product of glutathione and MG), which is most likely caused by S-nitrosylation of aldose reductase. The hemithioacetal is mainly converted into lactaldehyde, which is paralleled by a loss of reduced glutathione. Inhibition of aldose reductase in GLO1-/- cells is associated with an increased sensitivity against MG, elevated intracellular MG levels, associated modifications, as well as increased oxidative stress. Our data suggest that aldose reductase can compensate for the loss of GLO1. This might be of clinical importance within the context of neuronal diseases caused by an impaired glyoxalase system and elevated levels of dicarbonyl species, such as MG. PMID- 27956550 TI - Signal Integration at Elongation Factor 2 Kinase: THE ROLES OF CALCIUM, CALMODULIN, AND SER-500 PHOSPHORYLATION. AB - Eukaryotic elongation factor 2 kinase (eEF-2K), the only calmodulin (CaM) dependent member of the unique alpha-kinase family, impedes protein synthesis by phosphorylating eEF-2. We recently identified Thr-348 and Ser-500 as two key autophosphorylation sites within eEF-2K that regulate its activity. eEF-2K is regulated by Ca2+ ions and multiple upstream signaling pathways, but how it integrates these signals into a coherent output, i.e. phosphorylation of eEF-2, is unclear. This study focuses on understanding how the post-translational phosphorylation of Ser-500 integrates with Ca2+ and CaM to regulate eEF-2K. CaM is shown to be absolutely necessary for efficient activity of eEF-2K, and Ca2+ is shown to enhance the affinity of CaM toward eEF-2K. Ser-500 is found to undergo autophosphorylation in cells treated with ionomycin and is likely also targeted by PKA. In vitro, autophosphorylation of Ser-500 is found to require Ca2+ and CaM and is inhibited by mutations that compromise binding of phosphorylated Thr-348 to an allosteric binding pocket on the kinase domain. A phosphomimetic Ser-500 to aspartic acid mutation (eEF-2K S500D) enhances the rate of activation (Thr-348 autophosphorylation) by 6-fold and lowers the EC50 for Ca2+/CaM binding to activated eEF-2K (Thr-348 phosphorylated) by 20-fold. This is predicted to result in an elevation of the cellular fraction of active eEF-2K. In support of this mechanism, eEF-2K knock-out MCF10A cells reconstituted with eEF-2K S500D display relatively high levels of phospho-eEF-2 under basal conditions. This study reports how phosphorylation of a regulatory site (Ser-500) integrates with Ca2+ and CaM to influence eEF-2K activity. PMID- 27956551 TI - Recombinant Expression of the Full-length Ectodomain of LDL Receptor-related Protein 1 (LRP1) Unravels pH-dependent Conformational Changes and the Stoichiometry of Binding with Receptor-associated Protein (RAP). AB - LDL receptor-related protein 1 (LRP1) is a highly modular protein and the largest known mammalian endocytic receptor. LRP1 binds and internalizes many plasma components, playing multiple crucial roles as a scavenger and signaling molecule. One major challenge to studying LRP1 has been that it is difficult to express such a large, highly glycosylated, and cysteine-rich protein, limiting structural studies to LRP1 fragments. Here, we report the first recombinant expression of the complete 61 domains of the full-length LRP1 ectodomain. This advance was achieved with a multistep cloning approach and by using DNA dilutions to improve protein yields. We investigated the binding properties of LRP1 using receptor associated protein (RAP) as a model ligand due to its tight binding interaction. The LRP1 conformation was studied in its bound and unbound state using mass spectrometry, small-angle X-ray scattering, and negative-stain electron microscopy at neutral and acidic pH. Our findings revealed a pH-dependent release of the ligand associated with a conformational change of the receptor. In summary, this investigation of the complete LRP1 ectodomain significantly advances our understanding of this important receptor and provides the basis for further elucidating the mechanism of action of LRP1 in a whole and integrated system. PMID- 27956552 TI - Cytokine-induced MMP13 Expression in Human Chondrocytes Is Dependent on Activating Transcription Factor 3 (ATF3) Regulation. AB - Irreversible breakdown of cartilage extracellular matrix (ECM) by the collagenase matrix metalloproteinase 13 (MMP13) represents a key event in osteoarthritis (OA) progression. Although inflammation is most commonly associated with inflammatory joint diseases, it also occurs in OA and is thus relevant to the prevalent tissue destruction. Here, inflammation generates a cFOS AP-1 early response that indirectly affects MMP13 gene expression. To ascertain a more direct effect on prolonged MMP13 production we examined the potential molecular events occurring between the rapid, transient expression of cFOS and the subsequent MMP13 induction. Importantly, we show MMP13 mRNA expression is mirrored by nascent hnRNA transcription. Employing ChIP assays, cFOS recruitment to the MMP13 promoter occurs at an early stage prior to gene transcription and that recruitment of transcriptional initiation markers also correlated with MMP13 expression. Moreover, protein synthesis inhibition following early FOS expression resulted in a significant decrease in MMP13 expression thus indicating a role for different regulatory factors modulating expression of the gene. Subsequent mRNA transcriptome analyses highlighted several genes induced soon after FOS that could contribute to MMP13 expression. Specific small interfering RNA-mediated silencing highlighted that ATF3 was as highly selective for MMP13 as cFOS. Moreover, ATF3 expression was AP-1(cFOS/cJUN)-dependent and expression levels were maintained after the early transient cFOS response. Furthermore, ATF3 bound the proximal MMP13 AP-1 motif in stimulated chondrocytes at time points that no longer supported binding of FOS Consequently, these findings support roles for both cFOS (indirect) and ATF3 (direct) in effecting MMP13 transcription in human chondrocytes. PMID- 27956553 TI - Catalytic Mechanism of a Novel Glycoside Hydrolase Family 16 "Elongating" beta Transglycosylase. AB - Carbohydrates are complex macromolecules in biological metabolism. Enzymatic synthesis of carbohydrates is recognized as a powerful tool to overcome the problems associated with large scale synthesis of carbohydrates. Novel enzymes with significant transglycosylation ability are still in great demand in glycobiology studies. Here we report a novel glycoside hydrolase family 16 "elongating" beta-transglycosylase from Paecilomyces thermophila (PtBgt16A), which efficiently catalyzes the synthesis of higher polymeric oligosaccharides using beta-1,3/1,4-oligosaccharides as donor/acceptor substrates. Further structural information reveals that PtBgt16A has a binding pocket around the -1 subsite. The catalytic mechanism of PtBgt16A is partly similar to an exo glycoside hydrolase, which cleaves the substrate from the non-reducing end one by one. However, PtBgt16A releases the reducing end product and uses the remainder glucosyl as a transglycosylation donor. This catalytic mechanism has similarity with the catalytic mode of amylosucrase, which catalyzes the transglycosylation products gradually extend by one glucose unit. PtBgt16A thus has the potential to be a tool enzyme for the enzymatic synthesis of new beta-oligosaccharides and glycoconjugates. PMID- 27956555 TI - The influence of aetiology on the benefits of exercise training in patients with heart failure. AB - Background Exercise training improves neurovascular control and functional capacity in heart failure (HF) patients. However, the influence of the aetiology on these benefits is unknown. We compared the effects of exercise training on neurovascular control and functional capacity in idiopathic, ischaemic and hypertensive HF patients. Design Subjects consisted of 45 exercise-trained HF patients from our database (2000-2015), aged 40-70 years old, functional class II/III and ejection fraction <=40%, and they were divided into three groups: idiopathic ( n = 11), ischaemic ( n = 18) and hypertensive ( n = 16). Methods Functional capacity was determined by cardiopulmonary exercise testing. Muscle sympathetic nerve activity (MSNA) was recorded by microneurography. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Results Four months of exercise training significantly reduced MSNA and significantly increased FBF in all groups. However, the relative reduction in MSNA was greater in hypertensive patients compared with that in idiopathic patients (frequency: -34% vs . -15%, p = 0.01; incidence: -31% vs . -12%, p = 0.02). No differences were found between hypertensive patients and ischaemic patients. The relative increase in FBF was greater in hypertensive patients than in ischaemic and idiopathic patients (42% vs. 15% and 17%, respectively, p = 0.02). The relative increase in forearm vascular conductance was greater in hypertensive patients compared with those in ischaemic and idiopathic patients (57% vs . 13% and 26%, respectively, p = 0.001). Exercise training significantly and similarly increased peak oxygen consumption in all groups. Conclusion The exercise-induced improvement in neurovascular control is more pronounced in hypertensive HF patients than in idiopathic and ischaemic HF patients. The increase in functional capacity is independent of aetiology. PMID- 27956554 TI - The Protein Neddylation Pathway in Trypanosoma brucei: FUNCTIONAL CHARACTERIZATION AND SUBSTRATE IDENTIFICATION. AB - Protein posttranslational modifications such as neddylation play crucial roles in regulating protein function. Only a few neddylated substrates have been validated to date, and the role of neddylation remains poorly understood. Here, using Trypanosoma brucei as the model organism, we investigated the function and substrates of TbNedd8. TbNedd8 is distributed throughout the cytosol but enriched in the nucleus and the flagellum. Depletion of TbNedd8 by RNAi abolished global protein ubiquitination, caused DNA re-replication in postmitotic cells, impaired spindle assembly, and compromised the flagellum attachment zone filament, leading to flagellum detachment. Through affinity purification and mass spectrometry, we identified 70 TbNedd8-conjugated and -associated proteins, including known Nedd8 conjugated and -associated proteins, putative TbNedd8 conjugation system enzymes, proteins of diverse biological functions, and proteins of unknown function. Finally, we validated six Cullins as bona fide TbNedd8 substrates and identified the TbNedd8 conjugation site in three Cullins. This work lays the foundation for understanding the roles of protein neddylation in this early divergent parasitic protozoan. PMID- 27956557 TI - Breaking down the gut microbiome composition in multiple sclerosis. AB - BACKGROUND: The gut microbiome, which consists of a highly diverse ecologic community of micro-organisms, has increasingly been studied regarding its role in multiple sclerosis (MS) immunopathogenesis. This review critically examines the literature investigating the gut microbiome in MS. METHODS: A comprehensive search was performed of PubMed databases and ECTRIMS meeting abstracts for literature relating to the gut microbiome in MS. Controlled studies examining the gut microbiome in patients with MS were included for review. RESULTS: Identified studies were predominantly case-control in their design and consistently found differences in the gut microbiome of MS patients compared to controls. We examine plausible mechanistic links between these differences and MS immunopathogenesis, and discuss the therapeutic implications of these findings. CONCLUSIONS: Review of the available literature reveals potential immunopathogenic links between the gut microbiome and MS, identifies avenues for therapeutic advancement, and emphasizes the need for further systematic study in this emerging field. PMID- 27956556 TI - Electromyography and economy of walking in chronic heart failure and heart transplant patients. AB - Background Patients with chronic heart failure frequently report intolerance to exercise and present with changes in walk pattern, but information about heart transplant patients is lacking. Alterations of the gait pattern are related to interaction changes between the metabolism, neurological system and the mechanical demands of the locomotor task. The aim of this study was to investigate the electromyographic cost, coactivation and cost of transport of walking of chronic heart failure and heart transplant patients. Design This research was of an exploratory, cross-sectional design. Methods Twelve chronic heart failure patients, twelve healthy controls and five heart transplant patients participated in the study. Electromyographic data and oxygen uptake were collected simultaneously at five walking speeds. Results In the experimental groups, the electromyographic cost, percentage of coactivation in the leg and cost of transport were higher than in controls. The electromyographic cost was in line with the cost of transport. The minimum electromyographic cost matched with the self-selected walking speed in controls, while in chronic heart failure and heart transplant patients, it was reached at speeds higher than the self-selected walking speed. Conclusion The largest postural isometric activation and antagonist activation resulted in the highest metabolic demand. These findings are of great clinical relevance because they support the concept that interventions in order to improve the muscle performance in these patients can increase the self-selected walking speed and therefore the metabolic economy of walking. PMID- 27956560 TI - Marta Elian: Obituary. PMID- 27956559 TI - Clinical course of multiple sclerosis: A nationwide cohort study. AB - BACKGROUND: The course of multiple sclerosis (MS) has been studied in several cohorts; however, results have varied significantly. OBJECTIVE: To describe the clinical course of MS in a nationwide cohort of patients. METHOD: Data from the Swedish MS register (SMSreg) were used to estimate the median time to the sustained Expanded Disability Status Scale (EDSS) scores 3.0, 4.0 and 6.0, onset of secondary progressive multiple sclerosis (SPMS) and death using Kaplan-Meier method. A possible effect of first-line treatments on age at EDSS 6.0 and SPMS was estimated. RESULTS: In all, 12,703 patients were included. Median ages at EDSS scores 3.0, 4.0 and 6.0 were 55.4 (95% confidence interval (CI): 54.8-55.8), 60.7 (95% CI: 60.1-61.2) and 64.3 (95% CI: 63.6-64.7), respectively. Median age at SPMS was 57.4 (95% CI: 56.9-57.9). The median age at the time of death was 80.5 (95% CI: 79.9-81.1). Males and progressive-onset patients showed higher risks of disability worsening. On average, treated patients gained 1.6 years (95% CI: 0.2-3) to EDSS 6.0 as a result of treatment. CONCLUSION: Ages at disability milestones in this population-based cohort were higher than previously described in clinic- and regional-based samples. Nevertheless, MS patients die at younger age and live at an average almost 20 years with moderate and 30 years with severe disability. PMID- 27956562 TI - Cardioembolism as the unsuspected missing link between migraine and ischemic stroke. PMID- 27956563 TI - Ischemic stroke subtypes and migraine with visual aura in the ARIC study. AB - OBJECTIVE: To investigate the association among migraine, ischemic stroke, and stroke subtypes in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: In this ongoing, prospective, longitudinal community-based cohort study, participants were given an interview ascertaining migraine history in 1993-1995, and were followed for all vascular events, including stroke. All stroke events over the subsequent 20 years were adjudicated and classified into stroke subtypes by standard definitions. Cox proportional hazards models adjusted for stroke risk factors were used to study the relationship between migraine and ischemic stroke, overall, as well as stroke subtypes (cardioembolic, lacunar, or thrombotic). RESULTS: We identified 1,622 migraineurs among 12,758 participants. Mean age of the study population at the 3rd clinical visit was 59 years. When compared to nonheadache participants, there was a significant association between migraine with visual aura and ischemic stroke (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.2-2.6, p = 0.008). Migraine without visual aura was not significantly associated with ischemic stroke (HR 1.2, CI 1.0-1.8, p = 0.28) when compared to nonheadache participants. Among the 3 subtypes of ischemic stroke evaluated, migraine with visual aura was significantly associated only with cardioembolic stroke (HR 3.7, 95% CI 1.6-8.7, p = 0.003). CONCLUSION: In participants with migraine with visual aura in late middle age, increased risk of cardioembolic stroke was observed. Migraine with visual aura was linked to increased stroke risk, while migraine without visual aura was not, over the period of 20 years. These results are specific to older migraineurs. PMID- 27956564 TI - N-terminal pro-brain natriuretic peptide and subclinical brain small vessel disease. AB - OBJECTIVE: To study the association of N-terminal pro-brain natriuretic peptide (NT-proBNP) with several brain MRI markers of brain vascular disease in a sample of participants free of stroke and dementia. METHODS: NT-proBNP plasma level was determined by means of a sandwich immunoassay method in a cohort study comprising 278 hypertensive patients. The presence of silent brain infarcts, brain microbleeds, enlarged perivascular spaces, and white matter hyperintensity volumes was assessed by brain MRI. We performed univariate and multivariate analyses to determine whether NT-proBNP was independently associated with these imaging markers, individually or combined. RESULTS: Median age was 63 years, and 41.4% were women. NT-proBNP remained independently associated with silent brain infarcts (odds ratio [OR] per 1-SD increase in NT-proBNP 2.11, 95% confidence interval [CI] 1.44-3.10), brain microbleeds (OR 1.79, 95% CI 1.15-2.78), basal ganglia enlarged perivascular spaces (OR 1.55, 95% CI 1.12-2.15), and white matter hyperintensity volumes (beta 1.60, 95% CI 0.47-2.74), even after controlling for vascular risk factors, cardiovascular risk, atrial fibrillation, previous heart disease, duration of hypertension, and preventive treatments. A score combining several imaging markers was also related to NT-proBNP levels (common OR per 1-SD increase 1.74, 95% CI 1.21-2.50). CONCLUSIONS: NT-proBNP is independently associated with silent cerebrovascular lesions and could be a surrogate marker of vascular brain damage in hypertension. PMID- 27956566 TI - Leaving no man's land. PMID- 27956567 TI - False ictal-appearing EEG from a frontal sinus pseudomeningocele. PMID- 27956569 TI - Augmentation and impulsive behaviors in restless legs syndrome: Coexistence or association? PMID- 27956568 TI - String of pearls around the brainstem: A case of neurosarcoidosis. PMID- 27956570 TI - Spatial-temporal functional mapping of language at the bedside with electrocorticography. PMID- 27956565 TI - Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1. AB - OBJECTIVE: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1). METHODS: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8-15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population. RESULTS: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = -0.15, 95% confidence interval -0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval -0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo. CONCLUSIONS: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population. CLINICALTRIALSGOV IDENTIFIER: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits. PMID- 27956571 TI - Right Brain: Breaking bad news: Communication education for neurology trainees. PMID- 27956572 TI - Right Brain: Home is where the heart is. PMID- 27956573 TI - Teaching NeuroImages: Intracranial vertebral dissection in a 15-year-old boy with sickle cell disease. PMID- 27956577 TI - Introduction to the "Evaluating the Impact of Structural Policies on Health Inequalities and Their Social Determinants and Fostering Change" (SOPHIE) Project. AB - The SOPHIE Project (acronym for Structural Policies for Health Inequalities Evaluation) has focused on evaluating the impact of structural policies on health equity, considering as such all those policies that exert a powerful influence on the structural determinants of health (e.g., patterns of social stratification, living and working conditions) and thus on health-related exposures through intermediary determinants. In these sections of the International Journal of Health Services, we present some of the main findings of the SOPHIE Project. We include both articles that summarize all the evidence already published in the project on a thematic area (such as labor market, gender, or housing) and articles that present new, unpublished evidence on a specific health inequality or policy. PMID- 27956578 TI - The Cuban Response to the Ebola Epidemic in West Africa: Lessons in Solidarity. AB - In December 2013 the first case of Ebola appeared in Guinea. In September 2014 the United Nations (UN) and its specialized agency the World Health Organization (WHO) issued a call for medical collaboration in response to the medical crisis and social disaster caused by the Ebola virus epidemic in West Africa. Cuban authorities responded immediately to the call by offering specialized help for the epidemic, in collaboration with WHO. A group of 256 Cuban doctors, nurses and other health professionals provided direct care during the Ebola epidemic in Sierra Leone, Liberia and Equatorial Guinea from October 2014 to April 2015. This paper explains the main features of the Cuban health system, describes the development of Cuba's international medical cooperation approach, and highlights the work done by Cuban health collaborators in addressing the damage caused by the Ebola epidemic. Information used includes reports and documents of the Ministry of Public Health of Cuba, reports of WHO and PAHO, and articles published in scientific journals and newspaper articles. The response of the Cuban medical teams to the Ebola epidemic in West Africa is only one example of the Cuban efforts to strengthening health care provision in areas of need throughout the world. PMID- 27956574 TI - Longitudinal Association Between Serum Uric Acid and Arterial Stiffness: Results From the Baltimore Longitudinal Study of Aging. AB - Serum uric acid (SUA) has long been associated with increased cardiovascular risk, with arterial stiffness proposed as a mediator. However, evidence on the association between SUA and arterial stiffness is limited to contradicting cross sectional studies. In this analysis, we examined the longitudinal relationship between SUA and pulse wave velocity, a measure of arterial stiffness, in a community-dwelling population. We studied 446 women and 427 men participating in the BLSA (Baltimore Longitudinal Study of Aging), with 1409 and 1434 observations, respectively, over an average period of 6 years. At baseline, mean ages of women and men were 65+/-13 and 68+/-13 years; mean SUA, 4.6+/-1.1 and 5.7+/-1.3 mg/dL; mean pulse wave velocity, 8.1+/-1.7 and 8.6+/-1.9 m/s, respectively (P<0.0001). In gender-stratified models accounting for age, blood pressure, renal function, metabolic measures, and medications, there was a significant interaction between SUA and follow-up time in men (beta=0.69; P=0.0002) but not in women. Men, but not women, in the highest gender-specific SUA tertile at baseline (SUA>=6.2 mg/dL in men and SUA>=4.9 mg/dL in women) had a greater rate of pulse wave velocity increase over time than those in the lowest tertiles (beta=0.997; P=0.012). This gender difference was lost when the distribution of SUA in men and women was made comparable by excluding hyperuricemic men (SUA>=6.2 mg/dL). In conclusion, higher SUA was associated with greater increase in pulse wave velocity in men but not women; this association was lost when men with SUA>=6.2 mg/dL were not included, suggesting a threshold for SUA association with arterial stiffness, which is more frequently reached in men. PMID- 27956575 TI - Renal Denervation Reduces Monocyte Activation and Monocyte-Platelet Aggregate Formation: An Anti-Inflammatory Effect Relevant for Cardiovascular Risk. AB - Overactivation of renal sympathetic nervous system and low-grade systemic inflammation are common features of hypertension. Renal denervation (RDN) reduces sympathetic activity in patients with resistant hypertension. However, its effect on systemic inflammation has not been examined. We prospectively investigated the effect of RDN on monocyte activation and inflammation in patients with uncontrolled hypertension scheduled for RDN. Ambulatory blood pressure, monocyte, and monocyte subset activation and inflammatory markers were assessed at baseline, 3 months, and 6 months after procedure in 42 patients. RDN significantly lowered blood pressure at 3 months (150.5+/-11.2/81.0+/-11.2 mm Hg to 144.7+/-11.8/77.9+/-11.0 mm Hg), which was sustained at 6 months (144.7+/ 13.8/78.6+/-11.0 mm Hg). Activation status of monocytes significantly decreased at 3 months (P<0.01) and 6 months (P<0.01) after the procedure. In particular, classical monocyte activation was reduced at 6 months (P<0.05). Similarly, we observed a reduction of several inflammatory markers, including monocyte-platelet aggregates (3 months, P<0.01), plasma monocyte chemoattractant protein-1 levels (3 months, P<0.0001; 6 months, P<0.05), interleukin-1beta (3 months, P<0.05; 6 months, P<0.05), tumor necrosis factor-alpha (3 months, P<0.01; 6 months, P<0.05), and interleukin-12 (3 months, P<0.01; 6 months, P<0.05). A positive correlation was observed between muscle sympathetic nerve activity and monocyte activation before and after the procedure. These results indicate that inhibition of sympathetic activity via RDN is associated with a reduction of monocyte activation and other inflammatory markers in hypertensive patients. These findings point to a direct interaction between the inflammatory and sympathetic nervous system, which is of central relevance for the understanding of beneficial cardiovascular effects of RDN. PMID- 27956576 TI - Tripartite Motif 8 Contributes to Pathological Cardiac Hypertrophy Through Enhancing Transforming Growth Factor beta-Activated Kinase 1-Dependent Signaling Pathways. AB - Tripartite motif (TRIM) 8 functions as an E3 ubiquitin ligase, interacting with and ubiquitinating diverse substrates, and is implicated in various pathological processes. However, the function of TRIM8 in the heart remains largely uncharacterized. This study aims to explore the role of TRIM8 in the development of pathological cardiac hypertrophy. Mice and isolated neonatal rat cardiomyocytes overexpressing or lacking TRIM8 were examined in several experiments. The effect of aortic banding-induced cardiac hypertrophy was analyzed by echocardiographic, pathological and molecular analyses. Our results indicated that the TRIM8 overexpression in hearts exacerbated the cardiac hypertrophy triggered by aortic banding. In contrast, the development of pathological cardiac hypertrophy was profoundly blocked in TRIM8-deficient hearts. Mechanistically, our study suggests that TRIM8 may elicit cardiodetrimental effects by promoting the activation of transforming growth factor beta-activated kinase 1 (TAK1)-p38/JNK signaling pathways. Similar results were observed in cultured neonatal rat cardiomyocytes treated with angiotensin II. The rescue experiments using the TAK1-specific inhibitor 5z-7-ox confirmed the requirement of TAK1 activation in TRIM8-mediated pathological cardiac hypertrophy. Furthermore, TRIM8 contributed to TAK1 activation by binding to and promoting TAK1 ubiquitination. In conclusion, our study demonstrates that TRIM8 plays a deleterious role in pressure overload-induced cardiac hypertrophy by accelerating the activation of TAK1-dependent signaling pathways. PMID- 27956579 TI - Debate on the Chernobyl Disaster: Response to Alison Rosamund Katz. PMID- 27956580 TI - Visual Discomfort From Flash Afterimages of Riloid Patterns. AB - Op-art-based stimuli have been shown to be uncomfortable, possibly due to a combination of fixational eye movements (microsaccades) and excessive cortical responses. Efforts have been made to measure illusory phenomena arising from these stimuli in the absence of microsaccades, but there has been no attempt thus far to decouple the effects of the cortical response from the effect of fixational eye movements. This study uses flash afterimages to stabilise the image on the retina and thus reduce the systematic effect of eye movements, in order to investigate the role of the brain in discomfort from op-art-based stimuli. There was a relationship between spatial frequency and the magnitude of the P300 response, showing a similar pattern to that of discomfort judgements, which suggests that there might be a role of discomfort and excessive neural responses independently from the effects of microsaccades. PMID- 27956581 TI - Can Magic Deception Be Detected at an Unconscious Level? AB - Magicians present magic tricks that seem to defy the laws of nature, entertaining us by manipulating our attention, perception, and awareness. However, although we are unaware of these manipulations at the level of conscious experience, we may still be aware of them at an unconscious level. We examined whether people can detect a magic deception outside of conscious awareness using an indirect measure. In the present study, we used the Cups and Balls magic trick, which is the transposition of balls between two cups. Participants viewed a video of the magic performance and were required to indicate the position of the ball in a direct self-report measure and completed the Single Category Implicit Association Test as an indirect measure. The results showed that the indirect measure of trick detection had higher accuracy than the direct measure. Our results suggest that while humans cannot consciously detect the magic deception, they do have a sense of what occurred on an unconscious level. PMID- 27956582 TI - Angiotensin-converting enzyme insertion/deletion gene polymorphism in Egyptian children with systemic lupus erythematosus: a possible relation to proliferative nephritis. AB - Introduction Angiotensin-converting enzyme (ACE) is crucial in the pathogenesis of systemic lupus erythematosus through angiotensin II which regulates vascular tone and endothelial functions. Objectives To study the frequency of ACE insertion/deletion (I/D) gene polymorphism in Egyptian children with systemic lupus erythematosus and its possible relation to the renal pathology in cases with lupus nephritis. Subjects and methods The frequency of ACE gene insertion/deletion polymorphism genotypes was determined in 78 Egyptian children with systemic lupus erythematosus and compared to a matched group of 140 healthy controls using polymerase chain reaction. Results The DD genotype of the ACE gene was higher in systemic lupus erythematosus patients when compared to controls ( P<0.0001; odds ratio (OR) 2.4; 95% confidence interval (CI) 1.7-3.3) and the D allele was more frequent than the I allele in systemic lupus erythematosus patients in comparison to controls ( P < 0.0001; OR = 2.2; 95% CI = (1.6-3.1). In the lupus nephritis group, the DD genotype was significantly higher in those with proliferative lupus nephritis when compared to those with non-proliferative lupus nephritis ( P = 0.02; OR = 1.45; 95% CI = 1.4-1.6). Also, patients with proliferative lupus nephritis showed a higher frequency of the D allele ( P < 0.001; OR = 1.98; 95% CI = 1.3-2.9). Conclusion The D allele and DD genotype of the ACE gene appear to be a risk factor for the susceptibility of systemic lupus erythematosus and occurrence of proliferative nephritis in Egyptian children. PMID- 27956583 TI - Metabolic Signaling Regulates Alternative Splicing during Photomorphogenesis. PMID- 27956584 TI - Do Phytochromes and Phytochrome-Interacting Factors Need to Interact? PMID- 27956585 TI - ABI5 Is a Regulator of Seed Maturation and Longevity in Legumes. AB - The preservation of our genetic resources and production of high-quality seeds depends on their ability to remain viable and vigorous during storage. In a quantitative trait locus analysis on seed longevity in Medicago truncatula, we identified the bZIP transcription factor ABSCISIC ACID INSENSITIVE5 (ABI5). Characterization of Mt-abi5 insertion mutant seeds revealed that both the acquisition of longevity and dormancy were severely impaired. Using transcriptomes of developing Mt-abi5 seeds, we created a gene coexpression network and revealed ABI5 as a regulator of gene modules with functions related to raffinose family oligosaccharide (RFO) metabolism, late embryogenesis abundant (LEA) proteins, and photosynthesis-associated nuclear genes (PhANGs). Lower RFO contents in Mt-abi5 seeds were linked to the regulation of SEED IMBIBITION PROTEIN1 Proteomic analysis confirmed that a set of LEA polypeptides was reduced in mature Mt-abi5 seeds, whereas the absence of repression of PhANG in mature Mt abi5 seeds was accompanied by chlorophyll and carotenoid retention. This resulted in a stress response in Mt-abi5 seeds, evident from an increase in alpha tocopherol and upregulation of genes related to programmed cell death and protein folding. Characterization of abi5 mutants in a second legume species, pea (Pisum sativum), confirmed a role for ABI5 in the regulation of longevity, seed degreening, and RFO accumulation, identifying ABI5 as a prominent regulator of late seed maturation in legumes. PMID- 27956587 TI - Engaging Men in Prenatal Health Promotion: A Pilot Evaluation of Targeted e Health Content. AB - Pregnancy outcomes in the United States continue to rank among the worst in the developed world. Traditional maternal-child health promotion tends to focus exclusively on women, leaving men out of programs that can affect family health. Scholars advocate including men in prenatal health to reduce maternal and infant mortality and morbidity. This study explored the perceived role of men in prenatal health, the use of an e-health application, and participant-suggested ways of improving the application moving forward. This study interviewed men in a large Southwestern U.S. city with an average age of 26.0 years ( N = 23). The sample was 52% White, 26% Hispanic, 9% Asian, 9% multiracial or other, and 4% Black. Participants were asked about pregnancy health and used a pregnancy related e-health application on a tablet computer. Participants provided opinions on content, ease of use of tablets, and recommendations for a stronger application. Despite perceived barriers such as time constraints, financial burdens, and an unclear role, men believe it is important to be involved in pregnancy health. Most found the application to contain useful and interesting information. Participants recommended the addition of videos and interactive modules to make the application stronger. This study explored the use of a targeted e-health application to introduce men to prenatal health education. Results indicate men feel favorable to this type of intervention. Additional refinement of the application could include interactive tools or "push content" to further engage men in this important topic. PMID- 27956586 TI - DNA Methylation Influences the Expression of DICER-LIKE4 Isoforms, Which Encode Proteins of Alternative Localization and Function. AB - Plant RNA silencing operates via RNA-directed DNA-methylation (RdDM) to repress transcription or by targeting mRNAs via posttranscriptional gene silencing (PTGS). These pathways rely on distinct Dicer-like (DCL) proteins that process double-stranded RNA (dsRNA) into small-interfering RNAs (siRNAs). Here, we explored the expression and subcellular localization of Arabidopsis thaliana DCL4. DCL4 expression predominates as a transcription start site isoform encoding a cytoplasmic protein, which also represents the ancestral form in plants. A longer DCL4 transcript isoform encoding a nuclear localization signal, DCL4NLS, is present in Arabidopsis, but DNA methylation normally suppresses its expression. Hypomethylation caused by mutation, developmental reprogramming, and biotic stress correlates with enhanced DCL4NLS expression, while hypermethylation of a DCL4 transgene causes a reduction in DCL4NLS expression. DCL4NLS functions in a noncanonical siRNA pathway, producing a unique set of 21-nucleotide-long "disiRNAs," for DCL4NLS isoform-dependent siRNAs, through the nuclear RdDM dsRNA synthesis pathway. disiRNAs originate mostly from transposable elements (TEs) and TE-overlapping/proximal genes, load into the PTGS effector ARGONAUTE1 (AGO1), and display a subtle effect on transcript accumulation together with overlapping 24 nucleotide siRNAs. We propose that, via PTGS, disiRNAs could help to tighten the expression of epigenetically activated TEs and genes using the methylation-state responsive DCL4NLS. PMID- 27956589 TI - Correction: Identification and treatment of the Staphylococcus aureus reservoir in vivo. PMID- 27956588 TI - Modeling synovial sarcoma metastasis in the mouse: PI3'-lipid signaling and inflammation. AB - Solid tumor metastasis is a complex biology, impinged upon by a variety of dysregulated signaling pathways. PI3'-lipid signaling has been associated with metastasis and inflammation in many cancers, but the relationship between tumor cell-intrinsic PI3'-lipid signaling and inflammatory cell recruitment has remained enigmatic. Elevated PI3'-lipid signaling associates with progression of synovial sarcoma, a deadly soft tissue malignancy initiated by a t(X;18) chromosomal translocation that generates an SS18-SSX fusion oncoprotein. Here, we show in genetically engineered mouse models of locally induced expression of SS18 SSX1 or SS18-SSX2 that Pten silencing dramatically accelerated and enhanced sarcomagenesis without compromising synovial sarcoma characteristics. PTEN deficiency increased tumor angiogenesis, promoted inflammatory gene expression, and enabled highly penetrant spontaneous pulmonary metastasis. PTEN-deficient sarcomas revealed infiltrating myeloid-derived hematopoietic cells, particularly macrophages and neutrophils, recruited via PI3'-lipid-induced CSF1 expression in tumor cells. Moreover, in a large panel of human synovial sarcomas, enhanced PI3' lipid signaling also correlated with increased inflammatory cell recruitment and CSF1R signal transduction in both macrophages and endothelial cells. Thus, both in the mouse model and in human synovial sarcomas, PI3'-lipid signaling drives CSF1 expression and associates with increased infiltration of the monocyte/macrophage lineage as well as neutrophils. PMID- 27956591 TI - Novel Molecular Spectroscopic Multimethod Approach for Monitoring Water Absorption/Desorption Kinetics of CAD/CAM Poly(Methyl Methacrylate) Prosthodontics. AB - Water absorbed to poly(methyl methacrylate) (PMMA)-based CAD/CAM (computer assisted design/computer-assisted manufacturing) prosthodontics can alter their properties including hardness and stability. In the present contribution, water absorption and desorption kinetics under defined experimental conditions were monitored employing several supplementary and advanced Fourier transform infrared (FT-IR) spectroscopic techniques in combination with multivariate analysis (MVA). In this synergistic vibrational spectroscopic multimethod approach, first a novel near-infrared (NIR) diffuse fiber optic probe reflection spectroscopic method was established for time-resolved analysis of water uptake within seven days under controlled conditions. Near-infrared water absorbance spectra in a wavenumber range between 5288-5100 cm-1 (combination band) and 5424-5352 cm-1 (second overtone) were used establishing corresponding calibration and validation models to quantify the amount of water in the milligram range. Therefore, 14 well defined samples exposed to prior optimized experimental conditions were taken into consideration. The average daily water uptake conducting reference analysis was calculated as 22 mg/day for one week. Additionally, in this study for the first time NIR two-dimensional correlation spectroscopy (2D-COS) was conducted to monitor and interpret the spectral dynamics of water absorption on the prosthodontics in a wavenumber range of 5100-5300 cm-1. For sensitive time resolved recording of water desorption, a recently developed high-temperature, high-pressure FT-IR reaction cell with water-free ultra-dry in situ and operando operation was applied. The reaction cell, as well as the sample holder, was fully made of quartz glass, with no hot metal or ceramic parts in the vicinity of the high temperature zone. Applying a temperature gradient in the range of 25-150 C, mid-infrared (MIR) 2D-COS was successfully conducted to get insights into the dynamic behavior of O-H (1400-1800 cm-1) absorption bands with increasing temperature over time and the release of CO2 (2450 cm-1) from the polymers. In addition, an ATR FT-IR imaging setup was optimized in order to investigate the surface homogeneity of the PMMA-based resins with a spatial resolution to 2 um. From this vibrational spectroscopic multimethod approach and the collection of several analytical data, conclusions were drawn as to which degree the surface structure and/or its porosity have an impact onto the amount of water absorption. PMID- 27956590 TI - "Artificial But Better Than Nothing". AB - OBJECTIVE: To investigate patient, staff, and carer responses to an environmental intervention in an oncology clinic waiting room and evaluate the acceptability of artificial plant materials. Design Postintervention: Cross-sectional survey study. SETTING: Oncology outpatient clinic waiting room located in a metropolitan comprehensive cancer center in Australia. MAIN OUTCOME MEASURE: Observer ratings of perceived qualities and effects of lifelike (fake) plants while spending time in the waiting room. PARTICIPANTS: Convenience sample ( N = 143) consisted of 73 cancer patients, 13 staff, 52 carers, and 5 "others" aged between 24 and 89 years ( M = 56, SD = 14.5). INTERVENTION: Artificial plant arrangements, hanging installations, two movable green walls, and one rock garden on wheels placed throughout the outpatients' clinic waiting room. RESULTS: Eighty-one percent (115/142) of respondents noticed the green features when first entering the waiting room and 67% (90/134) noticed they were artificial. Eighty-one percent (115/142) indicated "like/like a lot" when reporting their first reaction to the green features. Forty-eight percent (68/143) were positively affected and 23% (33/143) were very positively affected. Eighty-one percent (110/135) agreed/strongly agreed that "The greenery brightens the waiting room," 62% (80/130) agreed/strongly agreed that they "prefer living plants," and 76% (101/133) agreed/strongly agreed that "'lifelike' plants are better than no plants." Comments included mostly positive appraisals and occasional adverse reactions to artificial plants. No significant differences were found between patients', staff, and carers' reactions. CONCLUSIONS: The environmental intervention positively impacted patients', staff, and carers' perceptions of the oncology waiting room environment. Patients, staff, and carers mostly accepted artificial plants as an alternative design solution to real plants. PMID- 27956592 TI - Short Distance Standoff Raman Detection of Extra Virgin Olive Oil Adulterated with Canola and Grapeseed Oils. AB - A short distance standoff Raman technique is demonstrated for detecting economically motivated adulteration (EMA) in extra virgin olive oil (EVOO). Using a portable Raman spectrometer operating with a 785 nm laser and a 2-in. refracting telescope, adulteration of olive oil with grapeseed oil and canola oil is detected between 1% and 100% at a minimum concentration of 2.5% from a distance of 15 cm and at a minimum concentration of 5% from a distance of 1 m. The technique involves correlating the intensity ratios of prominent Raman bands of edible oils at 1254, 1657, and 1441 cm-1 to the degree of adulteration. As a novel variation in the data analysis technique, integrated intensities over a spectral range of 100 cm-1 around the Raman line were used, making it possible to increase the sensitivity of the technique. The technique is demonstrated by detecting adulteration of EVOO with grapeseed and canola oils at 0-100%. Due to the potential of this technique for making measurements from a convenient distance, the short distance standoff Raman technique has the promise to be used for routine applications in food industry such as identifying food items and monitoring EMA at various checkpoints in the food supply chain and storage facilities. PMID- 27956593 TI - Spectral and Color Changes of Ag/TiO2 Photochromic Films Deposited on Diffusing Paper and Transparent Flexible Plastic Substrates. AB - Giving paper and polymer photochromic properties under laser irradiation is challenging due to the low resistance of these materials to heat, their flexibility, and their possibly irregular structure. However, we could successfully deposit TiO2/Ag/TiO2 layers stacking on flexible white glossy paper and transparent polyethylene terephalate (PET) substrates using a reactive magnetron sputtering technique, and tailor coloration changes after laser irradiation, alternating visible and ultraviolet (UV) wavelengths. The sample colors are characterized by a panel of chromas depending on the irradiation conditions. We demonstrate that these chroma changes are due to morphological changes of Ag nanoparticles (NPs) after visible laser irradiation of the colored as-deposited sample. The process exhibits a good reversibility after subsequent UV irradiation due to the growth of new metallic Ag NPs. The colors displayed in diffuse reflection by the paper samples are more saturated than the ones displayed in regular transmission by PET samples. We demonstrate the efficiency of the photochromic process on such support by printing high resolution patterns exhibiting different colors depending on the observation conditions. PMID- 27956594 TI - Improving Spectral Results Using Row-by-Row Fourier Transform of Spatial Heterodyne Raman Spectrometer Interferogram. AB - This work describes a method of applying the Fourier transform to the two dimensional Fizeau fringe patterns generated by the spatial heterodyne Raman spectrometer (SHRS), a dispersive interferometer, to correct the effects of certain types of optical alignment errors. In the SHRS, certain types of optical misalignments result in wavelength-dependent and wavelength-independent rotations of the fringe pattern on the detector. We describe here a simple correction technique that can be used in post-processing, by applying the Fourier transform in a row-by-row manner. This allows the user to be more forgiving of fringe alignment and allows for a reduction in the mechanical complexity of the SHRS. PMID- 27956595 TI - Optical Properties of Europium Tetracycline Complexes in the Presence of High Density Lipoproteins (HDL) Subfractions. AB - Standard lipoprotein measurements of triglycerides, total cholesterol, low density lipoproteins (LDL), and high-density lipoproteins (HDL) fail to identify many lipoprotein abnormalities that contribute to cardiovascular heart diseases (CHD). Studies suggested that the presence of CHD is more strongly associated with the HDL subspecies than with total HDL cholesterol levels. The HDL particles can be collected in at least three subfractions, the HDL2b, HDL2a, and HDL3. More specifically, atherosclerosis is associated with low levels of HDL2. In this work, the optical spectroscopic properties of europium tetracycline (EuTc) complex in the presence of different HDL subspecies was studied. The results show that the europium spectroscopic properties in the EuTc complex are influenced by sizes and concentrations of subclasses. Eu3+ emission intensity and lifetime can discriminate the subfractions HDL3 and HDL2b. PMID- 27956596 TI - Near-Infrared Spectroscopic Evaluation of the Water Content of Molded Polylactide under the Effect of Crystallization. AB - During melt processing, the moisture inside polylactide (PLA) easily induces hydrolysis, which deteriorates the mechanical and thermal properties of the product. The state of dryness of resin pellets must be monitored to prevent PLA hydrolysis. In this study, near-infrared (NIR) spectroscopy was applied to measure water content in PLA. In addition, the shape of the NIR spectrum is also affected by crystallization, which could lead to a reduction in the accuracy of evaluating the water content. The objective of this research is to construct a robust model for estimating the water content with varying dispersive extents of crystallization. Two methods for estimating water content measured during a drying process were conducted: the integration of absorbance and partial least squares (PLS) regression were conducted to estimate the water contents in PLA considering the effect of crystallization. The slope of the calibration line of the water content obtained from integrating absorbance varied between PLA with different crystallinities. This is due to the overlap between the NIR band of water and that of PLA crystal in the range of 5100-5400 cm-1. We found that the shape of the NIR spectrum was changed by crystallization, and the crystallinity, compared to the thickness of lamellae, was the dominant factor determining such a change of NIR spectra. The PLS model of water content constructed from only amorphous PLA showed large error of estimation in crystallized PLA. In contrast, the PLS model constructed from both amorphous and crystallized PLA estimated the water contents with lower errors. This was because latent variables obtained from both amorphous and crystallized PLA cancelled the effect of crystallization on NIR spectra. PMID- 27956597 TI - Tet38 Efflux Pump Affects Staphylococcus aureus Internalization by Epithelial Cells through Interaction with CD36 and Contributes to Bacterial Escape from Acidic and Nonacidic Phagolysosomes. AB - We previously reported that the Tet38 efflux pump is involved in internalization of Staphylococcus aureus by A549 lung epithelial cells. A lack of tet38 reduced bacterial uptake by A549 cells to 36% of that of the parental strain RN6390. Using invasion assays coupled with confocal microscopy imaging, we studied the host cell receptor(s) responsible for bacterial uptake via interaction with Tet38. We also assessed the ability of S. aureus to survive following alkalinization of the phagolysosomes by chloroquine. Antibody to the scavenger receptor CD36 reduced the internalization of S. aureus RN6390 by A549 cells, but the dependence on CD36 was reduced in QT7 tet38, suggesting that an interaction between Tet38 and CD36 contributed to S. aureus internalization. Following fusion of the S. aureus-associated endosomes with lysosomes, alkalinization of the acidic environment with chloroquine led to a rapid increase in the number of S. aureus RN6390 bacteria in the cytosol, followed by a decrease shortly thereafter. This effect of chloroquine was not seen in the absence of intact Tet38 in mutant QT7. These data taken together suggest that Tet38 plays a role both in bacterial internalization via interaction with CD36 and in bacterial escape from the phagolysosomes. PMID- 27956598 TI - The Lyme Disease Pathogen Borrelia burgdorferi Infects Murine Bone and Induces Trabecular Bone Loss. AB - Lyme disease is caused by members of the Borrelia burgdorferi sensu lato species complex. Arthritis is a well-known late-stage pathology of Lyme disease, but the effects of B. burgdorferi infection on bone at sites other than articular surfaces are largely unknown. In this study, we investigated whether B. burgdorferi infection affects bone health in mice. In mice inoculated with B. burgdorferi or vehicle (mock infection), we measured the presence of B. burgdorferi DNA in bones, bone mineral density (BMD), bone formation rates, biomechanical properties, cellular composition, and two- and three-dimensional features of bone microarchitecture. B. burgdorferi DNA was detected in bone. In the long bones, increasing B. burgdorferi DNA copy number correlated with reductions in areal and trabecular volumetric BMDs. Trabecular regions of femora exhibited significant, copy number-correlated microarchitectural disruption, but BMD, microarchitectural, and biomechanical properties of cortical bone were not affected. Bone loss in tibiae was not due to increased osteoclast numbers or bone resorbing surface area, but it was associated with reduced osteoblast numbers, implying that bone loss in long bones was due to impaired bone building. Osteoid producing and mineralization activities of existing osteoblasts were unaffected by infection. Therefore, deterioration of trabecular bone was not dependent on inhibition of osteoblast function but was more likely caused by blockade of osteoblastogenesis, reduced osteoblast survival, and/or induction of osteoblast death. Together, these data represent the first evidence that B. burgdorferi infection induces bone loss in mice and suggest that this phenotype results from inhibition of bone building rather than increased bone resorption. PMID- 27956599 TI - Mimicking transient activation of protein kinases in living cells. AB - Physiological stimuli activate protein kinases for finite periods of time, which is critical for specific biological outcomes. Mimicking this transient biological activity of kinases is challenging due to the limitations of existing methods. Here, we report a strategy enabling transient kinase activation in living cells. Using two protein-engineering approaches, we achieve independent control of kinase activation and inactivation. We show successful regulation of tyrosine kinase c-Src (Src) and Ser/Thr kinase p38alpha (p38), demonstrating broad applicability of the method. By activating Src for finite periods of time, we reveal how the duration of kinase activation affects secondary morphological changes that follow transient Src activation. This approach highlights distinct roles for sequential Src-Rac1- and Src-PI3K-signaling pathways at different stages during transient Src activation. Finally, we demonstrate that this method enables transient activation of Src and p38 in a specific signaling complex, providing a tool for targeted regulation of individual signaling pathways. PMID- 27956600 TI - Revealing the dual streams of speech processing. AB - Several dual route models of human speech processing have been proposed suggesting a large-scale anatomical division between cortical regions that support motor-phonological aspects vs. lexical-semantic aspects of speech processing. However, to date, there is no complete agreement on what areas subserve each route or the nature of interactions across these routes that enables human speech processing. Relying on an extensive behavioral and neuroimaging assessment of a large sample of stroke survivors, we used a data driven approach using principal components analysis of lesion-symptom mapping to identify brain regions crucial for performance on clusters of behavioral tasks without a priori separation into task types. Distinct anatomical boundaries were revealed between a dorsal frontoparietal stream and a ventral temporal-frontal stream associated with separate components. Collapsing over the tasks primarily supported by these streams, we characterize the dorsal stream as a form-to articulation pathway and the ventral stream as a form-to-meaning pathway. This characterization of the division in the data reflects both the overlap between tasks supported by the two streams as well as the observation that there is a bias for phonological production tasks supported by the dorsal stream and lexical semantic comprehension tasks supported by the ventral stream. As such, our findings show a division between two processing routes that underlie human speech processing and provide an empirical foundation for studying potential computational differences that distinguish between the two routes. PMID- 27956601 TI - Lipid metabolic changes in an early divergent fungus govern the establishment of a mutualistic symbiosis with endobacteria. AB - The recent accumulation of newly discovered fungal-bacterial mutualisms challenges the paradigm that fungi and bacteria are natural antagonists. To understand the mechanisms that govern the establishment and maintenance over evolutionary time of mutualisms between fungi and bacteria, we studied a symbiosis of the fungus Rhizopus microsporus (Mucoromycotina) and its Burkholderia endobacteria. We found that nonhost R. microsporus, as well as other mucoralean fungi, interact antagonistically with endobacteria derived from the host and are not invaded by them. Comparison of gene expression profiles of host and nonhost fungi during interaction with endobacteria revealed dramatic changes in expression of lipid metabolic genes in the host. Analysis of the host lipidome confirmed that symbiosis establishment was accompanied by specific changes in the fungal lipid profile. Diacylglycerol kinase (DGK) activity was important for these lipid metabolic changes, as its inhibition altered the fungal lipid profile and caused a shift in the host-bacterial interaction into an antagonism. We conclude that adjustments in host lipid metabolism during symbiosis establishment, mediated by DGKs, are required for the mutualistic outcome of the Rhizopus-Burkholderia symbiosis. In addition, the neutral and phospholipid profiles of R. microsporus provide important insights into lipid metabolism in an understudied group of oleaginous Mucoromycotina. Lastly, our study revealed that the DGKs involved in the symbiosis form a previously uncharacterized clade of DGK domain proteins. PMID- 27956602 TI - Pathway swapping: Toward modular engineering of essential cellular processes. AB - Recent developments in synthetic biology enable one-step implementation of entire metabolic pathways in industrial microorganisms. A similarly radical remodelling of central metabolism could greatly accelerate fundamental and applied research, but is impeded by the mosaic organization of microbial genomes. To eliminate this limitation, we propose and explore the concept of "pathway swapping," using yeast glycolysis as the experimental model. Construction of a "single-locus glycolysis" Saccharomyces cerevisiae platform enabled quick and easy replacement of this yeast's entire complement of 26 glycolytic isoenzymes by any alternative, functional glycolytic pathway configuration. The potential of this approach was demonstrated by the construction and characterization of S. cerevisiae strains whose growth depended on two nonnative glycolytic pathways: a complete glycolysis from the related yeast Saccharomyces kudriavzevii and a mosaic glycolysis consisting of yeast and human enzymes. This work demonstrates the feasibility and potential of modular, combinatorial approaches to engineering and analysis of core cellular processes. PMID- 27956603 TI - Uhrf1 controls the self-renewal versus differentiation of hematopoietic stem cells by epigenetically regulating the cell-division modes. AB - Hematopoietic stem cells (HSCs) are able to both self-renew and differentiate. However, how individual HSC makes the decision between self-renewal and differentiation remains largely unknown. Here we report that ablation of the key epigenetic regulator Uhrf1 in the hematopoietic system depletes the HSC pool, leading to hematopoietic failure and lethality. Uhrf1-deficient HSCs display normal survival and proliferation, yet undergo erythroid-biased differentiation at the expense of self-renewal capacity. Notably, Uhrf1 is required for the establishment of DNA methylation patterns of erythroid-specific genes during HSC division. The expression of these genes is enhanced in the absence of Uhrf1, which disrupts the HSC-division modes by promoting the symmetric differentiation and suppressing the symmetric self-renewal. Moreover, overexpression of one of the up-regulated genes, Gata1, in HSCs is sufficient to phenocopy Uhrf1-deficient HSCs, which show impaired HSC symmetric self-renewal and increased differentiation commitment. Taken together, our findings suggest that Uhrf1 controls the self-renewal versus differentiation of HSC through epigenetically regulating the cell-division modes, thus providing unique insights into the relationship among Uhrf1-mediated DNA methylation, cell-division mode, and HSC fate decision. PMID- 27956604 TI - Can sub-Saharan Africa feed itself? AB - Although global food demand is expected to increase 60% by 2050 compared with 2005/2007, the rise will be much greater in sub-Saharan Africa (SSA). Indeed, SSA is the region at greatest food security risk because by 2050 its population will increase 2.5-fold and demand for cereals approximately triple, whereas current levels of cereal consumption already depend on substantial imports. At issue is whether SSA can meet this vast increase in cereal demand without greater reliance on cereal imports or major expansion of agricultural area and associated biodiversity loss and greenhouse gas emissions. Recent studies indicate that the global increase in food demand by 2050 can be met through closing the gap between current farm yield and yield potential on existing cropland. Here, however, we estimate it will not be feasible to meet future SSA cereal demand on existing production area by yield gap closure alone. Our agronomically robust yield gap analysis for 10 countries in SSA using location-specific data and a spatial upscaling approach reveals that, in addition to yield gap closure, other more complex and uncertain components of intensification are also needed, i.e., increasing cropping intensity (the number of crops grown per 12 mo on the same field) and sustainable expansion of irrigated production area. If intensification is not successful and massive cropland land expansion is to be avoided, SSA will depend much more on imports of cereals than it does today. PMID- 27956605 TI - Alternative stable states and the sustainability of forests, grasslands, and agriculture. AB - Endangered forest-grassland mosaics interspersed with expanding agriculture and silviculture occur across many parts of the world, including the southern Brazilian highlands. This natural mosaic ecosystem is thought to reflect alternative stable states driven by threshold responses of recruitment to fire and moisture regimes. The role of adaptive human behavior in such systems remains understudied, despite its pervasiveness and the fact that such ecosystems can exhibit complex dynamics. We develop a nonlinear mathematical model of coupled human-environment dynamics in mosaic systems and social processes regarding conservation and economic land valuation. Our objective is to better understand how the coupled dynamics respond to changes in ecological and social conditions. The model is parameterized with southern Brazilian data on mosaic ecology, land use profits, and questionnaire results concerning landowner preferences and conservation values. We find that the mosaic presently resides at a crucial juncture where relatively small changes in social conditions can generate a wide variety of possible outcomes, including complete loss of mosaics; large amplitude, long-term oscillations between land states that preclude ecosystem stability; and conservation of the mosaic even to the exclusion of agriculture/silviculture. In general, increasing the time horizon used for conservation decision making is more likely to maintain mosaic stability. In contrast, increasing the inherent conservation value of either forests or grasslands is more likely to induce large oscillations-especially for forests-due to feedback from rarity-based conservation decisions. Given the potential for complex dynamics, empirically grounded nonlinear dynamical models should play a larger role in policy formulation for human-environment mosaic ecosystems. PMID- 27956606 TI - Episode of intense chemical weathering during the termination of the 635 Ma Marinoan glaciation. AB - Cryogenian (~720-635 Ma) global glaciations (the snowball Earth) represent the most extreme ice ages in Earth's history. The termination of these snowball Earth glaciations is marked by the global precipitation of cap carbonates, which are interpreted to have been driven by intense chemical weathering on continents. However, direct geochemical evidence for the intense chemical weathering in the aftermath of snowball glaciations is lacking. Here, we report Mg isotopic data from the terminal Cryogenian or Marinoan-age Nantuo Formation and the overlying cap carbonate of the basal Doushantuo Formation in South China. A positive excursion of extremely high delta26Mg values (+0.56 to +0.95)-indicative of an episode of intense chemical weathering-occurs in the top Nantuo Formation, whereas the siliciclastic component of the overlying Doushantuo cap carbonate has significantly lower delta26Mg values (<+0.40), suggesting moderate to low intensity of chemical weathering during cap carbonate deposition. These observations suggest that cap carbonate deposition postdates the climax of chemical weathering, probably because of the suppression of carbonate precipitation in an acidified ocean when atmospheric CO2 concentration was high. Cap carbonate deposition did not occur until chemical weathering had consumed substantial amounts of atmospheric CO2 and accumulated high levels of oceanic alkalinity. Our finding confirms intense chemical weathering at the onset of deglaciation but indicates that the maximum weathering predated cap carbonate deposition. PMID- 27956607 TI - Correction for Bicknell and Goodhill, Emergence of ion channel modal gating from independent subunit kinetics. PMID- 27956608 TI - Self-organization of actin networks by a monomeric myosin. AB - The organization of actomyosin networks lies at the center of many types of cellular motility, including cell polarization and collective cell migration during development and morphogenesis. Myosin-IXa is critically involved in these processes. Using total internal reflection fluorescence microscopy, we resolved actin bundles assembled by myosin-IXa. Electron microscopic data revealed that the bundles consisted of highly ordered lattices with parallel actin polarity. The myosin-IXa motor domains aligned across the network, forming cross-links at a repeat distance of precisely 36 nm, matching the helical repeat of actin. Single particle image processing resolved three distinct conformations of myosin-IXa in the absence of nucleotide. Using cross-correlation of a modeled actomyosin crystal structure, we identified sites of additional mass, which can only be accounted for by the large insert in loop 2 exclusively found in the motor domain of class IX myosins. We show that the large insert in loop 2 binds calmodulin and creates two coordinated actin-binding sites that constrain the actomyosin interactions generating the actin lattices. The actin lattices introduce orientated tracks at specific sites in the cell, which might install platforms allowing Rho-GTPase-activating protein (RhoGAP) activity to be focused at a definite locus. In addition, the lattices might introduce a myosin-related, force sensing mechanism into the cytoskeleton in cell polarization and collective cell migration. PMID- 27956609 TI - Growth rate of crystalline ice and the diffusivity of supercooled water from 126 to 262 K. AB - Understanding deeply supercooled water is key to unraveling many of water's anomalous properties. However, developing this understanding has proven difficult due to rapid and uncontrolled crystallization. Using a pulsed-laser-heating technique, we measure the growth rate of crystalline ice, G(T), for 180 K < T < 262 K, that is, deep within water's "no man's land" in ultrahigh-vacuum conditions. Isothermal measurements of G(T) are also made for 126 K <= T <= 151 K. The self-diffusion of supercooled liquid water, D(T), is obtained from G(T) using the Wilson-Frenkel model of crystal growth. For T > 237 K and P ~ 10-8 Pa, G(T) and D(T) have super-Arrhenius ("fragile") temperature dependences, but both cross over to Arrhenius ("strong") behavior with a large activation energy in no man's land. The fact that G(T) and D(T) are smoothly varying rules out the hypothesis that liquid water's properties have a singularity at or near 228 K at ambient pressures. However, the results are consistent with a previous prediction for D(T) that assumed no thermodynamic transitions occur in no man's land. PMID- 27956610 TI - Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy. AB - Although neutrophils are known to be fundamental in controlling innate immune responses, their role in regulating adaptive immunity is just starting to be appreciated. We report that human neutrophils exposed to pregnancy hormones progesterone and estriol promote the establishment of maternal tolerance through the induction of a population of CD4+ T cells displaying a GARP+CD127loFOXP3+ phenotype following antigen activation. Neutrophil-induced T (niT) cells produce IL-10, IL-17, and VEGF and promote vessel growth in vitro. Neutrophil depletion during murine pregnancy leads to abnormal development of the fetal-maternal unit and reduced empbryo development, with placental architecture displaying poor trophoblast invasion and spiral artery development in the maternal decidua, accompanied by significantly attenuated niT cell numbers in draining lymph nodes. Using CD45 congenic cells, we show that induction of niT cells and their regulatory function occurs via transfer of apoptotic neutrophil-derived proteins, including forkhead box protein 1 (FOXO1), to T cells. Unlike in women with healthy pregnancies, neutrophils from blood and placental samples of preeclamptic women fail to induce niT cells as a direct consequence of their inability to transfer FOXO1 to T cells. Finally, neutrophil-selective FOXO1 knockdown leads to defective placentation and compromised embryo development, similar to that resulting from neutrophil depletion. These data define a nonredundant function of neutrophil-T cell interactions in the regulation of vascularization at the maternal-fetal interface. PMID- 27956613 TI - Twenty-first century approaches to ancient problems: Climate and society. AB - By documenting how humans adapted to changes in their environment that are often much greater than those experienced in the instrumental record, archaeology provides our only deep-time laboratory for highlighting the circumstances under which humans managed or failed to find to adaptive solutions to changing climate, not just over a few generations but over the longue duree Patterning between climate-mediated environmental change and change in human societies has, however, been murky because of low spatial and temporal resolution in available datasets, and because of failure to model the effects of climate change on local resources important to human societies. In this paper we review recent advances in computational modeling that, in conjunction with improving data, address these limitations. These advances include network analysis, niche and species distribution modeling, and agent-based modeling. These studies demonstrate the utility of deep-time modeling for calibrating our understanding of how climate is influencing societies today and may in the future. PMID- 27956611 TI - Biasing genome-editing events toward precise length deletions with an RNA-guided TevCas9 dual nuclease. AB - The CRISPR/Cas9 nuclease is commonly used to make gene knockouts. The blunt DNA ends generated by cleavage can be efficiently ligated by the classical nonhomologous end-joining repair pathway (c-NHEJ), regenerating the target site. This repair creates a cycle of cleavage, ligation, and target site regeneration that persists until sufficient modification of the DNA break by alternative NHEJ prevents further Cas9 cutting, generating a heterogeneous population of insertions and deletions typical of gene knockouts. Here, we develop a strategy to escape this cycle and bias events toward defined length deletions by creating an RNA-guided dual active site nuclease that generates two noncompatible DNA breaks at a target site, effectively deleting the majority of the target site such that it cannot be regenerated. The TevCas9 nuclease, a fusion of the I-TevI nuclease domain to Cas9, functions robustly in HEK293 cells and generates 33- to 36-bp deletions at frequencies up to 40%. Deep sequencing revealed minimal processing of TevCas9 products, consistent with protection of the DNA ends from exonucleolytic degradation and repair by the c-NHEJ pathway. Directed evolution experiments identified I-TevI variants with broadened targeting range, making TevCas9 an easy-to-use reagent. Our results highlight how the sequence-tolerant cleavage properties of the I-TevI homing endonuclease can be harnessed to enhance Cas9 applications, circumventing the cleavage and ligation cycle and biasing genome-editing events toward defined length deletions. PMID- 27956612 TI - Interrogating the Escherichia coli cell cycle by cell dimension perturbations. AB - Bacteria tightly regulate and coordinate the various events in their cell cycles to duplicate themselves accurately and to control their cell sizes. Growth of Escherichia coli, in particular, follows a relation known as Schaechter's growth law. This law says that the average cell volume scales exponentially with growth rate, with a scaling exponent equal to the time from initiation of a round of DNA replication to the cell division at which the corresponding sister chromosomes segregate. Here, we sought to test the robustness of the growth law to systematic perturbations in cell dimensions achieved by varying the expression levels of mreB and ftsZ We found that decreasing the mreB level resulted in increased cell width, with little change in cell length, whereas decreasing the ftsZ level resulted in increased cell length. Furthermore, the time from replication termination to cell division increased with the perturbed dimension in both cases. Moreover, the growth law remained valid over a range of growth conditions and dimension perturbations. The growth law can be quantitatively interpreted as a consequence of a tight coupling of cell division to replication initiation. Thus, its robustness to perturbations in cell dimensions strongly supports models in which the timing of replication initiation governs that of cell division, and cell volume is the key phenomenological variable governing the timing of replication initiation. These conclusions are discussed in the context of our recently proposed "adder-per-origin" model, in which cells add a constant volume per origin between initiations and divide a constant time after initiation. PMID- 27956615 TI - Childhood poverty and adult psychological well-being. AB - Childhood disadvantage has repeatedly been linked to adult physical morbidity and mortality. We show in a prospective, longitudinal design that childhood poverty predicts multimethodological indices of adult (24 y of age) psychological well being while holding constant similar childhood outcomes assessed at age 9. Adults from low-income families manifest more allostatic load, an index of chronic physiological stress, higher levels of externalizing symptoms (e.g., aggression) but not internalizing symptoms (e.g., depression), and more helplessness behaviors. In addition, childhood poverty predicts deficits in adult short-term spatial memory. PMID- 27956614 TI - Molecular profiling of single circulating tumor cells from lung cancer patients. AB - Circulating tumor cells (CTCs) are established cancer biomarkers for the "liquid biopsy" of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non-small cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a high-throughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring. PMID- 27956616 TI - Human-environment interactions in population and ecosystem health. PMID- 27956617 TI - Assembly of long error-prone reads using de Bruijn graphs. AB - The recent breakthroughs in assembling long error-prone reads were based on the overlap-layout-consensus (OLC) approach and did not utilize the strengths of the alternative de Bruijn graph approach to genome assembly. Moreover, these studies often assume that applications of the de Bruijn graph approach are limited to short and accurate reads and that the OLC approach is the only practical paradigm for assembling long error-prone reads. We show how to generalize de Bruijn graphs for assembling long error-prone reads and describe the ABruijn assembler, which combines the de Bruijn graph and the OLC approaches and results in accurate genome reconstructions. PMID- 27956619 TI - Past-focused environmental comparisons promote proenvironmental outcomes for conservatives. AB - Conservatives appear more skeptical about climate change and global warming and less willing to act against it than liberals. We propose that this unwillingness could result from fundamental differences in conservatives' and liberals' temporal focus. Conservatives tend to focus more on the past than do liberals. Across six studies, we rely on this notion to demonstrate that conservatives are positively affected by past- but not by future-focused environmental comparisons. Past comparisons largely eliminated the political divide that separated liberal and conservative respondents' attitudes toward and behavior regarding climate change, so that across these studies conservatives and liberals were nearly equally likely to fight climate change. This research demonstrates how psychological processes, such as temporal comparison, underlie the prevalent ideological gap in addressing climate change. It opens up a promising avenue to convince conservatives effectively of the need to address climate change and global warming. PMID- 27956618 TI - Substitutions of short heterologous DNA segments of intragenomic or extragenomic origins produce clustered genomic polymorphisms. AB - In a screen for unexplained mutation events we identified a previously unrecognized mechanism generating clustered DNA polymorphisms such as microindels and cumulative SNPs. The mechanism, short-patch double illegitimate recombination (SPDIR), facilitates short single-stranded DNA molecules to invade and replace genomic DNA through two joint illegitimate recombination events. SPDIR is controlled by key components of the cellular genome maintenance machinery in the gram-negative bacterium Acinetobacter baylyi. The source DNA is primarily intragenomic but can also be acquired through horizontal gene transfer. The DNA replacements are nonreciprocal and locus independent. Bioinformatic approaches reveal occurrence of SPDIR events in the gram-positive human pathogen Streptococcus pneumoniae and in the human genome. PMID- 27956620 TI - Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice. AB - White matter stroke is a distinct stroke subtype, accounting for up to 25% of stroke and constituting the second leading cause of dementia. The biology of possible tissue repair after white matter stroke has not been determined. In a mouse stroke model, white matter ischemia causes focal damage and adjacent areas of axonal myelin disruption and gliosis. In these areas of only partial damage, local white matter progenitors respond to injury, as oligodendrocyte progenitors (OPCs) proliferate. However, OPCs fail to mature into oligodendrocytes (OLs) even in regions of demyelination with intact axons and instead divert into an astrocytic fate. Local axonal sprouting occurs, producing an increase in unmyelinated fibers in the corpus callosum. The OPC maturation block after white matter stroke is in part mediated via Nogo receptor 1 (NgR1) signaling. In both aged and young adult mice, stroke induces NgR1 ligands and down-regulates NgR1 inhibitors during the peak OPC maturation block. Nogo ligands are also induced adjacent to human white matter stroke in humans. A Nogo signaling blockade with an NgR1 antagonist administered after stroke reduces the OPC astrocytic transformation and improves poststroke oligodendrogenesis in mice. Notably, increased white matter repair in aged mice is translated into significant poststroke motor recovery, even when NgR1 blockade is provided during the chronic time points of injury. These data provide a perspective on the role of NgR1 ligand function in OPC fate in the context of a specific and common type of stroke and show that it is amenable to systemic intervention to promote recovery. PMID- 27956621 TI - Expression of KIR2DS1 by decidual natural killer cells increases their ability to control placental HCMV infection. AB - The combination of the activating killer cell Ig-like receptor 2DS1 (KIR2DS1) expressed by maternal decidual natural killer cells (dNK) and the presence of its ligand, the HLA-C allotype HLA-C2, expressed by fetal trophoblasts, reduces the risk of developing pregnancy complications. However, no molecular or cellular mechanism explains this genetic correlation. Here we demonstrate that KIR2DS1+ dNK acquired higher cytotoxic function than KIR2DS1- dNK when exposed to human cytomegalovirus (HCMV)-infected decidual stromal cells (DSC), particularly when DSCs express HLA-C2. Furthermore, dNK were unable to degranulate or secrete cytokines in response to HCMV-infected primary fetal extravillous trophoblasts. This emphasizes the immunological challenge to clear placental viral infections within the immune-privileged placenta. Activation of dNK through KIR2DS1/HLA-C2 interaction increases their ability to respond to placental HCMV infection and may limit subsequent virus-induced placental pathology. This mechanism is directly related to how KIR2DS1 expressed by dNK reduces development of severe pregnancy complications such as miscarriages and preterm delivery. PMID- 27956622 TI - beta2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury. AB - Following cardiac injury, early immune cell responses are essential for initiating cardiac remodeling and tissue repair. We previously demonstrated the importance of beta2-adrenergic receptors (beta2ARs) in the regulation of immune cell localization following acute cardiac injury, with deficient leukocyte infiltration into the damaged heart. The purpose of this study was to investigate the mechanism by which immune cell-expressed beta2ARs regulate leukocyte recruitment to the heart following acute cardiac injury. Chemokine receptor 2 (CCR2) expression and responsiveness to C-C motif chemokine ligand 2 (CCL2) mediated migration were abolished in beta2AR knockout (KO) bone marrow (BM), both of which were rescued by beta2AR reexpression. Chimeric mice lacking immune cell specific CCR2 expression, as well as wild-type mice administered a CCR2 antagonist, recapitulated the loss of monocyte/macrophage and neutrophil recruitment to the heart following myocardial infarction (MI) observed in mice with immune cell-specific beta2AR deletion. Converse to beta2AR ablation, beta2AR stimulation increased CCR2 expression and migratory responsiveness to CCL2 in BM. Mechanistically, G protein-dependent beta2AR signaling was dispensable for these effects, whereas beta-arrestin2-biased beta2AR signaling was required for the regulation of CCR2 expression. Additionally, activator protein 1 (AP-1) was shown to be essential in mediating CCR2 expression in response to beta2AR stimulation in both murine BM and human monocytes. Finally, reconstitution of beta2ARKO BM with rescued expression of a beta-arrestin-biased beta2AR in vivo restored BM CCR2 expression as well as cardiac leukocyte infiltration following MI. These results demonstrate the critical role of beta-arrestin2/AP-1-dependent beta2AR signaling in the regulation of CCR2 expression and recruitment of leukocytes to the heart following injury. PMID- 27956624 TI - No growth stimulation of Canada's boreal forest under half-century of combined warming and CO2 fertilization. AB - Considerable evidence exists that current global temperatures are higher than at any time during the past millennium. However, the long-term impacts of rising temperatures and associated shifts in the hydrological cycle on the productivity of ecosystems remain poorly understood for mid to high northern latitudes. Here, we quantify species-specific spatiotemporal variability in terrestrial aboveground biomass stem growth across Canada's boreal forests from 1950 to the present. We use 873 newly developed tree-ring chronologies from Canada's National Forest Inventory, representing an unprecedented degree of sampling standardization for a large-scale dendrochronological study. We find significant regional- and species-related trends in growth, but the positive and negative trends compensate each other to yield no strong overall trend in forest growth when averaged across the Canadian boreal forest. The spatial patterns of growth trends identified in our analysis were to some extent coherent with trends estimated by remote sensing, but there are wide areas where remote-sensing information did not match the forest growth trends. Quantifications of tree growth variability as a function of climate factors and atmospheric CO2 concentration reveal strong negative temperature and positive moisture controls on spatial patterns of tree growth rates, emphasizing the ecological sensitivity to regime shifts in the hydrological cycle. An enhanced dependence of forest growth on soil moisture during the late-20th century coincides with a rapid rise in summer temperatures and occurs despite potential compensating effects from increased atmospheric CO2 concentration. PMID- 27956623 TI - Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5. AB - Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5'-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment. PMID- 27956625 TI - Clarifying intact 3D tissues on a microfluidic chip for high-throughput structural analysis. AB - On-chip imaging of intact three-dimensional tissues within microfluidic devices is fundamentally hindered by intratissue optical scattering, which impedes their use as tissue models for high-throughput screening assays. Here, we engineered a microfluidic system that preserves and converts tissues into optically transparent structures in less than 1 d, which is 20* faster than current passive clearing approaches. Accelerated clearing was achieved because the microfluidic system enhanced the exchange of interstitial fluids by 567-fold, which increased the rate of removal of optically scattering lipid molecules from the cross-linked tissue. Our enhanced clearing process allowed us to fluorescently image and map the segregation and compartmentalization of different cells during the formation of tumor spheroids, and to track the degradation of vasculature over time within extracted murine pancreatic islets in static culture, which may have implications on the efficacy of beta-cell transplantation treatments for type 1 diabetes. We further developed an image analysis algorithm that automates the analysis of the vasculature connectivity, volume, and cellular spatial distribution of the intact tissue. Our technique allows whole tissue analysis in microfluidic systems, and has implications in the development of organ-on-a-chip systems, high-throughput drug screening devices, and in regenerative medicine. PMID- 27956626 TI - Phosphorylation of the Mdm2 oncoprotein by the c-Abl tyrosine kinase regulates p53 tumor suppression and the radiosensitivity of mice. AB - The p53 tumor suppressor acts as a guardian of the genome by preventing the propagation of DNA damage-induced breaks and mutations to subsequent generations of cells. We have previously shown that phosphorylation of the Mdm2 oncoprotein at Ser394 by the ATM kinase is required for robust p53 stabilization and activation in cells treated with ionizing radiation, and that loss of Mdm2 Ser394 phosphorylation leads to spontaneous tumorigenesis and radioresistance in Mdm2S394A mice. Previous in vitro data indicate that the c-Abl kinase phosphorylates Mdm2 at the neighboring residue (Tyr393) in response to DNA damage to regulate p53-dependent apoptosis. In this present study, we have generated an Mdm2 mutant mouse (Mdm2Y393F) to determine whether c-Abl phosphorylation of Mdm2 regulates the p53-mediated DNA damage response or p53 tumor suppression in vivo. The Mdm2Y393F mice develop accelerated spontaneous and oncogene-induced tumors, yet display no defects in p53 stabilization and activity following acute genotoxic stress. Although apoptosis is unaltered in these mice, they recover more rapidly from radiation-induced bone marrow ablation and are more resistant to whole-body radiation-induced lethality. These data reveal an in vivo role for c-Abl phosphorylation of Mdm2 in regulation of p53 tumor suppression and bone marrow failure. However, c-Abl phosphorylation of Mdm2 Tyr393 appears to play a lesser role in governing Mdm2-p53 signaling than ATM phosphorylation of Mdm2 Ser394. Furthermore, the effects of these phosphorylation events on p53 regulation are not additive, as Mdm2Y393F/S394A mice and Mdm2S394A mice display similar phenotypes. PMID- 27956628 TI - Stratospheric solar geoengineering without ozone loss. AB - Injecting sulfate aerosol into the stratosphere, the most frequently analyzed proposal for solar geoengineering, may reduce some climate risks, but it would also entail new risks, including ozone loss and heating of the lower tropical stratosphere, which, in turn, would increase water vapor concentration causing additional ozone loss and surface warming. We propose a method for stratospheric aerosol climate modification that uses a solid aerosol composed of alkaline metal salts that will convert hydrogen halides and nitric and sulfuric acids into stable salts to enable stratospheric geoengineering while reducing or reversing ozone depletion. Rather than minimizing reactive effects by reducing surface area using high refractive index materials, this method tailors the chemical reactivity. Specifically, we calculate that injection of calcite (CaCO3) aerosol particles might reduce net radiative forcing while simultaneously increasing column ozone toward its preanthropogenic baseline. A radiative forcing of -1 W?m 2, for example, might be achieved with a simultaneous 3.8% increase in column ozone using 2.1 Tg?y-1 of 275-nm radius calcite aerosol. Moreover, the radiative heating of the lower stratosphere would be roughly 10-fold less than if that same radiative forcing had been produced using sulfate aerosol. Although solar geoengineering cannot substitute for emissions cuts, it may supplement them by reducing some of the risks of climate change. Further research on this and similar methods could lead to reductions in risks and improved efficacy of solar geoengineering methods. PMID- 27956627 TI - Histone deacetylases control module-specific phenotypic plasticity in beetle weapons. AB - Nutritional conditions during early development influence the plastic expression of adult phenotypes. Among several body modules of animals, the development of sexually selected exaggerated traits exhibits striking nutrition sensitivity, resulting in positive allometry and hypervariability distinct from other traits. Using de novo RNA sequencing and comprehensive RNA interference (RNAi) for epigenetic modifying factors, we found that histone deacetylases (HDACs) and polycomb group (PcG) proteins preferentially influence the size of mandibles (exaggerated male weapon) and demonstrate nutrition-dependent hypervariability in the broad-horned flour beetle, Gnatocerus cornutus RNAi-mediated HDAC1 knockdown (KD) in G. cornutus larvae caused specific curtailment of mandibles in adults, whereas HDAC3 KD led to hypertrophy. Notably, these KDs conferred opposite effects on wing size, but little effect on the size of the core body and genital modules. PcG RNAi also reduced adult mandible size. These results suggest that the plastic development of exaggerated traits is controlled in a module-specific manner by HDACs. PMID- 27956630 TI - Profile of Harris A. Lewin. PMID- 27956629 TI - CRISPR screen identifies the NCOR/HDAC3 complex as a major suppressor of differentiation in rhabdomyosarcoma. AB - Dysregulated gene expression resulting from abnormal epigenetic alterations including histone acetylation and deacetylation has been demonstrated to play an important role in driving tumor growth and progression. However, the mechanisms by which specific histone deacetylases (HDACs) regulate differentiation in solid tumors remains unclear. Using pediatric rhabdomyosarcoma (RMS) as a paradigm to elucidate the mechanism blocking differentiation in solid tumors, we identified HDAC3 as a major suppressor of myogenic differentiation from a high-efficiency Clustered regularly interspaced short palindromic repeats (CRISPR)-based phenotypic screen of class I and II HDAC genes. Detailed characterization of the HDAC3-knockout phenotype in vitro and in vivo using a tamoxifen-inducible CRISPR targeting strategy demonstrated that HDAC3 deacetylase activity and the formation of a functional complex with nuclear receptor corepressors (NCORs) were critical in restricting differentiation in RMS. The NCOR/HDAC3 complex specifically functions by blocking myoblast determination protein 1 (MYOD1)-mediated activation of myogenic differentiation. Interestingly, there was also a transient up-regulation of growth-promoting genes upon initial HDAC3 targeting, revealing a unique cancer-specific response to the forced transition from a neoplastic state to terminal differentiation. Our study applied modifications of CRISPR/CRISPR associated endonuclease 9 (Cas9) technology to interrogate the function of essential cancer genes and pathways and has provided insights into cancer cell adaptation in response to altered differentiation status. Because current pan HDAC inhibitors have shown disappointing results in clinical trials of solid tumors, therapeutic targets specific to HDAC3 function represent a promising option for differentiation therapy in malignant tumors with dysregulated HDAC3 activity. PMID- 27956633 TI - Neuroadaptive technology enables implicit cursor control based on medial prefrontal cortex activity. AB - The effectiveness of today's human-machine interaction is limited by a communication bottleneck as operators are required to translate high-level concepts into a machine-mandated sequence of instructions. In contrast, we demonstrate effective, goal-oriented control of a computer system without any form of explicit communication from the human operator. Instead, the system generated the necessary input itself, based on real-time analysis of brain activity. Specific brain responses were evoked by violating the operators' expectations to varying degrees. The evoked brain activity demonstrated detectable differences reflecting congruency with or deviations from the operators' expectations. Real-time analysis of this activity was used to build a user model of those expectations, thus representing the optimal (expected) state as perceived by the operator. Based on this model, which was continuously updated, the computer automatically adapted itself to the expectations of its operator. Further analyses showed this evoked activity to originate from the medial prefrontal cortex and to exhibit a linear correspondence to the degree of expectation violation. These findings extend our understanding of human predictive coding and provide evidence that the information used to generate the user model is task-specific and reflects goal congruency. This paper demonstrates a form of interaction without any explicit input by the operator, enabling computer systems to become neuroadaptive, that is, to automatically adapt to specific aspects of their operator's mindset. Neuroadaptive technology significantly widens the communication bottleneck and has the potential to fundamentally change the way we interact with technology. PMID- 27956631 TI - The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development. AB - Oncogenic isocitrate dehydrogenase (IDH)1 and IDH2 mutations at three hotspot arginine residues cause an enzymatic gain of function that leads to the production and accumulation of the metabolite 2-hydroxyglutarate (2HG), which contributes to the development of a number of malignancies. In the hematopoietic system, mutations in IDH1 at arginine (R) 132 and in IDH2 at R140 and R172 are commonly observed in acute myeloid leukemia, and elevated 2HG is observed in cells and serum. However, in angioimmunoblastic T-cell lymphoma (AITL), mutations are almost exclusively restricted to IDH2 R172, and levels of 2HG have not been comprehensively measured. In this study, we investigate the expression pattern of mutant IDH2 in the AITL tumor microenvironment and measure levels of 2HG in tissue and serum of AITL patients. We find that mutant IDH2 expression is restricted to the malignant T-cell component of AITL, and that 2HG is elevated in tumor tissue and serum of patients. We also investigate the differences between the three hotspot mutation sites in IDH1 and IDH2 using conditional knock-in mouse models. These studies show that in the lymphoid system, mutations in IDH2 at R172 produce high levels of 2HG compared with mutations at the other two sites and that lymphoid development is impaired in these animals. These data provide evidence that IDH2 R172 mutations may be the only variants present in AITL because of their capacity to produce significant amounts of the oncometabolite 2HG in the cell of origin of this disease. PMID- 27956632 TI - Increased burden of deleterious variants in essential genes in autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease. PMID- 27956634 TI - Brief treatment with a highly selective immunoproteasome inhibitor promotes long term cardiac allograft acceptance in mice. AB - Constitutive proteasomes (c-20S) are ubiquitously expressed cellular proteases that degrade polyubiquitinated proteins and regulate cell functions. An isoform of proteasome, the immunoproteasome (i-20S), is highly expressed in human T cells, dendritic cells (DCs), and B cells, suggesting that it could be a potential target for inflammatory diseases, including those involving autoimmunity and alloimmunity. Here, we describe DPLG3, a rationally designed, noncovalent inhibitor of the immunoproteasome chymotryptic subunit beta5i that has thousands-fold selectivity over constitutive beta5c. DPLG3 suppressed cytokine release from blood mononuclear cells and the activation of DCs and T cells, diminished accumulation of effector T cells, promoted expression of exhaustion and coinhibitory markers on T cells, and synergized with CTLA4-Ig to promote long-term acceptance of cardiac allografts across a major histocompatibility barrier. These findings demonstrate the potential value of using brief posttransplant immunoproteasome inhibition to entrain a long-term response favorable to allograft survival as part of an immunomodulatory regimen that is neither broadly immunosuppressive nor toxic. PMID- 27956635 TI - Low-stringency selection of TEM1 for BLIP shows interface plasticity and selection for faster binders. AB - Protein-protein interactions occur via well-defined interfaces on the protein surface. Whereas the location of homologous interfaces is conserved, their composition varies, suggesting that multiple solutions may support high-affinity binding. In this study, we examined the plasticity of the interface of TEM1 beta lactamase with its protein inhibitor BLIP by low-stringency selection of a random TEM1 library using yeast surface display. Our results show that most interfacial residues could be mutated without a loss in binding affinity, protein stability, or enzymatic activity, suggesting plasticity in the interface composition supporting high-affinity binding. Interestingly, many of the selected mutations promoted faster association. Further selection for faster binders was achieved by drastically decreasing the library-ligand incubation time to 30 s. Preequilibrium selection as suggested here is a novel methodology for specifically selecting faster-associating protein complexes. PMID- 27956636 TI - Accomplishing simple, solubility-based separations of rare earth elements with complexes bearing size-sensitive molecular apertures. AB - Rare earth (RE) metals are critical components of electronic materials and permanent magnets. Recycling of consumer materials is a promising new source of rare REs. To incentivize recycling, there is a clear need for the development of simple methods for targeted separations of mixtures of RE metal salts. Metal complexes of a tripodal hydroxylaminato ligand, TriNOx3-, featured a size sensitive aperture formed of its three eta2-(N,O) ligand arms. Exposure of cations in the aperture induced a self-associative equilibrium comprising RE(TriNOx)THF and [RE(TriNOx)]2 species. Differences in the equilibrium constants Kdimer for early and late metals enabled simple separations through leaching. Separations were performed on RE1/RE2 mixtures, where RE1 = La-Sm and RE2 = Gd Lu, with emphasis on Eu/Y separations for potential applications in the recycling of phosphor waste from compact fluorescent light bulbs. Using the leaching method, separations factors approaching 2,000 were obtained for early-late RE combinations. Following solvent optimization, >95% pure samples of Eu were obtained with a 67% recovery for the technologically relevant Eu/Y separation. PMID- 27956637 TI - Experimental and theoretical evidence for bilayer-by-bilayer surface melting of crystalline ice. AB - On the surface of water ice, a quasi-liquid layer (QLL) has been extensively reported at temperatures below its bulk melting point at 273 K. Approaching the bulk melting temperature from below, the thickness of the QLL is known to increase. To elucidate the precise temperature variation of the QLL, and its nature, we investigate the surface melting of hexagonal ice by combining noncontact, surface-specific vibrational sum frequency generation (SFG) spectroscopy and spectra calculated from molecular dynamics simulations. Using SFG, we probe the outermost water layers of distinct single crystalline ice faces at different temperatures. For the basal face, a stepwise, sudden weakening of the hydrogen-bonded structure of the outermost water layers occurs at 257 K. The spectral calculations from the molecular dynamics simulations reproduce the experimental findings; this allows us to interpret our experimental findings in terms of a stepwise change from one to two molten bilayers at the transition temperature. PMID- 27956638 TI - Palmitoylation regulates glutamate receptor distributions in postsynaptic densities through control of PSD95 conformation and orientation. AB - Postsynaptic density protein 95 (PSD95) and synapse-associated protein 97 (SAP97) are homologous scaffold proteins with different N-terminal domains, possessing either a palmitoylation site (PSD95) or an L27 domain (SAP97). Here, we measured PSD95 and SAP97 conformation in vitro and in postsynaptic densities (PSDs) using FRET and EM, and examined how conformation regulated interactions with AMPA-type and NMDA-type glutamate receptors (AMPARs/NMDARs). Palmitoylation of PSD95 changed its conformation from a compact to an extended configuration. PSD95 associated with AMPARs (via transmembrane AMPAR regulatory protein subunits) or NMDARs [via glutamate ionotropic receptor NMDA-type subunit 2B (GluN2B) subunits] only in its palmitoylated and extended conformation. In contrast, in its extended conformation, SAP97 associates with NMDARs, but not with AMPARs. Within PSDs, PSD95 and SAP97 were largely in the extended conformation, but had different orientations. PSD95 oriented perpendicular to the PSD membrane, with its palmitoylated, N-terminal domain at the membrane. SAP97 oriented parallel to the PSD membrane, likely as a dimer through interactions of its N-terminal L27 domain. Changing PSD95 palmitoylation in PSDs altered PSD95 and AMPAR levels but did not affect NMDAR levels. These results indicate that in PSDs, PSD95 palmitoylation, conformation, and its interactions are dynamic when associated with AMPARs and more stable when associated with NMDARs. Altogether, our results are consistent with differential regulation of PSD95 palmitoylation in PSDs resulting from the clustering of palmitoylating and depalmitoylating enzymes into AMPAR nanodomains segregated away from NMDAR nanodomains. PMID- 27956639 TI - RNA polymerase gate loop guides the nontemplate DNA strand in transcription complexes. AB - Upon RNA polymerase (RNAP) binding to a promoter, the sigma factor initiates DNA strand separation and captures the melted nontemplate DNA, whereas the core enzyme establishes interactions with the duplex DNA in front of the active site that stabilize initiation complexes and persist throughout elongation. Among many core RNAP elements that participate in these interactions, the beta' clamp domain plays the most prominent role. In this work, we investigate the role of the beta gate loop, a conserved and essential structural element that lies across the DNA channel from the clamp, in transcription regulation. The gate loop was proposed to control DNA loading during initiation and to interact with NusG-like proteins to lock RNAP in a closed, processive state during elongation. We show that the removal of the gate loop has large effects on promoter complexes, trapping an unstable intermediate in which the RNAP contacts with the nontemplate strand discriminator region and the downstream duplex DNA are not yet fully established. We find that although RNAP lacking the gate loop displays moderate defects in pausing, transcript cleavage, and termination, it is fully responsive to the transcription elongation factor NusG. Together with the structural data, our results support a model in which the gate loop, acting in concert with initiation or elongation factors, guides the nontemplate DNA in transcription complexes, thereby modulating their regulatory properties. PMID- 27956640 TI - Loss of O-GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration. AB - O-GlcNAc glycosylation (or O-GlcNAcylation) is a dynamic, inducible posttranslational modification found on proteins associated with neurodegenerative diseases such as alpha-synuclein, amyloid precursor protein, and tau. Deletion of the O-GlcNAc transferase (ogt) gene responsible for the modification causes early postnatal lethality in mice, complicating efforts to study O-GlcNAcylation in mature neurons and to understand its roles in disease. Here, we report that forebrain-specific loss of OGT in adult mice leads to progressive neurodegeneration, including widespread neuronal cell death, neuroinflammation, increased production of hyperphosphorylated tau and amyloidogenic Abeta-peptides, and memory deficits. Furthermore, we show that human cortical brain tissue from Alzheimer's disease patients has significantly reduced levels of OGT protein expression compared with cortical tissue from control individuals. Together, these studies indicate that O-GlcNAcylation regulates pathways critical for the maintenance of neuronal health and suggest that dysfunctional O-GlcNAc signaling may be an important contributor to neurodegenerative diseases. PMID- 27956642 TI - DNA demethylation is initiated in the central cells of Arabidopsis and rice. AB - Cytosine methylation is a DNA modification with important regulatory functions in eukaryotes. In flowering plants, sexual reproduction is accompanied by extensive DNA demethylation, which is required for proper gene expression in the endosperm, a nutritive extraembryonic seed tissue. Endosperm arises from a fusion of a sperm cell carried in the pollen and a female central cell. Endosperm DNA demethylation is observed specifically on the chromosomes inherited from the central cell in Arabidopsis thaliana, rice, and maize, and requires the DEMETER DNA demethylase in Arabidopsis DEMETER is expressed in the central cell before fertilization, suggesting that endosperm demethylation patterns are inherited from the central cell. Down-regulation of the MET1 DNA methyltransferase has also been proposed to contribute to central cell demethylation. However, with the exception of three maize genes, central cell DNA methylation has not been directly measured, leaving the origin and mechanism of endosperm demethylation uncertain. Here, we report genome-wide analysis of DNA methylation in the central cells of Arabidopsis and rice-species that diverged 150 million years ago-as well as in rice egg cells. We find that DNA demethylation in both species is initiated in central cells, which requires DEMETER in Arabidopsis However, we do not observe a global reduction of CG methylation that would be indicative of lowered MET1 activity; on the contrary, CG methylation efficiency is elevated in female gametes compared with nonsexual tissues. Our results demonstrate that locus-specific, active DNA demethylation in the central cell is the origin of maternal chromosome hypomethylation in the endosperm. PMID- 27956644 TI - Decentralization can help reduce deforestation when user groups engage with local government. AB - Policy makers around the world tout decentralization as an effective tool in the governance of natural resources. Despite the popularity of these reforms, there is limited scientific evidence on the environmental effects of decentralization, especially in tropical biomes. This study presents evidence on the institutional conditions under which decentralization is likely to be successful in sustaining forests. We draw on common-pool resource theory to argue that the environmental impact of decentralization hinges on the ability of reforms to engage local forest users in the governance of forests. Using matching techniques, we analyze longitudinal field observations on both social and biophysical characteristics in a large number of local government territories in Bolivia (a country with a decentralized forestry policy) and Peru (a country with a much more centralized forestry policy). We find that territories with a decentralized forest governance structure have more stable forest cover, but only when local forest user groups actively engage with the local government officials. We provide evidence in support of a possible causal process behind these results: When user groups engage with the decentralized units, it creates a more enabling environment for effective local governance of forests, including more local government-led forest governance activities, fora for the resolution of forest-related conflicts, intermunicipal cooperation in the forestry sector, and stronger technical capabilities of the local government staff. PMID- 27956641 TI - On the role of water density fluctuations in the inhibition of a proton channel. AB - Hv1 is a transmembrane four-helix bundle that transports protons in a voltage controlled manner. Its crucial role in many pathological conditions, including cancer and ischemic brain damage, makes Hv1 a promising drug target. Starting from the recently solved crystal structure of Hv1, we used structural modeling and molecular dynamics simulations to characterize the channel's most relevant conformations along the activation cycle. We then performed computational docking of known Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI) and analogs. Although salt-bridge patterns and electrostatic potential profiles are well-defined and distinctive features of activated versus nonactivated states, the water distribution along the channel lumen is dynamic and reflects a conformational heterogeneity inherent to each state. In fact, pore waters assemble into intermittent hydrogen-bonded clusters that are replaced by the inhibitor moieties upon ligand binding. The entropic gain resulting from releasing these conformationally restrained waters to the bulk solvent is likely a major contributor to the binding free energy. Accordingly, we mapped the water density fluctuations inside the pore of the channel and identified the regions of maximum fluctuation within putative binding sites. Two sites appear as outstanding: One is the already known binding pocket of 2GBI, which is accessible to ligands from the intracellular side; the other is a site located at the exit of the proton permeation pathway. Our analysis of the waters confined in the hydrophobic cavities of Hv1 suggests a general strategy for drug discovery that can be applied to any ion channel. PMID- 27956643 TI - Arabidopsis male sexual lineage exhibits more robust maintenance of CG methylation than somatic tissues. AB - Cytosine DNA methylation regulates the expression of eukaryotic genes and transposons. Methylation is copied by methyltransferases after DNA replication, which results in faithful transmission of methylation patterns during cell division and, at least in flowering plants, across generations. Transgenerational inheritance is mediated by a small group of cells that includes gametes and their progenitors. However, methylation is usually analyzed in somatic tissues that do not contribute to the next generation, and the mechanisms of transgenerational inheritance are inferred from such studies. To gain a better understanding of how DNA methylation is inherited, we analyzed purified Arabidopsis thaliana sperm and vegetative cells-the cell types that comprise pollen-with mutations in the DRM, CMT2, and CMT3 methyltransferases. We find that DNA methylation dependency on these enzymes is similar in sperm, vegetative cells, and somatic tissues, although DRM activity extends into heterochromatin in vegetative cells, likely reflecting transcription of heterochromatic transposons in this cell type. We also show that lack of histone H1, which elevates heterochromatic DNA methylation in somatic tissues, does not have this effect in pollen. Instead, levels of CG methylation in wild-type sperm and vegetative cells, as well as in wild-type microspores from which both pollen cell types originate, are substantially higher than in wild-type somatic tissues and similar to those of H1-depleted roots. Our results demonstrate that the mechanisms of methylation maintenance are similar between pollen and somatic cells, but the efficiency of CG methylation is higher in pollen, allowing methylation patterns to be accurately inherited across generations. PMID- 27956646 TI - Engagement in and continuity of HIV care among African and Caribbean Black women living with HIV in Ontario, Canada. AB - Engagement in care is a key component of the HIV care cascade, yet there are knowledge gaps regarding how to assess HIV care engagement. This study aimed to develop a tool to assess HIV care engagement and to assess associations between HIV care engagement and quality of life (QOL) among African, Caribbean and Black (ACB) women living with HIV (WLWH). We conducted a cross-sectional survey with ACB WLWH across Ontario, Canada. We developed the 'HIV Engagement in and Continuity of Care Scale' (HECCS). We conducted exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) to test the scale's factor structure. We conducted structural equation modeling (SEM) with maximum likelihood estimation to examine the associations between the HECCS and QOL. EFA yielded four factors: access to care, care by doctor/health professionals, control of HIV care, and appointment timekeeping. The CFA of the HECCS demonstrated good model fit: chi2 (DF: 1; n = 173) = 1.175, p = 0.278; CFI: 0.998; Tucker-Lewis Index (TLI): 0.990; RMSEA: 0.032. The HECCS was associated with increased QOL. The model fit the data well: chi2 (DF: 31, n = 173) = 51.19, p = 0.013; CFI = 0.955; TLI = 0.934; RMSEA = 0.062. Engagement in and continuity of care is multifaceted. We recommend interventions to promote the institutional capacity to better engage ACB WLWH in HIV care. PMID- 27956647 TI - False-negative syphilis treponemal enzyme immunoassay results in an HIV-infected case-patient. AB - We present a case report of a false-negative syphilis treponemal enzyme immunoassay test result in an HIV-infected male. While treponemal tests are widely considered to be more sensitive and specific than non-treponemal tests, our findings point to potential challenges using the reverse sequence syphilis screening algorithm. PMID- 27956648 TI - Abdominal Aortic Aneurysm With Renal Arteries Originating Above the Superior Mesenteric Artery. AB - A 63-year-old female presented to clinic following an incidental finding of an abdominal aortic aneurysm (AAA). Preoperative imaging was consistent with an infrarenal AAA over 5-cm in diameter with both renal arteries originating above the superior mesenteric artery (SMA). The patient subsequently underwent an endovascular aneurysm repair (EVAR) using the AFX stent-graft (Endologix, Inc, Irvine, Calif). Notably, the proximal stent-graft piece was unsheathed with the image intensifier in a lateral position to ensure deployment below the SMA. Postoperative course was unremarkable and the patient is currently recovering well. PMID- 27956645 TI - Amino terminal pro brain natriuretic peptide predicts all-cause mortality in patients with chronic obstructive pulmonary disease: Systematic review and meta analysis. AB - Natriuretic peptides (NPs) are a family of prognostic biomarkers in patients with heart failure (HF). HF is one of the most frequent comorbidities in patients with chronic obstructive pulmonary disease (COPD). However, the prognostic role of NP in COPD patients remains unclear. The aim of this meta-analysis was to evaluate the relation between NP and all-cause mortality in COPD patients. We performed a systematic review and meta-analysis of observational studies assessing prognostic implications of elevated NP levels on all-cause mortality in COPD patients. Nine studies were considered for qualitative analysis for a total of 2788 patients. Only two studies focused on Mid Regional-pro Atrial Natriuretic Peptide (MR proANP) and brain natriuretic peptide (BNP), respectively, but seven studies focused on pro-BNP (NT-proBNP) and were included in the quantitative analysis. Elevated NT-proBNP values were related to increased risk of all-cause mortality in COPD patients both with and without exacerbation (hazard ratio (HR): 2.87, p < 0.0001 and HR: 3.34, p = 0.04, respectively). The results were confirmed also after meta-regression analysis for confounding factors (previous cardiovascular history, hypertension, HF, forced expiratory volume at 1 second and mean age). NT proBNP may be considered a reliable predictive biomarker of poor prognosis in patients with COPD. PMID- 27956649 TI - Introduction: histories of asylums, insanity and psychiatry in Scotland. AB - This paper introduces a special issue on 'Histories of asylums, insanity and psychiatry in Scotland', situating the papers that follow in an outline historiography of work in this field. Using Allan Beveridge's claims in 1993 about the relative lack of research on the history of psychiatry in Scotland, the paper reviews a range of contributions that have emerged since then, loosely distinguishing between 'overviews' - work addressing longer-term trends and broader periods and systems - and more detailed studies of particular 'individuals and institutions'. There remains much still to do, but the present special issue signals what is currently being achieved, not least by a new generation of scholars in and on Scotland. PMID- 27956651 TI - Development of fat-reduced sausages: Influence of binary and ternary combinations of carrageenan, inulin, and bovine plasma proteins. AB - The aim of this work was to study the influence of the binary and ternary combinations of bovine plasma proteins (BPP), inulin (I) and kappa-carrageenan (C) in the overall quality of fat-reduced sausages. The influence of these components over different properties (chemical composition, weight loss after cooking, emulsion stability, texture profile and sensory analysis of fat-reduced sausages) was studied and compared against two samples, one without fat reduction and another a fat-reduced sample without addition of texturing agents. In this sense, a full factorial experimental design of two levels with central point was used. The samples containing BPP+I and BPP+C showed a synergy in which the binary combinations presented higher values of moisture and protein content than the samples containing the individual components. The reduction of fat content increases the values of hardness and decreases the values of springiness. Samples with 5% BPP (w/w) and binary combinations of BPP+C and BPP+I had the best stability values (low total fluid loss), demonstrating a significant synergistic effect by combining BPP+C. Similar results were obtained from the study of weight loss after cooking. However, both studies showed a destabilization of the sample BPP+I+C as emulsion stability decreased and weight loss increased after cooking compared to binary combinations ( P < 0.05). Samples with a binary combination of BPP+C and BPP+I do not present a statistically significant difference in the chewiness with respect to a not-fat-reduced commercial sample ( P > 0.05). The less acceptable sample for flavor and texture was the one containing only BPP. However, when BPP combined with I or C, a major acceptability was obtained, demonstrating the synergistic effect of these binary combinations. Therefore, our studies revealed that the binary combinations of BPP with I or C are good alternatives for the development of fat-reduced sausage. PMID- 27956650 TI - Seven years of progress in tobacco control: an evaluation of the effect of nations meeting the highest level MPOWER measures between 2007 and 2014. AB - OBJECTIVE: Since WHO released the package of six MPOWER measures to assist nations with implementing the WHO Framework Convention for Tobacco Control (FCTC), 88 countries adopted at least one highest level MPOWER measure. We estimated the subsequent reduction in smoking-related deaths from all new highest level measures adopted between 2007 and 2014. METHODS: Policy effect sizes based on previously validated SimSmoke models were applied to the number of smokers in each nation to determine the reduction in the number of smokers from policy adoption. On the basis of research that half of all smokers die from smoking, we derived the smoking-attributable deaths (SADs) averted of those smokers alive today. FINDINGS: In total, 88 countries adopted at least one highest level MPOWER policy between 2007 and 2014, resulting in almost 22 million fewer projected SADs. The largest number of future SADs averted was due to increased cigarette taxes (7.0 million), followed by comprehensive smoke-free laws (5.4 million), large graphic health warnings (4.1 million), comprehensive marketing bans (3.8 million) and comprehensive cessation interventions (1.5 million). CONCLUSIONS: These findings demonstrate the immense public health impact of tobacco control policies adopted globally since the WHO-FCTC and highlight the importance of more countries adopting highest level MPOWER measures to reduce the global burden of tobacco use. Substantial additional progress could be made, especially if heavily populated nations with high smoking prevalence were to reach highest level MPOWER measures. PMID- 27956653 TI - Environmental Enteric Dysfunction and the Fecal Microbiota in Malawian Children. AB - Environmental enteric dysfunction (EED) is often measured with a dual sugar absorption test and implicated as a causative factor in childhood stunting. Disturbances in the gut microbiota are hypothesized to be a mechanism by which EED is exacerbated, although this supposition lacks support. We performed 16S ribosomal RNA gene sequencing of fecal samples from 81 rural Malawian children with varying degrees of EED to determine which bacterial taxa were associated with EED. At the phyla level, Proteobacteria abundance is reduced with severe EED. Among bacterial genera, Megasphaera, Mitsuokella, and Sutterella were higher in EED and Succinivibrio, Klebsiella, and Clostridium_XI were lower in EED. Bacterial diversity did not vary with the extent of EED. Though EED is a condition that is typically believed to affect the proximal small bowel, and our focus was on stool, our data do suggest that there are intraluminal microbial differences that reflect, or plausibly lead to, EED. PMID- 27956654 TI - Adapting and Evaluating a Rapid, Low-Cost Method to Enumerate Flies in the Household Setting. AB - Diarrhea is a leading cause of death among children under 5 years of age worldwide. Flies are important vectors of diarrheal pathogens in settings lacking networked sanitation services. There is no standardized method for measuring fly density in households; many methods are cumbersome and unvalidated. We adapted a rapid, low-cost fly enumeration technique previously developed for industrial settings, the Scudder fly grill, for field use in household settings. We evaluated its performance in comparison to a sticky tape fly trapping method at latrine and food preparation areas among households in rural Kenya. The grill method was more sensitive; it detected the presence of any flies at 80% (433/543) of sampling locations versus 64% (348/543) of locations by the sticky tape. We found poor concordance between the two methods, suggesting that standardizing protocols is important for comparison of fly densities between studies. Fly species identification was feasible with both methods; however, the sticky tape trap allowed for more nuanced identification. Both methods detected a greater presence of bottle flies near latrines compared with food preparation areas (P < 0.01). The grill method detected more flies at the food preparation area compared with near the latrine (P = 0.014) while the sticky tape method detected no difference. We recommend the Scudder grill as a sensitive fly enumeration tool that is rapid and low cost to implement. PMID- 27956655 TI - Undergraduate Global Health Degrees: The Time is Right. PMID- 27956656 TI - Transverse Myelitis as an Unusual Complication of Dengue Fever. AB - Dengue fever is the most common arbovirus disease, and presents with a large spectrum of clinical manifestations ranging from asymptomatic disease through to the development of dengue hemorrhagic fever. These extreme cases can lead to dengue shock syndrome, and sometimes death. Spinal cord involvement in dengue virus (DENV) infections is rare. Here, we report a case in which the patient developed acute transverse myelitis (TM) without paraparesis following a DENV infection. This case highlights the importance of physicians' awareness of the possible link between DENV and TM in endemic areas. PMID- 27956657 TI - Metasynthetic Madness: What Kind of Monster Have We Created? AB - From its origins in the 1990s, the qualitative health research metasynthesis project represented a methodological maneuver to capitalize on a growing investment in qualitatively derived study reports to create an interactive dialogue among them that would surface expanded insights about complex human phenomena. However, newer forms positioning themselves as qualitative metasynthesis but representing a much more technical and theoretically superficial form of scholarly enterprise have begun to appear in the health research literature. It seems imperative that we think through the implications of this trend and determine whether it is to be afforded the credibility of being a form of qualitative scholarship and, if so, what kind of scholarship it represents. As the standardization trend in synthesis research marches forward, we will need clarity and a strong sense of purpose if we are to preserve the essence of what the qualitative metasynthesis project was intended to be all about. PMID- 27956658 TI - When Are Caregivers More Likely to Offer Sugary Drinks and Snacks to Infants? A Qualitative Thematic Synthesis. AB - Many children consume more sugar than is recommended, and caregivers often find it difficult to change this habit once established. This thematic synthesis aims to identify the "critical situations" where caregivers may be more likely to offer infants sugary drinks and snacks. This thematic synthesis is reported in accordance with the statement for enhancing transparency in reporting the synthesis of qualitative research (ENTREQ). Our confidence in the findings of our synthesis was assessed using the CERQual (Confidence in the Evidence From Reviews of Qualitative Research Approach). We included 16 studies from the United States, the United Kingdom, Australia, and Denmark. We identified eight "critical situations" when caregivers may be more likely to offer sugary drinks and snacks to infants. Interventions that seek to reduce sugar intake for caries prevention in infants and young children may be more successful if they provide caregivers with practical parenting strategies to replace the nonnutritive functions of sugary foods and drinks, as opposed to taking an information-giving approach. PMID- 27956659 TI - Online Peer-to-Peer Communities in the Daily Lives of People With Chronic Illness: A Qualitative Systematic Review. AB - This qualitative systematic review investigated how individuals with chronic illness experience online peer-to-peer support and how their experiences influence daily life with illness. Selected studies were appraised by quality criteria focused upon research questions and study design, participant selection, methods of data collection, and methods of analysis. Four themes were identified: (a) illness-associated identity work, (b) social support and connectivity, (c) experiential knowledge sharing, and (d) collective voice and mobilization. Findings indicate that online peer-to-peer communities provide a supportive space for daily self-care related to chronic illness. Online communities provided a valued space to strengthen social ties and exchange knowledge that supported offline ties and patient-doctor relationships. Individuals used online communities to exchange experiential knowledge about everyday life with illness. This type of knowledge was perceived as extending far beyond medical care. Online communities were also used to mobilize and raise collective awareness about illness-specific concerns. PMID- 27956660 TI - Understanding Help-Seeking Behavior in Depression: A Qualitative Synthesis of Patients' Experiences. AB - Despite decades of evidence-based interventions, depression remains a great challenge for public health due to enormous treatment gap and lag which, at least partially, result from low professional help-seeking by people suffering from depressive symptoms. In this article, we aim to gain a better understanding of help-seeking behavior in depression, and how to intervene effectively decreasing treatment gap and delay by using a meta-ethnography approach-an interpretive technique to systematically synthesize qualitative data. It integrates views and experiences of 474 individuals with depression across 20 papers. Findings suggest several interrelated major concepts-help-seeking as a threat to identity, social networks as a conflict or support, and alternative coping strategies as the main factor for treatment delay-as well as multiple relational, structural, attitudinal, cognitive, culture-specific, or gender-specific barriers. A model of help-seeking as a threat to identity is developed and discussed in the context of existing research. PMID- 27956661 TI - In Memoriam: A Tribute to Daniel J. Sargent, Ph.D. PMID- 27956664 TI - What is the rationale for preoperative medical evaluations? A closer look at surgical risk and common terminology. PMID- 27956665 TI - Time to move the goalposts? Do we need new targets for developing i.v. anaesthetics? PMID- 27956666 TI - Glycaemic control during cataract surgery under loco-regional anaesthesia: a growing problem and we are none the wiser. PMID- 27956667 TI - The suffering and satisfaction of Schrodinger's cat. PMID- 27956669 TI - Genetic polymorphisms and their association with the prevalence and severity of chronic postsurgical pain: a systematic review. AB - BACKGROUND: Although several patient characteristic, clinical, and psychological risk factors for chronic postsurgical pain (CPSP) have been identified, genetic variants including single nucleotide polymorphisms have also become of interest as potential risk factors for the development of CPSP. The aim of this review is to summarize the current evidence on genetic polymorphisms associated with the prevalence and severity of CPSP in adult patients. METHODS: A systematic review of the literature was performed, and additional literature was obtained by reference tracking. The primary outcome was CPSP, defined as pain at least 2 months after the surgery. Studies performed exclusively in animals were excluded. RESULTS: Out of the 1001 identified studies, 14 studies were selected for inclusion. These studies described 5269 participants in 17 cohorts. A meta analysis was not possible because of heterogeneity of data and data analysis. Associations with the prevalence or severity of CPSP were reported for genetic variants in the COMT gene, OPRM1, potassium channel genes, GCH1, CACNG, CHRNA6, P2X7R, cytokine-associated genes, human leucocyte antigens, DRD2, and ATXN1 CONCLUSIONS: Research on the topic of genetic variants associated with CPSP is still in its initial phase. Hypothesis-free, genome-wide association studies on large cohorts are needed in this field. In addition, future studies may also integrate genetic risk factors and patient characteristic, clinical, and psychological predictors for CPSP. PMID- 27956670 TI - Review of perioperative falls. AB - : Falls are a known public health problem, and there is increasing recognition of the importance of perioperative falls for risk prediction and quality assessment. Our objective was to review existing literature regarding the occurrence, injuries, and risk factors of preoperative and postoperative falls. A systematized search of PubMed entries between 1947 and November 2015 produced 24 articles that met inclusion criteria. Most studied orthopaedic surgery patients older than 65 yr. Four were rated 'good' quality. Interrater reliability for the quality assessment was moderate (kappa = 0.77). In the 3-12 months before surgery, the proportion of preoperative patients who fell ranged from 24 to 48%. Injuries were common (70%). The rate of postoperative falls ranged from 0.8 to 16.3 per 1000 person-days, with a gradual decline in the months after surgery. Injuries from postoperative falls occurred in 10-70% of fallers, and 5-20% experienced a severe injury. Risk factors were not well studied. Prospective studies reported a higher percentage of falls and fall-related injuries than retrospective studies, suggesting that there may be underdetection of falls and injuries with retrospective studies. Perioperative falls were more common than falls reported in the general community, even up to 12 months after surgery. Surgery-related falls may therefore occur beyond the hospitalization period. Future studies should use a prospective design, validated definitions, and broader populations to study perioperative falls. In particular, investigations of risk factors and follow-up after hospitalization are needed. REGISTRY NUMBER: PROSPERO registration number CRD42015029971. PMID- 27956671 TI - Defining oliguria during cardiopulmonary bypass and its relationship with cardiac surgery-associated acute kidney injury. AB - BACKGROUND: While urine flow rate <=0.5 ml kg-1 h-1 is believed to define oliguria during cardiopulmonary bypass (CPB), it is unclear whether this definition identifies risk for acute kidney injury (AKI) . The purpose of this retrospective study was to evaluate if urine flow rate during CPB is associated with AKI. METHODS: Urine flow rate was calculated in 503 patients during CPB. AKI in the first 48 h after surgery was defined by the Kidney Disease: Improving Global Outcomes classification. Adjusted risk factors associated with AKI and urine flow rate were assessed. RESULTS: Patients with AKI [n=149 (29.5%)] had lower urine flow rate than those without AKI (P<0.001). The relationship between urine flow and AKI risk was non-linear, with an inflection point at 1.5 ml kg-1 h 1 Among patients with urine flow <1.5 ml kg-1 h-1, every 0.5 ml kg-1 h-1 higher urine flow reduced the adjusted risk of AKI by 26% (95% CI 13-37; P<0.001). Urine flow rate during CPB was independently associated with the risk for AKI. Age up to 80 years and preoperative diuretic use were inversely associated with urine flow rate; mean arterial pressure on CPB (when <87 mmHg) and CPB flow were positively associated with urine flow rate. CONCLUSIONS: Urine flow rate during CPB <1.5 ml kg-1 h-1 identifies patients at risk for cardiac surgery-associated AKI. Careful monitoring of urine flow rate and optimizing mean arterial pressure and CPB flow might be a means to ensure renal perfusion during CPB. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00769691 and NCT00981474. PMID- 27956672 TI - Rotation thromboelastometry velocity curve predicts blood loss during liver transplantation. AB - BACKGROUND: Patients undergoing liver transplantation (LT) have a high risk of bleeding. The goal of this study was to assess whether the first derivative of the velocity waveform (V-curve) generated by whole blood rotation thromboelastometry (ROTEM(r)) can predict blood loss during LT. METHODS: Preoperative V-curve parameters were retrospectively evaluated in 198 patients. Patients were divided into quartiles based on blood loss: low (LBL) in the first quartile and high (HBL) in the higher quartiles. A subgroup analysis was performed with patients stratified according to cirrhosis aetiology. A logistic regression model and receiver operator characteristics (ROC) curve were used to test the capacity of the V-curve, to discriminate between LBL and HBL. RESULTS: In the HBL group, the V-curve showed a lower maximum velocity of clot generation (MaxVel), a lower area under maximum velocity curve (AUC), and a higher time-to maximum velocity (t-MaxVel) than in the LBL group. t-MaxVel was the only parameter showing a capacity to discriminate between the two groups, with a ROC area of 0.69 (95% CI; 0.62-0.74). The ROC area was 0.78 (95% CI; 0.75-0.83) for the 148 patients with cirrhosis, 0.73 (0.60-0.82) for patients with viral hepatitis and 0.83 (0.78-0.96) for patients with alcoholic hepatitis, the group that showed the best discriminative capacity. Moderate but significant correlations were found between all parameters of V-curve and BL. CONCLUSIONS: Pre-transplant V-curve obtained from ROTEM is a promising tool for predicting BL risk during LT, particularly in patients with cirrhosis. PMID- 27956668 TI - The inflammasome as a target for pain therapy. AB - The interleukin-1 family of cytokines are potent inducers of inflammation and pain. Proteolytic activation of this family of cytokines is under the control of several innate immune receptors that coordinate to form large multiprotein signalling platforms, termed inflammasomes. Recent evidence suggests that a wide range of inflammatory diseases, cancers, and metabolic and autoimmune disorders, in which pain is a common complaint, may be coordinated by inflammasomes. Activation of inflammasomes results in cleavage of caspase-1, which subsequently induces downstream initiation of several potent pro-inflammatory cascades. Therefore, it has been proposed that targeting inflammasome activity may be a novel and effective therapeutic strategy for these pain-related diseases. The purpose of this narrative review article is to provide the reader with an overview of the activation and regulation of inflammasomes and to investigate the potential therapeutic role of inflammasome inhibition in the treatment of diseases characterized by pain, including the following: complex regional pain syndrome, gout, rheumatoid arthritis, inflammatory pain, neuropathic pain, chronic prostatitis, chronic pelvic pain syndrome, and fibromyalgia. We conclude that the role of the inflammasome in pain-associated diseases is likely to be inflammasome subtype and disease specific. The currently available evidence suggests that disease-specific targeting of the assembly and activity of the inflammasome complex may be a novel therapeutic opportunity for the treatment of refractory pain in many settings. PMID- 27956673 TI - Prospective observational study of the effect of dual antiplatelet therapy with tranexamic acid treatment on platelet function and bleeding after cardiac surgery. AB - BACKGROUND: The bleeding impact of dual antiplatelet therapy (DAPT), aspirin and clopidogrel, maintained until coronary artery bypass graft surgery (CABG), is still a matter of debate. The lack of preoperative antiplatelet activity measurement and heterogeneity of antifibrinolytic protocols in prior studies make the conclusions questionable. The aim of this prospective study was to determine, after preoperative antiplatelet activity measurement, if the maintenance of DAPT until CABG increases bleeding in patients treated with tranexamic acid (TA). METHODS: This observational study included 150 consecutive patients, 89 treated with aspirin and 61 treated with DAPT, undergoing a first-time planned on-pump CABG with TA treatment. Antiplatelet activity was measured with platelet aggregation tests and quantification of VASP phosphorylation. Postoperative bleeding at 24 h was recorded and propensity score analysis was performed. RESULTS: Based on VASP assay, 54% of patients showed high on-clopidogrel platelet activity inhibition. Postoperative bleeding at 24 h increased by 22% in the DAPT group, compared with the aspirin group (680 [95% CI: 360-1670] vs 558 [95%CI: 267 1270] ml, P < 0.01), consistent with increased blood transfusion (21% vs 7%, P = 0.01); a higher incidence of mediastinitis did not reach statistical significance (15% vs 4%, P = 0.05). Bleeding correlated with the extent of clopidogrel antiplatelet effect, with the best correlation for the VASP assay. CONCLUSIONS: Maintenance of DAPT until the day of CABG in patients treated with TA, increased postoperative bleeding at 24 h in parallel with preoperative antiplatelet activity induced by clopidogrel. PMID- 27956675 TI - Linear and non-linear heart rate metrics for the assessment of anaesthetists' workload during general anaesthesia. AB - BACKGROUND: Excessive workload may impact the anaesthetists' ability to adequately process information during clinical practice in the operation room and may result in inaccurate situational awareness and performance. This exploratory study investigated heart rate (HR), linear and non-linear heart rate variability (HRV) metrics and subjective ratings scales for the assessment of workload associated with the anaesthesia stages induction, maintenance and emergence. METHODS: HR and HRV metrics were calculated based on five min segments from each of the three anaesthesia stages. The area under the receiver operating characteristics curve (AUC) of the investigated metrics was calculated to assess their ability to discriminate between the stages of anaesthesia. Additionally, a multiparametric approach based on logistic regression models was performed to further evaluate whether linear or non-linear heart rate metrics are suitable for the assessment of workload. RESULTS: Mean HR and several linear and non-linear HRV metrics including subjective workload ratings differed significantly between stages of anaesthesia. Permutation Entropy (PeEn, AUC=0.828) and mean HR (AUC=0.826) discriminated best between the anaesthesia stages induction and maintenance. In the multiparametric approach using logistic regression models, the model based on non-linear heart rate metrics provided a higher AUC compared with the models based on linear metrics. CONCLUSIONS: In this exploratory study based on short ECG segment analysis, PeEn and HR seem to be promising to separate workload levels between different stages of anaesthesia. The multiparametric analysis of the regression models favours non-linear heart rate metrics over linear metrics. PMID- 27956676 TI - Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial. AB - BACKGROUND: Decreased plasma fibrinogen concentration shortly after injury is associated with higher blood transfusion needs and mortality. In North America and the UK, cryoprecipitate transfusion is the standard-of-care for fibrinogen supplementation during acute haemorrhage, which often occurs late during trauma resuscitation. Alternatively, fibrinogen concentrate (FC) can be beneficial in trauma resuscitation. However, the feasibility of its early infusion, efficacy and safety remain undetermined. The objective of this trial was to evaluate the feasibility, effect on clinical and laboratory outcomes and complications of early infusion of FC in trauma. METHODS: Fifty hypotensive (systolic arterial pressure <=100 mm Hg) adult patients requiring blood transfusion were randomly assigned to either 6 g of FC or placebo, between Oct 2014 and Nov 2015 at a tertiary trauma centre. The primary outcome, feasibility, was assessed by the proportion of patients receiving the intervention (FC or placebo) within one h of hospital arrival. Plasma fibrinogen concentration was measured, and 28-day mortality and incidence of thromboembolic events were assessed. RESULTS: Overall, 96% (43/45) [95% CI 86-99%] of patients received the intervention within one h; 95% and 96% in the FC and placebo groups, respectively (P=1.00). Plasma fibrinogen concentrations remained higher in the FC group up to 12 h after admission with the largest difference at three h (2.9 mg dL - 1 vs. 1.8 mg dL - 1; P<0.01). The 28-day mortality and thromboembolic complications were similar between groups. CONCLUSIONS: Early infusion of FC is feasible and increases plasma fibrinogen concentration during trauma resuscitation. Larger trials are justified. PMID- 27956677 TI - Effects of pneumoperitoneum and Trendelenburg position on intracranial pressure assessed using different non-invasive methods. AB - BACKGROUND: The laparoscopic approach is becoming increasingly frequent for many different surgical procedures. However, the combination of pneumoperitoneum and Trendelenburg positioning associated with this approach may increase the patient's risk for elevated intracranial pressure (ICP). Given that the gold standard for the measurement of ICP is invasive, little is known about the effect of these common procedures on ICP. METHODS: We prospectively studied 40 patients without any history of cerebral disease who were undergoing laparoscopic procedures. Three different methods were used for non-invasive estimation of ICP: ultrasonography of the optic nerve sheath diameter (ONSD); transcranial Doppler based (TCD) pulsatility index (ICPPI); and a method based on the diastolic component of the TCD cerebral blood flow velocity (ICPFVd). The ONSD and TCD were measured immediately after induction of general anaesthesia, after pneumoperitoneum insufflation, after Trendelenburg positioning, and again at the end of the procedure. RESULTS: The ONSD, ICPFVd, and ICPPI increased significantly after the combination of pneumoperitoneum insufflation and Trendelenburg positioning. The ICPFVd showed an area under the curve of 0.80 [95% confidence interval (CI) 0.70-0.90] to distinguish the stage associated with the application of pneumoperitoneum and Trendelenburg position; ONSD and ICPPI showed an area under the curve of 0.75 (95% CI 0.65-0.86) and 0.70 (95% CI 0.58-0.81), respectively. CONCLUSIONS: The concomitance of pneumoperitoneum and the Trendelenburg position can increase ICP as estimated with non-invasive methods. In high-risk patients undergoing laparoscopic procedures, non-invasive ICP monitoring through a combination of ONSD ultrasonography and TCD-derived ICPFVd could be a valid option to assess the risk of increased ICP. PMID- 27956678 TI - Trainee anaesthetist diagnosis of intraneural injection-a study comparing B-mode ultrasound with the fusion of B-mode and elastography in the soft embalmed Thiel cadaver model. AB - BACKGROUND: The incidence of intraneural injection during trainee anaesthetist ultrasound guided nerve block varies between 16% in experts and up to 35% in trainees. We hypothesized that elastography, an ultrasound-based technology that presents colour images of tissue strain, had the potential to improve trainee diagnosis of intraneural injection during UGRA, when integrated with B-Mode ultrasound onto a single image. METHODS: We recorded 40 median nerve blocks randomly allocated to 0.25 ml, 0.5 ml, 1 ml volumes to five sites, on both arms of two soft embalmed cadavers, using a dedicated B-Mode ultrasound and elastography transducer. We wrote software to fuse elastogram and B-Mode videos, then asked 20 trainee anaesthetists whether injection was intraneural or extraneural when seeing B-Mode videos, adjacent B-Mode and elastogram videos, fusion elastography videos or repeated B-Mode ultrasound videos. RESULTS: Fusion elastography improved the diagnosis of intraneural injection compared with B-Mode ultrasound, Diagnostic Odds Ratio (DOR) (95%CI) 21.7 (14.5 - 33.3) vs DOR 7.4 (5.2 - 10.6), P < 0.001. Compared with extraneural injection, intraneural injection was identified on fusion elastography as a distinct, brighter translucent image, geometric ratio 0.33 (95%CI: 0.16 - 0.49) P < 0.001. Fusion elastography was associated with greater trainee diagnostic confidence, OR (95%CI) 1.89 (1.69 - 2.11), P < 0.001, and an improvement in reliability, Kappa 0.60 (0.55 - 0.66). CONCLUSIONS: Fusion elastography improved the accuracy, reliability and confidence of trainee anaesthetist diagnosis of intraneural injection. PMID- 27956680 TI - Analgesic efficacy of bilateral continuous transversus abdominis plane blocks using an oblique subcostal approach in patients undergoing laparotomy for gynaecological cancer: a prospective, randomized, triple-blind, placebo controlled study. AB - BACKGROUND: The analgesic efficacy of continuous transversus abdominis plane (TAP) blocks in comparison with that of single-injection TAP blocks is not clear. This randomized, triple-blind, placebo-controlled trial investigated the benefits of adding continuous TAP blocks to single-injection TAP blocks after a laparotomy. METHODS: Eighty consecutive patients undergoing midline laparotomy for gynaecological cancer were randomized and received bilateral TAP infusions with either ropivacaine 0.1% (n=40, Rop group) or normal saline (n=40, NS group) at 10 ml h-1 per side for 50 h after surgery. After surgery, bilateral oblique subcostal TAP blocks were performed using ropivacaine 0.1%, 50 ml per side, and then catheters were threaded into the bilateral TAPs. Subsequently, continuous TAP infusions and patient-controlled i.v. morphine administration were initiated. The primary outcome was cumulative morphine consumption by 24 h after TAP catheter placement. Secondary outcomes included pain scores, postoperative nausea and vomiting severity, and time to first ambulation and flatus. RESULTS: The cumulative morphine consumption (median [interquartile range]) 24 h after TAP catheter placement was lower in the Rop group (0.25 [0.11-0.48] mg kg-1) than in the NS group (0.44 [0.24-0.73] mg kg-1; 95% confidence interval difference in medians, -0.30 to - 0.03; P=0.01). No statistically significant differences were observed in the secondary outcomes, except for reduced pain scores in the Rop group obtained during coughing 1 and 24 h after TAP catheter placement. CONCLUSIONS: Addition of continuous TAP blocks to single-injection TAP blocks reduces pain and morphine consumption after a laparotomy for gynaecological cancer. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry identification number UMIN000013449 (http://www.umin.ac.jp/ctr/index.htm). PMID- 27956681 TI - Interactions between veno-venous extracorporeal membrane oxygenation and cardiac function: an echocardiographic study upon weaning. PMID- 27956679 TI - Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial. AB - BACKGROUND: Previous animal and clinical studies showed that nitrous oxide may produce long-term analgesia. The aim of this study was to evaluate the effect of nitrous oxide in preventing chronic postsurgical pain. We also explored whether methylenetetrahydrofolate reductase gene polymorphisms (1298A>C, 667C>T) would enhance nitrous oxide analgesia. METHODS: We conducted a telephone interview at 12 months after surgery on 2924 (41.1%) patients enrolled in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia-II trial. Pain at the wound site was recorded using the modified brief pain inventory and the neuropathic pain questionnaire. General health status was measured using the EQ-5D questionnaire. Genotyping was performed in a subset of 674 Asian patients in Hong Kong. RESULTS: At 12 months after surgery, 356 (12.2%) patients reported chronic postsurgical pain at the wound site and 112 (3.8%) patients had severe pain and required regular analgesic interventions. Nitrous oxide did not affect the rate of chronic postsurgical pain (11.8% nitrous oxide group; 12.5% no nitrous oxide group), relative risk (95% confidence intervals): 0.94 (0.75-1.17), P=0.57. However, in a planned subgroup analysis, nitrous oxide reduced the risk of chronic postsurgical pain in Asian patients, relative risk (95% confidence intervals): 0.70 (0.50 0.98), P=0.031. Patients who were homozygous for either gene polymorphism and who received nitrous oxide during surgery were less likely to report chronic postsurgical pain. CONCLUSIONS: Nitrous oxide administration had no impact on chronic postsurgical pain, but benefits may still be possible in Asian patients and patients with variants in methylenetetrahydrofolate reductase gene. CLINICAL TRIAL REGISTRATION: NCT00430989. PMID- 27956682 TI - Upper trunk block: description of a supraclavicular approach of upper trunk at the points of its division. PMID- 27956683 TI - Association between the availability of videolaryngoscopes and the incidence of emergency surgical airway in the perioperative setting of a large academic medical centre: a retrospective observational study. PMID- 27956684 TI - The trend interchangeability method. PMID- 27956685 TI - Objective description of mask ventilation. PMID- 27956686 TI - Multidisciplinary management to decrease perioperative complications in senile patients with hypoxaemia in high altitudes during primary hip arthroplasty: data from our cohort study. PMID- 27956687 TI - Subscapularis and sub-omohyoid plane blocks: an alternative to peripheral nerve blocks for shoulder analgesia. PMID- 27956688 TI - Evaluation of artery and vein differentiation methods using ultrasound imaging among medical students. PMID- 27956689 TI - Unusual position of J-guide wire during ultrasound-guided subclavian vein catheterization. PMID- 27956690 TI - Ultrasound-guided posterior cord and selective suprascapular block for shoulder surgery. PMID- 27956691 TI - "Oh excellent air bag" under the influence of nitrous oxide, 1799-1920. PMID- 27956692 TI - The impact of the acute respiratory distress syndrome on outcome after oesophagectomy. PMID- 27956696 TI - Targeting the Nuclear Cathepsin L CCAAT Displacement Protein/Cut Homeobox Transcription Factor-Epithelial Mesenchymal Transition Pathway in Prostate and Breast Cancer Cells with the Z-FY-CHO Inhibitor. AB - The epithelial mesenchymal transition (EMT) promotes tumor migration and invasion by downregulating epithelial markers such as E-cadherin and upregulating mesenchymal markers such as vimentin. Cathepsin L (Cat L) is a cysteine protease that can proteolytically activate CCAAT displacement protein/cut homeobox transcription factor (CUX1). We hypothesized that nuclear Cat L may promote EMT via CUX1 and that this could be antagonized with the Cat L-specific inhibitor Z FY-CHO. Mesenchymal prostate (ARCaP-M and ARCaP-E overexpressing Snail) and breast (MDA-MB-468, MDA-MB-231, and MCF-7 overexpressing Snail) cancer cells expressed lower E-cadherin activity, higher Snail, vimentin, and Cat L activity, and a p110/p90 active CUX1 form, compared to epithelial prostate (ARCaP-E and ARCaP-Neo) and breast (MCF-7 and MCF-7 Neo) cancer cells. There was increased binding of CUX1 to Snail and the E-cadherin promoter in mesenchymal cells compared to epithelial prostate and breast cells. Treatment of mesenchymal cells with the Cat L inhibitor Z-FY-CHO led to nuclear-to-cytoplasmic relocalization of Cat L, decreased binding of CUX1 to Snail and the E-cadherin promoter, reversed EMT, and decreased cell migration/invasion. Overall, our novel data suggest that a positive feedback loop between Snail-nuclear Cat L-CUX1 drives EMT, which can be antagonized by Z-FY-CHO. Therefore, Z-FY-CHO may be an important therapeutic tool to antagonize EMT and cancer progression. PMID- 27956698 TI - Blockade of Metallothioneins 1 and 2 Increases Skeletal Muscle Mass and Strength. AB - Metallothioneins are proteins that are involved in intracellular zinc storage and transport. Their expression levels have been reported to be elevated in several settings of skeletal muscle atrophy. We therefore investigated the effect of metallothionein blockade on skeletal muscle anabolism in vitro and in vivo We found that concomitant abrogation of metallothioneins 1 and 2 results in activation of the Akt pathway and increases in myotube size, in type IIb fiber hypertrophy, and ultimately in muscle strength. Importantly, the beneficial effects of metallothionein blockade on muscle mass and function was also observed in the setting of glucocorticoid addition, which is a strong atrophy-inducing stimulus. Given the blockade of atrophy and the preservation of strength in atrophy-inducing settings, these results suggest that blockade of metallothioneins 1 and 2 constitutes a promising approach for the treatment of conditions which result in muscle atrophy. PMID- 27956697 TI - Epithelial Hypoxia-Inducible Factor 2alpha Facilitates the Progression of Colon Tumors through Recruiting Neutrophils. AB - Inflammation is a significant risk factor for colon cancer. Recent work has demonstrated essential roles for several infiltrating immune populations in the metaplastic progression following inflammation. Hypoxia and stabilization of hypoxia-inducible factors (HIFs) are hallmark features of inflammation and solid tumors. Previously, we demonstrated an important role for tumor epithelial HIF 2alpha in colon tumors; however, the function of epithelial HIF-2alpha as a critical link in the progression of inflammation to cancer has not been elucidated. In colitis-associated colon cancer models, epithelial HIF-2alpha was essential in tumor growth. Concurrently, epithelial disruption of HIF-2alpha significantly decreased neutrophils in the colon tumor microenvironment. Intestinal epithelial HIF-2alpha-overexpressing mice demonstrated that neutrophil recruitment was a direct response to increased epithelial HIF-2alpha signaling. High-throughput RNA sequencing (RNA-seq) analysis of HIF-2alpha-overexpressing mice in conjunction with data mining from the Cancer Genome Atlas showed that the neutrophil chemokine CXCL1 gene was highly upregulated in colon tumor epithelium in a HIF-2alpha-dependent manner. Using selective peptide inhibitors of the CXCL1 CXCR2 signaling axis identified HIF-2alpha-dependent neutrophil recruitment as an essential mechanism to increase colon carcinogenesis. These studies demonstrate that HIF-2alpha is a novel regulator of neutrophil recruitment to colon tumors and that it is essential in shaping the protumorigenic inflammatory microenvironment in colon cancer. PMID- 27956699 TI - Dormant Pluripotent Cells Emerge during Neural Differentiation of Embryonic Stem Cells in a FoxO3-Dependent Manner. AB - One major concern over the clinical application of embryonic stem cell (ESC) derived cells is the potentiation of latent tumorigenicity by residual undifferentiated cells. Despite the use of intensive methodological approaches to eliminate residual undifferentiated cells, the properties of these cells remain elusive. Here, we show that under a serum-free neural differentiation condition, residual undifferentiated cells markedly delay progression of their cell cycle without compromising their pluripotency. This dormant pluripotency was maintained during reculture of the cells under a serum-free condition, whereas upon serum stimulation, the cells exited the dormant state and restarted proliferation and differentiation into all three germ layers. Microarray analysis revealed a set of genes that is significantly upregulated in the dormant ESCs compared with their levels of regulation in proliferating ESCs. Among them, we identified the transcription factor Forkhead box O3 (FoxO3) to be an essential regulator of the maintenance of pluripotency in dormant ESCs. Our study demonstrates that the transition into the dormant state endows residual undifferentiated cells with FoxO3-dependent and leukemia inhibitory factor/serum-independent pluripotency. PMID- 27956700 TI - mTORC1 and -2 Coordinate Transcriptional and Translational Reprogramming in Resistance to DNA Damage and Replicative Stress in Breast Cancer Cells. AB - mTOR coordinates growth signals with metabolic pathways and protein synthesis and is hyperactivated in many human cancers. mTOR exists in two complexes: mTORC1, which stimulates protein, lipid, and ribosome biosynthesis, and mTORC2, which regulates cytoskeleton functions. While mTOR is known to be involved in the DNA damage response, little is actually known regarding the functions of mTORC1 compared to mTORC2 in this regard or the respective impacts on transcriptional versus translational regulation. We show that mTORC1 and mTORC2 are both required to enact DNA damage repair and cell survival, resulting in increased cancer cell survival during DNA damage. Together mTORC1 and -2 enact coordinated transcription and translation of protective cell cycle and DNA replication, recombination, and repair genes. This coordinated transcriptional-translational response to DNA damage was not impaired by rapalog inhibition of mTORC1 or independent inhibition of mTORC1 or mTORC2 but was blocked by inhibition of mTORC1/2. Only mTORC1/2 inhibition reversed cancer cell resistance to DNA damage and replicative stress and increased tumor cell killing and tumor control by DNA damage therapies in animal models. When combined with DNA damage, inhibition of mTORC1/2 blocked transcriptional induction more strongly than translation of DNA replication, survival, and DNA damage response mRNAs. PMID- 27956701 TI - The Chromatin-Associated Phf12 Protein Maintains Nucleolar Integrity and Prevents Premature Cellular Senescence. AB - Pf1, also known as Phf12 (plant homeodomain [PHD] zinc finger protein 12), is a member of the PHD zinc finger family of proteins. Pf1 associates with a chromatin interacting protein complex comprised of MRG15, Sin3B, and histone deacetylase 1 (HDAC1) that functions as a transcriptional modulator. The biological function of Pf1 remains largely elusive. We undertook the generation of Pf1 knockout mice to elucidate its physiological role. We demonstrate that Pf1 is required for mid- to late gestation viability. Pf1 inactivation impairs the proliferative potential of mouse embryonic fibroblasts (MEFs) and is associated with a significant decrease in bromodeoxyuridine incorporation; an increase in senescence-associated beta galactosidase (SA-beta-Gal) activity, a marker of cellular senescence; and elevated levels of phosphorylated H2AX (gamma-H2A.X), a marker associated with DNA double-strand breaks. Analysis of transcripts differentially expressed in wild-type and Pf1-deficient cells revealed the impact of Pf1 in multiple regulatory arms of the ribosome biogenesis pathways. Strikingly, assessment of the morphology of the nucleoli exposed an abnormal nucleolar structure in Pf1 deficient cells. Finally, proteomic analysis of the Pf1-interacting complexes highlighted proteins involved in ribosome biogenesis. Taken together, our data reveal an unsuspected function for the Pf1-associated chromatin complex in the ribosomal biogenesis and senescence pathways. PMID- 27956702 TI - Snail-Modulated MicroRNA 493 Forms a Negative Feedback Loop with the Insulin-Like Growth Factor 1 Receptor Pathway and Blocks Tumorigenesis. AB - In this study, we have identified one microRNA, microRNA 493 (miR-493), which could simultaneously and directly regulate multiple genes downstream of the insulin-like growth factor 1 receptor (IGF1R) pathway, including IGF1R, by binding with complementary sequences in the 3' untranslated region (UTR) of mRNAs of IGF1R, insulin receptor substrate 1 (IRS1), and mitogen-activated protein kinase 1 (MAPK1), thereby potentiating their inhibitory function at multiple levels in development and progression of cancers. This binding was further confirmed by pulldown of miR with AGO-2 antibody. Further, results from head and neck samples showed that miR-493 levels were significantly downregulated in tumors, with a concomitant increase in the expression of IGF1R and key downstream effectors. Functional studies from miR-493 overexpression cells and nude-mouse models revealed the tumor suppressor functions of miR-493. Regulation studies revealed that Snail binds to the miR-493 promoter and represses it. We found the existence of a dynamic negative feedback loop in the regulation of IGF1R and miR 493 mediated via Snail. Our study showed that nicotine treatment significantly decreases the levels of miR-493-with a concomitant increase in the levels of Snail-an indication of progression of cells toward tumorigenesis, reestablishing the role of tobacco as a major risk factor for head and neck cancers and elucidating the mechanism behind nicotine-mediated tumorigenesis. PMID- 27956706 TI - Evaluating HER2 in Gastroesophageal Cancer. AB - New evidence-based guidelines for HER2 testing in patients with gastroesophageal adenocarcinoma aim to improve treatment by determining who might benefit from targeted therapies. PMID- 27956704 TI - Tgif1 and Tgif2 Repress Expression of the RabGAP Evi5l. AB - Mouse embryos conditionally lacking Tgif1 and Tgif2 have holoprosencephaly and defects in left-right asymmetry. To identify pathways affected by loss of Tgif function during embryogenesis, we performed transcriptome profiling on whole mouse embryos. Among the genes with altered expression in embryos lacking Tgifs were a number with links to cilium function. One of these, Evi5l, encodes a RabGAP that is known to block the formation of cilia when overexpressed. Evi5l expression is increased in Tgif1; Tgif2-null embryos and in double-null mouse embryo fibroblasts (MEFs). Knockdown of Tgifs in a human retinal pigment epithelial cell line also increased EVI5L expression. We show that TGIF1 binds to a conserved consensus TGIF site 5' of the human and mouse Evi5l genes and represses Evi5l expression. In primary MEFs lacking both Tgifs, the number of cells with primary cilia was significantly decreased, and we observed a reduction in the transcriptional response to Shh pathway activation. Reducing Evi5l expression in MEFs lacking Tgifs resulted in a partial restoration of cilium numbers and in the transcriptional response to activation of the Shh pathway. In summary, this work shows that Tgifs regulate ciliogenesis and suggests that Evi5l mediates at least part of this effect. PMID- 27956703 TI - Astrocyte Elevated Gene 1 Interacts with Acetyltransferase p300 and c-Jun To Promote Tumor Aggressiveness. AB - Astrocyte elevated gene 1 (AEG-1) is an oncoprotein that strongly promotes the development and progression of cancers. However, the detailed underlying mechanisms through which AEG-1 enhances tumor development and progression remain to be determined. In this study, we identified c-Jun and p300 to be novel interacting partners of AEG-1 in gliomas. AEG-1 promoted c-Jun transcriptional activity by interacting with the c-Jun/p300 complex and inducing c-Jun acetylation. Furthermore, the AEG-1/c-Jun/p300 complex was found to bind the promoter of c-Jun downstream targeted genes, consequently establishing an acetylated chromatin state that favors transcriptional activation. Importantly, AEG-1/p300-mediated c-Jun acetylation resulted in the development of a more aggressive malignant phenotype in gliomas through a drastic increase in glioma cell proliferation and angiogenesis in vitro and in vivo Consistently, the AEG-1 expression levels in clinical glioma specimens correlated with the status of c Jun activation. Taken together, our results suggest that AEG-1 mediates a novel epigenetic mechanism that enhances c-Jun transcriptional activity to induce glioma progression and that AEG-1 might be a novel, potential target for the treatment of gliomas. PMID- 27956705 TI - ArfGAP Domain-Containing Protein 2 (ADAP2) Integrates Upstream and Downstream Modules of RIG-I Signaling and Facilitates Type I Interferon Production. AB - Transcription of type I interferon genes during RNA virus infection requires signal communication between several pattern recognition receptor (PRR)-adaptor complexes located at distinct subcellular membranous compartments and a central cytoplasmic TBK1-interferon regulatory factor 3 (IRF3) kinase-transcription factor module. However, how the cell integrates signal transduction through spatially distinct modules of antiviral signaling pathways is less defined. RIG-I is a major cytosolic PRR involved in the control of several RNA viruses. Here we identify ArfGAP domain-containing protein 2 (ADAP2) as a key novel scaffolding protein that integrates different modules of the RIG-I pathway, located at distinct subcellular locations, and mediates cellular antiviral type I interferon production. ADAP2 served to bridge the mitochondrial membrane-bound upstream RIG I adaptor MAVS and the downstream cytosolic complex of NEMO (regulatory subunit of TBK1), TBK1, and IRF3, leading to IRF3 phosphorylation. Furthermore, independently, ADAP2 also functioned as a major orchestrator of the interaction of TBK1 with NEMO and IRF3. Mutational and in vitro cell-free reconstituted RIG-I signaling assay-based analyses identified that the ArfGAP domain of ADAP2 mediates the interferon response. TRAF3 acted as a trigger for ADAP2 to recruit RIG-I pathway component proteins into a single macromolecular complex. This study provides important novel insights into the assembly and integration of different modules of antiviral signaling cascades. PMID- 27956708 TI - Structural Analysis of Variable Domain Glycosylation of Anti-Citrullinated Protein Antibodies in Rheumatoid Arthritis Reveals the Presence of Highly Sialylated Glycans. AB - Recently, we showed the unexpectedly high abundance of N-linked glycans on the Fab-domain of Anti-Citrullinated Protein Antibodies (ACPA). As N-linked glycans can mediate a variety of biological functions, we now aimed at investigating the structural composition of the Fab-glycans of ACPA-IgG to better understand their mediated biological effects. ACPA-IgG and noncitrulline specific (control) IgG from plasma and/or synovial fluid of nine ACPA positive rheumatoid arthritis patients were affinity purified. The N-linked glycosylation of total, Fc and F(ab')2 fragments, as well as heavy and light chains of ACPA-IgG and control IgG were analyzed by UHPLC and MALDI-TOF mass spectrometry. The Fc-glycosylation of ACPA-IgG and IgG was analyzed at the glycopeptide level using LC-MS. The structural analyses revealed that ACPA-IgG molecules contain highly sialylated glycans in their Fab-domain. Importantly, Fab-glycans were estimated to be present on over 90% of ACPA-IgG, which is five times higher than in control IgG isolated from the same patients. This feature was more prominent on ACPA isolated from synovial fluid compared with peripheral blood. These observations provide the first evidence pointing to the ability of ACPA-IgG to mediate novel immunological activities, for example through binding specific lectins via hyper sialylated Fab-glycans. PMID- 27956709 TI - Surgical Repair of Congenital Left Atrial Aneurysm and Mitral Valve Insufficiency in a Four-Year-Old Child. AB - Left atrial aneurysm is an extremely rare anomaly, which can be associated with supraventricular arrhythmia, compression of coronary arteries, intracardiac thrombus, life-threatening systemic embolization, pulmonary venous obstruction, mitral valve insufficiency, and congestive heart failure. Herein, we report a four-year-old boy who had a giant aneurysm of the left atrium and severe mitral regurgitation. The aneurysm and mitral valve cleft causing severe mitral regurgitation were successfully repaired. PMID- 27956707 TI - A Luciferase-fragment Complementation Assay to Detect Lipid Droplet-associated Protein-Protein Interactions. AB - A critical challenge for all organisms is to carefully control the amount of lipids they store. An important node for this regulation is the protein coat present at the surface of lipid droplets (LDs), the intracellular organelles dedicated to lipid storage. Only limited aspects of this regulation are understood so far. For the probably best characterized case, the regulation of lipolysis in mammals, some of the major protein players have been identified, and it has been established that this process crucially depends on an orchestrated set of protein-protein interactions. Proteomic analysis has revealed that LDs are associated with dozens, if not hundreds, of different proteins, most of them poorly characterized, with even fewer data regarding which of them might physically interact. To comprehensively understand the mechanism of lipid storage regulation, it will likely be essential to define the interactome of LD associated proteins.Previous studies of such interactions were hampered by technical limitations. Therefore, we have developed a split-luciferase based protein-protein interaction assay and test for interactions among 47 proteins from Drosophila and from mouse. We confirmed previously described interactions and identified many new ones. In 1561 complementation tests, we assayed for interactions among 487 protein pairs of which 92 (19%) resulted in a successful luciferase complementation. These results suggest that a prominent fraction of the LD-associated proteome participates in protein-protein interactions.In targeted experiments, we analyzed the two proteins Jabba and CG9186 in greater detail. Jabba mediates the sequestration of histones to LDs. We successfully applied our split luciferase complementation assay to learn more about this function as we were e.g. able to map the interaction between Jabba and histones. For CG9186, expression levels affect the positioning of LDs. Here, we reveal the ubiquitination of CG9186, and link this posttranslational modification to LD cluster induction. PMID- 27956711 TI - Correction: GDF11/BMP11 activates both smad1/5/8 and smad2/3 signals but shows no significant effect on proliferation and migration of human umbilical vein endothelial cells. PMID- 27956710 TI - Birth mass is the key to understanding the negative correlation between lifespan and body size in dogs. AB - Larger dog breeds live shorter than the smaller ones, opposite of the mass lifespan relationship observed across mammalian species. Here we use data from 90 dog breeds and a theoretical model based on the first principles of energy conservation and life history tradeoffs to explain the negative correlation between longevity and body size in dogs. We found that the birth/adult mass ratio of dogs scales negatively with adult size, which is different than the weak interspecific scaling in mammals. Using the model, we show that this ratio, as an index of energy required for growth, is the key to understanding why the lifespan of dogs scales negatively with body size. The model also predicts that the difference in mass-specific lifetime metabolic energy usage between dog breeds is proportional to the difference in birth/adult mass ratio. Empirical data on lifespan, body mass, and metabolic scaling law of dogs strongly supports this prediction. PMID- 27956714 TI - Auranofin Suppresses Plasminogen Activator Inhibitor-2 Expression through Annexin A5 Induction in Human Prostate Cancer Cells. AB - Auranofin has been developed as antirheumatic drugs, which is currently under clinical development for the treatment of chronic lymphocytic leukemia. Previous report showed that auranofin induced apoptosis by enhancement of annexin A5 expression in PC-3 cells. To understand the role of annexin A5 in auranofin mediated apoptosis, we performed microarray data analysis to study annexin A5 controlled gene expression in annexin A5 knockdown PC-3 cells. Of differentially expressed genes, plasminogen activator inhibitor (PAI)-2 was increased by annexin A5 siRNA confirmed by qRT-PCR and western blot. Treatment with auranofin decreased PAI-2 and increased annexin A5 expression as well as promoting apoptosis. Furthermore, auranofin-induced apoptosis was recovered by annexin A5 siRNA but it was promoted by PAI-2 siRNA. Interestingly, knockdown of annexin A5 rescued PAI-2 expression suppressed by auranofin. Taken together, our study suggests that induction of annexin A5 by auranofin may enhance apoptosis through suppression of PAI-2 expression in PC-3 cells. PMID- 27956713 TI - Characterization of a Biflaviolin Synthase CYP158A3 from Streptomyces avermitilis and Its Role in the Biosynthesis of Secondary Metabolites. AB - Streptomyces avermitilis produces clinically useful drugs such as avermectins and oligomycins. Its genome contains approximately 33 cytochrome P450 genes and they seem to play important roles in the biosynthesis of many secondary metabolites. The SAV_7130 gene from S. avermitilis encodes CYP158A3. The amino acid sequence of this enzyme has high similarity with that of CYP158A2, a biflaviolin synthase from S. coelicolor A3(2). Recombinant S. avermitilis CYP158A3 was heterologously expressed and purified. It exhibited the typical P450 Soret peak at 447 nm in the reduced CO-bound form. Type I binding spectral changes were observed when CYP158A3 was titrated with myristic acid; however, no oxidative product was formed. An analog of flaviolin, 2-hydroxynaphthoquinone (2-OH NQ) displayed similar type I binding upon titration with purified CYP158A3. It underwent an enzymatic reaction forming dimerized product. A homology model of CYP158A3 was superimposed with the structure of CYP158A2, and the majority of structural elements aligned. These results suggest that CYP158A3 might be an orthologue of biflaviolin synthase, catalyzing C-C coupling reactions during pigment biosynthesis in S. avermitilis. PMID- 27956712 TI - Induction of Integrin Signaling by Steroid Sulfatase in Human Cervical Cancer Cells. AB - Steroid sulfatase (STS) is an enzyme responsible for the hydrolysis of aryl and alkyl sulfates. STS plays a pivotal role in the regulation of estrogens and androgens that promote the growth of hormone-dependent tumors, such as those of breast or prostate cancer. However, the molecular function of STS in tumor growth is still not clear. To elucidate the role of STS in cancer cell proliferation, we investigated whether STS is able to regulate the integrin signaling pathway. We found that overexpression of STS in HeLa cells increases the protein and mRNA levels of integrin beta1 and fibronectin, a ligand of integrin alpha5beta1. Dehydroepiandrosterone (DHEA), one of the main metabolites of STS, also increases mRNA and protein expression of integrin beta1 and fibronectin. Further, STS expression and DHEA treatment enhanced phosphorylation of focal adhesion kinase (FAK) at the Tyr 925 residue. Moreover, increased phosphorylation of ERK at Thr 202 and Tyr 204 residues by STS indicates that STS activates the MAPK/ ERK pathway. In conclusion, these results suggest that STS expression and DHEA treatment may enhance MAPK/ERK signaling through up-regulation of integrin beta1 and activation of FAK. PMID- 27956715 TI - Intravenous Administration of Substance P Attenuates Mechanical Allodynia Following Nerve Injury by Regulating Neuropathic Pain-Related Factors. AB - This study aimed to investigate the analgesic effect of substance P (SP) in an animal model of neuropathic pain. An experimental model of neuropathic pain, the chronic constriction injury (CCI) model, was established using ICR mice. An intravenous (i.v.) injection of SP (1 nmole/kg) was administered to the mice to examine the analgesic effects of systemic SP on neuropathic pain. Behavioral testing and immunostaining was performed following treatment of the CCI model with SP. SP attenuated mechanical allodynia in a time-dependent manner, beginning at 1 h following administration, peaking at 1 day post-injection, and decaying by 3 days post-injection. The second injection of SP also increased the threshold of mechanical allodynia, with the effects peaking on day 1 and decaying by day 3. A reduction in phospho-ERK and glial fibrillary acidic protein (GFAP) accompanied the attenuation of mechanical allodynia. We have shown for the first time that i.v. administration of substance P attenuated mechanical allodynia in the maintenance phase of neuropathic pain using von Frey's test, and simultaneously reduced levels of phospho-ERK and GFAP, which are representative biochemical markers of neuropathic pain. Importantly, glial cells in the dorsal horn of the spinal cord (L4- L5) of SP-treated CCI mice, expressed the anti-inflammatory cytokine, IL-10, which was not seen in vehicle saline-treated mice. Thus, i.v. administration of substance P may be beneficial for improving the treatment of patients with neuropathic pain, since it decreases the activity of nociceptive factors and increases the expression of anti-nociceptive factors. PMID- 27956719 TI - "The Possible Innovative Use of Bifidobacterium longum W11 in Association With Rifaximin: A New Horizon for Combined Approach?": Erratum. PMID- 27956717 TI - Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors. AB - Desensitization and acute tolerance are terms used to describe the attenuation of receptor responsiveness by prolonged or intermittent exposure to an agonist. Unlike desensitization of G protein-coupled receptors (GPCRs), which is commonly explained by steric hindrance caused by the beta-arrestins that are translocated to the activated receptors, molecular mechanisms involved in the acute tolerance of GPCRs remain unclear. Our studies with several GPCRs and related mutants showed that the acute tolerance of GPCRs could occur independently of agonist induced beta-arrestin translocation. A series of co-immunoprecipitation experiments revealed a correlation between receptor tolerance and interactions among receptors, beta-arrestin2, and Gbetagamma. Gbetagamma displayed a stable interaction with receptors and beta-arrestin2 in cells expressing GPCRs that were prone to undergo tolerance compared to the GPCRs that were resistant to acute tolerance. Strengthening the interaction between Gbetagamma and beta-arrestin rendered the GPCRs to acquire the tendency of acute tolerance. Overall, stable interaction between the receptor and Gbetagamma complex is required for the formation of a complex with beta-arrestin, and determines the potential of a particular GPCR to undergo acute tolerance. Rather than turning off the signal, beta-arrestins seem to contribute on continuous signaling when they are in the context of complex with receptor and Gbetagamma. PMID- 27956718 TI - Rising Incidence of Colorectal Cancer Among Young Hispanics in Texas. AB - GOALS: To investigate trends in colorectal cancer (CRC) incidence and survival among Hispanics in Texas. BACKGROUND: The incidence of CRC is rising among young adults in the United States. Given Texas' large Hispanic population, investigating CRC trends in Texas may provide valuable insight into the future of CRC epidemiology in an ever-diversifying US population. STUDY: Data from the Texas Cancer Registry (1995 to 2010) were used to calculate age-adjusted CRC rates based on the 2000 US standard population. Annual percentage change (APC) and 5-year cancer-specific survival (CSS) rates were reported by age, race/ethnicity, stage, and anatomic location. RESULTS: Of 123,083 CRC cases, 11% occurred in individuals below 50 years old, 26% of whom were Hispanic. Incidence was highest among African Americans (AAs; 76.3/100,000), followed by non-Hispanic whites (NHWs; 60.2/100,000) and Hispanics (50.8/100,000). Although overall CRC incidence declined between 1995 and 2010 (APC, -1.8%; P<0.01), trends differed by age and race/ethnicity. Among individuals 50 years and above, the rate of decline was statistically significant among NHWs (APC, -2.4%; P<0.01) and AAs (APC, 1.3%; P<0.01) but not among Hispanics (APC, -0.6%; P=0.13). In persons aged 20 to 39 years, CRC incidence rose significantly among Hispanics (APC, 2.6%; P<0.01) and NHWs (APC, 2.4%; P<0.01), but not AAs (APC, 0.3%; P=0.75). CSS rates among Hispanics and NHWs were comparable across most age groups and cancer stages, whereas CSS rates among AAs were generally inferior to those observed among NHWs and Hispanics. CONCLUSIONS: Although CRC incidence has declined in Texas, it is rising among young Hispanics and NHWs while declining more slowly among older Hispanics than among older NHWs and AAs. PMID- 27956716 TI - Therapeutic Potential of Medicinal Plants and Their Constituents on Lung Inflammatory Disorders. AB - Acute bronchitis and chronic obstructive pulmonary diseases (COPD) are essentially lung inflammatory disorders. Various plant extracts and their constituents showed therapeutic effects on several animal models of lung inflammation. These include coumarins, flavonoids, phenolics, iridoids, monoterpenes, diterpenes and triterpenoids. Some of them exerted inhibitory action mainly by inhibiting the mitogen-activated protein kinase pathway and nuclear transcription factor-kappaB activation. Especially, many flavonoid derivatives distinctly showed effectiveness on lung inflammation. In this review, the experimental data for plant extracts and their constituents showing therapeutic effectiveness on animal models of lung inflammation are summarized. PMID- 27956720 TI - Indication for and Limitation of the Facial Dismasking Flap Approach for Skull Base Surgery to Achieve the Best Esthetical and Functional Results. AB - BACKGROUND: The facial dismasking flap (FDF) approach to operations on the deep skull base region consists of a coronal incision and a circumpalpebral incision. This approach provides a wide surgical field for extirpation of deep extended craniofacial tumors without leaving any undesirable scars on the face. Therefore, the FDF approach can provide satisfactory esthetical and functional results. Meanwhile, in some cases, especially in patients with a history of skull base surgery or orbital extension, patients are not fully satisfied even when the FDF approach is used. In this study, we evaluated the indication for and limitation of the FDF approach. METHODS: We reviewed 26 patients who underwent the FDF approach for skull base surgery. The patients were 16 men and 10 women, and average age was 37 years. Of these patients, 21 were treated using a hemi-FDF approach, and the remaining 5 were subjected to a bilateral FDF approach. Patients were divided into 2 groups in this study: group A (11 patients), patients with no history of skull base surgery and orbital extension; and group B (15 patients), patients with a history of skull base surgery and/or orbital extension. RESULTS: There was no FDF loss or facial palsy in either group A or group B. In group A, there was no lagophthalmos or scar contracture of the eyelid. In group B, there were 5 cases (33%) of ectropion and lagophthalmos and 7 of eyelid scar contracture (46%). As for esthetical evaluation, group B showed a significantly higher rate of facial asymmetry than group A. Moreover, in group A, the total ratings for above average reached 90.9%, whereas in group B, nearly half of the patients (48.9%) gave ratings of fair and poor. CONCLUSIONS: The FDF approach could be a good option for skull base surgery. In particular, patients without a history of skull base surgery and orbital extension could obtain satisfactory esthetical and functional outcomes. However, the procedure had limited effectiveness for patients with a history of skull base surgery or orbital extension because esthetical and functional outcomes inevitably became worse. PMID- 27956721 TI - Otologic and Audiologic Outcomes in Pediatric Patients With Velo-Cardio-Facial (22q11 Deletion) Syndrome. AB - OBJECTIVE: The focus of this study was to evaluate the prevalence, type, and severity of hearing impairment in patients with velo-cardio-facial syndrome (VCFS) and to compare these characteristics with patient demographics and other otologic factors. STUDY DESIGN: Retrospective analysis of the AudGen Database. SETTING: Tertiary academic referral center. PATIENTS: Pediatric patients in AudGenDB with a diagnosis of velo-cardio-facial syndrome or DiGeorge syndrome. INTERVENTIONS: Appropriate audiologic, otologic, and demographic data were recorded. MAIN OUTCOME MEASURE: Four hundred six patients met inclusion criteria. Data for each patient were selected based on their encounters with earliest complete audiometric data, and hearing loss (HL) was defined as greater than 15 dB HL at any threshold by pure tone or greater than 20 dB HL by soundfield audiometry. The patients were then stratified by type and severity of HL, and available otologic and medical conditions were documented. RESULTS: Two hundred forty eight (60.7%) patients had HL. Of the 391 individual HL ears, 127 had conductive, 22 had sensorineural, 115 had mixed, and 127 had unspecified hearing loss. 57% of the loss was bilateral. Patients with mixed HL had significantly worse pure-tone averages (PTAs). CONCLUSION: HL is prevalent in patients with VCFS. The hearing loss is primarily of conductive origin, with a predisposition to be bilateral, with mixed HL typically have more severe loss. There were a large number of patients with sensorineural hearing loss components as well. Further studies are needed to investigate the causal nature of the hearing impairment in VCFS, to better aid otolaryngologist and audiologists when assessing these patients. PMID- 27956723 TI - The Effect of Scala Tympani Morphology on Basilar Membrane Contact With a Straight Electrode Array: A Human Temporal Bone Study: Erratum. PMID- 27956722 TI - Effect of Goggle Slippage on the Video Head Impulse Test Outcome and Its Mechanisms. AB - OBJECTIVES: The aim of this study was to quantitatively measure the tightness of the goggle strap during the video head impulse test (vHIT) and to identify slippage-induced artifacts according to tightness. We aimed to elucidate the mechanism of faulty gain caused by goggle slippage and explain the typical artifacts associated with it. SUBJECTS AND METHODS: An endotracheal tube cuff manometer was coupled to the EyeSeeCam vHIT system (Interacoustics, Assens, Denmark) to monitor strap tightness. The instantaneous gain (40, 60, and 80 ms) and regression gain were compared in eight healthy subjects under the following strap tightness conditions: loose (25 cm H2O), tight (35 cm H2O), and very tight (45 cm H2O). To elucidate the mechanism of faulty gain caused by goggle slippage, a fake fixed pupil with a vestibule ocular reflex (VOR) gain of 0 was attached to the subject's eyelid. The faulty gain recording pattern was analyzed as the tightness of the strap was decreased. RESULTS: The most common slippage-induced artifacts were: 1) initial backward eye movement toward the head movement, 2) acceleration bumps, 3) high gain, and 4) deceleration bumps. At 40 ms, the gain was significantly lower in the 25 cm H2O condition (0.68 +/- 0.32 cm H2O) compared with the 45 cm H2O condition (0.90 +/- 0.26 cm H2O). At 80 ms, the gain was higher for the 25 cm H2O condition (1.24 +/- 0.27 cm H2O) compared with the 45 cm H2O condition (1.16 +/- 0.30 cm H2O). These findings were progressively more obvious as the tightness of the strap decreased in a dose-dependent manner. When the fake pupil was recorded, initial backward eye movement toward the head movement (negative VOR gain) and eye tracing mimicking a small VOR (positive VOR gain) were recorded, despite the fake pupil having absolutely no movement. These artifact recordings are presumed to be related to the faulty low (40 ms) and high (80 ms) gain calculation. CONCLUSIONS: Slippage-induced artifacts are presumed to be because of the slingshot-like movement of the goggles during head movement in three different phases (lagging, overshooting, and bouncing of the goggles). Monitoring the pressure of the strap tightness may be a solution for minimizing this slippage. A strap tightness of at least 45 cm H2O is required for reliable vHIT recording and gain calculations. PMID- 27956724 TI - Natural Disasters: Planning for Psychological First Aid. AB - Natural disasters leave survivors suffering physically, psychologically, and spiritually. An EF4 tornado on April 27, 2011, in Tuscaloosa, Alabama, known as April's Fury, raised the question of how mental health practitioners (MHPs) might respond to address psychological needs, rather than being exclusively assigned to offer physical support immediately following a disaster. This article proposes planning ahead for MHPs to provide psychological first aid (PFA) in the immediate aftermath of a catastrophe. Combating psychological issues early will hopefully help reduce the development of posttraumatic stress disorder (PTSD) or prolonged grief disorder (PGD) in survivors. PMID- 27956725 TI - Resilience As a Life Practice: Lessons from Mother Seton. AB - One method for developing personal resilience is to listen to the stories of others who developed resilience. This article highlights the elements of spiritual practice, relationships, and education, as experienced by the first American saint, Elizabeth Ann Seton. Seton worked through immense suffering, demonstrating integration, adjustment, and growth. Her life story is an example of resilience as a practice that nurses can learn from today. PMID- 27956726 TI - Effect of Surgery Start Time on Day of Discharge in Anterior Cervical Discectomy and Fusion Patients. AB - STUDY DESIGN: Retrospective cohort. OBJECTIVE: To compare time to discharge for anterior cervical discectomy and fusions (ACDF) when performed as either a first case versus later surgical start times. SUMMARY OF BACKGROUND DATA: ACDF is a commonly performed spinal procedure that typically has a short acute recovery period. With an increasing focus on reducing hospital costs and a shift toward outpatient surgical practices, early patient discharge has become a priority for hospitals and physicians alike. However, the impact of surgery start time on the ability for same-day discharge has not been explored in spine surgery. METHODS: A surgical database of patients who underwent ACDF from 2013 to 2015 was reviewed. Patients were stratified into two cohorts: those whose surgery was the first of the day (early cohort), and those who underwent later surgeries. Baseline patient characteristics and perioperative variables were compared between cohorts using Student t test and chi test. Same-day discharge was tested for association with surgical start time using Poisson regression with robust error variance controlling for preoperative variables. RESULTS: A total of 106 patients, divided into early and late cohorts of 60 and 46 patients, respectively, were included in the analysis. There were no significant differences in pre- or perioperative characteristics between cohorts (). Same-day discharge was achieved in 36.8% (n = 39) of all ACDF patients. The later cohort was significantly more likely to require an overnight stay compared with the early cohort (RR = 1.61 +/- 0.30; P = 0.010).(Table is included in full-text article.)CONCLUSION.: Patients undergoing ACDF later in the day are at a higher risk for staying overnight than those who have the first surgery of the day. These results may influence operative scheduling, as performing ACDFs early in the day may result in a greater likelihood of same-day discharge, eliminating the increased resource utilization associated with an overnight hospital stay. LEVEL OF EVIDENCE: 4. PMID- 27956728 TI - Kingella Kingae Chest Mass Mimicking a Tumor in an 11-Month-Old Baby. AB - Kingella kingae has been recognized as a common etiology of pediatric osteoarticular infections, especially among children younger than 5 years of age. In recent years, there have been reported cases of unusual manifestations. We report a rare case of a chest mass mimicking a tumor in an 11-month-old baby. PMID- 27956727 TI - Assessment of Cytokine and Chemokine Signatures as Potential Biomarkers of Childhood Community-acquired Pneumonia Severity: A Nested Cohort Study in India. AB - BACKGROUND: Pediatric community-acquired pneumonia (CAP) is a leading cause of childhood mortality in developing countries. In resource-poor settings, pneumonia diagnosis is commonly made clinically, based on World Health Organization guidelines, where breathing difficulty or cough and age-adjusted tachypnea suffice to establish diagnosis. Also, the severity of CAP is generally based on clinical features and existing biomarkers do not reliably correlate to either clinical severity or outcome. Here, we asked whether systemic immune and inflammatory mediators could act as biomarkers predicting CAP severity or outcome. METHODS: Serum from a subset of a CAP cohort (n = 196), enrolled in India, classified according to World Health Organization criteria as having pneumonia or severe pneumonia, was used for simultaneous measurement of 21 systemic cytokines and chemokines. RESULTS: We found significantly higher IL-6, IL-8, IL-13, IFN-gamma and lower CCL22 concentrations in patients with severe compared with mild CAP (P values: 0.019, 0.036, 0.006, 0.016 and 0.003, respectively). Based on higher MIP-1alpha, IL-8, IL-17 or lower CCL22 response pattern at the time of enrolment, children with fatal outcome showed markedly different pattern of inflammatory response compared with children classified with the same disease severity, but with nonfatal outcome (P values: 0.043, 0.017, 0.008 and 0.020, respectively). CONCLUSIONS: Our results suggest a relation between an elevated mixed cytokine response and CAP severity on one hand, and a bias toward uncontrolled neutrophilic inflammation in subjects with fatal outcome on the other. Collectively our findings contribute to increased knowledge on new biomarkers that can potentially predict severity and outcome of childhood CAP in the future. PMID- 27956729 TI - Bilateral Dacryoadenitis: Don't Forget Tuberculosis! AB - Tuberculous dacryoadenitis occurs rarely. It should be suspected in children presenting with unremitting inflammation of the lacrimal gland despite standard antibiotic and/or anti-inflammatory treatment, and a thorough systemic evaluation should be undertaken to identify a primary infectious site. We present an adolescent girl in whom bilateral dacryoadenitis was the first sign of pulmonary tuberculosis. PMID- 27956730 TI - Antimicrobial Susceptibility and Molecular Detection of Pertactin-producing and Pertactin-Deficient Bordetella pertussis. AB - Resurgence of Bordetella pertussis in recent years in the United States has coincided with a dramatic rise in pertactin-deficient strains. Limited data exist on detectability by nucleic acid amplification testing and antimicrobial susceptibility of pertactin-deficient B. pertussis. This study compares 15 pertactin-producing and 15 pertactin-deficient B. pertussis isolates. Pertactin producing and pertactin-deficient strains were equally detected by nucleic acid amplification testing and were susceptible to antibiotics. PMID- 27956731 TI - Practical and illustrated summary of updated BI-RADS for ultrasonography. AB - The American College of Radiology released the fifth edition of the Breast Imaging-Reporting and Data System (BI-RADS) in 2014 (copyright 2013), which includes the expanded second edition of the ultrasound BI-RADS lexicon. This review provides a practical summary of the updated lexicon, including selective illustrations with original clinical images, a discussion of overarching concepts, and examples of current clinical applications. PMID- 27956733 TI - Metastatic renal cell carcinoma in the thyroid gland: ultrasonographic features and the diagnostic role of core needle biopsy. AB - PURPOSE: The aims of this study were to present the ultrasonographic (US) features of metastatic renal cell carcinoma (RCC) in the thyroid gland and to evaluate the diagnostic utility of fineneedle aspiration (FNA) and core needle biopsy (CNB). METHODS: Eight patients with nine metastatic RCC nodules in the thyroid glands who were treated from January 2002 to March 2015 in a single tertiary hospital were consecutively selected and retrospectively reviewed. US features and clinical history were obtained from the institution's medical database. FNA was performed nine times on eight nodules and CNB was performed six times on six nodules. The diagnostic utility of FNA and CNB was evaluated. RESULTS: All nine nodules showed mass formation without diffuse thyroid involvement. On ultrasonography, metastatic RCC nodules were solid (100%), hypoechoic (100%), and ovalshaped nodules with a well-defined smooth margin (88.9%) and increased vascularity (100%, with 55% showing extensive vascularity). No calcifications were noted in any nodules. Lymph node metastasis and direct extension to nearby structures beyond the thyroid gland were not found. One FNA (11%) was able to confirm metastatic RCC, whereas all six CNBs confirmed metastatic RCC. CONCLUSION: Metastatic RCC appears as oval-shaped hypoechoic solid nodules with well-defined smooth margins, no calcifications, and increased vascularity on ultrasonography. Characteristic US features along with a previous history of RCC should raise clinical suspicion, and CNB should be performed to make an accurate diagnosis. PMID- 27956732 TI - Current role of transient elastography in the management of chronic hepatitis B patients. AB - Liver fibrosis is an important prognostic factor for chronic hepatitis B (CHB), and accurate evaluation of the stage of liver fibrosis is crucial in establishing management strategies. While liver biopsy is still considered the gold standard for staging liver fibrosis or cirrhosis, transient elastography (TE), a noninvasive means of assessing liver fibrosis, has come to play an increasing role in this process. After extensive validation, TE is now regarded as a reliable surrogate maker for grading the severity of liver fibrosis in CHB patients. It can detect the extent of fibrosis in a patient and can also be used to evaluate longitudinal changes in liver fibrosis over time with or without interventional management, such as antiviral therapy. However, several confounders hinder the effective assessment of liver fibrosis using TE, such as extensive liver necroinflammation, hepatic congestion, and cholestasis. TE has limited use in obese patients or patients with ascites. Although TE has several limitations, due to its accessibility and safety, it is a valuable tool for the initial evaluation and follow-up in patients with CHB. PMID- 27956734 TI - Emphysema and Airflow Obstruction in Non-Smoking Coal Miners with Pneumoconiosis. AB - BACKGROUND Accumulating evidence shows that functional impairment in subjects with coal workers' pneumoconiosis (CWP) is principally due to emphysema and airflow obstruction, rather than underlying restrictive mechanisms. However, cigarette smoking has remained a major confounder. The aim of this study was to assess whether coal dust exposure was associated with emphysema and/or airflow obstruction in the absence of smoking history. MATERIAL AND METHODS The subjects evaluated for possible pneumoconiosis between 2013 and 2015 were retrospectively enrolled into this study. After excluding those with history of smoking, tuberculosis, or lung cancer, the study population was a total of 57 subjects. The emphysema severity and airflow obstruction were quantified by computed tomographic densitometry analysis and spirometry, respectively. For comparability regarding emphysema, 9 age- and sex-matched nonsmoker (n=9) control subjects without known lung disease were randomly selected from a radiology database. RESULTS Emphysema severity was significantly higher in the CWP group compared with the control group (15% vs. 4%, p<0.001). The median percent emphysema and percentage of those with FEV1/FVC <0.7 was 13% and 37% in subjects with simple CWP and 18% and 67% in subjects with complicated CWP, respectively. Percent emphysema and Perc15 (15th percentile of the attenuation curve) was correlated with FEV1/FVC (r=-0.45, r=-0.47) and FEF25-75 (r=-0.36, r=-0.56), respectively, but not with perfusion score. A linear regression analysis showed that factors associated with emphysema were FEV1/FVC (beta=-0.24, p=0.009) and large opacity (beta=-3.97, p=0.079), and factors associated with FEV1/FVC were percent emphysema (beta=-0.51, p=0.018) and tenure (beta=-0.63, p=0.044). CONCLUSIONS Our results support the observation that coal dust exposure is associated with emphysema and airflow obstruction, independent of smoking status. PMID- 27956735 TI - Increased Incidence of Thrombotic Microangiopathy After ABO-Incompatible Living Donor Liver Transplantation. AB - BACKGROUND Thrombotic microangiopathy (TMA) is a severe life-threatening complication associated with solid organ transplantation. We retrospectively investigated the incidence, risk factors, and appropriate treatment of TMA following adult living donor liver transplantation (LDLT). MATERIAL AND METHODS The subjects were 129 adult patients who underwent LDLT in our department from 1997 to 2014. Patients with TMA were identified retrospectively based on diagnostic criteria. We calculated the incidence of TMA and performed a risk factor analysis for TMA occurrence. We also assessed our past treatments for TMA and sought to identify the most appropriate form of treatment. RESULTS Thirteen patients were identified as having TMA. The incidence of TMA in the study cohort was 10.1% but was especially high (37.9%) among ABO-incompatible cases. A univariate analysis revealed that ABO incompatibility, usage of tacrolimus, usage of rituximab, and cold ischemic time >=50 minutes are risk factors for occurrence of TMA (p<0.10). Multivariate analysis demonstrated that ABO incompatibility was the only independent risk factor for TMA (p=0.009). Initiation of treatment on the day of TMA diagnosis was associated with better survival. CONCLUSIONS ABO incompatibility is an independent risk factor for TMA following adult LDLT. Our results suggest that early initiation of treatment is crucial for improving the outcomes. PMID- 27956737 TI - Effects of aspartame-, monk fruit-, stevia- and sucrose-sweetened beverages on postprandial glucose, insulin and energy intake. AB - BACKGROUND: Substituting sweeteners with non-nutritive sweeteners (NNS) may aid in glycaemic control and body weight management. Limited studies have investigated energy compensation, glycaemic and insulinaemic responses to artificial and natural NNS. OBJECTIVES: This study compared the effects of consuming NNS (artificial versus natural) and sucrose (65 g) on energy intake, blood glucose and insulin responses. METHODS: Thirty healthy male subjects took part in this randomised, crossover study with four treatments: aspartame-, monk fruit-, stevia- and sucrose-sweetened beverages. On each test day, participants were asked to consume a standardised breakfast in the morning, and they were provided with test beverage as a preload in mid-morning and ad libitum lunch was provided an hour after test beverage consumption. Blood glucose and insulin concentrations were measured every 15 min within the first hour of preload consumption and every 30 min for the subsequent 2 h. Participants left the study site 3 h after preload consumption and completed a food diary for the rest of the day. RESULTS: Ad libitum lunch intake was significantly higher for the NNS treatments compared with sucrose (P=0.010). The energy 'saved' from replacing sucrose with NNS was fully compensated for at subsequent meals; hence, no difference in total daily energy intake was found between the treatments (P=0.831). The sucrose-sweetened beverage led to large spikes in blood glucose and insulin responses within the first hour, whereas these responses were higher for all three NNS beverages following the test lunch. Thus, there were no differences in total area under the curve (AUC) for glucose (P=0.960) and insulin (P=0.216) over 3 h between the four test beverages. CONCLUSIONS: The consumption of calorie-free beverages sweetened with artificial and natural NNS have minimal influences on total daily energy intake, postprandial glucose and insulin compared with a sucrose-sweetened beverage. PMID- 27956736 TI - Transplantation of Human Embryonic Stem Cells in Patients with Multiple Sclerosis and Lyme Disease. AB - BACKGROUND Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease in which the myelin sheath of nerve cells is damaged. It can cause delayed neurologic symptoms similar to those seen in Lyme disease (LD) patients. Thymus derived T-cells (myelin reactive) migrate to the blood brain barrier and stimulate an inflammatory cascade in the central nervous system. Cell based therapies play an important role in treating neurological diseases such as MS and LD. CASE REPORT Human embryonic stem cell (hESC) therapy was used to treat two patients with both MS and LD. The hESCs were administered via different routes including intramuscular, intravenous, and supplemental routes (e.g., deep spinal, caudal, intercostal through eye drops) to regenerate the injured cells. Both the patients showed remarkable improvement in their functional skills, overall stamina, cognitive abilities, and muscle strength. Furthermore, the improvement in the patients' conditions were assessed by magnetic resonance tractography and single photon emission computed tomography (SPECT). CONCLUSIONS Therapy with hESCs might emerge as an effective and safe treatment for patients with both MS and LD. Well-designed clinical trials and follow-up studies are needed to prove the long-term efficacy and safety of hESC therapy in the treatment of patients with MS and LD. PMID- 27956738 TI - Plastic CD34 and CD38 expression in adult B-cell precursor acute lymphoblastic leukemia explains ambiguity of leukemia-initiating stem cell populations. PMID- 27956740 TI - Enrichment of factors regulating canonical Wnt signaling among autism risk genes. PMID- 27956739 TI - Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder. AB - ANK3, encoding the adaptor protein Ankyrin-G (AnkG), has been implicated in bipolar disorder by genome-wide association studies. ANK3 has multiple alternative first exons, and a bipolar disorder-associated ANK3 variant has been shown to reduce the expression of exon 1b. Here we identify mechanisms through which reduced ANK3 exon 1b isoform expression disrupts neuronal excitation inhibition balance. We find that parvalbumin (PV) interneurons and principal cells differentially express ANK3 first exon subtypes. PV interneurons express only isoforms containing exon 1b, whereas excitatory principal cells express exon 1e alone or both 1e and 1b. In transgenic mice deficient for exon 1b, PV interneurons lack voltage-gated sodium channels at their axonal initial segments and have increased firing thresholds and diminished action potential dynamic range. These mice exhibit an Ank3 gene dosage-dependent phenotype including behavior changes modeling bipolar disorder, epilepsy and sudden death. Thus ANK3's important association with human bipolar susceptibility may arise from imbalance between AnkG function in interneurons and principal cells and resultant excessive circuit sensitivity and output. AnkG isoform imbalance is a novel molecular endophenotype and potential therapeutic target. PMID- 27956741 TI - Role of the adipose PPARgamma-adiponectin axis in susceptibility to stress and depression/anxiety-related behaviors. AB - Adaptive responses to stressful stimuli involving behavioral, emotional and metabolic changes are orchestrated by the nervous and endocrine systems. Adipose tissue has been recognized as a highly active metabolic and endocrine organ, secreting adipokines that operate as hormones to mediate the crosstalk with other organs including the brain. The role of adipose tissue in sensing and responding to emotional stress and in behavioral regulation, however, remains largely unknown. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a key transcriptional factor controlling adipokine gene expression. Here we show that chronic social defeat stress decreases messenger RNA and protein levels of PPARgamma in adipose tissue of susceptible but not resilient mice, which was correlated with social avoidance behavior. A corresponding reduction in adipose adiponectin production was observed in susceptible mice. Rosiglitazone, a blood-brain barrier-impermeant PPARgamma selective agonist, elicited antidepressant- and anxiolytic-like behavioral effects in wild-type mice, with a concurrent increase in plasma adiponectin levels. These effects of rosiglitazone were absent in mice lacking adiponectin but having normal PPARgamma expression in adipose tissue and brain. Moreover, pretreatment with the PPARgamma-selective antagonist GW9662 blocked rosiglitazone induced adiponectin expression and antidepressant/anxiolytic-like effects. Together, these results suggest that the behavioral responses to rosiglitazone are mediated through PPARgamma-dependent induction of adiponectin. Our findings support an important role for the adipose PPARgamma-adiponectin axis in susceptibility to stress and negative emotion-related behaviors. Selectively targeting PPARgamma in adipose tissue may offer novel strategies for combating depression and anxiety. PMID- 27956743 TI - Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice. AB - Genetic susceptibility and environmental factors (such as stress) can interact to affect the likelihood of developing a mood disorder. Stress-induced changes in the hippocampus have been implicated in mood disorders, and mutations in several genes have now been associated with increased risk, such as brain-derived neurotrophic factor (BDNF). The hippocampus has important anatomical subdivisions, and pyramidal neurons of the vulnerable CA3 region show significant remodeling after chronic stress, but the mechanisms underlying their unique plasticity remain unknown. This study characterizes stress-induced changes in the in vivo translating mRNA of this cell population using a CA3-specific enhanced green fluorescent protein (EGFP) reporter fused to the L10a large ribosomal subunit (EGFPL10a). RNA-sequencing after isolation of polysome-bound mRNAs allows for cell-type-specific, genome-wide characterization of translational changes after stress. The data demonstrate that acute and chronic stress produce unique translational profiles and that the stress history of the animal can alter future reactivity of CA3 neurons. CA3-specific EGFPL10a mice were then crossed to the stress-susceptible BDNF Val66Met mouse line to characterize how a known genetic susceptibility alters both baseline translational profiles and the reactivity of CA3 neurons to stress. Not only do Met allele carriers exhibit distinct levels of baseline translation in genes implicated in ion channel function and cytoskeletal regulation, but they also activate a stress response profile that is highly dissimilar from wild-type mice. Closer examination of genes implicated in the mechanisms of neuroplasticity, such as the NMDA and AMPA subunits and the BDNF pathway, reveal how wild-type mice upregulate many of these genes in response to stress, but Met allele carriers fail to do so. These profiles provide a roadmap of stress-induced changes in a genetically homogenous population of hippocampal neurons and illustrate the profound effects of gene-environment interactions on the translational profile of these cells. PMID- 27956744 TI - Patient-specific models of microglia-mediated engulfment of synapses and neural progenitors. AB - Engulfment of synapses and neural progenitor cells (NPCs) by microglia is critical for the development and maintenance of proper brain circuitry, and has been implicated in neurodevelopmental as well as neurodegenerative disease etiology. We have developed and validated models of these mechanisms by reprogramming microglia-like cells from peripheral blood mononuclear cells, and combining them with NPCs and neurons derived from induced pluripotent stem cells to create patient-specific cellular models of complement-dependent synaptic pruning and elimination of NPCs. The resulting microglia-like cells express appropriate markers and function as primary human microglia, while patient matched macrophages differ markedly. As a demonstration of disease-relevant application, we studied the role of C4, recently implicated in schizophrenia, in engulfment of synaptic structures by human microglia. The ability to create complete patient-specific cellular models of critical microglial functions utilizing samples taken during a single clinical visit will extend the ability to model central nervous system disease while facilitating high-throughput screening. PMID- 27956742 TI - 17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression. AB - To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-beta deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series. PMID- 27956745 TI - Altered brain processing of decision-making in healthy first-degree biological relatives of suicide completers. AB - Suicidal behavior is heritable, with the transmission of risk being related to the transmission of vulnerability traits. Previous studies suggest that risky decision-making may be an endophenotype of suicide. Here, we aimed at investigating brain processing of decision-making in relatives of suicide completers in order to shed light on heritable mechanisms of suicidal vulnerability. Seventeen healthy first-degree biological relatives of suicide completers with no personal history of suicidal behavior, 16 relatives of depressed patients without any personal or family history of suicidal behavior, and 19 healthy controls were recruited. Functional 3 T magnetic resonance imaging scans were acquired while participants underwent the Iowa Gambling Task, an economic decision-making test. Whole-brain analyses contrasting activations during risky vs safe choices were conducted with AFNI and FSL. Individuals with a family history of suicide in comparison to control groups showed altered contrasts in left medial orbitofrontal cortex, and right dorsomedial prefrontal cortex. This pattern was different from the neural basis of familial depression. Moreover, controls in comparison to relatives showed increased contrast in several regions including the post-central gyrus, posterior cingulate and parietal cortices, and cerebellum (culmen) in familial suicide; and inferior parietal, temporal, occipital, anteromedial and dorsolateral prefrontal cortices, and cerebellum (vermis) in familial depression. These findings most likely represent a complex combination of vulnerability and protective mechanisms in relatives. They also support a significant role for deficient risk processing, and ventral and dorsal prefrontal cortex functioning in the suicidal diathesis. PMID- 27956746 TI - Schizophrenia copy number variants and associative learning. AB - Large-scale genomic studies have made major progress in identifying genetic risk variants for schizophrenia. A key finding from these studies is that there is an increased burden of genomic copy number variants (CNVs) in schizophrenia cases compared with controls. The mechanism through which these CNVs confer risk for the symptoms of schizophrenia, however, remains unclear. One possibility is that schizophrenia risk CNVs impact basic associative learning processes, abnormalities of which have long been associated with the disorder. To investigate whether genes in schizophrenia CNVs impact on specific phases of associative learning we combined human genetics with experimental gene expression studies in animals. In a sample of 11 917 schizophrenia cases and 16 416 controls, we investigated whether CNVs from patients with schizophrenia are enriched for genes expressed during the consolidation, retrieval or extinction of associative memories. We show that CNVs from cases are enriched for genes expressed during fear extinction in the hippocampus, but not genes expressed following consolidation or retrieval. These results suggest that CNVs act to impair inhibitory learning in schizophrenia, potentially contributing to the development of core symptoms of the disorder. PMID- 27956750 TI - Epigenomics: Deciphering non-coding variation with 3D epigenomics. PMID- 27956747 TI - Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior. AB - The bed nucleus of the stria terminalis (BNST) is a brain region important for regulating anxiety-related behavior in both humans and rodents. Here we used a chemogenetic strategy to investigate how engagement of G protein-coupled receptor (GPCR) signaling cascades in genetically defined GABAergic BNST neurons modulates anxiety-related behavior and downstream circuit function. We saw that stimulation of vesicular gamma-aminobutyric acid (GABA) transporter (VGAT)-expressing BNST neurons using hM3Dq, but neither hM4Di nor rM3Ds designer receptors exclusively activated by a designer drug (DREADD), promotes anxiety-like behavior. Further, we identified that activation of hM3Dq receptors in BNST VGAT neurons can induce a long-term depression-like state of glutamatergic synaptic transmission, indicating DREADD-induced changes in synaptic plasticity. Further, we used DREADD assisted metabolic mapping to profile brain-wide network activity following activation of Gq-mediated signaling in BNST VGAT neurons and saw increased activity within ventral midbrain structures, including the ventral tegmental area and hindbrain structures such as the locus coeruleus and parabrachial nucleus. These results highlight that Gq-mediated signaling in BNST VGAT neurons can drive downstream network activity that correlates with anxiety-like behavior and points to the importance of identifying endogenous GPCRs within genetically defined cell populations. We next used a microfluidics approach to profile the receptorome of single BNST VGAT neurons. This approach yielded multiple Gq-coupled receptors that are associated with anxiety-like behavior and several potential novel candidates for regulation of anxiety-like behavior. From this, we identified that stimulation of the Gq-coupled receptor 5-HT2CR in the BNST is sufficient to elevate anxiety-like behavior in an acoustic startle task. Together, these results provide a novel profile of receptors within genetically defined BNST VGAT neurons that may serve as therapeutic targets for regulating anxiety states and provide a blueprint for examining how G-protein-mediated signaling in a genetically defined cell type can be used to assess behavior and brain-wide circuit function. PMID- 27956748 TI - Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism. AB - Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases. To further the understanding of familial autism, we performed whole exome sequencing on five families in which second- and third-degree relatives were affected. By focusing on novel and protein-altering variants, we identified a small set of candidate genes. Among these, a novel private missense C1143F variant in the second intracellular loop of the voltage-gated sodium channel NaV1.7, encoded by the SCN9A gene, was identified in one family. Through electrophysiological analysis, we show that NaV1.7C1143F exhibits partial loss-of function effects, resulting in slower recovery from inactivation and decreased excitability in cultured cortical neurons. Furthermore, for the same intracellular loop of NaV1.7, we found an excess of rare variants in a case control variant-burden study. Functional analysis of one of these variants, M932L/V991L, also demonstrated reduced firing in cortical neurons. However, although this variant is rare in Caucasians, it is frequent in Latino population, suggesting that genetic background can alter its effects on phenotype. Although the involvement of the SCN1A and SCN2A genes encoding NaV1.1 and NaV1.2 channels in de novo ASD has previously been demonstrated, our study indicates the involvement of inherited SCN9A variants and partial loss-of-function of NaV1.7 channels in the etiology of rare familial ASD. PMID- 27956751 TI - Synthesis and Cytotoxic Evaluation of Pyrrole Hetarylazoles Containing Benzimidazole/Pyrazolone/1,3,4-Oxadiazole Motifs. AB - Azomethine linked pyrrole bishetarylazoles containing benzimidazole/pyrazolone/1,3,4-oxadiazole were synthesized in satisfactory yields. Their structures were confirmed by IR, 1H-NMR, 13C-NMR and elemental analysis. Evaluation for the cytotoxic activities In vitro against a panel of breast cancer cell lines (MDA-AB-231, BT-474 and Ishikawa cells) revealed that the pyrrole-benzimidazole hybrids are more potent than the pyrazolone and 1,3,4 oxadiazole hybrids in all cell lines. Compound (9) displayed promising cytotoxicity against BT-474 cell line with IC50 values, 7.7 uM. PMID- 27956674 TI - Patient reported outcome of adult perioperative anaesthesia in the United Kingdom: a cross-sectional observational study. AB - BACKGROUND: Understanding the patient perspective on healthcare is central to the evaluation of quality. This study measured selected patient-reported outcomes after anaesthesia in order to identify targets for research and quality improvement. METHODS: This cross-sectional observational study in UK National Health Service hospitals, recruited adults undergoing non-obstetric surgery requiring anaesthesia care over a 48 h period. Within 24 h of surgery, patients completed the Bauer questionnaire (measuring postoperative discomfort and satisfaction with anaesthesia care), and a modified Brice questionnaire to elicit symptoms suggestive of accidental awareness during general anaesthesia (AAGA). Patient, procedural and pharmacological data were recorded to enable exploration of risk factors for these poor outcomes. RESULTS: 257 hospitals in 171 NHS Trusts participated (97% of eligible organisations). Baseline characteristics were collected on 16,222 patients; 15,040 (93%) completed postoperative questionnaires. Anxiety was most frequently cited as the worst aspect of the perioperative experience. Thirty-five per cent of patients reported severe discomfort in at least one domain: thirst (18.5%; 95% CI 17.8-19.1), surgical pain (11.0%; 10.5-11.5) and drowsiness (10.1%; 9.6-10.5) were most common. Despite this, only 5% reported dissatisfaction with any aspect of anaesthesia related care. Regional anaesthesia was associated with a reduced burden of side effects. The incidence of reported AAGA was one in 800 general anaesthetics (0.12%) CONCLUSIONS: Anxiety and discomfort after surgery are common; despite this, satisfaction with anaesthesia care in the UK is high. The inconsistent relationship between patient-reported outcome, patient experience and patient satisfaction supports using all three of these domains to provide a comprehensive assessment of the quality of anaesthesia care. PMID- 27956752 TI - Functionalizing the gamma-Position of alpha-Diazo-beta-ketoesters. AB - Although alpha-diazo-beta-ketoesters are synthetically versatile intermediates, methodology for introducing this functionality into complex molecules is still limited, most frequently involving a carboxylic acid precursor, which is then activated and transformed into a beta-ketoester, with the diazo group being subsequently added with a diazo transfer reagent. While introducing this highly functional moiety in a convergent one step process would be ideal, such an objective is limited by the relatively few studies which address functionalization of the alpha-diazo-beta-ketoester at the gamma-position. In the present investigation, we evaluate strategies, both new and established, for functionalizing alpha-diazo-beta-ketoesters, particularly with regard to generating compounds prospectively useful in the synthesis of C1-substituted carbapenems. We report the first delta-aldehydo-alpha-diazo-beta-ketoester as well as a method for its oxidation to the corresponding methyl ester, and the formation of a new substituted pyrazole under basic conditions. PMID- 27956754 TI - Visualizing Forensic Publication Impacts and Collaborations: Presenting at a Scientific Venue Leads to Increased Collaborations between Researchers and Information Professionals. AB - The Information Services Office (ISO) of the National Institute of Standards and Technology (NIST) proactively sought out an opportunity to present the findings of a study that showed the impact of NIST's forensic research output to its internal customers and outside researchers. ISO analyzed the impact of NIST's contributions to the peer-reviewed forensic journal literature through citation analysis and network visualizations. The findings of this study were compiled into a poster that was presented during the Forensics@NIST Symposium in December 2014. ISO's study informed the forensic research community where NIST has had some of the greatest scholarly impact. This paper describes the methodology used to assess the impact of NIST's forensic publications and shares the results, outcomes, and impacts of ISO's study and poster presentation. This methodology is adaptable and applicable to other research fields and to other libraries. It has improved the recognition of ISO's capabilities within NIST and resulted in application of the methodology to additional scientific disciplines. PMID- 27956753 TI - The Serotonin Transporter Promoter Variant, Stress, and Attentional Biases in Middle Childhood. AB - Although evidence suggests that 5-HTTLPR variants may shape risk for depression, the influence is likely complex, and involves effects on endophenotypes. We examined associations between 5-HTTLPR and biases in attention to affective stimuli in a sample of girls and a sample of both boys and girls. Children with at least one short (S) variant of the 5-HTTLPR polymorphism had lower positive attentional bias scores in both samples. This association was qualified by an interaction with stress in one sample, such that links between the S allele and decreased positive attentional bias was significant only when life stress was elevated. This difference in findings between the two samples was explained by sex differences in samples; the GXE interaction was significant only in boys. Findings are discussed in the context of sex differences in GXE. PMID- 27956756 TI - Predicting Energy Performance of a Net-Zero Energy Building: A Statistical Approach. AB - Performance-based building requirements have become more prevalent because it gives freedom in building design while still maintaining or exceeding the energy performance required by prescriptive-based requirements. In order to determine if building designs reach target energy efficiency improvements, it is necessary to estimate the energy performance of a building using predictive models and different weather conditions. Physics-based whole building energy simulation modeling is the most common approach. However, these physics-based models include underlying assumptions and require significant amounts of information in order to specify the input parameter values. An alternative approach to test the performance of a building is to develop a statistically derived predictive regression model using post-occupancy data that can accurately predict energy consumption and production based on a few common weather-based factors, thus requiring less information than simulation models. A regression model based on measured data should be able to predict energy performance of a building for a given day as long as the weather conditions are similar to those during the data collection time frame. This article uses data from the National Institute of Standards and Technology (NIST) Net-Zero Energy Residential Test Facility (NZERTF) to develop and validate a regression model to predict the energy performance of the NZERTF using two weather variables aggregated to the daily level, applies the model to estimate the energy performance of hypothetical NZERTFs located in different cities in the Mixed-Humid climate zone, and compares these estimates to the results from already existing EnergyPlus whole building energy simulations. This regression model exhibits agreement with EnergyPlus predictive trends in energy production and net consumption, but differs greatly in energy consumption. The model can be used as a framework for alternative and more complex models based on the experimental data collected from the NZERTF. PMID- 27956755 TI - Matrix Metalloproteinases as a Pleiotropic Biomarker in Medicine and Biology. PMID- 27956758 TI - Weighting for Health: Management, Measurement and Self-surveillance in the Modern Household. AB - Histories of late nineteenth- and early twentieth-century medicine emphasise the rise of professional and scientific authority, and suggest a decline in domestic health initiatives. Exploring the example of weight management in Britain, we argue that domestic agency persisted and that new regimes of measurement and weighing were adapted to personal and familial preferences as they entered the household. Drawing on print sources and objects ranging from prescriptive literature to postcards and 'personal weighing machines', the article examines changing practices of self-management as cultural norms initially dictated by ideals of body shape and function gradually incorporated quantified targets. In the twentieth century, the domestic management of health-like the medical management of illness-was increasingly technologised and re-focused on quantitative indicators of 'normal' or 'pathological' embodiment. We ask: in relation to weight, how did quantification permeate the household, and what did this domestication of bodily surveillance mean to lay users? PMID- 27956757 TI - How social media influence college students' smoking attitudes and intentions. AB - Building on the influence of presumed influence (IPI) model, this study examines how smoking- related messages on social media influence college students' smoking. We surveyed 366 college students from three U.S. Midwestern universities in 2012 and examined the effects of expression and reception of smoking-related messages on smoking using path analysis. We found that the expression and reception of prosmoking messages not only directly affected smoking but also had indirect effects on smoking through (1) perceived peer expression of prosmoking messages and (2) perceived peer smoking norms. For antismoking messages, only reception had a significant indirect influence on smoking through (1) perceived peer reception of antismoking messages and (2) perceived peer smoking norms. In conclusion, social media function as an effective communication channel for generating, sharing, receiving, and commenting on smoking-related content and are thus influential on college students' smoking. PMID- 27956759 TI - The Records of Stannington Children's Sanatorium: Charting Half a Century of Tuberculosis Care. AB - This article explores the historic records of Stannington Children's Tuberculosis Sanatorium focusing largely on the 5,041 patient records and 14,660 radiographs that make up the bulk of the collection and span from the 1930s to the 1960s. By taking a handful of illustrations from within the collection, it aims to demonstrate the various avenues of research available as well as the unique nature of the collection owing to its focus on children, with the comprehensive nature of its records making it invaluable. The sanatorium's records are made particularly pertinent by the fact that they span the pre- to the post-antibiotic era charting changes in treatment as well as offering details on a range of other issues such as social background and stigma. PMID- 27956760 TI - Neuroinflammation Induced by Surgery Does Not Impair the Reference Memory of Young Adult Mice. AB - Postoperative cognitive dysfunction (POCD) increases morbidity and mortality after surgery. But the underlying mechanism is not clear yet. While age is now accepted as the top one risk factor for POCD, results from studies investigating postoperative cognitive functions in adults have been controversial, and data about the very young adult individuals are lacking. The present study investigated the spatial reference memory, IL-1beta, IL-6, and microglia activation changes in the hippocampus in 2-month-old mice after anesthesia and surgery. We found that hippocampal IL-1beta and IL-6 increased at 6 hours after surgery. Microglia were profoundly activated in the hippocampus 6 to 24 hours after surgery. However, no significant behavior changes were found in these mice. These results indicate that although anesthesia and surgery led to neuroinflammation, the latter was insufficient to impair the spatial reference memory of young adult mice. PMID- 27956761 TI - NEMO-Binding Domain Peptide Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Inhibiting the NF-kappaB Signaling Pathway. AB - The aim of the present study is to investigate the protective effects and relevant mechanisms exerted by NEMO-binding domain peptide (NBD) against lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in mice. The ALI model was induced by intratracheally administered atomized LPS (5 mg/kg) to BABL/c mice. Half an hour before LPS administration, we treated the mice with increasing concentrations of intratracheally administered NBD or saline aerosol. Two hours after LPS administration, each group of mice was sacrificed. We observed that NBD pretreatment significantly attenuated LPS-induced lung histopathological injury in a dose-dependent manner. Western blotting established that NBD pretreatment obviously attenuated LPS-induced IkappaB-alpha and NF-kappaBp65 activation and NOX1, NOX2, and NOX4 overexpression. Furthermore, NBD pretreatment increased SOD and T-AOC activity and decreased MDA levels in lung tissue. In addition, NBD also inhibited TNF-alpha and IL-1beta secretion in BALF after LPS challenge. In conclusion, NBD protects against LPS-induced ALI in mice. PMID- 27956763 TI - The Effect of Immunonutrition on the Postoperative Complications in Thymoma with Myasthenia Gravis. AB - Object. To test whether preoperative immunonutrition is efficacious in reducing postoperative complications in patients of thymoma with myasthenia gravis (MG). Material and Methods. A total of 244 patients operated on for thymoma with myasthenia gravis were prospectively assigned to two groups, each receiving seven day preoperative and seven-day postoperative nutrition. The patients in immunonutrition group were given oral immunonutrition (IN). The patients in control group received oral standard nutrition. Immunonutritional and inflammatory biomarkers (IgA, IgG, IgM, CD3t, CD4t, CD8t, CD4t/CD8t ratio, NK cell, prealbumin, albumin, white blood cells counts, and C-reactive protein) and clinical variables (age, gender, BMI, performance status, type of thymoma, type of MG, operative time, pathology, operative approach, postoperative complications, quantity of drainage, hospital stays) were examined. Results. A significant reduction in the length of hospital stay, quantity of drainage, and postoperative complications was observed in the IN group (p < 0.05). An increase in the level of IgA, IgG, IgM, CD3+T, CD4+T, CD4+T/CD8+T, WBC, CRP, and NK-cell in the IN group was observed after thymectomy, while a decrease was seen with regard to prealbumin and albumin (p < 0.05). Conclusion. Preoperative immunonutrition support is effective in reducing postoperative complications in patients of thymoma with MG. It helps to lower the risk of postoperative infectious complications and hospital stays. PMID- 27956764 TI - Relationship of prepartum udder and teat measurements with subsequent milk production traits in primiparous Nili-Ravi buffaloes. AB - AIM: This study was conducted to find out the relationship of prepartum udder and teat measurements with subsequent milk production traits in primiparous Nili-Ravi buffaloes. MATERIALS AND METHODS: A total of 12 Nili-Ravi buffalo heifers were selected from Buffalo Farm, Central Institute for Research on Buffaloes, Regional Station- Bir Dosanjh, Nabha, Patiala, Punjab. The udder length (UL), udder width (UW), udder depth, teat length (TL), teat diameter (TD), and teat distances were measured at fortnightly interval from 60 days prepartum until calving. After calving, 60 days total milk yield (TDMY), peak yield (PY), and days taken to attain PY (DPY) were also recorded. The correlation coefficients of various prepartum udder and teat measurements since 60 days prepartum to calving with 60 days TDMY, PY, and DPY were calculated to find out the relationship between the traits in primiparous Nili-Ravi buffaloes. RESULTS: The result envisaged that all udder and teat measurements were increased gradually toward the date of calving in primiparous buffaloes. The UL, UW, left fore (LF) and right rear (RR)TL, RRTD, and the distance between LF to left rear (LR) teat were positively correlated with 60 days TDMY. The UL and UW depicted positive but nonsignificant correlation with PY. Fore TLs showed positive correlation where as TDs and teat distances had a negative correlation with the DPY in primiparous Nili-Ravi buffaloes. CONCLUSION: It was concluded that milk production performance could be assessed on the basis of prepartum udder and teat measurements in primiparous Nili-Ravi buffaloes. PMID- 27956762 TI - Tolerance in Kidney Transplantation: What Is on the B Side? AB - Regulatory B cells (Breg) are in the spotlight for their role in immune homeostasis maintenance and tolerance achievement as in the last years the correlation with functional and increased Breg numbers in autoimmune diseases and transplantation has been extensively proven. Their study is, however, in its infancy with still little knowledge and consensus on their origin, phenotype, and mechanism of action. All this hampers the pursuit of an effective Breg induction method for therapeutic purposes. In this review we aim to summarize the studies on human Breg and their implication in kidney transplantation and to further discuss the issues surrounding therapeutic applications of this cell subset. PMID- 27956765 TI - Clinico-anesthetic changes following administration of propofol alone and in combination of meperidine and pentazocine lactate in dogs. AB - AIM: The aim of this study is to find out the effect of propofol and its combination with meperidine and pentazocine lactate on certain clinico-anesthetic profiles in dogs. MATERIALS AND METHODS: 15 apparently healthy mongrel dogs of either sex of about 1 year of age were randomly divided into three groups of five dogs each. The animals of Group I were administered propofol intravenously alone "to effect," whereas meperidine at 2 mg/kgb.wt. and pentazocine lactate at 2 mg/kg b.wt. were injected intramuscularly 15 min before propofol "to effect" in Groups II and III, respectively. Atropine sulfate at 0.04 mg/kgb.wt. was injected intramuscularly 20 min before each treatment. Rectal temperature, heart rate, respiration rate, and anesthetic indices were recorded before and at 5, 10, 20, 30, and 60 min of induction. RESULTS: As compared to Group I, the animals of Groups II and III exhibited a significant decrease (p<0.05) in the level of rectal temperature, respiration rate, and heart rate. Duration of recumbency, time of standing, time of recovery as well as the duration of analgesia were longer in pentazocine lactate (Group III) followed by meperidine (Group II) as compared to propofol alone (Group I). Meperidine treated dogs showed defecation and muscle twitching during anesthesia. CONCLUSION: Meperidine and pentazocine are suitable opioids used in combination with propofol for achieving surgical anesthesia and helpful in reduction of propofol dose. PMID- 27956766 TI - Enterohemorrhagic Escherichia coli O157 in milk and dairy products from Libya: Isolation and molecular identification by partial sequencing of 16S rDNA. AB - AIM: The aim of this work was to isolate and molecularly identify enterohemorrhagic Escherichia coli (EHEC) O157 in milk and dairy products in Libya, in addition; to clear the accuracy of cultural and biochemical identification as compared with molecular identification by partial sequencing of 16S rDNA for the existing isolates. MATERIALS AND METHODS: A total of 108 samples of raw milk (cow, she-camel, and goat) and locally made dairy products (fermented cow's milk, Maasora, Ricotta and ice cream) were collected from some regions (Janzour, Tripoli, Kremiya, Tajoura and Tobruk) in Libya. Samples were subjected to microbiological analysis for isolation of E. coli that was detected by conventional cultural and molecular method using polymerase chain reaction and partial sequencing of 16S rDNA. RESULTS: Out of 108 samples, only 27 isolates were found to be EHEC O157 based on their cultural characteristics (Tellurite Cefixime-Sorbitol MacConkey) that include 3 isolates from cow's milk (11%), 3 isolates from she-camel's milk (11%), two isolates from goat's milk (7.4%) and 7 isolates from fermented raw milk samples (26%), isolates from fresh locally made soft cheeses (Maasora and Ricotta) were 9 (33%) and 3 (11%), respectively, while none of the ice cream samples revealed any growth. However, out of these 27 isolates, only 11 were confirmed to be E. coli by partial sequencing of 16S rDNA and E. coli O157 Latex agglutination test. Phylogenetic analysis revealed that majority of local E. coli isolates were related to E. coli O157:H7 FRIK944 strain. CONCLUSION: These results can be used for further studies on EHEC O157 as an emerging foodborne pathogen and its role in human infection in Libya. PMID- 27956768 TI - Influence of drinking water containing Aloe vera (Aloe barbadensis Miller) gel on growth performance, intestinal microflora, and humoral immune responses of broilers. AB - AIM: The risk of bacteria resistance to specific antibiotics possibly by continuous subtherapeutical administration of antibiotic growth promoters (AGPs) in poultry feed led to a ban on the use of AGP in poultry production. As a result of this ban, alternative substances for poultry growth promotion and disease prevention are being investigated, among which phytogenic and herbal products have received increased attention as natural additives because they have been accepted by consumers as natural additives. The effect of water supplementation of Aloe vera (AV) as an AGP substitute on performance, intestinal microflora, and immune responses of broilers. MATERIALS AND METHODS: The five experimental treatments were allocated to four replicates. The following treatments were applied (1) a basal broiler diet (C) and normal drinking water, (2) 0.5% AV gel in drinking water, (3) 0.75% AV gel in drinking water, (4) 1% AV gel in drinking water, and (5) diet C supplemented with flavophospholipol at 4.5 mg/kg and drinking normal water. Vaccines against influenza disease and sheep red blood cell (SRBC) were administrated to immunological stimuli. The populations of Lactobacilli spp. and coliforms were enumerated in ileum. RESULTS: Body weight of broilers supplemented with different levels of AV increased compared with control group (p<0.05). Birds supplemented with antibiotic had the best feed-to-gain ratio (F:G) in different periods. Supplementation of 0.5% and 0.75% AV improved F: G entire experimental period compared with control group (p<0.05). Coliform bacteria were reduced in broilers supplemented with different levels of AV or antibiotic (p<0.05). The Lactobacilli spp. population in birds supplemented with 0.75%, 1% AV or antibiotic significantly was higher than other groups (p<0.05). Supplementation with 1% AV led to greater antibody titers against SRBC compared with other groups (p<0.05). CONCLUSION: These findings demonstrated a possibility of supplementing broiler drinking water with 1% AV gel as an alternative for AGP substitution. PMID- 27956769 TI - Acute phase response in lame crossbred dairy cattle. AB - AIM: The study was undertaken to study acute phase response based on acute phase proteins (APPs) such as C-reactive protein (CRP), haptoglobin (Hp), serum amyloid A (SAA), and fibrinogen in lame crossbred dairy cattle. MATERIALS AND METHODS: Lame animals (n=30) were selected within 3-7 days of being noticed as lame by the farm veterinarian, from a local dairy farm in southeast Ludhiana over a period of 6 months, stratified proportionately with respect to stage of lactation with non lame healthy cows (n=10). All the cows were otherwise healthy and did not have any other inflammatory problems such as pneumonia, enteritis, mastitis, or any kind of acute uterine inflammation. Blood samples were collected from all the animals; serum and plasma samples were separated and stored at -20 degrees C. The levels of CRP, Hp, and SAA were estimated using Sandwich ELISA, whereas fibrinogen was estimated by heat precipitation method. RESULTS: SAA levels in lame cows were significantly higher (22.19+/-0.85 ug/ml), approximately 3 times as compared to non-lame cows (8.89+/-0.72 ug/ml), whereas serum Hp concentration was approximately 20 times higher in the lame cattle (21.71+/-3.32 mg/dl) as compared to non-lame cows (1.17+/-0.07 mg/dl). Fibrinogen also increased in the lame cattle (3.97+/-0.22 g/L) as compared to non-lame group (1.40+/-0.17 g/L). Serum CRP levels analyzed in the lame cattle for the first time in the present study, and significant high concentration was appreciated in lame cattle (4.41+/ 0.33 mg/L) as compared to non-lame cattle (0.61+/-0.14 mg/L). Lame cattle were having more of sole hemorrhages, sole ulcers, and white line lesions as compared to non-lame cattle. CONCLUSION: It can be concluded that lame cattle exhibit high levels of APPs including CRP, Hp, SAA, and fibrinogen as compared to non-lame cattle. PMID- 27956767 TI - Anaplasma species of veterinary importance in Japan. AB - Anaplasma species of the family Anaplasmataceae, order Rickettsiales are tick borne organisms that can cause disease in animals and humans. In Japan, all recognized species of Anaplasma (except for Anaplasma ovis) and a potentially novel Anaplasma sp. closely related to Anaplasma phagocytophilum have been reported. Most of these detected tick-borne pathogens are believed to be lowly pathogenic in animals in Japan although the zoonotic A. phagocytophilum has recently been reported to cause clinical signs in a dog and in humans. This review documents the studies and reports about Anaplasma spp. in Japan. PMID- 27956770 TI - In vitro evaluation of different varieties of maize fodder for their methane generation potential and digestibility with goat rumen liquor. AB - AIM: To evaluate the methane generation potential and digestibility of different (normal and three high-quality protein maize [HQPM]) varieties of maize fodder with goat rumen liquor in vitro. MATERIALS AND METHODS: Methane production potential and digestibility of different varieties of maize fodder were tested in in vitro gas production test. Seven varieties of maize, four normal (HTHM 5101, DHM 117, HM 5, and Shaktiman/900 M Gold), and three high-quality protein (HQPM 5, HQPM 7, and HQPM 9/Vivek) were grown in different plots under the same environmental and agro-climatic conditions. Fodders were harvested at 45-50 days of sowing, and the representative samples of fodder from different varieties of maize were collected for analysis. Dried and grinded form of these maize fodder varieties was tested for gas, methane, and digestibility using goat rumen microflora in in vitro gas syringes. RESULTS: Gas production (ml/g dry matter [DM]) was highest for HM5 variety (97.66, whereas lowest for HQPM 9 variety (64.22). Gas production (ml/g degraded DM [DDM]) and methane (%) were statistically similar in different varieties of maize fodder. The methane production expressed as ml/g DM and ml/g DDM was significantly (p<0.05) highest for HM 5 (14.22 and 26.62) and lowest for DHM 117 variety (7.47 and 14.13). The in vitro DM digestibility (%) and in vitro organic matter digestibility (%) varied from 47.48 (HQPM 5) to 52.05 (HQPM 9) and 50.03 (HQPM 7) to 54.22 (HM 5), respectively. CONCLUSION: The present study concluded that DHM 117 maize variety fodder has lowest methane generation potential and incorporating it in the dietary regime of ruminants may contribute to lower methane production. PMID- 27956771 TI - Prevalence and burden of gastrointestinal parasites in cattle and buffaloes in Jabalpur, India. AB - AIM: The study was conducted to determine the prevalence and burden of gastrointestinal (GI) parasites in cattle and buffaloes of Jabalpur, Madhya Pradesh. MATERIALS AND METHODS: The presence of helminths eggs and coccidial oocysts in fecal samples were detected using standard qualitative and quantitative methods. Identification of eggs or oocysts was done on the basis of morphology and size of the eggs or oocysts. RESULTS: Out of 120 cattle and buffaloes examined, 73.33% were found positive for eggs of one or more species of GI parasite. The prevalence of parasitic infection was higher in cattle (75%) as compared to that of buffaloes (70.45%), but the difference was nonsignificant (p>0.05). Sex wise prevalence of GI parasites was higher in males as compared to that of females, but the difference was nonsignificant (p>0.05). The animals above 2 years of age were more affected by GI parasites as compared to animals of 6 months - 2 years of age, but the age wise differences were nonsignificant (p>0.05). Single parasitic infections were more common than mixed infections. The monthly prevalence of GI parasites in cattle and buffaloes were highest in the month of September (81.81%) and least in December (61.11%). The eggs/oocysts per gram in most of the animals, was in the range of 201-300. CONCLUSION: GI parasites are problem in cattle and buffaloes of Jabalpur, Madhya Pradesh. The prevalence rate of GI parasites varied with month. The burden of parasitic infection was moderate in most animals warranting treatment. PMID- 27956773 TI - Laboratory animal models for esophageal cancer. AB - The incidence of esophageal cancer is rapidly increasing especially in developing countries. The major risk factors include unhealthy lifestyle practices such as alcohol consumption, smoking, and chewing tobacco to name a few. Diagnosis at an advanced stage and poor prognosis make esophageal cancer one of the most lethal diseases. These factors have urged further research in understanding the pathophysiology of the disease. Animal models not only aid in understanding the molecular pathogenesis of esophageal cancer but also help in developing therapeutic interventions for the disease. This review throws light on the various recent laboratory animal models for esophageal cancer. PMID- 27956772 TI - Biocomputational analysis of evolutionary relationship between toll-like receptor and nucleotide-binding oligomerization domain-like receptors genes. AB - AIM: The active domains (TIR and NACHT) of the pattern recognition receptors (PRRs: Toll-like receptors [TLRs] and nucleotide-binding oligomerization domain [NOD]-like receptors [NLR], respectively) are the major hotspots of evolution as natural selection has crafted their final structure by substitution of residues over time. This paper addresses the evolutionary perspectives of the TLR and NLR genes with respect to the active domains in terms of their chronological fruition, functional diversification, and species-specific stipulation. MATERIALS AND METHODS: A total of 48 full-length cds (and corresponding peptide) of the domains were selected as representatives of each type of PRRs, belonging to divergent animal species, for the biocomputational analyses. The secondary and tertiary structure of the taurine TIR and NACHT domains was predicted to compare the relatedness among the domains under study. RESULTS: Multiple sequence alignment and phylogenetic tree results indicated that these host-specific PRRs formed entirely different clusters, with active domains of NLRs (NACHT) evolved earlier as compared to the active domains of TLRs (TIR). Each type of TLR or NLR shows comparatively less variation among the animal species due to the specificity of action against the type of microbes. CONCLUSION: It can be concluded from the study that there has been no positive selection acting on the domains associated with disease resistance which is a fitness trait indicating the extent of purifying pressure on the domains. Gene duplication could be a possible reason of genesis of similar kinds of TLRs (virus or bacteria specific). PMID- 27956774 TI - Evaluation of five treatments to control intestinal parasites in sheep in Ayapango, state of Mexico. AB - AIM: Intestinal parasites are one of the most common problems in sheep production systems. However, the strategies used to eliminate these parasites have not yielded satisfactory results. Therefore, the aim of this study was to determine the effect of five anthelmintics (with different active ingredients) on the parasite load in sheep. MATERIALS AND METHODS: In this study, 107 Rambouillet breed sheep were randomly assigned to five groups. Next, fecal samples were taken directly from the rectum and sent to the laboratory for analysis. We then dewormed each group of sheep using different anthelmintic products: Ivermectin 1%/clorsulon 10%, levamisole 12%, closantel sodium 5%, ivermectin 10%, and closantel 5%/albendazole 3.75% with a dosage corresponding to each sheep. At 15 days post-treatment, we took fecal samples and performed a coproparasitoscopic study, using the Faust flotation technique to assess the presence or absence of parasite eggs and the McMaster technique to quantify eggs. RESULTS: Ivermectin/clorsulon was more effective in eliminating parasites than other anthelmintics used, especially in Haemonchus spp. CONCLUSION: The results of this study indicate that using ivermectin/clorsulon decreases the number of eggs in feces and is one alternative in controlling parasites in sheep, leading to a reduction in the incidence of health problems, and consequently, improved productivity. PMID- 27956775 TI - Relationship between hepcidin and oxidant/antioxidant status in calves with suspected neonatal septicemia. AB - AIM: This study has been conducted for the purpose of determining serum hepcidin, total antioxidant status (TAS), total oxidant status (TOS), and Fe levels in calves with suspected neonatal septicemia before and after treatment and the clinical significance of hepcidin in calves with suspected neonatal septicemia. MATERIALS AND METHODS: The study material consisted of 15 calves of different ages and sexes brought to the Training, Research and Application Center at the Kafkas University Faculty of Veterinary Medicine with suspected neonatal septicemia. 8.5 mL of blood was drawn from the jugular vein of each animal into coagulant tubes before and after treatment for one-off biochemical analyses and centrifuged. After this, the serum was separated. Hepcidin, TAS, TOS, and Fe levels in the serum were measured. RESULTS: While pre-treatment hepcidin levels were 58.42+/-3.46 ng/mL, post-treatment levels were 46.87+/-2.98 ng/mL (p<0.05). Pre-treatment Fe levels were 60.13+/-7.27 ug/dl, while post-treatment levels were 83.1+/-8.09 ug/dl (p<0.05). The changes in the TAS and TOS levels were also found to be statistically significant. CONCLUSION: In light of the fact that hepcidin plays a role function in the regulation of Fe as well as the fact that Fe is a significant nutritional source for many microorganisms, it was concluded that hepcidin may play a significant role in nutritional immunity and the pathogenesis of diseases. PMID- 27956776 TI - Prevalence of ketosis in dairy cows in milk shed areas of Odisha state, India. AB - AIM: The present study was conducted to ascertain the prevalence of ketosis in dairy cows in dairy herds, milksheds, and mixed population of milk cows selected randomly in milkshed areas of Odisha state, India. MATERIALS AND METHODS: The investigation was conducted in 280 private dairy herds with variable herd size of 10-15 cows comprising crossbred Jersey cows (CBJ), crossbred Holstein Friesian (CHF) cows, and indigenous local breeds. The analysis of urine (Rothera's test), milk (Ross test), and blood samples of 2760 test cows were conducted through qualitative assessment by Rothera's test and Ross test, respectively, for the presence of ketone bodies to screen the ketotic animals. Cut-points have been decided based on beta-hydroxybutyric acid level (>=1.2-1.4 mmol/L) in milk. RESULTS: We noted positive cases of ketosis with a prevalence rate of 36.7% (1014/2760) entailing 27.2% in clinical ketosis and 9.6% in subclinical ketosis. The breed wise incident rate was recorded to be the highest (38.0%) in CBJs. The age-wise prevalence rate was found to be the highest (40.8%) in the age group of 5.5-6.5 years. The season wise prevalence rate in 5th calver was recorded to be the highest (38.6%) in summer season as compared to other seasons. The prevalence of ketosis was observed to be the highest at 56.7% on the first stage of lactation at the 1st month after 2 weeks. The incidence rates for clinical and subclinical ketosis were found to be 25.2%; 12.2%, 26.6%; 11.2% and 30.3%; 2.9% in CBJ, CHF and indigenous cows, respectively. The breed wise overall prevalence rate was recorded to be 38.0% in CBJ, 37.8% in CHF, and 33.2% in indigenous cows. CONCLUSION: Ketosis and subclinical ketosis is highly prevalent metabolic disorder and has severe effect on the production status of affected animal and needs to be prevented, rather than treated, by maintaining cows in good and healthy conditions. We have attempted to give great attention for diagnosis, management, and control of this disease during risk stage to prevent economic loss sustained by the dairy farmers of Eastern India. PMID- 27956777 TI - Helminth infections in domestic dogs from Russia. AB - Dogs are the hosts for a wide helminth spectrum including tapeworms, flatworms, and nematodes. These parasites affect the dog health and cause morbidity and mortality, especially in young and old animals. Some species, as Toxocara canis, Ancylostoma caninum, Dipylidium caninum, and Echinococcus spp. are well-known zoonotic parasites worldwide, resulting in high public health risks. Poor data about canine helminth species and prevalence are available in Russia, mainly due to the absence of official guidelines for the control of dog parasites. Moreover, the consequent low quality of veterinary monitoring and use of preventive measures, the high rate of environmental contamination by dog feces and the increase of stray dog populations, make the control of the environmental contamination by dog helminths very difficult in this country. This paper reviews the knowledge on canine helminth fauna and prevalence in Russia. Practical aspects related to diagnosis, treatment, and control of parasitic diseases of dogs in Russia are discussed. PMID- 27956778 TI - Study of antimicrobial resistance due to extended spectrum beta-lactamase producing Escherichia coli in healthy broilers of Jabalpur. AB - AIM: To study the prevalence of antimicrobial resistance due to extended spectrum beta-lactamase (ESBL)-producing Escherichia coli in samples collected from the ceca of healthy broilers of poultry sale outlets (PSOs) Jabalpur. MATERIALS AND METHODS: A total of 400 cecal swab samples were taken randomly from freshly slaughtered poultry of 39 PSOs located at four different zones or areas of Jabalpur and were screened for the presence of ESBL-producing E. coli using standard methods. Further they were characterized phenotypically by standard methods. RESULTS: All the 400 samples were screened for E. coli producing ESBL enzyme. Among the samples positive for E. coli 135 were positive for ESBL E. coli giving an overall prevalence of 33.5%. CONCLUSION: This study related to the prevalence of ESBL-producing E. coli in healthy broilers in Jabalpur is indicative of antibiotic resistance prevalent in the healthy birds which are used for human consumption as well. It also signifies resistance prevalent against beta-lactam antibiotics including third and fourth generations of cephalosporins. PMID- 27956779 TI - Inhibition of bovine platelets aggregation in response to Hyalomma anatolicum salivary gland proteins/peptides. AB - AIM: Ticks are obligate ectoparasites that have an impact on wide range of vertebrates and also act as a potential vector for the transmission of tropical theileriosis, babesiosis, etc., causing significant loss to livestock production worldwide. While feeding, they introduce their saliva containing different bioactive molecules into the host. These molecules have the capability to counteract the host hemostatic mechanism to suck host blood successfully. Therefore, the study was aimed to isolate anti-platelet aggregating peptides from salivary gland extract (SGE) of Hyalomma anatolicum ticks, a commonly available tick in India. MATERIALS AND METHODS: Female H. anatolicum salivary glands were dissected out and SGE was prepared by homogenizing it in a suitable buffer under ice. Extract so obtained was fractionated by gel filtration chromatography using Sephacryl S-200 column. Total protein concentration in fractions was estimated and bovine platelets were isolated, stimulated with thrombin (positive control), treated with Gly-Pro-Arg-Pro amide (negative control) and with salivary gland fractions for identification of proteins/peptides having anti-platelet aggregating activities. RESULTS: Proteins/peptides present in various salivary gland fractions inhibited the bovine platelet aggregation and the percent inhibition ranged between 33% and 35.8%. CONCLUSION: The results suggests that the fractions of H. anatolicum salivary glands possess thrombin-induced anti platelet aggregating activity and which could be further exploited for raising anti-tick vaccine and also for therapeutic purpose. PMID- 27956780 TI - Benefits of pomegranate (Punica granatum Linn) fruit extracts to weight changes, total protein, and uric acid in white rats (Rattus norvegicus) as an animal model of acute renal failure. AB - AIM: The occurrence of acute renal failure (ARF) cases continues to increase every year. Some of the cases are due to nephrotoxic effect caused by overdose of antibiotic consumption or abuse of the drug, gentamicin. An antibiotic therapy that can be used to overcome in such a case is the pomegranate extracts. However, until now, studies using pomegranate for cases of ARF have not been done. This study aims to determine changes in body weight, the levels of total protein (TP), and the levels of serum uric acid (UA) as a result of the pomegranate extract consumption. MATERIALS AND METHODS: A total number of 32 rats (Rattus norvegicus) were divided into four groups randomly. One group was assigned as the control group (P0) and given intraperitoneal (i.p.) saline and 0.3% carboxy methyl cellulose sodium (CMC) Na; P1 was provided with 80 mg/kg bw/i.p. gentamicin and 0.3% CMC Na orally, P2 was supplied with 80 mg/kg bw/i.p. gentamicin and ellagic acid in 0.3% CMC Na, and P3 was given 80 mg/kg bw/i.p. gentamicin and 150 mg/kg bw pomegranate extract in 0.3% CMC Na. The provision of treatment was carried out in 8 days and followed by making the overthrow of body weight and blood sampling for the examination of study variables. RESULTS: The results taken by doing the analysis of variance method for the four treatment groups show that the control group (P0) has significant differences from P1, P2, and P3 (p<0.05), but there are no significant differences among the other three treatment groups. Meanwhile, the average values of serum UA levels among P1, P2, and P3 indicate significant differences. CONCLUSION: In conclusion, the administration of pomegranate extracts in the treatment of nephrotoxicity toward rats is effective to maintain normal body weight, normal TP levels, and the UA blood serum of the rats. As this study is a preventive therapy, it needs further researches about the effective dose as a curative therapy, its level of effectiveness and its long-term side effects. PMID- 27956781 TI - Comparison of veterinary health services expectations and perceptions between oncologic pet owners, non-oncologic pet owners and veterinary staff using the SERVQUAL methodology. AB - AIM: Client satisfaction gained great importance in health care as a measurement of service quality. One of the most popular methods to evaluate client satisfaction is the SERVQUAL inquiry which measures service quality by evaluating client expectations and services towards a service in five dimensions: Tangibles, Empathy, Assurance, Reliability and Responsiveness. MATERIALS AND METHODS: In order to evaluate if owners of pets with cancer constitute a distinctive group from the general pet owner population and if these differences were perceived by the hospital staff we applied a SERVQUAL questionnaire to 51 owners of pet with cancer, 68 owners from the general pet population and 14 staff members. RESULTS: Owners of oncologic pets had different expectations of an ideal service granting importance to Assurance questions (6.75 vs 6.5, p= 0.045) while showing unmet needs in Reliability and Empathy dimensions. Veterinarians failed to understand these specificities and over evaluated characteristics of Tangible dimension (6.75 vs 6.25, p=0.027). CONCLUSION: Owners of pet with cancer seem to constitute a specific subpopulation with special needs and veterinary staff should invest resources towards Assurance instead of privileging tangible aspects of veterinary services. By aligning professionals expectations with those of pet owners veterinarians can achieve better client satisfaction, improved compliance and stronger doctor-owner relationships. PMID- 27956782 TI - Chronic exposure to indoxacarb and pulmonary expression of toll-like receptor-9 in mice. AB - AIM: Chronic exposure to indoxacarb and pulmonary expression of toll-like receptor 9 (TLR-9) in mice. MATERIALS AND METHODS: In this study, healthy male Swiss albino mice (n=30) aging 8-10 weeks were used to evaluate TLR-9 expression in lungs of mice following indoxacarb exposure with and without lipopolysaccharide (LPS). Indoxacarb was administered orally dissolved in groundnut oil at 4 and 2 mg/kg/day for 90 days. On day 91, five animals from each group were challenged with LPS/normal saline solution at 80 ug/animal. The lung tissues were processed for real time and immunohistochemical studies. RESULTS: LPS resulted increase in fold change m-RNA expression level of TLR-9 as compare to control, while indoxacarb (4 mg/kg) alone and in combination with LPS resulted 16.21-fold change and 29.4-fold change increase in expression of TLR-9 m-RNA, respectively, as compared to control. Similarly, indoxacarb (2 mg/kg) alone or in combination with LPS also altered TLR-9 expression. Further at protein level control group showed minimal expression of TLR-9 in lungs as compare to other groups, however, LPS group showed intense positive staining in bronchial epithelium as well as in alveolar septal cells. Indoxacarb at both doses individually showed strong immuno-positive reaction as compare to control, however when combined with LPS resulted intense staining in airway epithelium as compare to control. CONCLUSION: Chronic oral administration of indoxacarb for 90 days (4 and 2 mg/kg) alters expression of TLR-9 at m-RNA and protein level and co exposure with LPS exhibited synergistic effect. PMID- 27956783 TI - Value added by Spirulina platensis in two different diets on growth performance, gut microbiota, and meat quality of Japanese quails. AB - AIM: The growth promoting effect of the blue-green filamentous alga Spirulina platensis (SP) was observed on meat type Japanese quail with antibiotic growth promoter alternative and immune enhancing power. MATERIALS AND METHODS: This study was conducted on 180 Japanese quail chicks for 4 weeks to find out the effect of diet type (vegetarian protein diet [VPD] and fish meal protein diet [FMPD])- Spirulina dose interaction (1 or 2 g/kg diet) on growth performance, gut microbiota, and sensory meat quality of growing Japanese quails (1-5 weeks old). RESULTS: Data revealed improvement (p<0.05) of weight gain, feed conversion ratio and European efficiency index due to 1, 2 g (SP)/kg VPD, and 2 g (SP)/kg FMPD, respectively. There was a significant decrease of ileum mean pH value by 1 g (SP)/kg VPD. Concerning gut microbiota, there was a trend toward an increase in Lactobacilli count in both 1; 2 g (SP)/kg VPD and 2 g (SP)/kg FMPD. It was concluded that 1 or 2 g (SP)/kg vegetarian diet may enhance parameters of performance without obvious effect on both meat quality and gut microbiota. Moreover, 1 and/or 2 g (SP) may not be invited to share fish meal based diet for growing Japanese quails. CONCLUSION: Using of SP will support the profitable production of Japanese quails fed vegetable protein diet. PMID- 27956784 TI - Allelic and genotypic frequencies in polymorphic Booroola fecundity gene and their association with multiple birth and postnatal growth in Chhotanagpuri sheep. AB - AIM: Chhotanagpuri breed of sheep reared for mutton in Jharkhand, India, having problem of low litter size and body weight. The response of genetic improvement for traits with low heritability through traditional selection method is time consuming. Therefore, marker-assisted selection based on a polymorphism study of suitable candidate gene can response quickly. Thus, this study was aimed at identification of different allelic and genotypic frequencies of Booroola fecundity (FecB) gene and its association with multiple birth and postnatal growth in Chhotanagpuri sheep. MATERIALS AND METHODS: DNA isolation and gene specific amplification of FecB gene was performed from blood samples of from 92 Chhotanagpuri lambs maintained under similar feeding and management conditions. Custom nucleotide sequencing and single-strand conformational polymorphism analysis were performed to identify different genotypes with respect to the target gene. Statistical analysis was performed for determination of allelic and genotypic frequencies of FecB gene polymorphisms and its association with multiple birth and postnatal growth of lambs from birth to 52 weeks age. RESULTS: "AA," "AB," and "BB" genotypes were found at locus-1 as it is polymorphic for FecB gene while locus-2 was found to be monomorphic for FecB gene. Higher frequency of "A" allele at locus-1 was found in single born lambs, whereas "B" allele was predominant among multiple born lambs. The lambs having "BB" genotype weighed significantly (p<=0.01) heavier than those of "AB" and "AA" genotype at 52 weeks of age. CONCLUSION: "BB" genotype has emerged as favored genotype for multiple births and better growth indicator. Therefore, homozygous lambs for "B" allele should be selected and utilized in breeding program for better growth rate. PMID- 27956786 TI - Prophylactic effect of Nigella sativa against lead acetate induced changes in spermiogram, reproductive hormones and gonadal histology of rats. AB - AIM: This study was designed to evaluate the prophylactic effect of Nigella sativa (NS) treatment on toxic effects induced by lead acetate (LA) on the reproductive hormones, spermiogram and gonadal histology of rats. MATERIALS AND METHODS: A total of 20 Sprague-Dawley rats were divided into four groups of five rats each. Group 1 (negative control [NC]) was the NC and was given distilled water, Group 2 served as the positive control (PC) and was administered 10 mg/kg/day of LA per overall survival (OS), Group 3 (T1) was administered 200 mg/kg/daily of NS per OS for a month, and Group 4 (T2) was pretreated with 200 mg/kg/daily of NS per OS for 1 month, followed by 10 mg/kg/daily of LA alone per OS for another. The rats were euthanized at the end of the experimental period for collection of blood and the right caudal epididymis and testis. Serum was used for determination of reproductive hormones by using radioimmunoassay kits. The epididymal segment was cut and homogenized in phosphate-buffered saline, and the homogenate was used for determination of the spermiogram parameters such as sperm concentration, sperm viability, percentage of live sperm, motility and abnormality. Both the epididymis and testis were fixed in 10% buffered formalin for histological processing. RESULTS: The sperm concentration, general, and individual motilities were higher (p<0.05) in the NC and T1 animals, while the T2 had intermediate and the PC had lower (p<0.05) values of each parameter. The percentage sperm viability was higher (p<0.05) in the T1 and lower (p<0.05) in the PC group. However, percentage abnormality was lower in T1, comparable in NC and T2, and higher (p<0.05) in PC. Spermatogenic cell population and epididymal sperm reserve (ESR) were optimal in control and pretreated animals, while the PC had lower spermatids and ESR. The concentration of estradiol (EST) was lower (p<0.05) in the PC and T2, while leuteinizing hormone (LH) concentration was lower (p<0.05) in the PC, and comparable (p>0.05) between control and T2. The concentration of follicle-stimulating hormone (FSH) was comparable (p>0.05) in all groups, while testosterone (TS) hormone concentration was lower (p<0.05) in the PC and higher in the control and T1 groups. CONCLUSION: This study showed the preventive effects of NS administration against alterations in reproductive hormnes, sperm parameters and gonadal histology caused by LA in rats. PMID- 27956785 TI - Seroprevalence of Rotavirus infection in pig population of Arunachal Pradesh. AB - AIM: This study was conducted to find out the seroprevalence of Rotavirus(RV) infection among the pig population of Arunachal Pradesh. MATERIALS AND METHODS: Serums samples were collected from piglets of age ranging from 1 week to 6 months and the sows associated with the piglets that were reared under organized and unorganized system of management in six different districts of Arunachal Pradesh. The prevalence of RV specific antibodies was detected using a polyclonal antibody based indirect enzyme-linked immunosorbent assay (i-ELISA). RESULTS: The study revealed that out of 394 serum samples, 255 (64.72%) samples were found to be positive for RV-specific antibody in i-ELISA. Considering the samples from different districts, Papumpare district of Arunachal Pradesh showed highest numbers of seropositive animals (68.75%) followed by upper Subansiri (64.91%) while West Siang district showed lowest positivity rate (61.22%). CONCLUSION: As considerable seropositivity was recorded among pig population of Arunachal Pradesh in this study, there is urgent need to establish high-impact and cost effective public health intervention tools, key among them being the introduction of strict hygiene practice and RV vaccination program, to greatly reduce the number of deaths due to diarrheal diseases. To the authors' knowledge, this is the first report on the prevalence of RV infection from pigs of Arunachal Pradesh. PMID- 27956787 TI - Occurrence and antimicrobial resistance of pathogenic Escherichia coli and Salmonella spp. in retail raw table eggs sold for human consumption in Enugu state, Nigeria. AB - AIM: This study was conducted to investigate the occurrence of pathogenic Escherichia coli and Salmonella species in retail raw table eggs sold for human consumption in Enugu State and to determine the resistance of these pathogens to antimicrobials commonly used in human and veterinary practices in Nigeria. MATERIALS AND METHODS: A total of 340 raw table eggs comprising 68 composite samples (5 eggs per composite sample) were collected from five selected farms (13 composite samples from the farms) and 10 retail outlets (55 composite samples from the retail outlets) in the study area over a period of 4-month (March-June, 2014). The eggs were screened for pathogenic E. coli and Salmonella species following standard procedures within 24 h of sample collection. Isolates obtained were subjected to in-vitro antimicrobial susceptibility test with 15 commonly used antimicrobials using the disk diffusion method. RESULTS: About 37 (54.4%) and 7 (10.3%) of the 68 composite samples were positive for pathogenic E. coli and Salmonella species, respectively. The shells showed significantly higher (p<0.05) contaminations than the contents for both microorganisms. The eggs from the farms showed higher contamination with pathogenic E. coli than eggs from the retail outlets while the reverse was the case for Salmonella species even though they were not significant (p>0.05). The organisms obtained showed a multiple drug resistance. They were completely resistant to nitrofurantoin, sulfamethoxazole/trimethoprim, penicillin G and oxacillin. In addition to these, Salmonella spp. also showed 100% resistance to tetracycline. The pathogenic E. coli isolates obtained were 100% susceptible to gentamicin, neomycin, ciprofloxacin, and amoxicillin-clavulanic acid while Salmonella spp. showed 100% susceptibility to erythromycin, neomycin, and rifampicin. Both organisms showed varying degrees of resistance to streptomycin, amoxicillin, vancomycin, and doxycycline. CONCLUSION: From the results of the study, it can be concluded that the raw table eggs marketed for human consumption in Enugu State, Nigeria is contaminated with pathogenic E. coli and Salmonella species that showed multiple drug resistance to antimicrobial agents commonly used in veterinary and human practice. PMID- 27956788 TI - Steroid and metabolic hormonal profile of porcine serum vis-a-vis ovarian follicular fluid. AB - AIM: This study was conducted to understand whether serum level of the steroid and metabolic hormones may be indicative of their level in ovarian follicular fluid (FF) in porcine, and its influence on fertility. MATERIALS AND METHODS: Ovaries from pigs (n=32) of two genetic groups, namely, native (Ghungroo; n=16) and crossbred (Hampshire * Ghungroo; n=16) were collected. Both the genetic groups comprised gilts (n=8) and sows (n=8), and sows were in luteal phase of estrus cycle. FF was aspirated from small, medium and large follicles, and centrifuged for the collection of supernatant for further analysis. Blood samples were collected from the same animals, and serum was separated. Hormones, namely, cortisol, T3, T4 and testosterone were estimated by radioimmunoassay. Two-way ANOVA was used for analysis of data considering genetic background (native or crossbred), stage of reproductive life (gilt or sow), and source of sample (serum or FF) as fixed effects. RESULTS: It was observed that all the hormones except cortisol differed significantly (p<0.01) based on genetic background. Stage of reproductive life and source of sample did not affect the studied hormonal level. Within the genetic groups, stage of reproductive life influenced T3 (p<0.01), cortisol (p<0.05) and testosterone (p<0.01) level in crossbred pigs as compared to T3 (p<0.01) only in native pigs. The level of T3 in serum, as well as FF, was higher (p<0.01) in Ghungroo gilts compared to sows. However, a reverse of this was observed in the case of crossbred pigs. The level of cortisol (p<0.05) and testosterone (p<0.01) was higher in crossbred sows than gilts in both serum and FF. CONCLUSION: The study revealed that serum level of the steroid and metabolic hormones is indicative of their level in the ovarian FF. Further, varying level of steroid and metabolic hormones in pigs based on genetic background may be due to variation in body size, rate of energy metabolism and stage of (re)productive life. PMID- 27956789 TI - Honeybee product therapeutic as stem cells homing for ovary failure. AB - AIM: Complexity of the method of isolation, cultivation in vitro and the expensive cost of transplantation process of stem cells, it would require an innovation to homing and differentiation of stem cells and increase folliculogenesis. The stem cells homing was achieved through the provision of food or beverages derived from natural materials like honeybee product. Through honeybee product, there will be homing of stem cells and accompany with the sources from the body itself will take place in regeneration of the ovary. MATERIALS AND METHODS: Female rats model of degenerative ovary was obtained through food fasting but still have drinking water for 5 days. It caused malnutrition and damage of the ovarian tissue. The administration of 50% honeybee product (T1) was performed for 10 consecutive days, while the positive control group (T0+) was fasted and not given honeybee product and the negative control (T0-) not fasted and without honeybee product. Observations were taken for homing of stem cells, raised of folliculogenesis, differentiation of stem cells, and regeneration of the ovarian tissue using routine H&E staining. RESULTS: Homing of stem cells shown the vascular endothelial growth factor and granulocyte colony stimulating factor expression; enhancement of folliculogenesis was indicated by an increase of follicle dee Graaf count; enhancement of differentiation of stem cells was indicated by growth differentiation factor-9 expression; and regeneration of ovarian tissue indicated by intact ovarian tissue with growing follicles. CONCLUSION: Honeybee product can be induced endogenous stem cells in regeneration of ovary failure due to malnutrition. PMID- 27956790 TI - Amelioration of Gamma-hexachlorocyclohexane (Lindane) induced renal toxicity by Camellia sinensis in Wistar rats. AB - AIM: A study to assess the toxic effects of gamma-hexachlorocyclohexane (gamma HCH) (lindane) and ameliorative effects of Camellia sinensis on renal system has been carried out in male Wistar rats. MATERIALS AND METHODS: Four groups of rats with 18 each were maintained under standard laboratory hygienic conditions and provided feed and water ad libitum. gamma-HCH was gavaged at 20 mg/kg b.wt. using olive oil as vehicle to Groups II. C. sinensis at 100 mg/kg b.wt. was administered orally in distilled water to Group IV in addition to gamma-HCH 20 mg/kg b.wt. up to 45 days to study ameliorative effects. Groups I and III were treated with distilled water and C. sinensis (100 mg/kg b.wt.), respectively. Six rats from each group were sacrificed at fortnight intervals. Serum was collected for creatinine estimation. The kidney tissues were collected in chilled phosphate buffer saline for antioxidant profile and in also 10% buffered formalin for histopathological studies. RESULTS: gamma-HCH treatment significantly increased serum creatinine and significantly reduced the renal antioxidative enzymes catalase, superoxide dismutase, and glutathione peroxidase. Grossly, severe congestion was noticed in the kidneys. Microscopically, kidney revealed glomerular congestion, atrophy, intertubular hemorrhages, degenerative changes in tubular epithelium with vacuolated cytoplasm, desquamation of epithelium and urinary cast formation. A significant reduction in serum creatinine levels, significant improvement in renal antioxidant enzyme activities and near to normal histological appearance of kidneys in Group IV indicated that the green tea ameliorated the effects of gamma-HCH, on renal toxicity. CONCLUSION: This study suggested that C. sinensis extract combined with gamma-HCH could enhance antioxidant/detoxification system which consequently reduced the oxidative stress thus potentially reducing gamma-HCH toxicity and tissue damage. PMID- 27956791 TI - Percutaneous ablation of pancreatic cancer. AB - Pancreatic ductal adenocarcinoma is a highly aggressive tumor with an overall 5 year survival rate of less than 5%. Prognosis and treatment depend on whether the tumor is resectable or not, which mostly depends on how quickly the diagnosis is made. Chemotherapy and radiotherapy can be both used in cases of non-resectable pancreatic cancer. In cases of pancreatic neoplasm that is locally advanced, non resectable, but non-metastatic, it is possible to apply percutaneous treatments that are able to induce tumor cytoreduction. The aim of this article will be to describe the multiple currently available treatment techniques (radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation), their results, and their possible complications, with the aid of a literature review. PMID- 27956793 TI - Epidemiology of pancreatic cancer. AB - Cancer of the pancreas remains one of the deadliest cancer types. Based on the GLOBOCAN 2012 estimates, pancreatic cancer causes more than 331000 deaths per year, ranking as the seventh leading cause of cancer death in both sexes together. Globally, about 338000 people had pancreatic cancer in 2012, making it the 11th most common cancer. The highest incidence and mortality rates of pancreatic cancer are found in developed countries. Trends for pancreatic cancer incidence and mortality varied considerably in the world. A known cause of pancreatic cancer is tobacco smoking. This risk factor is likely to explain some of the international variations and gender differences. The overall five-year survival rate is about 6% (ranges from 2% to 9%), but this vary very small between developed and developing countries. To date, the causes of pancreatic cancer are still insufficiently known, although certain risk factors have been identified, such as smoking, obesity, genetics, diabetes, diet, inactivity. There are no current screening recommendations for pancreatic cancer, so primary prevention is of utmost importance. A better understanding of the etiology and identifying the risk factors is essential for the primary prevention of this disease. PMID- 27956794 TI - Galectin-3 and IL-33/ST2 axis roles and interplay in diet-induced steatohepatitis. AB - Immune reactivity and chronic low-grade inflammation (metaflammation) play an important role in the pathogenesis of obesity-associated metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases that include liver steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from hepatic steatosis to NASH and fibrosis through the development of proinflammatory and profibrotic processes in the liver, including increased hepatic infiltration of innate and adaptive immune cells, altered balance of cytokines and chemokines, increased reactive oxygen species generation and hepatocellular death. Experimental models of dietary-induced NAFLD/NASH in mice on different genetic backgrounds or knockout mice with different immune reactivity are used for elucidating the pathogenesis of NASH and liver fibrosis. Galectin-3 (Gal-3), a unique chimera-type beta-galactoside binding protein of the galectin family has a regulatory role in immunometabolism and fibrogenesis. Mice deficient in Gal-3 develop pronounced adiposity, hyperglycemia and hepatic steatosis, as well as attenuated liver inflammation and fibrosis when fed an obesogenic high-fat diet. Interleukin (IL)-33, a member of the IL-1 cytokine family, mediates its effects through the ST receptor, which is present on immune and nonimmune cells and participates in immunometabolic and fibrotic disorders. Recent evidence, including our own data, suggests a protective role for the IL-33/IL-33R (ST2) signaling pathway in obesity, adipose tissue inflammation and atherosclerosis, but a profibrotic role in NASH development. The link between Gal-3 and soluble ST2 in myocardial fibrosis and heart failure progression has been demonstrated and we have recently shown that Gal-3 and the IL-33/ST2 pathway interact and both have a profibrotic role in diet induced NASH. This review discusses the current evidence on the roles of Gal-3 and the IL-33/ST2 pathway and their interplay in obesity-associated hepatic inflammation and fibrogenesis that may be of interest in the development of therapeutic interventions to prevent and/or reverse obesity-associated hepatic inflammation and fibrosis. PMID- 27956795 TI - Gene polymorphisms of pathogenic Helicobacter pylori in patients with different types of gastrointestinal diseases. AB - Helicobacter pylori (H. pylori) is a kind of chronic infectious pathogen which can cause chronic gastritis, peptic ulcer, gastric cancer and other diseases. The genetic structure of the pathogenic genes of H. pylori varies largely, which contributes to the differences in virulence among various strains, and in clinical symptoms. Virulence genes of H. pylori can be categorized into three main classes: those related to adhesion and colonization, those related to gastric mucosal injury, and others. This review focuses on the relationship between genetic polymorphisms of the three classes of virulence genes of H. pylori and diseases. Most of the genetic polymorphisms of the main virulence factors of H. pylori are summarized in this paper. PMID- 27956792 TI - Fatty liver is associated with an increased risk of diabetes and cardiovascular disease - Evidence from three different disease models: NAFLD, HCV and HIV. AB - Fatty liver, which frequently coexists with necro-inflammatory and fibrotic changes, may occur in the setting of nonalcoholic fatty liver disease (NAFLD) and chronic infections due to either hepatitis C virus (HCV) or human immunodeficiency virus (HIV). These three pathologic conditions are associated with an increased prevalence and incidence of cardiovascular disease (CVD) and type 2 diabetes (T2D). In this multidisciplinary clinical review, we aim to discuss the ever-expanding wealth of clinical and epidemiological evidence supporting a key role of fatty liver in the development of T2D and CVD in patients with NAFLD and in those with HCV or HIV infections. For each of these three common diseases, the epidemiological features, pathophysiologic mechanisms and clinical implications of the presence of fatty liver in predicting the risk of incident T2D and CVD are examined in depth. Collectively, the data discussed in this updated review, which follows an innovative comparative approach, further reinforce the conclusion that the presence of fatty/inflamed/fibrotic liver might be a shared important determinant for the development of T2D and CVD in patients with NAFLD, HCV or HIV. This review may also open new avenues in the clinical and research arenas and paves the way for the planning of future, well-designed prospective and intervention studies. PMID- 27956797 TI - Ex vivo response to mucosal bacteria and muramyl dipeptide in inflammatory bowel disease. AB - AIM: To evaluate how mucosal bacteria impact on the spontaneous and muramyl dipeptide (MDP)-induced inflammation in Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Colonic mucosal biopsies were collected from children with active or remissive CD, UC and controls. Two tissue samples were taken from inflamed mucosal segments (in patients with active disease) or from non-inflamed mucosa [in patients in remission or in healthy controls (HC)]. Experiments were performed in the presence or absence of antibiotics, to assess whether the disease-associated microbiota can modulate the cytokine response ex vivo. For this purpose, each specimen was half-cut to compare spontaneous and MDP-induced inflammation in the presence of live bacteria (LB) or antibiotics. After 24 h of culture, an array of 17 cytokines was assessed in supernatants. Statistical analyses were performed to find significant differences in single cytokines or in patterns of cytokine response in the different groups. RESULTS: We demonstrated that subjects with CD display a spontaneous production of inflammatory cytokines including granulocyte-colony stimulating factor (G-CSF), interleukin (IL) 6, IL8, IL10 and IL12, that was not significantly influenced by the addition of antibiotics. UC specimens also displayed a trend of increased spontaneous secretion of several cytokines, which however was not significant due to broader variability among patients. After the addition of antibiotics, spontaneous IL8 secretion was significantly higher in UC than in controls. In HC, a trend towards the weakening of spontaneous IL8 production was observed in the presence of live mucosal bacteria with respect to the presence of antibiotics. In contrast, in the presence of LB UC showed an increasing trend of spontaneous IL8 production, while MDP stimulation resulted in lower IL8 production in the presence of antibiotics. We also showed that subjects with CD seem to have a lowered production of IL8 in response to MDP in the presence of LB. Only with the addition of antibiotics, likely reducing the contribution of LB, multivariate statistical analysis could identify the combination of measures of G-CSF, tumor necrosis factor alpha, IL4 and IL17 as a good discriminator between CD and UC. CONCLUSION: We showed that the presence of LB or antibiotics can significantly influence the inflammatory response ex vivo in inflammatory bowel diseases. PMID- 27956796 TI - Infliximab does not increase colonic cancer risk associated to murine chronic colitis. AB - AIM: To explore the influence of Infliximab (IFX) on cancer progression in a murine model of colonic cancer associated to chronic colitis. METHODS: AOM/DSS model was induced in C57BL/6 mice. Mice were injected with IFX (5 mg/kg) during each DSS cycle while control mice received saline. Body weight, occult blood test and stool consistency were measured to calculate the disease activity index (DAI). Mice were sacrificed at week 10 and colons were analyzed macroscopically and microscopically for number of cancers and degree of inflammation. MTT assay was performed on CT26 to evaluate the potential IFX role on metabolic activity and proliferation. Cells were incubated with TNF-alpha or IFX or TNF-alpha plus IFX, and cell vitality was evaluated after 6, 24 and 48 h. The same setting was used after pre-incubation with TNF-alpha for 24 h. RESULTS: IFX significantly reduced DAI and body weight loss in mice compared with controls, preserving also colon length at sacrifice. Histological score was also reduced in treated mice. At macroscopic analysis, IFX treated mice showed a lower number of tumor lesions compared to controls. This was confirmed at microscopic analysis, although differences were not statistically significant. In vitro, IFX treated CT26 maintained similar proliferation ability at MTT test, both when exposed to IFX alone and when associated to TNF-alpha. CONCLUSION: IFX did not increase colonic cancer risk in AOM-DSS model of cancer on chronic colitis nor influence directly the proliferation of murine colon cancer epithelial cells. PMID- 27956798 TI - Angiopoietin-2/angiopoietin-1 as non-invasive biomarker of cirrhosis in chronic hepatitis C. AB - AIM: To evaluate the efficacy of peripheral blood concentrations of angiopoietins (Ang) as cirrhosis biomarkers of chronic hepatitis C (CHC). METHODS: Ang1 and Ang2 serum levels were measured by enzyme-linked immunosorbent assays (ELISA) in samples from 179 cirrhotic and non-cirrhotic CHC patients, classified according to the METAVIR system. Groups were compared by non-parametric Mann-Whitney U test. Subsequently, the association of peripheral concentrations of angiopoietins with the stage of fibrosis was analyzed using Spearman correlation test. Finally, the accuracy, sensitivity and specificity of circulating angiopoietins for cirrhosis diagnosis were determined by the study of the respective area under the curve of receiver operator characteristics (AUC-ROC). RESULTS: Peripheral blood concentrations of Ang1 and Ang2 in CHC patients were significantly related to fibrosis. While Ang1 was decreased in cirrhotic subjects compared to non cirrhotic (P < 0.0001), Ang2 was significantly increased as CHC progressed to the end stage of liver disease (P < 0.0001). Consequently, Ang2/Ang1 ratio was notably amplified and significantly correlated with fibrosis (P < 0.0001). Interestingly, the individual performance of each angiopoietin for the diagnosis of cirrhosis reached notable AUC-ROC values (above 0.7, both), but the Ang2/Ang1 ratio was much better (AUC-ROC = 0.810) and displayed outstanding values of sensitivity (71%), specificity (84%) and accuracy (82.1%) at the optimal cut-off (10.33). Furthermore, Ang2/Ang1 ratio improved the performance of many other previously described biomarkers or scores of liver cirrhosis in CHC. CONCLUSION: Ang2/Ang1 ratio might constitute a useful tool for monitoring the progression of chronic liver disease towards cirrhosis and play an important role as therapeutic target. PMID- 27956799 TI - Transient receptor potential vanilloid 1-immunoreactive signals in murine enteric glial cells. AB - AIM: To investigate the possible involvement of transient receptor potential vanilloid 1 (TRPV1) in maturation of enteric glial cells (EGCs). METHODS: Immunohistochemical and immunocytochemical techniques were used to analyze EGC markers in myenteric plexus (MP) as well as cultured MP cells and EGCs using TRPV1 knockout (KO) mice. RESULTS: We detected TRPV1-immunoreactive signals in EGC in the MP of wild-type (WT) but not KO mice. Expression of glial fibrillary acidic protein (GFAP) immunoreactive signals was lower at postnatal day (PD) 6 in KO mice, though the difference was not clear at PD 13 and PD 21. When MP cells were isolated and cultured from isolated longitudinal muscle-MP preparation from WT and KO mice, the yield of KO EGC was lower than that of WT EGC, while the yield of KO and WT smooth muscle cells showed no difference. Addition of BCTC, a TRPV1 antagonist, to enriched EGC culture resulted in a decrease in the protein ratio of GFAP to S100B, another EGC/astrocyte-specific marker. CONCLUSION: These results address the possibility that TRPV1 may be involved in the maturation of EGC, though further studies are necessary to validate this possibility. PMID- 27956800 TI - Anticancer effect of linalool via cancer-specific hydroxyl radical generation in human colon cancer. AB - AIM: To investigate the anticancer mechanisms of the monoterpenoid alcohol linalool in human colon cancer cells. METHODS: The cytotoxic effect of linalool on the human colon cancer cell lines and a human fibroblast cell line was examined using the WST-8 assay. The apoptosis-inducing effect of linalool was measured using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and flow cytometry with Annexin V. Oxidative stress was investigated by staining for diphenyl-1-pyrenylphosphine, which is a cellular lipid peroxidation marker, and electron spin resonance spectroscopy. Sixteen SCID mice xenografted with human cancer cells were randomized into 3 groups for in vivo analysis: control and low-dose and high-dose linalool groups. The control group was administered tap water orally every 3 d. The linalool treatment groups were administered 100 or 200 MUg/kg linalool solution orally for the same period. All mice were sacrificed under anesthesia 21 d after tumor inoculation, and tumors and organs were collected for immunohistochemistry using an anti-4-hydroxynonenal antibody. Tumor weights were measured and compared between groups. RESULTS: Linalool induced apoptosis of cancer cells in vitro, following the cancer specific induction of oxidative stress, which was measured based on spontaneous hydroxyl radical production and delayed lipid peroxidation. Mice in the high-dose linalool group exhibited a 55% reduction in mean xenograft tumor weight compared with mice in the control group (P < 0.05). In addition, tumor-specific lipid peroxidation was observed in the in vivo model. CONCLUSION: Linalool exhibited an anticancer effect via cancer-specific oxidative stress, and this agent has potential for application in colon cancer therapy. PMID- 27956801 TI - Naringenin protects against isoniazid- and rifampicin-induced apoptosis in hepatic injury. AB - AIM: To explore the protective effects and mechanisms of naringenin (NRG) on hepatic injury induced by isoniazid (INH) and rifampicin (RIF). METHODS: Male mice were randomly divided into four groups and treated for 14 d as follows: normal control group was administered intragastrically with normal saline solution alone; model group was administered intragastrically with INH (100 mg/kg) and RIF (100 mg/kg); low- and high-dosage NRG pretreatment groups were administered intragastrically with different doses of NRG (50 or 100 mg/kg) 2 h before INH and RIF challenge. Mice were killed 16 h after the last dose of drug treatment to determine activity of serum transaminases. Oxidative stress was evaluated by measuring hepatic glutathione (GSH) and superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Histopathological changes in hepatic tissue were observed under the optical microscope. Hepatocyte apoptosis was measured by TUNEL assay and caspase-3 activation. Expression of Bcl-2 and Bax in liver was determined by western blot. RESULTS: Both low- and high-dosage NRG pretreatment obviously alleviated serum levels of alanine aminotransferase and aspartate aminotransferase, liver index, hepatic MDA content, and increased hepatic GSH content and SOD activity compared with the INH and RIF-treated group (44.71 +/- 8.15 U/L, 38.22 +/- 6.64 U/L vs 58.15 +/- 10.54 U/L; 98.36 +/- 14.78 U/L, 92.41 +/- 13.59 U/L vs 133.05 +/- 19.36 U/L; 5.34% +/- 0.26%, 4.93% +/- 0.25% vs 5.71% +/- 0.28%; 2.76 +/- 0.67 nmol/mgprot, 2.64 +/- 0.64 nmol/mgprot vs 4.49 +/- 1.12 nmol/mgprot; 5.91 +/- 1.31 mg/gprot, 6.42 +/- 1.42 mg/gprot vs 3.11 +/- 0.73 mg/gprot; 137.31 +/- 24.62 U/mgprot, 148.83 +/- 26.75 U/mgprot vs 102.34 +/- 19.22 U/mgprot; all P < 0.01 or 0.05). Histopathological evaluation showed obvious necrosis and inflammatory cell infiltration in liver of mice administered INH and RIF; however, mice pretreated with NRG showed minor hepatic injury. In addition, INH and RIF resulted in hepatocyte apoptosis, and NRG pretreatment dramatically suppressed INH- and RIF-induced hepatocytes apoptosis. Furthermore, NRG-mediated anti-apoptotic effects seemed to be in connection with its regulation of Bax and Bcl-2 protein expression in hepatic tissue. CONCLUSION: NRG might attenuate INH- and RIF-induced hepatic injury via suppression of oxidative stress and hepatocyte apoptosis. PMID- 27956802 TI - Effects of omega-3 fatty acids on toll-like receptor 4 and nuclear factor-kappaB p56 in lungs of rats with severe acute pancreatitis. AB - AIM: To determine the effects of omega-3 fatty acids (omega-3FA) on the toll-like receptor 4 (TLR4)/nuclear factor kappaB p56 (NF-kappaBp56) signal pathway in the lungs of rats with severe acute pancreatitis (SAP). METHODS: A total of 56 Sprague-Dawley rats were randomly divided into 4 groups: control group, SAP saline group, SAP-soybean oil group and SAP-omega-3FA group. SAP was induced by the retrograde infusion of sodium taurocholate into the pancreatic duct. The expression of TLR4 and NF-kappaBp56 in the lungs was evaluated by immunohistochemistry and Western blot analysis. The levels of inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha in the lungs were measured by enzyme-linked immunosorbent assay. RESULTS: The expression of TLR4 and NF-kappaBp56 in lungs and of inflammatory cytokines in serum significantly increased in the SAP group compared with the control group (P < 0.05), but was significantly decreased in the omega-3FA group compared with the soybean oil group at 12 and 24 h (P < 0.05). CONCLUSION: During the initial stage of SAP, omega-3FA can efficiently lower the inflammatory response and reduce lung injury by triggering the TLR4/NF-kappaBp56 signal pathway. PMID- 27956803 TI - Association between Helicobacter pylori status and metachronous gastric cancer after endoscopic resection. AB - AIM: To investigate the effect of Helicobacter pylori (H. pylori) status test and H. pylori eradication on the occurrence of metachronous gastric cancer (MGC) after endoscopic submucosal dissection (ESD) of early gastric cancer (EGC) and risk factors of MGC. METHODS: The authors retrospectively reviewed the medical records of 433 patients (441 lesions) who underwent ESD for EGC from January 2005 to January 2015 in Yeungnam University Hospital. Patients were categorized into two groups; the H. pylori tested group (n = 257) and the H. pylori non-tested group (n = 176) based on performance of H. pylori status test after ESD of EGC. The H. pylori tested group was further categorized into three subgroups based on H. pylori status; the H. pylori-eradicated subgroup (n = 120), the H. pylori persistent subgroup (n = 42), and the H. pylori-negative subgroup (n = 95). Incidences of MGC and risk factors of MGC were identified. RESULTS: Median follow up duration after ESD was 30.00 mo (range, 6-107 mo). Total 15 patients developed MGC during follow-up. MGC developed in 11 patients of the H. pylori tested group (7 in the H. pylori-negative subgroup, 3 in the H. pylori-eradicated subgroup, and 1 in the H. pylori-persistent subgroup) and 4 patients of the H. pylori non tested group (P > 0.05). The risk factors of MGC were endoscopic mucosal atrophy in the H. pylori tested group and intestinal metaplasia in all patients. CONCLUSION: H. pylori eradication and H. pylori status test seems to have no preventive effect on the development of MGC after ESD for EGC. The risk factors of MGC development were endoscopic mucosal atrophy in the H. pylori tested group alone and intestinal metaplasia in all patients. PMID- 27956804 TI - Prognostic implications of FGFR1 and MYC status in esophageal squamous cell carcinoma. AB - AIM: To investigate the clinicopathological features and prognostic implications of combined MYC and fibroblast growth factor receptor 1 (FGFR1) status in esophageal squamous cell carcinomas (ESCCs). METHODS: All patients with ESCC (n = 180) underwent surgical resection at Seoul National University Hospital sometime between 2000 and 2013. A tissue microarray was constructed using cores obtained from representative tumor areas of formalin-fixed, paraffin-embedded tissue blocks. FGFR1 and MYC copy numbers were quantified using fluorescence in situ hybridization. The level of MYC expression was determined using immunohistochemistry. FGFR1 and MYC amplification status was compared between primary and metastatic lymph nodes. Univariate and multivariate survival analyses were performed according to adjuvant therapy status. RESULTS: FGFR1 and MYC amplifications were observed in 21.4% (37/173) and 54.2% (91/168) of patients, respectively, while MYC expression was observed in 58.9% (106/180) of patients. There was a positive correlation between MYC amplification and overexpression (P = 0.002). Although FGFR1 amplification was not associated with MYC amplification or expression, 12.3% (20/163) of patients exhibited both FGFR1 amplification and MYC expression. There was also a correlation in FGFR1 amplification status between matched primary tumors and metastatic lymph nodes (P < 0.001). MYC expression was higher in ESCCs with pT1 (P < 0.001) and in those with no lymph node metastasis (P = 0.023). MYC expression was associated with prolonged disease free survival (P = 0.036) and overall survival (OS) (P = 0.017) but was not an independent prognostic factor. FGFR1 amplification was an independent predictor for prolonged OS in all patients (P = 0.029) and in those who did not receive adjuvant therapy (P = 0.013). Combined FGFR1 amplification and MYC expression predicted better OS in patients who did not receive adjuvant therapy (P = 0.034) but not in those who did receive adjuvant therapy. CONCLUSION: FGFR1 amplification and MYC expression have prognostic implications in resected ESCCs with respect to adjuvant therapy. The role of FGFR1-targeted therapy in ESCC remains to be explored. PMID- 27956806 TI - Therapeutic efficacy and stent patency of transhepatic portal vein stenting after surgery. AB - AIM: To evaluate portal vein (PV) stenosis and stent patency after hepatobiliary and pancreatic surgery, using abdominal computed tomography (CT). METHODS: Percutaneous portal venous stenting was attempted in 22 patients with significant PV stenosis (> 50%) - after hepatobiliary or pancreatic surgery - diagnosed by abdominal CT. Stents were placed in various stenotic lesions after percutaneous transhepatic portography. Pressure gradient across the stenotic segment was measured in 14 patients. Stents were placed when the pressure gradient across the stenotic segment was > 5 mmHg or PV stenosis was > 50%, as observed on transhepatic portography. Patients underwent follow-up abdominal CT and technical and clinical success, complications, and stent patency were evaluated. RESULTS: Stent placement was successful in 21 patients (technical success rate: 95.5%). Stents were positioned through the main PV and superior mesenteric vein (n = 13), main PV (n = 2), right and main PV (n = 1), left and main PV (n = 4), or main PV and splenic vein (n = 1). Patients showed no complications after stent placement. The time between procedure and final follow-up CT was 41-761 d (mean: 374.5 d). Twenty stents remained patent during the entire follow-up. Stent obstruction - caused by invasion of the PV stent by a recurrent tumor - was observed in 1 patient in a follow-up CT performed after 155 d after the procedure. The cumulative stent patency rate was 95.7%. Small in-stent low-density areas were found in 11 (55%) patients; however, during successive follow-up CT, the extent of these areas had decreased. CONCLUSION: Percutaneous transhepatic stent placement can be safe and effective in cases of PV stenosis after hepatobiliary and pancreatic surgery. Stents show excellent patency in follow-up abdominal CT, despite development of small in-stent low-density areas. PMID- 27956805 TI - IFIT1 polymorphisms predict interferon-alpha treatment efficiency for hepatitis B virus infection. AB - AIM: To investigate the association between interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) polymorphisms and interferon-alpha (IFNalpha) treatment efficiency among Chinese hepatitis B virus (HBV) infection patients. METHODS: Two hundred and twenty five newly diagnosed chronic hepatitis B (CHB) patients were enrolled in the study. All of these patients received IFNalpha treatment for a course of 48 wk, and were followed up for 24 wk after the treatment was end. Clinical information about virological response, hepatitis B e antigen (HBeAg) seroconversion rate and combined response at the end of the treatment, as well as the sustained response by the time of following up 24 wk after the treatment, was collected. Four tag-single nucleotide polymorphisms (SNPs) of IFIT1 were selected and assessed for their association with these clinical outcomes. RESULTS: At the end of the treatment, HBeAg seroconversion was observed in 27.1% patients. Thirty-six point nine percent patients achieved virological response, and 15.6% patients exhibited combined response. Sustained response was obtained in 26.2% patients. The main HBV genotype of the study was genotype B. Patients who infected with HBV genotype B or C showed better treatment efficiency, no matter which clinical outcome was considered. Among the four SNPs assessed, rs303218 (A > G) was found to be significantly associated with the end point virological response when assuming additive model [OR = 0.64 (95%CI: 0.42-0.96), P = 0.032]. Patients who carried rs303218 GG genotype had a rather higher rate of achieving virological response (response rate: 52%, OR = 0.40, 95%CI: 0.18-0.91; P = 0.028) when compared to those had AA genotype (response rate: 27%). The most significant interaction was observed in patients who had relative lower baseline aspartate transaminase. No association between SNPs and HBeAg seroconversion, combined response or sustained response was observed. CONCLUSION: IFIT1 involves in the regulation of IFNalpha treatment for CHB and its polymorphism rs303218 can predict the end point virological response. The finding requires further validation. PMID- 27956808 TI - Clinical features of HBsAg seroclearance in hepatitis B virus carriers in South Korea: A retrospective longitudinal study. AB - AIM: To investigate the characteristic features of hepatitis B surface antigen (HBsAg) seroclearance among Korean hepatitis B virus (HBV) carriers. METHODS: Carriers with HBsAg seroclearance were selected by analyzing longitudinal data collected from 2003 to 2015. The period of time from enrollment to the negative conversion of HBsAg (HBsAg-NC) was compared by stratifying various factors, including age, sex, hepatitis B e antigen (HBeAg), HBV DNA, sequential changes in the signal-to-cutoff ratio of HBsAg (HBsAg-SCR), as measured by qualitative HBsAg assay, and chronic liver disease on ultrasonography (US-CLD). Quantification of HBV DNA and HBsAg (HBsAg-QNT) in the serum was performed by commercial assay. RESULTS: Among the 1919 carriers, 90 (4.7%) exhibited HBsAg-NC at 6.2 +/- 3.6 years after registration, with no differences observed among the different age groups. Among these carriers, the percentages of those with asymptomatic liver cirrhosis (LC) and hepatocellular carcinoma (HCC) at registration were 31% and 7.8%, respectively. The frequency of HBsAg-NC significantly differed according to the HBV DNA titer and US-CLD. HBeAg influenced HBsAg-NC in the 40-50 and 50-60 year age groups. HBsAg-SCR < 1000 was correlated with an HBsAg-QNT < 200 IU/mL. A gradual decrease in the HBsAg-SCR to < 1000 predicted HBsAg-NC. Six patients developed HCC after registration, including two before and four after HBsAg-NC. The rate at which the patients developed new HCC after HBsAg seroclearance was 4.8%. LC with excessive drinking and vertical infection were found to be risk factors for HCC in the HBsAg-NC group. CONCLUSION: HCC surveillance should be continued after HBsAg seroclearance. An HBsAg-SCR < 1000 and its decrease in sequential testing are worth noting as predictive markers of HBsAg loss. PMID- 27956807 TI - Attempt to calculate the prevalence and features of chronic hepatitis C infection in Tuscany using administrative data. AB - AIM: To evaluate this prevalence in Tuscan populations that was known and unknown to the Tuscan Regional Health Service in 2015. METHODS: Tuscan Health administrative data were used to evaluate hepatitis C virus (HCV) infected people known to the Regional Health Service. Residents in Tuscany with a HCV exemption code (070.54) were identified. Using the universal code attributed to each resident, these patients were matched with hospital admission codes identified by the International Classification of Diseases, Ninth Revision (ICD-9), Clinical Modification, and with codes for dispensing drugs to patients by local and hospital pharmacies. Individuals were considered only once. Capture-recapture analysis was used to evaluate the HCV-infected population unknown to the Regional Health Service. RESULTS: In total, 14526 individuals were living on 31/12/2015 with an exemption code for HCV. In total, 9524 patients were treated with pegylated interferon + ribavirin and/or direct-acting antiviral drugs during the last 10 years, and 13879 total hospital admissions were noted in the last 15 years. After data linkage, the total number was 25918. After applying the Capture Recapture analysis, the number of unknown HCV-infected people was 23497. Therefore, the total number of chronic HCV-infected people was 38643, excluding those achieved sustained virological response to previous treatment. CONCLUSION: Our results show a prevalence of HCV infected people of 1%. Tuscan administrative data could be useful for calculating health care costs and health planning in the coming years. PMID- 27956809 TI - Disease-specific miR-34a as diagnostic marker of non-alcoholic steatohepatitis in a Chinese population. AB - AIM: To assess disease-specific circulating microRNAs (miRNAs) in non-alcoholic steatohepatitis (NASH) patients. METHODS: A total of 111 biopsy-proven non alcoholic fatty liver disease (NAFLD) or chronic hepatitis B (CHB) patients and healthy controls from mainland China were enrolled to measure their serum levels of miR-122, -125b, -146b, -16, -21, -192, -27b and -34a. The correlations between serum miRNAs and histological features of NAFLD were determined. The diagnostic value of miRNA in NASH and significant fibrosis was analyzed and compared with that of cytokeratin-18 (CK-18), fibrosis-4 (FIB-4), and aspartate aminotransferase to platelet ratio index (APRI), respectively. RESULTS: Circulating miR-122, -16, -192 and -34a showed differential expression levels between NAFLD and CHB patients, and miR-34a had an approximately 2-fold increase in NAFLD samples compared with that of CHB samples (P < 0.01). Serum miR-122, 192 and -34a levels were correlated with steatosis (R = 0.302, 0.323 and 0.470, respectively, P < 0.05) and inflammatory activity (R = 0.445, 0.447 and 0.517, respectively, P < 0.01); only serum miR-16 levels were associated with fibrosis (R = 0.350, P < 0.05) in patients with NAFLD. The diagnostic value of miR-34a for NASH (area under the receiver operating characteristic, 0.811, 95%CI: 0.670 0.953) was superior to that of alanine aminotransferase, CK-18, FIB-4 and APRI in NAFLD, but miR-16 showed a limited performance in the diagnosis of significant fibrosis in NASH. CONCLUSION: Circulating miR-34a may serve as a disease-specific noninvasive biomarker for the diagnosis of NASH. PMID- 27956810 TI - Hepatitis E virus: Western Cape, South Africa. AB - AIM: To conduct a prospective assessment of anti-hepatitis E virus (HEV) IgG seroprevalence in the Western Cape Province of South Africa in conjunction with evaluating risk factors for exposure. METHODS: Consenting participants attending clinics and wards of Groote Schuur, Red Cross Children's Hospital and their affiliated teaching hospitals in Cape Town, South Africa, were sampled. Healthy adults attending blood donor clinics were also recruited. Patients with known liver disease were excluded and all major ethnic/race groups were included to broadly represent local demographics. Relevant demographic data was captured at the time of sampling using an interviewer-administered confidential questionnaire. Human immunodeficiency virus (HIV) status was self-disclosed. HEV IgG testing was performed using the Wantai(r) assay. RESULTS: HEV is endemic in the region with a seroprevalence of 27.9% (n = 324/1161) 95%CI: 25.3%-30.5% (21.9% when age-adjusted) with no significant differences between ethnic groups or HIV status. Seroprevalence in children is low but rapidly increases in early adulthood. With univariate analysis, age >= 30 years old, pork and bacon/ham consumption suggested risk. In the multivariate analysis, the highest risk factor for HEV IgG seropositivity (OR = 7.679, 95%CI: 5.38-10.96, P < 0.001) was being 30 years or older followed by pork consumption (OR = 2.052, 95%CI: 1.39-3.03, P < 0.001). A recent clinical case demonstrates that HEV genotype 3 may be currently circulating in the Western Cape. CONCLUSION: Hepatitis E seroprevalence was considerably higher than previously thought suggesting that hepatitis E warrants consideration in any patient presenting with an unexplained hepatitis in the Western Cape, irrespective of travel history, age or ethnicity. PMID- 27956811 TI - Spontaneous rupture of hepatic metastasis from a thymoma: A case report. AB - Bleeding resulting from spontaneous rupture of the liver is an infrequent but potentially life threatening complication that may be associated with an underlying liver disease. A hepatocellular carcinoma or hepatic adenoma is frequently reported is such cases. However, hemoperitoneum resulting from a hepatic metastatic thymoma is extremely rare. Here, we present a case of a 62 year-old man with hypovolemic shock induced by ruptured hepatic metastasis from a thymoma. At the first hospital admission, the patient had a 45-mm anterior mediastinal mass that was eventually diagnosed as a type A thymoma. The mass was excised, and the patient was disease-free for 6 years. He experienced sudden onset right upper quadrant pain and was again admitted to our hospital. We noted large hemoperitoneum with a 10-cm encapsulated mass in S5/8 and a 2.3-cm nodular lesion in the right upper quadrant of the abdomen. He was diagnosed with hepatic metastasis from the thymoma, and he underwent chemotherapy and surgical excision. PMID- 27956813 TI - Epileptic Encephalopathy Due to BRAT1 Pathogenic Variants. AB - Investigators from Institut fur Medizinische Genetik und Humangenetik have highlighted the role of compound heterozygous BRAT1 variants in two German brothers with variable presentations of intractable epilepsy, poor development, postnatal microcephaly, hypertonia, apnea, and infantile/childhood death. PMID- 27956812 TI - Pediatric living donor liver transplantation for congenital hepatic fibrosis using a mother's graft with von Meyenburg complex: A case report. AB - This is the first report of living donor liver transplantation (LDLT) for congenital hepatic fibrosis (CHF) using a mother's graft with von Meyenburg complex. A 6-year-old girl with CHF, who suffered from recurrent gastrointestinal bleeding, was referred to our hospital for liver transplantation. Her 38-year-old mother was investigated as a living donor and multiple biliary hamartoma were seen on her computed tomography and magnetic resonance imaging scan. The mother's liver function tests were normal and she did not have any organ abnormality, including polycystic kidney disease. LDLT using the left lateral segment (LLS) graft from the donor was performed. The donor LLS graft weighed 250 g; the graft recipient weight ratio was 1.19%. The operation and post-operative course of the donor were uneventful and she was discharged on post-operative day (POD) 8. The graft liver function was good, and the recipient was discharged on POD 31. LDLT using a graft with von Meyenburg complex is safe and useful. Long-term follow-up is needed with respect to graft liver function and screening malignant tumors. PMID- 27956814 TI - Ocular Manifestation of CACNA1A Pathogenic Variants. AB - Investigators from The Children's Hospital at Westmead in New South Wales; The Queensland University of Technology in Brisbane; Sydney Children's Hospital in New South Wales and Laboratoire de Genetique in Paris investigated children with a proven heterozygous missense pathogenic variant in the CACNA1A gene. PMID- 27956815 TI - Neurocognitive Functions and Behavior in Joubert Syndrome. AB - Investigators from multiple Italian pediatric neurology and neurogenetics departments studied cognitive functions, behavior, and adaptive functioning in large cohort of 54 patients with Joubert syndrome (JS) as part of a prospective, multi-center study. PMID- 27956816 TI - Is research quality in orthopedic manual therapy trials stagnating? Reflections and pathways for improving research quality and advance our profession. PMID- 27956817 TI - A systematic review of orthopaedic manual therapy randomized clinical trials quality. AB - Study Design: Systematic review and meta-analysis. Objectives: To conduct a systematic review and meta-analysis of randomized clinical trials (RCTs) in the orthopaedic manual therapy (OMT) literature from January 2010 to June 2014 in order to determine if the CONSORT checklist and Cochrane Risk of Bias (RoB) assessment tools: (1) are reliable; (2) have improved the reporting and decreased the risk of bias in RCTs in the OMT literature; (3) differ based on journal impact factor (JIF); and (4) scores are associated with each other. Background: The CONSORT statement is used to improve the accuracy of reporting within RCTs. The Cochrane RoB tool was designed to assess the risk of bias within RCTs. To date, no evaluation of the quality of reporting and risk of bias in OMT RCTs has been published. Methods: Relevant RCTs were identified by a literature review from January 2010 to June 2014. The identified RCTs were assessed by two individual reviewers utilizing the 2010 CONSORT checklist and the RoB tool. Agreement and a mean composite total score for each tool were attained in order to determine if the CONSORT and RoB tools were reliable and varied by year and impact factor. Results: A total of 72 RCTs in the OMT literature were identified. A number of categories within the CONSORT and RoB tools demonstrated prevalence adjusted bias-adjusted kappa (PABAK) scores of less than 0.20 and from 0.20 to 0.40. The total CONSORT and RoB scores were correlated to each other (r = 0.73; 95% CI 0.60 to 0.82; p < 0.0001). There were no statistically significant differences in CONSORT or RoB scores by year. There was a statistically significant correlation between both CONSORT scores and JIF (r = 0.64, 95% CI 0.47 to 0.76; p < 0.0001), and between RoB scores and JIF (r = 0.42, 95% confidence interval 0.21-0.60; p < 0.001). There was not a statistically significant correlation between JIF and year of publication. Conclusion: Our findings suggest that the CONSORT and RoB have a number of items that are unclear and unreliable, and that the quality of reporting in OMT trials has not improved in recent years. Improvements in reporting are necessary to allow advances in OMT practice. Level of Evidence: 1A. PMID- 27956818 TI - A comparison between different modes of real-time sonoelastography in visualizing myofascial trigger points in low back muscles. AB - OBJECTIVE: Currently, there is a lack of objective means to quantify myofascial trigger points (MTrPs) and their core features. Our research compares (1) MTrPs and surrounding myofascial tissue using two-dimensional grayscale ultrasound (2DGSUS) and vibration sonoelastography (VSE); (2) the accuracy of both modes in visualizing MTrPs; (3) 'active' and 'latent' MTrPs, using VSE; and (4) the accuracy of both modes in visualizing deep and superficially located MTrPs. METHODS: Fifty participants with more than two MTrPs in their quadratus lumborum, longissimus thoracis, piriformis, and gluteus medius muscles were assigned to an active MTrP (low back pain) group or a latent (currently pain free) MTrP group. MTrP identification was based on their essential criteria. An electronic algometer measured repeatedly the tenderness of MTrPs with reference to pressure pain threshold values. A handheld vibrator was applied over MTrPs, while VSE and 2DGSUS readings were taken using an EUB-7500 ultrasound scanner. RESULTS: There was a significant difference between MTrP strain and that of the immediately surrounding myofascial tissue, as measured using VSE (P = 0.001). VSE visualized all superficial and deep MTrPs with an accuracy of 100% (for both groups); the blinded results obtained using 2DGSUS achieved 33% and 35% accuracy, respectively. There was no significant difference found between the tissue strain ratios of active and latent MTrPs (P = 0.929). DISCUSSION: Sonoelastography can visualize superficial and deep MTrPs, and differentiate them from surrounding myofascial structure through tissue stiffness and echogenicity. VSE was more accurate than 2DGSUS in visualizing and imaging MTrPs. PMID- 27956819 TI - Measurement of outcomes for patients with centralising versus non-centralising neck pain. AB - OBJECTIVE: The purpose of this study is to determine whether individuals with neck pain who demonstrate centralisation of symptoms have more favourable outcome than individuals who do not demonstrate centralisation. METHODS: Eleven subjects with neck pain were evaluated and treated by two physical therapists certified in Mechanical Diagnosis and Therapy (MDT). Eleven physical therapy patients underwent a routine initial evaluation and were treated 2-3 times per week using MDT principles and other physical therapy interventions. The Neck Disability Index (NDI) tool was administered at the initial examination, approximately 2 weeks following the initial examination, each subsequent re-evaluation, and at discharge from the study to measure changes in functional outcomes for each subject. Patients continued with treatments until they were discharged or removed from the study. Four subjects were referred back to their physician by treating physical therapist secondary to non-centralisation (NC) and worsening of symptoms. RESULTS: Of the 11 subjects, six demonstrated centralisation (CEN) and five demonstrated NC. At initial evaluation, the average NDI score for the CEN group was 51.0 (SD +/- 19.4) and 56.4 (SD +/- 17.6) for the NC group. For the CEN group, the average change in NDI score between initial evaluation and discharge was 41.2 (SD +/- 13.2 and 12.2 (SD +/- 13.0) for the NC group. The correlation coefficient of CEN and change in NDI score was 0.772 and was statistically significant (P = 0.005). CONCLUSIONS: In this limited sample, people with neck pain demonstrated more favourable outcomes when the CEN phenomenon was observed. Future research on CEN should be investigated with a larger sample size and with a greater number of clinicians trained in the MDT approach. PMID- 27956820 TI - In vivo measurements of humeral movement during posterior glenohumeral mobilizations. AB - OBJECTIVES: The purpose of this study was to quantify in vivo posterior translational movements occurring in the glenohumeral joint during posterior mobilizations and to determine the intratester reliability of those posterior translational movements. METHODS: Twenty-eight individuals (17 females, 11 males) participated in this study. One physical therapist utilized a Kaltenborn approach to apply three grades of posterior humeral mobilization. A hand held dynamometer was used to quantify the force used during each grade of mobilization. Ultrasound imaging was used to visualize and measure posterior humeral movement. Statistical analysis included descriptive statistics for force and posterior movement, intraclass correlation coefficient (ICC) for intrarater reliability of force and posterior movement during each grade of mobilization and paired t-tests to compare movement and force between grades of mobilization. RESULTS: Mean posterior movement (mm) measurements were 3.0, 8.2 and 10.7 for grade I, grade II and grade III mobilizations, respectively. Mean force (Newtons) measurements used during mobilization were 41.7, 121.5 and 209.4 for grade I, grade II and grade III mobilizations, respectively. The ICCs ranged from 0.849 to 0.905 for movement and from 0.717 to 0.889 for force. Force and measurement values were significantly different between grades of mobilization and between dominant and non-dominant arms. Gender was found to be significantly associated with force. DISCUSSION: Mean movements and mean forces occurring during posterior mobilization increased with increasing grades. Intratester reliability was high for all grades of manual mobilization supporting the use of subjective feedback to determine appropriate force application. Quantification of forces and movements helps to clarify parameters that can serve as a reference for clinical practice. PMID- 27956821 TI - Shoulder muscle activity during the modified dynamic relocation test and side lying shoulder external rotation: a cross-sectional study on asymptomatic individuals. AB - OBJECTIVES: (1) to compare activity levels between monitored muscles during the dynamic relocation test (DRT); (2) to assess changes in muscle activation variability over 10 trials; (3) to assess within-muscle difference activity levels between the DRT and the unloaded side-lying shoulder external rotation exercise. METHODS: This is a cross-sectional, laboratory-based, repeated measures study. Thirty asymptomatic individuals performed the DRT and unloaded side-lying external rotation. The order of exercises was randomized. Superficial electromyography was used for recording the supraspinatus, infraspinatus, middle deltoid, posterior deltoid, pectoralis major, and latissimus dorsi muscles. The main outcome measures were mean muscle activity, expressed as % of maximal isometric voluntary contraction. RESULTS: We found significant between-muscles differences in activity (Ft = 14.11, p < 0.001) during the DRT. Post hoc analysis suggested between-trial variability did not change over the 10 trials, (F = 18.2, p < 0.001). Within-muscle comparisons between the DRT and side-lying shoulder external rotation suggested significant differences between these exercises (F = 32.37, p < 0.001). CONCLUSIONS: considering the monitored muscles, supraspinatus, infraspinatus, pectoralis major, and latissimus dorsi are the main muscles contracting during the DRT. Of all monitored muscles, supraspinatus muscle was the only one presenting higher activity levels during the DRT when compared to the unloaded side-lying shoulder external rotation. PMID- 27956822 TI - Immediate improvement in the cranio-cervical flexion test associated with MDT based interventions: a case report. AB - The patient in this case study presented with constant idiopathic neck pain and left lower scapular pain (greater than 3 months) and was treated based on the principles of Mechanical Diagnosis and Therapy (MDT). Retraction exercises produced centralization of the lower scapular pain to the upper part of the scapula at the initial visit. At the first visit, the performance level on the Cranio-Cervical Flexion Test (CCFT) was <=20 mmHg before the treatment. At the conclusion of the treatment during which centralization occurred, the CCFT level improved to 24 mmHg. At the second visit, all symptoms were abolished and cervical range of motion (ROM) was fully restored by performing repeated extension in lying from a retracted position with clinician's traction. The CCFT levels before and immediately after the treatment were 24 and 26 mmHg, respectively. At the third visit (1 week after the initial visit), he noted that all daily activities could be performed without pain. The CCFT level was maintained at 26mmHg. The patient in this study showed immediate improvement in the CCFT through the treatments based on MDT. This suggests a possible link between MDT interventions and motor control of the cervical spine and a need to further investigate this relationship. PMID- 27956823 TI - Relationship between macular thickness measurement and signal strength using Stratus optical coherence tomography. AB - PURPOSE: To examine the relationship between signal strength and macular thickness as measured by Stratus optical coherence tomography (OCT)'s fast macular thickness protocol in healthy subjects. METHODS: In this prospective cross-sectional study 79 eyes of 42 healthy subjects were enrolled. The age, gender, and eye (right vs left) of each subject were recorded. The Stratus OCT fast macular thickness scan protocol was used and the macular thickness was measured with retinal thickness map analysis. Each eye was imaged at least six times to acquire images with signal strengths of 4, 5, 6, 7, 8, and 9 out of 10 via adjustment of the focusing knob. The OCT parameters included in the analysis were thickness in the central 1 mm and in the different quadrants in the 3-mm area. RESULTS: Overall 79 eyes of 42 patients with a mean age of 38.4+/-12.4 were included. There was no significant difference between the signal strength measurements obtained with different signal strengths in the central thickness (P=0.20). In the superior, nasal, inferior, and temporal quadrants, a signal strength of 8 demonstrated up to 3 um thicker measurements than a signal strength of 5 (P<0.05). In general linear regression analysis, after accounting for age and gender, signal strength did not remain a significant predictor of thickness in any quadrant. CONCLUSIONS: When using fast map macular measurements, a signal strength of 5 is clinically as efficient as a signal strength of 8 in measuring macular thickness in all quadrants. Insisting on higher signal strength may not be necessary. PMID- 27956824 TI - Short-term visual result after simultaneous photorefractive keratectomy and small aperture cornea inlay implantation. AB - PURPOSE: To report the short-term results of simultaneous photorefractive keratectomy (PRK) and small-aperture cornea inlay implantation (KAMRA) surgery in treating presbyopia. METHODS: Simultaneous PRK and KAMRA inlay surgery was performed on 21 patients from July 2015 to March 2016. Follow-up exams were conducted at 1, 3, and 6 months postoperatively. Our patients were also divided preoperatively into three categories: myopic, hyperopic, and emmetropic. Over the 6-month period, the main outcome measures were uncorrected near visual acuity (UNVA), changes in best-corrected distance visual acuity, and mean spherical equivalent refraction. RESULTS: At 6-month follow-up, 83% (10/12) of patients had a monocular UNVA of 20/40 or better, and 75% had a binocular UNVA of 20/40 (J5) or better. At 6 months, the overall mean refractive spherical equivalent (MRSE) was -0.60 D (+/-0.42 standard deviation [SD], range: -1.38 to -0.13) with a mean change of -0.43 D (+/-1.19 SD, range: -1.5 to 2.63) compared to preoperative data. Overall, 91% (10/11) of patients were within a +/-0.5 D range of our target -0.75 D for KAMRA use. One-hundred percent (5/5) of the hyperopes, 50% (1/2) of emmetropes, and 100% (4/4) of myopes met the targeted range. At 6 months, the MRSE for the hyperopic subgroup (n=5) was 0.33 D (+/-0.20 SD), the MRSE for the emmetropic subgroup (n=2) was -1.19 D (+/-0.19 SD), and the MRSE for the myopic subgroup (n=4) was -0.66 D (+/-0.36 SD). CONCLUSION: Based on preliminary results and a small sample size, it seems that simultaneous PRK and KAMRA is effective and predictable. There are multiple advantages in performing simultaneous PRK and KAMRA including a shorter recovery time and less steroid use than the two surgeries performed separately. PMID- 27956825 TI - Ustekinumab in treatment of Crohn's disease: design, development, and potential place in therapy. AB - Crohn's disease is characterized by a dysregulation of both innate and adaptive immunity responses. Interleukin-12/23 (IL-12/23) pathway has been found to be a major driver of inflammation in adaptive immune responses. Ustekinumab is a fully human immunoglobulin G1 kappa monoclonal antibody that blocks the p40 subunit of IL-12 and IL-23 and prevents their interaction with their cell surface receptor and further cytokine activation. It is currently approved in the management of plaque psoriasis and psoriatic arthritis. Very promising data have emerged through phase II and phase III trials (UNITI-1, UNITI-2, and IM-UNITI) for both induction and maintenance of clinical response and remission in moderate-to severe Crohn's disease, resulting in approval by the Food and Drug Administration for this condition. This article reviews the immunology of the IL-12/23 pathway, available data regarding the initial designing of ustekinumab, drug development through clinical trials including pharmacokinetics, efficacy, and safety, and its potential place in the treatment of Crohn's disease. PMID- 27956826 TI - Nonmotor gastrointestinal disorders in older patients with Parkinson's disease: is there hope? AB - Despite the fact that nonmotor symptoms (NMS) like gastrointestinal (GI) complaints are frequently reported in Parkinson's disease (PD), no therapeutic guidelines are available. This study aimed to manage some lower GI-NMS in a group of patients with PD. A total of 40 patients (17 males, 23 females; mean age 76.05+/-2.09 years) were randomly selected for this study. Patients were confirmed to have PD (modified Hoehn-Yars scale: 2.075+/-0.4) who had undergone levodopa or dopamine agonist treatment. In the non-motor symptoms questionnaire (NMS-Quest), regarding GI complaints, the following were recorded: abdominal pain, bloating, and constipation of mild-to-moderate severity. Laboratory studies, abdominal ultrasound, and upper and lower digestive endoscopies were performed to rule out organic issues. All patients increased their water intake to 2 L/d and alimentary fiber to 20-25 g/d. Twenty patients received trimebutine 200 mg three times daily half an hour before meals. The other 20 patients received probiotics (60 mg per-tablet of two lactic bacteria: Lactobacillus acidophilus and Bifidobacterium infantis), 2*/d, 1 hour after meals for 3 months along with the reassessment of GI complaints. Our results demonstrated that there were significant statistical differences in all assessed symptoms in the first group: 1.55+/-0.51 vs 0.6+/-0.5 (P<0.0001) for abdominal pain; 1.6+/-0.5 vs 0.45+/-0.51 (P<0.0001) for bloating; and 1.5+/-0.51 vs 0.85+/-0.67 (P=0.0014) for constipation with incomplete defecation. The second group displayed statistical differences only for abdominal pain 1.45+/-0.51 vs 1.05+/-0.69 (P=0.00432) and bloating 1.4+/-0.5 vs 0.3+/-0.47 (P<0.0001). For constipation with incomplete defecation, there was a slight improvement. Thus, there was no significant statistical difference: 1.35+/-0.49 vs 1.15+/-0.49 (P=0.2040). In conclusion, lower GI-NMS are frequently present, isolated or associated with other autonomic issues, even before the diagnosis of PD. Treatment with probiotics could improve abdominal pain and bloating as much as with trimebutine, but less for constipation with incomplete evacuation, where trimebutine showed better results. PMID- 27956827 TI - Efficacy and safety of prostate artery embolization on lower urinary tract symptoms related to benign prostatic hyperplasia: a systematic review and meta analysis. AB - BACKGROUND: Prostate artery embolization (PAE) is emerging and is a promising minimally invasive therapy that improves lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH). The purpose of this article was to evaluate the efficacy and safety of PAE on LUTS related to BPH. MATERIALS AND METHODS: A literature review was performed to identify all published articles of PAE for BPH. The sources included MEDLINE, EMBASE and Cochrane Library from 1980 to 2016. A systematic review and meta-analysis was conducted. The outcome measurements were combined by calculating the mean difference with 95% confidence interval. Statistical analysis was carried out using Review Manager 5.3.0. RESULTS: Twelve studies involving 840 participants were included. Compared with baseline, the International Index of Erectile Function (IIEF-5; International Prostate Symptom Score) scores, the quality of life scores, peak urinary flow rate (Qmax) and postvoid residual volume all had significant improvements during the 24-month follow-up (all P<0.00001). Both prostate volume (PV) and prostate specific antigen had significant decrease during the 12-month follow-up (P<0.00001 and P=0.005, respectively), except postoperative 24 months (P=0.47 and P=0.32, respectively). The IIEF-5 short form scores had significant increase at postoperative 6 months (P=0.002) and 12 months (P<0.0001), except postoperative 1 month (P=0.23) and 24 months (P=0.21). For large volume (PV >=80 mL) BPH, the results were similar. There were no life-threatening complications. CONCLUSION: PAE is an effective, safe and well-tolerable treatment for LUTS related to BPH, including large volume (PV >=80 mL) BPH, with a good short-term follow-up. Studies with large number of cases and longer follow-up time are needed to validate our results. PMID- 27956828 TI - Successful aging: considering non-biomedical constructs. AB - OBJECTIVES: Successful aging continues to be applied in a variety of contexts and is defined using a number of different constructs. Although previous reviews highlight the multidimensionality of successful aging, a few have focused exclusively on non-biomedical factors, as was done here. METHODS: This scoping review searched Ovid Medline database for peer-reviewed English-language articles published between 2006 and 2015, offering a model of successful aging and involving research with older adults. RESULTS: Seventy-two articles were reviewed. Thirty-five articles met the inclusion criteria. Common non-biomedical constructs associated with successful aging included engagement, optimism and/or positive attitude, resilience, spirituality and/or religiosity, self-efficacy and/or self-esteem, and gerotranscendence. DISCUSSION: Successful aging is a complex process best described using a multidimensional model. Given that the majority of elders will experience illness and/or disease during the life course, public health initiatives that promote successful aging need to employ non biomedical constructs, facilitating the inclusion of elders living with disease and/or disability. PMID- 27956829 TI - Telemonitoring of home exercise cycle training in patients with COPD. AB - BACKGROUND: Regular physical activity is associated with reduced mortality in patients with chronic obstructive pulmonary disease (COPD). Interventions to reduce time spent in sedentary behavior could improve outcomes. The primary purpose was to investigate the impact of telemonitoring with supportive phone calls on daily exercise times with newly established home exercise bicycle training. The secondary aim was to examine the potential improvement in health related quality of life and physical activity compared to baseline. METHODS: This prospective crossover-randomized study was performed over 6 months in stable COPD patients. The intervention phase (domiciliary training with supporting telephone calls) and the control phase (training without phone calls) were randomly assigned to the first or the last 3 months. In the intervention phase, patients were called once a week if they did not achieve a real-time monitored daily cycle time of 20 minutes. Secondary aims were evaluated at baseline and after 3 and 6 months. Health-related quality of life was measured by the COPD Assessment Test (CAT), physical activity by the Godin Leisure Time Exercise Questionnaire (GLTEQ). RESULTS: Of the 53 included patients, 44 patients completed the study (forced expiratory volume in 1 second 47.5%+/-15.8% predicted). In the intervention phase, daily exercise time was significantly higher compared to the control phase (24.2+/-9.4 versus 19.6+/-10.3 minutes). Compared to baseline (17.6+/-6.1), the CAT-score improved in the intervention phase to 15.3+/-7.6 and in the control phase to 15.7+/-7.3 units. The GLTEQ-score increased from 12.2+/ 12.1 points to 36.3+/-16.3 and 33.7+/-17.3. CONCLUSION: Telemonitoring is a simple method to enhance home exercise training and physical activity, improving health-related quality of life. PMID- 27956830 TI - Enhancing the specificity of polymerase chain reaction by graphene oxide through surface modification: zwitterionic polymer is superior to other polymers with different charges. AB - Graphene oxides (GOs) with different surface characteristics, such as size, reduction degree and charge, are prepared, and their effects on the specificity of polymerase chain reaction (PCR) are investigated. In this study, we demonstrate that GO with a large size and high reduction degree is superior to small and nonreduced GO in enhancing the specificity of PCR. Negatively charged polyacrylic acid (PAA), positively charged polyacrylamide (PAM), neutral polyethylene glycol (PEG) and zwitterionic polymer poly(sulfobetaine) (pSB) are used to modify GO. The PCR specificity-enhancing ability increases in the following order: GO-PAA < GO-PAM < GO-PEG < GO-pSB. Thus, zwitterionic polymer modified GO is superior to other GO derivatives with different charges in enhancing the specificity of PCR. GO derivatives are also successfully used to enhance the specificity of PCR for the amplification of human mitochondrial DNA using blood genomic DNA as template. Molecular dynamics simulations and molecular docking are performed to elucidate the interaction between the polymers and Pfu DNA polymerase. Our data demonstrate that the size, reduction degree and surface charge of GO affect the specificity of PCR. Based on our results, zwitterionic polymer-modified GO may be used as an efficient additive for enhancing the specificity of PCR. PMID- 27956832 TI - Assessment of suicidality in children and adolescents with diagnosis of high functioning autism spectrum disorder in a Turkish clinical sample. AB - OBJECTIVES: Considering that suicide is one of the most common reasons of adolescent death worldwide, there is a lack of clinical awareness on suicidal behaviors of children and adolescents with autism spectrum disorder (ASD). The present study aims to assess the rate of suicidality (suicidal ideation, behaviors and attempts) and associated risk factors for suicidality in high functioning ASD. METHODS: Medical records of 55 adolescents (six girls, 49 boys), aged between 7-20 years, with diagnosis of ASD were reviewed. The participants were all able to speak fluently and had no significant limitations in intellectual functioning. Clinical assessment of participants was carried out on the basis of Diagnostic and Statistical Manual of Mental Disorders 4th Edition, Text Revision criteria and Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Eskin's Suicide Screening Questionnaire and sociodemographic data form including detailed history of suicidal behaviors were used. The study group was also divided into suicidal and non-suicidal groups for the purpose of comparing the results. RESULTS: The rate of suicidal behaviors was 29% and suicide attempt was 12.7%. Types of suicidality were behaviors (43.7%), thoughts (37.5%), and verbal declarations (18.7%). A number of bizarre acts were recorded. Rates of comorbid psychiatric disorders such as mood disorders, anxiety disorders and disruptive behaviors were 23.6%, 43.6% and 65.4% respectively. Groups with the psychotic features, positive family history for suicidal behaviors and completed suicide showed more suicidality than the non-suicidal group. CONCLUSION: Consistent with the previous findings, rate of suicidality is higher in individuals with ASD. The type of suicidal behaviors showed some differences compared to typically developing individuals. The presence of psychotic features and positive family history for suicidality may be risk factors for suicidality in children and adolescents with ASD. To prevent suicide and implement protective health care systems, identifying the population at risk is crucial. PMID- 27956831 TI - A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy. AB - Small molecule-based nanodrugs with nanoparticles (NPs) that are mainly composed of small molecules, have been considered as a promising candidate for a next generation nanodrug, owing to their unique properties. Vorinostat (SAHA) is a canonical US Food and Drug Administration-approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma. However, the lack of efficacy against solid tumors hinders its progress in clinical use. Herein, a novel nanodrug of SAHA was developed based on disulfide-linked prodrug SAHA-S-S VE. SAHA-S-S-VE could self-assemble into 148 nm NPs by disulfide-induced mechanisms, which were validated by molecular dynamics simulations. Under reduced conditions, the redox-responsive behavior of SAHA-S-S-VE was investigated, and the HDAC inhibition results verified the efficient release of free SAHA. With a biocompatible d-a-tocopheryl polyethylene glycol succinate (TPGS) functionalization, the SAHA-S-S-VE/TPGS NPs exhibited low critical aggregation concentration of 4.5 MUM and outstanding stability in vitro with drug-loading capacity of 24%. In vitro biological assessment indicated that SAHA-S-S-VE/TPGS NPs had significant anticancer activity against HepG2. Further in vivo evaluation demonstrated that the resulting NPs could be accumulated in the tumor region and inhibit the tumor growth effectively. This approach, which turned SAHA into a self-assembled redox-responsive nanodrug, provided a new channel for the use of HDAC inhibitor in solid tumor therapy. PMID- 27956834 TI - An observational postmarketing safety registry of patients in the UK, Germany, and Switzerland who have been prescribed Sativex(r) (THC:CBD, nabiximols) oromucosal spray. AB - The global exposure of Sativex(r) (Delta9-tetrahydrocannabinol [THC]:cannabidiol [CBD], nabiximols) is estimated to be above 45,000 patient-years since it was given marketing approval for treating treatment-resistant spasticity in multiple sclerosis (MS). An observational registry to collect safety data from patients receiving THC:CBD was set up following its approval in the UK, Germany, and Switzerland, with the aim of determining its long-term safety in clinical practice. Twice a year, the Registry was opened to prescribing physicians to voluntarily report data on patients' use of THC:CBD, clinically significant adverse events (AEs), and special interest events. The Registry contains data from 941 patients with 2,213.98 patient-years of exposure. Within this cohort, 60% were reported as continuing treatment, while 83% were reported as benefiting from the treatment. Thirty-two percent of patients stopped treatment, with approximately one third citing lack of effectiveness and one quarter citing AEs. Psychiatric AEs of clinical significance were reported in 6% of the patients, 6% reported falls requiring medical attention, and suicidality was reported in 2%. Driving ability was reported to have worsened in 2% of patients, but improved in 7%. AEs were more common during the first month of treatment. The most common treatment-related AEs included dizziness (2.3%) and fatigue (1.7%). There were no signals to indicate abuse, diversion, or dependence. The long-term risk profile from the Registry is consistent with the known (labeled) safety profile of THC:CBD, and therefore supports it being a well-tolerated and beneficial medication for the treatment of MS spasticity. No evidence of new long-term safety concerns has emerged. PMID- 27956833 TI - Inflammation-modulating cytokine profile and lipid interaction in HIV-related risk factors for cardiovascular diseases. AB - HIV infection and antiretroviral therapy (ART) are associated with changes in plasma levels of lipoproteins, thus posing the risk of cardiovascular complications in infected individuals. The alteration in plasma lipoprotein levels results from dysregulation of inflammation-modulating cytokines that control lipid metabolism. Little is understood regarding the relationship between the cytokines and serum lipid levels, which have been reported to be altered in adults receiving ART. The objective of this study was to describe the profiles of inflammation-modulating cytokines and their relationship to lipids as cardiovascular disease (CVD) risk factors in HIV infection. This observational cross-sectional study measured plasma levels of interleukin (IL)-10, tumor necrosis factor-alpha (TNF)-alpha, IL-4, total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-c) in HIV-infected and uninfected adults. A total of 219 HIV-infected participants were enrolled from an HIV treatment center; of them, 187 were receiving ART and 32 were ART naive, while 65 were HIV-uninfected blood donors. HIV-infected individuals had higher levels of IL-10 (HIV-infected ART-naive [P=0.0024] and ART-receiving [P=0.033]) than their uninfected counterparts. ART-naive subjects had significantly higher plasma levels of IL-10 than ART-receiving subjects (P=0.0014). No significant difference was observed in plasma levels of IL-4 and TNF-alpha across the three groups. Regarding plasma lipoproteins, HDL-c levels were reduced in HIV ART-naive (P=0.002) and ART receiving (P=0.015) subjects compared to HIV-uninfected subjects. Similarly, TC levels were lower in the HIV-infected than in the HIV-uninfected group regardless of whether the patients were undergoing ART or not (P<0.001). IL-10 levels correlated with TC levels in the HIV-uninfected group but not in the HIV-infected groups. Levels of HDL-c were reduced, while IL-10 plasma concentrations were elevated in HIV-infected individuals. A correlation observed in HIV-uninfected individuals between anti-inflammatory cytokine IL-10 and TC was lost in HIV infected individuals. Clinical significance of these differences needs to be ascertained with respect to HIV-related CVD risk. PMID- 27956835 TI - Comparison of the glottic view during video-intubation in super obese patients: a series of cases. AB - Videolaryngoscopes improve the view of the entry to the larynx in morbidly obese patients. Super obesity is one of the risk factors for difficult mask ventilation as well as difficult intubation. Super obese patients should be intubated awake either with a fiber-optic scope or with a videolaryngoscope. The glottic view during video-intubation in super obese patients using different devices was compared. The McGrath MAC (MGM) was used in all patients and then compared to the King Vision (KV) in three patients, the APA videolaryngoscope in two patients and the Airtraq Avant with a video camera in four patients. The pictures were of the same patient for two used devices. All obtained images were analyzed using the Percentage of Glottic Opening (POGO) scale. The POGO score for the MGM was better than for the KV and the APA but comparable to the Airtraq device. The images were processed electronically, and the best view of the laryngeal inlet that was obtained by the evaluated devices in the same patient was superimposed onto the other one and then compared. PMID- 27956836 TI - Relationships between Th1/Th2 cytokine profiles and chest radiographic manifestations in childhood Mycoplasma pneumoniae pneumonia. AB - BACKGROUND: Mycoplasma pneumoniae pneumonia (MPP) is one of the most common childhood community-acquired pneumonias, and the chest radiograph usually shows bronchial pneumonia, segmental/lobar pneumonia, or segmental/lobar pneumonia with pleural effusion. The imbalance of Th1/Th2 function after Mycoplasma pneumoniae infection is an important immunological mechanism of MPP. In this study, we aimed to evaluate the correlations between Th1/Th2 cytokine profiles and chest radiographic manifestations in MPP children. PATIENTS AND METHODS: A total of 87 children with MPP were retrospectively reviewed in this study. According to the chest radiographic manifestations, they were divided into the following three groups: bronchial MPP group, segmental/lobar MPP group, and segmental/lobar MPP with pleural effusion group. Clinical features and changes in Th1/Th2 cytokines were further analyzed. RESULTS: The incidence of tachypnea and cyanosis was higher in children with segmental/lobar MPP with pleural effusion than in those with segmental/lobar or bronchial MPP. The peak body temperature of segmental/lobar MPP was higher than that of bronchial MPP, and the duration of fever and hospitalization was positively correlated with the severity of MPP. MPP children's chest radiograph showed a relationship with the changes in Th1/Th2 cytokines. Serum interleukin-4, interleukin-10 (IL-10), interferon-gamma, and tumor necrosis factor-alpha (TNF-alpha) of segmental/lobar MPP were significantly higher than those of bronchial MPP, and serum IL-10 (cutoff value: 27.25 pg/mL) can be used as a diagnostic predictor for segmental/lobar MPP. Serum TNF-alpha and interleukin-6 of segmental/lobar MPP with pleural effusion were significantly higher than those of segmental/lobar MPP without pleural effusion. Serum TNF alpha (cutoff value: 60.25 pg/mL) can be used as a diagnostic predictor for segmental/lobar MPP with pleural effusion. CONCLUSION: There were significant correlations between Th1/Th2 cytokine profiles and chest radiographic manifestations in MPP children. Serum IL-10 and TNF-alpha can be used as an optimal predictor for segmental/lobar MPP and segmental/lobar MPP with pleural effusion, respectively. PMID- 27956837 TI - A stress-related explanation to the increased blood pressure and its course following ischemic stroke. AB - BACKGROUND: A hypertensive response after ischemic stroke is frequent, yet its pathophysiology is unknown. Mechanisms related to local ischemic damage, major vascular occlusion, and psychological stress due to acute illness have been proposed. We assessed the natural course of blood pressure (BP) within the first 24 h in groups of ischemic stroke patients with different characteristics. We hypothesized that a consistent BP reduction, regardless of stroke location, time window from debut to admission and presence of persistent vascular occlusion, would favor a stress-related mechanism as an important cause of the hypertensive response after ischemic stroke. METHODS: Ischemic stroke patients (n=1067) were prospectively registered, and BP was measured on admission and <3 h, 3-6 h, 6-12 h and 12-24 h after admission. Patients were categorized according to the location of diffusion-weighted imaging (DWI) lesions (cortical, large subcortical, mixed cortico-subcortical, lacunar, cerebellar, brain stem or multiple), time window (admitted within or after 6 h of symptom onset) and presence of persistent proximal middle cerebral artery (MCA) occlusion versus normal findings on magnetic resonance angiography (MRA) at 24 h. RESULTS: A reduction in systolic BP and diastolic BP from baseline to 12-24 h was found across all DWI locations except for diastolic BP in cerebellar (P=0.072) lesions. Apart from diastolic BP in patients with normal MRA findings at 24 h (P=0.060), a significant fall in systolic BP and diastolic BP at 12-24 h was registered, irrespective of whether patients were admitted within 6 h or after 6 h of stroke onset or had persistent MCA occlusion versus normal MRA findings. CONCLUSION: We found a relatively consistent decline in BP within 24 h after admission across different stroke locations in patients admitted within or after 6 h of stroke onset and in patients with persistent MCA occlusion. Our findings suggest that a systemic factor such as psychological stress may be an important contributor to the frequently elevated BP on admission in patients with ischemic stroke. PMID- 27956839 TI - Portulacerebroside A inhibits adhesion, migration, and invasion of human leukemia HL60 cells and U937 cells through the regulation of p38/JNK signaling pathway. AB - Acute myeloid leukemia (AML) is a highly malignant hematopoietic tumor. This study aimed to explore the effect of portulacerebroside A (PCA) on the adhesion, migration, and invasion in human leukemia HL60 cells and U937 cells and clarify the possible mechanisms involved, which could provide potential strategies for the treatment of AML. By methyl thiazolyl tetrazolium analysis, it was found that PCA (1-10 MUM) suppressed the cell viability in a time- and dose-dependent manner. A total of 1, 2, and 5 MUM of PCA dramatically inhibited the adhesion, migration, and invasion of HL60 cells and U937 cells in a dose-dependent manner. Phosphorylation level of JNK and P38 protein level was measured by Western blot. After the real-time quantification polymerase chain reaction and Western blot detection of the total RNA and protein, messenger RNA, and protein expression levels of Ras homologous C (RhoC), metastasis-associated gene 1 (MTA1) and matrix metalloproteinase-2/9 (MMP-2/9) were decreased significantly in a dose-dependent manner. The phosphorylation level of c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (P38) was decreased dramatically in HL60 cells and U937 cells after PCA treatment. In conclusion, PCA significantly inhibits the adhesion, migration, and invasion of HL60 cells and U937 cells by suppressing the p38/JNK pathway and regulating the expressions of related genes. PMID- 27956838 TI - Double gene siRNA knockdown of mutant p53 and TNF induces apoptosis in triple negative breast cancer cells. AB - Apoptosis is the major downregulated pathway in cancer. Simultaneous inhibition using specific small interfering RNA (siRNA) of two key player genes, p53 and TNF, is an interesting and feasible strategy when it comes to investigating various molecular pathways and biological processes in triple-negative breast cancer (TNBC), which is one of the most aggressive and therapeutically unresponsive forms of breast cancers. Our present research focuses on evaluating the impact of double p53-siRNA and TNF-siRNA knockdown at a cellular level, and also evaluating cell proliferation, apoptosis, induction of autophagy, and gene expression by using reverse transcription polymerase chain reaction array approaches. Simultaneous inhibition of p53 and TNF in Hs578T TNBC human cell line revealed a panel of up- and downregulated genes involved in apoptosis. Furthermore, the effects of double gene knockdown were validated in a second TNBC cell line, MDA-MB-231, by using reverse transcription polymerase chain reaction TaqMan assay. All our findings help in understanding the functional mechanisms of extrinsic apoptosis, cell signaling pathways, and the mechanisms involved in tumor cell survival, growth, and death in TNBC. PMID- 27956840 TI - Association of telomerase reverse transcriptase promoter mutations with clinicopathological features and prognosis of thyroid cancer: a meta-analysis. AB - The clinicopathological and prognostic significance of telomerase reverse transcriptase (TERT) promoter mutations have been widely investigated in thyroid cancer; however, the results are still discrepant. Systematic searches were performed in PubMed, Web of Science, Scopus, Ovid, and the Cochran Library databases for relevant articles prior to April 2016. Mutation rates were synthesized by R statistical software. The odds ratio or standardized mean difference with 95% confidence interval was pooled by Stata. A total of 22 studies with 4,907 cases were included in this meta-analysis. TERT promoter mutations tended to present in aggressive histological types including poorly differentiated thyroid cancer (33.37%), anaplastic thyroid cancer (38.69%), and tall-cell variant papillary thyroid cancer (30.23%). These promoter mutations were likely to exist in older patients and males and were well associated with larger tumor size, extrathyroidal extension, vascular invasion, lymph node metastasis, distant metastasis, advanced tumor stage, disease recurrence/persistence, and mortality. In addition, TERT promoter mutations (especially C228T) tended to coexist with BRAFV600E mutation, which indicated more aggressive tumor behavior. Therefore, TERT promoter mutations may be promising biomarkers for early diagnosis, risk stratification, prognostic prediction, and management of thyroid cancer. PMID- 27956841 TI - Role of p14ARF and p15INK4B promoter methylation in patients with lung cancer: a systematic meta-analysis. AB - BACKGROUND: The cyclin-dependent kinase inhibitors p14ARF and p15INK4B are tumor suppressor genes that have been reported to be silenced through promoter methylation in many human cancers. However, the strength of association between p14ARF or p15INK4B promoter methylation and lung cancer remains unclear. Thus, we first determined whether p14ARF and p15INK4B promoter methylation played a key role in the carcinogenesis of lung cancer. METHODS: Eligible studies were selected from the online electronic databases. The pooled odds ratios or hazard ratios and 95% confidence intervals were calculated and summarized. RESULTS: Finally, 12 studies with 625 lung cancer samples and 488 nontumor samples were included under the fixed-effects model. The pooled odds ratio showed that p14ARF promoter methylation was observed to be significantly higher in non-small-cell lung cancer (NSCLC) than in nontumor samples (P<0.001). No significant correlation was found between p15INK4B promoter methylation and lung cancer (P=0.27). Subgroup analysis of ethnicity revealed that p14ARF promoter methylation was significantly related to the risk of NSCLC in Asian and Caucasian populations. Subgroup analysis of sample type demonstrated that p14ARF promoter methylation was correlated with the risk of NSCLC in tissue samples (P<0.001), but not in bronchoalveolar lavage fluid and blood samples. P14ARF promoter methylation from one study was not significantly correlated with overall survival of patients with NSCLC. Promoter methylation of p14ARF and p15INK4B was not correlated with clinicopathological characteristics, such as gender status, smoking status, tumor differentiation, and tumor stage (P>0.05). CONCLUSION: Our findings suggested that p14ARF promoter methylation may play an important role in the carcinogenesis of lung cancer, but not p15INK4B promoter methylation. Promoter methylation of p14ARF and p15INK4B was not associated with clinicopathological parameters. However, more extensive large-scale studies are essential to further validate our study. PMID- 27956842 TI - Role of a proprietary propolis-based product on the wait-and-see approach in acute otitis media and in preventing evolution to tracheitis, bronchitis, or rhinosinusitis from nonstreptococcal pharyngitis. AB - Antipyretics and/or anti-inflammatory drugs along with a wait-and-see approach are the only treatments recommended in early acute otitis media (AOM) or viral pharyngitis. Propolis has been widely investigated for its antibacterial, antiviral, and anti-inflammatory properties and could perhaps be administered as an add-on therapy during watchful waiting in AOM or for better control of symptoms in nonstreptococcal pharyngitis. However, propolis has well-known problems of poor solubility and low oral bioavailability. We therefore analyzed a proprietary propolis-based product (Propolisina(r)) developed to overcome these limitations, in a retrospective, open-label, controlled study of Streptococcus pyogenes-negative children with a diagnosis of AOM or pharyngitis. Our results show that the use of propolis supplement for 72 hours lessens the severity of AOM and viral pharyngitis, reduces the use of antipyretics and anti-inflammatory drugs, and decreases the rate of evolution to tracheitis, bronchitis, and rhinosinusitis. Our study shows that propolis could be used as a safe add-on therapy in case of AOM and/or viral pharyngitis. PMID- 27956843 TI - Lung protective mechanical ventilation strategies in cardiothoracic critical care: a retrospective study. AB - A body of evidence supports the use of low tidal volumes in ventilated patients without lung pathology to slow progress to acute respiratory distress syndrome (ARDS) due to ventilator associated lung injury. We undertook a retrospective chart review and tested the hypothesis that tidal volume is a predictor of mortality in cardiothoracic (medical and surgical) critical care patients receiving invasive mechanical ventilation. Independent predictors of mortality in our study included: type of surgery, albumin, H+, bilirubin, and fluid balance. In particular, it is important to note that cardiac, thoracic, and transplant surgical patients were associated with lower mortality. However, our study did not sample equally from The Berlin Definition of ARDS severity categories (mild, moderate, and severe hypoxemia). Although our study was not adequately powered to detect a difference in mortality between these groups, it will inform the development of a large prospective cohort study exploring the role of low tidal volume ventilation in cardiothoracic critically ill patients. PMID- 27956845 TI - Choroidal tuberculoma as a presenting sign of tuberculosis. AB - Choroidal tuberculoma is a rare ocular form of tuberculosis (TB) that raises both a diagnostic and a therapeutical challenge, especially when occurring without other manifestations of the disease. This study reports the case of a 27-year-old woman who had a unilateral drop of vision (20/100) with ocular pain. Her fundus examination revealed an elevated juxtapapillary choroidal mass measuring 892 um in diameter, as calculated by optical coherence tomography (OCT), and associated with a serous retinal detachment involving the macula. The diagnosis of choroidal tuberculoma was established by positive QuantiFERON-TB and tuberculin skin test. Laboratory and imaging workup ruled out pulmonary and systemic TB as well as other possible etiologies. Antituberculosis therapy was started and led to an improved visual acuity (20/30) and a shrinkage of the tuberculoma to a diameter of 499 um at 3 months. This is one of the few reported cases of solitary choroidal tuberculoma in a patient with no other sign of TB. It sheds light on the place of OCT in the diagnosis and follow-up of the choroidal mass, in terms of measuring the size of the mass and revealing the associated serous retinal detachment and the distinctive "contact sign" between the neurosensory retina and the retinal pigment epithelium (RPE)-choriocapillaris layer surmounting the tuberculoma. PMID- 27956846 TI - Repository corticotropin injection in patients with refractory psoriatic arthritis: a case series. AB - PURPOSE: Although numerous treatment options are available for patients with psoriatic arthritis (PsA), a need for effective and tolerable treatments remains for patients with refractory disease who have failed previous therapies and continue to experience tender and/or swollen joints, pain, and disease activity. Repository corticotropin injection (RCI) is believed to produce steroidogenic, steroid-independent, anti-inflammatory, and immunomodulatory effects in patients with rheumatic disorders, such as PsA. Limited literature exists on the use of RCI in patients with refractory PsA. The objective of this case series is to provide information on the clinical features of patients with refractory PsA and their response to RCI. PATIENTS: Nine patients treated with RCI for refractory PsA were retrospectively identified and included in the case series. RESULTS: All the nine patients experienced at least transient improvements in their active skin and joint disease. In some patients, it was necessary to titrate the RCI to an appropriate dose. RCI was used in some patients to bridge with another PsA therapy, such as apremilast or certolizumab. RCI was well tolerated, but discontinued in three patients due to preexisting conditions (hypertension and hyperglycemia). CONCLUSION: RCI may be a safe and effective option for patients with refractory PsA who failed therapy with multiple previous treatments. PMID- 27956844 TI - Helminth infection during pregnancy: insights from evolutionary ecology. AB - Helminths are parasitic nematodes and trematodes, grouped together because of morphological similarities and commonalities in the effects infections have on hosts. These include complications such as anemia and biasing of immune responses, which can alter susceptibility for other diseases. For pregnant women, these complications might have implications for pregnancy outcomes or neonatal health. Here, I review studies of helminth infections during pregnancy, and ask the following questions: Do helminths affect maternal health or pregnancy outcomes? Are there consequences of maternal infection for infants? What are the effects of antihelminth treatment during pregnancy? The evidence suggests that the answers to these questions depend on the particular helminth species in question, maternal nutritional status, and the presence or absence of comorbid infection with other species, such as malaria. Moreover, there may also be unexpected consequences of treatment, as maternal infections can affect the priming of infant immune systems, with potential effects on infants later in life. These complex interactions suggest that a consideration of the evolutionary history of human-helminth interactions, as well as the ecological context of infections, can help to clarify an understanding of these host-parasite interactions and provide direction for future investigations. PMID- 27956848 TI - Micro-CTvlab: A web based virtual gallery of biological specimens using X-ray microtomography (micro-CT). AB - BACKGROUND: During recent years, X-ray microtomography (micro-CT) has seen an increasing use in biological research areas, such as functional morphology, taxonomy, evolutionary biology and developmental research. Micro-CT is a technology which uses X-rays to create sub-micron resolution images of external and internal features of specimens. These images can then be rendered in a three dimensional space and used for qualitative and quantitative 3D analyses. However, the online exploration and dissemination of micro-CT datasets are rarely made available to the public due to their large size and a lack of dedicated online platforms for the interactive manipulation of 3D data. Here, the development of a virtual micro-CT laboratory (Micro-CTvlab) is described, which can be used by everyone who is interested in digitisation methods and biological collections and aims at making the micro-CT data exploration of natural history specimens freely available over the internet. NEW INFORMATION: The Micro-CTvlab offers to the user virtual image galleries of various taxa which can be displayed and downloaded through a web application. With a few clicks, accurate, detailed and three dimensional models of species can be studied and virtually dissected without destroying the actual specimen. The data and functions of the Micro-CTvlab can be accessed either on a normal computer or through a dedicated version for mobile devices. PMID- 27956847 TI - Predictors for Moderate to Severe Acute Postoperative Pain after Cesarean Section. AB - Background. Moderate to severe postoperative pain affects performance of daily activities and it contributes to persistent postoperative pain. In patients submitted to cesarean section, this pain can also interfere with women's ability to care for their babies, to effectively breastfeed, and to satisfactorily interact with their children. Factors influencing the pain perception during the immediate postoperative period have not been widely pursued. Objective. To investigate the incidence and predicting factors of postoperative pain after cesarean section. Methods. A prospective longitudinal study with 1,062 women submitted to cesarean section. We collected sociodemographic, clinical, surgical, and health behavior data. We used the 11-point Numerical Pain and the Hospital Anxiety and Depression Scales. We performed logistic analysis to identify predictors of moderate to severe postoperative pain. Results. The incidence of moderate-severe postoperative pain was 78.4% (CI: 95%: 75.9%-80.8%). The preoperative anxiety (OR = 1.60; CI 95%: 1.22-2.30) and intrathecal morphine with fentanyl (OR = 0,23; CI 95%: 0.08-0.66) were significantly associated with moderate-severe postoperative pain report. Conclusion. The preoperative anxiety increases the risk of moderate-severe postoperative pain in women submitted to cesarean section. The intrathecal morphine with fentanyl added to bupivacaine was a protective factor against this pain. PMID- 27956849 TI - First record of the monotypic genus Acanopsilus Kieffer, 1908 (Hymenoptera: Diaprioidea: Diapriidae) from the Eastern Palaearctic region. AB - BACKGROUND: The monotypic genus Acanopsilus (Hymenoptera: Diapriidae), is hitherto known only from Europe, where it is widely distributed. NEW INFORMATION: The genus is here recorded for the first time from South Korea and China, which constitutes the first formal record of the species from the entire Eastern Palaearctic region. A detailed redescription and photographs of Acanopsilus heterocerus (Haliday, 1857) are provided. Also, Acanopsilus brevinervis Kieffer, 1909 is proposed as junior synonym of Anommatium ashmeadi Mayr, 1856 (syn. nov.). PMID- 27956850 TI - The African Crane Database (1978-2014): Records of three threatened crane species (Family: Gruidae) from southern and eastern Africa. AB - BACKGROUND: The International Crane Foundation (ICF) / Endangered Wildlife Trust's (EWT) African Crane Conservation Programme has recorded 26 403 crane sightings in its database from 1978 to 2014. This sightings collection is currently ongoing and records are continuously added to the database by the EWT field staff, ICF/EWT Partnership staff, various partner organizations and private individuals. The dataset has two peak collection periods: 1994-1996 and 2008 2012. The dataset collection spans five African countries: Kenya, Rwanda, South Africa, Uganda and Zambia; 98% of the data were collected in South Africa. Georeferencing of the dataset was verified before publication of the data. The dataset contains data on three African crane species: Blue Crane Anthropoides paradiseus, Grey Crowned Crane Balearica regulorum and Wattled Crane Bugeranus carunculatus. The Blue and Wattled Cranes are classified by the IUCN Red List of Threatened Species as Vulnerable and the Grey Crowned Crane as Endangered. NEW INFORMATION: This is the single most comprehensive dataset published on African Crane species that adds new information about the distribution of these three threatened species. We hope this will further aid conservation authorities to monitor and protect these species. The dataset continues to grow and especially to expand in geographic coverage into new countries in Africa and new sites within countries. The dataset can be freely accessed through the Global Biodiversity Information Facility data portal. PMID- 27956852 TI - Two new records of palm species for Gabon: Sclerosperma profizianum Valk. & Sunder. and Eremospatha quiquecostulata Becc. AB - BACKGROUND: Gabon is an important center of biodiversity in Central Africa. The country contains to date 27 species of palms. However, palms are generally poorly collected as these massive plants are hard to press and curate. Thus, our understanding remains incomplete, especially in Central Africa. NEW INFORMATION: We report three new records of two palm species for Gabon: Sclerosperma profizianum Valk. & Sunder. and Eremospatha quiquecostulata Becc.. The former species was collected in southeast Gabon, near Ndindi, while the later was collected in the Massif du Chaillu and Monts de Cristal National Park (Crystal Mountains National Park). The total number of palm species for Gabon is now 29, making it an important centre of palm diversity in Central Africa. PMID- 27956851 TI - Cyanobacteria of Greece: an annotated checklist. AB - BACKGROUND: The checklist of Greek Cyanobacteria was created in the framework of the Greek Taxon Information System (GTIS), an initiative of the LifeWatchGreece Research Infrastructure (ESFRI) that has resumed efforts to compile a complete checklist of species reported from Greece. This list was created from exhaustive search of the scientific literature of the last 60 years. All records of taxa known to occur in Greece were taxonomically updated. NEW INFORMATION: The checklist of Greek Cyanobacteria comprises 543 species, classified in 130 genera, 41 families, and 8 orders. The orders Synechococcales and Oscillatoriales have the highest number of species (158 and 153 species, respectively), whereas these two orders along with Nostocales and Chroococcales cover 93% of the known Greek cyanobacteria species. It is worth mentioning that 18 species have been initially described from Greek habitats. The marine epilithic Ammatoidea aegea described from Saronikos Gulf is considered endemic to this area. Our bibliographic review shows that Greece hosts a high diversity of cyanobacteria, suggesting that the Mediterranean area is also a hot spot for microbes. PMID- 27956853 TI - Salix transect of Europe: patterns in the most abundant chrysomelid beetle (Coleoptera: Chrysomelidae) herbivores of willow from Greece to Arctic Norway. AB - BACKGROUND: Chrysomelid beetles associated with willow (Salix spp.) were surveyed at 41 sites across Europe, from Greece (lat. 38.8 degrees N) to arctic Norway (lat. 69.7 degrees N). NEW INFORMATION: In all, 34 willow-associated chrysomelid species were encountered, of which eight were very abundant. The abundant species were: Crepidodera aurata Marsham, 1802 at 27 sites, Phratora vitellinae (Linnaeus, 1758) at 21 sites, Galerucella lineola (Fabricius, 1781) at 19 sites, Crepidodera fulvicornis (Fabricius, 1792) at 19 sites, Plagiodera versicolora (Laicharting, 1781) at 11 sites, Crepidodera plutus (Latreille, 1804) at nine sites, Chrysomela vigintipunctata Scopoli, 1763 at nine sites and Gonioctena pallida (Linnaeus, 1758) at eight sites. The mean number of willow associated chrysomelid morphospecies at each site was 4.2. Around 20% of the total variance in chrysomelid distribution could be accounted for by latitude, but this is mainly due to distinctive occurrence patterns at the northern and southern parts of the transect. There was a paucity of chrysomelids at Greek sites and a distinctively northern faunal composition at sites north of Poland. Considerable site-to-site variation in colour was noted, except in G. lineola, which was chromatically invariant. PMID- 27956854 TI - Marine Bryozoa of Greece: an annotated checklist. AB - BACKGROUND: Until today, a complete checklist of Bryozoa of the Greek seas had never been published and species records were scattered in several taxonomic and ecological studies. The aim of this paper is to produce a first checklist of marine bryozoan species of Greece, in the framework of the Greek Taxon Information System (GTIS) initiative of the LifeWatchGreece Research Infrastructure (ESFRI), by reviewing the existing literature and following the recent trends in the taxonomy of this group. . NEW INFORMATION: The marine bryozoan fauna of Greece comprises 237 species, classified in 127 genera, 66 families, 3 orders, and 2 classes. The vast majority belongs to the class Gymnolaemata (177 Cheilostomatida and 21 Ctenostomatida), while the remaining 39 species are Stenolaemata (all Cyclostomatida). Among these species, 12 are considered endemic to the eastern Mediterranean, while another 12 species are non indigenous. PMID- 27956855 TI - First detection of the adventive large rove beetle Ocypus nitens (Schrank) in Canada and an update of its Nearctic distribution using data generated by the public. AB - The adventive rove beetle Ocypus nitens (Staphylinidae: Staphylininae) is newly recorded in Canada (Ontario) and the state of Vermont, and additional range expansion is documented. The updated distribution of this large, conspicuous species is based mostly on data from digital photographs posted by users of the online community BugGuide. All available data are summarized and made available as a DarwinCore dataset, and an updated distribution map is provided. Citizen generated distributional data continues to be a valuable ally in the detection of adventive insects and the study of their distributional dynamics. PMID- 27956856 TI - Multiple Antibiotic Resistance Plasmids Allow Scalable,?PCR-Mediated DNA Manipulation and Near-Zero Background Cloning. AB - We have constructed two plasmids that can be used for cloning as templates for PCR- -based gene disruption, mutagenesis and the construction of DNA chromosome translocation cassettes. To our knowledge, these plasmids are the first vectors that confer resistance to ampicillin, kanamycin and hygromycin B in bacteria, and to geneticin (G418) and hygromycin B in Saccharomyces cerevisiae simultaneously. The option of simultaneously using up to three resistance markers provides a highly stringent control of recombinant selection and the almost complete elimination of background resistance, while unique restriction sites allow easy cloning of chosen genetic material. Moreover, we successfully used these new vectors as PCR templates for the induction of chromosome translocation in budding yeast by the bridge-induced translocation system. Cells in which translocation was induced carried chromosomal rearrangements as expected and exhibited resistance to both, G418 and hygromycin B. These features make our constructs very handy tools for many molecular biology applications. PMID- 27956857 TI - The Use of Peptide Markers of Carp and Herring Allergens as an Example of Detection of Sequenced and Non-Sequenced Proteins. AB - The objective of this study is to identify fish protein markers for detecting multiple species based on a comparative proteomic approach that relies on fragments with identical sequences. The possibilities and challenges of the use of peptides obtained from carp (Cyprinus carpio) and herring (Clupea harengus) proteins are discussed. A bioinformatic analysis was followed by an LC-MS/MS experiment to identify markers predicting the presence of fish allergenic proteins. Selected myosin peptides were found in carp protein hydrolysates with known sequences and in herring protein hydrolysates with unknown sequences. The results obtained for carp and herring proteins myosin and parvalbumin indicate that proteins with unknown sequences can be identified by peptide markers. Such markers can be designed by disregarding the principle that peptides should be unique (present in one sequence). The challenge is to determine a group of proteins that can be detected by peptide identification. PMID- 27956858 TI - HPTLC Fingerprinting and Cholinesterase Inhibitory and Metal-Chelating Capacity of Various Citrus Cultivars and?Olea europaea. AB - Inhibitory activity of thirty-one ethanol extracts obtained from albedo, flavedo, seed and leaf parts of 17 cultivars of Citrus species from Turkey, the bark and leaves of Olea europaea L. from two locations (Turkey and Cyprus) as well as caffeic acid and hesperidin was tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), related to the pathogenesis of Alzheimer's disease, using ELISA microtiter assays at 500 ug/mL. Metal-chelating capacity of the extracts was also determined. BChE inhibitory effect of the Citrus sp. extracts was from (7.7+/-0.7) to (70.3+/-1.1) %, whereas they did not show any inhibition against AChE. Cholinesterase inhibitory activity of the leaf and bark ethanol extracts of O. europaea was very weak ((10.2+/-3.1) to (15.0+/-2.3) %). The extracts had either no or low metal-chelating capacity at 500 ug/mL. HPTLC fingerprinting of the extracts, which indicated a similar phytochemical pattern, was also done using the standards of caffeic acid and hesperidin with weak cholinesterase inhibition. Among the screened extracts, the albedo extract of C. limon 'Interdonato', the flavedo extracts of 'Kara Limon' and 'Cyprus' cultivars and the seed extract of C. maxima appear to be promising as natural BChE inhibitors. PMID- 27956859 TI - Correlation Between Phytochemical and Mineral Contents and Antioxidant Activity of Black Glutinous Rice Bran, and ?Its Potential Chemopreventive Property. AB - In this work total anthocyanin content (TAC), total flavonoid content (TFC), total phenolic content (TPC) and minerals found in five black glutinous rice cultivars (MS, SK, PY, PC and KK) from Thailand were analyzed. The antioxidant activity of anthocyanin-rich black glutinous rice bran extracts against nitric oxide radical (NO), superoxide radical (O2Z) and lipid peroxyl radical (LOO) was also determined. Potential chemopreventive property of rice bran extract was screened based on cellular bioassays for phase II detoxification enzyme induction. Quinone reductase (QR) induction in murine hepatoma cells was used as a marker for this effect. Rice bran extract of cultivar KK had the highest TAC, of SK the highest TFC and of PC the highest TPC. The best antioxidants against NO, O2Z and LOO were cultivars KK, MS, and SK, respectively. Overall, TAC, TFC and TPC had a combinatorial effect on the antioxidant activities of all extracts; none of them dominated. Minerals may not play a role in the antioxidant activity of the extracts because most correlations between them and the antioxidant activity were unpredictable. However, rice bran contained high mass fractions of some essential minerals on dry mass basis, including Zn (103-133 ug/g), Se (11-18 ug/g) and Cu (3.8-7.1 ug/g). Chemopreventive study indicated that PC cultivar was the most potent chemopreventor with the lowest concentration of an inducer needed to double the QR activity (CD value) of 0.7 ug/mL. These findings showed that black glutinous rice bran is rich in phytochemicals and some essential minerals, and has a potential chemopreventive property. PMID- 27956860 TI - Effect of Tween 80 and Acetone on the Secretion, ?Structure and Antioxidant Activities of Exopolysaccharides from Lentinus tigrinus. AB - In this study, the effects of the addition of Tween 80 and acetone on secretion, structure and antioxidant activities of Lentinus tigrinus exopolysaccharides (EPS) were investigated. It was found that Tween 80 and acetone displayed a stimulatory effect on EPS secretion. The EPS obtained by the addition of Tween 80 (EPS-T), acetone (EPS-A) and control (EPS--C) were purified by Sepharose CL-6B gel filtration chromatography and molecular mass of purified fractions was estimated to be 22.1, 137 and 12 kDa, respectively. Monosaccharide composition analysis indicated that EPS-T, EPS-A and EPS-C were mainly composed of glucose and mannose. Congo Red test indicated that EPS-T and EPS-A had a highly ordered conformation of triple helix, while EPS-C had a random coil conformation. Furthermore, EPS-A exhibited higher DPPH scavenging and antiproliferative activities than EPS--C and EPS-T, which might be attributed to the molecular mass. PMID- 27956861 TI - Biochemical Evaluation of Phenylalanine Ammonia Lyase from Endemic Plant Cyathobasis fruticulosa (Bunge) Aellen. for the Dietary Treatment of Phenylketonuria. AB - Enzyme substitution therapy with the phenylalanine ammonia lyase (PAL) is a new approach to the treatment of patients with phenylketonuria (PKU). This enzyme is responsible for the conversion of phenylalanine to trans-cinnamic acid. We assessed the PAL enzyme of the endemic plant Cyathobasis fruticulosa (Bunge) Aellen. for its possible role in the dietary treatment of PKU. The enzyme was found to have a high activity of (64.9+/-0.1) U/mg, with the optimum pH, temperature and buffer (Tris-HCl and l-phenylalanine) concentration levels of pH=8.8, 37 degrees C and 100 mM, respectively. Optimum enzyme activity was achieved at pH=4.0 and 7.5, corresponding to pH levels of gastric and intestinal juice, and NaCl concentration of 200 mM. The purification of the enzyme by 1.87 fold yielded an activity of 98.6 U/mg. PAL activities determined by HPLC analyses before and after purification were similar. Two protein bands, one at 70 and the other at 23 kDa, were determined by Western blot analysis of the enzyme. This enzyme is a potential candidate for serial production of dietary food and biotechnological products. PMID- 27956862 TI - Effect of Encapsulation on Antimicrobial Activity of?Herbal Extracts with Lysozyme. AB - Resistance of microorganisms to antibiotics has increased. The use of natural components with antimicrobial properties can be of great significance to reduce this problem. The presented work is focused on the study of the effect of encapsulation of selected plant and animal antimicrobial substances (herbs, spices, lysozyme and nisin) on their activity and stability. Antimicrobial components were packaged into liposomes and polysaccharide particles (alginate, chitosan and starch). Antimicrobial activity was tested against two Gram-positive (Bacillus subtilis and Micrococcus luteus) and two Gram-negative (Escherichia coli and Serratia marcescens) bacteria. Encapsulation was successful in all types of polysaccharide particles and liposomes. The prepared particles exhibited very good long-term stability, especially in aqueous conditions. Antimicrobial activity was retained in all types of particles. Liposomes with encapsulated herb and spice extracts exhibited very good inhibitory effect against all tested bacterial strains. Most of herbal extracts had very good antimicrobial effect against the tested Gram-negative bacterial strains, while Gram-positive bacteria were more sensitive to lysozyme particles. Thus, particles with co-encapsulated herbs and lysozyme are more active against different types of bacteria, and more stable and more effective during long-term storage. Particles with encapsulated mixture of selected plant extracts and lysozyme could be used as complex antimicrobial preparation with controlled release in the production of food and food supplements, pharmaceutical and cosmetic industries. PMID- 27956863 TI - Inhibitory Effect of Lactococcin BZ Against Listeria innocua and Indigenous Microbiota of Fresh Beef. AB - In this study, the effect of lactococcin BZ on microbiological quality of fresh beef is investigated. For this purpose, the meat samples were treated with various amounts of lactococcin BZ (200-2500 AU/mL), a bacteriocin produced by Lactococcus lactis spp. lactis BZ, and kept at 4-5 degrees C for 12 days. During storage, the microbiological properties of the meat samples with or without lactococcin BZ were determined. Inhibitory effect of lactococcin BZ depended on its amount. The higher the amount of lactococcin BZ, the higher the inhibitory activity. Treatment with lactococcin BZ at the level of 2500 AU/mL resulted in 4.87, 3.50 and 3.94 log cycle decrease in the counts of mesophilic, psychrotrophic and lactic acid bacteria, respectively, and 1.90.104 and 1.04.102 CFU/g reduction in coliform and faecal coliform bacteria, respectively, at the end of storage as compared to their initial numbers in the control sample. However, the counts of these bacteria in control samples increased during storage. Also, lactococcin BZ at 1600 AU/mL showed very strong antilisterial effect against Listeria innocua in fresh meat and reduced the cell numbers from 6.04 log CFU/g to undetectable level on the 6th day of storage. In conclusion, lactococcin BZ has a potential use as a biopreservation agent to improve safety and shelf life of raw beef. PMID- 27956864 TI - Proteome Changes in biceps femoris Muscle of Iranian?One-Humped Camel and Their Effect on Meat Quality Traits. AB - In this study physicochemical and quality traits of biceps femoris and longissimus thoracis muscles of male and female Iranian one-humped camel were determined during 14 days of refrigeration storage. Analysis of variance of the results showed that only shear force and temperature were affected by the gender (p<0.05). Anatomical location of the muscle influenced the meat properties except for drip loss (p<0.05). Also, except for cooking loss, ageing influenced the physicochemical and quality properties of meat; during 14 days of storage, proteolysis resulted in an increase of L* and b* values, drip loss and myofibrillar fragmentation index, and the decrease of a* value, expressed juice, shear force and sarcomere length. Proteome changes (myofibrillar proteins) during storage were investigated. Gel analysis revealed that 19 protein spots were significantly changed during 24, 72 and 168 h post-mortem. Fifteen spots were identified by MALDI-TOF/TOF mass spectrometer. Correlation analysis revealed significant correlations of actin, troponin T, capping protein, heat shock proteins (HSP) and desmin with physicochemical and quality properties of meat (p<0.05). Actin might be a potential protein marker for colour, tenderness and water-holding capacity, and HSP27 and desmin are good candidate markers for colour and tenderness, respectively. PMID- 27956865 TI - Direct Treatment of Isada Krill under Subcritical Water Conditions to Produce Seasoning with Shrimp-Like Flavour. AB - Characterization, sensory evaluation, and astaxanthin stability of isada krill under various subcritical water conditions were investigated to optimize the quality of krill extract and residue for producing food seasoning. Raw krill (82% wet basis moisture content) without additional water was treated in a pressure resistant vessel for 10 min at a temperature range of 100-240 degrees C. The yield of water-soluble protein was maximized by treatment at 200 degrees C and decreased with treatment at higher temperatures. The degradation of large molecules and the concomitant production of small molecules depended on the treatment temperature. Astaxanthin in the krill was unstable at temperatures higher than 140 degrees C. The odour intensities of krill extract and residue increased with higher treatment temperature; however, the highest intensity of pleasant shrimp-like flavour was obtained by treatment at 140 degrees C. Subjective preference scores were the highest for extract and residue obtained at 140 degrees C. Thus, treatment at 140 degrees C is the most promising method for production of seasoning with shrimp-like flavour from isada krill. PMID- 27956866 TI - Potential of Lactobacillus reuteri from Spontaneous ?Sourdough as a Starter Additive for Improving Quality Parameters of Bread. AB - Retardation of microbial spoilage of bread can be achieved by the use of spontaneous sourdough with an antimicrobial activity. This study was undertaken to identify lactic acid bacteria naturally occurring in spontaneous sourdough and use them for quality improvement and prolonging shelf life of rye, wheat and rye with wheat bread. Identification of isolates from spontaneous sourdough by pyrosequencing assay showed that Lactobacillus reuteri were dominant lactic acid bacteria. The isolates showed a wide range of antimicrobial activity and displayed a synergistic activity against other lactobacilli, some lactococci and foodborne yeasts. The best application of spontaneous sourdough was noticed in the rye bread with the lowest crumb firmness of the final product, although the sensory results of wheat and rye with wheat bread did not statistically differ from control bread. L. reuteri showed a high preserving capacity against fungi during storage. This may be due to bacteriocins and various fatty acids secreted into the growth medium that were identified by agar well diffusion assay and gas chromatography. L. reuteri showing high antimicrobial activity have the potential to be used as a starter additive that could improve safety and/or shelf life of bread. PMID- 27956868 TI - The Effect of Dry Yeast Fermentation on Chemical Composition and Protein Characteristics of Blue Lupin Seeds. AB - The effect of 24-hour fermentation of lupin seeds by different yeast strains on their chemical composition was determined. After fermentation, the mass fraction of proteins increased and their in vitro digestibility and biological activity significantly improved. The amino acid profile of fermented products was similar to that of raw lupin seeds. The significant reduction in the mass fraction of oligosaccharides and phytate, but not of alkaloids was found. The pH level of fermented products decreased as a consequence of the increase of lactic and propionic acid mass fractions. The most favourable changes in the chemical composition of blue lupin seeds were obtained in fermentation with Saccharomyces cerevisiae baker's yeast and Fermivin 7013 strain. PMID- 27956867 TI - Vinegar Production from Jabuticaba (Myrciaria jaboticaba) Fruit Using Immobilized Acetic Acid Bacteria. AB - Cell immobilization comprises the retention of metabolically active cells inside a polymeric matrix. In this study, the production of jabuticaba (Myrciaria jaboticaba) vinegar using immobilized Acetobacter aceti and Gluconobacter oxydans cells is proposed as a new method to prevent losses of jabuticaba fruit surplus. The pulp of jabuticaba was processed and Saccharomyces cerevisiae CCMA 0200 was used to ferment the must for jabuticaba wine production. Sugars, alcohols (ethanol and glycerol) and organic acids were assayed by high-performance liquid chromatography. Volatile compounds were determined by gas chromatography-flame ionization detector. The ethanol content of the produced jabuticaba wine was approx. 74.8 g/L (9.5% by volume) after 168 h of fermentation. Acetic acid fermentation for vinegar production was performed using a mixed culture of immobilized A. aceti CCT 0190 and G. oxydans CCMA 0350 cells. The acetic acid yield was 74.4% and productivity was 0.29 g/(L.h). The vinegar had particularly high concentrations of citric (6.67 g/L), malic (7.02 g/L) and succinic (5.60 g/L) acids. These organic acids give a suitable taste and flavour to the vinegar. Seventeen compounds (aldehydes, higher alcohols, terpene, acetate, diether, furans, acids, ketones and ethyl esters) were identified in the jabuticaba vinegar. In conclusion, vinegar was successfully produced from jabuticaba fruits using yeast and immobilized mixed cultures of A. aceti and G. oxydans. To the best of our knowledge, this is the first study to use mixed culture of immobilized cells for the production of jabuticaba vinegar. PMID- 27956870 TI - An optimal tuning strategy for tidal turbines. AB - Tuning wind and tidal turbines is critical to maximizing their power output. Adopting a wind turbine tuning strategy of maximizing the output at any given time is shown to be an extremely poor strategy for large arrays of tidal turbines in channels. This 'impatient-tuning strategy' results in far lower power output, much higher structural loads and greater environmental impacts due to flow reduction than an existing 'patient-tuning strategy' which maximizes the power output averaged over the tidal cycle. This paper presents a 'smart patient tuning strategy', which can increase array output by up to 35% over the existing strategy. This smart strategy forgoes some power generation early in the half tidal cycle in order to allow stronger flows to develop later in the cycle. It extracts enough power from these stronger flows to produce more power from the cycle as a whole than the existing strategy. Surprisingly, the smart strategy can often extract more power without increasing maximum structural loads on the turbines, while also maintaining stronger flows along the channel. This paper also shows that, counterintuitively, for some tuning strategies imposing a cap on turbine power output to limit loads can increase a turbine's average power output. PMID- 27956869 TI - Antioxidant and Angiotensin-Converting Enzyme Inhibitory Activity of Eucalyptus camaldulensis and Litsea glaucescens Infusions Fermented with Kombucha Consortium. AB - Physicochemical properties, consumer acceptance, antioxidant and angiotensin converting enzyme (ACE) inhibitory activities of infusions and fermented beverages of Eucalyptus camaldulensis and Litsea glaucescens were compared. Among physicochemical parameters, only the pH of fermented beverages decreased compared with the unfermented infusions. No relevant changes were reported in consumer preference between infusions and fermented beverages. Phenolic profile measured by UPLC MS/MS analysis demonstrated significant concentration changes of these compounds in plant infusions and fermented beverages. Fermentation induced a decrease in the concentration required to stabilize 50% of DPPH radical (i.e. lower IC50). Additionally, it enhanced the antioxidant activity measured by the nitric oxide scavenging assay (14% of E. camaldulensis and 49% of L. glaucescens); whereas relevant improvements in the fermented beverage were not observed in the lipid oxidation assay compared with unfermented infusions. The same behaviour was observed in the inhibitory activity of ACE; however, both infusions and fermented beverages had lower IC50 than positive control (captopril). The present study demonstrated that fermentation has an influence on the concentration of phenolics and their potential bioactivity. E. camaldulensis and L. glaucescens can be considered as natural sources of biocompounds with antihypertensive potential used either as infusions or fermented beverages. PMID- 27956871 TI - Formal groups and Z-entropies. AB - We shall prove that the celebrated Renyi entropy is the first example of a new family of infinitely many multi-parametric entropies. We shall call them the Z entropies. Each of them, under suitable hypotheses, generalizes the celebrated entropies of Boltzmann and Renyi. A crucial aspect is that every Z-entropy is composable (Tempesta 2016 Ann. Phys.365, 180-197. (doi:10.1016/j.aop.2015.08.013)). This property means that the entropy of a system which is composed of two or more independent systems depends, in all the associated probability space, on the choice of the two systems only. Further properties are also required to describe the composition process in terms of a group law. The composability axiom, introduced as a generalization of the fourth Shannon-Khinchin axiom (postulating additivity), is a highly non-trivial requirement. Indeed, in the trace-form class, the Boltzmann entropy and Tsallis entropy are the only known composable cases. However, in the non-trace form class, the Z-entropies arise as new entropic functions possessing the mathematical properties necessary for information-theoretical applications, in both classical and quantum contexts. From a mathematical point of view, composability is intimately related to formal group theory of algebraic topology. The underlying group-theoretical structure determines crucially the statistical properties of the corresponding entropies. PMID- 27956872 TI - Length filtration of the separable states. AB - We investigate the separable states rho of an arbitrary multi-partite quantum system with Hilbert space [Formula: see text] of dimension d. The length L(rho) of rho is defined as the smallest number of pure product states having rho as their mixture. The length filtration of the set of separable states, [Formula: see text], is the increasing chain [Formula: see text], where [Formula: see text]. We define the maximum length, [Formula: see text], critical length, Lcrit, and yet another special length, Lc, which was defined by a simple formula in one of our previous papers. The critical length indicates the first term in the length filtration whose dimension is equal to [Formula: see text]. We show that in general d<=Lc<=Lcrit<=Lmax<=d2. We conjecture that the equality Lcrit=Lc holds for all finite-dimensional multi-partite quantum systems. Our main result is that Lcrit=Lc for the bipartite systems having a single qubit as one of the parties. This is accomplished by computing the rank of the Jacobian matrix of a suitable map having [Formula: see text] as its range. PMID- 27956873 TI - Gravity-capillary waves in finite depth on flows of constant vorticity. AB - This paper considers two-dimensional periodic gravity-capillary waves propagating steadily in finite depth on a linear shear current (constant vorticity). A perturbation series solution for steady periodic waves, accurate up to the third order, is derived using a classical Stokes expansion procedure, which allows us to include surface tension effects in the analysis of wave-current interactions in the presence of constant vorticity. The analytical results are then compared with numerical computations with the full equations. The main results are (i) the phase velocity is strongly dependent on the value of the vorticity; (ii) the singularities (Wilton singularities) in the Stokes expansion in powers of wave amplitude that correspond to a Bond number of 1/2 and 1/3, which are the consequences of the non-uniformity in the ordering of the Fourier coefficients, are found to be influenced by vorticity; (iii) different surface profiles of capillary-gravity waves are computed and the effect of vorticity on those profiles is shown to be important, in particular that the solutions exhibit type 2-like wave features, characterized by a secondary maximum on the surface profile with a trough between the two maxima. PMID- 27956874 TI - Globalization and pollution: tele-connecting local primary PM2.5 emissions to global consumption. AB - Globalization pushes production and consumption to geographically diverse locations and generates a variety of sizeable opportunities and challenges. The distribution and associated effects of short-lived primary fine particulate matter (PM2.5), a representative of local pollution, are significantly affected by the consumption through global supply chain. Tele-connection is used here to represent the link between production and consumption activity at large distances. In this study, we develop a global consumption-based primary PM2.5 emission inventory to track primary PM2.5 emissions embodied in the supply chain and evaluate the extent to which local PM2.5 emissions are triggered by international trade. We further adopt consumption-based accounting and identify the global original source that produced the emissions. We find that anthropogenic PM2.5 emissions from industrial sectors accounted for 24 Tg globally in 2007; approximately 30% (7.2 Tg) of these emissions were embodied in export of products principally from Brazil, South Africa, India and China (3.8 Tg) to developed countries. Large differences (up to 10 times) in the embodied emissions intensity between net importers and exporters greatly increased total global PM2.5 emissions. Tele-connecting production and consumption activity provides valuable insights with respect to mitigating long-range transboundary air pollution and prompts concerted efforts aiming at more environmentally conscious globalization. PMID- 27956876 TI - Thirty per cent contrast in secondary-electron imaging by scanning field-emission microscopy. AB - We perform scanning tunnelling microscopy (STM) in a regime where primary electrons are field-emitted from the tip and excite secondary electrons out of the target-the scanning field-emission microscopy regime (SFM). In the SFM mode, a secondary-electron contrast as high as 30% is observed when imaging a monoatomic step between a clean W(110)- and an Fe-covered W(110)-terrace. This is a figure of contrast comparable to STM. The apparent width of the monoatomic step attains the 1 nm mark, i.e. it is only marginally worse than the corresponding width observed in STM. The origin of the unexpected strong contrast in SFM is the material dependence of the secondary-electron yield and not the dependence of the transported current on the tip-target distance, typical of STM: accordingly, we expect that a technology combining STM and SFM will highlight complementary aspects of a surface while simultaneously making electrons, selected with nanometre spatial precision, available to a macroscopic environment for further processing. PMID- 27956875 TI - Self-assembling iron oxyhydroxide/oxide tubular structures: laboratory-grown and field examples from Rio Tinto. AB - Rio Tinto in southern Spain has become of increasing astrobiological significance, in particular for its similarity to environments on early Mars. We present evidence of tubular structures from sampled terraces in the stream bed at the source of the river, as well as ancient, now dry, terraces. This is the first reported finding of tubular structures in this particular environment. We propose that some of these structures could be formed through self-assembly via an abiotic mechanism involving templated precipitation around a fluid jet, a similar mechanism to that commonly found in so-called chemical gardens. Laboratory experiments simulating the formation of self-assembling iron oxyhydroxide tubes via chemical garden/chemobrionic processes form similar structures. Fluid mechanical scaling analysis demonstrates that the proposed mechanism is plausible. Although the formation of tube structures is not itself a biosignature, the iron mineral oxidation gradients across the tube walls in laboratory and field examples may yield information about energy gradients and potentially habitable environments. PMID- 27956877 TI - Anomalous diffusion and transport in heterogeneous systems separated by a membrane. AB - Diffusion of particles in a heterogeneous system separated by a semipermeable membrane is investigated. The particle dynamics is governed by fractional diffusion equations in the bulk and by kinetic equations on the membrane, which characterizes an interface between two different media. The kinetic equations are solved by incorporating memory effects to account for anomalous diffusion and, consequently, non-Debye relaxations. A rich variety of behaviours for the particle distribution at the interface and in the bulk may be found, depending on the choice of characteristic times in the boundary conditions and on the fractional index of the modelling equations. PMID- 27956878 TI - Closed-form evaluation of two-dimensional static lattice sums. AB - Closed-form formulae for the conditionally convergent two-dimensional (2D) static lattice sums S2 (for conductivity) and T2 (for elasticity) are deduced in terms of the complete elliptic integrals of the first and second kind. The obtained formulae yield asymptotic analytical formulae for the effective tensors of 2D composites with circular inclusions up to the third order in concentration. Exact relations between S2 and T2 for different lattices are established. In particular, the value S2=pi for the square and hexagonal arrays is discussed and T2=pi/2 for the hexagonal is deduced. PMID- 27956879 TI - Contact probing of stretched membranes and adhesive interactions: graphene and other two-dimensional materials. AB - Contact probing is the preferable method for studying mechanical properties of thin two-dimensional (2D) materials. These studies are based on analysis of experimental force-displacement curves obtained by loading of a stretched membrane by a probe of an atomic force microscope or a nanoindenter. Both non adhesive and adhesive contact interactions between such a probe and a 2D membrane are studied. As an example of the 2D materials, we consider a graphene crystal monolayer whose discrete structure is modelled as a 2D isotropic elastic membrane. Initially, for contact between a punch and the stretched circular membrane, we formulate and solve problems that are analogies to the Hertz-type and Boussinesq frictionless contact problems. A general statement for the slope of the force-displacement curve is formulated and proved. Then analogies to the JKR (Johnson, Kendall and Roberts) and the Boussinesq-Kendall contact problems in the presence of adhesive interactions are formulated. General nonlinear relations among the actual force, displacements and contact radius between a sticky membrane and an arbitrary axisymmetric indenter are derived. The dimensionless form of the equations for power-law shaped indenters has been analysed, and the explicit expressions are derived for the values of the pull-off force and corresponding critical contact radius. PMID- 27956880 TI - Optimal energy harvesting from vortex-induced vibrations of cables. AB - Vortex-induced vibrations (VIV) of flexible cables are an example of flow-induced vibrations that can act as energy harvesting systems by converting energy associated with the spontaneous cable motion into electricity. This work investigates the optimal positioning of the harvesting devices along the cable, using numerical simulations with a wake oscillator model to describe the unsteady flow forcing. Using classical gradient-based optimization, the optimal harvesting strategy is determined for the generic configuration of a flexible cable fixed at both ends, including the effect of flow forces and gravity on the cable's geometry. The optimal strategy is found to consist systematically in a concentration of the harvesting devices at one of the cable's ends, relying on deformation waves along the cable to carry the energy towards this harvesting site. Furthermore, we show that the performance of systems based on VIV of flexible cables is significantly more robust to flow velocity variations, in comparison with a rigid cylinder device. This results from two passive control mechanisms inherent to the cable geometry: (i) the adaptability to the flow velocity of the fundamental frequencies of cables through the flow-induced tension and (ii) the selection of successive vibration modes by the flow velocity for cables with gravity-induced tension. PMID- 27956881 TI - The mixed coupled nonlinear Schrodinger equation on the half-line via the Fokas method. AB - In this paper, we implement the Fokas method to study initial-boundary value problems of the mixed coupled nonlinear Schrodinger equation formulated on the half-line with Lax pairs involving 3*3 matrices. The solution can be written in terms of the solution to a 3*3 Riemann-Hilbert problem. The relevant jump matrices are explicitly expressed in terms of the matrix-value spectral functions s(k) and S(k), which are determined by the initial values and boundary values at x=0, respectively. Some of these boundary values are unknown; however, using the fact that these specific functions satisfy a certain global relation, the unknown boundary values can be expressed in terms of the given initial and boundary data. PMID- 27956882 TI - Analytic materials. AB - The theory of inhomogeneous analytic materials is developed. These are materials where the coefficients entering the equations involve analytic functions. Three types of analytic materials are identified. The first two types involve an integer p. If p takes its maximum value, then we have a complete analytic material. Otherwise, it is incomplete analytic material of rank p. For two dimensional materials, further progress can be made in the identification of analytic materials by using the well-known fact that a 90 degrees rotation applied to a divergence-free field in a simply connected domain yields a curl free field, and this can then be expressed as the gradient of a potential. Other exact results for the fields in inhomogeneous media are reviewed. Also reviewed is the subject of metamaterials, as these materials provide a way of realizing desirable coefficients in the equations. PMID- 27956883 TI - Electrodynamics of spoof plasmons in periodically corrugated waveguides. AB - States of the electromagnetic field confined near a periodically corrugated surface of a perfect conductor, spoof surface plasmon polaritons (SSPP), are approached systematically based on the developed adaptation of the mode matching technique to the transfer matrix formalism. Within this approach, in the approximation of narrow grooves, systems with arbitrary transversal structure can be investigated straightforwardly, thus lifting the restrictions of the effective medium description and usual implementations of mode matching. A compact expression for the SSPP coupling parameter accounting for the effect of higher Bloch modes is found. The results of the general analysis are applied for studying the effect of dielectric environment on SSPP spectra. It is shown that the effective SSPP plasma frequency is unaffected by the dielectric constant of the medium outside of the grooves and the main effect of sufficiently wide dielectric slabs covering the corrugated surface is described by simple rescaling of the maximal value of the Bloch wavenumber and the coupling parameter. Additionally, in the case of a thin dielectric layer, it is shown that SSPP are sensitive to variation of the thickness of the layer on the sub-wavelength scale. PMID- 27956884 TI - On the continuum limit for a semidiscrete Hirota equation. AB - In this paper, we propose a new semidiscrete Hirota equation which yields the Hirota equation in the continuum limit. We focus on the topic of how the discrete space step delta affects the simulation for the soliton solution to the Hirota equation. The Darboux transformation and explicit solution for the semidiscrete Hirota equation are constructed. We show that the continuum limit for the semidiscrete Hirota equation, including the Lax pair, the Darboux transformation and the explicit solution, yields the corresponding results for the Hirota equation as [Formula: see text]. PMID- 27956885 TI - Guided wave tomography with an improved scattering model. AB - Producing accurate thickness maps of corrosion damage is of great importance for assessing life in the petrochemical industry. Guided wave tomography provides a solution for this, by sending guided waves through the region of interest, then using tomographic imaging techniques to reconstruct the thickness map, importantly eliminating the need to take measurements at all points across the surface. However, to achieve accurate maps, the imaging algorithm must account for the way in which the guided waves interact with corrosion defects, and the complex scattering which occurs. Traditional approaches have exploited the dispersive nature of guided waves: a velocity map is produced from a dataset, then converted to thickness using the dispersion relationship. However, these relationships are derived for plates of constant thickness, which is not the case in the majority of defects, causing significant inaccuracies to exist in the images. This paper develops a more sophisticated inversion solution which accounts for the full-guided wave scattering, enabling more accurate images with resolution better than a wavelength, compared with two wavelengths previously. This is demonstrated with simulated and experimental data. The speed and stability of the algorithm in the presence of random noise and systematic errors is also demonstrated. PMID- 27956886 TI - Thermal convection in a magnetized conducting fluid with the Cattaneo-Christov heat-flow model. AB - By substituting the Cattaneo-Christov heat-flow model for the more usual parabolic Fourier law, we consider the impact of hyperbolic heat-flow effects on thermal convection in the classic problem of a magnetized conducting fluid layer heated from below. For stationary convection, the system is equivalent to that studied by Chandrasekhar (Hydrodynamic and Hydromagnetic Stability, 1961), and with free boundary conditions we recover the classical critical Rayleigh number [Formula: see text] which exhibits inhibition of convection by the field according to [Formula: see text] as [Formula: see text], where Q is the Chandrasekhar number. However, for oscillatory convection we find that the critical Rayleigh number [Formula: see text] is given by a more complicated function of the thermal Prandtl number [Formula: see text], magnetic Prandtl number [Formula: see text] and Cattaneo number C. To elucidate features of this dependence, we neglect [Formula: see text] (in which case overstability would be classically forbidden), and thereby obtain an expression for the Rayleigh number that is far less strongly inhibited by the field, with limiting behaviour [Formula: see text], as [Formula: see text]. One consequence of this weaker dependence is that onset of instability occurs as overstability provided C exceeds a threshold value CT(Q); indeed, crucially we show that when Q is large, [Formula: see text], meaning that oscillatory modes are preferred even when C itself is small. Similar behaviour is demonstrated in the case of fixed boundaries by means of a novel numerical solution. PMID- 27956887 TI - Small-on-large geometric anelasticity. AB - In this paper, we are concerned with finding exact solutions for the stress fields of nonlinear solids with non-symmetric distributions of defects (or more generally finite eigenstrains) that are small perturbations of symmetric distributions of defects with known exact solutions. In the language of geometric mechanics, this corresponds to finding a deformation that is a result of a perturbation of the metric of the Riemannian material manifold. We present a general framework that can be used for a systematic analysis of this class of anelasticity problems. This geometric formulation can be thought of as a material analogue of the classical small-on-large theory in nonlinear elasticity. We use the present small-on-large anelasticity theory to find exact solutions for the stress fields of some non-symmetric distributions of screw dislocations in incompressible isotropic solids. PMID- 27956889 TI - Self-locking degree-4 vertex origami structures. AB - A generic degree-4 vertex (4-vertex) origami possesses one continuous degree-of freedom for rigid folding, and this folding process can be stopped when two of its facets bind together. Such facet-binding will induce self-locking so that the overall structure stays at a pre-specified configuration without additional locking elements or actuators. Self-locking offers many promising properties, such as programmable deformation ranges and piecewise stiffness jumps, that could significantly advance many adaptive structural systems. However, despite its excellent potential, the origami self-locking features have not been well studied, understood, and used. To advance the state of the art, this research conducts a comprehensive investigation on the principles of achieving and harnessing self-locking in 4-vertex origami structures. Especially, for the first time, this study expands the 4-vertex structure construction from single component to dual-component designs and investigates their self-locking behaviours. By exploiting various tessellation designs, this research discovers that the dual-component designs offer the origami structures with extraordinary attributes that the single-component structures do not have, which include the existence of flat-folded locking planes, programmable locking points and deformability. Finally, proof-of-concept experiments investigate how self-locking can effectively induce piecewise stiffness jumps. The results of this research provide new scientific knowledge and a systematic framework for the design, analysis and utilization of self-locking origami structures for many potential engineering applications. PMID- 27956888 TI - Photophysics of sunscreen molecules in the gas phase: a stepwise approach towards understanding and developing next-generation sunscreens. AB - The relationship between exposure to ultraviolet (UV) radiation and skin cancer urges the need for extra photoprotection, which is presently provided by widespread commercially available sunscreen lotions. Apart from having a large absorption cross section in the UVA and UVB regions of the electromagnetic spectrum, the chemical absorbers in these photoprotective products should also be able to dissipate the excess energy in a safe way, i.e. without releasing photoproducts or inducing any further, harmful, photochemistry. While sunscreens are tested for both their photoprotective capability and dermatological compatibility, phenomena occurring at the molecular level upon absorption of UV radiation are largely overlooked. To date, there is only a limited amount of information regarding the photochemistry and photophysics of these sunscreen molecules. However, a thorough understanding of the intrinsic mechanisms by which popular sunscreen molecular constituents dissipate excess energy has the potential to aid in the design of more efficient, safer sunscreens. In this review, we explore the potential of using gas-phase frequency- and time-resolved spectroscopies in an effort to better understand the photoinduced excited-state dynamics, or photodynamics, of sunscreen molecules. Complementary computational studies are also briefly discussed. Finally, the future outlook of expanding these gas-phase studies into the solution phase is considered. PMID- 27956890 TI - Eliminating incident subtraction in diffraction tomography. AB - Diffraction tomography is a powerful algorithm for producing high-resolution quantitative reconstructions across a wide range of applications. A major drawback of the method is that it operates on the scattered field, which cannot generally be directly measured, but must instead be calculated by subtracting the incident field, i.e. the equivalent field with no scatterer present. Unfortunately, often the incident field is not measurable and hence must be estimated, causing errors. This paper highlights an important, but not widely recognized, result: for particular widely used formulations of the algorithm, the subtraction of the incident field is unnecessary, and the algorithm can actually be applied directly to measured signals. The theory behind this is derived, showing that the incident field will vanish under far-field conditions, and the result is demonstrated in practice. Tests with subsampled arrays show that aliasing artefacts can appear, but can be removed with a filter at the expense of resolution. The incident field also has no effect for a variety of array configurations tested. Finally, the performance in the presence of both correlated and uncorrelated errors is confirmed, in all cases demonstrating that the incident field has a negligible effect on the final reconstruction. PMID- 27956891 TI - NADP-Dependent Aldehyde Dehydrogenase from Archaeon Pyrobaculum sp.1860: Structural and Functional Features. AB - We present the functional and structural characterization of the first archaeal thermostable NADP-dependent aldehyde dehydrogenase AlDHPyr1147. In vitro, AlDHPyr1147 catalyzes the irreversible oxidation of short aliphatic aldehydes at 60-85 degrees S, and the affinity of AlDHPyr1147 to the NADP+ at 60 degrees S is comparable to that for mesophilic analogues at 25 degrees S. We determined the structures of the apo form of AlDHPyr1147 (3.04 A resolution), three binary complexes with the coenzyme (1.90, 2.06, and 2.19 A), and the ternary complex with the coenzyme and isobutyraldehyde as a substrate (2.66 A). The nicotinamide moiety of the coenzyme is disordered in two binary complexes, while it is ordered in the ternary complex, as well as in the binary complex obtained after additional soaking with the substrate. AlDHPyr1147 structures demonstrate the strengthening of the dimeric contact (as compared with the analogues) and the concerted conformational flexibility of catalytic Cys287 and Glu253, as well as Leu254 and the nicotinamide moiety of the coenzyme. A comparison of the active sites of AlDHPyr1147 and dehydrogenases characterized earlier suggests that proton relay systems, which were previously proposed for dehydrogenases of this family, are blocked in AlDHPyr1147, and the proton release in the latter can occur through the substrate channel. PMID- 27956892 TI - Differences in the working pattern among wound, ostomy, and continence nurses with and without conducting the specified medical act: a multicenter time and motion study. AB - BACKGROUND: To overcome the shortage of medical care delivery in the rapidly aging Japanese society, the Ministry of Health, Labour and Welfare in 2010 started to train the nurses to be able to conduct the specified medical acts. The Japanese Nursing Association conducted the educational program to train the wound, ostomy, and continence nurses for the specified medical act of wound care. However, the difference between wound, ostomy, and continence nurses who conducted the medical act and those who did not was not clear. The aim of this study was to determine how trained wound, ostomy, and continence nurses spend their time during their entire shift in an acute hospital setting. METHODS: In this prospective observational study, we selected those wound, ostomy, and continence nurses who received advanced training in the wound management program (T-WN) in 2011-2012. Wound, ostomy, and continence nurses who did not receive the training (N-WN) were also recruited as controls. We conducted a time and motion study during subject's day shifts for 1 week. We calculated the time spent on tasks based on a task classification code that was created to facilitate a two group comparison. RESULTS: Six T-WNs and five N-WNs were our analysis subjects. T WNs spent significantly more time on direct care than did N-WNs (p = 0.00). Moreover, in the sub-categories s of direct care, T-WN spent significantly more time on "treatment" than did N-WN (p = 0.01). T-WN spent significantly more time on treatment with (p = 0.03) or without (p = 0.01) physicians than did N-WN. In the treatment activities, T-WN performed significantly more time on foot care (p = 0.01), wound cleansing (p = 0.01) and conservative sharp wound debridement (p = 0.01) than did N-WN. Frequencies of direct care interventions for the patients was significantly different between T-WN and N-WN (p = 0.04). CONCLUSIONS: T-WNs frequently engaged in direct care provided treatment for patients with chronic wounds. PMID- 27956893 TI - Eosinophilic disorders of the gastro-intestinal tract: an update. AB - Eosinophilic diseases of the gastrointestinal tract, including eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE), are rare chronic pathologies of the digestive system, with an immuno-mediated pathogenesis. Recent data suggest that, together with the "classic" IgE-response to allergens, also a delayed hypersensitivity mechanism could be involved in the development of eosinophilic disorders. EoE and EGE were studied only in the latest decades and as a consequence accurate data are not yet available, concerning not only pathogenesis, but also epidemiology, treatment and outcomes. The diagnosis of EoE is centered on endoscopic findings but the certainty is obtained by histological examination from biopsy samples, that has a sensitivity of 100% when based on five samples. The currently available treatments include topical corticosteroids, specific diets and endoscopic treatment. Concerning EGE, three subtypes (mucosal, muscular, and serosal) were identified. The diagnosis is based, as for EoE, on endoscopic and histological assessment, and the treatment includes pharmacological and dietetic approaches. Further studies are warranted in order to better define the etiology and pathogenesis of eosinophilic diseases of the gastrointestinal tract, and thus to develop more appropriate and specific therapies. PMID- 27956895 TI - Advances in Neural Networks and Hybrid-Metaheuristics: Theory, Algorithms, and Novel Engineering Applications. PMID- 27956896 TI - SABE Colombia: Survey on Health, Well-Being, and Aging in Colombia-Study Design and Protocol. AB - Objective. To describe the design of the SABE Colombia study. The major health study of the old people in Latin America and the Caribbean (LAC) is the Survey on Health, Well-Being, and Aging in LAC, SABE (from initials in Spanish: SAlud, Bienestar & Envejecimiento). Methods. The SABE Colombia is a population-based cross-sectional study on health, aging, and well-being of elderly individuals aged at least 60 years focusing attention on social determinants of health inequities. Methods and design were similar to original LAC SABE. The total sample size of the study at the urban and rural research sites (244 municipalities) was 23.694 elderly Colombians representative of the total population. The study had three components: (1) a questionnaire covering active aging determinants including anthropometry, blood pressure measurement, physical function, and biochemical and hematological measures; (2) a subsample survey among family caregivers; (3) a qualitative study with gender and cultural perspectives of quality of life to understand different dimensions of people meanings. Conclusions. The SABE Colombia is a comprehensive, multidisciplinary study of the elderly with respect to active aging determinants. The results of this study are intended to inform public policies aimed at tackling health inequalities for the aging society in Colombia. PMID- 27956894 TI - Modeling Axonal Defects in Hereditary Spastic Paraplegia with Human Pluripotent Stem Cells. AB - BACKGROUND: Cortical motor neurons, also known as upper motor neurons, are large projection neurons whose axons convey signals to lower motor neurons to control the muscle movements. Degeneration of cortical motor neuron axons is implicated in several debilitating disorders, including hereditary spastic paraplegia (HSP) and amyotrophic lateral sclerosis (ALS). Since the discovery of the first HSP gene, SPAST that encodes spastin, over 70 distinct genetic loci associated with HSP have been identified. How the mutations of these functionally diverse genes result in axonal degeneration and why certain axons are affected in HSP remains largely unknown. The development of induced pluripotent stem cell (iPSC) technology has provided researchers an excellent resource to generate patient specific human neurons to model human neuropathologic processes including axonal defects. METHODS: In this article, we will frst review the pathology and pathways affected in the common forms of HSP subtypes by searching the PubMed database. We will then summurize the findings and insights gained from studies using iPSC based models, and discuss the challenges and future directions. RESULTS: HSPs, a heterogeneous group of genetic neurodegenerative disorders, are characterized by lower extremity weakness and spasticity that result from retrograde axonal degeneration of cortical motor neurons. Recently, iPSCs have been generated from several common forms of HSP including SPG4, SPG3A, and SPG11 patients. Neurons derived from HSP iPSCs exhibit disease-relevant axonal defects, such as impaired neurite outgrowth, increased axonal swellings, and reduced axonal transport. CONCLUSION: These patient-derived neurons offer unique tools to study the pathogenic mechanisms and explore the treatments for rescuing axonal defects in HSP, as well as other diseases involving axonopathy. PMID- 27956897 TI - Gestational Diabetes Mellitus and Future Cardiovascular Risk: An Update. AB - The prevalence of gestational diabetes mellitus is increasing in parallel with the rising prevalence of type 2 diabetes and obesity around the world. Current evidence strongly suggests that women who have had gestational diabetes mellitus are at greater risk of cardiovascular disease later in life. Given the growing prevalence of gestational diabetes mellitus, it is important to identify appropriate reliable markers of cardiovascular disease and specific treatment strategies capable of containing obesity, diabetes, and metabolic syndrome in order to reduce the burden of cardiovascular disease in the women affected. PMID- 27956898 TI - Association between Sleep Duration and Measurable Cardiometabolic Risk Factors in Healthy Korean Women: The Fourth and Fifth Korean National Health and Nutrition Examination Surveys (KNHANES IV and V). AB - Study Objectives. To examine the association between sleep duration and prevalence of metabolic syndrome (MetS) and its components in healthy Korean women. Design. Cross-sectional study, using the Fourth and Fifth Korean National Health and Nutrition Examination Surveys. Methods. Among 8505 women (25-70 years) from KNHANES IV and V, participants were classified into five sleep groups based on self-reported sleep duration. MetS and its components were defined using the criteria set forth in National Cholesterol Education Program-Adult Treatment Panel III. We used multivariate logistic regression analysis. Results. After adjusting for various confounders, shorter sleep duration (<=6 h) was found to have an association with low risk of reduced high-density lipoprotein cholesterol and increased triglycerides, whereas very long sleep duration was found to have high risk of increased triglycerides. However, abdominal obesity showed an opposite trend: short sleep duration was associated with higher risk of abdominal obesity than long sleep duration. Fasting glucose levels increased as sleep duration increased, but without significance. Moreover, blood pressure was not significantly associated with sleep duration. Consequently, MetS was less prevalent in those with short sleep duration. Conclusions. Sleep duration was positively associated with MetS, especially dyslipidemia and fasting hyperglycemia, but inversely associated with abdominal obesity. PMID- 27956899 TI - Body Composition in Adult Patients with Thalassemia Major. AB - Objective. To assess body composition in adult male and female patients with thalassemia major by dual-energy X-ray absorptiometry (DXA) and to compare the findings with a group of healthy age-matched controls. Methods. Our study group included sixty-two patients (27 males, mean age 36 years, and 35 females, mean age 36.4 years) and fifteen age-matched healthy controls. All patients had an established diagnosis of thalassemia major and followed a regular blood transfusion scheme since childhood and chelation treatment. Fat, lean, and bone mineral density (BMD) were assessed with dual-energy X-ray absorptiometry. Ferritin levels and body mass index of all patients and controls were also recorded. Student t-test and Wilcoxon test were performed and statistical significance was set at p < 0.05. Results. BMD and whole body lean mass are lower in both male and female adult patients compared with controls (p < 0.01 in both groups), whereas whole body fat mass was found to have no statistically significant difference compared to controls. Regional trunk fat around the abdomen was found to be lower in male patients compared to controls (p = 0.02). Conclusion. Severe bone loss and diminished lean mass are expected in adult male and female patients with thalassemia major. Fat changes seem to affect mainly male patients. PMID- 27956901 TI - Spontaneous Tumour Lysis Syndrome in a Multiple Myeloma. AB - The tumor lysis syndrome (TLS) is a collection of metabolic abnormalities that occur in consequence of the release of intracellular contents following lysis of tumor cells. TLS occurs spontaneously or after chemotherapy. Spontaneous TLS is uncommon occurrence in multiple myeloma (MM). We define a case of a 70-year-old woman patient who was found to have MM with spontaneous TLS, following a compression fracture of the T-12 vertebrae. While serum uric acid and phosphorous levels were high, low calcium levels were identified. There were also acute kidney injury and metabolic acidosis. Upon the diagnosis of TLS, she was treated with hydration, allopurinol, sodium bicarbonate, and calcium gluconate. The improvement of her laboratory data was observed. We submitted this case in order to draw attention to the presentation of MM with spontaneous TLS. PMID- 27956900 TI - Mixed Phenotype Acute Leukemia Presenting as Leukemia Cutis. AB - Leukemia cutis (LC) is defined as infiltration of the skin by leukemic cells resulting in clinically recognizable cutaneous lesions. It is common in congenital leukemia and acute myeloid leukemia. However, LC has rarely been reported with mixed phenotypic acute leukemia (MPAL). We report the case of a lady who presented with erythematous papular and nodular lesions all over the body. Skin biopsy showed leukemic infiltration and bone marrow aspiration showed MPAL of the T/myeloid with monocytic differentiation lineage. This is the first report of an adult patient with MPAL of the T/myeloid with monocytic differentiation type presenting with leukemia cutis. She was started on chemotherapy with Hyper-CVAD. There is complete resolution of the skin lesions and she has achieved bone marrow remission after the first cycle of chemotherapy. PMID- 27956902 TI - Vitamin D Effects on Osteoblastic Differentiation of Mesenchymal Stem Cells from Dental Tissues. AB - 1alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the active metabolite of vitamin D (Vit D), increases intestinal absorption of calcium and phosphate, maintaining a correct balance of bone remodeling. Vit D has an anabolic effect on the skeletal system and is key in promoting osteoblastic differentiation of human Mesenchymal Stem Cells (hMSCs) from bone marrow. MSCs can be also isolated from the immature form of the tooth, the dental bud: Dental Bud Stem Cells (DBSCs) are adult stem cells that can effectively undergo osteoblastic differentiation. In this work we investigated the effect of Vit D on DBSCs differentiation into osteoblasts. Our data demonstrate that DBSCs, cultured in an opportune osteogenic medium, differentiate into osteoblast-like cells; Vit D treatment stimulates their osteoblastic features, increasing the expression of typical markers of osteoblastogenesis like RUNX2 and Collagen I (Coll I) and, in a more important way, determining a higher production of mineralized matrix nodules. PMID- 27956903 TI - Comprehensive Screening of Cell Surface Markers Expressed by Adult-Derived Human Liver Stem/Progenitor Cells Harvested at Passage 5: Potential Implications for Engraftment. AB - Mesenchymal stromal cells (MSCs) are known to have potential therapeutic benefits for a number of diseases. However, many studies report low engraftment levels, regardless of the target organ. One possible explanation could be that MSCs do not express the necessary receptors for engraftment. Indeed, MSCs appear to use a similar mechanism to leukocytes to engraft into injured organs, relying on various receptors for rolling, firm adhesion, and transmigration. In this study, we conducted an extensive surface molecule screening of adult-derived human liver stem/progenitor cells (ADHLSC) in an attempt to shed some light on this subject. We observed that ADHLSCs lack expression of most of the costimulatory molecules tested. Furthermore, study of the adhesion molecule profile of ADHLSCs revealed that they do not express selectin ligands or LFA-1 which are, respectively, involved in the rolling process and the firm adhesion. In addition, ADHLSCs slightly express VLA-4 and lose expression of CXCR4 altogether on their surface during culture expansion. However, ADHLSCs express all the integrin couples and matrix metalloproteinases needed to bind and integrate the extracellular matrix once the endothelial barrier is crossed. Collectively, these results suggest that binding to the endothelium may be the critical weak point in the engraftment process. PMID- 27956905 TI - Molecular Characterization of Cryptosporidium spp. in Wild Rodents of Southwestern Iran Using 18s rRNA Gene Nested-PCR-RFLP and Sequencing Techniques. AB - Background. Rodents could act as reservoir for Cryptosporidium spp. specially C. parvum, a zoonotic agent responsible for human infections. Since there is no information about Cryptosporidium infection in rodents of Ahvaz city, southwest of Iran, hence, this survey was performed to determine the prevalence and molecular characterization of Cryptosporidium spp. in this region. Materials and Methods. One hundred rodents were trapped from different regions of Ahvaz city. Intestine contents and fecal specimens of rodents were studied using both microscopy examination to identify oocyst and nested-polymerase chain reaction (PCR) technique for 18s rRNA gene detection. Eventually restriction fragment length polymorphism (RFLP) method using SspI and VspI restriction enzymes was carried out to genotype the species and then obtained results were sequenced. Results. Three out of 100 samples were diagnosed as positive and overall prevalence of Cryptosporidium spp. was 3% using both modified Ziehl-Neelsen staining under light microscope and nested-PCR (830 bp) methods. Afterwards, PCR RFLP was performed on positive samples and C. parvum pattern was identified. Finally PCR-RFLP findings were sequenced and presence of C. parvum was confirmed again. Conclusions. Our study showed rodents could be potential reservoir for C. parvum. So an integrated program for control and combat with them should be adopted and continued. PMID- 27956906 TI - Prevalence of beta-lactam allergy: a retrospective chart review of drug allergy assessment in a predominantly pediatric population. AB - BACKGROUND: Research suggests that 90% of patients labeled beta-lactam allergic are able to tolerate penicillins following further assessment. This study aims to define and describe the frequency of true beta-lactam allergy following allergy patient evaluation in a predominantly pediatric population. METHODS: 306 primary care patients referred between January 2010 and June 2015 were assessed for a suspected beta-lactam allergy. Patient demographics, history and test results were extracted from electronic medical records. Testing performed was based on specialist recommendation following review of patient history. RESULTS: 34% of the study participants had intradermal testing. Oral challenge was given to 96.7% of the sample. 96% of patients with a prior history of beta-lactam allergy were advised that they could re-introduce beta-lactam antibiotics following evaluation. CONCLUSIONS: Among patients with a documented beta-lactam allergy or a recent history of a reaction there is a low rate of 'true' beta-lactam allergy. Consistent evaluation of beta-lactam antibiotic allergies can reduce rates of broad spectrum antibiotic prescribing, among other harmful consequences. PMID- 27956904 TI - Antibacterial Action of Curcumin against Staphylococcus aureus: A Brief Review. AB - Curcumin, the major constituent of Curcuma longa L. (Zingiberaceae family) or turmeric, commonly used for cooking in Asian cuisine, is known to possess a broad range of pharmacological properties at relatively nontoxic doses. Curcumin is found to be effective against Staphylococcus aureus (S. aureus). As demonstrated by in vitro experiment, curcumin exerts even more potent effects when used in combination with various other antibacterial agents. Hence, curcumin which is a natural product derived from plant is believed to have profound medicinal benefits and could be potentially developed into a naturally derived antibiotic in the future. However, there are several noteworthy challenges in the development of curcumin as a medicine. S. aureus infections, particularly those caused by the multidrug-resistant strains, have emerged as a global health issue and urgent action is needed. This review focuses on the antibacterial activities of curcumin against both methicillin-sensitive S. aureus (MSSA) and methicillin resistant S. aureus (MRSA). We also attempt to highlight the potential challenges in the effort of developing curcumin into a therapeutic antibacterial agent. PMID- 27956908 TI - Analysis of feline and canine allergen components in patients sensitized to pets. AB - BACKGROUND: Component resolved allergen diagnosis allows for a precise evaluation of the sensitization profiles of patients sensitized to felines and canines. An accurate interpretation of these results allows better insight into the evolution of a given patients sensitizations, and allows for a more precise evaluation of their prognoses. METHODS: 70 patients (42 women and 28 men, aged 18-65, with the average of 35.5) with a positive feline or canine allergy diagnosis were included in the research group. 30 patients with a negative allergy diagnosis were included in the control group. The total IgE levels of all patients with allergies as well as their allergen-specific IgE to feline and canine allergens were measured. Specific IgE levels to canine (Can f 1, Can f 2, Can f 3, Can f 5) and feline (Fel d 1, Fel d 2, Fel d 4) allergen components were also measured with the use of the ImmunoCap method. RESULTS: Monosensitization for only one canine or feline component was found in 30% of patients. As predicted, the main feline allergen was Fel d 1, which sensitized as many as 93.9% of patients sensitized to felines. Among 65 patients sensitized to at least one feline component, for 30 patients (46.2%) the only sensitizing feline component was Fel d 1. Only 19 patients in that group (63.3%) were not simultaneously sensitized to dogs and 11 (36.7%), the isolated sensitization to feline Fel d 1 notwithstanding, displayed concurrent sensitizations to one of the canine allergen components. Fel d 4 sensitized 49.2% of the research group.64.3% of patients sensitized to canine components had heightened levels of specific IgE to Can f 1. Monosensitization in that group occurred for 32.1% of the patients. Sensitization to Can f 5 was observed among 52.4% of the patients. CONCLUSIONS: Concurrent sensitizations to a few allergic components, not only cross-reactive but also originating in different protein families, are a significant problem for patients sensitized to animals. PMID- 27956909 TI - Left Ventricular Function after Arterial Switch Operation as Assessed by Two Dimensional Speckle-Tracking Echocardiography in Patients with Simple Transposition of the Great Arteries. AB - Background: The late postoperative course for children with transposition of the great arteries (TGA) with an intact ventricular septum (IVS) is very important because the coronary arteries may be at risk of damage during arterial switch operation (ASO). We sought to investigate left ventricular function in patients with TGA/IVS by echocardiography. Methods: From March 2011 to December 2012, totally 20 infants (12 males and 8 females) with TGA/IVS were evaluated via 2 dimensional speckle-tracking echocardiography (2D STE) more than 6 months after they underwent ASO. A control group of age-matched infants and children was also studied. Left ventricular longitudinal strain (S), strain rate (SR), time to peak systolic longitudinal strain (TPS), and time to peak systolic longitudinal strain rate (TPSR) were measured and compared between the 2 groups. Results: Mean +/- SD of age at the time of study in the patients with TGA/IVS was 15 +/- 5 months, and also age at the time of ASO was 12 +/- 3 days. Weight was 3.13 +/- 0.07 kg at birth and 8.83 +/- 1.57 kg at the time of ASO. Global strain (S), Time to peak strain rate (TPSR), and Time to peak strain (TPS) were not significantly different between the 2 groups, whereas global strain rate (SR) was significantly different (p value < 0.001). In the 3-chamber view, the values of S in the lateral, septal, inferior, and anteroseptal walls were significantly different between the 2 groups (p value < 0.001), and SR in the posterior wall was significantly different between the 2 groups (p value < 0.001). There were no positive correlations between S and SR in terms of the variables of heart rate, total cardiopulmonary bypass time, and aortic cross-clamp time. There were no statistically significant differences between the 2 groups regarding S, SR, TPS, and TPSR in the anteroseptal and posterior walls in the 3-chamber view and in the lateral and septal walls in the 4-chamber view. Conclusion: We showed that between 6 and 18 months after a successful ASO, the parameters of S, SR, and global TPS were normal in our patients with TGA/IVS. However, LV myocardial TPSR did not normalize in this time period. PMID- 27956910 TI - Mutation Analysis of Three Exons of Myosin-Binding Protein C3 in Patients with Hypertrophic Cardiomyopathy. AB - Background: Hypertrophic cardiomyopathy is a genetic disorder with a prevalence rate of 0.2% in the general population. It comes from mutations in sarcomeric proteins. Cardiac myosin-binding protein C3 is one of the critical genes in hypertrophic cardiomyopathy (HCM) and sudden cardiac death, accounting for about 20% of HCM-causing mutations. Genetic testing is recommended in patients with HCM. The aim of the current study was to find possible disease-causing mutations in 3 exons of the gene myosin-binding protein C (MYBPC3) in patients with HCM. Methods: Fifty subjects with documented known HCM were enrolled in the study. The patients were referred to the hospitals affiliated to Tehran University of Medical Sciences between 2008 and 2011. Peripheral blood samples were collected, as well as clinical and demographic data. The nucleotide sequences of the exons number 7, 16, and 18 of MYBPC3, whose relevance to the disease was previously reported, were amplified by polymerase chain reaction. Direct DNA sequencing was applied, and the Chromas software was used to analyze the sequences to find possible disease-causing mutations. Results: The study population comprised 73% male and 27% female patients. The mean age of the patients was 33.9 +/- 20.08 years. Family history of sudden cardiac death was reported in 48.2% of the patients. About 79% of the studied subjects had a history of at least 1 other affected relative in their families. Laboratory findings did not show mutations or any nucleotide changes in the sequences of the 3 target exons in the genomic DNA of the studied patients with HCM. Conclusion: The nucleotide sequences of the exons number 7, 16, and 18 of MYBPC3 were not mutated in the 50 studied subjects with HCM. PMID- 27956907 TI - Lymphocyte Kv1.3-channels in the pathogenesis of chronic obstructive pulmonary disease: novel therapeutic implications of targeting the channels by commonly used drugs. AB - In patients with chronic obstructive pulmonary disease (COPD), over-activated T lymphocytes produce pro-inflammatory cytokines and proliferate in situ in the lower airways and pulmonary parenchyma, contributing substantially to the pathogenesis of the disease. Despite our understanding of the molecular mechanisms by which lymphocytes are activated, we know little about the physiological mechanisms. T-lymphocytes predominantly express delayed rectifier K+-channels (Kv1.3) in their plasma membranes and these channels play crucial roles in inducing the lymphocyte activation and proliferation. In the pathogenesis of chronic inflammatory diseases, such as chronic kidney disease (CKD) or inflammatory bowel disease (IBD), these channels, which are overexpressed in proliferating lymphocytes within the inflamed organs, are responsible for the progression of the diseases. Since the over-activation of cellular immunity is also mainly involved in the pathogenesis of COPD, this disease could share similar pathophysiological features as those of CKD or IBD. From a literature review including ours, it is highly likely that the Kv1.3 channels are overexpressed or over-activated in T-lymphocytes isolated from patients with COPD, and that the overexpression of the channels would contribute to the development or progression of COPD. The involvement of the channels leads to novel therapeutic implications of potentially useful Kv1.3-channel inhibitors, such as calcium channel blockers, macrolide antibiotics, HMG-CoA reductase inhibitors and nonsteroidal anti-inflammatory drugs, in the treatment of COPD. PMID- 27956911 TI - Association between Latest Activated Sites in the Left Ventricle and Akinetic Segments in Patients with Ischemic Cardiomyopathy. AB - Background: It is not clear whether the latest activation sites in the left ventricle (LV) are matched with infracted regions in patients with ischemic cardiomyopathy (ICM). We aimed to investigate whether the latest activation sites in the LV are in agreement with the region of akinesia in patients with ICM. Methods: Data were analyzed in 106 patients (age = 60.5 +/- 12.1 y, male = 88.7%) with ICM (ejection fraction <= 35%) who were refractory to pharmacological therapy and were referred to the echocardiography department for an evaluation of the feasibility of cardiac resynchronization therapy. Wall motion abnormalities, time to peak systolic myocardial velocity (Ts) of 6 basal and 6 mid-portion segments of the LV, and 4 frequently used dyssynchrony indices were measured using 2-dimensional echocardiography and tissue Doppler imaging (TDI). To evaluate the influence of the electrocardiographic pattern, we categorized the patients into 2 groups: patients with QRS <= 120 ms and those with QRS >120 ms. Results: A total of 1 272 segments were studied. The latest activation sites (with longest Ts) were most frequently located in the mid-anterior (n = 32, 30.2%) and basal-anterior segments (n = 29, 27.4%), while the most common sites of akinesia were the mid-anteroseptal (n = 65, 61.3%) and mid-septal (n = 51, 48.1%) segments. Generally, no significant concordance was found between the latest activated segments and akinesia either in all the patients or in the QRS groups. Detailed analysis within the segments indicated a good agreement between akinesia and delayed activation in the basal-lateral segment solely in the patients with QRS duration <= 120 ms (Phi = 0.707; p value <= 0.001). Conclusion: The akinetic segment on 2-dimensional echocardiogram was not matched with the latest activation sites in the LV determined by TDI in patients with ICM. PMID- 27956912 TI - Improvement of Heart Failure by Human Amniotic Mesenchymal Stromal Cell Transplantation in Rats. AB - Background: Recently, stem cells have been considered for the treatment of heart diseases, but no marked improvement has been recorded. This is the first study to examine the functional and histological effects of the transplantation of human amniotic mesenchymal stromal cells (hAMSCs) in rats with heart failure (HF). Methods: This study was conducted in the years 2014 and 2015. 35 male Wistar rats were randomly assigned into 5 equal experimental groups (7 rats each) as 1- Control 2- Heart Failure (HF) 3- Sham 4- Culture media 5- Stem Cell Transplantation (SCT). Heart failure was induced using 170 mg/kg/d of isoproterenol subcutaneously injection in 4 consecutive days. The failure confirmed by the rat cardiac echocardiography on day 28. In SCT group, 3*106 cells in 150 ul of culture media were transplanted to the myocardium. At the end, echocardiographic and hemodynamic parameters together with histological evaluation were done. Results: Echocardiography results showed that cardiac ejection fraction in HF group increased from 58/73 +/- 9% to 81/25 +/- 6/05% in SCT group (p value < 0.001). Fraction shortening in HF group was increased from 27/53 +/- 8/58% into 45/55 +/- 6/91% in SCT group (p value < 0.001). Furthermore, hAMSCs therapy significantly improved mean diastolic blood pressure, mean arterial pressure, left ventricular systolic pressure, rate pressure product, and left ventricular end-diastolic pressure compared to those in the HF group, with the values reaching the normal levels in the control group. A marked reduction in fibrosis tissue was also found in the SCT group (p value < 0.001) compared with the animals in the HF group. Conclusion: The transplantation of hAMSCs in rats with heart failure not only decreased the level of fibrosis but also conferred significant improvement in heart performance in terms of echocardiographic and hemodynamic parameters. PMID- 27956913 TI - Myxoma Immediately above the Junction of the Inferior Vena Cava and the Right Atrium: A Rare Cause of Budd-Chiari Syndrome. AB - The Budd-Chiari syndrome (BCS) is a rare disorder caused by the obstruction of the hepatic veins or the inferior vena cava (IVC) at the suprahepatic level. This syndrome is developed by either hepatic vein thrombosis or mechanical venous obstruction and leads to centrilobular hepatic congestion with the subsequent development of fibrosis and cirrhosis. Intracardiac tumors have been rarely reported as a cause of the BCS. These tumors usually originate from the atrial septum. Very rarely, they arise either from the junction of the IVC and the right atrium or from the Eustachian valve. There are a few case reports in the literature where atrial tumors have caused the BCS. In these cases, the tumors were malignant, and the patients died shortly after being diagnosed. We describe a 71-year-old female patient who presented with a 3-month history of abdominal pain and protrusion. On physical examination, blood pressure and pulse rate were normal. Jugular venous pressure was about 10 cm. Cardiac examination revealed a systolic murmur, grade IV/VI, in the left sternal border without radiation. Echocardiography showed a large mass (about 6*4 cm) in the right atrium with close contact to the origin of the IVC, obstructing it. Cardiac magnetic resonance imaging, with and without gadolinium, also confirmed the diagnosis. The patient underwent surgery, and the myxoma was removed. The tumor was a large solid mass, 5*4 cm in size, which originated immediately above the entrance of the IVC. The patient is in good condition 1 year afterward. We emphasize that atrial myxomas should be considered in the differential diagnosis of tumors that cause chronic BCS. PMID- 27956914 TI - Successful Treatment of a Left Main Thrombus by Intracoronary Eptifibatide Infusion in a 36-Year-Old Patient. AB - The acute coronary syndrome due to the left main coronary artery (LMCA) thrombosis is a clinically rare and catastrophic event. We describe a young man (smoker, alcoholic, and drug abuser) with a history of recent surgery and typical chest pain who had non-occlusive LMCA thrombosis in coronary angiography. The thrombosis was successfully treated with two 180 u/kg intracoronary boluses of eptifibatide, which was continued through an intravenous infusion at 2 u/kg/min for 48 hours postprocedurally. Control angiography, performed 3 days later, revealed that the LMCA was free of thrombosis. The patient had no complaints, including chest pain, and remained completely asymptomatic during the next 30 days' follow-up. PMID- 27956915 TI - Anomalous Origin of the Right Coronary Artery from the Midportion of the Left Anterior Descending Artery: A Rare Coronary Anomaly. AB - The anomalous origin of the right coronary artery (RCA) as a branch from the left anterior descending artery (LAD) is a very rare variation of the single coronary artery anomaly. The anomalous vessel arises from the proximal or midportion of the LAD and courses anterior to the pulmonary artery trunk in most instances. In this case report, a 61-year-old woman is introduced who underwent coronary angiography following inferoposterior myocardial infarction, in which an anomalous RCA was seen originating from the midportion of the LAD. There was also a separate small artery originating from the right coronary sinus, which was most probably a right atrial branch. PMID- 27956917 TI - Multiple Biatrial Thromboses in a Patient with End-Stage Nonobstructive Hypertrophic Cardiomyopathy. PMID- 27956916 TI - H1N1 Influenza Patient Saved by Extracorporeal Membrane Oxygenation: First Report from Iran. AB - Respiratory failure is a serious complication of H1N1 influenza that, if not properly managed, can cause death. When mechanical ventilation is not effective, the only way to save the patient's life is extracorporeal membrane oxygenation (ECMO). A prolonged type of cardiopulmonary bypass, ECMO is a high-cost management modality compared to other conventional types and its maintenance requires skilled personnel. Such staff usually comprises the members of open heart surgical teams. Herein, we describe a patient with H1N1 influenza and severe respiratory failure not improved by mechanical ventilation who was admitted to Masih Daneshvari Medical Center in March 2015. She was placed on ECMO, from which she was successfully weaned 9 days later. The patient was discharged from the hospital after 52 days. Follow-up till 11 months after discharge revealed completely active life with no problem. There should be a close collaboration among infectious disease specialists, cardiac anesthetists, cardiac surgeons, and intensivists for the correct timing of ECMO placement, subsequent weaning, and care of the patient. This team work was the key to our success story. This is the first patient to survive H1N1 with the use of ECMO in Iran. PMID- 27956918 TI - The Applications and Features of Liquid Chromatography-Mass Spectrometry in the Analysis of Traditional Chinese Medicine. AB - With increasingly improved separation of complex samples and detection of unknown material capabilities, liquid chromatography coupled with mass spectrometry (LC MS) has been widely used in traditional Chinese medicine (TCM) research. This article describes the principles of liquid chromatography (LC) and mass spectrometry (MS) and their advantages and disadvantages in qualitative and quantitative analysis of TCM. We retrieved research literatures about the application of LC-MS in TCM published during the past five years at home and abroad. To better guide the analysis of TCM, this review mainly focuses on the applications category of LC-MS, how often different kinds of LC-MS are used, and the qualitative and quantitative ability of various LC-MS in the study of TCM. PMID- 27956919 TI - Cardiovascular Effects of the Essential Oil of Croton argyrophylloides in Normotensive Rats: Role of the Autonomic Nervous System. AB - Cardiovascular effects of the essential oil of Croton argyrophylloides Muell. Arg. (EOCA) were investigated in normotensive rats. In saline-pretreated anesthetized or conscious rats, intravenous (i.v.) injection of the EOCA induced dose-dependent hypotension. Dose-dependent tachycardia was observed only in conscious rats. In anesthetized rats, cervical bivagotomy failed to enhance EOCA induced hypotension but unmasked significant bradycardia. In conscious rats, i.v. pretreatment with methylatropine, but not with atenolol or L-NAME, reduced both hypotensive and tachycardiac responses to EOCA. However, hexamethonium pretreatment reverted the EOCA-induced tachycardia into significant bradycardia without affecting the hypotension. In aortic ring preparations precontracted with phenylephrine, EOCA induced a concentration-dependent relaxation that was significantly reduced by vascular endothelium removal and pretreatment with atropine, indomethacin, or glibenclamide but remained unaffected by pretreatment with L-NAME or TEA. It is concluded that i.v. treatment with EOAC decreased blood pressure probably through an active vascular relaxation rather than withdrawal of sympathetic tone. Muscarinic receptor stimulation, liberation of the endothelium derived prostacyclin, and opening KATP channels are partially involved in the aortic relaxation induced by EOCA and in turn in the mediation of EOCA-induced hypotension. EOCA-induced tachycardia in conscious rats appears to be mediated reflexly through inhibition of vagal drive to the heart. PMID- 27956920 TI - Simplified Tai Chi Program Training versus Traditional Tai Chi on the Functional Movement Screening in Older Adults. AB - Background. The present study aimed to evaluate and compare the effect of two different types of Tai Chi programs on the Functional Movement Screening (FMS) in older adults. Methods. Ninety older adults (65.5 +/- 4.6 years old) who met the eligibility criteria were randomized into three different groups based on a ratio of 1 : 1 : 1: a traditional Tai Chi exercise (TTC), a simplified Tai Chi exercise (TCRT), or a control group (routine activity). The FMS consisted of the deep squat, hurdle step, in-line lunge, shoulder mobility, active straight leg rise, trunk stability push-up, and rotatory stability, which was used to measure physical function before the present study and after six months of Tai Chi interventions. Results. Seventy-nine participants completed the present study (control = 27, TTC = 23, and TCRT = 29). Significant improvement on the FMS tests between the baseline and after the six-month intervention was observed in both Tai Chi programs, whereas no significant improvement was observed in the control group. In addition, participants in the TCRT group demonstrated greater improvement than those in the TTC group. Conclusions. The TCRT is more effective in improving the physical function in older adults when compared to the traditional Tai Chi modality, particularly for improving balance. PMID- 27956921 TI - Factors Affecting Recruitment and Attrition in Randomised Controlled Trials of Complementary and Alternative Medicine for Pregnancy-Related Issues. AB - Background. Randomised controlled trials (RCTs) investigating Complementary and Alternative Medicine (CAM) for pregnancy-related issues have encountered issues with recruitment and attrition. Little is known about the cause of these issues. Methods. Data was gathered from an antenatal CAM randomised controlled trial. During foetal anomaly appointments, women meeting inclusion criteria were invited to participate in the trial. Numbers of women invited and eligible were recorded. Reasons for noninterest were noted and analysed. Focus groups exploring trial experience of participants were also conducted. Findings. Of the 428 women invited to participate, 376 were eligible and just under a quarter participated. Reasons for nonparticipation included concerns about CAM and lack of interest in participation in research. Other factors negatively affecting recruitment included recruitment timing, competition for participants, limited support from staff, and inadequate trial promotion. Factors encouraging recruitment included being interested in research and seeking pain relief. Reasons for dropping out were time constraints, travel issues, work commitments, and pregnancy issues. Several women in the sham and usual care group dropped out due to dissatisfaction with treatment allocation. Conclusion. CAM researchers must explore problems encountered with recruitment and attrition so that evidence-based implementation strategies to address the issues can be developed. PMID- 27956923 TI - Balneotherapy Together with a Psychoeducation Program for Benzodiazepine Withdrawal: A Feasibility Study. AB - Benzodiazepines should be prescribed on a short-term basis, but a significant proportion of patients (%) use them for more than 6 months, constituting a serious public health issue. Indeed, few strategies are effective in helping patients to discontinue long-term benzodiazepine treatments. The aim of this study was to assess the feasibility and the impact of a program including cognitive behavioural therapy, psychoeducation, and balneotherapy in a spa resort to facilitate long-term discontinuation of benzodiazepines. We conducted a prospective multicentre cohort study. Patients with long-term benzodiazepine use were recruited with the aim of anxiolytic withdrawal by means of a psychoeducational program and daily balneotherapy during 3 weeks. The primary efficacy outcome measure was benzodiazepine use 6 months after the program, compared to use at baseline. A total of 70 subjects were enrolled. At 6 months, overall benzodiazepine intake had decreased by 75.3%, with 41.4% of patients completely stopping benzodiazepine use. The results also suggest a significantly greater improvement in anxiety and depression symptoms among patients who discontinued benzodiazepines compared to patients who only reduced their use. Our findings suggest that balneotherapy in association with a psychoeducative program is efficient in subjects with benzodiazepine addiction. PMID- 27956924 TI - Evidence for Non-Opponent Coding of Colour Information in Human Visual Cortex: Selective Loss of "Green" Sensitivity in a Subject with Damaged Ventral Occipito Temporal Cortex. AB - Damage to ventral occipito-temporal extrastriate visual cortex leads to the syndrome of prosopagnosia often with coexisting cerebral achromatopsia. A patient with this syndrome resulting in a left upper homonymous quadrantanopia, prosopagnosia, and incomplete achromatopsia is described. Chromatic sensitivity was assessed at a number of locations in the intact visual field using a dynamic luminance contrast masking technique that isolates the use of colour signals. In normal subjects chromatic detection thresholds form an elliptical contour when plotted in the Commission Internationale d'Eclairage, (x-y), chromaticity diagram. Because the extraction of colour signals in early visual processing involves opponent mechanisms, subjects with Daltonism (congenital red/green loss of sensitivity) show symmetric increase in thresholds towards the long wavelength ("red") and middle wavelength ("green") regions of the spectrum locus. This is also the case with acquired loss of chromatic sensitivity as a result of retinal or optic nerve disease. Our patient's results were an exception to this rule. Whilst his chromatic sensitivity in the central region of the visual field was reduced symmetrically for both "red/green" and "yellow/blue" directions in colour space, the subject's lower left quadrant showed a marked asymmetry in "red/green" thresholds with the greatest loss of sensitivity towards the "green" region of the spectrum locus. This spatially localized asymmetric loss of "green" but not "red" sensitivity has not been reported previously in human vision. Such loss is consistent with selective damage of neural substrates in the visual cortex that process colour information, but are spectrally non-opponent. PMID- 27956922 TI - Phytochemical and Pharmacological Studies on the Genus Psoralea: A Mini Review. AB - The genus Psoralea, which belongs to the family Fabaceae, comprises ca. 130 species distributed all over the world, and some of the plants are used as folk medicine to treat various diseases. Psoralea corylifolia is a typical example, whose seeds have been widely used in many traditional Chinese medicine formulas for the treatment of various diseases such as leucoderma and other skin diseases, cardiovascular diseases, nephritis, osteoporosis, and cancer. So, the chemical and pharmacological studies on this genus were performed in the past decades. Here, we give a mini review on this genus about its phytochemical and pharmacological studies from 1910 to 2015. PMID- 27956926 TI - Bilateral Tonic Pupils in the Absence of Pupillary Cholinergic Supersensitivity. AB - We report a 24-year-old woman with a presenting complaint of bilateral dilated pupils. The pupils were found to be dilated in bright and dim room lighting with minimal light reaction, showed an accommodation response, but did not demonstrate cholinergic supersensitivity. Neurological examination and neuro-imaging of the patient were normal. Syphilis serology was negative. This case emphasises that tonic pupil may be found in the absence of pupillary cholinergic supersensitivity. PMID- 27956925 TI - Bilateral Homonymous Hemianopia with Sparing of the Vertical Meridian. AB - A 19-year-old woman, who was 16 weeks post partum, collapsed with loss of consciousness. Following awakening she suffered abrupt loss of vision. Partial recovery occurred, although she has been left with bilateral homonymous hemianopia with sparing of vision just to the left of the vertical meridian. Magnetic resonance imaging demonstrated bilateral occipital infarcts, sparing the lips of the calcarine sulcus on the right. This is compatible with our expectation that the vertical meridian of the retinotopic map is represented at the superior and inferior lips of the calcarine sulcus. PMID- 27956927 TI - Germinoma of the Corpus Callosum. AB - A case is described of a young man presenting with diabetes insipidus and a junctional scotoma. A diffuse infiltrating mass centred in the corpus callosum and suprasellar area is found, which on pathological examination proved to be a primary intracranial germinoma. The case illustrates that rarely the corpus callosum can be involved by this tumour and that diagnosis may be delayed in atypical presentations. PMID- 27956928 TI - Ocular Flutter Following Adenoviral Conjunctivitis in an Adult. AB - A 37-year-old female presented with ocular flutter and a transient rhombo encephalitis following acute adenoviral kerato-conjunctivitis. Clinicians are made aware of the possibility of a transient encephalitic illness following adenoviral conjunctivitis. PMID- 27956929 TI - Optic Neuropathy from Cobalt Toxicity in a Patient who Ingested Cattle Magnets. AB - Cobalt is a widely used in the industrial production of hard metals. Cobalt ingestion has been reported to cause widespread systemic toxicity, but its effects on vision have been sparsely reported. The authors report the case of a patient who ingested cattle magnets, which remained in his stomach for an unknown duration of time. These magnets largely consist of cobalt that gradually leached into his blood stream, resulting in protean systemic manifestations, which included optic atrophy. PMID- 27956930 TI - Orbital and Cavernous Sinus Lymphoma Masquerading as Post-Herpetic Neuralgia. AB - We report an unusual case of adult-onset B-cell lymphoma in the cavernous sinus presenting as post-herpetic neuralgia; additionally, we review the literature regarding primary B-cell lymphomas of the cavernous sinus. This case demonstrates the importance of maintaining a suspicion for malignancy when an atypical clinical course is seen, even when presented with seemingly common or innocuous disease. PMID- 27956932 TI - A Supranuclear Disorder of Ocular Motility as a Rare Initial Presentation of Motor Neurone Disease. AB - A case is described of motor neurone disease presenting with an ocular motor disorder characterised by saccadic intrusions, impaired horizontal and vertical saccades, and apraxia of eyelid opening. The occurrence of eye movement abnormalities in motor neurone disease is discussed. PMID- 27956931 TI - Posterior Reversible Encephalopathy Syndrome and Anti-Angiogenic Agents: A Case Report. AB - Posterior reversible encephalopathy syndrome is an increasingly recognised clinico-radiological entity, associated with several medical conditions (such as systemic arterial hypertension) and characterised by seizures, altered mental status, headaches, and visual symptoms. Magnetic resonance imaging is a key component in this diagnosis, with hyperintense foci in T2-weighted images, corresponding to vasogenic oedema. The pathophysiology is not fully understood but probably involves loss of auto-regulation of cerebral vasculature or endothelial dysfunction or both. A 56-year-old male, suffering from a gastro intestinal stromal tumour with hepatic metastasis resistant to imatinib, on therapy with sunitinib, came to the Emergency Department because of headaches, hallucinations, and loss of vision. There was no previous history of high blood pressure. A hypertensive crisis was diagnosed; ophthalmological examination on admission showed no light perception bilaterally. Brain imaging displayed bilateral parieto-occipital and frontal vasogenic oedema, consistent with the clinical diagnosis of posterior reversible encephalopathy syndrome. After treatment of hypertension and suspension of sunitinib, the patient recovered from his symptoms. Control imaging showed no oedema. Angiogenesis inhibitors, such as sunitinib and bevacizumab, can cause hypertension, one of the many medical conditions associated with the posterior reversible encephalopathy syndrome. This syndrome should be considered in cases of acute visual loss, particularly in view of its reversible nature when diagnosed and treated promptly. PMID- 27956933 TI - Anti-GQ1b-Negative Miller Fisher Syndrome with Acute Areflexic Mydriasis and Cholinergic Supersensitivity. AB - Miller Fisher syndrome is a rare variant of Guillain-Barre syndrome and it is characterised by ophthalmoplegia, ataxia, and areflexia. Pupillomotor involvement occurs in approximately half of the patients with the disorder. The authors report a patient with acute areflexic mydriasis, external ophthalmoplegia, areflexia, and ataxia. Although the pupils were unreactive to light and near stimuli, administration of 0.1% pilocarpine resulted in marked miosis, suggesting cholinergic supersensitivity. Antibodies against GM1, GD1b, and GQ1b were negative. This is the first report of acute areflexic mydriasis with cholinergic supersensitivity in anti-GQ1b-negative Miller Fisher syndrome. PMID- 27956934 TI - Suicidal ideation and suicide attempts among asthma. AB - BACKGROUND: The present study aimed to investigate the mental health status in patients with asthma and assess the effects of asthma on suicidal ideation and attempts using a representative sample from Korea. METHODS: Individual-level data were obtained from 228,744 participants (6372 with asthma and 222,372 without asthma) of the 2013 Korean Community Health Survey. Demographic characteristics, socioeconomic status, physical health status, and mental health status were compared between patients with asthma and population without asthma. Multivariable logistic regression was performed to investigate the independent effects of the asthma on suicidal ideation and attempts. RESULTS: A depressed mood for 2 or more continuous weeks was reported by 12.0% of subjects with asthma and 5.7% of controls (p < 0.001). Suicidal thoughts were reported by 21.4% of patients with asthma and 9.8% of controls (p < 0.001). Suicidal attempts were reported by 1.0% of the patients with asthma and 0.4% of controls (p < 0.001). Following adjustment for age, sex, income, education, job, marital status, smoking, alcohol, exercise, and presence of diabetes mellitus, hypertension, stroke, arthritis, and depression, the ORs for suicidal ideation with asthma were 1.53 (95% CI 1.42-1.65) and that for suicidal attempts was 1.32 (95% CI 1.01 1.73). CONCLUSIONS: We found that asthma increased the risk for suicidal ideation and attempts, even controlling for the effects of socioeconomic status, physical health status, comorbid chronic medical diseases, and depressive mood. Our finding suggests that asthma per se may be an independent risk factor for suicidality. PMID- 27956935 TI - An Analytical Study of Prostate-Specific Antigen Dynamics. AB - The purpose of this research is to carry out a quantitative study of prostate specific antigen dynamics for patients with prostatic diseases, such as benign prostatic hyperplasia (BPH) and localized prostate cancer (LPC). The proposed PSA mathematical model was implemented using clinical data of 218 Japanese patients with histological proven BPH and 147 Japanese patients with LPC (stages T2a and T2b). For prostatic diseases (BPH and LPC) a nonlinear equation was obtained and solved in a close form to predict PSA progression with patients' age. The general solution describes PSA dynamics for patients with both diseases LPC and BPH. Particular solutions allow studying PSA dynamics for patients with BPH or LPC. Analytical solutions have been obtained and solved in a close form to develop nomograms for a better understanding of PSA dynamics in patients with BPH and LPC. This study may be useful to improve the diagnostic and prognosis of prostatic diseases. PMID- 27956936 TI - A Computational Model for Investigating Tumor Apoptosis Induced by Mesenchymal Stem Cell-Derived Secretome. AB - Apoptosis is a programmed cell death that occurs naturally in physiological and pathological conditions. Defective apoptosis can trigger the development and progression of cancer. Experiments suggest the ability of secretome derived from mesenchymal stem cells (MSC) to induce apoptosis in cancer cells. We develop a hybrid discrete-continuous multiscale model to further investigate the effect of MSC-derived secretome in tumor growth. The model encompasses three biological scales. At the molecular scale, a system of ordinary differential equations regulate the expression of proteins involved in apoptosis signaling pathways. At the cellular scale, discrete equations control cellular migration, phenotypic switching, and proliferation. At the extracellular scale, a system of partial differential equations are employed to describe the dynamics of microenvironmental chemicals concentrations. The simulation is able to produce both avascular tumor growth rate and phenotypic patterns as observed in the experiments. In addition, we obtain good quantitative agreements with the experimental data on the apoptosis of HeLa cancer cells treated with MSC-derived secretome. We use this model to predict the growth of avascular tumor under various secretome concentrations over time. PMID- 27956937 TI - Erratum to: Molecular Detection of Epstein - Barr virus in Nasopharyngeal Carcinoma among Sudanese population. AB - [This corrects the article DOI: 10.1186/s13027-016-0104-7.]. PMID- 27956938 TI - Displaced populations due to humanitarian emergencies and its impact on global eradication and elimination of vaccine-preventable diseases. AB - Populations affected by humanitarian emergencies may require unique strategies to ensure access to life-saving vaccines and attain sufficiently high population immunity to interrupt virus circulation. Vaccination strategies among displaced populations should not be an afterthought and must be part of the vaccine preventable disease eradication and elimination initiatives from the start. PMID- 27956939 TI - A review of mental health recovery programs in selected industrialized countries. AB - The concept of recovery has gained increasing attention and many mental health systems have taken steps to move towards more recovery oriented practice and service structures. This article represents a description of current recovery oriented programs in participating countries including recovery measurement tools. Although there is growing acceptance that recovery needs to be one of the key domains of quality in mental health care, the implementation and delivery of recovery oriented services and corresponding evaluation strategies as an integral part of mental health care have been lacking. PMID- 27956940 TI - Facilitating the interpretation of pedobarography: the relative midfoot index as marker for pathologic gait in ankle osteoarthritic and contralateral feet. AB - BACKGROUND: Pedobarography offers dynamic information about the foot, but the interpretation of its large data is challenging. In a prior study it was shown that attention can be restricted to pedobarographic midfoot load data. We aim to verify this observation in ankle osteoarthritic and contralateral feet. METHODS: We assessed both feet of 120 patients with end-stage ankle osteoarthritis (OA) and 35 healthy volunteers with AOFAS-score and dynamic pedobarography in barefoot condition. We introduce a new parameter, the Relative Midfoot Index (RMI), representing the depth of the midfoot weighted by the maximal force (MF) in the hindfoot and forefoot. Main outcome measures were the RMI, MF and contact times in the hindfoot, midfoot and forefoot. Ankle OA, contralateral and healthy feet were compared with ANOVA. RESULTS: The RMI was significantly smaller in OA feet (0.65 +/- 0.19) and contralateral feet (0.69 +/- 0.15) than in healthy feet (0.84 +/- 0.08, p < 0.0001). There was no significant difference between OA and contralateral feet. The RMI showed a correlation of 0.48 with the AOFAS score. Contralateral and OA feet were significantly different from healthy feet (p < 0.001) in all parameters except the hindfoot MF. An RMI <0.8 showed a positive predictive value of 80% and sensitivity of 78% for being unhealthy. CONCLUSION: The RMI assists the interpretation of pedobarographic parameters and provides a user-friendly indicator for unhealthy foot conditions with a cut-off value of 0.8. The contralateral feet of ankle OA patients differed significantly from healthy feet and are therefore not suitable as control group. Level of Evidence: 3 case control study. PMID- 27956941 TI - Accumulation of intestinal tissue 3-deoxyglucosone attenuated GLP-1 secretion and its insulinotropic effect in rats. AB - BACKGROUND: Our recent findings support the idea that 3-deoxyglucosone (3DG), a dietary composition, has been suggested as an independent factor for the development of prediabetes. Secretion of glucagon-like peptide-1 (GLP-1) has been suggested to be impaired in T2DM and in conditions associated with hyperglycemia. Since low oral bioavailability of 3DG has been indicated in a single administration study, in the present study we examined if 3DG is capable of accumulating in intestinal tissue of rats after 2-week administration of 3DG, and the 3DG treatment affects GLP-1 secretion and glucose tolerance. METHODS: Rats were administered by gastric gavage for 2 weeks. We measured 3DG contents of intestinal tissues (by HPLC), plasma levels of total GLP-1 (by ELISA), insulin and glucagon (both by radioimmunoassay) and blood glucose concentrations. The expressions of the sweet receptor subunits (TAS1R2, TAS1R3) and its downstream molecule TRPM5 in duodenum and colon tissues of rats were quantified by WB. We examined GLP-1 secretion in enteroendocrine STC-1 cells exposured to 3DG. RESULTS: 3DG treatment for 2 weeks increased 3DG content of intestinal tissues, fasting blood glucose concentration, and reduced plasma concentrations of GLP-1 and insulin at fasting and 15 and 180 min after the glucose load and oral glucose tolerance in conjunction with increased plasma glucagon concentrations. The expressions of TAS1R2, TAS1R3 and TRPM5 were shown to be reduced whereas 3DG treatment did not affect plasma dipeptidyl peptidase-4 activity, indicating an impaired GLP-1 secretion in 3DG-treated rats. This idea was further supported by the fact that exposure to 3DG directly decrease GLP-1 secretion in STC-1. CONCLUSION: It is the first demonstration that 3DG was capable of accumulating in intestinal tissue and thereby decreased secretion of GLP-1 and insulin in a similar manner. 3DG-treated rats developed impaired glucose regulation (IGR) with obviously pancreatic islet cell dysfunction. It is further concluded that a decrease in the biological function of GLP-1 resulting from the decreased GLP-1 secretion is the most likely mechanism for the impaired insulin secretion, which ultimately promoted the development of IGR. These results will also contribute to a better understanding of the significance for restoring physiological GLP-1 secretion. PMID- 27956943 TI - Organ Atrophy Induced by Sorafenib and Sunitinib - Quantitative Computed Tomography (CT) Evaluation of the Pancreas, Thyroid Gland and Spleen. AB - BACKGROUND: To evaluate organ atrophy induced by sorafenib and sunitinib, we retrospectively reviewed the CT scans of renal cell carcinoma (RCC) patients receiving molecular targeted therapy (MTT) using sorafenib or sunitinib, and performed volumetric analysis of the pancreas, thyroid gland, and spleen. MATERIAL/METHODS: Thirteen RCC patients receiving MTT were assigned as the evaluation cases (MTT group), while thirteen additional RCC patients not receiving MTT were retrieved as the Control group. We evaluated the baseline and follow-up CT studies. The volume of the three organs estimated by CT volumetry was compared between the baseline and follow-up CTs. The atrophic ratio of the organ volume in the follow-up CT to that in the baseline CT was calculated, and compared between the MTT and Control groups. RESULTS: All measured organs in the MTT group showed statistically significant volume loss, while no significant change was observed in the Control group. Mean atrophic ratio in the MTT group was 0.74, 0.58, and 0.82 for the pancreas, thyroid and spleen, respectively. The differences in atrophic ratios between both groups were all statistically significant (P<0.05). CONCLUSIONS: Single-agent sorafenib or sunitinib therapy induced statistically significant atrophy in the pancreas, thyroid, and spleen. PMID- 27956944 TI - Management of Alphacute Non-Variceal Upper Gastrointestinal Bleeding: Drugs, Endoscopic Hemostasis, or Both? AB - Acute upper gastrointestinal bleeding remains one of the most frequent and emergent conditions in everyday clinical practice and a challenge for doctors. Peptic ulcer is responsible for more than half of acute upper gastrointestinal bleeding and is the most frequent cause of serious non-variceal bleeding. Despite progress in diagnosis and management in these patients, the recurrence of bleeding remains an important problem. Several drugs and endoscopic techniques, alone or in combination, have been evaluated in many studies and there is presently enough experience in terms of their efficacy. Endoscopic hemostasis is more effective than any other therapeutic intervention in the treatment of patients with non-variceal upper gastrointestinal bleeding. In patients with high risk of rebleeding spots, the combination of endoscopic hemostasis with high dose proton pump inhibitors is the most effective strategy to reduce bleeding recurrences and the need for surgery. PMID- 27956942 TI - Obesity and hypertensive heart disease: focus on body composition and sex differences. AB - There is evidence that hypertension is frequently associated with overweight/obesity even in kids and adolescents. Either conditions influence development of left ventricular (LV) hypertrophy (LVH), through different biological and hemodynamic mechanisms: obesity is conventionally thought to elicit a coherent growth of LV chamber dimensions and myocardial wall thickness (eccentric LV geometry), whereas a more accentuated increase in wall-thickness (concentric LV geometry) is attributed to hypertension. While during youth these differences are visible, proportion of LV concentric geometry, the most harmful LV geometric pattern, sharply raises in obese individuals during middle age, and becomes the most frequent geometric patterns among obese-hypertensive individuals. Two conditions with elevated hemodynamic impact, severe obstructive sleep apnea and masked hypertension contribute to the development of such a geometric pattern, but non-hemodynamic factors, and specifically body composition, also influence prevalence of concentric LV geometry. Contrasting a general belief, it has been observed that adipose mass strongly influences LV mass, particularly in women, especially when fat-free mass is relatively deficient. Thus, though blood pressure control is mandatory for prevention and reduction of LVH in obese hypertensive patients, without reduction of visceral adiposity regression of LVH is difficult. Future researches should be addressed on (1) assessing whether LVH resulting from alteration of body composition carries the same prognosis as pressure overload LVH; (2) defining tissue characterization of the hypertrophic heart in obese-hypertensive patients; (3) evaluating whether assessment of hemodynamic loading conditions and biological markers can help defining management of the association of obesity with hypertension. PMID- 27956945 TI - Management of Variceal Hemorrhage. AB - Variceal hemorrhage is a frequent and lethal complication of portal hypertension. Bleeding occurs in 30%-40% of patients with cirrhosis and varices. The first episode of variceal bleeding is associated with a high mortality as well as a high incidence of re-bleeding. Thus, management of variceal hemorrhage should be categorized into 3 phases: primary prophylaxis (prevention of the first episode of bleeding), emergency treatment (management of acute bleeding), and secondary prophylaxis (prevention of re-bleeding). Modalities involved include pharmacological, endoscopic, surgical, interventional radiological therapy and balloon tamponade. This review summarizes the current choices of management during each phase, and concentrates on the following questions, what can we do to prevent the formation and development of varices; how can we predicate the risk of bleeding; what should we do in case of bleeding; what is the first-line therapy; what should we do when current therapy fails; when should we give up and what is the optimal strategy for secondary prophylaxis. PMID- 27956947 TI - Combined Intestinal and Biliary Stenting in Gastric Outlet and Biliary Obstruction. AB - BACKGROUND: Combined intestinal and biliary stenting is one of the effective palliative methods for patients with malignant gastric outlet and biliary obstruction. This study was to evaluate the effect of combined intestinal and biliary stenting in the palliation of gastric outlet and biliary obstruction. METHODS: Thirty-two patients with malignant gastric outlet and biliary obstruction underwent combined intestinal and biliary stenting. Intestinal stents were implanted by means of endoscopy and X-ray guidance. The subsequent biliary stents were implanted by percutaneous transhepatic cholangial drainage. The biliary stent pass through the side hole of intestinal stent mesh and its distal segment was located in the lumen of intestinal stent. RESULTS: Thirty-four intestinal stents and 32 biliary stents for 32 patients were implanted successfully. No lethal complications occurred. The average survival was 164 days. CONCLUSIONS: The combined intestinal and biliary stenting is an effective and safe method for palliation of gastric outlet and biliary obstructions. The short-term results are satisfactory. PMID- 27956948 TI - Carcinoid Tumors of Digestive Organs: a Clinicopathologic Study of 13 Cases. AB - The author investigated clinicopathologic features of 13 cases of carcinoid tumor in the digestive organs. The 13 cases of carcinoid were identified from 18,267 pathological specimens of digestive organs in the last 10 years in our pathology laboratory. The tumor locations were rectum in 9 cases, duodenum in 2 cases, liver in 1 case, and stomach in 1 case. The age of the patients ranged from 52 to 82 years with a mean of 63 years. Male to female ratio was 7 : 6. The presenting symptoms were abnormal pain in 3 cases and asymptomatic in 10 cases. None of the cases showed carcinoid syndrome. The diameter ranged from 5 mm to 25 mm in gastrointestinal carcinoids, and 60 mm in the hepatic carcinoid. The treatment was endoscopic mucosal resection in 10 cases and surgical resection in 3 cases. The outcome is good except for hepatic atypical carcinoid which showed metastases and died of systemic metastasis. Histologically, 12 carcinoid tumors were typical carcinoids, and one (liver) was atypical carcinoid. Organoid pattern was present in 12 cases. Trabecular arrangement, ribbon arrangement, rosette formation, and pseudoglandular arrangement were recognized in 12 cases, in 8 cases, in 7 cases, and in 5 cases, respectively. Immunohistochemically, tumor cells were positive for at least one of pan-neuroendocrine markers including chromogranin, synaptophysin, neuron-specific enolase, CD56, and glucagon. Of these, synaptophysin was positive in 11/13 (85%), neuron-specific enolase 10/13 (80%), chromogranin 8/13 (62%), CD56 6/13 (46%), and glucagon 4/13 (31%). In summary, the author reported the incidence of digestive organ carcinoid tumors, and the clinicopathologic features of the 13 cases with carcinoid. PMID- 27956946 TI - Protective Effects of Proanthocyanidin on Cerulein-induced Acute Pancreatic Inflammation in Rats. AB - BACKGROUND: The aim of this study was to assess the possible protective effect of proanthocyanidin against cerulein-induced acute pancreatic inflammation (AP) and oxidative injury. METHODS: Sprague-Dawley rats were pretreated with proanthocyanidine (100 mg/kg, orally) or saline 15 min before cerulein was given by 20 ug/kg subcutaneously at 1-h intervals within 4 hours. Six hours after cerulein or saline injections, the animals were killed by decapitation. Blood samples were collected to analyze amylase, lipase, and proinflammatory cytokines (TNF-alpha and IL-1b). Pancreas tissues were taken for the determination of tissue glutathione (GSH) and malondialdehyde (MDA) levels, Na+, K+-ATPase and myeloperoxidase (MPO) activities. Formation of reactive oxygen species in pancreatic tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes, while the extent of tissue injury was analyzed microscopically. RESULTS: Acute pancreatitis caused a significant decrease in tissue GSH level and Na+, K+-ATPase activity, which was accompanied with significant increases in the pancreatic MDA, luminol and lucigenin chemiluminescences (CL) levels and MPO activity. Similarly TNF-alpha and IL-1beta levels were elevated in the pancreatic group as compared to control group. On the other hand, proanthocyanidin treatment reversed all these biochemical indices, as well as histopathological alterations that were induced by cerulein. CONCLUSIONS: Proanthocyanidine can ameliorate pancreatic injury induced by cerulein in rats, this result suggests that proanthocyanidin may have utility in treating acute pancreatititis. PMID- 27956949 TI - Colorectal Carcinoma Screening in Lagos, Nigeria, Are We Doing it Right? AB - BACKGROUND: Screening for colorectal cancer (CRC) has proven effective in reducing disease mortality and is also cost effective. Recent reports indicate that colorectal cancer is not uncommon and presents with advanced disease in Nigeria. Thus this study was aimed at reviewing the practice of CRC screening among medical practitioners in Nigeria. METHODS: A self-administered questionnaire was utilized to obtain data for this study, which was distributed to over 500 practising doctors in Lagos, Nigeria from September to November 2007. The data obtained from the questionnaire include basic demographics, type of practice, duration in years of medical practice described as short (<= 5 years), medium (5 to 10 years) or long (> 10 years), and knowledge regarding CRC, as well as CRC screening techniques and methodologies. RESULTS: There were 300 respondents with a mean age (SD) of 33 (7.8) years and an age range of 23 - 67 years. In terms of duration of medical practice, 190 (63%) were short, 43 (14%) medium and 67 (23%) long. Majority (65%) of the respondents were in teaching hospitals, 18.5% in private hospitals and 5.7% were in general (community) hospitals. The knowledge of the clinical features as well as the risk factors of CRC was fair in over 75% of the respondents. Most respondents, 265 (87.8%), agreed that CRC was worth screening for; 21 (5%) did not. In all, 246 (82%) gave reasons for their responses. However, just over half of the respondents employed one of the following: faecal occult blood test (FOBT), double contrast barium enema (DCBE), flexible sigmoidoscopy, colonoscopy, or a combination of any of the techniques for screening. Usage of CT colonography was low. Screening rates by respondents for other malignancies in this survey was higher than that of CRC (prostate 95%, breast 97%, cervix 99%), though the most commonly encountered malignancy was breast cancer. On the contrary, for surveillance purposes, barely half of the respondents used FOBT annually or colonoscopy every 10 years, while less than half employed DCBE, sigmoidoscopy and CT colonography. CONCLUSIONS: Although awareness of CRC screening in this study is high, its performance is very low and highly variable in form in our region. There is a need to improve the practice of CRC screening through sensitising of medical practitioners to the need for screening, increase knowledge with regard to the relative merits of available methodologies for screening/surveillance of CRC and provide all necessary diagnostic resources and possible formulation of effective local guidelines. PMID- 27956950 TI - Hindbrain Effects of L-Glutamate on Gastric Motility in Rats. AB - BACKGROUND: There are no unanimous standpoints about the dorsal motor nucleus of the vagus (DMV) and nucleus of solitary tract (NTS) involving in the regulation of gastric motility up to now. METHODS: In this study, we injected L-Glutamate (L Glu), an incitant neurotransmitter in the central neural system, into DMV and NTS to further investigate the effects of the two nuclei on gastric motility. A latex balloon connected with a pressure transducer was inserted into the pylorus through the fundus for continuous recording of the change of gastric smooth muscle contractile curves. RESULTS: L-Glu (10 nmol in 0.1 ul) microinjected into right DMV and NTS significantly inhibited gastric motility. We compared the effects of L-Glu (10 nmol) microinjected into the two nuclei, the L-Glu microinjected into right NTS had the greater inhibitory effect on gastric motility than microinjected into the right DMV. The physiological saline microinjection evoked no significant effect on gastric motility. CONCLUSIONS: L Glu microinjected into right DMV and NTS evoked significant inhibition on gastric motility in rats. At equal dose of L-Glu, NTS had the greater inhibitory effect than DMV. PMID- 27956951 TI - Acute Aflatoxicosis Resulting in Fulminant Hepatic Failure and Rhabdomyolysis. AB - BACKGROUND: Aflatoxins are known contaminants of foods. High dose exposure, particularly to Aflatoxin B1 (AFB1) may cause acute aflatoxicosis. Outbreaks have been reported in developing nations but are virtually un-documented in the developed world. CASE REPORT: A 28 year old, healthy male presented with nausea, vomiting and abdominal pain. The patient deteriorated rapidly to a state of agitation and shock. The clinical picture, encephalopathy and laboratory results indicated fulminant hepatic failure, rhabdomyolysis and multi-system organ failure. Canned food the patient consumed almost exclusively contained AFB1 at a level of 19.6 ppb. Alternate diagnoses were ruled out and a presumptive diagnosis of acute aflatoxicosis was made. After 45 days of intensive supportive therapy, the patient was discharged with no significant sequels. CONCLUSIONS: The diagnosis of aflatoxicosis was based on the clinical picture, the finding of high levels of AFB1 in foods the patient consumed, and after alternate diagnoses' were sufficiently excluded. We conclude that chronic exposure to moderately elevated levels of aflatoxin B1 may result in acute aflatoxicosis and fulminant hepatic failure. PMID- 27956952 TI - Hepatic Portal Venous Gas with Pneumatosis Intestinalis. AB - Hepatic portal venous gas with pneumatosis intestinalis are radiological clues of intestinal ischemia. Prompt evaluation and a high index of clinical suspicion for the diagnosis of acute mesenteric ischemia are necessary given the high mortality of this condition. We present a case of mesenteric ischemia, radiological clues to diagnosis, and associated mechanisms. PMID- 27956953 TI - Adenosquamous Carcinoma of the Stomach: Report of Two Cases. AB - The author reports two cases of adenosquamous carcinoma of stomach. The first case is an 87-year-old woman who was admitted to our hospital because of nausea and vomiting. Endoscopy revealed a large type 4 tumor in the stomach, and biopsy showed squamous cell carcinoma. Total gastrectomy, cholecystectomy, splenectomy and lymph node dissection were performed. Pathologically, the gastric tumor consisted of a mixture of adenocarcinoma (30% in area) and squamous cell carcinoma (70% in areas). The adenocarcinoma consisted of signet ring cell carcinoma, poorly differentiated carcinoma, and tubular adenocarcinoma. Carcinoma cells invaded into the serosa. The gall bladder, lymph nodes and peritoneum showed metastases of adenocarcinoma. The patient died of five months after operation. The second case is a granulocyte-colony stimulating factor producing carcinoma. A 77-year-old woman was admitted to our hospital because of epigastralgia. Marked leukocytosis was present without inflammation. Endoscopic examination revealed a large type 3 tumor, and biopsy showed squamous cell carcinoma. Gastrectomy and lymph node dissection was performed. Pathologically the gastric tumor was composed of a mixture of adenocarcinoma (10%) and squamous cell carcinoma (90%). The carcinoma invaded into subserosa. Lymphovascular permeation is present. The adenocarcinoma element consisted of signet ring cell carcinoma. Tumor cells were immunohistochemically positive for granulocyte-colony stimulating factor. The lymph nodes showed metastases of signet ring cell carcinoma. The patient showed systemic metastasis, and died eight months after the operation. PMID- 27956954 TI - Chronic Idiopathic Thrombocytopenia Purpura and Helicobacter pylori Eradication: A case study. AB - Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated thrombocytopenia. ITP is the result of accelerated platelet destruction by the reticuloendothelial system, primarily the spleen. The prevalence of Helicobacter pylori infection and the effect of its eradication were monitored in an ITP patient over a period of 12 months. Eradication of Helicobacter pylori led to the increased platelet count and provides a new insight for a non-immunosuppressive treatment in selective ITP patients. PMID- 27956955 TI - Molecular Mechanisms Associated with the Induction of Ubiquinone by Peroxisome Proliferators. PMID- 27956956 TI - Inactivation of Digestive Proteases by Deconjugated Bilirubin and the Physiological Significance of Fasting Hyperbilirubinemia. AB - It has been observed more than a century ago that in humans as well as in many animals, there was a significantly increase in blood bilirubin level during fasting. However, the physiological significance for this increase remains largely unknown. As it is found that digestive proteases are inactivated by free (or deconjugated) bilirubin, here I suggested that fasting hyperbilirubinemia would be a mechanism to save bilirubin during fasting to meet the anticipated increased needs to protect the gut against the damage by the increased luminal pancreatic proteases during and after feeding. PMID- 27956957 TI - Differences in Managing Anticoagulants and Antiplatelets for Gastrointestinal Endoscopy between East and West. AB - Decreasing the bleeding risk associated with gastrointestinal (GI) endoscopic procedures and minimizing the thromboembolic risk of withdrawing medications are very important for the patients taking anticoagulants and antiplatelets. Western guidelines on managing anticoagulation and antiplatelet medications in GI endoscopy suggest a polypectomy with aspirin medication or a biopsy with warfarin medication. However, Eastern endoscopists' adherence to Western guidelines may be responsible for Easteners experiencing massive bleedings. During the cessation of drugs, it should be emphasized that Asians may be predisposed to different forms of embolism more likely to be of the cerebrovascular system, whereas Westerners more likely to be of the cardiovascular variety. To better understand the differences between the East and West, differences in drug metabolism should be considered that results in greater body weight-normalized plasma unbound clearance of drug in Easterners. Taken as a whole, different managements are required for GI endoscopy in patients on anticoagulation and/or antiplatelet medications based on differences in metabolism of drugs, risk of hemorrhage, and forms of thromboembolism. PMID- 27956958 TI - Diagnostic Capability of Capsule Endoscopy in Small Bowel Diseases. AB - Capsule Endoscopy (CE) is a recently developed noninvasive technique for imaging of small bowel pathologies. It is a swallowable wireless mini-camera for getting images of the gastrointestinal (GI) mucosa. General indications of CE are obscure bleeding, iron deficiency anemia, Crohn disease, abdominal pain, polyposis coli, celiac disease and small bowel tumors. Obstruction must be excluded with small bowel radiography before using CE. Bowel preparation can be recommended for good visualization. The main indication is obscure GI bleeding. Even though useful for the other indications in selected cases, large polypoid lesions may be missed. Diagnostic capability of CE and double balloon enteroscopy (DBE) are similar and CE is a good complemantary method for DBE. PMID- 27956959 TI - Is There a Role for Sonde Enteroscopy in Patients with Obscure Gastrointestinal Bleeding? A Comparison with Capsule Endoscopy. AB - BACKGROUND: In the 1980's and 1990's combined Push and Sonde Enteroscopy was the primary endoscopic tool used to evaluate the small intestine in patients with obscure gastrointestinal bleeding (OGIB). It was available in only a few centers due to the technical difficulties associated with its use. The introduction of wireless capsule endoscopy in 2001 revolutionalized small bowel endoscopic imaging making Sonde enteroscopy a rarely used procedure despite the lack of studies comparing the efficacy of the two modalities. The aim of this study was to restrospectively compare the findings of Sonde enteroscopy with capsule endoscopy in patients with OGIB. METHODS: Design: One hundred patients who underwent Sonde enteroscopy and 101 patients who underwent capsule endoscopy were retrospectively studied. Setting: All patients had their procedures completed by physicians within the same gastroenterology practice. Patients: All patients who underwent either Sonde enteroscopy or capsule endoscopy were enrolled. Interventions: None. Main outcome measurements: Outcome was defined as the number of patients in which a distinct bleeding site could be identified. RESULTS: A total of 100 patients underwent Push and Sonde enteroscopy and a potential bleeding site was identified in 55 (55%) patients. A total of 101 patients underwent capsule endoscopy and a potential bleeding site was identified in 60 (59%) patients. A one-tailed P value showed no statistically significant difference in the diagnostic yield between the procedures. CONCLUSIONS: Capsule endoscopy is at least as efficacious as Push/Sonde enteroscopy in evaluating patients with OGIB. We can comfortably retire Sonde enteroscopy as a diagnostic tool. PMID- 27956961 TI - Benign Tumors of the Esophagus: A Histopathologic Study of 49 Cases among 931 Consecutive Esophageal Biopsies. AB - The author reviewed 931 consecutive esophageal biopsies in the last 15 year in out pathology laboratory of our hospital in search for benign esophageal tumors. As the results, 41 cases (4.4%) of squamous papilloma, 4 cases (0.4%) of granular cell tumor, 3 cases (0.3%) of leiomyoima, and 1 case (0.1%) tubular adenoma were identified. The 41 cases of squamous papillma were located in the cervical esophagus in 6 cases, in the proximal esophagus in 12 cases, in the middle esophagus in 11 cases, and in the distal esophagus in 12 cases. The squamous papilloma was immunohistochemically positive for various cytokeratins. It was endoscopically recognized as small polypoid tumor. The age ranged from 35 years to 81 years with a mean of 51 years. Male to female ratio was 25:16. The 4 cases of granular cell tumor were located in the proximal esophagus in 3 cases, and in the middle esophagus in 1 case. The granular cell tumor was immunohistochemically positive for vimentin, S100 protein, and neuron-specific enolase. It was endoscopically recognized by elevated small lesions. The ages of were 36, 45, 67 and 78 years, and male to female ratio was 1:3. The 1 case of tubular adenoma was located in the distal esophagus. Histologically, it was associated with heterotopic gastric mcusa, and immunohistochemically faintly positive for p53 protein and Ki-67 antigen. It was endoscopically a slightly elevated lesion. The patient was 46 year-old man. The 3 cases of leiomyoma were located in the cervical esophagus in 1 case and in the proximal esophagus in 2 cases. It was immunohistochemically positive for vimentin, alpha-smooth muscle actin, and desmin. It was endoscopically recognized as a submucosal tumor. The ages were 34, 45, and 85 years. Male to female ratio was 1:2. PMID- 27956960 TI - Dietary Fat Feeding Alters Lipid Peroxidation in Surfactant-like Particles Secreted by Rat Small Intestine. AB - BACKGROUND: Long-term feeding of fish oil (n-3) and corn oil (n-6) markedly enhances levels of lipid peroxidation within isolated rat enterocytes. The effect is 10-fold greater at the villus tip than in the crypt region, correlating with the distribution of deleterious oxidative systems (glutathione reductase) in the tip and beneficial systems (superoxide dismutase) at the base of the villus. Because of this vertical gradient of peroxidation, the process was thought to play a role in apoptosis of enterocytes at the villus tip. Surfactant-like particles (SLPs) are membranes secreted by the enterocyte and a component of these membranes is directed to the intestinal surface overlying villus tips. One suggested role for SLPs has been to protect the mucosal surface from the harsh luminal conditions that might enhance apoptotic loss of enterocytes. The hypothesis to be tested was whether SLP lipids, like those in enterocytes, were also peroxidized, although they were external to the cellular processes that seem to oxidize enterocyte lipids, or whether SLP were immune to these biological processes. Feeding with groundnut oil (n-9) was compared with fish oil (n-3) and corn oil (predominantly n-6) to determine whether oils with various lipid composition would affect peroxidation in both SLP and enterocytes. METHODS: After an overnight fast, Wistar rats were fed 2 mL of dietary oil by gavage. Five hours later SLPs and underlying microvillus membranes (MVM) were isolated and analyzed for generation of thiobarbituric acid reactive substances (TBARS) and for hydrolase activities, at baseline and after addition of an Fe+2/ascorbate system to induce peroxidation. RESULTS: In vitro lipid peroxidation using the Fe2+/ascorbate system produced greater peroxidation than in MVM. Intestinal alkaline phosphatase (IAP), sucrase and lactase activities were decreased in SLPs, but were unaltered in MVM except for IAP. The activities of maltase, trehalase, Leucine aminopeptidase and gamma-glutamyltranspeptidase, were unaffected both in SLPs and MVM under these conditions. CONCLUSIONS: SLPs are more susceptible to oxidative damage than are the underlying MVMs. This may reflect results of a hostile luminal environment. It is not clear whether SLPs are acting as a lipid 'sink' to protect the MVM from greater oxidation, or are providing an initial stimulus for apoptosis of villus tip enterocytes, or both. PMID- 27956962 TI - Expression of C-Reactive Protein in Rectal Cancer. AB - BACKGROUND: The possible involvement of inflammation on colorectal carcinogenesis has potential prognostic, preventive and therapeutic implications. We investigated immunohistochemically whether C-reactive protein is expressed in human primary rectal adenocarcinoma and assessed its relationship with clinicopathological findings. METHODS: Ninety-one rectal cancer samples and 22 normal control samples were immunohistochemically analysed. RESULTS: Cell accumulation of C-reactive protein was observed in 65 (71%) out of 91 patients with rectal adenocarcinoma and in all 22 control cases (p < 0.01). No significant difference was observed regarding to clinicopathological features or survival rates, but a linear correlation between the positivity proportion of C-reactive protein and Dukes-Turnbull stage (p = 0.005) was observed. CONCLUSIONS: These data suggest that C-reactive protein might play a role in rectal carcinogenesis, but seems not to affect prognosis. Additional studies are warranted in larger population samples. PMID- 27956963 TI - Bioinformatics Analysis and Validation of the Expressed Sequences Tag in Human Colorectal Adenocarcinoma. AB - BACKGROUND: This study was to investigate some new pathological genes in colorectal adenocarcinoma of human. METHODS: Human colorectal adenocarcinoma tissues and normal colorectal tissues were taken and suppression subtractive hybridization (SSH) and cDNA microarray techniques were employed. From differentially expressed 86 expressed sequence tags (EST), 10 EST of the SSH were selected as seed sequence for bioinformatics analyses, semi-quantitative RT-PCR and PCR-sequencing. Each lane of semi-quantitative RT-PCR was analyzed by Q1 software. RESULTS: Among these 10 EST, it has been found that ES274070, ES274071, ES274076 and ES274081 may play role in the onset of colorectal adenocarcinoma in human. CONCLUSIONS: The ES274070, ES274071, ES274076 and ES274081 are related to the onset of human colorectal adenocarcinoma. PMID- 27956965 TI - Esophageal Carcinoma with Triplicate Differentiation into Squamous Cell Carcinoma, Small Cell Carcinoma and Adenocarcinoma: a Case Report. AB - Esophageal carcinoma with multiple differentiation is very rare. The author herein reports a case of esophageal carcinoma with triplicate differentiation (squamous cell carcinoma, small cell carcinoma, and adenocarcinoma). A 78-year old man was admitted to our hospital because of dysphagia. An endoscopic examination revealed a polypoid tumor (3 x 4 x 3 cm) in the distal esophagus, and biopsy was obtained. The biopsy showed a tumor composed of moderately differentiated squamous cell carcinoma, small cell carcinoma, and adenocarcinoma. The proportions of them were 40% in squamous cell carcinoma component, 50% in small cell carcinoma component, and 10% in adenocarcinoma. There were gradual merges among them. Immunohistochemically, squamous cell carcinoma component was positive for cytokeratins and p53 protein. The Ki-67 labeling was 43%. The small cell carcinoma component was positive for cytokeratin, p53 protein, CD56, and KIT. The Ki-67 labeling was 95%. The adenocarcinoma component was positive for mucins, cytokeratin, p53 protein and CEA. The KI-67 labeling was 52%. The author speculates that this carcinoma arise from totipotent stem cell of the esophagus. The patient was treated by chemoradiation therapy, but died of systemic metastasis 13 months after the initial manifestation. PMID- 27956964 TI - Acute Liver Failure and Myelosuppression due to Parvovirus B19 Infection: A Case Report. AB - Parvovirus B19 has been associated with different diseases, such as erythema infectiosum, arthropathy and transient aplastic crisis. However, parvovirus B19 infection presenting as hepatic dysfunction and myelosuppression is rarely reported in adult patients. Herein, we report an adult case of acute parvovirus B19 infection presented with acute liver failure and myelosuppression. After being treated with gamma globulin, the patient's liver function and bone marrow test improved. We conclude that the parvovirus B19 infection should be considered as a possible cause of acute liver injury and bone marrow suppression. The antibody for B19 virus should be routinely tested in patients with liver dysfunction and/or myelosuppression of unclear etiology. PMID- 27956966 TI - Ileal Varices Treated with Balloon-Occluded Retrograde Transvenous Obliteration. AB - A 55-year-old man with hepatitis B virus antigen-positive liver cirrhosis was admitted to our hospital with anal bleeding. Colonoscopy revealed blood retention in the entire colon, but no bleeding lesion was found. Computed tomography images showed that vessels in the ileum were connected to the right testicular vein, and we suspected ileal varices to be the most probable cause of bleeding. We immediately performed double balloon enteroscopy, but failed to find any site of bleeding owing to the difficulty of fiberscope insertion with sever adhesion. Using a balloon catheter during retrograde transvenous venography, we found ileal varices communicating with the right testicular vein (efferent vein) with the superior mesenteric vein branch as the afferent vein of these varices. We performed balloon occluded retrograde transvenous obliteration by way of the efferent vein of the varices and have detected no further bleeding in this patient one year after treatment. PMID- 27956967 TI - A 36-Year Retained T-tube Fragment Presenting with Cholangitis. AB - The use of a T-tube to drain the biliary tree after choledochotomy has been a common surgical practice. Inadvertent fracture of the T-tube limb during removal is a rare occurrence which can lead to several complications. We report a case of cholangitis caused by a T-tube fragment retained in the common bile duct 36 years after cholecystectomy. PMID- 27956968 TI - The Evolution in the Management of Gastric Lymphoma. AB - The management of gastric lymphoma is a rapidly changing field. The classification and staging of lymphomas have been revised in the past two decades, reflecting diagnostic advances that include the use of immunohistochemical stains and cell-surface markers. Furthermore, the use of CT scanning and endoscopic ultrasound has revolutionized the non-operative diagnostic modalities available. Despite these advances, the future of gastric lymphoma research lies in the development of therapeutic regimens. PMID- 27956970 TI - Marked Variations in Colon Cancer Epidemiology: Sex-specific and Race/Ethnicity specific Disparities. AB - BACKGROUND: Recent studies have reported on the changing epidemiology of colon cancer. Given this cancer's high prevalence and mortality, defining high risk groups will be important to guide improvements in cancer screening programs. METHODS: A retrospective cohort study of a large population-based cancer registry in the United States from 1973-2004 was performed to analyze the race and sex specific disparities in colon cancer epidemiology. RESULTS: Blacks and females demonstrated the greatest proportions of proximal cancers: the incidence rate of proximal cancers among black males was more than double that of Asian males (25.2 per 100,000/year vs 11.7 per 100,000/year, p < 0.0001) and the rate among black females was twice that of Asian females (21.9 per 100,000/year vs 11.4 per 100,000/year, p < 0.0001). Blacks as a group had the highest rates of advanced cancers: the rate among black males was nearly double that of Hispanic males (17.1 per 100,000/year vs 8.7 per 100,000/year, p < 0.0001) and the rate of advanced cancers among black females was twice that of Hispanic females (12.4 per 100,000/year vs 6.2 per 100,000/year, p < 0.0001). CONCLUSIONS: This study demonstrates marked disparities in the sex-specific and race/ethnicity-specific epidemiology of colon cancer. These differences likely represent unequal access to health care resources and race and sex-specific variations in cancer biology. An individualized approach incorporating these disparities would benefit future research and guidelines for improvements in cancer screening programs. PMID- 27956971 TI - Hepatocyte Paraffin 1 Immunoreactivity in Early Colon Carcinogenesis. AB - BACKGROUND: This study was aimed at evaluating the correlation between Hepatocyte paraffin 1 (Hep par 1) and colorectal cancer. METHODS: To this end, 50 intestinal biopsies were analyzed including 10 colorectal polyps with low grade dysplasia, 10 with high grade dysplasia, 10 colorectal adenocarcinomas, 10 specimens of normal ileum and 10 of normal colon mucosa. Tissue sections were immunostained for Hep par 1 utilizing a commercial antibody. Normal colonic mucosa did not express Hep par 1. RESULTS: Immunoreactivity for Hep par 1 was detected in 20% of polyps with low grade dysplasia, 50% of polyps with high grade dysplasia and 60% of colorectal carcinomas. Hep par 1 was frequently detected in the deepest areas of adenocarcinomas mainly in infiltrating tumour cells. CONCLUSIONS: Our data show that Hep par 1 immunoreactivity in human colon carcinogenesis is correlated with progression from low grade to high grade dysplasia and adenocarcinoma. In clinical practice, our data show that caution should be taken in utilizing Hep par 1 as the sole tool in differentiating hepatocellular carcinoma from a liver metastasis of colon adenocarcinoma. Our data encourage further investigations into the potential role played by Hep par 1 in gastrointestinal carcinogenesis. PMID- 27956969 TI - Approach to Solid Liver Masses in the Cirrhotic Patient. AB - Liver masses in cirrhosis are increasingly being recognized with the use of new imaging modalities. The majority of these lesions are detected by ultrasound, enhanced CT and MRI. The most likely diagnosis of a solid liver lesion in a cirrhotic liver is hepatocellular carcinoma, followed by high grade or low grade dysplastic nodule, and cholangiocarcinoma. Lymphoma and liver metastasis are extremely rare. Diagnosis is made by contrast enhanced ultrasound, multi detector (MDCT) and MRI. Fine needle core biopsy (FNCB) or aspiration (FNAB) or both may be required in doubtful cases. If uncertainty persists on the nature of the lesion, surgical liver resection is recommended. This review discusses the main characteristics of the most common solid liver masses in cirrhotic patient. PMID- 27956972 TI - Epidemiological Survey of Hepatitis C Virus Infection in Fife, Scotland. AB - BACKGROUND: HCV infection is of growing public health importance in Scotland. We aim to establish: patient demographics; risk category; year/country of probable infection; referral/follow-up status; and genotypic variance of HCV in Fife. METHODS: Details of all HCV antibody positive patients, referred and assessed at specialist clinics in NHS Fife, until 1st of May 2007 were obtained retrospectively from the Fife hepatitis C database. RESULTS: In these patients, the ratio of males: female was 2:1, mean age was 36 years, representing a relatively young population, 27.4% of the patients consumed alcohol and 52.4% were smokers. Twelve patients were HIV/HCV co-infected (3.3%). Among the patients, 6.8% had serological evidence of past HBV exposure, 0.5% of patients were HCV/HBV co-infected and 18.8% were vaccinated. Eighty-six percent acquired HCV through injecting drug use and most cases were relatively newly acquired. Referral numbers were on the increase. Thirty-three of patients were under follow up. Sixty-five percent of patients were genotype 2/3 and 35% were Genotype 1. CONCLUSIONS: Clear patterns were observed in terms of age group, gender, geographical distribution and risk category to facilitate the effective targeting of resources. HCV population in Fife are relatively young, have acquired HCV recently and are mostly of genotype 2/3. This may have a favourable influence on disease progression and cost implications of treating HCV in Fife. PMID- 27956973 TI - Percutaneous Biliary Stent Placement in Palliation of Malignant Bile Duct Obstruction. AB - BACKGROUND: To summarize the experiences with the technique of percutaneous biliary stent placement for treatment of malignant biliary obstruction in patients with different types of biliary obstruction. METHODS: Percutaneous biliary stent placement was performed in 126 patients with malignant biliary obstruction. The etiology included 56 cases of cholangiocarcinoma, 28 cases of pancreatic cancer, 12 cases of ampullary carcinoma, 10 cases of primary hepatic carcinoma, 8 cases of gastric cancer metastasis, 6 cases of gallbladder carcinoma, and 6 cases of liver metastasis of colon cancer. The obstructed lesion predominantly involved the common bile duct in 42 patients, common hepatic duct in 39 patients, and hilar bile duct in 45 patients. When the bile duct was punctured successfully under fluoroscopy, the guide wire was explored to across the obstruction segment under the assistant of catheter, then the stent was inserted along the super-slippery guide wire. In patients with hilar hepatic duct lesions involving both left and right hepatic ducts, the both ducts were punctured and bilateral stenting was performed. A 8.5 F internal/external drainage catheter was inserted. The liver function test and ultrasound were performed one week after the procedure to observe the decrease of bilirubin and alleviation of biliary obstruction. RESULTS: A total of 166 stents were implanted in 126 patients. In the 42 patients with common bile duct obstruction, each patient was implanted one stent. In the 39 patients with common hepatic duct obstruction, each patient was impanted one stent. In the 45 patients with hilur bile duct obstruction, 38 patients were placed 2 stents, one patient was placed with 3 stents, and the rest were placed with one stent. The serum total bilirubin decreased from 309.2 +/- 158.3 umol/L before the procedure to148.5 +/- 98.0 umol/L one week after the procedure (P < 0.001). Alkaline phosphatase and alanine aminotransferase significantly decreased (P < 0.001). Five cases died within 1 month (4%) after the procedure. Complications occurred in 9 cases (7.1%). Six patients underwent combined duodenal self-expandable metal stent placement successfully. CONCLUSIONS: The percutaneous biliary stent placement is a safe and effective palliative therapy for malignant biliary obstruction by improving liver function and 1ife quality. PMID- 27956974 TI - Comparative Hepatoprotective Effect of Vitamins A and E Against Gasoline Vapor Toxicity in Male and Female Rats. AB - BACKGROUND: Plasma alanine transferase(ALT), aspartate transferase(AST), alpha glutamyl transferase(GGT), and alkaline phosphatase(ALP) activities are known biomarkers in assessing hepatic functional integrity. A remarkable rise in the activities of these enzymes normally signifies hepatotoxicity of chemical agent(s) in the biological system. Exposure to 17.8 cm3h-1m-3 of PMS blend unleaded gasoline vapors (UGV) for 6 hr/day, 5 days/week for 20 weeks have been reported to cause hepatotoxicity in rats. METHODS: In this study, the comparative hepatoprotective effect of vitamins A (retinol) and E (alpha-tocopherol) against UGV-induced toxicity was assessed in male and female rats. Retinol and alpha tocopherol at prophylactic dosage (400 and 200 IU/kg/day, respectively) were separately administered orally to the test rats concomitant with exposure to UGV in the last two weeks of the experiment. RESULTS: The results of this study indicated that exposure to UGV caused significant increase (P < 0.05) in the activities of serum ALT, AST, ALP, GGT and bilirubin in male and female rats. Oral administration of prophylactic doses of retinol and alpha-tocopherol produced a significant decrease (P < 0.05) in the activities of these parameters in male and female test rats, compared with the non-treated test rats; but insignificant increase(P >= 0.05), compared with the control. However, the hepatoprotective effect of alpha-tocopherol was observed to be more potent than that of retinol. CONCLUSIONS: The result of this study demonstrated that the hepatoprotective potency of alpha-tocopherol against gasoline vapors toxicity was higher than that of retinol in male and female rats, although the female gender of the animal model responded to treatment with both vitamins better than the males. Hence, the work suggested the beneficial effects of both vitamins against hepatotoxicity in individuals frequently exposed to gasoline vapors. PMID- 27956975 TI - Obstructive Jaundice Due to Hilar Bile Duct Compression with Encasement of the Right Hepatic Artery. AB - A 68-year-old woman had a solitary 12.0 cm hepatic cyst with a septum. The cyst was located near the hepatic hilum and she presented with obstructive jaundice caused by compression of the hilar bile duct. Stenosis of the common hepatic duct was detected at the porta hepatis on endoscopic retrograde cholangiography (ERC), and encasement of the right hepatic artery at the same level was revealed by abdominal angiography. Transpapillary cholangioscopy showed compression and mucosal erosions of the hilar bile duct. After transpapillary cholangioscopy, the hepatic cyst became infected, for which emergency percutaneous transhepatic drainage was performed. As a result, the patient's obstructive jaundice subsided. The mucosal erosions of the bile duct that existed at a site corresponding to the encasement of the right hepatic artery also improved. In conclusion, bile duct stenosis was considered to be caused by compression due to the hepatic cyst and the right hepatic artery. PMID- 27956976 TI - Isolated Esophageal Injury Following Blunt Thoracic Trauma: A Rarity. AB - Esophageal injury following blunt trauma to chest is an extremely rare event, with only a limited number of cases being reported in the world literature. We report a case of perforation of the lower thoracic esophagus following a crush injury to the chest in a 14 year old child. An appropriately placed chest drain and decompression gastrostomy resulted in complete resolution of the esophageal leak within four weeks. This case report demonstrates that a conservative approach to lower thoracic esophageal perforations can be carried out successfully without the added morbidity of thoracotomy and risks of direct repair. PMID- 27956977 TI - Graft Versus Host Diseases Presenting Endoscopically as a Tubular Structure Mimicking a Worm. PMID- 27956978 TI - Hepatobiliary Manifestations of Sickle Cell Anemia. AB - Sickle cell anemia is one of the common hemoglobinopathies around the world. It results from a single change of one amino acid valine instead of glutamic acid in the hemoglobin beta change. This change leads to polymerization of the hemoglobin when the oxygen saturation is lowered, resulting in deformity of the red blood cells and microvascular occlusion. Sickle cell anemia can affect any part of the body and one of the main organs to be affected is the hepatobiliary system either directly from the sicklening process or indirectly as a result of chronic hemolysis and multiple blood transfusions. This manifests in several clinical conditions which poses diagnostic and therapeutic dilemmas to the treating physicians. These hepatobiliary manifestations will be outlined in this review. PMID- 27956979 TI - Treatment of Liver Trauma: Operative or Conservative Management. AB - BACKGROUND: The liver is one of the most frequently damaged organs when abdominal trauma occurs. Currently, a conservative management constitutes the treatment of choice in patients with hemodynamic stability. The aim of this study is to evaluate the results of an operative and conservative management of 143 patients with liver injury treated in a single institution. METHODS: A retrospective study of the patients admitted with the diagnosis of liver trauma was performed from 1992-2008. The patients were classified according to the intention to treatment: Group I, operative management; Group II, conservative management. Variables analyzed included demographic data, injury classification, associated lesions, surgical treatment, transfusions, morbi-mortality, and hospital stay. We established two periods (1992-1999; 2000-2008) in order to compare diagnosis and management. RESULTS: A total of 143 patients were analyzed. Thirty-one percent correspond to severe injuries. Conservative treatment was followed in 60.8 % with surgery undertaken in 14.9 % of patients from this group due to failure of conservative treatment. Immediate surgery was carried out in 38.2 %. Total mortality was 14 %. Morbidity (35.7-38.5 %) in the group of immediate surgery and failure of conservative management is similar, but not in mortality (28.6-15.4 %). In the second group (2000-2008) there are more patients with conservative treatment, with a low percentage of failure of this treatment and morbi mortality. CONCLUSIONS: Conservative treatment is an adequate treatment in a great number of patients. Failure of conservative treatment did not show a higher incidence of complications or mortality but it should be performed in centers with experienced surgeons. PMID- 27956980 TI - Clinical Research on the Relation Between Body Mass Index, Motilin and Slow Transit Constipation. AB - BACKGROUND: Constipation is a common clinical symptom but its etiology remains unknown. The aims of the study are to discuss the relation between body mass index (BMI), motilin and the slow transit constipation (STC). METHODS: A total of 178 patients with STC and 123 healthy volunteers as controls were divided into three groups according to the BMI, group A (BMI <20), group B (BMI 20-25), and group C (BMI > 25). Fasting and one hour postprandial plasma motilin were measured and the results were analyzed. RESULTS: There was significant difference in the constituent ratio between STC patients and healthy controls (p < 0.05). The percentage of group A, B and C in STC patients was 49.4% (88/178), 23.0% (41/178) and 27.6% (49/178), respectively; and group A had a higher percentage. Plasma motilin of fasting and one hour postprandial in STC patients of group A was significantly lower than that of group B and C (p < 0.05), but there was no difference between group B and C (p > 0.05). There was no significant difference in the results of plasma motilin of fasting and one hour postprandial among the three groups of healthy controls (p > 0.05). Plasma motilin of fasting and one hour postprandial in STC patients of group A was significantly lower than those healthy controls of group A (p < 0.05). The same results of plasma motilin of fasting and one hour postprandial could be seen in group B and C, respectively (p < 0.05). CONCLUSIONS: A higher proportion of low BMI sufferers was found in the STC patients. The reason may be related to the lower release of the plasma motilin. PMID- 27956981 TI - Simplified Early Predictors of Severe Acute Pancreatitis: A Prospective Study. AB - BACKGROUND: To propose simple tests for the prediction of severe acute pancreatitis (SAP), which are accurate and could be performed at emergency departments and outpatient clinics. METHODS: A prospective study was performed on 149 patients admitted with acute pancreatitis. Body mass index (BMI), plain chest radiograph, blood biochemical data were obtained at the time of admission; white cell, lymphocyte and platelet counts, hematocrit level, prothrombin time, PaO2, creatinine, calcium, blood sugar, total protein, aspartate aminotransferase, total bilirubin, amylase, lipase and C-reaction protein were determined. Patients were graded into severe and mild acute pancreatitis based on CT Balthazar grading system. RESULTS: Twenty-seven patients were diagnosed to have SAP and 122 patients considered mild acute pancreatitis. Comparing parameters between both groups; significant factors (P < 0.05) were blood sugar level, haematocrit level, BMI and presence of pleural effusion in chest X-ray. The hematocrit at admission and at approximately 24 hours was significantly higher among patients with SAP. Twenty-two of 27 cases of severe disease and only 10 of 122 cases of mild acute pancreatitis diagnosed to have pleural effusion (P < 0.001). CONCLUSION: BMI, blood glucose >= 190 mg/dL, hematocrit level >= 43 % and pleural effusion detected by plain chest radiograph are simple tests and provide significant predictive power for clinical decision-making. PMID- 27956982 TI - Effect of Aqueous Extract of Psidium Guajava Leaves on Liver Enzymes, Histological Integrity and Hematological Indices in Rats. AB - BACKGROUND: Serum alanine aminotransferase (ALT), aspartate aminotransferase(AST), alkaline phosphatase (ALP), albumin and total protein levels, as well as the tissue histological assay are known to be useful in assessing the functional integrity of the liver. Also, assessment of red and white blood cells count, hematocrit and hemoglobin concentrations is useful in determining the effect of some chemical substances on hemotopoietic system. In recent times, reports from medicinal plants research indicate that extracts from some plants are both hepatotoxic and hematotoxic, while others on the other hand are reported to be hepatoprotective and hematopoietic in action. This study considers the effects of aqueous extract of Psidium guajava (P. guajava) leaves on the histology and biochemical indices of liver function as well as hematological indices in rats. METHODS: In this study, phytochemical screening of the aqueous extract of P. guajava leaves was carried out. Also, male and female rats were administered with 200 mg/kg body weight oral daily doses of aqueous extract of P. guajava leaves for a period of 30 days. At the end of the administration period, the rats were anaesthesized with chloroform vapors and dissected for the collection of blood and liver tissues which were used for the hematopoietic and liver functions investigations. RESULTS: Preliminary phytochemical analysis of the plant leaves showed the presence of alkaloids, flavonoids, glycosides, polyphenols, reducing compounds, saponins and tannins. Liver function tests revealed that the serum ALT, AST and ALP, as well as the concentrations of total protein and albumin in male and female rats were not significantly (P > 0.05) affected by the oral administration of the extract. Histopathological study also did not show any adverse alteration in the morphological architecture of the liver tissues in both sexes of the animal model. However, red blood cell counts, hemotocrit and hemoglobin concentrations increased significantly (P < 0.05) on administration of the extract in both male and female rats. It was therefore observed that the effect of the extract on male rats was not significantly different (P > 0.05) from that obtained for the female rats. CONCLUSIONS: The results of this present study suggested that aqueous extract of Psidium guajava leaves may be hepatoprotective, and not hepatotoxic, with hematopoietic potentials in both male and female rats. These findings are therefore of clinical importance given the various reported medicinal potentials of the plant. PMID- 27956983 TI - Primary Pure Squamous Cell Carcinoma of the Duodenum: A Case Report. AB - Only two cases of squamous cell carcinoma of the duodenum have been reported in the literature. The author herein reports a case of squamous cell carcinoma of the duodenum. A 75-year-old man was admitted to our hospital because of nausea, vomiting, and weakness. An endoscopic examination revealed a duodenal tumor. The tumor was circumferential elevated one with duodenal obstruction, and located in the descending part near and distal to the ampulla of Vater. Imaging modalities also detected the duodenal tumor, but did not show tumors of other locations including the pancreas. The duodenal tumor was different from ampullary tumor and pancreatic tumor. Six biopsies were obtained from the duodenal tumor. All the six biopsies showed malignant cells arranged in a medullary pattern. The malignant cells showed hyperchromatic nuclei, and mitotic figures were scattered. Keratinization and intercellular bridges were recognized. The pathologic features were interpreted as a squamous cell carcinoma of the duodenum. The carcinoma was pure squamous cell carcinoma without differentiation into adenocarcinoma or endocrine carcinoma. Operation was not possible because of the patient's age and weakness. The patient was treated by chemotherapy and radiation, but he showed a downhill course. Metastases emerged, and he died of systemic metastasis 17 months after the first presentation. Autopsy was not performed. PMID- 27956984 TI - Two Atypical Cases of Nodular Gastritis: A Poorly Differentiated Gastric Adenocarcinoma and a Pseudo-Low Grade Gastric MALT Lymphoma. AB - Nodular gastritis is a Helicobacter pylori-related gastritis with endoscopically proven gooseflesh skin-like nodularity in the gastric antrum. Although an association between nodular gastritis and gastric malignancies has been suggested, there is neither a treatment strategy nor a treatment guideline for this condition because of its relative rarity. We have recently experienced two cases of diffuse-type nodular gastritis invading both the antrum and corpus of the stomach with atypical findings that required specific treatments in two young females. The first patient was diagnosed with a suspicious low grade gastric mucosa associated lymphoid tissue (MALT) lymphoma lesion on a diffuse-type nodular gastritis, and was cured by H. pylori eradication. The second patient was diagnosed with a signet cell type gastric cancer on a diffuse-type nodular gastritis, and was cured by surgical resection. When considering the nature and significance of these gastric lesions, a link between nodular gastritis and gastric malignancy should be considered, especially in young women who have diffuse-type nodular gastritis involving both the antrum and corpus of the stomach. PMID- 27956985 TI - Relatively Long Survival in Hepatocellular Carcinoma Presenting With Carcinoid Syndrome. AB - Hepatocelluar carcinoma is one of the commonest cancers in Nigeria. Some patients may manifest a variety of paraneoplastic syndromes. Carcinoid syndrome is an extremely rare presentation of hepatocellular carcinoma. A 57-year old man presented with recurrent facial flushing and diarrhea, tricuspid regurgitation, and very high level of urinary hydroxyindoleacetic acid (HIAA) as the first manifestation of a multicentric hepatic lesion which proved histologically to be hepatocellular carcinoma. The lesions also exhibited arterial hypervascularization on contrast enhanced computerized tomography. The patient is still alive after 6 years of symptoms. PMID- 27956986 TI - Gastro-colic Fistula due to Acid Ingestion. AB - Corrosive ingestion can cause serious damage to the upper gastrointestinal tract. The acute consequences could range from mild erythema to gangrene and perforation. Delayed consequences could be strictures of the oesophagus presenting as dysphagia or gastric, pyloric and antral stenosis presenting as gastric outlet obstruction. Gastro-colic fistula as a complication of acid ingestion is a rare clinical entity. We report this case of a patient who presented with complaints of dysphagia and recurrent vomiting of foul smelling brownish vomitus two months following suicidal acid (sulphuric acid) ingestion. The presence of a gastro-colic fistula was confirmed with a barium meal examination. PMID- 27956988 TI - Effect of Hospital Characteristics on the Quality of Laparoscopic Gastrectomy in Japan. AB - BACKGROUND: Laparoscopic gastrectomy (LG) is becoming more widely indicated, although its application has not been investigated sufficiently in community based gastrointestinal research because the small number of gastric cancers in western countries might have limited its use. However, concerns have been raised regarding variations in the quality of care with LG. To contribute to improving the efficient utilization of costly surgical innovations, we determined the impact of hospital characteristics on LG care. METHODS: Among 3,914 LG patients in 58 academic and 200 community hospitals between 2006 and 2008, we examined patient demographics, comorbidity, complications, partial or total gastrectomy, care process, hospital patient volume, hospital ownership and teaching status, and fiscal year. Hospital LG volume was divided into three quintile categories (lower volume, LV; intermediate volume, IV; or higher volume, HV) that consisted of an approximately equal number of patients. Dependent variables were operating time (OT), length of stay (LOS) and total charge (TC). The impact of hospital characteristics on these variables was assessed using multivariate analysis. RESULTS: Twenty-seven academic hospitals out of 193 LV hospitals treated 271 (21%) LG patients, 20 of 44 IV hospitals treated 596 (47%), and 11 of 21 HV hospitals treated 748 (55%). Although mortality or complications did not vary significantly between LV, IV and HV hospitals, the latter were associated with longer OT or LOS and more TC. More blood transfusions were required in HV hospitals once indicated. Hospital ownership or teaching status did not explain the variation in complications. Teaching and national hospitals consumed more resources, and municipal and private hospitals reduced OT more than national hospitals. CONCLUSIONS: A volume-quality relationship was recognized. As intraoperative transfusion prolongs OT and results in more complications, clinical societies or policy makers should introduce this new technique concurrently with quality improvement initiatives that aim to reduce unnecessary OT at targeted institutions. Hospitals varied in terms of LOS and TC, therefore, policy makers should also monitor resource utilization to enhance the efficiency of LG care under restrictive fiscal policies. PMID- 27956989 TI - ERCP in Patients With Sickle Cell Disease: Diagnostic and Therapeutic Dilemmas. AB - BACKGROUND: Cholestatic jaundice (CJ) in patients with sickle cell disease (SCD) poses diagnostic and therapeutic dilemmas. This is an evaluation of the role of ERCP in SCD. METHODS: A total of 224 SCD patients with CJ had ERCP. The indications for ERCP were based on clinical and biochemical evidence of CJ and ultrasound findings. RESULTS: The indications were: CJ only in79, CJ and dilated ducts in 103, and CJ and biliary stones in 42. The ERCP findings were: (A) For those with CJ only: ERCP was normal in 45, showed dilated ducts with no stones in 13, dilated ducts with stones in 16, normal CBD with a stone in 1; (B) For those with CJ, dilated ducts: ERCP was normal in 17, showed dilated ducts with stones in 47, dilated ducts without stones in 28, normal CBD with a stone in 1, a choledochoduodenal fistula in 2; (C) For those with CJ and duct stones: ERCP was normal in 2, showed dilated ducts with stones in 21, dilated ducts without stones in 14, normal CBD with a stone in 1. CONCLUSIONS: ERCP was unnecessary in a significant number (27%) of patients. This is especially so for those with CJ only (57%). These should be evaluated further prior to ERCP. There was also a significant number (19%) who had ES for duct dilatation without an obstruction. The reason for this dilatation is not known and the value of ES in this group needs to be investigated further. PMID- 27956987 TI - Eosinophilic Esophagitis: Current Aspects of a Recently Recognized Disease. AB - Eosinophilic esophagitis (EoE) is a chronic clinicopathological entity characterized by large numbers of intraepithelial eosinophils infiltrating the esophageal mucosa. The inflammation leads to alterations in the caliber and the motility of the organ, which determines esophageal symptoms, especially dysphagia and frequent food impaction. Firstly described in 1978, EoE represents today an increasingly recognized disease, with cases coming from all developed countries and rising epidemiology. The origin of EoE has been related to allergy to food components or inhalants, and a number of studies support a Th2-type reaction in the origin of the disease. Thus, several treatment strategies based on controlling the exposition to triggering allergens or therapies using anti allergic drugs have demonstrated efficacy in EoE. Since EoE frequently presents with esophageal stenosis, endoscopic dilation has been also used in treating these patients, but a high risk of complications has been documented. However, single treatment strategies have not been compared to a placebo group in most of studies, and we do not know the long-term consequences of eosinophilic inflammation, esophageal fibrous remodeling or its possible modifications using different therapies. Furthermore, we lack of a common accepted therapeutic end point to assess the efficacy of the treatment: from mere resolution of symptoms to full control of esophageal inflammation. This article summarizes the current knowledge about the epidemiology, origin and pathogenesis of the disease, and discuses several practical questions, especially those related to how the affected patients should be treated. PMID- 27956991 TI - Regenerative Potential of Aqueous Extract of Neem Azadirachta indica on the Stomach and Ileum Following Ethanol-induced Mucosa Lesion in Adult Wistar Rats. AB - BACKGROUND: The aim of this study was to examine whether neem Azadirachta indica possesses regenerative potential on the stomach and ileum at 500 mg/kg dose given every 12 hours after mucosa lesion was brought by the administration of 1 ml of 50% ethanol for 21 consecutive days in adult Wistar rats. METHODS: Adult male Wistar rats used in the study were divided into 3 groups: group A received oral normal saline and served as control; group B received 1.0 ml of 50% ethanol orally every 12 hours; and group C received neem extract (500 mg/kg) orally 12 hours after ethanol (50%, 1.0 ml) administration to verify its regenerative potential. The experiment lasted for 21 days after which the animals were sacrificed following chloroform inhalation and the stomach and ileum excised and processed for histological and morphometric examinations. RESULTS: Ethanol treated rats showed marked gross mucosal lesions in the stomach and ileum. Ulcerated mucosa with marked apoptotic bodies and destruction of glandular elements were evident in the animals (group B). Neem extract administered 12 hours after the ethanol administration showed regenerative potential against ethanol-induced mucosal damage. This was characterized by mild restoration of the ulcerated mucosa epithelium and reorganization of the cyto-architechtural outline in group C. CONCLUSIONS: Our investigation suggests that neem extract has a regenerative potential and may be adopted in the management of gastrointestinal disorders such as ulcer. PMID- 27956992 TI - Gastrointestinal Stromal Tumor: Cause of Gastrointestinal Bleeding. AB - Gastrointestinal stromal tumors (GISTs) are rare tumors and can be a cause of gastrointestibnal bleeding, when other causes have already been excluded. This mesenchymal tumors can be diagnosed hardly, and they should be included in any differential diagnosis. Our case illustrates the difficulty of diagnosis and sometimes shows how non-invasive test can be few helpful. Surgery is very often indicated, and becomes therapeutic and diagnostic. GIST tumors are rare and surgical resection with curative intent is the treatment of choice. PMID- 27956990 TI - Traumatic Transection of Pancreas at the Neck: Feasibility of Parenchymal Preserving Strategy. AB - BACKGROUND: To assess the feasibility and safety of a pancreas preserving operative technique in the management of isolated complete pancreatic neck transection following blunt abdominal trauma. METHODS: Two patients with isolated blunt fracture of the pancreatic neck underwent pancreas preserving procedure comprising of oversewing of the proximal pancreas and Roux-en-Y pancreatico jejunostomy to the distal remnant. A feeding jejunostomy tube was placed for postoperative nutritional support in these patients. Both patients received subcutaneous octreotide 300 ug/day. RESULTS: Their ages ranged from 15 years to 20 years, mode of injury was bicycle handle-bar injury (n = 2). Both had pancreatic transection at neck in the line of superior mesenteric vessels. One had ascites. These patients had pancreas parenchyma preserving surgery - internal drainage of the left remnant in a Roux-en-Y jejunal loop. The postoperative course was uneventful in these and both are well on follow-up. CONCLUSIONS: Pancreas preserving strategy - suture of head side of pancreas and an internal drainage of left remnant with a Roux-en-Y jejunal loop is feasible and safe and should be considered in selected cases. Substantial amount of normal pancreatic parenchyma is preserved. PMID- 27956993 TI - Erythema Annulare Centrifugum: A Rare Skin Finding of Autoimmune Hepatitis. AB - Erythema annulare centrifugum is characterized by dermal perivascular lymphocytic infiltrates. It is often associated with infections, autoimmune or neoplastic diseases but in most cases the cause is unexplained. A case of erythema annulare centrifugum related to autoimmune hepatitis in a 24-year-old woman is described in this case report. Clinical response of the autoimmune hepatitis to a combination therapy with corticosteroids and azothiopurine was achieved. Although partially regressed for the first 12 months of theraphy, the skin lesions did not disappear completely. However, after 18 months of continious treatment there was no skin lesion. PMID- 27956994 TI - Synchronous Perforation of the Ileum and Meckel's Diverticulum Due to Tuberculosis. AB - Perforation of the Meckel's diverticulum due to tuberculosis is a rare phenomenon. A 45 years old male who presented with perforation peritonitis was found to have a synchronous dual perforation involving the ileum and the Meckel's diverticulum, due to intestinal tuberculosis. In addition to this, the Meckel's diverticulum was found to have a daughter diverticulum (diverticulum within diverticulum), which was probably pulsion or traction diverticulum as it did not have all layers of the intestinal wall. Such daughter diverticulum associated with a Meckel's diverticulum is very unusual. All these factors make this a unique case which is hence reported here. PMID- 27956995 TI - Does Timing of Colon Procedures Affect Outcomes in D-IBS Trials? AB - BACKGROUND: Sigmoidoscopy/colonoscopy is usually performed prior to enrollment into clinical trials of irritable bowel syndrome (IBS). Two main reasons are to rule out alternative diagnoses and to ensure that colitis is not present. However, the possible impact of a recent versus remote colon procedure on symptoms in IBS trials has not been evaluated. The aim of this study was to evaluate the effect of timing of colon procedures on symptoms in IBS trials. METHODS: Post hoc analyses were conducted using placebo patients with diarrhea predominant IBS in a phase 2 trial. Pain, frequency, consistency, and urgency were analyzed using repeated measures models during the first 7 days of treatment and over the entire 12-week treatment period. RESULTS: Fifty-two placebo patients were grouped by whether they had a colon exam performed between screening and randomization (Group 1) or had a normal colon procedure during the 3 years prior to screening for this trial (Group 2). Average screening symptom scores were comparable between the two groups. Evaluation of various symptoms showed that there were no consistent significant differences between the two groups in pain, frequency, consistency, or urgency. CONCLUSIONS: After the required 3-day post procedure recovery period, there was no evidence that colonoscopy timing affected subsequent IBS symptoms. PMID- 27956996 TI - Factor structures of the Swedish Version of the RFIPC: Investigating the Validity of Measurements of IBD Patients' Worries and Concerns. AB - BACKGROUND: Worries and concerns of patients with IBD comprise an important negative factor in their HRQOL. The Rating Form of Inflammatory Bowel Disease Patient Concerns (RFIPC) was developed to describe the nature and degree of the worries and concerns of IBD patients. In the original version, the specific issues of worries are divided into four separate factors. These factors provide useful information about HRQOL and the kind of worries and concerns which are most important to the patient. However, the Swedish version of the RFIPC is often scored using a single sum score, implying that all the specific issues of worries stem from a single general worry factor. The aim of this study was to validate the factor structure of the Swedish version of the RFIPC. METHODS: A sample consisting of 195 patients with IBD filled out the RFIPC. Confirmatory factor analysis was performed to examine fit of three hypothesized models of factor structure. Spearman's correlation and Mann-Whitney analysis were used to follow up the results. RESULTS: The single-factor model displayed poor fit indices. The four-factor model marked substantive improvement, but still remains inadequate. The final four-factor model permitting correlated error terms between some items displayed the most adequate fit. CONCLUSIONS: The factorial structure of the RFIPC, as suggested in the original version, was able to be replicated with a slight modification in the Swedish version. The separate factors identified in this structure provide more detailed information about the worries and concerns of IBD patients as these components of worries are different related to HRQOL and general health. PMID- 27956997 TI - Techniques and Outcomes of Endoscopic Decompression Using Transanal Drainage Tube Placement for Acute Left-sided Colorectal Obstruction. AB - BACKGROUND: If it is possible, endoscopic decompression for acute left-sided colorectal obstruction will be effective in critically ill patients. This study was to evaluate the techniques and outcomes of transanal drainage tube placement following urgent colonoscopy in management of acute left-sided colorectal obstruction. METHODS: From January 2000 to December 2009, 69 consecutive patients (36 males, age 38 to 94, mean = 71) were hospitalized because of acute left-sided colorectal obstruction. Urgent colonoscopy was performed within 12 hours of entry for diagnosis and treatment (mean time, 6.5 hours). Endoscopic decompression using a transanal drainage tube was attempted. Clinical success, methods used, and complications were retrospectively evaluated. RESULTS: The cause of obstruction was colorectal carcinoma in 66 patients (96%). The site of obstruction was sigmoid colon in 37 (54%), rectum in 20 (29%), and descending colon in 12 (17%). Out of 69 patients, endoscopic decompression using the transanal drainage tube was successful in 66 (96%). The use of combination of transanal drainage tube and the equipped guidewire enabled endoscopic decompression was successful in 45 patients (65%), though a small-diameter upper endoscope was used in 2 patients to introduce the guidewire beyond the obstruction. Perforation during the placement developed in 2 patients and one patient was unsuccessful. CONCLUSIONS: Transanal drainage tube placement following urgent colonoscopy was effective in the management of acute left-sided colorectal obstruction. In the majority of patients, the materials and methods used for the transanal drainage tube placement were simple and easy. PMID- 27956998 TI - Prevention of Biliary Duct Injury in Laparoscopic Cholecystectomy Using Optical Fiber Illumination in Common Bile Duct. AB - BACKGROUND: Biliary duct injury (BDI) is one of the most common complications in laparoscopic cholectecystomy (LC), in this study, we have tried to place an illuminating optical fiber via endoscopy in the CBD during LC, the biliary duct anatomy can be clearly delineated, thus CBD injury is avoided. METHODS: Sixteen patients with chronic cholecystitis or/and cholelithiasis from February 2007 to June 2008 were performed LC with placement of optical fiber in CBD, the fiber with cold light illuminates the whole extrahepatic biliary system. Three 6-mm titanium clips were applied to the soft tissue surrounding the hepatic duct, CBD and the cystic duct confluence with CBD, respectively; one titanium clip was applied to the surface of cystic duct near the infundibulum of gallbladder. The cytic duct, CBD and common hepatic duct were clearly identified and delineated in the operating field and LC was performed. RESULTS: All the 16 patients were performed LC using this procedure successfully, there were no LC-related complications, nor complications related to endoscopic retrograde cholangiopanceatography (ERCP). CONCLUSIONS: The endoscopically placed optical fiber in the CBD can clearly identify the CBD, Calot's triangle and the common hepatic duct, this can reduce the bile duct injury in LC and imporve the safety of LC. PMID- 27956999 TI - Severe Life Threatening Rectal Bleed After Prostate Biopsy Requiring Angiographic Therapy: A Case Report. AB - Rectal bleeding is often seen in patients who undergo transrectal ultrasound guided prostate biopsy. It is usually mild and stops spontaneously. We report what we believe is the first case of life threatening rectal bleeding following this procedure which was successfully treated with angiographic embolization. An endoscopic injection of epinephrine done on admission achieved only temporary hemostasis and the patient developed a second episode of massive rectal bleeding that warranted angiographic treatment. We present this case in detail and review other alternatives for treating fulminant rectal bleed which is a consequence of this procedure. PMID- 27957000 TI - Subcutaneous Emphysema, Pneumothorax and Pneumomediastinum Following Endoscopic Sphincterotomy. AB - Retroperitoneal perforation during therapeutic endoscopic retrograde cholangiopancreatography (ERCP) is uncommon and is usually manifested by abdominal pain, fever and leukocytosis. We report the case of a patient with post ERCP subcutaneous emphysema, pneumomediastinum and pneumothorax treated conservatively. A 79-year-old woman with a diagnosis of choledocholitiasis was referred to our institution for an elective outpatient therapeutic ERCP. At the end of the procedure, subcutaneous emphysema was observed, and a thoracic computed tomography revealed a right pneumothorax and pneumomediastinum. Supportive care was instituted and she was discharged asymptomatic after 10 days of hospitalization. Subcutaneous emphysema, pneumothorax and pneumomediastinum are potencial complications of ERCP and sphincterotomy. We review the other cases previously reported and discuss the management. PMID- 27957002 TI - Glypican-3-Expressing Hepatocellular Carcinoma in a Non-Cirrhotic Patient with Nonalcoholic Steatohepatitis: Case Report and Literature Review. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Nonalcoholic steatohepatitis (NASH) is now considered as the major cause of cryptogenic cirrhosis, which can progress to HCC. Glypican-3 is a member of the Heparan Sulfate Proteoglycan (HSP) family that plays a role in cell growth, differentiation, and migration. Glypican-3 is significantly up-regulated in a majority of HCCs compared to normal and benign liver samples. Glypican-3 protein is detectable in around 40-53% of HCC patients whereas it is not detectable in the serum of healthy individuals. There are several reports of HCC arising in the setting of non-cirrhotic NASH. This report describes a case of HCC that expressed Glypican-3 and arose in a 47-year-old female with noncirrhotic NASH. PMID- 27957001 TI - Thyroid Metastasis of Gastric Cancer: A Rare Occasion With Poor Prognosis. AB - A 68-year-old man was diagnosed as having advanced gastric cancer. Computed tomography showed a thyroid tumor with trachea deviation. This tumor exhibited mosaic echogenecity in ultrasonography. Signet-ring cell carcinoma was found by means of fine needle aspiration biopsy. This tumor gradually became swollen and the thyroid hormone levels in blood were increased without any clinical symptom. Shortly, he died from his illness in the 29th hospital day. Autopsy disclosed that the left lobe of the thyroid gland was highly invaded by malignant cells and that lymphogenic rather than angiogenic metastasis was highly probable. Thyroid metastasis of gastric cancer is extremely rare. The prognosis is very poor. Ultrasonography is a very useful modality especially when coupled with recently developed fine needle aspiration biopsy in differential diagnosis of thyroid tumors once malignancy is suspected. Therapeutic strategy largely depends on the nature of primary malignant tumor. If the tumor is slowly progressive such as renal cell carcinoma and breast cancer, extirpation of thyroid tumors may extend life expectancy. In conclusion, the metastatic thyroid tumor of gastric cancer is rare and shows poor prognosis. Fine needle aspiration biopsy under ultrasonography is strongly recommended as a useful diagnostic tool. PMID- 27957003 TI - Lipomatous Polyp Presenting With Intestinal Intussusception in Adults: Report of Four Cases. AB - Intussusception is a relatively common cause of intestinal obstruction in children but a rare, and uncommon clinical entity in adults accounting for 1%. Lipoma accounts for 4% of all benign tumors of the gut. Most of these are seen in the large intestine, usually submucosal and around ileocecal valve. These are often asymptomatic. Though these lesions are benign, it continues to present difficulties in the preoperative differentiation between malignant and benign colonic neoplasm. PMID- 27957004 TI - The Unusual Suspect: A Case of Non-occlusive Mesenteric Ischemia in a Patient With Cirrhosis. AB - Acute mesenteric ischemia has a variety of etiologies. Non-occulusive mesenteric ischemia accounts for 20-30% of patients with acute mesenteric ischemia. We describe a case of non-occulusive jejunal ischemia leading to infarction that occurred in a patient with cirrhosis and no previous history of cardiovascular disease. PMID- 27957005 TI - Community-Based Appraisal of the Effects of Parenteral Nutrition Versus Enteral Nutrition on the Quality of Care for Patients With Acute Pancreatitis. AB - BACKGROUND: Enteral nutrition (EN) rather than parenteral nutrition (PN) has been advocated in treatment guidelines for acute pancreatitis (AP) as endorsed in randomized studies or meta-analyses. The findings derived from those studies would recognize the criticism of smaller sample sizes or limited patient case mixes. To determine the generalizability of those findings, community-based appraisal on the advantages of EN over PN is required. Using a Japanese administrative database between 2006 and 2010, we determine whether EN is superior to PN in the real clinical settings. METHODS: A total of 24,913 patients diagnosed with AP at admission in 1,000 hospitals were identified. Among them, we analyzed 1,803 patients of >= 15 years who received EN or PN for AP across 480 hospitals. Among three nutrition categories of PN only, EN only and PN with EN, we examined patient characteristics, comorbidities, complications, AP severity score determined by the Ministry of Health, Labor and Welfare, surgical procedures for the biliary/pancreatic system, use of artificially assisted ventilation and hemodialysis proxy of multiple organ failures and hospital teaching status. To identify the variables associated with PN use, a logistic regression model was used and the propensity score (PS) was calculated to control for the selection bias of patient case-mix preferring PN use. Then, we compared mortality, length of hospital stay (LOS), total charges (TC) and commencement day of oral food intake between EN and PN. RESULTS: A total of 1,191 PN patients, 330 EN patients and 282 mixed EN and PN patients were identified. EN was indicated for patients with mild AP and procedures for the pancreas. PS matching analysis indicated that PN had a higher mortality compared with EN, and PN significantly increased LOS and TC compared with EN. PN deterred the commencement of oral food intake. CONCLUSIONS: Community-based study has shown that EN was employed in the less severe case-mixed. Even though considering that selection bias, EN was still superior to PN in AP. Physicians should be aware of the guidelines for the advocacy of EN and need to carefully consider the indications for EN to optimize the quality of AP care. PMID- 27957006 TI - Urgency as an Endpoint in Irritable Bowel Syndrome. AB - BACKGROUND: The choice of endpoints is crucial for proper evaluation of agents in clinical trials of irritable bowel syndrome (IBS). In a recently published draft guidance for IBS from the United States Food and Drug Administration (FDA), urgency was not considered an appropriate primary endpoint. The FDA's position is that it is not clear how patients with diarrhea-predominant IBS (D-IBS) "define or describe urgency". The aims of this study were to evaluate the association of urgency with stool frequency and consistency in patients with D-IBS and to describe results from patient interviews on their understanding of the term urgency. METHODS: A retrospective analysis of clinical trial data in patients with D-IBS was conducted. Analyses focused on the relationship of urgency to stool frequency and consistency. Interviews were conducted with patients with D IBS to test their understanding of the term urgency. RESULTS: On the days that patients reported urgency, as compared to the days that patients did not report urgency, they had more frequent bowel movements (3.9 versus 1.8) and looser stools (Bristol Stool Score: 5.4 versus 4.2). The differences for both parameters, evaluated on the days with or without urgency, were statistically significant. In patient interviews, patients with D-IBS had a clear understanding of the concept and terminology of urgency and considered it one of their two most bothersome symptoms. CONCLUSIONS: Urgency should be considered a suitable co primary endpoint in D-IBS studies. PMID- 27957007 TI - Significance of Serum Alpha-Glutathione S-Transferase Assessment in Hepatitis C Patients with Different Alanine Aminotransferase Patterns. AB - BACKGROUND: Alpha-Glutathione S-transferase (alpha-GST) is a liver enzyme which showed properties making it useful in assessment of liver cell damage. A number of studies demonstrated its early elevation in different hepatic insults, but its pattern in HCV was controversial. Consequently, we planned this work to study the significance of Serum Alpha-Glutathione S-Transferase (alpha-GST) assessment in hepatitis C patients with different alanine aminotransferase (ALT) patterns. METHODS: Sixty-five untreated male patients with history of hepatitis C virus (HCV) positive antibodies and 21 healthy age- and sex-matched control subjects were enrolled in this study. Sera were collected for confirmation of the presence of HCV antibodies (by ELISA) as well as for assessment of the levels of alpha GST, ALT, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase, total proteins, albumin and HCV RNA. HCV RNA was detected by the reverse transcription polymerase chain reaction (RT-PCR). Based on ALT level, patients were divided into three groups. Twelve patients with normal ALT levels (NALT), 29 with near normal ALT levels (NNALT), and 24 with high ALT levels (HALT). All data were statistically analyzed for significance and correlation as well as sensitivity, specificity, positive and negative predictive values. RESULTS: The mean value of alpha-GST in HCV patients was significantly higher compared to the control with 82% sensitivity, 85% specificity, 98% positive predictive value and 63% negative predictive value. These results were more or less similar to the results of ALT and higher than the results of all the other assayed liver function tests. The sensitivity, and positive and negative predictive values of alpha-GST were lower than aminotransferases, but higher than the other assayed liver function tests in NNALT and HALT groups. Nevertheless, in NALT, these parameters were higher for alpha-GST than all the other assayed liver function tests including aminotransferases. CONCLUSIONS: Assay of alpha-GST has an adjuvant in evaluation of liver cell damage in HCV patients. However, its role is much more valuable in patients with normal aminotransferases for early detection of liver cell damage. PMID- 27957008 TI - Esophageal Intraepithelial Neutrophil Infiltration is Common in Nigerian Patients With Non-Erosive Reflux Disease. AB - BACKGROUND: Non-erosive reflux disease (NERD) is a variant of gastroesophageal reflux disease (GERD) in which patients with typical reflux symptoms have no evidence of erosive esophagitis at endoscopy. An objective diagnostic tool for NERD remains an unmet need for clinicians and researchers. This study was designed to determine the types of histological alterations seen in Nigerian patients with NERD. METHODS: This was a prospective cross-sectional study in which mucosal biopsy was taken from the lower esophagus in patients with NERD. Similar biopsy was also taken from patients with nonulcer dyspepsia who served as controls. The materials were processed and examined histologically. RESULTS: There were 68 patients with NERD and 60 patients with nonulcer dyspepsia. Intraepithelial neutrophil infiltration was significantly more frequent in patients with NERD compared to those with nonulcer dyspepsia (47.1% vs 13.3%, P = 0.0326). Epithelial proliferative chnges in the form of basal cell hyperplasia and papilla elongation were minimal (11.8% and 3.3% respectively). CONCLUSIONS: Nigerian patients with NERD have a high degree of esophageal intraepithelial neutrophil infiltration and a low prevalence of epithelial proliferative changes. This may be related to the relative rarity of Barrett's esophagus in Nigerians. PMID- 27957009 TI - Role of Alendronate in Managing Osteoporosis in Celiac Disease - Illustrative Case Report. AB - Management of bone density loss, as the result of calcium malabsorption in celiac disease, is critical in preventing premature bone fracture. As many of these patients need follow-up with primary care providers, internists are expected to be aware of screening and prompt management of osteopenia or osteoporosis in celiac disease. We present a case of a 32-year-old man with celiac disease who was diagnosed with osteoporosis. He was treated with calcium, vitamin D and alendronate which improved bone mineral density. This case illustrates the importance of using bisphosphonate in treating osteoporosis in celiac disease. PMID- 27957010 TI - Gastrointestinal Hemorrhage Secondary to Duodenal Cystic Dystrophy in Heterotopic Pancreas. AB - Cystic dystrophy of the duodenal wall (CDDW) is a complication of heterotopic pancreatic tissue located in the wall of the gastrointestinal tract, characterized by the presence of multiple small cysts, usually found in the wall of the second part of the duodenum. Gastrointestinal hemorrhage due to CDDW is a rare complication. We report the case of a 50-year-old man who was admitted to our hospital for persistent vomiting. The imaging tests confirmed the diagnosis of CDDW. During his stay in hospital, the patient had a gastrointestinal hemorrhage secondary to this disorder, which made it necessary to perform a Roux en-Y gastrojejunostomy (Billroth III). PMID- 27957011 TI - Wilson's Disease Presenting as Resistant Rickets. AB - Wilson's disease is most common disorder of cooper metabolism. It has varied clinical presentations. We report a 12 years old female child presenting with genu valgum progressed over 6 months. Careful examination, high index of suspicion and investigations confirmed Wilson's disease. PMID- 27957012 TI - Traumatic Pseudoaneurysm of Superior Rectal Artery - an Unusual Cause of Massive Lower Gastrointestinal Bleed: A Case Report. AB - Traumatic pseudoaneurysm of superior rectal artery is an unusual cause of massive lower gastrointestinal bleed. We are reporting the first case as we could not come across any similar report in the literature. Patient underwent exploratory laparotomy, diversion sigmoid loop colostomy, perineal wound debridement and antiseptic dressing for traumatic perineal wound. Patient had repeated episode of massive lower gastrointestinal bleeding and was diagnosed as a case of bleeding from superior rectal artery pseudoaneurysm which was managed by selective superior rectal artery embolization after failure of surgical treatment. PMID- 27957013 TI - Small Duct Primary Sclerosing Cholangitis in Association With Hepatitis C Virus Infection: A Case Report. AB - Small duct primary sclerosing cholangitis (PSC) is characterized by cholestatic liver function tests, histological evidence of PSC but absence of classic cholangiographic findings. Large duct or classic PSC in association with hepatitis C virus (HCV) infection has rarely been reported. However to the best of our knowledge small duct PSC in association with HCV infection has not been reported. We report this case of small duct PSC in a patient with HCV infection. HCV infection in our patient was successfully treated with ribavirin and peg interferon alfa-2a, as evidenced by undetectable HCV ribonucleic acid levels. However, the patient had persistently elevated liver function tests suggestive of cholestasis. Endoscopic retrograde cholangiopancreatography (ERCP) revealed normal architecture of bile ducts. Hence patient underwent liver biopsy and its histopahological findings were suggestive of PSC. He had colonoscopy along with biopsy and inflammatory bowel disease (IBD) was ruled out. PMID- 27957014 TI - Criteria for Referring Patients With Outpatient Gastroenterological Disease for Specialist Consultation: A Review of the Literature. AB - BACKGROUND: Demands on gastroenterology are growing, as a result of the high prevalence of digestive diseases, the impact of colon cancer screening programs and an aging population. Prioritizing referrals to gastroenterology would assist in managing wait times. Our objectives were (1) to assess whether there were consistent criteria to guide referrals from family physicians for gastroenterological outpatient consultation and (2) to determine if there were different levels of urgency or priority in referral criteria. METHODS: We conducted a scoping review, searching Medline, Embase and Cochrane databases from 1997 to 2009, using the terms referral, triage, consultation and at least one from a list of gastroenterology-specific search terms. Of 2978 initial results, 51 papers were retrieved, and 20 were retained after review by two reviewers. Additional publications were identified through hand searches of retained papers, website searches and nomination by a panel of specialists. RESULTS: Thirty-four papers, reports or websites were retained. No referral criteria covered the spectrum of disorders that might be referred by family physicians to gastroenterologists. Criteria for referral were most commonly listed for suspected colorectal cancer, followed by suspected upper GI cancer, hepatitis, and functional disorders. CONCLUSIONS: A clinical panel comprised of gastroenterologists and primary care providers, informed by this literature review, are completing the work of formulating a Gastroenterology Priority Referral Score, and plan to test the reliability and validity of the tool for determining the relative urgency for referral from primary care to gastroenterology. PMID- 27957015 TI - The Impact of Obesity on Colorectal Surgery: A Survey of Canadian Surgeons. AB - BACKGROUND: Over 1.7 billion adults worldwide are considered overweight or obese, with the prevalence of obesity in Canada increasing rapidly. Obesity has been shown to affect surgical outcomes such as local recurrence of cancer and wound infections following colorectal surgery. The objective of this study was to determine the perception/attitudes of Canadian surgeons toward the impact of obesity on the practice of colorectal surgery. METHODS: A twenty-question survey was administered to Canadian surgeons through mail and email solicited via the Canadian Association of General Surgeons over a period of 2010-2011. The questions focused on surgeon demographics, experience with laparoscopic colon resections and their perception of the impact of obesity toward surgical proficiency and complications. RESULTS: One hundred seventy-seven Canadian surgeons completed the survey. There was a wide range of experience among surgeons in terms of years of practice and number of colon resections performed per year. The majority (72.9%) reported having primary general surgical training. A majority of surgeons (57.7%) identified obesity as a risk factor for colorectal surgery. Furthermore, a majority agreed that obesity is a risk factor for wound infection (97.2%), stomal retraction (90.4%) and stomal herniation (82.5%). While obesity was not considered a contraindication to laparoscopic colon surgery, it was considered to increase operative time (98.3%), cardiovascular (80.2%) and respiratory (95.4%) complications. CONCLUSION: The majority of surgeons across Canada believe obesity is a risk factor for post-operative complications following laparoscopic colorectal surgery. However, the majority did not consider obesity a contraindication for laparoscopic colon resection. Surgical and peri operative colorectal protocols may need to be re-assessed to identify methods to manage the obese patient more effectively. PMID- 27957016 TI - Predictability of Gastric Intestinal Metaplasia by Mottled Patchy Erythema Seen on Endoscopy. AB - BACKGROUND: Intestinal metaplasia (IM) is regarded as a premalignant lesion. However, endoscopic diagnosis of IM has been considered difficult. Using endoscopy, we found a unique pattern of erythema, "Mottled Patchy Erythema (MPE)," which includes severe IM. Helicobacter pylori (Hp) infection itself can cause erythema, which reflects histologic changes in the gastric mucosa. Therefore we enrolled Hp eradication patients to validate the relation between MPE and pathologic findings. METHODS: We enrolled patients with chronic gastritis who underwent successful Hp eradication at least 6 months before the study. We defined MPE as multiple flat or depressed erythematous lesions. When encountering MPE on endoscopy, we performed biopsy on both the MPE site and non-MPE site. The non-MPE site was defined as an adjacent mucosa located within 3 cm of the MPE site. All biopsy specimens were evaluated immunohistochemically for IM subtype using MUC2, MUC5AC, MUC6, CD10, and CDX2 stains. The degree of IM was defined according to the Updated Sydney System. The diagnostic accuracy of the MPE findings for pathologic IM was calculated. The relation between MPE and IM subtype was also assessed. RESULTS: A total of 102 patients were selected for the study. Of these, 55 (54%) patients had MPE. Biopsy specimens were taken from the MPE sites and non-MPE sites from these 55 patients. The IM percentages and median scores of IM were both significantly higher at the MPE sites (P < 0.001) than at the non-MPE sites. The sensitivity and specificity for MPE in the detection of histologic IM were 72.7% and 84.1%, respectively. No significant associations were observed in the expression of MUC2, MUC5AC, MUC6, CD10, and CDX2 between the MPE sites and non-MPE sites. There were no significant differences in the ratios (complete/incomplete) of IM subtypes between the two groups. CONCLUSIONS: MPE is a useful endoscopic finding to detect histologic IM without the use of chromoendoscopy and magnifying endoscopy. However, the IM subtype is difficult to identify. In the era of Hp eradication, MPE has the potential to become a predictive finding for the risk of gastric cancer. PMID- 27957017 TI - Efficacy of Narrow Band Imaging System Combined With Magnifying Endoscopy for Differentiating Type IIa Early Gastric Cancer From Adenoma. AB - BACKGROUND: It is not always possible for endoscopists to differentiate early gastric cancer from adenoma in 0-IIa type neoplasia. The aim of this study was to assess the relationships between images obtained with a narrow band image system combined with magnifying endoscopy (MENBI) and histological findings, especially vascular patterns, to distinguish adenoma from type IIa early gastric cancer (EGC IIa). METHODS: We postoperatively confirmed and evaluated 46 elevated lesions, 32 adenomas and 14 EGC IIa in patients who had undergone endoscopic submucosal dissection. We randomly selected three sites from each neoplasm. The selected sites were classified as four irregular microvascular patterns (IMVPs). In addition, the selected sites were divided into two groups based on the presence of corkscrews. RESULTS: Regarding IMVP subcategories, (1) slight intrastructural irregular microvascular patterns (ISIMVPs) accounted for 84%, (2) severe ISIMVPs accounted for 6%, (3) fine networks (FNs) accounted for 10%, and (4) corkscrews accounted for 0 of cases in the adenomas. The corresponding proportions in the EGC IIa were (1) 24%, (2) 31%, (3) 45%, and (4) 0. Slight ISIMVPs, severe ISIMVPs, and FNs reliably distinguished the two diseases: P < 0.001 for slight ISMVPs; P < 0.001 for severe ISIMVPs; P < 0.001 for FNs. The presence of corkscrews was observed in 9.5% of EGC IIa and 0 of adenoma cases (P = 0.008). CONCLUSIONS: MENBI can be used to differentiate EGC IIa from gastric adenoma based on IMVPs classifications and the presence of corkscrews. PMID- 27957018 TI - Predicting Acute Pancreatitis Severity: Comparison of Prognostic Scores. AB - BACKGROUND: Acute pancreatitis has a broad clinical spectrum, from mild illness to multiple organ failure and death. Prognostic scores have been developed or adapted to predict disease severity. This study aimed to compare the prognostic scores according to sensitivity and specificity, receiver operating characteristic curves and area under the curve. Statistical correlation with disease severity, length of hospital stay, mortality and complication rates. METHODS: Retrospective analysis of the clinical data of patients admitted to an Internal Medicine ward with the diagnosis of acute pancreatitis over a ten year period. Evaluation of prognostic scores: Ranson, Glasgow-Imrie, Balthazar, APACHE II (admission and at 48 hours) and C-reactive protein (48 hours), was carried out as well as statistical analysis using Microsoft Excel 2007(r) and SPSS 16(r). The confidence interval used was 95%. RESULTS: Data from 193 clinical files was collected. However, 67 were excluded due to lack of information. According to the Atlanta criteria, 90 cases were deemed as mild and 36 severe. The mortality rate was 6% and the local complication rate was 9.3%. Ranson, Glasgow and APACHE II scores had significant correlation with mortality. Apart from C-reactive protein levels at 48 hours, all scores had significant correlation with disease severity. The scores with best area under the curve correlation were APACHE II (48 hours): 0.892, Ranson: 0.879, and APACHE II (admission): 0.861. CONCLUSIONS: The most accurate prognostic scores in this study were APACHE II (48 hours) and Ranson. APACHE II at admission was a good indicator, impaired only by high false positive ratio. PMID- 27957019 TI - Usefulness of Pyloromyotomy With Transhiatal Esophagectomy in Improving Gastric Emptying. AB - INTRODUCTION: Pyloromyotomy is a pyloric drainage procedure routinely done during transhiatal esophagectomy (THE) to prevent delayed gastric emptying (GE) resulting from truncal vagotomy. However, controversy still surrounds the need for pyloric drainage following esophageal substitution with gastric conduit after esophagectomy. The aim of this study was to determine the usefulness of pyloromyotomy in improving the postoperative gastric emptying time. METHODS: Forty patients with esophageal cancer underwent THE. 20 patients underwent THE without pyloromyotomy (group A), while the other 20 patients (group B) underwent THE with pyloromyotomy. Using Technetium-99 m, gastric scintigraphy-using gamma camera, was done for all the patients 6 months post-surgery to measure the gastric half emptying time (T50). RESULTS: For the liquid phase, the mean (T50) in the patients without pyloromytomy (group A) was 74.5 +/- 56.71 minutes +/- SD versus 62.85 +/- 59.35 minutes +/- SD in the patients with pyloromytomy (group B) which is not significant (P = 0.529). For the solid phase, the mean (T50) in patients of group A was 139.40 +/- 94.156 minutes +/- SD versus 141.15 +/- 48.423 minutes +/- SD in group B (P value 0.941) which is also not significant. CONCLUSION: Six months after THE, pyloromyotomy done with THE showed no significant value on affecting the mean gastric emptying time compared to those underwent THE without pyloromyotomy. PMID- 27957020 TI - Incarceration and Perforation of a Sliding Hiatus Hernia: Report of a Case. AB - The potentially serious complications of paraoesophageal hiatus hernias are known but its counterpart the sliding hernia, is thought to be more benign in nature. We describe a 72 year old female admitted with epigastric pain after gorging on her Christmas meal, who proved a diagnostic difficulty for both the medical and surgical registrars and was found to have a perforated incarcerated sliding hiatus hernia on CT scan. A transhiatal oesophagectomy was performed as laparotomy findings confirmed a gangrenous perforated stomach and a gangrenous lower oesophagus. She recovered fully from the operation and is well to date. This case provides evidence that sliding hernias can cause serious complications and may be difficult to differentiate from other cardiovascular and abdominal pathologies. A high index of suspicion is required by medical professionals treating chest and epigastric pain. PMID- 27957021 TI - Treatment of Fulminant Autoimmune Hepatitis: Corticosteroid Therapy or Liver Transplantation? A Case Report and Literature Review. AB - Autoimmune hepatitis initially presenting as fulminant hepatic failure is rare in clinical practice. Although corticosteroid is considered as a good therapeutic agent in treating autoimmune hepatitis in the literature, the effect of corticosteroid in treating fulminant autoimmune hepatitis is still controversial. Because corticosteroid therapy for fulminant autoimmune hepatitis can sometimes overlook any future treatment such as delay the timing of liver transplantation and precipitate postoperative complications. We report a case of a 41-year-old female who was admitted to our hosptal because of acute hepatitis with severe jaundice. Type 1 autoimmune hepatitis complicated by fulminant hepatic failure was diagnosed on the basis of her clinical course and laboratory findings. Although we prescribed aggressive medical treatment, plasma transfusion, and plasma exchange therapy, her liver function deteriorated progressively and she developed hepatic coma later. Finally, her fulminant hepatic fuilure gained dramatic improvement after receiving an orthotopic liver transplant from her younger brother. High MELD score and poor treatment response of corticosteroid therapy are indicators of poor prognosis and need of prompt OLT. Moreover, the preoperative interventions should be applied carefully ensuring that they do not delay OLT or precipitate postoperative complications such as infection, bleeding, or poor wound healing. PMID- 27957022 TI - Metastatic Malignant Melanoma of the Small Intestines Diagnosed by Capsule Endoscopy. AB - Malignant melanoma is a fairly common tumor that shows an unusual predilection to metastasize to the small intestines. The time interval between the diagnosis of metastasizing melanoma and the initial diagnosis is variable. This as well as the non specific symptoms and the fact that the small bowel is inaccessible both radiologically and endoscopically lead to delay in diagnosis. We present a case of metastatic malignant melanoma to the small intestines diagnosed several years post excision by capsule endoscopy. Metastatic melanoma in the small bowel should be suspected in any patient with a previous history of malignant melanoma who develops non specific gastrointestinal symptoms. Capsule endoscopy which is non invasive, convenient to the patient and devoid of radiation should form part of their diagnostic investigation. PMID- 27957023 TI - Proton Pump Inhibitors Interfere With Zinc Absorption and Zinc Body Stores. AB - BACKGROUND: Proton pump inhibitors (PPIs) cause a sharp elevation of gastro duodenal luminal pH which in turn has resulted in reports of reduced absorption of magnesium and certain other nutrients. METHODS: Gastroesophageal reflux disease (GERD) patients on long-term PPI therapy (> 6 months) or healthy test subjects (not on any acid preventive or neutralizing medication) were administered oral doses of zinc gluconate (26.2 mg zinc, twice daily) for 14 days followed by 5 cc venous blood samples. Plasma was analyzed for total zinc content by atomic absorption spectrophotometry. Baseline plasma and red blood cell zinc levels were also measured in these two groups when not taking any zinc supplementation. RESULTS: Plasma zinc levels of healthy controls increased by 126% during the period of zinc supplementation compared to only a 37% increase for individuals on long-term PPI therapy. On their normal diet (with no zinc supplementation), PPI-users had a 28% lower plasma zinc level than healthy controls (P < 0.005). CONCLUSIONS: PPI use dramatically reduces supplemental zinc uptake and can result in decreased zinc body stores. Certain individuals on long term PPI therapy, such as infants being treated for colic, may be at risk for decreased systemic levels of trace metals needed for developmental, regenerative and immunological requirements. PMID- 27957025 TI - Day Care Laparoscopic Cholecystectomy: Next Standard of Care for Gall Stone Disease. AB - BACKGROUND: To access the feasibility, safety and success of day care laparoscopic cholecystectomy in a tertiary center in India. METHODS: This is a retrospective analysis of prospectively collected data between 2004 and 2009 from a tertiary center in north India. All patients of symptomatic gallstone diseases having age less than 70 years, American Society of Anesthesiologists (ASA) grade I and grade II, living within 20 Kilometers of the hospital, availability of a responsible adult care taker at home, access to a telephone and a means of transportation to hospital if needed, underwent laparoscopic cholecystectomy under the care of the two participating surgeons, were considered for day care laparoscopic cholecystectomy. Clinical and operative data were recorded prospectively. All patients were discharged 6 to 8 hours after surgery with the advice to contact the surgical team over phone whenever necessary or on the day after discharge. RESULTS: A total of 602 laparoscopic cholecystectomies were performed over a period of 6years, among them 309 (51.32%) were operated on day care basis. Nine patients in day care procedure group had conversion to open procedure (5 due to distorted anatomy of calot's triangle, 2 due to common bile duct stones, 1 due to bile duct injury and 1 due to bleeding from cystic artery stump). One patient had myocardial infarction and 3 had nausea and vomiting which failed to resolve by intravenous ondensteron and all these (13) patients (4.20%) needed unplanned admission to the hospital. Two hundred and ninety-six patients (95.79%) were discharged on same day. CONCLUSIONS: In conclusion day care laparoscopic cholecystectomy is feasible, safe and equally effective in selected patients in Indian setup. PMID- 27957024 TI - Microvessel Density (Chalkley Method) in a Series of 79 Gastrointestinal Stromal Tumors. AB - BACKGROUND: Evaluation of the MVD (modified Chalkley method) in a series of 79 cases of GISTs diagnosed by the Pathology Service at the HCPA (Hospital de Clinicas de Porto Alegre) from January 1993 to December 2009. METHODS: Seventy nine cases of GISTs were submitted to immunohistochemical analysis for CD31, an endothelial marker, to analyze MVD. Hot spots were identified for each case, and the mean numbers of stained blood vessels collected through Chalkley count, with the use of a 25 point grid, placed onto a scanned image. Images were analysed through an image analysis system. We used a cutoff of six vessels. RESULTS: Our series was composed of 42 males and 37 females and presented an average age of 58.9 years. GISTs were predominately located in the stomach (45.6%) followed by the small intestine (38.0%). Sixty seven GISTs (84.8%) showed an average of less than six vessels stained by CD31 (MVD) and 12 (15.2%) GISTs an average of more than six vessels. A statistically significant difference was observed between survival rate of patients having GISTs with MVD of <= 6 vessels (mean = 2.4, CI 95%: 1.67 - 3.17) and patients having GISTs with MVD of >= 6 vessels (mean = 2.4, CI 95%: 1.67 - 3.17), P = 0.001. No association for MVD was observed related to sex, age, histological type, risk category, location and metastasis. CONCLUSIONS: Seventy nine cases of GISTs diagnosed at a single center in South Brazil were studied for MVD (Chalkley method). There was a statistically significant difference between MVD and the survival rate for these patients. The use of Chalkley method in GISTs may be helpful to evaluate clinical outcome. PMID- 27957026 TI - Helicobacter Pylori DNA in Liver Tissues From Chronic Hepatitis C Egyptian Patients. AB - BACKGROUND: Hepatitis C virus (HCV) is considered the most common etiology of chronic liver disease in Egypt, which may progress to cirrhosis and hepatocellular carcinoma (HCC). Previous studies have documented an association between Helicobacter pylori (H. pylori) infection and liver cirrhosis with or without HCC. This study aimed to investigate the presence of H. pylori DNA in the liver tissue of Egyptian patients with chronic hepatitis C (CHC). METHODS: Fifty two CHC Egyptian patients were enrolled in this study. Plasma anti-H. pylori IgG was assessed with ELISA. Liver biopsies were tested for presence of Helicobacter DNA using genus specific nested polymerase chain reaction (PCR) and species was identified by sequencing. RESULTS: Anti-H. pylori IgG was detected in 31/52 (59.6%) CHC patients while Helicobacter DNA was detected in 6 (11.5%) patients, all were H. Pylori by sequencing. Helicobacter DNA was more frequent in patients with high stage liver fibrosis (33.3%) than in those with low stage fibrosis (2.7%) (P = 0.006). There was no association between the presence of H. pylori DNA in the liver and age, gender of patients, liver function tests, AFP levels or viral load. CONCLUSIONS: These data confirm the presence of H. pylori DNA in liver of some CHC Egyptian patients and suggest an association of this bacterium with progression of liver fibrosis. PMID- 27957027 TI - Coeliac Disease in the 21st Century: No Longer "Kids' Stuff". AB - BACKGROUND: We aimed to determine if Coeliac disease (CD) can be still be considered a predominantly paediatric disorder, in spite of the increased incidence of adult-onset CD reported in recent years. METHODS: An observational, descriptive, and retrospective study was developed at two Spanish hospitals. Data was collected and analyzed from all paediatric and adult patients newly diagnosed with CD throughout the year 2010. CD diagnoses were based on a concordant clinical history, serology, HLA-DQ compatibility, the presence of mucosal lesions in duodenal biopsies with gluten dependence of symptoms, and histological lesions. RESULTS: A total of 79 patients were diagnosed with CD throughout 2010, of which 68 (86.1%) were adults. Classic symptoms (diarrhoea and iron-deficiency anaemia) were more frequent in children (90.9%), being present in only 54.4% of adults (p = 0.02). Adult patients showed, mainly, abdominal pain, dyspepsia, and GERD-related symptoms. Villous atrophy (Marsh III) was present in 63.7% of children, but only in 19.1% of adults (p = 0.004). Positive tTGA was present in 81.8% of the children and only in 19.1% of the adults (p = 0.004). Haemoglobin levels were significantly lower in children (p = 0.025), but no differences were observed in iron and ferritin blood levels. CONCLUSIONS: Our study shows that adult-onset CD was the predominant presentation in two hospitals in Spain in the year 2010. Therefore, CD can no longer be considered a predominantly paediatric disorder. Marsh I and negative tTGA titters are characteristic in most of adults. New diagnostic algorithms are needed to improve correct diagnosis of CD in adults. PMID- 27957028 TI - Colonoscopy Leads to A Diagnosis of A Jejunal Gastrointestinal Stromal Tumour (GIST). AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal (GI) tract, but are the least common of small intestinal malignant neoplasms. While GI bleeding is the most common clinical presentation of GISTs, intussusception and obstruction are uncommon, as GISTs rarely grow into the lumen. We describe an unusual case of a 50-year-old male who presented with intermittent obscure, overt GI bleeding requiring multiple hospital admissions and blood transfusions. His work-up included abdominal CT imaging, small bowel follow-through, gastroscopies, push enteroscopy, colonoscopies, and anterograde and retrograde double-balloon enteroscopies. Complicating his presentation were colonic angiodysplasias and the development of recurrent venous thromboembolism requiring anticoagulation. Within an hour after an apparently uncomplicated colonoscopy, he developed an acute abdomen secondary to a jejunal intussusception, which led to a laparoscopic small bowel resection and the diagnosis of a jejunal GIST. Given his GIST had no high-risk features, ongoing surveillance with abdominal CT imaging was arranged. This case illustrates the complex presentation and diagnostic difficulty of a jejunal GIST causing obscure, overt GI bleeding and this is the first reported case of a jejunal intussusception following colonoscopy. Due to its submucosal location, multiple endoscopic approaches had failed to diagnose the GIST prior to surgery. PMID- 27957029 TI - A Male Patient With Systemic Lupus Erythematosus Presenting With Fulminant Hepatitis. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease with unknown etiology. Although liver dysfunction is rare in SLE, 25 - 50% of patients may develop abnormal liver functions. Here, we described a case presented as fulminant hepatitis and diagnosed as SLE. PMID- 27957030 TI - Acute Necrotizing Esophagitis Followed by Duodenal Necrosis. AB - Acute Necrotizing Esophagitis is an uncommon pathology, characterized by endoscopic finding of diffuse black coloration in esophageal mucosa and histological presence of necrosis in patients with upper gastrointestinal bleeding. The first case of acute necrotizing esophagitis followed by duodenal necrosis, in 81 years old woman with a positive history of Type 2 Diabetes Mellitus, Hypertension, and usual intake of Nonsteroidal Anti-inflammatory drugs, is reported. Although its etiology remains unknown, the duodenal necrosis suggests that ischemia could be the main cause given that the branches off the celiac axis provide common blood supply to the distal esophageal and duodenal tissue. The massive gastroesophagic reflux and NSAID intake could be involved. PMID- 27957032 TI - Giant Gastric Antral Ulcer Developing After Short-Term NSAID Administration. AB - A 61-year-old man took loxoprofen sodium hydrate, a prodrug NSAID, for acute upper respiratory infection for 5 days, developed melena 2 days later, and was admitted to our hospital. Upper gastrointestinal endoscopy revealed a giant and deeply undermined ulcer mainly in the greater curvature of the antrum, which occupied halfway around the lumen. His medical history was unremarkable. He was negative for Helicobacter pylori infection, and was diagnosed with NSAID-induced acute gastric ulcer in the absence of other causes of gastric ulcer. Giant gastric ulcers, as in this patient, are rare. Moreover, deeply undermined or huge gastric ulcers sometimes develop during the long-term administration of NSAIDs, but very rarely after their short-term administration, which prompted us to report this case. PMID- 27957031 TI - Giant Diverticulum of the Duodenum. AB - A 50-year old female presented herself with abdominal bloating and pain in the Emergengy Department. The symptoms persisted and a clinical evaluation was made. A lesion suspect for a giant duodenal diverticulum was seen on the CT-scan, which was confirmed by enteroclysis. Surgical resection was performed. The diagnosis was histological confirmed after surgery. Small bowel diverticula are relatively common, with an estimated 5 - 22% incidence in the healthy population. They are usually asymptomatic, but can present with abdominal pain and weight loss. Complications such as bleeding and perforation can occur. Surgical resection is the treatment of choice in symptomatic patients. PMID- 27957033 TI - Two-Year Follow-up in Atrial Fibrillation Patients Referred for Catheter Ablation of the Atrioventricular Node. AB - INTRODUCTION: At the present time there is still concern regarding the long-term deleterious effects of right ventricular apical pacing in patients referred for auriculoventricular node ablation (AVNA). Furthermore, scarce information is available regarding differences in the follow up according to the baseline cardiopathy and predictors associated with a worse outcome. METHODS: 104 consecutives patients referred for AVNA were retrospectively analyzed. Patients included were seen in the outpatient clinic at 6, 12 and 24 months post ablation (mean follow-up 24 +/- 2 months). An echocardiogram two years after the procedure was obtained in 68 patients. Three categories were done according to the change in the left ventricular function (LVEF) (increase, decrease or absence of change, defined as less than 10% variation in either LVEF). RESULTS: After two years of follow up there was a decrease in the rate of hospital admission (from 0.9 admission/year to 0.35, p<0.001), an increase in the functional status in at least one NYHA class in 58 patients, and an increase in the global LVEF (from 48.9% to 54,1%; p<0.001). Valvular replacement and LVEF less than 50% were independently associated with a decrease in the LVEF. Regarding safety issues, one patient who presented a polymorphic ventricular tachycardia (Torsade de pointes) 60 minutes after the ablation. CONCLUSIONS: AVNA results in a decrease in hospital admission rates and an improvement in functional status. Baseline LVEF < 50% and mitral valvulopathy were multivariate predictor of LVEF decline, hence, it is our belief that, in this particular population, the "ablate and pace" strategy is not the most suitable option, and or maybe a biventricular pacemaker should be implanted or an AF ablation reconsidered." Finally, although it is a safe procedure and rate of complications were low, there is a potential risk of fatal complications. PMID- 27957034 TI - The Effects of Ranolazine on Paroxysmal Atrial Fibrillation in Patients with Coronary Artery Disease: A Preliminary Observational Study. AB - The impact of ranolazine, an anti-ishemic agent with antiarrhythmic properties, on paroxysmal atrial fibrillation (PAF) in patients with coronary artery disease (CAD) remains unclear. Pacing devices can be useful tools for disclosing even asymptomatic PAF. Purpose of this study is to assess the effect of ranolazine on atrial fibrillation (AF), in patients with CAD, PAF and a dual-chamber pacemaker. We studied 74 patients with CAD, PAF, and sick sinus syndrome or atrio ventricular block, treated with pacemakers capable to detect PAF episodes. The total time in AF, AF burden, and the number of PAF episodes within the last 6 months before enrolment in the study, mean AF duration per episode, and the QTc interval were initially assessed. Subsequently, patients were randomized into additional treatment with ranolazine (375 mg twice daily) or placebo. Following six months of treatment, all parameters were reassessed and compared to those before treatment. Ranolazine was associated with shorter total AF duration (81.56+/-45.24 hours versus 68.71+/-34.84 hours, p=0.002), decreased AF burden (1.89+/-1.05% versus 1.59+/-0.81%, p=0.002), and shortened mean AF duration (1.15+/-0.41 hours versus 0.92+/-0.35 hours, p=0.01). In the placebo group no such differences were observed. In both groups, no significant differences in the number of PAF episodes and QTc duration were observed. We conclude that in patients with CAD and PAF, ranolazine reduces the total time in AF, AF burden, and mean AF duration. These findings may imply additional antiarrhythmic properties of ranolazine on atrial myocardium and might indicate the necessity of its use in ischemic patients with PAF. PMID- 27957036 TI - The Safetyof Dabigatran Versus Warfarin in Patients Undergoing Atrial Fibrillation Ablation. AB - The safety and optimal strategy of the use of dabigatran versus uninterrupted warfarin in atrial fibrillation ablation is currently unclear. We performed a retrospective analysis between July 2011-October 2012 of all patients undergoing an AF ablation who received uninterrupted warfarin therapy (199) and the routine cessation of Dabigatran therapy (126) 4 days pre-ablation. Major safety endpoints included: pericardial effusion (requiring pericardiocentesis), peripheral thromboembolism, CVA, and groin hematoma requiring blood transfusion. Minor endpoints included pericardial effusion and groin hematoma. Dabigatran was restarted the following day after ablation. The warfarin group was older, had a higher CHADS2, CHA2DS2VASc and HASBLED scores and greater prevalence of aortic plaque. The major complication rate was 2.0% in the warfarin group and 2.4% in the dabigatran group (P= 0.83). The minor complication rate was 2.5% in the warfarin group and <1% in the dabigatran group (P= 0.27). In the dabigatran group, there was one renal thromboembolic event 4 days post-ablation. All patients in the warfarin group who suffered a major complication required a blood transfusion. Cessation of dabigatran therapy 4 days pre AF ablation has a comparable safety profile to uninterrupted warfarin therapy. PMID- 27957037 TI - Hyperuricemia and Risk of Atrial Fibrillation. AB - The association between SUA levels and AF is currently poorly known. We reviewed the literature on the association with AF and hyperuricemia.The association between SUA level and AF has been demonstrated. SUA levels are associated with an increased risk for future AF in both sexes. And elevated SUA levels strongly correlate with an increased incidence of AF in patients with type 2 diabetes mellitus. Moreover, hyperuricemia was in connection with endothelial dysfunction, oxidative stress, systemic inflammatory markers, insulin resistance and LA size. PMID- 27957035 TI - Atrial Fibrillation and Its Association with Endocrine Disorders. AB - Atrial Fibrillation (AF) is the most common arrhythmia affecting millions of people and the number is rising, it is therefore important to understand the risk factors causing AF. Risk factors such as hypertension, heart failure, coronary heart disease, and type 2 diabetes mellitus increase the risk of AF, however, the underlying etiology in a majority of patients remains elusive. Many of the endocrine disorders have been implicated in causing AF and an in depth knowledge of these disorders helps in early diagnosis and treatment. Due to the high prevalence of AF and its complications, it is therefore important to recognize these risk factors and have a low threshold for suspicion while other common causes are being excluded. In this review we summarize the issues related to AF and endocrine disorders. A better understanding of the relationship may lead to the development of the primary preventive strategies, fostering a more preventive and predictive approach that may result in decreased incidence of AF and its associated complications and provide personalized treatment options. For this review we carried out a search of Pubmed, the words or combination of words we used for our search include Endocrine disorders, metabolic disorders, Dyslipidemia, Diabetes mellitus type 2, Vitamin D, Hyperthyroidism, Primary aldosteronism, Pheochromocytoma, Obesity, Hypercalcemia, Hypogonadism, Medications, and Atrial fibrillation. We also retrieved articles from the references of retrieved articles. PMID- 27957039 TI - Atrial Fibrillation Ablation by the Epicardial Approach. AB - Catheter ablation is an effective treatment for atrial fibrillation (AF). However, over long-term follow-up, it is becoming clear that AF often recurs and repeat ablation is required. With the goal of improving efficacy, particularly in those patients with risk factors for poor outcomes using a standard endocardial ablation technique, surgical epicardial ablation has emerged as an alternative methodology. Since its advent in the 1980s, surgical ablation techniques have continued to evolve. New ablation tools make a minimally invasive surgical approach possible. And most recently, we have seen the development of a hybrid (epicardial and endocardial) approach to AF ablation, which can draw upon the advantages of both options. PMID- 27957038 TI - Cytochrome P450-2D6 Genotype Definition May Improve Therapy for Paroxysmal Atrial Fibrillation A Case of Syncope Following "Pill-in-the-Pocket" Quinidine plus Propafenone. AB - Classes 1A, 1C and III anti-arrhythmics may be ineffective or induce adverse events including potentially fatal arrhythmias when administered in recommended doses. Serum levels of these medications vary widely during conventional dosing due in large part to variations in cytochrome P450-2D6 isoenzyme activity which metabolizes most antiarrhythmics in addition to over 25% of other commonly prescribed medications. 2D6 activity is also profoundly inhibited by some antiarrhythmics and other commonly used medications and varies widely between the individuals of all populations, a pattern which has resulted in separation of subjects into 4 phenotypes and genotypes consisting of poor metabolizers (PM), intermediate metabolizers (IM), efficient metabolizers (EM), and ultra-rapid metabolizers (UM). Patients with a phenotype PM classification almost universally are also genotype PM due to the possession of two inactive 2D6 alleles, with this PM pattern often inducing supratherapeutic and toxic antiarrhythmic blood levels during conventional antiarrhythmic therapy. UM individuals have supranormal levels of 2D6 activity often created by the presence of 3 or more active alleles which often induce subtherapeutic and ineffective drug levels during antiarrhythmic administration in conventional doses. We searched for evidence relating Cytochrome P450-2D6 phenotypes or genotypes to antiarrhythmic metabolism in order to judge whether this analysis might contribute to improved safety and effectiveness of antiarrhythmic medications commonly utilized in the treatment of atrial fibrillation. The available evidence strongly supported these possibilities. We also describe a patient in whom knowledge of his IM/PM CYP2D6 genotype might have prevented the only episode of syncope and myocardial stunning which developed during his 28 years of "Pill-in-a-Pocket" therapy. PMID- 27957041 TI - Sustained Dissociated Irregular Tachycardia in Two Pulmonary Veins After Radiofrequency Ablation of Atrial Fibrillation. AB - A 64-year-old woman underwent radiofrequency ablation of atrial fibrillation. After pulmonary vein (PV) isolation, she converted into sinus rhythm. However, irregular PV tachycardia "trapped" in the right and left superior pulmonary vein (RSPV/LSPV) sustained. Fifteen minutes after RSPV isolation, the RSPV tachycardia terminated. However, sustained LSPV tachycardia was still present after one hour. Three months later, a relapse of AF was confirmed and the patient underwent re ablation. Re-conductance was observed in the RSPV and LSPV. PMID- 27957040 TI - The Role of Renal Sympathetic Denervation in Atrial Fibrillation. AB - Endocardial catheter ablation is a widely used alternative for the treatment of atrial fibrillation (AF). Despite technical improvements, and increased understanding of mechanism, and acquired technical experience over many years, the results are not yet optimal. This results in an ongoing search for new therapeutic approaches. Because cardiac sympathetic drive is potentially responsible for triggering and sustaining AF, modulation of sympathetic tone has been proposed as a viable treatment objective. The early attempts to test this concept were limited by nature=highly intrusive techniques but new approaches and targets have been recently introduced. Specifically, renal nerve ablation has been introduced and the first attempts to employ this technique for treatment of cardiac arrhythmias give as a promise of new therapeutic avenues in near future. This review focuses on the possible role of renal denervation in treatment of atrial fibrillation, the contemporary evidence supporting this approach, and the ongoing trials to establish its therapeutic role. PMID- 27957042 TI - Exploring The Obesity Paradox In Atrial Fibrillation. AFBAR (Atrial Fibrillation Barbanza Area) Registry Results. AB - INTRODUCTION AND OBJECTIVES: Previous studies have described an inverse relationship between obesity and adverse events in a variety of conditions. Our aim was to investigate the relationship between obesity and prognosis in patients with atrial fibrillation. METHODS: We studied 746 patients who were prospectively included, between January and April 2008, in the AFBAR (Atrial Fibrillation in BARbanza area) registry. Patients were categorized into 3 body mass index groups using baseline measurements: normal (< 25 kg/m2), overweight (25-30 kg/m2), and obese (>=30 kg/m2). Survival free from the composite endpoint hospitalization for cardiovascular causes or all-cause mortality was compared across the 3 body mass index groups. A multivariable Cox proportional hazard regression was also performed to determine the independent effect of obesity as well as overweight, with respect to normal body mass index as a reference category, regarding the study endpoint. Median follow-up time was 36 (28-36) months. RESULTS: 49.3% were obese and 38.2% had overweight. The composite endpoint rate was 70.9%, 67.5%, and 57.6% for obese, overweight, and normal weight patients, respectively (log rank test; p=0.02). An inverse association of obesity with a favorable prognosis persisted even after multivariable adjustment: hazard ratio 0.668; 95% confidence interval 0.449-0.995; p=0.047. Hazard ratio of overweight, however, was 0.741; 95% confidence interval: 0.500-1.098; p=0.096. CONCLUSIONS: Obesity, defined as a body mass index >= 30 kg/m2, is associated with better prognosis in a community based cohort of patients with atrial fibrillation. PMID- 27957043 TI - Silent Cerebral Events after Atrial Fibrillation Ablation - Overview and Current Data. AB - Silent cerebral lesions (SCL) have been identified on brain magnetic resonance imaging (MRI) in apparently asymptomatic patients after cardiovascular procedures. After atrial fibrillation (AF) ablation incidences range from 1 to over 40% depending upon different factors. MRI definition should include diffusion weighted imaging (DWI) to detect hyperintensities (bright spots) due to acute brain ischemia correlated with a hypointensity in the apparent diffusion coefficient mapping (ADC-map) to rule out artifacts. The genesis of SCL appears to be multifactorial and appears to be a result of embolic events either from gaseous or solid particles. The MRI pattern appears to be comparable not hinting towards a specific mechanism. One may distinguish two different MRI definition: one, more sensitive, for silent ischemic events (SCE) not proven to be related to cell death (DWI positive but FLAIR negative); and one for SCL that are due to edema caused by cell death which will lead to glial cell scar formation (DWI positive and FLAIR positive). For ease of data interpretation, future studies should ensure both definitions, and that DWI and FLAIR data is acquired using identical slice thickness and orientation. Risk factors associated with increased SCL-incidences involve patient-specific, technology-associated and procedural determinants. When using a high-sensitive MRI definition differences in SCE-rates in between technologies appear to be less prominent. Further studies on the effects of different periprocedural anticoagulation regimen, different steps of the ablation procedure and new technologies are needed. For now, SCL incidence may determine the thrombogenic potential of an ablation technology and further studies to reduce or avoid SCL generation are desirable. It appears reasonable, that any SCE should be avoided. PMID- 27957044 TI - Stroke Risk Predictor Scoring Systems in Atrial Fibrillation. AB - An effective risk stratification which could help us identify high-risk patients who should take oral anticoagulants (OACs) is the key step for stroke prevention in atrial fibrillation (SPAF). Several scoring systems were available to estimate the risk of stroke in AF, including CHADS2, CHA2DS2-VASc, R2CHADS2 and ATRIA scores, which were constituted of different clinical risk factors. Recently, several new OACs (NOACs) were demonstrated to be at least as effective as warfarin in stroke prevention and were much safer regarding the risk of intra cranial hemorrhage. In the era of NOACs, the roles of scoring schemes have shifted to identify patients with a truly low-risk of thromboembolic events, in whom OACs were not recommended. The CHA2DS2-VASc score is powerful in selecting "truly low-risk" patients who do not require anticoagulation. Whether the new emerging scoring systems, R2CHADS2 and ATRIA scores, could further improve the stroke prediction in AF deserves a further study. ("SPAF", the same as the initials of a series of studies about aspirin, warfarin and stroke prevention in AF, was used as the abbreviation for "stroke prevention in atrial fibrillation" in this review article.). PMID- 27957045 TI - Post-Procedural Dabigatran Versus Interrupted Warfarin Therapy Following Catheter Ablation for Atrial Fibrillation. AB - PURPOSE: Patients undergoing catheter ablation for atrial fibrillation (AF) are at a higher risk of thromboembolic events post-procedure and therefore require therapeutic anticoagulation after ablation. Anticoagulation strategies include performing the procedure on or off therapeutic warfarin, though the latter approach requires post-procedure bridging therapy with low molecular-weight heparin (LMWH) until a therapeutic INR is achieved. The purpose of this study is to compare the safety and efficacy of post-ablation dabigatran as compared to warfarin with LMWH bridging. METHODS: We performed a single-center retrospective analysis of consecutive patients who underwent catheter ablation for AF between January 2010 and December 2012 and received either post-procedure warfarin with a LMWH bridge or dabigatran. Warfarin was started the night of ablation; LMWH was started the next morning and continued until the INR was >= 2.0. Dabigatran was started the morning post-ablation. RESULTS: The analysis included 324 patients. Of these, mean age was 60 +/- 9 years, 78% were male, 81% had CHADS2 scores of 0 or 1, and 181 (56%) received dabigatran post-ablation. Patients who received dabigatran had lower CHADS2 scores and were more likely to be in NYHA Class I. At 30-days post-procedure, there were 0 thromboembolic or bleeding complications in the dabigatran group versus 4 (2.8%) in the warfarin group (p=0.037). There were no deaths in either group at 30 days post-ablation. CONCLUSIONS: Post-ablation dabigatran appears safe and efficacious compared to an interrupted warfarin strategy with LMWH bridging. PMID- 27957046 TI - Efficacy And Safety of Dabigatran Etexilate Utilization With Concomitant Dual Antiplatelet Therapy In Atrial Fibrillation. AB - The necessity to add two antiplatelet agents to an oral anticoagulant (OAC) often arises in patients with atrial fibrillation (AF) in routine clinical practice. The majority of AF patients have an indication for continuous OAC, and coronary artery disease co-exists in 25% of these patients. The increasing use of drug eluting stents to minimize intrastent restenosis necessitates long-term dual antiplatelet therapy with Aspirin plus Clopidogrel to reduce the risk of early and late stent thrombosis. Combined aspirin-clopidogrel therapy, however, is less effective in preventing stroke compared with OAC alone in AF patients, and OAC alone is insufficient to prevent stent thrombosis. The management of AF patients presenting with an acute coronary syndrome poses similar management complexities. Since AF and coronary artery disease with stent placement are common, it is relatively frequent to treat patients with both these conditions, where triple antithrombotic therapy with Aspirin, Clopidogrel and an OAC would be needed. Dabigatran etexilate, an oral direct thrombin inhibitor, has shown that compared with Warfarin given at a dose of 150 mg twice daily significantly reduces stroke with less intracranial bleeding, and at a dose of 110 mg twice daily has similar efficacy with less bleeding. Although, Dabigatran maintained its overall favorable profile compared with Warfarin in patients on dual antiplatelet therapy, we should always bear in mind for the sake of our AF patients that combining dual antiplatelet therapy with chronic anticoagulation with Dabigatran, as well as with Warfarin, significantly increases bleeding risk. This triple therapy association should be evaluated in the individual patient after carefully balancing bleeding versus thrombotic risk. PMID- 27957047 TI - Atrial Fibrillation in Athletes: The Role of Exercise. AB - There is growing evidence that atrial fibrillation (AF) is prevalent in athletes and even in individuals participating in intense long term exercise at a non competitive level. Several causes have been described for these phenomena including atrial remodeling, atrial fibrosis, inflammation, autonomic activation, body fluid changes and changes in blood volume and pressure. This article reviews the epidemiology, pathophysiological mechanisms and management options of AF in regards to exercise. PMID- 27957048 TI - Acute Atrial Fibrillation as an Unusual Form of Cardiotoxicity in Chronic Lithium Overdose. AB - Lithium overdose primarily results in neurologic toxicity; however a number of important cardiac side effects have previously been reported, including nonspecific T-wave changes, ST-segment changes, QTc prolongation, sinus node dysfunction, atrioventricular blocks and ventricular dysrhythmias. Atrial fibrillation due to such toxicity is very uncommon. The current paper describes a patient who developed acute atrial fibrillation due to chronic lithium overdose. PMID- 27957049 TI - Predictors of Atrial Fibrillation Recurrence after Catheter Ablation. AB - Atrial fibrillation (AF) catheter ablation is a well-known treatment option for patients with drug refractory AF. The increasing number of electrophysiology laboratories able to perform this procedure will create in the next years an economic issue, which each cardiac electrophysiologist will have to face with. Identification of predictors of recurrence of AF after catheter ablation is therefore of primary importance to reduce health costs and improve long-term results of this intervention. The aim of this review is to give a brief overview on what have been published already in the literature on the topic and henceforth to increase the awareness of cardiac electrophysiophysiologists on the importance of selection of the right candidates to this intervention. PMID- 27957050 TI - The New Novel Oral Anticoagulants (NOACs) In Patients With Atrial Fibrillation: Dogma, Dilemmas, And Decisions On Dosing. PMID- 27957051 TI - Frequent Atrial Fibrillation in CYP2D6 Deficiency. PMID- 27957052 TI - Exploring New Frontiers. PMID- 27957053 TI - CETP TaqIB Polymorphism, Serum Lipid Levels And Risk Of Atrial Fibrillation: A Case-Control Study. AB - The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from high-density lipoproteins (HDL) to triglyceride (TG)-rich lipoproteins. A consistent number of investigations has suggested an association between the TaqIB polymorphism of the CETP gene, plasma HDL-C levels and the risk of cardiovascular disease, but the results are controversial. The aim of this study was to determine if the TaqIB polymorphism might be related to the presence of atrial fibrillation (AF). We conducted a case-control study, enrolling 109 Caucasian unrelated patients coming from Salento (Southern Italy) with documented AF and 109 controls selected from the same ward. The CETP TaqIB genotypes were determined by RFLP-PCR. The subjects with the B2B2 genotype seem to be more susceptible to AF development (OR=2.28, 95% CI 1.06-4.89, p=0.032). The AF incidence is higher if we consider only the female subgroup (OR=5.14, 95% CI 1.57 16.82, p=0.0061). In the AF female subgroup the B2B2 patients had a statistically significant decrease of HDL-C levels (1.50 +/- 0.35 vs 2.07 +/- 0.42; p=0.012) and statistically higher TG levels (1.34 +/- 0.46 vs 0.77 +/- 0.14; p=0.027) and TG/HDL-C ratio (2.14 +/- 0.80 vs 0.88 +/- 0.23; p=0.007) when compared to B2B2 female control subjects. When we analyzed the linkage between the TaqIB polymorphism and the promoter variant (-629C/A), we found that 100% of the B2 alleles of the TaqIB polymorphism were associated with the A alleles of the -629 promoter polymorphism in our subjects. This study suggests that in post menopausal women atrial fibrillation could be promoted by the association of CETP B2B2/AA genotype with higher triglycerides values. PMID- 27957055 TI - Management of Atrial Fibrillation in Patients With Kidney Disease. AB - The increasing burden of Chronic Kidney Disease (CKD) is highly relevant to cardiologists, as cardiovascular mortality is 10-30 times higher amongst people with End-stage Renal Disease (ESRD), comparing with general population. One of the commonest associations is the increased frequency of atrial fibrillation (AF) amongst those experiencing CKD. Overall, we know that AF is the most common cardiac arrhythmia. AF leads to a substantial risk of mortality and morbidity, from stroke and thromboembolism, heart failure, reduced cognitive function and impaired quality of life. However, most clinical trials in AF (for example, for stroke prevention in AF with anticoagulation therapy) have largely excluded patients with significant renal impairment. In this review article, we will focus on stroke prevention in AF, and the clinical impact of CKD and its implications for management. PMID- 27957056 TI - Ventricular Rate Stabilization In Patients With Permanent Atrial Fibrillation And Single-Chamber Ventricular Pacemaker: RARE-PEARL Study. AB - Background: In patients with permanent atrial fibrillation (AF) rate irregularity can cause symptoms and impair the pumping function of the heart. Ventricular pacing at a rate close to the mean spontaneous ventricular rate can result in a more stable ventricular rate. Specific algorithms for automatic Ventricular Rate Stabilization (VRS) were designed and implemented in commercially available pacemakers. To assess this dynamic rate control we designed the RARE-PEARL study: prospective, randomized, cross-over, double-blinded. Methods: Patients with permanent AF, symptomatic episodes of brady-tachycardia, left ventricular ejection fraction (LVEF) >40%, NYHA class I/II/III, were eligible for enrolment. Each patient (n = 67) was implanted with a single-chamber VVIR pacemaker (models C20 or T20, Vitatron BV, The Netherlands) equipped with the VRS algorithm. At the end of a four week stabilization period, patients were randomized to VRS algorithm ON or OFF (2 months) and then crossed-over for the second phase (2 months). Primary endpoint was patient's preference. Results: Sixty six patients ended the study: 19 (29%) had no preference; 15 (23%) preferred algorithm OFF, 32 (48%) algorithm ON (p<0.0001, algorithm ON vs OFF). In 58% of patients the algorithm ON caused an increase of ventricular pacing percentage > 10%. The ventricular pacing percentage was 82+/-10% with algorithm ON vs 59+/-26% with algorithm OFF (p<0.0001). Symptoms did not differ significantly. Conclusions: The VRS algorithm significantly increases the ventricular pacing percentage in patients with permanent AF. This pacing function is preferred by the majority of patients implanted with a single-chamber VVIR pacemaker. PMID- 27957054 TI - The Role Of Renin Angiotensin System In Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most prevalent arrhythmia and its incidence is on the rise. AF causes significant morbidity and mortality leading to rising AF related health care costs. There is experimental and clinical evidence from animal and human studies that suggests a role for the renin angiotensin system (RAS) in the etiopathogenesis of AF. This review appraises the current understanding of RAS antagonism, using angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB) and aldosterone antagonists (AA), for prevention of AF. RAS antagonism has proven to be effective for primary and secondary prevention of AF in subjects with heart failure and left ventricular (LV) dysfunction.However, most of the evidence for the protective effect of RAS antagonism is from clinical trials that had AF as a secondary outcome or from unspecified post-hoc analyses. The evidence for prevention in subjects without heart failure and with normal LV function is not as clear. RAS antagonism, in the absence of concomitant antiarrhythmic therapy, was not shown to reduce post cardioversion AF recurrences. RAS antagonism in subjects undergoing catheter ablation has also been ineffective in preventing AF recurrences. PMID- 27957057 TI - Diastolic Function in Normal Sinus Rhythm vs. Chronic Atrial Fibrillation: Comparison by Fractionation of E-wave Deceleration Time into Stiffness and Relaxation Components. AB - Although the electrophysiologic derangement responsible for atrial fibrillation (AF) has been elucidated, how AF remodels the ventricular chamber and affects diastolic function (DF) has not been fully characterized. The previously validated Parametrized Diastolic Filling (PDF) formalism models suction-initiated filling kinematically and generates error-minimized fits to E-wave contours using unique load (xo), relaxation (c), and stiffness (k) parameters. It predicts that E-wave deceleration time (DT) is a function of both stiffness and relaxation. Ascribing DTs to stiffness and DTr to relaxation such that DT=DTs+DTr is legitimate because of causality and their predicted and observed high correlation (r=0.82 and r=0.94) with simultaneous (diastatic) chamber stiffness (dP/dV) and isovolumic relaxation (tau), respectively. We analyzed simultaneous echocardiography-cardiac catheterization data and compared 16 age matched, chronic AF subjects to 16, normal sinus rhythm (NSR) subjects (650 beats). All subjects had diastatic intervals. Conventional DF parameters (DT, AT, Epeak, Edur, E-VTI, E/E') and E-wave derived PDF parameters (c, k, DTs, DTr) were compared. Total DT and DTs, DTr in AF were shorter than in NSR (p<0.005), chamber stiffness, (k) in AF was higher than in NSR (p<0.001). For NSR, 75% of DT was due to stiffness and 25% was due to relaxation whereas for AF 81% of DT was due to stiffness and 19% was due to relaxation (p<0.005). We conclude that compared to NSR, increased chamber stiffness is one measurable consequence of chamber remodeling in chronic, rate controlled AF. A larger fraction of E-wave DT in AF is due to stiffness compared to NSR. By trending individual subjects, this method can elucidate and characterize the beneficial or adverse long-term effects on chamber remodeling due to alternative therapies in terms of chamber stiffness and relaxation. PMID- 27957058 TI - Atrial Calpains: Mediators of Atrialmyopathies in Atrial Fibrillation. AB - Atrial fibrillation (AF) is associated with substantial structural changes at cell and tissue level. Cellular hypertrophy, disintegration of sarcomeres, mitochondrial swelling and apoptosis have been described as typical histo morphologic alterations in AF. Main initiators for cellular alterations in fibrillating atrial myocytes are cytosolic calcium overload and oxidative stress. Calpains are intracellular Ca2+- activated proteases and important mediators of calcium overload. Activation of calpains and down-regulation of the calpain inhibitor, calpastatin, contribute to myocardial damage in fibrillating atria. Thus, deregulations of the expression, activity, or subcellular localization of calpain within atrial myocytes have been established as important mediators of atrial myopathy during AF. PMID- 27957059 TI - Sex Differences In Outcomes Of Ablation Of Atrial Fibrillation. AB - Sex-related differences in the presentation, treatment, and outcomes of cardiovascular disease have been reported in many areas of cardiovascular medicine, including the clinical course and treatment of atrial fibrillation (AF). Women appear to be more symptomatic, have a lower quality of life, and are less tolerant of antiarrhythmic drugs than men. However, the rate of referral of women for catheter ablation of AF is significantly lower than men, and women are referred much later after failing more antiarrhythmic drugs. There is a trend toward a lower success rate and a higher failure rate for catheter-based AF ablation in women. This finding may be related to the later referral of women for the procedure, resulting in high risk features such as more severe hypertension, greater left atrial size, and more persistent AF at the time of the procedure, all of which are associated with future recurrences. The complication rate from AF ablation is significantly higher in women, particularly with respect to bleeding and vascular complications such as hematomas and pseudoaneurysms. Individualized care including earlier referrals, pre-procedural case planning, and close monitoring intra- and post procedure may improve the outcomes for women with catheter ablation of AF. PMID- 27957060 TI - Atrial Fibrillation In Heart Failure: New Directions In Diagnosis, Risk Assessment And Risk Reduction. AB - Heart failure and atrial fibrillation are common conditions which frequently co exist. In patients with established systolic and diastolic dysfunction, atrial fibrillation increases the risk of stroke, mortality and reduces quality of life. Recent advances in implantable device technology have improved the detection of atrial fibrillation and reduced the time to intervention. Rate control remains the mainstay of treatment to improve symptoms in patients with heart failure. Currently evidence does not suggest that the routing use of a rhythm control strategy is beneficial, other than improving symptoms in patients resistant to or intolerant of rate control medications. Atrial fibrillation ablation in heart failure is safe and may be effective in maintaining sinus rhythm. Patients with AF and heart failure have more severe strokes and require longer hospital admissions. Warfarin has traditionally been the drug of choice to reduce the risk of stroke in patients with AF and heart failure, although it use is no longer recommended in patients with heart failure and sinus rhythm. Newer oral anticoagulants offer improved stroke prevention in patients with heart failure albeit at a higher drug cost. Alternative methods of stroke reduction such as left atrial appendage occlusion are emerging, although evidence for their benefit in patients with heart failure has not yet been published. PMID- 27957061 TI - How To Achieve Durable Pulmonary Vein Antral Isolation? AB - The inability to achieve durable pulmonary vein isolation(PVI) remains a major limitation to a catheter ablation for thew treatment of atrial fibrillation(AF), potentially resulting in AF recurrence.In this review,we discuss the research performed investigating methods to improve lesion permanence for the goal of durable PVI.Investigations evaluted procedural techniques,various catheres utilized, adjunctive pharamacologic therapy and novel energy sources designed to improve ablation lesion permanence are discussed. PMID- 27957064 TI - A Case Of Difficult Epicardial Access For Ablation Of Ventricular Tachcyardia. AB - We present a case of a 67-year-old patient with nonischemic cardiomyopathy and recurrent sustained ventricular tachycardia of epicardial origin referred for ablation. Due to two previous episodes of cardiac tamponade secondary to implantable cardioverter-defibrillator lead perforation at the time of device implant, the patient had significant pericardial adhesions making epicardial access and ablation challenging. PMID- 27957062 TI - Monitoring Atrial Fibrillation After Catheter Ablation. AB - Although catheter ablation is an effective treatment for recurrent atrial fibrillation (AF), there is no consensus on the definition of success or follow up strategies. Symptoms are the major motivation for undergoing catheter ablation in patients with AF, however it is well known that reliance on perception of AF by patients after AF ablation results in an underestimation of recurrence of the arrhythmia. Because symptoms of AF occurrence may be misleading, a reliable assessment of rhythm outcome is essential for the definition of success in both clinical care and research trials. Continuous rhythm monitoring over long periods of time is superior to intermittent recording using external monitors to detect the presence of AF episodes and to quantify the AF burden. Today, new devices implanted subcutaneously using a minimally invasive technique have been developed for continuous AF monitoring. Implantable devices keep detailed information about arrhythmia recurrences and might allow identification of very brief episodes of AF, the significance of which is still uncertain. In particular, it is not known whether there is any critical value of daily AF burden that has a prognostic significance. This issue remains an area of active discussion, debate and investigation. Further investigation is required to determine if continuous AF monitoring with implantable devices is effective in reducing stroke risk and facilitating maintenance of sinus rhythm after AF ablation. PMID- 27957063 TI - Stroke And Bleeding Risk Assessment: Where Are We Now? AB - Atrial fibrillation (AF) is one of major problems of the contemporary cardiology. Ischaemic stroke is a common complication of the AF, and effective prophylaxis requires treatment with oral anticoagulants. The purpose of this current review article is to provide an overview of the various stroke and bleeding risk assessment scores that help decision making with respect to thromboprophylaxis. Particular focus is made on the currently guideline-recommended stroke and bleeding risk scores, such as CHA2DS2-VASc (congestive heart failure or left ventricular dysfunction, hypertension, age >=75, diabetes, stroke, vascular disease, age 65-74 and sex category [female]) and HAS-BLED (uncontrolled hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly [e.g. age >65, frail condition], drugs [e.g. aspirin, nonsteroidal anti-inflammatory drugs]/excessive alcohol) is made. Future directions for improvement of predictive ability of risk assessment with clinical factors and biomarkers are also discussed. PMID- 27957065 TI - Contact Force Assessment In Catheter Ablation Of Atrial Fibrillation. AB - The efficacy of catheter ablation of atrial fibrillation (AF) remains limited. Increase of success would require more durable lesions without increased risk of complications, such as of steam pop and cardiac perforation. Recently, novel technologies have been developed to estimate real-time catheter-tissue contact force (CF). This paper reviews three available tools for assessment of CF and data on experimental or clinical experience. Experimental data with open irrigated catheter showed that lesion size was greater with applications of lower power (like 30 W) and greater CF (e.g. 30 to 40 g) than vice versa with high power and low CF. Impedance drop in the first 5 seconds was significantly correlated to catheter CF. Perforation was achieved more rapidly with the ablation catheter in a sheath despite the same CF because the sheath prevents catheter buckling. Clinical experience confirmed poor relationship between CF and either unipolar amplitude, bipolar amplitude, or impedance. Within the left atrium, the most common high CF site was found at the anterior/rightward LA roof, directly beneath the ascending aorta (confirmed by merging the CT image and map). Importantly, several studies showed that the use of CF leads to shorter procedure with less fluoroscopy time and less RF applications. CF assessment was also found to be associated with higher proportion of durable lesions. Finally, pilot studies showed that CF measurement could be associated with better clinical efficacy AF ablation. PMID- 27957066 TI - The Evolving Utility Of Intracardiac Echocardiography In Cardiac Procedures. AB - Intracardiac echocardiography (ICE) has gained increasing use in electrophysiology due to the need to visualize key anatomic structures. Precise guidance for transseptal puncture and visualization of the pulmonary veins are common essential uses for ICE, but many operators adept at ICE imaging have developed additional and specific uses. With heavy use of ICE guidance, electrophysiologists demonstrated feasibility of left atrial ablation with minimal use of fluoroscopy. With the advent of 3D mapping-integrated ICE, rendering of contours for the left atrium, aortic cusps, and left ventricular structures such as the papillary muscles have become possible. Improved understanding of the anatomy of these areas can facilitate mapping and ablation of these structurally complex sites. Additional uses of scar-visualization and integration into voltage maps have been explored. Left atrial appendage imaging has been an area of interest in the ICE community, although technological improvements are likely needed to make this more reliably complete. A new real time 3D ICE catheter has also been developed, and work is in progress to delineate potential uses for this new frontier. Increasingly routine use of ICE has led to improved real-time guidance of all percutaneous cardiac procedures. PMID- 27957068 TI - Catheter Ablation Without Fluoroscopy: Current Techniques And Future Direction. AB - Background: Catheter ablation is the treatment of choice for most forms of SVT. Traditionally, fluoroscopy has been the primary tool for visualizing catheter position. However, newer, 3-dimensional mapping technologies offer multiple options for minimizing fluoroscopy use. We review our 8 year experience of a zero fluoroscopy approach using the Ensite system, and discuss our current techniques. Methods: From January 2006 to October 2013, we performed 524 catheter ablation procedures with a zero-fluoroscopy approach. The Ensite system was used exclusively. Early in the study, NavX mode was employed. In the later time period, Velocity mode was used. The Ensite system allowed easy access to all right sided arrhythmias. For left sided arrhythmias, TEE was added to aid with transseptal puncture. Results: Reviewing 524 consecutive procedures, mean age was 14 years (range 7 weeks to 65 years). Mean weight was 60.7 kg (range 3 to 174 kg). Mean procedure time was 142 minutes (range 42 - 402 minutes). There were no complications. Twenty -five patients required the use of fluoroscopy, mostly as part of simultaneous diagnostic or interventional cath procedures. There was only one instance in which fluoroscopy was used when not anticipated at the start of the procedure. With this data available, and seeing that fluoroscopy is rarely needed unexpectedly, we hypothesized that catheter ablation no longer requires a traditional cath lab. We present our early approach to ablation outside the catheterization lab. Conclusions: Three dimensional mapping systems can eliminate fluoroscopy use in virtually all routine ablation procedures. As technology improves, ablation procedures will shift beyond the traditional cath lab. PMID- 27957070 TI - Exploring Atrial Fibrillation Pathophysiology, Gender Differences and More.... PMID- 27957069 TI - Putative Role of Right Atrial Ablation in Atrial Fibrillation. PMID- 27957067 TI - Effect Of Catheter Ablation On Quality Of Life In Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice, affecting approximately 1% of the overall population. While rarely life threatening, AF is almost universally associated with increased morbidity and mortality, predominantly through an increased risk of thromboembolic events, left ventricular dysfunction, as well as significant impairments in functional capacity and health-related quality of life (HRQOL).[1-8] Improvement in HRQOL, with a secondary reduction of disability and health-care resource utilization, is one of the major therapeutic goals in the management of AF. PMID- 27957072 TI - Selective Versus Total Pulmonary Vein Isolation In Atrial Fibrillation Ablation. AB - One of the great discoveries in cardiac electrophysiology was the recognition of the crucial role of pulmonary vein (PV) myocardial sleeves for the initiation of atrial fibrillation (AF). Based on this concept, catheter ablation aiming at electrical isolation of all pulmonary veins has become the routine approach for of paroxysmal AF. Another concept implies selective isolation only of arrhythmogenic PVs. Based on the most important studies dealing with both approaches, we describe pros and cons of selective compared to complete pulmonary vein isolation (PVI) and illustrate why selective PVI has not found widespread acceptance in the electrophysiologic community. PMID- 27957073 TI - Atrial Fibrillation After Robotic Cardiac Surgery. AB - Atrial fibrillation is one of the commonest complications after cardiac surgery and it is associated with considerable morbidity and increase in mortality. Recently, robotic approach to many heart operations has become feasible and reproducible. We here investigate and review the incidence of atrial fibrillation after robotic cardiac surgery. We found that its incidence is overall low and less than in conventional heart surgery. PMID- 27957071 TI - Preserving Cognitive Function in Patients with Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and is associated with significant morbidity and mortality. Its prevalence increases with increasing age, and is one of the leading causes of thromboembolism, including ischemic stroke. The prevalence of cognitive dysfunction also increases with increasing age. Although several studies have shown a strong correlation between AF and cognitive dysfunction in patients with and without overt stroke, a direct causative link has yet to be established. Rhythm vs rate control and anticoagulation regimens have been extensively investigated, particularly with the introduction of the novel anticoagulants. With catheter ablation becoming more prevalent for the management of AF and the ongoing development of various new energy sources and catheters, an additional thromboembolism risk is introduced. As cognitive dysfunction decreases the patient's ability to self-care and manage a complex disease such as AF, this increases the burden to our healthcare system. Therefore as the prevalence of AF increases in the general population, it becomes more imperative that we strive to optimize our methods to preserve cognitive function. This review gives an overview of the current evidence behind the association of AF with cognitive dysfunction, and discusses the most up-to-date medical and procedural treatment strategies available for decreasing thromboembolism associated with AF and its treatment, which may lead to preserving cognitive function. PMID- 27957074 TI - A Case Of Acute Thromboembolic Renal Infarction Associated with Paroxysmal Atrial Fibrillation. AB - Infarction of the kidney is an uncommon condition that can result from obstruction or decrease of renal arterial flow. The diagnosis is often delayed because it can mimic many other pathologic states, including pyelonephritis, renal colic, acute abdomen, pancreatitis and more. A high index of suspicion is important for prompt diagnosis. We describe a 20-year-old man presented with abdominal and right flank pain and hematuria. A computed tomography scan with intravenous contrast showed partial infarction of right renal parenchyma and selective renal angiography showed complete occlusion of the right renal artery which was also supplied by an accessory renal artery. Electrocardiography showed normal sinus rhythm. Transthoracic and transesophageal echocardiographic findings were unremarkable except for mild spontaneous echo contrast (SEC) in the left atrial appendage. Subsequent 48-hour holter monitor revealed frequent premature atrial complexes and paroxysmal atrial fibrillation (PAF). Development of thromboembolic renal infarction was attributed to the presence of PAF and concurrent SEC in the left atrial appendage (LAA). Low molecular weight heparin(LMWH) was followed by oral anticoagulant and an electrophysiologic study was planned for the management of PAF after 4 weeks of anticoagulation. PMID- 27957075 TI - The Role Of Contact Force In Atrial Fibrillation Ablation. AB - During radiofrequency (RF) ablation, low electrode-tissue contact force (CF) is associated with ineffective RF lesion formation, whereas excessive CF may increase the risk of steam pop and perforation. Recently, ablation catheters using two technologies have been developed to measure real-time catheter-tissue CF. One catheter uses three optical fibers to measure microdeformation of a deformable body in the catheter tip. The other catheter uses a small spring connecting the ablation tip electrode to the catheter shaft with a magnetic transmitter and sensors to measure microdeflection of the spring. Pre-clinical experimental studies have shown that 1) at constant RF power and application time, RF lesion size significantly increases with increasing CF; 2) the incidence of steam pop and thrombus also increase with increasing CF; 3) modulating RF power based on CF (i.e, high RF power at low CF and lower RF power at high CF) results in a similar and predictable RF lesion size. In clinical studies in patients undergoing pulmonary vein (PV) isolation, CF during mapping in the left atrium and PVs showed a wide range of CF and transient high CF. The most common high CF site was located at the anterior/rightward left atrial roof, directly beneath the ascending aorta. There was a poor relationship between CF and previously used surrogate parameters for CF (unipolar or bipolar atrial potential amplitude and impedance). Patients who underwent PV isolation with an average CF of <10 g experienced higher AF recurrence, whereas patients with ablation using an average CF of > 20g had lower AF recurrence. AF recurred within 12 months in 6 of 8 patients (75%) who had a mean Force-Time Integral (FTI, area under the curve for contact force vs. time) < 500 gs. In contrast, AF recurred in only 4 of 13 patients (21%) with ablation using a mean FTI >1000 gs. In another study, controlling RF power based on CF prevented steam pop and impedance rise without loss of lesion effectiveness. These studies confirm that CF is a major determinant of RF lesion size and future systems combining CF, RF power and application time may provide real-time assessment of lesion formation. PMID- 27957076 TI - Observations Of Electrical Coupling Index Using the ContactTM System During Pulmonary Vein Electrical Isolation Procedures. AB - The Contact (St Jude Medical) System uses a novel impedance- based measure of Electrical Coupling Index (ECI) to assess the quality of catheter tip to endocardium contact. We sought to establish average ECI measurements and behaviour during pulmonary vein (PV) isolation procedures. Forty-five patients undergoing PV isolation for atrial fibrillation (AF) were studied.'Non-contact' and upper range 'in-contact' catheter positioning was performed for system calibration. ECI measurements were recorded pre-ablation at 14 standardized locations around the PV antra. The mean ECI non-contact value was 77 +/- 11 (range 63-107); the mean upper range in-contact value was 111 +/- 16 (range 81 145). Mean ECI values pre-ablation around the PV antra ranged from 85 +/- 18 to 107 +/- 19. A trend towards higher mean ECI values was noted with increasing body mass index (BMI). Pre-ablation mean ECI values were 92 +/- 10 (BMI 20-25), 95 +/- 12 (BMI 26-30) and 104 +/- 11 (BMI >30) (p< 0.01 for 20-25 vs. >30). A positive correlation was noted for mean pre-ablation ECI values and BMI (r=0.50). An expected range of ECI values during PV isolation has been documented in this study. Observed ECI values correlate with patient BMI. The potential limitations of the current generation Contact System and scope for future clinical applications are discussed. PMID- 27957077 TI - Superior Vena Cava Isolation In Ablation Of Atrial Fibrillation. AB - Superior vena cava (SVC) is one of the most important non-pulmonary vein (PV) origins of atrial fibrillation (AF). SVC isolation (SVCI) is effective especially in patients with paroxysmal AF from SVC origin. However, SVCI should be carefully performed because of potential complications such as phrenic nerve paralysis, SVC stenosis, and sinus node injury There are two major different approaches to treat SVC focus in the ablation of AF. The conventional approach is to perform SVCI only if AF from the SVC origin is actually recognized using pacing maneuvers and/or isoproterenol infusions. Another approach is the empiric empiricprophylactic SVCI in addition to PV isolation in all cases. The rate of AF freedom one year after initial AF ablation by empiric SVCI was almost same as the conventional method (85-90% AF freedom). Additionally, the conventional method has also a good result even 5 years after ablation (,73.3% AF freedom). Because of the excellent result in the conventional approach and possible complications after the SVCI, the empiric SVCI + PVI in all AF cases is still controversial. Patients with a long SVC myocardial sleeve are possible candidates for empiric SVCI in addition to PVI. PMID- 27957078 TI - Complications From Left Atrial Appendage Exclusion Devices. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and has been identified as an independent risk factor for stroke. Prevention of thromboembolic events has been based on oral anticoagulation (OAC) using Vitamin K antagonists (VKA). However, long-term OAC medication is limited by an increased bleeding risk and a low patient compliance. Relying on the observation that the majority of cardiac thrombi originate from the left atrial appendage (LAA) different devices aiming for LAA closure have been proposed. This review will discuss contemporary LAA closure devices with special emphasis on procedure related complications. PMID- 27957079 TI - Treatment Or Cure Of Right Ventricular Outflow Tract Tachycardia. AB - Right ventricular outflow tract (RVOT) ventricular tachycardias (VT) occur in the absence of structural heart disease and are called idiopathic ventricular arrhythmias. These arrhythmias are thought to be produced by adenosine-sensitive, cyclic AMP mediated, triggered activity and are commonly observed in adolescents and young adults. In the ECG, they appear with a wide QRS complex, a left bundle branch block morphology and, usually, an inferior QRS axis. In the last few years, there has been an increasing number of reports suggesting the possibility of a curative treatment of RVOT VT by means of catheter ablation. This paper reviews the rate of cure of such arrhythmias by discussing the effects of catheter ablation on symptoms, arrhythmia detection, possibility of induction, and short- and long-term follow-up studies. PMID- 27957080 TI - Techniques To Improve Left Atrial Appendage Imaging. AB - The clinical importance of the left atrial appendage (LAA) is increasingly recognized. The assessment of the unique anatomy and function of the LAA is especially important in the setting of atrial fibrillation (AF). AF is the most commonly occurring cardiac arrhythmia, and the association of LAA thrombi and AF has been well established. Transesophageal echocardiography (TEE) is a widely available imaging tool to exclude the potential presence of LAA thrombus prior to cardioversion in patients with AF. Commercially available products containing microbubbles to enhance ultrasound images, termed "ultrasound contrast agents" (UCA) are indicated for use with transthoracic echocardiography to improve cardiac structure and function assessment, but can also be used with TEE as an adjunctive tool to assess the LAA. Integrative multimodality imaging techniques can be used in evaluation of the LAA as indicated in various clinical scenarios including: stroke risk assessment, decision-making prior to cardioversion in AF, placement and assessment percutaneous transcatheter LAA occlusion procedures, and assessment of results of procedural or surgical exclusion of LAA. In this article, various imaging techniques that are available for non-invasive visualization of the LAA will be reviewed along with the clinical importance of assessment of LAA anatomy and function. PMID- 27957082 TI - Use Of Rate And Rhythm Control Drugs In Patients Younger Than 65 Years With Atrial Fibrillation. AB - Little is known about the use of pharmacologic rhythm or rate control in younger atrial fibrillation (AF) patients in clinical practice. Using commercial health data from 2006 through 2010, patients aged <65 years with an initial AF encounter were categorized as receiving pharmacologic rhythm- or rate-control treatment. Factors associated with each treatment were determined. Cox models with inverse propensity-weighted estimators were used to compare times to AF, heart failure, cardiovascular, non-cardiovascular, and any-cause hospitalizations. Of 79,232 patients meeting the study criteria, 12,408 (16%) received a rhythm-control drug and 66,824 (84%) received only rate-controlling drugs. Only 2% and 0.1%, respectively, received electrical cardioversion and AF ablation during the initial AF encounter. Patients who were men (OR 1.10, 95% CI 1.06-1.15), had index encounters in later years (2010 versus 2006: OR 1.34, 95% CI 1.23-1.45), were in the southern United States, and had other cardiac comorbidities were more likely to receive a rhythm-control drug. There was a greater risk of AF (HR 1.40, 95% CI 1.31-1.50), cardiovascular (HR 1.26, 95% CI 1.20-1.33), and all-cause (HR 1.11, 95% CI 1.07-1.16) hospitalizations in the rhythm-control group, but there was no difference between groups in heart failure (HR 1.01, 95% CI 0.88-1.17) or non-cardiovascular (HR 1.04, 95% CI 0.99-1.09) hospitalizations. Among younger AF patients receiving initial pharmacologic treatment, antiarrhythmic drugs were used less frequently than only rate-controlling drugs, and were associated with a higher risk of subsequent hospitalization. PMID- 27957083 TI - The Unique MediGuide Technology For CRT Lead Placement And Catheter Ablation. AB - Electrophysiologic procedures such as catheter ablation and/or cardiac resynchronization therapy (CRT) are usually performed under fluoroscopic guidance alone. Currently, we are witnessing the birth of a new era in which many patients can be safely and effectively treated without the use of fluoroscopy. Using MediGuide technology continuous fluoroscopy is no longer required to ascertain the position of the device/catheter, which minimizes the radiation exposure for both the physician and patient, with a further benefit by minimal need for contrast agent. This novel system provides real time tracking of devices projected into live fluoroscopy or pre-recorded cine-angiography. MediGuide technology is an important step forward facilitating complex ablation procedures such as AF ablation and CRT implantation. PMID- 27957081 TI - Management Of Pulmonary Vein Stenosis Following Catheter Ablation Of Atrial Fibrillation. AB - There is limited literature available regarding PV (pulmonary vein) stenosis management. Starting from its incidence, subsequent follow up using imaging technologies to monitor the success and the way of managing different groups pose varied opinions. However, with newer technological advancements and better understanding of mechanism of the atrial fibrillation ablation, the incidence of PV stenosis secondary to catheter ablation is declining. This paper highlights the current trends and future of management of PV stenosis secondary to catheter ablation for atrial fibrillation. PMID- 27957084 TI - State Of The Art In Left Atrial Appendage Ligation - The Lariat. AB - Percutaneous left atrial appendage ligation (LAA) techniques have come to the forefront of management of atrial fibrillation (AF) patients who are at high risk of stroke and are unsuitable for oral anticoagulation therapy. LARIAT is a novel percutaneous endo-epicardial ligation technique for LAA exclusion. This technique is increasingly becoming popular for LAA exclusion in AF patients. A few studies have validated the efficacy of LARIAT in mitigating stroke risk in AF patients with contraindications to anticoagulation. Additionally a few studies have suggested that AF burden decreases after the LARIAT procedure. In this review paper we discuss the indications, technique and the latest advances in the LAA exclusion using the LARIAT system. PMID- 27957085 TI - Electrical And Hemodynamic Evalution Of Ventricular And Supraventricular Tachycardias With An Implantable Dual-Chamber Pacemaker. AB - The discrimination between ventricular (VT) and supraventricular tachycardia (SVT) and the evaluation of their hemodynamic impact are essential issues in the arrhythmia management. A new pacing device features a tachycardia diagnostic system relying on simultaneous recording of the transvalvular impedance (TVI) and a special integrated electric signal derived by the whole set of endocardial electrodes (iECG). The iECG waveform is sensitive to the pattern of ventricular activation, similarly to the surface ECG. The TVI increases in systole and decreases in diastole and the amplitude of this cyclic fluctuation is an expression of the effectiveness of the pump function. In order to test the value of these signals in the analysis of a tachycardia, we have assessed the iECG and TVI modifications induced by different SVTs and tolerated and non-tolerated VTs, during electrophysiological (EP) studies. In case of SVT, the ventricular component of the iECG maintained the same morphology as in sinus rhythm. The peak peak amplitude of the TVI fluctuation was reduced to 66 +/- 11 % of the individual sinus rhythm reference, but the signal was present at every beat and showed a remarkable stability (variation coefficient 0.19 +/- 0.01). In case of VT, the ventricular component of the iECG was strikingly different than in sinus rhythm. Regular TVI fluctuation was observed with tolerated VTs (peak-peak amplitude 74 +/- 6 %; variation coefficient 0.21 +/- 0.04). In contrast, with non tolerated VTs the TVI amplitude was depressed below 40%, and the signal was virtually absent in the event of very fast VT or VF. Our results confirm that the iECG is a reliable tool to quickly discriminate VTs from SVTs and that TVI can provide information on the severity of the hemodynamic impairment produced by a tachycardia, with potential clinical benefit in the follow-up of pacemaker patients. Furthermore, the application of these signals to automatic algorithms of arrhythmia recognition might improve the specificity of therapy administration by an implantable defibrillator (ICD). PMID- 27957086 TI - The Rate Of Complications Associated With Concomitant Use Of Dabigatran With Cryoballoon Ablation For Atrial Fibrillation. AB - INTRODUCTION: Catheter ablation is an evolving therapeutic strategy for the management of atrial fibrillation (AF). It is associated with a risk of thromboembolic events. The peri-procedural anticoagulation management with warfarin has been successful in mitigating this risk. However, introduction of novel oral anticoagulants like dabigatran offers more flexibility in anticoagulation approaches. Previous studies had evaluated the safety and efficacy of dabigatran in the radiofrequency ablation, but data related to cryoballoon ablation is lacking. METHODS AND RESULTS: We performed a retrospective observational study involving patients who underwent cryoballoon ablation for drug-refractory, symptomatic AF while on dabigatran in periprocedural period. Thromboembolic, hemorrhagic or other complications occurring within the first 30 days after the ablation procedure were analyzed. Our study population comprised of 50 patients with mean age of 58.96 +/- 3.54 years with 76% (n=38) being male. We found 3 (6%) minor complications in peri procedural period including 2 groin hematomas and 1 trace asymptomatic pericardial effusion. There were no major intraprocedural or post procedural hemorrhagic or thromboembolic events. None of patients with the minor complications required significant additional workup or extended hospital stay. All the patients were able to continue dabigatran for 30 days without any additional side effects or complications. CONCLUSION: Dabigatran is a safe and efficacious agent in patients undergoing cryoballoon AF ablation. PMID- 27957087 TI - Destruction Of Medium Already Afected By Destructive Disorder: Fibrillating Atria Conceptually Need Therapeutic Help Rather Than Surgical Or Ablative Destruction. AB - Atrial fibrillation (AF) as the most common supraventricular arrhythmia is scarcely amenable to contemporary treatment. Due to the diverse origin and variable clinical course of AF there is a broad spectrum of therapy options. However, optimal AF management has not become a gold standard yet. In general, the recurrence rate of AF is most often clinically unacceptable despite drug, surgical and/or ablation therapy. Substrate-based approach and ongoing ablation of atrial wall in its selected areas including the vicinity of pulmonary veins can be harmful. Applied physical factors do produce total disintegration of cardiomyocites - both intra- and inter-cellular damage which, in turn, leads to functional hypo-/inactivation of atria irrespective of whether the sinus rhythm is restored or not. In fact, iatrogenic phenomenon of ablation-induced atrial incompetence did emerge. Heterogeneity in clinical results reflects the uncertainty regarding the efficacy, risks and benefits of invasive AF therapy. In this regard the overall burden of AF may increase when using current therapy methods. Applicability of destructive techniques is yet to be fully elucidated and discussed. We hypothesize that currently used ablation and/or surgical techniques are potentially harmful since the success rates are likely achieved through violation of atrial myocardium. That is why a new and well-designed therapeutic strategy is needed. Invention of highly selective curative methods producing fibrillatory/electric blockage with concomitant saving of atrial transport function is to be encouraged. PMID- 27957088 TI - Who Needs Pharmacologic Therapy? AB - Treatment of atrial fibrillation has evolved significantly in the last ten years, with ablation becoming a far more common form of treatment for this most common type of arrhythmias. However, while ablation has become more common, certain populations derive continued benefit from the use of pharmacologic therapy for treatment. We review the use of pharmacologic therapy and novel considerations for treatment of atrial fibrillation. PMID- 27957090 TI - Exploring New Frontiers in Atrial Fibrillation. PMID- 27957089 TI - Nonfluoroscopic Ablation of Atrial Fibrillation Using Cryoballoon. AB - BACKGROUND: The conventional method of cryoballoon ablation of atrial fibrillation involves the use of fluoroscopy for visual guidance. The use of fluoroscopy is accompanied by significant radiation risks to the patient and the medical staff. Herein, we report our experience in performing successful nonfluoroscopic pulmonary vein isolation using cryoballoon ablation in 5 consecutive patients with paroxysmal atrial fibrillation. METHODS AND RESULTS: Five consecutive patients with paroxysmal atrial fibrillation underwent cryoballoon ablation for pulmonary vein isolation using a nonfluoroscopic approach. Pre-procedural cardiac computed tomography or cardiac magnetic resonance imaging was not performed in any patient. A total of twenty pulmonary veins were identified and successfully isolated (100%) with the guidance of intracardiac echocardiography and 3-dimensional electroanatomic mapping. No fluoroscopy was used for the procedures. There were no major procedural adverse events. CONCLUSION: In an unselected group of patients undergoing cryoballoon ablation, a nonfluoroscopic approach is feasible and can be performed safely and effectively while eliminating the risks associated with radiation to both the patient and the medical staff. PMID- 27957091 TI - New Technologies In Atrial Fibrillation Ablation. AB - Atrial fibrillation (AF) is a major public health issue worldwide, the incidence of which is likely to continue to rise. With the birth of pulmonary vein isolation(PVI), cardiac ablation has emerged as key strategy for the treatment of AF. PVI using traditional point by point radiofrequency ablation is time consuming and technically challenging. Refining patient selection for PVI also remains an important goal. New ablative strategies using catheter-based balloon technologies, such as cryothermy and laser-based systems, may simplify PVI. In addition, new MRI-based techniques offer the hope of refining patient selection prior to ablation. Lastly, FIRM mapping represents an entirely new approach to AF ablation via the targeting of mechanisms that perpetuate AF rather than simply targeting triggers alone. PMID- 27957092 TI - Vasovagal Syncope As A Manifestation Of An Evolutionary Selected Trait. AB - Some observations suggest that typical (emotional or orthostatic) vasovagal syncope (VVS) is not a disease, but rather a manifestation of a non-pathological trait. We conducted an extensive bibliographic research on the vasovagal reactions in animals, including humans, in order to investigate the possible factors that may explain the origin and evolution of VVS. We found two processes which appear relevant for the investigation of VVS evolution: fear/threat bradycardia (alarm bradycardia) in animals, mainly during tonic immobility and vasovagal reflex during hemorrhagic shock (thoracic hypovolemia) both in animals and humans. The available data suggest that VVS in humans, alarm bradycardia in animals and the vasovagal reflex during hemorrhagic shock share the same physiological mechanisms and that is indicative of a common evolutionary root. However, during the vasovagal reflex loss of consciousness occurs in humans, but it is absent (or extremely rare) in animals. That can be explained as a by product due to the erect position and the large brain evolved in our species. If the vasovagal reflex persisted for millions of years along the vertebrates evolutionary history, we can reasonably assume that it has a function and it is not harmful. It could be neutral or beneficial, but the available data suggest it is beneficial; likely, it evolved as an advantageous response to stressful and possibly dangerous heart conditions. Emotional or orthostatic vasovagal reflex is preceded by enhanced sympathetic activity, which is harmful and possibly dangerous. The transient inhibition of the sympathetic system, together with activation of the vagal tone , characterizes VVS. The consequent slowing of the heart rate induced by the vasovagal reflex may constitute a beneficial break of the cardiac pump, thereby reducing myocardial oxygen consumption. We suggest that typical VVS should be regarded as a selected response, which probably evolved in the ancient past as a defense mechanism of the organism within some ancestral group(s) of vertebrates. PMID- 27957093 TI - Atrial Fibrillation Radiofrequency Ablation: Safety Using Contact Force Catheter In A Low-Volume Centre. AB - The tip-to-tissue contact force (CF) has been identified as a potential determinant of lesion quality during radiofrequency (RF) ablation. The aim of this paper is to report the experience of a single low-volume centre in the atrial fibrillation (AF) ablation procedure with an RF catheter capable of measuring this parameter. CF data and their possible implications on patient safety are presented. Thirty-nine consecutive patients suffering of paroxysmal or permanent AF received percutaneous ablation with the novel catheter studied. Procedural characteristics, CF applied and safety events related to the procedure were reported. During RF application the mean CF value was 17 +/- 3 g, with a maximum mean value of 37 +/- 8 g. CF value never exceeded 62 g and in the 74% of the RF applications ranged between 10 g and 30 g. No complication related to the catheter manipulation or to the energy delivered was observed. This study of a single centre with a low level of experience in AF ablation suggests that the ability to measure CF may provide additional useful information to the operator. It ensures uniform ablations, with little variability in the catheter manipulations, and it avoids excessive contact forces increasing the patient safety. PMID- 27957094 TI - Risks Related To Fluoroscopy Radiation Associated With Electrophysiology Procedures. AB - The benefits of cardiac imaging are immense, and modern cardiac electrophysiology (EP) requires the extensive and versatile use of a variety of cardiac imaging and radiology-based techniques. In the cardiac electrophysiology lab, doses can range around a reference effective dose (ED) of 15 milliSievert corresponding to 750 chest x-rays for a cardiac radiofrequency ablation, ranging from less than 2 to > 60 mSv. The reference dose for a regular pacemaker or ICD implant is 4 mSv (range 1.4-17) and for a CRT implant is 22 mSv (range 2.2-95). Doses on the order of magnitude of 10-100 milliSievert (mSv) correspond to a low (albeit definite, not negligible) additional lifetime risk of fatal and non-fatal cancer from between 1 in 1000 (10 mSv) to 1 in 100 (100 mSv). The increasing use and complexity of cardiac electrophysiology techniques have not been matched by increasing awareness and knowledge by prescribers and practitioners. The protection of doctors is just as important as protection of patients. Most experienced (and most exposed) interventional cardiologists and electrophysiologists have an exposure per annum of around 5 mSv, two to three times higher than diagnostic radiologists, with a typical cumulative lifetime attributable risk on the order of magnitude of 1 cancer (fatal and non-fatal) per 100 exposed subjects. Operator dose per procedure correlates somewhat with the patient dose, but may be typically 1000 times lower depending upon the shielding employed (one unit of incidence scatter dose for the operator when 1000 units of incident dose are given to the patient). However, adequate radiation protection training and diligent protection can reduce this radiation exposure by 90%. The priority given to radioprotection in every cardiology department is an effective strategy for primary prevention of cancer, a strong indicator of the quality of the cardiology division, and the most effective shielding for enhancing the safety of patients, doctors, and staff. PMID- 27957096 TI - Clinical Relevance Of Systematic CRT Device Optimization. AB - Cardiac Resynchronization Therapy (CRT) is known as a highly effective therapy in advanced heart failure patients with cardiac dyssynchrony. However, still one third of patients do not respond (or sub-optimally respond) to CRT. Among the many contributors for the high rate of non-responders, the lack of procedures dedicated to CRT device settings optimization (parameters to regulate AV synchrony and VV synchrony) is known as one of the most frequent. The most recent HF/CRT Guidelines do not recommend to carry-out optimization procedures in every CRT patient; they simply state those procedures "could be useful in selected patients", even though their role in improving response has not been proven. Echocardiography techniques still remain the gold-standard reference method to the purpose of CRT settings optimization. However, due to its severe limitations in the routine of CRT patients management (time and resource consuming, scarce reproducibility, inter and intra-operator dependency), echocardiography optimization is widely under-utilized in the real-world of CRT follow-up visits. As a consequence, device-based techniques have been developed to by-pass the need for repeated echo examinations to optimize CRT settings. In this report the available device-based optimization techniques onboard on CRT devices are shortly reviewed, with a specific focus on clinical outcomes observed in trials comparing these methods vs. clinical practice or echo-guided optimization methods. Particular emphasis is dedicated to hemodynamic methods and automaticity of optimization algorithms (making real the concept of "ambulatory CRT optimization"). In fact a hemodynamic-based approach combined with a concept of frequent re-optimization has been associated - although retrospectively - with a better clinical outcome on the long-term follow-up of CRT patients. Large randomized trials are ongoing to prospectively clarify the impact of automatic optimization procedures. PMID- 27957097 TI - ICD Therapy In RVOT-VT And Early Stage ARVD/C Patients. AB - Implantable cardioverter-defibrillators (ICDs) improve the survival of patients with ischemic or non-ischemic cardiomyopathy and a reduced ejection fraction. However, the efficacy of ICD therapy in patients with right ventricular outflow tract ventricular tachycardia (RVOT-VT) and early stage arrhythmogenic right ventricular dysplasia / cardiomyopathy (ARVD/C) has not been well clarified. Although the prognosis of RVOT-VT is generally good, malignant forms of RVOT-VT resulting in polymorphic VT have been reported by several investigators. Radiofrequency catheter ablation is still effective in such patients, and thus an ICD implantation is usually not required. On the other hand, according to the current guidelines in patients with ARVD/C, an ICD implantation is recommended for secondary prevention when the patients develop sustained VT or VF. An ICD implantation may also be considered for primary prevention in high-risk patients: extensive disease, family history of sudden cardiac death, or undiagnosed syncope. Since an ICD implantation in the early stage of ARVD/C is controversial, physicians should well consider its risks and benefits. Early intervention with ICD therapy in ARVD/C patients may reduce the arrhythmic death rate but increases the device related complications especially in younger patients. PMID- 27957095 TI - Anatomic Challenges In Pediatric Catheter Ablation. AB - Pediatric patients present unique anatomic challenges for catheter ablation. Small patient size requires special adaptation and understanding to perform safe procedures when clinically indicated. The anatomic variations of congenital heart disease also create problems that require pre-procedural preparation for each case in addition to a specialized understanding of a vast anatomic variation and surgical repairs. This understanding coupled with the knowledge of the pathophysiology of arrhythmia disorders and the biophysics of catheter ablation technology are required to perform successful and safe ablation procedures in this special population. PMID- 27957098 TI - Control Of Hypertension Improves The Outcome Of Therapies For Paroxysmal And Persistent Atrial Fibrillation. AB - Hypertension is known to increase the risk of atrial fibrillation. It has a role to play in atrial fibrosis and remodeling which tends to propagate further atrial fibrillation. Current anti arrhythmic therapy is unsatisfactory due to its toxicity. Management of hypertension offers an attractive target for improving therapy of atrial fibrillation. We examine the current evidence for anti hypertensive therapy in atrial fibrillation. PMID- 27957099 TI - Watchman Device: Left Atrial Appendage Closure For Stroke Prophylaxis In Atrial Fibrillation. AB - A concerning proportion of patients with atrial fibrillation (AF) with indications for oral anticoagulation (OAC) discontinue OAC or are never prescribed OAC therapy and many AF patients with the highest risk for embolic events off OAC also have the greatest risk for hemorrhagic complications on OACs. Medium-term efficacy and safety data provide evidence that the WATCHMAN device, the most studied device and the only one with randomized and medium-term follow up data, may be a viable alternative to chronic warfarin therapy in nonvalvular AF patients. In addition to presenting key data pertaining to LAA closure techniques including the WATCHMAN device, this review will discuss crucial WATCHMAN implantation technical points. PMID- 27957100 TI - Focal Impulse And Rotor Mapping (FIRM): Conceptualizing And Treating Atrial Fibrillation. AB - Current approaches for the ablation of atrial fibrillation are often effective, but only partially rooted in mechanistic understanding. Accordingly, they are unable to predict whether a given patient will or will not do well, or which lesions sets should or should not be performed - in any given patient. This goal would require clearer mechanistic definition of what sustains AF after it has been triggered (i.e. electrophysiological substrates). There are two schools of thought. The first proposes disorganized activity that self-sustains with no 'driver', and the second describes drivers that then cause disorganization. Interestingly, these mechanisms can be separated in human studies by mapping approach - proponents of the disorganized hypothesis studying small atrial areas at high resolution, and proponents of the driver model studying wide fields-of view at varying resolutions. Focal impulse and rotor modulation (FIRM) mapping combines a wide field of view with physiologically based signal filtering and phase analysis, and has revealed that human AF is often sustained by rotors. In the CONFIRM Trial, targeting stable AF rotors/sources for ablation improved the single-procedure efficacy for paroxysmal and persistent AF over conventional ablation alone, as now confirmed by independent laboratories. FIRM mapping gives a mechanistic foundation to predict whether any selected lesions should intersect AF sources in any given patient and which mechanisms may cause recurrence. Rotors of varying characteristics have now been shown by many groups. These insights have reinvigorated interest in AF mapping, and rationalizing these findings will likely translate into improved therapy for our patients. PMID- 27957103 TI - Retrospective Evaluation Of Novel Percutaneous Left Atrial Appendage Ligation Using The LARIAT Suturing Device: Single Center Initial Experience. AB - BACKGROUND: The left atrial appendage (LAA) is the source of considerable thromboemboli responsible for embolic strokes in patients with atrial fibrillation (AF). The LARIATTM suturing device has been used to ligate the LAA and negate the use of systemic anticoagulation. However, its efficacy and stroke outcome is still unknown. METHODS: We retrospectively evaluated the clinical status and risk of occurrence of systemic emobolic events, strokes, transient ischemic attacks, and procedure related complications in patients after LAA ligation using the LARIATTM device. RESULTS: Permanent suture was successfully delivered in 21 patients. Mean follow up time was 17.2+-3.3 months. The average HAS-BLED score was 3.3+/-1.1. Only 1 patient developed clinical symptoms of stroke 7 days post procedure. One patient had uncomplicated perioperative bleeding not requiring blood transfusion. One patient developed transient ECG changes of ischemia during mapping for ablation following the LAA ligation and subsequently, underwent bypass surgery. Three patient developed post-procedural pericarditis and were medically managed. Three patients died from non-LAA ligation related conditions including congestive heart failure, lung cancer, and severe coronary disease. We observed a 32% and 30% reduction in the annual risk of stroke when compared to the expected risk of stroke based on the CHADS2 and CHA2DS2-VASc score respectively. CONCLUSION: LAA ligation using the LARIATTM suturing device is clinically feasible in carefully selected patients. This study has the longest follow up period to date, however further studies are required to determine the efficacy of stroke reduction and long-term clinical outcomes. PMID- 27957102 TI - Management Of Atrial Fibrillation In Patients With Heart Failure. AB - Atrial fibrillation (AF) and heart failure (HF) are common conditions that frequently coexist. Both conditions share risk factors, are associated with increased morbidity and mortality, and may worsen the other. The presence of heart failure and symptoms associated with it may influence both the approach to management (i.e., rate versus rhythm control) and the treatment options available for AF patients. The presence of HF increases the stroke risk with atrial fibrillation, and thromboembolic risk reduction is paramount. Some patients with HF tolerate AF poorly and therefore , a rhythm control strategy may be preferred. More insight into the success rates with catheter ablation in heart failure has been gleaned from recent studies. PMID- 27957104 TI - One-Shot Ablation For PV Isolation. AB - Atrial fibrillation ablation has evolved considerably over the last few years. In this article we review current and past catheter ablation techniques, with a special focus on new simplified systems that allow a faster and simpler procedure, so called "one-shot" atrial fibrillation ablation. PMID- 27957101 TI - The Growing Culture Of A Minimally Fluoroscopic Approach In Electrophysiology Lab. AB - Most of interventional procedures in cardiology are carried out under fluoroscopic imaging guidance. Besides other peri-interventional risks, radiation exposure should be considered for its stochastic (inducing malignancy) and deterministic effects on health (tissue reactions like erythema, hair loss and cataracts). In this article we analized the radiation risk from cardiovascular imaging to both patients and medical staff and discusses how customize the X-ray system and how to implement shielding measures in the cath lab. Finally, we reviewed the most recent developments and the latest findings in catheter navigation and 3D electronatomical mapping systems that may help to reduce patient and operator exposure. PMID- 27957105 TI - New Insights On Ablation Of Persistent Atrial Fibrillation: Evidence From The SARA Trial. AB - Since Haissaguerre et al first described the pathogenic role of pulmonary vein firing as a crucial mechanism triggering atrial fibrillation, catheter ablation has been recommended as a curative treatment. Several trials have demonstrated that ablation is an effective treatment in most patients with paroxysmal atrial fibrillation and low-grade remodelled atria. In patients with persistent AF, there is substantially less evidence, mostly based on non-randomized studies, supporting this recommendation. The available scientific evidence as well as the current approaches to treating persistent AF patients are discussed in this article. Further, we describe the main findings of the SARA trial and put them into perspective. PMID- 27957106 TI - Catheter Ablation Of Atrial Fibrillation In The Elderly: Risk Benefit Analysis. AB - Over the past decade, catheter ablation has emerged as an important therapeutic option and reserved for drug refractory symptomatic paroxysmal and persistent atrial fibrillation (AF). Although elderly population constitutes the significant amount of AF patients, literature data is inadequate regarding the use of catheter ablation for elderly AF patients. Since there has been significant improvement in efficacy and safety of the AF ablation in last decade, it has become widespread accross the whole world. As the life expectancy continues to grow in population and outcomes of catheter ablation for AF further improve, higher number of elderly patients are likely to undergo catheter ablation for AF. Therefore, in this paper we reviewed the published literature to date regarding the clinical efficacy and safety of catheter ablation for AF in elderly patients. PMID- 27957109 TI - A Difficult Case Of Left Atrial Flutter. AB - A 55-year-old male was referred for a third ablation procedure because of recurrent atrial fibrillation. During re-isolation of the inferior right pulmonary vein the patient developed an atypical flutter with an clockwise activation pattern around the mitral annulus. Linear ablation at the left mitral isthmus transformed but did not terminate the tachycardia. The cavotricuspid isthmus proved to be a second critical isthmus and linear ablation at this site terminated the tachycardia. PMID- 27957107 TI - Improvements In AF Ablation Outcome Will Be Based More On Technological Advancement Versus Mechanistic Understanding. AB - Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. Catheter ablation has proven more effective than antiarrhythmic drugs in preventing clinical recurrence of AF, however long-term outcome remains unsatisfactory. Ablation strategies have evolved based on progress in mechanistic understanding, and technologies have advanced continuously. This article reviews current mechanistic concepts and technological advancements in AF treatment, and summarizes their impact on improvement of AF ablation outcome. PMID- 27957108 TI - Beverages Of Daily Life: Impact Of Caffeine On Atrial Fibrillation. AB - In recent years, clinical and observational studies reported that caffeine consumption was associated with cardiac arrhythmias, affected heart rate variability, and subsequently increased cardiovascular risk. The analysis of these paper shows that data are controversial and strongly depends on methodology. Moderate intake of caffeine seems to have protective effects on arrhythmias, on contrary high intake of caffeine seems to be associated with increased risk of atrial fibrillation. There is a deep difference when we analysed intake of caffeine from coffee compared to other sources. In very recent time an increase in caffeinated beverages, namely energy drinks, has been reported in young people and several arrhythmic complications has been observed. A review of literature is presented. PMID- 27957110 TI - World Atrial Fibrillation Awareness Day - High Time To Spread The Word. PMID- 27957111 TI - Gut To Heart: Acid Reflux Disease In Atrial Fibrillation And The Role Of Proton Pump Inhibitor. PMID- 27957113 TI - How To Follow Atrial Fibrillation Ablation Patients? AB - Catheter ablation is an established treatment option for symptomatic atrial fibrillation (AF), with circumferential pulmonary vein isolation being considered the cornerstone of the procedure. However, this is a complex intervention with potential major complications and with common arrhythmia recurrences. There is consensus among experts that all patients should be seen in follow-up regularly after AF ablation. To date there are limited data regarding the best methodology for routine clinical follow-up of this population. This review summarizes a contemporary insight into management of late complications following AF ablation, post-procedural anticoagulation and arrhythmia monitoring strategies, in order to prevent thromboembolic events, detect and treat arrhythmia recurrences, and discuss the use of upstream therapies after AF ablation. PMID- 27957112 TI - Evaluation Of Patients With Early Repolarization Syndrome. AB - In recent years, the early repolarization pattern has emerged as a risk factor for malignant ventricular arrhythmias and sudden cardiac death. The identification of the subset of patients who are at high risk of sudden death represents a significant challenge to the clinician. Multiple clinical and ECG features have been associated with an increased risk of sudden deathin however the majority of risk factors confer a small increase in absolute risk. The present article reviews current evidence and potential management strategies in patients with early repolarization. PMID- 27957115 TI - EHRA(European Heart Rhythm Association) EP-Wires Surveys: What Is Common Practice In Device Management? AB - Guidelines and recommendations within the field of electrophysiological (EP) practice are usually drawn from the results of multicentre trials, often conducted in selected centers and under special circumstances. In contrast, daily practice is generally influenced by many factors, which may be different from those that are considered in strictly controlled scientific conditions. Even though patient registries may mirror daily practice, the enrollment of consecutive patients for longer periods of time for such purpose within the health care community is costly and time consuming. A short form of survey directed to physicians, could within a reasonable time frame highlight areas where the evidence base for clinical practice and implementation of guidelines needs to be augmented. Such short form of surveys, called EP Wires, are on-line surveys carefully constructed to give a picture of daily cardiac EP practice in Europe without burdening the responders with extensive data collection. The network of centers formed, are contacted on a regular basis every month. It is the purpose of this summary to present the result of four such EP wires, all of which concern devices, with special emphasis on centre differences and adherence to guidelines. PMID- 27957114 TI - Mechanisms And Management Of Thrombo-Embolism In Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia in the general population and in patients with a history of cardiovascular disease. AF is becoming an outbreak particularly for the western countries as it increases with advancing age; furthermore, AF has a negative social impact because it is associated with stroke and myocardial infarction. Thrombosis generated in the left atrial appendage with ensuing embolism in the cerebral circulation is considered the most important cause of ischemic stroke. In addition to thrombo embolism, AF is characterized by a constellation of atherosclerotic risk factors, including hypertension, dyslipidaemia and diabetes, which may predispose to serious clinical complications of atherosclerosis such myocardial infarction. Even if interventional trials with oral anticoagulants such as warfarin reduced by about 60% the risk of stroke, AF patients still disclose an elevated residual cardiovascular risk, which may severely complicate the clinical course and management of AF. Recent trials with new oral anticoagulants (NOACs) are opening a new scenario for the treatment of AF, which could improve its management, as NOACs apparently would not require monitoring. However, important caveats are emerging in the real world of AF management, which are questioning the concept that NOACs do not need monitoring. Thus, issues related to compliance and large variability in blood concentration may negatively influence the cost/effectiveness benefit of NOACs. This review will focus on pathophysiology of thrombo-embolism and athero-thrombosis and the impact of old and new anticoagulants in the real world of AF management. PMID- 27957116 TI - Left Atrial Diastolic Dysfunction And Pulmonary Venous Hypertension In Atrial Fibrillation: Clinical, Hemodynamic And Echocardiographic Characteristics. AB - BACKGROUND: Left ventricular diastolic dysfunction has been well described; diastolic abnormalities of the LA are less frequently recognized and poorly understood. OBJECTIVE: The purpose of this study was to investigate the clinical, hemodynamic and echocardiographic features of left atrial (LA) diastolic dysfunction. METHODS: Patients with atrial fibrillation (AF), severe LA enlargement, and pulmonary venous hypertension (PVH, Group 1) were compared to patients with pulmonary arterial hypertension (PAH), normal LA size and sinus rhythm (Group 2). All underwent right heart catheterization and transthoracic echo to evaluate hemodynamics and LA function. Mitral regurgitation was evaluated by transesophageal echocardiography. LA diastolic function was measured by comparing filling fraction, pulmonary venous flow and compliance. RESULTS: Right atrial, pulmonary artery systolic and mean pressures were similar. Mean wedge pressure were increased in Group 1, 20.8+/-2.6 versus 9.7+/-2.8 mm of Hg (p<0.0001). The most striking hemodynamic difference was large V wave in Group 1 without significant mitral regurgitation. LA filling fraction was abnormal in Group 1, 11.4%+/-8.5 compared to Group 2, 111.5%+/-44 (p<0.0001). LA compliance was 0.39+/-0.27 ml/m2/mmHg in Group 1 versus 6.8+/-4.54 ml/m2/mmHg in Group 2 (p=0.001). There was a strong negative correlation between the V wave and LA filling fraction (r= 0.756, p<0.001). The ratio of the height of the transmitral E wave divided by the S/D ratio (the LA diastolic dysfunction index) correlated very strongly with the V wave (r=0.907, p<0.001). CONCLUSION: LA diastolic dysfunction is present in some patients with long standing AF and PVH. LA diastolic dysfunction, in addition to left ventricular diastolic dysfunction, may contribute to the syndrome of heart failure with preserved left ventricular systolic function. PMID- 27957117 TI - A Challenging Case Of Ventricular Arrhythmia In A Patient With Myocarditis: ICD Yes/No After Ablation. AB - In patients with myocarditis, early diagnosis and appropriate therapy are mandatory, as well as close clinical follow-up with particular regard to progression of disease and ventricular arrhythmia recurrences. The management of ventricular arrhythmias should follow current guidelines for ICD implantation, but new therapeutic options could be evaluated in these patients, such as combined epicardial/endocardial ablation and external wearable defibrillator. Particularly, depressed left ventricular ejection fraction (LVEF) represents the only risk marker for sudden cardiac death currently used in myocarditis, although the use of a single risk factor has limited utility. On this regard, combined analysis of myocardial tissue structure by cardiac magnetic resonance (CMR) and endomyocardial biopsy, in association with resting cardiac systolic function, could improve predictive accuracy for SCD in patients with myocarditis. PMID- 27957118 TI - How To Better Identify Patients That Do Not Benefit From Prophylactic ICD Therpy. AB - The implantable cardioverter defibrillator (ICD) has been demonstrated to improve survival by reducing sudden cardiac death (SCD) in patients with a low left ventricular ejection fraction (LVEF). Randomised trial data suggest that this mortality reduction is not constant among those implanted with a device, and has raised the significance of non-sudden cardiac death (non-SCD) as an important mode of death predicting limited benefit from ICD therapy. In this review article we explore the role of non-SCD and the risk prediction models that may aid identification of low LVEF patients unlikely to gain significant benefit from ICD therapy. PMID- 27957119 TI - Non-Inducibility Or Termination As Endpoints Of Atrial Fibrillation Ablation: What Is The Role? AB - Catheter ablation is widely used to treat drug-refractory, symptomatic atrial fibrillation (AF). However, beyond pulmonary vein isolation, there remains little consensus on the recommended approach to ablation both in paroxysmal or persistent AF patients. Although ancillary ablation strategies are often used, the lack of a clear endpoint for AF ablation makes it challenging to evaluate their importance. Non-inducibility and termination of AF during AF ablation have been advocated as potential endpoints. Several studies have attempted to assess their role in an AF ablation protocol. However, the data for non-inducibility and termination as endpoints are mixed. Moreover, there are a number of limitations in the studies reported and limitations of the endpoints themselves. It is likely that non-inducibility or termination of AF during AF ablation may be markers of less structural remodeling rather than true endpoints for ablation. Herein, we review the relevant literature on the topic of inducibility and termination with respect to AF ablation and attempt to draw conclusions with guidance to further investigation. PMID- 27957120 TI - Experimental Evidence Of The Role Of Renal Sympathetic Denervation For Treating Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity and mortality. In addition to mechanisms such as atrial stretch and atrial remodeling, also the activity of the autonomic nervous system has been suggested to contribute to the progression from paroxysmal to persistent AF. Catheter-based renal denervation (RDN) was introduced as a minimally invasive approach to reduce renal and whole body sympathetic activation which may result in atrial antiarrhythmic effects under some pathophysiological conditions. This review focuses on the potential effects of RDN on different arrhythmogenic mechanisms in the atrium and discusses potential anti-remodeling effects in hypertension, heart failure, and sleep apnea. PMID- 27957121 TI - Non-Invasive Estimation Of Left Atrial Dominant Frequency In Atrial Fibrillation From Different Electrode Sites: Insight From Body Surface Potential Mapping. AB - The dominant driving sources of atrial fibrillation are often found in the left atrium, but the expression of left atrial activation on the body surface is poorly understood. Using body surface potential mapping and simultaneous invasive measurements of left atrial activation our aim was to describe the expression of the left atrial dominant fibrillation frequency across the body surface. 20 patients in atrial fibrillation were studied. The spatial distributions of the dominant atrial fibrillation frequency across anterior and posterior sites on the body surface were quantified. Their relationship with invasive left atrial dominant fibrillation frequency was assessed by linear regression analysis, and the coefficient of determination was calculated for each body surface site. The correlation between intracardiac and body surface dominant frequency was significantly higher with posterior compared with anterior sites (coefficient of determination 67+/-8% vs 48+/-2%, p<0.001). The site with largest coefficient of determination was 79.6% (p<0.001) and was a posterior site. In comparison with the site closest to lead V1 it had a coefficient of determination of 23.0% (p=0.033), and with the posterior body surface site closest to lead V9 had a coefficient of determination of 70.3% (p<0.001). Left atrial dominant fibrillation frequency was more closely represented at posterior body surface sites. PMID- 27957122 TI - Indications For AF Ablation: Before Or After The Failure Of Antiarrhythmic Drug Therapy? AB - Catheter ablation of atrial fibrillation (AF) is considered to be better than anti-arrhythmic drug therapy in terms of maintaining sinus rhythm, and therefore, it has rapidly evolved to become a commonly performed procedure in major hospitals throughout the world. However, on the basis of the evidence currently available, we support the current guidelines recommending antiarrhythmic drugs as a first-line treatment in most patients with AF except younger patients with symptomatic paroxysmal AF with no evidence of structural heart disease, given the risk of fatal complications associated with the ablation procedure. We would like to emphasize that center volume and individual procedure experience are significant determinants of procedure-related complications. As another effect of AF ablation, preventing atrial remodeling and progression to persistent AF is also noteworthy. Further long-term data is needed to answer the question of whether ablation can prevent or delay the advance of structural remodeling and improve life prognosis, particularly in younger patients. PMID- 27957123 TI - Silent Atrial Fibrillation: A Critical Review. AB - Atrial fibrillation (AF) in the most common cardiac arrhythmia, and is associated with an increased risk of thromboembolic events. Silent AF is an asymptomatic form of AF incidentally diagnosed during a routine test or manifesting as an arrhythmia-related complication. Although recent trials have clearly demonstrated that patients with sub-clinical AF are at increased risk of stroke, the real incidence of this form of AF is still unknown. In fact, studies about silent AF had been performed only in specific subgroups of patients such as those with implantable cardiac devices, with recent cryptogenic stroke or transient ischemic attack, and recently undergoing AF ablation. Continuous ECG-monitoring in patients without implantable cardiac devices may improve silent AF detection but its cost-effectiveness actually is not well established in all kind of patients. Moreover, recent data have revealed that only a small number of these patients may have sub-clinical AF within the month prior to their stroke suggesting a lack of temporal relationship between the stroke and the AF episode. This paper will review available data on different diagnostic tools for silent AF detection with a focus on their cost-effectiveness, analyzing the direct correlation between the arrhythmia and embolic events, and discussing areas of uncertainty where further research is required. PMID- 27957124 TI - Non Invasive ECG Mapping To Guide Catheter Ablation. AB - Since more than 100 years, 12-lead electrocardiography (ECG) is the standard-of care tool, which involves measuring electrical potentials from limited sites on the body surface to diagnose cardiac disorder, its possible mechanism and the likely site of origin. Several decades of research has led to the development of a 252-lead-ECG and CT-scan based, three dimensional, electro-imaging modality to non-invasively map abnormal cardiac rhythms including fibrillation. These maps provide guidance towards ablative therapy and thereby help advance the management of complex heart rhythm disorders. Here, we describe the clinical experience obtained using non-invasive technique in mapping the electrical disorder and guide the catheter ablation of atrial arrhythmias (premature atrial beat, atrial tachycardia, atrial fibrillation), ventricular arrhythmias (premature ventricular beats) and ventricular pre-excitation (Wolff-Parkinson-White syndrome). PMID- 27957125 TI - My Patient Taking A Novel Oral Anticoagulant Needs Surgery, Device Implantation, Or Ablation. AB - Atrial fibrillation (AF) is a highly prevalent chronic condition and a growing number of patients are on chronic anticoagulation therapy with novel oral anticoagulant (NOAC) agents: dabigatran, rivaroxaban, and apixaban. Many of these patients are expected to require invasive procedures. There is no clear consensus regarding the peri-procedural management of patients using NOACs, as to how to minimize both bleeding risk and thromboembolism risk. This review of the current available literature is designed to help formulate peri-procedural anticoagulation strategies for patients with AF taking NOACs who are being considered for catheter ablation, device implant, or other surgery. To help frame the discussion, we offer 3 case vignettes that we will revisit to at the end of the review of the existing literature. Case 1: A 62 year-old female with hypertension, diabetes, and symptomatic paroxysmal AF who is prescribed dabigatran for thromboembolism prevention. She has failed attempts at maintaining sinus rhythm with antiarrhythmic drugs. She is now being considered for catheter ablation of AF. Case 2: A 76 year-old male with hypertension, diabetes, prior stroke, and ischemic cardiomyopathy who has persistent drug-refractory AF. He is maintained on chronic anticoagulation with dabigatran for thromboembolism prevention. He has an implantable cardioverter-defibrillator (ICD) which requires a generator change. Case 3: A 58 year-old male with hypertension and paroxysmal AF who takes rivaroxaban for thromboembolic prophylaxis and is being considered for a knee replacement surgery. PMID- 27957127 TI - Happy Holidays. PMID- 27957126 TI - The Optimal Treatment For Atrial Fibrillation In Less Developed Countries. AB - Atrial fibrillation (AF) is the most common arrhythmia and is a major cardiovascular challenge due to its close association with increased morbidity and mortality. Although the incidence and prevalence of AF is slightly lower in developing countries than in developed countries, the AF-associated risk of stroke is similar. Treatment of AF is far from satisfactory in developing countries, which may be due to limited health-care resources and social and racial characteristics that differ from Western populations. Chronic rate control is still the main treatment strategy of persistent AF because anti-arrhythmic drugs have only a modest long-term effect on maintenance of sinus rhythm, and no superior impact in terms of cardiovascular outcomes. With the development of ablation techniques and strategies, more AF patients received catheter ablation, although the benefit, complications, and high recurrence rate associated with AF ablation remain under investigation. Improvement in antithrombotic therapy of AF has been observed, although still fewer patients receive oral anticoagulants in developing countries than in Western countries. Novel treatment for the prevention of thromboembolism, such as new oral anticoagulants with different mechanisms of action or the percutaneous transcatheter closure of the left atrial appendage, has recently been introduced in developing countries as an alternative option for the prevention of AF-associated strokes. More data are needed regarding upstream therapy. PMID- 27957128 TI - Importance Of Delayed Enhanced Cardiac MRI In Idiopathic RVOT-VT: Differentiating Mimics Including Early Stage ARVC And Cardiac Sarcoidosis. AB - A detailed understanding of cardiac anatomy and pathophysiology is necessary to optimize catheter ablation procedural success for patients with symptomatic ventricular tachycardia (VT)/premature ventricular contractions (PVCs) of outflow tract origin. Comprehensive imaging with cardiac magnetic resonance imaging (cMRI) is now at the forefront of procedural planning for complex ventricular arrhythmia ablation for patients with structural heart disease, but is increasingly used in patients with presumed "idiopathic" outflow VT/PVCs as well. cMRI with late gadolinium enhancement (LGE) can localize small regions of myocardial scar from previous myocardial infarction, fibrosis from non-ischemic cardiomyopathy, or edema/fibrosis from inflammatory disorders and help define targets for ablation. LGE, in combination with structural assessment, can help differentiate true idiopathic outflow VT/PVCs from those caused by early stage disease secondary to more significant pathology, such as arrhythmogenic right ventricular cardiomyopathy or cardiac sarcoidosis. We review the benefits of cMRI with LGE for patients with VT/PVCs of outflow origin. PMID- 27957130 TI - Evaluation Of Two Thromboembolism (TE) Risk Methods And Oral Anticoagulation Use Among Cardiac Device Patients With Atrial Tachyarrhythmias (AT). AB - BACKGROUND: In the implantable cardiac device (CD) population, not only can clinically silent atrial tachyarrythmias (AT) be detected, but an associated AT burden can be documented. There are two methods of determining stroke risk: CHADS2 and CHA2DS2-VASc. Recommendations for initiating anticoagulation based on stroke risk profiles and/or AT burden remain unclear for device-detected AT. OBJECTIVE: Aims of this study were to reveal the AT burden among CD patients, determine CHADS2 and CHA2DS2-VASc scores among patients with an AT burden, and evaluate current practices for anticoagulation. METHODS: Records were reviewed from patients undergoing a new CD implant within the last three years from two device clinics. Continuous variables were expressed as mean with standard deviation (SD) and categorical variables were stated as numbers and percentages. The categorical variables were compared using the Chi2 Square test and the continuous variables were compared using the independent 2-sided t-test. RESULTS: There were 275 CD patients enrolled. Eighty-seven had an AT burden and 188 patients did not have an AT burden. CD patients with AT burden were older than those without AT burden [69 (11), p=0.007]. Patients with AT burden had more hypertension and previous history of stroke (p=0.038, p=0.005) compared to those without AT burden. Both the CHADS2 and CHA2DS2-VASc mean scores were higher in patients with an AT burden (p=0.018 and p=0.041). Thirty patients with a previous history of AT were on anticoagulation (p=<0.001) prior to implant. Forty-eight patients had a new diagnosis of AT (NDAT) and 46% (n=22) were started on anticoagulation. CONCLUSIONS: An AT burden was detected in 32% of patients with at least 75% falling within a high-risk category using both scores. However, less than half of NDAT patients were started on anticoagulation. The use of oral anticoagulation in practice remains inconsistent and further randomized trials are recommended. PMID- 27957129 TI - Von Willebrand Factor Plasma Levels Variability In Nonvalvular Atrial Fibrillation. AB - Atrial Fibrillation (AF) is the most common cardiac arrhythmia of clinical significance; it increases the risk of mortality due to stroke. The mechanisms behind cerebral thromboembolism in AF are associated with a prothrombotic state, demonstrated by higher levels of von Willebrand Factor (vWF), a multimeric glycoprotein that plays a crucial role in platelet adhesion and aggregation and it has been proposed as a biomarker of endothelial dysfunction. Plasma vWF levels are elevated in patients with nonvalvular Atrial Fibrillation (NVAF) associated to the presence of cardiovascular risk factors. The variability in vWF plasma levels in healthy subjects has a wide distribution, but there is no description available of the variability in AF patients and among types of AF. The aim of this study was to determine the variability of vWF plasma concentrations in patients with NVAF, associated to cardiovascular risk factors. Search strategy included PubMed and Ovid. Keywords used were "Atrial Fibrillation" and "von Willebrand Factor". It includes original articles, with analysis of plasma vWF levels by ELISA, without acute stroke. Review articles and meta-analysis were excluded. Reviewed studies include 22 trials and 6542 patients with nonvalvular AF associated to cardiovascular disease risk factors: age, sex, hypertension, heart failure, diabetes mellitus, prior stroke, coronary artery disease. Variability in vWF plasma levels was wide, with minimum values of 77 IU/dl and maximum values of 245 IU/dl and a mean of 146 IU/dl. Age of patients ranged between 54 and 78 years, and the percentage of males ranged between 23% and 80%. According to type of AF vWF levels were as follows, in paroxysmal AF: 92-264 IU/dl; persistent AF: 76-234 IU/dl; permanent AF: 91-247 IU/dl. The variability in vWF plasma levels is affected by risk factors and the AF type, however vWF levels in AF patients are higher when compared with healthy subjects. PMID- 27957131 TI - New Imaging Technologies To Characterize Arrhythmic Substrate. AB - The cornerstone of the new imaging technologies to treat complex arrhythmias is the electroanatomic (EAM) mapping. It is based on tissue characterization and in particular on determination of low potential region and dense scar definition. Recently, the identification of fractionated isolated late potentials increased the specificity of the information derived from EAM. In addition, non-invasive tools and their integration with EAM, such as cardiac magnetic resonance imaging and computed tomography scanning, have been shown to be helpful to characterize the arrhythmic substrate and to guide the mapping and the ablation. Finally, intracardiac echocardiography, known to be useful for several practical uses in the setting of electrophysiological procedures, it has been also demonstrated to provide important informations about the anatomical substrate and may have potential to identify areas of scarred myocardium. PMID- 27957132 TI - Electroanatomical mapping of atrial fibrillation: Review of the current techniques and advances. AB - The number of atrial fibrillation (AF) catheter ablations performed annually has been increasing exponentially in the western countries in the last few years. This is clearly related to technological advancements, which have greatly contributed to the improvements in catheter ablation of AF. In particular, state of-the-art electroanatomical mapping systems have greatly facilitated mapping processes and have enabled complex AF ablation strategies. In this review, we outline contemporary and upcoming electroanatomical key technologies focusing on new mapping tools and strategies in the context of AF catheter ablation. PMID- 27957133 TI - Rate Control Strategy Elevated To Primary Treatment For Atrial Fibrillation: Has The Last Word Already Been Spoken? AB - In the last decade, we were able to see the light shed by several trials and observational studies that dealt with the appropriate manner of treating patients with atrial fibrillation (AF). Recently the AF management by cardiologists has become more aggressive, in part because of an improved comprehension of this rhythm disturbance, as well as, the availability of new treatment strategies. Increasing awareness of AF as a disease rather than as an acceptable alternative to sinus rhythm has led to search for clear arguments to support a certain strategy as a gold standard. In this respect, the decision of whether to restore sinus rhythm, or to control the ventricular rate and allow AF to persist is of critical importance. The results of randomized, controlled trials addressing this matter shed some light on the proper way of treatment for these AF patients. The AFFIRM and RACE trials and their respective sub-studies showed surprising results. The vast majority of physicians were surprised to learn that the rate control strategy was elevated to the position of primary treatment for the AF management instead of the all-time recognized rhythm control approach to restoration and maintenance of sinus rhythm. The use of anticoagulants in the trials was different in the treatment strategies. There was a greater anticoagulant use in the rate control arm because of the belief that anticoagulation can be discontinued in the rhythm control arm when sinus rhythm was restored and maintained for one month. On the other hand, only pharmacological agents were used to maintain sinus rhythm in those trials, however, there is increasing evidence that AF ablation can restore and maintain sinus rhythm in a great proportion of patients. Indeed, there are some limitations and several interesting aspects of these trials and other studies that will be discussed. The last word has not been spoken yet. PMID- 27957134 TI - Should Adenosine Test be Performed Systematically at the End of Atrial Fibrillation Ablation Procedure? AB - Pulmonary vein (PV) reconnection is a major limitation of atrial fibrillation (AF) ablation and is a significant contributor for arrhythmia recurrence, particularly in patients with paroxysmal AF. Recent technological advances, including the use of steerable sheaths and force sensing catheters resulted in reduced incidence of PV reconnection; however its incidence remains unacceptably high. Additional efforts to reduce pulmonary vein reconnection include the use adenosine to detect dormant PV to left atrial (LA) electrical conduction as well as identification of non-PV triggers. While this strategy is associated with an increased detection rate of reconnection that can be further targeted with ablation, its effect on long-term arrhythmia control is controversial. Still, adenosine-induced PV reconnection appears to be an independent predictor of arrhythmia recurrence despite additional ablation. We favor its use in patients with paroxysmal AF as an additional step for risk stratification and prediction of arrhythmia recurrence. PMID- 27957135 TI - Which Is The Appropriate Arrhythmia Burden To Offer RF Ablation For RVOT Tachycardias? AB - Premature ventricular complexes (PVCs) and ventricular tachycardia (VT) in patients with structurally normal hearts originate from the right ventricular outflow tract (RVOT) in the majority of cases. In the last few decades catheter ablation of these arrhythmias has been proven to be effective. RVOT VT/PVCs may cause disabling symptoms or arrhythmia induced cardiomyopathy. However, the PVC burden at which catheter ablation should be recommended is still controversial. What adds to the controversy is why some patients with only a low number of PVCs can be highly symptomatic and may even develop arrhythmia induced cardiomyopathy, whilst others may have a higher PVC/VT burden and remain asymptomatic and do not develop cardiomyopathy for a long period of time. Therefore, although catheter ablation of RVOT PVCs has high success and low complication rates, the time point of when ablation should be recommended is currently still under debate. This review discusses the treatment strategies and prognosis for RVOT tachycardias and focuses on the question of which arrhythmia burden is appropriate to offer RF ablation. PMID- 27957136 TI - Echocardiographic Parameters Associated With Asymmetrical Structural Remodeling In Patients With Or Without Atrial Fibrillation. AB - OBJECTIVES: Left atrial (LA) dilation can evolve into asymmetrical remodeling. The aim of this study was to determine the echocardiographic parameters associated with LA asymmetric structural remodeling (ASR) in patients with and without nonvalvular atrial fibrillation (AF). METHODS AND RESULTS: A total of 170 patients with a dilated LA were prospectively enrolled. ASR was defined as an atrium shape that is no longer ellipsoidal (LA basal dimension measured at the junction between the pulmonary vein and atrium greater than the mitral annular dimension). Symmetric structural remodeling (SSR) was defined as all other cases. Echocardiographic parameters of LA function and left ventricular diastolic function, measured by pulsed-wave Doppler and Tissue Doppler Imaging, were analyzed to identify the parameters associated with ASR. The mean age of the patients was 67 +/- 11 years. Forty-one percent had a stable sinus rhythm (SR), and 59% had AF. LA-ASR was detected in 66% of the patients: 55% with AF and 45% with SR (p=0.002). The mean LA-ASR and LA-SSR volume indexes were 49 +/- 14 ml/m2 and 29 +/- 13 ml/m2, respectively (p<0.001). LA systolic myocardial velocity (p=0.036) and peak systolic pulmonary venous flow velocity (p=0.033) were the parameters best associated with ASR. The sensitivity and specificity of both parameters, based on ROC curve analysis, were 77 and 70%, respectively. The AUC was 0.765 (95% CI: 0.662-0.849, p=0.0001). CONCLUSION: LA dilation is associated with a great number of asymmetrical structural remodeling. Echocardiographic parameters that reflect LA reservoir function are best associated with asymmetrical remodeling. PMID- 27957138 TI - Renal Denervation And Pulmonary Vein Isolation In Patients With Drug Resistant Hypertension And Symptomatic Atrial Fibrillation. AB - Systemic hypertension is the most consistent modifiable risk factor for atrial fibrillation (AF) in adults with consistent data from both animal models and human studies suggesting a consistent pattern of autonomic imbalance underlying both conditions. Relative sympathetic nervous system activation is a demonstrably common attendant to the local mechanisms in pulmonary veins that sustain persistent or recurrent AF and may represent a new objective for adjunctive treatment. Established management of AF aims to achieve durable control through either pharmacologic or catheter-based interventions. The introduction of catheter-based renal denervation as a safe, alternate approach to target the sympathetic nervous system therapeutically represents a potential opportunity to treat the shared pathophysiological mechanisms with minimal additional treatment burden when added in this context. Preliminary investigations have demonstrated both proof-of-concept and the technical feasibility of combined renal denervation and AF ablation procedures with the suggestion of benefit in terms of freedom from AF recurrence. The available data is promising but absolute confirmation of efficacy remains unconfirmed in the absence of more definitive evidence. This paper reviews the role of autonomic imbalance in the initiation and maintenance of AF by summarizing the observations from both experimental models and clinical studies from the perspective of potential therapeutic overlap between catheter based treatments. PMID- 27957137 TI - Right Ventricular Outflow Tract Arrhythmias: Benign Or Early Stage Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia? AB - Ventricular arrhythmias (VAs) arising from the right ventricular outflow tract (RVOT) are a common and heterogeneous entity. Idiopathic right ventricular arrhythmias (IdioVAs) are generally benign, with excellent ablation outcomes and long-term arrhythmia-free survival, and must be distinguished from other conditions associated with VAs arising from the right ventricle: the differential diagnosis with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is therefore crucial because VAs are one of the most important causes of sudden cardiac death (SCD) in young individuals even with early stage of the disease. Radiofrequency catheter ablation (RFCA) is a current option for the treatment of VAs but important differences must be considered in terms of indication, purposes and procedural strategies in the treatment of the two conditions. In this review, we comprehensively discuss clinical and electrophysiological features, diagnostic and therapeutic techniques in a compared analysis of these two entities. PMID- 27957140 TI - Complete Isolation of the Left Atrial Posterior Wall (Box Lesion) to Treat Longstanding Persistent Atrial Fibrillation. AB - INTRODUCTION: The left atrial posterior wall has been shown to play na important role in AF pathophysiology. OBJECTIVE: Evaluate the efficacy of an ablation strategy designed to completely isolate the LA posterior wall, on top of PV isolation. Methods and Results: 25 pts (72% male age 65 +/- 12 years) undergoing AF ablation for persistent or long term persistent AF. Mean AF duration was 11 +/ 3 months and mean LA diameter was 4.8 +/- 0.4 mm. After complete PVI, a "Roof Line" was created between the top of each contralateral set of lesions and a "floor line" closed the posterior wall in a "Box" fashion, connecting the bottom of each set of contralateral lesions. After an average follow-up of 16 +/- 2 months, 20 patients (80%) were free of any atrial arrhythmia recurrences (18 of whom off drugs). Five patients (20%) had sustained atypical flutter and required a new ablation procedure. All these patients had mitral isthmus dependent flutters and no electrical conduction in the PVs or posterior wall were detected. CONCLUSIONS: Complete LA posterior wall isolation on top of PV is associated with good outcomes in patients with persistent and long-standing persistent AF when performed using meticulous bidirectional isolation criteria and adenosine infusion. Recurrences occur predominately as perimitral flutter, without gaps in the posterior wall. PMID- 27957139 TI - J Wave Syndrome: Clinical Diagnosis, Risk Stratification and Treatment. AB - J wave syndrome has emerged from a benign electrocardiographic abnormality to a proarrythmic state and a significant cause of idiopathic ventricular fibrillation responsible for sudden cardiac death. Electrical genesis, genetics and ionic mechanisms of J wave syndromes are active areas of research. Typically two of these viz., Early repolarization syndrome (ER) and Brugada syndrome (BrS) are fairly well characterized enabling correct diagnosis in most patients. In early repolarization syndrome, J waves are seen in inferior (2,3, avF) or lateral leads (V4, V5, V6), while in Brugada syndrome they are best seen in right precordial leads (V1-V3). The first part of repolarization of ventricular myocardium is governed by Ito current i.e., rapid outward potassium current. The proposed mechanism of ventricular fibrillation (VF) and ventricular tachycardia (VT) storms is faster Ito current in the epicardium than in the endocardium resulting in electrical gradient that forms the substrate for phase 2 re-entry. Prevention of Ito current with quinidine supports this mechanism. Morphological features of benign variety of J wave syndrome and malignant/ proarrythmic variety have now been fairly well characterized. J waves are very common in young, athletes and blacks; risk stratification for VF/sudden cardiac death (SCD) is not easy. Association of both ER syndrome and Brugada syndrome with other disease states like coronary artery disease is being reported frequently. Those with ECG abnormality as the only manifestation are difficult to manage. Certain ECG patterns are more proarrythmic. Individuals resuscitated from VF definitely need an implantable cardiac defibrillator (ICD) but in others there is no consensus regarding therapy. Role of electrophysiology study to provoke ventricular tachycardia or fibrillation is not yet well defined. Radiofrequency ablation of epicardial substrate in right ventricle in Brugada syndrome is reported and is also under critical evaluation. In this review we shall discuss some interesting historical features, epidemiology, electrocardiographic features, and ionic mechanisms on pathogenesis, clinical features, risk stratification and treatment issues in J wave syndromes. Brugada syndrome is not discussed in this review. PMID- 27957142 TI - 3D Intracardiac Echocardiography/CartoSoundTM Imaging of Esophagus Guided Left Atrial Posterior Wall Ablation for Atrial Fibrillation. AB - Two imaging cases highlight the important role of 3D ICE/CartosoundTM in the intracardiac echocardiographic imaging of esophagus and CartosoundTM guidance of radiofrequency lesions delivered safely at the left atrial posterior wall adjacent to esophagus during atrial fibrillation ablation. PMID- 27957141 TI - Cryptogenic Stroke And Role Of Loop Recorder. AB - Ischemic stroke is an important cause of morbidity and mortality when untreated. Identifying atrial fibrillation is important because atrial fibrillation ischemic related strokes are associated with an increased risk of disability and death compared with strokes of other etiologies and tend to recur without anticoagulation. However, atrial fibrillation detection can be difficult when it is asymptomatic and paroxistic and may be the underlying cause of some cryptogenic strokes or strokes of unknown origin. In this review, the different methods of cardiac monitoring to detect atrial fibrillation in patients with cryptogenic stroke are summarized, with a focus on loop recorder monitoring. PMID- 27957143 TI - Initial Experience with A Novel Flexible-Tip Irrigated Ablation Catheter in a Case of Paroxysmal Atrial Fibrillation. AB - AF ablation can be curative or reduce the symptoms of AF. However, success rates are suboptimal while procedure times can be long. Since AF ablation depends on excellent tip to tissue contact, ease of use and signal quality, a new ablation catheter (FlexAbilityTM Ablation Catheter, St Jude Medical, St Paul, MN) was designed for use during complex ablation. We report an initial case of its use during paroxysmal AF. PMID- 27957144 TI - Another Successful Year of Learning and Education in Atrial Fibrillation ! PMID- 27957145 TI - Idiopathic Ventricular Tachycardia: Transcatheter Ablation or Antiarrhythmic Drugs? AB - INTRODUCTION: Ventricular tachycardia or frequent premature ventricular contractions (PVCs) can occur in the absence of any detectable structural heart disease. In this clinical setting, these arrhythmias are termed idiopathic. Usually, they carry a benign prognosis and any potential ablative intervention is carried out if patients are highly symptomatic or, more importantly, if frequent ventricular arrhythmias can lead to ventricular dysfunction. METHODS: In this paper, different forms of idiopathic ventricular tachycardia are reviewed. Outflow tract ventricular tachycardia from the right ventricle is the most frequent form of the so-called idiopathic ventricular tachycardia. Other forms of idiopathic ventricular arrhythmias include ventricular tachycardia/PVCs arising from tricuspid annulus, from the mitral annulus, inter-fascicular ventricular tachycardia and papillary muscle ventricular tachycardia. When interventional treatment is deemed necessary, detailed mapping ( earliest activation during VT/PVC, pace mapping ) is crucial as to identify the successful ablation site. Catheter ablation more than antiarrhythmic drug treatment is usually highly effective in eliminating idiopathic ventricular arrhythmias and providing prevention of recurrence. CONCLUSIONS: Idiopathic VTs are not considered life threatening arrhythmias and, prevention of recurrences is often achieved by means of catheter ablation that provides an improvement of quality of life. The overall acute success rate of catheter ablation is about 85-90% with a long-term prevention of arrhythmia recurrence of about 75-80%. It is advisable that the procedure is carried out by electrophysiologists with expertise in VT catheter ablation and extensive knowledge of cardiac anatomy as to ensure a high success rate and reduce the likelihood of major complications. PMID- 27957146 TI - Catheter Ablation of Atrial Fibrillation Without Radiation Exposure Using A 3D Mapping System. AB - Transcatheter ablation procedures have been traditionally performed under fluoroscopic guidance. However, x-ray exposure is afflicted by the risk of developing malignancies as well as other deterministic effects of radiation. For this reason, radiation doses in the interventional laboratory should be reduced "As Low As Reasonably Achievable", with respect to the safety of the patients and the medical staff. This is of utmost importance in atrial fibrillation (AF) ablations, which are usually lengthy procedures. With the improvement of technology, the development of additional imaging tools and the widespread of 3D electroanatomic mapping systems (EAM), near-zero fluoroscopy AF ablation procedure is becoming a reality, limiting fluoroscopy use mainly to guide transseptal puncture. In the present paper we reviewed the risks to health related to x-ray exposure and we discussed the current state of knowledge of catheter ablation of AF without fluoroscopy in the 3D EAM system era. PMID- 27957147 TI - Significance and Management Strategies for Patients with Asymptomatic Atrial Fibrillation. AB - Atrial fibrillation (AF) is a common and refractory arrhythmia. Prevalence of AF increases with age. Asymptomatic AF is a state of asymptomatic episodes of arrhythmia and its exact prevalence remains unknown. Ablation and therapy with antiarrhythmic agents may predispose to asymptomatic AF. Detection of silent AF is crucial for prevention of ischaemic stroke. Progress in continuous ECG monitoring by Holter ECG, telemetry methods or implantable devices can provide a useful tools for identifying silent AF. Simple screening procedures like pulse examination and ambulatory ECG may be helpful in arrhythmia detection and logically - ischemic stroke prevention. PMID- 27957149 TI - Successful Ablation of Single Reentrant Ventricular Tachycardia Arising from Peri Aortic Scar in a Patient with an Apparently Normal Heart. AB - Peri-aortic region is one of the arrhythmogenic foci associated not only with idiopathic ventricular tachycardia (VT), but also scar-related VT in patients with an apparently normal heart.[1-3] A recent study reported that the patients with scar-related VT were significantly older, had a frequent history of hypertension, and inducibility of multiple monomorphic VTs compared to the patients with idiopathic VT.[2] However, whether these clinical features are the causes of the peri-aortic scar or innocent by-standers, remain uncertain. Here, we present a relatively young normotensive patient with a peri-aortic scar and emphasize the importance of cardiac MRI to detect latent arrhthmogenic substrates. PMID- 27957148 TI - Integrated Chronic Care Management For Patients With Atrial Fibrillation - A Rationale For Redesigning Atrial Fibrillation Care. AB - Atrial Fibrillation (AF) is a highly prevalent heart rhythm disturbance, often associated with underlying (cardio)vascular disease. Due to this the management of AF is often complex and current practice calls for a more comprehensive, multifactorial and patient-centred approach. Therefore an Integrated Chronic Care approach in AF was developed and implemented in terms of a nurse-led specialized outpatient clinic for patients with AF. A randomised controlled trial comparing the nurse-led approach with usual care demonstrated superiority in terms of cardiovascular hospitalization and death as well as cost-effectiveness in terms of Quality Adjusted Life Years (QALYs) and life years, in favour of the nurse-led approach. Implementing such approach can be difficult since daily practice can be persistent. To highlight the importance of integrated care wherein the nurse fulfils a significant role, and to provide a guide in developing and continuing such approach, this paper presents the theoretical framework of the AF-Clinic based on the principles of the Taxonomy for Integrated Chronic Atrial Fibrillation Management. PMID- 27957150 TI - The Atrial Fibrillation Therapies after ER visit: Outpatient Care for Patients with Acute AF - The AFTER3 Study. AB - BACKGROUND: Visits to the emergency room (ER) for atrial fibrillation/flutter (AF) are common, but follow-up care is rarely systematically organized and is often delayed. PURPOSE: We conducted a pilot program to develop a systematic, protocol-based system of care for patients presenting to the ER with a primary diagnosis of AF. METHODS: Consecutive patients presenting to the ER with ECG documented AF at an urban teaching hospital were treated according to a guideline based care protocol, including a patient toolkit at ER discharge, and systematic referral to a rapid access AF clinic. Consenting patients received questionnaires on AF knowledge, patient satisfaction, and the AFEQT questionnaire at first visit and three-month follow-up. RESULTS: Of the 321 patients with AF, 244 (76%) were discharged from the ER and 166 (68%) were referred to the AF clinic for urgent follow-up. Among 166 referred, 144 (87%) were seen, within a median 10.5 days (IQR 6-16.5 days); 128 (89%) patients agreed to participate in the study and 81% received a toolkit in the ER. The mean age of patients seen in AF clinic was 63.6+/-13.2 years and 59% were male. Eighty-seven percent were aware of their diagnosis, stroke risk (82%), possible complications (90%), treatment options (86%) and benefits of adherence (86%). Severity of Atrial Fibrillation class was > 2 in 51% at baseline; AFEQT scores increased from baseline (56.4+/-25.5) to three months post-ER visit (76.4+/-20.0), a moderately large improvement in QOL (p<0.0001). Seventy eight percent of patients with CHA2DS2-VASc score > 1 were treated with an oral anticoagulant. CONCLUSIONS: A systematic program to improve patient transition of care from the ER to community clinic was associated with prompt, guideline-based care, and high levels of patient disease awareness. Quality of life scores improved substantially between the index ER visit and 3 months post-visit. PMID- 27957151 TI - Improved Resource Utilization With Similar Efficacy During Early Adoption of Cryoballoon Pulmonary Vein Isolation as Compared to Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. AB - BACKGROUND: Cryoballoon pulmonary vein isolation (PVI) is an alternative to radiofrequency (RF) PVI for the treatment of paroxysmal atrial fibrillation (AF). Treatment effect, complication rates, and hospital length of stay are not well established with early use of cryoballoon PVI as compared to more experienced performance of RF PVI. PURPOSE: We reviewed the early experience of cryoballoon PVIs for paroxysmal AF performed by 3 operators at our institution compared to their most recent RF PVIs. All repeat procedures were excluded. Patients were assessed for recurrence of AF at 6 months after the procedure, including a 3 month blanking period. Complications, procedure time, and hospital length of stay were recorded. METHODS: Consecutive patients presenting to the ER with ECG documented AF at an urban teaching hospital were treated according to a guideline based care protocol, including a patient toolkit at ER discharge, and systematic referral to a rapid access AF clinic. Consenting patients received questionnaires on AF knowledge, patient satisfaction, and the AFEQT questionnaire at first visit and three-month follow-up. RESULTS: Final analysis included 50 cryoballoon PVIs and 50 RF PVIs. There was no significant difference in baseline characteristics or percentage of patients wearing a home monitor (80% for cryoballoon vs 80% for RF). Symptomatic improvement was experienced by 96% of cryoballoon PVI as compared to 86% of RF PVI patients (p=0.08). Freedom from AF at 6 months was similar between the two groups (70% for cryoballoon and 70% for RF, p=1). Complications were seen in 6% of cryoballoon procedures as compared to 10% of RF procedures (p=0.46). Hospital length of stay was significantly shorter in the cryoballoon group (1.6 vs 3.4 nights, p=0.003). CONCLUSION: At the time of its adoption, cryoballoon PVI is associated with shorter procedure times and hospital length of stay as compared to RF PVI in experienced operators while maintaining similar efficacy outcomes and complication rates. PMID- 27957152 TI - Predictors of Atrial Fibrillation Risk in Hypertrophic Cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disease that predisposes individuals to the development of arrhythmias. The most common sustained arrhythmia is atrial fibrillation (AF). Compared with the general population, patients with HCM are more prone to the development of AF. To avoid embolic complications and the clinical deterioration caused by the development of AF in HCM, identifying patients with a tendency toward AF might affect the management of HCM. In this review, we evaluated the predictors of AF development in patients with HCM. PMID- 27957153 TI - Seasonal Variation in Paroxysmal Atrial Fibrillation: A Systematic Review. AB - INTRODUCTION: A variety of cardiovascular diseases have been demonstrated to have seasonal variations with peaks in the winter and troughs in the summer. Studies regarding atrial fibrillation (AF) have had varying results and this review describes the current data regarding the seasonal variation of AF and mechanisms mediating this seasonal fluctuation. METHODS: A systematic review was conducted of PubMed, EBSCO and OVID for manuscripts describing the association between seasonal variation and the occurrence of AF. Studies meeting eligibility criteria were assessed for quality and reporting bias. Data was extracted in regards to the following associations: seasonal variation and AF paroxysms, temperature and AFparoxysms, duration of daylight and AF paroxysms, barometric pressure and AF paroxysms, alcohol and AF paroxysms, as well as seasonal variation and AF related stroke. RESULTS: A total of 15 studies were identified for inclusion. Of these, 11 studies assessed seasonal variation and the remaining 4 studies assessed seasonal variation in AF related stroke. AF paroxysms peaked in winter with a trough in summer. There was an inverse correlation between temperatures as well barometric pressure and the occurrence of AF paroxysms and a positive correlation with duration of daylight. CONCLUSIONS: The rate of occurrence of paroxysmal AF varies by seasons and is greatest during winter and least in summer. PMID- 27957154 TI - Late Outcome of Atrial Fibrillation Ablation Program at Unity Point Health Methodist in Peoria Illinois. AB - STUDY METHOD: The objective of this study was to evaluate the long term efficacy and safety of the atrial fibrillation program at Unity Point Health Methodist in Peoria. METHODS: A retrospective analysis was performed on patients who had atrial fibrillation procedures at Unity Point Methodist from February 19 th 2010 to September 26 th 2014. Patients were enrolled and information obtained through the patient's medical records. RESULTS: The study consisted of 53 patients, 65 percent of patients were paroxysmal, and 35 percent had chronic or persistent atrial fibrillation. The mean age was 66 +/- 23 (45 to 89 years). The average CHADS-Vasc Score is score is 2.13. Baseline co-morbidities included 34 individuals with HTN, 10 with Diabetes, and 4 with coronary artery disease. The average EF was 55% +/-25 (30% to 70%) and the average LA diameter 41 +/-15 mm (25 56). The average number of antiarrhythmic was 1.5 prior to ablation. After a mean follow-up of 28 +/- 29 months (range, 3 to 57 months), freedom from AF was 94% overall (51 of 53 patients, including 52 were on antiarrhythmic drugs), 94% for paroxysmal AF (34 of 36 patients, including 24 of whom discontinued their antiarrhythmic drugs), and 94% for persistent AF (16 of 17 patients, including 9 no longer on antiarrhythmic drugs). 76 percent experienced a decrease in their antiarrhythmic medications of which 60 percent discontinued antiarrhythmic altogether. Out of the 53 patients, there were three major but completely reversible transient complications. Two of the complications were related to pericardial effusion that was successfully drained with no recurrence. The last complication was phrenic nerve injury in a patient who showed complete recovery 4 month after the procedure. CONCLUSIONS: Long-term results of atrial fibrillation ablation at Unity Point Health Methodist showed safety and efficacy of the program in the treatment of symptomatic atrial fibrillation in both paroxysmal and persistent groups. PMID- 27957156 TI - Spring Momentum!! PMID- 27957155 TI - Elimination Of Triggers Without An Additional Substrate Modification Is Not Sufficient In Patients With Persistent Atrial Fibrillation. AB - Atrial fibrillation (AF) is a multifactorial disease with complex pathophysiology. Although restoring sinus rhythm delays the progression of atrial remodeling, non-pharmacologic intervention, such as radiofrequency catheter ablation (RFCA), should be done based on the background pathophysiology of the disease. While circumferential pulmonary vein isolation (CPVI) has been known to be the cornerstone of AF catheter ablation, a clinical recurrence rate after CPVI is high in patients with persistent AF (PeAF). Step-wise linear ablation, complex fractionate atrial electrogram (CFAE)-guided ablation, rotor ablation, ganglionate plexus ablation, and left atrial appendage isolation may improve the ablation success rate after CPVI. But, there are still substantial AF recurrences after such liberal atrial substrate ablation, and current ablation techniques regarding substrate modification still have limitations. Therefore, more understanding about AF pathophysiology and early precise intervention may improve clinical outcome of AF management. Keeping in mind "more touch, more scar," operators should generate most efficient substrate modification to achieve better long-term clinical outcome. PMID- 27957157 TI - Understanding and Managing Atrial Fibrillation in Patients with Kidney Disease. AB - Chronic kidney disease (CKD) is on the rise due to the increased rate of related comorbidities such as diabetes and hypertension. Patients with CKD are at higher risk of cardiovascular events and atrial fibrillation is more common in this patient population. It is estimated that the prevalence of chronic atrial fibrillation in patients with CKD is two to three times higher than general population. Furthermore, patients with CKD are less likely to stay in sinus rhythm. Atrial fibrillation presents a major burden in this population due to difficult treatment decisions in the setting of a lack of evidence from randomized clinical trials. Patients with CKD have higher risk of stroke with more than half having a CHADS2 score >= 2. Anticoagulation have been shown to significantly decrease embolic stroke risk, however bleeding complications such as hemorrhagic stroke is twofold higher with warfarin. Although newer novel anticoagulation drugs have shown promise with lower intracranial hemorrhage risk in comparison to warfarin, lack clinical trial data in CKD and the unavailability of an antidote remains an issue. In this review, we discuss the treatment options available including anticoagulation and the evidence behind them in patients with chronic kidney disease suffering from atrial fibrillation. PMID- 27957159 TI - How To Identify & Treat Epicardial Origin Of Outflow Tract Tachycardias. AB - The right ventricle outflow tract (RVOT) is the most common site of origin of idiopathic ventricular arrhythmias. The typical outflow tract arrhythmias pattern on ECG is an inferior axis deviation and left bundle branch block when originated on the RVOT and right bundle branch block morphology when originated on the left ventricular outflow tract (LVOT). There are several ECG tricks for different locations of origin. An increased Maximum Deflection Index (MDI) suggests epicardial origin of arrhythmia. In general the result of ablation is very good, but sometimes there are difficult and unsuccessful procedures. The origin in the aortic cusps and epicardium are the reason for failure in some cases. When they are epicardial, the arrhythmias can be accessed by the venous system or by subxiphoid epicardial mapping. PMID- 27957160 TI - Influence of Age and Gender on Complications of Catheter Ablation for Atrial Fibrillation. AB - BACKGROUND: Despite catheter ablation (CA) has become an accepted treatment option for symptomatic, drug-resistant atrial fibrillation (AF), safety of this procedure continues to be cause for concern. OBJECTIVE: Aim of the present multicenter study was to assess the influence of age and gender on incidence and severity of early CA complications. METHODS: From January 1, 2011 to December 31, 2011, data from 2,323 consecutive patients who underwent CA (mean age 59.1+10.9; 72.3% male) for AF in 29 Italian centres were collected. All complications occurring to the patients from admission to 30th post-procedural day were recorded. RESULTS: Complications occurred in 94 patients (4.0%); of these 7 (0.30%) developed permanent sequelae. There was a significant trend toward a greater incidence of complications with increasing age-group. In particular, the incidence of complications was 35/1066 (3.3%) in patients <60 year-old vs 59/1257 (4.7%) in those > 60 year-old (p=0.03). All 7 patients with permanent sequeale were older than 60. Females had a higher incidence of complications both among younger [13/231 (5.6%) vs 22/915 (2.5%), p=0.02] and older patients [32/405 (7.9%) vs 27/739 (3.5%) p=0.001]. In subjects older than 60, 5/405 (1.2%) females and 2/176 (0.3%) males (p=0.04) suffered from permanent sequelae. CONCLUSIONS: Older patients and females are a subgroup at higher risk of complications during AF ablation. A particular care should be taken when performing CA in this clinical setting. PMID- 27957158 TI - A Questionable Indication For ICD Extraction After Successful VT Ablation. AB - Sustained ventricular tachyarrhythmias represent a kind of complication shared by a number of clinical presentations of heart disease, sometimes leading to sudden cardiac death. Many efforts have been made in the fight against such a complication, mainly being represented by the implantable cardioverter defibrillator (ICD). In recent years, catheter ablation has grown as a means to effectively treat patients with sustained ventricular arrhythmias, in the contest of different cardiac substrates. Since carrying an ICD is associated with a potential risk deriving from its possible infective or malfunctioning complications, and given the current effectiveness of lead extraction procedures, it has been thought not to be unreasonable to ask ourselves about how to deal with ICD patients who have been successfully treated by means of ablation of their ventricular arrhythmias. To date, no control data have been published on transvenous lead extraction in the setting of VT ablation. In this paper we will review the current evidence about ICD therapy, catheter ablation of ventricular arrhythmias and lead extraction, trying to outline some considerations about how to face this new clinical issue. PMID- 27957161 TI - Optimizing CRT - Do We Need More Leads and Delivery Methods. AB - Cardiac resynchronization therapy (CRT) is an established therapeutic option in symptomatic heart failure with reduced ejection fraction and evidence of left ventricular (LV) conduction delay (QRS width >=120 ms), especially when typical left bundle branch block is present. The rationale behind CRT is restoration of aberrant LV electrical activation. As there is considerable heterogeneity of the LV electrical activation pattern among CRT candidates, an individualized approach with targeting of the LV lead in the region of latest electrical activation while avoiding scar tissue may enhance CRT response. Echocardiography, electro anatomic mapping, and cardiac magnetic resonance imaging with late gadolinium enhancement are helpful to guide such targeted LV lead placement. However, an important limitation remains the anatomy of the coronary sinus, which often does not allow concordant LV lead placement in the optimal region. Epicardial LV lead placement through minimal invasive surgery or endocardial LV lead placement through transseptal punction may overcome this limitation, obviously with an increased complication risk. Furthermore, recent pacing algorithms suggest superiority of LV-only versus biventricular pacing in patients with preserved atrio ventricular (AV) conduction and a typical LBBB pattern. Finally, pacing from only one LV site might not overcome the wide electrical dispersion often seen in patients with LV conduction delays. Therefore, multisite pacing has gained significant interest to improve CRT response. The use of multiple LV leads may potentially lead to more favorable reverse remodeling, improved functional capacity and quality of life in CRT candidates, but adverse events and a shorter battery span are more frequent because of the extra lead. The use of one multipolar LV lead increases the number of pacing configurations within the same coronary sinus side branch (within small distances from each other) without the use of an additional lead. Small observational studies suggest that more effective resynchronization can be achieved with this approach. Finally, there are many reasons for non effective CRT delivery in carefully selected patients with an adequately implanted device. Multidisciplinary, post implantation care inside a dedicated CRT clinic ensures optimal CRT delivery, improves response rate and should be considered standard of care. PMID- 27957162 TI - Conjoined Inferior Pulmonary Veins during Pulmonary Vein Isolation: Prevalence and Novel Approach for Pulmonary Vein Isolation with Cryoballoon. AB - Cardiac resynchronization therapy is an established treatment modality in heart failure. Though non-response is a serious issue. To address this issue, a good understanding of the electrical activation during left bundle branch block, biventricular, as well as right- and left ventricular pacing is needed. This way by interpreting the 12-lead electrocardiogram, possible reasons for suboptimal treatment can be identified and addressed. This article reviews the literature on QRS morphology in cardiac resynchronization therapy and its meaning in optimization of therapy. PMID- 27957165 TI - Cost-Effectiveness of Dabigatran Exilate in Treatment of Atrial Fibrillation. AB - BACKGROUND: Dabigatran exilate has emerged as a highly effective tool in treating atrial fibrillation, AF). Its relative convenience in terms of cost and overall utility with respect to other anti-coagulants, however, has not been explored in much detail yet. METHODS AND RESULTS: We run a Markovian disease simulation model based on a cohort of 1000 randomly generated patients which were sub-grouped by average risk of hemorrhage and average risk of stroke to compare treatments with Aspirin, Warfarin and Dabigatran. Quality-adjusted life-year, QALYs) for the patients were projected over up to 30 years with mortality statistics database and properly adjusted after every 5-year survival from the starting date. If managed within the prescribed range, Warfarin offers the highest outcome in terms of QALYs: 7.93 versus 7.61 for the Aspirin treatment and 7.57 for highest dose treatment with Dabigatran. Dabigatran outperformed the other treatments in patients at high risk of major stroke, provided Warfarin was not managed optimally. The incremental cost-effectiveness ratio for Dabigatran versus sub optimally managed Warfarin was ?7,759.48/QALY meaning that every year in perfect health earned with Dabigatran cost less than ?8,000 more than the alternative treatment with Warfarin. CONCLUSIONS: The therapy with high-dose Dabigatran proved the most clinically safe solution for patients at high risk of stroke unless Warfarin therapy was excellent. PMID- 27957163 TI - ECG Patterns In Cardiac Resynchronization Therapy. AB - Cardiac resynchronization therapy is an established treatment modality in heart failure. Though non-response is a serious issue. To address this issue, a good understanding of the electrical activation during underlying intrinsic ventricular activation, biventricular as well as right- and left ventricular pacing is needed. By interpreting the 12-lead electrocardiogram, possible reasons for suboptimal treatment can be identified and addressed. This article reviews the literature on QRS morphology in cardiac resynchronization therapy and its role in optimization of therapy. PMID- 27957164 TI - Intracardiac Echocardiography in Catheter Ablation for Atrial Fibrillation: It Is Better to See What You Are Doing? AB - Current advanced technology allows the accurate three-dimensional reconstruction of cardiac structures using multiple images from two-dimensional intracardiac echocardiography (ICE). This technology is applicable to atrial fibrillation (AF) ablation and provides real-time anatomical information on relevant atrial structures and myocardial thickness as well as suitable sites for transseptal puncture. ICE allows radiofrequency to be delivered away from structures resistant to ablation and the monitoring of possible complications during AF ablation. Visualization of the inside of both atria during the procedure may contribute to safe and effective AF ablation. The purpose of this review was to elucidate the utility of ICE in AF ablation. PMID- 27957166 TI - Radiation Dose is Significantly Reduced by Use of Contact Force Sensing Catheter During Circumferential Pulmonary Vein Isolation. AB - The creation of a durable radiofrequency (RF) lesion depends on several parameters, including catheter tip electrode size and composition, tip orientation, temperature, RF pulse duration, power, blood flow, and catheter to tissue contact. The development of new contact force (CF) sensor catheters has allowed the measurement of the tip to tissue CF during the RF ablation procedure. Here, we describe the clinical experience obtained using CF catheters for atrial fibrillation ablation, with a specific focus on the impact of CF technology on acute procedural data (procedure and fluoroscopy time). PMID- 27957167 TI - A Difficult Case of Atrial Tachycardia. AB - A 60-year-old male with a history of prior ablation of typical cavotricuspid isthmus-dependent atrial flutter presented to us with recurrent palpitations. The surface 12-lead EKG was consistent with atrial tachycardia, for which an ablation was planned. The patient was found to have multiple marcroreentrant left atrial tachycardias utilizing areas of scar as substrate. Isthmuses of tissue with fractionated electrograms associated with scar were targeted for ablation. PMID- 27957169 TI - Rotor, Rotor Everywhere.... Nor any Place to Find.... PMID- 27957168 TI - Cardiac Plug I and Amulet Devices: Left Atrial Appendage Closure for Stroke Prophylaxis in Atrial Fibrillation. AB - Percutaneous left atrial appendage (LAA) occlusion has emerged as an exciting and effective modality for stroke prophylaxis in patients with non-valvular atrial fibrillation who are deemed too high risk for anticoagulation with warfarin or newer anticoagulants. The Amplatzer devices have been used in LAA occlusion for more than a decade, starting with off label use of an atrial septal occluder device for LAA occlusion. This was followed by introduction of a dedicated Amplatzer cardiac plug (ACP) 1 for LAA occlusion, and more recently, the second generation Amulet device, with reported better stability enhancing features, has been introduced. Both these devices are widely used outside the United States, however in the US only the WATCHMAN device has been FDA approved. Unlike the WATCHMAN device, where the evidence is continuously building as the data from two pivotal randomized controlled trials are emerging, most of the evidence for ACP devices is from pooled multicenter registry data. In this article, we review the device design, implantation techniques and the most recently published evidence for both the Amplatzer cardiac plug 1 and the newer Amulet device. Our goal is to summarize the most recent literature and discuss the current role of the Amplatzer devices in the exciting and rapidly growing field of percutaneous LAA occlusion. PMID- 27957170 TI - Left Atrial Appendage Thrombus Resolution with Reduced Dose Apixaban. AB - A 63 year old woman with a history of persistent atrial fibrillation and CHADSVASC score of 2, suffered a massive stroke with a hemorrhagic transformation, 2 days following an appendectomy and reversal of warfarin anticoagulation with vitamin K. A left atrial appendage occlusive device (LAAOD) was considered for stroke prevention given the risk of recurrent cerebral hemorrhage. A transesophageal echocardiography (TEE) however, revealed left atrial appendage (LAA) clots which precluded the use of a LAAOD. A computed tomography revealed only partial resolution of the right hemispheric hematoma. Apixaban 2.5 mg twice daily was successful in resolving the LAA clots within 2 months without aggravating her cerebral hematoma which continued to resolve. This is the first case, to our knowledge showing reduced-dose Apixaban to completely resolve left atrial thrombus. Our case also addresses the issue of bridging following reversal of warfarin anticoagulation with vitamin K. PMID- 27957171 TI - Risk of Ischemic Stroke and Stroke Prevention in Patients with Atrial Fibrillation and Renal Dysfunction. AB - Chronic kidney disease (CKD) has been identified as an important risk factor for new-onset atrial fibrillation (AF) and would significantly increase the risk of AF-related strokes. Stroke prevention in AF patients with CKD is a big challenge, especially for patients with end-stage renal disease (ESRD) undergoing long-term dialysis. In addition to an increase risk of stroke, renal dysfunction was also associated with a higher risk of hemorrhage due to dysregulation of coagulation and uremia-mediated platelet dysfunction. Therefore, the net clinical benefit balancing stroke risk reduction and increased risk of bleeding should be weighed carefully before initiating oral anti-coagulants for ESRD patients. Several studies investigating whether warfarin should be used for stroke prevention in AF patients with ESRD have been published and showed inconsistent results. Since none of these studies was a prospective and randomized trial, the best strategy for stroke prevention in AF patients with ESRD undergoing dialysis remained unknown and more data are necessary to answer this issue. PMID- 27957173 TI - Lack of Atorvastatin Protective Effect Against Atrial Fibrillation in CETP TaqIB2B2 Genotype. AB - There has been some evidence for a role of statins in reducing the risk of atrial fibrillation, but the response to statin treatment varies considerably due to environmental and genetic factors. One of these is related to CETP expression. So we assessed whether CETP TaqIB polymorphism influences atrial fibrillation occurrence after treatment with statins. 200 unrelated dyslipidemic Caucasian patients (146 men and 54 women; mean age 75+/-8) from Salento (Southern Italy), assigned to atorvastatin treatment, and 158 normolipidemic subjects (119 men and 39 women; mean age 75+/-11), selected from the same ward, were enrolled. All patients were followed at six-month intervals. CETP TaqIB polymorphism was genotyped by RFLP-PCR. During a mean follow-up time of 71+/-6 months, 64 patients (32%) of the group treated with atorvastatin and 70 subjects (44%) of the group without atorvastatin experienced at least one episode of AF, with a statistically significant difference (p = 0,0208) between the two groups. No significant differences were observed between the two groups with regard to demographic and echocardiographic data, to clinical history and pharmacological treatment. While in patients not assuming atorvastatin there was no significant difference (p = 1) between TaqIB genotype and atrial fibrillation occurence, in subjects treated with atorvastatin B2B2 genotype was more frequent in patients with atrial fibrillation (p = 0,0001). According to these data the subjects with the B2B2 genotype seem to be more susceptible to atrial fibrillation development (RR 2,74; IC 95% 1,92-3,90; p<0.025). Our data seem to provide a further evidence for the hypothesis that statins may have adverse effect in subjects with genetically low CETP levels. Because statins reduce CETP activity up to 30%, we hypothesize that such CETP activity reduction by statins, in patients with low CETP levels induced by polymorphism, may counteract the beneficial effect of statins on atrial fibrillation. PMID- 27957172 TI - Lone Atrial Fibrillation: Risk Factors, Triggers And Ablation Techniques. AB - BACKGROUND: Since its introduction in 1953, lone atrial fibrillation (LAF) has not been defined with any consistency, resulting in an enormous variation in the way the term is used. Inherent to this, results from studies vary considerably. Many predisposing factors and pathogenic influences have been discovered over the past years, which raise the question if the term LAF should still be used and if the treatment should be different from non-lone atrial fibrillation (non-LAF). Therefore this systematic review on LAF provides an overview of risk factors and triggers, the second part focuses on the application of catheter and surgical ablation techniques. METHODS: A systematic literature search was performed in the PubMed database. All identified articles were screened and checked for eligibility by the two authors. Additional literature was sought by screening the references of eligible articles. CONCLUSIONS: Insufficient evidence exists to consider LAF as a real, isolated and useful entity. A re-definition or even avoiding the use of the term LAF might be appropriate. PMID- 27957174 TI - Cryoablation Versus Radiofrequency Ablation in AVNRT: Same Goal, Different Strategy. AB - Catheter ablation is nowadays the first therapeutic option for AVNRT, the most common benign supraventricular tachycardia. Both cryotherapy and radiofrequency energy may be used to ablate the slow pathway. This paper compares both techniques, evaluates results published in literature and gives feedback on some typical aspects of cryo- and RF ablation. Although both techniques have satisfying success rates in AVNRT ablation, with a higher safety profile of cryoablation towards creation of inadvertent atrioventricular block, it remains paramount that the operator respects the distinctive traits of each technique in order to obtain an optimal result in every patient. PMID- 27957175 TI - Co-Morbidities and Cardiac Resynchronization Therapy: When Should They Modify Patient Selection? AB - Cardiac resynchronization therapy (CRT) improves symptoms, reduces heart failure related hospitalizations and death in selected patients with heart failure. Based on thousands of patients enrolled in major clinical landmark trials, current guidelines describe in relatively precise terms which cardiac patients should receive a device. However, clinical trials often excluded sicker patients leaving clinicians with the dilemma of how to treat real-life patients with major co morbidities, frailty, and increasing age, who are otherwise candidates for CRT implantation. This review investigates results from clinical trials and available observational data on the influence of co-morbidities on CRT benefit in order to provide better insight of when and why co-morbidities should modify patient selection for CRT. PMID- 27957176 TI - Phased RF Ablation: Results and Concerns. AB - Treatment of atrial fibrillation (AF) with catheter ablation has proven to be a safe and effective treatment modality which is offered to an increasing number of patients in many centers. Pulmonary vein isolation (PVI) is an established cornerstone of AF ablation strategies. Athough the isolation of the pulmonary veins (PVs) with irrigated focal radiofrequency (RF) catheters using a point-by point method is considered as the gold standard, it can be challenging to create contiguous lesions, time consuming, and require advanced three dimensional (3D) mapping and navigational systems. The phased RF ablation system was designed to address many of these challenges associated with conventional focal RF ablation. In this review, we describe the main features of phased RF ablation and summarize the data available on clinical outcome with this technology. PMID- 27957177 TI - Systolic and Diastolic Function by Tissue Doppler Imaging Predicts Mortality in Patients with Atrial Fibrillation. AB - AIM: Tissue Doppler Imaging (TDI) detects early signs of left ventricular dysfunction. The prognostic potential of TDI in patients with atrial fibrillation (AF) has, however, not yet been clarified. This study evaluates the prognostic value of TDI in patients with atrial fibrillation. METHODS AND RESULTS: In total, echocardiograms from 313 patients with AF during examination were analyzed offline. Longitudinal systolic velocity (s'), early diastolic velocity (e') and longitudinal displacement (LD) were measured by color TDI. During a median follow up of 891 days, 64 patients (20%) died. TDI was significantly associated with all cause mortality, and the risk of dying increased significantly per 1 cm/s decrease in s' (HR of 1.31, 95% CI 1.05-1.63; p=0.018) and e' (HR of 1.17, 95% CI 1.01-1.35; p=0.038) respectively, even after adjustment for age, gender, heart rate, aortic stenosis, DM and LVEF quartiles. LD also proved to be a significant predictor of outcome after multivariate adjustment (HR 1.23; 95% CI 1.05-1.44; p=0.012). The population was stratified according to high or low s' and e'. Patients with low s' and e' had more than three times the risk of mortality compared to the patients with high s' and e' (HR 3.64; 95% CI 1.83-7.26; p<0.001) and remained in significantly higher risk after adjustment for various risk factors. CONCLUSIONS: Both systolic and diastolic performance, as assessed by TDI, are strong predictors of mortality in patients with atrial fibrillation, and especially the combination of systolic and diastolic dysfunction is a significant prognostic marker. PMID- 27957178 TI - Cardiac Magnetic Resonance for Ventricular Arrhythmia Therapies in Patients with Coronary Artery Disease. AB - Cardiac magnetic resonance (CMR) imaging is currently gold standard for myocardial tissue characterization and scar assessment. CMR serves potential prognostic information in patients with coronary artery disease (CAD) for both ventricular arrhythmia risk, as well as it may also be used for guiding VT ablation procedures. This review is focused on the usefulness of CMR for ventricular arrhythmia therapies in patients with CAD. PMID- 27957181 TI - ABIM and Regulatory Vagaries....What is the True Value of Repeated Testing? PMID- 27957179 TI - Lone AF: is There a Rationale? AB - Although atrial fibrillation (AF) development has been demonstrated to be associated with underlying cardiovascular conditions such as hypertension, valvular heart disease or diabetes mellitus; in a subset of relatively younger patients, no cardiopulmonary disease diagnosis can be established. AF patients younger than 60 years without clinical or echocardiographic evidence of cardiopulmonary disease are defined as lone AF patients. Despite the decrease in lone AF prevalence due to advances in understanding of AF pathogenesis, there are still issues yet to be resolved. Future studies are needed to demonstrate the cost- effectiveness of the routine use of more advanced diagnostic tools, such as non- invasive assessment of endothelial function, autoimmune markers or genetic screening and whether they would have clinical implications on treatment of lone AF. This review focuses on the suggested mechanisms in lone AF initiation and maintenance. PMID- 27957180 TI - Anticoagulation in Heart Failure: a Review. AB - Heart failure (HF) with reduced left ventricular function inflicts a large and growing burden of morbidity and mortality in the US and across the globe. One source of this burden is stroke. While it appears that HF itself may impose some risk of stroke, it is in the presence of other risk factors, like atrial fibrillation, that the greatest risks are observed. Therapeutic anticoagulation is the mainstay of risk reduction strategies in this population. While warfarin was the only available therapy for anticoagulation for many decades, there are now four direct oral anticoagulants available. In three of these four, outcomes in the specific subgroup of patients with heart failure have been examined. In this review, we provide some pathophysiologic basis for the risk of stroke in heart failure. In addition, the available therapeutic options for stroke risk prevention in heart failure are described in detail including how these options are incorporated into relevant professional society guidelines. PMID- 27957182 TI - A Review Of The Relevant Embryology, Pathohistology, And Anatomy Of The Left Atrial Appendage For The Invasive Cardiac Electrophysiologist. AB - The three-dimensional morphology of the left atrial appendage provides the substrate for thrombus generation, and is a harbinger for embolic material due to its direct connection to the left-sided circulation. Appreciating the development of the appendage from mesodermal layer to its adult form provides the basis to improve exclusion from the atrial circulation, and thereby can lead to a significant reduction in stroke risk. This process also provides insight into the role of the left atrial appendage as an endocrine organ, its involvement in fluid homeostasis, and its connection to the autonomic nervous system. Knowledge of the surrounding structural arrangement is critical to identify landmarks from both an endocardial and epicardial perspective to improve targeted device placement. Furthermore, correlation of the left atrial appendage body, neck, and ostium to the surrounding anatomy can also improve both procedural efficacy and safety. In addition, a working knowledge of the regional anatomy adds a prudent degree of awareness for procedural complications, and allows for early identification and timely intervention as these situations arise. A detailed understanding of the left atrial appendage embryology, histology, and gross anatomy is imperative to identify the correct device and approach for each individual patient. In addition, this increased awareness can identify areas that are in need of further innovation, and thus provide the ability to adapt and refine existing technologies to overcome pitfalls currently facing catheter-based approaches. PMID- 27957183 TI - Optimization Of Stroke Prophylaxis Strategies In Nonvalvular AF -Drugs, Devices Or Both? AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia with the prevalence increasing over time. AF probably afflicts >=2% of worldwide adult population and increases with age.[1-3] In the Framingham Heart Study, the lifetime risk of having at least one episode of AF for 40-year-old men and women was 26% and 23% respectively.[4]. PMID- 27957184 TI - Left Atrial Appendage Ligation And Exclusion Technology In The Incubator. AB - Stroke is the most feared complication of atrial fibrillation (AF). Targeting the left atrial appendage (LAA) mechanically is attractive as a means to simultaneously reduce stroke risk, the need for anticoagulation, and hemorrhagic complications in patients with non-valvular AF. The results of the PROTECT-AF and PREVAIL randomized clinical trials support this approach as a viable therapeutic alternative to warfarin in selected patients and add to accumulating evidence regarding the importance of the LAA in thromboembolism in AF. A number of devices for percutaneous LAA closure are under investigation or development. In this article, key design features of these ligation and exclusion technologies will be discussed, with a focus on aspects of LAA morphology, relational anatomy, thrombosis, and thromboembolism relevant for successful device development and deployment. PMID- 27957186 TI - Very Long-Term Results Of Atrial Fibrillation Ablation Confirm That This Therapy Is Really Effective. AB - Catheter ablation -in general- is a highly effective and "curative" intervention for a broad spectrum of supraventricular and ventricular arrhythmias. After a successful procedure eliminating a simple arrhythmia substrate, the recurrence rate is low and the short term success correlates well with the long term freedom from the arrhythmia. PMID- 27957185 TI - Diagnosis and Therapy of Atrial Fibrillation: The Past, The Present and The Future. AB - Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia. It is a progressive disease, which makes treatment difficult. The progression of AF is caused by the accumulation of damage in cardiomyocytes which makes the atria more vulnerable for AF. Especially structural remodeling and electrical remodeling, together called electropathology are sustainable in the atria and impair functional recovery to sinus rhythm after cardioversion. The exact electropathological mechanisms underlying persistence of AF are at present unknown. High resolution wavemapping studies in patients with different types of AF showed that longitudinal dissociation in conduction and epicardial breakthrough were the key elements of the substrate of longstanding persistent AF. A double layer of electrically dissociated waves propagating transmurally can explain persistence of AF (Double Layer Hypothesis) but the molecular mechanism is unknown. Derailment of proteasis -defined as the homeostasis in protein synthesis, folding, assembly, trafficking, guided by chaperones, and clearance by protein degradation systems - may play an important role in remodeling of the cardiomyocyte. As current therapies are not effective in attenuating AF progression, step-by-step analysis of this process, in order to identify potential targets for drug therapy, is essential. In addition, novel mapping approaches enabling assessment of the degree of electropathology in the individual patient are mandatory to develop patient-tailored therapies. The aims of this review are to 1) summarize current knowledge of the electrical and molecular mechanisms underlying AF 2) discuss the shortcomings of present diagnostic instruments and therapeutic options and 3) to present potential novel diagnostic tools and therapeutic targets. PMID- 27957188 TI - Atrioventricular Junction Ablation In Atrial Fibrillation: Choosing The Right Patient And Pacing Device. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia and despite advancements in rhythm control through direct catheter ablation, maintaining sinus rhythm is not possible in a large proportion of AF patients, who therefore are subject to a rate control strategy only. Nonetheless, in some of these patients pharmacological rate control may be ineffective, often leaving the patient highly symptomatic and at risk of developing tachycardia-induced cardiomyopathy and heart failure (HF). Catheter ablation of the atrioventricular junction (AVJ) with subsequent permanent pacemaker implantation provides definite rate control and represents an attractive therapeutic option when pharmacological rate control is not achieved. In patients with reduced ventricular function, cardiac resynchronization therapy (CRT) should be considered over right ventricular apical (RVA) pacing in order to avoid the deleterious effects associated with a high amount of chronic RVA pacing. Another group of patients that may also benefit from AVJ ablation are HF patients with concomitant AF receiving CRT. In this patient cohort AVJ ablation ensures near 100% biventricular pacing, thus allowing optimization of the therapeutic effects of CRT. PMID- 27957187 TI - Outcomes Of Cryoballoon Ablation Of Atrial Fibrillation: A Comprehensive Review. AB - Over the last decade, cryoballoon ablation has emerged as an effective alternate strategy to point-by-point radiofrequency ablation for treatment of symptomatic atrial fibrillation. There are several reasons for this. First, the acute and long-term safety and efficacy associated with cryoablation appear comparable to that of radiofrequency ablation in patients with both paroxysmal and also persistent atrial fibrillation. Second, cryoablation offers certain advantages over conventional radiofrequency ablation including a gentler learning curve, shorter ablation and procedure times as well as lack of need for costly electroanatomical mapping technologies commonly utilized with radiofrequency ablation. Lastly, with the recent advent of the second-generation cryoballoon, the effectiveness of cryoablation has further improved dramatically. This comprehensive review examines the gradual evolution of the cryoablation tools as well as the rationale and data in support of the currently-available cryoballoon technologies for catheter ablation of atrial fibrillation. PMID- 27957190 TI - Atrial Flutter In A Tetralogy Of Fallot Operated Patient: Importance Of A Rapid And Curative Treatment. AB - A 51 male, affected by Tetralogy of Fallot, underwent a left Blalock-Taussig anastomosis at the age of two years and an aorto - right pulmonary artery tube graft when 8 years old. Complete surgical correction was performed at age 21 with closure of the ventricular septal defect and a large patch over the right outflow tract, shunts were discontinued. Then it was well up to 51 years old when he began to suffer shortness of breath with minimal exertion. with ECG evidence of supraventricular tachycardia. Suggestive signs of a typical atrial flutter led to early electrophysiological assesment and successful cavo-tricuspid isthmus ablation was successfully performed. . Echocardiographic and magnetic resonance imaging and ergospirometry provided complete informations on anatomic and hemodynamic conditions but no other interventional procedure was necessary. PMID- 27957189 TI - Review And Insights Into The Bleeding Mechanism Incited By Antithrombotic Therapy: Mechanistic Nuances Of Dual Pro-Hemorrhagic Substrate Incorporating Drug Induced Microvascular Leakage. AB - In patients with atrial fibrillation antithrombotic prophylaxis for stroke is associated with an increased risk of bleeding. Cerebrovascular risk-benefit ratio for oral anticoagulation therapies continues to be debated. Macro and/or microhematomas as well as visible or cryptic ones may appear unexpectedly in any anatomic region. The diagnostic and prognostic value of subcutaneous hematomas (petechia, ecchymosis, bruise) potentially predisposing intracerebral micro- or macrobleeding might be reconsidered. Hypothetically, subcutaneous hemorrhagic events are "transparent" signs and reflect the coexistence of remote vulnerable sites that are potential bleeding sources. Obviously vigilance is needed for early signs of drug-related petechiae evaluation to determine whether it is a local/superficial subtlety or a systemic problem. Any bleeding complication, regardless of its scale and anatomical location, might be treated as a worrisome clinical symptom requiring subtle correction of antithrombotic regimen. The focus of this article is to review the current knowledge of drug-related hemorrhage with special emphasis on underlying mechanisms and links between the visible bleeding (predominantly subcutaneous) and remote (such as cerebral) hemorrhagic sources. To mitigate inappropriate therapy, we should consider new conceptual insights and more individualized approaches to achieve an optimal balance of efficacy and safety. We hypothesize that bleeding complications occur as a result of two factors - impact of antithrombotic drugs and related detrimental effect on microvascular network. Most likely the microvasculature undergoes pro-hemorrhagic medication stress leading to unfavorable vascular wall "fenestration" with ensuing consequences. If so, it suggests the presence of dual substrate responsible for hemorrhagic events. PMID- 27957192 TI - Innappropriate Sinus Tachycardia After Superior Vena Cava Isolation In Addition To Pulmonary Veins Isolatin Of Paroxysmal Atrial Fibrillation Cryoballoon Ablation. AB - We report a case of persistent inappropriate sinus tachycardia (IST) after pulmonary vein and superior vena cava (SVC) isolation with cryoballoon ablation for paroxysmal atrial fibrillation (PAF). After the cryoballoon ablation (CBA) procedure, the patient presented with sinus tachycardia of 105 beats/minute. The patient was successfully treated with metoprolol and ivabradine therapy. PMID- 27957191 TI - Review Of Obesity And Atrial Fibrillation: Exploring The Paradox. AB - There is a well established association between obesity and atrial fibrillation (AF). Nevertheless, the effects of obesity in the outcomes of patients with AF has not been investigated since a few years before. In this regard, several studies have demonstrated a better clinical prognosis of AF in overweight and obese populations. In the present manuscrit, we aimed to explore the main articles in which the "obesity paradox in AF" was found. PMID- 27957195 TI - A Grand Tribute To A Pioneer In Electrophysiology. PMID- 27957194 TI - Preferential Conduction Properties Along The Left Lateral Ridge And The Arrhythmogenicity Of The Left Pulmonary Veins In Patients With Atrial Fibrillation. AB - PURPOSE: In this study, we examined the hypothesis that the preferential conduction property along left lateral ridge (LLR) might affect the arrhythmogenicity of left pulmonary veins (LPVs). METHODS: The study population included 40 consecutive AF patients. Radiofrequency energy (RF) was sequentially delivered along the LLR from a lower to upper manner during postero-lateral CS pacing during an isoproterenol infusion. RESULTS: The conduction time during pacing from the CS was significantly prolonged during radiofrequency (RF) deliveries (before vs. after, upper; 91+/-26ms vs. 127+/-38ms, p<0.001, lower; 86+/-21ms vs. 103+/-22ms, p<0.001). Remarkable prolongation of more than 30ms was observed in 19 of 40 patients (48%) (both LPVs, 6; only the upper LPVs, 12; and only the lower LPV, 1). Sites with a remarkable prolongation were observed at the carina between the LPVs,[4] anterior site of the upper LPV carina,[10] anterior wall of the lower LPV,[3] and bottom of the lower LPVs [2] Thirty-three arrhythmogenic foci (AMF) from the LPVs were observed in 23/40 patients (56%). The conduction time during pacing from the LPVs during the RF delivery was significantly longer in the patients with AMF from the upper LPV than in those patients without (107+/-36ms vs. 146+/-40ms, p<0.01). CONCLUSION: The LLR includes the preferential conduction properties between the CS and LPVs, and the observation of the serial changes during the RF delivery could provide us information about the LPVs arrhythmogenicity. PMID- 27957193 TI - Pre-Implant Assessment For Optimal LV Lead Placement In CRT: ECG, ECHO, or MRI? AB - Cardiac resynchronization therapy (CRT) improves cardiac function in many patients with ventricular dyssynchrony. The optimal use of imaging for pre implantation assessment remains a subject of debate. Here, we review the literature to date on the utility of echocardiography and cardiac MR, as well as conventional ECG, in choosing the best site for LV lead implantation. Prior to the use of imaging for pre-implantation evaluation, LV leads were placed empirically, based on average responses from population-level studies. Subsequently, patient-specific approaches have been used to maximize response. Both echocardiography and cardiac MR allow determination of areas of latest mechanical activation. Some studies have found improved response when pacing is applied at or near the site of latest mechanical activation. Similarly, both echocardiography and cardiac MR provide information about the location of any myocardial scar, which should be avoided when placing the LV lead due to variable conduction and high capture thresholds. Alternative approaches include targeting the region of latest electrical activation via measurement of the QLV interval and methods based on intraoperative hemodynamic measurements. Each of these modalities offers complementary insights into LV lead placement, so future directions include multimodality pre-implantation evaluation, studies of which are ongoing. Emerging technologies such as leadless implantable pacemakers may free implanting electrophysiologists from the constraints of the coronary sinus, making this information more useful and making non-response to CRT increasingly rare. PMID- 27957196 TI - World Atrial Fibrillation Day - Is It Time To Recognize The Beast? PMID- 27957198 TI - Coagulation Testing For New Oral Anticoagulants. AB - Atrial fibrillation is the most common and important cardiac rhythm disorder, which increases the risk of stroke and mortality. New oral anticoagulants are an alternative for vitamin K antagonists to prevent stroke in patients with non valvular atrial fibrillation. New oral anticoagulants do not require routine monitoring of coagulation. However, the quantitative assessment of the anticoagulant effect drug levels may be needed in emergency situations, such as a serious bleeding or need for urgent surgery, or in patient with renal or hepatic insufficiency. In the paper we focus on the coagulation testing for new oral anticoagulants. PMID- 27957197 TI - Heart Failure With Reduced Ejection Fraction And A Narrow QRS Complex: Combination Of A Subcutaneous Defibrillator With Cardiac Contractility Modulation. AB - Cardiac contractility modulation (CCM) is a relatively new electrical therapy for heart failure patients with reduced ejection fraction. The majority of patients eligible for CCM will also need an implantable cardioverter-defibrillator (ICD). To-date, three pacing electrodes are mandatory for CCM therapy because the current CCM signal delivery algorithm requires sequential intracardiac sensing of a p-wave, followed by appropriately timed ventricular activation by the two ventricular septal leads. As there is no device combining CCM with ICD functions, most CCM patients will need multiple intracardiac electrodes, which increase the cumulative risk for complications such as systemic infections, thrombosis of central venous lines, insulation failures or lead fractures. The long-term complications associated with trans-venous ICD leads have led to the development of a totally subcutaneous implantable cardioverter-defibrillator (S-ICD). In this essay the two technologies CCM and S-ICD are reviewed. Additionally, we present their successful combination on the basis of a case report on the first patient receiving both devices. PMID- 27957199 TI - Sudden Death After Transcatheter Aortic Valve Implantation. Are Bradyarrhythmias Always The Cause? AB - Transcatheter Aortic-Valve Implantation (TAVI) is considered to be highly effective in the treatment of high-risk patients with severe aortic stenosis. After TAVI, the rate of pacemaker implantation is 6.5%-40%. Some reports of sudden death after TAVI are mostly attributed to bradyarrhythmias. We report the case of three patients who experienced sudden cardiac death or aborted sudden cardiac death after TAVI. All patients were affected from ischemic heart disease with an ejection fraction of approximately 40% and underwent pacemaker implantation (PM) after the procedure due to 1rst degree atrioventricular block (AV) and left bundle branch block (LBBB). One of the patients died suddenly 30 days after the procedure. The PM interrogation revealed many episodes of non sustain ventricular tachycardias (NSVT) and one episode of ventricular fibrillation (VF) that led to death. The other two patients had syncope and during PM interrogation episodes of ventricular tachycardia >12 sec were recorded. Patients affected by ischemic heart disease undergoing TAVI, especially with borderline coronary lesions should receive particular attention in order to avoid potentially lethal ventricular arrhythmias. In addition, the physiopathologic mechanism of sudden arrhythmic death in these patients needs to be clarified. PMID- 27957201 TI - The Late Electrophysiological Consequences Of Posterior Wall Isolation In Patients With Atrial Fibrillation. AB - INTRODUCTION: There are many different lesion sets that are used for the surgical ablation of atrial fibrillation (AF). One such pattern is the 'box set', a single ring of scar delivered anterior to the pulmonary veins, which aims to electrically isolate the posterior wall from the rest of the heart. However it remains unclear whether posterior wall isolation (PWI) is an effective lesion set for maintenance of sinus rhythm and whether it is necessary to achieve complete bidirectional block. We investigated the long-term integrity of the 'box set' lesion created during surgical AF ablation by epicardial High Intensity Focussed Ultrasound (HIFU). All patients had documented persistent or recurrent paroxysmal AF prior to surgery. We correlated this with subsequent success or failure in the abolition of atrial fibrillation. METHODS: With regional ethical and R&D approval, 101 patients who had previously undergone HIFU AF ablation greater than 4 years ago were screened for inclusion in the study. 17 patients agreed to late electrophysiological study: 11 with on-going AF and 6 in normal sinus rhythm. Clinical history and 7-day holters were used to define the NSR group. We performed a diagnostic EP study using a transseptal approach in fully anticoagulated patients (INR>2.0 and ACT maintained at >300s). A catheter was placed in the coronary sinus (CS) and a circular multipolar mapping catheter was used to map the left atrium and pulmonary veins. Patients in atrial fibrillation were cardioverted. We recorded whether posterior wall (PW) and pulmonary vein (PV) isolation had been achieved at the surgical procedure. In selected cases we recorded a voltage map using either CARTO (Biosense- Webster) or NavX (St Jude Medical) to identify areas of ablation scar. RESULTS: All 11 patients with AF had absence of PW+PV isolation with fractionated electrograms recorded across the PW. In the 6 patients with long-term freedom from AF, PW+PV isolation was confirmed in 4 (67%) and in 1 there was prolonged conduction across the box-set lesion with CS to PW activation time of around 200ms versus 45ms from mid-CS to left atrial appendage. Of the 4 patients with confirmed PW+PV isolation, 1 had dissociated spontaneous atrial potentials within the box set area and the other 3 had electrical silence throughout with inability to capture the posterior wall pacing at 10mA at multiple sites. CONCLUSIONS: There appears to be a clear correlation between the successful restoration of long-term sinus rhythm and isolation / delayed conduction from the pulmonary veins and posterior wall. Given the advent of hybrid atrial fibrillation ablation techniques designed to deliver this lesion set, these findings are timely and highly relevant. PMID- 27957202 TI - Haemodynamic Alterations Induced By Cardiac Pacing: Is Clinical Evaluation Sufficient Or Do We Need Long-Term Device Monitoring? AB - Cardiac pacing may induce haemodynamic alterations. RV pacing may have deleterious effects including a decrease of LV function as well as an increase of heart failure hospitalizations and mortality. Biventricular pacing is established in patients with heart failure and left bundle branch block or chronic AV block to improve haemodynamics. In the future, device optimization employing quadripolar leads or multisite pacing may further increase the rate of responders. However, cinical evaluation represents the most important tool to recognize the necessity for device optimization. Device algorithms are not yet successfully established to replace clinical and echocardiographic evaluation. PMID- 27957200 TI - Better Lesion Creation And Assessment During Catheter Ablation. AB - Permanent destruction of abnormal cardiac tissue responsible for cardiac arrhythmogenesis whilst avoiding collateral tissue injury forms the cornerstone of catheter ablation therapy. As the acceptance and performance of catheter ablation increases worldwide, limitations in current technology are becoming increasingly apparent in the treatment of complex arrhythmias such as atrial fibrillation. This review will discuss the role of new technologies aimed to improve lesion formation with the ultimate goal of improving arrhythmia-free survival of patients undergoing catheter ablation of atrial arrhythmias. PMID- 27957204 TI - The Impact Of Real-Time Three Dimensional Transoesophageal Echocardiography Before Transcatheter Radiofrequency Ablation Of Atrial Fibrillation In Patients With Prosthetic Mechanical Mitral Valve. AB - Atrial fibrillation is the most common arrhythmia following valvular heart surgery. Radiofrequence catheter ablation of atrial fibrillation in patients with prothetic mechanical mitral valve is feasible and relatively safe in experienced center. Implementation of real-time three dimensional transoesophageal echocardiography in atrial fibrillation can demonstrate on-line left atrial and left atrial appendix spontaneous echo contrast and thrombus. This condition makes the electrophysiologist allerted for the expected complications. PMID- 27957203 TI - Patient Taking A Novel Oral Anticoagulant Presents With Major GI Bleeding. AB - Novel Oral Anticoagulants (NOACs) such as Dabigatran, Rivaroxaban, Apixaban and Edoxaban are becoming increasingly popular choices for anticoagulation in place of oral Vitamin K Antagonists in various clinical settings. However, they are thought to be associated with an increased risk of gastrointestinal bleeding. Moreover, no specific antidote is available which can rapidly reverse the anti coagulant action of NOACs raising concern that gastrointestinal bleeding with NOACs could carry a worse prognosis than that associated with conventional agents. In this review, we describe a case of gastrointestinal bleeding in the setting of NOAC use, followed by a brief overview of the pivotal trials involving NOACs. Clinical issues such as pathophysiology, diagnosis and management of NOAC induced GI bleeding have been described. Future trials will help elucidate the true incidence, risk factors and preventive strategies for NOAC associated gastrointestinal bleeding. PMID- 27957205 TI - Cardioversion Of Atrial Fibrillation And Oral Anticoagulation. AB - The risk of thromboembolic events is a major concern in cardioversion of atrial fibrillation. The vast majority of these events occur in the first week following cardioversion. Processes promoting thrombus formation occur early and thrombus may appear in the left atrium within 48 hours of atrial fibrillation. The risk of thromboembolic events also increases with the presence of stroke risk factors. Thus, the current guidelines recommend that also patients with acute atrial fibrillation should undergo cardioversion under cover of unfractionated or low molecular weight heparin followed by oral anticoagulation for at least 4 weeks in patients at moderate-to-high risk for stroke. Delay of cardioversion < 12 hours from the symptom onset seems to cause a marked increase in the risk of stroke. Thus, short term anticoagulation should be considered also for patients with a low CHA2DS2VASc score if the delay to cardioversion is 12-48 hours. PMID- 27957206 TI - ICD Implantation Practice Within Europe: How To Explain The Differences Beyond Economy? AB - Implantable cardioverter defibrillators (ICD) offer the potential to prevent sudden cardiac death and demonstrated a survival benefit in high risk cardiac patients. ICD implantation rates vary significantly throughout the countries all over Europe although there are no major differences in cardiovascular morbidity among countries. ICD implantation rates in each European country may be influenced by economic factors, including the gross domestic product, its percentage devoted to public health, and organization of the health system. However, ICD implantation rates vary substantially also among countries with a high gross domestic product. Beyond economy, other important factors that may influence ICD implantation rates are lack of guidelines awareness and poor guidelines adherence especially when treating specific subgroup of patients (such as elderly and those with non ischemic cardiomyopathies). PMID- 27957207 TI - Development Of A Novel Scoring System That Determines The Success Of Atrial Fibrillation Ablation As Part Of Cardiac Surgery. AB - BACKGROUND: Radiofrequency ablation therapy for the treatment of atrial fibrillation (AF) can be performed as a concomitant procedure alongside cardiac surgery, but carries the risks of increased bypass time and damage to the sinoatrial node. This study aims to assess the efficacy of concomitant surgical AF ablation and develop a novel scoring system to predict post-procedural return to sinus rhythm. METHODS: A review of the Leeds General Infirmary surgical database was conducted to list all patients who had undergone valvular or coronary bypass surgery with concomitant AF ablation between Jan 2012 - Dec 2013 (n = 76). Follow-up was obtained retrospectively using patient notes, clinic letters and echocardiographic data. Primary outcome was freedom from AF at median follow up (383 days). A novel scoring system was created through analysis of previous literature and evaluated using a receiver operating characteristic (ROC) curve. RESULTS: At median follow up 50.9% of patients undergoing the procedure were free from AF. The novel scoring system was shown to adequately predict post procedural return to sinus rhythm (ROC AUC = 0.7708). CONCLUSION: A novel scoring system was shown to predict procedural success in patients undergoing concomitant AF ablation alongside cardiac surgery. These results can be further validated using larger patient cohorts. PMID- 27957208 TI - Variations in Anticoagulation Practices Following the Maze Procedure. AB - The current real-world anticoagulation practices following left atrial appendectomy in the context of the Maze procedure are unknown. This is a cohort study of all patients who underwent the Maze procedure with amputation of the left atrial appendage from June 2005 to November 2012. Data was prospectively collected at regular intervals with an interview and Holter monitoring. All patients received anticoagulation for 3 months. Those then kept on anticoagulation and those for whom anticoagulation was stopped were compared in terms of death, bleeding and incidence of stroke. In total, there were 113 patients, of whom 66 were treated with anticoagulation (Group A) and 47 were not (Group B). There were no significant baseline differences between the two groups, including the presence of atrial fibrillation (A:19.7%, B:10.6%, p=0.30), CHADS2 score (A:1.41+/-1.05, B:1.15+/-1.08, p=0.19), and left atrial size (A:48.3+/ 7.1mm, B:47.6+/-7.8 mm, p=0.57). There were 275 patient-years of follow-up, with an average of 2.43 years per patient. Only two patients experienced strokes, both in Group A (p=0.27). Of the 5 bleeding events, 4 occurred in the first 3 months while on anticoagulation and the remaining event occurred in Group A at 3 years post-operatively (p=0.10). No standardized approach to anticoagulation after the Maze procedure is apparent in real-world practice in an urban Canadian setting. Patients who undergo the Maze procedure with amputation of the left atrial appendage are at a low risk of stroke, but the optimal anticoagulation strategy requires further investigation. PMID- 27957209 TI - Atrial Fibrillation Ablation Using Magnetic Navigation Comparison With Conventional Approach During Long-Term Follow-Up. AB - Atrial fibrillation (AF) ablation targeting the circumferential isolation of pulmonary veins (PVI) is an established therapeutic alternative in symptomatic AF patients resistant to anti-arrhythmic medications. The procedure is technically challenging and multiple difficulties must be overcome in order to achieve a successful outcome. The magnetic navigation system (MNS) is a remote catheter control technology which has advantages such as a traumatic catheter design improving the procedural safety, a reduced amount of radiation exposure to both the patient and physician, unrestricted and reproducible catheter maneuverability that allows the access to difficult anatomical situations, and an improved catheter stability leading to better energy delivery. Due to these advantages, MNS is increasingly being used for AF ablation and both acute and chronic success rates are comparable with the conventional technique. The new developments in navigation systems, catheters and new three-dimensional mapping systems are very promising to obviate these concerns. However, MNS is related to longer radiofrequency (RF) application duration and procedure time. PMID- 27957210 TI - Current Role And Future Prospects Of Magnetic Resonance Imaging In The Field Of Atrial Fibrillation Ablation. AB - Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, and catheter ablation of AF has become a first-line treatment for symptomatic drug refractory AF. However, this is a complex procedure and recurrences after a single ablation procedure are frequent. New technologies are needed to simplify the procedure and improve results, and cardiac magnetic resonance (CMR) has emerged as a useful tool to stratify the risk of recurrence, guide the ablation procedure, and monitor the post-ablation remodeling process. This review summarizes the current role of CMR in the field of AF ablation and offers a perspective on its future potential. PMID- 27957211 TI - CoolLoop(r) First: A First In Man Study To Test A Novel Circular Cryoablation System In Paroxysmal Atrial Fibrillation. AB - INTRODUCTION: Pulmonary vein (PV) isolation is the mainstay of catheter treatment of paroxysmal atrial fibrillation (AF). The CoolLoop(r) cryoablation catheter (AFreeze(r) GmbH; Innsbruck, Austria) was developed to create wide and complete circular lesions around the PVs. In this study we evaluated feasibility and safety of this novel ablation system in humans. METHODS: 10 patients (6M/4F; 57.6+/-7.6y) with paroxysmal AF were included in 2 referral centers. The CoolLoop(r) catheter was positioned at each PV antrum using a steerable transseptal sheath. Subsequently, 2-6 double-freezes over 5min were performed at each vein and PV-isolation was assessed thereafter using a circular mapping catheter. During cryoablation of the right PVs, pacing was used to monitor phrenic nerve function. RESULTS: The CoolLoop(r) catheter could be successfully positioned at each PV. A mean of 5.6+/-1.8 cryoablations were performed in the LSPV, 5.2+/-1.6 in the LIPV, 6.3+/-2.5 in the RSPV and 5.4+/-1.6 in the RIPV, respectively. Mean procedure time was 251+/-60min and mean fluoroscopy time was 44.0+/-13.2min. 6 / 10 LSPV, 6 / 10 LIPV, 5 / 10 RSPV and 6 / 10 RIPV could be isolated exclusively using the novel cryoablation system. One patient developed groin hematoma and a brief episode of ST-elevation due to air embolism was observed in another subject. No other clinical complications occurred during 3 months of follow up. CONCLUSIONS: PV-isolation for paroxysmal atrial fibrillation using the CoolLoop(r) catheter is feasible and appears safe. Clinical long term efficacy still needs to be evaluated and will be compared with established catheters used for AF ablation. PMID- 27957212 TI - A Review Of Clinical Trials On LARIAT Device. AB - The risk of embolic stroke is 5 times higher among patients with atrial fibrillation (AF) compared with those without AF. More than 90% of thrombi form in the left atrial appendage (LAA) in AF. The purpose of this review is to determine the efficacy and safety of the left atrial appendage (LAA) closure via a percutaneous LAA ligation approach, thus preventing a stroke among patients with AF and contraindication to oral anticoagulant therapy. PMID- 27957214 TI - Does the FDA Owe Us an Explanation? AB - The approval process for new medications sometimes appears to require pharmacokinetic data in some circumstances and clinical trial data in others. This editorial calls for more clarity and transparency in the process and uses three examples to raise the issue. PMID- 27957213 TI - Atrioesophageal Fistula: A Review. AB - Catheter ablation of atrial ablation (AF) has become an important therapy in recent years. As with all evolving techniques, unexpected complication may occur. Atrioesophageal fistula is a very rare complication of AF catheter ablation. Described for the first time in two very experienced centers in 2004, this complication is the most dreadful and lethal among all the others related to AF catheter ablation. Its clinical presentation is extremely variable. Rapid diagnosis and surgical therapy may prevent death. This review article will summarize the risk factors, diagnosis, treatment and possible preventive strategies for this condition. PMID- 27957215 TI - Winter is Almost Here. PMID- 27957216 TI - Proarrhythmic Effects Of Antiarrhythmic Drugs: Case Study Of Flecainide Induced Ventricular Arrhythmias During Treatment Of Atrial Fibrillation. AB - PURPOSE: Flecainide is a class 1C antiarrhythmic drug especially used for the management of supraventricular arrhythmia. Flecainide also has a recognized proarrhythmic effect in patients treated for ventricular tachycardia. It is used to treat a variety of cardiac arrhythmias including paroxysmal atrial fibrillation, paroxysmal supraventricular tachycardia and ventricular tachycardia. Flecainide has local anesthetic effects and belongs to the class 1C AADs that block sodium channels, thereby slowing conduction through the heart. It selectively increases anterograde and retrograde accessory pathway refractoriness. The action of flecainide in the heart prolongs the PR interval and widens the QRS complex. The proarrhythmic effects however noted are not widely reported. METHOD: We report a case of paroxysmal atrial fibrillation with structurally normal heart who was treated with oral Flecainide. There were no adverse events and no QTc prolongation was noted on ECG. Despite subjective improvement a repeat Holter detected him to have multiple short non sustained ventricular arrhythmias. RESULTS: Development of ventricular arrhythmias, salvos and non-sustained ventricular tachycardia after a month of initiation of oral flecainide detected by 24 hours ECG Holter lead to discontinuation of flecainide and subsequent early electrophysiological studies and successful ablation. CONCLUSION: Initiation of oral Flecainide in a case of atrial fibrillation with subjective improvement and regular ECG monitoring, no QTc prolongation can still lead to development of dangerous ventricular arrhythmias. A cautious approach and thorough investigations and follow up are recommended. PMID- 27957218 TI - Electrical Storm: Incidence, Prognosis and Therapy. AB - The term "electrical storm" indicates a life-threatening clinical condition characterized by the recurrence of hemodynamically unstable ventricular tachycardia and/or ventricular fibrillation, in particular in patients with ICD implanted for primary or secondary prevention. Although there isn't a shared definition of electrical storm, nowadays the most accepted definition refers to three or more separate arrhythmia episodes leading to ICD therapies including antitachycardia pacing or shock occurring over a single 24 hours' time period. Clinical presentation can be dramatic and triggering mechanism are not clear at all yet, but electrical storm is associated with high mortality rates and low patients quality of life, both in the acute phase and in the long term. The first line therapy is based on antiarrhythmic drugs to suppress electrical storm, but in refractory patients, interventions such as catheter ablation or in some cases surgical cardiac sympathetic denervation might be helpful. Anyhow, earlier interventional management can lead to better outcomes than persisting with antiarrhythmic pharmacologic therapy and, when available, an early interventional approach should be preferred. PMID- 27957219 TI - Syncope And Atrial Fibrillation: Which Is The Chicken And Which Is The Egg? AB - Syncope and atrial fibrillation are both common entities and frequently occur together in an acute clinical scenario. Treatment of each in this presentation requires acquiring a good history and understanding the presentation of the patient. In this manuscript, there are 5 case studies that demonstrate common misperceptions when attempting to treat syncope when it presents with the arrhythmia atrial fibrillation. Rarely, does atrial fibrillation cause syncope. However, when a patient presents in atrial fibrillation, it becomes the focus of therapy rather than trying to define the etiology of the syncopal episode. It may be that well thought out algorithms to treat atrial fibrillation in an acute setting are replacing deductive thinking particularly when it comes to diagnosing the cause of a syncopal spell. PMID- 27957217 TI - Ischemic Stroke: Risk Stratification, Warfarin Teatment and Outcome Measure. AB - Stroke is a focal neurological syndrome of vascular basis, which may be due to ischemic thrombo-embolism or intra-cerebral haemorrhage. This condition has to be treated on emergency basis as it may cause an irreversible neurological damage. Warfarin has been a widely used oral anti-coagulant in treating ischemic stroke patients. This review highlights the benefits and challenges of warfarin treatment in stroke patients and discusses about the importance of risk stratification scores and bleeding scores in estimating the bleeding risk associated with warfarin treatment. This review also highlights the use of stroke outcome measures in identifying the patients with post-stroke disabilities to provide patient specific treatment. PMID- 27957220 TI - Mapping Atrial Fibrillation: 2015 Update. AB - Atrial fibrillation requires a trigger that initiates the arrhythmia and substrate that favors perpetuation. Cardiac mapping is necessary to locate triggers and substrate so that an ablation strategy can be optimized. The most commonly used cardiac mapping approach is isochronal or activation mapping, which aims to create a spatial model of electrical wavefront propagation. Historically, activation mapping has been successful for mapping point source and single or double wave reentrant arrhythmias, while mapping multiple wavelets or driving sources that underlie most episodes of atrial fibrillation remains challenging. In the multiple wavelet model of AF there is no particular area critical to sustain atrial fibrillation, and a "critical mass" of atrium is required to maintain AF. Recent studies suggest endocardial and epicardial dissociation may play an important role. Investigation of driving sources that sustain AF has focused on the presence of rotors. Rotors in human AF have now been observed using multiple imaging modalities, however ablation strategies targeting rotors remain of unproven benefit. In addition, substrate mapping of AF is now feasible. Increasing degrees of atrial fibrosis on delayed enhancement magnetic resonance imaging (DE-MRI) has been shown to correlate with poor procedural outcomes for AF ablation, which suggests the increased burden of scar promotes more complex and extensive arrhythmia substrate. Atrial fibrosis is also identifiable using electrogram voltage tagging in an electro-anatomic mapping system. Patient specific ablation strategies targeting areas of fibrosis are currently under investigation. Recent technological advances have facilitated greater understanding of the potential role for AF mapping and has allowed initiation of clinical studies to evaluate the effectiveness of mapping-based intervention. Multi-modality mapping is likely to play an increasingly important role in AF ablation, but is currently limited by the inability to simultaneously record and interpret electrical signals from both atria and from both the epicardium and endocardium. PMID- 27957221 TI - Periprocedural Management of Non-Vitamin K Oral Anticoagulants in Chronic Kidney Disease: A Review of Existing Heterogeneity and Contemporary Evidence. AB - Non vitamin-K oral anticoagulants (NOAC) have considerably enhanced anticoagulation practice for non-valvular atrial fibrillation with specific advantages of fixed dosing, non-fluctuant therapeutic levels and obviation of therapeutic level monitoring. NOAC pharmacology is remarkable for considerable renal excretion. Heterogeneity in the precise time cut-offs for discontinuation of NOACs prior to elective surgical or percutaneous procedures arise from the non linear variations of drug excretion with different levels of creatinine clearances as in chronic kidney disease. Multiple authors have suggested cut-offs leading to ambiguity among practicing clinicians. Recent data pertaining to systemic thromboembolism, stroke and major bleeding derived from randomized controlled clinical trials have simplified the periprocedural management of NOACs. This review focusses on heterogeneity in the management of NOACs in patients with CKD in this peculiar scenario and highlights the contemporary evidence to support a unified approach towards perioperative management of NOACs. Multiple antidotes targeted towards binding of specific NOACs have been developed and are in the testing phase, thereby offering immense potential for rapid and complete reversal of NOAC activity in emergent procedures and major bleeding episodes. Targeted research on thromboembolism, stroke and major bleeding following temporary periprocedural interruption of NOACs using multicentric registries could further expand the clinical utility of these agents. PMID- 27957222 TI - Subclinical Atrial Tachyarrhythmias:Implantable Devices and Remote Monitoring. AB - Atrial fibrillation (AF) and Atrial Tachyarrhythmias (AT) are the most common clinical arrhythmias and their worst issue is a well-recognized correlation with ischemic stroke. High incidence of "subclinical" AF/ATs has been demonstrated in several trials (TRENDS, ASSERT, CRYSTAL AF, EMBRACE) in patients with both cardiac implantable electronic devices (CIEDS) and external loop recorders. Moreover, a relationship between device-detected AF/ATs and stroke risk has been observed in the same studies. However, while the net clinical benefit of the antithrombotic treatment is well established in patients with "clinical" atrial fibrillation, there may be a lower benefit in patients with device-detected arrhythmias. Subclinical AF/ATs may be considered as a marker of stroke risk rather than the proximate cause and their burden may be used in combination with CHA2DS2-VASC and HAS-BLED scores to identify high-risk population who deserves anticoagulation. Today the remote monitoring associated with the CIEDs is effective in the early detecting of AF/ATs by avoiding delays in the therapy evaluation, as demonstrated by several trials (TRUST, CONNECT, COMPAS). However clinical evidence for stroke risk reduction by remote monitoring is still awaited; the recent trial IMPACT failed to demonstrate that the handling of the anticoagulation therapy guided by device-detected ATs and remote monitoring improves the patients' outcome. The challenges for clinicians are to deal with the huge data entry, to define new organizational models, to improve device patient management and to continuously update AF guidelines in according to the great amount of data offered by the new technology. PMID- 27957223 TI - Peak Early Diastolic Transmitral Velocity As A Surrogate Marker Of Short-Term Atrial Fibrillation Recurrence After Electrical Cardioversion. AB - OBJECTIVES: The aim of this study was to assess if peak early diastolic transmitral velocity (E-wave) can be used as a surrogate marker of short-term atrial fibrillation (AF) recurrence. METHODS: We prospectively studied 57 consecutive patients who underwent electrical cardioversion (ECV) for AF and successfully converted to sinus rhythm. N-terminal brain natriuretic peptide levels (BNP) before and after ECV was measured in all patients. The follow-up included physical examination and a 12-lead electrocardiogram 14 days and one month after the ECV. RESULTS: In 42.1% patients AF recurred during one-month follow-up period. Gender, presence of mitral regurgitation, treatment with angiotensin II receptor blocker and left atrium diameter independently influenced E-wave velocity before ECV. E-wave velocity fell immediately after successful ECV (94.0+/-27 cm/s vs 79.7+/-23 cm/s, P<0.0001). E-wave velocity before ECV>94 cm/s and E-wave velocity after ECV >80 cm/s were predictors of one-month AF recurrence [(Hazard Ratio) HR=3.62 with 95% CI=1.49-8.78 and HR=3.76 with 95% CI=1.40-10.10, respectively]. E-wave velocity before and E-wave velocity after ECV remained predictors of AF recurrence but only in non-hypertensive patients (HR=1.01 with 95% C.I=1.01-1.03 and HR=1.03 with 95% C.I=1.01-1.06, respectively). Similarly, BNP levels before and after ECV were associated with an increased the risk of AF recurrence (HR=1.14 with 95% C.I 1.01-1.28 and HR= 1.16 with 95% C.I 1.03- 1.31, respectively). The addition of BNP levels to E-wave velocity before ECV appeared to have incremental value on short-term AF recurrence but at a marginally statistical significance (LR chi2=3.28, p=0.07). CONCLUSIONS: E-wave velocity before and after ECV appears to be a marker of short-term recurrence of AF. PMID- 27957224 TI - Routine Implant of Biventricular Devices Guided by an Electroanatomic Mapping System - Ready for Prime-Time? AB - Biventricular devices play an important adjunctive role in the treatment of heart failure. However, biventricular device implantation is associated with significant radiation exposure and a high proportion of non-response to cardiac resynchronization therapy (CRT). The use of electroanatomic mapping (EAM) during biventricular device implantation may help overcome these issues. This article will review the literature on the role of EAM in biventricular device implantation. PMID- 27957225 TI - What Does The Blanking Period Blank? AB - In the management of paroxysmal, drug-refractory atrial fibrillation, pulmonary vein isolation has become a widely accepted treatment option. Currently, the arrhythmias following any form of myocardial ablation are not considered within a period of three months, known as "the blanking period". Although this period is authority- rather than evidence-based, it has become universally recognized. Indeed, several mechanisms play a role to determine the transient increased risk of post-procedural atrial tachyarrhythmias, occurring early after the procedure. Acute inflammatory changes may be responsible for immediate recurrence, since application of ablative energy on atrial tissue has a pro-inflammatory- and potentially arrhythmogenic effect. Atrial arrhythmias within the first 3 months after ablation are very common (35% to 65% of cases) and their significance as predictor of late recurrences is more significant during the first month. Furthermore, the current biological evidences indicate that the edema of the surrounding and ablated tissue is no longer present after 1 month. In our letter we advocate the reasons why a blanking period of four weeks should appear more reasonable, fostering its clinical importance and utility. PMID- 27957226 TI - Atrial Fibrillation in Cardiac Sarcoidosis. AB - Sarcoidosis is a systemic granulomatous disease that affects the myocardium. Although ventricular arrhythmias are well known manifestations of cardiac involvement, there is increasing evidence that a significant proportion of patients with cardiac sarcoidosis (CS) also have atrial arrhythmias, atrial fibrillation being the most frequent. The incidence and mechanism of atrial fibrillation in CS is not precisely known. The management of atrial fibrillation in patients with CS is currently done according to the general guidelines for management of atrial fibrillation. Evidence is emerging regarding the additional role of immunosuppression for the treatment of atrial arrhythmias in CS. This paper reviews the incidence, possible mechanisms and treatment strategies of atrial fibrillation in patients with CS. PMID- 27957229 TI - Comparison of Phrenic Nerve Injury during Atrial Fibrillation Ablation between Different Modalities, Pathophysiology and Management. AB - Atrial fibrillation ablation has emerged as an effective tool in the management of symptomatic atrial fibrillation. Currently, the electrophysiologists are striving to maximize the success while minimizing complications. Phrenic nerve injury (PNI) is one of the concerning complications, especially in cases of cryoballoon ablation. Due to anatomical proximity to atrial tissue, phrenic nerve is particularly susceptible to injury. With evolving monitoring techniques it is now possible to minimize the likelihood of a permanent PNI. However, the challenge remains to detect PNI at the earliest and to avoid further damage to the nerve. In this review, we discuss pertinent anatomical principles, techniques to avoid PNI and management in cases where PNI is encountered. PMID- 27957228 TI - Atrial Fibrillation In Athletes: Pathophysiology, Clinical Presentation, Evaluation and Management. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia in athletes, especially in middle-aged athletes. Studies have demonstrated that athletes who engage in endurance sports such as runners, cyclists and skiers are more prone to AF than other athletes. The effects of exercise on the onset and progression of AF is complex. Triggers of AF in athletes may include atrial ectopy and sports supplements. Substrates for AF in athletes include atrial remodeling, fibrosis, and inflammation. Modulators of AF in athletes include autonomic activation, electrolyte abnormalities, and possibly, gastroesophageal reflux. Management of AF in athletes with rate-controlling agents and antiarrhythmic drugs remains a challenge and can be associated with impaired athletic performance. The value of catheter ablation is emerging and should be considered in suitable athletes with AF. PMID- 27957231 TI - Safety and Feasibility of Contrast Injection During Pulmonary Vein Isolation with the nMARQTM Multi-Electrode Catheter. AB - INTRODUCTION: Pulmonary vein isolation (PVI) using the irrigated multi-electrode ablation system (nMARQTM) remains challenging in complex atrial anatomy cases and when CARTOMERGETM technology is not available, due to absence of a leading guide wire. OBJECTIVES: Our objective was to assess feasibility and safety of PVI using nMARQTM catheter with intra-procedural contrast injections through the deflectable sheath compared to nMARQTM alone. METHODS: This is a prospective non randomized observational study of 78 consecutive patients who underwent PVI only with nMARQTM. The first group (n=37, 64+/-10.5 years, 62% male, 13.5% persistent AF) underwent the procedure with the guidance of signal mapping, fluoroscopy, and electro-anatomical mapping (EAM) alone. Since 12/2013 an automatic closed-loop contrast media injector was added to improve catheter location (n=41, 62.5+/-11 years, 71% male, 34% persistent AF). RESULTS: Total procedure time was 78+/-19 and 85.5+/-18.5 minutes, and mean fluoroscopy time was 30+/-9 and 29.5+/-8.7 minutes for the first and second groups, respectively (NS); acute success rate was 97% and 97.5%, with a mean of 14.7+/-5 and 17.6+/-5.4 RF applications, respectively (p=0.02); and mean total burning time of 10.3+/-3.6 and 12+/-4 minutes, respectively (p=0.08). Mean contrast used was 60+/-18 mL versus 203+/-65 mL, with no effect on renal function or major complications. One year freedom from AF was 77% and 83%, respectively (p=0.5). CONCLUSIONS: Addition of contrast injections to standard nMARQTM procedure is feasible and safe. It has no benefit in routine use but further studies may confirm its potential added value to EAM in catheter localization by newly trained operators and in selective cases of large/common PV anatomy. PMID- 27957230 TI - Managing Antiplatelet Therapy and Anticoagulants in Patients with Coronary Artery Disease and Atrial Fibrillation. AB - Oral anticoagulation (OAC) is essential in patients with atrial fibrillation (AF). Interestingly coronary artery disease coexists in 20-30% of these patients.[1,2] Balancing the risk of bleeding and thromboembolism is very important for the management of patients on OAC, especially than when such patients require percutaneous coronary intervention (PCI). Lack of data and clear societal guidelines for peri-procedural and post-procedural management of anticoagulated patients has resulted in diverse clinical practices among clinicians, hospitals, and countries. Furthermore with expanding number of available oral antiplatelet and anticoagulant agents, the uncertainty regarding optimal combination therapy in this growing pool of the patients with overlapping clinical indications is also growing. Given the high proportion of patients with atherothrombosis and requiring OAC for conditions particularly like AF, it is important that physicians are aware of the clinical implications and management of these overlapping syndromes. In this article we discuss; this evolving dilemma of peri-procedural and post-procedural management of anticoagulated patient's, burden of the disease, available data, risk factors that could identify high risk patients and propose a well-balanced management strategy. PMID- 27957232 TI - Home Screening for Detecting Subclinical Atrial Fibrillation. AB - The advent of cardiac implanted electronic devices with accurate atrial arrhythmia diagnostic capabilities has revealed a large burden of "silent " atrial fibrillation that is present in the cardiac population. Many studies have been completed, and many more are ongoing, to determine the correct treatment course when these atrial arrhythmias are detected. Alongside the development of accurate atrial diagnostics within the devices, has been the growth an entire network of wireless home monitoring capability. It is now possible to see, over the internet, individual patients' atrial arrhythmia burden on every day. This capability has tremendous promise for patient care, with the possibility of reducing strokes, decreasing heart failure, preventing cardiomyopathies, and likely substantially reducing health care costs. As this innovative diagnostic capability is generating large amounts of data, protocols for what should be done with the plethora of new information are being developed. In the pages that follow, we will present what is known about home monitoring for silent atrial fibrillation, and present the results of recent studies published in this arena. PMID- 27957234 TI - Left Atrial Appendage Tachycardia Termination With A LARIAT Suture Ligation. AB - Left atrial appendage (LAA) is a known trigger for left atrial tachycardia (AT). The use of LARIAT epicardial suture for termination of AT arising from LAA is not yet reported. A 66-year-old female had a history of hypertension, diabetes, sick sinus syndrome, labile INR, and symptomatic persistent AF. She underwent radiofrequency ablation after failed cardioversion and multiple antiarrhythmics. She was in AT originating from LAA on activation map. Radiofrequency endocardial LAA isolation was performed. However, the AT recurred with increased burden and symptoms. Due to her multiple hospitalization for spontaneous bleeds and labile INR, a Lariat epicardial suture ligation of her LAA was performed. With application of the Lariat suture, electrical isolation was achieved and the AT terminated. She remained AT free at 18 months. Our case is the first to illustrate the utility of LARIAT suture in electrical isolation of the LAA in addition to its mechanical exclusion. PMID- 27957236 TI - Welcome To 2016. PMID- 27957235 TI - Cardiac Resynchronization in Patients with Atrial Fibrillation. AB - Atrial fibrillation (AF) occurs in one of four patients undergoing cardiac resynchronization therapy (CRT).-Without special therapy, the prognosis of AF patients with CRT has been generally worse than those in sinus rhythm. The importance of a high percentage of biventricular pacing (BIV%) was confirmed in a large study where the mortality was inversely associated with BIV% both in the presence of normal sinus and atrial paced rhythm and with AF. The greatest reduction in mortality was observed with BIV% >98%. Patients with BIV% >99.6% experienced a 24% reduction in mortality (p < 0.001) while those with BIV% <94.8% had a 19% increase in mortality. The optimal BIV% cut-point was 98.7%. This cutoff would appear mandatory but it would be best to approach 100%. Careful evaluation of device interrogation data upon which the BiV% is based is essential because the memorized data can vastly overestimate the percentage of truly resynchronized beats since it does not account for fusion and pseudofusion between intrinsic (not paced) and paced beats. The recently published randomized CERTIFY trial provides unequivocal proof of the value of AV junctional (AVJ) ablation in CRT patients with AF. This trial confirmed the favorable results of AVJ ablation by many other studies and two important meta-analyses and therefore established the firm recommendation that the procedure should be performed in most, if not all, patients with permanent AF as well as those with frequent and prolonged episodes of paroxysmal AF. Patients after AVJ have improved mortality with a mortality similar to those in sinus rhythm. The AVJ ablation procedure carries the theoretical risk of device failure and death in pacemaker dependent patients. An inappropriate first ICD shock for AF seems to increase mortality. Increased long-term mortality after an inappropriate shock may be due to the underlying atrial arrhythmia substrate as opposed to the effect of the shock itself. PMID- 27957233 TI - Who Needs Catheter Ablation And Which Approach? AB - Catheter ablation therapy for atrial fibrillation (AF) has gained a significant role during maintenance of sinus rhythm compared to anti-arrhythmic medication. Catheter ablation techniques are also improved and progressed over years in parallel to better understanding of disease mechanisms and technological advancements. However, due to invasive nature of the therapy with its pertinent procedural risks, both appropriate patient selection and use of relevant approach should be considered by all electrophysiologists before decide to perform catheter ablation. PMID- 27957237 TI - Drug-Metabolizing Enzymes and Metabolic Diseases: Role of Antioxidants. PMID- 27957227 TI - Electrophysiological Perspectives on Hybrid Ablation of Atrial Fibrillation. AB - To overcome limitations of minimally invasive surgical ablation as a standalone procedure in eliminating atrial fibrillation (AF), hybrid approaches incorporating adjunctive endovascular catheter ablation have been proposed in recent years. The endovascular component targets residual conduction gaps and identifies additional electrophysiological targets with the goal of minimizing recurrent atrial arrhythmia. We performed a systematic review of published studies of hybrid AF ablation, analyzing 432 pooled patients (19% paroxysmal, 29% persistent, 52% long-standing persistent) treated using three different approaches: A. bilateral thoracoscopy with bipolar radiofrequency (RF) clamp based approach; B. right thoracoscopic suction monopolar RF catheter-based approach; and C. subxiphoid posterior pericardioscopic ("convergent") approach. Freedom from recurrence off antiarrhythmic medications at 12 months was seen in 88.1% [133/151] for A, 73.4% [47/64] for B, and 59.3% [80/135] for C, with no significant difference between paroxysmal (76.9%) and persistent/long-standing persistent AF (73.4%). Death and major surgical complications were reported in 8.5% with A, 0% with B and 8.6% with C. A critical appraisal of hybrid ablation is presented, drawing from experiences and insights published over the years on catheter ablation of AF, with a discussion of the rationale underlying hybrid ablation, its strengths and limitations, where it may have a unique role in clinical management of patients with AF, which questions remain unanswered and areas for further investigation. PMID- 27957238 TI - Colonic and Hepatic Modulation by Lipoic Acid and/or N-Acetylcysteine Supplementation in Mild Ulcerative Colitis Induced by Dextran Sodium Sulfate in Rats. AB - Lipoic acid (LA) and N-acetylcysteine (NAC) are antioxidant and anti-inflammatory agents that have not yet been tested on mild ulcerative colitis (UC). This study aims to evaluate the action of LA and/or NAC, on oxidative stress and inflammation markers in colonic and hepatic rat tissues with mild UC, induced by dextran sodium sulfate (DSS) (2% w/v). LA and/or NAC (100 mg.kg.day-1, each) were given, once a day, in the diet, in a pretreatment phase (7 days) and during UC induction (5 days). Colitis induction was confirmed by histological and biochemical analyses (high performance liquid chromatography, spectrophotometry, and Multiplex(r)). A redox imbalance occurred before an immunological disruption in the colon. NAC led to a decrease in hydrogen peroxide (H2O2), malondialdehyde (MDA) levels, and myeloperoxidase activity. In the liver, DSS did not cause damage but treatments with both antioxidants were potentially harmful, with LA increasing MDA and LA + NAC increasing H2O2, tumor necrosis factor alpha, interferon gamma, and transaminases. In summary, NAC exhibited the highest colonic antioxidant and anti-inflammatory activity, while LA + NAC caused hepatic damage. PMID- 27957239 TI - Oxidative Stress and Liver Cancer: Etiology and Therapeutic Targets. AB - Accumulating evidence has indicated that oxidative stress (OS) is associated with the development of hepatocellular carcinoma (HCC). However, the mechanisms remain largely unknown. Normally, OS occurs when the body receives any danger signal from either an internal or external source-and further induces DNA oxidative damage and abnormal protein expression, placing the body into a state of vulnerability to the development of various diseases such as cancer. There are many factors involved in liver carcinogenesis, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD). The relationship between OS and HCC has recently been attracting increasing attention. Therefore, elucidation of the impact of OS on the development of liver carcinogenesis is very important for the prevention and treatment of liver cancer. This review focuses mainly on the relationship between OS and the development of HCC from the perspective of cellular and molecular mechanisms and the etiology and therapeutic targets of HCC. PMID- 27957240 TI - Oral Exposure to Atrazine Induces Oxidative Stress and Calcium Homeostasis Disruption in Spleen of Mice. AB - The widely used herbicide atrazine (ATR) can cause many adverse effects including immunotoxicity, but the underlying mechanisms are not fully understood. The current study investigated the role of oxidative stress and calcium homeostasis in ATR-induced immunotoxicity in mice. ATR at doses of 0, 100, 200, or 400 mg/kg body weight was administered to Balb/c mice daily for 21 days by oral gavage. The studies performed 24 hr after the final exposure showed that ATR could induce the generation of reactive oxygen species in the spleen of the mice, increase the level of advanced oxidation protein product (AOPP) in the host serum, and cause the depletion of reduced glutathione in the serum, each in a dose-related manner. In addition, DNA damage was observed in isolated splenocytes as evidenced by increase in DNA comet tail formation. ATR exposure also caused increases in intracellular Ca2+ within splenocytes. Moreover, ATR treatment led to increased expression of genes for some antioxidant enzymes, such as HO-1 and Gpx1, as well as increased expression of NF-kappaB and Ref-1 proteins in the spleen. In conclusion, it appears that oxidative stress and disruptions in calcium homeostasis might play an important role in the induction of immunotoxicity in mice by ATR. PMID- 27957242 TI - Performance of cold-preserved rat liver Microorgans as the biological component of a simplified prototype model of bioartificial liver. AB - AIM: To develop a simplified bioartificial liver (BAL) device prototype, suitable to use freshly and preserved liver Microorgans (LMOs) as biological component. METHODS: The system consists of 140 capillary fibers through which goat blood is pumped. The evolution of hematocrit, plasma and extra-fiber fluid osmolality was evaluated without any biological component, to characterize the prototype. LMOs were cut and cold stored 48 h in BG35 and ViaSpan(r) solutions. Fresh LMOs were used as controls. After preservation, LMOs were loaded into the BAL and an ammonia overload was added. To assess LMOs viability and functionality, samples were taken to determine lactate dehydrogenase (LDH) release and ammonia detoxification capacity. RESULTS: The concentrations of ammonia and glucose, and the fluids osmolalities were matched after the first hour of perfusion, showing a proper exchange between blood and the biological compartment in the minibioreactor. After 120 min of perfusion, LMOs cold preserved in BG35 and ViaSpan(r) were able to detoxify 52.9% +/- 6.5% and 53.6% +/- 6.0%, respectively, of the initial ammonia overload. No significant differences were found with Controls (49.3% +/- 8.8%, P < 0.05). LDH release was 6.0% +/- 2.3% for control LMOs, and 6.2% +/- 1.7% and 14.3% +/- 1.1% for BG35 and ViaSpan(r) cold preserved LMOs, respectively (n = 6, P < 0.05). CONCLUSION: This prototype relied on a simple design and excellent performance. It's a practical tool to evaluate the detoxification ability of LMOs subjected to different preservation protocols. PMID- 27957243 TI - Pancreatic hyperechogenicity associated with hypoadiponectinemia and insulin resistance: A Japanese population study. AB - AIM: To examine the relationship between pancreatic hyperechogenicity and risk factors for metabolic syndrome. METHODS: A general population-based survey of lifestyle-related diseases was conducted from 2005 to 2006 in Japan. The study involved 551 participants older than 40 year of age. Data for 472 non-diabetic adults were included in the analysis. The measures included the demographic factors, blood parameters, results of a 75 g oral glucose tolerance test, and abdominal ultrasonography. The echogenicity of the pancreas and liver was compared, and then the subjects were separated into two groups: cases with pancreatic hyperechogenicity (n = 208) and cases without (controls, n = 264). The differences between both groups were compared using an unpaired t-test or Fisher's exact test. Multiple logistic regression analysis was used to determine the relationship between the pancreatic hyperechogenicity and clinical and biochemical parameters. RESULTS: Subjects with pancreatic hyperechogenicity had decreased serum adiponectin concentration compared to control subjects [8.9 (6.5, 12.8) vs 11.1 (7.8, 15.9), P < 0.001] and more frequently exhibited features of metabolic syndrome. Logistic regression analysis showed that the following variables were significantly and independently associated with pancreatic hyperechogenicity: Presence of hypoadiponectinemia, increased body mass index (BMI), higher homeostasis model assessment of insulin resistance (HOMA-IR) score, and presence of fatty liver. Similar associations were also observed in subjects with pancreatic hyperechogenicity without fatty liver. Multivariate association analysis of data from participants without fatty liver showed that hypoadiponectinemia was significantly associated with pancreatic hyperechogenicity (OR = 0.93, 95%CI: 0.90 - 0.97, P < 0.001). This association was independent of other confounding variables. Additionally, an increased BMI and higher HOMA-IR score were significantly associated with pancreatic hyperechogenicity. CONCLUSION: Pancreatic hyperechogenicity is independently associated with increased BMI, insulin resistance, and hypoadiponectinemia in the general population. PMID- 27957244 TI - Neglected features of lifestyle: Their relevance in non-alcoholic fatty liver disease. AB - AIM: To investigated in non-alcoholic-fatty-liver-disease (NAFLD), with ultrasound (US)-detected fatty liver, and in a group of non-alcoholic and otherwise healthy subjects, relationship of neglected features of lifestyle with NAFLD and obesity. METHODS: Five hundred and thirty-two NAFLD and 667 non-NAFLD healthy subjects, age 21-60 years were studied. Severity of liver steatosis was assessed by US bright liver score. The adherence to mediterranean diet score (AMDS) was assessed on the basis of a 1-wk recall computerized questionnaire which included a detailed physical activity reports (Baecke questionnaire). The western dietary profile score, as a simplified paradigm of unhealthy diet, a questionnaire quantifying sun exposure score and a sleep habits questionnaires provided a further comprehensive lifestyle assessment. RESULTS: Body mass index (BMI), insulin resistance (HOMA), and triglycerides, poorer adherence to a mediterranean diet profile, sedentary habits, minor sun exposure and use of "western diet" foods are greater in NAFLD. Multiple linear regression analysis, weighted by years of age, displays BMI, HOMA and AMDS as the most powerful independent predictors of fatty liver severity; however, also the physical activity score, the western diet habit and the sun exposure score are acting inside the model with significant independent effects. CONCLUSION: Articulated clinical intervention, according to our results, are justified in NAFLD and can be pursued addressing by focused intervention nutritional profile, physical exercise mainly in open-air subsets for enhancing sun exposure and healthier sleep duration and rhythm. PMID- 27957245 TI - Can platelet count/spleen diameter ratio be used for cirrhotic children to predict esophageal varices? AB - AIM: To determine the laboratory and radiologic parameters, including the platelet count (PC)-to-spleen diameter (SD) ratio as a non-invasive marker that may predict the presence of esophageal varices (EV) in children with cirrhosis. METHODS: Eighty-nine patients with cirrhosis, but without a history of variceal bleeding were prospectively included. The children were grouped into 6-12 and 12 18 years of age groups. These groups were also divided into 2 sub-groups (presence and absence of EV). All of the patients underwent a complete biochemical and radiologic evaluation. The PC (n/mm3)-to-SD (mm) ratio was calculated for each patient. RESULTS: Sixty-nine of 98 (70.4%) patients had EV. The presence of ascites in all age groups was significantly associated with the presence of EV. There were no differences in serum albumin levels, PC, SD and the PC-to-SD ratio between the presence and absence of EV groups in both age groups (P > 0.05). CONCLUSION: Laboratory and radiologic parameters, including the PC-to SD ratio as a non-invasive marker (except for the presence of ascites), was inappropriate for detecting EV in children with cirrhosis. PMID- 27957241 TI - Recent advances in the diagnosis and treatment of primary biliary cholangitis. AB - Primary biliary cholangitis (PBC), formerly referred to as primary biliary cirrhosis, is an infrequent progressive intrahepatic cholestatic autoimmune illness that can evolve into hepatic fibrosis, hepatic cirrhosis, hepatic failure, and, in some cases, hepatocellular carcinoma. The disease itself is characterized by T-lymphocyte-mediated chronic non-suppurative destructive cholangitis and elevated serum levels of extremely specific anti-mitochondrial autoantibodies (AMAs). In this article, we will not only review epidemiology, risk factors, natural history, predictive scores, radiologic approaches (e.g., acoustic radiation force impulse imaging, vibration controlled transient elastography, and magnetic resonance elastography), clinical features, serological characteristics covering biochemical markers, immunoglobulins, infections markers, biomarkers, predictive fibrosis marker, specific antibodies (including AMAs such as AMA-M2), anti-nuclear autoantibodies [such as anti multiple nuclear dot autoantibodies (anti-sp100, PML, NDP52, anti-sp140), anti rim-like/membranous anti-nuclear autoantibodies (anti-gp210, anti-p62), anti centromere autoantibodies, and some of the novel autoantibodies], histopathological characteristics of PBC, diagnostic advances, and anti-diastole of PBC. Furthermore, this review emphasizes the recent advances in research of PBC in terms of therapies, including ursodeoxycholic acid, budesonide, methotrexate, obeticholic acid, cyclosporine A, fibrates such as bezafibrate and fenofibrate, rituximab, mesenchymal stem cells transplant, and hepatic transplant. Currently, hepatic transplant remains the only optimal choice with acknowledged treatment efficiency for end-stage PBC patients. PMID- 27957246 TI - Elevation of serum urokinase plasminogen activator receptor and liver stiffness in postoperative biliary atresia. AB - AIM: To investigate serum urokinase-type plasminogen activator receptor (uPAR) and liver stiffness in biliary atresia (BA) and examine the correlation of circulating uPAR, liver stiffness, and clinical outcomes in postoperative BA children. METHODS: Eighty-five postKasai BA children and 24 control subjects were registered. Circulating uPAR was measured using enzyme-linked immunosorbent essay. Liver stiffness was analyzed using transient elastography. RESULTS: BA children had significantly greater circulating uPAR and liver stiffness scores than control subjects (P < 0.001). Circulating uPAR and liver stiffness were substantially higher in jaundiced BA children than non-jaundiced BA children (P < 0.001). In addition, circulating uPAR was positively associated with serum aspartate aminotransferase (r = 0.507, P < 0.001), alanine aminotransferase (r = 0.364, P < 0.001), total bilirubin (r = 0.559, P < 0.001), alkaline phosphatase (r = 0.325, P < 0.001), and liver stiffness scores (r = 0.508, P < 0.001). CONCLUSION: Circulating uPAR and liver stiffness values were greater in BA children than healthy controls. The increased circulating uPAR was associated with liver dysfunction in BA. As a consequence, serum uPAR and liver stiffness may be used as noninvasive biomarkers indicating the progression of liver fibrosis in postKasai BA. PMID- 27957247 TI - Bibliometric analysis of top 100 cited articles in nonalcoholic fatty liver disease research. AB - AIM: To identify and assess the research situation of top 100 cited articles in nonalcoholic fatty liver disease (NAFLD). METHODS: The global scientific research articles in the Science Citation Index-Expanded relevant to NAFLD were retrieved and listed according to their citation times from the most to the least. The 100 most frequently cited original articles were selected to systematically evaluate their bibliometric parameters including times cited, publication year, journals, subject categories, and the highly related concepts of NAFLD, which reflected the history and current situation, publication distribution of leading countries and institutes as well as the research hotspots of NAFLD. RESULTS: Top 100 cited articles in NAFLD were published from 1965 to 2015 with a citation ranging of 227 to 2151 times since publication, in which the United States was the most predominant country and Mayo Clin was the most productive institution. The majority of the top 100 cited articles were concentrated in SCI subject category of Gastroenterology and Hepatology. Hepatology and Gastroenterology is the top journal that published over half 100 top-cited articles. The significant peak of top cited articles present in the first half of the 2000s while the highest mean number of citation presents in first half of the 1980s. In addition, concepts related to pathology characteristics, epidemiology and medicalization, metabolic syndrome and its combination of symptoms including insulin resistance, biomarkers of lipid metabolism and obesity are listed as the highly related concepts. CONCLUSION: The 100 top-cited articles marked with the leading countries, institutions, journals, hotspots and development trend in NAFLD field that could provide the foundation for further investigations. PMID- 27957248 TI - Mechanisms of the alternative activation of macrophages and non-coding RNAs in the development of radiation-induced lung fibrosis. AB - Radiation-induced lung fibrosis (RILF) is a common side effect of thoracic irradiation therapy and leads to high mortality rates after cancer treatment. Radiation injury induces inflammatory M1 macrophage polarization leading to radiation pneumonitis, the first stage of RILF progression. Fibrosis occurs due to the transition of M1 macrophages to the anti-inflammatory pro-fibrotic M2 phenotype, and the resulting imbalance of macrophage regulated inflammatory signaling. Non-coding RNA signaling has been shown to play a large role in the regulation of the M2 mediated signaling pathways that are associated with the development and progression of fibrosis. While many studies show the link between M2 macrophages and fibrosis, there are only a few that explore their distinct role and the regulation of their signaling by non-coding RNA in RILF. In this review we summarize the current body of knowledge describing the roles of M2 macrophages in RILF, with an emphasis on the expression and functions of non coding RNAs. PMID- 27957250 TI - Mechanisms and clinical significance of early recurrences of atrial arrhythmias after catheter ablation for atrial fibrillation. AB - Early recurrence of atrial arrhythmias (ERAA) after ablation is common and strongly predicts late recurrences and ablation failure. However, since arrhythmia may eventually resolve in up to half of patients with ERAA, guidelines do not recommend immediate reintervention for ERAA episodes occurring during a 3 mo post-ablation blanking period. Certain clinical demographic, electrophysiologic, procedural, and ERAA-related characteristics may predict a higher likelihood of long-term ablation failure. In this review, we aim to discuss potential mechanisms of ERAA, and to summarize the clinical significance, prognostic implications, and treatment options for ERAA. PMID- 27957249 TI - Physiology of in-situ arterial revascularization in coronary artery bypass grafting: Preoperative, intraoperative and postoperative factors and influences. AB - Surgical revascularization with coronary artery bypass grafting (CABG) has become established as the most effective interventional therapy for patients with moderately severe and severe stable ischemic heart disease (SIHD). This recommendation is based on traditional 5-year outcomes of mortality and avoidance of myocardial infarction leading to reintervention and/or cardiac death. However, these results are confounded in that they challenge the traditional CABG surgical tenets of completeness of anatomic revascularization, the impact of arterial revascularization on late survival, and the lesser impact of secondary prevention following CABG on late outcomes. Moreover, the emergence of physiologic-based revascularization with percutaneous cardiovascular intervention as an alternative strategy for revascularization in SIHD raises the question of whether there are similar physiologic effects in CABG. Finally, the ongoing ISCHEMIA trial is specifically addressing the importance of the physiology of moderate or severe ischemia in optimizing therapeutic interventions in SIHD. So it is time to address the role that physiology plays in surgical revascularization. The long standing anatomic framework for surgical revascularization is no longer sufficient to explain the mechanisms for short-term and long-term outcomes in CABG. Novel intraoperative imaging technologies have generated important new data on the physiologic blood flow and myocardial perfusion responses to revascularization on an individual graft and global basis. Long-standing assumptions about technical issues such as competitive flow are brought into question by real-time visualization of the physiology of revascularization. Our underestimation of the impact of Guideline Directed Medical Therapy, or Optimal Medical Therapy, on the physiology of preoperative SIHD, and the full impact of secondary prevention on post-intervention SIHD, must be better understood. In this review, these issues are addressed through the perspective of multi-arterial revascularization in CABG, which is emerging (after 30 years) as the "standard of care" for CABG. In fact, it is the physiology of these arterial grafts that is the mechanism for their impact on long-term outcomes in CABG. Moreover, a better understanding of all of these preoperative, intraoperative and postoperative components of the physiology of revascularization that will generate the next, more granular body of knowledge about CABG, and enable surgeons to design and execute a better surgical revascularization procedure for patients in the future. PMID- 27957251 TI - Clinical characteristics and prognostic impact of atrial fibrillation in patients with chronic heart failure. AB - AIM: To assess the prevalence, clinical characteristics and independent prognostic impact of atrial fibrillation (AF) in chronic heart failure (CHF) patients, and the potential protective effect of disease-modifying medications, particularly beta-blockers (BB). METHODS: We retrospectively reviewed the charts of patients referred to our center since January 2004, and collected all clinical information available at their first visit. We assessed mortality to the end of June 2015. We compared patients with and without AF, and assessed the association between AF and all-cause mortality by multivariate Cox regression and Kaplan Meyer analysis, particularly accounting for ongoing treatment with BB. RESULTS: A total of 903 patients were evaluated (mean age 68 +/- 12 years, 73% male). Prevalence of AF was 19%, ranging from 10% to 28% in patients <= 60 and >= 77 years, respectively. Besides the older age, patients with AF had more symptoms (New York Heart Association II-III 60% vs 44%), lower prevalence of dyslipidemia (23% vs 37%), coronary artery disease (28% vs 52%) and left bundle branch block (9% vs 16%). On the contrary, they more frequently presented with an idiopathic etiology (50% vs 24%), a history of valve surgery (13% vs 4%) and received overall more devices implantation (31% vs 21%). The use of disease-modifying medications (i.e., BB and ACE inhibitors/angiotensin receptor blockers) was lower in patients with AF (72% vs 80% and 71% vs 79%, respectively), who on the contrary were more frequently treated with symptomatic and antiarrhythmic drugs including diuretics (87% vs 69%) and digoxin (51% vs 11%). At a mean follow-up of about 5 years, all-cause mortality was significantly higher in patients with AF as compared to those in sinus rhythm (SR) (45% vs 34%, P value < 0.05 for all previous comparisons). However, in a multivariate analysis including the main significant predictors of all-cause mortality, the univariate relationship between AF and death (HR = 1.49, 95%CI: 1.15-1.92) became not statistically significant (HR = 0.98, 95%CI: 0.73-1.32). Nonetheless, patients with AF not receiving BB treatment were found to have the worst prognosis, followed by patients with SR not receiving BB therapy and patients with AF receiving BB therapy, who both had similarly worse survival when compared to patients with SR receiving BB therapy. CONCLUSION: AF was highly prevalent and associated with older age, worse clinical presentation and underutilization of disease-modifying medications such as BB in a population of elderly patients with CHF. AF had no independent impact on mortality, but the underutilization of BB in this group of patients was associated to a worse long-term prognosis. PMID- 27957252 TI - Riata silicone defibrillation lead with normal electrical measures at routine ambulatory check: The role of high-voltage shock testing. AB - AIM: To describe our experience with shock testing for the evaluation of patients with RiataTM leads. METHODS: Among 51 patients with normal baseline electrical parameters, 20 died during follow-up. Of the remaining 31 patients, 15 underwent the test: In 10 cases a defibrillation testing with ventricular fibrillation (VF) induction and in 5 cases a R-wave-synchronized shock (> 20 J, without inducing VF). The test was performed under sedation with Midazolam. RESULTS: Twelve patients (80%) had a normal behavior during shock testing: In 8 cases induced VF was correctly detected and treated; in 4 cases of R-wave-synchronized shock electrical parameters remained stable and normal. Three patients (20%) failed the test. One patient with externalized conductors showed a sudden drop of high voltage impedance (< 10 Ohm) after a 25 J R-wave-synchronized shock. Two other patients with externalized conductors, undergoing defibrillation testing, showed a short-circuit during shock delivery and the implantable cardioverter defibrillator was unable to interrupt VF. CONCLUSION: In RiataTM leads the delivery of a low current during routine measurement of high-voltage impedance may not reveal a small short circuit, that can only be evident by attempting to deliver a true shock, either for spontaneous arrhythmias or in the context of a shock testing. PMID- 27957253 TI - Increased levels of circulating platelet-derived microparticles in psoriasis: Possible implications for the associated cardiovascular risk. AB - AIM: To evaluate platelet activation markers in psoriasis patients, compared to controls, and investigate their association with the inflammatory burden of psoriasis. METHODS: Forty psoriatic patients without cardiovascular disease, and 12 healthy controls were subjected to measurement of baseline platelet CD62P, CD63 and CD42b expression, platelet-leukocyte complexes, i.e., platelet-monocyte complexes (PMC), platelet-neutrophil complexes (PNC) and platelet-lymphocyte complexes, and concentrations of platelet-derived microparticles (PMPs) using flow cytometry. Both larger-size (0.5-0.9 MUm) and smaller-size (< 0.5 MUm) PMPs were determined. Serum interleukin (IL)-12 and IL-17 levels were also measured by enzyme-linked immunosorbent assay. The severity of psoriasis was evaluated by the Psoriasis Area Severity Index (PASI). RESULTS: PMP concentrations were significantly higher in psoriasis patients than controls [mean +/- standard error of mean (SEM): 22 +/- 5/MUL vs 11 +/- 6/MUL; P = 0.018), for both smaller-size (10 +/- 2/MUL vs 4 +/- 2/MUL; P = 0.033) and larger-size (12 +/- 3/MUL vs 6 +/- 4/MUL; P = 0.014) PMPs. Platelet CD62P, CD63 and CD42b expression and circulating PMC and PNC were similar between the two groups. Lower circulating PLC were observed in psoriasis patients compared to controls (mean +/- SEM: 16% +/- 3% vs 23% +/- 6%; P = 0.047). Larger-size PMPs were related with IL-12 levels (P < 0.001) and smaller-size PMPs with both IL-12 and IL-17 levels (P < 0.001). Total PMPs also correlated with IL-12 (P < 0.001). CD63 expression was positively correlated with both IL-12 and IL-17 (P < 0.05). Increased PASI score was associated with increased levels of larger-size PMPs (r = 0.45; P = 0.011) and increased CD63 expression (r = 0.47; P < 0.01). CONCLUSION: PMPs, known to be predictive of cardiovascular outcomes, are increased in psoriasis patients, and associated with high inflammatory disease burden. Enhanced platelet activation may be the missing link leading to cardiovascular events in psoriatic patients. PMID- 27957254 TI - Outcomes and long-term survival of coronary artery surgery: The controversial role of opium as risk marker. AB - AIM: To study survival in isolated coronary artery bypass graft (CABG) patients and to evaluate the impact of preoperative chronic opium consumption on long-term outcome. METHODS: Cohort of 566 isolated CABG patients as Tehran Heart Center cardiac output measurement was conducted. Daily evaluation until discharge as well as 4- and 12-mo and 6.5-year follow-up information for survival status were fulfilled for all patients. Long-term 6.5-year overall and opium-stratified survival, adjusted survival curves based on opium consumption as well as possible predictors of all-cause mortality using multiple cox regression were determined by statistical analysis. RESULTS: Six point five-year overall survival was 91.8%; 86.6% in opium consumers and 92.7% in non-opium consumers (P = 0.035). Patients with positive history of opium consumption significantly tended to have lower ejection fraction (EF), higher creatinine level and higher prevalence of myocardial infarction. Multiple predictors of all-cause mortality included age, body mass index, EF, diabetes mellitus and cerebrovascular accident. The hazard ratio (HR) of 2.09 for the risk of mortality in opium addicted patients with a borderline P value (P = 0.052) was calculated in this model. Further adjustment with stratification based on smoking and opium addiction reduced the HR to 1.20 (P = 0.355). CONCLUSION: Simultaneous impact of smoking as a confounding variable in most of the patients prevents from definitive judgment on the role of opium as an independent contributing factor in worse long-term survival of CABG patients in addition to advanced age, low EF, diabetes mellitus and cerebrovascular accident. Meanwhile, our findings do not confirm any cardio protective role for opium to improve outcome in coronary patients with the history of smoking. Further studies are needed to clarify pure effect of opium and warrant the aforementioned findings. PMID- 27957255 TI - Pulmonary vein thrombosis in a patient with polycythemia vera. AB - Pulmonary vein thrombosis (PVT) is a rarely encountered disease entity with varied clinical presentations. It is usually associated with lung carcinoma, lung surgeries and as a complication of the radiofrequency catheter ablation procedure for atrial fibrillation. Its clinical manifestations can vary from mild hemoptysis to lung infarction with hemodynamic compromise. A 76-year-old male presented with a 2-d history of pleuritic left sided chest pain. His past medical history included polycythemia vera, atrial fibrillation, coronary artery disease, pulmonary embolism and pulmonary hypertension. Chest radiograph was normal, troponins were normal and the 12-lead electrocardiogram did not show any ischemic changes. A computerized tomography pulmonary angiogram revealed a filling defect in the left lower lobe pulmonary vein. He was treated with subcutaneous enoxaparin and his symptoms improved. This case highlights a rare etiology of chest pain and the first reported case of the association of polycythemia vera and pulmonary vein thrombosis. A high index of suspicion is required for appropriate diagnostic work up. PVT can mimic pulmonary embolism. The diagnostic work up and treatment strategies depend on acuity of presentation. PMID- 27957256 TI - Effect of different mixing methods on the physical properties of Portland cement. AB - BACKGROUND: The Portland cement is hydrophilic cement; as a result, the powder-to liquid ratio affects the properties of the final mix. In addition, the mixing technique affects hydration. The aim of this study was to evaluate the effect of different mixing techniques (conventional, amalgamator and ultrasonic) on some selective physical properties of Portland cement. MATERIAL AND METHODS: The physical properties to be evaluated were determined using the ISO 6786:2001 specification. One hundred sixty two samples of Portland cement were prepared for three mixing techniques for each physical property (each 6 samples). Data were analyzed using descriptive statistics, one-way ANOVA and post hoc Tukey tests. Statistical significance was set at P<0.05. RESULTS: The mixing technique had no significant effect on the compressive strength, film thickness and flow of Portland cement (P>0.05). Dimensional changes (shrinkage), solubility and pH increased significantly by amalgamator and ultrasonic mixing techniques (P<0.05). The ultrasonic technique significantly decreased working time, and the amalgamator and ultrasonic techniques significantly decreased the setting time (P<0.05). CONCLUSIONS: The mixing technique exerted no significant effect on the flow, film thickness and compressive strength of Portland cement samples. Key words:Physical properties, Portland cement, mixing methods. PMID- 27957258 TI - Prevalence and distribution of selected dental anomalies among saudi children in Abha, Saudi Arabia. AB - BACKGROUND: Dental anomalies are not an unusual finding in routine dental examination. The effect of dental anomalies can lead to functional, esthetic and occlusal problems. The Purpose of the study was to determine the prevalence and distribution of selected developmental dental anomalies in Saudi children. MATERIAL AND METHODS: The study was based on clinical examination and Panoramic radiographs of children who visited the Pediatric dentistry clinics at King Khalid University College of Dentistry, Saudi Arabia. These patients were examined for dental anomalies in size, shape, number, structure and position. Data collected were entered and analyzed using statistical package for social sciences version. RESULTS: Of the 1252 children (638 Boys, 614 girls) examined, 318 subjects (25.39%) presented with selected dental anomalies. The distribution by gender was 175 boys (27.42%) and 143 girls (23.28%). On intergroup comparison, number anomalies was the most common anomaly with Hypodontia (9.7%) being the most common anomaly in Saudi children, followed by hyperdontia (3.5%). The Prevalence of size anomalies were Microdontia (2.6%) and Macrodontia (1.8%). The prevalence of Shape anomalies were Talon cusp (1.4%), Taurodontism (1.4%), Fusion (0.8%).The prevalence of Positional anomalies were Ectopic eruption (2.3%) and Rotation (0.4%). The prevalence of structural anomalies were Amelogenesis imperfecta (0.3%) Dentinogenesis imperfecta (0.1%). CONCLUSIONS: A significant number of children had dental anomaly with Hypodontia being the most common anomaly and Dentinogenesis imperfecta being the rare anomaly in the study. Early detection and management of these anomalies can avoid potential orthodontic and esthetic problems in a child. Key words:Dental anomalies, children, Saudi Arabia. PMID- 27957257 TI - Antimicrobial efficacy of different concentration of sodium hypochlorite on the biofilm of Enterococcus faecalis at different stages of development. AB - BACKGROUND: Persistent infection of the root canal due to the presence of resistance bacterial species, such as Enterococcus faecalis, has always been one of the most important reasons for endodontic treatment failure. This study investigated the antimicrobial efficacy of 1%, 2.5 % and 5% sodium hypochlorite in eliminating E. faecalis biofilms at different stages of development. MATERIAL AND METHODS: In this study 4-, 6- and 10-week-old E. faecalis biofilms were subjected to one of the following approaches: phosphate-buffered saline solution (PBS) or 1%, 2.5% and 5% NaOCl. Dentin chip suspensions were used for colony forming unit (CFU) counting to estimate remaining E. faecalis counts. Statistical comparison of the means was carried out with Kruskal-Wallis test, and pair-wise comparisons were made by Mann-Whitney U test, at a significance level of P<0.05. RESULTS: The results showed that 2.5% and 5% NaOCl completely eliminated E. faecalis biofilms in three stages of biofilm development, whereas 1% NaOCl resulted in 85.73%, 81.88% and 78.62% decreases in bacterial counts in 4-, 6- and 10-week-old biofilms, respectively, which was significantly more than those with PBS (p<0.05). CONCLUSIONS: The bacteria in mature and old biofilms were more resistant to 1% NaOCl than were the bacteria in young biofilms. Overall survival rate and residual bacteria increased with biofilm aging. Key words:Antibacterial, biofilm, E. faecalis, sodium hypochlorite. PMID- 27957260 TI - Periapical healing outcome following single visit endodontic treatment in patients with type 2 diabetes mellitus. AB - BACKGROUND: The prevalence of apical periodontitis in diabetes mellitus patients is high. The altered immunity in diabetes affects the healing process of periapical tissue. Single visit endodontic treatment has shown to increase the periapical healing rate with better patient compliance. Hence the present study aims at evaluating the clinical and radiographic healing outcome of single visit endodontic treatment, in type 2 diabetes mellitus patients with periapical disease. MATERIAL AND METHODS: Eighty patients with periapical disease were divided into 2 groups of 40 each: Group I, Control subjects and Group II, Type 2 diabetics. Glycosylated hemoglobin levels were assessed preoperatively and at follow up intervals in diabetics. Pre-operative assessment of periapical status was done using CPDR (Clinical periapical diagnosis of root), QLDR (Qualitative radiographic diagnosis of tooth) and QTDR (Quantitative radiographic diagnosis of tooth) criteria. Postoperative healing was evaluated following single-visit endodontic treatment by Strindberg criteria. RESULTS: Group 2 subjects had chronic and exacerbating lesions with significantly larger lesions (p=0.029). 100 % clinical healing outcome in diabetic group was seen in two months. Group 2 showed 85% success in one year on radiographic evaluation. Poor controlled diabetics showed failure compared to fair and good controlled. CONCLUSIONS: Type 2 diabetics had chronic and larger sized lesions when compared to control subjects. The periapical lesions in patients with poor diabetic control showed failure. The clinical and radiographic healing outcome of single visit endodontic therapy was delayed in diabetic patients. Key words:Apical periodontitis, diabetes mellitus type 2, endodontics, periapical lesion, strindberg criteria. PMID- 27957259 TI - Effect of a novel commercial potassium-oxalate containing tooth-desensitizing mouthrinse on the microhardness of resin composite restorative materials with different monomer compositions. AB - BACKGROUND: The effects of mouthrinses on dental resin composites have been investigated extensively. However, there is little information available regarding the effects of 'newly developed mouthrinse' formulations on the microhardness of different monomer based composite systems. Therefore, the aim of this study was to investigate the effect of a novel potassium-oxalate containing desensitizing mouthrinse on the microhardness of different monomer based composite materials. MATERIAL AND METHODS: A hundred and twenty specimens (6mm in diameter and 2mm in height) were prepared for composite resin groups (methacrylate based, DX-511 monomer based and silorane monomer based) and for storage solution groups (artificial saliva and potassium oxalate-containing tooth desensitizing mouthrinse). After allowing post-polimerization the baseline Knoop microhardness measurements for all specimens were recorded. The specimens were stored in 20 mL mouthwash and artificial saliva for 12 hours at 37oC. The post immersion microhardness values of all specimens were also recorded. Data were subjected to ANOVA/Scheffe's test at a significance level of 0.05. The intra group (pre and post immersion values) comparison of the mean microhardness values of the specimens was done using Wilcoxon signed rank test. RESULTS: The microhardness of the silorane based composite was not affected significantly (p>0.05). The hardness values of the DX-511 monomer based composite and the methacrylate based composite exhibited a slight but not significant microhardness change compared to the baseline values (p>0.05). CONCLUSIONS: Studies reported that the effect of mouthrinses on microhardness changes of composite resins may be material dependent, and the hardness change susceptibility of a restorative material may be attributed to its resin matrix or filler type. However, dental monomers as well as the oral care products have an ever-evolving technology and future studies should consider newer products. Potassium oxalate containing mouthrinses, especially alcohol-free ones, may be used safely with dental composites with newly developed low-shrink monomer compositions. Key words:Microhardness, monomers, mouthrinses, potassium-oxalate. PMID- 27957261 TI - p53, p63 and p73 expression and angiogenesis in keratocystic odontogenic tumors. AB - BACKGROUND: Keratocystic odontogenic tumors (KCOTSs) are odontogenic tumors previously referred to as odontogenic keratocysts. Several studies have reported that KCOT behavior is more like that of a benign neoplasm than a cyst. KCOTs are locally destructive and exhibit a high recurrence rate. The objective of this study is to characterize the expression of p53, p63 and p73 in KCOTs together with the relationship between their expression and KCOT angiogenesis and recurrence. MATERIAL AND METHODS: Standard indirect immunohistochemistry using monoclonal antibodies specific to human p53, p63, p73 and CD105 was performed in formalin-fixed paraffin-embedded tissue sections of 39 KCOT samples. Grading of p53, p63 and p73 immunohistochemical staining was divided into three groups, whereas microvessel density (MVD) was presented as the mean +/- standard deviation. Associations between p53, p63 and p73 expression and clinical pathological parameters were analyzed by Fisher's exact test, whereas associations among MVD levels, clinical and pathological parameters and p53, p63 and p73 expression were analyzed by the Mann-Whitney U test. Correlations among p53, p63, p73 and MVD levels were analyzed using Spearman's correlation coefficients. For all analyses, p< 0.05 was considered to indicate statistical significance. RESULTS: p53, p63 and p73 expression was noted in 23, 32 and 26 of 39 KCOT cases, respectively. The mean MVD was 26.7 +/- 15.8 per high-power field. In addition, correlations between the expression levels of p53, p63, p73 and MVD in KCOT were examined. Statistically significant positive relationships were noted for all proteins (p<0.001). CONCLUSIONS: Three members of the p53 protein family are expressed in KCOTs, and their expression relates to angiogenesis in these tumors. Key words:p53, p63, p73, angiogenesis, keratocystic odontogenic tumors. PMID- 27957262 TI - Mechanical properties and DIC analyses of CAD/CAM materials. AB - BACKGROUND: This study compared two well-known computer-aided-design/computer aided-manufactured (CAD/CAM) blocks (Paradigm MZ100 [3M ESPE] and Vitablocs Mark II [Vita] in terms of fracture toughness (Kic), index of brittleness (BI) and stress/strain distributions. MATERIAL AND METHODS: Three-point bending test was used to calculate the fracture toughness, and the relationship between the Kic and the Vickers hardness was used to calculate the index of brittleness. Additionally, digital image correlation (DIC) was used to analyze the stress/strain distribution on both materials. RESULTS: The values for fracture toughness obtained under three-point bending were 1.87Pa?m (+/-0.69) for Paradigm MZ100 and 1.18Pa?m (+/-0.17) for Vitablocs Mark II. For the index of brittleness, the values for Paradigm and Vitablocs were 73.13MUm-1/2 (+/-30.72) and 550.22MUm 1/2 (+/-82.46). One-way ANOVA was performed to find differences (alpha=0.05) and detected deviation between the stress/strain distributions on both materials. CONCLUSIONS: Both CAD/CAM materials tested presented similar fracture toughness, but, different strain/stress distributions. Both materials may perform similarly when used in CAD/CAM restorations. Key words:Ceramic, CAD/CAM, hybrid materials, composite resin, fracture toughness. PMID- 27957263 TI - Different modalities for treatment of recurrent aphthous stomatitis. A Randomized clinical trial. AB - BACKGROUND: The underlying etiology of recurrent aphthous stomatitis (RAS) is unclear and treatment aims to provide symptomatic and faster relief. This study compared the efficacy of diode laser, a herbal combination of Acacia nilotica and Licorice (A and L) and Amlexanox in the management of RAS. MATERIAL AND METHODS: Sixty patients with minor aphthae were selected and randomly divided into four groups of 15 each. Group I and II received adhesive preparations of a herbal mixture of A and L and a 2 mg Amlexanox paste respectively, group III received diode laser and the fourth group (control) used a placebo. Ulcer size, pain score were recorded on days 1, 2 and 5. RESULTS: Laser group showed the statistically highest mean percentage (%) of reduction in pain scores and ulcer size than the other groups. The mean % of reduction in pain scores was 43.3+20.0 at day 2 and 67.8+21.5 % at day 5 in the laser group while Amlexanox group demonstrated a 29.8 +11.3 and 61.9+24.5 mean % of reduction in pain scores at day 2 and 5 respectively. A and L group showed a lower mean % of reduction in pain scores than laser and Amlexanox groups with a 22.2+10.5 and 43.4+15.8 mean % reduction in pain scores at day 2 and day 5 respectively. Similarly the highest mean % of reduction in ulcer size was seen in the laser group being 52.7+19.8 at day 2 and 85.1+22.0 at day 5, while it was 48.1+16.5 at day 2 and 77.8+28.7 at day 5 in the Amlexanox group and 42.0+11.5 at day 2 and 63.0+20.5 at day 5 in the A and L group. CONCLUSIONS: All treatment modalities reduced pain and ulcer size than placebo group. Laser therapy demonstrated the highest percentage of reduction of pain score and ulcer size. Key words:Aphthous stomatitis, laser, herbal plants, Acacia nilotica, Licorice. PMID- 27957264 TI - Comparison of the shaping ability of RaCe, FlexMaster, and ProFile nickel titanium instruments in severely curved root canals. AB - BACKGROUND: This in vitro study compared the shaping ability of RaCe, FlexMaster, and ProFile rotary nickel-titanium instruments in severely curved root canals of extracted teeth. MATERIAL AND METHODS: Sixty maxillary molars with curvatures ranging from 25 degrees to 65 degrees were embedded in a muffle system and portioned into five horizontal sections (thickness 1.2 mm), starting from the apex. Canals were divided into three groups (n = 20, each) and were prepared with RaCe, FlexMaster, or ProFile rotary nickel-titanium instruments and the TriAuto ZX handpiece using a crown-down preparation technique. We evaluated the difference between pre- and postoperative root canal cross-sections, loss of working length, instrument failure, and preparation time. The root canal area before and after the intervention was determined using an area-measuring software. The data were analyzed statistically using a one-way ANOVA followed by a Kruskal-Wallis multiple-comparison Z-value test. RESULTS: Specimens treated with FlexMaster showed the greatest change from preoperative cross-sections, followed by RaCe and ProFile. The cross-sectional changes induced by RaCe and FlexMaster preparation differed significantly from those produced by ProFile. Loss of working length, instrument failure, and preparation time did not differ significantly between the groups. CONCLUSIONS: Root canal preparation with the three instruments did not lead to any significant alteration of the original root anatomy or working length. Thus, we conclude that RaCe, FlexMaster, and ProFile instruments are of comparable efficiency and usefulness in the preparation of severely curved root canals. Key words:Endodontics, root canal preparation, rotary, extracted teeth, nickel-titanium. PMID- 27957265 TI - Metaplastic changes in the epithelium of radicular cysts: A series of 711 cases. AB - BACKGROUND: This study was aimed to evaluate the prevalence of metaplastic changes in the epithelium of radicular cysts and to investigate how they relate to the clinical and radiographic characteristics of the cysts, based on a large series of radicular cysts. MATERIAL AND METHODS: Biopsies of cysts of endodontic origin that were examined at the Department of Oral Pathology between 2004 and 2011 have been re-evaluated for this study. Only cases that were re-confirmed with clinical and histological diagnoses of a radicular or residual radicular cyst were included. The included cases were evaluated for the prevalence of metaplastic changes in the form of mucous secreting cells (MSC) or ciliated cells (CC). The relations between the metaplastic changes and the cyst type (radicular or residual radicular), as well as demographic, clinical and radiographic parameters, were statistically evaluated using Fischer and chi-square tests. Significance was set at p<0.05. RESULTS: A total of 711 cysts were included: 677 were radicular cysts (95%) and 34 (5%) were residual radicular cysts. 23 cases had histopathological diagnoses other than radicular or residual radicular cysts and were excluded from the study. MSC were present in 47 (6.6%) cysts. MSC were significantly more common in residual radicular cysts than in radicular cysts [8 (23.5%) and 39 (5.8%), respectively; p<0.001]. MSC-containing cysts were commonly found in asymptomatic patients (10.5%, p<0.001), and usually presented with well defined radiographic borders (7.2%, p<0.05). CC were present in 34 (4.8%) cysts, with a markedly high prevalence in the maxillary molar sextant (15%, p<0.001). CONCLUSIONS: In the epithelium of radicular and residual radicular cysts the presence of specific metaplastic changes may be related to cyst type, symptomatology, radiographic findings and tooth location. Key words:Radicular cyst, metaplasia, mucous secreting cells, ciliated cells. PMID- 27957266 TI - Dynamic thermo-mechanical properties of various flowable resin composites. AB - BACKGROUND: This study compared the storage modulus (E'), the loss modulus (E'') and the loss tangent (tan delta) of various flowable resin composites. MATERIAL AND METHODS: Grandio Flow (GRF), GrandioSo Heavy Flow (GHF), Filtek Supreme XTE (XTE) and Filtek Bulk Fill (BUL) flowable resins and Clinpro Sealant (CLI) ultra flowable pit and fissure sealant resin were used. 25 samples were tested using a dynamical mechanical thermal analysis system in bending mode. Measurements were taken within a temperature range of 10 to 55 degrees C. The results were statistically analyzed using mixed-effect and repeated-measure analysis of variance followed by paired multiple comparisons. RESULTS: For all the materials, the E' values decrease with temperature, whereas the tan delta values increase. Irrespective of the temperature, GHF and GRF present E' and E'' values significantly higher than all the other materials and CLI presents values significantly lower than all the other materials. Observation of the values for all the materials reveals a linear progression of the tan delta values with temperature. CONCLUSIONS: A variation in temperature within a physiological range generates modifications in mechanical properties without damaging the material, however. Filler content in volume terms appears to be the crucial parameter in the mechanical behavior of tested materials. Key words:Dynamic mechanical thermal analysis, elastic modulus, filler content, flowable resin composites, loss modulus, loss tangent. PMID- 27957267 TI - Psycho-social impact of orthogathic sugery. AB - BACKGROUND: Orthognathic surgery is a branch of maxillofacial surgery. It carries out the treatment of the facial skeleton asymmetries and deformities. The patients who ask for this surgery are often young people who usually refer symptoms related to dental malocclusion, difficulty eating and temporo-mandibular pain. These physical symptoms are often accompanied by psychological symptoms triggered by their physical appearance such as low self-esteem, self-confidence and negativism about their social and emotional future. MATERIAL AND METHODS: Patients with skeletal malformation of facial bones, consisting in Class II, III, open bite and asymmetries, underwent to orthognathic surgery in our center agreed to participate voluntarily in this study. They answered a questionnaire regarding several psychosocial variables. RESULTS: Orthognathic surgery helps to improve patient's psychosocial well-being. CONCLUSIONS: Patients with dentofacial deformitiesexperience physical and psychological, oftentimes underestimated by society. A combination of orthodontic treatment and reconstructive surgery is often a necessity to restore function and psychosocial well-being. Key words:Orthogathic surgery, psychosocial consequences, mood, emotions, sense of power, motivation, satisfaction, social changes, satisfaction. PMID- 27957269 TI - Morphological patterns of lip prints in an Iranian population. AB - BACKGROUND: Lip prints are verified to be unique to an individual and stable over time; hence they have potential for human identification purposes. The aim of this study was to assess the individuality and variability of lip prints in an Iranian population for the first time. We also sought to assess the possibility of sex determination via lip printing. MATERIAL AND METHODS: Lip prints of 96 individuals including 22 males and 74 females were recorded on a plain white paper using a dark-colored lipstick and 50 mm of Scotch tape. Each lip print was divided into six sextants and studied independently by two observers using a magnifying lens to examine the lip grooves. The Suzuki and Tsuchihashi's classification was used to define the lip patterns and the data were statistically analyzed. RESULTS: In the present study, no identically similar lip prints were observed. Type V was the most predominant pattern recorded in the study sample (33.16%), followed by type I (24.13%), type II (18.75%), type IV (11.63%), type I' (9.72%) and type III (2.60%). In addition, no statistically significant difference was observed in the lip print patterns of males and females. CONCLUSIONS: It can be concluded that lip prints are unique and their analysis may enable human identification. Key words:Forensic anthropology, forensic dentistry, forensic medicine, iran, lip. PMID- 27957268 TI - Evaluation of mineral content in healthy permanent human enamel by Raman spectroscopy. AB - BACKGROUND: An understanding of tooth enamel mineral content using a clinically viable method is essential since variations in mineralization may serve as an early precursor of a dental health issues, and may predict progression and architecture of decay in addition to assessing the success and effectiveness of the remineralization strategies. MATERIAL AND METHODS: Twenty two human incisor teeth were obtained in compliance with the NIH guidelines and site specifically imaged with Raman microscope. The front portion of the teeth was divided into apical, medium and cervical regions and subsequently imaged with Raman microscope in these three locations. RESULTS: Measured mineralization levels have varied substantially depending on the regions. It was also observed that, the cervical enamel is the least mineralization as a populational average. CONCLUSIONS: Enamel mineralization is affected by a many factors such as are poor oral hygiene, alcohol consumption and high intake of dietary carbohydrates, however the net effect manifests as overall mineral content of the enamel. Thus an early identification of the individual with overall low mineral content of the enamel may be a valuable screening tool in determining a group with much higher than average caries risk, allowing intervention before development of caries. Clinically applicable non-invasive techniques that can quantify mineral content, such as Raman analysis, would help answer whether or not mineralization is associated with caries risk. Key words:Enamel, Raman spectroscopy, mineral content, dental caries. PMID- 27957270 TI - "Dentists' and dietitians' recommendations of snacks and dental caries experience among kindergarteners". AB - BACKGROUND: Parents receive diet recommendations for their children from dentists and dietitians, but a conflict of diet suggestions has been reported. This research was conducted to investigate dental caries experiences in children consuming snacks that were recommended by dentists and/or dietitians. MATERIAL AND METHODS: A total of 442 kindergarteners under went dental examinations, and their caregivers filled out questionnaires. Snacks were sorted by name. Three dentists and three dietitians determined whether they would recommend these snacks. The snacks were divided into four categories: snacks recommended by both groups, snacks recommended by neither, snacks recommended only by dentists, and snacks recommend only by dieticians. Children were assigned to particular groups based on their primary snack consumption. The children's caries experiences (dft) were compared among the four groups. RESULTS: The agreement level on the recommended snacks between dietitians and dentists was moderate (Kappa=0.43). Thirty-nine snacks were identified; 13 recommended by neither, 4 recommended by dietitians, 7 were recommended only by dentists, and 15 were recommended by both. The mean (standard deviation) of dft amongthe children was 4.66 (3.81), 2.66 (3.17), 3.21 (3.37), and 4.02 (4.02), and respectively. The ANOVA and Tukey post hoc tests indicated that children who consumed snacks recommended only by one professional, dietitian or dentist, have significantly fewer dental caries than children who consumed snacks recommended by neither professional. (ANOVA: F=4.494, p=0.004, Tukey post-hoc test: p=0.007 and p=0.046, respectively). CONCLUSIONS: Dentists can recommend snacks that are nutrient dense, even though it contains sucrose. Key words:Child, dental caries, snacks, dentist, nutritionists. PMID- 27957271 TI - In vitro evaluation of the sealing ability of three newly developed root canal sealers: A bacterial microleakage study. AB - BACKGROUND: The purpose of this study was to compare the sealing ability of MTA Fillapex, Apatite Root Canal Sealer and AH26 sealers. MATERIAL AND METHODS: The present in vitro study was carried out on 142 extracted single-rooted human mature teeth. The teeth were randomly divided into three experimental groups (n=44) and two control groups (n=5). Three root canal sealers were MTA Fillapex, Apatite Root Canal Sealer and AH26. The teeth in the control groups were either filled with no sealer or made completely impermeable. The root canals were prepared and obturated with gutta-percha and one of the sealers. The teeth were sterilized with ethylene oxide gas prior to the bacterial leakage assessment using Enterococcus faecalis. Leakage was evaluated every 24 hours for 90 days. Data were analyzed with descriptive statistical methods and chi-squared test. If the data were significant, a proper post hoc test was used. Statistical significance was set at P<0.05. RESULTS: The positive control specimens exhibited total bacterial penetration whilst the negative control specimens showed no evidence of bacterial penetration. At the end of the study, the analysis of microleakage with chi-squared test showed no significant differences between the experimental groups (P<0.05). The results of chi-squared test analyzing the pair wise differences between the groups considering the numerical values for leakage day indicated the lowest leakage with AH26 and the highest with Apatite root sealer. CONCLUSIONS: According to the results of the present study, sealing ability of AH26 was significantly higher than that of MTA Fillapex and Apatite Root Canal Sealer. Key words:Mineral Trioxide aggregate, root canal obturation, dental seal. PMID- 27957272 TI - The effect of diode laser and topical steroid on serum level of TNF-alpha in oral lichen planus patients. AB - BACKGROUND: Oral lichen planus (OLP) is a common chronic inflammatory mucosal disease with a multifactorial etiology. It is a T-cell mediated autoimmune disease in which the cytotoxic CD8+T cells trigger apoptosis of the basal cells of oral epithelium. Various treatment regimens have been employed for management of symptomatic OLP. This study was carried out to evaluate the effect of topical steroids as well as laser on the clinical signs and symptoms detected by reticular, atrophic, erosive score (RAE score) and tumor necrosis factor- alpha (TNF-alpha) level in the serum of patients with symptomatic OLP. MATERIAL AND METHODS: The study was conducted on twenty-four patients (18 females and 6 males) with symptomatic OLP that were allocated into two groups. Each included twelve patients. The first group treated either with diode laser (970nm SIROLaser Advance class IIIb, SIRONA The Dental Company, Germany) twice weekly with maximum of ten sessions while the second group were treated with topical corticosteroids (0.1% triamcinolone acetonide orabase, Kenacort-A Orabase Pomad, DEVA HOLDING A.S, Istanbul, Turkey) for four weeks. RESULTS: Corticosteroids group showed less clinical signs and symptoms of reticular, atrophic, erosive RAE score (p=0.02) and TNF-alpha serum level (p=0.028) than diode laser group with no reported therapy side effects or complications in any of the treated patients. CONCLUSIONS: Topical steroids reduce pain, reticular, atrophic, erosive RAE score and TNF-alpha serum level more than laser treatment. Moreover, laser treatment can be used as an alternative treatment when steroids are contraindicated for the treatment of symptomatic OLP. Key words:Oral lichen planus, diode laser, topical steroid, RAE score, TNF-alpha. PMID- 27957273 TI - Electromyographic biofeedback training for reducing muscle pain and tension on masseter and temporal muscles: A pilot study. AB - BACKGROUND: Due to the absence of agreement about an effective unified treatment for temporomandibular disorders, non-invasive therapies such as EMG-biofeedback generate a greater interest. Furthermore, most studies to the present show methodological deficiencies that must be solved in the future, which makes important to emphasize this line of studies. MATERIAL AND METHODS: Fourteen patients were selected for this case series study, and replied to a questionnaire concerning awareness of bruxism, painful muscles, and muscle tension. They also practiced an intraoral exploration (occlusal analysis and mandibular dynamics), and an extraoral exploration of the head and neck muscles and the temporomandibular joint. Before each session, patients responded to a questionnaire about the subjective perceived improvement. In each session, a period of three minutes of pre-biofeedback EMG activity of right masseter and temporal muscles was registered, then patients performed 30 iterations of visual EMG-biofeedback training and finally, a period of three minutes of post-EMG activity was also registered for those muscles. Patients performed four sessions. RESULTS: A decrease in painful symptoms was found for all patients since the first session. EMG activity decreases (p<0,05) in both muscles during the biofeedback training stage, in the four sessions. It is also observed a decrease (p<0,05) in EMG activity in the masseter muscle at the post-biofeedback stage, in the second and third sessions. There is likewise a decrease in EMG post biofeedback activity of the temporal muscle (p<0,05) in sessions two, three, and four. CONCLUSIONS: EMG-biofeedback training produces a decrease in EMG activity in both masseter and temporal muscles during the session. This decrease persists during the post-biofeedback period since the second session. Also there is a decrease in painful symptoms for all patients. Key words:Muscle tension, muscle pain, EMG-biofeedback, masseter muscle, temporal muscle. PMID- 27957274 TI - Effect of toothpastes containing different NaF concentrations or a SnF2/NaF combination on root dentine erosive lesions, in vitro. AB - BACKGROUND: Fluoride toothpastes presumably offer some protection against acid erosion. However, uncertainty exists towards fluoride's efficacy relatively to the concentration and the type of chemical compound used. This in vitro study evaluated the relative efficacy of toothpastes containing sodium fluoride in different concentrations or a stabilized stannous fluoride/sodium fluoride system on root dentine erosion. MATERIAL AND METHODS: Bovine dentin specimens were allocated into four groups (n=10): control (no F), 1450ppm F (as NaF), 5000ppm F (as NaF) and 1450ppm F (1100ppm as stabilized SnF2 and 350ppm as NaF)/sodium hexamethaphosphate. The specimens were submitted to 6 daily cycles of erosion (0.3% v/v citric acid, pH=3.2, 20 min) and remineralization (~22h), interspersed by 2-min immersions in 1:3 w/v of dentifrice/distilled water slurries. Subsequently, they were subjected to a 24-h acid resistance test (0.3% v/v citric acid, pH=3.2) without any further treatments. Surface loss was quantified by contact profilometry. Data were analysed through one-way ANOVA and Bonferroni's tests (p<=0.05). RESULTS: In both experiments, all fluoride groups, showed significantly less tissue loss compared to the control (p<0.001-p=0.018). During erosion cycling, no significant differences were found among the fluoride groups. During the acid resistance test, the 5000ppm F toothpaste produced significantly superior effect than both 1450ppm F products (p=0.010, (p<0.001), which performed similarly. CONCLUSIONS: Under less aggressive erosive conditions, fluoride toothpastes did not differ in their ability to protect dentine surfaces. However, in severely erosive environment, the 5000ppm F toothpaste performed superiorly to the other tested products. Key words:Dentine, sodium fluoride, stannous fluoride, tooth erosion, toothpaste, contact profilometry. PMID- 27957275 TI - A comparative study of aesthetic perceptions of malocclusion among general practice dentists, orthodontists and the public using a visual analogue scale (VAS) and the IOTN-AC. AB - BACKGROUND: Perception of malocclusion varies among individuals and among patients and practitioners. Although several indices that tend to coincide in many aspects and unify criteria, no single index has been recognised as the most suitable for assessing orthodontic treatment need. Moreover, orthodontists are not always aware of the differences in perception of malocclusion between patients and practitioners. OBJETIVES: To examine the perception of dental anaesthetics amongst dentists, orthodontists and the general population, study the relationship between the perception of dental aesthetics and the severity of the malocclusion, using the visual analogue scale and the IOTN-AC, and investigate relationships among the resulting data. STUDY DESIGN: Frontal intraoral photographs of 24 cases were classified by the severity of their malocclusion according to the DAI index. The photographs were examined by 150 individuals (30 orthodontists, 30 general dental practitioners and 90 members of the general population), who assessed them on a visual analogue scale and according to the IOTN-AC. RESULTS: The orthodontists gave the lowest scores on the visual analogue scale, although the differences between the three groups were not significant. For DAI grades 1, 3 and 4, significant differences were found in the IOTN-AC assessments. Here too, the orthodontist group was the most critical. CONCLUSIONS: In general, in all three groups, both the visual analogue scale and IOTN-AC scores increased or decreased in line with the severity of the malocclusion according to the DAI. However, the correlation between these scores was low. The orthodontists scored the malocclusions more critically than the general dentists or the general population with the IOTN-AC, but this difference was not found with the visual analogue scale. Key words:IOTN-AC, DAI, malocclusion. PMID- 27957276 TI - Quality of life and oral health in elderly. AB - BACKGROUND: We want to assess quality of life in elderly patients in relation to the number of remaining teeth, the number of ingested drugs and xerostomia and to determine the correlation between an increased intake of drugs and a greater feeling of dry mouth and to know the most commonly used measures to control xerostomia. MATERIAL AND METHODS: 30 subjects aged between 65 and 95 years (14 males, 16 females) completed the OHIP questionnaire to determine quality of life. For oral status, the number of remaining teeth according to WHO criteria and xerostomia using the xerostomia index (XI) were studied. In cases of dry mouth sensation, the measures to alleviate it were asked. RESULTS: The average quality of life according to the OHIP rate is 19.23 (Dt = 10.58), being 56 the worst quality of life. The Pearson correlation coefficient indicates that quality of life is not related to the number of remaining teeth (r = -0.046; p = 0.810) nor the number of ingested drugs (r = 0.226; p = 0.23) but a greater sensation of dry mouth is related to a poorer quality of life (r = 0.678; p = 0.230). There is no association between the number of ingested drugs and the xerostomia index (r = 0.144; p = 0.447). The most frequently measures used against dry mouth were drinking water (21 subjects) and sugarless candies (15 subjects). CONCLUSIONS: Quality of life is not related to the number of remaining teeth nor the number of ingested drugs. However, a higher level of xerostomia was significantly associated with a poorer quality of life. There is no association between the number of drugs ingested and xerostomia index. Sugarless candies and drinking water are the more frequently used measures to alleviate dry mouth. Key words:Quality of life, oral health, elderly. PMID- 27957277 TI - Intraoral lipomas: Review of literature and report of two clinical cases. AB - BACKGROUND: Lipomas are benign mesenchymal tumors composed of mature adipocytes. They are classified according to their histological pattern and their etiology remains unclear. Objectives: To present two cases and review the literature. MATERIAL AND METHODS: A search was conducted in the Medline / PubMed and Scielo data bases of the last 10 years (2004-2014) with the keywords " intraoral lipoma OR oral cavity lipoma". RESULTS: 46 articles with 95 cases (56 women and 39 men) were reviewed. The average age was found to be 52.28 years (52.28 +/- 18.55); and most of them occurred between the 4th and 6th decade of life. Lipomas occur mostly in the buccal mucosa (n = 36, 37.9%), followed by the tongue (n = 23, 24.2%) and other locations (n = 36, 37.9%). The most common histologic pattern was simple lipomas (n = 40, 42%), followed by fibrolipomas (n = 18, 18.9%) and other types (n = 37, 39.1%). The average tumor size was 19.77 +/- 16.26mm. CONCLUSIONS: Lipomas are a relatively rare finding in the oral cavity. Surgical excision is the treatment of choice and recurrence is not expected. Key words:Benign oral tumor, oral lipoma, lipoma, oral cavity. PMID- 27957278 TI - Prevention of dental caries: A review of effective treatments. AB - BACKGROUND: The objective of this study is to review medical and non medical treatments for prevention of caries. MATERIAL AND METHODS: A comprehensive literature search of the most relevant and updated published studies from 01/01/2002 through December 2015 in PubMed/MEDLINE, Embase and Scopus databases regarding the efficacy of strategies and treatments aiming to prevent the development of caries was performed selecting papers on the basis of the Evidence based Medicine Criteria. RESULTS: We identified thirty systematic reviews on prevention of caries. Analyzing the data the retrieved literature, performance of prevention treatments seems to be high. CONCLUSIONS: Prevention treatments may have a relevant impact on the avoiding the development of caries planning. Key words:Dental caries, prevention, fluoride. PMID- 27957279 TI - Implications of apixaban for dental treatments. AB - BACKGROUND: Anticoagulation therapy is used in several conditions to prevent or treat thromboembolism. Recently, new oral anticoagulants have been introduced as alternatives to warfarin and acenocoumarol. In Europe, the European Medicines Agency has approved dabigatran, rivaroxaban and apixaban. Their advantages include: predictable pharmacokinetics, drug interactions and limited food, rapid onset of action and short half-life. However, they lack a specific reversal agent. MATERIAL AND METHODS: A literature search was conducted through November 2015 for publications in the ISI Web of Knowledge, PubMed, Scopus and Cochrane Library using the keywords "apixaban", "rivaroxaban", "dabigatran", "new oral anticoagulants", "dental treatment" and "dental implications". We included studies published in English and Spanish over the last 10 years. RESULTS: Apixaban has been recently introduced in the daily medical practices for the control of thromboembolism. The number of patients taking apixaban is increasing. Management of patients on anticoagulation therapy requires that dentists can accurately assess the patient prior to dental treatments. It is important for dentists to have a sound understanding of the mechanisms of action and management guidelines for patients taking new oral anticoagulants. CONCLUSIONS: The dentist should consider carefully the management of patients on apixaban. This paper sets out a clinical guidance of dental practitioners treating these patients. There is a need for further clinical studies in order to establish more evidence-based guidelines for dental patients requiring apixaban. Key words:Apixaban, new oral anticoagulants, dental treatment. PMID- 27957280 TI - The influence of teriparatide in induced tooth movement: A systematic review. AB - BACKGROUND: Teriparatide is a synthetic drug similar than PTH (parathyroid hormone), which is currently used as long-term treatment option for patients with bone chronic diseases, as osteoporosis; and this drug can interfere in a positive way in orthodontic movement. Objectives: The medical literature was assessed in the present systematic review in order to determine the level of scientific evidence supporting the influence of teriparatide in induced tooth movement. MATERIAL AND METHODS: The PRISMA Checklist was followed in this systematic review. Four electronic databases (PubMed; Scopus; ScienceDirect; OpenGrey) were searched without implementing restrictions of year, status, and language of publications. The inclusion criteria consisted of selecting only experimental studies comparing the influence of teriparatide in tooth movement of male Wistar rats. The exclusion criteria consisted of experiments with female rats or other experimental animals, and animals with pathologic conditions. The eligible studies were evaluated based on methodological quality. Two trained examiners performed all the research steps. RESULTS: The initial sample comprised 700 studies, which was reduced to 664 after the exclusion of duplicates (n=36). Three articles were selected for the final qualitative analysis. The local administration of parathyroid hormone (PTH) 1-34 or PTH 1-84 revealed major effectiveness when compared with control groups and systematic administration. Additionally, the dilution of PTH 1-34 within methyl cellulose (MC) gel increased the time range for drug release, enabling to reduce the drug concentration without decreasing the effectiveness of tooth movement. CONCLUSIONS: Teriparatide demonstrated potential acceleration of tooth movement in Wistar rats depending on the drug concentration; drug administration; and time for drug release. Key words:Teriparatide, tooth movement, parathyroid hormone, orthodontics. PMID- 27957281 TI - Malignant changes developing from odontogenic cysts: A systematic review. AB - The aim of this study was to systematically review scientific literature in orderto describe the characteristics and prognosis of malignant entities developing from odontogenic cysts. A search in Pubmed (MEDLINE) and Cochrane databases was conducted. The inclusion criteria were articles published in English related to the malignisation of odontogenic cysts in humans. The exclusion criteria were articles that do not specify the type of odontogenic cyst, malignisation of parakeratinised keratocysts, the presence of an ameloblastic carcinoma and metastasis from distant primary tumours. The selected articles were classified according to Strength of Recommendation Taxonomy criteria. Statistical analysis of the data was carried out using statistical package software SPSS version 22.0. From the 1,237 articles initially obtained, the authors included 3 case series and 45 case reports in the end. Descriptive analysis showed that men have a disposition for malignisation from odontogenic cysts and they frequently appear at the posterior mandible, with pain and swelling being the most frequent signs and symptoms. Follicular cysts were the entities that underwent the most malignant changes with well differentiated squamous cell carcinomas being the most prevalent type of malignancy. The real prognosis of this malignancy is not known because of the heterogeneity of available studies. Key words:Odontogenic cysts, squamous cell carcinoma, neoplastic cell transformation, oral cancer. PMID- 27957283 TI - Treatment and restoration of adult dentoalveolar trauma: A clinical case report. AB - Adult dentoalveolar trauma most often occurs in the context of sports activities and traffic accidents. Coronal fractures are the most common type of lesion, followed by tooth luxation. We present the case of a 25-year-old woman who suffered alveolar bone damage and coronal fractures of the upper incisors, with extrusive luxation of the right central incisor, as the result of a fall. On the first visit, manual reduction of the buccal plate was carried out under local anesthesia, with repositioning of the right central incisor and splinting to the neighboring teeth. Composites were used to restore the coronal fractures. After one month, both upper central incisors and the right lateral incisor were subjected to endodontic treatment. Internal bleaching of the right lateral incisor was also carried out, due to pigmentation secondary to pulp necrosis. At follow-up 5 months later, the alveolar bone fracture was seen to have healed. Definitive anterior restorative treatment with porcelain veneers was therefore carried out. After two years the patient remains asymptomatic and in good dental condition. Key words:Dental trauma, extrusive luxation, dento-alveolar fracture, esthetic restoration. PMID- 27957282 TI - Atypical methotrexate ulcerative stomatitis with features of lymphoproliferative like disorder: Report of a rare ciprofloxacin-induced case and review of the literature. AB - Methotrexate (MTX) is an established immunomodulating agent used in low doses (LDMTX) to treat several autoimmune diseases. Ulcerative stomatitis (US) may be observed as a long-term LDMTX adverse effect showing a wide histopathologic spectrum. A 73-year old female presented with painful oral ulcers of 5 days duration. The patient had been under treatment for rheumatoid arthritis with LDMTX, while one week before presentation she was prescribed ciprofloxacin for a urinary infection. Histopathologic examination of a lingual ulcer revealed a polymorphous lymphohistiocytic proliferation with scattered binucleated atypical lymphocytes. Immunohistochemically, most cells were of T-cell lineage while the EBER test was negative and a diagnosis of MTX-induced reactive ulceration was rendered. MTX cessation resulted in complete resolution of the ulcers with no recurrences reported so far. The clinical and histopathologic features of MTX induced oral ulcers are not always diagnostic and a detailed history and an extensive clinicopathologic investigation may be needed to exclude a lymphoproliferative disorder. Key words:Atypical oral ulcers, ciprofloxacin, lymphoproliferative disorders, methotrexate. PMID- 27957284 TI - Report of a case of acinic cell carcinoma of the upper lip and review of Japanese cases of acinic cell carcinoma of the minor salivary glands. AB - Acinic cell carcinoma (ACC) is a malignant tumor of the salivary glands. The majority of ACCs occur in the parotid gland, and ACCs of the minor salivary glands (MSGs) are relatively infrequent. We describe here a patient with ACC of the upper lip. The patient was a 31-year-old male who presented with a nodular mass on the left upper lip. The preoperative diagnosis was benign tumor or cyst, and the lesion was surgically excised. The histological diagnosis was ACC. The postoperative course was uneventful. No recurrence or metastasis was detected at 13 months postoperatively. In addition, we retrospectively reviewed 21 reported Japanese patients with ACC of the MSGs. In 7 of the 21 patients, the preoperative diagnosis was benign tumor, and the tumors were resected without preoperative biopsy. Kaplan-Meier analysis showed that disease-free survival was worse in patients who underwent resection with a preoperative diagnosis of benign tumor than in patients who underwent resection with a preoperative diagnosis of malignant tumor. The rate of recurrence was higher for ACCs assumed to be benign lesions on a purely clinical basis, or without an accurate preoperative biopsy. ACCs of the MSGs are easy to be misdiagnosed for benign lesions such as mucous cysts or hemangiomas. Correct preoperative diagnosis and initial therapy may therefore be the most important prognostic factors. Key words:Acinic cell carcinoma, Kaplan-Meier analysis, minor salivary glands, prognosis, upper lip. PMID- 27957285 TI - Dental implants after the use of bichat's buccal fat pad for the sealing of oro antral communications. A case report and literature review. AB - Oro-antral communications are frequent complications in oral surgery, and generally occur after molar extractions, maxillary sinus elevations or dental implant procedures. The presence of these defects may increase the morbidity and often need a surgical approach. The present report describes an oro-antral communication in a 52-year-old female who presented a 2 week-course of painless nasal obstruction and rhinorrea after a right maxillary sinus floor elevationwith simultaneous dental implant placement. Based on the anamnesis, clinical examination and a computed tomographyof the paranasal sinuses, a diagnosis of odontogenic rhinosinusitis associated with a 1.5 cm diameter oro-antral communicationwas establishedand its surgical closure using Bichat's buccal fat pad was planned.After 15 months, the patient was successfully rehabilitated with an implant-supported 3 unit fixed partial denture. Key words:Dental implants, buccal fat pad, oro-antral communications. PMID- 27957286 TI - Experiences of Iranian physicians regarding do not resuscitate: a directed content analysis. AB - One of the major advances in medicine has been the use of cardiopulmonary resuscitation (CPR) procedure since the 1960s in order to save human lives. This procedure has so far saved thousands of lives. Although CPR has helped to save lives, in some cases, it prolongs the process of dying, suffering, and pain in patients. This study was conducted to explain the experience of Iranian physicians regarding do not resuscitate order (DNR). This study was a directed qualitative content analysis which analyzed the perspective of 8 physicians on different aspects of DNR guidelines. Semi-structured, in-depth interview was used to collect data (35 to 60 minutes). First, literature review of 6 main categories, including clinical, patient and family, moral, legal, religious, and economic aspects, was carried out through content analysis. At the end of each session, interviews were transcribed verbatim. Then, the text was broken into the smallest meaningful unit (code) and the codes were classified into main categories. The codes were classified into 6 main categories, which were extracted from the literature. In the clinical domain 4 codes, in patient and family 3 codes, in moral domain 4 codes, in religious domain 3 codes, and in economic domain 1 code were extracted. According to the findings of this study, it can be said that Iranian physicians approve the DNR order as it provides dying patients with a dignified death. However, they do not issue DNR order due to the lack of legal and religious support. Nevertheless, if legislators and the Iranian jurisprudence pass a bill in this regard, physicians with the help of clinical guidelines can issue DNR order for dying patients who require it. PMID- 27957287 TI - The doctor-patient relationship: toward a conceptual re-examination. AB - The nature of the doctor-patient relationship as a keystone of care necessitates philosophical, psychological and sociological considerations. The present study investigates concepts related to these three critical views considered especially important. From the philosophical viewpoint, the three concepts of "the demands of ethics "," ethical phenomenology and "the philosophy of the relationship" are of particular importance. From a psychological point of view, the five concepts of "communication behavior patterns" (including submissiveness, dominance, aggression, and assertiveness), "psychic distance", "emotional quotient", "conflict between pain relief and truth-telling", and "body language" have received specific emphasis. Lastly, from the sociological perspective, the three notions of "instrumental action", "communicative action", and "reaching agreement in the light of communicative action" are the most significant concepts to reconsider in the doctor-patient relationship. It should be added, however, that from the sociological point of view, the doctor-patient relationship goes beyond a two-person interaction, as the moral principles of doctors and patients depend on medical and patient ethics respectively. The theoretical foundations of the doctor-patient relationship will finally help establish the different dimensions of medical interactions. This can contribute to the development of principles and multidisciplinary bases for establishing practical ethical codes and will eventually result in a more effective doctor-patient relationship. PMID- 27957289 TI - Efficacy of Endoscopic Ultrasonography in Evaluation of Undetermined Etiology of Common Bile Duct Dilatation on Abdominal Ultrasonography. AB - BACKGROUND The cause of common bile duct (CBD) dilatation cannot be determined by imaging modalities in many patients. The aim of this study was to assess the value of endoscopic ultrasonography (EUS) in detecting the cause of CBD dilatation in patients in whom ultrasonography could not demonstrate the cause of dilation. METHODS Prospectively, 152 consecutive patients who were referred for evaluation of dilated CBD (diameter >=7 mm) of undetermined origin by ultrasonography were included in this study. All the patients underwent EUS. Final diagnoses were determined by using endoscopic retrograde cholangiopancreatography (ERCP), EUS-guided fine needle aspiration (FNA), surgical exploration, or follow-up for at least 10 months. Patients with choledocholithiasis were referred for ERCP and sphincterotomy, and patients with operable tumors were referred for surgery.Patients with inoperable tumors underwent biliary stenting with or without tchemoradiotherapy. RESULTS 152 patients (54% female) with dilated CBD were included. Mean (+/-SD) age of the patients was 60.4 (+/-17.3) years. The mean CBD diameter for all study group in transabdominal ultrasonography and EUS were 11.7 millimeter and 10.1 millimeter, respectively. Most of the patients with dilated CBD and abnormal liver function test (LFT) had an important finding in EUS and follow-up diagnosis including peri ampullary tumors. Mean diameter of CBD in patients with and without abnormal LFT were 10.5 IU/L and 12.1 IU/L, respectively. Final diagnoses included choledocholithiasis in 32 (21.1%),passed CBD stone in 35 (23%), opium-induced CBD dilation in 14 (9.2%), post-cholecystectomy states in 20 (13.1%), ampullary adenoma/carcinoma in 15 (15.8%), cholangiocarcinoma in 14 (9.2%), and pancreatic head cancer in9 (5.9%) patients. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of EUS for patients with abnormal EUS were 89.5%, 100.0%, 100.0%, 91.2%, and 90.9%, respectively. CONCLUSION After diagnosis of CBD dilation by transabdominal ultrasonography, EUS may be a reasonable choice for determining the etiology of dilated CBD and tumor staging. PMID- 27957288 TI - Esophageal Cancer in Golestan Province, Iran: A Review of Genetic Susceptibility and Environmental Risk Factors. AB - Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor that is typically diagnosed only when the tumor has gained remarkable size, extended to peripheral tissues, and led to dysphagia. Five-year survival of advanced cancer is still very poor (19%), even with improved surgical techniques and adjuvant chemoradiation therapy. Therefore, early detection and prevention are the most important strategies to reduce the burden of ESCC. Our review will focus on the studies conducted in Golestan province, an area with a high prevalence of ESCC in northern Iran. We review three aspects of the research literature on ESCC: epidemiological features, environmental factors (including substance abuse, environmental contaminants, dietary factors, and human papillomavirus [HPV]), and molecular factors (including oncogenes, tumor suppressor genes, cell cycle regulatory proteins, and other relevant biomarkers). Epidemiological and experimental data suggest that some chemicals and lifestyle factors, including polycyclic aromatic hydrocarbons (PAHs), cigarette smoking, opium use, and hot tea drinking are associated with the development of ESCC in Golestan. HPV infects the esophageal epithelium, but so far, no firm evidence of its involvement in esophageal carcinogenesis has been provided. Some of these factors, notably hot tea drinking, may render the esophageal mucosa more susceptible to injury by other carcinogens. There are few studies at molecular level on ESCC in Golestan. Increasing awareness about the known risk factors of ESCC could potentially reduce the burden of ESCC in the region. Further studies on risk factors, identifying high risk populations, and early detection are needed. PMID- 27957290 TI - Magnetic Resonance Enterography in 300 Known Cases of Crohn's Disease: An Initial Report from a Referral Center in Iran. AB - BACKGROUND Magnetic resonance enterography (MRE) has become the modality of choice in assessment of patients with Crohn's disease (CD). We aimed to present our experience on 300 patients with CD who underwent MRE during the first 30 months after setting up MRE for the first time in a referral center in Iran. METHODS Patients with a definite diagnosis of CD based on either ileocolonoscopy or histopathological studies were included in the final report and categorized into four phenotypes of inactive, active, stricturing, and penetrating disease. RESULTS This was a case series study on 300 patients with known CD out of 594 referred subjects. The most prevalent phenotype was inactive observed in 162 (54.0%) patients followed by stricturing in 44 (14.7%), active in 40 (13.3%), penetrating in 27(9%), and active on chronic in 27 (9%) cases. The number of referred patients increased from 51 cases in the first 6 months to 165 in the last 6 months. CONCLUSION This study presents the first report on the application of MRE in Iran as superb modality for management of CD. The growing number of referred patients indicates that MRE has been successful in addressing the most critical concerns of clinicians on determining the dominant disease phenotype. PMID- 27957292 TI - The Effect of Zinc Supplementationon the Symptoms of Gastroesophageal Reflux Disease; a Randomized Clinical Trial. AB - BACKGROUND Currently, it has been demonstrated that gastroesophageal reflux disease (GERD) is one of the most important disorders of the digestive system and the commixture of regular diet has a significant influence on its incidence, symptoms, and prognosis. The purpose of this study was to evaluate the effect of zinc supplementation, in combination with PPIs(Proton pump inhibitors), on the improvement of GERD symptoms. METHODS In a randomized double blind clinical trial, patients with reflux symptoms, who had obtained Reflux Disease Questionnaire (RDQ) score more than 8, were included and all the demographic features were recorded. Then, using upper gastrointestinal (GI) endoscopy, all the patients were divided into two groups as having non-erosive reflux disorder (NERD),or erosive reflux disorder (ERD). At the next step, based on random block statistical method, we divided the two groups into two subgroups; the drug subgroup [treated with PPIs (40 mg pantoprazole/daily), changing life style, and 220 mgzinc capsules daily] and the placebo subgroup [treated with PPIs, changing life style, and placebo]. After 3 months, we analyzed all data and the RDQ questionnaire was filled out for each patient. This project has been registered in Iranian Registry of Clinical Trials (IRCT) and all data were analyzed using SPSS software version 2. RESULTS A total of 140 patients (81 women and 59 men) with mean age of 42.78+/-11.5 years were included with 70 patients in each group. The most frequent presentations were heart burn (45.7%), and acid regurgitation (39.3%). The RDQ scores decreased after intervention in both drug (p<0.001) and placebo groups (p<0.001), which were statistically significant. But the difference of RDQ scores between the drug group and placebo group was not statistically significant (p=0.086). CONCLUSION Zinc supplementation cannot improve the severity of GERD. PMID- 27957291 TI - A Survey on Migraine Prevalence in Patients with Inflammatory Bowel Disease - A Single Centre Experience. AB - BACKGROUND It is hypothesized that migraine may be related to inflammatory bowel disease (IBD), therefore in this cross-sectional study we evaluated the prevalence of migraine in patients with IBD. METHODS In this cross-sectional study 80 patients with IBD and 80 patients without IBD referring to a private gastroenterology clinic from May to January 2014 were evaluated regarding the prevalence of migraine, severity of migraine based on Headache Impact Test (HIT 6), and habits related to headache. RESULTS 160 participants with the mean age of 35 years were evaluated. The prevalence of migraine in the case group was significantly higher than the control (21.3% vs. 8.8%, p=0.027). Moreover, duration of each attack (hours) in IBD group was significantly higher than the control group (p<0.001) while the duration of migraine involvement (months) and number of attacks was higher in the control group (p=0.019 and 0.048, respectively). Headache other than migraine in the control group was significantly higher than the IBD group(p<0.001). Disability in the case group was more than the control group but the difference was not significant. The correlation between the severity of disability related to migraine (based on HIT 6) and severity of IBD (based on May oscore & Crohn's disease activity index (CDAI)) was not significant (r=0.16, p=0.58). Moreover the correlation between the duration of IBD and migraineprevalence was not significant (r=-0.14, p=0.19). CONCLUSION We found that the prevalence of migraine in patients with IBD is significantly more than normal population. More studies are needed to highlight the correlation between migraine and IBD. PMID- 27957293 TI - Hesa-A Effects on Cell Cycle Signaling in Esophageal Carcinoma Cell Line. AB - BACKGROUND Hesa-A is a natural compound with anticancer properties. The exact mechanism of its action in esophageal cancer is not clear, yet. The aim of this study was to evaluate the cell toxicity effect of Hesa-A on the esophageal carcinoma cell lines, KYSE-30, and cell cycle genes expression. METHODS In this study, we tested cell toxicity with MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5 Diphenyltetrazolium Bromide) assay and flow cytometry to evaluatet he cell cycle arrest. Real time polymerase chain reaction was used to assess the expression of P53, P16, P21, cyclin D1, and cyclin B1 genes. RESULTS Our results showed that Hesa-A is effective in the expression of cell cycling check point proteins. Hesa A induced an arrest in G2 phase of esophageal cell cycle. The levels of P53 (>13 times), P21 (>21 times), P16, cyclin B1, and cyclin D1 genes were increased 48 hours after Hesa-A treatment. CONCLUSION P21 and P16 expression were the potential mechanisms for G2 arrest of KYSE-30 esophageal cancer cell line by Hesa A. PMID- 27957294 TI - Adult Celiac Disease: Patients Are Shorter Compared with Their Peers in the General Population. AB - BACKGROUND Delay in diagnosis of celiac disease (CD) occurs frequently, although its consequences are mostly not known. One of the presented symptoms in pediatric patients with CD is the short stature. However, far too little attention has been paid to physical features including height of adult patients with CD. This study was undertaken to evaluate whether patients suffering from CD are shorter in comparison with the general population without CD. As well, we evaluated probable correlations between demographic and physical features, main complains, serum anti tTG level, and intestinal pathology damage between short (lower quartile) versus tall stature (upper quartile) patients with CD. METHODS This was a retrospective cross-sectional study on 219 adult patients diagnosed as having CD in the Celiac Disease Center, between June 2008 and June 2014 in Mashhad, Iran. The exclusion criteria were ages less than 18 and more than 60 years. Height was compared with a group of 657 age- and sex matched control cases from the healthy population. The probable influencing factors on height such as intestinal pathology, serum level of anti-tissue transglutaminase(anti-tTG), serum vitamin D, and hemoglobin level at the time of diagnosis were assessed and were compared in short (lower quartile) versus tall stature (upper quartile) patients with CD. RESULTS Both male (n=65) and female (n=154) patients with CD were shorter than their counterpart in the general population (males: 168.5+/-8.6 to 171.3+/-7.2cm, p <0.01 and females: 154.8+/-10.58 to 157.8+/-7.2 cm, p <0.01). Spearman linear correlation showed height in patient with CD was correlated with serum hemoglobin (p <0.001, r=0.285) and bone mineral density (p<0.001) and not with serum vitamin D levels (p =0.024, r=0.237), but was not correlated with anti-tTG serum levels (p=0.97). CD patients with upper and lower quartile of height in men and women had no significant difference in the anti-tTG level and degree of duodenal pathology(Marsh grade). Anemia as main complaint was more prevalent in shorter versus taller men. CONCLUSION Adults with CD are shorter compared with healthy adults. There is a direct correlation between height and anemia and bone mineral density. This finding highlights the importance of early detection and treatment of CD. PMID- 27957295 TI - Review of Clinical Spectrum of Gastroesophageal Reflux Disease in a General Population; A Study from South-East Iran. AB - BACKGROUND Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal problems worldwide. The aim of this study was to evaluate the clinical spectrum, prevalence, and some of the variables that are supposed to be the risk factors of this chronic disorder. METHODS This population- based cross sectional study was conducted in a one-stage randomized clustered sample of adult inhabitants in Kerman city in 2011-2012. A total of 2265 subjects with age range of 15-85 years were enrolled. Face to face interview was performed for all the subjects. GERD was defined as at least weekly heart burn and/or acid regurgitation during the past year. Association of GERD with factors like demographic variables, medical condition, diet and life habits were analyzed. RESULTS A total of 2265 subjects including 988 (43.8%) male and 1275 (56.3%) female patients were evaluated. The prevalence of GERD was 28%. The prevalence was higher in female patients and with aging. There was also a significant association between GERD and the following risk factors: lower educational level (p <0.0001), higher body mass index (p =003), presence of depression(p<0.0001), and anxiety (p <0=0001). CONCLUSION GERD as a common disorder in our region was seen more in elderly and female patients and was associated with some anthropometric, metabolic, medical conditions, and behavioral habits. PMID- 27957296 TI - Correlation Between Cut-off Level of Tissue Transglutaminase Antibody and Marsh Classification. AB - : BACKGROUND Duodenal biopsy is required for diagnosis of celiac disease in adults, although some studies have suggested adequate accuracy of serology alone. OBJECTIVE: We aimed to assess the correlation between anti-tissue transglutaminase (tTG) titer and pathological findings and to define the specific level of tTG for predicting celiac disease in adults without the need for biopsy sampling. METHODS This descriptive study was done on 299 participants. The tTG titer and pathological findings of duodenal biopsy samples were used for this study. Analysis of Receiver operating characteristic (ROC) curve was used to find a cut-off point of anti-tTG antibody for mucosal atrophy. RESULTS Mean tTG titers was significantly higher in patients graded as Marsh III>= 3 (p=0.023). ROC curve analysis showed 89.1% sensitivity for cut-off point>=76.5 IU/mL of anti-tTG. For Marsh>= II, specificity was 28% and positive predictive value was 91%.CON CLUSION There is a linear correlation between increasing tTG level and Marsh I to III. Specificity of tTG titer more than 200 was 100% for Marsh >2. PMID- 27957297 TI - Perforated Meckel's Diverticulum in a 3-day-old Neonate; A Case Report. AB - Perforation of Meckel's diverticulum is a rare complication in neonatal period. A 3-dayold term male neonate was transferred to our emergency room due to bowel perforation. Surgical exploration was done and perforated Meckel's diverticulum was detected. Pathological report of the tissue showed inflamed diverticulum with heterotopic gastric mucosa. This is the first report of Meckel's diverticulum perforation in a neonate in our country. PMID- 27957298 TI - Resolution of Bile Duct Adenoma over Follow-up Period; A Case Report. AB - Bile duct adenoma (BDA) is a rare neoplasm of bile ducts with various clinical manifestations and imaging appearances. A few cases of BDA and their predisposing factors have been described. We report a 35-year-old woman with right upper quadrant pain who consumed oral contraceptive pills. Ultrasound study revealed three hypoechoic subcapsular liver masses; two of them were hypodense in computed tomography. Fine needle biopsy of the largest mass showed bile duct adenoma. Liver masses disappeared after discontinuing the pills over a 2-year follow-up. BDAs can manifest in imaging. Although previous studies have not reported tumor resolution over a follow-up period, we suggest paying more attention to predisposing factors in order to give an opportunity for tumor resolution by risk factor elimination. PMID- 27957299 TI - Conference Report: International Conference on Health Sciences and Medical Technologies, Tlemcen, Algeria 27-29 September 2016 ICHSMT'16. AB - The International Conference on Health Sciences and Medical Technologies (ICHSMT'16) was held in Tlemcen, Algeria from 27-29 September 2016. The conference was organized by the University Of Tlemcen, in partnership with Electronic Physician Journal, Mehr Publishing, and Mehrafarin Scientific Publishing. There were participants from 14 nations who presented their research in poster or oral presentations. There were also some keynote speakers who gave talks on topics such as community health, ethics of publishing medical research, and scientific writing. PMID- 27957300 TI - Efficacy of egg yolk and nitroglycerin ointment as treatments for acute anal fissures: A randomized clinical trial study. AB - BACKGROUND: Acute anal fissure as a common disease in society has several etiologies and manifestations such as severe anal pain and bleeding. Nitroglycerin ointment 0.2% is the most common topical treatment used. The most common side effect of nitroglycerin is headache, which is annoying for patients and often leads to discontinuation of the drug. OBJECTIVE: Comparison of egg yolk as a natural substance with analgesic and anti-inflammatory properties and minimal side effects with nitroglycerin ointment in the treatment of acute anal fissure. METHODS: This randomized clinical trial was carried out during a 10-day period in the Gastroenterology clinic of Ghaem Hospital, Mashhad, Iran (year 2015). 126 patients who filled the inclusion criteria were enrolled. The patients were randomly divided into two groups. Nitroglycerin ointment (0.2%) was applied by patients in the first group, twice daily for 10 days. For the second group, one egg yolk once a day was administered rectally up to 10 days. The pain and bleeding severity were recorded every two days up to 10 days after finishing the treatment course, based on visual scale. RESULTS: The results showed that egg yolk caused a significant reduction in pain and bleeding compared with nitroglycerin (p<0.05). At the beginning of the study, the difference in pain intensity between the two groups was not statistically significant (p-value = 0.25). However, it became significant in the following days. Changes in the frequency of rectorrhagia were also significant in both groups, showing a major decrease in the number of rectorrhagia cases (p<0.001). CONCLUSION: Egg yolk is more efficient than nitroglycerin in the treatment of acute anal fissure. In addition, lack of any side effects results in the completion of the treatment course by the patients. TRIAL REGISTRATION: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct ID: IRCT2015050718915N3. FUNDING: This work was supported by a grant from the Vice Chancellor of Research of Mashhad University of Medical Sciences. PMID- 27957301 TI - Factors affecting length of stay in teaching hospitals of a middle-income country. AB - INTRODUCTION: The length of stay (LOS) in hospitals is a widely used and important criteria for evaluating hospital performance. The aim of this study was to determine factors affecting LOS in teaching hospitals of Qazvin Providence. METHODS: In this cross-sectional study, patients' health records were randomly selected from archives in teaching hospitals of Qazvin in 2013. Data were collected through a data entry form and were analyzed using Kolmogorov-Smirnov, Kruskal-Wallis, and Mann-Whitney U tests at the significant level of 0.05. RESULTS: The mean of hospital LOS was 5.45 +/- 6.14 days. Age, employment, marital status, history of previous admission, patient condition at discharge, method of payment, and type of treatment had an impact on LOS (p<0.05). Other factors, including gender, place of residence, and type of admission, did not affect LOS. CONCLUSION: Because hospitals consume a perceptible part of resources in a health system, controlled and optimized use of its resources help to save a lot. Therefore, this study showed many clinical and nonclinical factors affect LOS in evaluating these factors, which may reduce inappropriate hospital stays and decrease costs. PMID- 27957303 TI - The evaluation of serum homocysteine, folic acid, and vitamin B12 in patients complicated with preeclampsia. AB - INTRODUCTION: Increased plasma homocysteine may be associated with adverse pregnancy outcomes, such as preeclampsia. The aim of this study was to determine the plasma homocysteine, serum folate, and vitamin B12 levels in preeclamptic pregnant women. METHODS: This case-control study was conducted in 2016 in Ahwaz on 51 pregnant women with preeclampsia and 51 healthy pregnant women of the same gestational age, who served as controls. The case group also was subdivided into severe and non-severe preeclampsia. Patients' data were collected through a questionnaire and medical records. Serum homocysteine, folic acid, and vitamin B12 were analyzed using chemiluminescent assay. The results were compared between two groups. Statistical analyses were done using IBM-SPSS 20.0. A Kolmogorov Smirnov test, independent samples t-test, Mann-Whitney test, and Chi-square test were used for data analysis. RESULTS: No different demographic characteristics were found among the groups. Pregnant women complicated with preeclampsia displayed significantly higher serum homocysteine levels (p < 0.001) and lower serum folate (p = 0.005) and vitamin B12 levels (p < 0.001) compared to controls. A statistically significant inverse correlation was evident between serum homocysteine and serum folate levels in preeclamptic patients (p = 0.005; r = 0.389). In addition, an inverse correlation was identified between homocysteine and serum vitamin B12, but it was not statistically significant (p = 0.160; r = 0.200). Significant differences occurred in serum homocysteine and folate levels between the severe and non-severe subgroups (p < 0.001, p < 0.001). CONCLUSION: Women complicated with preeclampsia displayed higher maternal serum homocysteine and lower serum folate and vitamin B12. Further studies are needed to confirm if the prescription of folic acid and vitamin B12 in women with a deficiency of these vitamins could decrease the level of serum homocysteine and, therefore, reduce the risk of preeclampsia or, if it occurred, its severity. PMID- 27957302 TI - Challenges of Implementation of the National Phenylketonuria Screening Program in Iran: A Qualitative Study. AB - INTRODUCTION: Newborn screening (NBS) is a public health measure aimed at identification of early cases, management of afflicted infants, and making efforts to reduce the morbidity and mortality among newborns. All countries may face challenges in implementation of screening programs. The present study aimed to determine the challenges of implementation of the National Phenylketonuria (PKU) Screening Program in Iran. METHODS: In this qualitative study, 38 health policymakers, managers, and PKU experts in Iran were purposively selected as the respondents in 2015. The semi-structured interview was used for collecting the required data and information. After transcription of interviews, their content was analyzed using framework analysis. RESULTS: The results were categorized into five main themes and 22 subthemes. The main themes extracted from data were management challenges, diagnosis challenges, treatment challenges, care challenges, and patients' family problems. Each category consisted of several subthemes. CONCLUSION: Considering the challenges of implementing this program, some measures such as increased stability of managers in the health system, greater interaction of the Ministry of Health and Medical Education with the heath stakeholders, improving the level of parents' awareness, the use of efficient information systems, support and legal backing for requiring parents who refuse newborn screening for various reasons, and appropriate insurance coverage seem necessary to be taken. PMID- 27957304 TI - Life Expectancy and its Socioeconomic Determinants in Iran. AB - INTRODUCTION: Life expectancy at birth (LEB) is closely associated with the degree of economic and social development in developed and developing countries. This study aimed to examine the socioeconomic factors affecting LEB in Iran from 1985 to 2013. METHODS: Time series analysis was used to examine the effects of key explanatory factors (GDP per capita, number of doctors per 10,000 population, degree of urbanization, food availability, CO2 emission, total fertility rate, inflation rate, and literacy rate) on LEB in Iran from 1985 to 2013. Study data were retrieved from the Central Bank of Iran (CBI), Iranian Statistical Center (ISC), and World Bank. Augmented Dickey Fuller (ADF) and Banergy, Dolado, and Master (BDM) tests, Engle Granger approach, and an ordinary least-square (OLS) model were used to achieve the aim of the study. Data analysis was performed by Stata V.12 software. RESULTS: Our findings indicated that GDP per capita (p=0.003), number of doctors per 10,000 population (p=0.036), literacy rate (p=0.0001), and food availability (p=0.0001) have a positive and significant statistically effect on LEB. The relationship between total fertility rate and LEB was negative and significant (p=0.023). In addition, the effect of degree urbanization (p=0.811), CO2 emission (p=0.185), and inflation rate (p=0.579) on LEB were not significant. CONCLUSION: GDP per capita, number of doctors per 10,000 population, food availability, literacy rate, and total fertility were identified as the main factors affecting life expectancy in Iran. The study, however, suggests that life expectancy in Iran could be improved if attention is given to factors that reside outside of the health sector. PMID- 27957305 TI - A comparative study of cisplatin-based definitive chemo-radiation in non metastatic squamous cell carcinoma of the esophagus. AB - INTRODUCTION: Esophageal cancer is the seventh most frequent malignancy in Iranian men and the fourth most common cancer in Iranian women. It is also among the 10 most frequent cancers in the world. Definitive chemo-radiation using cisplatin with 5-fluorouracil (5-FU) is known as the standard of care among various chemotherapy regimens used with esophageal cancer patients who are not eligible for surgery. Cisplatin with paclitaxel and cisplatin with irinotecan also have been used often during the past five years. The aim of this research was to compare overall survival (OS) and hematological toxicity rates between these regimens. METHODS: This single-institutional study included 55 patients who were treated with definitive chemo-radiation in the radiation-oncology ward at Shohada-e-Tajrish Hospital in Tehran, Iran, between 2006 and 2013. They received one of four regimens, i.e., cisplatin, cisplatin with 5-FU (old chemotherapy regimens), cisplatin with paclitaxel, or cisplatin with irinotecan (new chemotherapy regimens) as part of their definitive chemo-radiation with curative intent. The Kaplan-Meier estimator was used to estimate the overall survival times, which were compared by using the Breslow test. RESULTS: The follow-up period was between 26-109 months, with a median of 72 months. OS was not different between the old and new chemotherapy regimen groups (p = 0.18). Hematological toxicity (leucopenia) in the old chemotherapy regimen groups (10%) was significantly lower than in the new chemotherapy regimen groups (43%, p = 0.012). But OS in cisplatin or cisplatin with 5-FU scheme was statistically better than with the cisplatin with paclitaxel scheme (p = 0.026, p = 0.028, respectively). CONCLUSION: This study showed that OS are similar in both the old and new chemotherapy treatment regimens in esophageal cancer patients who were treated with definitive chemo-radiation. The new chemotherapy treatment regimens should be used with caution as an alternative treatment of cisplatin with 5-FU for further evaluation. PMID- 27957306 TI - The Impact of Healthcare Reform Plan on the Rate of Vaginal Delivery and Cesarean Section in Shiraz (Iran) in 2015. AB - INTRODUCTION: The uncontrolled increase in the rate of cesarean section is one of the most controversial issues, and is a primary challenge among health policy makers. This study was conducted to examine the impact of the Iranian health evolution plan on vaginal delivery rate and cesarean section. METHODS: This cross sectional study was carried out in 2014. Maternal health data for 2013 and 2014 were used in this study and changes in vaginal delivery and cesarean section were compared before and after the reform, using t-test and Wilkinson test. RESULTS: According to the findings of this study, 64.7% of deliveries in 2013 were performed using cesarean section while it was 58.6% in 2014 (p= 0.772), of which no significant changes were observed. In addition, the percentage of vaginal delivery in 2013 and 2014 were 35.3% and 41.4% respectively (p= 0.00), so a significant increase was found for vaginal delivery. CONCLUSION: Healthcare reform has led to an increase in the number of vaginal deliveries in hospitals affiliated to Shiraz University of Medical Sciences (SUMS). Due to the limited number of hospitals adhering to the healthcare reform plan to increase vaginal delivery (using private midwife and implementing painless delivery), the reform for decreasing the cesarean rate was not effective enough. PMID- 27957307 TI - Ten years of experience in clinicopathologic characteristics, treatment and outcome of patients with nasopharyngeal pathologies in Yazd, Iran. AB - INTRODUCTION: Although there are some studies regarding the clinical characteristics and outcome of nasopharyngeal tumors, one such study from Iran has not been reported to date. This study aimed to evaluate the clinical features, treatment, and consequences of nasopharyngeal lesions. METHODS: In this cross sectional study, we conducted a retrospective review of patients who were diagnosed with nasopharyngeal pathologies and treated at Shahid Sadoughi Hospital and Shahid Ramazanzadeh Radiotherapy Center in Yazd, Iran, over a period of 10 years (from 2005 to 2014). The variables in the study were the patient's hospital registration number, date, name, age, gender, address, topography, clinical symptoms, morphology, stage, types of treatment, and survival for each subject. Survival data were analyzed using Kaplan-Meier estimates, and multivariate analysis was performed using the Cox regression method. Statistical analyses were performed using IBM-SPSS, version 22. RESULTS: In the study, there were 123 patients, 85 males and 38 females, who had nasopharyngeal lesions. The mean age at diagnosis was 41.51 +/- 20.33 years. There were 83 patients with malignant neoplasms and 40 patients with non-malignant lesions. The most common malignant tumor was nasopharyngeal carcinoma, and the most common benign lesion was angiofibroma. Survival analysis was performed for the 83 patients who had malignant neoplasms, and survival was found to be 94.5 +/- 4.32 months. There were significant differences in survival based on the stage of the disease, histological type, and the type of treatment (p = 0.001, 0.02, and 0.003, respectively). CONCLUSION: In our institutional study, malignant tumors were more common than benign lesions. Patients with nasopharyngeal carcinoma presented relatively late and at an advanced stage. Regular follow-up is necessary for early detection, recurrence, or metastases of malignant tumors. PMID- 27957308 TI - Single-incision laparoscopy surgery: a systematic review. AB - BACKGROUND: Laparoscopic surgery is a modern surgical technique in which operations are performed far from their location through small incisions elsewhere in the body. OBJECTIVE: This systematic review is aimed to overview single-incision laparoscopy surgery. METHODS: This systematic review was carried out by searching studies in PubMed, Medline, Web of Science, and IranMedex databases. The initial search strategy identified about 87 references. In this study, 54 studies were accepted for further screening and met all our inclusion criteria [in English, full text, therapeutic effects of single-incision laparoscopy surgery and dated mainly from the year 1990 to 2016]. The search terms were "single-incision," "surgery," and "laparoscopy." RESULTS: Single incision laparoscopy surgery is widely used for surgical operations in cholecystectomy, sleeve gastrectomy, cholecystoduodenostomy, hepatobiliary disease, colon cancer, obesity, appendectomy, liver surgery, rectosigmoid cancer, vaginal hysterectomy, vaginoplasty, colorectal lung metastases, pyloroplasty, endoscopic surgery, hernia repair, nephrectomy, rectal cancer, colectomy and uterus-preserving repair, bile duct exploration, ileo-ileal resection, lymphadenectomy, incarcerated inguinal hernia, anastomosis, congenital anomaly, colectomy for cancer. CONCLUSION: Based on the findings, single-incision laparoscopy surgery is a scarless surgery with minimal access. Although it possesses lots of benefits, including less incisional pain and scars, cosmesis, and the ability to convert to standard multiport laparoscopic surgery, it has some disadvantages, for example, less freedom of movement, fewer number of ports that can be used, and the proximity of the instruments to each other during the operation. PMID- 27957309 TI - Hepatocyte transplantation in children with liver cell failure. AB - Patients with hepatic failure and liver-based metabolic disorders require management which is both costly and complex. Hepatocyte transplantation has been very encouraging as an alternative to organ transplantation for liver disease treatment, and studies in rodents, show that transplants involving isolated liver cells can reverse hepatic failure, and correct various metabolic deficiencies of the liver. This 2016 review is based on a literature search using PubMed including original articles, reviews, cases and clinical guidelines. The search terms were "hepatocyte transplantation", "liver transplantation", "liver cell failure", "metabolic liver disorders", "orthotropic liver transplantation", "hepatocytes" and "stem cell transplantation". The goal of this review is to summarize the significance of hepatocyte transplantation, the sources of hepatocytes and the barriers of hepatocyte transplantation using a detailed review of literature. Our review shows that treatment of patients with liver disease by hepatocyte transplantation has expanded exponentially, especially for patients suffering from liver-based metabolic disorders. Once hepatocyte transplantation has been shown to effectively replace organ transplantation for a portion of patients with life-threatening liver metabolic diseases and those with liver failure it will make cell therapy effective and available for a broad population of patients with liver disorders. PMID- 27957310 TI - Evaluation of Patients' Rights Observance According to Patients' Rights Charter in Educational Hospitals Affiliated to Mashhad University of Medical Sciences: Medical Staffs' Views. AB - INTRODUCTION: To supply quality services and healthcare, it is evident that medical ethics and patients' rights, while providing medical and healthcare services need to be observed. This study was conducted to evaluate observance of the Patients' Rights Charter among medical staff of educational hospitals affiliated to Mashhad University of Medical Sciences. METHODS: This cross sectional study was conducted in four educational hospitals in Mashhad on eighty physicians, nurses, nurse aids and medical students. Data were collected using a two-part inventory of patients' rights, including demographic data and inventory of patients' rights observance. Data analysis was conducted using SPSS-16 as well as descriptive statistics, independent t-test, chi-square, Spearman correlation coefficient and Pearson correlation. RESULTS: Mean age of subjects was 36.3+/ 8.3. Observance of human rights was perfect by 84.4 percent of subjects. The highest amount of observance of patients' rights was related to the area of respecting patients' privacy and observing the principle of confidentiality, which was evaluated to be perfect by all subjects (100%). The lowest value of patients' rights observance was related to presenting appropriate and adequate information for patients, which was perfect among 48.1% of subjects. There was no significant relation between personal details (age, gender, education and career) and observance of patients' rights (p>0.05). CONCLUSION: Although in this study, the observance of patients' rights by medical staff is optimal in most areas, the area of providing appropriate and adequate information needs to be promoted. Therefore, it is suggested that more stringent regulatory policies be compiled and implemented to the items of Patients' Rights Charter along with training courses, to strengthen medical staff's awareness in this regard. PMID- 27957311 TI - Evaluation of Antioxidant Activity of R. Slooffiae, R. Mucilaginosa Extracts. AB - INTRODUCTION: Antioxidants are health beneficial compounds that can protect cells and macromolecules from the damage of reactive oxygen species (ROS). The aims of this study were to compare the total antioxidant and carotenoid production in R. Slooffiae and R. Mucilaginosa. METHODS: To isolate the carotenoid pigment, cells were suspended in acetone and broken using a homogenizer, followed by centrifugation, and supernatant was separated. For analytical method, pigments were measured spectrophotometrically at 450 nm. The B-carotene bleaching and 1, 1 diphenyl-2-picrylhdrazyl (DPPH) assay were used to determine antioxidant properties of R. Slooffiae and R. Mucilaginosa by measuring the decrease in absorbance at 470 and 517 nm. RESULTS: The results showed that the content of total carotenoid in R. Slooffiae was higher than R. Mucilaginosa and it presented higher ability to show antioxidant activity. The mean total antioxidant activity of ascorbic acid was the highest (97.11 +/- 6.11%), followed by BHT (64.71 +/- 5.41%), R. sloofias extract (57.91 +/- 7.34%) and R. Mucilaginosa (39.32 +/- 5.85%). The EC50 of ascorbic acid was the strongest (0.252 +/- 0.000 mg/ml), followed by BHT (0.612 +/- 0.009 mg/ml) and R. Slooffiae (0.658 +/- 0.033 mg/ml). There was significant difference observed between the EC50 of R. Slooffiae and BHT. CONCLUSION: It was found that both strains have ability to produce carotenoid and show antioxidant ability; however, R. Slooffiae had more potential in producing carotenoid and showing antioxidant ability than R. Mucilaginosa. Further study is required, in order to utilize this strain in the food, pharmaceuticals and cosmetics industries. PMID- 27957312 TI - A Healthy Young Woman with Acute Respiratory Distress Syndrome: an unfamiliar face of a familiar disease. AB - The presented case features a rare manifestation of pulmonary tuberculosis in a previously healthy young woman who had acute presentation of tuberculous pneumonia complicated by acute respiratory distress syndrome. In developing countries, mycobacterium tuberculosis is an important cause of community-acquired pneumonia (CAP). TB can present as an acute process and should be included in the differential diagnosis of CAP. This case is special in its manifestation from several clinical perspectives, including the lack of an underlying medical condition or immune defect and the development of acute respiratory distress syndrome (ARDS) in non-miliary and non-disseminated tuberculosis. In conclusion, the diagnosis of TB should be considered in all patients who present with CAP in endemic regions. PMID- 27957313 TI - Identifying the Challenges of Iran's Health Houses and Presenting a Solution. AB - INTRODUCTION: After more than three decades of network system design, epidemiological transition, as well as the change in needs and expectations of rural communities, have brought some challenges for Iran's health houses. So, this study is aimed at identifying these challenges through a qualitative study. METHODS: This was a qualitative and phenomenological study which was carried out in three phases in Iran in 2015. In the first phase, the required data was collected through semi-structured interviews with selected experts, health workers and referrals to Iran's health houses, so that all were selected purposefully. In the second phase, two expert panels were conducted to provide solutions. In the third phase the strengths, weaknesses, opportunities and threats were evaluated using the Strengths, Weaknesses, Opportunities, Threats (SWOT) method. The data of the first two phases were analyzed using the Collaizi method. RESULTS: Fourteen subthemes under five themes of ; quality of provided services, human resources, infrastructure, inter-sectorial and intra-sectorial relations, and contextual factors were identified as the challenges of Iran's health houses, and consist of fourteen sub themes. Continuous education of health workers, equipping and renovating old buildings, improving inter and intra sectorial relationships and the proportionating workload with a number of workers, were the most important solutions. CONCLUSION: The study showed that, over time, many of the functions of Iran's health houses have been faced with problems, therefore, training the manpower, equipping Iran's health houses and creating better public spaces and building culture are recommended to enhance the effectiveness and revisions based on the study. PMID- 27957314 TI - The Relationship between Anterior Chamber Depth, Axial Length and Intraocular Lens Power among Candidates for Cataract Surgery. AB - INTRODUCTION: Basic anatomical parameters in ophthalmology are variable in different countries according to ethnic groups, genetics and some environmental factors. The aim of this study was to determine the relationship between axial length (AL), anterior chamber depth (ACD) and intraocular lens power (IOL) in a referral center from eastern Iran among patients who had cataract surgery, in comparison to studies from other regions of the world. METHODS: In a cross sectional retrospective study from 2011 to 2013, the records of 698 cataract patients referring to Khatam Al Anbia general hospital in Mashhad, Iran were evaluated. We divided patients, based on their AL and ACD, into three separate groups and compared their results. The SPSS software was used for data analysis. The Chi-Square test and the Independent-samples t-test were used to compare qualitative and quantitative data between two groups, respectively. The Kendall and the Pearson product-moment correlation tests were used to assess the relationship between AL and ACD. The linear Regression model was used to obtain a mathematical model to estimate ACD, using AL, age and sex. RESULTS: Among individuals who had normal AL (between 22-24.5mm), there was a positive correlation between AL and ACD (p<0.001, r=0.17), however, among individuals with short (AL<22mm) or long sightedness (AL>24.5mm), no significant correlation was detected. We also found that older people have shorter AL (p=0.001 and r=-0.287). Men have an average longer AL (23.7+/-2.4mm vs. 22.9+/-2.1mm; p<0.001) and deeper ACD compared to women (2.93+/-0.45mm vs. 2.82+/-0.42mm, p=0.002). CONCLUSION: Our findings were mostly similar to previous literature from other regions of the world and although some anatomical variations may exist regarding ophthalmic anatomy, factors like race and geographical area have little effect on the relationship between ACD, AL and IOL power calculation, furthermore our results support the use of third and fourth generation formulas for IOL power calculation. PMID- 27957315 TI - Validating the Farsi version of the Pregnancy Worries and Stress Questionnaire (PWSQ): An exploratory factor analysis. AB - INTRODUCTION: Biological, environmental, inter- and intrapersonal changes during the antenatal period can result in anxiety and stress in pregnant women. It is pivotal to identify potential stressors and prevent their foetal and maternal consequences. The present study was conducted to validate and examine the factor structure of the Farsi version of the Pregnancy Worries and Stress Questionnaire (PWSQ). METHODS: In 2015, 502 Iranian healthy pregnant women, referred to selected hospitals in Tehran for prenatal care at 8-39 weeks of pregnancy, were recruited through a randomized cluster sampling. The PWSQ was translated into Farsi, and its validity and reliability were examined using exploratory factor analysis by SPSS version 21. RESULTS: The content validity of items on the PWSQ was between 0.63-1. The content validity index for relevance, clarity and simplicity were 0.92, 0.98, and 0.98, respectively, with a mean of 0.94. The Kaiser-Meyer-Olkin measure of sampling adequacy was 0.863. Test-retest reliability showed high internal consistency (alpha=0.89; p<0.0001). CONCLUSION: The psychometric evaluation and exploratory factor analysis showed that the translated questionnaire is a valid and reliable tool to identify stress in Iranian pregnant women. Application of the questionnaire can facilitate the diagnosis of stress in pregnant women and assist health care providers in providing timely support and minimizing negative outcomes of stress and anxiety in pregnant women and their infants. PMID- 27957316 TI - Effect of Folic Acid therapy on Homocysteine Level in patients with Atherosclerosis or Buerger's Disease and in Healthy individuals: A clinical trial. AB - BACKGROUND: Hyperhomocysteinemia is considered a risk factor for atherosclerosis and some other vascular diseases such as Buerger's disease. OBJECTIVE: The aim of this study was to measure the Homocysteine levels in 3 different groups of participants (Buerger's disease, atherosclerosis patients, and healthy cases) and determine the therapeutic effect of folic acid therapy on homocysteine levels for these three groups. METHODS: This nonrandomized clinical trial study was conducted in the vascular and endovascular surgery research center of Mashhad University of Medical Sciences in Mashhad, Iran. This interventional study consisted of 44 participants of which 22 patients had Buerger's disease and a control group of 22 healthy individuals, all of which were enrolled in this study. All of the study's participants had their serum homocysteine levels measured both before and after 12 weeks of folic acid (5mg/day) therapy. The data analysis used fo data analysis was a Chi square and t-test or their non parametrical equivalents for data analysis by means of Statistical Package for the Social Sciences (SPSS) version 16. RESULTS: The homocysteine levels were found to be significantly higher in patients with Buerger's disease as compared to other groups before treatment with folic acid (Buerger = 21.8 +/- 8.5 Mm/L, atherosclerosis = 17.3 +/- 6.9, healthy = 13.8 +/- 3.1; p < 0.001). After treatment with folic acid at 5 mg/daily for 12 weeks, the new plasma homocysteine levels did not show any significant difference (p = 0.38) between the Buerger's disease group (14.6 +/- 4.5 Mm/L) and atherosclerosis group (13.9 +/- 4.7), but it was found to besignificantly higher in both groups when compared to the healthy group (10.7 +/- 3.9, p<0.05). The plasma homocysteine level was reduced significantly when compared to its initial level in all 3 groups. The comparison of differences among three groups was found not to be significant (p=0.41). CONCLUSIONS: It seems that supplementary therapy with folic acid at a dose of 5 mg daily may reduce the serum homocysteine levels significantly and may have a role in the development of vascular diseases such as Buerger's disease. We suggest that folic acid should be considered as a routine agent in the Buerger's disease therapeutic regime. CLINICAL TRIAL REGISTRATION: The trial was registered at the Thai Clinical Trials Registry (http://www.clinicaltrials.in.th) with the ID: TCTR20160601003. FUNDING: This study was not funded by any organization. PMID- 27957318 TI - A Systematic Review of Anti-malarial Properties, Immunosuppressive Properties, Anti-inflammatory Properties, and Anti-cancer Properties of Artemisia Annua. AB - Artemisia annua belongs to the asteraceae family, indigenous to the mild climate of Asia. The aim of this study was to overview its anti-malarial properties, immunosuppressive properties, anti-inflammatory properties and anti-cancer properties. This systematic review was carried out by searching studies in PubMed, Medline, Web of Science, and IranMedex databases. The initial search strategy identified approximately ninety eight references. In this study, forty six studies were accepted for further screening and met all of our inclusion. The search terms were "Artemisia annua", "therapeutic properties", "and pharmacological effects". Artemisia annua is commonly used for its anti-malarial, immunosuppressive anti-inflammatory properties. Artemisia annua contributes to the treatment of various diseases such as diabetes, heart diseases, arthritis and eczema and possesses various effects such as antibacterial, antioxidant, anticoccidial, and antiviral effects. Furthermore, it was said to be good for cancer treatment. In this study, anti-malarial, immunosuppressive, anti inflammatory properties of this plant are presented using published articles in scientific sites. PMID- 27957317 TI - Mandibular Subcondylar Fractures: A Review on Treatment Strategies. AB - Condylar injuries are often subjected to discussion and controversy in maxillofacial surgery as they constitute many of the facial fractures. The condylar area has a great clinical value due to its important components. Vital components in this area are susceptible to functional disability due to either the fracture itself or the subsequent surgical intervention. Each of the strategies for the management of these fractures has its advantages and disadvantages. As there are controversies around management of condylar fractures, different treatment modalities are suggested in literature, so this paper reviews different treatment strategies of the following types of fractures in adults: 1-Closed reduction with maxillomandibular fixation, 2-Open reduction with internal fixation, 3-Endoscopic-assisted reduction with internal fixation. In conclusion, we declare that the endoscopic surgery is certainly a good replacement for approaches through the skin, for subcondylar fractures, but still more randomized clinical trials are needed to be carried out on this issue. PMID- 27957320 TI - Pazopanib: a novel treatment option for aggressive fibromatosis. AB - BACKGROUND: Aggressive fibromatosis (AF), also known as desmoid tumor, is an uncommon soft tissue neoplasm. AF does not metastasize, but it is locally invasive and its propensity for recurrence after conservative resection is well documented. No effective cytotoxic treatment has been reported, hence there is a need for novel treatment strategies. CASE PRESENTATION: We present the case of an AF successfully treated with an oral tyrosine kinase inhibitor, pazopanib, with mild side effects. As far as we know, this is the first case of AF with complete response to pazopanib. CONCLUSION: Pazopanib might be an effective treatment option for AF. PMID- 27957321 TI - Social characteristics associated with disparities in smoking rates in Israel. AB - BACKGROUND: Cigarette smoking is a major cause of health disparities. We aimed to determine social characteristics associated with smoking status and age at smoking initiation in the ethnically-diverse population of Israel. METHODS: This is a cross-sectional survey, based on data collected during 2010 by the Israel Bureau of Statistics, in a representative nationwide sample of 7,524 adults (>=20 years). Information collected by personal interviews included a broad set of demographic and socio-economic characteristics and detailed information on smoking habits. Associations between social characteristics and smoking habits were tested in multivariable regression models. RESULTS: Current smoking was more frequent among men than among women (30.9 % vs. 16.8 %; p < 0.0001). In multivariable regression analysis, the association of some social characteristics with smoking status differed by gender. Lower socioeconomic status (reflected by higher rate of unemployment, lower income, possession of fewer material assets, difficulty to meet living expenses) and lower educational level were significantly associated with current smoking among men but not among women. Family status other than being married was associated with higher likelihood of being a current smoker, while being traditional or observant was associated with a lower likelihood of ever smoking among both gender groups. Arab minority men and male immigrants from the former Soviet Union countries were more frequently current smokers than Israeli-born Jewish men [adjusted odds ratio (95 % confidence interval): 1.53 (1.22, 1.93) and 1.37 (1.01-1.87), respectively]. Compared to Israeli-born men, the age at smoking initiation was younger among male immigrants, and older among Arab minority men [adjusted hazard ratio (95 % confidence interval): 1.360 (1.165-1.586), and 0.849 (0.749-0.962), respectively]. While the prevalence of current smoking was lower in younger birth cohorts, the age at smoking initiation among ever-smokers declined as well. CONCLUSIONS: Among several subgroups within the Israeli population the smoking uptake is high, e.g. Arab men, men who are less affluent, who have lower educational level, and male immigrants. These subgroups should be prioritized for intervention to reduce the burden of smoking. To be effective, gender, cultural background and socioeconomic characteristics should be considered in the design and implementation of culturally-congruent tobacco control and smoking prevention and cessation interventions. PMID- 27957322 TI - A mutually beneficial collaboration between the European Academy of Allergy and Clinical Immunology Junior Members and Clinical and Translational Allergy. AB - The European Academy of Allergy and Clinical Immunology (EAACI) Junior Members (JM) comprise the largest EAACI section with around 4000 clinicians and scientists under 35 years of age working in the field of allergy and clinical immunology. The Junior Member collaboration with Clinical and Translational Allergy Journal is a mutually beneficial relationship providing Junior Members of EAACI with excellent opportunities to publish their work in the Journal, enhance their visibility in their respective field, and get involved with Journal-related activities and processes. In the future, this collaboration will grow, not only by the consolidation of these activities, but also by the implementation of new initiatives, such as a platform for discussing and/or publishing Junior Members' dissertations in the Journal. From the CTA perspective, the collaboration presents an opportunity to promote a new generation of allergists with experience of conducting and presenting research, with improved skills in critical review. PMID- 27957323 TI - Relationship between hospital ward design and healthcare-associated infection rates: a systematic review and meta-analysis. AB - BACKGROUND: The influence of the hospital's infrastructure on healthcare associated colonization and infection rates has thus far infrequently been examined. In this review we examine whether healthcare facility design is a contributing factor to multifaceted infection control strategies. METHODS: We searched PubMed/MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) from 1990 to December 31st, 2015, with language restriction to English, Spanish, German and French. RESULTS: We identified three studies investigating accessibility of the location of the antiseptic hand rub dispenser. Each of them showed a significant improvement of hand hygiene compliance or agent consumption with the implementation of accessible dispensers near the patient bed. Nine eligible studies evaluated the impact of single-patient rooms on the acquisition of healthcare-associated colonization and infections in comparison to multi-bedrooms or an open ward design. Six of these studies showed a significant benefit of single-patient bedrooms in reducing the healthcare-associated colonization and infection rate, whereas three studies found that single-patient rooms are neither a protective nor risk factor. In meta-analyses, the overall risk ratio for acquisition of healthcare-associated colonization and infection was 0.55 (95% CI: 0.41 to 0.74), for healthcare-associated colonization 0.52 (95% CI: 0.32 to 0.85) and for bacteremia 0.64 (95% CI: 0.53 to 0.76), all in favor of patient care in single-patient bedrooms. CONCLUSION: Implementation of single patient rooms and easily accessible hand rub dispensers located near the patient's bed are beneficial for infection control and are useful parts of a multifaceted strategy for reducing healthcare-associated colonization and infections. PMID- 27957319 TI - Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. AB - BACKGROUND: Autism spectrum disorders (ASD) are complex conditions whose pathogenesis may be attributed to gene-environment interactions. There are no definitive mechanisms explaining how environmental triggers can lead to ASD although the involvement of inflammation and immunity has been suggested. Inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a permissive blood-brain barrier (BBB), can be part of the chain of events leading to these disorders. Our goal was to investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD. METHODS: Postmortem cerebral cortex and cerebellum tissues from ASD, schizophrenia (SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and HC were analyzed for gene and protein expression profiles. Tight junctions and other key molecules associated with the neurovascular unit integrity and function and neuroinflammation were investigated. RESULTS: Claudin (CLDN)-5 and -12 were increased in the ASD cortex and cerebellum. CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL 8, tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased in the SCZ cerebellum. Differences between SCZ and ASD were observed for most of the genes analyzed in both brain areas. CLDN-5 protein was increased in ASD cortex and cerebellum, while CLDN-12 appeared reduced in both ASD and SCZ cortexes. In the intestine, 75% of the ASD samples analyzed had reduced expression of barrier forming TJ components (CLDN-1, OCLN, TRIC), whereas 66% had increased pore forming CLDNs (CLDN-2, -10, -15) compared to controls. CONCLUSIONS: In the ASD brain, there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity. While these findings seem to be specific for ASD, the possibility of more distinct SCZ subgroups should be explored with additional studies. PMID- 27957324 TI - Eosinophil protein X and childhood asthma: A systematic review and meta-analysis. AB - BACKGROUND: There are no reference guidelines for health care providers regarding appropriate use and interpretation of urine eosinophil protein X (u-EPX) in clinical practice. Currently, there are no clear-cut clinical or laboratory parameters to diagnose asthma in young children. OBJECTIVE: In this study, we (1) systematically reviewed and qualitatively appraised the epidemiological evidence to determine diagnostic u-EPX cut points for pediatric asthma, and (2) performed a meta-analysis to provide u-EPX estimates for diagnosing pediatric asthma. METHODS: Research articles in literature were identified from PubMed/Medline and Web of Science databases from 1966 to August 2015. Children <18 years of age were included. Both serum and urine EPX were included. Twenty-seven studies met the inclusion criteria for the systematic review and nine studies for the meta analysis. Details regarding EPX analyses, treatment efficacy, and outcomes were assessed. For meta-analyses, effect estimates were abstracted using standardized means. RESULTS: Over 70% of studies found a significant relationship between u EPX and childhood asthma. There was 1.94 times higher standardized means of u-EPX among acute asthmatics compared to healthy controls (confidence interval [CI]: 1.67-2.22). Similarly, the difference in standardized means between asymptomatic asthmatics and healthy controls was 1.58 times higher (CI: 1.27-1.88). CONCLUSIONS AND CLINICAL RELEVANCE: Despite differences in sample sizes, EPX processing and measurement, and ages of children, a consistent trend of higher EPX levels with childhood asthma was revealed. PMID- 27957325 TI - Immunogenicity of a peptide-based anti-IgE conjugate vaccine in non-human primates. AB - The anti-human immunoglobulin E (IgE) monoclonal antibody, omalizumab (Xolair(r), Genentech, South San Fransisco, CA), is effective in the treatment of poorly controlled moderate to severe allergic asthma and chronic idiopathic urticaria. It acts by specifically binding to the constant domain (Cepsilon3) of free human IgE in the blood and interstitial fluid. Although efficacious, use of omalizumab is limited due to restrictions on patient weight and pre-existing IgE levels, and frequent dosing (q2-4 weeks). A vaccine inducing anti-IgE antibodies has the potential for similar clinical benefits with less frequent dosing and relatively lower cost of goods. We developed a vaccine containing two IgE peptide-conjugates targeting the Cepsilon3 domain of human IgE. As part of preclinical evaluation of the vaccine to optimize formulation and dose prior to initiating clinical studies, we evaluated the vaccine in non-human primates, and demonstrate the induction of anti-peptide antibodies that can bind to conformationally intact human IgE and are capable, at least in some animals, of substantial lowering circulating IgE levels. PMID- 27957326 TI - Increased rhinovirus replication in nasal mucosa cells in allergic subjects is associated with increased ICAM-1 levels and endosomal acidification and is inhibited by L-carbocisteine. AB - Increased viral replication and cytokine production may be associated with the pathogenesis of asthma attacks in rhinovirus (RV) infections. However, the association between increased RV replication and enhanced expression of intercellular adhesion molecule-1 (ICAM-1), a receptor for a major RV group, in airway epithelial cells has remained unclear. Furthermore, the inhibitory effects of mucolytics, which have clinical benefits in asthmatic subjects, are uncertain. Human nasal epithelial (HNE) cells were infected with type 14 rhinovirus (RV14), a major RV group. RV14 titers and cytokine concentrations, including interleukin (IL)-6 and IL-8, in supernatants, RV14 RNA replication and susceptibility to RV14 infection were higher in HNE cells obtained from subjects in the allergic group (allergic subjects) than in those from subjects in the non-allergic group (non allergic subjects). ICAM-1 expression and the number and fluorescence intensity of acidic endosomes from which RV14 RNA enters the cytoplasm were higher in HNE cells from allergic subjects, though substantial amounts of interferon (IFN) gamma and IFN-lambda were not detected in the supernatant. The abundance of p50 and p65 subunits of transcription factor nuclear factor kappa B (NF-kappaB) in nuclear extracts of the cells from allergic subjects was higher compared to non allergic subjects, and an inhibitor of NF-kappaB, caffeic acid phenethyl ester, reduced the fluorescence intensity of acidic endosomes as well as RV titers and RNA. Furthermore, a mucolytic agent, L-carbocisteine, reduced RV14 titers and RNA levels, cytokine release, ICAM-1 expression, the fluorescence intensity of acidic endosomes, and NF-kappaB activation. The increased RV14 replication observed in HNE cells from allergic subjects might be partly associated with enhanced ICAM-1 expression and decreased endosomal pH through NF-kappaB activation. L Carbocisteine inhibits RV14 infection by reducing ICAM-1 and acidic endosomes and may, therefore, modulate airway inflammation caused by RV infection in allergic subjects. PMID- 27957327 TI - Altered expression of Butyrophilin (BTN) and BTN-like (BTNL) genes in intestinal inflammation and colon cancer. AB - Several Butyrophilin (BTN) and Btn-like (BTNL) molecules control T lymphocyte responses, and are genetically associated with inflammatory disorders and cancer. In this study, we present a comprehensive expression analysis of human and murine BTN and BTNL genes in conditions associated with intestinal inflammation and cancer. Using real-time PCR, expression of human BTN and BTNL genes was analyzed in samples from patients with ulcerative colitis, irritable bowel syndrome, and colon tumors. Expression of murine Btn and Btnl genes was examined in mouse models of spontaneous colitis (Muc2-/-) and intestinal tumorigenesis (ApcMin/+). Our analysis indicates a strong association of several of the human genes with ulcerative colitis and colon cancer; while especially BTN1A1, BTN2A2, BTN3A3, and BTNL8 were significantly altered in inflammation, colonic tumors exhibited significantly decreased levels of BTNL2, BTNL3, BTNL8, and BTNL9 as compared to unaffected tissue. Colonic inflammation in Muc2-/- mice significantly down regulated the expression of particularly Btnl1, Btnl4, and Btnl6 mRNA, and intestinal polyps derived from ApcMin/+ mice displayed altered levels of Btn1a1, Btn2a2, and Btnl1 transcripts. Thus, our data present an association of BTN and BTNL genes with intestinal inflammation and cancer and represent a valuable resource for further studies of this gene family. PMID- 27957328 TI - Anti-asthmatic and anxiolytic effects of Herissantia tiubae, a Brazilian medicinal plant. AB - Herissantia tiubae (HtE) is a Brazilian plant used in folk medicine to treat inflammatory diseases. Our aim was to determine whether the HtE has anti inflammatory and anxiolytic effects in a murine model of asthma. Ovalbumin (OVA) sensitized BALB/c mice were treated with HtE (50, 100, or 200 mg/kg) or dexamethasone before each OVA challenge. After the last challenge, animals were subjected to anxiety tests and respiratory measurements. Following euthanasia, we quantified immune cells in the bronchoalveolar lavage (BAL), serum IgE titer and cytokine levels, cellular infiltration and mucus content in the lung tissues, and cellular composition of the mediastinal lymph nodes. OVA challenge in sensitized animals caused: (1) reduction of mean respiratory and dominant respiratory rate (from 398 +/- 12 to 286 +/- 20 cicles per minute (cpm) and from 320 +/- 14 to 162 +/- 15 cpm, respectively); (2) increase in behavioral markers of anxiety tests; (3) substantial pro-inflammatory effects, including rise in OVA-specific IgE titer (from 0 to 1:2048) and these inflammatory effect diminished the titer to 1:512 after HtE treatment; rise in plasma IL-13 (from 13 ng/mL in saline to 227 ng/mL in OVA and HtE treatment restored to 1.29 ng/mL; rise in total BAL cell count (from 0.742 cells/mL in saline to 11.77 cells/mL in OVA), with prominent eosinophilia. H. tiubae extract affected respiratory parameters similarly to aminophylline, behavioral changes comparable to diazepam, and inflammation being as efficient as dexamethasone. H. tiubae extract (HtE) possesses both anti inflammatory and anxiolytic properties in the murine model of asthma. PMID- 27957329 TI - Adipose-derived mesenchymal stromal cells modulate experimental autoimmune arthritis by inducing an early regulatory innate cell signature. AB - Modulation of innate immune responses in rheumatoid arthritis and other immune mediated disorders is of critical importance in the clinic since a growing body of information has shown the key contribution of dysregulated innate responses in the progression of the disease. Mesenchymal stromal cells (MSCs) are the focus of intensive efforts worldwide due to their key role in tissue regeneration and modulation of inflammation. In this study, we define innate immune responses occurring during the early course of treatment with a single dose of expanded adipose-derived MSCs (eASCs) in established collagen-induced arthritis. eASCs delay the progression of the disease during the early phase of the disease. This is accompanied by a transient induction of Ly6C+ monocytes that differentiate into IL10+F4/80+ cells in arthritic mice. Strikingly, the induced IL10+F4/80+ myeloid cells preferentially accumulated in the draining lymph nodes. This effect was accompanied with a concomitant declining of their frequencies in the spleens. Our results show that eASCs attenuate the arthritic process by inducing an early innate cell signature that involves a transient induction of Ly6C+ monocytes in periphery that differentiate into IL10+F4/80+ macrophages. Our findings demonstrate that early regulatory innate cell responses, involving the monocyte compartment, are targeted by the eASCs during the onset of collagen-induced inflammation. PMID- 27957332 TI - Uncertainty estimation for temperature measurement with diagnostic ultrasound. AB - BACKGROUND: Ultrasound therapies are promising, non-invasive applications with potential to significantly improve, e.g. cancer therapies like viro- or immunotherapy or surgical applications. However, a crucial step towards their breakthrough is still missing: affordable and easy-to-handle quality assurance tools for therapy devices and ways to verify treatment planning algorithms. This deficiency limits the safety and comparability of treatments. METHODS: To overcome this deficiency accurate spatial and temporal temperature maps could be used. In this paper, the suitability of temperature calculation based on time shifts of diagnostic ultrasound backscattered signals (echo-time-shift) is investigated and associated uncertainties are estimated. Different analysis variations were used to calculate the time-shifts: discrete and continuous methods as well as different frames as a reference for temperature calculation (4 s before, 16 s before the frame of interest, base frame). A sigmoid function was fitted and used to calculate temperatures. Two-dimensional temperature maps recorded during and after therapeutic ultrasound sonication were examined. All experiments were performed in agar-graphite phantoms mimicking non-fatty tissue, with high-intensity focused ultrasound being the source of heating. RESULTS: Continuous methods are more accurate than discrete ones, and uncertainties of calculated temperatures are in general lower, the earlier the reference frame was recorded. Depending on the purpose of the measurement, a compromise has to be made between the following: calculation accuracy (early reference frame), tolerance towards small movements (late reference frame), reproducing large temperature changes or cooling processes (reference frame at a certain point in time), speed of the algorithm (discrete (fast) vs. continuous (slower) shift calculation), and spatial accuracy (interval size for index-shift calculation). Within the range from 20 degrees C to 44 degrees C, uncertainties as low as 12.4 % are possible, being mainly due to medium properties. CONCLUSIONS: Temperature measurements using the echo-time-shift method might be useful for validation of treatment plan algorithms. This might also be a comparatively accurate, fast, and affordable method for laboratory and clinical quality assessment. Further research is necessary to improve filter algorithms and to extend this method to multiple foci and the usage of temperature-dependent tissue quantities. We used an analytical approach to investigate the uncertainties of temperature measurement. Different analysis variations are compared to determine temperature distribution and development over time. PMID- 27957330 TI - Evidence of perturbed germinal center dynamics, but preserved antibody diversity, in end-stage renal disease. AB - INTRODUCTION: End-stage renal disease (ESRD) is associated with increased infectious susceptibility and with reduced vaccine responses consistent with compromised humoral immunity. Whether the compromised humoral immunity is due to reduced antibody diversity (reduced somatic hypermutation [SHM]) or altered germinal center (GC) dynamics is not known. The GC-derived chemokine CXCL13 as well as peripheral T follicular helper cells (pTFH) reflect GC dynamics, but have, similar to SHM, never been characterized in relation to ESRD. METHODS: Serum CXCL 13 was determined by ELISA. PTFH were flow-cytometrically defined as CD4+ CD45RA- CCR7+ CXCR5+ lymphocytes. Apoptotic lymphocyte subsets were in addition annexin V+. SHM was determined, by next-generation sequencing and bioinformatics, as nucleotide mutations within the IgG VH (comprising the important antigen-binding domains of IgG, CDR1, and CDR2). RESULTS: Elevated CXCL13 levels characterized ESRD (n = 19; [median] 90 pg/ml, P < 0.01) (controls, n = 18; 62 pg/ml). ESRD pTFH frequencies (n = 19; 11.6% [of CD4+ memory T cells], P < 0.02*, *Bonferroni corrected) (controls, n = 22; 14.9%) and concentrations (n = 19; 0.03 * 109/L, P < 0.02*) (controls, n = 22; 0.07 * 109/L) were reduced. ESRD pTFH were more apoptotic (n = 9; 25.7%, P = 0.04*) (controls, n = 10; 15.9%). SHM did not discriminate between ESRD (n = 10; 7.4%, P = 0.21) and controls (n = 10; 8.4%). CONCLUSIONS: Elevated CXCL13 levels, reduced pTFH levels, and increased pTFH apoptosis suggest that perturbed GC dynamics, and not reduced antibody diversity, underlie the diminished vaccine responses and the compromised humoral immunity in ESRD. However, largely preserved SHM provides a rationale for pursuing vaccination in relation to ESRD. PMID- 27957331 TI - IL-6-specific autoantibodies among APECED and thymoma patients. AB - INTRODUCTION: Both autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and the rare thymoma patients with chronic mucocutaneous candidiasis (CMC) have neutralizing autoantibodies to Th17 cytokines and significant defects in production of IL-22 and IL-17F by their T cells. The cause of these defects is unknown. We hypothesized that they might result from autoimmunity against upstream cytokines normally responsible for generating and maintaining Th17 cells. METHODS: Luciferase immunoprecipitation (LIPS) was used to screen for autoantibodies to IL-6, IL-1beta, TGF-beta3, IL-21, and IL-23 in patients with APECED or thymoma. We used Western blotting to assess the conformation-dependence of the IL-6 autoantibodies and flow cytometric analysis of intracellular phospho STAT3 induction to assess IL-6-neutralizing capacity in IgGs isolated from patient and control sera. We also used Luminex xMAP to measure serum cytokine levels. RESULTS: We found autoantibodies binding to conformational epitopes of IL 6 in 19.5% of 41 patients with APECED and 12.5% of 104 with thymoma-especially in those with long disease durations. The autoantibodies were predominantly of IgG1 subclass and failed to neutralize IL-6 activity. Notably, serum levels of the IL 6 and IL-17A cytokines were higher in anti-IL-6 seropositive than-negative APECED patients or healthy controls. We also detected autoantibody binding to IL-23 in 27.9% of thymoma patients, resulting from cross-recognition through the p40 subunit it shares with IL-12. CONCLUSIONS: IL-6 and IL-17A elevation in these seropositive patients suggests that antibody-binding may protect IL-6 from degradation and prolong its half-life in vivo. PMID- 27957335 TI - Using circulating reproductive hormones for sex determination of Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) in the Saco River estuary, Maine. AB - The Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) is a long-lived, anadromous fish species ranging from Labrador, CA to Florida, USA. In the Saco River, located in the Gulf of Maine, this species was not present during a survey study ending in 1982, but was found inhabiting the estuary in 2007. Although the reason for the return of this sturgeon to this river system remains unknown, research on basic life-history information is necessary to facilitate the conservation of this federally protected species. Given the conservation status of the species, the present study used circulating sex steroid hormones to determine the sex of 288 Atlantic sturgeon captured between 2012 and 2014 in the Saco River estuary located in the Gulf of Maine. Overall, the sex was determined for 93% of Atlantic sturgeon sampled. Mean hormone values were similar to other Atlantic sturgeon reproductive studies. The findings indicate the validity of sex steroid hormones as a singular method for sex determination in wild Atlantic sturgeon. Results also indicated a likely 1:1 (male:female) sex ratio in the system, except in 2014 when a 1:3 ratio was observed. It is not believed that the Saco River estuary is used for spawning, as several impassable dams block access to spawning habitat. However, this area might provide crucial foraging for growth and development of juveniles and a habitat for adults forgoing spawning. PMID- 27957334 TI - Parasites, stress and reindeer: infection with abomasal nematodes is not associated with elevated glucocorticoid levels in hair or faeces. AB - Stress hormones (glucocorticoids), incorporated into hair/fur and faeces, have been proposed as biomarkers of overall health in wildlife. Although such biomarkers may be helpful for wildlife conservation and management, their use has rarely been validated. There is a paucity of studies examining the variation of stress hormones in mammals and how they relate to other health measures, such as parasitism. Parasites are ubiquitous in wildlife and can influence the fitness of individual animals and populations. Through a longitudinal experiment using captive reindeer (Rangifer tarandus tarandus), we tested whether animals infected with Ostertagia gruehneri, a gastrointestinal nematode with negative impacts on fitness of the host, had higher stress levels compared with those that had been treated to remove infection. Faecal samples were collected weekly for 12 weeks (June-September) and hair was collected at the start and end of the study; glucocorticoids were quantified using enzyme immunoassays. Contrary to what was expected, infected reindeer had similar levels of cortisol in hair and slightly lower glucocorticoid metabolites in faeces compared with uninfected reindeer. Faecal corticosterone levels were higher than faecal cortisol levels, and only corticosterone increased significantly after a handling event. These results suggest that reindeer may use a tolerance strategy to cope with gastrointestinal nematodes and raise the question as to whether moderate infection intensities with nematodes are beneficial to the host. By removing nematodes we may have altered the gut microbiota, leading to the observed elevated faecal glucocorticoid metabolite levels in the treated reindeer. These findings demonstrate the importance of considering both cortisol and corticosterone in physiological studies, as there is mounting evidence that they may have different functionalities. PMID- 27957333 TI - High thermal tolerance of a rainbow trout population near its southern range limit suggests local thermal adjustment. AB - Transformation of earth's ecosystems by anthropogenic climate change is predicted for the 21st century. In many regions, the associated increase in environmental temperatures and reduced precipitation will have direct effects on the physiological performance of terrestrial and aquatic ectotherms and have already threatened fish biodiversity and important fisheries. The threat of elevated environmental temperatures is particularly salient for members of the Oncorhynchus genus living in California, which is the southern limit of their range. Here, we report the first assessments of the aerobic capacity of a Californian population of wild Oncorhynchus mykiss Walbaum in relationship to water temperature. Our field measurements revealed that wild O. mykiss from the lower Tuolumne River, California maintained 95% of their peak aerobic scope across an impressive temperature range (17.8-24.6 degrees C). The thermal range for peak performance corresponds to local high river temperatures, but represents an unusually high temperature tolerance compared with conspecifics and congeneric species from northern latitudes. This high thermal tolerance suggests that O. mykiss at the southern limit of their indigenous distribution may be locally adjusted relative to more northern populations. From fisheries management and conservation perspectives, these findings challenge the use of a single thermal criterion to regulate the habitat of the O. mykiss species along the entirety of its distribution range. PMID- 27957336 TI - Physical condition and stress levels during early development reflect feeding rates and predict pre- and post-fledging survival in a nearshore seabird. AB - The effects of acute environmental stressors on reproduction in wildlife are often difficult to measure because of the labour and disturbance involved in collecting accurate reproductive data. Stress hormones represent a promising option for assessing the effects of environmental perturbations on altricial young; however, it is necessary first to establish how stress levels are affected by environmental conditions during development and whether elevated stress results in reduced survival and recruitment rates. In birds, the stress hormone corticosterone is deposited in feathers during the entire period of feather growth, making it an integrated measure of background stress levels during development. We tested the utility of feather corticosterone levels in 3- to 4 week-old nestling brown pelicans (Pelecanus occidentalis) for predicting survival rates at both the individual and colony levels. We also assessed the relationship of feather corticosterone to nestling body condition and rates of energy delivery to nestlings. Chicks with higher body condition and lower corticosterone levels were more likely to fledge and to be resighted after fledging, whereas those with lower body condition and higher corticosterone levels were less likely to fledge or be resighted after fledging. Feather corticosterone was also associated with intracolony differences in survival between ground and elevated nest sites. Colony-wide, mean feather corticosterone predicted nest productivity, chick survival and post-fledging dispersal more effectively than did body condition, although these relationships were strongest before fledglings dispersed away from the colony. Both reproductive success and nestling corticosterone were strongly related to nutritional conditions, particularly meal delivery rates. We conclude that feather corticosterone is a powerful predictor of reproductive success and could provide a useful metric for rapidly assessing the effects of changes in environmental conditions, provided pre-existing baseline variation is monitored and understood. PMID- 27957337 TI - National complicated acute diverticulitis (CADS) study: a protocol for a prospective observational scoping study for acute diverticulitis. AB - BACKGROUND: Diverticular disease is a widely prevalent disease in western society, and acute diverticulitis is a common acute surgical presentation. However, there is a lack of level 1 evidence addressing the multifaceted presentations associated with acute diverticulitis. There is also a lack of robust epidemiological data that could be used to meaningfully inform randomised controlled trials. The National CADS project aims to generate baseline data for a cohort of patients managed for clinically suspected acute diverticulitis and evaluate the impact of variability in the management approach on patient outcomes in the short (3 months) and long (2 years) term. METHOD: A Unit policy questionnaire will be completed by the principal investigator from all participating centres prior to study initiation. All patients aged above 18 years admitted with clinical suspicion of acute diverticulitis will be included from UK hospitals providing acute surgical care. Demographic, clinical, inpatient stay and outpatient follow-up data will be collected for index admissions between July and September 2014, 3 months follow-up and finally a 2-year follow-up. RESULTS: The study attracted participation from 108 centres nationally and has so far generated data on 2500 patients admitted between 1 July 2014 and 30 September 2014. Short-term follow-up data have been obtained for this cohort. CONCLUSIONS: The National CADS study is currently ongoing with the long-term outcomes data anticipated to be submitted in autumn of 2016. PMID- 27957338 TI - Comparison of the Optical Quality between Small Incision Lenticule Extraction and Femtosecond Laser LASIK. AB - Purpose. To investigate the visual quality after SMILE and Femto-LASIK. Methods. About 123 eyes from 63 patients were enrolled in this study. The parameters were measured preoperatively and 1 week, 1 month, and 3 months postoperatively using Sirius System. Results. The MTF curve increase slightly from low to high frequency at 3 mm and 6 mm pupil diameter after SMILE surgery (P < 0.05) during the follow-up time comparing with the preoperative values. And the SR has a significant increase at various pupil diameters as well (P < 0.05). However, there was little increase for MTF at intermediate to high frequency at 3 mm pupil diameter after Femto-LASIK procedure (P < 0.05). And the SR had only significant increase at 3 mm pupil diameter. Between SMILE and Femto-LASIK, there was no statistic difference both in MTF and SR (P > 0.05) at 3 mm pupil diameter at vertical and horizontal meridian. However, significant difference was found in MTF at low to mediate frequency at 6 mm pupil diameter at vertical meridian at 1 week postoperatively (P < 0.05). Conclusions. Both SMILE and Femto-LASIK show a great improvement in optical quality at small diameter. It was found that SMILE shows better optical quality than Femto-LASIK at larger pupil diameter, which might be good for the night vision. PMID- 27957339 TI - Gender and Racial Differences in the Cardiovascular Risk Factors among Overweight and Obese Rural Adults, Kuching and Samarahan Division, Sarawak, Malaysia. AB - Objective. This study aimed to determine whether gender and ethnic differences had an effect on cardiovascular risk factors in overweight and obese rural adults in Sarawak. Design and Setting. This was a cross-sectional study conducted in rural communities in Kuching and Samarahan division, Malaysia. Data was obtained using a set of questionnaire (sociodemographic data and physical activity), measurement of blood pressure, height, weight (body mass index, BMI), body fat percentage, fasting blood sugar, and lipid profile from three ethnic groups-Iban, Malay, and Bidayuh. Analysis of data was done using SPSS version 23.0. Results. A total of 155 respondents participated in the study (81.6% response rate). The levels of physical activity, BMI status, body fat, hypercholesterolemia, and hyperglycemia were similar across the three ethnic groups and both females and males. Iban and Bidayuh had significant higher Atherogenic Index of Plasma (AIP) when compared to the Malay (Bidayuh OR = 0.30, 95% CI 0.12, 0.78; Iban OR = 0.29, 95% CI 0.12, 0.69). Conclusions. The relationship between cardiovascular risk factors varied according to ethnic groups and gender. A better understanding of these differences would help in the design and implementation of intervention programme for the prevention of cardiovascular disease. PMID- 27957340 TI - Diagnosis of Peripheral Lung Lesions via Conventional Flexible Bronchoscopy with Multiplanar CT Planning. AB - Background. Conventional flexible bronchoscopy has limited sensitivity in the diagnosis of peripheral lung lesions and is dependent on lesion size. However, advancement of CT imaging offers multiplanar reconstruction facilitating enhanced preprocedure planning. This study aims to report efficacy and safety while considering the impact of patient selection and multiplanar CT planning. Method. Prospective case series of patients with peripheral lung lesions suspected of having lung cancer who underwent flexible bronchoscopy (forceps biopsy and lavage). Endobronchial lesions were excluded. Patients with negative results underwent CT-guided transthoracic needle aspiration, surgical biopsy, or clinical radiological surveillance to establish the final diagnosis. Results. 226 patients were analysed. The diagnostic yield of bronchoscopy was 80.1% (181/226) with a sensitivity of 84.2% and specificity of 100%. In patients with a positive CT Bronchus sign, the diagnostic yield was 82.4% compared to 72.8% with negative CT Bronchus sign (p = 0.116). Diagnostic yield was 84.9% in lesions > 20 mm and 63.0% in lesions <= 20 mm (p = 0.001). Six (2.7%) patients had transient hypoxia and 2 (0.9%) had pneumothorax. There were no serious adverse events. Conclusion. Flexible bronchoscopy with appropriate patient selection and preprocedure planning is more efficacious in obtaining a diagnosis in peripheral lung lesions compared to historical data. This trial is registered with ClinicalTrials.gov Identifier: NCT01374542. PMID- 27957341 TI - Surface Projection of Interosseous Foramen of the Leg: Cadaver Study. AB - Purpose. This study was conducted to identify the surface projection of the interosseous foramen and associated structures of the proximal leg using the average clinician's thumb width as a quick measurement to assist in differential diagnosis and treatment. Methods. Twelve cadavers (5 males and 7 females, age range = 51-91 years, and mean age = 76.9) were dissected for analysis. Location and size of interosseous foramen, location of anterior tibial artery, location of deep fibular nerve, and corresponding arterial branches were measured and converted into thumb widths. Results. Mean thumb width measured among the cadavers was 17.94 +/- 3.9 mm. The interosseous foramen measured was approximately 1 thumb width vertically (18.47 +/- 3.0 mm) and 1/2 thumb width horizontally (7.32 +/- 2.1 mm) and was located approximately 1 thumb width distally to the tibial tuberosity (20.81 +/- 6.8 mm) and 2 thumb widths (37.47 +/ 4.7 mm) lateral to the tibial ridge. The anterior tibial artery and deep fibular nerve converged approximately 4 thumb widths (74.31 +/- 14.8 mm) inferior to the tibial tuberosity and 2 thumb widths (33.46 +/- 4.9 mm) lateral to the tibial ridge. Conclusion. Clinicians may identify anatomical structures of the proximal leg with palpation using the thumb width for measurement. PMID- 27957342 TI - Effectiveness of Moderate Intensity Interval Training as an Index of Autonomic Nervous Activity. AB - The purpose of this study was to examine the effects of moderate intensity interval training from the change of the autonomic nervous activity. Ten male volunteers aged 21-22 years were studied. After 10-minute rest in a seated position, the subjects were asked to perform the strength of moderate cycling exercise in ergometer. Cycling rate was done in 50 times/min. Load resistance of the ergometer was set to 2.0 kgm. Subjects paused the exercise when the heart rate becomes 120 beats/min. Subjects have resumed the exercise when the heart rate returns to the value at rest. This trial was repeated twice. The experiment was ended when the heart rate of the subjects has returned to resting level. When the heart rate during exercise is maintained to less than 120 beats/min, sympathetic nerve activity during exercise did not work actively compared to the baseline. Vagus nerve activity after exercise cessation exceeds the baseline. It is clarified that the exercise as well as activating the vagus nerve activity stimulates the total autonomic nervous activity. It has revealed that at the time of interval training at moderate load the vagus nerve activity can be carried out. PMID- 27957343 TI - Cholesterol Efflux Capacity of Apolipoprotein A-I Varies with the Extent of Differentiation and Foam Cell Formation of THP-1 Cells. AB - Apolipoprotein A-I (apoA-I), the main protein component of high-density lipoprotein (HDL), has many protective functions against atherosclerosis, one of them being cholesterol efflux capacity. Although cholesterol efflux capacity measurement is suggested to be a key biomarker for evaluating the risk of development of atherosclerosis, the assay has not been optimized till date. This study aims at investigating the effect of different states of cells on the cholesterol efflux capacity. We also studied the effect of apoA-I modification by homocysteine, a risk factor for atherosclerosis, on cholesterol efflux capacity in different states of cells. The cholesterol efflux capacity of apoA-I was greatly influenced by the extent of differentiation of THP-1 cells and attenuated by excessive foam cell formation. N-Homocysteinylated apoA-I indicated a lower cholesterol efflux capacity than normal apoA-I in the optimized condition, whereas no significant difference was observed in the cholesterol efflux capacity between apoA-I in the excessive cell differentiation or foam cell formation states. These results suggest that cholesterol efflux capacity of apoA-I varies depending on the state of cells. Therefore, the cholesterol efflux assay should be performed using protocols optimized according to the objective of the experiment. PMID- 27957344 TI - Digital Tip Amputations from the Perspective of the Nail. AB - The management strategy proposed herein for fingertip amputations advocates secondary healing with preservation of appearance as well as function. Conservative healing is more likely to result in a sensate, nontender, and cosmetically acceptable fingertip compared to surgical management in many clinical scenarios. This manuscript examines in detail the extent of fingertip injury and defines the relationship of injury to final fingertip outcome. A classification is presented, which allows adequate initial counseling regarding prognosis, and predicts the need for secondary corrective surgery. PMID- 27957345 TI - Protective Effect of Edaravone on Glutamate-Induced Neurotoxicity in Spiral Ganglion Neurons. AB - Glutamate is an important excitatory neurotransmitter in mammalian brains, but excessive amount of glutamate can cause "excitotoxicity" and lead to neuronal death. As bipolar neurons, spiral ganglion neurons (SGNs) function as a "bridge" in transmitting auditory information from the ear to the brain and can be damaged by excessive glutamate which results in sensorineural hearing loss. In this study, edaravone, a free radical scavenger, elicited both preventative and therapeutic effects on SGNs against glutamate-induced cell damage that was tested by MTT assay and trypan blue staining. Ho.33342 and PI double staining revealed that apoptosis as well as necrosis took place during glutamate treatment, and apoptosis was the main type of cell death. Oxidative stress played an important role in glutamate-induced cell damage but pretreatment with edaravone alleviated cell death. Results of western blot demonstrated that mechanisms underlying the toxicity of glutamate and the protection of edaravone were related to the PI3K pathway and Bcl-2 protein family. PMID- 27957347 TI - High Dose, Prolonged Epsilon Aminocaproic Acid Infusion, and Recombinant Factor VII for Massive Postoperative Retroperitoneal Hemorrhage following Splenectomy. AB - The antifibrinolytic agent epsilon-aminocaproic acid is used to decrease procedural blood loss in a variety of high risk surgeries. The utility of recombinant factor VII administration in massive hemorrhage has also been reported in a variety of settings, though the impact in a surgical context remains unclear. We describe the case of a patient who underwent massive open splenectomy and developed diffuse retroperitoneal bleeding on postoperative day one. Massive transfusion was initiated, but attempts to control hemorrhage with surgical and interventional radiology approaches were unsuccessful, as was recombinant factor VII administration. Commencement of a high dose aminocaproic acid infusion was followed by a prominent rise in fibrinogen levels and stabilization of the hemorrhage. Indications, dosages, and adverse effects of epsilon-aminocaproic acid as described in the literature are reviewed. PMID- 27957348 TI - Exercise-Stress Echocardiography Reveals Systolic Anterior Motion of the Mitral Valve as a Cause of Syncopes in a Cardiac Amyloidosis Patient. AB - Patients with cardiac amyloidosis are at increased AV-block and syncope risk. Therefore, a prophylactic pacemaker is often implanted. However, this case illustrates that other mechanisms should be ruled out prior to pacemaker implantation. The patient studied had mitral valve thickening without increased left ventricular outflow track (LVOT) velocity. However, bicycle exercise-stress test with simultaneous echocardiography revealed a stepwise decrease in blood pressure, a substantial increase in the LVOT velocity, and severe systolic anterior motion of the mitral valve. The patients' symptoms were likely explained by these findings. Therefore, a comprehensive clinical evaluation is warranted prior to pacemaker implantation in cardiac amyloidosis patients. PMID- 27957349 TI - A Case of Buccal Abscess from an Impacted Wisdom Tooth in an Elderly Person with Malnutrition. AB - We report a case of buccal abscess caused by an impacted wisdom tooth in an extremely elderly person with malnutrition. The patient was a 94-year-old man, who complained that he had found it hard to open his mouth and that his cheek had been swollen for the previous 2 weeks. He had a shallow oral wound caused by an improperly fitting denture; however, the wound became infected. We performed incisional drainage of the abscess under local anesthesia. The swelling disappeared and he was able to open his mouth 55 mm. The elderly have a high risk of healing failure of injuries and it has been reported that infection in a host in a compromised state is severely intractable. This elderly patient was in a compromised state because of malnutrition. Cases such as this one will increase as the elderly population increases. Dentists need to consider the quality of life of patients with a longer life expectancy and should offer patients several treatment options before their general condition deteriorates. PMID- 27957346 TI - Vagus Nerve Stimulation Enhances Extinction of Conditioned Fear in Rats and Modulates Arc Protein, CaMKII, and GluN2B-Containing NMDA Receptors in the Basolateral Amygdala. AB - Vagus nerve stimulation (VNS) enhances the consolidation of extinction of conditioned fear. High frequency stimulation of the infralimbic cortex (IL) produces long-term potentiation in the basolateral amygdala (BLA) in rats given VNS-paired extinction training, whereas the same stimulation produces long-term depression in sham-treated rats. The present study investigated the state of synaptic plasticity-associated proteins in the BLA that could be responsible for this shift. Male Sprague-Dawley rats were separated into 4 groups: auditory fear conditioning only (fear-conditioned); fear conditioning + 20 extinction trials (extended-extinction); fear conditioning + 4 extinction trials paired with sham stimulation (sham-extinction); fear conditioning + 4 extinction trials paired with VNS (VNS-extinction). Freezing was significantly reduced in extended extinction and VNS-extinction rats. Western blots were used to quantify expression and phosphorylation state of synaptic plasticity-associated proteins such as Arc, CaMKII, ERK, PKA, and AMPA and NMDA receptors. Results show significant increases in GluN2B expression and phosphorylated CaMKII in BLA samples from VNS- and extended-extinction rats. Arc expression was significantly reduced in VNS-extinction rats compared to all groups. Administration of the GluN2B antagonist ifenprodil immediately after fear extinction training blocked consolidation of extinction learning. Results indicate a role for BLA CaMKII induced GluN2B expression and reduced Arc protein in VNS-enhanced extinction. PMID- 27957350 TI - Laser Photobiomodulation for a Complex Patient with Severe Hydroxyurea-Induced Oral Ulcerations. AB - Patients affected by polycythemia vera (PV), a myeloproliferative neoplasm characterized by an elevated red blood cell mass, are at high risk of vascular and thrombotic complications. Conventional therapeutic options aim at reducing vascular and thrombotic risk; low-dose aspirin and phlebotomy are first-line recommendations, for patients at low risk of thrombotic events, whereas cytoreductive therapy, usually hydroxyurea (HU) or interferon alpha, is recommended for high-risk patients. In the present study, we report the case of a patient with persistent oral ulcerations, possibly related to long-lasting HU treatment, firstly treated with topic and systemic corticosteroids and then more effectively with the addition of low-level laser therapy. Laser photobiomodulation has achieved pain control and has contributed to the healing of oral ulcers without any adverse effect; this has permitted a reduction in the dose of systemic corticosteroids and the suspension of the use of the topic ones, due to the long-term stability of oral health, even after the interruption of low level laser therapy sessions. PMID- 27957351 TI - The Biochemical Profile of Familial Hypocalciuric Hypercalcemia and Primary Hyperparathyroidism during Pregnancy and Lactation: Two Case Reports and Review of the Literature. AB - Background. Primary hyperparathyroidism (PHPT) and Familial Hypocalciuric Hypercalcemia (FHH) result in different maternal and fetal complications in pregnancy. Calcium to creatinine clearance ratio (CCCR) is commonly used to help distinguish these two conditions. Physiological changes in calcium handling during pregnancy and lactation can alter CCCR, making it a less useful tool to distinguish PHPT from FHH. Cases. A 25-year-old female presented with hypercalcemia and an inappropriately normal PTH. Her CCCR was 0.79% before pregnancy and rose to 1.99% in her second trimester. The proband's mother and neonate had asymptomatic hypercalcemia. Genetic analysis revealed a CaSR mutation consistent with FHH. A 19-year-old female presented with a history of nephrolithiasis who underwent emergent caesarean section at 29 weeks of gestation for severe preeclampsia. At delivery, she was diagnosed with hypercalcemia with an inappropriately normal PTH and a CCCR of 2.67%, which fell to 0.88% during lactation. Parathyroidectomy cured her hypercalcemia. Pathology confirmed a parathyroid adenoma. Conclusion. These cases illustrate the influence of pregnancy and lactation on renal calcium indices, such as the CCCR. To avoid diagnostic error of women with hypercalcemia during pregnancy and lactation, calcium biochemistry of first-degree relatives and genetic testing of select patients are recommended. PMID- 27957352 TI - Nonislet Cell Tumor Hypoglycemia in a Patient with Adrenal Cortical Carcinoma. AB - Nonislet cell tumor hypoglycemia (NICTH) is a rare but serious paraneoplastic syndrome in which a tumor secretes incompletely processed precursors of insulin like growth factor-II (IGF-II), causing hypoglycemia. Here, we report an exceptional case of NICTH caused by nonfunctioning adrenocortical carcinoma in a 39-year-old male with recurrent hypoglycemia. The patient's serum IGF-II/IGF-I ratio had increased to 27.8. The serum level of the IGF-II/IGF-I ratio was normalized after removal of the tumor, and the hypoglycemic attacks no longer occurred after the operation. PMID- 27957353 TI - Short-Term PTH(1-34) Therapy in Children to Correct Severe Hypocalcemia and Hyperphosphatemia due to Hypoparathyroidism: Two Case Studies. AB - The standard treatment of hypoparathyroidism is to control hypocalcemia using calcitriol and calcium supplementation. However, in severe cases this approach is insufficient, and the risks of intravenous (i.v.) calcium administration and prolonged hospitalization must be considered. While the use of recombinant human parathyroid hormone 1-34 [rhPTH(1-34)] for long-term control of hypocalcemia has been established, the benefits of short-term rhPTH(1-34) treatment in children have not been explored. We report two patients with hypoparathyroidism treated with rhPTH(1-34). Patient 1 is a 10-year-old female with polyglandular autoimmune syndrome type 1. Patient 2 is a 12-year-old female with hypoparathyroidism after total thyroidectomy. Both patients showed poor response to i.v. and oral calcium and calcitriol, and patient 1 did not respond to phosphate binders. Patient 1 had rapid increase in serum calcium with a decrease in serum phosphate after a 3-day course of subcutaneous rhPTH(1-34). Patient 2 had normalization of calcium and phosphate levels after a 7-day course of rhPTH(1-34). These cases support a role for rhPTH(1-34) in the acute management of hypoparathyroidism in hospitalized patients to more rapidly correct hypocalcemia and hyperphosphatemia, shorten hospitalization, and reduce the need for frequent i.v. calcium boluses. PMID- 27957354 TI - Breast Cancer Metastasis to the Stomach That Was Diagnosed after Endoscopic Submucosal Dissection. AB - A 52-year-old woman presented with stage IIB primary breast cancer (cT2N1M0), which was treated using neoadjuvant chemotherapy (epirubicin, cyclophosphamide, and paclitaxel). However, the tumor persisted in patchy areas; therefore, we performed modified radical mastectomy and axillary lymph node dissection. Routine endoscopy at 8 months revealed a depressed lesion on the gastric angle's greater curvature, and histology revealed signet ring cell proliferation. We performed endoscopic submucosal dissection for gastric cancer, although immunohistochemistry revealed that the tumor was positive for estrogen receptor, mammaglobin, and gross cystic disease fluid protein-15 (E-cadherin-negative). Therefore, we revised the diagnosis to gastric metastasis from the breast cancer. PMID- 27957356 TI - Pneumomediastinum Secondary to Barotrauma after Recreational Nitrous Oxide Inhalation. AB - We present a case of a seventeen-year-old patient, admitted in the care of the surgical team following inhalation of nitrous oxide at high pressure, leading to extensive pneumomediastinum and surgical emphysema. We discuss the subsequent investigations and management for this patient. In the absence of history of airway injury and respiratory problems including asthma and with no oesophageal perforation on investigations, the diagnostic and management challenges encountered have been discussed which will help in future management of similar cases. PMID- 27957355 TI - A Case of Chronic Calcific Nonalcoholic Pancreatitis. AB - Tropical Calcific Pancreatitis (TCP) is a type of chronic calcific nonalcoholic pancreatitis. Similar to nonalcoholic chronic pancreatitis, it presents in the second and third decades of life; however this type is reported mostly in the developing tropical and subtropical countries. It is associated with the formation of pancreatic calculi and a high probability of developing insulin dependent diabetes mellitus. Epidemiologic studies have shown that these patients have an increased risk of developing pancreatic carcinoma. The etiology of TCP remains uncertain, with the current consensus suggesting genetics as well as possible toxicity from consuming large amounts of cassava, a tuber. Definite diagnosis of TCP requires younger age of onset, history of malnutrition, and presence of diabetes mellitus along with extensive pancreatic calcification and ductal calculi. When patients meet most but not all of these conditions the term Idiopathic Chronic Pancreatitis (ICP) is used. This is a case of a 44-year-old man who presented with most features seen in TCP, and however, was diagnosed with ICP. PMID- 27957357 TI - Total Body Irradiation without Chemotherapy as Conditioning for an Allogeneic Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia. AB - Current therapies for acute myeloid leukemia (AML), failing induction, are rarely effective. We report our experience in 4 patients with AML who received 16 Gy TBI prior to allogeneic hematopoietic cell transplantation (alloHCT), between June 2010 and May 2011. Patients were 20 to 55 years of age, 2 with relapsed disease and 2 with AML failing induction. An HLA-matched graft from related or unrelated donor was infused on day 0. All but one, who received a CD34+-selected graft, received methotrexate and tacrolimus +/- antithymocyte globulin, as GVHD prophylaxis. The other patient received tacrolimus alone. Neutrophil and platelet engraftment occurred at a median of 18 and 14 days, respectively. Patients were discharged at a median of 28 days. There were no unexpected toxicities in the first 30 days. One patient had cytomegalovirus (CMV) viremia and anorexia, at two months. One patient had grade 2 acute GVHD of the skin. One patient developed chronic GVHD of the eyes, mouth, skin, joints, and lung at 4 months. Two patients died from relapse of their leukemia at days 65 and 125. Two patients remain in remission beyond day 1500. 16 Gy TBI followed by an alloHCT for AML, failing induction, is feasible and tolerable. PMID- 27957358 TI - Bortezomib, Ifosfamide, Carboplatin, and Etoposide in a Patient with HIV-Negative Relapsed Plasmablastic Lymphoma. AB - Plasmablastic lymphoma (PBL) is a rare subtype of diffuse large B cell lymphoma (DLBCL), often associated with HIV infection. We present a case of a 53-year-old HIV-negative man with untreated hepatitis C viral infection who presented with abdominal pain and lymphadenopathy. Lymph node and bone marrow biopsies were consistent with plasmablastic lymphoma. He had partial response (PR) to 6 cycles of EPOCH but disease progressed seven weeks later. Repeat biopsy was consistent with plasmablastic lymphoma. Three cycles of bortezomib, ifosfamide, carboplatin, and etoposide (B-ICE) chemotherapy resulted in a partial response (PR). Five months later, he presented with widespread lymphadenopathy and tumor lysis syndrome with circulating blasts. Flow cytometry revealed a different population of lymphoma cells, this time positive for CD5, CD19, CD20, and CD22, with dim expression of CD45 and CD38. The patient died on the first day of ESHAP chemotherapy. There are no treatment recommendations or standard of care for plasmablastic lymphoma. A literature search yielded 10 cases in which bortezomib was administered in either HIV-positive or HIV-negative PBL. Six reported a partial response, 3 reported a complete response, and 1 was a near-complete response. Bortezomib, in combination with chemotherapy, may be an effective treatment option in PBL as reported here. PMID- 27957359 TI - Disseminated Cryptococcal Disease in Non-HIV, Nontransplant Patient. AB - Disseminated cryptococcal infection carries a high risk of morbidity and mortality. Typical patients include HIV individuals with advanced immunosuppression or solid organ or hematopoietic transplant recipients. We report a case of disseminated cryptococcal disease in a 72-year-old male who was immunocompromised with chronic lymphocytic leukemia and ongoing chemotherapy. The patient presented with a subacute history of constitutional symptoms and headache after he received five cycles of FCR chemotherapy (fludarabine/cyclophosphamide/rituximab). Diagnosis of disseminated cryptococcal disease was made based on fungemia in peripheral blood cultures with subsequent involvement of the brain, lungs, and eyes. Treatment was started with liposomal amphotericin, flucytosine, and fluconazole as induction. He was discharged after 4 weeks of hospitalization on high dose fluconazole for consolidation for 2 months, followed by maintenance therapy. PMID- 27957360 TI - Primary Cutaneous Actinomycosis along with the Surgical Scar on the Hand. AB - Primary cutaneous actinomycosis is a rare clinical form with variable presentation. The tumoral presentation of actinomycosis as pseudocarcinomatous or sarcomatous masses is completely rare. The management of cutaneous actinomycosis needs proper antibiotic treatment and surgical resection would not be adequate alone. Herein, we report a case of primary cutaneous actinomycosis on the dorsal surface of the hand as draining and infiltrated lesions along with the scar of previous tumor excision that had not received proper antibiotics after the surgery. PMID- 27957361 TI - Symptomatic Acute Hepatitis C Infection Following a Single Episode of Unprotected Sexual Intercourse. AB - A previously healthy 23-year-old MSM presented with jaundice, systemic upset, and rash 2 months after a single episode of unprotected sexual intercourse. Liver biochemistry was grossly deranged, with markedly elevated transaminases and hyperbilirubinaemia. Serology was positive for genotype 1a hepatitis C virus (HCV) and in the absence of other causes, acute HCV infection was suspected. He was subsequently successfully treated with pegylated interferon and ribavirin for 24 weeks and made a full clinical and biochemical recovery. PMID- 27957363 TI - Aseptic Meningitis Caused by Lassa Virus: Case Series Report. AB - The Lassa virus is known to cause disease in different organ systems of the human body, with varying clinical manifestations. The features of severe clinical disease may include bleeding and/or central nervous system manifestations. Whereas Lassa fever encephalopathy and encephalitis are well described in the literature, there is paucity of data on Lassa virus meningitis. We present the clinical description, laboratory diagnosis, and management of 4 consecutive cases of aseptic meningitis associated with Lassa virus infection without bleeding seen in a region of Nigeria known to be endemic for both the reservoir rodent and Lassa fever. The 4 patients recovered fully following intravenous ribavirin treatment and suffered no neurologic complications. PMID- 27957362 TI - Mycoplasma hominis Induces Mediastinitis after a Tonsillar Abscess. AB - Mycoplasma hominis is commonly involved in genitourinary tract infections. We report a 59-year-old man who developed a M. hominis-associated mediastinitis following acute tonsillar infection. PMID- 27957364 TI - A Case of a Gastrointestinal Stromal Tumor Diagnosed at the Postpartum Period. AB - Introduction. We discuss a rare gastrointestinal stromal tumor (GIST) case detected at the 10th postpartum week and we want to pay attention to the challenges and improvements in the diagnosis, surgery, chemotherapy, and follow up of this rare tumor accompanied with the review of the current literature. Case Presentation. A 32-year-old multiparous woman presented with abdominal swelling 10 weeks after her second vaginal birth. Abdominal examination revealed a mass starting from the pelvic level and extending to the right upper quadrant. Radiological examinations showed a solid, multiloculated, and hypervascular mass starting from the pelvis and extending to the transverse colon. En bloc mass with a 20 cm jejunal segment resection and a left pelvic side wall peritonectomy with omentectomy was performed. The pathologic examination revealed a high-risk GIST which originated from the jejunum and disseminated to the peritoneum. The patient has been given imatinib 400 mg/day since then. She did not reveal any progression during the 15-month follow-up postoperatively. Conclusion. GIST tumors are rare and there is not sufficient information in the literature regarding its management. In this patient having high risk GIST and GIST sarcomatosis we successfully treated the patient by surgery and adjuvant imatinib chemotherapy. PMID- 27957365 TI - Corrigendum to "Diagnosis and Treatment of Mucinous Appendiceal Neoplasm Presented as Acute Appendicitis". AB - [This corrects the article DOI: 10.1155/2016/2161952.]. PMID- 27957367 TI - Bimatoprost Induced Serous Macular Detachment after Cataract Surgery. AB - We report a case of bimatoprost induced serous macular detachment and choroidal folds following uneventful cataract surgery. A 66-year-old male using topical bimatoprost in both eyes for open angle glaucoma underwent uneventful cataract surgery in the right eye. Postoperatively, he was restarted on topical bimatoprost and antibiotic-steroids combination drops. One week after surgery, he presented with conjunctival hyperemia, serous macular detachment, and choroidal folds at the posterior pole. Fundus fluorescein angiography showed perifoveal leaks in early stage with pooling of dye in late stage. Discontinuation of bimatoprost led to resolution of serous detachment and choroidal folds within 3 weeks with significant improvement in visual acuity. Occurrence of serous macular detachment and choroidal folds in this case could be probably related to the proinflammatory property of bimatoprost. Hence, it should be used with caution in the immediate postoperative period after cataract surgery. PMID- 27957366 TI - Severe Corticosteroid-Induced Ocular Hypertension Requiring Bilateral Trabeculectomies in a Patient with Takayasu's Arteritis. AB - We present a rare case of severe corticosteroid-induced ocular hypertension (OHT) after prolonged systemic corticosteroid use in a young woman with Takayasu's arteritis. As she did not sufficiently respond to ocular antihypertensive therapies, bilateral enhanced trabeculectomies were required to normalize her intraocular pressures. The systemic side effects of corticosteroids are well known, yet steroid-induced OHT and glaucoma remain silent causes of ocular morbidity. This case highlights the importance of IOP-monitoring in visually asymptomatic patients on systemic corticosteroids. It further emphasizes the need to raise awareness of the potential ocular side effects of steroids amongst physicians, in particular those looking after patients with autoimmune and inflammatory diseases. PMID- 27957368 TI - Transnasal, Transethmoidal Endoscopic Removal of a Foreign Body in the Medial Extraconal Orbital Space. AB - Intraorbital foreign bodies are located within the orbit but outside the ocular globe. Though not uncommon, removal of these objects poses a challenge for surgeons. External approaches have been the most frequently used but are associated with increased complications and morbidity. An endoscopic endonasal approach can be an appropriate and less complicated technique in these cases. We report a case of a chronic intraorbital foreign body located within the medial extraconal space lateral to the lamina papyracea and behind the lacrimonasal duct, which was successfully removed using a transnasal, transethmoidal endoscopic technique. Neither postoperative complications nor ocular impairment was reported. The patient improved and remains asymptomatic. The transnasal transethmoidal endoscopic approach can be used as a safer and less invasive alternative when removing foreign bodies from the medial orbital compartment. PMID- 27957369 TI - Angiofibroma Originating outside the Nasopharynx: A Management Dilemma. AB - Background. Angiofibroma is a benign tumor, consisting of fibrous tissue with varying degrees of vascularity, characterized by proliferation of stellate and spindle cells around the blood vessels. It most commonly arises from the nasopharynx, although it may rarely arise in extranasopharyngeal sites. Case Report. A 46-year-old male presented with left side nasal obstruction and epistaxis for one month. Clinical nasal examination revealed left sided polypoidal mass arising from the vestibular region of the lateral nasal wall. Results. CT scan and MRI showed highly vascular soft tissue mass occupying the anterior part of the left nostril. Preoperative selective embolization followed by transnasal excision was performed. Histopathological examination confirmed the diagnoses of nasal vestibular angiofibroma. Conclusion. Extranasopharyngeal angiofibroma is a very rare pathology. It should be kept in mind as a differential diagnosis with any unilateral nasal vestibular mass causing nasal obstruction and epistaxis. A biopsy without further investigation can cause life threatening bleeding in the patient. PMID- 27957370 TI - Refractory Obstructive Sleep Apnea in a Patient with Diffuse Idiopathic Skeletal Hyperostosis. AB - Diffuse Idiopathic Skeletal Hyperostosis (DISH) can cause ossification of ligaments and may affect the spine. We report a case of obstructive sleep apnea in a patient with significant upper airway narrowing secondary to cervical DISH. This patient had an initial apnea-hypopnea index (AHI) of 145 events/hour and was treated with uvulopalatopharyngoplasty, genial tubercle advancement, hyoid suspension, septoplasty, inferior turbinoplasties, and radiofrequency ablations to the tongue base which reduced his AHI to 40 events/hour. He redeveloped symptoms, was started on positive airway pressure (PAP) therapy, and later underwent a maxillomandibular advancement which improved his AHI to 16.3 events/hour. A few years later his AHI was 100.4 events/hour. His disease has gradually progressed over time and he was restarted on PAP therapy. Despite PAP titration, years of using PAP therapy, and being 100 percent compliant for the past three months (average daily use of 7.6 hours/night), he has an AHI of 5.1 events/hour and has persistent hypersomnia with an Epworth Sleep Scale questionnaire score of 18/24. At this time he is pending further hypersomnia work up. DISH patients require prolonged follow-up to monitor the progression of disease, and they may require unconventional measures for adequate treatment of obstructive sleep apnea. PMID- 27957371 TI - A Rare Cause of Nasal Obstruction: Metastatic Renal Cell Carcinoma. AB - Introduction. Renal cell carcinoma can present with several interesting symptoms, paraneoplastic syndromes, and unusual metastatic sites. Head and neck region is one of the rare locations for renal cell carcinoma metastasis. Case Report. A 50 year-old man was admitted to the hospital with nasal congestion and snoring. Physical examination revealed nasal serous secretion. First taken biopsy was misinterpreted. The symptoms of the patient were not revealed and he was readmitted to the hospital. On radiologic examination, a vascular rich mass in maxillary sinus extending to the nasal cavity was observed. Biopsy was diagnosed as renal cell carcinoma metastasis. Herein, we present a patient with renal cell carcinoma presenting nasal obstruction and snoring as first and recurrent symptom. PMID- 27957372 TI - Nephroblastoma Arising from Primary Testicular Germ Cell Tumor: A Case Report and Literature Review. AB - Adult extrarenal nephroblastoma is a very rare tumor. Nephroblastoma arising from primary testicular germ cell tumor is exceedingly rare. To our knowledge, only three cases have been reported in the English literature. We report a case of a 19-year-old man who presented with a large right testicle. Image studies showed a large retroperitoneal mass along with liver and lung metastases. Orchiectomy demonstrated a mixed germ cell tumor composed of yolk sac tumor, embryonal carcinoma, and mature and immature teratoma with a significant portion of nephroblastoma. The patient received chemotherapy and no recurrence was noted during six months of followup. WT-1 expression was also studied due to the lack of consistency of its expression in testicular nephroblastoma in the literature. We also present a discussion and review of the literature due to its rarity, which indicate an adverse prognosis for patients with nephroblastoma components receiving standard chemotherapeutical regimes for testicular germ cell tumors. PMID- 27957373 TI - A Rare Case Report of Thoracic Ectopia Cordis: An Obstetrician's Point of View in Multidisciplinary Approach. AB - Ectopia cordis is a rare congenital anomaly associated with the heart positioned outside of the thoracic cavity either partially or completely. It can be associated with other congenital abnormalities. Overall, the prognosis for infants with ectopia cordis is very poor but depends greatly on the type and severity of ectopia cordis and intracardiac and associated malformations. We present one case of a fetus with prenatally diagnosed thoracic ectopia cordis with intracardiac defects and omphalocele, all the abnormalities seen in pentalogy of Cantrell except a diaphragmatic defect. Considering poor prognosis for fetus, conservative management of prenatal care has been chosen. At the 42nd gestational week, during the active stage of labor, due to fetal distress, cesarean section was performed at a tertiary level hospital. The condition of the infant was impairing rapidly and the newborn succumbed within 24 hours. We discuss the perinatal care concerning this rare anomaly. PMID- 27957374 TI - Two Different Life-Threatening Cases: Presenting with Torticollis. AB - Acquired torticollis can be the result of several different pathological mechanisms. It is generally related to trauma, tumors, and inflammatory processes of the cervical muscles, nerves, and vertebral synovia. Although upper respiratory tract and neck inflammation are common causes of acute febrile torticollis in children, diseases with as yet undefined relationships may also result in torticollis. This is the case of spinal arachnoid cyst and pneumonia. PMID- 27957375 TI - Cardiovascular Malformations in CHARGE Syndrome with DiGeorge Phenotype: Two Case Reports. AB - Both CHARGE syndrome and DiGeorge anomaly are frequently accompanied by cardiovascular malformations. Some specific cardiovascular malformations such as interrupted aortic arch type B and truncus arteriosus are frequently associated with 22q11.2 deletion syndrome, while conotruncal defects and atrioventricular septal defects are overrepresented in patients with CHARGE syndrome. CHD7 gene mutation is identified in approximately two-thirds of patients with CHARGE syndrome, and chromosomal microdeletion at 22q11.2 is found in more than 95% of patients with 22q11.2 deletion syndrome. CHARGE syndrome is occasionally accompanied by DiGeorge phenotype. We report two patients with dysmorphic features of both CHARGE syndrome and 22q11.2 deletion syndrome. Although both of the two cases did not have 22q11.2 deletion, they had typical dysmorphic features of 22q11.2 deletion syndrome including cardiovascular malformations such as interrupted aortic arch type B. They also had characteristic features of CHARGE syndrome including ear malformation, genital hypoplasia, limb malformation, and endocrinological disorders. CHD7 gene mutation was confirmed in one of the two cases. When a patient with cardiovascular malformations frequently associated with 22q11.2 deletion syndrome does not have 22q11.2 deletion, we suggest that associated malformations characteristic of CHARGE syndrome should be searched for. PMID- 27957376 TI - Case Report of a Child after Hematopoietic Cell Transplantation with Acute Aspergillus Tracheobronchitis as a Cause for Respiratory Failure. AB - Rapid respiratory failure due to invasive mycosis of the airways is an uncommon presentation of Aspergillus infection, even in immunocompromised patients, and very few pediatric cases have been reported. Patients with Aspergillus tracheobronchitis present with nonspecific symptoms, and radiologic studies are often noninformative, leading to a delay in diagnosis. Prompt initiation of adequate antifungal therapies is of utmost importance to improve outcome. We report the case of a 9-year-old girl with chronic myelogenous leukemia who developed respiratory distress 41 days after hematopoietic cell transplantation and rapidly deteriorated despite multiple interventions and treatment modalities. PMID- 27957377 TI - Rare Case of Posterior Reversible Leukoencephalopathy Syndrome Secondary to Acute Chest Syndrome. AB - We present a case of 29/m with a history of sickle cell disease who presented to the emergency department with sudden onset of chest, trunk, extremity, and back pain, consistent in quality and severity with the patient's usual pain crises. Soon after admission to the medical unit for acute chest syndrome (ACS), the patient developed sudden onset of hypertension associated with left sided hemiplegia, lethargy, dysarthria, aphasia, and left sided facial droop. Neuroimaging revealed that on MRI Brain there was multifocal extensive signal abnormality and a small focal areas of hemorrhage compatible with posterior reversible leukoencephalopathy syndrome (PRES). Patient was treated with levetiracetam and phenytoin and improved soon afterwards, with resolution seen on follow-up MRI two months later. PMID- 27957378 TI - Laparoscopic Repair of Morgagni Hernia: Three-Case Presentation and the Literature. AB - Introduction. Morgagni hernia is a rare form of congenital diaphragmatic hernia. Case Presentation. We present three cases of Morgagni hernia with GI symptoms treated by laparoscopic surgery. Discussion. Hernial sac was excised in two cases and left in situ in one case. There was no recurrence in symptoms after 30 months from surgery. PMID- 27957379 TI - Ollier's Disease of the Iliac Bone with Sacroiliac Joint Involvement in an Adolescent Patient. AB - Ollier's disease of the hip bone involving the sacroiliac joint has not yet been reported in the English-language literature in both the mature and immature skeletons. The authors present such a unique case in an adolescent girl that posed a significant diagnostic challenge secondary to the rarity of the lesion and atypical clinical picture. PMID- 27957380 TI - Palpable Mass on the Head after Minor Trauma. AB - Temporal artery is superficially exhibited and easily traumatized. Rarely, a minor and blunt trauma, especially in elderly who are under anticoagulants, can cause a pseudoaneurysm. Diagnosis should be based, primarily, on history and physical examination and secondarily on duplex ultrasound scanning which will lead to confirmation and preoperative planning. The therapeutical plan consists of surgical ligation and excision of the aneurysm. Surgery can be performed under local anesthesia with no postoperative major or minor complications. Endovascular approach consists of catheter embolization and remains a second option due to the risk of complications and the inconclusive results. On this review, authors present a case of an 80-year-old male with a pseudoaneurysm of superficial temporal artery. PMID- 27957381 TI - Errors and Predictors of Confidence in Condom Use amongst Young Australians Attending a Music Festival. AB - Objectives. To determine the confidence and ability to use condoms correctly and consistently and the predictors of confidence in young Australians attending a festival. Methods. 288 young people aged 18 to 29 attending a mixed-genre music festival completed a survey measuring demographics, self-reported confidence using condoms, ability to use condoms, and issues experienced when using condoms in the past 12 months. Results. Self-reported confidence using condoms was high (77%). Multivariate analyses showed confidence was associated with being male (P < 0.001) and having had five or more lifetime sexual partners (P = 0.038). Reading packet instructions was associated with increased condom use confidence (P = 0.011). Amongst participants who had used a condom in the last year, 37% had experienced the condom breaking and 48% had experienced the condom slipping off during intercourse and 51% when withdrawing the penis after sex. Conclusion. This population of young people are experiencing high rates of condom failures and are using them inconsistently or incorrectly, demonstrating the need to improve attitudes, behaviour, and knowledge about correct and consistent condom usage. There is a need to empower young Australians, particularly females, with knowledge and confidence in order to improve condom use self-efficacy. PMID- 27957382 TI - Study of the Antioxidant Property Variation of Cornelian Cherry Fruits during Storage Using HPTLC and Spectrophotometric Assays. AB - Cornus species fruits are well known as a rich source of antioxidant compounds responsible for their diverse health benefits. The present study aims to investigate the variation of the total antioxidant capacity of Cornelian cherry (Cornus mas L.) fruits during storage, using high-performance thin-layer chromatography (HPTLC) and two spectrophotometric assays based on different mechanisms: the 2,2-azinobis(3-ethylbenzothiazolyne-6-sulphonic acid) radical cation (ABTS+?) assay and the ferric reducing antioxidant power (FRAP) assay. The fruit extract was stored at room temperature (22 degrees C) for 19 days. No major differences in the total antioxidant capacity were observed during this period, indicating that storage does not have any deleterious effect on the antioxidant properties of the investigated fruits extract. The antioxidant capacity varied between 12.91 and 12.83 umol Trolox/g fruit as determined by the HPTLC method and from 36.13 to 33.93 umol Trolox/g fruit as determined by the ABTS assay. PMID- 27957383 TI - Direct Analysis in Real Time Mass Spectrometry for the Nondestructive Investigation of Conservation Treatments of Cultural Heritage. AB - Today the long-term conservation of cultural heritage is a big challenge: often the artworks were subjected to unknown interventions, which eventually were found to be harmful. The noninvasive investigation of the conservation treatments to which they were subjected to is a crucial step in order to undertake the best conservation strategies. We describe here the preliminary results on a quick and direct method for the nondestructive identification of the various interventions of parchment by means of direct analysis in real time (DART) ionization and high resolution time-of-flight mass spectrometry and chemometrics. The method has been developed for the noninvasive analysis of the Dead Sea Scrolls, one of the most important archaeological discoveries of the 20th century. In this study castor oil and glycerol parchment treatments, prepared on new parchment specimens, were investigated in order to evaluate two different types of operations. The method was able to identify both treatments. In order to investigate the effect of the ion source temperature on the mass spectra, the DART-MS analysis was also carried out at several temperatures. Due to the high sensitivity, simplicity, and no sample preparation requirement, the proposed analytical methodology could help conservators in the challenging analysis of unknown treatments in cultural heritage. PMID- 27957384 TI - Mitigating the Risk of Transfusion-Transmitted Dengue in Australia. AB - Dengue viruses (DENV 1-4) are a risk to transfusion safety, with several transfusion-transmitted (TT) cases reported globally. DENV 1-4 are endemic in over 100 countries, with seasonal outbreaks occurring in northeastern Australia. To mitigate TT-DENV risk in Australia, fresh blood components are not manufactured from donors returning from any area (domestic/overseas) with known dengue transmission. Alternatively, TT-DENV risk may be mitigated using an appropriate blood donor screening assay. We aimed to determine the rate of dengue infection in donors during dengue outbreaks in Australia. Plasma samples were collected from blood donors during local dengue outbreaks. All samples were tested for the presence of DENV RNA and selected samples were tested for DENV antigen (nonstructural protein 1, NS1) with two assays. No donors residing in high risk areas had detectable levels of DENV RNA or NS1 and no cases of DENV viremia were detected in blood donors residing in areas of Australia experiencing DENV outbreaks. Definitive conclusions could not be drawn from this study; however, the lack of detection of DENV RNA or antigen in donations suggests that the current risk of TT-DENV is low and maintaining the fresh component restriction for "at-risk" donors is appropriate. PMID- 27957386 TI - Ten genes and two topologies: an exploration of higher relationships in skipper butterflies (Hesperiidae). AB - Despite multiple attempts to infer the higher-level phylogenetic relationships of skipper butterflies (Family Hesperiidae), uncertainties in the deep clade relationships persist. The most recent phylogenetic analysis included fewer than 30% of known genera and data from three gene markers. Here we reconstruct the higher-level relationships with a rich sampling of ten nuclear and mitochondrial markers (7,726 bp) from 270 genera and find two distinct but equally plausible topologies among subfamilies at the base of the tree. In one set of analyses, the nuclear markers suggest two contrasting topologies, one of which is supported by the mitochondrial dataset. However, another set of analyses suggests mito-nuclear conflict as the reason for topological incongruence. Neither topology is strongly supported, and we conclude that there is insufficient phylogenetic evidence in the molecular dataset to resolve these relationships. Nevertheless, taking morphological characters into consideration, we suggest that one of the topologies is more likely. PMID- 27957385 TI - AR-12 Inhibits Chaperone Proteins Preventing Virus Replication and the Accumulation of Toxic Misfolded Proteins. PMID- 27957387 TI - Pests, diseases and crop protection practices in the smallholder sweetpotato production system of the highlands of Papua New Guinea. AB - Sweetpotato (Ipomea batatans) is a food crop of global significance. The storage roots and foliage of crop are attacked by a wide range of pests and diseases. Whilst these are generally well controlled in developed countries using approaches such as clean planting material and monitoring with pheromone traps to guide insecticide use, research into methods suitable for developing countries has lagged. In Papua New Guinea (PNG), sweetpotato is grown extensively as a subsistence crop and commercial production as a cash crop is developing. We report results from a survey of 33 smallholder producers located in the Highlands of PNG where the crop is of particular importance. Surveys of interviewees' crops showed high levels of pest and disease impact to foliage, stems and storage roots, especially in crops that were several years old. Weevils (Curculionidae) were reportedly the most damaging pests and scab (caused by the fungus Elisnoe batatus) the most damaging disease. Most producers reported root damage from the former and foliar damage from the latter but the general level of knowledge of pest and disease types was low. Despite the apparency of pest and disease signs and symptoms and recognition of their importance by farmers, a large majority of producers reported practiced no active pest or disease management. This was despite low numbers of farmers reporting use of traditional cultural practices including phytosanitary measures and insecticidal plants that had the scope for far wider use. Only one respondent reported use of insecticide though pesticides were available in nearby cities. This low level of pest and disease management in most cases, likely due to paucity in biological and technical knowledge among growers, hampers efforts to establish food security and constrains the development of sweetpotato as a cash crop. PMID- 27957388 TI - MicroRNA biogenesis pathway genes polymorphisms and cancer risk: a systematic review and meta-analysis. AB - MicroRNAs (miRNAs) may promote the development and progression of human cancers. Therefore, components of the miRNA biogenesis pathway may play critical roles in human cancer. Single nucleotide polymorphisms (SNPs) or mutations in genes involved in the miRNA biogenesis pathway may alter levels of gene expression, affecting disease susceptibility. Results of previous studies on genetic variants in the miRNA biogenesis pathway and cancer risk were inconsistent. Therefore, a meta-analysis is needed to assess the associations of these genetic variants with human cancer risk. We searched for relevant articles from PubMed, Web of Science, CNKI, and CBM through Jun 21, 2016. In total, 21 case-control articles met all of the inclusion criteria for the study. Significant associations were observed between cancer risk and the DGCR8polymorphism rs417309 G >A (OR 1.22, 95% CI [1.04-1.42]), as well as the DICER1 polymorphism rs1057035 TT (OR 1.13, 95% CI [1.05-1.22]). These SNPs exhibit high potential as novel diagnostic markers. Future studies with larger sample sizes and more refined analyses are needed to shed more light on these findings. PMID- 27957389 TI - Expression and characterization of thermostable glycogen branching enzyme from Geobacillus mahadia Geo-05. AB - The glycogen branching enzyme (EC 2.4.1.18), which catalyses the formation of alpha-1,6-glycosidic branch points in glycogen structure, is often used to enhance the nutritional value and quality of food and beverages. In order to be applicable in industries, enzymes that are stable and active at high temperature are much desired. Using genome mining, the nucleotide sequence of the branching enzyme gene (glgB) was extracted from the Geobacillus mahadia Geo-05 genome sequence provided by the Malaysia Genome Institute. The size of the gene is 2013 bp, and the theoretical molecular weight of the protein is 78.43 kDa. The gene sequence was then used to predict the thermostability, function and the three dimensional structure of the enzyme. The gene was cloned and overexpressed in E. coli to verify the predicted result experimentally. The purified enzyme was used to study the effect of temperature and pH on enzyme activity and stability, and the inhibitory effect by metal ion on enzyme activity. This thermostable glycogen branching enzyme was found to be most active at 55 degrees C, and the half-life at 60 degrees C and 70 degrees C was 24 h and 5 h, respectively. From this research, a thermostable glycogen branching enzyme was successfully isolated from Geobacillus mahadia Geo-05 by genome mining together with molecular biology technique. PMID- 27957390 TI - Harmine stimulates proliferation of human neural progenitors. AB - Harmine is the beta-carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin positive) derived from pluripotent stem cells. After 4 days of treatment, the pool of proliferating hNPCs increased by 71.5%. Harmine has been reported as a potent inhibitor of the dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A), which regulates cell proliferation and brain development. We tested the effect of analogs of harmine, an inhibitor of DYRK1A (INDY), and an irreversible selective inhibitor of monoamine oxidase (MAO) but not DYRK1A (pargyline). INDY but not pargyline induced proliferation of hNPCs similarly to harmine, suggesting that inhibition of DYRK1A is a possible mechanism to explain harmine effects upon the proliferation of hNPCs. Our findings show that harmine enhances proliferation of hNPCs and suggest that inhibition of DYRK1A may explain its effects upon proliferation in vitro and antidepressant effects in vivo. PMID- 27957391 TI - The unique deep sea-land connection: interactive 3D visualization and molecular phylogeny of Bathyhedyle boucheti n. sp. (Bathyhedylidae n. fam.)-the first panpulmonate slug from bathyal zones. AB - The deep sea comprises vast unexplored areas and is expected to conceal significant undescribed invertebrate species diversity. Deep waters may act as a refuge for many relictual groups, including elusive and enigmatic higher taxa, but the evolutionary pathways by which colonization of the deep sea has occurred have scarcely been investigated. Sister group relationships between shallow water and deep sea taxa have been documented in several invertebrate groups, but are unknown between amphibious/terrestrial and deep-sea species. Here we describe in full and interactive 3D morphoanatomical detail the new sea slug species Bathyhedyle boucheti n. sp., dredged from the continental slope off Mozambique. Molecular and morphological analyses reveal that it represents a novel heterobranch gastropod lineage which we establish as the new family Bathyhedylidae. The family is robustly supported as sister to the recently discovered panpulmonate acochlidian family Aitengidae, which comprises amphibious species living along the sea shore as well as fully terrestrial species. This is the first marine-epibenthic representative among hedylopsacean Acochlidiida, the first record of an acochlidian from deep waters and the first documented panpulmonate deep-sea slug. Considering a marine mesopsammic ancestor, the external morphological features of Bathyhedyle n. gen. may be interpreted as independent adaptations to a benthic life style in the deep sea, including the large body size, broad foot and propodial tentacles. Alternatively, the common ancestor of Bathyhedylidae and Aitengidae may have been a macroscopic amphibious or even terrestrial species. We hypothesize that oophagy in the common ancestor of Aitengidae and Bathyhedylidae might explain the impressive ecological and evolutionary flexibility in habitat choice in the Acochlidiida. PMID- 27957392 TI - Identification of canine papillomavirus by PCR in Greyhound dogs. AB - BACKGROUND: Corns are hard protuberances that occur on the digital footpads of Greyhound dogs. The cause of these lesions is unknown and there is little information about them in the veterinary literature. We received anecdotal examples of dog to dog spread of corns suggesting an infectious cause. The aim of this study was to determine if papillomavirus (PV) is associated with Greyhound corns. METHODS: We examined four corns from two unrelated adult Greyhound dogs that resided in Florida and Washington, respectively, for PV by PCR. The samples were obtained by owner coring of two lesions from one dog and laser removal of two lesions from the other dog. Total nucleic acid was extracted and DNA was amplified using two PCR primer sets that have been shown to amplify a broad range of PVs from humans and animals: FAP59/ FAP64 and MY11/ MY09. The DNA sequences were compared with all sequences in GenBank. Formalin-fixed, paraffin-embedded tissue from the footpads of four dogs with other inflammatory dermatoses were also examined. RESULTS: PV DNA was amplified from all four corn lesions, while no PV DNA was amplified from other tissues. Comparison of the 444-bp sequences amplified by the MY11/ MY09 primers identified two different PVs. One showed 96% nucleotide sequence similarity with the L1 gene of canine PV type 12. The other showed 78% similarity to canine PV type 16 and, therefore, represents a novel PV. In one of the corns, infection by two of the identified PVs was found. DISCUSSION: These results suggest PV infection could be involved in the pathogenesis of corns in Greyhound dogs. PMID- 27957394 TI - Perception of color emotions for single colors in red-green defective observers. AB - It is estimated that inherited red-green color deficiency, which involves both the protan and deutan deficiency types, is common in men. For red-green defective observers, some reddish colors appear desaturated and brownish, unlike those seen by normal observers. Despite its prevalence, few studies have investigated the effects that red-green color deficiency has on the psychological properties of colors (color emotions). The current study investigated the influence of red green color deficiency on the following six color emotions: cleanliness, freshness, hardness, preference, warmth, and weight. Specifically, this study aimed to: (1) reveal differences between normal and red-green defective observers in rating patterns of six color emotions; (2) examine differences in color emotions related to the three cardinal channels in human color vision; and (3) explore relationships between color emotions and color naming behavior. Thirteen men and 10 women with normal vision and 13 men who were red-green defective performed both a color naming task and an emotion rating task with 32 colors from the Berkeley Color Project (BCP). Results revealed noticeable differences in the cleanliness and hardness ratings between the normal vision observers, particularly in women, and red-green defective observers, which appeared mainly for colors in the orange to cyan range, and in the preference and warmth ratings for colors with cyan and purple hues. Similarly, naming errors also mainly occurred in the cyan colors. A regression analysis that included the three cone contrasts (i.e., red-green, blue-yellow, and luminance) as predictors significantly accounted for variability in color emotion ratings for the red green defective observers as much as the normal individuals. Expressly, for warmth ratings, the weight of the red-green opponent channel was significantly lower in color defective observers than in normal participants. In addition, the analyses for individual warmth ratings in the red-green defective group revealed that luminance cone-contrast was a significant predictor in most red-green defective individuals. Together, these results suggest that red-green defective observers tend to rely on the blue-yellow channel and luminance to compensate for the weak sensitivity of long- and medium-wavelength (L-M) cone-contrasts, when rating color warmth. PMID- 27957393 TI - Stress responses of the oil-producing green microalga Botryococcus braunii Race B. AB - Plants react to biotic and abiotic stresses with a variety of responses including the production of reactive oxygen species (ROS), which may result in programmed cell death (PCD). The mechanisms underlying ROS production and PCD have not been well studied in microalgae. Here, we analyzed ROS accumulation, biomass accumulation, and hydrocarbon production in the colony-forming green microalga Botryococcus braunii in response to several stress inducers such as NaCl, NaHCO3, salicylic acid (SA), methyl jasmonate, and acetic acid. We also identified and cloned a single cDNA for the B. braunii ortholog of the Arabidopsis gene defender against cell death 1 (DAD1), a gene that is directly involved in PCD regulation. The function of B. braunii DAD1 was assessed by a complementation assay of the yeast knockout line of the DAD1 ortholog, oligosaccharyl transferase 2. Additionally, we found that DAD1 transcription was induced in response to SA at short times. These results suggest that B. braunii responds to stresses by mechanisms similar to those in land plants and other organisms. PMID- 27957395 TI - Aging and cardiovascular complexity: effect of the length of RR tachograms. AB - As we age, our hearts undergo changes that result in a reduction in complexity of physiological interactions between different control mechanisms. This results in a potential risk of cardiovascular diseases which are the number one cause of death globally. Since cardiac signals are nonstationary and nonlinear in nature, complexity measures are better suited to handle such data. In this study, three complexity measures are used, namely Lempel-Ziv complexity (LZ), Sample Entropy (SampEn) and Effort-To-Compress (ETC). We determined the minimum length of RR tachogram required for characterizing complexity of healthy young and healthy old hearts. All the three measures indicated significantly lower complexity values for older subjects than younger ones. However, the minimum length of heart-beat interval data needed differs for the three measures, with LZ and ETC needing as low as 10 samples, whereas SampEn requires at least 80 samples. Our study indicates that complexity measures such as LZ and ETC are good candidates for the analysis of cardiovascular dynamics since they are able to work with very short RR tachograms. PMID- 27957396 TI - Selective enhancement of attentional networks in college table tennis athletes: a preliminary investigation. AB - The purpose of the study was to investigate the characteristics of the attentional network in college table tennis athletes. A total of 65 college students categorized as table tennis athlete group or non-athlete group participated in the study. All participants completed the attentional network test (ANT) which measured the alerting, orienting and executive control networks. The results showed a significant difference between the athlete and non-athlete group for executive control network (p < 0.01), while no differences were observed for alerting (p > 0.05) or orienting (p > 0.05) networks. These results combined suggest that college table tennis athletes exhibited selectively enhanced executive control of attentional networks. PMID- 27957397 TI - Validation of internal reference genes for relative quantitation studies of gene expression in human laryngeal cancer. AB - BACKGROUND: The aim of this study was to determine the expression stabilities of 12 common internal reference genes for the relative quantitation analysis of target gene expression performed by reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) in human laryngeal cancer. METHODS: Hep-2 cells and 14 laryngeal cancer tissue samples were investigated. The expression characteristics of 12 internal reference gene candidates (18S rRNA, GAPDH, ACTB, HPRT1, RPL29, HMBS, PPIA, ALAS1, TBP, PUM1, GUSB, and B2M) were assessed by RT qPCR. The data were analyzed by three commonly used software programs: geNorm, NormFinder, and BestKeeper. RESULTS: The use of the combination of four internal reference genes was more appropriate than the use of a single internal reference gene. The optimal combination was PPIA + GUSB + RPL29 + HPRT1 for both the cell line and tissues; while the most appropriate combination was GUSB + RPL29 + HPRT1 + HMBS for the tissues. CONCLUSIONS: Our recommended internal reference genes may improve the accuracy of relative quantitation analysis of target gene expression performed by the RT-qPCR method in further gene expression research on laryngeal tumors. PMID- 27957399 TI - Shallow water sea slugs (Gastropoda: Heterobranchia) from the northwestern coast of the Sea of Japan, north of Peter the Great Bay, Russia. AB - The coast of northern Primorye region, north of Peter the Great Bay has been sparsely studied in regards to its molluscan fauna, with just a few works reviewing the distribution of local mollusks. This work presents a survey of the shallow water heterobranch sea slugs currently occurring around Kievka Bay to Oprichnik Bay, Russia. Thirty-nine species of sea slugs were found in this study and the new species Cadlina olgae sp. nov., described herein. Most (24) of the species occurring in the area have widespread ranges in the northern Pacific Ocean. The eight species are endemic for the Sea of Japan and adjacent part of the Sea of Okhotsk. Seven other occur also in northern Atlantic and Arctic waters. Thirteen found species are not known from Peter the Great Bay but known from adjacent northern Pacific waters. The finding of a previously undescribed species emphasizes the need of further surveys, particularly in subtidal and deeper waters, in order to improve the knowledge on this neglected fauna in Primorye. PMID- 27957398 TI - Multiple-file vs. single-file endodontics in dental practice: a study in routine care. AB - BACKGROUND: Little is known about the differences of rotary multiple file endodontic therapy and single-file reciprocating endodontic treatment under routine care conditions in dental practice. This multicenter study was performed to compare the outcome of multiple-file (MF) and single-file (SF) systems for primary root canal treatment under conditions of general dental practice regarding reduction of pain with a visual analogue scale (VAS 100), improvement of oral-health-related quality of life (OHRQoL) with the german short version of the oral health impact profile (OHIP-G-14) and the speed of root canal preparation. MATERIALS AND METHODS: Ten general dental practitioners (GDPs) participated in the study as practitioner-investigators (PI). In the first five month period of the study, the GDPs treated patients with MF systems. After that, the GDPs treated the patients in the second five-month period with a SF system (WaveOne). The GDPs documented the clinical findings at the beginning and on completion of treatment. The patients documented their pain and OHRQoL before the beginning and before completion of treatment. RESULTS: A total of 599 patients were included in the evaluation. 280 patients were in the MF group, 319 were in the SF WaveOne group. In terms of pain reduction and improvement in OHIP-G-14, the improvement in both study groups (MF and SF) was very similar based on univariate analysis methods. Pain reduction was 34.4 (SD 33.7) VAS (MF) vs. 35.0 (SD 35.4) VAS (SF) (p = 0.840) and the improvement in OHIP-G-14 score was 9.4 (SD 10.3) (MF) vs. 8.5 (SD 10.2) (SF) (p = 0.365). The treatment time per root canal was 238.9 s (SD 206.2 s) (MF) vs. 146.8 sec. (SD 452.8 sec) (SF) (p = 0.003). DISCUSSION: Regarding improvement of endodontic pain and OHRQoL measure with OHIP G-14, there were no statistical significant differences between the SF und the MF systems. WaveOne-prepared root canals significantly faster than MF systems. PMID- 27957400 TI - Meta-analysis reveals that seed-applied neonicotinoids and pyrethroids have similar negative effects on abundance of arthropod natural enemies. AB - BACKGROUND: Seed-applied neonicotinoids are widely used in agriculture, yet their effects on non-target species remain incompletely understood. One important group of non-target species is arthropod natural enemies (predators and parasitoids), which contribute considerably to suppression of crop pests. We hypothesized that seed-applied neonicotinoids reduce natural-enemy abundance, but not as strongly as alternative insecticide options such as soil- and foliar-applied pyrethroids. Furthermore we hypothesized that seed-applied neonicotinoids affect natural enemies through a combination of toxin exposure and prey scarcity. METHODS: To test our hypotheses, we compiled datasets comprising observations from randomized field studies in North America and Europe that compared natural-enemy abundance in plots that were planted with seed-applied neonicotinoids to control plots that were either (1) managed without insecticides (20 studies, 56 site-years, 607 observations) or (2) managed with pyrethroid insecticides (eight studies, 15 site years, 384 observations). Using the effect size Hedge's d as the response variable, we used meta-regression to estimate the overall effect of seed-applied neonicotinoids on natural-enemy abundance and to test the influence of potential moderating factors. RESULTS: Seed-applied neonicotinoids reduced the abundance of arthropod natural enemies compared to untreated controls (d = -0.30 +/- 0.10 [95% confidence interval]), and as predicted under toxin exposure this effect was stronger for insect than for non-insect taxa (QM = 8.70, df = 1, P = 0.003). Moreover, seed-applied neonicotinoids affected the abundance of arthropod natural enemies similarly to soil- or foliar-applied pyrethroids (d = 0.16 +/- 0.42 or 0.02 +/- 0.12; with or without one outlying study). Effect sizes were surprisingly consistent across both datasets (I2 = 2.7% for no-insecticide controls; I2 = 0% for pyrethroid controls), suggesting little moderating influence of crop species, neonicotinoid active ingredients, or methodological choices. DISCUSSION: Our meta-analysis of nearly 1,000 observations from North American and European field studies revealed that seed-applied neonicotinoids reduced the abundance of arthropod natural enemies similarly to broadcast applications of pyrethroid insecticides. These findings suggest that substituting pyrethroids for seed-applied neonicotinoids, or vice versa, will have little net affect on natural enemy abundance. Consistent with previous lab work, our results also suggest that seed-applied neonicotinoids are less toxic to spiders and mites, which can contribute substantially to biological control in many agricultural systems. Finally, our ability to interpret the negative effect of neonicotinoids on natural enemies is constrained by difficulty relating natural enemy abundance to biological control function; this is an important area for future study. PMID- 27957401 TI - Bamboo tea: reduction of taxonomic complexity and application of DNA diagnostics based on rbcL and matK sequence data. AB - BACKGROUND: Names used in ingredient lists of food products are trivial and in their nature rarely precise. The most recent scientific interpretation of the term bamboo (Bambusoideae, Poaceae) comprises over 1,600 distinct species. In the European Union only few of these exotic species are well known sources for food ingredients (i.e., bamboo sprouts) and are thus not considered novel foods, which would require safety assessments before marketing of corresponding products. In contrast, the use of bamboo leaves and their taxonomic origin is mostly unclear. However, products containing bamboo leaves are currently marketed. METHODS: We analysed bamboo species and tea products containing bamboo leaves using anatomical leaf characters and DNA sequence data. To reduce taxonomic complexity associated with the term bamboo, we used a phylogenetic framework to trace the origin of DNA from commercially available bamboo leaves within the bambusoid subfamily. For authentication purposes, we introduced a simple PCR based test distinguishing genuine bamboo from other leaf components and assessed the diagnostic potential of rbcL and matK to resolve taxonomic entities within the bamboo subfamily and tribes. RESULTS: Based on anatomical and DNA data we were able to trace the taxonomic origin of bamboo leaves used in products to the genera Phyllostachys and Pseudosasa from the temperate "woody" bamboo tribe (Arundinarieae). Currently available rbcL and matK sequence data allow the character based diagnosis of 80% of represented bamboo genera. We detected adulteration by carnation in four of eight tea products and, after adapting our objectives, could trace the taxonomic origin of the adulterant to Dianthus chinensis (Caryophyllaceae), a well known traditional Chinese medicine with counter indications for pregnant women. PMID- 27957402 TI - The relationship between cannabis use and measures of anxiety and depression in a sample of college campus cannabis users and non-users post state legalization in Colorado. AB - As part of an ongoing research program into the relationship between cannabis use and emotion processing, participants were assessed on their level of cannabis exposure using the Recreational Cannabis Use Examination, a measure developed specifically to assess cannabis use in Colorado post state legalization. Three groups were created based on self-reported use: a control group who have never used, a casual user group and a chronic user group. Each participant also completed two measures of mood assessment, the Center for Epidemiologic Studies Depression Scale and the State-Trait Anxiety Inventory. Relationships between cannabis use groups and scores on these measures were then analyzed using both correlations and multivariate analysis of variance. Results indicate a relationship between casual cannabis use and scoring highly for depressive symptomatology on the Center for Epidemiologic Studies Depression Scale. There were no significant relationships between cannabis use and scores on the State Trait Anxiety Inventory. PMID- 27957403 TI - The effects of the gender-culture interaction on self-reports of depressive symptoms: cross-cultural study among Egyptians and Canadians. AB - PURPOSE: Research in depression has revealed differences in the way depressed individuals across cultures report their symptoms. This literature also points to possible differences in symptom reporting patterns between men and women. Using data from a larger dataset (Beshai et al. 2016), the current study examined whether non-depressed and depressed Egyptian and Canadian men and women differed in their self-report of the various domains of the Beck Depression Inventory -II (BDI-II). METHOD: We recruited a total of 131 depressed and non-depressed participants from both Egypt (n = 29 depressed; n = 29 non-depressed) and Canada (n = 35 depressed; n = 38 non-depressed). Depression status was ascertained using a structured interview. All participants were asked to complete the BDI-II along with other self-report measures of depression. BDI-II items were divided into two subscales in accordance with Dozois, Dobson & Ahnberg (1998) factor analysis: cognitive-affective and somatic-vegetative subscales. RESULTS: We found a significant three-way interaction effect on the cognitive-affective (F(1,121) = 9.51, p = .003) and main effect of depression status on somatic-vegetative subscales (F(1,121) = 42.80, p < .001). Post hoc analyses revealed that depressed Egyptian men reported lower scores on the cognitive-affective subscale of the BDI II compared to their depressed Canadian male counterparts. CONCLUSIONS: These results suggest that males across cultures may differentially report cognitive symptoms of depression. These results also suggest that clinicians and clinical scientists need to further examine the interaction effect of culture and gender when investigating self-reported symptoms of depression. PMID- 27957404 TI - Effects of Real-World Versus Virtual Environments on Joint Excursions in Full Body Reaching Tasks. AB - Starting from an upright standing posture and reaching for a target that requires some forward bending of the trunk can involve many different configurations of the trunk and limb segments. We sought to determine if configurations of the limb and trunk segments during our standardized full-body reaching tasks were influenced by the visual environment. This paper examined movement patterns of healthy participants ([Formula: see text], eight female and nine male) performing full body reaching tasks to: 1) real-world targets; 2) virtual targets presented on a 3-D television; and 3) virtual targets presented using a head-mounted display. For reaches performed in the virtual world, the avatar was presented from a third-person perspective for the 3-D television and from a first-person perspective for the head-mounted display. Reaches to virtual targets resulted in significantly greater excursions of the ankle, knee, hip, spine, and shoulder compared with reaches made to real-world targets. This resulted in significant differences in the forward and downward displacements of the whole-body center of mass between the visual environments. Visual environment clearly influences how subjects perform full-body reaching tasks to static targets. Because a primary goal of virtual reality within rehabilitation is often to restore movement following orthopedic or neurologic injury, it is important to understand how visual environment will affect motor behavior. The present findings suggest that the existing game systems that track and present avatars from a third-person perspective elicit significantly different motor behavior when compared with the same tasks being presented from a first-person perspective. PMID- 27957405 TI - Smart Helmet: Wearable Multichannel ECG and EEG. AB - Modern wearable technologies have enabled continuous recording of vital signs, however, for activities such as cycling, motor-racing, or military engagement, a helmet with embedded sensors would provide maximum convenience and the opportunity to monitor simultaneously both the vital signs and the electroencephalogram (EEG). To this end, we investigate the feasibility of recording the electrocardiogram (ECG), respiration, and EEG from face-lead locations, by embedding multiple electrodes within a standard helmet. The electrode positions are at the lower jaw, mastoids, and forehead, while for validation purposes a respiration belt around the thorax and a reference ECG from the chest serve as ground truth to assess the performance. The within-helmet EEG is verified by exposing the subjects to periodic visual and auditory stimuli and screening the recordings for the steady-state evoked potentials in response to these stimuli. Cycling and walking are chosen as real-world activities to illustrate how to deal with the so-induced irregular motion artifacts, which contaminate the recordings. We also propose a multivariate R-peak detection algorithm suitable for such noisy environments. Recordings in real-world scenarios support a proof of concept of the feasibility of recording vital signs and EEG from the proposed smart helmet. PMID- 27957406 TI - Oxyhydroxy Silicate Colloids: A New Type of Waterborne Actinide(IV) Colloids. AB - At the near-neutral and reducing aquatic conditions expected in undisturbed ore deposits or in closed nuclear waste repositories, the actinides Th, U, Np, and Pu are primarily tetravalent. These tetravalent actinides (AnIV) are sparingly soluble in aquatic systems and, hence, are often assumed to be immobile. However, AnIV could become mobile if they occur as colloids. This review focuses on a new type of AnIV colloids, oxyhydroxy silicate colloids. We herein discuss the chemical characteristics of these colloids and the potential implication for their environmental behavior. The binary oxyhydroxy silicate colloids of AnIV could be potentially more mobile as a waterborne species than the well-known mono component oxyhydroxide colloids. PMID- 27957407 TI - Immobilization of Cellulase on Magnetic Nanocarriers. AB - The constant increase in the number of sustainable products on the global markets demands new biotechnological processing strategies such as the purification and recovery of biocatalysts. Superparamagnetic iron oxide nanoparticles exhibit excellent recovery properties as carrier materials in enzyme catalysis. We present the simple and fast electrostatic assembly of cellulase (CEL) and low priced silica-coated magnetic nanoparticles, which demonstrates stable enzyme bonding and excellent colloidal stability. The high CEL loading (0.43 g g-1), without leaching of biocatalyst and high recovery yields (75 %), could be sustained over ten magnetic recycling steps. The highlight of this study is the preservation of a high enzymatic activity and, therefore, the outstandingly high lifecycle stability. PMID- 27957408 TI - New Synthesis of Gold- and Silver-Based Nano-Tetracycline Composites. AB - A new synthetic methodology of water-soluble gold and silver nanoparticles (AuNPs@TC and AgNPs@TC), using the antibiotic tetracycline (TC) as co-reducing and stabilizing agent, is reported. Both colloids exhibit high water stability. The average sizes obtained were 25+/-10 and 15+/-5 nm, respectively. Both composites were tested against TC-resistant bacteria, presenting an increasing antibacterial effect in the case of AgNPs@TC. The sensing towards metal ions was also explored. An interesting and reversible affinity of AuNPs@TC towards AlIII cations in an aqueous system was also observed. PMID- 27957409 TI - Community health center patients' response to and beliefs about outreach promoting clinical preventive services. AB - We sought community health center (CHC) patients' feedback regarding an outreach intervention promoting primary prevention of cardiovascular disease to patients at increased risk. We performed a telephone survey that assessed whether patients recalled receiving the intervention, what actions occurred in response to the intervention, and patient attitudes regarding receipt of preventive service messages from their CHC. Participants (n = 80) were 89% male, and 59% were black. Among the 88% of respondents who reported a healthcare visit, 84% reported a discussion about cholesterol or heart disease risk with their provider, of these 44% reported a statin was recommended and 89% reported currently taking it. Participants reported high acceptability of receiving preventive service messages, but were less likely to agree that they wanted to receive preventive service messages via text or email compared to other modes of contact. Our results show that outreach programs to promote indicated preventive services were viewed positively by this patient group. We also identified areas where the CVD prevention program may have lost effectiveness. PMID- 27957410 TI - Community to clinic navigation to improve diabetes outcomes. AB - Rural residents experience rates of Type 2 Diabetes Mellitus (T2DM) that are considerably higher than their urban or suburban counterparts. Two primary modifiable factors, self-management and formal clinical management, have potential to greatly improve diabetes outcomes. "Community to Clinic Navigation to Improve Diabetes Outcomes," is the first known randomized clinical trial pilot study to test a hybrid model of diabetes self-management education plus clinical navigation among rural residents with T2DM. Forty-one adults with T2DM were recruited from two federally qualified health centers in rural Appalachia from November 2014-January 2015. Community health workers provided navigation, including helping participants understand and implement a diabetes self management program through six group sessions and, if needed, providing assistance in obtaining clinic visits (contacting providers' offices for appointments, making reminder calls, and facilitating transportation and dependent care). Pre and post-test data were collected on T2DM self-management, physical measures, demographics, psychosocial factors, and feasibility (cost, retention, and satisfaction). Although lacking statistical significance, some outcomes indicate trends in positive directions, including diet, foot care, glucose monitoring, and physical health, including decreased HbA1c and triglyceride levels. Process evaluations revealed high levels of satisfaction and feasibility. Due to the limited intervention dose, modest program expenditures (~$29,950), and a severely affected population most of whom had never received diabetes education, outcomes were not as robust as anticipated. Given high rates of satisfaction and retention, this culturally appropriate small group intervention holds promise for hard to reach rural populations. Modifications should include expanded recruitment venues, sample size, intervention dosage and longer term assessment. PMID- 27957411 TI - The contribution of the USDA school breakfast and lunch program meals to student daily dietary intake. AB - In the United States, the National School Breakfast (SBP) and School Lunch Program (NSLP) meals are provided for free or at a reduced price to eligible children, and are a nutrition safety net for low income children. Consuming both meals could provide 58% of daily intake. This paper evaluates the contribution of SBP and NSLP meals to the dietary intakes of 5-18 year old children participating in the National Health and Nutrition Examination Surveys (NHANES) from 2007 through 2012. The participants completed 24-hour dietary recalls. Least-square means and standard errors of the mean for energy and food group intakes for the total day and by school meal, and the percent of daily energy and food groups contributed by school meals were computed by analysis of covariance, with BMI, ethnicity, sex, age and poverty level as covariates. Of the 7800 participating children aged 5-18 years in the entire dataset, 448 consumed both SBP-NSLP meals on a weekday. Almost one-half (47%) of the day's energy intake was provided by the two school meals. For the major food groups, the contribution of school meals ranged from between 40.6% for vegetables to 77.1% for milk. Overall, these results provide important information on contribution of the SBP and NSLP meals to low income children's daily dietary intake. PMID- 27957412 TI - Interleukin-6 signaling in podocyte hypertrophy. PMID- 27957413 TI - Diagnosis and treatment of patients with IgA nephropathy in Japan. AB - Chronic kidney disease (CKD) is a worldwide public health problem that affects millions of people from all racial and ethnic groups. Although CKD is not one specific disease, it is a comprehensive syndrome that includes IgA nephropathy. As reported by the Japanese Society of Nephrology, 13.0 million people have CKD. In Japan, major causes of end-stage kidney disease are type 2 diabetic nephropathy, chronic glomerulonephritis, especially IgA nephropathy, hypertensive nephrosclerosis, and polycystic kidney disease. IgA nephropathy is characterized by polymeric IgA1 with aberrant galactosylation (galactose-deficient IgA1) increased in the blood and deposited in the glomerular mesangial areas, as well as partially in the capillary walls. The tonsils are important as one of the responsible regions in this disease. The clarification of the mechanism of galactose-deficient IgA1 production will pave the way for the development of novel therapies. The results of future research are eagerly awaited. At present, the most important therapeutic goals in patients with IgA nephropathy are the control of hypertension, the decrease of urinary protein excretion, and the inhibition of progression to end-stage kidney disease. Several investigators have reported that renin-angiotensin-aldosterone system inhibitors reduce levels of urinary protein excretion and preserve renal function in patients with IgA nephropathy. In Japan, tonsillectomy and steroid pulse therapy are more effective for patients with IgA nephropathy. PMID- 27957414 TI - Current characteristics of dialysis therapy in Korea: 2015 registry data focusing on elderly patients. AB - Because of increases in the elderly population and diabetic patients, the proportion of elderly among dialysis patients has rapidly increased during the last decades. The mortality and morbidity of these elderly dialysis patients are obviously much higher than those of young patients, but large analytic studies about elderly dialysis patients' characteristics have rarely been published. The registry committee of the Korean Society of Nephrology has collected data about dialysis therapy in Korea through an Internet online registry program and analyzed the characteristics. A survey on elderly dialysis patients showed that more than 50% of elderly (65 years and older) patients had diabetic nephropathy as the cause of end-stage renal disease, and approximately 21% of elderly dialysis patients had hypertensive nephrosclerosis. The proportion of elderly hemodialysis (HD) patients with native vessel arteriovenous fistula as vascular access for HD was lower than that of young (under 65 years) HD patients (69% vs. 80%). Although the vascular access was poor and small surface area dialyzers were used for the elderly HD patients, the dialysis adequacy data of elderly patients were better than those of young patients. The laboratory data of elderly dialysis patients were not very different from those of young patients, but poor nutrition factors were observed in the elderly dialysis patients. Although small surface area dialyzers were used for elderly HD patients, the urea reduction ratio and Kt/V were higher in elderly HD patients than in young patients. PMID- 27957415 TI - The role of local IL6/JAK2/STAT3 signaling in high glucose-induced podocyte hypertrophy. AB - BACKGROUND: Interleukin-6 (IL6) is an important regulator of cellular hypertrophy through the gp130/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway. We tested the hypothesis that IL6 and its downstream gp130/JAK2/STAT3 pathway participated in high glucose (HG)-induced podocyte hypertrophy. METHODS: IL6 levels in the media and lysates of podocytes were measured by enzyme-linked immunosorbent assay. Western blots were performed to determine the protein expression levels of gp130/JAK2/STAT3 among podocytes cultured with normal glucose (NG), NG + mannitol, NG + recombinant IL6, HG, and HG + IL6-neutralizing antibodies (IL6NAb). Immunoprecipitation was examined to determine whether gp130 interacted with JAK2 in response to HG or IL6. Podocyte hypertrophy was verified using protein/cell counts and flow cytometry. RESULTS: IL6 levels were significantly increased in the media and lysates of podocytes cultured in HG compared with the NG groups. The nuclear phospho-STAT3/STAT3 ratio was increased by HG and NG + IL6 and was attenuated in the HG + IL6NAb groups, indicating that nuclear STAT3 was activated following JAK2 and cytosolic STAT3 activation in response to IL6 secreted by HG-stimulated podocytes. Immunoprecipitation showed increased phospho-JAK2 recruitment to gp130 in the HG and NG + IL6 groups, and the addition of IL6NAb in the HG group significantly abrogated these increases. Podocyte hypertrophy was significantly increased in the HG and NG + IL6 compared with the NG condition and was diminished by the addition of IL6NAbs to the HG group. CONCLUSION: IL6 might play a prominent role in the local activation of JAK2/STAT3 in podocyte hypertrophy under HG conditions. In vivo studies examining this pathway are warranted. PMID- 27957416 TI - Plasma renin activity and risk of cardiovascular and mortality outcomes among individuals with elevated and nonelevated blood pressure. AB - BACKGROUND: We sought to evaluate plasma renin activity (PRA) levels and risk of mortality and cardiovascular events among individuals with elevated blood pressure [systolic blood pressure (SBP) >= 140 mmHg] and those with controlled blood pressure (SBP < 140 mmHg) in a large diverse population. METHODS: A retrospective cohort study between January 1, 2007, and December 31, 2013, among adults (>= 18 years) within an integrated health system was conducted. Subjects were categorized by SBP into 2 groups: SBP < 140 mmHg and SBP >= 140 mmHg and then further categorized into population-based PRA tertiles within each SBP group. Cox proportional hazard modeling was used to estimate hazard ratios for cardiovascular and mortality outcomes among tertiles of PRA levels. RESULTS: Among 6,331 subjects, 32.6% had SBP >= 140 mmHg. Multivariable hazard ratios and 95% confidence interval for PRA tertiles T2 and T3 compared to T1 in subjects with SBP >= 140 mmHg were 1.42 (0.99-2.03) and 1.61 (1.12-2.33) for ischemic heart events; 1.40 (0.93-2.10) and 2.23 (1.53-3.27) for congestive heart failure; 1.10 (0.73-1.68) and 1.06 (0.68-1.66) for cerebrovascular accident; 1.23 (0.94 1.59) and 1.43 (1.10-1.86) for combined cardiovascular events; and 1.39 (0.97 1.99) and 1.35 (0.92-1.97) for all-cause mortality, respectively. Among the SBP < 140 mmHg group, there was no relationship between PRA levels and outcomes. CONCLUSION: Higher PRA levels demonstrated increased risk for ischemic heart events and congestive heart failure and a trend toward higher mortality among individuals with SBP >= 140 mmHg but not among those with SBP < 140 mmHg. PMID- 27957417 TI - Comparison of clinical characteristics of patients with acute kidney injury after intravenous versus inhaled colistin therapy. AB - BACKGROUND: The aim of this study was to investigate the incidence and clinical characteristics of intravenous (IV) or inhaled (IH) colistin-associated acute kidney injury (AKI) using the Risk, Injury, Failure, Loss, End-stage Renal Disease criteria. METHODS: From 2010 to 2014, 160 patients were treated with IV or IH colistin. Of these, we included 126 patients who received colistin for > 72 hours for the treatment of pneumonia and compared the incidence and clinical characteristics of patients in the IV (n = 107) and IH (n = 19) groups. RESULTS: The patients included 104 men and 22 women, with a mean age of 69 years (range, 24-91 years). The mortality rate was 45%, and AKI occurred in 75 (60%) patients. At the end of therapy, the bacteriologic cure rate was 66%. There were no differences in the clinical characteristics between the IV and IH groups except for age. In comparison with patients in the IV group, the patients in the IH group were older (74 +/- 8 vs. 68 +/- 12 years, P = 0.026). The incidence of AKI was not different between the 2 groups (62 vs. 47%, P = not significant), and there was no difference in the severity of AKI according to the Risk, Injury, Failure, Loss, End-stage Renal Disease criteria. Of the 83 patients with AKI, 6 and 1 patients underwent renal replacement therapy, respectively. CONCLUSION: The incidence of AKI in patients with colistin therapy is 60% in our center. It seems that IH colistin therapy could not be better in safety than IV colistin therapy. PMID- 27957418 TI - Beneficial effects of tonsillectomy plus steroid pulse therapy on inflammatory and tubular markers in patients with IgA nephropathy. AB - BACKGROUND: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. Tonsillectomy plus steroid pulse therapy has been able to induce clinical remission in early-stage IgAN. However, its possible effect on systemic and local cytokines and tubular markers has not been fully investigated. METHODS: We obtained serum and urine samples from 38 patients just before renal biopsy and third steroid pulse therapy. Markers of tubular damage such as N-acetyl-beta-d-glucosaminidase, and kidney injury molecule-1 and inflammation such as interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 were measured by immunoassay. RESULTS: Before renal biopsy, only urinary inflammatory markers, except MCP-1, were associated with glomerular (proteinuria) and/or tubular damage markers. Proteinuria, hematuria, and estimated glomerular filtration rate dramatically improved after therapy. In addition, levels of serum IL-6 and ICAM-1 and all urinary markers declined significantly; however, serum MCP-1 and VCAM-1 levels did not. None of the urinary markers correlated with the serum inflammatory markers. CONCLUSION: Tonsillectomy plus steroid pulse therapy for patients with IgAN might be useful for improving not only glomerular damage marker but also tubular damage markers through the improvement of local renal inflammation. PMID- 27957419 TI - Pulmonary vein isolation alone and combined with renal sympathetic denervation in chronic kidney disease patients with refractory atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) commonly occurs in association with chronic kidney disease (CKD), resulting in adverse outcomes. Combining pulmonary vein isolation (PVI) and renal sympathetic denervation (RSD) may reduce the recurrence of AF in patients with CKD and hypertension. We considered that RSD could reduce the recurrence of AF in patients with CKD by modulating sympathetic hyperactivity. Our goal was to compare the impact of PVI + RSD with that of PVI alone in patients with concurrent AF and CKD. METHODS: This was a single-center, prospective, longitudinal, randomized, double-blind study. Forty-five patients with controlled hypertension, symptomatic paroxysmal AF and/or persistent AF, stage 2 or 3 CKD, and a dual-chamber pacemaker were enrolled from January 2014 to January 2015. We assessed the 30-second recurrence of AF recorded by the pacemaker, 24-hour ambulatory blood pressure measurements, estimated glomerular filtration rate, albuminuria, echocardiographic parameters, and safety of RSD. RESULTS: No patient developed procedural or other complications. The ambulatory blood pressure measurements did not differ within the PVI + RSD group or between the PVI + RSD and PVI groups throughout the study. Significantly more patients in the PVI + RSD group than in the PVI group were free of AF at the 12-month follow up evaluation. The PVI group had an unacceptable response to ablation with respect to changes in echocardiographic parameters, whereas these parameters improved in the PVI + RSD group. CONCLUSION: PVI + RSD were associated with a lower AF recurrence rate than PVI alone; it also improved renal function and some echocardiographic parameters. These encouraging data will serve as baseline information for further long-term studies on larger patient populations. PMID- 27957420 TI - Technique failure in Korean incident peritoneal dialysis patients: a national population-based study. AB - BACKGROUND: Technique failure is an important issue for peritoneal dialysis (PD) patients. In this study, we aimed to analyze technique failure rate in detail and to determine the predictors for technique failure in Korea. METHODS: We identified all patients who had started dialysis between January 1, 2005, and December 31, 2008, in Korea, using the Korean Health Insurance Review and Assessment Service database. A total of 7,614 PD patients were included, and the median follow-up was 24.9 months. RESULTS: The crude incidence rates of technique failure in PD patients were 54.1 per 1,000 patient-years. The cumulative 1-, 2-, and 3-year technique failure rates of PD patients were 4.9%, 10.3%, and 15.6%, respectively. However, those technique failure rates by Kaplan-Meier analysis were overestimated compared with the values by competing risks analysis, and the differences increased with the follow-up period. In multivariate analyses, diabetes mellitus and Medical Aid as a crude reflection of low socioeconomic status were independent risk factors in both the Cox proportional hazard model and Fine and Gray subdistribution model. In addition, cancer was independently associated with a lower risk of technique failure in the Fine and Gray model. CONCLUSION: Technique failure was a major concern in patients initiating PD in Korea, especially in diabetic patients and Medical Aid beneficiaries. The results of our study offer a basis for risk stratification for technique failure. PMID- 27957421 TI - Acute interstitial nephritis induced by Solanum nigrum. AB - Acute interstitial nephritis (AIN) is an important cause of reversible acute kidney injury and pathologically characterized by inflammatory infiltrate in the renal interstitium. Solanum nigrum (S. nigrum) is a medicinal plant member of the Solanaceae family. Although S. nigrum has been traditionally used to treat various ailments such as pain, inflammation, and fever, it has also been reported to have a toxic effect, resulting in anticholinergic symptoms. However, there have been no reports of AIN caused by S. nigrum. Here, we report the first case of biopsy-confirmed AIN after ingestion of S. nigrum. The patient was successfully treated using corticosteroid therapy. PMID- 27957422 TI - Unmasked chronic renal function deterioration after unilateral adrenalectomy in patients with primary aldosteronism. AB - We report 2 cases of chronic estimated glomerular filtration rate (eGFR) decline after unilateral adrenalectomy due to primary aldosteronism. The patients were diagnosed with unilateral adrenal cortical adenoma releasing aldosterone. Two patients were examined for hypertension and hypokalemia. Unilateral laparoscopic adrenalectomy was performed in both cases, and pathology confirmed adrenal cortical adenoma. After adrenalectomy, hypertension and hypokalemia improved to within normal range. However, the eGFR decreased postoperatively, and abdominal computed tomography scan showed decreased kidney size compared to previous images. Kidney biopsy was performed to delineate the exact cause of renal function deterioration and revealed hypertensive changes with chronic interstitial changes, indicating that glomerular hyperfiltration with aldosterone excess masked renal function damage. Physicians have to consider the probability of postadrenalectomy eGFR decline related to chronic hypertensive change. PMID- 27957424 TI - Bullous skin lesions in a patient with end-stage renal disease combined with myeloma and primary amyloidosis. PMID- 27957423 TI - Crystalline podocytopathy and tubulopathy without overt glomerular proteinuria in a patient with multiple myeloma. AB - Crystalline nephropathy is a rare yet well-known condition associated with multiple myeloma and other light chain-secreting disorders. Paraproteins that are resistant to proteolysis crystallize within proximal tubular cells and cause light-chain proximal tubulopathy, which presents clinically as Fanconi syndrome. Podocytes are rarely affected, and the crystalline inclusions within podocytes are typically precipitated, yielding significant glomerular proteinuria. Here we report a case of extensive crystalline inclusions primarily within podocytes and proximal tubules that presented only with Fanconi syndrome and renal insufficiency. Despite the presence of extensive crystalline inclusions in podocytes and diffuse foot process effacement, the patient had no clinical evidence suggestive of podocyte injury. PMID- 27957425 TI - Melanotic Xp11 Translocation Renal Cancer Managed With Radical Nephrectomy and IVC Tumor Thrombectomy. AB - Melanotic Xp11 translocation renal cancer is a rarely observed neoplasm primarily affecting adolescents and young adults. Given the paucity of data describing this malignancy, its natural history and subsequent long-term management are not well understood. We report a case of melanotic Xp11 translocation with tumor thrombus extension managed with radical nephrectomy and inferior vena cava (IVC) tumor thrombectomy. To our knowledge, this is the first case report to describe use of conventional tumor thrombectomy techniques in a patient with melanotic Xp11 translocation renal cancer. PMID- 27957427 TI - A Rare Case of Hematuria; Primary Amyloidosis of the Bladder Neck. AB - Primary and localized amyloidosis of the urinary tract is considered to be a rare clinical entity with approximately 160 cases documented in the literature. Here we present a case of a 77 year old gentleman with painless visible hematuria. Flexible cystoscopy revealed abnormal and polypoidal bladder mucosa. Transurethral resection of these lesions revealed histology with congo-red staining and positive green-apple birefringence, these findings are consistent with amyloidosis. There has so far been no sign of recurrence in this gentleman, with routine cystoscopic surveillance. Here we present a literature review on the presentation, diagnosis and management of this rare condition. PMID- 27957426 TI - Mesothelial Inclusions in Pelvic Lymph Nodes Initially Diagnosed as Metastatic Prostate Cancer; the Utility of Second Opinions and Genomic Testing in the Setting of Unexpected Results. AB - Benign mesothelial inclusions in pelvic lymph nodes may be mistaken for metastatic disease in the setting of pelvic malignancy. In this case-report a patient with Low-Risk prostate cancer (confirmed by biopsy and genomic testing) underwent radical prostatectomy with pelvic lymph node dissection. The initial pathological diagnosis was organ-confined Gleason 3 + 3 = 6 cancer with metastasis to a pelvic lymph node. Upon review of the pathological specimen and immunohistochemical staining the lymph node tissue concerning for metastatic disease was recharacterized as mesothelial in origin. This case illustrates the importance of second opinions and immunohistochemistry for unexpected or unusual pathological findings. PMID- 27957428 TI - Isolated Hepatic Metastasis from Prostate Carcinoma. AB - Worldwide, prostate cancer is considered the second most common cancer in men. Most common sites for metastatic disease are lymph nodes and bones. However, isolated liver metastasis from prostate cancer is rare. We present a 75 year-old male with prostate adenocarcinoma diagnosed 7 years ago. With rising PSA, he underwent imaging and found to have isolated hepatic metastasis. After left hepatic lobectomy, his PSA dramatically decreased to < 0.01. Physicians should be aware of isolated hepatic metastasis in patients with prostate cancer. Metastasectomy should be considered in such case, and combined medical and surgical approach may prolong the overall survival. PMID- 27957429 TI - Relationship between level of HbA1C and breast cancer. AB - BACKGROUND: Diabetes and cancer are public health issues worldwide; studies have shown that diabetes is related to increased breast cancer mortality. The purpose of this study was to examine associations between HbA1C and obesity with tumor stage and mortality among breast cancer patients. METHODS: Data for 82 patients with breast cancer (36-89 years of age, diagnosed /treated 1999-2009) were provided by the University of Arkansas for Medical Sciences (UAMS) Data Trust Warehouse. Survival time was estimated from start date of service to date of last follow-up or date of death. The Kaplan-Meier method provided analysis of survival curves for two groups of HbA1C (HbA1C < 6.5% vs HbA1C >= 6.5%) and two groups of BMI (BMI < 30 vs BMI >= 30 kg/m2); survival curves were compared using log-rank tests. Associations between HbA1C and BMI, and between HbA1C and tumor stage were determined by chi-square. RESULTS: The relationship between tumor stages and HbA1C was not statistically significant (X2 = 0.093, p = 0.47, df = 1). The relationship between obesity and HbA1C was statistically significant (X2 = 6.13, p = 0.013, df = 1). Log-rank tests did not show statistically significant differences between survival curves (HbA1C curves, p = 0.4; Obesity curves, p = 0.09). CONCLUSION: While there was a statistically significant association between HbA1C and obesity, there were no significant associations found with this analysis. However, there are clinically meaningful relationships based on observed trends. Future directions for research may involve exploring a larger sample of patients and the role of therapeutic regimens on blood sugar control and BMI of breast cancer patients and influence on cancer prognosis. PMID- 27957431 TI - Potential Effect of Medical Insurance on Medicare: Evidence from China. AB - BACKGROUND: With the increased range of medical insurance coverage in China, the proportion of medical expenditure shouldered by individuals is declining. The problem is the rapidly growing scale of medical expenditures challenges the sustainability of medical insurance funds. METHODS: This study used the Heckman selection model, survival analysis, and ordered probit model to evaluate the effect of medical insurance on the expenditures in outpatient and inpatient health care, survival time, and improvement of self-rated health of test subjects, respectively. RESULTS: Medical insurance exerts a differential effect on the expenditures in outpatient and inpatient health care. On average, the expenditures in outpatient and inpatient health care of test subjects participating in premium health insurance plans increased by 38.6% and 72.6%, respectively. Participation in medical insurance plans exhibits no significant correlation with the survival time of test subjects, but their self-rated health shows a significant correlation (P < 0.01). CONCLUSION: Although medical insurance does not significantly reduce mortality or prolong the survival time of test subjects, it improves their health status. This study suggests that the Chinese government should eliminate deductible medical insurance payments and utilize medical resources on minor ailment treatment and disease prevention to improve the health status of people. PMID- 27957432 TI - Factors Associated with the Social Support of Hemodialysis Patients. AB - BACKGROUND: Support has been gradually acknowledged as a significant factor that exerts a positive influence on hemodialysis patients' lives as well as on the outcome of the disease. The purpose was to explore factors associated with social support of hemodialysis patients. METHODS: The sample studied consisted of 258 patients undergoing hemodialysis in public hospitals in Athens, Greece during 2015. Data collection was performed by the method of the interview using a specially designed questionnaire, which included the Multidimensional Scale of Perceived Social Support for the assessment of social support from significant others, family and friends as well as patients' socio-demographic, clinical and other characteristics. RESULTS: Of the 258 participants, 53.9% were male and 65% were over 60 yr. Regard to social support, patients felt highly supported by their significant others and their family (median 6 for both subscales) and less by their friends (median 4.5 neutral support levels). In terms of patients' characteristics, statistically significant association of support from significant others and family was observed with marital status (P<0.001 and P<0.001 respectively), place of residence (P<0.001 and P<0.001 respectively) and the number of children (P=0.002 and P=0.007 respectively). Furthermore, statistically significant association of support from friends was observed with age (P <0.001), marital status (P=0.002), and place of residence (P=0.017). CONCLUSION: Socio-demographic, clinical characteristics and patients' perceptions are associated with perceived Social Support. Provision of holistic individualized care to hemodialysis patients demands assessment of social support in the daily clinical practice. PMID- 27957430 TI - Signaling mechanisms implicated in cranial sutures pathophysiology: Craniosynostosis. AB - Normal extension and skull expansion is a synchronized process that prevails along the osteogenic intersections of the cranial sutures. Cranial sutures operate as bone growth sites allowing swift bone generation at the edges of the bone fronts while they remain patent. Premature fusion of one or more cranial sutures can trigger craniosynostosis, a birth defect characterized by dramatic manifestations in appearance and functional impairment. Up until today, surgical correction is the only restorative measure for craniosynostosis associated with considerable mortality. Clinical studies have identified several genes implicated in the pathogenesis of craniosynostosis syndromes with useful insights into the underlying molecular signaling events that determine suture fate. In this review, we exploit the intracellular signal transduction pathways implicated in suture pathobiology, in an attempt to identify key signaling molecules for therapeutic targeting. PMID- 27957434 TI - A Bio Medical Waste Identification and Classification Algorithm Using Mltrp and Rvm. AB - BACKGROUND: We aimed to extract the histogram features for text analysis and, to classify the types of Bio Medical Waste (BMW) for garbage disposal and management. METHODS: The given BMW was preprocessed by using the median filtering technique that efficiently reduced the noise in the image. After that, the histogram features of the filtered image were extracted with the help of proposed Modified Local Tetra Pattern (MLTrP) technique. Finally, the Relevance Vector Machine (RVM) was used to classify the BMW into human body parts, plastics, cotton and liquids. RESULTS: The BMW image was collected from the garbage image dataset for analysis. The performance of the proposed BMW identification and classification system was evaluated in terms of sensitivity, specificity, classification rate and accuracy with the help of MATLAB. When compared to the existing techniques, the proposed techniques provided the better results. CONCLUSION: This work proposes a new texture analysis and classification technique for BMW management and disposal. It can be used in many real time applications such as hospital and healthcare management systems for proper BMW disposal. PMID- 27957433 TI - Nursing Strategies for Patients with Chronic Renal Failure Undergoing Maintenance Hemodialysis Treatment by Arteriovenous Fistula. AB - BACKGROUND: We aimed to analyze the effect of nursing strategies on patients with chronic renal failure (CRF) undergoing maintenance hemodialysis (MHD) treatment by puncturing on arteriovenous fistula (AVF). METHODS: Ninety-two patients with chronic renal failure undergoing maintenance hemodialysis (MHD) between Jan 2014 and Jan 2015 were included in the study (all undergoing AVF, dialysis for 2-3 sessions per week, 4-5 h per session) and randomly divided into control group and observation group. Patients in control group were given standard nursing care and patients in observation group were given professional nursing of internal fistula. The complication rate and dysfunction rate during internal fistula perioperative period, fistula usage time and effect on life quality of patients of these two groups were compared (during 18-month follow-up). RESULTS: The complication rate and dysfunction rate during internal fistula perioperative period of the observation group were significantly lower than that of the control group, and the difference was statistically significant (P<0.05). The median time of internal fistula usage was significantly prolonged, and the health index, emotion index and psychology index quality-of-life in the observation group were significantly higher than that of the control group (P<0.05). CONCLUSION: Professional nursing strategies of internal fistula can prolong service time, decrease complications and improve life quality for patients undergoing maintenance hemodialysis treatment via arteriovenous fistula. PMID- 27957435 TI - SPD-based Logistics Management Model of Medical Consumables in Hospitals. AB - BACKGROUND: With the rapid development of health services, the progress of medical science and technology, and the improvement of materials research, the consumption of medical consumables (MCs) in medical activities has increased in recent years. However, owing to the lack of effective management methods and the complexity of MCs, there are several management problems including MC waste, low management efficiency, high management difficulty, and frequent medical accidents. Therefore, there is urgent need for an effective logistics management model to handle these problems and challenges in hospitals. METHODS: We reviewed books and scientific literature (by searching the articles published from 2010 to 2015 in Engineering Village database) to understand supply chain related theories and methods and performed field investigations in hospitals across many cities to determine the actual state of MC logistics management of hospitals in China. RESULTS: We describe the definition, physical model, construction, and logistics operation processes of the supply, processing, and distribution (SPD) of MC logistics because of the traditional SPD model. With the establishment of a supply-procurement platform and a logistics lean management system, we applied the model to the MC logistics management of Anhui Provincial Hospital with good effects. CONCLUSION: The SPD model plays a critical role in optimizing the logistics procedures of MCs, improving the management efficiency of logistics, and reducing the costs of logistics of hospitals in China. PMID- 27957436 TI - Framework for Establishment of a Comprehensive and Standardized Administration System for Prevention and Control of Tuberculosis in College Student Community in China. AB - BACKGROUND: College student community is the one with high risk of tuberculosis (TB). A systemic and standardized administration model for prevention and control of TB is significance in controlling TB spread in universities. Currently, the universities in China have not established the comprehensive and standardized administration system for TB prevention and control in college student community. METHODS: Firstly, the literature research and brainstorming method (n=13) were used to construct the clause and sub-clause pool for the administration of TB prevention and control within college student community in 2014. Secondly, a total of twenty experts in the field of TB prevention and control who are representatives of the east, west, south and north parts of China were selected and invited to participate the Delphi letter-inquiry. After two rounds of letter inquiry, the opinions of the experts reached a consensus and the framework for the administration system was constructed. RESULTS: A framework for the administration system was constructed, which included 8 first class indexes, 26 second class indexes and 104 third class indexes. CONCLUSION: The results are highly scientific and reliable, which can be helpful for improving the systemic and standardized levels for the administration of TB prevention and control in universities in China and perhaps in other developing counties with high TB burden as well. PMID- 27957437 TI - Health Research Governance: Introduction of a New Web-based Research Evaluation Model in Iran: One-decade Experience. AB - BACKGROUND: Governance is one of the main functions of Health Research System (HRS) that consist of four essential elements such as setting up evaluation system. The goal of this study was to introduce a new web based research evaluation model in Iran. METHODS: Based on main elements of governance, research indicators have been clarified and with cooperation of technical team, appropriate software was designed. Three main steps in this study consist of developing of mission-oriented program, creating enabling environment and set up Iran Research Medical Portal as a center for research evaluation. RESULTS: Fifty two universities of medical sciences in three types have been participated. After training the evaluation focal points in all of medical universities, access to data entry and uploading all of documents were provided. Regarding to mission - based program, the contribution of medical universities in knowledge production was 60% for type one, 31% for type two and 9% for type three. The research priorities based on Essential National Health Research (ENHR) approach and mosaic model were gathered from universities of medical sciences and aggregated to nine main areas as national health research priorities. Ethical committees were established in all of medical universities. CONCLUSION: Web based research evaluation model is a comprehensive and integrated system for data collection in research. This system is appropriate tool to national health research ranking. PMID- 27957438 TI - Molecular Characterization of Animal Fasciola spp. Isolates from Kermanshah, Western Iran. AB - BACKGROUND: We evaluated the genetic diversity of samples identified morphologically as Fasciola spp. from sheep, cattle and goat from Kermanshah Province, western Iran using PCR-RFLP method. METHODS: We used PCR-RFLP analysis of ribosomal ITS1 fragment using RsaI restriction enzyme to investigate the genetic characteristics of Fasciola species obtained from different hosts (16 sheep, 28 cattle, 4 goats). The species of Fasciola were confirmed by sequencing the 700 bp region of ribosomal ITS1 gene. RESULTS: In Kermanshah, F. hepatica was present in 96% of the samples, F. gigantica was found only in two cattle sample. No hybrid forms were detected in the present study. CONCLUSION: Our results contribute to clarify the dark spots of Fasciola genotyping in different parts of Iran. PMID- 27957439 TI - Can Opium Use Contribute to a Higher Risk of Colorectal Cancers? A Matched Case control Study in Iran. AB - BACKGROUND: Colorectal cancers (CRCs) including colon, rectum and anal cancers are the third most prevalent cancers in the world. There are strong evidence showing the risk of the cigarette smoking, alcohol use, low physical activity and some types of diets in CRCs; however, few studies explored the relationship between opium use and CRCs. This study aimed to investigate the association between opioid use and the incidence of CRCs. METHODS: In a population-based matched case-control study in Kerman, Iran, 175 patients with colorectal cancers and 350 healthy controls (matched for age, sex, and place of residence) were interviewed from Sep 2014 to Nov 2014. Opium and its derivatives, cigarette, alcohol, and diet use were collected using a valid and reliable questionnaire. Conditional logistic regression was used to estimate odds ratios with 95% confidence intervals. RESULTS: The use of opioids was associated with an increased risk of CRCs (adjusted odds ratio= 4. 5, 95% CI: 2. 4-8. 7). In addition, a dose-response relationship was observed between the cumulative use of opioids and the incidence of CRCs (with low use OR=3. 7; 95% CI: 1. 5-8. 6 and high use OR= 8. 0; 95% CI: 2. 9-21. 7). This dose-response relationship was also strong in patients with colon cancers, with OR= 3. 9 (95% CI: 1. 5-9. 9) and 9. 4 (95% CI: 3. 3-27. 0) for the low and high uses of opioids, respectively. CONCLUSION: Opioid use can lead to an increased risk of CRCs. Therefore, it is necessary to implement preventive policies to control the use of opioids. PMID- 27957440 TI - Non-auditory Effect of Noise Pollution and Its Risk on Human Brain Activity in Different Audio Frequency Using Electroencephalogram Complexity. AB - BACKGROUND: Noise pollution is one of the most harmful ambiance disturbances. It may cause many deficits in ability and activity of persons in the urban and industrial areas. It also may cause many kinds of psychopathies. Therefore, it is very important to measure the risk of this pollution in different area. METHODS: This study was conducted in the Department of Medical Physics and Biomedical Engineering, Tehran University of Medical Sciences from June to September of 2015, in which, different frequencies of noise pollution were played for volunteers. 16-channel EEG signal was recorded synchronously, then by using fractal dimension and relative power of Beta sub-band of EEG, the complexity of EEG signals was measured. RESULTS: As the results, it is observed that the average complexity of brain activity is increased in the middle of audio frequency range and the complexity map of brain activity changes in different frequencies, which can show the effects of frequency changes on human brain activity. CONCLUSION: The complexity of EEG is a good measure for ranking the annoyance and non-auditory risk of noise pollution on human brain activity. PMID- 27957441 TI - Therapeutic Effect of Scrophularia striata Ethanolic Extract against Localized Cutaneous Leishmaniasis Caused by Leishmania major (MRHO/IR/75/ER). AB - BACKGROUND: We evaluated the effect of the ethanolic extract of Scrophularia striata on the Iranian strain of Leishmania major (MRHO/IR/75/ER) both in vitro and in vivo conditions. METHODS: The effective dose (ED) of ethanolic extract of S. striata were determined using MTT assay on the growth of promastigote forms of L. major in axenic culture media. Then, the ED50 of S. striata on mice peritoneal macrophages was determined using calculation of amastigote forms on mice peritoneal macrophages. For in vivo experiments, the therapeutic effects of various concentrations of S. striata on infected BALB/c mice was studied. A total of 75 infected mice were randomly divided into five groups: two groups (10% and 50% of S. striata) as experimental and three as control (ethanol 50%, Glucantime(r) and no treatment). The efficacy were determined by comparing the diameters of lesions and the microscopically examinations. RESULTS: The effect of S. striata extract (0/625%, 1/25%, 2/5%, 5%, 10%, 20% and 50%) on peritoneal macrophages of Balb/c mice infected with L.major in tissue-culture slides was assessed. S. striata extract (10%) removed the L.major amastigotes-infected macrophages significantly after 24 h (P < 0.05). The higher concentrations of S. striata ethanolic extract (20%, and 50%) had highly toxic effects on macrophages, resulted in the disintegration of the cytoplasm of macrophages after 48 and 72 h. In concentration 10% of S. striata, more than 85% of L. major amastigotes infected macrophages were damaged without cytotoxicity effects on macrophages. The higher concentrations had toxic effects on cultured macrophages. CONCLUSION: S. striata ethanolic extract 10% had anti leishmanial effects in both in vivo and in vitro. PMID- 27957442 TI - Frequency of Cutaneous Leishmaniasis and Species Identification in Suspected Individuals from Golestan Province, Northern Iran in 2014. AB - BACKGROUND: Leishmaniasis is a zoonotic disease caused by species of protozoa of the genus Leishmania. In recent years, incidence of cutaneous leishmaniasis has increasing trend in Golestan Province, North of Iran. The aim of the present study was to identify the frequency of cutaneous leishmaniasis using PCR-RFLP in patients referred to Kalaleh Health Center, during 2013-14. METHODS: This descriptive cross-sectional study was conducted on 70 individuals with suspected cutaneous leishmaniasis that referred to health center of Kalaleh County, Golestan Province, Northern Iran, from Sep 2013 to Nov 2014. Samples of cutaneous lesions were examined microscopically. DNA was extracted from all of the positive smears and PCR was done on ITS-1 gene. RFLP was performed using HaeIII enzyme for species identification. RESULTS: Totally, 38 out of the 70 (54.3%) suspected individuals including 22 males (57.9%) were found positive by microscopic examination. All of microscopically positive samples were confirmed to be positive for Leishmania DNA (approximately 340 bp bands were detected). RFLP revealed 140 bp and 200 bp bands (approximate size), indicative of L. major. CONCLUSION: The detected species of studied region was L. major. Cutaneous leishmaniasis has high prevalence in Kalaleh County, thus more studies on leishmaniasis in the animal reservoirs, comparison of homology of animal and human isolates and a survey regarding natural infection of vectors in this region is highly recommended. PMID- 27957443 TI - Some Biochemical Markers in Patients with Alzheimer's Disease. AB - BACKGROUND: Metal ions effect on homeostasis of Alzheimer's disease (AD) patients. The aim of this study was to assess the metal ions (Iron, Zinc and Copper) and CBC in patients with AD in comparison with normal range. METHODS: The samples of study were 17 patients with AD in Tehran's aging centers in 2015, selected as an access sample. Blood samples were analyzed in a pathobiology laboratory. Data were analyzed by one sample t-test. RESULTS: According to the normal range, provided by laboratory, there is a significant difference between zinc in patients with AD and normal reference interval (alpha=0.01). The comparison of CBC of the AD patients with normal group showed also some decreases. CONCLUSION: Zinc value in AD patients is significantly lower than normal range. It should be repeated by a larger sample size. PMID- 27957445 TI - The Temporal Decline of Social Support among Colorectal Cancer Survivors: First Year Prospective Study. PMID- 27957444 TI - A Novel Mutation in the OFD1 Gene in a Family with Oral-Facial-Digital Syndrome Type 1: A Case Report. AB - Oral-facial-digital syndrome as heterogeneous developmental conditions is characterized by abnormalities in the oral cavity, facial features and digits. Furthermore, central nervous system (CNS) abnormalities can also be part of this developmental disorder. At least 13 forms of OFDS based on their pattern of signs and symptoms have been identified so far. Type 1 which is now considered to be a ciliopathy accounts for the majority of cases. It is transmitted in an X-linked dominant pattern and caused by mutations in OFD1 gene, which can result in embryonic male lethality. In this study, we present a family suffering from orofaciodigital syndrome type I who referred to Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences in 2015. Two female siblings and their mother shared a novel 2-base pair deletion (c.1964-1965delGA) in exon 16 of OFD1 gene. Clinically, the sibling had oral, facial and brain abnormalities, whereas their mother is very mildly affected. She also had history of recurrent miscarriage of male fetus. PMID- 27957446 TI - Advantages and Disadvantages of Studying the Family as a Context Approach When Dealing with a School Aged Child Diagnosed with Attention Deficit Hyperactivity Disorder. PMID- 27957447 TI - Health-related Quality of Life for Scientific Editors in China. PMID- 27957448 TI - Oropharyngeal Airway Dimensional Changes after Treatment with Trainer for Kids (T4K) in Class II Retrognathic Children. PMID- 27957449 TI - The Effect of Cigarette Smoking on the Therapeutic Success of Dental Implants. PMID- 27957450 TI - The Antioxidant Effect of Rosmarinus officinalis L. Hydro Alcoholic Extract on Wheat. PMID- 27957451 TI - Exploring the Relationships between Internet Usage and Family Values of College Students. PMID- 27957452 TI - Molecular Analysis of MEFV Gene Polymorphisms and Mutations in Iranian Azeri Patients with Rheumatoid Arthritis. PMID- 27957453 TI - How to Get Rid of Calculi? PMID- 27957454 TI - Clinical Problem: Cancer Biopsy. PMID- 27957455 TI - The Association between GSTM1, GSTT1 Genetic Variants and Gastric Carcinoma Susceptibility in Chinese: A Systematic Review Article. AB - BACKGROUND: Glutathione S-transferases (GSTs) have been investigated as potential carcinoma susceptible genes. However, the relationship between GSTs (GSTM1, GSTT1) variants and gastric carcinoma (GC) risk has been controversial in Chinese population. METHODS: A comprehensive literature search strategy (PubMed, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Wan fang Database, etc.) was launched. Crude odds ratios (ORs) and confidence intervals (95% CI) were applied to estimate the strength of the association. RESULTS: Significant associations between GSTs genetic polymorphisms and GC were evidenced under random-effects model (OR GSTM1 =1.56, 95% CI: 1.39 to 1.76, I2=50.7%, P<0.0001; OR GSTT1 =1.24, 95% CI: 1.10 to 1.39, I2=43.6%, P=0.014; OR GSTM1-GSTT1 =1.51, 95% CI: 1.26 to 1.81, I2=59.7%, P=0.004). The pooled ORs were not qualitatively changed when any single study was omitted by sensitivity analysis. CONCLUSION: Our results indicated an increased GC risk in Chinese population with GSTM1 and GSTT1 null genotype and GSTM1-GSTT1 dual null genotype. Further multi center studies are needed to investigate the gene-gene and gene-environment interactions on the susceptibility of GC. PMID- 27957456 TI - Impact of Article Page Count and Number of Authors on Citations in Disability Related Fields: A Systematic Review Article. AB - BACKGROUND: Citation metrics and total publications in a field has become the gold standard for rating researchers and viability of a field. Hence, stimulating demand for citation has led to a search for useful strategies to improve performance metric index. Meanwhile, title, abstract and morphologic qualities of the articles attract researchers to scientific publications. Yet, there is relatively little understanding of the citation trend in disability related fields. We aimed to provide an insight into the factors associated with citation increase in this field. Additionally, we tried to know at what page number an article might appear attractive to disability researchers needs. Thus, our focus is placed on the article page count and the number of authors contributing to the fields per article. METHODS: To this end, we evaluated the quantitative characteristics of top cited articles in the fields with a total citation (>=50) in the Web of Science (WoS) database. Using one-way independent ANOVA, data extracted spanning a period of 1980-2015 were analyzed, while the non-parametric data analysis uses Kruskal-Walis test. RESULTS: Articles with 11 to 20 pages attract more citations followed by those within the range of zero to 10. Articles with upward 21 pages are the least cited. Surprisingly, articles with more than two authors are significantly (P<0.05) less cited and the citation decreases as the number of authors increased. CONCLUSION: Collaborative studies enjoy wider utilization and more citation, yet discounted merit of additional pages and limited collaborative research in disability field is revealed in this study. PMID- 27957458 TI - Public Health in Serbia through the Lens of Security: A Review Article. AB - BACKGROUND: In recent years, the concept of health security has received an international dimension. However, despite evident links between health and security the concept of health security is not used in either academic or political discourse in Serbia. It comes as no surprise then that even though the issue of security challenges is present in Serbian legislation, it has not been incorporated into the National Security Strategy, by which health threats would be recognized as one of contemporary security priorities. METHODS: The method applied is descriptive and analytical, in keeping with social studies research methodology and the aims of this study. RESULTS: The 20th and the 21st century in Serbia have both been marked by events indicating a clear link between health and security. The most telling example of this connection is the events of the 1990s, namely civil wars, sanctions and the NATO bombing. The results of our research show that poor health conditions, an increasing number of reemerging diseases and pandemics of new diseases can have serious implications for the functioning of the state and devastating consequences for its population. What is most at risk are people's lives, capability for work, the entire economy and the capacities of the army and overall national security. CONCLUSION: The results of this study indicate an inextricable link between health and security and the necessity of viewing health through the lens of health security and incorporating it as such into the National Security Strategy. PMID- 27957457 TI - Coffee and the Risk of Lymphoma: A Meta-analysis Article. AB - BACKGROUND: Coffee is implicated in the susceptibility to several cancers. However, the association between coffee and lymphoma remains unclear. This meta analysis aimed to assess quantitatively the association between coffee and the incidence of lymphoma. METHODS: A literature search was performed for cohort and case-control studies published using PubMed, Cochrane, and EMBASE databases. Studies were included if they reported relative ratios (RR) and corresponding 95% confidence intervals (CIs) of lymphoma with respect to coffee consumption. Pooled relative risk (RR) and its 95% confidence interval (CI) were calculated. All P values are two tailed. RESULTS: Seven studies met the inclusion criteria, which included three cohort and four case-control studies. Compared with did not or seldom drink coffee per day, being no significantly association between coffee and risk of lymphoma (pooled RR: 1.05, 95%CI: 0.89-1.23). In the subgroup analysis, no significant association between coffee and lymphoma risk was detected not only in different study types (cohort studies RR: 1.29; 95% CI, 0.92 1.80; case control studies RR: 0.99; 95% CI, 0.82-1.99) but also in different regions (Europe RR: 1.21; 95% CI: 0.99-1.47; USA RR: 0.85; 95% CI, 0.62-1.15; Asia RR: 1.08, 95% CI: 0.84-1.40) and coffee consumption status (>=4cups/d 1.03, 95% CI: 0.69-1.56; < 4cups/d RR: 1.06, 95% CI: 0.89-1.26). The funnel plot revealed no evidence for publication bias. CONCLUSION: There was no sufficient evidence to support coffee consumption association with the risk of lymphoma. Further well-designed large-scaled cohort studies are needed to provide conclusions that are more definitive. PMID- 27957459 TI - Technological Ecosystems in Health Informatics: A Brief Review Article. AB - BACKGROUND: The existing models of information technology in health sciences have full scope of betterment and extension. The high demand pressures, public expectations, advanced platforms all collectively contribute towards hospital environment, which has to be kept in kind while designing of advanced technological ecosystem for information technology. Moreover, for the smooth conduct and operation of information system advanced management avenues are also essential in hospitals. It is the top priority of every hospital to deal with the essential needs of care for patients within the available resources of human and financial outputs. In these situations of high demand, the technological ecosystems in health informatics come in to play and prove its importance and role. The present review article would enlighten all these aspects of these ecosystems in hospital management and health care informatics. METHODS: We searched the electronic database of MEDLINE, EMBASE, and PubMed for clinical controlled trials, pre-clinical studies reporting utilizaiono of ecosysyem advances in health information technology. RESULTS: The primary outcome of eligible studies included confirmation of importance and role of advances ecosystems in health informatics. It was observed that technological ecosystems are the backbone of health informatics. CONCLUSION: Advancements in technological ecosystems are essential for proper functioning of health information system in clinical setting. PMID- 27957460 TI - Determination the Research Priorities in the Field of HIV/AIDS in Iran: A Systematic Review Article. AB - BACKGROUND: HIV and AIDS have many different epidemiological, social and political aspects. The aim of this study was to determine the research priorities according to the necessary aspects of HIV and AIDS in Iran. METHODS: The national and international databases were searched to obtain the published articles regarding HIV and AIDS in Iran. All Epidemiologic studies were included in this review for assess research priorities. RESULTS: Of 3059 retrieved references, 362 studies were included. The most studies were conducted in Tehran, Kermanshah, Fars and Kerman provinces. The cross-sectional studies with 71.55% have higher proportion. Studies related to adherence to treatment (0.55%), drug resistance (0.83%) and experience, perception and behavior of HIV/AIDS patients (0.83%) had the lowest proportion of conducted studies. Proportion of studies regarding prevention of HIV was 2.76%. The authors of studies on female sex workers (FSWs) (63.64%) and prisoners (58.82%) suggested further studies on these groups. CONCLUSION: According to our results, the high-risk groups such as female sex workers, injecting drug users and prisoners are in priority for research. Moreover, topics related to the prevention of HIV and AIDS, adherence to treatment and antiretroviral drug resistance are other research priorities in Iran. PMID- 27957461 TI - The Association between Socio-economic Context at Individual and Neighbourhood Levels, Wellbeing and Lifestyle Behaviours of Young Iranian Women. AB - BACKGROUND: This study explored the relationship between socio-economic characteristics at the individual and neighbourhood levels, and wellbeing and lifestyle behaviours of young Iranian women. METHODS: Cluster convenience sampling was used to select 391 Iranian women participated in this cross sectional survey in Shiraz, Iran in 2013. A scale adapted from the British General Household Social Capital questionnaire was used to assess neighbourhood socio-economic characteristics. The satisfaction with life scale, WHO quality of life scale, and the International Health and Behaviours Survey were used to measure wellbeing outcomes and lifestyle behaviours. RESULTS: Findings showed participants were dissatisfied with their neighbourhood socio-economic conditions (M: 36.3+/-9.8, score range: 11-60) as well as the availability of leisure facilities (M: 1.8, score range: 1-5) in their local areas. Correlations and regression analysis revealed that better neighbourhood socio-economic characteristics were positively associated with better wellbeing outcomes as well as healthier lifestyle behaviours. CONCLUSION: These findings suggest the need for transitioning economies to be cognisant of the importance of social policy and strategies for enhancing neighbourhood socioeconomic status in order to enhance wellbeing outcomes for sub-populations, including young women. PMID- 27957462 TI - A Stochastic Model for the Ethanol Pharmacokinetics. AB - BACKGROUND: The aim of this study was to propose a new stochastic model to study the time course of ethanol elimination in human bodies. METHODS: The times and amount of alcohol ingested are assumed to be random in controllable intervals. Constant elimination rate follows zero order kinetics and is replaced by first order kinetics when the effects of alcohol increase due to alcohol ingestion. Simulation studies of three different models were made to compare the statistical characteristics of the ethanol effects obtained using analytical expressions. For each model, three cases were considered depending on the drinking pattern and by classifying the drinker as heavy, normal or sparse. RESULTS: From the model formulation, we noted that as the rate of drinking increases for a given elimination rate, the expected time between overflows goes towards zero. Furthermore, as the average amount of alcohol in each drink increases, the corresponding time between overflows decreases. CONCLUSION: Variations in times of alcohol intakes as well as the amount of alcohol consumption can be accounted through the final created formula. The model proves that overflows occur when alcohol is ingested before the adverse effects of alcohol from the previous drink are completely eliminated. Being the first stochastic model of such a kind, we do hope that it will throw more light on interpreting experimental data of alcohol abuse. PMID- 27957463 TI - Evaluating the High Risk Groups for Suicide: A Comparison of Logistic Regression, Support Vector Machine, Decision Tree and Artificial Neural Network. AB - BACKGROUND: We aimed to assess the high-risk group for suicide using different classification methods includinglogistic regression (LR), decision tree (DT), artificial neural network (ANN), and support vector machine (SVM). METHODS: We used the dataset of a study conducted to predict risk factors of completed suicide in Hamadan Province, the west of Iran, in 2010. To evaluate the high-risk groups for suicide, LR, SVM, DT and ANN were performed. The applied methods were compared using sensitivity, specificity, positive predicted value, negative predicted value, accuracy and the area under curve. Cochran-Q test was implied to check differences in proportion among methods. To assess the association between the observed and predicted values, O coefficient, contingency coefficient, and Kendall tau-b were calculated. RESULTS: Gender, age, and job were the most important risk factors for fatal suicide attempts in common for four methods. SVM method showed the highest accuracy 0.68 and 0.67 for training and testing sample, respectively. However, this method resulted in the highest specificity (0.67 for training and 0.68 for testing sample) and the highest sensitivity for training sample (0.85), but the lowest sensitivity for the testing sample (0.53). Cochran Q test resulted in differences between proportions in different methods (P<0.001). The association of SVM predictions and observed values, O coefficient, contingency coefficient, and Kendall tau-b were 0.239, 0.232 and 0.239, respectively. CONCLUSION: SVM had the best performance to classify fatal suicide attempts comparing to DT, LR and ANN. PMID- 27957464 TI - Systemic Approach for Health Risk Assessment of Ambient Air Concentrations of Benzene in Petrochemical Environments: Integration of Fuzzy Logic, Artificial Neural Network, and IRIS Toxicity Method. AB - BACKGROUND: Reliable methods are crucial to cope with uncertainties in the risk analysis process. The aim of this study is to develop an integrated approach to assessing risks of benzene in the petrochemical plant that produces benzene. We offer an integrated system to contribute imprecise variables into the health risk calculation. METHODS: The project was conducted in Asaluyeh, southern Iran during the years from 2013 to 2014. Integrated method includes fuzzy logic and artificial neural networks. Each technique had specific computational properties. Fuzzy logic was used for estimation of absorption rate. Artificial neural networks can decrease the noise of the data so applied for prediction of benzene concentration. First, the actual exposure was calculated then it combined with Integrated Risk Information System (IRIS) toxicity factors to assess real health risks. RESULTS: High correlation between the measured and predicted benzene concentration was achieved (R2= 0.941). As for variable distribution, the best estimation of risk in a population implied 33% of workers exposed less than 1*10 5 and 67% inserted between 1.0*10-5 to 9.8*10-5 risk levels. The average estimated risk of exposure to benzene for entire work zones is equal to 2.4*10-5, ranging from 1.5*10-6 to 6.9*10-5. CONCLUSION: The integrated model is highly flexible as well as the rules possibly will be changed according to the necessities of the user in a different circumstance. The measured exposures can be duplicated well through proposed model and realistic risk assessment data will be produced. PMID- 27957465 TI - Changes in Back Compressive Force When Measuring Maximum Acceptable Weight of Lift in Iranian Male Students. AB - BACKGROUND: Low back pain caused by work, ranked the second after cardiovascular diseases, are among the most common reasons of patients' referral to the physicians in Iran. This study aimed to determine the changes in back compressive force when measuring maximum acceptable weight of lift in Iranian male students. METHODS: This experimental study was conducted in 2015 on 15 young male students were recruited from Tehran University of Medical Science. Each participant performed 18 different lifting tasks involving three lifting frequencies, with three lifting heights, and two box sizes. Each set of experiments was conducted during the 20 min work period using free-style lifting technique. The back compressive force evaluated with hand-calculation back compressive force method. Finally, Pearson correlation test, analysis of variance (ANOVA) and t-test were used for data analysis. RESULTS: The mean of back compressive force (BCF) for the small and large boxes at a frequency of 1lift/min at heights of F - K height, were 1001.02 (+/-86.74), 1210.57 (+/-93.77) Ib, respectively. There was a significant difference between mean BCF in terms of frequencies of lifts (P=0.02). The result revealed significant difference between frequencies of 1 lift/min and 6.67 lift/min (P=0.01). There was a significant difference between mean BCF in terms of the sizes of the two boxes (P=0.001). There was a significant relationship between the BCF and maximum acceptable weight of lift in all test conditions (P=0.001). CONCLUSION: BCF is affected by box size, lifting frequency and weight of load. PMID- 27957467 TI - First Report on Infant Acute Urticaria after Mother's Parenteral Use of Meglumine Antimoniate (Glucantime): A Case Report. AB - Pentavalent antimonials are still the first drug of choice for the treatment of cutaneous leishmaniasis (CL). Like other treatments, they can cause adverse reactions including musculoskeletal pain, gastrointestinal disturbances, and mild to moderate headaches. In this paper, we report the first case of an infant who developed acute urticaria after her mother's parenteral use of meglumine antimoniate (glucantime). PMID- 27957466 TI - Bed Capacity Planning Using Stochastic Simulation Approach in Cardiac-surgery Department of Teaching Hospitals, Tehran, Iran. AB - BACKGROUND: To determine the hospital required beds using stochastic simulation approach in cardiac surgery departments. METHODS: This study was performed from Mar 2011 to Jul 2012 in three phases: First, collection data from 649 patients in cardiac surgery departments of two large teaching hospitals (in Tehran, Iran). Second, statistical analysis and formulate a multivariate linier regression model to determine factors that affect patient's length of stay. Third, develop a stochastic simulation system (from admission to discharge) based on key parameters to estimate required bed capacity. RESULTS: Current cardiac surgery department with 33 beds can only admit patients in 90.7% of days. (4535 d) and will be required to over the 33 beds only in 9.3% of days (efficient cut off point). According to simulation method, studied cardiac surgery department will requires 41-52 beds for admission of all patients in the 12 next years. Finally, one-day reduction of length of stay lead to decrease need for two hospital beds annually. CONCLUSION: Variation of length of stay and its affecting factors can affect required beds. Statistic and stochastic simulation model are applied and useful methods to estimate and manage hospital beds based on key hospital parameters. PMID- 27957468 TI - Hashimoto Encephalopathy with an Unusual Presentation of Status Epilepticus Seizures: A Case Report. AB - A 33 yr old man, previously diagnosed with hypothyroidism, presented with decreased level of consciousness and generalized tonic-clonic (GTC) seizure to Namazi hospital, Shiraz, Iran, during April 2015. The patient later referred with another episode of seizure like attack for which he received phenytoin, carbamazepine and levothyroxine and was discharged. During his last admission, the patient was admitted with chief complaints of decreased consciousness and four GTC attacks. On admission, the patients had aphasia, ataxia, loss of verbal communication, eye contact and complete loss of obedience. Thyroid function tests showed low levels of T3 and T4 with high levels of thyroid stimulating hormone. Other blood tests were all either normal or slightly abnormal. Lumbar puncture and CSF analysis had a high titer of Anti-TPO antibodies. With high suspicion of Hashimoto encephalopathy, pulsed methyl prednisolone (10 mg) was administered, however the patient showed little improvement. Therefore, plasmaphresis was started, to which the patient showed dramatic response. PMID- 27957469 TI - OrthoMTAtm A Newly Developed Mineral Trioxide Aggregate (MTA) Cements in Outpatients Attending Public Oral Health Korean Adolescents. PMID- 27957470 TI - Body Image Dissatisfaction vs Muscle Dysmorphia. PMID- 27957471 TI - Understanding the Relationship between Optimistic Personality and Anxiety among College Students: The Mediating Role of Coping Style. PMID- 27957472 TI - Diagnosis and Treatment of Crossed Testicular Ectopia. PMID- 27957473 TI - Ulinastatin and Thymosin a1 Therapy in Adult Patients with Severe Sepsis: A Meta analysis with Trial Sequential Analysis of Randomized Controlled Trials. PMID- 27957474 TI - Effect of Drinking Water on the Decrease of Blood Pressure in Hot Working Condition of Prison's Kitchen. PMID- 27957475 TI - Perceived Risk of Violence in Various Hospital Levels and Departments in Urban and Rural China. PMID- 27957476 TI - Strategic Purchasing of Healthcare Services in Developing Countries: A New Approach Is Required. PMID- 27957477 TI - Crimean-Congo Haemorrhagic Fever in Persian Traditional Medicine. PMID- 27957478 TI - Role of Smoking in Lung Cancer in United States. PMID- 27957479 TI - CXCL12 retargeting of an adenovirus vector to cancer cells using a bispecific adapter. AB - Ad vectors are promising delivery vehicles for cancer therapeutic interventions. However, their application is limited by promiscuous tissue tropism and hepatotoxicity. This limitation can be avoided by altering the native tropism of Ads so that they can be redirected to the target cells through alternate cellular receptors. The CXCR4 chemokine receptor belongs to a large superfamily of G protein-coupled receptors and is known to be upregulated in a wide variety of cancers, including breast cancer and melanoma. These receptors have been associated with cancer cell survival, progression, and metastasis. In the current study, an Ad to cancer cells overexpressing CXCR4 by using a bispecific adapter, sCAR-CXCL12, was retargeted. The sCAR-CXCL12 adapter contained the soluble ectodomain form of the native Ad5 receptor (sCAR), which was fused to a mature human chemokine ligand, CXCL12, through a short peptide linker. A dramatic increase in the infectivity of cancer cells using a targeted Ad vector compared with an untargeted vector was observed. Furthermore, sCAR-CXCL12 attenuated Ad infection of liver ex vivo and in vivo and enhanced Ad vector infection of xenograft tumors implanted in immunodeficient SCID-bg mice. Thus, the sCAR-CXCL12 adapter could be used to retarget Ad vectors to chemokine receptor-positive tumors. PMID- 27957480 TI - The Utility of Infliximab Therapeutic Drug Monitoring among Patients with Inflammatory Bowel Disease and Concerns for Loss of Response: A Retrospective Analysis of a Real-World Experience. AB - Background. Infliximab (IFX) therapeutic drug monitoring (TDM) allows for objective decision making in patients with inflammatory bowel disease (IBD) and loss of response. Questions remain about whether IFX TDM improves outcomes. Methods. Patients with IBD who had IFX TDM due to concerns for loss of response were considered for inclusion. Serum IFX trough concentration and anti-drug antibody (ADA) concentrations were measured. Patients were grouped by TDM results: group 1, low IFX/high ADA; group 2, low IFX/low ADA; group 3, therapeutic IFX. Changes in management were analyzed according to groupings; remission rates were assessed at 6 months. Results. 71 patients were included of whom 37% underwent an appropriate change in therapy. Groups 1 (67%) and 2 (83%) had high adherence compared to only 9% in group 3. At 6 months, 57% had achieved remission. More patients who underwent an appropriate change in therapy achieved remission, though this did not reach statistical significance (69% versus 49%; P = 0.098). Conclusions. A trend towards increased remission rates was associated with appropriate changes in management following TDM results. Many patients with therapeutic IFX concentrations did not undergo an appropriate change in management, potentially reflecting a lack of available out-of-class options at the time of TDM or due to uncertainty of the meaning of the reported therapeutic range. PMID- 27957481 TI - Respiratory infection rates differ between geographically distant paediatric cystic fibrosis cohorts. AB - Respiratory infections are a major cause of pulmonary decline in children with cystic fibrosis (CF). We compared the prevalence of infection in early life at geographically distant CF treatment centres participating in the same surveillance programme in Australia. Lower airway microbiology, inflammation and structural lung disease at annual review were evaluated for 260 children 0-8 years old with CF at 1032 visits to CF treatment centres in Melbourne or Perth. Melbourne patients were more likely to be culture-positive for common respiratory pathogens at all age groups (odds ratio (OR) 1.85, 95% CI 1.33-2.58). Subjects <2 years old in Melbourne were also more likely to have neutrophil elastase present (OR 3.11, 95% CI 1.62-5.95). Bronchiectasis (OR 2.02, 95% CI 1.21-3.38) and air trapping (OR 2.53, 95% CI 1.42-4.51) in subjects 2-5 years old was more common in Melbourne subjects. The severity of structural lung disease was also worse in Melbourne patients >5 years old. Patients at both centres had a similar rate of hospitalisations and prescribed antibiotics. No procedural differences were identified that could explain the disparity between pathogen prevalence. Geographical differences in early acquisition of infection may contribute to variability in outcomes between CF centres. PMID- 27957482 TI - Sleep quality disturbances and cognitive functioning in elderly patients with COPD. AB - Information about the association between cognitive functions, such as copying function, and sleep disturbances in patients with chronic obstructive pulmonary disease (COPD) is lacking. This cross-sectional observational study aimed to investigate the association between copying function and self-reported sleep quality disturbances and disease severity in an elderly COPD population. Cognitive function performances, assessed using the Mini-Mental State Examination, were compared in 562 ambulatory COPD patients with and without sleep disturbances; assessed using the Established Populations for Epidemiologic Studies of the Elderly questionnaire; and stratified by Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades. Sleep disturbances overall were not correlated with cognitive functioning. A trend was revealed towards worse design copying in patients with sleep disturbances overall. GOLD I patients with difficulties falling asleep and nocturnal awakenings had worse copying ability compared to GOLD I patients without these sleep disturbances. Copying ability was worse for GOLD III than GOLD I, orientation was worse for GOLD II than GOLD I and language was worse for GOLD II and III than GOLD I. To conclude, sleep disturbances seem to be a weak correlate of cognitive functioning, and are not a marker of disease severity. PMID- 27957483 TI - Is there an association between altered baroreceptor sensitivity and obstructive sleep apnoea in the healthy elderly? AB - Obstructive sleep apnoea (OSA) is associated with a rise in cardiovascular risk in which increased sympathetic activity and depressed baroreceptor reflex sensitivity (BRS) have been proposed. We examined this association in a sample of healthy elderly subjects with unrecognised OSA. 801 healthy elderly (aged >=65 years) subjects undergoing clinical, respiratory polygraphy and vascular assessment were examined. According to the apnoea-hypopnoea index (AHI), the subjects were stratified into no OSA, mild-moderate OSA and severe OSA cases. OSA was present in 62% of the sample, 62% being mild-moderate and 38% severe. No differences were found for BRS value according to sex and OSA severity. 54% of the group had normal BRS value, 36% mild impairment and 10% severe dysfunction. BRS was negatively associated with body mass index (p=0.006), 24-h systolic (p=0.001) and diastolic pressure (p=0.001), and oxygen desaturation index (ODI) (p=0.03). Regression analyses revealed that subjects with lower BRS were those with hypertension (OR 0.41, 95% CI 0.24-0.81; p=0.002) and overweight (OR 0.42, 95% CI 0.25-0.81; p=0.008), without the effect of AHI and ODI. In the healthy elderly, the presence of a severe BRS dysfunction affects a small amount of severe cases without effect on snorers and mild OSA. Hypertension and obesity seem to play a great role in BRS impairment. PMID- 27957484 TI - Lipoxin A4 promotes lung epithelial repair whilst inhibiting fibroblast proliferation. AB - Therapy that promotes epithelial repair whilst protecting against fibroproliferation is critical for restoring lung function in acute and chronic respiratory diseases. Primary human alveolar type II cells were used to model the effects of lipoxin A4in vitro upon wound repair, proliferation, apoptosis and transdifferention. Effects of lipoxin A4 upon primary human lung fibroblast proliferation, collagen production, and myofibroblast differentiation were also assessed. Lipoxin A4 promoted type II cell wound repair and proliferation, blocked the negative effects of soluble Fas ligand/tumour necrosis factor alpha upon cell proliferation, viability and apoptosis, and augmented the epithelial cell proliferative response to bronchoaveolar lavage fluid (BALF) from acute respiratory distress syndrome (ARDS). In contrast, Lipoxin A4 reduced fibroblast proliferation, collagen production and myofibroblast differentiation induced by transforming growth factor beta and BALF from ARDS. The effects of Lipoxin A4 were phosphatidylinositol 3'-kinase dependent and mediated via the lipoxin A4 receptor. Lipoxin A4 appears to promote alveolar epithelial repair by stimulating epitheial cell wound repair, proliferation, reducing apoptosis and promoting trans-differentiation of alveolar type II cells into type I cells. Lipoxin A4 reduces fibroblast proliferation, collagen production and myofibroblast differentiation. These data suggest that targeting lipoxin actions may be a therapeutic strategy for treating the resolution phase of ARDS. PMID- 27957485 TI - The impact of a dedicated physiotherapist clinic for children with dysfunctional breathing. AB - Dysfunctional breathing is a significant cause of morbidity, adversely affecting an individual's quality of life. There is currently no data from paediatric centres on the impact of breathing retraining for dysfunctional breathing. Symptoms and quality of life were measured in 34 subjects referred sequentially for breathing retraining to the first dedicated paediatric dysfunctional breathing clinic in the UK. Data were obtained prior to the first intervention (time point 1), at discharge (time point 2) and by post 6 months later (time point 3). The mean (interquartile range) age of participants was 13.3 (9.1-16.3) years, with 52% female. Data were obtained at time points 2 and 3 in 23 and 13 subjects, respectively. Statistically significant improvements were observed in symptom scores, child quality of life and parental proxy quality of life between time points 1 and 2 (p<0.0001), while there was no significant difference in the data at time point 3 as compared with time point 2. This study suggests that physiotherapist-led breathing retraining offers significant benefit to young people with dysfunctional breathing which is maintained for at least 6 months after treatment is completed. Future studies will provide more information on the long-term effects of interventions for dysfunctional breathing. PMID- 27957487 TI - Effect of Anodal-tDCS on Event-Related Potentials: A Controlled Study. AB - We aim to measure the postintervention effects of A-tDCS (anodal-tDCS) on brain potentials commonly used in BCI applications, namely, Event-Related Desynchronization (ERD), Event-Related Synchronization (ERS), and P300. Ten subjects were given sham and 1.5 mA A-tDCS for 15 minutes on two separate experiments in a double-blind, randomized order. Postintervention EEG was recorded while subjects were asked to perform a spelling task based on the "oddball paradigm" while P300 power was measured. Additionally, ERD and ERS were measured while subjects performed mental motor imagery tasks. ANOVA results showed that the absolute P300 power exhibited a statistically significant difference between sham and A-tDCS when measured over channel Pz (p = 0.0002). However, the difference in ERD and ERS power was found to be statistically insignificant, in controversion of the the mainstay of the litrature on the subject. The outcomes confirm the possible postintervention effect of tDCS on the P300 response. Heightening P300 response using A-tDCS may help improve the accuracy of P300 spellers for neurologically impaired subjects. Additionally, it may help the development of neurorehabilitation methods targeting the parietal lobe. PMID- 27957486 TI - Comparison of Two Base Materials Regarding Their Effect on Root Canal Treatment Success in Primary Molars with Furcation Lesions. AB - Introduction. The aim of this study was to compare MTA with another base material, IRM, which is generally used on pulpal floor after root canal treatment, regarding their effect on the success of root canal treatment of primary teeth with furcation lesions. Materials and Methods. Fifty primary teeth with furcation lesions were divided into 2 groups. Following root canal treatment, the pulpal floor was coated with MTA in the experimental group and with IRM in the control group. Teeth were followed up considering clinical (pain, pathological mobility, tenderness to percussion and palpation, and any soft tissue pathology and sinus tract) and radiographical (pathological root resorption, reduced size or healing of existing lesion, and absence of new lesions at the interradicular or periapical area) criteria for 18 months. For the statistical analysis, Fisher's exact test and Pearson's chi-square tests were used and a p value of <0.05 was considered to be statistically significant. Results. Although there were no statistically significant differences between two groups in terms of treatment success, lesions healed significantly faster in the MTA group. Conclusion. In primary teeth with furcation lesions, usage of MTA on the pulpal floor following root canal treatment can be a better alternative since it induced faster healing. PMID- 27957488 TI - Oxymatrine Inhibits Proliferation and Migration While Inducing Apoptosis in Human Glioblastoma Cells. AB - Oxymatrine (OMT), an alkaloid derived from the traditional Chinese medicine herb Sophora flavescens Aiton, has been shown to exhibit anticancer properties on various types of cancer cells. In this study, we investigate the anticancer properties of OMT on human glioblastoma (GBM) cells and evaluate their underlying mechanisms. MTT assays were performed and demonstrated that OMT significantly inhibits the proliferation of GBM cells. Flow cytometry suggested that OMT at a concentration of 10-5 M may induce apoptosis in U251 and A172 cells. Western blot analyses demonstrated a significant increase in the expression of Bax and caspase 3 and a significant decrease in expression of Bcl-2 in both U251 and A172 cells. Additionally, OMT was found by transwell and high-content screening assays to decrease the migratory ability of the evaluated GBM cells. These findings suggest that the antitumor effects of OMT may be the result of inhibition of cell proliferation and migration and the induction of apoptosis by regulating the expression of apoptosis-associated proteins. OMT may represent a novel anticancer therapy for the treatment of GBM. PMID- 27957489 TI - HIV-1 Epidemiology, Genetic Diversity, and Primary Drug Resistance in the Tyumen Oblast, Russia. AB - Introduction. Specific molecular epidemic features of HIV infection in Tyumen Oblast (TO), Russia, were studied. Methods. The genome sequences encoding HIV-1 protease-reverse transcriptase, integrase, and major envelope protein were examined for 72 HIV-1 specimens isolated from the TO resident infected in 2000 2015. Results. The recorded prevalence of HIV-1 subtype A (A1) is 93.1%; HIV-1 subtype B continues to circulate in MSM risk group (1.4%). Solitary instances of HIV-1 recombinant forms, CRF63_02A1 (1.4%) and CRF03_AB (1.4%), were detected as well as two cases of HIV-1 URF63_A1 (2.8%). Phylogenetic analysis showed no HIV-1 clustering according to the duration of infection and risk groups but revealed different epidemic networks confirming that HIV infection spread within local epidemic foci. A high incidence of CXCR4-tropic HIV-1 variants and a higher rate of secondary mutations influencing the virus fitness (K20R, L10V, and I) are observed among the virus specimens isolated from newly infected individuals. Conclusions. The current HIV-1 epidemic in TO develops within the local epidemic networks. Similar to the previous period, HIV-1 subtype A is predominant in TO with sporadic cases of importation of HIV-1 recombinant forms circulating in adjacent areas. PMID- 27957490 TI - Prevalence and Clinical Features of Atopic Dermatitis in China. AB - Background. The epidemiology of atopic dermatitis (AD) in Chinese outpatients is yet to be clarified. Objectives. To investigate population-based prevalence and clinical features of AD in Chinese outpatients. Methods. A multicenter cross sectional study was conducted in outpatients with eczema or dermatitis from 39 tertiary hospitals in 15 provinces. Results. This study included 682 patients diagnosed with AD, with the mean age of 28.8 +/- 20.1 years and the median course of 5.3 +/- 6.9 years. AD patients had more severe itching (30.4% versus 13.8%, p < 0.001) and clinically suspected bacterial infection (21.7% versus 16.1%, p < 0.001) than those of other types of dermatitis. Older patients were more susceptible to have a history of flexion dermatitis (p < 0.001), bacterial infection (p = 0.005), and severe itching (p < 0.001). Outpatients with clinically suspected bacterial infection had 3.53-fold increased risk of AD than those without it (p < 0.001). The morbidity rate of AD in the (20-25 degrees N) region is 2.86 times higher than that in the (40-45 degrees N) region [OR (95% CI): 0.352 (0.241-0.514), p < 0.001]. Conclusions. AD is characterized by unique clinical/demographic features. Bacterial infection and latitude region may have an impact on the incidence of AD in China. PMID- 27957491 TI - Teaching Life-Saving Manoeuvres in Primary School. AB - Introduction. In the event of sudden cardiac arrest (SCA) early intervention provided by a layperson can be life-saving. Teaching first aid in primary school may increase the lifelong ability and motivation of young people to take action in an emergency. Objective. The aim of this article is to report a training experience on BLSD (Basic Life Support and Defibrillation) designed for a group of pupils in an Italian primary school, with assessment of its effectiveness at a distance. Methods. The assessment was carried out using a multiple choice questionnaire on a sample of 130 pupils aged 11-12, 62 trained in BLSD and 68 as a control group. The trained group also performed an emergency simulation to assess their learning of practical skills. Results. Using the t test, significant differences emerged in the questionnaire scores between the case-control group. The results of the skill test were positive, even for the most difficult manoeuvres such as opening airways, assessing breathing, or using an AED (Automated External Defibrillator). Conclusion. Although there are still some open questions regarding the ability to retain these skills in the medium/long term, the study shows that life-saving manoeuvres can be effectively taught to primary school pupils. PMID- 27957492 TI - Effect of Dynamic Interaction between microRNA and Transcription Factor on Gene Expression. AB - MicroRNAs (miRNAs) are endogenous noncoding RNAs which participate in diverse biological processes in animals and plants. They are known to join together with transcription factors and downstream gene, forming a complex and highly interconnected regulatory network. To recognize a few overrepresented motifs which are expected to perform important elementary regulatory functions, we constructed a computational model of miRNA-mediated feedforward loops (FFLs) in which a transcription factor (TF) regulates miRNA and targets gene. Based on the different dynamic interactions between miRNA and TF on gene expression, four possible structural topologies of FFLs with two gate functions (AND gate and OR gate) are introduced. We studied the dynamic behaviors of these different motifs. Furthermore, the relationship between the response time and maximal activation velocity of miRNA was investigated. We found that the curve of response time shows nonmonotonic behavior in Co1 loop with OR gate. This may help us to infer the mechanism of miRNA binding to the promoter region. At last we investigated the influence of important parameters on the dynamic response of system. We identified that the stationary levels of target gene in all loops were insensitive to the initial value of miRNA. PMID- 27957494 TI - The Gut Microbial Community of Antarctic Fish Detected by 16S rRNA Gene Sequence Analysis. AB - Intestinal bacterial communities are highly relevant to the digestion, nutrition, growth, reproduction, and a range of fitness in fish, but little is known about the gut microbial community in Antarctic fish. In this study, the composition of intestinal microbial community in four species of Antarctic fish was detected based on 16S rRNA gene sequencing. As a result, 1 004 639 sequences were obtained from 13 samples identified into 36 phyla and 804 genera, in which Proteobacteria, Actinobacteria, Firmicutes, Thermi, and Bacteroidetes were the dominant phyla, and Rhodococcus, Thermus, Acinetobacter, Propionibacterium, Streptococcus, and Mycoplasma were the dominant genera. The number of common OTUs (operational taxonomic units) varied from 346 to 768, while unique OTUs varied from 84 to 694 in the four species of Antarctic fish. Moreover, intestinal bacterial communities in individuals of each species were not really similar, and those in the four species were not absolutely different, suggesting that bacterial communities might influence the physiological characteristics of Antarctic fish, and the common bacterial communities might contribute to the fish survival ability in extreme Antarctic environment, while the different ones were related to the living habits. All of these results could offer certain information for the future study of Antarctic fish physiological characteristics. PMID- 27957493 TI - The Relationship between MC1R Mutation and Plumage Color Variation in Pigeons. AB - The polymorphisms of MC1R gene play a crucial role in coat color variation in mammals; however, the relationship is still unclear in pigeons. In this study, we sequenced 741 bp fragment of the MC1R for 39 individuals with five plumage color patterns (gray plumage, n = 12; black plumage, n = 9; white plumage, n = 3; spotted plumage, n = 12; red plumage, n = 3). A total of three single nucleotide polymorphisms (SNPs) were detected, including G199A, G225A, and A466G, which subsequently determined four haplotypes (H1-H4). Among them, H1 is the predominant haplotype. Association analysis revealed that H1 and H3 were significantly associated with the black plumage trait (P < 0.05), while the H4 was significantly associated with gray plumage trait (P < 0.05). Furthermore, only diplotype H1H1 was significantly associated with black and gray traits of pigeons. Collectively, our study suggested an association between genetic variation of MC1R and plumage color in pigeon. PMID- 27957495 TI - Increased Activity of the Intracardiac Oxytocinergic System in the Development of Postinfarction Heart Failure. AB - Aim. The present study was designed to test the hypothesis that the development of postinfarction heart failure is associated with a change of activity of the intracardiac oxytocinergic system. Methods. Experiments were performed on male Sprague-Dawley rats subjected to myocardial infarction or sham surgery. Four weeks after the surgery, blood samples were collected and the samples of the left ventricle (LV) and right ventricle (RV) were harvested for evaluation of the mRNA expression (RT-PCR) of oxytocin (OT), oxytocin receptor (OTR), natriuretic peptides, and the level of OT and OTR protein (ELISA). The concentration of N terminal B-type natriuretic peptide was measured to determine the presence of heart failure. Results. Plasma NT-proBNP concentration was higher in the infarcted rats. In the infarcted rats, the expression of OT mRNA and the OT protein level were higher in the RV. There were no significant differences between infarcted and noninfarcted rats in the expression of OT mRNA and in the OT protein level in the fragments of the LV. In both the left and the right ventricles, OTR mRNA expression was lower but the level of OTR protein was higher in the infarcted rats. Conclusions. In the present study, we indicate that postinfarction heart failure is associated with an increased activity of the intracardiac oxytocinergic system. PMID- 27957496 TI - Evaluation of Lethal Giant Larvae as a Schistosomiasis Vaccine Candidate. AB - Schistosomiasis is a neglected tropical disease of humans, and it is considered to be the second most devastating parasitic disease after malaria. Eggs produced by normally developed female worms are important in the transmission of the parasite, and they responsible for the pathogenesis of schistosomiasis. The tumor suppressor gene lethal giant larvae (lgl) has an essential function in establishing apical-basal cell polarity, cell proliferation, differentiation, and tissue organization. In our earlier study, downregulation of the lgl gene induced a significant reduction in the egg hatching rate of Schistosoma japonicum (Sj) eggs. In this study, the Sjlgl gene was used as a vaccine candidate against schistosomiasis, and vaccination achieved and maintained a stable reduction of the egg hatching rate, which is consistent with previous studies, in addition to reducing the worm burden and liver egg burden in some trials. PMID- 27957498 TI - Tumorigenicity and Validity of Fluorescence Labelled Mesenchymal and Epithelial Human Oral Cancer Cell Lines in Nude Mice. AB - Tumorigenicity and metastatic activity can be visually monitored in cancer cells that were labelled with stable fluorescence. The aim was to establish and validate local and distant spread of subcutaneously previously injected fluorescence transduced human tongue cancer cell lines of epithelial and mesenchymal phenotype in nude mice. A total of 32 four-week-old male athymic Balb/c nude mice were randomly allocated into 4 groups (n = 8). A single dose of 0.3 mL PBS containing 1 * 107 of four different cancer cell-lines (UM1, UM1-GFP, UM2, and UM2-RFP) was injected subcutaneously into the right side of their posterolateral back. Validity assessment of the labelled cancer cells' tumorigenicity was assessed by physical examination, imaging, and histology four weeks after the injection. The tumor take rate of cancer cells was similar in animals injected with either parental or transduced cancer cells. Transduced cancer cells in mice were easily detectable in vivo and after cryosection using fluorescent imaging. UM1 cells showed increased tumor take rate and mean tumor volume, presenting with disorganized histopathological patterns. Fluorescence labelled epithelial and mesenchymal human tongue cancer cell lines do not change in tumorigenicity or cell phenotype after injection in vivo. PMID- 27957499 TI - beta-Lactoglobulin Influences Human Immunity and Promotes Cell Proliferation. AB - beta-Lactoglobulin (LG) is suspected to enhance or modulate human immune responses. Moreover, LG is also hypothesized to increase human cell proliferation. However, these potential functions of LG have not been directly or thoroughly addressed. In this study, we demonstrated that LG is a potent stimulator of cell proliferation using a hybridoma cell (a splenocyte fused with a myeloma cell) model. LG's ability to promote cell proliferation was lost when the protein is denatured. To further investigate the influence of LG's conformation on cell proliferation, we chemically modified LG by either carboxymethylation (CM) or acetylation and observed significantly reduced cell proliferation when the protein structure was altered. Furthermore, we proved that LG enhances cell proliferation via receptor-mediated membrane IgM receptor. These data indicated that nondenatured LG is the major component in milk that modulates cell proliferation. Collectively, our study showed that LG plays a key role in enhancing immune responses by promoting cell proliferation through IgM receptor. PMID- 27957500 TI - The Effect of Altitude on Intraocular Pressure in Vitrectomized Eyes with Sulfur Hexafluoride Tamponade by the Friedenwald Method: Rabbit Animal Model. AB - The aim of this study is to assess the change in intraocular pressure after a road trip, in eyes with different levels of filling with gas tamponade. Five rabbit eyes were subject to pars plana vitrectomy and gas tamponade (filling percentage: 25%, 50%, and 100% of nonexpansile SF6, 100% saline solution, and 100% room air). A sixth eye was injected with 0.35 cc of undiluted SF6 without vitrectomy. Guided by global positioning system, they were driven to the highest point of the highway connecting Mexico City with Puebla city and back, stopping every 300 m to assess intraocular pressure. The rabbit's scleral rigidity and estimation for human eyes were done by using the Friedenwald nomogram. Maximum altitude was 3209 m (Delta949 m). There were significant differences in intraocular pressure on the rabbit eyes filled with SF6 at 100%, 50%, 25%, and 100% room air. Per every 100 m of altitude rise, the intraocular pressure increased by 1.53, 1.0046, 0.971, and 0.97 mmHg, respectively. Using the human Friedenwald rigidity coefficient, the human eye estimate for intraocular pressure change was 2.1, 1.8, 1.4, and 1.1 mmHg per every 100 m of attitude rise. Altitude changes have a significant impact on intraocular pressure. The final effect depends on the percentage of vitreous cavity fill and scleral rigidity. PMID- 27957497 TI - Deregulated MicroRNAs in Biliary Tract Cancer: Functional Targets and Potential Biomarkers. AB - Biliary tract cancer (BTC) is still a fatal disease with very poor prognosis. The lack of reliable biomarkers for early diagnosis and of effective therapeutic targets is a major demanding problem in diagnosis and management of BTC. Due to the clinically silent and asymptomatic characteristics of the tumor, most patients are diagnosed at an already advanced stage allowing only for a palliative therapeutic approach. MicroRNAs are small noncoding RNAs well known to regulate various cellular functions and pathologic events including the formation and progression of cancer. Over the last years, several studies have shed light on the role of microRNAs in BTC, making them potentially attractive therapeutic targets and candidates as biomarkers. In this review, we will focus on the role of oncogenic and tumor suppressor microRNAs and their direct targets in BTC. Furthermore, we summarize and discuss data that evaluate the diagnostic power of deregulated microRNAs as possible future biomarkers for BTC. PMID- 27957501 TI - Analysis of Important Gene Ontology Terms and Biological Pathways Related to Pancreatic Cancer. AB - Pancreatic cancer is a serious disease that results in more than thirty thousand deaths around the world per year. To design effective treatments, many investigators have devoted themselves to the study of biological processes and mechanisms underlying this disease. However, it is far from complete. In this study, we tried to extract important gene ontology (GO) terms and KEGG pathways for pancreatic cancer by adopting some existing computational methods. Genes that have been validated to be related to pancreatic cancer and have not been validated were represented by features derived from GO terms and KEGG pathways using the enrichment theory. A popular feature selection method, minimum redundancy maximum relevance, was employed to analyze these features and extract important GO terms and KEGG pathways. An extensive analysis of the obtained GO terms and KEGG pathways was provided to confirm the correlations between them and pancreatic cancer. PMID- 27957502 TI - Assessment of Temperature Rise and Time of Alveolar Ridge Splitting by Means of Er:YAG Laser, Piezosurgery, and Surgical Saw: An Ex Vivo Study. AB - The most common adverse effect after bone cutting is a thermal damage. The aim of our study was to evaluate the bone temperature rise during an alveolar ridge splitting, rating the time needed to perform this procedure and the time to raise the temperature of a bone by 10 degrees C, as well as to evaluate the bone carbonization occurrence. The research included 60 mandibles (n = 60) of adult pigs, divided into 4 groups (n = 15). Two vertical and one horizontal cut have been done in an alveolar ridge using Er:YAG laser with set power of 200 mJ (G1), 400 mJ (G2), piezosurgery unit (G3), and a saw (G4). The temperature was measured by K-type thermocouple. The highest temperature gradient was noted for piezosurgery on the buccal and lingual side of mandible. The temperature rises on the bone surface along with the increase of laser power. The lower time needed to perform ridge splitting was measured for a saw, piezosurgery, and Er:YAG laser with power of 400 mJ and 200 mJ, respectively. The temperature rise measured on the bone over 10 degrees C and bone carbonization occurrence was not reported in all study groups. Piezosurgery, Er:YAG laser (200 mJ and 400 mJ), and surgical saw are useful and safe tools in ridge splitting surgery. PMID- 27957503 TI - Usher syndrome in Denmark: mutation spectrum and some clinical observations. AB - BACKGROUND: Usher syndrome (USH) is a genetically heterogeneous deafness blindness syndrome, divided into three clinical subtypes: USH1, USH2 and USH3. METHODS: Mutations in 21 out of 26 investigated Danish unrelated individuals with USH were identified, using a combination of molecular diagnostic methods. RESULTS: Before Next Generation Sequencing (NGS) became available mutations in nine individuals (1 USH1, 7 USH2, 1 USH3) were identified by Sanger sequencing of USH1C,USH2A or CLRN1 or by Arrayed Primer EXtension (APEX) method. Mutations in 12 individuals (7 USH1, 5 USH2) were found by targeted NGS of ten known USH genes. Five novel pathogenic variants were identified. We combined our data with previously published, and obtained an overview of the USH mutation spectrum in Denmark, including 100 unrelated individuals; 32 with USH1, 67 with USH2, and 1 with USH3. Macular edema was observed in 44 of 117 individuals. Olfactory function was tested in 12 individuals and found to be within normal range in all. CONCLUSION: Mutations that lead to USH1 were predominantly identified in MYO7A (75%), whereas all mutations in USH2 cases were identified in USH2A. The MYO7A mutation c.93C>A, p.(Cys31*) accounted for 33% of all USH1 mutations and the USH2A c.2299delG, p.(Glu767Serfs*21) variant accounted for 45% of all USH2 mutations in the Danish cohort. PMID- 27957504 TI - Increased Age-Dependent Risk of Death Associated With lukF-PV-Positive Staphylococcus aureus Bacteremia. AB - BACKGROUND: Panton-Valentine leucocidin is a Staphylococcus aureus virulence factor encoded by lukF-PV and lukS-PV that is infrequent in S aureus bacteremia (SAB), and, therefore, little is known about risk factors and outcome of lukF PV/lukS-PV-positive SAB. METHODS: This report is a register-based nationwide observational cohort study. lukF-PV was detected by polymerase chain reaction. Factors associated with the presence of lukF-PV were assessed by logistic regression analysis. Adjusted 30-day hazard ratios of mortality associated with lukF-PV status were computed by Cox proportional hazards regression analysis. RESULTS: Of 9490 SAB cases, 129 were lukF-PV-positive (1.4%), representing 14 different clonal complexes. lukF-PV was associated with younger age, absence of comorbidity, and methicillin-resistant S aureus. In unadjusted analysis, mortality associated with lukF-PV-positive SAB was comparable to SAB. However, lukF-PV-positive SAB nonsurvivors were significantly older and had more comorbidity. Consequently, by adjusted analysis, the risk of 30-day mortality was increased by 70% for lukF-PV-positive SAB compared with SAB (hazard ratio, 1.70; 95% confidence interval, 1.20-2.42; P = .003). CONCLUSIONS: lukF-PV-positive SAB is rare in Denmark but associated with a significantly increased risk of mortality. Although the risk of lukF-PV-positive SAB was highest in the younger age groups, >80% of deaths associated with lukF-PV-positive SAB occurred in individuals older than 55 years. PMID- 27957506 TI - Use of Nucleic Acid Amplification Tests in Tuberculosis Patients in California, 2010-2013. AB - BACKGROUND: Nucleic acid amplification tests (NAATs) have been used as a diagnostic tool for tuberculosis (TB) in the United States for many years. We sought to assess NAAT use in TB patients in California during a period of time when NAAT availability increased throughout the world. METHODS: We conducted a retrospective review of surveillance data from 6051 patients with culture confirmed pulmonary TB who were reported to the California TB registry during 2010-2013. RESULTS: Only 2336 of 6051 (39%) TB patients had a NAAT for diagnosis before culture results. Although 90% (N = 2101) with NAAT had positive test results, 9% (N = 217) had falsely negative NAAT results, and 0.8% (N = 18) had indeterminate NAAT results. The median time from specimen collection to TB treatment initiation was shorter when NAAT was used (3 vs 14 days, P < .0001), and patients with a positive NAAT result initiated treatment earlier than patients with a falsely negative result (1 vs 11 days from NAAT report, P < .0001). We confirmed the increased sensitivity of NAAT compared with acid-fast bacilli (AFB) smear microscopy in our study population; 92 of 145 AFB smear negative patients had positive NAATs. Median time from specimen collection to NAAT result report differed by health jurisdiction, from 1 to 11 working days. CONCLUSIONS: Increased use of NAATs in diagnosis of pulmonary TB could decrease the time-to-treatment initiation and consequently decrease transmission. However, differential use and access to NAAT may prevent full realization of NAAT benefits in California. PMID- 27957505 TI - Bacterial Colonization and Antibiotic Resistance in a Prospective Cohort of Newborn Infants During the First Year of Life. AB - BACKGROUND: Infants are virtually sterile at birth and frequently use antibiotics; our objective was to (1) characterize the longitudinal colonization with bacterial pathogens and associated antibiotic resistance in a cohort of community-dwelling infants in Northeast Ohio and (2) describe longitudinal concurrent antibiotic and daycare exposures. METHODS: For 35 newborns, nasopharyngeal swabs were cultured for Streptococcus pneumoniae, anterior nasal for Staphylococcus aureus, and perirectal for extended-spectrum beta-lactamase (ESBL)-producing Gram-negative enteric bacteria, at 3-month intervals for 12 months. Infant and household antibiotics and daycare exposure were assessed longitudinally. RESULTS: Thirteen infants received perinatal or nursery antibiotics. By 3 months, at least 22 were colonized with Gram-negative bacteria; 2 with S pneumoniae (type 19A, resistant; 15C, susceptible), 5 with methicillin susceptible S aureus. By 12 months, at least 22 of 35 infants received antibiotics, 20 had household members with antibiotics, and 12 attended daycare; 7 more had household members with daycare exposure. The ESBL-producing organisms were not identified. At least 10 infants were colonized at some time with an antibiotic-resistant organism, 3 more with pathogens displaying intermediate resistance. Pathogen colonization and resistance were intermittent and inconsistent. CONCLUSIONS: In a community-based cohort followed from birth, early antibiotic and daycare exposures are common, especially considering perinatal maternal exposures. Colonization patterns of Gram-negative bacteria, S pneumoniae, S aureus, and resistant pneumococci are strikingly dynamic. Further research can identify key areas for potential interventions to maximize clinical antibiotic outcomes while minimizing future resistance. PMID- 27957507 TI - Antibodies to inositol 1,4,5-triphosphate receptor 1 in patients with cerebellar disease. AB - OBJECTIVE: To describe newly identified autoantibodies associated with cerebellar disorders. DESIGN/METHODS: We first screened the sera of 15 patients with cerebellar ataxia, without any known associated autoantibodies, with immunocytochemistry on mouse brain. After characterization and validation of a newly identified antibody, 85 additional patients with suspected autoimmune cerebellar disease were screened using a cell-based assay. RESULTS: Immunoglobulin G from one of the first 15 patients demonstrated a distinct staining pattern on Purkinje neurons. This autoantibody, as characterized further by immunoprecipitation and mass spectrometry, was binding inositol 1,4,5 triphosphate receptor 1 (IP3R1), an intracellular channel that mediates the release of Ca2+ from intracellular stores. Anti-IP3R1 specificity was then validated with a cell-based assay. On this basis, screening of 85 other patients with cerebellar disease revealed 2 additional IP3R1-positive patients. All 3 patients presented with cerebellar ataxia; the first was eventually diagnosed with primary progressive multiple sclerosis, the second had a homozygous CAG insertion at the gene TBP, and the third was thought to have a neurodegenerative disease. CONCLUSIONS: We independently identified an autoantibody against IP3R1, a protein highly expressed in Purkinje neurons, confirming an earlier report. Because a mouse knockout model for IP3R1 exhibits ataxia and epilepsy, this autoantibody may have a functional role. The heterogeneity of the antibody positive patients suggests that this antibody may either have a direct involvement in disease pathogenesis or it is a surrogate marker secondary to cerebellar injury. Anti-IP3R1 antibodies should be further explored in various ataxic and epileptic syndromes as they may denote a marker of response to immunotherapies. PMID- 27957509 TI - Characteristics and pharmacodynamics of severe neuroinflammation in a child with neurolupus. PMID- 27957510 TI - Systematic Postoperative Nausea Prophylaxis Feedback Improves Clinical Performance in Anesthesiology Residents. AB - BACKGROUND: Electronic medical records can generate a wealth of information regarding compliance with perioperative clinical guidelines as well as patient outcomes. Utilizing this information to provide resident physicians with measures of their own clinical performance may positively impact residents' clinical performance. We hypothesize that providing residents with objective measures of their individual adherence to evidence based postoperative nausea and vomiting (PONV) management protocols will improve their compliance with standardized treatment methods. METHODS: We conducted a retrospective baseline analysis of junior anesthesiology residents' compliance with PONV prophylaxis guidelines for high-risk patients. This was followed by a prospective cohort study, before and after an educational intervention, a 15 minute lecture on PONV prophylaxis. The number of pharmacologic prophylactic interventions were tabulated for each operative case and reported back to individual residents in blind and anonymous fashion. The primary outcome was the use of two or more prophylactic interventions for a high-risk patient, while the secondary outcome was the use of three or more prophylactic interventions. A follow up survey was administered to participating residents regarding the use of their individualized clinical performance. RESULTS: After implementation of feedback, patients received a significantly higher amount of PONV prophylactic treatments (p=0.001, means of 1.35 vs. 1.99). Comparison of percentage compliance was 38% vs 73%, respectively (p<0.001). In a follow up survey, residents received the feedback intervention well and had no significant concern in the dissemination of deidentified performance outcomes publically. CONCLUSIONS: Resident compliance with PONV treatment guidelines was improved merely by auditing performance and providing individualized feedback. High-risk patients appear to receive more prophylactic agents after performance feedback and may be more effective than a more commonly used educational intervention to address the same topic. Providing direct performance feedback may be a useful tool for integration into graduate medical education programs. PMID- 27957508 TI - Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration. AB - OBJECTIVE: To report on a novel neuronal target antigen in 3 patients with autoimmune cerebellar degeneration. METHODS: Three patients with subacute to chronic cerebellar ataxia and controls underwent detailed clinical and neuropsychological assessment together with quantitative high-resolution structural MRI. Sera and CSF were subjected to comprehensive autoantibody screening by indirect immunofluorescence assay (IFA) and immunoblot. Immunoprecipitation with lysates of hippocampus and cerebellum combined with mass spectrometric analysis was used to identify the autoantigen, which was verified by recombinant expression in HEK293 cells and use in several immunoassays. Multiparameter flow cytometry was performed on peripheral blood and CSF, and peripheral blood was subjected to T-cell receptor spectratyping. RESULTS: Patients presented with a subacute to chronic cerebellar and brainstem syndrome. MRI was consistent with cortical and cerebellar gray matter atrophy associated with subsequent neuroaxonal degeneration. IFA screening revealed strong immunoglobulin G1 reactivity in sera and CSF with hippocampal and cerebellar molecular and granular layers, but not with a panel of 30 recombinantly expressed established neural autoantigens. Neurochondrin was subsequently identified as the target antigen, verified by IFA and immunoblot with HEK293 cells expressing human neurochondrin as well as the ability of recombinant neurochondrin to neutralize the autoantibodies' tissue reaction. Immune phenotyping revealed intrathecal accumulation and activation of B and T cells during the acute but not chronic phase of the disease. T-cell receptor spectratyping suggested an antigen-specific T-cell response accompanying the formation of antineurochondrin autoantibodies. No such neurochondrin reactivity was found in control cohorts of various neural autoantibody-associated neurologic syndromes, relapsing-remitting multiple sclerosis, cerebellar type of multiple system atrophy, hereditary cerebellar ataxias, other neurologic disorders, or healthy donors. CONCLUSION: Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration. PMID- 27957511 TI - Assessing the Academic Productivity of Foundation for Anesthesia Education and Research (FAER) Resident Scholars. AB - BACKGROUND: The Foundation for Anesthesia Education and Research Resident Scholar Program (RSP) supports academically promising anesthesiology residents to attend mentoring seminars at the American Society of Anesthesiologists annual meeting. The objective of this study was to describe the career paths of RSP participants. METHODS: Prior RSP participants were surveyed regarding their academic productivity and their evaluation of the RSP experience. Univariate statistics were used to characterize the survey results. RESULTS: A total of 882 RSP participants were surveyed. The response rate was 26%. Seventy-two percent of respondents had worked in an academic institution, and 45% (95% CI: 38%-51%) were currently at an academic institution, which is higher than the national average of 18% (P<0.001). CONCLUSIONS: This program may be a model for supporting the development of future academic anesthesiologists. PMID- 27957512 TI - Gender Diversity in Anesthesiology Programs: The Role of Current Residents and Department Leadership in the 2014 Match Results. AB - BACKGROUND: Nearly half of graduates of American medical colleges are women, yet the percentage of women entering accredited anesthesiology programs remains less than 40%. There are obviously many factors that influence the choice of a residency training program, from geography to reputation to the atmosphere, composition and camaraderie of the department. We examined whether a greater number of current female residents, a female Chair, or a female Program Director were associated with a program matching a greater number of female candidates in the 2014 NRMP Match. METHODS: An electronic questionnaire was sent to all 132 ACGME-accredited anesthesiology programs immediately following the 2014 Match seeking information on the gender mix of their current residents, the gender of the Chair and Program Director, and the gender composition of their newly-matched candidates. RESULTS: The percentage of current female residents was significantly associated with the percentage of incoming female residents (p = 0.013). There was no association between the percentage of new female residents obtained in the Match and the presence of a female Chair or Program Director. CONCLUSIONS: The results of the 2013 NRMP anesthesiology match indicate that programs with a higher proportion of female residents were able to sustain that diversity and successfully match a higher percentage of female candidates. No correlation was seen with Chair and Program Director gender, suggesting further work is needed to define the influence of female role models on female applicants' choice of anesthesiology residency programs. PMID- 27957513 TI - APEP - Anesthesiology Preceptorship Enrichment Program...A Popular Student Curriculum AND a Recruiting Tool? AB - BACKGROUND: APEP- Anesthesiology Preceptorship Enrichment Program, is a 7-month curriculum for MS1s and MS2s, providing early clinical exposure to anesthesiology. APEP students meet monthly with their anesthesiology preceptors in an intraoperative setting and review basic science lecture material with an anesthesia focus. APEP is a consistently popular annual curriculum, yet its effectiveness as a recruiting tool was unknown. This curriculum was evaluated for its effectiveness in attracting students into anesthesiology. METHODS: Annual surveys were sent to APEP students querying if they were MORE or LESS interested in anesthesiology as a career choice after APEP participation. Because the survey was not anonymous, follow up data was obtained for each MS1 and MS2, confirming their match into anesthesiology. Non-survey data was also reviewed for students' APEP involvement, career choice and match results. RESULTS: Of the 77 APEP students surveyed from 2006-2010, 54/77 (70%) were MORE interested in anesthesiology as a career choice after participating in APEP and 23 of the 54 (43%) applied to/matched into anesthesiology. Collected data also reinforced APEP's supporting role in developing student interest into the field of anesthesiology. From 2008-2012, of the 45 students who matched into anesthesiology, 28 (62%) were involved with APEP. Since the launch of APEP, there has been a 57% increase in students from the previous five years matching into anesthesiology which is 18 percentage points higher than the national upward trend. CONCLUSIONS: APEP is an educational tool that is effective for attracting students into the field of anesthesiology. PMID- 27957514 TI - Goal-Oriented Anesthesia Week for MS III Students. AB - BACKGROUND: Third year medical students at our institution are required to complete a one-week rotation in anesthesia as part of their required twelve week surgery clerkship. During this constrained time, our aim was to provide students with a focused and goal-oriented preview of anesthesiology which would allow students going into various fields to have an appreciation of the field. CURRICULUM DESIGN: The one-week curriculum is a combination of lecture, simulation, operating room teaching and hands on experience aimed at providing students with some fundamentals of procedural skills and a knowledge base of anesthesia. To address the basic knowledge component, students are assigned a daily topic to review and discuss with their assigned resident mentor. From a procedural perspective, students gain basic airway management and IV skills during a half day in the Electroconvulsive Therapy (ECT) clinic where they primarily learn bag-mask ventilation and peripheral IV techniques. They additionally have a preoperative evaluation lecture and an airway simulation workshop. CURRICULUM EVALUATION: At the end of the rotation, students are required to fill out an online survey. Feedback from the survey was used to help further modify the goal-oriented curriculum. CONCLUSIONS: The results of the survey overall revealed students had an overwhelmingly positive experience during their week in the newly designed curriculum. Continued feedback will help us with further curriculum modifications as necessary. PMID- 27957515 TI - Ultrasound Skill and Application of Knowledge Assessment using an Innovative OSCE Competition-Based Simulation Approach. AB - BACKGROUND: Despite Point-of Care Ultrasound (PoC US) rapidly becoming an important tool in perioperative medicine structured education, PoC US is currently rarely integrated into the anesthesiology residency curriculum. The aim of this project was to assess the current ultrasound skills of anesthesiology residents at one institution and evaluate the needs for development of a formal ultrasound curriculum. METHODS: A event containing 6 different OSCE PoC US stations was developed with following stations: vascular, peripheral nerve block, lung ultrasound, transthoracic echocardiography (TTE) human model, pathologic TTE (simulator), and inferior vena cava (IVC) evaluation (simulator). The ability to obtain an US image or to interpret the US information was evaluated using a checklist and global rating scale. After IRB approval, anesthesiology residents participated in this event (n=30; PGY 2-4). RESULTS: All residents were able to identify vascular structures and demonstrated sufficient ultrasound skill for lung anatomy IVC assessment. The lowest scores were observed for performing and interpreting TTE. There were no differences in resident ultrasound skills for all OSCE stations except minor differences between PGY 2 and PGY 4 in TTE pathology station. While more advanced residents had more clinical exposure to ultrasound for procedures and point-of-care diagnosis, we did not find growth in ultrasound skill level. Despite performing sufficient ultrasound guided peripheral nerve blocks, PGY 4 residents were not able to consistently identify common nerve block targets. CONCLUSIONS: Our findings indicate that exposure and clinical use of ultrasound for procedures and point-of-care diagnosis is not sufficient for developing competency in PoC US and that a formal curriculum throughout the entire anesthesiology residency is needed to ensure PoC US competency. PMID- 27957516 TI - Standard-dose vs. low-dose CT protocols in the evaluation of localized lung lesions: Capability for lesion characterization-iLEAD study. AB - OBJECTIVE: To determine the lesion characterization capability by low dose CT for localized lung lesions in comparison with standard dose CT. SUBJECTS AND METHODS: Approval for this study was granted by our Institutional Review Board. Fifty-two consecutive patients (36 males and 16 females, median age of 71 years.) who had CT examinations for evaluation of lung lesions comprise the study population. Two chest CT scans were performed with current time product of 50 and 150 mAs at 120 kVp, with the same scan length with a 16 detector-row CT scanner. Three readers evaluated 52 target lesions and assigned an overall impression score to each target lesion, using a 5 point scale from 1 (definitely benign) to 5 (definitely malignant). Six features of the lesions including lesion type, margin characteristics, calcification, lobulation, speculation, and pleural indentation were also reported with 5-point scales. The weighted kappa analyses and receiver operating characteristic analysis were used for analysis. RESULTS: The mean kappa value between low-and standard-dose CT was 0.82 for overall impression of the lesions, showing almost perfect agreement. Area under the curve of low-dose CT (Az = 0.74) had no significant difference from that of standard-dose CT (Az = 0.74) (p = 0.61). The kappa values for six lesion features ranged from 0.45 to 0.83, showing moderate to almost perfect agreement. CONCLUSION: Lesion characterization capability by low-dose CT images was comparable to that by standard-dose CT images and therefore sufficient for evaluation of localized lung lesions. PMID- 27957517 TI - Crohn's disease Activity: Abdominal Computed Tomography Histopathology Correlation. AB - PURPOSE: Crohn's disease is a type of inflammatory bowel disease affecting estimated 4 million people worldwide. Therapy stratification of Crohn's disease (CD) is mainly based on the inflammatory activity being assessed by endoscopic biopsy and clinical criteria. Cross-sectional imaging allows for the assessment of structural characteristics of the entire gastrointestinal tract including small bowel loops and may provide potential non-invasive image-based biomarkers for the inflammatory activity of CD. The aim of this study was to explore the predictive value of Computed Tomography-based morphologic patterns for inflammatory activity in CD. MATERIAL AND METHODS: 42 patients diagnosed with CD were included in a retrospective study (13 male, 29 female, median age 32 years). Abdominal CT imaging was carried out on symptomatic patients at a single institution 0-10 days prior to endoscopic biopsy or surgery using a protocol optimized for the characterization of structural bowel alterations. Image data were initially reviewed independently by three radiologists and discrepancies were settled in consensus with a focus on mesenteric fat stranding and combing, mesenteric adenopathy, mesenteric abscess, intraperitoneal free fluid, fistula, skip lesions, highest wall thickness and the localization of the affected bowel. The extent of inflammatory activity in the bowel wall was determined subsequently by histological analysis. RESULTS: All intestinal and extraintestinal CT findings except the mesenteric comb sign showed a tendency towards higher extent or prevalence in patients with high histological inflammatory activity score, especially median bowel wall thickness (6.0 mm vs. 3.5 mm), mesenteric abscesses (32% vs. 0%) and mesenteric adenopathy (94% vs. 45%). Spearman rank order correlation coefficient indicated a significant correlation of bowel wall thickness (r = 0.40, p < 0.05), mesenteric adenopathy (r = 0.54, p < 0.05), mesenteric abscess (r = 0.33, p < 0.05) and mesenteric fat stranding (r = 0.33, p < 0.05) with the histological inflammatory activity score. CONCLUSION: CT-based biomarkers including wall thickness, mesenteric fat stranding, mesenteric lymphadenopathy and mesenteric abscess positively correlated with the histological inflammatory activity score and therefore provided additional information for therapy stratification in symptomatic patients with CD, particularly as most of these biomarkers are hidden from endoscopy. PMID- 27957518 TI - Diffusion-weighted MR imaging of pancreatic cancer: A comparison of mono exponential, bi-exponential and non-Gaussian kurtosis models. AB - OBJECTIVES: To compare two Gaussian diffusion-weighted MRI (DWI) models including mono-exponential and bi-exponential, with the non-Gaussian kurtosis model in patients with pancreatic ductal adenocarcinoma. MATERIALS AND METHODS: After written informed consent, 15 consecutive patients with pancreatic ductal adenocarcinoma underwent free-breathing DWI (1.5T, b-values: 0, 50, 150, 200, 300, 600 and 1000 s/mm2). Mean values of DWI-derived metrics ADC, D, D*, f, K and DK were calculated from multiple regions of interest in all tumours and non tumorous parenchyma and compared. Area under the curve was determined for all metrics. RESULTS: Mean ADC and DK showed significant differences between tumours and non-tumorous parenchyma (both P < 0.001). Area under the curve for ADC, D, D*, f, K, and DK were 0.77, 0.52, 0.53, 0.62, 0.42, and 0.84, respectively. CONCLUSION: ADC and DK could differentiate tumours from non-tumorous parenchyma with the latter showing a higher diagnostic accuracy. Correction for kurtosis effects has the potential to increase the diagnostic accuracy of DWI in patients with pancreatic ductal adenocarcinoma. PMID- 27957520 TI - On Priming Action: Conclusions from a Meta-Analysis of the Behavioral Effects of Incidentally-Presented Words. AB - This paper presents a summary of the conclusions drawn from a meta-analysis of the behavioral impact of presenting words connected to an action or a goal representation (Weingarten et al., 2016). The average and distribution of 352 effect sizes from 133 studies (84 reports) revealed a small behavioral priming effect (dFE = 0.332, dRE = 0.352), which was robust across methodological procedures and only minimally biased by the publication of positive (vs. negative) results. More valued behavior or goal concepts (e.g., associated with important outcomes or values) were associated with stronger priming effects than were less valued behaviors. In addition, opportunities for goal satisfaction appeared to decrease priming effects. PMID- 27957521 TI - Dataset of the absorption, emission and excitation spectra and fluorescence intensity graphs of fluorescent cyanine dyes for the quantification of low amounts of dsDNA. AB - This article describes data related to a research article entitled "Fluorescent cyanine dyes for the quantification of low amounts of dsDNA" (B. Bruijns, R. Tiggelaar, J. Gardeniers, 2016) [1]. Six cyanine dsDNA dyes - EvaGreen, SYBR Green, PicoGreen, AccuClear, AccuBlue NextGen and YOYO-1 - are investigated and in this article the absorption spectra, as well as excitation and emission spectra, for all six researched cyanine dyes are given, all recorded under exactly identical experimental conditions. The intensity graphs, with the relative fluorescence in the presence of low amounts of dsDNA, are also provided. PMID- 27957519 TI - Low dose chest CT protocol (50 mAs) as a routine protocol for comprehensive assessment of intrathoracic abnormality. AB - PURPOSE: To determine the diagnostic capability of low-dose CT (50 mAs) in comparison to standard-dose CT (150 mAs). MATERIALS AND METHODS: Fifty-nine consecutive patients underwent two non-contrast chest CT scans with different current-time products (50 and 150 mAs at 120 kVp) on a 64-detector row CT scanner. Three board certified chest radiologists independently reviewed 118 series of 2 mm-thick images (2 series for each of 59 patients) in a random order. The readers assessed abnormal findings including emphysema, ground-glass opacity, reticular opacity, micronodules, bronchiectasis, honeycomb, nodules (>5 mm), aortic aneurysm, coronary artery calcification, pericardial and pleural effusion, pleural thickening, mediastinal tumor and lymph node enlargement. Five-point scale from 1 (definitely absent) to 5 (definitely present) was used to record the results. The rates of score agreement between two images were calculated. Deviation of one observer's score from other two observers was compared between low dose CT and standard dose CT. RESULTS: Mean agreement rate of the lung parenchymal findings between low dose CT and standard dose CT images was 0.836 (range, 0.746-0.926). Mean agreement rates for mediastinal and pleural findings were 0.920 (range, 0.735-1.000). There was no statistically significant difference in the deviation of the observers' scores between low-dose CT and standard-dose CT. CONCLUSION: Low dose CT protocol at 50 mAs can produce the screening results consistent with standard dose CT protocol (150 mAs), supporting routine use of low dose chest CT protocol. PMID- 27957522 TI - Staphylococcus simulans: An emerging cutaneous pathogen. PMID- 27957523 TI - Recurrent acral angioosteoma cutis in a pregnant patient. PMID- 27957524 TI - Fetal Hemodynamic Parameters in Low Risk Pregnancies: Doppler Velocimetry of Uterine, Umbilical, and Middle Cerebral Artery. AB - Objective. To elaborate curves of longitudinal reference intervals of pulsatility index (PI) and systolic velocity (SV) for uterine (UtA), umbilical (UA), and middle cerebral arteries (MCA), in low risk pregnancies. Methods. Doppler velocimetric measurements of PI and SV from 63 low risk pregnant women between 16 and 41 weeks of gestational age. Means (+/-SD) for intervals of gestational age and percentiles 5, 50, and 95 were calculated for each parameter. The Intraclass Correlation Coefficients (ICC) were also estimated for assessing intra- and intervariability of measurements. Results. Mean PI of UtA showed decreasing values during pregnancy, but no regular pattern was identified for mean SV. For UA, PI decreased and SV increased along gestation. MCA presented PI increasing values until 32-35 weeks. SV showed higher levels with increasing gestation. High ICC values indicated good reproducibility. Conclusions. Reference intervals for the assessment of SV and PI of UtA, UA, and MCA were established. These reference intervals showed how a normal pregnancy is expected to progress regarding these Doppler velocimetric parameters and are useful to follow high risk pregnancies. The comparison between results using different curves may provide insights about the best patterns to be used. PMID- 27957525 TI - Intake, Nutrient Apparent Digestibility, and Ruminal Constituents of Crossbred Dorper * Santa Ines Sheep Fed Diets with Babassu Mesocarp Flour. AB - The aim of this study was to evaluate the effect on intake, apparent digestibility, and ruminal constituents of sheep in response to the addition of increasing levels of babassu mesocarp flour (BMF) to the diet. Twenty crossbred sheep (29.17 +/- 2.23 kg) were used in a randomized complete block design. Lambs were confined for 21 days, with 16 days for diet adaptation and 5 days for data collection, in which they were fed an isonitrogenous diet (16.5 +/- 0.2 CP, DM basis) containing 70% of concentrate and 30% (DM basis) of Tifton 85 hay. Increasing levels of BMF were 0, 10, 20, and 30% (DM basis). There was a quadratic effect (P < 0.05) on the DM intake, nutrients intake, and digestibility of CP and NFC. The digestibility of DM, OM, TC, and NDF decreased linearly, while EE digestibility increased linearly with increasing levels of BMF. The high NDF content presented in the chemical composition of the babassu mesocarp flour ranked the same as fibrous food, which can limit the inclusion in the diet of high production animals. So, babassu mesocarp flour is an alternative for energy source in lambs feed and can be added at levels up to 10%. PMID- 27957526 TI - Mammalian FMRP S499 Is Phosphorylated by CK2 and Promotes Secondary Phosphorylation of FMRP. AB - The fragile X mental retardation protein (FMRP) is an mRNA-binding regulator of protein translation that associates with 4-6% of brain transcripts and is central to neurodevelopment. Autism risk genes' transcripts are overrepresented among FMRP-binding mRNAs, and FMRP loss-of-function mutations are responsible for fragile X syndrome, the most common cause of monogenetic autism. It is thought that FMRP-dependent translational repression is governed by the phosphorylation of serine residue 499 (S499). However, recent evidence suggests that S499 phosphorylation is not modulated by metabotropic glutamate receptor class I (mGluR-I) or protein phosphatase 2A (PP2A), two molecules shown to regulate FMRP translational repression. Moreover, the mammalian FMRP S499 kinase remains unknown. We found that casein kinase II (CK2) phosphorylates murine FMRP S499. Further, we show that phosphorylation of FMRP S499 permits phosphorylation of additional, nearby residues. Evidence suggests that these nearby residues are modulated by mGluR-I and PP2A pathways. These data support an alternative phosphodynamic model of FMRP that is harmonious with prior studies and serves as a framework for further investigation. PMID- 27957527 TI - Deletion of the Mouse Homolog of CACNA1C Disrupts Discrete Forms of Hippocampal Dependent Memory and Neurogenesis within the Dentate Gyrus. AB - L-type voltage-gated calcium channels (LVGCCs) have been implicated in various forms of learning, memory, and synaptic plasticity. Within the hippocampus, the LVGCC subtype, CaV1.2 is prominently expressed throughout the dentate gyrus. Despite the apparent high levels of CaV1.2 expression in the dentate gyrus, the role of CaV1.2 in hippocampal- and dentate gyrus-associated forms of learning remain unknown. To address this question, we examined alternate forms of hippocampal-dependent associative and spatial memory in mice lacking the mouse ortholog of CACNA1C (Cacna1c), which encodes CaV1.2, with dentate gyrus function implicated in difficult forms of each task. We found that while the deletion of CaV1.2 did not impair the acquisition of fear of a conditioned context, mice lacking CaV1.2 exhibited deficits in the ability to discriminate between two contexts, one in which the mice were conditioned and one in which they were not. Similarly, CaV1.2 knock-out mice exhibited normal acquisition and recall of the location of the hidden platform in a standard Morris water maze, but were unable to form a memory of the platform location when the task was made more difficult by restricting the number of available spatial cues. Within the dentate gyrus, pan-neuronal deletion of CaV1.2 resulted in decreased cell proliferation and the numbers of doublecortin-positive adult-born neurons, implicating CaV1.2 in adult neurogenesis. These results suggest that CaV1.2 is important for dentate gyrus associated tasks and may mediate these forms of learning via a role in adult neurogenesis and cell proliferation within the dentate gyrus. PMID- 27957529 TI - Contrast Enhancement without Transient Map Expansion for Species-Specific Vocalizations in Core Auditory Cortex during Learning. AB - Tonotopic map plasticity in the adult auditory cortex (AC) is a well established and oft-cited measure of auditory associative learning in classical conditioning paradigms. However, its necessity as an enduring memory trace has been debated, especially given a recent finding that the areal expansion of core AC tuned to a newly relevant frequency range may arise only transiently to support auditory learning. This has been reinforced by an ethological paradigm showing that map expansion is not observed for ultrasonic vocalizations (USVs) or for ultrasound frequencies in postweaning dams for whom USVs emitted by pups acquire behavioral relevance. However, whether transient expansion occurs during maternal experience is not known, and could help to reveal the generality of cortical map expansion as a correlate for auditory learning. We thus mapped the auditory cortices of maternal mice at postnatal time points surrounding the peak in pup USV emission, but found no evidence of frequency map expansion for the behaviorally relevant high ultrasound range in AC. Instead, regions tuned to low frequencies outside of the ultrasound range show progressively greater suppression of activity in response to the playback of ultrasounds or pup USVs for maternally experienced animals assessed at their pups' postnatal day 9 (P9) to P10, or postweaning. This provides new evidence for a lateral-band suppression mechanism elicited by behaviorally meaningful USVs, likely enhancing their population-level signal-to noise ratio. These results demonstrate that tonotopic map enlargement has limits as a construct for conceptualizing how experience leaves neural memory traces within sensory cortex in the context of ethological auditory learning. PMID- 27957528 TI - Arp2/3 and VASP Are Essential for Fear Memory Formation in Lateral Amygdala. AB - The actin cytoskeleton is involved in key neuronal functions such as synaptic transmission and morphogenesis. However, the roles and regulation of actin cytoskeleton in memory formation remain to be clarified. In this study, we unveil the mechanism whereby actin cytoskeleton is regulated to form memory by exploring the roles of the major actin-regulatory proteins Arp2/3, VASP, and formins in long-term memory formation. Inhibition of Arp2/3, involved in actin filament branching and neuronal morphogenesis, in lateral amygdala (LA) with the specific inhibitor CK-666 during fear conditioning impaired long-term, but not short-term, fear memory. The inactive isomer CK-689 had no effect on memory formation. We observed that Arp2/3 is colocalized with the actin-regulatory protein profilin in LA neurons of fear-conditioned rats. VASP binding to profilin is needed for profilin-mediated stabilization of actin cytoskeleton and dendritic spine morphology. Microinjection of poly-proline peptide [G(GP5)3] into LA, to interfere with VASP binding to profilin, impaired long-term but not short-term fear memory formation. Control peptide [G(GA5)3] had no effect. Inhibiting formins, which regulate linear actin elongation, in LA during fear conditioning by microinjecting the formin-specific inhibitor SMIFH2 into LA had no effect on long-term fear memory formation. We conclude that Arp2/3 and VASP, through the profilin binding site, are essential for the formation of long-term fear memory in LA and propose a model whereby these proteins subserve cellular events, leading to memory consolidation. PMID- 27957530 TI - Ipsilateral and Contralateral Retinal Ganglion Cells Express Distinct Genes during Decussation at the Optic Chiasm. AB - The increasing availability of transcriptomic technologies within the last decade has facilitated high-throughput identification of gene expression differences that define distinct cell types as well as the molecular pathways that drive their specification. The retinal projection neurons, retinal ganglion cells (RGCs), can be categorized into distinct morphological and functional subtypes and by the laterality of their projections. Here, we present a method for purifying the sparse population of ipsilaterally projecting RGCs in mouse retina from their contralaterally projecting counterparts during embryonic development through rapid retrograde labeling followed by fluorescence-activated cell sorting. Through microarray analysis, we uncovered the distinct molecular signatures that define and distinguish ipsilateral and contralateral RGCs during the critical period of axonal outgrowth and decussation, with more than 300 genes differentially expressed within these two cell populations. Among the differentially expressed genes confirmed through in vivo expression validation, several genes that mark "immaturity" are expressed within postmitotic ipsilateral RGCs. Moreover, at least one complementary pair, Igf1 and Igfbp5, is upregulated in contralateral or ipsilateral RGCs, respectively, and may represent signaling pathways that determine ipsilateral versus contralateral RGC identity. Importantly, the cell cycle regulator cyclin D2 is highly expressed in peripheral ventral retina with a dynamic expression pattern that peaks during the period of ipsilateral RGC production. Thus, the molecular signatures of ipsilateral and contralateral RGCs and the mechanisms that regulate their differentiation are more diverse than previously expected. PMID- 27957532 TI - Temporary Depletion of Microglia during the Early Postnatal Period Induces Lasting Sex-Dependent and Sex-Independent Effects on Behavior in Rats. AB - Microglia are the primary immune cells of the brain and function in multiple ways to facilitate proper brain development. However, our current understanding of how these cells influence the later expression of normal behaviors is lacking. Using the laboratory rat, we administered liposomal clodronate centrally to selectively deplete microglia in the developing postnatal brain. We then assessed a range of developmental, juvenile, and adult behaviors. Liposomal clodronate treatment on postnatal days 0, 2, and 4 depleted microglia with recovery by about 10 days of age and induced a hyperlocomotive phenotype, observable in the second postnatal week. Temporary microglia depletion also increased juvenile locomotion in the open field test and decreased anxiety-like behaviors in the open field and elevated plus maze. These same rats displayed reductions in predator odor-induced avoidance behavior, but increased their risk assessment behaviors compared with vehicle-treated controls. In adulthood, postnatal microglia depletion resulted in significant deficits in male-specific sex behaviors. Using factor analysis, we identified two underlying traits-behavioral disinhibition and locomotion-as being significantly altered by postnatal microglia depletion. These findings further implicate microglia as being critically important to the development of juvenile and adult behavior. PMID- 27957533 TI - Characterizing Population EEG Dynamics throughout Adulthood. AB - For decades, electroencephalography (EEG) has been a useful tool for investigating the neural mechanisms underlying human psychological processes. However, the amount of time needed to gather EEG data means that most laboratory studies use relatively small sample sizes. Using the Muse, a portable and wireless four-channel EEG headband, we obtained EEG recordings from 6029 subjects 18-88 years in age while they completed a category exemplar task followed by a meditation exercise. Here, we report age-related changes in EEG power at a fine chronological scale for delta, theta, alpha, and beta bands, as well as peak alpha frequency and alpha asymmetry measures for both frontal and temporoparietal sites. We found that EEG power changed as a function of age, and that the age related changes depended on sex and frequency band. We found an overall age related shift in band power from lower to higher frequencies, especially for females. We also found a gradual, year-by-year slowing of the peak alpha frequency with increasing age. Finally, our analysis of alpha asymmetry revealed greater relative right frontal activity. Our results replicate several previous age- and sex-related findings and show how some previously observed changes during childhood extend throughout the lifespan. Unlike previous age-related EEG studies that were limited by sample size and restricted age ranges, our work highlights the advantage of using large, representative samples to address questions about developmental brain changes. We discuss our findings in terms of their relevance to attentional processes and brain-based models of emotional well being and aging. PMID- 27957531 TI - Noradrenaline from Locus Coeruleus Neurons Acts on Pedunculo-Pontine Neurons to Prevent REM Sleep and Induces Its Loss-Associated Effects in Rats. AB - Normally, rapid eye movement sleep (REMS) does not appear during waking or non REMS. Isolated, independent studies showed that elevated noradrenaline (NA) levels inhibit REMS and induce REMS loss-associated cytomolecular, cytomorphological, psychosomatic changes and associated symptoms. However, the source of NA and its target in the brain for REMS regulation and function in health and diseases remained to be confirmed in vivo. Using tyrosine hydroxylase (TH)-siRNA and virus-coated TH-shRNA in normal freely moving rats, we downregulated NA synthesis in locus coeruleus (LC) REM-OFF neurons in vivo. These TH-downregulated rats showed increased REMS, which was prevented by infusing NA into the pedunculo-pontine tegmentum (PPT), the site of REM-ON neurons, normal REMS returned after recovery. Moreover, unlike normal or control-siRNA- or shRNA injected rats, upon REMS deprivation (REMSD) TH-downregulated rat brains did not show elevated Na-K ATPase (molecular changes) expression and activity. To the best of our knowledge, these are the first in vivo findings in an animal model confirming that NA from the LC REM-OFF neurons (1) acts on the PPT REM-ON neurons to prevent appearance of REMS, and (2) are responsible for inducing REMSD associated molecular changes and symptoms. These observations clearly show neuro physio-chemical mechanism of why normally REMS does not appear during waking. Also, that LC neurons are the primary source of NA, which in turn causes some, if not many, REMSD-associated symptoms and behavioral changes. The findings are proof-of-principle for the first time and hold potential to be exploited for confirmation toward treating REMS disorder and amelioration of REMS loss associated symptoms in patients. PMID- 27957534 TI - Deforestation-driven food-web collapse linked to emerging tropical infectious disease, Mycobacterium ulcerans. AB - Generalist microorganisms are the agents of many emerging infectious diseases (EIDs), but their natural life cycles are difficult to predict due to the multiplicity of potential hosts and environmental reservoirs. Among 250 known human EIDs, many have been traced to tropical rain forests and specifically freshwater aquatic systems, which act as an interface between microbe-rich sediments or substrates and terrestrial habitats. Along with the rapid urbanization of developing countries, population encroachment, deforestation, and land-use modifications are expected to increase the risk of EID outbreaks. We show that the freshwater food-web collapse driven by land-use change has a nonlinear effect on the abundance of preferential hosts of a generalist bacterial pathogen, Mycobacterium ulcerans. This leads to an increase of the pathogen within systems at certain levels of environmental disturbance. The complex link between aquatic, terrestrial, and EID processes highlights the potential importance of species community composition and structure and species life history traits in disease risk estimation and mapping. Mechanisms such as the one shown here are also central in predicting how human-induced environmental change, for example, deforestation and changes in land use, may drive emergence. PMID- 27957536 TI - Monkey vocal tracts are speech-ready. AB - For four decades, the inability of nonhuman primates to produce human speech sounds has been claimed to stem from limitations in their vocal tract anatomy, a conclusion based on plaster casts made from the vocal tract of a monkey cadaver. We used x-ray videos to quantify vocal tract dynamics in living macaques during vocalization, facial displays, and feeding. We demonstrate that the macaque vocal tract could easily produce an adequate range of speech sounds to support spoken language, showing that previous techniques based on postmortem samples drastically underestimated primate vocal capabilities. Our findings imply that the evolution of human speech capabilities required neural changes rather than modifications of vocal anatomy. Macaques have a speech-ready vocal tract but lack a speech-ready brain to control it. PMID- 27957535 TI - Receptor dimer stabilization by hierarchical plasma membrane microcompartments regulates cytokine signaling. AB - The interaction dynamics of signaling complexes is emerging as a key determinant that regulates the specificity of cellular responses. We present a combined experimental and computational study that quantifies the consequences of plasma membrane microcompartmentalization for the dynamics of type I interferon receptor complexes. By using long-term dual-color quantum dot (QD) tracking, we found that the lifetime of individual ligand-induced receptor heterodimers depends on the integrity of the membrane skeleton (MSK), which also proved important for efficient downstream signaling. By pair correlation tracking and localization microscopy as well as by fast QD tracking, we identified a secondary confinement within ~300-nm-sized zones. A quantitative spatial stochastic diffusion-reaction model, entirely parameterized on the basis of experimental data, predicts that transient receptor confinement by the MSK meshwork allows for rapid reassociation of dissociated receptor dimers. Moreover, the experimentally observed apparent stabilization of receptor dimers in the plasma membrane was reproduced by simulations of a refined, hierarchical compartment model. Our simulations further revealed that the two-dimensional association rate constant is a key parameter for controlling the extent of MSK-mediated stabilization of protein complexes, thus ensuring the specificity of this effect. Together, experimental evidence and simulations support the hypothesis that passive receptor confinement by MSK-based microcompartmentalization promotes maintenance of signaling complexes in the plasma membrane. PMID- 27957538 TI - Polymerization of a divalent/tetravalent metal-storing atom-mimicking dendrimer. AB - The phenylazomethine dendrimer (DPA) has a layer-by-layer electron density gradient that is an analog of the Bohr atom (atom mimicry). In combination with electron pair mimicry, the polymerization of this atom-mimicking dendrimer was achieved. The valency of the mimicked atom was controlled by changing the chemical structure of the dendrimer. By mimicking a divalent atom, a one dimensional (1D) polymer was obtained, and by using a planar tetravalent atom mimic, a 2D polymer was obtained. These poly(dendrimer) polymers could store Lewis acids (SnCl2) in their unoccupied orbitals, thus indicating that these poly(dendrimer) polymers consist of a series of nanocontainers. PMID- 27957537 TI - Implantable microcoils for intracortical magnetic stimulation. AB - Neural prostheses that stimulate the neocortex have the potential to treat a wide range of neurological disorders. However, the efficacy of electrode-based implants remains limited, with persistent challenges that include an inability to create precise patterns of neural activity as well as difficulties in maintaining response consistency over time. These problems arise from fundamental limitations of electrodes as well as their susceptibility to implantation and have proven difficult to overcome. Magnetic stimulation can address many of these limitations, but coils small enough to be implanted into the cortex were not thought strong enough to activate neurons. We describe a new microcoil design and demonstrate its effectiveness for both activating cortical neurons and driving behavioral responses. The stimulation of cortical pyramidal neurons in brain slices in vitro was reliable and could be confined to spatially narrow regions (<60 MUm). The spatially asymmetric fields arising from the coil helped to avoid the simultaneous activation of passing axons. In vivo implantation was safe and resulted in consistent and predictable behavioral responses. The high permeability of magnetic fields to biological substances may yield another important advantage because it suggests that encapsulation and other adverse effects of implantation will not diminish coil performance over time, as happens to electrodes. These findings suggest that a coil-based implant might be a useful alternative to existing electrode-based devices. The enhanced selectivity of microcoil-based magnetic stimulation will be especially useful for visual prostheses as well as for many brain-computer interface applications that require precise activation of the cortex. PMID- 27957539 TI - Dramatic influence of patchy attractions on short-time protein diffusion under crowded conditions. AB - In the dense and crowded environment of the cell cytoplasm, an individual protein feels the presence of and interacts with all surrounding proteins. While we expect this to strongly influence the short-time diffusion coefficient Ds of proteins on length scales comparable to the nearest-neighbor distance, this quantity is difficult to assess experimentally. We demonstrate that quantitative information about Ds can be obtained from quasi-elastic neutron scattering experiments using the neutron spin echo technique. We choose two well characterized and highly stable eye lens proteins, bovine alpha-crystallin and gammaB-crystallin, and measure their diffusion at concentrations comparable to those present in the eye lens. While diffusion slows down with increasing concentration for both proteins, we find marked variations that are directly linked to subtle differences in their interaction potentials. A comparison with computer simulations shows that anisotropic and patchy interactions play an essential role in determining the local short-time dynamics. Hence, our study clearly demonstrates the enormous effect that weak attractions can have on the short-time diffusion of proteins at concentrations comparable to those in the cellular cytosol. PMID- 27957541 TI - Timing of the formation and migration of giant planets as constrained by CB chondrites. AB - The presence, formation, and migration of giant planets fundamentally shape planetary systems. However, the timing of the formation and migration of giant planets in our solar system remains largely unconstrained. Simulating planetary accretion, we find that giant planet migration produces a relatively short-lived spike in impact velocities lasting ~0.5 My. These high-impact velocities are required to vaporize a significant fraction of Fe,Ni metal and silicates and produce the CB (Bencubbin-like) metal-rich carbonaceous chondrites, a unique class of meteorites that were created in an impact vapor-melt plume ~5 My after the first solar system solids. This indicates that the region where the CB chondrites formed was dynamically excited at this early time by the direct interference of the giant planets. Furthermore, this suggests that the formation of the giant planet cores was protracted and the solar nebula persisted until ~5 My. PMID- 27957540 TI - Breakdown of Hooke's law of elasticity at the Mott critical endpoint in an organic conductor. AB - The Mott metal-insulator transition, a paradigm of strong electron-electron correlations, has been considered as a source of intriguing phenomena. Despite its importance for a wide range of materials, fundamental aspects of the transition, such as its universal properties, are still under debate. We report detailed measurements of relative length changes DeltaL/L as a function of continuously controlled helium-gas pressure P for the organic conductor kappa (BEDT-TTF)2Cu[N(CN)2]Cl across the pressure-induced Mott transition. We observe strongly nonlinear variations of DeltaL/L with pressure around the Mott critical endpoint, highlighting a breakdown of Hooke's law of elasticity. We assign these nonlinear strain-stress relations to an intimate, nonperturbative coupling of the critical electronic system to the lattice degrees of freedom. Our results are fully consistent with mean-field criticality, predicted for electrons in a compressible lattice with finite shear moduli. We argue that the Mott transition for all systems that are amenable to pressure tuning shows the universal properties of an isostructural solid-solid transition. PMID- 27957542 TI - Ultrathin high-resolution flexographic printing using nanoporous stamps. AB - Since its invention in ancient times, relief printing, commonly called flexography, has been used to mass-produce artifacts ranging from decorative graphics to printed media. Now, higher-resolution flexography is essential to manufacturing low-cost, large-area printed electronics. However, because of contact-mediated liquid instabilities and spreading, the resolution of flexographic printing using elastomeric stamps is limited to tens of micrometers. We introduce engineered nanoporous microstructures, comprising polymer-coated aligned carbon nanotubes (CNTs), as a next-generation stamp material. We design and engineer the highly porous microstructures to be wetted by colloidal inks and to transfer a thin layer to a target substrate upon brief contact. We demonstrate printing of diverse micrometer-scale patterns of a variety of functional nanoparticle inks, including Ag, ZnO, WO3, and CdSe/ZnS, onto both rigid and compliant substrates. The printed patterns have highly uniform nanoscale thickness (5 to 50 nm) and match the stamp features with high fidelity (edge roughness, ~0.2 MUm). We derive conditions for uniform printing based on nanoscale contact mechanics, characterize printed Ag lines and transparent conductors, and achieve continuous printing at a speed of 0.2 m/s. The latter represents a combination of resolution and throughput that far surpasses industrial printing technologies. PMID- 27957543 TI - Three-dimensional Majorana fermions in chiral superconductors. AB - Using a systematic symmetry and topology analysis, we establish that three dimensional chiral superconductors with strong spin-orbit coupling and odd-parity pairing generically host low-energy nodal quasiparticles that are spin nondegenerate and realize Majorana fermions in three dimensions. By examining all types of chiral Cooper pairs with total angular momentum J formed by Bloch electrons with angular momentum j in crystals, we obtain a comprehensive classification of gapless Majorana quasiparticles in terms of energy-momentum relation and location on the Fermi surface. We show that the existence of bulk Majorana fermions in the vicinity of spin-selective point nodes is rooted in the nonunitary nature of chiral pairing in spin-orbit-coupled superconductors. We address experimental signatures of Majorana fermions and find that the nuclear magnetic resonance spin relaxation rate is significantly suppressed for nuclear spins polarized along the nodal direction as a consequence of the spin-selective Majorana nature of nodal quasiparticles. Furthermore, Majorana nodes in the bulk have nontrivial topology and imply the presence of Majorana bound states on the surface, which form arcs in momentum space. We conclude by proposing the heavy fermion superconductor PrOs4Sb12 and related materials as promising candidates for nonunitary chiral superconductors hosting three-dimensional Majorana fermions. PMID- 27957545 TI - Lowering coefficient of friction in Cu alloys with stable gradient nanostructures. AB - The coefficient of friction (COF) of metals is usually high, primarily because frictional contacts induce plastic deformation underneath the wear surface, resulting in surface roughening and formation of delaminating tribolayers. Lowering the COF of metals is crucial for improving the reliability and efficiency of metal contacts in engineering applications but is technically challenging. Refining the metals' grains to nanoscale cannot reduce dry-sliding COFs, although their hardness may be elevated many times. We report that a submillimeter-thick stable gradient nanograined surface layer enables a significant reduction in the COF of a Cu alloy under high-load dry sliding, from 0.64 (coarse-grained samples) to 0.29, which is smaller than the COFs of many ceramics. The unprecedented stable low COF stems from effective suppression of sliding-induced surface roughening and formation of delaminating tribolayer, owing to the stable gradient nanostructures that can accommodate large plastic strains under repeated sliding for more than 30,000 cycles. PMID- 27957544 TI - A single splice site mutation in human-specific ARHGAP11B causes basal progenitor amplification. AB - The gene ARHGAP11B promotes basal progenitor amplification and is implicated in neocortex expansion. It arose on the human evolutionary lineage by partial duplication of ARHGAP11A, which encodes a Rho guanosine triphosphatase-activating protein (RhoGAP). However, a lack of 55 nucleotides in ARHGAP11B mRNA leads to loss of RhoGAP activity by GAP domain truncation and addition of a human-specific carboxy-terminal amino acid sequence. We show that these 55 nucleotides are deleted by mRNA splicing due to a single C->G substitution that creates a novel splice donor site. We reconstructed an ancestral ARHGAP11B complementary DNA without this substitution. Ancestral ARHGAP11B exhibits RhoGAP activity but has no ability to increase basal progenitors during neocortex development. Hence, a single nucleotide substitution underlies the specific properties of ARHGAP11B that likely contributed to the evolutionary expansion of the human neocortex. PMID- 27957546 TI - Erratum for the Research Article: "Origin of uranium isotope variations in early solar nebula condensates" by F. L. H. Tissot, N. Dauphas, L. Grossman. AB - [This corrects the article on p. e1501400 in vol. 2, PMID: 26973874.]. PMID- 27957548 TI - A novel WDR45 mutation in a patient with beta-propeller protein-associated neurodegeneration. AB - Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic diseases characterized by progressive extrapyramidal symptoms and focal iron accumulation in the basal ganglia. beta-Propeller protein-associated neurodegeneration (BPAN), also known as static encephalopathy of childhood with neurodegeneration in adulthood or NBIA 5, is an X-linked dominant subtype of NBIA.1 Brain MRI studies consistently demonstrate iron accumulation in the globus pallidus and substantia nigra with a subset of patients also demonstrating a halo of hyperintense signal surrounding a thin region of hypointense signal in the substantia nigra on T1-weighted imaging.2 The majority of patients with BPAN are female, but several affected males with identical phenotypes have been described, most likely harboring postzygotic mutations leading to somatic mosaicism.3 BPAN has been shown to be caused by heterozygous mutations in WDR45 at Xp11.23. To date, all mutations have been de novo, with no affected relatives.1,3,4 We report here on a patient with BPAN with a novel c.597_598 deletion mutation in WDR45. PMID- 27957547 TI - Clinical and genetic study of hereditary spastic paraplegia in Canada. AB - OBJECTIVE: To describe the clinical, genetic, and epidemiologic features of hereditary spastic paraplegia (HSP) in Canada and to determine which clinical, radiologic, and genetic factors determine functional outcomes for patients with HSP. METHODS: We conducted a multicenter observational study of patients who met clinical criteria for the diagnosis of HSP in the provinces of Alberta, Ontario, and Quebec from 2012 to 2015. Characteristics of the participants were analyzed using descriptive statistics. The main outcome measure for a subset of the cohort (n = 48) was the Spastic Paraplegia Rating Scale. We also used the SPATAX-EUROSPA disability stage (disability score) to assess disability (n = 65). RESULTS: A total of 526 patients were identified with HSP across the country, and 150 patients had a confirmed genetic diagnosis. Mutations were identified in 15 different genes; the most common were SPAST (SPG4, 48%), ATL1 (SPG3A, 16%), SPG11 (8%), SPG7 (7%), and KIAA0196 (SPG8, 5%). The diagnosis of SPG4 was associated with older age at symptom onset (p = 0.0017). SPG4 and SPG3A were less associated with learning disabilities compared to other subtypes of HSP, and SPG11 was strongly associated with progressive cognitive deficits (odds ratio 87.75, 95% confidence interval 14.04-548.24, p < 0.0001). SPG3A was associated with better functional outcomes compared to other HSP subtypes (p = 0.04) on multivariate analysis. The strongest predictor of significant disability was abnormal brain MRI (p = 0.014). CONCLUSIONS: The most important predictors of disability in our HSP cohort were SPG11 mutations and abnormal brain MRI. Accurate molecular characterization of well-phenotyped cohorts and international collaboration are essential to establish the natural history of these rare neurodegenerative disorders. PMID- 27957550 TI - Erratum to "Potential tree species for use in urban areas in temperate and oceanic climates". AB - [This corrects the article DOI: 10.1016/j.heliyon.2016.e00154.]. PMID- 27957549 TI - beta-arrestin 2 attenuates cardiac dysfunction in polymicrobial sepsis through gp130 and p38. AB - Sepsis is an exaggerated systemic inflammatory response to persistent bacteria infection with high morbidity and mortality rate clinically. beta-arrestin 2 modulates cell survival and cell death in different systems. However, the effect of beta-arrestin 2 on sepsis-induced cardiac dysfunction is not yet known. Here, we show that beta-arrestin 2 overexpression significantly enhances animal survival following cecal ligation and puncture (CLP)-induced sepsis. Importantly, overexpression of beta-arrestin 2 in mice prevents CLP-induced cardiac dysfunction. Also, beta-arrestin 2 overexpression dramatically attenuates CLP induced myocardial gp130 and p38 mitogen-activated protein kinase (MAPK) phosphorylation levels following CLP. Therefore, beta-arrestin 2 prevents CLP induced cardiac dysfunction through gp130 and p38. These results suggest that modulation of beta-arrestin 2 might provide a novel therapeutic approach to prevent cardiac dysfunction in patients with sepsis. PMID- 27957551 TI - Issues in defining/extracting collocations in Japanese and Korean: Empirical implications for building a collocation database. AB - Collocations in Japanese and Korean have been studied extensively based on statistical tools. The criteria for collocations in these languages, however, have not been fully established in the literature, and it is not obvious whether all statistically significant combinations of words could be regarded as collocations. In this article, we point out empirical problems in extracting collocations in Japanese and Korean, and provide a standard for identifying collocations (to be separated from "free combination" and "idiom") in these languages. We concentrate on the discussion of empirical aspects of collocation research, rather than the statistical analyses of collocational patterns. As a preliminary to developing a database for Japanese-Korean contrastive work on collocations, the present study focuses on ten "Chinese-words" (). We show that (i) the co-occurring verbs for eight Chinese-words in Korean all carry over to Japanese (but not vice versa); (ii) in the other two cases, Korean exhibits co occurring verbs not found in Japanese; (iii) language-specific patterns of verb co-occurring are also observed in some instances. Overall, it is indicated that a much wider variety of co-occurring verbs are found in Japanese than in Korean. PMID- 27957553 TI - The incidence of invasive pneumococcal serotype 3 disease in the Danish population is not reduced by PCV-13 vaccination. AB - Since 2010, Denmark has included the 13-valent pneumococcal conjugated vaccine (PCV-13) in the childhood immunization programme. However, serotype 3 remains as an important cause of invasive pneumococcal disease (IPD) in Denmark. IPD surveillance data (1999-2016) was used to calculate the incidence and age distribution of serotype 3 IPD, and the effect of PCV-13 on serotype 3 IPD incidence was examined. The incidence of serotype 3 IPD in the age group below 65 years was 0.51/100,000 pre PCV-13, and 0.45/100,000 post PCV-13. In the group 0-4 years, serotype 3 IPD incidence was 0.28/100,000 pre PCV-13, and 0.16/100,000 post PCV-13. Serotype 3 IPD incidence in the elderly showed a mean of 4.27/100,000 pre PCV-13, and 4.32/100,000 post PCV-13. PCV-13 childhood immunization in Denmark has not lead to a reduction of the incidence of IPD caused by serotype 3. The reason behind this missing effect needs to be investigated further. PMID- 27957554 TI - Morningness-eveningness in a large sample of German adolescents and adults. AB - People differ in their sleep-wake behavior. This individual difference is conceptualized in different aspects, such as wake up times, bed times, times of peak performance, as well as in morning affect. A total of 14,987 visitors of an exhibition in the LWL State Museum of Natural History, Munster (Germany), did the survey on chronotype and gave their consent that these data can be used for a scientific study. Age groups were coded into 5-year bins. Mean age (mean +/- SD) was 28.2 +/- 17.5 years. There were 8075 females (54%) and 6912 males in the sample. The German version of the rMEQ (reduced Morningness-Eveningness Questionnaire) was used for data collection. The data showed clear age effects. Younger children are more morning oriented and become rapidly evening oriented during puberty, while the more attenuated turn towards morningness occurs from the age of 20 years. Then between the ages 25 to 30 morningness-eveningness remained rather stable. Significant gender differences existed in the reproductive age, i.e., the age groups 20 to 50 (corresponding to the age 16-50 years). In other age groups, no gender differences could be detected. Seasonal effects were also found. Chronotype score was lowest during the summer months (and more evening oriented). Based on the single item analysis of the five questions of the rMEQ, we found age group differences in all items. Gender differences occurred in all items except item 1, which deals with the preferred wake-up time. Men always scored significantly lower (i.e. more evening oriented) than women except in item 2 (tiredness after awakening). Seasonal effects were only significant in item 3, which is related to preferred bed times. People showed a later bed time preference during summer. The classification of chronotypes according to the cut-off scores provided by Adan and Almirall (1991) and by using the 20/80 percentile provided identical cut-off scores (values of 11 and below for evening types and 18 and above for morning types). PMID- 27957552 TI - Heterogeneous regulation of bacterial natural product biosynthesis via a novel transcription factor. AB - Biological diversity arises among genetically equal subpopulations in the same environment, a phenomenon called phenotypic heterogeneity. The life cycle of the enteric bacterium Photorhabdus luminescens involves a symbiotic interaction with nematodes as well as a pathogenic association with insect larvae. P. luminescens exists in two distinct phenotypic forms designated as primary (1 degrees ) and secondary (2 degrees ). In contrast to 1 degrees cells, 2 degrees cells are non pigmented due to the absence of natural compounds, especially anthraquinones (AQs). We identified a novel type of transcriptional regulator, AntJ, which activates expression of the antA-I operon responsible for AQ production. AntJ heterogeneously activates the AQ production in single P. luminescens 1 degrees cells, and blocks AQ production in 2 degrees cells. AntJ contains a proposed ligand-binding WYL-domain, which is widespread among bacteria. AntJ is one of the rare examples of regulators that mediate heterogeneous gene expression by altering activity rather than copy number in single cells. PMID- 27957555 TI - Sensory and rapid instrumental methods as a combined tool for quality control of cooked ham. AB - In this preliminary investigation, different commercial categories of Italian cooked pork hams have been characterized using an integrated approach based on both sensory and fast instrumental measurements. For these purposes, Italian products belonging to different categories (cooked ham, "selected" cooked ham and "high quality" cooked ham) were evaluated by sensory descriptive analysis and by the application of rapid tools such as image analysis by an "electronic eye" and texture analyzer. The panel of trained assessors identified and evaluated 10 sensory descriptors able to define the quality of the products. Statistical analysis highlighted that sensory characteristics related to appearance and texture were the most significant in discriminating samples belonged to the highest (high quality cooked hams) and the lowest (cooked hams) quality of the product whereas the selected cooked hams, showed intermediate characteristics. In particular, high quality samples were characterized, above all, by the highest intensity of pink intensity, typical appearance and cohesiveness, and, at the same time, by the lowest intensity of juiciness; standard cooked ham samples showed the lowest intensity of all visual attributes and the highest value of juiciness, whereas the intermediate category (selected cooked ham) was not discriminated from the other. Also physical-rheological parameters measured by electronic eye and texture analyzer were effective in classifying samples. In particular, the PLS model built with data obtained from the electronic eye showed a satisfactory performance in terms of prediction of the pink intensity and presence of fat attributes evaluated during the sensory visual phase. This study can be considered a first application of this combined approach that could represent a suitable and fast method to verify if the meat product purchased by consumer match its description in terms of compliance with the claimed quality. PMID- 27957556 TI - RBM5 reduces small cell lung cancer growth, increases cisplatin sensitivity and regulates key transformation-associated pathways. AB - Small cell lung cancer (SCLC) is the most aggressive type of lung cancer, with almost 95% of patients succumbing to the disease. Although RBM5, a tumor suppressor gene, is downregulated in the majority of lung cancers, its role in SCLC is unknown. Using the GLC20 SCLC cell line, which has a homozygous deletion encompassing the RBM5 gene locus, we established stable RBM5 expressing sublines and investigated the effects of RBM5 re-expression. Transcriptome and target identification studies determined that RBM5 directly regulates the cell cycle and apoptosis in SCLC cells, as well as significantly downregulates other important transformation-associated pathways such as angiogenesis and cell adhesion. RNA sequencing of paired non-tumor and tumor SCLC patient specimens showed decreased RBM5 expression in the tumors, and expression alterations in the majority of the same pathways that were altered in the GLC20 cells and sublines. Functional studies confirmed RBM5 expression slows SCLC cell line growth, and increases sensitivity to the chemotherapy drug cisplatin. Overall, our work demonstrates the importance of RBM5 expression to the non-transformed state of lung cells and the consequences of its deletion to SCLC development and progression. PMID- 27957557 TI - Nanoscale imaging of magnetization reversal driven by spin-orbit torque. AB - We use scanning electron microscopy with polarization analysis to image deterministic, spin-orbit torque-driven magnetization reversal of in-plane magnetized CoFeB rectangles in zero applied magnetic field. The spin-orbit torque is generated by running a current through heavy metal microstrips, either Pt or Ta, upon which the CoFeB rectangles are deposited. We image the CoFeB magnetization before and after a current pulse to see the effect of spin-orbit torque on the magnetic nanostructure. The observed changes in magnetic structure can be complex, deviating significantly from a simple macrospin approximation, especially in larger elements. Overall, however, the directions of the magnetization reversal in the Pt and Ta devices are opposite, consistent with the opposite signs of the spin Hall angles of these materials. Our results elucidate the effects of current density, geometry, and magnetic domain structure on magnetization switching driven by spin-orbit torque. PMID- 27957558 TI - Editorial: Periodontal education - back to basics. PMID- 27957559 TI - Randomised Clinical Trial on Resin Infiltration and Fluoride Varnish vs Fluoride Varnish Treatment Only of Smooth-surface Early Caries Lesions in Deciduous Teeth. AB - PURPOSE: To clinically evaluate the effectiveness of resin infiltration in conjunction with fluoride varnish treatment vs fluoride varnish treatment alone on facial smooth-surface caries lesions in deciduous teeth. MATERIALS AND METHODS: This randomised clinical trial was conducted in 419 children aged 18-71 months with at least two active smooth-surface caries lesions in deciduous teeth (ICDAS II score 2). Eighty-one participants met the inclusion criteria and were allocated to one of the two treatment groups: resin infiltration and fluoride varnish (RI+FV) (n = 41) and fluoride varnish only (FV) (n = 40). The prevalence of treated white spot lesions (WSL) was scored. Fluoride varnish was applied in both groups every 3 months for a year. RESULTS: The mean baseline age of children was 3.8 +/- 1.3 years. The effectiveness of resin infiltration measured as the percentage of children who did not present any progression of the treated lesions amounted to 43.1%. After one year, 92.1% of the infiltrated lesions (RI+FV) and 70.6% of the FV lesions had not progressed (p < 0.001). CONCLUSION: Resin infiltration in conjunction with fluoride varnish treatment of early facial smooth-surface caries lesions in deciduous teeth is superior to fluoride varnish treatment alone for reducing lesion progression. PMID- 27957560 TI - Auditory and Nonauditory Effects of Ultrasonic Scaler Use and Its Role in the Development of Permanent Hearing Loss. AB - PURPOSE: To evaluate the negative auditory and non-auditory effects developed immediately after using ultrasonic scalers and their potential role in the development of permanent hearing loss. MATERIALS AND METHODS: The auditory functions of 60 dental clinicians were evaluated with the pure tone audiometry test (PTA), tympanogram and the otoacoustic emission test (OAE) before and immediately after using ultrasonic scalers. The paired t-test was used to evaluate the difference in the pre- and post-exposure recordings for all three tests. RESULTS: There was a significant increase in the PTA and tympanogram test results, along with reduced OAE values immediately after using ultrasonic scalers. Hearing ability dropped by 63% to 66% immediately after using ultrasonic scalers. The maximum hearing disability was noted for low-frequency thresholds. The reduction was greater in the left than in the right ear. CONCLUSIONS: Noise emitting devices such as ultrasonic scalers produce significant immediate auditory and non-auditory changes. It is important that dentists recognise the initial signs of hearing damage and adopt appropriate measures while working to prevent the development of permanent hearing impairment in future. PMID- 27957561 TI - An Examination of the Past Behaviour-Intention Relationship in the Case of Brushing Children's Teeth. AB - PURPOSE: The present study sought to apply the expanded theory of planned behaviour (TPB) to the prediction of mothers' intention to brush their children's teeth and examine the mediating role of the variables of the TPB on the relationship between past behaviour and the intention. MATERIALS AND METHODS: This cross-sectional study was carried out among 211 mothers with children ages 2 to 5 years. Participants completed measures of the TPB (i.e. attitude, subjective norm, perceived control and intention) and past behaviour in relation to brushing. Regression analyses were conducted to explore the predictors of mothers' intention. Mediation was assessed using Preacher and Hayes' INDIRECT.SPSS macro. RESULTS: The TPB explained 25% of the variance in brushing intention, with attitude, subjective norms and perceived behavioural control making significant contributions. Past behaviour explained an additional 3% of the variance in intention. Analysis showed that TPB variables only partially mediate the effect of past behaviour on intention. CONCLUSIONS: Our findings revealed that mothers' intention to brush their children's teeth is under the control of both past behaviour and psychological factors. Accordingly, interventions to improve children's toothbrushing should focus on the motivational (e.g. attitude) as well as the habitual determinants (e.g. environmental cues). However, given the low explanatory power of our model, it may be necessary to incorporate other psychological and environmental variables into an explanation of the mothers' intention to brush their children's teeth. PMID- 27957562 TI - Relationship Between Oral Health Knowledge, Attitude and Practices of Primary School Teachers and Their Oral Health-related Quality of Life: A Cross-sectional Study. AB - PURPOSE: To measure oral health (OH) knowledge, attitude and practices (KAP) of primary school teachers and to evaluate the relationship between these measures and oral health-related quality of life (OHRQoL). MATERIALS AND METHODS: A total of 1013 school teachers from all regions of Kuwait were randomly selected in this cross-sectional study. A questionnaire on demographics, knowledge, attitude, practices and OHRQoL was used. Frequencies and means (SD) were used for data description. Correlations between KAP and OHRQoL were evaluated using Pearson's correlation coefficient. Associations between practice-specific knowledge and its corresponding practice as well as knowledge and practices and OHRQoL were determined using the chi-squared test. RESULTS: About 71% of the participants were females, 57% were 30-50 years old, and 75% had a college education. The mean (95%CI) knowledge score was 60.2% (57.2-62.0), ranging from 15.4% to 93%. The well-known OH facts were the importance of brushing twice a day with fluoridated toothpaste, the cariogenic effect of sticky, sugary foods and snacks, as well as the damage that soft drinks can cause to teeth. The least known facts were replacement frequency of toothbrush, parent's supervision of children's brushing and the benefit of regular flossing. Weak but significant correlations were found between KAP components and OHRQoL (p < 0.05). All practice-specific OH knowledge was significantly associated with its practice, except brushing and flossing (p > 0.05). Self-esteem was the mostly frequently affected OHRQoL construct by improper OH practices. CONCLUSION: Oral health knowledge by itself is not enough to change improper OH practices. Developing behaviourchanging interventions based on OHRQoL outcomes may be beneficial. PMID- 27957564 TI - Parental Opinions on Children's Oral Health Counselling and Readiness to Change Health Habits. AB - PURPOSE: To study new programmes in health promotion of 6- to 36-month-old children included in the public dental service (PDS) of Vantaa and compare them with the previously used programme by assessing parents' opinions on the oral health counselling and their readiness to make changes in oral health habits. An additional aim was to study parents' readiness to change their child's health habits in relation to the child's MS colonisation, health habits and parents' education. MATERIALS AND METHODS: The subjects consisted of the parents of first born children examined at age two (n = 647). The link to the study was e-mailed to the parents (n = 586) after their child's two-year visit. The dental professionals were trained to do plaque testing, observe dental decay and control the progression of caries lesions, utilise the oral health counselling programmes and deliver client-centered counselling. Data were statistically analysed using Pearson's Chi-Square and logistic regression. RESULTS: The response rate was 68%. In the opinion of 91% of the respondents, the information received was at least somewhat useful. The respondents in the new programmes were more likely to report at least intending to change their own health habits (p = 0.032). There was, however, no programme-related difference in readiness for change their child's health habits. Respondents who made/intend to make changes reported a lower level of education and their children were more likely to have had positive MS scores compared to children whose parents reported having made no changes. CONCLUSIONS: It may be possible to promote beneficial habits by delivering oral health counselling to parents, who would thus serve as better role models for their children. The findings indicate that the changes occurred in the families who needed it most. PMID- 27957563 TI - Dental Attendance and Self-reported Oral Health Status of Renal Dialysis Patients: A Comparison of Results with the UK Adult Dental Health Survey. AB - PURPOSE: To compare the oral health status of renal patients attending a dialysis unit at a London teaching hospital with an age- and sex-matched sample from the Adult Dental Health Survey UK (ADHS) 2009. MATERIALS AND METHODS: Questions adapted from the ADHS 2009 national survey were used to interview renal dialysis patients about their oral health, oral hygiene and dental visits. Any significant differences between the two groups were statistically analysed using the chi squared (chi2) test. RESULTS: Two hundred renal dialysis patients participated. More renal dialysis patients were edentulous (p < 0.0001) and those who were dentate had fewer teeth (p < 0.0001) compared to the ADHS 2009 participants. Although 12% of the renal dialysis patients had difficulty in finding a dentist, 77% were linked to a dental practice, but fewer reported that they had previously been shown how to brush their teeth compared to the dentate ADHS group (p < 0.0001). The frequency of brushing (twice daily) was similar in the dialysis and ADHS groups. CONCLUSION: Awareness for good oral health needs to be raised in this group of medically compromised patients regularly attending a hospital unit. The responsibility for achieving this goal needs to be shared by both dialysis teams and oral health care professionals. We suggest an 'oral health toolkit' be made available in dialysis units for both professionals and patients. PMID- 27957566 TI - Association of Alimentary Factors and Nutritional Status with Caries in Children of Leon, Mexico. AB - PURPOSE: To determine the association between types of food consumed, nutritional status (BMI) and caries in schoolchildren. MATERIAL AND METHODS: A cross sectional study was performed with 224 schoolchildren 6 to 12 years of age. DMFT/ dmft indices, level of oral hygiene, nutritional status as quantified by BMI and types of food consumed were determined in all participants. Data were analysed using multiple linear regression with significance set at p < 0.05. RESULTS: Caries prevalence was 36%. In the multiple linear regression analysis adjusted for BMI, variables related to a higher number of caries were younger age and lower intake of vitamin D, calcium and fiber, with higher consumption of phosphorous and carbohydrates (R2 = 0.30; p < 0.0001 for the model). Sweetened softdrinks and chewy candy were risk factors for higher caries prevalence, while consuming milk and carrots were protectors. CONCLUSION: Caries in schoolchildren is highly prevalent in this community and is related to younger age and lower intake of vitamin D, calcium and fiber, but a higher consumption of phosphorous and carbohydrates. No relationship was found between caries and nutritional status. PMID- 27957565 TI - Effectiveness of DIAGNOdent in Detecting Root Caries Without Dental Scaling Among Community-dwelling Elderly. AB - PURPOSE: The purpose of this clinical research was to analyze the effectiveness of DIAGNOdent in detecting root caries without dental scaling. MATERIALS AND METHODS: The status of 750 exposed, unfilled root surfaces was assessed by visual tactile examination and DIAGNOdent before and after root scaling. The sensitivity and specificity of different cut-off DIAGNOdent values in diagnosing root caries with reference to visual-tactile criteria were evaluated on those root surfaces without visible plaque/calculus. The DIAGNOdent values from sound and carious root surfaces were compared using the nonparametric Mann-Whitney U-test. The level of statistical significance was set at 0.05. RESULTS: On root surfaces without plaque/calculus, significantly different (p < 0.05) DIAGNOdent readings were obtained from sound root surfaces (12.2 +/- 11.1), active carious root surfaces (37.6 +/- 31.7) and inactive carious root surfaces (20.9 +/- 10.5) before scaling. On root surfaces with visible plaque, DIAGNOdent readings obtained from active carious root surfaces (29.6 +/- 20.8) and inactive carious root surfaces (27.0 +/- 7.2) were not statistically significantly different (p > 0.05). Furthermore, on root surfaces with visible calculus, all DIAGNOdent readings obtained from sound root surfaces were > 50, which might be misinterpreted as carious. After scaling, the DIAGNOdent readings obtained from sound root surfaces (8.1 +/- 11.3), active carious root surfaces (37.9 +/- 31.9) and inactive carious root surfaces (24.9 +/- 11.5) presented significant differences (p < 0.05). A cut-off value between 10 and 15 yielded the highest combined sensitivity and specificity in detecting root caries on root surfaces without visible plaque/calculus before scaling, but the combined sensitivity and specificity are both around 70%. CONCLUSION: These findings suggest that on exposed, unfilled root surfaces without visible plaque/calculus, DIAGNOdent can be used as an adjunct to the visual-tactile criteria in detecting root-surface status without pre-treatment by dental scaling. PMID- 27957568 TI - Reversible photo/thermoswitchable dual-color fluorescence through single-crystal to-single-crystal transformation. AB - Reversible photo/thermoswitchable dual-color green-to-blue fluorescence is reported here, which is mainly due to a single-crystal-to-single-crystal (SCSC) transformation of the chromophore from a supramolecular aggregation to a covalently bonded polymer. PMID- 27957567 TI - Rapid capillary mixing experiments for the analysis of hydrophobic membrane complexes directly from aqueous lipid bilayer solutions. AB - In this study the gas-phase conformer preferences of Gramicidin A (GA), a linear antimicrobial pentadecapeptide, were investigated directly from aqueous solutions of lipid vesicle bilayers using a mixing tee-electrospray ionization (MT-ESI) setup coupled with ion mobility mass spectrometry (IM-MS). The required time for GA sample preparation was decreased by approximately 50% using MT-ESI when compared to previously reported methods which required freeze-drying of samples. Using an MT-ESI approach to analyze samples of GA associated with POPC (16:0, 18:1 PC) and DEPC (22:1 PC) lipid bilayers yielded dimer conformer preferences comparable to results obtained using more lengthy protocols. GA analogues that contain leucine to lysine substitutions were analyzed; these analogues yielded more hydrophilic GA dimers owing to the hydrophilicity of lysine head groups. The conformer preferences of lipid bilayer associated hydrophilic GA analogues can be obtained owing to disassociation of lipids during the fast mixing time MT-ESI process. The data for both GA analogues associated with negatively charged POPC/POPG (16:0, 18:1 PC/PG) lipid bilayers reveal a preference for antiparallel double helix (ADH) formation. The adoption of nascent conformers for both GA analogues was observed using MT-ESI for samples associated with DMPC/DMPG (12:0 PC/PG) bilayers. PMID- 27957569 TI - On-chip integration of droplet microfluidics and nanostructure-initiator mass spectrometry for enzyme screening. AB - Biological assays often require expensive reagents and tedious manipulations. These shortcomings can be overcome using digitally operated microfluidic devices that require reduced sample volumes to automate assays. One particular challenge is integrating bioassays with mass spectrometry based analysis. Towards this goal we have developed MUNIMS, a highly sensitive and high throughput technique that integrates droplet microfluidics with nanostructure-initiator mass spectrometry (NIMS). Enzyme reactions are carried out in droplets that can be arrayed on discrete NIMS elements at defined time intervals for subsequent mass spectrometry analysis, enabling time resolved enzyme activity assay. We apply the MUNIMS platform for kinetic characterization of a glycoside hydrolase enzyme (CelE CMB3A), a chimeric enzyme capable of deconstructing plant hemicellulose into monosaccharides for subsequent conversion to biofuel. This study reveals NIMS nanostructures can be fabricated into arrays for microfluidic droplet deposition, NIMS is compatible with droplet and digital microfluidics, and can be used on chip to assay glycoside hydrolase enzyme in vitro. PMID- 27957570 TI - Lanthanide doped ultrafine hybrid nanostructures: multicolour luminescence, upconversion based energy transfer and luminescent solar collector applications. AB - We herein demonstrate novel inorganic-organic hybrid nanoparticles (HNPs) composed of inorganic NPs, NaY0.78Er0.02Yb0.2F4, and an organic beta-diketonate complex, Eu(TTA)3Phen, for energy harvesting applications. Both the systems maintain their core integrity and remain entangled through weak interacting forces. HNPs incorporate the characteristic optical behaviour of both the systems i.e. they give an intense red emission under UV excitation, due to Eu3+ in organic complexes, and efficient green upconversion emission of Er3+ in inorganic NPs for NIR (980 nm) excitation. However, (i) an energy transfer from Er3+ (inorganic NPs) to Eu3+ (organic complex) under NIR excitation, and (ii) an increase in the decay time of 5D0 -> 7F2 transition of Eu3+ for HNPs as compared to the Eu(TTA)3Phen complex, under different excitation wavelengths, are added optical characteristics which point to an important role of the interface between both the systems. Herein, the ultra-small size (6-9 nm) and spherical shape of the inorganic NPs offer a large surface area, which improves the weak interaction force between both the systems. Furthermore, the HNPs dispersed in the PMMA polymer have been successfully utilized for luminescent solar collector (LSC) applications. PMID- 27957571 TI - Topological insulating states in 2D transition metal dichalcogenides induced by defects and strain. AB - First-principles calculations and extensive analyses reveal that the H phase of two-dimensional (2D) transition metal dichalcogenides (TMDs) can be tuned to topological insulators by introducing square-octagon (4-8) defects and by applying equi-biaxial tensile strain simultaneously. The 2D structure composed of hexagonal rings with 4-8 defects, named sho-TMD, is dynamically and thermally stable. The critical equi-biaxial tensile strain for the topological phase transition is 4%, 6%, and 4% for sho-MoS2, sho-MoSe2 and sho-WS2, respectively, and the corresponding nontrivial band gap induced by the spin-orbit coupling is 2, 8, and 22 meV, implying the possibility of observing the helical conducting edge states that are free of backscattering in experiment. It is equally interesting that the size of the energy band gap of the H-phase can be flexibly tuned by changing the concentration of 4-8 defects while the feature of the quasi direct band gap semiconductor remains. These findings add additional traits to the TMD family, and provide a new strategy for engineering the electronic structure and the band topology of 2D TMDs for applications in nanoelectronics and spintronics. PMID- 27957572 TI - Nano-rescaling of gold films on polystyrene: thermal management for SERS. AB - Nano-textured Au surfaces were prepared on pre-stretched 2D polystyrene (PS) sheets sputtered with different thicknesses of Au. The Au-coated PS was subjected to thermal annealing above the glass transition temperature at ~150 degrees C, thus undergoing surface area rescaling via a volume phase transition. The yellow color of the Au changed from the typical mirror-like appearance to a diffusive dark yellow, progressing to dark brown at the smallest feature size, hence, electromagnetic energy was coupled into the substrate. While the surface area footprint is the same after shrinking the PS, the roughness can be modified from the nano- to the micro-scale for different initial thicknesses of sputtered Au. The nanometer-sized features of surface wrinkles on the Au films make them suitable for surface-enhanced Raman scattering (SERS) sensors that can reach ~104 counts per s per mW. The thermal diffusivity of the contracted surfaces was determined by a non-contact temperature wave method and was larger than that of PS (alpha ? 1.1 * 10-7 m2 s-1) with a linear scaling on the Au thickness: each 10 nm addition of Au increased the diffusivity by 4%. This allows improved heat dissipation from the laser irradiated spot during SERS measurements. PMID- 27957573 TI - Vivid structural colors with low angle dependence from long-range ordered photonic crystal films. AB - Structural colored materials have attracted increasing attention due to their vivid color effects and non-photobleaching characteristics. However, the angle dependence of these structural colors severely restricts their practical applications, for example, in display and sensing devices. Here, a new strategy for obtaining low angle dependent structural colors is demonstrated by fabricating long-range ordered photonic crystal films. By using spheres with high refractive indices as building blocks, the angle dependence of the obtained colors has been strongly suppressed. Green, golden yellow and red structural colored films with low angle dependence were obtained by using 145 nm, 165 nm and 187 nm Cu2O spheres as building blocks, respectively. SEM images confirmed the long-range highly ordered arrays of the Cu2O photonic crystal films. Reflectance spectra and digital photographs clearly demonstrate the low angle dependence of these structural colors, which is in sharp comparison with the case of polystyrene (PS) and SiO2 photonic crystal films. Furthermore, these structural colors are vivid with high color saturation, not only under black background, but also under white background and natural light without adding any light-absorbing agents. These low angle dependent structural colors endow Cu2O photonic crystal films with great potential in practical applications. Our findings may broaden the strategies for the design and fabrication of angle independent structural colored materials. PMID- 27957574 TI - Self-assembly of precisely defined DNA nanotube superstructures using DNA origami seeds. AB - We demonstrate a versatile process for assembling micron-scale filament architectures by controlling where DNA tile nanotubes nucleate on DNA origami assemblies. "Nunchucks," potential mechanical magnifiers of nanoscale dynamics consisting of two nanotubes connected by a dsDNA linker, form at yields sufficient for application and consistent with models. PMID- 27957575 TI - An electrohydrodynamic technique for rapid mixing in stationary droplets on digital microfluidic platforms. AB - This paper presents an electrohydrodynamic technique for rapid mixing of droplets in open and closed digital microfluidic (DMF) platforms. Mixing is performed by applying a high frequency AC voltage to the coplanar or parallel electrodes, inducing circulation zones inside the droplet which results in rapid mixing of the content. The advantages of the proposed method in comparison to conventional mixing methods that operate based on transporting the droplet back and forth and side to side include 1) a shorter mixing time (as fast as 0.25 s), 2) the use of a fewer number of electrodes, reducing the size of the chip, and 3) the stationary nature of the technique which reduces the chance of cross contamination and surface biofouling. Mixing using the proposed method is performed to create a uniform mixture after merging a water droplet with another droplet containing either particles or dye. The results show that increasing the frequency, and or the amplitude of the applied voltage, enhances the mixing process. However, actuation with a very high frequency and voltage may result in shedding pico-liter satellite droplets. Therefore, for each frequency there is an effective range of the amplitude which provides rapid mixing and avoids shedding satellite droplets. Also, the increase in the gap height between the two plates (for the closed DMF platforms) significantly enhances the mixing efficiency due to the lower viscous effects. Effects of the addition of salts and DNA to the samples were also studied. The electrothermal effect decreased for these cases, which was solved by increasing the frequency of the applied voltage. To assure the high frequency actuation does not increase the sample temperature excessively, the temperature change was monitored using a thermal imaging camera and it was found that the increase in temperature is negligible. PMID- 27957576 TI - 3D multi-energy deconvolution electron microscopy. AB - Three-dimensional (3D) characterization of nanomaterials is traditionally performed by either cross-sectional milling with a focused ion beam (FIB), or transmission electron microscope tomography. While these techniques can produce high quality reconstructions, they are destructive, or require thin samples, often suspended on support membranes. Here, we demonstrate a complementary technique allowing non-destructive investigation of the 3D structure of samples on bulk substrates. This is performed by imaging backscattered electron (BSE) emission at multiple primary beam energies - as the penetration depth of primary electrons is proportional to the beam energy, depth information can be obtained through variations in the beam acceleration. The detected signal however consists of a mixture of the penetrated layers, meaning the structure's three-dimensional geometry can only be retrieved after deconvolving the BSE emission profile from the observed BSE images. This work demonstrates this novel approach by applying a blind source separation deconvolution algorithm to multi-energy acquired BSE images. The deconvolution can thereby allow a 3D reconstruction to be produced from the acquired images of an arbitrary sample, showing qualitative agreement with the true depth structure, as verified through FIB cross-sectional imaging. PMID- 27957577 TI - Image processing and analysis system for development and use of free flow electrophoresis chips. AB - We present an image processing and analysis system to facilitate detailed performance analysis of free flow electrophoresis (FFE) chips. It consists of a cost-effective self-built imaging setup and a comprehensive customizable software suite. Both components were designed modularly to be accessible, adaptable, versatile, and automatable. The system provides tools for i) automated identification of chip features (e.g. separation zone and flow markers), ii) extraction and analysis of stream trajectories, and iii) evaluation of flow profiles and separation quality (e.g. determination of resolution). Equipped with these tools, the presented image processing and analysis system will enable faster development of FFE chips and applications. It will also serve as a robust detector for fluorescence-based analytical applications of FFE. PMID- 27957578 TI - Correction: Ni-based heterogeneous catalyst from a designed molecular precursor for the efficient electrochemical water oxidation. AB - Correction for 'Ni-based heterogeneous catalyst from a designed molecular precursor for the efficient electrochemical water oxidation' by Denis A. Kuznetsov et al., Chem. Commun., 2016, 52, 9255-9258. PMID- 27957579 TI - Water-tunable solvatochromic and nanoaggregate fluorescence: dual colour visualisation and quantification of trace water in tetrahydrofuran. AB - While investigating the unique optical properties of aminobenzopyranoxanthenes (ABPXs), organic fluorescent dyes with the fusion of two rhodamines, we have found that the spirolactone form of ABPXs exhibited solvatochromic fluorescence in organic solvents. Detailed spectrophotometric and theoretical analyses showed that the solvatochromic fluorescence of ABPXs originated from the photo-excited charge separation in solvents of different dipolarities. Further studies revealed that fluorescent nanoaggregates were also formed in highly concentrated solution. The intriguing dual fluorescence properties of ABPXs were tunable in response to the water content, and served as a new detection principle for naked-eye visualisation (above 0.5 wt%) and quantification (0.010-0.125 wt%) of water in tetrahydrofuran. PMID- 27957581 TI - Correction: Synthesis of a fluorescent photoaffinity probe of OSW-1 by site selective acylation of an inactive congener and biological evaluation. AB - Correction for 'Synthesis of a fluorescent photoaffinity probe of OSW-1 by site selective acylation of an inactive congener and biological evaluation' by K. Sakurai et al., Chem. Commun., 2017, DOI: . PMID- 27957580 TI - Halochromic coordination polymers based on a triarylmethane dye for reversible detection of acids. AB - Chromeazurol B (Na2HL) is a pH-sensitive (halochromic) dye based on a hydroxytriarylmethane core and two carboxylate functional groups, which makes it suitable for the synthesis of coordination polymers. Two new coordination polymers [NaZn4(H2O)3(L)3].3THF.3H2O (1) and [Zn3(H2O)3(MU2-OH2)(MU3 OH)(HL)2(H2L)].2THF.3H2O (2) incorporating Chromeazurol B linkers have been prepared and characterised. The structure of 1 comprises pentanuclear heterometallic {Zn4Na} nodes linked by six L3- anions to give a layered structure with a honeycomb topology. 2 crystallizes as a double-chain ribbon (ladder) structure with two types of metal node: a mononuclear Zn(ii) cation and tetranuclear {Zn(ii)}4 cluster. Chromeazurol B anions link each tetranuclear cluster to four individual Zn(ii) cations and each Zn(ii) cation with four tetranuclear clusters. Both compounds show pH-sensitivity in water solution which can be observed visually, giving the first example of a halochromic coordination polymer. The halochromic properties of 1 towards HCl vapors were systematically investigated. As-synthesized violet-grey 1 reversibly changes color from orange to pink in the presence of vapors of 2 M and 7 M HCl, respectively. The coordination of the Chromeazurol B anion at each color stage was examined by diffuse reflectance spectroscopy and FT-IR measurements. The remarkable stability of 1 to acid and the observed reversible and reproducible color changes provide a new design for multifunctional sensor materials. PMID- 27957582 TI - Electrodeposition of zinc nanoplates from an ionic liquid composed of 1 butylpyrrolidine and ZnCl2: electrochemical, in situ AFM and spectroscopic studies. AB - The mixtures of 1-butylpyrrolidine and ZnCl2 result in the formation of an ionic liquid, which can be used as an electrolyte for zinc electrodeposition. The feasibility of electrodepositing Zn from these electrolytes was investigated at RT and at 60 degrees C. The synthesized mixtures are rather viscous. Toluene was added to the mixtures to decrease the viscosity of the ILs. Vibrational spectroscopy was employed for the characterization of the liquids. The electrochemical behaviour of the liquids was evaluated by cyclic voltammetry. The electrode/electrolyte interface of this IL was probed by Atomic Force Microscopy (AFM). The suitable range for the electrodeposition of Zn was found to be >=28.6 mol% of ZnCl2. Zn deposition occurs mainly from the cationic species of [ZnClxLy]+ (where x = 1, y = 1-2, and L = 1-butylpyrrolidine) in these electrolytes. This is in contrary to the well investigated chlorozincate ionic liquids where the deposition of Zn occurs mainly from anionic chlorozincates. Nanoplates of Zn were obtained from these mixtures of 1-butylpyrrolidine and ZnCl2. PMID- 27957583 TI - Longitudinal growth dynamics of term symmetric and asymmetric small for gestational age infants. AB - ABSTRACT: Background: Available information on auxological attainments of symmetric and asymmetric SGA (small for gestational age) infants presents conflicting views. The complete absence of longitudinal data on growth patterns of both types of Indian SGA infants prompted us to undertake this study. Aim: To study distance and velocity growth pattern of weight and crown-heel length (CHL) of symmetric and asymmetric SGA infants. Subjects & Methods: Weight and CHL amongst full-term 100 symmetric SGA, 100 asymmetric SGA and 100 AGA infants from upper socio-economic strata were mixed-longitudinally measured at birth, 1, 3, 6, 9 and 12 months in the Department of Pediatrics, PGIMER, Chandigarh, India. Results: The symmetric SGA infants measured significantly lighter and shorter than asymmetric infants. SGA infants of both types and sexes possessed significantly (p <= 0.001) lower weight and length values than AGA, normal Indian and western infants. Weight and CHL growth velocities demonstrated inconsistent trends. Peak growth velocity for weight and CHL of symmetric, asymmetric SGA and AGA infants was attained between 1-3 months. Average z-scores for weight and CHL were found to be lesser amongst symmetric SGA as compared to asymmetric infants, revealing compromised catch-up growth. Conclusion: The poorer postnatal auxological attainments of SGA infants as compared to normal infants reveals continuation of effect of intra-uterine nutritional insult during infancy, which measured significantly more in symmetric than asymmetric SGA infants. PMID- 27957584 TI - Evolution of laparoscopic liver resection at Singapore General Hospital: a nine year experience of 195 consecutive resections. AB - INTRODUCTION: We aimed to analyse the changing trends, safety and outcomes associated with the adoption of laparoscopic liver resection (LLR) at a single centre. METHODS: A retrospective review of patients who underwent LLR from 2006 to 2014 at our institution was performed. To explore the evolution of LLR, the study was divided into three equal consecutive time periods (Period 1: 2006-2008, Period 2: 2009-2011, and Period 3: 2012-2014). RESULTS: Among 195 patients who underwent LLR, 24 (12.3%) required open conversions, 68 (34.9%) had resection of tumours in the difficult posterosuperior segments and 12 (6.2%) underwent major (>= 3 segments) hepatectomies. Median operation time was 210 (range 40-620) minutes and median postoperative stay was 4 (range 1-26) days. Major postoperative morbidity (> Grade II) occurred in 11 (5.6%) patients and 90-day/in hospital mortality was 1 (0.5%). During the study, the number of LLRs performed showed an increasing trend (Period 1: n = 22; Period 2: n = 19; Period 3: n = 154). Other statistically significant trends were: (a) increase in malignant neoplasms resected; (b) increase in resections of difficult posterosuperior segments; (c) longer median operation time; and (d) decrease in open conversion rates. CONCLUSION: Over the study period, the number of LLRs increased rapidly. LLR was increasingly performed for malignant neoplasms and lesions located in the difficult posterosuperior segments, resulting in longer operation times. However, open conversion rates decreased, and there was no change in postoperative morbidity and other perioperative outcomes. PMID- 27957586 TI - Erratum to: "Mismanagement" oder "misunderstanding"? PMID- 27957585 TI - Coronary artery calcium score and coronary computed tomography angiography for patients with asymptomatic polyvascular (non-coronary) atherosclerosis. AB - INTRODUCTION: The primary endpoint of this study was to determine the prevalence of coronary artery disease (CAD) and coronary artery calcium score (CACS) using coronary computed tomography angiography (CCTA) among patients with polyvascular atherosclerosis (PVA). Secondary endpoints were to evaluate the prevalence of cardiovascular risk factors and determine the predictors of PVA. METHODS: The presence of atherosclerotic disease was assessed using ultrasonographic vascular examination in 515 asymptomatic patients. All patients with presence of stenosis over 50% and moderate-to-severe cardiovascular risk profile underwent CCTA to identify atherosclerotic coronary disease. RESULTS: Among 515 participants, 143 patients had no evidence of atherosclerotic plaque. Of the 372 patients with atherosclerotic plaque, 184 patients had single-vessel disease, 111 patients had double-vessel disease and 77 patients had triple-vessel disease; among these patients, those who also presented with stenosis > 50% underwent CCTA. Coronary stenosis categories included: normal (6.4%); haemodynamically insignificant (34.6%); intermediate (28.7%); significant (26.6%); and total artery occlusion (3.7%). Based on the coronary vessel involved, the patients were categorised as having single- (41.0%), double- (42.0%) or triple- (17.0%) coronary disease. CACS was significantly higher in patients with double- or triple-vessel disease when compared to those with single-vessel disease. CONCLUSION: Our study confirmed not only the high sensitivity of CCTA for highlighting CAD, but also its negative predictive value for excluding the presence of coronary stenosis or ischaemia. We found good correlation between PVA and CACS, and were able to confirm the risk factors for PVA. PMID- 27957587 TI - Vertebral fracture assessment by dual X-ray absorptiometry: reply to comments by Fechtenbaum et al. PMID- 27957588 TI - Vertebral fracture assessment by dual X-ray absorptiometry. PMID- 27957590 TI - [Inclusion of oxaliplatin in the multimodal treatment of locally advanced rectal cancer]. PMID- 27957589 TI - Radiotherapy for aneurysmal bone cysts : A rare indication. AB - BACKGROUND: Aneurysmal bone cysts (ABC) are rapidly growing benign osseous lesions composed of blood-filled channels separated by fibrous septa. Since the value of external beam radiotherapy (EBRT) for ABC has not been well defined, the German Cooperative Group on Radiotherapy for Benign Diseases performed the national register study described herein. PATIENTS AND METHODS: Five German institutions collected data regarding clinical features, treatment concepts, and outcome for patients with ABC who had been referred for local EBRT over the past 30 years. RESULTS: Between 1990 and 2015, 10 patients with ABC were irradiated (5 female/5 male). Median age was 23 years (range 14-40 years). Involved sites were: spine (n = 3), sacrum/pelvis (n = 2), shoulder/scapula (n = 2), humerus (n = 1), femur (n = 1), and radius (n = 1). The median EBRT total and fractional doses were 28 Gy (range 5-40 Gy) and 2 Gy (range 1-2 Gy), respectively. Median follow up was 65 months (range 12-358 months). Persistent pain relief was achieved for all patients. However, long-term follow-up response data were only available for 7/10 patients. All 7 patients exhibited a radiological response and experienced no recurrent disease activity or pain during follow-up. Acute and late radiogenic toxicities >= grade 3 and secondary malignancies were also not observed. CONCLUSION: Primary or adjuvant EBRT seems to be an effective and safe treatment option for persistent or recurrent ABC. Fractionated doses below 30 Gy may be recommended. PMID- 27957591 TI - [Value of postoperative stereotaxic body radiation therapy for spinal metastases]. PMID- 27957592 TI - [Lateral unicompartmental knee arthroplasty - a challenge]. AB - OBJECTIVE: Joint surface replacement in the lateral compartment by unicondylar knee arthroplasty. INDICATIONS: Lateral unicompartmental osteoarthritis of the knee joint, avascular necrosis of the lateral femoral condyle. CONTRAINDICATIONS: Full thickness cartilage defect in the central part of the medial compartment or in the medial aspect of the patellofemoral joint. Instability/contracture of cruciate and collateral ligaments, valgus deformity >15 degrees , valgus deformity not passively correctable, flexion deformity >15 degrees , an intraoperative flexion <100 degrees , failed upper tibial osteotomy, rheumatoid arthritis. SURGICAL TECHNIQUE: Leg positioning in leg holder. Minimally invasive parapatellar lateral arthrotomy. Exposure of the lateral compartment and removal of osteophytes. Attachment of the tibial saw guide. Horizontal cut 7-8 mm below the original tibial plateau with protection of the lateral collateral ligament. Vertical saw cut via an incision in the central aspect of the patellar ligament with an internal rotation of 20 degrees . Femoral preparation. Insertion of the intramedullary rod, positioning of the femoral drill guide directing to the anterior superior iliac spine and drilling the holes. Insertion of the posterior resection guide. Saw cut with protection of the lateral collateral ligament. Insertion of the 0 mm spigot and first milling. Measurement of the extension gap. Insertion of the corresponding spigot (never use a spigot >5 mm). Milling and insertion of the trial components. Application of the anti-impingement guide and anterior and posterior resection of bone. Final preparation of the tibial plateau. Cementing of the components. POSTOPERATIVE MANAGEMENT: Mobilization under full weight-bearing with two crutches. RESULTS: With a mean follow-up of 1.7-4 years, the dislocation rate is about 0-6.6%. Revision-free survival is 90 98%. PMID- 27957593 TI - [Rotation or derotation osteotomy of the tibia]. AB - OBJECTIVE: Corrections for congenital or posttraumatic malrotation of the lower leg, considering alignment of the contralateral leg, with an osteotomy and fixation using locking compression plates (LCP). INDICATIONS: Posttraumatic deformity due to malunion. Increased tibial torsion in residual clubfoot deformity as long as the foot has been realigned. Idiopathic internal or external rotational deformity if the child is regularly tripping and falling, has psychological problems (other children making fun of the child because of the unusual gait), or is bothered by the deformity (age > 10 years, relative indication). CONTRAINDICATIONS: Rotational deformities at other levels, mainly the hip. Children under the age of 3 years due to the remodeling potential during growth. SURGICAL TECHNIQUE: Osteotomy at supramalleolar level and fixation with 3.5 mm 90 degrees locking plate. Perpendicular osteotomy at the intersection of midshaft to distal shaft. After achieving the desired correction, fixation by a straight four-hole 3.5-mm locking plate. POSTOPERATIVE MANAGEMENT: Following fixation of the osteotomy with the four hole 3.5 mm LCP, a lower leg cast is recommended for 4-5 weeks. Applying the 3.5 mm 90 degrees LCP allows immediate postoperative full weight bearing. Osteotomy material should be removed 1 year postoperatively. RESULTS: Assuming an uneventful postoperative course, consolidation of the fracture can be expected within 4-6 weeks. The stable fixation with locking plates provides stability without loss of correction at follow-up. PMID- 27957594 TI - Adding exercise or subtracting sitting time for glycaemic control: where do we stand? AB - While regular structured exercise is a well-established (though arguably under utilised) cornerstone in the prevention and management of type 2 diabetes, population adherence to recommended exercise guidelines remains stubbornly low. Indeed, most adults are exposed to environmental settings (at work, in automobile travel and in the domestic environment) that may not only limit their physical activity, but also promote sitting for prolonged periods of time. However, recent experimental evidence indicates that reducing and breaking up sitting time may also be a useful strategy to improve glycaemic control. In this issue of Diabetologia, Duvivier and colleagues report findings which suggest that reducing sitting time with standing and light-intensity activity could be a potential alternative to structured exercise for improving glycaemic control in type 2 diabetes patients. We review and discuss the findings of this study, its potential clinical implications, and a number of knowledge gaps and opportunities that could be considered in the interest of future research. The findings from Duvivier and colleagues should encourage healthcare practitioners, researchers and type 2 diabetes patients to consider the whole spectrum of physical activity, from sedentary behaviour through to structured exercise. PMID- 27957595 TI - Soft tissue changes in the orofacial region after rapid maxillary expansion : A cone beam computed tomography study. AB - OBJECTIVE: Rapid maxillary expansion (RME) is usually used for expanding the maxillary bony segments. Many studies have assessed the dental and skeletal effects of the expansion treatment but few studies evaluated soft tissue changes using cone beam computed tomography (CBCT) images. This study aims to compare soft tissue changes after RME in prepubertal and postpubertal subjects using CBCT images. The null hypothesis of this study is there is no difference between prepubertal and postpubertal patients in soft tissue changes after RME treatment. MATERIALS AND METHODS: A total of 28 patients (10 males, 18 females) with a bonded type of rapid maxillary expander were included in this study. The patients were divided into two subgroups according to cervical vertebral maturation stage. Prepubertal and postpubertal groups were obtained. Following the selection of CBCT images from the archive, pretreatment (T0) and postretention measurements (T1) were performed. Nine linear and one angular measurement for a total of 10 measurements were evaluated on each CBCT image. The mean differences between T0 and T1 measurements were compared by using the paired-samples t test and significance was set at P < 0.05. RESULTS: The largest median increase was found in cheek projection of the prepubertal group. Changes in soft tissue nasal base, philtrum width, upper lip length, columella width, columella height, and cheek projection were statistically significant (P < 0.001) in both groups. No significant differences were observed in soft tissue alar base, nostril width, nostril height, and nasolabial angle. CONCLUSION: Some significant changes in facial soft tissues were observed after RME treatment but there were no significant differences between prepubertal and postpubertal subjects. The null hypothesis is accepted because there were no significant differences between the groups. PMID- 27957596 TI - The biodegradable spacer as a novel treatment modality for massive rotator cuff tears: a prospective study with 5-year follow-up. AB - BACKGROUND: The management of massive, irreparable rotator cuff tears (RCT) is challenging and associated with high failure rates. There are no current consensus or definitive guidelines concerning the optimal surgical treatment for this devastating condition. This study was designed to confirm the long-term safety and efficacy of the biodegradable inflatable InSpaceTM system in patients with massive reparable or irreparable RCTs. METHODS: In this open-label, single arm, prospective study, subjects with massive RCT underwent subacromial implantation with the biodegradable spacer. Follow-up visits were scheduled according to routine clinical practice. Shoulder function was evaluated using Total Constant Score (TCS). RESULTS: Twenty-four patients were treated and assessed. Four patients had partial tears, and in three of them RC repair was performed. These patients were not included in the efficacy analyses. Of the participating subjects who reached the 5-year follow-up, 84.6% of the patients showed a clinically significant improvement of at least 15 points in their score, while 61.54% showed at least 25 points of improvement. Only 10% of the treated patients showed no improvement or worsening in the shoulder score comparing to their baseline. An overall improvement in the total CS commencing at 3 months and sustained by 6 months through to 5 years of follow-up (P < 0.0001) was demonstrated. CONCLUSIONS: We conclude that in this initial cohort, arthroscopic implantation of InSpaceTM system represented an effective alternative to the existing arthroscopic procedures in patients with painful massive RCT refractory to conservative management. Further randomized controlled trials comparing the clinical and functional outcomes after implantation of the InSpaceTM device are warranted. PMID- 27957597 TI - Financial strain and birth weight: the mediating role of psychological distress. AB - The effects of financial strain during pregnancy have received limited attention. In addition, data examining the pathways by which SES indicators contribute to birth weight are lacking. The objective of the current study was to examine the potential pathway of psychological distress in the relationship between financial strain and birth weight. Participants consisted of 138 pregnant women who completed measures assessing financial strain, depressive symptoms, pregnancy specific distress, perceived stress, and general anxiety during pregnancy (mean gestational age = 18.5, SD = 7.2). Birth outcome data were obtained via medical record review. Simple and parallel mediation models were conducted using PROCESS. Simple mediation models showed that depressive symptoms (95% CI -24.65, -0.90) and pregnancy-specific distress (95% CI -37.31, -5.91), but not perceived stress (95% CI -31.17, 4.69) or anxiety (95% CI -25.84, 5.57), served as mediators in the relationship between financial strain and birth weight. When depressive symptoms and pregnancy-specific distress were included in the same mediation model, only pregnancy-specific distress remained significant. Financial strain was positively associated with all facets of psychological distress and negatively associated with birth weight during pregnancy. The current study demonstrated the mechanistic role of pregnancy-specific distress in the link between financial strain and birth weight in a racially diverse sample. Interventions targeting pregnancy-specific distress may mitigate the effects of financial strain on birth weight. Studies examining whether pregnancy-specific distress accounts for the relationship between other types of stressor exposures and birth weight would be informative. PMID- 27957598 TI - Clinical and microbiological features of Actinotignum bacteremia: a retrospective observational study of 57 cases. AB - The purpose of this study was to investigate the incidence, clinical presentation, and prognosis of Actinotignum bacteremia in southern Sweden. Actinotignum isolates in blood cultures were identified retrospectively between 1st January 2012 and 31st March 2016 through searches in the clinical microbiology laboratory database. The population covered by this laboratory is approximately 1.3 million. Matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS) was used for species determination. Etests were used for minimum inhibitory concentration (MIC) determination. The patients' medical charts were reviewed. Fifty-eight episodes in fifty-seven patients with Actinotignum bacteremia were identified (A. schaalii = 53, A. sanguinis = 1, A. urinale = 2, and Actinotignum species = 3), which corresponds to an incidence of 11 cases per million inhabitants. Fifty-one percent of the isolates were in pure culture. The MICs were low for beta-lactam antibiotics, whereas high MICs were recorded for ciprofloxacin and trimethoprim. Patients had a median age of 82 years, 72% were male, and a majority had underlying urological conditions. Thirty-six of the patients were diagnosed with a focus from the urinary tract. Thirty-one patients developed severe sepsis and nine patients died during the hospital stay. Our study is the largest of Actinotignum bacteremia and demonstrates that it is a condition with a significant fatality that affects elderly persons with underlying conditions. beta-Lactams represent a rational treatment option. PMID- 27957599 TI - Evaluation of the BioFire FilmArray(r) GastrointestinalPanel in a Midwestern Academic Hospital. AB - The BioFire FilmArray(r) Gastrointestinal Panel (GIP) was implemented to replace traditional stool culture and enzyme immunoassay (EIA) testing for stool pathogens. The purpose of this study was to evaluate the detection rate, incidence of coinfection, and culture recovery rate of gastrointestinal (GI) pathogens detected by the GIP over a 1-year period. A total of 2257 stools collected from January to December 2015 were tested using the GIP. Clostridium difficile colonization was also evaluated by an antigen/toxin EIA and confirmatory polymerase chain reaction (PCR). The GIP detected one pathogen in 911 (40.4%) specimens. Coinfections were detected in 176 (7.8%) of these specimens. The most frequently detected pathogens were C. difficile (15.2%), norovirus (8.9%), enteropathogenic Escherichia coli (7.1%), enteroaggregative E. coli (3.4%), Campylobacter spp. (2.3%), and sapovirus (2.0%). Each of the remaining GIP targets had a detection rate of <=1.6%. The recovery of bacteria for public health investigations varied, with rates as high as 77% for Salmonella to as low as 30% for Yersinia enterocolitica. Of stools positive for C. difficile on the GIP that were tested by EIA, only 42.7% (88/206) were found to be producing detectable toxin. Overall, the implementation of the GIP resulted in high detection rates of GI pathogens, including the frequent detection of coinfections. This is a promising test to streamline the testing of agents causing infectious gastroenteritis from multiple tests down to a single order with limited hands-on time. Ongoing studies will need to assess the impact that the GIP has on downstream patient care and public health practices. PMID- 27957601 TI - Reply to a letter to the editor: Dexamethasone intravitreal implant in retinal vein occlusion: real-life data from a prospective, multicenter clinical trial. PMID- 27957600 TI - Vitreoretinal interface abnormalities in patients treatedwith ranibizumab for diabetic macular oedema. AB - PURPOSE: Intravitreal anti-vascular endothelial growth factor (VEGF) agents are effective in the treatment of central involving diabetic macular oedema (DMO). Vitreoretinal interface abnormalities (VRIA) are common in patients with DMO, and the effect of these on the response to anti-VEGF treatment is unclear. Furthermore the effect of anti-VEGF agents on the VRIA itself is uncertain. METHOD: Prospective study of consecutive patients treated with ranibizumab (RZB) for DMO as part of routine clinical care in one eye unit over a 1-year period. Visual acuity (Va), central retinal thickness (CRT) and injection frequency data was recorded on an electronic database. Treatment was initiated with four monthly RZB injections and then a monthly PRN regime. All patients underwent high-density spectral-domain optical coherence tomography (SDOCT) at baseline and 12 months. The SDOCTs were graded by two observers masked to the outcome. RESULTS: One hundred and four eyes (77 patients) were included in the analysis. The mean age was 62 years, and 62% were male. The mean presenting vision was 62 letters and CRT 472 MUm. Eighty eyes retained stable Va, and 17 had an improvement in Va. At baseline, 39 eyes had associated focal vitreomacular adhesion (VMA) and by 12 months this reduced to 30 (p = 0.04), with 12 releasing VMA and three developing it. Patients with VMA had significantly better final Va than those without VMA. Improvement in CRT was greatest in those where VMA released during the study. Forty-five eyes had some degree of foveal involving epiretinal membrane (ERM) at baseline, and 28 were considered to have clinically significant ERM. There was no clinically relevant change in ERM during the study. Patients with significant ERM at baseline had a lower final vision. Multivariate analysis showed that ERM and more severe retinopathy at baseline were predictive of less visual improvement (p < 0.01). Shorter intraretinal cyst length, ERM and the absence of VMA at baseline were predictive of a worsened anatomical response (p < 0.001). CONCLUSION: VRIA are related to outcome in patients treated with RZB. ERM was associated with a worsened visual and anatomic response, and VMA with an improved anatomical response particularly when spontaneous VMA release occurred during treatment. The presence and severity of ERM was not affected by RZB treatment. PMID- 27957602 TI - Erratum to: Dexamethasone intravitreal implant in retinal vein occlusion: real life data from a prospective, multicenter clinical trial. PMID- 27957603 TI - Structure and functioning of oil cavities in the shoot apex of Metrodorea nigra A. St.-Hil. (Rutaceae). AB - This study investigates the histology and subcellular features of secretory cavities during the development of the shoot apex of Metrodorea nigra A. St.-Hil. in order to better understand the functioning of these glands. This Rutaceae species is a very suitable model for studying secretory cavity life span, since the shoot apex exhibits both dormant and growth stages during its annual cycle. Shoot apices were collected during the dormant and growth stages from populations of M. nigra growing under natural conditions. Materials were processed using standard techniques for light and electron microscopy. The secretory cavities originate under the protodermis, and their initiation is restricted to the early developmental stage of shoot organs, which are protected by a hood-shaped structure. Secretory cavities have a multi-seriate epithelium surrounding a lumen that expands schizolysigenously. Oil production begins before lumen formation. When the shoot apex resumes development after the dormant stage, the glands remain active in oil secretion in the developing shoot apex and fully expanded leaves. The mature epithelial cells are flattened and exhibit very thin walls, large oil bodies, leucoplasts surrounded by endoplasmic reticulum, and mitochondria with unusual morphology. The tangential walls of the epithelial cells facing the lumen undergo continuous peeling. The vacuole extrusion appears to be the primary mode of release oil into the lumen, in an exocytotic way. The continuity of oil secretion is ensured by the replacement of the damaged inner epithelial cells by divisions in the parenchyma layer that surround the oil gland, likely a meristematic sheath. PMID- 27957605 TI - Population genetic data for ten miniSTR loci in the Sri Lankan population. AB - Allele frequencies and forensically important parameters of ten autosomal miniSTR loci, D1S1677, D2S1776, D10S1248, D11S4463, D12SATA, D14S1434, D17S974, D18S853, D20S482, and D22S1045, were obtained for 278 unrelated adults from the Sri Lankan population. The combined power of discrimination and probability of exclusion was found to be 0.999999999621539 and 0.9979620, respectively. No significant deviations from Hardy-Weinberg equilibrium were observed except for D20S482 which conformed to HW expectations only after the application of a Bonferroni correction. The study suggests the potential use of these miniSTRs as a supplement or as a stand-alone STR marker system for the analysis of highly degraded evidence in Sri Lanka. PMID- 27957606 TI - Recent Emergence of a Chytrid Fungal Pathogen in California Cascades Frogs (Rana cascadae). AB - The pathogenic fungus Batrachochytrium dendrobatidis (Bd) has been associated with global amphibian declines, but it is often difficult to discern the relative importance of Bd as a causal agent in declines that have already occurred. Retrospective analyses of museum specimens have allowed researchers to associate the timing of Bd arrival with the timing of past amphibian declines. Cascades frogs (Rana cascadae) have experienced dramatic declines in northern California, but it is not clear whether the onset of these declines corresponds to the arrival of Bd. We used quantitative real-time PCR assays of samples collected from museum specimens to determine historical Bd prevalence in the northern California range of Cascades frogs. We detected Bd in 13 of 364 (3.5%) Cascades frog specimens collected between 1907 and 2003, with the first positive result from 1978. A Bayesian analysis suggested that Bd arrived in the region between 1973 and 1978, which corresponds well with the first observations of declines in the 1980s. PMID- 27957607 TI - 2D u-Particle Image Velocimetry and Computational Fluid Dynamics Study Within a 3D Porous Scaffold. AB - Transport properties of 3D scaffolds under fluid flow are critical for tissue development. Computational fluid dynamics (CFD) models can resolve 3D flows and nutrient concentrations in bioreactors at the scaffold-pore scale with high resolution. However, CFD models can be formulated based on assumptions and simplifications. MU-Particle image velocimetry (PIV) measurements should be performed to improve the reliability and predictive power of such models. Nevertheless, measuring fluid flow velocities within 3D scaffolds is challenging. The aim of this study was to develop a MUPIV approach to allow the extraction of velocity fields from a 3D additive manufacturing scaffold using a conventional 2D MUPIV system. The MU-computed tomography scaffold geometry was included in a CFD model where perfusion conditions were simulated. Good agreement was found between velocity profiles from measurements and computational results. Maximum velocities were found at the centre of the pore using both techniques with a difference of 12% which was expected according to the accuracy of the MUPIV system. However, significant differences in terms of velocity magnitude were found near scaffold substrate due to scaffold brightness which affected the MUPIV measurements. As a result, the limitations of the MUPIV system only permits a partial validation of the CFD model. Nevertheless, the combination of both techniques allowed a detailed description of velocity maps within a 3D scaffold which is crucial to determine the optimal cell and nutrient transport properties. PMID- 27957604 TI - A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury. AB - BACKGROUND: In order to improve injury assessment of brain injuries, protein markers of pathophysiological processes and tissue fate have been introduced in the clinic. The most studied protein "biomarker" of cerebral damage in traumatic brain injury (TBI) is the protein S100B. The aim of this narrative review is to thoroughly analyze the properties and capabilities of this biomarker with focus on clinical utility in the assessment of patients suffering from TBI. RESULTS: S100B has successfully been implemented in the clinic regionally (1) to screen mild TBI patients evaluating the need to perform a head computerized tomography, (2) to predict outcome in moderate-to-severe TBI patients, (3) to detect secondary injury development in brain-injured patients and (4) to evaluate treatment efficacy. The potential opportunities and pitfalls of S100B in the different areas usually refer to its specificity and sensitivity to detect and assess intracranial injury. CONCLUSION: Given some shortcomings that should be realized, S100B can be used as a versatile screening, monitoring and prediction tool in the management of TBI patients. PMID- 27957608 TI - Fundamental Principles of Tremor Propagation in the Upper Limb. AB - Although tremor is the most common movement disorder, there exist few effective tremor-suppressing devices, in part because the characteristics of tremor throughout the upper limb are unknown. To clarify, optimally suppressing tremor requires a knowledge of the mechanical origin, propagation, and distribution of tremor throughout the upper limb. Here we present the first systematic investigation of how tremor propagates between the shoulder, elbow, forearm, and wrist. We simulated tremor propagation using a linear, time-invariant, lumped parameter model relating joint torques and the resulting joint displacements. The model focused on the seven main degrees of freedom from the shoulder to the wrist and included coupled joint inertia, damping, and stiffness. We deliberately implemented a simple model to focus first on the most basic effects. Simulating tremorogenic joint torque as a sinusoidal input, we used the model to establish fundamental principles describing how input parameters (torque location and frequency) and joint impedance (inertia, damping, and stiffness) affect tremor propagation. We expect that the methods and principles presented here will serve as the groundwork for future refining studies to understand the origin, propagation, and distribution of tremor throughout the upper limb in order to enable the future development of optimal tremor-suppressing devices. PMID- 27957614 TI - Annual Report 2016. PMID- 27957611 TI - Barrier function in the peripheral and central nervous system-a review. AB - The peripheral (PNS) and central nervous system (CNS) are delicate structures, highly sensitive to homeostatic changes-and crucial for basic vital functions. Thus, a selection of barriers ensures the protection of the nervous system from noxious blood-borne or surrounding stimuli. In this chapter, anatomy and functioning of the blood-nerve (BNB), the blood-brain (BBB), and the blood-spinal cord barriers (BSCB) are presented and the key tight junction (TJ) proteins described: claudin-1, claudin-3, claudin-5, claudin-11, claudin-12, claudin-19, occludin, Zona occludens-1 (ZO-1), and tricellulin are by now identified as relevant for nerval barriers. Different diseases can lead to or be accompanied by neural barrier disruption, and impairment of these barriers worsens pathology. Peripheral nerve injury and inflammatory polyneuropathy cause an increased permeability of BNB as well as BSCB, while, e.g., diseases of the CNS such as amyotrophic lateral sclerosis, multiple sclerosis, spinal cord injury, or Alzheimer's disease can progress and worsen through barrier dysfunction. Moreover, the complex role and regulation of the BBB after ischemic stroke is described. On the other side, PNS and CNS barriers hamper the delivery of drugs in diseases when the barrier is intact, e.g., in certain neurodegenerative diseases or inflammatory pain. Understanding of the barrier - regulating processes has already lead to the discovery of new molecules as drug enhancers. In summary, the knowledge of all of these mechanisms might ultimately lead to the invention of drugs to control barrier function to help ameliorating or curing neurological diseases. PMID- 27957612 TI - Aural Acoustic Stapedius-Muscle Reflex Threshold Procedures to Test Human Infants and Adults. AB - Power-based procedures are described to measure acoustic stapedius-muscle reflex threshold and supra-threshold responses in human adult and infant ears at frequencies from 0.2 to 8 kHz. The stimulus set included five clicks in which four pulsed activators were placed between each pair of clicks, with each stimulus set separated from the next by 0.79 s to allow for reflex decay. Each click response was used to detect the presence of reflex effects across frequency that were elicited by a pulsed broadband-noise or tonal activator in the ipsilateral or contralateral test ear. Acoustic reflex shifts were quantified in terms of the difference in absorbed sound power between the initial baseline click and the later four clicks in each set. Acoustic reflex shifts were measured over a 40-dB range of pulsed activators, and the acoustic reflex threshold was objectively calculated using a maximum 10 likelihood procedure. To illustrate the principles underlying these new reflex tests, reflex shifts in absorbed sound power and absorbance are presented for data acquired in an adult ear with normal hearing and in two infant ears in the initial and follow-up newborn hearing screening exams, one with normal hearing and the other with a conductive hearing loss. The use of absorbed sound power was helpful in classifying an acoustic reflex shift as present or absent. The resulting reflex tests are in use in a large study of wideband clinical diagnosis and monitoring of middle-ear and cochlear function in infant and adult ears. PMID- 27957615 TI - Characterization and tissue distribution of neuropeptide F in the eyestalk and brain of the male giant freshwater prawn, Macrobrachium rosenbergii. AB - We previously analyzed the central nervous system (CNS) transcriptome and found three isotypes of long neuropeptide F (MrNPF-I, -II, -III) and four isoforms of short NPF (sMrNPF) in the giant freshwater prawn, Macrobrachium rosenbergii. We now validate the complete sequences of the MrNPF-I and -II precursor proteins, which show high similarity (91-95 %) to NPFs of the penaeus shrimp (PsNPF). MrNPF I and -II precursors share 71 % amino acid identity, whereas the mature 32-amino acid MrNPF-I and 69-amino-acid MrNPF-II are identical, except for a 37-amino-acid insert within the middle part of the latter. Both mature MrNPFs are almost identical to PsNPF-I and -II except for four amino acids at the mid-region of the peptides. Reverse transcription plus the polymerase chain reaction revealed that transripts of MrNPF-I and -II were expressed in various parts of CNS including the eyestalk, brain and thoracic and abdominal ganglia, with the highest expression occurring in the brain and thoracic ganglia and with MrNPF-I showing five- to seven-fold higher expression than MrNPF-II. These peptides were also expressed in the midgut hindgut, and hepatopancreas, with MrNPF-I expression in the former two organs being at the same level as that in the brain and thoracic ganglia and about 4-fold higher than NPF-II. The expression of NPFs was also detected in the testes and spermatic duct but appeared much weaker in the latter. Other tissues that also expressed a considerable amount of NPF-I included the hematopoeitic tissue, heart and muscle. By immunohistochemistry, we detected MrNPFs in neurons of clusters 2, 3 and 4 and neuropils ME, MT and SG of the optic ganglia, neurons in cluster 6 and neuropils AMPN, PMPN, PT, PB and CB of the medial protocerebrum, neurons in clusters 9 and 11 and neurophils ON and OGTN of the deutocerebrum and neurons in clusters 14, 15 and 16 and neuropils TN and AnN of the tritocerebrum. Because of their high degree of conservation and strong and wide-spread expression in tissues other than CNS, we believe that, in addition to being a neuromodulator in controlling feeding, MrNPFs also play critical roles in tissue homeostasis. This should be further explored. PMID- 27957617 TI - Neuromyotonia as an unusual neurological complication of primary Sjogren's syndrome: case report and literature review. AB - Primary Sjogren's syndrome (PSS) is a systemic autoimmune disorder characterized by chronic inflammation of exocrine glands such as the lachrymal and salivary glands, leading to xerophthalmia and xerostomia. Neurological manifestations are sometimes found in patients with PSS. A variety of neurological complications has been reported in patients with PSS, and both the central nervous system (CNS) and peripheral nervous system (PNS) can be involved in PSS. Several forms of neuropathy, including polyneuropathy, cranial neuropathy, and multiple mononeuropathy, are often seen in PSS patients. Herein, we report for the first time typical neuromyotonia (NMT) symptoms appearing in a patient with PSS. Neuromyotonia is a rare disorder caused by the hyperexcitability of peripheral nerves, causing spontaneous and continuous muscle contraction. We provide an overview of the literature relating to neurological involvement in PSS, and the etiology of acquired NMT. We also discuss the existence of contactin-associated protein-like 2 (Caspr2) antibodies in NMT patients. PMID- 27957616 TI - Developmental pathways in lung regeneration. AB - The key processes of lung development have been elucidated in the past several decades, helping to identify and characterize the resident progenitor cells that ultimately generate the mature organ. The adult lung is a complex organ consisting in scores of different cell lineages that are remarkably quiescent in the absence of injury. Despite low cellular turnover, the lung can respond quickly and dramatically to acute damage, with spatially restricted stem and progenitor cells re-entering the cell cycle and differentiating to promote repair. The findings from lung developmental biology are now being used to examine the mechanisms that underlie lung regeneration. The use of in vitro models such as pluripotent stem cells and new methods of gene editing have provided models for understanding lung disease and exploring the mechanisms of lung regeneration and have raised the prospect of correcting lung dysfunction. We outline the way that basic studies into lung developmental biology are now being applied to lung regeneration, opening up new avenues of research that may ultimately be harnessed for treatments of lung disease. PMID- 27957618 TI - Autologous whole blood versus corticosteroid local injection in treatment of plantar fasciitis: A randomized, controlled multicenter clinical trial. AB - Plantar fasciitis is the most common cause of heel pain. Local injection modalities are among treatment options in patients with resistant pain. The aim of the present study was to evaluate the effect of local autologous whole blood compared with corticosteroid local injection in treatment of plantar fasciitis. In this randomized controlled multicenter study, 36 patients with chronic plantar fasciitis were recruited. Patients were allocated randomly into three treatment groups: local autologous blood, local corticosteroid injection, and control groups receiving no injection. Patients were assessed with visual analog scale (VAS), pressure pain threshold (PPT), and plantar fasciitis pain/disability scale (PFPS) before treatment, as well as 4 and 12 weeks post therapy. Variables of pain and function improved significantly in both corticosteroid and autologous blood groups compared to control group. At 4 weeks following treatment, patients in corticosteroid group had significantly lower levels of pain than patients in autologous blood and control groups (higher PPT level, lower PFPS, and VAS). After 12 weeks of treatment, both corticosteroid and autologous blood groups had lower average levels of pain than control group. The corticosteroid group showed an early sharp and then more gradual improvement in pain scores, but autologous blood group had a steady gradual drop in pain. Autologous whole blood and corticosteroid local injection can both be considered as effective methods in the treatment of chronic plantar fasciitis. These treatments decrease pain and significantly improve function compared to no treatment. PMID- 27957619 TI - Depressive symptoms and structural disease progression in knee osteoarthritis: data from the Osteoarthritis Initiative. AB - Depressive symptoms are associated with increases in pain and functional limitations in knee osteoarthritis (OA). The aim was to determine whether depressive symptoms are also associated with greater structural knee OA progression. Four years of annual radiographic and clinical assessments from the Osteoarthritis Initiative were analyzed. The Center for Epidemiological Studies Depression Scale was used to identify depressive symptoms (threshold = >=16) at the baseline visit. Propensity scores were used to match participants with and without baseline depressive symptoms on multiple potential confounders. Assessment of radiographic knee OA was based on changes in individual radiographic features, which included osteophyte (OST) grade and joint space narrowing (JSN) grade. Mixed effect models were used to examine structural progression between depressed and non-depressed participants with definitive radiographic knee OA. Depressive symptoms were significantly associated with a higher risk of OST progression (odds ratio [OR] = 1.74; 95% confidence interval [CI]: 1.01, 3.00) and a non-significant lower risk of JSN progression (OR = 0.40; 95% CI: 0.14, 1.15) 1 year after baseline. Conversely, there was a non significant lower risk of OST progression (OR = 0.71; 95% CI: 0.28, 1.79) and higher risk of JSN progression (OR = 1.89; 95% CI: 0.71, 5.06) from year 3 to year 4 of follow-up. However, the patterns of OST progression and JSN progression were not significantly different between the depressed and non-depressed (P = 0.25 and 0.15, respectively). The findings provide no evidence that depressive symptoms have a detectable effect on changes in radiographic disease severity in knee OA. PMID- 27957620 TI - Topical interventions to prevent acute radiation dermatitis in head and neck cancer patients: a systematic review. AB - PURPOSE: The purpose of the study is to evaluate the effects of pharmacological and non-pharmacological topical controls in the prevention of radiation dermatitis. METHODS: Relevant clinical trials were identified through electronic searching databases CINAHL, CENTRAL, LILACS, PubMed, Scopus, and Web of Science. Handsearching and gray literature searches were also performed to find additional references. Primary outcomes of interest were the development of radiation dermatitis and the time of occurrence of radiation dermatitis. RESULTS: Thirteen randomized clinical trials were included in this review. The trials were published in Chinese, English, or French, from 1980 to 2015. Pharmacological interventions used in the trials were trolamine, aloe vera, allantoin, Lianbai liquid, sucralfate, Na-sucrose octasulfate, olive oil, hialuronic acid, and dexpanthenol. Non-pharmacological topical controls were usual care/institution routine, aqueous cream, mild soap, water thermal gel, placebo, and no intervention. CONCLUSIONS: There was no strong evidence that indicates differences between topical pharmacological interventions or non-pharmacological topical controls in the prevention of acute radiation dermatitis among patients with head and neck cancer undergoing radiotherapy. PMID- 27957622 TI - Sleep disturbances in advanced cancer patients admitted to a supportive/palliative care unit. AB - The aim of this study was to assess the prevalence of sleep disturbances and possible correlations with associated factors in a sample of patients admitted to an acute palliative/supportive care unit.A consecutive sample of patients with advanced cancer was prospectively assessed for a period of 6 months. Epidemiological and clinical data, treatments received in the last month, Karnofsky status, Edmonton Symptom Assessment System (ESAS), and concomitant medical treatment were also recorded. Patients were administered the Athens Insomnia Scale (AIS) and the Hospital Anxiety and depression scale (HADS).Two hundred nineteen patients met the inclusion criteria. The mean age was 65.4 years (SD 12.4), and 111 patients were males. The mean Karnofsky status was 46.6 (SD = 12). All patients had consistent sleep disturbances (AIS >=6), with a large number of patients having intense-maximum sleep disturbances. No relationships of AIS with gender, age, primary diagnosis, socio-educational factors, and anticancer treatments were found. AIS score was significantly associated with Karnofsky; intensities of pain, asthenia, anorexia, anxiety, depression, drowsiness, and well-being; and the use of corticosteroids and benzodiazepines. There was a positive correlation of HADS anxiety and HADS depression with sleep disturbances (p = 0.000). In the multivariate analysis, AIS increased only with the level of anxiety and depression assessed by HADS.Sleep disturbances were ubiquitous in advanced cancer patients admitted to a supportive/palliative care unit and were strongly correlated with psychological distress. Assessment of sleep disorders is mandatory in this population for the obvious interference with quality of life. PMID- 27957621 TI - Efficacy, feasibility, and acceptability of a novel technology-based intervention to support physical activity in cancer survivors. AB - PURPOSE: Physical activity is known to minimize the long-term side effects of cancer treatment. Yet, rates of physical activity participation by cancer survivors are significantly lower compared to the general population. The purpose of this pilot study was to examine the efficacy, feasibility, and acceptability of a technology-based intervention to promote maintenance of physical activity after completing an exercise-based oncology rehabilitation program. METHODS: The pre-post 4-week intervention included support delivered through tailored text messages, Fitbit(r) self-monitoring, and brief health coaching sessions. The primary outcome measure was accelerometer-assessed physical activity levels. Self efficacy, self-regulation, social support, fatigue, sleep disturbance, depression, and Fitbit(r) step counts were assessed as secondary outcomes. RESULTS: Twenty-four participants (20 females; mean age = 57.9 years +/- 10.4) completed the intervention. Mean daily step counts and weekly minutes of moderate to-vigorous intensity physical activity were maintained after the intervention, as compared to baseline levels achieved at the end of 12 weeks of exercise-based oncology rehabilitation. Both self-regulation (goal setting, relapse prevention) and fatigue severity increased significantly post intervention as compared to baseline (p = 0.05 and p = 0.02, respectively). Qualitative responses demonstrated overall satisfaction with intervention components. CONCLUSIONS: Results demonstrate efficacy of the intervention for maintenance of physical activity levels achieved during exercise-based oncology rehabilitation. Low attrition and high satisfaction provide evidence for both the acceptability and feasibility of the intervention components. Exercise interventions post oncology treatment provide multiple benefits for cancer survivors, yet continued maintenance after program completion is challenging. Technological options offer low-cost, accessible modes to deliver continued monitoring and support beyond traditional facility-based programs. PMID- 27957623 TI - Real-life data in 115 chronic migraine patients treated with Onabotulinumtoxin A during more than one year. AB - BACKGROUND: OnabotulinumtoxinA (OnabotA) is effective in Chronic Migraine (CM) during first year of treatment and longer. In real clinical setting, CM patients with acute Medication Overuse (MO) or concurrently receiving oral preventatives are treated with OnabotA. We aim to assess evolution of CM patients beyond first year on OnabotA. METHODS: Data were retrospectively collected in three headache units. We analyzed cases who had received at least five sessions of OnabotA according to PREEMPT protocol. We continued OnabotA therapy when a reduction of number of headache days of at least 30% was achieved. RESULTS: We included 115 patients (98 females, 17 males) who completed 7.6 +/- 2.3 (5-13) OnabotA procedures. Previously they had not responded to topiramate and, at least, one other preventative. Age at inclusion was 45.3 +/- 12 (14-74) years, and latency between CM onset and OnabotA therapy was 43.1 +/- 38.2 (6-166) months. At first OnabotA session 92 patients (80%) fulfilled MO criteria and 107 (93%) received a concurrent oral preventative. In 42 cases (36.5%) OnabotA dose was increased over 155 units. After first year in 57 out of 92 patients (61.9%) MO was discontinued. Among those receiving preventatives, in 52 out of 107 they were retired (48.6%). In 22 cases (19.1%) OnabotA administration was delayed to the fourth or fifth month and in 12 (10.4%) it was temporally stopped. Finally, in 18 patients (15.7%) OnabotA was discontinued due to lack of efficacy beyond first year of treatment. CONCLUSION: Our results suggest that discontinuation of acute medication overuse and oral preventive therapies are achievable objectives in long-term using of OnabotA in CM patients. PMID- 27957624 TI - Network meta-analysis of migraine disorder treatment by NSAIDs and triptans. AB - BACKGROUND: Migraine is a neurological disorder resulting in large socioeconomic burden. This network meta-analysis (NMA) is designed to compare the relative efficacy and tolerability of non-steroidal anti-inflammatory agents (NSAIDs) and triptans. METHODS: We conducted systematic searches in database PubMed and Embase. Treatment effectiveness was compared by synthesizing direct and indirect evidences using NMA. The surface under curve ranking area (SUCRA) was created to rank those interventions. RESULTS: Eletriptan and rizatriptan are superior to sumatriptan, zolmitriptan, almotriptan, ibuprofen and aspirin with respect to pain-relief. When analyzing 2 h-nausea-absence, rizatriptan has a better efficacy than sumatriptan, while other treatments indicate no distinctive difference compared with placebo. Furthermore, sumatriptan demonstrates a higher incidence of all-adverse-event compared with diclofenac-potassium, ibuprofen and almotriptan. CONCLUSION: This study suggests that eletriptan may be the most suitable therapy for migraine from a comprehensive point of view. In the meantime ibuprofen may also be a good choice for its excellent tolerability. Multi component medication also attracts attention and may be a promising avenue for the next generation of migraine treatment. PMID- 27957625 TI - A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants. AB - BACKGROUND: Cluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology. Complex genetic factors are likely to play a role in CH etiology; however, no confirmed gene associations have been identified. The aim of this study is to identify genetic variants influencing risk to CH and to explore the potential pathogenic mechanisms. METHODS: We have performed a genome wide association study (GWAS) in a clinically well-defined cohort of 99 Italian patients with CH and in a control sample of 360 age-matched sigarette smoking healthy individuals, using the Infinium PsychArray (Illumina), which combines common highly-informative genome-wide tag SNPs and exonic SNPs. Genotype data were used to carry out a genome-wide single marker case-control association analysis using common SNPs, and a gene-based association analysis focussing on rare protein altering variants in 745 candidate genes with a putative role in CH. RESULTS: Although no single variant showed statistically significant association at the genome-wide threshold, we identified an interesting suggestive association (P = 9.1 * 10-6) with a common variant of the PACAP receptor gene (ADCYAP1R1). Furthermore, gene-based analysis provided significant evidence of association (P = 2.5 * 10-5) for a rare potentially damaging missense variant in the MME gene, encoding for the membrane metallo-endopeptidase neprilysin. CONCLUSIONS: Our study represents the first genome-wide association study of common SNPs and rare exonic variants influencing risk for CH. The most interesting results implicate ADCYAP1R1 and MME gene variants in CH susceptibility and point to a role for genes involved in pain processing. These findings provide new insights into the pathogenesis of CH that need further investigation and replication in larger CH samples. PMID- 27957626 TI - Dynamic contrast-enhanced magnetic resonance imaging of the wrist in children with juvenile idiopathic arthritis. AB - BACKGROUND: Dynamic contrast-enhanced MRI provides information on the heterogeneity of the synovium, the primary target of disease in children with juvenile idiopathic arthritis (JIA). OBJECTIVE: To evaluate the feasibility of dynamic contrast-enhanced MRI in the wrist of children with JIA using conventional descriptive measures and time-intensity-curve shape analysis. To explore the association between enhancement characteristics and clinical disease status. MATERIALS AND METHODS: Thirty-two children with JIA and wrist involvement underwent dynamic contrast-enhanced MRI with movement-registration and were classified using validated criteria as clinically active (n = 27) or inactive (n = 5). Outcome measures included descriptive parameters and the classification into time-intensity-curve shapes, which represent the patterns of signal intensity change over time. Differences in dynamic contrast-enhanced MRI outcome measures between clinically active and clinically inactive disease were analyzed and correlation with the Juvenile Arthritis Disease Activity Score was determined. RESULTS: Comprehensive evaluation of disease status was technically feasible and the quality of the dynamic dataset was improved by movement registration. The conventional descriptive measure maximum enhancement differed significantly between clinically active and inactive disease (P = 0.019), whereas time-intensity-curve shape analysis showed no differences. Juvenile Arthritis Disease Activity Score correlated moderately with enhancing volume (P = 0.484). CONCLUSION: Dynamic contrast-enhanced MRI is a promising biomarker for evaluating disease status in children with JIA and wrist involvement. Conventional descriptive dynamic contrast-enhanced MRI measures are better associated with clinically active disease than time-intensity-curve shape analysis. PMID- 27957628 TI - Combined effects of fermentation temperature and pH on kinetic changes of chemical constituents of durian wine fermented with Saccharomyces cerevisiae. AB - This study investigated the effects of temperature (20 and 30 degrees C) and pH (pH 3.1, 3.9) on kinetic changes of chemical constituents of the durian wine fermented with Saccharomyces cerevisiae. Temperature significantly affected growth of S. cerevisiae EC-1118 regardless of pH with a higher temperature leading to a faster cell death. The pH had a more significant effect on ethanol production than temperature with higher production at 20 degrees C (5.95%, v/v) and 30 degrees C (5.56%, v/v) at pH 3.9, relative to that at pH 3.1 (5.25 and 5.01%, v/v). However, relatively higher levels of isobutyl alcohol and isoamyl alcohol up to 64.52 +/- 6.39 and 56.27 +/- 3.00 mg/L, respectively, were produced at pH 3.1 than at pH 3.9 regardless of temperature. In contrast, production of esters was more affected by temperature than pH, where levels of ethyl esters (ethyl esters of octanoate, nonanoate, and decanoate) and acetate esters (ethyl acetate and isoamyl acetate) were significantly higher up to 2.13 +/- 0.23 and 4.61 +/- 0.22 mg/L, respectively, at 20 degrees C than at 30 degrees C. On the other hand, higher temperature improved the reduction of volatile sulfur compounds. This study illustrated that temperature control would be a more effective tool than pH in modulating the resulting aroma compound profile of durian wine. PMID- 27957629 TI - Bacillus amyloliquefaciens SC06 alleviates the oxidative stress of IPEC-1 via modulating Nrf2/Keap1 signaling pathway and decreasing ROS production. AB - Oxidative stress (OS) plays a major role in the gastrointestinal disorders. Although probiotics were reported to repress OS, few researches compared the antioxidant ability of different Bacillus strains and deciphered the mechanisms. To select a Bacillus strain with higher antioxidant capacity, we used H2O2 to induce intestinal porcine epithelial cell 1 (IPEC-1) OS model. The most suitable H2O2 concentration and incubation time were determined by the half lethal dose and methyl thiazolyl tetrazolium. Correlation analysis was performed to choose a sensitive indicator for OS. As for the comparison of Bacillus, cells were divided into control, Bacillus treatment, H2O2 treatment, and Bacillus pre-protection + H2O2 treatment. Bacillus were co-cultured with IPEC-1 for 3 h in Bacillus and Bacillus pre-protection + H2O2 treatments. Then, based on OS model, 300 MUmol/L H2O2 was added into medium of H2O2 and Bacillus pre-protection + H2O2 treatments for another 12 h. Antioxidant and apoptosis gene expressions were detected to screen the target strain. Nuclear factor erythroid-derived 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein1 (Keap1) pathway, reactive oxygen species (ROS) production, mitochondrial membrane potential (Deltapsim), apoptosis, and necrosis were analyzed. Results revealed that heme oxygenase-1 (HO 1) gene expression had a positive correlation with H2O2 induction. Moreover, Bacillus amyloliquefaciens SC06 (SC06)-meditated IPEC-1 showed the best antioxidant capacity though modulating Nrf2 phosphorylation. Deltapsim was elevated, while ROS generation was reduced with SC06 pre-protection, resulting in decreased apoptosis and necrosis. Altogether, HO-1 expression could be regarded as an OS indicator. The regulation of Nrf2/Keap1 pathway and ROS production by SC06 are involved in alleviating OS of IPEC-1. PMID- 27957627 TI - Blood pressure response to catheter-based renal sympathetic denervation in severe resistant hypertension: data from the Greek Renal Denervation Registry. AB - BACKGROUND/INTRODUCTION: The efficacy of catheter-based renal sympathetic denervation (RDN) in terms of blood pressure (BP) reduction has been questioned, while "real-world" data from registries are needed. In this study, we report the complete set of 12-month data on office and ambulatory BP changes as well as the predictors for BP response to RDN from a national registry. METHODS: In 4 Greek hospital centers, 79 patients with severe drug-resistant hypertension (age 59 +/- 10 years, 53 males, body mass index 33 +/- 5 kg/m2; office BP and 24-h ambulatory BP were 176 +/- 15/95 +/- 13 and 155 +/- 14/90 +/- 12 mmHg, respectively, 4.4 +/- 0.9 antihypertensive drugs) underwent RDN and were followed-up for 12 months in the Greek Renal Denervation Registry. Bilateral RDN was performed using percutaneous femoral approach and standardized techniques. RESULTS: Reduction in office systolic/diastolic BP at 6 and 12 months from baseline was -30/-12 and 29/-12 mmHg, while the reduction in 24-h ambulatory BP was -16/-9 and -15/-9 mmHg, respectively (p < 0.05 for all). Patients that were RDN responders (85%, n = 58), defined as an at least 10-mmHg decrease in office systolic BP at 12 months, compared to non-responders were younger (57 +/- 9 vs 65 +/- 8 years, p < 0.05), had higher baseline office systolic BP (176 +/- 17 vs 160 +/- 11 mmHg, p < 0.05) and 24-h systolic BP (159 +/- 13 vs 149 +/- 11 mmHg, p < 0.05). Stepwise logistic regression analysis revealed that age, obesity parameters, and baseline office BP were independent predictors of RDN response (p < 0.05 for both), but not the type of RDN catheter or the use of aldosterone antagonists. At 12 months, there were no significant changes in renal function and any new serious device or procedure-related adverse events. CONCLUSIONS: In our "real-world" multicenter national registry, the efficacy of renal denervation in reducing BP as well as safety is confirmed during a 12-month follow-up. Moreover, younger age, obesity, and higher levels of baseline systolic BP are independently related to better BP response to RDN. PMID- 27957631 TI - Virgibacillus ainsalahensis sp. nov., a Moderately Halophilic Bacterium Isolated from Sediment of a Saline Lake in South of Algeria. AB - A Gram-positive, moderately halophilic, endospore-forming bacterium, designated MerVT, was isolated from a sediment sample of a saline lake located in Ain Salah, south of Algeria. The cells were rod shaped and motile. Isolate MerVT grew at salinity interval of 0.5-25% NaCl (optimum, 5-10%), pH 6.0-12.0 (optimum, 8.0), and temperature between 10 and 40 degrees C (optimum, 30 degrees C).The polar lipids comprised diphosphatidylglycerol, phosphatidylglycerol, a glycolipid, a phospholipid, and two lipids, and MK-7 is the predominant menaquinone. The predominant cellular fatty acids were anteiso C15:0 and anteiso C17:0. The DNA G+C content was 45.3 mol%. Phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that strain MerVT was most closely related to Virgibacillus halodenitrificans (gene sequence similarity of 97.0%). On the basis of phenotypic, chemotaxonomic properties, and phylogenetic analyses, strain MerVT (=DSM = 28944T) should be placed in the genus Virgibacillus as a novel species, for which the name Virgibacillus ainsalahensis is proposed. PMID- 27957632 TI - Epileptic seizure, as the first symptom of hypoparathyroidism in children, does not require antiepileptic drugs. AB - OBJECTIVE: Patients with hypoparathyroidism exhibit metabolic disorders (hypocalcemia) and brain structural abnormalities (brain calcifications). Currently, studies have determined whether antiepileptic drug (AED) treatment is required for epileptic seizures in children with hypoparathyroidism. METHOD: This study aims to evaluate the data of two medical centers in Beijing based on the diagnosis of epileptic seizures as the first symptom of hypoparathyroidism in children. RESULT: A total of 42 patients were included and assigned into AED and non-AED treatment groups in a 1:2 matched case-control study. Results show that the seizure outcome after 1 year of AED treatment is not significantly different from that of the control. In the subgroup analysis of patients with subcortical calcifications, the seizure outcome is still not significantly different from that of the control. CONCLUSION: Thus, AED treatment cannot improve the seizure outcomes in children with parathyroid disorder, even in such cases as suspected structural seizure caused by subcortical calcifications. Clinicians must take adequate considerations on the use of AEDs in these patients. Epileptic seizures, as the first symptom of hypoparathyroidism in children, do not require epilepsy drugs. PMID- 27957630 TI - Characterization of Gastric Microbiota in Twins. AB - Contribution of host genetic backgrounds in the development of gastric microbiota has not been clearly defined. This study was aimed to characterize the biodiversity, structure and composition of gastric microbiota among twins. A total of four pairs of twins and eight unrelated individuals were enrolled in the study. Antral biopsies were obtained during endoscopy. The bacterial 16S rRNA gene was amplified and pyrosequenced. Sequences were analyzed for the composition, structure, and alpha and beta diversities of gastric microbiota. Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria, and Fusobacteria were the most predominant phyla of gastric microbiota. Each individual, twins as well as unrelated individuals, harbored a microbiota of distinct composition. There was no evidence of additional similarity in the richness and evenness of gastric microbiota among co-twins as compared to unrelated individuals. Calculations of thetaYC and PCoA demonstrated that the structure similarity of gastric microbial community between co-twins did not increase compared to unrelated individuals. In contrast, the structure of microbiota was altered enormously by Helicobacter pylori infection. These results suggest that host genetic backgrounds had little effect in shaping the gastric microbiota. This property of gastric microbiota could facilitate the studies discerning the role of microbiota from genetic grounds in the pathogenesis. PMID- 27957633 TI - An aggressive parameningeal rhabdomyosarcoma with multiple spinal cord metastases: a case report and review of the literature. AB - PURPOSE: Spinal cord metastasis from rhabdomyosarcoma (RMS) is extremely rare, with three cases reported to date. Herein, we report an aggressive case of RMS of the infratemporal fossa who which developed spinal cord metastases during treatment. CASE PRESENTATION: A 6-year-old girl presented with an enlarging painless mass around her right ear for 3 months. An enhanced magnetic resonance imaging (MRI) revealed a 5 * x4 * x4.5 5 cm mass on her right infratemporal fossa. A tru-cut biopsy was performed, and histopathologic examination revealed the diagnosis of rhabdomyosarcoma. At the time of the diagnosis, cerebrospinal fluid cytology was negative for malignant cells. The patient underwent induction chemotherapy. There was minimal response to chemotherapy, and the patient underwent curative radiotherapy. However, by 12th fraction of RT, the patient developed a progressive weakness on her lower extremity. Spinal MRI revealed multiple gross masses in different parts of the spinal cord. The local radiotherapy was changed toas craniospinal radiotherapy. However, two 2 weeks after the completion of the RT, the patient developed sepsis and expired because of septic shock. CONCLUSION: Parameningeal RMS is a peculiar subgroup of RMS, which needs an aggressive approach. Despite aggressive approach, meningeal spread is the most important cause of the treatment failure. We should keept in mind that during the treatment, there can be meningeal spread towards to either the brain or spinal cord; therefore, we should follow -up the patients closely from this aspect. PMID- 27957634 TI - Optimal pediatric dosing of anti-platelet agents for pipeline stent embolization a case report and review of the literature. AB - BACKGROUND: Various strategies are emerging for dosing antiplatelet therapies in preparation for pipeline stent embolization in adults. Hyper-response is associated with hemorrhagic complications. Hypo-response is associated with thromboembolic events. Dosing of antiplatelet agents is highly variable, with little consensus among experts for adults-and even more so for children. To date, pipeline stents have been deployed in 11 pediatric patients, ages 4-15. A variety of clopidogrel and aspirin dosing regimens have been used, with response tested in only three patients, who were all therapeutic. Thrombotic events occurred in two patients, neither of whom were tested. CASE: We describe here the first case of a hemorrhagic complication in a hyper-responsive pediatric patient undergoing placement of a pipeline stent. DISCUSSION: As the use of endovascular therapies requiring dual anti-platelet agents becomes more established, there is an increasing need to develop titration protocols that minimizes the risk of thrombotic and hemorrhagic events. PMID- 27957635 TI - Gadoxetic acid-enhanced magnetic resonance imaging characteristics of hepatocellular carcinoma occurring in liver transplants. AB - OBJECTIVES: Characteristics of hepatocellular carcinoma (HCC) on magnetic resonance (MR) images were compared in patients who did or did not undergo liver transplantation (LT), and we evaluated the relationship of these findings with overall survival (OS) and time-to-tumour recurrence (TTR) after transplantation. METHODS: The enhancement pattern of gadoxetic acid-enhanced MR images of 25 patients with recurrent HCCs (LT group) and 25 surgically confirmed HCC patients in the non-transplanted (control) group were compared. Typical enhancement was defined as 1) arterial enhancement and delayed wash-out and 2) absence of typical features of cholangiocarcinoma consisting of arterial rim enhancement and target appearance on hepatobiliary phase images. OS and TTR were analyzed in the LT group according to these patterns using the log-rank test. RESULTS: HCCs in the LT group significantly more often had an atypical enhancement pattern (16/25, 64.0%) than those in the control group (5/25, 20.0%; p = 0.004). However, OS and TTR did not differ significantly according to these enhancement patterns of recurrent HCC (p > 0.05). CONCLUSION: Although enhancement patterns of recurrent HCC in transplanted liver did not affect OS and TTR, these HCCs that arise after LT frequently revealed atypical enhancement on gadoxetic acid-enhanced MR imaging. KEY POINTS: * Recurrent HCCs after LT showed atypical enhancement on gadoxetic acid-enhanced MRI. *They showed absence of delayed wash-out or cholangiocarinoma-like features. * Enhancement patterns of recurrent HCCs did not affect OS and TTR. PMID- 27957636 TI - Bony morphology of the hip in professional ballet dancers compared to athletes. AB - OBJECTIVES: To compare hip bony morphology between ballet dancers and a sporting control group and to determine the relationship with hip pain. METHODS: Thirty three professional ballet dancers and 33 age- and sex-matched athletes completed questionnaires, including the Copenhagen Hip and Groin Outcome Score (HAGOS), and underwent clinical testing and 3.0-T magnetic resonance imaging to measure acetabular coverage with lateral centre edge angles, femoral head-neck junction concavity with alpha angles at anterior and superior positions, femoral neck shaft angles, and acetabular version angles. RESULTS: Bony morphological measures fell within normal ranges. Dancers had higher neck-shaft angles (dancers 134.6 +/ 4.6 degrees /athletes130.8 +/- 4.7 degrees , p = 0.002), lower acetabular version angles (13.5 +/- 4.7 degrees /17.1 +/- 4.7 degrees , p = 0.003), lower superior alpha angles (38.9 +/- 6.9 degrees /46.7 +/- 10.6 degrees , p < 0.001), similar anterior alpha angles (43.6 +/- 8.1/46 +/- 7 degrees , p = 0.2), and similar lateral centre edge angles (28.8 +/- 4.6 degrees /30.8 +/- 4.5 degrees , p = 0.07) compared to athletes. Abnormal morphology was detected in dancers: 3% acetabular dysplasia (athletes 0), 15% borderline dysplasia (6%), 24% cam morphology (33%), 24% coxa valga (6%), and 21% acetabular retroversion (18%). The HAGOS pain scores correlated moderately with acetabular version (r = -0.43, p = 0.02) in dancers, with no other correlation between pain and morphological parameters in either group. CONCLUSIONS: Professional ballet dancers have hip bony morphology that differentiates them from athletes. Hip pain correlated poorly with bony morphology. KEY POINTS: * Ballet dancers have hip bony morphology that may allow extreme hip motion. * Morphological parameter means fell within normal reference intervals in dancers. * Bony morphology correlates poorly with hip pain. * The risk of hip injury due to abnormal morphology requires prospective studies. PMID- 27957637 TI - PI-RADS version 2: quantitative analysis aids reliable interpretation of diffusion-weighted imaging for prostate cancer. AB - OBJECTIVES: To determine whether apparent diffusion coefficient (ADC) ratio aids reliable interpretation of diffusion-weighted imaging (DWI) for prostate cancer (PCa). METHODS: Seventy-six consecutive patients with PCa who underwent DWI and surgery were included. Based on pathologic tumour location, two readers independently performed DWI scoring according to the revised Prostate Imaging Reporting and Data System (PI-RADSv2). ADC ratios of benign to cancerous prostatic tissue were then measured independently and compared between cases showing concordant and discordant DWI scores >=4. Area under the curve (AUC) and threshold of ADC ratio were analyzed for DWI scores >=4. RESULTS: The rate of inter-reader disagreement for DWI score >=4 was 11.8% (9/76). ADC ratios were higher in concordant vs. discordant DWI scores >=4 (median, 1.7 vs. 1.1-1.2; p < 0.001). For DWI scores >=4, the AUCs of ADC ratios were 0.970 for reader 1 and 0.959 for reader 2. In patients with an ADC ratio >1.3, the rate of inter-reader disagreement for DWI score >=4 decreased to 5.9-6.0%. An ADC ratio >1.3 yielded 100% (reader 1, 54/54; reader 2, 51/51) positive predictive value for clinically significant cancer. CONCLUSION: ADC ratios may be useful for reliable interpretation of DWI score >=4 in PI-RADSv2. KEY POINTS: * The ADC ratio correlated positively with DWI score of PI-RADSv2. * ADC ratio >1.3 was associated with concordant interpretation of DWI score >=4. * ADC ratio >1.3 was associated with high PPV for clinically significant cancer. * ADC ratio is useful for reliable interpretation of DWI scoring in PI-RADSv2. PMID- 27957638 TI - Early perfusion changes within 1 week of systemic treatment measured by dynamic contrast-enhanced MRI may predict survival in patients with advanced hepatocellular carcinoma. AB - OBJECTIVES: To correlate early changes in the parameters of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) within 1 week of systemic therapy with overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC). METHODS: Eighty-nine patients with advanced HCC underwent DCE-MRI before and within 1 week following systemic therapy. The relative changes of six DCE-MRI parameters (Peak, Slope, AUC, Ktrans, Kep and Ve) of the tumours were correlated with OS using the Kaplan-Meier model and the double-sided log-rank test. RESULTS: All patients died and the median survival was 174 days. Among the six DCE-MRI parameters, reductions in Peak, AUC, and Ktrans, were significantly correlated with one another. In addition, patients with a high Peak reduction following treatment had longer OS (P = 0.023) compared with those with a low Peak reduction. In multivariate analysis, a high Peak reduction was an independent favourable prognostic factor in all patients [hazard ratio (HR), 0.622; P = 0.038] after controlling for age, sex, treatment methods, tumour size and stage, and Eastern Cooperative Oncology Group performance status. CONCLUSIONS: Early perfusion changes within 1 week following systemic therapy measured by DCE-MRI may aid in the prediction of the clinical outcome in patients with advanced HCC. KEY POINTS: * DCE-MRI is helpful to evaluate perfusion changes of HCC after systemic treatment. * Early perfusion changes within 1 week after treatment may predict overall survival. * High Peak reduction was an independent favourable prognostic factor after systemic treatment. PMID- 27957639 TI - Treatment Efficacy and Safety of Ethanol Ablation for Thyroglossal Duct Cysts: A Comparison with Surgery. AB - OBJECTIVE: To compare the efficacy and safety of ethanol ablation (EA) for thyroglossal duct cyst (TGDC) against surgery. METHODS: This study included 345 patients (289, surgery; 56, EA) treated for TGDC at four institutions between May 2005 and June 2014. Surgery (whole surgery and Sistrunk operation which is the current standard surgical method) and EA were compared with respect to the treatment failure and complication rates. The cost of EA and surgery was also compared. The Cox regression hazard model and linear regression were used for the adjustment of covariates. RESULTS: EA demonstrated higher treatment failures (19.6% vs. 2.4%, p < 0.001[whole surgery] and 1.2%, p = 0.004 [Sistrunk operation]), but fewer complications (1.8% vs. 10.0%, p = 0.04 [whole surgery] and 10.2%, p = 0.06 [Sistrunk operation]), and lower cost (?423,801 vs. ?1,435,707 [whole surgery]) than surgery. EA achieved 85.7% of treatment success up to second session. The mean volume reduction rate after EA was 82.3% at last follow-up. Young age and EA were correlated with treatment failure (p = 0.01 and 0.001, respectively). CONCLUSION: Both surgery and EA had acceptable treatment efficacy in the management of TGDC. Although there is a higher likelihood of treatment failure with EA, it has a better safety profile than surgery. KEY POINTS: * Both surgery and ethanol ablation show acceptable treatment efficacy for TGDC. * Considering treatment failure, surgery manages TGDC more effectively than EA. * EA is safer than surgery and presents no major complications. * EA could be an alternative treatment for TGDC in selected patients. PMID- 27957640 TI - Diagnostic performance of reduced-dose CT with a hybrid iterative reconstruction algorithm for the detection of hypervascular liver lesions: a phantom study. AB - OBJECTIVES: To investigate the diagnostic performance of reduced-dose CT with a hybrid iterative reconstruction (IR) algorithm for the detection of hypervascular liver lesions. METHODS: Thirty liver phantoms with or without simulated hypervascular lesions were scanned with a 320-slice CT scanner with control-dose (40 mAs) and reduced-dose (30 and 20 mAs) settings. Control-dose images were reconstructed with filtered back projection (FBP), and reduced-dose images were reconstructed with FBP and a hybrid IR algorithm. Objective image noise and the lesion to liver contrast-to-noise ratio (CNR) were evaluated quantitatively. Images were interpreted independently by 2 blinded radiologists, and jackknife alternative free-response receiver-operating characteristic (JAFROC) analysis was performed. RESULTS: Hybrid IR images with reduced-dose settings (both 30 and 20 mAs) yielded significantly lower objective image noise and higher CNR than control-dose FBP images (P < .05). However, hybrid IR images with reduced-dose settings had lower JAFROC1 figure of merit than control-dose FBP images, although only the difference between 20 mAs images and control-dose FBP images was significant for both readers (P < .01). CONCLUSIONS: An aggressive reduction of the radiation dose would impair the detectability of hypervascular liver lesions, although objective image noise and CNR would be preserved by a hybrid IR algorithm. KEY POINTS: * A half-dose scan with a hybrid iterative reconstruction preserves objective image quality. * A hybrid iterative reconstruction algorithm does not improve diagnostic performance. * An aggressive dose reduction would impair the detectability of low-contrast lesions. PMID- 27957641 TI - High-resolution ultrasound visualization of the recurrent motor branch of the median nerve: normal and first pathological findings. AB - PURPOSE: To evaluate in a prospective study the possibility of visualization and diagnostic assessment of the recurrent motor branch (RMB) of the median nerve with high-resolution ultrasound (HRUS). MATERIALS AND METHODS: HRUS with high frequency probes (18-22 MhZ) was used to locate the RMB in eight fresh cadaveric hands. To verify correct identification, ink-marking and consecutive dissection were performed. Measurement of the RMB maximum transverse-diameter, an evaluation of the origin from the median nerve and its course in relation to the transverse carpal ligament, was performed in both hands of ten healthy volunteers (n = 20). Cases referred for HRUS examinations for suspected RMB lesions were also assessed. RESULTS: The RMB was clearly visible in all anatomical specimens and all volunteers. Dissection confirmed HRUS findings in all anatomical specimens. Mean RMB diameter in volunteers was 0.7 mm +/- 0.1 (range, 0.6-1). The RMB originated from the radial aspect in 11 (55%), central aspect in eight (40%) and ulnar aspect in one (5%) hand. Nineteen (95%) extraligamentous courses and one (5%) subligamentous course were detected. Three patients with visible RMB abnormalities on HRUS were identified. CONCLUSION: HRUS is able to reliably visualize the RMB, its variations and pathologies. KEY POINTS: * Ultrasound allows visualization of the recurrent motor branch of the median nerve. * Ultrasound may help clinicians to assess patients with recurrent motor branch pathologies. * Patient management may become more appropriate and targeted therapy could be improved. PMID- 27957642 TI - Radiology response in the emergency department during a mass casualty incident: a retrospective study of the two terrorist attacks on 22 July 2011 in Norway. AB - OBJECTIVES: To describe the use of radiology in the emergency department (ED) in a trauma centre during a mass casualty incident, using a minimum acceptable care (MAC) strategy in which CT was restricted to potentially severe head injuries. METHODS: We retrospectively studied the initial use of imaging on patients triaged to the trauma centre following the twin terrorist attacks in Norway on 22 July 2011. RESULTS: Nine patients from the explosion and 15 from the shooting were included. Fourteen patients had an Injury Severity Score >15. During the first 15 h, 22/24 patients underwent imaging in the ED. All 15 gunshot patients had plain films taken in the ED, compared to three from the explosion. A CT was performed in 18/24 patients; ten of these were completed in the ED and included five non-head CTs, the latter representing deviations from the MAC strategy. No CT referrals were delayed or declined. Mobilisation of radiology personnel resulted in a tripling of the staff. CONCLUSIONS: Plain film and CT capacity was never exceeded despite deviations from the MAC strategy. An updated disaster management plan will require the radiologist to cancel non-head CTs performed in the ED until no additional MCI patients are expected. KEY POINTS: * Minimum acceptable care (MAC) should replace normal routines in mass casualty incidents. * MAC implied reduced use of imaging in the emergency department (ED). * CT in ED was restricted to suspected severe head injuries during MAC. * The radiologist should cancel all non-head CTs in the ED during MAC. PMID- 27957643 TI - Should the automatic exposure control system of CT be disabled when scanning patients with endoaortic stents or mechanical heart valves? A phantom study. AB - OBJECTIVES: To estimate the impact of endoaortic stents/mechanical heart valves on the output of an automatic exposure control (AEC) system and CT radiation dose. METHODS: In this phantom study, seven stents and two valves were scanned with varying tube voltage (80/100/120 kVp), AEC activation (enabled/disabled) and prosthesis (present/absent), for a total of 540 scans. For each prosthesis, the dose-length product (DLP) was compared between scans with the AEC enabled and disabled. Percentage confidence levels for differences due to the prosthesis were calculated. RESULTS: Differences between results with the AEC enabled and disabled were not statistically significant (p >= 0.059). In the comparison with and without the prosthesis, DLP was unchanged at 80 kVp and 100 kVp, while a slight increase was observed at 120 kVp. The radiation dose varied from 1.8 mGy to 2.4 mGy without the prosthesis and from 1.8 mGy to 2.5 mGy with the prosthesis (confidence level 37-100%). CONCLUSIONS: The effect of the prosthesis on the AEC system was negligible and not clinically relevant. Therefore, disabling the AEC system when scanning these patients is not likely to provide a benefit. KEY POINTS: * CT-AEC system is not impaired in patients with endoaortic prostheses/heart valves. * Negligible differences may be observed only at 120 kVp. * Disabling the AEC system in these patients is not recommended. PMID- 27957644 TI - Tip malposition of peripherally inserted central catheters: a prospective randomized controlled trial to compare bedside insertion to fluoroscopically guided placement. AB - OBJECTIVE: Peripherally inserted central catheter (PICC) use continues to increase, leading to the development of a blind bedside technique (BST) for placement. The aim of our study was to compare the BST with the fluoroscopically guided technique (FGT), with specific regard to catheter tip position (CTP). MATERIALS AND METHODS: One hundred eighty patients were randomized to either the BST or the FGT. All procedures were done by the same interventional team and included postprocedural chest X-ray to assess CTP. Depending on the international guidelines for optimal CTP, patients were classified in three types: optimal, suboptimal not needing repositioning, and nonoptimal requiring additional repositioning procedures. Fisher's test was used for comparisons. RESULTS: One hundred seventy-one PICCs were successful inserted. In the BST groups, 23.3% of placements were suboptimal and 30% nonoptimal, requiring repositioning. In the FGT group, 5.6% were suboptimal and 1.1% nonoptimal. Thus, suboptimal and nonoptimal CTP were significantly lower in the FGT group (p < 0.001). CONCLUSION: Tip malposition rates are high when using blind BST, exposing the patient to an increased risk of deep venous thrombosis and catheter malfunction. Using the FGT or emerging technologies that could help tip positioning are recommended, especially for long-term indications. KEY POINTS: * Bedside and fluoroscopy guided techniques are commonly used for PICC placement. * Catheter malposition is the major technical issue with the bedside technique. * Catheter malposition occurred in 53% of patients with the bedside technique. PMID- 27957645 TI - Cyberbullying Among Greek High School Adolescents. AB - OBJECTIVE: To investigate the presence of cyberbullying among Greek students and the efficacy of proposed preventive interventions. METHODS: Three types of high schools (private, experimental and public) with different politics on on-line aggression were enrolled. All students of the aforementioned schools were asked to complete an anonymous questionnaire. RESULTS: Around 62 % of the high school students experienced cyberbullying by electronic means, especially by cell phone, mostly the public school students (p 0.008). The bully was a stranger in more than 40 % of the cases. Over 60 % of the victims had not seeked help but dealt with the attack on their own. Only 20 % of the victims manifested sleep or eating disorders, physical/ psychological symptoms or changes in their social life as a consequence of the cyber-attack. CONCLUSIONS: Cyberbullying is a usual phenomenon among high school students. The bully is frequently unacquainted to the victim. Most of the victims are not physically or psychologically affected by the cyber attack and do not share the event with anyone. There was a slight difference in the response of the students to cyberbullying among the different school politics of on-line aggression. PMID- 27957646 TI - Acute Toxicity Evaluation of Glycosylated Gd3+-Based Silica Nanoprobe. AB - PURPOSE: Early stage diseases diagnosed using magnetic resonance imaging (MRI) techniques is of high global interest as a potent noninvasive modality. MRI contrast agents are improved through modifications in structural and physicochemical properties of the applied nanoprobes. But, the potential toxic effects of nanoprobes upon exposure to biological systems are still a major concern. PROCEDURE: In this study, the acute toxicity of glycosylated Gd3+-based silica mesoporous nanospheres (GSNs) as a MRI contrast agent was evaluated in Balb/c mice. In order to evaluate in vivo toxicity of GSN, preclinical studies, daily weight monitoring, hematological/blood chemistry tests, and histological assessment were conducted. Magnetic resonance relaxivities of GSN was determined using a MRI scanner. RESULTS: The obtained results suggest that in vivo toxicity of GSN was mostly influenced by nanoparticle surface area, functionality, and nanoparticle zeta potential. The maximum tolerated dose (MTD) increased in the following order: mesoporous silica nanospheres (MSNs) at 1 mg/mice < GSN (aspect ratio 1, 2, 8) at 40 mg/mice. The results also indicate GSN, one of the best cell imaging contrast agent, which does not show any significant toxicity on multiple vital organs following injection of 20 mg/mice, while a significant T1-weighted enhancement was observed in whole body of a Balb/c mice 15 min postinjection of (5 MUmol/kg) of body weight of GSN. CONCLUSIONS: These results shed light on the functionality of MSNs to minimize in vivo toxicity. Also, glyconanoprobe can be beneficially used for nanomedicine and cellular imaging applications without any significant toxicity. PMID- 27957648 TI - Autophagy-from molecular mechanisms to clinical relevance. AB - Autophagy is a lysosomal degradation pathway of eukaryotic cells that is highly conserved from yeast to mammals. During this process, cooperating protein complexes are recruited in a hierarchic order to the phagophore assembly site (PAS) to mediate the elongation and closure of double-membrane vesicles called autophagosomes, which sequester cytosolic components and deliver their content to the endolysosomal system for degradation. As a major cytoprotective mechanism, autophagy plays a key role in the stress response against nutrient starvation, hypoxia, and infections. Although numerous studies reported that impaired function of core autophagy proteins also contributes to the development and progression of various human diseases such as neurodegenerative disorders, cardiovascular and muscle diseases, infections, and different types of cancer, the function of this process in human diseases remains unclear. Evidence often suggests a controversial role for autophagy in the pathomechanisms of these severe disorders. Here, we provide an overview of the molecular mechanisms of autophagy and summarize the recent advances on its function in human health and disease. PMID- 27957647 TI - Dosimetry in Micro-computed Tomography: a Review of the Measurement Methods, Impacts, and Characterization of the Quantum GX Imaging System. AB - PURPOSE: X-ray micro-computed tomography (MUCT) is a widely used imaging modality in preclinical research with applications in many areas including orthopedics, pulmonology, oncology, cardiology, and infectious disease. X-rays are a form of ionizing radiation and, therefore, can potentially induce damage and cause detrimental effects. Previous reviews have touched on these effects but have not comprehensively covered the possible implications on study results. Furthermore, interpreting data across these studies is difficult because there is no widely accepted dose characterization methodology for preclinical MUCT. The purpose of this paper is to ensure in vivo MUCT studies can be properly designed and the data can be appropriately interpreted. PROCEDURES: Studies from the scientific literature that investigate the biological effects of radiation doses relevant to MUCT were reviewed. The different dose measurement methodologies used in the peer reviewed literature were also reviewed. The CT dose index 100 (CTDI100) was then measured on the Quantum GX MUCT instrument. A low contrast phantom, a hydroxyapatite phantom, and a mouse were also imaged to provide examples of how the dose can affect image quality. RESULTS: Data in the scientific literature indicate that scenarios exist where radiation doses used in MUCT imaging are high enough to potentially bias experimental results. The significance of this effect may relate to the study outcome and tissue being imaged. CTDI100 is a reasonable metric to use for dose characterization in MUCT. Dose rates in the Quantum GX vary based on the amount of material in the beam path and are a function of X-ray tube voltage. The CTDI100 in air for a Quantum GX can be as low as 5.1 mGy for a 50 kVp scan and 9.9 mGy for a 90 kVp scan. This dose is low enough to visualize bone both in a mouse image and in a hydroxyapatite phantom, but applications requiring higher resolution in a mouse or less noise in a low-contrast phantom benefit from longer scan times with increased dose. CONCLUSIONS: Dose management should be considered when designing MUCT studies. Dose rates in the Quantum GX are compatible with longitudinal MUCT imaging. PMID- 27957649 TI - Responses of primary cultured haemocytes derived from the marine gastropod Haliotis tuberculata to an industrial effluent exposure. AB - This study assessed the responses of primary cultured haemocytes from the marine gastropod Haliotis tuberculata exposed to the increasing concentrations of industrial effluent (0, 0.5, 1, 10, 15 and 20%) discharged into the Tunisian coastal area. Analyses showed the presence of metals such as cadmium (Cd), chromium (Cr), copper (Cu), manganese (Mn), zinc (Zn), nickel (Ni) and lead (Pb) in the effluent. The effects of this mixture of pollutants on abalone haemocyte parameters were reflected by a significant decrease of cell viability, phagocytotic activity and reactive oxygen species (ROS) production as well as morphological and lysosomal membrane alterations. Thus, these results indicated that our primary culture system represents a suitable in vitro model for monitoring of anthropogenic contaminants in aquatic environments. PMID- 27957650 TI - Roles of SALL2 in tumorigenesis. AB - The proteins p150Sal2 (product of SALL2) and p53 share growth arrest and pro apoptotic functions by independently inducing p21Cip1/Waf1 and BAX, and both proteins are targeted by the human papilloma virus E6 protein, leading to blockage of growth arrest in infected cells. Loss of both p53 and Sall2 in mice causes significantly higher mortality and metastasis rates compared with p53 single mutant mice. Therefore, p150Sal2 seems to have strong potential as a novel cancer biomarker for early diagnosis and risk prediction. Loss of SALL2 expression is observed in many cases of human serous ovarian carcinoma, whereas normal ovarian epithelial cells maintain high levels of the p150Sal2 protein, supporting an important tumor suppressive role for p150Sal2 in the human ovary. In contrast, p150Sal2 is a transcription factor required to convert differentiated glioblastoma cells into stem-like tumor-propagating cells, suggesting that its functional roles are dependent on tissue types and cellular context. The function of p150Sal2 in normal and diseased cells and possible therapeutic approaches are discussed in this review. PMID- 27957652 TI - Performance of beef heifers supplemented with sodium lasalocid. AB - This study was conducted on 78 13-month-old crossbred beef heifers that weighed 215 kg in Southern Rio Grande do Sul (RS) State, Brazil. We evaluated the performance of beef heifers that were reared in a pasture system that received a mineral supplement energy-type protein with added sodium lasalocid (LAS). The heifers were randomly and uniformly divided into 2 groups, with 39 animals in each group. One group of animals received a mineral supplement energy-type protein without sodium lasalocid (CON), and the other group received a mineral supplement energy-type protein with added LAS. The mean feed intake, the body weight (BW), the average daily gain (ADG), the body condition score (BCS), and ovarian cyclicity were recorded, and economic parameters were calculated. No differences in supplement intake were observed between the groups, which ensures adequate intake of the other components of the mineral mixture, which are part of the nutritional requirements for the production process. Similarly, no difference in the ADG was observed between treatments. We observed that the heifers in the LAS group had a higher BW gain (51 kg) that the CON heifers (40 kg; P < 0.05). In addition, LAS-supplemented heifers had a higher BCS (3.53) than CON heifers (3.38) at the end of the experiment (P < 0.05). The heifers supplemented with LAS had a higher profitability than the CON heifers, even with the higher cost of the supplement containing LAS; this effect was due to the higher live BW at the end of the study. We concluded that the administration of a mineral supplement energy type protein with added LAS has beneficial effects on beef heifers in terms of production and economic feasibility. PMID- 27957653 TI - Harvesting of the Microalga Nannochloropsis sp. by Bioflocculation with Mung Bean Protein Extract. AB - Harvesting microalgae from medium is a major challenge due to their small size and low concentrations. In an attempt to find a cost-effective and eco-friendly harvesting technique, mung bean (Vigna radiata) protein extract (MBPE) was used for flocculation of Nannochloropsis sp. The effects of parameters such as pH, flocculant dose, algae concentration, and mixing time were used to study the flocculation efficiency (FE) of MBPE. Optimum parameters of MBPE dosage of 20 mL L-1 and a mixing rate of 300 rpm for 6 min achieved a FE of >92% after 2 h of settling time. MBPE-aggregated microlga flocs were characterized by microscopy. Zeta potential values decreased with increasing flocculant dose, and the values obtained were -6.93 +/- 0.60, -5.36 +/- 0.64, and -4.44 +/- 0.22 for doses of 10, 20, and 30 mL L-1, respectively. In conclusion, MBPE flocculants used in this study are safe, nontoxic, and pollution free, so they could be used for an effective, convenient, and rapid harvesting of microalgae in an eco-friendly approach. These methods are sustainable and could be applied in industrial scale for aquaculture nutrition. PMID- 27957651 TI - Carnosic acid protects non-alcoholic fatty liver-induced dopaminergic neuron injury in rats. AB - Non-alcoholic fatty liver disease (NAFLD) has been reported to induce cognitive impairments of hippocampus and may influence central nervous system. In the present study, we investigated whether carnosic acid (CA) ameliorates dopaminergic neuron injury in a rat model of NAFLD. In order to induce NAFLD, rats were fed with high-fat diet (HFD) for 10 weeks. We found that continued CA administration reduced lipid accumulation marked by decreases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels, and an increase in high-density lipoprotein cholesterol (HDL-C) level in the serum. H&E staining revealed that feeding CA reduced lipid droplets accumulation, and alleviated oxidative stress by increasing in superoxide dismutase (SOD) level and decreasing in malondialdehyde (MDA) level in the liver. In addition, by measuring several parameters of gait analysis, we demonstrated that CA treatment ameliorated behavioral impairments, as evidenced by decreased duration and maximum variation, accompanied by increased average speed and cadence. Furthermore, CA treated-animals displayed an increase in the contents of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacelic acid (DOPAC) and elevated the expressions of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) as well as the TH protein in the striatum. Together, these findings suggest that CA may be an effective agent in protecting rats from NAFLD-induced dopaminergic neuron injury. PMID- 27957655 TI - Death Anxiety Resilience; a Mixed Methods Investigation. AB - Research was conducted examining how death anxiety influenced PTSD and mental health among people who have experienced a life-threatening event. This study was conducted using undergraduate university students in Lithuania. The study used a mixed-method design and in phase 1, participants (N = 97) completed self-report questionnaires that gathered information on demographics, death anxiety, trauma and well-being. Data indicated a significant correlation between death anxiety and PTSD, but not psychiatric co-morbidity. Phase 2 attempted to further explore the phenomenological experience of participants with full PTSD, and 6 semi structured interviews were conducted. IPA analysis found three major themes in response to the life-threatening event; self-efficacy, religious coping and existential attitude. Overall these coping mechanisms allowed participants to develop resilience against the effects of death anxiety and minimize its negative impact on mental health. PMID- 27957656 TI - Variation in Major Depressive Disorder Onset by Place of Origin Among U.S. Latinos. AB - Using a nationally representative sample of 2514 U.S. Latinos, this study examined the extent to which major depressive disorder (MDD) onset differs by place of origin and the factors associated with it. The Kaplan-Meier method estimated the survival and hazard functions for MDD onset by place of origin, and Cox proportional hazards models identified its associative factors. Approximately 13% of the sample had experienced MDD in their lifetimes. Cuban respondents showed the highest survival function, while Puerto Ricans showed the lowest. With the entire sample, the smoothed hazard function showed that the risk of MDD onset peaked in the late 20s and early 80s. Puerto Rican respondents showed the highest risk of MDD during their 20s and 30s, whereas Cuban respondents showed a relatively stable pattern over time. The results from the Cox proportional hazards model indicated that age, sex, and marital status were significantly related to MDD onset (p < .05). In addition, the effect of U.S.-born status on MDD onset was greater among Mexican respondents than among Puerto Ricans. Findings from the present study demonstrate that different Latino subgroups experience different and unique patterns of MDD onset over time. Future research should account for the role of immigration status in examining MDD onset. PMID- 27957658 TI - Aggregation, Validation, and Generalization of Qualitative Data - Methodological and Practical Research Strategies Illustrated by the Research Process of an empirically Based Typology. AB - The article deals with the question of how aggregated data which allow for generalizable insights can be generated from single-case based qualitative investigations. Thereby, two central challenges of qualitative social research are outlined: First, researchers must ensure that the single-case data can be aggregated and condensed so that new collective structures can be detected. Second, they must apply methods and practices to allow for the generalization of the results beyond the specific study. In the following, we demonstrate how and under what conditions these challenges can be addressed in research practice. To this end, the research process of the construction of an empirically based typology is described. A qualitative study, conducted within the framework of the Luxembourg Youth Report, is used to illustrate this process. Specifically, strategies are presented which increase the likelihood of generalizability or transferability of the results, while also highlighting their limitations. PMID- 27957657 TI - Adverse Childhood Experiences among Men with Schizophrenia. AB - Individuals who suffered traumatic events or adverse experiences during their childhood have an increased risk of developing during adulthood physical problems, aggressive behavior, and psychiatric disorders, such as schizophrenia. Patients diagnosed with schizophrenia have higher rates of traumatic experiences during childhood than the general population, and those who suffered multiple traumatic events have an increased risk of disease relapse. The current study aims to determine the prevalence of different types of adverse experiences during childhood among a male patient sample with schizophrenia. An Observational descriptive cross-sectional study was conducted at Jose T. Borda Hospital, in Buenos Aires, Argentina. Participants included 51 male patients between the ages of 18 and 63 years with a diagnosis of schizophrenia. Semi-structured interviews were conducted, applying a socio-demographic questionnaire, SCID I and II scales to assess psychiatric diagnosis, and the Adverse Childhood Experiences (ACE) Questionnaire to evaluate the presence of adverse childhood experiences. Statistical analyses were conducted using SPSS 22 software. We observed that 94% of participants had experienced at least one adverse childhood experience. Most (63%) suffered from 4 or more disruptive child events. A high prevalence of family history of mental illness was found, also emotional abuse and neglect. Most traumatic events occurred within the family group. It was found a moderately significant relationship between patients who suffered adverse events and the presence of auditory hallucinations. PMID- 27957659 TI - Erratum to: Reappraisal of Conventional Diagnosis for Dermatophytes. PMID- 27957660 TI - Capsule Commentary on Mazer et. al., A Pilot Study of the Chronology of Present Illness: Restructuring the HPI to Improve Physician Cognition and Communication. PMID- 27957662 TI - Faces of Lyme. PMID- 27957661 TI - "It's been an Experience, a Life Learning Experience": A Qualitative Study of Hospitalized Patients with Substance Use Disorders. AB - BACKGROUND: Individuals with substance use disorders (SUD) have high rates of chronic illness and readmission, yet few are engaged in addiction treatment. Hospitalization may be a reachable moment for initiating and coordinating addiction care, but little is known about motivation for change in the inpatient setting. OBJECTIVE: To explore the experiences of hospitalized adults with SUD and to better understand patient and system level factors impacting readiness for change. DESIGN: We performed a qualitative study using individual interviews. The study was nested within a larger mixed-methods needs assessment. PARTICIPANTS AND SETTING: Hospitalized adults admitted to medical or surgical units at an urban academic medical center who reported high-risk alcohol or drug use on AUDIT-C or single-item drug use screener. APPROACH: We conducted a thematic analysis, using an inductive approach at a semantic level. KEY RESULTS: Thirty-two patients participated. The mean age was 43 years; 75% were men, and 68% identified as white. Participants reported moderate to high-risk alcohol (39%), amphetamine (46%), and opioid (65%) use. Emergent themes highlight the influence of hospitalization at the patient, provider, and health system levels. Many patients experienced hospitalization as a wake-up call, where mortality was motivation for change and hospitalization disrupted substance use. However, many participants voiced complex narratives of social chaos, trauma, homelessness, and chronic pain. Participants valued providers who understood SUD and the importance of treatment choice. Patient experience suggests the importance of peers in the hospital setting, access to medication-assisted treatment, and coordinated care post-discharge. CONCLUSIONS: This study supports that hospitalization offers an opportunity to initiate and coordinate addiction care, and provides insights into patient, provider, and health system factors which can leverage the reachability of this moment. PMID- 27957663 TI - Advancing the Understanding of Social Determinants of Health Through Geospatial Analysis. PMID- 27957664 TI - Capsule Commentary on Kern et al., Healthcare Fragmentation and the Frequency of Radiology and Other Diagnostic Tests: a Cross-Sectional Study. PMID- 27957666 TI - Decreased Expression of Selenoproteins as a Poor Prognosticator of Gastric Cancer in Humans. AB - The aim of the present study was to analyze the selenoprotein expression levels in gastric cancer patients. We enrolled 40 patients (29 males, 11 females) who were recently diagnosed with gastric cancer and 50 healthy people (30 males, 20 females) as controls. The expression of 25 selenoprotein genes (Dio1, Dio2, Dio3, Gpx1, Gpx2, Gpx3, Gpx4, Gpx6, SelH, SelI, SelK, SelM, SelN, SelO, SelP, SelS, SelT, SelV, SelW, SelX, Sel15, Sps2, TR1, TR2, and TR3) in human gastric cancer tissues, para-carcinoma tissues, adjacent normal gastric tissues, erythrocytes, and lymphocytes in the gastric cancer group and healthy control group was analyzed by qRT-PCR. Here, we showed that among the 25 selenoproteins, 13 selenoproteins in erythrocytes (Gpx1, Gpx4, Sel15, TR1, TR2, SelH, SelK, SelM, SelO, SelS, SelV, SelW, and Sps2), 15 selenoproteins in lymphocytes (Gpx1, Gpx4, Sel15, TR1, TR2, SelH, SelK, SelN, SelO, SelS, SelT, SelV, SelX, SelW, and Sps2) and 13 selenoproteins in gastric cancer and para-carcinoma tissues (Dio1, Dio2, Dio3, Gpx1, Gpx4, Sel15, SelH, SelK, SelM, SelS, SelT, SelW, and Sps2) were significantly decreased (P < 0.05) in the gastric cancer group compared to the control group. In summary, the decreasing expression of selenoprotein genes in gastric cancer patients play an important role in the gastric cancer, although further studies are needed to better understand our findings. PMID- 27957665 TI - The Influence of Lithium and/or Selenium Treatment on Homeostasis of Chosen Bioelements in Rats. AB - Lithium is widely used in medicine and the therapy is often long term. Apart from beneficial effects, its application can cause diverse side effects. The current study was performed with the aim of the evaluation of the effect of lithium and/or selenium administration on magnesium, calcium and silicon levels in rats. The study was performed on rats divided into four groups (six animals each): control-received saline, Li-received Li2CO3 (2.7 mg Li/kg b.w.), Se-received Na2SeO3.H2O (0.5 mg Se/kg b.w.), and Li+Se-received simultaneously Li2CO3 and Na2SeO3.H2O (2.7 and 0.5 mg Se/kg b.w.). The administration was performed in form of water solutions by a stomach tube once a day for 6 weeks. In the organs (liver, kidney, brain, spleen, heart, lung and femoral muscle), the concentrations of magnesium, calcium and silicon were determined. Lithium significantly increased Ca in the kidney, brain and spleen. Coadministration of selenium reversed this effect. No changes of magnesium in organs were observed. Silicon was affected only in spleen-an increase vs. control was observed in all studied groups. The beneficial influence of coadministration of selenium in case of calcium lets us suggest that an issue of its possible use as an adjuvant alleviating side effects in lithium-treated subjects is worth being continued. PMID- 27957668 TI - Are All Program Elements Created Equal? Relations Between Specific Social and Emotional Learning Components and Teacher-Student Classroom Interaction Quality. AB - School-based social and emotional learning (SEL) programs are presented to educators with little understanding of the program components that have the greatest leverage for improving targeted outcomes. Conducted in the context of a randomized controlled trial, the present study used variation in treatment teachers' (N = 143) implementation of four core components of the Responsive Classroom approach to examine relations between each component and the quality of teachers' emotional, organizational, and instructional interactions in third, fourth, and fifth grade classrooms (controlling for pre-intervention interaction quality and other covariates). We also examined the extent to which these relations varied as a function of teachers' baseline levels of interaction quality. Indices of teachers' implementation of Morning Meeting, Rule Creation, Interactive Modeling, and Academic Choice were derived from a combination of teacher-reported surveys and classroom observations. Ratings of teacher-student classroom interactions were aggregated across five observations conducted throughout the school year. Structural path models indicated that teachers' use of Morning Meeting and Academic Choice related to higher levels of emotionally supportive interactions; Academic Choice also related to higher levels of instructional interactions. In addition, teachers' baseline interaction quality moderated several associations such that the strongest relations between RC component use and interaction quality emerged for teachers with the lowest baseline interaction quality. Results highlight the value of examining individual program components toward the identification of program active ingredients that can inform intervention optimization and teacher professional development. PMID- 27957667 TI - Clinical Cancer Genetics Disparities among Latinos. AB - The three major hereditary cancer syndromes in Latinos (Hereditary Breast and Ovarian Cancer, Familial Adenomatous Polyposis and Lynch Syndrome) have been shown to exhibit geographic disparities by country of origin suggesting admixture based disparities. A solid infrastructure of clinical genetics geared towards diagnosis and prevention could aid in reducing the mortality of these cancer syndromes in Latinos. Currently, clinical cancer genetic services in Latin America are scarce. Moreover, limited studies have investigated the mutational spectrum of these cancer syndromes in Latinos resulting in gaps in personalized medicine affecting diagnosis, treatment and prevention. The following commentary discusses available genotype and clinical information on hereditary cancer in Latinos and highlights the limited access for cancer genetic services in Latin America including barriers to genetic testing and alternatives for providing better access to genetic services. In this review, we discuss the status of clinical genetic cancer services for both US Latinos and those Latinos living in Latin America. PMID- 27957669 TI - Erratum to: Epidemiology for primary brain tumors: a nationwide population-based study. PMID- 27957671 TI - Medical student resilience strategies: A content analysis of medical students' portfolios. AB - INTRODUCTION: Stress and burnout among medical students is a well-recognized concern. A student's ability to employ resilience strategies to self-regulate behaviour is critical to the student's future career as a physician. METHODS: We retrospectively reviewed a sampling of year 1, 2 and 5 portfolio essays focused on the Personal Development competency and performance milestones, written by 49 students from three different classes in a 5-year programme devoted to training physician investigators. Two medical educators used a framework established by Jensen and colleagues (2008) to identify the nature and prevalence of various resilience strategies (valuing the physician role, self-awareness, personal arena, professional arena, professional support and personal support) medical students reported in portfolio essays. RESULTS: All students documented at least one strategy in their essays each year. In all years, the most commonly documented strategies were in the personal arena (95.7% of year 1, 98% of year 2 and 87.8% of year 5 portfolios). The least frequently documented strategy in all years was professional support (42.8% of year 1, 38.8% of year 2, and 28.6% of year 5 portfolios). Year 5 portfolios discussed personal support strategies (79.6%) more frequently than year 1 (53.1%) and year 2 (59.2%) portfolios. DISCUSSION: The results suggest that medical students can identify stressors and articulate resilience strategies that can be employed to potentially address them. PMID- 27957672 TI - Spatial Distribution of Adult Anthonomus grandis Boheman (Coleoptera: Curculionidae) and Damage to Cotton Flower Buds Due to Feeding and Oviposition. AB - The cotton boll weevil Anthonomus grandis Boheman (Coleoptera: Curculionidae) is the main pest in cotton crop around the world, directly affecting cotton production. In order to establish a sequential sampling plan, it is crucial to understand the spatial distribution of the pest population and the damage it causes to the crop through the different developmental stages of cotton plants. Therefore, this study aimed to investigate the spatial distribution of adults in the cultivation area and their oviposition and feeding behavior throughout the development of the cotton plants. The experiment was conducted in Maracaju, Mato Grosso do Sul, Brazil, in the 2012/2013 and 2013/2014 growing seasons, in an area of 10,000 m2, planted with the cotton cultivar FM 993. The experimental area was divided into 100 plots of 100 m2 (10 * 10 m) each, and five plants per plot were sampled weekly throughout the crop cycle. The number of flower buds with feeding and oviposition punctures and of adult A. grandis was recorded throughout the crop cycle in five plants per plot. After determining the aggregation indices (variance/mean ratio, Morisita's index, exponent k of the negative binomial distribution, and Green's coefficient) and adjusting the frequencies observed in the field to the distribution of frequencies (Poisson, negative binomial, and positive binomial) using the chi-squared test, it was observed that flower buds with punctures derived from feeding, oviposition, and feeding + oviposition showed an aggregated distribution in the cultivation area until 85 days after emergence and a random distribution after this stage. The adults of A. grandis presented a random distribution in the cultivation area. PMID- 27957670 TI - Residual effects of emotion are reflected in enhanced visual activity after sleep. AB - Research has investigated how sleep affects emotional memory and how emotion enhances visual processing, but these questions are typically asked by re presenting an emotional stimulus at retrieval. For the first time, we investigate whether sleep affects neural activity during retrieval when the memory cue is a neutral context that was previously presented with either emotional or nonemotional content during encoding. Participants encoded scenes composed of a negative or neutral object on a neutral background either in the morning (preceding 12 hours awake; wake group) or evening (preceding 12 hours including a night of sleep; sleep group). At retrieval, participants viewed the backgrounds without their objects, distinguishing new backgrounds from those previously studied. Occipital activity was greater within the sleep group than the wake group specifically during the successful retrieval of neutral backgrounds that had been studied with negative (but not neutral) objects. Moreover, there was enhanced connectivity between the middle occipital gyrus and hippocampus following sleep. Within the sleep group, the percentage of REM sleep obtained correlated with activity in the middle occipital gyrus, lingual gyrus, and cuneus during the successful retrieval of neutral backgrounds previously paired with negative objects. These results confirm that emotion affects neural activity during retrieval even when the cues themselves are neutral, and demonstrate, for the first time, that this residual effect of emotion on visual activity is greater after sleep and may be maximized by REM sleep. PMID- 27957673 TI - An Architect Cicada in Brazilian Rainforest: Guyalna chlorogena (Walker). AB - To study the noteworthy nest building behavior of the nymph of the Brazilian Rainforest cicada Guyalna chlorogena (Walker) during the last year of its underground life, we monitored a large number of edifices, consisting of a vertical well (up to 1 m deep) with a turret (20 to 40 cm tall) on top, and we also performed experiments. We have shown that the buildings are occupied by a single nymph, male or female, which increases the height of its turret each night by about 3 cm, during a short active growing phase. The nymph softens and reshapes the apex by pushing upwards a lump of freshly mixed soaked clay, without any opening present, i. e., without ever exposing itself to the outside. We also established that the nymph is very active once its building is achieved. For example, it restores the height of the turret to its original value when shortening and opens the top of its building in case of variation of environmental parameters. Finally, we have shown how the nymph opens its edifice to reach the outside for molting into an adult stage (imago). With this work, we contributed to a better understanding of the nesting behavior of Amazon cicadas. PMID- 27957674 TI - Social Media Use for Cancer Education at a Community-Based Cancer Center in South Korea. AB - The main purpose of this study was to evaluate the effectiveness of the education system using social media. Eight educational video clips were developed instructing the viewer on cancer-related issues such as prevention, treatment, and survivorship. Each video was made with participation of medical professors and posted on a YouTube channel. A mobile phone application was produced containing a scheduler function, introduction of a community cancer center program, and cancer information. A medical blog was established to provide stationary materials such as images and articles. Descriptive analysis was done by Google analytics. From May of 2014 to June of 2016, 15,247 total views were recorded on the YouTube channel, and the average view duration was about 3 min. The most popular video was about chemotherapy treatment; 5409 (36%) people watched this video, and 3615 (23.5%) people viewed a video on balanced dietary habits. As well as South Korea, 1,113 (7%) views were confirmed in the United States and 175 (1%) in Japan. The equipment used to watch the contents were mobile phones (59%), laptops (33%), and tablets (6%). Five hundred people installed the smartphone application from March of 2015 to July of 2016. Three hundred eighty-three medical contents were posted on the blog since March of 2015. Cancer education is necessary to address the education needs of patients with cancer and their caregivers. Education based on social media could be an effective method that reaches beyond geographical boundaries. PMID- 27957675 TI - The Importance of L-Arginine:NO:cGMP Pathway in Tolerance to Flunitrazepam in Mice. AB - The goal of the study was to investigate the effects of drugs modifying L arginine:NO:cGMP pathway on the development of tolerance to flunitrazepam (FNZ) induced motor impairment in mice. FNZ-induced motor incoordination was assessed on the 1st and 8th days of experiment, using the rotarod and chimney tests. It was found that (a) both a non-selective nitric oxide synthase (NOS) inhibitor: N G-nitro-L-arginine methyl ester (L-NAME) and an unselective neuronal NOS inhibitor: 7-nitroindazole (7-NI) inhibited the development of tolerance to the motor-impairing effects of FNZ in the rotarod and the chimney tests and (b) both a NO precursor: L-arginine and a selective inhibitor of phosphodiesterase 5 (PDE5): sildenafil did not affect the development of tolerance to FNZ-induced motor impairment in mice. Those findings provided behavioural evidence that NO could contribute an important role in the development of tolerance to FNZ in mice. PMID- 27957677 TI - Comparison between microzooplankton population in polluted and moderately polluted coastal waters of Port Blair, South Andaman. AB - We report on the seasonal and spatial variations of microzooplankton between polluted and moderately polluted coastal waters of South Andaman Island, in relation to certain physicochemical and biological parameters. Microzooplankton communities were studied and recorded for 1 year (September 2011 to August 2012) during the northeast monsoon, the intermonsoon, and the southwest monsoon periods. We recorded a total of 75 species belonging to 29 genera, of which polluted waters encompassed 71 species (28 genera). In contrast, only 59 species (22 genera) were recorded in the moderately polluted waters. We discovered that taxonomic composition, biomass, and abundance of microzooplankton not only varied spatially but also altered seasonally. It is noteworthy to state that the northeast monsoon played a significant role in controlling the abundance of microzooplankton in South Andaman coastal waters. PMID- 27957676 TI - Injection of Anti-proBDNF in Anterior Cingulate Cortex (ACC) Reverses Chronic Stress-Induced Adverse Mood Behaviors in Mice. AB - Foraging behavior is a species-specific behavior which is considered to involve the decision making and higher cognitive functions. We previously established a novel method to detect the foraging behavior in chronic unpredictable mild stress (CUMS)-induced depression mice, in which the food foraging activity of mice was significantly reduced. Furthermore, it is generally assumed that the bilateral anterior cingulate cortex (ACC) is related to foraging activity in rat. Brain derived neurotrophic factor (BDNF) is widely expressed in many regions of the brain and is down-regulated in depressive patients. However, the relationship between the precursor of brain-derived neurotrophic factor (proBDNF) and depression has not been fully elucidated. The results showed that CUMS in mice induced anxiety- and depression-like behaviors and significant reduction in BDNF messenger RNA (mRNA) in the brain. In this study, we evaluated the effect of anti BDNF and anti-proBDNF in the ACC on the CUMS-induced depression mice. In contrast to the normal IgG group (normal IgG microinjection into the ACC), bilateral ACC treatment with anti-proBDNF microinjection not only reversed depressive activity but also significantly increased the amount of foraged food and BDNF mRNA in the brain. There was no significant alteration in the group of anti-BDNF microinjection into the ACC. Our data indicate that the proBDNF signaling pathway might down-regulate the foraging activity in CUMS rodents and be involved in the depression. PMID- 27957678 TI - Haemato-biochemical, non-specific immunity, antioxidant capacity and histopathological changes in Labeo rohita fingerlings fed rubber protein isolate. AB - A 60-day feeding trial was conducted to evaluate the haemato-biochemical, innate immune response, antioxidant capacity and histopathological changes in Labeo rohita fingerlings fed rubber protein isolates (RPI). One hundred and eighty fingerlings (average weight 4.45 +/- 0.01 g) were distributed into five experimental groups in triplicate and fed with isonitrogenous and isocaloric diets. Soybean protein isolate (SPI) served as the reference diet (Control), and the treatment diets were formulated as RPI25, RPI50, RPI75 and RPI100 replacing 25, 50, 75 and 100% of SPI protein, respectively. The growth performance indices like final body weight (9.54-10.27 g), net weight gain (5.09-5.84 g), metabolic growth rate (4.54-5.02) and feed efficiency ratio (0.60-0.65) among the various groups were not significantly different (P > 0.05). All the haematological parameters, except red blood cells, showed no significant differences compared with the control group (P > 0.05). The immuno-biochemical parameters like albumin, globulin, total immunoglobulin, respiratory burst and lysozyme activities among the various groups did not differ significantly (P > 0.05). The stress enzyme such as superoxide dismutase (SOD), catalase (CAT) and oxidative stress marker malondialdehyde (MDA) showed no significant difference (P > 0.05). Histopathological examination of the liver revealed no marked changes. In summary, the results showed that RPI was well utilised by the fish and its inclusion did not generate any oxidative-induced stress, thus, RPI may be suggested as a potential replacement for SPI in fish diets without any detrimental effects. Hence, protein isolation offers a unique opportunity for the utilisation of rubber seed meal. PMID- 27957679 TI - Downstream mRNA Target Analysis in Neonatal Hypoxic-Ischaemic Encephalopathy Identifies Novel Marker of Severe Injury: a Proof of Concept Paper. AB - Human microRNA miR-374a is downregulated in the umbilical cord blood (UCB) of infants with hypoxic-ischaemic encephalopathy (HIE). The downstream targets of this microRNA (miRNA) are unclear, but one putative target is the activin-A receptor type IIb (ACVR2B). ACVR2B is required for activin-A function and previous reports have shown alterations of activin-A levels in neonatal HIE. Our aim was to investigate the expression of the potential downstream targets of miR 374a, activin-A and ACVR2B, at birth in a cohort of full-term infants with perinatal asphyxia (PA) only, and those with PA who developed clinical and electrographic HIE. UCB was drawn and processed immediately after delivery. Levels of serum activin-A were measured using ELISA. mRNA levels of ACVR2B in whole blood were quantified using qRT-PCR. Outcome was assessed at 3 years of age using standardised developmental assessment. In total, 171 infants were enrolled: 88 healthy controls, 56 PA and 27 HIE. A statistically significant elevation of median (IQR) ACVR2B was detected in infants with severe HIE compared to moderate/mild HIE, PA and control groups (3.3 (2.94-3.67) vs. 0.91 (0.55-1.21) vs. 0.88 (0.57-1.38) vs. 0.84 (0.74-1.24), p values = 0.04, 0.027 and 0.025, respectively). Although serum activin-A levels were elevated in infants with severe HIE, this elevation did not reach significance. ACVR2B may be a potential novel marker of HIE severity. This is the first study to examine the relationship between activin-A, its receptor AVCR2B and potentially upstream miRNA miR-374a in a cohort of carefully categorised and phenotyped infants. We have shown that miRNA analysis, combined with downstream target exploration, may yield novel biomarkers for the prediction of HIE severity. PMID- 27957681 TI - Dynamic Regulation of Hypothalamic DMXL2, KISS1, and RFRP Expression During Postnatal Development in Non-Human Primates. AB - The neurobiological mechanism of puberty onset in primates is currently only partly understood. A recent study reported an important role of Dmx-like 2 (DMXL2), a gene encoding rabconnectin-3alpha vesicular protein, in human subjects with mental retardation and neuroendocrine impairment of reproduction. To further characterize the potential role of DMXL2 in the regulation of reproduction, we analyzed the expression of DMXL2 in hypothalami of newborn, infantile, juvenile, pubertal, and postpubertal female and male common marmoset monkeys. Additionally, as the relative hypothalamic levels of gonadotropin-inhibitory hormone (GnIH) transcript during postnatal development are unknown in primates, we also quantified messenger RNA (mRNA) levels of RFRP, a gene encoding GnIH. Moreover, the transcript levels of kisspeptin, a well-known regulator of the hypothalamic neurohormonal axis controlling reproduction, were also checked. Transcript and protein levels of DMXL2 and Kiss1 transcript levels increase from the newborn to the infantile and from the juvenile (prepubertal) to the pubertal and the postpubertal period. We also noted a clear upsurge in RFRP transcript levels in the prepubertal period. In conclusion, the hypothalamic expressions of Kiss1 and DMXL2 mRNA increase during infantile, pubertal, and adult stages compared to newborn and juvenile stages in common marmoset monkeys. In contrast, the expression of RFRP mRNA upsurges in juvenile monkeys. Further mechanistic studies are needed to characterize the potential inhibitory role of the GnIH-GPR147 signaling in the prepubertal period and the role of DMXL2 in the molecular cascade regulating the neuroendocrine reproductive axis in primates. PMID- 27957682 TI - Dissociation of JNK Activation from Elevated Levels of Reactive Oxygen Species, Cytochrome c Release, and Cell Death in NGF-Deprived Sympathetic Neurons. AB - Withdrawal of nerve growth factor (NGF) from sympathetic neurons causes their apoptotic death. Activation of c-Jun NH2-terminal kinase (JNK) may contribute to this death by the induction and phosphorylation of pro-apoptotic Bcl-2 proteins, such as Bax, that are involved in cytochrome c release from mitochondria and reactive oxygen species (ROS) production. Induction of either JNK or ROS may stimulate the other, and both may regulate release of apoptogenic factors from the mitochondria. In order to discern the relationship between JNK and ROS in apoptosis, we treated NGF-deprived, mouse sympathetic neurons with a JNK inhibitor and examined the effect on several important apoptotic events. Block of JNK activation prevented induction of c-Jun expression and resulted in a dose dependent, yet surprisingly modest, increase in cell survival after 48 h of NGF deprivation. JNK suppression was also not sufficient to prevent the elevation in ROS or the release of cytochrome c from the mitochondria in NGF-deprived sympathetic neurons. Bax deletion prevents apoptotic death of NGF-deprived neurons by preventing release of cytochrome c from their mitochondria. It also prevents increased ROS on NGF deprivation. However, we found that induction of c Jun in cells lacking Bax was equivalent to that in wild-type neurons. Our results suggest that while JNK activation plays an important role in many forms of apoptosis, it may not be a crucial regulator of Bax-dependent events involved in the apoptotic death of mouse sympathetic neurons deprived of NGF and that ROS is not involved in its activation in these cells. PMID- 27957680 TI - Administration of 17beta-Estradiol Improves Motoneuron Survival and Down regulates Inflammasome Activation in Male SOD1(G93A) ALS Mice. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease manifested by the progressive loss of upper and lower motoneurons. The pathomechanism of ALS is complex and not yet fully understood. Neuroinflammation is believed to significantly contribute to disease progression. Inflammasome activation was recently shown in the spinal cord of human sporadic ALS patients and in the SOD1(G93A) mouse model for ALS. In the present study, we investigated the neuroprotective and anti-inflammatory effects of 17beta-estradiol (E2) treatment in pre-symptomatic and symptomatic male SOD1(G93A) mice. Symptomatic mice with E2 substitution exhibited improved motor performance correlating with an increased survival of motoneurons in the lumbar spinal cord. Expression of NLRP3 inflammasome proteins and levels of activated caspase 1 and mature interleukin 1 beta were significantly reduced in SOD1(G93A) mice supplemented with E2. PMID- 27957683 TI - Heterogeneity of Brain Ribosomal Genes Expression Following Positive Fighting Experience in Male Mice as Revealed by RNA-Seq. AB - Repeated positive fighting experience in daily agonistic interactions is accompanied by changes of brain neurotransmitter activity and genes' expression in male mice. This paper is focused on the analysis of ribosomal genes expression data as revealed by whole-transcriptome analysis (RNA-Seq) in five brain regions of male mice with long repeated experience of aggression accompanied by wins (winners). Downregulation of most Rps, Rpl, Mrps, and Mrpl genes was found in the midbrain raphe nuclei and striatum and upregulation-in the hippocampus and hypothalamus of the winners. There were no changes in ribosomal gene expression in the ventral tegmental area. The data allow considering the alteration in ribosomal gene expression as an animal model of ribosomal dysfunction developed under positive fighting experience in male mice. PMID- 27957685 TI - TRPM2 Promotes Neurotoxin MPP+/MPTP-Induced Cell Death. AB - In neurons, Ca2+ is essential for a variety of physiological processes that regulate gene transcription to neuronal growth and their survival. 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ions (MPP+) are potent neurotoxins that selectively destroys the dopaminergic (DA) neurons and mimics Parkinson's disease (PD) like symptoms, but the mechanism as how MPP+/MPTP effects DA neuron survival is not well-understood. In the present study, we found that MPP+ treatment increased the level of reactive oxygen species (ROS) that activates and upregulates the expression and function of melastatin-like transient receptor potential (TRPM) subfamily member, melastatin like transient receptor potential channel 2 (TRPM2). Correspondingly, TRPM2 expression was also increased in substantia nigra of MPTP-induced PD mouse model and PD patients. ROS-mediated activation of TRPM2 resulted in an increased intracellular Ca2+, which in turn promoted cell death in SH-SY5Y cells. Intracellular Ca2+ overload caused by MPP+-induced ROS also affected calpain activity, followed by increased caspase 3 activities and activation of downstream apoptotic pathway. On the other hand, quenching of H2O2 by antioxidants, resveratrol (RSV), or N-acetylcysteine (NAC) effectively blocked TRPM2-mediated Ca2+ influx, decreased intracellular Ca2+ overload, and increased cell survival. Importantly, pharmacological inhibition of TRPM2 or knockdown of TRPM2 using siRNA, but not control siRNA, showed an increased protection by preventing MPP+ induced Ca2+ increase and inhibited apoptosis. Taken together, we show here a novel role for TRPM2 expression and function in MPP+-induced dopaminergic neuronal cell death. PMID- 27957684 TI - Huntingtin polyQ Mutation Impairs the 17beta-Estradiol/Neuroglobin Pathway Devoted to Neuron Survival. AB - Among several mechanisms underlying the well-known trophic and protective effects of 17beta-estradiol (E2) in the brain, we recently reported that E2 induces the up-regulation of two anti-apoptotic and neuroprotectant proteins: huntingtin (HTT) and neuroglobin (NGB). Here, we investigate the role of this up-regulation. The obtained results indicate that E2 promotes NGB-HTT association, induces the localization of the complex at the mitochondria, and protects SK-N-BE neuroblastoma cells and murine striatal cells, which express wild-type HTT (i.e., polyQ7), against H2O2-induced apoptosis. All E2 effects were completely abolished in HTT-knocked out SK-N-BE cells and in striatal neurons expressing the mutated form of HTT (mHTT; i.e., polyQ111) typical of Huntington's disease (HD). As a whole, these data provide a new function of wild-type HTT which drives E2-induced NGB in mitochondria modulating NGB anti-apoptotic activity. This new function is lost by HTT polyQ pathological expansion. These data evidence the existence of a novel E2/HTT/NGB neuroprotective axis that may play a relevant role in the development of HD therapeutics. PMID- 27957686 TI - Curcumin Attenuates Colistin-Induced Neurotoxicity in N2a Cells via Anti inflammatory Activity, Suppression of Oxidative Stress, and Apoptosis. AB - Neurotoxicity is an unwanted side-effect seen in patients receiving therapy with the "last-line" polymyxin antibiotics. This is the first study to show that colistin-induced neurotoxicity in neuroblastoma-2a (N2a) cells gives rise to an inflammatory response involving the IL-1beta/p-IkappaB-alpha/NF-kappaB pathway. Pretreatment with curcumin at 5, 10, and 20 MUM for 2 h prior to colistin (200 MUM) exposure for 24 h, produced an anti-inflammatory effect by significantly down-regulating the expression of the pro-inflammatory mediators cyclooxygenase-2 (COX-2), phosphorylation of the inhibitor of nuclear factor-kappa B (NF-kappaB) (p-IkappaB)-alpha, and concomitantly NF-kappaB levels. Moreover, curcumin significantly decreased intracellular reactive oxygen species (ROS) production and increased the activities of the anti-ROS enzymes superoxide dismutase, catalase, and the intracellular levels of glutathione. Curcumin pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation, and subsequent apoptosis. Overall, our findings demonstrate for the first time, a potential role for curcumin for treating polymyxin-induced neurotoxicity through the modulation of NF-kappaB signaling and its potent anti oxidative and anti-apoptotic effects. PMID- 27957687 TI - Evaluation of an enzyme immunoassay for the detection of the mycotoxin tenuazonic acid in sorghum grains and sorghum-based infant food. AB - An enzyme-linked immunosorbent assay (ELISA) for the Alternaria mycotoxin tenuazonic acid (TeA) was evaluated by comparative analysis of naturally contaminated sorghum grains and sorghum-based infant food, using a stable isotope dilution LC-MS assay (SIDA; limit of detection (LOD) 1.0 MUg/kg) as the reference method. LODs of the ELISA were 30 MUg/kg in sorghum grains and 220 MUg/kg in sorghum-based infant cereals. With SIDA, 100% of the samples (n = 28) had been positive for TeA in a concentration range of 6-584 MUg/kg (mean 113 MUg/kg). The ELISA consistently detected TeA in all naturally contaminated samples at cut-off levels of 30-60 MUg/kg (sorghum) and 200-300 MUg/kg (infant cereals), as based on corresponding to SIDA values. Although the ELISA was much less sensitive than the SIDA method, it may be useful as a screening method for sorghum and sorghum-based infant foods and can be employed to identify samples containing elevated concentrations of TeA in food, well below the proposed level of concern (500 MUg/kg). PMID- 27957688 TI - Biochar characteristics produced from rice husks and their sorption properties for the acetanilide herbicide metolachlor. AB - Rice husk biochar (RHBC) was prepared for use as adsorbents for the herbicide metolachlor. The characteristics and sorption properties of metolachlor adsorbed by the RHBC prepared at different pyrolysis temperatures were determined by analysis of physico-chemical characteristics, Fourier transform infrared spectroscopy (FTIR), Boehm titration, scanning electron microscopy (SEM), and thermodynamics and kinetics adsorption. With increasing pyrolysis temperature, the RHBC surface area greatly increased (from 2.57 to 53.08 m2 g-1). RHBC produced at the highest temperature (750 degrees C) had the greatest surface area; SEM also showed the formation of a porous surface on RH-750 biochar. The sorption capacity of RHBC also increased significantly with increasing pyrolysis temperature and was characterized by the Freundlich constant K f for the adsorption capacity increasing from 125.17-269.46 (pyrolysis at 300 degrees C) to 339.94-765.24 (pyrolysis at 750 degrees C). The results indicated that the surface area and pore diameter of RHBC produced with high pyrolysis temperature (i.e., 750 degrees C) had the greatest impact on the adsorption of metolachlor. The FTIR, Boehm titration, and SEM analysis showed that the greatest number of surface groups were on RHBC produced at the lowest temperature (300 degrees C). The biochars produced at different pyrolysis temperatures had different mechanisms of adsorbing metolachlor, which exhibited a transition from hydrogen bonds dominant at low pyrolytic temperature to pore-filling dominant at higher pyrolytic temperature. PMID- 27957689 TI - Securitization product design for China's environmental pollution liability insurance. AB - The environmental catastrophic accidents in China over the last three decades have triggered implementation of myriad policies by the government to help abate environmental pollution in the country. Consequently, research into environmental pollution liability insurance and how that can stimulate economic growth and the development of financial market in China is worthwhile. This study attempts to design a financial derivative for China's environmental pollution liability insurance to offer strong financial support for significant compensation towards potential catastrophic environmental loss exposures, especially losses from the chemical industry. Assuming the risk-free interest rate is 4%, the market portfolio expected return is 12%; the financial asset beta coefficient is 0.5, by using the capital asset pricing model (CAPM) and cash flow analysis; the principal risk bond yields 9.4%, single-period and two-period prices are 103.85 and 111.58, respectively; the principal partial-risk bond yields 10.09%, single period and two-period prices are 103.85 and 111.58, respectively; and the principal risk-free bond yields 8.94%, single-period and two-period prices are 107.99 and 115.83, respectively. This loss exposure transfer framework transfers the catastrophic risks of environmental pollution from the traditional insurance and reinsurance markets to the capital market. This strengthens the underwriting capacity of environmental pollution liability insurance companies, mitigates the compensation risks of insurers and reinsurers, and provides a new channel to transfer the risks of environmental pollution. PMID- 27957690 TI - Photodegradation of ethylene by use of TiO2 sol-gel on polypropylene and on glass for application in the postharvest of papaya fruit. AB - The papaya is a commercially important fruit commodity worldwide. Being a climacteric fruit, it is highly perishable. Thus, for the transportation of papaya fruit for long distances without loss of quality, it is necessary to avoid the autocatalytic effect of ethylene in accelerating the ripening of the fruit. This work addresses the application of heterogeneous photocatalysis to the degradation of ethylene. A TiO2 sol-gel supported on polypropylene (PP) and on glass was used as the catalytic material, and a UV-A lamp was employed as the radiation source. Initially, a concentration of 500 ppbv ethylene was exposed to the catalyst material irradiated by UV-A radiation. A sensitive photoacoustic spectrometer was used to monitor the photocatalytic activity. The TiO2 sol-gel supported on the glass substrate was more efficient than on the PP in degrading the ethylene. Under direct UV-A exposure, the skin appearance of 'Golden' papaya was damaged, depreciating the fruit quality and thus preventing its commercialization. However, the feasibility of the heterogeneous photocatalysis to preserve the fruit quality was achieved when ethylene was removed from the storage ambient using fans, and then, this plant hormone was degraded by a reactor set apart in a ventilation closed system. PMID- 27957691 TI - Speciation and precipitation of heavy metals in high-metal and high-acid mine waters from the Iberian Pyrite Belt (Portugal). AB - Acid mine waters (AMW) collected during high- and low-flow water conditions from the Lousal, Aljustrel, and Sao Domingos mining areas (Iberian Pyrite Belt) were physicochemically analyzed. Speciation calculation using PHREEQC code confirms the predominance of Men+ and Me-SO4 species in AMW samples. Higher concentration of sulfate species (Me-SO4) than free ion species (Men+, i.e., Al, Fe, and Pb) were found, whereas opposite behavior is verified for Mg, Cu, and Zn. A high mobility of Zn than Cu and Pb was identified. The sulfate species distribution shows that Fe3+-SO42-, SO42-, HSO4-, Al-SO4, MgSO40, and CaSO40 are the dominant species, in agreement with the simple and mixed metal sulfates and oxy hydroxysulphates precipitated from AMW. The saturation indices (SI) of melanterite and epsomite show a positive correlation with Cu and Zn concentrations in AMW, which are frequently retained in simple metal sulfates. Lead is well correlated with jarosite and alunite (at least in very acid conditions) than with simple metal sulfates. The Pb for K substitution in jarosite occurs as increasing Pb concentration in solution. Lead mobility is also controlled by anglesite precipitation (a fairly insoluble sulfate), where a positive correlation was ascertained when the SI approaches equilibrium. The zeta potential of AMW decreased as pH increased due to colloidal particles aggregation, where water species change from SO42- to OH- species during acid to alkaline conditions, respectively. The AMW samples were supersaturated in schwertmannite and goethite, confirmed by the Men+-SO4, Men+-Fe-O-OH, or Men+-S-O Fe-O complexes identified by attenuated total reflectance infrared spectroscopy (ATR-IR). The ATR-IR spectrum of an AMW sample with pH 3.5 (sample L1) shows well defined vibration plans attributed to SO4 tetrahedron bonded with Fe (oxy)hydroxides and the Men+ sorbed by either SO4 or Fe-(oxy)hydroxides. For samples with lower pH values (pH ~ 2.5-samples SD1 and SD4), the vibration plans attributed to Men+ sorption are not evidenced, indicating its release in solution. The sorption of heavy metals on the first precipitated simple metal sulfates was ascertained by scanning electron microscopy coupled with X-ray spectrometry (SEM-EDX), where X-ray maps of Cu and Zn confirm a distribution of both metals in the melanterite structure. PMID- 27957692 TI - Heavy metals mobility associated with the molybdenum mining-concentration complex in the Buryatia Republic, Germany. AB - Mining of Dzhida ore deposits in Russia has caused the formation of a large tailings dam with technogenic sands and contamination of nearby district soils. Geochemical fractions of technogenic sands were divided by a sequential extraction procedure. The sampling points with maximum concentration of Pb, Cu, and Zn were selected for investigation of heavy metal mobility. Two previously described methods of heavy metal fractionation using selective extraction were applied: a procedure developed by the Community Bureau of Reference of the Commission of the European Communities (BCR procedure) and Tessier's fractionation scheme. Despite some differences in Pb extractions, the two procedures describe equally well the distribution of heavy metals on geochemical fractions. BCR procedure was chosen as a fast method of heavy metal mobile form estimation. For considered mining object, it is revealed that there are different characters of heavy metal mobility sequence in the soils Zn > Cu > Pb and technogenic sands Pb > Zn > Cu. PMID- 27957693 TI - Adsorption of metribuzin from aqueous solution using magnetic and nonmagnetic sustainable low-cost biochar adsorbents. AB - Switchgrass biochar (SGB) was made by fast pyrolysis in an auger-fed reactor at 425 degrees C with a solid residence time of 60 s in the pyrolysis zone during bio-oil production. Magnetic switchgrass biochar (MSGB) was prepared by iron oxide precipitation onto the biochar surface using an aqueous Fe3+/Fe2+ solution followed by NaOH treatment. Both the SGB and the MSGB were characterized by FTIR, SEM, SEM-EDX, TGA, pHpzc, elemental analysis, and surface area measurements. Batch sorption studies of metribuzin from aqueous solutions were carried out at different pH values, adsorbate concentrations, and temperatures. The adsorption of metribuzin onto both biochars was highest at a pH of 2. Adsorption isotherms were evaluated from 25 to 45 degrees C using the Freundlich, Langmuir, Redlich Peterson, Toth, Sips, Koble-Corrigan, and Radke-Prausnitz adsorption models. Langmuir adsorption capacities at pH 2 were Q 0SGB ~ 151, 223, and 205 mg/g and Q 0MSGB ~ 155, 205, and 155 mg/g at 25, 35, and 45 degrees C, respectively. Low cost magnetization of the biochar occurred without significant loss of absorption capacity, enabling facile separation of slurried biochar from liquids following contaminate absorption. Graphical abstract ?. PMID- 27957694 TI - Biodegradation of high concentrations of mixed polycyclic aromatic hydrocarbons by indigenous bacteria from a river sediment: a microcosm study and bacterial community analysis. AB - This study assessed the biodegradation of mixtures of polycyclic aromatic hydrocarbons (PAHs) by indigenous bacteria in river sediment. Microcosms were constructed from sediment from the Chao Phraya River (the main river in Thailand) by supplementation with high concentrations of fluorene, phenanthrene, pyrene (300 mg kg-1 of each PAH), and acenaphthene (600 mg kg-1). Fluorene and phenanthrene were completely degraded, whereas 50% of the pyrene and acenaphthene were removed at the end of the incubation period (70 days). Community analyses revealed the dynamics of the bacterial profiles in the PAH-degrading microcosms after PAH exposure. Actinobacteria predominated and became significantly more abundant in the microcosms after 14 days of incubation at room temperature under aerobic conditions. Furthermore, the remaining PAHs and alpha diversity were positively correlated. The sequencing of clone libraries of the PAH-RHDalpha genes also revealed that the dioxygenase genes of Mycobacterium sp. comprised 100% of the PAH-RHDalpha library at the end of the microcosm setup. Moreover, two PAH-degrading Actinobacteria (Arthrobacter sp. and Rhodococcus ruber) were isolated from the original sediment sample and showed high activity in the degradation of phenanthrene and fluorene in liquid cultivation. This study reveals that indigenous bacteria had the ability to degrade high concentrations of mixed PAHs and provide clear evidence that Actinobacteria may be potential candidates to play a major role in PAH degradation in the river sediment. PMID- 27957695 TI - Global warming potential and greenhouse gas emission under different soil nutrient management practices in soybean-wheat system of central India. AB - Soil nutrient management is a key component contributing to the greenhouse gas (GHG) flux and mitigation potential of agricultural production systems. However, the effect of soil nutrient management practices on GHG flux and global warming potential (GWP) is less understood in agricultural soils of India. The present study was conducted to compare three nutrient management systems practiced for nine consecutive years in a soybean-wheat cropping system in the Vertisols of India, in terms of GHG flux and GWP. The treatments were composed of 100% organic (ONM), 100% inorganic (NPK), and integrated nutrient management (INM) with 50% organic + 50% inorganic inputs. The gas samples for GHGs (CO2, CH4, and N2O) were collected by static chamber method at about 15-day interval during 2012-13 growing season. The change in soil organic carbon (SOC) content was estimated in terms of the changes in SOC stock in the 0-15 cm soil over the 9-year period covering 2004 to 2013. There was a net uptake of CH4 in all the treatments in both soybean and wheat crop seasons. The cumulative N2O and CO2 emissions were in the order of INM > ONM > NPK with significant difference between treatments (p < 0.05) in both the crop seasons. The annual GWP, expressed in terms of CH4 and N2O emission, also followed the same trend and was estimated to be 1126, 1002, and 896 kg CO2 eq ha-1 year-1 under INM, ONM, and NPK treatments, respectively. However, the change in SOC stock was significantly higher under ONM (1250 kg ha-1 year-1) followed by INM (417 kg ha-1 year-1) and least under NPK (198 kg ha-1 year-1) treatment. The wheat equivalent yield was similar under ONM and INM treatments and was significantly lower under NPK treatment. Thus, the GWP per unit grain yield was lower under ONM followed by NPK and INM treatments and varied from 250, 261, and 307 kg CO2 eq Mg-1 grain yield under ONM, NPK, and INM treatments, respectively. PMID- 27957696 TI - The association between continuous positive airway pressure therapy and liver disease development in obstructive sleep apnea/hypopnea syndrome patients: a nationwide population-based cohort study in Taiwan. AB - PURPOSE: Studies on the association between continuous positive airway pressure (CPAP) treatment and liver diseases such as non-alcoholic fatty liver disease (NAFLD) and cirrhosis in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) are limited. To the best of our knowledge, none exists that makes use of a national database in an Asian population. This study aims to evaluate the effects of CPAP treatment on patients with these two disorders in a retrospective, population-based study in Taiwan. METHODS: Using the Taiwan National Health Insurance claims database, this study collected the data of OSAHS patients diagnosed between 2000 and 2008 and divided them into CPAP treatment and non-CPAP treatment groups. All subjects were followed up until 2010. Liver disease incidence and risk were calculated. RESULTS: The CPAP group had a lower cumulative incidence rate of developing liver disease than the non-CPAP group within the observation periods (p < 0.001). After adjusting for age, gender, urbanization level, and comorbidities, the CPAP treatment group showed a lower risk of developing liver disease compared with the non-CPAP treatment group (sub aHR of 0.66 (95% CI 0.55-0.80), p < 0.001). CONCLUSIONS: Our observations suggest that CPAP treatment may play an important role to delay the progression of liver disease in OSAHS patients and decreases the incidence of liver disease among OSAHS patients. Thus, CPAP therapy may be a feasible way to decrease the risk of liver disease among patients with OSAHS. PMID- 27957697 TI - Benefit of SLIT and SCIT for Allergic Rhinitis and Asthma. AB - Allergen immunotherapy (AIT) has been in use since more than one century, when Leonard Noon experimentally proved its efficacy in hayfever (Noon, in Lancet 1:1572-3, 1911). Since then, AIT was administered only as subcutaneous injections (SCIT) until the sublingual route (SLIT) was proposed in 1986. The use of SLIT was proposed following several surveys from the USA and UK that repeatedly reported fatalities due to SCIT (Lockey et al. in J Allergy Clin Immunol 75(1): 166, 1985; Lockey et al. in J Allergy Clin Immunol 660-77, 1985; Committee on the safety of medicines. CSM update. Desensitizing vaccines. Br Med J, 293: 948, 1986). These reports raised serious concerns about the safety and the risk/benefit ratio of AIT. Many cases of life-threatening events with SCIT were due to avoidable human errors in administration, but a relevant fraction of them remained unexplained and unpredictable (Aaronson and Gandhi in J Allergy Clin Immunol 113: 1117-21, 2014). Subsequently, in a few years, SLIT gained credibility and was included in the official documents and guidelines (Table 1) (Bousquet et al. in J Allergy Clin Immunol 108(5 Supp):S146-S150, 2001; Canonica et al. in Allergy 64 (Supp 91):1-59, 2009) as a viable alternative to traditional SCIT. Of note, the local bronchial (aerosol) and the intranasal route of administration were attempted after the 1970s as alternatives to SCIT: the bronchial route was soon abandoned due to the poor efficacy and/or side effects, and the local nasal route, although effective and safe, was judged substantially impractical (Canonica and Passalacqua in J Allergy Clin Immunol 111: 437-48, 2003). In contrast to SCIT, SLIT was tested in very large clinical trials (need references), including hundreds of patients and with dose-ranging experimental designs, so that some products (tablets) for grass, mite, and ragweed were officially approved as commercial drugs by regulatory agencies such as the Food and Drug Administration and the European Medicines Agency and the optimal content for the maintenance dose was identified for selected allergens. In parallel, the knowledge on the mechanisms of action of AIT was rapidly refined, leading to further improvements, such as the chemically modified extracts and the use of adjuvants to enhance efficacy and safety. In addition, in the last 10 years, there has been an increasing scientific and clinical interest in AIT applied to food allergies, in particular in children, with the use of orally administered extracts (Albin and Nowak-Wegrzyn in Immunol Allergy Clin North Am 35: 77-100, 2015). The results are so far encouraging, at least for cow's milk, egg, and peanut, although the use of treatment is still restricted to clinical trials or within specialized centers. Finally, the introduction of molecular- or component resolved diagnosis has allowed detailing the prescription of AIT, by better delineating true sensitization versus cross-reactivity (Canonica et al. in World Allergy Organ J 6(1):17, 2013). This latter point is also in strict relation to the use of recombinant, engineered or highly purified molecules, instead of raw extracts, for the desensitization process. PMID- 27957698 TI - Letter to the Editor Concerning the Publication: "Efficacy of First-Time Intragastric Balloon in Weight Loss: a Systematic Review and Meta-Analysis of Randomized Controlled Trials". PMID- 27957700 TI - Comment on: Systematic Review and Meta-Analysis of Occupational Outcomes After Bariatric Surgery. PMID- 27957701 TI - Autonomic Cardiovascular Control and Executive Function in Chronic Hypotension. AB - BACKGROUND: Chronic low blood pressure (hypotension) is characterized by complaints such as fatigue, reduced drive, dizziness, and cold limbs. Additionally, deficits in attention and memory have been observed. Autonomic dysregulation is considered to be involved in the origin of this condition. PURPOSE: The study explored autonomic cardiovascular control in the context of higher cognitive processing (executive function) in hypotension. METHODS: Hemodynamic recordings were performed in 40 hypotensive and 40 normotensive participants during execution of four classical executive function tasks (number letter task, n-back task, continuous performance test, and flanker task). Parameters of cardiac sympathetic control, i.e., stroke volume, cardiac output, pre-ejection period, total peripheral resistance, and parasympathetic control, i.e., respiratory sinus arrhythmia and baroreflex sensitivity, were obtained. RESULTS: The hypotensive group exhibited lower stroke volume and cardiac output, as well as higher pre-ejection period and baroreflex sensitivity during task execution. Increased error rates in hypotensive individuals were observed in the n-back and flanker tasks. In the total sample, there were positive correlations of error rates with pre-ejection period, baroreflex sensitivity and respiratory sinus arrhythmia, and negative correlations with cardiac output. CONCLUSIONS: Group differences in stroke volume, cardiac output, and pre-ejection period suggest diminished beta-adrenergic myocardial drive during executive function processing in hypotension, in addition to increased baroreflex function. Although further research is warranted to quantify the extent of executive function impairment in hypotension, the results from correlation analysis add evidence to the notion that higher sympathetic inotropic influences and reduced parasympathetic cardiac influences are accompanied by better cognitive performance. PMID- 27957699 TI - Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: a Joint Statement by International Diabetes Organizations. AB - BACKGROUND: Despite growing evidence that bariatric/metabolic surgery powerfully improves type 2 diabetes (T2D), existing diabetes treatment algorithms do not include surgical options. AIM: The 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference, was convened in collaboration with leading diabetes organizations to develop global guidelines to inform clinicians and policymakers about benefits and limitations of metabolic surgery for T2D. METHODS: A multidisciplinary group of 48 international clinicians/scholars (75% nonsurgeons), including representatives of leading diabetes organizations, participated in DSS-II. After evidence appraisal (MEDLINE [1 January 2005-30 September 2015]), three rounds of Delphi-like questionnaires were used to measure consensus for 32 data-based conclusions. These drafts were presented at the combined DSS-II and 3rd World Congress on Interventional Therapies for Type 2 Diabetes (London, U.K., 28-30 September 2015), where they were open to public comment by other professionals and amended face-to-face by the Expert Committee. RESULTS: Given its role in metabolic regulation, the gastrointestinal tract constitutes a meaningful target to manage T2D. Numerous randomized clinical trials, albeit mostly short/midterm, demonstrate that metabolic surgery achieves excellent glycemic control and reduces cardiovascular risk factors. On the basis of such evidence, metabolic surgery should be recommended to treat T2D in patients with class III obesity (BMI >=40 kg/m2) and in those with class II obesity (BMI 35.0-39.9 kg/m2) when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy. Surgery should also be considered for patients with T2D and BMI 30.0-34.9 kg/m2 if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications. These BMI thresholds should be reduced by 2.5 kg/m2 for Asian patients. CONCLUSIONS: Although additional studies are needed to further demonstrate long term benefits, there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with T2D and obesity. To date, the DSS-II guidelines have been formally endorsed by 45 worldwide medical and scientific societies. Health care regulators should introduce appropriate reimbursement policies. PMID- 27957703 TI - EPSM 2016, Engineering and Physical Sciences in Medicine : 6-10 November 2016, Sydney, Australia. PMID- 27957702 TI - Imaging of plantar fascia disorders: findings on plain radiography, ultrasound and magnetic resonance imaging. AB - Plantar fascia (PF) disorders commonly cause heel pain and disability in the general population. Imaging is often required to confirm diagnosis. This review article aims to provide simple and systematic guidelines for imaging assessment of PF disease, focussing on key findings detectable on plain radiography, ultrasound and magnetic resonance imaging (MRI). Sonographic characteristics of plantar fasciitis include PF thickening, loss of fibrillar structure, perifascial collections, calcifications and hyperaemia on Doppler imaging. Thickening and signal changes in the PF as well as oedema of adjacent soft tissues and bone marrow can be assessed on MRI. Radiographic findings of plantar fasciitis include PF thickening, cortical irregularities and abnormalities in the fat pad located deep below the PF. Plantar fibromatosis appears as well-demarcated, nodular thickenings that are iso-hypoechoic on ultrasound and show low-signal intensity on MRI. PF tears present with partial or complete fibre interruption on both ultrasound and MRI. Imaging description of further PF disorders, including xanthoma, diabetic fascial disease, foreign-body reactions and plantar infections, is detailed in the main text. Ultrasound and MRI should be considered as first- and second-line modalities for assessment of PF disorders, respectively. Indirect findings of PF disease can be ruled out on plain radiography. Teaching Points * PF disorders commonly cause heel pain and disability in the general population.* Imaging is often required to confirm diagnosis or reveal concomitant injuries.* Ultrasound and MRI respectively represent the first- and second-line modalities for diagnosis.* Indirect findings of PF disease can be ruled out on plain radiography. PMID- 27957704 TI - The Gatekeeper. PMID- 27957705 TI - The Successful Integration of Psychiatry and Neurology in a Combined Clerkship. PMID- 27957706 TI - Synthesis of Carboxylic Acids and Esters from CO2. AB - The achievements in the synthesis of carboxylic acids and esters from CO2 have been summarized and discussed. PMID- 27957708 TI - Hypertension in Pregnancy. AB - Hypertensive disorders of pregnancy remain an unresolved and unpreventable problem in obstetrics. They remain one of the leading member of deadly triad causing maternal mortality, the other two being hemorrhage and sepsis which are preventable. The incidence of hypertensive disorders worldwide is 12 %. We have discussed various terminologies used to describe hypertension during pregnancy, risk factors, etiopathogenesis, pathophysiology, management guidelines, complications and long term consequences of hypertensive disorders of pregnancy in this chapter. PMID- 27957707 TI - Association of oral endothelin receptor antagonists with risks of cardiovascular events and mortality: meta-analysis of randomized controlled trials. AB - BACKGROUND: Endothelin receptor antagonists (ERAs) are widely used in a variety of disorders, including pulmonary artery hypertension, systemic sclerosis, diabetic and kidney diseases, and several tumors. However, reported adverse events, especially increased risks of cardiovascular disease (CVD) morbidity and mortality, have cast doubt on their potential clinical application. Therefore, we conducted this meta-analysis to confirm whether ERAs increased CVD risk and mortality. METHODS: We systematically searched PubMed (1966-2015), EMBASE (1974 2015), ClinicalTrials.gov, and the Cochrane Controlled Clinical Trials Register Database for randomized controlled trials published between Jan 1, 1990 and Mar 18, 2015. Inclusion criteria included a study duration of more than 3 weeks, the use of a randomized control group receiving an oral ERA or placebo, and the availability of outcome data for cardiovascular events and all-cause death. RESULTS: A total of 33 trials met the inclusion criteria. There were 8098 cases in the ERA group and 5074 cases in the placebo group. Compared with the control group, the risk ratio (RR) for all-cause death in the ERA group was 0.983 [95% confidence interval (CI), 0.883 to 1.094, P = 0.754]. The summary RR for cardiovascular events was 1.651 in the ERA group (95% CI, 1.164 to 2.34, P = 0.005). The pooled results showed that ERAs treatment could lead to more edema, anemia, and abnormal transaminase levels. Also, there was an increased proportion of discontinued therapy in the ERA treatment because of side effects (RR = 1.322, 95% CI, 1.036 to 1.686, P = 0.025). There were no significant differences in the experienced episodes of headache and dyspnea between the active therapy and control groups. CONCLUSIONS: ERAs therapy is not significantly associated with increased all-cause death, but there are more cardiovascular events and edema or fluid retention, anemia, and liver enzymes disorder. Large clinical randomized controlled studies are needed to further confirm the safety of the clinical application of ERAs. PMID- 27957710 TI - Recent Advances in the Genetics of Hypertension. AB - Hypertension is a silent killer worldwide, caused by both genetic and environmental factors. Until now, genetic and genomic association studies of hypertension are reporting different degree of association on hypertension. Hence, it is essential to gather all the available information on the reported genetic loci and to determine if any biomarker(s) is/are significantly associated with hypertension. Current review concluded the potential biomarkers for hypertension, with regards to electrolyte and fluid transports, as well as sodium/potassium ions homeostasis, which are supported by the results of case controls and meta-analyses. PMID- 27957709 TI - Reduction of Chemically Stable Multibonds: Nitrogenase-Like Biosynthesis of Tetrapyrroles. AB - The sophisticated biochemistry of nitrogenase plays a fundamental role for the biosynthesis of tetrapyrrole molecules, acting as key components of photosynthesis and methanogenesis. Three nitrogenase-like metalloenzymes have been characterized to date. Synthesis of chlorophylls and bacteriochlorophylls involves the reduction of the C17-C18 double bond of the conjugated ring system of protochlorophyllide which is catalyzed by the multi-subunit enzyme dark operative protochlorophyllide oxidoreductase (DPOR). Subsequently, biosynthesis of all bacteriochlorophylls requires the reduction of the C7-C8 double bond by a second nitrogenase-like enzyme termed chlorophyllide oxidoreductase (COR). Mechanistically, DPOR and COR make use of a reductase component which links ATP hydrolysis to conformational changes. This dynamic switch protein is triggering the transient association between the reductase and the core catalytic protein complex, thereby facilitating the transduction of electrons via two [4Fe4S] clusters. X-ray crystallographic structural investigations in combination with biochemical experiments revealed the molecular basis of the underlying energy transduction mechanism. The unique nickel-containing tetrapyrrole cofactor F430 is located in the active site of methyl-coenzyme M reductase, which is catalyzing the final step of methane formation in methanogenic archaea. The nitrogenase-like protein NflH/NflD has been proposed to catalyze one or more ring reduction steps during the biosynthesis of F430. The present working hypothesis mirrors a DPOR and COR related enzyme mechanism of NflH/NflD. Furthermore, nfl-encoded proteins were suggested as "simplified" ancestors lying basal in the phylogenetic tree between nitrogenase and DPOR/COR. PMID- 27957712 TI - Photophysical and Photoprototropic Characteristics of 2-Aminobenzothiazole in beta-Cyclodextrin Medium. AB - The formation of stable inclusion complexes between neutral and monocationic species of 2-aminobenzothiazole (2ABT) with beta-CDx is observed with significant enhancement in absorbance and fluorescence intensity. The stoichiometry of the 2ABT and 2ABTH? with beta-CDx is found to be 1:1 at pH 6.8 and 1.1. Their binding constant values for neutral and monocationic species are found to be 1239.3 and 1259.2 M-1, respectively. Lifetime analysis, FT-IR spectral and SEM image analysis strongly supports the formation of the inclusion complex between 2ABT and beta-CDx. Photoprototropic study shows that there is no remarkable difference in the pK a and pK a* in aqueous and beta-CDx media, which is rules out the formation of the inclusion complex with -NH2 group of 2ABT inside the cavity of beta-CDx i.e., the -NH2 group of 2ABT is in aqueous environment. Based on stoichiometry, binding constant and acidity constant values, the structure of the 1:1 complex is proposed. PMID- 27957711 TI - The Role of Beta-Blockers in the Treatment of Hypertension. AB - IMPORTANCE: Two major guide-line committees (JNC-8 and NICE UK) have dropped beta blockers as first-line therapy in the treatment of hypertension. Also, recent meta-analyses (that do not take age into account) have concluded that beta blockers are inappropriate first-line agents in the treatment of hypertension. This review seeks to shed some light on the "rights and wrongs" of such actions and conclusions. OBJECTIVES: Because the pathophysiology of primary/essential hypertension differs in elderly and younger subjects, the latter being closely linked to obesity and increased sympathetic nerve activity, the author sought to clarify the efficacy of beta-blockers in the younger/middle-aged group in reducing the risk of death, and cardiovascular end-points. EVIDENCE ACQUISITION: Four searches were undertaken, utilising PubMed up to 31st Dec 2015. One search was under the terms "hypertension AND obesity AND sympathetic nerve activity". A second was "hypertension AND plasma noradrenaline/norepinephrine AND survival". A third was "beta-blockers or adrenergic beta-antagonists AND hypertension AND age AND stroke or myocardial infarction or death". A fourth was "meta-analysis of beta-blockers AND hypertension AND age AND death, stroke, myocardial infarction" RESULTS: Diastolic (with or without systolic) hypertension, in contrast to isolated systolic hypertension, occurs primarily in younger subjects, and is linked to overweight/obesity and increased sympathetic nerve activity. In younger/middle-aged hypertensive subjects, high plasma norepinephrine levels are linked (independent of blood pressure) to an increased risk of future cardiovascular events and death. High resting heart rates (a surrogate for high sympathetic nerve activity) likewise predict premature all-cause death, coronary heart disease and cardiovascular events in younger hypertensive subjects. In this younger/middle-aged hypertensive group, antihypertensive agents that increase sympathetic nerve activity (diuretics, dihydropyridine calcium blockers, and angiotensin receptor blockers (ARBs)) do not decrease (and may increase) the risk of myocardial infarction, and are therefore inappropriate first-line agents in this age-group. By contrast, in younger/middle-aged hypertensive subjects (less than 60 years old), meta-analysis has shown that beta-blockers are significantly superior to randomised placebo, and at least as effective as randomised comparator agents, in reducing death/stroke/myocardial infarction. In this younger/middle-aged hypertensive group beta-blockers have been shown (vs randomised placebo or diuretics) to reduce the risk of myocardial infarction by 35-50 %, and stroke by 50-55 % (vs placebo), in non-smoker men. Atenolol was at least as effective as ACE-inhibition (captopril) in reducing all 7 cardiovascular endpoints (including stroke which was reduced by 50 %), vs less tight control of blood pressure, in obese hypertensive subjects with type-2 diabetes (UKPDS study); and after 20 years follow-up, atenolol was significantly (23 %) superior to the ACE-inhibitor in reducing the risk of all-cause death (beta-blockers have anti-cancer properties, which maybe relevant). CONCLUSIONS AND RELEVANCE: Primary/essential hypertension in younger/middle-age is underpinned by high sympathetic nerve activity. In this age-group high resting heart rates and high plasma norepinephrine levels (independent of blood pressure) are linked to premature cardiovascular events and death. Thus, anti-hypertensive agents that increase sympathetic nerve activity ie diuretics, dihydropyridine calcium blockers, and ARBs, are inappropriate first-line choices in this younger age group. Beta-blockers perform well vs randomised placebo and other antihypertensive agents regarding reduced risk of death/stroke/myocardial infarction in younger (<60 years) hypertensive subjects, and are a reasonable first-line choice of therapy (certainly in men). These facts should be reflected in the recommendations of guideline committees around the world. PMID- 27957713 TI - Drill wobble - effect on femoral tunnel aperture during anterior cruciate ligament reconstruction. AB - BACKGROUND: In anterior cruciate ligament reconstruction performed using cortical button fixation on the femur, we have observed a "wobble" effect that can occur when a cannulated femoral drill is used over a guide pin that is not securely fixed in bone. Our study assessed the effect of drill "wobble" on femoral tunnel aperture in sawbones. METHODS: Femoral tunnels were drilled in sawbones, which had been divided in two groups of 10 each, per drilling technique. The "wobble" technique group had the smaller cortical button drill passed before drilling the graft socket with the bigger diameter femoral drill. In contrast, in the "non wobble" technique group, the smaller cortical button drill was passed after drilling the graft socket. The aperture dimensions: antero-posterior, proximo distal and oblique, as well as the length of each tunnel, were measured. RESULTS: While the average dimensions of the tunnels were similar between the two techniques, there was significantly more variation in the antero-posterior measurements for the wobble technique as compared to the non-wobble technique (mean 7.3 mm, SD 0.28 mm, and mean 7.3 mm, SD 0.11 mm, respectively; Brown Forsythe test, p 0.02). CONCLUSION: We conclude that using the "socket first" "non-wobble" technique is a single surgical technical step surgeons can employ to decrease variability in tunnel aperture and size. PMID- 27957714 TI - Association of Lipid Peroxidation and Brain-Derived Neurotrophic Factor with Executive Function in Adolescent Bipolar Disorder. AB - BACKGROUND: Executive dysfunction is common and impairing in youth bipolar disorder (BD), and oxidative stress (OS) and brain-derived neurotrophic factor (BDNF) have been implicated in executive deficits of adult BD. This study aimed to determine the association between OS and executive dysfunction in BD adolescents and the influence of BDNF on this association. METHODS: Serum levels of lipid hydroperoxides (LPH) and 4-hydroxy-2-nonenal (4-HNE) and BDNF levels were measured in 29 BD and 25 control adolescents. The intra-extra-dimensional (IED) set-shifting task assessed executive function. Lower IED scores indicated better performance. High and low BDNF subgroups were defined by median split. RESULTS: IED Z-scores were impaired in the BD group compared to controls, whereas biomarker levels were not significantly different between groups. LPH-BDNF correlations were significantly different between BD and controls (Z = 2.046, p = 0.041). In high BDNF BD subjects, LPH was significantly positively correlated with IED completed stage trials (rho = 0.755, p = 0.001) and pre-extra dimensional shift errors (rho = 0.588, p = 0.017). Correlations were opposite in controls. In a linear model, LPH, BDNF, and the LPH-BDNF interaction each significantly explained variance of IED total trials (adjusted) (model r 2 = 0.187, F = 2.811, p = 0.035). CONCLUSIONS: There is a negative association between LPH and executive function in BD adolescents, which may be modulated by BDNF. LPH and BDNF may be useful biomarkers of executive function in BD. These findings highlight the importance of examining multiple peripheral biomarkers in relation to cognitive functions in BD adolescents. Future studies should explore these factors in longitudinal designs to determine the directionality of observed associations. PMID- 27957716 TI - Native ESI Mass Spectrometry Can Help to Avoid Wrong Interpretations from Isothermal Titration Calorimetry in Difficult Situations. AB - We studied by native ESI-MS the binding of various DNA-polymerase-derived peptides onto DNA-polymerase processivity rings from Escherichia coli, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. These homodimeric rings present two equivalent specific binding sites, which leads to successive formation during a titration experiment of singly- and doubly occupied rings. By using the ESI-MS free-ring spectrum as a ruler, we derived by robust linear regression the fractions of the different ring species at each step of a titration experiment. These results led to accurate Kd values (from 0.03 to 0.5 MUM) along with the probability of peptide loss due to gas phase dissociation (GPD). We show that this good quality is due to the increased information content of a titration experiment with a homodimer. Isothermal titration calorimetry (ITC) led with the same binding model to Kd(ITC) values systematically higher than their ESI-MS counterparts and, often, to poor fit of the ITC curves. A processing with two competing modes of binding on the same site requiring determination of two (Kd, DeltaH) pairs greatly improved the fits and yielded a second Kd(ITC) close to Kd(ESI-MS). The striking features are: (1) ITC detected a minor binding mode (~20%) of 'low-affinity' that did not appear with ESI-MS; (2) the simplest processing of ITC data with only one (Kd, DeltaH) pair led wrongly to the Kd of the low-affinity binding mode but to the DeltaH of the high-affinity binding mode. Analogous misleading results might well exist in published data based on ITC experiments. Graphical Abstract ?. PMID- 27957717 TI - Emotional Understanding, Reactivity, and Regulation in Young Children with ADHD Symptoms. AB - The goal of the present study was to examine whether young children with attention-deficit/hyperactivity disorder (ADHD) symptoms experience difficulties with emotional understanding, reactivity, and regulation. Participants were 64 children, 4 to 7 years of age (43 boys, 20 girls), 29 with ADHD symptoms and 34 typically developing children. Children completed an emotion matching task and parents reported on child lability and emotional regulation. Children also completed a frustrating computer task. Facial expressions of emotions were coded and children self reported affect during the task. Parent reports indicated heightened lability and impaired emotional regulation abilities in children with ADHD symptoms. Compared to typically developing children, children with ADHD symptoms demonstrated emotional understanding impairments in matching similar expressions and matching expressions to situations, but not in producing expression labels or matching expression labels to images. Self-reports of negative affect during the frustration task indicated that children with ADHD symptoms experienced more difficulty with emotional regulation than typically developing children. Behavioral observations during the frustration task indicated that the two groups demonstrated a similar increase in expressed negative affect during frustration; however, children with ADHD symptoms showed higher levels of negative affect across all four conditions of the task. This study suggests that the deficits documented in older children with ADHD are already evident during the preschool years, and distinct from the developmentally appropriate emotional dysregulation seen in typically developing preschoolers. PMID- 27957715 TI - Anxiolytic effects of muscarinic acetylcholine receptors agonist oxotremorine in chronically stressed rats and related changes in BDNF and FGF2 levels in the hippocampus and prefrontal cortex. AB - RATIONALE: In depressive disorders, one of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic plasticity in the hippocampus and cerebral cortex. Previously, we showed that the muscarinic acetylcholine receptor (mAChR) agonist oxotremorine (Oxo) increases neuronal plasticity in hippocampal neurons via FGFR1 transactivation. OBJECTIVES: Here, we aimed to explore (a) whether Oxo exerts anxiolytic effect in the rat model of anxiety depression-like behavior induced by chronic restraint stress (CRS), and (b) if the anxiolytic effect of Oxo is associated with the modulation of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), and phosphorylated Erk1/2 (p-Erk1/2) levels in the dorsal or ventral hippocampus and in the medial prefrontal cortex. METHODS: The rats were randomly divided into four groups: control unstressed, CRS group, CRS group treated with 0.2 mg/kg Oxo, and unstressed group treated with Oxo. After 21 days of CRS, the groups were treated for 10 days with Oxo or saline. The anxiolytic role of Oxo was tested by using the following: forced swimming test, novelty suppressed feeding test, elevated plus maze test, and light/dark box test. The hippocampi and prefrontal cortex were used to evaluate BDNF and FGF2 protein levels and p Erk1/2 levels. RESULTS: Oxo treatment significantly attenuated anxiety induced by CRS. Moreover, Oxo treatment counteracted the CRS-induced reduction of BDNF and FGF2 levels in the ventral hippocampus and medial prefrontal cerebral cortex CONCLUSIONS: The present study showed that Oxo treatment ameliorates the stress induced anxiety-like behavior and rescues FGF2 and BDNF levels in two brain regions involved in CRS-induced anxiety, ventral hippocampal formation, and medial prefrontal cortex. PMID- 27957718 TI - Dynamic Viscoelasticity and Surface Properties of Porcine Left Anterior Descending Coronary Arteries. AB - The aim of this study was, for the first time, to measure and compare quantitatively the viscoelastic properties and surface roughness of coronary arteries. Porcine left anterior descending coronary arteries were dissected ex vivo. Viscoelastic properties were measured longitudinally using dynamic mechanical analysis, for a range of frequencies from 0.5 to 10 Hz. Surface roughness was calculated following three-dimensional reconstructed of surface images obtained using an optical microscope. Storage modulus ranged from 14.47 to 25.82 MPa, and was found to be frequency-dependent, decreasing as the frequency increased. Storage was greater than the loss modulus, with the latter found to be frequency-independent with a mean value of 2.10 +/- 0.33 MPa. The circumferential surface roughness was significantly greater (p < 0.05) than the longitudinal surface roughness, ranging from 0.73 to 2.83 and 0.35 to 0.92 um, respectively. However, if surface roughness values were corrected for shrinkage during processing, circumferential and longitudinal surface roughness were not significantly different (1.04 +/- 0.47, 0.89 +/- 0.27 um, respectively; p > 0.05). No correlation was found between the viscoelastic properties and surface roughness. It is feasible to quantitatively measure the viscoelastic properties of coronary arteries and the roughness of their endothelial surface. PMID- 27957720 TI - 99mTc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study. AB - BACKGROUND: Biologicals directed against tumour necrosis factor (TNF) have proven their efficacy in the treatment of spondyloarthritis and rheumatoid arthritis. We present a radiolabelling method for certolizumab pegol (CZP), a commercially available humanized Fab'-fragment directed against TNF. A biodistribution and dosimetry study was conducted. Tc-S-HYNIC CZP was synthesized. The in vitro TNF neutralizing activity was tested by exposing L929s-cells to various concentrations 99mTc-S-HYNIC CZP and measuring TNF-induced cytotoxicity. For biodistribution and dosimetry, WB images and blood and urine sampling were performed up to 24 h pi. Cumulative activities were estimated using mono exponential fitting, and organ doses were estimated using OLINDA/EXM. The effective dose was calculated using the International Commission on Radiological Protection 103 recommendations. The uptake of the tracer in the peripheral joints was assessed visually and semiquantitatively. RESULTS: In vitro tests showed blocking of TNF cytotoxicity by the 99mTc-S-HYNIC CZP formulation comparable to the effect obtained with the unlabelled CZP with or without the HYNIC linker. We analysed eight patients with rheumatoid arthritis or spondyloarthritis. The highest mean absorbed organ doses were recorded for kidneys, spleen, and liver: 56 (SD 7), 34 (SD 6), and 33 (SD 7) MUGy/MBq. The effective dose was 6.1 (SD 0.9) mSv for a mean injected activity of 690 (SD 35) MBq. The urinary excretion was 15.1% (SD 8.1) of the IA at 22.5 h. Blood analysis yielded a distribution half life of 1.2 h (SD 1.5) and an elimination half-life of 26.9 h (SD 2.7). Visual analysis of the scans revealed marked tracer accumulation in the clinically affected peripheral joints. In addition, there was a statistically significant higher uptake of the tracer in the swollen joints (median uptake ratio compared to background of 3.3 in rheumatoid arthritis and 2.4 in peripheral spondyloarthritis) compared to clinically negative joints (respectively 1.3 and 1.6). CONCLUSIONS: We present a radiolabelling technique for CZP, a Fab'-fragment directed against TNF and currently used as a therapeutic agent in rheumatology. An effective dose of 6.1 mSv (SD 0.9) was estimated. We confirmed the uptake of this new radiopharmaceutical in clinically affected peripheral joints. PMID- 27957719 TI - Development of Improved HDAC6 Inhibitors as Pharmacological Therapy for Axonal Charcot-Marie-Tooth Disease. AB - Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy, with an estimated prevalence of 1 in 2500. The degeneration of motor and sensory nerve axons leads to motor and sensory symptoms that progress over time and have an important impact on the daily life of these patients. Currently, there is no curative treatment available. Recently, we identified histone deacetylase 6 (HDAC6), which deacetylates alpha-tubulin, as a potential therapeutic target in axonal CMT (CMT2). Pharmacological inhibition of the deacetylating function of HDAC6 reversed the motor and sensory deficits in a mouse model for mutant "small heat shock protein B1" (HSPB1)-induced CMT2 at the behavioral and electrophysiological level. In order to translate this potential therapeutic strategy into a clinical application, small drug-like molecules that are potent and selective HDAC6 inhibitors are essential. To screen for these, we developed a method that consisted of 3 distinct phases and that was based on the pathological findings in the mutant HSPB1-induced CMT2 mouse model. Three different inhibitors (ACY-738, ACY-775, and ACY-1215) were tested and demonstrated to be both potent and selective HDAC6 inhibitors. Moreover, these inhibitors increased the innervation of the neuromuscular junctions in the gastrocnemius muscle and improved the motor and sensory nerve conduction, confirming that HDAC6 inhibition is a potential therapeutic strategy in CMT2. Furthermore, ACY-1215 is an interesting lead molecule as it is currently tested in clinical trials for cancer. Taken together, these results may speed up the translation of pharmacological inhibition of HDAC6 into a therapy against CMT2. PMID- 27957721 TI - Computational simulation of the predicted dosimetric impact of adjuvant yttrium 90 PET/CT-guided percutaneous ablation following radioembolization. AB - BACKGROUND: 90Y PET/CT post-radioembolization imaging has demonstrated that the distribution of 90Y in a tumor can be non-uniform. Using computational modeling, we predicted the dosimetric impact of post-treatment 90Y PET/CT-guided percutaneous ablation of the portions of a tumor receiving the lowest absorbed dose. A cohort of fourteen patients with non-resectable liver cancer previously treated using 90Y radioembolization were included in this retrospective study. Each patient exhibited potentially under-treated areas of tumor following treatment based on quantitative 90Y PET/CT. 90Y PET/CT was used to guide electrode placement for simulated adjuvant radiofrequency ablation in areas of tumor receiving the lowest dose. The finite element method was used to solve Penne's bioheat transport equation, coupled with the Arrhenius thermal cell-death model to determine 3D thermal ablation zones. Tumor and unablated tumor absorbed dose metrics (average dose, D50, D70, D90, V100) following ablation were compared, where D70 is the minimum dose to 70% of tumor and V100 is the fractional tumor volume receiving more than 100 Gy. RESULTS: Compared to radioembolization alone, 90Y radioembolization with adjuvant ablation was associated with predicted increases in all tumor dose metrics evaluated. The mean average absorbed dose increased by 11.2 +/- 6.9 Gy. Increases in D50, D70, and D90 were 11.0 +/- 6.9 Gy, 13.3 +/- 10.9 Gy, and 11.8 +/- 10.8 Gy, respectively. The mean increase in V100 was 7.2 +/- 4.2%. All changes were statistically significant (P < 0.01). A negative correlation between pre-ablation tumor volume and D50, average dose, and V100 was identified (rho < - 0.5, P < 0.05) suggesting that adjuvant radiofrequency ablation may be less beneficial to patients with large tumor burdens. CONCLUSIONS: This study has demonstrated that adjuvant 90Y PET/CT-guided radiofrequency ablation may improve tumor absorbed-dose metrics. These data may justify a prospective clinical trial to further evaluate this hybrid approach. PMID- 27957722 TI - Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft. AB - BACKGROUND: Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl-3H(N)]-3'-fluoro-3'-deoxythythymidine ([3H]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498). The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [18F]FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [18F]FLT. RESULTS: The dynamic pattern of [18F]FLT levels in the tumor significantly changed after the treatment. The rate constant of [18F]FLT phosphorylation (k3) was significantly higher in the treatment group (0.111 +/- 0.027 [1/min]) than in the control group (0.082 +/- 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [18F]FLT forward transport (K1) to reverse transport (k2), between the two groups (0.556 +/- 0.073 and 0.641 +/- 0.052 [mL/g] in the control group). CONCLUSIONS: Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic modeling could provide improved understanding of the biochemical processes involved in tumor responses to therapy. PMID- 27957724 TI - High titer heterologous rhamnolipid production. AB - Heterologous mono-rhamnolipid production by Pseudomonas putida KT2440 pSynPro8oT_rhlAB using glucose as the single carbon source was characterized in fed-batch bioreactor cultivations. For the described experiments, a defined mineral salt medium was used, and a two phase glucose feeding profile was applied, which yielded a final rhamnolipid concentration of 14.9 g/L. Applying the feeding profile, glucose stayed almost constant until 28 h of cultivation and decreased afterwards to limiting levels. Until the end of cultivation 253.0 +/- 0.1 g glucose was added to the bioreactor of which a total of 252.0 +/- 0.6 g glucose was metabolized. By modeling the fed-batch bioreactor cultivations the time courses of generated biomass, rhamnolipid and consumed glucose were described. The model was furthermore used to derive key process parameters from the collected data. The obtained values for the specific product formation rates (qRL) reached 18 mg/(g h) and yield coefficients (YRL/S) 10 mg/g respectively. PMID- 27957723 TI - Low kidney uptake of GLP-1R-targeting, beta cell-specific PET tracer, 18F-labeled [Nle14,Lys40]exendin-4 analog, shows promise for clinical imaging. AB - BACKGROUND: Several radiometal-labeled, exendin-based tracers that target glucagon-like peptide-1 receptors (GLP-1R) have been intensively explored for beta cell imaging. The main obstacle has been the high uptake of tracer in the kidneys. This study aimed to develop a novel GLP1-R-specific tracer, with fluorine-18 attached to exendin-4, to label beta cells for clinical imaging with PET (positron emission tomography). We hypothesized that this tracer would undergo reduced kidney uptake. 18F-labeled [Nle14,Lys40]exendin-4 analog ([18F]exendin-4) was produced via Cu-catalyzed click chemistry. The biodistribution of [18F]exendin-4 was assessed with ex vivo organ gamma-counting and in vivo PET imaging. We also tested the in vivo stability of the radiotracer. The localization of 18F radioactivity in rat and human pancreatic tissue sections was investigated with autoradiography. Receptor specificity was assessed with unlabeled exendin-3. Islet labeling was confirmed with immunohistochemistry. The doses of radiation in humans were estimated based on biodistribution results in rats. RESULTS: [18F]exendin-4 was synthesized with high yield and high specific activity. Results showed specific, sustained [18F]exendin-4 uptake in pancreatic islets. In contrast to previous studies that tested radiometal-labeled exendin based tracers, we observed rapid renal clearance of [18F]exendin-4. CONCLUSIONS: [18F]exendin-4 showed promise as a tracer for clinical imaging of pancreatic beta cells, due to its high specific uptake in native beta cells and its concomitant low kidney radioactivity uptake. PMID- 27957725 TI - Glutamine, fish oil and antioxidants in critical illness: MetaPlus trial post hoc safety analysis. AB - BACKGROUND: The role of plasma glutamine, fish oil and antioxidants concentrations in the treatment effect of immune-modulating high-protein versus high-protein enteral nutrition on 6-month mortality in critically ill patients is explored, as unexpected negative outcomes of recent large randomized controlled trials on immune-modulating nutrients have raised questions about safety of these interventions. METHODS: Post hoc analysis of the MetaPlus randomized controlled trial which was performed in a total of 301 medical, surgical and trauma critically ill patients in fourteen European intensive care units. Patients received either immune-modulating (glutamine, fish oil and antioxidant enriched) high-protein (IMHP) or isocaloric high-protein (HP) enteral nutrition. Six-month mortality and baseline, day 4 and day 8 plasma concentrations of glutamine, (eicosapentaenoicacid + decosahexaenoicacid)/long-chain fatty acid plasma level ratio ((epa + dha)/lcf ratio), selenium, vitamin c, vitamin e and zinc were measured. RESULTS: The harmful treatment effect of the IMHP versus HP enteral nutrition on 6-month mortality was only demonstrated in the medical subgroup (HR 2.52, 95% CI 1.36-4.78, P = 0.004). Among medical patients, when corrected for age groups and APACHE-II scores, there were no statistically significant associations between baseline plasma levels and 6-month mortality, except for zinc (HR 1.06, 95% CI 1.00-1.12, P = 0.026). IMHP feeding resulted in statistically significant increase in plasma levels of glutamine, vitamin e, vitamin c and (epa + dha)/lcf ratio from baseline to day 4, while only the change from baseline to day 4 of (epa + dha)/lcf ratio was statistically significant associated with 6-month mortality (HR 1.18, 95% CI 1.02-1.35, P = 0.021) and identified as mediator for the harmful treatment effect of IMHP enteral nutrition among medical ICU patients. CONCLUSION: We hypothesize that the harmful effect of IMHP compared to HP enteral nutrition in a heterogeneous group of critically ill patients is limited to the medical critically ill patients and mediated by an early increase in (epa + dha)/lcf ratio. Trial Registration Dutch Trial Register 26 January 2010 (NTR2181 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2181 ). PMID- 27957726 TI - Homogeneous Diffusion Solid Model as a Realistic Approach to Describe Adsorption onto Materials with Different Geometries. AB - In this work, the adsorption kinetics of p-nitrophenol (PNP) onto several commercial activated carbons (ACs) with different textural and geometrical characteristics was studied. For this aim, a homogeneous diffusion solid model (HDSM) was used, which does take the adsorbent shape into account. The HDSM was solved by means of the finite element method (FEM) using the commercial software COMSOL. The different kinetic patterns observed in the experiments carried out can be described by the developed model, which shows that the sharp drop of adsorption rate observed in some samples is caused by the formation of a concentration wave. The model allows one to visualize the changes in concentration taking place in both liquid and solid phases, which enables us to link the kinetic behaviour with the main features of the carbon samples. PMID- 27957727 TI - Determination of electrostatic force and its characteristics based on phase difference by amplitude modulation atomic force microscopy. AB - Electrostatic force measurement at the micro/nano scale is of great significance in science and engineering. In this paper, a reasonable way of applying voltage is put forward by taking an electrostatic chuck in a real integrated circuit manufacturing process as a sample, applying voltage in the probe and the sample electrode, respectively, and comparing the measurement effect of the probe oscillation phase difference by amplitude modulation atomic force microscopy. Based on the phase difference obtained from the experiment, the quantitative dependence of the absolute magnitude of the electrostatic force on the tip-sample distance and applied voltage is established by means of theoretical analysis and numerical simulation. The results show that the varying characteristics of the electrostatic force with the distance and voltage at the micro/nano scale are similar to those at the macroscopic scale. Electrostatic force gradually decays with increasing distance. Electrostatic force is basically proportional to the square of applied voltage. Meanwhile, the applicable conditions of the above laws are discussed. In addition, a comparison of the results in this paper with the results of the energy dissipation method shows the two are consistent in general. The error decreases with increasing distance, and the effect of voltage on the error is small. PMID- 27957728 TI - Controllable Preparation of V2O5/Graphene Nanocomposites as Cathode Materials for Lithium-Ion Batteries. AB - Transition metal oxides and graphene composites have been widely reported in energy storage and conversion systems. However, the controllable synthesis of graphene-based nanocomposites with tunable morphologies is far less reported. In this work, we report the fabrication of V2O5 and reduced graphene oxide composites with nanosheet or nanoparticle-assembled subunits by adjusting the solvothermal solution. As cathode materials for lithium-ion batteries, the nanosheet-assembled V2O5/graphene composite exhibits better rate capability and long-term cycling stability. The V2O5/graphene composites can deliver discharge capacities of 133, 131, and 122 mAh g-1 at 16 C, 32 C, and 64 C, respectively, in the voltage range of 2.5-4.0 V vs. Li/Li+. Moreover, the electrodes can retain 85% of their original capacity at 1C rate after 500 cycles. The superior electrochemical performances are attributed to the porous structures created by the connected V2O5 nanosheets and the electron conductivity improvement by graphene. PMID- 27957729 TI - Well-Dispersed Cu2ZnSnS4 Nanocrystals Synthesized from Alcohols and Their Applications for Polymer Photovoltaics. AB - In this work, we report on a simple non-injection synthesis routine for the preparation of well-dispersed monocrystalline Cu2ZnSnS4 (CZTS) nanoparticles (NPs). The nanocrystal morphology was investigated by scanning and transmission electron microscopy, and its phase composition was studied by X-ray diffraction and Raman analyses. Cu2ZnSnS4 nanoparticles prepared using ethanolamine and diethanolamine as chemical stabilizers showed a high purity and a suitable size for polymer solar cell applications. The fabricated CZTS NPs are shown to be easily dispersed in a polymer/fullerene aromatic solution as well as the hybrid photovoltaic active layer. Thanks to the increment in the light absorption and electrical conductivity of the active layer, solar cells with a small amount of CZTS nanoparticles resulted in a clear enhancement of the photovoltaic performance. The short-circuit current density is increased from 9.90 up to 10.67 mA/cm2, corresponding to an improvement in the power conversion efficiency (PCE) from 3.30 to 3.65%. PMID- 27957730 TI - Pharmacokinetic modeling of a novel hypoxia PET tracer [18F]HX4 in patients with non-small cell lung cancer. AB - BACKGROUND: [18F]HX4 is a promising new PET tracer developed to identify hypoxic areas in tumor tissue. This study analyzes [18F]HX4 kinetics and assesses the performance of simplified methods for quantification of [18F]HX4 uptake. To this end, eight patients with non-small cell lung cancer received dynamic PET scans at three different time points (0, 120, and 240 min) after injection of 426 +/- 72 MBq [18F]HX4, each lasting 30 min. Several compartment models were fitted to time activity curves (TAC) derived from various areas within tumor tissue using image derived input functions. RESULTS: Best fits were obtained using the reversible two-tissue compartment model with blood volume parameter (2T4k+VB). Simplified measures correlated well with VT estimates (tumor-to-blood ratio (TBr) R 2 = 0.96, tumor-to-muscle ratio R 2 = 0.94, standardized uptake value R 2 = 0.89). CONCLUSIONS: [18F]HX4 shows reversible kinetics in tumor tissue: 2T4k+VB. TBr based on static imaging at 2 or 4 h can be used for quantification of [18F]HX4 uptake. PMID- 27957731 TI - Development of Rapid and Economical Colorimetric Screening Method for p Phenylenediamine in Variety of Biological Matrices and its Application to Eleven Fatal Cases of p-Phenylenediamine Poisoning. AB - A rapid colorimetric method for detection of p-phenylenediamine (PPD) in various biological samples is developed. The o-cresol test for acetaminophen detection has been modified to detect PPD in blood, urine, gastric contents, and liver. After precipitating protein with trichloroacetic acid solution (2 mL, 10% w/v), biological specimens were required to convert PPD metabolites to PPD by acid hydrolysis. Finally, o-cresol solution (1 mL, 1% w/v), hydrogen peroxide (200 MUL, 3%v/v), and concentrated ammonium hydroxide (0.5 mL) were added in the biological samples. The presence of PPD was indicated by formation of violet color which was turned to bluish green color within 10-15 min. The limit of detection was found to be 2 mg/L in blood, urine, and gastric contents and 2 mg/Kg in liver. This method is also free from any potential interference by p aminophenol, acetaminophen, and other amine drugs under test conditions. This method was successfully employed to thirteen fatal cases of PPD poisoning. PMID- 27957732 TI - Chronic vulvovaginal candidiasis in patients using a levonorgestrel-containing intrauterine device. AB - Chronic vulvovaginal candidiasis is usually responsive to therapy with oral antifungals. We present a case series of 13 patients with this condition who were also using a levonorgestrel intrauterine system (LNG-IUS). All cases responded to ongoing oral fluconazole therapy while the LNG-IUS was in situ. The LNG-IUS was removed in six patients and of these, two experienced clinical improvement with lower fluconazole dosage requirements and three experienced complete resolution of symptoms. One remains on fluconazole 100 mg daily. PMID- 27957733 TI - Veterans' Location in Health Professional Shortage Areas: Implications for Access to Care and Workforce Supply. AB - OBJECTIVE: To describe the distribution of Veterans in areas of the United States where there are potentially inadequate supplies of health professionals, and to explore opportunities suggested by this distribution for fostering health workforce flexibility. DATA SOURCES: County-level data from the 2015-2016 Health Resources and Services Administration's (HRSA's) Area Health Resources Files (AHRF) were used to estimate Veteran populations in HRSA-designated health professional shortage areas (HPSAs). This information was then linked to 2015 VA health facility information from the Department of Veterans Affairs. STUDY DESIGN: Potential Veteran populations living in Shortage Area Counties with no VHA facilities were estimated, and the composition of these populations was explored by Census division and state. PRINCIPAL FINDINGS: Nationwide, approximately 24 percent of all Veterans and 23 percent of Veterans enrolled in VHA health care live in Shortage Area Counties. These estimates mask considerable variation across states. CONCLUSIONS: An examination of Veterans residing in Shortage Area Counties suggests extensive maldistribution of health services across the United States and the continued need to find ways to improve health care access for all Veterans. Effective avenues for doing so may include increasing health workforce flexibility through expansion of nurse practitioner scopes of practice. PMID- 27957734 TI - Impact of Wisconsin Medicaid Policy Change on Dental Sealant Utilization. AB - BACKGROUND: In September 2006, Wisconsin Medicaid changed its policy to allow nondentists to become certified Medicaid providers and to bill for sealants in public health settings. OBJECTIVE: This study examined changes in patterns of dental sealant utilization in first molars of Wisconsin Medicaid enrollees associated with a policy change. DATA SOURCE: The Electronic Data Systems of Medicaid Evaluation and Decision Support for Wisconsin from 2001 to 2009. STUDY DESIGN: Retrospective claims data analysis of Wisconsin Dental Medicaid for children aged 6-16 years. PRINCIPAL FINDINGS: A total of 479,847 children followed up for 1,441,300 person-years with 64,546 visits were analyzed. The rate of visits for sealants by dentists increased significantly from 3 percent per year prepolicy to 11 percent per year postpolicy, and that of nondentists increased from 18 percent per year to 20 percent after the policy change, but this was not significant. Non-Hispanic blacks had the lowest visit rates for sealant application by dentists and nondentists pre- and postpolicy periods. CONCLUSIONS: The Wisconsin Medicaid policy change was associated with increased rates of visits for dental sealant placement by dentists. The rate of visits with sealant placements by nondentists increased at the same rate pre- and postpolicy change. PMID- 27957735 TI - Residue analysis and risk assessment of tebuconazole in jujube (Ziziphus jujuba Mill). AB - In this study, a sensitive and reliable analytical method, based on a modified Quick, Easy, Cheap, Effective, Rugged and Safe procedure, was established for determination of tebuconazole in jujube. After extraction with acetonitrile, the samples were cleaned up by dispersive solid-phase extraction with primary secondary amine, and determined by high-performance liquid chromatography tandem mass spectrometry. At fortification levels of 0.01, 0.1 and 2.0 mg kg-1 , the average recoveries of tebuconazole in jujube were in the range 97.6-101.9%, with relative standard deviations of 1.5-3.5%. The dissipation and residual levels of tebuconazole in jujube under field conditions were investigated. Tebuconazole dissipated relatively slowly in jujube, with a half-life of 33.0 days. The terminal residue experiments of tebuconazole in jujube were conducted in four locations in China and the risk was evaluated using risk quotients (RQ). RQ values were found to be significantly lower than RQ = 1, indicating that the risk to human health of using the recommended doses of tebuconazole in jujube was not significant. This study could provide guidance for the safe and reasonable use of tebuconazole in jujube and serve as a reference for the establishment of limit of maximum residue in China. PMID- 27957736 TI - Simultaneous Identification of Four "Legal High" Plant Species in a Multiplex PCR High-Resolution Melt Assay. AB - The international prevalence of "legal high" drugs necessitates the development of a method for their detection and identification. Herein, we describe the development and validation of a tetraplex multiplex real-time polymerase chain reaction (PCR) assay used to simultaneously identify morning glory, jimson weed, Hawaiian woodrose, and marijuana detected by high-resolution melt using LCGreen Plus(r) . The PCR assay was evaluated based on the following: (i) specificity and selectivity-primers were tested on DNA extracted from 30 species and simulated forensic samples, (ii) sensitivity-serial dilutions of the target DNA were prepared, and (iii) reproducibility and reliability-sample replicates were tested and remelted on different days. The assay is ideal for cases in which inexpensive assays are needed to quickly detect and identify trace biological material present on drug paraphernalia that is too compromised for botanical microscopic identification and for which analysts are unfamiliar with the morphology of the emerging "legal high" species. PMID- 27957737 TI - Application of a liquid chromatography-tandem mass spectrometry method to the pharmacokinetics, tissue distribution and excretion in the study of anemoside B4, a novel antiviral agent candidate, in rats. AB - A simple, sensitive and reliable LC-MS/MS method was developed and validated for the quantification of anemoside B4, a potential antiviral constituent isolated from Pulsatilla chinensis in rat plasma, tissue, bile, urine and feces. All biological samples were prepared by protein precipitation method, and ginsenoside Rg1 was chosen as the internal standard (IS). The analyte and IS were separated using a C18 column (2.1 * 50 mm, 1.8 MUm) and a mobile phase consisting of 0.1% formic acid in water (v/v) and acetonitrile running at a flow rate of 0.2 mL/min for 5 min. The multiple reaction monitoring transitions were monitored at m/z 1219.5-749.5 for anemoside B4 and 845.4-637.4 for ginsenoside-Rg1 in electrospray ionization negative mode. The calibration curve was linear in the range of 10 2000 ng/mL for all biological matrices with a lower limit of quantification of 10 ng/mL. The validated method was successfully applied to a pharmacokinetics, tissue distribution and excretion study. These preclinical data will be beneficial for further development of anemoside B4 in future studies. PMID- 27957738 TI - Quantitative analysis of single-nucleotide polymorphisms by pyrosequencing with di-base addition. AB - We have developed and validated a novel method for quantitative detection of SNPs by using pyrosequencing with di-base addition (PDBA). Based on the principle that the signal intensity is proportional to the template concentration within a linear concentration range, linear formula (Y = AX + B) for each genotype is established, and the relationship between two genotypes of a single SNP can be resolved by corresponding linear formulas. Here, PDBA assays were developed to detect variants rs6717546 and rs4148324, and the linear formulas for each genotype of rs6717546 and rs4148324 were established. The method allowed to quantitatively determine each genotype and showed 100% accordant results against a panel of defined mixtures. A set of 24 template fragments containing variants rs6717546 or rs4148324 was tested to evaluate the method. Our results showed that allele frequency of each genotype was accurately quantified, with results comparable to those of conventional pyrosequencing. Furthermore, this method was capable of detecting alleles with frequencies as low as 3%, which was more sensitive than ~5 to ~7% level detected by conventional pyrosequencing. This method offers high sensitivity, reproducibility, and relatively low costs, and thus could provide a much-needed approach for quantitative analysis of SNPs in clinical samples. PMID- 27957739 TI - Migratory-stage sea lamprey Petromyzon marinus stop responding to conspecific damage-released alarm cues after 4 h of continuous exposure in laboratory conditions. AB - This study investigated the length of avoidance response of migratory-stage sea lamprey Petromyzon marinus exposed continuously to conspecific damage-released alarm cues for varying lengths of time in laboratory stream channels. Ten replicate groups of P. marinus, separated by sex, were exposed to either deionized water control or to P. marinus extract for 0, 2 or 4 h continuously. Petromyzon marinus maintained their avoidance response to the conspecific damage released alarm cue after continuous exposure to the alarm cue for 0 and 2 h but not 4 h. Beyond being one of the first studies in regards to sensory-olfactory adaptation-acclimation of fishes to alarm cues of any kind, these results have important implications for use of conspecific alarm cues in P. marinus control. For example, continuous application of conspecific alarm cue during the day, when P. marinus are inactive and hiding, may result in sensory adaptation to the odour by nightfall when they migrate upstream. PMID- 27957740 TI - Impact of Enroll America on the Number of Individuals Covered through the Federally Facilitated Marketplace. AB - OBJECTIVE: To assess the impact of Enroll America's field outreach activities on the number of individuals enrolled in Marketplace coverage during the first open enrollment period. DATA SOURCES/STUDY SETTING: Marketplace enrollment for the initial open enrollment period linked with data on Enroll America's field activities and baseline local-area demographic, economic, and health services characteristics. STUDY DESIGN: We used a quasi-experimental design, comparing Marketplace enrollment during the first open enrollment period in local areas drawn from Enroll America field states to a comparison group of local areas drawn from states that were not served by Enroll America's field effort, but that otherwise match up well with Enroll America states. PRINCIPAL FINDINGS: We find evidence of a large, positive effect of Enroll America's field outreach on Marketplace enrollment in non-Medicaid expansion states. Across model specifications, the Enroll America effects on Marketplace enrollment ranged between 10 and 15 percent, with most estimates statistically significant at the 5 percent level. CONCLUSIONS: Enroll America played an important role in the success of individual states' efforts to boost Marketplace enrollment. Enroll American's evidence-driven, grassroots approach could serve as a model for others interested in conducting similar outreach campaigns for Affordable Care Act related coverage. PMID- 27957741 TI - Quantitative Determination of Cannabinoids in Cannabis and Cannabis Products Using Ultra-High-Performance Supercritical Fluid Chromatography and Diode Array/Mass Spectrometric Detection. AB - Ultra-high-performance supercritical fluid chromatography (UHPSFC) is an efficient analytical technique and has not been fully employed for the analysis of cannabis. Here, a novel method was developed for the analysis of 30 cannabis plant extracts and preparations using UHPSFC/PDA-MS. Nine of the most abundant cannabinoids, viz. CBD, ?8 -THC, THCV, ?9 -THC, CBN, CBG, THCA-A, CBDA, and CBGA, were quantitatively determined (RSDs < 6.9%). Unlike GC methods, no derivatization or decarboxylation was required prior to UHPSFC analysis. The UHPSFC chromatographic separation of cannabinoids displayed an inverse elution order compared to UHPLC. Combining with PDA-MS, this orthogonality is valuable for discrimination of cannabinoids in complex matrices. The developed method was validated, and the quantification results were compared with a standard UHPLC method. The RSDs of these two methods were within +/-13.0%. Finally, chemometric analysis including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were used to differentiate between cannabis samples. PMID- 27957742 TI - A Modified Electrostatic Adsorption Apparatus for Latent Fingerprint Development on Unfired Cartridge Cases. AB - Visualization of latent fingerprints on metallic surfaces by the method of applying electrostatic charging and adsorption is considered as a promising chemical-free method, which has the merit of nondestruction, and is considered to be effective for some difficult situations such as aged fingerprint deposits or those exposed to environmental extremes. In fact, a portable electrostatic generator can be easily accessible in a local forensic technology laboratory, which is already widely used in the visualization of footwear impressions. In this study, a modified version of this electrostatic apparatus is proposed for latent fingerprint development and has shown great potential in visualizing fingerprints on metallic surfaces such as cartridge cases. Results indicate that this experimental arrangement can successfully develop aged latent fingerprints on metal surfaces, and we demonstrate its effectiveness compared with existing conventional fingerprint recovery methods. PMID- 27957743 TI - Pharmacokinetics and tissue distribution of coptisine in rats after oral administration by liquid chromatography-mass spectrometry. AB - Coptisine, one of the main components isolated from Coptidis rhizoma, has been reported to have many beneficial pharmacological effects including anti inflammatory, anti-hypercholesterolemia, neuroprotective and cardioprotective properties. However, to date the information related to the in vivo pharmacokinetics (PK) of coptisine is very limited. The purposes of our study are to establish a fast and sensitive quantification method of coptisine using liquid chromatography-mass spectrometry (LC-MS) and evaluate the PK profile of coptisine in rats. The calibration curve for coptisine was linear from 0.78 to 50 ng/mL. After single-dose oral administration of coptisine, the mean peak plasma concentration values for groups treated with 30, 75 and 150 mg/kg doses ranged from 44.15 to 66.89 ng/mL, and the mean area under the concentration-time curve values ranged from 63.24 to 87.97 mg/L h. The absolute bioavailability was calculated to range from 1.87 to 0.52%. Coptisine remained in all analyzed samples at low concentrations after oral administration of 30 mg/kg. PMID- 27957744 TI - Characteristics and Frequency of Chipping Effects in Near-Contact Gunshot Wounds. AB - The presence of "chipping" or "flaking" around the edges of gunshot entry wounds has been described among the characteristics of gunshot wounds in bone. In this study, the real frequency of such a peculiar feature was investigated. The presence of "chipping" was assessed on 22 gunshot wounds fired at a near-contact range on bovine ribs with 9-mm bullets. As controls, five samples were shot with a 3 cm range, and five from 40 cm. In 77% of cases shot at near-contact range, a detachment of small fragments of the upper layers of bone was detected, mainly with a circumferential disposition, whereas this feature was lacking in control samples. The study demonstrated the frequency of "chipping" and that it may probably be due to a combined ballistic effect of impact of the bullet itself and expansion of gases. It may be thus considered indicative of close-range shots. PMID- 27957745 TI - Exploring New Zealand prescription data using sequence symmetry analyses for predicting adverse drug reactions. AB - WHAT IS KNOWN AND OBJECTIVE: Prescription sequence symmetry analyses (PSSA) is a ubiquitous tool employed in pharmacoepidemiological research to predict adverse drug reactions (ADRs). Several studies have reported the advantage of PSSA as a method that can be applied to a large prescription database with computational ease. The objective of this study was to validate New Zealand (NZ) prescription database as a potential source for identifying ADRs using the PSSA method. METHODS: We analysed de-identified individual-level prescription data for people aged 65 years and above for the period 2005 to 2014 from the pharmaceutical collections supplied by the NZ Ministry of Health. We selected six positive controls that have been previously investigated and reported for causing ADRs. The six positive controls identified were amiodarone (repeated twice), frusemide, simvastatin, lithium and fluticasone. Amiodarone and lithium have been reported to induce thyroid dysfunction. Simvastatin reported to cause muscle cramps while fluticasone is well documented to cause oral candidiasis. Thyroxine was identified as a marker drug to treat hypothyroidism associated with amiodarone and lithium. Carbimazole was identified as a marker drug to treat hyperthyroidism associated with amiodarone use. Quinine sulphate was identified as a marker drug to treat muscle cramps associated with statins. In addition, we also analysed six negative controls that are unlikely to be associated with ADRs. The main outcome measure is to determine associations with ADRs using adjusted sequence ratios (ASR), and 95% confidence intervals RESULTS AND DISCUSSION: Our analyses confirmed a significant signal for all six positive controls. Significant positive associations were noted for amiodarone [ASR = 3.57, 95% CI (3.17-4.02)], and lithium chloride induced hypothyroidism [ASR = 3.43, 95% CI (2.55-4.70)]. Amiodarone was also strongly associated with hyperthyroidism [ASR = 8.81 95% CI (5.86-13.77)]. Simvastatin was associated with muscle cramps [ASR = 1.69, 95% CI (1.61-1.77)]. Fluticasone was positively associated with oral candidiasis [ASR = 2.34, 95% CI (2.19-2.50)]. Frusemide was associated with hypokalaemia [ASR = 2.94, 95% CI (2.83-3.05]). No strong associations were noted for the negative pairs. It is important to highlight that PSSA automatically controls for all confounding factors including unknown and unmeasured confounding variables, plus the effect of temporal trend in prescriptions, and hence allows a more robust ADR detection especially when confounding factors are difficult to determine or measure. WHAT IS NEW AND CONCLUSION: New Zealand prescription database can be a potential source to identify ADRs engaging the PSSA method, and this could complement pharmacovigilance surveillance in NZ. The PSSA can be an important method for post-marketing surveillance and monitoring of ADRs which have relatively short latency. However, the predictive validity of PSSA will be compromised in certain scenarios, particularly when sample size is small, when new drugs are in the market and data are sparse. PMID- 27957747 TI - Protocols for treating patients with end-stage renal disease: a survey of nephrology fellowships. AB - RATIONALE/BACKGROUND: Approximately 14% of Americans are living with chronic kidney disease (CKD). The prevalence of end-stage renal disease (ESRD), the result of progressing CKD continues to rise by 21,000 per year. Currently, the only antibiotic prophylaxis guidelines for patients with ESRD undergoing dental treatment were published by the AHA in 2003. Presented in three parts, the first and second parts of this study found no consistent protocols amongst U.S. dental schools and U.S. GPRs and AEGDs, respectively. The goal of the third part of the project was to determine the current protocol being used to treat ESRD patients at U.S. nephrology fellowship programs. METHODS AND MATERIALS: An 18 multiple choice question survey was e-mailed to 130 directors of nephrology fellowships within the U.S. regarding renal treatment protocol details and antibiotic prophylaxis for patients with renal disease. RESULTS: Note that, 34.6% of respondents reported having an established renal treatment protocol. For programs with a protocol, 69% of programs reported following AHA guidelines. CONCLUSION: There is a lack of consistent, established protocols amongst U.S. nephrology fellowships. It is suggested that updated and evidence based guidelines for the safe treatment of patients be developed. PMID- 27957746 TI - The impact of olodaterol on the risk of mortality and serious adverse events: a systematic review and meta-analysis. AB - AIMS: Olodaterol is a novel inhaled long-acting beta2 -agonist (LABA) that showed efficacy as a bronchodilator for patients with chronic obstructive pulmonary disease (COPD) and asthma. However, it is unclear whether olodaterol reduces mortality; the safety issues of olodaterol have not been fully evaluated. METHODS: Randomized controlled trials comparing olodaterol with placebo for patients with COPD or asthma, which evaluated mortality or serious adverse events, were included. Eighteen trials reporting mortality and 26 trials reporting nonfatal serious adverse events were included. RESULTS: Inhaled olodaterol did not reduce the risk of mortality (Peto fixed OR 1.31; 95% CI 0.90 1.89) and had no significant impacts on nonfatal serious adverse events (Peto fixed OR 1.03; 95% CI 0.91-1.15). CONCLUSIONS: Inhaled olodaterol has no impact on mortality risk in clinical trials conducted on patients with COPD and asthma. However, the interpretation is limited by a high OR (1.31) and a wide CI that includes the hazardous effect. We could not find any relationship between inhaled olodaterol use and nonfatal serious adverse events. PMID- 27957748 TI - Fatal Injuries of Law Enforcement/Correctional Officers Attacked with Sharp-Edged Weapons. AB - According to the National Law Enforcement Memorial Fund, there were 117 law enforcement fatalities in the United States in 2015. Assaults with sharp-edged weapons have resulted in a total of over 400 fatalities in the United States. The goal of the current research was to examine sharp-edged weapon assaults against law enforcement and correctional agents that resulted in a fatal outcome. A total of twelve autopsy reports were reviewed from across the United States. Four cases involved law enforcement officers, seven involved correctional officers, and one was an off-duty border officer. The male-to-female ratio was 11:1. A total of 70.2% of the wounds analyzed were stab wounds (n = 85), and 29.8% of the wounds were slash wounds (n = 36). Based on this review, the neck, shoulder, and chest regions were the most vulnerable to single fatal stab/slash wounds. Multiple stab/slash wounds often resulted in exsanguination. The use of body armor was only noted in one case. PMID- 27957750 TI - Allergic contact dermatitis caused by efinaconazole: positive patch test reactions up to 0.1% pet. PMID- 27957749 TI - Dynamics of volume-averaged intracellular Ca2+ in a rat CNS nerve terminal during single and repetitive voltage-clamp depolarizations. AB - KEY POINTS: The intracellular concentration of free calcium ions ([Ca2+ ]i ) in a nerve terminal controls both transmitter release and synaptic plasticity. The rapid triggering of transmitter release depends on the local micro- or nanodomain of highly elevated [Ca2+ ]i in the vicinity of open voltage-gated Ca2+ channels, whereas short-term synaptic plasticity is often controlled by global changes in residual [Ca2+ ]i , averaged over the whole nerve terminal volume. Here we describe dynamic changes of such global [Ca2+ ]i in the calyx of Held - a giant mammalian glutamatergic nerve terminal, which is particularly suited for biophysical studies. We provide quantitative data on Ca2+ inflow, Ca2+ buffering and Ca2+ clearance. These data allow us to predict changes in [Ca2+ ]i in the nerve terminal in response to a wide range of stimulus protocols at high temporal resolution and provide a basis for the modelling of short-term plasticity of glutamatergic synapses. ABSTRACT: Many aspects of short-term synaptic plasticity (STP) are controlled by relatively slow changes in the presynaptic intracellular concentration of free calcium ions ([Ca2+ ]i ) that occur in the time range of a few milliseconds to several seconds. In nerve terminals, [Ca2+ ]i equilibrates diffusionally during such slow changes, such that the globally measured, residual [Ca2+ ]i that persists after the collapse of local domains is often the appropriate parameter governing STP. Here, we study activity-dependent dynamic changes in global [Ca2+ ]i at the rat calyx of Held nerve terminal in acute brainstem slices using patch-clamp and microfluorimetry. We use low concentrations of a low-affinity Ca2+ indicator dye (100 MUm Fura-6F) in order not to overwhelm endogenous Ca2+ buffers. We first study voltage-clamped terminals, dialysed with pipette solutions containing minimal amounts of Ca2+ buffers, to determine Ca2+ binding properties of endogenous fixed buffers as well as the mechanisms of Ca2+ clearance. Subsequently, we use pipette solutions including 500 MUm EGTA to determine the Ca2+ binding kinetics of this chelator. We provide a formalism and parameters that allow us to predict [Ca2+ ]i changes in calyx nerve terminals in response to a wide range of stimulus protocols. Unexpectedly, the Ca2+ affinity of EGTA under the conditions of our measurements was substantially lower (KD = 543 +/- 51 nm) than measured in vitro, mainly as a consequence of a higher than previously assumed dissociation rate constant (2.38 +/- 0.20 s-1 ), which we need to postulate in order to model the measured presynaptic [Ca2+ ]i transients. PMID- 27957751 TI - Onychomadesis caused by efinaconazole. PMID- 27957752 TI - Contact allergy trends in Singapore - a retrospective study of patch test data from 2009 to 2013. PMID- 27957753 TI - Occupational allergic contact dermatitis caused by benzisothiazolinone in printing ink and soap. PMID- 27957754 TI - Allergic contact cheilitis caused by olaflur in toothpaste. PMID- 27957755 TI - Occupational allergic contact dermatitis caused by tetracaine in an otorhinolaryngologist. PMID- 27957757 TI - Photoprotection and photodermatitis: a case. PMID- 27957758 TI - Enzyme Tunnels and Gates As Relevant Targets in Drug Design. AB - Many enzymes contain tunnels and gates that are essential to their function. Gates reversibly switch between open and closed conformations and thereby control the traffic of small molecules-substrates, products, ions, and solvent molecules into and out of the enzyme's structure via molecular tunnels. Many transient tunnels and gates undoubtedly remain to be identified, and their functional roles and utility as potential drug targets have received comparatively little attention. Here, we describe a set of general concepts relating to the structural properties, function, and classification of these interesting structural features. In addition, we highlight the potential of enzyme tunnels and gates as targets for the binding of small molecules. The different types of binding that are possible and the potential pharmacological benefits of such targeting are discussed. Twelve examples of ligands bound to the tunnels and/or gates of clinically relevant enzymes are used to illustrate the different binding modes and to explain some new strategies for drug design. Such strategies could potentially help to overcome some of the problems facing medicinal chemists and lead to the discovery of more effective drugs. PMID- 27957759 TI - Systematic review: recurrent autoimmune liver diseases after liver transplantation. AB - BACKGROUND: Autoimmune liver diseases (AILD) constitute the third most common indication for liver transplantation (LT) worldwide. Outcomes post LT are generally good but recurrent disease is frequently observed. AIMS: To describe the frequency and risk factors associated with recurrent AILD post-LT and provide recommendations to reduce the incidence of recurrence based on levels of evidence. METHODS: A systematic review was performed for full-text papers published in English-language journals, using the keywords 'autoimmune hepatitis (AIH)', 'primary biliary cholangitis and/or cirrhosis (PBC)', 'primary sclerosing cholangitis (PSC)', 'liver transplantation' and 'recurrent disease'. Management strategies to reduce recurrence after LT were classified according to grade and level of evidence. RESULTS: Survival rates post-LT are approximately 90% and 70% at 1 and 5 years and recurrent disease occurs in a range of 10-50% of patients with AILD. Recurrent AIH is associated with elevated liver enzymes and IgG before LT, lymphoplasmacytic infiltrates in the explants and lack of steroids after LT (Grade B). Tacrolimus use is associated with increased risk; use of ciclosporin and preventive ursodeoxycholic acid with reduced risk of PBC recurrence (all Grade B). Intact colon, active ulcerative colitis and early cholestasis are associated with recurrent PSC (Grade B). CONCLUSIONS: Recommendations based on grade A level of evidence are lacking. The need for further study and management includes active immunosuppression before liver transplantation and steroid use after liver transplantation in autoimmune hepatitis; selective immunosuppression with ciclosporin and preventive ursodeoxycholic acid treatment for primary biliary cholangitis; and improved control of inflammatory bowel disease or even colectomy in primary sclerosing cholangitis. PMID- 27957756 TI - Allergic contact dermatitis caused by exfoliating socks. PMID- 27957760 TI - Isolation and characterization of antiproliferative peptides from Chinese three striped box turtle (Cuora trifasciata). AB - In this study, the whole proteins from a Chinese three-striped box turtle (Cuora trifasciata) were extracted and hydrolyzed using three proteases (alcalase, papain, and protamex). By orthogonal experiments, the optimal hydrolysis conditions for producing peptides with the highest cancer cells growth inhibition activity were determined. Such as, the maximum inhibition on MCF-7 cancer cells (92.37% at 1 mg/mL) was achieved by papain hydrolysis (pH 8, 37 degrees C, enzyme-to-substrate ratio (E/S) 1.5%), and the maximum inhibition on HepG2 cancer cells (94.16% at 1 mg/mL) was reached by protamex hydrolysis (pH 8, 40 degrees C, E/S 2%). Using ultrafiltration and Sephadex G-15 column chromatography, two polypeptides M2 and F4 were isolated. At 500 MUg/mL, M2 exhibited 74.7% and 62.9% of antiproliferation activities on MCF-7 and HepG2 cancer cells, respectively; and F4 displayed good inhibitory effects on MCF-7 (70.59%) and HepG2 (78.6%) cancer cells. M2 and F4 had lower inhibition (<20%) than drug 5-FU (>60%) on normal liver cells L-O2. Moreover, three peptides, EMLQPPL, PGKPLFL, and SCCSCDED, were identified; their inhibitory effects on cancer cells were confirmed after synthesis. These data, for the first time, demonstrated that Cuora trifasciata-derived proteins could be used for preparing antiproliferation peptides. PMID- 27957762 TI - Serum TNF-alpha levels in children with congenital heart disease undergoing cardiopulmonary bypass: A cohort study in China and a meta-analysis of the published literature. AB - OBJECTIVE: To investigate the changes in tumor necrosis factor alpha (TNF-alpha) serum levels after cardiopulmonary bypass (CPB) in children with congenital heart disease (CHD), followed by a meta-analysis to analyze the clinical value of TNF alpha in CPB. METHODS: Our cohort study enrolled 67 CHD children, assigned into off-pump group (n=32) and CPB group (n=35). The TNF-alpha serum levels in two groups were detected by ELISA before the operation (T1), at the end of the operation (0 hour, T2), and after 24 hours of the operation (T3). For meta analysis, literature search was conducted to identify published case-control articles about the changes of TNF-alpha serum levels with CPB of CHD. RESULTS: The TNF-alpha levels in CPB group were lower than that in the off-pump group at T3 (P=.006). TNF-alpha level at T3 was significantly lower than that at T1 and T2 (all P<.05). Meta-analysis results further confirmed that the TNF-alpha levels of CHD children were dramatically decreased at T3 as compared to that at T1 and T2 (both P<.001). CONCLUSION: The TNF-alpha serum levels showed a transient and dramatic decline after 24 hours of CPB, and it may act as an important biological indicator for monitoring the efficacy of CPB in CHD children. PMID- 27957761 TI - Pharmacologic therapies for severe steroid refractory hospitalized ulcerative colitis: A network meta-analysis. AB - BACKGROUND AND AIM: A limited option of therapies is available for hospitalized patients with severe steroid refractory ulcerative colitis (UC). Furthermore, there exists a paucity of direct comparisons between them. To provide a comparative evaluation of the efficacy and safety of pharmacologic therapies, we conducted a network meta-analysis combined with a benefit-risk analysis of randomized controlled trials (RCTs) performed in hospitalized patients with severe steroid refractory UC. METHODS: Electronic databases were searched through November 2015 for RCTs evaluating the efficacy of therapies for severe steroid refractory hospitalized UC. The outcomes were clinical response, colectomy free rate, and severe adverse events leading to discontinuation of therapy. The primary endpoints were the rank of therapies based on network meta-analysis combined with benefit-risk analysis between clinical response and severe adverse events as well as colectomy free rate and severe adverse events. RESULTS: Eight RCTs of 421 patients were identified. Cyclosporine, infliximab, and tacrolimus as well as placebo were included in our analysis. Network meta-analysis with benefit risk analysis simultaneously assessing clinical response and severe adverse events demonstrated the rank order of efficacy as infliximab, cyclosporine, tacrolimus, and placebo. Similar analysis for colectomy-free rate and severe adverse events demonstrated the same rank order of efficacy. The differences among infliximab, cyclosporine, and tacrolimus were small in all analyses. CONCLUSION: The results of the present comprehensive benefit-risk assessment using network meta-analysis provide RCT-based evidence on efficacy and safety of infliximab, cyclosporine, and tacrolimus for hospitalized patients with severe steroid refractory UC. PMID- 27957763 TI - Possible genes responsible for developmental delay observed in patients with rare 2q23q24 microdeletion syndrome: Literature review and description of an additional patient. AB - Cases of 2q23q24 microdeletion syndrome are rare. Patients with chromosomal deletions in this region often show language impairment and/or developmental delay of variable severity. Previous genotype-phenotype correlation study suggested GALNT13 and KCNJ3 as possible candidate genes for such phenotypes. We identified a new overlapping deletion in a patient with severe developmental delay. The identified deletion extended toward the distal 2q24.1 region, and more severe phenotypes in the present patient were considered to be related to the additionally deleted genes including NR4A2 and GPD2. Previously reported chromosomal translocation and the mutation identified in GPD2 suggested that this gene would be responsible for the developmental delay. Re-evaluation for the critical region for behavior abnormalities commonly observed in the patients with overlapping deletions of this region suggested that KCNJ3 rather than GALNT13 may be responsible for abnormal behaviors, although there was phenotypic variability. Combinatory deletions involving KCNJ3 and GPD2 may lead to more severe developmental delay. Further studies would be necessary to establish clearer genotype-phenotype correlation in patients with 2q23q24 microdeletion syndrome. PMID- 27957764 TI - Mechanisms of Undersensing by a Noise Detection Algorithm That Utilizes Far-Field Electrograms With Near-Field Bandpass Filtering. AB - BACKGROUND: Implantable cardioverter defibrillators (ICDs) must establish a balance between delivering appropriate shocks for ventricular tachyarrhythmias and withholding inappropriate shocks for lead-related oversensing ("noise"). To improve the specificity of ICD therapy, manufacturers have developed proprietary algorithms that detect lead noise. The SecureSenseTM RV Lead Noise discrimination (St. Jude Medical, St. Paul, MN, USA) algorithm is designed to differentiate oversensing due to lead failure from ventricular tachyarrhythmias and withhold therapies in the presence of sustained lead-related oversensing. METHODS AND RESULTS: We report 5 patients in whom appropriate ICD therapy was withheld due to the operation of the SecureSense algorithm and explain the mechanism for inhibition of therapy in each case. Limitations of algorithms designed to increase ICD therapy specificity, especially for the SecureSense algorithm, are analyzed. CONCLUSION: The SecureSense algorithm can withhold appropriate therapies for ventricular arrhythmias due to design and programming limitations. Electrophysiologists should have a thorough understanding of the SecureSense algorithm before routinely programming it and understand the implications for ventricular arrhythmia misclassification. PMID- 27957765 TI - Empirically supported psycho-oncology practices: Reflection based on some research findings in Hong Kong. PMID- 27957766 TI - Evaluation of a novel point-of-care test kit, ABSOGENTM PCT, in semi-quantitative measurement of procalcitonin in whole blood. AB - BACKGROUND: In response to inflammation, procalcitonin plasma concentrations increase more rapidly than other acute-phase reactants and higher values are associated with severe disease. Procalcitonin measurements assist in determining whether antibiotic therapy should be used. point-of-care testing (POCT) is performed for early decision making about additional testing or therapy. The ABSOGENTM PCT (Bumyoungbio, Inc., Suwon, Korea) is a rapid novel semi quantitative immunochromatographic PCT assay that analyses whole blood samples. We compared the patient quantitative test results to ABSOGENTM PCT test results. METHODS: Whole blood was loaded onto an ABSOGENTM PCT cartridge and incubated for 10 minutes. The color intensity of the band of the cartridge was measured using an accompanying device and with the naked eye. The results were graded as negative (<0.1 ng/mL), low (0.1 to <1.0 ng/mL), middle (1.0-2.0 ng/mL), and high (>2.0 ng/mL). A total of 158 specimens with procalcitonin levels measured from 0 to 18.96 ng/mL were used for comparison study. RESULTS: The concordance rate between ABSOGENTM PCT using the reader and quantitative assay, between ABSOGENTM PCT using naked eyes and quantitative assay, and between ABSOGENTM PCT using the reader and naked eyes for the same category was 83.5% (P=.040), 78.5% (P<.001), and 82.3% (P=.001), respectively. The concordance rates for the +/-1 categories were all 100%. CONCLUSION: ABSOGENTM PCT is an accurate assay. It is easy to use, simple, fast, portable. The assay has potential value in clinical applications, especially in emergency care. PMID- 27957768 TI - Effect of methoxyl groups on the NMR spectra: configuration and conformation of natural and synthetic indanic and tetralinic structures. AB - Here, we studied the influence of the methoxyl groups attached at C-7 and C-2' of natural and synthetic 1-arylindanes on the chemical shift of the signal of bibenzylic hydrogen and carbon atoms and J1,2 coupling constants. This influence was also analysed in natural 1-aryltetralins and related compounds that possess methoxyl and/or hydroxyl groups bound at C-8 and C-2'. The methoxyl groups attached at C-7 in indanes or at C-8 in tetralins produce a deshielding signal at H-1 and shield at C-1 and a strong decrease in the value of J1,2 due to the pseudoequatorial location adopted by the aryl group bound at C-1, avoiding an 'A1,3 strain'. Furthermore, compounds with hydroxyl or methoxyl groups in C-2', in the absence of substituents of C-7 or C-8, present a strong deshielding signal at H-1, strong shield of the C-1 signal and a decrease in the value of J1,2 . This is attributed to the stereoelectronic effects of the methoxyl or hydroxyl groups, which we have called 'Asarone effect'. NOESY experiments were conducted to confirm the configuration and conformation of some of the compounds included in this work. This study shows that both effects, A1,3 strain and Asarone effect, must be taken into account when the structure of natural indanes and tetralins is analysed by using 1 H-NMR and 13 C-NMR spectra. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27957767 TI - Ethylene carbodiimide-fixed donor splenocytes combined with alpha-1 antitrypsin induce indefinite donor-specific protection to mice cardiac allografts. AB - Peritransplant infusion of ethylene carbodiimide-fixed donor splenocytes (ECDI SPs) induces protection of islet and cardiac allografts. However, pro inflammatory cytokine production during the peritransplantation period may negate the effect of ECDI-SPs. Therefore, we hypothesized that blocking pro-inflammatory cytokine secretion while increasing levels of anti-inflammatory cytokines would enhance the tolerance-induced efficacy of ECDI-SPs. The objective of this study was to determine the effectiveness of using ECDI-SPs combined with a short course of alpha1-antitrypsin (AAT) for induction of tolerance. Using a mice cardiac transplant model, we demonstrated that ECDI-SPs + AAT effectively induced indefinite mice cardiac allograft protection in a donor-specific fashion. This effect was accompanied by modulation of cytokines through decreasing levels of pro-inflammatory cytokines (including IFN-gamma, TNF-alpha, IL-1beta, IL-6, IL 17, and IL-23) and increasing levels of anti-inflammatory cytokines (including IL 10, IL-13, and TGF-beta), and by inhibition of effector T cells (Teff) and expansion of regulatory T cells (Tregs). Therefore, we concluded that combined ECDI-SPs and AAT appeared to modulate the expression of cytokines and regulate the Teff:Treg balance to create a support milieu for graft protection. Our strategy of combining ECDI-SPs and AAT provides a promising approach for inducing donor-specific transplant tolerance. PMID- 27957769 TI - Microarray Analysis of Antibodies Induced with Synthetic Antitumor Vaccines: Specificity against Diverse Mucin Core Structures. AB - Glycoprotein research is pivotal for vaccine development and biomarker discovery. Many successful methodologies for reliably increasing the antigenicity toward tumor-associated glycopeptide structures have been reported. Deeper insights into the quality and specificity of the raised polyclonal, humoral reactions are often not addressed, despite the fact that an immunological memory, which produces antibodies with cross-reactivity to epitopes exposed on healthy cells, may cause autoimmune diseases. In the current work, three MUC1 antitumor vaccine candidates conjugated with different immune stimulants are evaluated immunologically. For assessment of the influence of the immune stimulant on antibody recognition, a comprehensive library of mucin 1 glycopeptides (>100 entries) is synthesized and employed in antibody microarray profiling; these range from small tumor associated glycans (TN , STN , and T-antigen structures) to heavily extended O glycan core structures (type-1 and type-2 elongated core 1-3 tri-, tetra-, and hexasaccharides) glycosylated in variable density at the five different sites of the MUC1 tandem repeat. This is one of the most extensive glycopeptide libraries ever made through total synthesis. On tumor cells, the core 2 beta-1,6-N acetylglucosaminyltransferase-1 (C2GlcNAcT-1) is down-regulated, resulting in lower amounts of the branched core 2 structures, which favor formation of linear core 1 or core 3 structures, and in particular, truncated tumor-associated antigen structures. The core 2 structures are commonly found on healthy cells and the elucidation of antibody cross-reactivity to such epitopes may predict the tumor-selectivity and safety of synthetic vaccines. With the extended mucin core structures in hand, antibody cross-reactivity toward the branched core 2 glycopeptide epitopes is explored. It is observed that the induced antibodies recognize MUC1 peptides with very high glycosylation site specificity. The nature of the antibody response is characteristically different for antibodies directed to glycosylation sites in either the immune-dominant PDTR or the GSTA domain. All antibody sera show high reactivity to the tumor-associated saccharide structures on MUC1. Extensive glycosylation with branched core 2 structures, typically found on healthy cells, abolishes antibody recognition of the antisera and suggests that all vaccine conjugates preferentially induce a tumor-specific humoral immune response. PMID- 27957770 TI - Substrate Ablation for Treatment of Atrial Fibrillation: Back to Basics. PMID- 27957771 TI - Differentiation of isomeric para- and meta-substituted 2,5-diphenyl-1,3,4 oxadiazole derivatives of anthracene by electrospray ionization tandem mass spectrometry. PMID- 27957772 TI - Qualitatively understanding patients' and health professionals' experiences of the BRECONDA breast reconstruction decision aid. AB - OBJECTIVE: Women diagnosed with breast cancer or ductal carcinoma in situ and those with a genetic susceptibility to developing this disease face the challenging decision of whether or not to undergo breast reconstruction following mastectomy. As part of a large randomized controlled trial, this qualitative study examined women's experiences of using the Breast RECONstruction Decision Aid (BRECONDA) and health professionals' feedback regarding the impact of this resource on patients' knowledge and decision making about breast reconstruction. METHOD: Semistructured interviews were conducted with women who accessed the BRECONDA intervention (N = 36) and with their healthcare providers (N = 6). All interviews were transcribed verbatim and subjected to thematic analysis by 3 independent coders. RESULTS: Participants reported an overall positive impression, with all interviewees endorsing this decision aid as a useful resource for women considering reconstructive surgery. Thematic analysis of patient interviews revealed 4 themes: overall impressions and aesthetics; personal relevance and utility; introducing BRECONDA; and advantages and suggested improvements. Analysis of health professionals' interviews also revealed 4 themes: need for BRECONDA, impact of BRECONDA, potential difficulties that may arise in using the decision aid, and recommending BRECONDA to patients. Patients indicated that they derived benefit from this resource at all stages of their decision-making process, with the greatest perceived benefit being for those early in their breast reconstruction journey. CONCLUSION: These findings support the use of BRECONDA as an adjunct to clinical consultation and other information sources. PMID- 27957773 TI - Dental workforce availability and dental services utilization in Appalachia: a geospatial analysis. AB - OBJECTIVES: There is considerable variation in dental services utilization across Appalachian counties, and a plausible explanation is that individuals in some geographical areas do not utilize dental care due to dental workforce shortage. We conducted an ecological study on dental workforce availability and dental services utilization in Appalachia. METHODS: We derived county-level (n = 364) data on demographic and socioeconomic characteristics and dental services utilization in Appalachia from the 2010 Behavioral Risk Factor Surveillance System (BRFSS) using person-level data. We obtained county-level dental workforce availability and physician-to-population ratio estimates from Area Health Resources File and linked them to the county-level BRFSS data. The dependent variable was the proportion using dental services within the last year in each county (ranging from 16.6% to 91.0%). We described the association between dental workforce availability and dental services utilization using ordinary least squares regression and spatial regression techniques. Spatial analyses consisted of bivariate local indicators of spatial association (LISA) and geographically weighted regression (GWR). RESULTS: Bivariate LISA showed that counties in the central and southern Appalachian regions had significant (P < 0.05) low-low spatial clusters (low dental workforce availability, low percent dental services utilization). GWR revealed considerable local variations in the association between dental utilization and dental workforce availability. In the multivariate GWR models, 8.5% (t-statistics > 1.96) and 13.45% (t-statistics > 1.96) of counties showed positive and statistically significant relationships between the dental services utilization and workforce availability of dentists and dental hygienists, respectively. CONCLUSIONS: Dental workforce availability was associated with dental services utilization in the Appalachian region; however, this association was not statistically significant in all counties. The findings suggest that program and policy efforts to improve dental services utilization need to focus on factors other than increasing the dental workforce availability for many counties in Appalachia. PMID- 27957774 TI - Pediatric anaphylaxis in the operating room for anesthesia residents: a simulation study. AB - BACKGROUND: Pediatric intraoperative emergencies are rare but it is crucial for an anesthesia resident to be proficient in their management. Even the more common emergencies like anaphylaxis may not happen frequently for this proficiency to occur. Simulation increases exposure to these rare events in a safe learning environment to improve skills and build confidence while standardizing curriculum. OBJECTIVE: Anesthesia residents participated in a simulated case of intraoperative pediatric anaphylaxis to evaluate knowledge and performance gaps. The study also sought to determine whether a difference exists between second- (CA2) and third-year (CA3) anesthesia residents when managing pediatric anaphylaxis and cardiopulmonary arrest. METHODS: Anesthesia residents completed a standardized programmed simulation of intraoperative anaphylaxis in a 5-year old undergoing tonsillectomy and adenoidectomy. Anaphylaxis presented and progressed to bradycardia and pulseless electrical activity if anaphylaxis went unnoticed or untreated. Key time points were recorded. A scripted debriefing and written evaluation followed. RESULTS: Average time to diagnose anaphylaxis was 7.6 min, and time to give epinephrine was 6.5 min. Thirty-five percent of residents started epinephrine infusion following initial bolus. Average time calling for help between CA3 and CA2 residents was 2.5 min vs 5 min (P = 0.01). CA3 residents verbalized a broader differential, including malignant hyperthermia and pneumothorax. Progression to pulseless electrical activity occurred in 65% of sessions prior to epinephrine being administered. No resident initiated chest compressions for bradycardia. CONCLUSIONS: Important performance deficits were seen in senior anesthesia residents during a simulated case of pediatric intraoperative anaphylaxis. Although CA3 performed better, deficits still existed. Anesthesia residents and training programs should partner in developing additional training recognizing anaphylaxis, pulseless electrical activity, and indication for chest compressions in a child. PMID- 27957776 TI - Health and mineral nutrition status of yaks in southern Mustang, Nepal. AB - Biochemical values and mineral concentrations in blood plasma were investigated to evaluate the statuses of health and mineral nutrition among yaks in Mustang District, Nepal. In total, 118 plasma samples of female yaks collected in April and September/October of 2013-2015 were offered. Seventy-four percent of yaks showed lower plasma total-cholesterol concentrations than the lowest limit of reference range (100 mg/dL) and the values in spring (83.41 mg/dL) were lower (P < 0.05) than those in autumn (95.05 mg/dL). All the yaks had lower plasma albumin concentrations than the lowest limit of reference range (3.0 g/dL) and 66% of yaks showed lower plasma inorganic phosphorus concentrations than the critical level of phosphorus deficiency (4.5 mg/dL). Thirty-five percent of yaks showed lower plasma calcium concentrations than the lowest limit of normal range (8 mg/dL) and the concentrations were lower in spring than in autumn (P < 0.01). Seventy-five percent of yaks presented lower copper concentrations than the critical level (0.65 mg/L) and the concentrations were lower in spring than in autumn (P < 0.01). Since the low plasma total-cholesterol might have indicated shortage of dry matter and energy intake, attention should be paid to the nutritional statuses of energy, phosphorus, calcium and copper in winter and early spring. PMID- 27957775 TI - Landscape of Pleiotropic Proteins Causing Human Disease: Structural and System Biology Insights. AB - Pleiotropy is the phenomenon by which the same gene can result in multiple phenotypes. Pleiotropic proteins are emerging as important contributors to rare and common disorders. Nevertheless, little is known on the mechanisms underlying pleiotropy and the characteristic of pleiotropic proteins. We analyzed disease causing proteins reported in UniProt and observed that 12% are pleiotropic (variants in the same protein cause more than one disease). Pleiotropic proteins were enriched in deleterious and rare variants, but not in common variants. Pleiotropic proteins were more likely to be involved in the pathogenesis of neoplasms, neurological, and circulatory diseases and congenital malformations, whereas non-pleiotropic proteins in endocrine and metabolic disorders. Pleiotropic proteins were more essential and had a higher number of interacting partners compared with non-pleiotropic proteins. Significantly more pleiotropic than non-pleiotropic proteins contained at least one intrinsically long disordered region (P < 0.001). Deleterious variants occurring in structurally disordered regions were more commonly found in pleiotropic, rather than non pleiotropic proteins. In conclusion, pleiotropic proteins are an important contributor to human disease. They represent a biologically different class of proteins compared with non-pleiotropic proteins and a better understanding of their characteristics and genetic variants can greatly aid in the interpretation of genetic studies and drug design. PMID- 27957777 TI - Photoinduced Thiol-ene Chemistry Applied to the Synthesis of Self-Assembling Elastin-Inspired Glycopeptides. AB - Synthetic (glyco)peptides inspired by proteins able to self-assemble are appealing biomaterials in the field of tissue engineering and regenerative medicine. Herein, for the first time, taking advantage of thiol-ene chemistry coupled to solid-phase peptide synthesis, a self-assembling peptide inspired by elastin protein was bioconjugated to three carbohydrates in order to obtain the corresponding glycopeptides. They were studied at the molecular and supramolecular level. The results show that the carbohydrate influences the molecular conformation of the glycopeptide and its self-aggregation properties as well. As future perspective, the results could enable us to tune the final self aggregation properties of the glycopeptide by changing the sugar moiety. PMID- 27957778 TI - Assessment of TP53 Polymorphisms and MDM2 SNP309 in Premenopausal Breast Cancer Risk. AB - Germline polymorphic variants in cancer predisposition genes such as TP53 have been shown to impact the risk of premenopausal cancer. Accordingly, the aim of this study was to assess the spectrum of polymorphisms in TP53 and its negative regulatory gene, MDM2 (SNP309:T>G) in patients with premenopausal breast cancer. Our findings in a cohort of 40 female patients demonstrate no significant correlation between the studied polymorphisms and risk of premenopausal breast cancer. Although one polymorphism is found in high frequency in this cohort (rs1800372:A>G, 9.0%), it was not associated with the risk of developing cancer before the age of 35 years in an extended cohort of 1,420 breast cancer cases. Functional studies of the rs1800372:A>G polymorphic allele reveal that it does not affect p53 transactivation function. Further study of variants or mutations in other cancer susceptibility genes is warranted to refine our understanding of the germline contribution to premenopausal breast cancer susceptibility. PMID- 27957779 TI - Patients with soft tissue sarcoma comprise a higher probability of comorbidities than cancer-free individuals. A secondary data analysis. AB - Soft tissue sarcoma comprises a heterogeneous group of solid malignant tumours. Comorbidities are important prognostic factors for survival and adversely impact quality of life. We examined the complex relationship between soft tissue sarcoma and comorbidities over time in a large population-based sample. The study uses routine data from the German statutory healthcare system (n = 2,615,865). Case identification of soft tissue sarcoma and comorbid diseases was based on ICD-10 codes and diagnostic modifiers. Uni- and multivariate regression models were used to obtain risk estimates for chronic somatic and mental comorbidities in soft tissue sarcoma patients compared to a cancer-free control group. At diagnosis, patients with soft tissue sarcoma were significantly more likely to be affected with prevalent bronchial asthma, >=1 cardiovascular risk factor (hypertension, angina pectoris, heart failure, peripheral arterial disease and thrombosis), back pain, depression, anxiety disorder and adjustment disorder than cancer-free controls. During the course of disease, sarcoma patients were at a significantly higher risk to develop incident depression, anxiety disorder and adjustment disorder. Comorbidities need to be considered in clinical decision making regarding the treatment of soft tissue sarcoma patients. Psycho-oncological treatment should be incorporated into medical care of patients with sarcoma. PMID- 27957780 TI - An ultrahigh-performance chromatography/tandem mass spectrometry quantitative method for trace analysis of potential endocrine disrupting steroid hormones in estuarine sediments. AB - RATIONALE: Estuaries are dynamic ecosystems, providing vital habitat for unique organisms of great ecological and commercial importance. The influx of natural and synthetic steroid hormones into estuaries poses risks to these organisms and to broader ecosystem health. However, detecting these trace level pollutants in estuarine water and sediment requires improved analytical techniques. METHODS: We describe an optimized ultrahigh-performance chromatography/tandem mass spectrometry (UHPLC/MS/MS) method for simultaneous quantitation of four classes of steroid hormones (estrogens, glucocorticoids, androgens and progestins) in sediment samples collected from an Alabama estuary. Sediment samples were homogenized using Hydromatrix (HM) sorbent and extracted with methanol and water (70%, v/v). Centrifuged extracts were purified using an Agilent Bond Elut QuEChERS dispersive-SPE kit to eliminate interfering substances that could negatively influence the ionization process. Chromatographic separation was achieved on a Poroshell 120 Phenyl-Hexyl column using an Agilent 1290 Infinity II UHPLC pump. Quantitation was carried out using an Agilent triple quadrupole mass spectrometer equipped with a JetStream/ESI source in dual mode. RESULTS: Chromatographic separation and better peak resolution were accomplished on an Agilent Poroshell 120 Phenyl-Hexyl column using a binary gradient method with a mobile phase consisting of 1 mM ammonium fluoride in water and a mixture of methanol/acetonitrile. A dynamic multiple reaction monitoring (MRM) method was developed by optimizing various MS parameters. The method was used to analyze target steroid hormones in estuarine sediments. A total of ten steroid hormones were detected at trace amounts in estuarine sediments. CONCLUSIONS: The optimized analytical method described here involves reasonably simple sample preparation and simultaneous trace level quantitation of four classes (estrogens, glucocorticoids, androgens and progestins) of steroid hormones in a single experimental run. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27957781 TI - Efficient Synthetic Routes to (+/-)-Hippolachnin A, (+/-)-Gracilioethers E and F and the Alleged Structure of (+/-)-Gracilioether I. AB - Two monocyclic members in the gracilioether family were synthesized in only three steps. The monocyclic products were further elaborated into advanced precursors to hippolachnin A and gracilioether E, respectively. Gracilioether F and the alleged structure for gracilioether I were also synthesized using a late-stage C(sp3 )-H thermo-oxidation. PMID- 27957782 TI - Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha. AB - The vagus nerve is a central component of cholinergic anti-inflammatory pathways. We sought to evaluate the effect of bilateral transcutaneous cervical vagal nerve stimulation (t-VNS) on validated parameters of autonomic tone and cytokines in 20 healthy subjects. 24 hours after t-VNS, there was an increase in cardiac vagal tone and a reduction in tumor necrosis factor-alpha in comparison to baseline. No change was seen in blood pressure, cardiac sympathetic index or other cytokines. These preliminary data suggest that t-VNS exerts an autonomic and a subtle antitumor necrosis factor-alpha effect, which warrants further evaluation in larger controlled studies. PMID- 27957783 TI - Russian Caucasians have a higher risk of erosive reflux disease compared with East Asians: A direct endoscopic comparison. AB - BACKGROUND: Erosive reflux disease (ERD) is prevalent in the West, and its incidence is increasing in the East. The differences between the West and East, especially in body composition, have not been investigated thoroughly. METHODS: Subjects who underwent esophagogastroduodenoscopy and body composition analysis during health screening were analyzed retrospectively. Russian Caucasians who visited Korea were propensity matched with native Koreans. Endoscopy results were analyzed to identify ERD and gastroesophageal flap valve (GEFV) status. Body composition and laboratory results were compared to identify risk factors for ERD. KEY RESULTS: 32 279 subjects underwent health screening with 1496 Russian Caucasians propensity matched with 1496 Koreans. ERD prevalence was 20.2% for Caucasians and 9.8% for Koreans (P<.001). Caucasians had significantly greater body mass index (BMI) and were more sarcopenic. Significant risk factors for ERD were Caucasian ethnicity (OR 1.629, 95% CI 1.265-2.099, P<.001), male gender (OR 2.374, 95% CI 1.883-2.993, P<.001), greater BMI (OR 1.067, 95% CI 1.041-1.093, P<.001), and abnormal GEFV (OR 2.730, 95% CI 2.194-3.397, P<.001). H. pylori seropositivity (OR 0.614, 95% CI 0.488-0.774, P<.001) and atrophic gastritis (OR 0.547, 95% CI 0.411-0.728, P<.001) were significantly preventive. CONCLUSIONS & INFERENCES: Caucasian ethnicity is a significant risk factor for ERD. Greater BMI, male gender and abnormal GEFV are associated with ERD, and H. pylori seropositivity and atrophic gastritis are preventive. Further studies are needed to assess the differences in ERD between Caucasians and East Asians. PMID- 27957784 TI - d-Cycloserine enhanced extinction of cocaine-induced conditioned place preference is attenuated in serotonin transporter knockout rats. AB - d-Cycloserine (DCS), a partial NMDA receptor agonist, has been proposed as a cognitive enhancer to facilitate the extinction of drug-related memories. However, it is unknown whether there are individual differences in the efficacy of DCS. Here, we set out to investigate the influence of serotonin transporter (5 HTT) genotype on DCS treatment outcome and the underlying neural mechanism. To that end, we first determined the mRNA levels of several NMDA receptor subunits and observed a reduction in NR1/NR2C receptors in the ventromedial prefrontal cortex and nucleus accumbens of 5-HTT-/- compared with 5-HTT+/+ rats. Based on this finding, we hypothesized a lower sensitivity to DCS in the 5-HTT-/- rats. To test this, rats were trained in a cocaine-induced conditioned place preference (CPP) paradigm. A significant extinction of CPP was observed in 5-HTT+/+ rats receiving 1 mg/kg i.v. DCS, while a similar effect was found in the 5-HTT-/- rats only after 5 mg/kg. Following CPP, we tested if DCS were able to reduce FosB/?FosB protein expression, a molecular switch for cocaine-seeking behaviour. We observed an overall lower number of FosB/?FosB positive cells in 5-HTT-/- ventromedial prefrontal cortex and amygdala and an overall effect of DCS treatment on the number of positive cells in the nucleus accumbens. In conclusion, in this study, we show that the dosing of DCS to facilitate the extinction of cocaine-seeking behaviour is, at least partially, determined by 5 HTT genotype. PMID- 27957786 TI - Impaired intention-to-treat survival after listing for liver transplantation in children with biliary atresia compared to other chronic liver diseases: 20 years' experience from the Nordic countries. AB - Biliary atresia (BA) is the most common indication for LT in children. We investigated whether this diagnosis per se, compared to other chronic liver diseases (OCLD), had an influence on patient survival. Data from 421 Scandinavian children, 194 with BA and 227 with OCLD, listed for LT between 1990 and 2010 were analyzed. The intention-to-treat survival and influencing risk factors were studied. Patients with BA had higher risk of death after listing than patients with OCLD. The youngest (<1 year) and smallest (<10 kg) children with the highest bilirubin (>510 MUmol/L), highest INR (>1.6), and highest PELD score (>20) listed during 1990s had the worst outcome. Given the same PELD score, patients with BA had higher risk of death than patients with OCLD. For adolescents, low weight/BMI was the only prognostic marker. Impaired intention-to-treat survival in patients with BA was mainly explained by more advanced liver disease in younger ages and higher proportion of young children in the BA group rather than diagnosis per se. PELD score predicted death, but seemed to underestimate the severity of liver disease in patients with BA. Poor nutritional status and severe cholestasis had negative impact on survival, supporting the "sickest children first" allocation policy and correction of malnutrition before surgery. PMID- 27957785 TI - A thymidylate synthase polymorphism is associated with increased risk for bone toxicity among children treated for acute lymphoblastic leukemia. AB - BACKGROUND: Bone fractures and osteonecrosis frequently complicate therapy for childhood acute lymphoblastic leukemia (ALL). Bone toxicity has been associated with exposure to corticosteroids and methotrexate (MTX) and age greater than 10 years. We tested whether common genetic polymorphisms were associated with bone toxicity during treatment for ALL. PROCEDURE: A total of 615 of 794 children enrolled on Dana Farber Cancer Institute ALL Consortium protocol 05-001 (NCT00400946) met eligibility criteria for inclusion in this analysis. Nineteen candidate polymorphisms were selected a priori, targeting genes related to glucocorticoid metabolism, oxidative damage, and folate physiology. Polymorphisms were genotyped using either PCR-based allelic discrimination or PCR product length analysis. RESULTS: Twenty percent of subjects were homozygous for two 28 bp repeats (2R/2R, where 2R is two 28-nucleotide repeats within the 5' untranslated region [UTR] of the thymidylate synthase [TS] gene) within the 5' UTR of the gene for TS. This 2R/2R genotype was associated with increased risk of osteonecrosis among children younger than 10 years at diagnosis (multivariable hazard ratio [HR] 2.71; 95% confidence interval [CI] 1.23-5.95; P = 0.013), and with bone fracture among children >= 10 years (multivariable HR 2.10; 95% CI 1.11 3.96; P = 0.022). No significant association was observed between TS genotype and red blood cell (RBC) folate, RBC MTX, or relapse risk. CONCLUSIONS: A common genetic variant is associated with increased risk of osteonecrosis among children younger than 10 years at diagnosis and with bone fractures among older children. These findings suggest that children and adolescents with the 2R/2R TS genotype should be closely monitored for the development of bone toxicity during therapy for ALL, and support a clinical trial testing the efficacy of protective interventions specifically in this vulnerable population. PMID- 27957788 TI - Surgical management of children with intractable functional constipation; experience of a single tertiary children's hospital. AB - BACKGROUND: Children with intractable functional constipation (FC) may eventually require surgery. However, guidelines regarding the surgical management of children with intractable FC are lacking. The aim of this study was to describe the surgical management of FC in children. METHODS: A retrospective chart review was performed of children with FC (according to the Rome III criteria) who underwent ileostomy, colostomy or (sub)total colectomy at a tertiary hospital. Treatment success was defined as no longer fulfilling the Rome III-FC-criteria or having a functional ostomy. In addition, a self-developed questionnaire was administered to parents by telephone to assess postsurgical satisfaction (yes-no question and rated on a scale of 1-10). KEY RESULTS: Thirty-seven patients (68% female) were included; median age at first surgery was 12 years (range 1.6-17.6). The initial surgical procedure consisted of ileostomy (n=21), colostomy (n=10), sigmoid resection (n=5) and subtotal colectomy (n=1). Success criteria were fulfilled by 85% of the patients. Postsurgical satisfaction of parents was 91% with a median postoperative satisfaction score of 8 (range 2-10), and 97% would opt for the same procedure(s) if necessary. Thirty patients (81%) experienced stoma problems, with 12 patients (32%) requiring stoma-revisions. Other complications occurred in 16 patients (43%). CONCLUSIONS & INFERENCES: Surgery can improve symptoms in children with intractable FC. Despite morbidity and complications, parental satisfaction is high. Prospective, high-quality research is necessary to develop guidelines for the diagnostic work-up and surgical management in children with intractable FC. PMID- 27957787 TI - Macrophage polarization: a key event in the secondary phase of acute spinal cord injury. AB - Acute spinal cord injury (SCI) has become epidemic in modern society. Despite advances made in the understanding of the pathogenesis and improvements in early recognition and treatment, it remains a devastating event, often producing severe and permanent disability. SCI has two phases: acute and secondary. Although the acute phase is marked by severe local and systemic events such as tissue contusion, ischaemia, haemorrhage and vascular damage, the outcome of SCI are mainly influenced by the secondary phase. SCI causes inflammatory responses through the activation of innate immune responses that contribute to secondary injury, in which polarization-based macrophage activation is a hallmarker. Macrophages accumulated within the epicentre and the haematoma of the injured spinal cord play a significant role in this inflammation. Depending on their phenotype and activation status, macrophages may initiate secondary injury mechanisms and/or promote CNS regeneration and repair. When it comes to therapies for SCI, very few can be performed in the acute phase. However, as macrophage activation and polarization switch are exquisitely sensitive to changes in microenvironment, some trials have been conducted to modulate macrophage polarization towards benefiting the recovery of SCI. Given this, it is important to understand how macrophages and SCI interrelate and interact on a molecular pathophysiological level. This review provides a comprehensive overview of the immuno-pathophysiological features of acute SCI mainly from the following perspectives: (i) the overview of the pathophysiology of acute SCI, (ii) the roles of macrophage, especially its polarization switch in acute SCI, and (iii) newly developed neuroprotective therapies modulating macrophage polarization in acute SCI. PMID- 27957789 TI - Real-world outcomes of treatment for acute lymphoblastic leukemia during adolescence in a financially restricted environment: Results at a single center in Latin America. AB - OBJECTIVE: There is a paucity of the studies of adolescents with acute lymphoblastic leukemia (ALL). This is more noticeable in low- and middle-income countries. The international 5-year event-free survival (EFS) and overall survival (OS) for this age group is around 80%, with pediatric-inspired protocols offering better results. METHODS: A retrospective analysis of adolescents aged 16 20 diagnosed with ALL during the period 2004-2015 treated with a high-risk pediatric protocol at an academic center from a middle-income country was performed. Five-year OS and EFS were estimated by the Kaplan-Meier analysis. Hazard ratios of relapse and death were estimated by the Cox regression model. RESULTS: Five-year EFS and OS for 57 adolescents were 23.3% and 48.9%, respectively. From the 41 patients who achieved complete remission, 24 (58.5%) relapsed. Bone marrow and central nervous system were the most frequent sites of relapse. Hazard ratio of treatment failure and death for patients with organomegaly at diagnosis was 2.026 and 2.970, respectively. Treatment-related toxicity developed in 31 (54.4%) patients and febrile neutropenia was the most frequent in 14 (24.6%) cases. Twelve patients (21.1%) had poor adherence to treatment. CONCLUSIONS: High relapse rate and low 5-year EFS compared with international standards, was documented. Use of intensified pediatric regimens, adherence to proven effective medications, improved supportive care, and prevention of abandonment are necessary to improve survival rates in these patients. PMID- 27957791 TI - Development of a Novel Index for Analysis of Electronically Excited States. AB - Concerning the major factors in the context of excited states analyses, namely charge centroids of the orbitals involved in the excitations, the distance between orbital centroids, and overlap integrals, a new metric-the Omega index-is proposed to assign the character and optical properties of electronically excited states. Using several molecules from different classes and also a well-studied standard database for time-dependent density functional theory (TD-DFT) studies as benchmark criteria, accountability of the developed index is numerically assessed for local, charge transfer, and Rydberg excitations. It is shown that the nature of excited states can be discriminated using the Omega index, where its superior performance for those situations in which the previous descriptors were not helpful is also unveiled. Relationships are also examined between the Omega index and optical properties of some molecules under study in the framework of the sum-over-state approach. It is observed that there are correlations between the proposed index and computed hyperpolarizabilities based on the sum over-state scheme. These findings offer the possibility of estimating excited state properties of large systems from simple descriptors without explicitly performing calculations of high-order response functions. PMID- 27957790 TI - Transcranial Doppler in hemoglobin SC disease. AB - BACKGROUND: Stroke is a severe clinical disorder in sickle cell disease (SCD), and few studies have evaluated transcranial Doppler (TCD) flow velocities in hemoglobin SC disease (HbSC). The guidelines for stroke risk are based on evaluations in sickle cell anemia (SCA) or HbS/beta thalassemia. PROCEDURE: In this study, we compare cerebral blood flow in patients with SCD stratified by genotypes. A total of 1,664 pediatric patients with SCD underwent TCD velocity screening, and the time-averaged maximum mean velocity (TAMM) was determined in the middle cerebral artery (MCA), anterior cerebral artery (ACA), and distal intracranial internal carotid artery (ICA). RESULTS: Abnormal velocities were not identified in the ACA; therefore, we only use ICA and MCA velocities. TAMM from the left and right in the ICA and MCA was 134.3 +/- 32.0 and 134.4 +/- 32.6 cm/s in patients with SCA, and 105.2 +/- 20.6 and 104.7 +/- 20.0 cm/s in the patients with HbSC, respectively. Mean TAMM between right and left ICA/MCA was 134.5 +/- 30.5 cm/s in the SCA group, and 104.9 +/- 19.3 cm/s in the HbSC group. Notably, our data show that TCD velocities were significantly lower among the patients with HbSC compared to SCA. TAMM was negatively correlated with hemoglobin and hematocrit in both genotypes. CONCLUSION: These results suggest that a different cut-off value for abnormal TCD velocities could be considered for patients with HbSC. Additional studies are warranted to determine the actual risk of stroke in HbSC genotype associated with this possible TCD risk value. PMID- 27957792 TI - Gender difference in oxidative stress: a new look at the mechanisms for cardiovascular diseases. AB - Gender differences are present in many diseases and are especially prevalent in cardiovascular disease. Males tend to suffer from myocardial infarctions earlier than females, and a woman's risk of cardiovascular disease increases after menopause, suggesting a cardio-protective role of estrogen. However, hormone replacement therapy did not decrease the risk of cardiovascular disease in post menopausal women; thus, other mechanisms may be involved besides estrogen. Oxidative stress plays an important role in the development of cardiovascular diseases such as coronary artery disease. Gender is also associated with differences in oxidative stress. Under physiological conditions, females appear to be less susceptible to oxidative stress. This may be due to the antioxidant properties of estrogen, gender differences in NADPH-oxidase activity or other mechanism(s) yet to be defined. This review strives to discuss gender differences in general terms followed by a more detailed examination of gender differences with oxidative stress and various associated diseases and the possible mechanisms underlying these differences. PMID- 27957793 TI - Vascular endothelial growth factor-D modulates oxidant-antioxidant balance of human vascular endothelial cells. AB - Vascular endothelial growth factor-D (VEGF-D) is an angiogenic and lymphangiogenic glycoprotein that facilitates tumour growth and distant organ metastasis. Our previous studies showed that VEGF-D stimulates the expression of proteins involved in cell-matrix interactions and promoting the migration of endothelial cells. In this study, we focused on the redox homoeostasis of endothelial cells, which is significantly altered in the process of tumour angiogenesis. Our analysis revealed up-regulated expression of proteins that form the antioxidant barrier of the cell in VEGF-D-treated human umbilical endothelial cells and increased production of reactive oxygen and nitrogen species in addition to a transient elevation in the total thiol group content. Despite a lack of changes in the total antioxidant capacity, modification of the antioxidant barrier induced by VEGF-D was sufficient to protect cells against the oxidative stress caused by hypochlorite and paraquat. These results suggest that exogenous stimulation of endothelial cells with VEGF-D induces an antioxidant response of cells that maintains the redox balance. Additionally, VEGF-D-induced changes in serine/threonine kinase mTOR shuttling between the cytosol and nucleus and its increased phosphorylation at Ser-2448, lead us to the conclusion that the observed shift in redox balance is regulated via mTOR kinase signalling. PMID- 27957794 TI - BRD7 mediates hyperglycaemia-induced myocardial apoptosis via endoplasmic reticulum stress signalling pathway. AB - Bromodomain-containing protein 7 (BRD7) is a tumour suppressor that is known to regulate many pathological processes including cell growth, apoptosis and cell cycle. Endoplasmic reticulum (ER) stress-induced apoptosis plays a key role in diabetic cardiomyopathy (DCM). However, the molecular mechanism of hyperglycaemia induced myocardial apoptosis is still unclear. We intended to determine the role of BRD7 in high glucose (HG)-induced apoptosis of cardiomyocytes. In vivo, we established a type 1 diabetic rat model by injecting a high-dose streptozotocin (STZ), and lentivirus-mediated short hairpin RNA (shRNA) was used to inhibit BRD7 expression. Rats with DCM exhibited severe myocardial remodelling, fibrosis, left ventricular dysfunction and myocardial apoptosis. The expression of BRD7 was up regulated in the heart of diabetic rats, and inhibition of BRD7 had beneficial effects against diabetes-induced heart damage. In vitro, H9c2 cardiomyoblasts was used to investigate the mechanism of BRD7 in HG-induced apoptosis. Treating H9c2 cardiomyoblasts with HG elevated the level of BRD7 via activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and increased ER stress induced apoptosis by detecting spliced/active X-box binding protein 1 (XBP-1s) and C/EBP homologous protein (CHOP). Furthermore, down-regulation of BRD7 attenuated HG-induced expression of CHOP via inhibiting nuclear translocation of XBP-1s without affecting the total expression of XBP-1s. In conclusion, inhibition of BRD7 appeared to protect against hyperglycaemia-induced cardiomyocyte apoptosis by inhibiting ER stress signalling pathway. PMID- 27957796 TI - Involvement of AMPK in regulating the degradation of MAD2B under high glucose in neuronal cells. AB - Although our recent study has demonstrated that mitotic spindle assembly checkpoint protein (MAD2B) mediates high glucose-induced neuronal apoptosis, the mechanisms for MAD2B degradation under hyperglycaemia have not yet been elucidated. In this study, we first found that the activation of adenosine 5' monophosphate (AMP)-activated protein kinase (AMPK) was decreased in neurons, accompanied with the increased expression of MAD2B. Mechanistically, we demonstrated that activation of AMPK with its activators such as AICAR and metformin decreased the expression of MAD2B, indicating a role of AMPK in regulating the expression of MAD2B. Moreover, activation of AMPK prevented neuronal cells from high glucose-induced injury as demonstrated by the reduced expression of cyclin B1 and percentage of apoptosis as detected by TUNEL. We further found that when total protein synthesis was suppressed by chlorhexidine, the degradation of MAD2B was slower in high glucose-treated neurons and was mainly dependent on the ubiquitin-proteasome system. Finally, it was indicated that high glucose inhibited the ubiquitination of MAD2B, which could be reversed by activation of AMPK. Collectively, this study demonstrates that AMPK acts as a key regulator of MAD2B expression, suggesting that activation of AMPK signalling might be crucial for the treatment of high glucose-induced neuronal injury. PMID- 27957795 TI - Refining anti-inflammatory therapy strategies for bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD) is a severe lung disease of preterm infants, which is characterized by fewer, enlarged alveoli and increased inflammation. BPD has grave consequences for affected infants, but no effective and safe therapy exists. We previously showed that prophylactic treatment with interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD induced by perinatal inflammation and hyperoxia. Here, we used the same BPD model to assess whether an alternative anti-inflammatory agent, protein C (PC), is as effective as IL-1Ra against BPD. We also tested whether delayed administration or a higher dose of IL 1Ra affects its ability to ameliorate BPD and investigated aspects of drug safety. Pups were reared in room air (21% O2 ) or hyperoxia (65% or 85% O2 ) and received daily injections with vehicle, 1200 IU/kg PC, 10 mg/kg IL-1Ra (early or late onset) or 100 mg/kg IL-1Ra. After 3 or 28 days, lung and brain histology were assessed and pulmonary cytokines were analysed using ELISA and cytokine arrays. We found that PC only moderately reduced the severe impact of BPD on lung structure (e.g. 18% increased alveolar number by PC versus 34% by IL-1Ra); however, PC significantly reduced IL-1beta, IL-1Ra, IL-6 and macrophage inflammatory protein (MIP)-2 by up to 89%. IL-1Ra at 10 mg/kg prevented BPD more effectively than 100 mg/kg IL-1Ra, but only if treatment commenced at day 1 of life. We conclude that prophylactic low-dose IL-1Ra and PC ameliorate BPD and have potential as the first remedy for one of the most devastating diseases preterm babies face. PMID- 27957797 TI - Increased corneal sub-basal nerve density in patients with Sjogren syndrome treated with topical cyclosporine A. AB - BACKGROUND: To evaluate quantitative and qualitative changes in sub-basal corneal nerves (SBN) via in vivo confocal microscopy in patients with Sjogren syndrome dry eye (SSDE) treated with topical cyclosporine A (CsA). DESIGN: Prospective, observational, non-randomized study. PARTICIPANTS: Thirty eyes of 30 patients with SSDE refractory to conventional treatment treated with CsA 0.05% twice daily for 6 months. Fifteen eyes of 15 healthy, age and gender matched, volunteers constituted the control group at baseline. METHODS: A clinical evaluation of dry eye, corneal sensation using Cochet-Bonnet esthesiometry and in vivo confocal microscopy analysis of the central cornea were performed prospectively at baseline for all patients, and after 6 months of treatment with CsA. MAIN OUTCOME MEASURES: Density, number, reflectivity and tortuosity of SBN, dendritic cell (DC) density, esthesiometry, and dry eye signs and symptoms. RESULTS: Topical CsA 0.05% improved clinical signs and symptoms, and increased corneal sensitivity. Following treatment, SBN density was significantly increased (P < 0.0001) associated with a decreased in DC density (P < 0.0001). The increase in SBN density after treatment was positively correlated with baseline SBN density (R2 = 0.33; P = 0.0008) and negatively correlated with baseline Ocular Surface Disease Index (R2 = 0.28; P = 0.002), Oxford score (R2 = 0.31; P = 0.002), and DC density (R2 = 0.37; P = 0.0003). CONCLUSIONS: Topical CsA led to an increase in corneal SBN density, improving clinical signs and symptoms of SSDE. Our results also suggest an improved response to treatment in patients with less initial nerve damage. PMID- 27957798 TI - Evaluation of the need for chest X-rays in the management of asymptomatic, intraluminal vascular access device occlusion in childhood cancer. AB - BACKGROUND: Venous access device (VAD) occlusion from intraluminal thrombus is a common complication during childhood cancer treatment. Current practice at many institutions is to assess VAD position with a chest X-ray (CXR) prior to intraluminal administration of tissue plasminogen activator (tPA). We aimed to determine the utility of this practice. PROCEDURE: A retrospective chart review of children with newly diagnosed cancer with a VAD, treated at The Hospital for Sick Children between 2010 and 2011, was performed. Episodes of line occlusion were identified both by reviewing patient CXRs for indication and identifying tPA doses dispensed. These episodes were reviewed to determine whether CXR findings resulted in management other than tPA. Cases in which the X-ray resulted in a change in management were further reviewed to determine whether administration of tPA could have resulted in potential patient harm. RESULTS: A total of 330 patients with newly diagnosed cancer with VADs were identified. Eighty-five (25.8%) patients experienced 123 episodes of VAD occlusion. VAD occlusions occurred more frequently in patients with tunneled external central venous lines (16/39, 41.5%) and peripherally inserted central catheters (PICC) (27/73, 37.0%) versus PORT (42/216, 19.4%; P = 0.001). There were nine (8.1%) episodes of VAD occlusion evaluated with a CXR in which the findings led to a change in management other than administering tPA. In each case, multiple specialists independently concluded that administration of tPA would have been unlikely to cause patient harm. CONCLUSION: Routine CXRs prior to the administration of tPA for asymptomatic VAD occlusion can safely be omitted. PMID- 27957799 TI - Outcome and prognostic factors in high-risk childhood adrenocortical carcinomas: A report from the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT). AB - OBJECTIVES: The aim of this retrospective international analysis was to evaluate the role of risk factors in pediatric patients with adrenocortical carcinoma (ACC) observed in European countries (2000-2013) in an attempt to identify factors associated with poor prognosis. PROCEDURES: Data were retrieved from databases of Germany, France, Poland, and Italy, which form the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT). Patients were less than 18 years old, with at least one of the following tumor-related risk factors: metastases, volume more than 200 cm3 , Cushing syndrome, vascular or regional lymph node invasion, initial biopsy, or incomplete excision. Role of patients' age was also evaluated. RESULTS: Eighty-two patients were evaluated: 62 with localized disease and 20 with metastases. The 3-year progression-free survival (PFS) and overall survival (OS) were 39% and 55% for the whole population, respectively, and 51% and 73% for localized diseases, respectively. Concerning the whole population, PFS and OS were influenced by distant metastases, tumor volume, lymph node involvement, age, and presence of two or more risk factors. Factors significant only at OS were vascular involvement and incomplete surgery. At multivariable analysis, the main factors at PFS were volume more than 200 cm3 (hazard ratio [HR]: 2.6, 95% confidence interval [CI]: 1.18-5.70) and presence of distant metastases (HR: 8.26, 95% CI: 3.49-19.51). The OS was significantly influenced by the presence of metastases (P < 0.0001). Concerning patients with localized tumors, the only significant prognostic factor was volume more than 200 cm3 with a HR of 4.38 (95% CI: 1.60-12.00) for PFS and of 3.68 (95% CI: 1.02 13.30) for OS. CONCLUSIONS: Distant metastases and large tumor volume were the main unfavorable prognostic factors. Presence of two or more factors related to ACC was associated with an aggressive behavior of disease. PMID- 27957800 TI - CARD9 gene silencing with siRNA protects rats against severe acute pancreatitis: CARD9-dependent NF-kappaB and P38MAPKs pathway. AB - We previously reported the up-regulation of caspase recruitment domain 9 (CARD9) expressions in severe acute pancreatitis (SAP) patients, but little is known about its regulation. In this study, small interfering RNA (siRNA) was used to reduce the levels of CARD9 expression in sodium taurocholate-stimulated SAP rats. CARD9 was overexpressed in SAP rats, which correlated with the severity of pancreatitis. When compared to the untreated group, the cohort that received the siRNA treatment demonstrated a significant reduction in pancreatic injury, neutrophil infiltration, myeloperoxidase activity and pro-inflammatory cytokines. Furthermore, siRNAs showed that the reduction of CARD9 in SAP rats down-regulated the expression of NF-kappaBp65 and P38MAPK which are involved in the transcription and release of a wide variety of inflammatory cytokines. These findings provide evidence that CARD9 is up-regulated in SAP rats and acts as a potential therapeutic target for the treatment thereof. Blocking the activation of NF-kappaB and P38MAPK via siRNA-mediated gene knock-down of CARD9 appears to reduce the inflammatory response in pancreatic tissue. PMID- 27957801 TI - Genomic characterization of pediatric B-lymphoblastic lymphoma and B lymphoblastic leukemia using formalin-fixed tissues. AB - BACKGROUND: Recurrent genomic changes in B-lymphoblastic leukemia (B-ALL) identified by genome-wide single-nucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, B-lymphoblastic lymphoma (B-LBL), is limited by the low incidence and lack of fresh tissue for genomic testing. PROCEDURE: We used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalin-fixed paraffin-embedded pediatric B-LBL (n = 23) and B-ALL (n = 55). RESULTS: Similar to B-ALL, CDKN2A/B deletions were the most common alteration identified in 6/23 (26%) B-LBL cases. Eleven of 23 (48%) B-LBL patients were hyperdiploid, but none showed triple trisomies (chromosomes 4, 10, and 17) characteristic of B-ALL. IKZF1 and PAX5 deletions were observed in 13 and 17% of B-LBL, respectively, which was similar to the reported frequency in B-ALL. Immunoglobulin light chain lambda (IGL) locus deletions consistent with normal light chain rearrangement were observed in 5/23 (22%) B-LBL cases, compared with only 1% in B-ALL samples. None of the B-LBL cases showed abnormal, isolated VPREB1 deletion adjacent to IGL locus, which we identified in 25% of B-ALL. CONCLUSIONS: Our study demonstrates that the copy number profile of B-LBL is distinct from B-ALL, suggesting possible differences in pathogenesis between these closely related diseases. PMID- 27957802 TI - Drug-Loaded Mesoporous Tantalum Oxide Nanoparticles for Enhanced Synergetic Chemoradiotherapy with Reduced Systemic Toxicity. AB - Combining chemotherapy and radiotherapy (chemoradiotherapy) has been widely applied in many clinical practices, showing promises in enhancing therapeutic outcomes. Nontoxic nanocarriers that not only are able to deliver chemotherapeutics into tumors, but could also act as radiosensitizers to enhance radiotherapy would thus be of great interest in the development of chemoradiotherapies. To achieve this aim, herein mesoporous tantalum oxide (mTa2 O5 ) nanoparticles with polyethylene glycol (PEG) modification are fabricated. Those mTa2 O5 -PEG nanoparticles could serve as a drug delivery vehicle to allow efficient loading of chemotherapeutics such as doxorubicin (DOX), whose release appears to be pH responsive. Meanwhile, owing to the interaction of Ta with X ray, mTa2 O5 -PEG nanoparticles could offer an intrinsic radiosensitization effect to increase X-ray-induced DNA damages during radiotherapy. As a result, DOX-loaded mTa2 O5 -PEG (mTa2 O5 -PEG/DOX) nanoparticles can offer a strong synergistic therapeutic effect during the combined chemoradiotherapy. Furthermore, in chemoradiotherapy, such mTa2 O5 -PEG/DOX shows remarkably reduced side effects compared to free DOX, which at the same dose appears to be lethal to animals. This work thus presents a new type of mesoporous nanocarrier particularly useful for the delivery of safe and effective chemoradiotherapy. PMID- 27957803 TI - Enhancement of Ferromagnetism in Nonmagnetic Metal Oxide Nanoparticles by Facet Engineering. AB - Ferromagnetism in semiconducting metal oxide nanoparticles has been intensively investigated due to their potential applications in spintronics, information storage, and biomedicine. Ferromagnetism can be produced in nonmagnetic metal oxide nanoparticles by a variety of methods or factors, but the saturated magnetization is typically of the order of 10-4 emu g-1 and too small to be useful in practice. In this work, it is demonstrated theoretically and experimentally that stronger ferromagnetism can be achieved in undoped nonmagnetic metal oxide semiconductors by exposing some specific polar crystal facets with carvings of special bonds via the interaction with underlying vacancies. In2 O3 microcubes with completely enclosed {001} polar facets show two orders of magnitude enhancement at room temperature compared to nanoparticles with an irregular morphology. The surface magnetic domains on the {001} facets account for the significantly enhanced ferromagnetism. The technique and concept described here can be extended to other types of metal oxide nanostructures to spur their application to spintronics. PMID- 27957804 TI - In-depth characterization of the tomato fruit pericarp proteome. AB - Since the genome of Solanum lycopersicum L. was published in 2012, some studies have explored its proteome although with a limited depth. In this work, we present an extended characterization of the proteome of the tomato pericarp at its ripe red stage. Fractionation of tryptic peptides generated from pericarp proteins by off-line high-pH reverse-phase phase chromatography in combination with LC-MS/MS analysis on a Fisher Scientific Q Exactive and a Sciex Triple-TOF 6600 resulted in the identification of 8588 proteins with a 1% FDR both at the peptide and protein levels. Proteins were mapped through GO and KEGG databases and a large number of the identified proteins were associated with cytoplasmic organelles and metabolic pathways categories. These results constitute one of the most extensive proteome datasets of tomato so far and provide an experimental confirmation of the existence of a high number of theoretically predicted proteins. All MS data are available in the ProteomeXchange repository with the dataset identifiers PXD004947 and PXD004932. PMID- 27957805 TI - Systematic functional analysis of the Ras GTPase family unveils a conserved network required for anterograde protein trafficking. AB - Phylogeny is often used to compare entire families of genes/proteins. We previously showed that classification of Caenorhabditis elegans Rho GTPases on the basis of their enzymatic properties was significantly different from sequence alignments. To further develop this concept, we have developed an integrated approach to classify C. elegans small GTPases based on functional data comprising affinity for GTP, sub-cellular localization, tissue distribution and silencing impact. This analysis led to establish a novel functional classification for small GTPases. To test the relevance of this classification in mammals, we focused our attention on the human orthologs of small GTPases from a specific group comprising arf-1.2, evl-20, arl-1, Y54E10BR.2, unc-108 and rab-7. We then tested their involvement in protein secretion and membrane traffic in mammalian systems. Using this approach we identify a novel network containing 18 GTPases, and 23 functionally interacting proteins, conserved between C. elegans and mammals, which is involved in membrane traffic and protein secretion. PMID- 27957806 TI - Allogenic human serum, a clinical grade serum supplement for promoting human periodontal ligament stem cell expansion. AB - Exposing human periodontal ligament stem cells (hPDLSCs) to animal proteins during cell expansion would compromise quality and safety of the hPDLSCs for clinical applications. The current study aimed to evaluate the replacement of animal-based serum by human serum for the expansion of hPDLSCs. hPDLSCs were cultured in culture media supplemented with four types of serums: Group A: fetal bovine serum (FBS); Group B: allogeneic human male AB serum (HS); Group C: in house autologous (Auto-HS); and Group D: in-house allogeneic human serums (Allo HS). Exhibitions of mesenchymal stem cell characteristics of hPDLSCs were examined. Then, growth and osteogenic (OS) differentiation potential of hPDLSCs in FBS and HS at passages 5 and 15 were compared to investigate the effects of serum supplements on growth and expansion stability of the expanded hPDLSCs. After that, growth and OS differentiation of hPDLSCs in Auto- and Allo-HS were investigated. Flow cytometrical analyses, functional differentiations, cell growth kinetic, cytogenetic analysis, alkaline phosphatase and calcium content assays, and oil red O and von Kossa staining were performed. Results showed that at passage 5, HS promoted growth and OS differentiation of hPDLSCs and extensive cell expansion, decreased growth and differentiation potential of the expanded hPDLSCs, particularly in HS. Growth and OS differentiation of hPDLSCs in Auto-HS and Allo-HS were not different. In summary, allogeneic human serum could be a replacement to FBS for hPDLSC expansion. In vitro cell expansion of hPDLSCs should be minimal to ensure optimal cell quality. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27957807 TI - Sequential hydrophile and lipophile solubilization as an efficient method for decellularization of porcine aortic valve leaflets: Structure, mechanical property and biocompatibility study. AB - Antigenicity of xenogeneic tissues is the major obstacle to increased use of these materials in clinical medicine. Residual xenoantigens in decellularized tissue elicit the immune response after implantation, causing graft failure. With this in mind, the potential use is proposed of three protein solubilization-based protocols for porcine aortic valve leaflets decellularization. It was demonstrated that hydrophile solubilization alone achieved incomplete decellularization; lipophile solubilization alone (LSA) completely removed all cells and two most critical xenoantigens - galactose-alpha(1,3)-galactose (alpha Gal) and major histocompatibility complex I (MHC I) - but caused severe alterations of the structure and mechanical properties; sequential hydrophile and lipophile solubilization (SHLS) resulted in a complete removal of cells, alpha Gal and MHC I, and good preservation of the structure and mechanical properties. In contrast, a previously reported method using Triton X-100, sodium deoxycholate and IGEPAL CA-630 resulted in a complete removal of all cells and MHC I, but with remaining alpha-Gal epitope. LSA- and SHLS-treated leaflets showed significantly reduced leucocyte activation (polymorphonuclear elastase) upon interaction with human blood in vitro. When implanted subdermally in rats for 6 weeks, LSA- or SHLS-treated leaflets were presented with more biocompatible implants and all four decellularized leaflets were highly resistant to calcification. These findings illustrate that the SHLS protocol could be considered as a promising decellularization method for the decellularization of xenogeneic tissues in tissue engineering and regenerative medicine. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27957808 TI - GRAIN INCOMPLETE FILLING 2 regulates grain filling and starch synthesis during rice caryopsis development. AB - Rice grain filling determines grain weight, final yield and grain quality. Here, a rice defective grain filling mutant, gif2, was identified. Grains of gif2 showed a slower filling rate and a significant lower final grain weight and yield compared to wild-type. The starch content in gif2 was noticeably decreased and its physicochemical properties were also altered. Moreover, gif2 endosperm cells showed obvious defects in compound granule formation. Positional cloning identified GIF2 to encode an ADP-glucose pyrophosphorylase (AGP) large subunit, AGPL2; consequently, AGP enzyme activity in gif2 endosperms was remarkably decreased. GIF2 is mainly expressed in developing grains and the coded protein localizes in the cytosol. Yeast two hybrid assay showed that GIF2 interacted with AGP small subunits OsAGPS1, OsAGPS2a and OsAGPS2b. Transcript levels for granule bound starch synthase, starch synthase, starch branching enzyme and starch debranching enzyme were distinctly elevated in gif2 grains. In addition, the level of nucleotide diversity of the GIF2 locus was extremely low in both cultivated and wild rice. All of these results suggest that GIF2 plays important roles in the regulation of grain filling and starch biosynthesis during caryopsis development, and that it has been preserved during selection throughout domestication of modern rice. PMID- 27957809 TI - Fitness consequences of altering floral circadian oscillations for Nicotiana attenuata. AB - Ecological interactions between flowers and pollinators are all about timing. Flower opening/closing and scent emissions are largely synchronized with pollinator activity, and a circadian clock regulates these rhythms. However, whether the circadian clock increases a plant's reproductive success by regulating these floral rhythms remains untested. Flowers of Nicotiana attenuata, a wild tobacco, diurnally and rhythmically open, emit scent and move vertically through a 140 degrees arc to interact with nocturnal hawkmoths. We tethered flowers to evaluate the importance of flower positions for Manduca sexta-mediated pollinations; flower position dramatically influenced pollination. We examined the pollination success of phase-shifted flowers, silenced in circadian clock genes, NaZTL, NaLHY, and NaTOC1, by RNAi. Circadian rhythms in N. attenuata flowers are responsible for altered seed set from outcrossed pollen. PMID- 27957810 TI - Self-Propelled Soft Protein Microtubes with a Pt Nanoparticle Interior Surface. AB - Human serum albumin (HSA) microtubes with an interior surface composed of Pt nanoparticles (PtNPs) are self-propelled in aqueous H2 O2 medium. They can capture cyanine dye and Escherichia coli (E. coli) efficiently. Microtubes were prepared by wet templating synthesis by using a track-etched polycarbonate (PC) membrane with alternate filtrations of aqueous HSA, poly-l-arginine (PLA), and citrate-PtNPs. Subsequent dissolution of the PC template yielded uniform hollow cylinders made of (PLA/HSA)8 PLA/PtNP stacking layers (1.16+/-0.02 MUm outer diameter, ca. 23 MUm length). In aqueous H2 O2 media, the soft protein microtubes are self-propelled by jetting O2 bubbles from the open-end terminus. The effects of H2 O2 and surfactant concentrations on the velocity were investigated. The swimming microtube captured cyanine dye in the HSA component of the wall. Addition of an intermediate gamma-Fe3 O4 layer allowed manipulation of the direction of movement of the tubule by using a magnetic field. Because the exterior surface is positively charged, the bubble-propelled microtubes adsorbed E. coli with high efficiency. The removal ratio of E. coli by a single treatment reached 99 %. PMID- 27957811 TI - Sensitivity enhancing injection from a sample reservoir and channel interface in microchip electrophoresis. AB - The stacking of a cationic analyte (i.e., rhodamine B) at the interface between a sample reservoir and channel in a microchip electrophoresis device is described for the first time. Stacking at negative polarity was by micelle to solvent stacking where the dye was prepared in a micellar solution (5 mM sodium dodecyl sulfate in 25 mM phosphoric acid, pH 2.5) and the channel was filled with high methanol content background solution (70% methanol in 50 mM phosphoric acid, pH 2.5). The injection of the stacked dye into the channel was by simple reversal of the voltage polarity with the sample solution and background solution at the anodic and cathodic reservoirs of the straight channel, respectively. The enrichment of rhodamine B at the interface and injection of the stacked dye into the channel was clearly visualized using an inverted fluorescence microscope. A notable sensitivity enhancement factor of up to 150 was achieved after 2 min at 1 kV of micelle to solvent stacking. The proposed technique will be useful as a concentration step for analyte mixtures in simple and classical cross-channel microchip electrophoresis devices or for the controlled delivery of enriched reagents or analytes as narrow plugs in advanced microchip electrophoresis devices. PMID- 27957813 TI - Neurocognitive functioning in adults with congenital heart disease. AB - OBJECTIVE: Adults with congenital heart disease (CHD) are at increased risk of psychological disorders and cognitive deficiencies due to structural/acquired neurological abnormalities and neurodevelopmental disorders as children. However, limited information is known about the neuropsychological functioning of adults with CHD. This study screened neuropsychological abilities and explored group differences related to cardiac disease severity and neurological risk factors in adults with CHD. DESIGN: Participants completed brief neuropsychological testing. Information about neurobehavioral and psychological symptoms, employment, education, and disability were also collected from the patient and a family member. RESULTS: Forty-eight participants with adult CHD completed neuropsychological testing. Visuospatial skills and working memory were worse than expected compared to the typical population. Frequency of neurological comorbidities (e.g., stroke, seizures) was higher in those with more severe heart disease (e.g., single ventricle or cyanotic disease), and executive functioning was weaker in those with neurological comorbidities. Those with more severe heart disease were more likely to be unemployed and to receive disability benefits, but educational attainment did not differ. Those who received disability performed worse on tasks of executive functioning. CONCLUSIONS: Findings suggest concerns about neuropsychological functioning that need to be more comprehensively assessed in adults with CHD. Understanding the cognitive limitations of this aging population can help guide access to resources, transition of care, and medical care engagement, thus improving quality of care and quality of life. PMID- 27957812 TI - Interrelationships among mediators of cellular zinc homeostasis in healthy and type 2 diabetes mellitus populations. AB - SCOPE: The involvement of zinc in multiple physiological systems requires tight control of cellular zinc concentration. This study aims to explore the relationships among selected mediators of cellular zinc homeostasis in an apparently healthy (AH) population and a cohort with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: Baseline data of three trials forming two cohorts, AH (n = 70) and T2DM (n = 42), were used for multivariate analyses to identify groupings within ten zinc transporter and metallothionein (MT) gene expressions, stratified by health status. Multiple regression models were used to explore relationships among zinc transporter/MT groupings and plasma zinc. Gene expression of zinc transporters and MTs, with the exception of ZnT6, were significantly lower in the T2DM cohort (p < 0.01). Cluster analysis showed that the groupings of zinc transporters and MTs were largely similar between the two cohorts, with the exception for ZnT1 and ZIP7. Zinc transporters and MTs were significant determinants of plasma zinc (r2 = 0.48, p = 0.001) in the AH cohort, but not in the T2DM cohort. CONCLUSION: The current study suggests altered cellular zinc homeostasis in T2DM and supports the use of multiple zinc transporters and MTs groupings to further understand zinc homeostasis in health and T2DM. PMID- 27957814 TI - A doxycycline inducible, adenoviral bone morphogenetic protein-2 gene delivery system to bone. AB - We report the novel use of a tuneable, non-integrating viral gene delivery system to bone that can be combined with clinically approved biomaterials in an 'off-the shelf' manner. Specifically, a doxycycline inducible Tet-on adenoviral vector (AdTetBMP-2) in combination with mesenchymal stromal cells (MSCs), fibrin and a biphasic calcium phosphate ceramic (MBCP(r)) was used to repair large bone defects in nude rats. Bone morphogenetic protein-2 (BMP-2) transgene expression could be effectively tuned by modification of the doxycycline concentration. The effect of adenoviral BMP-2 gene delivery upon bone healing was investigated in vivo in 4 mm critically sized, internally fixated, femoral defects. MSCs were transduced either by direct application of AdTetBMP-2 or by pre-coating MBCP granules with the virus. Radiological assessment scores post-mortem were significantly improved upon delivery of AdTetBMP-2. In AdTetBMP-2 groups, histological analysis revealed significantly more newly formed bone at the defect site compared with controls. Newly formed bone was vascularized and fully integrated with nascent tissue and implanted biomaterial. Improvement in healing outcome was achieved using both methods of vector delivery (direct application vs. pre-coating MCBP). Adenoviral delivery of BMP-2 enhanced bone regeneration achieved by the transplantation of MSCs, fibrin and MBCP in vivo. Importantly, our in vitro and in vivo data suggest that this can be achieved with relatively low (ng/ml) levels of the growth factor. Our model and novel gene delivery system may provide a powerful standardized tool for the optimization of growth factor delivery and release for the healing of large bone defects. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27957815 TI - Evolution of graft morphology and function after recellularization of decellularized rat livers. AB - Decellularization of livers is a well-established procedure. Data on different reseeding techniques or the functional evolution and reorganization processes of repopulated grafts remains limited. A proprietary, customized bioreactor was established to repopulate decellularized rat livers (n = 21) with primary rat hepatocytes (150 * 106 cells) via the hepatic artery and to subsequently evaluate graft morphology and function during 7 days of ex vivo perfusion. Grafts were analysed at 1 h, 6 h, 12 h, 24 h, 3 days, 5 days and 7 days after recellularization (all n = 3) by immunohistological evaluation, hepatocyte related enzyme (aspartate transaminase, alanine transaminase and lactate dehydrogenase) and albumin measurement in the perfusate. This appears to be the first available protocol for repopulation of rat livers via the hepatic artery. Within the first 24 h after repopulation, the hepatocytes seemed to migrate out of the vascular network and form clusters in the parenchymal space around the vessels. Graft function increased for the first 24 h after repopulation with a significantly higher function compared to standard two-dimensional culture after 24 h. Thereafter, graft function constantly decreased with significantly lower values after 6 days and 7 days of perfusion, although histologically viable hepatocytes were found even after this period. The data suggests that, owing to a constant loss of function, repopulated grafts should potentially be implanted as soon as cell engraftment and graft re-organization are completed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27957817 TI - Monocarboxylate Transporter-1 Mediates the Protective Effects of Neutral-pH Bicarbonate/Lactate-Buffered Peritoneal Dialysis Fluid on Cell Viability and Apoptosis. AB - We investigated the effects of bicarbonate/lactate-buffered peritoneal dialysis fluid (B/L-PDF) and lactate-buffered PDF (L-PDF) on cell viability and apoptosis, focusing on monocarboxylate transporters (MCTs). MCT-1 transports lactate into cells. Cell viability and apoptosis of human peritoneal mesothelial cells (HPMCs) were examined by water-soluble tetrazolium salt-1 and TUNEL assays, respectively. The relative number of viable HPMCs was significantly decreased by L-PDF at 48 h (8.8 +/- 0.4%) compared with cells cultured in M199, but not by B/L-PDF (66.7 +/- 1.1%). Apoptosis was markedly induced by L-PDF at 48 h (69.3 +/- 16.2%), but not by B/L-PDF (2.6 +/- 0.3%). Knockdown of MCT-1 by small interfering RNA (siRNA) attenuated the L-PDF-induced reduction of viable cells and increased apoptosis compared with control siRNA, but MCT-4 knockdown had no effect. B/L-PDF had lesser effects on cell viability and apoptosis of HPMCs compared with L-PDF. These results suggest that B/L-PDF biocompatibility occurs by avoiding the induction of apoptosis in HPMCs. PMID- 27957816 TI - Ascorbic acid drives the differentiation of mesoderm-derived embryonic stem cells. Involvement of p38 MAPK/CREB and SVCT2 transporter. AB - SCOPE: Here we tested the hypothesis that ascorbic acid (AA) is a signaling molecule acting on stem cells via the differentiation of mesoderm derivatives, including myocytes, osteocytes, and adipocytes. MATERIAL AND METHODS: Investigations used a murine embryonic stem cell line CGR8 able to differentiate into different cell types and treated or not with ascorbic acid. Differentiation was tracked mainly through cellular anatomy (including presence of beating cardiomyocytes) and expression of specific markers. CONCLUSION: The study demonstrated that AA drives mesoderm-derived stem cell differentiation toward myogenesis and osteogenesis and also inhibits adipogenesis. Further experiments found that AA competes with retinoic acid (RA) to drive cell differentiation in a dose-dependent manner: AA inhibited neurogenic differentiation and stimulated myogenesis whereas RA did the reverse. The AA-dependent differentiation of embryonic stem cells was shown to involve a p38 MAPK/CREB pathway, probably stimulated by cAMP via adenylate cyclases. In addition, SVCT2, the intracellular transporter of AA, acted as a receptor. Finally, we showed that activation/repression of specific differentiation markers is associated with epigenetic changes in their associated promoters. We discuss the impact of these findings in terms of obesity and aging. PMID- 27957819 TI - Mechanistic Insights into the Carbon Dioxide/Cyclohexene Oxide Copolymerization Reaction: Is One Metal Center Enough? AB - A detailed study on the mechanism for the alternating copolymerization of cyclohexene oxide (CHO) and CO2 mediated by an [Al{amino-tri(phenolate)}]/NBu4 I binary catalyst system was performed by using DFT-based methods. Four potential mechanisms (one monometallic and three bimetallic) were considered for the first propagation cycle of the CHO/CO2 copolymerization. The obtained Gibbs free energies provided a rationale for the relative high activity of a non-covalent dimeric structure formed in situ and thus for the feasibility of a bimetallic mechanism to obtain polycarbonates quantitatively. Gibbs free energies also indicated that the alternating copolymerization was favored over the cyclic carbonate formation. PMID- 27957820 TI - Inter-Method Variability of Ferritin and Transferrin Saturation Measurement Methods in Patients on Hemodialysis. AB - Serum ferritin level and transferrin saturation (TSAT) are widely used to evaluate iron status in patients with chronic kidney disease, and are also important variables for performing statistical analyses. Many guidelines have set control targets or upper limits for these markers. Inter-method variability is an important consideration in iron control and statistical analysis. We used 10 ferritin assay kits and five iron/unsaturated iron-binding capacity/total iron binding capacity assay kits to determine ferritin levels and TSAT in 114 patients on maintenance dialysis, and evaluated measurement bias using Passing-Bablok regression analyses. The variance of distributions categorized by differences in assay kits was examined using Fisher's exact test. Slopes ranged from 1.00 to 1.63 (1.00 to 0.61) for ferritin and 1.00 to 1.10 (1.00 to 0.91) for TSAT. The distribution according to the 2015 JSDT Guideline for Renal Anemia in Chronic Kidney Disease significantly changed (P = 0.01). TSAT thus provides more precise control than ferritin in multi-center comparisons where no particular assay is specified. Developers must reduce variability in serum ferritin assay kits. Researchers must analyze measured values by taking into account the propagation of errors, and clinicians must evaluate laboratory data carefully. PMID- 27957818 TI - Optimal pharmacological treatment and adherence to medication in secondary prevention of cardiovascular events in Spain: Results from the CAPS study. AB - INTRODUCTION: Despite the large amount of evidence supporting the use of antiplatelet agents, beta-blockers, angiotensin antagonists, and lipid-lowering statins in patients with stable coronary artery disease, several studies have documented underprescription of optimal medical treatment (OMT) in Spain. AIMS: The present study aimed to describe the current trend of pharmacological prescription in secondary prevention treatment for cardiovascular diseases (CVDs) in a Spanish cohort. METHODS: This study was a multicenter, observational, cross sectional study (CAPS study, FER-CAR-2014-01) in the context of only one visit. Adherence levels to the prescribed medication, the reasons for not prescription of each medication, the existence of possible associations between sociodemographic features, different CVDs, and different drugs with treatment compliance were also analyzed in patients who have suffered cardiovascular effects. RESULTS: Six hundred and twelve patients (68.5+/-10.7 years old; 78% males) were included. OMT was prescribed in 40.8% of the patients. The main reason for not prescribing was due to the physician's discretion. Adherence to medication, measured by the Morisky-Green questionnaire, was 45.8%, and it was positively related to the presence of coronary events (OR 1.80; 95% CI: 1.05 3.21) but not with any drug type. Moreover, a higher educational background implied a higher percentage of adherence to medication. Finally, nonadherent patients were prescribed more daily medicine intakes. CONCLUSIONS: Low adherence to guideline-oriented treatment as well as low adherence to medication was found by a self-reported questionnaire. Enhancing adherence to guideline-recommended therapy and reducing treatment complexity seem to be reasonable strategies to improve adherence to secondary prevention medications. PMID- 27957821 TI - The effect of serum on the proliferation of bone marrow-derived mesenchymal stem cells from aged donors and donors with or without chronic heart failure. AB - Many clinical studies of regenerative medicine using bone marrow-derived mesenchymal stem cells (MSCs) have been conducted globally. We initiated clinical studies using MSCs in 2001 and have now treated over 100 cases with patients aged 0-92 years. In a few cases involving patients with chronic heart failure (CHF), we observed that MSCs proliferated poorly. This contrasts with cell therapy studies wherein MSCs of patients with CHF were used for treatment. The effects of serum on the proliferation of MSCs from donors with normal heart function and with CHF have not been reported. Moreover, whether cell therapy is effective for elderly patients remains uncertain. Therefore, characterization of MSCs from aged donors and/or donors with CHF is urgently required. We retrospectively analysed the population doubling times (PDTs) of MSCs between the first and second passages. Although we had data for many samples of well-expanded MSCs from aged donors, a positive correlation was observed between donor age and PDT. A trend towards reduced variance in PDTs was observed in MSCs supplemented with fetal bovine serum (FBS) compared with those supplemented with autologous serum. When autologous serum was used, the average PDT of MSCs from donors with CHF was significantly longer than that of MSCs from donors without CHF. In contrast, when FBS was used, similar PDTs were observed in MSCs from donors with and without CHF. Thus, FBS promotes MSC expansion even from donors with CHF and MSC-based regenerative medicine might be feasible even for elderly patients. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27957822 TI - Laparoscopic-assisted abdominoperineal resection combined with en-bloc prostatectomy using the trans-sacral approach for locally invasive rectal cancer: A case report. AB - Laparoscopic-assisted abdominoperineal resection and en-bloc prostatectomy using the trans-sacral approach for locally invasive rectal cancer that invades only the prostate is useful in order to avoid total pelvic exenteration. The patient was a 63-year-old man with cT4b (prostate) N1M0, stage IIIC rectal cancer. Curative resection was performed. Histopathological findings did not indicate definitive invasion into the prostate gland. The patient was discharged from the hospital on postoperative day 32 with an anastomotic leak and a ureteral catheter. The patient is able to urinate and has had no cancer recurrence. Laparoscopic bladder-preserving surgery for locally invasive rectal cancer can preserve postoperative quality of life and provides oncological curability. PMID- 27957823 TI - Effect of nutrient levels during the far-off period on postpartum productivity in dairy cows. AB - The present study aimed to determine the effects of differing nutrient levels during the far-off period on postpartum metabolism and milk production in lactating cows. Twenty-six multiparous cows were assigned to three dietary treatments in the far-off period: a low-energy diet (L, n = 9, 80% intake of the total digestible nutrients requirement), a moderate-energy diet (M, n = 8, 105%) and a high-energy diet (H, n = 9, 130%). During the close-up period, all cows were provided with 105% intake. After parturition, all cows were fed a lactation diet. The BCS recovery was slow, and low milk yield was found in the H group. In the L group, BCS recovery was favorable after parturition, and lactation persistence was increased. The L group had low rumen endotoxin activity and a high initial ovulation rate after parturition. These findings indicate that a high-energy diet during the far-off period has a deleterious effect on milk production. In contrast, the restricted diet in the far-off period increased adaptability with respect to peri-parturition metabolic changes, improved the post-parturition nutritional state, and increased milk production. Furthermore, it suggests that the nutrient levels in the far-off period affect rumen endotoxin activity and reproductive function after parturition. PMID- 27957824 TI - Physical fitness level affects perception of chronic stress in military trainees. AB - This study investigated whether physical fitness affects the perception of chronic stress in military trainees while controlling for established factors influencing stress perception. The sample consisted of 273 men (20.23 +/- 1.12 years, 73.56 +/- 10.52 kg, 1.78 +/- 0.06 m). Physical fitness was measured by progressive endurance run (maximum oxygen uptake; VO2 max), standing long jump, seated shot put, trunk muscle strength, and one leg standing test. Perceived stress was measured using the Perceived Stress Questionnaire in Weeks 1 and 11 of basic military training (BMT). VO2 max and four influencing variables (perceived stress in Week 1, neuroticism, transformational leadership style, and education level) explained 44.44% of the variance of the increase in perceived stress during 10 weeks of BMT (R2 = 0.444, F = 23.334, p < .001). The explained variance of VO2 max was 4.14% (R2 = 0.041), with a Cohen's f2 effect size of 0.045 (assigned as a small effect by Cohen, ). The results indicate a moderating influence of good aerobic fitness on the varied level of perceived stress. We conclude that it is advisable to provide conscripts with a specific endurance training program prior to BMT for stress prevention reasons. PMID- 27957825 TI - Advanced Functional Polymers for Medicine. PMID- 27957826 TI - MiR-199b-5p inhibits osteogenic differentiation in ligamentum flavum cells by targeting JAG1 and modulating the Notch signalling pathway. AB - Ossification of the ligamentum flavum (OLF) is a pathology almost only reported in East Asian countries. The leading cause of OLF is thoracic spinal canal stenosis and myelopathy. In this study, the role of miR-199b-5p and jagged 1 (JAG1) in primary ligamentum flavum cell osteogenesis was examined. MiR-199b-5p was found to be down-regulated during osteogenic differentiation in ligamentum flavum cells, while miR-199b-5p overexpression inhibited osteogenic differentiation. In addition, JAG1 was found to be up-regulated during osteogenic differentiation in ligamentum flavum cells, while JAG1 knockdown via RNA interference caused an inhibition of Notch signalling and osteogenic differentiation. Moreover, target prediction analysis and dual luciferase reporter assays supported the notion that JAG1 was a direct target of miR-199b 5p, with miR-199b-5p found to down-regulate both JAG1 and Notch. Further, JAG1 knockdown was demonstrated to block the effect of miR-199b-5p inhibition. These findings imply that miR-199b-5p performs an inhibitory role in osteogenic differentiation in ligamentum flavum cells by potentially targeting JAG1 and influencing the Notch signalling pathway. PMID- 27957828 TI - Protective effects of low-dose rosuvastatin on isoproterenol-induced chronic heart failure in rats by regulation of DDAH-ADMA-NO pathway. AB - AIMS: Cardiovascular disease is the leading cause of death with high morbidity and mortality, and chronic heart failure is the terminal phase of it. This study aimed to investigate the protective effects of the low-dose rosuvastatin on isoproterenol-induced chronic heart failure and to explore the possible related mechanisms. METHODS: Male Sprague Dawley rats were given isoproterenol 5 mg/kg once a day for 7 days to establish heart failure model by subcutaneous injection. Simultaneously, low-dose rosuvastatin (5 mg/kg) was orally administrated from day 1 to day 14. Protective effects were evaluated by hemodynamic parameter, histopathological variables, serum asymmetric dimethylarginine (ADMA), cardiac troponin I (cTnI), brain natriuretic peptide (BNP) and myocardial nitric oxide (NO), and the levels of dimethylarginine dimethylaminohydrolase 2 (DDAH2), arginine methyltransferases 1 (PRMT1) and endothelial nitric oxide synthase (eNOS) expression were analyzed. RESULTS: Therapeutic rosuvastatin (5 mg/kg) significantly attenuated isoproterenol-induced hypertrophy, remodeling and dysfunction of ventricle, reduced the increased serum content of ADMA, cTnI, and BNP, and elevated myocardial NO in rats (P<.05). Besides, rosuvastatin also significantly inhibited fibrosis of myocardium, normalized the increased PRMT1 and decreased DDAH2 expression. CONCLUSIONS: Low-dose rosuvastatin exerted cardioprotective effects on isoproterenol-induced heart failure in rats by modulating DDAH-ADMA-NO pathway, and it may present the new therapeutic value in ameliorating chronic heart failure. PMID- 27957827 TI - Sanguinarine inhibits growth and invasion of gastric cancer cells via regulation of the DUSP4/ERK pathway. AB - Sanguinarine, a bioactive benzophenanthridine alkaloid extracted from plants of the Papaveraceae family, has shown antitumour effects in multiple cancer cells. But the therapeutic effects and regulatory mechanisms of sanguinatine in gastric cancer (GC) remain elusive. This study was aimed to investigate the correlation of dual-specificity phosphatase 4 (DUSP4) expression with clinicopathologic features and overall survival in patients with GC and explore the effects of sanguinarine on tumour growth and invasion in GC cells (SGC-7901 and HGC-27) and underlying molecular mechanisms. Immunohistochemical analysis showed that decreased DUSP4 expression was associated with the sex, tumour size, depth of invasion and distant metastasis in patients with GC. Functional experiments including CCK-8, Transwell and flow cytometry analysis indicated that sanguinarine or DUSP4 overexpression inhibited GC cell viability and invasive potential, and induced cell apoptosis and cycle arrest in S phase, but DUSP4 knockdown attenuated the antitumour activity of sanguinarine. Further observation demonstrated that sanguinarine up-regulated the expression of DUSP4 and Bcl-2 associated X protein (Bax), but down-regulated phosphorylated extracellular signal-regulated kinase (p-ERK), proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 2 (MMP-2) and B-cell lymphoma 2 (Bcl-2) expression. Taken together, our findings indicate that sanguinarine inhibits growth and invasion of GC cells through regulation of the DUSP4/ERK pathway, suggesting that sanguinarine may have potential for use in GC treatment. PMID- 27957829 TI - Mechanism of the OH Radical Addition to Adenine from Quantum-Chemistry Determinations of Reaction Paths and Spectroscopic Tracking of the Intermediates. AB - The OH radical is a well-known mediator in the oxidation of biological structures like DNA. Over the past decades, the precise events taking place after reaction of DNA nucleobases with OH radical have been widely investigated by the scientific community. Thirty years after the proposal of the main routes for the reaction of *OH with adenine ( Vieira , A. ; Steenken , S. J. Am. Chem. Soc. 1990 , 112 , 6986 - 6994 ), the present work demonstrates that the OH radical addition to C4 position is a minor pathway. Instead, the dehydration process is mediated by the A5OH adduct. Conclusions are based on density functional theory calculations for the ground-state reactivity and highly accurate multiconfigurational computations for the excited states of the radical intermediates. The methodology has been also used to study the mechanism giving rise to the mutagens 8-oxoA and FAPyA. Taking into account the agreement between the experimental data and the theoretical results, it is concluded that addition to the C5 and C8 positions accounts for at least ~44.5% of the total *OH reaction in water solution. Finally, the current findings suggest that hydrophobicity in the DNA/RNA surroundings facilitates the formation of 8-oxoA and FAPyA. PMID- 27957831 TI - Plasmon-Induced Hot Electrons on Mesoporous Carbon for Decomposition of Organic Pollutants under Outdoor Sunlight Irradiation. AB - In this study, a 4 in. CMK-8-Nafion membrane was fabricated using three dimensional cubic ordered mesoporous carbon CMK-8 blended with a Nafion polymer. Plasmon-resonance hot electrons and holes from Au nanoparticles (NPs) combined with this CMK-8-Nafion membrane resulted in the effective decomposition of methyl orange (MO) due to the synergetic work of hot carriers with mesoporous carbon; a sample of Au/CMK-8-Nafion exposed to outdoor sunlight radiation for 150 min successfully removed 97% of MO. Fourier transform infrared spectroscopy (FTIR) was employed to examine the generation of hydroxyl groups (OH-) during decomposition. Finally, the spatial distribution of hydroxyl groups was also investigated across the different coverage densities of plasmonic Au NPs. PMID- 27957830 TI - Aptamer-Conjugated Graphene Quantum Dots/Porphyrin Derivative Theranostic Agent for Intracellular Cancer-Related MicroRNA Detection and Fluorescence-Guided Photothermal/Photodynamic Synergetic Therapy. AB - Multifunctional theranostic platform coupling diagnostic and therapeutic functions holds great promise for personalized nanomedicine. Nevertheless, integrating consistently high performance in one single agent is still challenging. This work synthesized a sort of porphyrin derivatives (P) with high singlet oxygen generation ability and graphene quantum dots (GQDs) possessing good fluorescence properties. The P was conjugated to polyethylene glycol (PEG)ylated and aptamer-functionalized GQDs to gain a multifunctional theranostic agent (GQD-PEG-P). The resulting GQD-PEG-P displayed good physiological stability, excellent biocompatibility and low cytotoxicity. The intrinsic fluorescence of the GQDs could be used to discriminate cancer cells from somatic cells, whereas the large surface facilitated gene delivery for intracellular cancer-related microRNA (miRNA) detection. Importantly, it displayed a photothermal conversion efficiency of 28.58% and a high quantum yield of singlet oxygen generation up to 1.08, which enabled it to accomplish advanced photothermal therapy (PTT) and efficient photodynamic therapy (PDT) for cancer treatment. The combined PTT/PDT synergic therapy led to an outstanding therapeutic efficiency for cancer cell treatment. PMID- 27957832 TI - Degradation Mechanisms in Blue Phosphorescent Organic Light-Emitting Devices by Exciton-Polaron Interactions: Loss in Quantum Yield versus Loss in Charge Balance. AB - We study the relative importance of deterioration of material quantum yield and charge balance to the electroluminescence stability of PHOLEDs, with a special emphasis on blue devices. Investigations show that the quantum yields of both host and emitter in the emission layer degrade due to exciton-polaron interactions and that the deterioration in material quantum yield plays the primary role in device degradation under operation. On the other hand, the results show that the charge balance factor is also affected by exciton-polaron interactions but only plays a secondary role in determining device stability. Finally, we show that the degradation mechanisms in blue PHOLEDs are fundamentally the same as those in green PHOLEDs. The limited stability of the blue devices is a result of faster deterioration in the quantum yield of the emitter. PMID- 27957833 TI - Mix and Match: Coassembly of Amphiphilic Dendrimers and Phospholipids Creates Robust, Modular, and Controllable Interfaces. AB - Self-assembly of supramolecular structures has become an attractive means to create new biologically inspired materials and interfaces. We report the first robust hybrid bilayer systems readily coassembled from amphiphilic dendrimers and a naturally occurring phospholipid. Both concentration and generation of the dendrimers have direct impacts on the biophysical properties of the coassemblies. Raising the dendrimer concentration increases the hybrid bilayer stability, while changes in the generation and the concentration of the embedded dendrimers impact the fluidity of the coassembled systems. Multivalent dendrimer amine terminals allow for nondestructive in situ derivatization, providing a convenient approach to decorate and modulate the local environment of the hybrid bilayer. The coassembly of lipid/dendrimer interfaces offers a unique platform for the creation of hybrid systems with modular and precisely controllable behavior for further applications in sensing and drug delivery. PMID- 27957834 TI - Enhanced Polarization Ratio of Electrospun Nanofibers with Increased Intrachain Order by Postsolvent Treatments. AB - Polarized emission that is beneficial to lighting and display applications can be demonstrated by aligning emissive chromophores, which can be achieved using an electrospinning technique. We investigate the photophysical properties of nanofibers based on poly[2-methoxy-5-(2-ethylhexyloxy)-1,4 phenylenevinylene]/poly(ethylene oxide) blends both with and without postsolvent treatments. Two different solvents were sequentially used in an attempt to extract the insulating electrospinnable polymer and increase the polarization ratio of the nanofiber meshes by molecular reorganization. The polarization ratio of emission from the nanofiber meshes treated with N,N-dimethylformamide (DMF) following treatment with acetonitrile solvents was found to be increased. An increase in the 0-0 emission vibronic intensity relative to that of the 0-1 peak and a reduction in the photoluminescence (PL) bandwidth were found. In addition, the PL decays faster and the parallel component along the nanofiber axis increases after the DMF treatment, indicating that the radiative recombination process becomes faster. Our results consistently show that postsolvent treatment promotes stronger J-aggregate character, with longer coherence lengths of the exciton along the long axis of the nanofibers, due to enhanced intrachain order. PMID- 27957835 TI - Structural Properties of Phospholipid-based Bilayers with Long-Chain Alcohol Molecules in the Gel Phase. AB - The structural properties of two-component gel-phase bilayers of distearylphosphatidylcholine (DSPC) and alcohol molecules with different compositions and chain lengths (12-24 carbons long) are studied via molecular dynamics simulations. Several bilayer properties, including area per lipid, tilt angle, chain interdigitation, and headgroup offset, are studied for each system and compared, revealing important structural implications depending upon headgroup size and chain length. While tail tilt is the primary mechanism for single-component bilayers to balance tail attraction and headgroup repulsion, our results demonstrate that the lipid mixtures studied adjust this balance via an offset between the depths of the different molecular species in the bilayer; this behavior is found to depend both on composition and on the length of alcohol molecules relative to the length of DSPC tails. It is shown that the structural properties of bilayers with asymmetric tail lengths depend strongly on the bilayer composition, while the composition has less influence on mixed-component bilayers with nearly symmetric tail lengths. These findings are explained on the basis of the interdigitation between bilayer leaflets and how interdigitation is related to other structural properties. PMID- 27957836 TI - Regioselective Iron-Catalyzed [2 + 2 + 2] Cycloaddition Reaction Forming 4,6 Disubstituted 2-Aminopyridines from Terminal Alkynes and Cyanamides. AB - Iron complexes bound by redox-active pyridine dialdimine (PDAI) ligands catalyze the cycloaddition of two terminal alkynes and one cyanamide. The reaction is both chemo- and regioselective, as only 4,6-disubstituted 2-aminopyridine products are formed in moderate to high yields. Isolation of an iron azametallacycle (4) suggests that catalyst deactivation occurs with a large excess of cyanamide over longer reaction times. Fe-catalyzed cycloaddition allowed for a straightforward synthesis of a variety of aminopyridines, including known estrogen receptor ligands. PMID- 27957838 TI - Theoretical Investigation of Regioselectivity and Stereoselectivity in AIBN/HSnBu3-Mediated Radical Cyclization of N-(2-Iodo-4,6-dimethylphenyl)-N,2 dimethyl-(2E)-butenamide. AB - In this study, we employed the density functional method to simulate AIBN/HSnBu3 mediated radical cyclizations with different axially chiral conformers of N-(2 iodo-4,6-dimethylphenyl)-N,2-dimethyl-(2E)-butenamide as substrates. We constructed a reaction potential energy profile using the Gibbs free energies of the located stationary points. The thermodynamic and kinetic data of the profile were further used to evaluate the regioselectivity, stereoselectivity, and product distribution of the cyclizations. Additionally, we compared the present HSnBu3-mediated radical cyclization with the experimentally available Heck reaction and found that such a radical cyclization can convert (M,Z) and (P,Z) o iodoanilide substrates to centrally chiral products with high chirality transfer. The goal of this study was to estimate the practicality of theoretically predicting the memory of chirality in such radical cyclizations. The present results can provide a strategy from a theoretical viewpoint for experimentally synthesizing highly stereoselective carbocyclic and heterocyclic compounds using radical cyclization methods. PMID- 27957837 TI - Efficient and Flexible Preparation of Biosynthetic Microperoxidases. AB - Heme peptides and their derivatives, also called microperoxidases (MPs), are employed as heme protein active site models, catalysts, and charge-transfer chromophores. In this work, two approaches to the biosynthesis of novel MPs are described. In one method, heme peptides are expressed as C-terminal tags to the protein azurin and the MP is liberated by proteolytic cleavage by an endopeptidase. In an alternative approach, heme peptides are expressed as N terminal tags to the cysteine protease domain (CPD) of the Vibrio cholerae MARTX toxin. Once activated by inositol hexakisphosphate, CPD undergoes autocleavage at an N-terminal leucine residue to liberate the MP. Purification is aided by use of a histidine-immobilized Sepharose column that binds exposed heme [Asher, W. A., and Bren, K. L. (2010) Protein Sci. 19, 1830-1839]. These methods provide efficient and adaptable routes to the preparation of a wide range of biosynthetic heme peptides. PMID- 27957840 TI - All-Solid-State Reference Electrode with Heterogeneous Membrane. AB - Novel reference electrodes with a solid contact coated by a heterogeneous polymer membrane are described. The electrodes are obtained using Ag nanoparticles, AgBr, KBr suspended in tetrahydrofuran solution of PVC and DOS and deposited on Ag substrate, or another substrate covered with Ag, by drop casting. After a short period of soaking in a KBr solution, stable and reproducible formal potentials of -157 +/- 2 mV (vs Ag/AgCl/3 M KCl) were observed, and the solid-contact reference electrodes were ready to use. It is shown that the described reference electrodes are relatively insensitive to the changes in the sample matrix, the concentrations of ions, the pH and the redox potential. These electrodes can also be fabricated in miniaturized form, and thus used to produce miniaturized multielectrode probes. PMID- 27957839 TI - Multifold Electrical Conductance Enhancements at Metal-Bismuth Telluride Interfaces Modified Using an Organosilane Monolayer. AB - Controlling electrical transport across metal-thermoelectric interfaces is key to realizing high efficiency devices for solid state refrigeration and waste-heat harvesting. We obtain up to 17-fold increases in electrical contact conductivity Sigmac by inserting a mercaptan-terminated organosilane monolayer at Cu-Bi2Te3 and Ni-Bi2Te3 interfaces, yielding similar Sigmac for both metals by offsetting an otherwise 7-fold difference. The Sigmac improvements are underpinned by silane moiety-induced inhibition of Cu diffusion, promotion of high-conductivity interfacial nickel telluride formation, and mercaptan-induced reduction of Bi2Te3 surface oxides. Our findings should enable incorporating nanomolecular layers with appropriately chosen terminal moieties in thermoelectric device metallization schemes without metal diffusion barriers. PMID- 27957841 TI - Constructing Fluorine-Free and Cost-Effective Superhydrophobic Surface with Normal-Alcohol-Modified Hydrophobic SiO2 Nanoparticles. AB - Superhydrophobic coatings have drawn much attention in recent years for their wide potential applications. However, a simple, cost-effective, and environmentally friendly approach is still lacked. Herein, a promising approach using nonhazardous chemicals was proposed, in which multiple hydrophobic functionalized silica nanoparticles (SiO2 NPs) were first prepared as core component, through the efficient reaction between amino group containing SiO2 NPs and the isocyanate containing hydrophobic surface modifiers synthesized by normal alcohols, followed by simply spraying onto various substrates for superhydrophobic functionalization. Furthermore, to further improve the mechanical durability, an organic-inorganic composite superhydrophobic coating was fabricated by incorporating cross-linking agent (polyisocyanate) into the mixture of hydrophobic-functionalized SiO2 NPs and hydroxyl acrylic resin. The hybrid coating with cross-linked network structures is very stable with excellent mechanical durability, self-cleaning property and corrosion resistance. PMID- 27957842 TI - Small Details Matter: The 2'-Hydroxyl as a Conformational Switch in RNA. AB - While DNA is mostly a primary carrier of genetic information and displays a regular duplex structure, RNA can form very complicated and conserved 3D structures displaying a large variety of functions, such as being an intermediary carrier of the genetic information, translating such information into the protein machinery of the cell, or even acting as a chemical catalyst. At the base of such functional diversity is the subtle balance between different backbone, nucleobase, and ribose conformations, finely regulated by the combination of hydrogen bonds and stacking interactions. Although an apparently simple chemical modification, the presence of the 2'OH in RNA has a profound effect in the ribonucleotide conformational balance, adding an extra layer of complexity to the interactions network in RNA. In the present work, we have combined database analysis with extensive molecular dynamics, quantum mechanics, and hybrid QM/MM simulations to provide direct evidence on the dramatic impact of the 2'OH conformation on sugar puckering. Calculations provide evidence that proteins can modulate the 2'OH conformation to drive sugar repuckering, leading then to the formation of bioactive conformations. In summary, the 2'OH group seems to be a primary molecular switch contributing to specific protein-RNA recognition. PMID- 27957843 TI - Role of Core Electrons in Quantum Dynamics Using TDDFT. AB - The explicit simulation of time dependent electronic processes requires computationally onerous routes involving the temporal integration of motion equations for the charge density. Efficiency optimization of these methods typically relies on increasing the integration time-step and on the reduction of the computational cost per step. The implicit representation of inner electrons by effective core potentials-or pseudopotentials-is a standard practice in localized-basis quantum-chemistry implementations to improve the efficiency of ground-state calculations, still preserving the quality of the output. This article presents an investigation on the impact that effective core potentials have on the overall efficiency of real time electron dynamics with TDDFT. Interestingly, the speedups achieved with the use of pseudopotentials in this kind of simulation are on average much more significant than in ground-state calculations, reaching in some cases a factor as large as 600*. This boost in performance originates from two contributions: on the one hand, the size of the density matrix, which is considerably reduced, and, on the other, the elimination of high-frequency electronic modes, responsible for limiting the maximum time step, which vanish when the core electrons are not propagated explicitly. The latter circumstance allows for significant increases in time-step, that in certain cases may reach up to 3 orders of magnitude, without losing any relevant chemical or spectroscopic information. PMID- 27957844 TI - A Theoretical Mechanistic Study of the Asymmetric Desymmetrization of a Cyclic meso-Anhydride by a Bifunctional Quinine Sulfonamide Organocatalyst. AB - Cinchona alkaloids and their derivatives are widely used as organocatalysts in asymmetric synthesis. In particular, sulfonamide derivatives of cinchona alkaloids are highly enantioselective desymmetrization catalysts in the ring opening of a variety of cyclic anhydrides. To better understand the mechanism of catalysis, as well as to identify the basis for enantioselectivity by this catalyst, we have performed DFT calculations of this reaction with a cyclic meso anhydride. Herein, we report calculations for two reaction pathways, one concerted and one stepwise, for the production of each enantiomer of the desymmetrized product using the complete sulfonamide catalyst I. Our results are consistent with both the enantioselectivity of this transformation and the catalytic role of the quinuclidine moiety. We find that the stepwise pathway is the relevant pathway in the production of the major enantiomer. Our calculations highlight the role of differential distortion of the anhydride-methanol complex in the transition state as the factor leading to stereoselectivity. PMID- 27957845 TI - Chemopreventive Potential of Powdered Red Wine Pomace Seasonings against Colorectal Cancer in HT-29 Cells. AB - This study evaluates the antiproliferative and antigenotoxic actions of powdered red wine pomace seasonings (Sk-S, seedless; W-S, whole; Sd-S, seeds). In vitro gastrointestinal digested and colonic fermented fractions of the seasonings were used as cell treatments. Phenolic acids from Sk-S showed the highest bioaccessibility in the small intestine, whereas polyphenols contained in Sd-S might be the most fermentable in the colon. Dietary fiber from Sk-S was the best substrate for short chain fatty acids production by gut microbiota. Colon cancerous (HT-29) cell viability was inhibited by 50% (IC50 values) at treatment concentrations ranging from 845 (Sk-S) to 1085 (Sd-S) MUg/mL prior digestion, but all digested fractions exhibited similar antiproliferative activities (mean IC50 = 814 MUg/mL). Oxidative DNA damage in cells was also attenuated by the treatments (200 MUg/mL, 24 h preincubation), with all colonic fermented fractions displaying similar genoprotective action. These results suggest the potential of red wine pomace seasonings as chemopreventive agents in colorectal cancer. PMID- 27957846 TI - Enhanced Emission from Single Isolated Gold Quantum Dots Investigated Using Two Photon-Excited Fluorescence Near-Field Scanning Optical Microscopy. AB - New approaches in molecular nanoscopy are greatly desired for interrogation of biological, organic, and inorganic objects with sizes below the diffraction limit. Our current work investigates emergent monolayer-protected gold quantum dots (nanoclusters, NCs) composed of 25 Au atoms by utilizing two-photon-excited fluorescence (TPEF) near-field scanning optical microscopy (NSOM) at single NC concentrations. Here, we demonstrate an approach to synthesize and isolate single NCs on solid glass substrates. Subsequent investigation of the NCs using TPEF NSOM reveals that, even when they are separated by distances of several tens of nanometers, we can excite and interrogate single NCs individually. Interestingly, we observe an enhanced two-photon absorption (TPA) cross section for single Au25 NCs that can be attributed to few-atom local field effects and to local field induced microscopic cascading, indicating their potential for use in ultrasensitive sensing, disease diagnostics, cancer cell therapy, and molecular computers. Finally, we report room-temperature aperture-based TPEF NSOM imaging of these NCs for the first time at 30 nm point resolution, which is a ~5-fold improvement compared to the previous best result for the same technique. This report unveils the unique combination of an unusually large TPA cross section and the high photostability of Au NCs to (non-destructively) investigate stable isolated single NCs using TPEF NSOM. This is the first reported optical study of monolayer-protected single quantum clusters, opening some very promising opportunities in spectroscopy of nanosized objects, bioimaging, ultrasensitive sensing, molecular computers, and high-density data storage. PMID- 27957847 TI - Highly Luminescent WS2 Quantum Dots/ZnO Heterojunctions for Light Emitting Devices. AB - Sonication induced vertical fragmentation of two-dimensional (2D) WS2 nanosheets into highly luminescent, monodispered, zero-dimensional (0D) quantum dots (QDs) is reported. The formation of 0D structures from 2D sheets and their surface/microstructure characterization are revealed from their microscopic and spectroscopic investigations. Size dependent optical properties of WS2 nanostructures have been explored by UV-vis absorption and photoluminescence spectroscopy. Interestingly, it is observed that, below a critical dimension (~2 nm), comparable to the Bohr exciton radius, the tiny nanocrystals exhibit strong emission. Finally, the electroluminescence characteristics are demonstrated for the first time, by forming a heterojunction of stabilizer free WS2 QDs and ZnO thin films. The signature of white light emission in the light emitting device is attributed to the adequate intermixing of emission characteristics of WS2 QDs and ZnO. The observation of white electroluminescence may pave the way to fabricate prototype futuristic efficient light emitting devices. PMID- 27957848 TI - Ultrafast Elementary Photochemical Processes of Organic Molecules in Liquid Solution. AB - Ultrafast photochemical reactions in liquids occur on similar or shorter time scales compared to the equilibration of the optically populated excited state. This equilibration involves the relaxation of intramolecular and/or solvent modes. As a consequence, the reaction dynamics are no longer exponential, cannot be quantified by rate constants, and may depend on the excitation wavelength contrary to slower photochemical processes occurring from equilibrated excited states. Such ultrafast photoinduced reactions do no longer obey the Kasha-Vavilov rule. Nonequilibrium effects are also observed in diffusion-controlled intermolecular processes directly after photoexcitation, and their proper description gives access to the intrinsic reaction dynamics that are normally hidden by diffusion. Here we discuss these topics in relation to ultrafast organic photochemical reactions in homogeneous liquids. Discussed reactions include intra- and intermolecular electron- and proton-transfer processes, as well as photochromic reactions occurring with and without bond breaking or bond formation, namely ring-opening reactions and cis-trans isomerizations, respectively. PMID- 27957849 TI - What Is the Preferred Conformation of Phosphatidylserine-Copper(II) Complexes? A Combined Theoretical and Experimental Investigation. AB - Phosphatidylserine (PS) has previously been found to bind Cu2+ in a ratio of 1 Cu2+ ion per 2 PS lipids to form a complex with an apparent dissociation constant that can be as low as picomolar. While the affinity of Cu2+ for lipid membranes containing PS lipids has been well characterized, the structural details of the Cu-PS2 complex have not yet been reported. Coordinating to one amine and one carboxylate moiety on two separate PS lipids, the Cu-PS2 complex is unique among ion-lipid complexes in its ability to adopt both cis and trans conformations. Herein, we determine which stereoisomer of the Cu-PS2 complex is favored in lipid bilayers using density functional theory calculations and electron paramagnetic resonance experiments. It was determined that a conformation in which the nitrogen centers are cis to each other is the preferred binding geometry. This is in contrast to the complex formed when two glycine molecules bind to Cu2+ in bulk solution, where the cis and trans isomers exist in equilibrium, indicating that the lipid environment has a significant steric effect on the Cu2+ binding conformation. These findings are relevant for understanding lipid oxidation caused by Cu2+ binding to lipid membrane surfaces and will help us understand how ion binding to lipid membranes can affect their physical properties. PMID- 27957850 TI - Comparative Toxicogenomic Responses to the Flame Retardant mITP in Developing Zebrafish. AB - Monosubstituted isopropylated triaryl phosphate (mITP) is a major component of Firemaster 550, an additive flame retardant mixture commonly used in polyurethane foams. Developmental toxicity studies in zebrafish established mITP as the most toxic component of FM 550, which causes pericardial edema and heart looping failure. Mechanistic studies showed that mITP is an aryl hydrocarbon receptor (AhR) ligand; however, the cardiotoxic effects of mITP were independent of the AhR. We performed comparative whole genome transcriptomics in wild-type and ahr2hu3335 zebrafish, which lack functional ahr2, to identify transcriptional signatures causally involved in the mechanism of mITP-induced cardiotoxicity. Regardless of ahr2 status, mITP exposure resulted in decreased expression of transcripts related to the synthesis of all-trans-retinoic acid and a host of Hox genes. Clustered gene ontology enrichment analysis showed unique enrichment in biological processes related to xenobiotic metabolism and response to external stimuli in wild-type samples. Transcript enrichments overlapping both genotypes involved the retinoid metabolic process and sensory/visual perception biological processes. Examination of the gene-gene interaction network of the differentially expressed transcripts in both genetic backgrounds demonstrated a strong AhR interaction network specific to wild-type samples, with overlapping genes regulated by retinoic acid receptors (RARs). A transcriptome analysis of control ahr2-null zebrafish identified potential cross-talk among AhR, Nrf2, and Hif1alpha. Collectively, we confirmed that mITP is an AhR ligand and present evidence in support of our hypothesis that mITP's developmental cardiotoxic effects are mediated by inhibition at the RAR level. PMID- 27957851 TI - Conduction Channel Formation and Dissolution Due to Oxygen Thermophoresis/Diffusion in Hafnium Oxide Memristors. AB - Transition-metal-oxide memristors, or resistive random-access memory (RRAM) switches, are under intense development for storage-class memory because of their favorable operating power, endurance, speed, and density. Their commercial deployment critically depends on predictive compact models based on understanding nanoscale physicochemical forces, which remains elusive and controversial owing to the difficulties in directly observing atomic motions during resistive switching, Here, using scanning transmission synchrotron X-ray spectromicroscopy to study in situ switching of hafnium oxide memristors, we directly observed the formation of a localized oxygen-deficiency-derived conductive channel surrounded by a low-conductivity ring of excess oxygen. Subsequent thermal annealing homogenized the segregated oxygen, resetting the cells toward their as-grown resistance state. We show that the formation and dissolution of the conduction channel are successfully modeled by radial thermophoresis and Fick diffusion of oxygen atoms driven by Joule heating. This confirmation and quantification of two opposing nanoscale radial forces that affect bipolar memristor switching are important components for any future physics-based compact model for the electronic switching of these devices. PMID- 27957852 TI - mer, fac, and Bidentate Coordination of an Alkyl-POP Ligand in the Chemistry of Nonclassical Osmium Hydrides. AB - Nonclassical and classical osmium polyhydrides containing the diphosphine 9,9 dimethyl-4,5-bis(diisopropylphosphino)xanthene (xant(PiPr2)2), coordinated in kappa3-mer, kappa3-fac, and kappa2-P,P fashions, have been isolated during the cyclic formation of H2 by means of the sequential addition of H+ and H- or H- and H+ to the classical trihydride OsH3Cl{xant(PiPr2)2} (1). This complex adds H+ to form the compressed dihydride dihydrogen complex [OsCl(H...H)(eta2 H2){xant(PiPr2)2}]+ (2). Under argon, cation 2 loses H2 and the resulting unsaturated fragment dimerizes to give [(Os(H...H){xant(PiPr2)2})2(MU-Cl)2]2+ (3). During the transformation the phosphine changes its coordination mode from mer to fac. The benzofuran counterpart of 1, OsH3Cl{dbf(PiPr2)2} (4; dbf(PiPr2)2 = 4,6-bis(diisopropylphosphino)dibenzofuran), also adds H+ to afford the benzofuran counterpart of 2, [OsCl(H...H)(eta2-H2){xant(PiPr2)2}]+ (5), which in contrast to the latter is stable and does not dimerize. Acetonitrile breaks the chloride bridge of 3 to form the dihydrogen [OsCl(eta2-H2)(CH3CN){xant(PiPr2)2}]+ (6), regenerating the mer coordination of the diphosphine. The hydride ion also breaks the chloride bridge of 3. The addition of KH to 3 leads to 1, closing a cycle for the formation of H2. Complex 1 reacts with a second hydride ion to give OsH4{xant(PiPr2)2} (7) as consequence of the displacement of the chloride. Similarly to the latter, the oxygen atom of the mer-coordinated diphosphine of 7 has a tendency to be displaced by the hydride ion. Thus, the addition of KH to 7 yields [OsH5{xant(PiPr2)2}]- (8), containing a kappa2-P,P-diphosphine. Complex 8 is easily protonated to afford OsH6{xant(PiPr2)2} (9), which releases H2 to regenerate 7, closing a second cycle for the formation of molecular hydrogen. PMID- 27957853 TI - Characterization of the Direct Interaction between Hybrid Sensor Kinases PA1611 and RetS That Controls Biofilm Formation and the Type III Secretion System in Pseudomonas aeruginosa. AB - One of the leading causes of morbidity and mortality in cystic fibrosis (CF) patients is pulmonary infection with Pseudomonas aeruginosa, and the pathophysiology of pulmonary infection in CF is affected by the lifestyle of this micro-organism. RetS-GacS/A-RsmA is a key regulatory pathway in P. aeruginosa that determines the bacterium's lifestyle choice. Previously, we identified PA1611, a hybrid sensor kinase, as a new player in this pathway that interacts with RetS and influences biofilm formation and type III secretion system. In this study, we explored the structural and mechanistic basis of the interaction between PA1611 and RetS. We identified the amino acid residues critical for PA1611-RetS interactions by molecular modeling. These residues were then targeted for site-directed mutagenesis. Amino acid substitutions were carried out at seven key positions in PA1611 and at six corresponding key positions in RetS. The influence of such substitutions in PA1611 on the interaction was analyzed by bacterial two-hybrid assays. We carried out functional analysis of these mutants in P. aeruginosa for their effect on specific phenotypes. Two residues, F269 and E276, located within the histidine kinase A and histidine kinase-like ATPase domains of PA1611 were found to play crucial roles in the PA1611-RetS interaction and had profound effects on phenotypes. Corresponding mutations in RetS demonstrated similar results. We further confirmed that these mutations in PA1611 function through the GacS/GacA-RsmY/Z signaling pathway. Collectively, our findings provide a noncognate sensor kinase direct interaction model for a signaling pathway, key for lifestyle selection in P. aeruginosa, and targeting such interaction may serve as a novel way of controlling infections with P. aeruginosa. PMID- 27957854 TI - Indocyanine Green-Loaded Silver Nanoparticle@Polyaniline Core/Shell Theranostic Nanocomposites for Photoacoustic/Near-Infrared Fluorescence Imaging-Guided and Single-Light-Triggered Photothermal and Photodynamic Therapy. AB - Photoacoustic (PA)/near-infrared fluorescence (NIRF) dual-modal imaging-guided phototherapy has been wide explored very recently. However, the development of high-efficiency and simplified-performed theranostic system for amplifying imaging-guided photothermal therapy/photodynamic therapy (PTT/PDT) is still a great challenge. Herein, a single-light-triggered indocyanine green (ICG)-loaded PEGylation silver nanoparticle core/polyaniline shell (Ag@PANI) nanocomposites (ICG-Ag@PANI) for PA/NIRF imaging-guided enhanced PTT/PDT synergistic effect has been successfully constructed. In this study, the synthesized Ag@PANI nanocomposites are utilized not only as the promising photothermal agent but also as potential nanovehicles for loading photosensitizer ICG via pi-pi stacking and hydrophobic interaction. The as-prepared ICG-Ag@PANI possesses many superior properties such as strong optical absorption in the near-infrared (NIR) region, enhanced photostability of ICG, as well as outstanding NIR laser-induced local hyperthermia and reactive oxygen species (ROS) generation. In the in vivo study, PA/NIRF dual-modal imaging confirms the accumulation and distribution of ICG Ag@PANI in the tumor region via enhanced permeability and retention (EPR) effect. Moreover, the PTT effect of ICG-Ag@PANI rapidly raised the tumor temperature to 56.8 degrees C within 5 min. It is also demonstrated that the cytotoxic ROS generation ability of ICG is well maintained after being loaded onto Ag@PANI nanocomposites. Remarkably, in comparison with PTT or PDT alone, the single 808 nm NIR laser-triggered combined PTT/PDT therapy exhibits enhanced HeLa cells lethality in vitro and tumor growth inhibition in vivo. PMID- 27957855 TI - Effect of Out-of-Plane Alkyl Group's Position in Dye-Sensitized Solar Cell Efficiency: A Structure-Property Relationship Utilizing Indoline-Based Unsymmetrical Squaraine Dyes. AB - Squaraine dyes are promising chromophores to harvest visible and near-infrared (NIR) photons. A series of indoline-based unsymmetrical squaraine (SQ) dyes that contain alkyl chains at sp3 C- and N- atoms of indoline moieties with a carboxylic acid anchoring group were synthesized. The optical and electrochemical properties of the SQ dyes in solution were nearly identical as there was no change in the D-A-D SQ framework; however, remarkable changes with respect to the power conversion efficiencies (PCE) were observed depending upon the position of alkyl groups in the dye. Introduction of alkyl groups to the indoline unit that was away from anchoring unit were helped in more dye loading with controlled organization of dyes on surface, increased charge transfer resistance, long electron lifetime, and hence higher PCE than that of the corresponding isomer in which the alkyl groups funtionalized indoline unit contains the carboxylic acid anchoring group. Careful analysis of incident photon-to-current conversion efficiency (IPCE) profiles indicated the presence of aggregated structure on the TiO2 surface that contributes to the charge injection in the presence of a coadsorbent. A dye-sensitized solar cell (DSSC) device made out of SQ5 was achieved an efficiency of 9.0%, with an open-circuit potential (Voc) of 660 mV and short-circuit current density (Jsc) of 19.82 mA/cm2, under simulated AM 1.5G illumination (100 mW/cm2). The IPCE profile of SQ5 shows an onset near to 750 nm with a good quantum efficiency (>80%) in the range of 550-700 nm, indicating the importance of self-organization of dyes on the TiO2 surface for an efficient charge injection. This present investigation revealed the importance of position of alkyl groups in the squaraine-based dyes for the better PCE. PMID- 27957857 TI - N-type Self-Doping of Fluorinate Conjugated Polyelectrolytes for Polymer Solar Cells: Modulation of Dipole, Morphology, and Conductivity. AB - For the conjugated polyelectrolytes (CPEs) interlayers, many studies focus on the modulation of interfacial dipoles in the polymer solar cells (PSCs) by altering the side polar groups but usually ignore the functions of conjugated backbone engineering (CBE) through the delicate design to improve their functions. Herein, novel alcohol-soluble CPEs by incorporation of fluorinate benzene onto the backbone, namely PFf1B and PFf4B, have been synthesized to modulate the interfacial dipoles and charge mobility. A favorable bidipole composed of ion induced dipole and F hydrogen bond-induced dipole was discovered to be responsible for the tunable work function of indium tin oxide (ITO) electrode. Moreover, a desirable nanowires morphology of the upper active layer has also been obtained with the help of the self-assembly of fluorinated CPEs. More intriguingly, an unusual n-type doping favored by fluorine-induced electron transfer (FIET) was observed in these CPEs, leading to the improvement in the electron mobility. As a consequence, these fluorinated CPEs were demonstrated with a general application in the PSCs based on various active layers. Note that PFf4B with the highest loading of F atoms can work efficiently in a thickness of up to 31.8 nm, which broke the thickness limitation of most reported CPEs interlayer. PMID- 27957858 TI - Bioinspired Coordination Micelles Integrating High Stability, Triggered Cargo Release, and Magnetic Resonance Imaging. AB - Catechol-Fe3+ coordinated micelles show the potential for achieving on-demand drug delivery and magnetic resonance imaging in a single nanoplatform. Herein, we developed bioinspired coordination-cross-linked amphiphilic polymeric micelles loaded with a model anticancer agent, doxorubicin (Dox). The nanoscale micelles could tolerate substantial dilution to a condition below the critical micelle concentration (9.4 +/- 0.3 MUg/mL) without sacrificing the nanocarrier integrity due to the catechol-Fe3+ coordinated core cross-linking. Under acidic conditions (pH 5.0), the release rate of Dox was significantly faster compared to that at pH 7.4 as a consequence of coordination collapse and particle de-cross-linking. The cell viability study in 4T1 cells showed no toxicity regarding placebo cross linked micelles. The micelles with improved stability showed a dramatically increased Dox accumulation in tumors and hence the enhanced suppression of tumor growth in a 4T1 tumor-bearing mouse model. The presence of Fe3+ endowed the micelles T1-weighted MRI capability both in vitro and in vivo without the incorporation of traditional toxic paramagnetic contrast agents. The current work presented a simple "three birds with one stone" approach to engineer the robust theranostic nanomedicine platform. PMID- 27957856 TI - High-throughput Identification of DNA-Encoded IgG Ligands that Distinguish Active and Latent Mycobacterium tuberculosis Infections. AB - The circulating antibody repertoire encodes a patient's health status and pathogen exposure history, but identifying antibodies with diagnostic potential usually requires knowledge of the antigen(s). We previously circumvented this problem by screening libraries of bead-displayed small molecules against case and control serum samples to discover "epitope surrogates" (ligands of IgGs enriched in the case sample). Here, we describe an improved version of this technology that employs DNA-encoded libraries and high-throughput FACS-based screening to discover epitope surrogates that differentiate noninfectious/latent (LTB) patients from infectious/active TB (ATB) patients, which is imperative for proper treatment selection and antibiotic stewardship. Normal control/LTB (10 patients each, NCL) and ATB (10 patients) serum pools were screened against a library (5 * 106 beads, 448 000 unique compounds) using fluorescent antihuman IgG to label hit compound beads for FACS. Deep sequencing decoded all hit structures and each hit's occurrence frequencies. ATB hits were pruned of NCL hits and prioritized for resynthesis based on occurrence and homology. Several structurally homologous families were identified and 16/21 resynthesized representative hits validated as selective ligands of ATB serum IgGs (p < 0.005). The native secreted TB protein Ag85B (though not the E. coli recombinant form) competed with one of the validated ligands for binding to antibodies, suggesting that it mimics a native Ag85B epitope. The use of DNA-encoded libraries and FACS-based screening in epitope surrogate discovery reveals thousands of potential hit structures. Distilling this list down to several consensus chemical structures yielded a diagnostic panel for ATB composed of thermally stable and economically produced small molecule ligands in place of protein antigens. PMID- 27957859 TI - Prospects for Applying Synthetic Biology to Toxicology: Future Opportunities and Current Limitations for the Repurposing of Cytochrome P450 Systems. AB - The 30 years since the inception of Chemical Research in Toxicology, game changing advances in chemical and molecular biology, the fundamental disciplines underpinning molecular toxicology, have been made. While these have led to important advances in the study of mechanisms by which chemicals damage cells and systems, there has been less focus on applying these advances to prediction, detection, and mitigation of toxicity. Over the last ~15 years, synthetic biology, the repurposing of biological "parts" in systems engineered for useful ends, has been explored in other areas of the biomedical and life sciences, for such applications as detecting metabolites, drug discovery and delivery, investigating disease mechanisms, improving medical treatment, and producing useful chemicals. These examples provide models for the application of synthetic biology to toxicology, which, for the most part, has not yet benefited from such approaches. In this perspective, we review the synthetic biology approaches that have been applied to date and speculate on possible short to medium term and "blue sky" aspirations for synthetic biology, particularly in clinical and environmental toxicology. Finally, we point out key hurdles that must be overcome for the full potential of synthetic biology to be realized. PMID- 27957860 TI - Unprecedented Enhancement of Noble Gas-Noble Metal Bonding in NgAu3+ (Ng = Ar, Kr, and Xe) Ion through Hydrogen Doping. AB - Behavior of gold as hydrogen in certain gold compounds and a very recent experimental report on the noble gas-noble metal interaction in Ar complexes of mixed Au-Ag trimers have motivated us to investigate the effect of hydrogen doping on the Ng-Au (Ng = Ar, Kr, and Xe) bonding through various ab initio based techniques. The calculated results show considerable strengthening of the Ng-Au bond in terms of bond length, bond energy, stretching vibrational frequency, and force constant. Particularly, an exceptional enhancement of Ar-Au bonding strength has been observed in ArAuH2+ species as compared to that in ArAu3+ system, as revealed from the CCSD(T) calculated Ar-Au bond energy value of 32 and 72 kJ mol-1 for ArAu3+ and ArAuH2+, respectively. In the calculated IR spectra, the Ar-Au stretching frequency is blue-shifted by 65% in going from ArAu3+ to ArAuH2+ species. Similar trends have been obtained in the case of all Ar, Kr, and Xe complexes with Ag and Cu trimers. Among all the NgM3-kHk+ complexes (where k = 0-2), the strongest binding in NgMH2+ complex is attributed to significant enhancement in the covalent characteristics of the Ng-M bond and considerable increase in charge-induced dipole interaction, as shown from the topological analysis. PMID- 27957862 TI - Electron Filtering by an Intervening ZnS Thin Film in the Gold Nanoparticle Loaded CdS Plasmonic Photocatalyst. AB - In the gold nanoparticle (Au NP)-loaded CdS film on fluorine-doped tin oxide electrode (Au/CdS/FTO), the localized plasmonic resonance excitation-induced electron injection from Au NP to CdS has been proven by photoelectrochemical measurements. Formation of ZnS thin films between the Au NP and CdS film leads to a drastic increase of the photocurrent under visible-light irradiation (lambda > 610 nm) in a 0.1 M NaClO4 aqueous electrolyte solution due to the electron filtering effect. The photocurrent strongly depends on the thickness of the ZnS film, and the maximum value is obtained at a thickness as thin as 2.1 nm. Furthermore, the ZnS overlayer significantly stabilizes the photocurrent of the CdS/FTO electrode in a polysulfide/sulfide electrolyte solution even under the excitation of CdS (lambda > 430 nm). This work presents important information about the design for new plasmonic photocatalysts consisting of plasmonic metal NPs and chalcogenide semiconductors with high conduction band edge. PMID- 27957861 TI - Codelivery of Ponatinib and SAR302503 by Active Bone-Targeted Polymeric Micelles for the Treatment of Therapy-Resistant Chronic Myeloid Leukemia. AB - Point mutations in the BCR-ABL1 domain and primitive chronic myelogenous leukemia (CML) cells existing in the bone marrow environment insensitive to tyrosine kinase inhibitors (TKIs) have become two major challenges in the CML therapy. In this study, combined TKI ponatinib and JAK2 inhibitor SAR302503 short-term treatment effectively suppressed growth and promoted apoptosis of BaF3/T315I cells in cytokine-containing medium in vitro. SAR302503 prevented cytokine dependent resistance to ponatinib via inhibition of JAK2/STAT5 phosphorylation. Codelivery of ponatinib and SAR302503 by active bone-targeted polymeric micellar formulation greatly increased the drug accumulation in medullary cavity. The therapeutic efficacy of bone-targeted formulation was demonstrated in BaF3/T315I cells inoculated murine model with no dose-limited toxicity detectable in health mice. Thus, the intravenous injectable bone-homing ponatinib and SAR302503 micellar formulation represents a promising strategy for the treatment of therapy resistant CML. PMID- 27957863 TI - Why we need to implement intramolecular hydrogen-bonding considerations in drug discovery. PMID- 27957864 TI - Drug metabolism and liver disease: a drug-gene-environment interaction. AB - Despite the central role of the liver in drug metabolism, surprisingly there is lack of certainty in anticipating the extent of modification of the clearance of a given drug in a given patient. The intent of this review is to provide a conceptual framework in considering the impact of liver disease on drug disposition and reciprocally the impact of drug disposition on liver disease. It is proposed that improved understanding of the situation is gained by considering the issue as a special example of a drug-gene-environment interaction. This requires an integration of knowledge of the drug's properties, knowledge of the gene products involved in its metabolism, and knowledge of the pathophysiology of its disposition. This will enhance the level of predictability of drug disposition and toxicity for a drug of interest in an individual patient. It is our contention that advances in pharmacology, pharmacogenomics, and hepatology, together with concerted interests in the academic, regulatory, and pharmaceutical industry communities provide an ideal immediate environment to move from a qualitative reactive approach to quantitative proactive approach in individualizing patient therapy in liver disease. PMID- 27957865 TI - Edited abstracts from the fifth European Conference on Advances in Wound Management, to be held in Harrogate, 21-24 November, 1995. AB - PRESSURE SORES DOCUMENTATION OF WOUND HEALING AND QUALITY OF LIFE LEG ULCERS AND BANDAGING WOUND HEALING EDUCATION LEG ULCER TREATMENT PRESSURE SORE ASSESSMENT WOUND HEALING DELIVERY AND COST-EFFECTIVENESS WOUND HEALING DRESSING TRIALS STUDIES ON WOUND HEALING DRESSINGS LEG ULCER TRIALS DIABETIC WOUNDS WOUND HEALING RESEARCH STUDIES INFECTION AND HEALING WOUND HEALING STUDIES. PMID- 27957866 TI - Pyridazinone: an attractive lead for anti-inflammatory and analgesic drug discovery. AB - In spite of the availability of a large number of anti-inflammatory and analgesic agents, fighting pain and inflammation remains a common problem. The current review article discusses the need of novel therapeutic targets for risk-free anti inflammatory and analgesic therapy and summarizes some new agents in various stages of drug discovery pipeline. Pyridazin-3(2H)-ones are nitrogen-rich heterocyclic compounds of considerable medicinal interest due to their diverse biological activities. The current review article focuses on progressive development of this attractive scaffold for the design and synthesis of new pyridazinone-based anti-inflammatory and analgesic agents. Mechanistic insights into the anti-inflammatory and analgesic properties of pyridazinone derivatives and various synthetic techniques used for their synthesis are also described. PMID- 27957867 TI - Network analysis of knowledge and practices regarding sexual and reproductive health: a study among adolescent street girls in Kinshasa (DRC). AB - OBJECTIVES: The aim of the study was to ascertain the influence of knowledge and interventions in sexual and reproductive health and contraception practices among adolescent street girls from Kinshasa, Democratic Republic of the Congo. METHODS: A cross-sectional study was carried out among street girls between 12 and 21 years of age. A standardised questionnaire was used, encompassing socio demographic data and knowledge and practices regarding sexual and reproductive health. A network analysis was carried out. RESULTS: The study comprised 293 street girls. The mean age was 17.1 years (range 12-21 years) and the mean time spent living on the streets was 3.9 years (range 0-15 years). Commercial sex was reported by 78.5% (95% confidence interval [CI] 73.3%, 83.2%) as the main source of their income. During their last sexual intercourse, 44.0% (95%CI 38.1%, 50.4%) had not used a condom; 29.3% (95%CI 23.3%, 35.9%) had used hormonal contraception. Previous pregnancy was reported by 62.5% (95%CI 56.7%, 68.3%) and current pregnancy by 12.3% (95%CI 8.8%, 17.2%); 24.5% of previous pregnancies ended in voluntary termination, with a higher rate among the youngest street girls (12-15 years, 50.0%; p = 0.01). Time spent living on the streets was independently associated with pregnancy (odds ratio 1.2; 95%CI 1.1, 1.4). Practices and outcomes (previous or current pregnancy) were poorly correlated with knowledge about sexual and reproductive health. The network analysis confirmed the poor influence of exposure to intervention activities on sexual and reproductive health practices and outcomes, but did confirm a centrality effect of knowledge about HIV/AIDS. CONCLUSION: Street girls in Kinshasa are extremely vulnerable with regard to their sexual and reproductive health, especially the youngest street girls. Behavioural and biomedical interventions have had limited influence. Structural and societal changes are necessary to positively impact street girls' sexual and reproductive health. Knowledge about HIV/AIDS than about risk of pregnancy had a greater influence on sexual and reproductive health practices. PMID- 27957868 TI - Impact of smoking and preoperative electrophysiology on outcome after open carpal tunnel release. AB - BACKGROUND: The aim was to evaluate the influence of smoking and preoperative electrophysiology on the outcome of open carpal tunnel release. METHODS: This retrospective observational study evaluated the outcome in 493 patients (531 hands) primary operated for carpal tunnel syndrome. Data were collected from medical records, health evaluations, and QuickDASH questionnaires before surgery and 1 year after. RESULTS: Smokers had a higher QuickDASH score preoperatively as well as postoperatively, but the change in total score did not differ. The odds of having a postoperative QuickDASH score >10 were 2.5 times higher in smoking patients than in non-smoking patients. In 124/493 patients (25%), no clinically significant improvement was seen. Normal and extreme preoperative electrophysiology values were associated with higher postoperative scores. No correlation was found between preoperative QuickDASH scores and preoperative electrophysiology values. CONCLUSIONS: Smokers with carpal tunnel syndrome experience more symptoms preoperatively. Smokers have remaining symptoms after surgery. There is no correlation between preoperative QuickDASH scores and preoperative electrophysiology values. Patients with normal or near to normal preoperative electrophysiology results have limited improvement after surgery. PMID- 27957870 TI - Factors affecting healing. AB - Leg ulcers are not all the same and, although the majority are due to venous disease, many other diseases may produce a chronic ulcer on the leg. PMID- 27957869 TI - Authors' reply. PMID- 27957871 TI - Management practice at leg ulcer clinics. AB - These three papers, presented at a Journal of Wound Care master class, describe procedures used at specialist clinics for the care of patients with leg ulcers. PMID- 27957872 TI - Editorial. AB - Making education relevant to clinical practice Wound Care Awards, 1998. PMID- 27957873 TI - Challenges in diagnosis. AB - In an ideal world, all patients presenting with leg ulceration would undergo full investigations in order to confirm or refute the proposed aetiology. However, with economic constraints, it is imperative that available health resources are used to the maximum benefit. In our unit, selective investigation is based on the question of whether the result will alter the management of the patient. PMID- 27957875 TI - A Guide to Managing Leg Ulcers. PMID- 27957874 TI - Influence of well-known risk factors for hearing loss in a longitudinal twin study. AB - OBJECTIVE: The aim was to investigate the influence of environmental exposures on hearing loss in a twin cohort. STUDY SAMPLE: Male twins born 1914-1958, representing an unscreened population, were tested for hearing loss at two occasions, 18 years apart. DESIGN: Clinical audiometry and a questionnaire were performed at both time points in this longitudinal study. Noise and solvent exposure were assessed using occupational work codes and a job exposure matrix. Hearing impairment was investigated using two different pure tone averages: PTA4 (0.5, 1, 2, and 4 kHz) and HPTA4 (3, 4, 6, and 8 kHz). RESULTS: Age affected all outcome measures. Noise exposure between time point one and two affected the threshold shifts of PTA4 and HPTA4 more in participants with a pre-existing hearing loss at time point one. Lifetime occupational noise exposure was a risk factor especially for the low-frequency hearing threshold PTA4. Firearm use was a statistically significant risk factor for all outcome measures. CONCLUSIONS: Pre existing hearing loss can increase the risk of hearing impairment due to occupational noise exposure. An increased risk for NIHL was also seen in the group with exposures below 85 dB(A), a result that indicates awareness of NIHL should be raised even for those working in environments where sound levels are below 85 dB(A). PMID- 27957876 TI - A new function for miRNAs as regulators of autophagy. AB - Autophagy is a self-digestive process regulated by an intricate network of factors able either to ensure the prosurvival function of autophagy or to convert it in a death pathway. Recently, the involvement of miRNAs in the regulation of autophagy networks has been reported. This review will summarize the main features of these small noncoding endogenous RNAs, focusing on their relevance in cancer and finally addressing their impact on autophagy. PMID- 27957877 TI - A case for poroelasticity in skeletal muscle finite element analysis: experiment and modeling. AB - Finite element models of skeletal muscle typically ignore the biphasic nature of the tissue, associating any time dependence with a viscoelastic formulation. In this study, direct experimental measurement of permeability was conducted as a function of specimen orientation and strain. A finite element model was developed to identify how various permeability formulations affect compressive response of the tissue. Experimental and modeling results suggest the assumption of a constant, isotropic permeability is appropriate. A viscoelastic only model differed considerably from a visco-poroelastic model, suggesting the latter is more appropriate for compressive studies. PMID- 27957878 TI - Polyamine-trypanothione pathway: an update. AB - In trypanosomatids, polyamine and trypanothione pathways can be considered as a whole unique metabolism, where most enzymes are essential for parasitic survival and infectivity. Leishmania parasites and all the other members of the Trypanosomatids family depend on polyamines for growth and survival: the enzymes involved in the synthesis and utilization of spermidine and trypanothione, i.e., arginase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase and in particular trypanothione synthetase-amidase, trypanothione reductase and tryparedoxin-dependent peroxidase are promising targets for drug development. This review deals with recent structure-based studies on these enzymes, aimed at the discovery of inhibitors of this pathway. PMID- 27957880 TI - Practice Points. AB - PRESSURE SORE RISK ASSESSMENT. PMID- 27957879 TI - Lead intoxication due to ayurvedic medications as a cause of abdominal pain in adults. AB - BACKGROUND: Though a majority of cases of lead intoxication come from occupational exposures, traditional and folk remedies have also been reported to contain toxic amounts of lead. We present a large series of patients with lead poisoning due to intake of Ayurvedic medicines, all of whom presented with unexplained abdominal pain. METHODOLOGY: This was a retrospective, observational case series from a tertiary care center in India. The charts of patients who underwent blood lead level (BLL) testing as a part of workup for unexplained abdominal pain between 2005 and 2013 were reviewed. The patients with lead intoxication (BLLs >25 MUg/dl) were identified and demographics, history, possible risk factors, clinical presentation and investigations were reviewed. Treatment details, duration, time to symptomatic recovery, laboratory follow-up and adverse events during therapy were recorded. RESULTS: BLLs were tested in 786 patients with unexplained abdominal pain and high levels were identified in 75 (9.5%) patients, of which a majority (73 patients, 9.3%) had history of Ayurvedic medication intake and only two had occupational exposure. Five randomly chosen Ayurvedic medications were analyzed and lead levels were impermissibly high (14 34,950 ppm) in all of them. Besides pain in abdomen, other presenting complaints were constipation, hypertension, neurological symptoms and acute kidney injury. Anemia and abnormal liver biochemical tests were observed in all the 73 patients. Discontinuing the Ayurvedic medicines and chelation with d-penicillamine led to improvement in symptoms and reduction in BLLs in all patients within 3-4 months. CONCLUSION: The patients presenting with severe recurrent abdominal pain, anemia and history of use of Ayurvedic medicines should be evaluated for lead toxicity. Early diagnosis in such cases can prevent unnecessary investigations and interventions, and permits early commencement of the treatment. PMID- 27957881 TI - From the Journals. AB - HONEY AS A BURN TREATMENT SURGEONS' GLOVES THE ROLE OF ZINC IN WOUND HEALING. PMID- 27957882 TI - Letters. AB - USE OF MEPITEL IN SKIN CRAFT DONOR SITES USE OF MEPITEL ON PUNCH CRAFT SITES EPIDERMOLYSIS BULLOSA. PMID- 27957883 TI - Virtual anatomical reconstruction of large acetabular bone defects using a statistical shape model. AB - Custom implants are used to treat patients with large acetabular bone defects. To quantify the bone defect and to initialize the implant design, a virtual anatomical reconstruction of the bone needs to be performed. Our SSM-based reconstruction approach was used to overcome the limitations of the mirrored contralateral method and improves upon other SSM reconstruction techniques. The reconstruction errors for the acetabular direction, the hip joint center and the acetabular radius were, respectively: [Formula: see text], 2.6 mm and 0.7 mm. We believe that our method can be an essential tool in the planning and the design of custom implants. PMID- 27957884 TI - Edited abstracts from the sixth European Conference on Advances in Wound Management, to be held in Amsterdam on October 1-4, 1996. AB - LEG ULCERS PRESSURE SORES DIABETIC WOUNDS CLINICAL STUDIES WOUND HEALING EDUCATION EXPERIMENTAL STUDIES DRESSING AND PRODUCT TRIALS. PMID- 27957885 TI - Changing Ploidy as a Strategy: The Irish Potato Famine Pathogen Shifts Ploidy in Relation to Its Sexuality. AB - The oomycete Phytophthora infestans was the causal agent of the Irish Great Famine and is a recurring threat to global food security. The pathogen can reproduce both sexually and asexually, with high potential to adapt to various environments and great risk to break disease resistance genes in potato. As are other oomycetes, P. infestans is regarded to be diploid during the vegetative phase of its life cycle, although some studies reported trisomy and polyploidy. Using microsatellite fingerprinting, genome-wide assessment of single nucleotide polymorphisms, nuclear DNA quantification, and microscopic counting of chromosome numbers, we assessed the ploidy level of a comprehensive selection of isolates. All progenies from sexual populations of P. infestans in nature were found to be diploid, in contrast nearly all dominant asexual lineages, including the most important pandemic clonal lineages US-1 and 13_A2 were triploid. Such triploids possess significantly more allelic variation than diploids. We observed that triploid genotype can change to a diploid genome constitution when exposed to artificial stress conditions. This study reveals that fluctuations in the ploidy level may be a key factor in the adaptation process of this notorious plant destroyer and imposes an extra challenge to control this disease. PMID- 27957892 TI - Reviews. AB - PRESSURE DAMAGE: PREVENTION, DETECTION AND TREATMENT ABC OF DERMATOLOGY (3rd edn) ABC OF DIABETES (4th edn) A COLOUR GUIDE TO THE NURSING MANAGEMENT OF CHRONIC WOUNDS (2nd edn). PMID- 27957886 TI - Self-rated psychopathic traits in a sample of treatment-seeking adolescent girls with internalizing and externalizing disorders: comparisons to girls in the community. AB - BACKGROUND: Psychopathy research has thus far focused mostly on child, male, and delinquent samples, but the results are most likely non-generalizable to adolescent girls with mental health disorders. AIM: The present study aimed to compare self-rated psychopathic traits between female psychiatric outpatients and girls in the community, and to investigate how psychopathic traits relate to psychiatric disorders. METHOD: The outpatient sample comprised 163 girls aged 15 17-years recruited from municipal mental health services. Psychiatric diagnoses were assessed based on the ICD-10 classification. The community sample comprised 355 girls from secondary, vocational, and high schools. The Youth Psychopathic trait Inventory (YPI) served as a self-assessment tool. RESULTS: Treatment seeking girls exhibit a more impulsive and irresponsible lifestyle than do girls in the community. Girls with externalizing psychopathology, unlike those with an internalizing disorder, exhibit more deficient affective experience than do girls in the community. Psychopathic traits associate with having a psychiatric disorder, a depressive disorder, ADHD, and a conduct disorder. CONCLUSIONS: The psychiatric examination of treatment-seeking adolescent girls would likely benefit from screening for psychopathy and its underlying components. PMID- 27957894 TI - From the Journals. AB - PRESSURE ULCER RISK ASSESSMENT IN INTENSIVE CARE SETTINGS MRSA IN BURN PATIENTS LONG-STRETCH AND SHORT- STRETCH BANDAGING HEALING RATES AND TREATMENT COSTS IN COMPRESSION BANDAGING. PMID- 27957896 TI - Letters. AB - ULTRASOUND THERAPY AND WOUND HEALING NUTRITION AND PRESSURE DAMAGE. PMID- 27957897 TI - Encouraging innovation and creative practice. AB - One of the key factors that helps us to sustain the commitment to do well and be creative is positive feedback, the most valuable source being the satisfied patient. Feedback from colleagues is also important and it is often their enthusiasm and support that gives us the inspiration to develop new ideas. PMID- 27957899 TI - Readers' Questions. AB - COMBINING HYDROGEL AND FOAM DRESSINGS ACCURATE ASSESSMENT OF VASCULAR DISEASE CONTROLLING BLEEDING IN FRAGILE FUNGATING WOUNDS. PMID- 27957900 TI - From the Journals. AB - REPLACEMENT DERMIS TRIAL COMPRESSION BANDAGING AND ARTERIAL DISEASE MEASURING WOUNDS. PMID- 27957901 TI - From the Journals. AB - PROBLEMS ASSOCIATED WITH ANTIBIOTIC RESISTANCE ANTIBACTERIAL PROPERTIES OF TEA TREE OIL LEG ULCERATION AND ETHNIC BACKGROUND. PMID- 27957902 TI - Wound-healing problems associated with cancers. AB - This update presents a guide to the factors associated with malignant tumours that have an adverse effect on wound healing in patients with cancer. PMID- 27957903 TI - The challenge of effective professional practice. AB - After we have finished formal education we must continue to update our knowledge to remain effective practitioners. This may involve acknowledging that a treatment which previously appeared to be the most effective according to the best evidence available, is no longer recommended because of new evidence. If we are not able to change our minds, we will become fossilised practitioners, dinosaurs heading towards extinction. PMID- 27957904 TI - Letters. AB - HYDROGELS AND FOAM DRESSINGS IN COMBINATION CONTROLLING BLEEDING IN FUNGATING WOUNDS HYDROSTATIC LEG ULCERS COMMUNITY LEG ULCER CLINICS. PMID- 27957905 TI - Letters. AB - ALTERNATING-PRESSURE MATTRESS REPLACEMENTS. PMID- 27957906 TI - An infected wound in a patient with necrotising fasciitis. AB - This case study describes the management of a patient with rheumatoid arthritis and diabetes mellitus who presented with necrotising fasciitis. PMID- 27957907 TI - Guidelines for pressure sore prevention and management. AB - A discussion on how an NHS community trust developed guidelines to assist in the allocation of pressure-relieving equipment. PMID- 27958191 TI - Wet or Dry? A Review of Intravenous Fluid Administration in Anesthesia Practice. AB - Fluid therapy has dramatically changed since its early inception nearly 200 years ago. Administration of intravenous fluid (IVF) has evolved from a "drip" technique to the algorithmic approach of the anesthetic fluid plan, and is now moving toward Goal-Directed Fluid Therapy. As the science and culture of fluid management evolves, anesthetists must remain focused on "why" anesthetic fluid matters. The purpose of IVF administration is to support tissue perfusion and maintain euvolemia. As the evidence underlying perioperative practice matures and the science of anesthesia races to meet the evolving demands of surgery, anesthetists must align knowledge generation with the individualized needs of the patient. The future of perioperative IVF therapy will be patient centric. In the near future, anesthetists will know the patient's blood volume before, during, and after the surgery. They will no longer depend on inaccurate surrogates to estimate, but have the knowledge to titrate fluids to maintain a zero balance. Practice will move away from algorithms and toward individualized fluid administration based on reproducible end points. Decisions about fluid selection, timing, and volume will be driven by patient- and case-specific requirements as specific as when a patient is typed and crossed for blood transfusion. The greatest challenge for the anesthetist in perioperative fluid therapy is to move beyond the dogmatic practices of the past and toward fluid therapy guided by patient centric evidence. PMID- 27958190 TI - ONCOLOGISTS' BARRIERS AND FACILITATORS FOR ONCOTYPE DX USE: QUALITATIVE STUDY. AB - BACKGROUND: Oncotype DX (ODX), a tumor gene profiling test, has been incorporated into clinical guidelines to aid in adjuvant chemotherapy decision making for early-stage, hormone receptor positive breast cancer patients. Despite United States (U.S.) guidelines, less than half of eligible women receive testing. Reasons for low usage are unclear: Our objective was to better understand U.S. oncologists' ODX uptake and how they use ODX during adjuvant chemotherapy decision making. METHODS: We conducted semi-structured, ~30-minute phone interviews with medical and surgical oncologists in one U.S. State using purposive sampling. Oncologists were included if they saw greater than or equal to five breast cancer patients per week. Recruitment ended upon thematic saturation. Interviews were recorded, transcribed, and double-coded using template analysis. RESULTS: During analysis, themes emerged across three domains. First, organizational factors (i.e., departmental structure, ODX marketing, and medical/insurance guidelines) influenced ease of ODX use. Second, oncologists referenced the influence of interpersonal factors (e.g., normative beliefs and peer use of ODX) over their own practices and recommendations. Third, intrapersonal factors (e.g., oncologist attitudes, perceived barriers, and research gaps) were discussed: although oncologists largely held positive attitudes about ODX, they reported challenges with interpreting intermediate scores for treatment decisions and explaining test results to patients. Finally, oncologists identified several research gaps. CONCLUSIONS: As more tumor gene profiling tests are incorporated into cancer care for treatment decision making, it is important to understand their use in clinical practice. This study identified multi-level factors that influence ODX uptake into clinical practice, providing insights into facilitators and modifiable barriers that can be leveraged for improving ODX uptake to aid treatment decision making. PMID- 27958189 TI - Cost-effectiveness analysis of Chlamydia trachomatis screening in Dutch pregnant women. AB - Chlamydia trachomatis infections during pregnancy may have serious consequences for women and their offspring. Chlamydial infections are largely asymptomatic. Hence, prevention is based on screening. The objective of this study was to estimate the cost-effectiveness of C. trachomatis screening during pregnancy. We used a health-economic decision analysis model, which included potential health outcomes of C. trachomatis infection for women, partners and infants, and premature delivery. We estimated the cost-effectiveness from a societal perspective using recent prevalence data from a population-based prospective cohort study among pregnant women in the Netherlands. We calculated the averted costs by linking health outcomes with health care costs and productivity losses. Cost-effectiveness was expressed as net costs per major outcome prevented and was estimated in base-case analysis, sensitivity, and scenario analysis. In the base case analysis, the costs to detect 1000 pregnant women with C. trachomatis were estimated at ?527,900. Prevention of adverse health outcomes averted ?626,800 in medical costs, resulting in net cost savings. Sensitivity analysis showed that net cost savings remained with test costs up to ?22 (test price ?19) for a broad range of variation in underlying assumptions. Scenario analysis showed even more cost savings with targeted screening for women less than 30 years of age or with first pregnancies only. Antenatal screening for C. trachomatis is a cost-saving intervention when testing all pregnant women in the Netherlands. Savings increase even further when testing women younger than 30 years of age or with pregnancies only. PMID- 27958192 TI - Haoranjiania flava gen. nov., sp. nov., a new member of the family Chitinophagaceae, isolated from activated sludge. AB - A novel Gram-stain-negative, non-spore-forming and short rod-shaped bacterium, strain LIP-5T, isolated from an activated sludge in a pesticide factory in Xinyi, China, was investigated for its taxonomic position by a polyphasic approach. Cell growth occurred at 16-42 degrees C (optimum, 30 degrees C), in the presence of 0-3.0 % (w/v) NaCl (optimum, without NaCl) and at pH 6.0-9.0 (optimum, pH 7.0). Phylogenetic analysis based on 16S rRNA gene sequence comparisons showed that the isolate was a member of the family Chitinophagaceae, with the closest relatives being Arachidicoccus rhizosphaerae Vu-144T (93.5 % similarity), followed by Heliimonas saccharivorans L2-4T (90.5 %) and Chitinophaga ginsengisoli Gsoil 052T (89.6 %). Menaquinone 7 (MK-7) was the predominant respiratory ubiquinone and phosphatidylethanolamine and unidentified lipids were the major polar lipids. The major cellular fatty acids of strain LIP-5T were anteiso-C15 : 0 and iso-C15 : 0, and there were also moderate amounts of iso-C17 : 0 3-OH and C17 : 0 2-OH. The DNA G+C content was 42.3 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain LIP-5T was classified as representing a novel species of a new genus, for which the name Haoranjiania flava gen. nov., sp. nov. is proposed. The type strain of Haoranjiania flava is LIP-5T (=CCTCC AB 2015365T=KCTC 42956T). PMID- 27958193 TI - Lily and Yuh Nung Jan. AB - Lily and Yuh Nung Jan's collaboration started with the identification of Shaker as the first known potassium channel gene and has flourished to produce over 100 former students and postdocs who are now leading their own research groups. In an interview with Neuron, they reflect on their scientific discoveries, serendipity in science, and the value of curiosity-driven basic research. PMID- 27958194 TI - An analytical model and scaling of chordwise flexible flapping wings in forward flight. AB - Aerodynamic performance of biological flight characterized by the fluid structure interaction of a flapping wing and the surrounding fluid is affected by the wing flexibility. One of the main challenges to predict aerodynamic forces is that the wing shape and motion are a priori unknown. In this study, we derive an analytical fluid-structure interaction model for a chordwise flexible flapping two-dimensional airfoil in forward flight. A plunge motion is imposed on the rigid leading-edge (LE) of teardrop shape and the flexible tail dynamically deforms. The resulting unsteady aeroelasticity is modeled with the Euler Bernoulli-Theodorsen equation under a small deformation assumption. The two-way coupling is realized by considering the trailing-edge deformation relative to the LE as passive pitch, affecting the unsteady aerodynamics. The resulting wing deformation and the aerodynamic performance including lift and thrust agree well with high-fidelity numerical results. Under the dynamic balance, the aeroelastic stiffness decreases, whereas the aeroelastic stiffness increases with the reduced frequency. A novel aeroelastic frequency ratio is derived, which scales with the wing deformation, lift, and thrust. Finally, the dynamic similarity between flapping in water and air is established. PMID- 27958195 TI - Assessment of radiological protection systems among diagnostic radiology facilities in North East India. AB - This study aims to assess the adequacy level of radiological protection systems available in the diagnostic radiology facilities located in three capital cities of North East (NE) India. It further attempts to understand, using a multi disciplinary approach, how the safety codes/standards in diagnostic radiology framed by the Atomic Energy Regulatory Board (AERB) and the International Atomic Energy Agency (IAEA) to achieve adequate radiological protection in facilities, have been perceived, conceptualized, and applied accordingly in these facilities. About 30 diagnostic radiology facilities were randomly selected from three capitals of states in NE India; namely Imphal (Manipur), Shillong (Meghalaya) and Guwahati (Assam). A semi-structured questionnaire developed based on a multi disciplinary approach was used for this study. It was observed that radiological practices undertaken in these facilities were not exactly in line with safety codes/standards in diagnostic radiology of the AERB and the IAEA. About 50% of the facilities had registered/licensed x-ray equipment with the AERB. More than 80% of the workers did not use radiation protective devices, although these devices were available in the facilities. About 85% of facilities had no institutional risk management system. About 70% of the facilities did not carry out periodic quality assurance testing of their x-ray equipment or surveys of radiation leakage around the x-ray room, and did not display radiation safety indicators in the x-ray rooms. Workers in these facilities exhibited low risk perception about the risks associated with these practices. The majority of diagnostic radiology facilities in NE India did not comply with the radiological safety codes/standards framed by the AERB and IAEA. The study found inadequate levels of radiological protection systems in the majority of facilities. This study suggests a need to establish firm measures that comply with the radiological safety codes/standards of the AERB and IAEA to protect patients, workers and the public of this region. PMID- 27958196 TI - Atomic-layer-deposition-assisted ZnO nanoparticles for oxide charge-trap memory thin-film transistors. AB - ZnO nanoparticles (NPs) with monolayer structures were prepared by atomic layer deposition (ALD) to use for a charge-trap layer (CTL) for nonvolatile memory thin film transistors (MTFTs). The optimum ALD temperature of the NP formation was demonstrated to be 160 degrees C. The size and areal density of the ZnO NPs was estimated to be approximately 33 nm and 4.8 * 109 cm-2, respectively, when the number of ALD cycles was controlled to be 20. The fabricated MTFTs using a ZnO-NP CTL exhibited typical memory window properties, which are generated by charge trap/de-trap processes, in their transfer characteristics and the width of the memory window (MW) increased from 0.6 to 18.0 V when the number of ALD cycles increased from 5 to 30. The program characteristics of the MTFT were markedly enhanced by the post-annealing process performed at 180 degrees C in an oxygen ambient due to the improvements in the interface and bulk qualities of the ZnO NPs. The program/erase (P/E) speed was estimated to be 10 ms at P/E voltages of 14 and 17 V. The memory margin showed no degradation with the lapse in retention time for 2 * 104 s and after the repetitive P/E operations of 7 * 103 cycles. PMID- 27958197 TI - Awareness of ionizing radiation exposure among junior doctors and senior medical students in radiological investigations. AB - The awareness and knowledge of ionizing radiation exposure in radiological investigations among junior doctors and medical students were studied. The participants were year four to year six senior medical students enrolled at University of Dammam and interns in King Fahad University Hospital. The survey consisted of 22 questions designed online using the software 'QuestionPro' licensed to the University of Dammam. 100 hard copies were also distributed manually and collected. A total of 221 (88.5%) questionnaires were completed. 213 participants viewed, 151 started and 128 (84.7%) completed online. 93% of the distributed samples were completed. Overall knowledge was poor; 44% and 19% of the respondents thought incorrectly that MRI and ultrasound emit ionizing radiation, respectively. Respondents (92%; n = 203) underestimated the dose of abdominal spiral computed tomography (CT) and 4% thought no ionizing radiation involved in CT. 59% of respondents underestimated the radiation doses in nuclear medicine; bone scan 87%, PET/CT scan 67%, thyroid isotope scan 45% and PET scan 36%. 47% of the subjects had attended formal lectures, tutorials or workshops on radiation protection while 53% (n = 119) had not. For future education the majority stated they would prefer tutorials or workshops (42.3%) or problem-based learning/case studies (32.4%), while web-based modules would be their last choice (8.1%). PMID- 27958198 TI - Pressure dependence of the metal-insulator transition in kappa-(BEDT TTF)2Hg(SCN)2Cl: optical and transport studies. AB - The two-dimensional organic conductor kappa-(BEDT-TTF)2-Hg(SCN)2Cl exhibits a pronounced metal-insulator transition at [Formula: see text] K. From the splitting of the molecular vibrations, the phase transition can be unambiguously assigned to charge-ordering with [Formula: see text]. We have investigated the pressure evolution of this behavior by temperature-dependent electrical transport measurements and optical investigations applying hydrostatic pressure up to 12 kbar. The data reveal a mean-field like down-shift of [Formula: see text] with a critical pressure of [Formula: see text] kbar and a metallic state above the suppression of the charge-ordered state; no traces of superconductivity could be identified down to T = 1.5 K. As the charge order [Formula: see text] sets in abruptly with decreasing temperature, its size remains unaffected by pressure. However, the fraction of charge imbalanced molecules decreases until it is completely absent above 1.6 kbar. PMID- 27958199 TI - The world is your oyster! PMID- 27958200 TI - Update on pathology of ocular parasitic disease. AB - Parasites are a group of eukaryotic organisms that may be free-living or form a symbiotic or parasitic relationship with the hosts. Consisting of over 800,000 recognized species, parasites may be unicellular (Protozoa) or multicellular (helminths and arthropods). The association of parasites with human population started long before the emergence of civilization. Parasitic zoonotic diseases are prevalent worldwide including India. Appropriate epidemiological data are lacking on existing zoonotic parasitic diseases, and newer diseases are emerging in our scenario. Systemic diseases such as cysticercosis, paragonimiasis, hydatidosis, and toxoplasmosis are fairly common. Acquired Toxoplasma infections are rising in immune-deficient individuals. Amongst the ocular parasitic diseases, various protozoas such as Cystoidea, trematodes, tissue flagellates, sporozoas etc. affect humans in general and eyes in particular, in different parts of the world. These zoonoses seem to be a real health related problem globally. Recent intensification of research throughout the world has led to specialization in biological fields, creating a conducive situation for researchers interested in this subject. The basics of parasitology lie in morphology, pathology, and with recent updates in molecular parasitology, the scope has extended further. The current review is to address the recent update in ophthalmic parasites with special reference to pathology and give a glimpse of further research in this field. PMID- 27958201 TI - Evaluation and correlation of stress scores with blood pressure, endogenous cortisol levels, and homocysteine levels in patients with central serous chorioretinopathy and comparison with age-matched controls. AB - CONTEXT: Stress had been associated with the development of central serous chorioretinopathy (CSC). The study was designed to evaluate the effect of stress on other risk factors of CSC such as serum cortisol levels, serum homocysteine levels, and blood pressure (BP) in CSC patients. AIMS: To compare stress scores, serum cortisol and serum homocysteine levels, and BP of CSC patients with that of control population and to correlate stress scores of CSC patients with BP, serum cortisol levels, and serum homocysteine levels. MATERIALS AND METHODS: Stress scores, serum morning and evening cortisol levels, serum homocysteine levels, systolic and diastolic BP of 54 CSC patients were measured and compared with that of 54 age- and sex-related controls using Student's t-test. Stress scores of CSC patients were correlated with systolic and diastolic BP, serum morning and evening cortisol levels and serum homocysteine levels and Pearson correlation coefficient (r) were calculated. RESULTS: Stress scores, serum homocysteine levels, serum morning and evening cortisol levels, and systolic and diastolic BP were all elevated in CSC patients as compared with age- and sex-related controls (P < 0.05). Stress scores of CSC patients were found to correlate strongly with serum homocysteine levels, serum morning and evening cortisol levels, and systolic and diastolic BP, with r values 0.82, 0.8, 0.8, 0.8, and 0.81, respectively (P < 0.0001). CONCLUSIONS: Stress scores were elevated in CSC patients and were strongly correlated with serum homocysteine and cortisol levels and BP. PMID- 27958203 TI - A previously unidentified deletion in G protein-coupled receptor 143 causing X linked congenital nystagmus in a Chinese family. AB - BACKGROUND: Congenital nystagmus (CN) is characterized by conjugated, spontaneous, and involuntary ocular oscillations. It is an inherited disease and the most common inheritance pattern is X-linked CN. In this study, our aim is to identify the disease-causing mutation in a large sixth-generation Chinese family with X-linked CN. METHODS: It has been reported that mutations in four-point-one, ezrin, radixin, moesin domain-containing 7 gene (FRMD7) and G protein-coupled receptor 143 gene (GPR143) account for the majority patients of X-linked nystagmus. We collected 8 ml blood samples from members of a large sixth generation pedigree with X-linked CN and 100 normal controls. FRMD7 and GPR143 were scanned by polymerase chain reaction (PCR)-based DNA sequencing assays, and multiplex PCR assays were applied to detect deletions. RESULTS: We identified a previously unreported deletion covering 7 exons in GPR143 in a Chinese family. The heterozygous deletion from exon 3 to exon 9 of GPR143 was detected in all affected males in the family, while it was not detected in other unaffected relatives or 100 normal controls. CONCLUSIONS: This is the first report of molecular characterization in GPR143 gene in the CN family. Our results expand the spectrum of GPR143 mutations causing CN and further confirm the role of GPR143 in the pathogenesis of CN. PMID- 27958202 TI - Genomic identification of human vaccinia virus keratoconjunctivitis and its importance as a laboratory-acquired infection. AB - CONTEXT: Vaccinia virus (VACV) is a member of orthopoxvirus genus of the family Poxviridae. VACVs are enveloped, double-stranded DNA viruses. Several species of this family, for example, molluscum contagiosum, smallpox, deerpox, horsepox, rabbitpox, and VACVs may cause conjunctivitis. AIMS: Given the high incidence of keratoconjunctivitis in Iran (approximately 3.6%-53.9%) and insufficient clinical diagnostic measures, laboratory tests for detection of its causes and determination of accurate keratoconjunctivitis/conjunctivitis prevalence due to different pathogens are essential. SETTINGS AND DESIGN: In this research, conjunctival samples collected from 100 patients with keratoconjunctivitis signs were referred to an eye hospital of Iran. SUBJECTS AND METHODS: After DNA extraction, polymerase chain reaction (PCR) was carried out for detection of VACV. PCR-positive products were further subjected to DNA sequencing. STATISTICAL ANALYSIS USED: The results were analyzed using Chi-square test. RESULTS: In this study, 28% of the samples were positive and a statistically significant relationship obtained between working in medical or research laboratories and VACV prevalence (P < 0.05). CONCLUSIONS: This study showed a high rate of VACV keratoconjunctivitis, and therefore, further studies for its prevention and control are necessary. PMID- 27958204 TI - Results and safety profile of trainee cataract surgeons in a community setting in East Africa. AB - PURPOSE: To evaluate the results and safety profile of assistant medical officer ophthalmologists (AMO-O) performing cataract surgery in the last stage of their surgical training, before their appointment to local communities. METHODS: We retrospectively analyzed the records of patients who underwent cataract surgery by AMO-Os at Dar es Salaam, Comprehensive Community Based Rehabilitation for Tanzania Disability Hospital between September 2008 and June 2011. Surgical options were either extracapsular cataract extraction (ECCE) or manual small incision cataract surgery (MSICS), both with polymethylmethacrylate intraocular lens implantation. RESULTS: Four hundred and fourteen patients were included in the study. Two hundred and twenty-five (54%) underwent ECCE and 189 had MSICS. Mean logarithm of the minimum angle of resolution (logMAR) uncorrected visual acuity (UCVA) improved from 2.4 +/- 0.6 preoperatively to 1.3 +/- 0.8 1 week postoperatively (t-test, P < 0.001) and to 1.1 +/- 0.7 3 months postoperatively (t-test, P < 0.001). Mean logMAR best-corrected visual acuity (BCVA) was 0.7 +/- 0.5 1 week postoperatively and 0.6 +/- 0.5 3 months postoperatively. There was no significant difference in mean logMAR UCVA (P = 0.7) and BCVA (P = 0.7) postoperatively between ECCE and MSICS. 89.5% achieved BCVA better than 6/60 and 57.3% better than 6/18 with a follow-up of 3 months. Posterior capsule rupture and/or vitreous loss occurred in 34/414 patients (8.2%) and was more frequent (P = 0.047) in patients undergoing ECCE (10.2%) compared with MSICS (5.3%). CONCLUSION: AMO-O cataract surgeons at the end of their training offer significant improvement in the visual acuity of their patients. Continuous monitoring of outcomes will guide further improvements in surgical skills and minimize complications. PMID- 27958205 TI - Revision of trabeculectomy filtering blebs with mitomycin C: Long term results. AB - AIM: The aim of the study is to assess the outcomes of transconjunctival mitomycin C (MMC)-augmented revision in eyes with failed trabeculectomy. MATERIALS AND METHODS: This is a retrospective, noncomparative case series. One hundred and twenty-one eyes of 113 consecutive glaucoma patients with previously failed trabeculectomy who underwent transconjunctival revision with at least 12 months of follow-up were initially included in the study. The success was determined on the basis of intraocular pressure (IOP) alone. The main outcome measures were IOP, best-corrected distance visual acuity, complications, bleb appearance, lens status, visual field progression, and time between primary trabeculectomy and MMC revision. The main purpose of the study was to determine the efficacy of a single MMC-augmented needle revision. RESULTS: Mean follow-up was 2.3 years. Twelve months after revision, IOP had declined from 26.1 +/- 8.4 mmHg to 14.1 +/- 4.8 mmHg (P < 0.05) and remained 16.0 +/- 5.6 mmHg at 24 months, 15.7 +/- 5.8 mmHg at 48 months, and 15.2 +/- 4.0 mmHg at 60 months. Complete success was achieved in 53% of cases, 84% achieved qualified success, and 16% were classified as failures 12 months after revision. Early complications developed in 45 of the initial 121 eyes (37.2%). CONCLUSIONS: Transconjunctival MMC-augmented revision appears to be a safe and useful tool in reducing IOP and re-establishing filtration after trabeculectomy failure. This simple procedure has a high rate of success and helps avoid other surgical interventions which are more destructive for the conjunctiva. PMID- 27958206 TI - Pearl necklace sign in diabetic macular edema: Evaluation and significance. AB - PURPOSE: (1) The purpose of this study was to describe significance and prevalence of the newly reported pearl necklace spectral domain optical coherence tomography (SDOCT) sign, in diabetic macular edema (DMO), (2) to track the course of this sign over a period of at least 10 months. MATERIALS AND METHODS: The pearl necklace SDOCT sign refers to hyperreflective dots in a contiguous ring around the inner wall of cystoid spaces in the retina, recently described for the first time in 21 eyes with chronic exudative maculopathy. A retrospective analysis was performed of SDOCT images of all patients presenting to the DMO referral clinic of a tertiary eye care center, over a period of 24 months. Images of patients displaying this sign were sequentially analyzed for at least 10 months to track the course of the sign. RESULTS: Thirty-five eyes of 267 patients (13.1%) were found to display the pearl necklace sign. Twenty-eight eyes responded to intravitreal ranibizumab treatment with resolution of edema. In 21 eyes, the dots coalesced to form a clump, visible in the infrared fundus photograph as hard exudates; in seven eyes, dots disappeared without leaving visible exudates. In three eyes, the sign was seen in subfoveal cystoid spaces, with subsequent development of hard exudates, and drop in visual acuity of 20 letters or more. CONCLUSION: Pearl necklace SDOCT sign is not infrequent in DMO. This sign is a precursor to hard exudates in the majority of cases. If this sign is seen subfoveally, drop in visual acuity can be expected, despite treatment. PMID- 27958207 TI - Cataract surgery in mobile eye surgical unit: Safe and viable alternative. AB - AIM: The aim of this study was to evaluate the utility and safety of a mobile eye surgical unit (MESU) in providing quality cataract surgery for the indigent rural population with poor access to quality eye care. MATERIALS AND METHODS: Two buses connected by a vestibule were built to meet the requirements for a self sufficient operation theater (OT). In every camp, safe transportation of units, good alignment of buses, safe water, and maintenance of sterile environment were achieved with optimal utilization of OT. RESULTS: Two thousand and twenty-one patients in 21 remote locations underwent cataract surgery in MESU between 2012 and 2015. Visual outcome was 6/9 or better in 79.3%, posterior capsular rupture in 0.91%, zonulardialysis in 0.3%, aphakia in 0.2%, iridodialysis in 0.2%, and there was no incidence of endophthalmitis. CONCLUSION: MESU is a safe alternative in combating preventable blindness due to cataract in far-off villages and tribal areas by providing quality eye care at the patient's doorstep. This model has a great potential for duplication in other parts of India. PMID- 27958208 TI - Fluorescein angiography of subretinal neovascular membrane in parafoveal telangiectasia type II demonstrating retino-retinal, retino-subretinal anastomosis. PMID- 27958209 TI - Glial heterotopia in an adult: A rare orbital mass. AB - Heterotopic glial tissue is very rare in the orbit. Our case was an adult, which is unique since most cases reported in literature involve children. We describe a case of a 60-year-old man who presented with an orbital mass, which histopathologically revealed heterotopic glial tissue. PMID- 27958210 TI - Endoillumination (chandelier) assisted scleral buckling for a complex case of retinal detachment. AB - Endoilluminator-assisted scleral buckling combines the advantages of scleral buckling for its external approach and pars plana vitrectomy for its better visual visualization in the management of retinal detachment (RD). It has recently been proven to be safe and efficacious in simple cases. This report discusses successful management of a complex case of RD in a patient with the single functioning eye, where vitrectomy was expected to have a complicated course. PMID- 27958211 TI - Toric multifocal intraocular lens implantation in a case of bilateral anterior and posterior lenticonus in Alport syndrome. AB - We report the first case of toric multifocal intraocular lens (IOL) implantation in both the eyes of a young patient of Alport syndrome with anterior and posterior lenticonus with a successful outcome. An 18-year-old female patient presented with progressively blurred vision in both eyes since 4-5 years not improving with glasses. Refraction showed high myopia with astigmatism; however, the vision did not improve beyond 6/60 with glasses correction. Clinical examination on slit lamp showed anterior and posterior lenticonus bilaterally with a classical oil droplet appearance. We performed clear lens extraction by phacoemulsification with toric multifocal IOL implantation in both eyes. Postoperatively, the patient achieved an excellent refractive outcome with the unaided vision of 6/9, N6 in both eyes. PMID- 27958212 TI - Association of bilateral, multiple presumed retinal astrocytic proliferations with combined hamartoma of retina and retinal pigment epithelium in a 9-year-old male child with neurofibromatosis type 2. AB - Neurofibromatosis type 2 (NF-2) is characterized by multifocal proliferation of neural crest-derived cells. The characteristics finding of NF-2 is bilateral vestibular schwannomas. Combined hamartoma of retina and retinal epithelium (CHRRPE) is another associated finding. A 9 year-old-male child presented with left eye decreased vision for 3 months. Visual acuity was 0.0 and 0.8 LogMAR in the right and left eye, respectively. Left fundus showed an elevated, pigmented lesion with surface wrinkling and vascular tortuosity suggestive of CHRRPE with multiple presumed retinal astrocytic proliferations in mid-periphery. He had multiple cafe-au-lait spots. Optical coherence tomography confirmed clinical findings. Magnetic resonance imaging brain showed bilateral acoustic neuroma. Recognition of this rare finding as presenting feature of NF-2 can lead to earlier diagnosis which is vital to appropriate surveillance and possible surgical intervention. It is recommended that children with CHRRPE be screened for NF-2. PMID- 27958213 TI - Opsoclonus myoclonus ataxia syndrome due to falciparum malaria in two Indian children. AB - Opsoclonus-myoclonus ataxia (OMA) syndrome is rare in children, mostly caused by neuroblastoma. Here, we present two very rare cases presenting with OMA due to falciparum malaria. Both of them responded to a high dose of adrenocorticotrophin hormone and intravenous immunoglobulin without recurrence and complication. PMID- 27958214 TI - The "correct shake" for "handshake" in glued intrascleral fixation of intraocular lens. AB - We hereby describe the correct method to perform a "handshake technique" and easy transfer of haptics from one hand to another for glued intrascleral fixation of an intraocular lens (glued IOL). The procedure was implemented in 57 cases that necessitated the application of performing a glued IOL procedure and it resulted in an appropriate and easy externalization of haptic in all the cases. The surgeons' positioning with reference to the scleral flap is an essential component and the surgeon should always be positioned perpendicular to the plane of scleral flaps and the plane of haptic maneuver. The surgeons who intend to perform glued IOL should adopt this technical point. PMID- 27958215 TI - Congenital keratoglobus with blue sclera in two siblings with overlapping Marshall/Stickler phenotype. AB - We aimed to describe congenital keratoglobus with blue sclera in two siblings with overlapping Marshall/Stickler phenotype. Two sisters (ages four and six) with bilateral high astigmatism were evaluated by slit-lamp microscopy. Corneal topography and pachymetry maps were also obtained. Slit-lamp examination revealed that both corneas were globular in shape with peripheral corneal thinning. Pachymetry maps showed diffuse corneal thinning. Two siblings had in common the features of keratoglobus, blue sclera, atypical face, hearing loss, and hypermobile joints. We tentatively diagnosed the sisters as having an overlapping Marshall-Stickler phenotype based on clinical and radiological findings. Marshall Stickler syndrome may exist in the differential diagnosis of keratoglobus with blue sclera. PMID- 27958216 TI - Adaptive optics study of photoreceptors layer damage from presumed sun exposure: A case report. PMID- 27958217 TI - Decompression retinopathy after intravitreal bevacizumab and anterior chamber paracentesis in a patient with neovascular glaucoma. PMID- 27958218 TI - Comments regarding "A case of perforating injury of eyeball and traumatic cataract caused by acupuncture". PMID- 27958219 TI - Authors' reply. PMID- 27958220 TI - Efficacy and Safety of Medium-to-long-term Use of Tolterodine Extended Release with or without Tamsulosin in Patients with Benign Prostate Hyperplasia and Larger Prostate Size: A Double-blind, Placebo-controlled, Randomized Clinical Trial. AB - BACKGROUND: The medium-to-long-term use of antimuscarinics alone or in combination with an alpha-blocker in men with an enlarged prostate is still controversial. This double-blind, placebo-controlled, randomized clinical trial aimed to investigate the efficacy and safety of medium-to-long-term use of tolterodine extended release (ER) with or without tamsulosin in patients with benign prostate hyperplasia (BPH) and larger prostate size. METHODS: Totally, 152 patients (age >=50 years) with BPH, International Prostate Symptom Score (IPSS) >=12, quality-of-life (QoL) score >=3, and total prostate volume >=25 ml were enrolled in this study. The patients were randomized into four groups (n = 38 in each) to receive tolterodine ER placebo plus tamsulosin placebo, 0.2 mg tamsulosin plus tolterodine ER placebo, 4 mg tolterodine ER plus tamsulosin placebo, or tolterodine ER plus tamsulosin once daily for 24 weeks. IPSS (total, storage, and voiding subscales), QoL, maximum urinary flow rate (Qmax), and postvoid residual volume (PVR) were collected at baseline, and at weeks 4, 12, and 24. RESULTS: Compared with placebo, tolterodine ER plus tamsulosin significantly improved total IPSS (-7.15, -12.20, and -14.66 vs. -3.51, -5.78, and -7.23), storage IPSS (-3.56, -5.63, and -6.66 vs. -1.52, -1.21, and -2.43), voiding IPSS (-2.88, -5.10, and -6.48 vs. -1.52, -3.03, and -2.97), QoL (-1.21, 2.40, and -3.21 vs. -0.39, -1.41, and -1.60), Qmax (2.21, 7.97, and 9.72 ml/s vs. 2.15, 2.44, and 2.73 ml/s), and PVR (-17.88, -26.97, and -27.89 ml vs. -12.03, 11.16, and -16.73 ml) at weeks 4, 12, and 24, respectively; the differences were all statistically significant (P < 0.05). Adverse events (AEs) were not increased with treatment progression. Tolterodine ER alone did not improve total IPSS ( 4.61, -6.79, and -5.70), voiding IPSS (-0.64, -1.83, and -1.45), QoL (-0.69, 1.21, and -1.41), or Qmax(-0.79, 2.83, and 1.11 ml/s), compared with placebo (all P > 0.05). However, a gradual increase in PVR (10.03, 10.41, and 12.89 ml) and more urinary AEs suggestive of urinary retention (11/38 vs. 4/38) were observed. CONCLUSION: Medium-to-long-term use of tolterodine ER plus tamsulosin should be recommended in patients with BPH and an enlarged prostate volume. TRIAL REGISTRATION: www.chictr.org.cn, ChiCTR-TRC-09000596; http://www.chictr.org.cn/showproj.aspx?proj=8939. PMID- 27958221 TI - Long-term Effects of Antihypertensive Drug Use and New-onset Osteoporotic Fracture in Elderly Patients: A Population-based Longitudinal Cohort Study. AB - BACKGROUND: Antihypertensive drugs have been linked to new-onset osteoporotic fracture (NOF), and different classes of antihypertensive drugs may alter the risk for the development of NOF; however, the classic effect of different antihypertensive drugs on the development of NOF in the elderly has not been well studied during long-term follow-up. METHODS: In this study, we investigated the association between different classic antihypertensives and the development of NOF in the elderly. This was a longitudinal cohort study performed using data from claim forms submitted to the Taiwan Bureau of National Health Insurance in Central Taiwan, China including case patients with NOF aged 65-80 years from January 2002 to December 2012 and non-NOF controls. Prescriptions for antihypertensives before the index date were retrieved from a prescription database. We estimated the hazard ratios (HR s) of NOF associated with antihypertensive use. Non-NOF controls served as the reference group. RESULTS: A total of 128 patients with NOF were identified from among 1144 patients with hypertension during the study period. The risk of NOF after adjusting age, sex, comorbidities, and concurrent medications was higher among the users of angiotensin-converting enzyme (ACE) inhibitors (HR, 1.64; 95% confidence interval [CI], 1.01-2.66) than among nonusers. Patients who took calcium channel blockers (CCBs) (HR, 0.70; 95% CI, 0.49-0.99) were at a lower risk of developing NOF than nonusers. Loop diuretics, thiazide diuretics, angiotensin receptor blocker, beta blocker, and alpha-blocker were not associated with the risk of NOF. CONCLUSIONS: Elderly with hypertension who take CCBs are at a lower risk of NOF and that the use of ACE inhibitors was associated with a significantly increased risk of developing NOF during the 11-year follow-up. PMID- 27958222 TI - Effects of Ginseng Fruit Saponins on Serotonin System in Sprague-Dawley Rats with Myocardial Infarction, Depression, and Myocardial Infarction Complicated with Depression. AB - BACKGROUND: Our previous studies have demonstrated that the levels of 5 hydroxytryptamine (5-HT) and 5-HT 2A receptor (5-HT2AR) in serum and platelet were associated with depression and myocardial infarction (MI), and pretreatment with ginseng fruit saponins (GFS) before MI and depression had an effect on the 5 HT system. In this study, the effects of GFS on the 5-HT system in the Sprague Dawley (SD) rats with MI, depression, and MI + depression were evaluated. METHODS: A total of eighty SD rats were allocated to four groups: MI, depression, MI + depression, and control groups (n = 20 in each group). Each group included two subgroups (n = 10 in each subgroup): Saline treatment subgroup and GFS treatment subgroup. The levels of 5-HT, 5-HT2AR, and serotonin transporter (SERT) were quantified in serum, platelet lysate, and brain tissue through the enzyme linked immunosorbent assay method, respectively. RESULTS: Compared with those in the saline treatment subgroups, the levels of 5-HT in serum and platelet lysate statistically significantly increased in the GFS treatment subgroups of MI, depression, and MI + depression groups (serum: all P = 0.000; platelet lysate: P = 0.002, 0.000, 0.000, respectively). However, the 5-HT levels in brain homogenate significantly decreased in the GFS treatment subgroups compared with those in the saline treatment subgroups in MI and depression groups (P = 0.025 and 0.044 respectively), and no significant difference was observed between saline and GFS treatment subgroups in MI + depression group (P = 0.663). Compared with that in GFS treatment subgroup of control group, the 5-HT2AR levels in the platelet lysate significantly decreased in GFS treatment subgroups of MI, depression, and MI + depression groups (all P = 0.000). Compared to those in the saline treatment subgroups, the serum SERT levels significantly decreased in the GFS treatment subgroups in MI, depression, and MI + depression groups (P = 0.009, 0.038, and P = 0.001, respectively), while the SERT levels of platelet lysate significantly decreased in GFS treatment subgroup of MI group (P = 0.000), significantly increased in GFS treatment subgroup of depression group (P = 0.019), and slightly changed in GFS treatment subgroup of MI + depression group (P = 0.219). No significant changes for SERT levels in brain homogenate could be found between the saline and GFS treatment subgroups in MI, depression, and MI + depression groups (P = 0.421, 0.076 and P = 0.642). CONCLUSIONS: This study indicated that GFS might inhibit the reuptake of 5-HT from serum to platelet according to decreased 5-HT2AR in platelet and SERT in serum and platelet. The change of 5-HT in serum after GFS treatment was inconsistent with that in the brain. It seemed that GFS could not pass through the blood-brain barrier to affect the central serotonergic system. PMID- 27958223 TI - A Single-institution Experience with Open Irreversible Electroporation for Locally Advanced Pancreatic Carcinoma. AB - BACKGROUND: Locally advanced pancreatic carcinoma (LAPC) is characterized by poor prognosis despite recommended concurrent chemoradiotherapy. Irreversible electroporation (IRE) has emerged as a potential option for the management of unresectable pancreatic cancer. This study was conducted to evaluate the safety and short-term efficacy of open IRE for the treatment of LAPC. METHODS: Retrospective data of 25 consecutive patients receiving IRE for T3 lesions from July 2015 to June 2016 at a single center were analyzed. The perioperative and long-term IRE-related complications were reviewed to evaluate the safety of the procedure. The tumor reduction and biological response were analyzed through computed tomography/magnetic resonance imaging; the serum level of CA19-9 was measured as a secondary endpoint to evaluate the short-term efficacy of IRE. RESULTS: All patients were successfully treated; the median tumor size was 4.2 cm and the median IRE time was 36 min. Four intraoperative procedure-related complications were observed (16%): two transient hypertensive episodes, one hypotension case, and one transient supraventricular tachycardia case. Nine postoperative complications were described, including three Grade A pancreatic fistulas, three delayed gastric emptying, one acute pancreatitis, one upper gastrointestinal hemorrhage, and one portal vein thrombosis. The overall rate of stable disease was 28%, 36% achieved partial response, and lower serum CA19-9 levels were recorded in all patients at discharge. CONCLUSIONS: IRE is feasible for the treatment of LAPC and is a reasonable intervention strategy owing to its combined attributes of safety and efficacy. PMID- 27958224 TI - Comparison of Positron Emission Tomography Using 2-[18F]-fluoro-2-deoxy-D-glucose and 3-deoxy-3-[18F]-fluorothymidine in Lung Cancer Imaging. AB - BACKGROUND: The detection of solitary pulmonary nodules (SPNs) that may potentially develop into a malignant lesion is essential for early clinical interventions. However, grading classification based on computed tomography (CT) imaging results remains a significant challenge. The 2-[18F]-fluoro-2-deoxy-D glucose (18F-FDG) positron emission tomography (PET)/CT imaging produces both false-positive and false-negative findings for the diagnosis of SPNs. In this study, we compared 18F-FDG and 3-deoxy-3-[18F]-fluorothymidine (18F-FLT) in lung cancer PET/CT imaging. METHODS: The binding ratios of the two tracers to A549 lung cancer cells were calculated. The mouse lung cancer model was established (n = 12), and micro-PET/CT analysis using the two tracers was performed. Images using the two tracers were collected from 55 lung cancer patients with SPNs. The correlation among the cell-tracer binding ratios, standardized uptake values (SUVs), and Ki-67 proliferation marker expression were investigated. RESULTS: The cell-tracer binding ratio for the A549 cells using the 18F-FDG was greater than the ratio using 18F-FLT (P < 0.05). The Ki-67 expression showed a significant positive correlation with the 18F-FLT binding ratio (r = 0.824, P< 0.01). The tumor-to-nontumor uptake ratio of 18F-FDG imaging in xenografts was higher than that of 18F-FLT imaging. The diagnostic sensitivity, specificity, and the accuracy of 18F-FDG for lung cancer were 89%, 67%, and 73%, respectively. Moreover, the diagnostic sensitivity, specificity, and the accuracy of 18F-FLT for lung cancer were 71%, 79%, and 76%, respectively. There was an obvious positive correlation between the lung cancer Ki-67 expression and the mean maximum SUV of 18F-FDG and 18F-FLT (r = 0.658, P< 0.05 and r = 0.724, P< 0.01, respectively). CONCLUSIONS: The 18F-FDG uptake ratio is higher than that of 18F FLT in A549 cells at the cellular level. 18F-FLT imaging might be superior for the quantitative diagnosis of lung tumor tissue and could distinguish lung cancer nodules from other SPNs. PMID- 27958225 TI - Pediatric Infectious Endophthalmitis: A 271-case Retrospective Study at a Single Center in China. AB - BACKGROUND: Pediatric infectious endophthalmitis is a serious sight-threatening disease for children. The purpose of this study was to investigate the etiology, microbiological spectrum, and visual outcomes of infectious endophthalmitis in children at a single institution in China. METHODS: It is a retrospective study of the medical records of all patients under 14 years of age with histories of infectious endophthalmitis, treated at a single institution from January 1, 2009 to January 1, 2015. The clinical characteristics, etiology, microbiological spectrum, and management, as well as the visual outcomes, were analyzed. The Kappa test and Chi-square test were used in the statistical evaluation. RESULTS: A total of 271 children were identified, with a mean age of 5.61 +/- 2.93 years (range 5 months to 14 years). Ocular trauma (94.8%) and previous ocular surgery (3.0%) were the most common etiologies. Overall, 147 (54.2%) cases had positive cultures, and 176 organisms were isolated from these patients. A single species was isolated in 120 (81.6%) cases, with multiple organisms in 27 (18.4%) cases, and the most commonly identified organisms were coagulase-negative Staphylococcus and Streptococcus species, comprising 29.5% and 26.8% of the isolates, respectively. Moreover, of 176 isolates, 142 (80.8%) were Gram-positive organisms, 23 (13.0%) were Gram-negative organisms, and 11 (6.2%) were fungi. The final visual outcomes were 20/200 or better in 66 (24.4%) eyes, counting fingers to 20/200 in 34 (12.5%), hand motions in 30 (11.1%), light perception in 33 (12.2%), no light perception in 32 (11.8%), and 9 (3.3%) eyes were enucleated or eviscerated. The visual outcomes were not available in 67 (24.7%) patients. CONCLUSIONS: Penetrating ocular trauma is the most frequent cause of pediatric endophthalmitis in China. Streptococcus and Staphylococcus species are the most commonly identified organisms in exogenous pediatric endophthalmitis whereas Fusarium species are commonly seen in endogenous endophthalmitis. In this research, in spite of aggressive management with antibiotics and vitrectomy, the visual prognosis was found to be generally poor. PMID- 27958226 TI - Correlation of Vascular Endothelial Growth Factor Production with Photochemical Reaction-induced Retinal Edema. AB - BACKGROUND: Retinal edema is the major complication of retinal vein occlusion and diabetic retinopathy; it can damage visual function by influencing macular region. This study was to establish a rat retinal edema model and explore the related VEGF expression and observe the responses to anti-VEGF drugs in this model. METHODS: A rat retinal edema model was established by inducing photochemical reaction using a 532 nm laser after the intravenous injection of Erythrosin B. Immediately after the laser treatment, models were given intravitreal injections of Ranibizumab or Conbercept to inhibit VEGF expression, and the changes of retinal thickness were measured. Retinal edema was observed using fundus photography (FP), optical coherence tomography (OCT), and fluoresce in fundus angiography (FFA) at 0, 1, 2, 4, 7 and 14 days after intervention. The retinal VEGF expression was measured using enzyme-linked immunosorbent assay (ELISA) and western blotting at each time point. The rat retinal edema model was also used to verify the function of anti-VEGF polypeptide ZY1. RESULTS: Both retinal edema and vascular leakage were clearly observed at 1, 2 and 4 days after photochemical induction and the retinal thickness increased notably over the same period. The retinal VEGF expression peaked at day 1 and retina became thickening simultaneously. After the interventions, the VEGF expression of the Ranibizumab and Conbercept groups decreased at each time point compared to the edema group (26.90 +/- 3.57 vs. 40.29 +/- 6.68, F = 31.269 on day 1 and 22.36 +/- 1.12 vs. 29.92 +/- 0.93 F = 163.789 on day 2, both P < 0.01); the mean RT (278 +/- 4 vs. 288 +/- 3, F = 134.190 on day 1 and 274 +/- 7 vs. 284 +/- 6, F = 64.367 on day 2, both P < 0.05) and vascular leakage in these groups also decreased. The same results were observed in the ZY1 group, particularly at day 2 (P < 0.05). CONCLUSIONS: This retinal edema model induced by a photochemical reaction is reliable and repeatable. Induced edema increases expression of VEGF. This model can be used to test new drugs. PMID- 27958227 TI - Establishment of a Novel Mouse Model of Coronary Microembolization. AB - BACKGROUND: Coronary microembolization (CME) has been frequently seen in acute coronary syndromes and percutaneous coronary intervention. Small animal models are required for further studies of CME related to severe prognosis. This study aimed to explore a new mouse model of CME. METHODS: The mouse model of CME was established by injecting polystyrene microspheres into the left ventricular chamber during 15-s occlusion of the ascending aorta. Based on the average diameter and dosage used, 30 C57BL/6 male mice were randomly divided into five groups (n = 6 in each): 9 MUm/500,000, 9 MUm/800,000, 17 MUm/200,000, 17 MUm/500,000, and sham groups. The postoperative survival and performance of the mice were recorded. The mice were sacrificed 3 or 10 days after the surgery. The heart tissues were harvested for hematoxylin and eosin staining and Masson trichrome staining to compare the extent of inflammatory cellular infiltration and fibrin deposition among groups and for scanning transmission electron microscopic examinations to see the ultrastructural changes after CME. RESULTS: Survival analysis demonstrated that the cumulative survival rate of the 17 MUm/500,000 group was significantly lower than that of the sham group (0/6 vs. 6/6, P = 0.001). The cumulative survival rate of the 17 MUm/200,000 group was lower than those of the sham and 9 MUm groups with no statistical difference (cumulative survival rate of the 17 MUm/200,000, 9 MUm/800,000, 9 MUm/500,000, and sham groups was 4/6, 5/6, 6/6, and 6/6, respectively). The pathological alterations were similar between the 9 MUm/500,000 and 9 MUm/800,000 groups. The extent of inflammatory cellular infiltration and fibrin deposition was more severe in the 17 MUm/200,000 group than in the 9 MUm/500,000 and 9 MUm/800,000 groups 3 and 10 days after the surgery. Scanning transmission electron microscopic examinations revealed platelet aggregation and adhesion, microthrombi formation, and changes in cardiomyocytes. CONCLUSION: The injection of 500,000 polystyrene microspheres at an average diameter of 9 MUm is proved to be appropriate for the mouse model of CME based on the general conditions, postoperative survival rates, and pathological changes. PMID- 27958228 TI - Apoptotic Mechanism of Human Leukemia K562/A02 Cells Induced by Magnetic Ferroferric Oxide Nanoparticles Loaded with Wogonin. AB - BACKGROUND: Traditional Chinese medicine wogonin plays an important role in the treatment of leukemia. Recently, the application of drug-coated magnetic nanoparticles (MNPs) to increase water solubility of the drug and to enhance its chemotherapeutic efficiency has attracted much attention. Drugs coated with MNPs are becoming a promising way for better leukemia treatment. This study aimed to assess the possible molecular mechanisms of wogonin-coated MNP-Fe3O4 (Wog-MNPs Fe3O4) as an antileukemia agent. METHODS: After incubated for 48 h, the antiproliferative effects of MNPs, wogonin, or Wog-MNPs-Fe3O4on K562/A02 cells were determined by methyl thiazolyl tetrazolium (MTT) assay. The apoptotic rates of K562/A02 cells treated with either wogonin or Wog-MNPs-Fe3O4were determined by flow cytometer (FCM) assay. The cell cycle arrest in K562/A02 cells was determined by FCM assay. The elementary molecular mechanisms of these phenomena were explored by Western blot and reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: With cell viabilities ranging from 98.76% to 101.43%, MNP Fe3O4was nontoxic to the cell line. Meanwhile, the wogonin and Wog-MNPs-Fe3O4had little effects on normal human embryonic lung fibroblast cells. The cell viabilities of the Wog-MNPs-Fe3O4group (28.64-68.36%) were significantly lower than those of the wogonin group (35.53-97.28%) in a dose-dependent manner in 48 h (P < 0.001). The apoptotic rate of K562/A02 cells was significantly improved in 50 MUmol/L Wog-MNPs-Fe3O4group (34.28%) compared with that in 50 MUmol/L wogonin group (23.46%; P< 0.001). Compared with those of the 25 and 50 MUmol/L wogonin groups, the ratios of G0/G1-phase K562/A02 cells were significantly higher in the 25 and 50 MUmol/L Wog-MNPs-Fe3O4groups (all P< 0.001). The mRNA and protein expression levels of the p21 and p27 in the K562/A02 cells were also significantly higher in the Wog-MNPs-Fe3O4group compared with those of the wogonin group (all P< 0.001). CONCLUSIONS: This study demonstrated that MNPs were the effective drug delivery vehicles to deliver wogonin to the leukemia cells. Through increasing cells arrested at G0/G1-phase and inducing apoptosis of K562/A02 cells, MNPs could enhance the therapeutic effects of wogonin on leukemia cells. These findings indicated that MNPs loaded with wogonin could provide a promising way for better leukemia treatment. PMID- 27958229 TI - Epidemiological Study of Sepsis in China: Protocol of a Cross-sectional Survey. AB - BACKGROUND: Sepsis is the leading cause of death among critically ill patients. Herein, we conducted a national survey to provide data on epidemiology and treatment of sepsis in the clinical practice in China, which has no detailed epidemiological data available on sepsis. METHODS: This was a prospective cross sectional survey from December 1, 2015 to January 31, 2016 in all provinces/municipalities of the mainland of China. The primary outcome of this study was the incidence of sepsis, and the secondary outcome was its etiology in China. Patients with sepsis admitted to the Intensive Care Units were included in this study. The demographic, physiological, bacteriological, and therapeutic data of these patients were recorded. The incidence of sepsis was estimated using the data from the sixth census in China, reported by the Chinese National Health and Family Planning Commission and the National Bureau of Statistics as the standard population. The independent risk factors for increased mortality from sepsis were calculated. CONCLUSIONS: This study indicated the incidence and outcome of sepsis in China. It also showed the most common etiology of different sites and types of infection, which could guide empiric antibiotic therapy. Moreover, it provided information on the independent risk factors for increased mortality due to sepsis. The findings provide evidence to guide clinical management and may help improve the outcome in septic patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02448472; https://clinicaltrials.gov/show/NCT02448472. PMID- 27958230 TI - Neoadjuvant Chemoradiotherapy Improving Survival Outcomes for Esophageal Carcinoma: An Updated Meta-analysis. AB - BACKGROUND: The effectiveness of neoadjuvant chemoradiotherapy (NCRT) treatment for patients with esophageal carcinoma (EC) remains controversial. The aim of this study was to compare the effect of NCRT followed by surgery (NCRTS) with surgery alone (SA) for EC. METHODS: The PubMed, EMBASE, and the Cochrane Library databases were electronically searched up to August 2015 for all the published studies that investigated EC patients receiving either NCRTS or SA, and the reference lists were also manually examined for the eligible studies. The risk ratio (RR) with 95% confidence intervals (CI s) as effective size was determined to assess the 1-, 3-, 5-year survival rates (SRs), postoperative morbidity, and postoperative mortality. Heterogeneity was determined using the Q-test. The Begg's test and Egger's test were used for assessing any potential publication bias. RESULTS: Of 1120 identified studies, 16 eligible studies were included in this analysis (involving 2549 patients). Overall, the pooled results suggested that NCRTS was associated with significantly improved 1-year (RR: 1.07, 95% CI: 1.02-1.13), 3-year (RR: 1.26, 95% CI: 1.14-1.39), and 5-year (RR: 1.36, 95% CI: 1.18-1.56) SRs. However, the results also indicated that NCRTS had no or little effect on postoperative morbidity (RR: 0.93, 95% CI: 0.82-1.05) and postoperative mortality (RR: 1.17, 95% CI: 0.56-2.44). CONCLUSIONS: Compared with SA, NCRTS can increase 1-, 3-, and 5-year SRs in patients with EC. PMID- 27958231 TI - Radiofrequency Ablation versus Liver Resection for Colorectal Cancer Liver Metastasis: An Updated Systematic Review and Meta-analysis. AB - BACKGROUND: Controversial results about the therapeutic value of radiofrequency ablation (RFA) and liver resection (LR) in the treatment of colorectal cancer liver metastasis (CRCLM) have been reported. Thus, we performed the present meta analysis to summarize the related clinical evidences. METHODS: A systematic literature search was conducted using PubMed (Medline), EMBASE, Cochrane Library, and Web of Science, for all years up to April 2016. Pooled analyses of the overall survival (OS), progression-free survival (PFS), and morbidity rates were performed. RESULTS: A total of 14 studies were finally enrolled in the meta analysis. Patients treated by LR gained a longer OS and PFS than those of patients treated by RFA. Patients in the RFA group had lower morbidity rates than those of patients in the LR group. Publication bias analysis revealed that there was no significant publication bias in the meta-analysis. CONCLUSIONS: Patients with CRCLM gained much more survival benefits from LR than that from RFA. RFA rendered lower rates of morbidities. More well-designed randomized controlled trails comparing the therapeutic value of LR and RFA are warranted. PMID- 27958233 TI - Development of Evidence-based Recommendations: Implications for Preparing Expert Consensus Statements. PMID- 27958232 TI - Application of Multimodality Imaging Fusion Technology in Diagnosis and Treatment of Malignant Tumors under the Precision Medicine Plan. AB - OBJECTIVE: The arrival of precision medicine plan brings new opportunities and challenges for patients undergoing precision diagnosis and treatment of malignant tumors. With the development of medical imaging, information on different modality imaging can be integrated and comprehensively analyzed by imaging fusion system. This review aimed to update the application of multimodality imaging fusion technology in the precise diagnosis and treatment of malignant tumors under the precision medicine plan. We introduced several multimodality imaging fusion technologies and their application to the diagnosis and treatment of malignant tumors in clinical practice. DATE SOURCES: The data cited in this review were obtained mainly from the PubMed database from 1996 to 2016, using the keywords of "precision medicine", "fusion imaging", "multimodality", and "tumor diagnosis and treatment". STUDY SELECTION: Original articles, clinical practice, reviews, and other relevant literatures published in English were reviewed. Papers focusing on precision medicine, fusion imaging, multimodality, and tumor diagnosis and treatment were selected. Duplicated papers were excluded. RESULTS: Multimodality imaging fusion technology plays an important role in tumor diagnosis and treatment under the precision medicine plan, such as accurate location, qualitative diagnosis, tumor staging, treatment plan design, and real time intraoperative monitoring. Multimodality imaging fusion systems could provide more imaging information of tumors from different dimensions and angles, thereby offing strong technical support for the implementation of precision oncology. CONCLUSION: Under the precision medicine plan, personalized treatment of tumors is a distinct possibility. We believe that multimodality imaging fusion technology will find an increasingly wide application in clinical practice. PMID- 27958234 TI - Neurodegeneration in Diabetic Retinopathy: Current Concepts and Therapeutic Implications. PMID- 27958235 TI - A New Physical Examination Technique for Evaluating Valgus Knee Deformity: Swing Test. PMID- 27958236 TI - Only Self-control, Concerted Efforts Can Settle Rising Obesity in Adolescents. PMID- 27958237 TI - A Rare Case of Persistent Primitive Trigeminal Artery with Multiple Anomalies of Cerebral Vessels. PMID- 27958238 TI - Telemedicine and biomedical care in Africa: Prospects and challenges. AB - The use of information and communication technology for health care delivery, particularly in poor settings where access to medical services is inadequate, holds promise in expanding health care access. In rural or impoverished environment, where disease is prevalent, doctors are scarce, and health care infrastructure is inadequate, telemedicine holds a good prospect in improving the health conditions of the people. However, telemedical practice in Africa cannot be without challenges because some aspects are often difficult to implement in underdeveloped settings where ignorance and poverty are rife. Apart from nonavailability of facilities and poor communication, most Africans have different understanding of ailments, which often affect the health system. Considering the increasing disease burden in Africa and the need for tremendous progress in achieving the health component of the millennium development goals, telemedicine should be of concern to health policy makers. This paper critically examines the prospects and challenges of telemedical practice in Africa through a systematic review of 31 relevant publications which, in addition to the authors' knowledge and experience in biomedical care in Africa, supported the information as presented. PMID- 27958239 TI - Investigation of zoonotic infections in risk groups in Ordu University Hospital, Turkey. AB - AIMS: Zoonotic diseases, which are a major public health problem in our city, have a negative impact on public health and also cause economic losses due to yield losses of animals and deaths. This study was carried out to determine the seroprevalence of tularemia, bartonellosis, brucellosis, Q fever, and cystic echinococcosis in the risk groups for zoonotic infection. SUBJECTS AND METHODS: Ninety serum samples were taken from people in the risk groups in covering veterinarian, butchers, farmers and examined with the following tests: Microagglutination test for tularemia, indirect fluorescent antibody test (IFAT) for bartonellosis, standard tube agglutination test for brucellosis, IFAT IgG for Q fever, and enzyme-linked immunosorbent assay IgG test for cystic hydatid. STATISTICAL ANALYSIS USED: The Chi-square analysis was used to assess, and the logistic regression analysis was used to identify the risk factors. RESULTS: The analyzed all serum samples were found to be seronegative for tularemia, bartonellosis, and hydatid cyst antibodies. When analyzed for Coxiella burnetii with IgG antibody titers, it was determined that 23 samples (25.6%) were seropositivity. When brucellosis was analyzed with serological tests for Brucella, it was positive in seven samples (7.8%). CONCLUSIONS: In this study, examined in the risk groups in which it is located along black sea coast of Turkey for tularemia, bartonellosis, and hydatid cysts, seropositivity was not found. When Brucella was tested, 7.8% was found to be positive, and when analyzed in terms of Q fever, 25.6% of people were determined to be seropositive. In conclusion, in our region, Q fever seropositivity was found to be higher in the risk groups. Therefore, most of the zoonotic disease look like not so common in the region, out of tularemia. PMID- 27958240 TI - Oral mucosa and lung cancer: Are genetic changes in the oral epithelium associated with lung cancer? AB - AIM: To compare genetic aberrations in the oral epithelium of lung cancer patients with those without cancer. SUBJECTS AND METHODS: Buccal smears were performed to collect oral epithelium from each of the participants (smoker cancer patients n = 50, smoker control subjects n = 40, and nonsmoker control subjects n = 25). Cytogenetic changes in the samples were detected by micronuclei assay, whereas p53 and murine double minute 2 (MDM2) polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: p53 codon 72 polymorphism was seen in 44% of cancer patients versus 12.5% in smokers and 12% in nonsmokers of the control group. Similarly, MDM2 single nucleotide polymorphism 309 polymorphism was seen in 34% of patients with lung cancer as opposed to 12.5% of smokers (P = 0.038) and 8% of nonsmokers (P = 0.019) of the control group. CONCLUSION: A higher proportion of individuals with lung cancer demonstrate genetic damage to oral mucosa compared to those without cancer. PMID- 27958241 TI - Psychometric properties of a Turkish version of the oral health impact profile 14. AB - OBJECTIVES: The purpose of this study was to analyze and evaluate a Turkish translation of the oral health impact profile-14 (OHIP-14) in a Turkish population to provide an objective standard for future studies. METHODS: This cross-sectional research study consisted of three independent studies. Data were collected utilizing a personal interview and a review of periodontal records. This study was performed on 1205 subjects who were visiting for routine medical check-ups. The OHIP-14 was administered to measure oral health related to the quality of life, along with a questionnaire addressing demographic information, such as age, gender, and education. RESULTS: The reliability coefficient (Cronbach's alpha) of the Turkish version OHIP-14-TR (OHIP-14-TR) was reported to be nearly perfect in all 3 parts of our study (alpha 1: 0.82; alpha 2: 0.76; alpha 3: 0.91); additionally, values were greater than the recommended 0.70 threshold. Spearman's correlation coefficients showed that both OHIP scores significantly correlated with periodontal parameters, serving as proof of convergent validity (P < 0.01, P< 0.001). The principal component analysis with varimax rotation revealed seven factors. The OHIP-14-TR was more than 95% comprehensible. CONCLUSION: The OHIP-14-TR is a reliable, valid, and comprehensible scale for measuring oral health-related quality of life in the Turkish population. PMID- 27958242 TI - Rural posting experience, requests for transfer, and perspectives about critical factors for staff retention among primary health care workers in urban Kano, Nigeria. AB - BACKGROUND: Inadequate skilled manpower at rural posts is a serious impediment toward equitable and universal access to healthcare in Nigeria. OBJECTIVE: To examine the experiences of primary health care (PHC) workers on rural assignments, requests for transfer, and perspectives about critical factors for retention of healthcare workers at rural posts. MATERIALS AND METHODS: Using descriptive cross-sectional design, 262 PHC workers in Kano were studied. Data were collected using semi-structured questionnaires and analyzed on Statistical Package for Social Sciences version 22. Pearson's Chi-square and Fisher's exact tests were used to test for significant association between categorical variables. P <= 0.05 was considered significant. RESULTS: The mean age of the workers was 36.0 +/- 9 years. Majority were females (55.4%) and married (64.2%) with mean working experience of 13.0 +/- 8.0 years. Only 29 (11.2%) had rural posting experience. Mean duration of posting was 4.0 +/- 2.0 years; 19 (65.5%) sought re-deployment for lack of social amenities and good schools for children 19 (100.0%) and poor work environment 17 (89.5%). Common positive rural experiences mentioned were less work pressure 26 (89.7%), cordial relationship with colleagues and community members 24 (82.8%), and willingness of the community to partake in health activities 24 (82.8%). Common negative experiences reported include lack of social amenities 27 (93.1), lack of equipment and supplies in facilities 26 (89.7%), and stagnation 22 (75.9%). The workers' perspectives about critical factors for retention at rural posts include good facility infrastructure and functional equipment 240 (92.3%), good housing 237 (91.2%), potable water and electricity supply 238 (91.5%), good schools for staff's children 38 (91.5%), and good access of road to town 239 (91.9%). CONCLUSION AND RECOMMENDATION: While steering gear at upgrading basic infrastructures in rural areas, government should in the interim, ensure attractive working and living conditions at rural posts. PMID- 27958243 TI - Prevalence and predictors of placental malaria in human immunodeficiency virus positive women in Nigeria. AB - BACKGROUND: Human immunodeficiency virus (HIV)-infected pregnant women have alterations in cellular and humoral immunity that increase the risks to placental malaria infection. AIM: This study aimed at determining the prevalence and predictors of placental malaria among HIV-positive women in Nigeria. MATERIALS AND METHODS: It was a longitudinal cohort study of pregnant women receiving antenatal care at a tertiary hospital in Nigeria. Peripheral blood sample for packed cell volume estimation and placental blood sample for malaria parasite estimation were collected from each participant at a presentation in labor and upon delivery, respectively. RESULTS: The Prevalence of placenta malaria (68.6%) and anemia (66.7%) in HIV-positive women were significantly higher than the prevalence of placental malaria (35.3%) and anemia (44.1%) in HIV-negative control (P < 0.001 and P = 0.001 respectively). The employment status was the only sociodemographic factor significantly associated with the development of placental malaria in HIV-positive women (odds ratio: 21.60; 95% confidence interval: 7.1-66.2; P< 0.001). CONCLUSION: The prevalence of placental malaria is very high among HIV-positive women in Nigeria. Scaling up free distribution of insecticide treated nets in the short term and employment opportunities of HIV positive women, in the long run, may reduce the prevalence of placental malaria in our population. PMID- 27958244 TI - Dental pulp stone formation during orthodontic treatment: A retrospective clinical follow-up study. AB - OBJECTIVE: The aim of this study was two-fold: (1) To assess the incidence of dental pulp stone formation during orthodontic treatment, and (2) to determine the correlations between the presence of dental pulp stones and age, gender, and dental arches. MATERIALS AND METHODS: A sample of 545 patients (334 girls and 211 boys, age range; 12-22 years) who had undergone nonextraction orthodontic treatment were included in this study. 8442 teeth (T1) and 8410 teeth (T2), including the first and second maxillary and mandibular premolars and molars were evaluated from the pre- (T1) and post-treatment (T2) panoramic radiographs of the patients. The Pearson Chi-square test was used to investigate the associations between the presence of dental pulp stone, gender, age, tooth type and arches. RESULTS: Dental pulp stones were detected in 3% of the teeth at pretreatment panoramic radiographs and 5.2% of the teeth at posttreatment panoramic radiographs. Pulp stone prevalence increased pointedly (2.2%) in the pre- and post-treatment radiographs (P < 0.001). Also, there was a significant difference between the age groups (P < 0.001). In the maxilla, dental pulp stones were found significantly more than that in the mandible at T1 and T2 panoramic radiographs. Maxillary first molars exhibited dental pulp stones the most frequently, followed by the maxillary second molars and mandibular first molars. CONCLUSION: Orthodontic treatment may trigger the formation of dental pulp stones. However, further studies are required to determine the relationship between the pulp stone formation and orthodontic treatment. PMID- 27958245 TI - Epidemiology and clinical features of patients with hepatocellular carcinoma at a tertiary hospital in Jeddah. AB - BACKGROUND: This study describes the epidemiology and clinical features of hepatocellular carcinoma (HCC), and it investigates any association between Child Pugh's classification and HCC. MATERIALS AND METHODS: A retrospective chart review was performed for HCC cases diagnosed between 2008 and 2014 at King Abdulaziz University Hospital. We documented the age at cancer diagnosis, gender, occupation, ethnic origin, HCC etiology, Child-Pugh scores, tumor characteristics, alpha-fetoprotein (AFP), and alkaline phosphatase (ALP) levels at diagnosis, and treatment administered. The Chi-square test was used to determine differences between categorical variables. RESULTS: We included 128 patients. Hepatitis B and C viral infections were documented in 24.2% and 33.6% of the patients, respectively. Patients with tumors >5 cm were more likely to have Child's Class C disease, whereas those with tumors <=2 cm were more likely to have Child's Class A (P < 0.001). Similarly, patients with bilobular or metastatic tumors were more likely to have Child's Class C disease (P = 0.001 and 0.002, respectively). No difference in Child-Pugh score was found between patients with single or multiple tumors (P = 0.480). Furthermore, patients who were both hepatitis B and C positive were more likely to have Child's Class C disease (P = 0.018). Likewise, those who had abnormal AFP and ALP levels >=1000 ng/mL were more likely to have Child-Pugh's Class C liver disease (P = 0.021 in both cases). CONCLUSION: Hepatitis C and B infections were the main risk factors associated with HCC. PMID- 27958246 TI - The determination of the levels of burnout syndrome, organizational commitment, and job satisfaction of the health workers. AB - CONTEXT: The concept of burnout is an important element for efficiency in occupational groups such as health and education, which necessitate constant communication with people and have a busy schedule. AIMS: The determination of the levels of burnout syndrome, organizational commitment, and job satisfaction of the health workers. MATERIALS AND METHODS: A questionnaire consisting of four parts was prepared so as to measure the levels of organizational commitment, job satisfaction, and burnout of the medical staff of the institution. The data for this research were gained by a questionnaire sent to 370 medical staff (doctors, nurses, contract staff, and other employees). STATISTICAL ANALYSIS USED: Kolmogorov Smirnov test, t-test, ANOVA, Tukey multiple comparison test and Pearson's correlation analysis were used to this study. RESULTS: The average age of the employees taking part in the questionnaire was calculated as 34.30 years (min: 18 years, max: 59 years). The proportional value of the individuals with their 0-5 years working period in the institution was observed as 58.1%. An individual's interior work satisfaction, education level, hours worked at the hospital and their titles are also statistically important (P< 0.05). There is a positive correlation and significant relation between medical staffs' emotional exhaustion and desensitization (r = 0.573). There is a positive correlation and significant relation between normative commitment sub dimension, interior and exterior job satisfaction (r = 0.449, r = 0.472). CONCLUSIONS: Efforts to reduce the job burnout and psychological support for health care workers support motivation in order to provide better services to increase significantly. Thus, both personal productivity will be increased, and gain will be obtained in the institutional sense. PMID- 27958247 TI - Prevalence of mandibular and palatine tori among the Ibos in Enugu, South-East Nigeria. AB - CONTEXT: Torus mandibularis (TM) and torus palatinus (TP) are believed to occur commonly among black Africans. There is a dearth of literature on Nigerians. The few reported studies were done in the South-West Nigeria. This is the first report of the prevalence of tori among the Ibo-speaking ethnic group in the South East Nigeria. SETTINGS AND DESIGN: This is a prospective cross-sectional study of 3000 subjects of Ibo ethnic extraction attending a dental clinic in Enugu, South East Nigeria. MATERIALS AND METHODS: Three thousand subjects were examined for the isolated and concurrent occurrence of TM and TP. The subjects were seen over a 4-year period. The age, sex, ethnic group, type of tori based on location, and symptomatic awareness of tori presence were documented. STATISTICAL ANALYSIS USED: The data were analyzed with Statistical Package for Social Sciences (SPSS) version 17. The level of significance was P< 0.05. The Chi-square test showed no statistically significant difference between gender and type of tori (P = 0.34). Similarly, there was no statistically significant difference between the age groups and type of tori (P = 0.38). RESULTS: Two hundred and ninety-two subjects were clinically diagnosed with tori, of which females constituted 88%, and males constituted 12%. Isolated TM occurred in 56.8% (166 of 292) subjects, isolated TP in 17.5% (51 of 292) subjects, and concurrent tori (TM and TP) in 25.7% (75 of 292) subjects. The peak occurrence was in the fifth decade. The overall prevalence was 9.7%. The prevalences of TM (isolated and concurrent) and TP (isolated and concurrent) were 8.0% and 4.2%, respectively. CONCLUSIONS: The prevalence values are within the range of values reported in other Nigerian studies but differ widely with values from other ethnic groups from other countries. PMID- 27958248 TI - Can serums be replaced by Mueller-Hinton agar in germ tube test? AB - BACKGROUND: The germ tube test (GTT) is inexpensive, easy, and well-defined test that differentiates Candida albicans (excluding Candida dubliniensis and Candida africana) from other species. The aim of this study was to evaluate various serums (i.e., human, rabbit, horse, and fetal bovine serum) used in the GTT and Mueller-Hinton agar (MHA). MATERIALS AND METHODS: Fifty species isolated from various clinical samples that were defined as C. albicans by both conventional and DNA sequence analysis methods were included in the study. One to two colonies of C. albicans were mixed into 0.5-1 ml of fetal bovine serum, horse serum, rabbit serum, and human serum. Serums and MHA were incubated at 37 degrees C for GTT. They were removed from the incubator and evaluated after 30 min, 1 h, 2 h, and 3 h of incubation. The GTT was accepted to be positive only if germ tube was 1/2 the width and 3 times the length of the parent yeast cell and with no constriction at the point of origin. RESULTS: When the use of serums and MHA for GTT was statistically evaluated, according to the positive scoring, the best results were obtained with MHA and with rabbit, horse, and fetal bovine serum, respectively. The best definition over time statistically was the third hour. CONCLUSION: It is suggested that inexpensive MHA is a fast, appropriate, and reliable medium for the probable diagnosis of GTT and C. albicans; however, additional studies are still needed to define other Candida species. PMID- 27958249 TI - Physical growth and nutritional status assessment of school children in Enugu, Nigeria. AB - BACKGROUND: Physical growth of a child is a reflection of its state of nutrition. In some developing countries such as Nigeria with changing economy and rapidly growing population, the nutritional status of the children is a reflection of the general well-being of the society. MATERIALS AND METHODS: This was a descriptive cross-sectional study in which participants were selected using a multistage sampling method. Heights and weights of randomly selected school children aged 6 12 years were measured using standard protocols. Weight-for-age, height-for-age, and body mass index (BMI)-for-age expressed as Z-scores were used to characterize the nutritional status. Descriptive statistics was used to determine the frequency and standard deviations (SDs) of the anthropometric measurements. Age and gender differences in the mean body weight, height, and BMI were evaluated using an independent samples t-test. Significant levels were set at P< 0.05. RESULTS: A total of 1305 males and 1311 females were enrolled in the study. The mean age was 8.9 +/- 1.9 years. Their mean height, weight, and BMI were 136.6 +/- 10.2 cm, 29.7 +/- 7.7 kg, 15.7 +/- 2.4 kg/m2, respectively. Their mean +/- SD scores of the WAZ, HAZ, and BAZ were 0.33 +/- 1.20, 0.78 +/- 1.17, and - 0.51 +/- 1.27, respectively. A majority (78.9%, 2090/2616) were in the normal growth category. Wasting, overweight, obesity, underweight, and stunting were noted in 9.3% (243/2616), 6.3% (166/2616), 4.4% (117/2616), 0.9% (26/2616), and 0.4% (13/2616) of the children, respectively. Wasting was more in males (P = 0.069), and overweight was more in females (P = 0.138). CONCLUSION: A majority of the children have normal growth with the remainder in both extremes of malnutrition. Institution of school-feeding programs in all Nigerian schools as well as nutrition education/campaign directed at parents and their children will help forestall the double burden of under- and over-nutrition among our children. PMID- 27958250 TI - A novel quantitative light-induced fluorescence device for monitoring molar incisor hypomineralization. AB - BACKGROUND: The FluoreCam system is based on an innovative approach to the quantification of enamel health termed fluorescence enamel imaging (FEI). Enamel is both highly mineralized and semi-translucent. Because of its mineral composition, enamel will fluoresce when exposed to certain light wavelengths. The semi-translucent nature of enamel results in different enamel densities emitting different levels of fluorescence. As a result, with FEI technology, one can measure the density of tooth enamel by measuring its fluorescence when subjected to specific light wavelengths. PURPOSE: To determine the ability of visual examination and the instrumental procedures of the FluoreCam to monitor molar incisor hypomineralization (MIH) lesions. SUBJECTS AND METHODS: This study involved children with MIH at the Department of Paediatric Dentistry, Marmara University. In total, 11 patients with MIH were diagnosed on a visual MIH scale and evaluated with the FluoreCam. The equipment, data processing, and interaction between the equipment and operator were evaluated. RESULTS: Fluorescent images recorded with the custom software, the clinical view, and digital numeric values were evaluated to assess the potential for use of the device in clinical practice. CONCLUSION: These preliminary data from an ongoing clinical study suggest that measurements with the FluoreCam are useful in monitoring MIH. This technique also provides visual and quantitative feedback to patients. PMID- 27958251 TI - Flexible fiberoptic bronchoscopy in respiratory care: Diagnostic yield, complications, and challenges in a Nigerian Tertiary Center. AB - INTRODUCTION: Flexible fiberoptic bronchoscopy (FOB) is a key diagnostic and therapeutic procedure in pulmonology. Experience with fiberoptic bronchoscopy is scanty in most developing countries. OBJECTIVES: The goal of this study was to report our experience and clinical utility of fiberoptic bronchoscopy. METHODS: A review of bronchoscopy requests, services, and reports performed over a 5-year period was performed. Demographic characteristics were extracted. Indications for the procedures, type of bronchoscopic sampling done, final diagnosis, and complications were reported. Sensitivities, specificities, and overall diagnostic yield of the procedures were determined. RESULTS: About 163 diagnostic bronchoscopies were performed during the study. Ninety-nine patients with complete data were analyzed. Mean age was 54.8 +/- 19.2 years, with males constituting the majority, 56.6%. Suspected bronchial cancer and pleural effusion were the main indications for bronchoscopy (33% and 19.1%, respectively). A total of 80, 39, and 99 bronchial washings, brushings, and bronchial biopsies were performed, respectively. Bronchial cancer was confirmed in 51.5% and was diagnostic in 57% of suspected pleural effusion. Pulmonary tuberculosis was confirmed in 50% of suspected cases and additional 8 cases were diagnosed. The overall diagnostic yield of bronchoscopy was 62%. Specificities of bronchial brushing and washing cytology for excluding bronchial cancer were 90.9 and 83%, respectively, and sensitivities of detecting bronchial cancer were 64.3% and 59%, respectively, P< 0.05 each. Serious complication occurred in about 1%. There was no mortality. CONCLUSIONS: These results show that FOB is a useful and safe procedure with a low complication rate in our setting. PMID- 27958252 TI - Comparison of the body compositions in obese and nonobese individuals: Can learning body compositions motivate losing weight? AB - BACKGROUND: Obesity is one of the leading preventable causes of death worldwide. OBJECTIVE: To compare body compositions in obese and nonobese individuals. METHODS: This cross-sectional study constituted of 428 individuals. Body compositions were determined using the Tanita. RESULTS: Of all the participants, 300 (70.1%) were female. The prevalence of overweight and obesity was 30.8% and 47.7%, respectively. Having low educational level, female gender, not working, being married, and nonsmoker significantly increased more in obese than nonobese (P < 0.001). Total body water, visceral fat accumulation, body mass index, resting metabolic rate, fat-free mass, bone mass, and muscle mass were significantly higher in obese when compared to those with nonobese (P < 0.001). Thirteen percent of the participants were thinking of changing their diet and lifestyle to lose weight at the beginning. After learning their body compositions, the rate increased to 60% who decided to modify their lifestyle and asked for help to lose weight. This behavior change was significant in especially the overweighted participants (P = 0.025). CONCLUSION: The changes in body composition are associated with obesity and increased risk for certain cancers, cardiovascular disease, type 2 diabetes mellitus. Learning the health risks can motivate losing weight. Multicentered studies can be illuminating different cultural factors about obesity. PMID- 27958253 TI - Evaluation of mental foramen location in the 10-70 years age range using cone beam computed tomography. AB - INTRODUCTION: Mental foramen (MF) locations were determined according to gender and age in terms of the vertical distance from the surrounding anatomical structures and the vertical and horizontal size of the MF. MATERIALS AND METHODS: One hundred-seven male and 103 female patients in the age group between 10 and 70 years were included in our retrospective study and were examined using cone-beam computed tomography (CBCT). The right and the left MF locations were determined from panoramic and cross-sectional images. On the cross-sectional CBCT images, the distance of the MF upper limit from the alveolar crest edge, the distance of the MF lower limit from the lower edge of the mandible, and vertical size of the MF were measured. RESULTS: MF location differed in males and females (P < 0.001); it was generally located at the first and second premolar in females, and at the level of the second premolar in males. However, the MF location was not different on the right and left sides (P = 0.436). The distance of the MF from the surrounding anatomic structures were found to be lower in females than in males in all measurements (P < 0.001). The horizontal size of the MF was found to be less on the left side (P < 0.001). CONCLUSIONS: Knowing both the position and the distance of the MF from the surrounding anatomical structures is not only useful information for surgery, but will also help avoid complications such as paresthesia. PMID- 27958254 TI - Parental beliefs and practices regarding childhood fever in Turkish primary care. AB - BACKGROUND: Fever is a very common problem in pediatric age and is one of the most common reasons parents seek medical attention. We aimed to investigate beliefs, habits, and concerns of Turkish parents regarding their children's fever. MATERIALS AND METHODS: We performed a cross-sectional survey which was conducted as face-to-face interviews by family physicians from April to June 2014 in family healthcare centers in nine different cities in Turkey. Parents with a child with fever aged between 0 and 14 years were interviewed. The participants were asked questions about sociodemographic data, the definition and measurement of fever, antipyretics, and other interventions used to reduce fever before presenting to the primary care center. RESULTS: A total of 205 parents participated in this study. Ninety-four parents (45.8%) measured fever with a thermometer prior to presentation. Only 36 parents (38%) used the thermometer correctly. Thirty-eight parents (18.5%) knew the correct temperature definition of fever for the measured site. A mercury-in-glass thermometer was the choice for most parents (78%) and preferred site for measurement was axillary region (85%). The fever was treated prior to arrival by 171 parents (83.4%). Paracetamol was the most frequently used antipyretic. Fifty-four parents (31.5%) failed to administer the correct antipyretic dose, and 73 parents (42.6%) failed to give the antipyretics at proper intervals. One hundred and fifty-three parents (67%) believed that if not treated fever could cause convulsions. CONCLUSION: We conclude that parents share important misconceptions about definition, treatment, and consequences of childhood fever and tend to treat fever before seeking medical care with a substantial rate of wrong doses and wrong intervals. PMID- 27958255 TI - Evaluation of serum Vitamin B12 level and related nutritional status among apparently healthy obese female individuals. AB - OBJECTIVE: Obesity is a major public health problem and great risk for not only cardiovascular diseases but also cancer, musculoskeletal, and gynecological diseases. This study was aimed to investigate the association between serum Vitamin B12 (vitB12), body mass index (BMI), and nutritional status among obese women. METHODS: This cross-sectional study enrolled consecutive female subjects. The consumptions of red meat, fish, bovine liver, egg, and mushroom were recorded. According to the Dietary Reference Intakes, the patients were categorized as insufficiency and sufficiency. Three cutoff points were defined for vitB12 status: (1) Deficiency if vitB12 is <200 pg/mL; (2) insufficiency if vitB12 is 250-350 pg/mL, and (3) sufficient if vitB12 is >=350 pg/mL. According to BMI, the patients were assigned to nonobese and obese groups. BMI, serum vitB12 level, consumptions of red meat, fish, bovine liver, egg, and mushroom were evaluated and compared between two groups. RESULTS: Mean level of vitB12 was 247.8 +/- 10.4 pg/mL and significantly associated with consumption of egg (P = 0.031), bovine liver (P = 0.004), mushroom (P = 0.040), and red meat (P = 0.003). VitB12 was significantly higher in nonobese than obese group (282.5 +/- 106.8 vs. 242.5 +/- 107.5 pg/mL, P = 0.001). The ratio of vitB12 deficiency was significantly higher in obese than nonobese group (37.6% vs. 24.7%; P = 0.019). VitB12 level was negatively correlated with BMI (r = -0.155; P< 0.001), but not insulin resistance (r = -0.172; P = 0.062). CONCLUSION: Obesity was associated with low level of vitB12 in obese women, and more likely to be vitB12 deficient. Consumption of certain types of food contributes to increase vitB12 level. PMID- 27958256 TI - A survey of ponticulus posticus: Radiological analysis of atlas in an orthodontic population based on cone-beam computed tomography. AB - BACKGROUND: The ponticulus posticus (PP; Latin for little posterior bridge) has become an important anomaly of the atlas, as the use of the C1 lateral mass screw has become common in treating atlantoaxial instability. AIM: The purpose of this study was to retrospectively determine the prevalence and morphologic characteristics of PP in an orthodontic patient population using cervical three dimensional (3-D) cone beam computed tomography (CBCT) images. MATERIAL AND METHODS: A retrospective study was conducted by selecting cervical 3-D CBCT images of 374 adolescent population and examining them for the presence and type of PP. RESULTS: 161 patients with 298 complete or partial or bilateral or unilateral PPs were identified based on the 374 cervical 3-D CBCT scans. The prevalence of posticulus ponticus was founded 43.04% in adolescent population. CONCLUSION: Our results show that the presence of this anomaly should be carefully examined using preoperative lateral radiographs before lateral mass screw placement. If a PP is suspected or confirmed on radiographs, 3-D CBCT scanning should be considered before lateral mass screw placement into the posterior arch because of the variation in the size and shape of PPs and the possibility of injury. PMID- 27958257 TI - A case of rudimentary horn pregnancy diagnosed after failed attempts at pregnancy termination. AB - We report a case of rudimentary horn pregnancy at 12 weeks gestation with fetal demise misdiagnosed ultrasonographically as an intrauterine pregnancy in a private clinic. The patient was referred to a tertiary care hospital after failed attempts at terminating her pregnancy. A definitive diagnosis was made with ultrasonography and magnetic resonance imaging (MRI) before uterine rupture ensued. Excision of the rudimentary horn and the ipsilateral fallopian tube was carried out by laparotomy. Failure to terminate pregnancy after several attempts should alert the physician about the possibility of a uterine anomaly and a pelvic MRI scan may help in the diagnosis of a suspected rudimentary horn pregnancy. PMID- 27958258 TI - Case of twin pregnancy complicated by idiopathic thrombocytopenic purpura treated with intravenous immunoglobulin: Review of the literature. AB - Idiopathic thrombocytopenic purpura (ITP) is an acquired thrombocytopenia without other clear cause of thrombocytopenia. It is not common in a singleton pregnancy and less common in twin pregnancy. We report a 33-year-old ITP pluripara whose first pregnancy was uneventful. She carried twin pregnancy, complicated by recurrent very low platelets, and gave birth to preterm twins. This patient received multiple courses of intravenous immunoglobulin (IVIG) and showed a significant platelet count improvement with IVIG therapy. PMID- 27958259 TI - Immediate resolution of acute, choreatic hyperkinesias following intravenous fentanyl. AB - Acute hyperkinesia after discontinuation of tramadol in a patient with chronic pain using citalopram and pramipexole for restless legs syndrome (RLS) has not been reported. An 81-year-old female was admitted for increasing hyperkinesias of the whole body after she had discontinued tramadol 300 mg (taken during 3 months) without tapering 4 days earlier. In addition, she was on treatment with pramipexole (0.18 mg) for RLS for years, citalopram 10 mg/day for ~4 years, and fentanyl 75 MUg/day for 1 year. Hyperkinesias did not respond to benzodiazepines, quetiapine, biperiden, or valproic acid. Surprisingly, hyperkinetic bursts resolved immediately upon 15 mg fentanyl intravenously. Obviously, tramadol withdrawal had enhanced the preexisting RLS. Overdosing of pramipexole or serotonin syndrome was excluded. Sudden discontinuation of tramadol in a patient under pramipexole for RLS may cause severe, choreatic hyperkinesias for hours, which immediately resolve upon intravenous fentanyl. In patients under pramipexole for RLS and tramadol and fentanyl for chronic pain, sudden discontinuation of tramadol should be avoided to prevent induction of restless body syndrome. PMID- 27958260 TI - What every physician should know about the national guidelines for the control and management of sickle cell disease and the parent handbook for sickle cell disease in Nigeria. PMID- 27958261 TI - Serum uromodulin concentrations correlate with glomerular filtration rate in patients with chronic kidney disease. AB - INTRODUCTION Urinary uromodulin excretion has been associated with kidney diseases. However, serum uromodulin concentrations have not been extensively studied in patients with chronic kidney disease (CKD), and the results of published studies are inconsistent. OBJECTIVES The aims of the study were to evaluate serum uromodulin concentrations in patients with CKD and to assess the utility of serum uromodulin measurements for diagnosing CKD stages. PATIENTS AND METHODS This observational study included 170 patients with CKD stages 1 to 5, not treated by renal replacement therapy, and 30 healthy individuals. The serum levels of creatinine, cystatin C, and uromodulin were measured, and estimated glomerular filtration rate (eGFR) was calculated according to the 2012 CKD Epidemiology Collaboration cystatin-creatinine equation. RESULTS Among patients with CKD, serum uromodulin concentrations were significantly lower than in controls, and were strongly negatively correlated with renal retention markers (ie, serum creatinine and cystatin C) and strongly positively correlated with eGFR. An inverse, hyperbolic relationship between serum creatinine and uromodulin levels was analogous to the well-known association between serum creatinine concentrations and eGFR. A receiver-operating characteristic curve analysis showed a high diagnostic accuracy of the measurement of serum uromodulin concentrations in the assessment of CKD stages. CONCLUSIONS Serum uromodulin concentrations are closely correlated with eGFR, which is the recommended measure of renal function. As uromodulin is produced exclusively by renal tubular cells, the assessment of uromodulin levels in patients with CKD may be an alternative method for evaluating the number of functioning nephrons. PMID- 27958262 TI - Role of low-dose dobutamine echocardiography in predicting response to biventricular pacing. Results from the multicenter Viability in Cardiac Resynchronisation Therapy (ViaCRT) study. AB - INTRODUCTION The response to Cardiac Resynchronisation Therapy (CRT) varies significantly, resulting in lack of improvement among the substantial patients proportion. OBJECTIVES To identify mechanical dyssynchrony indices with combination of myocardial viability characteristics for predicting long-term response to CRT. PATIENTS AND METHODS ViaCRT was a multicentre study coordinated by the Working Group on Echocardiography of Polish Cardiac Society. 127 patients with heart failure were assessed prospectively. Cardiac dyssynchrony indices and low-dose dobutamine response were determined by echocardiography prior to CRT. Improvement in Wall Motion Score Index (WMSI) or LVEF exceeding 20% at peak stress identified preserved contractile reserve. RESULTS After 12 months there was significantly different survival between subsets with and without viability characterised by WMSI decrease, corresponding to 1 (4.4%) and 20 (19.4%) fatal events respectively (p=0.048). The predictive value of LVEF gain at Dobutamine Stress Echocardiography (DSE) study was only significant at 6 months, with all-cause death occurring in 1 (1.6%) and 7 (12.1%) of patients with viable and non-viable myocardium respectively (p=0.029). Multivariate regression analysis identified the presence of septal flash and interventricular dyssynchrony as independent indices with the ability to predict echocardiographic response alone at 12 months. CONCLUSIONS The study demonstrated a significant relationship between left ventricular contractile reserve at DSE and long-term all-cause mortality following CRT device implantation. Conversely, the presence of septal flash and interventricular dyssynchrony but not myocardial viability were predictive of the response to resynchronisation. The results indicate that interference of multiple different mechanisms may be responsible for the general effect following CRT. PMID- 27958263 TI - Phase-referenced nonlinear spectroscopy of the alpha-quartz/water interface. AB - Probing the polarization of water molecules at charged interfaces by second harmonic generation spectroscopy has been heretofore limited to isotropic materials. Here we report non-resonant nonlinear optical measurements at the interface of anisotropic z-cut alpha-quartz and water under conditions of dynamically changing ionic strength and bulk solution pH. We find that the product of the third-order susceptibility and the interfacial potential, chi(3) * Phi(0), is given by (chi1(3)-ichi2(3)) * Phi(0), and that the interference between this product and the second-order susceptibility of bulk quartz depends on the rotation angle of alpha-quartz around the z axis. Our experiments show that this newly identified term, ichi(3) * Phi(0), which is out of phase from the surface terms, is of bulk origin. The possibility of internally phase referencing the interfacial response for the interfacial orientation analysis of species or materials in contact with alpha-quartz is discussed along with the implications for conditions of resonance enhancement. PMID- 27958265 TI - Robust spin-orbit torque and spin-galvanic effect at the Fe/GaAs (001) interface at room temperature. AB - Interfacial spin-orbit torques (SOTs) enable the manipulation of the magnetization through in-plane charge currents, which has drawn increasing attention for spintronic applications. The search for material systems providing efficient SOTs, has been focused on polycrystalline ferromagnetic metal/non magnetic metal bilayers. In these systems, currents flowing in the non-magnetic layer generate-due to strong spin-orbit interaction-spin currents via the spin Hall effect and induce a torque at the interface to the ferromagnet. Here we report the observation of robust SOT occuring at a single crystalline Fe/GaAs (001) interface at room temperature. We find that the magnitude of the interfacial SOT, caused by the reduced symmetry at the interface, is comparably strong as in ferromagnetic metal/non-magnetic metal systems. The large spin-orbit fields at the interface also enable spin-to-charge current conversion at the interface, known as spin-galvanic effect. The results suggest that single crystalline Fe/GaAs interfaces may enable efficient electrical magnetization manipulation. PMID- 27958266 TI - Observation of a reversal of rotation in a sunspot during a solar flare. AB - The abrupt motion of the photospheric flux during a solar flare is thought to be a back reaction caused by the coronal field reconfiguration. However, the type of motion pattern and the physical mechanism responsible for the back reaction has been uncertain. Here we show that the direction of a sunspot's rotation is reversed during an X1.6 flare using observations from the Helioseismic and Magnetic Imager. A magnetic field extrapolation model shows that the corresponding coronal magnetic field shrinks with increasing magnetic twist density. This suggests that the abrupt reversal of rotation in the sunspot may be driven by a Lorentz torque that is produced by the gradient of twist density from the solar corona to the solar interior. These results support the view that the abrupt reversal in the rotation of the sunspot is a dynamic process responding to shrinkage of the coronal magnetic field during the flare. PMID- 27958264 TI - In vitro protease cleavage and computer simulations reveal the HIV-1 capsid maturation pathway. AB - HIV-1 virions assemble as immature particles containing Gag polyproteins that are processed by the viral protease into individual components, resulting in the formation of mature infectious particles. There are two competing models for the process of forming the mature HIV-1 core: the disassembly and de novo reassembly model and the non-diffusional displacive model. To study the maturation pathway, we simulate HIV-1 maturation in vitro by digesting immature particles and assembled virus-like particles with recombinant HIV-1 protease and monitor the process with biochemical assays and cryoEM structural analysis in parallel. Processing of Gag in vitro is accurate and efficient and results in both soluble capsid protein and conical or tubular capsid assemblies, seemingly converted from immature Gag particles. Computer simulations further reveal probable assembly pathways of HIV-1 capsid formation. Combining the experimental data and computer simulations, our results suggest a sequential combination of both displacive and disassembly/reassembly processes for HIV-1 maturation. PMID- 27958267 TI - Imaging high-speed friction at the nanometer scale. AB - Friction is a complicated phenomenon involving nonlinear dynamics at different length and time scales. Understanding its microscopic origin requires methods for measuring force on nanometer-scale asperities sliding at velocities reaching centimetres per second. Despite enormous advances in experimental technique, this combination of small length scale and high velocity remain elusive. We present a technique for rapidly measuring the frictional forces on a single asperity over a velocity range from zero to several centimetres per second. At each image pixel we obtain the velocity dependence of both conservative and dissipative forces, revealing the transition from stick-slip to smooth sliding friction. We explain measurements on graphite using a modified Prandtl-Tomlinson model, including the damped elastic deformation of the asperity. With its improved force sensitivity and small sliding amplitude, our method enables rapid and detailed surface mapping of the velocity dependence of frictional forces with less than 10 nm spatial resolution. PMID- 27958268 TI - Making brain-machine interfaces robust to future neural variability. AB - A major hurdle to clinical translation of brain-machine interfaces (BMIs) is that current decoders, which are trained from a small quantity of recent data, become ineffective when neural recording conditions subsequently change. We tested whether a decoder could be made more robust to future neural variability by training it to handle a variety of recording conditions sampled from months of previously collected data as well as synthetic training data perturbations. We developed a new multiplicative recurrent neural network BMI decoder that successfully learned a large variety of neural-to-kinematic mappings and became more robust with larger training data sets. Here we demonstrate that when tested with a non-human primate preclinical BMI model, this decoder is robust under conditions that disabled a state-of-the-art Kalman filter-based decoder. These results validate a new BMI strategy in which accumulated data history are effectively harnessed, and may facilitate reliable BMI use by reducing decoder retraining downtime. PMID- 27958269 TI - Serotonergic neuronal death and concomitant serotonin deficiency curb copulation ability of Drosophila platonic mutants. AB - Drosophila platonic (plt) males court females, but fail to copulate. Here we show that plt is an allele of scribbler (sbb), a BMP signalling component. sbb knockdown in larvae leads to the loss of approximately eight serotonergic neurons, which express the sex-determinant protein Doublesex (Dsx). Genetic deprivation of serotonin (5-HT) from dsx-expressing neurons results in copulation defects. Thus, sbb+ is developmentally required for the survival of a specific subset of dsx-expressing neurons, which support the normal execution of copulation in adults by providing 5-HT. Our study highlights the conserved involvement of serotonergic neurons in the control of copulatory mechanisms and the key role of BMP signalling in the formation of a sex-specific circuitry. PMID- 27958270 TI - Crystal Structure of Escherichia coli originated MCR-1, a phosphoethanolamine transferase for Colistin Resistance. AB - MCR-1 is a phosphoethanolamine (pEtN) transferase that modifies the pEtN moiety of lipid A, conferring resistance to colistin, which is an antibiotic belonging to the class of polypeptide antibiotics known as polymyxins and is the last-line antibiotic used to treat multidrug resistant bacterial infections. Here we determined the crystal structure of the catalytic domain of MCR-1 (MCR-1-ED), which is originated in Escherichia coli (E. coli). MCR-1-ED was found to comprise several classical beta-alpha-beta-alpha motifs that constitute a "sandwich" conformation. Two interlaced molecules with different phosphorylation status of the residue T285 could give rise to two functional statuses of MCR-1 depending on the physiological conditions. MCR-1, like other known pEtN transferases, possesses an enzymatic site equipped with zinc binding residues. Interestingly, two zinc ions were found to mediate intermolecular interactions between MCR-1-ED molecules in one asymmetric unit and hence concatenation of MCR-1, allowing the protein to be oligomer. Findings of this work shall provide important insight into development of effective and clinically useful inhibitors of MCR-1 or structurally similar enzymes. PMID- 27958271 TI - Nanoscopy of bacterial cells immobilized by holographic optical tweezers. AB - Imaging non-adherent cells by super-resolution far-field fluorescence microscopy is currently not possible because of their rapid movement while in suspension. Holographic optical tweezers (HOTs) enable the ability to freely control the number and position of optical traps, thus facilitating the unrestricted manipulation of cells in a volume around the focal plane. Here we show that immobilizing non-adherent cells by optical tweezers is sufficient to achieve optical resolution well below the diffraction limit using localization microscopy. Individual cells can be oriented arbitrarily but preferably either horizontally or vertically relative to the microscope's image plane, enabling access to sample sections that are impossible to achieve with conventional sample preparation and immobilization. This opens up new opportunities to super-resolve the nanoscale organization of chromosomal DNA in individual bacterial cells. PMID- 27958272 TI - Carbon storage in US wetlands. AB - Wetland soils contain some of the highest stores of soil carbon in the biosphere. However, there is little understanding of the quantity and distribution of carbon stored in our remaining wetlands or of the potential effects of human disturbance on these stocks. Here we use field data from the 2011 National Wetland Condition Assessment to provide unbiased estimates of soil carbon stocks for wetlands at regional and national scales. We find that wetlands in the conterminous United States store a total of 11.52 PgC, much of which is within soils deeper than 30 cm. Freshwater inland wetlands, in part due to their substantial areal extent, hold nearly ten-fold more carbon than tidal saltwater sites-indicating their importance in regional carbon storage. Our data suggest a possible relationship between carbon stocks and anthropogenic disturbance. These data highlight the need to protect wetlands to mitigate the risk of avoidable contributions to climate change. PMID- 27958273 TI - Extreme warming challenges sentinel status of kelp forests as indicators of climate change. AB - The desire to use sentinel species as early warning indicators of impending climate change effects on entire ecosystems is attractive, but we need to verify that such approaches have sound biological foundations. A recent large-scale warming event in the North Pacific Ocean of unprecedented magnitude and duration allowed us to evaluate the sentinel status of giant kelp, a coastal foundation species that thrives in cold, nutrient-rich waters and is considered sensitive to warming. Here, we show that giant kelp and the majority of species that associate with it did not presage ecosystem effects of extreme warming off southern California despite giant kelp's expected vulnerability. Our results challenge the general perception that kelp-dominated systems are highly vulnerable to extreme warming events and expose the more general risk of relying on supposed sentinel species that are assumed to be very sensitive to climate change. PMID- 27958274 TI - Trapping gases in metal-organic frameworks with a selective surface molecular barrier layer. AB - The main challenge for gas storage and separation in nanoporous materials is that many molecules of interest adsorb too weakly to be effectively retained. Instead of synthetically modifying the internal surface structure of the entire bulk-as is typically done to enhance adsorption-here we show that post exposure of a prototypical porous metal-organic framework to ethylenediamine can effectively retain a variety of weakly adsorbing molecules (for example, CO, CO2, SO2, C2H4, NO) inside the materials by forming a monolayer-thick cap at the external surface of microcrystals. Furthermore, this capping mechanism, based on hydrogen bonding as explained by ab initio modelling, opens the door for potential selectivity. For example, water molecules are shown to disrupt the hydrogen-bonded amine network and diffuse through the cap without hindrance and fully displace/release the retained small molecules out of the metal-organic framework at room temperature. These findings may provide alternative strategies for gas storage, delivery and separation. PMID- 27958276 TI - Stability of peatland carbon to rising temperatures. AB - Peatlands contain one-third of soil carbon (C), mostly buried in deep, saturated anoxic zones (catotelm). The response of catotelm C to climate forcing is uncertain, because prior experiments have focused on surface warming. We show that deep peat heating of a 2 m-thick peat column results in an exponential increase in CH4 emissions. However, this response is due solely to surface processes and not degradation of catotelm peat. Incubations show that only the top 20-30 cm of peat from experimental plots have higher CH4 production rates at elevated temperatures. Radiocarbon analyses demonstrate that CH4 and CO2 are produced primarily from decomposition of surface-derived modern photosynthate, not catotelm C. There are no differences in microbial abundances, dissolved organic matter concentrations or degradative enzyme activities among treatments. These results suggest that although surface peat will respond to increasing temperature, the large reservoir of catotelm C is stable under current anoxic conditions. PMID- 27958275 TI - ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. AB - Identifying genetic biomarkers of synthetic lethal drug sensitivity effects provides one approach to the development of targeted cancer therapies. Mutations in ARID1A represent one of the most common molecular alterations in human cancer, but therapeutic approaches that target these defects are not yet clinically available. We demonstrate that defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis. The data presented here provide the pre clinical and mechanistic rationale for assessing ARID1A defects as a biomarker of single-agent ATR inhibitor response and represents a novel synthetic lethal approach to targeting tumour cells. PMID- 27958277 TI - A genome-wide screen of bacterial mutants that enhance dauer formation in C. elegans. AB - Molecular pathways involved in dauer formation, an alternate larval stage that allows Caenorhabditis elegans to survive adverse environmental conditions during development, also modulate longevity and metabolism. The decision to proceed with reproductive development or undergo diapause depends on food abundance, population density, and temperature. In recent years, the chemical identities of pheromone signals that modulate dauer entry have been characterized. However, signals derived from bacteria, the major source of nutrients for C. elegans, remain poorly characterized. To systematically identify bacterial components that influence dauer formation and aging in C. elegans, we utilized the individual gene deletion mutants in E. coli (K12). We identified 56 diverse E. coli deletion mutants that enhance dauer formation in an insulin-like receptor mutant (daf-2) background. We describe the mechanism of action of a bacterial mutant cyaA, that is defective in the production of cyclic AMP, which extends lifespan and enhances dauer formation through the modulation of TGF-beta (daf-7) signaling in C. elegans. Our results demonstrate the importance of bacterial components in influencing developmental decisions and lifespan in C. elegans. Furthermore, we demonstrate that C. elegans is a useful model to study bacterial-host interactions. PMID- 27958278 TI - Neutrophil extracellular trap formation and circulating nucleosomes in patients with chronic myeloproliferative neoplasms. AB - The mechanisms underlying increased thrombotic risk in chronic myeloproliferative neoplasms (MPN) are incompletely understood. We assessed whether neutrophil extracellular traps (NETs), which promote thrombosis, contribute to the procoagulant state in essential thrombocythemia, polycythemia vera and myelofibrosis (MF) patients. Although MPN neutrophils showed increased basal reactive oxygen species (ROS), enhanced NETosis by unstimulated neutrophils was an infrequent finding, whereas PMA-triggered NETosis was impaired, particularly in MF, due to decreased PMA-triggered ROS production. Elevated circulating nucleosomes were a prominent finding and were higher in patients with advanced disease, which may have potential prognostic implication. Histone-MPO complexes, proposed as specific NET biomarker, were seldomly detected, suggesting NETs may not be the main source of nucleosomes in most patients, whereas their correlation with high LDH points to increased cell turn-over as a plausible origin. Lack of association of nucleosomes or NETs with thrombosis or activation markers does not support their use as predictors of thrombosis although prospective studies in a larger cohort may help define their potential contribution to MPN thrombosis. These results do not provide evidence for relevant in vivo NETosis in MPN patients under steady state conditions, although availability of standardized NET biomarkers may contribute to further research in this field. PMID- 27958280 TI - Corrigendum: No Change in the Mucosal Gut Microbiome is Associated with Celiac Disease-Specific Microbiome Alteration in Adult Patients. PMID- 27958279 TI - Brain Training with Video Games in Covert Hepatic Encephalopathy. AB - Despite the associated adverse outcomes, pharmacologic intervention for covert hepatic encephalopathy (CHE) is not the standard of care. We hypothesized that a video game-based rehabilitation program would improve white matter integrity and brain connectivity in the visuospatial network on brain magnetic resonance imaging (MRI), resulting in improved cognitive function in CHE subjects on measures consistent with the cognitive skill set emphasized by the two video games (e.g., IQ Boost-visual working memory, and Aim and Fire Challenge psychomotor speed), but also generalize to thinking skills beyond the focus of the cognitive training (Hopkins verbal learning test (HVLT)-verbal learning/memory) and improve their health-related quality of life (HRQOL). The trial included three phases over 8 weeks; during the learning phase (cognitive tests administered twice over 2 weeks without intervening intervention), training phase (daily video game training for 4 weeks), and post-training phase (testing 2 weeks after the video game training ended). Thirty CHE patients completed all visits with significant daily achievement on the video games. In a subset of 13 subjects that underwent brain MRI, there was a significant decrease in fractional anisotropy, and increased radial diffusivity (suggesting axonal sprouting or increased cross-fiber formation) involving similar brain regions (i.e., corpus callosum, internal capsule, and sections of the corticospinal tract) and improvement in the visuospatial resting-state connectivity corresponding to the video game training domains. No significant corresponding improvement in HRQOL or HVLT performance was noted, but cognitive performance did transiently improve on cognitive tests similar to the video games during training. Although multimodal brain imaging changes suggest reductions in tract edema and improved neural network connectivity, this trial of video game brain training did not improve the HRQOL or produce lasting improvement in cognitive function in patients with CHE. PMID- 27958283 TI - Erratum: The Royal Free Hospital Score: A Calibrated Prognostic Model for Patients With Cirrhosis Admitted to Intensive Care Unit. Comparison With Current Models and CLIF-SOFA Score. PMID- 27958282 TI - Distinct Abnormalities of Small Bowel and Regional Colonic Volumes in Subtypes of Irritable Bowel Syndrome Revealed by MRI. AB - OBJECTIVES: Non-invasive biomarkers which identify different mechanisms of disease in subgroups of irritable bowel syndrome (IBS) could be valuable. Our aim was to seek useful magnetic resonance imaging (MRI) parameters that could distinguish each IBS subtypes. METHODS: 34 healthy volunteers (HV), 30 IBS with diarrhea (IBS-D), 16 IBS with constipation (IBS-C), and 11 IBS with mixed bowel habit (IBS-M) underwent whole-gut transit and small and large bowel volumes assessment with MRI scans from t=0 to t=360 min. Since the bowel frequency for IBS-M were similar to IBS-D, IBS-M and IBS-D were grouped together and labeled as IBS non-constipation group (IBS-nonC). RESULTS: Median (interquartile range): fasting small bowel water content in IBS-nonC was 21 (10-42), significantly less than HV at 44 ml (15-70), P<0.01 as was the postprandial area under the curve (AUC) P<0.01. The fasting transverse colon volumes in IBS-C were significantly larger at 253 (200-329) compared with HV, IBS-nonC whose values were 165 (117 255) and 198 (106-270) ml, respectively, P=0.02. Whole-gut transit time for IBS-C was prolonged at 69 (51-111), compared with HV at 34 (4-63) and IBS-D at 34 (17 78) h, P=0.03. Bloating score (VAS 0-10 cm) correlated with transverse colon volume at t=405 min, Spearman r=0.21, P=0.04. CONCLUSIONS: The constricted small bowel in IBS-nonC and the dilated transverse colon in IBS-C point to significant differences in underlying mechanisms of disease. PMID- 27958284 TI - Pathophysiological Abnormalities in Functional Dyspepsia Subgroups According to the Rome III Criteria. AB - OBJECTIVES: The Rome III criteria proposed to subdivide functional dyspepsia (FD) into a postprandial distress syndrome (PDS) group, characterized by the presence of postprandial fullness and/or early satiety, and an epigastric pain syndrome (EPS) group, characterized by the presence of epigastric pain and/or epigastric burning. It has been suggested that different pathophysiological mechanisms underlie the symptom presentations in these subgroups that might determine treatment choices. The aim of this study was to investigate the prevalence of gastric sensorimotor dysfunction in the PDS, EPS, and overlap groups and to evaluate potential differential associations with dyspeptic symptom scores. METHODS: Consecutive FD patients fulfilling Rome III criteria were recruited and they scored frequency of dyspeptic symptoms (postprandial fullness, early satiety, nausea, bloating, epigastric pain, and epigastric burning) over the past 3 months (0-5; 1=once a month or less, 2=two or three times a month, 3=once a week, 4=several times a week, 5=every day). The cumulative symptom score was calculated by adding up the score of these dyspeptic symptoms. Based on these symptom scores, the patients were subdivided into subgroups according to the Rome III consensus: (i) PDS, characterized by postprandial fullness and/or early satiety at least several times a week, (ii) EPS, characterized by epigastric pain and/or epigastric burning at least once a week, and (iii) overlap, fulfilling the criteria for both PDS and EPS. Gastric sensitivity and gastric accommodation were measured using barostat testing, and solid gastric emptying was determined using the [14C]octanoate breath test. RESULTS: A total of 560 FD patients (165 men, age 41.8+/-0.7 years) were classified into PDS (n=131), EPS (n=50), and overlap (n=379) groups. The prevalence of gastric hypersensitivity, impaired gastric accommodation, and delayed gastric emptying were 37%, 37%, and 23%, respectively, without any differential distribution in Rome III subgroups (P=0.16, P=0.27, and P=0.39 respectively). Comparing the physiological parameters for these gastric sensorimotor functions, there was only a significant difference in the gastric half emptying time between subgroups, with the overlap group having a higher t1/2 (P<0.05) compared with the EPS group. In the overlap group, gastric hypersensitivity was associated with the severity of PDS symptoms (P=0.03), EPS symptoms (P=0.02), and the cumulative symptom score (P=0.02), whereas delayed gastric emptying was associated with nausea (P=0.02) and the cumulative symptom score (P=0.02). CONCLUSIONS: Except for gastric emptying in the overlap group, FD subgroups as defined by the Rome III criteria are not differentially associated with putative pathophysiological mechanisms. These observations question the utility of this classification for guiding therapeutic choices in clinical practice. PMID- 27958286 TI - On the Brink of Death: Managing Acute Liver Failure. PMID- 27958281 TI - Evolution After Anti-TNF Discontinuation in Patients With Inflammatory Bowel Disease: A Multicenter Long-Term Follow-Up Study. AB - OBJECTIVES: The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed. METHODS: This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included. RESULTS: A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn's disease and ulcerative colitis patients, respectively. In both Crohn's disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confidence interval (CI)=1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI=1.07 3.37) or discontinuation because of adverse events (HR=2.33; 95% CI=1.27-2.02) vs. a top-down strategy, colonic localization (HR=1.51; 95% CI=1.13-2.02) vs. ileal, and stricturing behavior (HR=1.5; 95% CI=1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn's disease patients, whereas treatment with immunomodulators after discontinuation (HR=0.67; 95% CI=0.51-0.87) and age (HR=0.98; 95% CI=0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe. CONCLUSIONS: The incidence rate of inflammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identified. Retreatment with the same anti-TNF drug was effective and safe. PMID- 27958287 TI - Ocular Radiation Threshold Projection Based off of Fluoroscopy Time During ERCP. AB - OBJECTIVES: Current international guidelines for ocular radiation exposure suggest a threshold of 20 millisieverts (mSv)/year. Although endoscopists wear lead aprons, use of protective eye wear is optional. This study was conducted to analyze the lens radiation exposure during endoscopic retrograde cholangiopancreatography (ERCP) for endoscopists to determine the time of fluoroscopy needed to warrant using lens protection during ERCP. METHODS: ERCP patients were prospectively enrolled. Indications, interventions, fluoroscopy time, dose, and attending +/- fellow involvement were recorded. Radiation exposure was collected from body dosimeters and dosimeters placed between the eyes. Cumulative radiation doses were obtained at study completion and averaged over the total fluoroscopy time to determine the mSv/hour exposure. RESULTS: A total of 187 cases were included. Attendings and fellows wore lens dosimeters in 178 and 126 cases, respectively, and body dosimeters in 174 and 128 cases, respectively. Attendings and fellows wore lens dosimeters throughout 15.89 and 11.24 h of fluoroscopy, respectively. The cumulative radiation dose absorbed per lens dosimeters was 5.35 mSv for attendings and 2.55 mSv for fellows. The projected lens absorption by the body dosimeters was 19.03 mSv for attendings and 5.21 mSv for fellows. The hourly fluoroscopy lens exposure was 0.34 mSv/hour for attendings and 0.23 mSv/hour for fellows. CONCLUSIONS: The amount of fluoroscopy hours needed to reach the currently suggested lens threshold limit (20 mSv/year) was 59.41 h for attendings and 88.17 h for fellows. Radioprotective eye wear should be worn by physicians with yearly fluoroscopy times in similarly structured practices that meet or exceed these thresholds. PMID- 27958288 TI - Mucosal Impedance: A New Way To Diagnose Reflux Disease and How It Could Change Your Practice. PMID- 27958285 TI - Postoperative Complications after Ileocecal Resection in Crohn's Disease: A Prospective Study From the REMIND Group. AB - OBJECTIVES: We sought to determine the frequency of and risk factors for early (30-day) postoperative complications after ileocecal resection in a well characterized, prospective cohort of Crohn's disease patients. METHODS: The REMIND group performed a nationwide study in 9 French university medical centers. Clinical-, biological-, surgical-, and treatment-related data on the 3 months before surgery were collected prospectively. Patients operated on between 1 September 2010 and 30 August 2014 were included. RESULTS: A total of 209 patients were included. The indication for ileocecal resection was stricturing disease in 109 (52%) cases, penetrating complications in 88 (42%), and medication-refractory inflammatory disease in 12 (6%). A two-stage procedure was performed in 33 (16%) patients. There were no postoperative deaths. Forty-three (21%) patients (23% of the patients with a one-stage procedure vs. 9% of those with a two-stage procedure, P=0.28) experienced a total of 54 early postoperative complications after a median time interval of 5 days (interquartile range, 4-12): intra abdominal septic complications (n=38), extra-intestinal infections (n=10), and hemorrhage (n=6). Eighteen complications (33%) were severe (Dindo-Clavien III IV). Reoperation was necessary in 14 (7%) patients, and secondary stomy was performed in 8 (4.5%). In a multivariate analysis, corticosteroid treatment in the 4 weeks before surgery was significantly associated with an elevated postoperative complication rate (odds ratio (95% confidence interval)=2.69 (1.15 6.29); P=0.022). Neither preoperative exposure to anti-tumor necrosis factor (TNF) agents (n=93, 44%) nor trough serum anti-TNF levels were significant risk factors for postoperative complications. CONCLUSIONS: In this large, nationwide, prospective cohort, postoperative complications were observed after 21% of the ileocecal resections. Corticosteroid treatment in the 4 weeks before surgery was significantly associated with an elevated postoperative complication rate. In contrast, preoperative anti-TNF therapy (regardless of the serum level or the time interval between last administration and surgery) was not associated with an elevated risk of postoperative complications. PMID- 27958292 TI - Imaging: Solid stress indicates tumour pathology. PMID- 27958290 TI - A metal-free electrocatalyst for carbon dioxide reduction to multi-carbon hydrocarbons and oxygenates. AB - Electroreduction of carbon dioxide into higher-energy liquid fuels and chemicals is a promising but challenging renewable energy conversion technology. Among the electrocatalysts screened so far for carbon dioxide reduction, which includes metals, alloys, organometallics, layered materials and carbon nanostructures, only copper exhibits selectivity towards formation of hydrocarbons and multi carbon oxygenates at fairly high efficiencies, whereas most others favour production of carbon monoxide or formate. Here we report that nanometre-size N doped graphene quantum dots (NGQDs) catalyse the electrochemical reduction of carbon dioxide into multi-carbon hydrocarbons and oxygenates at high Faradaic efficiencies, high current densities and low overpotentials. The NGQDs show a high total Faradaic efficiency of carbon dioxide reduction of up to 90%, with selectivity for ethylene and ethanol conversions reaching 45%. The C2 and C3 product distribution and production rate for NGQD-catalysed carbon dioxide reduction is comparable to those obtained with copper nanoparticle-based electrocatalysts. PMID- 27958289 TI - WSB1 overcomes oncogene-induced senescence by targeting ATM for degradation. AB - Oncogene-induced senescence (OIS) or apoptosis through the DNA-damage response is an important barrier of tumorigenesis. Overcoming this barrier leads to abnormal cell proliferation, genomic instability, and cellular transformation, and finally allows cancers to develop. However, it remains unclear how the OIS barrier is overcome. Here, we show that the E3 ubiquitin ligase WD repeat and SOCS box containing protein 1 (WSB1) plays a role in overcoming OIS. WSB1 expression in primary cells helps the bypass of OIS, leading to abnormal proliferation and cellular transformation. Mechanistically, WSB1 promotes ATM ubiquitination, resulting in ATM degradation and the escape from OIS. Furthermore, we identify CDKs as the upstream kinase of WSB1. CDK-mediated phosphorylation activates WSB1 by promoting its monomerization. In human cancer tissue and in vitro models, WSB1 induced ATM degradation is an early event during tumorigenic progression. We suggest that WSB1 is one of the key players of early oncogenic events through ATM degradation and destruction of the tumorigenesis barrier. Our work establishes an important mechanism of cancer development and progression in premalignant lesions. PMID- 27958291 TI - Sexual dimorphic function of IL-17 in salivary gland dysfunction of the C57BL/6.NOD-Aec1Aec2 model of Sjogren's syndrome. AB - Interleukin (IL)-17 is one of the critical inflammatory cytokines that plays a direct role in development of Sjogren's syndrome (SjS), a systemic autoimmune disease characterized by a progressive chronic attack against the exocrine glands. The expression levels of IL-17 are correlated with a number of essential clinical parameters such as focus score and disease duration in human patients. Significantly immunological differences of Th17 cells were detected at the onset of clinical disease in female SjS mice compared to males. To further define the role of IL-17 in SjS and elucidate its involvement in the sexual dimorphism, we examined the systemic effect of IL-17 by genetically ablating Il-17 in the C57BL/6.NOD-Aec1Aec2, spontaneous SjS murine model. The results indicate that IL 17 is a potent inflammatory molecule in the induction of chemoattractants, cytokines, and glandular apoptosis in males and females. Elimination of IL-17 reduced sialadenitis more drastically in females than males. IL-17 is highly involved in modulating Th2 cytokines and altering autoantibody profiles which has a greater impact on changing plasma cells and germinal center B cell populations in females than males. The result supports a much more important role for IL-17 and demonstrates the sexual dimorphic function of IL-17 in SjS. PMID- 27958294 TI - Targeted therapy: Sunitinib modulates MCL-1 and mTOR signalling. PMID- 27958293 TI - Small-cell lung cancer in 2016: Shining light on novel targets and therapies. PMID- 27958295 TI - Haematological cancer: Rituximab enhances responses to lenalidomide. PMID- 27958296 TI - Gynaecological cancer: PARP inhibition - moving beyond BRCA-mutated disease. PMID- 27958297 TI - Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer. AB - The treatment of patients with ovarian cancer is rapidly changing following the success of poly [ADP-ribose] polymerase (PARP) inhibitors in clinical trials. Olaparib is the first PARP inhibitor to be approved by the EMA and FDA for BRCA mutated ovarian cancer. Germ line BRCA mutation status is now established as a predictive biomarker of potential benefit from treatment with a PARP inhibitor; therefore, knowledge of the BRCA status of an individual patient with ovarian cancer is essential, in order to guide treatment decisions. BRCA testing was previously offered only to women with a family or personal history of breast and/or ovarian cancer; however, almost 20% of women with high-grade serous ovarian cancer are now recognized to harbour a germ line BRCA mutation, and of these, >40% might not have a family history of cancer and would not have received BRCA testing. A strategy to enable more widespread implementation of BRCA testing in routine care is, therefore, necessary. In this Review, we summarize data from key clinical trials of PARP inhibitors and discuss how to integrate these agents into the current treatment landscape of ovarian cancer. The validity of germ line BRCA testing and other promising biomarkers of homologous-recombination deficiency will also be discussed. PMID- 27958298 TI - Sarcoma in 2016: Evolving biological understanding and treatment of sarcomas. PMID- 27958299 TI - In vivo Assessment of Antioxidant and Wound Healing Improvement of a New Schiff Base Derived Co (II) Complex in Rats. AB - Co (II) complex (CMLA) was investigated to evaluate the rate of wound healing in rats. Animals were placed into four groups: gum acacia, Intrasite gel, 10 and 20 mg/ml of CMLA. Wounds were made on the dorsal neck area, then treated with Intrasite gel or CMLA; both of these treatments led to faster healing than with gum acacia. Histology of the wounds dressed with CMLA or Intrasite gel displayed a smaller scar width, required less time to heal and showed more collagen staining and fewer inflammatory cells in comparison to wounds dressed with the vehicle. Immunohistochemistry for Hsp70 and TGF-beta showed greater staining intensity in the treated groups compared to the vehicle group. Bax staining was less intense in treated groups compared to the vehicle group, suggesting that CMLA and Intrasite gel provoked apoptosis, responsible for the development of granulation tissue into a scar. CD31 protein analysis showed that the treated groups enhanced angiogenesis and increased vascularization compared to the control group. Furthermore, a significant increase in the levels of GPx and SOD and a decrease in MDA were also observed in the treated groups. This results suggest that CMLA is a potentially promising agent for the wounds treatment. PMID- 27958300 TI - Theoretical and Experimental Study of Light-assisted Polymerization by Multimechanism Action. AB - A novel bicomponent alkyd system was designed to decrease the usage of Cobalt based drier due to its latent carcinogensis. The system was polymerized using a Cobalt-salt complex as an air-sensitive drier and an isopropylthioxanthone photoinitiator as a light-sensitive accelerator, as well as using irradiation in the form of visible light. The combined influence of the two additives on autoxidation was analyzed using real-time infrared spectroscopy. The results show that isopropylthioxanthone can increase the efficiency of hydrogen abstraction at the beginning of the curing reaction. A linear free energy relationship was used to theoretically predict the hydrogen abstraction ability of photoinitiators. Nanosecond laser flash photolysis was used to obtain the quenching rate constants between alkyd monomers and isopropylthioxanthone according to the Stern-Volmer equation. The thermodynamic data of transition state theory, such as the activation energy, were calculated by using quantum chemistry program. The reaction rate constant and the Wigner tunneling factor were predicted from the result of quantum chemistry. The vertical excitation energy obtained from the time-dependent density functional theory was used to explain the anomalous behavior of the photoinitiators. These theoretical results fit well with the experimental result of linear free energy relationship. On the basis of these observed results, an accelerated mechanism of the photoassisted autoxidation of alkyd resins was proposed. PMID- 27958301 TI - Selective perturbation of cognitive conflict in the human brain-A combined fMRI and rTMS study. AB - We investigated if single and double conflicts are processed separately in different brain regions and if they are differentially vulnerable to TMS perturbation. Fifteen human volunteers performed a single (Flanker or Simon) conflict task or a double (Flanker and Simon) conflict task in a combined functional Magnetic Resonance Imaging (fMRI) and Transcranial Magnetic Stimulation (TMS) study. The fMRI approach aimed at localizing brain regions involved in interference resolution induced by single Flanker (stimulus-stimulus, S-S) and Simon (stimulus-response, S-R) conflicts as well as regions involved in the double conflict condition. The data revealed a distinct activation in the right intraparietal sulcus (IPS) for Flanker interference and in the right middle frontal gyrus (MFG) for the double interference condition. The causal functional role of these brain regions was then examined in the same volunteers by using offline TMS over right IPS and right MFG. TMS perturbation of the right IPS increased the Flanker effect, but had no effect in the Simon or double conflict condition. In contrast, perturbation of the right MFG had no effect on any of the conflict types. These findings suggest a causal role of the right IPS in the processing of the single conflict of Flanker (stimulus-stimulus) interference. PMID- 27958303 TI - Tunneling induced absorption with competing Nonlinearities. AB - We investigate tunneling induced nonlinear absorption phenomena in a coupled quantum-dot system. Resonant tunneling causes constructive interference in the nonlinear absorption that leads to an increase of more than an order of magnitude over the maximum absorption in a coupled quantum dot system without tunneling. Resonant tunneling also leads to a narrowing of the linewidth of the absorption peak to a sublinewidth level. Analytical expressions show that the enhanced nonlinear absorption is largely due to the fifth-order nonlinear term. Competition between third- and fifth-order nonlinearities leads to an anomalous dispersion of the total susceptibility. PMID- 27958302 TI - Structural Basis for Human PECAM-1-Mediated Trans-homophilic Cell Adhesion. AB - Cell adhesion involved in signal transduction, tissue integrity and pathogen infection is mainly mediated by cell adhesion molecules (CAM). One CAM member, platelet-endothelial-cell adhesion molecule-1 (PECAM-1), plays an important role in tight junction among endothelia cells, leukocyte trafficking, and immune response through its homophilic and heterophilic binding patterns. Both kinds of interactions, which lead to endogenous and exogenous signal transmission, are derived from extracellular immunoglobulin-like (IgL) domains and cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of PECAM-1. To date, the mechanism of trans-homophilic interaction of PECAM-1 remains unclear. Here, we present the crystal structure of PECAM-1 IgL1-2 trans-homo dimer. Both IgL 1 and 2 adopt the classical Ig domain conformation comprised of two layers of beta sheets possessing antiparallel beta-strands with each being anchored by a pair of cysteines forming a disulfide bond. The dimer interface includes hydrophobic and hydrophilic interactions. The Small-Angle X-ray Scattering (SAXS) envelope of PECAM-1 IgL1-6 supported such a dimer formation in solution. Cell adhesion assays on wildtype and mutant PECAM-1 further characterized the structural determinants in cell junction and communication. PMID- 27958304 TI - Influence of vacuum chamber impurities on the lifetime of organic light-emitting diodes. AB - We evaluated the influence of impurities in the vacuum chamber used for the fabrication of organic light-emitting diodes on the lifetime of the fabricated devices and found a correlation between lifetime and the device fabrication time. The contact angle of the ITO substrates stored the chamber under vacuum were used to evaluate chamber cleanliness. Liquid chromatography-mass spectrometry was performed on Si wafers stored in the vacuum chamber before device fabrication to examine the impurities in the chamber. Surprisingly, despite the chamber and evaporation sources being at room temperature, a variety of materials were detected, including previously deposited materials and plasticizers from the vacuum chamber components. We show that the impurities, and not differences in water content, in the chamber were the source of lifetime variations even when the duration of exposure to impurities only varied before and after deposition of the emitter layer. These results suggest that the impurities floating in the vacuum chamber significantly impact lifetime values and reproducibility. PMID- 27958305 TI - Imine-Linked Polymer Based Nitrogen-Doped Porous Activated Carbon for Efficient and Selective CO2 Capture. AB - The preparation of nitrogen-doped activated carbon (NACs) has received significant attention because of their applications in CO2 capture and sequestration (CCS) owing to abundant nitrogen atoms on their surface and controllable pore structures by carefully controlled carbonization. We report high-surface-area porous N-doped activated carbons (NAC) by using soft-template assisted self-assembly followed by thermal decomposition and KOH activation. The activation process was carried out under different temperature conditions (600 800 degrees C) using polyimine as precursor. The NAC-800 was found to have a high specific surface area (1900 m2 g-1), a desirable micropore size below 1 nm and, more importantly, a large micropore volume (0.98 cm3 g-1). NAC-800 also exhibits a significant capacity of CO2 capture i.e., over 6. 25 and 4.87 mmol g-1 at 273 K and 298 K respectively at 1.13 bar, which is one of among the highest values reported for porous carbons so far. Moreover, NAC also shows an excellent separation selectivity for CO2 over N2. PMID- 27958306 TI - Catalyst- and template-free low-temperature in situ growth of n-type CdS nanowire on p-type CdTe film and p-n heterojunction properties. AB - CdS is an important semiconductor used in optoelectronic devices. Simple techniques for growing CdS nanostructures are thus essential at a low cost. This study presents a novel method for growing single-crystal n-type CdS nanowires on p-type CdTe films by thermal annealing in an H2S/N2 mixed gas flow, which does not require the help of a catalyst or template. The formation process and growth mechanism of the nanowires are investigated. Well-dispersed whiskerlike CdS nanostructures are obtained at an appropriate annealing temperature and duration. We suggest that the stress-driving mechanism of nanowire formation may contribute to the growth of CdS nanowires, and that the evaporation of Te through the boundaries of the CdS grain seeds plays an important role in the sustainable growth of nanowire. In addition, CdS/CdTe heterojunction device is fabricated on Mo glass. The I-V characteristic of the heterojunction in dark shows typical rectifying diode behavior. The turn-on voltage can be regulated by annealing conditions. Meanwhile, the obvious photovoltaic effect is obtained on the in situ growth heterojunction prepared at low annealing temperature. Hence, this is a new fabricated method for CdTe-based materials in the field of energy conversion. PMID- 27958307 TI - Functional proteomics-aided selection of protease inhibitors for herbivore insect control. AB - Studies have reported the potential of protease inhibitors to engineer insect resistance in transgenic plants but the general usefulness of this approach in crop protection still remains to be established. Insects have evolved strategies to cope with dietary protease inhibitors, such as the use of proteases recalcitrant to inhibition, that often make the selection of effective inhibitors very challenging. Here, we used a functional proteomics approach for the 'capture' of Cys protease targets in crude protein extracts as a tool to identify promising cystatins for plant improvement. Two cystatins found to differ in their efficiency to capture Cys proteases of the coleopteran pest Leptinotarsa decemlineata also differed in their usefulness to produce transgenic potato lines resistant to this insect. Plants expressing the most potent cystatin at high level had a strong repressing effect on larval growth and leaf intake, while plants expressing the weakest cystatin showed no effect on both two parameters compared to untransformed parental line used for genetic transformation. Our data underline the relevance of considering the whole range of possible protease targets when selecting an inhibitor for plant pest control. They also confirm the feasibility of developing cystatin-expressing transgenics resistant to a major pest of potato. PMID- 27958309 TI - Voltage Fluctuation in a Supercapacitor During a High-g Impact. AB - Supercapacitors (SCs) are a type of energy storage device with high power density and long lifecycles. They have widespread applications, such as powering electric vehicles and micro scale devices. Working stability is one of the most important properties of SCs, and it is of significant importance to investigate the operational characteristics of SCs working under extreme conditions, particularly during high-g acceleration. In this paper, the failure mechanism of SCs upon high g impact is thoroughly studied. Through an analysis of the intrinsic reaction mechanism during the high-g impact, a multi-faceted physics model is established. Additionally, a multi-field coupled kinetics simulation of the SC failure during a high-g impact is presented. Experimental tests are conducted that confirm the validity of the proposed model. The key factors of failure, such as discharge currents and discharging levels, are analyzed and discussed. Finally, a possible design is proposed to avoid the failure of SCs upon high-g impact. PMID- 27958308 TI - Protective effect of mild endoplasmic reticulum stress on radiation-induced bystander effects in hepatocyte cells. AB - Radiation-induced bystander effect (RIBE) has important implications for secondary cancer risk assessment during cancer radiotherapy, but the defense and self-protective mechanisms of bystander normal cells are still largely unclear. The present study found that micronuclei (MN) formation could be induced in the non-irradiated HL-7702 hepatocyte cells after being treated with the conditioned medium from irradiated hepatoma HepG2 cells under either normoxia or hypoxia, where the ratio of the yield of bystander MN induction to the yield of radiation induced MN formation under hypoxia was much higher than that of normoxia. Nonetheless, thapsigargin induced endoplasmic reticulum (ER) stress and dramatically suppressed this bystander response manifested as the decrease of MN and apoptosis inductions. Meanwhile, the interference of BiP gene, a major ER chaperone, amplified the detrimental RIBE. More precisely, thapsigargin provoked ER sensor of PERK to initiate an instantaneous and moderate ER stress thus defensed the hazard form RIBE, while BiP depletion lead to persistently destroyed homeostasis of ER and exacerbated cell injury. These findings provide new insights that the mild ER stress through BiP-PERK-p-eIF2alpha signaling pathway has a profound role in protecting cellular damage from RIBE and hence may decrease the potential secondary cancer risk after cancer radiotherapy. PMID- 27958310 TI - SGA as a Risk Factor for Cerebral Palsy in Moderate to Late Preterm Infants: a System Review and Meta-analysis. AB - Small for gestational age (SGA) is an established risk factor for cerebral palsy (CP) in term infants. However, there is conflicting data on the association between SGA and CP in moderate to late preterm infants. The aim of the article was to explore the relationship between SGA and CP in the moderate to late preterm infants and its strength by meta-analysis. We performed a system search in OVID (EMBASE and MEDLINE) and WANFANG from inception to May 2016. The study specific risk estimates were pooled using the random-effect model. A total of seven studies were included in the meta-analysis, consisting of three cohort and four case-control studies. A statistically significant association was found between SGA and CP in moderate to late premature infants (OR: 2.34; 95% CI: 1.43 3.82). The association were higher in the several subgroups: 34-36 week gestational age (OR: 3.47; 95% CI: 1.29-9.31), SGA < 2SDs (OR: 3.48; 95% CI: 1.86 6.49), and malformation included in CP (OR: 3.00; 95% CI: 1.71-5.26). In moderate to late premature infants, SGA is a convenient and reliable predictor for CP. More studies are needed to explore the underlying mechanisms between SGA and CP association. PMID- 27958311 TI - Temporal binding of interval markers. AB - How we estimate the passage of time is an unsolved mystery in neuroscience. Illusions of subjective time provide an experimental access to this question. Here we show that time compression and expansion of visually marked intervals result from a binding of temporal interval markers. Interval markers whose onset signals were artificially weakened by briefly flashing a whole-field mask were bound in time towards markers with a strong onset signal. We explain temporal compression as the consequence of summing response distributions of weak and strong onset signals. Crucially, temporal binding occurred irrespective of the temporal order of weak and strong onset markers, thus ruling out processing latencies as an explanation for changes in interval duration judgments. If both interval markers were presented together with a mask or the mask was shown in the temporal interval center, no compression occurred. In a sequence of two intervals, masking the middle marker led to time compression for the first and time expansion for the second interval. All these results are consistent with a model view of temporal binding that serves a functional role by reducing uncertainty in the final estimate of interval duration. PMID- 27958313 TI - Designing perfect linear polarization converters using perfect electric and magnetic conducting surfaces. AB - We propose a kind of general framework for the design of a perfect linear polarization converter that works in the transmission mode. Using an intuitive picture that is based on the method of bi-directional polarization mode decomposition, it is shown that when the device under consideration simultaneously possesses two complementary symmetry planes, with one being equivalent to a perfect electric conducting surface and the other being equivalent to a perfect magnetic conducting surface, linear polarization conversion can occur with an efficiency of 100% in the absence of absorptive losses. The proposed framework is validated by two design examples that operate near 10 GHz, where the numerical, experimental and analytic results are in good agreements. PMID- 27958312 TI - Cerebral infarction pattern in tuberculous meningitis. AB - Tuberculous meningitis (TBM) causes significant morbidity and mortality. The primary objective was to re-examine the concept of "TB zone" and "ischaemic zone" in cerebral infarction in patients with tuberculous meningitis. The secondary objective was to evaluate cerebral infarction, vasculitis and vasospasm in tuberculous meningitis infections. Between 2009 and 2014, TBM patients were recruited. Neuroimaging was performed and findings of cerebral infarction, vasculitis and vasospasm were recorded. Infarcts were classified based on arterial supply and Hsieh's classification. Fifty-one TBM patients were recruited of whom 34 patients (67%) had cerebral infarction. Based on Hsieh's classification, 20 patients (59%) had infarcts in both "TB zone" and "ischaemic zones". 12 patients (35%) had infarcts in "ischaemic zone" and two (6%) patients had infarcts in "TB zone". In terms of vascular supply, almost all patients (35/36) had infarcts involving perforators and cortical branches. 25 patients (73%) and 14 patients (41%) had infarcts supplied by lateral lenticulostriate and medial lenticulostriate arteries respectively. 15 patients (37%) had vasculitis. Vasospasm was present in six patients (15%). 29 patients (85%) with cerebral infarction also had leptomeningeal enhancement (p = 0.002). In summary, infarcts involved mainly perforators and cortical branches, rather than "TB zone" versus "ischaemic zone". PMID- 27958314 TI - General calibration of microbial growth in microplate readers. AB - Optical density (OD) measurements of microbial growth are one of the most common techniques used in microbiology, with applications ranging from studies of antibiotic efficacy to investigations of growth under different nutritional or stress environments, to characterization of different mutant strains, including those harbouring synthetic circuits. OD measurements are performed under the assumption that the OD value obtained is proportional to the cell number, i.e. the concentration of the sample. However, the assumption holds true in a limited range of conditions, and calibration techniques that determine that range are currently missing. Here we present a set of calibration procedures and considerations that are necessary to successfully estimate the cell concentration from OD measurements. PMID- 27958315 TI - Observation of an exceptional point in a two-dimensional ultrasonic cavity of concentric circular shells. AB - We report observation of an exceptional point in circular shell ultrasonic cavities in both theory and experiment. In our theoretical analysis we first observe two interacting mode groups, fluid- and solid-based modes, in the acoustic cavities and then show the existence of an EP of these mode groups exhibiting a branch-point topological structure of eigenfrequencies around the EP. We then confirm the mode patterns as well as eigenfrequency structure around the EP in experiments employing the schlieren method, thereby demonstrating utility of ultrasound cavities as experimental platform for investigating non Hermitian physics. PMID- 27958316 TI - The key role of meteorites in the formation of relevant prebiotic molecules in a formamide/water environment. AB - We show that carbonaceous chondrite meteorites actively and selectively catalyze the formation of relevant prebiotic molecules from formamide in aqueous media. Specific catalytic behaviours are observed, depending on the origin and composition of the chondrites and on the type of water present in the system (activity: thermal > seawater > pure). We report the one-pot synthesis of all the natural nucleobases, of aminoacids and of eight carboxylic acids (forming, from pyruvic acid to citric acid, a continuous series encompassing a large part of the extant Krebs cycle). These data shape a general prebiotic scenario consisting of carbonaceous meteorites acting as catalysts and of a volcanic-like environment providing heat, thermal waters and formamide. This scenario also applies to the other solar system locations that experienced rich delivery of carbonaceous materials, and whose physical-chemical conditions could have allowed chemical evolution. PMID- 27958317 TI - Effective energy harvesting from a single electrode based triboelectric nanogenerator. AB - The arch-shaped single electrode based triboelectric nanogenerator (TENG) is fabricated using thin film of reduced graphene oxide nanoribbons (rGONRs) with polyvinylidene fluoride (PVDF) polymer used as binder to effectively convert mechanical energy into electrical energy. The incorporation of rGONRs in PVDF polymer enhances average surface roughness of rGONRs/PVDF thin film. With the combination of the enhancement of average roughness and production of functional groups, which indicate improve charge storage capacity of prepared film. Furthermore, the redox peaks obtained through cyclic voltammetry were identified more in rGONRs/PVDF composite in comparison to pristine rGONRs to confirm charge transfer capability of film. Herein, the output performance was discussed experimentally as well as theoretically, maximum voltage was obtained to be 0.35 V. The newly designed TENG to harvest mechanical energy and opens up many new avenues of research in the energy harvesting applications. PMID- 27958318 TI - A violation of universality in anomalous Fourier's law. AB - Since the discovery of long-time tails, it has been clear that Fourier's law in low dimensions is typically anomalous, with a size-dependent heat conductivity, though the nature of the anomaly remains puzzling. The conventional wisdom, supported by renormalization-group arguments and mode-coupling approximations within fluctuating hydrodynamics, is that the anomaly is universal in 1d momentum conserving systems and belongs in the Levy/Kardar-Parisi-Zhang universality class. Here we challenge this picture by using a novel scaling method to show unambiguously that universality breaks down in the paradigmatic 1d diatomic hard point fluid. Hydrodynamic profiles for a broad set of gradients, densities and sizes all collapse onto an universal master curve, showing that (anomalous) Fourier's law holds even deep into the nonlinear regime. This allows to solve the macroscopic transport problem for this model, a solution which compares flawlessly with data and, interestingly, implies the existence of a bound on the heat current in terms of pressure. These results question the renormalization group and mode-coupling universality predictions for anomalous Fourier's law in 1d, offering a new perspective on transport in low dimensions. PMID- 27958321 TI - Temperature-driven topological quantum phase transitions in a phase-change material Ge2Sb2Te5. AB - The Ge2Sb2Te5 is a phase-change material widely used in optical memory devices and is a leading candidate for next generation non-volatile random access memory devices which are key elements of various electronics and portable systems. Despite the compound is under intense investigation its electronic structure is currently not fully understood. The present work sheds new light on the electronic structure of the Ge2Sb2Te5 crystalline phases. We demonstrate by predicting from first-principles calculations that stable crystal structures of Ge2Sb2Te5 possess different topological quantum phases: a topological insulator phase is realized in low-temperature structure and Weyl semimetal phase is a characteristic of the high-temperature structure. Since the structural phase transitions are caused by the temperature the switching between different topologically non-trivial phases can be driven by variation of the temperature. The obtained results reveal the rich physics of the Ge2Sb2Te5 compound and open previously unexplored possibility for spintronics applications of this material, substantially expanding its application potential. PMID- 27958319 TI - Altered DNA methylation associated with an abnormal liver phenotype in a cattle model with a high incidence of perinatal pathologies. AB - Cloning enables the generation of both clinically normal and pathological individuals from the same donor cells, and may therefore be a DNA sequence independent driver of phenotypic variability. We took advantage of cattle clones with identical genotypes but different developmental abilities to investigate the role of epigenetic factors in perinatal mortality, a complex trait with increasing prevalence in dairy cattle. We studied livers from pathological clones dying during the perinatal period, clinically normal adult clones with the same genotypes as perinatal clones and conventional age-matched controls. The livers from deceased perinatal clones displayed histological lesions, modifications to quantitative histomorphometric and metabolic parameters such as glycogen storage and fatty acid composition, and an absence of birth-induced maturation. In a genome-wide epigenetic analysis, we identified DNA methylation patterns underlying these phenotypic alterations and targeting genes relevant to liver metabolism, including the type 2 diabetes gene TCF7L2. The adult clones were devoid of major phenotypic and epigenetic abnormalities in the liver, ruling out the effects of genotype on the phenotype observed. These results thus provide the first demonstration of a genome-wide association between DNA methylation and perinatal mortality in cattle, and highlight epigenetics as a driving force for phenotypic variability in farmed animals. PMID- 27958320 TI - Exchanges of genomic domains between poliovirus and other cocirculating species C enteroviruses reveal a high degree of plasticity. AB - The attenuated Sabin strains contained in the oral poliomyelitis vaccine are genetically unstable, and their circulation in poorly immunized populations can lead to the emergence of pathogenic circulating vaccine-derived polioviruses (cVDPVs). The recombinant nature of most cVDPV genomes and the preferential presence of genomic sequences from certain cocirculating non-polio enteroviruses of species C (EV-Cs) raise questions about the permissiveness of genetic exchanges between EV-Cs and the phenotypic impact of such exchanges. We investigated whether functional constraints limited genetic exchanges between Sabin strains and other EV-Cs. We bypassed the natural recombination events by constructing 29 genomes containing a Sabin 2 capsid-encoding sequence and other sequences from Sabin 2 or from non-polio EV-Cs. Most genomes were functional. All recombinant viruses replicated similarly in vitro, but recombination modulated plaque size and temperature sensitivity. All viruses with a 5'UTR from Sabin 2 were attenuated in mice, whereas almost all viruses with a non-polio 5'UTR caused disease. These data highlight the striking conservation of functional compatibility between different genetic domains of cocirculating EV-Cs. This aspect is only one of the requirements for the generation of recombinant cVDPVs in natural conditions, but it may facilitate the generation of viable intertypic recombinants with diverse phenotypic features, including pathogenicity. PMID- 27958322 TI - Genetically targeted 3D visualisation of Drosophila neurons under Electron Microscopy and X-Ray Microscopy using miniSOG. AB - Large dimension, high-resolution imaging is important for neural circuit visualisation as neurons have both long- and short-range patterns: from axons and dendrites to the numerous synapses at terminal endings. Electron Microscopy (EM) is the favoured approach for synaptic resolution imaging but how such structures can be segmented from high-density images within large volume datasets remains challenging. Fluorescent probes are widely used to localise synapses, identify cell-types and in tracing studies. The equivalent EM approach would benefit visualising such labelled structures from within sub-cellular, cellular, tissue and neuroanatomical contexts. Here we developed genetically-encoded, electron dense markers using miniSOG. We demonstrate their ability in 1) labelling cellular sub-compartments of genetically-targeted neurons, 2) generating contrast under different EM modalities, and 3) segmenting labelled structures from EM volumes using computer-assisted strategies. We also tested non-destructive X-ray imaging on whole Drosophila brains to evaluate contrast staining. This enabled us to target specific regions for EM volume acquisition. PMID- 27958323 TI - Differential transcription profiles of long non-coding RNAs in primary human brain microvascular endothelial cells in response to meningitic Escherichia coli. AB - Accumulating studies have indicated the influence of long non-coding RNAs (lncRNAs) on various biological processes as well as disease development and progression. However, the lncRNAs involved in bacterial meningitis and their regulatory effects are largely unknown. By RNA-sequencing, the transcriptional profiles of host lncRNAs in primary human brain microvascular endothelial cells (hBMECs) in response to meningitic Escherichia coli were demonstrated. Here, 25,257 lncRNAs were identified, including 24,645 annotated lncRNAs and 612 newly found ones. A total of 895 lncRNAs exhibited significant differences upon infection, among which 382 were upregulated and 513 were downregulated (>=2-fold, p < 0.05). Via bioinformatic analysis, the features of these lncRNAs, their possible functions, and the potential regulatory relationships between lncRNAs and mRNAs were predicted. Moreover, we compared the transcriptional specificity of these differential lncRNAs among hBMECs, human astrocyte cell U251, and human umbilical vein endothelial cells, and demonstrated the novel regulatory effects of proinflammatory cytokines on these differential lncRNAs. To our knowledge, this is the first time the transcriptional profiles of host lncRNAs involved in E. coli-induced meningitis have been reported, which shall provide novel insight into the regulatory mechanisms behind bacterial meningitis involving lncRNAs, and contribute to better prevention and therapy of CNS infection. PMID- 27958324 TI - The biogeography of soil archaeal communities on the eastern Tibetan Plateau. AB - The biogeographical distribution of soil bacterial communities has been widely investigated. However, there has been little study of the biogeography of soil archaeal communities on a regional scale. Here, using high-throughput sequencing, we characterized the archaeal communities of 94 soil samples across the eastern Tibetan Plateau. Thaumarchaeota was the predominant archael phylum in all the soils, and Halobacteria was dominant only in dry soils. Archaeal community composition was significantly correlated with soil moisture content and C:N ratio, and archaeal phylotype richness was negatively correlated with soil moisture content (r = -0.47, P < 0.01). Spatial distance, a potential measure of the legacy effect of evolutionary and dispersal factors, was less important than measured environmental factors in determining the broad scale archaeal community pattern. These results indicate that soil moisture and C:N ratio are the key factors structuring soil archaeal communities on the eastern Tibetan Plateau. Our findings suggest that archaeal communities have adjusted their distributions rapidly enough to reach range equilibrium in relation to past environmental changes e.g. in water availability and soil nutrient status. This responsiveness may allow better prediction of future responses of soil archaea to environmental change in these sensitive ecosystems. PMID- 27958325 TI - OnabotulinumtoxinA Urethral Sphincter Injection as Treatment for Non-neurogenic Voiding Dysfunction - A Randomized, Double-Blind, Placebo-Controlled Study. AB - Non-neurogenic voiding dysfunction including dysfunctional voiding and detrusor underactivity caused by a spastic or non-relaxing external urethral sphincter can theoretically be treated by injections of botulinum A toxin into the external urethral sphincter. This randomized, double-blind, placebo-controlled trial was designed to determine the clinical efficacy of onabotulinumtoxinA urethral sphincter injections in patients with dysfunctional voiding or detrusor underactivity. Patients with medically refractory dysfunctional voiding (n = 31) or detrusor underactivity (n = 31) were randomly allocated in a 2:1 ratio to receive either onabotulinumtoxinA (100 U) (n = 38) or placebo (normal saline) (n = 24). There were no significant differences in subjective or objective parameters between patients who received onabotulinumtoxinA and those who received saline injection therapy, and the overall success rate was 43.5% (reduction in Patient perception of Bladder Condition by >=2: onabotulinumtoxinA 36.8% vs placebo 54.2%, p = 0.114). The results were similar between the dysfunctional voiding and detrusor underactivity subgroups; however, a significant reduction in detrusor voiding pressure was only observed in dysfunctional voiding patients who received onabotulinumtoxinA. Repeat urethral sphincter onabotulinumtoxinA injections offered greater therapeutic effects in both dysfunctional voiding and detrusor underactivity patients. For patients with non-neurogenic voiding dysfunction, the success rate of onabotulinumtoxinA urethral sphincter injection was not superior to placebo. PMID- 27958326 TI - Calcium Channels and Oxidative Stress Mediate a Synergistic Disruption of Tight Junctions by Ethanol and Acetaldehyde in Caco-2 Cell Monolayers. AB - Ethanol is metabolized into acetaldehyde in most tissues. In this study, we investigated the synergistic effect of ethanol and acetaldehyde on the tight junction integrity in Caco-2 cell monolayers. Expression of alcohol dehydrogenase sensitized Caco-2 cells to ethanol-induced tight junction disruption and barrier dysfunction, whereas aldehyde dehydrogenase attenuated acetaldehyde-induced tight junction disruption. Ethanol up to 150 mM did not affect tight junction integrity or barrier function, but it dose-dependently increased acetaldehyde-mediated tight junction disruption and barrier dysfunction. Src kinase and MLCK inhibitors blocked this synergistic effect of ethanol and acetaldehyde on tight junction. Ethanol and acetaldehyde caused a rapid and synergistic elevation of intracellular calcium. Calcium depletion by BAPTA or Ca2+-free medium blocked ethanol and acetaldehyde-induced barrier dysfunction and tight junction disruption. Diltiazem and selective knockdown of TRPV6 or CaV1.3 channels, by shRNA blocked ethanol and acetaldehyde-induced tight junction disruption and barrier dysfunction. Ethanol and acetaldehyde induced a rapid and synergistic increase in reactive oxygen species by a calcium-dependent mechanism. N-acetyl-L cysteine and cyclosporine A, blocked ethanol and acetaldehyde-induced barrier dysfunction and tight junction disruption. These results demonstrate that ethanol and acetaldehyde synergistically disrupt tight junctions by a mechanism involving calcium, oxidative stress, Src kinase and MLCK. PMID- 27958327 TI - Widespread episodic thiamine deficiency in Northern Hemisphere wildlife. AB - Many wildlife populations are declining at rates higher than can be explained by known threats to biodiversity. Recently, thiamine (vitamin B1) deficiency has emerged as a possible contributing cause. Here, thiamine status was systematically investigated in three animal classes: bivalves, ray-finned fishes, and birds. Thiamine diphosphate is required as a cofactor in at least five life sustaining enzymes that are required for basic cellular metabolism. Analysis of different phosphorylated forms of thiamine, as well as of activities and amount of holoenzyme and apoenzyme forms of thiamine-dependent enzymes, revealed episodically occurring thiamine deficiency in all three animal classes. These biochemical effects were also linked to secondary effects on growth, condition, liver size, blood chemistry and composition, histopathology, swimming behaviour and endurance, parasite infestation, and reproduction. It is unlikely that the thiamine deficiency is caused by impaired phosphorylation within the cells. Rather, the results point towards insufficient amounts of thiamine in the food. By investigating a large geographic area, by extending the focus from lethal to sublethal thiamine deficiency, and by linking biochemical alterations to secondary effects, we demonstrate that the problem of thiamine deficiency is considerably more widespread and severe than previously reported. PMID- 27958328 TI - Distinct Interactions between Fronto-Parietal and Default Mode Networks in Impaired Consciousness. AB - Existing evidence suggests that the default-mode network (DMN) and fronto pariatal network (FPN) play an important role in altered states of consciousness. However, the brain mechanisms underlying impaired consciousness and the specific network interactions involved are not well understood. We studied the topological properties of brain functional networks using resting-state functional MRI data acquired from 18 patients (11 vegetative state/unresponsive wakefulness syndrome, VS/UWS, and 7 minimally conscious state, MCS) and compared these properties with those of healthy controls. We identified that the topological properties in DMN and FPN are anti-correlated which comes, in part, from the contribution of interactions between dorsolateral prefrontal cortex of the FPN and precuneus of the DMN. Notably, altered nodal connectivity strength was distance-dependent, with most disruptions appearing in long-distance connections within the FPN but in short-distance connections within the DMN. A multivariate pattern classification analysis revealed that combination of topological patterns between the FPN and DMN could predict conscious state more effectively than connectivity within either network. Taken together, our results imply distinct interactions between the FPN and DMN, which may mediate conscious state. PMID- 27958329 TI - CircRNA accumulation in the aging mouse brain. AB - Circular RNAs (circRNAs) are a newly appreciated class of RNAs expressed across diverse phyla. These enigmatic transcripts are most commonly generated by back splicing events from exons of protein-coding genes. This results in highly stable RNAs due to the lack of free 5' and 3' ends. CircRNAs are enriched in neural tissues, suggesting that they might have neural functions. Here, we sought to determine whether circRNA accumulation occurs during aging in mice. Total RNA-seq profiling of young (1 month old) and aged (22 month old) cortex, hippocampus and heart samples was performed. This led to the confident detection of 6,791 distinct circRNAs across these samples, including 675 novel circRNAs. Analysis uncovered a strong bias for circRNA upregulation during aging in neural tissues. These age-accumulation trends were verified for individual circRNAs by RT-qPCR and Northern analysis. In contrast, comparison of aged versus young hearts failed to reveal a global trend for circRNA upregulation. Age-accumulation of circRNAs in brain tissues was found to be largely independent from linear RNA expression of host genes. These findings suggest that circRNAs might play biological roles relevant to the aging nervous system. PMID- 27958330 TI - Highly efficient transduction of primary adult CNS and PNS neurons. AB - Delivery and expression of recombinant genes, a key methodology for many applications in biological research, remains a challenge especially for mature neurons. Here, we report easy, highly efficient and well tolerated transduction of adult peripheral and central neuronal populations of diverse species in culture using VSV-G pseudo-typed, recombinant baculovirus (BacMam). Transduction rates of up to 80% were reliably achieved at high multiplicity of infection without apparent neuro-cytopathic effects. Neurons could be transduced either shortly after plating or after several days in culture. Co-incubation with two different baculoviruses attained near complete co-localization of fluorescent protein expression, indicating multigene delivery. Finally, evidence for functional protein expression is provided by means of cre-mediated genetic recombination and neurite outgrowth assays. Recombinant protein was already detected within hours after transduction, thereby enabling functional readouts even in relatively short-lived neuronal cultures. Altogether, these results substantiate the usefulness of baculovirus-mediated transduction of mature neurons for future research in neuroscience. PMID- 27958331 TI - Improved genome-scale multi-target virtual screening via a novel collaborative filtering approach to cold-start problem. AB - Conventional one-drug-one-gene approach has been of limited success in modern drug discovery. Polypharmacology, which focuses on searching for multi-targeted drugs to perturb disease-causing networks instead of designing selective ligands to target individual proteins, has emerged as a new drug discovery paradigm. Although many methods for single-target virtual screening have been developed to improve the efficiency of drug discovery, few of these algorithms are designed for polypharmacology. Here, we present a novel theoretical framework and a corresponding algorithm for genome-scale multi-target virtual screening based on the one-class collaborative filtering technique. Our method overcomes the sparseness of the protein-chemical interaction data by means of interaction matrix weighting and dual regularization from both chemicals and proteins. While the statistical foundation behind our method is general enough to encompass genome-wide drug off-target prediction, the program is specifically tailored to find protein targets for new chemicals with little to no available interaction data. We extensively evaluate our method using a number of the most widely accepted gene-specific and cross-gene family benchmarks and demonstrate that our method outperforms other state-of-the-art algorithms for predicting the interaction of new chemicals with multiple proteins. Thus, the proposed algorithm may provide a powerful tool for multi-target drug design. PMID- 27958333 TI - Toxicity of nine insecticides on four natural enemies of Spodoptera exigua. AB - Spodoptera exigua, which feeds on various crops worldwide, has natural enemies that are susceptible to the insecticides used against S. exigua. We investigate the toxicity and residue risk of 9 insecticides on the development of H. axyridis, C. sinica, S. manilae and T. remus. S. manilae and T. remus adults were sensitive to all 9 insecticides (LC50 less than 2.75 mg a.i. liter-1), while H. axyridis and C. sinica adults were less sensitive (LC50 between 6 * 10-5 mg a.i. liter-1 and 78.95 mg a.i. liter-1). Emamectin benzoate, spinosad, indoxacarb, alpha-cypermethrin, chlorfenapyr and chlorantraniliprole showed no toxicity on H. axyridis, C. sinica, S. manilae and T. remus pupae with the recommended field concentrations. The risk analysis indicated that chlorantraniliprole is harmless to larvae of four natural enemies and adult of H. axyridis, C. sinica and S. manilae. Emamectin benzoate and spinosad had higher safety to the development of H. axyridis, C. sinica, S. manilae and T. remus with the risk duration less than 4d. Indoxacarb, tebufenozide, chlorfenapyr, methomyl, alpha-cypermethrin and chlorpyrifos showed dangerously toxic and long risk duration on S. manilae and T. remus adults. PMID- 27958334 TI - Invisibility cloak with image projection capability. AB - Investigations of invisibility cloaks have been led by rigorous theories and such cloak structures, in general, require extreme material parameters. Consequently, it is challenging to realize them, particularly in the full visible region. Due to the insensitivity of human eyes to the polarization and phase of light, cloaking a large object in the full visible region has been recently realized by a simplified theory. Here, we experimentally demonstrate a device concept where a large object can be concealed in a cloak structure and at the same time any images can be projected through it by utilizing a distinctively different approach; the cloaking via one polarization and the image projection via the other orthogonal polarization. Our device structure consists of commercially available optical components such as polarizers and mirrors, and therefore, provides a significant further step towards practical application scenarios such as transparent devices and see-through displays. PMID- 27958332 TI - Endotoxins are associated with visceral fat mass in type 1 diabetes. AB - Bacterial lipopolysaccharides (LPS), potent inducers of inflammation, have been associated with chronic metabolic disturbances. Obesity is linked to dyslipidemia, increased body adiposity, and endotoxemia. We investigated the cross-sectional relationships between serum LPS activity and body adiposity as well as inflammation in 242 subjects with type 1 diabetes. Body fat distribution was measured by DXA and serum LPS activity by the limulus amebocyte lysate end point assay. Since no interaction between visceral fat mass and sex was observed, data were pooled for the subsequent analyses. LPS was independently associated with visceral fat mass, when adjusted for traditional risk factors (age, sex, kidney status, hsCRP, insulin sensitivity). In the multivariate analysis, serum LPS activity and triglyceride concentrations had a joint effect on visceral fat mass, independent of these factors alone. A combination of high LPS and high hsCRP concentrations was also observed in those with the largest visceral fat mass. In conclusion, high serum LPS activity levels were associated with visceral fat mass in subjects with type 1 diabetes strengthening its role in the development of central obesity, inflammation and insulin resistance. PMID- 27958336 TI - Coupling the normal incident light into waveguide modes of DBR mirrors via a diffraction grating. AB - Here we numerically and experimentally demonstrate the conversion of normally incident light into the guiding modes of distributed Bragg reflector (DBRs) mirror. By fabricating a gold grating onto a 7.5 pairs TiO2/SiO2 DBR mirror, a series of asymmetrical resonances have been formed at the bandgap range of the DBR mirror. The detailed numerical calculations show that these Fano resonances are attributed to the coupling of incident waves into guiding modes of the DBR mirror. Compared with the other resonances, this coupling mechanism can be simply realized and it has also been revealed to be quite robust to the environmental changes, making the conversion between propagating waves and guiding waves to be practically interesting for many applications. PMID- 27958335 TI - Non-canonical integration events in Pichia pastoris encountered during standard transformation analysed with genome sequencing. AB - The non-conventional yeast Pichia pastoris is a popular host for recombinant protein production in scientific research and industry. Typically, the expression cassette is integrated into the genome via homologous recombination. Due to unknown integration events, a large clonal variability is often encountered consisting of clones with different productivities as well as aberrant morphological or growth characteristics. In this study, we analysed several clones with abnormal colony morphology and discovered unpredicted integration events via whole genome sequencing. These include (i) the relocation of the locus targeted for replacement to another chromosome (ii) co-integration of DNA from the E. coli plasmid host and (iii) the disruption of untargeted genes affecting colony morphology. Most of these events have not been reported so far in literature and present challenges for genetic engineering approaches in this yeast. Especially, the presence and independent activity of E. coli DNA elements in P. pastoris is of concern. In our study, we provide a deeper insight into these events and their potential origins. Steps preventing or reducing the risk for these phenomena are proposed and will help scientists working on genetic engineering of P. pastoris or similar non-conventional yeast to better understand and control clonal variability. PMID- 27958337 TI - Type 2 diabetes mellitus is associated with increased risks of sarcopenia and pre sarcopenia in Chinese elderly. AB - Sarcopenia is a condition characterized by progressive and generalized loss of skeletal muscle mass and function. In this study, we used a cross-sectional study with 1090 community-dwelling Chinese citizens aged 60 years and older to evaluate the association of type 2 diabetes mellitus (T2DM) with the risk of sarcopenia and pre-sarcopenia. Sarcopenia was defined using the Asian Working Group for Sarcopenia (AWGS) criteria that include both muscle mass and muscle function/physical activity. Pre-sarcopenia was defined as having low skeletal muscle index but with normal muscle/physical activity. The prevalence of sarcopenia and pre-sarcopenia was significantly higher in T2DM patients than in healthy controls (14.8% vs. 11.2%, p = 0.035 for sarcopenia, and 14.4% vs. 8.4%, p = 0.002 for pre-sarcopenia). In multivariate logistic regression analyses adjusting by age, gender, anti-diabetic medication, energy intake, protein intake, physical activity, and visceral fat area, we found that Chinese elderly with T2DM exhibited significantly increased risks of sarcopenia (OR = 1.37, 95% CI = 1.02-2.03) and pre-sarcopenia (OR = 1.73, 95% CI = 1.10-2.83) compared to non-diabetic individuals. This is the first study to evaluate the association of T2DM with the risks of sarcopenia and pre-sarcopenia in China. Among a group of community-dwelling Chinese elderly, T2DM was significantly associated with increased risks of sarcopenia and pre-sarcopenia. PMID- 27958338 TI - Ester-Modified Cyclometalated Iridium(III) Complexes as Mitochondria-Targeting Anticancer Agents. AB - Organometallic iridium complexes are potent anticancer candidates which act through different mechanisms from cisplatin-based chemotherapy regimens. Here, ten phosphorescent cyclometalated iridium(III) complexes containing 2,2' bipyridine-4,4'-dicarboxylic acid and its diester derivatives as ligands are designed and synthesized. The modification by ester group, which can be hydrolysed by esterase, facilitates the adjustment of drug-like properties. The quantum yields and emission lifetimes are influenced by variation of the ester substituents on the Ir(III) complexes. The cytotoxicity of these Ir(III) complexes is correlated with the length of their ester groups. Among them, 4a and 4b are found to be highly active against a panel of cancer cells screened, including cisplatin-resistant cancer cells. Mechanism studies in vitro indicate that they undergo hydrolysis of ester bonds, accumulate in mitochondria, and induce a series of cell-death related events mediated by mitochondria. Furthermore, 4a and 4b can induce pro-death autophagy and apoptosis simultaneously. Our study indicates that ester modification is a simple and feasible strategy to enhance the anticancer potency of Ir(III) complexes. PMID- 27958339 TI - Assessing the potential for Bluetongue virus 8 to spread and vaccination strategies in Scotland. AB - Europe has seen frequent outbreaks of Bluetongue (BT) disease since 2006, including an outbreak of BT virus serotype 8 in central France during 2015 that has continued to spread in Europe during 2016. Thus, assessing the potential for BTv-8 spread and determining the optimal deployment of vaccination is critical for contingency planning. We developed a spatially explicit mathematical model of BTv-8 spread in Scotland and explored the sensitivity of transmission to key disease spread parameters for which detailed empirical data is lacking. With parameters at mean values, there is little spread of BTv-8 in Scotland. However, under a "worst case" but still feasible scenario with parameters at the limits of their ranges and temperatures 1 degrees C warmer than the mean, we find extensive spread with 203,000 sheep infected given virus introduction to the south of Scotland between mid-May and mid-June. Strategically targeted vaccine interventions can greatly reduce BT spread. Specifically, despite BT having most clinical impact in sheep, we show that vaccination can have the greatest impact on reducing BTv infections in sheep when administered to cattle, which has implications for disease control policy. PMID- 27958340 TI - System-specific periodicity in quantitative real-time polymerase chain reaction data questions threshold-based quantitation. AB - Real-time quantitative polymerase chain reaction (qPCR) data are found to display periodic patterns in the fluorescence intensity as a function of sample number for fixed cycle number. This behavior is seen for technical replicate datasets recorded on several different commercial instruments; it occurs in the baseline region and typically increases with increasing cycle number in the growth and plateau regions. Autocorrelation analysis reveals periodicities of 12 for 96-well systems and 24 for a 384-well system, indicating a correlation with block architecture. Passive dye experiments show that the effect may be from optical detector bias. Importantly, the signal periodicity manifests as periodicity in quantification cycle (Cq) values when these are estimated by the widely applied fixed threshold approach, but not when scale-insensitive markers like first- and second-derivative maxima are used. Accordingly, any scale variability in the growth curves will lead to bias in constant-threshold-based Cqs, making it mandatory that workers should either use scale-insensitive Cqs or normalize their growth curves to constant amplitude before applying the constant threshold method. PMID- 27958341 TI - Downregulation of peroxiredoxin-3 by hydrophobic bile acid induces mitochondrial dysfunction and cellular senescence in human trophoblasts. AB - Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder characterised by raised bile acids in foetal-maternal circulation, which threatens perinatal health. During the progression of ICP, the effect of oxidative stress is underscored. Peroxiredoxin-3 (PRDX3) is a mitochondrial antioxidant enzyme that is crucial to balance intracellular oxidative stress. However, the role of PRDX3 in placental trophoblast cells under ICP is not fully understood. We demonstrated that the level of PRDX3 was downregulated in ICP placentas as well as bile acids-treated trophoblast cells and villous explant in vitro. Toxic levels of bile acids and PRDX3 knockdown induced oxidative stress and mitochondrial dysfunction in trophoblast cells. Moreover, silencing of PRDX3 in trophoblast cell line HTR8/SVneo induced growth arrest and cellular senescence via activation of p38-mitogen-activated protein kinase (MAPK) and induction of p21WAF1/CIP and p16INK4A. Additionally, enhanced cellular senescence, determined by senescence-associated beta-galactosidase staining, was obviously attenuated by p38-MAPK inhibitor SB203580. Our data determined that exposure to bile acid decreased PRDX3 level in human trophoblasts. PRDX3 protected trophoblast cells against mitochondrial dysfunction and cellular senescence induced by oxidative stress. Our results suggest that decreased PRDX3 by excessive bile acids in trophoblasts plays a critical role in the pathogenesis and progression of ICP. PMID- 27958342 TI - Longitudinal, observational study on associations between postoperative nutritional vitamin D supplementation and clinical outcomes in esophageal cancer patients undergoing esophagectomy. AB - Vitamin D can exert anticancer effect beyond bone and calcium metabolism. We aimed to investigate whether postoperative vitamin D supplementation affects quality of life (QOL) and survival in esophageal cancer (EC) patients. We utilized the widely used EORTC QLQ-C30 and QLQ-OES18 to assess QOL at EC diagnosis and 24 months after surgery. Generalized estimating equations (GEEs) were used to analysis the association of vitamin D supplement use with QOL. Kaplan-Meier method and Cox regression model were used to evaluate the prognostic value of vitamin D supplementation. The notably improved QOL were found among vitamin D supplementation users compared with non-users (p < 0.05). Kaplan-Meier analysis revealed that vitamin D supplement use was significantly associated with improved disease-free survival (DFS) (p = 0.030), but not related to overall survival (OS) (p = 0.303). The multivariable analysis further demonstrated vitamin D supplement use as an independent prognostic factor for DFS (p = 0.040; HR 0.610; 95% CI 0.381-0.978). In conclusion, these results showed that vitamin D supplement use could serve as a promising intervention to enhancing QOL and prolonging DFS in EC. PMID- 27958344 TI - The relationship between toll like receptor 4 gene rs4986790 and rs4986791 polymorphisms and sepsis susceptibility: A meta-analysis. AB - Accumulating evidences have demonstrated that lipopolysaccharide (LPS) represents the important etiologic factor for sepsis. Some previous studies have reported the relationship between common polymorphisms rs4986790 and rs4986791 in the coding gene for this receptor and the susceptibility to sepsis, but there were distinct divergences between those findings. We therefore designed this meta analysis incorporated 28 published articles containing 6,537 sepsis patients and 8,832 controls for a more comprehensive conclusion on this matter. Odds ratios (ORs) and 95% confidence interval (95% CIs) were calculated to evaluate the association of toll like receptor 4 gene polymorphisms rs4986790 and rs4986791 with sepsis risk. Heterogeneity between included studies was inspected using Q test, and sensitivity analysis was implemented via sequential deletion of each included study to investigate the stability of overall estimates. Funnel plot and Egger's test were adopted to examine publication bias across selected studies. We found no significant association for either the polymorphism rs4986790 or rs4986791 with sepsis susceptibility in total analysis under any genetic models. Neither did we after combining these two polymorphisms. The results of this meta analysis suggest that the rs4986790 and rs4986791 polymorphisms in toll like receptor 4 gene may have no statistically significant influence on sepsis susceptibility. PMID- 27958345 TI - Effects of light attenuation on the sponge holobiont- implications for dredging management. AB - Dredging and natural sediment resuspension events can cause high levels of turbidity, reducing the amount of light available for photosynthetic benthic biota. To determine how marine sponges respond to light attenuation, five species were experimentally exposed to a range of light treatments. Tolerance thresholds and capacity for recovery varied markedly amongst species. Whilst light attenuation had no effect on the heterotrophic species Stylissa flabelliformis and Ianthella basta, the phototrophic species Cliona orientalis and Carteriospongia foliascens discoloured (bleached) over a 28 day exposure period to very low light (<0.8 mol photons m-2 d-1). In darkness, both species discoloured within a few days, concomitant with reduced fluorescence yields, chlorophyll concentrations and shifts in their associated microbiomes. The phototrophic species Cymbastela coralliophila was less impacted by light reduction. C. orientalis and C. coralliophila exhibited full recovery under normal light conditions, whilst C. foliascens did not recover and showed high levels of mortality. The light treatments used in the study are directly relevant to conditions that can occur in situ during dredging projects, indicating that light attenuation poses a risk to photosynthetic marine sponges. Examining benthic light levels over temporal scales would enable dredging proponents to be aware of conditions that could impact on sponge physiology. PMID- 27958343 TI - HBV maintains electrostatic homeostasis by modulating negative charges from phosphoserine and encapsidated nucleic acids. AB - Capsid assembly and stability of hepatitis B virus (HBV) core protein (HBc) particles depend on balanced electrostatic interactions between encapsidated nucleic acids and an arginine-rich domain (ARD) of HBc in the capsid interior. Arginine-deficient ARD mutants preferentially encapsidated spliced viral RNA and shorter DNA, which can be fully or partially rescued by reducing the negative charges from acidic residues or serine phosphorylation of HBc, dose-dependently. Similarly, empty capsids without RNA encapsidation can be generated by ARD hyper phosphorylation in insect, bacteria, and human hepatocytes. De-phosphorylation of empty capsids by phosphatase induced capsid disassembly. Empty capsids can convert into RNA-containing capsids by increasing HBc serine de-phosphorylation. In an HBV replicon system, we observed a reciprocal relationship between viral and non-viral RNA encapsidation, suggesting both non-viral RNA and serine phosphorylation could serve as a charge balance buffer in maintaining electrostatic homeostasis. In addition, by comparing the biochemistry assay results between a replicon and a non-replicon system, we observed a correlation between HBc de-phosphorylation and viral replication. Balanced electrostatic interactions may be important to other icosahedral particles in nature. PMID- 27958347 TI - Local Dielectric Property Detection of the Interface between Nanoparticle and Polymer in Nanocomposite Dielectrics. AB - The interface between nanoparticles and polymer matrix is considered to have an important effect on the properties of nanocomposites. In this experimental study, electrostatic force microscopy (EFM) is used to study the local dielectric property of the interface of low density polyethylene (LDPE)/TiO2 nanocomposites at nanometer scale. The results show that the addition of TiO2 nanoparticles leads to a decrease in local permittivity. We then carry out the finite element simulation and confirm that the decrease of local permittivity is related to the effect of interface. According to the results, we propose several models and validate the dielectric effect and range effect of interface. Through the analysis of DSC and solid-state NMR results, we find TiO2 nanoparticles can suppress the mobility of local chain segments in the interface, which influences the dipolar polarization of chain segments in the interface and eventually results in a decrease in local permittivity. It is believed the results would provide important hint to the research of the interface in future research. PMID- 27958346 TI - Clinical Association of Chemokine (C-X-C motif) Ligand 1 (CXCL1) with Interstitial Pneumonia with Autoimmune Features (IPAF). AB - The term "interstitial pneumonia with autoimmune features" (IPAF) has been recently proposed. We here investigate the clinical characteristics of IPAF and evaluate the clinical implications of CXCL1-CXCR2 axis in IPAF. An increased plasma level of CXCL1 was exhibited in IPAF compared to idiopathic interstitial pneumonia (IIP), chronic obstructive pulmonary disease (COPD), and healthy controls. Additionally, plasma CXCL1 levels were clinically associated with diffusing capacity of the lungs for carbon monoxide (DLCO), erythrocyte sedimentation rate (ESR), and involved parenchyma extension in IPAF. Furthermore, circulating CXCL1 levels were highest in IPAF patients with acute exacerbations. CXCR2, the chemokine receptor for CXCL1, was readily observed in inflammatory aggregates and endothelial cells in IPAF lungs, but was lower in IIP lungs and healthy lungs. Interestingly, increased CXCL1 concentrations in BALF paralleled neutrophil counts in IPAF. Overall, the plasma concentrations of CXCL1 indicated the disease activity and prognosis in IPAF. Thus, the CXCL1/CXCR2 axis appears to be involved in the progression of IPAF. PMID- 27958348 TI - Laser Light-field Fusion for Wide-field Lensfree On-chip Phase Contrast Microscopy of Nanoparticles. AB - Wide-field lensfree on-chip microscopy, which leverages holography principles to capture interferometric light-field encodings without lenses, is an emerging imaging modality with widespread interest given the large field-of-view compared to lens-based techniques. In this study, we introduce the idea of laser light field fusion for lensfree on-chip phase contrast microscopy for detecting nanoparticles, where interferometric laser light-field encodings acquired using a lensfree, on-chip setup with laser pulsations at different wavelengths are fused to produce marker-free phase contrast images of particles at the nanometer scale. As a proof of concept, we demonstrate, for the first time, a wide-field lensfree on-chip instrument successfully detecting 300 nm particles across a large field of-view of ~30 mm2 without any specialized or intricate sample preparation, or the use of synthetic aperture- or shift-based techniques. PMID- 27958349 TI - Metabolite Profiling of Preneoplastic and Neoplastic Lesions of Oral Cavity Tissue Samples Revealed a Biomarker Pattern. AB - Oral cancer is a major health challenge in the Indian subcontinent and a dreadful form of cancers worldwide. The current study is focused on the identification of distinguished metabolites of oral cancer tissue samples in comparison with precancerous and control tissue samples using gas chromatography coupled with triple quadrupole tandem mass spectrometry and chemometric analyses. Metabolites obtained were identified through National Institute of Standards and Technology (NIST) mass spectral (Wiley registry) library. Mass Profiler Professional (MPP) software was used for the alignment and for all the statistical analysis. 31 compounds out of 735 found distinguishing among oral cancer, precancerous and control group samples using p-value <= 0.05. Partial Least Square Discriminant Analysis (PLSDA) model was generated using statistically significant metabolites gave an overall accuracy of 90.2%. Down-regulated amino acid levels appear to be the result of enhanced energy metabolism or up-regulation of the appropriate biosynthetic pathways, and required cell proliferation in cancer tissues. These results suggest that tissue metabolic profiles have great potential in detecting oral cancer and may aid in understanding its underlying mechanisms. PMID- 27958351 TI - Corrigendum: Increased water salinity applied to tomato plants accelerates the development of the leaf miner Tuta absoluta through bottom-up effects. PMID- 27958350 TI - Effect of acute pesticide exposure on bee spatial working memory using an analogue of the radial-arm maze. AB - Pesticides, including neonicotinoids, typically target pest insects by being neurotoxic. Inadvertent exposure to foraging insect pollinators is usually sub lethal, but may affect cognition. One cognitive trait, spatial working memory, may be important in avoiding previously-visited flowers and other spatial tasks such as navigation. To test this, we investigated the effect of acute thiamethoxam exposure on spatial working memory in the bumblebee Bombus terrestris, using an adaptation of the radial-arm maze (RAM). We first demonstrated that bumblebees use spatial working memory to solve the RAM by showing that untreated bees performed significantly better than would be expected if choices were random or governed by stereotyped visitation rules. We then exposed bees to either a high sub-lethal positive control thiamethoxam dose (2.5 ng-1 bee), or one of two low doses (0.377 or 0.091 ng-1) based on estimated field realistic exposure. The high dose caused bees to make more and earlier spatial memory errors and take longer to complete the task than unexposed bees. For the low doses, the negative effects were smaller but statistically significant, and dependent on bee size. The spatial working memory impairment shown here has the potential to harm bees exposed to thiamethoxam, through possible impacts on foraging efficiency or homing. PMID- 27958352 TI - Fossil record of stem groups employed in evaluating the chronogram of insects (Arthropoda: Hexapoda). AB - Insecta s. str. (=Ectognatha), comprise the largest and most diversified group of living organisms, accounting for roughly half of the biodiversity on Earth. Understanding insect relationships and the specific time intervals for their episodes of radiation and extinction are critical to any comprehensive perspective on evolutionary events. Although some deeper nodes have been resolved congruently, the complete evolution of insects has remained obscure due to the lack of direct fossil evidence. Besides, various evolutionary phases of insects and the corresponding driving forces of diversification remain to be recognized. In this study, a comprehensive sample of all insect orders was used to reconstruct their phylogenetic relationships and estimate deep divergences. The phylogenetic relationships of insect orders were congruently recovered by Bayesian inference and maximum likelihood analyses. A complete timescale of divergences based on an uncorrelated log-normal relaxed clock model was established among all lineages of winged insects. The inferred timescale for various nodes are congruent with major historical events including the increase of atmospheric oxygen in the Late Silurian and earliest Devonian, the radiation of vascular plants in the Devonian, and with the available fossil record of the stem groups to various insect lineages in the Devonian and Carboniferous. PMID- 27958353 TI - Complementary Log Regression for Sufficient-Cause Modeling of Epidemiologic Data. AB - The logistic regression model is the workhorse of epidemiological data analysis. The model helps to clarify the relationship between multiple exposures and a binary outcome. Logistic regression analysis is readily implemented using existing statistical software, and this has contributed to it becoming a routine procedure for epidemiologists. In this paper, the authors focus on a causal model which has recently received much attention from the epidemiologic community, namely, the sufficient-component cause model (causal-pie model). The authors show that the sufficient-component cause model is associated with a particular 'link' function: the complementary log link. In a complementary log regression, the exponentiated coefficient of a main-effect term corresponds to an adjusted 'peril ratio', and the coefficient of a cross-product term can be used directly to test for causal mechanistic interaction (sufficient-cause interaction). The authors provide detailed instructions on how to perform a complementary log regression using existing statistical software and use three datasets to illustrate the methodology. Complementary log regression is the model of choice for sufficient cause analysis of binary outcomes. Its implementation is as easy as conventional logistic regression. PMID- 27958354 TI - Unusual Five Copies and Dual Forms of nrdB in "Candidatus Liberibacter asiaticus": Biological Implications and PCR Detection Application. AB - "Candidatus Liberibacter asiaticus" (CLas), a non-culturable alpha proteobacterium, is associated with citrus Huanglongbing (HLB, yellow shoot disease) currently threatening citrus production worldwide. Here, the whole genome sequence of CLas strain A4 from Guangdong of China was analyzed. Five copies of nrdB, encoding beta-subunit of ribonucleotide reductase (RNR), a critical enzyme involving bacterial proliferation, were found. Three nrdB copies were in long form (nrdBL, 1,059 bp) and two were in short form (nrdBS, 378 bp). nrdBS shared >99% identity to 3' end of nrdBL and had no active site. Sequences of CLas nrdB genes formed a distinct monophyletic lineage among eubacteria. To make use of the high copy number feature, a nrdB-based primer set RNRf/RNRr was designed and evaluated using real-time PCR with 262 HLB samples collected from China and USA. Compared to the current standard primer set HLBas/HLBr derived from the 16S rRNA gene, RNRf/RNRr had Ct value reductions of 1.68 (SYBR Green PCR) and 1.77 (TaqMan PCR), thus increasing the detection sensitivity three-fold. Meanwhile, RNRf/RNRr was more than twice the stability of primer set LJ900f/LJ900r derived from multi-copy prophage. The nrdB-based PCR thereby provides a sensitive and reliable CLas detection with broad application, especially for the early diagnosis of HLB. PMID- 27958355 TI - Chimera states in uncoupled neurons induced by a multilayer structure. AB - Spatial coexistence of coherent and incoherent dynamics in network of coupled oscillators is called a chimera state. We study such chimera states in a network of neurons without any direct interactions but connected through another medium of neurons, forming a multilayer structure. The upper layer is thus made up of uncoupled neurons and the lower layer plays the role of a medium through which the neurons in the upper layer share information among each other. Hindmarsh-Rose neurons with square wave bursting dynamics are considered as nodes in both layers. In addition, we also discuss the existence of chimera states in presence of inter layer heterogeneity. The neurons in the bottom layer are globally connected through electrical synapses, while across the two layers chemical synapses are formed. According to our research, the competing effects of these two types of synapses can lead to chimera states in the upper layer of uncoupled neurons. Remarkably, we find a density-dependent threshold for the emergence of chimera states in uncoupled neurons, similar to the quorum sensing transition to a synchronized state. Finally, we examine the impact of both homogeneous and heterogeneous inter-layer information transmission delays on the observed chimera states over a wide parameter space. PMID- 27958356 TI - On-Chip Optical Nonreciprocity Using an Active Microcavity. AB - Optically nonreciprocal devices provide critical functionalities such as light isolation and circulation in integrated photonic circuits for optical communications and information processing, but have been difficult to achieve. By exploring gain-saturation nonlinearity, we demonstrate on-chip optical nonreciprocity with excellent isolation performance within telecommunication wavelengths using only one toroid microcavity. Compatible with current complementary metal-oxide-semiconductor process, our compact and simple scheme works for a very wide range of input power levels from ~10 microwatts down to ~10 nanowatts, and exhibits remarkable properties of one-way light transport with sufficiently low insertion loss. These superior features make our device become a promising critical building block indispensable for future integrated nanophotonic networks. PMID- 27958357 TI - Semen preparation methods and sperm telomere length: density gradient centrifugation versus the swim up procedure. AB - Previous studies have shown that both density gradient centrifugation (DGC) and swim up (SU) procedures can select spermatozoa with longer telomeres for assisted reproduction techniques (ART). However, it is unknown which approach is more effective. The aim of the present study was to compare the effects of these two methods on sperm telomere length (STL). A total of 150 normozoospermic subjects were recruited. STL, DNA fragmentation index (DFI), reactive oxygen species (ROS) content and progressive motility of semen samples were detected before and after the procedures of DGC and SU. When compared to raw semen, the average length of sperm telomeres was significantly longer after the two sperm preparation methods. However, no significant difference was found between the DGC and SU procedures. We also found that semen prepared by the two methods had lower DNA fragmentation, ROS content and sperm progressive motility. However, no significant difference was found in those parameters between the two procedures. This is the first study that compares the effects of the DGC and SU procedures on STL, and the results show that both methods can recover a sperm population with longer STL and better DNA integrity for ART. PMID- 27958359 TI - Evidence for the transition from primary to peritectic phase growth during solidification of undercooled Ni-Zr alloy levitated by electromagnetic field. AB - The Ni83.25Zr16.75 peritectic alloy was undercooled by electromagnetic levitation method up to 198 K. The measured dendritic growth velocity shows a steep acceleration at a critical undercooling of DeltaTcrit = 124 K, which provides an evidence of the transition of the primary growth mode from Ni7Zr2 phase to peritectic phase Ni5Zr. This is ascertained by combining the temperature-time profile and the evolution of the solidified microstructures. Below the critical undercooling, the solidified microstructure is composed of coarse Ni7Zr2 dendrites, peritectic phase Ni5Zr and eutectic structure. However, beyond the critical undercooling, only a small amount of Ni7Zr2 phase appears in the solidified microstructure. The dendritic growth mechanism of Ni7Zr2 phase is mainly governed by solute diffusion. While, the dendritic growth mechanism of Ni5Zr phase is mainly controlled by thermal diffusion and liquid-solid interface atomic attachment kinetics. PMID- 27958358 TI - Ultrathin Terahertz Quarter-wave plate based on Split Ring Resonator and Wire Grating hybrid Metasurface. AB - Planar metasurface based quarter-wave plates offer various advantages over conventional waveplates in terms of compactness, flexibility and simple fabrication; however they offer very narrow bandwidth of operation. Here, we demonstrate a planar terahertz (THz) metasurface capable of linear to circular polarization conversion and vice versa in a wide frequency range. The proposed metasurface is based on horizontally connected split ring resonators and is realized on an ultrathin (0.05lambda) zeonor substrate. The fabricated quarter waveplate realizes linear to circular polarization conversion in two broad frequency bands comprising 0.64-0.82 THz and 0.96-1.3 THz with an insertion loss ranging from -3.9 to -10 dB. By virtue of ultrathin sub wavelength thickness, the proposed waveplate design is well suited for application in near field THz optical systems. Additionally, the proposed metasurface design offers novel transmission phase characteristics that present further opportunities to realize dynamic polarization control of incident waves. PMID- 27958360 TI - Diagnostic test accuracy of loop-mediated isothermal amplification assay for Mycobacterium tuberculosis: systematic review and meta-analysis. AB - Diagnostic test accuracy of the loop-mediated isothermal amplification (LAMP) assay for culture proven tuberculosis is unclear. We searched electronic databases for both cohort and case-control studies that provided data to calculate sensitivity and specificity. The index test was any LAMP assay including both commercialized kits and in-house assays. Culture-proven M. tuberculosis was considered a positive reference test. We included 26 studies on 9330 sputum samples and one study on 315 extra-pulmonary specimens. For sputum samples, 26 studies yielded the summary estimates of sensitivity of 89.6% (95% CI 85.6-92.6%), specificity of 94.0% (95% CI 91.0-96.1%), and a diagnostic odds ratio of 145 (95% CI 93-226). Nine studies focusing on Loopamp MTBC yielded the summary estimates of sensitivity of 80.9% (95% CI 76.0-85.1%) and specificity of 96.5% (95% CI 94.7-97.7%). Loopamp MTBC had higher sensitivity and lower specificity for smear-positive sputa compared to smear-negative sputa. In-house assays showed higher sensitivity and lower specificity compared to Loopamp MTBC. LAMP promises to be a useful test for the diagnosis of TB, however there is still need to improve the assay to make it simpler, cheaper and more efficient to make it competitive against other PCR methods already available. PMID- 27958361 TI - Deficiency of AXL in Bone Marrow-Derived Cells Does Not Affect Advanced Atherosclerotic Lesion Progression. AB - AXL, a member of the TAM (Tyro3, Axl, MerTK) family of receptors, plays important roles in cell survival, clearance of dead cells (efferocytosis), and suppression of inflammation, which are processes that critically influence atherosclerosis progression. Whereas MerTK deficiency promotes defective efferocytosis, inflammation, and plaque necrosis in advanced murine atherosclerosis, the role of Axl in advanced atherosclerosis progression is not known. Towards this end, bone marrow cells from Axl-/- or wild-type mice were transplanted into lethally irradiated Ldlr-/- mice. These chimeric mice were then fed the Western-type diet (WD) for 17 weeks. We demonstrate that lesional macrophages in WT mice express Axl but that Axl deficiency in bone marrow-derived cells does not affect lesion size, cellularity, necrosis, or inflammatory parameters in advanced atherosclerotic plaques. Moreover, apoptosis of lesional cells was unaffected, and we found no evidence of defective lesional efferocytosis. In contrast to previously reported findings with MerTK deficiency, hematopoietic cell-Axl deficiency in WD-fed Ldlr-/- mice does not affect the progression of advanced atherosclerosis or lesional processes associated with TAM receptor signaling. These findings suggest a heretofore unappreciated TAM receptor hierarchy in advanced atherosclerosis. PMID- 27958362 TI - Aggregation and Gelation of Aromatic Polyamides with Parallel and Anti-parallel Alignment of Molecular Dipole Along the Backbone. AB - The understanding of macromolecular structures and interactions is important but difficult, due to the facts that a macromolecules are of versatile conformations and aggregate states, which vary with environmental conditions and histories. In this work two polyamides with parallel or anti-parallel dipoles along the linear backbone, named as ABAB (parallel) and AABB (anti-parallel) have been studied. By using a combination of methods, the phase behaviors of the polymers during the aggregate and gelation, i.e., the forming or dissociation processes of nuclei and fibril, cluster of fibrils, and cluster-cluster aggregation have been revealed. Such abundant phase behaviors are dominated by the inter-chain interactions, including dispersion, polarity and hydrogen bonding, and correlatd with the solubility parameters of solvents, the temperature, and the polymer concentration. The results of X-ray diffraction and fast-mode dielectric relaxation indicate that AABB possesses more rigid conformation than ABAB, and because of that AABB aggregates are of long fibers while ABAB is of hairy fibril clusters, the gelation concentration in toluene is 1 w/v% for AABB, lower than the 3 w/v% for ABAB. PMID- 27958363 TI - Wnt Ligands Differentially Regulate Toxicity and Translocation of Graphene Oxide through Different Mechanisms in Caenorhabditis elegans. AB - In this study, we investigated the possible involvement of Wnt signals in the control of graphene oxide (GO) toxicity using the in vivo assay system of Caenorhabditis elegans. In nematodes, the Wnt ligands, CWN-1, CWN-2, and LIN-44, were found to be involved in the control of GO toxicity. Mutation of cwn-1 or lin 44 gene induced a resistant property to GO toxicity and resulted in the decreased accumulation of GO in the body of nematodes, whereas mutation of cwn-2 gene induces a susceptible property to GO toxicity and an enhanced accumulation of GO in the body of nematodes. Genetic interaction assays demonstrated that mutation of cwn-1 or lin-44 was able to suppress the susceptibility to GO toxicity shown in the cwn-2 mutants. Loss-of-function mutations in all three of these Wnt ligand genes resulted in the resistance of nematodes to GO toxicity. Moreover, the Wnt ligands might differentially regulate the toxicity and translocation of GO through different mechanisms. These findings could be important in understanding the function of Wnt signals in the regulation of toxicity from environmental nanomaterials. PMID- 27958365 TI - Fabrication of Self-Ordered Alumina Films with Large Interpore Distance by Janus Anodization in Citric Acid. AB - Self-organized porous anodic alumina (PAA) formed by electrochemical anodization have become a fundamental tool to develop various functional nanomaterials. However, it is still a great challenge to break the interpore distance (Dint) limit (500 nm) by using current anodization technologies of mild anodization (MA) and hard anodization (HA). Here, we reported a new anodization mode named "Janus anodization" (JA) to controllably fabricate self-ordered PAA with large Dint at high voltage of 350-400 V. JA naturally occurs as anodizing Al foils in citric acid solution, which possessing both the characteristics of MA and HA. The process can be divided into two stages: I, slow pore nucleation stage similar to MA; II, unequilibrium self-organization process similar to HA. The as-prepared films had the highest modulus (7.0 GPa) and hardness (127.2 GPa) values compared with the alumina obtained by MA and HA. The optical studies showed that the black films have low reflectance (<10 %) in the wavelength range of 250-1500 nm and photoluminescence property. Dint can be tuned between 645-884 nm by controlling citric acid concentration or anodization voltage. JA is a potential technology to efficiently and controllably fabricate microstructured or hybrid micro- and nanostructured materials with novel properties. PMID- 27958364 TI - Perceived Occupational Stress is associated with Decreased Cortical Activity of the Prefrontal Cortex: A Multichannel Near-infrared Spectroscopy Study. AB - Despite an increasing number of reports on the associations between chronic occupational stress and structural and functional changes of the brain, the underlying neural correlates of perceived occupational stress is still not clear. Perceived stress reflects the extents to which situations are appraised as stressful at a given point in one's life. Using near-infrared spectroscopy, we investigated the associations between perceived occupational stress and cortical activity over the bilateral frontotemporal regions during a verbal fluency test. Sixty-eight participants (17 men, 51 women), 20-62 years of age were recruited. Perceived occupational stress was measured using the Chinese version of Job Content Questionnaire, and the Chinese version of the Copenhagen Burnout Inventory. We found statistically significant negative associations between occupational burnout and brain cortical activity over the fronto-polar and dorsolateral prefrontal cortex during the VFT (r = -0.343 to -0.464). In conclusion, our research demonstrated a possible neural basis of perceived occupational stress that are distributed across the prefrontal cortex. PMID- 27958366 TI - Soil aggregation and aggregating agents as affected by long term contrasting management of an Anthrosol. AB - Soil aggregation was studied in a 21-year experiment conducted on an Anthrosol. The soil management regimes consisted of cropland abandonment, bare fallow without vegetation and cropping system. The cropping system was combined with the following nutrient management treatments: control (CONTROL, no nutrient input); nitrogen, phosphorus and potassium (NPK); straw plus NPK (SNPK); and manure (M) plus NPK (MNPK). Compared with the CONTROL treatment, the abandonment treatment significantly increased the formation of large soil macroaggregates (>2 mm) and consequently improved the stability of aggregates in the surface soil layer due to enhancement of hyphal length and of soil organic matter content. However, in response to long-term bare fallow treatment aggregate stability was low, as were the levels of aggregating agents. Long term fertilization significantly redistributed macroaggregates; this could be mainly ascribed to soil organic matter contributing to the formation of 0.5-2 mm classes of aggregates and a decrease in the formation of the >2 mm class of aggregates, especially in the MNPK treatment. Overall, hyphae represented a major aggregating agent in both of the systems tested, while soil organic compounds played significantly different roles in stabilizing aggregates in Anthrosol when the cropping system and the soil management regimes were compared. PMID- 27958367 TI - Site-Selective Controlled Dealloying Process of Gold-Silver Nanowire Array: a Simple Approach towards Long-Term Stability and Sensitivity Improvement of SERS Substrate. AB - Limitations of achieving highly sensitive and stable surface-enhanced Raman scattering (SERS) substrate greatly concern the suitable method for fabrication of large-area plasmonic nanostructures. Herein we report a simple approach using template-based synthesis to create a highly ordered two-dimensional array of gold silver alloy nanowires, followed by the controlled dealloying process. This particular step of mild acid etching (15%v/v nitric acid for 5 min) allowed the formation of Raman hot spots on the nanowire tips while maintaining the integrity of highly active alloy composition and rigid nanowire array structure. Full consideration of SERS substrate performance was accomplished using 4 mercaptobenzoic acid (4-MBA) as a probe molecule. Exceedingly higher SERS signal (150-fold) can be achieved with respect to typical gold film substrate. Moreover, an excellent stability of SERS substrate was also determined for over 3 months storage time. In contrast to the previous studies which stability improvement was accomplished at a cost of sensitivity reduction, the simultaneous improvement of sensitivity and stability makes the controlled dealloying process an excellent choice of SERS substrate fabrication. In addition, uniformity and reproducibility studies indicated satisfactory results with the acceptable values of relative standard deviation. PMID- 27958369 TI - Broadband asymmetric light transmission through tapered metallic gratings at visible frequencies. AB - Asymmetric transmission phenomenon has attracted tremendous research interest due to its potential applications in integrated photonic systems. Broadband asymmetric transmission (BAT) is a highly desirable but challenging functionality to achieve in the visible regime due to the limitation of material dispersion. In this paper, we propose and numerically demonstrate that a tapered-metal-grating structure (TMGS) can achieve high-contrast BAT spectra covering the entire visible region. The transmission efficiency reaches ~95% for the forward illumination and ~35% for the backward illumination at the same wavelengths, respectively, and the corresponding transmission ratio is larger than 2.5 over a broadband wavelength regime. Such a design with high performance suggests applications for unidirectional optical transmission, optical diode, and so on. PMID- 27958368 TI - Preparation of Hollow Fe2O3 Nanorods and Nanospheres by Nanoscale Kirkendall Diffusion, and Their Electrochemical Properties for Use in Lithium-Ion Batteries. AB - A novel process for the preparation of aggregate-free metal oxide nanopowders with spherical (0D) and non-spherical (1D) hollow nanostructures was introduced. Carbon nanofibers embedded with iron selenide (FeSe) nanopowders with various nanostructures are prepared via the selenization of electrospun nanofibers. Ostwald ripening occurs during the selenization process, resulting in the formation of a FeSe-C composite nanofiber exhibiting a hierarchical structure. These nanofibers transform into aggregate-free hollow Fe2O3 powders via the complete oxidation of FeSe and combustion of carbon. Indeed, the zero- (0D) and one-dimensional (1D) FeSe nanocrystals transform into the hollow-structured Fe2O3 nanopowders via a nanoscale Kirkendall diffusion process, thus conserving their overall morphology. The discharge capacities for the 1000th cycle of the hollow structured Fe2O3 nanopowders obtained from the FeSe-C composite nanofibers prepared at selenization temperatures of 500, 800, and 1000 degrees C at a current density of 1 A g-1 are 932, 767, and 544 mA h g-1, respectively; and their capacity retentions from the second cycle are 88, 92, and 78%, respectively. The high structural stabilities of these hollow Fe2O3 nanopowders during repeated lithium insertion/desertion processes result in superior lithium ion storage performances. PMID- 27958370 TI - Comparative Systems Analyses Reveal Molecular Signatures of Clinically tested Vaccine Adjuvants. AB - A better understanding of the mechanisms of action of human adjuvants could inform a rational development of next generation vaccines for human use. Here, we exploited a genome wide transcriptomics analysis combined with a systems biology approach to determine the molecular signatures induced by four clinically tested vaccine adjuvants, namely CAF01, IC31, GLA-SE and Alum in mice. We report signature molecules, pathways, gene modules and networks, which are shared by or otherwise exclusive to these clinical-grade adjuvants in whole blood and draining lymph nodes of mice. Intriguingly, co-expression analysis revealed blood gene modules highly enriched for molecules with documented roles in T follicular helper (TFH) and germinal center (GC) responses. We could show that all adjuvants enhanced, although with different magnitude and kinetics, TFH and GC B cell responses in draining lymph nodes. These results represent, to our knowledge, the first comparative systems analysis of clinically tested vaccine adjuvants that may provide new insights into the mechanisms of action of human adjuvants. PMID- 27958371 TI - Atmospheric Deposition-Carried Zn and Cd from a Zinc Smelter and Their Effects on Soil Microflora as Revealed by 16S rDNA. AB - In this study, we investigated the influence of heavy metals (HM) on total soil bacterial population and its diversity pattern from 10 km distance of a Zinc smelter in Feng County, Qinling Mountain, China. We characterized and identified the bacterial community in a HM polluted soil using 16S rDNA technology. Out results indicated that the maximum soil HM concentration and the minimum bacterial population were observed in S2 soil, whereas bacterial diversity raised with the sampling distance increased. The bacterial communities were dominated by the phyla Proteobacteria, Acidobacteria and Actinobacteria in cornfield soils, except Fimicutes phylum which dominated in hilly area soil. The soil CEC, humic acid (HA)/fulvic acid (FA) and microbial OTUs increased with the sampling distance increased. Shewanella, Halomonas and Escherichia genera were highly tolerant to HM stress in both cultivated and non-cultivated soil. Finally, we found a consistent correlation of bacterial diversity with total HM and SOM along the sampling distance surrounding the zinc smelter, which could provide a new insight into the bacterial community-assisted and phytoremediation of HM contaminated soils. PMID- 27958372 TI - Global map of oxytocin/vasopressin-like neuropeptide signalling in insects. AB - Oxytocin and vasopressin mediate a range of physiological functions that are important for osmoregulation, reproduction, social behaviour, memory and learning. The origin of this signalling system is thought to date back ~600 million years. Oxytocin/vasopressin-like peptides have been identified in several invertebrate species and they appear to be functionally related across the entire animal kingdom. There is little information available about the biology of this peptide G protein-coupled receptor signalling system in insects. Recently over 200 insect genome/transcriptome datasets were released allowing investigation of the molecular structure and phylogenetic distribution of the insect oxytocin/vasopressin orthologue - inotocin peptides and their receptors. The signalling system is present in early arthropods and representatives of some early-diverging lineages. However, Trichoptera, Lepidoptera, Siphonaptera, Mecoptera and Diptera, lack the presence of inotocin genes, which suggests the peptide-receptor system was probably lost in their common ancestor ~280 million years-ago. In addition we detected several losses of the inotocin signalling system in Hemiptera (white flies, scale insects and aphids), and the complete absence in spiders (Chelicerata). This unique insight into evolutionarily patterns and sequence diversity of neuroendocrine hormones will provide opportunities to elucidate the physiology of the inotocin signalling system in one of the largest group of animals. PMID- 27958375 TI - Aniline-containing guests recognized by alpha,alpha',delta,delta'-tetramethyl cucurbit[6]uril host. AB - The host-guest complexation of symmetrical alpha,alpha',delta,delta'-tetramethyl cucurbit[6]uril (TMeQ[6]) and cucurbit[7]uril (Q[7]) with a series of aniline containing guests has been investigated by various experimental techniques including NMR, ITC, and X-ray crystallography. Experimental results indicate that both TMeQ[6] and Q[7] hosts can encapsulate aniline-containing guests to form stable inclusion complexes. However, the oval cavity of TMeQ[6] is more complementary in size and shape to the aromatic ring of the guests than the spherical cavity of Q[7]. Shielding and deshielding effects of the aromatic ring on guests lead to the remarkable chemical shifts of the TMeQ[6] host protons. The rotational restriction of the guests in the oval cavity of TMeQ[6] results in the large negative values of entropy. The X-ray crystal structure of the 1:1 inclusion complex between TMeQ[6] and N,N'-diethyl-benzene-1,4-diamine unambiguously reveals that the aromatic ring of the guest resides in the oval cavity of TMeQ[6]. PMID- 27958374 TI - Spatiotemporal analysis with a genetically encoded fluorescent RNA probe reveals TERRA function around telomeres. AB - Telomeric repeat-containing RNA (TERRA) controls the structure and length of telomeres through interactions with numerous telomere-binding proteins. However, little is known about the mechanism by which TERRA regulates the accessibility of the proteins to telomeres, mainly because of the lack of spatiotemporal information of TERRA and its-interacting proteins. We developed a fluorescent probe to visualize endogenous TERRA to investigate its dynamics in living cells. Single-particle fluorescence imaging revealed that TERRA accumulated in a telomere-neighboring region and trapped diffusive heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), thereby inhibiting hnRNPA1 localization to the telomere. These results suggest that TERRA regulates binding of hnRNPA1 to the telomere in a region surrounding the telomere, leading to a deeper understanding of the mechanism of TERRA function. PMID- 27958373 TI - Identification and characterization of human testis derived circular RNAs and their existence in seminal plasma. AB - Circular RNAs (circRNAs) have emerged as novel molecules of interest in gene regulation as other noncoding RNAs. Though they have been explored in some species and tissues, the expression and functions of circRNAs in human reproductive systems remain unknown. Here we revealed the expression profiles of circRNAs in human testis tissue using high-throughput sequencing. The conformation of these testis-derived circRNAs in seminal plasma was also investigated, aiming to provide a non-invasive liquid biopsy surrogate for testicular biopsy. We predicted >15,000 circRNAs in human testis, with most of them (10,792; 67%) new. In all the 5,928 circRNA forming genes, 1,017 are first reported by us to generate circRNAs. Interestingly, these genes are mostly related to spermatogenesis, sperm motility, fertilization, etc. The sequence feature, chromosome location, alternative splicing and other characteristics of the circRNAs in human testis were also explored. Moreover, we found that these testis-derived circRNAs could be stably detected in seminal plasma. Most of them were probably bound with proteins in seminal plasma and were very stable at room temperature. Our work has laid the foundations to decipher regulation mechanisms of circRNAs in spermatogenesis and to develop circRNAs as novel noninvasive biomarkers for male infertile diseases. PMID- 27958377 TI - A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform. PMID- 27958376 TI - High-resolution short-exposure small-animal laboratory x-ray phase-contrast tomography. AB - X-ray computed tomography of small animals and their organs is an essential tool in basic and preclinical biomedical research. In both phase-contrast and absorption tomography high spatial resolution and short exposure times are of key importance. However, the observable spatial resolutions and achievable exposure times are presently limited by system parameters rather than more fundamental constraints like, e.g., dose. Here we demonstrate laboratory tomography with few ten MUm spatial resolution and few-minute exposure time at an acceptable dose for small-animal imaging, both with absorption contrast and phase contrast. The method relies on a magnifying imaging scheme in combination with a high-power small-spot liquid-metal-jet electron-impact source. The tomographic imaging is demonstrated on intact mouse, phantoms and excised lungs, both healthy and with pulmonary emphysema. PMID- 27958379 TI - A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia. AB - This study was designed to investigate the mode of action of trabectedin in myelomonocytic leukemia cells by applying systems biology approaches to mine gene expression profiling data and pharmacological assessment of the cellular effects. Significant enrichment was found in regulons of target genes inferred for specific transcription factors, among which MAFB was the most upregulated after treatment and was central in the transcriptional network likely to be relevant for the specific therapeutic effects of trabectedin against myelomonocytic cells. Using the Connectivity Map, similarity among transcriptional signatures elicited by treatment with different compounds was investigated, showing a high degree of similarity between transcriptional signatures of trabectedin and those of the topoisomerase I inhibitor, irinotecan, and an anti-dopaminergic antagonist, thioridazine. The study highlights the potential importance of systems biology approaches to generate new hypotheses that are experimentally testable to define the specificity of the mechanism of action of drugs. PMID- 27958380 TI - Influence of IL6R gene polymorphisms in the effectiveness to treatment with tocilizumab in rheumatoid arthritis. AB - In the present study, we aimed to investigate the influence of clinical parameters and single-nucleotide polymorphisms of interleukin-6 receptor (rs12083537, rs2228145, rs4329505 and rs11265618) on response to tocilizumab, TCZ (European League Against Rheumatism (EULAR) response, remission, low disease activity (LDA) and improvement of DAS28). We performed a retrospective cohort study in patients with Rheumatoid Arthritis (RA) treated with TCZ for 12 months. Multivariable analysis showed that the only variable independently associated to satisfactory EULAR response (odds ratio (OR): 0.61; 95% of confidence interval (CI)95%: 0.42, 0.88; P=0.008), remission (OR: 0.51; CI95%: 0.35, 0.75; P=0.001), LDA (OR: 0.41; CI95%: 0.24, 0.72; P=0.002) and improvement in DAS28 (B=-0.32; CI95%): -0.47, -0.17; P=7.5 * 10-5) at 12 months was lower number of previous biological therapy (BT). High baseline DAS28 was also associated with a greater decrease in DAS28 at 12 months of treatment (B=0.99; CI95%: 0.79, 1.20; P=1.5 * 10-14). Those patients who were carriers of AA genotypes for rs12083537 (OR: 13.0; CI95%: 2.31, 72.91; P=0.004) and CC for rs11265618 (OR: 12.15; CI95%: 2.18, 67.81; P=0.004) had better LDA response at 12 months of treatment with TCZ. In conclusion, RA patients treated with TCZ showed better EULAR response, remission, LDA and DAS28 improvement rates when a lower number of BT were previously administered. The AA genotype for rs12083537 and CC for rs11265618 polymorphisms for may act as predictors of good response LDA. PMID- 27958382 TI - Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia. PMID- 27958381 TI - A polymorphism in the OPRM1 3'-untranslated region is associated with methadone efficacy in treating opioid dependence. AB - The MU-opioid receptor (MOR) is the primary target of methadone and buprenorphine. The primary neuronal transcript of the OPRM1 gene, MOR-1, contains a ~13 kb 3' untranslated region with five common haplotypes in European Americans. We analyzed the effects of these haplotypes on the percentage of opioid positive urine tests in European-Americans (n=582) during a 24-week, randomized, open-label trial of methadone or buprenorphine/naloxone (Suboxone) for the treatment of opioid dependence. A single haplotype, tagged by rs10485058, was significantly associated with patient urinalysis data in the methadone treatment group. Methadone patients with the A/A genotype at rs10485058 were less likely to have opioid-positive urine drug screens than those in the combined A/G and G/G genotypes group (relative risk=0.76, 95% confidence intervals=0.73-0.80, P=0.0064). Genotype at rs10485058 also predicted self-reported relapse rates in an independent population of Australian patients of European descent (n=1215) who were receiving opioid substitution therapy (P=0.003). In silico analysis predicted that miR-95-3p would interact with the G, but not the A allele of rs10485058. Luciferase assays indicated miR-95-3p decreased reporter activity of constructs containing the G, but not the A allele of rs10485058, suggesting a potential mechanism for the observed pharmacogenetic effect. These findings suggest that selection of a medication for opioid dependence based on rs10485058 genotype might improve outcomes in this ethnic group. PMID- 27958383 TI - Mature dendritic cell derived from cryopreserved immature dendritic cell shows impaired homing ability and reduced anti-viral therapeutic effects. AB - Cryopreservation is critical in reducing redundant operations and also in quality control in dendritic cell (DC) therapy. Full maturation and efficient homing of DCs to T cell-region constitute a crucial aspect of DC immunotherapy; however, the in vivo migration and distribution pattern, as well as the anti-viral effect of DCs that matured from cryopreserved immature DCs (cryoim-mDCs) remain to be revealed. In the present study, we compared cryoim-mDCs with DCs matured from fresh immature DCs (fmDCs) in the aspects of phenotypes, in vivo homing capacities as well as the anti-viral therapeutic effects to further clarify the effect of cryopreservation on DC-based cytotherapy. The results showed that cryopreservation impaired the homing ability of DCs which was associated with the reduced expression of CCR7 and disturbed cytoskeleton arrangement. Moreover, the antigen-specific CD8+ T cell response induced by cryoim-mDCs was much weaker than that induced by fmDCs in both the spleen and liver draining lymph nodes, which provided reduced protection from viral invasions. In conclusion, cryopreservation is a good method to keep the viability of immature DCs, however, the in vivo homing capacity and anti-viral therapeutic effect of DCs matured from frozen immature DCs were hindered to some extent. PMID- 27958384 TI - Efficacy and safety of endoscopic ultrasonography-guided interventional treatment for refractory malignant left-sided liver tumors: a case series of 26 patients. AB - This study aimed to compare the efficacy and safety of EUS-guided ethanol injection and 125I seed brachytherapy for malignant left-sided liver tumors which were difficult for trans-abdominal intervention. The study protocol was registered at Clinicaltrials.gov (NCT02816944). Twenty-six patients were consecutively and prospectively hospitalized for EUS-guided interventional treatment of refractory malignant left-sided liver tumors between June 2014 and June 2016. Liver masses were detected using EUS in 25 of 26 (96.2%) patients. EUS guided interventional treatment was completed uneventfully in 23 of 26 (88.5%) patients using anhydrous ethanol injection (n = 10) or iodine-125 seed implantation (n = 13). Six months later, complete response was achieved in 15 of 23 (65.2%) patients and partial response in 8 of 23 (34.8%) patients. Patients with tumor residual have second-look EUS-guided interventional treatment (n = 5), radiotherapy (n = 2) or surgical resection (n = 1). Complete response was achieved after repeated interventional treatment in 3 of 5 patients who underwent second EUS-guided intervention; 2 patients required additional surgical resection but one succeed. No significant complications occurred. Therefore EUS-guided 125I seed brachytherapy is an effective and safe treatment modality for radical operation or promising palliative control of malignant left-sided liver tumors refractory to trans-abdominal intervention. PMID- 27958385 TI - Updated postoperative nomogram incorporating the number of positive lymph nodes to predict disease recurrence following radical prostatectomy. AB - BACKGROUND: A significant number of patients with minimal lymph node disease at radical prostatectomy (RP) and pelvic lymph node dissection (PLND) have better than expected long-term outcomes. We explored whether stratification by number of positive nodes enhances our institutional prediction model for biochemical recurrence after RP. METHODS: A total of 7789 patients underwent RP and pelvic lymph node dissection from 1995 to 2012 at a tertiary referral center. We compared two recurrence prediction models: one incorporated lymph node invasion and the other tracked the number of positive nodes. Existing and updated models' discrimination was assessed using Harrell's c-index and calibration. The 10-fold cross-validation was performed to correct for model overfitting. RESULTS: Of the 491 patients (6.3%) harboring nodal disease, 387 (5.0%) had 1-2 positive nodes and 104 (1.3%) had ?3 positive nodes. Data on number of positive nodes did not improve the c-index for the cohort as a whole. When we assessed discrimination for node-positive patients only, c-index for the model with number of positive nodes was 0.01 (95% confidence interval 0.001-0.024) higher than the model with lymph node invasion. Illustrative examples were provided by reclassification tables using number of positive lymph nodes. For instance, 40 of 7789 patients would be reclassified with a cutoff point of 50% for biochemical recurrence at 1 year, and 36 of 7789 patients would be reclassified with a cutoff point of 40% for biochemical recurrence at 10 years. CONCLUSIONS: Stratification by number of positive lymph nodes provided additional discriminative ability for evaluating risk in node-positive patients. Pending external validation, this model could be used for patient counseling and clinical trial stratification in this subpopulation. PMID- 27958378 TI - Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group. AB - Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 * 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis. PMID- 27958386 TI - Detection of Fungus Infection on Petals of Rapeseed (Brassica napus L.) Using NIR Hyperspectral Imaging. AB - Infected petals are often regarded as the source for the spread of fungi Sclerotinia sclerotiorum in all growing process of rapeseed (Brassica napus L.) plants. This research aimed to detect fungal infection of rapeseed petals by applying hyperspectral imaging in the spectral region of 874-1734 nm coupled with chemometrics. Reflectance was extracted from regions of interest (ROIs) in the hyperspectral image of each sample. Firstly, principal component analysis (PCA) was applied to conduct a cluster analysis with the first several principal components (PCs). Then, two methods including X-loadings of PCA and random frog (RF) algorithm were used and compared for optimizing wavebands selection. Least squares-support vector machine (LS-SVM) methodology was employed to establish discriminative models based on the optimal and full wavebands. Finally, area under the receiver operating characteristics curve (AUC) was utilized to evaluate classification performance of these LS-SVM models. It was found that LS-SVM based on the combination of all optimal wavebands had the best performance with AUC of 0.929. These results were promising and demonstrated the potential of applying hyperspectral imaging in fungus infection detection on rapeseed petals. PMID- 27958387 TI - Performance Evaluation and Online Realization of Data-driven Normalization Methods Used in LC/MS based Untargeted Metabolomics Analysis. AB - In untargeted metabolomics analysis, several factors (e.g., unwanted experimental &biological variations and technical errors) may hamper the identification of differential metabolic features, which requires the data-driven normalization approaches before feature selection. So far, >=16 normalization methods have been widely applied for processing the LC/MS based metabolomics data. However, the performance and the sample size dependence of those methods have not yet been exhaustively compared and no online tool for comparatively and comprehensively evaluating the performance of all 16 normalization methods has been provided. In this study, a comprehensive comparison on these methods was conducted. As a result, 16 methods were categorized into three groups based on their normalization performances across various sample sizes. The VSN, the Log Transformation and the PQN were identified as methods of the best normalization performance, while the Contrast consistently underperformed across all sub datasets of different benchmark data. Moreover, an interactive web tool comprehensively evaluating the performance of 16 methods specifically for normalizing LC/MS based metabolomics data was constructed and hosted at http://server.idrb.cqu.edu.cn/MetaPre/. In summary, this study could serve as a useful guidance to the selection of suitable normalization methods in analyzing the LC/MS based metabolomics data. PMID- 27958388 TI - MAP kinase phosphatase 2 deficient mice develop attenuated experimental autoimmune encephalomyelitis through regulating dendritic cells and T cells. AB - Mitogen-activated protein kinase phosphatases (MKPs) play key roles in inflammation and immune mediated diseases. Here we investigated the mechanisms by which MKP-2 modulates central nervous system (CNS) inflammation in experimental autoimmune encephalomyelitis (EAE). Our results show that MKP-2 mRNA levels in the spinal cord and lymphoid organs of EAE mice were increased compared with naive controls, indicating an important role for MKP-2 in EAE development. Indeed, MKP-2-/- mice developed reduced EAE severity, associated with diminished CNS immune cell infiltration, decreased proinflammatory cytokine production and reduced frequency of CD4+ and CD8+ T cells in spleens and lymph nodes. In addition, MKP-2-/- CD11c+ dendritic cells (DCs) had reduced expression of MHC-II and CD40 compared with MKP-2+/+ mice. Subsequent experiments revealed that CD4+ T cells from naive MKP-2-/- mice had decreased cell proliferation and IL-2 and IL 17 production relative to wild type controls. Furthermore, co-culture experiments showed that bone marrow derived DCs of MKP-2-/- mice had impaired capability in antigen presentation and T cell activation. While MKP-2 also modulates macrophage activation, our study suggests that MKP-2 is essential to the pathogenic response of EAE, and it acts mainly via regulating the important antigen presenting DC function and T cell activation. PMID- 27958390 TI - Prevalence and treatment of LUTS in patients with Parkinson disease or multiple system atrophy. AB - The lower urinary tract is controlled by complex neural mechanisms not only in the periphery, but also in the central nervous systems (CNS). Thus, patients with a wide variety of neurological diseases often also have lower urinary tract symptoms (LUTS), including those with Parkinson disease (PD) or multiple system atrophy (MSA). LUTS are common comorbidities associated with both of these neurodegenerative diseases and are likely to impair patients' quality of life. The motor symptoms of PD and MSA often seem similar; however, the pathophysiology, and thus the treatment of LUTS differs considerably. Antimuscarinics are the first-line treatment of storage LUTS in patients with PD or MSA; however, care should be taken in the management of these patients, especially in those with MSA owing to the high risk of inefficient voiding, and thus an increased post-void residual volume. Other treatments of PD-related LUTS include alpha-adrenoceptor antagonists, which improve voiding dysfunction, transurethral resection of the prostate for bladder outlet obstruction owing to prostate enlargement, and neuromodulation and intradetrusor botulinum toxin injections for storage LUTS. However, more conservative treatments, including intermittent catheterization, are required for LUTS in patients with MSA, owing to the high incidence of impaired detrusor contractility and detrusor-sphincter dyssynergia. PMID- 27958389 TI - A novel pleuromutilin antibacterial compound, its binding mode and selectivity mechanism. AB - The increasing appearance of pathogenic bacteria with antibiotic resistance is a global threat. Consequently, clinically available potent antibiotics that are active against multidrug resistant pathogens are becoming exceedingly scarce. Ribosomes are a main target for antibiotics, and hence are an objective for novel drug development. Lefamulin, a semi-synthetic pleuromutilin compound highly active against multi-resistant pathogens, is a promising antibiotic currently in phase III trials for the treatment of community-acquired bacterial pneumonia in adults. The crystal structure of the Staphylococcus aureus large ribosomal subunit in complex with lefamulin reveals its protein synthesis inhibition mechanism and the rationale for its potency. In addition, analysis of the bacterial and eukaryotes ribosome structures around the pleuromutilin binding pocket has elucidated the key for the drug's selectivity. PMID- 27958392 TI - Prostate cancer: ERSPC calculator recalibrated for China. PMID- 27958391 TI - Diagnostic dilemmas in patients with upper tract urothelial carcinoma. AB - Upper tract urothelial carcinoma (UTUC) is a rare condition and recommendations based on a high level of evidence for diagnosis, treatment and follow-up monitoring are lacking. Current decision-making is often based on evidence from trials investigating urothelial carcinoma of the lower tract. Radical nephroureterectomy has been the standard of care for UTUC but kidney-sparing treatment using endoscopic approaches has been established for a select patient group with low-grade and low-stage disease. Optimal treatment choice requires correct tumour characterization. According to available recommendations, diagnostic work-up of UTUC includes evaluation by CT urography or MRI urography, cystoscopy and urine cytology. Ureterorenoscopy and lesion biopsy are grade C recommendations in patients with suspected UTUC. When kidney-sparing treatment is planned, ureterorenoscopy and biopsy should be considered and are the procedures of choice in most cases. These diagnostics have limitations and their accuracy varies in defining tumour characteristics and predicting grade and stage. Urinary tests have higher sensitivity than cytology for detection of lower tract urothelial carcinoma but evidence of their benefit in UTUCs is lacking. New optical and image enhancement techniques are being developed to facilitate real time diagnostics with increased accuracy. A new diagnostic algorithm for patients with suspected UTUC that integrates the diagnosis, treatment and clinical risk stratification is required. PMID- 27958393 TI - A contemporary update on Fournier's gangrene. AB - Despite advances in the evaluation, treatment, and pathophysiological understanding of necrotizing soft-tissue infections, Fournier's gangrene remains a life-threatening urological emergency. Although the condition can affect patients of any age and gender, it might be more prevalent in some high-risk groups with certain comorbidities. Several prognostic and diagnostic tools have been developed to assist with clinical decision-making once the diagnosis is made - primarily based on the physician's physical exam and potentially supported by laboratory and imaging findings. Expedited treatment with resuscitation, antibiotic administration, and rapid, wide surgical debridement are key elements of the initial management. These procedures must be followed by meticulous wound care and liberal use of planned subsequent surgical debridements. Once the patient has overcome the associated systemic illness, several reconstructive options for the genitalia and perineum can be considered to improve functionality and cosmesis. PMID- 27958395 TI - Multi-resolution community detection in massive networks. AB - Aiming at improving the efficiency and accuracy of community detection in complex networks, we proposed a new algorithm, which is based on the idea that communities could be detected from subnetworks by comparing the internal and external cohesion of each subnetwork. In our method, similar nodes are firstly gathered into meta-communities, which are then decided to be retained or merged through a multilevel label propagation process, until all of them meet our community criterion. Our algorithm requires neither any priori information of communities nor optimization of any objective function. Experimental results on both synthetic and real-world networks show that, our algorithm performs quite well and runs extremely fast, compared with several other popular algorithms. By tuning a resolution parameter, we can also observe communities at different scales, so this could reveal the hierarchical structure of the network. To further explore the effectiveness of our method, we applied it to the E-Coli transcriptional regulatory network, and found that all the identified modules have strong structural and functional coherence. PMID- 27958396 TI - Detailed study of bending effects in large mode area segmented cladding fibers. AB - This paper studies the bending effects on segmented cladding fibers (SCFs) in detail. Rod-type SCFs have offered large effective mode areas (EMAs) very successfully. The low-index segments in the design also enable the optical fibers to be bend-resistant. In this paper, the bending performance of the SCFs has been investigated by using the finite element method. The results indicate that SCFs can provide low-loss effective single-mode operation in a wide bandwidth under a bent configuration, due to the leakage losses of the higher-order modes (HOMs). A large ratio between the HOMs and the fundamental mode losses can be ensured, over a wide range of duty cycle, refractive index difference, and bending radius. Therefore, the required fabrication accuracy decreases. The mode loss ratio and EMA are independent of the bending orientation. Operating at 1550 nm and 10 cm bend radius, large EMA (754 MUm2) is achievable with a large loss ratio (>30). The trade-offs between loss, EMA, and bending are studied. The structure has potential for compact high power fiber lasers, amplifiers, and beam delivery applications. PMID- 27958397 TI - Chair-like pulses in an all-normal dispersion Ytterbium-doped mode-locked fiber laser. AB - We report, for what we believe is the first time, generation of stable chair-like pulses (a pulse shape with an initial long flat portion followed by a short high peak power portion resembling the shape of a chair) by mode locking of a Ytterbium (Yb)-doped fiber laser. Chair-like pulse shapes are achieved by implementing dual saturable absorbers, one based on a nonlinear optical loop mirror (NOLM) and the other based on nonlinear polarization rotation (NPR) inside the cavity. The transmission characteristics of the NOLM-NPR pair leading to the formation of chair-like pulses are numerically investigated. We also report the amplification characteristics of chair-like pulses in an external multistage Yb doped fiber amplifier setup at different repetition rates of the pulse train. It was found that the chair-like pulses are suitable for amplification, and more than 10 W of average power at 460 kHz repetition rate have been obtained at total pump power of ~20 W coupled to the power amplifier. At a lower repetition rate (115 kHz), ~8 W of average power were obtained corresponding to ~70 MUJ of pulse energy with negligible contribution from amplified spontaneous emission or stimulated Raman scattering. We believe that such an oscillator-amplifier system could serve as an attractive tool for micromachining applications. PMID- 27958394 TI - Proliferation and osteogenic differentiation of rat BMSCs on a novel Ti/SiC metal matrix nanocomposite modified by friction stir processing. AB - The aims of this study were to fabricate a novel titanium/silicon carbide (Ti/SiC) metal matrix nanocomposite (MMNC) by friction stir processing (FSP) and to investigate its microstructure and mechanical properties. In addition, the adhesion, proliferation and osteogenic differentiation of rat bone marrow stromal cells (BMSCs) on the nanocomposite surface were investigated. The MMNC microstructure was observed by both scanning and transmission electron microscopy. Mechanical properties were characterized by nanoindentation and Vickers hardness testing. Integrin beta1 immunofluorescence, cell adhesion, and MTT assays were used to evaluate the effects of the nanocomposite on cell adhesion and proliferation. Osteogenic and angiogenic differentiation were evaluated by alkaline phosphatase (ALP) staining, ALP activity, PCR and osteocalcin immunofluorescence. The observed microstructures and mechanical properties clearly indicated that FSP is a very effective technique for modifying Ti/SiC MMNC to contain uniformly distributed nanoparticles. In the interiors of recrystallized grains, characteristics including twins, fine recrystallized grains, and dislocations formed concurrently. Adhesion, proliferation, and osteogenic and angiogenic differentiation of rat BMSCs were all enhanced on the novel Ti/SiC MMNC surface. In conclusion, nanocomposites modified using FSP technology not only have superior mechanical properties under stress-bearing conditions but also provide improved surface and physicochemical properties for cell attachment and osseointegration. PMID- 27958398 TI - Linear depolarization of lidar returns by aged smoke particles. AB - We use the numerically exact (superposition) T-matrix method to analyze recent measurements of the backscattering linear depolarization ratio (LDR) for a plume of aged smoke at lidar wavelengths ranging from 355 to 1064 nm. We show that the unique spectral dependence of the measured LDRs can be modeled, but only by assuming expressly nonspherical morphologies of smoke particles containing substantial amounts of nonabsorbing (or weakly absorbing) refractory materials such as sulfates. Our results demonstrate that spectral backscattering LDR measurements can be indicative of the presence of morphologically complex smoke particles, but additional (e.g., passive polarimetric or bistatic lidar) measurements may be required for a definitive characterization of the particle morphology and composition. PMID- 27958399 TI - Combining sub-Nyquist sampling and chirp decomposition for a high-precision and speed absolute distance measurement method. AB - A high-precision and speed absolute distance measurement based on swept wavelength interferometry is reported. A powerful method combining sub-Nyquist sampling and chirp decomposition for dispersion mismatch compensation is proposed. A standard deviation of 0.72 MUm is obtained for the measurement of a target located at 3.9 m, which is better than the traditional method. The measurement can be completed in 1.9 s when the frequency range is 4.26 THz, which is much better than chirp decomposition without sub-Nyquist sampling. PMID- 27958400 TI - Numerical characterization of InP-based quantum dot semiconductor optical amplifier. AB - This paper is devoted to the development of a steady-state behavior of a quantum dot-semiconductor optical amplifier (QD-SOA). The investigated performance characteristics cover a wide range that includes material gain coefficient, spatial distribution of the occupation probabilities, fiber to fiber gain, gain spectrum as a function of the bias current, relaxation time, and capture time. A set of traveling-wave equations is used to model the signal and spontaneous photons along the device active region. The obtained results indicate a high gain that reaches 34 dB for an InAs/InGaAsP/InP-based QD-SOA, with a corresponding device length of 4 mm. The obtained signal-to-noise ratio is larger than 75 dB for all input powers without using an output filter. PMID- 27958401 TI - Design, fabrication, and verification of a three-dimensional autocollimator. AB - The autocollimator is an optical instrument for noncontact angle measurement with high resolution and a long detection range. It measures two-dimensional angles, i.e., pitch and yaw, but not roll. In this paper, we present a novelly structured autocollimator capable of measuring three-dimensional (3D) angles simultaneously. In this setup, two collimated beams of different wavelengths are projected onto a right-angle prism. One beam is reflected by the hypotenuse of the prism and received by an autocollimation unit for detecting pitch and yaw. The other is reflected by the two legs of the right-angle prism and received by a moire fringe imaging unit for detecting roll. Furthermore, a prototype is designed and fabricated. Experiments are carried out to evaluate its basic performance. Calibration results show that this prototype has angular RMS errors of less than 5 arcsec in all 3Ds over a range of 1000 arcsec at a working distance of 2 m. PMID- 27958402 TI - Synthesis of ultrathin TiO2/Ti films with tunable structural color. AB - A series of ultrathin TiO2/Ti films with iridescent structural colors were fabricated on high-purity titanium sheets via a one-step anodization procedure. Tunable color in the films can be obtained by adjusting the anodization time and can be adjusted across the entire visible range. It was found that all the films displayed highly saturated colors. Trichromatic coordinates of color x, y were delineated, and the color was identified by positioning the x and y values in the Commission International de I'Eclairage chromaticity diagram. Theoretical and experimental results of the changes in the structural color according to the principle of complementary colors are consistent with the experimental results. The TiO2/Ti films may have potential in color displays, decoration, and anticounterfeiting technology. PMID- 27958403 TI - Rigorous coupled-wave analysis equivalent-index-slab method for analyzing 3D angular misalignment in interlayer grating couplers. AB - The interlayer waveguide grating coupling efficiencies under angular (rotational) misalignments are simulated using the 3D rigorous coupled-wave analysis (3D-RCWA) together with the RCWA equivalent-index-slab (RCWA-EIS) method. As examples of conical diffraction, rotations about the two coordinate axes, x and z, defined by the vectors [1 0 0] and [0 0 1], respectively, as well as an arbitrary axis, defined by the vector [2 2 1], are simulated for binary rectangular-groove gratings. The interlayer grating coupling efficiency is approximated by the product of the top- and bottom-grating diffraction efficiencies (DEs). It is found that the bottom-grating DEs decrease about 25% when the bottom grating is rotated +/-0.1 rad (5.73 degrees ) about the z-axis. DEs slightly increase (5% to 10% depending on the grating structures) when the bottom grating is rotated +/ 0.1 rad about the x-axis. This is consistent with the diffraction behavior of an over-modulated grating. When the bottom grating is rotated about the vector [2 2 1], the change in DEs is asymmetric with a 100% decrease at a rotation angle -0.1 rad and a 67% decrease at a rotation angle +0.1 rad. The method is shown to be computationally efficient and numerically stable for grating structures with optimized parameters, and the resulting bottom-grating diffraction efficiencies demonstrate similar trends as those calculated by the 3D finite-difference time domain simulations. The procedure presented can be directly used in the analysis and design of interlayer waveguide grating coupling for optical interconnects in high-density integrated electronics. PMID- 27958404 TI - Virtual interferometer calibration method of a non-null interferometer for freeform surface measurements. AB - Non-null interferometry is a prospective method for aspheric and freeform surface measurements because of its potential versatility over null interferometry. Due to the existence of the retrace error, non-null testing usually has the drawbacks of low accuracy and inconvenient alignment of the surface under test (SUT). In this paper, a calibration method for freeform SUT in a non-null interferometer is introduced. This method calibrates the position and attitude of the SUT in a virtual interferometer with an optimization algorithm, and no accurate adjustment mechanism is required to adjust the SUT in the real interferometer. An application of this method in the digital moire interferometric technique (DMIT) is presented. The retrace error and the influence of the alignment error can be removed after calibration. Experimental results indicate that with this calibration method, the DMIT can achieve a measurement repeatability of lambda/20 (PV) when the freeform SUT has obvious alignment error. This is adequate for most aspheric and freeform surface measurements, especially when the vibration cannot be isolated completely and the freeform SUT is not easy to align. PMID- 27958405 TI - Radiometric calibration of tempospatially modulated polarization interference imaging spectrometer. AB - The tempospatially modulated polarization interference imaging spectrometer (TSMPIIS) nominated by the Ministry of Scence and Technology, takes part in the "Eleventh Five-Year National Science and Technology Exhibition." In order to improve the detecting precision of the TSMPIIS, its radiometric calibration scheme is proposed on the basis of the solar simulator, integrating sphere, monochromator, and spectroradiometer. Under the conditions of changing the exposure time and radiant brightness, the CCD linear responses for the TSMPIIS were first tested to validate the reliability of the radiometric calibration performed with a linear response model, and the linear errors were less than 0.15% and 1.15%, respectively. A novel method is put forward to calibrate the nonuniformity of CCD pixels, and the least squares method can commendably correct the uneven effect in the spatial direction. Besides, the absolute radiometric calibration establishes a corresponding relation between the dimensionless intensity output from the TSMPIIS and the target radiant brightness. The study lays the foundation for the engineering application of the TSMPIIS, such as remote sensing detection, and has an important significance for the development of our instrument and equipment technology with independent intellectual property rights. PMID- 27958406 TI - Single-acquisition wide-field superresolution for telescopes. AB - A simple optical setup is introduced here that is capable of improving the diffraction-limited angular resolution of a telescope at minimal cost to image quality. The system consists of, at minimum, an axicon and a convex lens located in the optical path of the telescope, which can increase the angular resolution by up to 38%. Analytical results for this resolution gain along with the Strehl ratio of this system are presented along with experimental results, which show a 30% improvement in single-acquisition image resolution with a Strehl ratio of 0.07, agreeing well with predicted values. With an ultrashallow axicon, large increases in Strehl ratio are possible, up to and beyond unity making higher angular resolution measurements possible with little cost to image quality or experimental complexity. PMID- 27958407 TI - Highly nonlinear polarization-maintaining photonic crystal fiber with nanoscale GaP strips. AB - A highly birefringent silica photonic crystal fiber (PCF) is proposed with nanoscale gallium phosphide strips at the core and modified spiral cladding air hole distribution. Optical properties of the PCF are simulated using the finite element method. Significant influences of low-refractive-index slot region confinement and high-index strips confinement are observed for two different modes. This introduces a high birefringence of ~0.58 at 1.55 MUm wavelength. Moreover, a high nonlinearity coefficient of the order of ~104 W 1 km-1 is achieved in the wavelength range from 1.4 to 1.7 MUm. The proposed fiber will find promising applications in coherent optical communications and sensing applications. PMID- 27958408 TI - Multi-stage classification method oriented to aerial image based on low-rank recovery and multi-feature fusion sparse representation. AB - Automatic classification of terrain surfaces from an aerial image is essential for an autonomous unmanned aerial vehicle (UAV) landing at an unprepared site by using vision. Diverse terrain surfaces may show similar spectral properties due to the illumination and noise that easily cause poor classification performance. To address this issue, a multi-stage classification algorithm based on low-rank recovery and multi-feature fusion sparse representation is proposed. First, color moments and Gabor texture feature are extracted from training data and stacked as column vectors of a dictionary. Then we perform low-rank matrix recovery for the dictionary by using augmented Lagrange multipliers and construct a multi-stage terrain classifier. Experimental results on an aerial map database that we prepared verify the classification accuracy and robustness of the proposed method. PMID- 27958409 TI - Temperature-induced spectrum response of volume grating as an effective strategy for holographic sensing in acrylamide polymer part I: sensing. AB - Temperature-induced diffraction spectrum responses of holographic gratings are characterized for exploring the temperature-sensing capability of a holographic sensor. Linear blue shift of peak wavelength and linear diffraction reduction are observed. It provides quantitative expressions for sensing applications. Inorganic nanoparticles are dispersed into the binder to improve sensing properties. Obvious improvement of sensing parameters, including wavelength shift and diffraction change, is confirmed. The sensitivity, response rate, and linear response region of holographic sensors are determined to evaluate sensing capacity. Influence of relative humidity on holographic sensing response is discussed. Expansion of humidity range provides a probability for extending the range of wavelength shift. Finally, the temperature response reversibility of a holographic sensor is evaluated. These experimental results can expand the practical application field of holographic sensing strategy and accelerate the development of holographic sensors. PMID- 27958410 TI - Temperature-induced spectrum response of a volume grating as an effective strategy for holographic sensing in an acrylamide polymer part II: physical mechanism. AB - The temperature response mechanism of a diffraction spectrum in a holographic grating is characterized. Two possible major factors, changes in the refractive index and thermal expansion, are measured and analyzed to identify the sensing physical mechanism. Average refractive indices at various temperatures and relative humidity values are independently measured. Thermal optical coefficients of polymers are estimated quantitatively to evaluate the temperature response capability of the refractive index. Angle selectivity of multiplexing gratings is scanned at various temperatures to obtain magnitudes of Bragg angle detuning. The linear thermal expansion coefficients are extracted by the nonlinear fitting reading angle dependence of angle detuning. The significance of the thermal optical coefficient and the thermal expansion coefficient for holographic sensing is discussed. Finally, the primary factor for temperature-induced wavelength blueshift is analyzed theoretically. PMID- 27958411 TI - Method of super-resolution based on array detection and maximum-likelihood estimation. AB - Conventional confocal fluorescence microscopy has demonstrated its ability to gain enhanced image resolution after the employment of pinholes, but the contradiction between resolution and signal to noise ratio hinders the further improvement of resolution. However, an array detector scheme for confocal microscopes solves this problem and is therefore of interest in restoring the data of array detectors to its original image. In this paper, we apply maximum likelihood estimation (MLE), which is a restoration method based on the Poisson distribution of the fluorescence sample, to restore the array-detection image. We set up a simulation and apply it to fluorescent beads and fixed cell samples to verify its effectiveness. The results show that, after the restoration, the lateral resolution is highly enhanced and the signal to noise ratio is remarkably improved. PMID- 27958412 TI - Analysis of an optical turbulence profile using complete ensemble empirical mode decomposition. AB - We obtain an intrinsic optical turbulence model using a data-driven method named complete ensemble empirical mode decomposition. First, the measured profile of a refractive index structure parameter is decomposed into a set of intrinsic mode functions and a residue. The components are tested against white noise to determine the statistical significance. Meanwhile, the physical meanings of the IMFs are revealed using meteorological data that agrees with previous research. Second, the effect of noisy oscillations, quasi-cyclical variations, and the trend on the overall profile are evaluated by the variance contribution rate. Third, the intrinsic optical turbulence model is defined. The combination of different IMFs with the residue forms intrinsic optical turbulence profiles, by which the stratification structures on different scales are embedded into the model. Comparison with other models highlights the virtue of the intrinsic optical turbulence model. PMID- 27958413 TI - Optical double-image encryption and authentication by sparse representation. AB - An optical double-image encryption and authentication method by sparse representation is proposed. The information from double-image encryption can be integrated into a sparse representation. Unlike the traditional double-image encryption technique, only sparse (partial) data from the encrypted data is adopted for the authentication process. Simulation results demonstrate that the correct authentication results are achieved even with partial information from the encrypted data. The randomly selected sparse encrypted information will be used as an effective key for a security system. Therefore, the proposed method is feasible, effective, and can provide an additional security layer for optical security systems. In addition, the method also achieved the general requirements of storage and transmission due to a high reduction of the encrypted information. PMID- 27958414 TI - Issues of laser safety of visual landing systems. AB - The paper discusses the methodic issues and theoretical results of determining the boundaries of laser hazard zones (LHZs) when the eye is exposed to direct and scattered radiation produced by a laser landing system (LLS). We consider algorithms for LHZ calculation when LLSs are observed under real conditions of exploitation. The LHZ calculations for single and multiple laser sources under different meteorological conditions are presented. Computer software is provided to calculate the dosimetry of laser radiation under real conditions of LLS operation. PMID- 27958415 TI - High-power lasers for directed-energy applications: comment. AB - Sprangle et al. [Appl. Opt.54, F201 (2015)APOPAI0003-693510.1364/AO.54.00F201] recently concluded that our experiments on coherent combining of laser beams over an atmospheric path [Opt. Lett.36, 4455 (2011)OPLEDP0146 959210.1364/OL.36.004455] were "effective only because at these low-power levels the linewidth of the lasers was very narrow... and the level of atmospheric turbulence was low...." These conclusions are inaccurate, not relevant to practical high-power coherently combined laser systems, and contradict our most recent experiments with coherent combining of 21 laser beams with a linewidth of about 1 GHz over 7 km distance. In this comment we also challenge the major conclusion of Sprangle et al. [Appl. Opt.54, F201 (2015)APOPAI0003 693510.1364/AO.54.00F201] and the more recently published paper by Nelson et al. [Appl. Opt.55, 1757 (2016)APOPAI0003-693510.1364/AO.55.001757] regarding inefficiency of coherent beam combining under typical atmospheric conditions. PMID- 27958416 TI - Liquid-crystal-grating-based optical displacement sensors. AB - The optical properties of liquid crystal (LC) gratings with a mobile glass substrate, which can be used for optical displacement applications, were investigated. LC gratings are composed of homogeneous and twisted nematic domains. The displacement measurement principle is based on the change in diffraction efficiency induced by varying the mixing ratio of two orientation domains, in response to the lateral shift of the mobile substrate. Improved conditions for the polarization direction of incident light, as well as the application of voltage for achieving higher sensitivities, were explored. A simple demonstration of an LC-grating-based displacement sensor was also conducted. PMID- 27958417 TI - Wideband and low-dispersion engineered slow light using liquid infiltration of a modified photonic crystal waveguide. AB - We present a wideband and low-dispersion slow-light photonic crystal waveguide with a large normalized delay-bandwidth product that can be exploited in many ultra-compact all-optical devices, such as modulators and switches. The proposed new approach is based on infiltrating optical fluid into the first and second rows of the shifted air holes adjacent to the line-defect waveguide in a hexagonal lattice of photonic crystal. The simulation results show that the normalized delay-bandwidth product can be enhanced to a large value of 0.469 with a wide bandwidth operation of 36.8 nm in the C-band frequency optical communication window. Furthermore, by means of two-dimensional finite-difference time-domain calculations, the low-dispersion slow-light propagation is demonstrated by simulating the temporal Gaussian pulse width broadening. PMID- 27958418 TI - Accurate testing of aspheric surfaces using the transport of intensity equation by properly selecting the defocusing distance. AB - In the last decade, the transport of intensity has been increasingly used in microscopy, wavefront sensing, and metrology. In this study, we verify by simulation and experiment the use of the transport of intensity equation (TIE) in the accurate testing of optical aspheric surfaces. Guided by simulation results and assuming that the experimental setup parameters and the conic constants are known, one can estimate an appropriate defocusing distance Deltaz that leads to an accurate solution of the TIE. In this paper, this method is verified through the construction of a non-nulled experiment for testing the 2D profile of an aspheric surface. The theoretical method and experimental results are compared to validate the results. Finally, to validate the TIE methodology, the phase distribution obtained by TIE is compared with the phase distribution obtained by a Shack-Hartmann sensor. PMID- 27958419 TI - Terahertz generation based on difference frequency generation by rotating fan-out poled LiNbO3. AB - Theoretical analysis of terahertz (THz) generation based on difference frequency generation (DFG) by rotating fan-out poled LiNbO3 is presented. The uncertainty of poling vectors during clockwise and counterclockwise rotation of the fan-out poled LiNbO3 at the center of the crystal input face is investigated. The poling period along the propagation direction of the input pump and signal waves during clockwise and counterclockwise rotation is calculated. The dependence of THz vectors on rotation angles is numerically simulated. The relative intensities of a THz wave during clockwise rotation of the fan-out poled LiNbO3 are calculated. PMID- 27958420 TI - Measurement of surface form error of an optical surface with reduced interferometric spatial coherence artifacts using a ring source and polarization phase-shifting interferometry. AB - We present a technique for the measurement of surface form error of an optical surface using a ring source and polarization phase-shifting interferometry (PPSI). The ring source, generated using a refracting axicon, is projected onto a rotating diffuser to reduce the spatial coherence noise generated by the spatially coherent He-Ne laser and to enhance the interference fringe contrast. PPSI is applied to extract the phase [and hence the optical path difference (OPD)] from the interference fringes formed by a Fizeau cavity using the ring source. The OPD values are least-square fitted to a plane and the surface form errors are evaluated from the deviations of the OPD values from the fitted reference plane. A two-step subtraction method to reduce the system errors and the effect of the ring source diameter on the effective measurement area of the test surface are discussed. The main advantage of the technique is that the perturbations in the Fizeau cavity are negligible during the phase shifts as the phase shifts between the interfering beams are introduced outside the cavity. PMID- 27958422 TI - First mesospheric wind images using the Michelson interferometer for airglow dynamics imaging. AB - The Michelson interferometer for airglow dynamics imaging (MIADI) is a ground based instrument that combines an imaging capability with the Doppler Michelson interferometry in order to remotely detect motions in the mesopause region using spectrally isolated airglow emissions: the O(S1) emission at 557.73 nm and the OH (6, 2) P1 (2) at 839.918 nm. A measurement and analysis approach has been developed that allows simultaneous images of the line-of-sight Doppler wind field and irradiance field to be obtained. A working field instrument was installed and tested at a field site outside Fredericton, NB (45.96 N, 66.65 W) during the summer of 2014. Successful measurements over a 6 h period were obtained on 31 July 2014. This paper describes the MIADI measurement and analysis approach and presents the work that has been done to extract images of the line-of-sight Doppler wind field and irradiances from these observations. The imaging capability is validated by identifying the presence of large-scale and small scale geophysical perturbations in the images. PMID- 27958421 TI - Higher Q factor and higher extinction ratio with lower detection limit photonic crystal-parallel-integrated sensor array for on-chip optical multiplexing sensing. AB - We introduce an alternative method to establish a nanoscale sensor array based on a photonic crystal (PhC) slab, which is referred to as a 1*4 monolithic PhC parallel-integrated sensor array (PhC-PISA). To realize this function, four lattice-shifted resonant cavities are butt-coupled to four output waveguide branches, respectively. By shifting the first to the two closest neighboring holes around the defect, a high Q factor over 1.5*104 has been obtained. Owing to the slightly different cavity spacing, each PhC resonator shows an independent resonant peak shift as the refractive index changes surrounding the resonant cavity. The specific single peak with a well-defined extinction ratio exceeds 25 dB. By applying the finite-difference time-domain (FDTD) method, we demonstrate that the sensitivities of each sensor in PhC-PISA S1=60.500 nm/RIU, S2=59.623 nm/RIU, S3=62.500 nm/RIU, and S4=51.142 nm/RIU (refractive index unit) are achieved, respectively. In addition, the negligible crosstalk and detection limit as small as 1*10-4 have been observed. The proposed sensor array as a desirable platform has great potential to realize optical multiplexing sensing and high density monolithic integration. PMID- 27958423 TI - Slow light in narrow-core hollow optical waveguide with low loss and large bandwidth. AB - A narrow-core hollow waveguide with low loss is proposed that exhibits slow light characteristics. The slow light is guided in air between the top and bottom mirrors, each based on high-index-contrast gratings. The proposed design shows a low propagation loss of 1.8 dB/cm at a 1-MUm-thick narrow air core, and the loss remains low for a broad range of wavelengths from 1200 to 1600 nm. Also, the flat band slow light is realized at a grating period of 0.8 MUm in 1-MUm-thick narrow air core. Further design analysis reveals a large fabrication tolerance of the proposed hollow structure with respect to the grating period. PMID- 27958424 TI - Spectral phase effects and control requirements of coherent beam combining for ultrashort ultrahigh intensity laser systems. AB - Based on the premise that further improvements to the size and damage threshold of large-aperture optical components are severely limited, coherent beam combining (CBC) is a promising way to scale up the available peak power of pulses for ultrashort ultrahigh intensity laser systems. Spectral phase effects are important issues and have a significant impact on the performance of CBC. In this work, we analyze systematically factors such as spectral dispersions and longitudinal chromatism, and get the general spectral phase control requirements of CBC for ultrashort ultrahigh intensity laser systems. It is demonstrated that different orders of dispersion influence intensity shape of the combined beam, and high-order dispersions affect the temporal contrast of the combined beam, while the number of the channels to be combined has little impact on the temporal Strehl ratio (SR) of the combined beam. In addition, longitudinal chromatism should be controlled effectively since it has a detrimental effect on the combined beam at the focal plane, both temporally and spatially. PMID- 27958425 TI - Naturalness index for a tone-mapped high dynamic range image. AB - High dynamic range (HDR) images can only be backward-compatible with existing low dynamic range (LDR) imaging systems after being processed by tone-mapping operators. Hence, the quality assessment (QA) of tone-mapped HDR images has become an important and challenging issue in HDR imaging research. In this paper, we propose a naturalness index for a tone-mapped image to predict its quality. First, we extract the statistical features of the tone-mapped image's luminance value and use it to evaluate the brightness naturalness with no reference information. Meanwhile, we use perceptive color, image contrast, and detail information to represent the image content and predict their naturalness qualities, respectively. Then, the four components of the naturalness qualities are combined to yield the overall naturalness quality of the tone-mapped image. Experimental results on a publicly available database demonstrated that, in comparison with a traditional LDR image QA method and a leading tone-mapped image QA method, the proposed method has better performance in evaluating a tone-mapped image's quality. PMID- 27958426 TI - Polarimetric characteristics of a class of hyperspectral radiometers. AB - The polarimetric characteristics of a class of hyperspectral radiometers commonly applied for above-water radiometry have been investigated by analyzing a sample of sensors. Results indicate polarization sensitivity increasing with wavelength and exhibiting values varying from sensor to sensor. In the case of radiance sensors, the maximum differences increase from approximately 0.4% at 400 nm to 1.3% at 750 nm. In the case of irradiance sensors, due to depolarizing effects of the diffusing collector, the maximum differences between horizontal and vertical polarization sensitivities vary from approximately 0.3% at 400 nm to 0.6% at 750 nm. Application of the previous results to above-water radiometry measurements performed in sediment dominated waters indicates that neglecting polarization effects may lead to uncertainties not exceeding a few tenths of a percent in remote sensing reflectance RRS determined in the 400-570 nm spectral interval. Conversely, uncertainties spectrally increase toward the near infrared, reaching several percent at 750 nm in the case of oligotrophic waters. PMID- 27958427 TI - Single-mode large-mode-area laser fiber with ultralow numerical aperture and high beam quality. AB - By using the chelate precursor doping technique, we report on an ytterbium-doped aluminophosphosilicate (APS) large-mode-area fiber with ultralow numerical aperture of 0.036 and effective fundamental mode area of ~550 MUm2. With a bend diameter of 600 mm, the bending loss of fundamental mode LP01 was measured to be <10-3 dB/m, in agreement with the corresponding simulation results, while that of higher order mode LP11 is >100 dB/m at 1080 nm. Measured in an all-fiber oscillator laser cavity, 592 W single-mode laser output was obtained at 1079.64 nm with high-beam quality M2 of 1.12. The results indicate that the chelate precursor doping technique is a competitive method for ultralow numerical aperture fiber fabrication, which is very suitable for developing single-mode seed lasers for high power laser systems. PMID- 27958428 TI - Barrier layer induced channeling effect of As ion implantation in HgCdTe and its influences on electrical properties of p-n junctions. AB - The HgCdTe layers (xCd~0.285 and 0.225) were grown by molecular beam epitaxy and liquid phase epitaxy, respectively, followed by the deposition of CdTe and ZnS films as barrier layers by thermal evaporation. Then, the p-on-n photodiodes were fabricated by AS ion implantation, Hg overpressure annealing, passivation, and metallization. The secondary ion mass spectrometry and transmission electron microscopy results indicate that the evaporated CdTe layer with a column structure induces the channeling effect of As ion implantation causing the device performance degradation. This effect could be suppressed by depositing a CdTe film with a layered structure through E-beam evaporation. Finally, the current-voltage (I-V) and capacitance-voltage (C-V) characteristics of these p-n junctions were estimated and analyzed. PMID- 27958429 TI - Urban monitoring from infrared satellite images. AB - Starting from an experimental campaign in Milan, the article describes how the infrared signal recorded by Landsat 8 sensors can be used to evaluate and monitor key urban scale environmental variables. The possibility of combining different spectral bands of the infrared signal with previously collected spectral bands is highlighted. The monitored variables have been mapped in geo-referenced images using Geographic Information System (GIS)instruments. In this way, a mapping database is created to be used as a benchmark to study urban heat islands and the environmental changes over the years. PMID- 27958431 TI - Lasers and infrared thermography: advantageous cooperation. AB - In a brief review, the beneficial outcomes that have arisen from simultaneous use of laser- and infrared thermography (IRT)-based techniques are demonstrated. The most recent literary and original experimental results collected from different research and practical areas are presented. It is shown that modern IRT acts as an indispensable laser partner in various biomedical and many other applications and technologies. And vice versa, the laser-based methods and techniques often serve as an appropriate research instrument enriching IRT measurement data with independently obtained information. PMID- 27958430 TI - Basic temperature correction of QWIP cameras in thermoelastic/plastic tests of composite materials. AB - The present work is concerned with the use of a quantum well infrared photodetector (QWIP) infrared camera to measure very small temperature variations, which are related to thermoelastic/plastic effects, developing on composites under relatively low loads, either periodic or due to impact. As is evident from previous work, some temperature variations are difficult to measure, being at the edge of the IR camera resolution and/or affected by the instrument noise. Conversely, they may be valuable to get either information about the material characteristics and its behavior under periodic load (thermoelastic), or to assess the overall extension of delaminations due to impact (thermo-plastic). An image post-processing procedure is herein described that, with the help of a reference signal, allows for suppression of the instrument noise and better discrimination of thermal signatures induced by the two different loads. PMID- 27958432 TI - Pulsed micro-laser line thermography on submillimeter porosity in carbon fiber reinforced polymer composites: experimental and numerical analyses for the capability of detection. AB - In this article, pulsed micro-laser line thermography (pulsed micro-LLT) was used to detect the submillimeter porosities in a 3D preformed carbon fiber reinforced polymer composite specimen. X-ray microcomputed tomography was used to verify the thermographic results. Then, finite element analysis was performed on the corresponding models on the basis of the experimental results. The same infrared image processing techniques were used for the experimental and simulation results for comparative purposes. Finally, a comparison of experimental and simulation postprocessing results was conducted. In addition, an analysis of probability of detection was performed to evaluate the detection capability of pulsed micro-LLT on submillimeter porosity. PMID- 27958433 TI - Detection and localization of gold nanoshells inside cells: near-field approximation. AB - The optical properties of metal nanoparticles play a fundamental role for their use in a wide range of applications. In hyperthermia treatment, for example, gold nanoshells (NSs, dielectric core+gold shell) pre-embedded in a cancer cell absorb energy when exposed to appropriate wavelengths of a laser beam and heat up, thereby destroying the cancer cell. In this process, nevertheless, healthy tissues (not targeted by the NSs) along the laser path are not affected; this is because most biological soft tissues have a relatively low light absorption coefficient in the near-infrared (NIR) regions-a characteristic known as the tissue optical window. Over such a window, NIR light transmits through the tissues with scattering-limited attenuation and minimal heating, thereby avoiding damage to healthy tissues. As a consequence, the identification of NSs assumed a fundamental role for the further development of such cancer treatment. Recently, we have demonstrated the possibility to identify 100-150 nm diameter gold NSs inside mouse cells using a scanning near-optical microscope (SNOM). In this paper, we provide a numerical demonstration that the SNOM is able to locate NSs inside the cell with a particle-aperture distance of about 100 nm. This result was obtained by developing an analytical approach based on the calculation of the dyadic Green function in the near-field approximation. The implications of our findings will remarkably affect further investigations on the interaction between NSs and biological systems. PMID- 27958434 TI - Detecting defects in marine structures by using eddy current infrared thermography. AB - Eddy current infrared (IR) thermography is a new nondestructive testing (NDT) technique used for the detection of cracks in electroconductive materials. By combining the well-established inspection methods of eddy current NDT and IR thermography, this technique uses induced eddy currents to heat test samples. In this way, IR thermography allows the visualization of eddy current distribution that is distorted in defect sites. This paper discusses the results of numerical modeling of eddy current IR thermography procedures in application to marine structures. PMID- 27958435 TI - Two-layer anti-reflection coating with mullite and polyimide foam for large diameter cryogenic infrared filters. AB - We have developed a novel two-layer anti-reflection (AR) coating method for large diameter infrared (IR) filters made of alumina, for use at cryogenic temperatures in millimeter wave measurements. Thermally sprayed mullite and polyimide foam (Skybond Foam) are used as the AR material. An advantage of the Skybond Foam is that the index of refraction is chosen between 1.1 and 1.7 by changing the filling factor. Combination with mullite is suitable for wide-band millimeter wave measurements with sufficient IR cutoff capability. We present the material properties, fabrication of a large-diameter IR filter made of alumina with this AR coating method, and characterizations at cryogenic temperatures. This technology can be applied to a low-temperature receiver system with a large diameter focal plane for next-generation cosmic microwave background polarization measurements, such as POLARBEAR-2 (PB-2). PMID- 27958436 TI - Optically stabilized Erbium fiber frequency comb with hybrid mode-locking and a broad tunable range of repetition rate. AB - We present an optically stabilized Erbium fiber frequency comb with a broad repetition rate tuning range based on a hybrid mode-locked oscillator. We lock two comb modes to narrow-linewidth reference lasers in turn to investigate the best performance of control loops. The control bandwidth of fast and slow piezoelectric transducers reaches 70 kHz, while that of pump current modulation with phase-lead compensation is extended to 32 kHz, exceeding laser intrinsic response. Eventually, simultaneous lock of both loops is realized to totally phase-stabilize the comb, which will facilitate precision dual-comb spectroscopy, laser ranging, and timing distribution. In addition, a 1.8-MHz span of the repetition rate is achieved by an automatic optical delay line that is helpful in manufacturing a secondary comb with a similar repetition rate. The oscillator is housed in a homemade temperature-controlled box with an accuracy of +/-0.02 K, which not only keeps high signal-to-noise ratio of the beat notes with reference lasers, but also guarantees self-starting at the same mode-locking every time. PMID- 27958437 TI - Thermal effects of laser marking on microstructure and corrosion properties of stainless steel. AB - Laser marking is an advanced technique used for modification of surface optical properties. This paper presents research on the influence of laser marking on the corrosion properties of stainless steel. Processes during the laser beam-surface interaction cause structure and color changes and can also be responsible for reduction of corrosion resistance of the surface. Corrosion tests, roughness, microscopic, energy dispersive x-ray, grazing incidence x-ray diffraction, and ferrite content analyses were carried out. It was found that increasing heat input is the most crucial parameter regarding the degradation of corrosion resistance of stainless steel. Other relevant parameters include the pulse length and pulse frequency. The authors found a correlation between laser processing parameters, grazing incidence x-ray measurement, ferrite content, and corrosion resistance of the affected surface. Possibilities and limitations of laser marking of stainless steel in the context of the reduction of its corrosion resistance are discussed. PMID- 27958438 TI - Carbon fiber composites inspection and defect characterization using active infrared thermography: numerical simulations and experimental results. AB - Composite materials are widely used in the aeronautic industry. One of the reasons is because they have strength and stiffness comparable to metals, with the added advantage of significant weight reduction. Infrared thermography (IT) is a safe nondestructive testing technique that has a fast inspection rate. In active IT, an external heat source is used to stimulate the material being inspected in order to generate a thermal contrast between the feature of interest and the background. In this paper, carbon-fiber-reinforced polymers are inspected using IT. More specifically, carbon/PEEK (polyether ether ketone) laminates with square Kapton inserts of different sizes and at different depths are tested with three different IT techniques: pulsed thermography, vibrothermography, and line scan thermography. The finite element method is used to simulate the pulsed thermography experiment. Numerical results displayed a very good agreement with experimental results. PMID- 27958439 TI - Diffraction and polarization effects in Earth radiation budget measurements. AB - Thermal radiation emitted and reflected from the Earth and viewed from near-Earth orbit may be characterized by its spectral distribution, its degree of coherence, and its state of polarization. The current generation of broadband Earth radiation budget instruments has been designed to minimize the effect of diffraction and polarization on science products. We used Monte Carlo ray-trace (MCRT) models that treat individual rays as quasi-monochromatic, polarized entities to explore the possibility of improving the performance of such instruments by including measures of diffraction and polarization during calibration and operation. We have demonstrated that diffraction and polarization sensitivity associated with typical Earth radiation budget instrument design features has a negligible effect on measurements. PMID- 27958440 TI - Active thermography inspection of protective glass contamination on laser scanning heads. AB - Industrial lasers are an expanding technology of welding and other materials processing. Lasers with optical scanning heads are often used, as these provide more versatility, accuracy, and speed. The output part of the scanning head is covered by a protective glass, which might get contaminated by various particles from the laser processing. This decreases the transmissivity of the glass, and it can affect the production quality. The contamination needs to be checked regularly, but a visual inspection might not always be effective. This paper proposes two alternative methods of inspecting the protective glass: flash-pulse active thermography, and laser active thermography. They are based on the thermal excitation of the glass and measuring the response with an infrared camera. The experimental setup and practical results are described and the advantages and disadvantages are discussed. The presented methods are proven to be effective in detecting the contamination of the glass. PMID- 27958442 TI - Comparison of quantitative defect characterization using pulse-phase and lock-in thermography. AB - Using optical excitation sources for active thermography enables a contactless, remote, and non-destructive testing of materials and structures. Currently, two kinds of temporal excitation techniques have been established: pulse or flash excitation, using mostly flash lamps; and periodic or lock-in excitation, using halogen lamps, LED, or laser arrays. From the experimental point of view, both techniques have their advantages and disadvantages. Concerning the comparison of the testing results of both techniques, only very few studies have been performed in the past. In this contribution, the phase values obtained at flat bottom holes in steel and CFRP and the spatial resolution measured at crossed notches in steel using flash and lock-in excitation are compared quantitatively. PMID- 27958441 TI - Innovative algorithm to evaluate the capabilities of visual, near infrared, and infrared technologies for the detection of veins for intravenous cannulation. AB - Intravenous cannulation is the process of inserting a cannula into a vein to administrate medication, fluids, or to take blood samples. The process of identification and of locating veins plays an important role during the intravenous cannulation procedure to reduce health care costs and the suffering of patients. This paper compares the three technologies used to assess their suitability and capability for the detection of veins to support the cannulation process. Three types of cameras are used in this study; a visual, an infrared, and a near infrared. The collected images, 103 in total, from the three technologies have been analyzed using a wide range of image processing techniques and compared with identification templates to evaluate the performance of each technology. The results show that the near infrared technology supported by suitable LED illumination is the most effective for the visualization of veins. However, infrared thermography is found to be successful when followed by a cold stimulation. PMID- 27958443 TI - Tri-band transparent conductive coating of indium tin oxide. AB - A tri-band transparent conductive indium tin oxide (In2O3:Sn, ITO) film for the visible, near-infrared (NIR) and mid-infrared (MIR) was deposited on a sapphire substrate by radio frequency (RF) magnetron sputtering. Deposition parameters, including RF power, substrate temperature, and oxygen flow rate, were optimized to improve the optical property without reducing the conductivity of the film by maximizing the Hall mobility and minimizing the carrier concentration. Films deposited at optimized conditions exhibit a Hall mobility of ~20 cm2 V-1 s-1, a carrier concentration of ~4.99*1020 cm-3, and a sheet resistance of 61.2 Omega/sq. Average transmissions of these films are 81.40% in the 0.4-1.6 MUm region and 60.81% in the 3.0-5.0 MUm region. An index-matching stack of MgF2 was developed, improving the transmittance to 90.55% and 73.20% in the regions above, respectively. These results make ITO film a promising alternative material to conventional metal mesh for missile domes shielding electromagnetic waves. PMID- 27958444 TI - Infrared thermographic inspection of water ingress in composite honeycomb panels. AB - Quantitative aspects of infrared thermographic detection of water in aviation honeycomb panels are discussed in the framework of both 1D analytical and 3D numerical models. A criterion for the transition from 3D to 1D test geometry is introduced, and the influence of the honeycomb cell structure on the modeling results is demonstrated. Optimal test conditions are formulated both theoretically and experimentally in two practical cases where the force of gravity causes the water to be against the facesheet at the bottom of the cells or where a water gap separates the water from the top facesheet. PMID- 27958445 TI - Thermography for skin temperature evaluation during dynamic exercise: a case study on an incremental maximal test in elite male cyclists. AB - The use of thermal imaging in monitoring the dynamic of skin temperature during prolonged physical exercise is central to assess athletes' ability to dissipate heat from the skin surface to the environment. In this study, seven elite cyclists completed an incremental maximal cycling test to evaluate their skin temperature response under controlled-environment conditions. Thermal images have been analyzed using a method based on maxima detection (Tmax). Data confirmed a reduction in skin temperature due to vasoconstriction during the exercise, followed by a temperature increment after exhaustion. A characteristic hot-spotted thermal pattern was found over the skin surface in all subjects. This research confirmed also the notable ability by highly trained cyclists to modify skin temperature during an incremental muscular effort. This study gives additional contributions for understanding the capability of the Tmax method applied to the thermoregulatory physiological processes. PMID- 27958446 TI - Thermography and machine learning techniques for tomato freshness prediction. AB - The United States and China are the world's leading tomato producers. Tomatoes account for over $2 billion annually in farm sales in the U.S. Tomatoes also rank as the world's 8th most valuable agricultural product, valued at $58 billion dollars annually, and quality is highly prized. Nondestructive technologies, such as optical inspection and near-infrared spectrum analysis, have been developed to estimate tomato freshness (also known as grades in USDA parlance). However, determining the freshness of tomatoes is still an open problem. This research (1) illustrates the principle of theory on why thermography might be able to reveal the internal state of the tomatoes and (2) investigates the application of machine learning techniques-artificial neural networks (ANNs) and support vector machines (SVMs)-in combination with transient step heating, and thermography for freshness prediction, which refers to how soon the tomatoes will decay. Infrared images were captured at a sampling frequency of 1 Hz during 40 s of heating followed by 160 s of cooling. The temperatures of the acquired images were plotted. Regions with higher temperature differences between fresh and less fresh (rotten within three days) tomatoes of approximately uniform size and shape were used as the input nodes for ANN and SVM models. The ANN model built using heating and cooling data was relatively optimal. The overall regression coefficient was 0.99. These results suggest that a combination of infrared thermal imaging and ANN modeling methods can be used to predict tomato freshness with higher accuracy than SVM models. PMID- 27958447 TI - 3D model of laser treatment by a moving heat source with general distribution of energy in the beam. AB - A three-dimensional model of direct heat treatment of a sample surface with a moving laser has been established utilizing the finite element method. Attention is devoted to the preparation of complex boundary conditions of a moving heat source. Boundary conditions of material heat treatment are defined in the form of the heat transfer coefficient with consideration of several effects. Those include general distribution of energy in the laser beam, laser motion velocity, laser axis position outside the sample, and utilization of multiple laser motion tracks over the sample. Various arrangements of sample heat treatment are proposed and computer simulated. Different velocities of laser motion, multiple motion over the same track, and simple motion over a number of tracks are investigated. The temperature distribution in the sample and the depths of material heat treatment are evaluated. The simulation model can be used for temperature prediction during laser surface treatment of materials. PMID- 27958448 TI - Hyperspectral characteristic analysis for leaf nitrogen content in different growth stages of winter wheat. AB - The spectral characteristics in the range of visible light and near-infrared shortwave (400-1000 nm) are analyzed using the ground measured hyperspectral data and leaf nitrogen content (LNC) data of different growth stages of winter wheat, which were acquired in 2013 and 2015. First, the quantitative models for monitoring the LNC at different growth stages of winter wheat were established using the main vegetation nitrogen spectral indices. By analyzing the simulation coefficient of the models, it is demonstrated that vegetation nitrogen spectral indices, which are calculated using these data in this study, should not be an effective quantitative estimate for winter wheat LNC. Second, a method for finding representation wavebands of hyperspectral data sensitive to the LNC of winter wheat is proposed based on the spectral correlation. Using the hyperspectral data, which were acquired in 2015 and the proposed method, the representation wavebands sensitive to the LNC of winter wheat are found. The finding results show that the representative wavebands are mainly located in the purple, red and near-infrared wavelength range, but the representative wavebands are different in different stages. The red edge effects of representative wavebands are obvious. Finally, based on the acquired representation wavebands corresponding to different growth stages of winter wheat, the quantitative models for monitoring the LNC at different growth stages of winter wheat were established using data acquired in 2015 and 2013. The modeling results show that the combination of representation wavebands found to correspond to different growth stages of winter wheat are effective and credible for monitoring the LNC. So, these research results lay the foundation for accurate quantitative monitoring of winter wheat LNC. PMID- 27958449 TI - Telescope array for extrasolar planet detection from the far side of the Moon. AB - We propose that an array of 4*4 small-diameter telescopes, possibly 1 m in radius, be placed on the far side of the Moon for continuous monitoring of nearby stars for the existence of a planetary companion, similar to the Earth, and feasible for human colonization. The advantages of this location include long intervals of darkness, availability of a rigid platform in the form of a moon body, and most importantly, the absence of the atmosphere that allows the complete transmission of radiation in the spectral range from UV to millimeter waves. The task is facilitated in that the telescopes would act as light "buckets" to collect photons during long integration periods. All other technology has already been demonstrated, as humans in person delivered optical elements to the Moon's surface during the Apollo era. The disadvantages are primarily operational, in terms of requiring the establishment of a human habitat on the Moon. Likewise, all aspects of constructing a large 75 m by 75 m mirror array on the Moon's surface will be challenging. Simultaneously, the decreased gravity requires less effort and less energy to perform the construction tasks. The absence of atmosphere permits the search to extend from less than 10 to 300 MUm to find Earth-like or even much colder planets. PMID- 27958450 TI - Advances in Infrared Technology and Applications: introduction. AB - The special issue of Applied Optics on Advanced Infrared Technology and Applications(AITA) arose out of the biannual conference of the same name, most recently held in Pisa, Italy, 29 September to 2 October, 2015. PMID- 27958451 TI - Automated assessment and tracking of human body thermal variations using unsupervised clustering. AB - The presented approach addresses a review of the overheating that occurs during radiological examinations, such as magnetic resonance imaging, and a series of thermal experiments to determine a thermally suitable fabric material that should be used for radiological gowns. Moreover, an automatic system for detecting and tracking of the thermal fluctuation is presented. It applies hue-saturated-value based kernelled k-means clustering, which initializes and controls the points that lie on the region-of-interest (ROI) boundary. Afterward, a particle filter tracks the targeted ROI during the video sequence independently of previous locations of overheating spots. The proposed approach was tested during experiments and under conditions very similar to those used during real radiology exams. Six subjects have voluntarily participated in these experiments. To simulate the hot spots occurring during radiology, a controllable heat source was utilized near the subject's body. The results indicate promising accuracy for the proposed approach to track hot spots. Some approximations were used regarding the transmittance of the atmosphere, and emissivity of the fabric could be neglected because of the independence of the proposed approach for these parameters. The approach can track the heating spots continuously and correctly, even for moving subjects, and provides considerable robustness against motion artifact, which occurs during most medical radiology procedures. PMID- 27958452 TI - Nonlinear laser dynamics induced by frequency shifted optical feedback: application to vibration measurements. AB - In this article, we study the nonlinear dynamics of a laser subjected to frequency shifted optical reinjection coming back from a vibrating target. More specifically, we study the nonlinear dynamical coupling between the carrier and the vibration signal. The present work shows how the nonlinear amplification of the vibration spectrum is related to the strength of the carrier and how it must be compensated to obtain accurate (i.e., without bias) vibration measurements. The theoretical predictions, confirmed by numerical simulations, are in good agreement with the experimental data. The main motivation of this study is the understanding of the nonlinear response of a laser optical feedback imaging sensor for quantitative phase measurements of small vibrations in the case of strong optical feedback. PMID- 27958453 TI - Precise parallel optical spectrum analysis using the advanced two-phonon light scattering combined with the cross-disperser technique. AB - We develop an advanced approach to the optical spectrometer with acousto-optical dynamic grating for the Guillermo Haro astrophysical observatory (Mexico). The progress consists of two principle novelties. First is the use of the acousto optical nonlinearity of two-phonon light scattering in crystals with linear acoustic losses. This advanced regime of light scattering exhibits a recently revealed additional degree of freedom, which allows tuning of the frequency of elastic waves and admits the nonlinear apodization improving the dynamic range. The second novelty is the combination of the cross-disperser with acousto-optical processing. A similar pioneering step provides an opportunity to operate over all the visible range in a parallel regime with maximal achievable resolution. The observation window of the optical spectrometer in that observatory is ~9 cm, so that the theoretical estimations of maximal performances for a low-loss LiNbO3 crystal for this optical aperture at lambda=405 nm give spectral resolution of 0.0523 A, resolving power of 77,400, and 57,500 spots. The illustrative proof-of-principle experiments with a 6 cm LiNbO3 crystal have been performed. PMID- 27958454 TI - Influence of finite conductivity on the excitation of phase resonances in metallic surfaces with cavities of circular cross sections. AB - Phase resonances have been investigated in the last few years, not only because of their striking features, such as extremely high quality factor and huge enhancement of the electromagnetic field inside cavities/grooves, but also for their promising applications. However, taking into account that these resonances are more efficiently excited in highly conducting structures, most of the studies have been devoted to explore this phenomenon at wavelengths in the infrared or larger, using different approaches for the boundary conditions. In this paper, we investigate the validity of the perfect conductor approximation and the surface impedance boundary condition to appropriately represent the electromagnetic response of a metallic surface comprising a finite number of subwavelength cavities of circular cross sections. Far- and near-field plots are shown and analyzed in order to investigate the validity ranges and discuss to what extent phase resonances can be excited at shorter wavelengths in these structures. PMID- 27958455 TI - Theoretical analysis of performance enhancement in GeSn/SiGeSn light-emitting diode enabled by Si3N4 liner stressor technique. AB - We comprehensively investigate the energy band diagrams, carrier distribution, spontaneous emission rate rsp, and the internal quantum efficiency etaIQE in the lattice-matched GeSn/SiGeSn double heterostructure light emitting diode (LED) wrapped in a Si3N4 liner stressor. The large tensile strain introduced into the device by the expansion of the Si3N4 liner is characterized by numerical simulation. A lower Sn composition required for the indirect to direct bandgap transition and a higher ratio of the electron occupation probability in the Gamma conduction valley are achieved in the tensile strained GeSn/SiGeSn LED in comparison with the relaxed device. Analytical calculation shows that the tensile strained LED wrapped in the Si3N4 liner stressor exhibits the improved rsp and etaIQE compared to the relaxed device. rsp and etaIQE also can be enhanced by increasing Sn composition, carrier injection density, and n-type doping concentration in the GeSn active layer. PMID- 27958456 TI - Online fabrication scheme of helical long-period fiber grating for liquid-level sensing. AB - We present a novel online fabrication scheme of helical long-period fiber gratings (H-LPFGs) by directly twisting a standard single-mode fiber (SMF) in a microheater. This is done by taking advantage of the inherent core-cladding eccentricity in SMF. We adopt a fiber optic rotary joint to eliminate the accompanying twisting spiral for real-time spectral monitoring and a stepping mechanical system to accurately control the twisting length in fabrication. As a consequence, low-cost and high-quality H-LPFGs can be readily fabricated. Meanwhile, by using this kind of H-LPFG, we design a simple and low-cost wavelength-interrogated liquid-level sensor with a high sensitivity of 0.1 nm/mm. PMID- 27958457 TI - Orthogonal basis for the optical transfer function. AB - We propose systems of orthogonal functions qn to represent optical transfer functions (OTF) characterized by including the diffraction-limited OTF as the first basis function q0=OTFperfect. To this end, we apply a powerful and rigorous theoretical framework based on applying the appropriate change of variables to well-known orthogonal systems. Here we depart from Legendre polynomials for the particular case of rotationally symmetric OTF and from spherical harmonics for the general case. Numerical experiments with different examples show that the number of terms necessary to obtain an accurate linear expansion of the OTF mainly depends on the image quality. In the rotationally symmetric case we obtained a reasonable accuracy with approximately 10 basis functions, but in general, for cases of poor image quality, the number of basis functions may increase and hence affect the efficiency of the method. Other potential applications, such as new image quality metrics are also discussed. PMID- 27958458 TI - Liquid sinusoidal pressure measurement by laser interferometry based on the refractive index of water. AB - A new method with laser interferometry is used to enhance the traceability for sinusoidal pressure calibration in water. The laser vibrometer measures the dynamic pressure based on the acousto-optic effect. The relation of the refractive index of water and the optical path length with the pressure's change is built based on the Lorentz-Lorenz equation, and the conversion coefficients are tested by static calibration in situ. A device with a piezoelectric transducer and resonant pressure pipe with water is set up to generate sinusoidal pressure up to 20 kHz. With the conversion coefficients, the reference sinusoidal pressure is measured by the laser interferometer for pressure sensors' dynamic calibration. The experiment results show that under 10 kHz, the measurement results between the laser vibrometer and a piezoelectric sensor are in basic agreement and indicate that this new method and its measurement system are feasible in sinusoidal pressure calibration. Some disturbing components including small amplitude, temperature change, pressure maldistribution, and glass windows' vibration are also analyzed, especially for the dynamic calibrations above 10 kHz. PMID- 27958459 TI - Modeling photon transport in turbid media for measuring colloidal concentration in drops using the time-shift technique. AB - Colloidal drops-suspensions, dispersions, emulsions-are widespread in the process industry but are difficult to characterize by size, velocity, and concentration of particulate matter in the drop. The present study investigates the use of the time-shift (TS) technique for such measurements. Numerically, a model based on ray tracing is developed, incorporating interactions with randomly placed monodispersed scattering centers within the spherical drop. The model creates a random walk propagation trajectory, known from radiative transfer problems. The model approximates Mie scattering from each internal particle with a Gaussian distribution. Experiments are performed using a conventional TS instrument, first with water as a reference and for validation, and then with different concentrations of a milk/water emulsion. Comparison of the modeled and received signals exhibits very good agreement, confirming the possibility of measuring the colloidal concentration in drops using the TS technique. PMID- 27958460 TI - Simplified analysis of sub-wavelength triangular gratings by simplified modal method. AB - A phase-equivalence of a triangular grating and a "corresponding" blazed structure is proposed. This equivalence is used to simplify the analysis of the grating, which otherwise would require the repetitive application of the simplified modal method to each lamellar grating that constitutes the triangular grating. The concept is used to arrive at an equation for the phase introduced by the triangular grating. The proposed model is verified by finite element simulations. A method of fabricating a triangular grating in quartz is presented. The proposed theory, along with optical testing, can be used as a non-destructive means by which to estimate the height of the triangular grating during the dry etching process. PMID- 27958461 TI - Spatial characterization of nanotextured surfaces by visual color imaging. AB - We present a method using an ordinary color camera to characterize nanostructures from the visual color of the structures. The method provides a macroscale overview image from which micrometer-sized regions can be analyzed independently, hereby revealing long-range spatial variations of the structures. The method is tested on injection-molded polymer line gratings, and the height and filling factor are determined with confidence intervals similar to more advanced imaging scatterometry setups. PMID- 27958462 TI - Edge detection based on Retinex theory and wavelet multiscale product for mine images. AB - The application of visual technology to mine robots has become a hot topic in the development of coal mine automatic production. Key techniques of robot control are the feature recognition of sampled videos and the perception of complex surroundings. However, it is difficult for features in underground images with dark hue and low target discrimination to be recognized and extracted, especially for reasons of the nonuniform illumination and heavy dust concentration in mines. Hence, an edge detection algorithm based on the Retinex theory and wavelet multiscale product is proposed in this paper for low-light-level mine image feature extraction, which employs a modified multiscale Retinex method to deal with the low frequency subplot after the wavelet decomposition, an improved fuzzy enhancement approach to handle high frequency components, and finally a revised multiscale product edge detection algorithm to obtain the ultima edge image. Compared with a variety of algorithms by detecting edges of both normal illuminated and underground images, experimental results show that with characteristics of high real-time performance and detection accuracy, the proposed algorithm can exactly meet the needs of surrounding environment perception for mine robots, which applies well to image edge detection in low illumination mines. PMID- 27958463 TI - Light scattered by optical coatings: numerical predictions and comparison to experiment for a global analysis. AB - Complex optical coatings may present highly disturbed scattering patterns, both spectrally and angularly. We show in this paper how the development of an accurate dedicated metrology allowed the optimization of numerical models. Our prediction is compared to our measurement. PMID- 27958464 TI - Comparative analysis of direct laser writing and nanoimprint lithography for fabrication of optical phase elements. AB - We report a comparison between two commercially available methods for printing phase shaping optical microstructures. Phase elements that convert a zero-order Hermite-Gaussian (HG00) mode into higher-order modes (HG10, HG01, HG20, and HG02) were fabricated by 3D direct laser writing (3D-DLW) and nanoimprint lithography (NIL). The structures in each method were characterized and the corresponding beam qualities were analyzed. The direct comparison of equivalent optical devices enables us to reveal the limitations and advantages of the two fabrication methods in order to optimize the fabrication of useful optical microstructure devices. 3D-DLW enables sharper edges and a straightforward lithography process, while NIL enables fabrication of thinner elements, and allows using a larger variety of optical materials including sol-gel glasses, which possess better surface optical quality. PMID- 27958465 TI - Simulation and experimental verification for imaging of gray-scale objects through scattering layers. AB - We analyze the imaging of gray-scale objects through highly scattering layers. The theoretical investigation with numerical simulations shows that the contrast of the speckle autocorrelations varies regularly with the change of the gray scale of the object. Therefore, gray information is well contained in the autocorrelations of the speckle patterns, and gray-scale objects are able to be exacted from these autocorrelations via speckle correlation technology. Combined with phase retrieval via the generalized approximate message passing algorithm, recovery of the objects is realized and accurate gray-scale reconstruction is demonstrated via numerical simulations. Experiment results further demonstrate the good performance of the scheme in the imaging of gray-scale objects through scattering layers. Particularly, this work will be beneficial for applications of imaging through turbid media in biomedical and biophotonics imaging. PMID- 27958466 TI - Quick acquisition and recognition method for the beacon in deep space optical communications. AB - In deep space optical communications, it is very difficult to acquire the beacon given the long communication distance. Acquisition efficiency is essential for establishing and holding the optical communication link. Here we proposed a quick acquisition and recognition method for the beacon in deep optical communications based on the characteristics of the deep optical link. To identify the beacon from the background light efficiently, we utilized the maximum similarity between the collecting image and the reference image for accurate recognition and acquisition of the beacon in the area of uncertainty. First, the collecting image and the reference image were processed by Fourier-Mellin. Second, image sampling and image matching were applied for the accurate positioning of the beacon. Finally, the field programmable gate array (FPGA)-based system was used to verify and realize this method. The experimental results showed that the acquisition time for the beacon was as fast as 8.1s. Future application of this method in the system design of deep optical communication will be beneficial. PMID- 27958467 TI - Glass thickness and index measurement using optical sampling by cavity tuning. AB - In this paper, we describe a method based on optical sampling by cavity tuning, which is capable of high-accuracy glass thickness and index measurement. By tuning the repetition frequency of the frequency comb, a series of cross correlation patterns can be obtained that correspond to the front and rear surfaces of the specimen and the co-operation mirror. Both the geometrical thickness and the optical thickness of the specimen can be measured via the cross correlation patterns, and consequently, the glass refractive index can be determined at the same time. The comparison with the reference value shows an agreement within 1.3 MUm for the thickness measurement, and within 5*10 4 for the refractive index measurement. PMID- 27958468 TI - Improving the absorption of a plasmonic absorber using a single layer of graphene at telecommunication wavelengths. AB - In this paper, a plasmonic absorber composed of a single layer of graphene over a metal film and separated by a 5 nm thin silica layer has been proposed. The metal film consists of two L-shaped grooves and a ring groove between the silver rods, and surrounding the silver cylindrical ring is a square of silica. The absorption of the proposed structure without the graphene is 0.85, and it is enhanced to 0.98 with a single layer of graphene in the near-infrared region. This absorption enhancement is because of the light and graphene interaction, which is reinforced by the localized surface plasmon resonance in the grooves. Our structure has the ability to control the absorption wavelength by changing the grooves depth and the L-shaped arms length. Also, the effects of the chemical potential and the thicknesses of the graphene and silica layer on the absorption spectrum have been investigated. Furthermore, we have shown that the proposed absorber can be dual band, if so desired, for optoelectronic components. PMID- 27958469 TI - Beam shaping for kilowatt fiber-coupled diode lasers by using one-step beam cutting-rotating of prisms. AB - The beam quality mismatch of laser diode stacks in both axes limits many direct applications for fiber or solid laser pumping and material processing. In this paper, a one-step cutting-rotating beam shaping system has been designed to homogenize the beam quality of two polarization-multiplexing laser diode stacks. Coupling laser diode stacks consisting of eight bars into a standard fiber with a core diameter of 600 MUm and an NA of 0.22 is achieved. The simulative result shows that the system will have an output power over 1056 W. By using the technique, the production of compact and high brightness fiber-coupling diode lasers can be directly used for laser cladding and laser surface hardening processes. PMID- 27958470 TI - Multi-subzone algorithm for absolute phase retrieval in digital fringe projection profilometry. AB - Codewords are important in encoded absolute phase retrieval techniques such as two-frequency, gray-code, and phase-coding. Each sinusoidal fringe is marked by a unique codeword so that an absolute fringe order can be determined by decoding the codeword. However, due to the limited number of unique codewords, sinusoidal fringe patterns do not contain high-frequency fringes without the use of additional patterns. A multi-subzone coding and decoding algorithm is thus proposed to overcome this limitation. Three multi-subzone coding methods based on two-frequency, gray-code, and phase-coding techniques are presented. The coding creates multiple subzones of unique codewords and the decoding enables it to use non-unique codewords to identify absolute fringe order. Specifically, the range of fringe order is estimated by the use of a wrapped phase map and the absolute fringe order is identified by a codeword. Experimental studies demonstrate the advantages of the proposed algorithm over existing coding methods. The proposed algorithm is suitable to measure objects with large step-height surface discontinuities. PMID- 27958471 TI - Interference and differentiation of the neighboring surface microcracks in distributed sensing with PPP-BOTDA. AB - Detection of cracks while at their early stages of evolution is important in health monitoring of civil structures. Review of technical literature reveals that single or sparsely distributed multiple cracks can be detected by Brillouin scattering-based optical fiber sensor systems. In a recent study, a pre-pump pulse Brillouin optical time-domain analysis (PPP-BOTDA) system was employed for detection of a single microcrack. Specific characteristics of the Brillouin gain spectrum, such as Brillouin frequency shift, and Brillouin gain spectrum width, were utilized in order to detect the formation and growth of microcracks with crack opening displacements as small as 25 MUm. In most situations, formations of neighboring microcracks are not detected due to inherent limitations of Brillouin based systems. In the study reported here, the capability of PPP-BOTDA for detection of two neighboring microcracks was investigated in terms of the proximity of the microcracks with respect to each other, i.e., crack spacing distance, crack opening displacement, and the spatial resolution of the PPP BOTDA. The extent of the study pertained both to theoretical as well as experimental investigations. The concept of shape index is introduced in order to establish an analytical method for gauging the influence of the neighboring microcracks in detection and microcrack differentiation capabilities of Brillouin based optical fiber sensor systems. PMID- 27958472 TI - Extended phase-matching properties of periodically poled potassium niobate crystals for mid-infrared polarization-entangled photon-pair generation. AB - We report the extended phase-matching (EPM) properties of two kinds of periodically poled potassium niobate (KNbO3 or KN) crystals (i.e., periodic 180 degrees - and 90 degrees -domain structures) that are highly useful for the generation of polarization-entangled photon pairs in the mid-infrared (IR) spectral region. Under the degenerate Type II spontaneous parametric downconversion process satisfying the EPM condition, an input single photon with a frequency of 2omega generates a pair of synchronized photons with identical frequencies of omega that are orthogonally polarized with respect to each other (i.e., the frequency-coincident, polarization-entangled biphoton states). Our simulation results illustrate that the EPM is achievable in the mid-IR spectral region: at the wavelengths of 3.80 MUm and 4.03 MUm for periodic 90 degrees - and 180 degrees -domain structures, respectively. We will describe in detail the EPM properties of both cases in terms of interaction types and the corresponding nonlinear optic coefficients, phase-matching bandwidths, and domain poling periods. The calculated EPM bandwidths are much broader than 200 nm in the mid-IR for both cases, exhibiting a great potential for nonlinear-optic signal processing in quantum communication systems operating in the mid-IR bands. PMID- 27958473 TI - Near-infrared tunable narrow filter in a periodic multi-nanolayer doped by a superconductor photonic quantum-well. AB - The transfer matrix method is employed to theoretically investigate the near infrared (NIR) narrow filter properties in a one-dimensional defective symmetric photonic crystal with a superconductor photonic quantum-well defect (PQW). The study investigates how the wavelength of the defect mode is affected by the stack number of the PQW defect structure, the thicknesses of PQW layers, the polarization, and the angle of incidence as well as the operating temperature. The results also show that the period of the PQW defect structure and the number of defect modes are independent of one another. This result differs from that of studies conducted on a common dielectric or metamaterial defect. It is noted that with an increase in the number of the defect period, the thickness of the superconductor layer, and the angle of incidence, the defect mode shows a blue shift for both wave polarizations. On the other hand, an opposite trend is observed as the thickness of the air layer and the operating temperature increase. The results also reveal that new tunable narrow filters and optical communication devices can be achieved at NIR region in this proposed structure. PMID- 27958474 TI - Envelope-based technique for liquid level sensors using an in-line fiber Mach Zehnder interferometer. AB - This paper proposes a sensor interrogation technique based on the analysis of the overall spectrum envelope of an in-line Mach-Zehnder interferometer structure with three different fibers. The interference pattern created by a level sensor of 120 mm was evaluated with both the traditional and the proposed interrogation techniques. The result shows that the technique here proposed improves the sensitivity of the sensor by more than an order of magnitude. Moreover, our new interrogation technique allows the length of an in-line Mach-Zehnder interferometer to be extended up to 470 mm while maintaining high linearity and sensitivity. PMID- 27958475 TI - Carrier-envelope offset frequency linewidth narrowing in a Cr:forsterite laser based frequency comb. AB - Cr:forsterite laser-based frequency combs are useful for spectroscopic purposes in the near-IR wavelength region. However, self-referenced Cr:forsterite combs tend to exhibit wide carrier-envelope offset frequency (f0) linewidths, which result in broad comb teeth. This can be attributed to significant frequency noise across the comb's spectral bandwidth. We have stabilized a prism-based Cr:forsterite laser comb and observed narrowing of the f0 linewidth from ~1.4 MHz down to ~100 kHz by changing only the prism insertion, and to 23 kHz by inserting a knife edge into the intracavity beam while keeping the same prism insertion. The noise dynamics of the Cr:forsterite laser frequency comb are investigated with the goal of explaining this f0 narrowing phenomenon. PMID- 27958476 TI - All-solid microstructured fibers with double cross linear arrays. AB - An all-solid microstructured fiber containing a pure silica core and the double cross linear arrays of high refractive index dielectric rods imbedded in the silica serving as the cladding is proposed. The bandgap and confinement loss (CL) are numerically investigated. The fiber has a lowest loss of 3.37 dB/km that can be achieved in the first-order photonic bandgap (PBG) and the bandwidth with transmission loss less than <0.05 dB/m is up to 550 nm. The effects of refractive index difference and geometric structure are discussed on the CL in the first-order PBG. The minimal attenuation can be reduced to 0.14 dB/km by choosing appropriate parameters. The bending property is also presented. PMID- 27958477 TI - Anisotropy of acousto-optic figure of merit for LiNbO3 crystals anisotropic diffraction: erratum. AB - We address the errors found in our recent analysis of anisotropy of the acousto optic figure of merit performed for the case of LiNbO3 crystals [Appl. Opt.55, 2439 (2016)APOPAI0003-693510.1364/AO.55.002439]. PMID- 27958478 TI - Face recognition with non-greedy information-optimal adaptive compressive imaging. AB - Adaptive compressive measurements can offer significant system performance advantages due to online learning over non-adaptive or static compressive measurements for a variety of applications, such as image formation and target identification. However, such adaptive measurements tend to be sub-optimal due to their greedy design. Here, we propose a non-greedy adaptive compressive measurement design framework and analyze its performance for a face recognition task. While a greedy adaptive design aims to optimize the system performance on the next immediate measurement, a non-greedy adaptive design goes beyond that by strategically maximizing the system performance over all future measurements. Our non-greedy adaptive design pursues a joint optimization of measurement design and photon allocation within a rigorous information-theoretic framework. For a face recognition task, simulation studies demonstrate that the proposed non-greedy adaptive design achieves a nearly two to three fold lower probability of misclassification relative to the greedy adaptive and static designs. The simulation results are validated experimentally on a compressive optical imager testbed. PMID- 27958479 TI - Interferometric surface mapping of a spherical proof mass for ultra precise inertial reference sensors. AB - In the context of our investigations on novel inertial reference sensors for space applications, we have explored a design utilizing an optical readout of a spherical proof mass. This concept enables full drag-free operations, hence reducing proof mass residual acceleration noise to a minimum. The main limitations of this sensor are errors in position determination of the center of mass of the proof mass due to the surface topography and the involved path length changes upon rotation. One solution is to apply a surface map for correction of the measurement data, thus improving the precision of position determination. This article presents the results of our one-dimensional interferometric surface topography measurements of a sphere, achieving uncertainties of ~10 nm, as a first step to realize a complete surface map. The measurement setup consists of two heterodyne interferometers positioned in an opposing configuration, which measure the surface topography while the sphere is continuously rotated by a rotation stage. PMID- 27958481 TI - Improved identification of the solution space of aerosol microphysical properties derived from the inversion of profiles of lidar optical data, part 2: simulations with synthetic optical data. AB - We developed a mathematical scheme that allows us to improve retrieval products obtained from the inversion of multiwavelength Raman/HSRL lidar data, commonly dubbed "3 backscatter+2 extinction" (3beta+2alpha) lidar. This scheme works independently of the automated inversion method that is currently being developed in the framework of the Aerosol-Cloud-Ecosystem (ACE) mission and which is successfully applied since 2012 [Atmos. Meas. Tech.7, 3487 (2014)10.5194/amt-7 3487-2014; "Comparison of aerosol optical and microphysical retrievals from HSRL 2 and in-situ measurements during DISCOVER-AQ 2013 (California and Texas)," in International Laser Radar Conference, July 2015, paper PS-C1-14] to data collected with the first airborne multiwavelength 3beta+2alpha high spectral resolution lidar (HSRL) developed at NASA Langley Research Center. The mathematical scheme uses gradient correlation relationships we presented in part 1 of our study [Appl. Opt.55, 9839 (2016)APOPAI0003-693510.1364/AO.55.009839] in which we investigated lidar data products and particle microphysical parameters from one and the same set of optical lidar profiles. For an accurate assessment of regression coefficients that are used in the correlation relationships we specially designed the proximate analysis method that allows us to search for a first-estimate solution space of particle microphysical parameters on the basis of a look-up table. The scheme works for any shape of particle size distribution. Simulation studies demonstrate a significant stabilization of the various solution spaces of the investigated aerosol microphysical data products if we apply this gradient correlation method in our traditional regularization technique. Surface-area concentration can be estimated with an uncertainty that is not worse than the measurement error of the underlying extinction coefficients. The retrieval uncertainty of the effective radius is as large as +/ 0.07 MUm for fine mode particles and approximately 100% for particle size distributions composed of fine (submicron) and coarse (supermicron) mode particles. The volume concentration uncertainty is defined by the sum of the uncertainty of surface-area concentration and the uncertainty of the effective radius. The uncertainty of number concentration is better than 100% for any radius domain between 0.03 and 10 MUm. For monomodal PSDs, the uncertainties of the real and imaginary parts of the CRI can be restricted to +/-0.1 and +/-0.01 on the domains [1.3; 1.8] and [0; 0.1], respectively. PMID- 27958480 TI - Improved identification of the solution space of aerosol microphysical properties derived from the inversion of profiles of lidar optical data, part 1: theory. AB - Multiwavelength Raman/high spectral resolution lidars that measure backscatter coefficients at 355, 532, and 1064 nm and extinction coefficients at 355 and 532 nm can be used for the retrieval of particle microphysical parameters, such as effective and mean radius, number, surface-area and volume concentrations, and complex refractive index, from inversion algorithms. In this study, we carry out a correlation analysis in order to investigate the degree of dependence that may exist between the optical data taken with lidar and the underlying microphysical parameters. We also investigate if the correlation properties identified in our study can be used as a priori or a posteriori constraints for our inversion scheme so that the inversion results can be improved. We made the simplifying assumption of error-free optical data in order to find out what correlations exist in the best case situation. Clearly, for practical applications, erroneous data need to be considered too. On the basis of simulations with synthetic optical data, we find the following results, which hold true for arbitrary particle size distributions, i.e., regardless of the modality or the shape of the size distribution function: surface-area concentrations and extinction coefficients are linearly correlated with a correlation coefficient above 0.99. We also find a correlation coefficient above 0.99 for the extinction coefficient versus (1) the ratio of the volume concentration to effective radius and (2) the product of the number concentration times the sum of the squares of the mean radius and standard deviation of the investigated particle size distributions. Besides that, we find that for particles of any mode fraction of the particle size distribution, the complex refractive index is uniquely defined by extinction and backscatter-related Angstrom exponents, lidar ratios at two wavelengths, and an effective radius. PMID- 27958482 TI - Second-order nonlinearity in ladder-plus-Y configuration in double quantum dot structure. AB - Second-order nonlinear susceptibility (SONS) in a ladder-plus-Y double quantum dot structure was modeled and then studied numerically under the application of an electric field. The density matrix theory was used to formulate the system while the orthogonalized plane waves for wetting layer-quantum dot (WL-QD) were considered to state the momentum matrix elements for this system. It is found that the momenta follow the smallest energy difference between states with an obvious overlap of the mediated states. Since WL-QD momenta are small, neglecting WL gives high SONS. Millimeter waves are predicted, and a huge SONS can be obtained by the application of more optical fields, which is important in medical and biological applications. The possibility of changing light speed between subluminal and superluminal was predicted here. This opens the way for many applications like multichannel waveguide-multichannel quantum information processing, real quality imaging, and temporal clock. PMID- 27958484 TI - Mode-coupling enhancement by pump astigmatism correction in a Ti:Sapphire femtosecond laser. AB - To pump a solid-state femtosecond laser cavity, a beam from a CW laser is focused by a single lens into the laser crystal. To increase the output power of the laser, the overlap of the laser mode with the pump mode should be maximized. This is particularly important in the so-called mode coupling and the Kerr-lens mode locking (KLM) operation, where the change in beam waist at the position of the gain medium is exploited to enhance the mode overlap with the pump laser in the crystal. In this paper, the astigmatism in the pump beam is reduced by tilting the pump lens. A Gaussian beam is propagated through the complete focusing system pump lens, tilted spherical mirror, and crystal cut at Brewster's angle-to show the astigmatism inside the crystal as a function of the tilt of the pump lens. A genetic algorithm is presented to optimize the mode coupling between the pump and laser beam inside the crystal by tilting the pump lens. Experimental results are presented to verify the design, showing an increase in the output power of the laser cavity of about 20%. PMID- 27958483 TI - Optical dosimetry probes to validate Monte Carlo and empirical-method-based NIR dose planning in the brain. AB - A three-dimensional photon dosimetry in tissues is critical in designing optical therapeutic protocols to trigger light-activated drug release. The objective of this study is to investigate the feasibility of a Monte Carlo-based optical therapy planning software by developing dosimetry tools to characterize and cross validate the local photon fluence in brain tissue, as part of a long-term strategy to quantify the effects of photoactivated drug release in brain tumors. An existing GPU-based 3D Monte Carlo (MC) code was modified to simulate near infrared photon transport with differing laser beam profiles within phantoms of skull bone (B), white matter (WM), and gray matter (GM). A novel titanium-based optical dosimetry probe with isotropic acceptance was used to validate the local photon fluence, and an empirical model of photon transport was developed to significantly decrease execution time for clinical application. Comparisons between the MC and the dosimetry probe measurements were on an average 11.27%, 13.25%, and 11.81% along the illumination beam axis, and 9.4%, 12.06%, 8.91% perpendicular to the beam axis for WM, GM, and B phantoms, respectively. For a heterogeneous head phantom, the measured % errors were 17.71% and 18.04% along and perpendicular to beam axis. The empirical algorithm was validated by probe measurements and matched the MC results (R2>0.99), with average % error of 10.1%, 45.2%, and 22.1% relative to probe measurements, and 22.6%, 35.8%, and 21.9% relative to the MC, for WM, GM, and B phantoms, respectively. The simulation time for the empirical model was 6 s versus 8 h for the GPU-based Monte Carlo for a head phantom simulation. These tools provide the capability to develop and optimize treatment plans for optimal release of pharmaceuticals in the treatment of cancer. Future work will test and validate these novel delivery and release mechanisms in vivo. PMID- 27958485 TI - Reconstruction method for fringe projection profilometry based on light beams. AB - A novel reconstruction method for fringe projection profilometry, based on light beams, is proposed and verified by experiments. Commonly used calibration techniques require the parameters of projector calibration or the reference planes placed in many known positions. Obviously, introducing the projector calibration can reduce the accuracy of the reconstruction result, and setting the reference planes to many known positions is a time-consuming process. Therefore, in this paper, a reconstruction method without projector's parameters is proposed and only two reference planes are introduced. A series of light beams determined by the subpixel point-to-point map on the two reference planes combined with their reflected light beams determined by the camera model are used to calculate the 3D coordinates of reconstruction points. Furthermore, the bundle adjustment strategy and the complementary gray-code phase-shifting method are utilized to ensure the accuracy and stability. Qualitative and quantitative comparisons as well as experimental tests demonstrate the performance of our proposed approach, and the measurement accuracy can reach about 0.0454 mm. PMID- 27958486 TI - Publishing, networking, and succeeding as a graduate student: editorial. AB - Editor-in-Chief Ron Driggers provides insight into how to position yourself for a successful career while still in graduate school. PMID- 27958487 TI - Intense femtosecond laser driven collimated fast electron transport in a dielectric medium-role of intensity contrast. AB - Ultra-high intensity (> 1018 W/cm2), femtosecond (~30 fs) laser induced fast electron transport in a transparent dielectric has been studied for two laser systems having three orders of magnitude different peak to pedestal intensity contrast, using ultrafast time-resolved shadowgraphy. Use of a 400 nm femtosecond pulse as a probe enables the exclusive visualization of the dynamics of highest density electrons (> 7 * 1021 cm-3) observed so far. High picosecond contrast (~109) results in greater coupling of peak laser energy to the plasma electrons, enabling long (~1 mm), collimated (divergence angle ~2 degrees ) transport of fast electrons inside the dielectric medium at relativistic speeds (~0.66c). In comparison, the laser system with a contrast of ~106 has a large pre-plasma, limiting the coupling of laser energy to the solid and yielding limited fast electron injection into the dielectric. In the lower contrast case, bulk of the electrons expand as a cloud inside the medium with an order of magnitude lower speed than that of the fast electrons obtained with the high contrast laser. The expansion speed of the plasma towards vacuum is similar for the two contrasts. PMID- 27958488 TI - Non-ideal axicon-generated Bessel beam application for intra-volume glass modification. AB - The extended focal depth of Bessel beams is a very attracting property for glass cutting applications. However, Bessel beam generation with a non-ideal conical lens induces beam pattern distortions. We present our novel results on bulk modifications of soda-lime glass using a non-ideal axicon-generated Bessel beam. Modelling of the Bessel beam pattern and experimental measurements indicated ellipticity of the central core diameter. That resulted in the formation of cracks in a transverse direction inside the bulk of glass. Furthermore, we demonstrate the possibility to control the transverse crack propagation direction, which is crucial in the case of glass cutting applications. PMID- 27958489 TI - Non-moving scanner design for OCT systems. AB - In this work, a novel beam scanner design based on non-moving parts is introduced which will eliminate the phase and inaccuracy problems of the mechanical scanners while providing two times imaging speed improvement for optical coherence tomography systems. The design is comprised of electro-optically activated switches that are placed on the sample arm. For the example considered here, lateral resolution of 20 um, and lateral scanning range of 1 mm are aimed at which resulted in a scanner size of 1 mm * 9 mm. Due to its compact size, proposed design can also be implemented in forward-looking endoscopic probes. PMID- 27958490 TI - Angular light modulator using optical blinds. AB - Spatial light modulator (SLM) is widely used in imaging applications for modulating light intensity and phase delay. In this paper, we report a novel device concept termed angular light modulator (ALM). Different from the SLM, the reported ALM employs a tunable blind structure to modulate the angular components of the incoming light waves. For spatial-domain light modulation, the ALM can be directly placed in front of an image sensor for selecting different angular light components. In this case, we can sweep the slat angle of the blind structure and capture multiple images corresponding to different perspectives. These images can then be back-projected for 3D tomographic refocusing. By using a fixed slat angle, we can also convert the incident-angle information into intensity variations for wavefront sensing or introduce a translational shift to the defocused object for high-speed autofocusing. For Fourier-domain light modulation, the ALM can be placed at the pupil plane of an optical system for reinforcing the light propagating trajectories. We show that a pupil-plane modulated system is able to achieve a better resolution for out-of-focus objects while maintaining the same resolution for in-focus objects. The reported ALM can be fabricated on the chip level and controlled by an external magnetic field. It may provide new insights for developing novel imaging and vision devices. PMID- 27958491 TI - Large field-of-view Fourier transform imaging spectrometer using dual-channel stitching. AB - A dual-channel lateral shearing beam splitter was used in a Fourier transform imaging spectrometer, forming a dual-channel imaging spectrometer, to investigate the usability of this technique for large field-of-view (FOV) spectral detection. The large FOV obtained by stitching together the different channels' individual FOVs greatly improved the spectral detection efficiency for large-area targets. This report describes the principle of the dual-rectangle lateral shearing beam splitter and the analysis of the lateral shearing distance, FOV, modulation, and method of dual-channel stitching. Large-FOV spectral images of a scene were acquired experimentally at visible wavelengths, confirming the effectiveness of this technique. PMID- 27958492 TI - Two-dimensional electronic spectroscopy in the ultraviolet by a birefringent delay line. AB - We introduce a 2D electronic spectroscopy setup in the UV spectral range in the partially collinear pump-probe geometry. The required interferometrically phase locked few-optical-cycle UV pulse pair is generated by combining a passive birefringent interferometer in the visible and nonlinear phase transfer. This is achieved by sum-frequency generation between the phase-locked visible pulse pair and narrowband infrared pulses. We demonstrate a pair of 16-fs, 330-nm pulses whose delay is interferometrically stable with an accuracy better than lambda/450. 2DUV maps of pyrene solution probed in the UV and visible spectral ranges are demonstrated. PMID- 27958493 TI - Automated aberration correction of arbitrary laser modes in high numerical aperture systems. AB - Controlling the point-spread-function in three-dimensional laser lithography is crucial for fabricating structures with highest definition and resolution. In contrast to microscopy, aberrations have to be physically corrected prior to writing, to create well defined doughnut modes, bottlebeams or multi foci modes. We report on a modified Gerchberg-Saxton algorithm for spatial-light-modulator based automated aberration compensation to optimize arbitrary laser-modes in a high numerical aperture system. Using circularly polarized light for the measurement and first-guess initial conditions for amplitude and phase of the pupil function our scalar approach outperforms recent algorithms with vectorial corrections. Besides laser lithography also applications like optical tweezers and microscopy might benefit from the method presented. PMID- 27958494 TI - Error-detected generation and complete analysis of hyperentangled Bell states for photons assisted by quantum-dot spins in double-sided optical microcavities. AB - We construct an error-detected block, assisted by the quantum-dot spins in double sided optical microcavities. With this block, we propose three error-detected schemes for the deterministic generation, the complete analysis, and the complete nondestructive analysis of hyperentangled Bell states in both the polarization and spatial-mode degrees of freedom of two-photon systems. In these schemes, the errors can be detected, which can improve their fidelities largely, far different from other previous schemes assisted by the interaction between the photon and the QD-cavity system. Our scheme for the deterministic generation of hyperentangled two-photon systems can be performed by repeat until success. These features make our schemes more useful in high-capacity quantum communication with hyperentanglement in the future. PMID- 27958495 TI - Instantaneous influence of dust storms on the optical scattering property of the ocean: a case study in the Yellow Sea, China. AB - Asian dust storms originating from arid or semi-arid regions of China or her adjacent regions have important impact on the atmosphere and water composition, and ecological environment of the Eastern China Seas. This research used data collected in the middle of the South Yellow Sea, China, during a dust storm event from 23 April to 24 April 2006 to analyze the instantaneous influence of dust storms on optical scattering properties, which are closely related to particle characteristics. The analysis results showed that the dust storm had a remarkable influence on the optical scattering property in the upper mixed layer of water, and dust particles drily deposited from the dust storm with an aerosol optical depth of nearly 2.5 into the water could induce a 0.14 m-1 change in the water optical scattering coefficient at 532 nm at the depth of 4 m. The duration of the instantaneous influence of the dust storm on the water optical scattering properties was short, and this influence disappeared rapidly within approximately 3 hours after the end of the dust storm. PMID- 27958496 TI - Experimental realization of a 2 * 2 polarization-independent split-ratio-tunable optical beam splitter. AB - We realized a polarization-independent split-ratio-tunable optical beam splitter supporting two input and output ports through a stable interferometer. By adjusting the angle of a half-wave plate in the interferometer, we can tune the beam splitter reflectivities for both input ports from 0 to 1, regardless of the input light polarization. High-fidelity polarization-preserving transmission from input to output ports was verified by complete quantum process tomography. Nearly optimal interference effects at the beam splitter with various split ratios were observed by two-photon Hong-Ou-Mandel interference for different input polarization states. Such a beam splitter could find a variety of applications in classical and quantum optical technologies. PMID- 27958497 TI - Integrated optical vortex beam receivers. AB - A simple and ultra-compact integrated optical vortex beam receiver device is presented. The device is based on the coupling between the optical vortex modes and whispering gallery modes in a micro-ring resonator via embedded angular gratings, which provides the selective reception of optical vortex modes with definitive total angular momentum (summation of spin and orbital angular momentum) through the phase matching condition in the coupling process. Experimental characterization confirms the correct detection of the total angular momentum carried by the vortex beams incident on the device. In addition, photonic spin-controlled unidirectional excitation of whispering-gallery modes in the ring receiver is also observed, and utilized to differentiate between left- and right-circular polarizations and therefore unambiguously identify the orbital angular momentum of incident light. Such characteristics provide an effective mode-selective receiver for the eigen-modes in orbital angular momentum fiber transmission where the circularly polarized OAM modes can be used as data communications channels in multiplexed communications or as photonic states in quantum information applications. PMID- 27958498 TI - Compact, lensless digital holographic microscope for remote microbiology. AB - In situ investigation of microbial life in extreme environments can be carried out with microscopes capable of imaging 3-dimensional volumes and tracking particle motion. Here we present a lensless digital holographic microscope approach that provides roughly 1.5 micron resolution in a compact, robust package suitable for remote deployment. High resolution is achieved by generating high numerical-aperture input beams with radial gradient-index rod lenses. The ability to detect and track prokaryotes was explored using bacterial strains of two different sizes. In the larger strain, a variety of motions were seen, while the smaller strain was used to demonstrate a detection capability down to micron scales. PMID- 27958499 TI - Accurate and fast 3D surface measurement with temporal-spatial binary encoding structured illumination. AB - Balancing the accuracy and speed for 3D surface measurement of object is crucial in many important applications. Binary encoding pattern utilizing the high-speed image switching rate of digital mirror device (DMD)-based projector could be used as the candidate for fast even high-speed 3D measurement, but current most schemes only enable the measurement speed, which limit their application scopes. In this paper, we present a binary encoding method and develop an experimental system aiming to solve such a situation. Our approach encodes one computer generated standard 8 bit sinusoidal fringe pattern into multiple binary patterns (sequence) with designed temporal-spatial binary encoding tactics. The binary pattern sequence is then high-speed and in-focus projected onto the surface of tested object, and then captured by means of temporal-integration imaging to form one sinusoidal fringe image. Further the combination of phase-shifting technique and temporal phase unwrapping algorithm leads to fast and accurate 3D measurement. The systematic accuracy better than 0.08mm is achievable. The measurement results with mask and palm are given to confirm the feasibility. PMID- 27958500 TI - Analytic optical-constant model derived from Tauc-Lorentz and Urbach tail. AB - Tauc-Lorentz model is commonly used to describe the dielectric constant of amorphous semiconductors as a function of few parameters. However, this model is not fully analytic and presents other mathematical shortcomings. A modified self consistent model based on the integration of [E'-(E + ia)]-1 functions using Tauc Lorentz's epsilon2 expression as a weight function is presented. This new model is analytic and meets all other mathematical requirements of optical constants. The main difference with TL model stands at photon energies close to or smaller than the bandgap energy. The new model has been satisfactorily tested on SiC optical constants. Additionally, an analytic extension of the new model has been also developed to include the Urbach tail. The complete model has been tested with Si3N4 optical constants, and it enables to extend the optical-constant characterization of materials down to zero energy. PMID- 27958501 TI - Optical properties of epitaxial CaxBa1 xNb2O6 thin film based rib-waveguide structure on (001) MgO for electro-optic applications. AB - In this work, optical properties of epitaxial CaxBa1 xNb2O6, CBN (x = 0.28) thin film based waveguides are studied at 1550 nm optical communications wavelength. CBN thin films are deposited epitaxially on MgO substrates using Pulsed Laser Deposition and characterized by prism coupling to extract the refractive index and propagation loss. It is shown that the 2 um-thick epitaxial CBN thin films have a refractive index close to the bulk form and the CBN planar waveguides have a propagation loss of 4.3 +/- 0.5 dB/cm. 1 cm-long rib waveguide structures were fabricated using a high density plasma etching. Their propagation losses were measured by the cutback method at 8.4 +/- 0.6 dB/cm. PMID- 27958502 TI - Extraction-controlled terahertz frequency quantum cascade lasers with a diagonal LO-phonon extraction and injection stage. AB - We report an extraction-controlled terahertz (THz)-frequency quantum cascade laser design in which a diagonal LO-phonon scattering process is used to achieve efficient current injection into the upper laser level of each period and simultaneously extract electrons from the adjacent period. The effects of the diagonality of the radiative transition are investigated, and a design with a scaled oscillator strength of 0.45 is shown experimentally to provide the highest temperature performance. A 3.3 THz device processed into a double-metal waveguide configuration operated up to 123 K in pulsed mode, with a threshold current density of 1.3 kA/cm2 at 10 K. The QCL structures are modeled using an extended density matrix approach, and the large threshold current is attributed to parasitic current paths associated with the upper laser levels. The simplicity of this design makes it an ideal platform to investigate the scattering injection process. PMID- 27958503 TI - 4*10 Gbit/s bidirectional transmission over 2 km of conventional graded-index OM1 multimode fiber using mode group division multiplexing. AB - We demonstrate 4 * 10 Gbit/s error-free bidirectional transmission over 2 km of conventional OM1 graded-index multimode fiber using OOK modulation and direct detection. We also perform field transmission to show reach and capacity boosts on legacy multimode infrastructure. Such transmission is enabled by selective mode group division multiplexing, based on multi-plane light conversion over 4 mode groups of the multimode fiber. PMID- 27958504 TI - Full-duty triangular pulse generation based on a polarization-multiplexing dual drive Mach-Zehnder modulator. AB - A simple and flexible photonic approach to generating a triangular microwave waveform using a single integrated polarization-multiplexing dual-drive Mach Zehnder modulator (PM-DMZM) and a polarizer is proposed and demonstrated, which needs no specific large modulation indices or an optical filter. In the proposed method, one sub-Mach-Zehnder modulator (MZM) in the PM-DMZM is driven by a fundamental frequency, which generates an optical signal composed of an optical carrier and a + 1st-order sideband along one polarization direction; and the other sub-MZM is driven by a frequency tripled signal, generating an optical carrier and a -1st-order sideband along the orthogonal polarization direction. By adjusting the polarization direction of the polarizer following the PM-DMZM, which changes the power ratio of the two sidebands, optical intensity with expression corresponding to the Fourier expansion of a triangular-shaped waveform is obtained. Different from the previously reported approaches, neither specific large modulation index nor optical filtering is required, which guarantees a large operational frequency range and improved robustness. A proof-of-concept experiment is carried out. 5-GHz triangular-shaped waveform signals are successfully generated with different modulation indices. PMID- 27958505 TI - Quantized phase coding and connected region labeling for absolute phase retrieval. AB - This paper proposes an absolute phase retrieval method for complex object measurement based on quantized phase-coding and connected region labeling. A specific code sequence is embedded into quantized phase of three coded fringes. Connected regions of different codes are labeled and assigned with 3-digit-codes combining the current period and its neighbors. Wrapped phase, more than 36 periods, can be restored with reference to the code sequence. Experimental results verify the capability of the proposed method to measure multiple isolated objects. PMID- 27958506 TI - Dual low coherence scanning interferometry for rapid large step height and thickness measurements. AB - In this investigation, we propose a dual low coherence scanning interferometer as the novel concept to measure large height steps on the topographic surface of a specimen and the thickness profile of a transparent optical plate. Dual low coherence characteristics by the tandem interferometric configuration can generate several discrete correlograms for the measured surfaces, which provide the possibility to reduce the scanning length of typical low coherence scanning interferometry significantly. Also, the spectrally-resolved interferometric method is combined to monitor the distance gaps between correlograms caused by the dual low coherence. To verify the proposed interferometry, a large height step specimen and a silicon wafer were used and the 3D surface and thickness profiles were rapidly and successfully measured. In addition, the technique which can identify each correlogram by the insertion of dispersive plates are suggested in this paper. PMID- 27958507 TI - Scalable waveguide design for three-level operation in Neodymium doped fiber laser. AB - We have constructed a double clad neodymium doped fiber laser operating on the three-level 4F3/2->4I9/2 transition. The laser has produced 11.5 W at 925 nm with 55% slope efficiency when pumped at 808 nm, comparable to the best previous results for a double-clad fiber configuration on this transition. Higher power pumping with both 808 nm and 880 nm sources resulted in an output of 27 W, albeit at lower slope efficiency. In both cases, output power was limited by available pump, indicating the potential for further power scaling. To suppress the stronger four-level 4F3/2->4I11/2 transition we developed a waveguide that provides spectral filtering distributed along the length of the fiber, based on an all-solid micro-structured optical fiber design, with resonant inclusions creating a leakage path to the cladding. The waveguide supports large mode areas and provides strong suppression at selectable wavelength bands, thus easing the restrictions on core and cladding sizes that limited power scaling of previous approaches. PMID- 27958508 TI - Raman enhanced polarization-insensitive wavelength conversion based on two-pump four-wave mixing. AB - Backward Raman amplification is applied to improve the conversion efficiency of two-orthogonal-pump four-wave mixing (FWM) with polarization insensitivity. Wavelength conversion with ~0dB efficiency and negligible polarization dependency is demonstrated by using a common highly nonlinear fiber without pump dithering. The conversion efficiency is increased by ~29dB with Raman enhancement. We also discuss the impact of the Raman pump power and the FWM pump powers on the performance of wavelength conversion. The results indicate that moderate pump powers without inducing significant spontaneous noise and stimulated Brillouin scattering are favorable to ensure high conversion efficiency and low excess noise for performance optimization. PMID- 27958509 TI - Diffraction-free pulsed optical beams via space-time correlations. AB - Diffraction places a fundamental limitation on the distance an optical beam propagates before its size increases and spatial details blur. We show here that imposing a judicious correlation between spatial and spectral degrees of freedom of a pulsed beam can render its transverse spatial profile independent of location along the propagation axis, thereby arresting the spread of the time averaged beam. Such correlation introduced into a beam with arbitrary spatial profile enables spatio-temporal dispersion to compensate for purely spatial dispersion that underlies diffraction. As a result, the spatio-temporal profile in the local time-frame of the pulsed beam remains invariant at all positions along the propagation axis. One-dimensional diffraction-free space-time beams are described - including non-accelerating Airy beams, despite the well-known fact that cosine waves and accelerating Airy beams are the only one-dimensional diffraction-free solutions to the monochromatic Helmholtz equation. PMID- 27958510 TI - Longitudinal iso-phase condition and needle pulses. AB - We study the properties of pulsed solutions to the scalar and vector wave equations composed of plane-waves with equal longitudinal spatial frequency. This condition guarantees that, at all times, the field profile is invariant in the longitudinal direction. Particular emphasis is placed on solutions with rotational symmetry. For these solutions, the wave concentrates strongly near the axis at a given time. We provide closed-form expressions for some of these fields, and show that their wavefronts are approximately spherical. Solutions carrying orbital and spin angular momenta are also considered. PMID- 27958511 TI - Digital holography based submicron thermometry. AB - Here we introduce a phase-shifting digital holography-based method to determine the temperature profile around an irradiated (sub-)micron spherical bead. The method utilizes a Mach-Zehnder interferometer implemented into an open setup microscope. The results of irradiated gold spheres with diameter of 400 nm and also silver-coated micron-sized silica beads embedded in silicone oil are presented. We show that the applied method is able to accurately determine the surface temperature with accuracy of 1 degrees C. Our experimental results perfectly confirm the theoretical prediction of temperature profile around the irradiated bead. PMID- 27958512 TI - Efficient complementary metamaterial element for waveguide-fed metasurface antennas. AB - We present a metamaterial element designed as an efficient radiator for waveguide fed metasurface antennas. The metamaterial element is an electrically-small, complimentary electric-LC (cELC) resonator designed to exhibit large radiated power while maintaining low ohmic losses. The shape of the element is tapered to simultaneously achieve broadband operation and suppression of cross polarization radiation. Full-wave numerical studies at the K-band are conducted to examine its performance when etched into a microstrip line. In this configuration, the element shows a radiation efficiency of 90.2% and a fractional bandwidth of 8.7%. To investigate the potential benefits of the proposed element in two-dimensional platforms, the radiative characteristics of the element are calculated when the element is embedded in a dielectric-filled parallel-plate waveguide. This efficient metamaterial element has potential application as a building block for metasurface devices used in imaging, sensing, wireless power transfer, and wireless communication systems. PMID- 27958513 TI - Compact spoof surface plasmon polaritons waveguide drilled with L-shaped grooves. AB - It has been recently demonstrated that a metallic surface with periodic grooves can support a laterally-confined surface wave called spoof plasmon polaritons (SSPPs). Here we propose a SSPPs waveguide drilled with L-shaped grooves which can support SSPPs efficiently. Dispersion relations based on the modal expansion method (MEM) are derived and discussed. Under the deep subwavelength condition, a concise formula for the dispersion relations is obtained. Our results show that the dispersion relations are sensitive to the transversal depths. The L-shaped groove is equivalent to a deeper rectangular groove, but more compact than the straight one. As an example of the applications, the rainbow-trapping effect is realized by changing the transversal depths of the L-shaped grooves. PMID- 27958514 TI - Low loss Type II regenerative Bragg gratings made with ultrafast radiation. AB - A novel type of fiber Bragg grating is produced by annealing a type I-like grating that is written with multiple infrared femtosecond laser pulses through a phase mask under conditions that are typically used to fabricate thermally stable type II gratings. This new grating is created through a process similar to a regenerative one and displays low loss and high resilience in a 1000 degrees C ambient environment. Such gratings are ideally suited for quasi-distributed sensing at high temperatures. PMID- 27958515 TI - Phase calibration unwrapping algorithm for phase data corrupted by strong decorrelation speckle noise. AB - Robust phase unwrapping in the presence of high noise remains an open issue. Especially, when both noise and fringe densities are high, pre-filtering may lead to phase dislocations and smoothing that complicate even more unwrapping. In this paper an approach to deal with high noise and to unwrap successfully phase data is proposed. Taking into account influence of noise in wrapped data, a calibration method of the 1st order spatial phase derivative is proposed and an iterative approach is presented. We demonstrate that the proposed method is able to process holographic phase data corrupted by non-Gaussian speckle decorrelation noise. The algorithm is validated by realistic numerical simulations in which the fringe density and noise standard deviation is progressively increased. Comparison with other established algorithms shows that the proposed algorithm exhibits better accuracy and shorter computation time, whereas others may fail to unwrap. The proposed algorithm is applied to phase data from digital holographic metrology and the unwrapped results demonstrate its practical effectiveness. The realistic simulations and experiments demonstrate that the proposed unwrapping algorithm is robust and fast in the presence of strong speckle decorrelation noise. PMID- 27958516 TI - High quality entanglement on a chip-based frequency comb. AB - We report an efficient energy-time entangled photon-pair source based on four wave mixing in a CMOS-compatible silicon photonics ring resonator. Thanks to suitable optimization, the source shows a large spectral brightness of 400 pairs of entangled photons /s/MHz for 500 MUW pump power, compatible with standard telecom dense wavelength division multiplexers. We demonstrate high-purity energy time entanglement, i.e., free of photonic noise, with near perfect raw visibilities (> 98%) between various channel pairs in the telecom C-band. Such a compact source stands as a path towards more complex quantum photonic circuits dedicated to quantum communication systems. PMID- 27958517 TI - All-optically controllable nanoparticle random laser in a well-aligned laser-dye doped liquid crystal. AB - This study reports for the first time an all-optically controllable nanoparticle random laser (NPRL) in a well-aligned laser-dye-doped liquid crystal (LDDLC) cell added with NPs and azo-dyes. Experimental results display that the NPRL can be obtained when the pumped energy exceeds the energy threshold (~3.5 MUJ/pulse). The occurrence of the NPRL is attributable to the enhancement of the fluorescence by the multi-scattering events of the fluorescence photons from the randomly distributed NPs in the diffusion rout of the well-aligned LDDLC cell. In addition, the lasing intensity of the NPRL can decrease with increasing irradiation time of one UV beam. Continuing irradiation of one green beam following the UV illumination can increasingly recover the lasing intensity of the NPRL. The all-optically reversible controllability of the NPRL is basically attributed to the successive UV-beam-induced increase and green-beam-induced decrease in the randomness of the LDDLC via their interactions with the curved cis and rod-like trans isomers after the accumulation of the trans->cis and cis >trans back isomerizations of the azo-dyes, respectively. The former and latter mechanisms can decrease and increase the laser-dye's absorption and thus the induced spontaneous emission, respectively. These consequences can decrease and increase the lasing intensity, or equivalently, increase and decrease the energy threshold for the occurrence of the NPRL, respectively. PMID- 27958518 TI - >MW peak power at 266 nm, low jitter kHz repetition rate from intense pumped microlaser. AB - Intense pulse pumped microlaser is proposed for high peak power and low timing jitter at high repetition rate. It is based on Intense and Fast Pulse Pump (IFPP) technique, in which fast pulse pumps up the upper-level population and then dumps it rapidly by Q-switching. That could come close to complete pumping efficiency to reduce thermal problems and contribute to suppress the timing jitter of passively Q-switched laser. In this work, linearly polarized 1064 nm beam from [100]-cut YAG/Nd3+:YAG and [110]-cut Cr4+:YAG passively Q-switched microlaser is directly guided into nonlinear crystals to obtain 532 nm and 266 nm output. By implementing IFPP concept, over 1 MW peak power, 215 ps pulse duration, 1 kHz pulses at 266 nm with reduced standard deviation timing jitter of 37 ns were obtained. PMID- 27958519 TI - Monolithic all-fiber repetition-rate tunable gain-switched single-frequency Yb doped fiber laser. AB - We report a monolithic gain-switched single-frequency Yb-doped fiber laser with widely tunable repetition rate. The single-frequency laser operation is realized by using an Yb-doped distributed Bragg reflection (DBR) fiber cavity, which is pumped by a commercial-available laser diode (LD) at 974 nm. The LD is electronically modulated by the driving current and the diode output contains both continuous wave (CW) and pulsed components. The CW component is set just below the threshold of the single-frequency fiber laser for reducing the requirement of the pump pulse energy. Above the threshold, the gain-switched oscillation is trigged by the pulsed component of the diode. Single-frequency pulsed laser output is achieved at 1.063 MUm with a pulse duration of ~150 ns and a linewidth of 14 MHz. The repetition rate of the laser output can be tuned between 10 kHz and 400 kHz by tuning the electronic trigger signal. This kind of lasers shows potential for the applications in the area of coherent LIDAR etc. PMID- 27958520 TI - Ultrafast all-fibre laser mode-locked by polymer-free carbon nanotube film. AB - This work for the first time reports the results on study of a polymer-free carbon nanotube (CNT) films used as a saturable absorber in an all-fibre laser. It is demonstrated that free-standing single-walled CNT films fabricated by an aerosol method are able to ensure generation of transform-limited pulses in an Er all-fibre ring laser with duration of several picoseconds and high quality of mode locking. The optimal average output power levels are identified, amounting to 0.4-0.5 mW depending on the linear transmission of the studied samples (60% or 80%). Application of polymer-free CNT films solves problems related to degradation of conventional polymer matrices of CNT-based saturable absorbers and paves the way to longer-lasting and more reliable saturable absorbers compatible with all-fibre laser configurations. PMID- 27958521 TI - Phase correlation between four-wave mixing and optical fields in double Lambda type atomic system. AB - We study the spectral features and phase of four-wave mixing (FWM) light according to the relative phase-noise of the optical fields coupled to a double Lambda-type atomic system of the 5S1/2-5P1/2 transition of 87Rb atoms. We observe that the spectral shape of the FWM spectrum is identical to that of the two-photon absorption (TPA) spectrum due to two-photon coherence and that it is independent of the relative phase-noise of the pump light. From these results, we clarify that the two-photon coherence plays a very important role in the FWM process. Furthermore, we measure the relative linewidth of the FWM signal to the probe and pump lasers by means of a beat interferometer. We confirmed that the phase of the FWM signal is strongly correlated with that of the pump laser under the condition of phase-locked probe and coupling lasers for two-photon coherence. PMID- 27958522 TI - Spatial solitons with complicated structure in nonlocal nonlinear media. AB - In nonlocal nonlinear media with a sine-oscillation response function, two kinds of spatial solitons with complicated structure, in-phase and out-of-phase bound state solitons, are obtained numerically in the case of the weak nonlocality. The in-phase bound-state soliton exhibits the symmetrical profile and the nonzero central value, and the out-of-phase bound-state soliton has the antisymmetrical profile and the zero central value. The two kinds of bound-state solitons form the degenerate modes subject to the same dependance of soliton power on the propagation constant. For those solitons there exist two abnormal properties: both the soliton propagation constants and the slope of the power versus propagation constants are negative. Both the in-phase and the out-of-phase bound state solitons are stable by the linear stability analysis, and the stability of the two kinds of solitons obey an inverted Vakhitov-Kolokolov stability criterion. We also discuss the way how to obtain a set of the soliton solutions from one numerical soliton solution via the transform invariance of the nonlocal nonlinear Schrodinger equation and the nonlinear Schrodinger equation. PMID- 27958523 TI - Dynamics of mode-coupling-induced microresonator frequency combs in normal dispersion. AB - We experimentally and theoretically investigate the dynamics of microresonator based frequency comb generation assisted by mode coupling in the normal group velocity dispersion (GVD) regime. We show that mode coupling can initiate intracavity modulation instability (MI) by directly perturbing the pump-resonance mode. We also observe the formation of a low-noise comb as the pump frequency is tuned further into resonance from the MI point. We determine the phase-matching conditions that accurately predict all the essential features of the MI and comb spectra, and extend the existing analogy between mode coupling and high-order dispersion to the normal GVD regime. We discuss the applicability of our analysis to the possibility of broadband comb generation in the normal GVD regime. PMID- 27958524 TI - Electro-optic chaotic system based on the reverse-time chaos theory and a nonlinear hybrid feedback loop. AB - A novel electro-optic chaos source is proposed on the basis of the reverse-time chaos theory and an analog-digital hybrid feedback loop. The analog output of the system can be determined by the numeric states of shift registers, which makes the system robust and easy to control. The dynamical properties as well as the complexity dependence on the feedback parameters are investigated in detail. The correlation characteristics of the system are also studied. Two improving strategies which were established in digital field and analog field are proposed to conceal the time-delay signature. The proposed scheme has the potential to be used in radar and optical secure communication systems. PMID- 27958525 TI - Mie resonance-enhanced pumping and detection efficiency for shallow nitrogen vacancy centers in diamond. AB - We investigate Mie resonances of a diamond nano-resonator as a means to enhance the pumping and detection efficiency of shallow nitrogen-vacancy color centers. We show it is possible to tune a couple of high-order modes of a single resonator to each absorption and emission spectrum of the color center, and thereby the resonator plays a dual role of pump field concentration and emission field guiding. Furthermore superposition of the resonator field and the uncoupled near field results in even stronger pump intensity in the shallow top layer of the resonator. We also examine possible coupling between adjacent resonators when they form a periodic array. This approach allows us to achieve lower excitation power and higher signal intensity at local sites defined by resonators providing a way to enhance wide-field metrology in the sampled region of shallow color centers. PMID- 27958526 TI - Coincidence detection of spatially correlated photon pairs with a monolithic time resolving detector array. AB - We demonstrate coincidence measurements of spatially entangled photons by means of a multi-pixel based detection array. The sensor, originally developed for positron emission tomography applications, is a fully digital 8*16 silicon photomultiplier array allowing not only photon counting but also per-pixel time stamping of the arrived photons with an effective resolution of 265 ps. Together with a frame rate of 500 kfps, this property exceeds the capabilities of conventional charge-coupled device cameras which have become of growing interest for the detection of transversely correlated photon pairs. The sensor is used to measure a second-order correlation function for various non-collinear configurations of entangled photons generated by spontaneous parametric down conversion. The experimental results are compared to theory. PMID- 27958527 TI - Model-blind characterization of thin-film optical constants with momentum resolved reflectometry. AB - Determining optical constants of thin material films is important for characterizing their electronic excitations and for the design of optoelectronic devices. Spectroscopic ellipsometry techniques have emerged as the predominant approach for measuring thin-film optical constants. However, ellipsometry methods suffer from complications associated with highly model-dependent, multi-parameter spectral fitting procedures. Here, we present a model-blind, momentum-resolved reflectometry technique that yields accurate and precise optical constants, with quantifiable error estimates, even for film thicknesses less than 50 nm. These capabilities are demonstrated by interrogating an optical absorption resonance in films of the polymer P(NDI2OD-T2). We show that this approach produces exceptional agreement with UV-Vis-NIR absorption measurements, while simultaneously avoiding the need to construct complicated multi-oscillator spectral models. Finally, we use this procedure to resolve subtle differences in the out-of-plane optical properties of different film morphologies that were previously obscured in ellipsometry measurements. PMID- 27958528 TI - Few-cycle pulse laser induced damage threshold determination of ultra-broadband optics. AB - A systematic study of few-cycle pulse laser induced damage threshold (LIDT) determination was performed for commercially-available ultra-broadband optics, (i.e. chirped mirrors, silver mirrors, beamsplitters, etc.) in vacuum and in air, for single and multi-pulse regime (S-on-1). Multi-pulse damage morphology at fluences below the single-pulse LIDT was studied in order to investigate the mechanisms leading to the onset of damage. Stark morphological contrast was observed between multi-pulse damage sites formed in air versus those in vacuum. One effect of vacuum testing compared to air included suppression of laser induced periodic surface structures (LIPSS) formation, possibly influenced by a reduced presence of damage debris. Another effect of vacuum was occasional lowering of LIDT, which appears to be due to the stress-strain performance of the coating design during laser irradiation and under the external stress of vacuum ambience. A fused silica substrate is also examined, and a non-LIPSS nanostructuring is observed on the surface. Possible mechanisms are discussed. PMID- 27958530 TI - Quantitative measurement of thermal lensing in diode-side-pumped Nd:YAG laser by use of digital holographic interferometry. AB - Thermal lensing in diode-side-pumped Nd:YAG laser has been measured quantitatively using digital holographic interferometry. A series of holograms, carrying the information of the laser rod under different pump currents, are recorded with a CCD and reconstructed numerically. The optical path difference induced by the thermal lensing and the corresponding evolution process under different currents are obtained accordingly. Further, the thermal lensing diopters, induced aberrations, and its Zernike coefficients are calculated. The proposed method can be applied in the thermal lensing measurement and the optimization design of a laser resonator. PMID- 27958529 TI - High-throughput time-stretch imaging flow cytometry for multi-class classification of phytoplankton. AB - Time-stretch imaging has been regarded as an attractive technique for high throughput imaging flow cytometry primarily owing to its real-time, continuous ultrafast operation. Nevertheless, two key challenges remain: (1) sufficiently high time-stretch image resolution and contrast is needed for visualizing sub cellular complexity of single cells, and (2) the ability to unravel the heterogeneity and complexity of the highly diverse population of cells - a central problem of single-cell analysis in life sciences - is required. We here demonstrate an optofluidic time-stretch imaging flow cytometer that enables these two features, in the context of high-throughput multi-class (up to 14 classes) phytoplantkton screening and classification. Based on the comprehensive feature extraction and selection procedures, we show that the intracellular texture/morphology, which is revealed by high-resolution time-stretch imaging, plays a critical role of improving the accuracy of phytoplankton classification, as high as 94.7%, based on multi-class support vector machine (SVM). We also demonstrate that high-resolution time-stretch images, which allows exploitation of various feature domains, e.g. Fourier space, enables further sub-population identification - paving the way toward deeper learning and classification based on large-scale single-cell images. Not only applicable to biomedical diagnostic, this work is anticipated to find immediate applications in marine and biofuel research. PMID- 27958531 TI - Demonstration of a compact bilayer inverse taper coupler for Si-photonics with enhanced polarization insensitivity. AB - We demonstrate a compact (30 MUm long) broadband bilayer inverse taper edge coupler for silicon photonics with a 1.7 dB coupling loss from a commercially available focused fiber with 5 MUm mode diameter. We compare the performance of our bilayer taper with a conventional SOI inverse taper coupler and show that our bilayer coupler achieves between 1.5 dB to 2 dB improvement in the coupling efficiencies for both the TE and TM polarizations. The dimensions and fabrication steps for our bilayer taper are simple and compatible with standard foundry processes. PMID- 27958532 TI - Dispersion relations and bending losses of cylindrical and spherical shells, slabs, and slot waveguides. AB - We derive formulas for whispering gallery mode resonances and bending losses in infinite cylindrical dielectric shells and sets of concentric cylindrical shells. The formulas also apply to spherical shells and to sections of bent waveguides. The derivation is based on a Wentzel-Kramers-Brillouin (WKB) treatment of Helmholtz equation and can in principle be extended to any number of concentric shells. A distinctive limit analytically arises in the analysis when two shells are brought at very close distance to one another. In that limit, the two shells act as a slot waveguide. If the two shells are sufficiently apart, we identify a structural resonance between the individual shells, which can either lead to a substantial enhancement or suppression of radiation losses. PMID- 27958533 TI - Extraordinary optical transmission inside a waveguide: spatial mode dependence. AB - We study the influence of the input spatial mode on the extraordinary optical transmission (EOT) effect. By placing a metal screen with a 1D array of subwavelength holes inside a terahertz (THz) parallel-plate waveguide (PPWG), we can directly compare the transmission spectra with different input waveguide modes. We observe that the transmitted spectrum depends strongly on the input mode. A conventional description of EOT based on the excitation of surface plasmons is not predictive in all cases. Instead, we utilize a formalism based on impedance matching, which accurately predicts the spectral resonances for both TEM and non-TEM input modes. PMID- 27958534 TI - Wavelength-spacing controllable, dual-wavelength synchronously mode locked Er:fiber laser oscillator based on dual-branch nonlinear polarization rotation technique. AB - A wavelength-spacing controllable, dual-wavelength synchronously mode locked Er:fiber laser oscillator based on dual-branch nonlinear polarization rotation (NPR) technique was presented. The center wavelengths were at 1542 nm and 1561 nm, which had pulse durations of 1.38 ps and 1.70 ps, respectively. Experimentally, the synchronous mode locking was achieved by precisely adjusting the cavity length of one branch. A tolerance in the cavity length mismatch of 0.46 mm for synchronous mode locking was demonstrated. The frequency difference of the two pulse trains was measured to be less than 1 mHz. Additionally, this synchronously mode locked dual-wavelength laser had a wavelength tunable range of about 5.6 nm, and a controllable wavelength spacing from 10.5 nm to 28.2 nm, corresponding to a tunable frequency difference from 1.32 THz to 3.26 THz. To the best of our knowledge, this is the first demonstration of synchronously mode locked dual-wavelength output directly from a Er:fiber laser oscillator, using dual-branch NPR technique. PMID- 27958535 TI - Simple and robust phase-locking of optical cavities with > 200 KHz servo bandwidth using a piezo-actuated mirror mounted in soft materials. AB - We present an approach to locking of optical cavities with piezoelectric actuated mirrors based on a simple and effective mechanical decoupling of the mirror and actuator from the surrounding mount. Using simple elastic materials (e.g. rubber or soft silicone gel pads) as mechanical dampers between the piezo-mirror compound and the surrounding mount, a firm and stable mounting of a relatively large mirror (8mm diameter) can be maintained that is isolated from external mechanical resonances, and is limited only by the internal piezo-mirror resonance of > 330 KHz. Our piezo lock showed positive servo gain up to 208 KHz, and a temporal response to a step interference within < 3 MUs. PMID- 27958536 TI - Phosphorescent ion-paired iridium(III) complex for ratiometric and time-resolved luminescence imaging of intracellular biothiols. AB - A novel phosphorescent probe based on ion-paired iridium(III) complex has been designed and synthesized by incorporating alpha,beta-unsaturated ketone moiety in the cationic component. The phosphorescent intensity of cationic component is sensitive to bithiols, such as cysteine and homocysteine, based on the addition reaction of bithiols with alpha,beta-unsaturated ketone moiety, while that of the anionic component remains unchanged. Thus, this ion-paired iridium(III) complex can be used for ratiometric luminescence sensing and imaging of intracellular biothiols with excellent sensing performance. Moreover, the long phosphorescence lifetime of the cationic component is also sensitive to bithiols. Hence, this ion paired iridium(III) complex has been further used for time-resolved luminescence imaging of intracellular biothiols. As far as we know, this is the first report about molecular probe for both ratiometric and time-resolved luminescence imaging of intracellular biothiols. PMID- 27958537 TI - Joint timing/frequency offset estimation and correction based on FrFT encoded training symbols for PDM CO-OFDM systems. AB - A joint timing offset (TO) and frequency offset (FO) estimation algorithm is proposed for polarization division multiplexing (PDM) coherent optical orthogonal frequency-division multiplexing (CO-OFDM) systems. It is realized by taking the advantage of the time-frequency property of the fractional Fourier transformation (FrFT) encoded training symbols. Compared with the classical Schmidl & Cox method, the proposed algorithm exhibits robust estimation result of timing offset with poor optical signal-to-noise ratio (OSNR) and nonlinear interference. For the frequency offset estimation, a quite large FO estimation ranges of [-5GHz + 5GHz] can be achieved. The mean normalized estimation error can be kept under 0.002 and the max normalized estimation error is no more than 0.008. The feasibility and effectiveness of the proposed joint estimation algorithm has been verified by experiments. The transmission performances with [-5GHz + 5GHz] FO are compared under the OSNR range from 14 to 27dB in a 106.8Gbit/s 16-ary quadrature amplitude modulation (16-QAM) PDM CO-OFDM transmission system. The proposed TO/FO estimation algorithm performs robustly and accurately without any induced BER degradations. PMID- 27958538 TI - Perfect vortex in three-dimensional multifocal array. AB - We proposed an approach for creating three-dimensional (3D) multifocal perfect vortices arrays by using a high numerical aperture objective. The position, orbital angular momentum states, number and diameter of the perfect vortices can be freely modulated by a special designed hybrid phase plate (HPP). HPP could be calculated by 3D phase shifting expression which is derived from Fourier transform theory of the Debye diffraction integral. Furthermore, we developed a novel pixel checkerboard method for adding phase information into the HPP. The segmentation of HPP is related to vortex quality and intensity uniformity. This method could fully use each pixel to modulate the light, since the spatial light modulator has to be used. Small size lattices could generate high quality and uniform intensity vortex arrays in tight focusing region, which may have potential applications in coupling, optical coding and decoding. PMID- 27958539 TI - Ultra-strong polarization dependence of surface lattice resonances with out-of plane plasmon oscillations. AB - The interplay between localized surface plasmon (LSP) resonances and their collective responses, known as surface lattice resonances (SLRs), in metal nanoparticle arrays can lead to resonances with high Q-factors (~100). These responses have in the past usually been studied for LSP resonances in the plane of the array of the nanoparticles (assumed to be nonmagnetic), thus restricting efficient coupling to particles separated along a specific direction. In the present study, we demonstrate that LSPs oscillating perpendicular to the plane of the surface can lead to stronger inter-particle coupling, which enhances the SLRs. This stronger coupling occurs because the out-of-plane oscillations can couple in all directions within the plane of the array. We study the resulting SLRs for square and hexagonal lattices using the discrete-dipole approximation, and we predict much larger Q-factors in the wavelength range near 650 nm. This prediction suggests that SLRs could be very useful in enhancing various optical processes, and in many applications such as sensing and nonlinear optical wave mixing. PMID- 27958540 TI - Reduced graphene oxide for fiber-optic toluene gas sensing. AB - A fiber-optic toluene gas sensor based on reduced graphene oxide (rGO) is demonstrated and its sensing property is investigated experimentally and theoretically. The rGO film is deposited on a side polished fiber (SPF), allowing the strong interaction between rGO film and propagating field and making the SPF sensitive to toluene gas. It is found that the sensor has good linearity and reversibility and can work at room temperature with the response and the recovery time of 256 s and the detection limit of 79 ppm. Moreover, a theoretical model for the sensor is established to analyze the sensing mechanism. Theoretical analysis indicates this type of sensor could work in a wide range of toluene gas concentration and shows that a significant rise in its sensitivity can be expected by adjusting the doping level or chemical potential of graphene. PMID- 27958541 TI - High-throughput imaging surface plasmon resonance biosensing based on an adaptive spectral-dip tracking scheme. AB - Imaging-based spectral surface plasmon resonance (lambdaSPR) biosensing is predominantly limited by data throughput because of the multiplied data capacity emerging from 2-dimensional sensor array sites and the many data points required to produce an accurate measurement of the absorption dip. Here we present an adaptive feedback approach to address the data throughput issue in lambdaSPR biosensing. A feedback loop constantly tracks the dip location while target molecule binding occurs at the sensor surface. An adaptive window is then imposed to reduce the number of data points that each pixel has to capture without compromising measurement accuracy. Rapid wavelength scanning is performed with a liquid crystal tunable filter (LCTF). With the use of a feedback loop, our demonstration system can produce a dip measurement within 700ms, thus confirming that the reported lambdaSPR approach is most suitable for real-time micro-array label-free biosensing applications. PMID- 27958542 TI - Snapshot depth sensitive Raman spectroscopy in layered tissues. AB - Depth sensitive Raman spectroscopy has been shown effective in the detection of depth dependent Raman spectra in layered tissues. However, the current techniques for depth sensitive Raman measurements based on fiber-optic probes suffer from poor depth resolution and significant variation in probe-sample contact. In contrast, those lens based techniques either require the change in objective sample distance or suffer from slow spectral acquisition. We report a snapshot depth-sensitive Raman technique based on an axicon lens and a ring-to-line fiber assembly to simultaneously acquire Raman signals emitted from five different depths in the non-contact manner without moving any component. A numerical tool was developed to simulate ray tracing and optimize the snapshot depth sensitive setup to achieve the tradeoff between signal collection efficiency and depth resolution for Raman measurements in the skin. Moreover, the snapshot system was demonstrated to be able to acquire depth sensitive Raman spectra from not only transparent and turbid skin phantoms but also from ex vivo pork tissues and in vivo human thumbnails when the excitation laser power was limited to the maximum permissible exposure for human skin. The results suggest the great potential of snapshot depth sensitive Raman spectroscopy in the characterization of the skin and other layered tissues in the clinical setting or other similar applications such as quality monitoring of tablets and capsules in pharmaceutical industry requiring the rapid measurement of depth dependent Raman spectra. PMID- 27958543 TI - Full-wave simulation of optical waveguides via truncation in the method of moments using PML absorbing boundary conditions. AB - Full-wave simulations of optical waveguides are often intractable due to their large electrical size. Naively focussing on a smaller part of the waveguide, e.g. to study coupling, offers no solution given the non-negligible interaction with the remaining parts of the structure. Thereto, in this paper, the coordinate stretching formulation of a perfectly matched layer is integrated into a method of moments based boundary integral equation solver in order to damp the interaction between multiple parts, allowing to focus on the part of interest. The new technique is validated using the classical example of scattering by a wedge. By truncation of the simulation domain to merely ten wavelengths from the tip, the advocated method is found to be both efficient and accurate compared to a traditional, analytical solution technique. Next, the method is applied to model a silicon polarization beam splitter excited by a Gaussian beam. PMID- 27958544 TI - Electric field enhancement with plasmonic colloidal nanoantennas excited by a silicon nitride waveguide. AB - We investigate the feasibility of CMOS-compatible optical structures to develop novel integrated spectroscopy systems. We show that local field enhancement is achievable utilizing dimers of plasmonic nanospheres that can be assembled from colloidal solutions on top of a CMOS-compatible optical waveguide. The resonant dimer nanoantennas are excited by modes guided in the integrated silicon nitride waveguide. Simulations show that 100-fold electric field enhancement builds up in the dimer gap as compared to the waveguide evanescent field amplitude at the same location. We investigate how the field enhancement depends on dimer location, orientation, distance and excited waveguide mode. PMID- 27958545 TI - Tapered fiber based Brillouin random fiber laser and its application for linewidth measurement. AB - A one-end pumping Brillouin random fiber laser (BRFL) based on a 5-km tapered fiber (TF) is demonstrated. The enhanced Rayleigh scattering and the increased power density from tapering in the TF provide good directionality and a high degree of coherent feedback. Both the transmitting and TF enhanced Rayleigh scattered pump lights formed effective bi-direction pumping for the Brillouin gain in the standing cavity configuration in the distributed way as the gain and random feedback in the same fiber. The linewidth of the laser shows ~1.17 kHz while the relative intensity noise (RIN) has been verified to be suppressed comparing with that of the two-end pumping of the standard single mode fiber (SMF). Furthermore, utilizing the proposed laser, a high-resolution (~kHz) linewidth measurement method is demonstrated without long delay fiber (>100km) and extra frequency shifter thanks to the acoustic frequency shift from fiber itself. PMID- 27958546 TI - Recollision dynamics in nonsequential double ionization of atoms by long wavelength pulses. AB - Recollision dynamics and electron correlation behavior are investigated for several long laser wavelengths (1200-3000 nm) in nonsequential double ionization (NSDI) of helium using three-dimensional classical ensembles. Numerical results show that for these long wavelengths NSDI events are mainly from the multiple return trajectory which is different from the case of 800 nm. Moreover, with increasing laser wavelength NSDI events move from the diagonal to the two axes in the correlated electron momentum distributions, and finally form an experimentally observed prominent V-shaped structure [Phys. Rev. X 5, 021034 (2015)] in the first and third quadrants. Back analysis indicates that the asymmetric energy sharing between the two electrons at recollision is responsible for the formation of the prominent V-shaped structure of 3000 nm. PMID- 27958547 TI - Space-division-multiplexed transmission of 3x3 multiple-input multiple-output wireless signals over conventional graded-index multimode fiber. AB - In this paper, we experimentally demonstrate space-division-multiplexed (SDM) transmission of IEEE 802.11ac-compliant 3-spatial-stream WLAN signals over 3 spatial modes of conventional 50um graded-index (GI) multimode fiber (MMF) employing non-mode-selective 3D-waveguide photonic lantern. Two kinds of scenarios, including fiber-only transmission and fiber-wireless hybrid transmission, were investigated by measuring error vector magnitude (EVM) performance for each stream and condition number (CN) of the channel matrix. The experimental results show that, SDM-based MMF link could offer a CN< 20dB well conditioned MIMO channel over up to 1km fiber length within 0-6GHz, achieving as low as 2.38%, 2.97% and 2.11% EVM performance for 1km MMF link at 2.4GHz, 5.8GHz, and 200m MMF link followed by 1m air distance at 2.7GHz, respectively. These results indicate the possibility to distribute wireless MIMO signals over existing in-building commercially-available MMFs with enormous cost-saving. PMID- 27958548 TI - Creation and measurement of broadband squeezed vacuum from a ring optical parametric oscillator. AB - We report a 65 MHz-bandwidth triangular-shaped optical parametric oscillator (OPO) for squeezed vacuum generation at 860 nm. The triangle structure of our OPO enables the round-trip length to reach 45 mm as a ring cavity, which provides a counter circulating optical path available for introducing a probe beam or generating another squeezed vacuum. Hence our OPO is suitable for the applications in high-speed quantum information processing where two or more squeezed vacua form a complicated interferometer, like continuous-variable quantum teleportation. With a homemade, broadband and low-loss homodyne detector, a direct measurement shows 8.4 dB of squeezing at 3 MHz and also 2.4 dB of squeezing at 100 MHz. PMID- 27958549 TI - Normalized detection by using the blow-away signal in cold atom interferometry. AB - We propose and realize a simple normalized detection scheme for cold atom interferometry. The detection of population in final atomic states is normalized to the blow-away fluorescence during initial state preparation. In this way, the detection system and procedure are both simplified. The reduced sensitivity to amplitude noise in atom interference signal is experimentally verified. Both amplitude noise in atom source and short term phase noise of interference fringes are suppressed by more than a factor of 10 with normalized detection. PMID- 27958550 TI - Broadband mid-infrared supercontinuum generation in 1-meter-long As2S3-based fiber with ultra-large core diameter. AB - In this study, the supercontinuum (SC) generation in a 1-m-long As2S3 fiber with a 200 MUm core diameter was demonstrated experimentally. The high-purity As2S3 fiber we used exhibited very low optical loss with a background loss of approximately 0.1 dB/m at a wavelength of 2-5 MUm. SC generation was studied by pumping the fiber at different wavelengths and different peak powers. A strong spectral broadening with a 30 dB spectral flatness spanning from 1.4 to 7.0 um was obtained when the fiber was pumped with 150 fs short pulses at 5.0 um. The SC generation in bent fiber was also studied. The result showed that the bending radius of the fiber will significantly affect the SC spectra bandwidth and the output power. The SC spectra in the used fiber could still be maintained when it was bent to a radius of 5 cm. PMID- 27958551 TI - Manipulating spin-dependent splitting of vector abruptly autofocusing beam by encoding cosine-azimuthal variant phases. AB - We report the realization of spin-dependent splitting of vector abruptly autofocusing beam (AAB) by encoding cosine-azimuthal variant phases. By employing the local spatial frequency (LSF), we reveal an approximation mapping relationship between focal field intensity of the two spin components and the pertinent phase distribution of input field. As well as theoretical analysis, we present experimental demonstrations of this guidance. Special focal field intensity, polarization and phase are realized by consciously managing the cosine azimuthal variant phase. This distinctive focal field of vector AAB may have a broad range of applications in harnessing the spin-orbit coupling, optical trapping and laser machining. PMID- 27958552 TI - 1.3-MUm dual-wavelength DFB laser chip with modulation bandwidth enhancement by integrated passive optical feedback. AB - We report a 1.3-MUm dual-wavelength distributed feedback (DFB) photonic integrated chip with modulation bandwidth enhancement using integrated optical feedback section. The dual-wavelength DFB lasers were realized using the upper separate confinement heterostructure (SCH) selective area growth (SAG) approach. A modified butt-joint technique was also adopted to achieve high-quality active passive interface and minimize unintentional intra-cavity optical feedbacks. The fabricated photonic chip exhibited stable single mode operations with a wavelength separation of 2.06 nm. The 3-dB modulation bandwidth was enhanced through the photon-photon resonance effect with f3dB > 17 GHz and open eyes up to 25 Gbit/s for both channels were also obtained. The design can also be scaled up to higher channel counts and higher data rate. PMID- 27958553 TI - Physical characterization of hematopoietic stem cells using multidirectional label-free light scatterings. AB - An experimental setup capable of measuring simultaneous 2D scattered light angular distribution from two directions to study cell morphology without the use of bio-labels was developed. Experiments with hematopoietic stem cells (CD34+ cells) show good agreement with detailed numerical simulations of light scattering. Numerical simulations and computer models of cells are used to identify physical features of cells with the largest scattering cross sections. This allows for determination of size, geometry of the nucleus and distribution of mitochondria in hematopoietic stem cells by means of our label free method. PMID- 27958554 TI - Modeling framework for piezoelectrically actuated MEMS tunable lenses. AB - WWe report a modeling framework for evaluating the performance of piezoelectrically actuated MEMS tunable lenses. It models the static opto electromechanical coupling for symmetric configurations of piezoelectric actuators based on the laminated-plate theory, linear piezoelectricity, and ray tracing. With these assumptions, it helps to find geometrical parameters for actuators on clamped square or circular diaphragms that give a diffraction limited tunable lens with minimum F-number. The tunable lens' optical performance and its focusing capability, alone and in combination with a paraxial fixed lens, were calculated in terms of object distance and actuation voltage. Using the modeling framework, we confirmed that the modulation transfer function for objects located at different distances remains the same after voltage adjustment. PMID- 27958555 TI - Electro-optically spectrum narrowed, multiline intracavity optical parametric oscillators. AB - We report on the first building of an active spectral narrowing mechanism in a pulsed, multiline optical parametric oscillator (OPO) based on a novel aperiodically poled lithium niobate (APPLN) device constructed using the aperiodic optical superlattice technique. The APPLN device functions simultaneously in the system as a multi-channel optical parametric down converter (OPDC) and an electro-optic (EO) gain spectral filter working on the corresponding (multiple) signal bands. When the APPLN OPO was installed in a diode pumped Nd:YVO4 laser system, highly narrowed dual-wavelength signal lines (at 1540 and 1550 nm) were observed at the output of the system through EO control of the APPLN. Correspondingly, an enhancement of the power spectral density of the source by a factor of ~7.8 with respect to the system operated in passive mode was found. PMID- 27958556 TI - 110-mJ 225-fs cryogenically cooled Yb:CaF2 multipass amplifier. AB - We report on a diode-pumped cryogenically cooled bulk Yb:CaF2 12-pass amplifier delivering 110-mJ, 1030-nm pulses at a 50-Hz repetition rate. The pulses have a spectral bandwidth of 13 nm and are compressed to 225 fs pulse duration in a double reflection grating based compressor having a transmission efficiency of >90%. The measured output beam quality is M2<1.1. A key feature of the amplifier design is the 4f relay imaging onto the gain medium with progressive beam magnification for the mitigation of the spatial gain narrowing effect. The number of passes in the amplifier is scalable by increasing the size of imaging mirrors. In order to prevent accumulation of nonlinear phase due to self-phase modulation in air, the amplifier is enclosed into a low-vacuum case. PMID- 27958557 TI - Alignment errors calibration for a channeled spectropolarimeter. AB - This paper presents a method to calibrate alignment errors for a channeled spectropolarimeter. A calibration model, including an alignment errors determination model and an alignment errors compensation model, is derived firstly. To determine the exact alignment errors of the high-order retarders and polarizer included in the spectropolarimeter, an auxiliary high-order retarder and a reference beam are used. The auxiliary high-order retarder does not affect the normal use of the spectropolarimeter and the polarization state of the reference beam needs not to be controlled accurately. Based on the determination results, the alignment errors are compensated by using a correction algorithm without any precise mechanical adjustments. Simulation results show that the alignment errors can be determined accurately and the errors of the reconstructed Stokes parameters due to the alignment errors are reduced effectively by the presented method. Finally, experimental results are summarized and analyzed to demonstrate the effectiveness of the calibration method. PMID- 27958558 TI - Monolithically integrated single quantum dots coupled to bowtie nanoantennas. AB - Deterministically integrating semiconductor quantum emitters with plasmonic nano devices paves the way towards chip-scale integrable, true nanoscale quantum photonic technologies. For this purpose, stable and bright semiconductor emitters are needed, which moreover allow for CMOS-compatibility and optical activity in the telecommunication band. Here, we demonstrate strongly enhanced light-matter coupling of single near-surface (< 10 nm) InAs quantum dots monolithically integrated into electromagnetic hot-spots of sub-wavelength sized metal nanoantennas. The antenna strongly enhances the emission intensity of single quantum dots by up to ~ 16*, an effect accompanied by an up to 3.4* Purcell enhanced spontaneous emission rate. Moreover, the emission is strongly polarised along the antenna axis with degrees of linear polarisation up to ~ 85 %. The results unambiguously demonstrate a pronounced coupling of individual quantum dots to state-of-the-art nanoantennas. Our work provides new perspectives for the realisation of quantum plasmonic sensors, step-changing photovoltaic devices, bright and ultrafast quantum light sources and efficient nano-lasers. PMID- 27958559 TI - Assessment of white for displays under dark- and chromatic-adapted conditions. AB - This study aims to investigate the white perception of mobile display devices under dark-adapted and chromatic-adapted conditions. The white perception was modeled with error ellipses and bivariate Gaussian distributions. The dark adapted white encompassed a rather large area centered around 7300 K, slightly above the Planckian locus. The chromatic-adapted whites were highly dependent on the ambient illuminant, and were not parallel to the Planckian locus. Combined, the white region encompassing 6179 to 7479 K in correlated color temperature and 0.0038 to 0.0144 in Duv was suggested. The results of this study are expected to be the basis for enhanced white appearance on mobile display devices. PMID- 27958560 TI - 2f-wavelength modulation Fabry-Perot photothermal interferometry. AB - Trace gas detection was performed by the principle of photothermal interferometry using a Fabry-Perot interferometer combined with wavelength modulation and second harmonic detection. The sensor employed a compact, low-volume gas cell in an overall robust set-up without the use of any moveable part. A quantum cascade laser was used as powerful mid-infrared excitation source to induce refractive index changes in the sample, whereas a near-infrared laser diode served as probe source to monitor the photo-induced variations. The functional principle of the selective sensor was investigated by detection of sulfur dioxide. For the targeted absorption band centered at 1379.78 cm-1 a 1 sigma minimum detection limit of about 1 parts per million by volume was achieved. The work demonstrates high potential for further sensor miniaturization down to a sample volume of only a few mm3. Limitations and possible improvements of the sensor regarding sensitivity are discussed. PMID- 27958561 TI - 3D printed dielectric rectangular waveguides, splitters and couplers for 120 GHz. AB - We use a 3D printer to fabricate rectangular dielectric single mode waveguides for 120 GHz. The rectangular waveguides consisting of polystyrene showed an attenuation of 6.3 dB/m, which is low enough for short devices. We also characterize 3D printed Y-splitters and a 1x3-splitter based on multimode interference. Further, we construct and measure a variable planar waveguide coupler which can be used as a 3-dB coupler, a cross-coupler and no coupler at all. PMID- 27958562 TI - Compact GaSb/silicon-on-insulator 2.0x MUm widely tunable external cavity lasers. AB - 2.0x um widely tunable external cavity lasers realized by combining a GaSb gain chip with a silicon photonics waveguide circuit for wavelength selection are demonstrated. Wavelength tuning over 58 nm from 2.01 to 2.07 um is demonstrated. In the silicon photonic integrated circuit, laser feedback is realized by using a silicon Bragg grating and continuous tuning is realized by using two thermally tuned silicon microring resonators (MRRs) and a phase section. The uncooled laser has maximum output power of 7.5 mW and threshold current density of 0.8 kA/cm2. The effect of the coupling gap of the MRRs on tunable laser performance is experimentally assessed. A side mode suppression ratio better than 52 dB over the full tuning range and in the optimum operation point of more than 60 dB is achieved for the laser with weakly coupled MRRs. PMID- 27958563 TI - Routing light with ultrathin nanostructures beyond the diffraction limit. AB - An open nanostructure consisting of a periodic chain of subwavelength nanoparticles for compressing and routing light beyond the diffraction limit is proposed. The open nanostructure is ultrathin and compact, with a size much smaller than the wavelength of light. We demonstrate that our ultrathin open nanostructure provides functions that can route and manipulate light at the subwavelength scale and can also sharply bend and split light beams below the diffraction limit while exhibiting broadband, incident-angle-tolerant, and robust against disorder. A physical picture based on all-angle self-collimation is presented to understand the manipulation of light using the ultrathin open nanostructure. Experimental and numerical observations validate our findings. This approach provides great flexibility in the design of nanophotonic devices for routing and manipulating light beyond the diffraction limit. PMID- 27958564 TI - Ultra-stability Yb-doped fiber optical frequency comb with 2 * 10-18/s stability in-loop. AB - We demonstrate a full control ultra-stability Yb-doped fiber optical frequency comb (OFC). The carrier-envelop offset frequency (fceo) and the repetition rate (fr) are locked with the standard phase locked loop (PLL) technique. The fceo is locked to the radio frequency (RF) synthesizer, and the Allan deviation is 1.2 * 10-17/s. The fr is locked to an ultra-stability continuous wave (CW) laser at 972 nm. The beat signal (fbeat) between the Yb-doped fiber OFC and CW laser is obtained with the signal to noise ratio (SNR) of 43 dB at 300 kHz resolution bandwidth (RBW). The time jitter of the fbeat signal is 278 as, which is integrated from 1 Hz to 10 MHz. The long-term stability is 575 MUHz in 3 hours, and the corresponding Allan deviation is 2 * 10-18/s, which is the best stability result in Yb-doped fiber OFC. The linewidth is narrowed from 200 kHz to subhertz magnitude limited by the instrument resolution bandwidth. PMID- 27958565 TI - Retrieval of ocean subsurface particulate backscattering coefficient from space borne CALIOP lidar measurements. AB - A new approach has been proposed to determine ocean subsurface particulate backscattering coefficient bbp from CALIOP 30 degrees off-nadir lidar measurements. The new method also provides estimates of the particle volume scattering function at the 180 degrees scattering angle. The CALIOP based layer integrated lidar backscatter and particulate backscattering coefficients are compared with the results obtained from MODIS ocean color measurements. The comparison analysis shows that ocean subsurface lidar backscatter and particulate backscattering coefficient bbp can be accurately obtained from CALIOP lidar measurements, thereby supporting the use of space-borne lidar measurements for ocean subsurface studies. PMID- 27958566 TI - FSR-free silicon-on-insulator microring resonator based filter with bent contra directional couplers. AB - High-speed optical interconnects drive the need for compact microring resonators (MRRs) with wide free spectral ranges (FSRs). A silicon-on-insulator MRR based filter with bent contra-directional couplers that exhibits an FSR-free response, at both the drop and through ports, while achieving a compact footprint is both theoretically and experimentally demonstrated. Also, using bent contra directional couplers in the couping regions of MRRs allowed us to achieve larger side-mode suppressions than MRRs with straight CDCs. The fabricated filter has a minimum suppression ratio of more than 15 dB, a 3dB-bandwidth of ~23 GHz, an extinction ratio of ~18 dB, and a drop-port insertion loss of ~1 dB. High-speed data transmission through our filter is also demonstrated at data rates of 12.5 Gbps, 20 Gbps, and 28 Gbps. PMID- 27958567 TI - High average power and energy microsecond pulse generation from an erbium-doped fluoride fiber MOPA system. AB - We reported a high average power and energy microsecond pulse erbium-doped fluoride fiber MOPA system centered at 2786.8 nm. The master oscillator was a passively Q-switched erbium-doped fluoride fiber laser based on SESAM in a linear cavity. Then a one-stage erbium-doped fluoride fiber amplifier was used to boost its average output power to 4.2 W and pulse energy to 58.87 MUJ. The pulse duration and repetition rate were 2.29 us and 71.73 kHz, respectively. To the best of our knowledge, the achieved average output power and pulse energy are the recorded levels for the passively Q-switched fiber lasers at 3 MUm wavelength region. PMID- 27958568 TI - White-light diffraction phase microscopy at doubled space-bandwidth product. AB - White light diffraction microscopy (wDPM) is a quantitative phase imaging method that benefits from both temporal and spatial phase sensitivity, granted, respectively, by the common-path geometry and white light illumination. However, like all off-axis quantitative phase imaging methods, wDPM is characterized by a reduced space-bandwidth product compared to phase shifting approaches. This happens essentially because the ultimate resolution of the image is governed by the period of the interferogram and not just the diffraction limit. As a result, off-axis techniques generates single-shot, i.e., high time-bandwidth, phase measurements, at the expense of either spatial resolution or field of view. Here, we show that combining phase-shifting and off-axis, the original space-bandwidth is preserved. Specifically, we developed phase-shifting diffraction phase microscopy with white light, in which we measure and combine two phase shifted interferograms. Due to the white light illumination, the phase images are characterized by low spatial noise, i.e., <1nm pathlength. We illustrate the operation of the instrument with test samples, blood cells, and unlabeled prostate tissue biopsy. PMID- 27958569 TI - Pressure-dependent refractive indices of gases by THz time-domain spectroscopy. AB - Noncontact terahertz time-domain spectroscopy was employed to measure pressure dependent refractive indices of gases such as helium (He), argon (Ar), krypton (Kr), oxygen (O2), nitrogen (N2), methane (CH4), and carbon dioxide (CO2). The refractive indices of these gases scaled linearly with pressure, for pressures in the 55-3,750 torr range. At the highest pressure, the refractive indices ((n-1) x 106) of He and CO2 were 170 and 2,390, respectively. The refractive index of CO2 was 14.1-fold higher than that of He, owing to the stronger polarizability of CO2. Although the studied gases differed in terms of their molecular structure, their refractive indices were strongly determined by polarizability. The measured refractive indices agreed well with the theoretical calculations. PMID- 27958570 TI - X-ray absorption tomography employing a conical shell beam. AB - We demonstrate depth-resolved absorption imaging by scanning an object through a conical shell of X-rays. We measure ring shaped projections and apply tomosynthesis to extract optical sections at different axial focal plane positions. Three-dimensional objects have been imaged to validate our theoretical treatment. The novel principle of our method is scalable with respect to both scan size and X-ray energy. A driver for this work is to complement previously reported methods concerning the measurement of diffracted X-rays for structural analysis. The prospect of employing conical shell beams to combine both absorption and diffraction modalities would provide enhanced analytical utility and has many potential applications in security screening, process control and diagnostic imaging. PMID- 27958571 TI - Comparison of attosecond streaking and RABBITT. AB - Recent progress in the generation of ultra-short laser pulses has enabled the measurement of photoionization time delays with attosecond precision. For single photoemission time delays the most common techniques are based on attosecond streaking and the reconstruction of attosecond beating by interference of two photon transitions (RABBITT). These are pump-probe techniques employing an extreme-ultraviolet (XUV) single attosecond pump pulse for streaking or an attosecond pump pulse train for RABBITT, and a phase-locked infrared (IR) probe pulse. These techniques can only extract relative timing information between electrons originating from different initial states within the same atom or different atoms. Here we address the question whether the two techniques give identical timing information. We present a complete study, supported by both experiments and simulations, comparing these two techniques for the measurement of the photoemission time delay difference between valence electrons emitted from the Ne 2p and Ar 3p ground states. We highlight not only the differences and similarities between the two techniques, but also critically investigate the reliability of the methods used to extract the timing information. PMID- 27958572 TI - Highly doped InP as a low loss plasmonic material for mid-IR region. AB - We study plasmonic properties of highly doped InP in the mid-infrared (IR) range. InP was grown by metal-organic vapor phase epitaxy (MOVPE) with the growth conditions optimized to achieve high free electron concentrations by doping with silicon. The permittivity of the grown material was found by fitting the calculated infrared reflectance spectra to the measured ones. The retrieved permittivity was then used to simulate surface plasmon polaritons (SPPs) propagation on flat and structured surfaces, and the simulation results were verified in direct experiments. SPPs at the top and bottom interfaces of the grown epilayer were excited by the prism coupling. A high-index Ge hemispherical prism provides efficient coupling conditions of SPPs on flat surfaces and facilitates acquiring their dispersion diagrams. We observed diffraction into symmetry-prohibited diffraction orders stimulated by the excitation of surface plasmon-polaritons in a periodically structured epilayer. Characterization shows good agreement between the theory and experimental results and confirms that highly doped InP is an effective plasmonic material aiming it for applications in the mid-IR wavelength range. PMID- 27958573 TI - X-ray ptychography with extended depth of field. AB - Ptychographic X-ray computed tomography is a coherent diffractive imaging method that offers nanometer-scale resolution with quantitative contrast. It offers the possibility to study relatively thick samples by using high energy X-ray photons and exploiting the phase contrast. However, the limited depth of field forces a compromise between resolution and sample thickness. Multi-slice techniques have been used to account for propagation effects within the sample, enabling imaging beyond the depth-of-field limit. Here we introduce and experimentally demonstrate our multi-slice algorithms that allow for the reconstruction of multiple object slices and the incident illumination, as well as the retrieval of unknown object thickness. Additionally, through numerical studies, we show that smaller scanning steps surprisingly increase the depth of field, which can be further extended by the use of multi-slice methods under conditions stated by theoretical expressions. The results presented here will be instrumental for the routine implementation of the technique for X-ray nanotomography. PMID- 27958574 TI - Spatial stabilization of deep-turbulence-induced anisoplanatic blur. AB - We explore the feasibility of post-detection restoration when imaging through deep turbulence characterized by extreme anisoplanatism. A wave-optics code was used to simulate relevant short-exposure point spread functions (PSFs) and their decorrelation as a function of point-source separation was computed. In addition, short-exposure images of minimally extended objects were simulated and shown to retain a central lobe that is clearly narrower than the long-exposure counterpart. This suggests that short-exposure image data are more informative than long-exposure data, even in the presence of extreme anisoplanatism. The implications of these findings for image restoration from a sequence of short exposure images are discussed. PMID- 27958575 TI - Gain-switched monolithic fiber laser with ultra-wide tuning range at 2 MUm. AB - We demonstrate a gain-switched thulium-doped fiber laser (TDFL) built in an all fiber format producing nanosecond pulses with variable wavelength in the 2 MUm waveband. The laser features tunable operation in an ultra-wide spectral region of 1765 - 2055 nm (24 THz). The nearly 300 nm tunability doubles the record tuning range of existing gain-switched fiber lasers, and to the best of our knowledge, presents the broadest tuning range that has been reported for a monolithic pulsed rare earth doped fiber laser to date. The TDFL can operate at a repetition rate of 2.5 - 100 kHz with a pulse width as short as ~200 ns. Influences of various system parameters on the laser performance are investigated in detail. PMID- 27958576 TI - 1.2W laser amplification at 1427nm on the 4F3/2 to 4I13/2 spectral line in an Nd3+ doped fused silica optical fiber. AB - A 9.3dB improvement in optical gain and a 100x improvement in total optical power over prior published experimental results from the 4F3/2 to 4I13/2 transition in an Nd3+ doped fused silica optical fiber is demonstrated. This is enabled via an optical fiber waveguide design that creates high spectral attenuation in the 1050-1120nm-wavelength range, a continuous spectral filter for the primary 4F3/2 to 4I11/2 optical transition. A maximum output power at 1427nm of 1.2W was attained for 43mW coupled seed laser power and 22.2W of coupled pump diode laser power at 880nm a net optical gain of 14.5dB. Reducing the coupled seed laser power to 2.5mW enabled the system to attain 19.3dB of gain for 16.5W of coupled pump power. Four issues limited results; non-optimal seed laser wavelength, amplified spontaneous emission on the 4F3/2 to 4I9/2 optical transition, low absorption of pump light from the cladding and high spectral attenuation in the 1350-1450nm range. Future fibers that mitigate these issues should lead to significant improvements in the efficiency of the laser amplifier, though the shorter wavelength region of the transition from 1310nm to >1350nm is still expected to be limited by excited state absorption. PMID- 27958577 TI - Robust design procedure for dielectric resonator metasurface lens array. AB - In this paper, we present a design strategy for single layer metasurface lenses based on dielectric resonators. This strategy is based on a robust optimization procedure for the resonator distribution in order to meet required performances (e.g. encircled energy, bandwidth, field of view, etc.). Possible deviations due to manufacturing errors are taken into account in the design procedure. This is applied to the design of array of microlenses for maskless lithography applications. The final design shows more uniform focusing performances (bandwidth 20 nm at 395 nm - 415 nm, field of view +/-60 mrad) and increased robustness against manufacturing errors, compared to designs based on analytic phase projections. PMID- 27958578 TI - Impact of input FBG reflectivity and forward pump power on RIN transfer in ultralong Raman laser amplifiers. AB - Relative intensity noise transfer from the pump to the signal in 2nd-order ultra long Raman laser amplifiers for telecommunications is characterized numerically and experimentally. Our results showcase the need for careful adjustment of the front FBG reflectivity and the relative contribution of forward pump power, and their impact on performance. Finally, our analysis is verified through a 10 * 30 GBaud DP-QPSK transmission experiment, showing a large Q factor penalty associated with the combination of high forward pumping and high reflectivities. PMID- 27958579 TI - Comparison of digital signal-signal beat interference compensation techniques in direct-detection subcarrier modulation systems. AB - Single-polarization direct-detection transceivers may offer advantages compared to digital coherent technology for some metro, back-haul, access and inter-data center applications since they offer low-cost and complexity solutions. However, a direct-detection receiver introduces nonlinearity upon photo detection, since it is a square-law device, which results in signal distortion due to signal signal beat interference (SSBI). Consequently, it is desirable to develop effective and low-cost SSBI compensation techniques to improve the performance of such transceivers. In this paper, we compare the performance of a number of recently proposed digital signal processing-based SSBI compensation schemes, including the use of single- and two-stage linearization filters, an iterative linearization filter and a SSBI estimation and cancellation technique. Their performance is assessed experimentally using a 7 * 25 Gb/s wavelength division multiplexed (WDM) single-sideband 16-QAM Nyquist-subcarrier modulation system operating at a net information spectral density of 2.3 (b/s)/Hz. PMID- 27958580 TI - Operation of slope-assisted Brillouin optical correlation-domain reflectometry: comparison of system output with actual frequency shift distribution. AB - Although the proof of concept for slope-assisted (SA-) Brillouin optical correlation-domain reflectometry (BOCDR) has been demonstrated, no reports on its detailed operation have been provided to date. We theoretically and experimentally investigate the relationship between the system output (power change distribution) of SA-BOCDR and the actual Brillouin frequency shift (BFS) distribution along the sensing fiber and show that these two are not identical. When the strained fiber section is much longer than the nominal spatial resolution, the actual distribution of the BFS (i.e., strain) is well reproduced by the power-change distribution. However, when the length of the strained section is equal to or only a few times the nominal resolution, the correct BFS distribution cannot be directly obtained. Even when the strained section is shorter than the nominal resolution, a shift in the power change can still be observed, which is not the case for standard BOCDR systems. This unique "beyond nominal-resolution" effect will be of great use in practical applications. PMID- 27958581 TI - Optical pulse division multiplexing-based OBI reduction for single wavelength uplink multiple access in IM/DD OFDMA-PON. AB - Orthogonal frequency division multiple access-based passive optical network (OFDMA-PON) is considered as a strong candidate for next-generation optical access network. In intensity modulation/direct detection system, OFDMA-PON downlink transmission is relatively stable, but critical issues exist in uplink multiple access. Because of different optical paths, optical beat interference (OBI) and timing offset effect are generated, which seriously disturb signal detection. We propose optical pulse division multiplexing-based OBI reduction. By considering both the spectrum broadening effect and the time domain near orthogonality, OBI could be reduced. We demonstrate that the spectral efficiency can be improved from 0.37 to 3.8 bit/s/Hz in 1-GHz signal bandwidth. PMID- 27958582 TI - Influence of phase transitions on green fluorescence intensity ratio in Er3+ doped K0.5Na0.5NbO3 ceramic. AB - The fluorescence intensity ratio (FIR) method is a non-contact temperature (T) measurement technique based on thermally coupled levels of rare earth ions in a doped host. Green fluorescence originating from 2H11/2 and 4S3/2 states of Er3+ doped K0.5Na0.5NbO3 (KNN) ceramic are studied in the temperature range of 300 K to 720 K. The fluorescence intensities change dramatically around phase transition points where the crystal symmetry changes, inducing deviation of the FIR from Boltzmann's law. The temperature determined by the FIR method deviates from thermocouple measurements by 7 K at the orthorhombic to tetragonal phase transition (TO-T) point and 13 K at the Curie point (TC). This finding gives guidance for developing fluorescent T sensors with ferroelectrics and may also provide a fluorescent method to detect phase transitions in ferroelectric materials. PMID- 27958583 TI - Tunable metamaterial-induced transparency with gate-controlled on-chip graphene metasurface. AB - We propose and numerically investigate a gate-controlled on-chip graphene metasurface consisting of a monolayer graphene sheet and silicon photonic crystal like substrate, to achieve an electrically-tunable induced transparency. The operation mechanism of the induced transparency of the on-chip graphene metasurface is analyzed. The tunable optical properties with different gate voltages and polarizations have been discussed. Additionally, the spectral feature of the on-chip graphene metasurface as a function of the refractive index of the local environment is also investigated. The result shows that the on-chip graphene metasurface as a refractive index sensor can achieve an overall figure of merit of 8.89 in infrared wavelength range. Our study suggests that the proposed structure is potentially attractive as optoelectronic modulators and refractive index sensors. PMID- 27958584 TI - Studying fermionic ghost imaging with independent photons. AB - Ghost imaging with thermal fermions is calculated via two-particle interference based on the superposition principle for different alternatives in Feynman's path integral theory. It is found that ghost imaging with fully polarized thermal fermions can be simulated by ghost imaging with fully polarized thermal bosons and classical particles. Photons in pseudothermal light are employed to experimentally study fermionic ghost imaging. Ghost imaging with thermal bosons and fermions is discussed based on the point-to-point (spot) correlation between the object and image planes. The employed method offers an efficient guidance for future ghost imaging with real thermal fermions, which may also be generalized to study other second-order interference phenomena with fermions. PMID- 27958585 TI - Characterization of optical systems for the ALPS II experiment. AB - ALPS II is a light shining through a wall style experiment that will use the principle of resonant enhancement to boost the conversion and reconversion probabilities of photons to relativistic WISPs. This will require the use of long baseline low-loss optical cavities. Very high power build up factors in the cavities must be achieved in order to reach the design sensitivity of ALPS II. This necessitates a number of different sophisticated optical and control systems to maintain the resonance and ensure maximal coupling between the laser and the cavity. In this paper we report on the results of the characterization of these optical systems with a 20 m cavity and discuss the results in the context of ALPS II. PMID- 27958586 TI - Computationally fast EM field propagation through axi-symmetric media using cylindrical harmonic decomposition. AB - We describe and provide a systematic procedure for computationally fast propagation of arbitrary vector electromagnetic (EM) fields through an axially symmetric medium. A cylindrical harmonic field propagator is chosen for this purpose and in most cases, this is the best and the obvious choice. Firstly, we describe the cylindrical harmonic decomposition technique in terms of both scalar and vector basis for a given input excitation field. Then we formulate a generalized discrete Fourier-Hankel transform to achieve efficient vector basis decomposition. We allow a slower, pre-computation step, that finds a representation of the axi-symmetric medium as a transfer matrix in a discrete, cylindrical-harmonic basis. We find this matrix from a series of axi-symmetric (2D) finite element simulations (also known as the 2.5D technique). This transfer matrix approach significantly reduces the computational load when the transverse size or range exceeds about 30 wavelengths. This matrix is independent of the input excitation field for a given space-bandwidth product and hence makes it reusable for different excitation fields. We numerically validate the above approaches for different axi-symmetric EM scattering media which include a hemispherical gradient-index Maxwell's fish-eye lens, a transformation optics designed spherical invisibility cloak, a thin aspheric lens, and a cylindrical perfect lens. PMID- 27958587 TI - High-speed spatial control of the intensity, phase and polarisation of vector beams using a digital micro-mirror device. AB - The dynamic spatial control of light fields is essential to a range of applications, from microscopy to optical micro-manipulation and communications. Here we describe the use of a single digital micro-mirror device (DMD) to generate and rapidly switch vector beams with spatially controllable intensity, phase and polarisation. We demonstrate local spatial control over linear, elliptical and circular polarisation, allowing the generation of radially and azimuthally polarised beams and Poincare beams. All of these can be switched at rates of up to 4kHz (limited only by our DMD model), a rate ~2 orders of magnitude faster than the switching speeds of typical phase-only spatial light modulators. The polarisation state of the generated beams is characterised with spatially resolved Stokes measurements. We also describe detail of technical considerations when using a DMD, and quantify the mode capacity and efficiency of the beam generation. The high-speed switching capabilities of this method will be particularly useful for the control of light propagation through complex media such as multimode fibers, where rapid spatial modulation of intensity, phase and polarisation is required. PMID- 27958588 TI - Progressive rear-view mirror for motorcycles. AB - In this work, we present the design and fabrication of a progressive rear-view mirror for motorcycles. In the context of physiological and physical background knowledge, we first analyze the geometric relationships among the profile of the mirror, the blind spot, the field of view, and the reflected image size. On the basis of Walker's eye model, the binocular disparity is further calculated according to the image size on each retina. We present the polynomial expansion that specifies our progressive mirror's profile, as well as the fused deposition modeling process for fabricating physical mirrors. Compared with a conventional aspheric or flat mirror, this progressive mirror can achieve a wider horizontal viewing angle and shows a more stable image, thus enhancing riding safety. PMID- 27958589 TI - Dispersion design in gradient index elements using ternary blends. AB - We show that a gradient-index element designed from a blend of three materials allows a designer to specify independently the element's refractive index and its change in refractive index with respect to wavelength. We show further the effectiveness of this approach by comparing modeled chromatic performance of deflectors consisting of a single material, a binary blend of materials, and a ternary blend. PMID- 27958590 TI - Single-shot digital holographic microscopy for quantifying a spatially-resolved Jones matrix of biological specimens. AB - Field-based polarization measurements are essential for the completeness of information when exploiting the complex nature of optical responses of target objects. Here, we demonstrate digital holographic microscopy for quantifying a polarization-sensitive map of an object with a single-shot measurement. Using the image-splitting device generating four different copies of an object image and a separate reference beam of an off-axis configuration enables single-shot and multi-imaging capability. With the use of two polarization filters, four complex field images containing an object's polarization response are obtained simultaneously. With this method, we can construct a complete set of 2-by-2 Jones matrix at every single point of the object's images, and thus clearly visualize the anisotropic structures of biological tissues with low level of birefringence. This method will facilitate the high-precision measurements for fast dynamics of the polarization properties of biological specimens. PMID- 27958591 TI - Bringing short-lived dissipative Kerr soliton states in microresonators into a steady state. AB - Dissipative Kerr solitons have recently been generated in optical microresonators, enabling ultrashort optical pulses at microwave repetition rates, that constitute coherent and numerically predictable Kerr frequency combs. However, the seeding and excitation of the temporal solitons is associated with changes in the intracavity power that can lead to large thermal resonance shifts and render the soliton states in most commonly used resonator platforms short lived. Here we describe a "power kicking" method to overcome this instability by modulating the power of the pump laser. With this method also initially very short-lived (of the order of 100 ns) soliton states can be brought into a steady state in contrast to techniques reported earlier which relied on an adjustment of the laser scan speed only. Once the soliton state is in a steady state it can persist for hours and is thermally self-locked. PMID- 27958592 TI - High-power dual-wavelength lasing in bimodal-sized InGaAs/GaAs quantum dots. AB - In this paper, we demonstrate high power, dual-wavelength (dual-lambda) lasing stemming from bimodal-sized InGaAs/GaAs quantum dots (QDs). The device exhibits simultaneous dual-lambda lasing at 1015.2 nm and 1023.0 nm with total power of 165.6 mW at 700 mA under room temperature continuous wave (CW) mode. Gaussian fitting analyses of the electroluminescence (EL) spectrum attribute the excellent performance to independent carrier transitions from the first excited states of large dot ensemble (LD ES1) and small dot ensemble (SD ES1), respectively. This formation provides a new possibility to achieve high power dual-lambda operation only using Fabry-Perot (FP) cavity, which is significant for compact size and low fabrication cost. PMID- 27958593 TI - Comparison of coherently coupled multi-cavity and quantum dot embedded single cavity systems. AB - Temporal group delays originating from the optical analogue to electromagnetically induced transparency (EIT) are compared in two systems. Similar transmission characteristics are observed between a coherently coupled high-Q multi-cavity array and a single quantum dot (QD) embedded cavity in the weak coupling regime. However, theoretically generated group delay values for the multi-cavity case are around two times higher. Both configurations allow direct scalability for chip-scale optical pulse trapping and coupled-cavity quantum electrodynamics (QED). PMID- 27958594 TI - 3D-printed diffractive elements induced accelerating terahertz Airy beam. AB - We first demonstrate the accelerating terahertz (THz) Airy beam with a 0.3-THz continuous wave. Two diffractive elements are designed and 3D-printed to form the generation system, which cannot only imprint the desired complex phase pattern but also perform the required Fourier transform (FT). We both numerically and experimentally demonstrate the propagation dynamics of the accelerating THz Airy beam and investigate its self-healing property during propagation in the free space. Our observations are in good agreement with the numerical simulations. Such an accelerating THz Airy beam could be able to develop novel THz imaging systems and robust THz communication links. PMID- 27958596 TI - Lipofilling as refinement procedure in maxillo-mandibular malformations. AB - Maxillo-mandibular asymmetry has numerous aetiologies: congenital, traumatic, iatrogenic and post-oncologic. Patients with congenital dentofacial malformations are generally submitted to orthognathic surgery and/or additional procedures (genioplasty, alloplastic implants) with satisfactory results. However, despite achieving skeletal symmetry, noticeable facial asymmetry may persist.This study was performed in 45 patients (29 women and 16 men) operated between December 2012 and June 2014. All patients were affected by maxilla-mandibular asymmetry and underwent orthognatic surgery for hard tissue correction of the deformity. Residual facial alterations were then treated with lipofilling refinement proceure. In all cases good integration of the grafted fat was observed in the recipient sites. Retrospective analysis of photographic documentation showed progressive volumetric decrease for up to approximately 6 months after surgery; after that graft volume remained relatively stable. There were no significant surgical complications, either from the fat harvest site or the reconstructed site. Mild oedema and bruising were frequent during the first post-operative week. No haematomas, infections, vascular or nervous injuries were recorded. Twenty-four patients felt the need to have a second procedure. A second fat transfer was performed in 22 cases, and a third in 2 (total of 69 procedures). Based on the observations of our study, fat grafting is a simple, effective and reproducible technique, with a high satisfaction rate and few disadvantages or complications. We demonstrated that the success of lipofilling is dependent on the treated aesthetic subunits of the face. The malar and lateral cheek regions seem to be highly favourable for fat grafting, unlike the upper and lower lips subunits. Composite procedures using orthognathic surgery and autologous fat provide the surgeon with an additional, more customisable option for patients with maxillo-mandibular malformations. PMID- 27958597 TI - Salvage total laryngectomy after conservation laryngeal surgery for recurrent laryngeal squamous cell carcinoma. AB - The aim of the present study was to evaluate the oncological efficacy of salvage total laryngectomy in patients who had previously undergone supracricoid partial laryngectomy or transoral laser microsurgery for treatment of laryngeal squamous cell carcinoma. We retrospectively reviewed the medical, surgical and pathological records of 35 patients who underwent salvage total laryngectomy after recurrence of laryngeal cancer (following supracricoid partial laryngectomy or transoral laser microsurgery). Kaplan-Meier survival curves as well as univariate and multivariate analyses of prognostic factors were performed. No statistically significant differences were seen comparing the supracricoid partial laryngectomy group with the transoral laser microsurgery group for overall survival and disease-specific survival at 3 years (OS = 38% vs. 52%, p = 0.16; DSS = 40% vs. 61%, p = 0.057) or locoregional control at 2 years (LRC = 40% vs. 54%, p = 0.056). A trend indicating worse survival and locoregional control for supracricoid partial laryngectomy patients emerged. Preservation of the osteocartilaginous frame in transoral laser microsurgery could hypothetically result in better salvageability of anterior recurrences with extralaryngeal spread. PMID- 27958595 TI - Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. AB - Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised by the occurrence of vestibular schwannomas (VSs), schwannomas of other cranial, spinal and cutaneous nerves, cranial and spinal meningiomas and/or other central nervous system (CNS) tumours (e.g., ependymomas, astrocytomas). Additional features include early onset cataracts, optic nerve sheath meningiomas, retinal hamartomas, dermal schwannomas (i.e., NF2-plaques), and (few) cafe-au-lait spots. Clinically, NF2 children fall into two main groups: (1) congenital NF2 - with bilateral VSs detected as early as the first days to months of life, which can be stable/asymptomatic for one-two decades and suddenly progress; and (2) severe pre-pubertal (Wishart type) NF2- with multiple (and rapidly progressive) CNS tumours other-than-VS, which usually present first, years before VSs [vs. the classical adult (Gardner type) NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature]. Some individuals can develop unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localised to one part of the peripheral nervous system [i.e., mosaic NF2] or multiple non-VS, non-intradermal cranial, spinal and peripheral schwannomas (histologically proven) [schwannomatosis]. NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin (ERM) proteins; mosaicNF2 is due to mosaic phenomena for the NF2 gene, whilst schwannomatosis is caused by coupled germ-line and mosaic mutations either in the SMARCB1 gene [SWNTS1; MIM # 162091] or the LZTR1 gene [SWNTS2; MIM # 615670] both falling within the 22q region and the NF2 gene. Data driven from in vitro and animal studies on the merlin pathway [e.g., post-translational and upstream/downstream regulation] allowed biologically targeted treatment strategies [e.g., Lapatinib, Erlotinib, Bevacizumab] aimed to multiple tumour shrinkage and/or regression and tumour arrest of progression with functional improvement. PMID- 27958598 TI - Advanced oxidation protein product levels as a marker of oxidative stress in paediatric patients with chronic tonsillitis. AB - We aimed to determine whether advanced oxidation protein product (AOPP) levels can serve as a marker of oxidative stress in paediatric patients with chronic tonsillitis. Thirty children with chronic tonsillitis and 30 healthy children (control group) were recruited from the Otorhinolaryngology (ORL) and Paediatric Surgery departments, respectively, of Dumlupinar University Hospital. In the patient group, blood samples were collected before tonsillectomy, and tonsil tissue was sampled during the operation. Blood samples were also obtained from the control subjects. AOPP levels in the serum and tonsil tissue were measured by the spectrophotometric method. Serum AOPP levels were significantly higher in the patient group (13.1 +/- 3.3 ng/ml) than in the control group (11.6 +/- 2.3 ng/ml; P < 0.05). In addition, the mean AOPP level (41.9 +/- 13.5 ng/mg protein) in the tonsil tissue in the patient group was significantly higher than the mean serum AOPP levels in the control and patient groups (P < 0.05). AOPP levels are elevated in the tonsil tissue and serum of patients with chronic tonsillitis compared to the serum AOPP levels in healthy controls. AOPPs may represent a novel class of pro-inflammatory molecules that are involved in oxidative stress in chronic tonsillitis. AOPPs may be used as a marker of oxidative stress in paediatric patients with chronic tonsillitis. PMID- 27958599 TI - Association between oral habits, mouth breathing and malocclusion. AB - The ratio of bad habits, mouth breathing and malocclusion is an important issue in view of prevention and early treatment of disorders of the craniofacial growth. While bad habits can interfere with the position of the teeth and normal pattern of skeletal growth, on the other hand obstruction of the upper airway, resulting in mouth breathing, changes the pattern of craniofacial growth causing malocclusion. Our crosssectional study, carried out on 3017 children using the ROMA index, was developed to verify if there was a significant correlation between bad habits/mouth breathing and malocclusion. The results showed that an increase in the degree of the index increases the prevalence of bad habits and mouth breathing, meaning that these factors are associated with more severe malocclusions. Moreover, we found a significant association of bad habits with increased overjet and openbite, while no association was found with crossbite. Additionally, we found that mouth breathing is closely related to increased overjet, reduced overjet, anterior or posterior crossbite, openbite and displacement of contact points. Therefore, it is necessary to intervene early on these aetiological factors of malocclusion to prevent its development or worsening and, if already developed, correct it by early orthodontic treatment to promote eugnatic skeletal growth. PMID- 27958600 TI - Comparison between videofluoroscopy, fiberoptic endoscopy and scintigraphy for diagnosis of oro-pharyngeal dysphagia. AB - The purpose of this study was to compare videofluoroscopy (VFS), fiberoptic endoscopic evaluation of swallowing (FEES) and oro-pharyngo- oesophageal scintigraphy (OPES) with regards to premature spillage, post-swallowing residue and aspiration to assess the reliability of these tests for detection of oro pharyngeal dysphagia. Sixty patients affected with dysphagia of various origin were enrolled in the study and submitted to VFS, FEES and OPES using a liquid and semi-solid bolus. As a reference, we used VFS. Both the FEES and the OPES showed good sensitivity with high overall values (>= 80% and >= 90% respectively). The comparison between FEES vs VFS concerning drop before swallowing showed good specificity (84.4% for semi-solids and 86.7% for liquids). In the case of post swallowing residue, FEES vs VFS revealed good overall validity (75% for semi solids) with specificity and sensitivity well balanced for the semi-solids. OPES vs. VFS demonstrated good sensitivity (88.6%) and overall validity (76.7%) for liquids. The analysis of FEES vs. VFS for aspiration showed that the overall validity was low (<= 65%). On the other hand, OPES demonstrated appreciable overall validity (71.7%). VFS, FEES and OPES are capable of detecting oro pharyngeal dysphagia. FEES gave significant results in the evaluation of post swallowing residues. PMID- 27958601 TI - Open partial horizontal laryngectomies: is it time to adopt a modular form of consent for the intervention? AB - Nowadays, open partial horizontal laryngectomies (OPHLs) are well-established procedures for treatment of laryngeal cancer. Their uniqueness is the possibility to modulate the intervention intraoperatively, according to eventual tumour extension. An OPHL procedure is not easy to understand: there are several types of procedures and the possibility to modulate the intervention can produce confusion and lack of adherence to the treatment from the patient. Even if the surgery is tailored to a patient's specific lesion, a unified consent form that discloses any possible extensions, including a total laryngectomy, is still needed. We reviewed the English literature on informed consent, and propose comprehensive Information and Consent Forms for OPHLs. The Information Form is intended to answer any possible questions about the procedure, while remaining easy to read and understand for the patient. It includes sections on laryngeal anatomy and physiology, surgical aims and indications, alternatives to surgery, complications, and physiology of the operated larynx. The Consent Form is written in a "modular" way: the surgeon defines the precise extension of the lesion, chooses the best OPHL procedure and highlights all possible expected extensions specific for the patient. Our intention, providing these forms both in Italian and in English, is to optimise communication between the patient and surgeon, improving surgical procedure arrangements and preventing any possible misunderstandings and medico-legal litigation. PMID- 27958603 TI - A connection between neurovascular conflicts within the cerebellopontine angle and vestibular neuritis, a case controlled cohort study. AB - This retrospective, observer blinded case-control study aims to compare the prevalence of neurovascular conflicts (NVCs) of the vestibulocochlear nerve and the anterior inferior cerebellar artery (AICA) in patients presenting with clinical signs of acute vestibular neuritis with and without subsequent objective vestibular function loss (VFL). 58 acute cases of clinically suspected acute vestibular neuritis were investigated with same day cranial MRI at a tertiary referral centre and compared to 61 asymptomatic controls. The prevalence of NVCs in cases with objective VFL were also compared to cases without VFL. Radiologists described the NVC as "no contact" (Grade 0), "contact < 2 mm" (Grade 1), "contact > 2 mm" (Grade 2) and "vascular loop presence" (Grade 3) without knowledge of neurotological data. Neurotological data was collected without knowledge of MRI findings. Vestibular function was tested by bithermic caloric irrigation. 26 cases (45%) showed caloric VFL (Group A), whereas 32 (55%) exhibited no VFL (Group B). Group A included 13 cases with NVCs (50%), Group B included 26 NVC cases (82%) (p = 0.012) and the control group included 16 individuals (26%) (p < 0.001 for comparison of all 3 groups). Group B had a significantly higher NVC Grading than Group A (p = 0.009). There was no statistically significant association between NVCs and either SNHL or tinnitus (p > 0.05). Our results suggest that patients presenting with clinical signs of acute vestibular neuritis who show symmetrical caloric vestibular function test results have a significantly higher NVC prevalence in the cerebellopontine angle. PMID- 27958602 TI - Severe to profound deafness may be associated with MYH9-related disease: report of 4 patients. AB - MYH9-related disease (MYH9-RD) is a rare genetic syndromic disorder characterised by congenital thrombocytopenia and is associated with the risk of developing progressive sensorineural hearing loss, nephropathy and presenile cataracts during childhood or adult life. All consecutive patients enrolled in the Italian Registry for MYH9-RD with severe to profound deafness were included in a retrospective study. The study population involved 147 Italian patients with MYH9 RD: hearing loss was identified in 52% of cases and only 4 patients (6%) presented severe to profound deafness at a mean age of 33 years. Deafness was associated with mild spontaneous bleeding in all patients and with kidney involvement in 3 cases. Cochlear implantation was carried out in 3 cases with benefit, and no major complications were observed. Diagnosis was performed about 28 years after the first clinical manifestation of MYH9-RD, which was never suspected by an otolaryngologist. The clinical and diagnostic aspects of 4 patients with severe to profound deafness are discussed with a focus on therapeutic implications. PMID- 27958605 TI - Unusual cyclic polymerization through Suzuki-Miyaura coupling of polyphenylene bearing diboronate at both ends with excess dibromophenylene. AB - The Suzuki-Miyaura coupling polymerization of p-dibromophenylene and m phenylenediboronic acid ester, as well as m-dibromophenylene and p phenylenediboronic acid ester, and the combination of two meta-phenylene monomers in the presence of the t-Bu3PPd(0) catalyst selectively afforded cyclic polyphenylenes with polyphenylene bearing boronate moieties at both ends when excess dibromophenylene was used. PMID- 27958604 TI - Template-free 3D titanium carbide (Ti3C2Tx) MXene particles crumpled by capillary forces. AB - Ti3C2Tx and other types of MXene nanosheets are an exciting new class of 2D materials. However, little has been reported on manipulating the shape of MXene nanosheets. Here, we demonstrate that flat Ti3C2Tx nanosheets encapsulated within spray-dried droplets can be scrolled, bent, and folded into 3D crumpled structures. This morphological change was observed to be reversible upon rehydration. PMID- 27958606 TI - From the molecule to the mole: improving heterogeneous copper catalyzed click chemistry using single molecule spectroscopy. AB - Single molecule spectroscopy (SMS) inspired the optimization of a heterogeneous 'click' catalyst leading to enhanced yields of the Cu-catalyzed reaction of azides with terminal alkynes. Changes in SMS data after optimization confirm the improvements in catalyst performance. PMID- 27958607 TI - Monodentate coordination of the normally chelating chiral diamine (R,R)-TMCDA. AB - After isolating an unusual binuclear, but monosolvated NaHMDS complex [{(R,R) TMCDA}.(NaHMDS)2]infinity which polymerises via intermolecular electrostatic NaMeHMDS interactions, further (R,R)-TMCDA was added to produce the discrete binuclear amide [{kappa2-(R,R)-TMCDA}.(NaHMDS)2{kappa1-(R,R)-TMCDA}], whose salient feature is the unique monodentate coordination of one of the chiral diamine ligands. PMID- 27958608 TI - Efficient preparation of carbamates by Rh-catalysed oxidative carbonylation: unveiling the role of the oxidant. AB - The synthesis of a wide variety of carbamates from amines, alcohols and carbon monoxide has been achieved by means of a Rh-catalysed oxidative carbonylation reaction that uses Oxone as a stoichiometric oxidant. In-depth studies on the reaction mechanism shed light on the intimate role of Oxone in the catalytic cycle. PMID- 27958609 TI - Efficiency of an mTOR Inhibitor in Kasabach-Merritt Phenomenon with Indolent Tufted Angioma: A Case Report. PMID- 27958610 TI - Overexpression of Psoriasin (S100A7) Contributes to Dysregulated Differentiation in Psoriasis. AB - Psoriasin, which is highly expressed in psoriasis, is encoded by a gene located within the epidermal differentiation complex. The aim of this study was to investigate the effect of endogenous psoriasin on disturbed keratinocyte differentiation in psoriasis. Immunohistochemical staining revealed a gradient of psoriasin expression in the psoriatic epidermis with highest expression in the suprabasal, differentiated layers. Induction of keratinocyte differentiation caused concurrent expression of psoriasin and the differentiation marker involucrin. The differentiation-induced psoriasin expression was found to be mediated by the protein kinase C pathway. The downregulation of psoriasin expression by small interfering RNA revealed that psoriasin mediates the expression of involucrin, desmoglein 1, transglutaminase 1 and CD24 in normal differentiation. The lentivirus-mediated overexpression of psoriasin, mimicking the psoriatic milieu, gave rise to an altered regulation of differentiation genes and an expression pattern reminiscent of that in psoriatic epidermis. These findings suggest that psoriasin contributes to the dysregulated differentiation process in the psoriasis epidermis. PMID- 27958611 TI - Methotrexate Use and Monitoring in Patients with Psoriasis: A Consensus Report Based on a Danish Expert Meeting. AB - Methotrexate (MTX) has been used in the treatment of psoriasis and other dermatological diseases for more than 50 years. However, there is limited evidence regarding its effect, dose and monitoring, and a lack of consensus regarding how the drug should be used in daily practice. Although the use of MTX is governed by guidelines, such as the European S3-Guidelines and the National Institute for Health and Care Excellence (NICE) guideline, it is important to discuss and adjust these guidelines to national standards. An expert meeting was held in Denmark at the end of 2014, in order to reach consensus regarding the use of MTX in dermatological practice in Denmark. Participants included dermatologists, hepatologists, paediatricians, clinical biochemists and a rheumatologist. Topics discussed were: liver disease monitoring, teratogenic effects of MTX, risk of cancer, and use of MTX in children. We report here the conclusions of this expert meeting regarding use of MTX in dermatological practice. PMID- 27958612 TI - Multiple Primary Melanomas: A Common Occurrence in Western Sweden. AB - Patients diagnosed with a single primary cutaneous melanoma are at increased risk of developing multiple primary melanomas. The aim of this study is to describe the epidemiology of multiple primary melanomas (invasive and in situ) in Western Sweden. Data from the Swedish Melanoma Registry from 1990 to 2013 revealed that 898 patients (7.4%) developed 2,037 multiple primary lesions and 11,254 patients developed single lesions. The proportion of subsequent lesions that were melanoma in situ was 47%, compared with 26% of first melanomas (p < 0.0001).The median and mean time to diagnosis of a subsequent melanoma was 38 and 58 months (95% confidence interval (CI), 53-62 months). In total, 49% of subsequent melanomas were detected within 3 years. Patients and physicians should be aware of the high proportion of multiple primary melanomas in Western Sweden, especially during the first years of follow-up. PMID- 27958613 TI - Opioid Receptors in Psoriatic Skin: Relationship with Itch. AB - Psoriasis is an inflammatory immunogenetic skin disease, often accompanied by itch. Opioid receptors are known regulators of itch sensation in the central nervous system. In the brain, MU-opioid receptors may potentiate itch, while activation of kappa-opioid receptors may reduce or even alleviate itch; however, the role of opioid receptors in itch perception in the skin is poorly understood. To further elucidate the role of opioid receptors in the neurobiology of psoriatic itch, punch biopsies of non-lesional and lesional skin of patients with psoriasis and healthy controls were studied. Real-time polymerase chain reaction and immunofluorescence microscopy were used to detect opioid receptor genes and protein expression, respectively. The OPRK1/kappa-opioid receptor pathway was found to be downregulated in lesional skin of psoriasis, correlating positively with itch sensation. In contrast, the OPRM1/MU-opioid receptor system was uniformly expressed by epidermal keratinocytes in all analysed groups. These findings suggest that imbalance of epidermal opioid receptors may result in disordered neuroepidermal homeostasis in psoriasis, which could potentiate transmission of itch. PMID- 27958614 TI - The relationship between location-specific epicardial adipose tissue volume and coronary atherosclerotic plaque burden in type 2 diabetic patients. AB - BACKGROUND AND AIM: Epicardial adipose tissue (EAT) is a metabolically active visceral fat depot that plays an important role in the pathogenesis of coronary atherosclerosis. Due to its asymmetrical distribution, the relation between location-specific EAT measurements and coronary atherosclerosis remains unclear. Our study investigated the relationship between location-specific EAT volume and coronary atherosclerotic plaque burden that was detected by coronary computed tomography angiography (CCTA) in type 2 diabetic patients without coronary artery disease (CAD) history. METHODS: A total of 157 consecutive diabetic patients who had undergone CCTA were included retrospectively. After evaluation of the CCTA images, the study population was divided into two groups according to the presence of coronary atherosclerosis. In both groups, total and left atrioventricular groove EAT volumes were measured. RESULTS: Total and left atrioventricular groove EAT volumes were significantly associated with coronary atherosclerosis, but only left atrioventricular groove EAT volumes were an independent predictor for CAD. Also, total and left atrioventricular groove EAT volumes were positively correlated with C-reactive protein values (p = 0.0001/p = 0.0001) and the number of coronary atherosclerotic segments (p = 0.0001/p = 0.0001). CONCLUSIONS: Left atrioventricular groove EAT volume is an independent predictor of CAD in type 2 diabetic patients without CAD history. Left atrioventricular groove EAT volume may be used to identify type 2 diabetic patients who may require early CAD intervention because of the potential risk of coronary atherosclerosis. PMID- 27958615 TI - Plasma osmolality predicts mortality in patients with heart failure with reduced ejection fraction. AB - BACKGROUND: Heart failure (HF) is a fatal disease. Plasma osmolality with individual impacts of sodium, blood urea nitrogen (BUN), and glucose has not been studied prognostically in patients with HF. AIM: This study aims to investigate the impact of serum osmolality on clinical endpoints in HF patients. METHODS: A total of 509 patients (383 males, 126 females) with HF with reduced ejection fraction in three HF centres were retrospectively analysed between January 2007 and December 2013. Follow-up data were completed for 496 patients. Plasma osmolality was calculated as (2 * Na) + (BUN/2.8) + (Glucose/18). Quartiles of plasma osmolality were produced, and the possible relationship between plasma osmolality and cardiovascular mortality was investigated. RESULTS: The mean follow-up was 25 +/- 22 months. The mean age was 56.5 +/- 17.3 years with a mean EF of 26 +/- 8%. The mean levels of plasma osmolality were as follows in the quartiles: 1st % = 280 +/- 6, 2nd % = 288 +/- 1, 3rd % = 293 +/- 2 (95% confidence interval [CI] 292.72-293.3), and 4th % = 301 +/- 5 mOsm/kg. The EF and B-type natriuretic peptide levels were similar in the four quartiles. Univariate and multivariate analyses in the Cox proportional hazard model revealed a significantly higher rate of mortality in the patients with hypo-osmolality. The Kaplan-Meier plot showed graded mortality curves with the 1st quartile having the worst prognosis, followed by the 4th quartile and the 2nd quartile, while the 3rd quartile was shown to have the best prognosis. CONCLUSIONS: Our study results suggest that normal plasma osmolality is between 275 and 295 mOsm/kg. However, being close to the upper limit of normal range (292-293 mOsm/kg) seems to be the optimal plasma osmolality level in terms of cardiovascular prognosis in patients with HF. PMID- 27958616 TI - The effect of atrial pacing site on electrophysiological properties of the atrioventricular junction and induction of atrioventricular nodal reentry in patients with typical atrioventricular nodal reentrant tachycardia. AB - BACKGROUND: Clinical studies in humans have shown the site of atrial stimulation to influence atrioventricular (AV) conduction times and refractory periods, the demonstration of dual AV nodal (AVN) pathways, and induction of AVN reentry. These studies often found conflicting results. Moreover, among enrolled patients a minority of them were found to have AVN reentrant tachycardia (AVNRT). AIM: The purpose of this study was to investigate the effect of right and left atrial pacing on the electrophysiological properties of the AV junction in the typical AVNRT population. METHODS: Ninety-two consecutive patients with typical AVNRT were included. Atrial pacing was performed from the high right atrium (HRA) and the left atrium via the proximal coronary sinus (CS). RESULTS: Stimulation from either the HRA or the CS could result in dual AVN physiology and AVNRT. No site dependent differences in the ease of induction of dual AVN pathways with variability of initiation from either site were found. However, AVNRT was easier to induce from the HRA. With CS pacing the leftward but not the rightward AVN approaches were the entry point to the AV node because of significantly shorter AH conduction times compared to HRA pacing. Conduction over the leftward AVN extensions could initiate the tachycardia with significantly shorter critical AH interval compared to conduction over the rightward AVN extensions; however, the AH interval during AVNRT and its cycle length were not significantly different. CONCLUSIONS: Rightward and leftward AVN extensions are regular features of the AV node. Their different electrophysiological properties lead to variation in the demonstration of discontinuous AVN conduction and AVNRT during right and left atrial pacing. Despite the observation that the left AVN extensions could compose the entry point to the reentrant circuit, there is no evidence that they constitute the critical component of sustained typical AVNRT. PMID- 27958617 TI - Results of the Fontan operation with no early mortality in 248 consecutive patients. AB - BACKGROUND: The Fontan operation has undergone several modifications and today is the primary way to treat a broad spectrum of congenital heart defects. AIM: The purpose of this study is to present the results of treatment of children with a single ventricle operated by the same surgical team and managed according to a uniform strategy. METHODS: In the years 2007-2015, in 248 children aged 3.7 +/- 2.6 years and weighing 14.6 +/- 6.1 kg with a single ventricle, Fontan surgery was performed. In 56 (22.6%) children surgery was based on the creation of an intra-atrial lateral tunnel, and in 192 (77.4%) patients extracardiac modification was performed. In most patients, the operation was carried out with the normothermic cardiopulmonary bypass, on a "beating heart" without aortic cross-clamp. The average cardiopulmonary bypass time was 53.9 +/- 23.9 min. The most common indication for surgery was hypoplastic left heart syndrome (53.6%). All patients with a single ventricle referred to our hospital for the Fontan procedure were enrolled into the surgery programme. RESULTS: All patients survived the operation and were discharged home. Thirty-six (14.5%) patients were extubated in the operating room, in other patients the mean duration of the mechanical ventilation was 9.7 +/- 16.1 h (median 7 h). The average time of hospitalisation in the whole study group was 17.5 +/- 18.5 days (median 15 days). After surgery, in four children transient seizures occurred, and three patients had an ischaemic stroke. CONCLUSIONS: Developing and obeying a fixed perioperative protocol is crucial for low mortality and small number of complications after Fontan operation. PMID- 27958619 TI - Evaluation of urgent multivisceral resections due to complications resulting from an advanced ovarian cancer. AB - BACKGROUND: Unlike other solid tumors (i.e. pancreas, gallbladder, stomach), an ovarian cancer is responsive to a systemic treatment with platinum derivates in 80% of patients. This apparent chemosensitivity justifies a broader surgical approach. A cytoreductive, "tumor-debulking" surgery is defined as an attempt to remove in a maximum degree all visible and detect-able lesions. Despite treatment, the advancement of the disease very often leads to complications defined as "surgical" and life-threatening. OBJECTIVES: The aim was to evaluate the efficacy and safety of palliative surgery in advanced ovarian cancer implicating acute surgical diseases of the abdominal cavity. MATERIAL AND METHODS: Between years 2005 and 2014 were operated 118 patients with an advanced ovarian cancer (FIGO III-IV) implicating acute and directly life-threatening diseases of the abdominal cavity, involving 132 surgical operations. The causes of these operations were: obstruction of the gastrointestinal tract - 91 patients; perforation of the gastrointestinal tract - 15; gastrointestinal bleeding - 9; intussusceptions - 3. RESULTS: Retrospective data for the 118 patients were analyzed. Safety and the perioperative mortality rate were assessed. Serious postoperative complications were recorded in 31 patients (anastomotic stoma - 9; bleeding requiring repeated surgery -3; recurring gastrointestinal obstruction - 16; liver failure after partial hepatic resection 3). Systemic compli-cations in the form of respiratory failure and cardiovascular disorders requiring cardiological treatment - 21. All patients required clinical nutrition, both parenteral and enteral. Deaths recorded - 3. 39 patients were rehospitalized within 30 days of surgery. 7 deaths were recorded in this group. CONCLUSIONS: Combining lifesaving surgery with cytoreduction allows further adjuvant treatment. Early rehospitalization occurring within less than 30 days is linked to increased mortality. PMID- 27958618 TI - Morphokinetic parameters as a source of information concerning embryo developmental and implantation potential. AB - OBJECTIVES: The aim of the study was to present the results of time-lapse observation and to verify whether morphokinetic parameters are associated with embryo developmental and implantation potential. MATERIAL AND METHODS: The analysed data concern the development of 1,060 embryos, 898 of which (84.72%) achieved the blastocyst stage and 307 were transferred into the uterine cavity. As a result, 126 (41.04%) biochemical pregnancies and 109 (35.50%) clinical pregnancies were observed. Time from fertilisation to further divisions into 2-9 blastomeres, first to fourth round of cleavage, second to third synchronisation parameters and the duration of stages after the first, second and third division were analysed. RESULTS: Most of the parameters in the group of embryos developed to the blastocyst stage reached lower values than in the non-developed group. Moreover, parameters in the first group clearly had less dispersion. The differences between the groups with and without a biochemical pregnancy were smaller than the differences in the analysis of development to the blastocyst stage. However, in the case of clinical pregnancy analysis, there were again larger differences between both groups. A strong correlation was found between the majority of absolute morphokinetic parameters. A weaker, but still statistically significant correlation, was established between relative and other parameters. CONCLUSIONS: Morphokinetic parameters are associated with embryo developmental and implantation potential and can be considered as predictors of their quality. However, the development of efficient pregnancy prediction models needs further research utilising information from all available parameters and using advanced biostatistical methods. PMID- 27958620 TI - Evolution in the approach to overlooked ureteral injuries after gynecological surgery. AB - OBJECTIVES: To analyzed the therapeutic results for patients with overlooked iatrogenic ureteral injuries after gynecological surgery, treated at the department since 1990. Before the era of endourology, ureteral injuries were operated on immediately after making a diagnosis. This approach was changed after the popularization of percutaneous nephrostomy (PN) and ureteral stenting using a JJ stent. MATERIAL AND METHODS: 27 patients who were diagnosed with a ureteral injury between the first and sixty-fourth day after injury were included. Only PN was performed in 21 patients (group A). In 6 patients, a JJ stent was introduced either immediately after making a diagnosis or after PN (group B). RESULTS: In group A, a good therapeutic result was obtained in only 6 patients (28.6%). Of the 12 patients subjected to PN up to two weeks after injury, 5 had a good result without a need for repair surgery. Of the 9 patients with an injury diagnosed after 3 weeks, only one had a good therapeutic outcome. In Group B, a good result was achieved in 5 out of 6 patients. In 2 patients, a JJ stent was introduced immediately after making the diagnosis, and, in 3 patients, after PN. A successful attempt to "tunnelize" a complete and long obstruction in the sixth patient failed. CONCLUSIONS: Attempting to introduce a JJ stent should be the treatment of choice in patients with an overlooked iatrogenic ureteral injury. If an attempt to introduce the JJ stent fails, PN should be performed as a first step to manage the injury. PMID- 27958621 TI - Data comparison between pharmacological induction of labour and spontaneous delivery. A single centre experience. AB - OBJECTIVES: To assess the differences in the maternal and fetal outcomes between pharmacological induced and sponta-neous labour in nulliparous women. MATERIAL AND METHODS: Observational cohort study carried out over a period of 2 years. INCLUSION CRITERIA: nulliparous sin-gleton pregnancies, with cephalic fetal presentation, elective labour induction with intra-vaginal prostaglandin E2 (PGE2) gel (Prepidil(r) 2 mg) at a gestational age of 41 weeks. CONTROL GROUP: patients who entered labour spontaneously at a gestational age of >= 40 weeks. The main demographic maternal characteristics and intra- and postpartum data were extracted from computer records and obstetrics diaries and were used for the analysis. RESULTS: One hundred and three patients with induction of labour and 97 with spontaneous labour were enrolled. Cesarean delivery was performed in 18 cases (17.5%), all in the induction group. There were no differences in newborn weights between the 2 groups while both the 1-minute and 5-minute Apgar scores were significantly higher in the spontaneous group (p = 0.014 and p = 0.0003, respectively). Women in the induction group had a significantly longer duration of I stage labour in comparison with spontaneous group (p < 0.0001). CONCLUSIONS: Primiparous women whose labour was induced spent a longer time in labour than women who presented in spontaneous labour. Clinicians should keep in mind that a slow rate of dilation in a woman being induced may be normal. For this reason, an arrest diagnosis needs to be carefully considered. PMID- 27958622 TI - Comparison of two different antibiotic regimens for the prophylaxisis of cases with preterm premature rupture of membranes: a randomized clinical trial. AB - OBJECTIVES: The aim of the study was to assess the effect of 1 g ampicillin prophylactic dosage whether it is as effective as the dosage of 2 g to prevent maternal and neonatal morbidity in a randomized manner. MATERIALS AND METHODS: One hundred and fourty eight singleton pregnant women with preterm premature rupture of membranes between 21 and 33 weeks of gestation were followed-up during the study period in our institution. We com-pared the efficacy of two different different dosages of ampicillin. The study population was randomized into 2 groups. In the group 1, 1 g of intravenous ampicillin was given every 6 hours. In the group 2, 2 g of intravenous ampicillin was given every 6 hours. RESULTS: There was no significant difference between groups interms of fetal complications (RDS, icterus, mortality, sepsis, transient tachypnea of newborn and the pneumonia), rate of intensive care unit admission, fetal gender, fever, rate of clinical chorioamnionitis, high white blood cell count and the CRP, rate of cases < 30 weeks (p > 0.05). There was a significant differ-ence between the groups for the rate of previous preterm premature rupture of membranes history, steroid administration and the need for tocolysis (p < 0.05). CONCLUSIONS: Although antibiotics seems to be innocent, several side effects have been introduced. It is reasonable to use the lowest dosages in shortest period in order to minimize these unwanted effects. PMID- 27958623 TI - Clinical expression of Holt-Oram syndrome on the basis of own clinical experience considering prenatal diagnosis. AB - OBJECTIVES: Holt-Oram syndrome manifests with defects of upper limbs, pectoral girdle and cardiovascular system. The aim of this paper was to present complex clinical picture of the syndrome and its variable expression on the example of the family diagnosed genetically on the neonatal ward, after proband's prenatal examination. MARETIAL AND METHODS: Nine family members were tested for TBX5 gene mutation. RESULTS: Four of family members were diagnosed with Holt-Oram syndrome and five had correct genetic test results. The diagnosis allowed to identify a genetic risk family and enabled to provide them with genetic counselling. CONCLUSIONS: Diagnosis of Holt-Oram syndrome is possible as early as in prenatal period and it can be verified by genetic tests. PMID- 27958624 TI - Analysis of the origin of birth defects in pregnant women from the Kujawy Pomerania Region. AB - OBJECTIVES: The aim of the study was to analyze the origin of birth defects in pregnant women from the Kujawy-Pomerania Region, and to identify factors affecting the formation of developmental disorders in the Province. MATERIAL AND METHODS: The correlation between maternal age and fetal defects was investigated. We also attempted to determine whether environmental or family factors play a role in the formation of fetal abnormalities. RESULTS: The analysis confirmed a correlation between the incidence of chromosomal aberrations and maternal age. CONCLUSIONS: Higher rates of neural tube defects were observed in fetuses born to mothers who did not take folic acid. The influence of other factors on developmental anomalies was not confirmed. PMID- 27958625 TI - Genital psoriasis: a hidden multidisciplinary problem - a review of literature. AB - Genital psoriasis is a variety of autoimmune dermatological disease - psoriasis with relapsing-remitting course, which can have an onset in all age groups. It is most often diagnosed at an advanced stage. Genital psoriasis is considered an embar-rassing condition and is often misjudged as a sexually transmitted disease or allergic reaction due to low social awareness of the disease. The manifestations of genital psoriasis may differ from typical genital dermatoses and with symptoms such as itch, erythroderma and vaginal discharge may mimic other diseases at an early stage. The diagnosis and treatment of genital psoriasis may be difficult and often requires a multidisciplinary approach. The aim of this article is to present the literature review of genital psoriasis concentrating on the clinical presentation, treatment and influence on the quality of patients' life and sexual activity disorders. PMID- 27958627 TI - Successful treatment of spontaneous heterotopic caesarean scar pregnancy by local potassium chloride injection with preservation of the intrauterine pregnancy. PMID- 27958626 TI - Genetic causes of recurrent miscarriages. AB - Recurrent miscarriage is an important problem in reproductive health, which affects 1-5% of couples. The aim of this article is to summarize current knowledge on the genetic causes of recurrent miscarriage. It presents the most common parental genetic disorders (karyotype abnormalities, recessive diseases carrier status, dominant diseases and thrombophilia) connected with recurrent pregnancy loss, as well as research into other possible genetic causes. This review also sets out to demonstrate changes in the embryonic/fetal genome that may lead to abortions, and discusses the methods used to assess miscarried material, together with their advantages and disadvantages. Knowledge of the genetic background of miscarriages is important for prognosis, as well as the potential planning of prenatal diagnostics in subsequent pregnancies. PMID- 27958628 TI - Non-simultaneous two-stage detection of spontaneous bilateral isthmic tubal pregnancy. PMID- 27958629 TI - Prosthetic materials for treating posterior vaginal wall prolapse and rectocele - own experience. AB - OBJECTIVES: This report describes results of posterior vaginal wall prolapse and rectocele treatment performing tension free reconstruction method with polypropylene mesh implantation. MATERIAL AND METHODS: In years 2001 to 20015, 71 female patients in age of 42-82 years were surgically treated. Besides difficult emptying they complained of feeling of heaviness in the pelvis (38%) and dyspareunia (16.9%). Defecography and magnetic resonance proved the presence of rectocele in 84.5%, enterocele in 38%, descending perineum in 28.2%, genital organ prolapse in 23.9%, and rectal prolapse in 22.5% cases. 37 patients with defects of low location have undergone implantation of prosthetic material from vaginal approach. In cases of high location and genital organ prolapse abdominal approach was done. RESULTS: Permanent reconstruction of the rectovaginal septum has been achieved in 70 patients (98%). Symptoms of dyschesia, pelvic plain, heavy straining were persisted in 4 patients (10.3%). 3 cases of mash erosions were diagnosed. One patient was reoperated. Among 6 other patients who needed futher surgical treatment only one was reoperated because of vaginal prolapse. 81.7% of patients was satisfied with their treatment. CONCLUSION: Using prosthetic materials in pelvic floor defects treatment is characterized by high efficacy and low complication percentage. PMID- 27958630 TI - Increased oxidative stress is associated with insulin resistance and infertility in polycystic ovary syndrome. AB - OBJECTIVES: The present study aims to investigate the role of oxidant-antioxidant status in young women with polycystic ovary syndrome (PCOS). MATERIAL AND METHODS: Seventy-one women with PCOS and 53 healthy controls are compared in aspect of demographic characteristics, biochemical data, hormones, and oxidant antioxidant status. RESULTS: The PCOS group had significantly lower zinc, higher malondialdehyde and gluthathione peroxidase and lower serum catalase levels than the control group (p = 0.016, p < 0.001, p = 0.043 and p = 0.025 respectively). The PCOS patients with IR had significantly higher malondialdehyde, lower catalase and serum zinc levels than the PCOS patients without IR (p = 0.015, p = 0.010, p = 0.001 respectively). The infertile PCOS patients had significantly higher malondialdehyde, lower catalase and serum zinc levels than the fertile PCOS patients (p = 0.022, p = 0.045,p = 0.001 respectively). There was a statistically significant and positive correlation between HOMA-IR and malondialdehyde values (r = 0.523, p = 0.001), between HOMA-IR and glutathione peroxidase values (r = 0.468, p = 0.001) and between HOMA-IR and zinc values (r = 0.601, p = 0.001). There was a statistically significant and negative correlation between HOMA-IR and catalase values (r = -0.493, p = 0.001). CONCLUSIONS: The patients with PCOS are under oxidative stress and this oxidative stress seems to be the highest in patients with IR and with infertility. Despite the prominent increase in the oxidative stress, there was a variation in the antioxidant response. PMID- 27958631 TI - New aspects of postmenopausal osteoporosis treatment with micronized estradiol and progesterone. AB - OBJECTIVES: The aim of the study was to assess the effectiveness of postmenopausal osteoporosis treatment with natural sex hormones. MATERIAL AND METHODS: The single-blind study included 210 women, randomly allocated to three different groups, with various methods of treatment: Group I (70 controls) received transcutaneous placebo for the course of one year, Group II (70 females, aged 52.2 +/- 3.1 years) used oral hormone supplementary therapy (HST), and Group III (70 females, aged 51.9 +/- 3.5 years) received transcutaneous modified hormone replacement therapy (MHRT), supplemented with intravaginal lutein, dietary minerals, and 1000 IU of vitamin D3/day. RESULTS: No increase in bone mineral density was observed in the control group. However, mineral density of the vertebral bodies was significantly higher after 3 and 5 years in the HST group (p < 0.05), and after 1 year in the MHRT group (p < 0.01). This increase was even more significant (p < 0.001) after 3 and 5 years in the MHRT group. CONCLUSIONS: Transcutaneous hormone therapy with micronized estradiol and progesterone is the treatment of choice in postmenopausal osteoporosis, as evidenced by bone mineral density and biochemical markers. PMID- 27958632 TI - Association between rs7901695 and rs7903146 polymorphisms of the TCF7L2 gene and gestational diabetes in the population of Southern Poland. AB - OBJECTIVES: The etiology of gestational diabetes mellitus (GDM) remains to be fully elucidated. Elevated risk for type 2 diabetes in patients with history of GDM and for GDM in women with familial history of diabetes may suggest that GDM and type 2 diabetes share a common genetic and environmental background. The TCF7L2 (Transcription Factor 7 Like 2) gene is one of the most important genetic factors of the established correlation with type 2 diabetes, and it may also play a role in the pathophysiology of GDM. The aim of the study was to assess the influence of two polymorphisms of the TCF7L2 gene (rs7901695 and rs7903146), which are associated with the development of type 2 diabetes, in women with GDM. MATERIAL AND METHODS: The study included 50 women with glucose tolerance disorders diagnosed for the first time during the current pregnancy. Single nucleotide polymorphisms (SNPs) were genotyped using allelic discrimination. The results were confirmed using the sequencing method. Selected clinical parameters were also analyzed. RESULTS: No correlation between the studied polymorphisms of the TCF7L2 gene and GDM was observed. Glycemic control with diet or diet and insulin was associated with better control of the weight gain during pregnancy. CONCLUSIONS: No correlation between rs7903146 and rs7901695 polymorphisms of the TCF7L2 gene and GDM was found. Glycemic control with diet or diet and insulin is associated with better control of the weight gain during pregnancy. PMID- 27958633 TI - Nasal bone in screening for T21 at 11-13 + 6 weeks of gestation - a multicenter study. AB - OBJECTIVES: Trisomy 21 is one of the most common chromosomal defects diagnosed prenatally. Screening for Down syndrome is based on maternal age, measurement of crown-rump length, nuchal translucency and fetal heart rate, together with free beta-hCG and PAPP-A at 11 to 13 + 6 weeks. Introduction of additional ultrasound marker of trisomy 21 (evaluation of the nasal bone) may result in increased DR and decreased invasive diagnostic testing rates (FPR). MATERIAL AND METHODS: Ultrasound scan with NB evaluation was performed in 5814 fetuses during routine screening for chromosomal defects at 11 to 13 + 6 weeks of gestation. DR and FPR coefficients were calculated for 4 levels of risk as cut-off points for screening model 1, based on MA, NT, and first trimester biochemistry, as well as for screening model 2, based on MA, NT, first trimester biochemistry and NB. RESULTS: There were 5708 normal cases, 71 cases of trisomy 21 and 35 cases of other chromosomal defects. NB was absent in 46 (64.8%) cases and present in 25 (35.3%) cases of trisomy 21, comparing to present NB in 5463 (95.7%) and absent in 245 (4.3%) of normal cases. CONCLUSIONS: First-semester screening with additional NB assessment significantly increases the detection rate for trisomy 21 and decreases the rate of false-positive results. Adding NB evaluation at the risk level of 1:50 causes only a small increase in detection rate. Invasive procedures should be performed in that group regardless NB assessment. PMID- 27958634 TI - Effect of morphological and functional changes in the secundines on biometric parameters of newborns from dichorionic twin pregnancies. AB - OBJECTIVES: The aim of the study was to determine if, and to what extent, structural and functional changes of the secundines influence biometric parameters of neonates from dichorionic twin pregnancies. MATERIAL AND METHODS: The study included neonates from dichorionic, diamniotic twin pregnancies, along with their secundines. Based on histopathological examination of the secundines, the mass and dimensions of the placenta, length and condition of the umbilical cord, chorionicity, focal lesions, and microscopic placental abnormalities were determined for 445 pairs of twins. Morphological development of examined twins was characterized on the basis of their six somatic traits, while birth status of the newborns was assessed based on their Apgar scores. Statistical analysis included Student t-tests, Snedecor's F-tests, post-hoc tests, non-parametric chi squared Pearson's tests, and determination of Spearman coefficients of rank correlation. RESULTS: The lowest values of analyzed somatic traits were observed in twins who had placentas with velamentous or marginal cord insertion. Inflammatory lesions in the placenta and placental abruption turned out to have the greatest impact of all analyzed abnormalities of the secundines. Inflammatory lesions in the placenta were associated with lower values of biometric parameters and a greater likelihood of preterm birth. Neonates with a history of placental abruption were characterized by significantly lower birth weight and smaller chest circumference. CONCLUSIONS: Morphological changes in the secundines have a limited impact on biometric parameters of neonates from dichorionic twin pregnancies. In turn, functional changes exert a significant effect and more often contribute to impaired fetal development. PMID- 27958635 TI - Influence of Apa1 (rs7975232), Taq1 (rs731236) and Bsm1 (rs154410) polymorphisms of vitamin D receptor on preterm birth risk in the Polish population. AB - OBJECTIVES: Vitamin D receptor (VDR) is expressed in the placenta and tissues related to the immune system occurrence of various variants of VDR may modify the effects of vitamin D on pregnancy. The aim of this study was to evaluate the association between the parturients' Apa1, Taq1, and Bsm1 polymorphisms of the VDR and their combinations and the risk of preterm birth in the Polish population. MATERIAL AND METHODS: Determination of polymorphism for VDR was assayed using the RT-PCR method. 199 Caucasian women at childbirth were qualified:100 patients who had a spontaneous preterm birth and 99 patients who had a term birth. RESULTS: Three separate genotypes of the Apa1, Taq1, and Bsm1 polymorphisms were detected. No significant differences in the frequency of particular genotypes in the compared groups were found. Some of the genotype combinations were significantly more frequent in the preterm group - the bb/AA/TT genotype (28.0% vs. 10.1%; p = 0.0013) and the BB/aa/tt genotype (14.0% vs. 4.04% p = 0.0277). The Bb/AA/Tt and the BB/Aa/tt genotypes were found only in the control group (16.1% and 7.0% of patients, respectively). The bb/aa/TT was significantly more frequent in the control group (2.0% vs. 11.1%; p = 0,0207). Two genotype combinations reduced the risk of preterm birth - the Bb/AA/Tt genotype by 94% (OR = 0.43, 95% CI: 0.002-0.885, p = 0.041) and the BB/Aa/tt genotype by 98% (OR = 0.029, 95% CI: 0.001-0.838, p = 0.039). CONCLUSIONS: Our result suggests that there may be a relationship between certain VDR genotype combinations and the risk of preterm birth. Further research is needed in order to substantiate this finding. PMID- 27958636 TI - Intrauterine growth restriction in pregnant women after kidney transplantation as a marker of preeclampsia. AB - OBJECTIVES: Delayed motherhood is associated with an increasing number of comorbidities such as glomerulonephritis, systemic lupus erythematosus, and diabetic nephropathy. Women after renal transplant belong to the group of patients who require a highly individualized approach to treatment and diagnosis. The aim of the study was to validate the commonly used diagnostic criteria for preeclampsia which seem to be irrelevant in patients with chronic renal insufficiency. MATERIAL AND METHODS: The course of pregnancy and delivery were retrospectively analyzed in 48 renal transplant patients. Two patients were excluded. Group I included 23 patients with eutrophic neonates, while Group II consisted of 23 patients with fetal hypotrophy (birth weight of < 10th percentile). RESULTS: The duration of pregnancy was 34.5 and 35 weeks in Groups I and II, respectively. Mean birth weight in Groups I and II was 2608.64 g and 2046.30 g, respectively (p = 0.002). Mean weight percentile in Groups I and II was 36.57 and 2.91, respectively (p < 0.000). Proteinuria in the first half of pregnancy occurred in 16 and 14 patients from Groups I and II, respectively, and increased in the second half of pregnancy in 6 and 6 patients from Groups I and II, respectively. Patients from Group II were more prone to urinary tract infections (0.43 vs. 0.79; p = 0.02). CONCLUSIONS: Current diagnostic criteria for preeclampsia are insufficient in case of pregnant women after kidney transplant. General criteria should be applied with special care in women with chronic kidney disease or in patients with systemic lupus erythematosus. As a predictive factor of neonatal morbidity, intrauterine growth restriction seems to be more valuable than typical markers of kidney function. PMID- 27958637 TI - Thromboprophylaxis in women undergoing gynecological surgery or assisted reproductive techniques: new advances and challenges. AB - Venous thromboembolism (VTE) affects 0.1-0.3% people each year. The risk of VTE following gynecological surgery and invasive procedures is well established and presents one of the major challenges in gynecological practice. Moreover, commonly use assisted reproductive techniques (ART) are reported to increase the risk of VTE. Despite continued efforts to reduce its incidence, postoperative VTE remains the second most common perioperative complication and the third most common cause of mortality. Several practice guidelines have been developed regarding prophylaxis and treatment of VTE. However, there is a large inconsistency between the recommendations and the medical practice in various centers. Moreover, prophylaxis in gynecological patients and women undergoing ART should be chosen individually for the patient, taking into account the possible risk factors for VTE and perioperative bleeding complications. Until recently, the percentage of women, who have not received anticoagulant prophylaxis or administrated it inadequately may reach 50%. This paper presents the current recommendations regarding thromboprophylaxis in women undergoing gynecological surgery or assisted reproductive techniques and addresses challenging practical issues in this field. PMID- 27958638 TI - A rare case of asymptomatic rupture of the uterine horn in the full-term pregnancy as a consequence of laparoscopic salpingectomy. PMID- 27958639 TI - New Charge-Transfer Complexes with 1,2,5-Thiadiazoles as Both Electron Acceptors and Donors Featuring an Unprecedented Addition Reaction. AB - The design and synthesis of novel charge-transfer (CT) complexes are of interest for fundamental chemistry and applications to materials science. In addition to the recently described first CT complex with both electron acceptor (A) and donor (D) groups belonging to the 1,2,5-thiadiazole series (1; A: 4-nitro-2,1,3 benzothiadiazole; D: 4-amino-2,1,3-benzothiadiazole), herein novel CT complexes 2 and 3 with 1,2,5-thiadiazoles as both A (4,6-dinitro-2,1,3-benzothiadiazole and [1,2,5]thiadiazolo[3,4-c][1,2,5]thiadiazole) and D (4-amino-2,1,3 benzothiadiazole) were synthesized. The series is completed by complex 4 with [1,2,5]thiadiazolo[3,4-c][1,2,5]thiadiazole as A and phenoxatellurine as D. Structures of complexes 2-4 were characterized by single-crystal X-ray diffraction (XRD), as well as solution and solid-state UV/Vis spectroscopy. Thermodynamics of their formation were obtained by density functional theory (DFT) calculations, their bonding situations were analyzed by quantum theory of atoms in molecules (QTAIM) calculations and dimer model energies of interactions quantified in the framework of the Hirshfeld surface (HS) analysis. With DFT calculations, the largest value of CT between D and A was found for complex 2, with 0.027 e in the XRD structure and 0.150 e in the optimized structure in MeCN. In the UV/Vis spectra, the lambdamax of the CT bands of 2-4 varied in the range lambda=517-705 nm. Model energy calculations for 1-4 revealed the importance of both dispersion interactions and hydrogen bonding between D and A as contributors to CT in the crystalline state. In an attempt to enlarge the CT value with bis[1,2,5-thiadiazolo][3,4-b;3',4'-e]pyrazine as A and 4-amino-2,1,3 benzoselenadiazole as D, an unprecedented 1:1 addition reaction was observed upon formation of a C-N bond between atom C7 of D and pyrazine atom N4 of A, accompanied by hydrogen atom transfer from C7 to another pyrazine atom N8 (compound 5). According to DFT calculations, the reaction is a multistep process featuring diradical intermediates and hydrogen atom intramolecular migration over four positions. Molecular and crystal structures of 5 (solvate with toluene) were elucidated by XRD and the crystal structure revealed a rather unusual porous framework. PMID- 27958640 TI - Addition of CsCl reduces ion suppression effects in the matrix-assisted laser desorption/ionization mass spectra of triacylglycerol/phosphatidylcholine mixtures and adipose tissue extracts. AB - RATIONALE: Ion suppression is a known disadvantage in mixture analysis. Matrix assisted laser desorption/ionization (MALDI) mass spectra of crude adipose tissue extracts are dominated by triacylglycerol (TAG) signals while less abundant phospholipids such as phosphatidylcholines (PC) and particularly phosphatidylethanolamines (PE) are suppressed. It is suggested that addition of an excess of cesium (Cs) ions helps to overcome this problem. METHODS: Selected lipid mixtures of known compositions and organic adipose tissue extracts were investigated by positive ion MALDI-time-of-flight mass spectrometry (TOF MS). 2,5 Dihydroxybenzoic acid (DHB) in methanol was used as the matrix. In selected cases the methanolic DHB solution was saturated by the addition of different solid alkali chlorides (such as NaCl, KCl, RbCl and CsCl). Studies on the solubilities of these salts in methanol and the interaction with DHB (by 13 C NMR) were also performed. RESULTS: Saturation of the DHB matrix with solid CsCl leads to tremendous intensity differences, i.e. the intensities of the TAG signals (which otherwise dominate the mass spectra) are significantly reduced. In contrast, the intensity of small signals of phospholipids increases considerably. Decrease in the TAG signal intensity is particularly caused by the considerable size of the Cs+ ion which prevents successful analyte ionization. CONCLUSIONS: The addition of CsCl improves the detectability of otherwise invisible or weak phospholipid ions. This is a simple approach to detect small amounts of phospholipids in the presence of an excess of TAG. No laborious and time-consuming separation of the total lipid extract into the individual lipid classes is required. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27958641 TI - Toward accurate and precise estimates of lion density. AB - Reliable estimates of animal density are fundamental to understanding ecological processes and population dynamics. Furthermore, their accuracy is vital to conservation because wildlife authorities rely on estimates to make decisions. However, it is notoriously difficult to accurately estimate density for wide ranging carnivores that occur at low densities. In recent years, significant progress has been made in density estimation of Asian carnivores, but the methods have not been widely adapted to African carnivores, such as lions (Panthera leo). Although abundance indices for lions may produce poor inferences, they continue to be used to estimate density and inform management and policy. We used sighting data from a 3-month survey and adapted a Bayesian spatially explicit capture recapture (SECR) model to estimate spatial lion density in the Maasai Mara National Reserve and surrounding conservancies in Kenya. Our unstructured spatial capture-recapture sampling design incorporated search effort to explicitly estimate detection probability and density on a fine spatial scale, making our approach robust in the context of varying detection probabilities. Overall posterior mean lion density was estimated to be 17.08 (posterior SD 1.310) lions >1 year old/100 km2 , and the sex ratio was estimated at 2.2 females to 1 male. Our modeling framework and narrow posterior SD demonstrate that SECR methods can produce statistically rigorous and precise estimates of population parameters, and we argue that they should be favored over less reliable abundance indices. Furthermore, our approach is flexible enough to incorporate different data types, which enables robust population estimates over relatively short survey periods in a variety of systems. Trend analyses are essential to guide conservation decisions but are frequently based on surveys of differing reliability. We therefore call for a unified framework to assess lion numbers in key populations to improve management and policy decisions. PMID- 27958642 TI - A tutorial on how to do a Mokken scale analysis on your test and questionnaire data. AB - Over the past decade, Mokken scale analysis (MSA) has rapidly grown in popularity among researchers from many different research areas. This tutorial provides researchers with a set of techniques and a procedure for their application, such that the construction of scales that have superior measurement properties is further optimized, taking full advantage of the properties of MSA. First, we define the conceptual context of MSA, discuss the two item response theory (IRT) models that constitute the basis of MSA, and discuss how these models differ from other IRT models. Second, we discuss dos and don'ts for MSA; the don'ts include misunderstandings we have frequently encountered with researchers in our three decades of experience with real-data MSA. Third, we discuss a methodology for MSA on real data that consist of a sample of persons who have provided scores on a set of items that, depending on the composition of the item set, constitute the basis for one or more scales, and we use the methodology to analyse an example real-data set. PMID- 27958643 TI - Nutrient-enriched formula versus standard formula for preterm infants following hospital discharge. AB - BACKGROUND: Preterm infants are often growth-restricted at hospital discharge. Feeding nutrient-enriched formula rather than standard formula to infants after hospital discharge might facilitate 'catch-up' growth and might improve development. OBJECTIVES: To compare the effects of nutrient-enriched formula versus standard formula on growth and development of preterm infants after hospital discharge. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (2016, Issue 8) in the Cochrane Library, MEDLINE, Embase and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; to 8 September 2016), as well as conference proceedings and previous reviews. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared the effects of feeding nutrient-enriched formula (postdischarge formula or preterm formula) versus standard term formula to preterm infants after hospital discharge . DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and extracted data independently. We analysed treatment effects as described in the individual trials and reported risk ratios and risk differences for dichotomous data, and mean differences (MDs) for continuous data, with respective 95% confidence intervals (CIs). We used a fixed effect model in meta-analyses and explored potential causes of heterogeneity by performing sensitivity analyses. We assessed quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We included 16 eligible trials with a total of 1251 infant participants. Trials were of variable methodological quality, with lack of allocation concealment and incomplete follow-up identified as major potential sources of bias. Trials (N = 11) that compared feeding infants with 'postdischarge formula' (energy density about 74 kcal/100 mL) versus standard term formula (about 67 kcal/100 mL) did not find consistent evidence of effects on growth parameters up to 12 to 18 months post term. GRADE assessments indicated that evidence was of moderate quality, and that inconsistency within pooled estimates was the main quality issue.Trials (N = 5) that compared feeding with 'preterm formula' (about 80 kcal/100 mL) versus term formula found evidence of higher rates of growth throughout infancy (weighted mean differences at 12 to 18 months post term: about 500 g in weight, 5 to 10 mm in length, 5 mm in head circumference). GRADE assessments indicated that evidence was of moderate quality, and that imprecision of estimates was the main quality issue.Few trials assessed neurodevelopmental outcomes, and these trials did not detect differences in developmental indices at 18 months post term. Data on growth or development through later childhood have not been provided. AUTHORS' CONCLUSIONS: Recommendations to prescribe 'postdischarge formula' for preterm infants after hospital discharge are not supported by available evidence. Limited evidence suggests that feeding 'preterm formula' (which is generally available only for in hospital use) to preterm infants after hospital discharge may increase growth rates up to 18 months post term. PMID- 27958644 TI - Effect of Perilla frutescens Extracts on Porcine Jejunal Epithelial Cells. AB - Green-leaved Perilla frutescens extracts were investigated on their effect on cell proliferation of the porcine jejunal epithelial cell line, IPEC-J2, as well as on the gene expression of cell cycle or cancer-related genes. Some extracted compounds were, however, susceptible to degradation in cell culture medium, whereas others were found to be stable during the entire experimental time. Control experiments also included the assessment of H2 O2 generation in cell culture medium caused by oxidation of natural extract compounds, which was proved to be absent at low extract concentrations. A fast and significant inhibition of cell growth at low physiological extract concentrations could be observed. This finding, along with an immediate downregulation of 67 kDa laminin receptor and cyclin D1 expression, can be accounted to the presence of Perilla frutescens extract. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27958646 TI - Reductive Elimination of Hydrogen from Bis(trimethylsilyl)methyltin Trihydride and Mesityltin Trihydride. AB - Alkyltin trihydride [(Me3 Si)2 CHSnH3 ] was synthesized and the reductive elimination of hydrogen from this species was investigated. A methyl-substituted N-heterocyclic carbene reacts with the organotrihydride in dependence on stoichiometry and solvent to give a series of products of the reductive elimination and dehydrogenative tin-tin bond formation. Besides characterization of the carbene adduct of the alkyltin(II) hydride, a Sn4 chain was also isolated, encompassing two stannyl-stannylene sites, which are stabilized each as NHC adducts. Complete dehydrogenation resulted to give either a carbene-stabilized distannyne or a metalloid Sn9 -cluster salt. Reductive elimination of hydrogen was also achieved with an excess of diethylmethylamine to give the alkyltin(II) hydride as a Lewis base free tetramer [(RSnH)4 ]. The method of cluster formation at low temperatures by hydrogen elimination was also transferred to the mesityl substituted tin trihydride MesSnH3 . In this case [(MesSn)10 ], showing a [5]prismane structure, was isolated in good yield and characterized. NMR spectroscopic features of the propellane-type cluster [Trip6 Sn6 ] are reported. PMID- 27958647 TI - Mass spectrometric study of thermodynamic properties in the Gd2 O3 -Y2 O3 system at high temperatures. AB - RATIONALE: The Gd2 O3 -Y2 O3 system possesses a number of practical applications, one of the most important of them being production of casting molds for gas turbine engine blades. The components of this system are often added to zirconia or hafnia to obtain high-temperature ceramics which are used for the development of thermal barrier coatings. However, Gd2 O3 and Y2 O3 are more volatile than zirconia or hafnia and may vaporize selectively during synthesis or usage of high temperature materials which may lead to changes in their physicochemical properties. Therefore, information on the vaporization processes and thermodynamic properties of the Gd2 O3 -Y2 O3 system is of great importance. METHODS: High-temperature Knudsen effusion mass spectrometry was used to study the vaporization processes and to determine the thermodynamic properties of the Gd2 O3 -Y2 O3 system. Measurements were performed with a MS-1301 mass spectrometer. Vaporization was carried out using a tungsten twin effusion cell containing the sample under study and pure Gd2 O3 as a reference substance. Electron ionization at an energy of 25 eV was employed. RESULTS: At the temperature of 2630 K, GdO, YO and O vapor species were identified over the samples in the Gd2 O3 -Y2 O3 system. The Gd2 O3 and Y2 O3 activities and the vaporization rates of samples as functions of composition in the Gd2 O3 -Y2 O3 system were derived from the partial pressures of the vapor species mentioned. Using these data the Gibbs energy of mixing and excess Gibbs energy of the hexagonal solid solution in this system were calculated at 2630 K. CONCLUSIONS: The thermodynamic properties of the Gd2 O3 -Y2 O3 system, such as the activities of components and the excess Gibbs energy, obtained in the present study using Knudsen mass spectrometry at 2630 K, demonstrated significant negative deviations from ideal behavior. The vaporization rates of the samples were found to decrease as the Y2 O3 content increased. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27958648 TI - Penalized partial likelihood inference of proportional hazards latent trait models. AB - The Cox proportional hazards model with a latent trait variable (Ranger & Ortner, 2012, Br. J. Math. Stat. Psychol., 65, 334) has shown promise in accounting for the dependency of response times from the same examinee. The model allows flexibility in shapes of response time distributions using the non-parametric baseline hazard rate while allowing parametric inference about the latent variable via exponential regression. The flexibility of the model, however, comes at the price of a significant increase in the complexity of estimating the model. The purpose of this study is to propose a new estimation approach to overcome this difficulty in model estimation. The new procedure is based on the penalized partial likelihood estimator in which the partial likelihood is maximized in the presence of a penalty function. The potential of the proposed method is corroborated by a series of simulation studies for fitting the proportional hazards latent trait model to psychological and educational testing data. The application of the estimation method to the hierarchical framework (van der Linden, 2007, Psychometrika, 72, 287) is also illustrated for jointly analysing response times and accuracy scores. PMID- 27958645 TI - Comparing identified and statistically significant lipids and polar metabolites in 15-year old serum and dried blood spot samples for longitudinal studies. AB - RATIONALE: The use of dried blood spots (DBS) has many advantages over traditional plasma and serum samples such as the smaller blood volume required, storage at room temperature, and ability to sample in remote locations. However, understanding the robustness of different analytes in DBS samples is essential, especially in older samples collected for longitudinal studies. METHODS: Here we analyzed the stability of polar metabolites and lipids in DBS samples collected in 2000-2001 and stored at room temperature. The identified and statistically significant molecules were then compared to matched serum samples stored at -80 degrees C to determine if the DBS samples could be effectively used in a longitudinal study following metabolic disease. RESULTS: A total of 400 polar metabolites and lipids were identified in the serum and DBS samples using gas chromatograph/mass spectrometry (GC/MS), liquid chromatography (LC)/MS, and LC/ion mobility spectrometry-MS (LC/IMS-MS). The identified polar metabolites overlapped well between the sample types, though only one statistically significant metabolite was conserved in a case-control study of older diabetic males with low amounts of high-density lipoproteins and high body mass indices, triacylglycerides and glucose levels when compared to non-diabetic patients with normal levels, indicating that degradation in the DBS samples affects polar metabolite quantitation. Differences in the lipid identifications indicated that some oxidation occurs in the DBS samples. However, 36 statistically significant lipids correlated in both sample types. CONCLUSIONS: The difference in the number of statistically significant polar metabolites and lipids indicated that the lipids did not degrade to as great of a degree as the polar metabolites in the DBS samples and lipid quantitation was still possible. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27958650 TI - Calmodulin Regulated Spectrin Associated Protein 1 mRNA is Directly Regulated by miR-126 in Primary Human Osteoblasts. AB - Vascularization is essential for bone development, fracture healing, and bone tissue engineering. We have previously described that coculture of primary human osteoblasts (hOBs) and human umbilical vein endothelial cells (HUVECs) improves differentiation of both cell types. Investigating the role of microRNAs (miRNAs) in this system, we found that miR-126 is highly upregulated in hOBs following coculturing with HUVECs. In this study we performed miR-126 gain-of-function and loss-of-function experiments in hOBs followed by microarray analysis in order to identify targets of miR-126. The transcript cluster IDs were sieved by applying cut-off criteria and by selecting transcripts which were upregulated following miR-126 downregulation and vice versa. The calmodulin regulated spectrin associated protein 1 (CAMSAP1) mRNA was confirmed to be differentially regulated by miR-126. Using the luciferase reporter assay it was demonstrated that CAMSAP1 is directly targeted by miR-126. In this study, we show that miR-126 and CAMSAP1 directly interact in hOBs. This finding has potential implications for tissue engineering applications. J. Cell. Biochem. 118: 1756-1763, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27958649 TI - Sorption and desorption of 17alpha-trenbolone and trendione on five soils. AB - The metabolites 17alpha-trenbolone and 17alpha-estradiol are principal metabolites in cattle excreta following the administration of Synovex(r) ONE, which contains trenbolone acetate and estradiol benzoate. As part of the environmental assessment of the use of Synovex ONE, data were generated to characterize the fate of 17alpha-trenbolone, and its metabolite trendione in the environment. Predictions of the fate and environmental concentrations of these hormones after land application require accurate estimates of the sorption of these compounds in soils. The sorption and desorption of 17alpha-trenbolone and trendione were measured at 5 nominal concentrations in 5 soils from different geologic settings using a batch equilibrium technique following guideline 106 of the Organisation for Economic Co-operation and Development. Both the sorption and desorption of 17alpha-trenbolone and trendione to soils were adequately described by the Freundlich sorption model and by linear partition coefficients. The mean sorption coefficients were 9.04 mL/g and 32.2 mL/g for 17alpha-trenbolone and trendione, respectively. The corresponding mean Freundlich sorption exponents were 0.88 and 0.98, respectively. Sorption of 17alpha-trenbolone and trendione was correlated principally with soil organic carbon. Average sorption coefficients normalized to soil organic carbon content (KOC ) were 460 mL/g and 1804 mL/g for 17alpha-trenbolone and trendione, respectively. The mean desorption coefficients were 22.1 mL/g and 43.8 mL/g for 17alpha-trenbolone and trendione, respectively. Calculated hysteresis coefficients based on the difference in the area between sorption and desorption isotherms indicated that sorption equilibrium was not fully reversible and hysteresis of desorption isotherms occurred for both 17alpha-trenbolone and trendione. Environ Toxicol Chem 2017;36:613-620. (c) 2016 SETAC. PMID- 27958651 TI - Peripheral Lipopolysaccharide Challenge Induces Long-Term Changes in Tyrosine Hydroxylase Regulation in the Adrenal Medulla. AB - Immune activation can alter the activity of adrenal chromaffin cells. The effect of immune activation by lipopolysaccharide (LPS) on the regulation of tyrosine hydroxylase (TH) in the adrenal medulla in vivo was determined between 1 day and 6 months after LPS injection. The plasma levels of eleven cytokines were reduced 1 day after LPS injection, whereas the level for interleukin-10 was increased. The levels of all cytokines remained at control levels until 6 months when the levels of interleukin-6 and -4 were increased. One day after LPS injection, there was a decrease in TH-specific activity that may be due to decreased phosphorylation of serine 31 and 40. This decreased phosphorylation of serine 31 and 40 may be due to an increased activation of the protein phosphatase PP2A. One week after LPS injection, there was increased TH protein and increased phosphorylation of serine 40 that this was not accompanied by an increase in TH specific activity. All TH parameters measured returned to basal levels between 1 month and 3 months. Six months after injection there was an increase in TH protein. This was associated with increased levels of the extracellular regulated kinase isoforms 1 and 2. This work shows that a single inflammatory event has the capacity to generate both short-term and long-term changes in TH regulation in the adrenal medulla of the adult animal. J. Cell. Biochem. 118: 2096-2107, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27958652 TI - Assessment of Research Capacity Among Nursing Faculty in a Clinical Intensive University in The Philippines. AB - BACKGROUND: Many nursing studies are conducted in the United States, Europe, and Australia, where only a fourth of the world's population resides. There is a need to promote nursing research in Asia to enhance the contextual relevance of their evidence-based nursing interventions. A first step toward this goal is to determine the perceived research capacity among nursing faculty in academic settings in the Philippines. METHODS: This study described the perceived research capacity among nursing faculty of the University of Santo Tomas - College of Nursing, Manila, Philippines. The study used a survey that contained four sections: subject demographics; knowledge and skill on research designs and research process; research involvement, services, and incentives; and factors affecting research involvement. Chi-square test of homogeneity and MANOVA analyzed the gathered data. RESULTS: Findings showed that the faculty perceived themselves as knowledgeable and skillful in conducting research. However, current teaching assignments hindered their capacity to conduct research. University sponsored incentives and college-based research services had also remained underutilized despite their availability. Overall, heavy teaching load was the greatest hindrance to research endeavors. CONCLUSION: Actions must be taken to reconfigure effort allocations with careful consideration of existing university and institutional bylaws. PMID- 27958653 TI - A Concept Analysis of Stigma Perceived by Military Service Members Who Seek Mental Health Services. AB - PROBLEM: The aim of this concept analysis is to clarify military service members' stigma associated with seeking mental health services (MHS). Since 2001, over 2 million military service members have been deployed for or assigned to support military operations. Many service members develop a mental health concern during or after a deployment. Although researchers have assessed perceptions of stigma associated with accessing MHS, defining stigma is difficult, and conceptual clarity regarding stigma is lagging behind studies focused on its effects. METHODS: Stigma was explored using Walker and Avant's method of concept analysis. Thirty articles were found in the PsycARTICLES, PsycINFO, and PubMed databases and selected for inclusion and synthesis. FINDINGS: Military service member stigma is a set of beliefs, based on the member's military and prior civilian enculturation, that seeking MHS would be discrediting or embarrassing, cause harm to career progression, or cause peers or superiors to have decreased confidence in the member's ability to perform assigned duties. CONCLUSIONS: Nurses are ideally suited and situated to play an important role in decreasing stigma inhibiting service members from seeking MHS. Healthcare providers and civilian and uniformed leaders must communicate the value of seeking MHS to ensure service members' health, unit readiness, and overall force preparedness. PMID- 27958654 TI - Beet molasses-based feeding strategy enhances recombinant thermostable glucose isomerase production by Escherichia coli BL21 (DE3). AB - The aim of this work was to develop an effective fed-batch feeding strategy to enhance recombinant glucose isomerase (r-GI) production by recombinant Escherichia coli BL21 (DE3) pLysS on an industrially relevant feedstock without the application of an exogenous inducer. Following the batch operation (0 < t < 7 H), the effects of pulse and/or continuous feeding of hydrolyzed beet molasses were investigated under five different feeding strategies. The two most promising strategies with respect to r-GI activity were (i) PM-0.05, designed with one pulse feed (t = 7 H) followed by a continuous feed and (ii) 2PMF -0.05, designed with two consecutive pulse feeds (t = 7 and 10 H) followed by a continuous feed. The continuous feeding of molasses for both fermentation strategies employed the same precalculated feeding rate, MUo = 0.05 H-1 . The maximum r-GI activities exhibited by PM-0.05 and 2PMF -0.05 were 29,050 and 30,642 U dm-3 , respectively. On the one hand, compared to PM-0.05 r-GI activity reached its maximum within a shorter cultivation time (?tmax = 2 H) at 2PMF -0.05, which could be preferable in terms of manufacturing costs and possible risks; on the other hand, PM-0.05 is a simpler fermentation regime compared to 2PMF -0.05 with respect to manipulations that should be considered in large-scale production. PMID- 27958655 TI - Immunohistochemical characterization of early and advanced knee osteoarthritis by NF-kappaB and iNOS expression. AB - This study was performed to determine the differences in grade of synovitis and expression of NF-kappaB and iNOS in knee synovial membrane between early and advanced stage of osteoarthritis (OA). Thirty synovial membrane intra-operative biopsies of patients (ten controls, ten with early and ten with advanced OA according to Kellgren-Lawrence radiological score) were immunohistochemically (NF kappaB and iNOS) and hystologically (Krenn synovitis score) analyzed and correlated to WOMAC clinical score and pain duration. Krenn synovitis score of patients with radiologically early OA was significantly higher than in patients with advanced OA (p < 0.001). NF-kappaB expression in both synovial intima (p < 0.001) and subintima (p < 0.001) was also higher in early OA. iNOS expression in subintima was significantly higher in early than in advanced OA (p < 0.001), while in intima iNOS showed no statistical difference between groups (p = 0.07). The lymphocytic nodules, located in synovial subintima, were significantly higher in advanced OA when compared to early OA (p = 0.006) and the control group (p < 0.001). These results suggest that in early OA, there is a localized inflammation of the synovial membrane with high expression of NF-kappaB and iNOS. In advanced OA, number of expressed factors is reduced, with the exception of intima cells that highly express iNOS, reflecting the ongoing localized inflammatory process of lower degree. In advanced OA, the density of the resident cells is reduced and lymphocytic nodules appear, confirming the important role of adaptive immunity in later OA stage. Clinical significance of this study is better understanding possibilities of preventive measures for synovitis and OA advancement. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1990-1997, 2017. PMID- 27958656 TI - Novel porcine model of implant-associated osteomyelitis: A comprehensive analysis of local, regional, and systemic response. AB - : Pigs are favorable experimental animals for infectious diseases in humans. However, implant-associated osteomyelitis (IAO) models in pigs have only been evaluated using high-inoculum infection (>108 CFU) models in 1975 and 1993. Therefore, the aim of this paper was to present a new low inoculum porcine model of human IAO based on 42 experimental pigs. The model was created by drilling an implant cavity in the tibial bone followed by insertion of a small steel implant and simultaneous inoculation of Staphylococcus aureus bacteria (n = 32) or saline (n = 10). The infected pigs were either inoculated with 104 CFU (n = 26) or 102 and 103 CFU (n = 6). All animals were euthanized 5 days after insertion of implants. Pigs receiving the high-inoculum infections showed a significantly higher volume of bone lesion, number of neutrophils around the implant, concentrations of acute phase proteins in serum, and enlargement of regional lymph nodes. A positive correlation was present between a high number of surrounding neutrophils and high values of all other parameters. Furthermore, a threshold of 40 neutrophils per 10 high power fields for the histopathological diagnosis of high grade IAO was defined. IN CONCLUSION: This paper describes a novel low-inoculum S. aureus porcine model of IAO which was demonstrated to be reliable, reproducible and discriminative to human IAO, and represents a requested and valuable tool in orthopedic research. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2211-2221, 2017. PMID- 27958658 TI - Degradation of phytosterols in tobacco waste extract by a novel Paenibacillus sp. AB - Phytosterols have been demonstrated to be precursors of polycyclic aromatic hydrocarbons (PAHs) formed during biomass pyrolysis. Here, a novel Paenibacillus sp. was evaluated for its ability to degrade phytosterols in tobacco waste extract (TWE). The optimal conditions for cell growth and stigmasterol (a representative of phytosterols) degradation were 37 degrees C, pH 7.0, 1.0 g/L yeast extract, and 6.0 g/L glucose. Paenibacillus sp. could degrade stigmasterol under high concentrations of glucose (up to 130 g/L) and tolerate wide pH (5.0 9.0) and temperature (25-42 degrees C) ranges. The new strain could degrade stigmasterol completely into CO2 and H2 O, and no intermediate steroids were detected during the degradation process. Phytosterol degradation in TWE was demonstrated by high-performance liquid chromatography-tandem mass spectrometry. Under optimal conditions (37 degrees C, pH 7.0, with the exponential-phase cells), the total degradation ratio of phytosterols reached 38.5% in TWE, including 45.2% of stigmasterol, 37.4% of beta-sitosterol, 27.3% of campesterol, and 28.7% of cholesterol. These results showed that Paenibacillus sp. is a candidate for phytosterol degradation in TWE and other biomass and is potentially useful in reducing the PAHs generated from biomass pyrolysis. PMID- 27958657 TI - Utility of enzyme-linked immunosorbent assays to test core antigen in the diagnosis and antiviral therapy management of hepatitis C virus infections. AB - In this study, we evaluate the performance of the enzyme-linked immunosorbent assays (ELISAs) for HCV Ag detection in the diagnosis and antiviral therapy management of HCV infections. For the diagnosis of an active HCV infection, the limit of detection of HCV Ag corresponding to HCV RNA level was approximately 7300 IU/mL; the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of HCV-Ag were 88.96, 100, 100, and 91.33%, respectively. The Pearson's correlation coefficient between HCV Ag and HCV RNA was 0.891. All patients with negative HCV Ag at interferon-alpha2alpha/ribavirin therapy week 1 achieved a sustained viral response (SVR), and the PPV was 100%; whereas in patients with positive HCV Ag at therapy weeks 12, the NPV for achieving non-response (NR) was 100%. The results showed that ELISAs for HCV Ag detection could be cost effectively applied to diagnose and evaluate the response to antiviral therapy for HCV infections. PMID- 27958659 TI - Differences in Trabecular Microstructure Between Black and White Women Assessed by Individual Trabecular Segmentation Analysis of HR-pQCT Images. AB - Black women have lower fracture risk compared with white women, which may be partly explained by improved volumetric bone mineral density (vBMD) and bone microarchitecture primarily within the cortical bone compartment. To determine if there are differences in trabecular microstructure, connectivity, and alignment according to race/ethnicity, we performed individual trabecular segmentation (ITS) analyses on high-resolution peripheral quantitative computed tomography (HR pQCT) scans of the distal radius and tibia in 273 peri- and postmenopausal black (n = 100) and white (n = 173) women participating in the Study of Women's Health Across the Nation in Boston. Unadjusted analyses showed that black women had greater trabecular plate volume fraction, plate thickness, plate number density, and plate surface area along with greater axial alignment of trabeculae, whereas white women had greater trabecular rod tissue fraction (p < 0.05 for all). Adjustment for clinical covariates augmented these race/ethnicity-related differences in plates and rods, such that white women had greater trabecular rod number density and rod-rod connectivity, whereas black women continued to have superior plate structural characteristics and axial alignment (p < 0.05 for all). These differences remained significant after adjustment for hip BMD and trabecular vBMD. In conclusion, black women had more plate-like trabecular morphology and higher axial alignment of trabeculae, whereas white women had more rod-like trabeculae. These differences may contribute to the improved bone strength and lower fracture risk observed in black women. (c) 2016 American Society for Bone and Mineral Research. PMID- 27958662 TI - Spatial analysis for regional behavior of patients with mental disorders in Japan. AB - AIM: The aim of our study was to clarify the geographical movement of patients treated in psychiatric facilities, which can provide important information on the resources and health-care system of psychiatric services. METHODS: We conducted an analysis of nationwide data on psychiatric patients, collected as an additional survey to the conventional '630 survey' in 2014. For the 151 848 initially admitted inpatients during 6 months and the 144 401 outpatients on a specific day, we identified whether a patient was admitted to a psychiatric facility located in the same medical area as his/her residence. We estimated percentages of being from (i) within the medical area, (ii) within the prefecture, and (iii) outside the prefecture, using a Bayesian statistical approach for each secondary medical area. RESULTS: The inpatients moved across wider areas than did the outpatients. Almost all inpatients and outpatients received their medical treatment at hospitals/clinics within their prefecture of residence. CONCLUSION: The current mental health medical system in Japan has been operating according to prefecture unit; thus, it may be appropriate to plan a medical system at a prefectural level. PMID- 27958660 TI - Angiotensin II reduces the surface abundance of KV 1.5 channels in arterial myocytes to stimulate vasoconstriction. AB - KEY POINTS: Several different voltage-dependent K+ (KV ) channel isoforms are expressed in arterial smooth muscle cells (myocytes). Vasoconstrictors inhibit KV currents, but the isoform selectivity and mechanisms involved are unclear. We show that angiotensin II (Ang II), a vasoconstrictor, stimulates degradation of KV 1.5, but not KV 2.1, channels through a protein kinase C- and lysosome dependent mechanism, reducing abundance at the surface of mesenteric artery myocytes. The Ang II-induced decrease in cell surface KV 1.5 channels reduces whole-cell KV 1.5 currents and attenuates KV 1.5 function in pressurized arteries. We describe a mechanism by which Ang II stimulates protein kinase C dependent KV 1.5 channel degradation, reducing the abundance of functional channels at the myocyte surface. ABSTRACT: Smooth muscle cells (myocytes) of resistance-size arteries express several different voltage-dependent K+ (KV ) channels, including KV 1.5 and KV 2.1, which regulate contractility. Myocyte KV currents are inhibited by vasoconstrictors, including angiotensin II (Ang II), but the mechanisms involved are unclear. Here, we tested the hypothesis that Ang II inhibits KV currents by reducing the plasma membrane abundance of KV channels in myocytes. Angiotensin II (applied for 2 h) reduced surface and total KV 1.5 protein in rat mesenteric arteries. In contrast, Ang II did not alter total or surface KV 2.1, or KV 1.5 or KV 2.1 cellular distribution, measured as the percentage of total protein at the surface. Bisindolylmaleimide (BIM; a protein kinase C blocker), a protein kinase C inhibitory peptide or bafilomycin A (a lysosomal degradation inhibitor) each blocked the Ang II-induced decrease in total and surface KV 1.5. Immunofluorescence also suggested that Ang II reduced surface KV 1.5 protein in isolated myocytes; an effect inhibited by BIM. Arteries were exposed to Ang II or Ang II plus BIM (for 2 h), after which these agents were removed and contractility measurements performed or myocytes isolated for patch-clamp electrophysiology. Angiotensin II reduced both whole-cell KV currents and currents inhibited by Psora-4, a KV 1.5 channel blocker. Angiotensin II also reduced vasoconstriction stimulated by Psora-4 or 4-aminopyridine, another KV channel inhibitor. These data indicate that Ang II activates protein kinase C, which stimulates KV 1.5 channel degradation, leading to a decrease in surface KV 1.5, a reduction in whole-cell KV 1.5 currents and a loss of functional KV 1.5 channels in myocytes of pressurized arteries. PMID- 27958661 TI - The ultimate and proximate mechanisms driving the evolution of long tails in forest deer mice. AB - Understanding both the role of selection in driving phenotypic change and its underlying genetic basis remain major challenges in evolutionary biology. Here, we use modern tools to revisit a classic system of local adaptation in the North American deer mouse, Peromyscus maniculatus, which occupies two main habitat types: prairie and forest. Using historical collections, we find that forest dwelling mice have longer tails than those from nonforested habitat, even when we account for individual and population relatedness. Using genome-wide SNP data, we show that mice from forested habitats in the eastern and western parts of their range form separate clades, suggesting that increased tail length evolved independently. We find that forest mice in the east and west have both more and longer caudal vertebrae, but not trunk vertebrae, than nearby prairie forms. By intercrossing prairie and forest mice, we show that the number and length of caudal vertebrae are not correlated in this recombinant population, indicating that variation in these traits is controlled by separate genetic loci. Together, these results demonstrate convergent evolution of the long-tailed forest phenotype through two distinct genetic mechanisms, affecting number and length of vertebrae, and suggest that these morphological changes-either independently or together-are adaptive. PMID- 27958663 TI - Effectiveness and safety of tolvaptan in liver cirrhosis patients with edema: Interim results of post-marketing surveillance of tolvaptan in liver cirrhosis (START study). AB - AIM: Loop diuretics and spironolactone are used in patients with hepatic edema, but they are sometimes associated with insufficient responses as well as adverse events. Tolvaptan, a vasopressin type 2 receptor antagonist, was approved for hepatic edema in 2013. A large-scale post-marketing surveillance study has been carried out to evaluate the effectiveness and safety of tolvaptan in real-world clinical settings. METHODS: Patients with hepatic cirrhosis with insufficient response to conventional diuretics were enrolled. The observational period was up to 6 months. Changes in body weight and clinical symptoms were measured to evaluate effectiveness. The incidence of adverse drug reactions was summarized as a safety measure. RESULTS: Of 970 patients enrolled, 463 were included in the safety analysis. Of this group, 340 were included in the effectiveness analysis. Decreases in body weight from baseline were -2.38 kg on day 7 and -3.52 kg on day 14. Ascites and bloated feeling was significantly improved within 14 days. The mean change in body weight depended on estimated glomerular filtration rate levels. The most frequently reported adverse drug reaction was thirst (6.9% of patients). Serum sodium level of >=146 mEq/L was observed in 12 patients (2.7%). CONCLUSIONS: In the real-world clinical setting, tolvaptan showed aquaretic effectiveness in patients with cirrhosis. The mean change in body weight depended on renal function. We recommend tolvaptan use for hepatic cirrhosis at a stage in which the renal function is maintained. PMID- 27958664 TI - Geometry, landmarks and the cerebral hemispheres: 2D spatial reorientation in split-brain patients. AB - A right-hemispheric superiority in spatial encoding based on geometric cues has been largely documented in a variety of species, together with a left-hemispheric specialization for encoding based on landmarks. In humans, hemispheric asymmetries for spatial encoding have been little explored. In this study, we compared a patient with a complete callosal resection (D.D.C.) and a patient with a wide callosal resection saving the splenium (A.P.), with healthy participants. In two 2D versions of the 'reorientation task', participants were asked to find the target corner of a rectangle-shaped environment, by exploiting either geometric information alone or the combination of geometric and landmark information. In Experiment 1, the landmark consisted of a coloured side of the rectangle; in Experiment 2, this cue was replaced by a coloured disc located inside the rectangle. In both experiments, the rectangular shape ensured the geometric cue. D.D.C. was always unable to recall the target, whereas A.P. correctly solved the task when only the geometric information was available, without difference with respect to the controls. Importantly, the performance of A.P. did not differ from controls' when the right hemisphere was tested with the landmark cues (the task being carried out using the left hand), whereas when the left hemisphere was tested (right-hand session) his performance was worse than controls' with the coloured side of the space, but it was better than controls' with the coloured disc. The results are discussed comparing them with data collected on other species, and with theories of spatial processing. PMID- 27958665 TI - Waste-to-Chemicals for a Circular Economy: The Case of Urea Production (Waste-to Urea). AB - The economics and environmental impact of a new technology for the production of urea from municipal solid waste, particularly the residue-derived fuel (RdF) fraction, is analyzed. Estimates indicate a cost of production of approximately ?135 per ton of urea (internal rate of return more than 10 %) and savings of approximately 0.113 tons of CH4 and approximately 0.78 tons of CO2 per ton of urea produced. Thus, the results show that this waste-to-urea (WtU) technology is both economically valuable and environmentally advantageous (in terms of saving resources and limiting carbon footprint) for the production of chemicals from municipal solid waste in comparison with both the production of urea with conventional technology (starting from natural gas) and the use of RdF to produce electrical energy (waste-to-energy). A further benefit is the lower environmental impact of the solid residue produced from RdF conversion. The further benefit of this technology is the possibility to realize distributed fertilizer production. PMID- 27958666 TI - Sinusitis in patients on tumor necrosis factor alpha inhibitors. AB - BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) inhibitors have revolutionized treatment of many inflammatory diseases. Sinusitis after initiation of TNF-alpha inhibitors has been observed, but has not been well described in the literature. We aim to characterize the clinical features of sinusitis in patients on anti-TNF-alpha therapy. METHODS: This is a retrospective chart review of 28 patients on a TNF-alpha inhibitor diagnosed with sinusitis by otolaryngologists at Duke University. Patient demographics, sinusitis characteristics, and treatment course were studied by chart review. RESULTS: The prevalence of sinusitis diagnosed and treated by an otolaryngologist was less than 1%. Of the 28 patients studied, 12 (42.9%) had a history of preexisting sinusitis and 16 (57.1%) had new-onset sinusitis. 71.4% were diagnosed with chronic rhinosinusitis without polyps (CRSsNP), with disease mainly involving the maxillary and ethmoid sinuses. No patients had major extrasinus complications or required hospital admission or intravenous (IV) antibiotics. 35.7% (n = 10), including 44% (7/16) of new-onset patients required a surgical intervention after initiating anti-TNF therapy. 14.3% (n = 4) of the cohort had improvement in sinonasal symptoms after stopping, changing, or holding doses of the TNF-alpha inhibitor. CONCLUSION: Anti-TNF-alpha therapy can be associated with new-onset sinusitis, mainly CRSsNP. Overall, the percentage of patients on a TNF-alpha inhibitor seeking consultation from an otolaryngologist is low. While some patients with new-onset sinusitis will require surgery, modification of anti-TNF alpha therapy should be considered as an option in the medical management of these patients. PMID- 27958668 TI - Stereodivergent Olefination of Enantioenriched Boronic Esters. AB - A stereodivergent coupling reaction between vinyl halides and boronic esters is described. This coupling process proceeds without a transition-metal catalyst, instead proceeding by electrophilic selenation or iodination of a vinyl boronate complex followed by stereospecific syn or anti elimination. Chiral, nonracemic boronic esters could be coupled with complete enantiospecificity. The process enables the highly stereoselective synthesis of either the E or Z alkene from a single isomer of a vinyl coupling partner. PMID- 27958667 TI - Thermoluminescence characterization of Ag-doped Li2 B4 O7 single crystal materials. AB - In this study, the thermoluminescence (TL) characteristics of Ag-doped and undoped lithium tetraborate (Li2 B4 O7 , LTB) materials, grown using the Czochralski method, were reported. The TL properties of LTB:Ag, such as glow curve structure, dose response, fading and reproducibility, were investigated. The glow curve of the Li2 B4 O7 :Ag single crystal consists of four peaks located at approximately 75, 130, 190 and 275 degrees C; in undoped LTB, the single crystal shows a broad glow curve with peaks at 65, 90, 125, 160 and 190 degrees C using a heating rate of 5 degrees C/s in the 50-350 degrees C temperature region. The high temperature peak of Ag-doped sample at 275 degrees C has a nonlinear dose response within the range from 33 mGy to 9 Gy. There is a linear response in the range of 33-800 mGy; after which, a sublinear region appears up to 9 Gy for Ag-doped LTB single crystal. For undoped single crystal, the dose response is supralinear for low doses and linear for the region between 1 and 9 Gy. The thermal fading ratio of the undoped material is almost 60% for the high temperature peak after 7 days. Ag-doped LTB single crystal exhibits different behaviour over a period of 7 days. PMID- 27958669 TI - An Orthogonal D2 O-Based Induction System that Provides Insights into d-Amino Acid Pattern Formation by Radical S-Adenosylmethionine Peptide Epimerases. AB - Radical S-adenosyl methionine peptide epimerases (RSPEs) are an enzyme family that accomplishes regiospecific and irreversible introduction of multiple d configured residues into ribosomally encoded peptides. Collectively, RSPEs can generate diverse epimerization patterns in a wide range of substrates. Previously, the lack of rapid methods to localize epimerized residues has impeded efforts to investigate the function and applicative potential of RSPEs. An efficient mass spectrometry-based assay is introduced that permits characterization of products generated in E. coli. Applying this to a range of non-natural peptide-epimerase combinations, it is shown that the d-amino acid pattern is largely but not exclusively dictated by the core peptide sequence, while the epimerization order is dependent on the enzyme-leader pair. RSPEs were found to be highly promiscuous, which allowed for modular introduction of peptide segments with defined patterns. PMID- 27958670 TI - Resveratrol attenuates mitochondrial dysfunction in the liver of intrauterine growth retarded suckling piglets by improving mitochondrial biogenesis and redox status. AB - SCOPE: Emerging evidence has identified mitochondrial biogenesis and oxidative phosphorylation as potential targets for the prevention and treatment of metabolic syndrome. This study investigated the effect of resveratrol (RSV) on hepatic mitochondrial function in intrauterine growth-retarded (IUGR) suckling piglets. METHODS AND RESULTS: Seven normal birth weight (NBW) and fourteen IUGR neonatal male piglets were selected. Piglets were fed control diets supplemented with 0 (NBW-CON), 0 (IUGR-CON), and 1.0 (IUGR-RSV) g RSV per kg of milk dry matter from 7 to 21 days of age (n = 7), respectively. Mitochondrial function, swelling, and redox status in the liver were assessed. Compared with NBW, IUGR impaired hepatic mitochondrial biogenesis and energy homeostasis of the control piglets. IUGR control piglets showed overproduction of superoxide radicals, increased concentration of malondialdehyde, and marked swelling in the mitochondria. RSV improved mitochondrial DNA content, ATP production, and fatty acid oxidation in the liver of IUGR piglets, along with an increased activity of sirtuin 1. RSV inhibited mitochondrial superoxide anion accumulation, increased complex III and manganese superoxide dismutase activities, and ameliorated mitochondrial swelling and lipid peroxidation in the IUGR piglets. CONCLUSION: RSV may have beneficial effects in improving hepatic mitochondrial function and redox status in the IUGR piglets. PMID- 27958672 TI - Adaptive Behavior of Dynamic Orthoester Cryptands. AB - The integration of dynamic covalent bonds into macrocycles has been a tremendously successful strategy for investigating noncovalent interactions and identifying effective host-guest pairs. While numerous studies have focused on the dynamic responses of macrocycles and larger cages to various guests, the corresponding constitutionally dynamic chemistry of cryptands remains unexplored. Reported here is that cryptands based on orthoester bridgeheads offer an elegant entry to experiments in which a metal ion selects its preferred host from a dynamic mixture of competing subcomponents. In such dynamic mixtures, the alkali metal ions Li+ , Na+ , K+ , Rb+ , and Cs+ exhibit pronounced preferences for the formation of cryptands of certain sizes and donor numbers, and the selection is rationalized by DFT calculations. Reported is also the first self-assembly of a chiral orthoester cryptate and a preliminary study on the use of stereoisomers as subcomponents. PMID- 27958671 TI - A highly selective and sensitive turn-on fluorescent probe for the detection of Al3+ and its bioimaging. AB - A novel fluorescent sensor, 1-((2-hydroxynaphthalen-1-yl)methylene)urea (ocn) has been designed and applied as a highly selective and sensitive fluorescent probe for recognition of Al3+ in Tris-HCl (pH = 7.20) solution. The probe ocn exhibits an excellent selectivity to Al3+ over other examined metal ions, anions and amino acids with a prominent fluorescence 'turn-on' at 438 nm. ocn binds to Al3+ with a 2:1 binding stoichiometry and the detection limit was 0.3 MUM. Furthermore, its capability of biological application was evaluated and the results showed that the sensor could be used to detect Al3+ in living cells. PMID- 27958673 TI - The Role of Surfactants in the Stability of NiO Nanofluids: An Experimental and DFT Study. AB - This study shows an analysis of the stability of nanofluids based on a eutectic mixture of diphenyl oxide and biphenyl, which is used as a heat transfer fluid (HTF) in concentrating solar energy, and NiO nanoparticles. Two surfactants are used to analyse the stability of the nanofluids: benzalkonium chloride (BAC) and 1-octadecanethiol (ODT). From an experimental perspective, the stability is analysed by means of UV/Vis spectroscopy, particle size measurements through the dynamic light-scattering technique, and zeta-potential measurements. The results show that the stability of the nanofluids improves with the use of BAC. DFT calculations are performed to understand the role played by the surfactants. The interaction of the surfactants with both the fluid and the NiO (100) surface is studied. Quantum theory of atoms in molecules (QTAIM) analysis shows that hydrogen bridge interactions favour the stability of the fluid-surfactant mixture. The more stabilising NiO-surfactant interaction involves the Ni-H interaction of the -SH and -CH3 groups of ODT and BAC. Also, nanofluids with BAC are favoured over those with ODT, which is in agreement with experimental results. The structural and electronic effects of incorporating the surfactant onto the NiO (100) surface are shown by using electron localisation function analysis, the non-covalent interaction index and projected density of states. PMID- 27958674 TI - Sulfonimidamides in Medicinal and Agricultural Chemistry. AB - The synthesis and evaluation of structural analogues and isosteres are of central importance in medicinal and agricultural chemistry. The sulfonamide functional group represents one of the most important amide isosteres in contemporary drug design, and about 500 such compounds have overcome both the pharmacological and regulatory hurdles that precede studies in humans. The mono aza analogues of sulfonamides, that is, sulfonimidamides, are rapidly gaining popularity as a novel functional group among synthetic chemists involved in the design of biologically active compounds for both pharmaceutical and agrochemical applications. Herein, we review these recent developments to showcase the promise of this functional group. PMID- 27958675 TI - Microbial and endogenous metabolic conversions of rye phytochemicals. AB - Rye is one of the main cereals produced and consumed in the hemiboreal climate region. Due to its use primarily as wholegrain products, rye provides a rich source of dietary fibre as well as several classes of phytochemicals, bioactive compounds with potentially positive health implications. Here, we review the current knowledge of the metabolic pathways of phytochemical classes abundant in rye, starting from the microbial transformations occurring during the sourdough process and colonic fermentation and continuing with the endogenous metabolism. Additionally, we discuss the detection of specific metabolites by MS in different phases of their journey from the cereal to the target organs and excretion. PMID- 27958676 TI - Refinement of needling classification for trabeculectomy blebs. PMID- 27958677 TI - Solid-phase nanoextraction of polychlorinated biphenyls in water and their determination by gas chromatography with electron capture detector. AB - A solid-phase nanoextraction method has been developed for the extraction and preconcentration of polychlorinated biphenyls using carboxyl multiwalled carbon nanotubes as a solid nano-sorbent. Parameters affecting extraction efficiency such as sorbent amount, desorption solvent type and volume, extraction time, pH, and salt content have been studied. Under optimized conditions, the correlation coefficient was up to 0.9989, the limits of detection was in the range of 1.4-3.5 ng/L, and limits of quantification was between 4.8 and 11.6 ng/L. The recoveries were in the range of 99-106% for different spiked analytes. The relative standard deviation for water samples spiked with two different spiking levels has been between 4 and 10%. The proposed sustainable method is rapid, easy to use, and small consumption of organic solvent for the detection and determination of trace levels of polychlorinated biphenyls in environmental waters. PMID- 27958678 TI - A Dinuclear Cobalt Cryptate as a Homogeneous Photocatalyst for Highly Selective and Efficient Visible-Light Driven CO2 Reduction to CO in CH3 CN/H2 O Solution. AB - A dinuclear cobalt complex [Co2 (OH)L1 ](ClO4 )3 (1, L1 =N[(CH2 )2 NHCH2 (m-C6 H4 )CH2 NH(CH2 )2 ]3 N) displays high selectivity and efficiency for the photocatalytic reduction of CO2 to CO in CH3 CN/H2 O (v/v=4:1) under a 450 nm LED light irradiation, with a light intensity of 100 mW cm-2 . The selectivity reaches as high as 98 %, and the turnover numbers (TON) and turnover frequencies (TOF) reach as high as 16896 and 0.47 s-1 , respectively, with the calculated quantum yield of 0.04 %. Such high activity can be attributed to the synergistic catalysis effect between two CoII ions within 1, which is strongly supported by the results of control experiments and DFT calculations. PMID- 27958679 TI - A Shifted Double-Diamond Titania Scaffold. AB - Photonic crystals are expected to be metamaterials because of their potential to control the propagation of light in the linear and nonlinear regimes. Biological single-network, triply periodic constant mean curvature surface structures are considered excellent candidates owing to their large complete band gap. However, the chemical construction of these relevant structures is rare and developing new structures from thermodynamically stable double-network self-organizing systems is challenging. Herein, we reveal that the shifted double-diamond titania scaffold can achieve a complete band gap. The largest (7.71 %) band gap is theoretically obtained by shifting 0.332 c with the dielectric contrast of titania (6.25). A titania scaffold with similar shifted double-diamond structure was fabricated using a reverse core-shell microphase-templating system with an amphiphilic diblock copolymer and a titania source in a mixture of tetrahydrofuran and water, which could result in a 2.05-3.78 % gap. PMID- 27958680 TI - Attomol-level ATP bioluminometer for detecting single bacterium. AB - We have developed an automated high-sensitive ATP bioluminometer for detecting single bacterium. The apparatus consists of a tube rack for setting reagents and samples, two washing baths for preventing sample carry-over from dispenser nozzle, and x-, y-, z- actuators for moving the dispenser, and an high-sensitive optical system. The reaction tube was selected to reduce the background signal intensities for the ATP bioluminescence measurement. The background signal intensity of the reaction tube was 18 RLU, which is almost the same as the dark counts of the photomultiplier (16 RLU). The ATP calibration curve was linear from 0 to 5 amol (its slope = 22.4 RLU/amol and 3.3 SD of the blank sample signal = 17.9 RLU), and the detection limit of 0.8 amol was obtained. The relationship between intracellular ATP and CFU in Escherichia coli (ATCC25922) was kept linearity from 0 to 20 CFU, and the intracellular ATP (amol) per CFU was calculated to be 3.3 amol/CFU (R2 = 0.9713). Moreover, the relationship between intracellular ATP and CFU in Staphylococcus aureus (ATCC25923) was also kept linearity from 0 to 30 CFU, and the amol/CFU was calculated to be 1.6 amol/CFU (R2 = 0.9847). The automated ATP bioluminometer has ultra-high sensitivity and will be a powerful tool for measuring ATP luminescence derived from small number of bacteria. PMID- 27958681 TI - Affinity-based Glycan Analysis. PMID- 27958683 TI - Do we need a better marker for successful ovarian cancer surgery? PMID- 27958684 TI - ASGO 4th International Workshop on Gynecologic Oncology. PMID- 27958682 TI - Chemoradiotherapy followed by consolidation chemotherapy involving paclitaxel and carboplatin and in FIGO stage IIIB/IVA cervical cancer patients. AB - OBJECTIVE: To evaluate the efficacy and toxicity of paclitaxel plus carboplatin (TC)-based concurrent chemoradiotherapy (CCRT) followed by consolidation chemotherapy in the International Federation of Gynecology and Obstetrics (FIGO) stage IIIB/IVA cervical cancer patients. METHODS: We reviewed the medical records of FIGO stage IIIB/IVA cervical cancer patients (n=30) who had been intended to be treated with TC-based CCRT followed by consolidation chemotherapy (TC-CCRT group) from April 2012-May 2016. Patients who had been treated with CCRT involving a single platinum agent (CCRT-group; n=52) or definitive radiotherapy alone (RT-group; n=74) from January 1997-September 2012 were also identified and used as historical controls. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Of the 30 patients included in the TC-CCRT-group, 22 patients (73.3%) completed the planned TC-based CCRT. The most frequently observed acute grade 3/4 hematological toxicities were leukopenia and neutropenia, and diarrhea was the most common acute grade 3/4 non hematological toxicity. After a median follow-up of 35 months, 9 patients (30.0%) had developed recurrent disease. The patients' estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 67.9% and 90.8%, respectively. In comparisons with historical control groups, the survival outcomes of TC-CCRT-group was significantly superior to CCRT-group in terms of OS (p=0.011) and significantly superior to RT-group in terms of both PFS (p=0.009) and OS (p<0.001). CONCLUSION: TC-based CCRT followed by consolidation chemotherapy is safe and effective. A randomized controlled study needs to be conducted to further evaluate the efficacy of this multimodal approach in this patient population. PMID- 27958686 TI - Prevalence of infectious agents in patients with systemic sclerosis:defining the control group. PMID- 27958685 TI - Pazopanib as a second line treatment for uterine and ovarian carcinosarcoma: a single institutional study. PMID- 27958687 TI - Rigorous evaluation of the patterns of nickel sensitization inchildren with atopic dermatitis is needed. PMID- 27958688 TI - Results of surgical interventions for critical limb ischemia due to vasculitis or collagen-tissue related disease. AB - BACKGROUND: In this study, we aimed to clarify both systemic and local prognosis after surgical interventions for critical limb ischemia (CLI) due to vasculitis or connective tissue related disease, and to search for any risk factors that can worsen the prognosis. METHODS: One hundred and ninety three patients that underwent surgical interventions for CLI between 2005 and 2014 were followed up for a median of 2.7 years. The patients were grouped into a group with vasculitis or connective tissue related disease (V) or with atherosclerosis (control: C). Two groups were retrospectively reviewed and compared. RESULTS: Thirty-one patients were grouped into the V group. At three years after intervention, V group showed significantly higher survival rate compared to C group (89% vs. 73%). On the other hand, limb survival rate after bypass surgery was significantly lower (74% vs. 94%), due to lower patency of the bypassed graft. Within V group, preoperative skin perfusion pressure of lower than 20 mmHg showed significantly worse prognosis of the limb. (HR 1.8; P=0.01) Regarding specific diseases, systemic scleroderma, rheumatoid arthritis and systemic lupus erythematosus tended to show worse prognosis. CONCLUSIONS: Patients with CLI due to vasculitis or connective tissue related disease have a longer life expectancy with lower limb salvage rate that can lead to low quality of the remaining life. PMID- 27958689 TI - Predictive value of a day orthostatic loading test for the reversibility of the great saphenous vein reflux after phlebectomy of all varicous tributaries. AB - BACKGROUND: The aim of this study was to evaluate predictive value of a day orthostatic loading test (DOL-test) for the reversibility of the great saphenous vein (GSV) reflux after phlebectomy of all varicose tributaries (VTs). METHODS: Prospective cohort study. Patients with reflux in the GSV were included. Patients were treated by phlebectomy for all VTs of the GSV. GSV reflux was measured during a Duplex ultrasound examination with DOL-based on: 1) reflux location and donor vein; 2) reflux extent (RE) of the GSV was evaluated according to the number of zones of reflux (NZR) which included three thigh and three calf zones; 3) reflux duration (RD); 4) peak reflux velocity (PRV) in GSV reflux point of initiation; 5) the diameter of the GSV; 6) orthostatic gradient (OG) - difference between evening and morning values of the GSV diameter. We included 87 lower limbs (LLs) in 65 patients (51 women and 15 men) aged from 29 to 53 (mean age 36.7) years. RESULTS: In twelve months after the surgery the amount of limbs with eliminated reflux constituted 77.0%. In LLs with incompetence of SFJ the reversibility of the GSV was observed in 59.0% of cases in 12 months after treatment. V LLs without incompetence of SFJ the reversibility constituted 91.7%. In LLs with resolved GSV reflux (N.=67) the initial evening RE constituted 3.76 and reduced in the morning to 1.51, P=0.000001. In LLs with persistent GSV reflux (N.=20) the initial evening RE constituted 3,75 and reduced in the morning to 3.00, P=0.028418. In LLs with resolved GSV reflux the initial evening RD constituted 2.10 s and reduced in the morning to 0.93 s, P=0.000001. In LLs with persistent GSV reflux the initial evening RD constituted 2.13 s and reduced in the morning to 1.82 s, P=0.043115. In LLs with resolved GSV reflux the initial evening PRV constituted 173.46 mm/s and reduced in the morning to 101.57 mm/s, P=0.000001. In LLs with persistent GSV reflux the initial evening PRV constituted 172.50 mm/ and reduced in the morning to 158.50 mm/s, P=0.007686. In LLs with resolved reflux the initial OG was 0.93 mm with the initial evening GSV diameter of 7.20 mm. After the surgery OG reduced to 0.59 mm, P=0.000001. The evening vein diameter decreased to 5.07 mm, P=0.000001. In LLs with persistent reflux the OG and the GSV diameter decreased from 0.55 mm to 0.51 mm, P=0.017961 and evening GSV diameter from 7.75 mm initially to 7.55 mm after the treatment, P=0.067890 respectively. CONCLUSIONS: Characterizing GSV with minimum volume loading, DOL test shows the degree of preservation of muscular-tonic properties of GSV and allows to predict the reversibility of the GSV reflux after phlebectomy. Being initially high, the GSV OG points that the potential of muscular-tonic function is saved. Its decrease after the surgery proves the decrease of the volume loading on GSV. PMID- 27958691 TI - Triple rule-out cardiac computed tomography: is it finally a reality? AB - Acute coronary syndrome (ACS), pulmonary embolism and acute aortic syndrome are the most common causes of life threatening chest pain. The triple rule-out CT (TRO CT) has emerged as a technology that can simultaneously visualize the coronary arteries, aorta and pulmonary arteries as well as other intrathoracic structures. It has been proposed as a one-stop imaging modality in patients who present to the emergency department with low to intermediate risk of ACS in whom pulmonary embolism and/or acute aortic syndrome are also considered. This review focuses on the TRO CT imaging technique, image quality, radiation dose, diagnostic accuracy, yield, efficiency and cost through a series of frequently asked questions. PMID- 27958690 TI - Granulocyte colony-stimulating factor improves the efficacy of autologous bone marrow-derived mononuclear cell transplantation treatment for lower limb ischemia. AB - BACKGROUND: The safety and efficacy of autologous bone marrow-derived mononuclear cell (BM-MNC) transplantation in the treatment of lower limb ischemia is becoming established, although common treatment protocols are not yet agreed upon. We hypothesized that bone marrow mobilization with granulocyte colony-stimulating factor (G-CSF) improves the safety and effectiveness of cellular therapy. METHODS: Forty-four patients were randomly assigned to receive two injections of G-CSF (300 ug) prior to BM-MNC transplantation. BM-MNC were harvested from all patients and injected as equal aliquots of at least 108 cells into the ischemic leg muscles below the lowest patent artery. RESULTS: After 3 months, patients receiving G-CSF reported increased subjective relief of symptoms and showed increased transcutaneous oxygen tension (TcPO2). After 6 months, patients showed greater improvement in TcPO2, ankle-brachial index, and angiographic score compared to control patients. There were no increased numbers of side effects in patients receiving G-CSF. CONCLUSIONS: G-CSF is safe and effective to mobilize BM MNC and may allow reduced volume of aspirated bone marrow, potentially reducing procedural complications. G-CSF should be considered for use in patients that are candidates for angiogenic therapy. G-CSF may increase the number of patients that are candidates for therapeutic angiogenesis. PMID- 27958692 TI - Diagnostic accuracy of intravascular ultrasound-derived minimal lumen area compared with fractional flow reserve. AB - INTRODUCTION: The use of fractional flow reserve (FFR) as the gold standard for functional assessment of intermediate coronary stenosis has been well documented. Intracoronary imaging techniques such as intravascular ultrasound (IVUS) have been used for additional coronary lesion resolution and some of its anatomic parameters have been studied as having possible correlation with FFR, particularly IVUS minimal lumen area (MLA). We performed a comprehensive review of the available literature in the area. EVIDENCE ACQUISITION: A Pubmed search was performed for all the literature involving comparison of diagnostic accuracy of IVUS-MLA with FFR. EVIDENCE SYNTHESIS: An extensive description of all the available data regarding IVUS-MLA diagnostic value regarding the FFR of stenotic lesions, for both non-left main (non-LM) and left main (LM) lesions. CONCLUSIONS: For non-LM lesions IVUS-MLA cutoff values to identify specific FFR thresholds have marked heterogeneity and perform particularly poorly in terms of specificity and positive predictive value. For LM lesions IVUS-MLA performs better and shows a better correlation with FFR, though more data is needed to confirmed that trend. PMID- 27958693 TI - CT myocardial perfusion: state of the science. AB - Non-invasive cardiac imaging has rapidly evolved during the last decade due to advancements in CT technologies. Coronary CT angiography (CCTA) has been shown to reliably assess the coronary anatomy and has established itself as the non invasive imaging technique with the highest sensitivity and specificity in the evaluation of patients with suspected coronary artery disease (CAD). However, this technique has previously been limited to a pure anatomical assessment. CT myocardial perfusion imaging (CT-MPI) is an increasingly rediscovered CT technique able to provide functional assessment of the myocardium and, when combined with CTA, allows for a comprehensive assessment of the coronary arteries, all done within a single modality. This review will describe the current knowledge in CT-MPI, including the varying techniques as well as a summary of the current literature. PMID- 27958694 TI - Transcatheter edge-to-edge mitral valve repair in heart failure. AB - Heart failure and severe mitral regurgitation (MR) are mutually dependent. Secondary MR is a consequence of chronic heart failure in patients with severely depressed left ventricular ejection fraction (LV-EF) and LV dilatation. Severe MR in heart failure patients worsens prognosis and accelerates LV dilatation and decline in LV-EF. Interventional therapies have changed clinical practice for heart failure patients with secondary MR. In this review we summarize the available data of patients with chronic heart failure undergoing transcatheter edge-to-edge mitral valve repair (TMVR) with the MitraClip(r) system for severe secondary mitral regurgitation. TMVR could be a therapeutic option with a favorable long-term outcome even in patients with severely depressed LV-EF. Selection criteria predicting mortality in patients undergoing TMVR comprise clinical, laboratory and echocardiographic parameters and can help for clinical decision-making. Ongoing randomized trials will influence the use of interventional treatment of MR in these high-risk patients. PMID- 27958695 TI - Aldosterone receptor antagonists decrease mortality and cardiovascular hospitalizations in chronic heart failure with reduced left ventricular ejection fraction, but not in chronic heart failure with preserved left ventricular ejection fraction: a meta-analysis of randomized controlled trials. AB - INTRODUCTION: Aldosterone receptor antagonists (ARAs) were introduced in the treatment of chronic heart failure (CHF), as a result of the demonstration of their protective effect on the failing heart. However, important questions remain unanswered regarding the clinical efficacy of the ARAs on the clinical and echocardiographic phenotype of heart failure, called heart failure with preserved left ventricular ejection fraction (HFpEF). EVIDENCE ACQUISITION: The aim of the present meta-analysis was to verify the impact of the ARAs on some hard endpoints, such as all-cause death and hospitalizations from cardiovascular cause, making a comparative evaluation of these outcomes in CHF patients with reduced left ventricular ejection fraction (HFREF) and in those with HFpEF, respectively. Only randomized controlled trials (RCTs) were incorporated in our meta-analysis. The studies were included if they met the following criteria: experimental groups included patients with CHF treated with ARAs in addition to the conventional therapy; control groups included patients with CHF receiving conventional therapy without ARAs. Outcomes of interest were all-cause mortality, cardiovascular hospitalizations, hyperkalemia, or gynecomastia. EVIDENCE SYNTHESIS: Overall, 15 RCTs comprising a total of 15671 patients were eligible for inclusion in the meta-analysis. ARA use in patients with heart failure was associated with a significant reduction in adverse outcomes. Indeed, a significant reduced odds of all-cause death among CHF patients treated with ARAs compared to controls was found (OR=0.79; 95% CI: 0.73-0.87). Subgroup analysis based on the HF type revealed a statistically significant benefit as regards all cause death for patients with HFREF (OR=0.77; 95% CI: 0.69-0.84), whereas a protective effect against the all-cause death was not attained by ARAs in the HFpEF subset (OR=0.91; 95% CI: 0.76-1.1). Furthermore reduced odds of CV hospitalizations was detected in the entire group of CHF patients under treatment with ARAs (OR=0.73; 95% CI: 0.61-0.89) as well as among HFREF patients treated with ARAs, compared to controls (OR=0.66; 95% CI: 0.51-0.85). Hyperkalemia was significantly more frequent with ARA use. In addition, subgroup analysis by ARA type documented that both nonselective and selective ARAs were similarly associated with increased odds of episodes of hyperkalemia compared to controls. Besides, ARA use was shown to be associated with the occurrence of gynecomastia. In particular, selective ARAs proved not to produce significant amounts of gynecomastia compared to controls (OR=0.74; 95% CI: 0.43-1.27), while nonselective ARAs did (OR 8.22; 95% CI: 4.9-13.81. CONCLUSIONS: Our meta-analysis provides further evidence that ARAs should be systematically used in patients with HFREF, in whom these drugs improve some hard clinical endpoints, such as all cause mortality and hospitalizations from cardiac cause. Conversely, based on the present meta-analysis, ARA usage in HFpEF patients is questionable since in this CHF setting no significant improvement in clinical endpoints has been demonstrated so far, in the face of the well-known risks of hyperkalemia and/or gynecomastia that chronic ARA therapy entails. Furthermore, new selective ARAs are not burdened by significant risk of gynecomastia, while are similar to nonselective ARAs with regard to the efficacy profile as well as to the risk of eliciting hyperkalemia. PMID- 27958696 TI - Multitechnique Determination of Halogens in Soil after Selective Volatilization Using Microwave-Induced Combustion. AB - A method for digestion of soils with high inorganic matter content (ranging from 50 to 92%) by microwave-induced combustion (MIC) is proposed for the first time for further halogens (F, Cl, Br, and I) determination by ion chromatography (IC) and also by inductively coupled plasma mass spectrometry (ICP-MS). Microcrystalline cellulose (100-500 mg), used as a combustion aid, was mixed with sample and water or NH4OH solutions (10-100 mmol L-1) were investigated for analytes absorption. The use of cellulose (400 mg) was mandatory to volatilize the halogens from soils with high inorganic matter. It was possible to use diluted absorbing solutions (up to 100 mmol L-1 NH4OH) for halogens retention, providing limits of quantification in the range of 0.06 (I) to 60 (Cl) MUg g-1. Accuracy was evaluated using certified reference materials (CRMs), spiked samples, and pyrohydrolysis method. Recoveries for halogens after spiked samples were in the range of 94 to 103% and the results after digestion of CRMs by MIC were in agreement better than 95% to certified values. Blanks were low, relative standard deviation was below 8% for all soils and no statistical difference was observed for results by pyrohydrolysis and MIC methods showing the feasibility of the proposed method for further halogens determination in soil samples. PMID- 27958697 TI - Enhanced Photoelectrocatalytic Reduction of Oxygen Using Au@TiO2 Plasmonic Film. AB - Novel Au@TiO2 plasmonic films were fabricated by individually placing Au nanoparticles into TiO2 nanocavity arrays through a sputtering and dewetting process. These discrete Au nanoparticles in TiO2 nanocavities showed strong visible-light absorption due to the plasmonic resonance. Photoelectrochemical studies demonstrated that the developed Au@TiO2 plasmonic films exhibited significantly enhanced catalytic activities toward oxygen reduction reactions with an onset potential of 0.92 V (vs reversible hydrogen electrode), electron transfer number of 3.94, and limiting current density of 5.2 mA cm-2. A superior ORR activity of 310 mA mg-1 is achieved using low Au loading mass. The isolated Au nanoparticle size remarkably affected the catalytic activities of Au@TiO2, and TiO2 coated with 5 nm Au (Au5@TiO2) exhibited the best catalytic function to reduce oxygen. The plasmon-enhanced reductive activity is attributed to the surface plasmonic resonance of isolated Au nanoparticles in TiO2 nanocavities and suppressed electron recombination. This work provides comprehensive understanding of a novel plasmonic system using isolated noble metals into nanostructured semiconductor films as a potential alternative catalyst for oxygen reduction reaction. PMID- 27958698 TI - Supramolecular Chemistry-Assisted Electrochemical Method for the Assay of Endogenous Peptidylarginine Deiminases Activities. AB - Peptidylarginine deiminase 4 (PAD4) is the only isoform of PADs located within the cell nucleus, which has been known to be related to several human diseases. In this work, we have proposed an electrochemical method for the assay of endogenous PAD4 activities as well as the studies of PAD4 inhibitors by making use of the supramolecular chemistry-assisted signal labeling. Specifically, peptide probes P1 and P2, which separately contain cysteine residues and tripeptides FGG (Phe-Gly-Gly), can be self-assembled onto the surface of the gold electrode and silver nanoparticles, respectively. In the meantime, the peptide probes can be connected together through cucurbit[8]uril-mediated host-guest interaction. Nevertheless, after trypsin-catalyzed digestion, FGG at the N terminal of P1 will be removed from the electrode surface, thereby inhibiting the connection of P1 and P2. Since PAD4 catalyzes the citrullination of arginine residue within P1, trypsin-catalyzed digestion of P1 can be prohibited by the addition of PAD4. Consequently, an obvious change of the electrochemical response can be obtained from the silver nanoparticles (AgNPs) immobilized on the electrode surface. Experimental results have shown that our method can display an improved sensitivity and specificity for both PAD4 assay and inhibitor screening, which may effectively trace endogenous PAD4 and the inhibitors in the cancer cells. Therefore, our method may have great potential for the diagnosis and treatment of PAD4-related diseases in the future. PMID- 27958699 TI - Single Fluorescent Probe for Dual-Imaging Viscosity and H2O2 in Mitochondria with Different Fluorescence Signals in Living Cells. AB - Mitochondria, as essential and interesting organelles within the eukaryotic cells, play key roles in a variety of pathologies, and its abnormalities are closely associated with Alzheimer's disease (AD) and other diseases. Studies have shown that the abnormal of viscosity and concentration of hydrogen peroxide in mitochondria were all associated with AD. Accordingly, the detection of viscosity and hydrogen peroxide in mitochondria has attracted great attention. However, it remains a great challenge to explore a single probe, which can dual-detect the viscosity and H2O2 in mitochondria. Herein, in two ways to prevent the twisted internal charge transfer (TICT) process, we designed and sythesized the first dual-detection fluorescent probe Mito-VH that can visualize viscosity and H2O2 in mitochondria with different fluorescence signals in living cells. PMID- 27958701 TI - Formation of N-Nitrosodimethylamine during Chloramination of Secondary and Tertiary Amines: Role of Molecular Oxygen and Radical Intermediates. AB - N-Nitrosodimethylamine (NDMA) is a carcinogenic disinfection byproduct from water chloramination. Despite the identification of numerous NDMA precursors, essential parts of the reaction mechanism such as the incorporation of molecular O2 are poorly understood. In laboratory model systems for the chloramination of secondary and tertiary amines, we investigated the kinetics of precursor disappearance and NDMA formation, quantified the stoichiometries of monochloramine (NH2Cl) and aqueous O2 consumption, derived 18O-kinetic isotope effects (18O-KIE) for the reactions of aqueous O2, and studied the impact of radical scavengers on NDMA formation. Although the molar NDMA yields from five N,N-dimethylamine-containing precursors varied between 1.4% and 90%, we observed the stoichiometric removal of one O2 per N,N-dimethylamine group of the precursor indicating that the oxygenation of N atoms did not determine the molar NDMA yield. Small 18O-KIEs between 1.0026 +/- 0.0003 and 1.0092 +/- 0.0009 found for all precursors as well as completely inhibited NDMA formation in the presence of radical scavengers (ABTS and trolox) imply that O2 reacted with radical species. Our study suggests that aminyl radicals from the oxidation of organic amines by NH2Cl and N-peroxyl radicals from the reaction of aminyl radicals with aqueous O2 are part of the NDMA formation mechanism. PMID- 27958702 TI - Fluorographene as a Mass Spectrometry Probe for High-Throughput Identification and Screening of Emerging Chemical Contaminants in Complex Samples. AB - Mass spectrometry techniques for high-throughput analysis of complex samples are of profound importance in many areas such as food safety, omics studies, and environmental health science. Here we report the use of fluorographene (FG) as a new mass spectrometry probe for high-throughput identification and screening of emerging chemical contaminants in complex samples. FG was facilely synthesized by one-step exfoliation of fluorographite. With FG as a matrix or probe in matrix assisted or surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (MALDI- or SELDI-TOF MS), higher sensitivity (detection limits at ppt or subppt levels), and better reproducibility were achieved than with other graphene-based materials due to the unique chemical structure and self-assembly properties of FG. The method was validated with different types of real complex samples. By using FG as a SELDI probe, we could easily detect trace amount of bisphenol S in paper products and high-fat canned food samples. Furthermore, we have successfully identified and screened as many as 28 quaternary ammonium halides in sewage sludge samples collected from municipal wastewater treatment plants. These results demonstrate that FG probe is a powerful tool for high throughput analysis of complex samples by MS. PMID- 27958700 TI - Tandem Mass Spectrometry in Combination with Product Ion Mobility for the Identification of Phospholipids. AB - Concerted tandem and traveling wave ion mobility mass spectrometry (CTS analysis) is a unique method that results in a four-dimensional data set including nominal precursor ion mass, product ion mobility, accurate mass of product ion, and ion abundance. This nontargeted lipidomics CTS approach was applied in both positive- and negative-ion mode to phospholipids present in human serum, and the data set was used to evaluate the value of product ion mobility in identifying lipids in a complex mixture. It was determined that the combination of diagnostic product ions and unique collisional cross-section values of product ions is a powerful tool in the structural identification of lipids in a complex biological sample. PMID- 27958703 TI - Wellbore Cement Porosity Evolution in Response to Mineral Alteration during CO2 Flooding. AB - Mineral reactions during CO2 sequestration will change the pore-size distribution and pore surface characteristics, complicating permeability and storage security predictions. In this paper, we report a small/wide angle scattering study of wellbore cement that has been exposed to carbon dioxide for three decades. We have constructed detailed contour maps that describe local porosity distributions and the mineralogy of the sample and relate these quantities to the carbon dioxide reaction front on the cement. We find that the initial bimodal distribution of pores in the cement, 1-2 and 10-20 nm, is affected differently during the course of carbonation reactions. Initial dissolution of cement phases occurs in the 10-20 nm pores and leads to the development of new pore spaces that are eventually sealed by CaCO3 precipitation, leading to a loss of gel and capillary nanopores, smoother pore surfaces, and reduced porosity. This suggests that during extensive carbonation of wellbore cement, the cement becomes less permeable because of carbonate mineral precipitation within the pore space. Additionally, the loss of gel and capillary nanoporosities will reduce the reactivity of cement with CO2 due to reactive surface area loss. This work demonstrates the importance of understanding not only changes in total porosity but also how the distribution of porosity evolves with reaction that affects permeability. PMID- 27958704 TI - Photoconversion of Chlorinated Saline Wastewater DBPs in Receiving Seawater is Overall a Detoxification Process. AB - Chlorine disinfection of wastewater effluents rich in bromide and iodide ions results in the formation of relatively toxic bromo- and iodo-disinfection byproducts (DBPs), especially highly toxic bromophenolic and iodophenolic DBPs, which could harm the marine ecosystem when they are discharged into receiving seawater along with the wastewater effluents. In this study, we investigated the conversion of three individual halophenolic DBPs (5-bromosalicylic acid, 2,5 dibromohydroquinone, and 2,4,6-triiodophenol) and two chlorinated saline wastewater DBP mixtures in seawater. The conversion products were analyzed with ultra performance liquid chromatography/electrospray ionization-triple quadrupole mass spectrometry, and the conversion of overall halo-DBPs in the wastewater DBP mixtures was monitored by measuring total organic halogen. The photoconversion induced variations in the toxicity were evaluated using the embryos of a marine polychaete. Halophenolic DBPs were found to undergo photoconversion in seawater. The conversion was triggered by photonucleophilic substitution: bromophenolic and iodophenolic DBPs were converted to their chlorophenolic or hydroxyphenolic analogues, via substituting the bromine and iodine atoms with chloride or hydroxide ions in seawater; chlorophenolic DBPs were converted to their hydroxyphenolic analogues, via substituting the chlorine atoms with hydroxide ions in seawater. The hydroxyphenolic analogues thus formed further decomposed and finally cleaved to aliphatic compounds. The photoconversion of chlorinated saline wastewater DBPs in receiving seawater was overall a dehalogenation and detoxification process. PMID- 27958706 TI - Effect of the CF3 Substituents on the Charge-Transfer Kinetics of High-Efficiency Cyclometalated Ruthenium Sensitizers. AB - Six thiocyanate-free complexes, DUY1-DUY6, were synthesized, and their application in a dye-sensitized solar cell was studied to explore the effect of the CF3 substituent positioned in the ancillary ligand and the structure of the anchoring ligand on the physicochemical properties, charge-transfer kinetics, and photovoltaic properties of ruthenium sensitizers. When the electron-withdrawing groups were installed on the cyclometalating ligands and their pi conjugation of the ancillary ligand was extended, the frontier orbital energy levels of the ruthenium complex appeared to be sufficient for effective electron injection and dye regeneration, at the same time having high light-harvesting ability. Two electron-withdrawing CF3 groups meta to the cyclometalated position reduce the electron density at the metal center less seriously than o-CF3 and p-CF3 groups. The sensitizers containing a m-CF3 group also reveal a more favorable distribution of beta lowest unoccupied spin orbital for interaction between the oxidized dyes and the iodide ion, which promotes dye regeneration. The absorption profiles of DUY1-DUY4 adsorbed a TiO2 film extended to longer wavelength compared to those in an N,N-dimethylformamide solution, especially DUY1 and DUY2 dyes, which have lambdamax red shifts of up to 30 nm. The DUY2-dyed cell exhibited the highest efficiency of 9.03%, while the power conversion efficiencies of DUY1-, DUY3-, DUY4-, and N719-based devices were 7.40%, 7.01%, 8.92%, and 8.63%, respectively. DUY5 and DUY6 (the side products of DUY3 and DUY4) without anchoring groups have very weak physical adsorption on a TiO2 anode. The corresponding cells exhibit very low efficiency (<0.1%), although both dyes have high light-harvesting ability and proper frontier orbital energy levels. PMID- 27958705 TI - Fate of Arsenic during Red River Water Infiltration into Aquifers beneath Hanoi, Vietnam. AB - Recharge of Red River water into arsenic-contaminated aquifers below Hanoi was investigated. The groundwater age at 40 m depth in the aquifer underlying the river was 1.3 +/- 0.8 years, determined by tritium-helium dating. This corresponds to a vertical flow rate into the aquifer of 19 m/year. Electrical conductivity and partial pressure of CO2 (PCO2) indicate that water recharged from the river is present in both the sandy Holocene and gravelly Pleistocene aquifers and is also abstracted by the pumping station. Infiltrating river water becomes anoxic in the uppermost aquifer due to the oxidation of dissolved organic carbon. Further downward, sedimentary carbon oxidation causes the reduction of As containing Fe-oxides. Because the release of arsenic by reduction of Fe-oxides is controlled by the reaction rate, arsenic entering the solution becomes highly diluted in the high water flux and contributes little to the groundwater arsenic concentration. Instead, the As concentration in the groundwater of up to 1 MUM is due to equilibrium-controlled desorption of arsenic, adsorbed to the sediment before river water started to infiltrate due to municipal pumping. Calculations indicate that it will take several decades of river water infiltration to leach arsenic from the Holocene aquifer to below the World Health Organization limit of 10 MUg/L. PMID- 27958707 TI - AFM-IR: Technology and Applications in Nanoscale Infrared Spectroscopy and Chemical Imaging. AB - Atomic force microscopy-based infrared spectroscopy (AFM-IR) is a rapidly emerging technique that provides chemical analysis and compositional mapping with spatial resolution far below conventional optical diffraction limits. AFM-IR works by using the tip of an AFM probe to locally detect thermal expansion in a sample resulting from absorption of infrared radiation. AFM-IR thus can provide the spatial resolution of AFM in combination with the chemical analysis and compositional imaging capabilities of infrared spectroscopy. This article briefly reviews the development and underlying technology of AFM-IR, including recent advances, and then surveys a wide range of applications and investigations using AFM-IR. AFM-IR applications that will be discussed include those in polymers, life sciences, photonics, solar cells, semiconductors, pharmaceuticals, and cultural heritage. In the Supporting Information , the authors provide a theoretical section that reviews the physics underlying the AFM-IR measurement and detection mechanisms. PMID- 27958708 TI - Iron, Copper, and Zinc Concentration in Abeta Plaques in the APP/PS1 Mouse Model of Alzheimer's Disease Correlates with Metal Levels in the Surrounding Neuropil. AB - The metal ions of iron, copper, and zinc have long been associated with the aggregation of beta-amyloid (Abeta) plaques in Alzheimer's disease; an interaction that has been suggested to promote increased oxidative stress and neuronal dysfunction. We examined plaque metal load in the hippocampus of APP/PS1 mice using X-ray fluorescence microscopy to assess how the anatomical location of Abeta plaques was influenced by the metal content of surrounding tissue. Immunohistochemical staining of Abeta plaques colocalized with areas of increased X-ray scattering power in unstained tissue sections, allowing direct X-ray based assessment of plaque metal levels in sections subjected to minimal chemical fixation. We identified and mapped 48 individual plaques in four subregions of the hippocampus from four biological replicates. Iron, Cu, and Zn areal concentrations (ng cm-2) were increased in plaques compared to the surrounding neuropil. However, this elevation in metal load reflected the local metal makeup of the surrounding neuropil, where different brain regions are enriched for different metal ions. After correcting for tissue density, only Zn levels remained elevated in plaques. This study suggests that the in vivo binding of Zn to plaques is not simply due to increased protein deposition. PMID- 27958709 TI - Influencing Antibody-Mediated Attenuation of Methamphetamine CNS Distribution through Vaccine Linker Design. AB - Active vaccination examining a single hapten engendered with a series of peptidic linkers has resulted in the production of antimethamphetamine antibodies. Given the limited chemical complexity of methamphetamine, the structure of the linker species embedded within the hapten could have a substantial effect on the ultimate efficacy of the resulting vaccines. Herein, we investigate linker effects by generating a series of methamphetamine haptens that harbor a linker with varying amino acid identity, peptide length, and associated carrier protein. Independent changes in each of these parameters were found to result in alterations in both the quantity and quality of the antibodies induced by vaccination. Although it was found that the consequence of the linker design was also dependent on the identity of the carrier protein, we demonstrate overall that the inclusion of a short, structurally simple, amino acid linker benefits the efficacy of a methamphetamine vaccine in limiting brain penetration of the free drug. PMID- 27958711 TI - Interfacial Redox Reactions Associated Ionic Transport in Oxide-Based Memories. AB - As an alternative to transistor-based flash memories, redox reactions mediated resistive switches are considered as the most promising next-generation nonvolatile memories that combine the advantages of a simple metal/solid electrolyte (insulator)/metal structure, high scalability, low power consumption, and fast processing. For cation-based memories, the unavailability of in-built mobile cations in many solid electrolytes/insulators (e.g., Ta2O5, SiO2, etc.) instigates the essential role of absorbed water in films to keep electroneutrality for redox reactions at counter electrodes. Herein, we demonstrate electrochemical characteristics (oxidation/reduction reactions) of active electrodes (Ag and Cu) at the electrode/electrolyte interface and their subsequent ions transportation in Fe3O4 film by means of cyclic voltammetry measurements. By posing positive potentials on Ag/Cu active electrodes, Ag preferentially oxidized to Ag+, while Cu prefers to oxidize into Cu2+ first, followed by Cu/Cu+ oxidation. By sweeping the reverse potential, the oxidized ions can be subsequently reduced at the counter electrode. The results presented here provide a detailed understanding of the resistive switching phenomenon in Fe3O4-based memory cells. The results were further discussed on the basis of electrochemically assisted cations diffusions in the presence of absorbed surface water molecules in the film. PMID- 27958712 TI - Facile Route to Transparent, Strong, and Thermally Stable Nanocellulose/Polymer Nanocomposites from an Aqueous Pickering Emulsion. AB - Cellulose nanofibril (CNF) is a promising nanofiller for polymer nanocomposite materials, and a critical challenge in designing these materials is organization of the nanostructure using a facile process. Here, we report a facile aqueous preparation process for nanostructured polystyrene (PS)/CNF composites via the formation of a CNF-stabilized Pickering emulsion. PS nanoparticles, with a narrow size distribution, were synthesized by free radical polymerization in water using CNF as a stabilizer. The nanoparticles were easily collected by filtration, and the resulting material had a composite structure of PS nanoparticles embedded in a CNF framework. The PS/CNF nanocomposite showed high optical transparency, strength, and thermal dimensional stability. Thus, this technique provides a simple and environmentally friendly method for the preparation of novel CNF/polymer nanocomposite materials. PMID- 27958713 TI - Inositol Phosphate Accumulation in Vivo Provides a Measure of Muscarinic M1 Receptor Activation. AB - The rationale for using M1 selective muscarinic acetylcholine receptor activators for the treatment of cognitive impairment associated with psychiatric and neurodegenerative disease is well-established in the literature. Here, we investigate measurement of inositol phosphate accumulation, an end point immediately downstream of the M1 muscarinic acetylcholine receptor signaling cascade, as an in vivo biochemical readout for M1 muscarinic acetylcholine receptor activation. Five brain penetrant M1-subtype selective activators from three structurally distinct chemical series were pharmacologically profiled for functional activity in vitro using recombinant cell calcium mobilization and inositol phosphate assays, and a native tissue hippocampal slice electrophysiology assay, to show that all five compounds presented a positive allosteric modulator agonist profile, within a narrow range of potencies. In vivo characterization using an amphetamine-stimulated locomotor activity behavioral assay and the inositol phosphate accumulation biochemical assay demonstrated that the latter has utility for assessing functional potency of M1 activators. Efficacy measured by inositol phosphate accumulation in mouse striatum compared favorably to efficacy in reversing amphetamine-induced locomotor activity, suggesting that the inositol phosphate accumulation assay has utility for the evaluation of M1 muscarinic acetylcholine receptor activators in vivo. The benefits of this in vivo biochemical approach include a wide response window, interrogation of specific brain circuit activation, an ability to model responses in the context of brain exposure, an ability to rank order compounds based on in vivo efficacy, and minimization of animal use. PMID- 27958714 TI - A Chemogenetic Receptor That Enhances the Magnitude and Frequency of Glycinergic Inhibitory Postsynaptic Currents without Inducing a Tonic Chloride Flux. AB - The gene transfer-mediated expression of inhibitory ion channels in nociceptive neurons holds promise for treating intractable pain. Chemogenetics, which involves expressing constructs activated by biologically inert molecules, is of particular interest as it permits tunable neuromodulation. However, current chloride-permeable chemogenetic constructs are problematic as they mediate a tonic chloride influx which over time would deplete the chloride electrochemical gradient and reduce inhibitory efficacy. Inflammatory pain sensitization can be caused by prostaglandin E2-mediated inhibition of glycinergic inhibitory postsynaptic currents in spinal nociceptive neurons. We developed a highly conducting (100 pS) inhibitory chemogenetic construct based on a human glycine receptor (alpha1Y279F,A288G) with high ivermectin sensitivity. When virally infected into spinal neurons, 10 nM ivermectin increased the magnitude and frequency of glycinergic postsynaptic currents without activating a tonic chloride flux. The construct should thus produce analgesia. Its human origin and the well-established biocompatibility of its ligand suggest it may be suited to human use. PMID- 27958715 TI - Highly Carboxylated Cellulose Nanofibers via Succinic Anhydride Esterification of Wheat Fibers and Facile Mechanical Disintegration. AB - We report herein the preparation of 4-6 nm wide carboxyl-functionalized cellulose nanofibers (CNF) via the esterification of wheat fibers with cyclic anhydrides (maleic, phtalic, and succinic) followed by an energy-efficient mechanical disintegration process. Remarkable results were achieved via succinic anhydride esterification that enabled CNF isolation by a single pass through the microfluidizer yielding a transparent and thick gel. These CNF carry the highest content of carboxyl groups ever reported for native cellulose nanofibers (3.8 mmol g-1). Compared to conventional carboxylated cellulose nanofibers prepared via Tempo-mediated oxidation of wheat fibers, the present esterified CNF display a higher molar-mass and a better thermal stability. Moreover, highly carboxylated CNF from succinic anhydride esterification were effectively integrated into paper filters for the removal of lead from aqueous solution and are potentially of interest as carrier of active molecules or as transparent films for packaging, biomedical or electronic applications. PMID- 27958716 TI - Comparison of Hydrophilicity and Mechanical Properties of Nanocomposite Membranes with Cellulose Nanocrystals and Carbon Nanotubes. AB - The inherent properties of hydrophilicity and mechanical strength of cellulose nanocrystals (CNCs) make them a possible alternative to carbon nanotubes (CNTs) that may present fewer objections to application water-treatment membranes. In this work, the hydrophilicity and mechanical properties of CNCs and CNTs nanocomposite poly(ether sulfone) (PES) membranes were characterized and compared. Membrane pore geometry was analyzed by scanning electron microscopy (SEM). Overall porosity and mean pore radius were calculated based on a wet-dry method. Results showed that PES polymers were loosely packed in the top layer of both the CNC- and CNT-composite membranes (CNC-M and CNT-M). The porosity of the CNC-M was greater than that of the CNT-M. Membrane hydrophilicity, measured by water-contact angle, free energy of cohesion, and water flux, was increased through the addition of either CNCs or functionalized CNTs to an otherwise hydrophobic polymer membrane. The hydrophilicity of the CNC-M was greater than the CNT-M. In addition, the Young's modulus and tensile strength was enhanced for both the CNC-M and CNT-M. While smaller concentrations of CNTs were required to achieve an equal increase in Young's modulus compared with the CNCs, the elasticity of the CNC-composite membranes was greater. PMID- 27958710 TI - Point-of-Care Diagnostics: Recent Developments in a Connected Age. PMID- 27958717 TI - Control of Complex Formation through Peripheral Substituents in Click-Tripodal Ligands: Structural Diversity in Homo- and Heterodinuclear Cobalt-Azido Complexes. AB - The azide anion is widely used as a ligand in coordination chemistry. Despite its ubiquitous presence, controlled synthesis of azido complexes remains a challenging task. Making use of click-derived tripodal ligands, we present here various coordination motifs of the azido ligands, the formation of which appears to be controlled by the peripheral substituents on the tripodal ligands with otherwise identical structure of the coordination moieties. Thus, the flexible benzyl substituents on the tripodal ligand TBTA led to the formation of the first example of an unsupported and solely MU1,1-azido-bridged dicobalt(II) complex. The more rigid phenyl substituents on the TPTA ligand deliver an unsupported and solely MU1,3-azido-bridged dicobalt(II) complex. Bulky diisopropylphenyl substituents on the TDTA ligand deliver a doubly MU1,1-azido-bridged dicobalt(II) complex. Intriguingly, the mononuclear copper(II) complex [Cu(TBTA)N3]+ is an excellent synthon for generating mixed dinuclear complexes of the form [(TBTA)Co(MU1,1-N3)Cu(TBTA)]3+ or [(TBTA)Cu(MU1,1-N3)Cu(TPTA)]3+, both of which contain a single unsupported MU1,1-N3 as a bridge. To the best of our knowledge, these are also the first examples of mixed dinuclear complexes with a MU1,1-N3 monoazido bridge. All complexes were crystallographically characterized, and selected examples were probed via magnetometry and high-field EPR spectroscopy to elucidate the electronic structures of these complexes and the nature of magnetic coupling in the various azido-bridged complexes. These results thus prove the power of click-tripodal ligands in generating hitherto unknown chemical structures and properties. PMID- 27958718 TI - C2-Symmetric P,N Ligands Derived from Carborane-Based Diphosphetanes: Synthesis and Coordination Chemistry. AB - Racemic carborane-based bisphosphanes were obtained by dismutation reactions between a carborane-based diphosphetane and diaryl dichalogenides. NMR spectroscopic and theoretical studies revealed a two-step mechanism explaining the high stereoselectivity of these reactions. The coordination chemistry of the multidentate P,N ligands 6c and 6d in copper(I) and silver(I) complexes was studied. While 6d acted exclusively as tetradentate ligand, 6c showed either tridentate or tetradentate coordination depending on the metal and the counterion. PMID- 27958719 TI - Detection of Metoprolol in Human Biofluids and Pharmaceuticals via Ion-Transfer Voltammetry at the Nanoscopic Liquid/Liquid Interface Array. AB - Metoprolol (MTP) is one of the most widely used antihypertensive drugs yet banned to use in sport competition. Therefore, there has been an increasing demand for developing simple, rapid, and sensitive methods suited to the identification and quantification of MTP in human biofluids. In this work, ultrathin silica nanochannel membrane (SNM) with perforated channels was employed to support nanoscale liquid/liquid interface (nano-ITIES) array for investigation of the ion transfer voltammetric behavior of MTP and for its detection in multiple human biofluids and pharmaceutical formulation. Several potential interfering substances, including small molecules, d-glucose, urea, ascorbic acid, glycine, magnesium chloride, sodium sulfate and large molecules, bovine serum albumin (BSA), were chosen as models of biological interferences to examine their influence on the ion-transfer current signal of MTP. The results confirmed that the steady-state current wave barely changed in the presence of small molecules. Although BSA displayed an apparent blockade on the transfer of MTP, the accurate determination of MTP in multiple human biofluids (i.e., urine, serum and whole blood) and pharmaceutical formulation were still feasible, thanks to the molecular sieving and antifouling abilities of SNM. A limit of detection (LOD) within the physiological level of MTP during therapy could be achieved for all cases, i.e., 0.5 and 1.1 MUM for 100 times diluted urine and serum, respectively, and 2.2 MUM for 1000 times diluted blood samples. These results demonstrated that the nano-ITIES array behaved as a simplified and integrated detection platform for ionizable drug analysis in complex media. PMID- 27958720 TI - A General Mechanism for the Propagation of Mutational Effects in Proteins. AB - Mutations in the hydrophobic interior of proteins are generally thought to weaken the interactions only in their immediate neighborhood. This forms the basis of protein engineering-based studies of folding mechanism and function. However, mutational work on diverse proteins has shown that distant residues are thermodynamically coupled, with the network of interactions within the protein acting as signal conduits, thus raising an intriguing paradox. Are mutational effects localized, and if not, is there a general rule for the extent of percolation and the functional form of this propagation? We explore these questions from multiple perspectives in this work. Perturbation analysis of interaction networks within proteins and microsecond long molecular dynamics simulations of several aliphatic mutants of ubiquitin reveal strong evidence of the distinct alteration of distal residue-residue communication networks. We find that mutational effects consistently propagate into the second shell of the altered site (even up to 15-20 A) in proportion to the perturbation magnitude and dissipate exponentially with a decay distance constant of ~4-5 A. We also report evidence for this phenomenon from published experimental nuclear magnetic resonance data that strikingly resemble predictions from network theory and molecular dynamics simulations. Reformulating these observations onto a statistical mechanical model, we reproduce the stability changes of 375 mutations from 19 single-domain proteins. Our work thus reveals a robust energy dissipation cum-signaling mechanism in the interaction network within proteins, quantifies the partitioning of destabilization energetics around the mutation neighborhood, and presents a simple theoretical framework for modeling the allosteric effects of point mutations. PMID- 27958721 TI - FAST: Size-Selective, Clog-Free Isolation of Rare Cancer Cells from Whole Blood at a Liquid-Liquid Interface. AB - Circulating tumor cells (CTCs) have great potential to provide minimally invasive ways for the early detection of cancer metastasis and for the response monitoring of various cancer treatments. Despite the clinical importance and progress of CTC based cancer diagnostics, most of the current methods of enriching CTCs are difficult to implement in general hospital settings due to complex and time consuming protocols. Among existing technologies, size-based isolation methods provide antibody-independent, relatively simple, and high throughput protocols. However, the clogging issues and lower than desired recovery rates and purity are the key challenges. In this work, inspired by antifouling membranes with liquid filled pores in nature, clog-free, highly sensitive (95.9 +/- 3.1% recovery rate), selective (>2.5 log depletion of white blood cells), rapid (>3 mL/min), and label-free isolation of viable CTCs from whole blood without prior sample treatment is achieved using a stand-alone lab-on-a-disc system equipped with fluid-assisted separation technology (FAST). Numerical simulation and experiments show that this method provides uniform, clog-free, ultrafast cell enrichment with pressure drops much less than in conventional size-based filtration, at 1 kPa. We demonstrate the clinical utility of the point-of-care detection of CTCs with samples taken from 142 patients suffering from breast, stomach, or lung cancer. PMID- 27958722 TI - Porphycenes and Related Isomers: Synthetic Aspects. AB - Porphyrins, called the pigments of life, have been studied for decades. However, the first constitutional isomer of porphyrin, porphycene, was not synthesized until 1986. This milestone marked the beginning of a new era in the field of porphyrinoids and presented opportunities for the creation of an abundance of new pigments. The unique structural and electronic features of these compounds give rise to interesting physical and optical properties with applications in biomedicine and materials science. This review focuses on the synthetic methodologies available for the preparation of porphycenes (functionalized porphycenes, extended porphycenes, benzoporphycenes, naphthoporphycenes, and heteroanalogues) and the other known isomers, namely, corrphycene, hemiporphycene, and isoporphycene. Although the classical synthetic approaches are discussed, particular emphasis is placed on improvements to the known methodologies and recent advances in the field. PMID- 27958723 TI - Thrombin Ultrasensitive Detection Based on Chiral Supramolecular Assembly Signal Amplified Strategy Induced by Thrombin-Binding Aptamer. AB - Thrombin plays a critical role in hemostasis and hemolysis. It is of high importance to develop a system toward thrombin detection with high sensitivity and high selectivity for both research and clinical diagnosis applications. In this paper, we developed a thrombin detection assay by taking advantage of the novel signal amplified strategy based on the chiral supramolecular assembly in physiological K+ background. This assay could detect thrombin as low concentration as about 2 pM and provided a highly specific selectivity among several common interferences. Furthermore, the assay can discriminate thrombin from other nonspecific analogous proteins with high selectivity and can be used to detect thrombin in diluted real human serum samples, which suggested its great potential for rapid detection of thrombin in the clinic. PMID- 27958724 TI - Engineering an Artificial Flavoprotein Magnetosensor. AB - Migratory birds use the Earth's magnetic field as a source of navigational information. This light-dependent magnetic compass is thought to be mediated by cryptochrome proteins in the retina. Upon light activation, electron transfer between the flavin adenine dinucleotide cofactor and tryptophan residues leads to the formation of a spin-correlated radical pair, whose subsequent fate is sensitive to external magnetic fields. To learn more about the functional requirements of this complex chemical compass, we have created a family of simplified, adaptable proteins-maquettes-that contain a single tryptophan residue at different distances from a covalently bound flavin. Despite the complete absence of structural resemblance to the native cryptochrome fold or sequence, the maquettes exhibit a strong magnetic field effect that rivals those observed in the natural proteins in vitro. These novel maquette designs offer unprecedented flexibility to explore the basic requirements for magnetic sensing in a protein environment. PMID- 27958725 TI - Is Quorum Signaling by Mycotoxins a New Risk-Mitigating Strategy for Bacterial Biocontrol of Fusarium verticillioides and Other Endophytic Fungal Species? AB - Bacterial endophytes are used as biocontrol organisms for plant pathogens such as the maize endophyte Fusarium verticillioides and its production of fumonisin mycotoxins. However, such applications are not always predictable and efficient. In this work, we hypothesize and review work that quorum sensing inhibitors are produced either by fungi or by pathogenic bacteria for competitive purposes, altering the efficiency of the biocontrol organisms. Recently, quorum sensing inhibitors have been isolated from several fungi, including Fusarium species, three of which are mycotoxins. Thus, we further postulate that other mycotoxins are inhibitors or quenching metabolites that prevent the protective abilities and activities of endophytic biocontrol bacteria within intercellular spaces. To test the aforementioned suppositions, we review work detailing the use of bioassay bacteria for several mycotoxins for quorum activity. We specifically focus on the quorum use of endophytic bacteria as biocontrols for mycotoxic fungal endophytes, such as the Fusarium species and the fumonisin mycotoxins. PMID- 27958726 TI - Transposed Paterno-Buchi Reaction. AB - A complementary strategy of utilizing pipi* excited state of alkene instead of npi* excited state of the carbonyl chromophore in a "transposed Paterno-Buchi" reaction is evaluated with atropisomeric enamides as the model system. Based on photophysical investigations, the nature of excited states and the reactive pathway was deciphered leading to atropselective reaction. This new concept of switching of excited-state configuration should pave the way to control the stereochemical course of photoreaction due to the orbital approaches required for photochemical reactivity. PMID- 27958727 TI - Electroreduction of Carbon Dioxide to Hydrocarbons Using Bimetallic Cu-Pd Catalysts with Different Mixing Patterns. AB - Electrochemical conversion of CO2 holds promise for utilization of CO2 as a carbon feedstock and for storage of intermittent renewable energy. Presently Cu is the only metallic electrocatalyst known to reduce CO2 to appreciable amounts of hydrocarbons, but often a wide range of products such as CO, HCOO-, and H2 are formed as well. Better catalysts that exhibit high activity and especially high selectivity for specific products are needed. Here a range of bimetallic Cu-Pd catalysts with ordered, disordered, and phase-separated atomic arrangements (Cuat:Pdat = 1:1), as well as two additional disordered arrangements (Cu3Pd and CuPd3 with Cuat:Pdat = 3:1 and 1:3), are studied to determine key factors needed to achieve high selectivity for C1 or C2 chemicals in CO2 reduction. When compared with the disordered and phase-separated CuPd catalysts, the ordered CuPd catalyst exhibits the highest selectivity for C1 products (>80%). The phase separated CuPd and Cu3Pd achieve higher selectivity (>60%) for C2 chemicals than CuPd3 and ordered CuPd, which suggests that the probability of dimerization of C1 intermediates is higher on surfaces with neighboring Cu atoms. Based on surface valence band spectra, geometric effects rather than electronic effects seem to be key in determining the selectivity of bimetallic Cu-Pd catalysts. These results imply that selectivities to different products can be tuned by geometric arrangements. This insight may benefit the design of catalytic surfaces that further improve activity and selectivity for CO2 reduction. PMID- 27958728 TI - Mechanistic Models of Chemical Exchange Induced Relaxation in Protein NMR. AB - Long-lived conformational states and their interconversion rates critically determine protein function and regulation. When these states have distinct chemical shifts, the measurement of relaxation by NMR may provide us with useful information about their structure, kinetics, and thermodynamics at atomic resolution. However, as these experimental data are sensitive to many structural and dynamic effects, their interpretation with phenomenological models is challenging, even if only a few metastable states are involved. Consequently, approximations and simplifications must often be used which increase the risk of missing important microscopic features hidden in the data. Here, we show how molecular dynamics simulations analyzed through Markov state models and the related hidden Markov state models may be used to establish mechanistic models that provide a microscopic interpretation of NMR relaxation data. Using ubiquitin and BPTI as examples, we demonstrate how the approach allows us to dissect experimental data into a number of dynamic processes between metastable states. Such a microscopic view may greatly facilitate the mechanistic interpretation of experimental data and serve as a next-generation method for the validation of molecular mechanics force fields and chemical shift prediction algorithms. PMID- 27958729 TI - Phosphinidene Reactivity of a Transient Vanadium P=N Complex. AB - Toward the preparation of a coordination complex of the heterodiatomic molecule PN, P=N-V(N[tBu]Ar)3 (1, Ar = 3,5-Me2C6H3), we report the use of ClPA (A = C14H10, anthracene) as a formal source of phosphorus(I) in its reaction with Na[NV(N[tBu]Ar)3] (Na[4]) to yield trimeric cyclo-triphosphane [PNV(N[tBu]Ar)3]3 (3) with a core composed exclusively of phosphorus and nitrogen. In the presence of NapS2 (peri-1,8-naphthalene disulfide), NapS2P-NV(N[tBu]Ar)3 (6) is instead generated in 80% yield, suggesting trapping of transient 1. Upon mild heating, 3 readily fragments into dimeric [PNV(N[tBu]Ar)3]2 (2), while in the presence of bis(trimethylsilyl)acetylene or cis-4-octene, the respective phosphirene (Ar[tBu]N)3VN-PC2(SiMe3)2 (7) or phosphirane (Ar[tBu]N)3VN-P(C8H16) (8) compounds are generated. Kinetic data were found to be consistent with unimolecular decay of 3, and [2+1]-cycloaddition with radical clocks ruled out a triplet intermediate, consistent with intermediate 1 reacting as a singlet phosphinidene. In addition, both 7 and 8 were shown to reversibly exchange cis-4-octene and bis(trimethylsilyl)acetylene, serving as formal sources of 1, a reactivity manifold traditionally reserved for transition metals. PMID- 27958730 TI - RNA Scanning of a Molecular Machine with a Built-in Ruler. AB - Advanced single-molecule techniques have enabled tracking of nanometer-scale movements of DNA and RNA motor proteins in real time. Previously, we reported an ATP-independent diffusion of transactivation response RNA binding protein (TRBP) on dsRNA, yet the mechanistic details remain elusive. Using single-molecule fluorescence assays, we demonstrate that the diffusion activity of TRBP is coordinated by an independent movement of two subdomains, dsRBD1 and dsRBD2, in which the diffusion distance is determined by the length of a flexible linker domain that connects the two dsRBDs. When the linker is shortened, the diffusion distance is reduced proportionally, suggesting a ruler-like function of the linker domain. Diffusion stalls upon encountering a physical barrier in the form of an RNA:DNA hybrid segment or bulky secondary structures, indicating a dsRNA scanning mode of TRBP. The results display a plausible mechanism of TRBP in scanning for pre-miRNA or pre-siRNA as proper substrates for the RNAi pathway. PMID- 27958731 TI - The Cushion Method: A New Technique for the Recovery of Hydrophilic Nanocarriers. AB - Microencapsulation of hydrophilic therapeutic agents such as proteins or nucleotides into a nanocarrier is frequently accomplished in inverse (water-in oil) emulsions. However, the redispersion of the nanocarriers in aqueous media often involves a complicated purification process, and the redispersion usually requires additional surfactants for its colloidal stability, which is not favored for biological applications. We propose a simple, fast, and mild method to recover hydrophilic nanocarriers prepared in inverse emulsions by temporary coating of the nanocarriers with biocompatible small molecules, so that the final aqueous dispersion of the nanocarriers can be dispersed with high recovery rate, minimal aggregation, and no additional surfactants. Such a method is termed the "cushion method" and was adopted in the preparation of chitosan nanocarriers. The nanocarriers recovered with the cushion method release encapsulated peptides in a pH-responsive manner and do not require surfactants for colloidal stabilization. PMID- 27958733 TI - Theoretical Study of the Gaseous Hydrolysis of NO2 in the Presence of Amines. AB - The effects on the hydrolysis of NO2 in the presence of methylamine and dimethylamine molecules were investigated by theoretical calculations of a series of the molecular clusters 2NO2-mH2O-CH3NH2 (m = 1-3) and 2NO2-mH2O-(CH3)2NH (m = 1, 2). With methylamine included in the clusters, the energy barrier is reduced by 3.2 kcal/mol from that with ammonia, and the corresponding products may form without an energy barrier. The results show that amines have larger effects than ammonia in promoting the hydrolysis of NO2 on thermodynamics. The additional water molecules can stabilize the transition states and the product complexes, and we infer that adding more water molecules in the reactions mainly act as solvent and promoting to form the methylamine nitrate (CH3NH3+NO3-). In addition, the interactions of CH3NH2 and (CH3)2NH on the hydration of HNO3 are also more effective than NH3, and the NH4NO3, CH3NH3NO3, and (CH3)2NH2NO3 complexes tend to form the larger aerosols with the increasing of water molecules. The equilibrium geometries, harmonic vibrational frequencies, and intensities of both HONO-CH3NH2 and HONO-NH3 complexes were investigated. Calculations predict that the binding energies of both HONO-CH3NH2 complexes are larger than HONO-NH3 complexes, and the OH stretching vibrational frequencies and intensities are most affected. The natural bond orbital analysis was performed to describe the donor-acceptor interactions on a series of complexes in the reactions 2NO2 + H2O + CH3NH2 and 2NO2 + H2O + (CH3)2NH, as well as the complexes of HONO-NH3 and HONO-CH3NH2. The results show that the interactions with amines are relatively larger, and the higher stabilization energies between CH3NH2 and HONO are found. PMID- 27958732 TI - Design and Synthesis of a New Series of 4-Heteroarylamino-1'-azaspiro[oxazole 5,3'-bicyclo[2.2.2]octanes as alpha7 Nicotinic Receptor Agonists. 1. Development of Pharmacophore and Early Structure-Activity Relationship. AB - The design and synthesis of a series of quinuclidine-containing spirooxazolidines ("spiroimidates") and their utility as alpha7 nicotinic acetylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for alpha7 over the highly homologous 5-HT3A receptor. Modification of the N-spiroimidate heterocycle substituent led to (1S,2R,4S)-N isoquinolin-3-yl)-4'H-4-azaspiro[bicyclo[2.2.2]octane-2,5'oxazol]-2'-amine (BMS 902483), a potent alpha7 partial agonist, which improved cognition in preclinical rodent models. PMID- 27958734 TI - Novel Irreversible Agonists Acting at the A1 Adenosine Receptor. AB - The A1 adenosine receptor (A1AR) is an important G protein-coupled receptor that regulates a range of physiological functions. Herein we report the discovery of novel irreversible agonists acting at the A1AR, which have the potential to serve as useful research tools for studying receptor structure and function. A series of novel adenosine derivatives bearing electrophilic substituents was synthesized, and four compounds, 8b, 15a, 15b, and 15d, were shown to possess similar potency and efficacy to the reference high efficacy agonist, NECA, in an assay of ERK1/2 phosphorylation assay. Insensitivity to antagonist addition in a real-time, label-free, xCELLigence assay was subsequently used to identify compounds that likely mediated their agonism through an irreversible interaction with the A1AR. Of these compounds, 15b and 15d were more directly validated as irreversible agonists of the A1AR using membrane-based [3H]DPCPX and [35S]GTPgammaS binding experiments. PMID- 27958735 TI - Identification of Picrasidine C as a Subtype-Selective PPARalpha Agonist. AB - Picrasidine C (1), a dimeric beta-carboline-type alkaloid isolated from the root of Picrasma quassioides, was identified to have PPARalpha agonistic activity by a mammalian one-hybrid assay from a compound library. Among the PPAR subtypes, 1 selectively activated PPARalpha in a concentration-dependent manner. Remarkably, 1 also promoted PPARalpha transcriptional activity by a peroxisome proliferator response element-driven luciferase reporter assay. Furthermore, 1 induced the expression of PPARalpha-regulated genes involved in lipid, glucose, and cholesterol metabolism, such as CPT-1, PPARalpha, PDK4, and ABCA1, which was abrogated by the PPARalpha antagonist MK-886, indicating that the effect of 1 was dependent on PPARalpha activation. This is the first report to demonstrate 1 to be a subtype-selective PPARalpha agonist with potential application in treating metabolic diseases, such as hyperlipidemia, atherosclerosis, and hypercholesterolemia. PMID- 27958737 TI - Development of a Simple Electron Transfer and Polarization Model and Its Application to Biological Systems. AB - Here we present a new method for point charge calculation which we call QET (charges by electron transfer). The intent of this work is to develop a method that can be useful for studying charge transfer in large biological systems. It is based on the intuitive framework of the QEQ method with the key difference being that the QET method tracks all pairwise electron transfers by augmenting the QEQ pseudoenergy function with a distance dependent cost function for each electron transfer. This approach solves the key limitation of the QEQ method which is its handling of formally charged groups. First, we parametrize the QET method by fitting to electrostatic potentials calculated using ab initio quantum mechanics on over 11,000 small molecules. On an external test set of over 2500 small molecules the QET method achieves a mean absolute error of 1.37 kcal/mol/electron when compared to the ab initio electrostatic potentials. Second, we examine the conformational dependence of the charges on over 2700 tripeptides. With the tripeptide data set, we show that the conformational effects account for approximately 0.4 kcal/mol/electron on the electrostatic potentials. Third, we test the QET method for its ability to reproduce the effects of polarization and electron transfer on 1000 water clusters. For the water clusters, we show that the QET method captures about 50% of the polarization and electron transfer effects. Finally, we examine the effects of electron transfer and polarizability on the electrostatic interaction between p38 and 94 small molecule ligands. When used in conjunction with the Generalized-Born continuum solvent model, polarization and electron transfer with the QET model lead to an average change of 17 kcal/mol on the calculated electrostatic component of DeltaG. PMID- 27958736 TI - Glycans Confer Specificity to the Recognition of Ganglioside Receptors by Botulinum Neurotoxin A. AB - The highly poisonous botulinum neurotoxins, produced by the bacterium Clostridium botulinum, act on their hosts by a high-affinity association to two receptors on neuronal cell surfaces as the first step of invasion. The glycan motifs of gangliosides serve as initial coreceptors for these protein complexes, whereby a membrane protein receptor is bound. Herein we set out to characterize the carbohydrate minimal binding epitope of the botulinum neurotoxin serotype A. By means of ligand-based NMR spectroscopy, X-ray crystallography, computer simulations, and isothermal titration calorimetry, a screening of ganglioside analogues together with a detailed characterization of various carbohydrate ligand complexes with the toxin were accomplished. We show that the representation of the glycan epitope to the protein affects the details of binding. Notably, both branches of the oligosaccharide GD1a can associate to botulinum neurotoxin serotype A when expressed as individual trisaccharides. It is, however, the terminal branch of GD1a as well as this trisaccharide motif alone, corresponding to the sialyl-Thomsen-Friedenreich antigen, that represents the active ligand epitope, and these compounds bind to the neurotoxin with a high degree of predisposition but with low affinities. This finding does not correlate with the oligosaccharide moieties having a strong contribution to the total affinity, which was expected to be the case. We here propose that the glycan part of the ganglioside receptors mainly provides abundance and specificity, whereas the interaction with the membrane itself and protein receptor brings about the strong total binding of the toxin to the neuronal membrane. PMID- 27958738 TI - Extreme Gradient Boosting as a Method for Quantitative Structure-Activity Relationships. AB - In the pharmaceutical industry it is common to generate many QSAR models from training sets containing a large number of molecules and a large number of descriptors. The best QSAR methods are those that can generate the most accurate predictions but that are not overly expensive computationally. In this paper we compare eXtreme Gradient Boosting (XGBoost) to random forest and single-task deep neural nets on 30 in-house data sets. While XGBoost has many adjustable parameters, we can define a set of standard parameters at which XGBoost makes predictions, on the average, better than those of random forest and almost as good as those of deep neural nets. The biggest strength of XGBoost is its speed. Whereas efficient use of random forest requires generating each tree in parallel on a cluster, and deep neural nets are usually run on GPUs, XGBoost can be run on a single CPU in less than a third of the wall-clock time of either of the other methods. PMID- 27958739 TI - Synthesis and Properties of 7-Deazapurine- and 8-Aza-7-deazapurine-Locked Nucleic Acid Analogues: Effect of the Glycosidic Torsion Angle. AB - Conformationally restricted nucleoside analogues 2',4'-BNA/LNA-7-deazaguanine (LNA-7cG) and 2',4'-BNA/LNA-8-aza-7-deazaguanine (LNA-8n7cG), which avoid extra hydrogen bond formation at the 7-position of the guanine nucleobase, were successfully synthesized and incorporated into oligonucleotides. While the LNA 7cG-containing oligonucleotides show high duplex-forming ability with complementary DNA and RNA similar to LNA-G, the LNA-8n7cG-containing oligonucleotide has lower binding affinity than that of natural 2' deoxyguanosine. This disparity in thermostability is also observed in 7 deazaadenosine analogues (LNA-7cA, LNA-8n7cA). Thermodynamic parameters and computational chemistry revealed that an inappropriate glycosidic torsion angle chi of 2',4'-BNA/LNA-8-aza-7-deazapurine analogues destabilizes duplex formation in contrast to 2',4'-BNA/LNA-7-deazapurine analogues. This result indicates that the nucleobase rotation angle plays an important role in duplex binding affinity. In addition, LNA-7cG-modified oligonucleotide effectively suppresses aggregation even in a guanine-rich sequence. PMID- 27958740 TI - Binding Affinity of Inorganic Mercury and Cadmium to Biomimetic Erythrocyte Membranes. AB - Inorganic mercury and cadmium are becoming increasingly prevalent due to industrial activity and have been linked to cardiovascular disease and diabetes. The binding affinity of Hg, Cd, and their mixtures to biomimetic erythrocyte membranes was investigated by isothermal titration calorimetry in physiologically relevant media (100 mM NaCl, pH 7.4, 37 degrees C). The thermodynamic parameters were not expressed per mole of lipid but as metals binding to liposomes. To our knowledge, this method is novel and provides a more intuitive approach to understand such interactions. The results demonstrated that Hg interacted with membranes in the following order: PC (phosphatidylcholine) > 85:15 PC/PE (phosphatidylethanolamine) > 85:15 PC/PS (phosphatidylserine), with the binding constants ranging from 10 to 233 M-1. In contrast, Cd interacted most readily with negatively charged PC/PS membranes but not with the remaining systems. Metal mixtures bind less to PC/PE membranes than the individual constituents. The large entropy contribution from these interactions suggests possible water release and/or reorganization upon Hg and Cd binding to membranes. zeta-Potential data indicate that the process may be electrostatically driven. It is imperative to consider the chemical speciation of these metals in the presence of chloride to better understand metal-lipid interactions and their impact on biomembranes. PMID- 27958741 TI - Effective and Reversible Switching of Emulsions by an Acid/Base-Mediated Redox Reaction. AB - To develop a fast, effective, and reversible strategy for phase separation and re emulsification of the surfactant-based emulsions, a strategy for using acid/base mediated redox reactions was established to switch the emulsions formed from a redox-responsive anionic surfactant of potassium dodecyl seleninate (C12SeO2K). Upon acidification, C12SeO2K was reduced by KI to give didodecyl diselenide (C12Se)2, a state of almost no surface or interfacial activity; upon basification, (C12Se)2 was oxidized by I2 to give C12SeO2K again. The fractional conversion of C12SeO2K in the reversible switching processes was close to 100%. Consequently, an unusually large change in interfacial tension (DeltaIFT) as high as ~27.1 mN m-1 was obtained at a wider concentration range starting from the critical micelle concentration of C12SeO2K; the highest IFT at the oil-water interface was obtained after an almost complete switch-off, giving an oil-aqueous solution interface very similar to that without any emulsifiers, which leads to the effective and fast phase separation of the C12SeO2K-based switchable emulsions. PMID- 27958742 TI - Chemical Modification of Conical Intersections in Photoisomerization Dynamics of Butadiene Derivatives. AB - Guided by a notion of symmetry-breaking modulation or control of the so-called symmetry-allowed conical intersection by shining laser pulses [ Arasaki , Y. ; et al. Phys. Chem. Chem. Phys. 2010 , 12 , 1239 ], we here explore a possibility of the modulation of the symmetry-allowed conical intersection by chemical substitution with functional groups. As a first case study, we choose photoisomerization dynamics of s-trans-1,3-butadiene H2C?CH-CH?CH2 with one of the terminal hydrogen atoms being replaced by -CF3. The target here is not the control of the rate of nonadiabatic transition but to know which one of the double bonds is more frequently isomerized in the radiationless quenching process on the way back to the ground state. We analyze when and how the symmetry is broken by tracking ab initio molecular dynamics paths, the mean-field paths with use of the nonadiabatic electron wavepacket dynamics, and the associated branching paths. PMID- 27958744 TI - Investigating the Consistency of Models for Water Splitting Systems by Light and Voltage Modulated Techniques. AB - The optimization of solar energy conversion devices relies on their accurate and nondestructive characterization. The small voltage perturbation techniques of impedance spectroscopy (IS) have proven to be very powerful to identify the main charge storage modes and charge transfer processes that control device operation. Here we establish the general connection between IS and light modulated techniques such as intensity modulated photocurrent (IMPS) and photovoltage spectroscopies (IMVS) for a general system that converts light to energy. We subsequently show how these techniques are related to the steady-state photocurrent and photovoltage and the external quantum efficiency. Finally, we express the IMPS and IMVS transfer functions in terms of the capacitive and resistive features of a general equivalent circuit of IS for the case of a photoanode used for solar fuel production. We critically discuss how much knowledge can be extracted from the combined use of those three techniques. PMID- 27958745 TI - An Empirical Dynamical Barrier for Statistical Theory of Low-Energy Reactive S(1D) + HD(j = 0), H2(j = 0) Collisions. AB - A simple model potential is proposed to describe the dynamical barrier in the mean interaction potential at small distances between the reactants in S(1D) + HD(1Sigma, v = 0, j = 0) reaction. The statistical theory of collision complex formation and complex decay is applied to calculate the total reaction cross sections and the cross sections for SH and SD productions in the range of low collision energies Ec = (0.4-60) meV. The results are compared with measured cross sections and results of hyperspherical close coupling calculations. As a check of consistency the same comparisons are presented for the case of S(1D) + H2(1Sigma, v = 0, j = 0) reaction. PMID- 27958746 TI - Effect of Methylation on the Photodynamical Behavior of Arylazoimidazoles: New Insight from Theoretical ab Initio Potential Energy Calculations and Molecular Dynamics Simulations. AB - Arylazoimidazoles are a series of azobenzene derivatives possessing the ability to undergo photoinduced trans-cis isomerization. Their isomerization quantum yields are found to be dependent on the excitation wavelength and chemical substituents. The current work investigated the ultrafast nonadiabatic decay behaviors of three arylazoimidazoles (Pai-H, Tai-H, and Tai-Me) after being photoexcited to the S1 and S2 states by means of high-level ab initio potential energy calculations and on-the-fly surface hopping dynamical simulations in gas phase to explore the effect of the methylation. The results found that the Pai-H with no methylation substituents only decay along a NNC bending reaction pathway for both the S1 and S2 states. The Tai-H with a methylation substituent on the six-membered ring can decay along both the NNC bending and twisting motion pathways for the S1 and S2 states. The Tai-Me has methylation substituents on both the six- and five-membered rings prefers to decay by a twisting motion in the S1 state, while a NNC bending channel is activated following excitation to the S2 state. The position and numbers of methylation substituents has important influence on the dynamical behaviors of arylazoimidazoles. The current work provides fundamental knowledge of the arylazoimidazoles and will be helpful for advanced and further exploration and application. PMID- 27958747 TI - "Though It Be but Little, It Is Fierce": Excited State Engineering of Conjugated Organic Materials by Fluorination. AB - Fluorination is frequently used to significantly change the properties of conjugated organic materials due to fluorine's exceptional properties; well-known is its impact on electronic structure, but it also impacts the geometry despite fluorine's small size. Less known, the changes in the electronic and geometrical properties may provoke drastic changes of the excited state properties like batho and hypsochromic shifts of absorption and emission bands (inter alia leading to excited state switching), hypo- and hyperchromic effects, spectral broadening, and changes of the nonradiative deactivation pathways. The state of the art on these issues is summarized in the current Perspective to stimulate further discussions on this intriguing subject. PMID- 27958743 TI - Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting MU Opioid Analgesic with Reduced Abuse Liability. AB - Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective MU-opioid receptor (MOR) agonist (EC50 = 1.2 nM, >8000 MU/kappa selectivity). 5 is a biased activator of MOR-induced G-protein signaling over beta-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands. In vivo studies with 5 demonstrate centrally mediated antinociception, significantly reduced rewarding effects, tolerance, and sedation. We propose that this novel MOR agonist may represent a valuable tool in distinguishing the pathways involved in MOR-induced analgesia from its side effects. PMID- 27958748 TI - Rh-Catalyzed Asymmetric Hydrogenation of 1,2-Dicyanoalkenes. AB - A highly efficient enantioselective hydrogenation of 1,2-dicyanoalkenes catalyzed by the complex of rhodium and f-spiroPhos has been developed. A series of 1,2 dicyanoalkenes were successfully hydrogenated to the corresponding chiral 1,2 dicyanoalkanes under mild conditions with excellent enantioselectivities (up to 98% ee). This methodology provides efficient access to the asymmetric synthesis of chiral diamines. PMID- 27958749 TI - Palladium-Catalyzed Tandem C-H Functionalization/Cyclization Strategy for the Synthesis of 5-Hydroxybenzofuran Derivatives. AB - A palladium-catalyzed benzoquinone C-H functionalization/cyclization strategy with terminal alkynes was employed for the synthesis of some biologically relevant 2,3-disubstituted 5-hydroxybenzofuran derivatives. The benzoquinone acts as a reactant as well as an oxidant. During the process, an additional alkyne functionality can be introduced at the C3 position of the benzofuran. Base, ligand, and external oxidant are not required in this protocol. PMID- 27958750 TI - Mechanistic Picture and Kinetic Analysis of Surface-Confined Ullmann Polymerization. AB - Surface-confined polymerization via Ullmann coupling is a promising route to create one- and two-dimensional covalent pi-conjugated structures, including the bottom-up growth of graphene nanoribbons. Understanding the mechanism of the Ullmann reaction is necessary to provide a platform for rationally controlling the formation of these materials. We use fast X-ray photoelectron spectroscopy (XPS) in kinetic measurements of epitaxial surface polymerization of 1,4 dibromobenzene on Cu(110) and devise a kinetic model based on mean field rate equations, involving a transient state. This state is observed in the energy landscapes calculated by nudged elastic band (NEB) within density functional theory (DFT), which assumes as initial and final geometries of the organometallic and polymeric structures those observed by scanning tunneling microscopy (STM). The kinetic model accounts for all the salient features observed in the experimental curves extracted from the fast-XPS measurements and enables an enhanced understanding of the polymerization process, which is found to follow a nucleation-and-growth behavior preceded by the formation of a transient state. PMID- 27958752 TI - Remote Asymmetric Induction Using Acetate-Type Vinylketene Silyl N,O-Acetals. AB - Remote asymmetric induction by the vinylogous Mukaiyama aldol reaction using the acetate-type vinylketene silyl N,O-acetal possessing a chiral auxiliary has been achieved. The silyl N,O-acetal derived from crotonate and l-valine afforded the O silylated 5R- and 5S-adducts selectively by treatment with SnCl4 and BF3.OEt2, respectively. The SnCl4-mediated isomerization of silyl dienol ether was found, and the resulting major isomer showed high reactivity to give gamma-adduct in high stereoselectivity. PMID- 27958751 TI - Distribution of Flunixin Residues in Muscles of Dairy Cattle Dosed with Lipopolysaccharide or Saline and Treated with Flunixin by Intravenous or Intramuscular Injection. AB - Twenty dairy cows received flunixin meglumine at 2.2 mg/kg bw, administered once daily by either the intravenous (IV) or intramuscular (IM) route for three consecutive days with either intravenous normal saline (NS) or lipopolysaccharide (LPS) providing a balanced design with five animals per group. Cows were sacrificed after a 4 day withdrawal period, and 13 muscle types were collected and assayed for flunixin by LC-MS/MS. After elimination of sample outliers, the main effects of route of administration (IV or IM), treatment (NS or LPS), and tissue type significantly (P < 0.05) affected flunixin residues, with no interaction (P > 0.05). Intramuscular (nonlabel) flunixin administration produced greater (P < 0.05) flunixin residues in muscle than the IV (label) administration, whereas LPS resulted in lower flunixin levels. Differences among the tissue levels indicate it is necessary to specify the tissue to be used for any monitoring of drug levels for consumer protection. PMID- 27958753 TI - Orthogonally Processable Carbazole-Based Polymer Thin Films by Nitroxide-Mediated Polymerization. AB - Cross-linking of hole-transporting polymer thin films in organic light emitting diodes (OLEDs) has been shown to increase device efficacy when subsequent layers are deposited from solution. This improvement, due to resistance of the films to dissolution, could also be achieved by covalently grafting the polymer film to the substrate. Using nitroxide-mediated polymerization (NMP), we synthesized a novel poly(9-(4-vinylbenzyl)-9H-carbazole) (poly(VBK)) copolymer which can be cross-linked and also developed two simple methods for the grafting-to or grafting-from, also known as surface-initiated polymerization, of poly(VBK) to indium tin oxide (ITO) substrates. All three of these methods produced thin films that could be orthogonally processed; that is, they resisted dissolution when the spin-coating of a subsequent layer was simulated. Similar electrochemical behavior for the poly(VBK) films was observed regardless of the technique used, suggesting that all three techniques could be used in the engineering of organic electronic devices. We expect that all three methods would be worth investigating in the solution-based assembly of OLEDs and other organic electronic devices. PMID- 27958754 TI - Iron-Catalyzed Sustainable Synthesis of Pyrrole. AB - Efficient, sustainable, highly regiospecific substituted pyrroles were synthesized using a well-defined, air stable, molecular iron(0) complex. The developed methodology is broadly applicable and tolerates a variety of functional groups. C-2, C-3, and C-2 & C-4 substituted pyrroles were synthesized in good yield. Symmetrical bis-pyrroles were accessible for the first time using an iron catalyst. On the basis of the experimental observation, we propose that the reaction proceeds through a hydrogen autotransfer process followed by second oxidation/intramolecular dehydrative condensation to provide the pyrrole. PMID- 27958755 TI - Amphiphilic Ferrocene-Containing PEG Block Copolymers as Micellar Nanocarriers and Smart Surfactants. AB - An important and usually the only function of most surfactants in heterophase systems is stabilizing one phase in another, for example, droplets or particles in water. Surfactants with additional chemical or physical handles are promising in controlling the colloidal properties by external stimuli. The redox stimulus is an attractive feature; however, to date only a few ionic redox-responsive surfactants have been reported. Herein, the first nonionic and noncytotoxic ferrocene-containing block copolymers are prepared, carrying a hydrophilic poly(ethylene glycol) (PEG) chain and multiple ferrocenes in the hydrophobic segment. These amphiphiles were studied as redox-sensitive surfactants that destabilize particles as obtained in miniemulsion polymerization. Because of the nonionic nature of such PEG-based copolymers, they can stabilize nanoparticles even after the addition of ions, whereas particles stabilized with ionic surfactants would be destabilized by the addition of salt. The redox-active surfactants were prepared by the anionic ring-opening polymerization of ferrocenyl glycidyl ether, with PEG monomethyl ether as the macroinitiator. The resultant block copolymers with molecular weights (Mn) between 3600 and 8600 g mol-1 and narrow molecular weight distributions (Mw/Mn = 1.04-1.10) were investigated via 1H nuclear magnetic resonance and diffusion ordered spectroscopy, size exclusion chromatography, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Furthermore, the block copolymers were used as building blocks for redox-responsive micelles and as redox-responsive surfactants in radical polymerization in miniemulsion to stabilize model polystyrene nanoparticles. Oxidation of iron to the ferrocenium species converted the amphiphilic block copolymers into double hydrophilic macromolecules, which led to the destabilization of the nanoparticles. This destabilization of nanoparticle dispersions may be useful for the formation of coatings and the recovery of surfactants. PMID- 27958757 TI - Highly Crumpled All-Carbon Transistors for Brain Activity Recording. AB - Neural probes based on graphene field-effect transistors have been demonstrated. Yet, the minimum detectable signal of graphene transistor-based probes is inversely proportional to the square root of the active graphene area. This fundamentally limits the scaling of graphene transistor-based neural probes for improved spatial resolution in brain activity recording. Here, we address this challenge using highly crumpled all-carbon transistors formed by compressing down to 16% of its initial area. All-carbon transistors, chemically synthesized by seamless integration of graphene channels and hybrid graphene/carbon nanotube electrodes, maintained structural integrity and stable electronic properties under large mechanical deformation, whereas stress-induced cracking and junction failure occurred in conventional graphene/metal transistors. Flexible, highly crumpled all-carbon transistors were further verified for in vivo recording of brain activity in rats. These results highlight the importance of advanced material and device design concepts to make improvements in neuroelectronics. PMID- 27958756 TI - High-Efficiency and Air-Stable Perovskite Quantum Dots Light-Emitting Diodes with an All-Inorganic Heterostructure. AB - Perovskite light-emitting diodes (PeLEDs), because of its fundamental scientific importance and practical applications in the fields of low-cost light source or display applications, have drawn worldwide attention in recent years. However, PeLEDs available today suffer from a compromise in their emission efficiency and operation stability. In this study, we designed and fabricated a stacking all inorganic multilayer structure by using inorganic perovskite CsPbBr3 quantum dots (QDs) as the emissive layer and inorganic n-type MgZnO and p-type MgNiO as the carrier injectors, respectively. Through energy band engineering of carrier injectors by Mg incorporation and their thickness optimization, PeLEDs with maximum luminance of 3809 cd/m2, luminous efficiency of 2.25 cd/A, and external quantum efficiency of 2.39% have been realized, which are much better than most PeLEDs from CH3NH3PbBr3 films, and comparable with the highest results reported on CsPbBr3 QDs LEDs. More importantly, the unencapsulated PeLEDs in a continuous current mode demonstrate a remarkable operation stability against water and oxygen degradation. After a continuous operation for 10 h under a dc bias (10.0 V), nearly 80% of the original efficiency of the PeLEDs has been retained, greatly superior to reference and other previously reported devices constructed with conventional organic carrier injectors. Our results obtained open possibilities for the design and development of high-efficiency and air-stable PeLEDs that are not dependent on expensive and less-stable organic carrier injectors. PMID- 27958758 TI - Calculation of Configurational Entropy Differences from Conformational Ensembles Using Gaussian Mixtures. AB - We present a novel, conceptually simple approach to calculate the configurational entropy difference between two conformational ensembles of a molecular system. The method estimates the full-dimensional probability density function of the system by a Gaussian mixture, using an efficient greedy learning algorithm with a cross-validation-based stopping criterion. An evaluation of the method on conformational ensembles corresponding to substates of five small peptide systems shows that excellent agreement is found with the exact entropy differences obtained from a full enumeration of conformations. Compared with the quasiharmonic method and two other, more recently developed methods, the Gaussian mixture method yields more accurate results at smaller sample sizes. We illustrate the power of the method by calculating the backbone torsion angle entropy difference between disulfide-bonded and nondisulfide-bonded states of tachyplesin, a 17-residue antimicrobial peptide, and between two substates in the native ensemble of the 58-residue bovine pancreatic trypsin inhibitor. PMID- 27958759 TI - Phase Transfer of Nanoparticles Using an Amphiphilic Ionic Liquid. AB - The phase transfer of nanoparticles (NPs) from water to organic solvents by an amphiphilic room-temperature ionic liquid (IL) was reported. The geminal IL modified with Pluronic P123 stabilizes a variety of NPs of different size and nature, such as Pd, Au, Ag, and SiO2 NPs. Their phase transfer into a hydrophobic environment was realized by raising the temperature and adding salts (such as NaCl and KBr), both of which have a common effect of breaking the hydrogen bonds of the IL with H2O. A more straightforward method of using an organic solvent working as a hydrogen bond donor (such as butyl alcohol) was then proposed. In this case, NaCl was no longer required. To further apply this strategy to the organic solvents that are generally incapable of forming hydrogen bonds (e.g., toluene), a small quantity of benzoic acid was added to the organic phase. By forming hydrogen bonds from benzoic acid to the IL, an even more facile approach was provided. FT-IR confirmed the hydrogen bonding between them. The phase transfer protocol does not rely on coordination bonding of ligands with a specific metal and is capable of the phase transfer of objects with large sizes and different natures. Thus, it has the potential for wide application. PMID- 27958760 TI - The Challenges and Issues of Undergraduate Student Retention and Attainment in UK Veterinary Medical Education. AB - Student retention and attainment has recently been identified as a key area for development in veterinary medical education enquiry. Woodfield's research on retention and attainment across the UK disciplines has yielded some unique information about the challenges and issues of students who study veterinary medicine and related subjects. The present literature review aims to expand on Woodfield's findings and explain important issues about retention and attainment across veterinary medicine. Overall, the subject of retention and attainment in undergraduate veterinary medical education needs a great deal more empirical attention, such as data on the retention and attainment of mature and widening access students, and the effects of students being placed at remote locations during their studies. Our findings also cover some unsurprising issues: the dominance of women in a profession that is principally lead by men, the underrepresentation of black and minority ethnic (BME) students in veterinary medicine, and the effects of content overload in the veterinary medical curriculum. Based on data gathered by Woodfield and our investigation of the scholarly and gray literatures, we offer an overview of gaps in current knowledge and recommendations for further research. PMID- 27958763 TI - Neuraminidase as an enzymatic marker for detecting airborne Influenza virus and other viruses. AB - Little information is available regarding the effectiveness of air samplers to collect viruses and regarding the effects of sampling processes on viral integrity. The neuraminidase enzyme is present on the surface of viruses that are of agricultural and medical importance. It has been demonstrated that viruses carrying this enzyme can be detected using commercial substrates without having to process the sample by methods such as RNA extraction. This project aims at evaluating the effects of 3 aerosol-sampling devices on the neuraminidase enzyme activity of airborne viruses. The purified neuraminidase enzymes from Clostridium perfringens, a strain of Influenza A (H1N1) virus, the FluMist influenza vaccine, and the Newcastle disease virus were used as models. The neuraminidase models were aerosolized in aerosol chambers and sampled with 3 different air samplers (SKC BioSampler, 3-piece cassettes with polycarbonate filters, and Coriolis MU) to assess the effect on neuraminidase enzyme activity. Our results demonstrated that Influenza virus and Newcastle disease virus neuraminidase enzymes are resistant to aerosolization and sampling with all air samplers tested. Moreover, we demonstrated that the enzymatic neuraminidase assay is as sensitive as RT-qPCR for detecting low concentrations of Influenza virus and Newcastle disease virus. Therefore, given the sensitivity of the assay and its compatibility with air sampling methods, viruses carrying the neuraminidase enzyme can be rapidly detected from air samples using neuraminidase activity assay without having to preprocess the samples. PMID- 27958764 TI - Death of the Safety Guidewire. PMID- 27958761 TI - Delay discounting, risk-taking, and rejection sensitivity among individuals with Internet and Video Gaming Disorders. AB - Background and aims There is a previous evidence for impulsivity in individuals with Internet and Video Gaming Disorders. The aim of this study was to examine whether Internet and video game addictions are associated with experiential delay discounting, risk-taking, and sensitivity to social rejection using computerized tasks and questionnaires. Methods Twenty participants (mean age 24, SD = 1.55) with high score on the Problematic Online Gaming Questionnaire (POGQ) were compared with 20 participants (mean age 24.8, SD = 1.34) with low score on the POGQ. They performed on computerized Balloon Analog Risk Task and Experiential Delay discounting Task (EDT), and filled in the sensitivity to social rejection questionnaire. Results Participants with high POGQ scores had lower measures of delay discounting, higher measures of risk-taking, and higher measures of sensitivity to social rejection compared with participants with low POGQ scores. Discussion The results of this study support the previous evidence of risk-taking and provide new evidence for difficulties in delay discounting and sensitivity to social rejection among those who score high on Internet and video games. Conclusions The results suggest that Internet- and video game-addicted individuals seek immediate gratification and cannot wait for later reward. Furthermore, these individuals spend time in the virtual world, where they feel safe, and avoid social interactions presumably due to fears of social rejection. PMID- 27958762 TI - CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL. AB - AIMS: Macropinocytosis has been implicated in cardiovascular and other disorders, yet physiological factors that initiate fluid-phase internalization and the signaling mechanisms involved remain poorly identified. The present study was designed to examine whether matrix protein thrombospondin-1 (TSP1) stimulates macrophage macropinocytosis and, if so, to investigate the potential signaling mechanism involved. RESULTS: TSP1 treatment of human and murine macrophages stimulated membrane ruffle formation and pericellular solute internalization by macropinocytosis. Blockade of TSP1 cognate receptor CD47 and NADPH oxidase 1 (Nox1) signaling, inhibition of phosphoinositide 3-kinase, and transcriptional knockdown of myotubularin-related protein 6 abolished TSP1-induced macropinocytosis. Our results demonstrate that Nox1 signaling leads to dephosphorylation of actin-binding protein cofilin at Ser-3, actin remodeling, and macropinocytotic uptake of unmodified native low-density lipoprotein (nLDL), leading to foam cell formation. Finally, peritoneal chimera studies suggest the role of CD47 in macrophage lipid macropinocytosis in hypercholesterolemic ApoE-/- mice in vivo. INNOVATION: Activation of a previously unidentified TSP1-CD47 signaling pathway in macrophages stimulates direct receptor-independent internalization of nLDL, leading to significant lipid accumulation and foam cell formation. These findings reveal a new paradigm in which delimited Nox1-mediated redox signaling, independent of classical lipid oxidation, contributes to early propagation of vascular inflammatory disease. CONCLUSIONS: The findings of the present study demonstrate a new mechanism of solute uptake with implications for a wide array of cell types, including macrophages, dendritic cells, and cancer cells, and multiple pathological conditions in which matrix proteins are upregulated. Antioxid. Redox Signal. 26, 886-901. PMID- 27958765 TI - Treatment of Non-Contained Infrabony Defects With Enamel Matrix Derivative Alone or in Combination With Biphasic Calcium Phosphate Bone Graft: A 12-Month Randomized Controlled Clinical Trial. AB - BACKGROUND: Use of enamel matrix derivative (EMD) when dealing with non-contained defects may be limited because EMD does not maintain a space itself. Use of combined therapy has been proposed, using a bone graft in combination with EMD to avoid collapse of the flap into the bony defect during healing time. Therefore, the aim of this study is to evaluate the clinical and radiologic healing response of non-contained infrabony defects after treatment with a combination of EMD and biphasic calcium phosphate (BC) or EMD alone. METHODS: Fifty-two patients with at least one infrabony defect >=3 mm in depth with a probing depth (PD) >=6 mm were randomly treated with EMD/BC or EMD alone. Clinical and radiographic parameters were evaluated at baseline, 6, and 12 months after surgery. To standardize the procedure, an acrylic stent and millimeter radiographic grid were used. The primary outcome was the change in clinical attachment level (CAL). RESULTS: Analysis of the data demonstrated a statistically significant difference from baseline within each group (P <0.05), with a difference in clinical and radiographic parameters at 6 and 12 months. After 1 year, mean PD reductions of 3.14 +/- 1.95 mm (39.6%) in the EMD/BC group and 3.30 +/- 1.89 mm (48.7%) in the EMD group were achieved. A mean CAL gain of 2.38 +/- 2.17 mm (24.9%) in the EMD/BC group and 2.65 +/- 2.18 mm (36.2%) in the EMD group were obtained. Reduction in the infrabony component was 2.71 +/- 1.79 mm (57.9%) in the test group and 2.60 +/- 2.03 mm (28.5%) in the control group. There were no statistically significant differences between treatment groups. CONCLUSIONS: It was concluded that treatment of non-contained infrabony defects with EMD, with or without BC, resulted in statistically significantly better results after 12 months compared with baseline measurements. In contrast, the combined approach did not result in a statistically significant improvement. PMID- 27958766 TI - Association of Serum Triglyceride Level and Gemfibrozil Consumption With Periodontal Status. AB - BACKGROUND: Hyperlipidemia is a major risk factor for cardiovascular diseases. Considering the suggested association between periodontal and cardiovascular diseases, this study sought to assess the association, if any, between serum triglyceride (TG) levels and gemfibrozil consumption with periodontal parameters. METHODS: This cross-sectional study was conducted on 90 participants, including 30 individuals with a normal lipid profile (group H), 30 patients with hypertriglyceridemia and not on medication (group N), and 30 patients with hypertriglyceridemia and taking gemfibrozil over a 3-month period (group M). Periodontal parameters including probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and plaque index were measured at four sites of each tooth. Serum levels of total cholesterol (TC), TG, low-density lipoprotein, and high-density lipoprotein were measured. RESULTS: Mean values for PD and CAL in the two hypertriglyceridemic groups were significantly higher than those of the H group (P <0.001). After controlling for confounding variables, significant linear correlations were noted between PD and BOP, PD and TC, PD and TG, and CAL and TG in each group (P <0.01). CONCLUSIONS: Patients with hypertriglyceridemia had worse periodontal status than healthy controls. Patients with hypertriglyceridemia who were taking gemfibrozil did not show significant differences in CAL and PD compared with untreated patients with hypertriglyceridemia. PMID- 27958768 TI - Dicer-Like 4 Is Involved in Restricting the Systemic Movement of Zucchini yellow mosaic virus in Nicotiana benthamiana. AB - Zucchini yellow mosaic virus (ZYMV) induces serious diseases in cucurbits. To create a tool to screen for resistance genes, we cloned a wild ZYMV isolate and inserted the visual marker Rosea1 to obtain recombinant clone ZYMV-Ros1. While in some plant-virus combinations Rosea1 induces accumulation of anthocyanins in infected tissues, ZYMV-Ros1 infection of cucurbits did not lead to detectable anthocyanin accumulation. However, the recombinant virus did induce dark red pigmentation in infected tissues of the model plant Nicotiana benthamiana. In this species, ZYMV-Ros1 multiplied efficiently in local inoculated tissue but only a few progeny particles established infection foci in upper leaves. We used this system to analyze the roles of Dicer-like (DCL) genes, core components of plant antiviral RNA silencing pathways, in ZYMV infection. ZYMV-Ros1 local replication was not significantly affected in single DCL knockdown lines nor in double DCL2/4 and triple DCL2/3/4 knockdown lines. ZYMV-Ros1 systemic accumulation was not affected in knockdown lines DCL1, DCL2, and DCL3. However in DCL4 and also in DCL2/4 and DCL2/3/4 knockdown lines, ZYMV-Ros1 systemic accumulation dramatically increased, which highlights the key role of DCL4 in restricting virus systemic movement. The effect of DCL4 on ZYMV systemic movement was confirmed with a wild-type version of the virus. PMID- 27958767 TI - Effect of a Connective Tissue Graft in Combination With a Single Flap Approach in the Regenerative Treatment of Intraosseous Defects [Formula: see text]. AB - BACKGROUND: In the attempt to limit the post-surgery increase in buccal gingival recession (bREC), effect of a connective tissue graft (CTG) when combined with a buccal single flap approach (SFA) in the regenerative treatment of intraosseous defects is evaluated. METHODS: Data related to 30 patients with an intraosseous defect treated with a buccal SFA with (SFA+CTG group; n = 15) or without (SFA group; n = 15) placement of a CTG and regenerative treatment were retrospectively derived at three clinical centers. bREC and probing parameters were assessed at presurgery and 6 months post-surgery. RESULTS: In addition to a significant attachment gain and probing depth reduction, adjunctive use of a CTG to a buccal SFA in the regenerative treatment of periodontal intraosseous defects associated with a buccal bone dehiscence resulted in a limited post-surgery bREC, a lower prevalence of defects with a clinically detectable apical displacement of the gingival margin, and an increase in gingival width and thickness. CONCLUSION: Adjunctive use of a CTG in the regenerative treatment of intraosseous defects associated with buccal bone dehiscence accessed by buccal SFA may support the stability of the gingival profile. PMID- 27958773 TI - Studies on the biofilm produced by Pseudomonas aeruginosa grown in different metal fatty acid salt media and its application in biodegradation of fatty acids and bioremediation of heavy metal ions. AB - Metal fatty acid salts (MFAS) in untreated industrial effluents cause environmental pollution. The use of biocompatible agents for remediation may help in reducing the harm caused to the ambient aquatic organism. Pseudomonas aeruginosa is a ubiquitous organism that thrives under harsh conditions and is resistant to toxic metal ions. The present study shows a proof-of-concept of using this organism in the biodegradation of MFAS. MFAS were prepared and we studied their effect on the growth of the planktonic form and the formation of biofilm by P. aeruginosa. We observed biofilm formation in the presence of all the MFAS when used as the sole carbon source, albeit the quantity of biofilm formed in the presence of cadmium and copper was less. There was no effect on the planktonic form of the organism but the formation of biofilm increased in the presence of magnesium palmitate. This study shows that metal ions play a pivotal role in the formation of biofilm. HPLC (high-performance liquid chromatography) analysis of the biofilm polysaccharide showed that hexose sugar was a major component when compared with pentose sugar. The structure of biofilm polysaccharide and the coordination of the metal ion with the biofilm polysaccharide were confirmed by FTIR (Fourier transform infrared spectroscopy) and Raman spectroscopy. PMID- 27958774 TI - Early-Stage Hyperoxia Is Associated with Favorable Neurological Outcomes and Survival after Severe Traumatic Brain Injury: A Post-Hoc Analysis of the Brain Hypothermia Study. AB - The effects of hyperoxia on the neurological outcomes of patients with severe traumatic brain injury (TBI) are still controversial. We examined whether the partial pressure of arterial oxygen (PaO2) and hyperoxia were associated with neurological outcomes and survival by conducting post-hoc analyses of the Brain Hypothermia (B-HYPO) study, a multi-center randomized controlled trial of mild therapeutic hypothermia for severe TBI. The differences in PaO2 and PaO2/fraction of inspiratory oxygen (P/F) ratio on the 1st day of admission were compared between patients with favorable (n = 64) and unfavorable (n = 65) neurological outcomes and between survivors (n = 90) and deceased patients (n = 39). PaO2 and the P/F ratio were significantly greater in patients with favorable outcomes than in patients with unfavorable neurological outcomes (PaO2: 252 +/- 122 vs. 202 +/- 87 mm Hg, respectively, p = 0.008; P/F ratio: 455 +/- 171 vs. 389 +/- 155, respectively, p = 0.022) and in survivors than in deceased patients (PaO2: 242 +/ 117 vs. 193 +/- 75 mm Hg, respectively, p = 0.005; P/F ratio: 445 +/- 171 vs. 370 +/- 141, respectively, p = 0.018). Similar tendencies were observed in subgroup analyses in patients with fever control and therapeutic hypothermia, and in patients with an evacuated mass or other lesions (unevacuated lesions). PaO2 was independently associated with survival (odds ratio 1.008, p = 0.037). These results suggested that early-stage hyperoxia might be associated with favorable neurological outcomes and survival following severe TBI. PMID- 27958775 TI - Distinct Molecular Signature of Murine Fetal Liver and Adult Hematopoietic Stem Cells Identify Novel Regulators of Hematopoietic Stem Cell Function. AB - During ontogeny, fetal liver (FL) acts as a major site for hematopoietic stem cell (HSC) maturation and expansion, whereas HSCs in the adult bone marrow (ABM) are largely quiescent. HSCs in the FL possess faster repopulation capacity as compared with ABM HSCs. However, the molecular mechanism regulating the greater self-renewal potential of FL HSCs has not yet extensively been assessed. Recently, we published RNA sequencing-based gene expression analysis on FL HSCs from 14.5-day mouse embryo (E14.5) in comparison to the ABM HSCs. We reanalyzed these data to identify key transcriptional regulators that play important roles in the expansion of HSCs during development. The comparison of FL E14.5 with ABM HSCs identified more than 1,400 differentially expressed genes. More than 200 genes were shortlisted based on the gene ontology (GO) annotation term "transcription." By morpholino-based knockdown studies in zebrafish, we assessed the function of 18 of these regulators, previously not associated with HSC proliferation. Our studies identified a previously unknown role for tdg, uhrf1, uchl5, and ncoa1 in the emergence of definitive hematopoiesis in zebrafish. In conclusion, we demonstrate that identification of genes involved in transcriptional regulation differentially expressed between expanding FL HSCs and quiescent ABM HSCs, uncovers novel regulators of HSC function. PMID- 27958776 TI - Autologous and Allogeneic Equine Mesenchymal Stem Cells Exhibit Equivalent Immunomodulatory Properties In Vitro. AB - The use of allogeneic bone marrow-derived mesenchymal stem cells (BMDMSCs) may provide an effective alternative to autologous BMDMSCs for treatment of equine musculoskeletal injuries. However, concerns have been raised regarding the potential safety and effectiveness of allogeneic BMDMSCs. We conducted studies to assess the immunological properties of equine allogeneic BMDMSCs compared with those of autologous BMDMSCs. For assessment of inherent immunogenicity, the relative ability of allogeneic and autologous BMDMSCs to stimulate spontaneous proliferation of equine lymphocytes was compared. The immunosuppressive activity of the two cell types was evaluated by adding autologous or allogeneic BMDMSCs to activated lymphocytes and assessing suppression of lymphocyte proliferation and IFNgamma production. Fifty-six allogeneic and 12 autologous combinations were evaluated. Studies were also done to elucidate mechanisms by which equine mesenchymal stem cells (MSCs) suppress lymphocyte function. Potential mechanisms evaluated included production of prostaglandin E2 (PGE2), nitric oxide, transforming growth factor-beta, and indoleamine 2,3-dioxygenase. We found that autologous and allogeneic BMDMSCs both induced mild but equivalent levels of spontaneous lymphocyte activation in vitro. In in vitro assays assessing the ability of BMDMSCs to suppress activated lymphocytes, both allogeneic and autologous BMDMSCs suppressed T cell proliferation and IFNgamma production to an equal degree. The primary mechanism of equine BMDMSC suppression of T cells was mediated by PGE2. We concluded that allogeneic and autologous BMDMSCs are equivalent in terms of their immunomodulatory properties, and stimulated peripheral blood mononuclear cells appear to trigger the immunosuppressive properties of MSCs. Therefore, both cell types appear to have equal potency in modulating inflammatory processes related to acute or chronic musculoskeletal injuries in the horse. PMID- 27958885 TI - Erratum. PMID- 27958884 TI - In Vivo Evaluation and Imaging of a Bilayered Self-Assembled Skin Substitute Using a Decellularized Dermal Matrix Grafted on Mice. AB - As time to final coverage is the essence for better survival outcome in severely burned patients, we have continuously strived to reduce the duration for the preparation of our bilayered self-assembled skin substitutes (SASS). These SASS produced in vitro by the self-assembly approach have a structure and functionality very similar to native skin. Recently, we have shown that a decellularized dermal matrix preproduced by the self-assembly approach could be used as a template to further obtain self-assembled skin substitute using a decellularized dermal template (SASS-DM) in vitro. Thus, the production period with patient cells was then reduced to about 1 month. Herein, preclinical animal experiments have been performed to confirm the integration and evolution of such a graft and compare the maturation of SASS and SASS-DM in vivo. Both tissues, reconstructed from adult or newborn cells, were grafted on athymic mice. Green fluorescent protein-transfected keratinocytes were also used to follow grafted tissues weekly for 6 weeks using an in vivo imaging system (IVIS). Cell architecture and differentiation were studied with histological and immunofluorescence analyses at each time point. Graft integration, macroscopic evolution, histological analyses, and expression of skin differentiation markers were similar between both skin substitutes reconstructed from either newborn or adult cells, and IVIS observations confirmed the efficient engraftment of SASS DM. In conclusion, our in vivo graft experiments on a mouse model demonstrated that the SASS-DM had equivalent macroscopic, histological, and differentiation evolution over a 6-week period, when compared with the SASS. The tissue engineered SASS-DM could improve clinical availability and advantageously shorten the time necessary for the definitive wound coverage of severely burned patients. PMID- 27958883 TI - Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1. AB - AIMS: Nonalcoholic fatty liver (NAFL) is a common liver disease associated with metabolic syndrome, obesity, and diabetes that is rising in prevalence worldwide. Various molecular perturbations of key regulators and enzymes in hepatic lipid metabolism cause NAFL. However, redox regulation through glutathione (GSH) adducts in NAFL remains largely elusive. Glutaredoxin-1 (Glrx) is a small thioltransferase that removes protein GSH adducts without having direct antioxidant properties. The liver contains abundant Glrx but its metabolic function is unknown. RESULTS: Here we report that normal diet-fed Glrx-deficient mice (Glrx-/-) spontaneously develop obesity, hyperlipidemia, and hepatic steatosis by 8 months of age. Adenoviral Glrx repletion in the liver of Glrx-/- mice corrected lipid metabolism. Glrx-/- mice exhibited decreased sirtuin-1 (SirT1) activity that leads to hyperacetylation and activation of SREBP-1 and upregulation of key hepatic enzymes involved in lipid synthesis. We found that GSH adducts inhibited SirT1 activity in Glrx-/- mice. Hepatic expression of nonoxidizable cysteine mutant SirT1 corrected hepatic lipids in Glrx-/- mice. Wild-type mice fed high-fat diet develop metabolic syndrome, diabetes, and NAFL within several months. Glrx deficiency accelerated high-fat-induced NAFL and progression to steatohepatitis, manifested by hepatic damage and inflammation. INNOVATION: These data suggest an essential role of hepatic Glrx in regulating SirT1, which controls protein glutathione adducts in the pathogenesis of hepatic steatosis. CONCLUSION: We provide a novel redox-dependent mechanism for regulation of hepatic lipid metabolism, and propose that upregulation of hepatic Glrx may be a beneficial strategy for NAFL. Antioxid. Redox Signal. 27, 313-327. PMID- 27959261 TI - [Acute carbon monoxide poisoning after water pipe tobacco smoking]. AB - Carbon monoxide poisoning is potentially lethal, and early recognition and treatment is essential. An 18-year-old man was admitted due to syncope and a carboxyhaemoglobin level of 17% after water pipe tobacco smoking. He received normo- and hyperbaric oxygen as treatment and was discharged after two days without neurological sequelae. This case is the first in Denmark, but recently seven similar cases have been reported. The number of young people smoking water pipe tobacco is increasing, and we fear that more cases like this will occur in the future. PMID- 27959260 TI - Zika Virus RNA Replication and Persistence in Brain and Placental Tissue. AB - Zika virus is causally linked with congenital microcephaly and may be associated with pregnancy loss. However, the mechanisms of Zika virus intrauterine transmission and replication and its tropism and persistence in tissues are poorly understood. We tested tissues from 52 case-patients: 8 infants with microcephaly who died and 44 women suspected of being infected with Zika virus during pregnancy. By reverse transcription PCR, tissues from 32 (62%) case patients (brains from 8 infants with microcephaly and placental/fetal tissues from 24 women) were positive for Zika virus. In situ hybridization localized replicative Zika virus RNA in brains of 7 infants and in placentas of 9 women who had pregnancy losses during the first or second trimester. These findings demonstrate that Zika virus replicates and persists in fetal brains and placentas, providing direct evidence of its association with microcephaly. Tissue based reverse transcription PCR extends the time frame of Zika virus detection in congenital and pregnancy-associated infections. PMID- 27959262 TI - [Lipoatrophy after insulin injections can be treated with lipofilling]. AB - Lipoatrophy is a known, albeit rare, side effect of insulin injections. We describe a case concerning a 17-year-old woman with insulin-dependent diabetes, who was treated with an insulin pump. In the areas surrounding the injection point subcutaneous lipoatrophy occurred. Such lipoatrophy is of cosmetic importance, and it may incur glycaemic imbalance due to altered and unpredictable absorption of insulin in the atrophied areas. With no spontaneous regeneration of the atrophied areas observed the patient was successfully treated with lipofilling in the atrophied areas. PMID- 27959263 TI - [Atypical presentation of tuberous sclerosis]. AB - Tuberous sclerosis complex (TSC) is an inherited disorder with a prevalence of 1/20,000. The diagnosis is based on clinical criteria and/or genetic testing. Most cases are found during childhood. Yet, the intra- and interfamiliar expressivity is variable, so the diagnosis should be considered in adults too. This is a case report about a 20-year-old female with an atypical presentation of TSC. The case highlights that TSC can be suspected in adults with a first-time seizure. The diagnosis is important because it leads to multidisciplinary follow up. PMID- 27959264 TI - [Hourglass neurinoma resulted in symptoms of polyneuropathy]. AB - Distal symmetric polyneuropathy (DSP) is a common condition where limited diagnostic evaluation is usually required. We present a case story of a 50-year old male who had symptoms of DSP, but electrodiagnostic testing suggested a more proximal lesion, and magnetic resonance imaging showed a spinal nerve root schwannoma. The patient recovered completely after surgery. This case exemplifies relevant use of electrodiagnostic testing. Based on a recent review, we briefly mention atypical features which should prompt further testing, emphasizing that evaluation should be reserved to a limited group of patients. PMID- 27959265 TI - [En sjaelden form for hydrocefalus]. PMID- 27959266 TI - Doubt and the decision-making process in obsessive-compulsive disorder. AB - The diagnosis of obsessive-compulsive disorder (OCD) is based on the presence of specific symptoms and their consequence in the lives of those that exhibit them. It is likely that these symptoms emerge from a neurocognitive vulnerability in the mental life of the individual which has a basis in neurophysiology. The prominence of doubt/uncertainty/lack of confidence (These terms are used interchangeably in this paper.), in the clinical presentation of many patients suffering from OCD leads to our consideration of the cognitive basis for this phenomenon. In this paper, we propose that OCD emerges from a perturbation in the decision-making process. Specifically, we hypothesize that there is diminished confidence, conviction, or certainty with regard to assimilating the information necessary to reach a decision. Recent advances in the neuroscience of decision making provide an opportunity to further our understanding of the vulnerability underlying OCD. PMID- 27959267 TI - Theoretical modeling of time-dependent skin temperature and heat losses during whole-body cryotherapy: A pilot study. AB - This article establishes the basics of a theoretical model for the constitutive law that describes the skin temperature and thermolysis heat losses undergone by a subject during a session of whole-body cryotherapy (WBC). This study focuses on the few minutes during which the human body is subjected to a thermal shock. The relationship between skin temperature and thermolysis heat losses during this period is still unknown and have not yet been studied in the context of the whole human body. The analytical approach here is based on the hypothesis that the skin thermal shock during a WBC session can be thermally modelled by the sum of both radiative and free convective heat transfer functions. The validation of this scientific approach and the derivation of temporal evolution thermal laws, both on skin temperature and dissipated thermal power during the thermal shock open many avenues of large scale studies with the aim of proposing individualized cryotherapy protocols as well as protocols intended for target populations. Furthermore, this study shows quantitatively the substantial imbalance between human metabolism and thermolysis during WBC, the explanation of which remains an open question. PMID- 27959268 TI - Endogenous erythropoietin and erythropoietin receptors in colorectal cancer; can we answer the questions? AB - Erythropoietin (Epo) is glycoprotein hormone which binds on erythropoietin receptors (EpoR) promoting proliferation and differentiation. Studies have shown that EpoR, apart from erythrocyte precursors, is expressed on no hematopoietic tissue and various tumor cells. Despite the progress in modern medicine, colorectal carcinoma (CRC) is still the leading cause of increased morbidity and mortality between oncology patients worldwide. Its precursors are benign villous adenomas, which in certain percentage progress to cancer. Anemia of chronic disease is common finding in CRC patients. Some of them are treated with Epo. Epo/EpoR seems to correlate with tumor progression and metastasizing. Therefore, the identification of at-risk group remains a clinical challenge. Vascular endothelial growth factor (VEGF) is a signal protein that stimulates angiogenesis and concentration of VEGF is positive correlated with tumor growth in numerous tumors. The importance of Epo in tumor pathogenesis has led to a growing interest in the potential prognostic value. By our point of view there are many open questions about role of Epo/EpoR in CRC. PMID- 27959269 TI - How lateral inhibition and fast retinogeniculo-cortical oscillations create vision: A new hypothesis. AB - : The role of the physiological processes involved in human vision escapes clarification in current literature. Many unanswered questions about vision include: 1) whether there is more to lateral inhibition than previously proposed, 2) the role of the discs in rods and cones, 3) how inverted images on the retina are converted to erect images for visual perception, 4) what portion of the image formed on the retina is actually processed in the brain, 5) the reason we have an after-image with antagonistic colors, and 6) how we remember space. This theoretical article attempts to clarify some of the physiological processes involved with human vision. The global integration of visual information is conceptual; therefore, we include illustrations to present our theory. Universally, the eyeball is 2.4cm and works together with membrane potential, correspondingly representing the retinal layers, photoreceptors, and cortex. Images formed within the photoreceptors must first be converted into chemical signals on the photoreceptors' individual discs and the signals at each disc are transduced from light photons into electrical signals. We contend that the discs code the electrical signals into accurate distances and are shown in our figures. The pre-existing oscillations among the various cortices including the striate and parietal cortex, and the retina work in unison to create an infrastructure of visual space that functionally "places" the objects within this "neural" space. The horizontal layers integrate all discs accurately to create a retina that is pre-coded for distance. Our theory suggests image inversion never takes place on the retina, but rather images fall onto the retina as compressed and coiled, then amplified through lateral inhibition through intensification and amplification on the OFF-center cones. The intensified and amplified images are decompressed and expanded in the brain, which become the images we perceive as external vision. SUMMARY: This is a theoretical article presenting a novel hypothesis about the physiological processes in vision, and expounds upon the visual aspect of two of our previously published articles, "A unified 3D default space consciousness model combining neurological and physiological processes that underlie conscious experience", and "Functional representation of vision within the mind: A visual consciousness model based in 3D default space." Currently, neuroscience teaches that visual images are initially inverted on the retina, processed in the brain, and then conscious perception of vision happens in the visual cortex. Here, we propose that inversion of visual images never takes place because images enter the retina as coiled and compressed graded potentials that are intensified and amplified in OFF-center photoreceptors. Once they reach the brain, they are decompressed and expanded to the original size of the image, which is perceived by the brain as the external image. We adduce that pre-existing oscillations (alpha, beta, and gamma) among the various cortices in the brain (including the striate and parietal cortex) and the retina, work together in unison to create an infrastructure of visual space thatfunctionally "places" the objects within a "neural" space. These fast oscillations "bring" the faculties of the cortical activity to the retina, creating the infrastructure of the space within the eye where visual information can be immediately recognized by the brain. By this we mean that the visual (striate) cortex synchronizes the information with the photoreceptors in the retina, and the brain instantaneously receives the already processed visual image, thereby relinquishing the eye from being required to send the information to the brain to be interpreted before it can rise to consciousness. The visual system is a heavily studied area of neuroscience yet very little is known about how vision occurs. We believe that our novel hypothesis provides new insights into how vision becomes part of consciousness, helps to reconcile various previously proposed models, and further elucidates current questions in vision based on our unified 3D default space model. Illustrations are provided to aid in explaining our theory. PMID- 27959270 TI - Speculations on vitamin K, VKORC1 genotype and autism. AB - Humans vary in the gene that encodes for Vitamin K epoxide reductase complex (VKORC1). Recent research has documented the protective effect of Vitamin K on neural cells and its role in maintaining normal neural development. Of interest, specific neural effects of Vitamin K overlap with key brain development aberrations, including those associated with autism. Furthermore, Vitamin K protects against oxidative stress associated with toxic exposure. Research on the neural effects is reviewed, and a small sample of severely autistic children of Somali descent residing in the Minneapolis/St. Paul area of Minnesota were genotyped and found to have a higher than expected genetic substitution that results in reduction in the efficiency of the Vitamin K cycle. The possibility that this genetic difference could play an etiological role in the development of autism is considered. PMID- 27959271 TI - Mirror therapy for rehabilitation following Achilles tendon rupture. PMID- 27959272 TI - Fetal Syndrome of Endocannabinoid Deficiency (FSECD) In Maternal Obesity. AB - The theory of a fetal origin of adult diseases links many pathological conditions to very early life events and is known as a "developmental programming" phenomenon. The mechanisms of this phenomenon are not quite understood and have been explained by inflammation, stress, etc. In particular the epidemic of obesity, with more than 64% of women being overweight or obese, has been associated with conditions in later life such as mental disorders, diabetes, asthma, and irritable bowel syndrome. Interestingly, these diseases were classified a decade ago as Clinical Syndrome of Endocannabinoid Deficiency (CECD), which was first described by Russo in 2004. Cannabinoids have been used for the treatment of chronic pain for millenniums and act through the mechanism of "kick-starting" the components of the endogenous cannabinoid system (ECS). ECS is a pharmacological target for the treatment of obesity, inflammation, cardiovascular and neuronal damage, and pain. We hypothesize that the deteriorating effect of maternal obesity on offspring health is explained by the mechanism of Fetal Syndrome of Endocannabinoid Deficiency (FSECD), which accompanies maternal obesity. Here we provide support for this hypothesis. PMID- 27959273 TI - Wound scabs protect regenerating tissue against harmful ultraviolet radiation. AB - Benefits attributed to wound scabs include prevention of blood loss and protection against infection. However, when formation of a wound scab is prevented, the risk of infection is reduced. Moreover, in the absence of a wound scab, wounds heal faster and scar formation is reduced. The question arises why we develop a wound scab. Here we show that wound scabs inhibit transmission of ultraviolet radiation (UVR). We compared the UVR transmittance of human wound scabs to sunscreen by measuring the sun protection factor (SPF) with diffuse transmittance spectroscopy. Three wound scabs showed SPFs of 70, 84, and 300, which is more effective than the most protective commercially available sun block. Because our results demonstrate that a wound scab offers natural protection against UVR, and because no beneficial trait is attributed to wound scabs, we hypothesize that the main function of wound scabs is to limit DNA damage in underlying cells during regeneration of wound tissue exposed to sunlight, thereby reducing the risk of developing skin cancer. PMID- 27959274 TI - High glycemic index diet in PCOS patients. The analysis of IGF I and TNF-alpha pathways in metabolic disorders. PMID- 27959276 TI - Identification and targeting of microRNAs modulating acquired chemotherapy resistance in Triple negative breast cancer (TNBC): A better strategy to combat chemoresistance. AB - Triple negative breast cancer (TNBC) is a heterogeneous form of malignant disease. Due to lack of proper therapeutic target treatment options are restricted and relies primarily on chemotherapeutic modality for treatment of patients. Despite significant early regression of the disease in response to chemotherapy, complete cure is not assured with development of resistant tumors which is difficult to manage clinically. In the last decades, the regulation and contribution of microRNAs in tumorigenesis including breast cancers have been well-documented. Thus, here it is hypothesized that by identifying the microRNAs responsible for chemoresistance in TNBC and targeting the microRNAs along with chemotherapeutic approaches might exert an improved response. To accomplish this, an in vivo screening has to be performed by transfecting tumor cell line with lentiviral pool of library expressing microRNAs. Following treatment of primary tumors in mice and growth of relapsed tumors, microRNA profile has to be analyzed by qRT-PCR and sequencing to detect the microRNAs contributing to the chemoresistance which can be targeted by anti-microRNA strategies. PMID- 27959275 TI - Is lithium essential for epididymal sperm maturation? AB - A wider biological role of ultratrace element lithium in the mammalian reproduction has been reported, however, presence of lithium in the epididymal luminal fluid (ELF) and its influence on sperm during maturation events in the epididymal regions are still unknown. A pilot study was carried out in Jamunapari buck which revealed that levels of lithium in the ELF diminished gradually and significantly (P<0.01) from caput to cauda epididymis, concomitantly, a distinct increase (P<0.01) in the spermatozoan motility, viability and hypo-osmotic reactive sperm were observed, except spermatozoan motility that was found absent in the caput epididymis. Therefore, we hypothesize that levels of lithium in the epididymal regions is one of the motility initiation and/or regulatory factor for epididymal sperm maturation essential for acquiring fertilizing competence of sperm cells, hence, lithium could also be considered as one of the biomarker of sperm maturation in any species. PMID- 27959277 TI - Endothelial dysfunction may play a key role in keloid and hypertrophic scar pathogenesis - Keloids and hypertrophic scars may be vascular disorders. AB - Keloids and hypertrophic scars are fibroproliferative disorders (FPDs) of the skin that result from abnormal healing of injured or irritated skin. They can be called pathological or inflammatory scars. Common causes are trauma, burn, surgery, vaccination, skin piercing, folliculitis, acne, and herpes zoster infection. The pathogenesis of these scars clearly involves local conditions such as delayed wound healing, wound depth, and the tension of the skin around the scars. Scar severity is also shaped by interactions between these local factors and genetic and systemic factors such as hypertension and sex hormones. Notably, to evaluate scar severity, the Japan Scar Workshop (JSW) has established the JSW Scar Scale. Our studies show that tension on the skin around the wound results in prolonged and/or repeated bouts of inflammation in the reticular layer of the dermis and that this inflammation generates abnormal numbers of blood vessels (as well as collagen and nerve fibers) in the dermal reticular layer. We hypothesize that local factors, such as the mechanobiology of the dermis and blood vessels, along with genetic and systemic factors promote pathological scar development by inducing endothelial dysfunction (i.e., vascular hyperpermeability) during the inflammatory stage of wound healing. The continued presence of these factors prolongs the influx of inflammatory cells and factors, thereby leading to fibroblast dysfunction. Evidence for this hypothesis includes the fact that all effective treatments of keloids, namely, radiotherapy, compression therapy, steroid administration, and long-pulsed Nd:YAG laser therapy, act, at least partly, by suppressing blood vessels. At present, keloids are classified as strongly inflammatory scars, while hypertrophic scars are considered to be mildly inflammatory scars. However, we propose that keloids and hypertrophic scars are simply manifestations of the same skin FPD and differ only in the degree of endothelial dysfunction and therefore inflammation. We therefore suggest that these pathological scars should be classified on the basis of the factor that causes the endothelial dysfunction. Thus, primary scars are caused by congenital endothelial dysfunction (e.g., a mutation prevents endothelial gaps from closing smoothly) while secondary scars are caused by endothelial dysfunction that results from aging, arterial sclerosis, and/or repeated/very strong local mechanical forces. We expect that primary keloids develop at younger ages and tend to become severe, while secondary keloids are seen in all ages and can vary in clinical severity. Thus, abnormal blood vessel regulation may underlie keloid and hypertrophic scar pathogenesis, which suggests that inhibiting abnormal angiogenesis and vascular hyperpermeability may be an important therapeutic approach. PMID- 27959278 TI - Modulatory potential of resveratrol during lung inflammatory disease. AB - Neutrophils are the first cells to achieve the sites of infection or inflammation in the lungs. The massive accumulation of these cells is associated with acute and chronic lung injury. Therefore, they have been implicated in the pathogenesis of many lung diseases through the release of reactive oxygen intermediates, proteolytic enzymes and Neutrophil Extracellular Traps (NETs). The excessive and continuous release of NETs, fibers composed by decondensed chromatin coated with neutrophil proteins, are associated to the impairment of lung function in different pathological settings. Flavonoids inhibit the respiratory burst of neutrophils in mammals. However, one of these flavonoids, resveratrol has a particular chemical property. It reduce Cu(II) to Cu(I) form with concomitant formation of reactive oxygen species, which can produce DNA breakage as reported in several in vitro models. We hypothesize that direct resveratrol administration in lungs can cleave DNA in NETs, improving lung function during acute airway infections or chronic inflammatory lung diseases. If the hypothesis is correct, the control of NET formation can be used to reduce the inflammatory environment in lung after neutrophil stimuli. Additionally, the production of proinflammatory cytokines by neutrophils could be also diminished by resveratrol administration. In this sense, this flavonoid provides a multifaceted opportunity for treatment of lung diseases with strong or chronic neutrophil activation. PMID- 27959279 TI - Inhibition of cancer cell mitosis by reducing the availability of phosphate. AB - The addition of phosphate groups is an essential requirement for the proper functioning of cyclin and cyclin dependent kinase which control various stages in the mitotic division of cancer cells. Thus limiting the availability of phosphate is likely to interfere with the metabolism of rapidly growing malignant cells. The human hormone glucagon and the anti metabolite mithramycin reduce serum phosphate by increasing phosphaturia and are both very effective in treating Paget's disease of bone, a precancerous condition. In this disorder large doses of glucagon given intravenously relieve bone pain and cause serum phosphate and alkaline phosphatase as well as urine hydroxyproline to fall, indicating a marked reduction in bone turnover. A constant iv infusion of glucagon was given to each of three patients all of whom had secondary malignant bone deposits. Two of the patients had primary prostate cancer and one had a squamous cell lung tumour. All three patients had relief of bone pain and a fall in serum alkaline phosphatase. Serum acid phosphatase also fell in the two patients with prostate cancer. It is proposed that the marked drop in serum phosphate due to glucagon causes intracellular phosphate to fall. This in turn disrupts the addition and removal of phosphate groups essential for the proper functioning of cyclin and cyclin dependent kinase. These two proteins control the transition from G1 to S (DNA synthesis phase) and G2 to M (mitotic phase) in the dividing cycle of malignant cells. Depriving a tumour of an essential ingredient used in phosphorylation reactions will disrupt its growth. It is also proposed that, by the same mechanism, glucagon induced hypophosphataemia renders malignant cells more sensitive to established chemotherapeutic agents and radiation waves. If this hypothesis proves to be correct, lowering intracellular phosphate may become an useful tool in cancer therapy. However extensive studies are necessary to determine whether mitosis in cancer cells can be advantageously disrupted by glucagon induced hypophosphataemia. PMID- 27959280 TI - Geographic associations between lactase phenotype, multiple sclerosis, and inflammatory bowel diseases; Does obesity trump geography? AB - Geographic patterns with diminishing rates from north to south toward the equator have been described for a number of diseases, putatively related largely to "western" lifestyle. Among these the inflammatory bowel diseases; Crohn's (CD) and Ulcerative colitis (UC) have been prominent in sharing distributions with a number of autoimmune diseases. One of the interesting associations is the epidemiologic similarity with multiple sclerosis (MS). However, in addition, at least some of these diseases also correlated inversely with lactase non persistent population (LNP) distributions. It is hypothesized that MS should also have an inverse relationship with LNP. We provide support for this by comparing published MS, CD, UC and LNP national rates to the beginning of the new millennium. Possible links among these diseases may be an evolutionary signature of new genes which may have accompanied emergence of lactase persistence millennia ago. The emergent phenotypic dichotomy also forced different assimilation responses to lactose digestion. While intestinal retention of lactase results in direct host enzymatic digestion, in LNP persons intestinal bacterial metabolism of lactose impacts on the host micro-flora. These microbial changes may play some role in altering rates of diseases including IBD and MS. However, since the late 20th century previously observed patterns are changing. Although industrialization is considered to play an important modifying role, the rising rates of obesity with an emphasis on diet, and microfloral pathogenesis, but with an independent geographic pattern may also facilitate altering rates and geographic distributions of both of these and other diseases. PMID- 27959281 TI - Architectonics of male amygdala. AB - The aim of this manuscript is to demonstrate that the known hormonally driven development of the male amygdalae, requires the vital use of stored memory in order that they are able to complete their recognised full structural architectonics. The hippocampus and the entorhinal cortex are strongly involved in the reception of testosterone which is the responsible hormone. The transfer of testosterone into memory and the mode of consolidation and storage of that memory are discussed. In regard to this activity, there have been suggestions concerning the possible effect of immune processes and also epigenesis and these are discussed. Finally, the controlled transfer to the male amygdala and the anabolic effect upon it are elucidated. The understanding of the hippocampal memory system is challenged by new evidence that has arisen. PMID- 27959282 TI - Neonates of diabetic mothers: The starting point for developing novel therapeutic approaches to ischemic heart and brain? AB - Diabetes mellitus represents the most common medical condition causing complications during pregnancy. However, there is still some controversy surrounding complications. Maternal hyperglycemia leads to fetal hyperglycemia. Offspring of diabetic mothers compensate excess glucose concentrations by producing higher levels of insulin causing transient hyperinsulinemia. Infants of diabetic mothers are at risk for congenital cardiac malformations, of which 40% are with hypertrophic cardiomyopathy. However, regardless of severity, cardiac hypertrophy is transient with echocardiographic resolution within the first months after birth. Neonates of diabetic mothers are more likely to suffer from macrosomia that predisposes the infant to birth asphyxia brain damage. However, there is no evidence for an increase in the incidence of brain injury from perinatal asphyxia in macrosomic babies of diabetic mothers in comparison to macrosomic newborns of non-diabetic mothers. We hypothesize that infants of diabetic mother may represent the starting point for developing novel approaches to the treatment and prevention of obstructive hypertrophic cardiomyopathy, AMI and stroke at every age. PMID- 27959283 TI - Neonates with sickle cell disease are vulnerable to blue light phototherapy induced oxidative stress and proinflammatory cytokine elevations. AB - Sickle cell disease is a frequent genetic anomaly characterized by altered molecular structure of hemoglobin resulting into crescent-like deformation of the red blood corpuscles. Neonatal jaundice is a frequent co-morbidity in sickle cell disease. Phototherapy induces isomerization of bilirubin rendering it extractable through urine and hence it is used as a routine treatment of neonatal jaundice. An exposure to light phototherapy as a treatment of neonatal jaundice induces oxidative stress. It is hypothesized that such exposure of neonates with sickle cell disease to the blue light phototherapy as a treatment of neonatal jaundice induces severe oxidative stress and increases the levels of proinflammatory cytokines. This hypothesis is supported with two case studies of sickle cell disease suffering neonates who were exposed to blue light phototherapy to treat jaundice. In both these cases, exposure to phototherapy induced oxidative stress (increased lipid peroxidation and superoxide dismutase, slight change in activity of catalase and GSH) and elevated the levels of proinflammatory cytokine (TNFalpha, IL-1, and IL-6) in the sickle cell disease suffering neonates. These observations warrant further investigations to determine the consequences and clinical significance of the blue phototherapy-induced oxidative and proinflammatory stress in Sickle cell disease suffering neonates exposed to phototherapy as a treatment of jaundice. PMID- 27959284 TI - The proposed use of cervical spinal cord stimulation for the treatment and prevention of cognitive decline in dementias and neurodegenerative disorders. AB - Cervical spinal cord stimulation is a well-established treatment for intractable neuropathic upper extremity pain. More than 20years ago it was demonstrated that cervical spinal cord stimulation could engender an increase in cerebral blood flow. Cerebral blood flow has been shown to be decreased in many patients with dementia and in various neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Furthermore, there is evidence that reduced cerebral blood flow worsens neurodegenerative disease and may also predict which patients progress from mild cognitive impairment to full blown Alzheimer's disease. Thus, the identification of decreased cerebral blood flow in patients with early cognitive problems may offer clinicians a window of opportunity to intervene and prevent further brain damage. Further evidence that supports augmenting cerebral blood flow as an effective strategy for preventing and treating cognitive brain dysfunction comes from experimental studies with omental transposition. The author proposes cervical spinal cord stimulation as a titratable, programmable extracranial neuromodulation technique to increase cerebral blood flow for the purposes of improving cognitive function and preventing cognitive deterioration in patients with dementias and neurodegenerative disorders. PMID- 27959285 TI - A potential method for identifying dural ossification by measuring the degree of spinal stenosis in thoracic ossification of ligamentum flavum. AB - Ossification of ligamentum flavum (OLF) is increasingly recognized as the major cause of thoracic spinal stenosis. The dura mater beneath ossified ligamentum flavum may also ossify when the spinal stenosis develops to a certain degree. Preoperative diagnosis of dural ossification (DO) is beneficial for surgical management of OLF. However, currently, accurate diagnosis method still could not be obtained. Based on the association between spinal stenosis and OLF/DO, a potential diagnosis method is proposed in this paper: identifying DO by measuring the degree of spinal stenosis in thoracic OLF. In the early stage of OLF, there is only mild spinal stenosis and no DO. With the progression of OLF, dura may also ossify and further compress the spinal cord, aggravating spinal stenosis. Before DO, the dura mater is presented as a low signal intensity. Once ossifying, the dura mater will be shown as a high signal intensity in CT. It will lead that the degree of spinal stenosis measured in axial CT scan obviously increases. Thus, it provides a possibility to find a critical value of it for distinguishing OLF patients with or without DO. PMID- 27959287 TI - Nursing error: an integrated review of the literature. AB - Nursing errors are complex and take place frequently in the care of patients. However, despite their significance, they have not been properly defined or addressed in the literature. This integrative review of the literature explored the concept of nursing error, explained its definitions and described its attributes and measurements. The databases of Medline, CINAHL, Google Scholar and SID were searched using a number of keywords, including malpractice, adverse events and mistake, with and without the word nurse. The aim was to determine the definition of nursing error, regardless of the contextual aspects, in various scientific systems. After reviewing the relevant literature, content analysis (in MAXQDA) was applied to classify the definitions, attributes and measurements obtained on the basis of their similarities and differences. Ultimately, a definition was established for the concept of nursing error. PMID- 27959286 TI - Shrimp Allergy: Analysis of Commercially Available Extracts for In Vivo Diagnosis. AB - BACKGROUND AND OBJECTIVE: Skin prick testing (SPT) with commercial extracts is the first step in the diagnosis of shrimp allergy, although its clinical efficiency is unknown. Objective: To analyze the clinical usefulness of all commercial crustacean extracts available for SPT in Italy. METHODS: We performed a multicenter study of 157 shrimp-allergic patients who underwent SPT with 5 commercial crustacean extracts and with house dust mite (HDM) extract. Commercial extracts were analyzed using SDS-PAGE and compared with a freshly prepared in house shrimp extract. IgE to Pen a 1/Pen m 1, Pen m 2, and Pen m 4 was determined, and immunoblot analysis was performed on a large number of sera. RESULTS: The skin reactions caused by commercial crustacean extracts were extremely heterogeneous, resulting in 32 clinical profiles, with marked differences in protein content and missing proteins at molecular weights corresponding to those of major shrimp allergens. Only strong Pen a 1/Pen m 1 reactors reacted to both HDM and all 5 commercial extracts in SPT. Most patients, including those who were tropomyosin-negative, reacted to HDM. Patients reacted to a large and variable array of proteins, and IgE reactivity was common at high molecular weights (>50 kDa). CONCLUSIONS: The in vivo diagnosis of shrimp allergy must continue to be based on SPT with fresh material. Shrimp-allergic patients frequently react to a number of ill-defined high-molecular-weight allergens, thus leaving currently available materials for component-resolved diagnosis largely insufficient. Mites and crustaceans probably share several allergens other than tropomyosin. PMID- 27959289 TI - Newer Intravenous Antibiotics in the Intensive Care Unit: Ceftaroline, Ceftolozane-Tazobactam, and Ceftazidime-Avibactam. PMID- 27959288 TI - Living kidney donation and masked nationalism in Israel. AB - This paper draws attention to a current trend of masked conditional-nationalist living kidney donation in Israel, to which the local transplant system has been turning a blind eye. The paper seeks to make the international transplant and bioethics communities aware of this disturbing trend. It also explains why it is wrong and suggests how to tackle it. Finally, it calls on the Israeli system to bring the practice to a halt for the benefit of all parties involved. PMID- 27959290 TI - Going Digital: What Does It Really Mean for Nursing? PMID- 27959291 TI - Hospital Value-Based Purchasing: Part 1, Overview of the Program. PMID- 27959292 TI - Building Respect and Reducing Incivility in the Workplace: Professional Standards and Recommendations to Improve the Work Environment for Nurses. PMID- 27959293 TI - Zeroing in on Safety: A Pediatric Approach to Preventing Catheter-Associated Urinary Tract Infections. PMID- 27959294 TI - Intensive Care Unit Nurses' Beliefs About Delirium Assessment and Management. AB - Delirium, the most frequent complication of hospitalized older adults, particularly in intensive care units (ICUs), can result in increased mortality rates and length of stay. Nurses are neither consistently identifying nor managing delirium in these patients. The purpose of this study was to explore ICU nurses' identification of delirium, actions they would take for patients with signs or symptoms of delirium, and beliefs about delirium assessment and management. In this cross-sectional study using qualitative descriptive methods guided by the theory of planned behavior, 30 ICU nurses' responses to patient vignettes depicting different delirium subtypes were explored. Descriptive and content analyses revealed that nurses did not consistently identify delirium; their actions varied in different vignettes. Nurses believed that they needed adequate staffing, balanced workload, interprofessional collaboration, and established policy and protocols to identify and manage delirium successfully. Research is needed to determine if implementing these changes increases recognition and decreases consequences of delirium. PMID- 27959295 TI - Intravenous Lipid Emulsion for Management of Systemic Toxic Effects of Drugs. AB - The incidence of toxic effects of drugs leading to emergency department visits has increased in the United States in the past several years. Most of these patients can be adequately managed by supportive care alone. However, pharmacological antidotes may be necessary, particularly in patients with hemodynamic instability. In severe cases refractory to conventional antidote therapy, rescue therapy with intravenous lipid emulsion (ILE) may be necessary. Traditionally, ILE has been used as an antidote of choice in treating toxic effects of local anesthetics. But data continue to emerge on the successful use of ILE to treat overdoses of drugs other than local anesthetics, particularly lipophilic medications. The recommended ILE dose is a 1.5 mL/kg bolus followed by infusion of 15 mL/kg per hour, with repeat dosing permissible for continued hemodynamic instability. Use of ILE should be considered early as a rescue therapy in the settings of lipophilic medication overdoses when cardiovascular compromise or cardiac arrest is present. PMID- 27959296 TI - Introduction to the Gastrointestinal and Liver Disease Symposium. PMID- 27959297 TI - Sepsis in Patients With Cirrhosis. AB - Patients with cirrhosis are at high risk for sepsis and sepsis-related mortality. Aggressive treatment aimed at avoidance of hypoperfusion and prompt identification and treatment of the causative organism can improve patients' survival. Fluid administration is the first-line treatment to improve perfusion to vital organs; however, care should be taken to assess true intravascular volume status. In patients with adequate intravascular volume, vasopressors are then added to support blood pressure. Complications of cirrhosis often worsen in the setting of sepsis. Portosystemic encephalopathy, pulmonary complications, renal complications, adrenal insufficiency, malnutrition, and insufficient glucose control all must be considered and treated to support a patient with cirrhosis through sepsis. The quality of care that these patients receive ultimately influences their survival. PMID- 27959298 TI - Acute Liver Failure. AB - Acute liver failure, also known as fulminant hepatic failure, is a rare life threatening disease that has a high mortality rate and affects many organ systems. Causes of acute liver failure vary-it can be attributed to drugs, viruses, and other uncommon sources. Complications of liver failure can include encephalopathy, cerebral edema, sepsis, renal failure, gastrointestinal bleeding, and respiratory failure. Fortunately, with advances in critical care medicine and emergent liver transplant, mortality rates have decreased in the past decade. This article reviews acute liver failure, its manifestations in different organ systems, and its treatment. PMID- 27959299 TI - Drug-Induced Liver Injury. AB - Drug-induced liver injury (DILI) can result from both idiosyncratic and intrinsic mechanisms. This article discusses the clinical impact of DILI from a broad range of medications as well as herbal and dietary supplements. Risk factors for idiosyncratic DILI (IDILI) are the result of multiple host, environmental, and compound factors. Some triggers of IDILI often seen in critical care include antibiotics, antiepileptic medications, statins, novel anticoagulants, proton pump inhibitors, inhaled anesthetics, nonsteroidal anti-inflammatory agents, methotrexate, sulfasalazine, and azathioprine. The mechanism of IDILI due to these medications varies, and the resulting damage can be cholestatic, hepatocellular, or mixed. The primary treatment of IDILI is to discontinue the causative agent. DILI due to acetaminophen is intrinsic because the liver damage is predictably aligned with the dose ingested. Acute acetaminophen ingestion can be treated with activated charcoal or N-acetylcysteine. Future areas of research include identification of mitochondrial stress biomarkers and of the patients at highest risk for DILI. PMID- 27959300 TI - Cholestatic Liver Injury: Care of Patients With Primary Biliary Cholangitis or Primary Sclerosing Cholangitis. AB - The most common causes of chronic cholestatic liver disease are primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Both disease processes are characterized by a destruction of intrahepatic and/or extrahepatic biliary ducts. The etiology is not entirely clear; however, there is an underlying autoimmune component contributing to both disease processes. Although PBC and PSC are often diagnosed and managed in the outpatient setting, in some instances, a patient may have jaundice, fatigue, and pruritus requiring evaluation and determination of the cholestatic cause. Patients with PSC should be monitored for evidence of cholangiocarcinoma, colon cancer, and gallbladder polyps as they are at an increased risk of malignant neoplasms. Liver transplant has the potential for improving quality of life, although disease recurrence is a risk. PMID- 27959301 TI - Peer Reviewers for 2016. PMID- 27959302 TI - Creating Clinical Research Protocols in Advanced Practice: Part II, Operational Steps to Improve Project Feasibility. PMID- 27959303 TI - Ethics in Everyday Practice: Pick Up Your Stethoscope. PMID- 27959304 TI - Peripheral Phlebitis Related to Amiodarone Infusion. PMID- 27959305 TI - Medication Therapy for Early-Onset Neonatal Sepsis. PMID- 27959306 TI - e-Liability and e-Documentation. PMID- 27959307 TI - The Nurse Practitioner as Surgical Assistant. PMID- 27959308 TI - Programs That Support a Healthy Work Environment. PMID- 27959309 TI - Benefits of Oral Care for Acute and Critically Ill Children. PMID- 27959310 TI - Decision Support Tool to Improve Glucose Control Compliance After Cardiac Surgery. AB - Hyperglycemia control is associated with improved outcomes in patients undergoing cardiac surgery. The Surgical Care Improvement Project metric (SCIP-inf-4) was introduced as a performance measure in surgical patients and included hyperglycemia control. Compliance with the SCIP-inf-4 metric remains suboptimal. A novel real-time decision support tool (DST) with guaranteed feedback that is based on the existing electronic medical record system was developed at a tertiary academic center. Implementation of the DST increased the compliance rate with the SCIP-inf-4 from 87.3% to 96.5%. Changes in tested clinical outcomes were not observed with improved metric compliance. This new framework can serve as a backbone for development of quality control processes for other metrics. Further and, ideally, multicenter studies are required to test if implementation of electronic DSTs will translate into improved resource utilization and outcomes for patients. PMID- 27959311 TI - Clinical Trial of an Educational Program to Decrease Monitor Alarms in a Medical Intensive Care Unit. AB - Clinical research to identify effective interventions for decreasing nonactionable alarms has been limited. The objective of this study was to determine if a staff educational program on customizing alarm settings on bedside monitors decreased alarms in a medical intensive care unit (MICU). A preintervention, postintervention, nonequivalent group design was used to evaluate an educational program on alarm management in a convenience sample of MICU nurses. A 15-minute session was provided in a 1-week period. The outcome variable (number of alarms for low oxygen saturation via pulse oximetry [SpO2]) was determined from monitor log files adjusted by patient census. Data were collected for 15 days before and after the intervention. chi2 analysis was used, with P less than .05 considered significant. After 1 week of education, low SpO2 alarms decreased from 502 to 306 alarms per patient monitored per day, a 39% reduction (P < .001). Instructions for nurses in the medical intensive care unit on individualizing alarm settings to patients' clinical condition decreased common monitor alarms by 39%. PMID- 27959312 TI - When You Think You Have Seen It All: New Interventions in Transplant. PMID- 27959313 TI - "Awake" Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplant. AB - Mortality of patients awaiting lung transplant remains a significant problem as the number of patients on the waiting list far surpasses the number of donor organs available. Interest in the use of "awake" extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplant has emerged because this strategy offers several benefits over mechanical ventilation. This article provides a review of relevant literature and discusses indications and complications of awake ECMO therapy, cannulation strategies, and nursing considerations for this patient population. PMID- 27959314 TI - Balloon Pumps Inserted via the Subclavian Artery: Bridging the Way to Heart Transplant. AB - Intra-aortic balloon pumps have traditionally been inserted via the femoral artery, limiting patients' activity and exposing patients to complications of immobility. For patients awaiting cardiac transplant, these complications may threaten a successful outcome, or at the least, complicate recuperation after transplant. A novel approach to insertion of balloon pumps via the subclavian artery is presented here, including routine nursing care, complications and related nursing actions, and experience with and advantages of this method. A team approach to care of these patients, including rehabilitation and exercise protocols, is recommended. PMID- 27959315 TI - Antibody-Mediated Rejection in Solid Organ Transplant. AB - Within a little more than a decade, the transplant of human organs for end-stage organ disease became a reality. The early barriers to successful long-term graft and patient survival were related to the inability to effectively control the immune system such that it would not attack the donor tissue but would still recognize and destroy invading organisms and cells. As immunosuppressive therapy has been refined and proper matching of donors and recipients has been improved, hyperacute rejection has become a rare occurrence and acute rejection has been markedly controlled. However, antibody-mediated rejection remains an important impediment to increased survival of transplanted organs. This article provides readers with a broad overview of the immune system, discusses mechanisms of transplant rejection, and details prevention, detection, and treatment of antibody-mediated rejection in solid organ transplant. PMID- 27959317 TI - Creating Clinical Research Protocols in Advanced Practice: Part I, Identifying the Fit and the Aim. PMID- 27959318 TI - The Mysterious U Wave. PMID- 27959316 TI - Clostridium difficile Infection and Fecal Microbiota Transplant. AB - Clostridium difficile infection (CDI) is a major source of morbidity and mortality for hospitalized patients. Although most patients have a clinical response to existing antimicrobial therapies, recurrent infection develops in up to 30% of patients. Fecal microbiota transplant is a novel approach to this complex problem, with an efficacy rate of nearly 90% in the setting of multiple recurrent CDI. This review covers the current epidemiology of CDI (including toxigenic and nontoxigenic strains, risk factors for infection, and recurrent infection), methods of diagnosis, existing first-line therapies in CDI, the role of fecal microbiota transplant for multiple recurrent CDIs, and the potential use of fecal microbial transplant for patients with severe or refractory infection. PMID- 27959320 TI - A model electrode of well-defined geometry prepared by direct laser-induced decoration of nanoporous templates with Au-Ag@C nanoparticles. AB - We present an original type of model electrode system consisting of bimetallic Au Ag nanoparticles embedded in an amorphous carbon matrix with an extremely well defined geometry of parallel, straight, cylindrical macropores. The samples are prepared in one step by direct laser deposition of the metal/carbon composite onto the inner walls of a porous 'anodic' alumina matrix serving as a template. The coating is homogeneous from top to bottom of the pores, and the amount of material deposited can be tuned by the duration of the deposition procedure. As a test system, we demonstrate that a bimetallic Ag-Au@C system is catalytically active for the electrochemical oxidation of glucose in alkaline solution, the anodic reaction of a direct glucose fuel cell. Furthermore, the electrocatalytic current density increases with the amount of Ag-Au@C NPs deposited, up to a point at which the pores are clogged with it. This type of model system allows for the systematic study of geometric effects in fuel cell electrodes. It can be generalized to a number of different nanoparticle compositions, and thereby, to various electrocatalytic reactions. PMID- 27959321 TI - Mechanically tunable sub-10-nm metal gap by stretching PDMS substrate. AB - Manipulating light in sub-10-nm or subnanometer metal nanogaps is crucial to study the strong interaction between electromagnetic waves and matters. However, the fabrication of metallic nanogaps with precisely controlled size and high throughput still remains a challenge. Here, we developed an approach to actively control the gap distance between adjacent metal nanoparticles from 140 nm to sub 10-nm or even 0 nm via mechanical stretching process. To demonstrate this method, we manufactured the gold disk arrays in a square lattice on the polydimethylsiloxane (PDMS) substrate through interference lithography and gold deposition, and sub-10-nm interparticle gap was achieved as exerting a strain of 100% to the PDMS substrate. Transmission spectra show a remarkable red shift of the dipole resonance with narrowing gap from 140 nm to sub-10-nm. Importantly, a universal scaling law between the gap distance in nanoscale and the stretching amount of PDMS substrate in macroscopic scale were demonstrated experimentally and theoretically. Our method can tune the gap distance continuously and reversibly, suggesting potential applications in surface-enhanced Raman scattering, single photon emitter and quantum tunneling of electric charge. PMID- 27959319 TI - Accumulation of spontaneous gammaH2AX foci in long-term cultured mesenchymal stromal cells. AB - Expansion of mesenchymal stromal/stem cells (MSCs) used in clinical practices may be associated with accumulation of genetic instability. Understanding temporal and mechanistic aspects of this process is important for improving stem cell therapy protocols. We used gammaH2AX foci as a marker of a genetic instability event and quantified it in MSCs that undergone various numbers of passage (3-22). We found that gammaH2AX foci numbers increased in cells of late passages, with a sharp increase at passage 16-18. By measuring in parallel foci of ATM phosphorylated at Ser-1981 and their co-localization with gammaaH2AX foci, along with differentiating cells into proliferating and resting by using a Ki67 marker, we conclude that the sharp increase in gammaH2AX foci numbers was ATM-independent and happened predominantly in proliferating cells. At the same time, gradual and moderate increase in gammaH2AX foci with passage number seen in both resting and proliferating cells may represent a slow, DNA double-strand break related component of the accumulation of genetic instability in MSCs. Our results provide important information on selecting appropriate passage numbers exceeding which would be associated with substantial risks to a patient-recipient, both with respect to therapeutic efficiency and side-effects related to potential neoplastic transformations due to genetic instability acquired by MSCs during expansion. PMID- 27959322 TI - Hybrid 3D-2D printing of bone scaffolds Hybrid 3D-2D printing methods for bone scaffolds fabrication. AB - It is a well-known fact that bone scaffold topography on micro- and nanometer scale influences the cellular behavior. Nano-scale surface modification of scaffolds allows the modulation of biological activity for enhanced cell differentiation. To date, there has been only a limited success in printing scaffolds with micro- and nano-scale features exposed on the surface. To improve on the currently available imperfect technologies, in our paper we introduce new hybrid technologies based on a combination of 2D (nano imprint) and 3D printing methods. The first method is based on using light projection 3D printing and simultaneous 2D nanostructuring of each of the layers during the formation of the 3D structure. The second method is based on the sequential integration of preliminarily created 2D nanostructured films into a 3D printed structure. The capabilities of the developed hybrid technologies are demonstrated with the example of forming 3D bone scaffolds. The proposed technologies can be used to fabricate complex 3D micro- and nanostructured products for various fields. PMID- 27959323 TI - Quantification of In-Contact Probe-Sample Electrostatic Forces with Dynamic Atomic Force Microscopy. AB - Atomic Force Microscopy (AFM) methods utilizing resonant mechanical vibrations of cantilevers in contact with a sample surface have shown sensitivities as high as few picometers for detecting surface displacements. Such a high sensitivity is harnessed in several AFM imaging modes. Here, we demonstrate a cantilever resonance-based method to quantify electrostatic forces on a probe in the probe sample junction in the presence of a surface potential or when a bias voltage is applied to the AFM probe. We find that the electrostatic forces acting on the probe tip apex can produce signals equivalent to a few pm of surface displacement. In combination with modeling, the measurements of the force were used to access the strength of the electrical field at the probe tip apex in contact with a sample. We find an evidence that the electric field strength in the junction can reach ca. 1 V/nm at a bias voltage of a few volts and is limited by non-ideality of the tip-sample contact. This field is sufficiently strong to significantly influence material states and kinetic processes through charge injection, Maxwell stress, shifts of phase equilibria, and reduction of energy barriers for activated processes. Besides, the results provide a baseline for accounting for the effects of local electrostatic forces in electromechanical AFM measurements as well as offer additional means to probe ionic mobility and field induced phenomena in solids. PMID- 27959324 TI - Electronic properties and transistors of the NbS2-MoS2-NbS2 nanoribbon heterostructure. AB - Based on density function theory(DFT) and nonequilibrium Green's functions(NEGF), we construct a NbS2-MoS2-NbS2 nanoribbon inplane heterostructure. The effects of the channel length, width, chirality and vacancy of the heterostructure on the transport properties are systematically investigated. The electron transport of the armchair-edge heterostructure device shows ballistic transport properties, while the zigzag-edge heterostructure device exhibits resonance tunneling transport properties. Further study indicates the NbS2-MoS2-NbS2 field effect transistors(FETs) to be excellent ambipolar transistors. The FETs have high performances with current on/off ratio 4.7*105 and subthreshold swing 90mV/decade with the channel length m=16 and width n=6. The increase of the channel length will sharply reduce the off-state current and enhance the performances of the devices significantly. PMID- 27959325 TI - Mechanical stress-induced switching kinetics of ferroelectric thin films at the nanoscale. AB - We investigate ferroelectric domain structure and piezoelectric response under variable mechanical compressive stress in Pb(Zr0.2TiO0.8)O3 (PZT) thin films using high-resolution piezoresponse force microscopy (PFM) and an in situ sample bending stage. Measurements reveal a drastic change in the ferroelectric domain structure which is presented along with details of the mediating switching process involving domain wall motion, nucleation, and domain wall roughening under an applied external mechanical stimulus. Furthermore, local PFM hysteresis loops reveal significant changes in the observed coercive biases under applied stress. The PFM hysteresis loops become strongly imprinted under increasing applied compressive stress. PMID- 27959326 TI - Neuroanatomy accounts for age-related changes in risk preferences. AB - Many decisions involve uncertainty, or 'risk', regarding potential outcomes, and substantial empirical evidence has demonstrated that human aging is associated with diminished tolerance for risky rewards. Grey matter volume in a region of right posterior parietal cortex (rPPC) is predictive of preferences for risky rewards in young adults, with less grey matter volume indicating decreased tolerance for risk. That grey matter loss in parietal regions is a part of healthy aging suggests that diminished rPPC grey matter volume may have a role in modulating risk preferences in older adults. Here we report evidence for this hypothesis and show that age-related declines in rPPC grey matter volume better account for age-related changes in risk preferences than does age per se. These results provide a basis for understanding the neural mechanisms that mediate risky choice and a glimpse into the neurodevelopmental dynamics that impact decision-making in an aging population. PMID- 27959327 TI - The evolution of sex-specific virulence in infectious diseases. AB - Fatality rates of infectious diseases are often higher in men than women. Although this difference is often attributed to a stronger immune response in women, we show that differences in the transmission routes that the sexes provide can result in evolution favouring pathogens with sex-specific virulence. Because women can transmit pathogens during pregnancy, birth or breast-feeding, pathogens adapt, evolving lower virulence in women. This can resolve the long-standing puzzle on progression from Human T-cell Lymphotropic Virus Type 1 (HTLV-1) infection to lethal Adult T-cell Leukaemia (ATL); a progression that is more likely in Japanese men than women, while it is equally likely in Caribbean women and men. We argue that breastfeeding, being more prolonged in Japan than in the Caribbean, may have driven the difference in virulence between the two populations. Our finding signifies the importance of investigating the differences in genetic expression profile of pathogens in males and females. PMID- 27959329 TI - Brain-derived neurotrophic factor increase during treatment in severe mental illness inpatients. AB - Meta-analytical evidence suggests that brain-derived neurotrophic factor (BDNF) is altered in various psychiatric disorders. However, meta-analyses may be hampered by the heterogeneity of BDNF assays, lack of BDNF standard values and heterogeneity among the populations included in the studies. To address these issues, our study aimed to test, in a 'true-to-life' setting, the hypothesis that the serum BDNF level is nonspecifically reduced in acute severe mental illness (SMI) patients and increases during inpatient treatment. Consecutive samples of 236 inpatients with SMI and 100 healthy controls were recruited. SMI includes schizophrenia and severe mood disorders, and is characterized in the sample by the presence of at least 2 years of psychiatric treatment and disability. Generalized estimating equations were used to analyze BDNF serum levels at admission and upon discharge controlled by confounding factors. BDNF levels increased significantly between admission and discharge in SMI patients. BDNF levels showed significant reductions compared with controls both at admission and upon discharge. In addition, BDNF levels showed no difference among SMI patient diagnostic subgroups (unipolar depression, bipolar depression, schizophrenia and manic episode). The increase but non-restoration of BDNF levels, even with the general acute improvement of clinical scores, may reflect the progression of the disorder characteristically seen in these patients. BDNF levels could be considered as a marker for the presence of a nonspecific psychiatric disorder and possibly a transdiagnostic and nonspecific marker of disease activity. PMID- 27959328 TI - Insights into psychosis risk from leukocyte microRNA expression. AB - Dysregulation of immune system functions has been implicated in schizophrenia, suggesting that immune cells may be involved in the development of the disorder. With the goal of a biomarker assay for psychosis risk, we performed small RNA sequencing on RNA isolated from circulating immune cells. We compared baseline microRNA (miRNA) expression for persons who were unaffected (n=27) or who, over a subsequent 2-year period, were at clinical high risk but did not progress to psychosis (n=37), or were at high risk and did progress to psychosis (n=30). A greedy algorithm process led to selection of five miRNAs that when summed with +1 weights distinguished progressed from nonprogressed subjects with an area under the receiver operating characteristic curve of 0.86. Of the five, miR-941 is human-specific with incompletely understood functions, but the other four are prominent in multiple immune system pathways. Three of those four are downregulated in progressed vs. nonprogressed subjects (with weight -1 in a classifier function that increases with risk); all three have also been independently reported as downregulated in monocytes from schizophrenia patients vs. unaffected subjects. Importantly, these findings passed stringent randomization tests that minimized the risk of conclusions arising by chance. Regarding miRNA-miRNA correlations over the three groups, progressed subjects were found to have much weaker miRNA orchestration than nonprogressed or unaffected subjects. If independently verified, the leukocytic miRNA biomarker assay might improve accuracy of psychosis high-risk assessments and eventually help rationalize preventative intervention decisions. PMID- 27959330 TI - Brain structure and intragenic DNA methylation are correlated, and predict executive dysfunction in fragile X premutation females. AB - DNA methylation of the Fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary has been associated with executive dysfunction in female carriers of a FMR1 premutation (PM: 55-199 CGG repeats), whereas neuroanatomical changes have been associated with executive dysfunction in PM males. To our knowledge, this study for the first time examined the inter-relationships between executive function, neuroanatomical structure and molecular measures (DNA methylation and FMR1 mRNA levels in blood) in PM and control (<44 CGG repeats) females. In the PM group, FMR1 intron 1 methylation was positively associated with executive function and cortical thickness in middle and superior frontal gyri, and left inferior parietal gyrus. By contrast, in the control group, FMR1 intron 1 methylation was negatively associated with cortical thickness of the left middle frontal gyrus and superior frontal gyri. No significant associations were revealed for either group between FMR1 mRNA and neuroanatomical structure or executive function. In the PM group, the lack of any significant association between FMR1 mRNA levels and phenotypic measures found in this study suggests that either FMR1 expression is not well conserved between tissues, or that FMR1 intron 1 methylation is linked to neuroanatomical and cognitive phenotype in PM females via a different mechanism. PMID- 27959332 TI - Schizophrenia and neighbourhood deprivation. PMID- 27959331 TI - Cortical grey matter volume reduction in people with schizophrenia is associated with neuro-inflammation. AB - Cortical grey matter volume deficits and neuro-inflammation exist in patients with schizophrenia, although it is not clear whether elevated cytokines contribute to the cortical volume reduction. We quantified cortical and regional brain volumes in fixed postmortem brains from people with schizophrenia and matched controls using stereology. Interleukin (IL)-6, IL-1beta, IL-8 and SERPINA3 messenger RNAs (mRNAs) were quantified in the contralateral fresh frozen orbitofrontal cortex. We found a small, but significant reduction in cortical grey matter (1.3%; F(1,85)=4.478, P=0.037) and superior frontal gyrus (6.5%; F(1,80)=5.700, P=0.019) volumes in individuals with schizophrenia compared with controls. Significantly reduced cortical grey matter (9.2%; F(1,24)=8.272, P=0.008) and superior frontal gyrus (13.9%; F(1,20)=5.374, P=0.031) volumes were found in cases with schizophrenia and 'high inflammation' status relative to schizophrenia cases with 'low inflammation' status in the prefrontal cortex. The expression of inflammatory mRNAs in the orbitofrontal cortex was significantly correlated with those in dorsolateral prefrontal cortex (all r>0.417, all P<0.022), except for IL-8. Moreover, average daily and lifetime antipsychotic intake negatively correlated with cortical grey matter and superior frontal gyrus volumes (all r<-0.362, all P<0.05). The results suggest that the reduction in cortical grey matter volume in people with schizophrenia is exaggerated in those who have high expression of inflammatory cytokines. Further, antipsychotic medication intake does not appear to ameliorate the reduction in brain volume. PMID- 27959333 TI - A single high dose of dexamethasone affects the phosphorylation state of glutamate AMPA receptors in the human limbic system. AB - Glucocorticoids (GC) released during stress response exert feedforward effects in the whole brain, but particularly in the limbic circuits that modulates cognition, emotion and behavior. GC are the most commonly prescribed anti inflammatory and immunosuppressant medication worldwide and pharmacological GC treatment has been paralleled by the high incidence of acute and chronic neuropsychiatric side effects, which reinforces the brain sensitivity for GC. Synapses can be bi-directionally modifiable via potentiation (long-term potentiation, LTP) or depotentiation (long-term depression, LTD) of synaptic transmission efficacy, and the phosphorylation state of Ser831 and Ser845 sites, in the GluA1 subunit of the glutamate AMPA receptors, are a critical event for these synaptic neuroplasticity events. Through a quasi-randomized controlled study, we show that a single high dexamethasone dose significantly reduces in a dose-dependent manner the levels of GluA1-Ser831 phosphorylation in the amygdala resected during surgery for temporal lobe epilepsy. This is the first report demonstrating GC effects on key markers of synaptic neuroplasticity in the human limbic system. The results contribute to understanding how GC affects the human brain under physiologic and pharmacologic conditions. PMID- 27959335 TI - Functional evaluation of a PTSD-associated genetic variant: estradiol regulation and ADCYAP1R1. AB - Posttraumatic stress disorder (PTSD) affects 5-10% percent of the US adult population with a higher prevalence among women compared with men. Although it remains unclear how biological sex associates with susceptibility to PTSD, one mechanism may involve a role for estrogen in a gene by environment interaction. We previously demonstrated a sex-dependent association between the pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) and PTSD, where carriers of a C allele at single-nucleotide polymorphism (SNP) rs2267735 within the PAC1 receptor gene (ADCYAP1R1) have increased symptoms of PTSD. This SNP is located within a predicted estrogen response element (ERE), which regulates gene transcription when bound to estradiol (E2) activated estrogen receptor alpha (ERalpha). In the current study, we examined E2 regulation of ADCYAP1R1 in vitro, in cell culture, and in vivo in mice and humans. We find in mice that fear conditioning and E2 additively increase ADCYAP1R1 expression. In vitro, we show that E2/ERalpha binds to the ADCYAP1R1 ERE, with less efficient binding to an ERE containing the C allele of rs2267735. In women with low serum E2, the CC genotype associates with lower ADCYAP1R1 expression, which further associates with higher PTSD symptoms. These findings lead to a model in which E2 induces the expression of ADCYAP1R1 through binding of ERalpha at the ERE as an adaptive response to stress. Inhibition of E2/ERalpha binding to the ERE containing the rs2267735 risk allele results in reduced expression of ADCYAP1R1, diminishing estrogen regulation as an adaptive stress response and increasing risk for PTSD. PMID- 27959334 TI - Implication of NOTCH1 gene in susceptibility to anxiety and depression among sexual abuse victims. AB - Sexual abuse contributes to the development of multiple forms of psychopathology, including anxiety and depression, but the extent to which genetics contributes to these disorders among sexual abuse victims remains unclear. In this translational study, we first examined gene expression in the brains of rodents exposed to different early-life conditions (long, brief or no maternal separation). Hypothesizing that genes revealing changes in expression may have relevance for psychiatric symptoms later in life, we examined possible association of those genes with symptoms of anxiety and depression in a human sample of sexual abuse victims. Changes in rodent brain gene expression were evaluated by means of correspondence and significance analyses of microarrays by comparing brains of rodents exposed to different early-life conditions. Tag single-nucleotide polymorphisms (SNPs) of resulting candidate genes were genotyped and tested for their association with symptoms of anxiety and depression (Hospital Anxiety and Depression Scale) in a sample of 361 sexual abuse victims, using multinomial logistic regression. False discovery rate was applied to account for multiple testing in the genetic association study, with q-value of 0.05 accepted as significant. We identified four genes showing differential expression among animals subjected to different early-life conditions as well as having potential relevance to neural development or disorders: Notch1, Gabrr1, Plk5 and Zfp644. In the human sample, significant associations were observed for two NOTCH1 tag SNPs: rs11145770 (OR=2.21, q=0.043) and rs3013302 (OR=2.15, q=0.043). Our overall findings provide preliminary evidence that NOTCH1 may be implicated in the susceptibility to anxiety and depression among sexual abuse victims. The study also underscores the potential importance of animal models for future studies on the health consequences of early-life stress and the mechanisms underlying increased risk for psychiatric disorders. PMID- 27959336 TI - Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions. AB - Differences in general cognitive function have been shown to be partly heritable and to show genetic correlations with several psychiatric and physical disease states. However, to date, few single-nucleotide polymorphisms (SNPs) have demonstrated genome-wide significance, hampering efforts aimed at determining which genetic variants are most important for cognitive function and which regions drive the genetic associations between cognitive function and disease states. Here, we combine multiple large genome-wide association study (GWAS) data sets, from the CHARGE cognitive consortium (n=53 949) and UK Biobank (n=36 035), to partition the genome into 52 functional annotations and an additional 10 annotations describing tissue-specific histone marks. Using stratified linkage disequilibrium score regression we show that, in two measures of cognitive function, SNPs associated with cognitive function cluster in regions of the genome that are under evolutionary negative selective pressure. These conserved regions contained ~2.6% of the SNPs from each GWAS but accounted for ~40% of the SNP-based heritability. The results suggest that the search for causal variants associated with cognitive function, and those variants that exert a pleiotropic effect between cognitive function and health, will be facilitated by examining these enriched regions. PMID- 27959337 TI - Peripheral blood gene expression profiles linked to monoamine metabolite levels in cerebrospinal fluid. AB - The blood-brain barrier separates circulating blood from the central nervous system (CNS). The scope of this barrier is not fully understood which limits our ability to relate biological measurements from peripheral to central phenotypes. For example, it is unknown to what extent gene expression levels in peripheral blood are reflective of CNS metabolism. In this study, we examine links between central monoamine metabolite levels and whole-blood gene expression to better understand the connection between peripheral systems and the CNS. To that end, we correlated the prime monoamine metabolites in cerebrospinal fluid (CSF) with whole-genome gene expression microarray data from blood (N=240 human subjects). We additionally applied gene-enrichment analysis and weighted gene co-expression network analyses (WGCNA) to identify modules of co-expressed genes in blood that may be involved with monoamine metabolite levels in CSF. Transcript levels of two genes were significantly associated with CSF serotonin metabolite levels after Bonferroni correction for multiple testing: THAP7 (P=2.8 * 10-8, beta=0.08) and DDX6 (P=2.9 * 10-7, beta=0.07). Differentially expressed genes were significantly enriched for genes expressed in the brain tissue (P=6.0 * 10-52). WGCNA revealed significant correlations between serotonin metabolism and hub genes with known functions in serotonin metabolism, for example, HTR2A and COMT. We conclude that gene expression levels in whole blood are associated with monoamine metabolite levels in the human CSF. Our results, including the strong enrichment of brain expressed genes, illustrate that gene expression profiles in peripheral blood can be relevant for quantitative metabolic phenotypes in the CNS. PMID- 27959338 TI - Analysis of complete genomes of the rubella virus genotypes 1E and 2B which circulated in China, 2000-2013. AB - Rubella viruses of genotypes 1E and 2B are currently the most frequently detected wild-type viruses in the world. Genotype 1E viruses from China have been genetically distinct from genotype 1E viruses found elsewhere, while genotype 2B viruses found in China are not distinguishable from genotype 2B viruses from other areas. Genetic clusters of viruses of both genotypes were defined previously using sequences of the 739-nt genotyping window. Here we report phylogenic analysis using whole genomic sequences from seven genotype 1E and three genotype 2B viruses which were isolated in China between 2000 and 2013 and confirm the subgrouping of current circulating genotypes 1E and 2B viruses. In addition, the whole genomic characterization of Chinese rubella viruses was clarified. The results indicated that the Chinese rubella viruses were highly conserved at the genomic level, and no predicted amino acid variations were found at positions where functional domains of the proteins were identified. Therefore, it gives us the idea that the rubella control and elimination goal should be achieved if vaccine immunization coverage continues maintaining at the high level. PMID- 27959339 TI - Radiative cooling to deep sub-freezing temperatures through a 24-h day-night cycle. AB - Radiative cooling technology utilizes the atmospheric transparency window (8-13 MUm) to passively dissipate heat from Earth into outer space (3 K). This technology has attracted broad interests from both fundamental sciences and real world applications, ranging from passive building cooling, renewable energy harvesting and passive refrigeration in arid regions. However, the temperature reduction experimentally demonstrated, thus far, has been relatively modest. Here we theoretically show that ultra-large temperature reduction for as much as 60 degrees C from ambient is achievable by using a selective thermal emitter and by eliminating parasitic thermal load, and experimentally demonstrate a temperature reduction that far exceeds previous works. In a populous area at sea level, we have achieved an average temperature reduction of 37 degrees C from the ambient air temperature through a 24-h day-night cycle, with a maximal reduction of 42 degrees C that occurs when the experimental set-up enclosing the emitter is exposed to peak solar irradiance. PMID- 27959340 TI - E-selectin Targeting PEGylated-thioaptamer Prevents Breast Cancer Metastases. AB - E-selectin is an adhesion molecule expressed on the luminal surface of inflamed blood vessels that mediates hematogenous metastasis by assisting shear-resistant adhesion of circulating tumor cells to the vessel surface under dynamic blood flow. Previously, we developed an E-selectin antagonistic thioaptamer (ESTA) for the prevention of hematogenous metastasis through the blockade of CD44high breast cancer cells (BCa) adhesion to E-selectin-expressing premetastatic endothelial niche. The current study focuses on developing a PEGylated E-selectin targeting thioaptamer with improved pharmaceutical properties. A serial deletion of stem loops reveled that loop-1 and -2 (ESTA7) are the minimally effective backbone structure necessary to obtain inhibition of the E-selectin/CD44 interaction and shear resistant adhesion of CD44high BCa to E-selectin-expressing human endothelial cells (HMVECs) at a level equal to ESTA. Chemical conjugation of methoxy-polyethylene-glycol (PEG) at the sizes of 5 and 10 kDa did not interfere with ESTA7-mediated shear-resistant adhesion. However, in vivo study demonstrated that only 10 kDa PEG-conjugated ESTA7 (ESTA7-p10) retains the activity to inhibit metastases at a level equal to parental ESTA. Additionally, a single intravenous injection of ESTA7-p10 inhibited the development of lung, brain, and bone metastases of MDA-MB-231, through the blockade of E-selectin. Moreover, PEGylation led to an extension of elimination half-life and increase of AUC, resulting in superior inhibition of metastasis development compared to parental ESTA with a longer interval between dosing in a spontaneous metastasis model. Lastly, repeated intravenous administration of ESTA7-p10 was tolerated in mice, highlighting the potential prophylactic application of ESTA7-p10 for metastasis prevention. PMID- 27959341 TI - A Novel PD-L1-targeting Antagonistic DNA Aptamer With Antitumor Effects. AB - The PD-1/PD-L1 axis is a major pathway involved in tumor immune evasion. Here, we report the novel PD-L1 antagonizing DNA aptamer (aptPD-L1) and demonstrate an integrated pipeline that expedites therapeutic aptamer development. Aptamer can exert antibody-mimic functions and is advantageous over antibody for its chemically synthetic nature, low immunogenicity, and efficient tissue penetration. Our results showed that aptPD-L1 blocked the binding between human PD-1 and PD-L1. Experiments using murine models showed that aptPD-L1 promoted in vitro lymphocyte proliferation and suppressed in vivo tumor growth without the induction of observable liver or renal toxicity. Analyses on the aptPD-L1-treated tumors further revealed elevated levels of infiltrating CD4+ and CD8+ T cells, intratumoral IL-2, TNF-alpha, interferon (IFN)-gamma and the C-X-C motif chemokines, CXCL9 and CXCL10. The CD8+ T cells in the aptPD-L1-treated tumors had higher CXCR3 expression level compared to the random-sequence oligonucleotides treated ones. Besides, the length and density of CD31+ intratumoral microvessels were significantly decreased in the aptPD-L1 treatment group. Collectively, our data suggested that aptPD-L1 helps T cell function restoration and modifies tumor microenvironment. These chemokines might orchestrate together to attract more T cells into the tumor tissues to form the positive amplification loop against tumor growth, indicating the translational potential of aptPD-L1 in cancer immunotherapy. PMID- 27959343 TI - Phage-inducible islands in the Gram-positive cocci. AB - The SaPIs are a cohesive subfamily of extremely common phage-inducible chromosomal islands (PICIs) that reside quiescently at specific att sites in the staphylococcal chromosome and are induced by helper phages to excise and replicate. They are usually packaged in small capsids composed of phage virion proteins, giving rise to very high transfer frequencies, which they enhance by interfering with helper phage reproduction. As the SaPIs represent a highly successful biological strategy, with many natural Staphylococcus aureus strains containing two or more, we assumed that similar elements would be widespread in the Gram-positive cocci. On the basis of resemblance to the paradigmatic SaPI genome, we have readily identified large cohesive families of similar elements in the lactococci and pneumococci/streptococci plus a few such elements in Enterococcus faecalis. Based on extensive ortholog analyses, we found that the PICI elements in the four different genera all represent distinct but parallel lineages, suggesting that they represent convergent evolution towards a highly successful lifestyle. We have characterized in depth the enterococcal element, EfCIV583, and have shown that it very closely resembles the SaPIs in functionality as well as in genome organization, setting the stage for expansion of the study of elements of this type. In summary, our findings greatly broaden the PICI family to include elements from at least three genera of cocci. PMID- 27959342 TI - Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer. AB - Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours. In addition, AIL blocks tumour growth and metastasis of CRPC. Finally, AIL possesses favourable drug-like properties such as good bioavailability, high solubility, lack of CYP inhibition and low hepatotoxicity. In general, AIL is a potential candidate for the treatment of CRPC. PMID- 27959346 TI - Valuing our trainees: the future of medicine in the UK. PMID- 27959344 TI - Co-occurrence of antibiotic and metal resistance genes revealed in complete genome collection. AB - The high frequency of antibiotic resistance is a global public health concern. More seriously, widespread metal pressure in the environment may facilitate the proliferation of antibiotic resistance via coselection of antibiotic resistance genes (ARGs) and metal resistance genes (MRGs). Given the lack of comprehensive understanding of the ARG and MRG coselection, in this study both abundance relationship and genetic linkage between ARGs and MRGs were rigorously investigated by performing a genomic analysis of a large complete genome collection. Many more ARGs were enriched in human-associated bacteria compared with those subjected to less anthropogenic interference. The signatures of ARG and MRG co-occurrence were much more frequent and the distance linkages between ARGs and MRGs were much more intimate in human pathogens than those less human associated bacteria. Moreover, the co-occurrence structures in the habitat divisions were significantly different, which could be attributed to their distinct gene transfer potentials. More exogenous ARGs and MRGs on the genomes of human pathogens indicated the importance of recent resistance acquisition in resistome development of human commensal flora. Overall, the study emphasizes the potential risk associated with ARG and MRG coselection of both environmental and medical relevance. PMID- 27959345 TI - New roles in hemicellulosic sugar fermentation for the uncultivated Bacteroidetes family BS11. AB - Ruminants have co-evolved with their gastrointestinal microbial communities that digest plant materials to provide energy for the host. Some arctic and boreal ruminants have already shown to be vulnerable to dietary shifts caused by changing climate, yet we know little about the metabolic capacity of the ruminant microbiome in these animals. Here, we use meta-omics approaches to sample rumen fluid microbial communities from Alaskan moose foraging along a seasonal lignocellulose gradient. Winter diets with increased hemicellulose and lignin strongly enriched for BS11, a Bacteroidetes family lacking cultivated or genomically sampled representatives. We show that BS11 are cosmopolitan host associated bacteria prevalent in gastrointestinal tracts of ruminants and other mammals. Metagenomic reconstruction yielded the first four BS11 genomes; phylogenetically resolving two genera within this previously taxonomically undefined family. Genome-enabled metabolic analyses uncovered multiple pathways for fermenting hemicellulose monomeric sugars to short-chain fatty acids (SCFA), metabolites vital for ruminant energy. Active hemicellulosic sugar fermentation and SCFA production was validated by shotgun proteomics and rumen metabolites, illuminating the role BS11 have in carbon transformations within the rumen. Our results also highlight the currently unknown metabolic potential residing in the rumen that may be vital for sustaining host energy in response to a changing vegetative environment. PMID- 27959347 TI - Antimicrobial resistance: are we at the dawn of the post-antibiotic era? PMID- 27959348 TI - Seven cases of sigmoid volvulus in Parkinson's disease. AB - Non-motor features of Parkinson's disease are receiving greater recognition. Constipation affects up to 50% of patients with Parkinson's disease and sigmoid volvulus remains an under recognised complication with mortality rates up to 50%. The incidence of sigmoid volvulus in the general population is 1.7/100,000/year. The specific incidence in Parkinson's disease is not known; however, this case series suggests that it is noticeably more than in the general population at 100/100,000/year. This paper highlights the importance of early recognition and treatment of constipation to prevent volvulus developing and thevarious treatments currently available. PMID- 27959349 TI - An unusual cause of falls in a young woman. AB - Nitrous oxide is commonly used as an analgesic and anaesthetic agent. Nitrous oxide is also in use in industry as an aerosol propellant and is now recognised as a recreational drug whose use is growing, especially among the young. Nitrous oxide from whipped cream canisters is inhaled to produce a dissociative, intoxicated state. Nitrous oxide is known to inactivate vitamin B12 via oxidation, which can precipitate a demyelinating myelopathy akin to the classical B12 deficiency syndrome, subacute combined degeneration of the spinal cord. This case describes a young woman with chronic pain and a poor nutritional state who took regular nitrous oxide as an opiate-sparing agent. She developed a progressive subacute myelopathy with a sensory level, profoundly impaired joint position sense, extensor plantars and required a wheelchair. Once diagnosed, she responded well to a regime of nitrous oxide withdrawal, high-dose B12 replacement and physiotherapy. The case illustrates the need for clinical teams to be able to dentify a nitrous oxide-precipitated myelopathy as its use as a drug of abuse increases; particularly in the case of malnourished patients who receive nitrous oxide surgically or obstetrically. PMID- 27959350 TI - Progressive multifocal leukoencephalopathy associated with infliximab. AB - A 69-year-old female with seropositive rheumatoid arthritis presented with progressive cognitive decline following treatment with infliximab and methotrexate. Cranial MRI showed non-enhancing white matter signal abnormality consistent with demyelination was seen in the antero-inferior left frontal lobe extending into the frontal opercular white matter and into the left temporal lobe white matter. Similar appearances were seen in the inferomedial right frontal lobe. Brain biopsy showed histological changes consistent with progressive multifocal leukoencephalopathy. The cerebrospinal fluid polymerase chain reaction was negative but brain tissue polymerase chain reaction was positive for JC virus. This case highlights the association of infliximab with progressive multifocal leukoencephalopathy in a patient with known seropositive rheumatoid arthritis. PMID- 27959351 TI - Fatal haemorrhage following fine needle aspiration of the thyroid. AB - Fine needle aspiration is routinely performed as part of the assessment of thyroid nodules. It is generally regarded as a very safe procedure, though rarely significant bleeding can occur in its aftermath. A 79-year-old female was referred for assessment of an incidental thyroid nodule which had been identified on computed tomography of the chest and extended into the retrosternal space. The patient was referred for fine needle aspiration under ultrasound guidance. Three passes were made with a 25 gauge needle into the nodule; a haemorrhagic aspirate was obtained and sent for cytological examination. Several hours later, the patient developed a cough and progressive breathlessness and died at home before she could be taken to hospital. The key finding from the post-mortem was extensive haemorrhage within the capsule of thyroid. In the absence of another identifiable aetiology, the cause of death was considered to be acute haemorrhage into the thyroid gland. Thyroid fine needle aspiration is generally a safe procedure, but it is important to recognise that, rarely, major complications can occur. PMID- 27959352 TI - Have the Testosterone Trials demonstrated the effectiveness of testosterone therapy in older men without classical hypogonadism? PMID- 27959353 TI - A new FRONTIER in dementia differential diagnosis? PMID- 27959355 TI - Embarking on a research project...or research for the absolute novice. AB - Research can be a difficult area for the novice to break into. A number of different obstacles face the new researcher, starting with selecting a suitable supervisor, writing a workable protocol and obtaining permissions from all the relevant organisations. This beginner's guide walks the fledging researcher through the required steps, including formulating a research question, designing a protocol and completing the Integrated Research Application System form to obtain the required permissions. The aim is to demystify the terms used in research and expose some of the pitfalls the authors experienced so that others can avoid them! Although challenges can arise throughout the research process, we aim to help you get underway. PMID- 27959354 TI - Delivering comprehensive geriatric assessment in new settings: advice for frontline clinicians. AB - Over the decades, as the principles of comprehensive geriatric assessment have been established, there have been attempts to apply its principles to settings other than acute hospital medical wards or the general communitydwelling older population, for example, to other settings where older people with infirmity are found. The purpose of this paper is to describe and reflect upon the application of and evidence for comprehensive geriatric assessment in these new settings and give some advice to clinicians about how to optimise their contributions to these processes. I will state my advice having first discussed intermediate care, emergency surgery (hip fracture), elective surgery, dementia and delirium care, emergency care, cancer care, and the care of residents of care homes (mindful of the irony of calling the latter a new setting, given that geriatric medicine originated in long term care). PMID- 27959356 TI - A history of Edinburgh's medical museums. AB - Edinburgh has a wealth of medical collections, thanks not only to its role in the Enlightenment and the diaspora of graduates from the large medical school, but also to recent developments in medical heritage. Concentrating on the collections of the University of Edinburgh's Anatomy Department and Surgeons' Hall Museums at the Royal College of Surgeons of Edinburgh, this paper charts the complex and connected histories of the material culture of anatomy, pathology and surgery in the city. What roles did museums play, from their 18th century origins to their 21st century resurgence, and who used them? PMID- 27959357 TI - Penicillin: promise, problems and practice in wartime Edinburgh. AB - While medical historians have paid ample attention to the introduction of antibiotics and their impact on hospital-based practice during and after the Second World War, the multiple issues surrounding their use in Scottish hospitalsare sorely lacking in current discussions. Drawing on an extensive yet underused range of materials including patient treatment records, oral histories and medical correspondence, this paper explores the introduction of penicillin for civilian treatment at the Royal Infirmary of Edinburgh during the closing stages of the War. It highlights the success of the drug in clinical treatment as well as its shortcomings, offering an alternative view of its initial impact on surgical practice. PMID- 27959358 TI - van Helmont's proposal for a randomised comparison of treating fevers with or without bloodletting and purging. AB - Around the year 1643, Joan Baptista van Helmont, a Flemish chemist, alchemist and physician who had devised what he claimed to be a new form of medicine, proposed a 'challenge' to traditional Galenic physicians to compare treatment of fever by traditional methods and by a regime which did not involve bloodletting and purging. Two groups of patients were to be treated and 'casting of lots' was to be used - in some way not specified in detail - to decide who received which treatment. This 'challenge' has been regarded as the first proposal for the use of randomisation in a clinical trial. This paper explains the background to the challenge and discusses what can be deduced from Helmont's text about the details of how he proposed that the 'trial' was to be carried out. It concludes that internal evidence in Helmont's writings makes it certain that no such 'trial' was ever conducted. It seems that the 'challenge' was probably a rhetorical device to support Helmont's vehement criticism of traditional Galenic medicine and its practitioners, and, in particular, toemphasise his absolute opposition to the use of bloodletting as a medicaltreatment. An appendix includes a short summary of Helmont's theories of the origins of disease and transcriptions of the passages of Helmont's Latin text translated in the article. PMID- 27959359 TI - Auscultation of the skull PMID- 27959360 TI - Arrested alpha-hydride migration activates a phosphido ligand for C-H insertion. AB - Bulky tris(carbene)borate ligands provide access to high spin iron(ii) phosphido complexes. The complex PhB(MesIm)3FeP(H)Ph is thermally unstable, and [PPh] group insertion into a C-H bond of the supporting ligand is observed. An arrested alpha hydride migration mechanism suggests increased nucleophilicity of the phosphorus atom facilitates [PPh] group transfer reactivity. PMID- 27959361 TI - Single-unit-cell thick Co9S8 nanosheets from preassembled Co14 nanoclusters. AB - Ultrathin two-dimensional (2D) nanomaterials composed of abundant and inexpensive 3d metal chalcogenides are competitive candidates for practical electrocatalysts for the oxygen evolution reaction (OER). However, the bottom-up synthesis of atomically thick nanosheets is difficult for materials with inherent non-layered host crystals. Here, we demonstrate the preparation of single-unit-cell thick Co9S8 nanosheets from preassembled Co14 nanoclusters (NCs) by virtue of the flexibility of NC self-assembly in colloidal solution. Due to their free-standing properties, the NC self-assembled architectures are capable of bearing sulfurization at elevated temperatures, thus producing ultrathin Co9S8 nanosheets. The nanosheets exhibit an OER overpotential as low as 0.27 V at 10 mA cm-2 in 0.1 M KOH, which is comparable to the performance of the best Co-based OER electrocatalysts. PMID- 27959362 TI - Vibrational blue shift of coordinated N2 in [Fe3O(OAc)6(N2)n]+: "non-classical" dinitrogen complexes. AB - We present "non-classical" dinitrogen Fe(iii) oxo acetate complexes in vacuo utilizing Infrared Photodissociation (IR-PD) at cryo temperatures. The IR-PD spectra reveal a blue shift of the N2 stretching vibration frequencies in the complexes. Density Functional Theory (DFT) calculations confirm the experiments and indicate strengthened N-N bonds due to pronounced sigma bonding and a lack of pi back donation. PMID- 27959363 TI - Optimization of Fe3O4 nanozyme activity via single amino acid modification mimicking an enzyme active site. AB - The Fe3O4 nanozyme was the first reported nanoparticle with intrinsic peroxidase like activity and has been widely used in biomedicine. To optimize its catalytic activity, we introduced histidine residues onto the Fe3O4 nanoparticle surface in order to mimic the enzymatic microenvironment of natural peroxidase enzymes. Our results show that modification with a single amino acid could more than ten-fold improve the apparent affinity (KM) of the Fe3O4 nanozyme for the substrate H2O2 and enhanced its catalytic efficiency (kcat/KM) up to twenty fold. Thus we not only optimized the activity of the Fe3O4 nanozyme, but also provide a new rationale for improving the efficiency of nanomaterial-based catalysts by utilizing strategies observed in nature. PMID- 27959365 TI - Photoinduced energy- and electron-transfer from a photoactive coordination cage to bound guests. AB - In a coordination cage which contains an array of twelve naphthyl chromophores surrounding a central cavity, photoinduced energy or electron-transfer can occur from the chromophore array to the bound guest in supramolecular host/guest complexes. PMID- 27959364 TI - An efficient two-photon fluorescent probe for human NAD(P)H:quinone oxidoreductase (hNQO1) detection and imaging in tumor cells. AB - A new quinone propionic acid locked TP fluorophore which can be used for human NAD(P)H:quinone oxidoreductase (hNQO1) detection was developed. The probe, TPQ, which displays high selectivity and anti-interference ability, was successfully applied to endogenous hNQO1 imaging and for the identification of different cancer cells. PMID- 27959367 TI - Electronic properties of layered phosphorus heterostructures. AB - Two-dimensional (2D) layered phosphorus possesses multiple structural phases with different properties. By using ab initio approaches, the electronic properties of vertical heterostructured compounds of different structural phases of layered phosphorus have been studied. Both type-I (symmetric) and type-II (staggered) band alignments have been realized in the van der Waals heterostructures. Through appropriate doping, the type-II band alignment can be further tuned to type-III (broken). The multiple types of band alignment suggest great potential of phase manipulated 2D phosphorus for next-generation novel electronics. PMID- 27959369 TI - Luminophores of tunable colors from ternary Ag-In-S and quaternary Ag-In-Zn-S nanocrystals covering the visible to near-infrared spectral range. AB - Ternary Ag-In-S or quaternary Ag-In-Zn-S nanocrystals were prepared from simple precursors (silver nitrate, indium(iii) chloride, zinc stearate in a mixture of DDT and ODE) by injecting a solution of elemental sulfur into OLA. Ternary nanocrystals were modified by depositing either a ZnS or a CdS shell, yielding type I and type II core/shell systems exhibiting photoluminescence QY in the range of 12-16%. Careful optimization of the reaction conditions allowed alloyed quaternary Ag-In-Zn-S nanocrystals exhibiting tunable photoluminescence in the spectral range of 520-720 nm with a QY of 48% and 59% for green and red radiations, respectively, to be obtained. 1H NMR analysis of the nanocrystal organic shell, after dissolution of its inorganic core, indicated that surfacial sulfur atoms were covalently bonded to aliphatic chains whereas surfacial cations were coordinated by amines and carboxylate anions. No thiol-type ligands were detected. Transfer of the prepared nanocrystals to water could be achieved in one step by exchanging the initial ligands for 11-mercaptoundecanoic ones resulting in a QY value of 31%. A new Ag-In-Zn-S nanocrystal preparation method was elaborated in which indium and zinc salts of fatty acids were used as cation precursors and DDT was replaced by thioacetamide. This original DDT-free method enabled similar tuning of the photoluminescence properties of the nanocrystals as in the previous method; however the measured photoluminescence QYs were three times lower. Hence, further optimization of the new method is required. PMID- 27959371 TI - Construction of 2D nanoporous networks by coupling on-surface dynamic imine chemistry and dipole-stabilized self-assembly. AB - Double-walled nanoporous networks based on the Schiff base reaction of nonplanar tripodic building blocks and subsequent dipole-directed self-assembly were fabricated on highly oriented pyrolytic graphite (HOPG) at the gas-solid interface. This is the first example of nonplanar molecules exploited as precursors for a surface reaction. PMID- 27959372 TI - Construction of a polyproline structure with hydrophobic exterior using octahydroindole-2-carboxylic acid. AB - The proline analogue (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (Oic) has been previously applied as a proline substitute in pharmocologically active peptides and as a structural component of the antihypertensive drug Perindopril. Herein, we describe the formation of an oligoproline structure by an Oic oligomer. A series of Oic oligomers were investigated to show the structural and energetic contribution of appended residues to the structure. NMR investigation of these oligomers revealed an all-trans amide bond structure, and we provide evidence that a cascade-like mechanism is responsible for the all-trans folding cooperativity. X-ray crystallography of the Oic-hexapeptide clearly demonstrates that the all-trans structure of the Oic oligomer is a polyproline II helix. Thus, as a hydrophobic proline analog with a highly stable trans-amide bond, Oic represents an ideal building block for hydrophobic sites of polyproline II structures in biologically relevant contexts. PMID- 27959373 TI - Exploration of photophysics of 2,2'-pyridil at room temperature and 77 K: a combined spectroscopic and quantum chemical approach. AB - The photophysics of 2,2'-pyridil has been explored thoroughly using steady state and time resolved fluorometric techniques at room temperature (RT) in liquid media as well as in glassy matrices at cryogenic temperature (77 K). Ethanol and methylcyclohexane are exploited for this purpose, as polar and non-polar media respectively. Notwithstanding the observation of multiple emissions from the fluorophore, the experiments unequivocally rule out emission from excited singlet states other than the S1 state, consistent with Kasha's rule. Among 1,2 dicarbonyl molecular systems, this behavior resembles that of alpha-furil, while it contradicts that of benzil and alpha-naphthil which exhibit S2 emissions. The dual fluorescence and dual phosphorescence of the fluorophore are ascribed to the emissions originating from the two conformers, namely near-trans and relaxed skew. Coexistence of the two conformers is substantiated by time resolved area normalized emission spectroscopy (TRANES) at both RT and 77 K. The potential energy curves (PECs) simulated from calculations based on density functional theory and its time dependent extension provide adequate support to the experimental observations. PMID- 27959374 TI - Nanoporous microstructures mediate osteogenesis by modulating the osteo-immune response of macrophages. AB - The osteoimmune environment plays indispensable roles in bone regeneration because the early immune environment that exists during the regenerative process promotes the recruitment and differentiation of osteoblastic lineage cells. The response of immune cells growing on nanotopographic surfaces and the microenvironment they generate should be considered when evaluating nanotopography-mediated osteogenesis, which are topics that are generally neglected in the field. In this study, we investigated the modulatory effects of nanoporous anodic alumina with different sized pores on macrophage responses and their subsequent effects on the osteogenic differentiation of bone marrow stromal cells (BMSCs). The nanopore structure and the pore size were found to be important adhesive cues for macrophages, which affected their spreading and cell shape, subsequently regulated the expression and activation of autophagy pathway components (LC3A/B, Beclin-1, Atg3, Atg7, and P62) and modulated the inflammatory response, osteoclastic activities, and release of osteogenic factors. Subsequently, the osteogenic pathways (Wnt and BMP) of BMSCs were found to be regulated by different nanopore-induced inflammatory environments, which affected the osteogenic differentiation outcomes. This study is the first to emphasize the effects of immune cells on nanotopography-mediated osteogenesis, which could lead to a new strategy for the development of advanced nanobiomaterials for tissue engineering, nanomedicine and immunotherapeutic applications. PMID- 27959375 TI - Patterning of L10 FePt nanoparticles with ultra-high coercivity for bit-patterned media. AB - L10-ordered FePt nanoparticles (NPs) with ultra-high coercivity were directly prepared from a new metallopolyyne using a one-step pyrolysis method. The chemical ordering, morphology and magnetic properties of the as-synthesized FePt NPs have been studied. Magnetic measurements show the coercivity of these FePt NPs is as high as 3.6 T. Comparison of NPs synthesized under the Ar and Ar/H2 atmospheres shows that the presence of H2 in the annealing environment influences the nucleation and promotes the growth of L10-FePt NPs. Application of this metallopolymer for bit-patterned media was also demonstrated using nanoimprint lithography. PMID- 27959376 TI - Stationary bubble formation and Marangoni convection induced by CW laser heating of a single gold nanoparticle. AB - Gold nanoparticles (Au NPs) efficiently convert incident light into heat under the resonant conditions of localized surface plasmon. Controlling mass transfer through plasmonic heating of Au NPs has potential applications such as manipulation and fabrication within a small space. Here, we describe the formation of stationary microbubbles and subsequent fluid convection induced by CW laser heating of Au NPs in water. Stationary bubbles of about 1-20 MUm in diameter were produced by irradiating individual Au NPs with a CW laser. Spatial profiles and velocity distribution of fluid convection around the microbubbles were visualized by the wide-field fluorescence imaging of tracer nanospheres. To evaluate the bubble-induced convection, numerical simulations were performed on the basis of general heat diffusion and Navier-Stokes equations. A comparison between the experimental and computational results revealed that a temperature derivative of surface tension at the bubble surface is a key factor to control the fluid convection. Temperature differences of a few Kelvin at the bubble surface resulted in convective velocities ranging from 102 to 103 MUm s-1. The convective velocity gradually increased with increasing bubble diameter. This article covers both natural and Marangoni convection induced by plasmonic heating of Au NPs. PMID- 27959377 TI - One-pot synthesis of a ceria-graphene oxide composite for the efficient removal of arsenic species. AB - Arsenic contamination has posed a health risk to millions of people around the world. In this study, we describe a simple and facile one-step hydrothermal synthesis of a ceria-graphene oxide (ceria-GO) composite for the efficient removal of arsenic species. The prepared ceria-GO composite materials exhibited almost complete (over 99.99%) and quick removal of both arsenic species within 0.1 mg L-1 of the initial concentration. The calculated adsorption capacities were 185 mg g-1 for As(iii) and 212 mg g-1 for As(v). It was found that Ce3+ is an active site and continuously adsorbs arsenic species; there is a concomitant change from Ce4+ to Ce3+ due to the solution redox environment. This increase in the Ce3+ concentration further facilitates the complete removal of arsenic species in solution. Thus our approach offers a promising potential for the treatment of arsenic-contaminated drinking water. PMID- 27959378 TI - Exploring nanoparticle porosity using nano-impacts: platinum nanoparticle aggregates. AB - The porosity of platinum nanoparticles (PtNPs) is explored for the first time using tag-redox coulometry (TRC). This is achieved by monitoring the reduction of the 4-nitrobenzenethiol (NTP)-tagged PtNPs on carbon electrodes via both immobilisation and nanoimpacts. The average charge per impact is measured and attributed to the reduction of NTP adsorbed on individual PtNPs. The number of NTP molecules and thus the "active surface area" of the PtNPs is calculated and compared with two models: fully solid and porous nanoparticles, and the extent of the particle porosity is revealed. This allows a fuller understanding of the (electro-)catalytic behaviour of nanoparticles by providing insight into their porosity and "true/active surface areas". PMID- 27959379 TI - Towards improved halogenated BODIPY photosensitizers: clues on structural designs and heavy atom substitution patterns. AB - The singlet oxygen (1O2) production quantum yield (PhiDelta) of 14 halogenated BODIPY dyes has been determined (0.01 < PhiDelta < 0.99). 1O2 production and photostability have been evaluated considering the BODIPY structure, the substitution pattern, and the number and type of heavy atoms and quenching rate constants of 1O2 by the sensitizer. In view of the experimental results and principal component analysis (PCA), guidelines for an improved design of efficient and photostable halo-BODIPY sensitizers are proposed. PMID- 27959380 TI - Sequencing and bioinformatics analysis of the differentially expressed genes in herniated discs with or without calcification. AB - The purpose of this study was to detect the differentially expressed genes between ossified herniated discs and herniated discs without ossification. In addition, we sought to identify a few candidate genes and pathways by using bioinformatics analysis. We analyzed 6 samples each of ossified herniated discs (experimental group) and herniated discs without ossification (control group). Purified mRNA and cDNA extracted from the samples were subjected to sequencing. The NOISeq method was used to statistically identify the differentially expressed genes (DEGs) between the 2 groups. An in-depth analysis using bioinformatics tools based on the DEGs was performed using Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction network analysis. The top 6 DEGs were verified using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A total of 132 DEGs was detected. A total of 129 genes in the ossified group were upregulated and 3 genes were found to be downregulated as compared to the control group. The top 3 cellular components in GO ontologies analysis were extracellular matrix components. GO functions were mainly related to the glycoprotein in the cell membrane and extracellular matrix. The GO process was related to completing response to stimulus, immune reflex and defense. The top 5 KEGG enrichment pathways were associated with infection and inflammation. Three of the top 20 DEGs [sclerostin (SOST), WNT inhibitory factor 1 (WIF1) and secreted frizzled related protein 4 (SFRP4)] were related to the inhibition of the Wnt pathway. The ossified discs exhibited a higher expression of the top 6 DEGs [SOST, joining chain of multimeric IgA and IgM (IGJ; also known as JCHAIN), defensin alpha 4 (DEFA4), SFRP4, proteinase 3 (PRTN3) and cathepsin G (CTSG)], with the associated P-values of 0.045, 0.000, 0.008, 0.010, 0.015 and 0.002, respectively, as calculated by the independent sample t-test. The gene expression profiling of the 2 groups revealed differential gene expression. Thus, our data suggest that Wnt pathway abnormality and local inflammation may be related to disc ossification. PMID- 27959381 TI - Nobiletin, a citrus flavonoid, activates vasodilator-stimulated phosphoprotein in human platelets through non-cyclic nucleotide-related mechanisms. AB - Nobiletin, a bioactive polymethoxylated flavone, has been described to possess a diversity of biological effects through its antioxidant and anti-inflammatory properties. Vasodilator-stimulated phosphoprotein (VASP) is a common substrate for cyclic AMP and cyclic GMP-regulated protein kinases [i.e., cyclic AMP dependent protein kinase (PKA; also known as protein kinase A) and cyclic GMP dependent protein kinase (PKG; also known as protein kinase G)] and it has been shown to be directly phosphorylated by protein kinase C (PKC). In the present study, we demonstrate that VASP is phosphorylated by nobiletin in human platelets via a non-cyclic nucleotide-related mechanism. This was confirmed by the use of inhibitors of adenylate cyclase (SQ22536) and guanylate cyclase [1H [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)], since they prevented VASP phosphorylation induced by nobiletin. Furthormore, this event was also not affected by specific inhibitors of PKA (H-89), PKG (KT5823) and PKC (Ro318220), representing cyclic nucleotide-dependent pathways upon nobiletin-induced VASP phosphorylation. Similarly, inhibitors of p38 mitogen-activated protein kinase (MAPK; SB203580), extracellular signal-regulated kinase 2 (ERK2; PD98059), c-Jun N-terminal kinase 1 (JNK1; SP600125), Akt (LY294002) and nuclear factor-kappaB (NF-kappaB; Bay11-7082) did not affect nobiletin-induced VASP phosphorylation. Moreover, electron spin resonance, dichlorofluorescein fluorescence and western blotting techniques revealed that nobiletin did not affect hydroxyl radicals (OH*), intracellular reactive oxygen species (ROS) and on protein carbonylation, respectively. Furthermore, the nobiletin-induced VASP phosphorylation was surprisingly reversed by the intracellular antioxidant, N-acetylcysteine (NAC), but not by the inhibitor of NADPH oxidase, diphenyleneiodonium chloride (DPI). It was surprising to observe the differential effects of nobiletin and NAC on VASP phosphorylation in human platelets, since they both have been reported to have antioxidant properties. The likely explanation for this discrepancy is that NAC may bind to allosteric sites on the receptor different from those that nobiletin binds to in human platelets. Taken together, our findings suggest that nobiletin induces VASP phosphorylation in human platelets through non-cyclic nucleotide related mechanisms. Nevertheless, the exact mechanisms responsible for these effects need to be further confirmed in future studies. PMID- 27959382 TI - Bach1 siRNA attenuates bleomycin-induced pulmonary fibrosis by modulating oxidative stress in mice. AB - Oxidative stress plays an essential role in inflammation and fibrosis. Bach1 is an important transcriptional repressor that acts by modulating oxidative stress and represents a potential target in the treatment of pulmonary fibrosis (PF). In this study, we knocked down Bach1 using adenovirus-mediated small interfering RNA (siRNA) to determine whether the use of Bach1 siRNA is an effective therapeutic strategy in mice with bleomycin (BLM)-induced PF. Mouse lung fibroblasts (MLFs) were incubated with transforming growth factor (TGF)-beta1 (5 ng/ml) and subsequently infected with recombined adenovirus-like Bach1 siRNA1 and Bach1 siRNA2, while an empty adenovirus vector was used as the negative control. The selected Bach1 siRNA with higher interference efficiency was used for the animal experiments. A mouse model of BLM-induced PF was established, and Bach1 siRNA (1x109 pfu) was administered to the mice via the tail vein. The results revealed that the Bach1 mRNA and protein levels were significantly downregulated by Bach1 siRNA. Furthermore, the MLFs infected with Bach1 siRNA exhibited increased mRNA and protein expression levels of heme oxygenase-1 and glutathione peroxidase 1, but decreased levels of TGF-beta1 and interleukin-6 in the cell supernatants compared with the cells exposed to TGF-beta1 alone. Bach1 knockdown by siRNA also enhanced the expression of antioxidant factors, but suppressed that of fibrosis related cytokines in mice compared with the BLM group. Finally, the inflammatory infiltration of alveolar and interstitial cells and the destruction of lung structure were significantly attenuated in the mide administered Bach1 siRNA compared with those in the BLM group. On the whole, our findings demonstrate that Bach1 siRNA exerts protective effects against BLM-induced PF in mice. Our data may provide the basis for the development of novel targeted therapeutic strategies for PF. PMID- 27959383 TI - Combination of metformin and sorafenib suppresses proliferation and induces autophagy of hepatocellular carcinoma via targeting the mTOR pathway. AB - The multi-kinase inhibitor sorafenib is the only drug for which randomized control trials have shown improved patient survival in advanced hepatocellular carcinoma (HCC). However, life expectancy is extended in these cases by only a few months. The anti-type II diabetes agent metformin was used in this study in an effort to find a more efficient approach to HCC treatment. Sorafenib effectively reversed the activation status of mTORC2 induced by metformin and enhanced the suppression of the mTORC1 and MAPK pathway by metformin in HCC cells, which may be responsible for reduced proliferation upon combined treatment. The metformin and sorafenib combination led to increased impaired proliferation and tumor inhibition of HCC in vitro and in vivo compared to single agent, which was partially bridged by disrupting the mTORC1/mTORC2 feedback loop. Metformin and sorafenib cooperated to promote apoptosis and autophagy in HCC cells. Pharmacological inhibition of autophagy sensitized HCC cells to metformin and sorefenib-induced apoptotic cell death. Therefore, the anti-autophagy treatment should be considered in metformin and sorafenib-based treatments in HCC cells. PMID- 27959384 TI - Pro-metastatic intracellular signaling of the elaidic trans fatty acid. AB - Trans fatty acids (TFAs) are risk factors of cardiovascular disorders, and a few studies have reported the cancer-promoting effects of TFAs. In the present study, we examined the effects and signaling of elaidic acid (EA), a TFA, in colorectal cancer (CRC) cells. Oral intake of EA increased the metastasis of CT26 mouse CRC cells by inducing the expression of stemness markers nucleostemin (NS) and CD133. Mechanisms underlying EA-induced signaling were confirmed by determining the binding of EA to G-protein coupled receptor 40 (GPR40) and GPR120 by performing surface protein internalization assay. We found that c-SRC mediated EGFR transactivation was induced by the binding of EA to GPR40 and GPR120. Moreover, EGFR signaling upregulated NS and Snail expression and downregulated E-cadherin expression in wild-type APC-containing CT26 cells, and upregulated NS, Wnt5a and CD44 expression in APC-null HT29 cells. These results indicate that EA enhances the stemness and epithelial-mesenchymal transition of CRC cells. These results also indicate the prominent metastatic potential of EA-treated cancer cells and highlight the important implications of EA on public health. PMID- 27959385 TI - Microtubule actin cross-linking factor 1, a novel target in glioblastoma. AB - Genetic heterogeneity is recognized as a major contributing factor of glioblastoma resistance to clinical treatment modalities and consequently low overall survival rates. This genetic diversity results in variations in protein expression, both intratumorally and between individual glioblastoma patients. In this regard, the spectraplakin protein, microtubule actin cross-linking factor 1 (MACF1), was examined in glioblastoma. An expression analysis of MACF1 in various types of brain tumor tissue revealed that MACF1 was predominately present in grade III-IV astroctyomas and grade IV glioblastoma, but not in normal brain tissue, normal human astrocytes and lower grade brain tumors. Subsequent genetic inhibition experiments showed that suppression of MACF1 selectively inhibited glioblastoma cell proliferation and migration in cell lines established from patient derived xenograft mouse models and immortalized glioblastoma cell lines that were associated with downregulation of the Wnt-signaling mediators, Axin1 and beta-catenin. Additionally, concomitant MACF1 silencing with the chemotherapeutic agent temozolomide (TMZ) used for the clinical treatment of glioblastomas cooperatively reduced the proliferative capacity of glioblastoma cells. In conclusion, the present study represents the first investigation on the functional role of MACF1 in tumor cell biology, as well as demonstrates its potential as a unique biomarker that can be targeted synergistically with TMZ as part of a combinatorial therapeutic approach for the treatment of genetically multifarious glioblastomas. PMID- 27959386 TI - PINK1 signaling in mitochondrial homeostasis and in aging (Review). AB - Mitochondrial dysfunction is involved in the pathology of Parkinson's disease, an age-associated neurodegenerative disorder. Phosphatase and tensin homolog (PTEN) induced putative kinase protein 1 (PINK1) is responsible for the most common form of recessive Parkinson's disease. PINK1 is a mitochondrial kinase that is involved in mitrochondrial quality control and promotes cell survival. PINK1 has been shown to protect against neuronal cell death induced by oxidative stress. Accordingly, PINK1 deficiency is associated with mitochondrial dysfunction as well as increased oxidative cellular stress and subsequent neuronal cell death. In addition, several mitochondrial chaperone proteins have been shown to be substrates of the PINK1 kinase. In this review, we discuss recent studies concerning the signaling cascades and molecular mechanisms involved in the process of mitophagy, which is implicated in neurodegeneration and in related aging associated with oxidative stress. Particular attention will be given to the molecular mechanisms proposed to explain the effects of natural compounds and/or food ingredients against oxidative stress. Knowledge of the molecular mechanisms involved in this cellular protection could be critical for developing treatments to prevent and control excessive progression of neurodegenerative disorders. PMID- 27959389 TI - Matrine-induced apoptosis in Hep3B cells via the inhibition of MDM2. AB - Matrine, an alkaloid component derived from the Sophora root, can inhibit cancer cell proliferation and induce autophagy via p53 associated pathways. However, numerous tumor cells lack functional p53 and little is known about the effect of matrine on the p53-deficient/mutant cancer cells. The present study aimed to assess anticancer effects of matrine in p53-deficient human Hep3B hepatoma cells. The present results demonstrated that matrine caused Hep3B cell apoptosis by suppressing gene expression of minute double-mutant (MDM)2. Notably, it was revealed that matrine inhibited MDM2 at the transcriptional level in a time- and dose-dependent manner. This MDM2 inhibition resulted in induction of the p53 family member, p73; however, the functions of p73 were not induced since matrine induced p73 failed to activate its target genes, p21 and p53 upregulated modulator of apoptosis. The matrine-induced downregulation of MDM2 led to an inhibition of inhibitor of apoptosis protein 3, which might serve a critical role in matrine-induced apoptosis in MDM2-overexpressing Hep3B cells. Finally, combination therapy of matrine with 100 uM epotoside successfully killed more Hep3B cells, suggesting that matrine can sensitize p53-deficient Hep3B cells to epotoside-induced apoptosis. PMID- 27959387 TI - Long-term exposure of MCF-7 breast cancer cells to ethanol stimulates oncogenic features. AB - Alcohol consumption is a risk factor for breast cancer. Little is known regarding the mechanism, although it is assumed that acetaldehyde or estrogen mediated pathways play a role. We previously showed that long-term exposure to 2.5 mM ethanol (blood alcohol ~0.012%) of MCF-12A, a human normal epithelial breast cell line, induced epithelial mesenchymal transition (EMT) and oncogenic transformation. In this study, we investigated in the human breast cancer cell line MCF-7, whether a similar exposure to ethanol at concentrations ranging up to peak blood levels in heavy drinkers would increase malignant progression. Short term (1-week) incubation to ethanol at as low as 1-5 mM (corresponding to blood alcohol concentration of ~0.0048-0.024%) upregulated the stem cell related proteins Oct4 and Nanog, but they were reduced after exposure at 25 mM. Long-term (4-week) exposure to 25 mM ethanol upregulated the Oct4 and Nanog proteins, as well as the malignancy marker Ceacam6. DNA microarray analysis in cells exposed for 1 week showed upregulated expression of metallothionein genes, particularly MT1X. Long-term exposure upregulated expression of some malignancy related genes (STEAP4, SERPINA3, SAMD9, GDF15, KRT15, ITGB6, TP63, and PGR, as well as the CEACAM, interferon related, and HLA gene families). Some of these findings were validated by RT-PCR. A similar treatment also modulated numerous microRNAs (miRs) including one regulator of Oct4 as well as miRs involved in oncogenesis and/or malignancy, with only a few estrogen-induced miRs. Long-term 25 mM ethanol also induced a 5.6-fold upregulation of anchorage-independent growth, an indicator of malignant-like features. Exposure to acetaldehyde resulted in little or no effect comparable to that of ethanol. The previously shown alcohol induction of oncogenic transformation of normal breast cells is now complemented by the current results suggesting alcohol's potential involvement in malignant progression of breast cancer. PMID- 27959390 TI - [Corrigendum] Increased expression levels of ppGalNAc-T13 in lung cancers: Significance in the prognostic diagnosis. AB - Following the publication of this article, the authors noted that there was an error in Fig. 4. The lines representing the two groups were indicated incorrectly in all graphs in Fig. 4. A corrected version of Fig. 4 is presented below. Furthermore, we regret any inconvenience this error may have caused. [the original article was published in the International Journal of Oncology 49: 1369 1376, 2016; DOI: 10.3892/ijo.2016.3638]. PMID- 27959388 TI - A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro. AB - Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotra-nsformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two-dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases. PMID- 27959391 TI - Tissue inhibitor of metalloproteinases 1, a novel biomarker of tuberculosis. AB - Tuberculosis (TB) is an important infectious disease of humans and other animals. Conventional diagnostic methods, including the tuberculin skin test, chest X-rays and bacterial culture, have certain innate disadvantages for the early, rapid and specific diagnosis of tuberculosis. The present study aimed to identify a novel diagnostic biomarker to overcome these disadvantages. The potential target identified in the present study was tissue inhibitor of metalloproteinases 1 (TIMP-1), which has previously been demonstrated to be critical in the immune response to TB. The concentration of TIMP-1 in the blood was determined using a commercial ELISA kit, and the relative mRNA expression levels following bacterial infection were detected by reverse transcription-quantitative polymerase chain reaction. Based on a clinical and microbiological diagnosis, the ELISA for plasma TIMP-1 had a sensitivity of 91.80% [95% confidence interval (CI): 85.44, 96.00] and a specificity of 91.41% (95% CI: 85.14, 95.63). In a THP-1 cell model, Bacillus Calmette-Guerin and Mycobacterium bovis significantly upregulated the mRNA expression levels of TIMP-1 post infection in a time-dependent manner (P=0.006 for BCG 24 h PI, P=3.2x10-7 for M. bovis 24 PI). The results of the present study indicate that plasma TIMP-1 may be a potential biomarker for the diagnosis of TB. PMID- 27959392 TI - Syringin prevents cardiac hypertrophy induced by pressure overload through the attenuation of autophagy. AB - Syringin, extracted from Eleutherococcus senticosus, is a major biologically active component of Chinese herbs. Studies have certified the multiple pharmacological properties of syringin. However, the role of syringin in cardiac hypertrophy and the mechanisms involved remain unclear. In this study, aortic banding was performed on mice in order to induce cardiac hypertrophy, and the animals were then treated with syringin for 7 weeks. Echocardiography and catheter-based measurements of hemodynamic parameters were performed to evaluate cardiac function at 8 weeks following aortic banding. Morphological and pathological changes were also evaluated. Alterations in the expression levels of hypertrophy- and autophagy-related markers [atrial natriuretic peptide (ANP), beta-myosin heavy chain MHC), alpha-MHC, B-type natriuretic peptide (BNP), autophagy-related gene (ATG)5, ATG7, beclin 1, light chain 3 (LC3) A/B] were measured by reverse transcription-quantitative PCR and western blot analysis. The effects of syringin on cardiomyocyte hypertrophy induced by angiotensin II in H9c2 cells were also investigated. The results revealed that syringin attenuated cardiac hypertrophy induced by aortic banding via the activation of AMP-activated protein kinase alpha (AMPKalpha) and autophagy-related signaling pathways. Thus, we our data suggest that syringin possesses therapeutic potential to attenuate the progression of cardiac hypertrophy. PMID- 27959393 TI - CD44-shRNA recombinant adenovirus inhibits cell proliferation, invasion, and migration, and promotes apoptosis in HCT116 colon cancer cells. AB - The cell-surface glycoprotein CD44 is closely associated with cell proliferation, tumor invasion, and metastasis. Previous studies have reported that knockdown of CD44 with short hairpin RNA (shRNA) reduced cell proliferation and migration, and induced apoptosis. However, more efficient means of delivering small interference RNA are still necessary. We developed an in vitro model of CD44-shRNA recombinant adenovirus (Ad-CD44-shRNA) and evaluated its ability to alter tumor invasion, migration, and apoptosis in human colon cancer cells. An shRNA against CD44 was used for knockdown of CD44 expression, and recombinant adenovirus was constructed using AD293 cells. The Ad-CD44-shRNA-treated HCT116 colon cancer cells showed a significant decrease in cell proliferation, migration, and invasion, while apoptosis was increased. The Ad-CD44-shRNA also decreased the phosphorylation of Akt and GSK-3beta. The levels of Bcl-2 and Bcl-xL expression were downregulated, whereas the expression levels of Bax, cleaved caspase-3 and -9, and PARP were increased in Ad-CD44-shRNA-treated colon cancer cells. These results support the feasibility of an adenovirus-mediated RNA interference therapy targeting human colon cancer via the CD44 as a potential future therapeutic intervention. PMID- 27959394 TI - miR-214 suppresses the osteogenic differentiation of bone marrow-derived mesenchymal stem cells and these effects are mediated through the inhibition of the JNK and p38 pathways. AB - In this study, we sought to investigate the expression of microRNA (miR)-214 on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) and explore the possible underlying mechanisms. We found that the overexpression of miR-214 effectively promoted the adipocyte differentiation of BMSCs in vitro, reduced alkaline phosphatase (ALP) activity and the gene expression of collagen type I (Col I), osteocalcin (OCN) and osteopontin (OPN) in the BMSCs. We further found that the overexpression of miR-214 suppressed the protein expression of fibroblast growth factor (FGF), phosphorylated c-Jun N terminal kinase (p-JNK) and phosphorylated p38 (p-p38) in the BMSCs. The downregulation of miR-214 promoted the osteogenic differentiation of BMSCs, and increased ALP activity and Col I, OCN and OPN gene expression in the BMSCs. It also increased FGF p-JNK and p-p38 protein expression in the BMSCs. The use of JNK inhibitor (SP600125) enhanced the inhibitory effects of miR-214 overexpression on osteogenic differentiation, ALP activity, and Col I, OCN and OPN gene expression in the BMSCs. Lastly, the use of p38 inhibitor (SB202190) also enhanced the inhibitory effects of miR-214 overexpression on ALP activity, and Col I, OCN and OPN gene expression in the BMSCs. These results provide a mechanism responsible for the suppressive effects of miR-214 on the osteogenic differentiation of BMSCs involving the inhibition of the JNK and p38 pathways. PMID- 27959395 TI - MicroRNA expression profiles and networks in CXCL12-stimulated human endometrial stromal cells. AB - The chemokine stromal cell-derived factor-1 (C-X-C motif chemokine ligand 12; CXCL12) is important in the recruitment of leukocytes to the peritoneal cavity and the regulation of endometriotic tissue growth in endometriosis patients. However, the alterations in microRNA (miRNA) expression induced by CXCL12 remain to be fully elucidated. The present study evaluated key miRNAs in CXCL12 stimulated endometrial stromal cells (ESCs), and investigated the underlying cellular regulatory mechanisms of CXCL12 in endometriosis by building networks between miRNAs, genes and gene ontologies (GOs). Differential expression of miRNAs and mRNAs induced by CXCL12 stimulation in ESCs was measured using miRNA and gene chips, and it was observed that 35 miRNAs and 1,671 mRNAs were differentially expressed. Using potential target genes of the 35 miRNAs, intersections of these genes were examined and 63 intersection genes were identified. A total of 39 GOs were obtained for these intersection genes, based on information from GO databases, including immune cell chemoattractants, inflammatory and immune responses, and pathological processes of endometriotic lesions in endometriosis. In addition, miRNA-gene networks were built according to the GO and Kyoto Encyclopedia of Genes and Genomes databases. The present study, to the best of our knowledge, provides the most complete miRNAome and mRNAome profiles, and the most detailed investigation of the underlying cellular regulatory mechanisms, of the effects of CXCL12 in endometriosis. These results may facilitate the complete elucidation of the role of CXCL12 in endometriosis, and its underlying epigenetic mechanisms. PMID- 27959397 TI - Engineering of the human vessel wall with hair follicle stem cells in vitro. AB - Hair follicle stem cells (HFSCs) are increasingly used as a stem cell paradigm in vascular tissue engineering due to the fact that they are a rich source of easily accessible multipotent adult stem cells. Promising results have been demonstrated with small diameter (less than 6 mm) tissue engineered blood vessels under low blood pressure, however engineering large vessels (>6 mm in diameter) remains a challenge due to the fact it demands a higher number of seed cells and higher quality biomechanical properties. The aim of the current study was to engineer a large vessel (6 mm in diameter) with differentiated smooth muscle cells (SMCs) induced from human (h)HFSCs using transforming growth factor-beta1 and platelet derived growth factor BB in combination with low-serum culture medium. The cells were seeded onto polyglycolic acid and then wrapped around a silicone tube and further cultured in vitro. A round vessel wall was formed subsequent to 8 weeks of culture. Histological examination indicated that layers of smooth muscle-like cells and collagenous fibres were oriented in the induced group. In contrast, disorganised cells and collagenous fibres were apparent in the undifferentiated group. The approach developed in the current study demonstrated potential for constructing large muscular vessels with differentiated SMCs induced from hHFSCs. PMID- 27959396 TI - Ulinastatin post-treatment attenuates lipopolysaccharide-induced acute lung injury in rats and human alveolar epithelial cells. AB - Ulinastatin (UTI), a serine protease inhibitor, possesses anti-inflammatory properties and has been suggested to modulate lipopolysaccharide (LPS)-induced acute lung injury (ALI). High-mobility group box 1 (HMGB1), a nuclear DNA-binding protein, plays a key role in the development of ALI. The aim of this study was to investigate whether UTI attenuates ALI through the inhibition of HMGB1 expression and to elucidate the underlying molecular mechanisms. ALI was induced in male rats by the intratracheal instillation of LPS (5 mg/kg). UTI was administered intraperitoneally 30 min following exposure to LPS. A549 alveolar epithelial cells were incubated with LPS in the presence or absence of UTI. An enzyme-linked immunosorbent assay was used to detect the levels of inflammatory cytokines. Western blot analysis was performed to detect the changes in the expression levels of Toll-like receptor 2/4 (TLR2/4) and the activation of nuclear factor kappaB (NF-kappaB). The results revealed that UTI significantly protected the animals from LPS-induced ALI, as evidenced by the decrease in the lung wet to dry weight ratio, total cells, neutrophils, macrophages and myeloperoxidase activity, associated with reduced lung histological damage. We also found that UTI post treatment markedly inhibited the release of HMGB1 and other pro-inflammatory cytokines. Furthermore, UTI significantly inhibited the LPS-induced increase in TLR2/4 protein expression and NF-kappaB activation in lung tissues. In vitro, UTI markedly inhibited the expression of TLR2/4 and the activation of NF-kappaB in LPS-stimulated A549 alveolar epithelial cells. The findings of our study indicate that UTI attenuates LPS-induced ALI through the inhibition of HMGB1 expression in rats. These benefits are associated with the inhibition of the activation of the TLR2/4-NF-kappaB pathway by UTI. PMID- 27959398 TI - Differential microRNA expression is associated with androgen receptor expression in breast cancer. AB - The androgen receptor (AR) is frequently expressed in breast cancer; however, its prognostic value remains unclear. AR expression in breast cancer has been associated with improved outcomes in estrogen receptor (ER)-positive breast cancer compared with ER-negative disease. Eliminating AR function in breast cancer is critically important for breast cancer progression. However, the mechanism underlying AR regulation remains poorly understood. The study of microRNAs (miRNAs) has provided important insights into the pathogenesis of hormone-dependent cancer. To determine whether miRNAs function in the AR regulation of breast cancer, the present study performed miRNA expression profiling in AR-positive and -negative breast cancer cell lines. A total of 153 miRNAs were differentially expressed in AR-positive compared with AR-negative breast cancer cells; 52 were upregulated and 101 were downregulated. A number of these have been extensively associated with breast cancer cell functions, including proliferation, invasion and drug-resistance. Furthermore, through pathway enrichment analysis, signaling pathways associated with the prediction targets of the miRNAs were characterized, including the vascular endothelial growth factor and mammalian target of rapamycin signaling pathways. In conclusion, the results of the present study indicated that the expression of miRNAs may be involved in the mechanism underlying AR regulation of breast cancer, and may improve understanding of the role of AR in breast cancer. PMID- 27959400 TI - Resistin aggravates the expression of proinflammatory cytokines in cerulein stimulated AR42J pancreatic acinar cells. AB - Resistin, an adipocytokine secreted by fat tissues, has been shown to be associated with increased local and systemic complications in acute pancreatitis (AP). However, the mechanism underlying the effect of resistin in the aggravation of AP remains to be elucidated. The aim of the present study was to investigate the functional consequences of exposing rat pancreatic acinar cells to resistin and to determine whether it amplifies proinflammatory signaling in an in vitro AP model. AR42J cells pretreated with recombinant resistin were activated by cerulein as an in vitro model of AP. The secretion of amylase was measured to evaluate the cytotoxic effect. The mRNA expression levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were determined using reverse transcription-quantitative polymerase chain reaction analysis. The nuclear protein expression levels of the nuclear factor (NF)-kappaB p65 subunit were determined using western blot analysis. Resistin treatment significantly increased the secretion of amylase, and the mRNA expression levels of TNF-alpha and IL-6 in the cerulein-induced in vitro AP model. High protein levels of the NF kappaB p65 subunit were observed in the nuclei of cells in the resistin-treated AP model, compared with the untreated AP model. Pretreatment of the in vitro resistin-treated AP model with the NF-kappaB inhibitor, pyrrolidine dithiocarbamate decreased the protein expression of the NF-kappaB p65 subunit in nuclei, and significantly attenuated the increased mRNA expression levels of TNF alpha and IL-6 induced by resistin. The results of the present study showed that resistin increased the production of the TNF-alpha and IL-6 proinflammatory cytokines via the NF-kappaB-dependent pathway during AP. Thus, the overproduction of obesity-associated resistin and the associated amplification of the inflammatory response may result in the aggravation of AP severity. PMID- 27959399 TI - Abnormalities in endocrine and immune cells are correlated in dextran-sulfate sodium-induced colitis in rats. AB - The interaction between the gut hormones and the immune system has been suggested to serve an important role in the pathophysiology of inflammatory bowel disease. The aims of the present study were to elucidate the possible abnormalities in the colonic endocrine cells in rats with dextran sodium sulfate (DSS)-induced colitis, and to determine whether they are correlated with alterations in the immune cells. A total of 24 male Wistar rats were divided into two groups: Control and DSS-induced colitis. Colonic tissues were harvested via postmortem laparotomy from all of the animals at the end of the experimental period, and fixed and sectioned for histology. The colonic endocrine and immune cells in those tissue samples were immunostained and their densities quantified by computerized image analysis. The densities of chromogranin A, serotonin, peptide YY and oxyntomodulin cells were significantly higher, and those of pancreatic peptide and somatostatin cells were lower in rats with DSS-induced colitis than in the controls. The densities of mucosal leukocytes, T and B lymphocytes, macrophages/monocytes, and mast cells were significantly higher than in the controls, and these changes were closely associated with the aforementioned changes in all endocrine cell types. These observations indicate an interaction between intestinal hormones and the immune system as represented by immune cells. PMID- 27959401 TI - Midazolam anesthesia protects neuronal cells from oxidative stress-induced death via activation of the JNK-ERK pathway. AB - Midazolam is an anesthetic agent commonly used during clinical and surgical procedures, which has been shown to exert ROS-suppressing and apoptosis modulating pharmacological activities in various cellular systems. However, the effects of midazolam on oxidative stress in neuronal cells require elucidation. The present study investigated the effects of midazolam on buthionine sulfoximine (BSO)- and hydrogen peroxide (H2O2)-induced oxidative stress in primary cortical neuronal cells. In addition, the effects of midazolam on middle cerebral artery occlusion (MCAO) in mice and on ethanol-induced neuroapoptosis in the brains of neonatal mice were determined. Subsequently, cell viability was detected using the MTT assay; intracellular reactive oxygen species (ROS) generation was determined using the 2',7'-dichlorodihydrofluorescein diacetate method with confocal microscopy; terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was conducted to detect apoptotic cells; immunohistochemistry was performed to detect activated caspase-3; neuronal deficit and infarct volume analyses were conducted; and quantitative polymerase chain reaction and western blotting were performed to detect the expression levels of genes and proteins associated with apoptosis and cell survival pathways. The results demonstrated that BSO (10 mM) and H2O2 (1 mM) suppressed proliferation of cortical neuronal cells by inducing apoptosis. These effects were suppressed following treatment with midazolam in a dose-dependent manner. In addition, BSO and H2O2 induced ROS generation in neuronal cells; however, this was effectively suppressed by midazolam (100 uM). Beneficial synergistic effects were detected when midazolam was used in combination with the known antioxidant trolox. BSO and H2O2 also suppressed the protein expression levels of c-Jun N-terminal kinases (JNK), phosphorylated (p)JNK, extracellular signal-regulated kinases (ERK)1/2, pERK1/2, AKT and nuclear factor-kappaB; however, expression was recovered following treatment with midazolam. Midazolam also activated protein kinase C-epsilon, which was suppressed by BSO, in cortical neuronal cells. In MCAO mice, midazolam post-conditioning significantly suppressed infarct size and reduced the number of TUNEL-positive cells. In addition, the expression levels of caspase-3 and poly (ADP-ribose) polymerase were suppressed in a dose-dependent manner. In neonatal mice, midazolam reduced ethanol-induced activated caspase-3 staining and apoptotic TUNEL staining. The results of the present study demonstrated that midazolam may protect against neuronal degeneration and neuroapoptosis induced by physiological and oxidative stress. PMID- 27959402 TI - Effects of herbal Epimedium on the improvement of bone metabolic disorder through the induction of osteogenic differentiation from bone marrow-derived mesenchymal stem cells. AB - Herbal Epimedium (HE) has been commonly used as a tonic, antirheumatic agent and in the treatment of bone-associated diseases including osteoporosis. Treatment for osteoporosis is important to increase bone mass density and maintain to balance of bone remodeling. The present study was performed to investigate the effects of HE on mouse bone marrow mesenchymal stem cell (mBMMSC) proliferation and osteogenic differentiation, using MTT assays, proliferating cell nuclear antigen (PCNA) detection and apoptosis and differentiation assays. HE was demonstrated to inhibit the proliferation of mBMMSCs up to 45.43+/-3.33% and to decrease the level of PCNA expression compared with untreated cells. HE also induced late apoptosis at 24 and 48 h after treatment up to 71.93 and 67.03%, respectively, while only 14.93% of untreated cells exhibited apoptosis. By contrast, HE induced differentiation of mBMMSCs into an osteogenic lineage at the beginning of three weeks after commencement of treatment. This suggested that HE is a candidate as an inducer of osteogenesis from bone marrow mesenchymal stem cells, and additionally has potential for use in the treatment of bone metabolic disorders such as osteoporosis. PMID- 27959403 TI - Bcl11b regulates enamel matrix protein expression and dental epithelial cell differentiation during rat tooth development. AB - Amelogenesis, beginning with thickened epithelial aggregation and ending with highly mineralized enamel formation, is a process mediated by a complex signaling network that involves several molecules, including growth and transcription factors. During early tooth development, the transcription factor B-cell CLL/lymphoma 11B (Bcl11b) participates in dental epithelial cell proliferation and differentiation. However, whether it affects the postnatal regulation of enamel matrix protein expression and ameloblast differentiation remains unclear. To clarify the role of Bcl11b in enamel development, the present study initially detected the protein expression levels of Bcl11b during tooth development using immunohistochemistry, from the embryonic lamina stage to the postnatal period, and demonstrated that Bcl11b is predominantly restricted to cervical loop epithelial cells at the cap and bell stages, whereas expression is reduced in ameloblasts. Notably, the expression pattern of Bcl11b during tooth development differed between rats and mice. Knockdown of Bcl11b by specific small interfering RNA attenuated the expression of enamel-associated genes, including amelogenin, X linked (Amelx), ameloblastin (Ambn), enamelin (Enam), kallikrein related peptidase 4 (Klk4), matrix metallopeptidase 20 and Msh homeobox 2 (Msx2). Chromatin immunoprecipitation assay verified that Msx2 was a transcriptional target of Bcl11b. However, overexpression of Msx2 resulted in downregulation of enamel-associated genes, including Ambn, Amelx, Enam and Klk4. The present study suggested that Bcl11b serves a potentially important role in the regulation of ameloblast differentiation and enamel matrix protein expression. In addition, a complex feedback regulatory network may exist between Bcl11b and Msx2. PMID- 27959404 TI - Upregulation of endoplasmic reticulum stress is associated with diaphragm contractile dysfunction in a rat model of sepsis. AB - Sepsis often causes diaphragm contractile dysfunction. Endoplasmic reticulum (ER) stress has been implicated in muscle contractile dysfunction. However, it remains unknown if ER stress occurs in the diaphragm during sepsis. In the present study, rats were divided into 4 groups and received placebo or one of three durations of endotoxin treatment (24, 48 h and 7 days). Isometric contractile force of the diaphragm was measured and lung wet-to-dry ratio (W/D) was calculated. Hematoxylin and eosin (H&E) staining of lung tissue was performed and electron microscopy assessed ER damage in the diaphragm during sepsis. The mRNA and protein expression of glucose-regulated protein 78 kDa (GRP78), glucose-regulated protein 94 kDa (GRP94), C/EBP homologous protein (CHOP), endoplasmic reticulum protein 44 (ERP44), protein disulfide-isomerase like protein (ERP57) and protein disulfide isomerase family A member 4 (ERP72) in diaphragm muscles were measured using reverse transcription-quantitative polymerase chain reaction and western blot analysis. The level of cleaved caspase-12 was analyzed by western blot analysis. The results demonstrated that sepsis increased lung W/D. H&E staining revealed that sepsis caused alveolar congestion, hemorrhage and rupture. Swollen and distended ER was observed using electron microscopy during sepsis and decreased diaphragm contractile function was also observed. The expression levels of ER stress markers (GRP78, GRP94, CHOP, ERP44, ERP57 and ERP72) and the level of cleaved caspase-12 were significantly elevated in septic rats compared with control rats, particularly in the 48 h group. In conclusion, the present study indicated that weakened diaphragm contraction and damaged ER in septic rats was associated with increased expression of ER stress markers. PMID- 27959405 TI - Anti-aging effects of melatonin on the myocardial mitochondria of rats and associated mechanisms. AB - The present study investigated the anti-aging effects of melatonin on the myocardial mitochondria of D-galactose-aged rats and associated mechanisms. A total of 30 male Sprague-Dawley (SD) rats were randomly divided into three equal groups: An accelerated aging group that received 125 mg/kg/day D-galactose; a melatonin-treated group of D-galactose-aged rats that received 10 mg/kg/day melatonin; and a control group receiving normal saline. ATP, ADP and AMP levels in the left ventricular myocardium of rats were determined by high performance liquid chromatography and the total adenylic acid number (TAN) was subsequently calculated. Bax, Bcl-2, and cytochrome c (cyt-c) protein expression levels in myocardial mitochondria and cytoplasm were quantified by western blot analysis. In the melatonin-treated group, ATP levels were significantly higher when compared with the untreated control group and the accelerated-ageing group (0.068 vs. 0.052 and 0.058; P=0.002 and P=0.045, respectively), and TAN was significantly increased in the melatonin-treated group when compared with controls (P=0.011). In addition, cyt-c levels in the cytoplasm, but not in the mitochondria, were significantly higher in the accelerated-aging group compared with the control and melatonin-treated groups (P=0.001 and P=0.002, respectively). Bcl-2 and Bax ratios were significantly higher in the control and melatonin-treated groups when compared with the accelerated-aging group (P=0.004 and P=0.032, respectively). These results suggest that melatonin exhibits a protective effect on mitochondrial function in a rat model of accelerated aging. PMID- 27959407 TI - Low-dose irradiation promotes proliferation of the human breast cancer MDA-MB-231 cells through accumulation of mutant P53. AB - Low-dose irradiation (LDIR) has been proven to have differential biological effects on normal mammalian somatic cells and cancer cells. Our previous study showed that p53 gene status is a critical factor regulating the effect of LDIR on cancer cells. We investigated the effect of LDIR on the breast cancer cell line MDA-MB-231 that harbors a mutant p53 gene, and the normal breast fibroblast cell line Hs 578Bst. In the present study, we showed that 150 mGy LDIR pormoted growth of MDA-MB-231 cells but not Hs 578Bst cells. Through cell cycle analyses, we found that LDIR accelerated cell cycle into S phase in MDA-MB-231 cells, but did not affect the cell cycle of Hs 578Bst cells. Using western blotting, we demonstrated that the expression of CDK4, CDK6 and cyclin D1 was upregulated in MDA-MB-231 cells after LDIR. Although LDIR increased ataxia-telangiectasia mutated (ATM) level in both MDA-MB-231 cells and Hs 578Bst cells and activated ATM/p53/p21 pathway, only the mutant type of p53 (mtp53) protein in MDA-MB-231 cells was shown to be accumulated after LDIR. Using ATM inhibitor or lentivirus mediated small interfering RNA (siRNA) to block the ATM/p53/p21 pathway in MDA-MB 231 cells, the LDIR-induced cell proliferation was abolished. When we introduced wild-type p53 (wtp53) protein into MDA-MB-231 cells, the LDIR-induced cell proliferation was also abolished. These findings suggest that normal p53 function is crucial in ATM/p53/p21 pathway activated by LDIR. The p53 status is the most probable reason leading to differential LDIR biological activities between breast tumor cells and normal breast cells. PMID- 27959406 TI - Ganoderma lucidum polysaccharides protect fibroblasts against UVB-induced photoaging. AB - Ganoderma lucidum has featured in traditional Chinese medicine for >1,000 years. Ganoderma polysaccharides (GL-PS), a major active ingredient in Ganoderma, confer immune regulation, antitumor effects and significant antioxidant effects. The aim of the present study was to investigate the efficacy and mechanism of GL-PS associated inhibition of ultraviolet B (UVB)-induced photoaging in human fibroblasts in vitro. Primary human skin fibroblasts were cultured, and a fibroblast photoaging model was built through exposure to UVB. Cell viability was measured by MTT assay. Aged cells were stained using a senescence-associated beta galactosidase staining (SA-beta-gal) kit. ELISA kits were used to analyze matrix metalloproteinase (MMP) -1 and C-telopeptides of Type I collagen (CICP) protein levels in cellular supernatant. ROS levels were quantified by flow cytometry. Cells exposed to UVB had decreased cell viability, increased aged cells, decreased CICP protein expression, increased MMP-1 protein expression, and increased cellular ROS levels compared with non-exposed cells. However, cells exposed to UVB and treated with 10, 20 and 40 ug/ml GL-PS demonstrated increased cell viability, decreased aged cells, increased CICP protein expression, decreased MMP-1 protein expression, and decreased cellular ROS levels compared with UVB exposed/GL-PS untreated cells. These results demonstrate that GL-PS protects fibroblasts against photoaging by eliminating UVB-induced ROS. This finding indicates GL-PS treatment may serve as a novel strategy for antiphotoaging. PMID- 27959408 TI - Involvement of xanthine oxidase and paraoxonase 1 in the process of oxidative stress in nonalcoholic fatty liver disease. AB - Xanthine oxidase (XOD) and paraoxonase 1 (PON1) are important enzymes in redox reactions in vivo, and are predominantly synthesized by the liver. The aim of the present study was to investigate the redox state in nonalcoholic fatty liver disease, and determine the association between the activities of XOD and PON1 and the severity of NAFLD. Sprague-Dawley rats were randomly divided into control, model and alpha-lipoic acid (high and low dose) groups. The rats in the NAFLD model were induced by feeding a high fat diet for 12 weeks and the in vitro cell model of hepatocyte steatosis was induced by treating L-02 cells with oleic acid for 24 h. The body weight, liver function, lipid and oxidative stress indices, and histological features of the liver were examined in the rats. Compared with the control group, the rats in the NAFLD model group showed impaired liver function, lipid disorders and damage from oxidative stress. The serum activity of XOD increased significantly from the 4th week and was markedly higher, compared with that in the control group, reaching a peak in the 12th week. The activity of PON1 was negatively correlated with that of XOD. Compared with the control cells, the activity of XOD and levels of free-fatty acids were significantly higher, and the activity of PON1 was significantly lower in the NAFLD L-02 cell model. All the above indicators were significantly improved by treatment with the antioxidant, alpha-lipoic acid. The activities of XOD and PON1 may be promising as markers in a noninvasive approach for detecting the severity of NAFLD clinically. alpha-lipoic acid had protective effects on the NAFLD rats, and the potential mechanism may be associated with the inhibition of oxidative stress and lipid peroxidation. PMID- 27959410 TI - Endoplasmic reticulum stress mediates sulforaphane-induced apoptosis of HepG2 human hepatocellular carcinoma cells. AB - Sulforaphane (SFN) is a naturally occurring chemopreventive agent, which effectively inhibits proliferation of HepG2 human hepatocellular carcinoma cells via mitochondria-mediated apoptosis. Endoplasmic reticulum stress is considered the most important cause of cell apoptosis; therefore, the present study aimed to determine whether the endoplasmic reticulum pathway was involved in SFN-induced apoptosis of HepG2 cells. An MTT assay was used to detect the inhibitory effects of SFN on HepG2 cells. Fluorescence microscopy was used to observe the morphological changes in apoptotic cells, and western blot analysis was conducted to detect the expression of binding immunoglobulin protein (Bip)/glucose regulated protein 78 (GRP78), X-box binding protein-1 (XBP-1) and BH3 interacting domain death agonist (Bid). Furthermore, flow cytometry was used to determine the apoptotic rate of HepG2 cells, and the protein expression of C/EBP homologous protein (CHOP)/growth arrest- and DNA damage-inducible gene 153 (GADD153) and caspase-12 in HepG2 cells. The results indicated that SFN significantly inhibited the proliferation of HepG2 cells; the half maximal inhibitory concentration values were 32.03+/-0.96, 20.90+/-1.96 and 13.87+/-0.44 umol/l, following treatment with SFN for 24, 48 and 72 h, respectively. Following 48 h of SFN treatment (10, 20 and 40 umol/l), the apoptotic rates of HepG2 cells were 31.8, 61.3 and 77.1%, respectively. Furthermore, after 48 h of exposure to SFN, the cells presented typical morphological alterations of apoptosis, as detected under fluorescence microscopy. Treatment with SFN for 48 h also significantly upregulated the protein expression levels of Bip/GRP78, XBP-1, caspase-12, CHOP/GADD153 and Bid in HepG2 cells. In conclusion, endoplasmic reticulum stress may be considered the most important mechanism underlying SFN-induced apoptosis in HepG2 cells. PMID- 27959411 TI - Novel copper complexes as potential proteasome inhibitors for cancer treatment (Review). AB - The use of metal complexes in the pharmaceutical industry has recently increased and as a result, novel metal-based complexes have initiated an interest as potential anticancer agents. Copper (Cu), which is an essential trace element in all living organisms, is important in maintaining the function of numerous proteins and enzymes. It has recently been demonstrated that Cu complexes may be used as tumor-specific proteasome inhibitors and apoptosis inducers, by targeting the ubiquitin-proteasome pathway (UPP). Cu complexes have demonstrated promising results in preclinical studies. The UPP is important in controlling the expression, activity and location of various proteins. Therefore, selective proteasome inhibition and apoptotic induction in cancer cells have been regarded as potential anticancer strategies. The present short review discusses recent progress in the development of Cu complexes, including clioquinol, dithiocarbamates and Schiff bases, as proteasome inhibitors for cancer treatment. A discussion of recent research regarding the understanding of metal inhibitors based on Cu and ligand platforms is presented. PMID- 27959409 TI - Galectin-3 inhibition ameliorates hypoxia-induced pulmonary artery hypertension. AB - Galectin-3 (Gal-3) is a beta-galactoside-binding lectin, which is important in inflammation, fibrosis and heart failure. The present study aimed to investigate the role and mechanism of Gal-3 in hypoxia-induced pulmonary arterial hypertension (PAH). Male C57BL/6J and Gal-3-/- mice were exposed to hypoxia, then the right ventricular systolic pressure (RVSP) and Fulton's index were measured, and Gal-3 mRNA and protein expression in the pulmonary arteries was analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting. Compared with the control, hypoxia increased the mRNA and protein expression levels of Gal-3 in wild type murine pulmonary arteries. Gal-3 deletion reduced the hypoxia-induced upregulation of RVSP and Fulton's index. Furthermore, human pulmonary arterial endothelial cells (HPAECs) and human pulmonary arterial smooth muscle cells (HPASMCs) were stimulated by hypoxia in vitro, and Gal-3 expression was inhibited by small interfering RNA. The inflammatory response of HPAECs, and the proliferation and cell cycle distribution of HPASMCs was also analyzed. Gal-3 inhibition alleviated the hypoxia-induced inflammatory response in HPAECs, including tumor necrosis factor-alpha and interleukin-1 secretion, expression of intercellular adhesion molecule-1 and adhesion of THP-1 monocytes. Gal-3 inhibition also reduced hypoxia-induced proliferation of HPASMCs, partially by reducing cyclin D1 expression and increasing p27 expression. Furthermore, Gal 3 inhibition suppressed HPASMC switching from a 'contractile' to a 'synthetic' phenotype. In conclusion, Gal-3 serves a fundamental role in hypoxia-induced PAH, and inhibition of Gal-3 may represent a novel therapeutic target for the treatment of hypoxia-induced PAH. PMID- 27959412 TI - Clinical diagnosis and mutation analysis of a Chinese family with Camurati Engelmann disease. AB - Camurati-Engelmann disease (CED) is a rare autosomal dominant bone disorder caused by a mutation in transforming growth factor beta1 (TGFbeta1). The present study aimed to identify a Chinese family with suspected CED based on the clinical symptoms, including pain in extremities, waddling gait, muscle weakness, cortical thickening of the diaphysis of the long bones, and sclerosis of the skull, facial bone, and pelvis. Molecular analysis revealed the presence of the p.Glu169Lys (E169K) mutation in exon 2 of TGFbeta1 in patients when compared with the controls. Therefore, the Chinese family was diagnosed with CED due to the presence of the E169K mutation. The present study emphasized the importance of clinical and genetic evidence for the diagnosis of CED. The data presented in the present study are of significance to clinicians, as well as genetic counselors, in the prenatal screening of CED. PMID- 27959413 TI - 17alpha-hydroxylase/17,20-lyase deficiency in congenital adrenal hyperplasia: A case report. AB - Congenital adrenal hyperplasia (CAH) is a rare autosomal recessive disorder caused by mutations in the cytochrome P450 family 17 subfamily A member 1 (CYP17A1) gene located on chromosome 10q24.3, which leads to a deficiency in 17alpha-hydroxylase/17,20-lyase. The disorder is characterized by low blood levels of estrogens, androgens and cortisol, which leads to a compensatory increase in adrenocorticotropic hormone levels that stimulate the production of mineralocorticoid precursors. This subsequently leads to hypertension, hypokalemia, primary amenorrhea and sexual infantilism. Over 90 distinct genetic lesions have been identified in patients with this disorder. The prevalence of common mutation of CYP17A1 gene differs among ethnic groups. Treatment of this disorder involves replacement of glucocorticoids and sex steroids. Estrogen alone is prescribed for patients who are biologically male with 17alpha-hydroxylase deficiencies that identify as female. However, genetically female patients may receive estrogen and progesterone supplementation. In the present study, a 17 year-old female with 17alpha-hydroxylase/17,20-lyase deficiency that presented with primary amenorrhea and sexual infantilism and no hypertension, was examined. The karyotype of the patient was 46, XX, and genetic analysis revealed the presence of a compound heterozygous mutation in exons 6 and 8, leading to the complete absence of 17alpha-hydroxylase/17,20-lyase activity. The patient was treated with prednisolone and ethinyl estradiol. In addition, a summary of the recent literature regarding CAH is presented. PMID- 27959414 TI - IL-17 contributed to the neuropathic pain following peripheral nerve injury by promoting astrocyte proliferation and secretion of proinflammatory cytokines. AB - Central neuroinflammation is important in the pathophysiological processes of neuropathic pain following peripheral nerve injury. Recently, interleukin-17 (IL 17) has been detected in different inflammatory conditions of the central nervous system and contributes to neuropathic pain associated with multiple sclerosis, experimental autoimmune encephalomyelitis. The present study, based on the rat model of spinal nerve ligation, analyzed the infiltration of cluster of differentiation (CD)4+ T cells and the expression of IL-17 in the spinal cord during the maintenance phase of neuropathic pain, and investigated central inflammatory reaction and astrocyte activation. The results demonstrated that the infiltrated CD4+ T cells in the spinal cord increased in the rat model of spinal nerve ligation, and immunofluorescence staining demonstrated that the CD4+/IL-17+ cells were located at superficial laminae of spinal dorsal horn. This was accompanied by significant upregulation of IL-17. Furthermore, the mRNA expression levels of IL-1beta and IL-6 were also significantly enhanced in model rats compared with the sham and control groups in the spinal dorsal horn. In vitro, the proliferation ability and secretion of proinflammatory cytokines notably increased in the IL-17-stimulated astrocytes. Results from the present study indicate that IL-17 may contribute to neuropathic pain by promoting the proliferation of astrocytes and secretion of proinflammatory cytokines in spinal nerve ligation-induced neuropathic pain. PMID- 27959415 TI - Promoter methylation attenuates SHP1 expression and function in patients with primary central nervous system lymphoma. AB - The Src homology region 2 domain-containing phosphatase-1 (SHP1) is a critical negative regulator involved in the JAK/STAT signaling pathway. The SHP1 gene has been proposed as a candidate tumor suppressor in solid and hematological malignancies and promoter methylation is an important biological process in controlling tumorigenesis. However, the detailed roles of SHP1 promoter methylation in the pathogenesis of primary central nervous system lymphoma (PCNSL) is largely unknown. In the present study, we evaluated the correlation between SHP1 expression and promoter methylation in patients with PCNSL. Thirty three patients with PCNSL were included. We evaluated SHP1 protein expression levels by immunohistochemistry and the SHP1 promoter methylation profile by pyrosequencing analysis. For cases (n=8) with a good yield of total protein, SHP1 phosphorylation (pSHP1) and STAT3 protein expression levels were further analyzed by western blot analysis to uncover the molecular impact of SHP1 promoter methylation on downstream signaling pathways. In this study, a lower expression of SHP1 protein level was observed in 16/33 cases (48.5%) of PCNSL. SHP1 promoter methylation was predominant in 29/33 cases (87.9%) with a mean methylation level of 31.7+/-36.5%. The mean methylation level of the SHP1 promoter was significantly elevated in patients with a lower SHP1 protein expression, compared with those showing a higher SHP1 protein expression (50.3+/-38.9 vs. 14.2+/ 24.0%, p=0.004). Further analysis showed that SHP1 protein expression was significantly decreased in patients with a higher SHP1 promoter methylation status (p=0.001), and such attenuation was correlated with a downregulation of pSHP1 (p=0.005) and an upregulation of STAT3 protein expression (p=0.020). Our data demonstrated that epigenetic alterations in the promoter region downregulated SHP1 expression in PCNSL patients. SHP1 promoter methylation was correlated with tyrosine phosphorylation and activation of transcription factor STAT3, which may contribute to the pathogenesis of PCNSL. Therapeutical regimens with epigenetic modifiers may be a potential option for patients with PCNSL. PMID- 27959417 TI - Apigenin induces both intrinsic and extrinsic pathways of apoptosis in human colon carcinoma HCT-116 cells. AB - Apigenin is one of the plant-originated flavones with anticancer activities. In this study, apigenin was assessed for its in vitro effects on a human colon carcinoma line (HCT-116 cells) in terms of anti-proliferation, cell cycle progression arrest, apoptosis and intracellular reactive oxygen species (ROS) generation, and then outlined its possible apoptotic mechanism for the cells. Apigenin exerted cytotoxic effect on the cells via inhibiting cell growth in a dose-time-dependent manner and causing morphological changes, arrested cell cycle progression at G0/G1 phase, and decreased mitochondrial membrane potential of the treated cells. Apigenin increased respective ROS generation and Ca2+ release and thereby, caused ER stress in the treated cells. Apigenin shows apoptosis induction towards the cells, resulting in enhanced portion of apoptotic cells. A mechanism involved ROS generation and endoplasmic reticulum stress was outlined for the apigenin-mediated apoptosis via both intrinsic mitochondrial and extrinsic pathways, based on the assayed mRNA and protein expression levels in the cells. With this mechanism, apigenin resulted in the HCT-116 cells with enhanced intracellular ROS generation and Ca2+ release together with damaged mitochondrial membrane, and upregulated protein expression of CHOP, DR5, cleaved BID, Bax, cytochrome c, cleaved caspase-3, cleaved caspase-8 and cleaved caspase 9, which triggered apoptosis of the cells. PMID- 27959416 TI - MicroRNA-1271 inhibits proliferation and promotes apoptosis of multiple myeloma cells through inhibiting smoothened-mediated Hedgehog signaling pathway. AB - MicroRNAs (miRNAs) have emerged as important regulators in multiple myeloma (MM). miR-1271 is a tumor suppressor in many cancer types. However, the biological role of miR-1271 in MM remains unclear. In the present study, we elucidated the biological role of miR-1271 in MM. Results showed that miR-1271 was significantly decreased in primary MM cells from MM patients and MM cell lines. Overexpression of miR-1271 inhibited proliferation and promoted apoptosis of MM cells. Conversely, suppression of miR-1271 showed the opposite effect. Bioinformatics algorithm analysis predicted that smoothened (SMO), the activator of Hedgehog (HH) signaling pathway, was a direct target of miR-1271 that was experimentally verified by a dual-luciferase reporter assay. Furthermore, overexpression of miR 1271 inhibited SMO expression and HH signaling pathway. Conversely, the restoration of SMO expression markedly abolished the effect of miR-1271 overexpression on cell proliferation, apoptosis and HH signaling pathway in MM cells. Taken together, the present study suggests that miR-1271 functions as a tumor suppressor that inhibits proliferation and promotes apoptosis of MM cells through inhibiting SMO-mediated HH signaling pathway. This finding implies that miR-1271 is a potential therapeutic target for the treatment of MM. PMID- 27959418 TI - CXCL7 promotes proliferation and invasion of cholangiocarcinoma cells. AB - CXCL7 is an important chemoattractant cytokine, which signals through binding to its receptor CXCR2. Recent studies have demonstrated that the CXCL7/CXCR2 signaling plays a promoting role in several common malignancies, including lung, renal, colon, and breast cancer. However, the regulatory role of CXCL7, in cholangiocarcinoma, as well as the underlying mechanism, has not been previously reported. Herein, we found more positive expression of CXCL7 in cholangiocarcinoma tissues compared to adjacent non-tumor tissues. High CXCL7 expression was significantly correlated with poor differentiation, lymph node metastasis, vascular invasion and advanced clinical stage, but was not associated with age, gender, or tumor size. Besides, the expression of CXCL7 was significantly associated with the Ki67 expression, but not associated with CA199, AFP, or P53 expression in cholangiocarcinoma. Moreover, the overall survival of cholangiocarcinoma patients with high CXCL7 expression was significantly shorter than those with low CXCL7 expression. In vitro study indicated that CXCL7 and CXCR2 were also positively expressed in several common cholangiocarcinoma cell lines, including HuCCT1, HuH28, QBC939, EGI-1, OZ and WITT. SiRNA-induced inhibition of CXCL7 significantly reduced the proliferation and invasion of QBC939 cells. On the contrary, overexpression of CXCL7 markedly promoted these malignant phenotypes of QBC939 cells. Of note, the conditioned medium of CXCL7 overexpresing human hepatic stellate cells could also promote the proliferation and invasion of QBC939 cells, suggesting that CXCL7 may also play an oncogenic role in cholangiocarcinoma in a paracrine-dependent manner, not only in an autocrine-dependent manner. Molecular assay data suggested that the AKT signaling pathway was involved in the CXCL7-mediated malignant phenotypes of QBC939 cells. In summary, our study suggests that CXCL7 plays a promoting role in regulating the growth and metastasis of cholangiocarcinoma. PMID- 27959419 TI - Antimicrobial resistance development following surgical site infections. AB - Surgical site infections (SSIs) determine an increase in hospitalization time and antibiotic therapy costs. The aim of this study was to identify the germs involved in SSIs in patients from the Clinical Emergency County Hospital of Craiova (SCJUC) and to assess their resistance to antimicrobials, with comparisons between surgical wards and the intensive care unit (ICU). The biological samples were subjected to classical bacteriological diagnostics. Antibiotic resistance was tested by disc diffusion. We used hierarchical clustering as a method to group the isolates based upon the antibiotic resistance profile. The most prevalent bacterial species isolated were Staphylococcus aureus (S. aureus; 50.72%), followed by Escherichia coli (E. coli; 17.22%) and Pseudomonas aeruginosa; 10.05%). In addition, at lower percentages, we isolated glucose-non-fermenting, Gram-negative bacteria and other Enterobacteriaceae. The antibiotic resistance varied greatly between species; the most resistant were the non-fermenting Gram-negative rods. E. coli exhibited lower resistance to third generation cephalosporins, quinolones and carbapenems. By contrast, Klebsiella was resistant to many cephalosporins and penicillins, and to a certain extent to carbapenems due to carbapenemase production. The non-fermenting bacteria were highly resistant to antibiotics, but were generally sensitive to colistin. S. aureus was resistant to ceftriaxone (100%), penicillin (91.36%), amoxicillin/clavulanate (87.50%), amikacin (80.00%) and was sensitive to levofloxacin, doxycycline, gentamycin, tigecycline and teicoplanin. The Enterobacteriaceae resistance was only slightly higher in the ICU, particularly to carbapenems (imipenem, 31.20% in the ICU vs. 14.30% in the surgical wards; risk ratio = 2.182). As regards Staphylococcus species, but for non-fermenting bacteria, even if the median was almost the same, the antibiotic resistance index values were confined to the upper limit in the ICU. The data gathered from this study may help infection control teams to establish effective guidelines for antibiotic therapies in various surgical procedures, in order to minimize the risk of developing SSIs by the efficient application of the anti-infection armamentarium. PMID- 27959420 TI - DEK protein overexpression predicts poor prognosis in pancreatic ductal adenocarcinoma. AB - DEK, a transcription factor, is involved in mRNA splicing, transcriptional control, cell division and differentiation. Recent studies suggest that DEK overexpression can promote tumorigenesis in a wide range of cancer cell types. However, little is known concerning the status of DEK in pancreatic ductal adenocarcinoma (PDAC). Based on the microarray data from Gene Expression Omnibus (GEO), the expression levels of DEK mRNA in PDAC tissues were significantly higher than levels in the adjacent non-tumor tissues. To explore the clinical features of DEK overexpression in PDAC, 87 PDAC and 52 normal pancreas tissues were selected for immunoenzyme staining of the DEK protein. Localization of the DEK protein was detected in PANC-1 pancreatic cancer cells using immunofluorescence (IF) staining. The correlations between DEK overexpression and the clinical features of PDAC were evaluated using the Chi-squared (chi2) and Fisher's exact tests. The survival rates were calculated by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazard models. The expression levels of DEK mRNA in PDAC tissues were significantly higher than that in the adjacent non tumor tissues. The DEK protein showed a primarily nuclear staining pattern in PDAC. The positive rate of the DEK protein was 52.9% (46/87) in PDAC, which was significantly higher than that in the adjacent normal pancreatic tissues (7.7%, 4/52). DEK overexpression in PDAC was correlated with tumor size, histological grade, tumor-node-metastasis (TNM) stage and overall survival (OS) rates. In addition, multivariate analysis demonstrated that DEK overexpression was an independent prognostic factor along with histological grade and TNM stage in patients with PDAC. In conclusion, DEK overexpression is associated with PDAC progression and may be a potential biomarker for poor prognostic evaluation in PDAC. PMID- 27959421 TI - Advances in the targeting of HIF-1alpha and future therapeutic strategies for glioblastoma multiforme (Review). AB - Cell metabolism can be reprogrammed by tissue hypoxia leading to cell transformation and glioblastoma multiforme (GBM) progression. In response to hypoxia, GBM cells are able to express a transcription factor called hypoxia inducible factor-1 (HIF-1). HIF-1 belongs to a family of heterodimeric proteins that includes HIF-1alpha and HIF-1beta subunits. HIF-1alpha has been reported to play a pivotal role in GBM development and progression. In the present review, we discuss the role of HIF-1alpha in glucose uptake, cancer proliferation, cell mobility and chemoresistance in GBM. Evidence from previous studies indicates that HIF-1alpha regulates angiogenesis, metabolic and transcriptional signaling pathways. Examples of such are the EGFR, PI3K/Akt and MAPK/ERK pathways. It affects cell migration and invasion by regulating glucose metabolism and growth in GBM cells. The present review focuses on the strategies through which to target HIF-1alpha and the related downstream genes highlighting their regulatory roles in angiogenesis, apoptosis, migration and glucose metabolism for the development of future GBM therapeutics. Combined treatment with inhibitors of HIF 1alpha and glycolysis may enhance antitumor effects in clinical settings. PMID- 27959422 TI - Luteolin suppresses the metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via downregulation of beta-catenin expression. AB - The metastasis of breast cancer is associated with dismal prognosis and high mortality due to the lack of effective treatment. Luteolin, a natural flavonoid compound, has been shown to exert antitumor activity in various types of cancers. However, the effects and mechanisms of luteolin on the metastasis of triple negative breast cancer (TNBC) remain elusive. In the present study, we found that pretreatment of highly metastatic TNBC cell lines with luteolin dose-dependently inhibited cell migration and invasion, and reversed epithelial-mesenchymal transition (EMT) as determined by altered morphological characteristics, downregulated epithelial markers and upregulated mesenchymal markers, and inhibited EMT-related transcription factors. In an in vivo metastasis experiment using a xenograft model, luteolin markedly inhibited lung metastases of breast cancer and the expression of EMT molecules vimentin and Slug in primary tumor tissues. Notably, luteolin also suppressed the expression of beta-catenin mRNA and protein in vitro and in vivo. Furthermore, overexpression of beta-catenin by adenoviruses blocked these benefits of luteolin on invasion and metastases of breast cancer. In conclusion, all these results indicated that luteolin effectively suppressed metastases of breast cancer by reversing EMT, which may be mediated by downregulation of beta-catenin. PMID- 27959423 TI - Comparative analysis of hepatocellular carcinoma and cirrhosis gene expression profiles. AB - Gene expression data of hepatocellular carcinoma (HCC) was compared with that of cirrhosis (C) to identify critical genes in HCC. A total of five gene expression data sets were downloaded from Gene Expression Omnibus. HCC and healthy samples were combined as dataset HCC, whereas cirrhosis samples were included in dataset C. A network was constructed for dataset HCC with the package R for performing Weighted Gene Co-expression Network Analysis. Modules were identified by cluster analysis with the packages flashClust and dynamicTreeCut. Hub genes were screened out by calculating connectivity. Functional annotations were assigned to the hub genes using the Database for Annotation, Visualization and Integration Discovery, and functional annotation networks were visualized with Cytoscape. Following the exclusion of outlier samples, 394 HCC samples and 47 healthy samples were included in dataset HCC and 233 cirrhosis samples were included in dataset C. A total of 6 modules were identified in the weighted gene co-expression network of dataset HCC (blue, brown, turquoise, green, red and yellow). Modules blue, brown and turquoise had high preservation whereas module yellow exhibited the lowest preservation. These modules were associated with transcription, mitosis, cation transportation, cation homeostasis, secretion and regulation of cyclase activity. Various hub genes of module yellow were cytokines, including chemokine (C-C motif) ligand 22 and interleukin-19, which may be important in the development of HCC. Gene expression profiles of HCC were compared with those of cirrhosis and numerous critical genes were identified, which may contribute to the progression of HCC. Further studies on these genes may improve the understanding of HCC pathogenesis. PMID- 27959424 TI - EphA4 may contribute to microvessel remodeling in the hippocampal CA1 and CA3 areas in a mouse model of temporal lobe epilepsy. AB - Unclustered and pre-clustered ephrin-A5-Fc have identical anti-epileptic effects in the dentate gyrus of hippocampus in a mouse model of temporal lobe epilepsy (TLE), and act through alleviating ephrin receptor A4 (EphA4)-mediated neurogenesis and angiogenesis. However, the effects of ephrin-A5-Fcs on EphA4 and angiogenesis in Cornu Ammonis (CA)1 and CA3 areas remain unclear. In the present study, male C57BL/6 mice underwent pilocarpine-induced TLE. The expression of EphA4 and ephrin-A5 proteins was analyzed by immunohistochemistry, and the mean density and diameter of platelet endothelial cell adhesion molecule-1-labeled microvessels in CA1 and CA3 were calculated in the absence or presence of two types of ephrin-A5-Fc intrahippocampal infusion. Microvessels perpendicular to the pyramidal cell layer decreased; however, microvessels that traversed the layer increased, and became distorted and fragmented. The mean densities and diameters of microvessels gradually increased and remained greater than those in the control group at 56 days post-status epilepticus (SE). The upregulation of EphA4 and ephrin-A5 proteins began at 7 days and was maintained until 28 days, subsequently decreasing slightly at 56 days post-SE. Blockade of EphA4 by unclustered-ephrin-A5-Fc effected a reduction in the mean density and mean diameter of microvessels in the CA1 and CA3 areas; conversely, activation of EphA4 by clustered-ephrin-A5-Fc induced an increase in these values. Ephrin-A5 ligand binding to EphA4 receptor may contribute to angiogenesis during epileptogenesis in the hippocampal CA1 and CA3 areas. PMID- 27959425 TI - Inhibition of casein kinase 2 prevents growth of human osteosarcoma. AB - High-dose chemotherapy and surgical treatment have improved the prognosis of osteosarcoma. However, more than 20% of patients with osteosarcoma still have a poor prognosis. We investigated the expression and function of casein kinase 2 (CK2) in osteosarcoma growth. We then examined the effects of CX-4945, a CK2 inhibitor, on osteosarcoma growth in vitro and in vivo to apply our findings to the clinical setting. We examined the expression of CK2alpha and CK2beta by western blot analysis, and performed WST-1 assays using CK2alpha and CK2beta siRNA or CX-4945. Flow cytometry and western blot analyses were performed to evaluate apoptotic cell death. Xenograft models were used to examine the effect of CX-4945 in vivo. Western blot analysis revealed upregulation of CK2alpha and CK2beta in human osteosarcoma cell lines compared with human osteoblast cells or mesenchymal stem cells. WST assay showed that knockdown of CK2alpha or CK2beta by siRNA inhibited the proliferation of human osteosarcoma cells. Treatment with 3 uM of CX-4945 inhibited osteosarcoma cell proliferation; however, the same concentration of CX-4945 did not affect the proliferation of human mesenchymal stem cells. Additionally, treatment with CX-4945 inhibited the proliferation of human osteosarcoma cells in a dose-dependent manner. Western blot and flow cytometry analyses showed that treatment with CX-4945 promoted apoptotic death of osteosarcoma cells. The xenograft model showed that treatment with CX-4945 significantly prevented osteosarcoma growth in vivo compared with control vehicle treatment. Our findings indicate that CK2 may be an attractive therapeutic target for treating osteosarcoma. PMID- 27959426 TI - 17beta-estradiol-induced growth of triple-negative breast cancer cells is prevented by the reduction of GPER expression after treatment with gefitinib. AB - Triple-negative breast cancers (TNBCs) are neither susceptible to endocrine therapy due to a lack of estrogen receptor alpha expression nor trastuzumab. TNBCs frequently overexpress epidermal growth factor receptor (EGFR) and membrane bound estrogen receptor, GPER. To a certain extent the growth of TNBCs is stimulated by 17beta-estradiol via GPER. We analyzed whether inhibition of EGFR by gefitinib reduces the expression of GPER and subsequent signal transduction in TNBC cells. Dependence of proliferation on 17beta-estradiol was determined using Alamar Blue assay. Expression of GPR30 and activation of c-src, EGFR and cAMP responsive element binding (CREB) protein by 17beta-estradiol was analyzed by western blotting. Expression of c-fos, cyclin D1 and aromatase was determined using RT-PCR. Gefitinib reduced GPER expression concentration- and time dependently. In HCC70 cells, GPER expression was reduced to 15+/-11% (p<0.05) after treatment with 200 nM gefitinib for four days, and in HCC1806 cells GPER expression was reduced to 39+/-5% (p<0.01) of the control. 17beta-estradiol significantly increased the percentage of HCC1806 cells within 7 days to 145+/ 29% of the control (HCC70, 110+/-8%). This increase in cell growth was completely prevented in both TNBC cell lines after GPR30 expression was downregulated by treatment with 200 nM gefitinib. In HCC1806 cells, activation of c-src was increased by 17beta-estradiol to 350+/-50% (p<0.01), and gefitinib reduced src activation to 110%. Similar results were obtained in the HCC70 cells. Phosphorylation of EGFR increased to 240+/-40% (p<0.05) in the HCC1806 cells treated with 17beta-estradiol (HCC70, 147+/-25%). Gefitinib completely prevented this activation. Phosphorylation of CREB and induction of c-fos, cyclin D1 and aromatase expression by 17beta-estradiol were all prevented by gefitinib. These experiments conclusively show that reduction of GPER expression is a promising therapeutic approach for TNBC. PMID- 27959428 TI - Expression pattern of DKK3, dickkopf WNT signaling pathway inhibitor 3, in the malignant progression of oral submucous fibrosis. AB - Oral squamous cell carcinoma (OSCC) is a common malignant neoplasm of the head and neck. Oral submucous fibrosis (OSF) is one of its pre-cancerous lesions; however, the key molecular events in the tumorigenesis of OSF remain elusive. Dickkopf WNT signaling pathway inhibitor 3 (DKK3) is one of the Wnt antagonists, and its downregulation and methylation have been reported in multiple malignancies, while no report of its expression in the carcinogenesis of OSF exists. In the present study, we investigated DKK3 expression at the protein and mRNA levels by immunochemical staining and semi-quantitative RT-PCR in normal oral, OSF and OSCC tissues. We found that DKK3 was readily expressed in normal oral mucous tissues, but was gradually increased in early, moderately advanced and advanced OSF tissues, and strongly expressed in OSCC tissues. DKK3 was localized in the cytoplasm during OSF progression. A rare mutation of DKK3 was observed in OSCC, along with increased copy numbers. Furthermore, through analysis of its co-expressed genes, DDK3 may deregulate Wnt signaling, p53 signaling, apoptosis, Ca2+ signaling and mitochondrial signaling pathways in OSCC pathogenesis. Thus, our results demonstrated that DKK3 is upregulated in the carcinogenesis of OSF, due to gain of copy number, which could be a potential tumor marker for the early detection of OSCC. PMID- 27959427 TI - Inhibiting the cytoplasmic location of HMGB1 reverses cisplatin resistance in human cervical cancer cells. AB - Cervical cancer is the fourth most common malignancy in women worldwide, and resistance to chemotherapy drugs is the biggest obstacle in the treatment of cervical cancers. In the present study, the molecular mechanisms underlying cisplatin resistance in human cervical cancer cells were investigated. When human cervical cancer cells were treated with 10 ug/ml of cisplatin for 24 and 48 h, high mobility group box 1 (HMGB1) protein expression levels significantly increased in a time-dependent manner. Comparisons between cisplatin-sensitive HeLa cells and cisplatin-resistant HeLa/DDP cells revealed higher levels of HMGB1 in HeLa/DDP cells than in HeLa cells. Additionally, the half maximal inhibitory concentration (IC50) value for cisplatin in HeLa/DDP cells was 5.3-fold that in HeLa cells. Analysis of the distribution of cellular components revealed that HMGB1 translocation from the nucleus to cytoplasm contributed to cisplatin resistance. This was further confirmed by demonstration that ethyl pyruvate treatment suppressed the cytoplasmic translocation of HMGB1, resulting in inhibition of HeLa cell proliferation. Furthermore, endogenous HMGB1 was inhibited with HMGB1-specific short hairpin (sh)RNA, and MTT assay results showed that interference with HMGB1 expression reduced cell viability and potentially reversed cisplatin resistance in HeLa cells. Transfection with HMGB1 shRNA was demonstrated to induce cell apoptosis in HeLa cells, as detected by FACS analysis. In addition, administration of recombinant HMGB1 protein in HeLa cells promoted cell autophagy, mediated by the phosphorylation of extracellular signal regulated kinase 1/2. Thus, cytoplasmic HMGB1 translocation and HMGB1-induced cell autophagy are proposed to contribute to cisplatin resistance by inhibiting apoptosis of cervical cancer cells. HMGB1 could, therefore, represent a novel therapeutic target for, and a diagnostic marker of, chemotherapy resistant cervical cancers. PMID- 27959429 TI - MicroRNA-194 suppresses prostate cancer migration and invasion by downregulating human nuclear distribution protein. AB - Human NudC nuclear distribution protein (hNUDC) is differentially expressed between normal and cancer cells. Based on its marked altered expression and its roles in modulating cell division, cytokineses and migration, a detailed understanding of the mechanisms regulating hNUDC expression in cancer cells is critical. In this study, we identified miR-194 as a downstream target of hNUDC and linked its expression to reduced metastatic capacity and tumorigenicity of prostate cancer (PCa) cells. Using miRNA target prediction programs, hNUDC mRNA was found to contain a potential binding site for miR-194 within its 3'UTR. A Reporter assay confirmed that post-transcriptional regulation of hNUDC was dependent on the miR-194 binding site. Forced expression of miR-194 in PCa cell lines, PC-3 and DU-145, led to a decrease in the mRNA and protein levels of hNUDC. Overexpression of miR-194 in these cells inhibited cell migration and invasion, and induced multinucleated cells. Our data showed that hNUDC knockdown by siRNA significantly reduced the migration and invasion in the PC-3 and DU-145 cells, phenocopying the results of miR-194 overexpression. Furthermore, lentivirus-mediated stable expression of miR-194 in PCa cells reduced the ability of colony formation as detected by a soft agar assay and exhibited significantly less tumorigenic ability in vivo. Our results suggest a novel role for miR-194 in effectively controlling cell metastatic processes in PCa cells via the regulation of hNUDC expression. PMID- 27959430 TI - Oxymatrine inhibits the migration of human colorectal carcinoma RKO cells via inhibition of PAI-1 and the TGF-beta1/Smad signaling pathway. AB - Transforming growth factor-beta1 (TGF-beta1) signaling has been shown to play a critical role in the development of epithelial-mesenchymal transition (EMT). PAI 1 is one of the most important target genes in the TGF-beta/Smad signaling pathway, which can hinder the degradation of ECM composition and may promote cell invasion and migration. Oxymatrine (OM) is an alkaloid extracted from the Chinese herb Sophora flavescens Ait and has been demonstrated to inhibit the growth of various types of cancer cells including colorectal cancer. However, the anticancer effect of OM in colorectal cancer remains unclear. In the present study, we detected the expression of E-cadherin, alpha-SMA, FN, TGF-beta1, PAI-1, Smad4, pP38 and pSmad2 in FHC, RKO and OM-treated RKO cells. We also detected pSmad2 and PAI-1 in RKO cells following the addition of SB203580 (a p38 MAPK inhibitor). The results showed that E-cadherin expression in RKO cells was significantly decreased, while PAI-1, TGF-beta1, alpha-SMA, FN, Smad4, pSmad2 and pP38 expression levels were significantly increased in the RKO cells compared to levels in the FHC cells, which was almost completely reversed by OM. OM alleviated EMT induced in colorectal cancer via inhibition of TGF-beta1/Smad signaling pathway activation by reducing P38-dependent increased expression of PAI-1. Hence, OM could be a novel therapeutic agent for colorectal cancer. PMID- 27959431 TI - BMP signaling pathways affect differently migration and invasion of esophageal squamous cancer cells. AB - Bone morphogenetic proteins (BMPs) are broadly involved in normal embryo development and abnormal pathological process such as cancer. The complexity and diversity of BMPs and their signaling pathways impose quite different or even conflicting effects on clinical traits of tumors. The aim of the present study was to investigate whether different BMPs, including BMP2, BMP4, BMP6 and BMP7, influence esophageal squamous cancer cell (ESCC) growth, invasion and metastasis. BMP6 and type I receptor ALK2 and type II receptor BMPRII, ActRIIA and ActRIIB were expressed in all ESCC cell lines. In addition, adenovirus-mediated BMP overexpression did not affect ECA-109 cell growth. BMP6/7 overexpression increased ECA-109 cell invasion and metastasis, activated SMAD1/5/8 signal pathway and induced downstream gene ID1 expression. While BMP2/4 overexpression reduced ECA-109 cell invasion and metastasis and obviously promoted ERK1/2, P-38 and JNK activation with weak SMAD1/5/8 phosphorylation. When BMP6/7 favorite type I receptor ALK2 or type II receptor BMPRII was interfered with by dominant negative mutation, BMP6/7-induced invasion and metastasis augmentation disappeared. Further investigation on clinical ESCC samples and non-tumorous adjacent tissue found that tumors with triple-positive BMP6, ALK2 and BMPRII had deeper growth than tumors with only BMP6 expression. These results suggested that different BMPs distinctly affected esophageal squamous cancer cell invasion and metastasis by employing different signal pathways. PMID- 27959432 TI - Bone marrow-derived mesenchymal stem cells modified with IGFBP-3 inhibit the proliferation of pulmonary artery smooth muscle cells. AB - Pulmonary arterial hypertension (PAH) is a common clinical cardiovascular disease, leading to the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and endothelial cells, and is associated with a high mortality rate. Recently, stem- and progenitor cell-mediated gene therapies have provided a novel approach for the treatment of PAH. However, the function of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) modified with the insulin-like growth factor binding protein-3 (IGFBP-3) gene in the regulation of PAH is not yet fully understood. In this study, we explored the biological role of IGFBP-3 modified hBM-MSCs in the proliferation of human PASMCs (hPASMCs), and also investigated the potential underlying molecular mechanisms. Our results revealed that IGFBP-3-modified hBM-MSCs inhibited the proliferation of angiotensin II stimulated hPASMCs following co-culture on cell culture inserts. In addition, total DNA synthesis and the protein levels of hPASMCs in co-culture were decreased. Moreover, the IGFBP-3-modified hBM-MSCs promoted apoptosis and downregulated the expression of B-cell lymphoma-2 (Bcl-2), but increased the expression of Bcl-2 associated X protein (Bax) in hPASMCs. Furthermore, the IGFBP 3-modified hBM-MSCs significantly induced a phenotypic change in the hPASMCs from the synthetic to the contractile phenotype in co-culture. Importantly, the levels of several related proteins in the hPASMCs, including phosphorylated (p-)insulin receptor substrate-1 (p-IRS-1), phosphoinositide 3-kinase (p-PI3K), serine/threonine-protein kinase (p-Akt), mitogen-activated protein kinase (p p38), p-Jun N-terminal kinase (p-JNK) and extracellular signal-regulated kinase (p-ERK), were markedly decreased by the IGFBP-3-modified hBM-MSCs following co culture. Taken together, our findings suggest that IGFBP-3-modified hBM-MSCs inhibit the proliferation and promote the apoptosis of hPASMCs, and promote the swithc to a contractile phenotype in more effectively than wild-type hBM-MSCs, possibly through the activation of the PI3K/Akt and Ras-mitogen-activated protein kinase (MAPK) signaling pathways. The findings of our study suggest that IGFBP-3 modified hBM-MSCs may be a promising therapeutic strategy for the treatment of PAH. PMID- 27959433 TI - Effect of RGD coupled MDA-7/IL-24 on apoptosis induction in a hepatocellular carcinoma cell line. AB - The melanoma differentiation-associated gene-7 (MDA-7) gene, also termed interleukin-24 (IL-24), is a tumor suppressor gene that induces apoptosis in a broad scope of malignant neoplastic cells. The apoptosis induction capacity of the MDA-7/IL-24 gene is partially associated with adhering to cognate receptors. The current study aimed to enhance the antitumor effect of IL-24. The intrinsic signal sequence of IL-24 replaced with a fused artificial signal (secrecon)-RGD4C sequence and its impact was evaluated in HepG2 cells. The modified SP.RGD.IL-24 and native IL-24 cDNA sequences were cloned into the pcDNA3.1 expression vector. Subsequently, the expression level, secretion efficacy and targeting propensity of the modified SP.RGD.IL-24 product compared with normal IL-24 by were determined by enzyme-linked immunosorbent assay. The constructs were then transfected into HepG2 and LX-2 cells as tumor and normal hepatic cell lines, respectively. The expression level of the pro-apoptotic DNA damage inducible transcript 3 (Gadd153) and BCL2 associated X apoptosis regulator (Bax) genes in the different groups were compared by reverse transcription-quantitative polymerase chain reaction. Additionally, the rate of apoptosis induction of modified and intact IL-24 sequences was compared by flow cytometry analysis of cells following their propidium iodide/annexin V staining. SP.RGD-IL-24 protein was expressed and secreted in a similar manner to native IL-24, however, the modified SP.RGD.IL-24 adhered to tumor cells more efficiently than IL-24 (P<0.05). SP.RGD.IL-24 significantly induced upregulation of Gadd153 and Bax in HepG2 cells compared with native IL-24 (P<0.05). However, neither had a significant impact on the expression level of pro-apoptotic genes in LX-2 cells. Flow cytometry analysis also indicated that modified SP.RGD.IL-24 induced apoptosis more than native IL-24 in HepG2 cells (P<0.05). In conclusion, the novel generated RGD-coupled IL-24 construct exhibited sufficient anticancer activity compared with the native IL-24. The results of the current study provide novel insights for the future of cytokine targeting and indicates its potential capacity as a valuable candidate for gene therapy methods. PMID- 27959434 TI - Age-associated expression of erythropoietin and its receptor in rat spiral ganglion neurons and its association with neuronal apoptosis and hearing alterations. AB - The present study aimed to determine the expression of erythropoietin (EPO) and the EPO receptor (EPOR) in spiral ganglion neurons (SGNs) in the inner ear of rats of various ages, and the associated neuronal apoptosis and hearing alterations. A total of 15 healthy rats (n=30 ears), were divided into three groups: i) A nominated infant group at post-natal day (PND) 12-14, ii) an adult group at PND 60 and iii) a 3-year postnatal aged group. Auditory brainstem response (ABR) measurements were performed on all rats. EPO and EPOR expression in the inner ear was detected by immunohistochemistry. In situ terminal deoxynucleotidyl transferase dUTP nick end labeling assays were performed to detect the apoptosis of SGNs. The average hearing thresholds of the ABR (decibels above normal hearing level) were 5.625+/-4.955 in the infant, 15.000+/-8.498 in the adult and 23.500+/-13.134 in the aged groups. Hearing thresholds for aged and adult rats increased significantly compared with infant rats. However, the difference in latencies of peak I was not significant (P>0.05). EPO in SGNs was detected during different developmental periods without significant alterations, but were reduced compared with Corti's organ or the stria vascularis. EPOR expression increased significantly from infant to adult stage, and this increased expression was maintained in the aged group. An age-associated increase in the apoptosis of SGNs was detected in all three groups (P=0.0347). The potential neuroprotective effects of EPO in SGNs may not be revealed during the aging process under natural conditions, and may be associated with spontaneous neuronal apoptosis and consequently, hearing diminution. However, the age-associated increase in EPOR in SGNs may exert a role in neuroprotection when necessary, for example in presbycusis. PMID- 27959435 TI - Oridonin promotes G2/M arrest in A549 cells by facilitating ATM activation. AB - Previous studies have demonstrated that oridonin, a tetracyclic diterpenoid compound extracted from Rabdosia rubescens, inhibits proliferation and induces apoptosis in several tumor cell lines. However, the mechanism by which oridonin inhibits the cell cycle remains poorly understood. In the present study, possible mechanisms by which oridonin affects cell cycle progression were explored in A549 lung cancer cells. Flow cytometry analysis indicated that oridonin inhibited the proliferation of A549 cells by inducing G2/M cell cycle arrest in a dose dependent manner. Western blot analysis revealed that in oridonin treated cells, phosphorylated (p-)ATM serine/threonine kinase (S1981), p-checkpoint kinase 2 (CHK2) (T68), p-p53, and phosphorylated H2A histone family member X protein levels were visibly increased, indicating that oridonin promoted G2/M arrest in A549 cells through the ATM-p53-CHK2 pathway. This data suggests that oridonin promotes G2/M arrest in A549 cells by facilitating ATM activation, which is likely a common mechanism in other tumor cell types when using this drug for cancer treatment. PMID- 27959436 TI - Novel CC2D2A compound heterozygous mutations cause Joubert syndrome. AB - Joubert syndrome (JS) is an autosomal recessive disorder, which is characterized by hypotonia, ataxia, psychomotor delay, and variable occurrences of oculomotor apraxia and neonatal breathing abnormalities. JS is clinically and genetically heterogeneous. The present study investigated a typical JS family. The 'molar tooth sign' was observed in the proband through magnetic resonance imaging. Other symptoms of JS include cerebellar vermis hypoplasia/dysplasia, oculomotor apraxia and intellectual disability. High-throughput sequencing revealed that JS was caused by coiled-coil and C2 domain containing 2A (CC2D2A) compound heterozygous mutations. One CC2D2A allele was affected with a missense mutation, c.2581G>A, which led to a p.Asp861Asn amino acid replacement. The other allele was affected with a c.2848C>T nonsense mutation, which resulted in a truncated CC2D2A protein (p.Arg950Ter). Both of these alterations are novel. Further investigation indicated that the proband's father was the c.2581G>A carrier, whereas the mother was the c.2848C>T carrier. These results indicated that JS in the proband was caused by novel compound heterozygous mutations in CC2D2A, which were inherited from both parents. These findings may be used to establish prenatal molecular diagnostic criteria, which may be beneficial in future pregnancies. PMID- 27959437 TI - Traditional medicine, Sobokchukeo-Tang, modulates the inflammatory response in adipocytes and macrophages. AB - Sobokchukeo-Tang (ST) is a well-known formula that is used for treating primary dysmenorrhea caused by blood stasis syndrome (BSS) in Korea and China. The current study investigated the anti-inflammatory and anti-adipogenesis effects of ST on adipocytes and macrophages. The anti-inflammatory efficacy of ST was evaluated in RAW 264.7 cells and differentiated THP-1 cells. To induce inflammation, the cells were treated with lipopolysaccharide (LPS; 1 ug/ml). Following the induction of inflammation, the levels of proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in the cell supernatant were detected using enzyme-linked immunosorbent assay. 3T3-L1 preadipocytes differentiated into adipocytes in response to insulin, isobutyl-1 methylxanthine and dexamethasone (MDI). To confirm the anti-adipogenesis efficacy of ST, we investigated Oil Red O staining was performed, triglyceride (TG) and leptin secretion were measured, and the protein expression of lipid metabolism associated factors was determined. ST significantly inhibited TNF-alpha and IL-6 production in the LPS-treated RAW 264.7 cells compared with LPS stimulation alone. In addition, the concentrations of IL-6 and TNF-alpha were significantly inhibited by ST in LPS-treated THP-1 cells. Lipid accumulation was reduced by ST, similarly to the positive control treatment, SB203580. In the ST-treated group, the TG and leptin concentrations were inhibited by up to 50 and 83%, respectively, compared with MDI induction only. The ST-treated group reduced the protein expression of peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer-binding protein alpha compared with MDI induction only. The results of the present study demonstrated that ST exerts anti-inflammatory effects on LPS-treated mouse and human macrophage cell lines. ST inhibited adipogenesis in MDI-induced 3T3-L1 adipocytes, as indicated by the significant reduction in TG and leptin concentrations without cytotoxicity. Thus, ST may be useful as a therapeutic agent for preventing lipid-associated diseases, including obesity and atherosclerosis. PMID- 27959439 TI - Alanine and arginine rich domain containing protein, Aard, is directly regulated by androgen receptor in mouse Sertoli cells. AB - Alanine and arginine rich domain containing protein (Aard) is specifically expressed in Sertoli cells (SCs) of mouse testis and the expression increases in an age-dependent manner. A number of previous studies have indicated that androgen and androgen receptor (AR) signaling pathways are particularly important for spermatogenesis in mouse SCs, however, the association between Aard and AR remain to be elucidated. The present study identified Aard as a gene that is directly regulated by AR in mouse SCs, which is important in spermatogenesis. The expression of AARD was significantly downregulated in the testes of Sertoli cell selective AR knockout mice compared with wild-type mice as analyzed by western blotting and immunofluorescence analyses. Quantitative polymerase chain reaction and western blotting indicated that AARD was predominantly expressed in adult mouse testis and its expression was increased in an age-dependent manner. In addition, AARD expression was upregulated by testosterone in primary SCs in vitro, which was confirmed by bioinformatics analysis and a dual-luciferase reporter assay. Finally, chromatin immunoprecipitation and electrophoretic mobility shift assays indicated that the ligand-bound AR activated Aard transcription via directly binding to the androgen-responsive element of the Aard promoter. To the best of our knowledge, the present study is the first to document that Aard is directly regulated by AR in mouse Sertoli cells. PMID- 27959438 TI - Dexmedetomidine attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress, mitochondrial dysfunction and apoptosis in rats. AB - Previous studies have identified that dexmedetomidine (DEX) treatment can ameliorate the acute lung injury (ALI) induced by lipopolysaccharide and ischemia reperfusion. However, the molecular mechanisms by which DEX ameliorates lung injury remain unclear. The present study investigated whether DEX, which has been reported to exert effects on oxidative stress, mitochondrial permeability transition pores and apoptosis in other disease types, can exert protective effects in lipopolysaccharide (LPS)-induced ALI by inhibiting oxidative stress, mitochondrial dysfunction and mitochondrial-dependent apoptosis. It was revealed that LPS-challenged rats exhibited significant lung injury, characterized by the deterioration of histopathology, vascular hyperpermeability, wet-to-dry weight ratio and oxygenation index (PaO2/FIO2), which was attenuated by DEX treatment. DEX treatment inhibited LPS-induced mitochondrial dysfunction, as evidenced by alleviating the cellular ATP and mitochondrial membrane potential in vitro. In addition, DEX treatment markedly prevented the LPS-induced mitochondrial dependent apoptotic pathway in vitro (increases of cell apoptotic rate, cytosolic cytochrome c, and caspase 3 activity) and in vivo (increases of |terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells, cleaved caspase 3, Bax upregulation and Bcl-2 downregulation). Furthermore, DEX treatment markedly attenuated LPS-induced oxidative stress, as evidenced by downregulation of cellular reactive oxygen species in vitro and lipid peroxides in serum. Collectively, the present results demonstrated that DEX ameliorates LPS-induced ALI by reducing oxidative stress, mitochondrial dysfunction and mitochondrial dependent apoptosis. PMID- 27959440 TI - kappa-carrageenan-derived pentasaccharide attenuates Abeta25-35-induced apoptosis in SH-SY5Y cells via suppression of the JNK signaling pathway. AB - beta-amyloid (Abeta)-mediated neuronal apoptosis is an important pathological feature of Alzheimer's disease (AD). Inhibiting apoptosis induced by Abeta may lead to the development of a potential therapeutic target for AD treatment. kappa carrageenan-derived pentasaccharide (KCP) extracted from marine red algae is involved in a variety of biological activities and may be an effective in the treatment of AD. The present study aimed to investigate the neuroprotective effect of KCP against Abeta25-35-induced neurotoxicity in SH-SY5Y cells, and to examine the potential underlying mechanisms. The results of the present study revealed that pretreatment with KCP significantly attenuated Abeta25-35-induced loss of cell viability and apoptosis, as evaluated by MTT assays and annexin V/propidium iodide staining, respectively, in a dose-dependent manner. Furthermore, KCP downregulated the protein expression levels of Abeta25-35 induced cleavage caspase 3 by inhibiting the overactivation of the JNK signaling pathway. The results of the present study indicated that KCP attenuated Abeta25 35-induced neuroblastoma cell cytotoxicity, suggesting that KCP may be a potential therapeutic agent for the treatment of AD. PMID- 27959441 TI - Protective effects of Cambodian medicinal plants on tert-butyl hydroperoxide induced hepatotoxicity via Nrf2-mediated heme oxygenase-1. AB - Liver diseases are considered to be primary contributors to morbidity and mortality rates in humans. Oxidative stress is critical in liver injury, and oxidant-induced liver injury may be caused by toxins, including tert-butyl hydroperoxide (t-BHP). The present study investigated the hepatoprotective activities of 64 crude ethanol extracts of Cambodian medicinal plants against t BHP-induced cytotoxicity in human liver-derived HepG2 cells, and assessed their cytoprotective mechanism pertaining to the expression of heme oxygenase (HO)-1 and nuclear factor E2-related factor 2 (Nrf2). Protective effects in HepG2 cells were determined by MTT assay. Protein expression levels of HO-1 and Nrf2 were determined by western blotting and mRNA expression levels were determined by reverse transcription-quantitative polymerase chain reaction. Of the 64 extracts, 19 extracts exhibited high hepatoprotective activities: Ampelocissus martini, Bauhinia bracteata, Bombax ceiba, Borassus flabellifer, Cardiospermum halicacabum, Cayratia trifolia, Cinnamomum caryophyllus, Cyperus rotundus, Dasymaschalon lomentaceum, Ficus benjamina, Mangifera duperreana, Morinda citrifolia, Pandanus humilis, Peliosanthes weberi, Phyllanthus emblica, Quisqualis indica, Smilax glabra, Tinospora crispa and Willughbeia cochinchinensis, with half maximal effective concentrations ranging between 59.23 and 157.80 ug/ml. Further investigations revealed that, of these 19 extracts, HO 1 and Nrf2 were expressed in P. weberi and T. crispa expressed in a dose dependent manner. In addition, the activities of reactive oxygen species were suppressed following treatment of these two extracts in t-BHP-induced HepG2 cells. These results indicated that, of the 64 Cambodian plants, P. weberi and T. crispa exhibited hepatoprotective effects on t-BHP-induced cytotoxicity in HepG2 cells, possibly by the induction of Nrf2-mediated expression of HO-1. Taken together, these results suggested that T. crispa or P. weberi may offer potential for therapeutic applications in liver disease characterized by oxidative stress. PMID- 27959442 TI - Lung cancer gene therapy: Transferrin and hyaluronic acid dual ligand-decorated novel lipid carriers for targeted gene delivery. AB - To achieve lung cancer gene therapy, nanocarriers decorated with different ligands were used. Surface decoration and nanoparticulate system will assist in targeting the gene to specific cells and tissues, such as cancers and diseased organs. The aim of this research was to develop a dual ligand-decorated nanocarriers, which could target the tumor cells through receptor-mediated pathways to increase the uptake of genetic materials. Transferrin (Tf) and hyaluronic (HA) containing polyethylene glycol-distearoylphosphatidylethanolamine (Tf-PEG-DSPE and HA-PEG-DSPE) ligands were synthesized. Novel Tf and HA ligand decorated, plasmid-enhanced green fluorescent protein loaded nanostructured lipid carriers (Tf/HA-pDNA NLC) was constructed. Physicochemical properties such as morphology, size, and zeta-potential as well as release properties were evaluated. The in vitro and in vivo gene transfection efficiency of Tf/HA-pDNA NLC was evaluated in lung adenocarcinoma A549 cells and lung cancer bearing animal models. Tf/HA-pDNA NLC displayed significantly higher transfection efficiency than undecorated DNA-NLCs and single ligand-decorated NLCs in vitro and in vivo. The newly constructed NLCs could successfully load gene; and Tf and HA functioned as excellent targeting ligands to improve the cell targeting ability of the gene-loaded nanocarriers. The resulting dual ligands decorated vectors could be a promising targeted gene delivery system for the lung cancer treatment. PMID- 27959443 TI - An epirubicin-peptide conjugate with anticancer activity is dependent upon the expression level of the surface transferrin receptor. AB - Epirubicin (EPI) is one of the most widely used anticarcinogens; however, serious side effects, including cardiomyopathy and congestive heart failure, limit its long-term administration. To overcome this problem, the HAIYPRH peptide ligand was used with EPI in the synthesis of a HAIYPRH-EPI conjugate. The anticancer activity and cellular uptake of the conjugate were measured and evaluated. The results of the present study indicated that the cytotoxicity of HAIYPRH-EPI was correlated with the expression of the cell surface transferrin receptor (TfR). The conjugate exerted high cytotoxicity and proapoptotic function when in an LN229 glioma cell line, which overexpresses surface TfR. It was hypothesized that transferrin (Tf) can promote cytotoxicity. Conversely, the conjugate exhibited very low cytotoxicity and proapoptotic function in a U87 glioma cell line, in which surface TfR expression was undetectable. In addition, fluorescence microscopy and flow cytometry methods were used to evaluate cellular uptake, and the results of these methods were consistent with the present hypotheses. The conjugate cellular uptake of the conjugate in LN229 cells was markedly higher compared with that in U87 cells, and it was hypothesized that Tf can enhance the uptake in LN229 cells. The cytotoxicity of HAIYPRH-EPI was dependent upon the expression of surface TfR. Considering that the majority of cancer cells have high rates of iron uptake and surface TfR is generally overexpressed on cancer cells, it was speculated by the authors that HAIYPRH-EPI may form part of an effective strategy for increasing the selectivity of EPI for cancer cells, as well as reducing its systemic toxicity. To confirm the hypothesis, the effects of HAIYPRH-EPI on non-cancerous cell lines were investigated. A future study will examine the side effects of HAIYPRH-EPI, using a suitable delivery system in an animal model. PMID- 27959444 TI - Gigantol attenuates the proliferation of human liver cancer HepG2 cells through the PI3K/Akt/NF-kappaB signaling pathway. AB - Gigantol is a phenolic substance extracted from plants in the genus Dendrobium and used in traditional Chinese medicine. In the present study, we aimed to investigate the growth inhibition and apoptotic effects of gigantol on human liver cancer cells through the PI3K/Akt/NF-kappaB signaling pathway. HepG2 cells were treated with different concentrations of gigantol (0-150 uM) for 12, 24 and 48 h. It was found that gigantol significantly inhibited the proliferation and induced apoptosis of the HepG2 cells. The results of fluorescence micrographs showed that a 48-h treatment with gigantol induced typical apoptotic morphological features, which were consistent with the flow cytometric analysis where 20% of apoptotic cells were detected in response to gigantol treatment. In addition, western blot analysis indicated that gigantol enhanced the activities of caspase-3, PARP and p53 and downregulated the expression of p-Akt/Akt. Collectively, the present data suggest that gigantol induces growth inhibition and apoptosis of HepG2 cells via the PI3K/Akt/NF-kappaB signaling pathway. PMID- 27959446 TI - The Met tyrosine kinase receptor as a therapeutic target and a potential cancer stem cell factor responsible for therapy resistance (Review). AB - The MET tyrosine kinase receptor plays an important role during tumor development and progression being responsible for proliferation, morphogenetic transformation, cell motility and invasiveness. High expression of the MET receptor has been shown to correlate with increased tumor growth and metastasis, poor prognosis and resistance to radiotherapy. Moreover, MET expression and activation has been shown to be associated with therapy resistance. The occurrence of resistance to targeted therapy might be related to the presence of cancer stem cells (CSCs). CSCs are a subpopulation of cells in the tumor that possess the ability of self-renewal, clonogenicity, radioresistance and self sustained protection from apoptosis. Recently, MET has been postulated as an essential factor supporting the functional stem cell phenotype in some tumors and as a CSC factor is believed to be responsible for therapy resistance. This review presents the results from recent studies identifying MET as a potential marker of CSCs and tumor initiating cells, demonstrating pivotal role of MET in supporting stem cell phenotype and indicating the role of MET in acquiring resistance to antitumor therapy. PMID- 27959445 TI - Delphinidin inhibits angiogenesis through the suppression of HIF-1alpha and VEGF expression in A549 lung cancer cells. AB - Delphinidin, a polyphenol that belongs to the group of anthocyanidins and is abundant in many pigmented fruits and vegetables, possesses important antioxidant, anti-inflammatory, anti-mutagenic and anticancer properties. In the present study, we investigated the inhibitory effects of delphinidin on vascular endothelial growth factor (VEGF) expression, an important factor involved in angiogenesis and tumor progression, in A549 human lung cancer cells. Delphinidin inhibited CoCl2- and epidermal growth factor (EGF)-induced VEGF mRNA expression and VEGF protein production. Delphinidin also decreased CoCl2- and EGF-stimulated expression of hypoxia-inducible factor (HIF)-1alpha, which is a transcription factor of VEGF. Delphinidin suppressed CoCl2- and EGF-induced hypoxia-response element (HRE) promoter activity, suggesting that the inhibitory effects of delphinidin on VEGF expression are caused by the suppression of the binding of HIF-1 to the HRE promoter. We also found that delphinidin specifically decreased the CoCl2- and EGF-induced HIF-1alpha protein expression by blocking the ERK and PI3K/Akt/mTOR/p70S6K signaling pathways, whereas the p38-mediated pathways were not involved. In animal models, EGF-induced new blood vessel formation was significantly inhibited by delphinidin. Therefore, our results indicate that delphinidin has a potentially new role in anti-angiogenic action by inhibiting HIF-1alpha and VEGF expression. PMID- 27959447 TI - Fibroblast growth factor 18 promotes proliferation and migration of H460 cells via the ERK and p38 signaling pathways. AB - Recently, fibroblast growth factor 18 (FGF18) expression was reported to be upregulated in colon cancer and ovarian cancer, and increased expression of FGF18 mRNA and protein is associated with tumor progression and poor overall survival in patients; however, its role in lung cancer remains to be explored. In the present study, the effect and underlying molecular mechanisms of FGF18 on H460 cells were investigated. Cell proliferation and cell cycle alterations were detected using a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and flow cytometry. A wound healing assay was conducted to detect cell migration. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to measure extracellular signal-regulated kinase (ERK), p38 and matrix metalloproteinase 26 (MMP26) expression. Knockdown of FGF18 using short interfering RNA (siRNA-FGF18) suppressed H460 cell proliferation, inhibited cell migration via the downregulation of MMP26 levels, with siRNA-FGF18 additionally inhibiting the ERK and p38 signaling pathway. The present study indicates that FGF18 serves an essential role in the growth and migration of non small cell lung cancer (NSCLC) cells by regulating the ERK, p38 signaling pathways and MMP26 protein levels, suggesting that FGF18 may be a potential molecular drug target for the treatment NSCLC. PMID- 27959448 TI - Bcl-2 overexpression contributes to laryngeal carcinoma cell survival by forming a complex with Hsp90beta. AB - Laryngeal carcinoma (LC) is one of the most common malignant tumors of all head and neck squamous cell carcinomas (HNSCCs). However, the molecular mechanism and genetic basis of the development of LC have not been fully elucidated. To explore the possible mechanism, targeted proteomic analysis was performed on Bcl-2 associated proteins from LC cells. According to our results, 35 proteins associated with Bcl-2 were identified and Hsp90beta was confirmed by co immunoprecipitation and western blot analysis. Protein-protein interaction (PPI) analysis indicated that Bcl-2-Hsp90beta interactions may be involved in the anti apoptotic progression of LC. Further results revealed that disruption of the Bcl 2-Hsp90beta interaction inhibited the anti-apoptotic ability of Bcl-2 and decreased the caspase activation in LC, which has broad implications for the better understanding of tumor formation, tumor cell survival and development of metastasis due to Bcl-2. Collectively, we report the mechanism by which Bcl-2 functions in LC as an anti-apoptotic factor in relation to its association with proteins and potentially identify a Bcl-2/Hsp90beta axis as a novel target for LC therapy. PMID- 27959449 TI - miR-204 regulates epithelial-mesenchymal transition by targeting SP1 in the tubular epithelial cells after acute kidney injury induced by ischemia reperfusion. AB - Acute kidney injury (AKI) is a disease where kidney function is lost almost instantaneously; it can develop very rapidly over few hours to maximum of few days. Despite the advent of technology, the clinical management against this disease is very poor, and most of the time it is life-threatening. AKI has been actively regulated by extracellular matrix proteins (ECM), however, its underlying mechanism of regulation during AKI progression is very poorly understood. In this study, we explored the integrated network of mRNA and microRNAs (miRNAs) that maintains the progression of ECM after induction of AKI by lethal ischemia. To identify key regulators of ECM, we screened large number of transcriptomes using laser capture microdissection (LCM) technique in addition to microarray and RT-qPCR. Our result clearly showed that 9 miRNAs including miR 21, miR-483, miR-5115, miR-204e, miR-128, miR-181c, miR-203, miR-204 and miR-204c were highly regulated, out of which miR-204 expression change (decrease) was most drastic during ischemia/reperfusion. Detail mechanistic study utilizing combined experimental and computational approach revealed that TGF-beta signaling pathway was potentially modulated by deregulated miRNA-204 through SP1, where the TGF beta signaling pathway plays a vital role in ECM regulation. Apart from targeting SP1 and antagonizing epithelial-mesenchymal transition (EMT) signaling our result also showed that miR-204 protects interstitial tissue of renal tubules from chronic fibrotic change. Altogether our study provides sufficient details of how miRNA mediated ECM regulation occur during AKI, which can be effectively utilized in future for better AKI management and diagnosis. PMID- 27959451 TI - ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1alpha. AB - Hepatocellular carcinoma (HCC) is the fifth most common solid cancer and the third most common cause of cancer-related mortality. HCC develops via a multistep process associated with genetic aberrations that facilitate HCC invasion and migration and promote metastasis. A growing body of evidence indicates that cancer stem cells (CSCs) are responsible for tumorigenesis, cancer cell invasion and metastasis. Despite the extremely small proportion of cancer cells represented by this subpopulation of HCC cells, CSCs play a key role in cancer metastasis and poor prognosis. ELK3 (Net/SAP-2/Erp) is a transcription factor that is activated by the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. It plays several important roles in various physiological processes, including cell migration, invasion, wound healing, angiogenesis and tumorigenesis. In the present study, we investigated the role of ELK3 in cancer cell invasion and metastasis in CD133+/CD44+ liver cancer stem cells (LCSCs). We isolated LCSCs expressing CD133 and CD44 from Huh7 HCC cells and evaluated their metastatic potential using invasion and migration assays. We found that CD133+/CD44+ cells had increased metastatic potential compared with non CD133+/CD44+ cells. We also demonstrated that ELK3 expression was upregulated in CD133+/CD44+ cells and that this aberration enhanced cell migration and invasion. In addition, we identified the molecular mechanism by which ELK3 promotes cancer cell migration and invasion. We found that silencing of ELK3 expression in CD133+/CD44+ LCSCs attenuated their metastatic potential by modulating the expression of heat shock-induced factor-1alpha (HIF-1alpha). Collectively, the results of the present study demonstrated that ELK3 overexpression promoted metastasis in CD133+/CD44+ cells by regulating HIF-1alpha expression and that silencing of ELK3 expression attenuated the metastatic potential of CD133+/CD44+ LCSCs. In conclusion, modulation of ELK3 expression may represent a novel therapeutic strategy for preventing HCC metastasis and invasion. PMID- 27959450 TI - Chemoradiotherapy and concurrent radiofrequency thermal therapy to treat primary rectal cancer and prediction of treatment responses. AB - The present study aimed to evaluate a previously reported predictive formula of output-limiting symptoms induced by radiofrequency (RF) to determine the efficacy of this neoadjuvant chemoradiation (NACR) and concurrent RF thermal therapy. The present study included 81 consecutive patients with confirmed diagnoses of rectal adenocarcinoma that was localized in the mid-low rectum (up to 12 cm from the anal verge) who received NACR [intensity-modulated radiotherapy (IMRT), 50 Gy/25 fractions, capecitabine 1,700 mg/m2/day for 5 days/week)] with concurrent thermal therapy (Thermotron-RF8, once a week for 5 weeks with 50 min irradiation). Patients with progressive disease (PD) did not receive RF outputs higher than the predicted value. Some patients who were predicted to receive more output in fact received more than the predicted output. In patients who were predicted to receive moderately higher outputs, 37.5% of the patients experienced pathological complete responses, which was the highest rate, while in those who did not receive more than the predicted output, 66.7% of the patients experienced PD, which was the highest rate in the present study. We speculate that RF thermal therapy may offset the chemoradiation effects in some patients. Adding thermal therapy as a multimodality therapy to NACR potentially affects patients with lower predicted outputs and actual observed outputs slightly higher than the predictive value. Our predictive equation for initial energy output, in which output-limiting symptoms can be used to predict treatment efficacy, consequently, can be used to decide whether to continue this treatment modality. PMID- 27959452 TI - Vitamin K4 inhibits the proliferation and induces apoptosis of U2OS osteosarcoma cells via mitochondrial dysfunction. AB - Vitamin K (VK) is a group of fat-soluble vitamins, which serve important roles in blood coagulation and bone metabolism. A recent study reported that several VK subtypes possess antitumor properties, however the antitumor effects of VK in osteosarcoma are unknown. The present study aimed to identify the antitumor effects of VK in osteosarcoma and the possible underlying mechanism of action. The effect of VK4 on cell viability was determined using a 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cellular and nuclear morphological changes were observed by phase contrast microscopy. Cell cycle analysis, apoptotic rate, mitochondrial membrane potential and levels of reactive oxygen species (ROS) were detected by flow cytometry. In vitro cancer cell migration activities were evaluated using a Wound healing assay and Transwell microplates. The results demonstrated that VK4 arrested the cells in S phase and induced apoptosis. Additional mechanistic studies indicated that the induction of apoptosis by VK4 was associated with the increased production of reactive oxygen species, dissipation of the mitochondrial membrane potential, decreased Bcl-2 family protein expression levels and activation of caspase-3. In conclusion, the results suggest that the sensitivity of U2OS osteosarcoma cells to VK4 may be as a result of mitochondrial dysfunction. As it is readily available for human consumption, VK4 may therefore present a novel therapeutic candidate for the treatment of patients with osteosarcoma. PMID- 27959453 TI - A novel therapy for ovarian cancer using real-time imaging. AB - The present study was designed to develop an activable, dual-targeted theranostic platform combining fluorescent and cytotoxic templates to provide a novel strategy for specific drug delivery and cellular imaging in ovarian cancer cells. Two compounds of a folic acid-prodrug-doxorubicin (Dox) scaffold were synthesized, and their antiproliferative activities were evaluated using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometric analysis. The process of drug release was investigated using fluorescence emission spectra assay and confocal laser scanning microscopy. The results showed that the synthesized compounds exhibited potent antitumor activities against ovarian cell lines. Among them, compound 1e exhibited the most potent activity demonstrating half maximal inhibitory concentration values of 0.85+/-0.10, 8.64+/ 0.37 and 0.81+/-0.03 uM against A2780, A2780/Dox and A2780/cisplatin cell lines. The fluorescence imaging of live cell lines also provided an easy and reliable method to monitor site-specific drug activities through turn-on systems induced by drug release. The results of the present study may assist in the treatment of ovarian cancer cells with strengthened efficiency and real-time imaging, which may be used as a multifunctional system for the optimization of anticancer drugs. PMID- 27959454 TI - Clinical significance of Wip1 overexpression and its association with the p38MAPK/p53/p16 pathway in NSCLC. AB - Wip1 is deregulated in numerous human malignancies. However, its roles in non small cell lung cancer (NSCLC) remain unclear. In the current study, the expression of Wip1 was investigated in NSCLC and its clinical significance was detected. Immunohistochemical staining was used to measure the expression of (wild-type p53 induced phosphatase 1) Wip1, p38 mitogen-activated protein kinase (MAPK), p53, p16 protein in a group of 60 NSCLC and 20 normal lung tissues. In addition, western blotting was performed to detect the Wip1 protein in fresh tissues. The correlations between clinical characteristics and Wip1 expression were analyzed using SPSS, version 16.0 software. The expression of Wip1 was positive in 63.3% (38/60) of NSCLC tissues, and in none of the normal lung tissues (0/20; P<0.01). In addition, Wip1 overexpression was significantly associated with tumor length and differentiation (P=0.008 and 0.03, respectively). The expression of Wip1 was negatively correlated with that of p38MAPK, p53 and p16 (r=-0.284, -0.352 and -0.348, respectively). The results of the current study demonstrated that Wip1 was frequently overexpressed in NSCLC, which may serve an essential role in the p38MAPK/p53/p16 signaling pathway. PMID- 27959457 TI - [Personality disorders, violence and criminal behaviour]. AB - Personality disorders, violence and criminal behaviour The importance of personality disorders for violent and criminal behaviour is illustrated by their high prevalence in prison populations. Especially antisocial personality disorder and antisocial personality traits are linked to violence. During diagnostic assessment of personality disorders, violence risk screening is recommended. Cognitive behaviour treatment focused on violent behaviour has some effect in criminal populations, but the antisocial personality traits are resistant to treatment. Evidence for pharmacological treatment of repetitive aggressive behaviour is weak. But, bensodiazepines seem to increase the risk of violent behaviour among patients with personality disorders. Antisocial personality traits diminish over time. This spontaneous decrease can be delayed by comorbidity such as other personality disorder, substance use disorder, psychosis and attention deficit disorders. Therefore it is recommended to actively treat these comorbid conditions. PMID- 27959458 TI - [Self-injurious behavior is common also without personality syndrome]. AB - Self-harm is prevalent in non-psychiatric populations as well as in psychiatric settings, and is common in patients with most psychiatric diagnoses. Persons with self-harm behaviour can be incorrectly diagnosed with borderline personality disorder. There is support for self-harm having an emotion regulating function. Most treatments for self-harm are lengthy and comprehensive and have been developed primarily for persons with borderline personality disorder. Emotion Regulation Group Therapy is an exception, and is given in the form of 14 sessions of group therapy. Persons who self-harm and do not fulfil formal criteria for having a borderline personality disorder are at risk for not receiving effective treatment for self-harm. PMID- 27959459 TI - [Compliance and patience is needed when meeting patients with personality disorder]. AB - Compliance and patience is needed when meeting patients with personality disorder To encounter patients with personality disorders in health care settings is often challenging. Most treatment studies published have included only patients with borderline personality disorder. Of evaluated psychological treatments in borderline personality disorder, dialectical behaviour therapy (DBT) has the strongest research support, followed by mentalization based therapy (MBT). Pharmacological treatment in personality disorders should focus on time-limited crisis intervention and treatment of comorbidity. There are few studies on inpatient care of persons with personality disorder. However, there are some interesting projects on brief self-directed inpatient stays as crisis intervention. There is a consensus to avoid long inpatient stays and coercive measures as far as possible. PMID- 27959455 TI - High expression of B23 is associated with tumorigenesis and poor prognosis in bladder urothelial carcinoma. AB - B23, a multifunctional nucleolar protein, is overexpressed in numerous cancers and is associated with tumorigenesis. However, the clinical significance and potential role of B23 in bladder urothelial carcinoma remains to be elucidated. The present study observed that the mRNA and protein expression levels of B23 were increased in bladder cancer cells and tissues. The overexpression of B23 contributed to tumorigenesis and was associated with poor prognosis in bladder cancer patients. Silencing of B23 by short hairpin RNA inhibited tumor cell growth and colony formation. In addition, knockdown of B23 suppressed the phosphorylation of extracellular signal-regulated kinase (ERK), resulting in the inactivation of the ERK signaling pathway. Therefore, the present study indicated that B23 promotes bladder cancer cell growth via activation of the ERK signaling pathway and is a novel potential biomarker for the diagnosis and prognosis of bladder cancer. PMID- 27959460 TI - [Personality disorders--description, definition and diagnosis]. AB - Personality disorders - description, definition and diagnosis Personality disorders are common, associated with a poor quality of life, functional limitations, worse health, and often remain undiagnosed. The aetiology is complex, with the influence of both genetic and environmental factors. A person centred approach based on empathic understanding is important for the diagnostic and therapeutic alliance. In case of conceivable comorbidity, the relative influence of all possible comorbid conditions shall be evaluated to avoid an excessive number of comorbid diagnoses. A detailed and carefully taken history is crucial for a valid diagnosis and for assessment of severity. PMID- 27959461 TI - [The patient you remember: often the one with personality syndrome]. PMID- 27959462 TI - [Neurobiological aspects of personality disorders and emotional instability]. AB - Neurobiological aspects of personality disorders and emotional instability ADHD and mental disorders encompassing emotional instability such as emotionally unstable personality disorder and antisocial personality disorder can potentially be explained by a suboptimal regulation of information processing in the brain. ADHD involves suboptimal function of non-emotional attentional regulatory processes and emotional instability involves suboptimal emotional regulation. A network including prefrontal areas, anterior cingulate cortex, basal ganglia and specific neuromodulatory systems such as the dopamine system are dysfunctional in both ADHD and emotional instability. One might suggest that a dimensional view better describes these mental states than categorical diagnoses. PMID- 27959463 TI - [A concern for everyone in health care]. PMID- 27959465 TI - ? PMID- 27959464 TI - [The new cancer drugs should be administered with individualized dosage]. PMID- 27959466 TI - [Work (dis)ability, psychiatry and society]. PMID- 27959468 TI - [It is still the case that only the parliament can revoke their own decisions] PMID- 27959467 TI - [A meeting can free health]. PMID- 27959469 TI - [Major flaws in palliative care]. PMID- 27959470 TI - Hypothesis testing of matrix graph model with application to brain connectivity analysis. AB - Brain connectivity analysis is now at the foreground of neuroscience research. A connectivity network is characterized by a graph, where nodes represent neural elements such as neurons and brain regions, and links represent statistical dependence that is often encoded in terms of partial correlation. Such a graph is inferred from the matrix-valued neuroimaging data such as electroencephalography and functional magnetic resonance imaging. There have been a good number of successful proposals for sparse precision matrix estimation under normal or matrix normal distribution; however, this family of solutions does not offer a direct statistical significance quantification for the estimated links. In this article, we adopt a matrix normal distribution framework and formulate the brain connectivity analysis as a precision matrix hypothesis testing problem. Based on the separable spatial-temporal dependence structure, we develop oracle and data driven procedures to test both the global hypothesis that all spatial locations are conditionally independent, and simultaneous tests for identifying conditional dependent spatial locations with false discovery rate control. Our theoretical results show that the data-driven procedures perform asymptotically as well as the oracle procedures and enjoy certain optimality properties. The empirical finite-sample performance of the proposed tests is studied via intensive simulations, and the new tests are applied on a real electroencephalography data analysis. PMID- 27959471 TI - Lumbar sympathectomy techniques for critical lower limb ischaemia due to non reconstructable peripheral arterial disease. AB - BACKGROUND: Critical lower limb ischaemia (CLI) is a manifestation of peripheral arterial disease (PAD) that is seen in patients with typical chronic ischaemic rest pain or patients with ischaemic skin lesions - ulcers or gangrene - for longer than 2 weeks. Critical lower limb ischaemia is the most severe form of PAD, and interventions to improve arterial perfusion become necessary. Although surgical bypass has been the gold standard for revascularisation, the extent or the site of disease may be such that the artery cannot be reconstructed or bypassed. These patients require other modalities of treatment, for example, vasodilatation by drugs or lumbar sympathectomy to relieve pain at rest and to avoid amputations. A systematic review of randomised controlled trials is required to evaluate the effects of lumbar sympathectomy in treating patients with CLI due to non-reconstructable PAD. OBJECTIVES: The objective of this review is to assess the effects of lumbar sympathectomy by open, laparoscopic and percutaneous methods compared with no treatment or compared with any other method of lumbar sympathectomy in patients with CLI due to non-reconstructable PAD. SEARCH METHODS: The Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (January 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 12). In addition, the CIS searched clinical trials databases for details of ongoing and unpublished studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any of the treatment modalities of lumbar sympathectomy, such as open, laparoscopic and chemical percutaneous methods, with no treatment or with any other method of lumbar sympathectomy for CLI due to non-reconstructable PAD were eligible. To decrease the bias of including participants that may be incorrectly diagnosed with CLI, review authors defined CLI as persistently recurring ischaemic rest pain requiring regular analgesia for more than two weeks, or ulceration or gangrene of the foot or toes, attributable to objectively proven arterial occlusive disease by measurement of ankle pressure of < 50 mmHg or toe pressure < 30 mmHg. We defined non-reconstructable PAD as a resting ankle brachial index (ABI) < 0.9 when no reasonable open surgical or endovascular revascularisation treatment option is available, as determined by individual trial vascular specialists. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies identified for potential inclusion in the review. We planned to conduct data collection and analysis in accordance with the Cochrane Handbook for Systematic Review of Interventions. MAIN RESULTS: We identified no studies that met the predefined inclusion criteria. To decrease the bias of including participants who may be incorrectly diagnosed with CLI, we based our inclusion criteria on objective tests, as described above. The randomised trials identified by the literature search were performed before such objective criteria for selection were applied and therefore were not eligible for inclusion in the review. AUTHORS' CONCLUSIONS: We identified no RCTs assessing effects of lumbar sympathectomy by open, laparoscopic and percutaneous methods compared with no treatment or compared with any other method of lumbar sympathectomy in patients with CLI due to non-reconstructable PAD. High-quality studies are needed. PMID- 27959473 TI - PSYCHOLOGY OF BOYS AT RISK: INDICATORS FROM 0-5. AB - In utero and during the first 5 years of life, boys face unique risks as a result of neurobiological and environmental factors. This introductory article to the Special Issue describes the background of this gender-specific inquiry and outlines some of those risks, drawing attention to the areas that will be covered in depth in the following contributions. We also describe the basis of this inquiry as the link between early life and the subsequent difficulties that adolescent boys and many young men face, and pay particular attention to the circumstances of young men of color and to the growing knowledge about the contributions of fathers to boys' development. PMID- 27959474 TI - Cyanuric Acid-Based Organocatalyst for Utilization of Carbon Dioxide at Atmospheric Pressure. AB - A organocatalytic system based on economical and readily available cyanuric acid has been developed for the synthesis of 2-oxazolidinones and quinazoline 2,4(1H,3H)-diones from propargylamines and 2-aminobenzonitriles under atmospheric pressure carbon dioxide. Notably, a low concentration of carbon dioxide in air was directly converted into 2-oxazolidinone in excellent yields without an external base. Through mechanistic investigation by in situ FTIR spectroscopy, cyanuric acid was demonstrated to be an efficient catalyst for carbon dioxide fixation. PMID- 27959472 TI - Polymer-based oral rehydration solution for treating acute watery diarrhoea. AB - BACKGROUND: Acute diarrhoea is one of the main causes of morbidity and mortality among children in low-income countries. Glucose-based oral rehydration solution (ORS) helps replace fluid and prevent further dehydration from acute diarrhoea. Since 2004, the World Health Organization (WHO) has recommended the osmolarity of less than 270 mOsm/L (ORS <= 270) versus greater than 310 mOsm/L formulation (ORS >= 310). Polymer-based ORS (for example, prepared using rice or wheat) slowly releases glucose and may be superior to glucose-based ORS. OBJECTIVES: To compare polymer-based oral rehydration solution (polymer-based ORS) with glucose-based oral rehydration solution (glucose-based ORS) for treating acute watery diarrhoea. SEARCH METHODS: We searched the following sources up to 5 September 2016: the Cochrane Infectious Diseases Group (CIDG) Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 9), MEDLINE (1966 to 5 September 2016), EMBASE (1974 to 5 September 2016), LILACS (1982 to 5 September 2016), and mRCT (2007 to 5 September 2016). We also contacted researchers, organizations, and pharmaceutical companies, and searched reference lists. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of people with acute watery diarrhoea (cholera and non-cholera associated) that compared polymer-based and glucose-based ORS (with identical electrolyte contents). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results and risk of bias, and extracted data. In multiple-treatment arms with two or more treatment groups, we combined outcomes as appropriate and compared collectively with the control group. MAIN RESULTS: Thirty-five trials that included 4284 participants met the inclusion criteria: 28 trials exclusively included children, five included adults, and two included both adults and children. Polymer-based ORS versus glucose-based ORS (osmolarity <= 270) Eight trials (752 participants) evaluated this comparison, and seven trials used rice as a polymer source. Polymer-based ORS may decrease mean stool output in the first 24 hours by 24 mL/kg (mean difference (MD) -24.60 mL/kg, 95% CI -40.69 to -8.51; one trial, 99 participants, low quality evidence). The average duration of diarrhoea may be reduced by eight hours (MD -8.24 hours, 95% CI -13.17 to -3.30; I2 statistic = 86%, five trials, 364 participants, low quality evidence) with polymer ORS but results are heterogeneous. Limited trials showed no observed difference in the risk of unscheduled use of intravenous fluid (RR 0.66, 95% CI 0.43 to 1.02; I2 statistic = 30%; four trials, 376 participants, very low quality evidence), vomiting (very low quality evidence), and hyponatraemia (very low quality evidence). Polymer-based ORS versus glucose-based ORS (osmolarity >= 310) Twenty-seven trials (3532 participants) evaluated this comparison using a variety of polymers. On average, polymer ORS may reduce the total stool output in the first 24 hours by around 65 mL/kg (MD -65.47 mL/kg, 95% CI -83.92 to -47.03; 16 trials, 1483 participants, low quality evidence), and may reduce the duration of diarrhoea by around eight hours (MD -8.57 hours; SD -13.17 to -4.03; 16 trials, 1137 participants, low quality evidence) with substantial heterogeneity. The proportion of participants that required intravenous hydration was low in most trials with fewer in the polymer ORS group (RR 0.75, 95% CI 0.57 to 0.98; 19 trials, 1877 participant, low quality evidence) . Subgroup analysis by type of pathogen suggested an effect on unscheduled intravenous fluid in those infected with mixed pathogens (RR 0.63, 95% CI 0.41 to 0.96; 11 trials, 928 participants, low quality evidence), but not in participants positive for Vibrio cholerae (RR 0.94, 95% CI 0.66 to 1.34; 7 trials, 535 participants, low quality evidence). No difference was observed in the number of patients who developed vomiting (RR 0.91, 95% CI 0.72 to 1.14; 10 trials, 584 participants, very low quality evidence), hyponatraemia (RR 1.82, 95% CI 0.52 to 6.44; 4 trials, 385 participants, very low quality evidence), hypokalaemia (RR 1.29, 95% CI 0.74 to 2.25; 2 trials, 260 participants, low quality evidence), or persistent diarrhoea (RR 1.28, 95% CI 0.68 to 2.41; 2 trials, 885 participants, very low quality evidence). AUTHORS' CONCLUSIONS: Polymer-based ORS shows advantages compared to glucose-based ORS (at >= 310 mOsm/L). Comparisons favoured polymer-based ORS over ORS <= 270 but analysis was underpowered. PMID- 27959475 TI - Color Fine-Tuning of Optical Materials Through Rational Design. AB - We report on the feasibility for color fine-tuning of optical materials using rational design principles based on chemical reasoning. For this purpose, a modular framework for the construction of symmetrical cap-linker-cap compounds, using triarylamine caps and oligothiophene linkers, is applied. The chosen structural scaffolds are heavily used in recent industrial applications and provide five possibilities for altering their electronic and steric properties: electron donor/acceptor groups, planarization/deplanarization, and modulation of the pi-conjugation length. Permutation of the used building blocks leads to a set of 54 different molecules, out of which 32 are synthesized and characterized in solution as well as in example fabricated OLED devices. This setup allows for color fine-tuning in the range of 412 nm to 540 nm with typical steps of 4 nm. In addition, to further benefit from the large experimental data set the spectroscopic results are used to benchmark quantum chemical computations, which show excellent agreement thus highlighting the potential of these calculations to guide future syntheses. PMID- 27959476 TI - Bogen's Critique of Linear-No-Threshold Default Assumptions. AB - In an article recently published in this journal, Bogen(1) concluded that an NRC committee's recommendations that default linear, nonthreshold (LNT) assumptions be applied to dose- response assessment for noncarcinogens and nonlinear mode of action carcinogens are not justified. Bogen criticized two arguments used by the committee for LNT: when any new dose adds to a background dose that explains background levels of risk (additivity to background or AB), or when there is substantial interindividual heterogeneity in susceptibility (SIH) in the exposed human population. Bogen showed by examples that SIH can be false. Herein is outlined a general proof that confirms Bogen's claim. However, it is also noted that SIH leads to a nonthreshold population distribution even if individual distributions all have thresholds, and that small changes to SIH assumptions can result in LNT. Bogen criticizes AB because it only applies when there is additivity to background, but offers no help in deciding when or how often AB holds. Bogen does not contradict the fact that AB can lead to LNT but notes that, even if low-dose linearity results, the response at higher doses may not be useful in predicting the amount of low-dose linearity. Although this is theoretically true, it seems reasonable to assume that generally there is some quantitative relationship between the low-dose slope and the slope suggested at higher doses. Several incorrect or misleading statements by Bogen are noted. PMID- 27959477 TI - A Case of Obsessive-Compulsive Disorder With Fear of Contamination of Percutaneous Endoscopic Gastrostomy Tube. PMID- 27959478 TI - Implementation Science Supports Core Clinical Competencies: An Overview and Clinical Example. AB - Objective: Instead of asking clinicians to work faster or longer to improve quality of care, implementation science provides another option. Implementation science is an emerging interdisciplinary field dedicated to studying how evidence based practice can be adopted into routine clinical care. This article summarizes principles and methods of implementation science, illustrates how they can be applied in a routine clinical setting, and highlights their importance to practicing clinicians as well as clinical trainees. Method: A hypothetical clinical case scenario is presented that explains how implementation science improves clinical practice. The case scenario is also embedded within a real world implementation study to improve metabolic monitoring for individuals prescribed antipsychotics. Results: Context, recipient, and innovation (ie, the evidence-based practice) factors affected improvement of metabolic monitoring. To address these factors, an external facilitator and a local quality improvement team developed an implementation plan involving a multicomponent implementation strategy that included education, performance reports, and clinician follow-up. The clinic remained compliant with recommended metabolic monitoring at 1-year follow up. Conclusions: Implementation science improves clinical practice by addressing context, recipient, and innovation factors and uses this information to develop and utilize specific strategies that improve clinical practice. It also enriches clinical training, aligning with core competencies by the Accreditation Council for Graduate Medical Education and American Boards of Medical Specialties. By learning how to change clinical practice through implementation strategies, clinicians are more able to adapt in complex systems of practice. PMID- 27959479 TI - What Would Block Grants or Limits on Per Capita Spending Mean for Medicaid? AB - Issue: President-elect Trump and some in Congress have called for establishing absolute limits on the federal government's spending on Medicaid, not only for the population covered through the Affordable Care Act's eligibility expansion but for the program overall. Such a change would effectively reverse a 50-year trend of expanding Medicaid in order to protect the most vulnerable Americans. Goal: To explore the two most common proposals for reengineering federal funding of Medicaid: block grants that set limits on total annual spending regardless of enrollment, and caps that limit average spending per enrollee. Methods: Review of existing policy proposals and other documents. Key findings and conclusions: Current proposals for dramatically reducing federal spending on Medicaid would achieve this goal by creating fixed-funding formulas divorced from the actual costs of providing care. As such, they would create funding gaps for states to either absorb or, more likely, offset through new limits placed on their programs. As a result, block-granting Medicaid or instituting "per capita caps" would most likely reduce the number of Americans eligible for Medicaid and narrow coverage for remaining enrollees. The latter approach would, however, allow for population growth, though its desirability to the new president and Congress is unclear. The full extent of funding and benefit reductions is as yet unknown. PMID- 27959480 TI - How High-Need Patients Experience Health Care in the United States. Findings from the 2016 Commonwealth Fund Survey of High-Need Patients. AB - Issue: Health care costs are highly concentrated among people with multiple chronic conditions, behavioral health problems, and those with physical limitations or disabilities. With a better understanding of these patients' challenges, health care systems and providers can address patients' complex social, behavioral, and medical needs more effectively and efficiently. Goal: To investigate how the challenges faced by this population affect their experiences with the health care system and examine potential opportunities for improvement. Methods: Analysis of the 2016 Commonwealth Fund Survey of High-Need Patients, June-September 2016. Key findings and conclusions: The health care system is currently failing to meet the complex needs of thesepatients. High-need patients have greater unmet behavioral health and social issues than do other adults and require greater support to help manage their complex medical and nonmedical requirements. Results indicate that with better access to care and good patient provider communication, high-need patients are less likely to delay essential care and less likely to go to the emergency department for nonurgent care, and thus less likely to accrue avoidable costs. For health systems to improve outcomes and lower costs, they must assess patients' comprehensive needs, increase access to care, and improve how they communicate with patients. PMID- 27959481 TI - Stereotactic radiosurgery. PMID- 27959482 TI - Exercise testing. PMID- 27959483 TI - Pediatric rehabilitation medicine. PMID- 27959484 TI - Transjugular intrahepatic portosystemic shunt. PMID- 27959485 TI - Unquantified Benefits and the Problem of Regulation Under Uncertainty. PMID- 27959486 TI - "Unique Identities and Vulnerabilities": the Case for Transgender Identity as a Basis for Asylum. PMID- 27959487 TI - Improving the Compatibility of Donor Polymers in Efficient Ternary Organic Solar Cells via Post-Additive Soaking Treatment. AB - In dual-donor ternary organic solar cells, the compatibility between the donor polymers plays important roles to control the conformational change and govern the photophysical behavior in the blend films. Here, we apply a post-additive soaking (PAS) approach to reconstruct the morphology in a ternary organic photovoltaic BHJ of PTB7-Th: PCDTBT: PC71BM. The PAS-treated device has a maximum power conversion efficiency (PCE) of about 8.7% in this ternary system. From the analyses of GIWAXS and GISAXS, the superior device performance is attributed to the favorable nanomorphology with optimum crystallinity of PTB7-Th and good intermixing of PCDTBT with PTB7-Th:PC71BM, leading to improved charge transport in the vertical direction. AFM and TRPL measurements clearly demonstrate PAS treated film envisages a homogeneous distribution of smaller PC71BM aggregates to facilitate the exciton dissociation and carrier extraction at the interface. The increased PCE ascribed to not only the enhancement of absorption and nonradiative Forster resonance energy transfer (FRET) between two donors (PCDTBT and PTB7-Th) but also the formation of a bicontinuous interpenetrating network of PC71BM. PMID- 27959488 TI - Versatile Functionalization of Poly(methacrylic acid) Brushes with Series of Proteolytically Cleavable Peptides for Highly Sensitive Protease Assay. AB - The development of new materials for fast and sensitive protease assay is in demand for timely diagnosis of diseases, such as cardiovascular disease, cancers, and Alzheimer disease. Herein, poly(methacrylic acid) (PMAA) brushes were synthesized from the surfaces of silica nanoparticles via surface-initiated atom transfer radical polymerization (ATRP), and functionalized with series of proteolytically cleavable peptides for highly sensitive protease assay. Upon the proteolytic cleavage of the peptides, a short peptide fragment with fluorescent tag (GGK-FITC) is released to the solution, which can be easily detected with a benchtop fluorescence microscope. The grafting densities of PMAA brushes and peptides can be readily tuned by controlling the monomer concentrations of sodium methacrylate in the ATRP reaction. Because of the three-dimensional architecture of PMAA brushes, the loading amount of peptides can reach 21.4% of the total weight of functionalized silica particles (22.4 peptides/nm2), which is much higher than direct immobilization on silica nanoparticles without polymer brushes. Because of the high loading density of peptides, the limit of detection (LOD) of trypsin can reach 1.4 pM in buffer solution or 2.6 nM in nondiluted serum. By rational design of peptide substrates, the peptide-functionalized PMAA brushes can be readily expanded to detect other proteases, such as matrix metalloproteinase-2 (MMP-2), a virtual biomarker for many cancers, with an LOD of 1.1 pM. The proteolytically cleavable peptide-functionalized PMAA brushes offer a starting point for fast and sensitive protease assay. PMID- 27959489 TI - Silicon-Rich Silicon Carbide Hole-Selective Rear Contacts for Crystalline-Silicon Based Solar Cells. AB - The use of passivating contacts compatible with typical homojunction thermal processes is one of the most promising approaches to realizing high-efficiency silicon solar cells. In this work, we investigate an alternative rear-passivating contact targeting facile implementation to industrial p-type solar cells. The contact structure consists of a chemically grown thin silicon oxide layer, which is capped with a boron-doped silicon-rich silicon carbide [SiCx(p)] layer and then annealed at 800-900 degrees C. Transmission electron microscopy reveals that the thin chemical oxide layer disappears upon thermal annealing up to 900 degrees C, leading to degraded surface passivation. We interpret this in terms of a chemical reaction between carbon atoms in the SiCx(p) layer and the adjacent chemical oxide layer. To prevent this reaction, an intrinsic silicon interlayer was introduced between the chemical oxide and the SiCx(p) layer. We show that this intrinsic silicon interlayer is beneficial for surface passivation. Optimized passivation is obtained with a 10-nm-thick intrinsic silicon interlayer, yielding an emitter saturation current density of 17 fA cm-2 on p type wafers, which translates into an implied open-circuit voltage of 708 mV. The potential of the developed contact at the rear side is further investigated by realizing a proof-of-concept hybrid solar cell, featuring a heterojunction front side contact made of intrinsic amorphous silicon and phosphorus-doped amorphous silicon. Even though the presented cells are limited by front-side reflection and front-side parasitic absorption, the obtained cell with a Voc of 694.7 mV, a FF of 79.1%, and an efficiency of 20.44% demonstrates the potential of the p+/p wafer full-side-passivated rear-side scheme shown here. PMID- 27959491 TI - Discovery of Inhibitors of MicroRNA-21 Processing Using Small Molecule Microarrays. AB - The identification of small molecules that bind to and perturb the function of microRNAs is an attractive approach for the treatment for microRNA-associated pathologies. However, there are only a few small molecules known to interact directly with microRNAs. Here, we report the use of a small molecule microarray (SMM) screening approach to identify low molecular weight compounds that directly bind to a pre-miR-21 hairpin. Compounds identified using this approach exhibit good affinity for the RNA (ranging from 0.8-2.0 MUM) and are not composed of a polycationic scaffold. Several of the highest affinity compounds inhibit Dicer mediated processing, while in-line probing experiments indicate that the compounds bind to the apical loop of the hairpin, proximal to the Dicer site. This work provides evidence that small molecules can be developed to bind directly to and inhibit miR-21. PMID- 27959490 TI - Chemical Biology of N5-Substituted Formamidopyrimidine DNA Adducts. AB - DNA nucleobases are the prime targets for chemical modifications by endogenous and exogenous electrophiles. Alkylation of the N7 position of guanine and adenine in DNA triggers base-catalyzed imidazole ring opening and the formation of N5 substituted formamidopyrimidine (N5-R-FAPy) lesions. Me-FAPy-dG adducts induced by exposure to methylating agents and AFB-FAPy-dG lesions formed by aflatoxin B1 have been shown to persist in cells and to contribute to toxicity and mutagenicity. In contrast, the biological outcomes of other N5-substituted FAPy lesions have not been fully elucidated. To enable their structural and biological evaluation, N5-R-FAPy adducts must be site-specifically incorporated into synthetic DNA strands using phosphoramidite building blocks, which can be complicated by their unusual structural complexity. N5-R-FAPy exist as a mixture of rotamers and can undergo isomerization between alpha, beta anomers and furanose-pyranose forms. In this Perspective, we will discuss the main types of N5-R-FAPy adducts and summarize the strategies for their synthesis and structural elucidation. We will also summarize the chemical biology studies conducted with N5-R-FAPy-containing DNA to elucidate their effects on DNA replication and to identify the mechanisms of N5-R-FAPy repair. PMID- 27959492 TI - Can Reduction of NO to N2O in Cytochrome c Dependent Nitric Oxide Reductase Proceed through a Trans-Mechanism? AB - As part of microbial denitrification, NO is reduced to N2O in the membrane bound enzyme nitric oxide reductase, NOR. The N-N coupling occurs in the diiron binuclear active site, BNC, and different mechanisms for this reaction step have been suggested. Computational studies have supported a so-called cis:b3 mechanism, in which the hyponitrite product of the reductive N-N bond formation coordinates with one nitrogen to the heme iron and with both oxygens to the non heme iron in the BNC. In contrast, experimental results have been interpreted to support a so-called trans-mechanism, in which the hyponitrite intermediate coordinates with one nitrogen atom to each of the two iron ions. Hybrid density functional theory is used here to perform an extensive search for possible intermediates of the NO reduction in the cNOR enzyme. It is found that hyponitrite structures coordinating with their negatively charged oxygens to the positively charged iron ions are the most stable ones. The hyponitrite intermediate involved in the suggested trans-mechanism, which only coordinates with the nitrogens to the iron ions, is found to be prohibitively high in energy, leading to a too slow reaction, which should rule out this mechanism. Furthermore, intermediates binding one NO molecule to each iron ion in the BNC, which have been suggested to initiate the trans-mechanism, are found to be too high in energy to be observable, indicating that the experimentally observed electron paramagnetic resonance signals, taken to support such an iron-nitrosyl dimer intermediate, should be reinterpreted. PMID- 27959493 TI - Droplet Microfluidic Flow Cytometer For Sorting On Transient Cellular Responses Of Genetically-Encoded Sensors. AB - Fluorescent biosensors are important measurement tools for in vivo quantification of pH, concentrations of metal ions and other analytes, and physical parameters such as membrane potential. Both the development of these sensors and their implementation in examining cellular heterogeneity requires technology for measuring and sorting cells based on the fluorescence levels before and after chemical or physical perturbations. We developed a droplet microfluidic platform for the screening and separation of cell populations on the basis of the in vivo response of expressed fluorescence-based biosensors after addition of an exogenous analyte. We demonstrate the capability to resolve the responses of two genetically encoded Zn2+ sensors at a range of time points spanning several seconds and subsequently sort a mixed-cell population of varying ratios with high accuracy. PMID- 27959495 TI - Highly Sensitive Detection of Organic Molecules on the Basis of a Poly(N isopropylacrylamide) Microassembly Formed by Plasmonic Optical Trapping. AB - We demonstrate that a poly(N-isopropylacrylamide) (PNIPAM) microassembly, formed by plasmonic optical trapping, can provide the platform for a highly sensitive detection technique for fluorescent and nonfluorescent organic molecules dissolved in aqueous solution. PNIPAM microassemblies can be easily formed by a combination with a photothermal effect and an enhanced optical force. These physical phenomena were obtained through resonant excitation of localized surface plasmon (LSP). Sparsely distributed fluorescent or nonfluorescent molecules dissolved in solution can be extracted into the PNIPAM assembly, resulting in an increase in fluorescence or Raman signals. In particular, we successfully detected quite small amounts of analytes (rhodamine B) at the 10-9 mol/L level. Using LSP is an alternative approach in analytical chemistry and can be used in addition to surface enhanced Raman scattering and surface enhanced fluorescence. PMID- 27959494 TI - Characterization of Protein Tyrosine Phosphatase 1B Inhibition by Chlorogenic Acid and Cichoric Acid. AB - Protein tyrosine phosphatase 1B (PTP1B) is a known regulator of the insulin and leptin signaling pathways and is an active target for the design of inhibitors for the treatment of type II diabetes and obesity. Recently, cichoric acid (CHA) and chlorogenic acid (CGA) were predicted by docking methods to be allosteric inhibitors that bind distal to the active site. However, using a combination of steady-state inhibition kinetics, solution nuclear magnetic resonance experiments, and molecular dynamics simulations, we show that CHA is a competitive inhibitor that binds in the active site of PTP1B. CGA, while a noncompetitive inhibitor, binds in the second aryl phosphate binding site, rather than the predicted benzfuran binding pocket. The molecular dynamics simulations of the apo enzyme and cysteine-phosphoryl intermediate states with and without bound CGA suggest CGA binding inhibits PTP1B by altering hydrogen bonding patterns at the active site. This study provides a mechanistic understanding of the allosteric inhibition of PTP1B. PMID- 27959496 TI - Facile Selective and Diverse Fabrication of Superhydrophobic, Superoleophobic Superhydrophilic and Superamphiphobic Materials from Kaolin. AB - As the starting material, kaolin is selectively and diversely fabricated to the superhydrophobic, superoleophobic-superhydrophilic, and superamphiphobic materials, respectively. The wettability of the kaolin surface can be selectively controlled and regulated to different superwetting states by choosing the corresponding modification reagent. The procedure is facile to operate, and no special technique or equipment is required. In addition, the procedure is cost effective and time-saving and the obtained super-repellent properties are very stable. The X-ray photoelectron spectroscopy analysis demonstrates different changes of kaolin particles surfaces which are responsible for the different super-repellency. The scanning electron microscopy displays geometric micro- and nanometer structures of the obtained three kinds of super-repellent materials. The results show that kaolin has good applications in many kinds of superwetting materials. The method demonstrated in this paper provides a new strategy for regulating and controlling the wettability of solid surfaces selectively, diversely, and comprehensively. PMID- 27959498 TI - Yolk-Shell TiO2@C Nanocomposite as High-Performance Anode Material for Sodium-Ion Batteries. AB - Yolk-shell TiO2@C nanocomposites have been synthesized successfully through a simple self-catalyzing solvothermal method. The structural and morphological characterizations reveal that TiO2@C nanocomposite has a yolk-shell microsphere morphology with diameters of 1-2 MUm, and both yolk and shell are composed of TiO2 nanoparticles (~10 nm). The as-prepared yolk-shell TiO2@C composites exhibit superior sodium storage properties, with a specific capacity of 210 mAh g-1, an outstanding cycle life of 85% capacity retention of 2000 cycles and extraordinary rate performance at 40 C rate. All the results indicate that the yolk-shell TiO2@C nanocomposite can be suggested as a promising anode material for high performance sodium-ion batteries. PMID- 27959497 TI - Inhibition of the Serotonin Transporter Is Altered by Metabolites of Selective Serotonin and Norepinephrine Reuptake Inhibitors and Represents a Caution to Acute or Chronic Treatment Paradigms. AB - Previous studies of transgenic mice carrying a single isoleucine to methionine substitution (I172M) in the serotonin transporter (SERT) demonstrated a loss of sensitivity to multiple antidepressants (ADs) at SERT. However, the ability of AD metabolites to antagonize SERT was not assessed. Here, we evaluated the selectivity and potency of these metabolites for inhibition of SERT in mouse brain-derived synaptosomes and blood platelets from wild-type (I172 mSERT) and the antidepressant-insensitive mouse M172 mSERT. The metabolites norfluoxetine and desmethylsertraline lost the selectivity demonstrated by the parent compounds for inhibition of wild-type mSERT over M172 mSERT, whereas desvenlafaxine and desmethylcitalopram retained selectivity. Furthermore, we show that the metabolite desmethylcitalopram accumulates in the brain and that the metabolites desmethylcitalopram, norfluoxetine, and desvenlafaxine inhibit serotonin uptake in wild-type mSERT at potencies similar to those of their parent compounds, suggesting that metabolites may play a role in effects observed following AD administration in wild-type and M172 mice. PMID- 27959499 TI - Particle Separation inside a Sessile Droplet with Variable Contact Angle Using Surface Acoustic Waves. AB - A sessile droplet of water carrying polystyrene microparticles of different diameters was uniformly exposed to high frequency surface acoustic waves (SAWs) produced by an interdigitated transducer (IDT). We investigated the concentration behavior of the microparticles as the SAWs generated a strong acoustic streaming flow (ASF) inside the water droplet and exerted a direct acoustic radiation force (ARF) on the suspended particles, the magnitude of which depended upon the particle diameter. As a result of the ARF, the microparticles were concentrated according to their diameters at different positions inside the sessile droplet placed in the path of the SAW, right in front of the IDT. The microparticle concentration behavior changed as the sessile droplet contact angle with the substrate was varied by adding surfactant to the water or by gradually evaporating the water. The positions at which the smaller and larger microparticles were concentrated remained distinguishable, even at very different experimental conditions. The long-term exposure of the droplets to the SAWs was accompanied by the gradual evaporation of the carrier fluid, which dynamically changed the droplet contact angle as well as the concentration of particles. Complete evaporation of the fluid left behind several concentrated yet separated clusters of particles on the substrate surface. The effect of the droplet contact angle on particles' concentration behavior and consequent separation of particles has been uniquely studied in this SAW-based report. PMID- 27959500 TI - Elucidating the Origin of Long Residence Time Binding for Inhibitors of the Metalloprotease Thermolysin. AB - Kinetic parameters of protein-ligand interactions are progressively acknowledged as valuable information for rational drug discovery. However, a targeted optimization of binding kinetics is not easy to achieve, and further systematic studies are necessary to increase the understanding about molecular mechanisms involved. We determined association and dissociation rate constants for 17 inhibitors of the metalloprotease thermolysin by surface plasmon resonance spectroscopy and correlated kinetic data with high-resolution crystal structures in complex with the protein. From the structure-kinetics relationship, we conclude that the strength of interaction with Asn112 correlates with the rate limiting step of dissociation. This residue is located at the beginning of a beta strand motif that lines the binding cleft and is commonly believed to align a substrate for catalysis. A reduced mobility of the Asn112 side chain owing to an enhanced engagement in charge-assisted hydrogen bonds prevents the conformational adjustment associated with ligand release and transformation of the enzyme to its open state. This hypothesis is supported by kinetic data of ZFPLA, a known pseudopeptidic inhibitor of thermolysin, which blocks the conformational transition of Asn112. Interference with this retrograde induced-fit mechanism results in variation of the residence time of thermolysin inhibitors by a factor of 74 000. The high conservation of this structural motif within the M4 and M13 metalloprotease families underpins the importance of this feature and has significant implications for drug discovery. PMID- 27959501 TI - Hierarchical Self-Assembly of Cu7Te5 Nanorods into Superstructures with Enhanced SERS Performance. AB - This paper reports a strategy to get self-assembly of Cu7Te5 nanorods into hierarchical superstructures: the side-by-side self-assembly of nanorods into microscale one-dimensional (1D) nanowires (primary structure), the side-by-side alignments of the 1D nanowires into two-dimensional (2D) nanowire bundles (secondary structure), and the further rolling up of the 2D bundles into three dimensional (3D) microtubes (tertiary structure). It was found that the oleylamine (OLA)/n-dodecanethiol (DDT) mixture as a binary capping agent was key to produce Cu7Te5 nanorods in the quantum size regime with high monodispersity, and this was a prerequisite for their hierarchical self-assembly based on elaborate control of the solvent evaporation process. The obtained Cu7Te5 microtube superstructures were used as SERS substrate and showed much stronger SERS enhancement than the as-prepared Cu7Te5 nanorods before assembly. This was probably ascribed to the remarkably enhanced local electromagnetic field arising from the plasmon coupling of Cu7Te5 nanorods in the well-assembled superstructures. PMID- 27959502 TI - Multi-yolk-shell SnO2/Co3Sn2@C Nanocubes with High Initial Coulombic Efficiency and Oxygen Reutilization for Lithium Storage. AB - The challenging problems of SnO2 anode material for lithium ion batteries are the poor electronic conductivity and the low oxygen reutilization due to the irreversibility of Li2O generated in the initial discharge leading to a theoretical initial Coulombic efficiency (ICE) of only 52.4%. Different from these strategies, this work proposes a novel strategy to level up the oxygen reutilization in SnO2 by introducing Co3Sn2 nanoalloys which can release Co atoms to reversibly react with Li2O instead. According to this protocol, multi-yolk shell SnO2/Co3Sn2@C nanocubes are designed and successfully prepared using hollow CoSn(OH)6 nanocubes as precursors followed a hydrothermal carbon coating and calcination treatment. The unique multi-yolk-shell nanostructure offers adequate breathing space for the volumetric deformation during long-term cycling. Moreover, the removal of Li2O allows a high electronic conductivity and resultant rate performance. As a result, the efficient reutilization of oxygen enables a high ICE of 71.7% and a reversible capacity of 1003 mA h g-1 after 200 cycles at 100 mA g-1. Cyclic voltammetry, cycling performance at different voltage windows, and X-ray photoelectron spectroscopy confirm the proposed mechanism. This strategy employing oxygen-poor metals or alloys provides a novel approach to enhance the oxygen reutilization in SnO2 for higher reversibility. PMID- 27959503 TI - Ultralong Sb2Se3 Nanowire-Based Free-Standing Membrane Anode for Lithium/Sodium Ion Batteries. AB - Metal chalcogenides have emerged as promising anode materials for lithium ion batteries (LIBs) and sodium ion batteries (SIBs). Herein, a free-standing membrane based on ultralong Sb2Se3 nanowires has been successfully fabricated via a facile hydrothermal synthesis combined with a subsequent vacuum filtration treatment. The as-achieved free-standing membrane constructed by pure Sb2Se3 nanowires exhibits good flexibility and integrity. Meanwhile, we investigate the lithium and sodium storage behavior of the Sb2Se3 nanowire-based free-standing membrane. When applied as the anode for LIBs, it delivers a reversible capacity of 614 mA h g-1 at 100 mA g-1, maintaining 584 mA h g-1 after 50 cycles. When applied as the anode for SIBs, it delivers a reversible capacity of 360 mA h g-1 at 100 mA g-1, retaining 289 mA h g-1 after 50 cycles. Such difference in electrochemical performance can be attributed to the more complex sodiation process relative to the corresponding lithiation process. This work may provide insight on developing Sb2Se3-based anode materials for high-performance LIBs or SIBs. PMID- 27959504 TI - Surface Ligand Density of Antibiotic-Nanoparticle Conjugates Enhances Target Avidity and Membrane Permeabilization of Vancomycin-Resistant Bacteria. AB - Many bacterial pathogens have now acquired resistance toward commonly used antibiotics, such as the glycopeptide antibiotic vancomycin. In this study, we show that immobilization of vancomycin onto a nanometer-scale solid surface with controlled local density can potentiate antibiotic action and increase target affinity of the drug. Magnetic nanoparticles were conjugated with vancomycin and used as a model system to investigate the relationship between surface density and drug potency. We showed remarkable improvement in minimum inhibitory concentration against vancomycin-resistant strains with values of 13-28 MUg/mL for conjugated vancomycin compared to 250-4000 MUg/mL for unconjugated vancomycin. Higher surface densities resulted in enhanced affinity toward the bacterial target compared to that of unconjugated vancomycin, as measured by a competition experiment using a surrogate ligand for bacterial Lipid II, N-Acetyl l-Lys-d-Ala-d-Ala. High density vancomycin nanoparticles required >64 times molar excess of ligand (relative to the vancomycin surface density) to abrogate antibacterial activity compared to only 2 molar excess for unconjugated vancomycin. Further, the drug-nanoparticle conjugates caused rapid permeabilization of the bacterial cell wall within 2 h, whereas no effect was seen with unconjugated vancomycin, suggesting additional modes of action for the nanoparticle-conjugated drug. Hence, immobilization of readily available antibiotics on nanocarriers may present a general strategy for repotentiating drugs that act on bacterial membranes or membrane-bound targets but have lost effectiveness against resistant bacterial strains. PMID- 27959505 TI - Droplet Microfluidic System with On-Demand Trapping and Releasing of Droplet for Drug Screening Applications. AB - 96-Well plate has been the traditional method used for screening drug compounds libraries for potential bioactivity. Although this method has been proven successful in testing dose-response analysis, the microliter consumption of expensive reagents and hours of reaction and analysis time call for innovative methods for improvements. This work demonstrates a droplet microfluidic platform that has the potential to significantly reduce the reagent consumption and shorten the reaction and analysis time by utilizing nanoliter-sized droplets as a replacement of wells. This platform is evaluated by applying it to screen drug compounds that inhibit the tau-peptide aggregation, a phenomena related to Alzheimer's disease. In this platform, sample reagents are first dispersed into nanolitre-sized droplets by an immiscible carrier oil and then these droplets are trapped on-demand in the downstream of the microfluidic device. The relative decrease in fluorescence through drug inhibition is characterized using an inverted epifluorescence microscope. Finally, the trapped droplets are released on-demand after each test by manipulating the applied pressures to the channel network which allows continuous processing. The testing results agree well with that obtained from 96-well plates with much lower sample consumption (~200 times lower than 96-well plate) and reduced reaction time due to increased surface volume ratio (2.5 min vs 2 h). PMID- 27959506 TI - Droplet-Based Multivolume Digital Polymerase Chain Reaction by a Surface-Assisted Multifactor Fluid Segmentation Approach. AB - Here we developed the surface-assisted multifactor fluid segmentation (SAMFS), an automated, fast, and flexible approach for generating a two-dimensional droplet array with tunable droplet volumes, for multivolume digital polymerase chain reaction (PCR). The SAMFS was developed based on the combination of robotic liquid handling and surface-assisted droplet generation techniques, where a continuous aqueous stream that flowed out from a capillary probe was segmented and immobilized on hydrophilic micropillars of a microchip into massive oil covered droplets with the probe rapidly scanning over the microchip. We studied various factors affecting the droplet generation process, including micropillar top area, distance between adjacent micropillars, aqueous stream flow rate, and microchip moving speed, and demonstrated a high droplet generation throughput up to 50 droplets/s and a largest droplet volume adjusting range from 0.25 to 350 nL. The SAMFS approach was adopted to form an oil-covered array of 994 droplets with four different volumes (1.2, 6, 30, and 150 nL droplets) required for multivolume digital PCR within 8 min. The droplet array system was applied in absolute quantification of plasmid DNA under the multivolume digital PCR mode with a dynamic range spanning 4 orders of magnitude, as well as measurement of HER2 expression levels in different breast cancer cell lines. The results are consistent to those obtained by quantitative real-time PCR method, while the present one has higher precision. PMID- 27959507 TI - Recent Advances in Electrochemiluminescence Analysis. PMID- 27959509 TI - Multifunctional Superelastic Foam-Like Boron Nitride Nanotubular Cellular-Network Architectures. AB - Construction of cellular architectures has been expected to enhance materials' mechanical tolerance and to stimulate and broaden their efficient utilizations in many potential fields. However, hitherto, there have been rather scarce developments in boron nitride (BN)-type cellular architectures because of well known difficulties in the syntheses of BN-based structures. Herein, cellular network multifunctional foams made of interconnective nanotubular hexagonal BN (h BN) architectures are developed using carbothermal reduction-assisted in situ chemical vapor deposition conversion from N-doped tubular graphitic cellular foams. These ultralight, chemically inert, thermally stable, and robust-integrity (supporting about 25,000 times of their own weight) three-dimensional-BN foams exhibit a 98.5% porosity, remarkable shape recovery (even after cycling compressions with 90% deformations), excellent resistance to water intrusion, thermal diffusion stability, and high strength and stiffness. They remarkably reduce the coefficient of thermal expansion and dielectric constant of polymeric poly(methyl methacrylate) composites, greatly contribute to their thermal conductivity improvement, and effectively limit polymeric composite softening at elevated temperatures. The foams also demonstrate high-capacity adsorption separation and removal ability for a wide range of oils and organic chemicals in oil/water systems and reliable recovery under their cycling usage as organic adsorbers. These created multifunctional foams should be valuable in many high end practical applications. PMID- 27959510 TI - Dynamic Exergy Method for Evaluating the Control and Operation of Oxy-Combustion Boiler Island Systems. AB - Exergy-based methods are widely applied to assess the performance of energy conversion systems; however, these methods mainly focus on a certain steady-state and have limited applications for evaluating the control impacts on system operation. To dynamically obtain the thermodynamic behavior and reveal the influences of control structures, layers and loops, on system energy performance, a dynamic exergy method is developed, improved, and applied to a complex oxy combustion boiler island system for the first time. The three most common operating scenarios are studied, and the results show that the flow rate change process leads to less energy consumption than oxygen purity and air in-leakage change processes. The variation of oxygen purity produces the largest impact on system operation, and the operating parameter sensitivity is not affected by the presence of process control. The control system saves energy during flow rate and oxygen purity change processes, while it consumes energy during the air in leakage change process. More attention should be paid to the oxygen purity change because it requires the largest control cost. In the control system, the supervisory control layer requires the greatest energy consumption and the largest control cost to maintain operating targets, while the steam control loops cause the main energy consumption. PMID- 27959508 TI - Transformation of the Non-Selective Aminocyclohexanol-Based Hsp90 Inhibitor into a Grp94-Seletive Scaffold. AB - Glucose regulated protein 94 kDa, Grp94, is the endoplasmic reticulum (ER) localized isoform of heat shock protein 90 (Hsp90) that is responsible for the trafficking and maturation of toll-like receptors, immunoglobulins, and integrins. As a result, Grp94 has emerged as a therapeutic target to disrupt cellular communication, adhesion, and tumor proliferation, potentially with fewer side effects compared to pan-inhibitors of all Hsp90 isoforms. Although, the N terminal ATP binding site is highly conserved among all four Hsp90 isoforms, recent cocrystal structures of Grp94 have revealed subtle differences between Grp94 and other Hsp90 isoforms that has been exploited for the development of Grp94-selective inhibitors. In the current study, a structure-based approach has been applied to a Grp94 nonselective compound, SNX 2112, which led to the development of 8j (ACO1), a Grp94-selective inhibitor that manifests ~440 nM affinity and >200-fold selectivity against cytosolic Hsp90 isoforms. PMID- 27959511 TI - Real-Time Imaging of Self-Organization and Mechanical Competition in Carbon Nanotube Forest Growth. AB - The properties of carbon nanotube (CNT) networks and analogous materials comprising filamentary nanostructures are governed by the intrinsic filament properties and their hierarchical organization and interconnection. As a result, direct knowledge of the collective dynamics of CNT synthesis and self organization is essential to engineering improved CNT materials for applications such as membranes and thermal interfaces. Here, we use real-time environmental transmission electron microscopy (E-TEM) to observe nucleation and self organization of CNTs into vertically aligned forests. Upon introduction of the carbon source, we observe a large scatter in the onset of nucleation of individual CNTs and the ensuing growth rates. Experiments performed at different temperatures and catalyst particle densities show the critical role of CNT density on the dynamics of self-organization; low-density CNT nucleation results in the CNTs becoming pinned to the substrate and forming random networks, whereas higher density CNT nucleation results in self-organization of the CNTs into bundles that are oriented perpendicular to the substrate. We also find that mechanical coupling between growing CNTs alters their growth trajectory and shape, causing significant deformations, buckling, and defects in the CNT walls. Therefore, it appears that CNT-CNT coupling not only is critical for self organization but also directly influences CNT quality and likely the resulting properties of the forest. Our findings show that control of the time-distributed kinetics of CNT nucleation and bundle formation are critical to manufacturing well-organized CNT assemblies and that E-TEM can be a powerful tool to investigate the mesoscale dynamics of CNT networks. PMID- 27959512 TI - Distinct Dynamic Modes Enable the Engagement of Dissimilar Ligands in a Promiscuous Atypical RNA Recognition Motif. AB - Conformational dynamics play a critical role in ligand binding, often conferring divergent activities and specificities even in species with highly similar ground state structures. Here, we employ time-resolved electrospray ionization hydrogen deuterium exchange (TRESI-HDX) to characterize the changes in dynamics that accompany oligonucleotide binding in the atypical RNA recognition motif (RRM2) in the C-terminal domain (CTD) of human La protein. Using this approach, which is uniquely capable of probing changes in the structure and dynamics of weakly ordered regions of proteins, we reveal that binding of RRM2 to a model 23-mer single-stranded RNA and binding of RRM2 to structured IRES domain IV of the hepatitis C viral (HCV) RNA are driven by fundamentally different dynamic processes. In particular, binding of the single-stranded RNA induces helical "unwinding" in a region of the CTD previously hypothesized to play an important role in La and La-related protein-associated RNA remodeling, while the same region becomes less dynamic upon engagement with the double-stranded HCV RNA. Binding of double-stranded RNA also involves less penetration into the RRM2 binding pocket and more engagement with the unstructured C-terminus of the La CTD. The complementarity between TRESI-HDX and Deltadelta nuclear magnetic resonance measurements for ligand binding analysis is also explored. PMID- 27959514 TI - Mercury Flows in China and Global Drivers. AB - Mercury (Hg) pollution control has become an urgent need at global and national scales. This study, for the first time, comprehensively examines Hg flows in Mainland China and uncovers domestic and external causal drivers of China's Hg emissions/releases. Results show that China's Hg input reaches 2643 t in 2010. China discharges 1368 t of Hg to the environment (to air, 633 t; water, 84 t; and land, 651 t). Embedded Hg transfers across production sectors via waste/byproduct flows reduce Hg releases to land, but lead to secondary Hg emissions to air. Such revelations of embedded Hg transfers adjusts China's comprehensive Hg control that would otherwise only tackle primary emitters. Domestic consumption causes 67% of China's Hg emissions/releases, and external consumption induces the remaining 33%. Besides traditional production-side Hg control measures, demand side measures and international joint efforts are required to effectively combat Hg pollution. Uncovering embedded and embodied Hg flows within the global economy can assist a paradigm shift necessary to make real progress in global Hg control and the implementation of the Minamata Convention on Mercury. PMID- 27959513 TI - Expression of HDAC2 but Not HDAC1 Transcript Is Reduced in Dorsolateral Prefrontal Cortex of Patients with Schizophrenia. AB - Postmortem brain studies support dysregulated expression of the histone deacetylase enzymes, HDAC1 and HDAC2, as a central feature in diseases including schizophrenia, bipolar disorder, and depression. Our objective was to investigate HDAC expression in a large postmortem sample set representing healthy and disease brains. We used >700 well-characterized samples from patients diagnosed with schizophrenia (n = 175), major depressive disorder (n = 135), and bipolar disorder (n = 61) to measure HDAC1 and HDAC2 transcript levels by quantitative real-time PCR in dorsolateral prefrontal cortex (DLPFC) and caudate compared to control samples. HDAC expression was calculated relative to the geometric mean of beta-2-microglobulin, beta-glucuronidase, and beta-actin. In adult-age DLPFC, HDAC2 was decreased by 34% in schizophrenia samples compared to controls (p < 10 4). HDAC2 was significantly upregulated in major depressive disorder samples by 17% versus controls (p = 0.002). Neither smoking history nor therapeutic drugs impacted HDAC2 levels and no HDAC1 patient-control differences were observed. In caudate, HDAC levels were unchanged between patient and control groups. In control DLPFC, age fetal week 14 to 97 years (n = 326), both HDAC1 and HDAC2 levels sharply declined around birth and stabilized thereafter. Using by far the largest postmortem sample set on this topic, our major finding (decreased HDAC2 transcript) showed notable specificity in disease (schizophrenia but not major depressive disorder), HDAC subtype (HDAC2 but not HDAC1) and brain region (DLPFC but not caudate). These differences shape understanding of regional components of neural circuitry in the diseased brain and set a benchmark to quantify HDAC density and distribution using in vivo neuroimaging tools. PMID- 27959515 TI - Artificial Cell Membrane Systems for Biosensing Applications. PMID- 27959516 TI - Interlaboratory Reproducibility of a Targeted Metabolomics Platform for Analysis of Human Serum and Plasma. AB - A critical question facing the field of metabolomics is whether data obtained from different centers can be effectively compared and combined. An important aspect of this is the interlaboratory precision (reproducibility) of the analytical protocols used. We analyzed human samples in six laboratories using different instrumentation but a common protocol (the AbsoluteIDQ p180 kit) for the measurement of 189 metabolites via liquid chromatography (LC) or flow injection analysis (FIA) coupled to tandem mass spectrometry (MS/MS). In spiked quality control (QC) samples 82% of metabolite measurements had an interlaboratory precision of <20%, while 83% of averaged individual laboratory measurements were accurate to within 20%. For 20 typical biological samples (serum and plasma from healthy individuals) the median interlaboratory coefficient of variation (CV) was 7.6%, with 85% of metabolites exhibiting a median interlaboratory CV of <20%. Precision was largely independent of the type of sample (serum or plasma) or the anticoagulant used but was reduced in a sample from a patient with dyslipidaemia. The median interlaboratory accuracy and precision of the assay for standard reference plasma (NIST SRM 1950) were 107% and 6.7%, respectively. Likely sources of irreproducibility were the near limit of detection (LOD) typical abundance of some metabolites and the degree of manual review and optimization of peak integration in the LC-MS/MS data after acquisition. Normalization to a reference material was crucial for the semi quantitative FIA measurements. This is the first interlaboratory assessment of a widely used, targeted metabolomics assay illustrating the reproducibility of the protocol and how data generated on different instruments could be directly integrated in large-scale epidemiological studies. PMID- 27959517 TI - The Ins and Outs of Lipid Flip-Flop. AB - Our current view of cellular membranes centers on the fluid-mosaic model, which envisions the cellular membrane as a "liquidlike" bilayer of lipids, cholesterol, and proteins that freely diffuse in two dimensions. In stark contrast, the exchange of materials between the leaflets of a bilayer was presumed to be prohibited by the large enthalpic barrier associated with translocating hydrophilic materials, such as a charged lipid headgroup, through the hydrophobic membrane core. This static picture with regard to lipid translocation (or "flip flop" as it is affectionately known) has been a long-held belief in the study of membrane dynamics. The current accepted membrane model invokes specific protein flippase (inward moving), floppase (outward moving), and scramblase (bidirectional) enzymes that assist in the movement of lipids between the leaflets of cellular membranes. The low rate of protein-free lipid flip-flop has also been a cornerstone of our understanding of the bilateral organization of cellular membrane components, specifically the asymmetric distribution of lipid species found in the luminal and extracellular leaflets of the plasma membrane of eukaryotic cells. Much of the previous work contributing to our current understanding of lipid flip-flop has utilized fluorescent- or spin-labeled lipids. However, there is growing evidence that these lipid probes do not accurately convey the dynamics and thermodynamics of native (unlabeled) lipid motion. This Account summarizes our research efforts directed toward developing a deep physical and chemical understanding of protein-free lipid flip-flop in phospholipid membrane models using sum-frequency vibrational spectroscopy (SFVS). Our use of SFVS enables the direct measurement of native lipid flip-flop in model membranes. In particular, we have explored the kinetic rates and activation thermodynamics of lipid translocation as a means of deciphering the underlying chemical and physical directors governing this process. By means of transition state theory, the contributions from enthalpy and entropy on the activation energy barrier to lipid flip-flop have been explored in detail for a variety of lipid species and membrane compositions. Specifically, the effect of lipid structure and packing and the inclusion of cholesterol and transmembrane peptides on the rates and thermodynamics of lipid translocation have been investigated in detail. It is our hope that these studies will provide a new perspective on lipid translocation in biological membranes and the role of lipid flip-flop in generating and maintaining cell membrane lipid asymmetry. PMID- 27959518 TI - Enantioselective Oxidative Homocoupling and Cross-Coupling of 2-Naphthols Catalyzed by Chiral Iron Phosphate Complexes. AB - Novel chiral iron phosphate complexes were prepared as catalysts for asymmetric oxidative coupling reactions. These catalysts were applied for the synthesis of enantio-enriched C1- and C2-symmetric BINOLs, in which the 3 and 3' positions are available for chemical modifications. It was proposed that the reaction takes place via an oxidative radical-anion coupling mechanism. A destructive BINOL racemization that competes with the enantioselective oxidative coupling of 2 naphthols was revealed, thereby offering new insights into this highly important reaction. PMID- 27959519 TI - Chemical Tuning of Magnetic Properties through Ru/Rh Substitution in Th7Fe3-type FeRh6-nRunB3 (n = 1-5) Series. AB - The new quaternary boride series FeRh6-nRunB3 (n = 1-5) was synthesized by arc melting and characterized by powder and single-crystal X-ray diffraction (XRD), energy-dispersive X-ray analysis, and superconducting quantum interference device magnetometry. Single-crystal structure refinement showed the distribution of the iron atoms in two of three possible crystallographic 4d metal sites in the structure (Th7Fe3-type, space group P63mc). Rietveld refinements of the powder XRD data indicated single-phase synthesis of all the members. A linear decrease of the lattice parameters and the unit cell volume with increasing Ru content was found, indicating Vegard's behavior. Susceptibility measurements show decreasing Curie temperature and magnetic moment (MUa5T) recorded at 5 T with increasing Ru content from TC = 295 K and MUa5T = 3.35 MUB (FeRh5RuB3) to TC = 205 K and MUa5T = 0.70 MUB (FeRhRu5B3). The measured coercivities lie between 1.0 and 2.2 kA/m indicating soft to semihard magnetic materials. PMID- 27959520 TI - Copper Catalyzed sp3 C-H Etherification with Acyl Protected Phenols. AB - A variety of acyl protected phenols AcOAr participate in sp3 C-H etherification of substrates R-H to give alkyl aryl ethers R-OAr employing tBuOOtBu as oxidant with copper(I) beta-diketiminato catalysts [CuI]. Although 1 degrees , 2 degrees , and 3 degrees C-H bonds may be functionalized, selectivity studies reveal a preference for the construction of hindered, 3 degrees C-OAr bonds. Mechanistic studies indicate that beta-diketiminato copper(II) phenolates [CuII]-OAr play a key role in this C-O bond forming reaction, formed via transesterification of AcOAr with [CuII]-OtBu intermediates generated upon reaction of [CuI] with tBuOOtBu. PMID- 27959522 TI - Three at a Time: Step by Step to Heterotermetallic Molecules. AB - New structural motifs in ternary metal alkoxides are demonstrated through synthetic strategies that enable overcoming statistical barriers and solution equilibrium. Tetradentate dimetalate unit, {M2(OiPr)9}- (M = Hf (1), Zr (2)), used to sequester the coordination sphere of the central metal atom (Ba), allowed step-by-step construction of termetallic molecules [{M'(OiPr)4}(HOiPr)Ba{M2(OiPr)9}] (M' = Al (3), Ga (4), M = Hf; M' = Al, M = Zr (5)). In contrast to a common "coordinative-fit" approach mainly used for bimetallic compounds, this stepwise rational construction using fast successive salt metathesis reactions circumvents general challenges in the syntheses of termetallic alkoxides by avoiding the thermodynamically preferred formation of bimetallic alkoxide molecules. The presented compounds exhibit for the first time gas phase stable termetallic alkoxide frameworks. PMID- 27959523 TI - Trophic Magnification of Parabens and Their Metabolites in a Subtropical Marine Food Web. AB - Despite the widespread use of parabens in a range of consumer products, little is known about bioaccumulation of these chemicals in aquatic environments. In this study, six parabens and four of their common metabolites were measured in abiotic (water, sediment) and biotic (fish including sharks, invertebrates, plants) samples collected from a subtropical marine food web in coastal Florida. Methyl paraben (MeP) was found in all abiotic (100%) and a majority of biotic (87%) samples. 4-Hydroxy benzoic acid (4-HB) was the most abundant metabolite, found in 97% of biotic and all abiotic samples analyzed. The food chain accumulation of MeP and 4-HB was investigated for this food web. The trophic magnification factor (TMF) of MeP was estimated to be 1.83, which suggests considerable bioaccumulation and biomagnification of this compound in the marine food web. In contrast, a low TMF value was found for 4-HB (0.30), indicating that this compound is metabolized and excreted along the food web. This is the first study to document the widespread occurrence of parabens and their metabolites in fish, invertebrates, seagrasses, marine macroalgae, mangroves, seawater, and ocean sediments and to elucidate biomagnification potential of MeP in a marine food web. PMID- 27959521 TI - The Dynamic Nonprime Binding of Sampatrilat to the C-Domain of Angiotensin Converting Enzyme. AB - Sampatrilat is a vasopeptidase inhibitor that inhibits both angiotensin I converting enzyme (ACE) and neutral endopeptidase. ACE is a zinc dipeptidyl carboxypeptidase that contains two extracellular domains (nACE and cACE). In this study the molecular basis for the selectivity of sampatrilat for nACE and cACE was investigated. Enzyme inhibition assays were performed to evaluate the in vitro ACE domain selectivity of sampatrilat. The inhibition of the C-domain (Ki = 13.8 nM) by sampatrilat was 12.4-fold more potent than that for the N-domain (171.9 nM), indicating differences in affinities for the respective ACE domain binding sites. Interestingly, replacement of the P2 group of sampatrilat with an aspartate abrogated its C-selectivity and lowered the potency of the inhibitor to activities in the micromolar range. The molecular basis for this selective profile was evaluated using molecular modeling methods. We found that the C domain selectivity of sampatrilat is due to occupation of the lysine side chain in the S1 and S2 subsites and interactions with Glu748 and Glu1008, respectively. This study provides new insights into ligand interactions with the nonprime binding site that can be exploited for the design of domain-selective ACE inhibitors. PMID- 27959524 TI - Pressure Dependence of Carbonate Exchange with [NpO2(CO3)3]4- in Aqueous Solutions. AB - The rates of ligand exchange into the geochemically important [NpO2(CO3)3]4- aqueous complex are measured as a function of pressure in order to complement existing data on the isostructural [UO2(CO3)3]4- complex. Experiments are conducted at pH conditions where the rate of exchange is independent of the proton concentration. Unexpectedly, the experiments show a distinct difference in the pressure dependencies of rates of exchange for the uranyl and neptunyl complexes. PMID- 27959525 TI - Accuracy of Coupled Cluster Excitation Energies in Diffuse Basis Sets. AB - We present a comprehensive statistical analysis on the accuracy of various excited state Coupled Cluster methods, accentuating the effect of diffuse basis sets on vertical excitation energies of valence and Rydberg-type states. Many popular approximate doubles and triples methods are benchmarked with basis sets up to aug-cc-pVTZ, with high level EOM-CCSDT results used as reference. The results reveal a serious deficiency of CC2 linear response and CIS(D) techniques in the description of Rydberg states, a feature not shown by the EOM-CCSD(2) and EOM-CCSD variants. The CC3 theory proves to be an accurate choice among the iterative approximate triples methods, while the novel perturbation-based CCSD(T)(a)* variant turns out to be the best way to include the effect of triple excitations in a noniterative way. PMID- 27959527 TI - A Theoretical Investigation of the Structure and Optical Properties of a Silver Cluster in Solid Form and in Solution. AB - Using density functional theory (DFT) and linear and quadratic response time dependent DFT, we investigated the structure and optical properties of a silver sulfide cluster with the interesting property of dual emission that was observed when in crystal form but not in solution. Since the dual fluorescence is observed only in the crystal, a supposition of stabilization of a higher-energy excited state by an excimer-like complex was analyzed by calculations for a cluster dimer, formed through pi-stacking of aromatic groups bonded to the sulfur atoms. However, because of the complexity of the system, a simple one-dimensional method for dimer optimization, which works moderately well in predicting the red-shifted fluorescence compared to its absorption in a naphthalene dimer, predicts only partially the red shift for the emission energy. Interestingly, calculations of the two-photon absorption (TPA) cross-section on the optimized isolated cluster as well as the crystal structure geometry indicate significant off-resonance TPA. While some materials have significantly larger TPA cross-sections, such a TPA cross-section off-resonance could be useful. The high density of states in the dimer system results in a higher probability for significant resonance enhancement and thus much larger TPA cross-sections. PMID- 27959526 TI - Chemical Probes and Engineered Constructs Reveal a Detailed Unfolding Mechanism for a Solvent-Free Multidomain Protein. AB - Despite the growing application of gas-phase measurements in structural biology and drug discovery, the factors that govern protein stabilities and structures in a solvent-free environment are still poorly understood. Here, we examine the solvent-free unfolding pathway for a group of homologous serum albumins. Utilizing a combination of chemical probes and noncovalent reconstructions, we draw new specific conclusions regarding the unfolding of albumins in the gas phase, as well as more general inferences regarding the sensitivity of collision induced unfolding to changes in protein primary and tertiary structure. Our findings suggest that the general unfolding pathway of low charge state albumin ions is largely unaffected by changes in primary structure; however, the stabilities of intermediates along these pathways vary widely as sequences diverge. Additionally, we find that human albumin follows a domain associated unfolding pathway, and we are able to assign each unfolded form observed in our gas-phase data set to the disruption of specific domains within the protein. The totality of our data informs the first detailed mechanism for multidomain protein unfolding in the gas phase, and highlights key similarities and differences from the known solution-phase pathway. PMID- 27959528 TI - Evaluation of Spin-Orbit Couplings with Linear-Response Time-Dependent Density Functional Methods. AB - A new versatile code based on Python scripts was developed to calculate spin orbit coupling (SOC) elements between singlet and triplet states. The code, named PySOC, is interfaced to third-party quantum chemistry packages, such as Gaussian 09 and DFTB+. SOCs are evaluated using linear-response (LR) methods based on time dependent density functional theory (TDDFT), the Tamm-Dancoff approximation (TDA), and time-dependent density functional tight binding (TD-DFTB). The evaluation employs Casida-type wave functions and the Breit-Pauli (BP) spin-orbit Hamiltonian with an effective charge approximation. For validation purposes, SOCs calculated with PySOC are benchmarked for several organic molecules, with SOC values spanning several orders of magnitude. The computed SOCs show little variation with the basis set, but are sensitive to the chosen density functional. The benchmark results are in good agreement with reference data obtained using higher-level spin-orbit Hamiltonians and electronic structure methods, such as CASPT2 and DFT/MRCI. PySOC can be easily interfaced to other third-party codes and other methods yielding CI-type wave functions. PMID- 27959529 TI - Correlation between Atmospheric Boundary Layer Height and Polybrominated Diphenyl Ether Concentrations in Air. AB - In this study, we aim to determine the correlation between the height of the atmospheric boundary layer (ABL) and the concentrations of polybrominated diphenyl ether (PBDE) congeners, in an effort to improve comprehension of the atmospheric behavior of PBDEs. We used the PBDE data in air (n = 298), which were measured by the Japan Ministry of Environment (JMOE) at 50 sites across Japan during the period 2009-2012. The height of the ABL, which directly affects the PBDE concentrations in the near-surface air, was estimated by employing data retrieved from the Japanese global reanalysis (JRA-55) database, using the parcel and Richardson number method. The ABL has shown a strong inverse relationship with BDE-47 and BDE-99 (p < 0.01). In contrast, there was less correlation between BDE-209 and the ABL (p = 0.258). These differing behaviors could be explained by differences in particle size distribution of PBDEs, where BDE-47 and BDE-99 are associated with gas phases and fine particles and BDE-209 is associated with coarse particles. To our knowledge, this paper represents the first large-scale analysis of correlations between the ABL and the concentrations of PBDEs in the air. PMID- 27959530 TI - Photoredox-Induced Functionalization of Alkenes for the Synthesis of Substituted Imidazolines and Oxazolidines. AB - A one-pot, three-component cascade reaction combining photoredox catalyzed radical addition and formal [3 + 2] annulation was developed. With this approach, highly concise syntheses of imidazoline and oxazolidine derivatives have been achieved. The advantages of this transformation are good to excellent yields, mild reaction conditions, operational simplicity, and easy accessibility of raw materials. PMID- 27959531 TI - Challenges and Opportunities in the Development of Serine Synthetic Pathway Inhibitors for Cancer Therapy. AB - Recent advances in the understanding of the relationship between cancer and metabolism have highlighted the relevance of the serine synthetic pathway (SSP), which consists of three successive enzymatic reactions. Enzymes of the SSP, such as phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT-1), were recently highlighted because they are amplified in a significant subset of human tumors, and their suppression by RNAi caused a decrease in cancer cell survival and growth. Currently, the discovery of drugs that inhibit these enzymes is still in its infancy, and the identification of suitable inhibitors could serve to understand the emerging biology of these metabolic enzymes. In this review, we present the SSP as a significant and novel emerging area for medicinal chemistry and we provide an overview of one of the key enzymes of the pathway, PHGDH. PMID- 27959533 TI - Entanglement in the Born-Oppenheimer Approximation. AB - The role of electron-nuclear entanglement on the validity of the Born-Oppenheimer (BO) approximation is investigated. Although nonadiabatic couplings generally lead to entanglement and to a failure of the BO approximation, surprisingly the degree of electron-nuclear entanglement is found to be uncorrelated with the degree of validity of the BO approximation. This is because while the degree of entanglement of BO states is determined by their deviation from the corresponding states in the crude BO approximation, the accuracy of the BO approximation is dictated, instead, by the deviation of the BO states from the exact electron nuclear states. In fact, in the context of a minimal avoided crossing model, extreme cases are identified where an adequate BO state is seen to be maximally entangled, and where the BO approximation fails but the associated BO state remains approximately unentangled. Further, the BO states are found to not preserve the entanglement properties of the exact electron-nuclear eigenstates, and to be completely unentangled only in the limit in which the BO approximation becomes exact. PMID- 27959532 TI - Conformational Landscape of the 1/1 Diacetyl/Water Complex Investigated by Infrared Spectroscopy and ab Initio Calculations. AB - The complexes of diacetyl with water have been studied experimentally by Fourier transform infrared (FTIR) spectroscopy coupled to solid neon matrix and supersonic jet, and anharmonic ab initio calculations. The vibrational analysis of neon matrix spectra over the 100-7500 cm-1 infrared range confirms the existence of two nearly isoenergetic one-to-one (1/1) diacetyl-water S1 and S2 isomers already evidenced in a previous argon matrix study. A third form (S3) predicted slightly less stable ( J. Mol. Mod. 2015 , 21 , 214 ) is not observed. The correct agreement obtained between neon matrix and anharmonic calculated vibrational frequencies is exploited in several cases to derive band assignments for the vibrational modes of a specific isomer. Thereafter, theoretical xij anharmonic coupling constants are used for the attribution of combination bands and overtones relative to the 1/1 dimer. Finally, the most stable isomer of the one-to-two (1/2) diacetyl-water complex is identified in the OH stretching region of water on the grounds of comparison of experimental and calculated vibrational shifts between water dimer and the three most stable 1/2 isomers. PMID- 27959534 TI - Structural Insights into the Post-Chemistry Steps of Nucleotide Incorporation Catalyzed by a DNA Polymerase. AB - DNA polymerases are essential enzymes that faithfully and efficiently replicate genomic information.1-3 The mechanism of nucleotide incorporation by DNA polymerases has been extensively studied structurally and kinetically, but several key steps following phosphodiester bond formation remain structurally uncharacterized due to utilization of natural nucleotides. It is thought that the release of pyrophosphate (PPi) triggers reverse conformational changes in a polymerase in order to complete a full catalytic cycle as well as prepare for DNA translocation and subsequent incorporation events. Here, by using the triphosphates of chain-terminating antiviral drugs lamivudine ((-)3TC-TP) and emtricitabine ((-)FTC-TP), we structurally reveal the correct sequence of post chemistry steps during nucleotide incorporation by human DNA polymerase beta (hPolbeta) and provide a structural basis for PPi release. These post-catalytic structures reveal hPolbeta in an open conformation with PPi bound in the active site, thereby strongly suggesting that the reverse conformational changes occur prior to PPi release. The results also help to refine the role of the newly discovered third divalent metal ion for DNA polymerase-catalyzed nucleotide incorporation. Furthermore, a post-chemistry structure of hPolbeta in the open conformation, following incorporation of (-)3TC-MP, with a second (-)3TC-TP molecule bound to the active site in the absence of PPi, suggests that nucleotide binding stimulates PPi dissociation and occurs before polymerase translocation. Our structural characterization defines the order of the elusive post-chemistry steps in the canonical mechanism of a DNA polymerase. PMID- 27959535 TI - Optical Imaging of Phase Transition and Li-Ion Diffusion Kinetics of Single LiCoO(2) Nanoparticles During Electrochemical Cycling. AB - Understanding the phase transition and Li-ion diffusion kinetics of Li-ion storage nanomaterials holds promising keys to further improve the cycle life and charge rate of the Li-ion battery. Traditional electrochemical studies were often based on a bulk electrode consisting of billions of electroactive nanoparticles, which washed out the intrinsic heterogeneity among individuals. Here, we employ optical microscopy, termed surface plasmon resonance microscopy (SPRM), to image electrochemical current of single LiCoO2 nanoparticles down to 50 fA during electrochemical cycling, from which the phase transition and Li-ion diffusion kinetics can be quantitatively resolved in a single nanoparticle, in operando and high throughput manner. SPRM maps the refractive index (RI) of single LiCoO2 nanoparticles, which significantly decreases with the gradual extraction of Li ions, enabling the optical read-out of single nanoparticle electrochemistry. Further scanning electron microscopy characterization of the same batch of nanoparticles led to a bottom-up strategy for studying the structure-activity relationship. As RI is an intrinsic property of any material, the present approach is anticipated to be applicable for versatile kinds of anode and cathode materials, and to facilitate the rational design and optimization toward durable and fast-charging electrode materials. PMID- 27959536 TI - Exact Product Formation Rates for Stochastic Enzyme Kinetics. AB - The rate of product formation is an important measure of the speed of enzyme reactions. Classical studies of enzyme reactions have been conducted in dilute solutions and under conditions that justified the substrate abundance assumption. However, such assumption is well-known to break down in the context of cellular biochemistry. Instead, the concentration of available substrate can become rate limiting. Here we use the chemical master equation to obtain expressions for the instantaneous and time averaged rate of product formation without invoking the conventional substrate abundance assumption. The expressions are derived for a broad range of enzyme reaction mechanisms, including those that involve one or many enzyme molecules, require multiple substrates, and exhibit cooperativity and substrate inhibition. Novel results include: (i) the relationship between the average rate of product formation (calculated over the time it takes for the reaction to finish) and the substrate concentration, for a Michaelis-Menten (MM) reaction with one enzyme molecule, is approximately given by a logarithmically corrected MM form; (ii) intrinsic noise decreases the sharpness of cooperative switches but enhances the filtering response of substrate inhibition; (iii) the relationship between the initial average rate of product formation and the initial substrate concentration for a MM reaction with no reversible reaction and with any number of enzyme and substrate molecules is a sum of Michaelis-Menten equations. PMID- 27959537 TI - Finite Temperature String Method with Umbrella Sampling: Application on a Side Chain Flipping in Mhp1 Transporter. AB - Protein conformational change is of central importance in molecular biology. Here we demonstrate a computational approach to characterize the transition between two metastable conformations in all-atom simulations. Our approach is based on the finite temperature string method, and the implementation is essentially a generalization of umbrella sampling simulations with Hamiltonian replica exchange. We represent the transition pathway by a curve in the conformational space, with the curve parameter taken as the reaction coordinate. Our approach can efficiently refine a transition pathway and compute a one-dimensional free energy as a function of the reaction coordinate. A diffusion model can then be used to calculate the forward and backward transition rates, the major kinetic quantities for the transition. We applied the approach on a local transition in the ligand-free Mhp1 transporter, between its outward-facing conformation and an intermediate conformation with the side chain of Phe305 flipped to the outside of the protein. Our simulations predict that the flipped-out position of this side chain has a free energy 6.5 kcal/mol higher than the original position in the crystal structure, and that the forward and backward transition rates are in the millisecond and submicrosecond time scales, respectively. PMID- 27959538 TI - Stiff Spring Approximation Revisited: Inertial Effects in Nonequilibrium Trajectories. AB - Use of harmonic guiding potentials is the most commonly adopted method for implementing steered molecular dynamics (SMD) simulations, performed to obtain potentials of mean force (PMFs) using Jarzynski's equality and other nonequilibrium work (NEW) theorems. The stiff spring approximation (SSA) of Schulten and co-workers enables calculation of the PMF by using the work performed along many SMD trajectories in NEW theorems. We discuss and demonstrate how a high spring constant, k, required for the validity of the SSA can violate another requirement of SSA, the validity of Brownian dynamics in the system under study. These result in skewed work distributions with their width increasing with k. The skew and broadening of work distributions result in biased estimation (through invoking NEW theorems) of the PMF. Remarkably, the skewness and the broadening of work distributions are independent of the average drift velocity and physical asymmetries and can only be attributed to using too-stiff springs. We discuss the proper upper limit for k such that the inertial effects are minimized. In the presence of inertial effects, using the peak value (rather than the statistical mean) of the work distributions vastly reduces the bias in the calculated PMFs and improves the accuracy. PMID- 27959539 TI - What Can and Cannot Be Learned from Molecular Dynamics Simulations of Bacterial Proton-Coupled Oligopeptide Transporter GkPOT? AB - We have performed an extensive set of all-atom molecular dynamics (MD) simulations of a bacterial proton-coupled oligopeptide transporter (POT) in an explicit membrane environment. We have characterized both the local and global conformational dynamics of the transporter upon the proton and/or substrate binding, within a statistical framework. Our results reveal a clearly distinct behavior for local conformational dynamics in the absence and presence of the proton at the putative proton binding residue E310. Particularly, we find that the substrate binding conformation is drastically different in the two conditions, where the substrate binds to the protein in a lateral/vertical manner, in the presence/absence of the proton. We do not observe any statistically significant distinctive behavior in terms of the global conformational changes in different simulation conditions, within the time scales of our simulations. Our extensive simulations and analyses call into question the implicit assumption of many MD studies that local conformational changes observed in short simulations could provide clues to the global conformational changes that occur on much longer time scales. The linear regression analysis of quantities associated with the global conformational fluctuations, however, provides an indication of a mechanism involving the concerted motion of the transmembrane helices, consistent with the rocker-switch mechanism. PMID- 27959541 TI - Conformational Dynamics of Lysine Methyltransferase Smyd2. Insights into the Different Substrate Crevice Characteristics of Smyd2 and Smyd3. AB - Smyd2, the SET and MYND domain containing protein lysine methyltransferase, targets histone and nonhistone substrates. Methylation of nonhistone substrates has direct implications in cancer development and progression. Dynamic regulation of Smyd2 activity and the structural basis of broad substrate specificity still remain elusive. Herein, we report on extensive molecular dynamics simulations on a full length Smyd2 in the presence and absence of AdoMet cofactor (covering together 1.3 MUs of sampling), and the accompanying conformational transitions. Additionally, dynamics of the C-terminal domain (CTD) and structural features of substrate crevices of Smyd2 and Smyd3 are compared. The CTD of Smyd2 exhibits conformational flexibility in both states. In the holo form, however, it undergoes larger hinge motions resulting in more opened configurations than the apo form, which is confined around the partially open starting X-ray configuration. AdoMet binding triggers increased elasticity of the CTD leading Smyd2 to adopt fully opened configurations, which completely exposes the substrate binding crevice. These long-range concerted motions highlight Smyd2's ability to target substrates of varying sizes. Substrate crevices of Smyd2 and Smyd3 show distinct features in terms of spatial, hydration, and electrostatic properties that emphasize their characteristic modes of substrates interaction and entry pathways for inhibitor binding. On the whole, our study shows how the elasticity and hinge motion of the CTD regulate its functional role and underpin the basis of broad substrate specificity of Smyd2. We also highlight the specific structural principles that guide substrate and inhibitor binding to Smyd2 and Smyd3. PMID- 27959540 TI - Unbiased False Discovery Rate Estimation for Shotgun Proteomics Based on the Target-Decoy Approach. AB - Target-decoy approach (TDA) is the dominant strategy for false discovery rate (FDR) estimation in mass-spectrometry-based proteomics. One of its main applications is direct FDR estimation based on counting of decoy matches above a certain score threshold. The corresponding equations are widely employed for filtering of peptide or protein identifications. In this work we consider a probability model describing the filtering process and find that, when decoy counting is used for q value estimation and subsequent filtering, a correction has to be introduced into these common equations for TDA-based FDR estimation. We also discuss the scale of variance of false discovery proportion (FDP) and propose using confidence intervals for more conservative FDP estimation in shotgun proteomics. The necessity of both the correction and the use of confidence intervals is especially pronounced when filtering small sets (such as in proteogenomics experiments) and when using very low FDR thresholds. PMID- 27959542 TI - Influence of Fimbriae on Bacterial Adhesion and Viscoelasticity and Correlations of the Two Properties with Biofilm Formation. AB - The surface polymers of bacteria determine the ability of bacteria to adhere to a substrate for colonization, which is an essential step for a variety of microbial processes, such as biofilm formation and biofouling. Capsular polysaccharides and fimbriae are two major components on a bacterial surface, which are critical for mediating cell-surface interactions. Adhesion and viscoelasticity of bacteria are two major physical properties related to bacteria-surface interactions. In this study, we employed atomic force microscopy (AFM) to interrogate how the adhesion work and the viscoelasticity of a bacterial pathogen, Klebsiella pneumoniae, influence biofilm formation. To do this, the wild-type, type 3 fimbriae deficient, and type 3 fimbriae-overexpressed K. pneumoniae strains have been investigated in an aqueous environment. The results show that the measured adhesion work is positively correlated to biofilm formation; however, the viscoelasticity is not correlated to biofilm formation. This study indicates that AFM-based adhesion measurements of bacteria can be used to evaluate the function of bacterial surface polymers in biofilm formation and to predict the ability of bacterial biofilm formation. PMID- 27959543 TI - Gas-Phase Synthesis of the Elusive Trisilicontetrahydride Species (Si3H4). AB - The bimolecular gas-phase reaction of ground-state atomic silicon (Si; 3P) with disilane (Si2H6; 1A1g) was explored under single-collision conditions in a crossed molecular beam machine at a collision energy of 21 kJ mol-1. Combined with electronic structure calculations, the results suggest the formation of Si3H4 isomer(s) along with molecular hydrogen via indirect scattering dynamics through Si3H6 collision complex(es) and intersystem crossing from the triplet to the singlet surface. The nonadiabatic reaction dynamics can synthesize the energetically accessible singlet Si3H4 isomers in overall exoergic reaction(s) ( 93 +/- 21 kJ mol-1). All reasonable reaction products are either cyclic or hydrogen-bridged suggesting extensive isomerization processes from the reactants via the initially formed collision complex(es) to the fragmenting singlet intermediate(s). The underlying chemical dynamics of the silicon-disilane reaction are quite distinct from the isovalent carbon-ethane system that does not depict any reactivity at all, and open the door for an unconventional gas phase synthesis of hitherto elusive organosilicon molecules under single-collision conditions. PMID- 27959544 TI - N-Carboxyanhydride-Mediated Fatty Acylation of Amino Acids and Peptides for Functionalization of Protocell Membranes. AB - Early protocells are likely to have arisen from the self-assembly of RNA, peptide, and lipid molecules that were generated and concentrated within geologically favorable environments on the early Earth. The reactivity of these components in a prebiotic environment that supplied sources of chemical energy could have produced additional species with properties favorable to the emergence of protocells. The geochemically plausible activation of amino acids by carbonyl sulfide has been shown to generate short peptides via the formation of cyclic amino acid N-carboxyanhydrides (NCAs). Here, we show that the polymerization of valine-NCA in the presence of fatty acids yields acylated amino acids and peptides via a mixed anhydride intermediate. Notably, Nalpha-oleoylarginine, a product of the reaction between arginine and oleic acid in the presence of valine NCA, partitions spontaneously into vesicle membranes and mediates the association of RNA with the vesicles. Our results suggest a potential mechanism by which activated amino acids could diversify the chemical functionality of fatty acid membranes and colocalize RNA with vesicles during the formation of early protocells. PMID- 27959545 TI - Efficient Photocatalytic Degradation of Norfloxacin in Aqueous Media by Hydrothermally Synthesized Immobilized TiO2/Ti Films with Exposed {001} Facets. AB - In this study, a novel immobilized TiO2/Ti film with exposed {001} facets was prepared via a facile one-pot hydrothermal route for the degradation of norfloxacin from aqueous media. The effects of various hydrothermal conditions (i.e., solution pH, hydrothermal time (HT) and HF concentration) on the growth of {001} faceted TiO2/Ti film were investigated. The maximum photocatalytic performance of {001} faceted TiO2/Ti film was observed when prepared at pH 2.62, HT of 3 h and at HF concentration of 0.02 M. The as-prepared {001} faceted TiO2/Ti films were fully characterized by field-emission scanning electron microscope (FE-SEM), X-ray diffraction (XRD), high resolution transmission electron microscope (HR-TEM), and X-ray photoelectron spectroscopy (XPS). More importantly, the as-prepared {001} faceted TiO2/Ti film exhibited excellent photocatalytic performance toward degradation of norfloxacin in various water matrices (Milli-Q water, tap water, river water and synthetic wastewater). The individual influence of various anions (SO42-, HCO3-, NO3-, Cl-) and cations (K+, Ca2+, Mg2+, Cu2+, Na+, Fe3+) usually present in the real water samples on the photocatalytic performance of as-prepared TiO2/Ti film with exposed {001} facet was investigated. The mechanistic studies revealed that *OH is mainly involved in the photocatalytic degradation of norfloxacin by {001} faceted TiO2/Ti film. In addition, norfloxacin degradation byproducts were investigated, on the basis of which degradation schemes were proposed. PMID- 27959546 TI - Time-Dependent Density Functional Theoretical Investigation of Photoinduced Excited-State Intramolecular Dual Proton Transfer in Diformyl Dipyrromethanes. AB - In recent research [ Chem. Commun. 2014 , 50 , 8667 ], it was found that photoinduced enolization occurred in 1,9-diformyl-5,5-diaryldipyrromethane (DAKK) by excited-state dual proton transfer resulting in a red-shifted absorption, a phenomena not observed in 1,9-diformyl-5,5-dimethyldipyrromethane (DMKK) and 1,9 diformyl-5-aryldipyrromethane (MAKK). The observation was supported by preliminary density functional theoretical (DFT) calculations. In the work reported here, a detailed and systematic study was undertaken considering four molecules, 1,9-diformyldipyrromethane (DHKK), DMKK, MAKK, and DAKK and their rotational isomers using DFT methods. Different processes, namely, cis-trans isomerization and single and double proton transfer processes, and their mechanistic details were investigated in the ground and excited states. From the simulation studies, it was seen that the presence of different substituents at the meso carbon does not affect the lambdaabs values during cis -> trans isomerization. However, enolization by proton transfer processes were found to be influenced by the substituents, as seen in the experiments. Enolization was observed to follow a stepwise mechanism, that is, diketo -> monoenol -> dienol. While monoenols showed negligible substituent effects on the lambdaabs values, a large red shift in lambdaabs was seen only in DAKK, in agreement with the experimental findings. This observation can be attributed to the lowering of the keto -> enol activation barrier, stabilization of DAEE in the S1 state, and the charge transfer nature of the transitions involved in DAEE. PMID- 27959547 TI - Assessing the Effect of Organoclays and Biochar on the Fate of Abscisic Acid in Soil. AB - The potential use of allelopathic and signaling compounds as environmentally friendly agrochemicals is a subject of increasing interest, but the fate of these compounds once they reach the soil environment is poorly understood. This work studied how the sorption, persistence, and leaching of the two enantiomers of the phytohormone abscisic acid (ABA) in agricultural soil was affected by the amendments of two organoclays (SA-HDTMA and Cloi10) and a biochar derived from apple wood (BC). In conventional 24-h batch sorption experiments, higher affinity toward ABA enantiomers was displayed by SA-HDTMA followed by Cloi10 and then BC. Desorption could be ascertained only in BC, where ABA enantiomers presented difficulties to be desorbed. Dissipation of ABA in the soil was enantioselective with S-ABA being degraded more quickly than R-ABA, and followed the order unamended > Cloi10-amended > BC-amended > SA-HDTMA-amended soil for both enantiomers. Sorption determined during the incubation experiment indicated some loss of sorption capacity with time in organoclay-amended soil and increasing sorption in BC-amended soil, suggesting surface sorption mechanisms for organoclays and slow (potentially pore filling) kinetics in BC-amended soil. The leaching of ABA enantiomers was delayed after amendment of soil to an extent that depended on the amendment sorption capacity, and it was almost completely suppressed by addition of BC due to its irreversible sorption. Organoclays and BC affected differently the final behavior and enantioselectivity of ABA in soil as a consequence of dissimilar sorption capacities and alterations in sorption with time, which will affect the plant and microbial availability of endogenous and exogenous ABA in the rhizosphere. PMID- 27959548 TI - Marine Primary Productivity as a Potential Indirect Source of Selenium and Other Trace Elements in Atmospheric Deposition. AB - Atmospheric processes play an important role in the supply of the trace element selenium (Se) as well as other essential trace elements to terrestrial environments, mainly via wet deposition. Here we investigate whether the marine biosphere can be identified as a source of Se and of other trace elements in precipitation samples. We used artificial neural network (ANN) modeling and other statistical methods to analyze relationships between a high-resolution atmospheric deposition chemistry time series (March 2007-January 2009) from Plynlimon (UK) and exposure of air masses to marine chlorophyll a and to other source proxies. Using ANN sensitivity analyses, we found that higher air mass exposure to marine productivity leads to higher concentrations of dissolved organic carbon (DOC) in rainfall. Furthermore, marine productivity was found to be an important but indirect factor in controlling Se as well as vanadium (V), cobalt (Co), nickel (Ni), zinc (Zn), and aluminum (Al) concentrations in atmospheric deposition, likely via scavenging by organic compounds derived from marine organisms. Marine organisms may thus play an indirect but important role in the delivery of trace elements to terrestrial environments and food chains. PMID- 27959549 TI - A Polyketide Synthase Encoded by the Gene An15g07920 Is Involved in the Biosynthesis of Ochratoxin A in Aspergillus niger. AB - The polyketide synthase gene An15g07920 was known in Aspergillus niger CBS 513.88 as putatively involved in the production of ochratoxin A (OTA). Genome resequencing analysis revealed that the gene An15g07920 is also present in the ochratoxin-producing A. niger strain 1062. Disruption of An15g07920 in A. niger 1062 removed its capacity to biosynthesize ochratoxin beta (OTbeta), ochratoxin alpha (OTalpha), and OTA. These results indicate that the polyketide synthase encoded by An15g07920 is a crucial player in the biosynthesis of OTA, in the pathway prior to the phenylalanine ligation step. The gene An15g07920 reached its maximum transcription level before OTA accumulation reached its highest level, confirming that gene transcription precedes OTA production. These findings will not only help explain the mechanism of OTA production in A. niger but also provide necessary information for the development of effective diagnostic, preventive, and control strategies to reduce the risk of OTA contamination in foods. PMID- 27959550 TI - Rational Ligand Design for an Efficient Biomimetic Water Splitting Complex. AB - Being an important biomimetic model catalyst for water oxidation, the dimanganese molecular complex [H2O(terpy)MnIII(MU-O)2MnIV(terpy)OH2]3+ (complex 1, terpy = 2,2':6',2"-terpyridine) has been investigated extensively by experimentalists. By carrying out density functional theory calculations, we explore theoretically the oxygen evolution mechanisms of complex 1. On the basis of understandings of the geometric and electronic structural features of complex 1, we explore the possibility of improving its catalytic efficiency through a rational design of ligands coordinated to the manganese ions. Recognizing that the rate-determining step of oxygen evolution is the formation of an O-O bond at a high-valent manganese center, we design a new complex, [H2O(2-bpnp)MnIII(MU-O)2MnIV(2 bpnp)OH2]3+ (complex 2, 2-bpnp = 2-([2,2'-bipyridin]-6-yl)-1,8-naphthyridine). It is verified that the proton-accepting 2-bpnp ligand leads to stabilized hydrogen bonding with surrounding water molecules, and hence, the barrier height associated with O-O bond formation is substantially reduced. Moreover, despite its larger size, the 2-bpnp ligand does not cause steric hindrance for the release of molecular oxygen. Consequently, the proposed complex 2 is expected to outperform the existing complex 1 regarding catalytic efficiency. This work highlights the potential usefulness of rational design toward reaching the high efficiency of the oxygen evolution center in photosystem II. PMID- 27959551 TI - Accurate Intermolecular Potential for the C60 Dimer: The Performance of Different Levels of Quantum Theory. AB - The self-assembly of molecular building blocks is a promising route to low-cost nanoelectronic devices. It would be very appealing to use computer-aided design to identify suitable molecules. However, molecular self-assembly is guided by weak interactions, such as dispersion, which have long been notoriously difficult to describe with quantum chemical methods. In recent years, several viable techniques have emerged, ranging from empirical dispersion corrections for DFT to fast perturbation and coupled-cluster theories. In this work, we test these methods for the dimer of the prototypical building block for nanoelectronics, C60 fullerene. Benchmark quality data is obtained from DFT-based symmetry-adapted perturbation theory (SAPT), the adiabatic-connection fluctuation dissipation (ACFD) theorem using an adiabatic LDA kernel, and domain-based local pair natural orbital (DLPNO) coupled-pair and coupled-cluster methods. These benchmarks are used to evaluate economical dispersion-corrected DFT methods, double-hybrid DFT functionals, and second-order Moller-Plesset theory. Furthermore, we provide analytical fits to the benchmark interaction curves, which can be used for a coarse-grain description of fullerene self-assembly. These analytical expressions differ significantly from those reported previously based on bulk data. PMID- 27959552 TI - Improved Minimum Mode Following Method for Finding First Order Saddle Points. AB - The minimum mode following method for finding first order saddle points on an energy surface is used, for example, in simulations of long time scale evolution of materials and surfaces of solids. Such simulations are increasingly being carried out in combination with computationally demanding electronic structure calculations of atomic interactions, so it is essential to reduce as much as possible the number of function evaluations needed to find the relevant saddle points. Several improvements to the method are presented here and tested on a benchmark system involving rearrangements of a heptamer island on a close packed crystal surface. Instead of using a uniform or Gaussian random initial displacement of the atoms, as has typically been done previously, the starting points are arranged evenly on the surface of a hypersphere and its radius is adjusted during the sampling of the saddle points. This increases the diversity of saddle points found and reduces the chances of reconverging on previously located saddle points. The minimum mode is estimated using the Davidson method, and it is shown that significant savings in the number of function evaluations can be obtained by assuming the minimum mode is unchanged until the atomic displacement exceeds a threshold value. The number of function evaluations needed for a recently published benchmark (S. T. Chill et al. J. Chem. Theory Comput. 2014, 10, 5476) is reduced to less than a third with the improved method as compared with the best previously reported results. PMID- 27959553 TI - Assessing the Future Vehicle Fleet Electrification: The Impacts on Regional and Urban Air Quality. AB - There have been significant advancements in electric vehicles (EVs) in recent years. However, the different changing patterns in emissions at upstream and on road stages and complex atmospheric chemistry of pollutants lead to uncertainty in the air quality benefits from fleet electrification. This study considers the Yangtze River Delta (YRD) region in China to investigate whether EVs can improve future air quality. The Community Multiscale Air Quality model enhanced by the two-dimensional volatility basis set module is applied to simulate the temporally, spatially, and chemically resolved changes in PM2.5 concentrations and the changes of other pollutants from fleet electrification. A probable scenario (Scenario EV1) with 20% of private light-duty passenger vehicles and 80% of commercial passenger vehicles (e.g., taxis and buses) electrified can reduce average PM2.5 concentrations by 0.4 to 1.1 MUg m-3 during four representative months for all urban areas of YRD in 2030. The seasonal distinctions of the air quality impacts with respect to concentration reductions in key aerosol components are also identified. For example, the PM2.5 reduction in January is mainly attributed to the nitrate reduction, whereas the secondary organic aerosol reduction is another essential contributor in August. EVs can also effectively assist in mitigating NO2 concentrations, which would gain greater reductions for traffic-dense urban areas (e.g., Shanghai). This paper reveals that the fleet electrification in the YRD region could generally play a positive role in improving regional and urban air quality. PMID- 27959554 TI - Stereoselective Synthesis of Lower and Upper Rim Functionalized Tetra-alpha Isomers of Calix[4]pyrroles. AB - Hydroxyaryl alkyl ketones with functionalized alkyl chains often fail to produce the corresponding tetra-alpha calix[4]pyrroles in Bronsted acid mediated condensations with pyrrole. A remarkable effect exerted by the addition of methyltrialkylammonium chloride during the acid-mediated syntheses of a series of meso-(tetrahydroxyaryl)-meso-tetraalkylcalix[4]pyrroles featuring alkyl terminal chloro or ester groups is reported. The ammonium salt enhances the cyclocondensation reaction and induces the almost exclusive formation of the tetra-alpha isomers. PMID- 27959555 TI - Synthesis of Diaziridines and Diazirines via Resin-Bound Sulfonyl Oximes. AB - Diazirines are one of the most prominent functionalities in labeling experiments in vivo and in vitro because they allow photochemical generation of carbenes. The strategy presented herein describes the formation of diaziridines, being essential precursors in diazirine syntheses, using solid-supported procedures with immobilized sulfonyl oximes. The solid-supported building blocks have been shown to be valuable intermediates for CuAAC and amidation reactions, offering the possibility to build complex compounds with diverse functionalities. PMID- 27959556 TI - Mixed-Mode Operation of Hybrid Phase-Change Nanophotonic Circuits. AB - Phase change materials (PCMs) are highly attractive for nonvolatile electrical and all-optical memory applications because of unique features such as ultrafast and reversible phase transitions, long-term endurance, and high scalability to nanoscale dimensions. Understanding their transient characteristics upon phase transition in both the electrical and the optical domains is essential for using PCMs in future multifunctional optoelectronic circuits. Here, we use a PCM nanowire embedded into a nanophotonic circuit to study switching dynamics in mixed-mode operation. Evanescent coupling between light traveling along waveguides and a phase-change nanowire enables reversible phase transition between amorphous and crystalline states. We perform time-resolved measurements of the transient change in both the optical transmission and resistance of the nanowire and show reversible switching operations in both the optical and the electrical domains. Our results pave the way toward on-chip multifunctional optoelectronic integrated devices, waveguide integrated memories, and hybrid processing applications. PMID- 27959557 TI - Magnetic-Field Sensitivity of Storage Modulus for Bimodal Magnetic Elastomers. AB - The magnetic-field dependence of the storage modulus for bimodal magnetic elastomers consisting of carbonyl iron with a diameter of 2.8 MUm (magnetic) and aluminum hydroxide with a diameter of 1.4 MUm (nonmagnetic) was measured, and the effect of nonmagnetic particles on the magnetic-field sensitivity of the storage modulus was investigated. The coefficient of the magnetic-field sensitivity for the monomodal magnetic elastomer increased from 0.018 to 0.026 mT-1 for the bimodal one by embedding nonmagnetic particles of 6.6 vol %. At volume fractions above 5.4 vol %, the bimodal magnetic elastomer exhibited significant nonlinear viscoelasticity at 0 mT and a high storage modulus at 500 mT, simultaneously, the coefficient of the magnetic-field sensitivity demonstrated high values. This strongly indicates that both the particles form a particle network at the off field, and they make a well-developed chain structure under magnetic fields. The time profiles of the storage modulus for bimodal magnetic elastomers can be fitted by a linear combination of two exponential functions with two characteristic times showing the alignment of magnetic particles. The alignment time for the fast and slow processes was distributed around 3.3 +/- 0.3 and 176 +/- 12 s, respectively. The alignment time was independent of the volume fraction of the nonmagnetic particles; however, the increment in the storage modulus for the fast process significantly increased at volume fractions above 5.4 vol %. It was also revealed that the coefficient of the magnetic-field sensitivity can be scaled by a power function of the increment in the storage modulus divided by the off-field modulus, DeltaG'/G'0, not only for the bimodal magnetic elastomers but also for the monomodal ones. PMID- 27959558 TI - Sodium Chloride Triggered the Fusion of Vesicle Composed of Fatty Acid Modified Protic Ionic Liquid: A New Insight into the Membrane Fusion Monitored through Fluorescence Lifetime Imaging Microscopy. AB - The development of stable vesicular assemblies and the understanding of their interaction and dynamics in aqueous solution are long-standing topics in the research of chemistry and biology. Fatty acids are known to form vesicle structure in aqueous solution depending on the pH of the medium. Protic ionic liquid of fatty acid with ethyl amine (oleate ethyl amine, OEA) as a component spontaneously forms a vesicle in aqueous solution. The general comparison of dynamics and interaction of these two vesicles have been drawn using fluorescence correlation spectroscopy (FCS) and fluorescence lifetime imaging microscopy (FLIM) measurements. Further, FLIM images of a single vesicle are taken at multiple wavelengths, and the solvation of the probe molecules has been observed from the multiwavelength FLIM images. The lifetime of the probe molecule in OEA vesicle is higher than that in simple fatty acid vesicles. Therefore, it suggests that the membrane of the OEA vesicle is more dehydrated compared to that of fatty acid vesicles, and it facilitates OEA vesicles to fuse themselves in the presence of electrolyte, sodium chloride (NaCl). However, under the same conditions, only fatty acid vesicles do not fuse. The fusion of OEA vesicles is successfully demonstrated by the time scan FLIM measurements. The different events in the fusion process are analyzed in the light of the reported model of vesicle fusion. Finally, the local viscosity of the water pool of the vesicle is determined using kiton red, as a molecular rotor. With addition of NaCl, the fluidity in the interior of the vesicle is increased which leads to disassembly of vesicle. The rich dynamic properties of this vesicular assembly and the FLIM based approach of vesicle fusion will provide better insight into the growth of a protocell membrane. PMID- 27959559 TI - Smoothed Biasing Forces Yield Unbiased Free Energies with the Extended-System Adaptive Biasing Force Method. AB - We report a theoretical description and numerical tests of the extended-system adaptive biasing force method (eABF), together with an unbiased estimator of the free energy surface from eABF dynamics. Whereas the original ABF approach uses its running estimate of the free energy gradient as the adaptive biasing force, eABF is built on the idea that the exact free energy gradient is not necessary for efficient exploration, and that it is still possible to recover the exact free energy separately with an appropriate estimator. eABF does not directly bias the collective coordinates of interest, but rather fictitious variables that are harmonically coupled to them; therefore is does not require second derivative estimates, making it easily applicable to a wider range of problems than ABF. Furthermore, the extended variables present a smoother, coarse-grain-like sampling problem on a mollified free energy surface, leading to faster exploration and convergence. We also introduce CZAR, a simple, unbiased free energy estimator from eABF trajectories. eABF/CZAR converges to the physical free energy surface faster than standard ABF for a wide range of parameters. PMID- 27959560 TI - Complex Filling Dynamics in Mesoporous Thin Films. AB - The fluid-front dynamics resulting from the coexisting infiltration and evaporation phenomena in nanofluidic systems has been investigated. More precisely, water infiltration in both titania and silica mesoporous films was studied through a simple experiment: a sessile drop was deposited over the film and the advancement of the fluid front into the porous structure was optically followed and recorded in time. In the case of titania mesoporous films, capillary infiltration was arrested at a given distance, and a steady annular region of the wetted material was formed. A simple model that combines Lucas-Washburn infiltration and surface evaporation was derived, which appropriately describes the observed filling dynamics and the annulus width in dissimilar mesoporous morphologies. In the case of wormlike mesoporous morphologies, a remarkable phenomenon was found: instead of reaching a steady infiltration-evaporation balance, the fluid front exhibits an oscillating behavior. This complex filling dynamics opens interesting possibilities to study the unusual nanofluidic phenomena and to discover novel applications. PMID- 27959561 TI - Perfectly Ordered Patterns Formed by a Heterogeneous Nucleation Process of Block Copolymer Self-Assembly Under Rectangular Confinement. AB - The heterogeneous nucleation process during the phase separation of binary blends of the AB diblock and the C homopolymer induced by rectangular confinement is studied by cell dynamics simulation based on the time-dependent Ginzburg-Landau theory. The main goal is to yield large-scale ordered hexagonal patterns by tailoring the surface potentials of the sidewalls. Our study reveals a crucial condition to induce the desired heterogeneous nucleation process in which the nucleated domain grains grow and merge into a defect-free pattern. Specifically, nucleations are induced simultaneously by two parallel sidewalls with a strong surface potential, whereas the spontaneous nucleation and the heterogeneous nucleation at the other two walls with a weak surface potential are suppressed. Moreover, the confinement effect of the other two walls can ensure that the two rows of nucleated domains have correlated positions. Importantly, we find that the ordering process under the crucial condition exhibits a high tolerance to the rectangular sizes. Only a few defects in thousands of domains are occasionally caused that are observed to be annihilated in a short-annealing time via various mechanisms. This study may provide a facile route to prepare large-scale ordered patterns via a simple rectangular confinement. PMID- 27959562 TI - Rolling Spheres on Bioinspired Microstructured Surfaces. AB - Microstructured surfaces, such as those inspired by nature, mediate surface interactions and are actively sought after to control wetting, adhesion, and friction. In particular, the rolling motion of spheres on microstructured surfaces in fluid environments is important for the transport of particles in microfluidic devices or in tribology. Here, we characterize the motion of smooth silicon nitride spheres (diameters 3-5 mm) as they roll down inclined planes decorated with hexagonal arrays of microwells and micropillars. For both types of patterned surfaces, we vary the area fraction of the micropatterned features from 0.04 to 0.96. We measure directly and independently the rotational and translational velocities of the spheres as they roll down planes with inclination angles that vary between 5 and 30 degrees . For a given area fraction, we find that spheres have a higher translational and rotational velocity on surfaces with microwells than on micropillars. We rely on the model of Smart and Leighton [Phys. Fluids A 5, 13 (1993)] to obtain an effective gap width and coefficient of friction for all microstructured surfaces investigated. We find that the coefficient of friction is significantly higher for a surface with micropillars than that for one with microwells, likely due to the presence of interconnected drainage channels that provide additional paths for the fluid flow and favor solid-solid contact on the surface with micropillars. We find that while the effective gap width at a very low solid fraction is equal to the height of the patterned features, the effective separation decreases exponentially as the surface coverage of microstructures increases, with little measured differences between the two geometries. Superposition of resistance functions is used to relate the rapid decrease in the effective gap height with increase in the surface coverage observed in experiments. PMID- 27959563 TI - Posttranscriptional Regulation in Adenovirus Infected Cells. AB - A deeper understanding of how viruses reprogram their hosts for production of progeny is needed to combat infections. Most knowledge on the regulation of cellular gene expression during adenovirus infection is derived from mRNA studies. Here, we investigated the changes in protein expression during the late phase of adenovirus type 2 (Ad2) infection of the IMR-90 cell line by stable isotope labeling in cell culture with subsequent liquid chromatography-high resolution tandem mass spectrometric analysis. Two biological replicates of samples collected at 24 and 36 h post-infection (hpi) were investigated using swapped labeling. In total, 2648 and 2394 proteins were quantified at 24 and 36 hpi, respectively. Among them, 659 and 645 were deregulated >1.6-fold at the two time points. The protein expression was compared with RNA expression using cDNA sequencing data. The correlation was surprisingly low (r = 0.3), and several examples of posttranscriptional regulation were observed; e.g., proteins related to carbohydrate metabolism were up-regulated at the protein level but unchanged at the RNA level, whereas histone proteins were down-regulated at the protein level but up-regulated at the RNA level. The deregulation of cellular gene expression by adenovirus is mediated at multiple levels and more complex than hitherto believed. PMID- 27959564 TI - Revised and Extended Values for Self-Diffusion Coefficients of 1-Alkyl-3 methylimidazolium Tetrafluoroborates and Hexafluorophosphates: Relations between the Transport Properties. AB - Earlier measurements of the self-diffusion coefficients of 1-alkyl-3 methylimidazolium (or [RMIM], R = alkyl) tetrafluoroborates and hexafluorophosphates have been revised and extended to 90 degrees C. The main changes are to DS+ and DS- for [HMIM][PF6] ([C6C1Im][PF6]) and DS- for [OMIM][BF4] ([C8C1Im][BF4]). New atmospheric pressure self-diffusion, density, and conductivity data are provided for [HMIM][BF4] ([C6C1Im][BF4]). Velocity cross-correlation, distinct diffusion, and Laity resistance coefficients have been calculated. There is no evidence for ion association. A new relation between the Nernst-Einstein deviation parameter (Delta) and resistance coefficients (rij) is derived; Delta tends toward 0.5 when the like-ion rii are much smaller than the unlike-ion rij, i.e., when the counterion interactions dominate. [OMIM]+ ion salts approach this limit. Stokes-Einstein-Sutherland and Walden plots overlap almost quantitatively for [BF4]-, [PF6]-, and Cl- salts with a common [RMIM]+ cation. That is, in thermodynamic states that have the same viscosity, the salt molar conductivities and hence ionic electrical mobilities of, say, [BMIM][BF4] and [BMIM][PF6] are almost equal, as are the corresponding Brownian or diffusive mobilities, (DSi/RT), for the cation, and also for these three small anions. PMID- 27959565 TI - Electric-Field Switchable Second-Harmonic Generation in Bilayer MoS2 by Inversion Symmetry Breaking. AB - We demonstrate pronounced electric-field-induced second-harmonic generation in naturally inversion symmetric 2H stacked bilayer MoS2 embedded into microcapacitor devices. By applying strong external electric field perturbations (|F| = +/-2.6 MV cm-1) perpendicular to the basal plane of the crystal, we control the inversion symmetry breaking and, hereby, tune the nonlinear conversion efficiency. Strong tunability of the nonlinear response is observed throughout the energy range (Eomega ~ 1.25-1.47 eV) probed by measuring the second-harmonic response at E2omega, spectrally detuned from both the A- and B exciton resonances. A 60-fold enhancement of the second-order nonlinear signal is obtained for emission at E2omega = 2.49 eV, energetically detuned by DeltaE = E2omega - EC = -0.26 eV from the C-resonance (EC = 2.75 eV). The pronounced spectral dependence of the electric-field-induced second-harmonic generation signal reflects the bandstructure and wave function admixture and exhibits particularly strong tunability below the C-resonance, in good agreement with density functional theory calculations. Moreover, we show that the field-induced second-harmonic generation relies on the interlayer coupling in the bilayer. Our findings strongly suggest that the strong tunability of the electric-field induced second-harmonic generation signal in bilayer transition metal dichalcogenides may find applications in miniaturized electrically switchable nonlinear devices. PMID- 27959566 TI - Benchmarking Cellulose Nanocrystals: From the Laboratory to Industrial Production. AB - The renewability, biocompatibility, and mechanical properties of cellulose nanocrystals (CNCs) have made them an attractive material for numerous composite, biomedical, and rheological applications. However, for CNCs to shift from a laboratory curiosity to commercial applications, researchers must transition from CNCs extracted on the bench scale to material produced on an industrial scale. There are a number of companies currently producing kilogram to ton per day quantities of sulfuric acid-hydrolyzed CNCs as well as other nanocelluloses, as described herein. With the recent intensification of industrially produced CNCs and the variety of cellulose sources, hydrolysis methods, and purification procedures, the characterization of these materials becomes critical. This has further been justified by the past two decades of research that demonstrate that the CNC stability and behavior are highly dependent on the surface chemistry, surface charge density, and particle size. This work outlines key test methods that should be employed to characterize these properties to ensure a "known" starting material and consistent performance. Of the sulfuric acid-extracted CNCs examined, industrially produced material compared well with laboratory-made CNCs, exhibiting similar charge density, colloidal and thermal stability, crystallinity, morphology, and self-assembly behavior. In addition, it was observed that further purification of CNCs using Soxhlet extraction in ethanol had minimal impact on the nanoparticle properties and is unlikely to be necessary for many applications. Overall, the current standing of industrially produced CNCs is positive, suggesting that the evolution to commercial-scale applications will not be hindered by CNC production. PMID- 27959568 TI - Surface-Engineered Polydopamine Particles as an Efficient Support for Catalytic Applications. AB - Mussel-inspired polydopamine (PDA) particles with the size of ~270 nm are used as a support of palladium (Pd) nanoparticles (NPs) for catalyst preparation. The surface morphology of the PDA particle has been modified via corrosion of CF3COOH. Surface chemistry of the obtained PDA particle has been engineered by the formation of a carboxylic acid-terminated alkanethiol monolayer. The obtained self-assembled monolayer-modified PDA (SAM-PDA) particles are used to load Pd NPs by simply adding H2PdCl4 solution to a suspension of SAM-PDA particles at room temperature. Transmission electron microscopy, energy-dispersive X-ray mapping, dynamic light scattering, X-ray diffraction, X-ray photoelectron spectroscopy, UV vis, and Fourier transform infrared are used to characterize the catalyst and to investigate the process. Uniform Pd NPs (2-3 nm) have been well-dispersed on the SAM-PDA particles via controllable surface engineering. Surface charges and interactions with a metal ion are regulated by the monolayer of carboxylic acids. The surface chemistry of PDA particles has been finely engineered for efficient loading of noble metal NPs. The obtained Pd/SAM-PDA catalyst has shown greatly increased activity and good reusability compared with Pd/PDA in the reduction of 4-nitrophenol (4-NP) by sodium borohydride or H2. The kinetic data of 4-NP hydrogenation catalyzed by Pd/SAM-PDA are fitted to a Langmuir-Hinshelwood (L-H) model, and the calculated apparent activation energy of this process is 40.77 kJ mol-1. PMID- 27959567 TI - Direct Substitution of Arylalkynyl Carbinols Provides Access to Diverse Terminal Acetylene Building Blocks. AB - To develop next generation antifolates for the treatment of trimethoprim resistant bacteria, synthetic methods were needed to prepare a diverse array of 3 aryl-propynes with various substitutions at the propargyl position. A direct route was sought whereby nucleophilic addition of acetylene to aryl carboxaldehydes would be followed by reduction or substitution of the resulting propargyl alcohol. The direct reduction, methylation, and dimethylation of these readily available alcohols provide efficient access to this uncommon functional array. In addition, an unusual silane exchange reaction was observed in the reduction of the propargylic alcohols. PMID- 27959570 TI - Competitive Adsorption of Naphthenic Acids and Polyaromatic Molecules at a Toluene-Water Interface. AB - The early-stage competitive co-adsorption of interfacially active naphthenic acids (NAs) and polyaromatic (PA) molecules to a toluene-water interface from the bulk toluene phase was studied using molecular dynamics (MD) simulation. The NA molecules studied had the same polar functional group but different cycloaliphatic nonpolar tails, and a perylene bisimide (PBI)-based molecule was used as a representative PA compound. The results from our simulations suggest that the size and structural features of NA molecules greatly influence the interfacial activity of PA molecules and partitioning of NA molecules at the toluene-water interface. At low concentrations of PA (~2.3 wt %) and NA (~0.4 wt %) molecules, NA molecules containing large cycloaliphatic rings (e.g., four rings) or with a very long aliphatic tail (e.g., carbon chain length of 14) were observed to impede the migration of PA molecules to the interface, whereas small NA molecules containing two cycloaliphatic rings had little effect on the adsorption of PA molecules at the toluene-water interface. At high NA concentrations, the adsorption of PA molecules (~5.75-17.25 wt %) was greatly hindered by the presence of small NA molecules (~1.6-4.8 wt %) due to the solvation of PA nanoaggregates in the bulk. Adsorption mechanisms of PA and NA molecules at toluene-water interfaces were clarified through a detailed analysis on the interactions among different species in the system. The results obtained from this work provide insights into designing appropriate chemical demulsifiers or co-demulsifiers for breaking water-in-oil emulsions of great industrial applications. PMID- 27959569 TI - Biochemical Characterization of Echinococcus multilocularis Antigen B3 Reveals Insight into Adaptation and Maintenance of Parasitic Homeostasis at the Host Parasite Interface. AB - Alveolar echinococcosis (AE) caused by Echinococcus multilocularis metacestode is frequently associated with deleterious zoonotic helminthiasis. The growth patterns and morphological features of AE, such as invasion of the liver parenchyme and multiplication into multivesiculated masses, are similar to those of malignant tumors. AE has been increasingly detected in several regions of Europe, North America, Central Asia, and northwestern China. An isoform of E. multilocularis antigen B3 (EmAgB3) shows a specific immunoreactivity against patient sera of active-stage AE, suggesting that EmAgB3 might play important roles during adaptation of the parasite to hosts. However, expression patterns and biochemical properties of EmAgB3 remained elusive. The protein profile and nature of component proteins of E. multilocularis hydatid fluid (EmHF) have never been addressed. In this study, we conducted proteome analysis of EmHF of AE cysts harvested from immunocompetent mice. We observed the molecular and biochemical properties of EmAgB3, including differential transcription patterns of paralogous genes, macromolecular protein status by self-assembly, distinct oligomeric states according to individual anatomical compartments of the worm, and hydrophobic ligand-binding protein activity. We also demonstrated tissue expression patterns of EmAgB3 transcript and protein. EmAgB3 might participate in immune response and recruitment of essential host lipids at the host-parasite interface. Our results might contribute to an in depth understanding of the biophysical and biological features of EmAgB3, thus providing insights into the design of novel targets to control AE. PMID- 27959571 TI - Receptor-Mediated Enhanced Cellular Delivery of Nanoparticles Using Recombinant Receptor-Binding Domain of Diphtheria Toxin. AB - Antibodies and peptides are often used to home nanoparticles (NPs) to specific cells. Here in this work, we have used recombinant receptor-binding domain of diphtheria toxin (RDT) as a homing molecule for NPs. Diphtheria toxin binds to heparin binding EGF-like growth factor (HB-EGF) through its receptor-binding domain. HB-EGF is often overexpressed as cell surface molecule in various types of cancer. We have prepared monodispersed, spherical PLGA NPs and coated these NPs with RDT. These NPs are characterized by FESEM and FT-IR spectroscopy. Using flow cytometry and fluorescence spectroscopy, we show that coating with RDT increases cellular uptake of PLGA NPs. We further show that RDT-coated nanoparticles are internalized through clathrin-dependent receptor-mediated endocytosis that can be reduced by specific inhibitor. These RDT-coated nanoparticles (RDT-NP) were further used for preferential delivery of Irinotecan, a chemotherapeutic agent, to cells overexpressing HB-EGF. We show that receptor mediated enhanced uptake of RDT-NPs increases the potency of irinotecan in these cells. PMID- 27959572 TI - Application of Protocols Devised to Study Bi(III) Complex Formation by Voltammetry: The Bi(III)-Picolinic Acid System. AB - Bi(III) coordination chemistry has been largely neglected due to the difficulties faced when studying these systems even though Bi(III) is used in various medicinal applications. This study of the Bi(III)-picolinic acid system by voltammetry applies the rigorous methodologies already developed to enable the study of Bi(III) systems starting in very acidic solutions to prevent precipitation. This includes calibrating the glass electrode accurately at these low pHs, compensating for the diffusion junction potential below pH 2 and determining the reduction potential of uncomplexed Bi(III) which cannot be directly measured. The importance of including nitrate from the background electrolyte as a competing species is highlighted, especially for data acquired below pH ~ 2. From analysis of the voltammetric data, it was not clear whether a ML3OH species formed in solution or whether it was a combination of ML4 and ML4OH. Information from crystal structures and electrospray ionization-mass spectrometry measurements was thus used to propose the most probable species model. The log beta values determined were 7.77 +/- 0.07 for ML, 13.89 +/- 0.07 for ML2, 18.61 +/- 0.01 for ML3, 22.7 +/- 0.2 for ML4, and 31.4 +/- 0.2 for ML4OH. Application of these methodologies thus opens the door to broaden our understanding of Bi(III) complexation. PMID- 27959573 TI - Earth Abundant Fe/Mn-Based Layered Oxide Interconnected Nanowires for Advanced K Ion Full Batteries. AB - K-ion battery (KIB) is a new-type energy storage device that possesses potential advantages of low-cost and abundant resource of K precursor materials. However, the main challenge lies on the lack of stable materials to accommodate the intercalation of large-size K-ions. Here we designed and constructed a novel earth abundant Fe/Mn-based layered oxide interconnected nanowires as a cathode in KIBs for the first time, which exhibits both high capacity and good cycling stability. On the basis of advanced in situ X-ray diffraction analysis and electrochemical characterization, we confirm that interconnected K0.7Fe0.5Mn0.5O2 nanowires can provide stable framework structure, fast K-ion diffusion channels, and three-dimensional electron transport network during the depotassiation/potassiation processes. As a result, a considerable initial discharge capacity of 178 mAh g-1 is achieved when measured for KIBs. Besides, K ion full batteries based on interconnected K0.7Fe0.5Mn0.5O2 nanowires/soft carbon are assembled, manifesting over 250 cycles with a capacity retention of ~76%. This work may open up the investigation of high-performance K-ion intercalated earth abundant layered cathodes and will push the development of energy storage systems. PMID- 27959574 TI - Porcine dorsal root ganglia ovarian neurons are affected by long lasting testosterone treatment. AB - We studied the effect of testosterone overdose on the number, distribution and chemical coding of ovarian neurons in the dorsal root ganglia (DRGs) in pigs. On day 3 of the estrous cycle, the ovaries of both the control and experimental gilts were injected with retrograde tracer Fast Blue. From day 4 of the estrous cycle to the expected day 20 of the second studied cycle, the experimental gilts were injected with testosterone, while the control gilts received oil. After the completion of the protocol the Th16-L5 DRGs were collected. Injections of testosterone increased the testosterone (~3.5 fold) and estradiol-17beta (~1.6 fold) levels in the peripheral blood, and reduced the following in the DRGs: the total number of the Fast Blue-positive perikarya, the population of perikarya in the L2-L4 ganglia, and the numbers of SP(+)/CGRP(+), SP(+)/PACAP(+), SP(+)/nNOS(+) and SP(-)/nNOS(+) perikarya. In the testosterone-injected gilts, the populations of SP(+)CGRP(-), small and large androgen receptors-expressing perikarya were increased. These results suggest that elevated androgen levels during pathological states may regulate the transmission of sensory modalities from the ovary to the spinal cord, and antidromic regulation of the ovarian functions. PMID- 27959575 TI - Effect of ginsenoside Rh-2 via activation of caspase-3 and Bcl-2-insensitive pathway in ovarian cancer cells. AB - Ginsenoside has been reported to have therapeutic effects for some types of cancer, but its effect on ovarian cancer cells has not been evaluated. In this study, we monitored the effects of ginsenoside-Rh2 (Rh2) on the inhibition of cell proliferation and the apoptotic process in the ovarian cancer cell line SKOV3 using an MTT assay and TUNEL assay. We found that Rh2 inhibited cell proliferation and significantly induced apoptosis. We confirmed the apoptotic effects of Rh2 using western blot analysis of apoptosis-related proteins. Specifically, the levels of cleaved poly ADP ribose polymerase (PARP) and cleaved caspase-3 significantly increased in SKOV3 cells treated with Rh2. Therefore, Rh2 clearly suppressed the growth of SKOV3 cells in vitro, which was associated with induction of the apoptosis pathway. Moreover, the migration assay showed that Rh2 inhibited the invasive ability of SKOV3 cells. Taken together, our results suggest that Rh2 has anticancer effects in SKOV3 cells through inhibition of cell proliferation and induction of apoptosis. Considering the therapeutic potential of Rh2, more studies should be carried out to facilitate the future application of this natural product as a potential anti-cancer agent. PMID- 27959576 TI - Effects of transgenic expression of dopamine beta hydroxylase (Dbh) gene on blood pressure in spontaneously hypertensive rats. AB - The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and left ventricular hypertrophy. Catecholamines play an important role in the pathogenesis of both essential hypertension in humans and in the SHR. Recently, we obtained evidence that the SHR harbors a variant in the gene for dopamine beta hydroxylase (Dbh) that is associated with reduced adrenal expression of Dbh mRNA and reduced DBH enzymatic activity which correlated negatively with blood pressure. In the current study, we used a transgenic experiment to test the hypothesis that reduced Dbh expression predisposes the SHR to hypertension and that augmentation of Dbh expression would reduce blood pressure. We derived 2 new transgenic SHR-Dbh lines expressing Dbh cDNA under control of the Brown Norway (BN) wild type promoter. We found modestly increased adrenal expression of Dbh in transgenic rats versus SHR non-transgenic controls that was associated with reduced adrenal levels of dopamine and increased plasma levels of norepinephrine and epinephrine. The observed changes in catecholamine metabolism were associated with increased blood pressure and left ventricular mass in both transgenic lines. We did not observe any consistent changes in brainstem levels of catecholamines or of mRNA levels of Dbh in the transgenic strains. Contrary to our initial expections, these findings are consistent with the possibility that genetically determined decreases in adrenal expression and activity of DBH do not represent primary determinants of increased blood pressure in the SHR model. PMID- 27959577 TI - Hyperosmotic environment blunts effectivity of ischemic preconditioning against ischemia-reperfusion injury and improves ischemic tolerance in non-preconditioned isolated rat hearts. AB - Several studies have shown that diabetes mellitus modulates heart resistance to ischemia and abrogates effectivity of cardioprotective interventions, such as ischemic preconditioning (IP). The aim of this study was to evaluate whether the effect of hyperglycemic conditions on the severity of ischemia-reperfusion (I/R) injury in preconditioned and non-preconditioned hearts (controls, C) is related to changes in osmotic activity of glucose. Experiments were performed in isolated rat hearts perfused according to Langendorff exposed to 30-min coronary occlusion/120-min reperfusion. IP was induced by two cycles of 5-min coronary occlusion/5-min reperfusion, prior to the long-term I/R. Hyperosmotic (HO) state induced by an addition of mannitol (11 mmol/l) to a standard Krebs-Henseleit perfusion medium significantly decreased the size of infarction and also suppressed a release of heart fatty acid binding protein (h-FABP - biomarker of cell injury) from the non-IP hearts nearly to 50 %, in comparison with normoosmotic (NO) mannitol-free perfusion. However, IP in HO conditions significantly increased the size of infarction and tended to elevate the release of h-FABP to the effluent from the heart. The results indicate that HO environment plays a cardioprotective role in the ischemic myocardium. On the other hand, increased osmolarity, similar to that in the hyperglycemic conditions, may play a pivotal role in a failure of IP to induce cardioprotection in the diabetic myocardium. PMID- 27959578 TI - PATIENT-CENTERED CARE OF THE PATIENT WITH OBESITY. PMID- 27959579 TI - Role of Clinical Decision Tools in the Diagnosis of Pulmonary Embolism. AB - OBJECTIVE: The purpose of this article is to describe the importance of clinical decision rules for pretest assessment of the probability of the presence of pulmonary embolism (PE), the effect of use of the rules on the yield of pulmonary CT angiography, and obstacles to implementation of the rules in clinical practice. CONCLUSION: Pulmonary CT angiography is the imaging modality of choice for evaluating patients with suspected PE. Despite increased use of pulmonary CTA, the diagnostic yield for PE remains low. Study results suggest a potential benefit to the use of clinical decision tools in the diagnostic workup of suspected PE. PMID- 27959581 TI - Quality Assurance in Breast Pathology: Lessons Learned From a Review of Amended Reports. AB - CONTEXT: -A review of amended pathology reports provides valuable information regarding defects in the surgical pathology process. OBJECTIVE: -To review amended breast pathology reports with emphasis placed on interpretative errors and their mechanisms of detection. DESIGN: -All amended pathology reports for breast surgical specimens for a 5-year period at a large academic medical center were retrospectively identified and classified based on an established taxonomy. RESULTS: -Of 12 228 breast pathology reports, 122 amended reports were identified. Most (88 cases; 72%) amendments were due to noninterpretative errors, including 58 report defects, 12 misidentifications, and 3 specimen defects. A few (34 cases; 27.9%) were classified as misinterpretations, including 14 major diagnostic changes (11.5% of all amendments). Among major changes, there were cases of missed microinvasion or small foci of invasion, missed micrometastasis, atypical ductal hyperplasia overcalled as ductal carcinoma in situ, ductal carcinoma in situ involving sclerosing adenosis mistaken for invasive carcinoma, lymphoma mistaken for invasive carcinoma, and amyloidosis misdiagnosed as fat necrosis. Nine major changes were detected at interpretation of receptor studies and were not associated with clinical consequences. Three cases were associated with clinical consequences, and of note, the same pathologist interpreted the corresponding receptor studies. CONCLUSIONS: -Review of amended reports was a useful method for identifying error frequencies, types, and methods of detection. Any time that a case is revisited for ancillary studies or other reasons, it is an opportunity for the surgical pathologist to reconsider one's own or another's diagnosis. PMID- 27959580 TI - Performance Analysis of Evolutionary Algorithms for Steiner Tree Problems. AB - The Steiner tree problem (STP) aims to determine some Steiner nodes such that the minimum spanning tree over these Steiner nodes and a given set of special nodes has the minimum weight, which is NP-hard. STP includes several important cases. The Steiner tree problem in graphs (GSTP) is one of them. Many heuristics have been proposed for STP, and some of them have proved to be performance guarantee approximation algorithms for this problem. Since evolutionary algorithms (EAs) are general and popular randomized heuristics, it is significant to investigate the performance of EAs for STP. Several empirical investigations have shown that EAs are efficient for STP. However, up to now, there is no theoretical work on the performance of EAs for STP. In this article, we reveal that the (1+1) EA achieves 3/2-approximation ratio for STP in a special class of quasi-bipartite graphs in expected runtime [Formula: see text], where [Formula: see text], [Formula: see text], and [Formula: see text] are, respectively, the number of Steiner nodes, the number of special nodes, and the largest weight among all edges in the input graph. We also show that the (1+1) EA is better than two other heuristics on two GSTP instances, and the (1+1) EA may be inefficient on a constructed GSTP instance. PMID- 27959582 TI - RAI1 Alternate Probe Identifies Additional Breast Cancer Cases as Amplified Following Equivocal HER2 Fluorescence In Situ Hybridization Testing: Experience From a National Reference Laboratory. AB - CONTEXT: -In 2013 the American Society of Clinical Oncology and College of American Pathologists updated the HER2 guidelines and changed the equivocal category for HER2 in situ hybridization testing to an average HER2 copy number of 4.0 to 5.9 with a HER2:CEP17 ratio of less than 2.0 and proposed retesting, with an option of using another control probe to avoid false-negative results. RAI1, located at band position 17p11.2, is a popular alternate probe locus for retesting equivocal changes. OBJECTIVE: -To review experience with the RAI1 alternate probe in HER2 fluorescence in situ hybridization equivocal breast cancers. DESIGN: -Primary and metastatic breast cancers with equivocal HER2 fluorescence in situ hybridization, retested with an alternate (RAI1) probe, were identified. HER2, RAI1, and CEP17 copy numbers, HER2 to control probe ratios, and genetic heterogeneity were recorded. Hematoxylin-eosin-stained slides were reviewed for type and grade of cancer. RESULTS: -Of 876 cases tested with CEP17 as the reference probe, 97 (11.1%) had equivocal HER2 fluorescence in situ hybridization results. Additional testing with the RAI1 probe classified 39.2% cases (38 of 97) as amplified with a HER2:RAI1 ratio ranging from 2.0 to 3.2 (mean, 2.37); 3.1% (3 of 97) were still unclassifiable because of a deletion of RAI1. CONCLUSIONS: -RAI1 identified close to 40% of original HER2 fluorescence in situ hybridization equivocal cases as amplified, making these patients eligible for targeted therapies. It is not known whether guidelines for US Food and Drug Administration-approved probes can be extrapolated to alternate probes when an alternate control probe shows losses or gains. Because of the lack of guidelines for reporting HER2 status with alternate probes, laboratories face challenges in interpreting results. PMID- 27959583 TI - Unusual Presentations of Gynecologic Tumors: Extragonadal Yolk Sac Tumor of the Vulva. AB - Extragonadal germ cell tumors are uncommon, and although they morphologically resemble their gonadal counterparts, unexpected gonadal presentation increases the potential for erroneous diagnoses. Yolk sac tumor is a malignant germ cell tumor characterized by an extraembryonic yolk sac line of differentiation, and relative to other germ cell tumors, is characterized by varied and diverse histologic patterns. When occurring outside of typical age parameters or in extragonadal locations, the histologic variability of yolk sac tumor and its tendency to mimic somatic tumors pose diagnostic challenges. Because extragonadal yolk sac tumor of the vulva is very rare, with only isolated case reports and small series in the literature, it is often not considered in the differential diagnosis. As both prognosis and management of yolk sac tumor differ significantly from those of somatic tumors, accurate diagnosis is essential. This review discusses histologic features of extragonadal yolk sac tumor, addresses somatic tumors arising in the vulva for which yolk sac tumor may be confused, and provides guidance with respect to the use of immunohistochemistry in the diagnosis of yolk sac tumor. PMID- 27959584 TI - Statistical Literacy Among Academic Pathologists: A Survey Study to Gauge Knowledge of Frequently Used Statistical Tests Among Trainees and Faculty. AB - CONTEXT: -Statistical literacy can be defined as understanding the statistical tests and terminology needed for the design, analysis, and conclusions of original research or laboratory testing. Little is known about the statistical literacy of clinical or anatomic pathologists. OBJECTIVE: -To determine the statistical methods most commonly used in pathology studies from the literature and to assess familiarity and knowledge level of these statistical tests by pathology residents and practicing pathologists. DESIGN: -The most frequently used statistical methods were determined by a review of 1100 research articles published in 11 pathology journals during 2015. Familiarity with statistical methods was determined by a survey of pathology trainees and practicing pathologists at 9 academic institutions in which pathologists were asked to rate their knowledge of the methods identified by the focused review of the literature. RESULTS: -We identified 18 statistical tests that appear frequently in published pathology studies. On average, pathologists reported a knowledge level between "no knowledge" and "basic knowledge" of most statistical tests. Knowledge of tests was higher for more frequently used tests. Greater statistical knowledge was associated with a focus on clinical pathology versus anatomic pathology, having had a statistics course, having an advanced degree other than an MD degree, and publishing research. Statistical knowledge was not associated with length of pathology practice. CONCLUSIONS: -An audit of pathology literature reveals that knowledge of about 12 statistical tests would be sufficient to provide statistical literacy for pathologists. On average, most pathologists report they can interpret commonly used tests but are unable to perform them. Most pathologists indicated that they would benefit from additional statistical training. PMID- 27959585 TI - The 21st Century Cures Act - A View from the NIH. PMID- 27959586 TI - JOURNAL CLUB: Utility of Repeat Core Needle Biopsy of Musculoskeletal Lesions With Initially Nondiagnostic Findings. AB - OBJECTIVE: The purpose of the present study is to assess the utility of repeat image-guided core needle biopsy (CNB) of musculoskeletal lesions in the setting of initially nondiagnostic CNB findings. MATERIALS AND METHODS: A retrospective review was conducted of 1302 consecutive CNBs performed on bone or soft-tissue lesions at a single institution. Pediatric cases and spine lesions were not included. All cases for which a repeat biopsy of the same lesion was performed because biopsy results were nondiagnostic were included in the study. Tumor characteristics, such as lesion size and type (i.e., bone vs soft tissue), were correlated with the diagnostic yield on repeat biopsy. Technical factors, including the modality used, the number of passes performed, the gauge of the biopsy device, the time between biopsies, the radiologist performing the procedure, and the portion of the lesion biopsied, were also correlated. RESULTS: Twenty-six of the 1302 CNBs (2.0%) performed had been referred for repeat biopsy. A diagnosis was obtained for 10 of these 26 cases (38.5%) after repeat CNB. For five of the cases (19.2%), repeat CNB yielded a diagnosis of malignancy. Overall, 11 cases ultimately had histologic findings indicating malignancy, and five of these cases (45.4%) had diagnostic findings after rebiopsy. Of the 14 cases that were found to be benign, five (35.7%) had diagnostic findings after rebiopsy. One case was lost to follow-up. A statistically significant difference in the diagnostic yield was found in association with an increase in the number of passes (p = 0.047) and an increase in time (p = 0.020) between biopsies. CONCLUSION: Repeat CNB of musculoskeletal lesions with initially nondiagnostic biopsy findings can be useful. Increasing the number of passes on the second biopsy attempt is recommended. PMID- 27959587 TI - The "Double" Tessier 7 Cleft: An Unusual Presentation of a Transverse Facial Cleft. AB - Congenital macrostomia, or Tessier number 7 cleft, is a rare craniofacial anomaly. We present a unique patient with bilateral macrostomia that consisted of a "double" transverse cleft on the left side and a single transverse cleft on the right side. A staged reconstructive approach was used to repair the "double" left sided clefts. This staged technique produced a satisfactory aesthetic and functional outcome. PMID- 27959588 TI - Exosome-Mediated Telomere Instability in Human Breast Epithelial Cancer Cells after X Irradiation. AB - In directly irradiating cells, telomere metabolism is altered and similar effects have been observed in nontargeted cells. Exosomes and their cargo play dominant roles in communicating radiation-induced bystander effects with end points related to DNA damage. Here we report novel evidence that exosomes are also responsible for inducing telomere-related bystander effects. Breast epithelial cancer cells were exposed to either 2 Gy X rays, or exposed to irradiated cell conditioned media (ICCM), or exosomes purified from ICCM. Compared to control cells, telomerase activity decreased in the 2 Gy irradiated cells and both bystander samples after one population doubling. At the first population doubling, telomere length was shorter in the 2 Gy irradiated sample but not in the bystander samples. By 24 population doublings telomerase activity recovered to control levels in all samples; however, the 2 Gy irradiated sample continued to demonstrate short telomeres and both bystander samples acquired shorter telomeres. RNase treatment of exosomes prevented the bystander effects on telomerase and telomere length that were observed at 1 population doubling and 24 population doublings, respectively. Thermal denaturation by boiling eliminated the reduction of telomere length in bystander samples, suggesting that the protein fraction of exosomes also contributes to the telomeric effect. RNase treatment plus boiling abrogated all telomere-related effects in directly irradiated and bystander cell populations. These findings suggest that both proteins and RNAs of exosomes can induce alterations in telomeric metabolism, which can instigate genomic instability in epithelial cancer cells after X-ray irradiation. PMID- 27959589 TI - Ipilimumab for Patients with Relapse after Allogeneic Transplantation. PMID- 27959590 TI - Body Fatness and Cancer. PMID- 27959591 TI - Body Fatness and Cancer. PMID- 27959592 TI - CDK4 and CDK6 Inhibition in Breast Cancer - A New Standard. PMID- 27959593 TI - Randomized Trial of Thymectomy in Myasthenia Gravis. PMID- 27959594 TI - Randomized Trial of Thymectomy in Myasthenia Gravis. PMID- 27959595 TI - Randomized Trial of Thymectomy in Myasthenia Gravis. PMID- 27959596 TI - Tabes Dorsalis and Argyll Robertson Pupils. PMID- 27959597 TI - Adding Value by Talking More. PMID- 27959598 TI - A New Cell-Cycle Target in Cancer - Inhibiting Cyclin D-Dependent Kinases 4 and 6. PMID- 27959599 TI - Covering Undocumented Immigrants - State Innovation in California. PMID- 27959600 TI - Case 24-2016: A Man with Malaise, Weakness, and Hypercalcemia. PMID- 27959601 TI - Case 24-2016: A Man with Malaise, Weakness, and Hypercalcemia. PMID- 27959602 TI - Fresh versus Frozen Embryos in Polycystic Ovary Syndrome. PMID- 27959603 TI - Fresh versus Frozen Embryos in Polycystic Ovary Syndrome. PMID- 27959604 TI - Acute Pancreatitis. PMID- 27959605 TI - Obeticholic Acid in Primary Biliary Cholangitis. PMID- 27959606 TI - Obeticholic Acid in Primary Biliary Cholangitis. PMID- 27959608 TI - Simvastatin in the Acute Respiratory Distress Syndrome. PMID- 27959609 TI - Case 35-2016. A 62-Year-Old Man with Dysphagia. PMID- 27959610 TI - Acetazolamide in Lithium-Induced Nephrogenic Diabetes Insipidus. PMID- 27959611 TI - Heterotopic Pregnancy. PMID- 27959612 TI - Out-of-Network Emergency-Physician Bills - An Unwelcome Surprise. PMID- 27959613 TI - Palbociclib and Letrozole in Advanced Breast Cancer. AB - BACKGROUND: A phase 2 study showed that progression-free survival was longer with palbociclib plus letrozole than with letrozole alone in the initial treatment of postmenopausal women with estrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We performed a phase 3 study that was designed to confirm and expand the efficacy and safety data for palbociclib plus letrozole for this indication. METHODS: In this double-blind study, we randomly assigned, in a 2:1 ratio, 666 postmenopausal women with ER positive, HER2-negative breast cancer, who had not had prior treatment for advanced disease, to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was progression-free survival, as assessed by the investigators; secondary end points were overall survival, objective response, clinical benefit response, patient-reported outcomes, pharmacokinetic effects, and safety. RESULTS: The median progression-free survival was 24.8 months (95% confidence interval [CI], 22.1 to not estimable) in the palbociclib letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) in the placebo-letrozole group (hazard ratio for disease progression or death, 0.58; 95% CI, 0.46 to 0.72; P<0.001). The most common grade 3 or 4 adverse events were neutropenia (occurring in 66.4% of the patients in the palbociclib-letrozole group vs. 1.4% in the placebo-letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib-letrozole group and in none of the patients in the placebo-letrozole group. Permanent discontinuation of any study treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib letrozole group and in 13 patients (5.9%) in the placebo-letrozole group. CONCLUSIONS: Among patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib-letrozole. (Funded by Pfizer; PALOMA-2 ClinicalTrials.gov number, NCT01740427 .). PMID- 27959614 TI - Diabetes and Cause-Specific Mortality in Mexico City. AB - BACKGROUND: Most large, prospective studies of the effects of diabetes on mortality have focused on high-income countries where patients have access to reasonably good medical care and can receive treatments to establish and maintain good glycemic control. In those countries, diabetes less than doubles the rate of death from any cause. Few large, prospective studies have been conducted in middle-income countries where obesity and diabetes have become common and glycemic control may be poor. METHODS: From 1998 through 2004, we recruited approximately 50,000 men and 100,000 women 35 years of age or older into a prospective study in Mexico City, Mexico. We recorded the presence or absence of previously diagnosed diabetes, obtained and stored blood samples, and tracked 12 year disease-specific deaths through January 1, 2014. We accepted diabetes as the underlying cause of death only for deaths that were due to acute diabetic crises. We estimated rate ratios for death among participants who had diabetes at recruitment versus those who did not have diabetes at recruitment; data from participants who had chronic diseases other than diabetes were excluded from the main analysis. RESULTS: At the time of recruitment, obesity was common and the prevalence of diabetes rose steeply with age (3% at 35 to 39 years of age and >20% by 60 years of age). Participants who had diabetes had poor glycemic control (mean [+/-SD] glycated hemoglobin level, 9.0+/-2.4%), and the rates of use of other vasoprotective medications were low (e.g., 30% of participants with diabetes were receiving antihypertensive medication at recruitment and 1% were receiving lipid-lowering medication). Previously diagnosed diabetes was associated with rate ratios for death from any cause of 5.4 (95% confidence interval [CI], 5.0 to 6.0) at 35 to 59 years of age, 3.1 (95% CI, 2.9 to 3.3) at 60 to 74 years of age, and 1.9 (95% CI, 1.8 to 2.1) at 75 to 84 years of age. Between 35 and 74 years of age, the excess mortality associated with previously diagnosed diabetes accounted for one third of all deaths; the largest absolute excess risks of death were from renal disease (rate ratio, 20.1; 95% CI, 17.2 to 23.4), cardiac disease (rate ratio, 3.7; 95% CI, 3.2 to 4.2), infection (rate ratio, 4.7; 95% CI, 4.0 to 5.5), acute diabetic crises (8% of all deaths among participants who had previously diagnosed diabetes), and other vascular disease (mainly stroke). Little association was observed between diabetes and mortality from cirrhosis, cancer, or chronic obstructive pulmonary disease. CONCLUSIONS: In this study in Mexico, a middle-income country with high levels of obesity, diabetes was common, glycemic control was poor, and diabetes was associated with a far worse prognosis than that seen in high-income countries; it accounted for at least one third of all deaths between 35 and 74 years of age. (Funded by the Wellcome Trust and others.). PMID- 27959615 TI - Developmental Mechanisms of Aortic Valve Malformation and Disease. AB - Normal aortic valves are composed of valve endothelial cells (VECs) and valve interstitial cells (VICs). VICs are the major cell population and have distinct embryonic origins in the endocardium and cardiac neural crest cells. Cell signaling between the VECs and VICs plays critical roles in aortic valve morphogenesis. Disruption of major cell signaling pathways results in aortic valve malformations, including bicuspid aortic valve (BAV). BAV is a common congenital heart valve disease that may lead to calcific aortic valve disease (CAVD), but there is currently no effective medical treatment for this beyond surgical replacement. Mouse and human studies have identified causative gene mutations for BAV and CAVD via disrupted VEC to VIC signaling. Future studies on the developmental signaling mechanisms underlying aortic valve malformations and the pathogenesis of CAVD using genetically modified mouse models and patient induced pluripotent stem cells may identify new effective therapeutic targets for the disease. PMID- 27959607 TI - Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease. AB - BACKGROUND: Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin 12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS: We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of >=100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS: The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P<=0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS: Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .). PMID- 27959617 TI - Senescence in COPD and Its Comorbidities. AB - Chronic obstructive pulmonary disease (COPD) is regarded as a disease of accelerated lung aging. This affliction shows all of the hallmarks of aging, including telomere shortening, cellular senescence, activation of PI3 kinase-mTOR signaling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence, and a low-grade chronic inflammation (inflammaging). Many of these pathways are driven by chronic exogenous and endogenous oxidative stress. There is also a reduction in antiaging molecules, such as sirtuins and Klotho, which further accelerate the aging process. COPD is associated with several comorbidities (multimorbidity), such as cardiovascular and metabolic diseases, that share the same pathways of accelerated aging. Understanding these mechanisms has helped identify several novel therapeutic targets, and several drugs and dietary interventions are now in development to treat multimorbidity. PMID- 27959616 TI - Coronary Artery Development: Progenitor Cells and Differentiation Pathways. AB - Coronary artery disease (CAD) is the number one cause of death worldwide and involves the accumulation of plaques within the artery wall that can occlude blood flow to the heart and cause myocardial infarction. The high mortality associated with CAD makes the development of medical interventions that repair and replace diseased arteries a high priority for the cardiovascular research community. Advancements in arterial regenerative medicine could benefit from a detailed understanding of coronary artery development during embryogenesis and of how these pathways might be reignited during disease. Recent research has advanced our knowledge on how the coronary vasculature is built and revealed unexpected features of progenitor cell deployment that may have implications for organogenesis in general. Here, we highlight these recent findings and discuss how they set the stage to interrogate developmental pathways during injury and disease. PMID- 27959618 TI - Mechanisms of Organ Injury and Repair by Macrophages. AB - Macrophages regulate tissue regeneration following injury. They can worsen tissue injury by producing reactive oxygen species and other toxic mediators that disrupt cell metabolism, induce apoptosis, and exacerbate ischemic injury. However, they also produce a variety of growth factors, such as IGF-1, VEGF alpha, TGF-beta, and Wnt proteins that regulate epithelial and endothelial cell proliferation, myofibroblast activation, stem and tissue progenitor cell differentiation, and angiogenesis. Proresolving macrophages in turn restore tissue homeostasis by functioning as anti-inflammatory cells, and macrophage derived matrix metalloproteinases regulate fibrin and collagen turnover. However, dysregulated macrophage function impairs wound healing and contributes to the development of fibrosis. Consequently, the mechanisms that regulate these different macrophage activation states have become active areas of research. In this review, we discuss the common and unique mechanisms by which macrophages instruct tissue repair in the liver, nervous system, heart, lung, skeletal muscle, and intestine and illustrate how macrophages might be exploited therapeutically. PMID- 27959620 TI - Microglia in Physiology and Disease. AB - As the immune-competent cells of the brain, microglia play an increasingly important role in maintaining normal brain function. They invade the brain early in development, transform into a highly ramified phenotype, and constantly screen their environment. Microglia are activated by any type of pathologic event or change in brain homeostasis. This activation process is highly diverse and depends on the context and type of the stressor or pathology. Microglia can strongly influence the pathologic outcome or response to a stressor due to the release of a plethora of substances, including cytokines, chemokines, and growth factors. They are the professional phagocytes of the brain and help orchestrate the immunological response by interacting with infiltrating immune cells. We describe here the diversity of microglia phenotypes and their responses in health, aging, and disease. We also review the current literature about the impact of lifestyle on microglia responses and discuss treatment options that modulate microglial phenotypes. PMID- 27959621 TI - Mitochondrial Dysfunction in Lung Pathogenesis. AB - Remarkable new roles for mitochondria in calcium handling, apoptosis, heme turnover, inflammation, and oxygen and nutrient sensing have been discovered for organelles that were once thought to be simple energy converters. Although deficits in mitochondrial function are often associated with energy failure and apoptosis, working cells maintain a mitochondrial reserve that affords the organelles distinct homeostatic sensing and regulatory abilities in lung cells. As primary intracellular sources of oxidants, mitochondria serve as critical monitors and modulators of vital oxidation-reduction processes, including mitochondrial biogenesis, mitophagy, inflammasome activation, cell proliferation, and prevention of fibrosis. These processes participate in disease pathogenesis in all lung regions mainly when interference with mitochondrial quality control mechanisms impedes their roles in maintenance of lung health. Sharper identification of mitochondrial-driven signaling mechanisms in specific lung cell types will better refine our understanding of respiratory disease pathogenesis and lead to new diagnostic and therapeutic measures to support mitochondrial quality. PMID- 27959622 TI - DWI for Assessment of Rectal Cancer Nodes After Chemoradiotherapy: Is the Absence of Nodes at DWI Proof of a Negative Nodal Status? AB - OBJECTIVE: When considering organ preservation in patients with rectal cancer with good tumor response, assessment of a node-negative status after chemoradiation therapy (CRT) is important. DWI is a very sensitive technique to detect nodes. The study aim was to test the hypothesis that the absence of nodes at DWI after CRT is concordant with a ypN0 status. MATERIALS AND METHODS: A retrospective study was performed of 90 patients with rectal cancer treated with CRT followed by restaging MRI at 1.5 T, including DWI (highest b value, 1000 s/mm2). Two independent readers counted the number of nodes visible in the mesorectal compartment on DW images obtained after CRT. The number of nodes on DWI (0 vs >= 1) was compared with the number of metastatic nodes at histopathology or long-term clinical follow-up (yN0 vs yN-positive status). RESULTS: Seventy-one patients had a yN0 status, and 19 had a yN-positive status. For 10 patients, no nodes were observed at DWI, which was concordant with a yN0 status in 100% of cases. In the other 61 patients with a yN0 status, the median number of nodes detected at DWI was three (range, 1-17 nodes). To differentiate between yN0 and yN-positive status, sensitivity was 100%, specificity was 14%, the positive predictive value was 24%, and the negative predictive value was 100%. CONCLUSION: Although the absence of nodes at DWI is not a frequent finding, it appears to be a reliable predictor of yN0 status after CRT in patients with rectal cancer. DWI may thus be a helpful adjunct in assessing response after CRT and may help select patients for organ-saving treatment. PMID- 27959619 TI - Macrophages and the Recovery from Acute and Chronic Inflammation. AB - In recent years, researchers have devoted much attention to the diverse roles of macrophages and their contributions to tissue development, wound healing, and angiogenesis. What should not be lost in the discussions regarding the diverse biology of these cells is that when perturbed, macrophages are the primary contributors to potentially pathological inflammatory processes. Macrophages stand poised to rapidly produce large amounts of inflammatory cytokines in response to danger signals. The production of these cytokines can initiate a cascade of inflammatory mediator release that can lead to wholesale tissue destruction. The destructive inflammatory capability of macrophages is amplified by exposure to exogenous interferon-gamma, which prolongs and heightens inflammatory responses. In simple terms, macrophages can thus be viewed as incendiary devices with hair triggers waiting to detonate. We have begun to ask questions about how these cells can be regulated to mitigate the collateral destruction associated with macrophage activation. PMID- 27959624 TI - Will There Be a Cure for Ebola? AB - Despite the unprecedented Ebola virus outbreak response in West Africa, no Ebola medical countermeasures have been approved by the US Food and Drug Administration. However, multiple valuable lessons have been learned about the conduct of clinical research in a resource-poor, high risk-pathogen setting. Numerous therapeutics were explored or developed during the outbreak, including repurposed drugs, nucleoside and nucleotide analogues (BCX4430, brincidofovir, favipiravir, and GS-5734), nucleic acid-based drugs (TKM-Ebola and AVI-7537), and immunotherapeutics (convalescent plasma and ZMapp). We review Ebola therapeutics progress in the aftermath of the West Africa Ebola virus outbreak and attempt to offer a glimpse of a path forward. PMID- 27959625 TI - Soft-Tissue Tumor Contrast Enhancement Patterns: Diagnostic Value and Comparison Between Ultrasound and MRI. AB - OBJECTIVE: The purpose of this study was to assess and compare contrast-enhanced ultrasound and MRI patterns in the diagnosis of soft-tissue masses. MATERIALS AND METHODS: Two hundred fifty-five consecutively registered patients with histologically confirmed soft-tissue masses were included in this retrospective study. The diagnostic properties of four predefined contrast enhancement (CE) patterns were assessed, and logistic regression analysis was performed to determine the correlation between diagnosis and CE pattern, lesion size, and patient age and sex. The influence of lesion size on the occurrence of inhomogeneous CE patterns in malignancies was also determined. RESULTS: Homogeneous CE patterns were highly specific for benignity, and inhomogeneous CE was moderately specific for malignancy in both ultrasound and MRI. A combination of homogeneous and inhomogeneous CE patterns led to 88.3% and 88.7% sensitivity, 66.7% and 59.7% specificity, 73.4% and 68.2% correct classification, 54.6% and 47.8% positive predictive value, 92.6% and 92.7% negative predictive value, 2.65 and 2.20 positive likelihood ratio, and 0.18 and 0.19 negative likelihood ratio for contrast-enhanced ultrasound and contrast-enhanced MRI. Cases with homogeneous CE in either ultrasound or MRI also were predominantly benign. The occurrence of inhomogeneous CE in malignant lesions increased with size. CONCLUSION: CE patterns in ultrasound and MRI offer additional information about the differentiation of an unknown soft-tissue mass. The results of this study showed that homogeneous or absent CE was specific for benign differentiation and that heterogeneous CE was linked to malignancy. The routine analysis of CE patterns should increase diagnostic reliability in unclear soft-tissue masses. PMID- 27959626 TI - The Pathogenesis of Ebola Virus Disease. AB - For almost 50 years, ebolaviruses and related filoviruses have been repeatedly reemerging across the vast equatorial belt of the African continent to cause epidemics of highly fatal hemorrhagic fever. The 2013-2015 West African epidemic, by far the most geographically extensive, most fatal, and longest lasting epidemic in Ebola's history, presented an enormous international public health challenge, but it also provided insights into Ebola's pathogenesis and natural history, clinical expression, treatment, prevention, and control. Growing understanding of ebolavirus pathogenetic mechanisms and important new clinical observations of the disease course provide fresh clues about prevention and treatment approaches. Although viral cytopathology and immune-mediated cell damage in ebolavirus disease often result in severe compromise of multiple organs, tissue repair and organ function recovery can be expected if patients receive supportive care with fluids and electrolytes; maintenance of oxygenation and tissue perfusion; and respiratory, renal, and cardiovascular support. Major challenges for managing future Ebola epidemics include establishment of early and aggressive epidemic control and earlier and better patient care and treatment in remote, resource-poor areas where Ebola typically reemerges. In addition, it will be important to further develop Ebola vaccines and to adopt policies for their use in epidemic and pre-epidemic situations. PMID- 27959623 TI - Nanobodies to Study G Protein-Coupled Receptor Structure and Function. AB - Ligand-induced activation of G protein-coupled receptors (GPCRs) is a key mechanism permitting communication between cells and organs. Enormous progress has recently elucidated the structural and dynamic features of GPCR transmembrane signaling. Nanobodies, the recombinant antigen-binding fragments of camelid heavy chain-only antibodies, have emerged as important research tools to lock GPCRs in particular conformational states. Active-state stabilizing nanobodies have elucidated several agonist-bound structures of hormone-activated GPCRs and have provided insight into the dynamic character of receptors. Nanobodies have also been used to stabilize transient GPCR transmembrane signaling complexes, yielding the first structural insights into GPCR signal transduction across the cellular membrane. Beyond their in vitro uses, nanobodies have served as conformational biosensors in living systems and have provided novel ways to modulate GPCR function. Here, we highlight several examples of how nanobodies have enabled the study of GPCR function and give insights into potential future uses of these important tools. PMID- 27959628 TI - Signaling and Immune Regulation in Melanoma Development and Responses to Therapy. AB - Melanoma is a complex and genomically diverse malignancy, and new genes and signaling pathways involved in pathogenesis continue to be discovered. Mechanistic insights into gene and immune regulation in melanoma have led to the development of numerous successful and innovative pharmacologic agents over recent years. Multiple targeted therapies and immunotherapies have already entered the clinic, becoming new standards of care and transforming the prognosis for many patients with malignant melanoma. In this review, we provide an overview of the current understanding of signaling and immune regulation in melanoma and implications for responses to treatment, organized in the framework of hallmark characteristics in cancer. PMID- 27959627 TI - Humanized Mouse Models of Clinical Disease. AB - Immunodeficient mice engrafted with functional human cells and tissues, that is, humanized mice, have become increasingly important as small, preclinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (IL2rgnull) in the early 2000s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers. Humanized mice are permitting significant progress in studies of human infectious disease, cancer, regenerative medicine, graft-versus-host disease, allergies, and immunity. Ultimately, use of humanized mice may lead to the implementation of truly personalized medicine in the clinic. This review discusses recent progress in the development and use of humanized mice and highlights their utility for the study of human diseases. PMID- 27959631 TI - The Microscope as a Tool for Disease Discovery-A Personal Voyage. AB - This review reflects the trajectory of my career in hematopathology, and my personal reflections on scientific advances in the field. During the course of more than 40 years, the approach to classification of hematological malignancies has evolved from descriptive approaches, based on either cytological or clinical features, to a modern approach, which incorporates cutting-edge technologies. My philosophy has focused on defining individual diseases, an approach that can best lead to an understanding of molecular pathogenesis. To quote Carolus Linnaeus ( 1 , p. 19), the father of taxonomy, "The first step in wisdom is to know the things themselves; this notion consists in having a true idea of the objects; objects are distinguished and known by classifying them methodically and giving them appropriate names. Therefore, classification and name-giving will be the foundation of our science." PMID- 27959629 TI - Complement Dysregulation and Disease: Insights from Contemporary Genetics. AB - The vertebrate complement system consists of sequentially interacting proteins that provide for a rapid and powerful host defense. Nearly 60 proteins comprise three activation pathways (classical, alternative, and lectin) and a terminal cytolytic pathway common to all. Attesting to its potency, nearly half of the system's components are engaged in its regulation. An emerging theme over the past decade is that variations in these inhibitors predispose to two scourges of modern humans. One, occurring most often in childhood, is a rare but deadly thrombomicroangiopathy called atypical hemolytic uremic syndrome. The other, age related macular degeneration, is the most common form of blindness in the elderly. Their seemingly unrelated clinical presentations and pathologies share the common theme of overactivity of the complement system's alternative pathway. This review summarizes insights gained from contemporary genetics for understanding how dysregulation of this powerful innate immune system leads to these human diseases. PMID- 27959630 TI - Necroptosis: Mechanisms and Relevance to Disease. AB - Necroptosis is a form of regulated cell death that critically depends on receptor interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain like (MLKL) and generally manifests with morphological features of necrosis. The molecular mechanisms that underlie distinct instances of necroptosis have just begun to emerge. Nonetheless, it has already been shown that necroptosis contributes to cellular demise in various pathophysiological conditions, including viral infection, acute kidney injury, and cardiac ischemia/reperfusion. Moreover, human tumors appear to obtain an advantage from the downregulation of key components of the molecular machinery for necroptosis. Although such an advantage may stem from an increased resistance to adverse microenvironmental conditions, accumulating evidence indicates that necroptosis-deficient cancer cells are poorly immunogenic and hence escape natural and therapy-elicited immunosurveillance. Here, we discuss the molecular mechanisms and relevance to disease of necroptosis. PMID- 27959634 TI - Emerging Concepts and Technologies for the Discovery of Microorganisms Involved in Human Disease. AB - Established infectious agents continue to be a major cause of human morbidity and mortality worldwide. However, the causative agent remains unknown for a wide range of diseases; many of these are suspected to be attributable to yet undiscovered microorganisms. The advent of unbiased high-throughput sequencing and bioinformatics has enabled rapid identification and molecular characterization of known and novel infectious agents in human disease. An exciting era of microbe discovery, now under way, holds great promise for the improvement of global health via the development of antimicrobial therapies, vaccination strategies, targeted public health measures, and probiotic-based preventions and therapies. Here, we review the history of pathogen discovery, discuss improvements and clinical applications for the detection of microbially associated diseases, and explore the challenges and strategies for establishing causation in human disease. PMID- 27959633 TI - Engineering Therapeutic T Cells: From Synthetic Biology to Clinical Trials. AB - Engineered T cells are currently in clinical trials to treat patients with cancer, solid organ transplants, and autoimmune diseases. However, the field is still in its infancy. The design, and manufacturing, of T cell therapies is not standardized and is performed mostly in academic settings by competing groups. Reliable methods to define dose and pharmacokinetics of T cell therapies need to be developed. As of mid-2016, there are no US Food and Drug Administration (FDA) approved T cell therapeutics on the market, and FDA regulations are only slowly adapting to the new technologies. Further development of engineered T cell therapies requires advances in immunology, synthetic biology, manufacturing processes, and government regulation. In this review, we outline some of these challenges and discuss the contributions that pathologists can make to this emerging field. PMID- 27959636 TI - Amyloidosis: Insights from Proteomics. AB - Amyloidoses are a spectrum of disorders caused by abnormal folding and extracellular deposition of proteins. The deposits lead to tissue damage and organ dysfunction, particularly in the heart, kidneys, and nerves. There are at least 30 different proteins that can cause amyloidosis. The clinical management depends entirely on the type of protein deposited, and thus on the underlying pathogenesis, and often requires high-risk therapeutic intervention. Application of mass spectrometry-based proteomic technologies for analysis of amyloid plaques has transformed the way amyloidosis is diagnosed and classified. Proteomic assays have been extensively used for clinical management of patients with amyloidosis, providing unprecedented diagnostic and biological information. They have shed light on the pathogenesis of different amyloid types and have led to identification of numerous new amyloid types, including ALECT2 amyloidosis, which is now recognized as one of the most common causes of systemic amyloidosis in North America. PMID- 27959632 TI - The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer. AB - Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy. PMID- 27959639 TI - Physicochemical Property Variation in Spider Silk: Ecology, Evolution, and Synthetic Production. AB - The unique combination of great stiffness, strength, and extensibility makes spider major ampullate (MA) silk desirable for various biomimetic and synthetic applications. Intensive research on the genetics, biochemistry, and biomechanics of this material has facilitated a thorough understanding of its properties at various levels. Nevertheless, methods such as cloning, recombination, and electrospinning have not successfully produced materials with properties as impressive as those of spider silk. It is nevertheless becoming clear that silk properties are a consequence of whole-organism interactions with the environment in addition to genetic expression, gland biochemistry, and spinning processes. Here we assimilate the research done and assess the techniques used to determine distinct forms of spider silk chemical and physical property variability. We suggest that more research should focus on testing hypotheses that explain spider silk property variations in ecological and evolutionary contexts. PMID- 27959640 TI - Bengt Saltin and exercise physiology: a perspective. AB - This perspective highlights some of the key contributions of Professor Bengt Saltin (1935-2014) to exercise physiology. The emergence of exercise physiology from work physiology as his career began is discussed as are his contributions in a number of areas. Saltin's open and question-based style of leadership is a model for the future of our field. PMID- 27959638 TI - Comparison of Vascular Plugs and Pushable Coils for Variceal Embolization After TIPS. AB - OBJECTIVE: Transjugular intrahepatic portosystemic shunt (TIPS) with variceal embolization is routinely performed to treat variceal bleeding. Embolization using vascular plugs is reported, but outcomes are not known. Outcomes and material costs of embolization using vascular plugs and coils are compared. MATERIALS AND METHODS: A single center's medical records of TIPS procedures (May 2003-December 2014) with variceal embolization were reviewed. Twenty patients with vascular plug embolization (age [+/- SD], 50 +/- 10 years; seven men and 13 women; median Model for End-Stage Liver Disease [MELD], 20; interquartile range [IQR], 14-23) were compared with an age-, sex-, and MELD-matched cohort who underwent coil embolization (age, 50 +/- 9 years; seven men and 13 women; median MELD, 17; IQR, 15-19; p = 0.52). Procedure details, primary outcome (rebleeding), secondary outcome (mortality), and costs were compared. RESULTS: Vascular plug use was associated with a lower fluoroscopy time (49.05 minutes [IQR, 36-62] vs 68 minutes [IQR, 49-76]; p = 0.006) and total procedure time (255 minutes [IQR, 205-290] for vascular plugs vs 275 minutes [IQR, 230-330]; p = 0.05). Total volume of contrast agent used was similar (180 mL [IQR, 155-234] for vascular plugs vs 210 mL [IQR, 185-261]; p = 0.14). In patients with at least a 30-day follow-up, rebleeding rates (2/17 [12%] for vascular plugs vs 4/15 [27%]; p = 0.40) and mortality (2/17 [12%] for vascular plugs vs 4/15 [27%]; p = 0.66) were similar. Per procedure, vascular plugs cost significantly more than coils ($1292 +/- $676 vs $228 +/- $292, p < 0.0001). CONCLUSION: The use of vascular plugs or coils has similar outcomes for variceal embolization after TIPS. The advantages of vascular plug use (i.e., reduced fluoroscopy or procedure time) may be offset by increased material cost, a trade-off that merits further study given current cost concerns in health care. PMID- 27959641 TI - Dietary intake and prospective changes in cardiometabolic risk factors in children and youth. AB - Only few studies examined the effect of diet on prospective changes in cardiometabolic (CM) risk factors in children and youth despite its importance for understanding the role of diet early in life for cardiovascular disease in adulthood. To test the hypothesis that dietary intake is associated with prospective changes in CM risk factors, we analyzed longitudinal observations made over a period of 2 years among 448 students (aged 10-17 years) from 14 schools in Canada. We applied mixed effect regression to examine the associations of dietary intake at baseline with changes in body mass index, waist circumference (WC), systolic and diastolic blood pressure (SBP and DBP), and insulin sensitivity score between baseline and follow-up while adjusting for age, sex, and physical activity. Dietary fat at baseline was associated with increases in SBP and DBP z scores (per 10 g increase in dietary fat per day: beta = 0.03; p < 0.05) and WC (beta = 0.31 cm; p < 0.05) between baseline and follow-up. Every additional gram of sodium intake at baseline was associated with an increase in DBP z score of 0.04 (p < 0.05) between baseline and follow-up. Intake of sugar, vegetables and fruit, and fibre were not associated with changes in CM risk factors in a statistically significant manner. Our findings suggest that a reduction in the consumption of total dietary fat and sodium may contribute to the prevention of excess body weight and hypertension in children and youth, and their cardiometabolic sequelae later in life. PMID- 27959635 TI - The Varied Roles of Notch in Cancer. AB - Notch receptors influence cellular behavior by participating in a seemingly simple signaling pathway, but outcomes produced by Notch signaling are remarkably varied depending on signal dose and cell context. Here, after briefly reviewing new insights into physiologic mechanisms of Notch signaling in healthy tissues and defects in Notch signaling that contribute to congenital disorders and viral infection, we discuss the varied roles of Notch in cancer, focusing on cell autonomous activities that may be either oncogenic or tumor suppressive. PMID- 27959637 TI - Immunopathogenesis of Chronic Rhinosinusitis and Nasal Polyposis. AB - Chronic rhinosinusitis (CRS) is a troublesome, chronic inflammatory disease that affects over 10% of the adult population, causing decreased quality of life, lost productivity, and lost time at work and leading to more than a million surgical interventions annually worldwide. The nose, paranasal sinuses, and associated lymphoid tissues play important roles in homeostasis and immunity, and CRS significantly impairs these normal functions. Pathogenic mechanisms of CRS have recently become the focus of intense investigations worldwide, and significant progress has been made. The two main forms of CRS that have been long recognized, with and without nasal polyps, are each now known to be heterogeneous, based on underlying mechanism, geographical location, and race. Loss of the immune barrier, including increased permeability of mucosal epithelium and reduced production of important antimicrobial substances and responses, is a common feature of many forms of CRS. One form of CRS with polyps found worldwide is driven by the cytokines IL-5 and IL-13 coming from Th2 cells, type 2 innate lymphoid cells, and probably mast cells. Type 2 cytokines activate inflammatory cells that are implicated in the pathogenic mechanism, including mast cells, basophils, and eosinophils. New classes of biological drugs that block the production or action of these cytokines are making important inroads toward new treatment paradigms in polypoid CRS. PMID- 27959642 TI - Using exercise training to understand control of skeletal muscle metabolism. AB - Bengt Saltin believed that exercise was the unsurpassed tool to study human integrative physiology. He demonstrated this over the course of his career by employing physical training as a model to advance our understanding of skeletal muscle metabolic control and the impact of physical activity on performance and health. Bengt was also a pioneer in advocating the concept of exercise is medicine. His scientific curiosity was perhaps exceeded only by his generosity. PMID- 27959643 TI - Bone Formation and the Wnt Signaling Pathway. PMID- 27959644 TI - Bone Formation and the Wnt Signaling Pathway. PMID- 27959645 TI - Diagnosing Myasthenia Gravis with an Ice Pack. PMID- 27959646 TI - Personal Health Budgets for Patients with Complex Needs. PMID- 27959647 TI - Vitamin D Deficiency - Is There Really a Pandemic? PMID- 27959648 TI - Mitochondrial Matchmaking. PMID- 27959649 TI - Hemothorax after Thoracentesis. PMID- 27959650 TI - Meaning and the Nature of Physicians' Work. PMID- 27959651 TI - Innate Immunity and Asthma Risk. PMID- 27959652 TI - Innate Immunity and Asthma Risk. PMID- 27959653 TI - Initiation of Renal-Replacement Therapy in the Intensive Care Unit. PMID- 27959654 TI - Initiation of Renal-Replacement Therapy in the Intensive Care Unit. PMID- 27959655 TI - Initiation of Renal-Replacement Therapy in the Intensive Care Unit. PMID- 27959656 TI - Genital Herpes. PMID- 27959657 TI - Genital Herpes. PMID- 27959658 TI - Embodying the Three Rs in Fiji. PMID- 27959659 TI - Fire-Related Inhalation Injury. PMID- 27959660 TI - Fire-Related Inhalation Injury. PMID- 27959661 TI - Fire-Related Inhalation Injury. PMID- 27959662 TI - Fire-Related Inhalation Injury. PMID- 27959663 TI - Heart Failure with Preserved Ejection Fraction. PMID- 27959664 TI - Case 34-2016. A 17-Year-Old Boy with Myopia and Craniofacial and Skeletal Abnormalities. PMID- 27959665 TI - Retrospective Analysis of the Safety and Cost Implications of Pediatric Contrast Enhanced Ultrasound at a Single Center. AB - OBJECTIVE: Because of concern over medical ionizing radiation exposure of children, contrast-enhanced ultrasound (CEUS) has generated interest as an inexpensive, ionizing radiation-free alternative to CT and MRI. CEUS has received approval for pediatric hepatic use but remains off-label for a range of other applications. The purposes of this study were to retrospectively analyze adverse incidents encountered in pediatric CEUS and to assess the financial benefits of reducing the number of CT and MRI examinations performed. MATERIALS AND METHODS: All pediatric (patients 18 years and younger) CEUS examinations performed between January 2008 and December 2015 were reviewed. All immediate reactions deemed due to contrast examinations were documented in radiology reports. Electronic patient records were examined for adverse reactions within 24 hours not due to an underlying pathologic condition. With tariffs from the U.K. National Institute of Clinical Excellence analysis, CEUS utilization cost ($94) was compared with the CT ($168) and MRI ($274) costs of the conventional imaging pathway. RESULTS: The records of 305 pediatric patients (187 boys, 118 girls; age range, 1 month-18 years) undergoing CEUS were reviewed. Most of the studies were for characterizing liver lesions (147/305 [48.2%]) and trauma (113/305 [37.1%]); the others were for renal, vascular, and intracavitary assessment (45/305 [14.8%]). No immediate adverse reactions occurred. Delayed adverse reactions occurred in two patients (2/305 [0.7%]). These reactions were transient hypertension and transient tachycardia. Neither was symptomatic, and both were deemed not due to the underlying disorder. The potential cost savings of CEUS were $74 per examination over CT and $180 over MRI. CONCLUSION: Pediatric CEUS is a safe and potentially cost-effective imaging modality. Using it allows reduction in the ionizing radiation associated with CT and in the gadolinium contrast administration, sedation, and anesthesia sometimes required for MRI. PMID- 27959666 TI - Hematocrit and Hemoglobin Levels of Nonhuman Apes at Moderate Altitudes: A Comparison with Humans. AB - Mortola, Jacopo P. and DeeAnn Wilfong. Hematocrit and hemoglobin levels of nonhuman apes at moderate altitudes: a comparison with humans. High Alt Med Biol. 17:323-335, 2016.-We asked to what extent the hematologic response (increase in hematocrit [Hct] and in blood hemoglobin concentration [Hb]) of humans to altitude hypoxia was shared by our closest relatives, the nonhuman apes. Data were collected from 29 specimens of 7 species of apes at 2073 m altitude (barometric pressure Pb = 598 mm Hg); additional data originated from apes located at a lower altitude (1493 m, Pb = 639 mm Hg). The human altitude profiles of Hct and Hb between sea level and 3000 m were constructed from a compilation of literature sources that (all combined) comprised data sets of 10,000-12,000 subjects for each gender. These human data were binned for 0-250 m altitude (sea level) and for each 500 m of progressively higher altitudes. Values of Hb and Hct of both men and women were significantly higher than at sea level at the 1500 bin (1250-1750 m); hence, the altitude threshold for the human hematological responses must be between 1000 and 1500 m. In the nonhuman apes, no increase in Hct or Hb was apparent at 1500 m; at 2000 m, the increase was significant only for the Hb of females. At either altitude in the group of nonhuman apes, the increase in Hct was much less than in humans, and that of Hb was significantly less at 1500 m. We conclude that lack of, or minimal, hematopoietic response to moderate altitude can occur in mammalian species that are not genetically adapted to high altitudes. Polycythemia is not a common response to altitude hypoxia and, at least at moderate altitudes, the degree of the human response may represent the exception among apes rather than the rule. PMID- 27959668 TI - ? PMID- 27959669 TI - Impacts of Petroleum-Derived Pollutants on Fish Development. AB - The teleost fish embryo is particularly sensitive to petroleum hydrocarbons (polycyclic aromatic hydrocarbons, PAHs) at two distinct stages of development. The first is early during cleavage stages when PAHs alter normal signaling associated with establishment of the dorsal-ventral axis. This disruption involves the Wnt/beta-catenin pathway and results in hyperdorsalized embryos that do not survive to hatching. The second, more sensitive period is during heart development, when oil and PAHs cause abnormal development of the heart as well as cardiac edema and arrhythmia. Even at extremely low levels (ng/L), PAHs cause subtle edema and altered contractility and heart rate, which impair swimming performance. Some PAHs are extremely phototoxic, such that exposures to trace concentrations result in severe membrane damage and mortality in sunlight. The developing fish embryo is a sensitive indicator of petroleum constituents in the environment, and healthy populations of fish likely require limited PAH exposure during development. PMID- 27959667 TI - Bench Evaluation of Four Portable Oxygen Concentrators Under Different Conditions Representing Altitudes of 2438, 4200, and 8000 m. AB - Bunel, Vincent, Amr Shoukri, Frederic Choin, Serge Roblin, Cindy Smith, Thomas Similowski, Capucine Morelot-Panzini, and Jesus Gonzalez. Bench evaluation of four portable oxygen concentrators under different conditions representing altitudes of 2438, 4200, and 8000 m. High Alt Med Biol. 17:370-374, 2016.-Air travel is responsible for a reduction of the partial pressure of oxygen (O2) as a result of the decreased barometric pressure. This hypobaric hypoxia can be dangerous for passengers with respiratory diseases, requiring initiation or intensification of oxygen therapy during the flight. In-flight oxygen therapy can be provided by portable oxygen concentrators, which are less expensive and more practical than oxygen cylinders, but no study has evaluated their capacity to concentrate oxygen under simulated flight conditions. We tested four portable oxygen concentrators during a bench test study. The O2 concentrations (FO2) produced were measured under three different conditions: in room air at sea level, under hypoxia due to a reduction of the partial pressure of O2 (normobaric hypoxia, which can be performed routinely), and under hypoxia due to a reduction of atmospheric pressure (hypobaric hypoxia, using a chamber manufactured by Airbus Defence and Space). The FO2 obtained under conditions of hypobaric hypoxia (chamber) was lower than that measured in room air (0.92 [0.89-0.92] vs. 0.93 [0.92-0.94], p = 0.029), but only one portable oxygen concentrator was unable to maintain an FO2 >= 0.90 (0.89 [0.89-0.89]). In contrast, under conditions of normobaric hypoxia (tent) simulating an altitude of 2438 m, none of the apparatuses tested was able to achieve an FO2 greater than 0.76. (0.75 [0.75 0.76] vs. 0.93 [0.92-0.94], p = 0.029). Almost all portable oxygen concentrators were able to generate a sufficient quantity of O2 at simulated altitudes of 2438 m and can therefore be used in the aircraft cabin. Unfortunately, verification of the reliability and efficacy of these devices in a patient would require a nonroutinely available technology, and no preflight test can currently be performed by using simple techniques such as hypobaric hypoxia. PMID- 27959670 TI - Preattachment Embryos of Domestic Animals: Insights into Development and Paracrine Secretions. AB - In mammalian species, endometrial receptivity is driven by maternal factors independently of embryo signals. When pregnancy initiates, paracrine secretions of the preattachment embryo are essential both for maternal recognition and endometrium preparation for implantation and for coordinating development of embryonic and extraembryonic tissues of the conceptus. This review mainly focuses on domestic large animal species. We first illustrate the major steps of preattachment embryo development, including elongation in bovine, ovine, porcine, and equine species. We next highlight conceptus secretions that are involved in the communication between extraembryonic and embryonic tissues, as well as between the conceptus and the endometrium. Finally, we introduce experimental data demonstrating the intimate connection between conceptus secretions and endometrial activity and how adverse events perturbing this interplay may affect the progression of implantation that will subsequently impact pregnancy outcome, postnatal health, and expression of production traits in livestock offspring. PMID- 27959671 TI - Neglected - Cancer Care and Mental Health in Rural America. PMID- 27959672 TI - Cost Containment and the Tale of Care Coordination. PMID- 27959673 TI - All-Payer Claims Databases - Uses and Expanded Prospects after Gobeille. PMID- 27959674 TI - Tinea Imbricata. PMID- 27959675 TI - Wasting Energy to Treat Obesity. PMID- 27959676 TI - Drugging the Undruggable Ras - Immunotherapy to the Rescue? PMID- 27959677 TI - Biologic and Clinical Perspectives on Thyroid Cancer. PMID- 27959678 TI - Biologic and Clinical Perspectives on Thyroid Cancer. PMID- 27959679 TI - Implantable Cardioverter-Defibrillators in Nonischemic Cardiomyopathy. PMID- 27959680 TI - CPAP in Obstructive Sleep Apnea. PMID- 27959681 TI - CPAP in Obstructive Sleep Apnea. PMID- 27959682 TI - Intensive Blood-Pressure Lowering in Cerebral Hemorrhage. PMID- 27959683 TI - Intensive Blood-Pressure Lowering in Cerebral Hemorrhage. PMID- 27959684 TI - T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. AB - We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11*1011 HLA-C*08:02-restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08:02. PMID- 27959685 TI - Screening for Babesia microti in the U.S. Blood Supply. AB - BACKGROUND: Babesia microti, a tickborne intraerythrocytic parasite that can be transmitted by means of blood transfusion, is responsible for the majority of cases of transfusion-transmitted babesiosis in the United States. However, no licensed test exists for screening for B. microti in donated blood. We assessed data from a large-scale, investigational product-release screening and donor follow-up program. METHODS: From June 2012 through September 2014, we performed arrayed fluorescence immunoassays (AFIAs) for B. microti antibodies and real-time polymerase-chain-reaction (PCR) assays for B. microti DNA on blood-donation samples obtained in Connecticut, Massachusetts, Minnesota, and Wisconsin. We determined parasite loads with the use of quantitative PCR testing and assessed infectivity by means of the inoculation of hamsters and the subsequent examination for parasitemia. Donors with test-reactive samples were followed. Using data on cases of transfusion-transmitted babesiosis, we compared the proportions of screened versus unscreened donations that were infectious. RESULTS: Of 89,153 blood-donation samples tested, 335 (0.38%) were confirmed to be positive, of which 67 (20%) were PCR-positive; 9 samples were antibody negative (i.e., 1 antibody-negative sample per 9906 screened samples), representing 13% of all PCR-positive samples. PCR-positive samples were identified all through the year; antibody-negative infections occurred from June through September. Approximately one third of the red-cell samples from PCR positive or high-titer AFIA-positive donations infected hamsters. Follow-up showed DNA clearance in 86% of the donors but antibody seroreversion in 8% after 1 year. In Connecticut and Massachusetts, no reported cases of transfusion transmitted babesiosis were associated with screened donations (i.e., 0 cases per 75,331 screened donations), as compared with 14 cases per 253,031 unscreened donations (i.e., 1 case per 18,074 unscreened donations) (odds ratio, 8.6; 95% confidence interval, 0.51 to 144; P=0.05). Overall, 29 cases of transfusion transmitted babesiosis were linked to blood from infected donors, including blood obtained from 10 donors whose samples tested positive on the PCR assay 2 to 7 months after the implicated donation. CONCLUSIONS: Blood-donation screening for antibodies to and DNA from B. microti was associated with a decrease in the risk of transfusion-transmitted babesiosis. (Funded by the American Red Cross and Imugen; ClinicalTrials.gov number, NCT01528449 .). PMID- 27959686 TI - Efficacy of Convalescent Plasma in Relation to Dose of Ebola Virus Antibodies. PMID- 27959687 TI - Case 37-2016. An 86-Year-Old Woman with Leukocytosis and Splenomegaly. PMID- 27959688 TI - Real-World Evidence - What Is It and What Can It Tell Us? PMID- 27959689 TI - Tongue Fasciculations in Organophosphate Poisoning. PMID- 27959690 TI - Variants in ANGPTL4 and the Risk of Coronary Artery Disease. PMID- 27959691 TI - Variants in ANGPTL4 and the Risk of Coronary Artery Disease. PMID- 27959693 TI - Interpreting Geographic Variations in Results of Randomized, Controlled Trials. PMID- 27959692 TI - Variants in ANGPTL4 and the Risk of Coronary Artery Disease. PMID- 27959694 TI - The Rising Price of Naloxone - Risks to Efforts to Stem Overdose Deaths. PMID- 27959695 TI - Prolonged Zika Virus Viremia during Pregnancy. PMID- 27959696 TI - When One Diagnosis Is Not Enough. PMID- 27959698 TI - The Future of Health Care Reform - Section 1332 Waivers and State-Led Reform. PMID- 27959697 TI - Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. AB - BACKGROUND: Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes. METHODS: We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology. RESULTS: A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77*10-7). CONCLUSIONS: In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.). PMID- 27959699 TI - Eliminating Cholera Transmission in Haiti. PMID- 27959703 TI - Knowing What We Don't Know - Improving Maintenance of Certification. PMID- 27959701 TI - Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. AB - BACKGROUND: The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. METHODS: In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed. RESULTS: A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. CONCLUSIONS: In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .). PMID- 27959702 TI - Thromboprophylaxis after Knee Arthroscopy and Lower-Leg Casting. AB - BACKGROUND: The use of thromboprophylaxis to prevent clinically apparent venous thromboembolism after knee arthroscopy or casting of the lower leg is disputed. We compared the incidence of symptomatic venous thromboembolism after these procedures between patients who received anticoagulant therapy and those who received no anticoagulant therapy. METHODS: We conducted two parallel, pragmatic, multicenter, randomized, controlled, open-label trials with blinded outcome evaluation: the POT-KAST trial, which included patients undergoing knee arthroscopy, and the POT-CAST trial, which included patients treated with casting of the lower leg. Patients were assigned to receive either a prophylactic dose of low-molecular-weight heparin (for the 8 days after arthroscopy in the POT-KAST trial or during the full period of immobilization due to casting in the POT-CAST trial) or no anticoagulant therapy. The primary outcomes were the cumulative incidences of symptomatic venous thromboembolism and major bleeding within 3 months after the procedure. RESULTS: In the POT-KAST trial, 1543 patients underwent randomization, of whom 1451 were included in the intention-to-treat population. Venous thromboembolism occurred in 5 of the 731 patients (0.7%) in the treatment group and in 3 of the 720 patients (0.4%) in the control group (relative risk, 1.6; 95% confidence interval [CI], 0.4 to 6.8; absolute difference in risk, 0.3 percentage points; 95% CI, -0.6 to 1.2). Major bleeding occurred in 1 patient (0.1%) in the treatment group and in 1 (0.1%) in the control group (absolute difference in risk, 0 percentage points; 95% CI, -0.6 to 0.7). In the POT-CAST trial, 1519 patients underwent randomization, of whom 1435 were included in the intention-to-treat population. Venous thromboembolism occurred in 10 of the 719 patients (1.4%) in the treatment group and in 13 of the 716 patients (1.8%) in the control group (relative risk, 0.8; 95% CI, 0.3 to 1.7; absolute difference in risk, -0.4 percentage points; 95% CI, -1.8 to 1.0). No major bleeding events occurred. In both trials, the most common adverse event was infection. CONCLUSIONS: The results of our trials showed that prophylaxis with low-molecular-weight heparin for the 8 days after knee arthroscopy or during the full period of immobilization due to casting was not effective for the prevention of symptomatic venous thromboembolism. (Funded by the Netherlands Organization for Health Research and Development; POT-KAST and POT-CAST ClinicalTrials.gov numbers, NCT01542723 and NCT01542762 , respectively.). PMID- 27959704 TI - Clarifying Stem-Cell Therapy's Benefits and Risks. PMID- 27959705 TI - Making An Impact on Clinical Practice and Research in China. PMID- 27959700 TI - Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. AB - BACKGROUND: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown. METHODS: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression free survival. RESULTS: The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%). CONCLUSIONS: Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .). PMID- 27959706 TI - Acute Kidney Injury in Critically Ill Children - An Ominous Legacy. PMID- 27959708 TI - Rethinking the Ban - The U.S. Blood Supply and Men Who Have Sex with Men. PMID- 27959710 TI - Maintaining Insurance Access under Trump - A Strategy. PMID- 27959707 TI - Epidemiology of Acute Kidney Injury in Critically Ill Children and Young Adults. AB - BACKGROUND: The epidemiologic characteristics of children and young adults with acute kidney injury have been described in single-center and retrospective studies. We conducted a multinational, prospective study involving patients admitted to pediatric intensive care units to define the incremental risk of death and complications associated with severe acute kidney injury. METHODS: We used the Kidney Disease: Improving Global Outcomes criteria to define acute kidney injury. Severe acute kidney injury was defined as stage 2 or 3 acute kidney injury (plasma creatinine level >=2 times the baseline level or urine output <0.5 ml per kilogram of body weight per hour for >=12 hours) and was assessed for the first 7 days of intensive care. All patients 3 months to 25 years of age who were admitted to 1 of 32 participating units were screened during 3 consecutive months. The primary outcome was 28-day mortality. RESULTS: A total of 4683 patients were evaluated; acute kidney injury developed in 1261 patients (26.9%; 95% confidence interval [CI], 25.6 to 28.2), and severe acute kidney injury developed in 543 patients (11.6%; 95% CI, 10.7 to 12.5). Severe acute kidney injury conferred an increased risk of death by day 28 after adjustment for 16 covariates (adjusted odds ratio, 1.77; 95% CI, 1.17 to 2.68); death occurred in 60 of the 543 patients (11.0%) with severe acute kidney injury versus 105 of the 4140 patients (2.5%) without severe acute kidney injury (P<0.001). Severe acute kidney injury was associated with increased use of mechanical ventilation and renal-replacement therapy. A stepwise increase in 28 day mortality was associated with worsening severity of acute kidney injury (P<0.001 by log-rank test). Assessment of acute kidney injury according to the plasma creatinine level alone failed to identify acute kidney injury in 67.2% of the patients with low urine output. CONCLUSIONS: Acute kidney injury is common and is associated with poor outcomes, including increased mortality, among critically ill children and young adults. (Funded by the Pediatric Nephrology Center of Excellence at Cincinnati Children's Hospital Medical Center and others; AWARE ClinicalTrials.gov number, NCT01987921 .). PMID- 27959711 TI - The End of Obamacare. PMID- 27959709 TI - A Fully Magnetically Levitated Circulatory Pump for Advanced Heart Failure. AB - BACKGROUND: Continuous-flow left ventricular assist systems increase the rate of survival among patients with advanced heart failure but are associated with the development of pump thrombosis. We investigated the effects of a new magnetically levitated centrifugal continuous-flow pump that was engineered to avert thrombosis. METHODS: We randomly assigned patients with advanced heart failure to receive either the new centrifugal continuous-flow pump or a commercially available axial continuous-flow pump. Patients could be enrolled irrespective of the intended goal of pump support (bridge to transplantation or destination therapy). The primary end point was a composite of survival free of disabling stroke (with disabling stroke indicated by a modified Rankin score >3; scores range from 0 to 6, with higher scores indicating more severe disability) or survival free of reoperation to replace or remove the device at 6 months after implantation. The trial was powered for noninferiority testing of the primary end point (noninferiority margin, -10 percentage points). RESULTS: Of 294 patients, 152 were assigned to the centrifugal-flow pump group and 142 to the axial-flow pump group. In the intention-to-treat population, the primary end point occurred in 131 patients (86.2%) in the centrifugal-flow pump group and in 109 (76.8%) in the axial-flow pump group (absolute difference, 9.4 percentage points; 95% lower confidence boundary, -2.1 [P<0.001 for noninferiority]; hazard ratio, 0.55; 95% confidence interval [CI], 0.32 to 0.95 [two-tailed P=0.04 for superiority]). There were no significant between-group differences in the rates of death or disabling stroke, but reoperation for pump malfunction was less frequent in the centrifugal-flow pump group than in the axial-flow pump group (1 [0.7%] vs. 11 [7.7%]; hazard ratio, 0.08; 95% CI, 0.01 to 0.60; P=0.002). Suspected or confirmed pump thrombosis occurred in no patients in the centrifugal-flow pump group and in 14 patients (10.1%) in the axial-flow pump group. CONCLUSIONS: Among patients with advanced heart failure, implantation of a fully magnetically levitated centrifugal-flow pump was associated with better outcomes at 6 months than was implantation of an axial-flow pump, primarily because of the lower rate of reoperation for pump malfunction. (Funded by St. Jude Medical; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755 .). PMID- 27959713 TI - Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. AB - BACKGROUND: In patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) with placement of stents, standard anticoagulation with a vitamin K antagonist plus dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor and aspirin reduces the risk of thrombosis and stroke but increases the risk of bleeding. The effectiveness and safety of anticoagulation with rivaroxaban plus either one or two antiplatelet agents are uncertain. METHODS: We randomly assigned 2124 participants with nonvalvular atrial fibrillation who had undergone PCI with stenting to receive, in a 1:1:1 ratio, low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months (group 1), very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months (group 2), or standard therapy with a dose-adjusted vitamin K antagonist (once daily) plus DAPT for 1, 6, or 12 months (group 3). The primary safety outcome was clinically significant bleeding (a composite of major bleeding or minor bleeding according to Thrombolysis in Myocardial Infarction [TIMI] criteria or bleeding requiring medical attention). RESULTS: The rates of clinically significant bleeding were lower in the two groups receiving rivaroxaban than in the group receiving standard therapy (16.8% in group 1, 18.0% in group 2, and 26.7% in group 3; hazard ratio for group 1 vs. group 3, 0.59; 95% confidence interval [CI], 0.47 to 0.76; P<0.001; hazard ratio for group 2 vs. group 3, 0.63; 95% CI, 0.50 to 0.80; P<0.001). The rates of death from cardiovascular causes, myocardial infarction, or stroke were similar in the three groups (Kaplan-Meier estimates, 6.5% in group 1, 5.6% in group 2, and 6.0% in group 3; P values for all comparisons were nonsignificant). CONCLUSIONS: In participants with atrial fibrillation undergoing PCI with placement of stents, the administration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a vitamin K antagonist plus DAPT for 1, 6, or 12 months. The three groups had similar efficacy rates, although the observed broad confidence intervals diminish the surety of any conclusions regarding efficacy. (Funded by Janssen Scientific Affairs and Bayer Pharmaceuticals; PIONEER AF-PCI ClinicalTrials.gov number, NCT01830543 .). PMID- 27959714 TI - Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease. AB - BACKGROUND: Both genetic and lifestyle factors contribute to individual-level risk of coronary artery disease. The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown. METHODS: Using a polygenic score of DNA sequence polymorphisms, we quantified genetic risk for coronary artery disease in three prospective cohorts - 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women's Genome Health Study (WGHS), and 22,389 in the Malmo Diet and Cancer Study (MDCS) - and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet. RESULTS: The relative risk of incident coronary events was 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low genetic risk (bottom quintile of polygenic scores) (hazard ratio, 1.91; 95% confidence interval [CI], 1.75 to 2.09). A favorable lifestyle (defined as at least three of the four healthy lifestyle factors) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor), regardless of the genetic risk category. Among participants at high genetic risk, a favorable lifestyle was associated with a 46% lower relative risk of coronary events than an unfavorable lifestyle (hazard ratio, 0.54; 95% CI, 0.47 to 0.63). This finding corresponded to a reduction in the standardized 10-year incidence of coronary events from 10.7% for an unfavorable lifestyle to 5.1% for a favorable lifestyle in ARIC, from 4.6% to 2.0% in WGHS, and from 8.2% to 5.3% in MDCS. In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category. CONCLUSIONS: Across four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease. Among participants at high genetic risk, a favorable lifestyle was associated with a nearly 50% lower relative risk of coronary artery disease than was an unfavorable lifestyle. (Funded by the National Institutes of Health and others.). PMID- 27959712 TI - Randomized Trial of Bilateral versus Single Internal-Thoracic-Artery Grafts. AB - BACKGROUND: The use of bilateral internal thoracic (mammary) arteries for coronary-artery bypass grafting (CABG) may improve long-term outcomes as compared with the use of a single internal-thoracic-artery plus vein grafts. METHODS: We randomly assigned patients scheduled for CABG to undergo single or bilateral internal-thoracic-artery grafting in 28 cardiac surgical centers in seven countries. The primary outcome was death from any cause at 10 years. The composite of death from any cause, myocardial infarction, or stroke was a secondary outcome. Interim analyses were prespecified at 5 years of follow-up. RESULTS: A total of 3102 patients were enrolled; 1554 were randomly assigned to undergo single internal-thoracic-artery grafting (the single-graft group) and 1548 to undergo bilateral internal-thoracic-artery grafting (the bilateral-graft group). At 5 years of follow-up, the rate of death was 8.7% in the bilateral graft group and 8.4% in the single-graft group (hazard ratio, 1.04; 95% confidence interval [CI], 0.81 to 1.32; P=0.77), and the rate of the composite of death from any cause, myocardial infarction, or stroke was 12.2% and 12.7%, respectively (hazard ratio, 0.96; 95% CI, 0.79 to 1.17; P=0.69). The rate of sternal wound complication was 3.5% in the bilateral-graft group versus 1.9% in the single-graft group (P=0.005), and the rate of sternal reconstruction was 1.9% versus 0.6% (P=0.002). CONCLUSIONS: Among patients undergoing CABG, there was no significant difference between those receiving single internal-thoracic-artery grafts and those receiving bilateral internal-thoracic-artery grafts with regard to mortality or the rates of cardiovascular events at 5 years of follow-up. There were more sternal wound complications with bilateral internal-thoracic-artery grafting than with single internal-thoracic-artery grafting. Ten-year follow-up is ongoing. (Funded by the British Heart Foundation and others; ART Current Controlled Trials number, ISRCTN46552265 .). PMID- 27959715 TI - A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. AB - BACKGROUND: Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol. METHODS: In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated. RESULTS: The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the gamma-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least squares mean reduction of 59.7% from baseline to day 84). CONCLUSIONS: In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442 .). PMID- 27959718 TI - Ending the Opioid Epidemic - A Call to Action. PMID- 27959719 TI - Acute Myeloid Leukemia - Many Diseases, Many Treatments. PMID- 27959720 TI - Inotuzumab Ozogamicin for Acute Lymphoblastic Leukemia. PMID- 27959721 TI - Inotuzumab Ozogamicin for Acute Lymphoblastic Leukemia. PMID- 27959722 TI - Treatment of Patients with Cirrhosis. PMID- 27959723 TI - Treatment of Patients with Cirrhosis. PMID- 27959724 TI - Treatment of Patients with Cirrhosis. PMID- 27959725 TI - Trouble on the Exchanges - Does the United States Owe Billions to Health Insurers? PMID- 27959726 TI - Large Hiatal Hernia. PMID- 27959727 TI - Thresholds for Abdominal Aortic Aneurysm Repair in England and the United States. AB - BACKGROUND: Thresholds for repair of abdominal aortic aneurysms vary considerably among countries. METHODS: We examined differences between England and the United States in the frequency of aneurysm repair, the mean aneurysm diameter at the time of the procedure, and rates of aneurysm rupture and aneurysm-related death. Data on the frequency of repair of intact (nonruptured) abdominal aortic aneurysms, in-hospital mortality among patients who had undergone aneurysm repair, and rates of aneurysm rupture during the period from 2005 through 2012 were extracted from the Hospital Episode Statistics database in England and the U.S. Nationwide Inpatient Sample. Data on the aneurysm diameter at the time of repair were extracted from the U.K. National Vascular Registry (2014 data) and from the U.S. National Surgical Quality Improvement Program (2013 data). Aneurysm related mortality during the period from 2005 through 2012 was determined from data obtained from the Centers for Disease Control and Prevention and the U.K. Office of National Statistics. Data were adjusted with the use of direct standardization or conditional logistic regression for differences between England and the United States with respect to population age and sex. RESULTS: During the period from 2005 through 2012, a total of 29,300 patients in England and 278,921 patients in the United States underwent repair of intact abdominal aortic aneurysms. Aneurysm repair was less common in England than in the United States (odds ratio, 0.49; 95% confidence interval [CI], 0.48 to 0.49; P<0.001), and aneurysm-related death was more common in England than in the United States (odds ratio, 3.60; 95% CI, 3.55 to 3.64; P<0.001). Hospitalization due to an aneurysm rupture occurred more frequently in England than in the United States (odds ratio, 2.23; 95% CI, 2.19 to 2.27; P<0.001), and the mean aneurysm diameter at the time of repair was larger in England (63.7 mm vs. 58.3 mm, P<0.001). CONCLUSIONS: We found a lower rate of repair of abdominal aortic aneurysms and a larger mean aneurysm diameter at the time of repair in England than in the United States and lower rates of aneurysm rupture and aneurysm-related death in the United States than in England. (Funded by the Circulation Foundation and others.). PMID- 27959729 TI - Acetaminophen versus Ibuprofen in Mild Persistent Asthma. PMID- 27959730 TI - Acetaminophen versus Ibuprofen in Mild Persistent Asthma. PMID- 27959728 TI - Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption. AB - BACKGROUND: The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). METHODS: We conducted two open label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART. RESULTS: A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 MUg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P=0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus. CONCLUSIONS: VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326 .). PMID- 27959732 TI - Publication of Secondary Analyses from Randomized Trials in Critical Care. PMID- 27959734 TI - Dizziness and Vertigo during MRI. PMID- 27959733 TI - Fifty Years of Expert Advice - Pharmaceutical Regulation and the Legacy of the Drug Efficacy Study. PMID- 27959731 TI - TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. AB - BACKGROUND: The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS: We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. RESULTS: Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. CONCLUSIONS: Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .). PMID- 27959735 TI - Perioperative Ledipasvir-Sofosbuvir for HCV in Liver-Transplant Recipients. PMID- 27959736 TI - Fully Implanted Brain-Computer Interface in a Locked-In Patient with ALS. AB - Options for people with severe paralysis who have lost the ability to communicate orally are limited. We describe a method for communication in a patient with late stage amyotrophic lateral sclerosis (ALS), involving a fully implanted brain computer interface that consists of subdural electrodes placed over the motor cortex and a transmitter placed subcutaneously in the left side of the thorax. By attempting to move the hand on the side opposite the implanted electrodes, the patient accurately and independently controlled a computer typing program 28 weeks after electrode placement, at the equivalent of two letters per minute. The brain-computer interface offered autonomous communication that supplemented and at times supplanted the patient's eye-tracking device. (Funded by the Government of the Netherlands and the European Union; ClinicalTrials.gov number, NCT02224469 .). PMID- 27959737 TI - Case 36-2016. A 50-Year-Old Man with Acute Liver Injury. PMID- 27959738 TI - Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis. PMID- 27959739 TI - Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis. PMID- 27959740 TI - Broadly Neutralizing Antibodies for HIV-1 Prevention or Immunotherapy. PMID- 27959741 TI - Von Willebrand's Disease. PMID- 27959742 TI - Nephron Protection in Diabetic Kidney Disease. PMID- 27959744 TI - Is Multiparametric MRI Useful for Differentiating Oncocytomas From Chromophobe Renal Cell Carcinomas? AB - OBJECTIVE: The purpose of this study was to retrospectively evaluate the diagnostic accuracy of multiparametric MRI to differentiate oncocytoma from chromophobe renal cell carcinoma (RCC). MATERIALS AND METHODS: In this retrospective study, 26 histologically confirmed oncocytomas and 16 chromophobe RCCs that underwent full MRI examination were identified in 42 patients (25 men and 17 women) over a 6-year period. Demographic data were recorded. Double-echo chemical-shift, dynamic contrast-enhanced T1- and T2-weighted images, and apparent diffusion coefficient (ADC) maps were reviewed independently by two radiologists blinded to pathologic results. Signal-intensity index (SII), tumor to-spleen signal-intensity ratio, ADC ratio, three wash-in indexes, and two washout indexes were calculated and compared using univariate and ROC analyses. Sensitivity and specificity analyses were performed to calculate diagnostic accuracy. RESULTS: All carcinomas and nine oncocytomas were resected; the remaining 17 oncocytomas were biopsied. Patient age (for oncocytomas: mean, 68.2 years; range, 43-84 years; for RCCs: mean, 60.8 years; range, 20-79 years) and tumor size (for oncocytomas: mean, 35.5 mm; range, 12-98 mm; for RCCs: mean, 37.2 mm; range, 9-101 mm) did not differ significantly across groups (p = 0.132 and 0.265, respectively). Good interobserver agreement was observed for all measurements but four. Oncocytomas presented significantly higher ADC (p = 0.002) and faster enhancement (p = 0.007-0.012) but lower SII (p = 0.03) than carcinomas. This combination provided sensitivity of 92.3% (24/26), specificity of 93.8% (15/16), and accuracy of 92.9% (39/42) for the detection of oncocytomas. CONCLUSION: Multiparametric MRI helps to accurately differentiate oncocytomas from chromophobe RCCs with high sensitivity and specificity. PMID- 27959743 TI - Autologous Adipose Stem Cell Therapy for Autonomic Nervous System Dysfunction in Two Young Patients. AB - Postural orthostatic tachycardia syndrome and neurocardiogenic syncope are clinical manifestations of autonomic nervous system dysfunction (dysautonomia) that can lead to impaired daily functions. We report two young patients presenting with dysautonomia and autoimmune disease who both received autologous adipose stem cells (ASCs) infusions. This report is the first description of ASCs therapy for patients with combined dysautonomia and autoimmune disease. Case 1: A 21-year-old female presented at 12 years of age with escalating severe dysautonomia with weight loss and gastrointestinal symptoms. She had elevated autoantibodies and cytokines and received multiple immune modulation therapies. Her dysautonomia was treated by volume expanders, vasoconstrictors, and beta blockers with mild improvement. She received ASCs about 2 years before this report with dramatic improvement in her dysautonomia and autoimmune symptoms with a 10 kg weight gain. Case 2: A 7-year-old boy presented at 2 years of age with polyarthritis. At 5 years of age, he manifested orthostatic intolerance. He received immune modulatory therapies with mild improvement. He received ASCs and showed marked improvement of his dysautonomia and immune symptoms. Dysautonomia symptoms of these two patients improved significantly after modulation of autoimmune components by ASC therapy. Favorable clinical responses of these two cases warrant further case-control studies. PMID- 27959745 TI - Driving after Concussion: Is It Safe To Drive after Symptoms Resolve? AB - Post-concussion impairments may result in unsafe driving performance, but little research is available to guide consensus on when concussed individuals should return to driving. The purpose of this study was to compare driving performance between individuals with and without a concussion and to explore relationships between neuropsychological and driving performance. Fourteen participants with concussion (age 20.2 +/- 0.9 years old) and 14 non-concussed age- and driving experience-matched controls (age 20.4 +/- 1.1 years old) completed a graded symptom checklist, a brief neuropsychological exam, and a 20.5 km driving simulation task. Participants with a concussion completed driving simulation within 48 h of becoming asymptomatic (15.9 +/- 9.0 days post-concussion). One-way analyses of variance were used to compare total number of crashes, tickets, and lane excursions, as well as standard deviation of lateral position (SDLP) and standard deviation of speed. Pearson's correlations were conducted to explore the relationship between the neuropsychological and driving performance separately by group (alpha = 0.05). Participants with a concussion committed more frequent lane excursions (concussed 10.9 +/- 4.5; controls 7.4 +/- 2.4; p = 0.017) and exhibited greater SDLP, compared with controls, during the first curve (concussed 45.7 +/- 21.3 cm, controls 27.4 +/- 6.1 cm; p = 0.030) and final curve (concussed 39.6 +/- 24.4 cm; controls 33.5 +/- 21.3 cm; p = 0.036). Poorer performance on symbol digit modalities (r = -0.54), Rey Osterrieth Complex Figure (r = -0.53), verbal memory (r = -0.77), and motor speed (r = -0.54) were correlated with more frequent lane excursions in the concussed group, but not in the control group. Despite being asymptomatic, concussed participants exhibited poorer vehicle control, especially when navigating curves. Driving impairments may persist beyond when individuals with a concussion have returned to driving. Our study provides preliminary guidance regarding which neuropsychological functions may best indicate driving impairment following concussion. PMID- 27959717 TI - Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease. AB - BACKGROUND: Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease. METHODS: In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median follow-up was 30 months. RESULTS: The median age of the patients was 66 years, and 72% were men; 43% were enrolled on the basis of the ABI and 57% on the basis of previous revascularization. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49). CONCLUSIONS: In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups. (Funded by AstraZeneca; EUCLID ClinicalTrials.gov number, NCT01732822 .). PMID- 27959746 TI - Salmeterol and Fluticasone Propionate in Children with Asthma. PMID- 27959749 TI - Cord-Blood Transplantation in Patients with Minimal Residual Disease. PMID- 27959747 TI - Salmeterol and Fluticasone Propionate in Children with Asthma. PMID- 27959748 TI - Cord-Blood Transplantation in Patients with Minimal Residual Disease. PMID- 27959751 TI - Neurogenic Megacolon in Spinal Cord Injury. PMID- 27959750 TI - Cord-Blood Transplantation in Patients with Minimal Residual Disease. PMID- 27959752 TI - Skin Mottling. PMID- 27959753 TI - Permanent Supportive Housing for Homeless People - Reframing the Debate. PMID- 27959754 TI - Postpartum Depression. PMID- 27959756 TI - Preventing HIV among Women - A Step Forward, but Much Farther to Go. PMID- 27959757 TI - The Nature of the P Value. PMID- 27959755 TI - Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B. AB - BACKGROUND: Severe combined immunodeficiency (SCID) is characterized by arrested T-lymphocyte production and by B-lymphocyte dysfunction, which result in life threatening infections. Early diagnosis of SCID through population-based screening of newborns can aid clinical management and help improve outcomes; it also permits the identification of previously unknown factors that are essential for lymphocyte development in humans. METHODS: SCID was detected in a newborn before the onset of infections by means of screening of T-cell-receptor excision circles, a biomarker for thymic output. On confirmation of the condition, the affected infant was treated with allogeneic hematopoietic stem-cell transplantation. Exome sequencing in the patient and parents was followed by functional analysis of a prioritized candidate gene with the use of human hematopoietic stem cells and zebrafish embryos. RESULTS: The infant had "leaky" SCID (i.e., a form of SCID in which a minimal degree of immune function is preserved), as well as craniofacial and dermal abnormalities and the absence of a corpus callosum; his immune deficit was fully corrected by hematopoietic stem cell transplantation. Exome sequencing revealed a heterozygous de novo missense mutation, p.N441K, in BCL11B. The resulting BCL11B protein had dominant negative activity, which abrogated the ability of wild-type BCL11B to bind DNA, thereby arresting development of the T-cell lineage and disrupting hematopoietic stem cell migration; this revealed a previously unknown function of BCL11B. The patient's abnormalities, when recapitulated in bcl11ba-deficient zebrafish, were reversed by ectopic expression of functionally intact human BCL11B but not mutant human BCL11B. CONCLUSIONS: Newborn screening facilitated the identification and treatment of a previously unknown cause of human SCID. Coupling exome sequencing with an evaluation of candidate genes in human hematopoietic stem cells and in zebrafish revealed that a constitutional BCL11B mutation caused human multisystem anomalies with SCID and also revealed a prethymic role for BCL11B in hematopoietic progenitors. (Funded by the National Institutes of Health and others.). PMID- 27959716 TI - Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. AB - BACKGROUND: The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. METHODS: Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated. RESULTS: A total of 24,081 patients were randomly assigned to the celecoxib group (mean [+/-SD] daily dose, 209+/-37 mg), the naproxen group (852+/-103 mg), or the ibuprofen group (2045+/-246 mg) for a mean treatment duration of 20.3+/-16.0 months and a mean follow-up period of 34.1+/-13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19). CONCLUSIONS: At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .). PMID- 27959758 TI - The Nature of the P Value. PMID- 27959759 TI - A Trial of Focused Ultrasound Thalamotomy for Essential Tremor. PMID- 27959760 TI - A Trial of Focused Ultrasound Thalamotomy for Essential Tremor. PMID- 27959761 TI - A Trial of Focused Ultrasound Thalamotomy for Essential Tremor. PMID- 27959762 TI - 70-Gene Signature in Early-Stage Breast Cancer. PMID- 27959763 TI - 70-Gene Signature in Early-Stage Breast Cancer. PMID- 27959764 TI - Scratching Below the Surface. PMID- 27959765 TI - TP53 and Histone H3.3 Mutations in Triple-Negative Lower-Grade Gliomas. PMID- 27959768 TI - PARP Inhibitors in Ovarian Cancer Treatment. PMID- 27959767 TI - Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. AB - BACKGROUND: Pharmacologic inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) are being evaluated in clinical trials for the treatment of cardiovascular disease. The effect of lowering low-density lipoprotein (LDL) cholesterol levels by inhibiting PCSK9 on the risk of cardiovascular events or diabetes is unknown. METHODS: We used genetic scores consisting of independently inherited variants in the genes encoding PCSK9 and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR; the target of statins) as instruments to randomly assign 112,772 participants from 14 studies, with 14,120 cardiovascular events and 10,635 cases of diabetes, to groups according to the number of LDL cholesterol-lowering alleles that they had inherited. We compared the effects of lower LDL cholesterol levels that were mediated by variants in PCSK9, HMGCR, or both on the risk of cardiovascular events and the risk of diabetes. RESULTS: Variants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter (0.26 mmol per liter) in the LDL cholesterol level: odds ratio for cardiovascular events, 0.81 (95% confidence interval [CI], 0.74 to 0.89) for PCSK9 and 0.81 (95% CI, 0.72 to 0.90) for HMGCR. Variants in these two genes were also associated with very similar effects on the risk of diabetes: odds ratio for each 10 mg per deciliter decrease in LDL cholesterol, 1.11 (95% CI, 1.04 to 1.19) for PCSK9 and 1.13 (95% CI, 1.06 to 1.20) for HMGCR. The increased risk of diabetes was limited to persons with impaired fasting glucose levels for both scores and was lower in magnitude than the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes. CONCLUSIONS: In this study, variants in PCSK9 had approximately the same effect as variants in HMGCR on the risk of cardiovascular events and diabetes per unit decrease in the LDL cholesterol level. The effects of these variants were independent and additive. (Funded by the Medical Research Council and the National Heart, Lung, and Blood Institute.). PMID- 27959769 TI - Clinical Genomics - Molecular Pathogenesis Revealed. PMID- 27959771 TI - Genetic diversity of currently circulating rubella viruses: a need to define more precise viral groups. AB - Recent studies have shown that the currently circulating rubella viruses are mostly members of two genotypes, 1E and 2B. Also, genetically distinct viruses of genotype 1G have been found in East and West Africa. This study used a Mantel test to objectively include both genetic diversity and geographic location in the definition of lineages, and identified statistically justified lineages (n=13) and sub-lineages (n=9) of viruses within genotypes 1G, 1E and 2B. Genotype 2B viruses were widely distributed, while viruses of genotype 1E as well as 1G and 1J were much more geographically restricted. This analysis showed that more precise groupings for rubella viruses are possible, which should improve the ability to track rubella viruses worldwide. A year-by-year analysis revealed gaps in surveillance that need to be resolved in order to support the surveillance needed for enhanced control and elimination goals for rubella. PMID- 27959772 TI - Cellular defence or viral assist: the dilemma of HDAC6. AB - Histone deacetylase 6 (HDAC6) is a unique cytoplasmic deacetylase that regulates various important biological processes by preventing protein aggregation and deacetylating different non-histone substrates including tubulin, heat shock protein 90, cortactin, retinoic acid inducible gene I and beta-catenin. Growing evidence has indicated a dual role for HDAC6 in viral infection and pathogenesis: HDAC6 may represent a host defence mechanism against viral infection by modulating microtubule acetylation, triggering antiviral immune response and stimulating protective autophagy, or it may be hijacked by the virus to enhance proinflammatory response. In this review, we will highlight current data illustrating the complexity and importance of HDAC6 in viral pathogenesis. We will summarize the structure and functional specificity of HDAC6, and its deacetylase- and ubiquitin-dependent activity in key cellular events in response to virus infection. We will also discuss how HDAC6 exerts its direct or indirect histone modification ability in viral lytic-latency switch. PMID- 27959773 TI - International Committee on Systematics of Prokaryotes Subcommittee on the taxonomy of Aerobic Bacteroidetes (formerly Flavobacterium and Cytophaga-like bacteria). Minutes of the meeting, 30 July 2014, Montreal, Canada. PMID- 27959774 TI - Increased circulating microRNAs miR-342-3p and miR-21-5p in natural sheep prion disease. AB - Scrapie is a transmissible spongiform encephalopathy (TSE), or prion disease, of sheep and goats. As no simple diagnostic tests are yet available to detect TSEs in vivo, easily accessible biomarkers could facilitate the eradication of scrapie agents from the food chain. To this end, we analysed by quantitative reverse transcription PCR a selected set of candidate microRNAs (miRNAs) from circulating blood plasma of naturally infected, classical scrapie sheep that demonstrated clear scrapie symptoms and pathology. Significant scrapie-associated increase was repeatedly found for miR-342-3p and miR-21-5p. This is the first demonstration, to our knowledge, of circulating miRNA alterations in any animal suffering from TSE. Genome-wide expression studies are warranted to investigate the true depth of miRNA alterations in naturally occurring TSEs, especially in presymptomatic animals, as the presented study demonstrates the potential feasibility of miRNAs as circulating TSE biomarkers. PMID- 27959766 TI - Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women. AB - BACKGROUND: The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODS: In this randomized, double blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTS: A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P=0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P=0.43 for treatment by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONS: Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226 .). PMID- 27959775 TI - Ruficoccus amylovorans gen. nov., sp. nov., an amylolytic and nitrate-reducing diazotroph of the family Puniceicoccaceae. AB - A novel amylolytic, nitrate-reducing and diazotrophic bacterium, designated strain CC-MHH0563T, isolated from a fermenter was assessed for its taxonomic status using a polyphasic approach. Cells of strain CC-MHH0563T were Gram staining-negative, catalase- and oxidase-positive, mesophilic and aerobic cocci, which produced reddish nondiffusible pigments. Growth was observed at 15-37 degrees C (optimal 25 degrees C), pH 6.0-8.0 (optimal pH 7.0) and salinity of 0 3 % (w/v). Strain CC-MHH0563T showed highest pairwise 16S rRNA gene sequence similarity to members of the genera Cerasicoccus(89.3-89.5 %), Coraliomargarita (87.8 %), Pelagicoccus(85.8-86.4 %) and Puniceicoccus (87.9 %), and established a discrete taxonomic lineage during phylogenetic analysis. The major fatty acids found in strain CC-MHH0563T were C14 : 0, anteiso-C15 : 0, C16 : 0, C17 : 0, C18 : 0 and C18 : 1omega9c. The polar lipid profile consisted of phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, two unknown aminolipids and two unknown aminophospholipids. The polyamine pattern showed a predominance of spermidine and a minor amount of cadaverine. The DNA G+C content was 57.4 mol% and the predominant quinone system was menaquinone-7. The low 16S rRNA gene sequence similarity values (<90.0 %) and a distinct phylogenetic clustering clearly distinguished strain CC-MHH0563T from other representatives of the family Puniceicoccaceae. Based on the discrete phylogenetic, phenotypic and chemotaxonomic traits together with the results of comparative 16S rRNA gene sequence analysis, strain CC-MHH0563T is considered to represent a novel genus and species of the family Puniceicoccaceae, for which the name Ruficoccus amylovorans gen. nov., sp. nov. is proposed. The type strain of the type species is CC-MHH0563T (=BCRC 80918T=JCM 31066T). PMID- 27959776 TI - Flavobacterium crassostreae sp. nov., isolated from Pacific oyster. AB - A yellow, rod-shaped, Gram-reaction-negative bacterial strain, designated LPB0076T, was isolated from a Pacific oyster. Results of 16S rRNA gene sequence analyses indicated that the strain represented a member of the genus Flavobacterium. It had the highest sequence similarity to the type strains of Flavobacterium frigidarium (97.6 %) and Flavobacterium omnivorum (97.0 %), and its similarities with all other species of the genus Flavobacterium were below 97.0 %. Its genome size (3.02 Mb), DNA G+C content (36.0 mol%), predominant cellular fatty acids (anteiso-C15 : 0, iso-C15 : 0 and C16 : 1omega7c and/or C17 : 1omega6c), and major polar lipid (phosphatidylethanolamine) were similar to those described previously for members of the genus Flavobacterium. In contrast, a number of phenotypic characteristics, including the inability to grow microaerophilically, absence of flexirubin-type pigments and gliding motility and differences in enzymatic reactions, clearly distinguished LPB0076T from other species of the genus Flavobacterium. The polyphasic data presented in this study indicate that this isolate should be classified as representing a novel species of the genus Flavobacterium. The name Flavobacterium crassostreae sp. nov. is therefore proposed for the isolate, with the type strain being LPB0076T (=KACC 18706T=JCM 31219T). PMID- 27959779 TI - Brevundimonas canariensis sp. nov., isolated from roots of Triticum aestivum. AB - A bacterial strain designated GTAE24T was isolated from a root of wheat growing in soil from the Canary Islands, Spain. Phylogenetic analyses based on 16S rRNA gene sequences placed the isolate in the genus Brevundimonas with Brevundimonas abyssalisTAR-001T as its closest relative at 99.4 % similarity. DNA-DNA hybridization studies showed an average of 38 % relatedness between strain GTAE24T and the type strain of B. abyssalis. Cells were Gram-stain-negative and motile by polar flagella. The strain was positive for oxidase and weakly positive for catalase. Gelatin, starch and casein were not hydrolysed. Growth was supported by many carbohydrates and organic acids as carbon source. Ubiquinone Q 10 was the predominant isoprenoid quinone and C18 : 1omega7c/C18 : 1omega6c (summed feature 8) and C16 : 0 were the major fatty acids. The major polar lipids were phosphatidylglycerol, 1,2-di-O-acyl-3-O-[d-glucopyranosyl-(1,4)-alpha-d glucopyranuronosyl] glycerol, 1,2-diacyl-3-O-[6'-phosphatidyl-alpha-d glucopyranosyl] glycerol, 1,2-di-O-acyl-3-O-alpha-d-glucopyranosyl glycerol, and 1,2-di-O-acyl-3-O-alpha-d-glucopyranuronosyl glycerol. The DNA G+C content was 63.9 mol%. Phylogenetic, chemotaxonomic and phenotypic analyses showed that strain GTAE24T should be considered as representing a novel species of the genus Brevundimonas, for which the name Brevundimonas canariensis sp. nov. is proposed. The type strain is GTAE24T (=LMG 29500T=CECT 9126T). PMID- 27959777 TI - Microbulbifer echini sp. nov., isolated from the gastrointestinal tract of a purple sea urchin, Heliocidaris crassispina. AB - A novel bacterium, designated as strain AM134T, was isolated from the gut of a purple sea urchin (Heliocidaris crassispina) gathered from the coastal waters of Dokdo, Korea. Strain AM134T was Gram-stain-negative, both catalase- and oxidase positive, strictly aerobic and showed a rod-coccus cell cycle. Optimum growth occurred at 30 degrees C, in the presence of 2 % (w/v) NaCl and at pH 7. The 16S rRNA gene sequence analysis showed that strain AM134T belonged to the genus Microbulbifer in the family Alteromonadaceae and had high 16S rRNA gene sequence similarity (>97 %) with Microbulbifer epialgicus F-104T (98.9 % similarity) and Microbulbifer variabilis Ni-2088T (98.6 % similarity). The polar lipid profile of strain AM134T was composed of phosphatidylethanolamine, phosphatidylserine, three unidentified aminophospholipids, two unidentified phospholipids, an unidentified amino lipid and six unidentified lipids. The major respiratory quinone was identified as ubiquinone-8 (Q-8). The major cellular fatty acids were summed feature 8 (C18 : 1omega6c and/or C18 : 1omega7c) and C16 : 0. The DNA-DNA hybridization analysis showed that the strain shared less than 28 % genomic relatedness with Microbulbifer epialgicus DSM 18651T (27+/-3 %) and Microbulbifer variabilis ATCC 700307T (15+/-1 %). The G+C content of the genomic DNA was 56.1 mol%. The results of the phylogenetic, phenotypic and genotypic analyses suggest that strain AM134T represents a novel species in the genus Microbulbifer, for which the name Microbulbifer echini is proposed. The type strain is AM134T (=KACC 18258T=JCM 30400T). PMID- 27959780 TI - Invitro antifungal susceptibilities of Candida species to liposomal amphotericin B, determined using CLSI broth microdilution, and amphotericin B deoxycholate, measured using the Etest. AB - The antifungal susceptibilities of 598 isolates of Candida spp. (bloodstream and other sterile sites) to liposomal amphotericin B (L-AmB) versus amphotericin B (AmB) were determined. MICs were calculated using the Clinical and Laboratory Standards Institute broth microdilution (M27-A3) method for L-AmB and the Etest method for AmB. The MIC50/MIC90 (ug ml-1) values for L-AmB broth microdilution and AmB Etest were 0.25/1 and 0.19/0.5, respectively. The overall essential agreement (+/-2 dilutions) was 91.5 %, ranging from 37.5 % (Candida lusitaniae) to 100 % (Candida glabrata and Candida krusei). Categorical agreement between the two methods was categorized based on a previously published breakpoint (susceptible/resistant MIC cut-off of 1 ug ml-1). The overall categorical agreement at the 48 h reading was 97.3 %, ranging from 72.7 % (C. krusei) to 100 % (Candida albicans). Major and very major discrepancies occurred in 2.3 and 0.3 %, respectively. Spearman's rho was 0.48 (P<0.0001). These results demonstrate the utility of the AmB Etest as a surrogate marker to predict the sensibility and resistance of Candida spp. to L-AmB and thus to support its use in antifungal treatment. PMID- 27959781 TI - Planctobacterium marinum gen. nov., sp. nov., a new member of the family Alteromonadaceae isolated from seawater. AB - A bacterial strain designated K7T was isolated from the South China Sea and characterized using a polyphasic taxonomic approach. Cells of strain K7T were Gram-stain-negative, aerobic, poly-beta-hydroxybutyrate-accumulating, motile by means of a monopolar flagellum, non-spore forming rods surrounded by a thick capsule and forming yellow colonies. Growth occurred at 4-35 degrees C (optimum, 25-30 degrees C), at pH 5.0-9.0 (optimum, pH 7.0) and with 0.5-10 % (w/v) NaCl [optimum, 1-4 % (w/v)]. The predominant fatty acids were summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0 and C18 : 1omega7c. The major isoprenoid quinone was Q-8 and the DNA G+C content was 46.5 mol%. The polar lipid profile consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylmonomethylethanolamine, one uncharacterized phospholipid, two uncharacterized aminophospholipids and five uncharacterized lipids. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain K7T formed a distinct lineage with respect to closely related genera in the family Alteromonadaceae. Strain K7T was most closely related to Aestuariibacter, Aliiglaciecola, Paraglaciecola and Glaciecola, and the levels of 16S rRNA gene sequence similarity with respect to the type species of related genera were less than 95 %. On the basis of the genotypic and phenotypic data, strain K7T represents a novel species of a new genus of the family Alteromonadaceae, for which the name Planctobacterium marinum gen. nov., sp. nov. is proposed. The type strain of Planctobacterium marinum is K7T (=BCRC 80901T=LMG 28835T=KCTC 42657T). PMID- 27959782 TI - CRISPR-based genome editing of clinically important Escherichia coli SE15 isolated from indwelling urinary catheters of patients. AB - Urinary tract infections (UTIs) are clinically important problems that lead to serious morbidity and mortality, and indwelling urinary catheters are a major factor of UTIs. In this study, we applied clustered regularly interspaced short palindromic repeats (CRISPR) genome editing to generate DeltaluxS mutant strains from clinical isolates of Escherichiacoli SE15, which is one of major pathogens and can cause colonization and biofilm formation in the catheter. A major regulatory pathway of such biofilm formation on medical devices is the quorum sensing mechanism via small molecule autoinducer-2 synthesized by LuxS enzyme. Here, we used the CRISPR-Cas9 system for precise deletion of luxS gene in clinical isolate E. coli SE15. To this end, we constructed a donor DNA for homologous recombination to delete 93 bases in the chromosomal target (luxS) and observed the success rate of luxS deletion to be 22.7 %. We conducted biofilm assay to observe decreased biofilm formation in the E. coil SE15 DeltaluxS mutants compared to wild-type E. coil SE15. Quantitative real-time PCR analysis of E. coil SE15 DeltaluxS mutants showed that the expression of luxS was below detection level. We also observed that the relative mRNA levels of biofilm formation-related genes, such as mqsR, pgaBC and csgEF, were significantly decreased in E. coil SE15 DeltaluxS mutants compared to wild-type. We conclude that genome editing by CRISPR-Cas9 system is an effective tool to dissect the molecular mechanism of biofilm formation in medically important strains, and the study may serve as a basis for developing novel medical intervention against UTIs caused by biofilm. PMID- 27959784 TI - Rhizobium oryziradicis sp. nov., isolated from rice roots. AB - Two Gram-stain-negative, aerobic, rod-shaped endophytic bacterial strains, N19T and N11-2, were isolated from fresh rice (Oryza sativa) roots during investigation of the rice endophytic bacterial diversity. The 16S rRNA gene sequence results indicated that the similarity between strains N19T and N11-2 was 100 %. Both of them belong to the genus Rhizobium, with close similarity to Rhizobium taibaishanense CCNWSX 0483T (97.7 %), followed by Rhizobium vitis NCPPB 3554T (97.5 %). The sequence similarities of the housekeeping genes recA, gyrB and glnA between the novel isolates and members of the established species of the genus Rhizobium were less than 87 %. The DNA-DNA hybridization rates between strains N19T and N11-2 were 87.9 % using the initial renaturation rate method. Based on draft genome sequences, strain N19T showed 18.2 % and 19.6 % DNA-DNA hybridization values to R. taibaishanense CCNWSX 0483T and R. vitis S4, which demonstrated that these new isolates represent a novel species in the genus Rhizobium. The main cellular fatty acids were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). The DNA G+C content of strain N19T was 58.7 mol% (Tm). The polar lipid profile of N19T consisted of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, an unknown lipid, two unknown aminolipids and an unidentified aminophospholipid. According to physiological and biochemical characteristics and genotypic data, strains N19T and N11-2 are considered to represent a novel species of the genus Rhizobium, for which the name Rhizobium oryziradicis sp. nov. is proposed, with N19T (=ACCC 19962T=KCTC 52413T) as the type strain. PMID- 27959783 TI - Human cytomegalovirus phosphoproteins are hypophosphorylated and intrinsically disordered. AB - Protein phosphorylation has important regulatory functions in cell homeostasis and is tightly regulated by kinases and phosphatases. The tegument of human cytomegalovirus (CMV) contains not only several proteins reported to be extensively phosphorylated but also cellular protein phosphatases (PP1 and PP2A). To investigate this apparent inconsistency, we evaluated the phosphorylation status of the tegument proteins pUL32 and pp65 by enzymatic dephosphorylation and MS. Enzymatic dephosphorylation with bacterial lambda phosphatase, but not with PP1, shifted the pUL32-specific signal on reducing SDS-PAGE from ~150 to ~148 kDa, a mass still much larger than the ~118 kDa obtained from our diffusion studies and from the calculated protein mass of ~113 kDa. Remarkably, inhibition of phosphatases through treatment with the phosphatase inhibitors calyculin A and okadaic acid resulted in a shift to ~190 or ~180 kDa, respectively, indicating that a considerable number of potential phosphorylated residues on pUL32 are not phosphorylated under normal conditions. MS revealed a general state of hypophosphorylation of CMV phosphoproteins with only 17 phosphorylated residues detected on pUL32 and 19 on pp65, respectively. Moreover, bioinformatics analysis shows that the C-terminal two-thirds of pUL32 are intrinsically disordered and that most phosphorylations map to this region. In conclusion, we show that important CMV tegument proteins are indeed phosphorylated, though to a lesser extent than previously reported, and the difference in mobility on SDS-PAGE and calculated mass of pUL32 may not be attributed to phosphorylation but more likely due to the partially intrinsically disordered nature of pUL32. PMID- 27959785 TI - Paenibacillus eucommiae sp. nov., isolated from a traditional Chinese medicinal herbal plant, Eucommia ulmoides Oliver. AB - The taxonomic status of a novel bacterium, designated strain CPCC 100226T, isolated from a traditional Chinese medicinal herbal plant, Eucommia ulmoides Oliver, was characterized by using a polyphasic approach. The aerobic isolate formed pale white colonies on tryptic soy agar. Cells were Gram-stain-positive, rod-shaped, motile and endospore-forming. Chemotaxonomic investigations revealed the presence of meso-diaminopimelic acid as the diagnostic diamino acid, MK-7 as the predominant menaquinone, anteiso-C15 : 0, iso-C15 : 0, iso-C16 : 0 and C16 : 0 as the major fatty acids, and the strain had a phospholipid pattern of phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol and unidentified aminophospholipids. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that the isolate was closely related to Paenibacillus aestuarii DSM 23861T with 95.1 % similarity. The G+C content of the genomic DNA was 47.9 mol%. On the basis of the genotypic and phenotypic data, the isolate is considered to represent a novel species of the genus Paenibacillus. The name proposed for this taxon is Paenibacillus eucommiae sp. nov. with CPCC 100226T (=DSM 26048T=KCTC 33054T) as the type strain. PMID- 27959786 TI - Planococcus versutus sp. nov., isolated from soil. AB - A taxonomic study was performed on a novel Gram-stain-positive, coccus-shaped, orange-pigmented motile bacterium, designated as strain L10.15T. The organism was isolated from a soil sample collected in Lagoon Island (close to Adelaide Island, western Antarctic Peninsula) using a quorum-quenching enrichment medium. Growth occurred at 4-30 degrees C, pH 6-11 and at moderately high salinity (0-15 %, w/v, NaCl), with optimal growth at 26 degrees C, at pH 7-8 and with 6 % (w/v) NaCl. 16S rRNA gene sequence analysis showed that strain L10.15T belonged to the genus Planococcus and was closely related to Planococcus halocryophilus Or1T (99.3 % similarity), Planococcus donghaensis JH1T (99.0 %), Planococcus antarcticus DSM 14505T (98.3 %), Planococcus plakortidis AS/ASP6 (II)T (97.6 %), Planococcus maritimus TF-9T (97.5 %), Planococcus salinarum ISL-6T (97.5 %) and Planococcus kocurii NCIMB 629T (97.5 %). However, the average nucleotide identity MUMmer analysis showed low genomic relatedness values of 71.1-81.7 % to the type strains of these closely related species of the genus Planococcus. The principal fatty acids were anteiso-C15 : 0, C16 : 1omega7c and anteiso-C17 : 0, and the major menaquinones of strain L10.15T were MK-5 (48 %), MK-6 (6 %) and MK-7 (44 %). Polar lipid analysis revealed the presence of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and aminophospholipid. The DNA G+C content was 39.4 mol%. The phenotypic and genotypic data indicate that strain L10.15T represents a novel species of the genus Planococcus, for which the name Planococcus versutus sp. nov. is proposed. The type strain is L10.15T (=DSM 101994T=KACC 18918T). PMID- 27959787 TI - Lysobacter solanacearum sp. nov., isolated from rhizosphere of tomato. AB - A bacterial strain, designated T20R-70T, was isolated from tomato rhizosphere soil collected in Yecheon-gun, Gyeongsangbuk-do in South Korea. Growth was observed within the ranges 10-40 degrees C (optimally at 28-30 degrees C), pH 7.0-8.0 (optimally at pH 7.0) and 0-1 % NaCl (optimally at 0 %). The 16S rRNA gene sequence showed the highest similarities with those of Lysobacter hankyongensis KTCe-2T (98.7 %), Lysobacter brunescens KCTC 12130T (98.0 %), 'Lysobacter daecheongensis' Dae08 (97.2 %) and Lysobacter oligotrophicus 107-E2T (97.1 %). The phylogenetic tree showed that strain T20R-70T formed a clade with Lysobacterhankyongensis KTCe-2T and Lysobacterbrunescens KCTC 12130T. The dominant fatty acids (>10 %) were iso-C15 : 0, iso-C16 : 0, iso-C17 : 1omega9c and summed feature 3 (including iso-C15 : 0 2-OH and/or iso-C16 : 1omega7c). The major polar lipids were phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylglycerol. The major respiratory quinone was Q-8. DNA-DNA hybridization data revealed that strain T20R-70T had a hybridization value of 42+/-4 % (mean+/-sd) to the most closely related species of the genus Lysobacter. The DNA G+C content was 63.0 mol%. The physiological, biochemical and chemotaxonomic data allowed the discrimination of the new isolate from its phylogenetic relatives. Strain T20R-70T is thus considered to be a representative of a novel species of the genus Lysobacter, for which the name Lysobactersolanacearum sp. nov. is proposed. The type strain is T20R-70T (=KACC 18656T=NBRC 111881T). PMID- 27959791 TI - Cell cycle arrest and apoptosis induced by enteroaggregative Escherichia coli in cultured human intestinal epithelial cells. AB - PURPOSE: Enteroaggregative Escherichia coli (EAEC) is an emerging enteric pathogen causing diarrhoeal diseases in multiple epidemiological and clinical settings. However, understanding of the pathogenesis of the disease caused by this organism is still suboptimal. Studies have indicated that enteric bacteria induced cell cycle arrest and apoptosis in host intestinal epithelial cells might play a vital role in the pathogenesis caused by these organisms. In this study an attempt was made to assess EAEC-induced apoptosis and cell cycle modulation in human intestinal epithelial cell lines. METHODOLOGY: INT-407 and HCT-15 cells were infected with EAEC-T8 (clinical isolate) as well as plasmid cured variant of EAEC-T8 (EAEC-pT8). Propidium iodide staining was done to select the time of infection and the incubation period of the infected culture. Apoptosis was further assessed in EAEC infected both the cell lines by annexin-V-FLUOS & propidium iodide, cell death detection ELISA, DNA strand breaks and microscopic analysis. Further, the DNA content of the EAEC-infected cells at different phases of cell cycle was also monitored. RESULTS: We have found that EAEC could induce apoptosis in human small intestinal as well as colonic epithelial cell lines, which was assessed by the expression of phosphatidylserine on host cell surface, internucleosomal cleavage of host cell DNA and microscopic analysis of the characteristic apoptotic features of these cells. EAEC was also found to arrest cells at S phase and G2-M phase of the cell cycle. CONCLUSIONS: EAEC-T8 could induce maximum apoptosis and cell cycle modulation in both small intestinal and colonic epithelial cells. Further, we have observed that the plasmid of this organism had maximum contribution to these processes. The outcome of this study has undoubtedly led to a better understanding of the basic mechanism of pathogenesis caused by EAEC. PMID- 27959788 TI - Alcaligenes endophyticus sp. nov., isolated from roots of Ammodendron bifolium. AB - A Gram-stain-negative, rod-shaped, motile bacterium, designated AER10T, was isolated from the roots of Ammodendron bifolium collected from Takeermohuer desert in Xinjiang Uygur Autonomous Region, northwestern China. Growth was found to occur from 10 to 45 degrees C, at pH 5.0-9.0, and could tolerate up to 10 % (w/v) NaCl. 16S rRNA gene sequence result indicated that the strain AER10T belongs to the genus Alcaligenes and was closely related to Alcaligenes aquatilis (98.4 %), Alcaligenes faecalissubsp. parafaecalis (98.4 %), Alcaligenes faecalissubsp. faecalis (98.1 %) and Alcaligenes faecalissubsp. phenolicus (97.9 %). However, the DNA-DNA hybridization values between the strain AER10T and the above strains were less than the threshold value (below 70 %) for the delineation of genomic species. The DNA G+C content was 53.3 mol%. Ubiquinone-8 (Q-8) was the only quinone system present. The major fatty acids were summed feature 8 (C18 : 1omega7c, 25 %), C16 : 0 (24.2 %), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c, 19.3 %) and cyclo-C17 : 0 (10.5 %). The polar lipid profile of the strain AER10T consists of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, two unidentified aminolipids and five unknown polar lipids. On the basis of the evidence presented in this study, strain AER10T is a representative of a novel species in the genus Alcaligenes, for which the name Alcaligenes endophyticus sp. nov. is proposed. The type strain is AER10T (=DSM 100498T=KCTC 42688T). PMID- 27959792 TI - Pressure in the Cochlea During Infrared Irradiation. AB - OBJECTIVE: The purpose of the study is to demonstrate laser-evoked pressure waves in small confined volumes such as the cochlea. METHODS: Custom-fabricated pressure probes were used to determine the pressure in front of the optical fiber in a small dish and patch pipettes to measure temperature changes. Pressure probes were inserted into scala tympani (ST) or vestibuli during laser stimulation. With a sensitive microphone the pressure was measured in the outer ear canal. RESULTS: Heating was spatially confined. The heat relaxation time was 35 ms. During laser stimulation in the cochlea at 17 MUJ/pulse, the pressure in the outer ear canal (EC) was 43.5 dB (re 20 MUPa). The corresponding intracochlear pressure was calculated to be about 78.5 dB (re 20 MUPa) using the middle ear reverse transfer function of -35 dB. At 164 MUJ/pulse, the pressure in the EC was on average 63 dB (re 20 MUPa) and the intracochlear pressure was estimated to be 98 dB (re 20 MUPa), which is similar to the value obtained with the pressure probe, 100 dB (re 20 MUPa). Side-emitting optical fibers were used to steer the beam path. The pressure values were independent of the orientation of the beam path. Evoked compound action potentials of the auditory nerve were maximum when spiral ganglion neurons were in the beam path. CONCLUSION: Pressure waves are generated during infrared laser stimulation. The intracochlear pressure was independent from the orientation of the beam path. SIGNIFICANCE: Neural responses required the spiral ganglion neurons to be directly irradiated. PMID- 27959794 TI - The Role of the Tumor Microenvironment in Glioblastoma: A Mathematical Model. AB - Glioblastoma multiforme is one of the deadliest human cancers and is characterized by tumor cells that hijack immune system cells in a deadly symbiotic relationship. Microglia and glioma infiltrating macrophages, which in principle should mount an immune response to the tumor, are subverted by tumor cells to facilitate growth in several ways. In this study, we seek to understand the interactions between the tumor cells and the microglia that enhance tumor growth, and for this purpose, we develop a mathematical and computational model that involves reaction-diffusion equations for the important components in the interaction. These include the densities of tumor and microglial cells, and the concentrations of growth factors and other signaling molecules. We apply this model to a transwell assay used in the laboratory to demonstrate that microglia can stimulate tumor cell invasion by secreting the growth factor TGF- beta. We show that the model can both replicate the major components of the experimental findings and make new predictions to guide future experiments aimed at the development of new therapeutic approaches. Sensitivity analysis is used to identify the most important parameters as an aid to future experimental work. This study is the first step in a program that involves development of detailed 3 D models of the mechanical and biochemical interactions between a glioblastoma and the tumor microenvironment. PMID- 27959795 TI - Improvement of Pyramidal Tract Side Effect Prediction Using a Data-Driven Method in Subthalamic Stimulation. AB - OBJECTIVE: subthalamic nucleus deep brain stimulation (STN DBS) is limited by the occurrence of a pyramidal tract side effect (PTSE) induced by electrical activation of the pyramidal tract. Predictive models are needed to assist the surgeon during the electrode trajectory preplanning. The objective of the study was to compare two methods of PTSE prediction based on clinical assessment of PTSE induced by STN DBS in patients with Parkinson's disease. METHODS: two clinicians assessed PTSE postoperatively in 20 patients implanted for at least three months in the STN. The resulting dataset of electroclinical tests was used to evaluate two methods of PTSE prediction. The first method was based on the volume of tissue activated (VTA) modeling and the second one was a data-driven based method named Pyramidal tract side effect Model based on Artificial Neural network (PyMAN) developed in our laboratory. This method was based on the nonlinear correlation between the PTSE current threshold and the 3-D electrode coordinates. PTSE prediction from both methods was compared using Mann-Whitney U test. RESULTS: 1696 electroclinical tests were used to design and compare the two methods. Sensitivity, specificity, positive- and negative-predictive values were significantly higher with the PyMAN method than with the VTA-based method (P < 0.05). CONCLUSION: the PyMAN method was more effective than the VTA-based method to predict PTSE. SIGNIFICANCE: this data-driven tool could help the neurosurgeon in predicting adverse side effects induced by DBS during the electrode trajectory preplanning. PMID- 27959796 TI - Summarizing Unconstrained Videos Using Salient Montages. AB - We present a novel method to summarize unconstrained videos using salient montages (i.e., a "melange" of frames in the video as shown in Fig. 1, by finding "montageable moments" and identifying the salient people and actions to depict in each montage. Our method aims at addressing the increasing need for generating concise visualizations from the large number of videos being captured from portable devices. Our main contributions are (1) the process of finding salient people and moments to form a montage, and (2) the application of this method to videos taken "in the wild" where the camera moves freely. As such, we demonstrate results on head-mounted cameras, where the camera moves constantly, as well as on videos downloaded from YouTube. In our experiments, we show that our method can reliably detect and track humans under significant action and camera motion. Moreover, the predicted salient people are more accurate than results from state of-the-art video salieny method [1] . Finally, we demonstrate that a novel "montageability" score can be used to retrieve results with relatively high precision which allows us to present high quality montages to users.We present a novel method to summarize unconstrained videos using salient montages (i.e., a "melange" of frames in the video as shown in Fig. 1, by finding "montageable moments" and identifying the salient people and actions to depict in each montage. Our method aims at addressing the increasing need for generating concise visualizations from the large number of videos being captured from portable devices. Our main contributions are (1) the process of finding salient people and moments to form a montage, and (2) the application of this method to videos taken "in the wild" where the camera moves freely. As such, we demonstrate results on head-mounted cameras, where the camera moves constantly, as well as on videos downloaded from YouTube. In our experiments, we show that our method can reliably detect and track humans under significant action and camera motion. Moreover, the predicted salient people are more accurate than results from state-of-the-art video salieny method [1] . Finally, we demonstrate that a novel "montageability" score can be used to retrieve results with relatively high precision which allows us to present high quality montages to users. PMID- 27959802 TI - Supporting One-Time Point Annotations for Gesture Recognition. AB - This paper investigates a new annotation technique that reduces significantly the amount of time to annotate training data for gesture recognition. Conventionally, the annotations comprise the start and end times, and the corresponding labels of gestures in sensor recordings. In this work, we propose a one-time point annotation in which labelers do not have to select the start and end time carefully, but just mark a one-time point within the time a gesture is happening. The technique gives more freedom and reduces significantly the burden for labelers. To make the one-time point annotations applicable, we propose a novel BoundarySearch algorithm to find automatically the correct temporal boundaries of gestures by discovering data patterns around their given one-time point annotations. The corrected annotations are then used to train gesture models. We evaluate the method on three applications from wearable gesture recognition with various gesture classes (10-17 classes) recorded with different sensor modalities. The results show that training on the corrected annotations can achieve performances close to a fully supervised training on clean annotations (lower by just up to 5 percent F1-score on average). Furthermore, the BoundarySearch algorithm is also evaluated on the ChaLearn 2014 multi-modal gesture recognition challenge recorded with Kinect sensors from computer vision and achieves similar results. PMID- 27959803 TI - Pre-Capture Privacy for Small Vision Sensors. AB - The next wave of micro and nano devices will create a world with trillions of small networked cameras. This will lead to increased concerns about privacy and security. Most privacy preserving algorithms for computer vision are applied after image/video data has been captured. We propose to use privacy preserving optics that filter or block sensitive information directly from the incident light-field before sensor measurements are made, adding a new layer of privacy. In addition to balancing the privacy and utility of the captured data, we address trade-offs unique to miniature vision sensors, such as achieving high-quality field-of-view and resolution within the constraints of mass and volume. Our privacy preserving optics enable applications such as depth sensing, full-body motion tracking, people counting, blob detection and privacy preserving face recognition. While we demonstrate applications on macro-scale devices (smartphones, webcams, etc.) our theory has impact for smaller devices. PMID- 27959804 TI - Cross-Convolutional-Layer Pooling for Image Recognition. AB - Recent studies have shown that a Deep Convolutional Neural Network (DCNN) trained on a large image dataset can be used as a universal image descriptor and that doing so leads to impressive performance for a variety of image recognition tasks. Most of these studies adopt activations from a single DCNN layer, usually a fully-connected layer, as the image representation. In this paper, we proposed a novel way to extract image representations from two consecutive convolutional layers: one layer is used for local feature extraction and the other serves as guidance to pool the extracted features. By taking different viewpoints of convolutional layers, we further develop two schemes to realize this idea. The first directly uses convolutional layers from a DCNN. The second applies the pre trained CNN on densely sampled image regions and treats the fully-connected activations of each image region as a convolutional layer's feature activations. We then train another convolutional layer on top of that as the pooling-guidance convolutional layer. By applying our method to three popular visual classification tasks, we find that our first scheme tends to perform better on applications which demand strong discrimination on lower-level visual patterns while the latter excels in cases that require discrimination on category-level patterns. Overall, the proposed method achieves superior performance over existing approaches for extracting image representations from a DCNN. In addition, we apply cross-layer pooling to the problem of image retrieval and propose schemes to reduce the computational cost. Experimental results suggest that the proposed method achieves promising results for the image retrieval task. PMID- 27959806 TI - Bayesian Quantification of Contrast-Enhanced Ultrasound Images With Adaptive Inclusion of an Irreversible Component. AB - Contrast Enhanced Ultrasound (CEUS) is a sensitive imaging technique to assess tissue vascularity and it can be particularly useful in early detection and grading of arthritis. In a recent study we have shown that a Gamma-variate can accurately quantify synovial perfusion and it is flexible enough to describe many heterogeneous patterns. However, in some cases the heterogeneity of the kinetics can be such that even the Gamma model does not properly describe the curve, with a high number of outliers. In this work we apply to CEUS data the single compartment recirculation model (SCR) which takes explicitly into account the trapping of the microbubbles contrast agent by adding to the single Gamma-variate model its integral. The SCR model, originally proposed for dynamic-susceptibility magnetic resonance imaging, is solved here at pixel level within a Bayesian framework using Variational Bayes (VB). We also include the automatic relevant determination (ARD) algorithm to automatically infer the model complexity (SCR vs. Gamma model) from the data. We demonstrate that the inclusion of trapping best describes the CEUS patterns in 50% of the pixels, with the other 50% best fitted by a single Gamma. Such results highlight the necessity of the use ARD, to automatically exclude the irreversible component where not supported by the data. VB with ARD returns precise estimates in the majority of the kinetics (88% of total percentage of pixels) in a limited computational time (on average, 3.6 min per subject). Moreover, the impact of the additional trapping component has been evaluated for the differentiation of rheumatoid and non-rheumatoid patients, by means of a support vector machine classifier with backward feature selection. The results show that the trapping parameter is always present in the selected feature set, and improves the classification. PMID- 27959808 TI - Wall-Less Flow Phantoms With Tortuous Vascular Geometries: Design Principles and a Patient-Specific Model Fabrication Example. AB - Flow phantoms with anatomically realistic geometry and high acoustic compatibility are valuable investigative tools in vascular ultrasound studies. Here, we present a new framework to fabricate ultrasound-compatible flow phantoms to replicate human vasculature that is tortuous, nonplanar, and branching in nature. This framework is based upon the integration of rapid prototyping and investment casting principles. A pedagogical walkthrough of our engineering protocol is presented in this paper using a patient-specific cerebral aneurysm model as an exemplar demonstration. The procedure for constructing the flow circuit component of the phantoms is also presented, including the design of a programmable flow pump system, the fabrication of blood mimicking fluid, and flow rate calibration. Using polyvinyl alcohol cryogel as the tissue mimicking material, phantoms developed with the presented protocol exhibited physiologically relevant acoustic properties [attenuation coefficient: 0.229+/ 0.032 dB/( [Formula: see text]) and acoustic speed: 1535+/-2.4 m/s], and their pulsatile flow dynamics closely resembled the flow profile input. As a first application of our developed phantoms, the flow pattern of the patient-specific aneurysm model was visualized by performing high-frame-rate color-encoded speckle imaging over multiple time-synchronized scan planes. Persistent recirculation was observed, and the vortex center was found to shift in position over a cardiac cycle, indicating the 3-D nature of flow recirculation inside an aneurysm. These findings suggest that phantoms produced from our reported protocol can serve well as acoustically compatible test beds for vascular ultrasound studies, including 3 D flow imaging. PMID- 27959812 TI - A Statistical Direct Volume Rendering Framework for Visualization of Uncertain Data. AB - With uncertainty present in almost all modalities of data acquisition, reduction, transformation, and representation, there is a growing demand for mathematical analysis of uncertainty propagation in data processing pipelines. In this paper, we present a statistical framework for quantification of uncertainty and its propagation in the main stages of the visualization pipeline. We propose a novel generalization of Irwin-Hall distributions from the statistical viewpoint of splines and box-splines, that enables interpolation of random variables. Moreover, we introduce a probabilistic transfer function classification model that allows for incorporating probability density functions into the volume rendering integral. Our statistical framework allows for incorporating distributions from various sources of uncertainty which makes it suitable in a wide range of visualization applications. We demonstrate effectiveness of our approach in visualization of ensemble data, visualizing large datasets at reduced scale, iso-surface extraction, and visualization of noisy data. PMID- 27959813 TI - Optimal Camera Placement for Motion Capture Systems. AB - Optical motion capture is based on estimating the three-dimensional positions of markers by triangulation from multiple cameras. Successful performance depends on points being visible from at least two cameras and on the accuracy of the triangulation. Triangulation accuracy is strongly related to the positions and orientations of the cameras. Thus, the configuration of the camera network has a critical impact on performance. A poor camera configuration may result in a low quality three-dimensional (3D) estimation and consequently low quality of tracking. This paper introduces and compares two methods for camera placement. The first method is based on a metric that computes target point visibility in the presence of dynamic occlusion from cameras with "good" views. The second method is based on the distribution of views of target points. Efficient algorithms, based on simulated annealing, are introduced for estimating the optimal configuration of cameras for the two metrics and a given distribution of target points. The accuracy and robustness of the algorithms are evaluated through both simulation and empirical measurement. Implementations of the two methods are available for download as tools for the community. PMID- 27959814 TI - A GPU-Accelerated Approach for Feature Tracking in Time-Varying Imagery Datasets. AB - We propose a novel parallel connected component labeling (CCL) algorithm along with efficient out-of-core data management to detect and track feature regions of large time-varying imagery datasets. Our approach contributes to the big data field with parallel algorithms tailored for GPU architectures. We remove the data dependency between frames and achieve pixel-level parallelism. Due to the large size, the entire dataset cannot fit into cached memory. Frames have to be streamed through the memory hierarchy (disk to CPU main memory and then to GPU memory), partitioned, and processed as batches, where each batch is small enough to fit into the GPU. To reconnect the feature regions that are separated due to data partitioning, we present a novel batch merging algorithm to extract the region connection information across multiple batches in a parallel fashion. The information is organized in a memory-efficient structure and supports fast indexing on the GPU. Our experiment uses a commodity workstation equipped with a single GPU. The results show that our approach can efficiently process a weather dataset composed of terabytes of time-varying radar images. The advantages of our approach are demonstrated by comparing to the performance of an efficient CPU cluster implementation which is being used by the weather scientists. PMID- 27959818 TI - Querying of Disparate Association and Interaction Data in Biomedical Applications. AB - In biomedical applications, network models are commonly used to represent interactions and higher-level associations among biological entities. Integrated analyses of these interaction and association data has proven useful in extracting knowledge, and generating novel hypotheses for biomedical research. However, since most datasets provide their own schema and query interface, opportunities for exploratory and integrative querying of disparate data are currently limited. In this study, we utilize RDF-based representations of biomedical interaction and association data to develop a querying framework that enables flexible specification and efficient processing of graph template matching queries. The proposed framework enables integrative querying of biomedical databases to discover complex patterns of associations among a diverse range of biological entities, including biomolecules, biological processes, organisms, and phenotypes. Our experimental results on the UniProt dataset show that the proposed framework can be used to efficiently process complex queries, and identify biologically relevant patterns of associations that cannot be readily obtained by querying each dataset independently. PMID- 27959817 TI - Chemical and Biological Sensing Using Diatom Photonic Crystal Biosilica With In Situ Growth Plasmonic Nanoparticles. AB - In this paper, we described a new type of bioenabled nano-plasmonic sensors based on diatom photonic crystal biosilica with in-situ growth silver nanoparticles and demonstrated label-free chemical and biological sensing based on surface-enhanced Raman scattering (SERs) from complex samples. Diatoms are photosynthetic marine micro-organisms that create their own skeletal shells of hydrated amorphous silica, called frustules, which possess photonic crystal-like hierarchical micro- & nanoscale periodic pores. Our research shows that such hybrid plasmonic biosilica nanostructures formed by cost-effective and eco-friendly bottom-up processes can achieve ultra-high limit of detection for medical applications, food sensing, water/air quality monitoring and geological/space research. The enhanced sensitivity comes from the optical coupling of the guided-mode resonance of the diatom frustules and the localized surface plasmons of the silver nanoparticles. Additionally, the nanoporous, ultra-hydrophilic diatom biosilica with large surface-to-volume ratio can concentrate more analyte molecules to the surface of the SERS substrates, which can help to detect biomolecules that cannot be easily adsorbed by metallic nanoparticles. PMID- 27959819 TI - A New Efficient Algorithm for the Frequent Gene Team Problem. AB - The focus of this paper is the frequent gene team problem. Given a quorum parameter MU and a set of m genomes, the problem is to find gene teams that occur in at least MU of the given genomes. In this paper, a new algorithm is presented. Previous solutions are efficient only when MU is small. Unlike previous solutions, the presented algorithm does not rely on examining every combination of MU genomes. Its time complexity is independent of MU. Under some realistic assumptions, the practical running time is estimated to be , where n is the maximum length of the input genomes. Experiments showed that the presented algorithm is extremely efficient. For any MU, it takes less than 1 second to process 100 bacterial genomes and takes only 10 minutes to process 2,000 genomes. The presented algorithm can be used as an effective tool for large scale genome analyses. PMID- 27959822 TI - Forward Stagewise Additive Model for Collaborative Multiview Boosting. AB - Multiview assisted learning has gained significant attention in recent years in supervised learning genre. Availability of high-performance computing devices enables learning algorithms to search simultaneously over multiple views or feature spaces to obtain an optimum classification performance. This paper is a pioneering attempt of formulating a mathematical foundation for realizing a multiview aided collaborative boosting architecture for multiclass classification. Most of the present algorithms apply multiview learning heuristically without exploring the fundamental mathematical changes imposed on traditional boosting. Also, most of the algorithms are restricted to two class or view setting. Our proposed mathematical framework enables collaborative boosting across any finite-dimensional view spaces for multiclass learning. The boosting framework is based on a forward stagewise additive model, which minimizes a novel exponential loss function. We show that the exponential loss function essentially captures the difficulty of a training sample space instead of the traditional "1/0" loss. The new algorithm restricts a weak view from overlearning and thereby preventing overfitting. The model is inspired by our earlier attempt on collaborative boosting, which was devoid of mathematical justification. The proposed algorithm is shown to converge much nearer to global minimum in the exponential loss space and thus supersedes our previous algorithm. This paper also presents analytical and numerical analyses of convergence and margin bounds for multiview boosting algorithms and we show that our proposed ensemble learning manifests lower error bound and higher margin compared with our previous model. Also, the proposed model is compared with traditional boosting and recent multiview boosting algorithms. In the majority of instances, the new algorithm manifests a faster rate of convergence on training set error and also simultaneously offers better generalization performance. The kappa-error diagram analysis reveals the robustness of the proposed boosting framework to labeling noise. PMID- 27959823 TI - Decoupled ARX and RBF Neural Network Modeling Using PCA and GA Optimization for Nonlinear Distributed Parameter Systems. AB - Modeling of distributed parameter systems is difficult because of their nonlinearity and infinite-dimensional characteristics. Based on principal component analysis (PCA), a hybrid modeling strategy that consists of a decoupled linear autoregressive exogenous (ARX) model and a nonlinear radial basis function (RBF) neural network model are proposed. The spatial-temporal output is first divided into a few dominant spatial basis functions and finite-dimensional temporal series by PCA. Then, a decoupled ARX model is designed to model the linear dynamics of the dominant modes of the time series. The nonlinear residual part is subsequently parameterized by RBFs, where genetic algorithm is utilized to optimize their hidden layer structure and the parameters. Finally, the nonlinear spatial-temporal dynamic system is obtained after the time/space reconstruction. Simulation results of a catalytic rod and a heat conduction equation demonstrate the effectiveness of the proposed strategy compared to several other methods. PMID- 27959833 TI - Adaptive Spectro-Temporal Filtering for Electrocardiogram Signal Enhancement. AB - Advances in low-cost portable electrocardiogram (ECG) devices have opened doors for numerous new applications, including fitness tracking, remote health, and peak athletic performance monitoring, to name a few. Many such devices, however, have been shown to be highly contaminated by movement and/or muscle contraction artifacts, which, in turn, can lead to erroneous heart rate and heart rate variability (HRV) analyses. Here, we propose a new denoising method based on adaptive spectro-temporal filtering for ECG enhancement. The algorithm relies on the so-called modulation spectral signal representation, which is shown to accurately separate ECG and noise components. The proposed method was tested on synthetic ECG signals corrupted with varying levels of recorded noise and on long term bedside noisy ECG recordings. Gains over a state-of-the-art wavelet-based denoising algorithm were achieved, particularly for very noisy scenarios. Overall, the proposed algorithm achieved a 61.8% gain in signal-to-noise ratio improvement, a three times reduction in average heart rate measurement error, and a 15% reduction in HRV measurement error relative to the benchmark, thus suggesting that it is an ideal candidate for ECG-based fitness/athletic monitoring applications. PMID- 27959832 TI - Automated Detection and Segmentation of Vascular Structures of Skin Lesions Seen in Dermoscopy, With an Application to Basal Cell Carcinoma Classification. AB - Blood vessels are important biomarkers in skin lesions both diagnostically and clinically. Detection and quantification of cutaneous blood vessels provide critical information toward lesion diagnosis and assessment. In this paper, a novel framework for detection and segmentation of cutaneous vasculature from dermoscopy images is presented and the further extracted vascular features are explored for skin cancer classification. Given a dermoscopy image, we segment vascular structures of the lesion by first decomposing the image using independent-component analysis into melanin and hemoglobin components. This eliminates the effect of pigmentation on the visibility of blood vessels. Using k means clustering, the hemoglobin component is then clustered into normal, pigmented, and erythema regions. Shape filters are then applied to the erythema cluster at different scales. A vessel mask is generated as a result of global thresholding. The segmentation sensitivity and specificity of 90% and 86% were achieved on a set of 500 000 manually segmented pixels provided by an expert. To further demonstrate the superiority of the proposed method, based on the segmentation results, we defined and extracted vascular features toward lesion diagnosis in basal cell carcinoma (BCC). Among a dataset of 659 lesions (299 BCC and 360 non-BCC), a set of 12 vascular features are extracted from the final vessel images of the lesions and fed into a random forest classifier. When compared with a few other state-of-art methods, the proposed method achieves the best performance of 96.5% in terms of area under the curve (AUC) in differentiating BCC from benign lesions using only the extracted vascular features. PMID- 27959829 TI - A Model-Based Machine Learning Approach to Probing Autonomic Regulation From Nonstationary Vital-Sign Time Series. AB - Physiological variables, such as heart rate (HR), blood pressure (BP) and respiration (RESP), are tightly regulated and coupled under healthy conditions, and a break-down in the coupling has been associated with aging and disease. We present an approach that incorporates physiological modeling within a switching linear dynamical systems (SLDS) framework to assess the various functional components of the autonomic regulation through transfer function analysis of nonstationary multivariate time series of vital signs. We validate our proposed SLDS-based transfer function analysis technique in automatically capturing 1) changes in baroreflex gain due to postural changes in a tilt-table study including ten subjects, and 2) the effect of aging on the autonomic control using HR/RESP recordings from 40 healthy adults. Next, using HR/BP time series of more than 450 adult ICU patients, we show that our technique can be used to reveal coupling changes associated with severe sepsis (AUC = 0.74, sensitivity = 0.74, specificity = 0.60). Our findings indicate that reduced HR/BP coupling is significantly associated with severe sepsis even after adjusting for clinical interventions (P 0.001). These results demonstrate the utility of our approach in phenotyping complex vital-sign dynamics, and in providing mechanistic hypotheses in terms of break-down of autoregulatory systems under healthy and disease conditions. PMID- 27959834 TI - Simplifying EHR Overview of Critically Ill Patients Through Vital Signs Monitoring. AB - This paper presents a novel data-driven approach to graphical presentation of text-based electronic health records (EHR) while maintaining all textual information. We have developed the Patient Condition Timeline (PCT) tool, which creates a timeline representation of a patients' physiological condition during admission. PCT is based on electronical monitoring of vital signs and then combining these into Early Warning Scores (EWS). Hereafter, techniques from Natural Language Processing (NLP) are applied on existing EHR to extract all entries. Finally, the two methods are combined into an interactive timeline featuring the ability to see drastic changes in the patients' health, and thereby enabling staff to see where in the EHR critical events have taken place. PMID- 27959835 TI - Selective Sampling Importance Resampling Particle Filter Tracking With Multibag Subspace Restoration. AB - The focus of this paper is a novel object tracking algorithm which combines an incrementally updated subspace-based appearance model, reconstruction error likelihood function and a two stage selective sampling importance resampling particle filter with motion estimation through autoregressive filtering techniques. The primary contribution of this paper is the use of multiple bags of subspaces with which we aim to tackle the issue of appearance model update. The use of a multibag approach allows our algorithm to revert to a previously successful appearance model in the event that the primary model fails. The aim of this is to eliminate tracker drift by undoing updates to the model that lead to error accumulation and to redetect targets after periods of occlusion by removing the subspace updates carried out during the period of occlusion. We compare our algorithm with several state-of-the-art methods and test on a range of challenging, publicly available image sequences. Our findings indicate a significant robustness to drift and occlusion as a result of our multibag approach and results show that our algorithm competes well with current state-of the-art algorithms. PMID- 27959836 TI - Adaptively Adjusted Event-Triggering Mechanism on Fault Detection for Networked Control Systems. AB - This paper studies the problem of adaptively adjusted event-triggering mechanism based fault detection for a class of discrete-time networked control system (NCS) with applications to aircraft dynamics. By taking into account the fault occurrence detection progress and the fault occurrence probability, and introducing an adaptively adjusted event-triggering parameter, a novel event triggering mechanism is proposed to achieve the efficient utilization of the communication network bandwidth. Both the sensor-to-control station and the control station-to-actuator network-induced delays are taken into account. The event-triggered sensor and the event-triggered control station are utilized simultaneously to establish new network-based closed-loop models for the NCS subject to faults. Based on the established models, the event-triggered simultaneous design of fault detection filter (FDF) and controller is presented. A new algorithm for handling the adaptively adjusted event-triggering parameter is proposed. Performance analysis verifies the effectiveness of the adaptively adjusted event-triggering mechanism, and the simultaneous design of FDF and controller. PMID- 27959837 TI - A New Conflict Resolution Method for Multiple Mobile Robots in Cluttered Environments With Motion-Liveness. AB - This paper presents a new conflict resolution methodology for multiple mobile robots while ensuring their motion-liveness, especially for cluttered and dynamic environments. Our method constructs a mathematical formulation in a form of an optimization problem by minimizing the overall travel times of the robots subject to resolving all the conflicts in their motion. This optimization problem can be easily solved through coordinating only the robots' speeds. To overcome the computational cost in executing the algorithm for very cluttered environments, we develop an innovative method through clustering the environment into independent subproblems that can be solved using parallel programming techniques. We demonstrate the scalability of our approach through performing extensive simulations. Simulation results showed that our proposed method is capable of resolving the conflicts of 100 robots in less than 1.23 s in a cluttered environment that has 4357 intersections in the paths of the robots. We also developed an experimental testbed and demonstrated that our approach can be implemented in real time. We finally compared our approach with other existing methods in the literature both quantitatively and qualitatively. This comparison shows while our approach is mathematically sound, it is more computationally efficient, scalable for very large number of robots, and guarantees the live and smooth motion of robots. PMID- 27959838 TI - Querying Beneficial Constraints Before Clustering Using Facility Location Analysis. AB - This paper examines the problem of querying beneficial constraints before clustering. Existing methods in this area choose constraints heuristically based on some prior assumptions on the usefulness of constraints. However, the usefulness and propagation of constraints are two important issues in the constraints selection that are not investigated simultaneously in most existing works. This paper addresses the problem of querying beneficial constraints using facility location analysis that is one of the most well-studied areas of the operations research. To this end, the source problem of querying beneficial constraints is transformed into an instance of target uncapacitated -facility location problem ( -UFL) and then is benefited from existing algorithms in the target space to find a solution to the -UFL problem. The solution to the -UFL problem is then transformed into a solution of the source problem of querying beneficial constraints. Both usefulness and propagation of constraints are achieved in this paper by respectively mapping them into the corresponding opening and service costs in target problem space and then minimizing the total cost in target space. The proposed method is based on an optimization framework and is entirely different from existing methods in the constraints selection that are limited to greedy approaches. A range of experiments is presented to compare the proposed method to alternatives and explore its behavior in the selection of clustering constraints. PMID- 27959839 TI - [Disseminated histoplasmosis in patients with AIDS. Buenos Aires, 2009-2014]. AB - A retrospective study was carried out on 171 cases of disseminated histoplasmosis diagnosed in HIV/AIDS patients during the period 2009-2014. Although HIV diagnosis rates remained stable over the study period, a sensible increase in the number of histoplasmosis cases was observed in the last three years. Disseminated histoplasmosis was prevalent in males with an average age of 37.8 years. At diagnosis, only 54/171 (31.6%) were receiving HAART, and CD4+ T-lymphocyte counts ranged from 4 to 264 cells/upsilon. Cutaneous lesions, including ulcerated papules or molluscoid plaques, were present in 110/171 (64.3%), with Histoplasma capsulatum being observed in all skin scraping specimens upon Giemsa staining. Respiratory manifestations were second in frequency with bronchoalveolar lavage showing a high diagnostic performance. Radiological findings included milliary patterns, interstitial infiltrates, and focalized condensations. Out of 141 blood cultures performed, H. capsulatum was isolated in 82 (58.2%). No significant difference in diagnostic performance was found between blood cultures and skin scraping (p = 0.6164). Other opportunistic infections were observed in 70/171 (40.9%) prior to or concomitantly with histoplasmosis. Association with Mycobacterium tuberculosis was recorded in 16/171 (9.4%) and one had a multi-drug resistant isolate. The severity of histoplasmosis determined the monotherapy with amphotericin B deoxycholate in 115 (67.3%), itraconazole in 42 (24.5%), and combined therapies in 14 (8.2%). Mortality was 19.9% (34/171). Finally, we emphasize that the higher prevalence in the last three years of the study should prompt the medical community to consider the diagnosis of histoplasmosis to reduce mortality of AIDS patients. PMID- 27959840 TI - [Clinical manifestations of organizing pneumonia]. AB - Organizing pneumonia is a clinical entity asociated with nonspecific symptoms and radiological findings and abnormalities in pulmonary function tests. It is defined by the characteristic histopathological pattern: filling of alveoli and respiratory bronchioles by plugs of granulation tissue. It can be idiopathic (COP) or secondary to other causes (SOP). It is an unusual finding and the clinical and radiographic findings are nonspecific. For specific diagnosis an invasive procedure has to be done, but often empirical treatment is started when there's a clinical suspicion. We describe the clinical characteristics of 13 patients with histological diagnosis of organizing pneumonia. Data was obtained from their medical records. The median age was 76 years and the median time to diagnosis from the onset of symptoms was 31 days. In 10 cases the diagnosis was made by transbronchial biopsy. 8 patients required hospitalization, 4 of them received high doses of steroids and 3 required ventilatory support. One patient died from a cause attributable to this entity and 5 relapsed. Dyspnea, cough and fever were the most frequent symptoms. Most patients had more than one tomographic pattern being the most common ground glass opacities and alveolar consolidation. Nine patients were diagnosed with COP and 4 with SOP. The most frequent underlying cause of SOP was drug toxicity. The clinical characteristics of the reported cases are consistent with previously published series. As an interesting feature, there was a group of patients that needed high doses of steroids and ventilatory support. PMID- 27959841 TI - Kidney stones: Composition, frequency and relation to metabolic diagnosis. AB - Nephrolithiasis is one of the most frequent urologic diseases. The aim of this paper is to study the composition and frequency of 8854 patient kidney stones and in a subset of them their metabolic risk factors to be related to their type of calculi. Physicochemical and crystallographic methods were used to assess kidney stone composition. In a subset of 715 patients, we performed an ambulatory metabolic protocol with diagnostic purposes. From the total sample 79% of stones were made of calcium salts (oxalate and phosphate), followed by uric acid stones in 16.5%, calcium salts and uric acid in 2%, other salts in 1.9% and cystine in 0.6%. Male to female ratio was almost three times higher in calcium salts and other types of stones, reaching a marked male predominance in uric acid stones, M/F 18.8 /1.0. The major risk factors for calcium stones are idiopathic hypercalciuria, followed by unduly acidic urine pH and hyperuricosuria. In uric acid stones unduly acidic urine pH and less commonly hyperuricosuria are the most frequent biochemical diagnosis. Our results show that analysis of kidney stones composition and the corresponding metabolic diagnosis may provide a scientific basis for the best management and prevention of kidney stone formation, as well as it may help us to study the mechanisms of urine stone formation. PMID- 27959842 TI - [HIV-1 resistance to antiretroviral drugs in pregnant women from Buenos Aires metropolitan area]. AB - The study aimed to determine the prevalence of antiretroviral resistance associated mutations in HIV-1 infected pregnant woman treated in Buenos Aires metropolitan area (period 2008-2014). A total of 136 women with viral load = 500 copies/ml were included: 77 (56.6%) were treatment-naive and 59 (43.4%) were antiretroviral-experienced patients either with current (n: 24) or previous (n = 35) antiretroviral therapy. Genotypic baseline resistance was investigated in plasma of antiretroviral-naive patients and antiretroviral-experienced patients. The resistance mutations were identified according to the lists of the World Health Organization and the International Antiviral Society, respectively. Frequencies of resistance associated mutations detected in 2008-2011 and 2012 2014 were compared. A total of 37 (27.2%) women presented at least one resistance associated mutation: 25/94 (26.5%) in 2008-2011 and 12/42 (28.5%) in 2012-2014 (p > 0.05). Among naives, 15 (19.5%) had at least one mutation: 10/49 (20.4%) in the period 2008-2011 and 5/28 (17.8%) in 2012-2014 (p > 0.05). The resistance mutations detected in naives were associated with non nucleoside reverse transcriptase inhibitors, being K103N the most common mutation in both periods. In antiretroviral experienced patients, 22/59 (37.3%) had at least one resistance mutation. This study demonstrates a high frequency of resistance associated mutations which remained stable in the period analyzed. These levels suggest an increased circulation of HIV-1 antiretroviral resistant strains in our setting compared to previous reports from Argentina. PMID- 27959843 TI - [Prevalence of thyroid dysfunction in patients with type 2 diabetes mellitus]. AB - Diabetes mellitus (DM) and thyroid dysfunction (TD) are two common endocrine disorders. The unrecognized subclinical TD may adversely affect metabolic control and increase cardiovascular risk. Our aim was to investigate the prevalence of TD in patients with type 2 diabetes mellitus in an observational cross-sectional study. Clinical and laboratory evaluation was performed to 205 consecutive outpatients at Endocrinology Diabetes and Nutrition Center in Concepcion City, Tucuman, Argentina. Thyroid dysfunction was classified as clinical hypothyroidism with TSH > 4.20 mUI / ml and FT4 < 0.93 ng / dl, subclinical hypothyroidism with TSH > 4.20 mUI / ml and free T4 0.93 to 1.70 ng / dl. Subclinical hyperthyroidism was considered with TSH < 0.27 mUI / ml and free T4 was in normal range (0.93 to 1.70 ng / dl); and clinical hyperthyroidism with TSH < 0.27 mUI / ml and free T4 > 1.70 mUI / ml. Autoimmunity was diagnosed with anti-TPO > 34 IU / ml. TD prevalence in type 2 diabetic patients was 48% (n = 92). In subjects who denied prior TD, the prevalence was 40% (n = 37), 15 with subclinical hypothyroidism (45%). In the whole study population prevalence of subclinical hypothyroidism was 8%. Globally, subclinical DT prevalence was 9% (n = 17) and anti-TPO 13% (n = 25). Early detection of thyroid dysfunction in patients with type 2 diabetes mellitus should be performed routinely, given the high rate of newly diagnosed cases, and increased cardiovascular risk associated with undiagnosed thyroid dysfunction. PMID- 27959844 TI - [Implementation of a telementoring model of medical education in psoriasis]. AB - The ECHO(r) (Extension for Community Healthcare Outcomes) project is a model of distance medical education. Its mission is to expand knowledge and evaluate the results of this action, both in the training of human resources in healthcare and in the accomplishment of the best medical practices in the community target. It is developed through case presentation videoconferencing, between experts in chronic and complex diseases and physicians, with the aim of reducing the healthcare asymmetries between large urban centers and peripherals areas. We have implemented this telementoring for dermatologists and residents who treat patients with psoriasis. After 10 sessions, a survey was conducted to evaluate the educational attainment of the participants. A significant improvement was found in their abilities to determine the severity of psoriasis, screening for arthritis, assessment of the patient before beginning systemic treatment and appropriate follow-up under different systemic therapies. ECHO replication model helped improve the skills of the participants in the management of this disease, and reduced professional isolation. PMID- 27959845 TI - [Inappropriate prescription in elderly inpatients]. AB - One of the causes of preventable adverse drug events (EAM) in the older adult population is the inappropriate prescription (PIM), i.e. that prescription where risks outweigh clinical benefits. The aim of this study is to determine the incidence of PIM with Beers criteria and Screening Tool of older person's prescriptions (STOPP), Potentially Prescribing Omissions (PPO) with Screening Tool to alert doctors to Right Treatments (START), and the average costs of hospitalization. This is an incidence study on a sample of patients over 64 years hospitalized, from January to July 2014 at a university hospital. According to Beers criteria, PIM incidence was 61.4%, 65.4% with STOPP and 27.6% PPO with START. The EAM rate calculated was 15.2/100 admissions and 18.6 EAM / 1000 patient days. The OR of EAM with PIM according to Beers and STOPP was 1.49 (IC95% 1.68-4.66) and 1.17 (IC95% 0.62-2.24) respectively. The average cost of hospitalization in patients with EAM were higher than without EAM (p = 0.020). PIM results are in line with most of the studies cited, but slightly higher for Beers and STOPP and lower for START, and the rate of EAM is lower than the data found by Kanaan (18.7% vs. 15.2%). PIM contributes to the appearance of EAM. The costs of hospitalizations with EAM are higher than those without EAM, achieving level of significance. PMID- 27959846 TI - [Sickle cell syndrome. Association between hemoglobin S and beta thalassemia]. AB - Sickle cell syndrome HbS/beta thalassemia is an inheritable mendelian type disease where two affected alleles are simultaneously present, one from HbS (betaS) and the other from beta thalassemia. That situation is mainly linked to individuals who share African and Mediterranean ancestors. The mutation responsible for HbS is a point mutation, whereas for beta thalassemia, there are more than 200 mutations that cause different degrees of deficiency synthesis of beta globin chain, which justifies the clinical and genetic heterogeneity of this syndrome. It is presented a clinical case of a young adult man with limited resources that consulted by longstanding bone pain. The patient presented anemia with a marked microcytosis. Hemoglobin electrophoresis was performed, an abnormal peak in position of HbS and high HbA2 fraction were detected. These last results indicated two possible molecular alterations simultaneously, for this reason the molecular study was performed looking for the most common beta thalassemia mutations in our population and, the point mutation responsible for S hemoglobinopathy. Clinical data and biochemical laboratory allowed the diagnosis of sickle cell syndrome. The molecular study confirmed the syndrome carrying mutations IVS-I nt 110 G > A, responsible for beta thalassemia and, codon 6 A > T (GAG -> GTG: Glu -> Val) responsible for S hemoglobinophaty. Since it is a disease of high health impact, it is important to provide genetic counseling to the whole family. PMID- 27959847 TI - [Pulmonary embolism after endoscopic injection with N-butyl-2-cyanoacrylate for gastric varices]. AB - Gastric varices occur in one-third of patients with portal hypertension. Bleeding from gastric varices remains a significant cause of death. Currently the first line of treatment for gastric varices is endoscopic obliteration with N-butyl-2 cyanoacrylate. Though relatively safe, this option has several well-known complications. We report the case of a 61-year-old male patient with cryptogenic cirrhosis, who presented with fever, tachycardia and hypoxemia after endoscopic obliteration with N-butyl-2-cyanoacrylate. Radiographic findings were consistent with pulmonary embolism of the sclerosing substance. The aim of this case report is to emphasize the clinical and radiological findings of this complication in order to distinguish it from other similar medical conditions and prevent a delay in diagnosis. PMID- 27959848 TI - [Tubulointerstitial nephritis syndrome and uveitis]. AB - Intermediate uveitis is described as inflammation in the anterior vitreous, ciliary body and the peripheral retina. It is a subset of uveitis where the vitreous is the major site of damage. It has been reported to be associated with many local and systemic inflammatory and infectious diseases. An infrequent cause is the tubulointerstitial nephritis and uveitis syndrome. We report a case of an acute visual acuity loss related with renal failure in a 64 years old woman with Hashimoto disease. It was an acute tubulointerstitial nephritis and uveitis syndrome case. PMID- 27959849 TI - [Relapses in inflammatory myopathies]. AB - Most studies about treatment of inflammatory myopathies consist of cross sectional analyses that do not assess long-term efficacy. In the present study we describe the follow-up of seven patients with inflammatory myopathies, 5 polymyositis and 2 dermatomyositis. We describe their clinical features, follow up, muscle enzyme levels, and treatment responses. We define the latter as treatment cycles, every one of which end when steroid doses need to be increased or a new immunosuppressive drug has to be added because of clinical worsening or sustained increases in muscle enzyme levels. Treatment can cause remission, partially control, or fail in achieving myositis improvement when it normalizes, stabilizes, or does not affect muscle enzymes or clinical features, respectively. We analyzed 20 cycles, in which remission was achieved in 14 cases, partial control in 5 instances, and treatment failure in one case. Remission occurred after an average of 139 +/- 98 days, whereas partial control took place in 160 +/ 100 days. Except in one case, all treatment cycles controlled or remitted the symptoms. However, in all patients the illness recurred with time. PMID- 27959850 TI - [Regulation of the beta-globin gene family expression, useful in the search for new therapeutic targets for hemoglobinopathies]. AB - Different hemoglobin isoforms are expressed during the embryonic, fetal and postnatal stages. They are formed by combination of polypeptide chains synthesized from the alpha- and beta-globin gene clusters. Based on the fact that the presence of high hemoglobin F levels is beneficial in both sickle cell disease and severe thalassemic syndromes, a revision of the regulation of the beta-globin cluster expression is proposed, especially regarding the genes encoding the y-globin chains (HBG1 and HBG2). In this review we describe the current knowledge about transcription factors and epigenetic regulators involved in the switches of the beta-globin cluster. It is expected that the consolidation of knowledge in this field will allow finding new therapeutic targets for the treatment of hemoglobinopathies. PMID- 27959851 TI - [Screening, diagnosis and treatment of chronic hepatitis C in clinical practice]. AB - Chronic hepatitis C (HCV) is a global health problem. Worldwide, 170 million people are chronically infected. In Latin America its prevalence is estimated between 1.0 and 2.3%, and in Argentina between 1.0 and 1.5%. Treatment efficacy has considerably improved in the last 2 or 3 years. Sustained virological response (SVR) rates around 90-95% can be achieved with the new direct acting antiviral agents (DAAs) currently available, with few side effects. It is necessary to increase the number of diagnosed patients, linking them to adequate management and treatment. Raising treatment rates will increase the percentage of cured patients, reducing the burden of disease. Primary care physicians' role is essential to achieve this goal. They must identify persons at risk, diagnose them and work with specialists to continue their medical care. Team working of generalists and specialists will permit that more HCV infected people can access to adequate care and treatment. PMID- 27959852 TI - [Spontaneous carotid recanalization]. PMID- 27959854 TI - [By a whisker: Charles Darwin and medicine]. PMID- 27959853 TI - [Giant abdominal abscess]. PMID- 27959855 TI - [Colon cancer with abdominal wall infiltration and clinical factors of poor prognosis]. PMID- 27959856 TI - [Scientific fraud]. PMID- 27959858 TI - Regulation of Glucose Handling by the Skeleton: Insights From Mouse and Human Studies. PMID- 27959859 TI - Type 1 Diabetes Prevention: A Goal Dependent on Accepting a Diagnosis of an Asymptomatic Disease. AB - Type 1 diabetes, a disease defined by absolute insulin deficiency, is considered a chronic autoimmune disorder resulting from the destruction of insulin-producing pancreatic beta-cells. The incidence of childhood-onset type 1 diabetes has been increasing at a rate of 3%-5% per year globally. Despite the introduction of an impressive array of therapies aimed at improving disease management, no means for a practical "cure" exist. This said, hope remains high that any of a number of emerging technologies (e.g., continuous glucose monitoring, insulin pumps, smart algorithms), alongside advances in stem cell biology, cell encapsulation methodologies, and immunotherapy, will eventually impact the lives of those with recently diagnosed or established type 1 diabetes. However, efforts aimed at reversing insulin dependence do not address the obvious benefits of disease prevention. Hence, key "stretch goals" for type 1 diabetes research include identifying improved and increasingly practical means for diagnosing the disease at earlier stages in its natural history (i.e., early, presymptomatic diagnosis), undertaking such efforts in the population at large to optimally identify those with presymptomatic type 1 diabetes, and introducing safe and effective therapeutic options for prevention. PMID- 27959860 TI - Using Genotype-Based Recall to Estimate the Effects of AMY1 Copy Number Variation in Substrate Metabolism. PMID- 27959861 TI - Human Pancreatic Islet Production: From Research Protocols to Standardized Multicenter Manufacturing. PMID- 27959862 TI - The Insulin-Like Growth Factor Axis: A New Player in Gestational Diabetes Mellitus? PMID- 27959864 TI - Erratum. Docosahexaenoic Acid-Derived Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) With Anti-inflammatory Properties. Diabetes 2016;65:2580-2590. PMID- 27959867 TI - Evaluation of virus reduction efficiency in wastewater treatment unit processes as a credit value in the multiple-barrier system for wastewater reclamation and reuse. AB - The virus reduction efficiency of each unit process is commonly determined based on the ratio of virus concentration in influent to that in effluent of a unit, but the virus concentration in wastewater has often fallen below the analytical quantification limit, which does not allow us to calculate the concentration ratio at each sampling event. In this study, left-censored datasets of norovirus (genogroup I and II), and adenovirus were used to calculate the virus reduction efficiency in unit processes of secondary biological treatment and chlorine disinfection. Virus concentration in influent, effluent from the secondary treatment, and chlorine-disinfected effluent of four municipal wastewater treatment plants were analyzed by a quantitative polymerase chain reaction (PCR) approach, and the probabilistic distributions of log reduction (LR) were estimated by a Bayesian estimation algorithm. The mean values of LR in the secondary treatment units ranged from 0.9 and 2.2, whereas those in the free chlorine disinfection units were from -0.1 and 0.5. The LR value in the secondary treatment was virus type and unit process dependent, which raised the importance for accumulating the data of virus LR values applicable to the multiple-barrier system, which is a global concept of microbial risk management in wastewater reclamation and reuse. PMID- 27959868 TI - Pathogenic features of heterotrophic plate count bacteria from drinking-water boreholes. AB - Evidence suggests that heterotrophic plate count (HPC) bacteria may be hazardous to humans with weakened health. We investigated the pathogenic potential of HPC bacteria from untreated borehole water, consumed by humans, for: their haemolytic properties, the production of extracellular enzymes such as DNase, proteinase, lipase, lecithinase, hyaluronidase and chondroitinase, the effect simulated gastric fluid has on their survival, as well as the bacteria's antibiotic susceptible profile. HuTu-80 cells acted as model for the human intestine and were exposed to the HPC isolates to determine their effects on the viability of the cells. Several HPC isolates were alpha- or beta-haemolytic, produced two or more extracellular enzymes, survived the SGF treatment, and showed resistance against selected antibiotics. The isolates were also harmful to the human intestinal cells to varying degrees. A novel pathogen score was calculated for each isolate. Bacillus cereus had the highest pathogen index: the pathogenicity of the other bacteria declined as follows: Aeromonas taiwanensis > Aeromonas hydrophila > Bacillus thuringiensis > Alcaligenes faecalis > Pseudomonas sp. > Bacillus pumilus > Brevibacillus sp. > Bacillus subtilis > Bacillus sp. These results demonstrated that the prevailing standards for HPCs in drinking water may expose humans with compromised immune systems to undue risk. PMID- 27959869 TI - Cyto- and genotoxic profile of groundwater used as drinking water supply before and after disinfection. AB - The assessment of the toxicological properties of raw groundwater may be useful to predict the type and quality of tap water. Contaminants in groundwater are known to be able to affect the disinfection process, resulting in the formation of substances that are cytotoxic and/or genotoxic. Though the European directive (98/83/EC, which establishes maximum levels for contaminants in raw water (RW)) provides threshold levels for acute exposure to toxic compounds, the law does not take into account chronic exposure at low doses of pollutants present in complex mixture. The purpose of this study was to evaluate the cyto- and genotoxic load in the groundwater of two water treatment plants in Northern Italy. Water samples induced cytotoxic effects, mainly observed when human cells were treated with RW. Moreover, results indicated that the disinfection process reduced cell toxicity, independent of the biocidal used. The induction of genotoxic effects was found, in particular, when the micronucleus assay was carried out on raw groundwater. These results suggest that it is important to include bio-toxicological assays as additional parameters in water quality monitoring programs, as their use would allow the evaluation of the potential risk of groundwater for humans. PMID- 27959866 TI - Quiescin-sulfhydryl oxidase inhibits prion formation in vitro. AB - Prions are infectious proteins that cause a group of fatal transmissible diseases in animals and humans. The scrapie isoform (PrPSc) of the cellular prion protein (PrPC) is the only known component of the prion. Several lines of evidence have suggested that the formation and molecular features of PrPSc are associated with an abnormal unfolding/refolding process. Quiescin-sulfhydryl oxidase (QSOX) plays a role in protein folding by introducing disulfides into unfolded reduced proteins. Here we report that QSOX inhibits human prion propagation in protein misfolding cyclic amplification reactions and murine prion propagation in scrapie infected neuroblastoma cells. Moreover, QSOX preferentially binds PrPSc from prion-infected human or animal brains, but not PrPC from uninfected brains. Surface plasmon resonance of the recombinant mouse PrP (moPrP) demonstrates that the affinity of QSOX for monomer is significantly lower than that for octamer (312 nM vs 1.7 nM). QSOX exhibits much lower affinity for N-terminally truncated moPrP (PrP89-230) than for the full-length moPrP (PrP23-231) (312 nM vs 2 nM), suggesting that the N-terminal region of PrP is critical for the interaction of PrP with QSOX. Our study indicates that QSOX may play a role in prion formation, which may open new therapeutic avenues for treating prion diseases. PMID- 27959870 TI - Household greywater treatment methods using natural materials and their hybrid system. AB - Discharge of household greywater into water bodies can lead to an increase in contamination levels in terms of the reduction in dissolved oxygen resources and rapid bacterial growth. Therefore, the quality of greywater has to be improved before the disposal process. The present review aimed to present a hybrid treatment system for the greywater generated from households. The hybrid system comprised a primary stage (a natural filtration unit) with a bioreactor system as the secondary treatment combined with microalgae for greywater treatment, as well as the natural flocculation process. The review discussed the efficiency of each stage in the removal of elements and nutrients. The hybrid system reviewed here represented an effective solution for the remediation of household greywater. PMID- 27959871 TI - Seasonal influence of environmental variables and artificial aeration on Escherichia coli in small urban lakes. AB - This study investigated patterns of Escherichia coli in urban lakes in Lubbock, Texas. Specific objectives were to (1) document seasonal patterns in abundance of E. coli over a 3-year period, (2) identify environmental factors, including effects of migratory geese and artificial aeration devices that may influence E. coli abundance, and (3) determine if E. coli abundance over time was similar for individual lakes. Water samples were collected monthly for 36 months from six lakes, three of which contained artificial aeration devices (fountains). Regression models were constructed to determine which environmental variables most influence E. coli abundance in summer and winter seasons. Escherichia coli is present in the lakes of Lubbock, Texas year-round and typically exceeds established bacterial thresholds for recreational waters. Models most frequently contained pH and dissolved oxygen as predictor variables and explained from 17.4% to 92.4% of total variation in E. coli. Lakes with fountains had a higher oxygen concentration during summer and contained consistently less E. coli. We conclude that solar irradiation in synergy with pH and dissolved oxygen is the primary control mechanism for E. coli in study lakes, and that fountains help control abundance of fecal bacteria within these systems. PMID- 27959872 TI - Survival of antibacterial resistance microbes in hospital-generated recycled wastewater. AB - Hospital wastewater has the potential to be a threat to the hospital environment as it can contain pathogenic bacteria that may facilitate the resistant nature of organisms within effluent or water treatment plants. The recycling of hospital wastewater should have good quality. This study was carried out to highlight the incidence of antibiotic resistant bacteria in hospital-generated recycled water. This study was conducted in a tertiary care teaching hospital during June 2013 June 2014. One hundred and forty wastewater samples were aseptically collected at different stages in the recycling plant. The samples were processed within 2 hours following standard procedures for identification of bacteria and the pathogenic bacteria were isolated. The mostly identified pathogens were Staphylococcus aureus (11.42%), Pseudomonas aeruginosa (9.28%), Enterococcus faecalis (10%) and Bacillus subtilis (8.57%) which were removed by treatment, but Escherichia coli (16.42%), Klebsiella pneumonia (8.57%), and Proteus mirabilis (11.42%) survived in the final sedimentation tank (lagoon) from where this water will be used for gardening purposes. An antibiogram study showed these pathogens were resistant to first-line antibiotics. Effluent treatment plants in hospitals should be monitored for the fulfillment of the guidelines and quality control of treated water to stop the emergence of multi-drug resistant bacteria in the hospital environment. PMID- 27959873 TI - Antibacterial and antiviral effectiveness of two household water treatment devices that use monobrominated hydantoinylated polystyrene. AB - Many different household water treatment (HWT) methods have been researched and promoted to mitigate the serious burden of diarrheal disease in developing countries. However, HWT methods using bromine have not been extensively evaluated. Two gravity-fed HWT devices (AquaSureTM and WaterbirdTM) were used to test the antimicrobial effectiveness of HaloPure(r) Br beads (monobrominated hydantoinylated polystyrene) that deliver bromine. As water flows over the beads, reactive bromine species are eluted, which inactivate microorganisms. To assess log10 reduction values (LRVs) for Vibrio cholerae, Salmonella enterica Typhimurium, bacteriophage MS2, human adenovirus 2 (HAdV2), and murine norovirus (MN), these organisms were added to potable water and sewage-contaminated water. These organisms were quantified before and after water treatment by the HWT devices. On average, 6 LRVs against Vibrio were attained, as well as 5 LRVs against Salmonella, 4 LRVs against MS2, 5 LRVs against HAdV2, and 3 LRVs against MN. Disinfection was similar regardless of whether sewage was present. Polymer beads delivering bromine to drinking water are a potentially effective and useful component of HWT methods in developing countries. PMID- 27959874 TI - Microbial quality and suitability of roof-harvested rainwater in rural villages for crop irrigation and domestic use. AB - The study aimed at assessing the microbiological quality and suitability of roof harvested rainwater (RHRW) for crop irrigation and domestic use. In total, 80 rainwater tanks (246 samples) across three rural villages (Ga-Molepane, Jericho and Luthngele) were visited. Culture-based techniques were used to isolate bacterial microbes and identities were confirmed using matrix-assisted laser desorption/ionization time of flight (MALDI-TOF-MS). Uncultured fungal populations were also identified using pyrosequencing. Salmonella spp. (3%), Listeria monocytogenes (22%), total coliforms (57.7%), Escherichia coli (30.5%), Enterococcus spp. (48.8%), Pseudomonas spp. (21.5%) were detected in RHRW samples after rainfall. Fungal sequences belonging to species known to cause fever, coughing and shortness of breath in humans (Cryptococcus spp.) were identified. This study indicates that RHRW quality can be affected by external factors such as faecal material and debris on rooftops. The use of untreated RHRW could pose a potential health risk if used for irrigation of crops or domestic use, especially in the case of a relative high population of immunocompromised individuals. This study does not dispute the fact that RHRW is an alternative irrigation water source but it recommends treatment before use for domestic purposes or for watering crops. PMID- 27959875 TI - Fecal indicator and Ascaris removal from double pit latrine content. AB - Since May 2006, the BRAC Water, Sanitation and Hygiene (WASH) Programme in Bangladesh has enabled more than 30 million people to achieve hygienic sanitation, contributing to an increase in sanitation coverage from 33 to 83% in programme areas and rapid progress towards universal access. In rural areas, most families have single pit latrines that need to be emptied when full. Since 2007, BRAC has promoted the use of hygienic double-pit latrines. Use of double-pit latrines, where appropriate, is also recommended in the Bangladeshi Draft National Water Supply and Sanitation Strategy. More than 800,000 double-pit latrines are in use in BRAC WASH areas, delaying the need for emptying and allowing time for the fecal matter to decompose while the resting pit is sealed. This paper focuses on a study undertaken by BRAC WASH to treat and safely use fecal material from double pit latrines as an organic fertilizer for rice and other crops. The study investigated the removal of pathogens from pit waste through simple solar drying and conducted analysis on nutrient properties of fecal sludge. The study showed a significant positive impact on developing organic fertilizer from fecal sludge. PMID- 27959877 TI - Synthesis of walnut shell modified with titanium dioxide and zinc oxide nanoparticles for efficient removal of humic acid from aqueous solutions. AB - The main aim of this research was to study the efficiency of modified walnut shell with titanium dioxide (TiO2) and zinc oxide (ZnO) in the adsorption of humic acid from aqueous solutions. This experimental study was carried out in a batch condition to determine the effects of factors such as contact time, pH, humic acid concentration, dose of adsorbents (raw walnut shell, modified walnut shell with TiO2 and ZnO) on the removal efficiency of humic acid. pHzpc of raw walnut shell, walnut shell modified with TiO2 and walnut shell modified with ZnO were 7.6, 7.5, and 8, respectively. The maximum adsorption capacity of humic acid at concentration of 30 mg/L, contact time of 30 min at pH = 3 in an adsorbent dose of 0.02 g of walnut shell and ZnO and TiO2 modified walnut shell were found to be 35.2, 37.9, and 40.2 mg/g, respectively. The results showed that the studied adsorbents tended to fit with the Langmuir model. Walnut shell, due to its availability, cost-effectiveness, and also its high adsorption efficiency, can be proposed as a promising natural adsorbent in the removal of humic acid from aqueous solutions. PMID- 27959876 TI - Degradation of gestodene (GES)-17alpha-ethinylestradiol (EE2) mixture by electrochemical oxidation. AB - Evidence of the negative effects of several pharmaceutical molecules, such as hormones and steroids, on the environment can be observed throughout the world. This paper presents the results of the anodic oxidation of the mixture of gestodene steroid hormones and 17 alpha-ethinylestradiol present in aqueous medium. The tests were conducted in an undivided cell containing a working volume of 50 mL, using a Na2SO4 solution as support electrolyte and boron-doped diamond electrodes. The experiments were adjusted to the structure of a 33 factorial design. The evaluated factors were: support electrolyte concentration (0.02, 0.05, and 0.10 M), pH of the reaction media (2, 3, and 4), and current density (16, 32, and 48 mA cm-2). Under the optimum conditions (0.02 M Na2SO4, pH 4, and current density of 32 mA cm-2), the degradation of at least 93% of the initial concentration of gestodene and 17alpha-ethinylestradiol was reached in a reaction time of 5 and 10 min, respectively. The complete degradation of both molecules required 15 min of reaction. Under these conditions, the degradation profile of the pharmaceutical mixture as each one of the active ingredients, followed a pseudo-first order kinetic behavior (kmix = 0.0321, kGES = 0.4206, and kEE2 = 0.3209 min-1). PMID- 27959878 TI - Exploring the relationships between small non-community drinking water system characteristics and water system performance in Ontario, Canada. AB - The objectives of this work were to investigate the relationships between characteristics of small non-community drinking water systems (SDWSs) and the performance of these systems with respect to Escherichia coli testing and risk ratings. Ontario-wide SDWS data were analysed using regression models with outcomes of (1) having an adverse E. coli test result in the 12 months prior to the last inspection and (2) the SDWS risk rating (high/medium vs. low risk) that is assigned by public health inspectors. Almost 34% (2,364/7,003) of SDWSs did not utilize treatment, more commonly for ground water than surface supplies (P < 0.001). The odds of having a positive E. coli test result were greater in systems using ground water with treatment (OR = 2.00; 95% CI 1.23-3.24) and surface water with treatment (OR = 1.97; 95% CI 1.05-3.71) compared to ground water with no treatment. The odds of having a water system rated high or medium compared to low risk was greater if the water system operated seasonally (OR = 1.36; 95% CI 1.17 1.59), had an adverse E. coli test result (OR = 1.66; 95% CI 1.09-2.53), and in specific facility types. This research helps to inform existing training opportunities available to SDWS operators in Ontario, and to better standardize the SDWS risk assessment process. PMID- 27959879 TI - Non-carcinogenic risk assessment of groundwater in South Gobi, Mongolia. AB - Thirty-nine groundwater samples were collected from wells near the Tavan Tolgoi and Oyu Tolgoi mines in Mongolia and at a relatively pristine site in northern Mongolia during August to September 2013, and analyzed for the concentrations of F-, NO3-, Hg, As, Al, V, Mn, Co, Ni, Cu, Zn, Se, Mo, Cd, Sb, and Pb. A probabilistic risk assessment found that >95% of the population in the areas was at risk from drinking well water. The hazard index (HI) was >1, indicating a non carcinogenic risk to human health. At Oyu Tolgoi, the hazard quotient (HQ) of the As concentration (mean 6.63 MUg/L) was >1. At the northern site, the 95th percentile HQ was <1 but the 95th percentile HI was >1. The ratios of nitrogen and oxygen stable isotopes indicated that NO3- contamination of groundwater at Oyu Tolgoi and Tavan Tolgoi was caused by livestock waste. Mercury accumulation in livestock was examined from concentrations in livestock forage and in hair and wool samples from livestock in the South Gobi region. Sheep wool had the same level of mercury as in Japan, but camel, horse, and goat hair had high levels. PMID- 27959880 TI - Association between heavy precipitation events and waterborne outbreaks in four Nordic countries, 1992-2012. AB - We conducted a matched case-control study to examine the association between heavy precipitation events and waterborne outbreaks (WBOs) by linking epidemiological registries and meteorological data between 1992 and 2012 in four Nordic countries. Heavy precipitation events were defined by above average (exceedance) daily rainfall during the preceding weeks using local references. We performed conditional logistic regression using the four previous years as the controls. Among WBOs with known onset date (n = 89), exceedance rainfall on two or more days was associated with occurrence of outbreak, OR = 3.06 (95% CI 1.38 6.78), compared to zero exceedance days. Stratified analyses revealed a significant association with single household water supplies, ground water as source and for outbreaks occurring during spring and summer. These findings were reproduced in analyses including all WBOs with known outbreak month (n = 186). The vulnerability of single households to WBOs associated with heavy precipitation events should be communicated to homeowners and implemented into future policy planning to reduce the risk of waterborne illness. PMID- 27959881 TI - Household water insecurity is associated with a range of negative consequences among pregnant Kenyan women of mixed HIV status. AB - Water insecurity (WI) is a serious and worsening problem worldwide, but its role in health outcomes among people living with HIV or pregnant women is unknown. We assessed experiences of WI in a cohort of 323 pregnant Kenyan women of mixed HIV status. The majority (77.7%) had at least one experience of WI in the previous month; it was associated with negative economic, nutrition, disease, and psychosocial outcomes. A standardized cross-culturally valid household WI scale would facilitate assessment of the prevalence and consequences of WI, and increased attention to WI could reveal an overlooked, but modifiable, cause of adverse HIV outcomes. PMID- 27959882 TI - Limited effectiveness of household sand filters for removal of arsenic from well water in North Vietnam. AB - Since well water utilized for domestic purposes in the Red River Delta of North Vietnam has been reported to be polluted by arsenic, barium, iron, and manganese, household sand filters consisting of various components are used. Information regarding the effectiveness of various sand filters for removal of the four toxic elements in well water is limited. In this study, arsenic levels in 13/20 of well water samples and 1/7 of tap water samples exceeded World Health Organization (WHO) health-based guideline value for drinking water. Moreover, 2/20, 6/20, and 4/20 of well water samples had levels exceeding the present and previous guideline levels for barium, iron, and manganese, respectively. Levels of iron and manganese, but not arsenic, in well water treated by sand filters were lower than those in untreated water, although previous studies showed that sand filters removed all of those elements from water. A low ratio of iron/arsenic in well water may not be sufficient for efficient removal of arsenic from household sand filters. The levels of barium in well water treated by sand filters, especially a filter composed of sand and charcoal, were significantly lower than those in untreated water. Thus, we demonstrated characteristics of sand filters in North Vietnam. PMID- 27959883 TI - Antibiotic susceptibility of Legionella strains isolated from public water sources in Macau and Guangzhou. AB - The purpose of this study was to investigate the susceptibility of waterborne strains of Legionella to eight antimicrobials commonly used in legionellosis therapy. The minimum inhibitory concentrations (MICs) of 66 environmental Legionella strains, isolated from fountains and cooling towers of public facilities (hotels, schools, and shopping malls) in Macau and Guangzhou, were tested using the microdilution method in buffered yeast extract broth. The MIC50/MIC90 values for erythromycin, cefotaxime (CTX), doxycycline (DOC), minocycline (MIN), azithromycin, ciprofloxacin, levofloxacin (LEV), and moxifloxacin were 0.125/0.5 mg/L, 4/8 mg/L, 8/16 mg/L, 4/8 mg/L, 0.125/0.5 mg/L, 0.031/0.031 mg/L, 0.031/0.031 mg/L, and 0.031/0.062 mg/L, respectively. Legionella isolates were inhibited by either low concentrations of macrolides and fluoroquinolones, or high concentrations of CTX and tetracycline drugs. LEV was the most effective drug against different Legionella species and serogroups of L. pneumophila isolates. The latter were inhibited in decreasing order by MIN > CTX >DOC, while non-L. pneumophila isolates were inhibited by CTX> MIN >DOC. In this study, we evaluated drug resistance of pathogenic bacteria from the environment. This may help predict the emergence of drug resistance, improve patient outcomes, and reduce hospitalization costs. PMID- 27959884 TI - Microbial source tracking of private well water samples across at-risk regions in southern Ontario and analysis of traditional fecal indicator bacteria assays including culture and qPCR. AB - Many people living in rural areas rely on privately owned wells as their primary source of drinking water. These water sources are at risk for fecal contamination of human, wildlife, and livestock origin. While traditional bacteriological testing involves culture-based methods, microbial source tracking (MST) assays present an opportunity to additionally determine the source of fecal contamination. This study investigated the main host sources of contamination in private well water samples with high levels of Escherichia coli (E. coli), using MST with human and multi-species specific markers. Fecal contamination of human origin was detected in approximately 50% of samples, indicating that current contamination prevention strategies require reconsideration. The relationship between cattle density and fecal contamination of bovine origin was investigated using a Bovine Bacteroidales specific MST assay. Regional variations of microbial sources were examined, and may inform local primary prevention strategies. Additionally, in order to assess MST and E. coli quantitative real time polymerase chain reaction (qPCR) assays as indicators of fecal contamination, these were compared to E. coli culture methods. Variation in results was observed across all assay methods investigated, suggesting the most appropriate routine bacteriological testing methodology cannot be determined without comparison to a method that directly detects the presence of fecal contamination. PMID- 27959885 TI - Potassium Aspartate Attenuates Brain Injury Induced by Controlled Cortical Impact in Rats Through Increasing Adenosine Triphosphate (ATP) Levels, Na+/K+-ATPase Activity and Reducing Brain Edema. AB - BACKGROUND Potassium aspartate (PA), as an electrolyte supplement, is widely used in clinical practice. In our previous study, we found PA had neuroprotective effects against apoptosis after cerebral ischemia/reperfusion in rats. In this study, we examine whether PA has protective effects on traumatic brain injury (TBI). MATERIAL AND METHODS TBI was induced by controlled cortical impact (CCI) in rats. Vehicle treatment (control) or PA treatment was administered intraperitoneally at 30 minutes after CCI. The modified neurological severity score (mNSS) and cortical lesion volume were examined. Brain edema and blood brain barrier (BBB) integrity were measured, as well as brain ATP contents, lactic acid levels, and Na+/K+-ATPase activities. RESULTS We found that CCI induced cortical injury in rats. Acute PA treatment at the dose of 62.5 mg/kg and 125 mg/kg significantly improved neurological deficits (p<0.05 and p<0.001, respectively) and decreased the cortical lesion volume (p<0.05 and p<0.001, respectively) compared with vehicle-only treatment. PA treatment at the dose of 125 mg/kg attenuated brain edema and ameliorated BBB integrity. In addition, PA treatment significantly reduced the loss of ATP (p<0.01), reduced lactic acid levels (p<0.001), and increased the activity of Na+/K+-ATPase (p<0.01). CONCLUSIONS Our results indicate PA has neuroprotective effects on TBI through increasing ATP levels, Na+/K+-ATPase activity, and reducing brain edema. It provides experimental evidence for the clinical application of PA. PMID- 27959886 TI - Crowdsourcing for translational research: analysis of biomarker expression using cancer microarrays. AB - BACKGROUND: Academic pathology suffers from an acute and growing lack of workforce resource. This especially impacts on translational elements of clinical trials, which can require detailed analysis of thousands of tissue samples. We tested whether crowdsourcing - enlisting help from the public - is a sufficiently accurate method to score such samples. METHODS: We developed a novel online interface to train and test lay participants on cancer detection and immunohistochemistry scoring in tissue microarrays. Lay participants initially performed cancer detection on lung cancer images stained for CD8, and we measured how extending a basic tutorial by annotated example images and feedback-based training affected cancer detection accuracy. We then applied this tutorial to additional cancer types and immunohistochemistry markers - bladder/ki67, lung/EGFR, and oesophageal/CD8 - to establish accuracy compared with experts. Using this optimised tutorial, we then tested lay participants' accuracy on immunohistochemistry scoring of lung/EGFR and bladder/p53 samples. RESULTS: We observed that for cancer detection, annotated example images and feedback-based training both improved accuracy compared with a basic tutorial only. Using this optimised tutorial, we demonstrate highly accurate (>0.90 area under curve) detection of cancer in samples stained with nuclear, cytoplasmic and membrane cell markers. We also observed high Spearman correlations between lay participants and experts for immunohistochemistry scoring (0.91 (0.78, 0.96) and 0.97 (0.91, 0.99) for lung/EGFR and bladder/p53 samples, respectively). CONCLUSIONS: These results establish crowdsourcing as a promising method to screen large data sets for biomarkers in cancer pathology research across a range of cancers and immunohistochemical stains. PMID- 27959888 TI - Smoking and risk of ovarian cancer by histological subtypes: an analysis among 300 000 Norwegian women. AB - BACKGROUND: We prospectively investigated the association between different measures of smoking exposure and the risk of serous, mucinous, and endometrioid ovarian cancers (OC) in a cohort of more than 300 000 Norwegian women. METHODS: We followed 300 398 women aged 19-67 years at enrolment until 31 December 2013 for OC incidence through linkage to national registries. We used Cox proportional hazards models with attained age as the underlying time scale to estimate multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for relevant confounders. RESULTS: During more than 5.9 million person years and a median follow-up time of 19 years, 2336 primary invasive (1647, 71%) and borderline (689, 29%) OC were identified (53% serous, 19% mucinous). Compared with never smokers, current smokers who had smoked for ?10 years had a higher risk of mucinous OC (HR10-19 years vs never=1.73, 95% CI 1.24-2.42; HR?20 vs never=2.26, 95% CI 1.77-2.89, Ptrend <0.001). When stratified by invasiveness, current smokers had a higher risk of invasive mucinous OC (HR=1.78, 95% CI 1.20 2.64) and borderline mucinous OC (HR=2.26 95% CI, 1.71-2.97) (Pheterogeneity=0.34) than never smokers. Smoking was not associated with serous or endometrioid OC. CONCLUSIONS: Using a very large cohort of women, the current analysis provides an important replication for a similar risk of invasive and borderline mucinous OC related to smoking. PMID- 27959887 TI - Increased micronucleus frequency in peripheral blood lymphocytes predicts the risk of bladder cancer. AB - BACKGROUND: Bladder cancer (BC) is among the most common malignancies worldwide. The identification of new biomarkers for early BC detection, recurrence/progression is urgently needed. The cytokinesis-block micronucleus assay (CBMN) evaluates chromosome damage in cultured human lymphocytes and micronuclei (MN) provide a convenient and reliable index of both chromosome breakage and loss. METHODS: Chromosomal damage (expressed as frequencies of MN, nucleoplasmic bridges and nuclear buds (NBUD)) was evaluated by CBMN assay in cryopreserved lymphocytes from 158 age/smoking-matched pairs of cases and controls in relation to BC risk, recurrence or progression. Moreover, non-muscle invasive BC (NMIBC) patients were characterised for 783 DNA repair gene polymorphisms for their possible association with the investigated cytogenetic end points. RESULTS: MN and NBUD frequencies were significantly higher in cases than in controls (P=0.001 and P=0.006, respectively), with the associations being stronger in NMIBC. In a logistic regression model, for each increase of one unit in the MN frequency, a 1.12 increased risk of developing NMIBC was observed. In NMIBC cases, 10 polymorphisms were associated with different MN frequencies after genotype stratification. CONCLUSIONS: A model including traditional BC risk factors, MN frequency and the selected polymorphisms differentially distributed in cases and controls improved BC patient identification. Understanding the meaning of systemic chromosomal damage in BC patients with respect to the general population may help to adopt specific prevention strategies and therapeutic intervention. PMID- 27959889 TI - Childhood neuroendocrine tumours: a descriptive study revealing clues for genetic predisposition. AB - BACKGROUND: Neuroendocrine tumours (NETs) are rare in children and limited data are available. We aimed to specify tumour and patient characteristics and to investigate the role of genetic predisposition in the aetiology of paediatric NETs. METHODS: Using the Dutch Pathology Registry PALGA, we collected patient- and tumour data of paediatric NETs in the Netherlands between 1991 and 2013 (N=483). RESULTS: The incidence of paediatric NETs in the Netherlands is 5.40 per one million per year. The majority of NETs were appendiceal tumours (N=441;91.3%). Additional surgery in appendiceal NETs was indicated in 89 patients, but performed in only 27 of these patients. Four out of five patients with pancreatic NETs were diagnosed with Von Hippel-Lindau disease (N=2) and Multiple Endocrine Neoplasia type 1 (N=2). In one patient with an appendiceal NET Familial Adenomatous Polyposis was diagnosed. On the basis of second primary tumours or other additional diagnoses, involvement of genetic predisposition was suggestive in several others. CONCLUSIONS: We identified a significant number of patients with a confirmed or suspected tumour predisposition syndrome and show that paediatric pancreatic NETs in particular are associated with genetic syndromes. In addition, we conclude that treatment guidelines for appendiceal paediatric NETs need revision and improved implementation. PMID- 27959890 TI - Combined oral contraceptive use before the first birth and epithelial ovarian cancer risk. AB - BACKGROUND: Combined oral contraceptive (COC) use reduces epithelial ovarian cancer (EOC) risk. However, little is known about risk with COC use before the first full-term pregnancy (FFTP). METHODS: This Canadian population-based case control study (2001-2012) included 854 invasive cases/2139 controls aged ?40 years who were parous and had information on COC use. We estimated odds ratios (aORs) and 95% confidence intervals (CI) adjusted for study site, age, parity, breastfeeding, age at FFTP, familial breast/ovarian cancer, tubal ligation, and body mass. RESULTS: Among parous women, per year of COC use exclusively before the FFTP was associated with a 9% risk reduction (95% CI=0.86-0.96). Results were similar for high-grade serous and endometrioid/clear cell EOC. In contrast, per year of use exclusively after the FFTP was not associated with risk (aOR=0.98, 95% CI=0.95-1.02). CONCLUSIONS: Combined oral contraceptive use before the FFTP may provide a risk reduction that remains for many years, informing possible prevention strategies. PMID- 27959891 TI - Promoting the Use of Common Oat Genetic Resources through Diversity Analysis and Core Collection Construction. AB - The assessment of diversity and population structure and construction of a core collection is beneficial for the efficient use and management of germplasm. A unique collection of common oat landraces, cultivated in the temperate climate of central Europe until the end of the twentieth century, is preserved in the Polish gene bank. It consists of 91 accessions that have never been used in breeding programs. In order to optimise the use of this genetic resource, we aimed to: (1) determine genetic and agro-morphological diversity, (2) identify internal genetic variation of the tested accessions, (3) form a core collection and (4) recognise the accessions useful for breeding programs or re-release for cultivation. The collection was screened using ISSR markers (1520 loci) and eight agro morphological traits. Uniquely, we performed molecular studies based on 24 individuals of every accession instead of bulk samples. Therefore, assessment of the degree of diversity within each population and the identification of overlapping gene pools were possible. The observed internal diversity (Nei unbiased coefficient) was in the range of 0.17-0.31. Based on combined genetic and agro-morphological data, we established the core collection composed of 21 landraces. Due to valuable compositions of important traits, some accessions were also identified as useful for breeding programs. The population structure and principal coordinate analysis revealed two major clusters. Based on the previous results, the accessions classified within the smaller one were identified as obsolete varieties instead of landraces. Our results show that the oat landraces are, in general, resistant to local races of diseases, well adapted to local conditions and, in some cases, yielding at the level of modern varieties. Therefore, in situ conservation of the landraces in the near future may be satisfactory for both farmers and researchers in terms of the genetic resources preservation. PMID- 27959893 TI - Restaurants in the Neighborhood, Eating Away from Home and BMI in China. AB - BACKGROUND: To investigate the association between environmental risk factors, eating away from home, and increasing BMI of Chinese adults. METHODS: Participants were selected from the recent four waves (2004, 2006, 2009, and 2011) of the China Health and Nutrition Survey (CHNS). 10633 participants, including 5084 men and 5549 women, were used in the analysis. 24-h dietary recall data for three consecutive days with information on the time and place of consumption were collected. Nearby restaurants were measured by the number of fast food outlets, indoor restaurants, and food stands in the neighborhood. Random effects multivariable regression was used to assess associations between these variables. RESULTS: People living in neighborhoods with large numbers of indoor restaurants are more likely to eat away from home (p<0.05). Higher frequency of eating away from home is positively associated with BMI, but this effect is only significant for men (p<0.05). Moreover, while eating dinner or breakfast away from home contributes to BMI increase for men (p<0.05), no such association is found for lunch. CONCLUSION: Eating dinner and breakfast away from home is positively associated with BMI for Chinese men. Labeling energy and portion size for the dishes served in indoor restaurants is recommended in China. PMID- 27959892 TI - FFA2 Contribution to Gestational Glucose Tolerance Is Not Disrupted by Antibiotics. AB - During the insulin resistant phase of pregnancy, the mRNA expression of free fatty acid 2 receptor (Ffar2) is upregulated and as we recently reported, this receptor contributes to insulin secretion and pancreatic beta cell mass expansion in order to maintain normal glucose homeostasis during pregnancy. As impaired gestational glucose levels can affect metabolic health of offspring, we aimed to explore the role of maternal Ffar2 expression during pregnancy on the metabolic health of offspring and also the effects of antibiotics, which have been shown to disrupt gut microbiota fermentative activity (the source of the FFA2 ligands) on gestational glucose homeostasis. We found that maternal Ffar2 expression and impaired glucose tolerance during pregnancy had no effect on the growth rates, ad lib glucose and glucose tolerance in the offspring between 3 and 6 weeks of age. To disrupt short chain fatty acid production, we chronically treated WT mice and Ffar2-/- mice with broad range antibiotics and further compared their glucose tolerance prior to pregnancy and at gestational day 15, and also quantified cecum and plasma SCFAs. We found that during pregnancy antibiotic treatment reduced the levels of SCFAs in the cecum of the mice, but resulted in elevated levels of plasma SCFAs and altered concentrations of individual SCFAs. Along with these changes, gestational glucose tolerance in WT mice, but not Ffar2-/- mice improved while on antibiotics. Additional data showed that gestational glucose tolerance worsened in Ffar2-/- mice during a second pregnancy. Together, these results indicate that antibiotic treatment alone is inadequate to deplete plasma SCFA concentrations, and that modulation of gut microbiota by antibiotics does not disrupt the contribution of FFA2 to gestational glucose tolerance. PMID- 27959894 TI - Sound-Induced Intracellular Ca2+ Dynamics in the Adult Hearing Cochlea. AB - Ca2+ signaling has been implicated in the initial pathophysiologic mechanisms underlying the cochlea's response to acoustic overstimulation. Intracellular Ca2+ signaling (ICS) waves, which occur in glia and retinal cells in response to injury to activate cell regulatory pathways, have been proposed as an early event in cochlear injury. Disruption of ICS activity is thought to underlie Connexin 26 associated hearing loss, the most common genetic form of deafness, and downstream sequelae of ICS wave activity, such as MAP kinase pathway activation, have been implicated in noise-induced hearing loss. However, ICS waves have only been observed in neonatal cochlear cultures and are thought to be quiescent after the onset of hearing. In this study, we employ an acute explant model of an adult, hearing cochlea that retains many in vivo physiologic features to investigate Ca2+ changes in response to sound. We find that both slow monotonic changes in intracellular Ca2+ concentration as well as discrete ICS waves occur with acoustic overstimulation. The ICS waves share many intrinsic features with their better-described neonatal counterparts, including ATP and gap-junction dependence, and propagation velocity and distance. This identification of ICS wave activity in the adult, hearing cochlea thus confirms and characterizes an important early detection mechanism for cochlear trauma and provides a target for interventions for noise-induced and Connexin 26-associated hearing loss. PMID- 27959895 TI - Unsupervised Cryo-EM Data Clustering through Adaptively Constrained K-Means Algorithm. AB - In single-particle cryo-electron microscopy (cryo-EM), K-means clustering algorithm is widely used in unsupervised 2D classification of projection images of biological macromolecules. 3D ab initio reconstruction requires accurate unsupervised classification in order to separate molecular projections of distinct orientations. Due to background noise in single-particle images and uncertainty of molecular orientations, traditional K-means clustering algorithm may classify images into wrong classes and produce classes with a large variation in membership. Overcoming these limitations requires further development on clustering algorithms for cryo-EM data analysis. We propose a novel unsupervised data clustering method building upon the traditional K-means algorithm. By introducing an adaptive constraint term in the objective function, our algorithm not only avoids a large variation in class sizes but also produces more accurate data clustering. Applications of this approach to both simulated and experimental cryo-EM data demonstrate that our algorithm is a significantly improved alterative to the traditional K-means algorithm in single-particle cryo-EM analysis. PMID- 27959896 TI - The Role of Regulatory B Cell-Like Malignant Cells and Treg Cells in the Mouse Model of BCL1 Tumor Dormancy. AB - Cancer dormancy is a clinical state in which residual tumor cells persist for long periods of time but do not cause detectable disease. In the mouse B cell lymphoma model (BCL1), dormancy can be induced and maintained by immunizing mice with a soluble form of the IgM expressed on the surface of the tumor cells. Immunization induces an anti-idiotype antibody response that maintains dormancy. Mice with dormant tumor have low numbers of BCL1 cells in their spleens that divide and are killed at the same rate. When the anti-Id antibodies wane, the tumor cells grow rapidly and kill the host. Spleens from tumor-bearing mice contain both effector (CD4+ and CD8+) and regulatory T cells (Tregs). In other tumor models, it has been reported that Tregs promote tumor progression by preventing effector cells from killing the tumor. In this report, we demonstrate that the tumor site with rapidly dividing BCL1 cells has fewer Tregs than the tumor site harboring dormant BCL1 cells. In both cases, the Tregs were equally suppressive in vitro. In spleens from mice with actively growing tumor, CD8+ but not CD4+ T cells were virtually absent. In vitro analysis demonstrated a tumor mediated elimination of CD8+ T cells that was contact dependent and involved the caspase-3 pathway. Most importantly, we found that the BCL1 cells expressed characteristics of B10 regulatory B cells, i.e., they were CD1dhiCD5+ and secreted high levels of IL-10. These BCL1 tumor cells can inhibit anti-tumor immune responses by depleting CD8+ effector T cells. PMID- 27959897 TI - Impact of Amendments on the Physical Properties of Soil under Tropical Long-Term No Till Conditions. AB - Tropical regions have been considered the world's primary agricultural frontier; however, some physico-chemical deficiencies, such as low soil organic matter content, poor soil structure, high erodibility, soil acidity, and aluminum toxicity, have affected their productive capacity. Lime and gypsum are commonly used to improve soil chemical fertility, but no information exists about the long term effects of these products on the physical attributes and C protection mechanisms of highly weathered Oxisols. A field trial was conducted in a sandy clay loam (kaolinitic, thermic Typic Haplorthox) under a no-tillage system for 12 years. The trial consisted of four treatments: a control with no soil amendment application, the application of 2.1 Mg ha-1 phosphogypsum, the application of 2.0 Mg ha-1 lime, and the application of lime + phosphogypsum (2.0 + 2.1 Mg ha-1, respectively). Since the experiment was established in 2002, the rates have been applied three times (2002, 2004, and 2010). Surface liming effectively increased water-stable aggregates > 2.0 mm at a depth of up to 0.2 m; however, the association with phosphogypsum was considered a good strategy to improve the macroaggregate stability in subsoil layers (0.20 to 0.40 m). Consequently, both soil amendments applied together increased the mean weight diameter (MWD) and geometric mean diameter (GMD) in all soil layers, with increases of up to 118 and 89%, respectively, according to the soil layer. The formation and stabilization of larger aggregates contributed to a higher accumulation of total organic carbon (TOC) on these structures. In addition to TOC, the MWD and aggregate stability index were positively correlated with Ca2+ and Mg2+ levels and base saturation. Consequently, the increase observed in the aggregate size class resulted in a better organization of soil particles, increasing the macroporosity and reducing the soil bulk density and penetration resistance. Therefore, adequate soil chemical management plays a fundamental role in improving the soil's physical attributes in tropical areas under conservative management and highly affected by compaction caused by intensive farming. PMID- 27959898 TI - Diastolic Left Ventricular Function in Relation to Urinary and Serum Collagen Biomarkers in a General Population. AB - Current knowledge on the pathogenesis of diastolic heart failure predominantly rests on case-control studies involving symptomatic patients with preserved ejection fraction and relying on invasive diagnostic procedures including endomyocardial biopsy. Our objective was to gain insight in serum and urinary biomarkers reflecting collagen turnover and associated with asymptomatic diastolic LV dysfunction. We randomly recruited 782 Flemish (51.3% women; 50.5 years). We assessed diastolic LV function from the early and late diastolic peak velocities of the transmitral blood flow and of the mitral annulus. By sequencing urinary peptides, we identified 70 urinary collagen fragments. In serum, we measured carboxyterminal propeptide of procollagen type 1 (PICP) as marker of collagen I synthesis and tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1), an inhibitor of collagen-degrading enzymes. In multivariable-adjusted analyses with Bonferroni correction, we expressed effect sizes per 1-SD in urinary collagen I (uCI) or collagen III (uCIII) fragments. In relation to uCI fragments, e' decreased by 0.183 cm/s (95% confidence interval, 0.017 to 0.350; p = 0.025), whereas E/e' increased by 0.210 (0.067 to 0.353; p = 0.0012). E/e' decreased with uCIII by 0.168 (0.021 to 0.316; p = 0.018). Based on age-specific echocardiographic criteria, 182 participants (23.3%) had subclinical diastolic LV dysfunction. Partial least squares discriminant analysis contrasting normal vs. diastolic LV dysfunction confirmed the aforementioned associations with the uCI and uCIII fragments. PICP and TIMP-1 increased in relation to uCI (p<0.0001), whereas these serum markers decreased with uCIII (p<=0.0006). Diastolic LV dysfunction was associated with higher levels of TIMP-1 (653 vs. 696 ng/mL; p = 0.013). In a general population, the non-invasively assessed diastolic LV function correlated inversely with uCI and serum markers of collagen I deposition, but positively with uCIII. These observations generalise previous studies in patients to randomly recruited people, in whom diastolic LV function ranged from normal to subclinical impairment, but did not encompass overt diastolic heart failure. PMID- 27959900 TI - Genomic Profile of Chronic Lymphocytic Leukemia in Korea Identified by Targeted Sequencing. AB - Chronic lymphocytic leukemia (CLL) is extremely rare in Asian countries and there has been one report on genetic changes for 5 genes (TP53, SF3B1, NOTCH1, MYD88, and BIRC3) by Sanger sequencing in Chinese CLL. Yet studies of CLL in Asian countries using Next generation sequencing have not been reported. We aimed to characterize the genomic profiles of Korean CLL and to find out ethnic differences in somatic mutations with prognostic implications. We performed targeted sequencing for 87 gene panel using next-generation sequencing along with G-banding and fluorescent in situ hybridization (FISH) for chromosome 12, 13q14.3 deletion, 17p13 deletion, and 11q22 deletion. Overall, 36 out of 48 patients (75%) harbored at least one mutation and mean number of mutation per patient was 1.6 (range 0-6). Aberrant karyotypes were observed in 30.4% by G-banding and 66.7% by FISH. Most recurrent mutation (>10% frequency) was ATM (20.8%) followed by TP53 (14.6%), SF3B1 (10.4%), KLHL6 (8.3%), and BCOR (6.25%). Mutations of MYD88 was associated with moderate adverse prognosis by multiple comparisons (P = 0.055). Mutation frequencies of MYD88, SAMHD1, EGR2, DDX3X, ZMYM3, and MED12 showed similar incidence with Caucasians, while mutation frequencies of ATM, TP53, KLHL6, BCOR and CDKN2A tend to be higher in Koreans than in Caucasians. Especially, ATM mutation showed 1.5 fold higher incidence than Caucasians, while mutation frequencies of SF3B1, NOTCH1, CHD2 and POT1 tend to be lower in Koreans than in Caucasians. However, mutation frequencies between Caucasians and Koreans were not significantly different statistically, probably due to low number of patients. Collectively, mutational profile and adverse prognostic genes in Korean CLL were different from those of Caucasians, suggesting an ethnic difference, while profile of cytogenetic aberrations was similar to those of Caucasians. PMID- 27959901 TI - Seasonal Variations in Surface Metabolite Composition of Fucus vesiculosus and Fucus serratus from the Baltic Sea. AB - Perennial macroalgae within the genus Fucus are known to exude metabolites through their outer thallus surface. Some of these metabolites have pro- and/or antifouling properties. Seasonal fluctuations of natural fouling pressure and chemical fouling control strength against micro- and macrofoulers have previously been observed in Fucus, suggesting that control strength varies with threat. To date, a study on the seasonal composition of surface associated metabolites, responsible for much of the fouling control, has not been done. We sampled individuals of the two co-occurring species F. vesiculosus and F. serratus at monthly intervals (six per species and month) during a one-year field study. We analysed the chemical composition of surface associated metabolites of both Fucus species by means of gas chromatography-mass spectrometry (GC-MS) to describe temporal patterns in chemical surface composition. Additionally, we correlated abiotic and biotic parameters recorded monthly within the sampled habitat with the variation in the chemical surface landscape of Fucus. Our study revealed that the chemical surface composition of both Fucus species exhibits substantial seasonal differences between spring/summer and autumn/winter months. Light and temperature explained most of the seasonal variability in surface metabolite composition of both Fucus species. A strong summerly up-regulation of eighteen saccharides and two hydroxy acids in F. vesiculosus as well as of four fatty acids and two saccharides in F. serratus was observed. We discuss how these up regulated molecules may have a complex effect on associated microfoulers, both promoting or decreasing fouling depending on metabolite and bacterial identity. These seasonal shifts in the surface metabolome seem to exert a compound control of density and composition of the Fucus associated biofilm. PMID- 27959899 TI - Effects of In Utero Thyroxine Exposure on Murine Cranial Suture Growth. AB - Large scale surveillance studies, case studies, as well as cohort studies have identified the influence of thyroid hormones on calvarial growth and development. Surveillance data suggests maternal thyroid disorders (hyperthyroidism, hypothyroidism with pharmacological replacement, and Maternal Graves Disease) are linked to as much as a 2.5 fold increased risk for craniosynostosis. Craniosynostosis is the premature fusion of one or more calvarial growth sites (sutures) prior to the completion of brain expansion. Thyroid hormones maintain proper bone mineral densities by interacting with growth hormone and aiding in the regulation of insulin like growth factors (IGFs). Disruption of this hormonal control of bone physiology may lead to altered bone dynamics thereby increasing the risk for craniosynostosis. In order to elucidate the effect of exogenous thyroxine exposure on cranial suture growth and morphology, wild type C57BL6 mouse litters were exposed to thyroxine in utero (control = no treatment; low ~167 ng per day; high ~667 ng per day). Thyroxine exposed mice demonstrated craniofacial dysmorphology (brachycranic). High dose exposed mice showed diminished area of the coronal and widening of the sagittal sutures indicative of premature fusion and compensatory growth. Presence of thyroid receptors was confirmed for the murine cranial suture and markers of proliferation and osteogenesis were increased in sutures from exposed mice. Increased Htra1 and Igf1 gene expression were found in sutures from high dose exposed individuals. Pathways related to the HTRA1/IGF axis, specifically Akt and Wnt, demonstrated evidence of increased activity. Overall our data suggest that maternal exogenous thyroxine exposure can drive calvarial growth alterations and altered suture morphology. PMID- 27959903 TI - Modeling Day-to-day Flow Dynamics on Degradable Transport Network. AB - Stochastic link capacity degradations are common phenomena in transport network which can cause travel time variations and further can affect travelers' daily route choice behaviors. This paper formulates a deterministic dynamic model, to capture the day-to-day (DTD) flow evolution process in the presence of degraded link capacity degradations. The aggregated network flow dynamics are driven by travelers' study of uncertain travel time and their choice of risky routes. This paper applies the exponential-smoothing filter to describe travelers' study of travel time variations, and meanwhile formulates risk attitude parameter updating equation to reflect travelers' endogenous risk attitude evolution schema. In addition, this paper conducts theoretical analyses to investigate several significant mathematical characteristics implied in the proposed DTD model, including fixed point existence, uniqueness, stability and irreversibility. Numerical experiments are used to demonstrate the effectiveness of the DTD model and verify some important dynamic system properties. PMID- 27959902 TI - Characterization of Swallowing Sound: Preliminary Investigation of Normal Subjects. AB - OBJECTIVE: The purpose of this study was to characterize the swallowing sound and identify the process of sound generation during swallowing in young healthy adults. METHODS: Thirty-three healthy volunteers were enrolled and allocated into three experimental groups. In experiment 1, a microphone was attached to one of eight cervical sites in 20 subjects, participants swallowed 5 ml water, and the sound waveform was recorded. In experiment 2, 10 subjects swallowed either 0, 5, 10, or 15 ml water during audio recording. In addition, participants consumed the 5 ml bolus in two different cervical postures. In experiment 3, the sound waveform and videofluoroscopy were simultaneously recorded while the three participants consumed 5 ml iopamidol solution. The duration and peak intensity ratio of the waveform were analyzed in all experimental groups. RESULTS: The acoustic analysis of the waveforms and videofluoroscopy suggested that the swallowing sound could be divided into three periods, each associated with a stage of the swallowing movement: the oral phase comprising posterior tongue and hyoid bone movement; the pharyngeal phase comprising larynx movement, hyoid bone elevation, epiglottis closure, and passage of the bolus through the esophagus orifice; and the repositioning phase comprising the return of the hyoid bone and larynx to their resting positions, and reopening of the epiglottis. CONCLUSION: Acoustic analysis of swallowing sounds and videofluoroscopy suggests that the swallowing sound could be divided into three periods associated with each process of the swallowing movement: the oral phase comprising the posterior movement of the tongue and hyoid bone; the pharyngeal phase comprising the laryngeal movement, hyoid bone elevation, epiglottis closure, and the bolus passage to the esophagus orifice; and the repositioning phase comprising the repositioning of the hyoid bone and larynx, and reopening of the epiglottis. PMID- 27959904 TI - Clinical Features and Outcomes of IPF Patients Hospitalized for Pulmonary Infection: A Japanese Cohort Study. AB - Many patients with idiopathic pulmonary fibrosis (IPF) undergo hospitalizations due to pulmonary infections. We retrospectively investigated the characteristics of hospitalizations due to pulmonary infection in patients with IPF to elucidate causative pathogens and mortality. We reviewed patients with IPF who were admitted between January 2008 and December 2014 for pulmonary infections including pneumonia and bronchitis. The causative pathogen, the relationship between the site of pneumonia and existing IPF radiological patterns on high resolution chest CT, and predictors of mortality were evaluated. Forty-eight IPF patients were hospitalized a totally of 81 times due to pulmonary infection during the study period. In the 48 first-time admissions after IPF diagnosis, causative pathogens were detected in 20 patients (41.6%). The most common pathogen was Haemophilus influenzae (14.5%) followed by Pseudomonas aeruginosa (4.1%), Staphylococcus aureus (4.1%), Branhamella catarrhalis (4.1%), and Klebsiella pneumoniae (4.1%). Among all 81 admissions, the most common pathogen was P. aeruginosa (12.3%), followed by H. influenzae (8.6%), S. aureus (6.1%) and Escherichia coli (4.9%). No relationship was observed between the detected pathogen and the site of pneumonia. The 30-day and hospital mortality rates were 14.5% and 18.7%, respectively. Pneumonia severity index on admission was significantly associated with both 30-day and hospital mortality. In conclusion, IPF patients hospitalized for pulmonary infections had high 30-day and hospital mortality. In contrast to community-acquired pneumonia, the causative pathogens mainly consisted of gram-negative bacteria. The PSI score may be a significant predictor of mortality. These results provide information for empiric antibiotic selection when treating IPF patients with pulmonary infections. PMID- 27959906 TI - Mapping the Prevalence of Physical Inactivity in U.S. States, 1984-2015. AB - BACKGROUND: Physical inactivity is a leading cause of morbidity, disability and premature mortality in the U.S. and worldwide. This study aimed to map the prevalence of physical inactivity across U.S. states over the past three decades, and estimate the over-time adjusted changes in the prevalence of physical inactivity in each state. METHODS: Individual-level data (N = 6,701,954) were taken from the 1984-2015 Behavioral Risk Factor Surveillance System (BRFSS), an annually repeated cross-sectional survey of state-representative adult population. Prevalence of self-reported leisure-time physical inactivity was estimated by state and survey year, accounting for the BRFSS sampling design. Logistic regressions were performed to estimate the changes in the prevalence of physical inactivity over the study period for each state, adjusting for individual characteristics including sex, age, race/ethnicity, education, marital status, and employment status. RESULTS: The prevalence of leisure-time physical inactivity varied substantially across states and survey years. In general, the adjusted prevalence of physical inactivity gradually declined over the past three decades in a majority of states. However, a substantial proportion of American adults remain physically inactive. Among the 50 states and District of Columbia, 45 had over a fifth of their adult population without any leisure-time physical activity, and 8 had over 30% without physical activity in 2015. Moreover, the adjusted prevalence of physical inactivity in several states (Arizona, North Carolina, North Dakota, Utah, West Virginia, and Wyoming) remained largely unchanged or even increased (Minnesota and Ohio) over the study period. CONCLUSIONS: Although the prevalence of physical inactivity declined over the past three decades in a majority of states, the rates remain substantially high and vary considerably across states. Closely monitoring and tracking physical activity level using the state physical activity maps can help guide policy and program development to promote physical activity and reduce the burden of chronic disease. PMID- 27959907 TI - Assessing Caribbean Shallow and Mesophotic Reef Fish Communities Using Baited Remote Underwater Video (BRUV) and Diver-Operated Video (DOV) Survey Techniques. AB - Fish surveys form the backbone of reef monitoring and management initiatives throughout the tropics, and understanding patterns in biases between techniques is crucial if outputs are to address key objectives optimally. Often biases are not consistent across natural environmental gradients such as depth, leading to uncertainty in interpretation of results. Recently there has been much interest in mesophotic reefs (reefs from 30-150 m depth) as refuge habitats from fishing pressure, leading to many comparisons of reef fish communities over depth gradients. Here we compare fish communities using stereo-video footage recorded via baited remote underwater video (BRUV) and diver-operated video (DOV) systems on shallow and mesophotic reefs in the Mesoamerican Barrier Reef, Caribbean. We show inconsistent responses across families, species and trophic groups between methods across the depth gradient. Fish species and family richness were higher using BRUV at both depth ranges, suggesting that BRUV is more appropriate for recording all components of the fish community. Fish length distributions were not different between methods on shallow reefs, yet BRUV recorded more small fish on mesophotic reefs. However, DOV consistently recorded greater relative fish community biomass of herbivores, suggesting that studies focusing on herbivores should consider using DOV. Our results highlight the importance of considering what component of reef fish community researchers and managers are most interested in surveying when deciding which survey technique to use across natural gradients such as depth. PMID- 27959905 TI - Ocular Blood Flow Measurements in Healthy White Subjects Using Laser Speckle Flowgraphy. AB - PURPOSE: To assess the feasibility and reliability of Laser Speckle Flowgraphy (LSFG) to measure ocular perfusion in a sample of healthy white subjects and to elucidate the age-dependence of the parameters obtained. METHODS: This cross sectional study included 80 eyes of 80 healthy, non-smoking white subjects of Western European descent between 19 and 79 years of age. A commercial LSFG instrument was applied to measure ocular blood flow at the optic nerve head (ONH) three successive times before and after pharmacological pupil dilation. The mean blur rate (MBR), a measure of relative blood flow velocity, was obtained for different regions of the ONH. Eight parameters of ocular perfusion derived from the pulse-waveform analysis of MBR including blowout time (BOT) and falling rate (FR) were also recorded. RESULTS: Artifact-free LSFG images meeting the quality criteria for automated image analysis were obtainable in 93.8% without pupil dilation and in 98.8% with pharmacological pupil dilation. Measurements of MBR showed excellent repeatability with intraclass correlation coefficients >= 0.937 and were barely affected by pupil dilation. The majority of pulse-waveform derived variables exhibited equally high repeatability. MBR-related blood flow indices exhibited significant age dependence (p<0.001). FR (r = 0.747, p<0.001) and BOT (r = -0.714, p<0.001) most strongly correlated with age. CONCLUSIONS: LSFG represents a reliable method for the quantitative assessment of ocular blood flow in white subjects. Our data affirms that the LSFG-derived variables FR and BOT may be useful biomarkers for age-related changes in ocular perfusion. PMID- 27959910 TI - Assessment and Accessibility of Phenotypic and Genotypic Diversity of Carrot (Daucus carota L. var. sativus) Cultivars Commercially Available in the United States. AB - Increased use of intellectual property rights over plant germplasm has led to a complicated landscape for exchange among plant breeders. Our goal was to examine phenotypic and genotypic diversity present in commercially available carrot (Daucus carota L. var. sativus) germplasm in relation to the freedom to operate the ability for plant breeders to access and use crop genetic diversity. A collection of 140 commercially available carrot cultivars were grown in replicated field trials in the Madison, WI area in 2013 and 2014. Phenotypic measurements were recorded for leaf and root characteristics. Illumina sequencing was used to conduct genotyping by sequencing analysis on all cultivars to understand the range of genetic diversity present. Additionally, the intellectual property rights associated with each cultivar was noted to determine the freedom to operate. We found that although one-third of the commercially available US carrot cultivars in our study are restricted through some form of intellectual property rights, the genetic and phenotypic variability of the protected cultivars does not represent a completely separate group from the available material. Phenotypic analyses including ANOVA and principal components analysis, suggest that many of the traits differed significantly based on market class, but not by whether the cultivar had freedom to operate. The principal components and Fst analyses on the genotyping by sequencing data revealed that carrot market classes (Fst = 0.065) and freedom to operate classes (Fst = 0.023) were not genetically distinct, and that principle components 1 and 2 account for only 10.1% of the total genotypic variation, implying that cultivated carrot germplasm in the US forms an unstructured population. Our findings suggest that the genetic diversity present in carrot cultivars that have freedom to operate is potentially large enough to support carrot breeding efforts in most market classes given present levels of intellectual property protection. PMID- 27959908 TI - Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis. AB - Otitis media (OM), inflammation of the middle ear, is a common cause of hearing loss in children and in patients with many different syndromic diseases. Studies of the human population and mouse models have revealed that OM is a multifactorial disease with many environmental and genetic contributing factors. Here, we report on otitis media-related hearing loss in asj (ages with stiffened joints) mutant mice, which bear a point mutation in the Enpp1 gene. Auditory evoked brainstem response (ABR) measurements revealed that around 90% of the mutant mice (Enpp1asj/asj) tested had moderate to severe hearing impairment in at least one ear. The ABR thresholds were variable and generally elevated with age. We found otitis media with effusion (OME) in all of the hearing-impaired Enpp1asj/asj mice by anatomic and histological examinations. The volume and inflammatory cell content of the effusion varied among the asj mutant mice, but all mutants exhibited a thickened middle ear epithelium with fibrous polyps and more mucin-secreting goblet cells than controls. Other abnormalities observed in the Enpp1 mutant mice include over-ossification at the round window ridge, thickened and over-calcified stapedial artery, fusion of malleus and incus, and white patches on the inside of tympanic membrane, some of which are typical symptoms of tympanosclerosis. An excessive yellow discharge was detected in the outer ear canal of older asj mutant mice, with 100% penetrance by 5 months of age, and contributes to the progressive nature of the hearing loss. This is the first report of hearing loss and ear pathology associated with an Enpp1 mutation in mice. The Enpp1asj mutant mouse provides a new animal model for studying tympanosclerotic otitis and otitis media with effusion, and also provides a specific model for the hearing loss recently reported to be associated with human ENPP1 mutations causing generalized arterial calcification of infancy and hypophosphatemic rickets. PMID- 27959911 TI - Projected Influences of Changes in Weather Severity on Autumn-Winter Distributions of Dabbling Ducks in the Mississippi and Atlantic Flyways during the Twenty-First Century. AB - Projected changes in the relative abundance and timing of autumn-winter migration are assessed for seven dabbling duck species across the Mississippi and Atlantic Flyways for the mid- and late 21st century. Species-specific observed relationships are established between cumulative weather severity in autumn winter and duck population rate of change. Dynamically downscaled projections of weather severity are developed using a high-resolution regional climate model, interactively coupled to a one-dimensional lake model to represent the Great Lakes and associated lake-effect snowfall. Based on the observed relationships and downscaled climate projections of rising air temperatures and reduced snow cover, delayed autumn-winter migration is expected for all species, with the least delays for the Northern Pintail and the greatest delays for the Mallard. Indeed, the Mallard, the most common and widespread duck in North America, may overwinter in the Great Lakes region by the late 21st century. This highlights the importance of protecting and restoring wetlands across the mid-latitudes of North America, including the Great Lakes Basin, because dabbling ducks are likely to spend more time there, which would impact existing wetlands through increased foraging pressure. Furthermore, inconsistency in the timing and intensity of the traditional autumn-winter migration of dabbling ducks in the Mississippi and Atlantic Flyways could have social and economic consequences to communities to the south, where hunting and birdwatching would be affected. PMID- 27959912 TI - Correction: Complex Breakpoints and Template Switching Associated with Non canonical Termination of Homologous Recombination in Mammalian Cells. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006410.]. PMID- 27959909 TI - Former Very Preterm Infants Show an Unfavorable Cardiovascular Risk Profile at a Preschool Age. AB - Cardiovascular disease is the leading cause of death worldwide. Evidence points towards an unfavorable cardiovascular risk profile of former preterm infants in adolescence and adulthood. The aim of this study was to determine whether cardiovascular risk predictors are detectable in former very preterm infants at a preschool age. Five- to seven-year-old children born at <32 weeks' gestational age were included in the study. Same-aged children born at term served as controls. Basic data of study participants were collected by means of follow-up databases and standardized questionnaires. At study visit, anthropometric data, blood pressure readings and aortic intima-media thickness were assessed. Blood samples were obtained after an overnight fast. In comparison to children born at term, former preterm infants had higher systolic and diastolic blood pressure readings (odds ratio [95% confidence interval] per 1-SD higher blood pressure level 3.2 [2.0-5.0], p<0.001 and 1.6 [1.1-1.2], p = 0.008), fasting glucose levels (OR [95% CI] 5.2 [2.7-10.1], p<0.001), homeostasis model assessment index (OR [95% CI] 1.6 [1.0-2.6], p = 0.036), and cholesterol levels (OR [95% CI] 2.1 [1.3-3.4], p = 0.002). Systolic prehypertension (23.7% vs. 2.2%; OR [95% CI] 13.8 [3.1-60.9], p = 0.001), elevated glucose levels (28.6% vs. 5.9%; OR [95% CI] 6.4 [1.4-28.8], p = 0.016), and hypercholesterolemia (77.4% vs. 52.9%; OR [95% CI] 3.0 [1.3-7.1], p = 0.010) were significantly more prevalent in the preterm group. As former very preterm infants display an unfavorable cardiovascular risk profile already at a preschool age, implementation of routine cardiovascular follow-up programs might be warranted. PMID- 27959913 TI - Executive Functions, Time Organization and Quality of Life among Adults with Learning Disabilities. AB - PURPOSE: This study compared the executive functions, organization in time and perceived quality of life (QoL) of 55 adults with learning disabilities (LD) with those of 55 matched controls (mean age 30 years). Furthermore, relationships and predictive relationships between these variables among the group with LD were examined. METHODS: All participants completed the Behavioral Rating Inventory of Executive Functions (BRIEF-A), the Time Organization and Participation (TOPS, A C) and the World Health Organization Quality of Life (WHOQOL) questionnaires. Chi square tests, independent t-tests and MANOVA were used to examine group differences in each of the subscales scores and ratings of each instrument. Pearson correlations and regression predictive models were used to examine the relationships between the variables in the group with LD. RESULTS: Adults with LD had significantly poorer executive functions (BRIEF-A), deficient organization in time abilities (TOPS A-B), accompanied with negative emotional response (TOPS- C), and lower perceived QoL (physical, psychological, social and environmental) in comparison to adults without LD. Regression analysis revealed that Initiation (BRIEF-A) significantly predicted approximately 15% of the participants' organization in time abilities (TOPS A, B scores) beyond group membership. Furthermore, initiation, emotional control (BRIEF-A subscales) and emotional responses following unsuccessful organization of time (TOPS-C) together accounted for 39% of the variance of psychological QoL beyond the contribution of group membership. CONCLUSIONS: Deficits in initiation and emotional executive functions as well as organization in time abilities and emotional responses to impairments in organizing time affect the QoL of adults with LD and thus should be considered in further research as well as in clinical applications. PMID- 27959916 TI - A Method for Evaluating the Efficacy of Antifouling Paints Using Mytilus galloprovincialis in the Laboratory in a Flow-Through System. AB - A laboratory test with a flow-through system was designed and its applicability for testing antifouling paints of varying efficacies was investigated. Six different formulations of antifouling paints were prepared to have increasing contents (0 to 40 wt.%) of Cu2O, which is the most commonly used antifouling substance, and each formulation of paint was coated on just one surface of every test plate. The test plates were aged for 45 days by rotating them at a speed of 10 knots inside a cylinder drum. A behavioral test was then conducted using five mussels (Mytilus galloprovincialis) that were pasted onto the coated surface of each aged test plate. The number of the byssus threads produced by each mussel generally decreased with increasing Cu2O content of the paint. The newly designed method was considered valid owing to the high consistency of its results with observations from the field experiment. PMID- 27959915 TI - Numerical Approach to Spatial Deterministic-Stochastic Models Arising in Cell Biology. AB - Hybrid deterministic-stochastic methods provide an efficient alternative to a fully stochastic treatment of models which include components with disparate levels of stochasticity. However, general-purpose hybrid solvers for spatially resolved simulations of reaction-diffusion systems are not widely available. Here we describe fundamentals of a general-purpose spatial hybrid method. The method generates realizations of a spatially inhomogeneous hybrid system by appropriately integrating capabilities of a deterministic partial differential equation solver with a popular particle-based stochastic simulator, Smoldyn. Rigorous validation of the algorithm is detailed, using a simple model of calcium 'sparks' as a testbed. The solver is then applied to a deterministic-stochastic model of spontaneous emergence of cell polarity. The approach is general enough to be implemented within biologist-friendly software frameworks such as Virtual Cell. PMID- 27959914 TI - Learning New Sensorimotor Contingencies: Effects of Long-Term Use of Sensory Augmentation on the Brain and Conscious Perception. AB - Theories of embodied cognition propose that perception is shaped by sensory stimuli and by the actions of the organism. Following sensorimotor contingency theory, the mastery of lawful relations between own behavior and resulting changes in sensory signals, called sensorimotor contingencies, is constitutive of conscious perception. Sensorimotor contingency theory predicts that, after training, knowledge relating to new sensorimotor contingencies develops, leading to changes in the activation of sensorimotor systems, and concomitant changes in perception. In the present study, we spell out this hypothesis in detail and investigate whether it is possible to learn new sensorimotor contingencies by sensory augmentation. Specifically, we designed an fMRI compatible sensory augmentation device, the feelSpace belt, which gives orientation information about the direction of magnetic north via vibrotactile stimulation on the waist of participants. In a longitudinal study, participants trained with this belt for seven weeks in natural environment. Our EEG results indicate that training with the belt leads to changes in sleep architecture early in the training phase, compatible with the consolidation of procedural learning as well as increased sensorimotor processing and motor programming. The fMRI results suggest that training entails activity in sensory as well as higher motor centers and brain areas known to be involved in navigation. These neural changes are accompanied with changes in how space and the belt signal are perceived, as well as with increased trust in navigational ability. Thus, our data on physiological processes and subjective experiences are compatible with the hypothesis that new sensorimotor contingencies can be acquired using sensory augmentation. PMID- 27959917 TI - Dual Roles for Membrane Association of Drosophila Axin in Wnt Signaling. AB - Deregulation of the Wnt signal transduction pathway underlies numerous congenital disorders and cancers. Axin, a concentration-limiting scaffold protein, facilitates assembly of a "destruction complex" that prevents signaling in the unstimulated state and a plasma membrane-associated "signalosome" that activates signaling following Wnt stimulation. In the classical model, Axin is cytoplasmic under basal conditions, but relocates to the cell membrane after Wnt exposure; however, due to the very low levels of endogenous Axin, this model is based largely on examination of Axin at supraphysiological levels. Here, we analyze the subcellular distribution of endogenous Drosophila Axin in vivo and find that a pool of Axin localizes to cell membrane proximal puncta even in the absence of Wnt stimulation. Axin localization in these puncta is dependent on the destruction complex component Adenomatous polyposis coli (Apc). In the unstimulated state, the membrane association of Axin increases its Tankyrase dependent ADP-ribosylation and consequent proteasomal degradation to control its basal levels. Furthermore, Wnt stimulation does not result in a bulk redistribution of Axin from cytoplasmic to membrane pools, but causes an initial increase of Axin in both of these pools, with concomitant changes in two post translational modifications, followed by Axin proteolysis hours later. Finally, the ADP-ribosylated Axin that increases rapidly following Wnt stimulation is membrane associated. We conclude that even in the unstimulated state, a pool of Axin forms membrane-proximal puncta that are dependent on Apc, and that membrane association regulates both Axin levels and Axin's role in the rapid activation of signaling that follows Wnt exposure. PMID- 27959919 TI - Modeling the Perception of Audiovisual Distance: Bayesian Causal Inference and Other Models. AB - Studies of audiovisual perception of distance are rare. Here, visual and auditory cue interactions in distance are tested against several multisensory models, including a modified causal inference model. In this causal inference model predictions of estimate distributions are included. In our study, the audiovisual perception of distance was overall better explained by Bayesian causal inference than by other traditional models, such as sensory dominance and mandatory integration, and no interaction. Causal inference resolved with probability matching yielded the best fit to the data. Finally, we propose that sensory weights can also be estimated from causal inference. The analysis of the sensory weights allows us to obtain windows within which there is an interaction between the audiovisual stimuli. We find that the visual stimulus always contributes by more than 80% to the perception of visual distance. The visual stimulus also contributes by more than 50% to the perception of auditory distance, but only within a mobile window of interaction, which ranges from 1 to 4 m. PMID- 27959918 TI - The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants. AB - BACKGROUND: The human malaria parasite Plasmodium vivax infects red blood cells through a key pathway that requires interaction between Duffy binding protein II (DBPII) and its receptor on reticulocytes, the Duffy antigen/receptor for chemokines (DARC). A high proportion of P. vivax-exposed individuals fail to develop antibodies that inhibit DBPII-DARC interaction, and genetic factors that modulate this humoral immune response are poorly characterized. Here, we investigate if DBPII responsiveness could be HLA class II-linked. METHODOLOGY/PRINCIPAL FINDINGS: A community-based open cohort study was carried out in an agricultural settlement of the Brazilian Amazon, in which 336 unrelated volunteers were genotyped for HLA class II (DRB1, DQA1 and DQB1 loci), and their DBPII immune responses were monitored over time (baseline, 6 and 12 months) by conventional serology (DBPII IgG ELISA-detected) and functional assays (inhibition of DBPII-erythrocyte binding). The results demonstrated an increased susceptibility of the DRB1*13:01 carriers to develop and sustain an anti-DBPII IgG response, while individuals with the haplotype DRB1*14:02-DQA1*05:03 DQB1*03:01 were persistent non-responders. HLA class II gene polymorphisms also influenced the functional properties of DBPII antibodies (BIAbs, binding inhibitory antibodies), with three alleles (DRB1*07:01, DQA1*02:01 and DQB1*02:02) comprising a single haplotype linked with the presence and persistence of the BIAbs response. Modelling the structural effects of the HLA DRB1 variants revealed a number of differences in the peptide-binding groove, which is likely to lead to altered antigen binding and presentation profiles, and hence may explain the differences in subject responses. CONCLUSIONS/SIGNIFICANCE: The current study confirms the heritability of the DBPII antibody response, with genetic variation in HLA class II genes influencing both the development and persistence of IgG antibody responses. Cellular studies to increase knowledge of the binding affinities of DBPII peptides for class II molecules linked with good or poor antibody responses might lead to the development of strategies for controlling the type of helper T cells activated in response to DBPII. PMID- 27959920 TI - Evaluation of Stem Cell-Derived Red Blood Cells as a Transfusion Product Using a Novel Animal Model. AB - Reliance on volunteer blood donors can lead to transfusion product shortages, and current liquid storage of red blood cells (RBCs) is associated with biochemical changes over time, known as 'the storage lesion'. Thus, there is a need for alternative sources of transfusable RBCs to supplement conventional blood donations. Extracorporeal production of stem cell-derived RBCs (stemRBCs) is a potential and yet untapped source of fresh, transfusable RBCs. A number of groups have attempted RBC differentiation from CD34+ cells. However, it is still unclear whether these stemRBCs could eventually be effective substitutes for traditional RBCs due to potential differences in oxygen carrying capacity, viability, deformability, and other critical parameters. We have generated ex vivo stemRBCs from primary human cord blood CD34+ cells and compared them to donor-derived RBCs based on a number of in vitro parameters. In vivo, we assessed stemRBC circulation kinetics in an animal model of transfusion and oxygen delivery in a mouse model of exercise performance. Our novel, chronically anemic, SCID mouse model can evaluate the potential of stemRBCs to deliver oxygen to tissues (muscle) under resting and exercise-induced hypoxic conditions. Based on our data, stem cell-derived RBCs have a similar biochemical profile compared to donor derived RBCs. While certain key differences remain between donor-derived RBCs and stemRBCs, the ability of stemRBCs to deliver oxygen in a living organism provides support for further development as a transfusion product. PMID- 27959922 TI - Immunotherapy in the Precision Medicine Era: Melanoma and Beyond. AB - In a Perspective, Mack Su and David Fisher discuss the development of immunotherapies for treatment of melanoma and other cancer types. PMID- 27959921 TI - Temporal Dynamics and Developmental Maturation of Salience, Default and Central Executive Network Interactions Revealed by Variational Bayes Hidden Markov Modeling. AB - Little is currently known about dynamic brain networks involved in high-level cognition and their ontological basis. Here we develop a novel Variational Bayesian Hidden Markov Model (VB-HMM) to investigate dynamic temporal properties of interactions between salience (SN), default mode (DMN), and central executive (CEN) networks-three brain systems that play a critical role in human cognition. In contrast to conventional models, VB-HMM revealed multiple short-lived states characterized by rapid switching and transient connectivity between SN, CEN, and DMN. Furthermore, the three "static" networks occurred in a segregated state only intermittently. Findings were replicated in two adult cohorts from the Human Connectome Project. VB-HMM further revealed immature dynamic interactions between SN, CEN, and DMN in children, characterized by higher mean lifetimes in individual states, reduced switching probability between states and less differentiated connectivity across states. Our computational techniques provide new insights into human brain network dynamics and its maturation with development. PMID- 27959923 TI - Patterns of Immune Infiltration in Breast Cancer and Their Clinical Implications: A Gene-Expression-Based Retrospective Study. AB - BACKGROUND: Immune infiltration of breast tumours is associated with clinical outcome. However, past work has not accounted for the diversity of functionally distinct cell types that make up the immune response. The aim of this study was to determine whether differences in the cellular composition of the immune infiltrate in breast tumours influence survival and treatment response, and whether these effects differ by molecular subtype. METHODS AND FINDINGS: We applied an established computational approach (CIBERSORT) to bulk gene expression profiles of almost 11,000 tumours to infer the proportions of 22 subsets of immune cells. We investigated associations between each cell type and survival and response to chemotherapy, modelling cellular proportions as quartiles. We found that tumours with little or no immune infiltration were associated with different survival patterns according to oestrogen receptor (ER) status. In ER negative disease, tumours lacking immune infiltration were associated with the poorest prognosis, whereas in ER-positive disease, they were associated with intermediate prognosis. Of the cell subsets investigated, T regulatory cells and M0 and M2 macrophages emerged as the most strongly associated with poor outcome, regardless of ER status. Among ER-negative tumours, CD8+ T cells (hazard ratio [HR] = 0.89, 95% CI 0.80-0.98; p = 0.02) and activated memory T cells (HR 0.88, 95% CI 0.80-0.97; p = 0.01) were associated with favourable outcome. T follicular helper cells (odds ratio [OR] = 1.34, 95% CI 1.14-1.57; p < 0.001) and memory B cells (OR = 1.18, 95% CI 1.0-1.39; p = 0.04) were associated with pathological complete response to neoadjuvant chemotherapy in ER-negative disease, suggesting a role for humoral immunity in mediating response to cytotoxic therapy. Unsupervised clustering analysis using immune cell proportions revealed eight subgroups of tumours, largely defined by the balance between M0, M1, and M2 macrophages, with distinct survival patterns by ER status and associations with patient age at diagnosis. The main limitations of this study are the use of diverse platforms for measuring gene expression, including some not previously used with CIBERSORT, and the combined analysis of different forms of follow-up across studies. CONCLUSIONS: Large differences in the cellular composition of the immune infiltrate in breast tumours appear to exist, and these differences are likely to be important determinants of both prognosis and response to treatment. In particular, macrophages emerge as a possible target for novel therapies. Detailed analysis of the cellular immune response in tumours has the potential to enhance clinical prediction and to identify candidates for immunotherapy. PMID- 27959924 TI - Impact of Lipid Composition and Receptor Conformation on the Spatio-temporal Organization of MU-Opioid Receptors in a Multi-component Plasma Membrane Model. AB - The lipid composition of cell membranes has increasingly been recognized as playing an important role in the function of various membrane proteins, including G Protein-Coupled Receptors (GPCRs). For instance, experimental and computational evidence has pointed to lipids influencing receptor oligomerization directly, by physically interacting with the receptor, and/or indirectly, by altering the bulk properties of the membrane. While the exact role of oligomerization in the function of class A GPCRs such as the MU-opioid receptor (MOR) is still unclear, insight as to how these receptors oligomerize and the relevance of the lipid environment to this phenomenon is crucial to our understanding of receptor function. To examine the effect of lipids and different MOR conformations on receptor oligomerization we carried out extensive coarse-grained molecular dynamics simulations of crystal structures of inactive and/or activated MOR embedded in an idealized mammalian plasma membrane composed of 63 lipid types asymmetrically distributed across the two leaflets. The results of these simulations point, for the first time, to specific direct and indirect effects of the lipids, as well as the receptor conformation, on the spatio-temporal organization of MOR in the plasma membrane. While sphingomyelin-rich, high-order lipid regions near certain transmembrane (TM) helices of MOR induce an effective long-range attractive force on individual protomers, both long-range lipid order and interface formation are found to be conformation dependent, with a larger number of different interfaces formed by inactive MOR compared to active MOR. PMID- 27959925 TI - Emotion Unchained: Facial Expression Modulates Gaze Cueing under Cognitive Load. AB - Direction of eye gaze cues spatial attention, and typically this cueing effect is not modulated by the expression of a face unless top-down processes are explicitly or implicitly involved. To investigate the role of cognitive control on gaze cueing by emotional faces, participants performed a gaze cueing task with happy, angry, or neutral faces under high (i.e., counting backward by 7) or low cognitive load (i.e., counting forward by 2). Results show that high cognitive load enhances gaze cueing effects for angry facial expressions. In addition, cognitive load reduces gaze cueing for neutral faces, whereas happy facial expressions and gaze affected object preferences regardless of load. This evidence clearly indicates a differential role of cognitive control in processing gaze direction and facial expression, suggesting that under typical conditions, when we shift attention based on social cues from another person, cognitive control processes are used to reduce interference from emotional information. PMID- 27959927 TI - Ridge Polynomial Neural Network with Error Feedback for Time Series Forecasting. AB - Time series forecasting has gained much attention due to its many practical applications. Higher-order neural network with recurrent feedback is a powerful technique that has been used successfully for time series forecasting. It maintains fast learning and the ability to learn the dynamics of the time series over time. Network output feedback is the most common recurrent feedback for many recurrent neural network models. However, not much attention has been paid to the use of network error feedback instead of network output feedback. In this study, we propose a novel model, called Ridge Polynomial Neural Network with Error Feedback (RPNN-EF) that incorporates higher order terms, recurrence and error feedback. To evaluate the performance of RPNN-EF, we used four univariate time series with different forecasting horizons, namely star brightness, monthly smoothed sunspot numbers, daily Euro/Dollar exchange rate, and Mackey-Glass time delay differential equation. We compared the forecasting performance of RPNN-EF with the ordinary Ridge Polynomial Neural Network (RPNN) and the Dynamic Ridge Polynomial Neural Network (DRPNN). Simulation results showed an average 23.34% improvement in Root Mean Square Error (RMSE) with respect to RPNN and an average 10.74% improvement with respect to DRPNN. That means that using network errors during training helps enhance the overall forecasting performance for the network. PMID- 27959926 TI - Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis. AB - BACKGROUND: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients. METHODS AND FINDINGS: We performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC) selected because they had either pCR (n = 18) or extensive residual disease (n = 11) after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144) and METABRIC (n = 278) cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02) and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05). Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D) TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021), and they had significantly higher mutation burden (p < 0.001) and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009). As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort. CONCLUSIONS: The comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in TNBC and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC. PMID- 27959928 TI - An Efficient Microarray-Based Genotyping Platform for the Identification of Drug Resistance Mutations in Majority and Minority Subpopulations of HIV-1 Quasispecies. AB - The response of human immunodeficiency virus type 1 (HIV-1) quasispecies to antiretroviral therapy is influenced by the ensemble of mutants that composes the evolving population. Low-abundance subpopulations within HIV-1 quasispecies may determine the viral response to the administered drug combinations. However, routine sequencing assays available to clinical laboratories do not recognize HIV 1 minority variants representing less than 25% of the population. Although several alternative and more sensitive genotyping techniques have been developed, including next-generation sequencing (NGS) methods, they are usually very time consuming, expensive and require highly trained personnel, thus becoming unrealistic approaches in daily clinical practice. Here we describe the development and testing of a HIV-1 genotyping DNA microarray that detects and quantifies, in majority and minority viral subpopulations, relevant mutations and amino acid insertions in 42 codons of the pol gene associated with drug- and multidrug-resistance to protease (PR) and reverse transcriptase (RT) inhibitors. A customized bioinformatics protocol has been implemented to analyze the microarray hybridization data by including a new normalization procedure and a stepwise filtering algorithm, which resulted in the highly accurate (96.33%) detection of positive/negative signals. This microarray has been tested with 57 subtype B HIV-1 clinical samples extracted from multi-treated patients, showing an overall identification of 95.53% and 89.24% of the queried PR and RT codons, respectively, and enough sensitivity to detect minority subpopulations representing as low as 5-10% of the total quasispecies. The developed genotyping platform represents an efficient diagnostic and prognostic tool useful to personalize antiviral treatments in clinical practice. PMID- 27959930 TI - The Impact of Setting the Standards of Health Promoting Hospitals on Hospital Indicators in Iran. AB - Hospitals play a critical role in the health promotion of the society. This study aimed to determine the impact of establishing standards of health promoting hospitals on hospital indicators in Shahroud. This applied study was a quasi experimental one which was conducted in 2013. Standards of health promoting hospitals were established as an intervention procedure in the Fatemiyeh hospital. Parameters of health promoting hospitals were compared in intervention and control hospitals before and after of intervention (6 months). The data were analyzed using chi-square and t-test. With the establishment of standards for health promotion hospitals, standard scores in intervention and control hospitals were found to be 72.26 +/- 4.1 and 16.26 +/- 7.5, respectively. T-test showed a significant difference between the mean scores of the hospitals under study (P = 0.001).The chi-square test also showed a significant relationship between patient satisfaction before and after the intervention so that patients' satisfaction was higher after the intervention (P = 0.001). Commenting on the short-term or long term positive impacts of establishing standards of health promoting hospitals on all hospital indicators is a bit difficult but preliminary results show the positive impact of the implementation of standards in case hospitals which has led to the improvement of many indicators in the hospital. PMID- 27959929 TI - Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study. AB - BACKGROUND: Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. METHODS AND FINDINGS: Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1. CONCLUSIONS: Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies. PMID- 27959931 TI - MATE2 Expression Is Associated with Cancer Cell Response to Metformin. AB - BACKGROUND: There is great interest in repurposing the commonly prescribed anti diabetic drug metformin for cancer therapy. Intracellular uptake and retention of metformin is affected by the expression of organic cation transporters (OCT) 1-3 and by multidrug and toxic compound extrusion (MATE) 1-2. Inside cells, metformin inhibits mitochondrial function, which leads to reduced oxygen consumption and inhibition of proliferation. Reduced oxygen consumption can lead to improved tumor oxygenation and radiation response. PURPOSE: Here we sought to determine if there is an association between the effects of metformin on inhibiting oxygen consumption, proliferation and expression of OCTs and MATEs in a panel of 19 cancer cell lines. RESULTS: There was relatively large variability in the anti proliferative response of different cell lines to metformin, with a subset of cell lines being very resistant. In contrast, all cell lines demonstrated sensitivity to the inhibition of oxygen consumption by metformin, with relatively small variation. The expression of OCT1 correlated with expression of both OCT2 and OCT3. OCT1 and OCT2 were relatively uniformly expressed, whereas expression of OCT3, MATE1 and MATE2 showed substantial variation across lines. There were statistically significant associations between resistance to inhibition of proliferation and MATE2 expression, as well as between sensitivity to inhibition of oxygen consumption and OCT3 expression. One cell line (LNCaP) with high OCT3 and low MATE2 expression in concert, had substantially higher intracellular metformin concentration than other cell lines, and was exquisitely sensitive to both anti-proliferative and anti-respiratory effects. In all other cell lines, the concentration of metformin required to inhibit oxygen consumption acutely in vitro was substantially higher than that achieved in the plasma of diabetic patients. However, administering anti-diabetic doses of metformin to tumor bearing mice resulted in intratumoral accumulation of metformin and reduced hypoxic tumor fractions. CONCLUSIONS: All cancer cells are susceptible to inhibition of oxygen consumption by metformin, which results in reduced hypoxic tumor fractions beneficial for the response to radiotherapy. High MATE2 expression may result in resistance to the anti-proliferative effect of metformin and should be considered as a negative predictive biomarker in clinical trials. PMID- 27959932 TI - The Impact of a Rights-Based Counselling Intervention to Reduce Stigma in People Affected by Leprosy in Indonesia. AB - BACKGROUND: This paper assesses the impact of a counselling intervention on reducing leprosy-related stigma in Cirebon District, Indonesia. The unique features of this intervention are its rights-based approach, the underlying Cognitive Behavioural Therapy (CBT) model, the three types of counselling and the lay and peer counsellors who were involved. METHODOLOGY/PRINCIPAL FINDINGS: Mixed methods (e.g. three scales, interviews, focus group discussions and reflection notes) were used to assess the impact of the intervention, which ran over a two year period. There was a control area with no interventions. The study participants were people affected by leprosy and other key persons (e.g. family members). The sample size differs per method, for example, data regarding 67 counselling clients and 57 controls from a cohort, and notes from 207 counselling clients were examined. The notes showed that most clients faced stigma on a daily basis, whether internalized, anticipated and/or enacted. A significant reduction was found between the before and after total scores of the SARI Stigma Scale (p value < 0.001), Participation Scale Short (p-value < 0.001) and WHO Quality of Life score (p-value < 0.001) among the counselling clients. While there is also an effect in the control group, it is much larger in the intervention group. Qualitative data indicates that knowledge and rights trigger change. Clients took steps to improve their life such as re-connecting with neighbours, helping in household activities and applying for jobs. Challenges include the wish to conceal their condition. CONCLUSION/SIGNIFICANCE: The findings show that the counselling intervention was effective in reducing stigma, promoting the rights of people with leprosy and facilitating their social participation. More research is needed on how to create a more sustainable intervention, preferably structurally embedded in the health or social services. PMID- 27959933 TI - Monogonont Rotifer, Brachionus calyciflorus, Possesses Exceptionally Large, Fragmented Mitogenome. AB - In contrast to the highly conserved mitogenomic structure and organisation in most animals (including rotifers), the two previously sequenced monogonont rotifer mitogenomes were fragmented into two chromosomes similar in size, each of which possessed one major non-coding region (mNCR) of about 4-5 Kbp. To further explore this phenomenon, we have sequenced and analysed the mitogenome of one of the most studied monogonont rotifers, Brachionus calyciflorus. It is also composed of two circular chromosomes, but the chromosome-I is extremely large (27 535 bp; 3 mNCRs), whereas the chromosome-II is relatively small (9 833 bp; 1 mNCR). With the total size of 37 368 bp, it is one of the largest metazoan mitogenomes ever reported. In comparison to other monogononts, gene distribution between the two chromosomes and gene order are different and the number of mNCRs is doubled. Atp8 was not found (common in rotifers), and Cytb was present in two copies (the first report in rotifers). A high number (99) of SNPs indicates fast evolution of the Cytb-1 copy. The four mNCRs (5.3-5.5 Kb) were relatively similar. Publication of this sequence shall contribute to the understanding of the evolutionary history of the unique mitogenomic organisation in this group of rotifers. PMID- 27959934 TI - Mice with an N-Ethyl-N-Nitrosourea (ENU) Induced Tyr209Asn Mutation in Natriuretic Peptide Receptor 3 (NPR3) Provide a Model for Kyphosis Associated with Activation of the MAPK Signaling Pathway. AB - Non-syndromic kyphosis is a common disorder that is associated with significant morbidity and has a strong genetic involvement; however, the causative genes remain to be identified, as such studies are hampered by genetic heterogeneity, small families and various modes of inheritance. To overcome these limitations, we investigated 12 week old progeny of mice treated with the chemical mutagen N ethyl-N-nitrosourea (ENU) using phenotypic assessments including dysmorphology, radiography, and dual-energy X-ray absorptiometry. This identified a mouse with autosomal recessive kyphosis (KYLB). KYLB mice, when compared to unaffected littermates, had: thoraco-lumbar kyphosis, larger vertebrae, and increased body length and increased bone area. In addition, female KYLB mice had increases in bone mineral content and plasma alkaline phosphatase activity. Recombination mapping localized the Kylb locus to a 5.5Mb region on chromosome 15A1, which contained 51 genes, including the natriuretic peptide receptor 3 (Npr3) gene. DNA sequence analysis of Npr3 identified a missense mutation, Tyr209Asn, which introduced an N-linked glycosylation consensus sequence. Expression of wild-type NPR3 and the KYLB-associated Tyr209Asn NPR3 mutant in COS-7 cells demonstrated the mutant to be associated with abnormal N-linked glycosylation and retention in the endoplasmic reticulum that resulted in its absence from the plasma membrane. NPR3 is a decoy receptor for C-type natriuretic peptide (CNP), which also binds to NPR2 and stimulates mitogen-activated protein kinase (MAPK) signaling, thereby increasing the number and size of hypertrophic chondrocytes. Histomorphometric analysis of KYLB vertebrae and tibiae showed delayed endochondral ossification and expansion of the hypertrophic zones of the growth plates, and immunohistochemistry revealed increased p38 MAPK phosphorylation throughout the growth plates of KYLB vertebrae. Thus, we established a model of kyphosis due to a novel NPR3 mutation, in which loss of plasma membrane NPR3 expression results in increased MAPK pathway activation, causing elongation of the vertebrae and resulting in kyphosis. PMID- 27959935 TI - A 45-Second Self-Test for Cardiorespiratory Fitness: Heart Rate-Based Estimation in Healthy Individuals. AB - Cardio-respiratory fitness (CRF) is a widespread essential indicator in Sports Science as well as in Sports Medicine. This study aimed to develop and validate a prediction model for CRF based on a 45 second self-test, which can be conducted anywhere. Criterion validity, test re-test study was set up to accomplish our objectives. Data from 81 healthy volunteers (age: 29 +/- 8 years, BMI: 24.0 +/- 2.9), 18 of whom females, were used to validate this test against gold standard. Nineteen volunteers repeated this test twice in order to evaluate its repeatability. CRF estimation models were developed using heart rate (HR) features extracted from the resting, exercise, and the recovery phase. The most predictive HR feature was the intercept of the linear equation fitting the HR values during the recovery phase normalized for the height2 (r2 = 0.30). The Ruffier-Dickson Index (RDI), which was originally developed for this squat test, showed a negative significant correlation with CRF (r = -0.40), but explained only 15% of the variability in CRF. A multivariate model based on RDI and sex, age and height increased the explained variability up to 53% with a cross validation (CV) error of 0.532 L ? min-1 and substantial repeatability (ICC = 0.91). The best predictive multivariate model made use of the linear intercept of HR at the beginning of the recovery normalized for height2 and age2; this had an adjusted r2 = 0. 59, a CV error of 0.495 L.min-1 and substantial repeatability (ICC = 0.93). It also had a higher agreement in classifying CRF levels (kappa = 0.42) than RDI-based model (kappa = 0.29). In conclusion, this simple 45 s self test can be used to estimate and classify CRF in healthy individuals with moderate accuracy and large repeatability when HR recovery features are included. PMID- 27959936 TI - A Low Dose of Dietary Quercetin Fails to Protect against the Development of an Obese Phenotype in Mice. AB - The purpose of this study was to examine the effect of a 40% high-fat diet (HFD) supplemented with a dietary attainable level of quercetin (0.02%) on body composition, adipose tissue (AT) inflammation, Non-Alcoholic Fatty-Liver Disease (NAFLD), and metabolic outcomes. Diets were administered for 16 weeks to C57BL/6J mice (n = 10/group) beginning at 4 weeks of age. Body composition and fasting blood glucose, insulin, and total cholesterol concentrations were examined intermittently. AT and liver mRNA expression (RT-PCR) of inflammatory mediators (F4/80, CD206 (AT only), CD11c (AT only) TLR-2 (AT only), TLR-4 (AT only), MCP-1, TNF-alpha, IL-6 (AT only), and IL-10 (AT only)) were measured along with activation of NFkappaB-p65, and JNK (western blot). Hepatic lipid accumulation, gene expression (RT-PCR) of hepatic metabolic markers (ACAC1, SREBP-1, PPAR gamma), protein content of Endoplasmic Reticulum (ER) Stress markers (BiP, phosphorylated and total EIF2alpha, phosphorylated and total IRE1alpha, CHOP), and hepatic oxidative capacity were assessed (western blot). Quercetin administration had no effect at mitigating increases in visceral AT, AT inflammation, hepatic steatosis, ER Stress, decrements in hepatic oxidative capacity, or the development of insulin resistance and hypercholesterolemia. In conclusion, 0.02% quercetin supplementation is not an effective therapy for attenuating HFD-induced obesity development. It is likely that a higher dose of quercetin supplementation is needed to elicit favorable outcomes in obesity. PMID- 27959939 TI - Two Novel Space-Time Coding Techniques Designed for UWB MISO Systems Based on Wavelet Transform. AB - In this paper two novel space-time coding multi-input single-output (STC MISO) schemes, designed especially for Ultra-Wideband (UWB) systems, are introduced. The proposed schemes are referred to as wavelet space-time coding (WSTC) schemes. The WSTC schemes are based on two types of multiplexing, spatial and wavelet domain multiplexing. In WSTC schemes, four symbols are transmitted on the same UWB transmission pulse with the same bandwidth, symbol duration, and number of transmitting antennas of the conventional STC MISO scheme. The used mother wavelet (MW) is selected to be highly correlated with transmitted pulse shape and such that the multiplexed signal has almost the same spectral characteristics as those of the original UWB pulse. The two WSTC techniques increase the data rate to four times that of the conventional STC. The first WSTC scheme increases the data rate with a simple combination process. The second scheme achieves the increase in the data rate with a less complex receiver and better performance than the first scheme due to the spatial diversity introduced by the structure of its transmitter and receiver. The two schemes use Rake receivers to collect the energy in the dense multipath channel components. The simulation results show that the proposed WSTC schemes have better performance than the conventional scheme in addition to increasing the data rate to four times that of the conventional STC scheme. PMID- 27959938 TI - The Effects of Ca2+ Concentration and E200K Mutation on the Aggregation Propensity of PrPC: A Computational Study. AB - The propensity of cellular prion protein to aggregation is reputed essential for the initiation of the amyloid cascade that ultimately lead to the accumulation of neurotoxic aggregates. In this paper, we extended and applied an already reported computational workflow [Proteins 2015; 83: 1751-1765] to elucidate in details the aggregation propensity of PrP protein systems including wild type, wild type treated at different [Ca2+] and E200K mutant. The application of the computational procedure to two segments of PrPC, i.e. 125-228 and 120-231, allowed to emphasize how the inclusion of complete C-terminus and last portion (120-126) of the neurotoxic segment 106-126 may be crucial to unveil significant and unexpected interaction properties. Indeed, the anchoring of N-terminus on H2 domain detected in the wild type resulted to be disrupted upon either E200K mutation or Ca2+ binding, and to unbury hydrophobic spots on the PrPC surface. A peculiar dinuclear Ca2+ binding motif formed by the C-terminus and the S2-H2 loop was detected for [Ca2+] > 5 mM and showed similarities with binding motifs retraced in other protein systems, thus suggesting a possible functional meaning for its formation. Therefore, we potentiated the computational procedure by including a tool that clusterize the minima of molecular interaction fields of a proteinand delimit the regions of space with higher hydrophobic or higher hydrophilic character, hence, more likely involved in the self-assembly process. Plausible models for the self-assembly of either the E200K mutated or Ca2+-bound PrPC were sketched and discussed. The present investigation provides for structure-based information and new prompts that may represent a starting point for future experimental or computational works on the PrPC aggregation. PMID- 27959937 TI - Knockdown of Ice-Binding Proteins in Brachypodium distachyon Demonstrates Their Role in Freeze Protection. AB - Sub-zero temperatures pose a major threat to the survival of cold-climate perennials. Some of these freeze-tolerant plants produce ice-binding proteins (IBPs) that offer frost protection by restricting ice crystal growth and preventing expansion-induced lysis of the plasma membranes. Despite the extensive in vitro characterization of such proteins, the importance of IBPs in the freezing stress response has not been investigated. Using the freeze-tolerant grass and model crop, Brachypodium distachyon, we characterized putative IBPs (BdIRIs) and generated the first 'IBP-knockdowns'. Seven IBP sequences were identified and expressed in Escherichia coli, with all of the recombinant proteins demonstrating moderate to high levels of ice-recrystallization inhibition (IRI) activity, low levels of thermal hysteresis (TH) activity (0.03 0.09 degrees C at 1 mg/mL) and apparent adsorption to ice primary prism planes. Following plant cold acclimation, IBPs purified from wild-type B. distachyon cell lysates similarly showed high levels of IRI activity, hexagonal ice-shaping, and low levels of TH activity (0.15 degrees C at 0.5 mg/mL total protein). The transfer of a microRNA construct to wild-type plants resulted in the attenuation of IBP activity. The resulting knockdown mutant plants had reduced ability to restrict ice-crystal growth and a 63% reduction in TH activity. Additionally, all transgenic lines were significantly more vulnerable to electrolyte leakage after freezing to -10 degrees C, showing a 13-22% increase in released ions compared to wild-type. IBP-knockdown lines also demonstrated a significant decrease in viability following freezing to -8 degrees C, with some lines showing only two thirds the survival seen in control lines. These results underscore the vital role IBPs play in the development of a freeze-tolerant phenotype and suggests that expression of these proteins in frost-susceptible plants could be valuable for the production of more winter-hardy crops. PMID- 27959940 TI - Stabilization of Human Serum Albumin by the Binding of Phycocyanobilin, a Bioactive Chromophore of Blue-Green Alga Spirulina: Molecular Dynamics and Experimental Study. AB - Phycocyanobilin (PCB) binds with high affinity (2.2 x 106 M-1 at 25 degrees C) to human serum albumin (HSA) at sites located in IB and IIA subdomains. The aim of this study was to examine effects of PCB binding on protein conformation and stability. Using 300 ns molecular dynamics (MD) simulations, UV-VIS spectrophotometry, CD, FT-IR, spectrofluorimetry, thermal denaturation and susceptibility to trypsin digestion, we studied the effects of PCB binding on the stability and rigidity of HSA, as well as the conformational changes in PCB itself upon binding to the protein. MD simulation results demonstrated that HSA with PCB bound at any of the two sites showed greater rigidity and lower overall and individual domain flexibility compared to free HSA. Experimental data demonstrated an increase in the alpha-helical content of the protein and thermal and proteolytic stability upon ligand binding. PCB bound to HSA undergoes a conformational change to a more elongated conformation in the binding pockets of HSA. PCB binding to HSA stabilizes the structure of this flexible transport protein, making it more thermostable and resistant to proteolysis. The results from this work explain at molecular level, conformational changes and stabilization of HSA structure upon ligand binding. The resultant increased thermal and proteolytic stability of HSA may provide greater longevity to HSA in plasma. PMID- 27959941 TI - Impact of Oral Treatment on Physical Function in Older Patients Hospitalized for Heart Failure: A Randomized Clinical Trial. AB - BACKGROUND: Frailty is a characteristic of older patients with heart failure, who undergo functional decline during hospitalization. At present, continuous intravenous infusion of diuretics is widely used for the treatment of hospitalized patients with heart failure. In this prospective, randomized, open label controlled trial, we tested whether an early switch from continuous intravenous infusion therapy to oral treatment with diuretics prevents functional decline in patients hospitalized for heart failure. METHODS: A total of 59 patients hospitalized for heart failure were randomized to either continuous intravenous infusion (n = 30) or oral medication (n = 29) within 48 h of admission. The primary outcome was the Barthel index, a universally utilized scale to assess the functional status of patients in their activities of daily living, assessed at 10 days. Secondary outcomes included the number of daily steps counted using pedometers and average hospital costs. RESULTS: Barthel index scores were significantly higher in the oral medication group than in the intravenous group (78.1 +/- 20.8 vs. 59.6 +/- 34.2, P = 0.029). The number of daily steps was significantly higher in the oral treatment group relative to the intravenous group (P < 0.001), and the average hospital costs were similar between the randomized groups. Multivariate analysis revealed that oral medication was a significant independent predictor of Barthel index score at day 10, and the number of daily steps was significantly associated with the patient's functional outcome. CONCLUSIONS: This trial showed that, in patients hospitalized for heart failure, oral medication increased functional independence during hospitalization compared with sustained continuous intravenous infusion, most likely because the release from the infusion line enabled the patients to be more mobile. Notably, these beneficial effects were achieved without increasing hospital costs. PMID- 27959942 TI - Structure-Function Analysis of the Transmembrane Protein AmpG from Pseudomonas aeruginosa. AB - AmpG is a transmembrane protein with permease activity that transports meuropeptide from the periplasm to the cytoplasm, which is essential for the induction of the ampC encoding beta-lactamase. To obtain new insights into the relationship between AmpG structure and function, comparative genomics analysis, secondary and tertiary structure modeling, site-directed mutational analyses and genetic complementation experiments were performed in this study. AmpGs from different genera of bacteria (Escherichia coli, Vibrio cholerae and Acinetobacter baumannii) could complement AmpG function in Pseudomonas aeruginosa. The minimal inhibitory concentration (MIC) to ampicillin is 512 MUg/ml for wild type strain PAO1, while it is 32 MUg/ml for an ampG deletion mutant strain (PAO1DeltaampG) with a corresponding decrease in the activity of the ampC-encoded beta-lactamase. Site-directed mutagenesis of conserved AmpG residues (G29, A129, Q131 and A197) resulted in a loss of function, resulting in a loss of resistance to ampicillin in PAO1DeltaampG. The G29A, G29V, A129T, A129V, A129D, A197S and A197D mutants had lower resistance to ampicillin and significantly decreased activity of the AmpC beta-lactamase. The G29A, G29V, A129V, A197S and A197D mutants had decreased ampG mRNA transcript levels. The A129T and A129D mutants had normal ampG mRNA transcript levels, but the function of the protein was drastically reduced. Our experimental results demonstrate that the conserved amino acids played essential roles in maintaining the function of AmpG. Combined with the AmpG structural information, these critical amino acids can be targeted for the development of new anti-bacterial agents. PMID- 27959943 TI - Circadian Patterns of Intraocular Pressure Fluctuation among Normal-Tension Glaucoma Optic Disc Phenotypes. AB - OBJECTIVE: To characterize the 24-h habitual-position intraocular pressure (IOP) patterns of optic disc phenotypes (ODPs) in untreated normal-tension glaucoma (NTG) and the relationships between nocturnal IOP elevation and various clinical factors. DESIGN: Prospective, cross-sectional, observational study. METHODS: Eighty-two NTG patients with focal ischemic (FI) ODP and 82 age- and disease severity-matched NTG patients with myopic glaucomatous (MG) ODP were recruited prospectively over 3 years. The IOP was recorded 11 times over a 24-hour (h) period by a single ophthalmologist using a hand-held tonometer (TonoPen(r)XL). A cosinor model was used to describe the 24-h IOP rhythm. Associations between nocturnal IOP elevation and both ocular and demographic variables were evaluated using the generalized estimating equation (GEE). RESULTS: Mean habitual-position IOP was significantly higher during nighttime than daytime in the FI group (16.44 vs. 14.23 mmHg, P < 0.001), but not in the MG group (15.91 vs. 15.70 mmHg, P = 0.82). The FI group also exhibited a significantly higher peak IOP during sleeping hours (P = 0.01) and lower trough IOP during the 24-h period than the MG group (P < 0.01). The MG group showed a significantly higher peak IOP during waking hours than the FI group (P < 0.01). Therefore, 24-h IOP fluctuation range was significantly higher in the FI group than the MG group (P = 0.013). In the FI group, peak habitual-position IOP and the highest frequency of IOP peaks occurred during sleeping hours (12 AM-6 AM). By contrast, IOP peaks in the MG group occurred during morning hours (8 AM-12 PM). The FI group showed an overall nocturnal acrophase in habitual-position IOP, with 45 patients (54.9%) having a nocturnal acrophase; 10 (12.2%), a diurnal acrophase; and 27 (32.9%), no evident acrophase. By contrast, the MG group showed no evident peak in habitual-position IOP, with 9 patients (10.9%) having a nocturnal acrophase; 43 (52.4%), a diurnal acrophase; and 30 (36.6%), no evident acrophase. In multivariate modeling using the GEE, ODP (P < 0.001) and spherical equivalent (SE, P = 0.001) were independently associated with nocturnal IOP elevation. CONCLUSIONS: Based on 24-h habitual-position IOP data, FI is associated with significant nocturnal IOP elevation, while no such nocturnal IOP elevation is observed in MG ODP. In untreated NTG, there are also significant differences in the 24-h IOP pattern between FI and MG ODPs. PMID- 27959945 TI - The In Vitro Stability of Circulating Tumour DNA. AB - OBJECTIVE: DNA from apoptotic cancer cells, present in the circulation, has the potential to facilitate genomic profiling and disease monitoring. However, only low fractions of total cell-free DNA originates from cancer cells, limiting the applicability of circulating tumour DNA (ctDNA). Optimal sample processing is consequently of uttermost importance. Therefore, we evaluated the in vitro stability of ctDNA. EXPERIMENTAL DESIGN: Blood was collected in 10 ml EDTA or Streck tubes. Three conditions (EDTA and Streck tubes in room temperature, EDTA tubes at five degrees) and four time points (plasma harvested from blood aliquots of each 10 ml tube in a time series up to 24 h) were investigated. Each condition was evaluated in five metastatic prostate cancer patients. Subsequently, three additional patients were collected enabling investigation of the in vitro stability in EDTA tubes up to 48 h. METHODS: The in vitro stability of ctDNA was interrogated by low-pass whole genome sequencing which allows for the identification of somatic copy-number alterations (CNAs). In silico simulations demonstrated that non-parametric testing could detect a 1% contamination by white blood cell DNA. Mutational profiling was performed by targeted, in-solution based hybridization capture and subsequent sequencing. The allelic fraction of individual mutations was used as an estimate of the in vitro stability. RESULTS: Somatic CNAs were detected in all patients. Surprisingly, the ctDNA levels at zero hours were not significantly different to 24 or 48 hour in vitro incubation in any investigated condition. Subsequently, mutational profiling corroborated the conclusions from the CNA analysis. CONCLUSIONS: The stability of ctDNA simplifies logistics without the requirement of immediate processing or applying fixatives to prevent white blood cell lysis. PMID- 27959944 TI - BEMER Electromagnetic Field Therapy Reduces Cancer Cell Radioresistance by Enhanced ROS Formation and Induced DNA Damage. AB - Each year more than 450,000 Germans are expected to be diagnosed with cancer subsequently receiving standard multimodal therapies including surgery, chemotherapy and radiotherapy. On top, molecular-targeted agents are increasingly administered. Owing to intrinsic and acquired resistance to these therapeutic approaches, both the better molecular understanding of tumor biology and the consideration of alternative and complementary therapeutic support are warranted and open up broader and novel possibilities for therapy personalization. Particularly the latter is underpinned by the increasing utilization of non invasive complementary and alternative medicine by the population. One investigated approach is the application of low-dose electromagnetic fields (EMF) to modulate cellular processes. A particular system is the BEMER therapy as a Physical Vascular Therapy for which a normalization of the microcirculation has been demonstrated by a low-frequency, pulsed EMF pattern. Open remains whether this EMF pattern impacts on cancer cell survival upon treatment with radiotherapy, chemotherapy and the molecular-targeted agent Cetuximab inhibiting the epidermal growth factor receptor. Using more physiological, three dimensional, matrix-based cell culture models and cancer cell lines originating from lung, head and neck, colorectal and pancreas, we show significant changes in distinct intermediates of the glycolysis and tricarboxylic acid cycle pathways and enhanced cancer cell radiosensitization associated with increased DNA double strand break numbers and higher levels of reactive oxygen species upon BEMER treatment relative to controls. Intriguingly, exposure of cells to the BEMER EMF pattern failed to result in sensitization to chemotherapy and Cetuximab. Further studies are necessary to better understand the mechanisms underlying the cellular alterations induced by the BEMER EMF pattern and to clarify the application areas for human disease. PMID- 27959946 TI - Endoplasmic Reticulum-Localized Transmembrane Protein Dpy19L1 Is Required for Neurite Outgrowth. AB - The endoplasmic reticulum (ER), including the nuclear envelope, is a continuous and intricate membrane-bound organelle responsible for various cellular functions. In neurons, the ER network is found in cell bodies, axons, and dendrites. Recent studies indicate the involvement of the ER network in neuronal development, such as neuronal migration and axonal outgrowth. However, the regulation of neural development by ER-localized proteins is not fully understood. We previously reported that the multi-transmembrane protein Dpy19L1 is required for neuronal migration in the developing mouse cerebral cortex. A Dpy19L family member, Dpy19L2, which is a causative gene for human Globozoospermia, is suggested to act as an anchor of the acrosome to the nuclear envelope. In this study, we found that the patterns of exogenous Dpy19L1 were partially coincident with the ER, including the nuclear envelope in COS-7 cells at the level of the light microscope. The reticular distribution of Dpy19L1 was disrupted by microtubule depolymerization that induces retraction of the ER. Furthermore, Dpy19L1 showed a similar distribution pattern with a ER marker protein in embryonic mouse cortical neurons. Finally, we showed that Dpy19L1 knockdown mediated by siRNA resulted in decreased neurite outgrowth in cultured neurons. These results indicate that transmembrane protein Dpy19L1 is localized to the ER membrane and regulates neurite extension during development. PMID- 27959948 TI - Effects of Constant Flickering Light on Refractive Status, 5-HT and 5-HT2A Receptor in Guinea Pigs. AB - PURPOSE: To investigate the effects of constant flickering light on refractive development, the role of serotonin (i.e.5-hydroxytryptamine, 5-HT)and 5-HT2A receptor in myopia induced by flickering light in guinea pigs. METHODS: Forty five guinea pigs were randomly divided into three groups: control, form deprivation myopia (FDM) and flickering light induced myopia (FLM) groups(n = 15 for each group). The right eyes of the FDM group were covered with semitransparent hemispherical plastic shells serving as eye diffusers. Guinea pigs in FLM group were raised with illumination of a duty cycle of 50% at a flash frequency of 0.5Hz. The refractive status, axial length (AL), corneal radius of curvature(CRC) were measured by streak retinoscope, A-scan ultrasonography and keratometer, respectively. Ultramicroscopy images were taken by electron microscopy. The concentrations of 5-HTin the retina, vitreous body and retinal pigment epithelium (RPE) were assessed by high performance liquid chromatography, the retinal 5-HT2A receptor expression was evaluated by immunohistofluorescence and western blot. RESULTS: The refraction of FDM and FLM eyes became myopic from some time point (the 4th week and the 6th week, respectively) in the course of the experiment, which was indicated by significantly decreased refraction and longer AL when compared with the controls (p<0.05). The concentrations of 5-HT in the retina, vitreous body and RPE of FDM and FLM eyes were significantly increased in comparison with those of control eyes (both p<0.05). Similar to FDM eyes, the expression of retinal 5-HT2A receptor in FLM eyes was significantly up regulated compared to that of control eyes (both p<0.05). Western blot analysis showed that retinal 5-HT2A receptor level elevated less in the FLM eyes than that in the FDM eyes. Moreover, the levels of norepinephrine and epinephrine in FDM and FLM groups generally decreased when compared with control groups (all p<0.05). CONCLUSIONS: Constant flickering light could cause progressive myopia in guinea pigs. 5-HT and 5-HT2A receptor increased both in form deprivation myopia and flickering light induced myopia, indicating that 5-HT possibly involved in myopic development via binding to5-HT2A receptor. PMID- 27959949 TI - Chinese Milk Vetch as Green Manure Mitigates Nitrous Oxide Emission from Monocropped Rice System in South China. AB - Monocropped rice system is an important intensive cropping system for food security in China. Green manure (GM) as an alternative to fertilizer N (FN) is useful for improving soil quality. However, few studies have examined the effect of Chinese milk vetch (CMV) as GM on nitrous oxide (N2O) emission from monocropped rice field in south China. Therefore, a pot-culture experiment with four treatments (control, no FN and CMV; CMV as GM alone, M; fertilizer N alone, FN; integrating fertilizer N with CMV, NM) was performed to investigate the effect of incorporating CMV as GM on N2O emission using a closed chamber-gas chromatography (GC) technique during the rice growing periods. Under the same N rate, incorporating CMV as GM (the treatments of M and NM) mitigated N2O emission during the growing periods of rice plant, reduced the NO3- content and activities of nitrate and nitrite reductase as well as the population of nitrifying bacteria in top soil at maturity stage of rice plant versus FN pots. The global warming potential (GWP) and greenhouse gas intensity (GHGI) of N2O from monocropped rice field was ranked as M1.77), high NMR (>12.31), and low albumin (<=40.0 g/L) level were significantly associated with a poorer survival in BSCCE. The median OS was significantly greater in low NLR (<=1.77) than in the high NLR (>1.77) patients (51.0 vs. 31.0 months; P = 0.008). In multivariate analyses, only the NLR was an independent prognostic factor for OS (hazard ratio (HR), 2.030; 95% confidence interval (CI), 1.262-3.264; P = 0.003). A high NLR was also an independent predictor of a poorer RFS in BSCCE (HR, 2.222; 95% CI, 1.407-3.508; P = 0.001); the median RFS for low (<=1.77) and high (> 1.77) NLR patients was 44.0 months and 14.0 months, respectively. NLR remained a strong prognostic indicator for OS in stage I/II patients and a preoperative NLR>1.77 was predictive of a poor RFS in both stage I/II and stage III patients. CONCLUSIONS: We show that the preoperative NLR, a convenient and cost-effective biomarker, may serve as a prognostic indicator for BSCCE patients following curative surgery. PMID- 27959960 TI - Nontuberculous Mycobacterial Infections in a French Hospital: A 12-Year Retrospective Study. AB - BACKGROUND: Nontuberculous mycobacteria (NTM) are environmental organisms associated with a range of infections. Reports of NTM epidemiology are mainly focused on pulmonary infections and isolations, and extrapulmonary infections are less frequently described. METHODS: We conducted a retrospective study of NTM infections at the Bordeaux University Hospital, France, between January 2002 and December 2013. We used the microbiologic component of the American Thoracic Society/Infectious Diseases Society of America's pulmonary NTM disease criteria to define cases of pulmonary NTM, and patients with isolates from a normally sterile site were classified as having extrapulmonary disease. RESULTS: In our setting, 170 patients were included. Pulmonary cases predominated (54.1%), followed by skin and soft tissue infections (22.9%), disseminated cases (10.6%), lymphadenitis (7.7%), bone and joint infections (2.9%) and the remaining 1.8% catheter-related infections. Overall, 16 NTM species were isolated. Mycobacterium avium (31.8%) and M. intracellulare (20%) were the most common species identified, followed by M. marinum (13.5%), M. kansasii (10.6%), M. xenopi (9.4%), rapidly growing mycobacteria (9.4%) and other slowly growing mycobacteria (5.3%). In general, NTM isolates were largely prevalent in people older than 50 (62.4%); patients aged 1-10 year-old exclusively yielded M. avium from lymph nodes, almost cases having being diagnosed after 2007. Among the 121 patients with complete follow-up, 78 (64.5%), 24 (19.8%), and 19 (15.7%) were cured, experienced relapse, or died, respectively. CONCLUSION: In our study, extrapulmonary NTM infections represented almost half of cases, consisting mainly in skin and soft tissue infections. The increase lymphadenitis cases in children after 2007 could be linked to the cessation of mandatory BCG vaccination in France. We observed similar cure rates (64%) between pulmonary and extrapulmonary infections. PMID- 27959962 TI - Correction: Effects of Chronologic Age and Young Child Exposure on Respiratory Syncytial Virus Disease among US Preterm Infants Born at 32 to 35 Weeks Gestation. AB - [This corrects the article DOI: 10.1371/journal.pone.0166226.]. PMID- 27959961 TI - Persistent Low-Level Replication of SIVDeltanef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection. AB - Defining the correlates of immune protection conferred by SIVDeltanef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVDeltanef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVDeltanef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVDeltanef antigenic load. In conclusion, maturation of SIVDeltanef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination. PMID- 27959963 TI - Comprehensive Chemical Characterisation of Byzantine Glass Weights. AB - The understanding of the glass trade in the first millennium CE relies on the characterisation of well-dated compositional groups and the identification of their primary production sites. 275 Byzantine glass weights from the British Museum and the Bibliotheque nationale de France dating to the sixth and seventh century were analysed by LA-ICP-MS. Multivariate statistical and graphical data analysis discriminated between six main primary glass types. Primary glass sources were differentiated based on multi-dimensional comparison of silica derived elements (MgO, Al2O3, CaO, TiO2, Fe2O3, ZrO2) and components associated with the alkali source (Li2O, B2O3). Along with Egyptian and Levantine origins of the glassmaking sands, variations in the natron source possibly point to the exploitation of two different natron deposits. Differences in strontium to calcium ratios revealed variations in the carbonate fractions in the sand. At least two cobalt sources were employed as colouring agents, one of which shows strong correlations with nickel, indicating a specific post-Roman cobalt source. Typological evidence identified chronological developments in the use of the different glass groups. Throughout the sixth century, Byzantine glass weights were predominately produced from two glasses that are probably of an Egyptian origin (Foy-2 and Foy-2 high Fe). Towards the second half of the sixth century a new but related plant-ash glass type emerged (Magby). Levantine I was likewise found among the late sixth- to early seventh-century samples. The use of different dies for the same batch testifies to large-scale, centralised production of the weights, while the same die used for different primary production groups demonstrates the co-existence of alternative sources of supply. Given the comprehensive design of our study, these results can be extrapolated to the wider early Byzantine glass industry and its changes at large. PMID- 27959964 TI - Proteomic Analysis of eIF5B Silencing-Modulated Proteostasis. AB - Protein translational machinery is an important component of the proteostasis network that maintains cellular proteostasis and regulates aging and other cellular processes. Ample evidence indicates that inhibition of translation initiation factor activities enhances stress resistance in model organisms. Eukaryotic translation initiation factor 5B (eIF5B) acts by joining the pre-40S subunit with the 60S ribosomal unit to form an 80S-like complex during protein translational initiation. Reduced eIF5B expression may disrupt proteostasis and trigger cellular processes associated with stress responses. In this study, the physiological effects of altered eIF5B expression were examined in 293T and HepG2 cells. Cells with eIF5B-knockdown (eIF5B-KN) grew more slowly than control cells, and had a lower level of intracellular reactive oxygen species (ROS), increased resistance to oxidative stress and enhanced autophagy. Proteomic analysis showed that eIF5B knockdown resulted in upregulation of 88 proteins and downregulation of 130 proteins compared with control cells. The differentially expressed proteins were associated with diverse cellular processes including amino acid metabolism, RNA processing and protein metabolism, and DNA synthesis. Autonomous downregulation of the mitogen-activated protein kinase (MAPK) signaling pathway was identified as confirmed by western blotting and qPCR. We proposed that deactivation of MAPK pathway modulated proteostasis and induced prolonged S-phase of the cell-cycle, contributing to the slow growth of eIF5B-KN cells. eIF5B silencing also inactivated the mTOR pathway, downregulated glutamine transporters, enhanced autophagy, and decreased 28S rRNA and 5.8S rRNA expression levels which were reversed by restoration of eIF5B expression. Taken together, these results suggest that eIF5B silencing provides a negative feedback to deactivate MAPK signaling, leading to reduced cell growth. These findings provide a useful resource to further biological exploration of the functions of protein synthesis in regulation of proteostasis and stress responses. PMID- 27959965 TI - Functional Analyses of the Crohn's Disease Risk Gene LACC1. AB - BACKGROUND: Genetic variation in the Laccase (multicopper oxidoreductase) domain containing 1 (LACC1) gene has been shown to affect the risk of Crohn's disease, leprosy and, more recently, ulcerative colitis and juvenile idiopathic arthritis. LACC1 function appears to promote fatty-acid oxidation, with concomitant inflammasome activation, reactive oxygen species production, and anti-bacterial responses in macrophages. We sought to contribute to elucidating LACC1 biological function by extensive characterization of its expression in human tissues and cells, and through preliminary analyses of the regulatory mechanisms driving such expression. METHODS: We implemented Western blot, quantitative real-time PCR, immunofluorescence microscopy, and flow cytometry analyses to investigate fatty acid metabolism-immune nexus (FAMIN; the LACC1 encoded protein) expression in subcellular compartments, cell lines and relevant human tissues. Gene-set enrichment analyses were performed to initially investigate modulatory mechanisms of LACC1 expression. A small-interference RNA knockdown in vitro model system was used to study the effect of FAMIN depletion on peroxisome function. RESULTS: FAMIN expression was detected in macrophage-differentiated THP-1 cells and several human tissues, being highest in neutrophils, monocytes/macrophages, myeloid and plasmacytoid dendritic cells among peripheral blood cells. Subcellular co-localization was exclusively confined to peroxisomes, with some additional positivity for organelle endomembrane structures. LACC1 co-expression signatures were enriched for genes involved in peroxisome proliferator-activated receptors (PPAR) signaling pathways, and PPAR ligands downregulated FAMIN expression in in vitro model systems. CONCLUSION: FAMIN is a peroxisome associated protein with primary role(s) in macrophages and other immune cells, where its metabolic functions may be modulated by PPAR signaling events. However, the precise molecular mechanisms through which FAMIN exerts its biological effects in immune cells remain to be elucidated. PMID- 27959966 TI - X-Linked Alport Dogs Demonstrate Mesangial Filopodial Invasion of the Capillary Tuft as an Early Event in Glomerular Damage. AB - BACKGROUND: X-linked Alport syndrome (XLAS), caused by mutations in the type IV collagen COL4A5 gene, accounts for approximately 80% of human Alport syndrome. Dogs with XLAS have a similar clinical progression. Prior studies in autosomal recessive Alport mice demonstrated early mesangial cell invasion as the source of laminin 211 in the glomerular basement membrane (GBM), leading to proinflammatory signaling. The objective of this study was to verify this process in XLAS dogs. METHODS: XLAS dogs and WT littermates were monitored with serial clinicopathologic data and kidney biopsies. Biopsies were obtained at set milestones defined by the onset of microalbuminuria (MA), overt proteinuria, onset of azotemia, moderate azotemia, and euthanasia. Kidney biopsies were analyzed by histopathology, immunohistochemistry, and electron microscopy. RESULTS: XLAS dogs showed progressive decrease in renal function and progressive increase in interstitial fibrosis and glomerulosclerosis (based on light microscopy and immunostaining for fibronectin). The only identifiable structural abnormality at the time of microalbuminuria was ultrastructural evidence of mild segmental GBM multilamination, which was more extensive when overt proteinuria developed. Co-localization studies showed that mesangial laminin 211 and integrin alpha8beta1 accumulated in the GBM at the onset of overt proteinuria and coincided with ultrastructural evidence of mild cellular interpositioning, consistent with invasion of the capillary loops by mesangial cell processes. CONCLUSION: In a large animal model, the induction of mesangial filopodial invasion of the glomerular capillary loop leading to the irregular deposition of laminin 211 is an early initiating event in Alport glomerular pathology. PMID- 27959969 TI - Redemptive Family Narratives: Olga Lengyel and the Textuality of the Holocaust: In Memoriam Elie Wiesel. AB - Memoirs written by Holocaust survivors and (in some cases) their testimonies retain a salience unmatched by other historical sources. This article discusses one such memoir, Olga Lengyel's Five Chimneys, alongside her 1998 testimony, aiming to engage with broader methodological issues relating to the history of the Holocaust, particularly those about memory, narrative and textuality. Through a detailed discussion of certain moments shaping Olga Lengyel's personal experience, both pre-and post-arrival in Auschwitz, the article captures the tensions and contradictions characterizing the harrowing story of one woman's loss of family in the Holocaust. PMID- 27959967 TI - Transfusion: -80 degrees C Frozen Blood Products Are Safe and Effective in Military Casualty Care. AB - INTRODUCTION: The Netherlands Armed Forces use -80 degrees C frozen red blood cells (RBCs), plasma and platelets combined with regular liquid stored RBCs, for the treatment of (military) casualties in Medical Treatment Facilities abroad. Our objective was to assess and compare the use of -80 degrees C frozen blood products in combination with the different transfusion protocols and their effect on the outcome of trauma casualties. MATERIALS AND METHODS: Hemovigilance and combat casualties data from Afghanistan 2006-2010 for 272 (military) trauma casualties with or without massive transfusions (MT: >=6 RBC/24hr, N = 82 and non MT: 1-5 RBC/24hr, N = 190) were analyzed retrospectively. In November 2007, a massive transfusion protocol (MTP; 4:3:1 RBC:Plasma:Platelets) for ATLS(r) class III/IV hemorrhage was introduced in military theatre. Blood product use, injury severity and mortality were assessed pre- and post-introduction of the MTP. Data were compared to civilian and military trauma studies to assess effectiveness of the frozen blood products and MTP. RESULTS: No ABO incompatible blood products were transfused and only 1 mild transfusion reaction was observed with 3,060 transfused products. In hospital mortality decreased post-MTP for MT patients from 44% to 14% (P = 0.005) and for non-MT patients from 12.7% to 5.9% (P = 0.139). Average 24-hour RBC, plasma and platelet ratios were comparable and accompanying 24-hour mortality rates were low compared to studies that used similar numbers of liquid stored (and on site donated) blood products. CONCLUSION: This report describes for the first time that the combination of -80 degrees C frozen platelets, plasma and red cells is safe and at least as effective as standard blood products in the treatment of (military) trauma casualties. Frozen blood can save the lives of casualties of armed conflict without the need for in-theatre blood collection. These results may also contribute to solutions for logistic problems in civilian blood supply in remote areas. PMID- 27959970 TI - Magnetic Resonance Thermometry-Guided Stereotactic Laser Ablation of Cavernous Malformations in Drug-Resistant Epilepsy: Imaging and Clinical Results. AB - BACKGROUND: Surgery is indicated for cerebral cavernous malformations (CCM) that cause medically refractory epilepsy. Real-time magnetic resonance thermography (MRT)-guided stereotactic laser ablation (SLA) is a minimally invasive approach to treating focal brain lesions. SLA of CCM has not previously been described. OBJECTIVE: To describe MRT-guided SLA, a novel approach to treating CCM-related epilepsy, with respect to feasibility, safety, imaging, and seizure control in 5 consecutive patients. METHODS: Five patients with medically refractory epilepsy undergoing standard presurgical evaluation were found to have corresponding lesions fulfilling imaging characteristics of CCM and were prospectively enrolled. Each underwent stereotactic placement of a saline-cooled cannula containing an optical fiber to deliver 980-nm diode laser energy via twist drill craniostomy. MR anatomic imaging was used to evaluate targeting prior to ablation. MR imaging provided evaluation of targeting and near real-time feedback regarding extent of tissue thermocoagulation. Patients maintained seizure diaries, and remote imaging (6-21 months post-ablation) was obtained in all patients. RESULTS: Imaging revealed no evidence of acute hemorrhage following fiber placement within presumed CCM. MRT during treatment and immediate post procedure imaging confirmed desired extent of ablation. We identified no adverse events or neurological deficits. Four of 5 (80%) patients achieved freedom from disabling seizures after SLA alone (Engel class 1 outcome), with follow-up ranging 12-28 months. Reimaging of all subjects (6-21 months) indicated lesion diminution with surrounding liquefactive necrosis, consistent with the surgical goal of extended lesionotomy. CONCLUSION: Minimally invasive MRT-guided SLA of epileptogenic CCM is a potentially safe and effective alternative to open resection. Additional experience and longer follow-up are needed. PMID- 27959968 TI - Enhanced Visualization of Subtle Outer Retinal Pathology by En Face Optical Coherence Tomography and Correlation with Multi-Modal Imaging. AB - PURPOSE: To present en face optical coherence tomography (OCT) images generated by graph-search theory algorithm-based custom software and examine correlation with other imaging modalities. METHODS: En face OCT images derived from high density OCT volumetric scans of 3 healthy subjects and 4 patients using a custom algorithm (graph-search theory) and commercial software (Heidelberg Eye Explorer software (Heidelberg Engineering)) were compared and correlated with near infrared reflectance, fundus autofluorescence, adaptive optics flood-illumination ophthalmoscopy (AO-FIO) and microperimetry. RESULTS: Commercial software was unable to generate accurate en face OCT images in eyes with retinal pigment epithelium (RPE) pathology due to segmentation error at the level of Bruch's membrane (BM). Accurate segmentation of the basal RPE and BM was achieved using custom software. The en face OCT images from eyes with isolated interdigitation or ellipsoid zone pathology were of similar quality between custom software and Heidelberg Eye Explorer software in the absence of any other significant outer retinal pathology. En face OCT images demonstrated angioid streaks, lesions of acute macular neuroretinopathy, hydroxychloroquine toxicity and Bietti crystalline deposits that correlated with other imaging modalities. CONCLUSIONS: Graph-search theory algorithm helps to overcome the limitations of outer retinal segmentation inaccuracies in commercial software. En face OCT images can provide detailed topography of the reflectivity within a specific layer of the retina which correlates with other forms of fundus imaging. Our results highlight the need for standardization of image reflectivity to facilitate quantification of en face OCT images and longitudinal analysis. PMID- 27959971 TI - Comparison of Co-Temporal Modeling Algorithms on Sparse Experimental Time Series Data Sets. AB - Multiple approaches for reverse-engineering biological networks from time-series data have been proposed in the computational biology literature. These approaches can be classified by their underlying mathematical algorithms, such as Bayesian or algebraic techniques, as well as by their time paradigm, which includes next state and co-temporal modeling. The types of biological relationships, such as parent-child or siblings, discovered by these algorithms are quite varied. It is important to understand the strengths and weaknesses of the various algorithms and time paradigms on actual experimental data. We assess how well the co temporal implementations of three algorithms, continuous Bayesian, discrete Bayesian, and computational algebraic, can 1) identify two types of entity relationships, parent and sibling, between biological entities, 2) deal with experimental sparse time course data, and 3) handle experimental noise seen in replicate data sets. These algorithms are evaluated, using the shuffle index metric, for how well the resulting models match literature models in terms of siblings and parent relationships. Results indicate that all three co-temporal algorithms perform well, at a statistically significant level, at finding sibling relationships, but perform relatively poorly in finding parent relationships. PMID- 27959972 TI - A New Map Location of Gene Stb3 for Resistance to Septoria Tritici Blotch in Wheat. AB - Septoria tritici blotch (STB), caused by Mycosphaerella graminicola (synonym: Zymoseptoria tritici; asexual stage: Septoria tritici), is an important disease of wheat worldwide. Management of the disease usually is by host resistance or fungicides. However, M. graminicola has developed insensitivity to most commonly applied fungicides so there is a continuing need for well-characterized sources of host resistance to accelerate the development of improved wheat cultivars. Gene Stb3 has been a useful source of major resistance, but its mapping location has not been well characterized. Based on linkage to a single marker, a previous study assigned Stb3 to a location on the short arm of chromosome 6D. However, the results from the present study show that this reported location is incorrect. Instead, linkage analysis revealed that Stb3 is located on the short arm of wheat chromosome 7A, completely linked to microsatellite (SSR) locus Xwmc83 and flanked by loci Xcfa2028 (12.4 cM distal) and Xbarc222 (2.1 cM proximal). Linkage between Stb3 and Xwmc83 was validated in BC1F3 progeny of other crosses, and analyses of the flanking markers with deletion stocks showed that the gene is located on 7AS between fraction lengths 0.73 and 0.83. This revised location of Stb3 is different from those for other STB resistance genes previously mapped in hexaploid wheat but is approximately 20 cM proximal to an STB resistance gene mapped on the short arm of chromosome 7Am in Triticum monococcum. The markers described in this study are useful for accelerating the deployment of Stb3 in wheat breeding programs. PMID- 27959973 TI - False Belief Performance of Children Adopted Internationally. AB - Purpose: The purpose of this study was to explore relationships among adoption, individual, and family variables on false belief performance of children adopted internationally (CAI). Method: Using a quasiexperimental design, thirty-five 4 year-old children adopted from Asian and Eastern European countries before age 2 years were compared with a U.S. group of 33 nonadopted 4-year-old children on a standardized English-language measure, 3 false belief tasks, and a go/no-go inhibition measure. Results: The adopted group differed significantly from the U.S. nonadopted group in expressive language and false belief performance. For the adopted group, inhibition measures were significantly correlated with core language scores. Core language scores and number of older siblings predicted false belief performance. Conclusions: Similar to children who are not adopted, language competence and living with older siblings positively influenced social understanding in CAI. Because CAI experience interrupted language acquisition and live with fewer older siblings, they are at risk of having weaker language competence and social understanding in their adopted language. When working with CAI, practitioners should assess social communication, language competence, and inhibition skills. They should assist adoptive families in providing socially mentored opportunities for their children to observe and interact with older children. PMID- 27959975 TI - Understanding Risk for Reading Difficulties in Children With Language Impairment. AB - Purpose: The purpose of this study was to retrospectively examine the preschool language and early literacy skills of kindergarten good and poor readers, and to determine the extent to which these skills predict reading status. Method: Participants were 136 children with language impairment enrolled in early childhood special education classrooms. On the basis of performance on a word recognition task given in kindergarten, children were classified as either good or poor readers. Comparisons were made across these 2 groups on a number of language and early literacy measures administered in preschool, and logistic regression was used to determine the best predictors of kindergarten reading status. Results: Twenty-seven percent of the sample met criterion for poor reading in kindergarten. These children differed from good readers on most of the skills measured in preschool. The best predictors of kindergarten reading status were oral language, alphabet knowledge, and print concept knowledge. Presence of comorbid disabilities was not a significant predictor. Classification accuracy was good overall. Conclusion: Results suggest that risk of reading difficulty for children with language impairment can be reliably estimated in preschool, prior to the onset of formal reading instruction. Measures of both language and early literacy skills are important for identifying which children are likely to develop later reading difficulties. PMID- 27959974 TI - Estimating Subglottal Pressure From Neck-Surface Acceleration During Normal Voice Production. AB - Purpose: The purpose of this study was to evaluate the potential for estimating subglottal air pressure using a neck-surface accelerometer and to compare the accuracy of predicting subglottal air pressure relative to predicting acoustic sound pressure level (SPL). Method: Indirect estimates of subglottal pressure (Psg') were obtained from 10 vocally healthy speakers during loud-to-soft repetitions of 3 different /p/-vowel gestures (/pa/, /pi/, /pu/) at 3 pitch levels in the modal register. Intraoral air pressure, neck-surface acceleration, and radiated acoustic pressure were recorded, and the root-mean-square amplitude of the acceleration signal was correlated with Psg' and SPL. Results: The coefficient of determination between accelerometer level and Psg' was high when data were pooled from all vowel and pitch contexts for each participant (r2 = .68 .93). These relationships were stronger than corresponding relationships between accelerometer level and SPL (r2 = .46-.81). The average 95% prediction interval for estimating Psg' using accelerometer level was +/-2.53 cm H2O, ranging from +/ 1.70 to +/-3.74 cm H2O across participants. Conclusions: Accelerometer signal amplitude correlated more strongly with Psg' than with SPL. Future work is warranted to investigate the robustness of the relationship in nonmodal voice qualities, individuals with voice disorders, and accelerometer-based ambulatory monitoring of subglottal pressure. PMID- 27959976 TI - New Frontiers of Medical Illustration. PMID- 27959977 TI - Research Across Borders. PMID- 27959979 TI - Congress Delivers Medical Twofer. PMID- 27959978 TI - Fixing Obamacare Takes Back Seat, Poll Finds. PMID- 27959980 TI - If at First You Don't Succeed. PMID- 27959981 TI - Label Error in Figure. PMID- 27959982 TI - Repeat Clostridium difficile Testing. PMID- 27959983 TI - Understanding County-Level, Cause-Specific Mortality: The Great Value-and Limitations-of Small Area Data. PMID- 27959984 TI - Firearm Deaths in the United States and Globally, 1990-2015. PMID- 27959986 TI - Genetically Modified Food Labeling: A "Right to Know"? PMID- 27959987 TI - From Internal Combustion to Electricity. PMID- 27959988 TI - Lack of Benefit for Liraglutide in Heart Failure. PMID- 27959989 TI - Expectations for Physicians Prescribing Marijuana. PMID- 27959990 TI - Factors Influencing Prescription Drug Costs in the United States. PMID- 27959991 TI - Factors Influencing Prescription Drug Costs in the United States. PMID- 27959992 TI - Lack of Benefit for Liraglutide in Heart Failure-Reply. PMID- 27959993 TI - Expectations for Physicians Prescribing Marijuana-Reply. PMID- 27959994 TI - Factors Influencing Prescription Drug Costs in the United States-Reply. PMID- 27959995 TI - Cannabis and Cannabinoids. PMID- 27959997 TI - JAMA Patient Page Neurology: Recovery After Stroke. PMID- 27959999 TI - A Piece of MyMind: Coauthors. PMID- 27960002 TI - Insurer Curbs Opioid Prescriptions. PMID- 27960001 TI - Enhancing the Scientific Integrity and Safety of Clinical Trials: Recommendations for Data Monitoring Committees. PMID- 27959996 TI - US County-Level Trends in Mortality Rates for Major Causes of Death, 1980-2014. AB - Importance: County-level patterns in mortality rates by cause have not been systematically described but are potentially useful for public health officials, clinicians, and researchers seeking to improve health and reduce geographic disparities. Objectives: To demonstrate the use of a novel method for county level estimation and to estimate annual mortality rates by US county for 21 mutually exclusive causes of death from 1980 through 2014. Design, Setting, and Participants: Redistribution methods for garbage codes (implausible or insufficiently specific cause of death codes) and small area estimation methods (statistical methods for estimating rates in small subpopulations) were applied to death registration data from the National Vital Statistics System to estimate annual county-level mortality rates for 21 causes of death. These estimates were raked (scaled along multiple dimensions) to ensure consistency between causes and with existing national-level estimates. Geographic patterns in the age standardized mortality rates in 2014 and in the change in the age-standardized mortality rates between 1980 and 2014 for the 10 highest-burden causes were determined. Exposure: County of residence. Main Outcomes and Measures: Cause specific age-standardized mortality rates. Results: A total of 80 412 524 deaths were recorded from January 1, 1980, through December 31, 2014, in the United States. Of these, 19.4 million deaths were assigned garbage codes. Mortality rates were analyzed for 3110 counties or groups of counties. Large between-county disparities were evident for every cause, with the gap in age-standardized mortality rates between counties in the 90th and 10th percentiles varying from 14.0 deaths per 100 000 population (cirrhosis and chronic liver diseases) to 147.0 deaths per 100 000 population (cardiovascular diseases). Geographic regions with elevated mortality rates differed among causes: for example, cardiovascular disease mortality tended to be highest along the southern half of the Mississippi River, while mortality rates from self-harm and interpersonal violence were elevated in southwestern counties, and mortality rates from chronic respiratory disease were highest in counties in eastern Kentucky and western West Virginia. Counties also varied widely in terms of the change in cause-specific mortality rates between 1980 and 2014. For most causes (eg, neoplasms, neurological disorders, and self-harm and interpersonal violence), both increases and decreases in county-level mortality rates were observed. Conclusions and Relevance: In this analysis of US cause-specific county-level mortality rates from 1980 through 2014, there were large between-county differences for every cause of death, although geographic patterns varied substantially by cause of death. The approach to county-level analyses with small area models used in this study has the potential to provide novel insights into US disease-specific mortality time trends and their differences across geographic regions. PMID- 27960003 TI - Health Workers' Risks for Respiratory Virus. PMID- 27960004 TI - Vocabulary Development in European Portuguese: A Replication Study Using the Language Development Survey. AB - Purpose: Our objective was to replicate previous cross-linguistic findings by comparing Portuguese and U.S. children with respect to (a) effects of language, gender, and age on vocabulary size; (b) lexical composition; and (c) late talking. Method: We used the Language Development Survey (LDS; Rescorla, 1989) with children (18-35 months) learning European Portuguese (n = 181) and English (n = 206). Results: In both languages, girls had higher vocabulary scores than boys and vocabulary scores increased with age. Portuguese LDS scores were significantly lower than English scores, but the effect size was small. Cross linguistic concordance of percentage use scores yielded a Q correlation of .50, with 64 of the "top 100" words being exact matches. Cross-linguistic concordance was highest for the youngest age group. In both languages, vocabulary composition in late talkers (children >= 24 months with < 50 words) was highly correlated with composition in vocabulary size-matched younger children. Conclusions: Results replicated previous Greek, Korean, and Italian LDS studies. The early lexicons of typical talkers and late talkers contained many of the same words, indicating considerable universality and suggesting good targets for clinical intervention. PMID- 27960005 TI - Writing Process Products in Intermediate-Grade Children With and Without Language Based Learning Disabilities. AB - Purpose: Difficulties with written expression are an important consideration in the assessment and treatment of school-age children. This study evaluated how intermediate-grade children with and without written language difficulties fared on a writing task housed within the Hayes and Berninger (2014) writing process framework. Method: Sixty-four children completed a writing task whereby they planned, wrote, and revised a narrative story across 3 days. Children had extended time to produce an outline, first draft, and final copy of their story. Language transcription approaches were used to obtain measures reflecting writing productivity, complexity, accuracy, and mechanics, in addition to measures of planning and revision. Results: Results indicated that children with writing difficulties produced poorer quality stories compared with their peers yet were not significantly different across all measures. Children with typical development produced longer stories with better spelling accuracy. Writing process measures predicted significant amounts of variance in writing quality across the sample. Discussion: Writing should be considered as part of language assessment and intervention, whether as the sole language difficulty or alongside difficulties with speaking, listening, or reading in children with language-based learning difficulties. Implications for translation of research to practice and service delivery are provided. PMID- 27960007 TI - Literate Language Intervention With High-Need Prekindergarten Children: A Randomized Trial. AB - Purpose: The present article reports on the implementation and results of a randomized intervention trial targeting the literate language skills of prekindergarten children without identified language disorders but with low oral language skills. Method: Children (N = 82; 45 boys and 37 girls) were screened-in and randomized to a business-as-usual control or to the pull-out treatment groups in which they received 4 instructional units addressing different sentence-level syntactic and semantic features: prepositions, conjunctions, adverbs, and negations. The intervention was delivered by paraprofessionals in small groups in the form of 20-min lessons 4 times a week for 12 weeks. Results: Overall, children receiving the supplemental instruction showed educationally meaningful gains in their oral language skills, relative to children in the control group. Significant group differences were found on researcher-designed oral language measures, with moderate to large effect sizes ranging from .44 to .88 on these measures. Conclusions: The intervention holds the potential to positively affect understanding and production of syntax and semantic features, such as prepositions and conjunctions, in young children with weak oral language skills. PMID- 27960006 TI - Experiments on Auditory-Visual Perception of Sentences by Users of Unilateral, Bimodal, and Bilateral Cochlear Implants. AB - Purpose: Five experiments probed auditory-visual (AV) understanding of sentences by users of cochlear implants (CIs). Method: Sentence material was presented in auditory (A), visual (V), and AV test conditions to listeners with normal hearing and CI users. Results: (a) Most CI users report that most of the time, they have access to both A and V information when listening to speech. (b) CI users did not achieve better scores on a task of speechreading than did listeners with normal hearing. (c) Sentences that are easy to speechread provided 12 percentage points more gain to speech understanding than did sentences that were difficult. (d) Ease of speechreading for sentences is related to phrase familiarity. (e) Users of bimodal CIs benefit from low-frequency acoustic hearing even when V cues are available, and a second CI adds to the benefit of a single CI when V cues are available. (f) V information facilitates lexical segmentation by improving the recognition of the number of syllables produced and the relative strength of these syllables. Conclusions: Our data are consistent with the view that V information improves CI users' ability to identify syllables in the acoustic stream and to recognize their relative juxtaposed strengths. Enhanced syllable resolution allows better identification of word onsets, which, when combined with place-of-articulation information from visible consonants, improves lexical access. PMID- 27960008 TI - A tiered, Bayesian approach to estimating of population variability for regulatory decision-making. AB - Characterizing human variability in susceptibility to chemical toxicity is a critical issue in regulatory decision-making, but is usually addressed by a default 10-fold safety/uncertainty factor. Feasibility of population-based in vitro experimental approaches to more accurately estimate human variability was demonstrated recently using a large (~1000) panel of lymphoblastoid cell lines. However, routine use of such a large population-based model poses cost and logistical challenges. We hypothesize that a Bayesian approach embedded in a tiered workflow provides efficient estimation of variability and enables a tailored and sensible approach to selection of appropriate sample size. We used the previously collected lymphoblastoid cell line in vitro toxicity data to develop a data-derived prior distribution for the uncertainty in the degree of population variability. The resulting prior for the toxicodynamic variability factor (the ratio between the median and 1% most sensitive individuals) has a median (90% CI) of 2.5 (1.4-9.6). We then performed computational experiments using a hierarchical Bayesian population model with lognormal population variability with samples sizes of n = 5 to 100 to determine the change in precision and accuracy with increasing sample size. We propose a tiered Bayesian strategy for fit-for-purpose population variability estimates: (1) a default using the data-derived prior distribution; (2) a pilot experiment using samples sizes of ~20 individuals that reduces prior uncertainty by > 50% with > 80% balanced accuracy for classification; and (3) a high confidence experiment using sample sizes of ~50-100. This approach efficiently uses in vitro data on population variability to inform decision-making. PMID- 27960009 TI - [Metabolic diseases and the kidney: a complex interplay]. PMID- 27960010 TI - [Lipid metabolism abnormalities in Chronic Kidney Disease]. AB - Regardless of the etiology of renal disease, patients with chronic kidney disease (CKD) develop profound qualitative and quantitative lipoprotein metabolism abnormalities because of the presence of alterations in apolipoproteins, lipid transfer proteins, lipolytic enzymes, and lipoprotein receptors from the earlier stages of the disease. As renal function deteriorates, triglyceride concentrations increase and high-density lipoprotein cholesterol (HDL) concentrations decline, while levels of low- density lipoprotein (LDL) cholesterol remain in the normal range or become slightly decreased. Meanwhile, there is a progressive accumulation of the more atherogenic small dense LDL particles. In stages 4 and 5 of CKD, there is decreased concentration of apolipoprotein A-containing lipoproteins, and increased concentrations of triglyceride-rich apolipoprotein B-containing lipoproteins. Patients with nephrotic syndrome and preserved glomerular filtration rate show a higher atherogenic profile, with markedly elevated plasma cholesterol, triglyceride concentrations, and increased very low (VLDL) and low density lipoprotein (LDL), intermediate density lipoprotein (IDL) and lipoprotein(a) levels. Depressed plasma HDL cholesterol concentrations are also commonly observed in patients with nephrotic syndrome. Unless nephrotic syndrome is present, lipid abnormalities are not commonly observed when the lipid profile is measured using standard quantitative methods. In particular, total and LDL cholesterol, the most common lipid parameters used to stratify the cardiovascular risk and assess the effect of treatment with statins, are usually normal and often low. However, there is evidence that some alterations of the qualitative profile of lipoprotein are characteristic of chronic kidney disease, and probably contribute to the high rate of atherosclerotic events observed in these patients. These qualitative abnormalities include increased levels of VLDL and IDL cholesterol, small dense and oxidized LDL particles and lipoprotein(a). Moreover, HDL cholesterol is usually low and dysfunctional, not acting as protective, but paradoxically as proatherogenic particles. The lipid profile of CKD shows similar features to the metabolic syndrome and type 2 diabetes, conditions well known to predispose to kidney disease, which in turn aggravates insulin resistance and promotes atherogenic dyslipidemia. PMID- 27960011 TI - [Lecithin:Cholesterol Acyltransferase Deficiency, from genes to therapy]. AB - LCAT synthesizes most of the plasma cholesteryl esters, and plays a major role in HDL metabolism. Mutations in the LCAT gene cause two syndromes, familial LCAT deficiency (FLD) and fish-eye disease (FED), both characterized by severe alterations in plasma lipoprotein profile. Renal disease is the major cause of morbidity and mortality in FLD cases, but an established therapy is not currently available. The present therapy of LCAT deficiency is mainly aimed at correcting the dyslipidemia associated with the disease and at delaying evolution of chronic nephropathy. LCAT deficiency represents a candidate disease for enzyme replacement therapy. In vitro and in vivo studies proved the efficacy of recombinant human LCAT (rhLCAT) in correcting dyslipidemia, and rhLCAT is presently under development. PMID- 27960012 TI - [Porphyrias and the Kidney]. PMID- 27960013 TI - [Antidiabetic Drugs and the Kidney]. PMID- 27960014 TI - [Diabetes Mellitus: etiology, pathophysiology and clinical classification]. PMID- 27960015 TI - [Corticosteroid induced diabetes mellitus: diagnosis and management]. AB - Steroid diabetes occurs in 20% (range 10-60%) of the persons treated with corticosteroid drugs. Steroid diabetes diagnosis often is omitted or late because the diagnostic sensitivity of fasting blood sugar is low, so the postprandial blood glucose must be monitored and the diagnosis should be made clinically, based on 2 hours after lunch blood glucose or OGTT. Steroid diabetes causes increased hospitalizations for acute diabetic complications; there are few data on the chronic complications. Steroid therapy increases the macrovascular complications in diabetic people, while globally does not increase the mortality. However, in solid organ transplant recipients steroid diabetes causes 60% increase of rejections, 90% of mortality and 150% of the annual costs and considerably worsens the prognosis of AGVHD in bone marrow transplants. The corticosteroids have negative actions on insulin resistance in muscle, liver and adipose tissue and on insulin secretion; hyperglycemia is mainly postprandial, in the afternoon and in the evening, also related to the pharmacokinetics of the drugs. There is insufficient evidence of the efficacy of specific treatments in randomized controlled trials and the treatment is based on pathophysiology, mechanisms of action of drugs and experience. The antidiabetic drug choosing criteria are the body weight, the underlying disease, the type and dose of the corticosteroid drugs, the way of administration, the blood glucose levels, the possible contraindications. New antidiabetic drugs can open therapeutic perspectives, yet still to be explored with ad hoc studies. Insulin is frequently needed, in single or multiple doses with different combinations. PMID- 27960016 TI - [Diabetes Mellitus in the Dialysis Patient]. PMID- 27960018 TI - [Extrarenal complications of Diabetes Mellitus]. PMID- 27960017 TI - [Recent advances in urate metabolism]. AB - In the last fifteen years, genomics and other -omics sciences have revolutionized our understanding of biological processes at the molecular level. An illustrative example is urate metabolism. Before the publication of the complete human genome, in 2003 it was believed that a single enzyme (urate oxidase) was responsible for uricolysis that is the conversion of urate into the more soluble allantoin. Now we know with great detail that this process requires the consecutive action of three enzymes that have been lost by gene inactivation in our hominoid ancestor. Similarly, a single urate transporter (URAT1) was known at that time. Now we have evidence that urate homeostasis depends on a complex set of transporters located on the epithelial cells of the kidney and the intestine. In this review article, we give an account of the recent discoveries on urate metabolism and how these discoveries can be applied to the development of novel drugs to treat hyperuricemia, tumor lysis syndrome and the Lesch-Nyhan disease. PMID- 27960019 TI - [Glomerular lipidosis]. AB - Lipidoses occur for an abnormal storage parenchymal deposition of lipids and products of their metabolism in large amounts or sometimes, involving only some particular tissue structures. The lipid storage is usually due to an inborn error causing an enzyme absence /deficiency in the primary lipidoses and to a complex metabolism alterations in the secondary forms. However, histologically all lipid depositions look very similar, and immunohistochemical investigation, clinical pictures knowledge and genetic tests need to make a correct diagnosis. Lipid deposition causes parenchymal structural changes especially of glomeruli resulting in renal function impairment and proteinuria and haematuria appearance. This manuscript gathers clinical and histological features present in these storage pathologies. Renal involvement is described in Anderson-Fabry disease, in hyperlipoproteinemias, in lecithin-cholesterol acyltransferase deficiency, in Gaucher disease and finally in secondary lipidoses features such as nephrotic syndrome, Alagille disease, and toxic or ischemic renal damage. Recently the replacement enzymatic therapy availability is substantially modifying the clinical picture and the outcome in some lipidoses such as Anderson-Fabry and Gaucher diseases. Therefore, it is import to be aware of these disorders, not only for making a correct diagnosis but also for starting, when it is possible, an effective therapy. PMID- 27960020 TI - [The Hyperoxalurias]. AB - Oxalate (Ox) is an end-product of metabolism, important for poor solubility of its calcium salt in biological fluids. Ox can therefore be found in about 70% of urinary calculi. Hyperoxaluria (HOx) defined as Ox exceeding 0.5 mmol)/day, may cause nephrolithiasis/nephrocalcinosis and may be classified as dietary (DH), enteric (EH) or primary (PH). Fractional intestinal absorption of Ox is less than 10%, but increases to over 20% at calcium intakes below 200 mg/day. DH is often related to low-calcium diets. EH is caused by non-absorbed fatty acids which bind to calcium and lower its concentration in the intestinal lumen. Ox forms more soluble complexes with other cations and results in HOx. Similar mechanisms may cause HOx following bariatric surgery. PHs are the most severe causes of HOx. Three types have so far been described, all being autosomic recessive. PH1 is due to mutations of AGXT gene encoding liver alanine-glyoxylate aminotransferase, PH2 is caused by mutations of GR-HPR gene encoding glyoxylate reductase and PH3 by mutations of HOGA1 encoding for hydroxyl-oxoglutarate aldolase. HOx results from deficient detoxification from glyoxylate, which is oxidized to Ox. The three PHs have different severity, though not always clinically distinguishable. They are identified through genetics and, in PH1, good genotype/phenotype correlations have been established. Thanks to early biochemical and genetic diagnosis, which are crucial to either prevent progression to ESRF or choose adequate transplantation strategies, the outlook of PH patients has dramatically improved in the last decades and will furtherly do in view of new therapeutic strategies. PMID- 27960021 TI - [Dyslipidemia in Kidney transplant recipients]. AB - The kidney transplant recipients' population shows pronounced alterations of the lipidic profile, with hypercholesterolemia (total cholesterol, LDL, VLDL), normal HDL and hypertriglyceridemia. Multiple factors contribute to the development of dyslipidemia, towards these, immunosuppressive therapy plays an important role. The impact on cardiovascular outcomes is less well defined than in general population. This work is a revaluation of the clinical approach to dyslipidemia in kidney transplant based on the more recent Guide Lines and literature. The use of statins in an adult transplanted population (eventually associated with ezetimibe) is safe and is a good compromise in terms of a cost/benefit analysis. Other hypolipidemic drugs are not usually suggested for the high incidence of side effects. Lifestyle changes are taking more and more relevance, and in the pediatric population is the only therapeutic act suggested. PMID- 27960022 TI - Preventing nephropathy in type 2 diabetes. PMID- 27960023 TI - [Diabetes after Kidney Transplantation]. AB - Abnormal glucose metabolism is one of the most important complication encountered after renal transplantation. Besides the well-known type 2 diabetes mellitus, there are other two abnormal conditions that must be mentioned, high fasting plasma glucose and impaired glucose tolerance. The last one is often misdiagnosed because it needs an oral glucose tolerance (OGT), rarely used in clinical practice. The 15-30% of patients on waiting list of renal transplantation have impaired glucose tolerance. Therefore OGT should be performed in non-diabetic patients and when glycosylated hemoglobin is > 5.8 %. At 1 year after renal transplantation, about 15% of patients develops de novo diabetes, 28% after 3 years. Besides traditional risk factors, a primary role is played by immunosuppressive drugs because they reduce both the synthesis and peripheral activity of insulin. Hence the therapy of diabetes after renal transplantation must look at the cautious management of immunosuppressive therapy, in particular of the drugs like corticosteroids and tacrolimus. In most cases, either reducing or weaning these drugs can help us to achieve an improving of glucose metabolism. PMID- 27960024 TI - [Hyperuricemia and Gout]. AB - Already known to ancient Egyptians, gout is one of the first diseases which have been described as a clinical entity. To date, gout is the most common form of inflammatory arthritis. Gout is defined by the deposition of monosodium urate crystals within tissues, causing episodes of acute arthritis and the development of tophi, nephrolithiasis, and urate nephropathy. Hyperuricemia, i.e. levels of serum uric acid above 6.8 mg / dL(404mol/L), is a condition necessary, yet not sufficient for gout to develop. The increasing incidence of risk factors such as hypertension, obesity, and renal failure together with an ever-growing life expectancy has led in recent decades to a significant increase in gout prevalence, which has more than doubled when compared to the 1960s. This article addresses the issue of gout by highlighting the role played by the kidneys in uric acid homeostasis; the clinical effect of crystal deposition in tissues, including the kidney; the more recent guidelines on diagnosis and management strategies, with special regard to the use of old and new drugs in renal patients. PMID- 27960025 TI - [Pancreas and islet transplantation: clinical indications and clinical results]. PMID- 27960026 TI - The Impact of a Topical Sexual Enhancement Cream on the Female Sexual Response and Its Relationship to Clitoral Blood Flow. AB - OBJECTIVE: The aim of this investigation was to determine, through two Investigational Review Board (IRB)-approved studies, if a new topical vasodilating cream (NTVC; Life Science Enhancement Corporation, Pittsburgh PA) could improve female sexual response. Study I subjectively evaluated sexual female response as accessed by a modification of the Female Intervention Efficacy Index (FIEI). FIEI was developed at the University of California as an immediate outcome measure of medical intervention to treat female sexual dysfunction.1 In Study II, 10 randomly selected positive responders from Study I were subsequently analyzed objectively with clitoral plethysmography in order to determine the effect of the NTVC and placebo on blood flow.2 RESULTS: In the subjective Study I (81 patients ranging in age from 18 to 63), a positive response trend for the NTVC was demonstrated compared to the placebo. In the objective Study II, 10 randomly selected patients who responded positive in Study I were objectively evaluated for response of increased blood flow in the clitoris after application of both the NTVC and placebo. The clitoral blood flow was shown to have increased with statistical significance for the NTVC in all 10 patients compared to the placebo, with the NTVC exhibiting an average 69% increase in clitoral blood flow. CONCLUSIONS: The female sexual response is complex. In the subjective Study I, the NTVC demonstrated positive trends for enhanced lubrication, genital sensation, intercourse, and overall sexual experience. In the objective Study II, 10 of the positive subjective responders from Study I were randomly selected to evaluate their response to the NTVC compared to the placebo. This was done via Doppler plethysmography (DP). All 10 patients demonstrated a statistically significant response rate for increase in clitoral blood flow using the NTVC compared to the placebo, with an average blood flow increase of 69%. This portion of the investigation demonstrates a significant positive end organ response to the NTVC. The positive subjective trends combined with the significant and substantial increase in clitoral blood flow may result in enhanced female sexual satisfaction. PMID- 27960027 TI - Visualization of 5-HT Receptors Using Radioligand-Binding Autoradiography. AB - Described in this unit are techniques to visualize the majority of serotonin (5 hydroxytryptamine, 5-HT) receptor subtypes in sections of frozen brain tissue using receptor autoradiography. Protocols for brain extraction and sectioning, radioligand exposure, autoradiogram generation, and data quantification are provided, as are the optimal incubation conditions for the autoradiographic visualization of receptors using agonist and antagonist radioligands. (c) 2016 by John Wiley & Sons, Inc. PMID- 27960028 TI - Overview on Research and Clinical Applications of Optogenetics. AB - Optogenetics is a method that uses light to control cells in living tissue, typically neurons, that have been modified to express light-sensitive ion channels and pumps. The approach facilitates neuromodulation in brain preparations and freely moving animals with unmatched spatial and temporal resolution. This optogenetics overview describes the vast array of light sensitive proteins available and the methods used to deliver them to tissue and modulate them with light. How these methods have so far enhanced our knowledge of fundamental neuroscience and psychiatric disease will be discussed as well as how they may contribute to drug discovery in the future. Finally, the potential rewards and risks of therapeutic gene transfer of optogenetic proteins in humans will be considered. (c) 2016 by John Wiley & Sons, Inc. PMID- 27960029 TI - Stability of Drugs, Drug Candidates, and Metabolites in Blood and Plasma. AB - Determination of drug or drug metabolite concentrations in biological samples, particularly in serum or plasma, is fundamental to describing the relationships between administered dose, route of administration, and time after dose for achieving the optimal clinical response. While a well-characterized, accurate analytical method is needed to define these parameters, it must also be established that the analyte concentration in the sample at the time of analysis is identical to the concentration at sample acquisition. This is necessitated by the fact that drugs and their metabolites are susceptible to degradation in samples due to metabolism or to physical and chemical processes, resulting in a lower measured concentration than was in the original sample. Careful examination of analyte stability during processing and storage and, if necessary, adjustment of procedures and conditions to maximize stability, are a critical component of method validation to ensure the accuracy of the data. The protocols provided in this unit address the stability of the analytes in whole blood and blood-derived samples prior to sample preparation for analysis. Issues addressed include sample acquisition, processing of whole blood, and storage of blood-derived samples. (c) 2016 by John Wiley & Sons, Inc. PMID- 27960031 TI - Functional Studies of Sodium Channels: From Target to Compound Identification. AB - Over the last six decades, voltage-gated sodium (Nav ) channels have attracted a great deal of scientific and pharmaceutical interest, driving fundamental advances in both biology and technology. The structure and physiological function of these channels have been extensively studied; clinical and genetic data have uncovered their implication in diseases such as epilepsy, arrhythmias, and pain, bringing them into focus as current and future drug targets. While different techniques have been established to record the activity of Nav channels, proper determination of their properties still presents serious challenges, depending upon the experimental conditions and the desired subtype of channel to be characterized. The aim of this unit is to review the characteristics of Nav channels, their properties, the cells in which they can be studied, and the currently available techniques. Topics covered include the determination of Nav channel biophysical properties as well as the use of toxins to discriminate between subtypes using electrophysiological or optical methods. Perspectives on the development of high-throughput screening assays with their advantages and limitations are also discussed to allow a better understanding of the challenges encountered in voltage-gated sodium channel preclinical drug discovery. (c) 2016 by John Wiley & Sons, Inc. PMID- 27960032 TI - NGWA News. PMID- 27960030 TI - Detection of Receptor Heteromerization Using In Situ Proximity Ligation Assay. AB - Although G protein-coupled receptor (GPCR) heteromerization has been extensively demonstrated in vitro using heterologous cells that overexpress epitope-tagged receptors, their presence in endogenous systems is less well established. This is because a criterion to identify receptor heteromerization is the demonstration that the two interacting receptors are present not only in the same cell but also in the same subcellular compartment in close enough proximity to allow for direct receptor-receptor interaction. This has been difficult to study in native tissues due to a lack of sensitive and selective tools not only capable of detecting low abundance proteins but also of demonstrating that they are in sufficiently close proximity to interact. The latter can be achieved using a proximity ligation assay (PLA). Detailed in this unit are protocols for demonstrating the presence of GPCR heteromers in endogenous cells as well as animal and human tissues, the controls required for these assays, and troubleshooting tips. (c) 2016 by John Wiley & Sons, Inc. PMID- 27960033 TI - Ten years of orangutan-related wildlife crime investigation in West Kalimantan, Indonesia. AB - Poaching for the pet trade is considered one of the main threats to orangutan survival, especially to the Bornean species (Pongo pygmaeus). However, there have been few attempts to quantify the number of individuals taken from the wild or to evaluate the drivers of the trade. Most orangutan poaching is thought to be opportunistic in nature, occurring in conjunction with deforestation for large scale agriculture. Using data from our long-term wildlife crime field investigation program collected from 2004 to 2014, we evaluated the prevalence of orangutan poaching and its spatial distribution in and around Gunung Palung National Park, in the regencies (districts) of Ketapang and Kayong Utara, West Kalimantan, Indonesia. Over the project period, investigators uncovered 145 cases of orangutans being illegally held captive for the pet trade. There was a significant correlation between the extent of oil palm and the number of cases reported from each sub-district in the landscape, supporting the widely held hypothesis that orangutan poaching is opportunistic, and we found no evidence of orangutan trading rings (i.e., international traders) targeting Gunung Palung National Park. Over the past decade, there only has been one prosecution of orangutan trading in West Kalimantan, and weak law enforcement by Indonesian authorities remains the most significant challenge in addressing wildlife trade. We offer four recommendations to address this, including that Indonesia dedicate at least $3 million more to addressing orangutan poaching and trade in Kalimantan and that the country's wildlife protection laws be revised and strengthened, with the new laws socialized to a wide audience, including government officials and all aspects of civil society. As oil palm begins to expand into Africa, this study also may help predict how this will affect gorillas, chimpanzees, and bonobos, encouraging proactive conservation action. PMID- 27960035 TI - Shape change in mouthguard sheets during thermoforming - part 2: effect of the anteroposterior position of the model on mouthguard thickness. AB - BACKGROUND/AIM: Mouthguards can reduce the risk of sports-related injuries, but the sheet material and thickness have a large effect on their efficacy and safety. The aim of this study was to investigate the effect of model position in the molding machine on the reduction in mouthguard thickness. MATERIALS AND METHODS: Ethylene vinyl acetate sheets and olefin copolymer sheets were used for thermoforming by a pressure- or a vacuum-forming machine. The working model was trimmed to the height of 25 mm at the maxillary central incisor and 20 mm at maxillary first molar. For both pressure forming and vacuum forming, the model was placed with the anterior rim of the model positioned 40, 30, 25, 20, or 10 mm from the front of the sheet frame. An additional test was carried out at 50 mm for vacuum forming. The sheet thickness after fabrication was determined for the incisal edge, labial surface, and buccal surface using a specialized caliper. The difference of the model position on the reduction in thickness in each forming device and sheet material was analyzed by one-way analysis of variance and Bonferroni's multiple comparison tests. RESULT: The reductions in thickness at the incisal edge and labial surface were about -60% and -50%, respectively, for the distance of 25 mm from the front of forming table. That position was the same as the height of the anterior part of the model for each molding machine and sheet material. The anterior thickness after molding became greater as the distance between the model and the sheet frame became smaller. CONCLUSION: The results showed that the thickness reduction was large when the distance from the model to the frame was small. This demonstrates the importance of centering the sheet and the model to achieve the most stable molding when positioning the model in the forming unit. PMID- 27960034 TI - Leukemogenic kinase FIP1L1-PDGFRA and a small ubiquitin-like modifier E3 ligase, PIAS1, form a positive cross-talk through their enzymatic activities. AB - Fusion tyrosine kinases play a crucial role in the development of hematological malignancies. FIP1L1-PDGFRA is a leukemogenic fusion kinase that causes chronic eosinophilic leukemia. As a constitutively active kinase, FIP1L1-PDGFRA stimulates downstream signaling molecules, leading to cellular proliferation and the generation of an anti-apoptotic state. Contribution of the N-terminal FIP1L1 portion is necessary for FIP1L1-PDGFRA to exert its full transforming activity, but the underlying mechanisms have not been fully characterized. We identified PIAS1 as a FIP1L1-PDGFRA association molecule by yeast two-hybrid screening. Our analyses indicate that the FIP1L1 portion of FIP1L1-PDGFRA is required for efficient association with PIAS1. As a consequence of the association, FIP1L1 PDGFRA phosphorylates PIAS1. Moreover, the kinase activity of FIP1L1-PDGFRA stabilizes PIAS1. Therefore, PIAS1 is one of the downstream targets of FIP1L1 PDGFRA. Moreover, we found that PIAS1, as a SUMO E3 ligase, sumoylates and stabilizes FIP1L1-PDGFRA. In addition, suppression of PIAS1 activity by a knockdown experiment resulted in destabilization of FIP1L1-PDGFRA. Therefore, FIP1L1-PDGFRA and PIAS1 form a positive cross-talk through their enzymatic activities. Suppression of sumoylation by ginkgolic acid, a small molecule compound inhibiting a SUMO E1-activating enzyme, also destabilizes FIP1L1-PDGFRA, and while the tyrosine kinase inhibitor imatinib suppresses FIP1L1-PDGFRA dependent cell growth, ginkgolic acid or siRNA of PIAS1 has a synergistic effect with imatinib. In conclusion, our results suggest that sumoylation by PIAS1 is a potential target in the treatment of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. PMID- 27960036 TI - Emerin self-assembly mechanism: role of the LEM domain. AB - At the nuclear envelope, the inner nuclear membrane protein emerin contributes to the interface between the nucleoskeleton and the chromatin. Emerin is an essential actor of the nuclear response to a mechanical signal. Genetic defects in emerin cause Emery-Dreifuss muscular dystrophy. It was proposed that emerin oligomerization regulates nucleoskeleton binding, and impaired oligomerization contributes to the loss of function of emerin disease-causing mutants. We here report the first structural characterization of emerin oligomers. We identified an N-terminal emerin region from amino acid 1 to amino acid 132 that is necessary and sufficient for formation of long curvilinear filaments. In emerin monomer, this region contains a globular LEM domain and a fragment that is intrinsically disordered. Solid-state nuclear magnetic resonance analysis identifies the LEM beta-fragment as part of the oligomeric structural core. However, the LEM domain alone does not self-assemble into filaments. Additional residues forming a beta structure are observed within the filaments that could correspond to the unstructured region in emerin monomer. We show that the delK37 mutation causing muscular dystrophy triggers LEM domain unfolding and increases emerin self assembly rate. Similarly, inserting a disulfide bridge that stabilizes the LEM folded state impairs emerin N-terminal region self-assembly, whereas reducing this disulfide bridge triggers self-assembly. We conclude that the LEM domain, responsible for binding to the chromatin protein BAF, undergoes a conformational change during self-assembly of emerin N-terminal region. The consequences of these structural rearrangement and self-assembly events on emerin binding properties are discussed. PMID- 27960037 TI - Influence of working model angle on the formation of a pressure-formed mouthguard. AB - BACKGROUND/AIM: Custom-made mouthguards are fabricated on working models. However, the influence of the working model to the mouthguard characteristics has not been clearly established. The aim of this study was to examine the influence of the angle of the working model on the formation of a pressure-formed mouthguard. MATERIALS AND METHODS: Mouthguard sheets of 3.8 mm ethylene vinyl acetate were pressure-formed onto working models. The angle of the working model formed by the labial surface of the central incisor and the base of the working model was set at 85 degrees , 90 degrees , and 95 degrees . The thickness of the mouthguard was measured at the labial surface of the central incisor, and the buccal and occlusal surfaces of the first molar. Differences in the thickness of the mouthguards were analyzed by two-way analysis of variance. RESULTS: Mouthguard thickness varied among the measured regions of the central incisors and first molars (P < 0.01). The thickness at the labial surface of the central incisor and buccal surface of the first molar was greatest for mouthguards formed using the working model with the angle set at 85 degrees (P < 0.01). CONCLUSIONS: The angle of the working model at the labial surface of the central incisor and the base of the working model should be maintained at an acute angle (e.g., 85 degrees ) to control the thickness at the central incisors and the first molars of pressure-formed mouthguards. PMID- 27960038 TI - Computational modelling of clot development in patient-specific cerebral aneurysm cases: comment. PMID- 27960039 TI - Physiologic and pathophysiologic roles of interaction between C-type lectin-like receptor 2 and podoplanin: partners from in utero to adulthood. AB - A platelet activation receptor, C-type lectin-like receptor 2 (CLEC-2), has been identified as a receptor for a platelet-activating snake venom, rhodocytin. CLEC 2 protein is highly expressed in platelets/megakaryocytes, and at lower levels in liver Kupffer cells. Recently, podoplanin has been revealed as an endogenous ligand for CLEC-2. Podoplanin is expressed in certain types of tumor cells, fibroblastic reticular cells (FRCs) in lymph nodes, kidney podocytes, and lymphatic endothelial cells, but not in vascular endothelial cells. CLEC-2 in platelets cannot have access to podoplanin under normal conditions, but they interact with each other under pathologic conditions or during developmental stages, and play various pathophysiologic roles. CLEC-2 facilitates hematogenous metastasis of podoplanin-expressing tumors. During development, the interaction between CLEC-2 and podoplanin in lymphatic endothelial cells or neuroepithelial cells facilitates blood-lymphatic vessel separation and cerebrovascular patterning and integrity, respectively. In adulthood, platelet CLEC-2 binding to FRCs is crucial for maintenance of the integrity of high endothelial venules in lymph nodes. Podoplanin-expressing FRC-like cells have recently been identified in the bone marrow, and facilitate megakaryocyte proliferation and proplatelet formation by binding to megakaryocyte CLEC-2. Podoplanin is inducibly expressed in liver monocytes and keratinocytes during Salmonella infection and wound healing, and regulates thrombus formation in the liver and controlled wound healing, respectively. By binding to unknown ligands, platelet CLEC-2 regulates the maintenance of vascular integrity during inflammation, thrombus stability under flow, and maintenance of quiescence of hematopoietic stem cells. Podoplanin is expressed in various cells, and additional roles of the CLEC-2-podoplanin interaction will be revealed in the future. PMID- 27960040 TI - Prediction and prioritization of neoantigens: integration of RNA sequencing data with whole-exome sequencing. AB - The importance of neoantigens for cancer immunity is now well-acknowledged. However, there are diverse strategies for predicting and prioritizing candidate neoantigens, and thus reported neoantigen loads vary a great deal. To clarify this issue, we compared the numbers of neoantigen candidates predicted by four currently utilized strategies. Whole-exome sequencing and RNA sequencing (RNA Seq) of four non-small-cell lung cancer patients was carried out. We identified 361 somatic missense mutations from which 224 candidate neoantigens were predicted using MHC class I binding affinity prediction software (strategy I). Of these, 207 exceeded the set threshold of gene expression (fragments per kilobase of transcript per million fragments mapped >=1), resulting in 124 candidate neoantigens (strategy II). To verify mutant mRNA expression, sequencing of amplicons from tumor cDNA including each mutation was undertaken; 204 of the 207 mutations were successfully sequenced, yielding 121 mutant mRNA sequences, resulting in 75 candidate neoantigens (strategy III). Sequence information was extracted from RNA-Seq to confirm the presence of mutated mRNA. Variant allele frequencies >=0.04 in RNA-Seq were found for 117 of the 207 mutations and regarded as expressed in the tumor, and finally, 72 candidate neoantigens were predicted (strategy IV). Without additional amplicon sequencing of cDNA, strategy IV was comparable to strategy III. We therefore propose strategy IV as a practical and appropriate strategy to predict candidate neoantigens fully utilizing currently available information. It is of note that different neoantigen loads were deduced from the same tumors depending on the strategies applied. PMID- 27960041 TI - Intravital Forster resonance energy transfer imaging reveals osteopontin-mediated polymorphonuclear leukocyte activation by tumor cell emboli. AB - Myeloid-derived suppressor cells (MDSCs) cause paraneoplastic leukemoid reactions and facilitate tumor cell metastasis. However, the interaction of MDSCs with tumor cells in live tissue has not been adequately visualized. To accomplish this task, we developed an intravital imaging protocol to observe metastasized tumor cells in mouse lungs. For visualization of the activation of MDSCs, bone marrow cells derived from transgenic mice expressing a Forster resonance energy transfer biosensor for ERK were implanted into host mice. Under a two-photon excitation microscope, numerous polymorphonuclear cells (PMNs) were found to infiltrate the lungs of tumor-bearing mice in which 4T1 mammary tumor cells were implanted into the footpads. By Forster resonance energy transfer imaging, we found ERK activation in PMNs around the 4T1 tumor emboli in the lungs. Because antibody array analysis implied the involvement of osteopontin (OPN) in the metastasis of 4T1 cells, we further analyzed the effect of OPN knockdown. The OPN knockdown in 4T1 cells did not affect the cell growth, but markedly suppressed lung metastasis of 4T1 cells and ERK activation in PMNs in the lung. Intravenous injection of recombinant OPN restored the lung metastasis of OPN-deficient 4T1 cells, suggesting that OPN functioned in a paracrine manner. It has been reported that ERK activation of neutrophils causes NETosis and that PMNs promote metastasis of tumor cells by NETosis. In agreement with previous reports, the NETosis inhibitor DNase I inhibited lung metastasis of 4T1 cells. These observations suggest that OPN promotes metastasis of 4T1 cells by activating PMNs and inducing NETosis. PMID- 27960042 TI - Obesity, physical activity and traumatic dental injuries in adolescents from East London. AB - BACKGROUND/AIMS: Evidence on the interplay between obesity, physical activity and traumatic dental injuries (TDIs) is still inconclusive and heavily based on cross sectional studies. The aim of this study was to explore the interrelationship of obesity and physical activity at age 11-12 years with TDI at age 15-16-years among schoolchildren from East London. MATERIALS AND METHOD: Data were analysed regarding 598 adolescents who participated in phases I and III of the Research with East London Adolescents Community Health Survey (RELACHS), a longitudinal, school-based study of adolescents in East London. Participants reported their level of physical activity and their height and weight were measured to estimate body mass index Z-scores (according to the UK growth reference) when they were 11 12 years old. Oral clinical examinations were conducted to assess TDI, overjet and lip coverage when participants were 15-16 years old. The associations of obesity and physical activity with TDI were evaluated in crude and adjusted models using binary logistic regression. RESULTS: Overall, 22.6% of adolescents were obese and 7.2% exercised for 7 h or more a week at baseline, while 18.1% of adolescents had experienced TDI by age 15-16 years. Physical activity (7+ hours per week) was significantly associated with TDI (odds ratio: 2.19; 95% confidence interval: 1.08-4.43) in the crude model. However, no significant associations were found between obesity and TDI (1.18; 95% CI: 0.72-1.93) or physical activity and TDI (1.96; 95% CI: 0.94-4.07) in adjusted models. CONCLUSION: This study found no evidence of any associations of obesity and physical activity with TDI among adolescents from East London. PMID- 27960043 TI - Incorporation of log odds of positive lymph nodes into the AJCC TNM classification improves prediction of survival in oral cancer. AB - OBJECTIVES: To assess the prognostic performance of a new N classification that incorporates the log odds of positive lymph nodes (LODDS) into the routinely used pathological N classification for oral squamous cell carcinoma (OSCC) patients. DESIGN: Retrospective cohort study utilising LODDS into pN category was performed, and the AJCC TNM stage and T-New N-M stage were compared with respect to 5-year disease-specific survival (DSS) rates. The discriminability was evaluated from the linear trend chi-square test, Akaike information criterion (AIC) and Harrell's c-statistic. SETTING: Medical centrer in Taiwan. PARTICIPANTS: A total of 463 patients received primary surgery and neck dissection between 2004 and 2013 for OSCC. MAIN OUTCOME MEASURES: The discriminability for 5-year DSS rates. RESULTS: The median follow-up period was 54 months, the mean patient age was 54 +/- 11 years and 428 patients (92.4%) were male. The patients with higher LODDS had worse 5-year DSS rates. Incorporation of LODDS into the prognostic model based on the seventh edition of the TNM classification significantly improved discriminative performance for 5-year DSS with a lower AIC (1883 versus 1897), and higher prediction accuracy (Harrell's c statistic: 0.768 versus 0.764). CONCLUSIONS: By utilising a merger of the LODDS and pN classifications to create a new N classification has better discriminatory and predictive ability than pathological TNM staging and could help identify high risk patients for intense adjuvant therapy. PMID- 27960045 TI - Editorial: Tell me, how do you define person-centredness? PMID- 27960046 TI - Radiographic evidence of traumatic injuries to primary incisors without accompanying clinical signs. AB - BACKGROUND/AIMS: In epidemiological studies, traumatic dental injuries in children are usually determined from clinical signs or parents' reports. Radiographs are used in dental trauma centers but not in field surveys. The aim of this study was to evaluate the proportion of patients who present with radiographic evidence of trauma without any clinical signs of a history of TDI. METHODS: The prevalence of traumatic dental injuries was assessed from the records of 674 preschool children at their first visit to a private dental practice. Evidence of the history of traumatic dental injuries was based on clinical and radiographic signs. Clinical signs consisted of enamel fracture, crown fracture with dentin exposure (with or without pulp exposure), internal coronal discoloration, and the presence of a draining sinus. Radiographic signs were as follows: root fracture, pulp canal obliteration, tube-like mineralization, internal resorption, arrested dentin deposition, external inflammatory root resorption, and a periapical radiolucency. RESULTS: Of the 674 children, 408 (60.5%) presented with clinical evidence of traumatic dental injuries. This included 195 (28.9%) with enamel fracture as the sole sign. Seventeen (2.5%) had radiographic signs of traumatic dental injuries without any clinical evidence of trauma, increasing the prevalence of traumatic dental injuries by 2.5-63.0%. Fifteen of these were pulp canal obliteration, one root fracture, and one with arrested dentin deposition. Clinical signs of traumatic dental injuries without radiographic evidence of trauma were present in 275 (40.8%) patients. CONCLUSION: Traumatic dental injuries based on both clinical and radiographic evidence are more prevalent than when based on clinical examination only. PMID- 27960044 TI - Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population. AB - Genome-wide association studies have linked genetic variants at 9p21.3 to the risk of multiple cancers. However, the roles of genetic variants at 9p21.3 in esophageal squamous cell carcinoma (ESCC) development are largely unknown. We evaluated the genetic variants at 9p21.3 reported in cancer genome-wide association studies with a case-control study including 2139 ESCC cases and 2273 controls in a Chinese population, and measured the mRNA expression levels of MTAP, CDKN2A, CDKN2B, and CDKN2B-AS1 in paired ESCC tumor and adjacent normal tissues. We found that the G allele of rs7023329 was significantly associated with a decreased risk of ESCC with a per-allele odds ratio of 0.84 (95% confidence interval, 0.77-0.91; P = 2.95 * 10-5 ). The rs7023329-G allele was related to a high expression of MTAP (P = 0.020). The rs1679013-C allele was independently associated with an increased risk of ESCC with a per-allele odds ratio of 1.12 (95% confidence interval, 1.01-1.24; P = 0.039). We also found that the carriers of the risk allele rs1679013-C had lower expression of CDKN2B than non-carriers (P = 0.035). CDKN2B was also significantly downregulated in ESCC tumor tissues compared with adjacent normal tissues (P = 3.50*10-5 ). Therefore, our findings indicate that genetic variants at 9p21.3 may modulate the expression of MTAP and CDKN2B and contribute to ESCC susceptibility. This may further advance our understanding of the 9p21.3 locus in cancer development. PMID- 27960047 TI - Incidence and risk factors of late recurrence in patients with salivary gland cancer. AB - OBJECTIVES: Recurrence in the late post-treatment period is relatively common in salivary gland cancer (SGC), but risk factors and survival associated with late recurrence have been rarely studied. We investigated the incidence and risk factors of SGC recurrence >5 years after treatment and associated survival. DESIGN: A retrospective cohort study. SETTING: University hospital. PARTICIPANTS: A total of 240 patients with previously untreated SGC who underwent definitive treatment. MAIN OUTCOME MEASURES: Late recurrence was defined as recurrence at a time point >5 years after treatment. Univariate and multivariable analyses were used to identify the association of clinicopathologic factors with recurrence free survival (RFS), cancer-specific survival (CSS) and late recurrence. RESULTS: Of the 240 patients, 124 (51.7%) patients developed recurrence during a median follow-up of 160.0 months (range 121.5-282.2 months). Sixteen (6.7%) patients developed late recurrence; the median time to late recurrence was 92.5 months (range 60.2-138.3 months) after treatment. Multivariable analysis showed that primary site, histologic grade and N classification were independent variables of both RFS and CSS (P < 0.05 each). Extraparenchymal extension was also an independent variable of CSS (P = 0.022). In addition, a non-parotid tumour location was a significant factor for late recurrence in multivariable analysis (P = 0.017). The median overall survival after the development of late recurrence was 79.7 months (range 0.2-163.4 months), significantly longer than that after early recurrence (19.7 months) (P = 0.043). CONCLUSION: Late recurrence occurs in some SGC patients. Long-term close surveillance may be required for patients with non-parotid SGC. PMID- 27960048 TI - Artificial neural networks predict the incidence of portosplenomesenteric venous thrombosis in patients with acute pancreatitis. AB - : Essentials Predicting the occurrence of portosplenomesenteric vein thrombosis (PSMVT) is difficult. We studied 72 patients with acute pancreatitis. Artificial neural networks modeling was more accurate than logistic regression in predicting PSMVT. Additional predictive factors may be incorporated into artificial neural networks. SUMMARY: Objective To construct and validate artificial neural networks (ANNs) for predicting the occurrence of portosplenomesenteric venous thrombosis (PSMVT) and compare the predictive ability of the ANNs with that of logistic regression. Methods The ANNs and logistic regression modeling were constructed using simple clinical and laboratory data of 72 acute pancreatitis (AP) patients. The ANNs and logistic modeling were first trained on 48 randomly chosen patients and validated on the remaining 24 patients. The accuracy and the performance characteristics were compared between these two approaches by SPSS17.0 software. Results The training set and validation set did not differ on any of the 11 variables. After training, the back propagation network training error converged to 1 * 10-20 , and it retained excellent pattern recognition ability. When the ANNs model was applied to the validation set, it revealed a sensitivity of 80%, specificity of 85.7%, a positive predictive value of 77.6% and negative predictive value of 90.7%. The accuracy was 83.3%. Differences could be found between ANNs modeling and logistic regression modeling in these parameters (10.0% [95% CI, -14.3 to 34.3%], 14.3% [95% CI, -8.6 to 37.2%], 15.7% [95% CI, -9.9 to 41.3%], 11.8% [95% CI, -8.2 to 31.8%], 22.6% [95% CI, -1.9 to 47.1%], respectively). When ANNs modeling was used to identify PSMVT, the area under receiver operating characteristic curve was 0.849 (95% CI, 0.807-0.901), which demonstrated better overall properties than logistic regression modeling (AUC = 0.716) (95% CI, 0.679-0.761). Conclusions ANNs modeling was a more accurate tool than logistic regression in predicting the occurrence of PSMVT following AP. More clinical factors or biomarkers may be incorporated into ANNs modeling to improve its predictive ability. PMID- 27960049 TI - Effect of bisphosphonates on root resorption after tooth replantation - a systematic review. AB - BACKGROUND/AIM: Replantation of avulsed teeth may lead to root resorption. Bisphosphonates (BPs), a class of drugs of used to treat resorptive diseases of the bone such as osteoporosis and Paget's disease, have been observed to exert an antiresorptive effect on periodontal bone as well. The antiresorptive properties of BPs could prove them useful in preventing root resorption of replanted avulsed teeth. The aim of this systematic review was to analyze and summarize the currently available literature concerning the use of BPs in preventing root resorption of avulsed teeth. MATERIALS AND METHODS: PubMed/MEDLINE, Google Scholar, ISI Web of Knowledge, and Embase databases were searched using keywords 'bisphosphonate', 'replantation', and 'tooth'. Quality assessment of each study was carried out. In addition, general characteristics and outcomes of each study were summarized. RESULTS: After exclusion of 116 irrelevant articles, 10 animal studies were included in this review. The majority of the studies suggest that surface application of zoledronate or alendronate reduces root resorption of replanted teeth in animal models. Surface treatment with etidronate had no significant effect on root resorption, and intracanal etidronate accelerated resorption. CONCLUSION: Surface application of zoledronate and alendronate reduces root resorption of replanted teeth in animal models. However, the efficacy of intracanal usage of BPs is still debatable. PMID- 27960050 TI - 8-Oxo-7,8-dihydroadenine and 8-Oxo-7,8-dihydroadenosine-Chemistry, Structure, and Function in RNA and Their Presence in Natural Products and Potential Drug Derivatives. AB - A description and history of the role that 8-oxo-7,8-dihydroadenine (8-oxoAde) and 8-oxo-7,8-dihydroadenosine (8-oxoA) have in various fields has been compiled. This Review focusses on 1) the formation of this oxidatively generated modification in RNA, its interactions with other biopolymers, and its potential role in the development/progression of disease; 2) the independent synthesis and incorporation of this modified nucleoside into oligonucleotides of RNA to display the progress that has been made in establishing its behavior in biologically relevant systems; 3) reported synthetic routes, which date back to 1890, along with the progress that has been made in the total synthesis of the nucleobase, nucleoside, and their corresponding derivatives; and 4) the isolation, total synthesis, and biological activity of natural products containing these moieties as the backbone. The current state of research regarding this oxidatively generated lesion as well as its importance in the context of RNA, natural products, and potential as drug derivatives is illustrated using all available examples reported to date. PMID- 27960051 TI - Identification and characterization of GmPDIL7, a soybean ER membrane-bound protein disulfide isomerase family protein. AB - : Most proteins synthesized in the endoplasmic reticulum (ER) possess intramolecular and intermolecular disulfide bonds, which play an important role in the conformational stability and function of proteins. Hence, eukaryotic cells contain protein disulfide bond formation pathways such as the protein disulfide isomerase (PDI)-ER oxidoreductin 1 (Ero1) system in the ER lumen. In this study, we identified soybean PDIL7 (GmPDIL7), a novel soybean ER membrane-bound PDI family protein, and determined its enzymatic properties. GmPDIL7 has a putative N terminal signal sequence, a thioredoxin domain with an active center motif (CGHC), and a putative C-terminal transmembrane region. Likewise, we demonstrated that GmPDIL7 is ubiquitously expressed in soybean tissues and is localized in the ER membrane. Furthermore, GmPDIL7 associated with other soybean PDI family proteins in vivo and GmPDIL7 mRNA was slightly upregulated under ER stress. The redox potential of recombinant GmPDIL7 expressed in Escherichia coli was -187 mV, indicating that GmPDIL7 could oxidize unfolded proteins. GmPDIL7 exhibited a dithiol oxidase activity level that was similar to other soybean PDI family proteins. However, the oxidative refolding activity of GmPDIL7 was lower than other soybean PDI family proteins. GmPDIL7 was well oxidized by GmERO1. Taken together, our results indicated that GmPDIL7 primarily plays a role as a supplier of disulfide bonds in nascent proteins for oxidative folding on the ER membrane. DATABASE: The nucleotide sequence data for the GmPDIL7 cDNA are available in the DNA Data Bank of Japan (DDBJ) databases under the accession numbers LC158001. ENZYME: Protein disulfide isomerase: EC 5.3.4.1. PMID- 27960052 TI - Asymmetric Light Excitation for Photodetectors Based on Nanoscale Semiconductors. AB - A photodetector is a key device to extend the cognition fields of mankind and to enrich information transfer. With the advent of emerging nanomaterials and nanophotonic techniques, new explorations and designs for photodetection have been constantly put forward. Here, we report the asymmetric-light-excitation photoelectric detectors with symmetric electrical contacts working at zero external bias. Unlike conventional photodetectors with symmetric contacts which are usually used as photoconductors or phototransistors showing no photocurrent at zero bias, in this device, the asymmetric-light-excitation structure is designed to ensure that only one Schottky junction between two metallic electrodes and semiconductors is illuminated. In this condition, a device can contribute to a photocurrent without bias. Furthermore, incident light with global illumination will be redistributed by the top Au patterns on devices. The achievement of detectors benefits from the designed redistribution of optical field on specific Schottky barriers within optically active regions and effective carrier collection, producing unidirectional photocurrent for large-scale detection applications. The response mechanisms, including excitations under different polarizations, wavebands, and tilted incidences, were systematically elaborated. Device performances including photocurrent, dynamic response, and detectivity were also carefully measured, demonstrating the possibility for applications in high-speed imaging sensors or integrated optoelectronic systems. The concept of asymmetric-light-excitation photodetectors shows wider availability to other nanomaterials for modern optoelectronics. PMID- 27960053 TI - Starch-Based Biological Microlasers. AB - Microlasers with good biocompatibility are of great significance to the detection of tiny changes in biological systems. Most current biolasers were realized through the introduction of biomaterials into various external resonators, resulting in an increase of difficulties in application. Here, we used starch as the host to build dye@starch microlasers by encapsulating guest organic laser dye into the interhelical structure of starch granules. The as-prepared dye@starch system with high transparency and ultrasmooth spherical surface functions as an efficient whispering gallery mode resonator for low threshold lasing. The obtained laser signal is closely related to the structural transformation of the starch matrix. Our results would provide a deep insight into the relationship between biostructure and lasing properties, facilitating the monitoring of the structural variances in biological processes through lasing signals. PMID- 27960054 TI - Role of Salt and Water in the Plasticization of PDAC/PSS Polyelectrolyte Assemblies. AB - In this work, we investigate the effect of salt and water on plasticization and thermal properties of hydrated poly(diallyldimethylammonium chloride) (PDAC) and poly(sodium 4-styrenesulfonate) (PSS) assemblies via molecular dynamics simulations and modulated differential scanning calorimetry (MDSC). Commonly, both water and salt are considered to be plasticizers of hydrated polyelectrolyte assemblies. However, the simulation results presented here show that while water has a plasticizing effect, salt can also have an opposite effect on the PE assemblies. On one hand, the presence of salt ions provides additional free volume for chain motion and weakens PDAC-PSS ion pairing due to electrostatic screening, which contributes toward plasticization of the complex. On the other hand, salt ions bind water in their hydration shells, which decreases water mobility and reduces the plasticization by hydration. Our MDSC results connect the findings to macroscopic PE plasticization and the glass-transition-like thermal transition Ttr under controlled PE hydration and salt content. This work identifies and characterizes the dual nature of salt both as plasticizer and hardener of PE assemblies and maps the interconnection of the influence of salt with the degree of hydration in the system. Our findings provide insight into the existing literature data, bear fundamental significance in understanding of hydrated polyelectrolyte assemblies, and suggest a direct means to tailor the mechanical characteristics of PE assemblies via interplay of water and salt. PMID- 27960055 TI - In Situ Atomic-Scale Probing of the Reduction Dynamics of Two-Dimensional Fe2O3 Nanostructures. AB - Atomic-scale structural dynamics and phase transformation pathways were probed, in situ, during the hydrogen-induced reduction of Fe2O3 nanostructure bicrystals using an environmental transmission electron microscope. Reduction commenced with the alpha-Fe2O3 -> gamma-Fe2O3 phase transformation of one part of the bicrystal, resulting in the formation of a two-phase structure of alpha-Fe2O3 and gamma Fe2O3. The progression of the phase transformation into the other half of the bicrystalline Fe2O3 across the bicrystalline boundary led to the formation of a single-crystal phase of gamma-Fe2O3 with concomitant oxygen-vacancy ordering on every third {422} plane, followed by transformation into Fe3O4. Further reduction resulted in the coexistence of Fe3O4, FeO, and Fe via the transformation pathway Fe3O4 -> FeO -> Fe. The series of phase transformations was accompanied by the formation of a Swiss-cheese-like structure, induced by the significant volume shrinkage occurring upon reduction. These results elucidated the atomistic mechanism of the reduction of Fe oxides and demonstrated formation of hybrid structures of Fe oxides via tuning the phase transformation pathway. PMID- 27960057 TI - Site-Selective Surface-Enhanced Raman Detection of Proteins. AB - Strategies for protein detection via surface-enhanced Raman spectroscopy (SERS) currently exploit the formation of randomly generated hot spots at the interfaces of metal colloidal nanoparticles, which are clustered together by intrusive chemical or physical processes in the presence of the target biomolecule. We propose a different approach based on selective and quantitative gathering of protein molecules at regular hot spots generated on the corners of individual silver nanocubes in aqueous medium at physiological pH. Here, the protein, while keeping its native configuration, experiences an intense local E-field, which boosts SERS efficiency and detection sensitivity. Uncontrolled signal fluctuations caused by variable molecular adsorption to different particle areas or inside clustered nanoparticles are circumvented. Advanced electron microscopy analyses and computational simulations outline a strategy relying on a site selective mechanism with superior Raman signal enhancement, which offers the perspective of highly controlled and reproducible routine SERS detection of proteins. PMID- 27960056 TI - Chemical Identification at the Solid-Liquid Interface. AB - Solid-liquid interfaces are decisive for a wide range of natural and technological processes, including fields as diverse as geochemistry and environmental science as well as catalysis and corrosion protection. Dynamic atomic force microscopy nowadays provides unparalleled structural insights into solid-liquid interfaces, including the solvation structure above the surface. In contrast, chemical identification of individual interfacial atoms still remains a considerable challenge. So far, an identification of chemically alike atoms in a surface alloy has only been demonstrated under well-controlled ultrahigh vacuum conditions. In liquids, the recent advent of three-dimensional force mapping has opened the potential to discriminate between anionic and cationic surface species. However, a full chemical identification will also include the far more challenging situation of alike interfacial atoms (i.e., with the same net charge). Here we demonstrate the chemical identification capabilities of dynamic atomic force microscopy at solid-liquid interfaces by identifying Ca and Mg cations at the dolomite-water interface. Analyzing site-specific vertical positions of hydration layers and comparing them with molecular dynamics simulations unambiguously unravels the minute but decisive difference in ion hydration and provides a clear means for telling calcium and magnesium ions apart. Our work, thus, demonstrates the chemical identification capabilities of dynamic AFM at the solid-liquid interface. PMID- 27960058 TI - Chemical vs Electrochemical Formation of Li2CO3 as a Discharge Product in Li O2/CO2 Batteries by Controlling the Superoxide Intermediate. AB - The Li-O2/CO2 battery with high capacity has recently been proposed as a new protocol to convert CO2. However, the fundamental mechanism for the reaction still remains hazy. Here, we investigated the discharge processes of Li-O2/CO2 (70%/30%) batteries in two solvents, dimethyl sulfoxide (DMSO) and 1,2 dimethoxyethane (DME). During discharge, both solvents initially show the reduction of oxygen. However, afterward, the solvent affects the reaction pathways of superoxide species by solvating Li+ with different strength, depending on the so-called donor number. More precisely, the initial formation of CO4*- is favored in DMSO at the expense of lithium superoxide formation that we observed in DME. Despite the different intermediate processes, X-ray diffraction showed that Li2CO3 was the final discharge product in both solvents. Moreover, we observed that CO2 cannot be reduced within the electrochemical stability window of DMSO and DME. PMID- 27960059 TI - Organic Ion-Pair Charge-Transfer (IPCT) Nanoparticles: Synthesis and Photoinduced Electrochromism. AB - We report fabrication of photoinduced-electrochromic (or photochromic) organic nanoparticles that can be regarded as a new class of photoswitchable nanomaterials. Ion association between dicationic benzyl viologen (BzV2+) and tetraphenylborate anion (TPB-) in water produces organic ion-pair charge-transfer type (IPCT) nanoparticles with a mean diameter of 15-20 nm. Electrostatic binding of BzV2+ with TPB- results in the prominent appearance of a new broad absorption band at 400-550 nm, which can be assign to the CT transition between these species. The IPCT nanoparticles show an interesting photoinduced electrochromic behavior caused by the electron transfer (ET) from TPB- to BzV2+, giving an intense blue-color dispersion. The feed charge stoichiometry (= [TPB-]/(2 * [BzV2+])) does not influence the kinetics of the photoinduced electrochromism, but it remarkably controls the reverse ET reaction (or retention time) in the nanoparticles; in the case of neutral stoichiometry, a very long-lived ET state can be observed, which is mainly due to decomposition of the oxidized TPB (sacrificial donor) and the resultant absence of the counterpart of benzyl viologen radical cations (BzV+*) for back ET reaction. On the other hand, the excess presence of TPB- does not cause the decomposition of oxidized TPB in the nanoparticle, making the reverse ET reaction faster, but a moderately long-lived ET state is still observable, which is probably originated from efficient electron diffusion or transport between molecules inside the nanoparticle. PMID- 27960060 TI - Toward a Quantitative Understanding of the Reduction Pathways of a Salt Precursor in the Synthesis of Metal Nanocrystals. AB - Despite the pivotal role played by the reduction of a salt precursor in the synthesis of metal nanocrystals, it is still unclear how the precursor is reduced. The precursor can be reduced to an atom in the solution phase, followed by its deposition onto the surface of a growing nanocrystal. Alternatively, the precursor can adsorb onto the surface of a growing nanocrystal, followed by reduction through an autocatalytic process. With Pd as an example, here we demonstrate that the pathway has a correlation with the reduction kinetics involved. Our quantitative analyses of the reduction kinetics of PdCl42- and PdBr42- by ascorbic acid at room temperature in the absence and presence of Pd nanocubes, respectively, suggest that PdCl42- was reduced in the solution phase while PdBr42- was reduced on the surface of a growing nanocrystal. Our results also demonstrate that the reduction pathway of PdBr42- by ascorbic acid could be switched from surface to solution by raising the reaction temperature. PMID- 27960061 TI - Hydration Leads to Efficient Reactions of the Carbonate Radical Anion with Hydrogen Chloride in the Gas Phase. AB - The carbonate radical anion CO3*- is a key intermediate in tropospheric anion chemistry. Despite its radical character, only a small number of reactions have been reported in the literature. Here we investigate the gas-phase reactions of CO3*- and CO3*-(H2O) with HCl under ultrahigh vacuum conditions. Bare CO3*- forms OHCl*- with a rate constant of 4.2 * 10-12 cm3 s-1, which corresponds to an efficiency of only 0.4%. Hydration accelerates the reaction, and ligand exchange of H2O against HCl proceeds with a rate of 2.7 * 10-10 cm3 s-1. Quantum chemical calculations reveal that OHCl*- is best described as an OH* hydrogen bonded to Cl , while the ligand exchange product is Cl-(HCO3*). Under tropospheric conditions, where CO3*-(H2O) is the dominant species, Cl-(HCO3*) is efficiently formed. These reactions must be included in models of tropospheric anion chemistry. PMID- 27960062 TI - In Situ Growth Strategy to Integrate Up-Conversion Nanoparticles with Ultrasmall CuS for Photothermal Theranostics. AB - In the theranostic field, a near-infrared (NIR) laser is located in the optical window, and up-conversion nanoparticles (UCNPs) could be potentially utilized as the imaging agents with high contrast. Meanwhile, copper sulfide (CuS) has been proposed as a photothermal agent with increased temperature under a NIR laser. However, there is still no direct and effective strategy to integrate the hydrophobic UCNPs with CuS until now. Herein, we propose an in situ growth routine based on the hydrophobic core/shell UCNPs combined with ultrasmall water soluble CuS triggered by single 808 nm NIR irradiation as the theranostic platform. Hydrophobic NaYF4:Yb,Er@NaYF4,Nd,Yb could be turned hydrophilic with highly dispersed and biocompatible properties through conjunction with transferred dopamine. The as-synthesized ultrasmall CuS (3 and 7 nm) served as a stable photothermal agent even after several laser-on/off cycles. Most importantly, comparing with the mix routine, the in situ growth routine to coat UCNPs with CuS is meaningful, and the platform is uniform and stable. Green luminescence-guided hyperthermia could be achieved under a single 808 nm laser, which was evidenced by in vitro and in vivo assays. This nanoplatform is applicable as a bioimaging and photothermal antitumor agent, and the in situ growth routine could be spread to other integration processes. PMID- 27960063 TI - Comment on "Meditation Programs for Psychological Stress and Well-Being". PMID- 27960064 TI - Multiple-Locus Variable Number Tandem Repeat Analysis of Klebsiella pneumoniae: Comparison with Pulsed-Field Gel Electrophoresis. AB - AIM: To assess whether multiple-locus variable-number tandem repeat analysis (MLVA) could replace pulsed-field gel electrophoresis (PFGE) for genotyping of Klebsiella pneumoniae, this study was conducted to compare the typeability, discriminatory power, and concordance of these methods. MATERIALS AND METHODS: We used the nine variable number tandem repeat (VNTR) loci scheme to test its suitability for differentiating 114 ESBL-producing K. pneumoniae isolates collected from different clinical specimens in three hospitals of Tehran, Iran between April and December 2011. PFGE with XbaI was performed and the results were compared with those obtained by typing with MLVA. RESULTS: MLVA and PFGE yielded 44 and 64 types, respectively. Simpson's Diversity Index of MLVA was 0.896 (a 95% confidence interval of 0.850-0.942) and of PFGE was 0.962 (a 95% confidence interval of 0.943-0.981). Congruence between PFGE and MLVA was low. The adjusted Wallace coefficient of PFGE to MLVA was 0.946; however, MLVA was less able to predict PFGE type (32.5%). A range of 2-12 alleles was identified at VNTR loci with Simpson's diversity values between 0.017 and 0.818. CONCLUSION: MLVA is a PCR-based typing method and is much easier and more rapid in comparison to PFGE. These data indicate that the MLVA typing scheme used in this study is discriminative and reliable for typing of K. pneumoniae. However, optimization of the VNTR markers is required to improve the discriminatory power of the method. PMID- 27960065 TI - Toward a Better Compression for DNA Sequences Using Huffman Encoding. AB - Due to the significant amount of DNA data that are being generated by next generation sequencing machines for genomes of lengths ranging from megabases to gigabases, there is an increasing need to compress such data to a less space and a faster transmission. Different implementations of Huffman encoding incorporating the characteristics of DNA sequences prove to better compress DNA data. These implementations center on the concepts of selecting frequent repeats so as to force a skewed Huffman tree, as well as the construction of multiple Huffman trees when encoding. The implementations demonstrate improvements on the compression ratios for five genomes with lengths ranging from 5 to 50 Mbp, compared with the standard Huffman tree algorithm. The research hence suggests an improvement on all such DNA sequence compression algorithms that use the conventional Huffman encoding. The research suggests an improvement on all DNA sequence compression algorithms that use the conventional Huffman encoding. Accompanying software is publicly available (AL-Okaily, 2016 ). PMID- 27960066 TI - Effectiveness of Shin'iseihaito in Asthmatic Patients with Upper Airway Diseases: A Retrospective Cohort Study. AB - BACKGROUND: Severe asthma is often associated with sinonasal diseases. Shin'iseihaito is a Japanese traditional herbal medicine, which is used to treat rhinosinusitis. However, its effectiveness in the treatment of asthma has not been elucidated. OBJECTIVE: The aims of this study were to examine the effectiveness of Shin'iseihaito in asthmatic patients with upper airway disease and to identify the characteristics of responders. METHODS: The medical records were retrospectively analyzed of asthmatic patients concomitant with upper airway disease in the outpatient department who had been administered Shin'iseihaito at least once from September 2011 to February 2015. They were classified into responders and non-responders, and the differences in characteristics were compared between the two groups. RESULTS: Shin'iseihaito was effective in 21/40 (52.5%) patients. There was no significant difference between responders and non responders with regard to age, sex, or age of asthma onset. However, the frequency of aspirin intolerance, the treatment step of asthma, and serum immunoglobulin E levels were significantly higher in responders than they were in non-responders (p = 0.022, p = 0.017, and p = 0.017, respectively). The frequency of occurrence of concomitant eosinophilic chronic rhinosinusitis was not significantly different in both groups. CONCLUSION: Shin'iseihaito could be a potential alternative for the treatment of asthma in patients with upper airway diseases. PMID- 27960068 TI - Monitoring and Preventing Congenital Zika Syndrome. PMID- 27960067 TI - Do Patients and Oncologists Discuss the Cost of Cancer Treatment? An Observational Study of Clinical Interactions Between African American Patients and Their Oncologists. AB - PURPOSE: Financial toxicity negatively affects patients with cancer, especially racial/ethnic minorities. Patient-oncologist discussions about treatment-related costs may reduce financial toxicity by factoring costs into treatment decisions. This study investigated the frequency and nature of cost discussions during clinical interactions between African American patients and oncologists and examined whether cost discussions were affected by patient sociodemographic characteristics and social support, a known buffer to perceived financial stress. Methods Video recorded patient-oncologist clinical interactions (n = 103) from outpatient clinics of two urban cancer hospitals (including a National Cancer Institute-designated comprehensive cancer center) were analyzed. Coders studied the videos for the presence and duration of cost discussions and then determined the initiator, topic, oncologist response to the patient's concerns, and the patient's reaction to the oncologist's response. RESULTS: Cost discussions occurred in 45% of clinical interactions. Patients initiated 63% of discussions; oncologists initiated 36%. The most frequent topics were concern about time off from work for treatment (initiated by patients) and insurance (initiated by oncologists). Younger patients and patients with more perceived social support satisfaction were more likely to discuss cost. Patient age interacted with amount of social support to affect frequency of cost discussions within interactions. Younger patients with more social support had more cost discussions; older patients with more social support had fewer cost discussions. CONCLUSION: Cost discussions occurred in fewer than one half of the interactions and most commonly focused on the impact of the diagnosis on patients' opportunity costs rather than treatment costs. Implications for ASCO's Value Framework and design of interventions to improve cost discussions are discussed. PMID- 27960070 TI - Comparison of Two Surface Cooling Devices for Temperature Management in a Neurocritical Care Unit. AB - Fever increases mortality and morbidity and length of stay in neurocritically ill patients. Various methods are used in the neuroscience intensive care unit (NSICU) to control fever. Two such methods involve the Arctic Sun hydrogel wraps and the Gaymar cooling wraps. The purpose of our study was to compare these two methods in neurocritical care patients who had temperature >37.5 degrees C for more than three consecutive hours and that was refractory to standard treatments. Data of patients requiring cooling wraps for treatment of hyperthermia at an NSICU at an academic, tertiary referral center were retrospectively reviewed. The average temperature before cooling was 38.5 degrees C +/- 0.38 degrees C and 38.4 degrees C +/- 0.99 degrees C for the Gaymar and Arctic Sun groups, respectively (p = 0.89). The Gaymar group took on average 16 +/- 21.9 hours to reach goal temperature, whereas the Arctic Sun group took 2.22 +/- 1.39 hours (p = 0.08). The average time outside of the target temperature was 57.0 +/- 58.0 hours in the Gaymar group compared with 13.7 +/- 17.1 hours in the Arctic Sun group (p = 0.04). Average duration of using the cooling wraps was similar between the two groups; 81.8% of patients had rebound hyperthermia in the Gaymar group compared with 20% in the Arctic Sun group (p = 0.0089). The Arctic Sun group had a nonsignificant increased incidence of shivering compared with the Gaymar group (40% vs. 18.18%, p = 0.36). We found that Arctic Sun surface cooling device was more efficient in attaining the target temperature, had less incidence of rebound hyperthermia, and was able to maintain normothermia better than Gaymar cooling wraps. The incidence of shivering tended to be more common in the Arctic Sun group. PMID- 27960069 TI - Stability of Chronic Hepatitis-Related Parameters in Serum Samples After Long Term Storage. AB - BACKGROUND: Serum samples are widely used in clinical research, but a comprehensive research of the stability of parameters relevant to chronic hepatitis and the effect of a relatively long-term (up to 10 years) storage on the stability have rarely been studied. AIMS: To investigate the stability of chronic hepatitis-related parameters in serum samples after long-term storage. MATERIALS AND METHODS: The storage stability of common clinical parameters such as total bile acid (TBA), total bilirubin (TBIL), potassium, cholesterol, and protein parameters such as alanine aminotransferase (ALT), creatine kinase (CK), gamma-glutamyltransferase (GGT), albumin, high-density lipoprotein (HDL) and also hepatitis B virus (HBV) DNA, hepatitis C virus (HCV) RNA, hepatitis B surface antigen (HBsAg), and chemokine (C-X-C motif) ligand 10 (CXCL10) were tested in serum samples after storing at -20 degrees C or -70 degrees C for 1, 2, 3, 7, 8, and 10 years. RESULTS: Levels of TBA, TBIL, and protein parameters such as ALT, CK, GGT, HDL, and HBsAg decreased significantly, but levels of potassium and cholesterol increased significantly after long-term storage, whereas blood glucose and triglycerides were stable during storage. HBV DNA remained stable at 70 degrees C but changed at -20 degrees C, whereas HCV RNA was stable after 1-, 2 , and 3-year storage. CXCL10 was still detectable after 8-year storage. CONCLUSIONS: Low temperatures (-70 degrees C/80 degrees C) are necessary for storage of serum samples in chronic hepatitis B research after long-term storage. PMID- 27960071 TI - Association Between TNF-alpha -308G/A Polymorphism and Risk of Immune Thrombocytopenia: A Meta-Analysis. AB - OBJECTIVE: Previous studies have investigated the association between tumor necrosis factor-alpha (TNF-alpha) -308G/A polymorphism and risk of immune thrombocytopenia (ITP), but the reported results have been inconsistent. Thus, a systematic meta-analysis was performed to resolve this discrepancy. METHODS: Electronic databases and the cited references of the obtained published articles were manually searched. Quality assessment of each study was conducted using the Newcastle-Ottawa Scale (NOS). All case-control studies were used to assess the strength of the association. Statistical analysis was performed using Stata version 12.0. RESULTS: Eight high-quality studies, including 947 patients and 1911 controls, were selected for the final meta-analysis. There was no significant association between TNF-alpha -308G/A polymorphism and ITP in overall and Asian populations. However, a significant positive association was observed between them in the dominant genetic model (AA+AG versus GG) in the Caucasian population (OR = 1.35, 95% confidence interval [CI]: 1.07-1.71, PH = 0.173). CONCLUSIONS: Our finding suggested that TNF-alpha -308G/A might be involved in development of ITP in the Caucasian population, but not in the Asian population. Among Caucasians the A allele (AA+AG) was associated with ITP. However, larger scale studies are required to confirm our findings. PMID- 27960073 TI - From bugs to beta cells. AB - Certain microbes in the intestine secrete protein that stimulates the proliferation of beta cells in the pancreas during development. PMID- 27960074 TI - Lectins bring benefits to bones. AB - The discovery that proteins called c-type lectins promote bone growth could lead to new treatments for age-related bone disorders. PMID- 27960072 TI - An alternative splicing switch shapes neurexin repertoires in principal neurons versus interneurons in the mouse hippocampus. AB - The unique anatomical and functional features of principal and interneuron populations are critical for the appropriate function of neuronal circuits. Cell type-specific properties are encoded by selective gene expression programs that shape molecular repertoires and synaptic protein complexes. However, the nature of such programs, particularly for post-transcriptional regulation at the level of alternative splicing is only beginning to emerge. We here demonstrate that transcripts encoding the synaptic adhesion molecules neurexin-1,2,3 are commonly expressed in principal cells and interneurons of the mouse hippocampus but undergo highly differential, cell type-specific alternative splicing. Principal cell-specific neurexin splice isoforms depend on the RNA-binding protein Slm2. By contrast, most parvalbumin-positive (PV+) interneurons lack Slm2, express a different neurexin splice isoform and co-express the corresponding splice isoform specific neurexin ligand Cbln4. Conditional ablation of Nrxn alternative splice insertions selectively in PV+ cells results in elevated hippocampal network activity and impairment in a learning task. Thus, PV-cell-specific alternative splicing of neurexins is critical for neuronal circuit function. PMID- 27960075 TI - A conserved bacterial protein induces pancreatic beta cell expansion during zebrafish development. AB - Resident microbes play important roles in the development of the gastrointestinal tract, but their influence on other digestive organs is less well explored. Using the gnotobiotic zebrafish, we discovered that the normal expansion of the pancreatic beta cell population during early larval development requires the intestinal microbiota and that specific bacterial members can restore normal beta cell numbers. These bacteria share a gene that encodes a previously undescribed protein, named herein BefA (beta Cell Expansion Factor A), which is sufficient to induce beta cell proliferation in developing zebrafish larvae. Homologs of BefA are present in several human-associated bacterial species, and we show that they have conserved capacity to stimulate beta cell proliferation in larval zebrafish. Our findings highlight a role for the microbiota in early pancreatic beta cell development and suggest a possible basis for the association between low diversity childhood fecal microbiota and increased diabetes risk. PMID- 27960078 TI - Dormancy Stems the Tide of Chemotherapy. AB - In this issue of Cancer Cell, Ebinger et al. describe rare, non-cycling blasts in acute lymphoblastic leukemia that combine the phenotypes of dormancy, stemness, and chemo-resistance. This novel in vivo model for dormant blasts will facilitate the dissection of the niche and the development of therapies targeting the leukemic microenvironment. PMID- 27960076 TI - A plasma membrane template for macropinocytic cups. AB - Macropinocytosis is a fundamental mechanism that allows cells to take up extracellular liquid into large vesicles. It critically depends on the formation of a ring of protrusive actin beneath the plasma membrane, which develops into the macropinocytic cup. We show that macropinocytic cups in Dictyostelium are organised around coincident intense patches of PIP3, active Ras and active Rac. These signalling patches are invariably associated with a ring of active SCAR/WAVE at their periphery, as are all examined structures based on PIP3 patches, including phagocytic cups and basal waves. Patch formation does not depend on the enclosing F-actin ring, and patches become enlarged when the RasGAP NF1 is mutated, showing that Ras plays an instructive role. New macropinocytic cups predominantly form by splitting from existing ones. We propose that cup shaped plasma membrane structures form from self-organizing patches of active Ras/PIP3, which recruit a ring of actin nucleators to their periphery. PMID- 27960077 TI - eIF2alpha-mediated translational control regulates the persistence of cocaine induced LTP in midbrain dopamine neurons. AB - Recreational drug use leads to compulsive substance abuse in some individuals. Studies on animal models of drug addiction indicate that persistent long-term potentiation (LTP) of excitatory synaptic transmission onto ventral tegmental area (VTA) dopamine (DA) neurons is a critical component of sustained drug seeking. However, little is known about the mechanism regulating such long lasting changes in synaptic strength. Previously, we identified that translational control by eIF2alpha phosphorylation (p-eIF2alpha) regulates cocaine-induced LTP in the VTA (Huang et al., 2016). Here we report that in mice with reduced p-eIF2alpha-mediated translation, cocaine induces persistent LTP in VTA DA neurons. Moreover, selectively inhibiting eIF2alpha-mediated translational control with a small molecule ISRIB, or knocking down oligophrenin-1-an mRNA whose translation is controlled by p-eIF2alpha-in the VTA also prolongs cocaine induced LTP. This persistent LTP is mediated by the insertion of GluR2-lacking AMPARs. Collectively, our findings suggest that eIF2alpha-mediated translational control regulates the progression from transient to persistent cocaine-induced LTP. PMID- 27960079 TI - Liver Cancer Checks in When Bile Acid Clocks Out. AB - In this issue of Cancer Cell, Kettner et al. identify the disruption of normal circadian rhythmicity as an independent risk factor for hepatocellular carcinoma (HCC) in experimental animals and reveal opposing roles for the nuclear receptors FXR and CAR in disease progression from non-alcoholic fatty liver disease (NAFLD) to HCC. PMID- 27960080 TI - A Novel Link between Inflammation and Cancer. AB - Immune checkpoint-blockade treatments targeting PD-1/PD-L1 have revolutionized cancer therapy. Hence, understanding the regulation of PD-L1 expression has major clinical relevance. In this issue of Cancer Cell, Lim et al. report that inflammation-induced and NF-kappaB-driven expression of deubiquitinating enzyme CSN5 leads to PD-L1 stabilization and immune suppression in tumors. PMID- 27960081 TI - To PFKFB3 or Not to PFKFB3, That Is the Question. AB - In this issue of Cancer Cell, Cantelmo et al. describe how reduction of PFKFB3 enzyme activity can promote vascular normalization. The authors show in turn how this affects vascular permeability and can ultimately improve the efficacy of chemotherapeutic agents. PMID- 27960082 TI - Origins of Brain Tumor Macrophages. AB - The ontogeny of brain-tumor-associated macrophages is poorly understood. New findings indicate that both resident microglia and blood-derived monocytes generate the pool of macrophages that infiltrate brain tumors of either primary or metastatic origin. PMID- 27960083 TI - S63845, an MCL-1 Selective BH3 Mimetic: Another Arrow in Our Quiver. AB - A recent study reports a novel small molecule inhibitor of MCL-1 with efficacy in killing MCL-1-dependent cancer cells in vitro and in vivo. With the advent of S63845, the targeting of BCL-2, BCL-XL, and MCL-1 is now possible in vivo, but optimal clinical use is yet to be determined. PMID- 27960084 TI - Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis. AB - Tumor-secreted extracellular vesicles (EVs) are critical mediators of intercellular communication between tumor cells and stromal cells in local and distant microenvironments. Accordingly, EVs play an essential role in both primary tumor growth and metastatic evolution. EVs orchestrate multiple systemic pathophysiological processes, such as coagulation, vascular leakiness, and reprogramming of stromal recipient cells to support pre-metastatic niche formation and subsequent metastasis. Clinically, EVs may be biomarkers and novel therapeutic targets for cancer progression, particularly for predicting and preventing future metastatic development. PMID- 27960085 TI - Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition. AB - Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and the lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, namely, reverse-engineering precision cancer prevention. PMID- 27960089 TI - Glycerophosphodiesterase GDE2 Promotes Neuroblastoma Differentiation through Glypican Release and Is a Marker of Clinical Outcome. PMID- 27960088 TI - Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment. AB - A destabilized tumor vasculature leads to limited drug delivery, hypoxia, detrimental tumor microenvironment, and even metastasis. We performed a side-by side comparison of ABTAA (Ang2-Binding and Tie2-Activating Antibody) and ABA (Ang2-Blocking Antibody) in mice with orthotopically implanted glioma, with subcutaneously implanted Lewis lung carcinoma, and with spontaneous mammary cancer. We found that Tie2 activation induced tumor vascular normalization, leading to enhanced blood perfusion and chemotherapeutic drug delivery, markedly lessened lactate acidosis, and reduced tumor growth and metastasis. Moreover, ABTAA favorably altered the immune cell profile within tumors. Together, our findings establish that simultaneous Tie2 activation and Ang2 inhibition form a powerful therapeutic strategy to elicit a favorable tumor microenvironment and enhanced delivery of a chemotherapeutic agent into tumors. PMID- 27960087 TI - Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP ribose) Polymerase Inhibitors. AB - Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and beta-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with beta lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and beta-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy. PMID- 27960091 TI - Inflammatory Bowel Disease 2017: Innovations and Changing Paradigms. PMID- 27960093 TI - One-trial overshadowing: Evidence for fast specific fear learning in humans. AB - Adaptive defensive actions necessitate a fear learning system that is both fast and specific. Fast learning serves to minimize the number of threat confrontations, while specific learning ensures that the acquired fears are tied to threat-relevant cues only. In Pavlovian fear conditioning, fear acquisition is typically studied via repetitive pairings of a single cue with an aversive experience, which is not optimal for the examination of fast specific fear learning. In this study, we adopted the one-trial overshadowing procedure from basic learning research, in which a combination of two visual cues is presented once and paired with an aversive electrical stimulation. Using on-line shock expectancy ratings, skin conductance reactivity and startle reflex modulation as indices of fear learning, we found evidence of strong fear after a single conditioning trial (fast learning) as well as attenuated fear responding when only half of the trained stimulus combination was presented (specific learning). Moreover, specificity of fear responding tended to correlate with levels of state and trait anxiety. These results suggest that one-trial overshadowing can be used as a model to study fast specific fear learning in humans and individual differences therein. PMID- 27960086 TI - Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors. AB - We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype. PMID- 27960090 TI - Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush. AB - Traumatic optic neuropathy (TON) is an acute injury of the optic nerve secondary to trauma. Loss of retinal ganglion cells (RGCs) is a key pathological process in TON, yet mechanisms responsible for RGC death remain unclear. In a mouse model of TON, real-time noninvasive imaging revealed a dramatic increase in leukocyte rolling and adhesion in veins near the optic nerve (ON) head at 9 hours after ON injury. Although RGC dysfunction and loss were not detected at 24 hours after injury, massive leukocyte infiltration was observed in the superficial retina. These cells were identified as T cells, microglia/monocytes, and neutrophils but not B cells. CXCL10 is a chemokine that recruits leukocytes after binding to its receptor C-X-C chemokine receptor (CXCR) 3. The levels of CXCL10 and CXCR3 were markedly elevated in TON, and up-regulation of CXCL10 was mediated by STAT1/3. Deleting CXCR3 in leukocytes significantly reduced leukocyte recruitment, and prevented RGC death at 7 days after ON injury. Treatment with CXCR3 antagonist attenuated TON-induced RGC dysfunction and cell loss. In vitro co-culture of primary RGCs with leukocytes resulted in increased RGC apoptosis, which was exaggerated in the presence of CXCL10. These results indicate that leukocyte recruitment in retinal vessels near the ON head is an early event in TON and the CXCL10/CXCR3 axis has a critical role in recruiting leukocytes and inducing RGC death. PMID- 27960094 TI - Metacognitive beliefs in the at-risk mental state: A systematic review and meta analysis. AB - Dysfunctional metacognitive beliefs are common among people with psychosis. In this meta-analysis we examined whether these are also present in people meeting at-risk mental state (ARMS) criteria. We also explored the relationship between metacognitive beliefs and symptoms in the ARMS group. An electronic database search of Ovid MEDLINE, PsycINFO and Embase from inception until August 2016 was conducted using keyword search terms synonymous with ARMS and metacognition. Eligible studies were original research articles that examined metacognitive beliefs using the Metacognitions Questionnaire (MCQ) among people meeting ARMS criteria. Studies included in the meta-analyses also reported comparison MCQ data acquired from healthy controls, help-seeking individuals, or people with psychotic disorders. Eleven eligible studies were identified, reporting data from six unique ARMS samples. People with ARMS did not differ from those with established psychotic disorders on any MCQ subscale, but they reported significantly more dysfunctional metacognitive beliefs than healthy or help seeking controls. Maladaptive metacognitive beliefs were associated with a range of symptoms in ARMS individuals, but evidence for associations with specific subthreshold psychotic phenomena was inconsistent. This evidence indicates how valuable assessment and treatment of dysfunctional metacognitive beliefs may be but suggests that specific aspects of methodology should be addressed. PMID- 27960095 TI - Low pre-treatment end-tidal CO2 predicts dropout from cognitive-behavioral therapy for anxiety and related disorders. AB - Recent clinical trial research suggests that baseline low end-tidal CO2 (ETCO2, the biological marker of hyperventilation) may predict poorer response to cognitive-behavioral therapy (CBT) for anxiety-related disorders. The present study examined the predictive value of baseline ETCO2 among patients treated for such disorders in a naturalistic clinical setting. Sixty-nine adults with a primary diagnosis of a DSM-5 anxiety disorder, obsessive-compulsive disorder, or posttraumatic stress disorder completed a 4-min assessment of resting ETCO2, and respiration rate (the first minute was analyzed). Lower ETCO2 was not associated with a diagnosis of panic disorder, and was associated with lower subjective distress ratings on certain measures. Baseline ETCO2 significantly predicted treatment dropout: those meeting cutoff criteria for hypocapnia were more than twice as likely to drop out of treatment, and ETCO2 significantly predicted dropout beyond other pre-treatment variables. Weekly measurement suggested that the lower-ETCO2 patients who dropped out were not responding well to treatment prior to dropout. The present results, along with previous clinical trial data, suggest that lower pre-treatment ETCO2 is a negative prognostic indicator for CBT for anxiety-related disorders. It is suggested that patients with lower ETCO2 might benefit from additional intervention that targets respiratory abnormality. PMID- 27960092 TI - The Vascular Impairment of Cognition Classification Consensus Study. AB - INTRODUCTION: Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily comparable, impacting on clinical diagnosis rates and in turn prevalence estimates, research, and treatment. METHODS: The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) involved participants (81% academic researchers) from 27 countries in an online Delphi consensus study. Participants reviewed previously proposed concepts to develop new guidelines. RESULTS: VICCCS had a mean of 122 (98-153) respondents across the study and a 67% threshold to represent consensus. VICCCS redefined VCI including classification of mild and major forms of VCI and subtypes. It proposes new standardized VCI associated terminology and future research priorities to address gaps in current knowledge. DISCUSSION: VICCCS proposes a consensus-based updated conceptualization of VCI intended to facilitate standardization in research. PMID- 27960096 TI - Carbohydrate-based aza-macrocycles by Richman-Atkins cyclization of glucopyranose precursors. AB - 2, 3-Di-omega-halo- as well as 2, 3-di-omega-toluenesulfonamide-alkylated glucopyranoside derivatives were prepared. Their condensation with alpha,omega bis-toluenesulfonamide components under varying Richman-Atkins conditions with alkali carbonate in DMF led to carbohydrate-linked aza-macrocycles displaying 14 , 17-, 18-, 21-, 24-, and 25-membered ring structures. Isomeric aza-macrocylic coronands of 20- as well as 30-membered ring size containing two saccharides could be obtained employing Richman-Atkins condensations of two functionalized sugar building units. PMID- 27960097 TI - Fluorescent mannosides serve as acceptor substrates for glycosyltransferase and sugar-1-phosphate transferase activities in Euglena gracilis membranes. AB - Synthetic hexynyl alpha-D-mannopyranoside and its alpha-1,6-linked disaccharide counterpart were fluorescently labelled through CuAAC click chemistry with 3 azido-7-hydroxycoumarin. The resulting triazolyl-coumarin adducts, which were amenable to analysis by TLC, HPLC and mass spectrometry, proved to be acceptor substrates for alpha-1,6-ManT activities in mycobacterial membranes, as well as alpha- and beta-GalT activities in trypanosomal membranes, benchmarking the potential of the fluorescent acceptor approach against earlier radiochemical assays. Following on to explore the glycobiology of the benign protozoan alga Euglena gracilis, alpha-1,3- and alpha-1,2-ManT activities were detected in membrane preparations, along with GlcT, Glc-P-T and GlcNAc-P-T activities. These studies serve to demonstrate the potential of readily accessible fluorescent glycans as substrates for exploring carbohydrate active enzymes. PMID- 27960098 TI - Enzymatic synthesis of human blood group P1 pentasaccharide antigen. AB - The enzymatic synthesis of biologically important and structurally unique human P1PK blood group type P1 pentasaccharide antigen is described. This synthesis features a three-step sequential one-pot multienzyme (OPME) glycosylation for the stepwise enzymatic chain elongation of readily available lactoside acceptor with cheap and commercially available galactose and N-acetylglucosamine as donor precursors. This enzymatic synthesis provides an operationally simple approach to access P1 pentasaccharide and its structurally related Gb3 and P1 trisaccharide epitopes. PMID- 27960099 TI - Study of cross - relaxation and molecular dynamics in the solid 3 (trifluoromethyl) benzoic acid by solid state NMR off - resonance. AB - Molecular dynamics of the solid 3-(trifluoromethyl) benzoic acid containing proton 1H and fluorine 19F nuclei was explored by the solid-state NMR off - resonance technique. Contrary to the previous experiments the proton nuclei system I relaxed in the off - resonance effective field B->e while fluorine nuclei system S was saturated for short time in comparison to the relaxation time T1I. New cross - relaxation solid - state NMR off - resonance experiments were conducted on a homebuilt pulse spectrometer operating at the on-resonance frequency of 30.2MHz, at the off - resonance frequency varied between 30.2 and 30.6MHz for protons and at the frequency of 28.411MHz for fluorines, respectively. Based on the experimental data the dispersions of the proton off - resonance spin - lattice relaxation rate rhorhoI, the fluorine off - resonance spin - lattice relaxation rate rhorhoS and the cross - relaxation rate sigmarho in the rotating frame were determined. PMID- 27960100 TI - Child pedestrian safety knowledge, behaviour and road injury in Cape Town, South Africa. AB - Pedestrian injuries are a leading cause of death among South African children, and young children residing in low-income communities are more at risk, due to various factors such as inadequate road infrastructure, exposure to traffic due to reliance on walking as a means of transport, and lack of supervision. This study used a cross-sectional, non-randomized self-report survey to assess pedestrian safety knowledge, road-crossing behaviour and pedestrian injuries of primary school children in selected low-income settings in Cape Town. The survey focused on three primary schools that had joined the Safe Kids Worldwide Model School Zone Project and was administered to 536 children aged 6-15 years, in their home language of isiXhosa. Descriptive and bivariate analyses as well as multivariate regression analyses were conducted to investigate potential predictor variables for pedestrian collision severity and unsafe road-crossing behaviour. Walking was the sole form of travel for 81% of the children, with a large proportion regularly walking unsupervised. Children who walk to or from school alone were younger and reported riskier road-crossing behaviour, although children who walk accompanied tended to have higher pedestrian collision severity. "Negligent Behaviour" related to road-crossing was significantly associated with higher pedestrian collision severity, with predictors of "Negligent Behaviour" including the lack of pedestrian safety knowledge and greater exposure to traffic in terms of time spent walking. More than half of the reported pedestrian collisions involved a bicycle, and older boys (10-15 years) were most at risk of experiencing a severe pedestrian injury. The findings substantiate emerging evidence that children in low-income settings are at greater risk for child pedestrian injury, and emphasise the need for evidence based safety promotion and injury prevention interventions in these settings. PMID- 27960101 TI - Sensitivity analyses of stopping distance for connected vehicles at active highway-rail grade crossings. AB - This paper performs sensitivity analyses of stopping distance for connected vehicles (CVs) at active highway-rail grade crossings (HRGCs). Stopping distance is the major safety factor at active HRGCs. A sensitivity analysis is performed for each variable in the function of stopping distance. The formulation of stopping distance treats each variable as a probability density function for implementing Monte Carlo simulations. The result of the sensitivity analysis shows that the initial speed is the most sensitive factor to stopping distances of CVs and non-CVs. The safety of CVs can be further improved by the early provision of onboard train information and warnings to reduce the initial speeds. PMID- 27960103 TI - Examining heterogeneity of obsessive-compulsive disorder: Evidence for subgroups based on motivations. AB - Obsessive-compulsive disorder (OCD) is a heterogeneous illness and evidence suggests that different clinical characteristics may relate to varying treatment outcomes. This study was designed to identify subgroups based on core motivational domains in a clinical sample of individuals with OCD, and to compare groups on clinical characteristics. Cluster analyses identified four subgroups including groups with relatively high or low levels of both harm avoidance (HA) and incompleteness (INC) motivations. A subgroup was identified that demonstrated a "traditional profile" marked by high motivation to avoid harm, and elevated levels of beliefs about responsibility/overestimation of threat. The model also contained a subgroup characterized by high incompleteness, low motivation to avoid harm, and higher levels of perfectionistic beliefs and intolerance of uncertainty. Findings reemphasize that current cognitive and behavioral models of OCD may be enhanced by integrating incompleteness/NJREs. PMID- 27960102 TI - Most suitable mother wavelet for the analysis of fractal properties of stride interval time series via the average wavelet coefficient method. AB - Human gait is a complex interaction of many nonlinear systems and stride intervals exhibiting self-similarity over long time scales that can be modeled as a fractal process. The scaling exponent represents the fractal degree and can be interpreted as a "biomarker" of relative diseases. The previous study showed that the average wavelet method provides the most accurate results to estimate this scaling exponent when applied to stride interval time series. The purpose of this paper is to determine the most suitable mother wavelet for the average wavelet method. This paper presents a comparative numerical analysis of 16 mother wavelets using simulated and real fractal signals. Simulated fractal signals were generated under varying signal lengths and scaling exponents that indicate a range of physiologically conceivable fractal signals. The five candidates were chosen due to their good performance on the mean square error test for both short and long signals. Next, we comparatively analyzed these five mother wavelets for physiologically relevant stride time series lengths. Our analysis showed that the symlet 2 mother wavelet provides a low mean square error and low variance for long time intervals and relatively low errors for short signal lengths. It can be considered as the most suitable mother function without the burden of considering the signal length. PMID- 27960104 TI - Digital RT-PCR method for hepatitis A virus and norovirus quantification in soft berries. AB - Raw fruits may harbour many pathogens of public health concern including enteric viruses, which are the leading cause of foodborne outbreaks. Recently, consumption of soft berries has been associated with increasing reports of norovirus and hepatitis A virus outbreaks in Europe. Due to their low infectious doses and low concentrations in food samples, an efficient and sensitive analytical method is required for virus detection. In this study we explored two different ways to improve the reference method for the detection of enteric viruses in soft fruits (ISO/TS 15216-1; 15216-2): an additional purification step after RNA extraction; and the detection of enteric viral genome by an absolute quantification method (microfluidic digital RT-PCR). Both of these approaches led to an improvement of enteric virus detection in soft berries by greatly lowering PCR inhibition, raising viral extraction efficiencies and enabling validation of controls using pure RNA extracts. The PCR inhibitor removal step can be easily included in the routine method. Absolute quantification by digital RT-PCR may be a relevant alternative method to standardize quantification of enteric viruses in foodstuffs. PMID- 27960106 TI - Aldose reductase deficiency leads to oxidative stress-induced dopaminergic neuronal loss and autophagic abnormality in an animal model of Parkinson's disease. AB - Fungicide exposure causes degeneration of dopaminergic neurons and contributes to Parkinson's disease (PD). Benomyl inhibits enzymes responsible for detoxifying the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde. Aldose reductase (AR) is known as tetrahydrobiopterin (BH4) reductase that generates BH4, a cofactor for tyrosine hydroxylase (TH) involved in dopamine synthesis. AR also acts as an aldehyde reductase involved in detoxifying 3,4 dihydroxyphenylacetaldehyde. In PD patients, the level of AR is significantly lower in the cerebellum. To determine if AR deficiency contributes to PD, AR wild type (AR+/+) and knockout (AR-/-) mice were administrated with 1-methyl-4-phenyl 1,2,3,6- tetrahydropyridine (MPTP). The MPTP-treated AR-/- mice showed more severe behavioral deficits and brain damage than that of AR+/+ mice. Contrary to expectation, under normal or MPTP-treated condition, AR-/- mice showed a significant elevation of BH4 and dopamine in the midbrain, suggesting that either AR does not contribute to BH4 production, or other BH4 synthetic pathways are induced. The AR-/- brain showed upregulation of peroxynitrite, inducible nitric oxide synthase and downregulation of antioxidant enzymes, Cu/Zn superoxide dismutase (SOD) and peroxiredoxin 2 (Prx2), which indicate an increase in oxidative stress. In line with the animal data, pretreating the SH-SY5Y cells with AR inhibitors (Fidarestat or Epalrestat) before MPP+ treatment, increased severe cell death and mitochondrial fragmentation with downregulation of SOD were observed when compared to the MPP+ treatment alone. Cycloxygenase 2 (COX2), which can lead to the oxidation of dopamine, was upregulated in AR-/- brains. Autophagic proteins, beclin-1 and LC3B were also downregulated. The loss of dopaminergic neurons was associated with activation of p-ERK1/2. These findings suggest that AR plays an important role in protecting dopaminergic neuron against neurotoxic metabolites in PD. PMID- 27960105 TI - Evaluation and comparison of diffusion MR methods for measuring apparent transcytolemmal water exchange rate constant. AB - Two diffusion-based approaches, CG (constant gradient) and FEXI (filtered exchange imaging) methods, have been previously proposed for measuring transcytolemmal water exchange rate constant kin, but their accuracy and feasibility have not been comprehensively evaluated and compared. In this work, both computer simulations and cell experiments in vitro were performed to evaluate these two methods. Simulations were done with different cell diameters (5, 10, 20MUm), a broad range of kin values (0.02-30s-1) and different SNR's, and simulated kin's were directly compared with the ground truth values. Human leukemia K562 cells were cultured and treated with saponin to selectively change cell transmembrane permeability. The agreement between measured kin's of both methods was also evaluated. The results suggest that, without noise, the CG method provides reasonably accurate estimation of kin especially when it is smaller than 10s-1, which is in the typical physiological range of many biological tissues. However, although the FEXI method overestimates kin even with corrections for the effects of extracellular water fraction, it provides reasonable estimates with practical SNR's and more importantly, the fitted apparent exchange rate AXR showed approximately linear dependence on the ground truth kin. In conclusion, either CG or FEXI method provides a sensitive means to characterize the variations in transcytolemmal water exchange rate constant kin, although the accuracy and specificity is usually compromised. The non-imaging CG method provides more accurate estimation of kin, but limited to large volume-of interest. Although the accuracy of FEXI is compromised with extracellular volume fraction, it is capable of spatially mapping kin in practice. PMID- 27960108 TI - A technique for evaluating bone ingrowth into 3D printed, porous Ti6Al4V implants accurately using X-ray micro-computed tomography and histomorphometry. AB - This paper investigates the application of X-ray micro-computed tomography (micro CT) to accurately evaluate bone formation within 3D printed, porous Ti6Al4V implants manufactured using Electron Beam Melting (EBM), retrieved after six months of healing in sheep femur and tibia. All samples were scanned twice (i.e., before and after resin embedding), using fast, low-resolution scans (Skyscan 1172; Bruker micro-CT, Kontich, Belgium), and were analysed by 2D and 3D morphometry. The main questions posed were: (i) Can low resolution, fast scans provide morphometric data of bone formed inside (and around) metal implants with a complex, open-pore architecture?, (ii) Can micro-CT be used to accurately quantify both the bone area (BA) and bone-implant contact (BIC)?, (iii) What degree of error is introduced in the quantitative data by varying the threshold values?, and (iv) Does resin embedding influence the accuracy of the analysis? To validate the accuracy of micro-CT measurements, each data set was correlated with a corresponding centrally cut histological section. The results show that quantitative histomorphometry corresponds strongly with 3D measurements made by micro-CT, where a high correlation exists between the two techniques for bone area/volume measurements around and inside the porous network. On the contrary, the direct bone-implant contact is challenging to estimate accurately or reproducibly. Large errors may be introduced in micro-CT measurements when segmentation is performed without calibrating the data set against a corresponding histological section. Generally, the bone area measurement is strongly influenced by the lower threshold limit, while the upper threshold limit has little or no effect. Resin embedding does not compromise the accuracy of micro-CT measurements, although there is a change in the contrast distributions and optimisation of the threshold ranges is required. PMID- 27960107 TI - Forebrain depletion of Rheb GTPase elicits spatial memory deficits in mice. AB - The precise molecular and cellular events responsible for age-dependent cognitive dysfunctions remain unclear. We report that Rheb (ras homolog enriched in brain) GTPase, an activator of mammalian target of rapamycin (mTOR), regulates memory functions in mice. Conditional depletion of Rheb selectively in the forebrain of mice obtained from crossing Rhebf/f and CamKIICre results in spontaneous signs of age-related memory loss, that is, spatial memory deficits (T-maze, Morris water maze) without affecting locomotor (open-field test), anxiety-like (elevated plus maze), or contextual fear conditioning functions. Partial depletion of Rheb in forebrain was sufficient to elicit memory defects with little effect on the neuronal size, cortical thickness, or mammalian target of rapamycin activity. Rheb depletion, however, increased the levels of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), a protein elevated in aging and Alzheimer's disease. Overall, our study demonstrates that forebrain Rheb promotes aging associated cognitive defects. Thus, molecular understanding of Rheb pathway in brain may provide new therapeutic targets for aging and/or Alzheimer's disease associated memory deficits. PMID- 27960110 TI - Drosophila miR-956 suppression modulates Ectoderm-expressed 4 and inhibits viral replication. AB - Small non-coding microRNAs (miRNAs) can modulate the outcome of virus infection. Here we explore the role of miRNAs in insect-virus interactions, in vivo, using the natural Drosophila melanogaster-Drosophila C virus (DCV) model system. Comparison of the miRNA expression profiles in DCV-infected and uninfected flies showed altered miRNA levels due to DCV infection, with the largest change in abundance observed for miR-956-3p. Knockout of miR-956 resulted to delayed DCV induced mortality and decreased viral accumulation compared to wild-type flies. A screen of 84 putative miR-956-3p target genes identified regulation of Ectoderm expressed 4 (Ect4) in miR-956 knockout flies and, separately, DCV infection. In Ect4 knockdown flies DCV-induced mortality occurred more quickly and virus accumulation was increased. Taken together, results suggest that the host protective and antiviral consequences of miR-956 suppression during in vivo infection of D. melanogaster with its natural pathogen DCV is conferred through miR-956-3p induction of its target Ect4. PMID- 27960109 TI - Role of H7 hemagglutinin in murine infectivity of influenza viruses following ocular inoculation. AB - H7 subtype influenza viruses have demonstrated an ocular tropism in humans, causing conjunctivitis and not respiratory symptoms in many infected individuals. However, the molecular determinants which confer ocular tropism are still poorly understood. Here, we used a murine model of ocular inoculation to demonstrate that H7 influenza viruses are more likely to cause infection following ocular exposure than are non-H7 subtype viruses. We included investigation regarding the potential role of several properties of influenza viruses with murine infectivity following ocular inoculation, including virus lineage, pathogenicity, and HA cleavage site composition. Furthermore, we examined the potential contribution of internal proteins to murine ocular infectivity. These studies establish a link between H7 subtype viruses and the risk of heightened infectivity in a mammalian species following ocular exposure, and support the development of non-traditional inoculation methods and models to best understand the human risk posed by influenza viruses of all subtypes. PMID- 27960111 TI - P1-independent replication and local movement of Rice yellow mottle virus in host and non-host plant species. AB - Sobemovirus P1 protein, characterized previously as a suppressor of posttranscriptional gene silencing, is required for systemic virus spread and infection in plants. Mutations in the ORF1 initiation codon do not affect viral replication indicating P1 is not necessary for this process. Wild type, recombinant and P1 deletion mutants of Cocksfoot mottle virus and Rice yellow mottle virus were used to infect oat, rice, wheat, barley, Arabidopsis thaliana and Nicotiana benthamiana plants. Wild type RYMV, RYMV without P1 and RYMV with CfMV P1 were detected in inoculated leaves of all tested plant species. We found that RYMV does not need P1 for replication and for local movement neither in host nor non-host species tested in this study. However, it is crucial for successful systemic spread of the virus in its host plant rice. Moreover, adding CfMV P1 into RYMV genome did not help it to overcome restriction to the inoculated leaf. PMID- 27960112 TI - Digit ratio (2D:4D) and month of birth: A link to the solstitial-melatonin testosterone effect. AB - BACKGROUND: Digit ratio (2D:4D) is a sexually dimorphic trait and its determination in utero is influenced by testosterone. The solstitial-melatonin testosterone hypothesis posits that melatonin inhibits the production of foetal testosterone and melatonin levels are at their lowest in months when light levels are high. AIMS: We test the relationship between 2D:4D, month-of-birth and light levels. STUDY DESIGN: We recruited participants whose year of birth was spread across the 20th Century. SUBJECTS: 323 Polish men and women. OUTCOME MEASURES: Finger lengths, month-of-birth, mean daylight hours per month in and around Poznan, Poland. RESULTS: Our sample was born between 1907 and 1997. In comparison to late-Spring births, late-Autumn births had low right-left 2D:4D (high prenatal testosterone). Regarding light levels, there were significant relationships between low right 2D:4D and right-left 2D:4D (high prenatal testosterone) and long days at the end of the 1st trimester. These relationships were strongest for participants born in the first half of the 20th Century. CONCLUSIONS: Participants born in the late-Autumn and who experienced long days in the 2nd and 3rd prenatal months had low 2D:4D. The effects were strongest for early 20th Century births where photoperiods would be less disrupted by artificial light. PMID- 27960114 TI - Identification and quantification of myosin heavy chain isoforms in bovine and porcine longissimus muscles by LC-MS/MS analysis. AB - To identify and quantify the myosin heavy chain (MHC) isoforms in porcine and bovine longissimus thoracis (LT) muscles, LC-MS/MS and label-free quantification were conducted. 2a, 2x, 2b and slow isoforms were identified in porcine LT muscle, whereas bovine LT muscle contained 2a, 2x and slow isoforms. The highest peak intensity (44.32%) of MHC 2b was observed in porcine LT muscle, whereas the peak intensity of MHC 2a was the highest (71.15%) in bovine LT muscle (p<0.05). MHC-based fiber compositions for porcine and bovine LT were also the highest in types IIB (61.13%) and IIA (61.90%), respectively (p<0.05). Spectral count and peak intensity had positive correlations with MHC-based fiber composition (p<0.01), however the spectral count and peak intensity of total peptides were not acceptable for MHC quantification because of the limited reliability of the protein and common peptide, respectively. Therefore, the peak intensity of unique peptides would be the most acceptable trait for MHC quantification. PMID- 27960113 TI - Tebufenozide induces G1/S cell cycle arrest and apoptosis in human cells. AB - Tebufenozide is a non-steroidal insect growth regulator and is extensively used to control pests, although it is considered to be safe for mammals and environmentally friendly. However, previous studies have found that tebufenozide is cytotoxic to man, although the exact mechanism remains elusive. This study will investigate the apoptotic molecular mechanisms which result from tebufenozide-induced DNA damage in HeLa cells. Our results demonstrate that tebufenozide could trigger arrest in G1/S phase related to a downregulation of cyclin E and cyclin-dependent kinase (CDK) 2 protein. In addition, Western blotting showed apoptosis was associated with the upregulation of p53, Bax and cleaved-PARP, as well as downregulation of Bcl-2 and PARP. Tebufenozide also regulated changes in mitochondrial permeability and reduced mitochondrial number and intracellular ATP production. Briefly, these results suggest that tebufenozide- induces cell cycle arrest and apoptosis through activating p53 protein in a Bax- and Bcl-2-triggered mitochondrial pathway. This work provides some scientific context for the safe use of tebufenozide in agriculture. PMID- 27960115 TI - Interactive effects of temperature and UVB radiation on methane emissions from different organs of pea plants grown in hydroponic system. AB - There is no information on variation of methane (CH4) emissions from plant organs exposed to multiple environmental factors. We investigated the interactive effects of temperature and ultraviolet-B (UVB) radiation on CH4 emissions from different organs of pea (Pisum sativum L. var. UT234 Lincoln). Plants were grown hydroponically under two temperatures (22/18 degrees C and 28/24 degrees C; 16h day/8h night) and two levels of UVB radiation [0 and 5kJm-2 d-1] in controlled environment growth chambers for ten days, after two weeks of initial growth under ambient temperatures. Methane emission, dry mass, growth index, electrical conductivity (EC), pectin, total chlorophyll content, gas exchange and flavonoids were measured in the appropriate plant organs - leaf, stem and root. Higher temperatures increased CH4 emissions, leaf mass ratio, and shoot: root mass ratio. Neither temperature nor UVB had significant effects on leaf, stem, root and total dry mass, EC, pectin, total chlorophyll, as well as specific leaf mass. Among plant organs, there were differences in CH4, EC, pectin and total chlorophyll. Methane and EC were highest for the stem and lowest for the leaf; leaf had highest, but stem had lowest, pectin content; total chlorophyll was highest in the leaf but lowest in the root. Higher temperatures decreased leaf flavonoids, net carbon dioxide assimilation, and water use efficiency. Overall, environmental stressors increased aerobic CH4 emission rates, which varied with plant organs. PMID- 27960116 TI - Facile and fast removal of oil through porous carbon spheres derived from the fruit of Liquidambar formosana. AB - Porous carbon spheres with a diameter of 1-2 cm were prepared via a simple carbonization of the fruit of Liquidambar formosana. After carbonization, the spherical structure and inner finger-like pores were maintained with high resistance to impact. Due to the porous structure and the hydrophobic nature, the carbonized fruit of Liquidambar formosana can float on the water surface and show a super-fast oil or organic solvent sorption ability (sorption saturation can be achieved within 1-2 min). Moreover, about 99% of adsorbed oil can be easily removed from spheres via organic solvent such as ethanol or hexane, which shows good recyclability of samples. In general, considering the low-cost and abundance of raw material collected from nature and the facile synthetic process (only by carbonization), the centimeter-sized porous spheres via the carbonization of fruit of Liquidambar formosana are very promising to be used for the application of oil or organic solvent spill cleanup. PMID- 27960117 TI - Factors controlling groundwater salinization and hydrogeochemical processes in coastal aquifers from southern Spain. AB - In detrital coastal aquifers, seawater and surface water may interact with groundwater in multiple ways. Understanding the interference of water fluxes in this type of environment is essential to effectively manage the groundwater resources in water-stressed regions, such as the Mediterranean coastal fringe. In this research, the characterization of the main hydrogeochemical processes and the interaction between surface water and groundwater in the Marbella-Estepona coastal aquifers (southern Spain) have been carried out by means of the combined use of different hydrogeochemical indicators along with isotope data. The results show that the diversity of source lithologies (peridotite, carbonate and/or metapelitic) substantially conditions the groundwater geochemistry. The analysis of ionic deltas made it possible a preliminary screening of the geochemical reactions that occur in the Marbella-Estepona aquifers, while the Discriminant Analysis allowed for a consistent classification of sampled groundwater types. The dissolution of calcite and dolomite determines the chemical composition of the groundwater from the eastern sector that are more conditioned by the rainwater infiltration. The dissolution of magnesium-bearing minerals (predominantly forming peridotite rocks) is observed in groundwater samples from the western and central sectors, whose chemical composition showed a greater influence of surface water. The spatial analysis of rCl-/Br- in groundwater has permitted to corroborate that saline intrusion is negligible, hardly affecting to its original water quality. The irregularly distributed recharge by precipitation (seasonal effect) and the atmospheric circulation of cloud fronts (coastal/continental effect) explains why most of groundwater sampled is isotopically impoverished with respect to the rainfall signature. The isotope approach also suggests the hydraulic relationship between surface water and groundwater in the study site. A deeper knowledge of spatial hydrogeochemical variations in coastal groundwater and the influence of water sources over them are crucial for a sustainable groundwater management and global change adaptation in equivalent Mediterranean water-stressed regions. PMID- 27960118 TI - Individual differences in nonverbal number skills predict math anxiety. AB - Math anxiety (MA) involves negative affect and tension when solving mathematical problems, with potentially life-long consequences. MA has been hypothesized to be a consequence of negative learning experiences and cognitive predispositions. Recent research indicates genetic and neurophysiological links, suggesting that MA stems from a basic level deficiency in symbolic numerical processing. However, the contribution of evolutionary ancient purely nonverbal processes is not fully understood. Here we show that the roots of MA may go beyond symbolic numbers. We demonstrate that MA is correlated with precision of the Approximate Number System (ANS). Individuals high in MA have poorer ANS functioning than those low in MA. This correlation remains significant when controlling for other forms of anxiety and for cognitive variables. We show that MA mediates the documented correlation between ANS precision and math performance, both with ANS and with math performance as independent variable in the mediation model. In light of our results, we discuss the possibility that MA has deep roots, stemming from a non verbal number processing deficiency. The findings provide new evidence advancing the theoretical understanding of the developmental etiology of MA. PMID- 27960119 TI - Revealing student nurses' perceptions of human dignity through curriculum co design. AB - Dignity is a slippery concept to define - yet it has been at the heart of media and policy debates around the provision of health and social care in recent years; particularly in the United Kingdom following the Mid-Staffordshire scandal and subsequent Francis Inquiry. This paper considers the concept of dignity in care from the perspective of student nurses. Thus, it allows us to discuss how professional nurses-to-be conceptualise dignity and also how they consider it should/could be taught at undergraduate and postgraduate levels of training, and as part of their Continuing Professional Development. It is only through understanding how student nurses conceptualise and experience human dignity, and the giving and receiving of dignity in care, that it will be possible to support its facilitation in the preparation of practitioners. This paper reports on findings from a series of participatory research workshops held with undergraduate nursing students in Scotland in 2013-14 that were designed to engage the students in the development of educational resources to support the teaching of dignity in care within the nursing curriculum. The outputs from each workshop, along with analysis of transcripts of the workshop discussions, demonstrate the value of co-design as a methodology for involving students in the development of interdisciplinary resources. We observed a desire from students to actively enhance their understandings of dignity - to be able to recognise it; to see dignity in care being practiced; to experience providing such care and to have the appropriate tools to reflect on their own experience. Overall, the research revealed a rich understanding of the ways in which human dignity is conceptualised by nursing students as an embodied practice, associated with memory and personal to an individual. It was understood by the students as shifting, experiential and fragile. PMID- 27960120 TI - Negotiating the (bio)medical gaze - Experiences of trans-specific healthcare in Sweden. AB - In Sweden as well as in other western countries persons with trans experiences have to go through a clinical evaluation in order to get access to gender confirming medical procedures. The aim of this study is to analyse care-users' experiences of navigating and negotiating access to gender-confirming medical procedures in Sweden. Biomedicalisation is used as a theoretical framework in order to analyse how technoscientific and neoliberal developments are parts of constructing specific experiences within trans-specific care. Constructivist grounded theory was used to analyse 14 interviews with persons having experiences of, or considering seeking, trans-specific healthcare. The participants experienced trans-specific healthcare as difficult to navigate because of waiting times, lack of support, provider ignorance and relationships of dependency between healthcare-users and providers. These barriers pushed the users to take responsibility for the care process themselves, through ordering hormones from abroad, acquiring medical knowledge and finding alternative support. Based on the participants' experiences, it can be argued that the shift of responsibility from care-providers to users is connected to a lack of resources within trans-specific care, to neoliberal developments within the Swedish healthcare system, but also to discourses that frame taking charge of the care process as an indicator that a person is in need of or ready for care. Thus, access to gender-confirming medical procedures is stratified, based on the ability and opportunity to adopt a charge taking role and on economic and geographic conditions. Based on the results and discussion, we conclude that trans-specific care ought to focus on supporting the care-seekers throughout the medical process, instead of the current focus on verifying the need for care. There is also a need for increased knowledge and financial resources. A separation between legal and medical gender reassignment could contribute to a better relationship between care-providers and care-users and increase the quality of care. PMID- 27960121 TI - The attitudes of pregnant women and midwives towards raised BMI in a maternity setting: A discussion of two repertory grid studies. AB - OBJECTIVES: Weight-related stereotypes may have a detrimental impact on interactions between midwives and pregnant women with a body mass index (BMI) outside the recommended range of 18-30kg/m2. This paper explores the reciprocal construal of midwives and pregnant women with a raised BMI and considers the clinical implications of these constructs. PARTICIPANTS: Ten pregnant women with a BMI>=30kg/m2 and 11 midwives and from an inner city maternity service were recruited. INTERVENTION: Participants provided information that allowed for the creation of a repertory grid; generating psychological constructs (perceptions or attitudes) identifying similarities and differences between pregnant women and midwives across a BMI range. FINDINGS: Midwives were extremely conscious of being perceived as judgemental. They construed all pregnant women as anxious and vulnerable, but attributed characteristics such as "less health-conscious" and "complacent" to those with a raised BMI. The ideal pregnant woman and ideal midwife were typically construed as more likely to have a BMI of 18-30kg/m2. Pregnant women with a BMI<=18kg/m2 were construed as lacking warmth. While midwives differentiated between the elements based on role, the pregnant women construed the elements according to their BMI. Similarly, they construed those with a BMI<=18kg/m2 as having an undesirable personality, and acknowledged weight related stereotypes for those with a raised BMI. CLINICAL IMPLICATIONS: It is possible these constructs impact on the way midwives care for and interact with women. Midwives may be supported through reflective clinical supervision and communication skills training to reduce the perceptions of stigma experienced by women with a raised BMI. It may be beneficial to involve pregnant women with a raised BMI in service development to ensure services meet their needs. PMID- 27960122 TI - A socioecological model of posttraumatic stress among Australian midwives. AB - OBJECTIVE: to develop a comprehensive model of personal, trauma event-related and workplace-related risk factors for posttraumatic stress subsequent to witnessing birth trauma among Australian midwives. DESIGN: a descriptive, cross-sectional design was used. PARTICIPANTS: members of the Australian College of Midwives were invited to complete an online survey. MEASUREMENTS: the survey included items about witnessing a traumatic birth event and previous experiences of life trauma. Trauma symptoms were assessed with the Posttraumatic Stress Disorder Symptom Scale Self-Report measure. Empathy was assessed with the Interpersonal Reactivity Index. Decision authority and psychological demand in the workplace were measured with the Job Content Questionnaire. Variables that showed a significant univariate association with probable posttraumatic stress disorder were entered into a multivariate logistic regression model. FINDINGS: 601 completed survey responses were analysed. The multivariable model was statistically significant and explained 27.7% (Nagelkerke R square) of the variance in posttraumatic stress symptoms and correctly classified 84.1% of cases. Odds ratios indicated that intention to leave the profession, a peritraumatic reaction of horror, peritraumatic feelings of guilt, and a personal traumatic birth experience were strongly associated with probable Posttraumatic Stress Disorder. CONCLUSIONS: risk factors for posttraumatic stress following professional exposure to traumatic birth events among midwives are complex and multi-factorial. Posttraumatic stress may contribute to attrition in midwifery. Trauma-informed care and practice may reduce the incidence of traumatic births and subsequent posttraumatic stress reactions in women and midwives providing care. PMID- 27960123 TI - Management of synchronous liver metastases and the recommendations of the second St. Gallen European Organisation for Research and Treatment of Cancer consensus conference on the management of rectal cancer. PMID- 27960124 TI - Yawning induced by focal electrical stimulation in the human brain. AB - The primary function of yawning is not fully understood. We report a case in which electrical stimulation of the putamen in the human brain consistently elicited yawning. A 46-year-old woman with intractable epilepsy had invasive depth electrode monitoring and cortical stimulation mapping as part of her presurgical epilepsy evaluation. The first two contacts of a depth electrode that was intended to sample the left insula were in contact with the putamen. Stimulation of these contacts at 6mA and 8mA consistently elicited yawning on two separate days. Engagement in arithmetic and motor tasks during stimulation did not result in yawning. When considering the role of the putamen in motor control and its extensive connectivity to cortical and brainstem regions, our findings suggest that it plays a key role in the execution of motor movements necessitated by yawning. Furthermore, given the role of the anterior insula in attention and focused tasks, activation of this area while engaged in arithmetic and motor tasks could inhibit the putaminal processing necessary for yawning. Many have hypothesized the function of yawning; however, it remains debatable whether yawning serves a primarily physiological or communicative function or perhaps both. PMID- 27960125 TI - Evaluating the effect of wood ultrastructural changes from mechanical treatment on kinetics of monomeric sugars and chemicals production in acid bisulfite treatment. AB - Currently, various chemical-mechanical treatments were widely used in biofuel production to achieve high total sugar yields. However, the interaction between two treatments was scarcely investigated. In this study, we employed a ball milling process to create ultrastructural changes for Douglas-fir (Pseudotsuga menziesii) micronized wood powders. The 0, 30, and 60min ball milled wood powders resulted in a crystallinity index of 0.41, 0.21, and 0.10 respectively. It was found that the ultrastructural changes accelerate monomeric sugars production without influencing the yield of sugar degradation products. The optimal acid bisulfite treatment time was substantially decreased from 120min to 40min as the cellulose crystallinity decreased. Meanwhile, total sugar yield increased from 65% to 92% and had a linear relation with a decrease of the cellulose crystallinity. PMID- 27960127 TI - Management of hot flashes in women with breast cancer receiving ovarian function suppression. AB - Most breast cancers express estrogen and/or progesterone receptors, allowing the opportunity to use anti-estrogen therapies, which have demonstrated substantial efficacy in both the metastatic and adjuvant settings. Young premenopausal women with early-stage high-risk or with metastatic hormone-receptor positive breast cancer may benefit from ovarian function suppression in addition to anti-estrogen medications. While these endocrine manipulations have successfully improved breast cancer outcomes, they may lead to a significant proportion of women experiencing vasomotor symptoms. While not life-threatening, vasomotor symptoms adversely impact quality of life and can result in early treatment discontinuation. For these reasons, supportive management of this treatment related toxicity is crucial, and clinicians caring for breast cancer patients and survivors should be familiar with the options available and the data behind them. This manuscript will review the pathophysiology, clinical manifestations, quality of life implications and non-estrogenic management options of vasomotor symptoms for women with breast cancer undergoing estrogen depletion. PMID- 27960126 TI - Associations between community-level disaster exposure and individual-level changes in disability and risk of death for older Americans. AB - Disasters occur frequently in the United States (US) and their impact on acute morbidity, mortality and short-term increased health needs has been well described. However, barring mental health, little is known about the medium or longer-term health impacts of disasters. This study sought to determine if there is an association between community-level disaster exposure and individual-level changes in disability and/or the risk of death for older Americans. Using the US Federal Emergency Management Agency's database of disaster declarations, 602 disasters occurred between August 1998 and December 2010 and were characterized by their presence, intensity, duration and type. Repeated measurements of a disability score (based on activities of daily living) and dates of death were observed between January 2000 and November 2010 for 18,102 American individuals aged 50-89 years, who were participating in the national longitudinal Health and Retirement Study. Longitudinal (disability) and time-to-event (death) data were modelled simultaneously using a 'joint modelling' approach. There was no evidence of an association between community-level disaster exposure and individual-level changes in disability or the risk of death. Our results suggest that future research should focus on individual-level disaster exposures, moderate to severe disaster events, or higher-risk groups of individuals. PMID- 27960128 TI - Effect of donor STAT4 polymorphism rs7574865 on clinical outcomes of pediatric acute leukemia patients after hematopoietic stem cell transplant. AB - STAT4 polymorphism, rs7574865 is linked to various autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Its T minor allele is associated with higher STAT4 mRNA and protein expression, indicating a stronger skewed immune response than the norm. Although widely studied in autoimmune disease patients and the general population, its effect on immunocompromised subjects is still unknown. Especially in situations, i.e. post-hematopoietic stem cell transplantation (post-HSCT), where control of the immune response is crucial. Hence, this study investigates if the presence of the T minor allele in donors would affect immunological response and clinical outcomes post-HSCT. Samples from 161 pediatric patients who underwent allogeneic HSCT for acute leukemia and showed complete chimerism by donor cells were obtained. Six clinical outcomes were investigated; hepatic veno-occlusive disease, acute graft-vs-host disease, chronic graft-vs-host disease, cytomegalovirus (CMV) infection, relapse and overall survival. The TT genotype was found to be significant in the occurrence of CMV infection (P=0.049), showing higher incidence of CMV infection compared to the others. Multivariate analysis confirmed that association of the TT genotype is independent from other variables in CMV infection occurrence (P=0.010). This is the first study on STAT4 polymorphism rs7574865 in allogeneic HSCT as well as immunocompromised patients. As the TT genotype is associated with autoimmune diseases, our results seem at a paradox with current evidence hinting at a different role of STAT4 in normal circumstances versus immunocompromised patients. Further investigation is needed to elicit the reason behind this and discover novel applications for better post-transplant outcomes. PMID- 27960129 TI - Researcher and institutional review board perspectives on the benefits and challenges of reporting back biomonitoring and environmental exposure results. AB - As the number of personal exposure studies expands and trends favor greater openness and transparency in the health sciences, ethical issues arise around reporting back individual results for contaminants without clear health guidelines. Past research demonstrates that research participants want their results even when the health implications are not known. The experiences of researchers and institutional review boards (IRBs) in studies that have reported personal chemical exposures can provide insights about ethical and practical approaches while also revealing areas of continued uncertainty. We conducted semi structured interviews with 17 researchers and nine IRB members from seven personal exposure studies across the United States to investigate their experiences and attitudes about the report-back process. Researchers reported multiple benefits of report-back, including increasing retention and recruitment, advancing environmental health literacy, empowering study participants to take actions to reduce exposures, encouraging shifts in government and industry practices, and helping researchers discover sources of exposure through participant consultation. Researchers also reported challenges, including maintaining ongoing contact with participants, adopting protocols for notification of high exposures to chemicals without health guidelines, developing meaningful report-back materials, and resource limitations. IRB members reported concern for potential harm to participants, such as anxiety about personal results and counterproductive behavior changes. In contrast, researchers who have conducted personal report-back in their studies said that participants did not appear overly alarmed and noted that worry can be a positive outcome to motivate action to reduce harmful exposures. While key concerns raised during the early days of report-back have been substantially resolved for scientists with report back experience, areas of uncertainty remain. These include ethical tensions surrounding the responsibility of researchers to leverage study results and resources to assist participants in policy or community-level actions to reduce chemical exposures, and how to navigate report-back to vulnerable populations. PMID- 27960131 TI - Prognosis of status epilepticus in patients requiring intravenous anesthetic drugs (a single center experience). AB - PURPOSE: There is concern about the safety of anesthetic drugs (IVADs) in the management of status epilepticus (SE). To clarify this aspect, we aimed to assess the factors associated with a poor prognosis in SE requiring anesthetics. METHOD: We analyzed all SE requiring IVADs between October 2011 and December 2015. Demographics, clinical data, etiology, SE duration, indications for sedation, electroencephalography features, complications and the prognosis at discharge were collected. Hypoxic etiology was ruled out. RESULTS: 73 patients needed IVADs. These were indicated as third-line treatment for SE in 58.9%, for decreased level of consciousness resulting from previous treatments in 27.4%, and for the underlying etiology in 13.7%. At discharge 41(56.2%) patients showed a bad outcome and 32 a good outcome. Outcome was poorer in patients with higher STESS (p=0.003), lower level of consciousness (p=0.025), non-convulsive SE in coma (p=0.040), potentially fatal etiology-PFE (p=0.006), longer duration (p=0.026), presence of complications (p=0.022), use of IVADs due to the underlying etiology (p=0.020), and periodic epileptiform discharges on electroencephalography (p=0.032). Following multivariate analysis, SE duration >12h (OR=3.266; 95%CI=1.077-9.908; p=0.037), STESS >=3 (OR=4.816; 95%CI=1.435 16.165; p=0.011), and PFE (OR=3.526; 95%CI=1.184-10.506; p=0.024) were independently associated with a poor functional prognosis. Regarding mortality, duration >12h (OR=7.07; 95%CI=1.836-27.220; p=0.004), low level of consciousness (OR=6.97; 95%CI=1.194-40.718; p=0.031), and presence of complications (OR=21.32; 95%CI=2.440-186.295; p=0.006) were independent predictors of death. CONCLUSIONS: Lengthy duration of SE in patients requiring IVADs is associated with a poorer prognosis and death. A STESS >=3 and the etiology seem mainly related to the functional status at discharge, whereas more severely impaired consciousness and complications during sedation are related to mortality. PMID- 27960130 TI - Is the severe pain after Milligan-Morgan hemorrhoidectomy still currently remaining a major postoperative problem despite being one of the oldest surgical techniques described? A case series of 117 consecutive patients. AB - INTRODUCTION: Surgery is the only curative method of hemorrhoidal disease. Currently the Milligan-Morgan hemorrhoidectomy is still considered the "gold standard", since it is the best performing technique. However, postoperative pain remains a major problem. We analize the postoperative analgesic requirements for this procedure in 117 patients. PRESENTATION OF CASES: Between 2012 and 2013, 117 consecutive patients undergoing Milligan-Morgan hemorroidectomy, with an analysis of sex, age, total vascular anal cushions removed, hospital stay, complications, and relation with postoperative analgesic requirements. Patients with documented allergy to NSAIDs or pyrazolones were excluded. Additionally 23 patients undergoing Milligan-Morgan hemorrhoidectomy associated to internal lateral sphincterotomy were also analyzed. RESULTS: The mean age of patients was 51.7 years. The 50.8% were women and 49.2% men. In 33.3% of cases, one vascular anal cushion was removed, 2 in 39.3%, and 3 in 27.4%. The average stay for the 3 groups was 2.0days. An analgesic dose average of 4.1 by day was given, with opioid requirements in 22.2% of cases. It was statistically significant that as more anal cushions were eliminated was higher the opioids need. No significant difference of opioids use was found regarding patients undergoing sphincterotomy as additional procedure. DISCUSSION: Postoperative pain after a Milligan-Morgan hemorrhoidectomy currently remains a problem for colorectal surgery teams. This involves the use of opioids comparable to other major surgeries, finally causing not negligible days of admission charge. A protocolized analgesic treatment, as we actually do in our center, should be implemented after a Milligan-Morgan hemorrhoidectomy for improving the postoperative period pain management. PMID- 27960132 TI - Compatibility of MRI and FDG-PET findings with histopathological results in patients with focal cortical dysplasia. AB - PURPOSE: The present study aimed to determine if the specific characteristics of fluorodeoxyglucose-positron emission tomography (FDG-PET) analyses of the FCD subgroups were compatible with the magnetic resonance imaging (MRI) and clinical findings of the patients in these subgroups. METHODS: This study included 71 patients who had a presurgical evaluation workup performed due to drug-resistant seizures, who underwent epilepsy surgery, and who were histopathologically diagnosed with FCD. Relationships involving MRI and FDG-PET findings and clinical data from pathological subgroups and patients were assessed. RESULTS: According to the International League Against Epilepsy (ILAE) classifications of FCD, 28 of the patients were type I and 43 were type II. FCD was visible on the MRI scans of 53 patients, and a majority of this group was classified as type II FCD (n=34). Of these 53 patients, FCD was located in the temporal area of 21 patients, the extratemporal area of 29 patients. Of the patients who exhibited FDG-PET hypometabolism (PET-positive), 23 were classified as temporal, 17 as frontal, 11 showed involvement of the posterior cortex. The age of seizure onset was younger in PET-positive patients (p=0.032), and histopathological analyses revealed that 23 patients had type I FCD and 30 patients had type II FCD. CONCLUSION: PET scans reveal a lesion by showing hypometabolism in patients who have refractory epilepsy and an early age of onset with FCD. The lesions of MRI-negative/PET positive FCD patients tend to be localized in the temporal lobe and that FCD may be localized in the frontal lobe of MRI-negative/PET-negative patients. However, the histopathological examinations of MRI-positive/PET-positive, MRI-negative/PET positive, and MRI-negative/PET-negative patients did not exhibit a particular histopathological subtype. PMID- 27960134 TI - Individualised gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: A prospective, observational study. AB - OBJECTIVE: The aim of this study was to evaluate an individualised gonadotrophin starting dose regimen for women with anovulatory infertility. STUDY DESIGN: We included 71 normogonadotrophic anovulatory infertile women in a prospective, observational study. All underwent one ovulation induction cycle in a flexible, low-dose step-up protocol. The gonadotrophin starting dose (75-150IU/day) was individualised according to a nomogram incorporating menstrual cycle pattern (oligo- or amenorrhoea), BMI, and mean ovarian volume. The number of women who fulfilled the criteria for human chorionic gonadotrophin (hCG) administration (one follicle >=17mm or 2-3 follicles >=15mm) was assessed. RESULTS: Of the 50 women (70.4%) who fulfilled the hCG criteria and underwent intrauterine insemination, 34 (47.9%) achieved monofollicular growth and 16 (22.5%) developed 2-3 mature follicles. Seventeen (23.9%) cycles were converted to in vitro fertilisation (IVF) due to the development of >3 mature follicles, and one (1.4%) cycle was cancelled due to risk of ovarian hyperstimulation syndrome. Baseline total antral follicle count was found to be significantly associated with fulfillment of the hCG criteria (OR 0.96, 95% CI: 0.92-0.99, P=0.01). CONCLUSIONS: The nomogram-based dose regimen was not considered suitable for ovulation induction due to a tendency to overestimate the gonadotrophin starting dose. However, the model may serve as a mild IVF regimen, especially in women prone to excessive follicle growth. PMID- 27960133 TI - Increased serum levels of macrophage activation marker sCD163 in Dengue patients. AB - BACKGROUND: Dengue viruses are known to infect and replicate in macrophages. Thus studying the host responsive molecules that are specifically released by macrophages during the course of dengue infection may provide better understanding on dengue immunopathogenesis. Soluble CD163 (sCD163) is a scavenger receptor, highly expressed on macrophages reported to be involved in some viral disease. The participation of sCD163 in dengue is not known. OBJECTIVE: The present study aimed to explore the role of sCD163 as a potential biomarker for predicting dengue disease. STUDY DESIGN: Using a case-control design, 82 dengue subjects consisting of 69 non-severe dengue (NSD) and 13 severe dengue (SD) along with 32 non-dengue other febrile illness (OFI) subjects and 30 healthy subjects were involved in the study. The serum concentration of sCD163 was determined in the study subjects at admission and around defervescence using ELISA. Statistical analysis was done using Mann-Whitney U test andWilcoxon signed rank test. RESULTS: The study recorded a significant increase in the sCD163 serum level at defervescence phase specifically among dengue group compared to OFI. sCD163 was also found to be significantly higher in secondary cases compared to primary at both admission and defervescence. Furthermore,a higher level of sCD163 was also observed in SD compared to NSD cases, although no statistical significance was observed CONCLUSION: The study substantiates the role of macrophage activation in dengue pathogenesis and further study is needed to decipher the exact role of sCD163 in the disease pathogenesis and to explore its potential as a marker for the early prediction of dengue severity. PMID- 27960136 TI - Polyethylene oxide (PEO)-hyaluronic acid (HA) nanofibers with kanamycin inhibits the growth of Listeria monocytogenes. AB - Listeria monocytogenes is well known to cause prosthetic joint infections in immunocompromised patients. In this study, polyethylene oxide (PEO) nanofibers, containing kanamycin and hyaluronic acid (HA), were prepared by electrospinning at a constant electric field of 10kV. PEO nanofibers spun with 0.2% (w/v) HA and 1% (w/v) kanamycin had a smooth, bead-free structure at 30-35% relative humidity. The average diameter of the nanofibers was 83+/-20nm. Attenuated total reflectance (ATR)-Fourier transform infrared (FTIR) spectroscopy indicated that kanamycin was successfully incorporated into PEO/HA matrix. The presence of kanamycin affects the thermal properties of PEO/HA nanofibers, as shown by differential scanning calorimetry (DSC) and thermogravimetric analyses (TGA). The kanamycin-PEO-HA nanofibers (1mg; 47+/-3MUg kanamycin) inhibited the growth of L. monocytogenes EDGe by 62%, as compared with PEO-HA nanofibers, suggesting that it may be used to coat prosthetic implants to prevent secondary infections. PMID- 27960135 TI - Impact of GnRHa pretreatment on the autotransplatation efficacy of cytopreserved rat ovarian tissue. AB - Pre-therapeutic cryopreservation of ovarian tissue and subsequent transplantation after disease remission has recently emerged as an option to restore endocrinal function and preserve fertility for patients subjected to gonadotoxic treatments such as chemotherapy. However, the relatively low survival rate of follicles after grafting the frozen-thawed ovarian tissue largely limited the application of this technique. Gonadotropin-releasing hormone analogues (GnRHa), owing to their endocrinal regulatory effect, have been successfully used for fertility preservation against gonadotoxic conditions such as cytotoxic agents based anti cancer therapy. In this study, we evaluated the potential protective effect of precedent GnRHa treatment before cryopreservation on freezing-thawing related follicular damages using a rat autoxenograft model. We have observed that GnRHa significantly increases the fraction of follicles with normal morphology, while presenting negnigible effect on the physiological recovery of the grafted follicular tissue, as demonstrated by the estrous cycle, folliculogenesis and post-autograft vascularization. Our data implicates that GnRHa pretreatment may effectively increase the efficacy of cryopreservation and the subsequent successful rate of transplantation. PMID- 27960137 TI - Knockdown of HOXA5 inhibits the tumorigenesis in esophageal squamous cell cancer. AB - Homeobox A5 (HOXA5) is a member of the homeobox (HOX) family and was upregulated in many types of tumors. However, its expression and role in esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, the aim of this study was to investigate the expression and function of HOXA5 in ESCC. Our results showed that HOXA5 was highly expressed in ESCC cell lines. The in vitro experiments demonstrated that knockdown of HOXA5 significantly inhibited the proliferation, migration and invasion of ESCC cells. Furthermore, the in vivo experiments showed that knockdown of HOXA5 significantly inhibited the tumor growth of ESCC in mice xenograft model. Finally, sh-HOXA5 inhibited the expression of beta-catenin, cyclin D1 and c-Myc in ESCC cells. Taken together, these data revealed that knockdown of HOXA5 suppressed the proliferation and metastasis partly by interfering with Wnt/beta-catenin signaling pathway in ESCC cells. Therefore, these findings suggest that HOXA5 may be a potential therapeutic target for the treatment of ESCC. PMID- 27960138 TI - Influence of different sizes of composite femora on the biomechanical behavior of cementless hip prosthesis. AB - BACKGROUND: For the biomechanical evaluation of cementless stems different sizes of composite femurs have been used in the literature. However, the impact of different specimen sizes on test results is unknown. METHODS: To determine the potential effect of femur size the biomechanical properties of a conventional stem (CLS Spotorno) were examined in 3 different sizes (small, medium and large composite Sawbones(r)). Primary stability was tested under physiologically adapted dynamic loading conditions measuring 3-dimensional micromotions. For the small composite femur the dynamic load needed to be adapted since fractures occurred when reaching 1700N. Additionally, surface strain distribution was recorded before and after implantation to draw conclusions about the tendency for stress shielding. FINDINGS: All tested sizes revealed similar micromotions only reaching a significant different level at one measurement point. The highest micromotions were observed at the tip of the stems exceeding the limit for osseous integration of 150MUm. Regarding strain distribution the highest strain reduction after implantation was registered in all sizes at the level of the lesser trochanter. INTERPRETATION: Specimen size seems to be a minor influence factor for biomechanical evaluation of cementless stems. However, the small composite femur is less suitable for biomechanical testing since this size failed under physiological adapted loads. For the CLS Spotorno osseous integration is unlikely at the tip of the stem and the tendency for stress shielding is the highest at the level of the lesser trochanter. PMID- 27960140 TI - A highly sensitive fluorescent chemosensor for selective detection of zinc (II) ion based on the oxadiazole derivative. AB - A novel fluorescent chemosensor based on the oxadiazole, 2-(2-hydroxyphenyl)-5-(4 methoxyphenyl)-1,3,4-oxadiazole, was designed and synthesized. The interaction of the oxadiazole with different metal ions had been investigated through UV-vis absorption and fluorescence spectra in 9:1 (v/v) ethanol-water (pH=7.0) solution. The oxadiazole showed a pronounced fluorescence enhancement at 430nm upon addition of Zn2+ in aqueous solution, whereas it had no apparent interference from other metal ions. The results indicated that the oxadiazole possessed high selectivity and sensitivity to Zn2+ ion. The stoichiometric ratio between the oxadiazole and Zn2+ ion was calculated to be 2:1 by Job plot experiment, meanwhile their binding modes was confirmed by 1H NMR and mass spectrometry. Their association constant was determined to be 1.95*105M-1 and the detection limit for Zn2+ ion was 6.14*10-7mol/L. PMID- 27960139 TI - Oxidative stress, inflammation and treatment response in major depression. AB - OBJECTIVE: Increased inflammation and oxidative stress have been shown in Major Depressive Disorder (MDD), although there is significant heterogeneity across studies. Whether markers of inflammation and oxidative stress are associated with antidepressant treatment response in MDD is currently unclear. The goals of the present study are to investigate markers of inflammation and oxidative stress in unmedicated MDD subjects and controls and test the relationship between these markers and antidepressant response in MDD subjects. METHODS: Interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, C-reactive protein, F2-isoprostanes, 8-OH 2 deoxyguanosine (8-OHdG), glutathione peroxidase, glutathione, and vitamin C were quantified in blood samples from 50 unmedicated MDD subjects and 55 healthy controls. Depression symptom severity was rated with the 17-item Hamilton Depression Rating Scale (HDRS). All subjects were somatically healthy and free from medications that could interfere with inflammation and oxidative stress markers. A subgroup of 22 MDD subjects underwent open-label selective serotonin reuptake inhibitor (SSRI) antidepressant treatment for eight weeks, after which blood sampling and the HDRS were repeated. Antidepressant treatment "response" was defined as >=50% decrease in HDRS ratings over 8 weeks of treatment. RESULTS: After controlling for the effects of age, sex, body mass index and smoking, MDD subjects had significantly higher levels of IL-6 (p<0.001), TNF-alpha (p<0.001), 8-OHdG (p=0.018), and F2-isoprostanes (p=0.012). Compared to Responders, Non responders to SSRI antidepressant treatment had higher levels of F2-isoprostanes at baseline (p=0.006), and after eight weeks of treatment (p=0.031). Non responders showed a significant increase in 8-OHdG over the course of treatment (p=0.021), whereas Responders showed a significant decrease in IL-6 over the course of treatment (p=0.019). CONCLUSION: Our results are in line with previous reports of increased levels of markers of inflammation and oxidative stress in MDD. Moreover, poorer antidepressant treatment response was related to higher baseline levels of the major oxidative stress marker, F2-isoprostanes, in vivo. Further, antidepressant response was associated with changes in oxidative (8 OHdG) and inflammatory (IL-6) markers. PMID- 27960142 TI - Determination of mutated genes in the presence of wild-type DNA by using molecular beacons as probe. AB - Low-abundance mutations in the presence of wild-type DNA can be determined using molecular beacon (MB) as probe. A MB is generally used as DNA probe because it can distinguish single-base mismatched target DNA from fully matched target DNA. However, the probe can not determine low-abundance mutations in the presence of wild-type DNA. In this study, this limitation is addressed by enhancing the stability of unpaired base-containing dsDNA with a hydrogen-bonding ligand, which was added after hybridization of the MB to the target DNA. The ligand formed hydrogen bonds with unpaired bases and stabilized the unpaired base-containing dsDNA if target DNA is mutated one. As a result, more MBs were opened by the mutant genes in the presence of the ligand and a further increase in the fluorescence intensity was obtained. By contrast, fluorescence intensity did not change if target DNA is wild-type one. Consequent increase in the fluorescence intensity of the MB was regarded as a signal derived from mutant genes. The proposed method was applied in synthetic template systems to determine point mutation in DNA obtained from PCR analysis. The method also allows rapid and simple discrimination of a signal if it is originated in the presence of mutant gene or alternatively by a lower concentration of wild gene. PMID- 27960141 TI - In vivo confocal Raman spectroscopy and molecular dynamics analysis of penetration of retinyl acetate into stratum corneum. AB - OBJECTIVE: The purpose of this study is to elucidate the behavior of retinyl acetate in penetrating human skin without the presence of enhancers by using confocal Raman spectroscopy and molecular dynamics simulation. METHODS: In this study, in vivo confocal Raman spectroscopy was combined with molecular dynamics simulation to investigate the transdermal permeation of the aqueous suspension of retinyl acetate. RESULTS: Permeation was measured after 30min, and retinyl acetate was found up to 20MUm deep inside the stratum corneum. The delivery of retinyl acetate inside a skin membrane model was studied by molecular dynamics. The membrane model that was used represented normal young skin containing a lipid bilayer with 25% ceramide, 36% fatty acid, 30% cholesterol, and 6% cholesterol sulfate. CONCLUSION: Spectroscopy data indicate that retinyl acetate permeates into the stratum corneum. Molecular dynamics data showed that retinyl acetate permeates in the membrane model and that their final location is deep inside the lipid bilayer. We showed, for the first time, a correlation between Raman permeation data and computational data. PMID- 27960143 TI - From research lab to standard environmental analysis tool: Will NASBA make the leap? AB - Nucleic acid sequence-based amplification (NASBA) is a sensitive and efficient molecular tool for amplification of RNA and has been widely adopted in clinical diagnostics. Monitoring of water and other environmental samples demands sensitive techniques, as potential pathogens may be in low concentrations and require only a few infectious units to infect their host. NASBA has qualities that should be advantageous for analysis of environmental samples, such as short reaction times, high sensitivity, and not readily affected by inhibitory substances that are often abundant in environmental samples. NASBA is well suited for incorporation into lab-on-a-chip (LOC) devices, as part of analysis systems that can be taken into the field for on-site screening. In this review, we explore advantages and drawbacks of NASBA as a tool for environmental analyses, and try to answer the question of whether it will be a recognised technique in the same manner as in clinical diagnostics. PMID- 27960144 TI - Adipic acid and autism spectrum disorders: A confounding role for environmental exposure to nitrous oxide. PMID- 27960145 TI - Visualized detection of single-base difference in multiplexed loop-mediated isothermal amplification amplicons by invasive reaction coupled with oligonucleotide probe-modified gold nanoparticles. AB - Loop-mediated isothermal amplification (LAMP) is a well-developed DNA amplification method with an ultra-high sensitivity, but it is difficult to recognize a single-base difference (like genotyping) in target-specific amplicons by conventional detection ways, such as the intercalation of dyes into dsDNA amplicons or the increase of solution turbidity along with the polymerization process. To allow genotyping based on LAMP suitable for POCT (point-of-care testing) or on-site testing, here we proposed a highly specific and cost effective method for detecting a single-base difference in LAMP amplicons. The method includes three key steps, sequence amplifier to amplify multiple fragments containing the single nucleotide polymorphisms (SNPs) of interest, allele identifier to recognize a targeted base in the amplicons by invasive reaction, and signal generator to yield signals by hybridization-induced assembly of oligonucleotide probe-modified gold nanoparticles. Because the allele identifier is sensitive to one base difference, it is possible to use multiplexed LAMP (mLAMP) to generate amplicon mixtures for multiple SNP typing. Genotyping of 3 different SNPs (CYP2C19*2, CYP2C19*3 and MDR1-C3435T) for guiding the dosage of clopidogrel is successfully carried out in a 3-plex LAMP on real clinical samples. As our method relies on the naked-eye detection and constant-temperature reaction, no expensive instrument is required for both target amplification and sequence identification, thus much suitable for inexpensive gene-guided personalized medicine in source-limited regions. PMID- 27960146 TI - Exploring the chemopreventive properties and perspectives of baicalin and its aglycone baicalein in solid tumors. AB - Solid tumors contain a huge mass of malignant tumors other than hematological malignancies. Novel therapies based on bio-safe agents against solid tumors are urgently required. Baicalin and its aglycone baicalein, the major bioactive flavones derived from Scutellaria baicalensis, have potential roles in the management of cancer. The chemopreventive properties governed by baicalin and baicalein were multi-fold, via apoptosis induction, autophagy triggering, cell cycle arrest, inhibition of 12-lipoxygenase and metastasis suppression. However, their poor solubility and low oral bioavailability severely limited the clinical application. This extensive review focused on the promising anti-cancer activities of baicalin and baicalein and new techniques to improve their bioavailability. PMID- 27960147 TI - Neural basis for inferring false beliefs and social emotions in others among individuals with schizophrenia and those at ultra-high risk for psychosis. AB - Inferring beliefs and social emotions of others has different neural substrates and possibly different roles in the pathophysiology of different clinical phases of schizophrenia. The current study investigated the neural basis for inferring others' beliefs and social emotions, as individual concepts, in 17 subjects at ultra-high risk for psychosis (UHR), 16 patients with schizophrenia and 20 healthy controls. Brain activity significantly differed from normal in both the left superior temporal sulcus (STS) and the inferior frontal gyrus (IFG) in the schizophrenia group while inferring others' beliefs, whereas those of UHR group were in the middle of those in the schizophrenia and healthy-control groups. Brain activity during inferring others' social emotions significantly differed in both the left STS and right IFG among individuals at UHR; however, there was no significant difference in the schizophrenia group. In contrast, brain activity differed in the left IFG of those in both the schizophrenia and UHR groups while inferring social emotion. Regarding the difference in direction of the abnormality, both the UHR and schizophrenia groups were characterized by hyper STS and hypo-IFG activations when inferring others' beliefs and emotions. These findings might reflect different aspects of the same pathophysiological process at different clinical phases of psychosis. PMID- 27960148 TI - Decreased response inhibition to sad faces during explicit and implicit tasks in females with depression: Evidence from an event-related potential study. AB - The present study aimed to investigate neural substrates of response inhibition to sad faces across explicit and implicit tasks in depressed female patients. Event-related potentials were obtained while participants performed modified explicit and implicit emotional go/no-go tasks. Compared to controls, depressed patients showed decreased discrimination accuracy and amplitudes of original and nogo-go difference waves at the P3 interval in response inhibition to sad faces during explicit and implicit tasks. P3 difference wave were positively correlated with discrimination accuracy and were independent of clinical assessment. The activation of right dorsal prefrontal cortex was larger for the implicit than for the explicit task in sad condition in health controls, but was similar for the two tasks in depressed patients. The present study indicated that selectively impairment in response inhibition to sad faces in depressed female patients occurred at the behavior inhibition stage across implicit and explicit tasks and may be a trait-like marker of depression. Longitudinal studies are required to determine whether decreased response inhibition to sad faces increases the risk for future depressive episodes so that appropriate treatment can be administered to patients. PMID- 27960149 TI - The Crucial Role of C18-Cer in Fat-Induced Skeletal Muscle Insulin Resistance. AB - BACKGROUND/AIMS: Muscle bioactive lipids accumulation leads to several disorder states. The most common are insulin resistance (IR) and type 2 diabetes. There is an ongoing debate which of the lipid species plays the major role in induction of muscle IR. Our aim was to elucidate the role of particular lipid group in induction of muscle IR. METHODS: The analyses were performed on muscle from the following groups of rats: 1. Control, fed standard diet, 2 HFD, fed high fat diet, 3. HFD/Myr, fed HFD and treated with myriocin (Myr), an inhibitor of ceramide de novo synthesis. We utilized [U13C] palmitate isotope tracer infusion and mass spectrometry to measure content and synthesis rate of muscle long-chain acyl-CoA (LCACoA), diacylglycerols (DAG) and ceramide (Cer). RESULTS: HFD led to intramuscular accumulation of LCACoA, DAG and Cer and skeletal muscle IR. Myr treatment caused decrease in Cer (most noticeable for stearoyl-Cer and oleoyl Cer) and accumulation of DAG, possibly due to re-channeling of excess of intramuscular LCACoA towards DAG synthesis. An improvement in insulin sensitivity at both systemic and muscular level coincided with decrease in ceramide, despite elevated intramuscular DAG. CONCLUSION: The improved insulin sensitivity was associated with decreased muscle stearoyl- and oleoyl-ceramide content. The results indicate that accumulation of those ceramide species has the greatest impact on skeletal muscle insulin sensitivity in rats. PMID- 27960150 TI - Bendamustine and Rituximab: Complete Response in a 62-Year-Old Female with an Aggressive Lymphoma and an Ejection Fraction of 20. AB - The treatment of diffuse large B-cell lymphoma in the presence of cardiac comorbidities can be challenging considering that the standard treatment regimen used for this aggressive subtype of non-Hodgkin lymphoma (NHL) consists of a combination of rituximab, cyclophosphamide, doxorubicin hydrochloride, Oncovin (vincristine), and prednisone (R-CHOP). The use of the anthracycline doxorubicin has been associated with arrhythmias and cardiomyopathy, making patients with cardiac dysfunction poor candidates for R-CHOP. As such, it is imperative to find alternative regimens that omit cardiac toxicity without compromising efficacy for this patient population. We report a case of composite NHL in a patient who received frontline bendamustine with rituximab with encouraging results. Our patient had a left ventricular ejection fraction of 20%, making her a poor candidate for anthracycline-based therapy. We opted to administer bendamustine with rituximab for a total of 6 cycles. She remains disease free 18 months after the completion of therapy. PMID- 27960151 TI - IL-35 Inhibits Angiogenesis through VEGF/Ang2/Tie2 Pathway in Rheumatoid Arthritis. AB - BACKGROUND/AIMS: The pro-angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietins (Angs) play a prominent role in synovial angiogenesis, an early and critical event in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-35 is an anti-inflammatory cytokine that attenuates collagen induced arthritis, however, the mechanisms involved are not fully understood. METHODS: The effects of IL-35 on endothelial cell migration, adhesion, and tube formation were examined using human umbilical vein endothelial cells (HUVEC) in vitro. The effects of IL-35 on vessel formation in vivo were examined using a murine Matrigel plugs model. MMP2/MMP9 and IL-6/IL-8 secretion were assessed by zymography and ELISA, respectively. The crosstalk between IL-35, VEGF, and Ang2 in HUVECs and RA synovial tissue explants was investigated. RESULTS: IL-35 inhibited basal and VEGF-induced HUVEC migration and adhesion in vitro as well as tube formation in vitro and in vivo. VEGF increased Ang2 secretion by HUVECs and RA synovial tissue explants, and exogenous Ang2 promoted HUVEC migration, adhesion, and tube formation with similar potency to VEGF. Blocking the Ang/Tie2 pathway with a Tie2 kinase antibody inhibited the proangiogenic effects of exogenous Ang2 and VEGF in HUVECs. IL-35 inhibited basal and VEGF-induced Ang2 secretion by HUVECs and RA synovial tissue explants; it also antagonized the proangiogenic effects of exogenous Ang2 in HUVECs. Moreover, IL-35 reduced basal and VEGF/Ang2-induced MMP2/MMP9 and IL-6/IL-8 secretion. CONCLUSION: These results suggested that IL-35 restrains RA angiogenesis and inflammation by downregulating basal and VEGF-induced Ang2 secretion as well as disrupting Ang2/Tie2 signal transduction. Our findings extend current understanding of mechanisms regulating RA angiogenesis and may support development of novel angiogenesis-targeting therapeutics for RA treatment. PMID- 27960152 TI - Effects of Diabetic Hyperglycemia on Central Ang-(1-7)-Mas-R-nNOS Pathways in Spontaneously Hypertensive Rats. AB - BACKGROUND/AIMS: Hypertension is a major cause of stroke, and diabetes can increase incidence of this disease. We determined the role played by central angiotensin-(1-7) [Ang-(1-7)] pathway in modulating spontaneously hypertension with diabetic hyperglycemia. METHODS: Western Blot analysis and ELISA were used to determine the protein expression of Ang-(1-7) and its signal pathway Mas-R nNOS in the cerebral cortex and hippocampus of spontaneously hypertensive rats (SHR) and control animals. In a subset of animals, diabetic hyperglycemia was induced by systemic injection of streptozotocin (STZ). We analyzed a relationship between the levels of central Ang-(1-7) and plasma brain natriuretic peptide (BNP) indicating a risk of ischemic stroke. We further examined the effects of Ang-(1-7) on arterial blood pressure. RESULTS: Our findings demonstrated for the first time that administration of STZ 1) attenuates the levels of Ang-(1-7) in the cerebral cortex and hippocampus, which are closely linked to plasma BNP; and 2) leads to downregulation of central Ang-(1-7)-Mas-R-nNOS pathways. Notably, STZ has greater effects in SHR. Additionally, inhibition of oxidative stress can largely improve downregulation of Ang-(1-7) in diabetic SHR. Moreover, central stimulation of Ang-(1-7) pathway or a blockade of oxidative stress improves systolic blood pressure in diabetic SHR. CONCLUSIONS: The Ang-(1-7) signaling pathway is engaged in the adaptive mechanisms associated with diabetic hypertension, suggesting that enhancing Ang-(1-7)-Mas-R-nNOS system is likely to be beneficial in preventing against cardiovascular and cerebrovascular dysfunction and vulnerability related to spontaneously hypertension, particularly to diabetic hypertension. PMID- 27960153 TI - CFTR Controls the Activity of NF-kappaB by Enhancing the Degradation of TRADD. AB - BACKGROUND/AIMS: Chronic lung infection in cystic fibrosis leads to an inflammatory response that persists because of the chronic presence of bacteria and ultimately leads to a catastrophic failure of lung function. METHODS: We use a combination of biochemistry, cell and molecular biology to study the interaction of TRADD, a key adaptor molecule in TNFalpha signaling, with CFTR in the regulation of NFkappaB. RESULTS: We show that Wt CFTR binds to and colocalizes with TRADD. TRADD is a key signaling intermediate connecting TNFalpha with activation of NFkappaB. By contrast, DeltaF508 CFTR does not bind to TRADD. NF-kappaB activation is higher in CFBE expressing DeltaF508 CFTR than in cells expressing Wt CFTR. However, this differential effect is abolished when TRADD levels are knocked down. Transfecting Wt CFTR into CFBE cells reduces NF-kappaB activity. However the reduction is abolished by the CFTR chloride transport inhibitor-172. Consistently, transfecting in the correctly trafficked CFTR conduction mutants G551D or S341A also fail to reduce NFkappaB activity. Thus CFTR must be functional if it is to regulate NF-kappaB activity. We also found that TNFalpha produced a greater increase in NF-kappaB activity in CFBE cells than in the same cell when Wt CFTR-corrected. Consistently, the effect is also abolished when TRADD is knocked down by shRNA. Thus, Wt CFTR control of TRADD modulates the physiological activation of NF-kappaB by TNFalpha. Based on studies with proteosomal and lysosomal inhibitors, the mechanism by which Wt CFTR, but not DeltaF508 CFTR, suppresses TRADD is by lysosomal degradation. CONCLUSION: We have uncovered a novel mechanism whereby Wt CFTR regulates TNFalpha signaling by enhancing TRADD degradation. Thus by reducing the levels of TRADD, Wt CFTR suppresses downstream proinflammatory NFkappaB signaling. By contrast, suppression of NF-kappaB activation fails in CF cells expressing DeltaF508 CFTR. PMID- 27960154 TI - Mesenchymal Stem Cells with Enhanced Bcl-2 Expression Promote Liver Recovery in a Rat Model of Hepatic Cirrhosis. AB - BACKGROUND/AIMS: Mesenchymal stem cell (MSC) transplantation has emerged as an option for the treatment of chronic hepatic cirrhosis, while its therapeutic efficacy could be improved. The bcl-2 gene is anti-apoptotic and can help cell survival and proliferation. Therefore, we explored whether transplanted MSCs with enhanced bcl-2 expression may be beneficial in the treatment of experimental cirrhosis in rats. METHODS: MSCs were isolated from rat bone marrow, expanded in vitro and transfected with adeno-associated virus (AAV) engineered the bcl-2 gene (AAV-bcl-2). Rats with cirrhosis induced by carbon tetrachloride (CCl4) were treated with AAV-bcl-2 infected BMSCs-AAV-bcl-2, with the cells traced in vivo post transplantation. Liver pathology and function were evaluated 7, 14, 21, and 28 days post transplantation, respectively. RESULTS: On day 7 post transplantation, the infused AAV-bcl-2 had integrated into the hepatocyte-like cells (HLCs) that expressed albumin (ALB), Cytokeratin 18 (CK18), and hepatocytes nuclear factor 4a (HNF4a). On day 28 post transplantation, rats in the cirrhosis + BMSCs-AAV-bcl-2 group showed the most dense HLCs, highest mRNA and protein levels of ALB, CK18, and HNF4a, compared to the other groups. Their liver function recovered most rapidly in 4 week observation, while histological sign of cirrhosis remained at the end of this period. CONCLUSION: BMSCs over expressing bcl-2 gene showed better survival, and enhanced the differentiation into hepatocytes-like cells, and appeared to promote the recovery of liver function in rats with experimental cirrhosis. PMID- 27960155 TI - Stimulation of Suicidal Erythrocyte Death by Ceritinib-Treatment of Human Erythrocytes. AB - BACKGROUND/AIMS: The anaplastic lymphoma kinase (ALK) inhibitor ceritinib is utilized for the treatment of ALK positive non-small cell lung carcinoma. Side effects of the drug include decrease of blood hemoglobin concentration. Possible causes of anemia include stimulation of suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling of eryptosis includes increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, staurosporine sensitive protein kinase C, SB203580 sensitive p38 kinase, D4476 sensitive casein kinase 1, and zVAD sensitive caspases. The present study explored, whether ceritinib induces eryptosis and, if so, to shed light on the cellular mechanisms involved. METHODS: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to ceritinib (1 ug/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter, significantly increased Fluo3-fluorescence, but did not significantly modify DCFDA fluorescence or ceramide abundance. The effect of ceritinib on annexin-V-binding was significantly blunted but not abolished by removal of extracellular Ca2+, by the kinase inhibitors staurosporine (1 uM), SB203580 (2 uM) and D4476 (10 uM), as well as by caspase inhibitor zVAD (10 uM). CONCLUSIONS: Ceritinib triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca2+ entry, as well as activation of kinases and Caspases. PMID- 27960156 TI - Effect of Tannic Acid on the Protective Properties of the in situ Formed Pellicle. AB - OBJECTIVES: In the present in situ/ex vivo study the impact of tannic acid on the erosion-protective properties of the enamel pellicle was tested. Additionally, the antiadherent and antibacterial effects of tannic acid were evaluated. METHODS: The pellicle was formed in situ on bovine enamel samples fixed on individual splints worn by 6 subjects. Following 1 min of pellicle formation the volunteers rinsed for 10 min with tannic acid. After further oral exposure for 19 min, 109 min, and 8 h overnight, respectively, slabs were incubated in HCl ex vivo (pH 2.0, 2.3, 3.0) over 120 s. Subsequently, kinetics of calcium and phosphate release were measured photometrically. Samples after a 1-min fluoride mouth rinse as well as enamel samples with and without a 30-min in situ pellicle served as controls. Antiadherent effects were evaluated after a 1-min rinse with tannic acid and oral exposure of the slabs overnight. DAPI (4',6-diamidino-2 phenylindole) combined with concanavalin A staining and live/dead staining was used for fluorescence microscopic visualization and quantification of adherent bacteria and glucans. Modification of the pellicle's ultrastructure by tannic acid was evaluated by transmission electron microscopy (TEM). RESULTS: Tannic acid significantly improved the erosion-protective properties of the pellicle in a pH-dependent manner. Bacterial adherence and glucan formation on enamel were significantly reduced after rinses with tannic acid as investigated by fluorescence microscopy. TEM imaging indicated that rinsing with tannic acid yielded a sustainable modification of the pellicle; it was distinctly more electron dense. CONCLUSION: Tannic acid offers an effective and sustainable approach for the prevention of caries and erosion. PMID- 27960157 TI - Chorein Sensitive Orai1 Expression and Store Operated Ca2+ Entry in Rhabdomyosarcoma Cells. AB - BACKGROUND: Chorein, a protein encoded by VPS13A (vacuolar protein sorting associated protein 13A), is defective in chorea acanthocytosis, a rare disease characterized by acanthocytosis of red blood cells and neuronal cell death with progressive hyperkinetic movement disorder, cognitive dysfunction, behavioral abnormalities and chronic hyperkalemia. Chorein is highly expressed in ZF rhabdomyosarcoma cells and counteracts apoptosis of those cells. Chorein is effective in part by interacting with and fostering stimulation of phosphoinositide-3-kinase (PI3K)-p85-subunit. PI3K dependent signaling includes the serum and glucocorticoid inducible kinase SGK1. The kinase activates NFkappaB with subsequent up-regulation of the Ca2+ channel subunit Orai1, which accomplishes store operated Ca2+ entry (SOCE). Orai1 and SOCE have been shown to confer survival of tumor cells. The present study thus explored whether chorein impacts on Orai1 expression and SOCE. METHODS: In rhabdomyosarcoma cells chorein, Orai1, NFkappaB and SGK1 transcript levels were quantified by RT-PCR, Orai1 protein abundance by Western blotting, FACS analysis and confocal laser microscopy, [Ca2+]i utilizing Fura-2 fluorescence, and SOCE from the increase of [Ca2+]i following store depletion with extracellular Ca2+ removal and inhibition of the sarcoendoplasmatic reticular Ca2+ ATPase with thapsigargin. RESULTS: The mRNA coding for chorein was most abundant in drug resistant, poorly differentiated human ZF rhabdomyosarcoma cells. Chorein silencing significantly decreased Orai1 transcript levels and Orai1 protein expression, as well as SGK1 and NFkappaB transcript levels. SOCE in ZF rhabdomyosarcoma cells was significantly blunted by chorein silencing, Orai1 inhibitor 2-APB (50 uM), SGK1 inhibitor EMD638683 (50 uM, 10 h) and NFkappaB inhibitor wogonin (50 uM, 24 h). CONCLUSION: Chorein is a stimulator of Orai1 expression and thus of store operated Ca2+ entry. The effect may involve SGK1 and NFkappaB. PMID- 27960158 TI - Risk Factors. AB - Studies investigating risk factors for intracranial atherosclerosis (ICAS) have been infrequent. However, due to recent availability of non-invasive vascular imaging techniques that can assess intracranial cerebral arteries, there are a growing number of studies on risk factors for ICAS. Conventional vascular risk factors such as hypertension, diabetes, hypercholesterolemia and cigarette smoking are risk factors for ICAS. However, it remains uncertain whether there is a difference in risk factors between ICAS and extracranial atherosclerosis (ECAS). It also remains unclear why ICAS is more common in Asians and Blacks than in Caucasians. Although we reviewed available evidences on these differences, the review was limited because studies were heterogeneous in the definition of risk factors, diagnostic method, and characteristics of study subjects (hospitalized vs. community) or cerebral vessels (symptomatic vs. asymptomatic). Nevertheless, it seems that hypercholesterolemia is more closely associated with ECAS than ICAS. The difference in hypercholesterolemia prevalence is one of the main reasons for racial differences in the location of cerebral atherosclerosis. Intracranial arteries contain higher antioxidant level than extracranial arteries and may be more vulnerable to risk factors that deplete antioxidants (e.g., metabolic syndrome and diabetes mellitus). Intracranial arteries may be more vulnerable to factors associated with hemodynamic stress (e.g., advanced, salt retaining hypertension and arterial tortuosity) because of a smaller diameter, thinner media and adventitia, and fewer elastic medial fibers than extracranial arteries. Additionally, non-atherosclerotic arterial diseases (e.g., moyamoya disease) that commonly occur in the intracranial arteries of East Asians may contaminate the reports of ICAS cases. Various genes, including RNF 213, might also explain racial differences in atherosclerotic location. Prospective, well designed risk factor and genetic studies should be performed in a homogeneous group of patients with diverse ethnicities. These efforts are essential in the prevention of atherosclerotic diseases based on adequate knowledge of the risk factors and pathogenesis. PMID- 27960159 TI - Fetal Congenital Lung Lesions, DICER1 Syndrome, and Family History as a Risk Assessment Tool. PMID- 27960160 TI - Biomarkers, Natural Course and Prognosis. AB - Increasing our knowledge about intracranial atherosclerosis (ICAS) natural history and prognostic factors is essential to improve its preventive therapy and thus reduce the dramatic clinical consequences caused by this entity. ICAS is characterized by a chronic and progressive course until it becomes symptomatic, mostly through complication of an unstable intracranial atherosclerotic plaque. Population-based studies in healthy subjects have shown that the prevalence of asymptomatic ICAS is higher in Asian than in Caucasian populations. In both settings, asymptomatic ICAS is associated with classical vascular risk factors and with the metabolic syndrome, and it is burdened with an increasing risk of having incident stroke and cognitive impairment. When it reaches its symptomatic stage, ICAS is a dynamic and aggressive condition, and affected patients are at high risk of having recurrent stroke and other major vascular events. The Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) trial has recently shown a robust impact of intensive medical therapy reducing the risk of clinical recurrence of symptomatic ICAS. However, even under best medical therapy and degree of risk factor control, symptomatic ICAS-related recurrence risk continues to be the highest among all stroke etiologic subtypes. The second part of the chapter reviews the current understanding of prognostic factors that may help discriminate the high-risk ICAS patients, divided into local factors (vulnerable ICAS plaque) and systemic factors (vulnerable ICAS patient). Regarding research on local factors, high-resolution magnetic resonance imaging (HRMRI) is an emerging technique that allows in vivo evaluation of intracranial arterial wall, which is displacing our research focus from intracranial stenosis degree towards intracranial atherosclerotic plaque composition and activity. Characterization of the vulnerable ICAS patient may be improved with biomarker research. The latest contributions in this field help support the hypothesis that inflammation determines the risk of progression and complication of this disease, as it occurs in atherosclerosis affecting extracranial arterial beds. PMID- 27960161 TI - Cannabinoid 2 Receptor Agonist Improves Systemic Sensitivity to Insulin in High Fat Diet/Streptozotocin-Induced Diabetic Mice. AB - BACKGROUND/AIMS: The endocannabinoid signalling (ECS) system has been known to regulate glucose homeostasis. Previous studies have suggested that the cannabinoid 2 (CB2) receptor may play a regulatory role on insulin secretion, immune modulation and insulin resistance. Given that diabetes and insulin resistance are attributable to elevated inflammatory tone, we investigated the role of CB2 receptor on glucose tolerance and insulin sensitivity in high-fat diet (HFD)/streptozotocin (STZ)-induced mice. METHODS: Diabetes was induced in male ICR mice by HFD/STZ and exposed to a CB2 receptor agonist, SER601, for 2- or 4-weeks via subcutaneous implantation of osmotic minipumps. Glucose and insulin tolerance tests were performed at the end of treatment. Islets were isolated for assessment of beta-cell function. Pancreases and skeletal muscles were also obtained for histological analyses. RESULTS: Despite a lack of impact on glucose tolerance, substantial improvement on insulin sensitivity was observed in SER601 treated mice, which could partly be attributed to improved islet beta-cell function, shown as increased glucose-induced insulin secretion and insulin content. No changes on islet macrophage infiltration or skeletal muscle fat deposition were detectable from SER601-treated mice. However, a major decrease in body weight was recorded at the end of 4-week SER601 exposure, accompanied by a lack of epididymal adipose mass in SER601-treated mice. CONCLUSION: Our data suggest a lipolytic role of SER601 in HFD/STZ-induced diabetic mice, which results in significant improvement of systemic insulin sensitivity. Thus, the CB2 receptor may be considered a promising target for therapeutic development against insulin resistance and obesity-related diabetes. PMID- 27960163 TI - Melatonin Induces Anti-Inflammatory Effects to Play a Protective Role via Endoplasmic Reticulum Stress in Acute Pancreatitis. AB - BACKGROUND/AIMS: Melatonin, which is mainly secreted by the pineal gland and released into blood, has anti-inflammatory properties in acute pancreatitis. Many studies show that melatonin can relieve inflammation in taurocholate-induced acute pancreatitis. However, the mechanisms of its anti-inflammatory effects are still undefined, especially the relationship between melatonin and endoplasmic reticulum stress. We explored the anti-inflammatory activity of melatonin in AR42J and rat models. METHODS: The CCK-8 assay was used to assess effects of melatonin on AR42J cell viability. Inflammatory degree and the expressions of endoplasmic reticulum stress related molecules were examined by quantitative RT PCR and western blotting. The degree of inflammation in the tissue was also accessed by pathological grading. Finally, we used the western blotting method to verify apoptosis and autophagy. RESULTS: Endoplasmic reticulum stress was obviously activated in early stage inflammation in AR42J and rat models. Melatonin could induce anti-inflammatory effects via endoplasmic reticulum stress. Melatonin significantly inhibited inflammatory cytokines and the expression of ERS-related molecules. Finally, it played a protective role by promoting apoptosis and autophagy of the cells, which were damaged in the process of inflammatory reaction. CONCLUSION: Melatonin induces anti-inflammatory effects via endoplasmic reticulum stress in acute pancreatitis to play a protective role. PMID- 27960162 TI - The mTORC2/Akt/NFkappaB Pathway-Mediated Activation of TRPC6 Participates in Adriamycin-Induced Podocyte Apoptosis. AB - BACKGROUND/AIMS: Although increased expression and gain function of transient receptor potential cation channel 6 (TRPC6) has been associated with the pathogenesis of some proteinuric glomerular diseases, it remains elusive how TRPC6 participates in the process of podocyte damage. METHODS: The potential signaling responsible for TRPC6 activation was investigated using immunoblot assays in an in vitro podocyte injury model induced by Adriamycin (ADR). Podocyte apoptosis was measured using FITC-conjugated Annexin V and Propidium Iodide staining. The channel activity of TRPC6 was assessed using the Ca2+ influx assay. RESULTS: Increase of TRPC6 expression was detected in ADR-treated podocytes, and TRPC6 knockdown significantly decreased ADR-induced podocytes apoptosis. Following ADR treatment, phospho-mTORSer2481 and phospho-AktSer473 was significantly increased in a time-dependent manner, whereas phospho-mTORSer2448 and phospho-p70S6KThr389 showed no change. ADR-induced apoptosis was prevented by ku0063794 (a dual mTOR complexes inhibitor), not by rapamycin (a specific mTORC1 inhibitor). Furthermore, nuclear translocation of NFkappaB/p65 was detected in ADR-treated podocytes, which was prevented by an Akt inhibitor triciribine. Of note, NFkappaB inhibitor PDTC prevented ADR-induced increase of TRPC6, and decreased ADR-induced apoptosis. We found that Akt activation and NFkappaB nuclear translocation was significantly inhibited by knockdown of mTORC2 protein Rictor, not by mTORC1 protein Raptor. In comparison with control, the Ca2+ influx was significantly increased in ADR-treated podocytes, which was remarkably prevented by TRPC6 knockdown. ADR-induced increase of TRPC6 channel activity was dramatically prevented by ku0063794, but not by rapamycin. Additionally, knockdown of Rictor, not Raptor, prevented ADR-induced increase of the Ca2+ influx. Moreover, the application of NFkappaB inhibitor PDTC also prevented the Ca2+ influx in ADR-treated podocytes. CONCLUSIONS: Our findings revealed that the mTORC2/Akt/NFkappaB pathway-mediated activation of TRPC6 participates in ADR induced podocyte apoptosis. PMID- 27960164 TI - Clinical Stroke Syndromes. AB - The main mechanism of stroke in patients who have extracranial atherosclerosis is artery to artery embolism, occasionally associated with hemodynamic disturbances. Although these mechanisms are also important in patients with intracranial atherosclerosis, branch occlusion and in-situ thrombotic occlusion play a relatively more important role in these patients. Accordingly, clinical stroke syndromes differ between extracranial atherosclerosis and intracranial atherosclerosis. In anterior circulation, middle cerebral artery atherosclerosis frequently produces subcortical infarction by way of branch occlusion. The clinical syndromes are similar to lacunar syndromes classically associated with small perforator artery diseases, although a larger size infarction can be accompanied by cortical dysfunction such as aphasia or neglect. In-situ thrombotic occlusion of the large intracranial anterior circulation arteries leads to larger infarction that results in cortical symptoms - however, parts of the cortex are usually spared due to relatively well developed collateral circulation associated with prolonged perfusion impairment. In the posterior circulation, intracranial atherosclerosis is common in the distal vertebral artery and basilar artery that often causes medullary and pontine infarction syndromes, mostly by way of branch occlusion. Posterior cerebral artery atherosclerosis produces pure midbrain or thalamic infarction through branch occlusion. Artery to artery embolisms from posterior fossa intracranial atherosclerosis lead to cortical infarction - cerebellar or temporo-occipital lobe infarction, producing ataxic syndromes, and visual field defects and associated neurobehavioral syndromes, respectively. PMID- 27960165 TI - Benign Oligemia in Subacute Stage Is Associated with Borderzone Infarction in Stroke Patients Caused by Intracranial Large Artery Disease. AB - BACKGROUND: CT perfusion (CTP) imaging provides quantitative evaluation of cerebral perfusion flow and volume. Our previous findings showed that benign oligemia caused by intracranial large artery disease may be existent in subacute stroke. AIMS: We aimed at comparing the topographic patterns and clinical outcome of stroke patients with and without persistent benign oligemia as defined by CTP imaging. METHODS: Consecutive ischemic stroke patients who were referred for CTP in 2009 were screened. The topographic patterns (cortical, borderzone or perforating artery territory infarcts) were assessed by diffusion-weighted imaging (DWI). The clinical outcome was defined by modified Rankin score at 6 months after stroke onset. RESULTS: Totally, 26 stroke patients were recruited. Benign oligemia in subacute stage was detected in 15 patients. The occurrence of borderzone infarction was higher in stroke patients with benign oligemia than those without (p = 0.036). CONCLUSIONS: The topographic pattern of DWI may be different between the intracranial arterial disease patients with and without benign oligemia on CTP in subacute stroke. PMID- 27960166 TI - Astragaloside IV Enhances Cisplatin Chemosensitivity in Non-Small Cell Lung Cancer Cells Through Inhibition of B7-H3. AB - BACKGROUND: Chemoresistance is a major obstacle to successful chemotherapy for human non-small cell lung cancer (NSCLC). Astragaloside IV, the component of Astragalus membranaceus, has been reported to exhibit anti-inflammation, anti cancer and immunoregulatory properties. In the present study, we investigated the role of astragaloside IV in the chemoresistance to cisplatin in NSCLC cells. METHODS: We established astragaloside IV-suppressed NSCLC cell lines including A549, HCC827, and NCI-H1299 and evaluated their sensitivity to cisplatin in vitro. In addition, we examined the mRNA and protein levels of B7-H3 in response to cisplatin-based chemotherapy. RESULTS: We showed that high doses of astragaloside IV (10, 20, 40 ng/ml) inhibited NSCLC cell growth, whereas low concentrations of astragaloside IV (1, 2.5, 5 ng/ml) had no obvious cytotoxicity on cell viability. Moreover, combined treatment with astragaloside IV significantly increased chemosensitivity to cisplatin in NSCLC cells. On the molecular level, astragaloside IV co-treatment significantly inhibited the mRNA and protein levels of B7-H3 in the presence of cisplatin. In addition, ectopic expression of B7-H3 diminished the sensitization role of astragaloside IV in cellular responses to cisplatin in NSCLC cells. CONCLUSION: These results demonstrate that astragaloside IV enhances chemosensitivity to cisplatin via inhibition of B7-H3 and that treatment with astragaloside IV and inhibition of B7 H3 serve as potential therapeutic approach for lung cancer patients. PMID- 27960167 TI - Intracranial Arteries - Anatomy and Collaterals. AB - Anatomy, physiology, and pathophysiology are inextricably linked in patients with intracranial atherosclerosis. Knowledge of abnormal or pathological conditions such as intracranial atherosclerosis stems from detailed recognition of the normal pattern of vascular anatomy. The vascular anatomy of the intracranial arteries, both at the level of the vessel wall and as a larger structure or conduit, is a reflection of physiology over time, from in utero stages through adult life. The unique characteristics of arteries at the base of the brain may help our understanding of atherosclerotic lesions that tend to afflict specific arterial segments. Although much of the knowledge regarding intracranial arteries originates from pathology and angiography series over several centuries, evolving noninvasive techniques have rapidly expanded our perspective. As each imaging modality provides a depiction that combines anatomy and flow physiology, it is important to interpret each image with a solid understanding of typical arterial anatomy and corresponding collateral routes. Compensatory collateral perfusion and downstream flow status have recently emerged as pivotal variables in the clinical management of patients with atherosclerosis. Ongoing studies that illustrate the anatomy and pathophysiology of these proximal arterial segments across modalities will help refine our knowledge of the interplay between vascular anatomy and cerebral blood flow. Future studies may help elucidate pivotal arterial factors far beyond the degree of stenosis, examining downstream influences on cerebral perfusion, artery-to-artery thromboembolic potential, amenability to endovascular therapies and stent conformation, and the propensity for restenosis due to biophysical factors. PMID- 27960168 TI - Ibrutinib-Induced Lymphocytosis: Cytological Features. PMID- 27960170 TI - Classification of Drug Hypersensitivity into Allergic, p-i, and Pseudo-Allergic Forms. AB - Drug hypersensitivity reactions (DHR) are clinically and functionally heterogeneous. Different subclassifications based on timing of symptom appearance or type of immune mechanism have been proposed. Here, we show that the mode of action of drugs leading to immune/inflammatory cell stimulation is a further decisive factor in understanding and managing DHR. Three mechanisms can be delineated: (a) some drugs have or gain the ability to bind covalently to proteins, form new antigens, and thus elicit immune reactions to hapten-carrier complexes (allergic/immune reaction); (b) a substantial part of immune-mediated DHR is due to a typical off-target activity of drugs on immune receptors like HLA and TCR (pharmacological interaction with immune receptors, p-i reactions); such p-i reactions are linked to severe DHR; and (c) symptoms of DHR can also appear if the drug stimulates or inhibits receptors or enzymes of inflammatory cells (pseudo-allergy). These three distinct ways of stimulations of immune or inflammatory cells differ substantially in clinical manifestations, time of appearance, dose dependence, predictability, and cross-reactivity, and thus need to be differentiated. PMID- 27960169 TI - Orbitofrontal Cortex Volume and Effortful Control as Prospective Risk Factors for Substance Use Disorder in Adolescence. AB - BACKGROUND: Orbitofrontal cortex (OFC) dysfunction has been proposed to increase the risk for developing a substance use disorder (SUD) during adolescence. In this study, we suggest that a reduction in OFC volumes might underlie temperament based risk factors for SUD, and examined whether smaller OFC volumes during early adolescence could predict later development of SUD. METHODS AND MATERIALS: Adolescents (n = 107; 58 male, 49 female) underwent structural MRI and completed a self-report measure of temperamental effortful control at age 12. At 3 subsequent assessments (aged 15, 16, and 18) SUD was assessed via a semi structured clinical interview. By the third assessment, 24 participants (22.4%) had received a lifetime diagnosis of SUD. RESULTS: Smaller volumes of the left OFC, right OFC, and left medial subregions predicted lifetime history of SUD by age 18. Volumes of the left OFC and left lateral subregions were positively correlated with effortful control, and left OFC volumes mediated the relationship between effortful control and SUD. CONCLUSIONS: Smaller volumes of the OFC and low effortful control during adolescence appear to be associated phenotypes that increase the risk of subsequent SUD. Further studies examining the temporal sequence of these risk factors are needed to fully understand this relationship. PMID- 27960171 TI - Are Basophils and Mast Cells Masters in HIV Infection? AB - The World Health Organization AIDS epidemic update estimates that more than 37 million people are living with HIV infection. Despite the unprecedented success of antiretroviral treatments, significant challenges remain in the fight against HIV. In particular, how uninfected cells capture HIV and transmit virions to target cells remains an unanswered question. Tissue mast cells and peripheral blood basophils can be exposed to virions or HIV products during infection. Several HIV proteins (i.e., envelope glycoproteins gp120 and gp41, Tat, and Nef) can interact with distinct surface receptors expressed by human basophils and mast cells and modulate their functional responses at different levels. Additionally, several groups have provided evidence that human mast cells can be infected in vitro, as well as in vivo, by certain strains of HIV. Recently, it has been demonstrated that basophils purified from healthy donors and intestinal mast cells can efficiently capture HIV on their cell surface and, cocultured with CD4+ T cells, they can transfer the virus to the cocultured cells leading to infection. Direct contact between human basophils or intestinal mast cells and CD4+ T cells can mediate viral trans-infection of T cells through the formation of viral synapses. Thus, basophils and mast cells can provide a cellular basis for capturing and then spreading viruses throughout the body. Collectively, these findings suggest that human basophils and mast cells play a complex and possibly distinct role in HIV infection, warranting further investigations. PMID- 27960172 TI - Effect of AST-120 in Chronic Kidney Disease Treatment: Still a Controversy? AB - AST-120 (kremezin; Kureha Chemical, Tokyo, Japan) is an oral spherical carbonaceous adsorbent, which was approved for clinical use in Japanese chronic kidney disease (CKD) patients in 1991. It adsorbs indole, the precursor of indoxyl sulfate, in the intestines and prevents indoxyl sulfate production. Indoxyl sulfate, initially identified as a major uremic toxin that causes uremic symptoms, contributes to CKD progression. Since AST-120 decreases serum indoxyl sulfate in a dose-dependent manner, multicenter prospective trials have been conducted in Japan in the 1980s; these trials were mostly in favor of the efficacy of AST-120 in delaying the initiation of dialysis in patients with advanced stage CKD. Many animal studies support the effects of AST-120 on renal outcomes as well as on cardiovascular complications. However, there are yet no reports that unequivocally demonstrate the improvement of hard renal endpoints and/or cardiovascular endpoints. This commentary briefly reviews the major outcomes of the recent clinical trials on AST-120. PMID- 27960173 TI - Fetal Heart-Rate Variability: Validation of a New Continuous, Noninvasive Computerized Analysis. AB - OBJECTIVE: We developed a computerized heart-rate variability index related to the fetal parasympathetic activity: the Fetal Stress Index (FSI). The objective was to determine whether the FSI is related to the visual analysis of the fetal heart rate (FHR). METHODS: Thirty tracings recorded at a labor ward were classified according to the NICHD categories: (I) normal FHR tracing, (II) intermediate risk of acidosis, and (III) high risk. FSI was calculated as minimum, maximum, and mean, and was evaluated before the onset of the FHR pattern, during the 10 min following, and between 10 and 20 min after that. RESULTS: The FSI for categories II and III was similar to that of category I before the onset of the FHR pattern. FSI min was lower just after the onset of the abnormal FHR in category III, compared with that of category I (33 vs. 43, p < 0.001). Between 10 and 20 min after the onset of the abnormal FHR, we observed a significant reduction in FSI min in categories II and III (44 vs. 39 vs. 29.7, p < 0.0001). CONCLUSION: Although further studies are necessary for the sake of clinical validation, FSI could constitute an interesting method for the evaluation of fetal well-being. PMID- 27960174 TI - Non-Atherosclerotic Intracranial Arterial Diseases. AB - Atherosclerosis is not the only cause of intracranial arterial disease. Arterial dissection, moyamoya disease, vascular inflammatory disease, vasospasm and immunologic disorders are important non-atherosclerotic intracranial arterial diseases. Identification of the correct etiology is important in establishing treatment strategies and assessing prognosis. Careful history taking and appropriate laboratory testing are essential. Although catheter angiography is the most important diagnostic tool to examine various intracranial arterial diseases, other diagnostic modalities such as CT angiography and MR angiography are nowadays widely used. High resolution vessel wall MRI also can assist in making the correct diagnosis as this can yield information regarding vessel wall pathology. Certain diseases such as infectious vasculopathies and moyamoya disease are more prevalent in certain parts of the world, and physicians practicing in these regions should be mindful of these disorders. In this chapter, these non-atherosclerotic intracranial arterial diseases are discussed. Moyamoya disease will be described in another chapter. PMID- 27960175 TI - Moyamoya Disease. AB - Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease characterized by progressive stenosis at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. Although its etiology is unknown, recent genetic studies have identified RNF213 in the 17q25-ter region as an important susceptibility gene of MMD among East Asian populations. A c.14576G>A polymorphism in RNF213 was identified in 95% of MMD patients with a family history and in 79% of sporadic cases, and patients carrying this polymorphism exhibited significantly earlier disease onset and a more-severe form of MMD. Due possibly to genetic differences, the prevalence of MMD is higher in East Asia (e.g., Korea and Japan) than in Western countries. The MMD prevalence peaks at two ages with different clinical presentations: around 10 years and at 30-45 years. Ischemic symptoms, including transient ischemic attacks, are the most important clinical manifestation in both children and adults. Intracranial hemorrhages are more frequent in adults than in children. Catheter angiography is a diagnostic method of choice. Magnetic resonance angiography and computed tomography angiography are noninvasive diagnostic methods. High-resolution vessel-wall magnetic resonance imaging also helps in diagnosing MMD by revealing concentric vessel-wall narrowing with basal collaterals. Surgical revascularization such as extracranial-intracranial bypass is the preferred procedure for MMD patients presenting with ischemic stroke. Surgical therapy may also be effective in patients with hemorrhages, based on recent observations in the Japan Adult Moyamoya trial. Procedure-related cerebral infarction and hyperperfusion syndrome are potential complications that can lead to neurological deterioration. PMID- 27960176 TI - The Unsolved Relationship of Alcohol and Asthma. PMID- 27960177 TI - Alterations in Fetal Leydig Cell Gene Expression during Fetal and Adult Development. AB - Fetal Leydig cells (FLCs) and adult Leydig cells (ALCs) develop in the mammalian prenatal and postnatal testes, respectively. In mice, FLCs emerge in the interstitial space of the testis as early as embryonic day 12.5 and thereafter increase in number during the fetal stage. We previously established a transgenic mouse line in which FLCs are labeled with EGFP and demonstrated that the EGFP labeled FLCs were present even in adult testes. However, the characteristics of FLCs during postnatal stages remained unclear. In the present study, a comparison of the transcriptomes of FLCs from prenatal and postnatal testes and of ALCs from adult testes revealed that FLCs gradually alter their characteristics across developmental stages and come to roughly resemble ALCs. Many cholesterogenic genes simultaneously expressed a unique alternation pattern, while many oxidative phosphorylation and beta-oxidation (both mitochondrial functions) genes showed a different unique pattern. These metabolic gene expression alterations might be triggered by milieu changes, such as nutrient and oxygen supply, from the prenatal to the postnatal period. PMID- 27960178 TI - Use and Disuse of Observational Research: The Case of Remote Monitoring in Heart Failure. PMID- 27960179 TI - Angioplasty and Stenting. AB - The high rate of recurrent strokes in patients with intracranial atherosclerotic disease (ICAS) despite medical therapy prompted intracranial angioplasty and/or stenting an adjunctive treatment option. The minute calibers of cerebral arteries, the relative paucity of supporting medial and adventitia layers, the presence of end-anastomosing perforator branches, and the vascular tortuosity from groin to head all demand specialized operative skills and dedicated tools. Since the stroke mechanism of ICAS is diverse, patient selection for endovascular treatment requires a sound understanding of the underlying pathophysiology. Patients with territorial cerebral hypo-perfusion associated with a high-grade steno-occlusive lesion may benefit most from endovascular revascularization. On the other hand, patients with atheromatous branch disease may stand a higher risk of perforator stroke from 'snow plowing' effect if angioplasty or stenting is inadvertently performed. A joint evaluation on the indication, procedural risks and benefits, and an individualized peri-operative care plan by a stroke neurologist and a neuro-interventionist is crucial prior to a procedure. Currently, the U.S. Food and Drug Administration approved Wingspan for patients who have developed two or more strokes despite aggressive medical management. The treatment indication will likely evolve in parallel with the advancement of endovascular techniques and our understanding of ICAS. PMID- 27960180 TI - Placental Growth during Normal Pregnancy - A Magnetic Resonance Imaging Study. AB - OBJECTIVE: To investigate normal human placental growth longitudinally throughout the second and third trimesters using MRI. METHODS: Twenty normal, first-time singleton pregnancies were scanned 7 times between the 14th and 38th week of gestation, at 4-week intervals, using MRI. Placental volumes were measured in both sagittal and transversal slices. All placentas were weighed after delivery to make a comparative study. RESULTS: Sixteen of the 20 women had increasing placental volumes from the 14th to 38th week of gestation. The 6th and 7th scan showed that 4 women had placentas of the same size. The mean placental volume increases linearly from the 14th till the 38th week of gestation, with a constant mean growth rate of 29.97 ml/week. The median placental volume extrapolated to delivery was to 856 ml (range 602-1,050 ml). The median weight of the exsanguinated placenta after delivery was 640 g (range 500-787 g). All pregnancies were carried to term, resulting in the delivery of healthy infants with good correlation between placental size and birth weight (R = 0.56, p = 0.009). CONCLUSION: Placental growth was measured systematically in a longitudinal study through the second and third trimesters using MRI. MRI provides a safe and feasible method to measure placental growth. The mean placental growth was linear throughout the second and third trimesters. PMID- 27960181 TI - Stroke Mechanisms. AB - Recent advances in neuroimaging technologies, such as diffusion weighted magnetic resonance imaging (MRI), perfusion weighted computed tomography (CT)/MRI, MR/CT angiography and Doppler ultrasonography allow us to determine the mechanisms of stroke and transient ischemic attack. In addition, high-resolution vessel wall MRI is nowadays increasingly used to understand the stroke mechanism in patients with intracranial atherosclerosis. Artery to artery embolism, hypoperfusion and the combination of the two are the important stroke mechanisms in patients with extracranial atherosclerosis. In addition to the above two, branch occlusion and in-situ thrombotic occlusion are important stroke mechanisms in patients with intracranial atherosclerosis. Branch occlusion leads to subcortical or brainstem infarcts indistinguishable from infarcts caused by small artery disease. In-situ thrombotic occlusion leads to larger territorial infarcts. However, whole territory infarcts are uncommon due to relatively well developed collateral circulation in these patients. The treatment strategy should be based on the correct understanding of the stroke mechanism in individual patients. PMID- 27960183 TI - Antithrombotic Therapy. AB - Symptomatic cerebral atherosclerosis including intracranial atherosclerosis (ICAS) is associated with a high risk of recurrent stroke. Antithrombotic agents are the mainstay of therapy in these patients. Several studies have found anticoagulation (warfarin) to increase the risk of bleeding events and have an efficacy no better than that of aspirin. Therefore, anticoagulants are not widely used unless patients develop recurrent ischemic symptoms despite receiving antiplatelet therapy. Because ICAS progression is not uncommon and the risk of stroke recurrence is high when aspirin monotherapy is used, dual antiplatelet agents may be needed at least in the early disease stage. The Trial of Cilostazol in Symptomatic Intracranial Stenosis (TOSS) found that aspirin plus cilostazol was significantly better than aspirin monotherapy in preventing progression (6.7 vs. 28.8%, p = 0.008). The TOSS II trial that compared aspirin plus cilostazol with aspirin plus clopidogrel found no significant difference in the progression rate (9.3% vs. 15.5%, p = 0.092). However, the overall changes in stenosis were more favorable (i.e., less progression and more regression) in the cilostazol group (p = 0.049). TOSS studies have limitations in that the end points were changes in magnetic resonance angiography results rather than clinical outcomes. Based on the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial results, and the fair outcome found in patients enrolled in the SAMMPRIS (Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis) trial, aspirin plus clopidogrel has been recommended in the early stage of symptomatic ICAS. However, the combination of aspirin and clopidogrel did not show superiority over aspirin monotherapy in ICAS patients in a recent CHANCE substudy. Considering that ICAS is the major pathology leading to stroke worldwide, further studies are needed to identify the best medication strategy in ICAS patients. Until then, physicians may choose appropriate antiplatelet agents after careful consideration of the characteristics of both the patients (i.e., degree of stenosis, stroke mechanism, risk of stroke, and risk of bleeding) and the antiplatelet agent (e.g., side effect, cost). PMID- 27960182 TI - Calcium-Phosphate-Osteopontin Particles Reduce Biofilm Formation and pH Drops in in situ Grown Dental Biofilms. AB - This 2-period crossover study investigated the effect of calcium-phosphate osteopontin particles on biofilm formation and pH in 48-h biofilms grown in situ. Bovine milk osteopontin is a highly phosphorylated glycoprotein that has been shown to interfere with bacterial adhesion to salivary-coated surfaces. Calcium phosphate-osteopontin particles have been shown to reduce biofilm formation and pH drops in a 5-species laboratory model of dental biofilm without affecting bacterial viability. Here, smooth surface biofilms from 10 individuals were treated ex vivo 6 times/day for 30 min with either calcium-phosphate-osteopontin particles or sterile saline. After growth, the amount of biofilm formed was determined by confocal microscopy, and pH drops upon exposure to glucose were monitored using confocal-microscopy-based pH ratiometry. A total of 160 biofilms were analysed. No adverse effects of repeated ex vivo treatment with calcium phosphate-osteopontin particles were observed. Particle treatment resulted in a 32% lower amount of biofilm formed (p < 0.05), but large inter-individual differences could be observed. Biofilm pH was significantly higher upon particle treatment, both shortly after the addition of glucose and after 30 min of incubation with glucose (p < 0.05). Calcium-phosphate-osteopontin particles may represent a new therapeutic approach to caries control and aim at directly targeting virulence factors involved in the caries process. Further studies are required to determine the effect of particle treatment on more acidogenic/aciduric biofilms as well as the remineralizing potential of the particles. PMID- 27960184 TI - Vessel and Vessel Wall Imaging. AB - Angiography is a useful, important, common imaging method, with digital subtraction angiography (DSA) remaining the gold standard for luminal imaging. Computed tomography angiography (CTA) is minimally invasive and quite accurate in the evaluation of stenosis. Magnetic resonance angiography (MRA) is a good screening tool with the least invasiveness. Angiography mostly represents intracranial artery disease as luminal stenosis, which is often not sufficient to evaluate intracranial vascular pathology. The modalities provide indirect information about vascular pathology because luminal change, such as stenosis, results from the changes of vessel walls. Vessel wall imaging using high resolution magnetic resonance imaging (HR-MRI) has been recently introduced for direct evaluation of vessel walls beyond just luminal information such as the severity of stenosis. HR-MRI for vessel walls can present the characteristic radiological findings for each intracranial artery disease such as atherosclerosis, dissection, moyamoya disease, and vasculitis. The radiological features are useful to differentiate among intracranial artery disease. This chapter discusses the role and radiological features of angiography and HR-MRI for vessel walls. PMID- 27960186 TI - Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer Patients Progressing after Docetaxel: A Prospective Single-Center Study. AB - PURPOSE: The present study aims to evaluate the efficacy of cabazitaxel in combination with prednisone treatment in Italian patients affected by hormone refractory metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel plus prednisone. METHODS: Thirty patients with mCRPC were enrolled between June 2013 and January 2016 (the last follow-up was in January 2016). Cabazitaxel was used according to the summary of product characteristics and administered at a dose of 25 mg/m2 every 3 weeks plus oral prednisone at a dose of 5-mg tablets twice a day continuously. The reduction in serum prostate specific antigen (PSA) was the primary endpoint while reducing pain, safety, progression-free survival, response rate and overall survival (OS) were secondary endpoints. RESULTS: Cabazitaxel was well tolerated, showing a manageable toxicity profile, associated with a modest objective response rate and a good reduction in PSA levels. Only 12 patients (40%) had a partial response, 10 patients (33%) showed stabilization of disease and 8 (27%) experienced disease progression. The median OS was 14.8 months (95% CI: 11.6-19.8). The linear regression analysis revealed that PSA response was an important predictor of OS, showing a positive correlation with OS (beta = 0.377, p < 0.01). CONCLUSIONS: Three-week treatment with cabazitaxel was found to be valid and was a well-tolerated treatment option for patients with mCRPC after a first-line docetaxel treatment. PMID- 27960185 TI - PHLDA1 Promotes Lung Contusion by Regulating the Toll-Like Receptor 2 Signaling Pathway. AB - BACKGROUND/AIMS: Lung contusion is a potentially lethal injury. Pleckstrin homology-like domain family A, member-1 (PHLDA1) is known to play crucial roles in cell proliferation and apoptosis. In this study, we investigated the biological role of PHLDA1 in lung contusion. METHODS: The expression levels of PHLDA1 and TLR2 were detected by real time PCR and western. The cytokines were determined by ELISA. The inflammatory factors were detected by flow cytometry. The lung injury was determined by HE staining. RESULTS: PHLDA1 gene and protein expression levels were up-regulated in a mouse lung-contusion model, together with increased neutrophil and macrophage contents. Down-regulation of PHLDA1 by interfering RNA (siPHLDA1 mice) decreased lung injury and neutrophil infiltration. Inflammatory factors, including interleukin (IL)-1beta, IL-6, mouse homolog of human growth-regulated oncogene-alpha (KC), tumor necrosis factor alpha, CC chemokine ligand (CCL) 2, and CCL12 were also decreased in siPHLDA1 mice. Expression levels of Toll-like receptor 2 (TLR2) were increased in the lung contusion mouse model, but were decreased when PHLDA1 was down-regulated. CONCLUSION: These results demonstrate that PHLDA1 plays a critical role in the development of progressive lung contusion and subsequent inflammation. This information furthers our understanding of the pathogenesis of lung contusion, and suggests that PHLDA1 blockade may represent a potential therapeutic strategy for the treatment of this injury. PMID- 27960187 TI - RNAi-Mediated Down-Regulation of CD47 Protects against Ischemia/Reperfusion Induced Myocardial Damage via Activation of eNOS in a Rat Model. AB - BACKGROUND/AIMS: Oxidative stress is strongly implicated in the pathogenesis of myocardial damage caused by ischemia reperfusion (I/R). Previous studies have confirmed that cardiac CD47 drives left ventricular heart failure. However, the role for CD47 in myocardial I/R injury (MIRI) has not previously been proposed. This study was designed to investigate whether down-regulation of CD47 using RNA interference (RNAi) technology can relieve inhibition of nitric oxide signaling and attenuate myocardial damage in a rat model of I/R. METHODS: Male Sprague Dawley rats (n = 40) were randomly allocated to four groups and pre-treated either with saline (Sham and I/R groups), or adenovirus expressing either control (Ad-EGFP-N) or CD47-targeting (Ad-EGFP-CD47) RNAi. After four days, the rat MIRI model was established by occluding the left anterior descending coronary artery for 30 min, followed by reperfusion for 3 h. Heart tissue was harvested and assessed by immunohistochemistry, western blot, and quantitative RT-PCR. Outcome measures included infarct size, myocardial enzyme (creatine kinase, creatine kinase-MB, and lactate dehydrogenase) levels in serum, markers of oxidative stress, and morphological changes to the myocardium. RESULTS: Delivery of Ad-EGFP CD47 RNAi into the myocardium remarkably decreased CD47 expression levels. Down regulation of CD47 was significantly associated with reduced infarct size and serum levels of myocardial enzymes, increased activity of endothelial nitric oxide synthase, increased levels of nitric oxide, and decreased levels of oxidative stress. CONCLUSION: These data indicate that down-regulation of CD47 exerts a protective effect against MIRI, which may be attributable to attenuation of oxidative stress via activation of the eNOS/NO signaling pathway. PMID- 27960188 TI - Effects of Vitamin E-Coated versus Conventional Membranes in Chronic Hemodialysis Patients: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Accruing evidence suggests that vitamin E-coated membranes (ViE-m) might improve the clinical management of chronic hemodialysis (HD) patients. METHODS: We conducted a systematic review and meta-analysis of RCTs comparing ViE m to conventional HD. Endpoints of interest were a series of biomarkers pertaining to anemia status, inflammation, oxidative stress and dialysis efficacy/status. RESULTS: Sixty studies were included. ViE-m significantly improved the Erythropoietin Resistance Index but had no impact on other anemia parameters. As for oxidative stress and inflammation, ViE-m produced a significant decrease in interleukin-6 levels, thiobarbituric acid reactive substances, plasma and red blood cell (RBC) malonylaldehyde and a significant increase in blood and RBC vitamin E. Conversely, ViE-m use had no impact on lipid profile, dialysis adequacy, blood pressure, albumin and uric acid. CONCLUSIONS: ViE-m might ameliorate anemia management by reducing oxidative stress and inflammation. Benefits of these bio-membranes on harder clinical outcomes are uncertain and need to be investigated by future, targeted trials. PMID- 27960189 TI - Surgical Therapy. AB - Many prior investigations have indicated the important role of medical treatment to prevent stroke in patients with intracranial atherosclerosis, with angioplasty and stenting occasionally being performed. In a subgroup of patients with severe hemodynamic impairment, extracranial-intracranial (EC-IC) bypass surgery may be considered. Additionally, in patients with massive infarctions due to middle cerebral artery (MCA) occlusion, the use of decompressive craniectomy may lower mortality rates and improve long-term quality of life. However, the benefit of these surgical procedures in patients with intracranial atherosclerosis has long been controversial. In this chapter, we review the surgical therapies for patients with intracranial atherosclerosis. This review does not include EC-IC bypass surgery for moyamoya disease, which is discussed in another chapter. PMID- 27960190 TI - Epidemiology. AB - Intracranial atherosclerotic occlusive disease is an important and possibly the most common cause of stroke worldwide. Asian, Black and certain Hispanic populations have a high risk of harboring intracranial occlusive disease. In this chapter we review the epidemiology of intracranial occlusive disease by primarily focusing on studies from China, Japan, Korea, and other Asian countries. In addition, we compare and contrast the information from Asian countries with that from North America and related regions. Finally, we explore hypotheses concerning the origin of race-ethnic differences in the distribution of extracranial and intracranial atherosclerotic disease. PMID- 27960192 TI - Transcranial Doppler. AB - Transcranial Doppler ultrasonography (TCD) is the only diagnostic modality that provides a reliable evaluation of intracranial blood flow patterns in real-time. The physiological information obtained from TCD is complementary to the anatomical details obtained from other neuroimaging modalities. TCD is relatively cheap, can be performed bedside, and allows monitoring in acute emergency settings. TCD criteria for intracranial stenosis have been validated against various forms of angiographic studies and serve as reliable tools for screening, diagnostic as well as follow up purposes. TCD findings of intracranial stenosis have acceptable accuracy parameters for anterior as well as posterior circulation. Extended applications of TCD, especially emboli monitoring and assessment of vasomotor reactivity, provide important information about the pathophysiology of cerebrovascular ischemia and risk stratification. Therefore, TCD has become an integral component of the armamentarium of stroke neurologists for understanding stroke etiopathogenesis, planning and monitoring definitive treatment and determining the prognosis. We present the basic principles of TCD, techniques of test performance, diagnostic methods as well as some of the advanced applications of TCD in patients with intracranial stenosis. PMID- 27960193 TI - Celecoxib safety revisited. PMID- 27960191 TI - Pathological Characteristics. AB - Within the intracranial vasculature, atherosclerosis occurs in two distinctive patterns: (1) in Western populations who have severe extracranial and systemic atherosclerosis, the severity of intracranial involvement is consistently less than that within extracranial arteries; and (2) in Asians, Africans, and Hispanics, who often have isolated intracranial arterial disease that is found to be more often accompanied by brain infarction than comparable extracranial atherosclerotic disease. Compared to coronary and extracranial carotid atherosclerosis, intracranial atherosclerosis has distinct pathological characteristics compared to that of extracranial arteries. Intracranial atherosclerosis (ICAS) had been understudied due to the relative inaccessibility of cerebral artery specimens under current treatment strategies. Acquiring post mortem cerebral vessel specimens for histology processing is the most direct method to analyze the pathological characteristics of ICAS, in order to analyze both lumen stenosis and plaque components contributing to brain infarctions. The developments in high resolution magnetic resonance imaging (HRMRI) make it feasible to assess human ICAS in vivo. It is nevertheless challenging to understand vessel wall changes within brain vasculature demonstrated on HRMRI, as well as to identify biomarkers for stroke risk stratification and treatment strategy modification. Knowledge about intracranial atherosclerosis remains limited due to lack of human arterial specimens, and the development of proper animal models of human cerebral atherosclerosis is necessary to explore the pathogenesis of intracranial atherosclerosis and to assess various strategies preventing or treating ICAS-related stroke. PMID- 27960194 TI - Drugs for psychotic disorders. PMID- 27960195 TI - Propositional Density in Spoken and Written Language of Czech-Speaking Patients With Mild Cognitive Impairment. AB - Purpose: Propositional density (PD) is a measure of content richness in language production that declines in normal aging and more profoundly in dementia. The present study aimed to develop a PD scoring system for Czech and use it to compare PD in language productions of older people with amnestic mild cognitive impairment (aMCI) and control participants matched on age, gender, and education. Method: Groups of patients with aMCI and cognitively healthy control participants (N = 20 each) provided short spoken and written language samples. Two samples were elicited for each modality, 1 describing recent events and 1 describing childhood memories. Series of neuropsychological tests were administered. The groups were compared using t-tests and the relations between measures using correlation coefficients. Results: PD was lower in spoken productions of patients with aMCI, compared with control participants, but only in language samples using remote memories. PD in these samples was related to verbal fluency and education but not to working memory. PD in written samples did not differ between participants with aMCI and control participants. Conclusions: PD in spoken language reflects the cognitive decline in people with aMCI, but the effect is relatively mild. The results support the existing findings that PD is related to verbal fluency. PMID- 27960196 TI - Visual Context Enhanced: The Joint Contribution of Iconic Gestures and Visible Speech to Degraded Speech Comprehension. AB - Purpose: This study investigated whether and to what extent iconic co-speech gestures contribute to information from visible speech to enhance degraded speech comprehension at different levels of noise-vocoding. Previous studies of the contributions of these 2 visual articulators to speech comprehension have only been performed separately. Method: Twenty participants watched videos of an actress uttering an action verb and completed a free-recall task. The videos were presented in 3 speech conditions (2-band noise-vocoding, 6-band noise-vocoding, clear), 3 multimodal conditions (speech + lips blurred, speech + visible speech, speech + visible speech + gesture), and 2 visual-only conditions (visible speech, visible speech + gesture). Results: Accuracy levels were higher when both visual articulators were present compared with 1 or none. The enhancement effects of (a) visible speech, (b) gestural information on top of visible speech, and (c) both visible speech and iconic gestures were larger in 6-band than 2-band noise vocoding or visual-only conditions. Gestural enhancement in 2-band noise-vocoding did not differ from gestural enhancement in visual-only conditions. Conclusions: When perceiving degraded speech in a visual context, listeners benefit more from having both visual articulators present compared with 1. This benefit was larger at 6-band than 2-band noise-vocoding, where listeners can benefit from both phonological cues from visible speech and semantic cues from iconic gestures to disambiguate speech. PMID- 27960198 TI - Preliminary Results From the US Zika Pregnancy Registry: Untangling Risks for Congenital Anomalies. PMID- 27960199 TI - [Using a Standardized Questionnaire for Coagulation Assessment in Children Undergoing Tonsillectomy]. PMID- 27960197 TI - Birth Defects Among Fetuses and Infants of US Women With Evidence of Possible Zika Virus Infection During Pregnancy. AB - Importance: Understanding the risk of birth defects associated with Zika virus infection during pregnancy may help guide communication, prevention, and planning efforts. In the absence of Zika virus, microcephaly occurs in approximately 7 per 10 000 live births. Objective: To estimate the preliminary proportion of fetuses or infants with birth defects after maternal Zika virus infection by trimester of infection and maternal symptoms. Design, Setting, and Participants: Completed pregnancies with maternal, fetal, or infant laboratory evidence of possible recent Zika virus infection and outcomes reported in the continental United States and Hawaii from January 15 to September 22, 2016, in the US Zika Pregnancy Registry, a collaboration between the CDC and state and local health departments. Exposures: Laboratory evidence of possible recent Zika virus infection in a maternal, placental, fetal, or infant sample. Main Outcomes and Measures: Birth defects potentially Zika associated: brain abnormalities with or without microcephaly, neural tube defects and other early brain malformations, eye abnormalities, and other central nervous system consequences. Results: Among 442 completed pregnancies in women (median age, 28 years; range, 15-50 years) with laboratory evidence of possible recent Zika virus infection, birth defects potentially related to Zika virus were identified in 26 (6%; 95% CI, 4%-8%) fetuses or infants. There were 21 infants with birth defects among 395 live births and 5 fetuses with birth defects among 47 pregnancy losses. Birth defects were reported for 16 of 271 (6%; 95% CI, 4%-9%) pregnant asymptomatic women and 10 of 167 (6%; 95% CI, 3%-11%) symptomatic pregnant women. Of the 26 affected fetuses or infants, 4 had microcephaly and no reported neuroimaging, 14 had microcephaly and brain abnormalities, and 4 had brain abnormalities without microcephaly; reported brain abnormalities included intracranial calcifications, corpus callosum abnormalities, abnormal cortical formation, cerebral atrophy, ventriculomegaly, hydrocephaly, and cerebellar abnormalities. Infants with microcephaly (18/442) represent 4% of completed pregnancies. Birth defects were reported in 9 of 85 (11%; 95% CI, 6%-19%) completed pregnancies with maternal symptoms or exposure exclusively in the first trimester (or first trimester and periconceptional period), with no reports of birth defects among fetuses or infants with prenatal exposure to Zika virus infection only in the second or third trimesters. Conclusions and Relevance: Among pregnant women in the United States with completed pregnancies and laboratory evidence of possible recent Zika infection, 6% of fetuses or infants had evidence of Zika-associated birth defects, primarily brain abnormalities and microcephaly, whereas among women with first-trimester Zika infection, 11% of fetuses or infants had evidence of Zika associated birth defects. These findings support the importance of screening pregnant women for Zika virus exposure. PMID- 27960200 TI - Systematic Review and Meta-analysis: Gene Association Studies in Neonatal Sepsis. AB - Background Association studies of various gene variants in neonatal sepsis show conflicting results. Objective We performed a systematic review of candidate gene association studies in neonatal sepsis to provide pooled estimates of risk for selected gene variants. Methods We performed a search using MeSH terms "infection," "sepsis," "infant," "genetic variation," "polymorphism," and "genetic association studies." We included studies evaluating associations between neonatal sepsis and genetic variants (2000-2015). We excluded case reports/series, commentaries, narrative reviews, and nonhuman research. We assessed quality of studies using STREGA guidelines. Following estimation of odds ratios (ORs), data were pooled using random effects models. Results Twenty eight of 1,404 identified studies were included. Meta-analyses were performed for interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), and IL-10 as these gene variants were tested in multiple studies. TNF-alpha 308GG genotype demonstrated trends toward increased sepsis risk in the primary analysis of culture-proven sepsis (OR 1.18, 95% confidence interval [CI] 0.97-1.44). IL-10 1082GG genotype was associated with lower sepsis odds in very low-birth-weight (VLBW) infants (OR 0.51, 95% CI 0.29-0.91). Conclusion We uncovered an association between IL-10 1082 gene variation and sepsis in VLBW infants but did not identify associations between neonatal sepsis and TNF-alpha 308 or IL-6 gene variation. Larger cohort replication studies are required to validate these findings. PMID- 27960201 TI - "We Sing from the Diaphragm a Lot!" PMID- 27960203 TI - Community-Acquired Pneumonia: A Global Perspective. PMID- 27960202 TI - Diaphragm Season. PMID- 27960204 TI - Community-acquired Pneumonia: A Global Perspective. AB - Community-acquired pneumonia (CAP) is a global disease responsible for a large proportion of deaths and having significant economic cost. As diagnostic tools have increased in sensitivity, our understanding of the etiology of CAP has begun to change with a significant increase in confirmed viral infections and the recognition that multiple pathogens are frequently present. Empiric therapy remains the standard of care and guidelines are mostly based on published data from the United States or Europe. Blindly applying guidelines without any consideration of local etiological differences can lead to a risk of under or overtreatment. Several pathogens are particularly problematic in the setting of CAP in some regions as they are not covered by standard guidelines; in particular, Mycobacterium tuberculosis, Burkholderia pseudomallei, and Acinetobacter baumanii. Overtreatment of patients meeting guideline criteria for healthcare-associated pneumonia is also a problem as this categorization probably only applies to a limited number of areas in the United States. New pathogens are emerging more frequently, as evidenced by severe acute respiratory syndrome, Middle East respiratory syndrome, influenza A H1N1 09, and avian influenza, all of which have global ramifications and good clinicians need to stay informed of evolving threats. There are clearly differences in outcomes from CAP across the globe, but accurately comparing them is difficult given the vast differences in age, comorbidities, and access to healthcare. Improved quality of outcome databases will be a key driver of quality improvement in coming years. PMID- 27960205 TI - The Role of Streptococcus pneumoniae in Community-Acquired Pneumonia. AB - Streptococcus pneumoniae (the pneumococcus) remains one of the most common causes of bacterial community-acquired pneumonia (CAP), encompassing infections mild enough to be treated on an outpatient basis, as well as those requiring hospital care, or even intensive care unit admission. This microorganism is associated with a significant burden of disease, causing substantial morbidity and mortality worldwide, and generating considerable health-care costs. The reason that pneumococcal CAP remains such a common cause of disease relates to the presence of several risk factors for this infection in patients throughout the world. Such risk factors include extremes of age, lifestyle factors, including smoking and alcohol abuse, and various underlying comorbid conditions, including congenital and acquired immunodeficiencies. This article will review various aspects of pneumococcal CAP, including the burden of pneumococcal disease, risk factors for pneumococcal infection, the occurrence of cardiovascular events in patients with pneumococcal CAP, the apparently pivotal role of pneumolysin, a major virulence factor of the pneumococcus, in the pathogenesis of severe infection and associated cardiac dysfunction, empiric antibiotic treatment for pneumococcal CAP, as well as adjunctive therapies, specifically those which target pneumolysin, and, finally, the mortality of such infections. PMID- 27960206 TI - Role of Atypical Pathogens in the Etiology of Community-Acquired Pneumonia. AB - Atypical pneumonia has been described for over 100 years, but some of the pathogens attributed to it have been identified only in the past decades. The most common pathogens are Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila. The epidemiology and pathophysiology of these three pathogens have been studied since their discovery, and are reviewed herein to provide better insight when evaluating these patients, which hopefully translates into improved care. The incidence of atypical pathogens has been shown to be approximately 22% worldwide, but this probably varies with location. The history and physical exam of a patient with atypical pneumonia reveals how patients share many signs and symptoms with their counterpart patients who have typical pneumonias; therefore, the diagnosis primarily depends on laboratory identification, which is evolving and improving. What started out as simple, but difficult to yield cultures, has progressed to modern molecular-based testing assays. Treatment is missed if an empiric regimen includes only monotherapy with a beta-lactam antimicrobial; so, many country guidelines, including the Infectious Diseases Society of America/American Thoracic Society guidelines for community-acquired pneumonia, recommend using a regimen containing either a macrolide or a fluorinated quinolone. Once an atypical pathogen has been identified, evidence trends toward favoring a quinolone, but more data are needed to confirm. The concept of using combination therapy in severe patients is also explored. PMID- 27960207 TI - Antibiotic Resistance in Community-Acquired Pneumonia Pathogens. AB - The overwhelming majority of cases of community-acquired pneumonia (CAP) can be treated with the standard antibiotic regimens of a macrolide and cephalosporin or a fluoroquinolone. Despite high rates, current levels of beta-lactam resistance generally do not result in treatment failure for patients with CAP when appropriate agents and doses are used. Following the introduction of the pneumococcal conjugate vaccines, the incidence of invasive pneumococcal disease declined drastically, coinciding with a decrease in penicillin resistance. Risk factors for methicillin-resistant S. aureus follow two patterns: (1) healthcare associated risk factors and (2) pneumonia from exotoxin-producing community acquired strains. The latter is associated with need for antibiotics which inhibit protein synthesis for optimal management. Since 2000, macrolide resistance in M. pneumoniae has rapidly emerged worldwide, especially in Asian countries. The inability to routinely culture H. influenzae suggests that macrolide and beta-lactam resistance, while present, is not a big issue. Unless risk factors for a hospital-associated strain are present, the most common Enterobacteriaceae to cause CAP, including Escherichia coli and Klebsiella, are generally susceptible to usual CAP antibiotics. Given the limited role of antibiotic resistance in CAP, a strong rationale is needed for use of antibiotics other than the standard beta-lactam/macrolide or fluoroquinolone regimens. PMID- 27960209 TI - Community-Acquired Pneumonia in Sub-Saharan Africa. AB - Community-acquired pneumonia (CAP) in sub-Saharan Africa is a common cause of adult hospitalization and is associated with significant mortality. Human immunodeficiency virus (HIV) prevalence in the region leads to differences in CAP epidemiology compared with most high-income settings: patients are younger, and coinfection with tuberculosis and opportunistic infections is common and difficult to diagnose. Resource limitations affect the availability of medical expertise as well as radiological and laboratory diagnostic services. These factors impact on key aspects of health care, including pathways of investigation, severity assessment, and the selection of empirical antimicrobial therapy. This review summarizes recent data from sub-Saharan Africa describing the burden, etiology, risk factors, and outcome of CAP. We describe the rational and context-appropriate approach to CAP diagnosis and management, including supportive therapy. Priorities for future research to inform strategies for CAP prevention and initial management are suggested. PMID- 27960208 TI - Community-Acquired Pneumonia in the Asia-Pacific Region. AB - Community-acquired pneumonia (CAP) is an important cause of mortality and morbidity worldwide. Aging population, dense urbanization, and poor access to health care make the Asia-Pacific region vulnerable to CAP. The high incidence of CAP poses a significant health and economic burden in this region. Common etiologic agents in other global regions including Streptococcus pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, Chlamydophila pneumoniae, Staphylococcus aureus, and respiratory viruses are also the most prevalent pathogens in the Asia-Pacific region. But the higher incidence of Klebsiella pneumoniae and the presence of Burkholderia pseudomallei are unique to the region. The high prevalence of antimicrobial resistance in S. pneumoniae and M. pneumoniae has been raising the need for more prudent use of antibiotics. Emergence and spread of community-acquired methicillin-resistant S. aureus deserve attention, while the risk has not reached significant level yet in cases of CAP. Given a clinical and socioeconomic importance of CAP, further effort to better understand the epidemiology and impact of CAP is warranted in the Asia Pacific region. PMID- 27960210 TI - Community-Acquired Pneumonia in Latin America. AB - Community-acquired pneumonia (CAP) is associated with significant morbidity and mortality in Latin America and the Caribbean (LAC) region. Poverty, socioeconomic factors, and malnutrition influence the incidence and outcome of CAP in LAC. In LAC, Streptococcus pneumoniae is the most frequent microorganism responsible for CAP, (incidence: 24-78%); the incidence of atypical microorganisms is similar to other regions of the world. Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) is a growing problem in the LAC region, with the Caribbean being the second most affected area worldwide after Sub-Saharan Africa. Pneumococcal pneumonia remains the most common cause of CAP in HIV-infected patients, but Pneumocystis jirovecii and tuberculosis (TB) are also common in this population. The heterogeneity of the health care systems and social inequity between different countries in LAC, and even between different settings inside the same country, is a difficult issue. TB, including multidrug-resistant TB, is several times more common in South American and Central American countries compared with North America. Furthermore, hantaviruses circulating in the Americas (new world hantaviruses) generate a severe respiratory disease called hantavirus pulmonary syndrome, with an associated mortality as high as 50%. More than 30 hantaviruses have been reported in the Western Hemisphere, with more frequent cases registered in the southern cone (Argentina, Chile, Uruguay, Paraguay, Bolivia, and Brazil). Respiratory viruses (particularly influenza) remain an important cause of morbidity and mortality, particularly in the elderly. Low rates of vaccination (against influenza as well as pneumococcus) may heighten the risk of these infections in low- and middle-income countries. PMID- 27960211 TI - The Modern Diagnostic Approach to Community-Acquired Pneumonia in Adults. AB - Respiratory tract infections, the majority of which are community acquired, are among the leading causes of death worldwide and a leading indication for hospital admission. The burden of disease demonstrates a "U"-shaped distribution, primarily affecting young children as the immune system matures, and older adults as the process of immunosenescence and accumulation of comorbidities leads to increased susceptibility to infection. Diagnosis of community-acquired pneumonia (CAP) is traditionally based on demonstration of a new infiltrate on a chest radiograph in a patient presenting with an acute respiratory illness or sepsis. Advances in diagnosis have been slow, and although there are increasing data on the value of computed tomography or lung ultrasound as more sensitive diagnostic methodologies, they are not widely used as initial diagnostic tests. There are a wide range of differential diagnoses and pneumonia "mimics" which should be considered in patients presenting with CAP. Once the diagnosis of CAP has been made, identifying the causative microorganism is the next stage in the diagnostic process. Traditional culture-based approaches are relatively insensitive and achieve a positive diagnosis in only 30 to 70% of cases, even when rigorously applied. Urinary antigen tests, polymerase chain reaction assays, and even next generation sequencing technologies have become available and are increasing the rates of positive diagnosis. In an era of increasing antimicrobial resistance, the accurate diagnosis of CAP and determining the causative pathogen are ever more important. Getting these both right is key in reducing both morbidity and mortality from CAP, and appropriate antimicrobial stewardship which is now an international healthcare priority. PMID- 27960212 TI - Severity Assessment and the Immediate and Long-Term Prognosis in Community Acquired Pneumonia. AB - Severity assessment is a crucial step in the initial management of patients with community-acquired pneumonia (CAP). While approximately half of patients are at low risk of death and can be safely treated as outpatients, around 20% are at increased risk. While CURB-65 (confusion, respiratory rate, blood pressure, urea) and pneumonia severity index (PSI) scores are equally useful as an adjunct to clinical judgment to identify patients at low risk, the so-called minor American Thoracic Society/Infectious Diseases Society of America criteria are predictive of patients in need of intensified treatment (i.e., mechanical ventilation and/or vasopressor treatment). Such patients represent medical emergencies. In elderly patients, CRB-65 (confusion, respiratory rate, blood pressure, age) is no longer predictive of low risk; instead, poor functional status is the best predictor of death. In addition to scores, assessment of oxygenation and unstable comorbidity, as well as lactate and biomarkers remain important to consider. The added value of combined clinical and biomarker risk stratification strategies should be evaluated in large prospective interventional trials.Survivors of hospitalized CAP have a considerable excess long-term mortality. Risk factors include age, male gender, and nursing home residency, as well as increased PSI and CURB-65 scores. Cardiovascular, pulmonary, renal, and neoplastic comorbidities are prominent causes of long-term mortality. Comorbidities are vulnerable to both the acute and chronic subclinical inflammatory challenge delivered by pulmonary infection and are thereby drivers of mortality. Biomarkers are promising in identifying patients at increased risk of long-term mortality. Future studies should develop consistent strategies of risk stratification and intervention to improve long-term outcomes of patients with CAP. PMID- 27960213 TI - Complication of Community-Acquired Pneumonia (Including Cardiac Complications). AB - Community-acquired pneumonia (CAP) represents an important public health problem and carries significant morbidity, mortality, and costs. The incidence of CAP is highest among children and elderly patients, but the mortality is much higher in patients older than 65 years. Despite the advances in medicine, the administration of antimicrobials, and the overall better care, there are still patients with CAP dying due to systemic complications all over the world. A continuum of CAP disease progression may involve multiple organs beyond the pulmonary parenchyma. These pulmonary and nonpulmonary complications are associated not only with mortality but also with the development of clinical failure, prolonged hospitalization, and the need for more intensive level of care. In this review, we present the characteristics of several CAP-related pulmonary and nonpulmonary organ dysfunction, such as those affecting the heart, kidneys, hematological, neurological, endocrine systems. Multiple severity of illness scores identified a series of systemic findings that indicate the organ dysfunctions and the associated related outcomes. However, further research is required to address the mechanisms, the management, and prevention of organ dysfunction in patients with CAP. PMID- 27960214 TI - Principles of Antibiotic Management of Community-Acquired Pneumonia. AB - Community-acquired pneumonia (CAP) encompasses a broad spectrum of disease severity and may require outpatient, inpatient, or intensive care management. Successful treatment hinges on expedient delivery of appropriate antibiotic therapy tailored to both the likely offending pathogens and the severity of disease. This review summarizes key principles in starting treatment and provides recommended empiric therapy regimens for each site of care. In addition, we discuss the antimicrobial and anti-inflammatory role macrolides play in CAP, as well as specific information for managing individual CAP pathogens such as community-acquired methicillin-resistant Staphylococcus aureus and drug-resistant Streptococcus pneumoniae. We also examine several novel antibiotics being developed for CAP and review the evidence guiding duration of therapy and current best practices for the transition of hospitalized patients from intravenous antibiotics to oral therapy. PMID- 27960215 TI - Nonantibiotic Adjunctive Therapies for Community-Acquired Pneumonia (Corticosteroids and Beyond): Where Are We with Them? AB - Community-acquired pneumonia (CAP) is a leading cause of hospitalization, morbidity, and mortality. Despite advances in antibiotic treatments, mortality among patients with CAP is still high. For this reason, interest has been focused on nonantibiotic therapeutic measures directed to the host response rather than the microorganism. The development of an efficacious adjunctive treatment has important implications for reducing mortality in CAP. Some clinical studies performed in the last decade have shown a clinically beneficial effect of corticosteroids, possibly by diminishing local and systemic inflammatory host response. Recent meta-analyses showed faster resolution of symptoms, shorter time to clinically stability, reduction of mechanical ventilation needed, and reduction of mortality in the most severe population, although some methodological limitations must be taken into account. In addition, some studies using statins also suggested improved outcomes due to its anti-inflammatory effect in CAP, although this requires further research. Other adjunctive therapies such as immunoglobulins and stem cells are being explored, but are not yet in the stage of clinical trials. In summary, the use of corticosteroids and other adjuvant treatments are promising in CAP, but more studies are needed to determine their impact on mortality. PMID- 27960216 TI - Dilatation of Vascular Prostheses in Ascending Aortic Position: A Long-Term Follow-Up Computed Tomography Study with Comparison of Different Measurement Methods. AB - BACKGROUND: The aim of this study was to evaluate long-term dilatation of Hemashield Gold and Hemashield Platinum vascular prostheses in ascending aortic position using different measurement methods to obtain precise results. METHODS: Between 1999 and 2007, 73 patients with Stanford type A dissection received ascending aortic replacement with Hemashield Gold and Hemashield Platinum prostheses. Measurements were performed using multiplanar reconstruction mode of electrocardiogram (ECG)-gated, multislice spiral computed tomography (MSCT) in strictly orthogonal cross-sectional planes. Different methods of measurement were compared and maximum dilatation was estimated for different time spans. RESULTS: Diameters calculated from the measured circumference showed a significant (p = 0.037) but clinically not relevant difference (0.1 mm) to the mean between the largest and the shortest cross-sectional diameter of the prosthesis. Dilatation after 24.2 +/- 10.2 months was 8.5 +/- 4.5%. Long-term dilatation after 91.8 +/- 34 months amounted to 11.8 +/- 4.2%. CONCLUSION: Based on ECG-gated MSCT images, the presented methods of measurement provided reliable results. Long-term analysis shows low dilatation rates for Hemashield prostheses, which therefore can be considered as safe from this point of view. Nevertheless, a maximal dilatation of 20% could be relevant in valve sparing root replacement. It remains unclear if a dilatation like this contributes to the formation of suture aneurysms. PMID- 27960218 TI - Saponins: Current Progress and Perspectives. PMID- 27960217 TI - Iatrogenic Catheter-Induced Acute Aortic Dissection Type A after Coronary Angiography-A Retrospective Consecutive Case Series. AB - Background Acute aortic dissection type A (AADA) is one of the most life threatening situations and surgical demanding procedures even today. Usually AADA develops spontaneously, but it can be related also to interventional procedures. Methods We analyzed the data of 14 patients surgically treated in our institution with catheter-induced AADA (ciAADA) during coronary angiography between January 2004 and December 2014. Data were compared with overall AADA patients in this time period (n = 288). Results Nine of the 14 patients were female. Subjects were significantly older compared to the AADA patients (69 +/- 11 vs. 62 +/- 11; p = 0.021). At admission, ciAADA patients were more often hemodynamically instable and mechanically ventilated. Twelve patients underwent replacement of the ascending aorta and two patients received a modified Bentall operation. Cardiopulmonary bypass time (210 +/- 92 vs. 172 +/- 51 min) and cross-clamp time (122 +/- 63 vs. 92 +/- 40 min) were significantly longer due to additional coronary artery bypass grafts in 71.4 versus 3.1% due to myocardial ischemia. Operative mortality (7.1 vs. 2.1%, p = 0.29) and 30-day mortality (50.0 vs. 10.7%, p < 0.001) were higher in the ciAADA group. Conclusion Coronary angiography-induced AADA is a rare but severe complication. Due to additional myocardial ischemia and preoperative hemodynamic instability, patients with ciAADA have adverse outcome compared to overall AADA patients. PMID- 27960219 TI - An MRI Evaluation of Patients Who Underwent Treatment with a Cell-Mediated Gene Therapy for Degenerative Knee Arthritis: A Phase IIa Clinical Trial. AB - Multiple therapies have been developed to slow down the progression of knee osteoarthritis (OA), with the aim of avoiding or delaying TKA. One such potential method is cell-mediated gene therapy, which utilizes allogeneic human chondrocytes modified to express transforming growth factor-beta1. Using magnetic resonance imaging (MRI), we evaluated patients who underwent treatment with this injection in a Phase II study and assessed structural changes in: (1) bone marrow edema lesions, (2) cartilage defect depth and surface area, (3) articular bone surface and osteophytes, and (4) meniscus structure and signal, as well as changes in (5) joint fluid, (6) periarticular inflammation, and (7) synovial inflammation. Twenty-seven patients (6 men and 21 women) who had late-stage OA were randomized 1:1 to receive a 3:1 mixture of nontransduced chondrocytes and genetically engineered chondrocytes, at doses of 6 * 106 cells (group 1) or 1.8 * 107 cells (group 2). MRI was performed at baseline (preinjection), and at 6 and 12 months postinjection. The whole-organ MRI score system was used to assess the aforementioned changes. Treatment was considered to be successful if patients experienced an improvement in or no change in their scores, indicating that the disease had not progressed. All patients in both cohorts individually demonstrated an improvement or no change in one or more of the assessment parameters. At 6 months, the low-dose cohort demonstrated worsening in mean scores in one parameter (bone surface and osteophytes), while the high-dose cohort demonstrated no worsening in mean scores. At 12 months, the low-dose cohort had worsening in the mean score in a subset of one parameter (cartilage signal intensity), and the high-dose cohort demonstrated worsening in mean scores in two parameters (bone surface osteophytes and periarticular inflammation). This is the first study to evaluate MRI changes in patients treated with this injection. These findings provide an impetus for further research on this topic, as well as a starting point for Phase III testing. PMID- 27960220 TI - [Switching the Treatment Regime from PRN (pro re nata, as needed) to T&E (Treat and Extend) for Intravitreal Therapy with Anti-VEGF Agents in Private Practice or Small Institutions]. AB - In everyday practice, intravitreal therapy in an "as needed" regimen (pro re nata, PRN) is less predictable and requires more visits (monitoring and injections taken together) with poorer functional results than with the treat and extend (T&E) regimen. Current literature supports the benefit of a switch. However, practical advice is still missing. This article provides "best practice" recommendations for private practice or smaller institutions for the change from PRN to T&E. The requirements are organisational adjustments, staff training, definition of the scenario triggering the switch (A - functional or anatomical deterioration; B - general switch at a predefined date), counselling of the patients, defining benchmarks for the follow-up of the switch and preparing for higher capacity utilisation during the transition (shorter treatment intervals during the switching phase). Guidance is provided for each phase (a, preparation; b, transition; and c, follow-up). PMID- 27960221 TI - [Extended Left Hemihepatectomy with Reconstruction of The Right Liver Vein in a Patient with an Intrahepatic Cholangiocellular Carcinoma]. AB - Extended left hemihepatectomy (left trisectionectomy) with resection of liver segments 1, 2, 3, 4 a/b, 5 and 8 is a challenging procedure. In well-selected patients, the indication for this procedure may offer the chance of curative resection for primary or secondary liver tumours in complicated locations. Morbidity and mortality are increased compared to non-extended liver resections. This procedure requires precise imaging and accurate surgical planning in due consideration of the remaining liver volume and additional factors such as preliminary damage of the liver parenchyma caused by chemotherapy or fibrosis/cirrhosis. Left trisectionectomy is necessary in tumours affecting either the middle and left hepatic vein or the blood vessels of the liver hilum to the left and middle liver sector. The procedure necessitates the preservation of the right hepatic vein and the portal-venous and arterial branches supplying segments 6 and 7, as well as the bile ducts of these segments. This video article illustrates the surgical procedure of extended left hemihepatectomy performed due to an intrahepatic cholangiocellular carcinoma, which centrally surrounds the left and middle hepatic vein and potentially infiltrates the right hepatic vein. This condition requires the tangential resection and reconstruction of the right hepatic vein. PMID- 27960222 TI - Factors Predisposing to Dislocation After Primary Total Hip Arthroplasty: A Multivariate Analysis of Risk Factors at 7 to 10 Years Follow-up. AB - BACKGROUND: Dislocation of primary THA (total hip arthroplasty) is one of the most undesirable complications with an incidence ranging from 2% to 5%. Several risk factors are described, related to the patient, surgery, or prosthetic design. The aim of the study was to assess risk factors and their potential influence on dislocation. MATERIALS AND METHODS: 387 primary THA were performed between September 2005 to December 2008 at our institute (Varese, Italy) through a modified posterior-lateral approach. Clinical evaluation was based on range of motion (ROM) and Harris Hip Score; femoral offset, acetabular inclination, and anteversion were measured on plain radiograms. Data were analyzed by SPSS software (SPSS, Inc., Chicago, Illinois). RESULTS: Excellent ROM and Harris Hip Scores were achieved in more than 95% of patients (p<0.05). The offset was restored in all patients. Most of the cases had their cup positioned in the "safe zone" (both inclination and anteversion). Six dislocations (1.87%) occurred: significant correlation was found between dislocation and preoperative diagnosis of femoral neck fracture. CONCLUSIONS: THA dislocation rate appears not to be related to patient biometric parameters and prosthesis design. Femoral neck fracture is reported as the major risk factor for this complication, probably caused by higher preoperative activity and lesser compliance of the patient. PMID- 27960223 TI - The impact of geographic unit of analysis on socioeconomic inequalities in cancer survival and distant summary stage - a population-based study. AB - OBJECTIVE: When using area-level disadvantage measures, size of geographic unit can have major effects on recorded socioeconomic cancer disparities. This study examined the extent of changes in recorded socioeconomic inequalities in cancer survival and distant stage when the measure of socioeconomic disadvantage was based on smaller Census Collection Districts (CDs) instead of Statistical Local Areas (SLAs). METHODS: Population-based New South Wales Cancer Registry data were used to identify cases diagnosed with primary invasive cancer in 2000-2008 (n=264,236). Logistic regression and competing risk regression modelling were performed to examine socioeconomic differences in odds of distant stage and hazard of cancer death for all sites combined and separately for breast, prostate, colorectal and lung cancers. RESULTS: For all sites collectively, associations between socioeconomic disadvantage and cancer survival and distant stage were stronger when the CD-based socioeconomic disadvantage measure was used compared with the SLA-based measure. The CD-based measure showed a more consistent socioeconomic gradient with a linear upward trend of risk of cancer death/distant stage with increasing socioeconomic disadvantage. Site-specific analyses provided similar findings for the risk of death but less consistent results for the likelihood of distant stage. CONCLUSIONS: The use of socioeconomic disadvantage measure based on the smallest available spatial unit should be encouraged in the future. Implications for public health: Disadvantage measures based on small spatial units can more accurately identify socioeconomic cancer disparities to inform priority settings in service planning. PMID- 27960224 TI - Tuberculosis and gender in the Asia-Pacific region. PMID- 27960225 TI - Gender differences in the dialysis treatment of Indigenous and non-Indigenous Australians. AB - OBJECTIVE: Access to dialysis treatment and the types of treatments employed in Australia differs by Indigenous status. We examined whether dialysis treatment utilisation in Indigenous and non-Indigenous Australians also differs by gender. METHODS: Using registry data we evaluated 21,832 incident patients (aged >=18 years) commencing dialysis, 2001-2013. Incidence rates were calculated and multivariate regression modelling used to examine differences in dialysis treatment (modality, location and vascular access creation) by race and gender. RESULTS: Dialysis incidence was consistently higher in Indigenous women compared to all other groups. Compared to Indigenous women, both non-Indigenous women and men were more likely to receive peritoneal dialysis as their initial treatment (non-Indigenous women RR=1.91, 95%CI 1.55-2.35; non-Indigenous men RR=1.73, 1.40 2.14) and were more likely to commence initial treatment at home (non-Indigenous women RR=2.07, 1.66-2.59; non-Indigenous men RR=1.95, 1.56-2.45). All groups were significantly more likely than Indigenous women to receive their final treatment at home. CONCLUSIONS: Contemporary dialysis treatment in Australia continues to benefit the dominant non-Indigenous population over the Indigenous population, with non-Indigenous men being particularly advantaged. Implications for Public Health: Treatment guidelines that incorporate a recognition of gender-based preferences and dialysis treatment options specific to Indigenous Australians may assist in addressing this disparity. PMID- 27960226 TI - Correlates of physical activity among Australian Indigenous and non-Indigenous adolescents. AB - OBJECTIVE: Physical inactivity is an important modifiable cause of the excess burden of disease among Indigenous Australians. We describe physical activity patterns and influencing factors, comparing Indigenous and non-Indigenous adolescents. METHODS: Indigenous (n=359) and non-Indigenous (n=637) adolescents aged 13-17 years from disadvantaged New South Wales regions completed a health and lifestyle survey. Socio-demographic, social, psychosocial and health correlates of out of school physical activity (high vs. low) among the whole sample, and stratified by Indigenous status were examined. RESULTS: Only 21% of Indigenous and 28% of non-Indigenous adolescents achieved higher levels of physical activity. Overall, higher levels were associated with being male; sports team membership; lower levels of TV viewing time and having an employed mother. Indigenous girls were less active than boys (OR=0.36; 85%CI=0.24-0.54), as were those whose mothers were unemployed (OR=0.66; 95%CI=0.40-1.09). Among non Indigenous adolescents, high levels of physical activity were associated with sports team membership (OR=2.28; 95%CI=1.39-3.74) and community involvement (OR=1.46; 95%CI=1.04-2.06). CONCLUSIONS: Physical activity levels were similarly low among disadvantaged Indigenous and non-Indigenous adolescents. Some influencing factors existed across the whole sample; others in stratification by Indigenous status. Implications for public health: Early and targeted, supportive approaches are necessary. Some apply to disadvantaged adolescents broadly; others are Indigenous or non-Indigenous specific. PMID- 27960227 TI - What do health consumers want to know about childhood vaccination? An evaluation of data from an Australian medicines call centre. AB - OBJECTIVES: Immunisation is crucial to population health. This study aimed to identify the information needs and concerns of health consumers regarding childhood vaccination. METHODS: We analysed 1,342 calls concerning childhood vaccination to an Australian pharmacist-operated medicines call centre (MCC). Data were available from September 2002 until June 2010. We identified key themes and compared these for callers from high and low immunisation coverage areas. RESULTS: Most calls related to safety concerns (60.4%), with many questions about vaccine constituents (31.6%). In low immunisation areas, a higher level of concern persisted about vaccine preservatives (mercury and thiomersal) despite their removal from vaccines in 2000. Of specific vaccines, the measles, mumps and rubella vaccine raised most questions (29.9%). Common motivations to call the MCC were 'inadequate information' (54%), 'second opinion' (21%) 'conflicting information' (9%) and 'worrying symptom' (6%). CONCLUSION AND IMPLICATIONS: The consistent number of vaccine-related calls, particularly about safety, demonstrates an information gap that can contribute to vaccination hesitancy. Health professionals need to know their local immunisation rate and associated carer concerns, to proactively address these information-related barriers to vaccination. PMID- 27960228 TI - Serve sizes and frequency of food consumption in Australian children aged 14 and 24 months. AB - OBJECTIVE: To describe the dietary intake of a sample of Australian children. METHODS: Three days (1*24 hour recall, 2*24 hour records) of dietary intake data were collected from 409 and 363 mother-child dyads (resident in Brisbane and South Australia) at 14 (T2) and 24 (T3) months of age respectively as part of the NOURISH and SAIDI studies. Data presented include foods consumed by >=10% of children, number of consumers and median serve size. RESULTS: Thirteen of 25 vegetables consumed by more than 10% of children at T2 were consumed by a lower proportion at T3 (9:1-5% less consumers; 4: 10-16% less). Eleven discretionary foods were consumed by greater than 10% of children at T2, and by T3, this number had almost doubled. CONCLUSIONS: Increased exposure to discretionary food and decreased exposure to vegetables is occurring in the transition toward family food, during a time of increasing independence and emerging neophobia. Implications for Public Health: The age-related decline in dietary quality is of concern, with potential concurrent impact on nutritional adequacy, development of food preferences and later eating patterns. Serve size data could be used to inform serve sizes for toddlers in future editions of the Australian Guide to Healthy Eating. PMID- 27960229 TI - Automated telephone communication systems for preventive healthcare and management of long-term conditions. AB - BACKGROUND: Automated telephone communication systems (ATCS) can deliver voice messages and collect health-related information from patients using either their telephone's touch-tone keypad or voice recognition software. ATCS can supplement or replace telephone contact between health professionals and patients. There are four different types of ATCS: unidirectional (one-way, non-interactive voice communication), interactive voice response (IVR) systems, ATCS with additional functions such as access to an expert to request advice (ATCS Plus) and multimodal ATCS, where the calls are delivered as part of a multicomponent intervention. OBJECTIVES: To assess the effects of ATCS for preventing disease and managing long-term conditions on behavioural change, clinical, process, cognitive, patient-centred and adverse outcomes. SEARCH METHODS: We searched 10 electronic databases (the Cochrane Central Register of Controlled Trials; MEDLINE; Embase; PsycINFO; CINAHL; Global Health; WHOLIS; LILACS; Web of Science; and ASSIA); three grey literature sources (Dissertation Abstracts, Index to Theses, Australasian Digital Theses); and two trial registries (www.controlled trials.com; www.clinicaltrials.gov) for papers published between 1980 and June 2015. SELECTION CRITERIA: Randomised, cluster- and quasi-randomised trials, interrupted time series and controlled before-and-after studies comparing ATCS interventions, with any control or another ATCS type were eligible for inclusion. Studies in all settings, for all consumers/carers, in any preventive healthcare or long term condition management role were eligible. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods to select and extract data and to appraise eligible studies. MAIN RESULTS: We included 132 trials (N = 4,669,689). Studies spanned across several clinical areas, assessing many comparisons based on evaluation of different ATCS types and variable comparison groups. Forty-one studies evaluated ATCS for delivering preventive healthcare, 84 for managing long term conditions, and seven studies for appointment reminders. We downgraded our certainty in the evidence primarily because of the risk of bias for many outcomes. We judged the risk of bias arising from allocation processes to be low for just over half the studies and unclear for the remainder. We considered most studies to be at unclear risk of performance or detection bias due to blinding, while only 16% of studies were at low risk. We generally judged the risk of bias due to missing data and selective outcome reporting to be unclear.For preventive healthcare, ATCS (ATCS Plus, IVR, unidirectional) probably increase immunisation uptake in children (risk ratio (RR) 1.25, 95% confidence interval (CI) 1.18 to 1.32; 5 studies, N = 10,454; moderate certainty) and to a lesser extent in adolescents (RR 1.06, 95% CI 1.02 to 1.11; 2 studies, N = 5725; moderate certainty). The effects of ATCS in adults are unclear (RR 2.18, 95% CI 0.53 to 9.02; 2 studies, N = 1743; very low certainty).For screening, multimodal ATCS increase uptake of screening for breast cancer (RR 2.17, 95% CI 1.55 to 3.04; 2 studies, N = 462; high certainty) and colorectal cancer (CRC) (RR 2.19, 95% CI 1.88 to 2.55; 3 studies, N = 1013; high certainty) versus usual care. It may also increase osteoporosis screening. ATCS Plus interventions probably slightly increase cervical cancer screening (moderate certainty), but effects on osteoporosis screening are uncertain. IVR systems probably increase CRC screening at 6 months (RR 1.36, 95% CI 1.25 to 1.48; 2 studies, N = 16,915; moderate certainty) but not at 9 to 12 months, with probably little or no effect of IVR (RR 1.05, 95% CI 0.99, 1.11; 2 studies, 2599 participants; moderate certainty) or unidirectional ATCS on breast cancer screening.Appointment reminders delivered through IVR or unidirectional ATCS may improve attendance rates compared with no calls (low certainty). For long-term management, medication or laboratory test adherence provided the most general evidence across conditions (25 studies, data not combined). Multimodal ATCS versus usual care showed conflicting effects (positive and uncertain) on medication adherence. ATCS Plus probably slightly (versus control; moderate certainty) or probably (versus usual care; moderate certainty) improves medication adherence but may have little effect on adherence to tests (versus control). IVR probably slightly improves medication adherence versus control (moderate certainty). Compared with usual care, IVR probably improves test adherence and slightly increases medication adherence up to six months but has little or no effect at longer time points (moderate certainty). Unidirectional ATCS, compared with control, may have little effect or slightly improve medication adherence (low certainty). The evidence suggested little or no consistent effect of any ATCS type on clinical outcomes (blood pressure control, blood lipids, asthma control, therapeutic coverage) related to adherence, but only a small number of studies contributed clinical outcome data.The above results focus on areas with the most general findings across conditions. In condition-specific areas, the effects of ATCS varied, including by the type of ATCS intervention in use.Multimodal ATCS probably decrease both cancer pain and chronic pain as well as depression (moderate certainty), but other ATCS types were less effective. Depending on the type of intervention, ATCS may have small effects on outcomes for physical activity, weight management, alcohol consumption, and diabetes mellitus. ATCS have little or no effect on outcomes related to heart failure, hypertension, mental health or smoking cessation, and there is insufficient evidence to determine their effects for preventing alcohol/substance misuse or managing illicit drug addiction, asthma, chronic obstructive pulmonary disease, HIV/AIDS, hypercholesterolaemia, obstructive sleep apnoea, spinal cord dysfunction or psychological stress in carers.Only four trials (3%) reported adverse events, and it was unclear whether these were related to the interventions. AUTHORS' CONCLUSIONS: ATCS interventions can change patients' health behaviours, improve clinical outcomes and increase healthcare uptake with positive effects in several important areas including immunisation, screening, appointment attendance, and adherence to medications or tests. The decision to integrate ATCS interventions in routine healthcare delivery should reflect variations in the certainty of the evidence available and the size of effects across different conditions, together with the varied nature of ATCS interventions assessed. Future research should investigate both the content of ATCS interventions and the mode of delivery; users' experiences, particularly with regard to acceptability; and clarify which ATCS types are most effective and cost-effective. PMID- 27960230 TI - The National Strongyloides Working Group in Australia 10 workshops on: commendations and recommendations. PMID- 27960231 TI - How efficient are New Zealand's District Health Boards at producing life expectancy gains for Maori and Europeans? AB - OBJECTIVE: Use data envelopment analysis (DEA) to measure the efficiency of New Zealand's District Health Boards (DHBs) at achieving gains in Maori and European life expectancy (LE). METHODS: Using life tables for 2006 and 2013, a two-output DEA model established the production possibility frontier for Maori and European LE gain. Confidence limits were generated from a 10,000 replicate Monte Carlo simulation. RESULTS: Results support the use of LE change as an indicator of DHB efficiency. DHB mean income and education were related to initial LE but not to its rate of change. LE gains were unrelated to either the initial level of life expectancy or to the proportion of Maori in the population. DHB efficiency ranged from 79% to 100%. Efficiency was significantly correlated with DHB financial performance. CONCLUSION: Changes in LE did not depend on the social characteristics of the DHB. The statistically significant association between efficiency and financial performance supports its use as an indicator of managerial effectiveness. Implications for public health: Efficient health systems achieve better population health outcomes. DEA can be used to measure the relative efficiency of sub-national health authorities at achieving health gain and equity outcomes. PMID- 27960232 TI - Digital pathology in clinical use: where are we now and what is holding us back? AB - Whole slide imaging is being used increasingly in research applications and in frozen section, consultation and external quality assurance practice. Digital pathology, when integrated with other digital tools such as barcoding, specimen tracking and digital dictation, can be integrated into the histopathology workflow, from specimen accession to report sign-out. These elements can bring about improvements in the safety, quality and efficiency of a histopathology department. The present paper reviews the evidence for these benefits. We then discuss the challenges of implementing a fully digital pathology workflow, including the regulatory environment, validation of whole slide imaging and the evidence for the design of a digital pathology workstation. PMID- 27960233 TI - Iatrogenic changes in the urinary tract. AB - A handful of therapeutic procedures are used to treat malignancies of the urinary tract, most frequently intravesical immunotherapy or chemotherapy, but also neoadjuvant systemic chemotherapy. These treatment modalities produce morphological changes in the urothelium that can be mistaken for carcinoma; in particular, these therapies frequently mimic urothelial carcinoma in situ (CIS) urothelial dysplasia or true invasive neoplasia. Drugs such as mitomycin C used after transurethral resection of bladder tumour to reduce recurrences, bacillus Calmette-Guerin (BCG) intravesical immunotherapy to treat high-risk non-muscle invasive bladder cancer and urothelial CIS and platin-based systemic chemotherapy to improve postcystectomy disease-specific survival are examples of therapy related atypia seen in the urinary tract. To complicate the pathologist's life, a number of systemic drugs in use to treat other diseases, such cyclophosphamide, used to treat some autoimmune disorders or certain haematological malignancies or, in the case of anaesthetics, ketamine, used increasingly as an illegal recreational drug, may produce similarly relevant atypical changes in the urothelium, and therefore need to be differentiated from intraepithelial neoplasia. Other less frequent procedures, such as photodynamic and laser therapy or the newer gene therapy to treat urothelial neoplasia, remain experimental. An immunohistochemical approach to reactive urothelium versus carcinoma in situ using p53, cytokeratin 20 and CD44 is also valid in the post-therapy setting. The pathologist should be aware of these novelties, as he or she plays a crucial role in evaluating treatment efficacy, but at the same time needs to avoid misdiagnosing secondary atypia as intraepithelial neoplasia. PMID- 27960234 TI - More than meets the eye: the changing face of histopathology. AB - This personal reflection on trends in histopathology over the past 50 years draws upon experience of professional training and practice in the specialty in the UK. Developments during this period often resulted from new therapies (and their adverse effects) necessitating greater precision in the histopathological classification of disease, for which morphology alone can be insufficient. Conversely, histopathology has contributed to advances in our understanding of disease, leading directly to novel and more effective treatments. New infections, some involving histopathology in their discovery, have also led to fresh diagnostic challenges. Increasingly, patients have benefited from fundamental changes in professionalism in pathology. Through audit, external quality assurance, continuing professional development, standardized reporting, and increasing specialization, the consistency and reliability of histopathological diagnoses have steadily improved. Regarding the specialty's future, some now see rivalry between the morphological and molecular approaches to diagnosis and classification, particularly for neoplastic disease. An integrated strategy led by the specialty is more likely to strengthen histopathology and ultimately to have the greatest benefit for patients. PMID- 27960235 TI - Modern therapies and iatrogenic changes in breast pathology. AB - Iatrogenic changes within the breast can provide challenges for the histopathologist in routine practice. Diagnostic procedures, such as core biopsies, result in reactive changes and can cause displacement of benign and malignant cells, the interpretation of which may cause difficulties in the resection specimen. Breast augmentation surgery with implants or injection of fillers, performed for cosmetic reasons or as part of a reconstructive process following removal of breast cancer, also produces reactive changes locally and at distant sites that may mimic cancer. The entity of implant-associated anaplastic large-cell lymphoma is now well recognized, with progress in our understanding of the underlying biological factors that drive its development. Chemotherapy and radiotherapy used in the treatment of breast cancer causes characteristic changes in normal breast tissue, and can alter the histological appearance and receptor status of the tumour. Radiotherapy to the breast, for breast cancer or childhood malignancies, increases the risk of developing a secondary malignancy in the breast long after treatment. In this review, we describe some of the iatrogenic changes that may be seen in histological specimens from the breast. PMID- 27960236 TI - Radiation-associated neoplasia: clinical, pathological and genomic correlates. AB - Ionizing radiation is an established risk factor for the development of benign and malignant tumours. The epidemiology of radiation-associated neoplasia has been studied over the decades in diverse populations, including Japanese atomic bomb survivors, exposed communities following the Chernobyl nuclear power plant disaster, and paediatric and adult populations receiving therapeutic irradiation. Radiation has been associated with an increased risk of neoplasia throughout the human body, with some sites showing a markedly increased relative risk of developing tumours (thyroid; soft tissues), depending on patient age and the context of exposure. Although the mechanisms of cellular injury and repair resulting from ionizing radiation are well described, the genomics of radiation induced tumours are still relatively poorly understood, with some exceptions, such as RET rearrangement in thyroid carcinomas following iodine-131 exposure and MYC amplification in cutaneous angiosarcoma following chest wall irradiation for breast cancer. This review will provide a general overview of the epidemiology, molecular mechanism, pathology and genomics of radiation-associated neoplasia in humans. PMID- 27960237 TI - The histopathological evaluation of drug-induced liver injury. AB - Drug-induced liver injury (DILI) presents unique challenges to the pathologist. It is not only an uncommon reason for liver biopsy, but the pathology of DILI is spread across the entire spectrum of hepatic injury patterns. It is important for the pathologist to suspect DILI when the histological changes are unusual or out of synchronicity with the patient's history. A systematic evaluation approach will yield the most information. It begins with the characterization of the general pattern of injury which, for most cases, will be found in a handful of necroinflammatory and cholestatic patterns. A careful assessment of the severity of injury across the various anatomic compartments will provide information on the probable natural history of the injury. Correlation of liver injury with the patient's medication history and clinical findings will help to narrow the differential diagnosis, particularly when it is recognized that most drugs have a limited range of histological findings and vary in their propensity to cause injury. This review provides an overview of the assessment of the liver biopsy and its use to confirm or exclude particular drugs as contributing to the patient's liver injury. PMID- 27960238 TI - Drug-induced nephropathies. AB - Drugs are associated frequently with the development of various types of acute and chronic kidney diseases. Nephrotoxicity is associated most commonly with injury in the tubulointerstitial compartment manifested as either acute tubular injury or acute interstitial nephritis. A growing number of reports has also highlighted the potential for drug-induced glomerular disease, including direct cellular injury and immune-mediated injury. Recognition of drug-induced nephropathies and rapid discontinuation of the offending agents are critical to maximizing the likelihood of renal function recovery. This review will focus on the pathology and pathogenesis of drug-induced acute interstitial nephritis and drug-induced glomerular diseases. PMID- 27960239 TI - Histopathology of vaccine-preventable diseases. AB - The widespread use of vaccines has been one of the most important medical advances in the last century, saving trillions of dollars and millions of lives. Despite local eradication of some infections, travellers returning from affected areas may cause outbreaks through reintroduction of pathogens to individuals who are unable to receive vaccines for medical reasons or who have declined vaccination for non-medical reasons. Infections that would otherwise be uncommonly encountered by anatomical pathologists should therefore remain in the differential diagnosis for immunocompromised and unvaccinated patients. We review here the histopathological features and ancillary testing required for diagnosis of all illnesses preventable by vaccines that are currently approved for use by the United States Food and Drug Administration, organized into three sections: viral infections preventable by routine vaccination (measles, mumps, rubella, varicella, rotavirus, polio, hepatitis A, hepatitis B, influenza, and human papillomavirus), bacterial infections preventable by routine vaccination (diptheria, tetanus, pertussis, Haemophilus influenzae, pneumococcus, and meningococcus), and infections with specific vaccine indications (anthrax, typhoid, tuberculosis, rabies, Japanese encephalitis, yellow fever, smallpox, and adenovirus). Histopathology for the less common diseases is illustrated in this review. Awareness of a patient's immune and/or vaccine status is a crucial component of the infectious disease work-up, especially for rare diseases that may not otherwise be seen. PMID- 27960240 TI - Postchemotherapy changes in testicular germ cell tumours: biology and morphology. AB - Advances in modern chemotherapy and targeted treatments have resulted in lengthened survival in a variety of tumour types in the last decade. Increasingly in the 21st century, postchemotherapy resections are considered as a possible mode of treatment. Due to their exquisite chemosensitivity, resection of postchemotherapy masses has long been part of the armamentarium of treatment in testicular germ cell neoplasia, which has resulted in a variety of new morphological variants being described after treatment. Here we discuss the possible reasons for germ cell tumour chemosensitivity and hypotheses on the biological pathways leading to resistance to treatment, as well as an outline of the diverse morphology of those tumours which prove recalcitrant to standard treatment methods. The large range of morphologies and their diagnostic challenges may throw light upon the future problems to be encountered in non-germ cell solid tumour pathology, as the resection of postchemotherapy masses becomes increasingly important in patient management. PMID- 27960241 TI - The changing landscape of gynaecological cancer diagnosis: implications for histopathological practice in the 21st century. AB - The era of molecular medicine has led to dramatically improved understanding of the genetic events that give rise to different types of cancers. In the case of gynaecological malignancies, this has resulted in distinct shifts in how these tumours are diagnosed in routine surgical pathology practice, with an increased emphasis on accurate subtype diagnosis. This has happened across all sites in the gynaecological tract and for most cell types, but in ways that are site-specific and may appear to be subtle, as in most instances the diagnostic terminology has not changed. For example, the diagnosis of clear cell carcinoma of the ovary is still in use, but the diagnostic criteria and clinical implications are different in 2017 from what they were in 2000. As a result, there can be a failure to appreciate how important these changes are and the resulting necessity of incorporating them into our daily practice. In this review we will describe changes in diagnostic surgical pathology occasioned by improved understanding of molecular events during pathogenesis, for cancers of ovary/tube, endometrium, cervix and vulva, and highlight how current practice differs from that of only a few years ago. PMID- 27960242 TI - Annual review issue: surgical pathology of 21st century medicine. PMID- 27960243 TI - Dr Basil C Morson - Obituary. PMID- 27960244 TI - Erratum. PMID- 27960246 TI - Challenges in managing a school-based measles outbreak in Melbourne, Australia, 2014. AB - OBJECTIVE: To identify barriers to control of a Victorian primary school-based measles outbreak. METHODS: Confirmed measles cases notified in Victoria in 2014 were reviewed. Surveillance data, correspondence, and investigation notes for the school-based outbreak were assessed regarding timeliness of diagnosis and notification, and adequacy of school-based immunisation records. RESULTS: Twenty three (31%) of the 75 measles cases notified in 2014 were school-aged (5-18 years); three had documentation of measles vaccination, 17 were unvaccinated, and three had unknown vaccination history. Eight measles outbreaks were identified, including a primary school-based outbreak with ten cases. Of the six unvaccinated pupils in the affected school, five (83%) contracted measles. The proportion of the school's prep students with documented vaccination records, as required by law, ranged from 39% in 2013 to 97% in 2014. CONCLUSIONS: Inadequately vaccinated students constitute a vulnerable population and schools are a potential site for measles outbreaks. Inadequate enforcement of school-based immunisation records impact the management and control of school-based measles outbreaks. Implications for Public Health: There is a need to educate clinicians on measles diagnosis and notification, and schools on the requirement to maintain up-to-date vaccination records. School entry is an opportunity to review student vaccination history and offer immunisations. PMID- 27960245 TI - Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants. AB - BACKGROUND: Chronic lung disease (CLD) occurs frequently in preterm infants. Bronchodilators have the potential effect of dilating small airways with muscle hypertrophy. Increased compliance and tidal volume and decreased pulmonary resistance have been documented with the use of bronchodilators in infants with CLD. Therefore, bronchodilators might have a role in the prevention and treatment of CLD. OBJECTIVES: To determine the effect of bronchodilators given as prophylaxis or as treatment for CLD on mortality and other complications of preterm birth in infants at risk for or identified as having CLD. SEARCH METHODS: On 2016 March 7, we used the standard strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2), MEDLINE (from 1966), Embase (from 1980) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; from 1982). We searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We applied no language restrictions. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials involving preterm infants were eligible for inclusion. Initiation of bronchodilator therapy for prevention of CLD had to occur within two weeks of birth. Treatment of patients with CLD had to be initiated before discharge from the neonatal unit. The intervention had to include administration of a bronchodilator by nebulisation, by metered dose inhaler (with or without a spacer device) or by intravenous or oral administration versus placebo or no intervention. Eligible studies had to include at least one of the following predefined clinical outcomes: mortality, CLD, number of days on oxygen, number of days on ventilator, patent ductus arteriosus (PDA), pulmonary interstitial emphysema (PIE), pneumothorax, intraventricular haemorrhage (IVH) of any grade, necrotising enterocolitis (NEC), sepsis and adverse effects of bronchodilators. DATA COLLECTION AND ANALYSIS: We used the standard method described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Two review authors extracted and assessed all data provided by each study. We reported risk ratio (RR), risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB) with 95% confidence interval (CI) for dichotomous outcomes and mean difference (MD) for continuous data. We assessed the quality of the evidence by using the GRADE approach. MAIN RESULTS: For this update, we identified one new randomised controlled trial investigating effects of bronchodilators in preterm infants. This study, which enrolled 73 infants but reported on 52 infants, examined prevention of CLD with the use of aminophylline. According to GRADE, the quality of the evidence was very low. One previously included study enrolled 173 infants to look at prevention of CLD with the use of salbutamol. According to GRADE, the quality of the evidence was moderate. We found no eligible trial that studied the use of bronchodilator therapy for treatment of individuals with CLD. Prophylaxis with salbutamol led to no statistically significant differences in mortality (RR 1.08, 95% CI 0.50 to 2.31; RD 0.01, 95% CI -0.09 to 0.11) nor in CLD (RR 1.03, 95% CI 0.78 to 1.37; RD 0.02, 95% CI -0.13 to 0.17). Results showed no statistically significant differences in other complications associated with CLD nor in preterm birth. Investigators in this study did not comment on side effects due to salbutamol. Prophylaxis with aminophylline led to a significant reduction in CLD at 28 days of life (RR 0.18, 95% CI 0.04 to 0.74; RD -0.35, 95% CI -0.56 to -0.13; NNTB 3, 95% CI 2 to 8) and no significant difference in mortality (RR 3.0, 95% CI 0.33 to 26.99; RD 0.08, 95% CI -0.07 to 0.22), along with a significantly shorter dependency on supplementary oxygen in the aminophylline group compared with the no treatment group (MD -17.75 days, 95% CI -27.56 to -7.94). Tests for heterogeneity were not applicable for any of the analyses, as each meta-analysis included only one study. AUTHORS' CONCLUSIONS: Data are insufficient for reliable assessment of the use of salbutamol for prevention of CLD. One trial of poor quality reported a reduction in the incidence of CLD and shorter duration of supplementary oxygen with prophylactic aminophylline, but these results must be interpreted with caution. Additional clinical trials are necessary to assess the role of bronchodilator agents in prophylaxis or treatment of CLD. Researchers studying the effects of bronchodilators in preterm infants should include relevant clinical outcomes in addition to pulmonary mechanical outcomes. We identified no trials that studied the use of bronchodilator therapy for treatment of CLD. PMID- 27960247 TI - To Close the Gap we need to identify the best (and worst) buys in Indigenous health. PMID- 27960248 TI - The price of healthy and unhealthy foods in Australian primary school canteens. AB - OBJECTIVE: To describe the price of Australian school canteen foods according to their nutritional value. METHODS: Primary school canteen menus were collected as part of a policy compliance randomised trial. For each menu item, dietitians classified its nutritional value; 'green' ('good sources of nutrients'), 'amber' ('some nutritional value'), 'red' ('lack adequate nutritional value') and assigned a food category (e.g. 'Drinks', 'Snacks'). Pricing information was extracted. Within each food category, ANOVAs assessed differences between the mean price of 'green', 'amber' and 'red' items, and post-hoc tests were conducted. RESULTS: Seventy of the 124 invited schools participated. There were significant differences in the mean price of 'green', 'amber' and 'red foods' across categories, with 'green' items more expensive than 'amber' items in main meal categories ('Sandwiches' +$0.43, 'Hot Foods' +$0.71), and the reverse true for non-meal categories ('Drinks' -$0.13, 'Snacks' -$0.18, 'Frozen Snacks' $0.25^). CONCLUSION: Current pricing may not encourage the purchasing of healthy main-meal items by and for students. Further investigation of pricing strategies that enhance the public health benefit of existing school canteen policies and practices are warranted. Implications for Public Health: Providing support to canteen managers regarding healthy canteen policies may have a positive impact on public health nutrition. PMID- 27960249 TI - Who is at risk of chronic disease? Associations between risk profiles of physical activity, sitting and cardio-metabolic disease in Australian adults. AB - OBJECTIVE: To examine the associations of physical activity (PA) and sitting time (sit) with cardio-metabolic diseases. METHODS: Cross-sectional data from the Australian National Nutrition and Physical Activity Survey 2011-2012 (n=9,435) were used to classify adults into low and high risk groups based on their physical activity and sitting behaviour profiles. Logistic regression models examined associations between low and high risk classifications (high PA-low sit; high PA-high sit; low PA-low sit; low PA-high sit;) and socio-demographic factors, and associations between low and high risk classifications and the prevalence of cardiovascular disease, Type 2 diabetes and metabolic syndrome. RESULTS: These results characterise chronic disease risk based on both physical activity and sitting behaviour. Adults with the highest risk lifestyle behaviour pattern (low PA-high sit) tended to be middle aged, male, at greater social disadvantage, smoke, report fair health, be abdominally obese and employed in administrative and driver occupations. These individuals had a substantially greater risk of cardiovascular disease and metabolic syndrome (OR=1.41, 95% CI 1.13, 1.75; OR= 2.37, 95% CI 1.63, 3.45, respectively). CONCLUSIONS: The findings highlight the importance of both sufficient physical activity and low sitting time for cardio-metabolic health. Implications for public health: Primary prevention focus should consider physical activity and reduced sitting time as well as provision of relevant advice for cardio-metabolic health. PMID- 27960250 TI - The impact of the Canterbury earthquakes on successful school leaving for adolescents. AB - OBJECTIVE: To examine the impact of the Canterbury earthquakes on the important adolescent transition period of school leaving. METHOD: Local and national data on school leaving age, attainment of National Certificate of Educational Achievement (NCEA) standards, and school rolls (total registered students for schools) were examined to clarify long-term trends and delineate these from any impacts of the Canterbury earthquakes. Results: Despite concerns about negative impacts, there was no evidence for increased school disengagement or poorer academic performance by students as a consequence of the earthquakes. CONCLUSION: Although there may have been negative effects for a minority, the possibility of post-disaster growth and resilience being the norm for the majority meant that negative effects on school leaving were not observed following the earthquakes. A range of post-disaster responses may have mitigated adverse effects on the adolescent population. Implications for Public Health: Overall long-term negative effects are unlikely for the affected adolescent population. The results also indicate that similar populations exposed to disasters in other settings are likely to do well in the presence of a comprehensive post-disaster response. PMID- 27960251 TI - Tropospheric GOM at the Pic du Midi Observatory-Correcting Bias in Denuder Based Observations. AB - Gaseous elemental mercury (GEM, Hg) emissions are transformed to divalent reactive Hg (RM) forms throughout the troposphere and stratosphere. RM is often operationally quantified as the sum of particle bound Hg (PBM) and gaseous oxidized Hg (GOM). The measurement of GOM and PBM is challenging and under mounting criticism. Here we intercompare six months of automated GOM and PBM measurements using a Tekran (TK) KCl-coated denuder and quartz regenerable particulate filter method (GOMTK, PBMTK, and RMTK) with RMCEM collected on cation exchange membranes (CEMs) at the high altitude Pic du Midi Observatory. We find that RMTK is systematically lower by a factor of 1.3 than RMCEM. We observe a significant relationship between GOMTK (but not PBMTK) and Tekran flushTK blanks suggesting significant loss (36%) of labile GOMTK from the denuder or inlet. Adding the flushTK blank to RMTK results in good agreement with RMCEM (slope = 1.01, r2 = 0.90) suggesting we can correct bias in RMTK and GOMTK. We provide a bias corrected (*) Pic du Midi data set for 2012-2014 that shows GOM* and RM* levels in dry free tropospheric air of 198 +/- 57 and 229 +/- 58 pg m-3 which agree well with in-flight observed RM and with model based GOM and RM estimates. PMID- 27960252 TI - Ag/AgxH3-xPMo12O40 Nanowires with Enhanced Visible-Light-Driven Photocatalytic Performance. AB - Photocatalysis, a promising technology platform to address the environmental problems, has been attracting considerable attention. In this paper, Ag/AgxH3 xPMo12O40 (simplified as Ag/AgHPMo12) nanowires have been synthesized by a facile solid reaction route and in situ photodeposited method. The results of SEM and TEM indicate that the diameters of AgHPMo12 nanowires are about 45 +/- 10 nm, and Ag nanoparticles with diameters in the range of 5-15 nm are uniformly anchored on the surface of AgHPMo12 nanowires. The Ag content in the Ag/AgHPMo12 composite was manipulated by the light irradiation time (Ag/AgHPMo12-x; x stands for the irradiation time; x = 2, 4, 6, 8 h, respectively). With increasing irradiation time, the light absorption of as-synthesized samples in the visible region was gradually enhanced. The Ag/AgHPMo12-4 exhibits the best photocatalytic performance for the degradation of methyl orange and reduction of Cr2O72- under visible-light (lambda > 420 nm) irradiation. The study of the photocatalytic mechanism reveals that both Ag and AgHPMo12 can be excited by visible light. The photoinduced electrons were transferred from AgHPMo12 to metallic Ag, and combined with the Ag plasmonic holes. The Ag plasmonic electrons were trapped by O2 to form .O2-, or directly reduced Cr2O72- to Cr3+. Meanwhile, the .O2- species and the photogenerated holes of AgHPMo12 were used to oxidize MO or i-PrOH; thus, they showed highly efficient and recyclable photocatalytic performance for removing the organic and inorganic pollutants. PMID- 27960253 TI - Stilbene Derivatives from Photorhabdus temperata SN259 and Their Antifungal Activities against Phytopathogenic Fungi. AB - Chemical investigation of an insect pathogenic enterobacterium, Photorhabdus temperata SN259, led to the isolation and identification of seven metabolites, which include three new compounds, 3-hydroxy-2-isopropyl-5-phenethylphenyl carbamate, 1, 2-(1-hydroxypropan-2-yl)-5-[2-phenylethyl]benzene-1,3-diol, 2, 2-(1 hydroxypropan-2-yl)-5-[(E)-2-phenylethenyl]benzene-1,3-diol, 3, and four known metabolites (4-7). Their structures were elucidated on the basis of MS and NMR data and by comparison with those reported previously. The activities of compounds 1-7 were evaluated against four phytopathogenic fungi (Pythium aphanidermatum, Rhizoctonia solani Kuhn, Exserohilum turcicum, and Fusarium oxysporum). In an agar medium assay, compounds 1 and 7 showed strong inhibition against P. aphanidermatum with EC50 values of 2.8 and 2.7 MUg/mL, respectively. By comparing the structure of compounds 1-7, we deduced that the acylamino group in compound 1 and the isopropyl group in compound 7 contribute to the inhibitory activity. PMID- 27960255 TI - Oxygen K Edge Scattering from Bulk Comb Diblock Copolymer Reveals Extended, Ordered Backbones above Lamellar Order-Disorder Transition. AB - The evolution of molecular morphology in bulk samples of comb diblock copolymer pNdc12-b-pNte21 across the lamellar order-disorder transition (ODT) is studied using resonant X-ray scattering at the oxygen K edge with the goal of determining whether the molecules remain extended or collapse above the ODT. The distinct spectral resonances of carbonyl oxygen on the backbone and ether oxygen in the pNte side chains combine with their different site symmetry within the molecule to yield strong differences in bulk structural sensitivity at all temperatures. Comparison with simple models for the disordered phase clearly reveals that disordering at the ODT corresponds to loss of positional order of molecules with extended backbones that retain orientational order, rather than backbone collapse into a locally isotropic disordered phase. This conclusion is facilitated directly by the distinct structural sensitivity at the two resonances. The roles of depolarized scattering in enhancing this sensitivity, and background fluorescence in limiting dynamic range in oxygen resonant scattering are discussed. PMID- 27960254 TI - Engineering the Protein Corona of a Synthetic Polymer Nanoparticle for Broad Spectrum Sequestration and Neutralization of Venomous Biomacromolecules. AB - Biochemical diversity of venom extracts often occurs within a small number of shared protein families. Developing a sequestrant capable of broad-spectrum neutralization across various protein isoforms within these protein families is a necessary step in creating broad-spectrum antivenom. Using directed synthetic evolution to optimize a nanoparticle (NP) formulation capable of sequestering and neutralizing venomous phospholipase A2 (PLA2), we demonstrate that broad-spectrum neutralization and sequestration of venomous biomacromolecules is possible via a single optimized NP formulation. Furthermore, this optimized NP showed selectivity for venomous PLA2 over abundant serum proteins, was not cytotoxic, and showed substantially long dissociation rates from PLA2. These findings suggest that it may show efficacy as an in vivo venom sequestrant and may serve as a generalized lipid-mediated toxin sequestrant. PMID- 27960256 TI - Pauli Repulsion-Induced Expansion and Electromechanical Properties of Graphene. AB - Because graphene has nearly zero density of states at the Dirac point, charging it must overcome Pauli repulsion. We show here that this repulsion causes graphene to expand, which is measurable with an optical edge-tracking method despite that graphene is the strongest material. The expansion increases quadratically with applied voltage as predicted by theory and has a coefficient of ~10-4 per V at 1 V. Graphene has many attractive properties, but it lacks piezoelectricity, which limits its electromechanical applications. The observed Pauli repulsion-induced expansion provides an alternative way to electrically control graphene dimension. It also provides a simple and direct method to measure the elastic properties of graphene and other low dimensional materials. PMID- 27960257 TI - Fabry-Perot Resonances in a Graphene/hBN Moire Superlattice. AB - While Fabry-Perot (FP) resonances and Moire superlattices are intensively studied in graphene on hexagonal boron nitride (hBN), the two effects have not been discussed in their coexistence. Here we investigate the FP oscillations in a ballistic pnp-junctions in the presence and absence of a Moire superlattice. First, we address the effect of the smoothness of the confining potential on the visibility of the FP resonances and carefully map the evolution of the FP cavity size as a function of densities inside and outside the cavity in the absence of a superlattice, when the cavity is bound by regular pn-junctions. Using a sample with a Moire superlattice, we next show that an FP cavity can also be formed by interfaces that mimic a pn-junction but are defined through a satellite Dirac point due to the superlattice. We carefully analyze the FP resonances, which can provide insight into the band-reconstruction due to the superlattice. PMID- 27960259 TI - Strong Fermi-Level Pinning at Metal/n-Si(001) Interface Ensured by Forming an Intact Schottky Contact with a Graphene Insertion Layer. AB - We report the systematic experimental studies demonstrating that a graphene layer inserted at metal/n-Si(001) interface is efficient to explore interface Fermi level pinning effect. It is confirmed that an inserted graphene layer prevents atomic interdiffusion to form an atomically abrupt Schottky contact. The Schottky barriers of metal/graphene/n-Si(001) junctions show a very weak dependence on metal work-function, implying that the metal Fermi-level is almost completely pinned at charge neutrality level close to the valence band edge of Si. The atomically impermeable and electronically transparent properties of graphene can be used generally to form an intact Schottky contact for all semiconductors. PMID- 27960258 TI - Mechanism of the Spontaneous and Directional Membrane Insertion of a 2 Transmembrane Ion Channel. AB - Protein insertion into membranes is a process occurring in every cell and every cellular compartment. Yet, many thermodynamic aspects of this fundamental biophysical process are not well understood. We investigated physicochemical parameters that influence protein insertion using the model protein KcsA, a 2 transmembrane ion channel. To understand what drives insertion and to identify individual steps of protein integration into a highly apolar environment, we investigated the contribution of electrostatic interactions and lipid composition on protein insertion on a single molecule level. We show that insertion of KcsA is spontaneous and directional as the cytosolic part of the protein does not translocate across the membrane barrier. Surprisingly, not hydrophobic residues but charged amino acids are crucial for the insertion of the unfolded protein into the membrane. Our results demonstrate the importance of electrostatic interactions between membrane and protein during the insertion process of hydrophobic polypeptides into the apolar membrane. On the basis of the observation that negatively charged lipids increase insertion events while high ionic strength in the surrounding aqueous phase decreases insertion events, a two step mechanism is proposed. Here, an initial electrostatic attraction between membrane and protein represents the first step prior to insertion of hydrophobic residues into the hydrocarbon core of the membrane. PMID- 27960260 TI - Homogeneous Nucleation of Ice Confined in Hollow Silica Spheres. AB - Ice nucleation is studied in hollow silica (HS) spheres. These hierarchical materials comprise ~3 nm pores within the silica network, which are confined to a ~20 nm shell of a hollow sphere (with diameters in the range ~190-640 nm). The multiple length scales involved in HS spheres affect the ice nucleation mechanism. We find homogeneous nucleation inside the water filled capsules, whereas heterogeneous nucleation prevails in the surrounding dispersion medium. We validate our findings for a series of hollow sphere sizes and demonstrate the absence of homogeneous nucleation in the case of polystyrene-silica core-shell particles. The present findings shed new light on the interplay between homogeneous and heterogeneous nucleation of ice with possible implications in undercooled reactions and the storage of reactive or biologically active substances. PMID- 27960261 TI - A Concise History of Mycotoxin Research. AB - Toxigenic fungi and mycotoxins entered human food supplies about the time when mankind first began to cultivate crops and to store them from one season to the next, perhaps 10,000 years ago. The storage of cereals probably initiated the transition by mankind from hunter-gatherer to cultivator, at the same time providing a vast new ecological niche for fungi pathogenic on grain crops or saprophytic on harvested grain, many of which produced mycotoxins. Grains have always been the major source of mycotoxins in the diet of man and his domestic animals. In the historical context, ergotism from Claviceps purpurea in rye has been known probably for more than 2000 years and caused the deaths of many thousands of people in Europe in the last millennium. Known in Japan since the 17th century, acute cardiac beriberi associated with the consumption of moldy rice was found to be due to citreoviridin produced by Penicillium citreonigrum. This toxin was believed to be only of historic importance until its reemergence in Brazil a few years ago. Other Penicillium toxins, including ochratoxin A, once considered to be a possible cause of Balkan endemic nephropathy, are treated in a historical context. The role of Fusarium toxins in human and animal health, especially T-2 toxin in alimentary toxic aleukia in Russia in the 1940s and fumonisins in equine leucoencephalomalasia, is set out in some detail. Finally, this paper documents the story of the research that led to our current understanding of the formation of aflatoxins in grains and nuts, due to the growth of Aspergillus flavus and its role, in synergy with the hepatitis B virus, in human liver cancer. During a period of climate change and greatly reduced crop diversity on a global basis, researchers tasked with monitoring the food system need to be aware of fungal toxins that might have been rare in their working careers that can reappear. PMID- 27960263 TI - Reactivity of Metal Clusters. AB - We summarize here the research advances on the reactivity of metal clusters. After a simple introduction of apparatuses used for gas-phase cluster reactions, we focus on the reactivity of metal clusters with various polar and nonpolar molecules in the gas phase and illustrate how elementary reactions of metal clusters proceed one-step at a time under a combination of geometric and electronic reorganization. The topics discussed in this study include chemical adsorption, addition reaction, cleavage of chemical bonds, etching effect, spin effect, the harpoon mechanism, and the complementary active sites (CAS) mechanism, among others. Insights into the reactivity of metal clusters not only facilitate a better understanding of the fundamentals in condensed-phase chemistry but also provide a way to dissect the stability and reactivity of monolayer-protected clusters synthesized via wet chemistry. PMID- 27960264 TI - Electrochemistry and Photoluminescence of Icosahedral Carboranes, Boranes, Metallacarboranes, and Their Derivatives. AB - Icosahedral boranes, carboranes, and metallacarboranes are extraordinarily robust compounds with desirable properties such as thermal and redox stability, chemical inertness, low nucleophilicity, and high hydrophobicity, making them attractive for several applications such as medicine, nanomaterials, molecular electronics, energy, catalysis, environmental chemistry, and other areas. The hydrogen atoms in these clusters can be replaced by convenient groups that open the way to a chemical alternative to conventional "organic" or "organometallic" realms. Icosahedral boron cluster derivatives have been reviewed from different perspectives; however, there is a need for a review dedicated to the redox and photophysical characteristics of easily accessible borane and carborane derivatives, which are excellent materials for a wide range of applications. This review deals with the redox properties and photoluminescence behavior of this collection of compounds, as well as their influence on the properties of materials and devices whose working principles are related to electron-transfer or electron-promotion phenomena. We hope that this review will be of great value to boron cluster scientists and researchers working in the photoluminescence and electrochemistry fields who are interested in exploring the possibilities of these unique and promising systems. PMID- 27960265 TI - Correction to Earth-Abundant Heterogeneous Water Oxidation Catalysts. PMID- 27960266 TI - Methods, Mechanism, and Applications of Photodeposition in Photocatalysis: A Review. AB - In this review, for a variety of metals and semiconductors, an attempt is made to generalize observations in the literature on the effect of process conditions applied during photodeposition on (i) particle size distributions, (ii) oxidation states of the metals obtained, and (iii) consequences for photocatalytic activities. Process parameters include presence or absence of (organic) sacrificial agents, applied pH, presence or absence of an air/inert atmosphere, metal precursor type and concentration, and temperature. Most intensively reviewed are studies concerning (i) TiO2; (ii) ZnO, focusing on Ag deposition; (iii) WO3, with a strong emphasis on the photodeposition of Pt; and (iv) CdS, again with a focus on deposition of Pt. Furthermore, a detailed overview is given of achievements in structure-directed photodeposition, which could ultimately be employed to obtain highly effective photocatalytic materials. Finally, we provide suggestions for improvements in description of the photodeposition methods applied when included in scientific papers. PMID- 27960267 TI - Triarylamine: Versatile Platform for Organic, Dye-Sensitized, and Perovskite Solar Cells. AB - Triarylamine (TAA) and related materials have dramatically promoted the development of organic and hybrid photovoltaics during the past decade. The power conversion efficiencies of TAA-based organic solar cells (OSCs), dye-sensitized solar cells (DSSCs), and perovskite solar cells (PSCs) have exceeded 11%, 14%, and 20%, which are among the best results for these three kinds of devices, respectively. In this review, we summarize the recent advances of the high performance TAA-based materials in OSCs, DSSCs, and PSCs. We focus our discussion on the structure-property relationship of the TAA-based materials in order to shed light on the solutions to the challenges in the field of organic and hybrid photovoltaics. Some design strategies for improving the materials and device performance and possible research directions in the near future are also proposed. PMID- 27960268 TI - Quaterpyridines as Scaffolds for Functional Metallosupramolecular Materials. AB - Quaterpyridine (qtpy) ligands have found significant applications as N heterocyclic scaffolds in self-assembly processes, in particular the formation of various metallosupramolecular architectures, limited, however, by difficulties in their synthesis. Recent progress in the preparative organic and organometallic chemistry of polypyridines has resulted in the elimination of the most serious drawbacks concerning qtpy synthesis, consequently giving rise to a renewed interest in this class of compounds. Herein, we endeavor to define the essential aspects of quaterpyridine chemistry and provide the reader with a perspective on the ways in which this field has begun to flourish. PMID- 27960269 TI - Asymmetric Hydrogenation of Nonaromatic Cyclic Substrates. AB - Chiral cyclic structures are found in numerous natural products, pharmaceutical compounds, and important synthetic intermediates. Asymmetric hydrogenation, allowing for the preparation of these complex targets in an environmentally benign and efficient manner, has received much attention over the past few years. This review summarizes the advances in the construction of chiral heterocycles and carbocycles (including cyclic amines, ethers, alcohols, and alkanes) via the asymmetric hydrogenation of nonaromatic cyclic substrates (including prochiral cyclic imines, ketones, and alkenes) using appropriate transition-metal complexes. PMID- 27960270 TI - Correction to Multivariable Sensors for Ubiquitous Monitoring of Gases in the Era of Internet of Things and Industrial Internet. PMID- 27960271 TI - Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications. AB - The ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) affords 1,5 disubstituted 1,2,3-triazoles in one step and complements the more established copper-catalyzed reaction providing the 1,4-isomer. The RuAAC reaction has quickly found its way into the organic chemistry toolbox and found applications in many different areas, such as medicinal chemistry, polymer synthesis, organocatalysis, supramolecular chemistry, and the construction of electronic devices. This Review discusses the mechanism, scope, and applications of the RuAAC reaction, covering the literature from the last 10 years. PMID- 27960272 TI - Innovation in Layer-by-Layer Assembly. AB - Methods for depositing thin films are important in generating functional materials for diverse applications in a wide variety of fields. Over the last half-century, the layer-by-layer assembly of nanoscale films has received intense and growing interest. This has been fueled by innovation in the available materials and assembly technologies, as well as the film-characterization techniques. In this Review, we explore, discuss, and detail innovation in layer by-layer assembly in terms of past and present developments, and we highlight how these might guide future advances. A particular focus is on conventional and early developments that have only recently regained interest in the layer-by layer assembly field. We then review unconventional assemblies and approaches that have been gaining popularity, which include inorganic/organic hybrid materials, cells and tissues, and the use of stereocomplexation, patterning, and dip-pen lithography, to name a few. A relatively recent development is the use of layer-by-layer assembly materials and techniques to assemble films in a single continuous step. We name this "quasi"-layer-by-layer assembly and discuss the impacts and innovations surrounding this approach. Finally, the application of characterization methods to monitor and evaluate layer-by-layer assembly is discussed, as innovation in this area is often overlooked but is essential for development of the field. While we intend for this Review to be easily accessible and act as a guide to researchers new to layer-by-layer assembly, we also believe it will provide insight to current researchers in the field and help guide future developments and innovation. PMID- 27960273 TI - Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs. AB - Nucleoside, nucleotide, and base analogs have been in the clinic for decades to treat both viral pathogens and neoplasms. More than 20% of patients on anticancer chemotherapy have been treated with one or more of these analogs. This review focuses on the chemical synthesis and biology of anticancer nucleoside, nucleotide, and base analogs that are FDA-approved and in clinical development since 2000. We highlight the cellular biology and clinical biology of analogs, drug resistance mechanisms, and compound specificity towards different cancer types. Furthermore, we explore analog syntheses as well as improved and scale-up syntheses. We conclude with a discussion on what might lie ahead for medicinal chemists, biologists, and physicians as they try to improve analog efficacy through prodrug strategies and drug combinations. PMID- 27960274 TI - Enantioselective Silver-Catalyzed Transformations. AB - This review collects the major progress in the field of enantioselective transformations promoted by chiral silver catalysts, covering the literature since 2008, well illustrating the power of these especially mild Lewis acid catalysts to provide novel asymmetric reactions. PMID- 27960262 TI - Chemical Glycoproteomics. AB - Chemical tools have accelerated progress in glycoscience, reducing experimental barriers to studying protein glycosylation, the most widespread and complex form of posttranslational modification. For example, chemical glycoproteomics technologies have enabled the identification of specific glycosylation sites and glycan structures that modulate protein function in a number of biological processes. This field is now entering a stage of logarithmic growth, during which chemical innovations combined with mass spectrometry advances could make it possible to fully characterize the human glycoproteome. In this review, we describe the important role that chemical glycoproteomics methods are playing in such efforts. We summarize developments in four key areas: enrichment of glycoproteins and glycopeptides from complex mixtures, emphasizing methods that exploit unique chemical properties of glycans or introduce unnatural functional groups through metabolic labeling and chemoenzymatic tagging; identification of sites of protein glycosylation; targeted glycoproteomics; and functional glycoproteomics, with a focus on probing interactions between glycoproteins and glycan-binding proteins. Our goal with this survey is to provide a foundation on which continued technological advancements can be made to promote further explorations of protein glycosylation. PMID- 27960275 TI - Phenolics of Selected Cranberry Genotypes (Vaccinium macrocarpon Ait.) and Their Antioxidant Efficacy. AB - Free, esterified, and bound phenolic fractions of berries from five different cranberry genotypes and two market samples were evaluated for their total phenolic, flavonoid, and monomeric anthocyanin contents as well as their antioxidant efficacy using TEAC, ORAC, DPPH radical, reducing power, and ferrous ion chelation capacity assays. HPLC-MS/MS analysis was performed for two of the rich sources (Pilgrim and wild clone NL2) of phenolics and high antioxidant activity. Among the genotypes, Pilgrim showed the highest phenolic and flavonoid contents and wild clones NL3 and NL2 showed the highest monomeric anthocyanin and proanthocyanidin content, respectively. Protocatechuic and syringic acids were detected only in Pilgrim, whereas luteolin 7-O-glucoside, quercetin 3-O rhamnoside, quercetin 3-O-galactoside, proanthocyanidin B-type, and myricetin 3-O galactoside were found in wild clone NL3 genotype. Moreover, proanthocyanin trimer A-type and dimer B-type predominated in the wild clone NL2, whereas proanthocyanidin dimer B and trimer A were predominant in Pilgrim. PMID- 27960277 TI - Laser-Induced Breakdown Spectroscopy Based Protein Assay for Cereal Samples. AB - Protein content is an important quality parameter in terms of price, nutritional value, and labeling of various cereal samples. However, conventional analysis methods, namely, Kjeldahl and Dumas, have major drawbacks such as long analysis time, titration mistakes, and carrier gas dependence with high purity. For this reason, there is an urgent need for rapid, reliable, and environmentally friendly technologies for protein analysis. The present study aims to develop a new method for protein analysis in wheat flour and whole meal by using laser-induced breakdown spectroscopy (LIBS), which is a multielemental, fast, and simple spectroscopic method. Unlike the Kjeldahl and Dumas methods, it has potential to analyze a high number of samples in considerably short time. In the study, nitrogen peaks in LIBS spectra of wheat flour and whole meal samples with different protein contents were correlated with results of the standard Dumas method with the aid of chemometric methods. A calibration graph showed good linearity with the protein content between 7.9 and 20.9% and a 0.992 coefficient of determination (R2). The limit of detection was calculated as 0.26%. The results indicated that LIBS is a promising and reliable method with its high sensitivity for routine protein analysis in wheat flour and whole meal samples. PMID- 27960276 TI - Production of Auroxanthins from Violaxanthin and 9-cis-Violaxanthin by Acidic Treatment and the Antioxidant Activities of Violaxanthin, 9-cis-Violaxanthin, and Auroxanthins. AB - Violaxanthin and 9-cis-violaxanthin (major epoxycarotenoids in fruit) were prepared from mango fruit, purified, and converted to other carotenoids under acidic conditions. The resulting carotenoid structures were then analyzed in detail. Not only violaxanthin but also 9-cis-violaxanthin were found to be converted to (8S,8'S)-, (8S,8'R)-, and (8R,8'R)-auroxanthin at an approximate ratio of 4:6:1. Antioxidant activities of violaxanthin, 9-cis-violaxanthin, (8S,8'S)-auroxanthin, and (8S,8'R)-auroxanthin were examined. They possessed potent lipid peroxidation inhibitory and very weak 1O2 quenching activities. PMID- 27960278 TI - Protein-Restricted Diet Regulates Lipid and Energy Metabolism in Skeletal Muscle of Growing Pigs. AB - The aim of this work was to study the lipid metabolism and energy status of skeletal muscle of pigs as affected by dietary protein restriction. Eighteen growing pigs were distributed into three treatments, and each group was fed one of three levels (20, 17, and 14%) of crude protein (CP) diets. Our results showed that pigs fed the 20% CP had greater (P < 0.05) gain:feed and muscle weight than those fed the 14% CP, but no differences between the 20 and 17% CP treatments. Additionally, protein restriction tended to increase (P = 0.07) the content of intramuscular fat (IMF) and up-regulated (P < 0.05) expression of lipogenic related genes. Energy status was changed and, concomitantly, AMP-activated protein kinase alpha pathway was inhibited by reducing the dietary protein level. These results indicate protein restriction could be useful to improve IMF content of pigs through regulating lipid metabolism and associated energy utilization in muscle. PMID- 27960280 TI - Identification of a Genetic Factor Required for High gamma-Isoform Concentration in Rice Vitamin E. AB - The gamma-isoforms of tocopherols (Tc) and tocotrienols (T3) possess high biological activities in comparison to the alpha-isoforms. The concentrations of Tc and T3 isoforms in rice (Oriza sativa) was cultivar-dependent. Using chromosome segment substitution lines (CSSLs) and near isogenic lines (NILs) of indica cultivar "Kasalath" in a japonica cultivar "Koshihikari" genetic background, the Kasalath genomic segment on chromosome 2 was determined to be responsible for the high gamma-isoform concentration: gamma-tocopherol methyltransferase (gamma-TMT) was identified as a candidate gene. An amino acid substitution in the coding region and several nucleotide polymorphisms, including an insertion of 10 base pairs in the promoter region, were identified. Gene expression analysis revealed that low expression levels of the gamma-TMT gene in Kasalath were not associated with the gamma-isoform concentration. Genetic variations in the coding region of the gamma-TMT gene may play a major role in determining the gamma-isoform concentration. This information could be used to breed rice with a high gamma-isoform content. PMID- 27960279 TI - Resveratrol Induces Cancer Cell Apoptosis through MiR-326/PKM2-Mediated ER Stress and Mitochondrial Fission. AB - Resveratrol (Res), a natural phytoalexin found in a variety of plants, has significant antitumor activity. Pyruvate kinase M2 (PKM2) has abnormally high expression in various tumor cells, and it has been implicated in the survival of tumors. However, whether and how Res inhibits PKM2 expression is poorly understood. In the present study, we found that treatment with Res inhibited cell proliferation and induced cell apoptosis. The IC50 values of Res against DLD1, HeLa, and MCF-7 cells were 75 +/- 4.54, 50 +/- 3.65, and 50 +/- 3.32 MUM, respectively. To elucidate mechanisms underlying its antitumor activities, serial experiments were performed. Results showed that reduction of PKM2 expression in tumor cells by Res treatment increased the expression of ER stress and mitochondrial fission proteins but reduced cell viability and the levels of fusion proteins. These phenomena were reversed by artificial overexpression of PKM2. Quantitative analyses showed that the expression of microRNA-326 (miR-326) was increased upon Res treatment. Treatment with the miR-326 mimic reduced PKM2 expression, promoting recovery from ER stress and mitochondrial fission. Overall, these results demonstrate that miR-326/PKM2-mediated ER stress and mitochondrial dysfunction participate in apoptosis induced by Res. These results provide novel insight into the molecular mechanisms by which Res suppresses tumors and further support for the use of Res as an antitumor drug. PMID- 27960281 TI - Drought Effects on Proanthocyanidins in Sainfoin (Onobrychis viciifolia Scop.) Are Dependent on the Plant's Ontogenetic Stage. AB - Sainfoin (Onobrychis viciifolia Scop.) is a forage legume, which improves animal health and the environmental impact of livestock farming due to its proanthocyanidin content. To identify the impact of drought on acetone/water extractable proanthocyanidin (PA) concentration and composition in the generative and vegetative stages, a rain exclosure experiment was established. Leaves of 120 plants from 5 different sainfoin accessions were sampled repeatedly and analyzed by UPLC-ESI-MS/MS. The results showed distinct differences in response to drought between vegetative and generative plants. Whereas vegetative plants showed a strong response to drought in growth (-56%) and leaf PA concentration (+46%), generative plants showed no response in growth (-2%) or PA concentration (-9%). The PA composition was stable across environments. The five accessions varied in PA concentrations and composition but showed the same pattern of response to the experimental treatments. These results show that the ontogenetic stage at which drought occurs significantly affects the plant's response. PMID- 27960283 TI - Metabolism of Quercetin and Naringenin by Food-Grade Fungal Inoculum, Rhizopus azygosporus Yuan et Jong (ATCC 48108). AB - Rhizopus azygosporus Yuan et Jong (ATCC 48108), a starter culture for fermented soybean tempeh, produces beta-glucosidases that cleave flavonoid glycosides into aglycones during fermentation. However, recent data suggest that fermentation of a flavonoid glycoside-rich extract with this strain did not result in the production of aglycones. Thus, in this paper, flavonoid metabolism of this strain was investigated. Incubation of flavonoid aglycones, naringenin and quercetin, with R. azygosporus resulted in the production of flavonoid glucosyl-, hydroxyl-, and sulfo-conjugated derivatives. Naringenin was completely metabolized within 96 h into eriodictyol sulfate and eriodictyol glucoside, whereas quercetin was partially metabolized into quercetin glucoside, diglucoside, sulfate, and glucosyl-sulfate. Most of these metabolites were found to be excreted by the fungi into the culture medium. Toxicity analysis revealed that incubation with both quercetin and naringenin did not exert inhibitory effects on fungal growth. This study presents an interesting mechanism of fungal detoxification of flavonoids in foods. PMID- 27960284 TI - Gas Purge Microextraction Coupled with Stable Isotope Labeling-Liquid Chromatography/Mass Spectrometry for the Analysis of Bromophenols in Aquatic Products. AB - A green, sensitive, and accurate method was developed for the extraction and determination of bromophenols (BPs) from aquatic products by using organic solvent-free gas purge microsyringe extraction (GP-MSE) technique in combination with stable isotope labeling (SIL) strategy. BPs were extracted by NaHCO3 buffer solution, with recoveries varying from 92.0% to 98.5%. The extracted solution was analyzed by SIL strategy, during which analytes and standards were labeled by 10 methyl-acridone-2-sulfonyl chloride (d0-MASC) and its deuterated counterpart d3 MASC, respectively. The labeling reaction was finished within 10 min with good stability. The liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) sensitivity of BPs was greatly enhanced due to the mass-enhancing property of MASC, while the matrix effect was effectively minimized by the SIL strategy. The limits of detection (LODs) were in the range of 0.10-0.30 MUg/kg, while the limits of quantitations (LOQs) were in the range of 0.32-1.0 MUg/kg. The proposed method also showed great potential in the qualitative analysis of other bromophenols in the absence of standard. PMID- 27960282 TI - Imidacloprid Promotes High Fat Diet-Induced Adiposity and Insulin Resistance in Male C57BL/6J Mice. AB - Imidacloprid, a neonicotinoid insecticide widely used in agriculture worldwide, has been reported to promote adipogenesis and cause insulin resistance in vitro. The purpose of the current study was to determine the effects of imidacloprid and its interaction with dietary fat in the development of adiposity and insulin resistance using male C57BL/6J mice. Imidacloprid (0.06, 0.6, or 6 mg/kg bw/day) was mixed in a low-fat (4% w/w) or high-fat (20% w/w) diet and given to mice ad libitum for 12 weeks. Imidacloprid significantly promoted high fat diet-induced body weight gain and adiposity. In addition, imidacloprid treatment with the high fat diet resulted in impaired glucose metabolism. Consistently, there were significant effects of imidacloprid on genes regulating lipid and glucose metabolisms, including the AMP-activated protein kinase-alpha (AMPKalpha) pathway in white adipose tissue and liver. These results suggest that imidacloprid may potentiate high fat diet-induced adiposity and insulin resistance in male C57BL/6J mice. PMID- 27960286 TI - Differentiation of Volatile Profiles from Stockpiled Almonds at Varying Relative Humidity Levels Using Benchtop and Portable GC-MS. AB - Contamination by aflatoxin, a toxic metabolite produced by Aspergillus fungi ubiquitous in California almond and pistachio orchards, results in millions of dollars of lost product annually. Current detection of aflatoxin relies on destructive, expensive, and time-intensive laboratory-based methods. To explore an alternative method for the detection of general fungal growth, volatile emission profiles of almonds at varying humidities were sampled using both static SPME and dynamic needle-trap SPE followed by benchtop and portable GC-MS analysis. Despite the portable SPE/GC-MS system detecting fewer volatiles than the benchtop system, both systems resolved humidity treatments and identified potential fungal biomarkers at extremely low water activity levels. This ability to resolve humidity levels suggests that volatile profiles from germinating fungal spores could be used to create an early warning, nondestructive, portable detection system of fungal growth. PMID- 27960285 TI - New Sweet-Tasting C21-Pregnane Glycosides from Pericarps of Myriopteron extensum. AB - Ten novel C21 pregnane glycosides, extensumside C-L (1-10), were isolated as highly sweet-tasting substances from the edible pericarps of Myriopteron extensum (Wight) K. Schum by sensory-guided fractionation and purification. Their structures were determined through 1D and 2D NMR, such as HSQC, HMBC, 1H-1H COSY, HSQC-TOCSY, and ROESY, as well as other spectroscopic analysis combined with chemical evidence. These compounds shared the same aglycone, 3beta,16alpha dihydroxy-pregn-5-en-20-one, and contained the deoxysugar chain and the glucose chain which were linked to C-3 and C-16 of the aglycone, respectively. The sweetness potency was evaluated by a human sensory panel test and preliminary structure-taste relationship was discussed. The sweetness intensities of these compounds are between 50 and 400 times greater than that of sucrose. Furthermore, quantitation analyses of compounds 1, 3, 4, and 6 in different parts of M. extensum indicated that the concentrations of these sweet components in the pericarps are obviously higher than those in stems and roots. PMID- 27960288 TI - Extraction and Liquid Chromatography-Tandem Mass Spectrometry Detection of 3 Monochloropropanediol Esters and Glycidyl Esters in Infant Formula. AB - A method was developed for the extraction of fatty acid esters of 3-chloro-1,2 propanediol (3-MCPD) and glycidol from infant formula, followed by quantitative analysis of the extracts using liquid chromatography-tandem mass spectrometry (LC MS/MS). These process-induced chemical contaminants are found in refined vegetable oils, and studies have shown that they are potentially carcinogenic and/or genotoxic, making their presence in edible oils (and processed foods containing these oils) a potential health risk. The extraction procedure involves a liquid-liquid extraction, where powdered infant formula is dissolved in water and extracted with ethyl acetate. Following shaking, centrifugation, and drying of the organic phase, the resulting fat extract is cleaned-up using solid-phase extraction and analyzed by LC-MS/MS. Method performance was confirmed by verifying the percent recovery of each 3-MCPD and glycidyl ester in a homemade powdered infant formula reference material. Average ester recoveries in the reference material ranged from 84.9 to 109.0% (0.6-9.5% RSD). The method was also validated by fortifying three varieties of commercial infant formulas with a 3 MCPD and glycidyl ester solution. Average recoveries of the esters across all concentrations and varieties of infant formula ranged from 88.7 to 107.5% (1.0 9.5% RSD). Based on the validation results, this method is suitable for producing 3-MCPD and glycidyl ester occurrence data in all commercially available varieties of infant formula. PMID- 27960287 TI - Nitenpyram, Dinotefuran, and Thiamethoxam Used as Seed Treatments Act as Efficient Controls against Aphis gossypii via High Residues in Cotton Leaves. AB - The effects of eight neonicotinoid seed treatments against the cotton aphid Aphis gossypii and its natural enemies in Bt cotton fields were evaluated, and the concentrations of these neonicotinoids in cotton leaves and soil were also investigated. The results showed that all neonicotinoid seed treatments efficiently reduced A. gossypii populations throughout the cotton seedling stage. The percentages of curly leaf plants in all of the neonicotinoid seed treatments were below the threshold for economic loss. Among the eight tested neonicotinoid seed treatments, nitenpyram, dinotefuran, and thiamethoxam showed high control efficiency against A. gossypii. Residues of the three neonicotinoids were higher than those of other neonicotinoids in cotton leaves. Moreover, residues of dinotefuran and nitenpyram remained at low levels in the soil. However, the abundance of natural enemies in the cotton field was to some extent influenced by neonicotinoid seed treatments. Therefore, neonicotinoids nitenpyram, dinotefuran, and thiamethoxam used as seed treatment can provide effective protection that should play an important role in the management of early-season A. gossypii in Bt cotton fields; however, the risks of neonicotinoids to the environment should also be considered. PMID- 27960289 TI - Correction to Daily Preharvest UV-C Light Maintains the High Stilbenoid Concentration in Grapes. PMID- 27960290 TI - Characterization of the Interactions between Titanium Dioxide Nanoparticles and Polymethoxyflavones Using Surface-Enhanced Raman Spectroscopy. AB - Nanosized titanium dioxide (TiO2) particles are commonly present in TiO2 food additives (E171) and have been associated with potential adverse effects on health. However, little knowledge is available regarding the interactions between TiO2 nanoparticles (NPs) and other food components, such as flavonoids. In this study, we aim to study the molecular interactions between TiO2 anatase NPs and three structurally closely related polymethoxyflavones (PMFs, flavonoids found in citrus fruits), namely, 3',4'-didemethylnobiletin (DDN), 5-demethylnobiletin (5DN), and 5,3',4'-tridemethylnobiletin (TDN), using ultraviolet-visible (UV-vis) spectrometry and surface-enhanced Raman spectroscopy (SERS). In the UV-vis absorption spectra, bathochromic effects were observed after DDN and TDN conjugated with TiO2 NPs. The results from SERS analysis clearly demonstrated that DDN and TDN could bind TiO2 NPs with the functional groups 3'-OH and 4'-OH on ring B and formed charge-transfer complexes. However, 5DN with functional groups C?O on ring C and 5-OH on ring A could not bind TiO2 NPs. Knowledge on the molecular interactions between TiO2 NPs and food components, such as flavonoids, will facilitate the understanding of the fate of TiO2 NPs during food processing and in the gastrointestinal tract after oral consumption. PMID- 27960291 TI - Inhibitory Effect of Methyl 2-(4'-Methoxy-4'-oxobutanamide) Benzoate from Jerusalem Artichoke (Helianthus tuberosus) on the Inflammatory Paracrine Loop between Macrophages and Adipocytes. AB - The interaction between macrophages and adipocytes is known to aggravate inflammation of the adipose tissue, leading to decreased insulin sensitivity. Hence, attenuation of the inflammatory paracrine loop between macrophages and adipocytes is deemed essential to ameliorate insulin resistance and diabetes mellitus type 2. Methyl 2-(4'-methoxy-4'-oxobutanamide) benzoate (compound 1), a newly isolated compound from Jerusalem srtichoke (JA), has not been biologically characterized yet. Here, we investigated whether JA-derived compound 1 attenuates the inflammatory cycle between RAW 264.7 macrophages and 3T3-L1 adipocytes. Compound 1 suppressed the inflammatory response of RAW 264.7 cells to lipopolysaccharide through decreased secretion of IL-1beta, IL-6, and TNF-alpha. Moreover, the mRNA expression of TNF-alpha, IL-6, IL-1beta, MCP-1, and Rantes and MAPK pathway activation in 3T3-L1 adipocytes, incubated in macrophage-conditioned media, were inhibited. These findings suggest an anti-inflammatory effect of a newly extracted compound against adipose tissue inflammation and insulin resistance. PMID- 27960293 TI - Novel Biobased Sodium Shellac for Wrapping Disperse Multiscale Emulsion Particles. AB - As a result of amphipathic oligomers driven by different forces including hydrophobic interaction, electrostatic interaction, H-bond, and heat, multiscale emulsion particles can be wrapped. In this paper we attempted to use sodium shellac as a novel biobased wrapping material. The H+, Ca+, and spray-drying methods were employed to solidify the complex vitamin E (VE) emulsion with sodium shellac to fabricate the beads. The VE loading and encapsulation efficiency were used to evaluate the wrapping process. The results show that the microscale VE emulsion particles could easily be wrapped by these three means. However, due to the high solid content of the nanoscale emulsion particles, it was difficult to wrap them by spray-drying method. The beads solidified by H+ had higher VE loading and encapsulation efficiency than those solidified by other methods and even grabbed the hydrophobic molecule VE from the emulsion micelles. At an RVS of 1:4, these two parameters, which are obtained by the nanoscale emulsion particle wrapping process, could reach 18.9 and 64.3% supported by the single driving force of hydrophobic interaction. Above all, this research introduced a novel wrapping material driven by different forces that can aggregate and wrap the emulsion micelles. It can be widely used in the medical, food, and cosmetics industries. PMID- 27960292 TI - Ankaflavin and Monascin Induce Apoptosis in Activated Hepatic Stellate Cells through Suppression of the Akt/NF-kappaB/p38 Signaling Pathway. AB - The increased proliferation of activated hepatic stellate cells (HSCs) is associated with hepatic fibrosis and excessive extracellular matrix (ECM)-protein production. We examined the inhibitory effects of the Monascus purpureus fermented metabolites, ankaflavin and monascin (15 and 30 MUM), on the Akt/nuclear factor (NF)-kappaB and p38 mitogen-activated protein kinase (MAPK) signaling pathways in HSC-T6 (activated hepatic stellate cell line). Ankaflavin and monascin (30 MUM) induced apoptosis and significantly inhibited cell growth (cell viabilities: 80.2 +/- 5.43% and 62.8 +/- 8.20%, respectively, versus control cells; P < 0.05). Apoptosis and G1 phase arrest (G1 phase percentages: 76.1 +/- 2.85% and 79.9 +/- 1.80%, respectively, versus control cells 65.9 +/- 4.94%; P < 0.05) correlated with increased p53 and p21 levels and caspase 3 activity and decreased cyclin D1 and Bcl-2-family protein levels (P < 0.05, all cases). The apoptotic effects of ankaflavin and monascin were HSC-T6-specific, suggesting their potential in treating liver fibrosis. PMID- 27960295 TI - Evaluation of Diuron Tolerance and Biotransformation by Fungi from a Sugar Cane Plantation Sandy-Loam Soil. AB - Microorganisms capable of degrading herbicides are essential to minimize the amount of chemical compounds that may leach into other environments. This work aimed to study the potential of sandy-loam soil fungi to tolerate the herbicide Herburon (50% diuron) and to degrade the active ingredient diuron. Verticillium sp. F04, Trichoderma virens F28, and Cunninghamella elegans B06 showed the highest growth in the presence of the herbicide. The evaluation of biotransformation showed that Aspergillus brasiliensis G08, Aspergillus sp. G25, and Cunninghamella elegans B06 had the greatest potential to degrade diuron. Statistical analysis demonstrated that glucose positively influences the potential of the microorganism to degrade diuron, indicating a cometabolic process. Due to metabolites founded by diuron biotransformation, it is indicated that the fungi are relevant in reducing the herbicide concentration in runoff, minimizing the environmental impact on surrounding ecosystems. PMID- 27960294 TI - Free Amino Acid Profile and Expression of Genes Implicated in Protein Metabolism in Skeletal Muscle of Growing Pigs Fed Low-Protein Diets Supplemented with Branched-Chain Amino Acids. AB - Revealing the expression patterns of genes involved in protein metabolism as affected by diets would be useful for further clarifying the importance of the balance among the branched-chain amino acids (BCAAs), which include leucine (Leu), isoleucine (Ile), and valine (Val). Therefore, we used growing pigs to explore the effects of different dietary BCAA ratios on muscle protein metabolism. The Leu:Ile:Val ratio was 1:0.51:0.63 (20% crude protein, CP), 1:1:1 (17% CP), 1:0.75:0.75 (17% CP), 1:0.51:0.63 (17% CP), and 1:0.25:0.25 (17% CP), respectively. Results showed that compared with the control group, low-protein diets with the BCAA ratio ranging from 1:0.75:0.75 to 1:0.25:0.25 elevated muscle free amino acid (AA) concentrations and AA transporter expression, significantly activated the mammalian target of rapamycin complex 1 pathway, and decreased serum urea nitrogen content and the mRNA expression of genes related to muscle protein degradation (P < 0.05). In conclusion, these results indicated that maintaining the dietary Leu:Ile:Val ratio within 1:0.25:0.25-1:0.75:0.75 in low protein diets (17% CP) would facilitate the absorption and utilization of free AA and result in improved protein metabolism and muscle growth. PMID- 27960296 TI - Identification of Quorum Sensing Signal Molecule of Lactobacillus delbrueckii subsp. bulgaricus. AB - Many bacteria in nature use quorum sensing (QS) to regulate gene expression. The quorum sensing system plays critical roles in the adaptation of bacteria to the surrounding environment. Previous studies have shown that during high-density fermentation, the autolysis of lactic acid bacteria was regulated by the QS system, and the two-component system (TCS, LBUL_RS00115/LBUL_RS00110) is involved in the autolysis of Lactobacillus delbrueckii subsp. bulgaricus. However, the QS signal molecule, which regulates this pathway, has not been identified. In this study, we compared the genome of Lactobacillus bulgaricus ATCC BAA-365 with the locus of seven lactobacillus QS systems; the position of the QS signal molecule of Lactobacillus bulgaricus ATCC BAA-365 was predicted by bioinformatics tool. Its function was identified by in vitro experiments. Construction of TCS mutant by gene knockout of LBUL_RS00115 confirmed that the signal molecule regulates the density of the flora by the TCS (LBUL_RS00115/LBUL_RS00110). This study indicated that quorum quenching and inhibition based on the signal molecule might serve as an approach to reduce the rate of autolysis of LAB and increase the number of live bacteria in fermentation. PMID- 27960297 TI - Preparation of Fucoxanthin-Loaded Nanoparticles Composed of Casein and Chitosan with Improved Fucoxanthin Bioavailability. AB - To facilitate the utilization of fucoxanthin (FX), a valuable marine carotenoid, in the food industry, FX-loaded casein nanoparticles (FX-CN) and chitosan-coated FX-CN (FX-CS-CN) were developed using the FX-enriched fraction from Phaeodactylum tricornutum. Two nanoscale particles (237 +/- 13 nm for FX-CN and 277 +/- 26 nm for FX-CN-CN) with spherical and smooth surfaces showed over 71% encapsulation efficiency and polydispersity index (PDI) value of 0.31-0.39 in water. Owing to the chitosan coating, FX-CS-CN showed a positive zeta potential (24.00 mV), whereas that of FX-CN was negative (-12.87 mV). In vitro simulated digestion demonstrated better FX bioaccessibility from the nanoparticles versus P. tricornutum powder (Pt-powder) and from FX-CN versus FX-CS-CN. However, in C57BL/6 mice, fucoxanthinol absorption to the blood circulation was two times higher for FX-CS-CN versus FX-CN, possibly due to increased retention or adsorption to mucin by the cationic biopolymer in the chitosan-coated particles. These results demonstrate that FX-CS-CN can enable the application of FX, with improved bioavailability and water dispersibility, in the food industry. PMID- 27960298 TI - Hydroxycinnamoyl Glucose and Tartrate Esters and Their Role in the Formation of Ethylphenols in Wine. AB - Synthesized p-coumaroyl and feruloyl l-tartrate esters were submitted to Brettanomyces bruxellensis strains AWRI 1499, AWRI 1608, and AWRI 1613 to assess their role as precursors to ethylphenols in wine. No evolution of ethylphenols was observed. Additionally, p-coumaroyl and feruloyl glucose were synthesized and submitted to B. bruxellensis AWRI 1499, which yielded both 4-ethylphenol and 4 ethylguaiacol. Unexpected chemical transformations of the hydroxycinnamoyl glucose esters during preparation were investigated to prevent these in subsequent synthetic attempts. Photoisomerization gave an isomeric mixture containing the trans-esters and undesired cis-esters, and acyl migration resulted in a mixture of the desired 1-O-beta-ester and two additional migrated forms, the 2-O-alpha- and 6-O-alpha-esters. Theoretical studies indicated that the photoisomerization was facilitated by deprotonation of the phenol, and acyl migration is favored during acidic, nonaqueous handling. Preliminary LC-MS/MS studies observed the migrated hydroxycinnamoyl glucose esters in wine and allowed for identification of feruloyl glucose in red wine for the first time. PMID- 27960299 TI - Mechanistic Studies of Pd(II)-Catalyzed Copolymerization of Ethylene and Vinylalkoxysilanes: Evidence for a beta-Silyl Elimination Chain Transfer Mechanism. AB - Copolymerizations of ethylene with vinyltrialkoxysilanes are reported using both a "traditional" cationic Pd(II) aryldiimine catalyst, t-1 (aryl = 2,6 diisopropylphenyl), and a "sandwich-type" aryldiimine catalyst, s-2 (aryl = 8 tolylnaphthyl). Incorporation levels of vinyltrialkoxysilanes between 0.25 and 2.0 mol % were achieved with remarkably little rate retardation relative to ethylene homopolymerizations. In the case of the traditional catalyst system, molecular weights decrease as the level of comonomer increases and only one trialkoxysilyl group is incorporated per chain. Molecular weight distributions of ca. 2 are observed. For the sandwich catalyst, higher molecular weights are observed with many more trialkoxysilyl groups incorporated per chain. Polymers with molecular weight distributions of ca. 1.2-1.4 are obtained. Detailed NMR mechanistic studies have revealed the formation of intermediate pi-complexes of the type (diimine)Pd(alkyl)(vinyltrialkoxysilane)+. 1,2-Migratory insertions of these complexes occur with rates similar to ethylene insertion and result in formation of observable five-membered chelate intermediates. These chelates are rapidly opened with ethylene forming alkyl ethylene complexes, a requirement for chain growth. An unusual beta-silyl elimination mechanism was shown to be responsible for chain transfer and formation of low molecular weight copolymers in the traditional catalyst system, t-1. This chain transfer process is retarded in the sandwich system. Relative binding affinities of ethylene and vinyltrialkoxysilanes to the cationic palladium center have been determined. The quantitative mechanistic studies reported fully explain the features of the bulk polymerization results. PMID- 27960301 TI - Nucleophilic T-Shaped (LXL)Au(I)-Pincer Complexes: Protonation and Alkylation. AB - We report the synthesis and reactivity of unusual T-shaped (LXL)Au(I)-pincer complexes, based on a carbazole framework flanked by two mesoionic carbenes (MICs). In contrast to other Au(I) complexes, these complexes react with electrophiles. Protonation and alkylation occur either at the metal or the ligand, depending on steric factors. Of particular interest, protonation at gold leads to an unprecedented cationic Au(III) hydride, which gives a 1H NMR resonance at delta -8.34 ppm. The reactivity of this "hydride", however, shows protic and not hydridic behavior. PMID- 27960300 TI - Catalytic Asymmetric Synthesis of Chiral gamma-Amino Ketones via Umpolung Reactions of Imines. AB - The first direct catalytic asymmetric synthesis of gamma-amino ketones was realized by the development of a highly diastereoselective and enantioselective C C bond-forming umpolung reaction of imines and enones under the catalysis of a new cinchona alkaloid-derived phase-transfer catalyst. In a loading ranging from 0.02 to 2.5 mol %, the catalyst activates a broad range of trifluoromethyl imines and aldimines as nucleophiles to engage in chemo-, regio-, diastereo- and enantioselective C-C bond-forming reactions with acyclic and cyclic enones, thereby converting these readily available prochiral starting materials into highly enantiomerically enriched chiral gamma-amino ketones in synthetically useful yields. Enabled by this unprecedented umpolung reaction of imines, conceptually new and concise routes were developed for the asymmetric synthesis of nitrogen-heterocycles such as pyrrolidines and indolizidines. PMID- 27960303 TI - Mechanism for Si-Si Bond Rupture in Single Molecule Junctions. AB - The stability of chemical bonds can be studied experimentally by rupturing single molecule junctions under applied voltage. Here, we compare voltage-induced bond rupture in two Si-Si backbones: one has no alternate conductive pathway whereas the other contains an additional naphthyl pathway in parallel to the Si-Si bond. We show that in contrast to the first system, the second can conduct through the naphthyl group when the Si-Si bond is ruptured using an applied voltage. We investigate this voltage induced Si-Si bond rupture by ab initio density functional theory calculations and molecular dynamics simulations that ultimately demonstrate that the excitation of molecular vibrational modes by tunneling electrons leads to homolytic Si-Si bond rupture. PMID- 27960302 TI - Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors. AB - Electrophilic small molecules are an important class of chemical probes and drugs that produce biological effects by irreversibly modifying proteins. Examples of electrophilic drugs include covalent kinase inhibitors that are used to treat cancer and the multiple sclerosis drug dimethyl fumarate. Optimized covalent drugs typically inactivate their protein targets rapidly in cells, but ensuing time-dependent, off-target protein modification can erode selectivity and diminish the utility of reactive small molecules as chemical probes and therapeutics. Here, we describe an approach to confer kinetic selectivity to electrophilic drugs. We show that an analogue of the covalent Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib bearing a fumarate ester electrophile is vulnerable to enzymatic metabolism on a time-scale that preserves rapid and sustained BTK inhibition, while thwarting more slowly accumulating off-target reactivity in cell and animal models. These findings demonstrate that metabolically labile electrophilic groups can endow covalent drugs with kinetic selectivity to enable perturbation of proteins and biochemical pathways with greater precision. PMID- 27960304 TI - Parameterization of Water Electrooxidation Catalyzed by Metal Oxides Using Fourier Transformed Alternating Current Voltammetry. AB - Detection and quantification of redox transformations involved in water oxidation electrocatalysis is often not possible using conventional techniques. Herein, use of large amplitude Fourier transformed ac voltammetry and comprehensive analysis of the higher harmonics has enabled us to access the redox processes responsible for catalysis. An examination of the voltammetric data for water oxidation in borate buffered solutions (pH 9.2) at electrodes functionalized with systematically varied low loadings of cobalt (CoOx), manganese (MnOx), and nickel oxides (NiOx) has been undertaken, and extensive experiment-simulation comparisons have been introduced for the first time. Analysis shows that a single redox process controls the rate of catalysis for Co and Mn oxides, while two electron transfer events contribute in the Ni case. We apply a "molecular catalysis" model that couples a redox transformation of a surface-confined species (effective reversible potential, Eeff0) to a catalytic reaction with a substrate in solution (pseudo-first-order rate constant, k1f), accounts for the important role of a Bronsted base, and mimics the experimental behavior. The analysis revealed that Eeff0 values for CoOx, MnOx, and NiOx lie within the range 1.9-2.1 V vs reversible hydrogen electrode, and k1f varies from 2 * 103 to 4 * 104 s-1. The k1f values are much higher than reported for any water electrooxidation catalyst before. The Eeff0 values provide a guide for in situ spectroscopic characterization of the active states involved in catalysis by metal oxides. PMID- 27960305 TI - All-Inorganic Perovskite Solar Cells. AB - The research field on perovskite solar cells (PSCs) is seeing frequent record breaking in the power conversion efficiency (PCE). However, organic-inorganic hybrid halide perovskites and organic additives in common hole-transport materials (HTMs) exhibit poor stability against moisture and heat. Here we report the successful fabrication of all-inorganic PSCs without any labile or expensive organic components. The entire fabrication process can be operated in ambient environment without humidity control (e.g., a glovebox). Even without encapsulation, the all-inorganic PSCs present no performance degradation in humid air (90-95% relative humidity, 25 degrees C) for over 3 months (2640 h) and can endure extreme temperatures (100 and -22 degrees C). Moreover, by elimination of expensive HTMs and noble-metal electrodes, the cost was significantly reduced. The highest PCE of the first-generation all-inorganic PSCs reached 6.7%. This study opens the door for next-generation PSCs with long-term stability under harsh conditions, making practical application of PSCs a real possibility. PMID- 27960307 TI - "pi-Hole-pi" Interaction Promoted Photocatalytic Hydrodefluorination via Inner Sphere Electron Transfer. AB - We describe a metal-free, photocatalytic hydrodefluorination (HDF) of polyfluoroarenes (FA) using pyrene-based photocatalysts (Py). The weak "pi-hole pi" interaction between Py and FA promotes the electron transfer against unfavorable energetics (DeltaGET up to 0.63 eV) and initiates the subsequent HDF. The steric hindrance of Py and FA largely dictates the HDF reaction rate, pointing to an inner-sphere electron transfer pathway. This work highlights the importance of the size and shape of the photocatalyst and the substrate in controlling the electron transfer mechanism and rates as well as the overall photocatalytic processes. PMID- 27960306 TI - Quinone 1 e- and 2 e-/2 H+ Reduction Potentials: Identification and Analysis of Deviations from Systematic Scaling Relationships. AB - Quinones participate in diverse electron transfer and proton-coupled electron transfer processes in chemistry and biology. To understand the relationship between these redox processes, an experimental study was carried out to probe the 1 e- and 2 e-/2 H+ reduction potentials of a number of common quinones. The results reveal a non-linear correlation between the 1 e- and 2 e-/2 H+ reduction potentials. This unexpected observation prompted a computational study of 134 different quinones, probing their 1 e- reduction potentials, pKa values, and 2 e /2 H+ reduction potentials. The density functional theory calculations reveal an approximately linear correlation between these three properties and an effective Hammett constant associated with the quinone substituent(s). However, deviations from this linear scaling relationship are evident for quinones that feature intramolecular hydrogen bonding, halogen substituents, charged substituents, and/or sterically bulky substituents. These results, particularly the different substituent effects on the 1 e- versus 2 e-/2 H+ reduction potentials, have important implications for designing quinones with tailored redox properties. PMID- 27960308 TI - Chemical Synthesis and Self-Assembly of a Ladderane Phospholipid. AB - Ladderane lipids produced by anammox bacteria constitute some of the most structurally fascinating yet poorly studied molecules among biological membrane lipids. Slow growth of the producing organism and the inherent difficulty of purifying complex lipid mixtures have prohibited isolation of useful amounts of natural ladderane lipids. We have devised a highly selective total synthesis of ladderane lipid tails and a full phosphatidylcholine to enable biophysical studies on chemically homogeneous samples of these molecules. Additionally, we report the first proof of absolute configuration of a natural ladderane. PMID- 27960310 TI - Co-opting a Bioorthogonal Reaction for Oncometabolite Detection. AB - Dysregulated metabolism is a hallmark of many diseases, including cancer. Methods to fluorescently detect metabolites have the potential to enable new approaches to cancer detection and imaging. However, fluorescent sensing methods for naturally occurring cellular metabolites are relatively unexplored. Here we report the development of a chemical approach to detect the oncometabolite fumarate. Our strategy exploits a known bioorthogonal reaction, the 1,3-dipolar cycloaddition of nitrileimines and electron-poor olefins, to detect fumarate via fluorescent pyrazoline cycloadduct formation. We demonstrate hydrazonyl chlorides serve as readily accessible nitrileimine precursors, whose reactivity and spectral properties can be tuned to enable detection of fumarate and other dipolarophile metabolites. Finally, we show this reaction can be used to detect enzyme activity changes caused by mutations in fumarate hydratase, which underlie the familial cancer predisposition syndrome hereditary leiomyomatosis and renal cell cancer. Our studies define a novel intersection of bioorthogonal chemistry and metabolite reactivity that may be harnessed to enable biological profiling, imaging, and diagnostic applications. PMID- 27960311 TI - Carbon-Carbon Bond-Forming Reductive Elimination from Isolated Nickel(III) Complexes. AB - This manuscript describes the design, synthesis, characterization, and reactivity studies of organometallic NiIII complexes of general structure TpNiIII(R)(R1) (Tp = tris(pyrazolyl)borate). With appropriate selection of the R and R1 ligands, the complexes are stable at room temperature and can be characterized by cyclic voltammetry, EPR spectroscopy, and X-ray crystallography. Upon heating, many of these NiIII compounds undergo C(sp2)-C(sp2) or C(sp3)-C(sp2) bond-forming reactions that are challenging at lower oxidation states of nickel. PMID- 27960309 TI - Vinylogous Dehydration by a Polyketide Dehydratase Domain in Curacin Biosynthesis. AB - Polyketide synthase (PKS) enzymes continue to hold great promise as synthetic biology platforms for the production of novel therapeutic agents, biofuels, and commodity chemicals. Dehydratase (DH) catalytic domains play an important role during polyketide biosynthesis through the dehydration of the nascent polyketide intermediate to provide olefins. Our understanding of the detailed mechanistic and structural underpinning of DH domains that control substrate specificity and selectivity remains limited, thus hindering our efforts to rationally re-engineer PKSs. The curacin pathway houses a rare plurality of possible double bond permutations containing conjugated olefins as well as both cis- and trans olefins, providing an unrivaled model system for polyketide dehydration. All four DH domains implicated in curacin biosynthesis were characterized in vitro using synthetic substrates, and activity was measured by LC-MS/MS analysis. These studies resulted in complete kinetic characterization of the all-trans-trienoate forming CurK-DH, whose kcat of 72 s-1 is more than 3 orders of magnitude greater than that of any previously reported PKS DH domain. A novel stereospecific mechanism for diene formation involving a vinylogous enolate intermediate is proposed for the CurJ and CurH DHs on the basis of incubation studies with truncated substrates. A synthetic substrate was co-crystallized with a catalytically inactive Phe substitution in the His-Asp catalytic dyad of CurJ-DH to elucidate substrate-enzyme interactions. The resulting complex suggested the structural basis for dienoate formation and provided the first glimpse into the enzyme-substrate interactions essential for the formation of olefins in polyketide natural products. This examination of both canonical and non-canonical dehydration mechanisms reveals hidden catalytic activity inherent in some DH domains that may be leveraged for future applications in synthetic biology. PMID- 27960312 TI - A Sacrificial Coating Strategy Toward Enhancement of Metal-Support Interaction for Ultrastable Au Nanocatalysts. AB - Supported gold (Au) nanocatalysts hold great promise for heterogeneous catalysis; however, their practical application is greatly hampered by poor thermodynamic stability. Herein, a general synthetic strategy is reported where discrete metal nanoparticles are made resistant to sintering, preserving their catalytic activities in high-temperature oxidation processes. Taking advantage of the unique coating chemistry of dopamine, sacrificial carbon layers are constructed on the material surface, stabilizing the supported catalyst. Upon annealing at high temperature under an inert atmosphere, the interactions between support and metal nanoparticle are dramatically enhanced, while the sacrificial carbon layers can be subsequently removed through oxidative calcination in air. Owing to the improved metal-support contact and strengthened electronic interactions, the resulting Au nanocatalysts are resistant to sintering and exhibit excellent durability for catalytic combustion of propylene at elevated temperatures. Moreover, the facile synthetic strategy can be extended to the stabilization of other supported catalysts on a broad range of supports, providing a general approach to enhancing the thermal stability and sintering resistance of supported nanocatalysts. PMID- 27960314 TI - Chain Length and Solvent Control over the Electronic Properties of Alkanethiolate Protected Gold Nanoparticles at the Molecule-to-Metal Transition. AB - Alkanethiolate protected gold nanoparticles are one of the most widely used systems in modern science and technology, where the emergent electronic properties of the gold core are valued for use in applications such as plasmonic solar cells, photocatalysis, and photothermal heating. Though choice in alkane chain length is not often discussed as a way in which to control the electronic properties of these nanoparticles, we show that the chain length of the alkyl tail exerts clear control over the electronic properties of the gold core, as determined by conduction electron spin resonance spectroscopy. The control exerted by chain length is reported on by changes to the g-factor of the metallic electrons, which we can relate to the average surface potential on the gold core. We propose that the surface potential is modulated by direct charge donation from the ligand to the metal, resulting from the formation of a chemical bond. Furthermore, the degree of charge transfer is controlled by differences between the dielectric constant of the medium and the ligand shell. Together, these observations are used to construct a simple electrostatic model that provides a framework for understanding how surface chemistry can be used to modulate the electronic properties of gold nanoparticles. PMID- 27960313 TI - Integrating Enzymatic Self-Assembly and Mitochondria Targeting for Selectively Killing Cancer Cells without Acquired Drug Resistance. AB - Targeting organelles by modulating the redox potential of mitochondria is a promising approach to kill cancer cells that minimizes acquired drug resistance. However, it lacks selectivity because mitochondria perform essential functions for (almost) all cells. We show that enzyme-instructed self-assembly (EISA), a bioinspired molecular process, selectively generates the assemblies of redox modulators (e.g., triphenyl phosphinium (TPP)) in the pericellular space of cancer cells for uptake, which allows selectively targeting the mitochondria of cancer cells. The attachment of TPP to a pair of enantiomeric, phosphorylated tetrapeptides produces the precursors (L-1P or D-1P) that form oligomers. Upon dephosphorylation catalyzed by ectophosphatases (e.g., alkaline phosphatase (ALP)) overexpressed on cancer cells (e.g., Saos2), the oligomers self-assemble to form nanoscale assemblies only on the surface of the cancer cells. The cancer cells thus uptake these assemblies of TPP via endocytosis, mainly via a caveolae/raft-dependent pathway. Inside the cells, the assemblies of TPP-peptide conjugates escape from the lysosome, induce dysfunction of mitochondria to release cytochrome c, and result in cell death, while the controls (i.e., omitting TPP motif, inhibiting ALP, or removing phosphate trigger) hardly kill the Saos2 cells. Most importantly, the repeated stimulation of the cancers by the precursors, unexpectedly, sensitizes the cancer cells to the precursors. As the first example of the integration of subcellular targeting with cell targeting, this study validates the spatial control of the assemblies of nonspecific cytotoxic agents by EISA as a promising molecular process for selectively killing cancer cells without inducing acquired drug resistance. PMID- 27960315 TI - Development and Analysis of a Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Acrylates Enabled by Chiral Anion Phase Transfer. AB - Enantioselective 1,1-diarylation of terminal alkenes enabled by the combination of Pd catalysis with a chiral anion phase transfer (CAPT) strategy is reported herein. The reaction of substituted benzyl acrylates with aryldiazonium salts and arylboronic acids gave the corresponding 3,3-diarylpropanoates in moderate to good yields with high enantioselectivies (up to 98:2 er). Substituents on the benzyl acrylate and CAPT catalyst significantly affect the enantioselectivity, and multidimensional parametrization identified correlations suggesting structural origins for the high stereocontrol. PMID- 27960317 TI - Performance of Fe-N/C Oxygen Reduction Electrocatalysts toward NO2-, NO, and NH2OH Electroreduction: From Fundamental Insights into the Active Center to a New Method for Environmental Nitrite Destruction. AB - Although major progress has recently been achieved through ex situ methods, there is still a lack of understanding of the behavior of the active center in non precious metal Fe-N/C catalysts under operating conditions. Utilizing nitrite, nitric oxide, and hydroxylamine as molecular probes, we show that the active site for the oxygen reduction reaction (ORR) is different under acidic and alkaline conditions. An in-depth investigation of the ORR in acid reveals a behavior which is similar to that of iron macrocyclic complexes and suggests a contribution of the metal center in the catalytic cycle. We also show that this catalyst is highly active toward nitrite and nitric oxide electroreduction under various pH values with ammonia as a significant byproduct. This study offers fundamental insight into the chemical behavior of the active site and demonstrates a possible use of these materials for nitrite and nitric oxide sensing applications or environmental nitrite destruction. PMID- 27960318 TI - F- Nucleophilic-Addition-Induced Allylic Alkylation. AB - Herein we present a novel strategy based on palladium-catalyzed allylic alkylation by taking advantage of the nucleophilic addition of external fluoride onto gem-difluoroalkenes as the initiation step. The merit of this protocol is highly appealing, as it enables a formal allylation of trifluoroethylarene derivatives through the in situ generation of beta-trifluorocarbanions, which otherwise are deemed to be problematic in deprotonative allylation. Furthermore, this strategy distinguishes itself by high modularity, operational simplicity, and wide substrate scope with respect to allyl carbonates, giving rise to a broad array of homoallyltrifluoromethane derivatives, which otherwise would not be easily obtained using existing synthetic methods. PMID- 27960316 TI - Palladium-Catalyzed Enantioselective Intermolecular Coupling of Phenols and Allylic Alcohols. AB - An enantioselective intermolecular coupling of oxygen nucleophiles and allylic alcohols to give beta-aryloxycarbonyl compounds is disclosed using a chiral pyridine oxazoline-ligated palladium catalyst under mild conditions. As opposed to the formation of traditional Wacker-type products, enantioselective migratory insertion is followed by beta-hydride elimination toward the adjacent alcohol. Deuterium labeling experiments suggest a syn-migratory insertion of the alkene into the Pd-O bond. A broad scope of phenols, various allylic alcohols, and an alkyl hydroperoxide are viable coupling partners in this process. PMID- 27960319 TI - Experimental Demonstration of an Electride as a 2D Material. AB - Because of their loosely bound electrons, electrides offer physical properties useful in chemical synthesis and electronics. For these applications and others, nanosized electrides offer advantages, but to-date no electride has been synthesized as a nanomaterial. We demonstrate experimentally that Ca2N, a layered electride in which layers of atoms are separated by layers of a 2D electron gas (2DEG), can be exfoliated into two-dimensional (2D) nanosheets using liquid exfoliation. The 2D flakes are stable in a nitrogen atmosphere or in select organic solvents for at least one month. Electron microscopy and elemental analysis reveal that the 2D flakes retain the crystal structure and stoichiometry of the parent 3D Ca2N. In addition, the 2D flakes exhibit metallic character and an optical response that agrees with DFT calculations. Together these findings suggest that the 2DEG is preserved in the 2D material. With this work, we bring electrides into the nanoregime and experimentally demonstrate a 2D electride, Ca2N. PMID- 27960320 TI - Enabling Forster Resonance Energy Transfer from Large Nanocrystals through Energy Migration. AB - The stringent distance dependence of Forster resonance energy transfer (FRET) has limited the ability of an energy donor to donate excitation energy to an acceptor over a Forster critical distance (R0) of 2-6 nm. This poses a fundamental size constraint (<8 nm or ~4R0) for experimentation requiring particle-based energy donors. Here, we describe a spatial distribution function model and theoretically validate that the particle size constraint can be mitigated through coupling FRET with a resonant energy migration process. By combining excitation energy migration and surface trapping, we demonstrate experimentally an over 600-fold enhancement over acceptor emission for large nanocrystals (30 nm or ~15R0) with surface-anchored molecular acceptors. Our work shows that the migration-coupled approach can dramatically improve sensitivity in FRET-limited measurement, with potential applications ranging from facile photochemical synthesis to biological sensing and imaging at the single-molecule level. PMID- 27960322 TI - Photocatalytic Asymmetric Epoxidation of Terminal Olefins Using Water as an Oxygen Source in the Presence of a Mononuclear Non-Heme Chiral Manganese Complex. AB - Photocatalytic enantioselective epoxidation of terminal olefins using a mononuclear non-heme chiral manganese catalyst, [(R,R-BQCN)MnII]2+, and water as an oxygen source yields epoxides with relatively high enantioselectivities (e.g., up to 60% enantiomeric excess). A synthetic mononuclear non-heme chiral Mn(IV) oxo complex, [(R,R-BQCN)MnIV(O)]2+, affords similar enantioselectivities in the epoxidation of terminal olefins under stoichiometric reaction conditions. Mechanistic details of each individual step of the photoinduced catalysis, including formation of the Mn(IV)-oxo intermediate, are discussed on the basis of combined results of laser flash photolysis and other spectroscopic methods. PMID- 27960323 TI - Palladium-Catalyzed Enantioselective alpha-Arylation of alpha-Fluoroketones. AB - The transition-metal-catalyzed alpha-arylation of carbonyl compounds is a widely practiced method for C-C bond formation. Several enantioselective versions of this process have been reported, but intermolecular, enantioselective coupling reactions of aryl electrophiles with alpha-fluoro carbonyl compounds have yet to be disclosed. We report enantioselective coupling of aryl and heteroaryl bromides and triflates with alpha-fluoroindanones catalyzed by palladium complexes of a BINOL-derived monophosphine and Segphos, respectively. The enolates were generated directly from alpha-fluoroindanones in the presence of potassium phosphate base during the reactions. We also report that reactions of alpha fluorotetralones occur in high yields and enantioselectivities when conducted with enolates generated by elimination of trifluoroacetate from trifluoromethyl beta-diketone hydrates. These reactions were catalyzed by palladium complexes of the commercially available bisphosphine Difluorphos. Thus, the formation of enantioenriched alpha-aryl-alpha-fluoroketones can be readily achieved by C-C bond formation when the appropriate palladium catalyst and alpha-fluoro enolate precursor were used. PMID- 27960324 TI - Schottky-Barrier-Free Contacts with Two-Dimensional Semiconductors by Surface Engineered MXenes. AB - Two-dimensional (2D) metal carbides and nitrides, called MXenes, have attracted great interest for applications such as energy storage. We demonstrate their potential as Schottky-barrier-free metal contacts to 2D semiconductors, providing a solution to the contact-resistance problem in 2D electronics. On the basis of first-principles calculations, we find that the surface chemistry strongly affects Fermi level of MXenes: O termination always increases the work function with respect to that of bare surface, OH always decreases it, whereas F exhibits either trend depending on the specific material. This phenomenon originates from the effect of surface dipoles, which together with the weak Fermi level pinning, enable Schottky-barrier-free hole (or electron) injection into 2D semiconductors through van der Waals junctions with some of the O-terminated (or all the OH terminated) MXenes. Furthermore, we suggest synthetic routes to control surface terminations based on calculated formation energies. This study enhances understanding of the correlation between surface chemistry and electronic/transport properties of 2D materials, and also gives predictions for improving 2D electronics. PMID- 27960325 TI - Probing Hydronium Ion Histidine NH Exchange Rate Constants in the M2 Channel via Indirect Observation of Dipolar-Dephased 15N Signals in Magic-Angle-Spinning NMR. AB - Water-protein chemical exchange in membrane-bound proteins is an important parameter for understanding how proteins interact with their aqueous environment, but has been difficult to observe in membrane-bound biological systems. Here, we demonstrate the feasibility of probing specific water-protein chemical exchange in membrane-bound proteins in solid-state MAS NMR. By spin-locking the 1H magnetization along the magic angle, the 1H spin diffusion is suppressed such that a water-protein chemical exchange process can be monitored indirectly by dipolar-dephased 15N signals through polarization transfer from 1H. In the example of the Influenza A full length M2 protein, the buildup of dipolar dephased 15N signals from the tetrad of His37 side chains have been observed as a function of spin-lock time. This confirms that hydronium ions are in exchange with protons in the His37 NH bonds at the heart of the M2 proton conduction mechanism, with an exchange rate constant of ~1750 s-1 for pH 6.2 at -10 degrees C. PMID- 27960327 TI - High Electrocatalytic Hydrogen Evolution Activity of an Anomalous Ruthenium Catalyst. AB - Hydrogen evolution reaction (HER) is a critical process due to its fundamental role in electrocatalysis. Practically, the development of high-performance electrocatalysts for HER in alkaline media is of great importance for the conversion of renewable energy to hydrogen fuel via photoelectrochemical water splitting. However, both mechanistic exploration and materials development for HER under alkaline conditions are very limited. Precious Pt metal, which still serves as the state-of-the-art catalyst for HER, is unable to guarantee a sustainable hydrogen supply. Here we report an anomalously structured Ru catalyst that shows 2.5 times higher hydrogen generation rate than Pt and is among the most active HER electrocatalysts yet reported in alkaline solutions. The identification of new face-centered cubic crystallographic structure of Ru nanoparticles was investigated by high-resolution transmission electron microscopy imaging, and its formation mechanism was revealed by spectroscopic characterization and theoretical analysis. For the first time, it is found that the Ru nanocatalyst showed a pronounced effect of the crystal structure on the electrocatalytic activity tested under different conditions. The combination of electrochemical reaction rate measurements and density functional theory computation shows that the high activity of anomalous Ru catalyst in alkaline solution originates from its suitable adsorption energies to some key reaction intermediates and reaction kinetics in the HER process. PMID- 27960326 TI - High Oxidation State Iridium Mono-MU-oxo Dimers Related to Water Oxidation Catalysis. AB - The highly active iridium "blue solution" chemical and electrochemical water oxidation catalyst obtained from Cp*IrL(OH) precursors (L = 2-pyridyl-2 propanoate) has been difficult to characterize as no crystal structure can be obtained because of the multiplicity of geometrical isomers present. Other data suggest complete loss of the Cp* ligand and the formation of a LIr-O-IrL unit. We have now developed a route to a series of well-defined Ir(IV,IV) mono-MU-oxo dimers, containing the closely related L2Ir-O-IrL2 unit. Unlike the catalyst, these model compounds are separable by silica gel chromatography and readily form single crystals. We report three stereoisomers with the formula ClL2Ir-O-IrL2Cl, which are fully characterized, including by X-ray crystallography, and are compared to the "blue solution". To the best of our knowledge, these species represent the first examples of structurally characterized dinuclear MU-oxo Ir(IV,IV) compounds without metal-carbon bonds. PMID- 27960328 TI - Water Dynamics in Cytoplasm-Like Crowded Environment Correlates with the Conformational Transition of the Macromolecular Crowder. AB - Polyethylene glycol (PEG) is a unique polymer material with enormous applicability in many industrial and scientific fields. Here, its use as macromolecular crowder to mimic the cellular environment in vitro is the focus of the present study. We show that femtosecond mid-IR pump-probe spectroscopy using three different IR probes, HDO, HN3, and azido-derivatized crowder, provides complete and stereoscopic information on water structure and dynamics in the cytoplasm-like macromolecular crowding environment. Our experimental results suggest two distinct subpopulations of water molecules: those that interact with other water molecules and those that are part of a hydration shell of crowder on its surface. Interestingly, water dynamics even in highly crowded environment remains bulk-like in spite of significant perturbation to the tetrahedral H bonding network of water molecules. That is possible because of the formation of water aggregates (pools) even in water-deficient PEGDME-water solutions. In such a crowded environment, the conformationally accessible phase space of the macromolecular crowder is reduced, similar to biopolymers in highly crowded cytoplasm. Nonetheless, the hydration water on the surface of crowders slows down considerably with increased crowding. Most importantly, we do not observe any coalescing of surface hydration water (of the crowder) with bulk-like water to generate collective hydration dynamics at any crowder concentration, contrary to recent reports. We anticipate that the present triple-IR-probe approach is of exceptional use in studying how conformational states of crowders correlate with structural and dynamical changes of water, which is critical in understanding their key roles in biological and industrial applications. PMID- 27960329 TI - Correction to "Programmable Microcapsules from Self-Immolative Polymers. PMID- 27960330 TI - Reshaping Lithium Plating/Stripping Behavior via Bifunctional Polymer Electrolyte for Room-Temperature Solid Li Metal Batteries. AB - High-energy rechargeable Li metal batteries are hindered by dendrite growth due to the use of a liquid electrolyte. Solid polymer electrolytes, as promising candidates to solve the above issue, are expected to own high Li ion conductivity without sacrificing mechanical strength, which is still a big challenge to realize. In this study, a bifunctional solid polymer electrolyte exactly having these two merits is proposed with an interpenetrating network of poly(ether acrylate) (ipn-PEA) and realized via photopolymerization of ion-conductive poly(ethylene oxide) and branched acrylate. The ipn-PEA electrolyte with facile processing capability integrates high mechanical strength (ca. 12 GPa) with high room-temperature ionic conductance (0.22 mS cm-1), and significantly promotes uniform Li plating/stripping. Li metal full cells assembled with ipn-PEA electrolyte and cathodes within 4.5 V vs Li+/Li operate effectively at a rate of 5 C and cycle stably at a rate of 1 C at room temperature. Because of its fabrication simplicity and compelling characteristics, the bifunctional ipn-PEA electrolyte reshapes the feasibility of room-temperature solid-state Li metal batteries. PMID- 27960331 TI - Transition-Metal-like Behavior of Main Group Elements: Ligand Exchange at a Phosphinidene. AB - (Phosphino)phosphaketenes (>P-P?C?O) behave as (phosphino)phosphinidene-carbonyl adducts (>P-P<-:C?O). CO scrambling was observed using 13C labeled CO, and exchange reactions with phosphines afford the corresponding (phosphino)phosphinidene-phosphine adducts (>P-P<-:PR3). The latter react with isonitriles and singlet carbenes giving (phosphino)phosphinidene-isonitrile (>P P<-:CNR) and -carbene adducts (>P-P<-:C<). Based on experimental results and DFT calculations, it is shown that these "ligand" exchange reactions occur via an associative mechanism as classically observed with transition metal complexes. PMID- 27960332 TI - Intrinsic Halide Segregation at Nanometer Scale Determines the High Efficiency of Mixed Cation/Mixed Halide Perovskite Solar Cells. AB - Compositional engineering of a mixed cation/mixed halide perovskite in the form of (FAPbI3)0.85(MAPbBr3)0.15 is one of the most effective strategies to obtain record-efficiency perovskite solar cells. However, the perovskite self organization upon crystallization and the final elemental distribution, which are paramount for device optimization, are still poorly understood. Here we map the nanoscale charge carrier and elemental distribution of mixed perovskite films yielding 20% efficient devices. Combining a novel in-house-developed high resolution helium ion microscope coupled with a secondary ion mass spectrometer (HIM-SIMS) with Kelvin probe force microscopy (KPFM), we demonstrate that part of the mixed perovskite film intrinsically segregates into iodide-rich perovskite nanodomains on a length scale of up to a few hundred nanometers. Thus, the homogeneity of the film is disrupted, leading to a variation in the optical properties at the micrometer scale. Our results provide unprecedented understanding of the nanoscale perovskite composition. PMID- 27960333 TI - Synthetic Uncleavable Ubiquitinated Proteins Dissect Proteasome Deubiquitination and Degradation, and Highlight Distinctive Fate of Tetraubiquitin. AB - Various hypotheses have been proposed regarding how chain length, linkage type, position on substrate, and susceptibility to deubiquitinases (DUBs) affect processing of different substrates by proteasome. Here we report a new strategy for the chemical synthesis of ubiquitinated proteins to generate a set of well defined conjugates bearing an oxime bond between the chain and the substrate. We confirmed that this isopeptide replacement is resistant to DUBs and to shaving by proteasome. Analyzing products generated by proteasomes ranked how chain length governed degradation outcome. Our results support that (1) the cleavage of the proximal isopeptide bond is not a prerequisite for proteasomal degradation, (2) by overcoming trimming at the proteasome, tetraUb is a fundamentally different signal than shorter chains, and (3) the tetra-ubiquitin chain can be degraded with the substrate. Together these results highlight the usefulness of chemistry to dissect the contribution of proteasome-associated DUBs and the complexity of the degradation process. PMID- 27960335 TI - Enhanced Activity and Acid pH Stability of Prussian Blue-type Oxygen Evolution Electrocatalysts Processed by Chemical Etching. AB - The development of upscalable oxygen evolving electrocatalysts from earth abundant metals able to operate in neutral or acidic environments and low overpotentials remains a fundamental challenge for the realization of artificial photosynthesis. In this study, we report a highly active phase of heterobimetallic cyanide-bridged electrocatalysts able to promote water oxidation under neutral, basic (pH < 13), and acidic conditions (pH > 1). Cobalt-iron Prussian blue-type thin films, formed by chemical etching of Co(OH)1.0(CO3)0.5.nH2O nanocrystals, yield a dramatic enhancement of the catalytic performance toward oxygen production, when compared with previous reports for analogous materials. Electrochemical, spectroscopic, and structural studies confirm the excellent performance, stability, and corrosion resistance, even when compared with state-of-the-art metal oxide catalysts under moderate overpotentials and in a remarkably large pH range, including acid media where most cost-effective water oxidation catalysts are not useful. The origin of the superior electrocatalytic activity toward water oxidation appears to be in the optimized interfacial matching between catalyst and electrode surface obtained through this fabrication method. PMID- 27960336 TI - Laser-Induced Explosion of Nitrated Carbon Nanotubes: Nonadiabatic and Reactive Molecular Dynamics Simulations. AB - Laser-initiated decomposition of carbon nanotubes (CNTs) can lead to medical, military, and other applications. In medicine, CNTs give rise to efficient remedies against diseases and malignant cells, since they encapsulate drug molecules, can be delivered inside living organisms, and absorb light that penetrates through biological tissues. As explosives, pyrotechnics, and propellants, CNTs can be activated remotely by a visible or infrared laser, avoiding the need for a detonating cord. The reported non-equilibrium investigation demonstrates the possibility of photoinduced polynitro-CNT explosion and provides a detailed chemical mechanism of the decomposition process, explicitly in the time domain. Nonadiabatic molecular dynamics (MD) performed with real-time time-dependent tight-binding density functional theory demonstrates that the photogenerated exciton deposits its energy into a broad range of phonon modes within less than a picosecond, resulting in a rapid polynitro-CNT heating. Following the heating, reactive MD demonstrates an explosion, during which the local temperature of polynitro-CNTs and its fragments rises as high as 4000 K. Photoexcitation of nitro groups by a high-energy laser is not required; the energy can be delivered to polynitro-CNTs using near infrared light within the biological window. Furthermore, the explosion is possible both with and without an external oxygen source. Anaerobic explosion could be particularly beneficial in confined biological and nanoscale environments. The products of the polynitro-CNT decomposition are nontoxic: carbon dioxide and molecular nitrogen. The in silico demonstration of the laser induced polynitro-CNT explosion, its chemical mechanism, and the time scales of physical and chemical transformations can be tested experimentally using time resolved laser techniques. PMID- 27960334 TI - A Peroxynitrite Dicopper Complex: Formation via Cu-NO and Cu-O2 Intermediates and Reactivity via O-O Cleavage Chemistry. AB - A mixed-valent Cu(I)Cu(II) complex, [CuI,II2(UN-O-)]2+ (1), reacts with NO(g) at 80 degrees C to form [CuI,II2(UN-O-)(NO)]2+ (2), best described as a mixed valent nitrosyl complex that has a nu(N-O) band at 1670 cm-1 in its infrared (IR) spectrum. Complex 2 undertakes a one-electron oxidation via the addition of O2(g) to generate a new intermediate, best described as a superoxide and nitrosyl adduct, [CuII2(UN-O-)(NO)(O2-)]2+ (3), based on its distinctively blue-shifted nu(N-O) band at 1853 cm-1. Over the course of 20 min at -80 degrees C, 3 is converted to the peroxynitrite (PN) complex [CuII2(UN-O-)(-OON?O)]2+ (4), which was characterized by low-temperature electrospray ionization mass spectrometry (ESI-MS) and IR spectroscopy; nu(N-O) absorptions at 1520 and 1640 cm-1 have been assigned as cis- and trans-conformers of the PN ligand in 4. Alternatively, the superoxide complex [CuII2(UN-O-)(O2*-)]2+ (5) is found to react with NO(g) to generate the same intermediate superoxide and nitrosyl adduct 3 (based on IR criteria), which likewise converts to the same PN complex 4. The O-O bond in 4 undergoes heterolysis in dichloromethane solvent and is postulated to produce nitronium ion, leading to ortho-nitration of 2,4-di-tert-butylphenol (DTBP). However, in 2-methyltetrahydrofuran as solvent, the O-O bond undergoes homolysis to generate *NO2 (detected spectrophotometrically) and a putative higher-valent complex, [CuII,III2(UN-O-)(O2-)]2+, that abstracts a H-atom from DTBP to give [CuII2(UN-O-)(OH)]2+ and a phenoxyl radical. The latter may dimerize to form the bis-phenol observed experimentally or couple with the *NO2 present, leading to o phenol nitration. PMID- 27960337 TI - New Mechanism for Photocatalytic Reduction of CO2 on the Anatase TiO2(101) Surface: The Essential Role of Oxygen Vacancy. AB - Photocatalytic reduction of CO2 into organic molecules is a very complicated and important reaction. Two possible pathways, the fast-hydrogenation (FH) path and the fast-deoxygenation (FdO) path, have been proposed on the most popular photocatalyst TiO2. We have carried out first-principles calculations to investigate both pathways on the perfect and defective anatase TiO2(101) surfaces to provide comprehensive understanding of the reaction mechanism. For the FH path, it is found that oxygen vacancy on defective surface can greatly lower the barrier of the deoxygenation processes, which makes it a more active site than the surface Ti. For the FdO path, our calculation suggests that it can not proceed on the perfect surface, nor can it proceed on the defective surface due to their unfavorable energetics. Based on the fact that the FH path can proceed both at the surface Ti site and the oxygen vacancy site, we have proposed a simple mechanism that is compatible with various experiments. It can properly rationalize the selectivity of the reaction and greatly simplify the picture of the reaction. The important role played by oxygen vacancy in the new mechanism is highlighted and a strategy for design of more efficient photocatalysts is proposed accordingly. PMID- 27960338 TI - Photoclickable MicroRNA for the Intracellular Target Identification of MicroRNAs. AB - MicroRNAs (miRNAs) are important gene regulators that bind with target genes and repress target gene expression at the post-transcriptional level. The identification of target genes associated with miRNAs inside different cells is a major challenge in miRNA chemical biology due to the lack of functional miRNAs bearing appropriate tags. Here we report photoclickable miRNAs as appropriately pretagged miRNAs that keep the intracellular function of miRNAs and allow the addition of molecular handles through photoclick reaction. The photoclickable miRNAs upon transfection inside cells were able to form functional complexes with target genes and repress target gene expression. Target genes associated with the photoclickable miRNAs in the complexes were then tagged with the molecular handle through photoclick reaction for pull-down and identification. Using photoclickable miR-106a, miR-27, and miR-122, we first verified that their intracellular function was comparable to that of intact miRNAs, which showed obvious advantage over corresponding biotinylated miRNAs. After attaching the biotin handle to the associated complexes containing the photoclickable miRNAs through the tetrazole-ene photoclick reaction, target genes previously bound with these miRNAs inside cells were successfully pulled town and analyzed. The application of this strategy was demonstrated by the identification of several new target genes of miR-122, followed by revealing a novel regulatory pathway in HepG2 cells with regard to the role of PEG10 in miR-122-promoted cell apoptosis. PMID- 27960339 TI - Dynamic, Reversible Oxidative Addition of Highly Polar Bonds to a Transition Metal. AB - The combination of Pt0 complexes and indium trihalides leads to compounds that form equilibria in solution between their In-X oxidative addition (OA) products (PtII indyl complexes) and their metal-only Lewis pair (MOLP) isomers (LnPt >InX3). The position of the equilibria can be altered reversibly by changing the solvent, while the equilibria can be reversibly and irreversibly driven toward the MOLP products by addition of further donor ligands. The results mark the first observation of an equilibrium between MOLP and OA isomers, as well as the most polar bond ever observed to undergo reversible oxidative addition to a metal complex. In addition, we present the first structural characterization of MOLP and oxidative addition isomers of the same compound. The relative energies of the MOLP and OA isomers were calculated by DFT methods, and the possibility of solvent-mediated isomerization is discussed. PMID- 27960341 TI - Modification of Charge Trapping at Particle/Particle Interfaces by Electrochemical Hydrogen Doping of Nanocrystalline TiO2. AB - Particle/particle interfaces play a crucial role in the functionality and performance of nanocrystalline materials such as mesoporous metal oxide electrodes. Defects at these interfaces are known to impede charge separation via slow-down of transport and increase of charge recombination, but can be passivated via electrochemical doping (i.e., incorporation of electron/proton pairs), leading to transient but large enhancement of photoelectrode performance. Although this process is technologically very relevant, it is still poorly understood. Here we report on the electrochemical characterization and the theoretical modeling of electron traps in nanocrystalline rutile TiO2 films. Significant changes in the electrochemical response of porous films consisting of a random network of TiO2 particles are observed upon the electrochemical accumulation of electron/proton pairs. The reversible shift of a capacitive peak in the voltammetric profile of the electrode is assigned to an energetic modification of trap states at particle/particle interfaces. This hypothesis is supported by first-principles theoretical calculations on a TiO2 grain boundary, providing a simple model for particle/particle interfaces. In particular, it is shown how protons readily segregate to the grain boundary (being up to 0.6 eV more stable than in the TiO2 bulk), modifying its structure and electron-trapping properties. The presence of hydrogen at the grain boundary increases the average depth of traps while at the same time reducing their number compared to the undoped situation. This provides an explanation for the transient enhancement of the photoelectrocatalytic activity toward methanol photooxidation which is observed following electrochemical hydrogen doping of rutile TiO2 nanoparticle electrodes. PMID- 27960340 TI - Spectroscopic Investigations of Catalase Compound II: Characterization of an Iron(IV) Hydroxide Intermediate in a Non-thiolate-Ligated Heme Enzyme. AB - We report on the protonation state of Helicobacter pylori catalase compound II. UV/visible, Mossbauer, and X-ray absorption spectroscopies have been used to examine the intermediate from pH 5 to 14. We have determined that HPC-II exists in an iron(IV) hydroxide state up to pH 11. Above this pH, the iron(IV) hydroxide complex transitions to a new species (pKa = 13.1) with Mossbauer parameters that are indicative of an iron(IV)-oxo intermediate. Recently, we discussed a role for an elevated compound II pKa in diminishing the compound I reduction potential. This has the effect of shifting the thermodynamic landscape toward the two electron chemistry that is critical for catalase function. In catalase, a diminished potential would increase the selectivity for peroxide disproportionation over off-pathway one-electron chemistry, reducing the buildup of the inactive compound II state and reducing the need for energetically expensive electron donor molecules. PMID- 27960342 TI - A Homoleptic Uranium(III) Tris(aryl) Complex. AB - The reaction of 3 equiv of Li-C6H3-2,6-(C6H4-4-tBu)2 (Terph-Li) with UI3(1,4 dioxane)1.5 led to the formation of the homoleptic uranium(III) tris(aryl) complex (Terph)3U (1). The U-C bonds are reactive: treatment with excess iPrN?C?NiPr yielded the double-insertion product [TerphC(NiPr)2]2U(Terph) (2). Complexes 1 and 2 were characterized by X-ray crystallography, which showed that the U-C bond length in 2 (2.624(4) A) is ~0.1 A longer than the average U-C bond length in 1 (2.522(2) A). Thermal decomposition of 1 yielded Terph-H as the only identifiable product; the process is unimolecular with activation parameters DeltaH? = 21.5 +/- 0.3 kcal/mol and DeltaS? = -7.5 +/- 0.8 cal.mol-1 K-1, consistent with intramolecular proton abstraction. The protonolysis chemistry of 1 was also explored, which led to the uranium(IV) alkoxide complex U(OCPh3)4(DME) (3.DME). PMID- 27960343 TI - Hydrogen Transfer Pathways during Zeolite Catalyzed Methanol Conversion to Hydrocarbons. AB - Hydrogen transfer is the major route in catalytic conversion of methanol to olefins (MTO) for the formation of nonolefinic byproducts, including alkanes and aromatics. Two separate, noninterlinked hydrogen transfer pathways have been identified. In the absence of methanol, hydrogen transfer occurs between olefins and naphthenes via protonation of the olefin and the transfer of the hydride to the carbenium ion. A hitherto unidentified hydride transfer pathway involving Lewis and Bronsted acid sites dominates as long as methanol is present in the reacting mixture, leading to aromatics and alkanes. Experiments with purely Lewis acidic ZSM-5 showed that methanol and propene react on Lewis acid sites to HCHO and propane. In turn, HCHO reacts with olefins stepwise to aromatic molecules on Bronsted acid sites. The aromatic molecules formed at Bronsted acid sites have a high tendency to convert to irreversibly adsorbed carbonaceous deposits and are responsible for the critical deactivation in the methanol to olefin process. PMID- 27960344 TI - Dynamic Exchange During Triplet Transport in Nanocrystalline TIPS-Pentacene Films. AB - The multiplication of excitons in organic semiconductors via singlet fission offers the potential for photovoltaic cells that exceed the Shockley-Quiesser limit for single-junction devices. To fully utilize the potential of singlet fission sensitizers in devices, it is necessary to understand and control the diffusion of the resultant triplet excitons. In this work, a new processing method is reported to systematically tune the intermolecular order and crystalline structure in films of a model singlet fission chromophore, 6,13 bis(triisopropylsilylethynyl) pentacene (TIPS-Pn), without the need for chemical modifications. A combination of transient absorption spectroscopy and quantitative materials characterization enabled a detailed examination of the distance- and time-dependence of triplet exciton diffusion following singlet fission in these nanocrystalline TIPS-Pn films. Triplet-triplet annihilation rate constants were found to be representative of the weighted average of crystalline and amorphous phases in TIPS-Pn films comprising a mixture of phases. Adopting a diffusion model used to describe triplet-triplet annihilation, the triplet diffusion lengths for nanocrystalline and amorphous films of TIPS-Pn were estimated to be ~75 and ~14 nm, respectively. Importantly, the presence of even a small fraction (<10%) of the amorphous phase in the TIPS-Pn films greatly decreased the ultimate triplet diffusion length, suggesting that pure crystalline materials may be essential to efficiently harvest multiplied triplets even when singlet fission occurs on ultrafast time scales. PMID- 27960345 TI - Bronsted Acid Catalysis-Structural Preferences and Mobility in Imine/Phosphoric Acid Complexes. AB - Despite the huge success of enantioselective Bronsted acid catalysis, experimental data about structures and activation modes of substrate/catalyst complexes in solution are very rare. Here, for the first time, detailed insights into the structures of imine/Bronsted acid catalyst complexes are presented on the basis of NMR data and underpinned by theoretical calculations. The chiral Bronsted acid catalyst R-TRIP (3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl 2,2'-diyl hydrogen phosphate) was investigated together with six aromatic imines. For each investigated system, an E-imine/R-TRIP complex and a Z-imine/R-TRIP complex were observed. Each of these complexes consists of two structures, which are in fast exchange on the NMR time scale; i.e., overall four structures were found. Both identified E-imine/R-TRIP structures feature a strong hydrogen bond but differ in the orientation of the imine relative to the catalyst. The exchange occurs by tilting the imine inside the complex and thereby switching the oxygen that constitutes the hydrogen bond. A similar situation is observed for all investigated Z-imine/R-TRIP complexes. Here, an additional exchange pathway is opened via rotation of the imine. For all investigated imine/R-TRIP complexes, the four core structures are highly preserved. Thus, these core structures are independent of electron density and substituent modulations of the aromatic imines. Overall, this study reveals that the absolute structural space of binary imine/TRIP complexes is large and the variations of the four core structures are small. The high mobility is supposed to promote reactivity, while the preservation of the core structures in conjunction with extensive pi-pi and CH-pi interactions leads to high enantioselectivities and tolerance of different substrates. PMID- 27960347 TI - NAD+ as a Hydride Donor and Reductant. AB - Reduced nicotinamide adenine dinucleotide (NADH) can generate a ruthenium-hydride intermediate that catalyzes the reduction of O2 to H2O2, which endows it with potent anticancer properties. A catalyst that could access a Ru-H intermediate using oxidized nicotinamide adenine dinucleotide (NAD+) as the H- source, however, could draw upon a supply of reducing equivalents 1000-fold more abundant than NADH, which would enable significantly greater H2O2 production. Herein, it is demonstrated, using the reduction of ABTS*- to ABTS2-, that NAD+ can function as a reductant. Mechanistic evidence is presented that suggests a Ru-H intermediate is formed via beta-hydride elimination from a ribose subunit in NAD+. The insight gained from the heretofore unknown ability of NAD+ to function as a reductant and H- donor may lead to undiscovered biological carbohydrate oxidation pathways and new chemotherapeutic strategies. PMID- 27960346 TI - Dual-Reporter Drift Correction To Enhance the Performance of Electrochemical Aptamer-Based Sensors in Whole Blood. AB - The continuous, real-time monitoring of specific molecular targets in unprocessed clinical samples would enable many transformative medical applications. Electrochemical aptamer-based (E-AB) sensors appear to be a promising approach to this end because of their selectivity (performance in complex samples, such as serum) and reversible, single-step operation. E-AB sensors suffer, however, from often-severe baseline drift when challenged in undiluted whole blood. In response we report here a dual-reporter approach to performing E-AB baseline drift correction. The approach incorporates two redox reporters on the aptamer, one of which serves as the target-responsive sensor and the other, which reports at a distinct, nonoverlapping redox potential, serving as a drift-correcting reference. Taking the difference in their relative signals largely eliminates the drift observed for these sensors in flowing, undiluted whole blood, reducing drift of up to 50% to less than 2% over many hours of continuous operation under these challenging conditions. PMID- 27960348 TI - Excitonic Interfacial Proton-Coupled Electron Transfer Mechanism in the Photocatalytic Oxidation of Methanol to Formaldehyde on TiO2(110). AB - CH3OH on a single-crystal rutile TiO2(110) surface is a widely studied model system for heterogeneous photocatalysis. Using spin-polarized density functional theory with a hybrid functional (HSE06), we study the photocatalytic oxidation of CH3OH adsorbed at a coordinately unsaturated Ti site as an excited-state process with triplet spin multiplicity. The oxidation to CH2O is stepwise and involves a CH3O intermediate. The first O-H dissociation step follows an excitonic interfacial proton-coupled electron transfer mechanism where the hole-electron (h e) pair generated during the excitation is bound, and the h is transferred to the adsorbate. The O-H dissociation paths associated with other h-e pairs are unreactive, and the moderate experimental efficiency is due to the different reactivity of the h-e pairs. The excited-state CH3O intermediate further deactivates through a seam of intersection between the ground and excited states. It can follow three different paths, regeneration of adsorbed CH3OH or formation of the ground-state CH3O anion or an adsorbed CH2O radical anion. The third channel corresponds to photochemical CH2O formation from CH3OH, where a single photon induces one electron oxidation and transfer of two protons. These results expand the current view on the photocatalysis of CH3OH on TiO2(110) by highlighting the role of excitons and showing that adsorbed CH3OH may also be an active species in the photocatalytic oxidation to CH2O. PMID- 27960349 TI - Biochemical Characterization of a Eukaryotic Decalin-Forming Diels-Alderase. AB - The trans-decalin structure formed by intramolecular Diels-Alder cycloaddition is widely present among bioactive natural products isolated from fungi. We elucidated the concise three-enzyme biosynthetic pathway of the cytotoxic myceliothermophin and biochemically characterized the Diels-Alderase that catalyzes the formation of trans-decalin from an acyclic substrate. Computational studies of the reaction mechanism rationalize both the substrate and stereoselectivity of the enzyme. PMID- 27960351 TI - Reversible Modulation of DNA-Based Hydrogel Shapes by Internal Stress Interactions. AB - We present the assembly of asymmetric two-layer hybrid DNA-based hydrogels revealing stimuli-triggered reversibly modulated shape transitions. Asymmetric, linear hydrogels that include layer-selective switchable stimuli-responsive elements that control the hydrogel stiffness are designed. Trigger-induced stress in one of the layers results in the bending of the linear hybrid structure, thereby minimizing the elastic free energy of the systems. The removal of the stress by a counter-trigger restores the original linear bilayer hydrogel. The stiffness of the DNA hydrogel layers is controlled by thermal, pH (i-motif), K+ ion/crown ether (G-quadruplexes), chemical (pH-doped polyaniline), or biocatalytic (glucose oxidase/urease) triggers. A theoretical model relating the experimental bending radius of curvatures of the hydrogels with the Young's moduli and geometrical parameters of the hydrogels is provided. Promising applications of shape-regulated stimuli-responsive asymmetric hydrogels include their use as valves, actuators, sensors, and drug delivery devices. PMID- 27960350 TI - A Janus Chelator Enables Biochemically Responsive MRI Contrast with Exceptional Dynamic Range. AB - We introduce a new biochemically responsive Mn-based MRI contrast agent that provides a 9-fold change in relaxivity via switching between the Mn3+ and Mn2+ oxidation states. Interchange between oxidation states is promoted by a "Janus" ligand that isomerizes between binding modes that favor Mn3+ or Mn2+. It is the only ligand that supports stable complexes of Mn3+ and Mn2+ in biological milieu. Rapid interconversion between oxidation states is mediated by peroxidase activity (oxidation) and l-cysteine (reduction). This Janus system provides a new paradigm for the design of biochemically responsive MRI contrast agents. PMID- 27960352 TI - Variable Doping Induces Mechanism Swapping in Electrogenerated Chemiluminescence of Ru(bpy)32+ Core-Shell Silica Nanoparticles. AB - The impact of nanotechnology on analytical science is hardly overlooked. In the search for ever-increasing sensitivity in biomedical sensors, nanoparticles have been playing a unique role as, for instance, ultrabright labels, and unravelling the intimate mechanisms which govern their functioning is mandatory for the design of ultrasentitive devices. Herein, we investigated the mechanism of electrogenerated chemiluminescence (ECL) in a family of core-shell silica-PEG nanoparticles (DDSNs), variously doped with a Ru(bpy)32+ triethoxysilane derivative, and displaying homogeneous morphological, hydrodynamic, and photophysical properties. ECL experiments, performed in the presence of 2 (dibutylamino)ethanol (DBAE) as coreactant, showed two parallel mechanisms of ECL generation: one mechanism (I) which involves exclusively the radicals deriving from the coreactant oxidation and a second one (II) involving also the direct anodic oxidation of the Ru(II) moieties. The latter mechanism includes electron (hole) hopping between neighboring redox centers as evidenced in our previous studies and supported by a theoretical model we have recently proposed. Quite unexpectedly, however, we found that the efficiency of the two mechanisms varies in opposite directions within the DDSNs series, with mechanism I or mechanism II prevailing at low and high doping levels, respectively. Since mechanism II has an intrinsically lower efficiency, the ECL emission intensity was also found to grow linearly with doping only at relatively low doping levels while it deviates negatively at higher ones. As the zeta-potential of DDSNs increases with the doping level from negative to slightly positive values, as a likely consequence of the accumulating cationic charge within the silica core, we attributed the observed change in the ECL generation mechanism along the DDSN series to a modulation of the electrostatic and hydrophobic/hydrophilic interactions between the DDSNs and the radical cationic species involved in the ECL generation. The results we report therefore show that the ECL intensity of a nanosized system cannot be merely incremented acting on doping, since other parameters come into play. We think that these results could serve as valuable indications to design more efficient ECL nano- and microsized labels for ultrasensitive bioanalysis. PMID- 27960353 TI - ZnTaO2N: Stabilized High-Temperature LiNbO3-type Structure. AB - By using a high-pressure reaction, we prepared a new oxynitride ZnTaO2N that crystallizes in a centrosymmetric (R3c) high-temperature LiNbO3-type structure (HTLN-type). The stabilization of the HTLN-type structure down to low temperatures (at least 20 K) makes it possible to investigate not only the stability of this phase, but also the phase transition to a noncentrosymmetric (R3c) LiNbO3-type structure (LN-type) which is yet to be clarified. Synchrotron and neutron diffraction studies in combination with transmission electron microscopy show that Zn is located at a disordered 12c site instead of 6a, implying an order-disorder mechanism of the phase transition. It is found that the closed d-shell of Zn2+, as well as the high-valent Ta5+ ion, is responsible for the stabilization of the HTLN-type structure, affording a novel quasitriangular ZnO2N coordination. Interestingly, only 3% Zn substitution for MnTaO2N induces a phase transition from LN- to HTLN-type structure, implying the proximity in energy between the two structural types, which is supported by the first-principles calculations. PMID- 27960354 TI - Transaminase Triggered Aza-Michael Approach for the Enantioselective Synthesis of Piperidine Scaffolds. AB - The expanding "toolbox" of biocatalysts opens new opportunities to redesign synthetic strategies to target molecules by incorporating a key enzymatic step into the synthesis. Herein, we describe a general biocatalytic approach for the enantioselective preparation of 2,6-disubstituted piperidines starting from easily accessible pro-chiral ketoenones. The strategy represents a new biocatalytic disconnection, which relies on an omega-TA-mediated aza-Michael reaction. Significantly, we show that the reversible enzymatic process can power the shuttling of amine functionality across a molecular framework, providing access to the desired aza-Michael products. PMID- 27960355 TI - Flexible, Linear Chains Act as Baffles To Inhibit the Intramolecular Rotation of Molecular Turnstiles. AB - In artificial molecular devices, flexible, linear chains typically exhibit very weak capability in inhibiting molecular motion. Herein, we describe the dynamic properties of a series of molecular turnstiles consisting of a rigid frame and a phenyl rotator flanked with linear alkoxymethyl substituents. The long, flexible substituents act as elastic baffles to inhibit the rotations of the rotator at medium to fast speeds on the NMR time scale. When the rotator moves slowly, the substituents become more relaxed, thus obtaining an opportunity to completely thread through the cavity of the turnstiles. These findings reveal a basic but missing correlation between steric hindrance and speed of motion for flexible, linear chains in dynamic molecular devices, thus opening up a new direction toward molecular machines with more elaborate dynamic functions. PMID- 27960356 TI - High-Conductive AZO Nanoparticles Decorated Ni-Rich Cathode Material with Enhanced Electrochemical Performance. AB - A facile solution route was employed for the preparation of an Al doped ZnO (AZO) coating layer, which was composed of many AZO nanoparticles. These nanoparticles have an average particle size of 50 nm and have been successfully decorated on the surface of NCM523. As cathode material for lithium ion batteries, the AZO decorated NCM523 exhibits superior lithium storage improvements according to good cyclic performance, enhanced rate performance (134.2 mAhg-1 after 200 cycles at 10 C), and high-temperature performance (148.9 mAhg-1 at 10 C at 60 degrees C). Such significant improvement could be attributed to the structural superiority of the AZO decoration on the surface of NCM523, which would stabilize the surface structure of the bulk, suppress the undesirable side reaction at the interface of the electrodes, and lead to the enhancement of the conductivity. The preparation of AZO-decorated NCM523 provides an effective method for the high-performance lithium ion batteries and has a certain reference for other materials. PMID- 27960357 TI - A Facile Bottom-Up Approach to Construct Hybrid Flexible Cathode Scaffold for High-Performance Lithium-Sulfur Batteries. AB - Lithium-sulfur batteries mostly suffer from the low utilization of sulfur, poor cycle life, and low rate performances. The prime factors that affect the performance are enormous volume change of the electrode, soluble intermediate product formation, poor electronic and ionic conductivity of S, and end discharge products (i.e., Li2S2 and Li2S). The attractive way to mitigate these challenges underlying in the fabrication of a sulfur nanocomposite electrode consisting of different nanoparticles with distinct properties of lithium storage capability, mechanical reinforcement, and ionic as well as electronic conductivity leading to a mechanically robust and mixed conductive (ionic and electronic conductive) sulfur electrode. Herein, we report a novel bottom-up approach to synthesize a unique freestanding, flexible cathode scaffold made of porous reduced graphene oxide, nanosized sulfur, and Mn3O4 nanoparticles, and all are three-dimensionally interconnected to each other by hybrid polyaniline/sodium alginate (PANI-SA) matrix to serve individual purposes. A capacity of 1098 mAh g-1 is achieved against lithium after 200 cycles at a current rate of 2 A g-1 with 97.6% of initial capacity at a same current rate, suggesting the extreme stability and cycling performance of such electrode. Interestingly, with the higher current density of 5 A g-1, the composite electrode exhibited an initial capacity of 1015 mA h g-1 and retained 71% of the original capacity after 500 cycles. The in situ Raman study confirms the polysulfide absorption capability of Mn3O4. This work provides a new strategy to design a mechanically robust, mixed conductive nanocomposite electrode for high-performance lithium-sulfur batteries and a strategy that can be used to develop flexible large power storage devices. PMID- 27960358 TI - Dopamine-Induced Formation of Ultrasmall Few-Layer MoS2 Homogeneously Embedded in N-Doped Carbon Framework for Enhanced Lithium-Ion Storage. AB - Molybdenum disulfide with a layered structure and high theoretical capacity is attracting extensive attention for high-performance lithium-ion batteries. In this study, a simple and scalable method by freeze-drying of (NH4)2MoS4 and dopamine mixed solutions along with subsequent calcination is developed to realize the self-assembly of hierarchical MoS2/carbon composite nanosheets via the effect of dopamine-induced morphology transformation, in which ultrasmall few layer MoS2 nanosheets were homogeneously embedded into a N-doped carbon framework (denoted as MoS2@N-CF). The embedded ultrasmall MoS2 nanosheets (~5 nm in length) in the composites consist of less than five layers with an expanded interlayer spacing of the (002) plane. When tested as anode materials for rechargeable Li ion batteries, the obtained MoS2@N-CF nanosheets exhibit outstanding electrochemical performance in terms of high specific capacity (839.2 mAh g-1 at 1 A g-1), high initial Coulombic efficiency (85.2%), and superior rate performance (702.1 mAh g-1 at 4 A g-1). Such intriguing electrochemical performance was attributed to the synergistic effect of uniform dispersion of few layer MoS2 into the carbon framework, expanded interlayer spacing, and enhanced electronic conductivity in the unique hierarchical architecture. This work provides a simple and effective strategy for the uniform integration of MoS2 with carbonaceous materials to significantly boost their electrochemical performance. PMID- 27960359 TI - Noncompetitive and Competitive Adsorption of Heavy Metals in Sulfur Functionalized Ordered Mesoporous Carbon. AB - In this work, sulfur-functionalized ordered mesoporous carbons were synthesized by activating the soft-templated mesoporous carbons with sulfur bearing salts that simultaneously enhanced the surface area and introduced sulfur functionalities onto the parent carbon surface. XPS analysis showed that sulfur content within the mesoporous carbons were between 8.2% and 12.9%. The sulfur functionalities include C-S, C?S, -COS, and SOx. SEM images confirmed the ordered mesoporosity within the material. The BET surface areas of the sulfur functionalized ordered mesoporous carbons range from 837 to 2865 m2/g with total pore volume of 0.71-2.3 cm3/g. The carbon with highest sulfur functionality was examined for aqueous phase adsorption of mercury (as HgCl2), lead (as Pb(NO3)2), cadmium (as CdCl2), and nickel (as NiCl2) ions in both noncompetitive and competitive mode. Under noncompetitive mode and at a pH greater than 7.0 the affinity of sulfur-functionalized carbons toward heavy metals were in the order of Hg > Pb > Cd > Ni. At lower pH, the adsorbent switched its affinity between Pb and Cd. In the noncompetitive mode, Hg and Pb adsorption showed a strong pH dependency whereas Cd and Ni adsorption did not demonstrate a significant influence of pH. The distribution coefficient for noncompetitive adsorption was in the range of 2448-4000 mL/g for Hg, 290-1990 mL/g for Pb, 550-560 mL/g for Cd, and 115-147 for Ni. The kinetics of adsorption suggested a pseudo-second-order model fits better than other models for all the metals. XPS analysis of metal adsorption carbons suggested that 7-8% of the adsorbed Hg was converted to HgSO4, 14% and 2% of Pb was converted to PbSO4 and PbS/PbO, respectively, and 5% Cd was converted to CdSO4. Ni was below the detection limit for XPS. Overall results suggested these carbon materials might be useful for the separation of heavy metals. PMID- 27960360 TI - Nonreduction-Active Hole-Transporting Layers Enhancing Open-Circuit Voltage and Efficiency of Planar Perovskite Solar Cells. AB - Inverted planar perovskite solar cells using poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) as the hole transporting layer (HTL) are very attractive because of their low-temperature and easy processing. However, the planar cells with the PEDOT:PSS HTL typically display lower open-circuit voltage (VOC) (about 0.90 V) than that of devices with TiO2-based conventional structure (1.0-1.1 V). The underlying reasons are still not clear. In this work, we report the PEDOT:PSS that is intrinsically p-doped can be chemically reduced by methylamine iodide (MAI) and MAPbI3. The reaction reduces the work function (WF) of PEDOT:PSS, which suppresses the efficient hole collection and yields lower VOC. To overcome this issue, we adopt undoped semiconducting polymers that are intrinsically nonreduction-active (NRA) as the HTL for inverted planar perovskite solar cells. The cells display enhanced VOC from 0.88 +/- 0.04 V (PEDOT:PSS HTL, reference cells) to 1.02 +/- 0.03 V (P3HT HTL) and 1.04 +/- 0.03 V (PTB7 and PTB-Th HTL). The power conversion efficiency (PCE) of the devices with these NRA HTL reaches about 17%. PMID- 27960361 TI - Triboluminescence and Metal Phosphor for Organic Light-Emitting Diodes: Functional Pt(II) Complexes with Both 2-Pyridylimidazol-2-ylidene and Bipyrazolate Chelates. AB - We report the utilization of both pyrid-2-yl-imidazolylidene and dianionic bipz chelates as constituents in syntheses of a new series of charge-neutral Pt(II) complexes 1-4, among which complex 4 revealed remarkable triboluminescence, i.e., generation of photoemission upon grinding or cracking of the solid sample. The triboluminescence is found to be sensitive to the subtle changes of the associated substituents of pyrid-2-yl-imidazolylidene chelate, as verified by the disappearance of the triboluminescence for complexes 1-3. Alternatively, the well ordered solid packing of 3, as indicated by the grazing incidence X-ray scattering experiment, serves as an ideal emitter for the fabrication of highly efficient OLEDs, rendering high external quantum efficienciy (25.9%) and luminesce efficiency (90 cd A-1) at the practical brightness of 100 cd m-2. The rather low roll-off in efficiency (24.4%, 85 cd A-1 at high brightness of 1000 cd m-2) is attributed to the short excited-state lifetime of 3 (~800 ns) in the solid state, which in turn is associated with the MMLCT transition character. PMID- 27960362 TI - Cobalt Oxide (CoOx) as an Efficient Hole-Extracting Layer for High-Performance Inverted Planar Perovskite Solar Cells. AB - CoOx is a promising hole-extracting layer (HEL) for inverted planar perovskite solar cells with device configuration ITO/CoOx/CH3NH3PbI3/PCBM/Ag. The devices fabricated according to a simple solution procedure showed the best photovoltaic performance attaining power conversion efficiency (PCE) of 14.5% under AM 1.5 G 1 sun irradiation, which is significantly superior to those of materials fabricated with a traditional HEL such as PEDOT:PSS (12.2%), NiOx (10.2%), and CuOx (9.4%) under the same experimental conditions. We characterized the chemical compositions with XPS, crystal structures with XRD, and film morphology with SEM/AFM techniques. Photoluminescence (PL) spectra and the corresponding PL decays for perovskite deposited on varied HEL films were recorded to obtain the hole-extracting characteristics, for which the hole-extracting times show the order CoOx (2.8 ns) < PEDOT:PSS (17.5 ns) < NiOx (22.8 ns) < CuOx (208.5 ns), consistent with the trend of their photovoltaic performances. The reproducibility and enduring stability of those devices were examined to show the outstanding long-term stability of the devices made of metal oxide HEL, for which the CoOx device retained PCE ~ 12% for over 1000 h. PMID- 27960363 TI - Facile Functionalization of Polymer Surfaces in Aqueous and Polar Organic Solvents via 3-Mercaptopropylsilatrane. AB - Surface modification of a polymer substrate with a mercapto functionality is crucial in many applications such as flexible circuitry and point-of-care biosensors. We present here a novel bifunctional molecular adhesive, 3 mercaptopropylsilatrane (MPS), as an interface between polymer and metal surfaces. Under ambient conditions, surface modification of polymer surfaces with a mercapto functionality can be achieved with low concentration (0.46 mM) of MPS in aqueous solvent (50% ethanol) in a short time (<30 min). Three popular polymers for optical sensors, polycarbonate, polyethylene terephthalate, and poly(methyl methacrylate), were employed as substrates, and MPS films formed on these substrates were examined and compared with that on a glass substrate. The films were characterized by UV-vis spectroscopy, water contact angle, X-ray photoelectron spectroscopy, and atomic force microscopy. MPS was also used as a bifunctional linker for the construction of a gold nanoparticle (AuNP) sub monolayer on these polymer surfaces. Under optimized preparation conditions, the absorbance and full width at half-maximum of the plasmon band are comparable to those of a AuNP-modified glass substrate. Hence, MPS may have a potential to be a key component in polymer substrate-based localized surface plasmon resonance sensors. A self-catalytic surface reaction mechanism is also proposed to account for the results. As compared to a glass surface with a high number of silanol groups, the successful formation of an MPS film on polymer surfaces with relatively few reactive sites is probably due to the lateral polymerization of MPS starting from a condensed MPS molecule on a reactive site of a polymer surface. PMID- 27960364 TI - Dual Functional Polymer Interlayer for Facilitating Ion Transport and Reducing Charge Recombination in Dye-Sensitized Solar Cells. AB - Dye-sensitized solar cells (DSSCs) present low-cost alternatives to conventional wafer-based inorganic solar cells and have remarkable power conversion efficiency. To further enhance performance, we propose a new DSSC architecture with a novel dual-functional polymer interlayer that prevents charge recombination and facilitates ionic conduction, as well as maintaining dye loading and regeneration. Poly(vinylidene fluoride-trifluoroethylene) (p(VDF TrFE)) was coated on the outside of a dye-sensitized TiO2 photoanode by a simple solution process that did not sacrifice the amount of adsorbed dye molecules in the DSSC device. Light-intensity-modulated photocurrent and photovoltage spectroscopy revealed that the proposed p(VDF-TrFE)-coated anode yielded longer electron lifetime and improved the injection of photogenerated electrons into TiO2, thereby reducing the electron transport time. Comparative cyclic voltammetry and UV-visible absorption spectroscopy based on a ferrocene ferrocenium external standard material demonstrated that p(VDF-TrFE) enhanced the power conversion efficiency from 7.67% to 9.11%. This dual functional p(VDF-TrFE) interlayer is a promising candidate for improving the performance of DSSCs and can also be employed in other electrochemical devices. PMID- 27960365 TI - Oxygen-Incorporated MoS2 Nanosheets with Expanded Interlayers for Hydrogen Evolution Reaction and Pseudocapacitor Applications. AB - Two-dimensional transition-metal dichalcogenides (TMDs) nanosheets have attracted tremendous research interest. Engineering the structure of MoS2 may result in desirable performance for energy applications. In this work, oxygen-incorporated MoS2 nanosheets with expanded interlayers have been synthesized by a solvothermal reaction. The oxygen-incorporated MoS2 nanosheets with rich defects demonstrate excellent hydrogen evolution reaction activity with a small Tafel slope of 42 mV decade-1 as well as excellent long-term stability. Interestingly, a large expanded ~8.40 A interlayer of (002) faces can be achieved by controlling the reaction time. This material also shows excellent long-term cycling stability (up to 20 000 cycles) as well as high specific capacitance for pseudocapacitors. We believe that the structural modification strategy can be applied for other TMDs to further optimize the performance for various applications. PMID- 27960366 TI - Nanofibrillated Cellulose Templated Membranes with High Permeance. AB - One of the most challenging aspects of using nanofibrillated cellulose (NFC) for membranes production is their limited permeance. When NFC membranes are produced from aqueous suspensions, depending on their grammage, the permeances are in the range of a few decades of L/(hm2MPa) not matching satisfactory filtration times. We present a fast and sustainable solution to increase the permeances of such membranes through a combination of solvent exchange of the NFC suspension with ethanol and the use of a removable template, a mixture of calcium compounds (CC). The effect of the CC/NFC ratio was screened for various concentrations. The permeance of water could be increased by as much as 2-3 times as compared to nontemplated membranes. Further, the membranes showed the ability for penetration of water-soluble macromolecules, contaminant rejection of suspended solid particles, and thus fluids (such as orange juice) could be concentrated, with a view to applications in food industry. PMID- 27960367 TI - Dopamine Modified Organic-Inorganic Hybrid Coating for Antimicrobial and Osteogenesis. AB - A hybrid coating composed of hydroxyapatite (HA), Ag nanoparticles (NPs), and chitosan (CS) was successfully prepared on a Ti substrate by a layer-by-layer assembly process. A polydopamine-assisted (PDA-assisted) coating showed a good bond with HA. Ag NPs were uniformly distributed into the hybrid coating through a solution method and ultraviolet light reduction. A CS nanofilm was deposited via spin-coating to control the release of Ag+ from the hybrid coating. The results disclosed that the 3-layer CS coating could efficiently control the release of Ag+ from the hybrid coating via the Fickian diffusion mechanism and that the PDA/HA/Ag/CS-1 coating exhibited antibacterial ratios of 63.0% and 51.8% against E. coli and S. aureus, respectively. Furthermore, the normal structure of E. coli was obviously destroyed by two types of Ag doped coatings. The cell viability assay showed that CS effectively reduced the cytotoxicity of the hybrid coating after a 7 day incubation. The hybrid coating presented high ALP activities at days 3 and 14. The results reveal that hybrid coatings can endow Ti implants with good antibacterial capability as well as cell viability and osteogenic activity. PMID- 27960369 TI - Enhanced Interfacial Strength and UV Shielding of Aramid Fiber Composites through ZnO Nanoparticle Sizing. AB - Here, a simple zinc oxide (ZnO) nanoparticle sizing is reported for aramid fibers that simultaneously provides interfacial reinforcement and UV absorption to develop improved fiber-reinforced composites. Through a one-step nanoparticle deposition, the modified aramid fiber showed an increase in interfacial shear strength of 18.9% with the addition of ZnO nanoparticles when tested by single fiber pullout. The aramid fibers were then treated with a hydrolysis process common to aramid fibers to oxidize the surface and elucidate the importance of oxygen functional groups at the interface. These oxidized fibers proved to further enhance the interface between the fiber surface and nanoparticle, leading to a 33.3% increase relative to the bare fiber. Additionally, due to the absorption properties of ZnO, the retainment of mechanical properties of coated fibers was determined after exposure to an artificial UV light source. After 24 h of exposure, fibers coated with ZnO nanoparticles retained 25% more tensile strength and 21% more modulus than uncoated bare fibers. This work shows that ZnO nanoparticles may serve as a novel, yet simple, multifunctional fiber sizing with which to increase the interfacial strength of aramid fiber composites and improve the resistance to UV irradiation, enabling stronger and more-durable structural fiber composites. PMID- 27960368 TI - Inducing Temporal and Reversible Autophagy by Nanotopography for Potential Control of Cell Differentiation. AB - Tuning autophagy has become a new strategy to control cell differentiation in tissue engineering. The nanosized surface is well-known for its ability to interfere with intracellular procedures, while its role in autophagy regulation is unclear. In this study, we found that a nanotube (NT) structure was able to induce enhanced mTOR-independent autophagy in osteoblasts compared to a flat surface. Further analysis revealed that autophagy was temporally promoted by NTs in the initial day contact and it was also reversible by exchanging the substrate nanotopographies. Actin filaments were significantly dispersed and there were numerous filopodia on the leading edge of cells grown on the NT surface. Intracellular Ca2+ was significantly increased on the NT surface. Moreover, the phenomenon was also found on different nanotopographies as well as in different cell lines. These indicated that cell membrane stretching might be the central regulation factor. Finally, we found that the NT surface exhibited enhanced autophagy-dependent osteogenic differentiation efficacy. In addition, the enhancement on NT surface could be remembered. In conclusion, the nanotopographic surface is able to induce temporal, reversible, and memorable autophagy via cell membrane stretching, which may be used as a versatile method to control cell differentiation. PMID- 27960370 TI - Heteroepitaxy of Fe3O4/Muscovite: A New Perspective for Flexible Spintronics. AB - Spintronics has captured a lot of attention since it was proposed. It has been triggering numerous research groups to make their efforts on pursuing spin related electronic devices. Recently, flexible and wearable devices are in a high demand due to their outstanding potential in practical applications. In order to introduce spintronics into the realm of flexible devices, we demonstrate that it is feasible to grow epitaxial Fe3O4 film, a promising candidate for realizing spintronic devices based on tunneling magnetoresistance, on flexible muscovite. In this study, the heteroepitaxy of Fe3O4/muscovite is characterized by X-ray diffraction, high-resolution transmission electron microscopy, and Raman spectroscopy. The chemical composition and magnetic feature are investigated by a combination of X-ray photoelectron spectroscopy and X-ray magnetic circular dichroism. The electrical and magnetic properties are examined to show the preservation of the primitive properties of Fe3O4. Furthermore, various bending tests are performed to show the tunability of functionalities and to confirm that the heterostructures retain the physical properties under repeated cycles. These results illustrate that the Fe3O4/muscovite heterostructure can be a potential candidate for the applications in flexible spintronics. PMID- 27960371 TI - Bifunctional MoO3-WO3/Ag/MoO3-WO3 Films for Efficient ITO-Free Electrochromic Devices. AB - Dielectric-metal-dielectric (DMD) trilayer films, served as both electrochromic (EC) film and transparent conductor (TC), have exhibited great potential application in low-cost, ITO-free electrochromic devices (ECDs). However, recent reports on the DMD-based ECDs revealed that the response time and the optical modulation properties were not very satisfactory. Here, the mixed MoO3-WO3 materials were first introduced as the dielectric layer to construct an EC-TC bifunctional MoO3-WO3/Ag/MoO3-WO3 (MWAMW) film, which demonstrates strong and broad-band optical modulation in the visible light region, fast color-switching time (2.7 s for coloration and 4.1 s for bleaching), along with high coloration efficiency (70 cm2 C-1). The electrical structure and electrochemical reaction kinetics analysis revealed that the improved EC performances are associated with the increased electron intervalence transition together with the fast charge transfer and ion-diffusion dynamics. PMID- 27960372 TI - Flexible and High-Performance Amorphous Indium Zinc Oxide Thin-Film Transistor Using Low-Temperature Atomic Layer Deposition. AB - Amorphous indium zinc oxide (IZO) thin films were deposited at different temperatures, by atomic layer deposition (ALD) using [1,1,1-trimethyl-N (trimethylsilyl)silanaminato]indium (INCA-1) as the indium precursor, diethlzinc (DEZ) as the zinc precursor, and hydrogen peroxide (H2O2) as the reactant. The ALD process of IZO deposition was carried by repeated supercycles, including one cycle of indium oxide (In2O3) and one cycle of zinc oxide (ZnO). The IZO growth rate deviates from the sum of the respective In2O3 and ZnO growth rates at ALD growth temperatures of 150, 175, and 200 degrees C. We propose growth temperature-dependent surface reactions during the In2O3 cycle that correspond with the growth-rate results. Thin-film transistors (TFTs) were fabricated with the ALD-grown IZO thin films as the active layer. The amorphous IZO TFTs exhibited high mobility of 42.1 cm2 V-1 s-1 and good positive bias temperature stress stability. Finally, flexible IZO TFT was successfully fabricated on a polyimide substrate without performance degradation, showing the great potential of ALD-grown TFTs for flexible display applications. PMID- 27960373 TI - Scalable-Production, Self-Powered TiO2 Nanowell-Organic Hybrid UV Photodetectors with Tunable Performances. AB - Hybrid inorganic-organic photoelectric devices draw considerable attention because of their unique features by combining the tunable functionality of organic molecules and the superior intrinsic carrier mobilities of inorganic semiconductors. An ordered thin layer of TiO2 nanowells is formed in situ with shallow nanoconcave patterns without cracking with scalable production by a facile and economic strategy, and these layers are used as building blocks to construct hybrid UV photodetectors (PDs). Organic conducting polymers (polyaniline (PANI) with various morphologies) have been exploited as p-type materials, enabling tunable photodetection performances at zero bias. The thin layer of n-type TiO2 nanowells is favorable for electron transport and light absorption with respect to their conventional nanotubular counterparts, while PANI acts as a hopping state or bridge to largely enhance the transition probability of the valence electrons in TiO2 to its conduction band, resulting in an increase in photocurrent in a self-powered mode. In particular, the lowest polyaniline loading sample (TP1) exhibits the highest responsivity (3.6 mA.W-1), largest on-off switching ratio (~103), excellent wavelength selectivity, fast response speed (3.8/30.7 ms), and good stability under 320 nm light illumination (0.56 mW.cm-2) without an external energy supply. This work might be of great value in developing tunable UV photoresponse materials with respect to low cost and a large area for future energy-efficient optoelectronic devices. PMID- 27960374 TI - Hydrothermal Synthesis and Catalytic Application of Ultrathin Rhodium Nanosheet Nanoassemblies. AB - Ultrathin noble metal nanosheets with atomic thickness exhibit abnormal electronic, surfacial, and photonic properties due to the unique two-dimensional (2D) confinement effect, which have attracted intensive research attention in catalysis/electrocatalysis. In this work, the well-defined ultrathin Rh nanosheet nanoassemblies with dendritic morphology are synthesized by a facile hydrothermal method with assistance of poly(allylamine hydrochloride) (PAH), where PAH effectively acts as the complexant and shape-directing agent. Transmission electron microscopy and atomic force microscopy images reveal the thickness of 2D Rh nanosheet with (111) planes is only ca. 0.8-1.1 nm. Nitrogen adsorption desorption measurement displays the specific surface area of the as-prepared ultrathin Rh nanosheet nanoassemblies is 139.4 m2 g-1, which is much bigger than that of homemade Rh black (19.8 m2 g-1). Detailed catalytic investigations display the as-prepared ultrathin Rh nanosheet nanoassemblies have nearly 20.4 fold enhancement in mass-activity for the hydrolysis of ammonia borane as compared with homemade Rh black. PMID- 27960375 TI - Hierarchical NiFe Layered Double Hydroxide Hollow Microspheres with Highly Efficient Behavior toward Oxygen Evolution Reaction. AB - The exploitation of highly efficiency and low-cost electrocatalysts toward oxygen evolution reaction (OER) is a meaningful route in renewable energy technologies including solar fuel and water splitting. Herein, NiFe-layered double hydroxide (NiFe-LDH) hollow microsphere (HMS) was designed and synthesized via a one-step in situ growth method by using SiO2 as a sacrificial template. Benefiting from the unique architecture, NiFe-LDH HMS shows highly efficient OER electrocatalytic activity with a preferable current density (71.69 mA cm-2 at eta = 300 mV) and a small onset overpotential (239 mV at 10 mA cm-2), which outperforms the 20 wt % commercial Ir/C catalyst. Moreover, it exhibits a remarkably low Tafel slope (53 mV dec-1) as well as a satisfactory long-time stability. Electrochemical studies reveal that this hierarchical structure facilitates a full exposure of active sites and facile ion transport kinetics, accounting for the excellent performance. It is expected that the NiFe-LDH microsphere material can serve as a promising non-noble-metal-based electrocatalyst toward water oxidation reaction. PMID- 27960376 TI - Graphene Sandwiched by Sulfur-Confined Mesoporous Carbon Nanosheets: A Kinetically Stable Cathode for Li-S Batteries. AB - The practical use of lithium-sulfur batteries for the next-generation energy storage, especially the automobiles, was hindered by low electronic conductivity of sulfur and the resulting poor rate capabilities. Here, we report a sulfur carbon composite by confining S into a graphene sandwiched in mesoporous carbon nanosheets with a two-dimensional ultrathin morphology, suitable mesopore size and large pore volume, and excellent electronic conductivity. Serving as cathode material for a Li-S battery, the elaborately designed S/C composite leads to "kinetically stable" transmissions of Li ions and electrons, triggering a stable electrochemistry and a record-breaking rate performance. In this way, the S/C composite has been proved a promising cathode material for high-rate Li-S batteries targeted at automobile storage. PMID- 27960377 TI - A Neutralized Noncharged Polyethylenimine-Based System for Efficient Delivery of siRNA into Heart without Toxicity. AB - Cationic polymers constitute an important class of materials in development of delivery vehicles for nucleic acid-based therapeutics. Among them, polyethylenimine (PEI) has been a classical cationic carrier intensively studied for therapeutic delivery of DNA, RNA, and short RNA molecules to treat diseases. However, the development of PEI for in vivo applications has been hampered by the inherent problems associated with the material, particularly its cytotoxicity and the instability of the nucleic acid complexation systems formed via electrostatic interactions. Here, we demonstrate a strategy to modify PEI polymers via hydrazidation to create neutralized, stable, and multifunctional system for delivering siRNA molecules. Through substitution of the primary amino groups of PEI with neutral hydrazide groups, cross-linked nanoparticles with surface decorated with a model targeting ligands were generated. The neutral cross-linked siRNA nanoparticles not only showed favorable biocompatibility and cell internalization efficiency in vitro but also allowed for significant tissue uptake and gene silencing efficiency in zebrafish heart in vivo. Our study suggests transformation of conventional branched PEI into a neutral polymer that can lead to a new category of nonviral carriers, and the resulting functional delivery systems may be further explored for development of siRNA therapeutics for treating cardiovascular disease/injury. PMID- 27960378 TI - Paclitaxel-Paclitaxel Prodrug Nanoassembly as a Versatile Nanoplatform for Combinational Cancer Therapy. AB - Recently, nanomedicine without drug carriers has attracted many pharmacists' attention. A novel paclitaxel-s-s-paclitaxel (PTX-s-s-PTX) conjugate with high drug loading (~78%, w/w) was synthesized by conjugating paclitaxel to paclitaxel by using disulfide linkage. The conjugate could self-assemble into uniform nanoparticles (NPs) with 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR) encapsulated within the core of PTX-s-s-PTX NPs for photothermal therapy (PTT). The DiR-loaded self-assembled nanoparticles (DSNs) had a mean diameter of about 150 nm and high stability in biological condition. A disulfide bond is utilized as a redox-responsive linkage to facilitate a rapid release of paclitaxel in tumor cells. DSNs indicated significant cytotoxicity as a result of the synergetic chemo-thermal therapy. DSNs were featured with excellent advantages, including high drug loading, redox-responsive releasing behavior of paclitaxel, capability of loading with photothermal agents, and combinational therapy with PTT. In such a potent nanosystem, prodrug and photothermal strategy are integrated into one system to facilitate the therapy efficiency. PMID- 27960379 TI - Improving the Selective Efficiency of Graphene-Mediated Enhanced Raman Scattering through Molecular Imprinting. AB - Enhancement of Raman scattering signal through graphene is an important property that could be exploited for producing innovative sensing devices with advanced properties. Because the enhancement of Raman scattering is due to only a chemical mechanism, the amplification of the signal is lower than that one produced by excitation of localized surface plasmons. The combination of a highly selective technique, which is molecular imprinting, with graphene-mediated enhanced Raman scattering, represents a new synergistic approach that we have developed in the present work. The careful material design has allowed obtaining a porous composite embedding exfoliated graphene and molecular cavities specifically designed for recognizing Rhodamine 6G. The molecularly imprinted porous samples have shown a signal enhancement that increases as a function of the number of molecular cavities, which are also accountable for the molecular recognition properties. Environmental ellipsometric porosimetry has shown no substantial difference between molecularly imprinted and not-imprinted films confirming that the signal enhancement of the imprinted samples is due to the molecular cavities. Interestingly, the most efficient sample has shown a Raman enhancement per cavity that exceeds the value of 1 * 1012 and a remarkable molecular selectivity allowing for a Rhodamine 6G signal amplification 4.5 higher than structural analogues such as Rhodamine B and methylene blue. The robust and flexible matrix ensures a good recyclability of the samples without lack of linear response. These results prove the great potential of molecular imprinting as a general strategy to provide selectivity to GERS-active substrates for a new generation of sensing devices. PMID- 27960380 TI - Electrochemically Identifying Degradation Pathways of Carbon-Supported Pt Catalysts Assists in Designing Highly Durable Catalysts. AB - Supported Pt catalysts are considered highly efficient in many applications because of their unique catalytic properties. Their poor durability hampers their use in practical applications, particularly in novel energy-conversion devices such as fuel cells. A facile electrochemical procedure that combines the evaluation of the electrochemical surface area with a breakthrough in direct electrochemical quantification of the Pt content was utilized. Catalytic performance-related factors and kinetics of Pt nanoparticle (Ptnano) growth on a carbon substrate were probed under high-temperature annealing and ambient temperature potential polarization, respectively. Apart from the Pt dissolution/redeposition pathway, we demonstrated that the crystal migration/coalescence pathway in catalyst degradation could not be ignored at ambient temperature. We report the enhanced durability and long-term activity of carbon-supported Pt catalysts, where the Ptnano surface was partially encapsulated by nonspecific noble metal clusters; inhibition of the migration/coalescence pathway and effective exposure of Ptnano surface active sites led to such enhancements. PMID- 27960381 TI - Targeted Photodynamic Killing of Breast Cancer Cells Employing Heptamannosylated beta-Cyclodextrin-Mediated Nanoparticle Formation of an Adamantane-Functionalized BODIPY Photosensitizer. AB - The targeted delivery of a photosensitizer (PS) into specific cancer cells is an effective way to enhance the efficacy and minimize the side effects of photodynamic therapy. Herein, heptamannosylated beta-cyclodextrin (beta-CD) was used to mediate the formation of an adamantane (Ad)-functionalized BODIPY PS nanoparticle via strong beta-CD/Ad complexation. The mannose-functionalized PS nanoparticles are selectively internalized by mannose-receptor-rich MDA-MB-231 breast cancer cells via receptor-mediated endocytosis, facilitating singlet oxygen generation to trigger apoptosis in cancer cells upon red-light irradiation. These nanoparticles exhibit excellent targeted delivery of the PS, leading to cancer cell death after irradiation both in vitro and in vivo. PMID- 27960382 TI - Attoliter Chemistry for Nanoscale Functionalization of Graphene. AB - The nanoscale, multiplexed functionalization of graphene in a device array is a critical step to realize graphene-based chemical and biosensors. We demonstrate that graphene can be functionalized with submicron resolution and in well-defined locations and patterns using reaction agents in attoliter quantities, utilizing dip-pen nanolithography or microchannel cantilever spotting. Specifically, we functionalize graphene with a biotin azide using click-chemistry and demonstrate the subsequent binding of fluorescently tagged streptavidin. The technique can be scaled up to multiplex functionalize graphene devices on a wafer-scale for sensor and biomedical applications. PMID- 27960383 TI - Highly Corrosion Resistant and Sandwich-like Si3N4/Cr-CrNx/Si3N4 Coatings Used for Solar Selective Absorbing Applications. AB - Highly corrosion resistant, layer-by-layer nanostructured Si3N4/Cr-CrNx/Si3N4 coatings were deposited on aluminum substrate by DC/RF magnetron sputtering. Corrosion resistance experiments were performed in 0.5, 1.0, 3.0, and 5.0 wt % NaCl salt spray at 35 degrees C for 168 h. Properties of the coatings were comprehensively investigated in terms of optical property, surface morphology, microstructure, elemental valence state, element distribution, and potentiodynamic polarization. UV-vis-near-IR spectrophotometer and FTIR measurements show that the change process in optical properties of Si3N4/Cr CrNx/Si3N4/Al coatings can be divided into three stages: a rapid active degradation stage, a steady passivation stage, and a transpassivation degradation stage. With the increase in the concentration of NaCl salt spray, solar absorptance and thermal emittance experienced a slight degradation. SEM images reveal that there is an increase in surface defects, such as microcracks and holes and -cracks. XRD and TEM measurements indicate that the phase structure changed partially and the content of CrOx and Al2O3 has increased. Auger electron spectroscopy shows that the elements of Cr, N, and O have undergone a minor diffusion. Electrochemical polarization curves show that the as-deposited Si3N4/Cr-CrNx/Si3N4/Al coatings have excellent corrosion resistance of 3633.858 kOmega, while after corroding in 5.0 wt % NaCl salt spray for 168 h the corrosion resistance dropped to 13.759 kOmega. However, these coatings still have an outstanding performance of high solar absorptance of 0.924 and low thermal emittance of 0.090 after corroding in 3.0 wt % NaCl salt spray for 120 h. Thus, the Si3N4/Cr-CrNx/Si3N4/Al coating is a good choice for solar absorber coatings applied in the high-saline environment. PMID- 27960384 TI - Multifunctional Redox-Responsive Mesoporous Silica Nanoparticles for Efficient Targeting Drug Delivery and Magnetic Resonance Imaging. AB - The convenient modification of mesoporous silica nanoparticles (MSN) can provide great opportunities for constructing a new generation of nanocarriers with multiple functions. In the current study, we fabricated a new multifunctional drug delivery system based on MSN capped by gadolinium-based bovine serum albumin complex (BSA-Gd) and hyaluronic acid (HA) via reductive-cleavable disulfide bond. In this multifunctional nanoparticle (MSN-ss-GHA), BSA-Gd component was prepared by biomineralization and acted as both smart gatekeeper and contrast agent for magnetic resonance (MR) imaging, while HA served as the targeted molecule to improve the specific affinity of MSN-ss-GHA toward cancer cells. The successful fabrication of MSN-ss-GHA was demonstrated by a series of physicochemical characterization. The redox-sensitive drug release behavior of doxorubicin hydrochloride (DOX) loaded MSN-ss-GHA (DOX@MSN-ss-GHA) was also verified. Comparatively, the MSN-ss-GHA exhibited excellent biocompatibility and distinctly enhanced cell uptake by 4T1 cells. More importantly, the improved in vitro MR imaging ability of MSN-ss-GHA over that of Gd-DTPA was also confirmed. The results also suggested that the DOX@MSN-ss-GHA could efficiently deliver DOX into 4T1 cells and showed enhanced cytotoxicity as compared to that of nontargeted nanocarrier. The in vivo experiment also demonstrated the negligible toxicity of MSN-ss-GHA and improved antitumor suppression of DOX@MSN-ss-GHA. Thus, this multifunctional MSN-based theranostic agent holds potential for efficient redox responsive targeting drug delivery and MR imaging. PMID- 27960385 TI - Mo1-xWxSe2-Based Schottky Junction Photovoltaic Cells. AB - We developed Schottky junction photovoltaic cells based on multilayer Mo1-xWxSe2 with x = 0, 0.5, and 1. To generate built-in potentials, Pd and Al were used as the source and drain electrodes in a lateral structure, and Pd and graphene were used as the bottom and top electrodes in a vertical structure. These devices exhibited gate-tunable diode-like current rectification and photovoltaic responses. Mo0.5W0.5Se2 Schottky diodes with Pd and Al electrodes exhibited higher photovoltaic efficiency than MoSe2 and WSe2 devices with Pd and Al electrodes, likely because of the greater adjusted band alignment in Mo0.5W0.5Se2 devices. Furthermore, we showed that Mo0.5W0.5Se2-based vertical Schottky diodes yield a power conversion efficiency of ~16% under 532 nm light and ~13% under a standard air mass 1.5 spectrum, demonstrating their remarkable potential for photovoltaic applications. PMID- 27960386 TI - Graphitic Carbon Nitride Nanosheets-Based Ratiometric Fluorescent Probe for Highly Sensitive Detection of H2O2 and Glucose. AB - Graphitic carbon nitride (g-C3N4) nanosheets, an emerging graphene-like carbon based nanomaterial with high fluorescence and large specific surface areas, hold great potential for biosensor applications. Current g-C3N4 nanosheets based fluorescent biosensors majorly rely on single fluorescent intensity reading through fluorescence quenching interactions between the nanosheets and metal ions. Here we report for the first time the development of a novel g-C3N4 nanosheets-based ratiometric fluorescence sensing strategy for highly sensitive detection of H2O2 and glucose. With o-phenylenediamine (OPD) oxidized by H2O2 in the presence of horseradish peroxidase (HRP), the oxidization product can assemble on the g-C3N4 nanosheets through hydrogen bonding and pi-pi stacking, which effectively quenches the fluorescence of g-C3N4 while delivering a new emission peak. The ratiometric signal variations enable robust and sensitive detection of H2O2. On the basis of the glucose converting into H2O2 through the catalysis of glucose oxidase, the g-C3N4-based ratiometric fluorescence sensing platform is also exploited for glucose assay. The developed strategy is demonstrated to give a detection limit of 50 nM for H2O2 and 0.4 MUM for glucose, at the same time, it has been successfully used for glucose levels detection in human serum. This strategy may provide a cost-efficient, robust, and high throughput platform for detecting various species involving H2O2-generation reactions for biomedical applications. PMID- 27960387 TI - Microwave-Assisted Synthesis of Highly Dispersed PtCu Nanoparticles on Three Dimensional Nitrogen-Doped Graphene Networks with Remarkably Enhanced Methanol Electrooxidation. AB - A well-dispersed PtCu alloy nanoparticles (NPs) on three-dimensional nitrogen doped graphene (PtCu/3D N-G) electrocatalyst has been successfully synthesized by a conventional hydrothermal method combined with a high-efficiency microwave assisted polyol process. The morphology, composition, and structures are well characterized by scanning electron microscopy, transmission electron microscopy, Raman spectroscopy, X-ray powder diffraction, and X-ray photoelectron spectroscopy. Cyclic voltammograms illustrate that the as-prepared PtCu/3D N-G electrocatalyst possesses the larger electrochemical active surface area, lower onset potential, higher current density, and better tolerance to CO poisoning than PtCu NPs on reduced graphene oxide and XC-72 carbon black in acid solution. In addition, long-time chronoamperometry reveals that the PtCu/3D N-G catalyst exhibits excellent stability even longer than 60 min toward acid methanol electrooxidation. The remarkably enhanced performance is related to the combined effects of uniformly interconnected three-dimensional porous graphene networks, nitrogen doping, modified Pt alloy NPs, and strong binding force between Pt alloy NPs and 3D N-G structures. PMID- 27960388 TI - Bionano Interaction Study on Antimicrobial Star-Shaped Peptide Polymer Nanoparticles. AB - 'Structurally nanoengineered antimicrobial peptide polymers' (SNAPPs), in the form of star-shaped peptide polymer nanoparticles, have been recently demonstrated as a new class of antimicrobial agents with superior in vitro and in vivo efficacy against Gram-negative pathogens, including multidrug-resistant species. Herein, we present a detailed bionano interaction study on SNAPPs by assessing their antimicrobial activities against several Gram-negative bacteria in complex biological matrices. Simulated body fluid and animal serum were used as test media to reveal factors that influence the antimicrobial efficacy of SNAPPs. With the exception of Acinetobacter baumannii, the presence of divalent cations at physiological concentrations reduced the antimicrobial efficacy of SNAPPs from minimum inhibitory concentrations (MICs) within the nanomolar range (40-300 nM) against Escherichia coli, Pseudomanas aeruginosa, and Klebsiella pneumoniae to 0.6-4.7 MUM. By using E. coli as a representative bacterial species, we demonstrated that the reduction in activity was due to a decrease in the ability of SNAPPs to cause outer and inner membrane disruption. This effect could be reversed through coadministration with a chelating agent. Interestingly, the potency of SNAPPs against A. baumannii was retained even under high salt concentrations. The presence of serum proteins was also found to affect the interaction of SNAPPs with bacterial membranes, possibly through intermolecular binding. Collectively, this study highlights the need to consider the possible interactions of (bio)molecules present in vivo with any new antimicrobial agent under development. We also demonstrate that outer membrane disruption/destabilization is an important but hitherto under-recognized target for the antimicrobial action of peptide-based agents, such as antimicrobial peptides (AMPs). Overall, the findings presented herein could aid in the design of more efficient peptide-based antimicrobial agents with uncompromised potency even under physiological conditions. PMID- 27960389 TI - Rapid, Microwave-Assisted Synthesis of Cubic, Three-Dimensional, Highly Porous MOF-205 for Room Temperature CO2 Fixation via Cyclic Carbonate Synthesis. AB - A dual-porous, three-dimensional, metal-organic framework [Zn4O(2,6-NDC)(BTB)4/3] (MOF-205, BET = 4200 m2/g) has been synthesized using microwave power as an alternative energy source for the first time, and its catalytic activity has been exploited for CO2-epoxide coupling reactions to produce five-membered cyclic carbonates under solvent-free conditions. Microwave synthesis was performed at different time intervals to reveal the formation of the crystals. Significant conversion of various epoxides was obtained at room temperature, with excellent selectivity toward the desired five-membered cyclic carbonates. The importance of the dual porosity and the synergistic effect of quaternary ammonium salts on efficiently catalyzed CO2 conversion were investigated using various experimental and physicochemical characterization techniques, and the results were compared with those of the solvothermally synthesized MOF-205 sample. On the basis of literature and experimental inferences, a rationalized mechanism mediated by the zinc center of MOF-205 for the CO2-epoxide cycloaddition reaction has been proposed. PMID- 27960390 TI - High Performance, 3D-Printable Dielectric Nanocomposites for Millimeter Wave Devices. AB - The creation of millimeter wave, 3D-printable dielectric nanocomposite is demonstrated. Alumina nanoparticles were combined with styrenic block copolymers and solvent to create shear thinning, viscoelastic inks that are printable at room temperature. Particle loadings of up to 41 vol % were achieved. Upon being dried, the highest-performing of these materials has a permittivity of 4.61 and a loss tangent of 0.00298 in the Ka band (26.5-40 GHz), a combination not previously demonstrated for 3D printing. These nanocomposite materials were used to print a simple resonator device with predictable pass-band features. PMID- 27960392 TI - Correction to Hydrothermal-Assisted Cold Sintering Process: A New Guidance for Low Temperature Ceramic Sintering. PMID- 27960391 TI - Dual-Functionality Fullerene and Silver Nanoparticle Antimicrobial Composites via Block Copolymer Templates. AB - We present the facile prepartion of C70 and Ag nanoparticle (NP) loaded block copolymer (BCP) thin films, with C70 and Ag NPs working in tandem to provide virucidal and bactericidal activities, respectively. Polystyrene-block-poly-4 vinylpyridine (PS-P4VP) was used as a template, allowing C70 integration into PS domains and in situ formation of Ag NPs in P4VP domains, while providing control of the nanoscale spatial distribution of functionality as a function of BCP molecular weight (MW). C70 loaded PS-P4VP films were found to generate significant amounts of 1O2 under visible light illumination with no apparent dependence on BCP MW. An analogous C70 loaded PS homopolymer film produced notably less 1O2, highlighting a possible critical role of morphology on C70 photoactivity. The antimicrobial activity of Ag NP and C70 loaded composites against the model PR772 bacteriophage and Escherichia coli was assessed, finding synergistic inactivation afforded by the dual functionality. BCPs were demonstrated as versatile platforms for the preparation of multifunctional antimicrobial coatings toward combating diverse microbial communities. PMID- 27960393 TI - Ultrasensitive and Multiple Disease-Related MicroRNA Detection Based on Tetrahedral DNA Nanostructures and Duplex-Specific Nuclease-Assisted Signal Amplification. AB - A highly sensitive and multiple microRNA (miRNA) detection method by combining three-dimensional (3D) DNA tetrahedron-structured probes (TSPs) to increase the probe reactivity and accessibility with duplex-specific nuclease (DSN) for signal amplification for sensitive miRNA detection was proposed. Briefly, 3D DNA TSPs labeled with different fluorescent dyes for specific target miRNA recognition were modified on a gold nanoparticle (GNP) surface to increase the reactivity and accessibility. Upon hybridization with a specific target, the TSPs immobilized on the GNP surface hybridized with the corresponding target miRNA to form DNA-RNA heteroduplexes, and the DSN can recognize the formed DNA-RNA heteroduplexes to hydrolyze the DNA in the heteroduplexes to produce a specific fluorescent signal corresponding to a specific miRNA, while the released target miRNA strands can initiate another cycle, resulting in a significant signal amplification for sensitive miRNA detection. Different targets can produce different fluorescent signals, leading to the development of a sensitive detection for multiple miRNAs in a homogeneous solution. Under optimized conditions, the proposed assay can simultaneously detect three different miRNAs in a homogeneous solution with a logarithmic linear range spanning 5 magnitudes (10-12-10-16) and achieving a limit of detection down to attomolar concentrations. Meanwhile, the proposed miRNA assay exhibited the capability of discriminating single bases (three bases mismatched miRNAs) and showed good eligibility in the analysis of miRNAs extracted from cell lysates and miRNAs in cell incubation media, which indicates its potential use in biomedical research and clinical analysis. PMID- 27960394 TI - Effect of the Dianhydride/Branched Diamine Ratio on the Architecture and Room Temperature Healing Behavior of Polyetherimides. AB - Traditional polyetherimides (PEIs) are commonly synthesized from an aromatic diamine and an aromatic dianhydride (e.g., 3,4'-oxidianiline (ODA) and 4,4' oxidiphtalic anhydride (ODPA)) leading to the imide linkage and outstanding chemical, thermal and mechanical properties yet lacking any self-healing functionality. In this work, we have replaced the traditional aromatic diamine by a branched aliphatic fatty dimer diamine (DD1). This led to a whole family of self-healing polymers not containing reversible chemical bonds, capable of healing at (near) room temperature yet maintaining very high elastomeric-like mechanical properties (up to 6 MPa stress and 570% strain at break). In this work, we present the effect of the DD1/ODPA ratio on the general performance and healing behavior of a room temperature healing polyetherimide. A dedicated analysis suggests that healing proceeds in three steps: (i) an initial adhesive step leading to the formation of a relatively weak interface; (ii) a second step at long healing times leading to the formation of an interphase with different properties than the bulk material and (iii) disappearance of the damaged zone leading to full healing. We argue that the fast interfacial adhesive step is due to van der Waals interactions of long dangling alkyl chains followed by an interphase formation due to polymer chain interdiffusion. An increase in DD1/ODPA ratio leads to an increase in the healing kinetics and displacement shift of the first healing step toward lower temperatures. An excess of DD1 leads to the cross linking of the polymer thereby restricting the necessary mobility for the interphase formation and limiting the self-healing behavior. The results here presented offer a new route for the development of room temperature self-healing thermoplastic elastomers with improved mechanical properties using fatty dimer diamines. PMID- 27960395 TI - Edge Dislocations Triggered Surface Instability in Tensile Epitaxial Hexagonal Nitride Semiconductor. AB - Understanding the semiconductor surface and its properties including surface stability, atomic morphologies, and even electronic states is of great importance not only for understanding surface growth kinetics but also for evaluating the degree to which they affect the devices' performance. Here, we report studies on the nanoscale fissures related surface instability in AlGaN/GaN heterostructures. Experimental results reveal that edge dislocations are actually the root cause of the surface instability. The nanoscale fissures are initially triggered by the edge dislocations, and the subsequent evolution is associated with tensile lattice-mismatch stress and hydrogen etching. Our findings resolve a long standing problem on the surface instability in AlGaN/GaN heterostructures and will also lead to new understandings of surface growth kinetics in other hexagonal semiconductor systems. PMID- 27960396 TI - Neovascularization Induced by the Hyaluronic Acid-Based Spongy-Like Hydrogels Degradation Products. AB - Neovascularization has been a major challenge in many tissue regeneration strategies. Hyaluronic acid (HA) of 3-25 disaccharides is known to be angiogenic due to its interaction with endothelial cell receptors. This effect has been explored with HA-based structures but a transitory response is observed due to HA burst biodegradation. Herein we developed gellan gum (GG)-HA spongy-like hydrogels from semi-interpenetrating network hydrogels with different HA amounts. Enzymatic degradation was more evident in the GG-HA with high HA amount due to their lower mechanical stability, also resulting from the degradation itself, which facilitated the access of the enzyme to the HA in the bulk. GG-HA spongy like hydrogels hyaluronidase-mediated degradation lead to the release of HA oligosaccharides of different amounts and sizes in a HA content-dependent manner which promoted in vitro proliferation of human umbilical cord vein endothelial cells (HUVECs) but not their migration. Although no effect was observed in human dermal microvascular endothelial cells (hDMECs) in vitro, the implantation of GG HA spongy-like hydrogels in an ischemic hind limb mice model promoted neovascularization in a material-dependent manner, consistent with the in vitro degradation profile. Overall, GG-HA spongy-like hydrogels with a sustained release of HA oligomers are valuable options to improve tissue vascularization, a critical issue in several applications in the tissue engineering and regenerative medicine field. PMID- 27960397 TI - Nanotextured Surface on Flexographic Printed ZnO Thin Films for Low-Cost Non Faradaic Biosensors. AB - In this work, the formation of a nanotextured surface is reported on flexographic printed zinc oxide thin films which provide an excellent platform for low-cost, highly sensitive biosensing applications. The ability to produce nanotextured surfaces using a high-throughput, roll-to-roll production method directly from precursor ink without any complicated processes is commercially attractive for biosensors that are suitable for large-scale screening of diseases at low cost. The zinc oxide thin film was formed by printing a zinc acetate precursor ink solution and annealing at 300 degrees C. An intricate nanotexturing of the film surface was achieved through 150 degrees C drying process between multiple prints. These surface nanostructures were found to be in the range of 100 to 700 nm in length with a width of 58 +/- 18 nm and a height of between 20 and 60 nm. Such structures significantly increase the surface area to volume ratio of the biosensing material, which is essential to high sensitivity detection of diseases. Nonfaradaic electrochemical impedance spectroscopy measurements were carried out to detect the pp65-antigen of the human cytomegalovirus using the printed device, which has a low limit of detection of 5 pg/mL. PMID- 27960399 TI - Nonvolatile Transistor Memory with Self-Assembled Semiconducting Polymer Nanodomain Floating Gates. AB - Organic field effect transistor based nonvolatile memory (OFET-NVM) with semiconducting nanofloating gates offers additional benefits over OFET-NVMs with conventional metallic floating gates due to the facile controllability of charge storage based on the energetic structure of the floating gate. In particular, an all-in-one tunneling and floating-gate layer in which the semiconducting polymer nanodomains are self-assembled in the dielectric tunneling layer is promising. In this study, we utilize crystals of a p-type semiconducting polymer in which the crystalline lamellae of the polymer are spontaneously developed and embedded in the tunneling matrix as the nanofloating gate. The widths and lengths of the polymer nanodomains are approximately 20 nm and a few hundred nanometers, respectively. An OFET-NVM containing the crystalline nanofloating gates exhibits memory performance with a large memory window of 10 V, programming/erasing switching endurance for over 500 cycles, and a long retention time of 5000 s. Moreover, the device performance is improved by comixing with an n-type semiconductor; thus, the solution-processed p- and n-type double floating gates capable of storing both holes and electrons allow for the multilevel operation of our OFET-NVM. Four highly reliable levels (two bits per cell) of charge trapping and detrapping are achieved using this OFET-NVM by accurately choosing the programming/erasing voltages. PMID- 27960398 TI - Highly Anisotropic Adhesive Film Made from Upside-Down, Flat, and Uniform Vertically Aligned CNTs. AB - We have created a multifunctional dry adhesive film with transferred vertically aligned carbon nanotubes (VA-CNTs). This unique VA-CNT film was fabricated by a multistep transfer process, converting the flat and uniform bottom of VA-CNTs grown on atomically flat silicon wafer substrates into the top surface of an adhesive layer. Unlike as-grown VA-CNTs, which have a nonuniform surface, randomly entangled CNT arrays, and a weak interface between the CNTs and substrates, this transferred VA-CNT film shows an extremely high coefficient of static friction (COF) of up to 60 and a shear adhesion force 30 times higher (12 N/cm2) than that of the as-grown VA-CNTs under a very small preloading of 0.2 N/cm2. Moreover, a near-zero normal adhesion force was observed with 20 mN/cm2 preloading and a maximum 100-MUm displacement in a piezo scanner, demonstrating ideal properties for an artificial gecko foot. Using this unique structural feature and anisotropic adhesion properties, we also demonstrate effective removal and assembly of nanoparticles into organized micrometer-scale circular and line patterns by a single brushing of this flat and uniform VA-CNT film. PMID- 27960400 TI - High-Performance MoS2/CuO Nanosheet-on-One-Dimensional Heterojunction Photodetectors. AB - van der Waals heterostructures based on stacked two-dimensional (2D) materials provide novel device structures enabling high-performance electronic and optoelectronic devices. While 2D-2D or 2D-bulk heterostructures have been largely explored for fundamental understanding and novel device applications, 2D-one dimensional (1D) heterostructures have been rarely studied because of the difficulty in achieving high-quality heterojunctions between 2D and 1D structures. In this study, we introduce nanosheet-on-1D van der Waals heterostructure photodetectors based on a wet-transfer printing of a MoS2 nanosheet on top of a CuO nanowire (NW). MoS2/CuO nanosheet-on-1D photodetectors show an excellent photocurrent rectification ratio with an ideality factor of 1.37, which indicates the formation of an atomically sharp interface and a high quality heterojunction in the MoS2/CuO heterostructure by wet-transfer-enhanced van der Waals bonding. Furthermore, nanosheet-on-1D heterojunction photodetectors exhibit excellent photodetection capabilities with an ultrahigh photoresponsivity (~157.6 A/W), a high rectification ratio (~6000 at +/-2 V), a low dark current (~38 fA at -2 V), and a fast photoresponse time (~34.6 and 51.9 ms of rise and decay time), which cannot be achievable with 1D-on-nanosheet heterojunction photodetectors. The wet-transfer printing of nanosheet-on-1D heterostructures introduced in this study provides a robust platform for the fundamental study of various combinations of 2D-on-1D heterostructures and their applications in novel heterojunction devices. PMID- 27960401 TI - Improving Surface Adsorption via Shape Control of Hematite alpha-Fe2O3 Nanoparticles for Sensitive Dopamine Sensors. AB - alpha-Fe2O3 nanoparticles (NPs) with morphologies varying from shuttle to drum were synthesized through an anion-assisted and surfactant-free hydrothermal method by simply varying the ratios of ethanol and water in solvent. Control experiments show that the structural evolution can be attributed to a small molecular-induced anisotropic growth mechanism in which the growth rate of alpha Fe2O3 NPs along the a-, b-, or c-axis was well-controlled. The detailed structural analysis through the high-resolution transmission electron microscope (HRTEM) indicated that shuttle-like Fe2O3 NP surface was covered by high-density atomic steps, which endowed them with the enhanced adsorption and sensor ability toward dopamine (DA). The XPS characterizations indicated that the percentages of the OC component follow the order of shuttle-like Fe2O3 (S-Fe2O3 for short) > pseudoshuttle-like Fe2O3 (Ps-Fe2O3 for short) > polyhedron-like Fe2O3 (Ph-Fe2O3 for short) > drum-like Fe2O3 (D-Fe2O3 for short). Benefits from these structural advantages, the S-Fe2O3 NPs-Nafion composite electrode exhibited remarkable electrochemical detection ability with a wide liner range from 0.2 MUM to 0.107 mM and a low detection limit of 31.25 nM toward DA in the presence of interferents. PMID- 27960402 TI - Thermoelectric Properties of Indium and Gallium Dually Doped ZnO Thin Films. AB - We investigated the effect of single and multidopants on the thermoelectrical properties of host ZnO films. Incorporation of the single dopant Ga in the ZnO films improved the conductivity and mobility but lowered the Seebeck coefficient. Dual Ga- and In-doped ZnO thin films show slightly decreased electrical conductivity but improved Seebeck coefficient. The variation of thermoelectric properties is discussed in terms of film crystallinity, which is subject to the dopants' radius. Small amounts of In dopants with a large radius may introduce localized regions in the host film, affecting the thermoelectric properties. Consequently, a 1.5 times increase in power factor, three times reduction in thermal conductivity, and 5-fold enhancement in the figure of merit ZT have been achieved at 110 degrees C. The results also indicate that the balanced control of both electron and lattice thermal conductivities through dopant selection are necessary to attain low total thermal conductivity. PMID- 27960403 TI - Construction of a Unique Two-Dimensional Hierarchical Carbon Architecture for Superior Lithium-Ion Storage. AB - Two-dimensional nanocarbons are intriguing functional materials for energy storage. However, the serious aggregation problems hinder their wider applications. To address this issue, we developed a unique two-dimensional hierarchical carbon architecture (2D-HCA) with ultrasmall graphene-like carbon nanosheets uniformly grown on hexagonal carbon nanoplates. The obtained 2D-HCA shows an interconnected porous structure and abundant heteroelement doping. When employed as anode for lithium ion batteries, it exhibits a high discharge capacity of 748 m Ah g-1 even after 400 cycles at 2 A g-1. PMID- 27960404 TI - Soybean Root-Derived Hierarchical Porous Carbon as Electrode Material for High Performance Supercapacitors in Ionic Liquids. AB - Soybeans are extensively cultivated worldwide as human food. However, large quantities of soybean roots (SRs), which possess an abundant three-dimensional (3D) structure, remain unused and produce enormous pressure on the environment. Here, 3D hierarchical porous carbon was prepared by the facile carbonization of SRs followed by chemical activation. The as-prepared material, possessing large specific surface area (2143 m2 g-1), good electrical conductivity, and unique 3D hierarchical porosity, shows outstanding electrochemical performance as an electrode material for supercapacitors, such as a high capacitance (276 F g-1 at 0.5 A g-1), superior cycle stability (98% capacitance retention after 10,000 cycles at 5 A g-1), and good rate capability in a symmetric two-electrode supercapacitor in 6 M KOH. Furthermore, the maximum energy density of as assembled symmetric supercapacitor can reach 100.5 Wh kg-1 in neat EMIM BF4. Moreover, a value of 40.7 Wh kg-1 is maintained at ultrahigh power density (63000 W kg-1). These results show that the as-assembled supercapacitor can simultaneously deliver superior energy and power density. PMID- 27960406 TI - Facilitation of Polymerase Chain Reaction with Poly(ethylene glycol)-Engrafted Graphene Oxide Analogous to a Single-Stranded-DNA Binding Protein. AB - Polymerase chain reaction (PCR), a versatile DNA amplification method, is a fundamental technology in modern life sciences and molecular diagnostics. After multiple rounds of PCR, however, nonspecific DNA fragments are often produced and the amplification efficiency and fidelity decrease. Here, we demonstrated that poly(ethylene glycol)-engrafted nanosized graphene oxide (PEG-nGO) can significantly improve the PCR specificity and efficiency. PEG-nGO allows the specificity to be maintained even after multiple rounds of PCR, allowing reliable amplification at low annealing temperatures. PEG-nGO decreases the nonspecific annealing of single-stranded DNA (ssDNA), such as primer dimerization and false priming, by adsorbing excess primers. Moreover, PEG-nGO interrupts the reannealing of denatured template DNA by preferentially binding to ssDNA. Thus, PEG-nGO enhances the PCR specificity by preferentially binding to ssDNA without inhibiting DNA polymerase, which is analogous to the role of ssDNA binding proteins. PMID- 27960405 TI - Improving Antiadhesion Effect of Thermosensitive Hydrogel with Sustained Release of Tissue-type Plasminogen Activator in a Rat Repeated-Injury Model. AB - Intraperitoneal adhesion occurs frequently after pelvic and abdominal surgery, which plays an enormous burden on patients. Various drugs and barrier agents were studied and used to prevent adhesions, but few of them were satisfactory. A thermosensitive hydrogel was developed in our previous work and was effective in preventing adhesions. But in our preliminary experiment, it showed limited activity in a more rigorous rat repeated-injury adhesion model, which was much closer to clinical. In this study, tissue-type plasminogen activator (tPA) loaded thermosensitive hydrogel (tPA-hydrogel) was prepared, which combined barrier functions with sustained release of antiadhesion drug. The obtained tPA-hydrogel was injectable and degraded in vivo gradually in four weeks. Both hematoxylin and eosin and Masson trichrome staining confirmed that the tPA-hydrogel exhibited excellent antiadhesion effects on repeated-injury adhesion. Scanning electron microscopy was used to observe the injured abdominal wall, and cecum remesothelialized after treated with tPA-hydrogel for 14 d. In addition, the PAI 1 and tPA levels were measured by enzyme-linked immunosorbent assay. Results showed the PAI-1 concentrations in peritoneal lavage fluids of tPA-hydrogel treated rats were lower than that of other groups, leading to decreased fibrin formation, while there were no significant differences observed in tPA blood levels at any point in time (P > 0.05). This study demonstrated that the effectiveness of thermosensitive hydrogel in preventing adhesions could be enhanced by delivering antiadhesion drugs, and the tPA-hydrogel might be a promising system for clinical application. PMID- 27960407 TI - Biomimic Hairy Skin Tactile Sensor Based on Ferromagnetic Microwires. AB - We present a multifunctional tactile sensor inspired by human hairy skin structure, in which the sensitive hair sensor and the robust skin sensor are integrated into a single device via a pair of Co-based ferromagnetic microwire arrays in a very simple manner. The sensor possesses a self-tunable effective compliance with respect to the magnitude of the stimulus, allowing a wide range of loading force to be measured. The sensor also exhibits some amazing functions, such as air-flow detection, material property characterization, and excellent damage resistance. The novel sensing mechanism and structure provide a new strategy for designing multifunctional tactile sensors and show great potential applications on intelligent robot and sensing in harsh environments. PMID- 27960408 TI - Stretchable and Thermally Stable Dual Emission Composite Films of On-Purpose Aggregated Copper Nanoclusters in Carboxylated Polyurethane for Remote White Light-Emitting Devices. AB - Stretchable, mechanically stable films with thermally stable dual emission peaked in the blue and orange spectral range are fabricated by condensation and aging of carboxylated polyurethane in the presence of on-purpose aggregated copper nanoclusters. The aggregation of copper clusters leads to the enhancement of their emission in the orange, while polyurethane matrix contributes with the blue emission band, with an overall photoluminescence quantum yield of the films as high as 18%. Composite Cu nanoclusters/polyurethane films are sufficiently transparent over the visible spectral range and are absorbing in the UV range; more than 90% of their emission intensity is preserved after 10 times of cycle of stretch and recovery, as well as aging of up to 10 h at 90 degrees C, making them useful for optoelectronic devices. Remote white light-emitting devices (LEDs) have been fabricated by placing a down-conversion layer of composite Cu nanoclusters/polyurethane film separated through a silicone resin spacer from the UV LED chip, with Commission Internationale de l'Eclairage color coordinates of (0.34, 0.29), and a high color rendering index of 87. PMID- 27960409 TI - An Intelligent and Tumor-Responsive Fe2+ Donor and Fe2+-Dependent Drugs Cotransport System. AB - Fe2+ plays an essential role for artemisinin (ART)-based drugs in anticancer therapy. As a result, it is important to realize these two agents' cotransport for improving antitumor efficacy. We utilized a kind of alternating magnetic field (AMF) and tumor-responsive material-mesoporous Fe3O4 (mFe3O4)-to encapsulate ART. After that, the outer surface of mFe3O4 was capped with multifunctional hyaluronic acid (HA), which was used not only as a smart gatekeeper but also as a tumor targeting moiety. In vitro and in vivo studies proved that ART can be encapsulated in HA-mFe3O4 and protected by HA coating which could effectively avoid premature release during in vivo circulation. HA mFe3O4/ART could be taken up by MCF-7 tumor cells via CD44 receptor-mediated endocytosis and locate at acidic lysosome. Subsequently, "HA gate" could be degraded by acidity and hyaluronidase. Then this system synchronously released Fe2+ and ART at the same site. Fe2+ can nonenzymatically convert ART to ROS for killing cancer cells. Under AMF irradiation, HA-mFe3O4 could not only effectively convert electromagnetic wave into heat for tumor thermal therapy but also generate high levels of reactive oxygen species (ROS) for tumor dynamic therapy. These results demonstrated that the antitumor efficacy of HA-mFe3O4/ART in vivo significantly enhanced 3.7 times compared with free ART. Combining with AMF, it further improved 3.9 times (V/V0 of 0.11), suggesting the successful combined application of HA-mFe3O4/ART and AMF for tumor treatment. It is believed that HA mFe3O4/ART is a promising system for Fe2+-dependent drugs to improve their therapeutic effect. PMID- 27960410 TI - High-Performance Asymmetric Supercapacitors of MnCo2O4 Nanofibers and N-Doped Reduced Graphene Oxide Aerogel. AB - The working potential of symmetric supercapacitors is not so wide because one type of material used for the supercapacitor electrodes prefers either positive or negative charge to both charges. To address this problem, a novel asymmetrical supercapacitor (ASC) of battery-type MnCo2O4 nanofibers (NFs)//N-doped reduced graphene oxide aerogel (N-rGOAE) was fabricated in this work. The MnCo2O4 NFs at the positive electrode store the negative charges, i.e., solvated OH-, while the N-rGOAE at the negative electrode stores the positive charges, i.e., solvated K+. An as-fabricated aqueous-based MnCo2O4//N-rGOAE ASC device can provide a wide operating potential of 1.8 V and high energy density and power density at 54 W h kg-1 and 9851 W kg-1, respectively, with 85.2% capacity retention over 3000 cycles. To understand the charge storage reaction mechanism of the MnCo2O4, the synchrotron-based X-ray absorption spectroscopy (XAS) technique was also used to determine the oxidation states of Co and Mn at the MnCo2O4 electrode after being electrochemically tested. The oxidation number of Co is oxidized from +2.76 to +2.85 after charging and reduced back to +2.75 after discharging. On the other hand, the oxidation state of Mn is reduced from +3.62 to +3.44 after charging and oxidized to +3.58 after discharging. Understanding in the oxidation states of Co and Mn at the MnCo2O4 electrode here leads to the awareness of the uncertain charge storage mechanism of the spinel-type oxide materials. High-performance ASC here in this work may be practically used in high-power applications. PMID- 27960412 TI - High-Performance Inverted Polymer Solar Cells with Zirconium Acetylacetonate Buffer Layers. AB - Inverted polymer solar cells incorporating solution-processed zirconium acetylacetonate (ZrAcac) buffer layers were demonstrated. The optimal device delivered a power conversion efficiency up to 9.2%, displaying ~20% improvement compared with the device of conventional configuration. The performance improvement by adopting ZrAcac as the cathode buffer layer is attributed to the enhanced light-harvesting, facilitated electron transport, and reduced bimolecular recombination loss. The morphology of ZrAcac buffer layer was found to be critical in achieving high performance, which was tunable through the selection of processing solvents. A flat and uniform ZrAcac film consisting of ~20 nm nanoscale aggregates deposited from a chloroform solution was proved to be highly effective, which only requires a short light-soaking time. PMID- 27960413 TI - Poly(ester urea)-Based Adhesives: Improved Deployment and Adhesion by Incorporation of Poly(propylene glycol) Segments. AB - The adhesive nature of mussels arises from the catechol moiety in the 3,4 dihydroxyphenylalanine (DOPA) amino acid, one of the many proteins that contribute to the unique adhesion properties of mussels. Inspired by these properties, many biomimetic adhesives have been developed over the past few years in an attempt to replace adhesives such as fibrin, cyanoacrylate, and epoxy glues. In the present work, we synthesized ethanol soluble but water insoluble catechol functionalized poly(ester urea) random copolymers that help facilitate delivery and adhesion in wet environments. Poly(propylene glycol) units incorporated into the polymer backbone impart ethanol solubility to these polymers, making them clinically relevant. A catechol to cross-linker ratio of 10:1 with a curing time of 4 h exceeded the performance of commercial fibrin glue (4.8 +/- 1.4 kPa) with adhesion strength of 10.6 +/- 2.1 kPa. These adhesion strengths are significant with the consideration that the adhesion studies were performed under wet conditions. PMID- 27960411 TI - Gemcitabine and Antisense-microRNA Co-encapsulated PLGA-PEG Polymer Nanoparticles for Hepatocellular Carcinoma Therapy. AB - Hepatocellular carcinoma (HCC) is highly prevalent, and the third most common cause of cancer-associated deaths worldwide. HCC tumors respond poorly to chemotherapeutic anticancer agents due to inherent and acquired drug resistance, and low drug permeability. Targeted drug delivery systems with significant improvement in therapeutic efficiency are needed for successful HCC therapy. Here, we report the results of a technique optimized for the synthesis and formulation of antisense-miRNA-21 and gemcitabine (GEM) co-encapsulated PEGylated PLGA nanoparticles (NPs) and their in vitro therapeutic efficacy in human HCC (Hep3B and HepG2) cells. Water-in-oil-in-water (w/o/w) double emulsion method was used to coload antisense-miRNA-21 and GEM in PEGylated-PLGA-NPs. The cellular uptake of NPs displayed time dependent increase of NPs concentration inside the cells. Cell viability analyses in HCC (Hep3B and HepG2) cells treated with antisense-miRNA-21 and GEM co-encapsulated NPs demonstrated a nanoparticle concentration dependent decrease in cell proliferation, and the maximum therapeutic efficiency was attained in cells treated with nanoparticles co encapsulated with antisense-miRNA-21 and GEM. Flow cytometry analysis showed that control NPs and antisense-miRNA-21-loaded NPs are not cytotoxic to both HCC cell lines, whereas treatment with free GEM and GEM-loaded NPs resulted in ~9% and ~15% apoptosis, respectively. Cell cycle status analysis of both cell lines treated with free GEM or NPs loaded with GEM or antisense-miRNA-21 displayed a significant cell cycle arrest at the S-phase. Cellular pathway analysis indicated that Bcl2 expression was significantly upregulated in GEM treated cells, and as expected, PTEN expression was noticeably upregulated in cells treated with antisense-miRNA-21. In summary, we successfully synthesized PEGylated-PLGA nanoparticles co- encapsulated with antisense-miRNA-21 and GEM. These co encapsulated nanoparticles revealed increased treatment efficacy in HCC cells, compared to cells treated with either antisense-miRNA-21- or GEM-loaded NPs at equal concentration, indicating that down-regulation of endogenous miRNA-21 function can reduce HCC cell viability and proliferation in response to GEM treatment. PMID- 27960414 TI - Fast and Low-Temperature (70 degrees C) Mineralization of Inkjet Printed Mesoporous TiO2 Photoanodes Using Ambient Air Plasma. AB - Hybrid mesoporous titania/silica electron-generating and transporting layers were prepared using wet-coating with a dispersion consisting of prefabricated titania nanoparticles and a methyl-silica binder. Titania/methyl-silica wet layers were deposited by inkjet printing and further mineralized by low-temperature atmospheric-pressure air plasma using diffuse coplanar surface barrier discharge (DCSBD) to form a titania/silica hybrid nanocomposite coating. Morphological analysis performed by scanning electron microscopy revealed no damage to the titania nanoparticles and chemical analysis performed by X-ray photoelectron spectroscopy disclosed a rapid decrease in carbon and increase in oxygen, indicating the oxidation effect of the plasma. The coatings were further electrochemically investigated with linear sweep voltammetry and chronoamperometry. The magnitude of photocurrent and photocatalytic activity were found to increase significantly with the plasma exposure on the order of 10s of seconds. The results obtained demonstrate the potential of DCSBD ambient air plasma for fast and low-temperature mineralization of titania mesoporous coatings. PMID- 27960415 TI - Pyrimidine-Based Mononuclear and Dinuclear Iridium(III) Complexes for High Performance Organic Light-Emitting Diodes. AB - Containing two nitrogen atoms, the electron-deficient pyrimidine ring has excellent coordinating capability with transition metal ions. However, compared with the widely used pyridine ring, applications of the pyrimidine ring in phosphorescent Ir(III) complexes are rare. In this research, two highly emissive pyrimidine-based mononuclear Ir(III) complexes and their corresponding dinuclear Ir(III) complexes were prepared with a simple one-pot reaction. The incorporation of the second Ir(III) center can lead to dramatic differences of both photophysical and electrochemical properties between the mono- and dinuclear complexes. Besides, these properties can also be fine-tuned with different substituents. Theoretical calculations have also been performed to understand their photophysical behaviors. The electroluminescent investigations demonstrate that the pyrimidine-based mono- and dinuclear Ir(III) complexes could show impressive device performance. The vacuum-deposited organic light-emitting diode (OLED) based on the mononuclear Ir(III) complex exhibited an external quantum efficiency (EQE) of 16.1% with almost no efficiency roll-off even at 10 000 cd m 2. More encouragingly, the solution-processed OLED based on the dinuclear Ir(III) complex achieved the outstanding EQE, current efficiency (CE), and power efficiency (PE) of 17.9%, 52.5 cd A-1, and 51.2 lm W-1, respectively, representing the highest efficiencies ever achieved by OLEDs based on dinuclear Ir(III) complexes. PMID- 27960416 TI - Self-Stable WP/C Support with Excellent Cocatalytic Functionality for Pt: Enhanced Catalytic Activity and Durability for Methanol Electro-Oxidation. AB - To endow catalyst support with excellent stability and cocatalytic activity toward methanol, oxidation reaction (MOR) is an effective way to strengthen the electrocatalytic activity of Pt-based catalysts. Tungsten phosphide/3D-corrugated porous carbon (WP/C) composite as Pt-support and cocatalyst for MOR is prepared via a synchronous synthesis method. Porous 3D-tufted structure and high surface area of WP/C with abundant oxygen-containing groups (such as C-O-C, C-O-H, or C OH) can significantly improve the exposure of active sites, which enlarge the contact area with electrolyte and facilitate the mass transfer and absorption of methanol for promoting the MOR activity in acidic electrolyte. Pt-WP/C exhibits a considerably higher mass activity (1559.3 mA mgPt-1) for MOR than that of Pt/C (488.2 mA mgPt-1), owing to the special activity of Wdelta+ and Pdelta- sites for the decomposition reaction of water. With the introduction of W species, more available P species (passivated or not) are activated for further enhancing the cocatalytic activity of WP for MOR. Furthermore, the CO tolerance and durability of Pt-WP/C are also remarkable, which should benefit from the fast surface transport of adsorbed CO on different crystalline faces of WP and the extremely stable WP-C structure originating from the existence of P-P chains between the adjacent WP particles, respectively. The design of the porous structure and cocatalytic effect of this catalyst support (WP/C) provides a promising method to drastically enhance MOR activity. PMID- 27960417 TI - Enhanced Interfacial Kinetics and High-Voltage/High-Rate Performance of LiCoO2 Cathode by Controlled Sputter-Coating with a Nanoscale Li4Ti5O12 Ionic Conductor. AB - The selection and optimization of coating material/approach for electrode materials have been under intensive pursuit to address the high-voltage induced degradation of lithium ion batteries. Herein, we demonstrate an efficient way to enhance the high-voltage electrochemical performance of LiCoO2 cathode by postcoating of its composite electrode with Li4Ti5O12 (LTO) via magnetron sputtering. With a nanoscale (~25 nm) LTO coating, the reversible capacity of LiCoO2 after 60 cycles is significantly increased by 40% (to 170 mAh g-1) at room temperature and by 118% (to 139 mAh g-1) at 55 degrees C. Meanwhile, the electrode's rate capability is also greatly improved, which should be associated with the high Li+ diffusivity of the LTO surface layer, while the bulk electronic conductivity of the electrode is unaffected. At 12 C, the capacity of the coated electrode reaches 113 mAh g-1, being 70% larger than that of the uncoated one. The surface interaction between LTO and LiCoO2 is supposed to reduce the space charge layer at the LiCoO2-electrolyte interface, which makes the Li+ diffusion much easier as evidenced by the largely enhanced diffusion coefficient of the coated electrode (an order of magnitude improvement). In addition, the LTO coating layer, which is electrochemically and structurally stable in the applied potential range, plays the role of a passivation layer or an artificial and friendly solid electrolyte interface (SEI) layer on the electrode surface. Such protection is able to impede propagation of the in situ formed irreversible SEI and thus guarantee a high initial columbic efficiency and superior cycling stability at high voltage. PMID- 27960418 TI - Aptamer-Binding Directed DNA Origami Pattern for Logic Gates. AB - In this study, an aptamer-substrate strategy is introduced to control programmable DNA origami pattern. Combined with DNA aptamer-substrate binding and DNAzyme-cutting, small DNA tiles were specifically controlled to fill into the predesigned DNA origami frame. Here, a set of DNA logic gates (OR, YES, and AND) are performed in response to the stimuli of adenosine triphosphate (ATP) and cocaine. The experimental results are confirmed by AFM imaging and time-dependent fluorescence changes, demonstrating that the geometric patterns are regulated in a controllable and programmable manner. Our approach provides a new platform for engineering programmable origami nanopatterns and constructing complex DNA nanodevices. PMID- 27960419 TI - Amphiphilic Cross-Linked Liquid Crystalline Fluoropolymer-Poly(ethylene glycol) Coatings for Application in Challenging Conditions: Comparative Study between Different Liquid Crystalline Comonomers and Polymer Architectures. AB - Linear and hyperbranched poly(ethylene glycol)-cross-linked amphiphilic fluoropolymer networks comprised of different liquid crystalline comonomers were developed and evaluated as functional coatings in extreme weather-challenging conditions. Through variation of the liquid-crystalline comonomer and hydrophilic:hydrophobic component ratios, several series of coatings were synthesized and underwent a variety of analyses including differential scanning calorimetry, water contact angle measurements and solution stability studies in aqueous media. These materials maintained an unprecedented reduction in the free water melting transition (Tm) temperature across the hyperbranched and linear versions. The coatings synthesized from hyperbranched fluoropolymers preserved the liquid crystalline character of the mesogenic components, as seen by polarized optical microscopy, and demonstrated stability in saltwater aqueous environments and in cold weather conditions. PMID- 27960421 TI - Metal-Free CVD Graphene Synthesis on 200 mm Ge/Si(001) Substrates. AB - Good quality, complementary-metal-oxide-semiconductor (CMOS) technology compatible, 200 mm graphene was obtained on Ge(001)/Si(001) wafers in this work. Chemical vapor depositions were carried out at the deposition temperatures of 885 degrees C using CH4 as carbon source on epitaxial Ge(100) layers, which were grown on Si(100), prior to the graphene synthesis. Graphene layer with the 2D/G ratio ~3 and low D mode (i.e., low concentration of defects) was measured over the entire 200 mm wafer by Raman spectroscopy. A typical full-width-at-half maximum value of 39 cm-1 was extracted for the 2D mode, further indicating that graphene of good structural quality was produced. The study also revealed that the lack of interfacial oxide correlates with superior properties of graphene. In order to evaluate electrical properties of graphene, its 2 * 2 cm2 pieces were transferred onto SiO2/Si substrates from Ge/Si wafers. The extracted sheet resistance and mobility values of transferred graphene layers were ~1500 +/- 100 Omega/sq and MU ~ 400 +/- 20 cm2/V s, respectively. The transferred graphene was free of metallic contaminations or mechanical damage. On the basis of results of DFT calculations, we attribute the high structural quality of graphene grown by CVD on Ge to hydrogen-induced reduction of nucleation probability, explain the appearance of graphene-induced facets on Ge(001) as a kinetic effect caused by surface step pinning at linear graphene nuclei, and clarify the orientation of graphene domains on Ge(001) as resulting from good lattice matching between Ge(001) and graphene nucleated on such nuclei. PMID- 27960420 TI - Rhipsalis (Cactaceae)-like Hierarchical Structure Based Microfluidic Chip for Highly Efficient Isolation of Rare Cancer Cells. AB - The circulating tumor cells (CTCs), originating from the primary tumor, play a vital role in cancer diagnosis, prognosis, disease monitoring, and precise therapy. However, the CTCs are extremely rare in the peripheral bloodstream and hard to be isolated. To overcome current limitations associated with CTC capture and analysis, the strategy incorporating nanostructures with microfluidic devices receives wide attention. Here, we demonstrated a three-dimensional microfluidic device (Rm-chip) for capturing cancer cells with high efficiency by integrating a novel hierarchical structure, the "Rhipsalis (Cactaceae)"-like micropillar array, into the Rm-chip. The PDMS micropillar array was fabricated by soft-lithography and rapid prototyping method, which was then conformally plated with a thin gold layer through electroless plating. EpCAM antibody was modified onto the surface of the micropillars through the thiol-oligonucleotide linkers in order to release captured cancer cells by DNase I treatment. The antibody-functionalized device achieved an average capture efficiency of 88% in PBS and 83.7% in whole blood samples. We believe the Rm-chip provided a convenient, economical, and versatile approach for cell analysis with wide potential applications. PMID- 27960422 TI - Flexible and Freestanding Supercapacitor Electrodes Based on Nitrogen-Doped Carbon Networks/Graphene/Bacterial Cellulose with Ultrahigh Areal Capacitance. AB - Flexible energy-storage devices based on supercapacitors rely largely on the scrupulous design of flexible electrodes with both good electrochemical performance and high mechanical properties. Here, nitrogen-doped carbon nanofiber networks/reduced graphene oxide/bacterial cellulose (N-CNFs/RGO/BC) freestanding paper is first designed as a high-performance, mechanically tough, and bendable electrode for a supercapacitor. The BC is exploited as both a supporting substrate for a large mass loading of 8 mg cm-2 and a biomass precursor for N CNFs by pyrolysis. The one-step carbonization treatment not only fabricates the nitrogen-doped three-dimensional (3D) nanostructured carbon composite materials but also forms the reduction of the GO sheets at the same time. The fabricated paper electrode exhibits an ultrahigh areal capacitance of 2106 mF cm-2 (263 F g 1) in a KOH electrolyte and 2544 mF cm-2 (318 F g-1) in a H2SO4 electrolyte, exceptional cycling stability (~100% retention after 20000 cycles), and excellent tensile strength (40.7 MPa). The symmetric supercapacitor shows a high areal capacitance (810 mF cm-2 in KOH and 920 mF cm-2 in H2SO4) and thus delivers a high energy density (0.11 mWh cm-2 in KOH and 0.29 mWh cm-2 in H2SO4) and a maximum power density (27 mW cm-2 in KOH and 37.5 mW cm-2 in H2SO4). This work shows that the new procedure is a powerful and promising way to design flexible and freestanding supercapacitor electrodes. PMID- 27960423 TI - Dual Physically Cross-Linked Double Network Hydrogels with High Mechanical Strength, Fatigue Resistance, Notch-Insensitivity, and Self-Healing Properties. AB - Double-network (DN) hydrogels with high strength and toughness have been developed as promising materials. Herein, we explored a dual physically cross linked polyacrylamide/xanthan gum (PAM/XG) DN hydrogel. The nonchemically cross linked PAM/XG DN hydrogels exhibited fracture stresses as high as 3.64 MPa (13 times higher than the pure PAM single network hydrogel) and compressive stresses at 99% strain of more than 50 MPa. The hydrogels could restore their original shapes after continuously loading-unloading tensile and compressive cyclic tests. In addition, the PAM/XG DN hydrogels demonstrated excellent fatigue resistance, notch-insensitivity, high stability in different harsh environments, and remarkable self-healing properties, which might result from their distinctive physical-cross-linking structures. The attenuated total reflectance infrared spectroscopy (ATR-IR) and dynamic thermogravimetric analysis (TGA) results indicated that there were no chemical bonds (only hydrogen bonds) between the XG and PAM networks. The PAM/XG DN hydrogel synthesis offers a new avenue for the design and construction of DN systems, broadening current research and applications of hydrogels with excellent mechanical properties. PMID- 27960424 TI - New Insight into a Cancer Theranostic Probe: Efficient Cell-Specific Delivery of SN-38 Guided by Biotinylated Poly(vinyl alcohol). AB - An optically modulated "turn-on" theranostic prodrug TP1 has been explored and formulated with biotinylated poly(vinyl alcohol) (biotinPVA) to obtain desired pharmacokinetics. TP1, consisting of the antineoplastic camptothecin analogue SN 38, and the fluorescent dye rhodol green have been covalently conjugated through a disulfide bond. Glutathione triggering the release of drug and fluorophore has been well established by UV-vis measurements through mass spectral analysis in physiological conditions. The biocompatible biotinPVA formulated prodrug (PTP1) showed remarkably higher stability against blood serum and cell-specific activation in contrast to that of TP1. Significantly, PTP1 permits monitoring of the delivery and release of well-known topoisomerase I inhibitor SN-38 by modulating fluorescence signal at lambdaem 550 nm within intracellular milieus. Moreover, theranostic probe PTP1 exhibited dose-dependent antiproliferative activity against receptor-positive HeLa cells, whereas it did not show such an effect against receptor-negative NIH3T3 cells. Finally, the cell-specific antiproliferative activity of PTP1 via the apoptotic pathway is an efficient approach in cancer theranostics. Thus, futuristic PTP1 could be a promising agent in which diagnostic and prognostic data will be monitored synergistically. PMID- 27960425 TI - Tunable Surface and Matrix Chemistries in Optically Printed (0-3) Piezoelectric Nanocomposites. AB - In this work, the impacts of varying surface modification, matrix parameters, and fabrication conditions on the performance of optically printed (0-3) piezoelectric polymer nanocomposites are examined. For example, we find that a 75% reduction in nanoparticle edge-length boosted the piezoelectric coefficient (d33) by over 100%. By optimizing the composition and fabrication conditions, 10% by mass loading barium titanate nanocomposites are able to yield d33 values of ~80 pC/N compared to <5 pC/N when parameters are not optimized. With a more complete understanding of how to enhance the performance of (0-3) piezoelectric polymer nanocomposites, these materials should find use in a wide range of applications. PMID- 27960426 TI - Carbon-Based CsPbBr3 Perovskite Solar Cells: All-Ambient Processes and High Thermal Stability. AB - The device instability has been an important issue for hybrid organic-inorganic halide perovskite solar cells (PSCs). This work intends to address this issue by exploiting inorganic perovskite (CsPbBr3) as light absorber, accompanied by replacing organic hole transport materials (HTM) and the metal electrode with a carbon electrode. All the fabrication processes (including those for CsPbBr3 and the carbon electrode) in the PSCs are conducted in ambient atmosphere. Through a systematical optimization on the fabrication processes of CsPbBr3 film, carbon based PSCs (C-PSCs) obtained the highest power conversion efficiency (PCE) of about 5.0%, a relatively high value for inorganic perovskite-based PSCs. More importantly, after storage for 250 h at 80 degrees C, only 11.7% loss in PCE is observed for CsPbBr3 C-PSCs, significantly lower than that for popular CH3NH3PbI3 C-PSCs (59.0%) and other reported PSCs, which indicated a promising thermal stability of CsPbBr3 C-PSCs. PMID- 27960427 TI - On the Mechanism of the Improved Operation Voltage of Rhombohedral Nickel Hexacyanoferrate as Cathodes for Sodium-Ion Batteries. AB - We reported a rhombohedral Na-rich nickel hexacyanoferrate (r-NiHCF) with high discharge voltage, which also possesses long cycle stability and excellent rate capability when serving as the cathode material of Na-ion batteries. First principles calculations suggest that the high working voltage of r-NiHCF is correlated to the asymmetric residence of Na+ ions in the rhombohedral framework in parallel with the low charge density at the Fe2+ ions. In both aqueous and ether-based electrolytes, r-NiHCF exhibits higher voltage than that of cubic NiHCF. Rate and cycle experiments indicate that r-NiHCF delivers a specific capacity of 66.8 mAh g-1 at the current density of 80 mA g-1, which is approximate to the theoretical capacity of r-NiHCF. A capacity retention of 96% can be achieved after 200 cycles. The excellent stability of r-NiHCF can be assigned to the absence of rhombohedral-cubic phase transition and negligible volume variation during electrochemical redox, as proven by the ex situ XRD patterns at different depths of charge/discharge and the DFT calculations, respectively. PMID- 27960428 TI - Fluorescence-Magnetism Functional EuS Nanocrystals with Controllable Morphologies for Dual Bioimaging. AB - Multiple functions incorporated in one single component material offer important applications in biosystems. Here we prepared a divalent state of rare earth EuS nanocrystals (NCs), which provides luminescent and magnetic properties, using both 1-Dodecanethiol (DT) and oleylamine (OLA) as reducing agents. The resultant EuS NCs exhibit controllable shapes, uniform size, and bright luminescence with a quantum yield as high as 3.5%. OLA as a surface ligand plays an important role in tunable morphologies, such as nanowires, nanorods, nanospheres et al. Another attractive nature of the EuS NCs is their paramagnetism at room temperature. In order to expand the biological applications, the resultant EuS NCs were modified with amphiphilic block copolymer F127 and transferred from oil to water phase. The excellent biocompatibility of EuS NCs is demonstrated as well as preservation of their luminescence and paramagnetic properties. The EuS NCs offer multifunction and great advantages of bright luminescence, paramagnetic, controllable morphologies, and good biocompatibility promising applications in the field of simultaneous magnetic resonance and fluorescence bioimaging. PMID- 27960429 TI - Oriented Pt Nanoparticles Supported on Few-Layers Graphene as Highly Active Catalyst for Aqueous-Phase Reforming of Ethylene Glycol. AB - Pt nanoparticles (NPs) strongly grafted on few-layers graphene (G) have been prepared by pyrolysis under inert atmosphere at 900 degrees C of chitosan films (70-120 nm thickness) containing adsorbed H2PtCl6. Preferential orientation of exposed Pt facets was assessed by X-ray diffraction of films having high Pt loading where the 111 and 222 diffraction lines were observed and also by SEM imaging comparing elemental Pt mapping with the image of the 111 oriented particles. Characterization techniques allow determination of the Pt content (from 45 ng to 1 MUg cm-2, depending on the preparation conditions), particle size distribution (9 +/- 2 nm), and thickness of the films (12-20 nm). Oriented Pt NPs on G exhibit at least 2 orders of magnitude higher catalytic activity for aqueous-phase reforming of ethylene glycol to H2 and CO2 compared to analogous samples of randomly oriented Pt NPs supported on preformed graphene. Oriented [Formula: see text]/fl-G undergoes deactivation upon reuse, the most probable cause being Pt particle growth, probably due to the presence of high concentrations of carboxylic acids acting as mobilizing agents during the course of the reaction. PMID- 27960430 TI - Quantitative Study of Interface/Interphase in Epoxy/Graphene-Based Nanocomposites by Combining STEM and EELS. AB - A quantitative study of the interphase and interface of graphene nanoplatelets (GNPs)/epoxy and graphene oxide (GO)/epoxy was carried out by combining scanning transmission electron microscopy (STEM) and electron energy-loss spectroscopy (EELS). The interphase regions between GNPs and epoxy matrix were clearly identified by the discrepancy of the plasmon peak positions in the low energy loss spectra due to different valence electron densities. The spectrum acquisitions were carried out along lines across the interface. An interphase thickness of 13 and 12.5 nm was measured for GNPs/epoxy and GO/epoxy, respectively. The density of the GNPs/epoxy interphase was 2.89% higher than that of the epoxy matrix. However, the density of the GO/epoxy interphase was 1.37% lower than that of the epoxy matrix. The interphase layer thickness measured in this work is in good agreement with the transition layer theory, which proposed an area with modulus linearly varying across a finite width. The results provide an insight into the interphase for carbon-based polymer composites that can help to design the functionalization of nanofillers to improve the composite properties. PMID- 27960431 TI - Review of Adaptive Programmable Materials and Their Bioapplications. AB - Adaptive programmable materials have attracted increasing attention due to their high functionality, autonomous behavior, encapsulation, and site-specific confinement capabilities in various applications. Compared to conventional materials, adaptive programmable materials possess unique single-material architecture that can maintain, respond, and change their shapes and dimensions when they are subjected to surrounding environment changes, such as alternation in temperature, pH, and ionic strength. In this review, the most-recent advances in the design strategies of adaptive programmable materials are presented with respect to different types of architectural polymers, including stimuli responsive polymers and shape-memory polymers. The diverse functions of these sophisticated materials and their significance in therapeutic agent delivery systems are also summarized in this review. Finally, the challenges for facile fabrication of these materials and future prospective are also discussed. PMID- 27960432 TI - Enhanced Pseudocapacitive Performance of alpha-MnO2 by Cation Preinsertion. AB - Although the theoretical capacitance of MnO2 is 1370 F g-1 based on the Mn3+/Mn4+ redox couple, most of the reported capacitances in literature are far below the theoretical value even when the material goes to nanoscale. To understand this discrepancy, in this work, the electrochemical behavior and charge storage mechanism of K+-inserted alpha-MnO2 (or KxMnO2) nanorod arrays in broad potential windows are investigated. It is found that electrochemical behavior of KxMnO2 is highly dependent on the potential window. During cyclic voltammetry cycling in a broad potential window, K+ ions can be replaced by Na+ ions, which determines the pseudocapacitance of the electrode. The K+ or Na+ ions cannot be fully extracted when the upper cutoff potential is less than 1 V vs Ag/AgCl, which retards the release of full capacitance. As the cyclic voltammetry potential window is extended to 0-1.2 V, enhanced specific capacitance can be obtained with the emerging of new redox peaks. In contrast, the K+-free alpha-MnO2 nanorod arrays show no redox peaks in the same potential window together with much lower specific capacitance. This work provides new insights on understanding the charge storage mechanism of MnO2 and new strategy to further improve the specific capacitance of MnO2-based electrodes. PMID- 27960433 TI - Engineering the Li Storage Properties of Graphene Anodes: Defect Evolution and Pore Structure Regulation. AB - A general and mild strategy for fabricating defect-enriched graphene mesh (GM) and its application toward the anode of Li-ion batteries (LIBs) has been reported. The GM with a pore size of 60-200 nm is achieved by employing Fe2O3 as the etching reagent that is capable of locally etching the graphene basal plane in a relatively mild manner. Upon different drying technologies, that is, oven drying and freeze-drying, GMs with different porous structure are obtained. The electrochemical Li storage properties of GMs in comparison with graphene aerogels (GAs) disclose that both defect sites and porous structure are crucial for the final anodic performances. We show that only when merged with rich porosity, the GM anode can achieve a better Li storage performance than that of GA. Moreover, we further fabricated nitrogen-doped GM (NGM) using urea as the nitrogen source with a freeze-drying process. Benefiting from the unique structural characteristics, that is, plentiful defects, abundant pores, and nitrogen doping, the NGM anode exhibits high Li storage capacity with good cyclic stability (1078 mAh g-1 even after 350 continuous cycles at a current density of 0.2 C) and outstanding rate capability. Our finding provides fundamental insights into the influence of defects and pore structure on the Li storage properties of graphene, which might be helpful for designing advanced graphene-based anodes for LIBs. PMID- 27960434 TI - Resistance of POSS Polyimide Blends to Hyperthermal Atomic Oxygen Attack. AB - Copolymers of polyhedral oligomeric silsesquioxane (POSS) and polyimide (PI) have shown remarkable resistance to atomic oxygen (AO) attack and have been proposed as replacements for Kapton on the external surfaces of spacecraft in the harsh oxidizing environment of low Earth orbit (LEO). POSS PI blends would be an economical alternative to the copolymers if they also resisted AO attack. Thus, blends of trisilanolphenyl (TSP) POSS and PI with different weight percentages of the Si7O9 POSS cage were cast into films and exposed to a hyperthermal AO beam, and they were characterized in terms of their recession, mass loss, surface morphology, and surface chemistry. In order to compare the AO resistance of the blends with POSS PI copolymers, samples of previously studied copolymers were also investigated in parallel with the blends. For all POSS PI materials, the AO resistance increased with increasing AO fluence and with increasing POSS cage loading. At similar POSS cage loadings and exposure conditions, the TSP POSS PI blends showed comparable erosion yields to the POSS PI copolymers, with specific samples of blends and copolymers achieving erosion yields as low as 0.066 * 10-24 cm3 atom-1 with an AO fluence of 5.93 * 1020 O atoms cm-2. SEM and XPS analyses indicated that passivating SiOx layers were formed on the surfaces of all POSS containing polymers during AO exposure. Thus, a TSP POSS PI blend is proposed as a low-cost variant of a POSS polyimide for use in extreme oxidizing environments, such as LEO. PMID- 27960435 TI - Fabricating Metallic Circuit Patterns on Polymer Substrates through Laser and Selective Metallization. AB - Nowadays, with the rapid development of portable electronics, wearable electronics, LEDs, microelectronics, and bioelectronics, the fabrication of metallic circuits onto polymer substrates with strong adhesion property is an ever-increasing challenge. In this study, the high-resolution and well-defined metallic circuits were successfully prepared on the polymer surface via laser direct structuring (LDS) based on copper hydroxyl phosphate [Cu2(OH)PO4], and the key mechanism of the selective metallization was systematically investigated. XPS confirmed that Cu0 (elemental copper) was formed through photochemical reduction reaction of Cu2(OH)PO4, after 1064 nm NIR pulsed laser irradiation. During the electroless plating, because it is the important active catalytic center, this newly formed Cu0 was the key factor to achieve the successful selective metallization. SEM revealed that after the electroless plating, the copper layer actually physically anchored into the polymer substrate, giving an excellent mechanical adhesion property of the obtained metallic patterns. In addition, the micro-Raman surface imaging approved the generation of the amorphous carbon on the polymer composites' surface after NIR laser irradiation, and the chemical reaction region caused by the pulsed laser spot was found at approximately 40 MUm. This environmentally friendly and effective strategy for fabricating circuit patterns on the polymer surface has a possible application in the printed circuit plate (PCB) industry. PMID- 27960436 TI - Influence of Molecular Aggregation on Electron Transfer at the Perylene Diimide/Indium-Tin Oxide Interface. AB - Chemisorption of an organic monolayer to tune the surface properties of a transparent conductive oxide (TCO) electrode can improve the performance of organic electronic devices that rely on efficient charge transfer between an organic active layer and a TCO contact. Here, a series of perylene diimides (PDIs) was synthesized and used to study relationships between monolayer structure/properties and electron transfer kinetics at PDI-modified indium-tin oxide (ITO) electrodes. In these PDI molecules, one of the imide substituents is a benzene ring bearing a phosphonic acid (PA) and the other is a bulky aryl group that is twisted out of the plane of the PDI core. The size of the bulky aryl group and the substitution of the benzene ring bearing the PA were both varied, which altered the extent of aggregation when these molecules were absorbed as monolayer films (MLs) on ITO, as revealed by both attenuated total reflectance (ATR) and total internal reflection fluorescence spectra. Polarized ATR measurements indicate that, in these MLs, the long axis of the PDI core is tilted at an angle of 33-42 degrees relative to the surface normal; the tilt angle increased as the degree of bulky substitution increased. Rate constants for electron transfer (ks,opt) between these redox-active modifiers and ITO were determined by potential-modulated ATR spectroscopy. As the degree of PDI aggregation was reduced, ks,opt declined, which is attributed to a reduction in the lateral electron self-exchange rate between adsorbed PDI molecules, as well as the heterogeneous conductivity of the ITO electrode surface. Photoelectrochemical measurements using a dissolved aluminum phthalocyanine as an electron donor showed that ITO modified with any of these PDIs is a more effective electron-collecting electrode than bare ITO. PMID- 27960437 TI - Highly Stable Carbon Nanotube/Polyaniline Porous Network for Multifunctional Applications. AB - Three-dimensional carbon nanotube (CNT) networks with high porosity and electrical conductivity have many potential applications in energy and environmental areas, but the network structure is not very stable due to weak inter-CNT interactions. Here, we coat a thin polyaniline (PANI) layer on as synthesized CNT sponge to obtain a mechanically and electrically stable network, and enable multifunctional applications. The resulting CNT/PANI network serves as stable strain sensors, highly compressible supercapacitor electrode with enhanced volume-normalized capacitance (632 F/cm3), and reinforced nanocomposites with the PANI as intermediate layer between the CNT fillers and polymeric matrix. Our results provide a simple and controllable method for achieving high-stability porous networks composed of CNTs, graphene, or other nanostructures. PMID- 27960438 TI - Superhydrophobic and Slippery Lubricant-Infused Flexible Transparent Nanocellulose Films by Photoinduced Thiol-Ene Functionalization. AB - Films comprising nanofibrillated cellulose (NFC) are suitable substrates for flexible devices in analytical, sensor, diagnostic, and display technologies. However, some major challenges in such developments include their high moisture sensitivity and the complexity of current methods available for functionalization and patterning. In this work, we present a facile process for tailoring the surface wettability and functionality of NFC films by a fast and versatile approach. First, the NFC films were coated with a layer of reactive nanoporous silicone nanofilament by polycondensation of trichlorovinylsilane (TCVS). The TCVS afforded reactive vinyl groups, thereby enabling simple UV-induced functionalization of NFC films with various thiol-containing molecules via the photo "click" thiol-ene reaction. Modification with perfluoroalkyl thiols resulted in robust superhydrophobic surfaces, which could then be further transformed into transparent slippery lubricant-infused NFC films that displayed repellency against both aqueous and organic liquids with surface tensions as low as 18 mN.m-1. Finally, transparent and flexible NFC films incorporated hydrophilic micropatterns by modification with OH, NH2, or COOH surface groups, enabling space-resolved superhydrophobic-hydrophilic domains. Flexibility, transparency, patternability, and perfect superhydrophobicity of the produced nanocellulose substrates warrants their application in biosensing, display protection, and biomedical and diagnostics devices. PMID- 27960439 TI - Influence of Polar Organic Solvents in an Ionic Liquid Containing Lithium Bis(fluorosulfonyl)amide: Effect on the Cation-Anion Interaction, Lithium Ion Battery Performance, and Solid Electrolyte Interphase. AB - Ionic liquid-organic solvent mixtures have recently been investigated as potential battery electrolytes. However, contradictory results with these mixtures have been shown for battery performance. In this manuscript, we studied the influence of the addition of polar organic solvents into the ionic liquid electrolyte 1 M lithium bis(fluorosulfonyl)amide (LiFSI)-1-butyl-1 methylpyrrolidinium bis(fluorosulfonyl)amide ([Py1,4]FSI) and tested it for lithium ion battery applications. From infrared and Raman spectroscopy, clear changes in the lithium solvation and cation-anion interactions in the ionic liquid were observed on addition of organic solvents. From the lithiation/delithiation studies on electrodeposited Ge, the storage capacity for the ionic liquid-highly polar organic solvent (acetonitrile) mixture was found to be the highest at low C-rates (0.425 C) compared to using an ionic liquid alone and ionic liquid-less polar solvent (dimethyl carbonate) mixtures. Furthermore, XPS and AFM were used to evaluate the solid electrolyte interphase (SEI) and to correlate its stability with Li storage capacity. PMID- 27960440 TI - Hydrotalcite-like Ni(OH)2 Nanosheets in Situ Grown on Nickel Foam for Overall Water Splitting. AB - Designing economical and high-efficiency electrocatalysts for overall water splitting is urgently needed but remains a long and arduous task. Herein, we synthesized hydrotalcite-like Ni(OH)2 nanosheets growing on Ni foam (Ni(OH)2/NF) via a facile one-pot hydrothermal method. With the assistance of a rotating oven, Ni(OH)2 nanosheets demonstrate a regular hexagonal morphology and homogeneous distribution. The resultant Ni(OH)2/NF electrode shows superior electrocatalytic activity and durability for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER), as well as the overall water splitting. The Ni(OH)2/NF electrode delivers 20 mA.cm-2 at an overpotential of 172 mV for HER, 50 mA.cm-2 at an overpotential of 330 mV for OER, and 10 mA.cm-2 at a cell voltage of 1.68 V for water electrolysis in 1.0 M KOH. The present study demonstrates a feasible and effective strategy to prepare highly efficient electrocatalysts for water electrolysis. PMID- 27960441 TI - A Novel Single-Ion-Conducting Polymer Electrolyte Derived from CO2-Based Multifunctional Polycarbonate. AB - This work demonstrates the facile and efficient synthesis of a novel environmentally friendly CO2-based multifunctional polycarbonate single-ion conducting polymer electrolyte with good electrochemistry performance. The terpolymerizations of CO2, propylene epoxide (PO), and allyl glycidyl ether (AGE) catalyzed by zinc glutarate (ZnGA) were performed to generate poly(propylene carbonate allyl glycidyl ether) (PPCAGE) with various alkene groups contents which can undergo clickable reaction. The obtained terpolymers exhibit an alternating polycarbonate structure confirmed by 1H NMR spectra and an amorphous microstructure with glass transition temperatures (Tg) lower than 11.0 degrees C evidenced by differential scanning calorimetry analysis. The terpolymers were further functionalized with 3-mercaptopropionic acid via efficient thiol-ene click reaction, followed by reacting with lithium hydroxide, to afford single-ion conducting polymer electrolytes with different lithium contents. The all-solid state polymer electrolyte with the 41.0 mol % lithium containing moiety shows a high ionic conductivity of 1.61 * 10-4 S/cm at 80 degrees C and a high lithium ion transference number of 0.86. It also exhibits electrochemical stability up to 4.3 V vs Li+/Li. This work provides an interesting design way to synthesize an all-solid-state electrolyte used for different lithium batteries. PMID- 27960442 TI - Ozone-Based Sequential Infiltration Synthesis of Al2O3 Nanostructures in Symmetric Block Copolymer. AB - Sequential infiltration synthesis (SIS) provides an original strategy to grow inorganic materials by infiltrating gaseous precursors in polymeric films. Combined with microphase-separated nanostructures resulting from block copolymer (BCP) self-assembly, SIS selectively binds the precursors to only one domain, mimicking the morphology of the original BCP template. This methodology represents a smart solution for the fabrication of inorganic nanostructures starting from self-assembled BCP thin films, in view of advanced lithographic application and of functional nanostructure synthesis. The SIS process using trimethylaluminum (TMA) and H2O precursors in self-assembled PS-b-PMMA BCP thin films was established as a model system, where the PMMA phase is selectively infiltrated. However, the temperature range allowed by polymeric material restricts the available precursors to highly reactive reagents, such as TMA. In order to extend the SIS methodology and access a wide library of materials, a crucial step is the implementation of processes using reactive reagents that are fully compatible with the initial polymeric template. This work reports a comprehensive morphological (SEM, SE, AFM) and physicochemical (XPS) investigation of alumina nanostructures synthesized by means of a SIS process using O3 as oxygen precursor in self-assembled PS-b-PMMA thin films with lamellar morphology. The comparison with the H2O-based SIS process validates the possibility to use O3 as oxygen precursor, expanding the possible range of precursors for the fabrication of inorganic nanostructures. PMID- 27960443 TI - Chiral Iridium(III) Complexes in Light-Emitting Electrochemical Cells: Exploring the Impact of Stereochemistry on the Photophysical Properties and Device Performances. AB - Despite hundreds of cationic bis-cyclometalated iridium(III) complexes having been explored as emitters for light-emitting electrochemical cells (LEECs), uniformly their composition has been in the form of a racemic mixture of Lambda and Delta enantiomers. The investigation of LEECs using enantiopure iridium(III) emitters, however, remains unprecedented. Herein, we report the preparation, the crystal structures, and the optoelectronic properties of two families of cyclometalated iridium(III) complexes of the form of [(C^N)2Ir(dtBubpy)]PF6 (where dtBubpy is 4,4'-di-tert-butyl-2,2'-bipyridine) in both their racemic and enantiopure configurations. LEEC devices using Lambda and Delta enantiomers as well as the racemic mixture of both families have been prepared, and the device performances were tested. Importantly, different solid-state photophysical properties exist between enantiopure and racemic emitters, which are also reflected in the device performances. PMID- 27960444 TI - Epitaxial Growth of MgxCa1-xO on GaN by Atomic Layer Deposition. AB - We demonstrate for the first time that a single-crystalline epitaxial MgxCa1-xO film can be deposited on gallium nitride (GaN) by atomic layer deposition (ALD). By adjusting the ratio between the amounts of Mg and Ca in the film, a lattice matched MgxCa1-xO/GaN(0001) interface can be achieved with low interfacial defect density. High-resolution X-ray diffraction (XRD) shows that the lattice parameter of this ternary oxide nearly obeys Vegard's law. An atomically sharp interface from cross-sectional transmission electron microscopy (TEM) confirmed the high quality of the epitaxy. High-temperature capacitance-voltage characterization showed that the film with composition Mg0.25Ca0.75O has the lowest interfacial defect density. With this optimal oxide composition, a Mg0.25Ca0.75O/AlGaN/GaN metal-oxide-semiconductor high-electron-mobility (MOS-HEMT) device was fabricated. An ultrahigh on/off ratio of 1012 and a near ideal SS of 62 mV/dec were achieved with this device. PMID- 27960445 TI - Copper Nanocrystals Encapsulated in Zr-based Metal-Organic Frameworks for Highly Selective CO2 Hydrogenation to Methanol. AB - We show that the activity and selectivity of Cu catalyst can be promoted by a Zr based metal-organic framework (MOF), Zr6O4(OH)4(BDC)6 (BDC = 1,4 benzenedicarboxylate), UiO-66, to have a strong interaction with Zr oxide [Zr6O4(OH)4(-CO2)12] secondary building units (SBUs) of the MOF for CO2 hydrogenation to methanol. These interesting features are achieved by a catalyst composed of 18 nm single Cu nanocrystal (NC) encapsulated within single crystal UiO-66 (Cu?UiO-66). The performance of this catalyst construct exceeds the benchmark Cu/ZnO/Al2O3 catalyst and gives a steady 8-fold enhanced yield and 100% selectivity for methanol. The X-ray photoelectron spectroscopy data obtained on the surface of the catalyst show that Zr 3d binding energy is shifted toward lower oxidation state in the presence of Cu NC, suggesting that there is a strong interaction between Cu NC and Zr oxide SBUs of the MOF to make a highly active Cu catalyst. PMID- 27960446 TI - MoS2 Field-Effect Transistor with Sub-10 nm Channel Length. AB - Atomically thin molybdenum disulfide (MoS2) is an ideal semiconductor material for field-effect transistors (FETs) with sub-10 nm channel lengths. The high effective mass and large bandgap of MoS2 minimize direct source-drain tunneling, while its atomically thin body maximizes the gate modulation efficiency in ultrashort-channel transistors. However, no experimental study to date has approached the sub-10 nm scale due to the multiple challenges related to nanofabrication at this length scale and the high contact resistance traditionally observed in MoS2 transistors. Here, using the semiconducting-to metallic phase transition of MoS2, we demonstrate sub-10 nm channel-length transistor fabrication by directed self-assembly patterning of mono- and trilayer MoS2. This is done in a 7.5 nm half-pitch periodic chain of transistors where semiconducting (2H) MoS2 channel regions are seamlessly connected to metallic phase (1T') MoS2 access and contact regions. The resulting 7.5 nm channel-length MoS2 FET has a low off-current of 10 pA/MUm, an on/off current ratio of >107, and a subthreshold swing of 120 mV/dec. The experimental results presented in this work, combined with device transport modeling, reveal the remarkable potential of 2D MoS2 for future sub-10 nm technology nodes. PMID- 27960447 TI - Anisotropic Pauli Spin Blockade of Holes in a GaAs Double Quantum Dot. AB - Electrically defined semiconductor quantum dots are attractive systems for spin manipulation and quantum information processing. Heavy-holes in both Si and GaAs are promising candidates for all-electrical spin manipulation, owing to the weak hyperfine interaction and strong spin-orbit interaction. However, it has only recently become possible to make stable quantum dots in these systems, mainly due to difficulties in device fabrication and stability. Here, we present electrical transport measurements on holes in a gate-defined double quantum dot in a GaAs/AlxGa1-xAs heterostructure. We observe clear Pauli spin blockade and demonstrate that the lifting of this spin blockade by an external magnetic field is highly anisotropic. Numerical calculations of heavy-hole transport through a double quantum dot in the presence of strong spin-orbit coupling show quantitative agreement with experimental results and suggest that the observed anisotropy can be explained by both the anisotropic effective hole g-factor and the surface Dresselhaus spin-orbit interaction. PMID- 27960448 TI - Exploring Nucleosome Unwrapping Using DNA Origami. AB - We establish a DNA origami based tool for quantifying conformational equilibria of biomolecular assemblies as a function of environmental conditions. As first application, we employed the tool to study the salt-induced disassembly of nucleosome core particles. To extract binding constants and energetic penalties, we integrated nucleosomes in the spectrometer such that unwrapping of the nucleosomal template DNA, leading from bent to more extended states was directly coupled to the conformation of the spectrometer. Nucleosome unwrapping was induced by increasing the ionic strength. The corresponding shifts in conformation equilibrium of the spectrometer were followed by direct conformation imaging using negative staining TEM and by FRET read out after gel electrophoretic separation of conformations. We find nucleosome dissociation constants in the picomolar range at low ionic strength (11 mM MgCl2), in the nanomolar range at intermediate ionic strength (11 mM MgCl2 with 0.5-1 M NaCl) and in the micromolar range at larger ionic strength (11 mM MgCl2 with >=1.5 M NaCl). Integration of up to four nucleosomes stacked side-by-side, as it might occur within chromatin fibers, did not appear to affect the salt-induced unwrapping of nucleosomes. Presumably, such stacking interactions are already effectively screened at the nucleosome unwrapping conditions. Our spectrometer provides a modular platform with a direct read out to study conformational equilibria for targets from small biomolecules up to large macromolecular assemblies. PMID- 27960449 TI - Catalytic Reduction of 4-Nitrophenol: A Quantitative Assessment of the Role of Dissolved Oxygen in Determining the Induction Time. AB - The reduction of 4-nitrophenol to 4-aminophenol by borohydride is one of the foremost model catalytic reactions because it allows for a straightforward assessment of catalysts using the kinetic parameters extracted from the real-time spectroscopic monitoring of an aqueous solution. Crucial to its standing as a model reaction is a comprehensive mechanistic framework able to explain the entire time evolution of the reaction. While much of this framework is in place, there is still much debate over the cause of the induction period, an initial time interval where no reaction seemingly occurs. Here, we report on the simultaneous monitoring of the spectroscopic signal and the dissolved oxygen content within the aqueous solution. It reveals that the induction period is the time interval required for the level of dissolved oxygen to fall below a critical value that is dependent upon whether Au, Ag, or Pd nanoparticles are used as the catalyst. With this understanding, we are able to exert complete control over the induction period, being able to eliminate it, extend it indefinitely, or even induce multiple induction periods over the course of a single reaction. Moreover, we have determined that the reaction product, 4-aminophenol, in the presence of the same catalyst reacts with dissolved oxygen to form 4-nitrophenolate. The implication of these results is that the induction period relates, not to some activation of the catalyst, but to a time interval where the reaction product is being rapidly transformed back into a reactant by a side reaction. PMID- 27960450 TI - Photon Transport in One-Dimensional Incommensurately Epitaxial CsPbX3 Arrays. AB - One-dimensional nanoscale epitaxial arrays serve as a great model in studying fundamental physics and for emerging applications. With an increasing focus laid on the Cs-based inorganic halide perovskite out of its outstanding material stability, we have applied vapor phase epitaxy to grow well aligned horizontal CsPbX3 (X: Cl, Br, or I or their mixed) nanowire arrays in large scale on mica substrate. The as-grown nanowire features a triangular prism morphology with typical length ranging from a few tens of micrometers to a few millimeters. Structural analysis reveals that the wire arrays follow the symmetry of mica substrate through incommensurate epitaxy, paving a way for a universally applicable method to grow a broad family of halide perovskite materials. The unique photon transport in the one-dimensional structure has been studied in the all-inorganic Cs-based perovskite wires via temperature dependent and spatially resolved photoluminescence. Epitaxy of well oriented wire arrays in halide perovskite would be a promising direction for enabling the circuit-level applications of halide perovskite in high-performance electro-optics and optoelectronics. PMID- 27960451 TI - Aluminum Film-Over-Nanosphere Substrates for Deep-UV Surface-Enhanced Resonance Raman Spectroscopy. AB - We report here the first fabrication of aluminum film-over nanosphere (AlFON) substrates for UV surface-enhanced resonance Raman scattering (UVSERRS) at the deepest UV wavelength used to date (lambdaex = 229 nm). We characterize the AlFONs fabricated with two different support microsphere sizes using localized surface plasmon resonance spectroscopy, electron microscopy, SERRS of adenine, tris(bipyridine)ruthenium(II), and trans-1,2-bis(4-pyridyl)-ethylene, SERS of 6 mercapto-1-hexanol (as a nonresonant molecule), and dielectric function analysis. We find that AlFONs fabricated with the 210 nm microspheres generate an enhancement factor of approximately 104-5, which combined with resonance enhancement of the adsorbates provides enhancement factors greater than 106. These experimental results are supported by theoretical analysis of the dielectric function. Hence our results demonstrate the advantages of using AlFON substrates for deep UVSERRS enhancement and contribute to broadening the SERS application range with tunable and affordable substrates. PMID- 27960452 TI - Experimental Demonstration of Demagnifying Hyperlens. AB - The emergence of optical metamaterials opens new opportunities for spatial pattern compression from the micro- to nanoscale. By exploiting strongly anisotropic optical properties of engineered nanostructures, we realize the first experimental demonstration of demagnifying hyperlens enabling optical patterning below the diffraction limit. We show that the diffraction-limited features on a mask can be demagnified to form the subwavelength patterns on the photoresist using visible light. PMID- 27960453 TI - Excitonic Valley Effects in Monolayer WS2 under High Magnetic Fields. AB - Transition-metal dichalcogenides can be easily produced as atomically thin sheets, exhibiting the possibility to optically polarize and read out the valley pseudospin of extremely stable excitonic quasiparticles present in these 2D semiconductors. Here, we investigate a monolayer of tungsten disulfide in high magnetic fields up to 30 T via photoluminescence spectroscopy at low temperatures. The valley degeneracy is lifted for all optical features, particularly for excitons, singlet and triplet trions, for which we determine the g factor separately. While the observation of a diamagnetic shift of the exciton and trion resonances gives us insight into the real-space extension of these quasiparticles, magnetic field-induced valley polarization effects shed light onto the exciton and trion dispersion relations in reciprocal space. The field dependence of the trion valley polarizations is in line with the predicted trion splitting into singlet and triplet configurations. PMID- 27960454 TI - Tandem Core-Shell Si-Ta3N5 Photoanodes for Photoelectrochemical Water Splitting. AB - Nanostructured core-shell Si-Ta3N5 photoanodes were designed and synthesized to overcome charge transport limitations of Ta3N5 for photoelectrochemical water splitting. The core-shell devices were fabricated by atomic layer deposition of amorphous Ta2O5 onto nanostructured Si and subsequent nitridation to crystalline Ta3N5. Nanostructuring with a thin shell of Ta3N5 results in a 10-fold improvement in photocurrent compared to a planar device of the same thickness. In examining thickness dependence of the Ta3N5 shell from 10 to 70 nm, superior photocurrent and absorbed-photon-to-current efficiencies are obtained from the thinner Ta3N5 shells, indicating minority carrier diffusion lengths on the order of tens of nanometers. The fabrication of a heterostructure based on a semiconducting, n-type Si core produced a tandem photoanode with a photocurrent onset shifted to lower potentials by 200 mV. CoTiOx and NiOx water oxidation cocatalysts were deposited onto the Si-Ta3N5 to yield active photoanodes that with NiOx retained 50-60% of their maximum photocurrent after 24 h chronoamperometry experiments and are thus among the most stable Ta3N5 photoanodes reported to date. PMID- 27960455 TI - Plasma-Assisted Synthesis of NiCoP for Efficient Overall Water Splitting. AB - Efficient water splitting requires highly active, earth-abundant, and robust catalysts. Monometallic phosphides such as Ni2P have been shown to be active toward water splitting. Our theoretical analysis has suggested that their performance can be further enhanced by substitution with extrinsic metals, though very little work has been conducted in this area. Here we present for the first time a novel PH3 plasma-assisted approach to convert NiCo hydroxides into ternary NiCoP. The obtained NiCoP nanostructure supported on Ni foam shows superior catalytic activity toward the hydrogen evolution reaction (HER) with a low overpotential of 32 mV at -10 mA cm-2 in alkaline media. Moreover, it is also capable of catalyzing the oxygen evolution reaction (OER) with high efficiency though the real active sites are surface oxides in situ formed during the catalysis. Specifically, a current density of 10 mA cm-2 is achieved at overpotential of 280 mV. These overpotentials are among the best reported values for non-noble metal catalysts. Most importantly, when used as both the cathode and anode for overall water splitting, a current density of 10 mA cm-2 is achieved at a cell voltage as low as 1.58 V, making NiCoP among the most efficient earth-abundant catalysts for water splitting. Moreover, our new synthetic approach can serve as a versatile route to synthesize various bimetallic or even more complex phosphides for various applications. PMID- 27960456 TI - Giant Hall Photoconductivity in Narrow-Gapped Dirac Materials. AB - Carrier dynamics acquire a new character in the presence of Bloch-band Berry curvature, which naturally arises in gapped Dirac materials (GDMs). Here, we argue that photoresponse in GDMs with small band gaps is dramatically enhanced by Berry curvature. This manifests in a giant and saturable Hall photoconductivity when illuminated by circularly polarized light. Unlike Hall motion arising from a Lorentz force in a magnetic field, which impedes longitudinal carrier motion, Hall photoconductivity arising from Berry curvature can boost longitudinal carrier transport. In GDMs, this results in a helicity-dependent photoresponse in the Hall regime, where photoconductivity is dominated by its Hall component. We find that the induced Hall conductivity per incident irradiance is enhanced by up to 6 orders of magnitude when moving from the visible regime (with corresponding band gaps) to the far infrared. These results suggest that narrow-gap GDMs are an ideal test-bed for the unique physics that arise in the presence of Berry curvature and open a new avenue for infrared and terahertz optoelectronics. PMID- 27960457 TI - Parallel Nanoshaping of Brittle Semiconductor Nanowires for Strained Electronics. AB - Semiconductor nanowires (SCNWs) provide a unique tunability of electro-optical property than their bulk counterparts (e.g., polycrystalline thin films) due to size effects. Nanoscale straining of SCNWs is desirable to enable new ways to tune the properties of SCNWs, such as electronic transport, band structure, and quantum properties. However, there are two bottlenecks to prevent the real applications of straining engineering of SCNWs: strainability and scalability. Unlike metallic nanowires which are highly flexible and mechanically robust for parallel shaping, SCNWs are brittle in nature and could easily break at strains slightly higher than their elastic limits. In addition, the ability to generate nanoshaping in large scale is limited with the current technologies, such as the straining of nanowires with sophisticated manipulators, nanocombing NWs with U shaped trenches, or buckling NWs with prestretched elastic substrates, which are incompatible with semiconductor technology. Here we present a top-down fabrication methodology to achieve large scale nanoshaping of SCNWs in parallel with tunable elastic strains. This method utilizes nanosecond pulsed laser to generate shock pressure and conformably deform the SCNWs onto 3D-nanostructured silicon substrates in a scalable and ultrafast manner. A polymer dielectric nanolayer is integrated in the process for cushioning the high strain-rate deformation, suppressing the generation of dislocations or cracks, and providing self-preserving mechanism for elastic strain storage in SCNWs. The elastic strain limits have been studied as functions of laser intensity, dimensions of nanowires, and the geometry of nanomolds. As a result of 3D straining, the inhomogeneous elastic strains in GeNWs result in notable Raman peak shifts and broadening, which bring more tunability of the electrical-optical property in SCNWs than traditional strain engineering. We have achieved the first 3D nanostraining enhanced germanium field-effect transistors from GeNWs. Due to laser shock induced straining effect, a more than 2-fold hole mobility enhancement and a 120% transconductance enhancement are obtained from the fabricated back-gated field effect transistors. The presented nanoshaping of SCNWs provide new ways to manipulate nanomaterials with tunable electrical optical properties and open up many opportunities for nanoelectronics, the nanoelectrical-mechanical system, and quantum devices. PMID- 27960458 TI - Magnetic Tandem Apoptosis for Overcoming Multidrug-Resistant Cancer. AB - Multidrug resistance (MDR) is a leading cause of failure in current chemotherapy treatment and constitutes a formidable challenge in therapeutics. Here, we demonstrate that a nanoscale magnetic tandem apoptosis trigger (m-TAT), which consists of a magnetic nanoparticle and chemodrug (e.g., doxorubicin), can completely remove MDR cancer cells in both in vitro and in vivo systems. m-TAT simultaneously activates extrinsic and intrinsic apoptosis signals in a synergistic fashion and downregulates the drug efflux pump (e.g., P-glycoprotein) which is one of the main causes of MDR. The tandem apoptosis strategy uses low level of chemodrug (in the nanomolar (nM) range) to eliminate MDR cancer cells. We further demonstrate that apoptosis of MDR cancer cells can be achieved in a spatially selective manner with single-cell level precision. Our study indicates that nanoscale tandem activation of convergent signaling pathways is a new platform concept to overcome MDR with high efficacy and specificity. PMID- 27960459 TI - Gigahertz All-Optical Modulation Using Reconfigurable Nanophotonic Metamolecules. AB - We report the design of reconfigurable metamolecules consisting a large array of nanowire featuring U-shaped cross section. These nanoscale metamolecules support colocalized electromagnetic resonance at optical frequencies and mechanical resonance at GHz frequencies with a deep-subdiffraction-limit spatial confinement (~lambda2/100). The coherent coupling of those two distinct resonances manifests a strong optical force, which is fundamentally different from the commonly studied forms of radiation forces, gradient forces, or photothermal induced deformation. The strong optical force acting upon the built-in compliance further sets the stage for allowing the metamolecules to dynamically change their optical properties upon the incident light. The all-optical modulation at the frequency at 1.8 GHz has thus been demonstrated experimentally using a monolayer of metamolecules. The metamolecules were conveniently fabricated using complementary metal-oxide-semiconductor-compatible metal deposition and nanoimprinting processes and thus offer promising potential in developing integrated all-optical modulator. PMID- 27960460 TI - Optical Torques on Upconverting Particles for Intracellular Microrheometry. AB - Precise knowledge and control over the orientation of individual upconverting particles is extremely important for full exploiting their capabilities as multifunctional bioprobes for interdisciplinary applications. In this work, we report on how time-resolved, single particle polarized spectroscopy can be used to determine the orientation dynamics of a single upconverting particle when entering into an optical trap. Experimental results have unequivocally evidenced the existence of a unique stable configuration. Numerical simulations and simple numerical calculations have demonstrated that the dipole magnetic interactions between the upconverting particle and trapping radiation are the main mechanisms responsible of the optical torques that drive the upconverting particle to its stable orientation. Finally, how a proper analysis of the rotation dynamics of a single upconverting particle within an optical trap can provide valuable information about the properties of the medium in which it is suspended is demonstrated. A proof of concept is given in which the laser driven intracellular rotation of upconverting particles is used to successfully determine the intracellular dynamic viscosity by a passive and an active method. PMID- 27960461 TI - Auxetic and Ferroelastic Borophane: A Novel 2D Material with Negative Possion's Ratio and Switchable Dirac Transport Channels. AB - Recently synthesized atomically thin boron sheets (that is, borophene) provide a fascinating template for new material property discovery. Here, we report findings of an extraordinary combination of unusual mechanical and electronic properties in hydrogenated borophene, known as borophane, from first-principles calculations. This novel 2D material has been shown to exhibit robust Dirac transport physics. Our study unveils that borophane is auxetic with a surprising negative Poisson's ratio stemming from its unique puckered triangle hinge structure and the associated hinge dihedral angle variation under a tensile strain in the armchair direction. Our results also identify borophane to be ferroelastic with a stress-driven 90 degrees lattice rotation in the boron layer, accompanied by a remarkable orientation switch of the anisotropic Dirac transport channels. These outstanding strain-engineered properties make borophane a highly versatile and promising 2D material for innovative applications in microelectromechanical and nanoelectronic devices. PMID- 27960462 TI - Twistable and Stretchable Sandwich Structured Fiber for Wearable Sensors and Supercapacitors. AB - Twistable and stretchable fiber-based electrochemical devices having high performance are needed for future applications, including emerging wearable electronics. Weavable fiber redox supercapacitors and strain sensors are here introduced, which comprise a dielectric layer sandwiched between functionalized buckled carbon nanotube electrodes. On the macroscopic scale, the sandwiched core rubber of the fiber acts as a dielectric layer for capacitive strain sensing and as an elastomeric substrate that prevents electrical shorting and irreversible structural changes during severe mechanical deformations. On the microscopic scale, the buckled CNT electrodes effectively absorb tensile or shear stresses, providing an essentially constant electrical conductance. Consequently, the sandwich fibers provide the dual functions of (1) strain sensing, by generating approximately 115.7% and 26% capacitance changes during stretching (200%) and giant twist (1700 rad.m-1 or 270 turns.m-1), respectively, and (2) electrochemical energy storage, providing high linear and areal capacitances (2.38 mF.cm-1 and 11.88 mF.cm-2) and retention of more than 95% of initial energy storage capability under large mechanical deformations. PMID- 27960463 TI - Stabilized Wide Bandgap Perovskite Solar Cells by Tin Substitution. AB - Wide bandgap MAPb(I1-yBry)3 perovskites show promising potential for application in tandem solar cells. However, unstable photovoltaic performance caused by phase segregation has been observed under illumination when y is above 0.2. Herein, we successfully demonstrate stabilization of the I/Br phase by partially replacing Pb2+ with Sn2+ and verify this stabilization with X-ray diffractometry and transient absorption spectroscopy. The resulting MAPb0.75Sn0.25(I1-yBry)3 perovskite solar cells show stable photovoltaic performance under continuous illumination. Among these cells, the one based on MAPb0.75Sn0.25(I0.4Br0.6)3 perovskite shows the highest efficiency of 12.59% with a bandgap of 1.73 eV, which make it a promising wide bandgap candidate for application in tandem solar cells. The engineering of internal bonding environment by partial Sn substitution is believed to be the main reason for making MAPb0.75Sn0.25(I1-yBry)3 perovskite less vulnerable to phase segregation during the photostriction under illumination. Therefore, this study establishes composition engineering of the metal site as a promising strategy to impart phase stability in hybrid perovskites under illumination. PMID- 27960465 TI - A Semimetal Nanowire Rectifier: Balancing Quantum Confinement and Surface Electronegativity. AB - For semimetal nanowires with diameters on the order of 10 nm, a semimetal-to semiconductor transition is observed due to quantum confinement effects. Quantum confinement in a semimetal lifts the degeneracy of the conduction and valence bands in a "zero" gap semimetal or shifts energy levels with a "negative" overlap to form conduction and valence bands. For semimetal nanowires with diameters less than 10 nm, the band gap energy can be significantly larger than the thermal energy at room temperature resulting in a new class of semiconductors suitable for nanoelectronics. As a nanowire's diameter is reduced, its surface-to-volume ratio increases rapidly leading to an increased impact of surface chemistry on its electronic structure. Energy level shifts to states in the vicinity of the Fermi energy with varying surface electronegativity are shown to be comparable in magnitude to quantum confinement effects arising in nanowires with diameters of a few nanometer; these two effects can counteract one another leading to semimetallic behavior at nanowire cross sections at which confinement effects would otherwise dominate. Abruptly changing the surface terminating species along the length of a nanowire can lead to an abrupt change in the surface electronegativity. This can result in the formation of a semimetal-semiconductor junction within a monomaterial nanowire without impurity doping nor requiring the formation of a heterojunction. Using density functional theory in tandem with a Green's function approach to determine electronic structure and charge transport, respectively, current rectification is calculated for such a junction. Current rectification ratios of the order of 103-105 are predicted at applied biases as low as 300 mV. It is concluded that rectification can be achieved at essentially molecular length scales with conventional biasing, while rivaling the performance of macroscopic semiconductor diodes. PMID- 27960464 TI - Correction to Photoelectrochemistry of Pristine Mono- and Few-Layer MoS2. PMID- 27960466 TI - In Situ Electrochemically Derived Nanoporous Oxides from Transition Metal Dichalcogenides for Active Oxygen Evolution Catalysts. AB - Transition metal dichalcogenides have been widely studied as active electrocatalysts for hydrogen evolution reactions. However, their properties as oxygen evolution reaction catalysts have not been fully explored. In this study, we systematically investigate a family of transition metal dichalcogenides (MX, M = Co, Ni, Fe; X = S, Se, Te) as candidates for water oxidation. It reveals that the transition metal dichalcogenides are easily oxidized in strong alkaline media via an in situ electrochemical oxidation process, producing nanoporous transition metal oxides toward much enhanced water oxidation activity due to their increased surface area and more exposed electroactive sites. The optimal cobalt nickel iron oxides that derived from their sulfides and selenides demonstrate a low overpotential of 232 mV at current density of 10 mA cm-2, a small Tafel slope of 35 mV per decade, and negligible degradation of electrochemical activity over 200 h of electrolysis. This study represents the discovery of nanoporous transition metal oxides deriving from their chalcogenides as outstanding electrocatalysts for water oxidation. PMID- 27960467 TI - Flexible Light-Emitting Nanocomposite Based on ZnO Nanotetrapods. AB - Flexible, light-emitting materials have shown promise in a wide range of applications. Here, we develop an inverse soft-lithography process for embedding zinc oxide nanotetrapods (ZnO NTP) uniformly and nondestructively into a host matrix. The crystalline NTPs were synthesized using a catalyst-free, environmentally friendly chemical vapor transport method. The fluorescent emission of the ZnO NTPs was measured before and after the embedding process. Cyclical mechanical bend tests (N > 100) were performed. The emission of the nanomaterial remains throughout. PMID- 27960468 TI - Heteroepitaxial Writing of Silicon-on-Sapphire Nanowires. AB - The heteroepitaxial growth of crystal silicon thin films on sapphire, usually referred to as SoS, has been a key technology for high-speed mixed-signal integrated circuits and processors. Here, we report a novel nanoscale SoS heteroepitaxial growth that resembles the in-plane writing of self-aligned silicon nanowires (SiNWs) on R-plane sapphire. During a low-temperature growth at <350 degrees C, compared to that required for conventional SoS fabrication at >900 degrees C, the bottom heterointerface cultivates crystalline Si pyramid seeds within the catalyst droplet, while the vertical SiNW/catalyst interface subsequently threads the seeds into continuous nanowires, producing self-oriented in-plane SiNWs that follow a set of crystallographic directions of the sapphire substrate. Despite the low-temperature fabrication process, the field effect transistors built on the SoS-SiNWs demonstrate a high on/off ratio of >5 * 104 and a peak hole mobility of >50 cm2/V.s. These results indicate the novel potential of deploying in-plane SoS nanowire channels in places that require high performance nanoelectronics and optoelectronics with a drastically reduced thermal budget and a simplified manufacturing procedure. PMID- 27960469 TI - Correction to Efficient Infrared-to-Visible Upconversion with Subsolar Irradiance. PMID- 27960470 TI - Very High Surface Area Mesoporous Thin Films of SrTiO3 Grown by Pulsed Laser Deposition and Application to Efficient Photoelectrochemical Water Splitting. AB - Very high surface area, self-assembled, highly crystalline mesoporous SrTiO3 (STO) thin films were developed for photoelectrochemical water splitting. Much improved performance of these mesoporous films compared to planar STO thin films and any other form of STO such as single crystal samples and nanostructures was demonstrated. The high performance resulted from very large surface area films and optimization of carrier concentration. PMID- 27960471 TI - Nanoscale Chemical Evolution of Silicon Negative Electrodes Characterized by Low Loss STEM-EELS. AB - Continuous solid electrolyte interface (SEI) formation remains the limiting factor of the lifetime of silicon nanoparticles (SiNPs) based negative electrodes. Methods that could provide clear diagnosis of the electrode degradation are of utmost necessity to streamline further developments. We demonstrate that electron energy-loss spectroscopy (EELS) in a scanning transmission electron microscope (STEM can be used to quickly map SEI components and quantify LixSi alloys from single experiments with resolutions down to 5 nm. Exploiting the low-loss part of the EEL spectrum allowed us to circumvent the degradation phenomena that have so far crippled the application of this technique on such beam-sensitive compounds. Our results provide unprecedented insight into silicon aging mechanisms in full cell configuration. We observe the morphology of the SEI to be extremely heterogeneous at the particle scale but with clear chemical evolutions with extended cycling coming from both SEI accumulation and a transition from lithium-rich carbonate-like compounds to lithium-poor ones. Thanks to the retrieval of several results from a single data set we were able to correlate local discrepancies in lithiation to the initial crystallinity of silicon as well as to the local SEI chemistry and morphology. This study emphasizes how initial heterogeneities in the percolating electronic network and the porosity affect SiNPs aggregates along cycling. These findings pinpoint the crucial role of an optimized formulation in silicon-based thick electrodes. PMID- 27960472 TI - Atomic Resolution Imaging of Halide Perovskites. AB - The radiation-sensitive nature of halide perovskites has hindered structural studies at the atomic scale. We overcome this obstacle by applying low dose-rate in-line holography, which combines aberration-corrected high-resolution transmission electron microscopy with exit-wave reconstruction. This technique successfully yields the genuine atomic structure of ultrathin two-dimensional CsPbBr3 halide perovskites, and a quantitative structure determination was achieved atom column by atom column using the phase information of the reconstructed exit-wave function without causing electron beam-induced sample alterations. An extraordinarily high image quality enables an unambiguous structural analysis of coexisting high-temperature and low-temperature phases of CsPbBr3 in single particles. On a broader level, our approach offers unprecedented opportunities to better understand halide perovskites at the atomic level as well as other radiation-sensitive materials. PMID- 27960473 TI - Coupled, Simultaneous Displacement and Dealloying Reactions into Fe-Ni-Co Nanowires for Thinning Nanowire Segments. AB - A new methodology is reported to shape template-assisted electrodeposition of Fe rich, Fe-Ni-Co nanowires to have a thin nanowire segment using a coupled displacement reaction with a more noble elemental ion, Cu(II), and at the same time dealloying predominantly Fe from Fe-Ni-Co by the reduction of protons (H+), followed by a subsequent etching step. The displacement/dealloyed layer was sandwiched between two trilayers of Fe-Ni-Co to facilitate the characterization of the reaction front, or penetration length. The penetration length region was found to be a function of the ratio of proton and Cu(II) concentration, and a ratio of 0.5 was found to provide the largest penetration rate, and hence the larger thinned length of the nanowire. Altering the etching time affected the diameter of the thinned region. This methodology presents a new way to thin nanowire segments connected to larger nanowire sections and also introduces a way to study the propagation of a reaction front into a nanowire. PMID- 27960474 TI - Highly Controlled Synthesis and Super-Radiant Photoluminescence of Plasmonic Cube in-Cube Nanoparticles. AB - The plasmonic properties of metal nanostructures have been heavily utilized for surface-enhanced Raman scattering (SERS) and metal-enhanced fluorescence (MEF), but the direct photoluminescence (PL) from plasmonic metal nanostructures, especially with plasmonic coupling, has not been widely used as much as SERS and MEF due to the lack of understanding of the PL mechanism, relatively weak signals, and the poor availability of the synthetic methods for the nanostructures with strong PL signals. The direct PL from metal nanostructures is beneficial if these issues can be addressed because it does not exhibit photoblinking or photobleaching, does not require dye-labeling, and can be employed as a highly reliable optical signal that directly depends on nanostructure morphology. Herein, we designed and synthesized plasmonic cube-in cube (CiC) nanoparticles (NPs) with a controllable interior nanogap in a high yield from Au nanocubes (AuNCs). In synthesizing the CiC NPs, we developed a galvanic void formation (GVF) process, composed of replacement/reduction and void formation steps. We unraveled the super-radiant character of the plasmonic coupling-induced plasmon mode which can result in highly enhanced PL intensity and long-lasting PL, and the PL mechanisms of these structures were analyzed and matched with the plasmon hybridization model. Importantly, the PL intensity and quantum yield (QY) of CiC NPs are 31 times and 16 times higher than those of AuNCs, respectively, which have shown the highest PL intensity and QY reported for metallic nanostructures. Finally, we confirmed the long-term photostability of the PL signal, and the signal remained stable for at least 1 h under continuous illumination. PMID- 27960475 TI - Polarization-Resolved Raman Study of Bulk-like and Davydov-Induced Vibrational Modes of Exfoliated Black Phosphorus. AB - Owing to its crystallographic structure, black phosphorus is one of the few 2D materials expressing strongly anisotropic optical, transport, and mechanical properties. We report on the anisotropy of electron-phonon interactions through a polarization-resolved Raman study of the four vibrational modes of atomically thin black phosphorus (2D phosphane): the three bulk-like modes Ag1, B2g, and Ag2 and the Davydov-induced mode labeled Ag(B2u). The complex Raman tensor elements reveal that the relative variation in permittivity of all Ag modes is irrespective of the atomic motion involved lowest along the zigzag direction, the basal anisotropy of these variations is most pronounced for Ag2 and Ag(B2u), and interlayer interactions in multilayer samples lead to reduced anisotropy. The bulk-forbidden Ag(B2u) mode appears for n >= 2 and quickly subsides in thicker layers. It is assigned to a Davydov-induced IR to Raman conversion of the bulk IR mode B2u and exhibits characteristics similar to Ag2. Although this mode is expected to be weak, an electronic resonance significantly enhances its Raman efficiency such that it becomes a dominant mode in the spectrum of bilayer 2D phosphane. PMID- 27960476 TI - Liquid Water- and Heat-Resistant Hybrid Perovskite Photovoltaics via an Inverted ALD Oxide Electron Extraction Layer Design. AB - Despite rapid advances in conversion efficiency (>22%), the environmental stability of perovskite solar cells remains a substantial barrier to commercialization. Here, we show a significant improvement in the stability of inverted perovskite solar cells against liquid water and high operating temperature (100 degrees C) by integrating an ultrathin amorphous oxide electron extraction layer via atomic layer deposition (ALD). These unencapsulated inverted devices exhibit a stable operation over at least 10 h when subjected to high thermal stress (100 degrees C) in ambient environments, as well as upon direct contact with a droplet of water without further encapsulation. PMID- 27960477 TI - Exciton Dipole-Dipole Interaction in a Single Coupled-Quantum-Dot Structure via Polarized Excitation. AB - We find that the exciton dipole-dipole interaction in a single laterally coupled GaAs/AlGaAs quantum dot structure can be controlled by the linear polarization of a nonresonant optical excitation. When the excitation intensity is increased with the linearly polarized light parallel to the lateral coupling direction [110], excitons (X1 and X2) and local biexcitons (X1X1 and X2X2) of the two separate quantum dots (QD1 and QD2) show a redshift along with coupled biexcitons (X1X2), while neither coupled biexcitons nor a redshift are observed when the polarization of the exciting beam is perpendicular to the coupling direction. The polarization dependence and the redshift are attributed to an optical nonlinearity in the exciton Forster resonant energy transfer interaction, whereby exciton population transfer between the two quantum dots also becomes significant with increasing excitation intensity. We have further distinguished coupled biexcitons from local biexcitons by their large diamagnetic coefficient. PMID- 27960478 TI - Photonic Multitasking Interleaved Si Nanoantenna Phased Array. AB - Metasurfaces provide unprecedented control over light propagation by imparting local, space-variant phase changes on an incident electromagnetic wave. They can improve the performance of conventional optical elements and facilitate the creation of optical components with new functionalities and form factors. Here, we build on knowledge from shared aperture phased array antennas and Si-based gradient metasurfaces to realize various multifunctional metasurfaces capable of achieving multiple distinct functions within a single surface region. As a key point, we demonstrate that interleaving multiple optical elements can be accomplished without reducing the aperture of each subelement. Multifunctional optical elements constructed from Si-based gradient metasurface are realized, including axial and lateral multifocus geometric phase metasurface lenses. We further demonstrate multiwavelength color imaging with a high spatial resolution. Finally, optical imaging functionality with simultaneous color separation has been obtained by using multifunctional metasurfaces, which opens up new opportunities for the field of advanced imaging and display. PMID- 27960479 TI - Rational Concept for Reducing Growth Temperature in Vapor-Liquid-Solid Process of Metal Oxide Nanowires. AB - Vapor-liquid-solid (VLS) growth process of single crystalline metal oxide nanowires has proven the excellent ability to tailor the nanostructures. However, the VLS process of metal oxides in general requires relatively high growth temperatures, which essentially limits the application range. Here we propose a rational concept to reduce the growth temperature in VLS growth process of various metal oxide nanowires. Molecular dynamics (MD) simulation theoretically predicts that it is possible to reduce the growth temperature in VLS process of metal oxide nanowires by precisely controlling the vapor flux. This concept is based on the temperature dependent "material flux window" that the appropriate vapor flux for VLS process of nanowire growth decreases with decreasing the growth temperature. Experimentally, we found the applicability of this concept for reducing the growth temperature of VLS processes for various metal oxides including MgO, SnO2, and ZnO. In addition, we show the successful applications of this concept to VLS nanowire growths of metal oxides onto tin-doped indium oxide (ITO) glass and polyimide (PI) substrates, which require relatively low growth temperatures. PMID- 27960480 TI - Ultrafast, Polarized, Single-Photon Emission from m-Plane InGaN Quantum Dots on GaN Nanowires. AB - We demonstrate single-photon emission from self-assembled m-plane InGaN quantum dots (QDs) embedded on the side-walls of GaN nanowires. A combination of electron microscopy, cathodoluminescence, time-resolved microphotoluminescence (MUPL), and photon autocorrelation experiments give a thorough evaluation of the QD structural and optical properties. The QD exhibits antibunched emission up to 100 K, with a measured autocorrelation function of g(2)(0) = 0.28(0.03) at 5 K. Studies on a statistically significant number of QDs show that these m-plane QDs exhibit very fast radiative lifetimes (260 +/- 55 ps) suggesting smaller internal fields than any of the previously reported c-plane and a-plane QDs. Moreover, the observed single photons are almost completely linearly polarized aligned perpendicular to the crystallographic c-axis with a degree of linear polarization of 0.84 +/- 0.12. Such InGaN QDs incorporated in a nanowire system meet many of the requirements for implementation into quantum information systems and could potentially open the door to wholly new device concepts. PMID- 27960481 TI - Using Geometry To Sense Current. AB - We describe a superconducting three-terminal device that uses a simple geometric effect known as current crowding to sense the flow of current and actuate a readout signal. The device consists of a "Y"-shaped current combiner, with two currents (sense and bias) entering separately through the top arms of the "Y", intersecting, and then exiting together through the bottom leg of the "Y". When current is added to or removed from one of the arms (e.g., the sense arm), the superconducting critical current in the other arm (i.e., the bias arm) is modulated. The current in the sense arm can thus be determined by measuring the critical current of the bias arm, or inversely, the sense current can be used to modulate the state of the bias arm. The dependence of the bias critical current on the sense current occurs due to the geometric current crowding effect, which causes the sense current to interact locally with the bias arm. Measurement of the critical current in the bias arm does not break the superconducting state of the sense arm or of the bottom leg, and thus, quantized currents trapped in a superconducting loop were able to be repeatedly measured without changing the state of the loop. Current crowding is a universal effect in nanoscale superconductors, and so this device has potential for applicability across a broad range of superconducting technologies and materials. More generally, any technology in which geometrically induced flow crowding exists in the presence of a strong nonlinearity might make use of this type of device. PMID- 27960482 TI - NaxMV(PO4)3 (M = Mn, Fe, Ni) Structure and Properties for Sodium Extraction. AB - NASICON (Na+ super ionic conductor) structures of NaxMV(PO4)3 (M = Mn, Fe, Ni) were prepared, characterized by aberration-corrected STEM and synchrotron radiation, and demonstrated to be durable cathode materials for rechargeable sodium-ion batteries. In Na4MnV(PO4)3, two redox couples of Mn3+/Mn2+ and V4+/V3+ are accessed with two voltage plateaus located at 3.6 and 3.3 V and a capacity of 101 mAh g-1 at 1 C. Furthermore, the Na4MnV(PO4)3 cathode delivers a high initial efficiency of 97%, long durability over 1000 cycles, and good rate performance to 10 C. The robust framework structure and stable electrochemical performance makes it a reliable cathode materials for sodium-ion batteries. PMID- 27960483 TI - Single Molecule Localization and Discrimination of DNA-Protein Complexes by Controlled Translocation Through Nanocapillaries. AB - Through the use of optical tweezers we performed controlled translocations of DNA protein complexes through nanocapillaries. We used RNA polymerase (RNAP) with two binding sites on a 7.2 kbp DNA fragment and a dCas9 protein tailored to have five binding sites on lambda-DNA (48.5 kbp). Measured localization of binding sites showed a shift from the expected positions on the DNA that we explained using both analytical fitting and a stochastic model. From the measured force versus stage curves we extracted the nonequilibrium work done during the translocation of a DNA-protein complex and used it to obtain an estimate of the effective charge of the complex. In combination with conductivity measurements, we provided a proof of concept for discrimination between different DNA-protein complexes simultaneous to the localization of their binding sites. PMID- 27960484 TI - Measurement of Heavy Ion Irradiation Induced In-Plane Strain in Patterned Face Centered-Cubic Metal Films: An in Situ Study. AB - Nanocrystalline Ag, Cu, and Ni thin films and their coarse grained counterparts are patterned using focused ion beam and then irradiated by Kr ions within an electron microscope at room temperature. Irradiation induced in-plane strain of the films is measured by tracking the location of nanosized holes. The magnitude of the strain in all specimens is linearly dose-dependent and the strain rates of nanocrystalline metals are significantly greater as compared to that of the coarse grained metals. Real-time microscopic observation suggests that substantial grain boundary migration and grain rotation are responsible for the significant in-plane strain. PMID- 27960485 TI - Atomic-Scale Mechanism on Nucleation and Growth of Mo2C Nanoparticles Revealed by in Situ Transmission Electron Microscopy. AB - With a similar electronic structure as that of platinum, molybdenum carbide (Mo2C) holds significant potential as a high performance catalyst across many chemical reactions. Empirically, the precise control of particle size, shape, and surface nature during synthesis largely determines the catalytic performance of nanoparticles, giving rise to the need of clarifying the underlying growth characteristics in the nucleation and growth of Mo2C. However, the high temperature annealing involved during the growth of carbides makes it difficult to directly observe and understand the nucleation and growth processes. Here, we report on the use of advanced in situ transmission electron microscopy with atomic resolution to reveal a three-stage mechanism during the growth of Mo2C nanoparticles over a wide temperature range: initial nucleation via a mechanism consistent with spinodal decomposition, subsequent particle coalescence and monomer attachment, and final surface faceting to well-defined particles with minimum surface energy. These microscopic observations made under a heating atmosphere offer new perspectives toward the design of carbide-based catalysts, as well as the tuning of their catalytic performances. PMID- 27960486 TI - Observation of Optical and Electrical In-Plane Anisotropy in High-Mobility Few Layer ZrTe5. AB - Transition metal pentatelluride ZrTe5 is a versatile material in condensed-matter physics and has been intensively studied since the 1980s. The most fascinating feature of ZrTe5 is that it is a 3D Dirac semimetal which has linear energy dispersion in all three dimensions in momentum space. Structure-wise, ZrTe5 is a layered material held together by weak interlayer van der Waals force. The combination of its unique band structure and 2D atomic structure provides a fertile ground for more potential exotic physical phenomena in ZrTe5 related to 3D Dirac semimentals. However, the physical properties of its few-layer form have yet to be thoroughly explored. Here we report strong optical and electrical in plane anisotropy of mechanically exfoliated few-layer ZrTe5. Raman spectroscopy shows a significant intensity change with sample orientations, and the behavior of angle-resolved phonon modes at the Gamma point is explained by theoretical calculations. DC conductance measurement indicates a 50% of difference along different in-plane directions. The diminishing of resistivity anomaly in few layer samples indicates the evolution of band structure with a reduced thickness. A low-temperature Hall experiment sheds light on more intrinsic anisotropic electrical transport, with a hole mobility of 3000 and 1500 cm2/V.s along the a axis and c-axis, respectively. Pronounced quantum oscillations in magnetoresistance are observed at low temperatures with the highest electron mobility up to 44 000 cm2/V.s. PMID- 27960487 TI - Epitaxial Growth of Multimetallic Pd@PtM (M = Ni, Rh, Ru) Core-Shell Nanoplates Realized by in Situ-Produced CO from Interfacial Catalytic Reactions. AB - Pt-based multimetallic core-shell nanoplates have received great attention as advanced catalysts, but the synthesis is still challenging. Here we report the synthesis of multimetallic Pd@PtM (M = Ni, Rh, Ru) nanoplates including Pd@Pt nanoplates, in which Pt or Pt alloy shells with controlled thickness epitaxially grow on plate-like Pd seeds. The key to achieve high-quality Pt-based multimetallic nanoplates is in situ generation of CO through interfacial catalytic reactions associated with Pd nanoplates and benzyl alcohol. In addition, the accurate control in a trace amount of CO is also of great importance for conformal growth of multimetallic core-shell nanoplates. The Pd@PtNi nanoplates exhibit substantially improved activity and stability for methanol oxidation reaction (MOR) compared to the Pd@Pt nanoplates and commercial Pt catalysts due to the advantages arising from plate-like, core-shell, and alloy structures. PMID- 27960488 TI - Unusually Stable Helical Coil Allotrope of Phosphorus. AB - We have identified an unusually stable helical coil allotrope of phosphorus. Our ab initio density functional theory calculations indicate that the uncoiled, isolated straight one-dimensional chain is equally stable as a monolayer of black phosphorus dubbed phosphorene. The coiling tendency and the attraction between adjacent coil segments add an extra stabilization energy of ~12 meV/atom to the coil allotrope, similar in value to the ~16 meV/atom interlayer attraction in bulk black phosphorus. Thus, the helical coil structure is essentially as stable as black phosphorus, the most stable phosphorus allotrope known to date. With an optimum radius of 2.4 nm, the helical coil of phosphorus may fit well and even form inside wide carbon nanotubes. PMID- 27960489 TI - Orientationally Ordered Silicon Nanocrystal Cuboctahedra in Superlattices. AB - Uniform silicon nanocrystals were synthesized with cuboctahedral shape and passivated with 1-dodecene capping ligands. Transmission electron microscopy, electron diffraction, and grazing incidence wide-angle and small-angle X-ray scattering show that these soft cuboctahedra assemble into face-centered cubic superlattices with orientational order. The preferred nanocrystal orientation was found to depend on the orientation of the superlattices on the substrate, indicating that the interactions with the substrate and assembly kinetics can influence the orientation of faceted nanocrystals in superlattices. PMID- 27960490 TI - Exceptional Resilience of Small-Scale Au30Cu25Zn45 under Cyclic Stress-Induced Phase Transformation. AB - Shape memory alloys that produce and recover from large deformation driven by martensitic transformation are widely exploited in biomedical devices and microactuators. Generally their actuation work degrades significantly within first a few cycles and is reduced at smaller dimensions. Further, alloys exhibiting unprecedented reversibility have relatively small superelastic strain, 0.7%. These raise the questions of whether high reversibility is necessarily accompanied by small work and strain and whether high work and strain is necessarily diminished at small scale. Here we conclusively demonstrate that these are not true by showing that Au30Cu25Zn45 pillars exhibit 12 MJ m-3 work and 3.5% superelastic strain even after 100 000 phase transformation cycles. Our findings confirm that the lattice compatibility dominates the mechanical behavior of phase-changing materials at nano to micron scales and points a way for smart microactuators design having the mutual benefits of high actuation work and long lifetime. PMID- 27960491 TI - Achieving Ultrahigh Carrier Mobility in Two-Dimensional Hole Gas of Black Phosphorus. AB - We demonstrate that a field-effect transistor (FET) made of few-layer black phosphorus (BP) encapsulated in hexagonal boron nitride (h-BN) in vacuum exhibits a room-temperature hole mobility of 5200 cm2/(Vs), being limited just by the phonon scattering. At cryogenic temperatures, the FET mobility increases up to 45 000 cm2/(Vs), which is five times higher compared to the mobility obtained in earlier reports. The unprecedentedly clean h-BN-BP-h-BN heterostructure exhibits Shubnikov-de Haas oscillations and a quantum Hall effect with Landau level (LL) filling factors down to v = 2 in conventional laboratory magnetic fields. Moreover, carrier density independent effective mass of m* = 0.26 m0 is measured, and a Lande g-factor of g = 2.47 is reported. Furthermore, an indication for a distinct hole transport behavior with up- and down-spin orientations is found. PMID- 27960492 TI - Signatures of Phonon and Defect-Assisted Tunneling in Planar Metal-Hexagonal Boron Nitride-Graphene Junctions. AB - Electron tunneling spectroscopy measurements on van der Waals heterostructures consisting of metal and graphene (or graphite) electrodes separated by atomically thin hexagonal boron nitride tunnel barriers are reported. The tunneling conductance, dI/dV, at low voltages is relatively weak, with a strong enhancement reproducibly observed to occur at around |V| ~ 50 mV. While the weak tunneling at low energies is attributed to the absence of substantial overlap, in momentum space, of the metal and graphene Fermi surfaces, the enhancement at higher energies signals the onset of inelastic processes in which phonons in the heterostructure provide the momentum necessary to link the Fermi surfaces. Pronounced peaks in the second derivative of the tunnel current, d2I/dV2, are observed at voltages where known phonon modes in the tunnel junction have a high density of states. In addition, features in the tunneling conductance attributed to single electron charging of nanometer-scale defects in the boron nitride are also observed in these devices. The small electronic density of states of graphene allows the charging spectra of these defect states to be electrostatically tuned, leading to "Coulomb diamonds" in the tunneling conductance. PMID- 27960494 TI - Photoinduced Force Mapping of Plasmonic Nanostructures. AB - The ability to image the optical near-fields of nanoscale structures, map their morphology, and concurrently obtain spectroscopic information, all with high spatiotemporal resolution, is a highly sought-after technique in nanophotonics. As a step toward this goal, we demonstrate the mapping of electromagnetic forces between a nanoscale tip and an optically excited sample consisting of plasmonic nanostructures with an imaging platform based on atomic force microscopy. We present the first detailed joint experimental-theoretical study of this type of photoinduced force microscopy. We show that the enhancement of near-field optical forces in gold disk dimers and nanorods follows the expected plasmonic field enhancements with strong polarization sensitivity. We then introduce a new way to evaluate optically induced tip-sample forces by simulating realistic geometries of the tip and sample. We decompose the calculated forces into in-plane and out of-plane components and compare the calculated and measured force enhancements in the fabricated plasmonic structures. Finally, we show the usefulness of photoinduced force mapping for characterizing the heterogeneity of near-field enhancements in precisely e-beam fabricated nominally alike nanostructures - a capability of widespread interest for precise nanomanufacturing, SERS, and photocatalysis applications. PMID- 27960493 TI - Mechanical Trapping of DNA in a Double-Nanopore System. AB - Nanopores have become ubiquitous components of systems for single-molecule manipulation and detection, in particular DNA sequencing where electric field driven translocation of DNA through a nanopore is used to read out the DNA molecule. Here, we present a double-pore system where two nanopores are drilled in parallel through the same solid-state membrane, which offers new opportunities for DNA manipulation. Our experiments and molecular dynamics simulations show that simultaneous electrophoretic capture of a DNA molecule by the two nanopores mechanically traps the molecule, increasing its residence time within the nanopores by orders of magnitude. Remarkably, by using two unequal-sized nanopores, the pore of DNA entry and exit can be discerned from the ionic current blockades, and the translocation direction can be precisely controlled by small differences in the effective force applied to DNA. The mechanical arrest of DNA translocation using a double-pore system can be straightforwardly integrated into any solid-state nanopore platform, including those using optical or transverse current readouts. PMID- 27960495 TI - Single Particle Nanoplasmonic Sensing in Individual Nanofluidic Channels. AB - Nanoplasmonics allows label-free optical sensing and spectroscopy at the single nanoparticle level by exploiting plasmonic excitations in metal nanoparticles. Nanofluidics offers exclusive possibilities for applying and controlling fluid flow and mass transport at the nanoscale and toward nanosized objects. Here, we combine these two concepts in a single device, by integrating single particle nanoplasmonic sensing with nanofluidics using advanced nanofabrication. The developed devices enable on-chip referenced parallel single particle nanoplasmonic sensing inside multiple individual nanofluidic channels with dimensions down to the 100 nm range. Beyond detailed discussion of the nanofabrication, general device characterization, and parallelized single particle plasmonic readout concepts, we demonstrate device function on two examples: (i) in situ measurements of local buffer concentrations inside a nanofluidic channel; (ii) real time binding kinetics of alkanethiol molecules to a single plasmonic nanonatenna sensor in a single nanochannel. Our concept thus provides a powerful solution for controlling mass transport to and from individual (plasmonic) nanoparticles, which in a long-term perspective offers unique opportunities for label-free detection of analyte molecules at low concentrations and for fundamental studies of fluids in extreme confinement. PMID- 27960496 TI - Hyperdislocations in van der Waals Layered Materials. AB - Dislocations are one-dimensional line defects in three-dimensional crystals or periodic structures. It is common that the dislocation networks made of interactive dislocations be generated during plastic deformation. In van der Waals layered materials, the highly anisotropic nature facilitates the formation of such dislocation networks, which is critical for the friction or exfoliation behavior for these materials. By transmission electron microscopy analysis, we found the topological defects in such dislocation networks can be perfectly rationalized in the framework of traditional dislocation theory, which we applied the name "hyperdislocations". Due to the strong pinning effect of hyperdislocations, the state of exfoliation can be easily triggered by 1 degrees twisting between two layers, which also explains the origin of disregistry and frictionlessness for all of the superlubricants that are widely used for friction reduction and wear protection. PMID- 27960497 TI - Laser Patterning of Optically Reconfigurable Transistor Channels in a Photochromic Diarylethene Layer. AB - Optical switching organic field-effect transistors (OFETs) provide a new direction for optoelectronics based on photochromic molecules. However, the patterning of OFETs is difficult because conventional fabrication processes, including lithography and ion etching, inevitably cause severe damage to organic molecules. Here, we demonstrate laser patterning of one-dimensional (1D) channels on an OFET with a photochromic diarylethene (DAE) layer. The main findings are (i) a number of 1D channels can be repeatedly written and erased in the DAE layer by scanning focused ultraviolet and visible light laser beams alternately between the source and drain electrodes, (ii) the conductivity (or resistivity) of the 1D channel can be controlled by the illumination conditions, such as the laser power density and the scan speed, and (iii) it is possible to draw an analogue adder circuit by optically writing 1D channels so that a portion of the channels overlaps and to perform optical summing operations by local laser illumination of the respective channels. These findings will open new possibilities for realizing various optically reconfigurable, low-dimensional organic transistor circuits, which are not possible with conventional thin film OFETs. PMID- 27960498 TI - Monitoring Electron-Photon Dressing in WSe2. AB - Optical pumping of solids creates a nonequilibrium electronic structure where electrons and photons combine to form quasiparticles of dressed electronic states. The resulting shift of electronic levels is known as the optical Stark effect, visible as a red shift in the optical spectrum. Here we show that in a pump-probe setup we can uniquely define a nonequilibrium quasiparticle bandstructure that can be directly measurable with photoelectron spectroscopy. The dynamical photon-dressing (and undressing) of the many-body electronic states can be monitored by pump-probe time and angular-resolved photoelectron spectroscopy (tr-ARPES) as the photon-dressed bandstructure evolves in time depending on the pump-probe pulse overlap. The computed tr-ARPES spectrum agrees perfectly with the quasi-energy spectrum of Floquet theory at maximum overlap and goes to the equilibrium bandstructure as the pump-probe overlap goes to zero. Additionally, we show how this time-dependent nonequilibrium quasiparticle structure can be understood to be the bandstructure underlying the optical Stark effect. The extension to spin-resolved ARPES can be used to predict asymmetric dichroic response linked to the valley selective optical excitations in monolayer transition metal dichalcogenides (TMDs). These results establish the photon dressed nonequilibrium bandstructures as the underlying quasiparticle structure of light-driven steady-state quantum phases of matter. PMID- 27960499 TI - Observation of Intervalley Biexcitonic Optical Stark Effect in Monolayer WS2. AB - Coherent optical driving can effectively modify the properties of electronic valleys in transition metal dichalcogenides. Here, we observe a new type of optical Stark effect in monolayer WS2, one that is mediated by intervalley biexcitons under the blue-detuned driving with circularly polarized light. We find that such helical optical driving not only induces an exciton energy downshift at the excitation valley but also causes an anomalous energy upshift at the opposite valley, which is normally forbidden by the exciton selection rules but now made accessible through the intervalley biexcitons. These findings reveal the critical, but hitherto neglected, role of biexcitons to couple the two seemingly independent valleys, and to enhance the optical control in valleytronics. PMID- 27960500 TI - The Mechanism of Ni-Assisted GaN Nanowire Growth. AB - Despite the numerous reports on the metal-catalyzed growth of GaN nanowires, the mechanism of growth is not well understood. Our study of the nickel-assisted growth of GaN nanowires using metalorganic chemical vapor deposition provides key insights into this process. From a comprehensive study of over 130 nanowires, we observe that as a function of thickness, the length of the nanowires initially increases and then decreases. We attribute this to an interplay between the Gibbs Thomson effect dominant in very thin nanowires and a diffusion induced growth mode at larger thickness. We also investigate the alloy composition of the Ni-Ga catalyst particle for over 60 nanowires using energy dispersive X-ray spectroscopy, which along with data from electron energy loss spectroscopy and high resolution transmission electron microscopy suggests the composition to be Ni2Ga3. At the nanowire growth temperature, this alloy cannot be a liquid, even taking into account melting point depression in nanoparticles. We hence conclude that Ni-assisted GaN nanowire growth proceeds via a vapor-solid-solid mechanism instead of the conventional vapor-liquid-solid mechanism. PMID- 27960501 TI - Hot Carrier Extraction from Multilayer Graphene. PMID- 27960503 TI - Tuning Nonlinear Mechanical Mode Coupling in GaAs Nanowires Using Cross-Section Morphology Control. AB - We investigate the nonlinear mechanical properties of GaAs nanowires with anisotropic cross-section. Fundamental and second order flexural modes are studied using laser interferometry with good agreement found between experiment and theory describing the nonlinear response under mechanical excitation. In particular, we demonstrate that the sign of the nonlinear coupling between orthogonal modes is dependent on the cross-section aspect ratio. The findings are of interest for applications such as amplitude to frequency conversion and vectorial force sensing. PMID- 27960502 TI - Efficient Colorful Perovskite Solar Cells Using a Top Polymer Electrode Simultaneously as Spectrally Selective Antireflection Coating. AB - Organometal halide perovskites have shown excellent optoelectronic properties and have been used to demonstrate a variety of semiconductor devices. Colorful solar cells are desirable for photovoltaic integration in buildings and other aesthetically appealing applications. However, the realization of colorful perovskite solar cells is challenging because of their broad and large absorption coefficient that commonly leads to cells with dark-brown colors. Herein, for the first time, we report a simple and efficient strategy to achieve colorful perovskite solar cells by using the transparent conducting polymer (poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate), PEDOT:PSS) as a top electrode and simultaneously as an spectrally selective antireflection coating. Vivid colors across the visible spectrum are attained by engineering optical interference effects among the transparent PEDOT:PSS polymer electrode, the hole-transporting layer and the perovskite layer. The colored perovskite solar cells display power conversion efficiency values from 12.8 to 15.1% (from red to blue) when illuminated from the FTO glass side and from 11.6 to 13.8% (from red to blue) when illuminated from the PEDOT:PSS side. The new approach provides an advanced solution for fabricating colorful perovskite solar cells with easy processing and high efficiency. PMID- 27960505 TI - Correction to A Selection for Assembly Reveals That a Single Amino Acid Mutant of the Bacteriophage MS2 Coat Protein Forms a Smaller Virus-like Particle. PMID- 27960504 TI - Lithographically Defined, Room Temperature Low Threshold Subwavelength Red Emitting Hybrid Plasmonic Lasers. AB - Hybrid plasmonic lasers provide deep subwavelength optical confinement, strongly enhanced light-matter interaction and together with nanoscale footprint promise new applications in optical communication, biosensing, and photolithography. The subwavelength hybrid plasmonic lasers reported so far often use bottom-up grown nanowires, nanorods, and nanosquares, making it difficult to integrate these devices into industry-relevant high density plasmonic circuits. Here, we report the first experimental demonstration of AlGaInP based, red-emitting hybrid plasmonic lasers at room temperature using lithography based fabrication processes. Resonant cavities with deep subwavelength 2D and 3D mode confinement of lambda2/56 and lambda3/199, respectively, are demonstrated. A range of cavity geometries (waveguides, rings, squares, and disks) show very low lasing thresholds of 0.6-1.8 mJ/cm2 with wide gain bandwidth (610 nm-685 nm), which are attributed to the heterogeneous geometry of the gain material, the optimized etching technique, and the strong overlap of the gain material with the plasmonic modes. Most importantly, we establish the connection between mode confinements and enhanced absorption and stimulated emission, which plays critical roles in maintaining low lasing thresholds at extremely small hybrid plasmonic cavities. Our results pave the way for the further integration of dense arrays of hybrid plasmonic lasers with optical and electronic technology platforms. PMID- 27960506 TI - Regioselective Atomic Rearrangement of Ag-Pt Octahedral Catalysts by Chemical Vapor-Assisted Treatment. AB - Thermal annealing is a common, and often much-needed, process to optimize the surface structure and composition of bimetallic nanoparticles for high catalytic performance. Such thermal treatment is often carried out either in air or under an inert atmosphere by a trial-and-error approach. Herewith, we present a new chemical vapor-assisted treatment, which can preserve the octahedral morphology of Ag-Pt nanoparticles while modifying the surface into preferred composition arrangements with site-selectivity for high catalytic activity. In situ environmental transmission electron microscope (ETEM) study reveals a relatively homogeneous distribution of Ag and Pt is generated on the surface of Ag-Pt nanoparticles upon exposure to carbon monoxide (CO), whereas Pt atoms preferably segregate to the edge regions when the gas atmosphere is switched to argon. Density functional theory (DFT) calculations suggest stabilization of Pt atoms is energetically favored in the form of mixed surface alloys when CO vapor is present. Without CO, Ag and Pt phase separate under the similar mild treatment condition. There exists a close correlation between the tunable surface structures and the catalytic activities of Ag-Pt octahedral nanoparticles. PMID- 27960507 TI - Dielectric Metasurface as a Platform for Spatial Mode Conversion in Nanoscale Waveguides. AB - We experimentally demonstrate a nanoscale mode converter that performs coupling between the first two transverse electric-like modes of a silicon-on-insulator waveguide. The device operates by introducing a nanoscale periodic perturbation in its effective refractive index along the propagation direction and a graded effective index profile along its transverse direction. The periodic perturbation provides phase matching between the modes, while the graded index profile, which is realized by the implementation of nanoscale dielectric metasurface consisting of silicon features that are etched into the waveguide taking advantage of the effective medium concept, provides the overlap between the modes. Following the device design and numerical analysis using three-dimensional finite difference time domain simulations, we have fabricated the device and characterized it by directly measuring the modal content using optical imaging microscopy. From these measurements, the mode purity is estimated to be 95% and the transmission relative to an unperturbed strip waveguide is as high as 88%. Finally, we extend this approach to accommodate for the coupling between photonic and plasmonic modes. Specifically, we design and numerically demonstrate photonic to plasmonic mode conversion in a hybrid waveguide in which photonic and surface plasmon polariton modes can be guided in the silicon core and in the silicon/metal interface, respectively. The same method can also be used for coupling between symmetric and antisymmetric plasmonic modes in metal-insulator-metal or insulator metal-insulator structures. On the basis of the current demonstration, we believe that such nanoscale dielectric metasurface-based mode converters can now be realized and become an important building block in future nanoscale photonic and plasmonic devices. Furthermore, the demonstrated platform can be used for the implementation of other chip scale components such as splitters, combiners couplers, and more. PMID- 27960508 TI - Ising-Type Magnetic Ordering in Atomically Thin FePS3. AB - Magnetism in two-dimensional materials is not only of fundamental scientific interest but also a promising candidate for numerous applications. However, studies so far, especially the experimental ones, have been mostly limited to the magnetism arising from defects, vacancies, edges, or chemical dopants which are all extrinsic effects. Here, we report on the observation of intrinsic antiferromagnetic ordering in the two-dimensional limit. By monitoring the Raman peaks that arise from zone folding due to antiferromagnetic ordering at the transition temperature, we demonstrate that FePS3 exhibits an Ising-type antiferromagnetic ordering down to the monolayer limit, in good agreement with the Onsager solution for two-dimensional order-disorder transition. The transition temperature remains almost independent of the thickness from bulk to the monolayer limit with TN ~ 118 K, indicating that the weak interlayer interaction has little effect on the antiferromagnetic ordering. PMID- 27960509 TI - Tunable Esaki Effect in Catalyst-Free InAs/GaSb Core-Shell Nanowires. AB - We demonstrate tunable bistability and a strong negative differential resistance in InAs/GaSb core-shell nanowire devices embedding a radial broken-gap heterojunction. Nanostructures have been grown using a catalyst-free synthesis on a Si substrate. Current-voltage characteristics display a top peak-to-valley ratio of 4.8 at 4.2 K and 2.2 at room temperature. The Esaki effect can be modulated-or even completely quenched-by field effect, by controlling the band bending profile along the azimuthal angle of the radial heterostructure. Hysteretic behavior is also observed in the presence of a suitable resistive load. Our results indicate that high-quality broken-gap devices can be obtained using Au-free growth. PMID- 27960510 TI - High-Efficiency Second-Harmonic Generation from Hybrid Light-Matter States. AB - We report a novel approach to modify the second order nonlinear optical (NLO) susceptibility of organic nanofiber crystals by hybridization with the optical modes of microcavities in the strong coupling regime. The wavelength dependence of the SHG efficiency displays two intense peaks corresponding to the so-formed light-matter hybrid states. Our results demonstrate an enhancement of the resonant SHG efficiency of the lower polariton by 2 orders of magnitude for the collectively coupled molecules as compared to that of the same material outside the microcavity. This study is a proof of principle that opens a new direction for NLO of organic materials in subwavelength resonators. PMID- 27960511 TI - Superstrength through Nanotwinning. AB - The theoretical strength of a material is the minimum stress to deform or fracture the perfect single crystal material that has no defects. This theoretical strength is considered as an upper bound on the attainable strength for a real crystal. In contradiction to this expectation, we use quantum mechanics (QM) simulations to show that for the boron carbide (B4C) hard ceramic, this theoretical shear strength can be exceeded by 11% by imposing nanoscale twins. We also predict from QM that the indentation strength of nanotwinned B4C is 12% higher than that of the perfect crystal. Further, we validate this effect experimentally, showing that nanotwinned samples are harder by 2.3% than the twin free counterpart of B4C. The origin of this strengthening mechanism is suppression of twin boundary (TB) slip within the nanotwins due to the directional nature of covalent bonds at the TB. PMID- 27960512 TI - Atomically Thin Graphene Windows That Enable High Contrast Electron Microscopy without a Specimen Vacuum Chamber. AB - Scanning electron microscopes (SEMs) require a high vacuum environment to generate and shape an electron beam for imaging; however, the vacuum conditions greatly limit the nature of specimens that can be examined. From a purely scattering physics perspective, it is not necessary to place the specimen inside the vacuum chamber-the mean free paths (MFPs) for electron scattering in air at typical SEM beam voltages are 50-100 MUm. This is the idea behind the airSEM, which removes the specimen vacuum chamber from the SEM and places the sample in air. The thickness of the gas layer is less than a MFP from an electron transparent window to preserve the shape and resolution of the incident beam, resulting in comparable imaging quality to an all-vacuum SEM. Present silicon nitride windows scatter far more strongly than the air gap and are currently the contrast and resolution limiting factor in the airSEM. Graphene windows have been used previously to wrap or seal samples in vacuum for imaging. Here we demonstrate the use of a robust bilayer graphene window for sealing the electron optics from the room environment, providing an electron transparent window with only a 2% drop in contrast. There is a 5-fold-increase in signal/noise ratio for imaging compared to multi-MFP-thick silicon nitride windows, enabling high contrast in backscattered, transmission, and surface imaging modes for the new airSEM geometry. PMID- 27960513 TI - The Bright Future for Electrode Materials of Energy Devices: Highly Conductive Porous Na-Embedded Carbon. AB - High electrical conductivity and large accessible surface area, which are required for ideal electrode materials of energy conversion and storage devices, are opposed to each other in current materials. It is a long-term goal to solve this issue. Herein, we report highly conductive porous Na-embedded carbon (Na@C) nanowalls with large surface areas, which have been synthesized by an invented reaction of CO with liquid Na. Their electrical conductivities are 2 orders of magnitude larger than highly conductive 3D graphene. Furthermore, almost all their surface areas are accessible for electrolyte ions. These unique properties make them ideal electrode materials for energy devices, which significantly surpass expensive Pt. Consequently, the dye-sensitized solar cells (DSSCs) with the Na@C counter electrode has reached a high power conversion efficiency of 11.03%. The Na@C also exhibited excellent performance for supercapacitors, leading to high capacitance of 145 F g-1 at current density of 1 A g-1. PMID- 27960514 TI - Natural Regulation of Energy Flow in a Green Quantum Photocell. AB - Manipulating the flow of energy in nanoscale and molecular photonic devices is of both fundamental interest and central importance for applications in light energy harvesting optoelectronics. Under erratic solar irradiance conditions, unregulated power fluctuations in a light-harvesting photocell lead to inefficient energy storage in conventional solar cells and potentially fatal oxidative damage in photosynthesis. Here, we compare the theoretical minimum energy fluctuations in nanoscale quantum heat engine photocells that incorporate one or two photon-absorbing channels and show that fluctuations are naturally suppressed in the two-channel photocell. This intrinsic suppression acts as a passive regulation mechanism that enables the efficient conversion of varying incident solar power into a steady output for absorption over a broad range of the solar spectrum on Earth. Remarkably, absorption in the green portion of the spectrum provides no inherent regulatory benefit, indicating that green light should be rejected in a photocell whose primary role is the regulation of energy flow. PMID- 27960516 TI - Metal-Free Carbon-Based Nanomaterial Coatings Protect Silicon Photoanodes in Solar Water-Splitting. AB - The decreasing cost of silicon-based photovoltaics has enabled significant increases in solar electricity generation worldwide. Silicon photoanodes could also play an important role in the cost-effective generation of solar fuels, but the most successful methods of photoelectrode passivation and performance enhancement rely on a combination of precious metals and sophisticated processing methods that offset the economic arguments for silicon. Here we show that metal free carbon-based nanomaterial coatings deposited from solution can protect silicon photoanodes carrying out the oxygen evolution reaction in a range of working environments. Purified semiconducting carbon nanotubes (CNTs) act as a hole extraction layer, and a graphene (Gr) capping layer both protects the CNT film and acts as a hole exchange layer with the electrolyte. The performance of semiconducting CNTs is found to be superior to that of metallic or unsorted CNTs in this context. Furthermore, the insertion of graphene oxide (GO) between the n Si and CNTs reduces the overpotential relative to photoanodes with CNTs deposited on hydrogen-passivated silicon. The composite photoanode structure of n Si/GO/CNT/Gr shows promising performance for oxygen evolution and excellent potential for improvement by optimizing the catalytic properties and stability of the graphene protective layer. PMID- 27960515 TI - Nanodiamond-Gadolinium(III) Aggregates for Tracking Cancer Growth In Vivo at High Field. AB - The ability to track labeled cancer cells in vivo would allow researchers to study their distribution, growth, and metastatic potential within the intact organism. Magnetic resonance (MR) imaging is invaluable for tracking cancer cells in vivo as it benefits from high spatial resolution and the absence of ionizing radiation. However, many MR contrast agents (CAs) required to label cells either do not significantly accumulate in cells or are not biologically compatible for translational studies. We have developed carbon-based nanodiamond-gadolinium(III) aggregates (NDG) for MR imaging that demonstrated remarkable properties for cell tracking in vivo. First, NDG had high relaxivity independent of field strength, a finding unprecedented for gadolinium(III) [Gd(III)]-nanoparticle conjugates. Second, NDG demonstrated a 300-fold increase in the cellular delivery of Gd(III) compared to that of clinical Gd(III) chelates without sacrificing biocompatibility. Further, we were able to monitor the tumor growth of NDG labeled flank tumors by T1- and T2-weighted MR imaging for 26 days in vivo, longer than was reported for other MR CAs or nuclear agents. Finally, by utilizing quantitative maps of relaxation times, we were able to describe tumor morphology and heterogeneity (corroborated by histological analysis), which would not be possible with competing molecular imaging modalities. PMID- 27960517 TI - Probing the Interaction of Quantum Dots with Chiral Capping Molecules Using Circular Dichroism Spectroscopy. AB - Circular dichroism (CD) induced at exciton transitions by chiral ligands attached to single component and core/shell colloidal quantum dots (QDs) was used to study the interactions between QDs and their capping ligands. Analysis of the CD line shapes of CdSe and CdS QDs capped with l-cysteine reveals that all of the features in the complex spectra can be assigned to the different excitonic transitions. It is shown that each transition is accompanied by a derivative line shape in the CD response, indicating that the chiral ligand can split the exciton level into two new sublevels, with opposite angular momentum, even in the absence of an external magnetic field. The role of electrons and holes in this effect could be separated by experiments on various types of core/shell QDs, and it was concluded that the induced CD is likely related to interactions of the highest occupied molecular orbitals of the ligands with the holes. Hence, CD was useful for the analysis of hole level-ligand interactions in quantum semiconductor heterostructures, with promising outlook toward better general understanding the properties of the surface of such systems. PMID- 27960518 TI - Ultraconfined Plasmonic Hotspots Inside Graphene Nanobubbles. AB - We report on a nanoinfrared (IR) imaging study of ultraconfined plasmonic hotspots inside graphene nanobubbles formed in graphene/hexagonal boron nitride (hBN) heterostructures. The volume of these plasmonic hotspots is more than one million-times smaller than what could be achieved by free-space IR photons, and their real-space distributions are controlled by the sizes and shapes of the nanobubbles. Theoretical analysis indicates that the observed plasmonic hotspots are formed due to a significant increase of the local plasmon wavelength in the nanobubble regions. Such an increase is attributed to the high sensitivity of graphene plasmons to its dielectric environment. Our work presents a novel scheme for plasmonic hotspot formation and sheds light on future applications of graphene nanobubbles for plasmon-enhanced IR spectroscopy. PMID- 27960519 TI - Confined Acoustic Phonons in Colloidal Nanorod Heterostructures Investigated by Nonresonant Raman Spectroscopy and Finite Elements Simulations. AB - Lattice vibrational modes in cadmium chalcogenide nanocrystals (NCs) have a strong impact on the carrier dynamics of excitons in such confined systems and on the optical properties of these nanomaterials. A prominent material for light emitting applications are CdSe/CdS core-shell dot-in-rods. Here we present a detailed investigation of the acoustic phonon modes in such dot-in-rods by nonresonant Raman spectroscopy with laser excitation energy lower than their bandgap. With high signal-to-noise ratio in the frequency range from 5-50 cm-1, we reveal distinct Raman bands that can be related to confined extensional and radial-breathing modes (RBM). Comparison of the experimental results with finite elements simulation and analytical analysis gives detailed insight into the localized nature of the acoustic vibration modes and their resonant frequencies. In particular, the RBM of dot-in-rods cannot be understood by an oscillation of a CdSe sphere embedded in a CdS rod matrix. Instead, the dot-in-rod architecture leads to a reduction of the sound velocity in the core region of the rod, which results in a redshift of the rod RBM frequency and localization of the phonon induced strain in vicinity of the core where optical transitions occur. Such localized effects potentially can be exploited as a tool to tune exciton-phonon coupling in nanocrystal heterostructures. PMID- 27960520 TI - A High-Performance Nb Nano-Superconducting Quantum Interference Device with a Three-Dimensional Structure. AB - A superconducting quantum interference device (SQUID) miniaturized into the nanoscale is promising in the inductive detection of a single electron spin. A nano-SQUID with a strong spin coupling coefficient, a low flux noise, and a wide working magnetic field range is highly desired in a single spin resonance measurement. Nano-SQUIDs with Dayem bridge junctions excel in a high working field range and in the direct coupling from spins to the bridge. However, the common planar structure of nano-SQUIDs is known for problems such as a shallow flux modulation depth and a troublesome hysteresis in current-voltage curves. Here, we developed a fabrication process for creating three-dimensional (3-D) niobium (Nb) nano-SQUIDs with nanobridge junctions that can be tuned independently. Characterization of the device shows up to 45.9% modulation depth with a reversible current-voltage curve. Owning to the large modulation depth, the measured flux noise is as low as 0.34 MUPhi0/Hz1/2. The working field range of the SQUID is greater than 0.5 T parallel to the SQUID plane. We believe that 3 D Nb nano-SQUIDs provide a promising step toward effective single-spin inductive detection. PMID- 27960521 TI - Selective-Area MOCVD Growth and Carrier-Transport-Type Control of InAs(Sb)/GaSb Core-Shell Nanowires. AB - We report the first selective-area growth of high quality InAs(Sb)/GaSb core shell nanowires on Si substrates using metal-organic chemical vapor deposition (MOCVD) without foreign catalysts. Transmission electron microscopy (TEM) analysis reveals that the overgrowth of the GaSb shell is highly uniform and coherent with the InAs(Sb) core without any misfit dislocations. To control the structural properties and reduce the planar defect density in the self-catalyzed InAs core nanowires, a trace amount of Sb was introduced during their growth. As the Sb content increases from 0 to 9.4%, the crystal structure of the nanowires changes from a mixed wurtzite (WZ)/zinc-blende (ZB) structure to a perfect ZB phase. Electrical measurements reveal that both the n-type InAsSb core and p-type GaSb shell can work as active carrier transport channels, and the transport type of core-shell nanowires can be tuned by the GaSb shell thickness and back-gate voltage. This study furthers our understanding of the Sb-induced crystal-phase control of nanowires. Furthermore, the high quality InAs(Sb)/GaSb core-shell nanowire arrays obtained here pave the foundation for the fabrication of the vertical nanowire-based devices on a large scale and for the study of fundamental quantum physics. PMID- 27960522 TI - Photoswitchable Rabi Splitting in Hybrid Plasmon-Waveguide Modes. AB - Rabi splitting that arises from strong plasmon-molecule coupling has attracted tremendous interests. However, it has remained elusive to integrate Rabi splitting into the hybrid plasmon-waveguide modes (HPWMs), which have advantages of both subwavelength light confinement of surface plasmons and long-range propagation of guided modes in dielectric waveguides. Herein, we explore a new type of HPWMs based on hybrid systems of Al nanodisk arrays covered by PMMA thin films that are doped with photochromic molecules and demonstrate the photoswitchable Rabi splitting with a maximum splitting energy of 572 meV in the HPWMs by controlling the photoisomerization of the molecules. Through our experimental measurements combined with finite-difference time-domain (FDTD) simulations, we reveal that the photoswitchable Rabi splitting arises from the switchable coupling between the HPWMs and molecular excitons. By harnessing the photoswitchable Rabi splitting, we develop all-optical light modulators and rewritable waveguides. The demonstration of Rabi splitting in the HPWMs will further advance scientific research and device applications of hybrid plasmon molecule systems. PMID- 27960524 TI - Strong Rashba-Edelstein Effect-Induced Spin-Orbit Torques in Monolayer Transition Metal Dichalcogenide/Ferromagnet Bilayers. AB - The electronic and optoelectronic properties of two-dimensional materials have been extensively explored in graphene and layered transition metal dichalcogenides (TMDs). Spintronics in these two-dimensional materials could provide novel opportunities for future electronics, for example, efficient generation of spin current, which should enable the efficient manipulation of magnetic elements. So far, the quantitative determination of charge current induced spin current and spin-orbit torques (SOTs) on the magnetic layer adjacent to two-dimensional materials is still lacking. Here, we report a large SOT generated by current-induced spin accumulation through the Rashba-Edelstein effect in the composites of monolayer TMD (MoS2 or WSe2)/CoFeB bilayer. The effective spin conductivity corresponding to the SOT turns out to be almost temperature-independent. Our results suggest that the charge-spin conversion in the chemical vapor deposition-grown large-scale monolayer TMDs could potentially lead to high energy efficiency for magnetization reversal and convenient device integration for future spintronics based on two-dimensional materials. PMID- 27960523 TI - The Effect of Cage Shape on Nanoparticle-Based Drug Carriers: Anticancer Drug Release and Efficacy via Receptor Blockade Using Dextran-Coated Iron Oxide Nanocages. AB - Although a range of nanoparticles have been developed as drug delivery systems in cancer therapeutics, this approach faces several important challenges concerning nanocarrier circulation, clearance, and penetration. The impact of reducing nanoparticle size on penetration through leaky blood vessels around tumor microenvironments via enhanced permeability and retention (EPR) effect has been extensively examined. Recent research has also investigated the effect of nanoparticle shape on circulation and target binding affinity. However, how nanoparticle shape affects drug release and therapeutic efficacy has not been previously explored. Here, we compared the drug release and efficacy of iron oxide nanoparticles possessing either a cage shape (IO-NCage) or a solid spherical shape (IO-NSP). Riluzole cytotoxicity against metastatic cancer cells was enhanced 3-fold with IO-NCage. The shape of nanoparticles (or nanocages) affected the drug release point and cellular internalization, which in turn influenced drug efficacy. Our study provides evidence that the shape of iron oxide nanoparticles has a significant impact on drug release and efficacy. PMID- 27960525 TI - Imaging the Long Transport Lengths of Photo-generated Carriers in Oriented Perovskite Films. AB - Organometal halide perovskite has emerged as a promising material for solar cells and optoelectronics. Although the long diffusion length of photogenerated carriers is believed to be a critical factor responsible for the material's high efficiency in solar cells, a direct study of carrier transport over long distances in organometal halide perovskites is still lacking. We fabricated highly oriented crystalline CH3NH3PbI3 (MAPbI3) thin-film lateral transport devices with long channel length (~120 MUm). By performing spatially scanned photocurrent imaging measurements with local illumination, we directly show that the perovskite films prepared here have very long transport lengths for photogenerated carriers, with a minority carrier (electron) diffusion length on the order of 10 MUm. Our approach of applying scanning photocurrent microscopy to organometal halide perovskites may be further used to elucidate the carrier transport processes and the vastly different carrier diffusion lengths (~100 nm to 100 MUm) in different types of organometal halide perovskites. PMID- 27960526 TI - New Ferroelectric Phase in Atomic-Thick Phosphorene Nanoribbons: Existence of in Plane Electric Polarization. AB - Ferroelectrics have many significant applications in electric devices, such as capacitor or random-access memory, tuning the efficiency of solar cell. Although atomic-thick ferroelectrics are the necessary components for high-density electric devices or nanoscale devices, the development of such materials still faces a big challenge because of the limitation of intrinsic mechanism. Here, we reported that in-plane atomic-thick ferroelectricity can be induced by vertical electric field in phosphorene nanoribbons (PNRs). Through symmetry arguments, we predicted that ferroelectric direction is perpendicular to the direction of external electric field and lies in the plane. Further confirmed by the comprehensive first-principles calculations, we showed that such ferroelectricity is induced by the electron-polarization, which is different from the structural distortion in traditional ferroelectrics and the recent experimental discovery of in-plane atomic-thick ferroelectrics (Science 2016, 353, 274). Moreover, we found that the value of electronic polarization in bilayer is much larger than that in monolayer. Our results show that electron-polarization ferroelectricity maybe the most promising candidate for atomic-thick ferroelectrics. PMID- 27960528 TI - Photocurrent Mapping in Single-Crystal Methylammonium Lead Iodide Perovskite Nanostructures. AB - We investigate solution-grown single-crystal methylammonium lead iodide (MAPbI3) nanowires and nanoplates with spatially resolved photocurrent mapping. Sensitive perovskite photodetectors with Schottky contacts are fabricated by directly transferring the nanostructures on top of prepatterned gold electrodes. Scanning photocurrent microscopy (SPCM) measurements on these single-crystal nanostructures reveal a minority charge carrier diffusion length up to 21 MUm, which is significantly longer than the values observed in polycrystalline MAPbI3 thin films. When the excitation energy is close to the bandgap, the photocurrent becomes substantially stronger at the edges of nanostructures, which can be understood by the enhancement of light coupling to the nanostructures. These perovskite nanostructures with long carrier diffusion lengths and strong photonic enhancement not only provide an excellent platform for studying their intrinsic properties but may also boost the performance of perovskite-based optoelectronic devices. PMID- 27960530 TI - Nondestructive Profilometry of Optical Nanofibers. AB - Single-mode optical nanofibers are a central component of a broad range of applications and emerging technologies. Their fabrication has been extensively studied over the past decade, but imaging of the final submicrometer products has been restricted to destructive or low-precision techniques. Here, we demonstrate an optical scattering-based scanning method that uses a probe nanofiber to locally scatter the evanescent field of a sample nanofibre. The method does not damage the sample nanofiber and is easily implemented by only using the same equipment as in a standard fiber-puller setup. We demonstrate the subnanometer radial resolution at video rates (0.7 nm in 10 ms) on single mode nanofibers, allowing for a complete high-precision profile to be obtained within minutes of fabrication. The method thus enables nondestructive, fast, and precise characterization of optical nanofibers, with applications ranging from optical sensors and cold atom traps to nonlinear optics. PMID- 27960527 TI - Split-Wedge Antennas with Sub-5 nm Gaps for Plasmonic Nanofocusing. AB - We present a novel plasmonic antenna structure, a split-wedge antenna, created by splitting an ultrasharp metallic wedge with a nanogap perpendicular to its apex. The nanogap can tightly confine gap plasmons and boost the local optical field intensity in and around these opposing metallic wedge tips. This three dimensional split-wedge antenna integrates the key features of nanogaps and sharp tips, i.e., tight field confinement and three-dimensional nanofocusing, respectively, into a single platform. We fabricate split-wedge antennas with gaps that are as small as 1 nm in width at the wafer scale by combining silicon V grooves with template stripping and atomic layer lithography. Computer simulations show that the field enhancement and confinement are stronger at the tip-gap interface compared to what standalone tips or nanogaps produce, with electric field amplitude enhancement factors exceeding 50 when near-infrared light is focused on the tip-gap geometry. The resulting nanometric hotspot volume is on the order of lambda3/106. Experimentally, Raman enhancement factors exceeding 107 are observed from a 2 nm gap split-wedge antenna, demonstrating its potential for sensing and spectroscopy applications. PMID- 27960529 TI - Strong Absorption Enhancement in Si Nanorods. AB - We report two orders of magnitude stronger absorption in silicon nanorods relative to bulk in a wide energy range. The local field enhancement and dipole matrix element contributions were disentangled experimentally by single-dot absorption measurements on differently shaped particles as a function of excitation polarization and photon energy. Both factors substantially contribute to the observed effect as supported by simulations of the light-matter interaction and atomistic calculations of the transition matrix elements. The results indicate strong shape dependence of the quasidirect transitions in silicon nanocrystals, suggesting nanostructure shape engineering as an efficient tool for overcoming limitations of indirect band gap materials in optoelectronic applications, such as solar cells. PMID- 27960531 TI - Anderson Localization of Thermal Phonons Leads to a Thermal Conductivity Maximum. AB - Our elastic model of ErAs disordered GaAs/AlAs superlattices exhibits a local thermal conductivity maximum as a function of length due to exponentially suppressed Anderson-localized phonons. By analyzing the sample-to-sample fluctuations in the dimensionless conductance, g, the transition from diffusive to localized transport is identified as the crossover from the multichannel to single-channel transport regime g ~ 1. Single parameter scaling is shown to hold in this crossover regime through the universality of the probability distribution of g that is independent of system size and disorder strength. PMID- 27960532 TI - Pseudodirect to Direct Compositional Crossover in Wurtzite GaP/InxGa1-xP Core Shell Nanowires. AB - Thanks to their uniqueness, nanowires allow the realization of novel semiconductor crystal structures with yet unexplored properties, which can be key to overcome current technological limits. Here we develop the growth of wurtzite GaP/InxGa1-xP core-shell nanowires with tunable indium concentration and optical emission in the visible region from 590 nm (2.1 eV) to 760 nm (1.6 eV). We demonstrate a pseudodirect (Gamma8c-Gamma9v) to direct (Gamma7c-Gamma9v) transition crossover through experimental and theoretical approach. Time resolved and temperature dependent photoluminescence measurements were used, which led to the observation of a steep change in carrier lifetime and temperature dependence by respectively one and 3 orders of magnitude in the range 0.28 +/- 0.04 <= x <= 0.41 +/- 0.04. Our work reveals the electronic properties of wurtzite InxGa1-xP. PMID- 27960533 TI - A cross-validation Delphi method approach to the diagnosis and treatment of personality disorders in older adults. AB - INTRODUCTION: The Delphi method is a consensus-building technique using expert opinion to formulate a shared framework for understanding a topic with limited empirical support. This cross-validation study replicates one completed in the Netherlands and Belgium, and explores US experts' views on the diagnosis and treatment of older adults with personality disorders (PD). METHODS: Twenty-one geriatric PD experts participated in a Delphi survey addressing diagnosis and treatment of older adults with PD. The European survey was translated and administered electronically. RESULTS: First-round consensus was reached for 16 out of 18 items relevant to diagnosis and specific mental health programs for personality disorders in older adults. Experts agreed on the usefulness of establishing criteria for specific types of treatments. The majority of psychologists did not initially agree on the usefulness of pharmacotherapy. Expert consensus was reached following two subsequent rounds after clarification addressing medication use. CONCLUSIONS: Study results suggest consensus among regarding psychosocial treatments. Limited acceptance amongst US psychologists about the suitability of pharmacotherapy for late-life PDs contrasted with the views expressed by experts surveyed in Netherlands and Belgium studies. PMID- 27960534 TI - PTSD symptoms among tsunami exposed mothers in Sri Lanka: the role of disaster exposure, culturally specific coping strategies, and recovery efforts. AB - BACKGROUND AND OBJECTIVES: Women in Sri Lanka have been uniquely exposed to a complex and protracted set of stressors stemming from a civil war conflict spanning over 25 years and the tsunami which struck Southeast Asia in 2004. This study investigates coping strategies and their association with trauma-related symptoms of tsunami-exposed mothers in Sri Lanka at two time points. DESIGN: Data for this study come from surveys administered in two waves of data collection to investigate both mothers' and adolescent children's post-tsunami mental health in early 2005, three months after the tsunami struck, and again in 2008, three years later. METHODS: Latent-variable structural equation modeling was used to test the study hypotheses among 160 tsunami-affected mothers in the Polhena village, Matara district, Sri Lanka. RESULTS: Among the various coping strategies examined, the use of cultural rituals as well as inner psychological strength was associated with lower levels of posttraumatic stress symptoms. In contrast, passive religious beliefs were associated with greater posttraumatic stress levels. CONCLUSIONS: The results of this study reveal the differential associations of various coping strategies including rituals used by mothers exposed to the tsunami in Sri Lanka and their posttraumatic stress symptom levels. PMID- 27960535 TI - En Bloc Transurethral Resection of Bladder Tumors: A New Standard? AB - OBJECTIVE: To assess safety and efficacy, namely pathological assessment of the specimen and recurrence rate, of en bloc transurethral resection (EBTUR) of bladder tumor. MATERIALS AND METHODS: We performed a systematic review of the available literature on PubMed. Seventeen articles, mainly prospective case series, were found. EBTUR is performed with a great variety of equipments, whereas the resection technique is similar. RESULTS: Overall, 895 patients have been submitted to EBTUR, accounting for 1191 lesions. Forty complications (4%) were computed. Only 10 (1%) were grade III, mostly bladder perforation or bleeding. Fifty-nine conversions (6.5%) to conventional transurethral resection (TUR) have been reported because of difficult locations of tumors or failure to extract the specimen. Several series, accounting for 763 patients, report about incidence of detrusor muscle in the specimen. Overall, 731 (96%) cases with detrusor muscle were computed. Tumor stage remained uncertain only in 12 (1.5%) cases. Follow-up data were available for 544 patients. Mean follow-up ranged from 9.3 to 40 months. Recurrence rate varied from 6% to 55%. Most of the recurrence occurred outside primary tumor site. Mean weighted follow-up across all series was 20 months, whereas overall recurrence rate was 23%. CONCLUSIONS: Irrespective of the technique adopted, EBTUR is a safe procedure. The presence of detrusor muscle in the specimen is high if compared with historical series of conventional TUR. Indeed, recurrence rate is comparable. The objective advantage of a proper histological assessment suggests to perform EBTUR instead of conventional TUR, when feasible. PMID- 27960537 TI - Has Sliding-Clip Renorrhaphy Eliminated the Need for Collecting System Repair During Robot-Assisted Partial Nephrectomy? AB - OBJECTIVE: We evaluated whether single-layer renorrhaphy (SLR) without collecting system (CS) closure is sufficient following robot-assisted partial nephrectomy (RAPN). PATIENTS AND METHODS: One hundred fifty consecutive patients underwent RAPN by a single surgeon and were prospectively labeled with regard to CS entry during surgery. Patients with CS entry were subdivided into two groups: those with classical renorrhaphy (CR) (i.e., two-layer repair) and those with SLR (i.e., without CS repair). Perioperative variables and outcomes were compared between CR and SLR groups. RESULTS: Ninety patients had CS entry during RAPN. Of these 90 patients, 64 had CR, and 26 had SLR, with mean ages of 62 and 59 years (p = 0.22), tumor sizes of 3.4 and 3.3 cm (p = 0.61), Mayo Adhesive Probability scores of 1.8 and 1.8 (p = 0.95), and radius, exophytic/endophytic, nearness to CS, and laterality scores of 8.5 and 8.0 (p = 0.16), respectively. Mean warm ischemia times (WITs) were 19.6 and 17.3 minutes (p = 0.04), hospital stays of 3.0 and 2.8 days (p = 0.62), and drain times of 2.9 and 2.7 days (p = 0.65), for the CR and SLR groups, respectively. Using the Clavien-Dindo classification, there were a total of six grade III or higher complications, with no difference between the CR and SLR subgroups (p = 1.0). Renal function using creatinine or glomerular filtration rate as surrogates showed no difference between groups preoperatively or up until 2 years postoperatively. CONCLUSIONS: Omitting CS repair during RAPN with SLR decreases WIT without altering complications, hospital stay, or drain time. Long-term renal function was not associated with CS repair. PMID- 27960536 TI - Oxidative Stress-Induced miR-200c Disrupts the Regulatory Loop Among SIRT1, FOXO1, and eNOS. AB - AIMS: Reactive oxygen species (ROS) play a pivotal role in different pathologic conditions, including ischemia, diabetes, and aging. We previously showed that ROS enhance miR-200c expression, causing endothelial cell (EC) apoptosis and senescence. Herein, we dissect the interaction among miR-200c and three strictly related proteins that modulate EC function and ROS production: sirtuin 1 (SIRT1), endothelial nitric oxide synthase (eNOS), and forkhead box O1 (FOXO1). Moreover, the role of miR-200c on ROS modulation was also investigated. RESULTS: We demonstrated that miR-200c directly targets SIRT1, eNOS, and FOXO1; via this mechanism, miR-200c decreased NO and increased the acetylation of SIRT1 targets, that is, FOXO1 and p53. FOXO1 acetylation inhibited its transcriptional activity on target genes, that is, SIRT1 and the ROS scavengers, catalase and manganese superoxide dismutase. In keeping, miR-200c increased ROS production and induced p66Shc protein phosphorylation in Ser-36; this mechanism upregulated ROS and inhibited FOXO1 transcription, reinforcing this molecular circuitry. These in vitro results were validated in three in vivo models of oxidative stress, that is, human skin fibroblasts from old donors, femoral arteries from old mice, and a murine model of hindlimb ischemia. In all cases, miR-200c was higher versus control and its targets, that is, SIRT1, eNOS, and FOXO1, were downmodulated. In the mouse hindlimb ischemia model, anti-miR-200c treatment rescued these targets and improved limb perfusion. Innovation and Conclusion: miR-200c disrupts SIRT1/FOXO1/eNOS regulatory loop. This event promotes ROS production and decreases NO, contributing to endothelial dysfunction under conditions of increased oxidative stress such as aging and ischemia. Antioxid. Redox Signal. 27, 328-344. PMID- 27960538 TI - Examining the relation between adolescent social anxiety, adolescent delinquency (abstention), and emerging adulthood relationship quality. AB - BACKGROUND AND OBJECTIVES: Social anxiety symptoms and delinquency are two prevalent manifestations of problem behavior during adolescence and both are related to negative interpersonal relationships in adolescence and emerging adulthood. This study examined the relation between social anxiety and delinquency in adolescence and the interplay between adolescent social anxiety and delinquency on perceived relationship quality in emerging adulthood. DESIGN AND METHODS: In a 10-year long prospective study (T1, n = 923; T2, n = 727; Mage T1 = 12; 49% female), we examined competing hypotheses using regression analyses: the protective perspective, which suggests social anxiety protects against delinquency; and the co-occurring perspective, which suggests social anxiety and delinquency co-occur leading to increased negative interpersonal outcomes. RESULTS: In adolescence, the relation between social anxiety and delinquency was consistent with the protective perspective. In emerging adulthood, consistent with the co-occurring perspective, ever-delinquents (but not delinquency abstainers) with higher social anxiety reported less perceived best friend, mother, and father support compared to delinquents with lower social anxiety. There was no interaction between anxiety and delinquency in predicting perceived conflict. CONCLUSION: This study highlights the importance of examining the relation between social anxiety and delinquency with regards to different interpersonal outcomes. PMID- 27960539 TI - C-X-C Chemokine Receptor Type 4 Plays a Crucial Role in Mediating Oxidative Stress-Induced Podocyte Injury. AB - AIMS: Oxidative stress plays a role in mediating podocyte injury and proteinuria. However, the underlying mechanism remains poorly understood. In this study, we investigated the potential role of C-X-C chemokine receptor type 4 (CXCR4), the receptor for stromal cell-derived factor 1alpha (SDF-1alpha), in mediating oxidative stress-induced podocyte injury. RESULTS: In mouse model of adriamycin nephropathy (ADR), CXCR4 expression was significantly induced in podocytes as early as 3 days. This was accompanied by an increased upregulation of oxidative stress in podocyte, as demonstrated by malondialdehyde assay, nitrotyrosine staining and secretion of 8-hydroxy-2'-deoxyguanosine in urine, and induction of NOX2 and NOX4, major subunits of NADPH oxidase. CXCR4 was also induced in human kidney biopsies with proteinuric kidney diseases and colocalized with advanced oxidation protein products (AOPPs), an established oxidative stress trigger. Using cultured podocytes and mouse model, we found that AOPPs induced significant loss of podocyte marker Wilms tumor 1 (WT1), nephrin, and podocalyxin, accompanied by upregulation of desmin both in vitro and in vivo. Furthermore, AOPPs worsened proteinuria and aggravated glomerulosclerosis in ADR. These effects were associated with marked activation of SDF-1alpha/CXCR4 axis in podocytes. Administration of AMD3100, a specific inhibitor of CXCR4, reduced proteinuria and ameliorated podocyte dysfunction and renal fibrosis triggered by AOPPs in mice. In glomerular miniorgan culture, AOPPs also induced CXCR4 expression and downregulated nephrin and WT1. Innovation and Conclusion: These results suggest that chemokine receptor CXCR4 plays a crucial role in mediating oxidative stress-induced podocyte injury, proteinuria, and renal fibrosis. CXCR4 could be a new target for mitigating podocyte injury, proteinuria, and glomerular sclerosis in proteinuric chronic kidney disease. Antioxid. Redox Signal. 27, 345 362. PMID- 27960540 TI - Pediatric Percutaneous Nephrolithotomy-Experience of a Tertiary Care Center. AB - OBJECTIVE: To present the experience of pediatric percutaneous nephrolithotomy (PCNL) of our center. MATERIALS AND METHODS: This study was conducted from 1995 to 2015, on patients <15 years of age having renal and upper ureteral stones who underwent PCNL. Stones were classified as per Guy's stone score (GSS). Standard bull's eye technique was used for subcostal puncture. To avoid supracostal puncture, puncture was done in full inspiration or by oblique tract. If these maneuvers failed, then supracostal puncture was done. Tract was dilated to 24F. RESULTS: Six hundred sixty PCNLs were performed on 639 patients. Puncture was subcostal in 87.6% cases with tract dilated as much as 24F. Pelvicaliceal system was most commonly accessed through middle calix (73.94%). Upper caliceal puncture (23.78%) was more frequently used in complete (82.35%) and partial staghorn (51%) stones. Two tracts were made in 16 (2.42%) cases, because of large stone burden. Average operative time was significantly longer in complex (45.43 minutes) compared to simple stones (29.39 minutes). Overall success rate was 94.39%, but it was significantly lower in partial (91.37%) and complete staghorn stones (82.35%). Complications were present in 21.66% cases and were classified according to Clavien grading. Majority of patients (97.9%) had minor complications (Clavien grade 1 & 2). On multivariate analysis, GSS >=2, stone size >200 mm2, and multiple caliceal, partial, and complete staghorn stones were predictors of failure and complications. CONCLUSION: PCNL is a minimally invasive surgical technique for removal of renal and upper ureteral stones, which have low morbidity rate, high success rate, and short hospital stay. Although the uses of smaller instruments are on the rise, procedure can still be safely performed in children using adult instruments. Supracostal approach if done cautiously does not increase morbidity rate. PMID- 27960541 TI - High-Frequency Dusting Versus Conventional Holmium Laser Lithotripsy for Intrarenal and Ureteral Calculi. AB - INTRODUCTION: The efficiency of holmium laser lithotripsy for urolithiasis depends upon several factors, including laser pulse energy and frequency and stone composition and retropulsion. This study investigates the complex interplay between these factors and quantifies lithotripsy efficiency using different laser settings in a benchtop kidney and ureter model. MATERIALS AND METHODS: In vitro caliceal and ex vivo porcine ureteral models were constructed. Calcium oxalate monohydrate stones were fragmented using a 200-MUm laser fiber. In the caliceal model, stone fragmentation and vaporization rates at settings of 0.6 J/5 Hz, 0.2 J/15 Hz, and 0.2 J/50 Hz were compared. In the ureteral model, fragmentation time, retropulsion rate, fragmentation rate, and fragmented stone weight were compared at settings of 0.6 J/5 Hz and 0.2 J/15 Hz. Retropulsive forces generated at 0.6 J/5 Hz, 0.2 J/15 Hz, and 0.2 J/50 Hz settings were compared. Analysis was performed using Student's t-test and one-way ANOVA. RESULTS: In the caliceal model, the 0.6 J/5 Hz setting fragmented and vaporized stones at a higher rate than the 0.2 J/15 Hz setting (0.072 vs. 0.049 mg/s; p < 0.001). However, when the 0.2 J energy setting was combined with the 50 Hz frequency, the fragmentation rate (0.069 mg/s) was similar to the fragmentation rate at 0.6 J/5 Hz (0.072 mg/s; p = 0.677). In the ureteral model, the 0.6 J/5 Hz setting produced higher fragmentation rates (0.089 vs. 0.049 mg/s; p < 0.001), but resulted in significantly lower fragmented stone weight overall (16.815 vs. 25.485 mg; p = 0.009) due to higher retropulsion rates (0.732 vs. 0.213 mm/s; p < 0.001). Retropulsive forces decreased significantly when pulse energy decreased from 0.6 to 0.2 J (0.907 vs. 0.223 N; p < 0.001). Frequency did not affect retropulsive force at 15 and 50 Hz settings (0.223 vs. 0.288 N; p = 0.509). CONCLUSIONS: Laser lithotripsy of calcium oxalate monohydrate stones in the ureter should be performed using the low-energy, moderate-frequency dusting setting to minimize retropulsion and maximize efficiency. In the renal calix, the low-energy high frequency setting performed similarly to the high-energy low-frequency setting. PMID- 27960542 TI - Welcome to volume 9 of Bioanalysis. AB - Welcome to volume 9 of Bioanalysis and Happy New Year to all of our readers. We would like to take the opportunity to look back 2016, which was another great year for us. We thank all our authors, readers and reviewers, as well as our Editorial Board members for their continued support. We very much look forward to working with everyone in 2017. PMID- 27960543 TI - Characterization of labeled reagents in ligand-binding assays by a surface plasmon resonance biosensor. AB - AIM: Ligand-binding assay (LBA) reagent labeling may change the binding characteristics of the reagent to its target and degrade its performance in LBAs. RESULTS: A surface plasmon resonance (SPR) biosensor was used to evaluate the impact of the biotin labeling process on reagent-binding kinetics and affinity for a specific target. The SPR results demonstrate that the biotin molar challenge ratio affects both association and dissociation rates for the labeled reagent binding to its target. The SPR results also predict the labeled reagent performance in LBAs. CONCLUSION: The methodology used in this study provides an example of using an SPR biosensor as an efficient way to analytically and functionally characterize critical reagents and to understand their performance postmodification in LBAs. PMID- 27960544 TI - Mass spectrometry in metabolomics: what lies ahead. PMID- 27960545 TI - Differential mobility spectrometry combined with multiple ion monitoring for bioanalysis of disulfide-bonded peptides with inefficient collision-induced dissociation fragmentation. AB - AIM: It is challenging to develop a multiple reaction monitoring (MRM) method for some disulfide-bonded peptides with inefficient collision-induced dissociation fragmentation. This study describes a new methodology using differential mobility spectrometry (DMS) combined with multiple ion monitoring (MIM) to enhance bioanalytical sensitivity for sunflower trypsin inhibitor. RESULTS: By combining DMS with MIM to monitor the intact precursor ion in Q1 and Q3 MS analyzers, a lower limit of quantitation at 0.125 ng/ml was achieved to quantify sunflower trypsin inhibitor in rat plasma, representing a 40-fold sensitivity improvement over MIM without DMS. CONCLUSION: DMS coupled with MIM method provides triple quadrupole MS users an effective means to overcome challenges in analyzing disulfide-bonded peptides or other analytes that do not have useful collision induced dissociation fragment ions for MRM analysis. PMID- 27960546 TI - Lipopeptides as therapeutics: applications and in vivo quantitative analysis. AB - A number of novel lipopeptides have been studied for their possible therapeutic potential. These studies should be supported by the appropriate analytical tools not only for novel potential drugs but also for their metabolites, precursors and side products. Lipopeptides have specific physicochemical properties that make them successful in medical applications. However, there are some difficulties with their qualitative and quantitative analyses in biological samples. Therefore, reliable, sensitive and robust analytical methods are in high demand. The main interest of our review is to describe a selection of specific and important properties of lipopeptides, and the analytical methods currently utilized for their characterization and determination in biological samples. A comparison of the pros and cons of immunomethods versus LC-MS methods is discussed in detail. PMID- 27960547 TI - The fourth China Bioanalysis Forum Annual Meeting. AB - The fourth China Bioanalysis Forum annual conference, co-organized with the Nanjing International Drug Metabolism Conference, was successfully held in Nanjing, China, between 24-26 June 2016. The theme of the conference was 'how to conduct regulated bioanalysis under China Food and Drug Administration (CFDA) regulations'. In addition, several hot topics including bioanalytical challenges, solutions for biomarkers, antidrug antibody (antibody-drug conjugates) and biologics were discussed. This Conference Report summarizes the major discussion topics from the conference. PMID- 27960548 TI - A simple and rapid LC-MS/MS method for quantitation of luseogliflozin in rat plasma and its application to a PK study. AB - AIM: Luseogliflozin is a novel sodium-dependent glucose cotransporter-2 inhibitor for the treatment of Type 2 diabetes mellitus. To assist pharmacokinetic and toxicodynamic studies, a rapid LC-MS/MS method were developed and validated for the quantitation of luseogliflozin in rat plasma. RESULTS: Sample preparation was carried out using simplified protein precipitation and liquid-liquid extraction procedures, and the run time was only 4 min. Extraction recovery was 92.9 to 95.3%, and the method was validated over the range 0.5 to 500 ng/ml for luseogliflozin with acceptable specificity, accuracy and precision. CONCLUSION: The validated method is considered suitable to quantify luseogliflozin in pharmacokinetic and pharmacodynamic/toxicodynamic studies in rats. PMID- 27960549 TI - A novel pretreatment method combining sealing technique with direct injection technique applied for improving biosafety. AB - AIM: People today have a stronger interest in the risk of biosafety in clinical bioanalysis. A safe, simple, effective method of preparation is needed urgently. METHODOLOGY/RESULTS: To improve biosafety of clinical analysis, we used antiviral drugs of adefovir and tenofovir as model drugs and developed a safe pretreatment method combining sealing technique with direct injection technique. The inter- and intraday precision (RSD %) of the method were <4%, and the extraction recoveries ranged from 99.4 to 100.7%. Meanwhile, the results showed that standard solution could be used to prepare calibration curve instead of spiking plasma, acquiring more accuracy result. CONCLUSION/DISCUSSION: Compared with traditional methods, the novel method not only improved biosecurity of the pretreatment method significantly, but also achieved several advantages including higher precision, favorable sensitivity and satisfactory recovery. With these highly practical and desirable characteristics, the novel method may become a feasible platform in bioanalysis. PMID- 27960550 TI - Ensuring the collection of high-quality dried blood spot samples across multisite clinical studies. AB - AIM: The quality of quantitative analytical measurements is dependent on the quality of the sample collected, and dried blood spots (DBS) are no exception. As the use of DBS has matured into late-stage clinical drug-development studies, it has become apparent that a simple and straightforward approach in a controlled single-site, first-time-into-human clinic, does not always translate into multicenter clinical studies. Using synthetic blood, a method of training and assessing clinical laboratory staff has been developed to ensure the quality of sampling. METHODS: A test kit comprising of synthetic blood, a pipetting aid, blank blood spot card, drying rack and training manual was sent to each clinical site for each technician to assess and approve prior to spotting PK samples. RESULTS: The development of a DBS training kit along with a step-by-step guide has been successfully implemented. CONCLUSION: The training kit has been 100% successful across three large multisite clinical studies. PMID- 27960551 TI - Date fruits inhibit hepatocyte apoptosis and modulate the expression of hepatocyte growth factor, cytochrome P450 2E1 and heme oxygenase-1 in carbon tetrachloride-induced liver fibrosis. AB - CONTEXT: Date fruits have protective effects against liver fibrosis; however their anti-apoptotic effects have not been investigated. OBJECTIVE: To investigate the modulating effects of date fruits on pro- and anti-apoptotic markers, cytochrome P450 2E1 (CYP2E1) and hepatocyte growth factor (HGF) in liver fibrosis. MATERIALS AND METHODS: Liver fibrosis was induced by injection of carbon tetrachloride (CCl4) for eight weeks. Date flesh extract (DFE) and pits extract (DPE) were taken daily concomitant with CCl4. Hepatocyte apoptosis was determined by measuring the expression of Fas, caspase-3, Bax, Bcl2 and hemeoxygenase-1 (HO-1). Hepatic levels of HGF and CYP2E1 were determined. RESULTS: Treatment with DFE and DPE significantly attenuated the elevated levels of Fas, caspase 3, Bax and CYP2E1 induced by CCl4. In addition, they alleviated the reduction in Bcl2, HGF and HO-1, the cytoprotective and anti-apoptotic factors in liver. Conclusions DFE and DPE treatment can ameliorate liver fibrosis by inhibiting hepatocyte apoptosis. PMID- 27960553 TI - Mortality of Patients with COPD and Pneumonia. PMID- 27960552 TI - Chemical composition, phytochemical constituents, antioxidant and anti inflammatory activities of Urtica urens L. leaves. AB - OBJECTIVE: The aim of this study was to investigate the chemical composition and antioxidant properties of Urtica urens L.(Uu) as well as its anti-inflammatory effect on carrageenan (CARR)-induced paw oedema in rats. METHODS: The leaves were extracted using ethanol (EtOH) and water. The extracts were analysed for proximate composition and antioxidant activity using standard chemical analysis methods. RESULTS: The proximate analysis showed that Uu leaves contained appreciable percentages of dry mass, ashes, carbohydrates, proteins, lipids, sugars, anthocyanin, carotenoid and fibre. Results showed that EtOH extract contained the highest amount of total phenolics, flavonoids, tannins, ortho diphenols and flavonols. It decreased the paw oedema after CARR administration, and ameliorated the activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and the malondialdehyde (MDA). CONCLUSIONS: Uu displayed a high potential as a natural source of minerals, phytochemicals and antioxidant properties. EtOH extract exhibited a significant inhibition against CARR-induced inflammation. PMID- 27960554 TI - An exploratory study of the influence of load and practice on segmental and articulatory variability in children with speech sound disorders. AB - This exploratory treatment study used phonetic transcription and speech kinematics to examine changes in segmental and articulatory variability. Nine children, ages 4 to 8 years old, served as participants, including two with childhood apraxia of speech (CAS), five with speech sound disorder (SSD) and two who were typically developing. Children practised producing agent + action phrases in an imitation task (low linguistic load) and a retrieval task (high linguistic load) over five sessions. In the imitation task in session one, both participants with CAS showed high degrees of segmental and articulatory variability. After five sessions, imitation practice resulted in increased articulatory variability for five participants. Retrieval practice resulted in decreased articulatory variability in three participants with SSD. These results suggest that short-term speech production practice in rote imitation disrupts articulatory control in children with and without CAS. In contrast, tasks that require linguistic processing may scaffold learning for children with SSD but not CAS. PMID- 27960555 TI - Regulation of Endothelial Cell Adherence and Elastic Modulus by Substrate Stiffness. AB - Although substrate stiffness has been previously reported to affect various cellular aspects, such as morphology, migration, viability, growth, and cytoskeletal structure, its influence on cell adherence has not been well examined. Here, we prepared three soft, medium, and hard polyacrylamide (PAAM) substrates and utilized AFM to study substrate elasticity and also the adhesion and mechanical properties of endothelial cells in response to changing substrate stiffness. Maximum detachment force and cell stiffness were increased with increasing substrate stiffness. Maximum detachment force values were 0.28 +/- 0.14, 0.94 +/- 0.27, and 1.99 +/- 0.59 nN while Young's moduli of cells were 218.85 +/- 38.73, 385.58 +/- 131.67, and 933.20 +/- 428.92 Pa for soft, medium, and hard substrates, respectively. Human umbilical vein endothelial cells (HUVECs) showed round to more spread shapes on soft to hard substrates, with the most organized and elongated actin structure on the hard hydrogel. Our results confirm the importance of substrate stiffness in regulating cell mechanics and adhesion for a successful cell therapy. PMID- 27960556 TI - Acetaminophen toxicity in rat and mouse hepatocytes in vitro. AB - CONTEXT: Acetaminophen (APAP) hepatotoxicity is often studied in primary cultures of hepatocytes of various species, but there are only few works comparing interspecies differences in susceptibility of hepatocytes to APAP in vitro. OBJECTIVES: The aim of our work was to compare hepatotoxicity of APAP in rat and mouse hepatocytes in primary cultures. MATERIALS AND METHODS: Hepatocytes isolated from male Wistar rats and C57Bl/6J mice were exposed to APAP for up to 24 h. We determined lactate dehydrogenase (LDH) activity in culture medium, activity of cellular dehydrogenases (WST-1) and activity of caspases 3 in cell lysate as markers of cell damage/death. We assessed content of intracellular reduced glutathione, production of reactive oxygen species (ROS) and malondialdehyde (MDA). Respiration of digitonin-permeabilized hepatocytes was measured by high resolution respirometry and mitochondrial membrane potential (MMP) was visualized (JC-1). RESULTS: APAP from concentrations of 2.5 and 0.75 mmol/L induced a decrease in viability of rat (p < 0.001) and mouse (p < 0.001) hepatocytes (WST-1), respectively. In contrast to rat hepatocytes, there was no activation of caspase-3 in mouse hepatocytes after APAP treatment. Earlier damage to plasma membrane and faster depletion of reduced glutathione were detected in mouse hepatocytes. Mouse hepatocytes showed increased glutamate + malate-driven respiration in state 4 and higher susceptibility of the outer mitochondrial membrane (OMM) to APAP-induced injury. CONCLUSION: APAP displayed dose-dependent toxicity in hepatocytes of both species. Mouse hepatocytes in primary culture however had approximately three-fold higher susceptibility to the toxic effect of APAP when compared to rat hepatocytes. PMID- 27960557 TI - The biologics of ulcerative colitis. AB - INTRODUCTION: Tumor necrosis factor alpha inhibitors dramatically changed the management of moderate-to-severe phenotypes of ulcerative colitis. The recent incoming of vedolizumab, which targets gut-specific leukocyte trafficking, provides a new biologic option for these patients. Areas covered: This review focuses on the rationale of use, efficacy, and safety profile of all biologics currently approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of ulcerative colitis, including tumor necrosis factor alpha inhibitors (Infliximab and biosimilars, adalimumab, and golimumab), and the more recent vedolizumab. Expert opinion: Although biologics have been available in clinical practice for ulcerative colitis for about 15 years, there are several aspects that have not been fully understood yet: we know that they work, but we still don't know which subsets of patients benefit more, and how to optimize their use. All these unresolved problems are at least partly due to the discrepancy observed between phase II/III clinical trials of all biologics currently used in ulcerative colitis and in clinical practice. PMID- 27960558 TI - Developing drugs that target the Wnt pathway: recent approaches in cancer and neurodegenerative diseases. AB - INTRODUCTION: Wnt/beta-catenin signaling is an evolutionarily conserved pathway that has a crucial role in embryonic and adult life. Dysregulation of Wnt/beta catenin pathway has been associated with various diseases, including cancer and neurodegenerative disorders, including Parkinson's disease (PD). Several molecular components of the signaling have been proposed as innovative targets for cancer therapy, and very recently, some of them have been also evaluated as potential therapeutic targets for PD. Areas covered: This review focuses on the role of Wnt/beta-catenin pathway in the pathogenensis of cancer and PD, examining some recent therapeutic approaches that are ongoing in preclinical and clinical studies. The possibilities that this signaling offers for diagnosis and prognosis of neoplastic diseases, and the concerns of targeting this pathway are also discussed. Expert opinion: Despite the stimulating results obtained in preclinical studies on cancer and other disease models, the clinical experience with Wnt modulators is still in its infancy, and is mainly restricted to anticancer therapy. Even with concerns of the safety of drugs targeting Wnt signaling, the attention of researchers worldwide is increasing to this issue in terms of their therapeutic potential for diseases such as PD, for which no cure exists. PMID- 27960559 TI - Investigational drugs for treating major depressive disorder. AB - INTRODUCTION: Treatment of patients suffering from major depression could be highly challenging for psychiatrists. Intractability as well as relapse is commonly seen among these patients, leading to functional impairment and poor quality of life. The present review discusses some of the novel investigational drugs that are under pre-clinical or clinical phases in the treatment of major depression. Areas covered: Molecules belonging to different classes such as triple reuptake inhibitors, opioid receptors, ionotropic and metabotropic glutamate receptors, and neurotrophin in the treatment of major depression are covered in this article. Expert opinion: Although the historical discovery of earlier antidepressant molecules (iproniazid and imipramine) is through serendipitous discovery, the present research focuses on discovering novel molecules based on our current pathophysiological knowledge of the disease condition. The fast-acting antidepressant property of N-methyl-d-aspartate (NMDA) receptor molecules, including ketamine is an exciting area of research. Other drug molecules such as amitifadine (triple reuptake inhibitor), ALKS-5461 (kappa receptor antagonist and mu opioidergic receptor agonist), rapastinel (NMDA glutamatergic receptor modulator) are under Phase-III clinical trials and could be approved in the near future for the treatment of major depression. PMID- 27960560 TI - Non human primate models for Alzheimer's disease-related research and drug discovery. AB - INTRODUCTION: Pathophysiological mechanisms underlying Alzheimer's disease (AD) remain insufficiently documented for the identification of accurate diagnostic markers and purposeful target discovery and development. Nonhuman primates (NHPs) have important translational value given their close phylogenetic relationship to humans and similar developmental paths in (neuro)anatomy, physiology, genetics, and neural functions, as well as cognition, emotion, and social behavior. Areas covered: This review deals with the past and future role of NHP-based research in AD pathophysiology, diagnosis and drug discovery, and touches upon ethical and legal aspects. Expert opinion: Aging NHPs are not complete phenocopies of human AD. Conceivably, no other species or experimental model will ever develop the full spectrum of AD-typical alterations. Nevertheless, partial - and even negative - models can increase knowledge of disease mechanisms. Modeling complex brain disorders should not be based on a single model or species. Understanding brain diseases relies on knowledge of healthy brain functioning, and given their close phylogenetic relationship to humans, NHPs serve excellent tools in this respect. NHP-based studies remain essential in the development and validation of radiopharmaceuticals for early diagnostic imaging biomarkers, as well as in the efficacy and safety evaluation of new therapeutic approaches, with active immunization or vaccination approaches as front runners. PMID- 27960562 TI - Keep in mind foetomaternal haemorrage in case of reduced foetal movements: a successful obstetric management. PMID- 27960561 TI - Dietary essential alpha-linolenic acid and linoleic acid differentially modulate TNFalpha-induced NFkappaB activity in FADS2-deficient HEK-293 cells. AB - The pro- or anti-inflammatory bioactivity of dietary essential linoleic acid (LA) and alpha-linolenic acid (ALA) is mainly attributed to rate-limiting delta-6 desaturase (D6D) activity. The aim of this study was to analyze mechanisms of D6D substrates ALA, LA and D6D-product gamma-linolenic acid (GLA) under D6D-deficient conditions. Fatty acid profiles (GC-MS), D6D gene expression (real-time RT-PCR) and NFkappaB activity (luciferase assay) were assessed in HEK293 cells. FADS2 gene expression was approved being marginal. Incubation with ALA or LA did not increase D6D products but their elongase products C20:3n-3 and C20:2n-6. Bypassing the D6D, GLA elevated C20:3n-6 and C20:4n-6. LA significantly increased (+18% at 60 MUM; p < .001), ALA reduced (-32% at 100 MUM; p < .001) and GLA did not specifically change NFkappaB activity. Our data indicate that D6D might not be essential for the distinct effects of LA and ALA on NFkappaB activity. PMID- 27960563 TI - Extraperitoneal leiomyoma of the round ligament of the uterus mimicking adnexal mass. PMID- 27960564 TI - Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) Levels and Its Association with Renal Allograft Rejection. AB - BACKGROUND: CCL2 is a chemoattractant for monocytes/macrophages, T cells, and natural killer cells. It is shown to be involved in the immunological responses against renal allograft. This study was conducted to access the role of urinary CCL2 expression in predicting the rejection episodes in renal transplant patients. METHOD: A total of 409 urine samples included in this study. The samples were consisted of (a) biopsy-proven graft rejection (n = 165); (b) non rejection (n = 93); (c) non-biopsy stable-graft (n = 42), and (d) healthy renal donors (n = 109). The samples were quantified for the CCL2 using the MCP-1/CCL2 ELISA kit. The data were analyzed using the Statistical Package for Social Sciences (SPSS(r)) and MedCalc(r) statistical software. RESULTS: Results showed that the CCL2 levels were significantly increased in rejection group when compared with the non-rejection, stable-graft, and control, P < 0.05. The receiver operating curve's characteristics illustrated that the urinary CCL2 level is a good predictor for graft rejection, with an area under the curve of 0.81 +/- 0.03 with optimum sensitivity and specificity of 87% and 62%, respectively, at a cut-off value of 198 pg/mL. Kaplan-Meier curve also showed better cumulative rejection-free graft survival time in group with less than 198 pg/mL of CCL2 as compared to those with expression levels of more than 198 pg/mL (30 weeks vs. 3 weeks; log-rank test, P < 0.001). CONCLUSION: In our study, noninvasive investigation of CCL2 levels in urine has showed potential to predict rejection episodes. It is suggested that the CCL2, with others markers, may help in early detection and monitoring of graft rejection episodes. PMID- 27960565 TI - Polymorphic eruption of pregnancy: Review of literature. AB - Polymorphic Eruption of Pregnancy (PEP) is one of the most common dermatosis related to pregnancy. PEP usually consists of pruritic papules and plaques appearing in the third trimester of pregnancy. It is more common in primigravidae and twin pregnancies. Although not associated with poorer foetal or maternal outcomes, it may be hard for pregnant women to endure. The diagnosis is easy if suspected, though sometimes it may be hard to distinguish from other dermatosis such as atopic eczema of pregnancy, pemphigoid gestationis or dermatitis. Topical treatment with emollients and low-medium potency steroids is usually effective but systemic steroid treatment may be required. PEP is self-limiting and resolves days or weeks after the first appearance or after delivery. In this article, the authors aim to review the literature published from 2000 onwards regarding the subject, either in English or Portuguese. PMID- 27960566 TI - A breakthrough in spontaneous coronary artery dissection pathogenesis: is it an inherited condition? PMID- 27960567 TI - Prenatal diagnosis of isolated foetal hydrocolpos secondary to congenital imperforate hymen mimicking ambiguous genitalia. PMID- 27960568 TI - Altered expression of hormone receptor, integrin beta3 and pinopode in the endometrium of luteal phase defect women. AB - OBJECTIVE: To invistigate estrogen receptor (ER), progesterone receptor (PR), integrin beta3, and pinopode expression in luteal phase deficiency (LPD) women. METHODS: There were 52 nulligravidas consecutive infertile patients undergoing a routine assistant reproduction consultation included in this study. An endometrial biopsy sample was randomly obtained between days 4 and 10 of the luteal phase. Endometrial morphology was examined with scanning electron microscopy. Expressions of ER, PR, integrin beta3 were determined in the endometrium of LPD patients with immunohistochemistry. RESULTS: The incidence of LPD was 15.3% (8/52) in this study. On day luteinizing hormone (LH) surge + 9~LH + 10, noted regressing pinopodes resembling a day LH + 7~LH + 8 in the endometrium of the control group. The expressions of ER and PR in glandular epithelium were significantly increased in endometrium of LPD than that in the control group (p < 0.05). In contrast, there was a statistically significant decrease expression of the integrin beta3 in women from the group of LPD (p < 0.05). CONCLUSION: The altered expression of ER and PR may be associated with the expression variation of integrin and pinopode formation in endometrium of LPD women. This alteration may imply the association of low rates of cycle fecundity and high rates of embryonic loss in LPD women. PMID- 27960569 TI - Maternal mortality in an academic institution in Upper Egypt. AB - Maternal mortality is a worldwide problem. Measuring maternal mortality and identifying its causes is essential, and should be assessed regularly for the purpose of planning, monitoring and evaluation of provided maternal health care. Quality of care indicators such as case fatality rate is used to measure the facility performance, in particular, quality and promptness of care. This descriptive study aimed to calculate maternal mortality ratio, quality of care indicators such as maternal mortality index, case fatality and direct obstetric case fatality rate for the Women's Health Hospital and identify causes of maternal mortality, and the main deficits in medical records. The Maternal mortality ratio was alarmingly high in Women's Health Hospital, Assiut University, Egypt reaching 225/100,000, however, those who delivered in the hospital, the MMR was 100.5/100,000. The leading causes of maternal death were obstetric haemorrhage (38.3%), complications of caesarean sections (27.7%) and pre-eclampsia/eclampsia (23.4%). Nearly half (42%) of the deaths occurred during vacations. Quality indicators revealed poor quality of health care. PMID- 27960570 TI - Clinical implications of estrone sulfate measurement in laboratory medicine. AB - Estrone sulfate (E1S) is the most abundant circulating estrogen and it has the potential to be used as a biomarker in certain conditions where estimation of low levels of estrogen or changes in relative levels of estrogens are important. This review will critically consider the role of estimating E1S for clinical laboratory practice. As E1S is an estrogen, a wider discussion of estrogens is included to contextualize the review. Assays have been available for a number of years for these estrogens and they have been measured in a number of clinical research studies. However, E1S remains a rarely ordered test. This review highlights the literature that suggests the possible advantages of measuring E1S in addition to, or possibly in place of, the more commonly measured estradiol (E2) and the less commonly measured estrone (E1). The potential biomarker role of E1S in risk stratification for breast cancer, in promotion of proliferation of endometrial cancer, in prognostic information in advanced prostatic carcinoma, and in the monitoring of response to certain hormonal therapy for malignancy is discussed. The methods available for the measurement of E1S are reviewed and the limitations of the current methodologies are described. In conclusion, E1S has some interesting potential applications in clinical laboratory medicine that require further investigation. PMID- 27960572 TI - A sensitive and a rapid multiplex polymerase chain reaction for the identification of Candida species in concentrated oral rinse specimens in patients with diabetes. AB - OBJECTIVES: Oral candidiasis is being frequently recognized in patients with diabetes, and is associated with multiple pathogens including Candida albicans, Candida parapsilosis, Candida glabrata and Candida tropicalis. The aim of this study was to evaluate a usefulness of a Multiplex Polymerase Chain Reaction as a rapid diagnostic tool for identification of four oral Candida pathogens in patients with diabetes. MATERIALS AND METHODS: A multiplex PCR was optimized to identify four Candida species in concentrated oral rinse samples. Common reverse primer, ITS4 and four species-specific forward primers targeting ITS1 and ITS2 regions of yeast genome were used. Species-specific single amplicon were detected by agarose gel electrophoresis. Performance efficacy of multiplex PCR was compared with phenotypic identification. RESULTS: Out of 100 oral rinse samples, 72 were culture positive and of these 43 were at risk of oral Candida infection (>600cfu/ml). Multiple Candida species including C. albicans, C. parapsilosis and C. tropicalis were identified in 22 samples which had risk of oral Candida infection. In total, 85 patients were positive for Candida by multiplex PCR and of them 49 had multiple Candida species. All 43 colonized specimens were also positive by multiplex PCR. C. albicans was the most predominant organism (75/85) followed by C. parapsilosis (47/85), C. tropicalis (17/85) and C. glabrata (6/85). In specimens with multiple species, the two most common organisms were C. albicans and C. parapsilosis. Multiplex PCR yielded a sensitivity of 10 Candida cells/ml of oral rinse sample. CONCLUSIONS: Multiplex PCR is found to be rapid, sensitive and specific than phenotypic identification methods in discriminating multiple Candida species in oral rinse specimens. PMID- 27960573 TI - Systematic Review of Knowledge Assessments for Glaucoma Patients. AB - Glaucoma is a chronic eye disease affecting millions of people worldwide; it is frequently treated with daily eyedrop medications when patients are asymptomatic. Patient education is an essential feature for adherence to treatments. Developing useful patient education interventions is predicated on understanding what glaucoma patients know about their disease and identifying gaps in their knowledge. Thirteen studies that have measured and described glaucoma patient knowledge using questionnaires were identified from the literature, including cross-sectional studies of disease knowledge and studies evaluating the efficacy of an educational intervention, both randomized controlled and observational. All studies found significant knowledge gaps in glaucoma patients. Both the controlled studies and the observational studies supported the efficacy of various educational interventions for improving glaucoma knowledge. PMID- 27960571 TI - Disseminated herpes zoster in chronic lymphocytic leukemia (CLL) patients treated with B-cell receptor pathway inhibitors. PMID- 27960574 TI - Prevalence of intrabony defects in a Swedish adult population. A radiographic epidemiological study. AB - AIM: The purpose of this radiographic study was to evaluate the prevalence of intrabony defects and to study the correlation between these defects and clinical variables in a Swedish adult population. Another aim was to study the combined relationship of intrabony defects and furcation involvement with clinical variables. MATERIALS AND METHODS: The present study was performed using bitewing and apical radiographs from 329 subjects. The clinical and radiographic data were collected from the study that was carried out in Jonkoping 2003. Intrabony defects were measured from the bottom of the pocket to the highest point of alveolar bone crest. Furcations were considered healthy if the furcation was filled with bone up to the fornix. SPSS was used to analyze the results. RESULTS: 2014 molars and 5898 non-molars were included in the study. The prevalence of intrabony defects was 2.2% in the whole population. Multivariate analysis showed that periodontal pockets (p < 0.0001), plaque (p < 0.001), age (p < 0.02) and gender (p < 0.03) had a significant relationship with the occurrence of intrabony defects. On the other hand, gingivitis, smoking habits and education level were not associated with intrabony defects. Multivariate analysis showed that the only variable associated with presence of intrabony defects and furcation involvement was presence of periodontal pockets (p < 0.0001). Whilst, gingivitis, education level, plaque, gender, age and smoking habits were not associated with the outcome. CONCLUSIONS: Mandibular second molars were most likely to display intrabony defects, whilst mandibular incisors were the least likely to do so. PMID- 27960575 TI - Assessing the impact of abuse-deterrent opioids (ADOs): identifying epidemiologic factors related to new entrants with low population exposure. AB - OBJECTIVE: Prescription opioid misuse and abuse is a serious public health concern that can lead to overdose, addiction, and death. The development of opioid formulations designed to deter misuse and abuse is considered an important step towards addressing the problem, but the extent to which abuse-deterrent opioids (ADOs) actually deter abuse in the community requires confirmation through epidemiologic studies. Epidemiologic evaluations of misuse and abuse present several unique challenges related to study design, sources of data, and methodology, particularly for new entrant ADOs with low population exposure. The purpose of this article is to review the critical methodologic issues that must be considered when designing an epidemiologic evaluation of prescription opioid misuse and abuse, and deterrence for new entrant ADOs. METHODS: A systematic feasibility assessment was conducted by critically evaluating and applying epidemiologic principles to combinations of epidemiology study design, study directionality, population, data source, clinical and patient-reported endpoints, type of comparator, effect size, and the ability to control for confounding variables. RESULTS: Ten epidemiologic factors were identified that are considered key to an epidemiologic evaluation, and the issues associated with each are summarized. CONCLUSION: Given the low population exposure of new entrant ADOs, there is limited feasibility in conducting the epidemiologic studies necessary to evaluate the effectiveness of these products in deterring abuse. Clear regulatory guidance is needed. PMID- 27960576 TI - Alcohol and Other Drug (AOD) Education for Hospital Staff: An Integrative Literature Review. AB - Alcohol and Other Drug (AOD) education amongst hospital staff is often inadequate. This leads to suboptimal care of patients and is a missed opportunity for early identification and treatment. This integrative review evaluates the core features of current education for hospital-based doctors and nurses in AOD, including country of origin, content, duration, and pedagogy. The majority of included studies were conducted in the USA (72%), target alcohol rather than AOD in general (72%), adopted a purely medical model of treatment (94%), and utilised a Screening, Brief Intervention, and Referral to Treatment (SBIRT) model (94%). The overall quality of the studies was weak-moderate, which led to small effect sizes in most studies and limits the generalizability of any conclusions. More high quality research trials are needed to establish the core features of effective AOD education for hospital staff. Future research should include a focus on the psychosocial context of addiction, other drug use and the impact of negative attitudes on care delivery. PMID- 27960577 TI - Endothelial Cell Count in Eye Bank Corneal Grafts: Impact of Death Cause and Donor Diseases. AB - PURPOSE: The purpose of this study is to analyze the impact of death causes and documented donor diseases on initial endothelial cell counts (after retrieval) and the development of corneal graft endothelia during organ culture. METHODS: The retrospective statistic analyses was conducted on a data set of 10,185 human corneas prepared at the Hamburg Eye Bank. RESULTS: Although we observed that death by gunshot trauma or alcoholism seems to be associated with marginally higher endothelium cell counts (independently from donor age), we could prove that only donor age is a relevant predictive parameter for the initial cell density of the endothelium and its development in vitro. CONCLUSION: We conclude that an extension of prospective quality parameters for donor selection additional to donor age (such as individual causes of death) is not necessary. PMID- 27960578 TI - Sutureless Scleral Tunnel Trabeculectomy: Evaluation of Feasibility and Effectiveness versus Conventional Trabeculectomy for Management of Primary Open Angle Glaucoma. AB - PURPOSE: To evaluate the intraocular pressure-lowering effect of sutureless scleral tunnel trabeculectomy with Mitomycin-C (MMC) compared to the standard trabeculectomy with MMC in patients with primary open angle glaucoma (POAG). METHODS: This was a masked, randomized, controlled comparison trial involving 34 eyes of 34 patients with bilateral POAG. Patients were randomized to receive sutureless sclera flap trabeculectomy with MMC or conventional trabeculectomy with MMC. The main outcome for comparison was the IOP-lowering effect of both procedures. Complete surgical success was considered if the patient's IOP was <22 mmHg and the IOP were lowered by more than 20% with the use of maximum two anti glaucoma medications. RESULTS: All surgeries passed uneventfully without intraoperative complications and all patients showed significantly (p<0.05) lower IOP on the first postoperative day compared to their respective preoperative IOP with non-significant (p>0.05) difference between both study groups. All patients, irrespective of operative procedure, maintained significantly (p<0.05) lower IOP compared to their respective preoperative IOP until the end of 12 months' follow up. There were no recorded serious postoperative complications in either groups, like wound leaks or endophthalmitis. CONCLUSION: Sutureless scleral tunnel trabeculectomy exhibits potential as an alternative to conventional trabeculectomy surgery. Over 12 months of follow-up, sutureless sclera flap trabeculectomy was safe and effective with an IOP-lowering effect comparable to that achieved with the conventional technique, but with increased rate of postoperative transient hypotony. PMID- 27960579 TI - Genus Distribution of Bacteria and Fungi Associated with Keratitis in a Large Eye Center Located in Southern China. AB - PURPOSE: To investigate the genus distribution of bacteria and fungi associated with keratitis in a large eye center located in Southern China and to compare the results with existing data from other areas in China. METHODS: All results of corneal microbiological examinations from 2009 to 2013 of patients who had been clinically diagnosed with bacterial or fungal keratitis were obtained chronologically and anonymously from the microbiology database at Zhongshan Ophthalmic Center. Smear/culture data were reviewed and analyzed. Antibiotic resistance of the harvested bacteria was also evaluated. RESULTS: Of 2973 samples, the microbial detection rate was 46.05%; in which 759 eyes (25.5%) were positive for bacteria, 796 eyes (26.8%) were positive for fungi, and 186 eyes (6.3%) were co-infected with both fungi and bacteria. The most common type of bacteria isolated was Staphylococcus epidermidis (31.9%), followed by Pseudomonas aeruginosa (12.4%). The most common type of fungus was Fusarium species (29.3%), followed by Aspergillus species (24.1%). For the bacteria harvested, mean antibiotic resistance was chloromycetin (34.6%), cephalosporins (20.0%), fluoroquinolones (18.6%), and aminoglycosides (10.5%). CONCLUSION: The genus distribution of organisms detected in keratitis cases in the largest eye center located in Southern China differs from those in other areas in China. In Southern China during the time period studied, S. epidermidis and Fusarium sp. were the most common pathogens of infectious keratitis. Monitoring the changing trend of pathogens as well as antibiotic resistance are warranted. PMID- 27960580 TI - Prevalence and Causes of Visual Impairment and Blindness among Cocoa Farmers in Ghana. AB - PURPOSE: To determine the prevalence and causes of visual impairment and blindness among cocoa farmers in Ghana in order to formulate early intervention strategies. METHODS: A cross-sectional study using multistage random sampling from four cocoa growing districts in Ghana was conducted from November 2013 to April 2014. A total of 512 cocoa farmers aged 40 years and older were interviewed and examined. The brief interview questionnaire was administered to elicit information on the demographics and socioeconomic details of participants. The examination included assessment of visual acuity (VA), retinoscopy, subjective refraction, direct ophthalmoscopy, slit-lamp biomicroscopy and intraocular pressure (IOP). For quality assurance, a random sample of cocoa farmers were selected and re-examined independently. RESULTS: Moderate to severe visual impairment (VA <6/18 to 3/60 in the better-seeing eye) was present in 89 participants (17.4%) and 27 (5.3%) were blind (presenting VA <3/60 in the better eye) defined using presenting VA. The main causes of visual impairment were cataract (45, 38.8%), uncorrected refractive error (42, 36.2%), posterior segment disorders (15, 12.9%), and corneal opacity (11, 9.5%). CONCLUSION: The prevalence of visual impairment and blindness among cocoa farmers in Ghana is relatively high. The major causes of visual impairment and blindness are largely preventable or treatable, indicating the need for early eye care service interventions. PMID- 27960581 TI - Distribution of Ocular Component Measures and Refraction in Brazilian School Children. AB - PURPOSE: To describe ocular component values and refraction in 6-17-year-old school children in Campinas, Brazil. METHODS: To obtain a representative sample, a total of 1100 6-17-year-old public school students in Campinas, Brazil, were randomly selected and divided into groups according to median ages 6 years (range 5-7 years), 10 years (range 9-11 years), 14 years (range 13-15 years), and 17 years (range 16-18 years). Cycloplegic autorefraction and ocular biometry were performed on each child. RESULTS: Parental consent for participation was obtained for 778 of the 1100 students (70.7%). Of these, 440 (56.6%) were female and 330 (44.4%) male. Sex distributions were similar for each median age group. Median age groups 6, 10, 14, and 17 years displayed significant trends of decreasing mean spherical equivalent refraction (SER; 0.96, 0.89, 0.57, and 0.23 diopters, D, respectively), mean lens thickness (3.50, 3.42, 3.41, and 3.45 mm, respectively), and mean lens power (23.6, 22.7, 21.8, and 21.2D, respectively), but significant trends of increasing mean anterior chamber depth (ACD; 3.00, 3.12, 3.16, and 3.15 mm, respectively), mean vitreous chamber depth (VCD; 16.0, 16.4, 16.6, and 16.8 mm, respectively), and mean axial length (22.5, 23.0, 23.2, 23.4 mm, respectively; all p for trend <0.001). CONCLUSIONS: Significant trends towards lower refractive power, increased prevalence of myopia, increased ACD, VCD, and axial length, and decreased lens power were associated with increasing age in these children. There were no significant changes in corneal thickness or corneal curvature. PMID- 27960582 TI - Ultrasound Biomicroscopy in Pseudophakic Patients with Unexplained Recurrent Hyphema or Vitreous Hemorrhage. AB - PURPOSE: To describe IOL haptic with iris or ciliary body touch on ultrasound biomicroscopy (UBM) in pseudophakic patients with unexplained recurrent hyphema or vitreous hemorrhage. METHODS: Retrospective chart review of 10 patients who presented with unexplained recurrent hyphema and or vitreous hemorrhage. RESULTS: There were eight posterior chamber intraocular lenses (PCIOL) and two sulcus lenses. Four cases had a history of glaucoma; two cases which had a history of trabeculectomy were found to have some bridging vessels along the sclerostomy requiring argon laser gonioplasty. No preceding trauma or retinal pathology was found. UBM revealed haptic-ciliary body or haptic-iris touch in cases with a PCIOL and haptic-iris touch in both sulcus lens cases. One case with a PCIOL did not reveal any haptic-iris or ciliary body touch and instead displacement of the optic temporally, though haptics remained intracapsular. CONCLUSIONS: UBM is a useful tool to evaluate haptic position in pseudophakic patients with unexplained recurrent hyphema and/or vitreous hemorrhage. This is the largest existing series of patients with this clinical entity reported from a single institution. PMID- 27960583 TI - Effect of Aging on Retinal Nerve Fiber Layer Thickness in Normal Asian Indian Eyes: A Longitudinal Study. AB - PURPOSE: To determine longitudinal retinal nerve fiber layer (RNFL) thickness measurement change with aging, after a period of 3 years using spectral optical coherence tomography/scanning laser ophthalmoscope (OCT/SLO). METHODS: A total of 50 eyes of 25 normal subjects underwent RNFL thickness measurement in 2008 and again in 2011 by a single operator, using spectral OCT/SLO. Measurements were compared at baseline and at follow-up. Linear mixed model analysis was used to measure the effect of age on RNFL thickness measurements over the 3 years. RESULTS: Mean RNFL thickness was 107.92 +/- 11.1 um in 2008 and 106.56 +/- 10.8 um in 2011. For every year increase in age, mean RNFL thickness showed a statistically significant decrease by -0.54 um (95% confidence interval, -0.76 to -0.31; p < 0.0001). There was a statistically significant loss of peripapillary RNFL thickness in most RNFL regions, except for the temporal quadrant (p = 0.37) and corresponding 7, 8, 9, and 10 o'clock hour sectors (p = 0.72, 0.75, 0.17, 0.14, respectively). CONCLUSION: RNFL thickness as measured by spectral OCT/SLO decreased significantly with advancing age over a period of 3 years, and was not uniform across the four quadrants. This age-related variation should be taken into account in RNFL thickness measurements when evaluating patients for diagnosis and follow-up of glaucoma. PMID- 27960584 TI - The Prevalence of Strabismus and Associated Risk Factors in a Southeastern Region of Brazil. AB - PURPOSE: To determine the prevalence of strabismus and associated risk factors in southeastern Brazil. METHODS: A cross-sectional, population-based study using a systematic sample from nine municipalities in a southeastern region of Brazil composed of 1852 individuals aged >=1 and <=12 years old was done. Visual acuity (VA), ocular alignment, and refractive error (RE) were evaluated. Strabismic individuals (strabismus group) were compared to orthotropic individuals (orthotropic group) to analyze risk factors linked to heterotropias. RESULTS: Prevalence of strabismus was 0.81% in this population. In the strabismus group, we found 40% with hyperopia, 6.67% with astigmatism, 3.33% with myopia, 6.67% with amblyopia, and 8.33% with moderate anisometropia. In the orthotropic group, 6.85% had hyperopia, 18.12% astigmatism, 14.82% myopia, 0.19% amblyopia, and 4.37% moderate anisometropia. CONCLUSION: The prevalence of strabismus in southeastern Brazil was 0.81%. Strabismic individuals had more hyperopia. Amblyopia and moderate anisometropia were associated with strabismus. PMID- 27960585 TI - Challenges for the application of optical stimulation in the cochlea for the study and treatment of hearing loss. AB - INTRODUCTION: Electrical stimulation has long been the most effective strategy for evoking neural activity from bionic devices and has been used with great success in the cochlear implant to allow deaf people to hear speech and sound. Despite its success, the spread of electrical current stimulates a broad region of neural tissue meaning that contemporary devices have limited precision. Optical stimulation as an alternative has attracted much recent interest for its capacity to provide highly focused stimuli, and therefore, potentially improved sensory perception. Given its specificity of activation, optical stimulation may also provide a useful tool in the study of fundamental neuroanatomy and neurophysiological processes. Areas covered: This review examines the advances in optical stimulation - infrared, nanoparticle-enhanced, and optogenetic-based - and its application in the inner ear for the restoration of auditory function following hearing loss. Expert opinion: Initial outcomes suggest that optogenetic based approaches hold the greatest potential and viability amongst optical techniques for application in the cochlea. The future success of this approach will be governed by advances in the targeted delivery of opsins to auditory neurons, improvements in channel kinetics, development of optical arrays, and innovation of opsins that activate within the optimal near-infrared therapeutic window. PMID- 27960587 TI - Combining Gene and Stem Cell Therapy for Peripheral Nerve Tissue Engineering. AB - Despite a substantially increased understanding of neuropathophysiology, insufficient functional recovery after peripheral nerve injury remains a significant clinical challenge. Nerve regeneration following injury is dependent on Schwann cells, the supporting cells in the peripheral nervous system. Following nerve injury, Schwann cells adopt a proregenerative phenotype, which supports and guides regenerating nerves. However, this phenotype may not persist long enough to ensure functional recovery. Tissue-engineered nerve repair devices containing therapeutic cells that maintain the appropriate phenotype may help enhance nerve regeneration. The combination of gene and cell therapy is an emerging experimental strategy that seeks to provide the optimal environment for axonal regeneration and reestablishment of functional circuits. This review aims to summarize current preclinical evidence with potential for future translation from bench to bedside. PMID- 27960586 TI - Long-Term Outcomes in Patients with Neovascular Age-Related Macular Degeneration Who Maintain Dry Macula after Three Monthly Ranibizumab Injections. AB - PURPOSE: To evaluate long-term changes in visual acuity and retinal microstructure in patients with neovascular age-related macular degeneration (AMD) who had maintained dry macula after initial treatment. METHODS: This retrospective observational study included 55 eyes that were diagnosed with neovascular AMD, were treated with three monthly ranibizumab injections, and maintained dry macula during a two-year follow-up. Best-corrected visual acuity (BCVA) at three months and at the final follow-up were compared, and the degree of visual improvement was compared between eyes with and without improvement of the ellipsoid zone. In addition, the incidence of improvement of the ellipsoid zone was compared between eyes with different extents of disruption. RESULTS: The mean follow-up period was 30.3 +/- 4.1 months. BCVA at three months and at the final follow-up was 0.51 +/- 0.46 and 0.45 +/- 0.49 (P<0.001). Among 35 eyes that exhibited >200 MUm of disruption of the ellipsoid zone, 15 (42.9%) showed improvement of the ellipsoid zone, and the improvement in BCVA was greater in these eyes than that in the remaining 20 eyes (P=0.021). A higher incidence of improvement of the ellipsoid zone was noted in eyes with 200 to 800 MUm of disruption than in eyes with >800 MUm of disruption (P<0.001). CONCLUSIONS: Long term improvement in visual acuity was noted in eyes that had maintained dry macula after three ranibizumab injections. The status of the ellipsoid zone at three months was closely associated with visual improvement. PMID- 27960588 TI - Investigation of Association between Autophagy-Related Gene Polymorphisms and Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma in a Spanish Population. AB - PURPOSE: Cellular stress conditions are important mechanisms implicated in the pathogenesis of pseudoexfoliation syndrome. One of the potential cellular responses to these stress conditions is induction of autophagy. The purpose of this study was to evaluate whether genetic variants in three critical genes of autophagy (ATG16L, ATG2B, ATG5) may be involved in the development of pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG) in a Spanish population. METHODS: 108 patients (64 XFS, 44XFG) and 118 healthy controls were evaluated. The analysis of genetic polymorphisms was performed by standard TaqMan allelic discrimination technique. RESULTS: No significant differences in either genotype distributions or allelic frequencies of the tested polymorphisms were found between patients with XFS/XFG and control subjects. CONCLUSIONS: Our results suggest that these three genes that are critical components of the autophagy pathway (ATG16L, ATG2B, ATG5) are not significant risk factors among Spanish patients with either XFS or XFG. PMID- 27960590 TI - Use of thermobalancing therapy in ageing male with benign prostatic hyperplasia with a focus on etiology and pathophysiology. AB - INTRODUCTION: We investigated if "thermobalancing" therapy (TT), using Dr Allen's therapeutic device (DATD) in men with benign prostatic hyperplasia (BPH), can aid in understanding the etiology and pathophysiology of BPH. METHODS: We compared urinary and other parameters of BPH patients who received TT over 6 months (treatment group) with those of healthy volunteers who had not received the treatment (control group). Dynamics of symptoms and indicators in each group were evaluated in comparison with their data at the beginning and end of the study. Parameters were the International Prostate Symptom Score (IPSS) for urinary symptoms and quality of life (QoL), ultrasound measurement of prostate volume (PV) and uroflowmetry (maximum flow rate, Qmax). TT effectiveness was examined in 124 men with BPH and PV <60 mL. We also investigated the data of five patients with BPH and PV >60 mL. RESULTS: TT decreased urinary symptoms and PV, increased Qmax and improved QoL in men with BPH, PV <60 mL, and in men with BPH, PV >60 mL. CONCLUSIONS: The present study demonstrated that TT is effective for BPH, suggesting that blood circulation plays a crucial role in its cause. The continuous heat exposure that does not exceed the normal body temperature terminates the trigger of BPH development, "micro-focus" of hypothermia, and the following spontaneous expansion of capillaries. TT could be considered to be a useful tool in BPH treatment. PMID- 27960591 TI - Immuno-oncology for renal cell carcinoma treatment: future perspectives for combinations and sequences with molecularly targeted agents. AB - INTRODUCTION: From a theoretical viewpoint, combining molecularly targeted agents endowed with antiangiogenic properties with immunotherapy makes sense in treatment of metastatic renal cell carcinoma (RCC); this neoplasm is highly angiogenesis-dependent, as well as potentially immunogenic. Areas covered: The authors performed a literature search looking for clinical trials aimed at evaluating efficacy and tolerability of combinations (or sequences) of molecularly targeted agents and different immunotherapeutic approaches in metastatic RCC. Expert opinion: Combinations of molecularly targeted agents with old immunotherapeutics (i.e., cytokines) seem to add little to the presently available treatment standards (mainly monotherapy with targeted agents). Newer combinations with immune checkpoint inhibitors are promising but cumulative toxicity is an important issue, although highly dependent on the different companion drugs. Combinations with vaccines are ongoing, but first available data are not encouraging. A more thorough comprehension of the complex effects of these combinations on the immune system is mandatory to develop less empiric treatments. PMID- 27960589 TI - Targeting Cancer Stem Cells with Natural Killer Cell Immunotherapy. AB - INTRODUCTION: Standard cytoreductive cancer therapy, such as chemotherapy and radiotherapy, are frequently resisted by a small portion of cancer cells with 'stem-cell' like properties including quiescence and repopulation. Immunotherapy represents a breakthrough modality for improving oncologic outcomes in cancer patients. Since the success of immunotherapy is not contingent on target cell proliferation, it may also be uniquely suited to address the problem of resistance and repopulation exerted by cancer stem cells (CSCs). Areas covered: Natural killer (NK) cells have long been known for their ability to reject allogeneic hematopoietic stem cells, and there are increasing data demonstrating that NK cells can selectively identify and lyse CSCs. The authors review the current knowledge of CSCs and NK cells and highlight recent studies that support the concept that NK cells are capable of targeting CSC in solid tumors, especially in the context of combination therapy simultaneously targeting non CSCs and CSCs. Expert opinion: Unlike cytotoxic cancer treatments, NK cells can target and eliminate quiescent/non-proliferating cells such as CSCs, and these enigmatic cells are an important source of relapse and metastasis. NK targeting of CSCs represents a novel and potentially high impact method to capitalize on the intrinsic therapeutic potential of NK cells. PMID- 27960592 TI - Mobile-phone radiation-induced perturbation of gene-expression profiling, redox equilibrium and sporadic-apoptosis control in the ovary of Drosophila melanogaster. AB - The daily use by people of wireless communication devices has increased exponentially in the last decade, begetting concerns regarding its potential health hazards. Drosophila melanogaster four days-old adult female flies were exposed for 30 min to radiation emitted by a commercial mobile phone at a SAR of 0.15 W/kg and a SAE of 270 J/kg. ROS levels and apoptotic follicles were assayed in parallel with a genome-wide microarrays analysis. ROS cellular contents were found to increase by 1.6-fold (x), immediately after the end of exposure, in follicles of pre-choriogenic stages (germarium - stage 10), while sporadically generated apoptotic follicles (germarium 2b and stages 7-9) presented with an averaged 2x upregulation in their sub-population mass, 4 h after fly's irradiation with mobile device. Microarray analysis revealed 168 genes being differentially expressed, 2 h post-exposure, in response to radiofrequency (RF) electromagnetic field-radiation exposure (>=1.25x, P < 0.05) and associated with multiple and critical biological processes, such as basic metabolism and cellular subroutines related to stress response and apoptotic death. Exposure of adult flies to mobile-phone radiation for 30 min has an immediate impact on ROS production in animal's ovary, which seems to cause a global, systemic and non targeted transcriptional reprogramming of gene expression, 2 h post-exposure, being finally followed by induction of apoptosis 4 h after the end of exposure. Conclusively, this unique type of pulsed radiation, mainly being derived from daily used mobile phones, seems capable of mobilizing critical cytopathic mechanisms, and altering fundamental genetic programs and networks in D. melanogaster. PMID- 27960593 TI - Rapid safety assessment of a seasonal intradermal trivalent influenza vaccine. AB - Seasonal influenza vaccine formulations must be updated annually to correspond to the influenza viruses in circulation. This was an uncontrolled, open-label, multi center phase IV study conducted in Belgium to comply with interim European Medicines Agency (EMA) guidelines for rapidly evaluating the safety of newly formulated seasonal influenza vaccines. Adult volunteers received one dose of the 2014-2015 Northern Hemisphere formulation of licensed intradermal trivalent influenza vaccine at either the standard dose (9ug hemagglutinin/strain for 18-59 year-olds) or the high dose (15ug hemagglutinin/strain for >= 60 year-olds). Vaccinees recorded their solicited reactions and unsolicited adverse events for 7 d after vaccination. Solicited reaction frequencies were compared to historical reference values obtained from previous clinical trials to determine if the new formulations were excessively reactogenic or allergenic. A total of 210 participants (105 per age group) were included and vaccinated in October 2014. In both groups, pain, erythema, and pruritus were the most common solicited injection site reactions, and headache and myalgia were the most common solicited systemic reactions. Although the frequencies of shivering in 18-59 year-olds and malaise in >= 60 year-olds were higher than historical reference values, they were not considered indicative of excessive reactogenicity because almost all of these reactions were mild. The study design was endorsed by the EMA and permitted the reactogenicity of both vaccine formulations to be assessed within one month by collecting adverse events for 7 d. Both formulations exhibited acceptable safety profiles although this should be confirmed through forthcoming enhanced post-marketing safety surveillance systems. PMID- 27960594 TI - Development of Islet Organoids from H9 Human Embryonic Stem Cells in Biomimetic 3D Scaffolds. AB - Success in the differentiating human embryonic stem cells (hESCs) into insulin secreting beta cells raises new hopes for diabetes treatment. In this work, we demonstrated the feasibility of developing islet organoids from hESCs within biomimetic 3D scaffolds. We showed that such a 3D microenvironment is critical to the generation of pancreatic endoderm and endocrine from hESCs. The organoids formed consisted of pancreatic alpha, beta, delta, and pancreatic polypeptide (PP) cells. A high-level co-expression of PDX1, NKX6.1, and NGN3 in these cells suggests the characteristics of pancreatic beta cells. More importantly, most insulin-secreting cells generated did not express glucagon, somatostatin, or PP. The expression of mature beta cell marker genes such as Pdx1, Ngn3, Insulin, MafA, and Glut2 was detected in these 3D-induced cell clusters. A high-level expression of C-peptide confirmed the de novo endogenous insulin production in these 3D induced cells. Insulin-secretory granules, an indication of beta cell maturity, were detected in these cells as well. Glucose challenging experiments suggested that these cells are sensitive to glucose levels due to their elevated maturity. Exposing the cells to a high concentration of glucose induced a sharp increase in insulin secretion. PMID- 27960595 TI - Meningococcal serogroup B vaccines: Estimating breadth of coverage. AB - Neisseria meningitidis serogroup B (MenB) is an important cause of invasive meningococcal disease. The development of safe and effective vaccines with activity across the diversity of MenB strains has been challenging. While capsular polysaccharide conjugate vaccines have been highly successful in the prevention of disease due to meningococcal serogroups A, C, W, and Y, this approach has not been possible for MenB owing to the poor immunogenicity of the MenB capsular polysaccharide. Vaccines based on outer membrane vesicles have been successful in the prevention of invasive MenB disease caused by the single epidemic strain from which they were derived, but they do not confer broad protection against diverse MenB strains. Thus, alternative approaches to vaccine development have been pursued to identify vaccine antigens that can provide broad protection against the epidemiologic and antigenic diversity of invasive MenB strains. Human factor H binding protein (fHBP) was found to be such an antigen, as it is expressed on nearly all invasive disease strains of MenB and can induce bactericidal responses against diverse MenB strains. A bivalent vaccine (Trumenba(r), MenB-FHbp, bivalent rLP2086) composed of equal amounts of 2 fHBP variants from each of the 2 immunologically diverse subfamilies of fHBP (subfamilies A and B) was the first MenB vaccine licensed in the United States under an accelerated approval pathway for prevention of invasive MenB disease. Due to the relatively low incidence of meningococcal disease, demonstration of vaccine efficacy for the purposes of licensure of bivalent rLP2086 was based on vaccine-elicited bactericidal activity as a surrogate marker of efficacy, as measured in vitro by the serum bactericidal assay using human complement. Because bacterial surface proteins such as fHBP are antigenically variable, an important component for evaluation and licensure of bivalent rLP2086 included stringent criteria for assessment of breadth of coverage across antigenically diverse and epidemiologically important MenB strains. This review describes the rigorous approach used to assess broad coverage of bivalent rLP2086. Alternative nonfunctional assays proposed for assessing vaccine coverage are also discussed. PMID- 27960596 TI - Heterologous boosting with recombinant VSV-846 in BCG-primed mice confers improved protection against Mycobacterium infection. AB - Tuberculosis (TB) remains a major health problem worldwide, and the development of effective vaccines is urgently needed. Vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacillus Calmette Guerin (BCG) as primer and modified vaccinia virus Ankara strain expressing the mycobacterial antigen Ag85A (MVA85A) as booster may increase the protective efficacy of BCG. In addition, vaccination with the recombinant viral vaccine vesicular stomatitis virus (VSV)-846 (Rv3615c, Mtb10.4, and Rv2660c) can elicit a remarkable T-cell-mediated immune response and provide an effective long-term protection after the BCG challenge. In this study, we used VSV-846 to boost BCG and evaluated its immunogenicity in BALB/c mice. In this prime-boost approach, boosting with VSV-846 significantly enhanced IFN-gamma CD4 T cell responses, which are crucial for anti-TB immune responses. Moreover, VSV-846 boosting significantly reduced pathology compared with mock vaccination, and decreased the bacterial loads in lung tissues compared with BCG or VSV-846 vaccination alone. The analysis of vaccine-induced immunity identified that polyfunctional T cells might contribute to the enhanced protection by VSV-846 boosting. This study proved that viral booster VSV-846 in mice improved the protection against mycobacteria infection, which could be helpful in designing an efficient vaccination strategy against TB in humans. PMID- 27960598 TI - A literature review on stress and coping strategies in nursing students. AB - BACKGROUND: While stress is gaining attention as an important subject of research in nursing literature, coping strategies, as an important construct, has never been comprehensively reviewed. AIM: The aims of this review were: (1) to identify the level of stress, its sources, and (2) to explore coping methods used by student nurses during nursing education. METHODS: This is a systematic review of studies conducted from 2000 to 2015 on stress and coping strategies in nursing students. CINAHL, MEDLINE, PsycINFO and PubMed were the primary databases for the search of literature. Keywords including "stress", "coping strategy", "nursing students" and "clinical practice" in 13 studies met the criteria. FINDINGS: Stress levels in nursing students range from moderate to high. Main stressors identified included stress through the caring of patients, assignments and workloads, and negative interactions with staff and faculty. Common coping strategies utilized by nursing students included problem-solving strategies such as developing objectives to resolve problems, adopting various strategies to solve problems, and finding the meaning of stressful events. CONCLUSION: Nurse educators may consider the use of formulation and implementation of empirically tested interventions to reduce stress while enhancing coping skills. PMID- 27960599 TI - Association of betatrophin with metabolic characteristics in overweight/obese and lean women with PCOS. AB - As a new hormone, betatrophin has gained attention as a potential new target to combat insulin resistance (IR) and diabetes. Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder among women of the reproductive age with long term sequelae which include IR and metabolic syndrome. The aim of this study is to evaluate the circulating plasma betatrophin levels in overweight/obese or lean women with or without PCOS and also to elucidate possible correlations with anthropometric and metabolic parameters. Thirty-two patients with PCOS as well as fifty-three control subjects were enrolled after obtaining informed written consent. Clinical and biochemical parameters of all subjects were determined. Plasma adiponectin, GLP-1 and betatrophin levels were measured by ELISA. Plasma betatrophin levels were significantly increased in lean patients with PCOS compared with lean and obese controls. Moreover, in PCOS group, betatrophin levels were significantly negatively correlated with waist hip ratio (WHR), fasting insulin level (FINS) and HOMA-IR, whereas, significantly positively correlated with adiponectin level. Multiple regression analysis showed that HOMA-IR was an independent factor influencing serum betatrophin levels. Further follow-up studies are needed to highlight whether and how increased betatrophin secretion play an important role in IR and carbohydrates metabolism in patients with PCOS. PMID- 27960600 TI - Boron removal by a composite sorbent: Polyethylenimine/tannic acid derivative immobilized in alginate hydrogel beads. AB - A novel composite material was prepared by the grafting of tannic acid on polyethylenimine (PEI), which allows an efficient sorption of boron (sorption capacity close to 0.89 mmol B g-1). The encapsulation of this chelating sorbent (finely crushed) facilitates its use (readily solid/liquid separation, use in fixed-bed columns) at the expense of a loss in sorption capacity (proportionally decreased by the introduction of alginate having poor efficiency for boron uptake). Sorption isotherms are modeled using the Langmuir equation, while the kinetic profiles are presented a good fit by pseudo-second order rate equation. In addition, the encapsulating matrix introduces supplementary resistance to intraparticle diffusion, especially when the resin is dried without control: freeze-drying partially limits this effect. The stability (at long-term storage) of the sorbent is improved when the sorbent is stored under nitrogen atmosphere. The presence of an excess of NaCl was investigated. The degradation of the hydrogel (by ion-exchange of Ca(II) with Na(I)) leads to a decrease in the sorption performance of composite material but the action of Ca(II) ions in the solutions re-stabilizes the hydrogel. PMID- 27960597 TI - Ivermectin: a complimentary weapon against the spread of malaria? AB - INTRODUCTION: Ivermectin has transformed the treatment of parasitic diseases and led to incommensurable benefits to humans and animals. Ivermectin is effective in treating several neglected infectious diseases and recently it has been shown to reduce malaria parasite transmission. Areas covered: Malaria control strategies could benefit from the addition of ivermectin to interrupt the transmission cycle if it is a long lasting formulation or repeatedly administered. In turn, this will help also to control neglected infectious diseases where the elimination goal has been slower to achieve. Despite the relevance of using ivermectin for integrated and sustained disease control, there are still essential questions that remain to be addressed about safety and practicality. The efficacy in various malaria ecologies and the interaction between control tools, either drugs or insecticides, are also important to assess. Expert commentary: Overlapping distribution of several infectious diseases reveals the benefit of integrating control programs against several infectious diseases into one strategy for cost effectiveness and to reach the elimination goals. The use of ivermectin to control malaria transmission will necessitate development and testing of long lasting formulations or repeated treatments, and implementation of these treatments with other disease control tools may increase the chance of successful and sustained control. PMID- 27960601 TI - Identification of dual kinase inhibitors of CK2 and GSK3beta: combined qualitative and quantitative pharmacophore modeling approach. AB - PTEN, a tumor suppressor protein, gets deactivated by casein kinase 2 (CK2) and glycogen synthase kinase 3beta (GSK3beta), which are the major causes of PI3K/AKT driven tumors. To surmount this problem, the multi-target inhibitor strategy may be of great significance. The goal of this study was to design dual-target inhibitors of CK2 and GSK3beta using a combination of pharmacophore modeling and molecular docking studies. The common feature-based (qualitative) and 3DQSAR based (quantitative) pharmacophore models were generated and validated. The best pharmacophore models (Pharm18 and Hypo1) comprised two hydrogen-bond acceptors, one hydrophobic, and one ring aromatic features. The models were used to screen various chemical database and top mapped compounds from each database were selected. They were processed for Lipinski filter, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis, and docking studies. We have obtained six hits with comparable dock score to the reported inhibitors. We have concluded Hit15 as a competent candidate based on its docking and Density Functional Theory (DFT) calculations. It showed 140.73 and 130.79 dock score in CK2 and GSK3beta, respectively. The electronic property of Hit 15 showed the lowest energy gap (0.021) compared to other hits and active ligands which suggest its higher reactivity. In conclusion, this study may assist in the development of new potent dual kinase inhibitors of CK2 and GSK3beta. Also, the overture effort of combined qualitative and quantitative modeling for the development of multi target inhibitors may support the future endeavors. PMID- 27960603 TI - Elderly people's perceptions of using Wii sports bowling - A qualitative study. AB - The Nintendo Wii is a gaming console with motion-sensitive controls that is making inroads into health care and rehabilitation. However, there is still limited knowledge on how elderly people perceive the use of such a product. The aim of this study was to examine how the use of the Wii Sports Bowling in an activity group was perceived by elderly people. The data consisted of observations and interviews with participants who used Wii Sports Bowling and was analysed with content analysis. The findings are described in three themes; 'The use of the Wii Sports game', 'Engagement in the game' and 'Social interaction around the activity'. Wii Sports Bowling was described as easier to play compared to real-life bowling and was enjoyable and a social activity. The opportunity to meet the group each week was important for the participants. Playing the game resulted in signs of immersion and a flow-like state. The Wii was perceived to be easy to use, to provide a way to socialize with peers and to give opportunities to participate in activities in a new way. More studies regarding elderly people's experiences and apprehensions regarding new technology such as gaming consoles and virtual reality are needed. PMID- 27960602 TI - Use of Immunosuppressive Medications for Treatment of Pediatric Intermediate Uveitis. AB - PURPOSE: To describe the treatment and outcomes of a cohort of pediatric intermediate uveitis (IU) patients, with a particular focus on the use of immunomodulatory therapy (IMT). METHODS: The disease course, treatment, and outcomes of 39 pediatric IU patients treated in the Uveitis Clinic at the University of Utah from 1999 to 2012 were reviewed, retrospectively. RESULTS: Mean age at presentation was 7.7 years (SD 3.1). In total, 95% had bilateral involvement. Out of 77 total eyes involved, the most frequent disease complications were ocular hypertension (0.71 events per person year, PPY), cataracts (events PPY = 0.39), and cystoid macular edema (events PPY = 0.33). A total of 20 patients received IMT; 19/20 were tapered off systemic corticosteroids without a uveitis recurrence; 75% of eyes had inactive disease at final follow-up (mean 37 months). CONCLUSIONS: The use of IMT, including biologic therapies, may effectively manage disease inflammation and reduce steroid dosages in pediatric IU patients. PMID- 27960604 TI - Correctional mental health administration. AB - Mental health administrators in correctional facilities have the complex task of balancing the clinical needs of incarcerated individuals and the safety and security missions of the facilities. This article describes the various structures of mental health administration within correctional facilities, the tasks commonly required of these professionals, and the skills necessary to be effective in this role. This editorial discusses the legal framework for mental healthcare in jails and prisons, staffing, cost containment, quality assurance and quality improvement, accreditation, peer review, morbidity and mortality reviews, utilization management, medication formularies, electronic health records, and innovative strategies as they apply to administrators of mental health services in correctional facilities. Throughout this article, practices are also included that have been found to be of value for managing a correctional mental health system. PMID- 27960605 TI - Correctional psychiatry: tools for the trade. PMID- 27960606 TI - Sociodemographic, sexual, reproductive and relationship characteristics of adolescents having an abortion in Portugal: a homogeneous or a heterogeneous group? AB - OBJECTIVES: The aims of the study were to describe the sociodemographic, sexual, reproductive and relational characteristics of adolescents having an abortion in Portugal and to explore the differences between three adolescent age groups. METHODS: We recruited a nationally representative sample of 224 adolescents (<16 years, n = 18; 16-17 years, n = 103; 18-19 years, n = 103) who had an abortion. Data were collected from 16 health care services that provide abortion. RESULTS: The adolescents were predominantly single, were from non-nuclear families, had low-socioeconomic status and were students. Mean age at first sexual intercourse was 15 years and mean gynaecological age was 5 years. Most had had multiple sexual partners, and for most it was their first pregnancy. At conception, the majority were involved in a long-term romantic relationship, were using contraception but did not identify the contraceptive failure that led to the pregnancy. Significant age group differences were found. Compared with the younger age groups, the 18-19 year age group was more frequently married or living with a partner, had finished school, had attained a higher educational level (as had their partner), intended to go to university, and had a greater number of sexual partners. Compared with the other groups, those under 16 years of age reported earlier age at menarche and at first sexual intercourse, and had a lower gynaecological age. CONCLUSIONS: Our study characterises the life contexts of Portuguese adolescents who had an abortion. It highlights the need to recognise the heterogeneity of this group according to age. The findings have important implications for the development of age-appropriate guidelines to prevent unplanned pregnancy. PMID- 27960607 TI - Evaluation of air quality zone classification methods based on ambient air concentration exposure. AB - : Air quality zones are used by regulatory authorities to implement ambient air standards in order to protect human health. Air quality measurements at discrete air monitoring stations are critical tools to determine whether an air quality zone complies with local air quality standards or is noncompliant. This study presents a novel approach for evaluation of air quality zone classification methods by breaking the concentration distribution of a pollutant measured at an air monitoring station into compliance and exceedance probability density functions (PDFs) and then using Monte Carlo analysis with the Central Limit Theorem to estimate long-term exposure. The purpose of this paper is to compare the risk associated with selecting one ambient air classification approach over another by testing the possible exposure an individual living within a zone may face. The chronic daily intake (CDI) is utilized to compare different pollutant exposures over the classification duration of 3 years between two classification methods. Historical data collected from air monitoring stations in Kuwait are used to build representative models of 1-hr NO2 and 8-hr O3 within a zone that meets the compliance requirements of each method. The first method, the "3 Strike" method, is a conservative approach based on a winner-take-all approach common with most compliance classification methods, while the second, the 99% Rule method, allows for more robust analyses and incorporates long-term trends. A Monte Carlo analysis is used to model the CDI for each pollutant and each method with the zone at a single station and with multiple stations. The model assumes that the zone is already in compliance with air quality standards over the 3 years under the different classification methodologies. The model shows that while the CDI of the two methods differs by 2.7% over the exposure period for the single station case, the large number of samples taken over the duration period impacts the sensitivity of the statistical tests, causing the null hypothesis to fail. Local air quality managers can use either methodology to classify the compliance of an air zone, but must accept that the 99% Rule method may cause exposures that are statistically more significant than the 3 Strike method. IMPLICATIONS: A novel method using the Central Limit Theorem and Monte Carlo analysis is used to directly compare different air standard compliance classification methods by estimating the chronic daily intake of pollutants. This method allows air quality managers to rapidly see how individual classification methods may impact individual population groups, as well as to evaluate different pollutants based on dosage and exposure when complete health impacts are not known. PMID- 27960608 TI - Call For Manuscripts: Special issue of "Issues in Mental Health Nursing" on the topic of Mental Health Wellness, Recovery, and Holism. PMID- 27960609 TI - Using the Theory of Planned Behavior to predict HPV vaccination intentions of college men. AB - OBJECTIVE: The purpose of this study was to test Theory of Planned Behavior (TPB) constructs in predicting human papillomavirus (HPV) vaccination behavioral intentions of vaccine-eligible college men. PARTICIPANTS: Participants were unvaccinated college men aged 18-26 years attending a large public university in the southeastern United States during Spring 2015. METHODS: A nonexperimental, cross-sectional study design was employed. Instrumentation comprised a qualitative elicitation study, expert panel review, pilot test, test-retest, and internal consistency, construct validity, and predictive validity assessments using data collected from an online self-report questionnaire. RESULTS: The sample consisted of 256 college men, and the final structural model exhibited acceptable fit of the data. Attitude toward the behavior (beta = .169) and subjective norm (beta = 0.667) were significant predictors of behavioral intention, accounting for 58% of its variance. CONCLUSIONS: Practitioners may utilize this instrument for the development and evaluation of TPB-based interventions to increase HPV vaccination intentions of undergraduate college men. PMID- 27960610 TI - Multimodal Imaging in Sympathetic Ophthalmia. AB - PURPOSE: To show the current status of multimodal imaging and its role in supporting an early diagnosis of sympathetic ophthalmia. METHODS: The diagnosis is mainly clinical supported with ancillary investigations; mainly fluorescein angiography and others, including indocyanine angiography optical coherence tomography (OCT), OCT enhanced depth imaging, autofluorescence imaging, and ultrasonography. RESULTS: Various imaging modalities such as OCT, autofluorescence imaging and angiography are critical in the diagnosis and management of sympathetic ophthalmia. The clinician must make adequate use of such ancillary investigations in the management of the patients. CONCLUSIONS: Sympathetic ophthalmia is a rare, bilateral inflammation of the uveal tract following penetrating trauma or surgery in one eye. The intraocular inflammation requires a prompt diagnosis so that the treatment can be initiated as early as possible. PMID- 27960611 TI - Elucidation of the anticancer potential and tubulin isotype-specific interactions of beta-sitosterol. AB - Beta-sitosterol (beta-SITO), a phytosterol present in many edible vegetables, has been reported to possess antineoplastic properties and cancer treatment potential. We have shown previously that it binds at a unique site (the 'SITO site') compared to the colchicine binding site at the interface of alpha- and beta-tubulin. In this study, we investigated the anticancer efficacy of beta-SITO against invasive breast carcinoma using MCF-7 cells. Since 'isotypes' of beta tubulin show tissue-specific expression and many are associated with cancer drug resistance, using computer-assisted docking and atomistic molecular dynamic simulations, we also examined its binding interactions to all known isotypes of beta-tubulin in alphabeta-tubulin dimer. beta-SITO inhibited MCF-7 cell viability by up to 50%, compared to vehicle-treated control cells. Indicating its antimetastatic potential, the phytosterol strongly inhibited cell migration. Immunofluorescence imaging of beta-SITO-treated MCF-7 cells exhibited disruption of the microtubules and chromosome organization. Far-UV circular dichroism spectra indicated loss of helical stability in tubulin when bound to beta-SITO. Docking and MD simulation studies, combined with MM-PBSA and MM-GBSA calculations revealed that beta-SITO preferentially binds with specific beta-tubulin isotypes (betaII and betaIII) in the alphabeta-tubulin dimer. Both these beta-tubulin isotypes have been implicated in drug resistance against tubulin-targeted chemotherapeutics. Our data show the tubulin-targeted anticancer potential of beta-SITO, and its potential clinical utility against betaII and betaIII isotype overexpressing neoplasms. PMID- 27960612 TI - How Much Should Thyroid Cancer Impact Plans for Pregnancy? PMID- 27960613 TI - Prevalence, clinical characteristics and echocardiography parameters of non resistant, resistant and refractory hypertension in Chinese. AB - OBJECTIVES: Refractory and resistant hypertension is defined as hypertension that is uncontrolled despite the use of multiple antihypertensives. The aim of the present study is to evaluate the prevalence, both in young and elderly, and the pattern of left ventricular hypertrophy (LVH) in South-Eastern Chinese patients with refractory, resistant and non-resistant hypertension. METHODS: A total of 1455 patients (age 60.3 +/- 13.9, male 55.7%) with essential hypertension were recruited. Refractory hypertension was defined as uncontrolled blood pressure (systolic/diastolic, >=140/90 mm Hg) on >=5 antihypertensive drug classes. Resistant hypertension was defined as uncontrolled blood pressure (systolic/diastolic, >=140/90 mm Hg) on 3 or <140/90 mm Hg on >=4 antihypertensive classes. RESULTS: Among the total population, 1273 (87.4%) patients were considered non-resistant hypertension; 170 (11.7%) with resistant hypertension and 12 (0.8%) with refractory hypertension. The prevalence of the three groups of hypertension were similar between patients age <60 or >=60. Patients with refractory hypertension had the most dilated LV dimension, greatest left ventricular mass index and highest prevalence of diastolic dysfunction than patients with resistant and non-resistant hypertension. In particular, all patients with refractory hypertension had either concentric or eccentric LVH. CONCLUSIONS: In South-Eastern Chinese patients, the prevalence of refractory and resistant hypertension was 0.8% and 11.7%, respectively. Furthermore, no difference was observed in the hypertensive patterns between patients age <60 and >=60. Importantly, patients with refractory hypertension had the worst LV remodeling with all suffering from either concentric or eccentric hypertrophy. PMID- 27960614 TI - Long-term individual shear rate therapy counterpulsation enhances plasma nitrite release in patients with PAD. AB - BACKGROUND: Individual shear rate therapy (ISRT) has been designed as a novel non invasive treatment option for peripheral artery disease (PAD) patients and has been shown to improve endothelial function and walking distance. The aim of this study was to elucidate the impact of ISRT on the level of nitric oxide in patient blood plasma and the expression of related molecular markers in peripheral blood mononuclear cells (PBMCs). Molecular diagnostic tests were performed for two ISRT trials. PATIENTS AND METHODS: In ISRT-1 26 healthy subjects underwent one session of treadmill training and one session of ISRT respectively in a cross-over design. In ISRT-2 14 PAD patients with a stable intermittent claudication underwent a 30 hours long-term treatment. Plasma nitrite release as well as the mRNA expression of NOS2 and key regulators of the kallikrein-kinin system were measured in PBMCs at different time points. RESULTS: Short-term ISRT revealed significantly decreased NOS2 expression in PBMCs of healthy volunteers and PAD patients. Long-term ISRT, in turn, demonstrated a significant plasma nitrite increase in PAD patients. CONCLUSIONS: We verified that long-term ISRT stimulates the vascular system and exerts a comparable effect to physical exercise in regards to NO release, which coincide with recent findings regarding an improvement of endothelial function. However, further studies are necessary to investigate the role for circulating leukocytes.?. PMID- 27960615 TI - Posttraumatic stress and depression may undermine abuse survivors' self-efficacy in the obstetric care setting. AB - INTRODUCTION: Posttraumatic stress symptoms (PTS) are associated with increased risk of obstetric complications among pregnant survivors of trauma, abuse and interpersonal violence, but little is known about how PTS affects women's actual experiences of obstetric care. This study investigated the rate at which abuse history was detected by obstetricians, whether abuse survivors experienced more invasive exams than is typically indicated for routine obstetric care, and whether psychological distress was associated with abuse survivors' sense of self efficacy when communicating their obstetric care needs. METHODS: Forty-one pregnant abuse survivors completed questionnaires about abuse history, current psychological distress and self-efficacy for communicating obstetric care needs and preferences. Electronic medical records (EMRs) were reviewed to examine frequency of invasive prenatal obstetric procedures (e.g. removal of clothing for external genital examination, pelvic exams and procedures) and to examine the detection rate of abuse histories during the initial obstetric visit. RESULTS: The majority of participants (83%) reported at least one past incident of violent physical or sexual assault. Obstetricians detected abuse histories in less than one quarter of cases. Nearly half of participants (46%) received invasive exams for non-routine reasons. PTS and depression symptoms were associated with lower self-efficacy in communicating obstetric care preferences. DISCUSSION: Women most at risk for experiencing distress during their obstetric visits and/or undergoing potentially distressing procedures may also be the least likely to communicate their distress to obstetricians. Results are discussed with implications for improving screening for abuse screening and distress symptoms as well as need for trauma-sensitive obstetric practices. PMID- 27960616 TI - Five-Year Incidence of Visual Impairment in Middle-Aged Iranians: The Shahroud Eye Cohort Study. AB - PURPOSE: To study the 5-year incidence of visual impairment and its causes and risk factors, in the middle-aged Iranian sample of the Shahroud Eye Cohort Study (ShECS). METHODS: Data from subjects who had participated in both phases of the ShECS were used to determine age- and sex-specific incidence rates of visual impairment using the World Health Organization (WHO) definitions for bilateral low vision (visual acuity, VA, >0.5 and <=1.3 LogMAR in the better eye) and blindness (VA worse than 1.3 LogMAR in the better eye). Risk ratios (RR) and 95% confidence intervals (CIs) were calculated using multivariable log-binomial regression. RESULTS: Of the 5079 ShECS I survivors, 4737 (93.3%) completed the 5 year follow-up. Their mean age at baseline was 50.9 +/- 6.2 years, and 58.9% were female. The incidence of visual impairment was 1.12% (95% CI 0.82-1.42%) by presenting VA and 0.19% (95% CI 0.07-0.32%) by best-corrected VA; leading causes of the former were uncorrected refractive error (81.3%) and diabetic retinopathy (15.1%). In the multivariable model, risk factors for incident visual impairment by presenting VA were older age (RR 1.05, p = 0.044), lower education (RR 0.89, p = 0.002), and diabetes (RR 3.74, p < 0.001). CONCLUSION: This is the first incidence study of visual impairment in a middle-aged Iranian population. Since age is a major risk factor, the number of visually impaired is expected to increase as the population ages, and less treatable causes such as diabetic retinopathy begin to surface. Measures for tackling uncorrected refractive error and enhancing diabetes screening and preventive programs are recommended. PMID- 27960618 TI - Histologic changes of mesenchymal stem cell repair of tympanic membrane perforation. AB - CONCLUSION: Mesenchymal stem-cells are good candidates for cell-therapy of chronic tympanic membranes perforations. OBJECTIVES: To determine the effects of cell-based therapy in tympanic membrane perforations. METHODS: Young C57BL/6 mice were anesthetized with intraperitoneal administration of ketamine and xylazine and randomly divided into three groups (n = 4 ears/group) that underwent bilateral sub-total pars tensa perforations of equal sizes using a sterile 27 gauge needle under a surgical microscope. Six-to-eight hours after injury, one group of mice did not receive treatment (acute perforation control), and the last two groups were treated with BM-MSCs embedded within HA scaffolds previously soaked in PBS to rinse culture media residues to avoid confounders and were euthanized 1 or 2 weeks after treatment. RESULTS: Untreated tympanic membrane perforations developed a hyper-cellular infiltrate surrounding the injury site, while BM-MSC treated eardrums showed a reduced inflammatory response after the first week and a restoration of the trilaminar configuration 2 weeks after treatment, mimicking a normal tympanic membrane. PMID- 27960617 TI - Nuclear DNA replication and repair in parasites of the genus Leishmania: Exploiting differences to develop innovative therapeutic approaches. AB - Leishmaniasis is a common tropical disease that affects mainly poor people in underdeveloped and developing countries. This largely neglected infection is caused by Leishmania spp, a parasite from the Trypanosomatidae family. This parasitic disease has different clinical manifestations, ranging from localized cutaneous to more harmful visceral forms. The main limitations of the current treatments are their high cost, toxicity, lack of specificity, and long duration. Efforts to improve treatments are necessary to deal with this infectious disease. Many approved drugs to combat diseases as diverse as cancer, bacterial, or viral infections take advantage of specific features of the causing agent or of the disease. Recent evidence indicates that the specific characteristics of the Trypanosomatidae replication and repair machineries could be used as possible targets for the development of new treatments. Here, we review in detail the molecular mechanisms of DNA replication and repair regulation in trypanosomatids of the genus Leishmania and the drugs that could be useful against this disease. PMID- 27960619 TI - We also CanFly! The 2nd MexFly drosophila research conference. AB - The 2nd Mexican Drosophila Research Conference (MexFly) took place on June 30th and July 1st, 2016 in Mexico City, at the Center for Research and Advanced Studies of the National Polytechnic Institute (Cinvestav). Principal investigators, postdocs, students, and technicians from Drosophila labs across Mexico attended. The guest speaker was Chris Rushlow from New York University, who presented work on Zelda, a key transcriptional activator of the early zygotic genome. Here we provide a brief report of the meeting, which sketches the present landscape of Drosophila research in Mexico. We also provide a brief historical note on one of the pioneers of the field in this country, Victor Salceda, personally trained by Theodosius Dobzhansky. Salceda presented at the meeting an update of his collaborative project with Dobzhansky on the distribution of Drosophila pseudoobscura chromosomal inversions, initiated over forty years ago. PMID- 27960620 TI - The GoSlo family of BK channel activators: A no-go for gamma subunits? PMID- 27960621 TI - Molecular mechanisms underlying histological and biochemical changes induced by nitrate in rat liver and the efficacy of S-Allylcysteine. AB - This study was designed to investigate structural and ultra-structural changes induced by nitrate in rat liver, examine their molecular basis, and evaluate the possible protective role of S-Allylcysteine (SAC). Adult male albino rats were assigned to: control, SAC, nitrate, and nitrate+ SAC groups. Serum ALT and AST were measured. Liver samples were processed for light and electron microscope examinations, biochemical analysis, real-time PCR, and immunohistochemistry of heat shock protein 70 (HSP70) and Bcl-2. Nitrate induced histopathological and biochemical alterations in rat liver. The underlying mechanisms included nitrosative and oxidative stress, inflammation, fibrosis, and apoptosis that are alleviated by SAC. PMID- 27960624 TI - Efficient estimation in two-stage randomized clinical trials using ranked sets. AB - Clinical trials designed for survival probability estimation of different treatment policies for chronic diseases like cancer, leukemia, and schizophrenia usually need randomization of treatments in two stages. Since complete remission is rare for these diseases, initially an induction therapy is given for patient's remission. Further treatment, which is often an expensive maintenance therapy, is administered only for the patients with remission. If the maintenance therapy is so expensive that the cost of the trial inflates, only a simple random sample of patients will be treated with the expensive maintenance due to budget constraint. In this article, we have implemented a design using ranked sets instead of simple randomization in the second stage and obtained an unbiased estimator of the overall survival distribution for a particular treatment combination. Through simulation studies under different conditions, we have found that the design we developed based on ranked sets gives an unbiased estimate of the population survival probability which is more efficient than the estimate obtained by the usual design. PMID- 27960622 TI - A future scenario of the global regulatory landscape regarding genome-edited crops. AB - The global agricultural landscape regarding the commercial cultivation of genetically modified (GM) crops is mosaic. Meanwhile, a new plant breeding technique, genome editing is expected to make genetic engineering-mediated crop breeding more socially acceptable because it can be used to develop crop varieties without introducing transgenes, which have hampered the regulatory review and public acceptance of GM crops. The present study revealed that product and process-based concepts have been implemented to regulate GM crops in 30 countries. Moreover, this study analyzed the regulatory responses to genome edited crops in the USA, Argentina, Sweden and New Zealand. The findings suggested that countries will likely be divided in their policies on genome edited crops: Some will deregulate transgene-free crops, while others will regulate all types of crops that have been modified by genome editing. These implications are discussed from the viewpoint of public acceptance. PMID- 27960623 TI - Surgical Management and Outcome of Open Globe Injuries with Posterior Segment Complications: A 10-Year Review. AB - PURPOSE: To describe the characteristics, management, and outcomes of open globe injured (OGI) eyes that underwent pars plana vitrectomy (PPV) for posterior segment complications. METHODS: Retrospective chart review of cases that underwent PPV for posterior segment complications associated with OGI between 2003-2012 at University Hospital, Newark, NJ. RESULTS: 120 eyes were identified and classified as follows: "early retinal detachment (RD)" (within 30 days of OGI), 64 (53%) eyes; "delayed RD" (>=30 days after OGI), 30 (25%) eyes; and "no RD," 26 (22%) eyes. Injuries included penetrating (39 (33%) eyes), rupture (60 (50%) eyes), and penetrating wounds with retained intraocular foreign body (21 (17%) eyes). Injuries in Zones I, II, and III were seen in 40 (35%) eyes), 38 (34%) eyes, and 35 (31%) eyes, respectively, with statistically different ocular trauma scores (p<0.01) associated with each zone of injury. Mean presenting and final logMAR VA were 2.20+/- 0.63 and 1.87 +/-0.60, respectively (p<0.01), with a mean follow-up of 3.2 years. Final overall anatomic success after surgeries was 98% for early RD and 95% for delayed RD. CONCLUSION: Despite a high anatomic success rate, the overall functional success rate for eyes with posterior segment trauma that undergo PPV is poor and comparable to other studies. PMID- 27960625 TI - Cognitive outcomes of pediatric stroke. AB - A limited number of longitudinal studies have investigated long-term neuropsychological development in the pediatric stroke population. This study retrospectively examines cognitive outcomes in 41 children with a history of stroke, with reference to age at stroke, laterality, region and mechanism of stroke. In the course of recovery, neuropsychological measures of intellectual functioning and memory were administered at two time points, whilst executive functioning, attention and academic skills were administered at one time point. As predicted, children with stroke performed significantly worse compared to normative expectations on all neuropsychological measures. Up to two thirds of children scored in the borderline impaired and impaired ranges on at least one domain of cognition. Performance on intellectual and memory assessment remained relatively stable over time. Younger age at stroke was found to be associated with poorer intellectual functioning. No effects of laterality of stroke on neuropsychological performance over time were found. Children with subcortical stroke demonstrated a greater improvement in immediate memory over time than children with cortical stroke. These findings reveal that children with stroke display long-term cognitive difficulties that typically remain stable over time. Attention and academic skills are particularly vulnerable to impairment. Further evidence that age at stroke is a significant factor in terms of cognitive outcome is provided, in support of the "early vulnerability" position. PMID- 27960626 TI - Food and Drug Administration Requires Strong Warnings for Opioid Analgesics, Prescription Opioid Cough Products, and Benzodiazepine Labeling Related to Serious Risks and Death From Combined Use. PMID- 27960627 TI - Comparative evaluation of a newly developed 13-valent pneumococcal conjugate vaccine in a mouse model. AB - Animal models facilitate evaluation of vaccine efficacy at relatively low cost. This study was a comparative evaluation of the immunogenicity and protective efficacy of a new 13-valent pneumococcal conjugate vaccine (PCV13) with a control vaccine in a mouse model. After vaccination, anti-capsular antibody levels were evaluated by pneumococcal polysaccharide (PnP) enzyme-linked immunosorbent assay (ELISA) and opsonophagocytic killing assay (OPA). Also, mice were challenged intraperitoneally with 100-fold of the 50% lethal dose of Streptococcus pneumoniae. The anti-capsular IgG levels against serotypes 1, 4, 7F, 14, 18C, 19A, and 19F were high (quartile 2 >1,600), while those against the other serotypes were low (Q2 <= 800). Also, the OPA titres were similar to those determined by PnP ELISA. Comparative analysis between new PCV13 and control vaccination group in a mouse model exhibited significant differences in serological immunity of a few serotypes and the range of anti-capsular IgG in the population. Challenge of wild-type or neutropenic mice with serotypes 3, 5, 6A, 6B, and 9V showed protective immunity despite of induced relatively low levels of anti-capsular antibodies. With comparison analysis, a mouse model should be adequate for evaluating serological efficacy and difference in the population level as preclinical trial. PMID- 27960629 TI - Preclinical study and clinical trial of a novel therapeutic vaccine against multi drug resistant tuberculosis. AB - [Purpose] Multi-drug resistant (MDR), Mycobacterium tuberculosis (TB) is a big problem in the world. We have developed novel TB therapeutic vaccine (HVJ-E/HSP65 DNA +IL-12 DNA). [Methods and Results] DNA vaccine expressing TB heat shock protein 65 and IL-12 was delivered by the hemagglutinating virus of Japan (HVJ) envelope. This vaccine provided remarkable protective efficacy and strong therapeutic efficacy against MDR-TB and XDR-TB in murine models. Furthermore, this vaccine provided therapeutic efficacy of prolongation of survival time of TB infected monkeys and augmented the immune responses. Therefore, the preclinical tests were studied for clinical trial. The injection of 100 MUg of the vaccine /mouse i.m. three times in two weeks induced significantly strong production of IFN-gamma and IL-2. 100 MUg and 200 MUg DNA vaccine/mouse i.m. augmented the production of these cytokines compared with 25 MUg DNA vaccine/mouse i.m.. The ratio of 100 MUg pDNA to 1AU HVJ-E enhanced the production of IFN-gamma and IL-2. The decrease in the number of M. tuberculosis in liver of mice was observed by the vaccination of 100MUg pDNA. By using these conditions, safety pharmacology study and toxicology test is being studied in monkeys administered by GMP level DNA vaccines. By the toxicology test using monkeys, high dose GMP level vaccine/ monkey is administrated. Safety pharmacological study of repeated administration is also being investigated in GLP level. Furthermore, we have planned to do clinical phase I trial. Targets are human patients with MDR-TB. The safety and tolerability of the vaccine will be evaluated. [Conclusion and recommendations] These data indicate that our novel vaccine might be useful against tuberculosis including XDR-TB and MDR-TB for human therapeutic clinical applications. PMID- 27960630 TI - Clinical significance of the ABCB1 and ABCG2 gene expression levels in acute lymphoblastic leukemia. AB - OBJECTIVES: Acute lymphoblastic leukemia (ALL) is a clonal disease that accounts for 20% of acute leukemias in adults. A high percentage of adult patients (ranging from 70 to 80%) reach complete remission; however, the 5-year survival rate is only 20-40%. One of the main obstacles to treatment success is the drug resistance of leukemic cells. Therefore, our research group analyzed the ABCB1 and ABCG2 gene expression levels in 61 patients diagnosed with ALL and assessed whether the levels affected the clinical parameters and 40-month survival rate. METHODS: The ABCB1 and ABCG2 gene expression levels were analyzed using real-time polymerase chain reaction in 61 patients diagnosed with ALL and 99 healthy donors as controls. The association between ABCB1 and ABCG2 gene expression levels and clinical variables was determined using the Chi-square test and Fisher's exact test. Overall survival (OS) was determined using the Kaplan-Meier method. RESULTS: The results showed high ABCB1 and ABCG2 gene levels, which were 4.5 and 2.3 times the levels of healthy donors, respectively. A total of 52% of the study patients expressed high ABCB1 levels and were significantly associated with the high-risk patient group and a decreased 40-month survival rate of 78%. Only 49% of the patients expressed high ABCG2 gene levels. No association was found between the clinical parameters and the ABCG2 gene expression levels. CONCLUSIONS: Early detection of ABCB1 gene expression levels could be important for the diagnosis and monitoring of ALL patients. PMID- 27960628 TI - Antibodies to watch in 2017. AB - Over 50 investigational monoclonal antibody (mAb) therapeutics are currently undergoing evaluation in late-stage clinical studies, which is expected to drive a trend toward first marketing approvals of at least 6-9 mAbs per year in the near-term. In the United States (US), a total of 6 and 9 mAbs were granted first approvals during 2014 and 2015, respectively; all these products are also approved in the European Union (EU). As of December 1, 2016, 6 mAbs (atezolizumab, olaratumab, reslizumab, ixekizumab, bezlotoxumab, oblitoxaximab) had been granted first approvals during 2016 in either the EU or US. Brodalumab, was granted a first approval in Japan in July 2016. Regulatory actions on marketing applications for brodalumab in the EU and US are not expected until 2017. In 2017, first EU or US approvals may also be granted for at least nine mAbs (ocrelizumab, avelumab, Xilonix, inotuzumab ozogamicin, dupilumab, sirukumab, sarilumab, guselkumab, romosozumab) that are not yet approved in any country. Based on announcements of company plans for regulatory submissions and the estimated completion dates for late-stage clinical studies, and assuming the study results are positive, marketing applications for at least 6 antibody therapeutics (benralizumab, tildrakizumab, emicizumab, galcanezumab, ibalizumab, PRO-140) that are now being evaluated in late-stage clinical studies may be submitted during December 2016* or 2017. Other 'antibodies to watch' in 2017 include 20 mAbs are undergoing evaluation in pivotal studies that have estimated primary completion dates in late 2016 or during 2017. Of these, 5 mAbs are for cancer (durvalumab, JNJ-56022473, ublituximab, anetumab ravtansine, glembatumumab vedotin) and 15 mAbs are for non-cancer indications (caplacizumab, lanadelumab, roledumab, tralokinumab, risankizumab, SA237, emapalumab, suptavumab, erenumab, eptinezumab, fremanezumab, fasinumab, tanezumab, lampalizumab, brolucizumab). Positive results from these studies may enable submission of marketing applications in 2017 or 2018, or provide justification for additional studies. *See note added in proof for update through December 31, 2016. PMID- 27960631 TI - Exploring the binding mechanism and kinetics of Piperine with snake venom secretory Phospholipase A2. AB - Secreted venom Phospholipase A2 is highly responsible for pharmacological effects like neurotoxicity, myotoxicity, hemolytic, anti-coagulation, and platelet aggregation. Neutralization of these pharmacological behaviors is one of the challenges existing for many decades and a potent drug compound for this is very much needed to control local effects of venom sPLA2. In this study, we investigated binding mechanism and kinetics of inhibition of Piperine (major constitute of Piper nigrum) with sPLA2 using DFT, MD simulation, MM-PBSA, and SPR method. Frontier MO properties were suggested that it procured better chemical reactivity and druglikeness and binding mode of Piperine with EcPLA2 defined that it occupied well in N-terminal hydrophobic cleft. The persistence of Piperine interactions with and without calcium ion was analyzed and confirmed by MD simulation analysis. The dPCA-based FEL shows the nature of apo- and Piperine bound conformational behavior of EcPLA2 including intermediate forms. Further, binding energy of Piperine was calculated by high-throughput MM-PBSA which states that calcium ion presence enhances the Piperine binding by additional electrostatic interactions. Finally, kinetics of inhibition between Piperine and EcPLA2 implied that it secured better binding affinity (KD: as 1.708 pM) and the result gives clear evidence for the binding mechanism and binding energy calculated. In conclusion, Piperine was authenticated with better drug ability, entrenched binding interaction, and robust kinetics of inhibition with EcPLA2 through which it can become an exceeding drug candidate for pharmacological as well as catalytic activity of sPLA2. PMID- 27960633 TI - The existential cost of economic insecurity: Threatened financial security undercuts meaning. AB - Financial security (i.e., a person's sense that they can afford the things they need now and in the foreseeable future) contributes to psychological health and well-being. In the present research, we explored the implications of financial security for perceptions of meaning in life. In Study 1, we found that perceptions of financial insecurity predicted perceptions of meaning in life above and beyond income. Further, income only predicted perceptions of meaning to the extent that it was associated with reduced financial insecurity. In Studies 2 and 3, we found that financial security threats undermined perceptions of meaning in life. Taken together, these studies suggest that maintaining financial security is important for a sense of meaning in life. PMID- 27960632 TI - Psychosocial correlates of cervical cancer screening among older Hispanic women. AB - Early detection through screening can reduce mortality rates of cervical cancer, and yet Hispanic women who have incidence rates higher than their non-Hispanic White counterparts are least likely to participate in cancer screening initiatives. This study utilized data from the 2008 wave of the Health and Retirement Study to investigate the psychosocial correlates associated with older Hispanic women's participation in cervical cancer screening services. Logistic regression models were used. Findings indicated that greater life satisfaction and religiosity were associated with a greater likelihood of participating in cervical cancer screening. Despite ongoing national conversations, evidence indicates there is agreement that underserved women need to be screened, particularly the older Hispanic population. PMID- 27960634 TI - Recommendations on statistics and benchmarks to assess photochemical model performance. AB - : Photochemical grid models are addressing an increasing variety of air quality related issues, yet procedures and metrics used to evaluate their performance remain inconsistent. This impacts the ability to place results in quantitative context relative to other models and applications, and to inform the user and affected community of model uncertainties and weaknesses. More consistent evaluations can serve to drive improvements in the modeling process as major weaknesses are identified and addressed. The large number of North American photochemical modeling studies published in the peer-reviewed literature over the past decade affords a rich data set from which to update previously established quantitative performance "benchmarks" for ozone and particulate matter (PM) concentrations. Here we exploit this information to develop new ozone and PM benchmarks (goals and criteria) for three well-established statistical metrics over spatial scales ranging from urban to regional and over temporal scales ranging from episodic to seasonal. We also recommend additional evaluation procedures, statistical metrics, and graphical methods for good practice. While we primarily address modeling and regulatory settings in the United States, these recommendations are relevant to any such applications of state-of-the-science photochemical models. Our primary objective is to promote quantitatively consistent evaluations across different applications, scales, models, model inputs, and configurations. The purpose of benchmarks is to understand how good or poor the results are relative to historical model applications of similar nature and to guide model performance improvements prior to using results for policy assessments. To that end, it also remains critical to evaluate all aspects of the model via diagnostic and dynamic methods. A second objective is to establish a means to assess model performance changes in the future. Statistical metrics and benchmarks need to be revisited periodically as model performance and the characteristics of air quality change in the future. IMPLICATIONS: We address inconsistent procedures and metrics used to evaluate photochemical model performance, recommend a specific set of statistical metrics, and develop updated quantitative performance benchmarks for those metrics. We promote quantitatively consistent evaluations across different applications, scales, models, inputs, and configurations, thereby (1) improving the user's ability to quantitatively place results in context and guide model improvements, and (2) better informing users, regulators, and stakeholders of model uncertainties and weaknesses prior to using results for policy assessments. While we primarily address U.S. modeling and regulatory settings, these recommendations are relevant to any such applications of state-of-the-science photochemical models. PMID- 27960635 TI - Cationic surfactant-modified biosorption of anionic dyes by dried Rhizopus arrhizus. AB - The biosorption of an anionic dye Remazol Black B onto a filamentous, dried fungus, Rhizopus arrhizus, was studied in the presence of the cationic surfactant cetyl trimethyl ammonium bromide (CTAB), which was used as a pH shifter. Without surfactant, the maximum dye uptake capacity was achieved at pH 2.0 and was 434.0 mg dye g-1 dried fungal biomass. Again, without surfactant, the highest dye uptake capacity, 27.8 mg dye g-1 dried biomass, occurred at pH 8.0 calculated from the Langmuir adsorption model. Addition of CTAB changed the pH at which the highest dye uptake was obtained. At an initial pH of 8.0 with different CTAB concentrations, the dye uptake capacity increased from 27.8 to 500.0 mg dye g-1 dried biomass. Furthermore, when 200 mg L-1 surfactant was added to the biosorption medium at pH 8.0, the amount of dye removed increased significantly. Four equilibrium adsorption models were applied to the results. The applicability of each isotherm was determined using regression correlation and fitting curves. According to the Langmuir model, without surfactant, the highest dye removal capacity at pH 8.0 was found to be 27.8 mg dye g-1 dried biomass, rising to 500.0 mg g-1 dried biomass with 200 mg L-1 CTAB. PMID- 27960636 TI - Foreword. PMID- 27960639 TI - Outer Retinal Tubulation in Subretinal Neovascularization Associated with Macular Telangiectasia Type 2. AB - PURPOSE: To describe characteristics of outer retinal tubulation (ORT) in eyes with subretinal neovascular membrane (SRNVM) associated with Macular Telangiectasia type 2 (MacTel type 2). METHODS: A retrospective analysis of longitudinal spectral domain optical coherence tomography (SD-OCT) scans of 46 eyes of 30 patients with SRNVM associated with MacTel type 2 was performed. To identify ORTs, each B-scan image of the macular cube (512 X 128) scan on the Cirrus(r) SD-OCT was reviewed. Changes in ORT characteristics, including location, size, reflectivity of the borders, and internal reflectivity, were noted during an average follow-up period of 18 months. RESULTS: Ten ORTs were detected in 7 of 46 eyes (15.2%); SRNVM showed no activity in six of these seven eyes. ORT was seen as round or ovoid hyporeflective spaces with hyperreflective borders, and measured 56 to 206 MUm in height and 120 to 357 MUm in width. An average of 1 bevacizumab injection (range: 0-2) was administered before at least one ORT was diagnosed. The mean interval between the last injection and detection of ORT was 10.2 months (range: 1-48 months). Over the 18-month follow-up period, ORTs were unchanged in four eyes, while in the remaining three eyes ORTs underwent structural changes. Five ORTs disappeared, four new ORTs appeared, and one ORT disappeared and reappeared. The size and the shape of ORT did not change, except in one case. CONCLUSION: Outer retinal tubulation can develop in eyes with MacTel type 2 associated SRNVM, with similar characteristics to ORT found in other degenerative diseases. ORTs may undergo dynamic structural modifications over time, with or without ongoing bevacizumab treatment. PMID- 27960638 TI - Agreement in Measurement of Optic Cup-to-Disc Ratio with Stereo Biomicroscope Funduscopy and Digital Image Analysis: Results from the Nigeria National Blindness and Visual Impairment Survey. AB - PURPOSE: To determine agreement in estimations of vertical cup-to-disc ratio (VCDR) between clinical stereo-biomicroscopic funduscopy and digital fundus image analysis. METHODS: Systematic sampling of 1-in-7 from a sample of 13,591 participants aged >=40 years gave a subsample who were examined in detail. VCDR was estimated clinically by 60 diopter aspheric lens biomicroscopic funduscopy (c VCDR) and by digital fundus images (i-VCDR) graded at the Moorfields Eye Hospital Reading Centre. Spearman's correlation coefficient, paired t-test and the Bland Altman method to assess limits of agreement (LOA) between the two methods were applied. RESULTS: Of 1759 participants in the subsample, 848 participants (48%) with normal frequency doubling technology (FDT) visual fields and data for i-VCDR and c-VCDR in both eyes (n = 1696 eyes) were included in the analysis. By absolute difference of VCDR values for each eye between the two methods, 1585 eyes (94%) differed by <=0.2. Mean i-VCDR was 0.381 (standard deviation, SD 0.156), and mean c-VCDR 0.321 (SD 0.145). i-VCDRs were significantly larger by a mean difference of 0.061 (SD 0.121; 95% confidence interval, CI, 0.055-0.066; p < 0.001). The 95% LOA assessed by the Bland-Altman method were lower limit -0.182 (95% CI -0.192 to -0.172) and upper limit 0.303 (95% CI 0.293-0.313). The 95% LOA intervals narrowed with higher VCDR. CONCLUSION: Digital image analysis and clinical assessment are two distinct methods to measure VCDR; with larger i-VCDRs in this survey. Applying i-VCDR cut-off values to c-VCDR measurements in the Nigeria Blindness Survey might have underestimated glaucoma prevalence. It is recommended that all participants in glaucoma surveys have VCDR by digital image measurement. PMID- 27960640 TI - Turkish doctors' cohort: healthy despite low screening. AB - OBJECTIVES: We aimed to determine the prevalence of chronic diseases and unhealthy lifestyle behaviors of Turkish doctors as compared with the general population and the frequency of compliance with preventive clinical practices among doctors. METHODS: This was an observational, prospective cohort study that enrolled graduates between 1975 and 2004 from six medical schools in Turkey. Data on demographics, disease conditions, and unhealthy lifestyle behaviors were gathered. Preventive care practices were analyzed with regards to age and gender. RESULTS: A total of 7228 doctors participated in the study. Comparison with the national data revealed higher hyperlipidemia and coronary artery disease rates. While 54.5% of the doctors had a doctor visit in the last 12 months, only 31.5% of those over 40 years of age reported a recent blood pressure measurement. Colon cancer screening rate over 50 years of age with any of the acceptable methods was only 3%. One-fourth of the female doctors over 40 years of age underwent mammography within the last two years. Only 7.1% of the doctors over 65 years of age and 10% of the doctors having an indication for a chronic disease had a pneumococcal vaccine, while nearly one-fifth had no hepatitis B vaccine. CONCLUSION: In this cohort of mainly middle-aged Turkish doctors, the age standardized rates of chronic diseases were lower than the rates in the general population except for the rates of hyperlipidemia and coronary artery disease. However, doctors did show quite low rates of receipt of screening practices. These results might provoke questions about how to use Turkish doctors' health behaviors to further improve doctors' and, relatedly, patients' health. PMID- 27960641 TI - Proparacaine-Induced Mydriasis During Strabismus Surgery. AB - AIM: To evaluate the mydriatic effect of proparacaine hydrochloride (PH) in children undergoing strabismus surgery under general anesthesia (GA). METHODS: This was a pilot, prospective, non-randomized, self-controlled interventional study. Nine children with esotropia or exotropia undergoing horizontal muscle squint surgery under GA at a tertiary eye care center were included. The six Group 1 patients underwent both eye surgeries, while the three Group 2 patients underwent single eye surgery. PH was instilled in one eye of Group 1 patients and both eyes of Group 2 patients. Change in pupil diameter (PD) was analyzed as the main outcome measure. RESULTS: Mean age of the patients was 4.67 +/- 2.64 years. In the study eyes, mean average baseline PD was 1.59 +/- 0.40 mm (range: 1.06 2.37), while postoperative average PD was 3.99 +/- 1.34 mm (range: 1.79-6.02). The mean baseline PC had increased from 5.51 +/- 1.09 mm to 12.6 +/- 3.58 mm at the end of the surgery. PD and PC increased in all of the study eyes while no change in PD or PC was seen in the control eyes of either of the groups. The dilated pupil was skewed horizontally towards the muscle being operated upon in all of the study eyes. CONCLUSIONS: PH has a mydriatic effect of its own. It penetrates through the bare sclera and leads on to skewed dilation of the pupil. Surgeons should consider this effect while judging pupil alignment at the end of the surgery. PMID- 27960644 TI - Cutaneous diffuse large B-cell lymphoma in an infant. PMID- 27960642 TI - The role of CDKN2A/B deletions in pediatric acute lymphoblastic leukemia. AB - The CDKN2A/B genes in the 9p21 chromosomal region are frequently involved in human cancer, including pediatric acute lymphoblastic leukemia (ALL). These genes encode 3 proteins that belong to the RB1 and TP53 pathways and act as tumor suppressors by regulating the G1/S checkpoint of the cell cycle. The prognostic value of deletions in the CDKN2A/B locus in ALL is controversial in part due to the limitations of the methodologies used. Further studies with advanced technologies are needed for elucidation. Future studies would also highlight whether CDK4/CDK6 selective inhibitors might be useful therapies for children with these genetic aberrations. PMID- 27960645 TI - Combined therapy in children and adolescents with classical Hodgkin's lymphoma: A report from the SFCE on MDH-03 national guidelines. AB - Hodgkin's lymphoma (HL) in children and adolescents is highly curable, but children are at risk of long-term toxicity. The MDH-03 guidelines were established in order to decrease the burden of treatment in good-responder patients, and this report should be considered a step toward further optimization of treatment within large collaborative trials. We report the therapy and long term outcomes of 417 children and adolescents treated according to the national guidelines, which were applied between 2003 and 2007 in France. The patients were stratified into three groups according to disease extension. Chemotherapy consisted of four cycles of VBVP (vinblastine, bleomycin, VP16, prednisone) in localized stages (G1/95 pts/23%), four cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, adriamycin, bleomycin, vinblastine) cycles in intermediate stages (G2/184 pts/44%) and three cycles of OPPA (vincristine, procarbazine, prednisone, adriamycin) plus three cycles of COPP in advanced stages (G3/138 pts/33%). Radiation therapy of the involved field was given to 97% of the patients, with the dose limited to 20 Gy in good responders (88%). With a median follow-up of 6.6 years, the 5-year event-free survival (EFS) and overall survival (OS) were 86.7% (83.1-89.7%) and 97% (94.5-98.1%), respectively. EFS and OS for G1, G2, and G3 were 98% and 100%, 81% and 97%, and 87% and 95%, respectively. Low-risk patients treated without alkylating agents and anthracycline had excellent outcomes and a low expected incidence of late effects. Intensification with a third OPPA cycle in high-risk group patients, including stage IV patients, allowed for very good outcomes, without increased toxicity. PMID- 27960646 TI - Varicella in pediatric oncology patients in the post-vaccine era-Analysis of routine hospital data from Bavaria (Germany), 2005-2011. AB - Varicella in oncology patients can result in serious complications. We analyzed trends in hospitalization rates and characteristics of pediatric oncology and non oncology patients hospitalized with varicella during the first 7 years after introduction of routine varicella vaccination. Our data included children <17 years of age with an International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) main or secondary discharge diagnosis of varicella identified by annual database queries in 22-29 pediatric hospitals in Bavaria (Germany) in 2005-2011. Of a total of 1,245 varicella-associated hospitalizations, 42 children (median age 4 years, interquartile range 3-5) had an underlying malignancy (67% with acute lymphoblastic leukemia). Overall, additional diagnoses potentially associated with varicella were reported less often in oncology than in non-oncology varicella patients (62% vs. 77%, p = 0.041), suggesting earlier hospitalization of high-risk patients. Acute hematological diagnoses (29% vs. 3%, p < 0.001) and coinfections (invasive 12% vs. 2%, p = 0.001; noninvasive 19% vs. 8%, p = 0.019) were more frequent, whereas neurological (5% vs. 19%, p = 0.023) and upper respiratory tract diagnoses (2% vs. 16%, p = 0.014) were less frequent in oncology compared to non-oncology varicella patients. Oncology varicella patients showed a longer hospital stay (median 5 vs. 3 days, p < 0.001). Hospitalization rates in non-oncology varicella patients declined constantly since 2006, from 114.8 (2006) to 30.5 (2011) per 1,000 pediatric beds. The rates of varicella-associated hospitalizations in oncology patients indicated an overall decreasing trend (3.8, 1.9, 4.6, 3.5, 0.4, 2.1 and 0.6 cases per 1,000 pediatric beds in 2005-2011). Thus, pediatric oncology patients potentially profit from herd protection effects, resulting from increasing vaccine coverage in the general population. PMID- 27960647 TI - Proton pump inhibitors use suppresses iron absorption in congenital dyserythropoietic anemia. AB - Congenital dyserythropoietic anemia type I (CDA I) is associated, as other anemic noninflammatory states, with ineffective erythropoiesis and increased iron absorption, which may lead to complication of iron overload. The latter complication requires iron-chelating therapy, which may be associated with adverse effects and toxicity. Gastric acid production is known to be an important factor that facilitates non-heme iron absorption. The purpose of this study was to examine whether treatment with proton pump inhibitors (PPIs) can decrease iron absorption in patients with CDA I. Eight CDA I patients (4 boys) aged 12-18 years with mild iron overload (not yet requiring chelating therapy) received 20 mg/d omeprazole for 6 months. Blood samples were obtained for ferritin, C-reactive protein, hemoglobin, calcium, and magnesium at baseline, at the end of months intervention and 6 months after its cessation. The mean ferritin level decreased from 585 +/- 180 ng/ml at baseline to 522 +/- 172 ng/ml at the end of 6-month treatment and 660 +/- 256 ng/ml 6 months after cessation of omeprazole treatment (p = 0.009). Omeprazole treatment caused a nonsignificant reduction in the mean iron level (iron 159 +/- 42, 136 +/- 54,167 +/- 34 ug/dl, p = 0.302). However, mean hemoglobin level was mildly but significantly reduced (Hg 10.0 +/- 0.8, 9.55 +/- 1.0, 10.4 +/- 10.7 g/dl, p = 0.002). No adverse effects were reported. Our investigation suggests that administration of PPI to patients with CDA I may reduce iron absorption and may lower iron overload and the need for chelation therapy. PMID- 27960649 TI - The impact of airborne particulate matter on pediatric hospital admissions for pneumonia among children in Jinan, China: A case-crossover study. AB - : This study aims to examine the effect of short-term changes in the concentration of particulate matter of diameter <=2.5 um (PM2.5) and <=10 um (PM10) on pediatric hospital admissions for pneumonia in Jinan, China. It explores confoundings factors of weather, season, and chemical pollutants. Information on pediatric hospital admissions for pneumonia in 2014 was extracted from the database of Jinan Qilu Hospital. The relative risk of pediatric hospital admissions for pneumonia was assessed using a case-crossover approach, controlling weather variables, day of the week, and seasonality. The single pollutant model demonstrated that increased risk of pediatric hospital admissions for pneumonia was significantly associated with elevated PM2.5 concentrations the day before hospital admission and elevated PM10 concentrations 2 days before hospital admission. An increment of 10 MUg/m3 in PM2.5 and PM10 was correlated with a 6% (95% CI 1.02--1.10) and 4% (95% CI 1.00-1.08) rise in number of admissions for pneumonia, respectively. In two pollutant models, PM2.5 and PM10 remained significant after inclusion of sulfur dioxide or nitrogen dioxide but not carbon monoxide. This study demonstrated that short-term exposure to atmospheric particulate matter (PM2.5/PM10) may be an important determinant of pediatric hospital admissions for pneumonia in Jinan, China. IMPLICATIONS: This study demonstrated that short-term exposure to atmospheric particulate matter (PM2.5/PM10) may be an important determinant of pediatric hospital admissions for pneumonia in Jinan, China, and suggested the relevance of pollutant exposure levels and their effects. As a specific group, children are sensitive to airborne particulate matter. This study estimated the short-term effects attribute to other air pollutants to provide references for relevant studies. PMID- 27960650 TI - First report of HTLV-1 truncated p12 protein in Brazil. PMID- 27960648 TI - Linking dietary patterns with gut microbial composition and function. AB - Emerging insights have implicated the gut microbiota as an important factor in the maintenance of human health. Although nutrition research has focused on how direct interactions between dietary components and host systems influence human health, it is becoming increasingly important to consider nutrient effects on the gut microbiome for a more complete picture. Understanding nutrient-host microbiome interactions promises to reveal novel mechanisms of disease etiology and progression, offers new disease prevention strategies and therapeutic possibilities, and may mandate alternative criteria to evaluate the safety of food ingredients. Here we review the current literature on diet effects on the microbiome and the generation of microbial metabolites of dietary constituents that may influence human health. We conclude with a discussion of the relevance of these studies to nutrition and public health and summarize further research needs required to realize the potential of exploiting diet-microbiota interactions for improved health. PMID- 27960651 TI - In-vehicle carbon dioxide concentration in commuting cars in Bangkok, Thailand. AB - : It is known that in-vehicle carbon dioxide (CO2) concentration tends to increase due to occupant exhalation when the HVAC (heating, ventilation, and air conditioning) air is in recirculation mode. Field experiments were conducted to measure CO2 concentration during typical commute in Bangkok, Thailand. The measured concentrations agreed with the concentration predicted using first-order mass balance equation, in both recirculating and outside air modes. The long-term transient decay of the concentration when the vehicle was parked and the HVAC system was turned off was also studied. This decay was found to follow Fickian diffusion process. The paper also provides useful operational details of the automotive HVAC system and fresh air ventilation exchange between cabin interior and exterior. IMPLICATIONS: Drivers in tropical Asian countries typically use HVAC recirculation mode in their automobiles. This behavior leads to excessive buildup of cabin CO2 concentration levels. The paper describes the CO2 buildup in a typical commute in Bangkok, Thailand. Auto manufacturers can potentially take measures to alleviate such high concentration levels. The paper also discusses the diffusion of CO2 through the vehicle envelope, an area that has never been investigated before. PMID- 27960652 TI - The undue burden of paying for abortion: An exploration of abortion fund cases. AB - The results of a secondary data analysis of 3,999 administrative cases from a national abortion fund, representing patients who received pledges for financial assistance to pay for an abortion from 2010 to 2015, are presented. Case data from the fund's national call center was analyzed to assess the impact of the fund and examine sample demographics which were compared to the demographics of national abortion patients. Procedure costs, patient resources, funding pledges, additional aid, and changes over time in financial pledges for second-trimester procedures were also examined. Results indicate that the fund sample differed from national abortion patients in that fund patients were primarily single, African American, and seeking funding for second trimester abortions. Patients were also seeking to fund expensive procedures, costing an average of over $2,000; patients were receiving over $1,000 per case in pledges and other aid; and funding pledges for second trimester procedures were increasing over time. Abortion funding assistance is essential for women who are not able to afford abortion costs, and it is particularly beneficial for patients of color and those who are younger and single. Repeal of policy banning public funding of abortion would help to eliminate financial barriers that impede abortion access. PMID- 27960653 TI - Experimental and modeling analyses for interactions between graphene oxide and quartz sand. AB - The aim of this study was to quantify the interactions between graphene oxide (GO) and quartz sand by conducting experimental and modeling analyses. The results show that both GO and quartz sand were negatively charged in the presence of 0-50 mM NaCl and 5 mM CaCl2 (GO = -43.10 to -17.60 mV, quartz sand = -40.97 to -8.44 mV). In the Derjaguin-Landau-Verwey-Overbeek (DLVO) energy profiles, the adhesion of GO to quartz sand becomes more favorable with increasing NaCl concentration from 0 to 10 mM because the interaction energy profile was compressed and the primary maximum energy barrier was lowered. At 50 mM NaCl and 5 mM CaCl2, the primary maximum energy barrier even disappeared, resulting in highly favorable conditions for GO retention to quartz sand. In the Maxwell model analysis, the probability of GO adhesion to quartz sand (alpham) increased from 2.46 * 10-4 to 9.98 * 10-1 at ionic strengths of 0-10 mM NaCl. In the column experiments (column length = 10 cm, inner diameter = 2.5 cm, flow rate = 0.5 mL min-1), the mass removal (Mr) of GO in quartz sand increased from 5.4% to 97.8% as the NaCl concentration was increased from 0 to 50 mM, indicating that the mobility of GO was high in low ionic strength solutions and decreased with increasing ionic strength. The Mr value of GO at 5 mM CaCl2 was 100%, demonstrating that Ca2+ had a much stronger effect than Na+ on the mobility of GO. In addition, the mobility of GO was lower than that of chloride (Mr = 1.4%) but far higher than that of multi-walled carbon nanotubes (Mr = 87.0%) in deionized water. In aluminum oxide-coated sand, the Mr value of GO was 98.1% at 0 mM NaCl, revealing that the mobility of GO was reduced in the presence of metal oxides. The transport model analysis indicates that the value of the dimensionless attachment rate coefficient (Da) increased from 0.11 to 4.47 as the NaCl concentration was increased from 0 to 50 mM. In the colloid filtration model analysis, the probability of GO sticking to quartz sand (alphaf) increased from 6.23 * 10-3 to 2.52 * 10-1 as the NaCl concentration was increased from 0 to 50 mM. PMID- 27960654 TI - A case of dose escalation of quetiapine in persistent insomnia disorder. AB - Quetiapine, an atypical antipsychotic drug, is recommended for the treatment of schizophrenia and mood disorders. In addition, given its sedative effects, a low dose of the agent is also widely used in the treatment of anxiety disorders, personality disorders, substance abuse, and sleep disturbances. In this case study, quetiapine was the first effective drug in reducing chronic insomnia in a male patient with a long treatment history. Because its effect declined over time, in the course of two years, a gradual dose increase led to a posology 50 times higher than the off-label dosage used to obtain sedation, i.e. 25-100 mg quetiapine administered once daily. This case raises awareness of the ease with which dose escalation of quetiapine occurs. The risk of side effects and, possibly, dependence and abuse underlines the importance of regular and careful patient monitoring. Given the unexpected effectiveness of the agent and the absence of side effects in the described case, we argue that in treatment resistant insomnia, a high dose of quetiapine may be justifiable in selected cases but also urge that further research on the long-term effects and potential adverse events of quetiapine for this indication is of the utmost importance. PMID- 27964698 TI - Development of the crop residue and rangeland burning in the 2014 National Emissions Inventory using information from multiple sources. AB - : Biomass burning has been identified as an important contributor to the degradation of air quality because of its impact on ozone and particulate matter. One component of the biomass burning inventory, crop residue burning, has been poorly characterized in the National Emissions Inventory (NEI). In the 2011 NEI, wildland fires, prescribed fires, and crop residue burning collectively were the largest source of PM2.5. This paper summarizes our 2014 NEI method to estimate crop residue burning emissions and grass/pasture burning emissions using remote sensing data and field information and literature-based, crop-specific emission factors. We focus on both the postharvest and pre-harvest burning that takes place with bluegrass, corn, cotton, rice, soybeans, sugarcane and wheat. Estimates for 2014 indicate that over the continental United States (CONUS), crop residue burning excluding all areas identified as Pasture/Grass, Grassland Herbaceous, and Pasture/Hay occurred over approximately 1.5 million acres of land and produced 19,600 short tons of PM2.5. For areas identified as Pasture/Grass, Grassland Herbaceous, and Pasture/Hay, biomass burning emissions occurred over approximately 1.6 million acres of land and produced 30,000 short tons of PM2.5. This estimate compares with the 2011 NEI and 2008 NEI as follows: 2008: 49,650 short tons and 2011: 141,180 short tons. Note that in the previous two NEIs rangeland burning was not well defined and so the comparison is not exact. The remote sensing data also provided verification of our existing diurnal profile for crop residue burning emissions used in chemical transport modeling. In addition, the entire database used to estimate this sector of emissions is available on EPA's Clearinghouse for Inventories and Emission Factors (CHIEF, http://www3.epa.gov/ttn/chief/index.html ). IMPLICATIONS: Estimates of crop residue burning and rangeland burning emissions can be improved by using satellite detections. Local information is helpful in distinguishing crop residue and rangeland burning from all other types of fires. PMID- 27964699 TI - A Review of Hypertension Management in Atrial Fibrillation. AB - Atrial fibrillation (AF) is one of the commonest arrhythmias in clinical practice and has major healthcare and economic implications. It is a growing epidemic with prevalence all set to double to 12 million by 2050. After adjusting for other associated conditions, hypertension confers a 1.5- and 1.4-fold risk of developing AF, for men and women respectively. Furthermore, in patients with AF, the presence of hypertension has a cumulative effect on the risk of stroke. Growing evidence suggests reversal or attenuation of various structural and functional changes predisposing to AF with the use of antihypertensive medications. Randomized trials have shown major reduction in the risk of stroke and heart failure with blood pressure reduction. However, such trials are lacking in AF patients specifically. The Joint National Committee-8 guidelines have not addressed the threshold or goal BP for patients with known AF. Furthermore, "J shaped" or "U-shaped" curves have been noted during hypertension management in patients with AF with published data demonstrating worse outcomes in patients with strict BP control to <110/60 mmhg similar to coronary artery disease. In this review, we outline the available literature on management of hypertension in patients with AF as well as the role of individual anti-hypertensive medications in reducing the incidence of AF Fig. 1. PMID- 27964700 TI - Parvalbumin as a Pleomorphic Protein. AB - Parvalbumin (PA) is a classical small, mostly cytosolic Ca2+-binding protein of the EF-hand superfamily expressed in vertebrates in a tissue- and cell-specific manner, serving as a magnesium/ calcium buffer. In the last decade novel data were published on structural peculiarities of PA, likely affecting its functionality. This review sums up these findings and discusses their potential physiological significance. PMID- 27964701 TI - Inductively Coupled Plasma Mass Spectrometry (ICP-MS) Applications in Quantitative Proteomics. AB - Recent advances in inductively coupled plasma mass spectrometry (ICP-MS) hyphenated to different separation techniques have promoted it as a valuable tool in protein/peptide quantification. These emerging ICP-MS applications allow absolute quantification by measuring specific elemental responses. One approach quantifies elements already present in the structure of the target peptide (e.g. phosphorus and sulphur) as natural tags. Quantification of these natural tags allows the elucidation of the degree of protein phosphorylation in addition to absolute protein quantification. A separate approach is based on utilising bi functional labelling substances (those containing ICP-MS detectable elements), that form a covalent chemical bond with the protein thus creating analogs which are detectable by ICP-MS. Based on the previously established stoichiometries of the labelling reagents, quantification can be achieved. This technique is very useful for the design of precise multiplexed quantitation schemes to address the challenges of biomarker screening and discovery. This review discusses the capabilities and different strategies to implement ICP-MS in the field of quantitative proteomics. PMID- 27964702 TI - Minichromosome Maintenance Complex is Required for Checkpoint Kinase 2 Chromatin Loading and its Phosphorylation to DNA Damage Response in SCC-4 Cells. AB - Checkpoint kinase 2 (Chk2) is a significant mediator of diverse responses to DNA damage. The present study was aimed to identify possible interactive proteins of Chk2 and try to clarify the underlying mechanism regarding Chk2 chromatin loading and its phosphorylation to DNA damage response in oral squamous cell carcinoma (OSCC). Differently tagged Chk2 and minichromosome maintenance (MCM) complex (MCM2, MCM3, MCM5, and MCM6) were overexpressed into SCC-4 cells. After 48 h of transfection cell fractionation was performed to localize proteins. In addition, immunoreactive species were detected by immunoprecipitation (IP) and immunoblot (IB) analysis, and protein-protein interaction between Chk2 and MCM complex was ensured by glutathione S-transferase (GST) pull-down assay. Expression of MCM2 and MCM6 was downregulated by small interfering RNA (siRNA), and the chromatin and non-chromatin fraction were analyzed. The expression of Chk2 phosphorylation (pT68-Chk2) was measured after administration of different dosages of siMCM2 (0.5 MUg, 1 MUg, and 2.5 MUg) and camptothecin (CPT). Our results showed that Chk2 directly interacts with MCM2, MCM3, MCM5, and MCM6 in SCC-4 cells. Downregulation of MCM2 and MCM6 markedly reduced Chk2 chromatin fraction, and downregulation of MCM2 decreased the expression of pT68-Chk2 to DNA damage response in a dose manner. Our results suggest that the interaction between Chk2 and MCM complex is required for Chk2 chromatin loading and its phosphorylation to DNA damage response in SCC-4 cells. PMID- 27964704 TI - Common SAR Derived from Linear and Non-linear QSAR Studies on AChE Inhibitors used in the Treatment of Alzheimer's Disease. AB - BACKGROUND: Deficits in cholinergic neurotransmission due to the degeneration of cholinergic neurons in the brain are believed to be one of the major causes of the memory impairments associated with AD. Targeting acetyl cholinesterase (AChE) surfaced as a potential therapeutic target in the treatment of Alzheimer's disease. The present study is pursued to develop quantitative structure activity relationship (QSAR) models to determine chemical descriptors responsible for AChE activity. METHODS: Two different sets of AChE inhibitors, dataset-I (30 compounds) and dataset-II (20 compounds) were investigated through MLR aided linear and SVM aided non-linear QSAR models. RESULTS: The obtained QSAR models were found statistically fit, stable and predictive on validation scales. These QSAR models were further investigated for their common structure-activity relationship in terms of overlapping molecular descriptors selection. Atomic mass weighted 3D Morse descriptors (MATS5m) and Radial Distribution Function (RDF045m) descriptors were found in common SAR for both the datasets. Electronegativity weighted (MATS5e, HATSe, and Mor17e) descriptors have also been identified in regulative roles towards endpoint values of dataset-I and dataset-II. CONCLUSION: The common SAR identified in these linear and non-linear QSAR models could be utilized to design novel inhibitors of AChE with improved biological activity. PMID- 27964706 TI - Low-Dose Methotrexate (LD-MTX) in Rheumatology Practice - A Most Widely Misunderstood Drug. AB - Methotrexate (MTX) was synthesised as a folate antagonist for use in treating childhood leukaemia in 1940s. Gubner and colleagues in 1953 used several log order lower doses of MTX that mimicked the anti-inflammatory properties of cortisone. They used it successfully in treating rheumatoid arthritis (RA). Their work was however overlooked because the Nobel Prize winning drug cortisone held sway in those days. With increasing awareness of the adverse effects of cortisone, interest was rekindled in discovering 'steroid-sparing' drugs. Hoffmeister and Willkens used low-dose MTX (LD-MTX) in treating RA patients in 1960s with impressive results. Pivotal trials in 1984-5 established the efficacy and safety of LD-MTX in treating RA that gained FDA approval in 1988. LD-MTX at doses <25-30 mg weekly as mini-pulses, is presently the standard-of-care for the treatment of RA. Its toxicities and adverse effects are rarely if ever life threatening. This is in contrast to the high-dose methotrexate (HD-MTX) for treating malignancies at doses that are several log-orders higher and usually cause serious toxicities. While LD-MTX acts mainly as an anti-inflammatory drug by increasing tissue adenosine levels besides other mechanisms, HD-MTX has anti proliferative cytotoxic action with different toxicity profile and adverse effects. In practical terms LD-MTX and HD-MTX are 2 different therapeutic agents. However, in developing countries like India the stigma attached to MTX as a cytotoxic 'cancer drug' still persists and most non-rheumatologists fear its use in RA. This review aims to allay such anxiety attached to LD-MTX so that they start using it in appropriate doses for treating RA. PMID- 27964707 TI - Editorial (Thematic Issue: Nanocomposites for Environmental Remediation and their Fascinating Attributes). PMID- 27964703 TI - Implications of Epigenetic Mechanisms and their Targets in Cerebral Ischemia Models. AB - BACKGROUND: Understanding the complexities associated with the ischemic condition and identifying therapeutic targets in ischemia is a continued challenge in stroke biology. Emerging evidence reveals the potential involvement of epigenetic mechanisms in the incident and outcome of stroke, suggesting novel therapeutic options of targeting different molecules related to epigenetic regulation. OBJECTIVE: This review summarizes our current understanding of ischemic pathophysiology, describes various in vivo and in vitro models of ischemia, and examines epigenetic modifications associated with the ischemic condition. METHOD: We focus on microRNAs, DNA methylation, and histone modifying enzymes, and present how epigenetic studies are revealing novel drug target candidates in stroke. CONCLUSION: Finally, we discuss emerging approaches for the prevention and treatment of stroke and post-stroke effects using pharmacological interventions with a wide therapeutic window. PMID- 27964705 TI - Biological Drugs in Guillain-Barre Syndrome: An Update. AB - BACKGROUND: Guillain-Barre Syndrome (GBS) is currently considered the most common global cause of acute flaccid paralysis. Currently, standard therapy for Guillain Barre Syndrome includes intravenous immunoglobulin or plasma exchange. Despite medical advances regarding these treatments, many treated patients do not reach full recovery. Therefore several biological agents have attracted the attentions from researchers during the last decades, and various studies have investigated their role in Guillain-Barre Syndrome. OBJECTIVE: The present study aims to address emerging biological approaches to GBS while considering their efficiency and safety in treating the disease. MATERIALS AND METHODS: An extensive electronic literature search was conducted by two researchers from April 2016 to July 2016. Original articles, clinical trials, systematic reviews (with or without meta-analysis) and case reports were selected. Titles and abstracts of papers were screened by reviewers to determine whether they met the eligibility criteria, and full texts of the selected articles were retrieved. RESULTS: Herein authors focused on the literature data concerning emerging biological therapeutic agents, namely anti-C5 monoclonal antibody (Eculizumab), anti-C1q monoclonal antibody, anti-T cell monoclonal antibody, anti-CD2 monoclonal antibody, anti L selectin monoclonal antibody, anti- CD20 monoclonal antibody (Rituximab), anti CD52 monoclonal antibody (Alemtuzumab) and cytokine targets. By far, none of these agents have been approved for the treatment of GBS by FDA. CONCLUSION: Literature findings represented in current review herald promising results for using these biological targets. Current review represents a summary of what is already in regards and what progress is required to improve the immunotherapeutic approach of treating GBS via future studies. PMID- 27964709 TI - The clinically excellent primary care physician: examples from the published literature. AB - Clinical excellence is the ultimate goal in patient care. Exactly what the clinically excellent primary care physician (PCP) looks like and her characteristics have not been explicitly described. This manuscript serves to illustrate clinical excellence in primary care, using primarily case reports exemplifying physicians delivering holistic and patient-centred care to their patients. With an ever increasing demand for accessible and accountable health care, an understanding of the qualities desirable in primary care providers is now especially relevant.A literature review was conducted to identify compelling stories showing how excellent PCPs care for their patients. In the 2397 published works reviewed, we were able to find case reports and studies that exemplified every domain of the description of clinical excellence proposed and published by the Miller Coulson Academy of Clinical Excellence (MCACE). After reviewing these reports, the authors felt that the domains of excellence, as described by the MCACE, are practically applicable and relevant for primary care physicians. It is our hope that this paper prompts readers to reflect on clinical excellence in primary care. PMID- 27964708 TI - Systematic analysis of the lysine acetylome in Fusarium graminearum. AB - BACKGROUND: Lysine acetylation in proteins is a ubiquitous and conserved post translational modification, playing a critical regulatory role in almost every aspect of living cells. Although known for many years, its function remains elusive in Fusarium graminearum, one of the most important necrotrophic plant pathogens with huge economic impact. RESULTS: By the combination of affinity enrichment and high-resolution LC-MS/MS analysis, large-scale lysine acetylome analysis was performed. In total, 577 lysine acetylation sites matched to 364 different proteins were identified. Bioinformatics analysis of the acetylome showed that the acetylated proteins are involved in a wide range of cellular functions and exhibit diverse subcellular localizations. Remarkably, 10 proteins involved in the virulence or DON (deoxynivalenol) biosynthesis were found to be acetylated, including 4 transcription factors, 4 protein kinases and 2 phosphatases. Protein-protein interaction network analysis revealed that acetylated protein complexes are involved in diversified interactions. CONCLUSIONS: This work provides the first comprehensive survey of a possible lysine acetylome in F. graminearum and reveals previously unappreciated roles of lysine acetylation in the regulation of diverse biological processes. This work provides a resource for functional analysis of acetylated proteins in filamentous fungi. PMID- 27964711 TI - Erratum to: The effects of arginase inhibitor on lung oxidative stress and inflammation caused by pneumoperitoneum in rats. PMID- 27964710 TI - First case report of inherited Rubinstein-Taybi syndrome associated with a novel EP300 variant. AB - BACKGROUND: Rubinstein-Taybi syndrome (RSTS; OMIM #180849, #613684) is a rare autosomal dominant genetic condition characterized by broad thumbs and halluces, facial dysmorphism, short stature and variable degree of intellectual disability. RSTS is associated with mutations in CREBBP and EP300 genes in 50-60% and 5-8% of cases, respectively. The majority of cases are de novo heterozygous mutations. CASE PRESENTATION: Here we describe a familial RSTS case, associated with a novel EP300 mutation. The proband was a 9 years old female, with mild learning difficulties. Her mother, who also had learning difficulties, was found to have short and broad thumbs. MLPA and panel-based NGS of CREBBP and EP300 were performed. A novel heterozygous frameshift mutation in exon 31 of the EP300 gene (c.7222_7223del; p.(Gln2408Glufs*39)) was found in both. CONCLUSIONS: This case represents the first case of inherited EP300-RSTS. The location of the frameshift deletion not affecting HAT domain and PHD finger, could explain the mild phenotype and the well-preserved intelligence. These patients are mildly affected, and this case highlights the possible missed diagnosis. We would recommend molecular testing of apparently healthy parents, and in the case of inherited mutations, of all adult first degree relatives at risk. PMID- 27964713 TI - Medical students' feedback regarding their clinical learning environment in primary healthcare: a qualitative study. AB - BACKGROUND: An increasing part of medical students' learning takes place in primary healthcare (PHC) but little is known about how the students perceive PHC as a clinical learning environment. This study aimed to explore medical students' perceptions of the clinical learning environment in PHC and how these vary with stage of education. METHODS: Free-text course evaluation comments from students in nine different semesters during spring 2014 were analysed using qualitative content analysis. The students had placements in PHC from the first semester, progressing through the whole 5.5 year medical programme, and this was their main clinical training environment during the final 11th semester. RESULTS: In total, 800 students (56%) agreed to participate in the study and 437 of these (54%) provided comments. Two overall themes were identified: the supervisor was the central factor that determined the meaningfulness of the placement at all stages of the education, and basic prerequisites for perceived clinical learning were to have an active role in an authentic clinical context and to be trusted to work independently with patients. The three main categories found under these themes were: i) the perceived relationship with the supervisor; ii) the perceived journey to become a doctor; and iii) the perceived structure and culture. CONCLUSION: The supervisor's role was perceived as central at all stages of the education but the focus changed for other aspects, related to the students' professional development. The need for trust and independence in patient work increased towards the end of the education. PMID- 27964712 TI - Genes associated with persistent lumbar radicular pain; a systematic review. AB - BACKGROUND: The aim of the present study was to provide an overview of the literature addressing the role of genetic factors and biomarkers predicting pain recovery in newly diagnosed lumbar radicular pain (LRP) patients. METHODS: The search was performed in Medline OVID, Embase, PsycInfo and Web of Science (2004 to 2015). Only prospective studies of patients with LRP addressing the role of genetic factors (genetic susceptibility) and pain biomarkers (proteins in serum) were included. Two independent reviewers extracted the data and assessed methodological quality. RESULTS: The search identified 880 citations of which 15 fulfilled the inclusion criteria. Five genetic variants; i.e., OPRM1 rs1799971 G allele, COMT rs4680 G allele, MMP1 rs1799750 2G allele, IL1alpha rs1800587 T allele, IL1RN rs2234677 A allele, were associated with reduced recovery of LRP. Three biomarkers; i.e., TNFalpha, IL6 and IFNalpha, were associated with persistent LRP. CONCLUSION: The present results indicate that several genetic factors and biomarkers may predict slow recovery in LRP. Still, there is a need for replication of the findings. A stricter use of nomenclature is also highly necessary. TRIAL REGISTRATION: The review is registered PROSPERO 20th of November 2015. Registration number is CRD42015029125 . PMID- 27964714 TI - Diuretic and antioxidant activities of the aqueous extract of leaves of Vepris heterophylla (Engl.) R. Let (Rutaceae) in rats. AB - BACKGROUND: Vepris heterophylla (Rutaceae) is a medicinal plant used empirically in African traditional medicine for many clinical conditions including edematous disorders and hypertension. V. heterophylla aqueous extract has been used in northern part of Cameroon by traditional healers for the treatment of arterial hypertension. The study aim was to assess the putative diuretic and antioxidant properties of V. heterophylla leaves aqueous extract. METHODS: Adult rats were administered with V. heterophylla leaves aqueous extract acutely (24 h) at doses 50, 100, 150, 200 and 250 mg/kg (per os). The two positive control groups received the diuretic drugs furosemide (5 mg/kg) and hydrochlorothiazide (HCTZ, 10 mg/kg), while negative control group received only an equivalent volume of distilled water. Urinary elimination of electrolytes in response to treatments was evaluated, together with changes in concentrations of creatinine, urea, aldosterone, glucose and albumin in urine and plasma. Various urinary indicators of kidney function and plasmatic markers of oxidative stress were also assessed. RESULTS: The findings indicated that the aqueous extract of V. heterophylla at doses ranging from 150 to 250 mg/kg caused a significant and dose-dependent increase of urinary water and electrolytes excretion in normal rats. The aqueous extract of the leaves of V. heterophylla accelerated the elimination of overloaded fluid. At the maximum of diuretic response, urinary osmolarity decreased significantly when compared with controls. Oral administration of aqueous extract at different doses produced a significant diuresis and slight increase in electrolytes (Na+, K+ and Cl-) excretion. The results obtained were compared with standard drug-furosemide (5 mg/kg) and hydrochlorothiazide (10 mg/kg). These effects were observed predominantly at 250 mg/kg dose. CONCLUSIONS: Our findings strongly suggest that V. heterophylla aqueous extract has diuretic and antioxidant activities, and deserves further studies considering the potential for the treatment of hypertension. PMID- 27964715 TI - Differential effects of palmitoleic acid on human lymphocyte proliferation and function. AB - BACKGROUND: Palmitoleic acid (PA) is a n-7 monounsaturated fatty acid (MUFA) secreted by adipose tissue and related to decreased insulin resistance in peripheral tissues. Evidences have been shown that PA also decreased proinflammatory cytokine expression in cultured macrophages. Although studies have shown that other fatty acids (FAs) modulate several lymphocyte functions, the specific effect of PA on these cells is unknown. The aim of the present study was to evaluate the possible influence of PA on activation and differentiation of human lymphocytes in comparison to oleic acid (OA). METHODS: Human lymphocytes were isolated from peripheral blood of health men and cultured in the presence of growing concentrations of PA or OA (5 to 200 MUM), for 24 h. After that, cells were collected and cytotoxicity evaluated by flow cytometry. Then, we analyzed proliferative capacity in lymphocytes treated with non toxic concentrations of PA and OA (25 and 50 MUM, respectively), in the presence or absence of concanavalin A (ConA). The Th1/Th2/Th17 cytokine production was determined by the Cytometric Bead Array. CD28 and CD95 surface expression and T regulatory cell percentage were determined by flow cytometry. RESULTS: We observed that PA is toxic to lymphocytes above 50 MUM. PA promoted a decrease of lymphocyte proliferation stimulated by ConA in both concentrations. PA also decreased CD28 externalization and increased CD95. On the other hand, OA did not alter these parameters. In the same way, PA reduced IL6, IFN-gamma, TNF-alpha and IL17A production in both concentration and IL2 only at 50 MUM (in the presence of ConA). OA promoted IFN gamma reduction in both concentrations and an increase of IL-2, IL4 and IL10 at 25 MUM. Both fatty acids decreased the percentage of T regulatory cells. CONCLUSION: In conclusion, PA promoted a suppressive effect on lymphocyte proliferation characterized by a decrease of Th1 and Th17 response, and co stimulatory molecule (CD28). However, OA increased lymphocyte proliferation through IL2 production and Th2 response. These results also show a more suppressive effect of PA on lymphocytes in comparison to OA. PMID- 27964716 TI - Incidence of medically attended influenza among residents of Shai-Osudoku and Ningo-Prampram Districts, Ghana, May 2013 - April 2015. AB - BACKGROUND: Influenza vaccination is recommended by the World Health Organization for high risk groups, yet few data exist on influenza disease burden in West Africa. METHODS: We estimated medically attended influenza-associated illness rates among residents of Shai-Osudoku and Ningo Pram-Pram Districts (SONPD), Ghana. From May 2013 to April 2015, we conducted prospective surveillance for severe acute respiratory illness (SARI) and influenza-like illness (ILI) in 17 health facilities. In 2015, we conducted a retrospective assessment at an additional 18 health facilities to capture all SONPD SARI and ILI patients during the study period. We applied positivity rates to those not tested to estimate total influenza cases. RESULTS: Of 612 SARI patients tested, 58 (9%) were positive for influenza. The estimated incidence of influenza-associated SARI was 30 per 100,000 persons (95% CI: 13-84). Children aged 0 to 4 years had the highest influenza-associated SARI incidence (135 per 100,000 persons, 95% CI: 120 152) and adults aged 25 to 44 years had the lowest (3 per 100,000 persons, 95% CI: 1-7) (p < 0.01). Of 2,322 ILI patients tested, 407 (18%) were positive for influenza. The estimated incidence of influenza-associated ILI was 844 per 100,000 persons (95% CI: 501-1,099). The highest incidence of influenza associated ILI was also among children aged 0 to 4 years (3,448 per 100,000 persons, 95% CI: 3,727 - 3,898). The predominant circulating subtype during May to December 2013 and January to April 2015 was influenza A(H3N2) virus, and during 2014 influenza B virus was the predominant circulating type. CONCLUSIONS: Influenza accounted for 9% and 18% of medically attended SARI and ILI, respectively. Rates were substantive among young children and suggest the potential value of exploring the benefits of influenza vaccination in Ghana, particularly in this age group. PMID- 27964717 TI - Impact of obstetric interventions on condition at birth in extremely preterm babies: evidence from a national cohort study. AB - BACKGROUND: To investigate perinatal decision-making and the use of obstetric interventions, we examined the effects of antenatal steroids, tocolysis, and delivery mode on birth in a good condition (defined as presence of an infant heart rate >100 at five minutes of age) and delivery-room (DR) death in extremely preterm deliveries. METHODS: Prospective cohort of all singleton births in England in 2006 at 22-26 weeks of gestation where the fetus was alive at the start of labour monitoring or decision to perform caesarean section. Odds ratios adjusted for potential confounders (aOR) were calculated using logistic regression. RESULTS: One thousand seven hundred twenty two singleton pregnancies were included. 1231 women received antenatal steroids, 437 tocolysis and 356 delivered by Caesarean section. In babies born vaginally, aOR between a partial course of steroids and improved condition at birth was 1.84, 95% CI: 1.20 to 2.82 and, for a complete course, 1.63, 95% CI: 1.08 to 2.47; for DR death, aORs were 0.34 (0.21 to 0.55) and 0.41 (0.26 to 0.64) for partial and complete courses of steroids. No association was seen for steroid use in babies delivered by Caesarean section. Tocolysis was associated with improved condition at birth (aOR 1.45, 95% CI: 1.05 to 2.0) and lower odds of death (aOR 0.48, 95% CI: 0.32 to 0.73). In women without spontaneous labour, Caesarean delivery at <=24 and 25 weeks was associated with improved condition at birth ((aORs 12.67 (2.79 to 57.60) and 4.94 (1.44 to 16.90), respectively) and lower odds of DR death (aORs 0.03 (0.01 to 0.21) and 0.13 (0.03 to 0.55)). There were no differences at 26 weeks gestation or in women with spontaneous labour. CONCLUSIONS: Antenatal steroids are strongly associated with improved outcomes in babies born vaginally. Tocolysis was associated with improvements in all analyses. Effects persisted after adjustment for perinatal decision-making. However, associations between delivery mode and birth outcomes may be attributable to case selection. PMID- 27964719 TI - Pathway collages: personalized multi-pathway diagrams. AB - BACKGROUND: Metabolic pathway diagrams are a classical way of visualizing a linked cascade of biochemical reactions. However, to understand some biochemical situations, viewing a single pathway is insufficient, whereas viewing the entire metabolic network results in information overload. How do we enable scientists to rapidly construct personalized multi-pathway diagrams that depict a desired collection of interacting pathways that emphasize particular pathway interactions? RESULTS: We define software for constructing personalized multi pathway diagrams called pathway-collages using a combination of manual and automatic layouts. The user specifies a set of pathways of interest for the collage from a Pathway/Genome Database. Layouts for the individual pathways are generated by the Pathway Tools software, and are sent to a Javascript Pathway Collage application implemented using Cytoscape.js. That application allows the user to re-position pathways; define connections between pathways; change visual style parameters; and paint metabolomics, gene expression, and reaction flux data onto the collage to obtain a desired multi-pathway diagram. We demonstrate the use of pathway collages in two application areas: a metabolomics study of pathogen drug response, and an Escherichia coli metabolic model. CONCLUSIONS: Pathway collages enable facile construction of personalized multi-pathway diagrams. PMID- 27964720 TI - Somatic comorbidity among migrants with posttraumatic stress disorder and depression - a prospective cohort study. AB - BACKGROUND: In a cohort of migrants in Denmark, we compared somatic disease incidence among migrants diagnosed with posttraumatic stress disorder (PTSD) and depression with migrants without a diagnosed psychiatric disorder. METHODS: The study builds on a unique cohort of migrants who obtained residence permit in Denmark from 1993 to 2010 (N = 92,104). The association with somatic disease was explored via register linkage. We used Poisson regression to model incidence rate ratios (IRR) adjusted for age, sex, income and region of origin. The Danish Data Protection Agency granted authorisation for the implementation of the project (No 2012-41-0065). RESULTS: Our results showed that migrants diagnosed with PTSD and depression had significantly higher rates of somatic diseases compared with migrants without diagnosed psychiatric disorders - especially, infectious disease (IRR, 1.89; 95% CI, 1.45-2.48; p < 0.01), neurological disease (IRR, 2.35; 95% CI, 1.91-2.91; p < 0.01) and pulmonary disease (IRR, 1.69; 95% CI, 1.37-2.00; p < 0.01). We further saw differences in the IRRs according to region of origin. CONCLUSION: Migrants with PTSD and depression had a significantly higher rates of somatic comorbidity compared with migrants without a diagnosed psychiatric disorder. The rates were especially high for infectious, neurological and pulmonary diseases. Our results further suggest difference in the rates of somatic comorbidity according to region of. Preventive and treatment services should pay special attention to improve the overall health of migrants with PTSD and depression. PMID- 27964721 TI - The economic impact of mental healthcare consumption before and after stroke in a cohort of stroke patients in the Netherlands: a record linkage study. AB - BACKGROUND: Post-stroke healthcare consumption is strongly associated with a mental health diagnosis. This study aimed to identify stroke patients who utilised mental healthcare facilities, explored their mental healthcare consumption pre-stroke and post-stroke, and examined possible predictors of costs incurred by mental healthcare consumption post-stroke. METHODS: Three databases were integrated, namely the Maastricht University Medical Centre (MUMC) Medical Administration, the Stroke Registry from the Department of Neurology at MUMC, and the Psychiatric Case Registry South-Limburg. Patients from the MUMC who suffered their first-ever stroke between January 1 2000 and December 31 2004 were included and their records were analysed for mental healthcare consumption from 5 years preceding to 5 years following their stroke (1995-2009). Regression analysis was conducted to identify possible predictors of mental healthcare consumption costs. RESULTS: A total of 1385 patients were included and 357 (25.8%) received services from a mental healthcare facility during the 10-year reference period around their stroke. The costs of mental healthcare usage increased over time and peaked 1 year post-stroke (?7057; 22% of total mental healthcare costs). The number of hospitalisation days and mental healthcare consumption pre-stroke were significant predictors of mental healthcare costs. Explained variances of these models (costs during the 5 years post-stroke: R 2 = 15.5%, costs across a 10 year reference period: R 2 = 4.6%,) were low. CONCLUSION: Stroke patients have a significant level of mental healthcare comorbidity leading to relatively high mental healthcare costs. There is a relationship between stroke and mental healthcare consumption costs, but results concerning the underlying factors responsible for these costs are inconclusive. PMID- 27964718 TI - Dhurrin metabolism in the developing grain of Sorghum bicolor (L.) Moench investigated by metabolite profiling and novel clustering analyses of time resolved transcriptomic data. AB - BACKGROUND: The important cereal crop Sorghum bicolor (L.) Moench biosynthesize and accumulate the defensive compound dhurrin during development. Previous work has suggested multiple roles for the compound including a function as nitrogen storage/buffer. Crucial for this function is the endogenous turnover of dhurrin for which putative pathways have been suggested but not confirmed. RESULTS: In this study, the biosynthesis and endogenous turnover of dhurrin in the developing sorghum grain was studied by metabolite profiling and time-resolved transcriptome analyses. Dhurrin was found to accumulate in the early phase of grain development reaching maximum amounts 25 days after pollination. During the subsequent maturation period, the dhurrin content was turned over, resulting in only negligible residual dhurrin amounts in the mature grain. Dhurrin accumulation correlated with the transcript abundance of the three genes involved in biosynthesis. Despite the accumulation of dhurrin, the grains were acyanogenic as demonstrated by the lack of hydrogen cyanide release from macerated grain tissue and by the absence of transcripts encoding dhurrinases. With the missing activity of dhurrinases, the decrease in dhurrin content in the course of grain maturation represents the operation of hitherto uncharacterized endogenous dhurrin turnover pathways. Evidence for the operation of two such pathways was obtained by metabolite profiling and time-resolved transcriptome analysis. By combining cluster- and phylogenetic analyses with the metabolite profiling, potential gene candidates of glutathione S-transferases, nitrilases and glycosyl transferases involved in these pathways were identified. The absence of dhurrin in the mature grain was replaced by a high content of proanthocyanidins. Cluster- and phylogenetic analyses coupled with metabolite profiling, identified gene candidates involved in proanthocyanidin biosynthesis in sorghum. CONCLUSIONS: The results presented in this article reveal the existence of two endogenous dhurrin turnover pathways in sorghum, identify genes putatively involved in these transformations and show that dhurrin in addition to its insect deterrent properties may serve as a storage form of reduced nitrogen. In the course of sorghum grain maturation, proanthocyanidins replace dhurrin as a defense compound. The lack of cyanogenesis in the developing sorghum grain renders this a unique experimental system to study CNglc synthesis as well as endogenous turnover. PMID- 27964722 TI - Hyperbranched polyglycerol is superior to glucose for long-term preservation of peritoneal membrane in a rat model of chronic peritoneal dialysis. AB - BACKGROUND: Replacing glucose with a better biocompatible osmotic agent in peritoneal dialysis (PD) solutions is needed in PD clinic. We previously demonstrated the potential of hyperbranched polyglycerol (HPG) as a replacement for glucose. This study further investigated the long-term effects of chronic exposure to HPG as compared to a glucose-based conventional PD solution on peritoneal membrane (PM) structure and function in rats. METHODS: Adult male Wistar rats received once-daily intraperitoneal injection of 10 mL of HPG solution (1 kDa, HPG 6%) compared to PhysionealTM 40 (PYS, glucose 2.27%) or electrolyte solution (Control) for 3 months. The overall health conditions were determined by blood chemistry analysis. The PM function was determined by ultrafiltration, and its injury by histological and transcriptome-based pathway analyses. RESULTS: Here, we showed that there was no difference in the blood chemistry between rats receiving the HPG and the Control, while PYS increased serum alkaline phosphatase, globulin and creatinine and decreased serum albumin. Unlike PYS, HPG did not significantly attenuate PM function, which was associated with smaller change in both the structure and the angiogenesis of the PM and less cells expressing vascular endothelial growth factor, alpha-smooth muscle actin and MAC387 (macrophage marker). The pathway analysis revealed that there were more inflammatory signaling pathways functioning in the PM of PYS group than those of HPG or Control, which included the signaling for cytokine production in both macrophages and T cells, interleukin (IL)-6, IL-10, Toll-like receptors, triggering receptor expressed on myeloid cells 1 and high mobility group box 1. CONCLUSIONS: The results from this experimental study indicate the superiority of HPG to glucose in the preservation of the peritoneum function and structure during the long-term PD treatment, suggesting the potential of HPG as a novel osmotic agent for PD. PMID- 27964724 TI - Antimicrobial resistance pattern: a report of microbiological cultures at a tertiary hospital in Tanzania. AB - BACKGROUND: Antimicrobial resistance has been declared by the World Health Organization as a threat to the public health. The aim of this study was to analyze antimicrobial resistance patterns of the common pathogens occurring at the Bugando Medical Centre (BMC), Mwanza, Tanzania to provide data for antimicrobial stewardship programmes. METHODS: A total of 3330 microbiological culture results scripts representing non-repetitive specimens reported between June 2013 and May 2015 were retrieved and analyzed for pathogens and their susceptibility patterns using STATA-11 software. RESULTS: Out of 3330 specimens, 439 (13.2%) had positive culture. Staphylococcus aureus (n = 100; 22.8%), Klebsiella pneumoniae (n = 65; 14.8%) and Escherichia coli (n = 41; 9.3%) were the most frequently isolated bacteria. Of 78 Staphylococcus aureus tested, 27 (34.6%) were found to be methicillin resistant Staphylococcus aureus (MRSA). Rates of resistance of Klebsiella pneumoniae and Escherichia coli isolates to third generation cephalosporins were 38.5% (25/65) and 29.3% (12/41) respectively. Staphylococcus aureus and Klesbiella pneumoniae were commonly isolated from bloodstream infections while Escherichia coli and Pseudomonas aeruginosa were the predominant isolates from urinary tract and wounds infections respectively. Of 23 Salmonella species isolated, 22 (95%) were recovered from the blood. Nine of the 23 Salmonella species isolates (39%) were found to be resistant to third generation cephalosporins. The resistance rate of gram negative bacteria to third generation cephalosporins increased from 26.5% in 2014 to 57.9% in 2015 (p = 0.004) while the rate of MRSA decreased from 41.2% in 2013 to 9.5% in 2015 (p = 0.016). Multidrug-resistant gram-negative isolates were commonly isolated from Intensive Care Units and it was noted that, the majority of invasive infections were due to gram-negative bacteria. CONCLUSION: There is an increase in proportion of gram-negative isolates resistant to third generation cephalosporins. The diversity of potential pathogens resistant to commonly prescribed antibiotics underscores the importance of sustained and standardized antimicrobial resistance surveillance and antibiotic stewardship programmes in developing countries. PMID- 27964723 TI - Fertility awareness and attitudes towards parenthood among Danish university college students. AB - BACKGROUND: Postponing parenthood has steadily increased during the past decades in Western countries. This trend has affected the size of families in the direction of fewer children born per couple. In addition, higher maternal age is associated with an increased risk of pregnancy-related complications such as prematurity and foetal death, while higher paternal age increases the risk of miscarriage and affects time-to-pregnancy. Hence, understanding the circumstances and reflections that influence the decision is greatly needed and little is known about potential gender difference influencing the choice. The aim was to investigate attitudes towards parenthood, intentions for childbirth and knowledge about fertility issues among men and women. METHODS: We conducted a cross sectional study based on a validated 49-item questionnaire among students, who attended selected mandatory lectures at a Danish university college in February to April 2016. The participation rate was 99%, and 517 completed the questionnaire. RESULTS: Though the majority of all participants wished to have children in the future (>86%), there was significant difference between the genders (p = 0.002). Women rated having children to be more important than men did (p < 0.001), while men rated higher the likelihood of abstaining from having children if faced with infertility (p = 0.003). Knowledge about fertility issues was similar between genders including poor knowledge about the age-related decline in female fertility. While women found it more important to have children before being 'too old' (p = 0.04), still more than 40% of all respondents intended to have their last child after the age of 35 years. For both genders the most important prerequisite for parenthood was having a partner to share responsibility with. Perceived or experienced life changes related to parenthood were generally positive such as personal development. CONCLUSION: The majority of respondents wished to have children, but many desired to have these after the biological decline in female fertility. The moderate knowledge level among both genders uncovered in this study is of concern. Future research should address the potential link between fertility knowledge and planning of parenthood. We may benefit from intervention studies examining the effect of routine preconception care. PMID- 27964725 TI - The enigma of primary and secondary encapsulating peritoneal sclerosis. AB - BACKGROUND: Encapsulating Peritoneal Sclerosis (EPS) describes a variety of diseases that are frequently confused with different names and different etiopathogeneses. The aim of this article is to report personal experience of focusing on correct classification and the status of current diagnosis and treatment. METHODS: A retrospective analysis was performed. Age, sex, ethnic origin, past medical history, symptoms and their duration, radiological tools and signs, laboratory tests, preoperative diagnosis, surgical approach, intraoperative findings, pathological findings, hospital stay, morbidity and mortality were studied. RESULTS: A total of seven patients, including six males and one female, aged from 24 to 72 years were observed. Four patients had recurrent abdominal colic pain for 3 months, 1, 2 and 9 years; two patients also reported recurrent attacks but without any specification of the duration. All seven patients presented at the emergency department with abdominal pain that was mainly diffused over the entire abdomen. Six patients were submitted to a CT scan. Only in two patients was the diagnosis of EPS made preoperatively. All seven patients were submitted to open surgery. The hospital stay was between 4 and 60 days. One patient had morbidity, and one patient died of MOF. CONCLUSIONS: Currently, the correct identification of EPS is more easily possible than in the past, but the diagnosis is still a challenge. Surgery must be performed as soon as possible to avoid a poorer quality of life. PMID- 27964726 TI - Cognition in chronic kidney disease: a systematic review and meta-analysis. AB - BACKGROUND: Cognitive impairment is common in people with chronic kidney disease (CKD) and associated with increased morbidity and mortality. Subtle changes can impact engagement with healthcare, comprehension, decision-making, and medication adherence. We aimed to systematically summarise evidence of cognitive changes in CKD. METHODS: We searched MEDLINE (March 2016) for cross-sectional, cohort or randomised studies that measured cognitive function in people with CKD (PROSPERO, registration number CRD42014015226). The CKD population included people with eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, in any research setting. We conducted a meta-analysis using random effects, expressed as standardised mean differences (SMD) with 95% confidence intervals (CI). Outcomes were performance in eight cognitive domains. Bias was assessed with the Newcastle Ottawa Scale (NOS). RESULTS: We identified 44 studies reporting sufficient data for synthesis (51,575 participants). Mean NOS score for cohort studies was 5.8/9 and for cross-sectional 5.4/10. Studies were deficient in NOS outcome and selection due to poor methods reporting and in comparison group validity of demographics and chronic disease status. CKD patients (eGFR < 60 mL/min/1.73 m2) performed worse than control groups (eGFR >= 60 mL/min/1.73 m2) on Orientation & Attention (SMD -0.79, 95% CI, -1.44 to -0.13), Language (SMD -0.63, 95% CI, -0.85 to -0.41), Concept Formation & Reasoning (SMD -0.63, 95% CI, -1.07 to -0.18), Executive Function (SMD -0.53, 95% CI, -0.85 to -0.21), Memory (SMD -0.48, 95% CI, -0.79 to -0.18), and Global Cognition (SMD -0.48, 95% CI, -0.72 to -0.24). Construction & Motor Praxis and Perception were unaffected (SMD -0.29, 95% CI, 0.90 to 0.32; SMD -1.12, 95% CI, -4.35 to 2.12). Language scores dropped with eGFR (<45 mL/min/1.73 m2 SMD -0.86, 95% CI, -1.25 to -46; 30 mL/min/1.73 m2 SMD 1.56, 95% CI, -2.27 to -0.84). Differences in Orientation & Attention were greatest at eGFR < 45 mL/min/1.73 m2 (SMD -4.62, 95% CI, -4.68 to -4.55). Concept Formation & Reasoning differences were greatest at eGFR < 45 mL/min/1.73 m2 (SMD 4.27, 95% CI, -4.23 to -4.27). Differences in Executive Functions were greatest at eGFR < 30 mL/min/1.73 m2 (SMD -0.54, 95% CI, -1.00 to -0.08). CONCLUSIONS: Cognitive changes occur early in CKD, and skills decline at different rates. Orientation & Attention and Language are particularly affected. The cognitive impact of CKD is likely to diminish patients' capacity to engage with healthcare decisions. An individual's cognitive trajectory may deviate from average. PMID- 27964728 TI - The use of self-reported symptoms as a proxy for acute organophosphate poisoning after exposure to chlorpyrifos 50% plus cypermethrin 5% among Nepali farmers: a randomized, double-blind, placebo-controlled, crossover study. AB - BACKGROUND: Previous studies stating a high prevalence of occupational acute pesticide poisoning in developing countries have mainly relied on measurements of the rather non-specific self-reported acute pesticide poisoning symptoms. Only a few studies have measured the biomarker plasma cholinesterase (PchE) activity, in addition to the symptoms, when assessing occupational acute pesticide poisoning. This study evaluated self-reported symptoms as a proxy for acute organophosphate poisoning among Nepali farmers by examining self-reported acute organophosphate poisoning symptoms and PchE activity in response to occupational acute organophosphate exposure. METHODS: We performed a randomized, double-blind, placebo-controlled, crossover trial among 42 Nepali commercial vegetable farmers. The farmers were randomly assigned (ratio 1:1) to a 2-h organophosphate (chlorpyrifos 50% plus cypermethrin 5%: moderately hazardous) spray session or a 2-h placebo spray session, and after 7 days' washout, the farmers were assigned to the other spray session. Before and after each spray session farmers were interviewed about acute organophosphate poisoning symptoms and PchE activity was measured. Analyses were conducted with a Two Sample T-test and Mann Whitney U test. RESULTS: We found no difference in the symptom sum or PchE activity from baseline to follow up among farmers spraying with organophosphate (symptom sum difference -1, p = 0.737; PchE mean difference 0.02 U/mL, p = 0.220), placebo (symptom sum difference 9, p = 0.394; PchE mean difference 0.02 U/mL, p = 0.133), or when comparing organophosphate to placebo (symptom p = 0.378; PchE p = 0.775). However, a high percentage of the farmers reported having one or more symptoms both at baseline and at follow up in the organophosphate spray session (baseline 47.6%, follow up 45.2%) and placebo spray session (baseline 35.7%, follow up 50.0%), and 14.3% of the farmers reported three or more symptoms after the organophosphate spray session as well as after the placebo spray session. CONCLUSION: We found a general presence of acute organophosphate symptoms among the farmers regardless of organophosphate exposure or poisoning. Thus, self reported acute organophosphate symptoms seem to be a poor proxy for acute organophosphate poisoning as the occurrence of these symptoms is not necessarily associated with acute organophosphate poisoning. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02838303 . Registered 19 July 2016. Retrospectively registered. PMID- 27964727 TI - Genetic variation of naturally growing olive trees in Israel: from abandoned groves to feral and wild? AB - BACKGROUND: Naturally growing populations of olive trees are found in the Mediterranean garrigue and maquis in Israel. Here, we used the Simple Sequence Repeat (SSR) genetic marker technique to investigate whether these represent wild var. sylvestris. Leaf samples were collected from a total of 205 trees at six sites of naturally growing olive populations in Israel. The genetic analysis included a multi-locus lineage (MLL) analysis, Rousset's genetic distances, Fst values, private alleles, other diversity values and a Structure analysis. The analyses also included scions and suckers of old cultivated olive trees, for which the dominance of one clone in scions (MLL1) and a second in suckers (MLL7) had been shown earlier. RESULTS: The majority of trees from a Judean Mts. population and from one population from the Galilee showed close genetic similarity to scions of old cultivated trees. Different from that, site-specific and a high number of single occurrence MLLs were found in four olive populations from the Galilee and Carmel which also were genetically more distant from old cultivated trees, had relatively high genetic diversity values and higher numbers of private alleles. Whereas in two of these populations MLL7 (and partly MLL1) were found in low frequency, the two other populations did not contain these MLLs and were very similar in their genetic structure to suckers of old cultivated olive trees that originated from sexual reproduction. CONCLUSIONS: The genetic distinctness from old cultivated olive trees, particularly of one population from Galilee and one from Carmel, suggests that trees at these sites might represent wild var. sylvestris. The similarity in genetic structure of these two populations with the suckers of old cultivated trees implies that wild trees were used as rootstocks. Alternatively, trees at these two sites may be remnants of old cultivated trees in which the scion-derived trunk died and was replaced by suckers. However, considering landscape and topographic environment at the two sites this second interpretation is less likely. PMID- 27964730 TI - Prior knowledge guided eQTL mapping for identifying candidate genes. AB - BACKGROUND: Expression quantitative trait loci (eQTL) mapping is often used to identify genetic loci and candidate genes correlated with traits. Although usually a group of genes affect complex traits, genes in most eQTL mapping methods are considered as independent. Recently, some eQTL mapping methods have accounted for correlated genes, used biological prior knowledge and applied these in model species such as yeast or mouse. However, biological prior knowledge might be very limited for most species. RESULTS: We proposed a data-driven prior knowledge guided eQTL mapping for identifying candidate genes. At first, quantitative trait loci (QTL) analysis was used to identify single nucleotide polymorphisms (SNP) markers that are associated with traits. Then co-expressed gene modules were generated and gene modules significantly associated with traits were selected. Prior knowledge from QTL mapping was used for eQTL mapping on the selected modules. We tested and compared prior knowledge guided eQTL mapping to the eQTL mapping with no prior knowledge in a simulation study and two barley stem rust resistance case studies. The results in simulation study and real barley case studies show that models using prior knowledge outperform models without prior knowledge. In the first case study, three gene modules were selected and one of the gene modules was enriched with defense response Gene Ontology (GO) terms. Also, one probe in the gene module is mapped to Rpg1, previously identified as resistance gene to stem rust. In the second case study, four gene modules are identified, one gene module is significantly enriched with defense response to fungus and bacterium. CONCLUSIONS: Prior knowledge guided eQTL mapping is an effective method for identifying candidate genes. The case studies in stem rust show that this approach is robust, and outperforms methods with no prior knowledge in identifying candidate genes. PMID- 27964732 TI - Erratum to: A randomized prospective controlled trial comparing the laryngeal tube suction disposable and the supreme laryngeal mask airway: the influence of head and neck position on oropharyngeal seal pressure. PMID- 27964729 TI - Development and psychometric properties of the Suicidality: Treatment Occurring in Paediatrics (STOP) Suicidality Assessment Scale (STOP-SAS) in children and adolescents. AB - BACKGROUND: To create a self-reported, internet-based questionnaire for the assessment of suicide risk in children and adolescents. METHODS: As part of the EU project 'Suicidality: Treatment Occurring in Paediatrics' (STOP project), we developed web-based Patient Reported Outcome Measures (PROMs) for children and adolescents and for proxy reports by parents and clinicians in order to assess suicidality. Based on a literature review, expert panels and focus groups of patients, we developed the items of the STOP Suicidality Assessment Scale (STOP SAS) in Spanish and English, translated it into four more languages, and optimized it for web-based presentation using the HealthTrackerTM platform. Of the total 19 questions developed for the STOP-SAS, four questions that assess low level suicidality were identified as screening questions (three of them for use with children, and all four for use with adolescents, parents and clinicians). A total of 395 adolescents, 110 children, 637 parents and 716 clinicians completed the questionnaire using the HealthTrackerTM, allowing us to evaluate the internal consistency and convergent validity of the STOP-SAS with the clinician-rated Columbia Suicide Severity Rating Scale (C-SSRS). Validity was also assessed with the receiver operating characteristic (ROC) area of the STOP-SAS with the C-SSRS. RESULTS: The STOP-SAS comprises 19 items in its adolescent, parent, and clinician versions, and 14 items in its children's version. Good internal consistency was found for adolescents (Cronbach's alpha: 0.965), children (Cronbach's alpha: 0.922), parents (Cronbach's alpha: 0.951) and clinicians (Cronbach's alpha: 0.955) versions. A strong correlation was found between the STOP-SAS and the C SSRS for adolescents (r:0.670), parents (r:0.548), clinicians (r:0.863) and children (r:0.654). The ROC area was good for clinicians' (0.917), adolescents' (0.834) and parents' (0.756) versions but only fair (0.683) for children's version. CONCLUSIONS: The STOP-SAS is a comprehensive, web-based PROM developed on the HealthTrackerTM platform, and co-designed for use by adolescents, children, parents and clinicians. It allows the evaluation of aspects of suicidality and shows good reliability and validity. PMID- 27964731 TI - Use of single molecule sequencing for comparative genomics of an environmental and a clinical isolate of Clostridium difficile ribotype 078. AB - BACKGROUND: How the pathogen Clostridium difficile might survive, evolve and be transferred between reservoirs within the natural environment is poorly understood. Some ribotypes are found both in clinical and environmental settings. Whether these strains are distinct from each another and evolve in the specific environments is not established. The possession of a highly mobile genome has contributed to the genetic diversity and ongoing evolution of C. difficile. Interpretations of genetic diversity have been limited by fragmented assemblies resulting from short-read length sequencing approaches and by a limited understanding of epigenetic regulation of diversity. To address this, single molecule real time (SMRT) sequencing was used in this study as it produces high quality genome sequences, with resolution of repeat regions (including those found in mobile elements) and can generate data to determine methylation modifications across the sequence (the methylome). RESULTS: Chromosomal rearrangements and ribosomal operon duplications were observed in both genomes. The rearrangements occurred at insertion sites within two mobile genetic elements (MGEs), Tn6164 and Tn6293, present only in the M120 and CD105HS27 genomes, respectively. The gene content of these two transposons differ considerably which could impact upon horizontal gene transfer; differences include CDSs encoding methylases and a conjugative prophage only in Tn6164. To investigate mechanisms which could affect MGE transfer, the methylome, restriction modification (RM) and the CRISPR/Cas systems were characterised for each strain. Notably, the environmental isolate, CD105HS27, does not share a consensus motif for m4C methylation, but has one additional spacer when compared to the clinical isolate M120. CONCLUSIONS: These findings show key differences between the two strains in terms of their genetic capacity for MGE transfer. The carriage of horizontally transferred genes appear to have genome wide effects based on two different methylation patterns. The CRISPR/Cas system appears active although perhaps slow to evolve. Data suggests that both mechanisms are functional and impact upon horizontal gene transfer and genome evolution within C. difficile. PMID- 27964733 TI - An examination of the effectiveness of health warning labels on smokeless tobacco products in four states in India: findings from the TCP India cohort survey. AB - BACKGROUND: In 2009, after many delays and changes, India introduced a single pictorial health warning label (HWL) on smokeless tobacco (SLT) packing-a symbolic image of a scorpion covering 40% of the front surface. In 2011, the scorpion was replaced with 4 graphic images. This paper tested the effectiveness of SLT HWLs in India and whether the 2011 change from symbolic to graphic images increased their effectiveness. METHODS: Data were from a cohort of 4733 adult SLT users (age15+) of the Tobacco Control Project (TCP) India Survey from 4 states. The surveys included key indicators of health warning effectiveness, including warning salience, and cognitive, emotional, and behavioral responses to the warnings. RESULTS: The HWL change from symbolic to graphic did not result in significant increases on any of the HWL outcome indicators. A substantial minority of SLT users were unaware that SLT packages contained HWLs (27% at both waves). Noticing the warnings was also remarkably low at both waves (W1 = 34.3%, W2 = 28.1%). These effects carried over to the cognitive and behavioural measures, where among those who noticed HWLs, about one-third reported forgoing SLT at least once because of the HWLs, and fewer than 20% reported that HWLs made them think about SLT risks or about quitting SLT. Even fewer reported avoiding HWLs (8.1 to 11.6%). Among those who quit using SLT by post-policy, awareness that SLT packaging contained HWLs was significantly greater at post-policy (86.8%) compared to pre-policy (77.8%, p = 0.02). Quitters were also significantly more aware of the post-policy HWLs compared to those who continued to use SLT (p < 0.001). CONCLUSIONS: Health warnings on SLT packages in India are low in effectiveness, and the change from the symbolic warning (pre-policy) to graphic HWLs (post-policy) did not lead to significant increases of effectiveness on any of the HWL indicators among those who continued to use SLT products, thus suggesting that changing an image alone is not enough to have an impact. There is a critical need to implement SLT HWLs in India that are more salient (large in size and on the front and back of the package) and impactful, which following from studies of HWLs on cigarette packaging, would have strong potential to increase awareness of the harms of SLT and to motivate quitting. PMID- 27964734 TI - Therapeutic properties in Tunisian hot springs: first evidence of phenolic compounds in the cyanobacterium Leptolyngbya sp. biomass, capsular polysaccharides and releasing polysaccharides. AB - BACKGROUND: In Tunisia, the use of hot spring waters for both health and recreation is a tradition dating back to Roman times. In fact, thermal baths, usually called "Hammam" are recommended as a therapeutic and prophylactic measure against many types of illness and toxicity. While the chemical concentration of thermal water is admittedly associated with its therapeutic effects, the inclusion in spa waters of efficient bioproduct additives produced by photosynthetic microorganisms and that act against oxidative stress may comprise a significant supplementary value for thermal centers. The aim of this study was to investigate the antioxidant potential of the Tunisian thermophilic cyanobacterium Leptolyngbya sp. and to determine its phytochemical constituents and phenolic profile. METHODS: BME (Biomass Methanolic Extract), CME (Capsular polysaccharides Methanolic Extract) and RME (Releasing polysaccharides Methanolic Extract) of Leptolyngbya sp. were examined for their antioxidant activities by means of DPPH, hydroxyl radical scavenging and ferrous ion chelating assays. Their total phenols, flavonoids, carotenoids, Mycosporine-like amino acids (MAAs) and vitamin C contents, as well as their phenolic profiles were also determined. RESULTS: BME has the highest content of phenols (139 +/- 1.2 mg/g), flavonoids (34.9 +/- 0.32 mg CEQ/g), carotenoids (2.03 +/- 0.56 mg/g) and vitamin C (15.7 +/ 1.55 mg/g), while the highest MAAs content (0.42 +/- 0.03 mg/g) was observed in CME. BME presented both the highest DPPH and hydroxyl radical scavenging ability with an IC50 of 0.07 and 0.38 mg/ml, respectively. The highest ferrous chelating capacity was detected in CME with an IC50 = 0.59 mg/ml. Phenolic profiles revealed the presence of 25 phenolic compounds with the existence of hydroxytyrosol, oleuropein, resveratrol and pinoresinol. CONCLUSION: The study demonstrated that the cyanobacterium Leptolyngbya sp. possesses abundant natural antioxidant products which may have prophylactic and therapeutic effects on many types of illness and toxicity. The present findings not only explain and reinforce the rationale behind traditional therapeutic practices in Tunisia in the exploitation of the country's hot springs, but support the addition of Leptolyngbya to thermal waters as a means to enhance the value and reputation of the curative nature of Tunisian thermal waters. PMID- 27964735 TI - Strength in numbers: patient experiences of group exercise within hospice palliative care. AB - BACKGROUND: Exercise is increasingly recognized as a core component of palliative rehabilitation. The group exercise model is often adopted as a means of reaching more patients with limited resource. Despite the growth of quantitative research examining this area of practice, few qualitative studies have looked at the patient experience of participating in group exercise in a palliative setting, and most exclude patients with a non-cancer diagnosis. METHODS: The aim of this study was to explore patients' experiences of participating in group exercise classes in a hospice setting. In this qualitative, phenomenological study, nine patients participating in a group exercise programme at a South London hospice completed semi-structured interviews. Participants were purposively sampled by gender, age, ethnicity and diagnosis; to include diagnoses across cancer, respiratory and neurological conditions. Transcripts were interpreted using thematic analysis. RESULTS: All patients reported positive experiences of participating in group exercise classes. Improvements reported in physical function had a positive effect on ability to complete activities of daily living and enhanced patient mood. Other reported psychosocial benefits included: promotion of self-management; space and opportunity for reflection; supportive relationships; sharing of information; and a deeper appreciation of patients' own abilities. CONCLUSION: This study highlights the positive experiences and value of group exercise classes to groups of people with diverse cancer and non-cancer conditions. The physical, emotional and psychosocial benefits suggest hospices and other palliative services should explore similar programmes as part of their rehabilitation services. The recognition that exercise groups can be mixed and need not be bespoke to one condition has positive cost and staff resource ramifications. PMID- 27964738 TI - Erratum to: The Oxford Nanopore MinION: delivery of nanopore sequencing to the genomics community. PMID- 27964736 TI - Feasibility of cardiovascular magnetic resonance derived coronary wave intensity analysis. AB - BACKGROUND: Wave intensity analysis (WIA) of the coronary arteries allows description of the predominant mechanisms influencing coronary flow over the cardiac cycle. The data are traditionally derived from pressure and velocity changes measured invasively in the coronary artery. Cardiovascular magnetic resonance (CMR) allows measurement of coronary velocities using phase velocity mapping and derivation of central aortic pressure from aortic distension. We assessed the feasibility of WIA of the coronary arteries using CMR and compared this to invasive data. METHODS: CMR scans were undertaken in a serial cohort of patients who had undergone invasive WIA. Velocity maps were acquired in the proximal left anterior descending and proximal right coronary artery using a retrospectively-gated breath-hold spiral phase velocity mapping sequence with high temporal resolution (19 ms). A breath-hold segmented gradient echo sequence was used to acquire through-plane cross sectional area changes in the proximal ascending aorta which were used as a surrogate of an aortic pressure waveform after calibration with brachial blood pressure measured with a sphygmomanometer. CMR-derived aortic pressures and CMR-measured velocities were used to derive wave intensity. The CMR-derived wave intensities were compared to invasive data in 12 coronary arteries (8 left, 4 right). Waves were presented as absolute values and as a % of total wave intensity. Intra-study reproducibility of invasive and non invasive WIA was assessed using Bland-Altman analysis and the intraclass correlation coefficient (ICC). RESULTS: The combination of the CMR-derived pressure and velocity data produced the expected pattern of forward and backward compression and expansion waves. The intra-study reproducibility of the CMR derived wave intensities as a % of the total wave intensity (mean +/- standard deviation of differences) was 0.0 +/- 6.8%, ICC = 0.91. Intra-study reproducibility for the corresponding invasive data was 0.0 +/- 4.4%, ICC = 0.96. The invasive and CMR studies showed reasonable correlation (r = 0.73) with a mean difference of 0.0 +/- 11.5%. CONCLUSION: This proof of concept study demonstrated that CMR may be used to perform coronary WIA non-invasively with reasonable reproducibility compared to invasive WIA. The technique potentially allows WIA to be performed in a wider range of patients and pathologies than those who can be studied invasively. PMID- 27964737 TI - Evidence-based decision support for pediatric rheumatology reduces diagnostic errors. AB - BACKGROUND: The number of trained specialists world-wide is insufficient to serve all children with pediatric rheumatologic disorders, even in the countries with robust medical resources. We evaluated the potential of diagnostic decision support software (DDSS) to alleviate this shortage by assessing the ability of such software to improve the diagnostic accuracy of non-specialists. METHODS: Using vignettes of actual clinical cases, clinician testers generated a differential diagnosis before and after using diagnostic decision support software. The evaluation used the SimulConsult(r) DDSS tool, based on Bayesian pattern matching with temporal onset of each finding in each disease. The tool covered 5405 diseases (averaging 22 findings per disease). Rheumatology content in the database was developed using both primary references and textbooks. The frequency, timing, age of onset and age of disappearance of findings, as well as their incidence, treatability, and heritability were taken into account in order to guide diagnostic decision making. These capabilities allowed key information such as pertinent negatives and evolution over time to be used in the computations. Efficacy was measured by comparing whether the correct condition was included in the differential diagnosis generated by clinicians before using the software ("unaided"), versus after use of the DDSS ("aided"). RESULTS: The 26 clinicians demonstrated a significant reduction in diagnostic errors following introduction of the software, from 28% errors while unaided to 15% using decision support (p < 0.0001). Improvement was greatest for emergency medicine physicians (p = 0.013) and clinicians in practice for less than 10 years (p = 0.012). This error reduction occurred despite the fact that testers employed an "open book" approach to generate their initial lists of potential diagnoses, spending an average of 8.6 min using printed and electronic sources of medical information before using the diagnostic software. CONCLUSIONS: These findings suggest that decision support can reduce diagnostic errors and improve use of relevant information by generalists. Such assistance could potentially help relieve the shortage of experts in pediatric rheumatology and similarly underserved specialties by improving generalists' ability to evaluate and diagnose patients presenting with musculoskeletal complaints. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02205086. PMID- 27964739 TI - Colonic thickening on computed tomography-does it correlate with endoscopic findings? A protocol for systematic review. AB - BACKGROUND: Colonic mural thickening is often a finding in standard computed tomography (CT) scans of the abdomen. It often presents clinician with a dilemma on when a further endoscopic evaluation is needed, especially in the absence of guidelines. The aim of this systematic review is to evaluate the significance of bowel wall thickening and to assess its correlation with endoscopy. METHODS: This systematic review will be reported in accordance with the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. The search strategy will initially be developed in MEDLINE and adapted for use in EMBASE, MEDLINE, NHS evidence and TRIP. Two reviewers will independently conduct a study selection, data extraction and risk of bias assessment for the screened studies. Data synthesis will be conducted using Review Manager software 5.3. The outcome of any dichotomous data will be presented as relative risk with confidence intervals. DISCUSSION: It is extremely useful for the practising clinician to know which patients need further endoscopic evaluation. Even though there are several studies on this issue, none of them have attempted to produce a systematic review. We hope this systematic review will provide a substantiate evidence for future clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016039378. PMID- 27964741 TI - Erratum to: Unexpected arterial wall and cellular inflammation in patients with rheumatoid arthritis in remission using biological therapy: a cross-sectional study. PMID- 27964742 TI - Data extraction for complex meta-analysis (DECiMAL) guide. AB - As more complex meta-analytical techniques such as network and multivariate meta analyses become increasingly common, further pressures are placed on reviewers to extract data in a systematic and consistent manner. Failing to do this appropriately wastes time, resources and jeopardises accuracy. This guide (data extraction for complex meta-analysis (DECiMAL)) suggests a number of points to consider when collecting data, primarily aimed at systematic reviewers preparing data for meta-analysis. Network meta-analysis (NMA), multiple outcomes analysis and analysis combining different types of data are considered in a manner that can be useful across a range of data collection programmes. The guide has been shown to be both easy to learn and useful in a small pilot study. PMID- 27964740 TI - LW-AFC, a new formula derived from Liuwei Dihuang decoction, ameliorates behavioral and pathological deterioration via modulating the neuroendocrine immune system in PrP-hAbetaPPswe/PS1DeltaE9 transgenic mice. AB - BACKGROUND: Accumulating evidence implicates the neuroendocrine immunomodulation (NIM) network in the physiopathological mechanism of Alzheimer's disease (AD). Notably, we previously revealed that the NIM network is dysregulated in the PrP hAbetaPPswe/PS1DeltaE9 (APP/PS1) transgenic mouse model of AD. METHODS: After treatment with a novel Liuwei Dihuang formula (LW-AFC), mice were cognitively evaluated in behavioral experiments. Neuron loss, amyloid-beta (Abeta) deposition, and Abeta level were analyzed using Nissl staining, immunofluorescence, and an AlphaLISA assay, respectively. Multiplex bead analysis, a radioimmunoassay, immunochemiluminometry, and an enzyme-linked immunosorbent assay (ELISA) were used to measure cytokine and hormone levels. Lymphocyte subsets were detected using flow cytometry. Data between two groups were compared using a Student's t test. Comparison of the data from multiple groups against one group was performed using a one-way analysis of variance (ANOVA) followed by a Dunnett's post hoc test or a two-way repeated-measures analysis of variance with a Tukey multiple comparisons test. RESULTS: LW-AFC ameliorated the cognitive impairment observed in APP/PS1 mice, including the impairment of object recognition memory, spatial learning and memory, and active and passive avoidance. In addition, LW-AFC alleviated the neuron loss in the hippocampus, suppressed Abeta deposition in the brain, and reduced the concentration of Abeta1-42 in the hippocampus and plasma of APP/PS1 mice. LW-AFC treatment also significantly decreased the secretion of corticotropin-releasing hormone and gonadotropin-releasing hormone in the hypothalamus, and adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone in the pituitary. Moreover, LW-AFC increased CD8+CD28+ T cells, and reduced CD4+CD25+Foxp3+ T cells in the spleen lymphocytes, downregulated interleukin (IL)-1beta, IL-2, IL-6, IL-23, granulocyte-macrophage colony stimulating factor, and tumor necrosis factor-alpha and -beta, and upregulated IL 4 and granulocyte colony stimulating factor in the plasma of APP/PS1 mice. CONCLUSIONS: LW-AFC ameliorated the behavioral and pathological deterioration of APP/PS1 transgenic mice via the restoration of the NIM network to a greater extent than either memantine or donepezil, which supports the use of LW-AFC as a potential agent for AD therapy. PMID- 27964743 TI - Using re-randomization to increase the recruitment rate in clinical trials - an assessment of three clinical areas. AB - BACKGROUND: Patient recruitment in clinical trials is often challenging, and as a result, many trials are stopped early due to insufficient recruitment. The re randomization design allows patients to be re-enrolled and re-randomized for each new treatment episode that they experience. Because it allows multiple enrollments for each patient, this design has been proposed as a way to increase the recruitment rate in clinical trials. However, it is unknown to what extent recruitment could be increased in practice. METHODS: We modelled the expected recruitment rate for parallel-group and re-randomization trials in different settings based on estimates from real trials and datasets. We considered three clinical areas: in vitro fertilization, severe asthma exacerbations, and acute sickle cell pain crises. We compared the two designs in terms of the expected time to complete recruitment, and the sample size recruited over a fixed recruitment period. RESULTS: Across the different scenarios we considered, we estimated that re-randomization could reduce the expected time to complete recruitment by between 4 and 22 months (relative reductions of 19% and 45%), or increase the sample size recruited over a fixed recruitment period by between 29% and 171%. Re-randomization can increase recruitment most for trials with a short follow-up period, a long trial recruitment duration, and patients with high rates of treatment episodes. CONCLUSIONS: Re-randomization has the potential to increase the recruitment rate in certain settings, and could lead to quicker and more efficient trials in these scenarios. PMID- 27964744 TI - Differential gene and protein expression of chemokines and cytokines in synovial fluid of patients with arthritis. AB - BACKGROUND: Psoriatic arthritis (PsA), an inflammatory musculoskeletal disease, develops in approximately 30% of patients with psoriasis. Previously, chemokine (C-X-C motif) ligand 10 (CXCL10) was identified as a predictive biomarker of PsA in patients with psoriasis and was reduced after development of PsA. The purpose of the present study was to explore messenger RNA (mRNA) and protein expression of CXCL10 and its receptor, chemokine (C-X-C motif) receptor 3 (CXCR3), in the joints of patients with PsA to gain insight into their role in the pathogenesis of the disease. METHODS: Sera from 47 patients with PsA and 33 healthy control subjects were compared for expression of CXCL10 by Luminex assay. Synovial fluid (SF) was obtained from patients with PsA (n = 40), osteoarthritis (OA; n = 14), gout (n = 8), and rheumatoid arthritis (RA; n = 11) during clinical care. SF mRNA and protein expression of CXCL10, interleukin-17A (IL-17A), CXCR3, TBX21, RORC and/or interferon gamma (IFNgamma) were compared among the above-mentioned disease groups, as well as in paired SF and serum samples from patients with PsA using real-time polymerase chain reaction and Luminex assays, respectively. RESULTS: Serum CXCL10 was significantly higher in patients with PsA than in control subjects (p = 0.0007). CXCL10, IL-17A, and TBX21 expression were elevated in SF cells of patients with PsA compared with those of patients with OA and gout, but not those of patients with RA. CXCR3 and RORC were elevated in PsA SF cells compared with all other patient groups. Concordant results were obtained for CXCL10 and IL-17A protein expression. IFNgamma was elevated in PsA SF compared with OA SF (p = 0.015). CXCL10 protein expression was substantially increased in SF (median 7283.9 pg/ml, interquartile range [IQR] 1330-10,362 pg/ml) compared with paired serum samples (median 282.06, IQR 180.7-395.8 pg/ml; p = 0.001), whereas IFNgamma was significantly reduced (SF median 6.03 pg/ml, IQR 4.47-8.94 pg/ml; versus serum median 23.70 pg/ml, IQR 3.2-104.6 pg/ml; p = 0.001). CONCLUSIONS: CXCL10 may have an important etiological role in PsA that is analogous to that in RA, and it is a candidate biomarker to distinguish PsA from healthy individuals and from patients with OA and gout. PMID- 27964745 TI - Fewer subsequent relapses and lower levels of IL-17 in Takayasu arteritis developed after the age of 40 years. AB - BACKGROUND: The clinical characteristics of Takayasu arteritis (TAK) developing in individuals older than 40 years (TAK >40) are little-known. METHOD: We retrospectively analyzed 43 patients with TAK treated at three hospitals in Japan from April 2000 to March 2016. From medical records we collected baseline variables at diagnosis including clinical symptoms, laboratory data, and subsequent relapses. We compared these indices in the patients with TAK onset at >40 years of age (TAK >40) to those with TAK onset <=40 years (TAK <=40). Multiplex cytokine/chemokine bead assays were performed using preserved serum supernatants from 24 patients with TAK and 40 healthy donors. RESULTS: Of the 43 patients, 20 had TAK >40; this group had significantly fewer instances of orthostatic hypotension (2 (10%) vs. 10 (43%), p = 0.019), carotid bruit (7 (35%) vs. 16 (70%), p = 0.034), and chest pain (0 (0%) vs. 6 (26%), p = 0.023) compared to patients with TAK <=40 (n = 23). The initial prednisolone dose was significantly lower in TAK >40 (median 30 mg vs. 40 mg per day, p = 0.024). Assessed by the log-rank test, the relapse-free survival rate after remission was significantly higher in the patients with TAK >40 (p = 0.029). The interleukin 17 levels were significantly lower in patients with TAK >40 compared to patients with TAK <=40 and healthy donors. CONCLUSION: Compared to TAK <=40, TAK >40 could be treated by lower initial doses of prednisolone to achieve remission, and with fewer relapses. These differences might be due to the difference of T helper 17 (Th17) activity suggested by the cytokine profiles. PMID- 27964746 TI - Alternate-locus aware variant calling in whole genome sequencing. AB - BACKGROUND: The last two human genome assemblies have extended the previous linear golden-path paradigm of the human genome to a graph-like model to better represent regions with a high degree of structural variability. The new model offers opportunities to improve the technical validity of variant calling in whole-genome sequencing (WGS). METHODS: We developed an algorithm that analyzes the patterns of variant calls in the 178 structurally variable regions of the GRCh38 genome assembly, and infers whether a given sample is most likely to contain sequences from the primary assembly, an alternate locus, or their heterozygous combination at each of these 178 regions. We investigate 121 in house WGS datasets that have been aligned to the GRCh37 and GRCh38 assemblies. RESULTS: We show that stretches of sequences that are largely but not entirely identical between the primary assembly and an alternate locus can result in multiple variant calls against regions of the primary assembly. In WGS analysis, this results in characteristic and recognizable patterns of variant calls at positions that we term alignable scaffold-discrepant positions (ASDPs). In 121 in house genomes, on average 51.8+/-3.8 of the 178 regions were found to correspond best to an alternate locus rather than the primary assembly sequence, and filtering these genomes with our algorithm led to the identification of 7863 variant calls per genome that colocalized with ASDPs. Additionally, we found that 437 of 791 genome-wide association study hits located within one of the regions corresponded to ASDPs. CONCLUSIONS: Our algorithm uses the information contained in the 178 structurally variable regions of the GRCh38 genome assembly to avoid spurious variant calls in cases where samples contain an alternate locus rather than the corresponding segment of the primary assembly. These results suggest the great potential of fully incorporating the resources of graph-like genome assemblies into variant calling, but also underscore the importance of developing computational resources that will allow a full reconstruction of the genotype in personal genomes. Our algorithm is freely available at https://github.com/charite/asdpex . PMID- 27964747 TI - Impact of communication strategies to increase knowledge, acceptability, and uptake of a new Woman's Condom in urban Lusaka, Zambia: study protocol for a randomized controlled trial. AB - BACKGROUND: Globally, 220 million women experience an unmet need for family planning. A newly designed female condom, the Woman's Condom (WC), has been developed featuring an improved design. It is the first dual-protection, female initiated contraceptive that is a premium, higher price point product. However, market availability alone will not increase uptake. In February 2016 the WC will be distributed with a strong media campaign and interpersonal communication (IPC) outreach intervention. The impact of these on knowledge, acceptability, and use of the WC will be measured. METHODS/DESIGN: A baseline survey of 2314 randomly selected 18- to 24-year-old sexually active men and women has been conducted. The WC and mass media will be introduced throughout 40 urban wards in and surrounding Lusaka, Zambia. The baseline survey will serve as a quasi-control arm to determine the impact of introducing the WC with mass media. Half of the wards will be randomly allocated to additionally receive the IPC intervention. A single blind randomized controlled trial will determine the impact of the IPC intervention on knowledge, uptake, and use of the WC. After one year, another 2314 individuals will be randomly selected to participate in the endline survey. We hypothesize that (1) the distribution and media campaign of the WC will increase overall condom use in selected urban wards, and specifically use of the WC; (2) the IPC intervention will significantly impact knowledge, acceptability, and use of the WC. The primary outcome measures are use of the WC, use of any condom, and willingness to use the WC. Secondary outcomes include measures of knowledge, acceptability, and choice of contraception. Odds ratios will be estimated to measure the effect of the intervention on the outcomes with 95% confidence intervals. All analyses will be based on the intention-to-treat principle. DISCUSSION: Increasing uptake of dual prevention measures (such as the WC) may reduce incidence of sexually transmitted infections/HIV and unplanned pregnancies. It is important to ensure young, urban adults have access to new contraceptive methods; and, understanding how mass media and IPC impact contraceptive knowledge, acceptability, and use is critical to reduce unmet need. TRIAL REGISTRATION: AEARCTR-0000899 . Registered on 26 October 2015. PMID- 27964748 TI - Non-coding single nucleotide variants affecting estrogen receptor binding and activity. AB - BACKGROUND: Estrogen receptor (ER) activity is critical for the development and progression of the majority of breast cancers. It is known that ER is differentially bound to DNA leading to transcriptomic and phenotypic changes in different breast cancer models. We investigated whether single nucleotide variants (SNVs) in ER binding sites (regSNVs) contribute to ER action through changes in the ER cistrome, thereby affecting disease progression. Here we developed a computational pipeline to identify SNVs in ER binding sites using chromatin immunoprecipitation sequencing (ChIP-seq) data from ER+ breast cancer models. METHODS: ER ChIP-seq data were downloaded from the Gene Expression Omnibus (GEO). GATK pipeline was used to identify SNVs and the MACS algorithm was employed to call DNA-binding sites. Determination of the potential effect of a given SNV in a binding site was inferred using reimplementation of the is-rSNP algorithm. The Cancer Genome Atlas (TCGA) data were integrated to correlate the regSNVs and gene expression in breast tumors. ChIP and luciferase assays were used to assess the allele-specific binding. RESULTS: Analysis of ER ChIP-seq data from MCF7 cells identified an intronic SNV in the IGF1R gene, rs62022087, predicted to increase ER binding. Functional studies confirmed that ER binds preferentially to rs62022087 versus the wild-type allele. By integrating 43 ER ChIP-seq datasets, multi-omics, and clinical data, we identified 17 regSNVs associated with altered expression of adjacent genes in ER+ disease. Of these, the top candidate was in the promoter of the GSTM1 gene and was associated with higher expression of GSTM1 in breast tumors. Survival analysis of patients with ER+ tumors revealed that higher expression of GSTM1, responsible for detoxifying carcinogens, was correlated with better outcome. CONCLUSIONS: In conclusion, we have developed a computational approach that is capable of identifying putative regSNVs in ER ChIP-binding sites. These non-coding variants could potentially regulate target genes and may contribute to clinical prognosis in breast cancer. PMID- 27964750 TI - Laminin 521 maintains differentiation potential of mouse and human satellite cell derived myoblasts during long-term culture expansion. AB - BACKGROUND: Large-scale expansion of myogenic progenitors is necessary to support the development of high-throughput cellular assays in vitro and to advance genetic engineering approaches necessary to develop cellular therapies for rare muscle diseases. However, optimization has not been performed in order to maintain the differentiation capacity of myogenic cells undergoing long-term cell culture. Multiple extracellular matrices have been utilized for myogenic cell studies, but it remains unclear how different matrices influence long-term myogenic activity in culture. To address this challenge, we have evaluated multiple extracellular matrices in myogenic studies over long-term expansion. METHODS: We evaluated the consequence of propagating mouse and human myogenic stem cell progenitors on various extracellular matrices to determine if they could enhance long-term myogenic potential. For the first time reported, we comprehensively examine the effect of physiologically relevant laminins, laminin 211 and laminin 521, compared to traditionally utilized ECMs (e.g., laminin 111, gelatin, and Matrigel) to assess their capacity to preserve myogenic differentiation potential. RESULTS: Laminin 521 supported increased proliferation in early phases of expansion and was the only substrate facilitating high-level fusion following eight passages in mouse myoblast cell cultures. In human myoblast cell cultures, laminin 521 supported increased proliferation during expansion and superior differentiation with myotube hypertrophy. Counterintuitively however, laminin 211, the native laminin isoform in resting skeletal muscle, resulted in low proliferation and poor differentiation in mouse and human cultures. Matrigel performed excellent in short-term mouse studies but showed high amounts of variability following long-term expansion. CONCLUSIONS: These results demonstrate laminin 521 is a superior substrate for both short-term and long-term myogenic cell culture applications compared to other commonly utilized substrates. Since Matrigel cannot be used for clinical applications, we propose that laminin 521 could possibly be employed in the future to provide myoblasts for cellular therapy directed clinical studies. PMID- 27964749 TI - Truncating de novo mutations in the Kruppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms. AB - BACKGROUND: Kruppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF genes encode proteins that recognize specific DNA motifs in gene promotors. They act as transcriptional co activators or -repressors via interaction with chromatin remodeling proteins and other transcription factors. Only few ZNF genes are currently linked to human disorders and identification of ZNF gene-associated human diseases may help understand their function. Here we provide genetic, statistical, and clinical evidence to support association of ZNF148 with a new intellectual disability (ID) syndrome disorder. METHODS: Routine diagnostic exome sequencing data were obtained from 2172 patients with ID and/or multiple congenital anomalies. RESULTS: In a cohort of 2172 patient-parent trios referred for routine diagnostic whole exome sequencing for ID and/or multiple congenital anomalies (MCA) in the period 2012-2016, four patients were identified who carried de novo heterozygous nonsense or frameshift mutations in the ZNF148 gene. This was the only ZNF gene with recurrent truncating de novo mutations in this cohort. All mutations resulted in premature termination codons in the last exon of ZNF148. The number of the de novo truncating mutations in the ZNF148 gene was significantly enriched (p = 5.42 * 10-3). The newly described ZNF148-associated syndrome is characterized by underdevelopment of the corpus callosum, mild to moderate developmental delay and ID, variable microcephaly or mild macrocephaly, short stature, feeding problems, facial dysmorphisms, and cardiac and renal malformations. CONCLUSIONS: We propose ZNF148 as a gene involved in a newly described ID syndrome with a recurrent phenotype and postulate that the ZNF148 is a hitherto unrecognized but crucial transcription factor in the development of the corpus callosum. Our study illustrates the advantage of whole exome sequencing in a large cohort using a parent-offspring trio approach for identifying novel genes involved in rare human diseases. PMID- 27964751 TI - Neurotoxicity and nephrotoxicity caused by combined use of lithium and risperidone: a case report and literature review. AB - BACKGROUND: Combination lithium, a mood stabilizer, and risperidone, an atypical antipsychotic drug, is widely used for treatment of psychotic disorders. Rare reports concern severe adverse drug reaction in multiple organic systems with their combined use. We report two episodes of neurotoxicity and nephrotoxicity in a patient following the combined use of lithium and risperidone. CASE PRESENTATION: A 55-year-old male had a diagnosis of schizoaffective disorder at the age of 51. He was initially treated with a combination of lithium and olanzapine 5 to 15 mg/day for 2 years. He was admitted to psychiatric ward at the age of 53 due to manic episode with psychotic feature. Because of poor blood sugar control, we switched olanzapine 20 mg/day to risperidone 4.5 mg/day with combination of lithium 900mg/day. The patient presented neurotoxicity, neuroleptic-malignant-syndrome like symptoms, and nephrotoxicity, elevation of blood creatinine and decreased urine output few days later. These signs were fully recovered within 2 days after we discontinued all medications and gave normal saline hydration. Then we re-administered decreased dosage of lithium 600 mg/day and risperidone 3 mg/day, and the similar episode occurred again 3 days later. All drugs were discontinued again, then his delirium resolved and abnormal data returned to normal 1 day later. Finally, the patient was treated with risperidone 2 mg/day as monotherapy, and no episode of neurotoxicity and nephrotoxicity appeared in the following 2 years. CONCLUSIONS: The case exemplifies neurotoxicity and nephrotoxicity after combined use of lithium and risperidone. These adverse effects resolved soon after discontinuing these medications and adequate hydration. Clinicians should be cautious about neurological and renal adverse effects. PMID- 27964753 TI - Oxytocin is implicated in social memory deficits induced by early sensory deprivation in mice. AB - Early-life sensory input plays a crucial role in brain development. Although deprivation of orofacial sensory input at perinatal stages disrupts the establishment of the barrel cortex and relevant callosal connections, its long term effect on adult behavior remains elusive. In this study, we investigated the behavioral phenotypes in adult mice with unilateral transection of the infraorbital nerve (ION) at postnatal day 3 (P3). Although ION-transected mice had normal locomotor activity, motor coordination, olfaction, anxiety-like behaviors, novel object memory, preference for social novelty and sociability, they presented deficits in social memory and spatial memory compared with control mice. In addition, the social memory deficit was associated with reduced oxytocin (OXT) levels in the hypothalamus and could be partially restored by intranasal administration of OXT. Thus, early sensory deprivation does result in behavioral alterations in mice, some of which may be associated with the disruption of oxytocin signaling. PMID- 27964752 TI - Extreme genomic erosion after recurrent demographic bottlenecks in the highly endangered Iberian lynx. AB - BACKGROUND: Genomic studies of endangered species provide insights into their evolution and demographic history, reveal patterns of genomic erosion that might limit their viability, and offer tools for their effective conservation. The Iberian lynx (Lynx pardinus) is the most endangered felid and a unique example of a species on the brink of extinction. RESULTS: We generate the first annotated draft of the Iberian lynx genome and carry out genome-based analyses of lynx demography, evolution, and population genetics. We identify a series of severe population bottlenecks in the history of the Iberian lynx that predate its known demographic decline during the 20th century and have greatly impacted its genome evolution. We observe drastically reduced rates of weak-to-strong substitutions associated with GC-biased gene conversion and increased rates of fixation of transposable elements. We also find multiple signatures of genetic erosion in the two remnant Iberian lynx populations, including a high frequency of potentially deleterious variants and substitutions, as well as the lowest genome-wide genetic diversity reported so far in any species. CONCLUSIONS: The genomic features observed in the Iberian lynx genome may hamper short- and long-term viability through reduced fitness and adaptive potential. The knowledge and resources developed in this study will boost the research on felid evolution and conservation genomics and will benefit the ongoing conservation and management of this emblematic species. PMID- 27964755 TI - XGR software for enhanced interpretation of genomic summary data, illustrated by application to immunological traits. AB - BACKGROUND: Biological interpretation of genomic summary data such as those resulting from genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) studies is one of the major bottlenecks in medical genomics research, calling for efficient and integrative tools to resolve this problem. RESULTS: We introduce eXploring Genomic Relations (XGR), an open source tool designed for enhanced interpretation of genomic summary data enabling downstream knowledge discovery. Targeting users of varying computational skills, XGR utilises prior biological knowledge and relationships in a highly integrated but easily accessible way to make user-input genomic summary datasets more interpretable. We show how by incorporating ontology, annotation, and systems biology network-driven approaches, XGR generates more informative results than conventional analyses. We apply XGR to GWAS and eQTL summary data to explore the genomic landscape of the activated innate immune response and common immunological diseases. We provide genomic evidence for a disease taxonomy supporting the concept of a disease spectrum from autoimmune to autoinflammatory disorders. We also show how XGR can define SNP-modulated gene networks and pathways that are shared and distinct between diseases, how it achieves functional, phenotypic and epigenomic annotations of genes and variants, and how it enables exploring annotation-based relationships between genetic variants. CONCLUSIONS: XGR provides a single integrated solution to enhance interpretation of genomic summary data for downstream biological discovery. XGR is released as both an R package and a web-app, freely available at http://galahad.well.ox.ac.uk/XGR . PMID- 27964754 TI - Imaging the mammary gland and mammary tumours in 3D: optical tissue clearing and immunofluorescence methods. AB - BACKGROUND: High-resolution 3D imaging of intact tissue facilitates cellular and subcellular analyses of complex structures within their native environment. However, difficulties associated with immunolabelling and imaging fluorescent proteins deep within whole organs have restricted their applications to thin sections or processed tissue preparations, precluding comprehensive and rapid 3D visualisation. Several tissue clearing methods have been established to circumvent issues associated with depth of imaging in opaque specimens. The application of these techniques to study the elaborate architecture of the mouse mammary gland has yet to be investigated. METHODS: Multiple tissue clearing methods were applied to intact virgin and lactating mammary glands, namely 3D imaging of solvent-cleared organs, see deep brain (seeDB), clear unobstructed brain imaging cocktails (CUBIC) and passive clarity technique. Using confocal, two-photon and light sheet microscopy, their compatibility with whole-mount immunofluorescent labelling and 3D imaging of mammary tissue was examined. In addition, their suitability for the analysis of mouse mammary tumours was also assessed. RESULTS: Varying degrees of optical transparency, tissue preservation and fluorescent signal conservation were observed between the different clearing methods. SeeDB and CUBIC protocols were considered superior for volumetric fluorescence imaging and whole-mount histochemical staining, respectively. Techniques were compatible with 3D imaging on a variety of platforms, enabling visualisation of mammary ductal and lobulo-alveolar structures at vastly improved depths in cleared tissue. CONCLUSIONS: The utility of whole-organ tissue clearing protocols was assessed in the mouse mammary gland. Most methods utilised affordable and widely available reagents, and were compatible with standard confocal microscopy. These techniques enable high-resolution, 3D imaging and phenotyping of mammary cells and tumours in situ, and will significantly enhance our understanding of both normal and pathological mammary gland development. PMID- 27964756 TI - Serum IL-33, a new marker predicting response to rituximab in rheumatoid arthritis. AB - BACKGROUND: Recent works have suggested a possible link between interleukin (IL) 33 and B-cell biology. We aimed to study the possible association between serum IL-33 detection and response to rituximab (RTX) in rheumatoid arthritis (RA) patients in different cohorts with an accurate enzyme-linked immunosorbent assay (ELISA). METHODS: Serum IL-33, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), and high serum immunoglobulin (Ig)G levels were assessed in 111 RA patients receiving a first course of 2 g RTX (cohort 1) in an observational study and in 74 RA patients treated with the same schedule in routine care (cohort 2). Univariate and multivariate analyses identified factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks. RESULTS: At week 24, 84/111 (76%) and 54/74 (73%) patients reached EULAR response in cohorts 1 and 2, respectively. Serum IL-33 was detectable in only 33.5% of the patients. In the combined cohorts, the presence of RF or anti-CCP (odds ratio (OR) 3.27, 95% confidence interval (CI) 1.13-9.46; p = 0.03), high serum IgG (OR 2.32, 95% CI 1.01-5.33; p = 0.048), and detectable serum IL-33 (OR 2.40, 95% CI 1.01-5.72; p = 0.047) were all associated with RTX response in multivariate analysis. The combination of these three factors increased the likelihood of response to RTX. When serum IL-33 detection was added to seropositivity and serum IgG level, 100% of the patients with the three risk factors (corresponding to 9% of the population) responded to RTX (OR versus patients with none of the three risk factors 29.61, 95% CI 1.30-674.79; p = 0.034). CONCLUSION: Detectable serum IL-33 may predict clinical response to RTX independently of, and synergistically with, auto-antibodies and serum IgG level. TRIAL REGISTRATION: NCT01126541 ; 18 May 2010. PMID- 27964757 TI - Discordant inflammation and pain in early and established rheumatoid arthritis: Latent Class Analysis of Early Rheumatoid Arthritis Network and British Society for Rheumatology Biologics Register data. AB - BACKGROUND: Rheumatoid arthritis (RA) disease activity is often measured using the 28-joint Disease Activity Score (DAS28). We aimed to identify and independently verify subgroups of people with RA that may be discordant with respect to self-reported and objective disease state, with potentially different clinical needs. METHODS: Data were derived from three cohorts: (1) the Early Rheumatoid Arthritis Network (ERAN) and the British Society for Rheumatology Biologics Register (BSRBR), (2) those commencing tumour necrosis factor (TNF) alpha inhibitors and (3) those using non-biologic drugs. In latent class analysis, we used variables related to pain, central pain mechanisms or inflammation (pain, vitality, mental health, erythrocyte sedimentation rate, swollen joint count, tender joint count, visual analogue scale of general health). Clinically relevant outcomes were examined. RESULTS: Five, four and four latent classes were found in the ERAN, BSRBR TNF inhibitor and non-biologic cohorts, respectively. The proportions of people assigned with >80% probability into latent classes were 76%, 58% and 72% in the ERAN, TNF inhibitor and non biologic cohorts, respectively. The latent classes displayed either concordance between measures indicative of mild, moderate or severe disease activity; discordantly worse patient-reported measures despite less markedly elevated inflammation; or discordantly less severe patient-reported measures despite elevated inflammation. Latent classes with discordantly worse patient-reported measures represented 12%, 40% and 21% of the ERAN, TNF inhibitor and non-biologic cohorts, respectively; contained more females; and showed worse function. In those latent classes with worse scores at baseline, DAS28 and function improved over 1 year (p < 0.001 for all comparisons), and scores differed less at follow up than at baseline. CONCLUSIONS: Discordant latent classes can be identified in people with RA, and these findings are robust across three cohorts with varying disease duration and activity. These findings could be used to identify a sizeable subgroup of people with RA who might gain added benefit from pain management strategies. PMID- 27964758 TI - Expression of acid-sensing ion channels and selection of reference genes in mouse and naked mole rat. AB - Acid-sensing ion channels (ASICs) are a family of ion channels comprised of six subunits encoded by four genes and they are expressed throughout the peripheral and central nervous systems. ASICs have been implicated in a wide range of physiological and pathophysiological processes: pain, breathing, synaptic plasticity and excitotoxicity. Unlike mice and humans, naked mole-rats do not perceive acid as a noxious stimulus, even though their sensory neurons express functional ASICs, likely an adaptation to living in a hypercapnic subterranean environment. Previous studies of ASIC expression in the mammalian nervous system have often not examined all subunits, or have failed to adequately quantify expression between tissues; to date there has been no attempt to determine ASIC expression in the central nervous system of the naked mole-rat. Here we perform a geNorm study to identify reliable housekeeping genes in both mouse and naked mole rat and then use quantitative real-time PCR to estimate the relative amounts of ASIC transcripts in different tissues of both species. We identify RPL13A (ribosomal protein L13A) and CANX (calnexin), and beta-ACTIN and EIF4A (eukaryotic initiation factor 4a) as being the most stably expressed housekeeping genes in mouse and naked mole-rat, respectively. In both species, ASIC3 was most highly expressed in dorsal root ganglia (DRG), and ASIC1a, ASIC2b and ASIC3 were more highly expressed across all brain regions compared to the other subunits. We also show that ASIC4, a proton-insensitive subunit of relatively unknown function, was highly expressed in all mouse tissues apart from DRG and hippocampus, but was by contrast the lowliest expressed ASIC in all naked mole rat tissues. PMID- 27964760 TI - Impact of body weight on the achievement of minimal disease activity in patients with rheumatic diseases: a systematic review and meta-analysis. AB - BACKGROUND: In this study, we evaluated the impact of obesity and/or overweight on the achievement of minimal disease activity (MDA) in patients with psoriatic arthritis (PsA) and patients with rheumatoid arthritis (RA) receiving an anti rheumatic treatment. Obesity can be considered a low-grade, chronic systemic inflammatory disease and some studies suggested that obese patients with rheumatic diseases exhibit a lower rate of low disease activity achievement during treatment with anti-rheumatic drugs. METHODS: A systematic search was performed in major electronic databases (PubMed, Web of Science, Scopus, Embase) to identify studies reporting MDA achievement in obese and/or overweight patients with RA or PsA and in normal-weight RA or PsA control subjects. Results were expressed as Odds Ratios (ORs) with pertinent 95% Confidence Intervals (95%CIs). RESULTS: We included 17 studies (10 on RA and 7 on PsA) comprising a total of 6693 patients (1562 with PsA and 5131 with RA) in the analysis. The MDA achievement rate was significantly lower in obese patients than in normal-weight subjects (OR 0.447, 95% CI 0.346-0.577, p < 0.001, I 2 = 62.6%, p < 0.001). Similarly, overweight patients showed a significantly lower prevalence of MDA achievement than normal-weight subjects (OR 0.867, 95% CI 0.757-0.994, p = 0.041, I 2 = 64%, p = 0.007). Interestingly, the effect of obesity on MDA was confirmed when we separately analyzed data on patients with RA and patients with PsA. In contrast, when we evaluated the effect of overweight, our results were confirmed for PsA but not for RA. A meta-regression analysis showed that follow-up duration, age, male sex, and treatment duration are covariates significantly affecting the effect of obesity/overweight on MDA achievement. CONCLUSIONS: The results of our meta-analysis suggest that obesity and overweight reduce the chances to achieve MDA in patients with rheumatic diseases receiving treatment with traditional or biologic disease-modifying antirheumatic drugs. PMID- 27964759 TI - Voluntary resistance wheel exercise from mid-life prevents sarcopenia and increases markers of mitochondrial function and autophagy in muscles of old male and female C57BL/6J mice. AB - BACKGROUND: There is much interest in the capacity of resistance exercise to prevent the age-related loss of skeletal muscle mass and function, known as sarcopenia. This study investigates the molecular basis underlying the benefits of resistance exercise in aging C57BL/6J mice of both sexes. RESULTS: This study is the first to demonstrate that long-term (34 weeks) voluntary resistance wheel exercise (RWE) initiated at middle age, from 15 months, prevents sarcopenia in selected hindlimb muscles and causes hypertrophy in soleus, by 23 months of age in both male and female C57BL/6J mice. Compared with 23-month-old sedentary (SED) controls, RWE (0-6 g of resistance) increased intramuscular mitochondrial density and oxidative capacity (measured by citrate synthase and NADH-TR) and increased LC3II/I ratios (a marker of autophagy) in exercised mice of both sexes. RWE also reduced mRNA expression of Gadd45alpha (males only) and Runx1 (females only) but had no effect on other markers of denervation including Chrng, Chrnd, Musk, and Myog. RWE increased heart mass in all mice, with a more pronounced increase in females. Significant sex differences were also noted among SED mice, with Murf1 mRNA levels increasing in male, but decreasing in old female mice between 15 and 23 months. CONCLUSIONS: Overall, long-term RWE initiated from 15 month of age significantly improved some markers of the mitochondrial and autophagosomal pathways and prevented age-related muscle wasting. PMID- 27964762 TI - New tools to analyze overlapping coding regions. AB - BACKGROUND: Retroviruses transcribe messenger RNA for the overlapping Gag and Gag Pol polyproteins, by using a programmed -1 ribosomal frameshift which requires a slippery sequence and an immediate downstream stem-loop secondary structure, together called frameshift stimulating signal (FSS). It follows that the molecular evolution of this genomic region of HIV-1 is highly constrained, since the retroviral genome must contain a slippery sequence (sequence constraint), code appropriate peptides in reading frames 0 and 1 (coding requirements), and form a thermodynamically stable stem-loop secondary structure (structure requirement). RESULTS: We describe a unique computational tool, RNAsampleCDS, designed to compute the number of RNA sequences that code two (or more) peptides p,q in overlapping reading frames, that are identical (or have BLOSUM/PAM similarity that exceeds a user-specified value) to the input peptides p,q. RNAsampleCDS then samples a user-specified number of messenger RNAs that code such peptides; alternatively, RNAsampleCDS can exactly compute the position specific scoring matrix and codon usage bias for all such RNA sequences. Our software allows the user to stipulate overlapping coding requirements for all 6 possible reading frames simultaneously, even allowing IUPAC constraints on RNA sequences and fixing GC-content. We generalize the notion of codon preference index (CPI) to overlapping reading frames, and use RNAsampleCDS to generate control sequences required in the computation of CPI. Moreover, by applying RNAsampleCDS, we are able to quantify the extent to which the overlapping coding requirement in HIV-1 [resp. HCV] contribute to the formation of the stem-loop [resp. double stem-loop] secondary structure known as the frameshift stimulating signal. Using our software, we confirm that certain experimentally determined deleterious HCV mutations occur in positions for which our software RNAsampleCDS and RNAiFold both indicate a single possible nucleotide. We generalize the notion of codon preference index (CPI) to overlapping coding regions, and use RNAsampleCDS to generate control sequences required in the computation of CPI for the Gag-Pol overlapping coding region of HIV-1. These applications show that RNAsampleCDS constitutes a unique tool in the software arsenal now available to evolutionary biologists. CONCLUSION: Source code for the programs and additional data are available at http://bioinformatics.bc.edu/clotelab/RNAsampleCDS/ . PMID- 27964763 TI - Subjective Qualitative Hand Hygiene Compliance Observation: A Feasibility Trial. PMID- 27964761 TI - Involvement of nucleoside diphosphate kinase b and elongation factor 2 in Leishmania braziliensis antimony resistance phenotype. AB - BACKGROUND: Nucleoside diphosphate kinase b (NDKb) is responsible for nucleoside triphosphates synthesis and it has key role in the purine metabolism in trypanosomatid protozoans. Elongation factor 2 (EF2) is an important factor for protein synthesis. Recently, our phosphoproteomic analysis demonstrated that NDKb and EF2 proteins were phosphorylated and dephosphorylated in antimony (SbIII) resistant L. braziliensis line compared to its SbIII-susceptible pair, respectively. METHODS: In this study, the overexpression of NDKb and EF2 genes in L. braziliensis and L. infantum was performed to investigate the contribution of these proteins in the SbIII-resistance phenotype. Furthermore, we examined the role of lamivudine on SbIII susceptibility in clones that overexpress the NDKb gene, and the effect of EF2 kinase (EF2K) inhibitor on the growth of EF2 overexpressing parasites. RESULTS: Western blot analysis demonstrated that NDKb and EF2 proteins are more and less expressed, respectively, in SbIII-resistant line of L. braziliensis than its wild-type (WTS) counterpart, corroborating our previous phosphoproteomic data. NDKb or EF2-overexpressing L. braziliensis lines were 1.6 to 2.1-fold more resistant to SbIII than the untransfected WTS line. In contrast, no difference in SbIII susceptibility was observed in L. infantum parasites overexpressing NDKb or EF2. Susceptibility assays showed that NDKb overexpressing L. braziliensis lines presented elevated resistance to lamivudine, an antiviral agent, but it did not alter the leishmanicidal activity in association with SbIII. EF2-overexpressing L. braziliensis clone was slightly more resistant to EF2K inhibitor than the WTS line. Surprisingly, this inhibitor increased the antileishmanial effect of SbIII, suggesting that this association might be a valuable strategy for leishmaniasis chemotherapy. CONCLUSION: Our findings represent the first study of NDKb and EF2 genes overexpression that demonstrates an increase of SbIII resistance in L. braziliensis which can contribute to develop new strategies for leishmaniasis treatment. PMID- 27964764 TI - Investigation of a national outbreak of STEC Escherichia coli O157 using online consumer panel control methods: Great Britain, October 2014. AB - In October 2014, Public Health England (PHE) identified cases of Shiga toxin producing Escherichia coli (STEC) serogroup O157 sharing a multiple locus variable-number tandem repeat analysis (MLVA) profile. We conducted a case control study using multivariable logistic regression to calculate adjusted odds ratios (aOR) and 95% confidence intervals (CI) testing a range of exposures. Cases were defined as laboratory-confirmed STEC O157 with the implicated MLVA profile, were UK residents aged ?18 years with symptom onset between 25 September and 30 October 2014, and had no history of travel abroad within 5 days of symptom onset. One hundred and two cases were identified. Cases were mostly female (65%; median age 49, range 2-92 years). It was the second largest outbreak seen in England, to date, and a case-control study was conducted using market research panel controls and online survey methods. These methods were instrumental in the rapid data collection and analysis necessary to allow traceback investigations for short shelf-life products. This is a new method of control recruitment and this is the first in which it was a standalone recruitment method. The case control study suggested a strong association between consumption of a ready-to eat food and disease (aOR 28, 95% CI 5.0-157) from one retailer. No reactive microbiological testing of food items during the outbreak was possible due to the short shelf-life of the product. Collaboration with industrial bodies is needed to ensure timely traceback exercises to identify contamination events and initiate appropriate and focused microbiological testing and implement control measures. PMID- 27964765 TI - Arginine-vasopressin therapy in hypotensive neonates and infants after cardiac surgery: response is unrelated to baseline ventricular function. AB - We hypothesised that infants with ventricular dysfunction after cardiac surgery have impaired haemodynamic response to arginine-vasopressin therapy. We retrospectively reviewed the medical records of neonates and infants treated with arginine-vasopressin within 48 hours of corrective or palliative cardiac surgery who underwent echocardiographic assessment of ventricular function before initiation of therapy. Patients were classified as "responders" if their systolic blood pressure increased by ?10% without increase in catecholamine score or if it was maintained with decreased catecholamine score. Response was assessed 1 hour after maximum upward titration of arginine-vasopressin. A total of 36 children (15 neonates) were reviewed (17 male). The median (interquartile) age was 10.4 weeks (1.1-26.9), and the median weight was 4.3 kg (3.2-5.8). Diagnoses included single ventricle (eight), arch abnormalities (five), atrioventricular septal defect (four), double-outlet right ventricle (three), tetralogy of Fallot (three), and others (13). In all, 12 patients (33%) had ventricular dysfunction. Only 15 (42%) responded favourably according to our definition 1 hour after the "target" arginine-vasopressin dose was achieved. Ventricular dysfunction was not associated with poor response. The overall mortality was 25%, but mortality in patients with ventricular dysfunction was 42%. Favourable response was associated with shorter ICU stay (9.5 days versus 19.5 days, p=0.01). We conclude that arginine-vasopressin fails to increase blood pressure in ~50% of hypotensive children after cardiac surgery. The response rate does not increase with duration of therapy. Ventricular function does not predict haemodynamic response. The mortality in this group is very high. Prospective comparison of vasopressin with other vasoactive agents and/or inotropes is warranted. PMID- 27964766 TI - Both high and low plasma levels of 25-hydroxy vitamin D increase blood pressure in a normal rat model. AB - The lower threshold plasma 25-hydroxy vitamin D (25(OH)D) level for optimal cardiovascular health is unclear, whereas the toxicity threshold is less clear. The aim of this study was to examine the cardiovascular-vitamin D dose-response curve in a normal rat model. Doses of cholecalciferol ranged from deficiency to toxic levels (equivalent to human doses of 0, 0.015, 0.25 and 3.75mg/d) for 4 weeks, and then cardiovascular health was examined using blood pressure telemetry and high-resolution ultrasound in normal male rats (n 16/group, 64 rats total). After 1 month, only the 0.25mg/d group had plasma 25(OH)D that was within current recommended range (100-125 nmol/l), and all groups failed to change plasma Ca or phosphate. Systolic blood pressure increased significantly (10-15 mmHg) in the rat groups with plasma 25(OH)D levels at both 30 and 561 nmol/l (groups fed 0 and 3.75mg/d) compared with the group fed the equivalent to 0.015mg/d (43 nmol/l 25(OH)D). Although not significant, the group fed the equivalent to 0.25mg/d (108 nmol/l 25(OH)D) also showed a 10 mmHg increase in systolic blood pressure. Carotid artery diameter was significantly smaller and wall thickness was larger, leading to higher peak carotid systolic blood velocity in these two groups. Despite these vascular changes, cardiac function did not differ among treatment groups. The key finding in this study is that arterial stiffness and systolic blood pressure both showed a U-shaped dose-response for vitamin D, with lowest values (best cardiovascular health) observed when plasma 25(OH)D levels were 43 nmol/l in normal male rats. PMID- 27964767 TI - Assessing Hospital Disaster Readiness Over Time at the US Department of Veterans Affairs. AB - : Introduction There have been numerous initiatives by government and private organizations to help hospitals become better prepared for major disasters and public health emergencies. This study reports on efforts by the US Department of Veterans Affairs (VA), Veterans Health Administration, Office of Emergency Management's (OEM) Comprehensive Emergency Management Program (CEMP) to assess the readiness of VA Medical Centers (VAMCs) across the nation. Hypothesis/Problem This study conducts descriptive analyses of preparedness assessments of VAMCs and examines change in hospital readiness over time. METHODS: To assess change, quantitative analyses of data from two phases of preparedness assessments (Phase I: 2008-2010; Phase II: 2011-2013) at 137 VAMCs were conducted using 61 unique capabilities assessed during the two phases. The initial five-point Likert-like scale used to rate each capability was collapsed into a dichotomous variable: "not-developed=0" versus "developed=1." To describe changes in preparedness over time, four new categories were created from the Phase I and Phase II dichotomous variables: (1) rated developed in both phases; (2) rated not-developed in Phase I but rated developed in Phase II; (3) rated not-developed in both phases; and (4) rated developed in Phase I but rated not- developed in Phase II. RESULTS: From a total of 61 unique emergency preparedness capabilities, 33 items achieved the desired outcome - they were rated either "developed in both phases" or "became developed" in Phase II for at least 80% of VAMCs. For 14 items, 70%-80% of VAMCs achieved the desired outcome. The remaining 14 items were identified as "low performing" capabilities, defined as less than 70% of VAMCs achieved the desired outcome. CONCLUSION: Measuring emergency management capabilities is a necessary first step to improving those capabilities. Furthermore, assessing hospital readiness over time and creating robust hospital readiness assessment tools can help hospitals make informed decisions regarding allocation of resources to ensure patient safety, provide timely access to high-quality patient care, and identify best practices in emergency management during and after disasters. Moreover, with some minor modifications, this comprehensive, all-hazards-based, hospital preparedness assessment tool could be adapted for use beyond the VA. Der Martirosian C , Radcliff TA , Gable AR , Riopelle D , Hagigi FA , Brewster P , Dobalian A . Assessing hospital disaster readiness over time at the US Department of Veterans Affairs. Prehsop Disaster Med. 2017;32(1):46-57. PMID- 27964768 TI - Evaluation of Hospitals' Disaster Preparedness Plans in the Holy City of Makkah (Mecca): A Cross-Sectional Observation Study. AB - BACKGROUND: Makkah (Mecca) is a holy city located in the western region of the Kingdom of Saudi Arabia. Each year, millions of pilgrims visit Makkah. These numbers impact both routine health care delivery and disaster response. This study aimed to evaluate hospitals' disaster plans in the city of Makkah. METHODS: Study investigators administered a questionnaire survey to 17 hospitals in the city of Makkah. Data on hospital characteristics and three key domains of disaster plans (general evaluation of disaster planning, structural feasibility of the hospitals, and health care worker knowledge and training) were collated and analyzed. RESULTS: A response rate of 82% (n=14) was attained. Ten (71%) of the hospitals were government hospitals, whereas four were private hospitals. Eleven (79%) hospitals had a capacity of less than 300 beds. Only nine (64%) hospitals reviewed their disaster plan within the preceding two years. Nine (64%) respondents were drilling for disasters at least twice per year. The majority of hospitals did not rely on a hazard vulnerability analysis (HVA) to develop their Emergency Operations Plan. Eleven (79%) hospitals had the Hospital Incident Command Systems (HICS) present in their plans. All hospitals described availability of some supplies required for the first 24 hours of a disaster response, such as: N95 masks, antidotes for nerve agents, and antiviral medications. Only five (36%) hospitals had a designated decontamination area. Nine (64%) hospitals reported ability to re-designate inpatient wards into an intensive care unit (ICU) format. Only seven (50%) respondents had a protocol for increasing availability of isolation rooms to prevent the spread of airborne infection. Ten (71%) hospitals had a designated disaster-training program for health care workers. CONCLUSIONS: Makkah has experienced multiple disaster incidents over the last decade. The present research suggests that Makkah hospitals are insufficiently prepared for potential future disasters. This may represent a considerable threat to the health of both residents and visitors to Makkah. This study demonstrated that there is significant room for improvement in most aspects of hospital Emergency Operations Plans, in particular: reviewing the plan and increasing the frequency of multi-agency and multi-hospital drills. Preparedness for terrorism utilizing chemical, biologic, radiation, nuclear, explosion (CBRNE) and infectious diseases was found to be sub-optimal and should be assessed further. Al-Shareef AS , Alsulimani LK , Bojan HM , Masri TM , Grimes JO , Molloy MS , Ciottone GR . Evaluation of hospitals' disaster preparedness plans in the holy city of Makkah (Mecca): a cross-sectional observation study. Prehosp Disaster Med. 2017;32 (1):33-45. PMID- 27964769 TI - Paramedic Application of a Triage Sieve: A Paper-Based Exercise. AB - : Introduction Triage is the systematic prioritization of casualties when there is an imbalance between the needs of these casualties and resource availability. The triage sieve is a recognized process for prioritizing casualties for treatment during mass-casualty incidents (MCIs). While the application of a triage sieve generally is well-accepted, the measurement of its accuracy has been somewhat limited. Obtaining reliable measures for triage sieve accuracy rates is viewed as a necessity for future development in this area. OBJECTIVE: The goal of this study was to investigate how theoretical knowledge acquisition and the practical application of an aide-memoir impacted triage sieve accuracy rates. METHOD: Two hundred and ninety-two paramedics were allocated randomly to one of four separate sub-groups, a non-intervention control group, and three intervention groups, which involved them receiving either an educational review session and/or an aide-memoir. Participants were asked to triage sieve 20 casualties using a previously trialed questionnaire. RESULTS: The study showed the non-intervention control group had a correct accuracy rate of 47%, a similar proportion of casualties found to be under-triaged (37%), but a significantly lower number of casualties were over-triaged (16%). The provision of either an educational review or aide-memoir significantly increased the correct triage sieve accuracy rate to 77% and 90%, respectively. Participants who received both the educational review and aide-memoir had an overall accuracy rate of 89%. Over triaged rates were found not to differ significantly across any of the study groups. CONCLUSION: This study supports the use of an aide-memoir for maximizing MCI triage accuracy rates. A "just-in-time" educational refresher provided comparable benefits, however its practical application to the MCI setting has significant operational limitations. In addition, this study provides some guidance on triage sieve accuracy rate measures that can be applied to define acceptable performance of a triage sieve during a MCI. Cuttance G , Dansie K , Rayner T . Paramedic application of a triage sieve: a paper-based exercise. Prehosp Disaster Med. 2017;32(1):3-13. PMID- 27964770 TI - Emotional processing during psychotherapy among women newly diagnosed with a gynecological cancer. AB - OBJECTIVE: Our aim was to compare changes in emotional processing by women newly diagnosed with gynecological cancer enrolled in either a coping and communication skills intervention (CCI) or a supportive counseling (SC) intervention. We examined the association between in-session emotional processing and patient rated therapeutic progress. METHOD: Three therapy sessions with 201 patients were rated for the depth of emotional processing (peak and mode) during emotion episodes (EEs) using the Experiencing Rating Scale (EXP). Participants completed measures of dispositional emotional expressivity, depressive symptoms, and cancer related distress before treatment began, as well as ratings of perceived progress in therapy after each session. RESULTS: Peak EXP ratings averaged between 2.7 and 3.1, indicating that women discussed events, their emotional reactions, and their private experiences in sessions. A small proportion of patients had high levels of processing, indicating deeper exploration of the meaning of their feelings and experiences. Women in SC were able to achieve a higher level of emotional processing during the middle and later sessions, and during cancer-related EEs in the later session. However, emotional processing was not significantly associated with a patient's perceived therapeutic progress with SC. In the CCI group, higher levels of emotional processing were associated with greater session progress, suggesting that it may play an important role in patient-rated treatment outcomes. SIGNIFICANCE OF RESULTS: Newly diagnosed gynecological cancer patients are able to attend to their emotions and personal experiences, particularly when discussing cancer-related issues during both short-term SC and prescriptive coping skills interventions. PMID- 27964771 TI - Exploring How Lay Rescuers Overcome Barriers to Provide Cardiopulmonary Resuscitation: A Qualitative Study. AB - BACKGROUND: Survival rates after out-of-hospital cardiac arrest (OHCA) vary considerably among regions. The chance of survival is increased significantly by lay rescuer cardiopulmonary resuscitation (CPR) before Emergency Medical Services (EMS) arrival. It is well known that for bystanders, reasons for not providing CPR when witnessing an OHCA incident may be fear and the feeling of being exposed to risk. The aim of this study was to gain a better understanding of why barriers to providing CPR are overcome. METHODS: Using a semi-structured interview guide, 10 lay rescuers were interviewed after participating in eight OHCA incidents. Qualitative content analysis was used. The lay rescuers were questioned about their CPR-knowledge, expectations, and reactions to the EMS and from others involved in the OHCA incident. They also were questioned about attitudes towards providing CPR in an OHCA incident in different contexts. RESULTS: The lay rescuers reported that they were prepared to provide CPR to anybody, anywhere. Comprehending the severity in the OHCA incident, both trained and untrained lay rescuers provided CPR. They considered CPR provision to be the expected behavior of any community citizen and the EMS to act professionally and urgently. However, when asked to imagine an OHCA in an unclear setting, they revealed hesitation about providing CPR because of risk to their own safety. CONCLUSION: Mutual trust between community citizens and towards social institutions may be reasons for overcoming barriers in providing CPR by lay rescuers. A normative obligation to act, regardless of CPR training and, importantly, without facing any adverse legal reactions, also seems to be an important factor behind CPR provision. Mathiesen WT , Bjorshol CA , Hoyland S , Braut GS , Soreide E . Exploring how lay rescuers overcome barriers to provide cardiopulmonary resuscitation: a qualitative study. Prehosp Disaster Med. 2017;32(1):27-32. PMID- 27964772 TI - Supplemental Nutrition Assistance Progam benefits and emergency room visits for hypoglycaemia. AB - OBJECTIVE: The present study examines the connection between the timing and size of Supplemental Nutrition Assistance Program (SNAP) benefits and the occurrence of emergency room (ER) visits for hypoglycaemia, a condition that is highly sensitive to short-term changes in nutritional intake. DESIGN: We used administrative data from Missouri SNAP and Medicaid to identify the timing of issuance and the benefit size of SNAP and the timing of ER claims for hypoglycaemia. We estimated the probability of submitting an ER claim for hypoglycaemia as a function of the calendar week, SNAP benefit week and the size of the SNAP benefit in models that controlled for individual demographic characteristics. SETTING: Missouri SNAP caseload from January 2010 to December 2013 linked to adult Medicaid claims data for the same time period. SUBJECTS: ER claims submitted to Medicaid (n 6 508 061). RESULTS: The results indicated no evidence of a SNAP benefit cycle or monthly cycle to ER claims for hypoglycaemia. However, the analysis did find that ER claims for hypoglycaemia are related to the size of the SNAP benefit. CONCLUSIONS: These results suggest that more generous SNAP benefits help households avoid nutritional fluctuations in the quality and quantity of food that might result in low blood sugar, thus necessitating fewer ER visits for hypoglycaemia. PMID- 27964773 TI - Another "Dear Esteemed Colleague" Journal Email Invitation? PMID- 27964774 TI - Risk of gestational diabetes mellitus in relation to maternal dietary calcium intake. AB - OBJECTIVE: The present study sought to examine the association between dietary Ca intake and risk of gestational diabetes mellitus (GDM). DESIGN: We assessed periconceptional (i.e. before conception and early pregnancy) Ca intake and consumption of foods rich in Ca using an FFQ among 3414 participants in a prospective cohort study. Diagnoses of GDM were abstracted from medical records. We used multivariable generalized linear regression models to derive estimates of relative risk (RR) for GDM and 95 % confidence intervals. SETTING: A prospective cohort of women in Seattle and Tacoma, WA, USA. SUBJECTS: Women (n 3414). RESULTS: A total of 169 GDM incident cases were identified in the cohort (4.96 %). Higher dietary Ca intake was inversely, although not statistically significantly, associated with GDM risk. After adjusting for confounders, the RR (95 % CI) for GDM according to successive increasing quartile of Ca intake was 1.00, 0.63 (0.41, 0.98), 0.66 (0.39, 1.11) and 0.57 (0.27, 1.21), respectively, with the lowest quartile as the reference (P trend=0.131). Compared with women in the first quartile for Ca intake, women in the higher three quartiles (>=795 v. <795 mg/d) had a 42 % (RR=0.58; 95 % CI 0.38, 0.90; P=0.015) lower GDM risk. GDM risk was inversely associated with low-fat dairy (P trend=0.032) and whole grains (P trend=0.019) consumption. CONCLUSIONS: These findings suggest that higher levels of periconceptional Ca intake, particularly intake of Ca-rich low-fat dairy products and whole grains, are associated with lower GDM risk. PMID- 27964775 TI - Hygiene on maternity units: lessons from a needs assessment in Bangladesh and India. AB - BACKGROUND: As the proportion of deliveries in health institutions increases in low- and middle-income countries, so do the challenges of maintaining standards of hygiene and preventing healthcare-associated infections (HCAIs) in mothers and babies. Adequate water, sanitation, and hygiene (WASH) and infection prevention and control (IPC) in these settings should be seen as integral parts of the broader domain of quality care. Assessment approaches are needed which capture standards for both WASH and IPC, and so inform quality improvement processes. DESIGN: A needs assessment was conducted in seven maternity units in Gujarat, India, and eight in Dhaka Division, Bangladesh in 2014. The WASH & CLEAN study developed and applied a suite of tools - a 'walkthrough checklist' which included the collection of swab samples, a facility needs assessment tool and document review, and qualitative interviews with staff and recently delivered women - to establish the state of hygiene as measured by visual cleanliness and the presence of potential pathogens, and individual and contextual determinants or drivers. RESULTS: No clear relationship was found between visually assessed cleanliness and the presence of pathogens; findings from qualitative interviews and the facility questionnaire found inadequacies in IPC training for healthcare providers and no formal training at all for ward cleaners. Lack of written policies and protocols, and poor monitoring and supervision also contributed to suboptimal IPC standards. CONCLUSIONS: Visual assessment of cleanliness and hygiene is an inadequate marker for 'safety' in terms of the presence of potential pathogens and associated risk of infection. Routine environmental screening of high-risk touch sites using simple microbiology could improve detection and control of pathogens. IPC training for both healthcare providers and ward cleaners represents an important opportunity for quality improvement. This should occur in conjunction with broader systems changes, including the establishment of functioning IPC committees, implementing standard policies and protocols, and improving health management information systems to capture information on maternal and newborn HCAIs. PMID- 27964776 TI - "Since both of us are using antiretrovirals, we have been supportive to each other": facilitators and barriers of pre-exposure prophylaxis use in heterosexual HIV serodiscordant couples in Kisumu, Kenya. AB - INTRODUCTION: Since 2015, the World Health Organization recommends pre-exposure prophylaxis (PrEP) for all persons at substantial risk for HIV, including HIV uninfected partners in serodiscordant relationships in resource-limited settings. As PrEP moves from clinical trials to real-world use, understanding facilitators of and barriers to PrEP initiation and adherence is critical to successful PrEP implementation and rollout. METHODS: We conducted 44 in-depth individual or couple interviews with 63 participants (30 without HIV and 33 with HIV) enrolled in the Partners Demonstration Project in Kisumu, Kenya, between August and September 2014. The semi-structured interviews discussed the following: 1) perceived advantages and disadvantages of antiretroviral therapy (ART)/PrEP; 2) reasons for accepting or declining ART/PrEP and 3) influence of prevention of transmission to partner or infant on ART/PrEP use. Transcripts from the interviews were iteratively analyzed using inductive content analysis. RESULTS: Our study identified three key factors that may facilitate initiation of PrEP in this population. First, participants using PrEP felt reduced stress and increased trust in their HIV serodiscordant relationships. Second, greater community-wide knowledge of PrEP was thought to likely increase PrEP acceptance. Third, greater education and counselling by providers on PrEP use was also considered to likely increase the adoption of PrEP. We also identified three key barriers to initiation of and adherence to PrEP. First, most participants who declined PrEP expressed doubts about the relative additional effectiveness of PrEP in combination with other prevention tools. Second, perceived stigma related to PrEP use was an important barrier to PrEP initiation. Third, many struggled with overcoming perceived side effects or logistical challenges of taking daily PrEP, particularly when they themselves were not ill. CONCLUSIONS: Leveraging the facilitators and overcoming barriers to PrEP uptake may enhance the successful rollout of PrEP among HIV serodiscordant couples in Kenya and other areas in sub Saharan Africa, thereby reducing sexual transmission of HIV. Further research focused on how best to provide counselling on combination HIV prevention tools in the context of PrEP use is a crucial next step to delivering PrEP. PMID- 27964778 TI - New footprints from Laetoli (Tanzania) provide evidence for marked body size variation in early hominins. AB - Laetoli is a well-known palaeontological locality in northern Tanzania whose outstanding record includes the earliest hominin footprints in the world (3.66 million years old), discovered in 1978 at Site G and attributed to Australopithecus afarensis. Here, we report hominin tracks unearthed in the new Site S at Laetoli and referred to two bipedal individuals (S1 and S2) moving on the same palaeosurface and in the same direction as the three hominins documented at Site G. The stature estimates for S1 greatly exceed those previously reconstructed for Au. afarensis from both skeletal material and footprint data. In combination with a comparative reappraisal of the Site G footprints, the evidence collected here embodies very important additions to the Pliocene record of hominin behaviour and morphology. Our results are consistent with considerable body size variation and, probably, degree of sexual dimorphism within a single species of bipedal hominins as early as 3.66 million years ago. PMID- 27964777 TI - Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994. AB - Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886-1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve. PMID- 27964779 TI - These feet were made for walking. AB - New fossil footprints excavated at the famous Laetoli site in Tanzania suggest that our bipedal ancestors had a wide range of body sizes. PMID- 27964780 TI - Reversion of hyperhydricity in pink (Dianthus chinensis L.) plantlets by AgNO3 and its associated mechanism during in vitro culture. AB - Hyperhydricity occurs frequently in plant tissue culture and can severely affect commercial micropropagation and genetic improvement of the cultured plantlets. Hyperhydric shoots are charaterzized by high water content, but how this occurs is still a subject of investigation. Silver ion (Ag+) can reduce the extent of hyperhydricity in plants, but its effect on the reversion of hyperhydric plantlets and the underlying mechanism of reversion has not been clarified. In this study, about 67% of the hyperhydric Dianthus chinensis L. plantlets were found to revert to normal condition when the plantlets were cultured in medium supplemented with 29.4MUmolL-1AgNO3. Water content and hydrogen peroxide (H2O2) content in the guard cells of these plantlets were reduced, while stomatal aperture and water loss rate were increased. AgNO3 also reduced the content of endogenous ethylene and expression of ethylene synthesis and ethylene signal transduction-associated genes. Reduced accumulation of ethylene consequently led to an increase in stomatal aperture mediated by decreased H2O2 content in the guard cells. These results adequately verified the role of AgNO3 in the reversion of hyperhydricity in D. chinensis L. and also provided clues for exploring the cause of excessive water accumulation in hyperhydric plants. PMID- 27964781 TI - Plant architecture and grain yield are regulated by the novel DHHC-type zinc finger protein genes in rice (Oryza sativa L.). AB - In many plants, architecture and grain yield are affected by both the environment and genetics. In rice, the tiller is a vital factor impacting plant architecture and regulated by many genes. In this study, we cloned a novel DHHC-type zinc finger protein gene Os02g0819100 and its alternative splice variant OsDHHC1 from the cDNA of rice (Oryza sativa L.), which regulate plant architecture by altering the tiller in rice. The tillers increased by about 40% when this type of DHHC type zinc finger protein gene was over-expressed in Zhong Hua 11 (ZH11) rice plants. Moreover, the grain yield of transgenic rice increased approximately by 10% compared with wild-type ZH11. These findings provide an important genetic engineering approach for increasing rice yields. PMID- 27964782 TI - The pathogen-inducible promoter of defense-related LsGRP1 gene from Lilium functioning in phylogenetically distinct species of plants. AB - A suitable promoter greatly enhances the efficiency of target gene expression of plant molecular breeding and farming; however, only very few promoters are available for economically important non-graminaceous ornamental monocots. In this study, an 868-bp upstream region of defense-related LsGRP1 of Lilium, named PLsGRP1, was cloned by genome walking and proven to exhibit promoter activity in Nicotiana benthamiana and Lilium 'Stargazer' as assayed by agroinfiltration-based beta-glucuronidase (GUS) expression system. Many putative biotic stress-, abiotic stress- and physiological regulation-related cis-acting elements were found in PLsGRP1. Serial deletion analysis of PLsGRP1 performed in Nicotiana tabacum var. Wisconsin 38 accompanied with types of treatments indicated that 868-bp PLsGRP1 was highly induced upon pathogen challenges and cold stress while the 131-bp 3' end region of PLsGRP1 could be dramatically induced by many kinds of abiotic stresses, biotic stresses and phytohormone treatments. Besides, transient GUS expression in a fern, gymnosperms, monocots and dicots revealed good promotor activity of PLsGRP1 in many phylogenetically distinct plant species. Thus, pathogen-inducible PLsGRP1 and its 131-bp 3'-end region are presumed potential as tools for plant molecular breeding and farming. PMID- 27964783 TI - Silencing of BnTT1 family genes affects seed flavonoid biosynthesis and alters seed fatty acid composition in Brassica napus. AB - TRANSPARENT TESTA1 (TT1) is a zinc finger protein that contains a WIP domain. It plays important roles in controlling differentiation and pigmentation of the seed coat endothelium, and can affect the expression of early biosynthetic genes and late biosynthetic genes of flavonoid biosynthesis in Arabidopsis thaliana. In Brassica napus (AACC, 2n=38), the functions of BnTT1 genes remain unknown and few studies have focused on their roles in fatty acid (FA) biosynthesis. In this study, BnTT1 family genes were silenced by RNA interference, which resulted in yellow rapeseed, abnormal testa development (a much thinner testa), decreased seed weight, and altered seed FA composition in B. napus. High-throughput sequencing of genes differentially expressed between developing transgenic B. napus and wild-type seeds revealed altered expression of numerous genes involved in flavonoid and FA biosynthesis. As a consequence of this altered expression, we detected a marked decrease of oleic acid (C18:1) and notable increases of linoleic acid (C18:2) and alpha-linolenic acid (C18:3) in mature transgenic B. napus seeds by gas chromatography and near-infrared reflectance spectroscopy. Meanwhile, liquid chromatography-mass spectrometry showed reduced accumulation of flavonoids in transgenic seeds. Therefore, we propose that BnTT1s are involved in the regulation of flavonoid biosynthesis, and may also play a role in FA biosynthesis in B. napus. PMID- 27964784 TI - Arabidopsis CBL interacting protein kinase 3 interacts with ABR1, an APETALA2 domain transcription factor, to regulate ABA responses. AB - Calcium (Ca2+) plays a vital role as a second messenger in several signaling pathways in plants. The calcineurin B-like proteins (CBLs) represent a family of plant calcium-binding proteins that function in propagating Ca2+ signals by interacting with CBL interacting protein kinases (CIPKs). Phosphorylation of CBL by CIPK is essential for the module to display full activity towards its target protein. Previous genetic analysis showed that the function of CBL9-CIPK3 module was implicated in negatively regulating seed germination and early development. In the present study, we have biochemically investigated the interaction of CBL9 CIPK3 module and our findings show that CBL9 is phosphorylated by CIPK3. Moreover, Abscisic acid repressor 1 (ABR1) is identified as the downstream target of CIPK3 and CIPK3-ABR1 function to regulate ABA responses during seed germination. Our study also indicates that the role of ABR1 is not limited to seed germination but it also regulates the ABA dependent processes in the adult stage of plant development. Combining our results, we conclude that the CBL9 CIPK3-ABR1 pathway functions to regulate seed germination and ABA dependent physiological processes in Arabidopsis. PMID- 27964785 TI - TRANSPARENT TESTA GLABRA 1 ubiquitously regulates plant growth and development from Arabidopsis to foxtail millet (Setaria italica). AB - TRANSPARENT TESTA GLABRA 1 of Arabidopsis thaliana (AtTTG1) is a WD40 repeat transcription factor that plays multiple roles in plant growth and development, particularly in seed metabolite production. In the present study, to determine whether SiTTG1 of the phylogenetically distant monocot foxtail millet (Setaria italica) has similar functions, we used transgenic Arabidopsis and Nicotiana systems to explore its activities. We found that SiTTG1 functions as a transcription factor. Overexpression of the SiTTG1 gene rescued many of the mutant phenotypes in Arabidopsis ttg1-13 plants. Additionally, SiTTG1 overexpression fully corrected the reduced expression of mucilage biosynthetic genes, and the induced expression of genes involved in accumulation of seed fatty acids and storage proteins in developing seeds of ttg1-13 plants. Ectopic expression of SiTTG1 restored the sensitivity of the ttg1-13 mutant to salinity and high glucose stresses during germination and seedling establishment, and restored altered expression levels of some stress-responsive genes in ttg1-13 seedlings to the wild type level under salinity and glucose stresses. Our results provide information that will be valuable for understanding the function of TTG1 from monocot to dicot species and identifying a promising target for genetic manipulation of foxtail millet to improve the amount of seed metabolites. PMID- 27964786 TI - Dynein light chain family genes in 15 plant species: Identification, evolution and expression profiles. AB - Dynein light chain (DLC) is one important component of the dynein complexes, which have been proved involving in a variety of cellular functions. However, higher plants lack all other components of the complexes except DLCs, suggesting that in plants, the DLC protein does not carry out the same function as it in animals. Therefore, the function of this family in plants is mysterious. In this study, we investigated the DLC gene family in 15 plant species and analyzed their expression profiles. In total, 128 DLC genes were identified from the 15 studied plant species and were divided into eight groups by their phylogenetic relation. Highly conserved gene structure and motif arrangement was discovered within each group, indicating their functional correlation. Genetic variation and recombination events were also detected in DLC genes. Through selection analyses, we also identified some significant site-specific constraints in most of the DLC paralogs. In addition, DLC genes presented various expression profiles in different development stages, or under different abiotic stresses or phytohormone treatments. This may be associated with a variety of cis-elements responding to stress and phytohormone in the upstream sequences of the DLC genes. Functional network analysis exhibited 123 physical or functional interactions. The results provide a foundation for exploring the characterization of the DLC genes in plants and offer insights for additional functional studies. PMID- 27964788 TI - A different perspective: Inflammatory rheumatic diseases and other organs. PMID- 27964787 TI - Curd development associated gene (CDAG1) in cauliflower (Brassica oleracea L. var. botrytis) could result in enlarged organ size and increased biomass. AB - The curd is a specialized organ and the most important product organ of cauliflower (Brassica oleracea L. var. botrytis). However, the mechanism underlying the regulation of curd formation and development remains largely unknown. In the present study, a novel homologous gene containing the Organ Size Related (OSR) domain, namely, CDAG1 (Curd Development Associated Gene 1) was identified in cauliflower. Quantitative analysis indicated that CDAG1 showed significantly higher transcript levels in young tissues. Functional analysis demonstrated that the ectopic overexpression of CDAG1 in Arabidopsis and cauliflower could significantly promote organ growth and result in larger organ size and increased biomass. Organ enlargement was predominantly due to increased cell number. In addition, 228 genes involved in the CDAG1-mediated regulatory network were discovered by transcriptome analysis. Among these genes, CDAG1 was confirmed to inhibit the transcriptional expression of the endogenous OSR genes, ARGOS and ARL, while a series of ethylene-responsive transcription factors (ERFs) were found to increased expression in 35S:CDAG1 transgenic Arabidopsis plants. This implies that CDAG1 may function in the ethylene-mediated signal pathway. These findings provide new insight into the function of OSR genes, and suggest potential applications of CDAG1 in breeding high-yielding crops. PMID- 27964790 TI - The eye and inflammatory rheumatic diseases: The eye and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis. AB - Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis are associated with potentially sight-threatening inflammatory eye disease. Although the ocular manifestations associated with ankylosing spondylitis and psoriatic arthritis are similar, such as anterior uveitis, this differs from rheumatoid arthritis where dry eye, peripheral ulcerative keratitis and scleritis are the major ocular complications. Apart from causing sight loss, these conditions are painful, debilitating, often recurrent or chronic and may require long-term therapy. Treatments such as ocular lubricant, topical corticosteroid, systemic corticosteroid and systemic immunosuppression are often similar for the underlying systemic disease. Yet for the treatment of the ocular complications, the evidence base is weak. Close collaboration with a rheumatologist is often essential, particularly in the management of these patients. PMID- 27964789 TI - Rheumatologic diseases as the cause of fever of unknown origin. AB - In 30% of patients with fever or inflammation of unknown origin (FUO/IUO), the cause is eventually found to be a rheumatologic disease such as autoimmune or granulomatous disease or vasculitis. Most of these patients suffer from an uncommon presentation of a common disease, instead of an uncommon disease. We demonstrate the diagnostic challenge with several cases. The workup of FUO is based on the identification of potential diagnostic clues (PDCs). In the absence of PDCs, a standardized diagnostic protocol should be followed, including early FDG-PET/CT. Other imaging techniques or invasive diagnostic techniques should be reserved for those in whom PDCs are present. PMID- 27964791 TI - Orofacial manifestations in patients with inflammatory rheumatic diseases. AB - The main orofacial manifestation of the inflammatory rheumatic diseases is that of Sjogren's syndrome. In addition, there is a constellation of orofacial manifestations of the inflammatory rheumatic diseases, many of which are extra articular with some constituting presenting signs of the underlying rheumatic disease. This review will discuss the orofacial manifestations in a variety of connective tissue diseases and will also allude to the oral adverse drug reactions that may occur as a consequence of therapy. PMID- 27964792 TI - Cardiovascular disease in inflammatory rheumatic diseases. AB - Chronic inflammatory rheumatic diseases (IRD), including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, are prevalent conditions worldwide, with a considerable burden on healthcare systems. They are associated with increased cardiovascular (CV) morbidity and mortality. In this review, we focused on the epidemiology, traditional CV risk factors, genetics, and the link between chronic inflammation, atherosclerosis, and CV disease. Remarkably, patients with IRD have higher vulnerability to atheromatous plaques. The risk of unstable plaques is higher in patients with rheumatoid arthritis than in controls. Active disease is a characteristic ascribed to vulnerability and rupture of plaques and a cause of thrombosis in IRD. Management of CV risk in patients with IRD includes optimal control of disease activity. CV risk stratification by applying risk charts is also essential. Imaging techniques might be useful to determine the actual CV risk of patients with IRD who are included in the category of intermediate or moderate CV risk. PMID- 27964793 TI - Lung involvement in inflammatory rheumatic diseases. AB - This chapter describes the involvement of the lung in systemic inflammatory joint disease (IJD) with a particular focus on rheumatoid arthritis, although the topics of pulmonary involvement in ankylosing spondylitis and psoriatic arthritis are also addressed. Interstitial lung disease is the most lethal pulmonary complication of IJD and the chapter describes recent advances in both our understanding of this complication and the therapeutic options that offer real hope for improved outcomes. Although less well recognised, airways disease is just as common and its association with IJD is described in some detail, with a section devoted to the recent surge in interest in bronchiectasis. Acute pulmonary infection is common in IJD and its management is reviewed in some detail. Although pleural disease is less common than it once was, its treatment is explored. We conclude by reviewing the relationship between the drug therapies employed in IJD and their effects on the lung. PMID- 27964794 TI - The role of the gastrointestinal tract in the pathogenesis of rheumatic diseases. AB - Dysregulation of the intestinal epithelial barrier in genetically susceptible individuals may lead to both intestinal and extraintestinal autoimmune disorders. There is emerging literature on the role of microbiota changes in the pathogenesis of systemic rheumatic diseases such as rheumatoid arthritis, spondyloarthropathies, and connective tissue diseases. Although the role of the gastrointestinal tract in the pathogenesis of spondyloartropathies is well defined and many studies underline the importance of gastrointestinal inflammation in modulating local and systemic inflammation, the data are inconclusive regarding the effect of dysbiosis on rheumatoid arthritis and connective tissue diseases. This review aims to summarize current data on the role of the gastrointestinal involvement and intestinal microbiota in the pathogenesis of systemic rheumatic disease. PMID- 27964795 TI - Metabolic abnormalities in patients with inflammatory rheumatic diseases. AB - Patients with rheumatoid arthritis (RA) experience an increased cardiometabolic risk factor burden that is substantially driven by systemic inflammation. This occurs less consistently in patients with ankylosing spondylitis (AS). Psoriatic arthritis most strongly associates with excess adiposity and metabolic risk. RA patients also often have systemic inflammation-induced proinflammatory high density lipoprotein (HDL) cholesterol particles and lean/muscle mass loss in association with increased adiposity, a condition termed rheumatoid cachexia, which further enhances cardiovascular risk. The presence of proinflammatory HDL and lean mass loss was also reported in patients with AS. Individualized aerobic and resistance exercise programs can improve body composition and metabolic risk factor profiles in RA and AS. Future studies should assess how long-term lifestyle changes can be effectuated and if these can influence cardiovascular events in inflammatory rheumatic diseases. Herein, we review the current evidence on metabolic abnormalities in inflammatory arthritis. We propose management strategies and a research agenda. PMID- 27964796 TI - Vasculitis and inflammatory arthritis. AB - Vasculitis has been described in most types of inflammatory arthritis. The best described and most widely recognised form is rheumatoid vasculitis. The incidence of systemic rheumatoid vasculitis has declined significantly following the general early use of methotrexate in the 1990s, and it is now a rare form of vasculitis. Treatment of rheumatoid vasculitis is conventionally with glucocorticoids and cyclophosphamide, but there is an increasing role for rituximab similar to that in other types of vasculitis. Despite these developments the mortality of rheumatoid vasculitis remains high. Vasculitis in other types of inflammatory arthritis is less well described and the treatment remains empirical. PMID- 27964797 TI - The role of psychological factors in inflammatory rheumatic diseases: From burden to tailored treatment. AB - Inflammatory rheumatic diseases have a long-lasting effect on patients' physical and psychological functioning, for instance, due to disabling symptoms and unpredictable disease course. Consequently, many patients show adjustment problems such as depressed mood, which in turn can negatively influence their disease outcome. Specific biopsychosocial factors have shown to affect this outcome. For example, daily stress, cognitive-behavioral risk factors such as pain catastrophizing and avoidance, and resilience factors such as optimism and social support influence the quality of life, physical symptoms of pain and fatigue, and inflammatory markers. Psychological interventions tackling these factors can have beneficial effects on physical and psychological functioning. Recent advances in screening for patients at risk, tailored treatment, and eHealth further broaden the efficiency and scope of these interventions while simultaneously optimizing patient empowerment. This chapter describes the biopsychosocial risk and resilience factors related to disease outcome and the possible benefits of psychological treatment strategies in inflammatory rheumatic diseases. PMID- 27964798 TI - Immunization in patients with inflammatory rheumatic diseases. AB - Immunization represents the most efficient and simplest intervention to prevent certain viral and bacterial infections in the general population as well as in the vulnerable population of patients with inflammatory rheumatic diseases treated with immunosuppressives. Here, we present an updated review of literature data regarding the safety and efficacy of immunizations against different pathogens in rheumatic patients treated with conventional immunosuppressives or the newer biologic agents while at the same time we provide practical guidance for the appropriate vaccine administration in this patient population. PMID- 27964800 TI - An adaptive large neighborhood search procedure applied to the dynamic patient admission scheduling problem. AB - OBJECTIVE: The aim of this paper is to provide an improved method for solving the so-called dynamic patient admission scheduling (DPAS) problem. This is a complex scheduling problem that involves assigning a set of patients to hospital beds over a given time horizon in such a way that several quality measures reflecting patient comfort and treatment efficiency are maximized. Consideration must be given to uncertainty in the length of stays of patients as well as the possibility of emergency patients. METHOD: We develop an adaptive large neighborhood search (ALNS) procedure to solve the problem. This procedure utilizes a Simulated Annealing framework. RESULTS: We thoroughly test the performance of the proposed ALNS approach on a set of 450 publicly available problem instances. A comparison with the current state-of-the-art indicates that the proposed methodology provides solutions that are of comparable quality for small and medium sized instances (up to 1000 patients); the two approaches provide solutions that differ in quality by approximately 1% on average. The ALNS procedure does, however, provide solutions in a much shorter time frame. On larger instances (between 1000-4000 patients) the improvement in solution quality by the ALNS procedure is substantial, approximately 3-14% on average, and as much as 22% on a single instance. The time taken to find such results is, however, in the worst case, a factor 12 longer on average than the time limit which is granted to the current state-of-the-art. CONCLUSION: The proposed ALNS procedure is an efficient and flexible method for solving the DPAS problem. PMID- 27964799 TI - Non-obvious correlations to disease management unraveled by Bayesian artificial intelligence analyses of CMS data. AB - OBJECTIVE: Given the availability of extensive digitized healthcare data from medical records, claims and prescription information, it is now possible to use hypothesis-free, data-driven approaches to mine medical databases for novel insight. The goal of this analysis was to demonstrate the use of artificial intelligence based methods such as Bayesian networks to open up opportunities for creation of new knowledge in management of chronic conditions. MATERIALS AND METHODS: Hospital level Medicare claims data containing discharge numbers for most common diagnoses were analyzed in a hypothesis-free manner using Bayesian networks learning methodology. RESULTS: While many interactions identified between discharge rates of diagnoses using this data set are supported by current medical knowledge, a novel interaction linking asthma and renal failure was discovered. This interaction is non-obvious and had not been looked at by the research and clinical communities in epidemiological or clinical data. A plausible pharmacological explanation of this link is proposed together with a verification of the risk significance by conventional statistical analysis. CONCLUSION: Potential clinical and molecular pathways defining the relationship between commonly used asthma medications and renal disease are discussed. The study underscores the need for further epidemiological research to validate this novel hypothesis. Validation will lead to advancement in clinical treatment of asthma & bronchitis, thereby, improving patient outcomes and leading to long term cost savings. In summary, this study demonstrates that application of advanced artificial intelligence methods in healthcare has the potential to enhance the quality of care by discovering non-obvious, clinically relevant relationships and enabling timely care intervention. PMID- 27964801 TI - Gesteme-free context-aware adaptation of robot behavior in human-robot cooperation. AB - BACKGROUND: Cooperative robotics is receiving greater acceptance because the typical advantages provided by manipulators are combined with an intuitive usage. In particular, hands-on robotics may benefit from the adaptation of the assistant behavior with respect to the activity currently performed by the user. A fast and reliable classification of human activities is required, as well as strategies to smoothly modify the control of the manipulator. In this scenario, gesteme-based motion classification is inadequate because it needs the observation of a wide signal percentage and the definition of a rich vocabulary. OBJECTIVE: In this work, a system able to recognize the user's current activity without a vocabulary of gestemes, and to accordingly adapt the manipulator's dynamic behavior is presented. METHODS AND MATERIAL: An underlying stochastic model fits variations in the user's guidance forces and the resulting trajectories of the manipulator's end-effector with a set of Gaussian distribution. The high-level switching between these distributions is captured with hidden Markov models. The dynamic of the KUKA light-weight robot, a torque-controlled manipulator, is modified with respect to the classified activity using sigmoidal-shaped functions. The presented system is validated over a pool of 12 naive users in a scenario that addresses surgical targeting tasks on soft tissue. The robot's assistance is adapted in order to obtain a stiff behavior during activities that require critical accuracy constraint, and higher compliance during wide movements. Both the ability to provide the correct classification at each moment (sample accuracy) and the capability of correctly identify the correct sequence of activity (sequence accuracy) were evaluated. RESULTS: The proposed classifier is fast and accurate in all the experiments conducted (80% sample accuracy after the observation of ~450ms of signal). Moreover, the ability of recognize the correct sequence of activities, without unwanted transitions is guaranteed (sequence accuracy ~90% when computed far away from user desired transitions). Finally, the proposed activity-based adaptation of the robot's dynamic does not lead to a not smooth behavior (high smoothness, i.e. normalized jerk score <0.01). CONCLUSION: The provided system is able to dynamic assist the operator during cooperation in the presented scenario. PMID- 27964802 TI - Analysis of correlation between pediatric asthma exacerbation and exposure to pollutant mixtures with association rule mining. AB - OBJECTIVES: Traditional studies on effects of outdoor pollution on asthma have been criticized for questionable statistical validity and inefficacy in exploring the effects of multiple air pollutants, alone and in combination. Association rule mining (ARM), a method easily interpretable and suitable for the analysis of the effects of multiple exposures, could be of use, but the traditional interest metrics of support and confidence need to be substituted with metrics that focus on risk variations caused by different exposures. METHODS: We present an ARM based methodology that produces rules associated with relevant odds ratios and limits the number of final rules even at very low support levels (0.5%), thanks to post-pruning criteria that limit rule redundancy and control for statistical significance. The methodology has been applied to a case-crossover study to explore the effects of multiple air pollutants on risk of asthma in pediatric subjects. RESULTS: We identified 27 rules with interesting odds ratio among more than 10,000 having the required support. The only rule including only one chemical is exposure to ozone on the previous day of the reported asthma attack (OR=1.14). 26 combinatory rules highlight the limitations of air quality policies based on single pollutant thresholds and suggest that exposure to mixtures of chemicals is more harmful, with odds ratio as high as 1.54 (associated with the combination day0 SO2, day0 NO, day0 NO2, day1 PM). CONCLUSIONS: The proposed method can be used to analyze risk variations caused by single and multiple exposures. The method is reliable and requires fewer assumptions on the data than parametric approaches. Rules including more than one pollutant highlight interactions that deserve further investigation, while helping to limit the search field. PMID- 27964803 TI - Web-video-mining-supported workflow modeling for laparoscopic surgeries. AB - MOTIVATION: As quality assurance is of strong concern in advanced surgeries, intelligent surgical systems are expected to have knowledge such as the knowledge of the surgical workflow model (SWM) to support their intuitive cooperation with surgeons. For generating a robust and reliable SWM, a large amount of training data is required. However, training data collected by physically recording surgery operations is often limited and data collection is time-consuming and labor-intensive, severely influencing knowledge scalability of the surgical systems. OBJECTIVE: The objective of this research is to solve the knowledge scalability problem in surgical workflow modeling with a low cost and labor efficient way. METHODS: A novel web-video-mining-supported surgical workflow modeling (webSWM) method is developed. A novel video quality analysis method based on topic analysis and sentiment analysis techniques is developed to select high-quality videos from abundant and noisy web videos. A statistical learning method is then used to build the workflow model based on the selected videos. To test the effectiveness of the webSWM method, 250 web videos were mined to generate a surgical workflow for the robotic cholecystectomy surgery. The generated workflow was evaluated by 4 web-retrieved videos and 4 operation-room recorded videos, respectively. RESULTS: The evaluation results (video selection consistency n-index >=0.60; surgical workflow matching degree >=0.84) proved the effectiveness of the webSWM method in generating robust and reliable SWM knowledge by mining web videos. CONCLUSION: With the webSWM method, abundant web videos were selected and a reliable SWM was modeled in a short time with low labor cost. Satisfied performances in mining web videos and learning surgery related knowledge show that the webSWM method is promising in scaling knowledge for intelligent surgical systems. PMID- 27964804 TI - The versatile platelet contributes to inflammation, infection, hemostasis, coagulation and cancer. PMID- 27964805 TI - IDF School of Diabetes - Tackling diabetes through education. PMID- 27964806 TI - Ocular microparticle formulations for 6-month delivery of anti-VEGF. PMID- 27964807 TI - Control of neglected zoonotic diseases. PMID- 27964808 TI - Putting nurses on governing boards: Time for an educational perspective. PMID- 27964809 TI - A Feminist Framework for Nurses on Boards. AB - Nurses' knowledge, skills, and expertise uniquely situate them to contribute to health care transformation as equal partners in organizational board governance. The Institute of Medicine, the 10,000 Nurses on Boards Coalition, and a growing number of nurse and health care scholars advocate nurse board leadership; however, nurses are rarely appointed as voting board members. When no room is made for nurses to take a seat at the table, the opportunity is lost to harness the power of nursing knowledge for health care transformation and social justice. No philosophical framework underpins the emerging focus on nurse board leadership. The purpose of this article is to add to the extant nursing literature by suggesting feminism as a philosophical framework for nurses on boards. Feminism contributes to the knowledge base of nursing as it relates to the expanding roles of nurses in health care transformation, policy, and social justice. Furthermore, a feminist philosophical framework for nurses on boards sets the foundation for new theory development and validates ongoing advancement of the nursing profession. PMID- 27964810 TI - Understanding Research Impact: A Review of Existing and Emerging Tools for Nursing. AB - Researchers and educators are required to show the impact they have in their field when they apply for promotion or extramural funding. There are several tools available for nursing faculty to consult as they build a research impact profile. This article highlights both traditional and more novel tools, the impact metrics they calculate, and why the tools are particularly relevant to the field of nursing. PMID- 27964811 TI - An Undergraduate Research Fellowship Program to Prepare Nursing Students for Future Workforce Roles. AB - It is important for nurses today and for those joining the workforce in the future to have familiarity and training with respect to interprofessional research, evidence-based practice, and quality improvement. In an effort to address this need, we describe a 10-week summer research program that immerses undergraduate nursing students in a broad spectrum of clinical and translational research projects as part of their exposure to advanced nursing roles. In doing so, the program increases the ability of the students to participate in research, effectively interact with academic medical center researchers, and incorporate elements of evidence-based practice into future nursing interventions. Their mentors are nurses practicing in roles as nurse researcher, advanced practice nurses involved in evidence-based practice or quality improvement, and clinical trials research nurses. Each student is matched with 3 of these mentors and involved in 3 different projects. Through this exposure, the students benefit from observing multiple nursing roles, taking an active role in research-related activities participating in interdisciplinary learning experiences. Overall, the program provides benefits to the students, who demonstrate measured improvement with respect to the program objectives, and to their mentors and each of the participating organizations. PMID- 27964812 TI - The Value of Preparing PhD Students as Research Mentors: Application of Kram's Temporal Mentoring Model. AB - The ability to successfully mentor others is an essential skill necessary for building and strengthening an infrastructure of well-prepared nurse faculty to accelerate advancements in nursing science. Mentoring is a fundamental part of the nurse faculty role, but new faculty are often unprepared to take on mentoring roles early in their academic career. Applied training in research mentoring initiated during doctor of philosophy (PhD) programs may better prepare future faculty to manage teaching and mentoring responsibilities earlier and with greater confidence. The unique opportunity exists for PhD students to engage in research mentoring with undergraduate nursing students, with probable benefits for both the mentor and the mentee. This manuscript uses Kram's temporal mentoring model as a guide to examine the training experiences of 3 PhD students mentoring undergraduate nursing students and discusses the benefits and challenges associated with these mentoring relationships. Collectively, these experiences provide preliminary support and guidance for the development and adoption of formal PhD mentor training programs to better prepare future PhD nursing faculty for their mentoring responsibilities. PMID- 27964813 TI - Determination of the Concepts "Profession" and "Role" in Relation to "Nurse Educator". AB - The aim of this study was to clarify the meanings and dimensions of the concepts "profession" and "role." The results from the concept determination were discussed in relation to the profession "nurse educator." This study is based on Koort's semantic analysis methods, using select parts of Eriksson's approach for concept determination, using dictionaries published between the years 1948 and 2015. The findings underline the complexity of the professional role of nurse educators. The nurse educator profession is based on society's trust and requires integration of ability, attitudes, norms, reflection, and theoretical knowledge, along with individual, organizational, and social conditions. Nurse educators must achieve a sufficient degree of pedagogical competence, subject competence, social competence and organizational competence in order to develop their professional role. When nurse educators define their function, a professional role takes form. PMID- 27964814 TI - Examining the Impact of Critical Multicultural Education Training on the Multicultural Attitudes, Awareness, and Practices of Nurse Educators. AB - Some nurse educators lack training in the educational methods that facilitate learning among underrepresented groups. Limited awareness of equitable pedagogical practices could threaten the academic achievement of underrepresented groups and hinder efforts to make the nursing profession more heterogeneous. Training in multicultural education could strengthen the capacity of educators to create culturally responsive learning environments. This quasi-experimental study examined the impact that training in critical multicultural education had on the multicultural attitudes, awareness, and practices of 37 nurse educators. A pre posttest design without a control group found that the training was an effective way to strengthen the multicultural awareness and attitudes of nurse educators, although there was little impact on the multicultural practices. The nation's capacity to improve the quality of health care hinges upon educators who can create inclusive learning environments and graduate diverse nurses. The findings could inform policies seeking to promote diversity and inclusion in nursing education. PMID- 27964816 TI - Using Simulation in a Psychiatric Mental Health Nurse Practitioner Doctoral Program. AB - The use and effectiveness of simulation with standardized patients in undergraduate and graduate nursing education programs is well documented. Simulation has been primarily used to develop health assessment skills. Evidence supports using simulation and standardized patients in psychiatric-mental health nurse practitioner (PMHNP) programs is useful in developing psychosocial assessment skills. These interactions provide individualized and instantaneous clinical feedback to the student from faculty, peers, and standardized patients. Incorporating simulation into advanced practice psychiatric-mental health nursing curriculum allows students to develop the necessary requisite skills and principles needed to safely and effectively provide care to patients. There are no documented standardized processes for using simulation throughout a doctor of nursing practice PMHNP curriculum. The purpose of this article is to describe a framework for using simulation with standardized patients in a PMHNP curriculum. Students report high levels of satisfaction with the simulation experience and believe that they are more prepared for clinical rotations. Faculty feedback indicates that simulated clinical scenarios are a method to ensure that each student experiences demonstrate a minimum standard of competency ahead of clinical rotations with live patients. Initial preceptor feedback indicates that students are more prepared for clinical practice and function more independently than students that did not experience this standardized clinical simulation framework. PMID- 27964815 TI - NEXus: Making Efficient Use of Limited Resources. AB - Faculty to teach and mentor doctoral nursing students are and will continue to be in short supply. Coupled with ever-increasing resource-constricted educational environments, doctoral programs are challenged to provide high-quality education with limited resources. The Nursing Education Exchange (NEXus) is a viable solution to help meet that challenge. This article presents an overview of the origins and evolution of NEXus, financial considerations, and basic steps for joining NEXus, along with 4 exemplars. NEXus has continued to grow since its inception in 2007. In 2015, the number of NEXus schools reached 20, with 11 schools offering both doctor of philosophy and doctor of nursing practice courses. Currently, NEXus offers over 160 courses, organized into 14 clusters such as gerontology and chronic illness. Recently, a collaboration between the National Hartford Centers of Gerontological Nursing Excellence and NEXus was formalized. This collaboration prepares faculty to address an aging population. In summary, in an era of increased demand for doctoral prepared nurses, a lack of qualified doctoral nursing faculty, and limited financial resources, the NEXus collaborative provides a model for optimal resource sharing. PMID- 27964818 TI - Survey of Nursing Students' Self-Reported Knowledge of Ebola Virus Disease, Willingness to Treat, and Perceptions of their Duty to Treat. AB - The purpose of this study was to explore nursing students' self-reported knowledge of Ebola Virus Disease (EVD), willingness to treat patients with EVD, and student perceptions of duty to treat patients with EVD. The researchers developed the Survey of Nursing Student Self-Reported Knowledge of EVD, Willingness to Treat, and Perceptions of Duty to Treat, a quantitative tool with open-ended questions to inform the responses. On-line survey software was used for gathering anonymous data. A mixture of descriptive, nonparametric, and parametric statistics were used to describe, compare, and examine relationships between variables. Results demonstrated that licensed students scored significantly higher on self-reported knowledge of EVD than their prelicensure student counterparts (P=.039). Licensed students and prelicensure students did not differ on self-assessed willingness to treat (P>.05). The students had significantly higher willingness-to-treat scores when self-reported knowledge scores were higher (P=.007) and when they were older (P=.004). Willingness to treat was not influenced by whether one was partnered or single (P>.05) or had children or did not have children (P>.05). In conclusion, basic EVD knowledge and training appears to be critical to ensure willingness to treat. However, it is imperative that students have an indepth understanding of the principles of infectious diseases in general. PMID- 27964817 TI - Influences of Sociocultural Factors Within the Clinical Learning Environment on Students' Perceptions of Learning: An Integrative Review. AB - : A persistent deficit in new graduate nurses' clinical reasoning skill exists. Clinical reasoning is best learned in the sociocultural clinical learning environment (CLE), yet many CLEs fail to engage nursing students in the cognitive work of nursing that promotes development of clinical reasoning. Despite two decades of recommendations to improve CLEs based on students' perceptions of learning, widespread improvement remains elusive. OBJECTIVE: The aim of this review was to synthesize what is known about the influence of sociocultural factors in the acute-care CLE on prelicensure nursing students' perceptions of learning, for the purpose of identifying factors that when modified may promote improvement of clinical reasoning skill. METHOD: The integrative review methodology was used to synthesize and identify gaps in evidence on students' perceptions of learning in the acute-care CLE. RESULTS: Global commonalities exist in the impact of the sociocultural CLE on students' perceptions of learning, including overall sociocultural atmosphere, membership in the health care team, supervisory relationships, peer relationships, and clinical education structure. CONCLUSIONS: This review provides evidence that modification of CLE factors and examination of their influence on measurable learning outcomes such as clinical reasoning are the necessary next steps to facilitate improvement of new graduate nurses' clinical reasoning skill. PMID- 27964819 TI - Revitalizing Learning Outcomes for Adult Gerontology Advanced Practice Programs. AB - The implementation of the Consensus Model for Advanced Practice Registered Nurse Regulation has defined the model for advanced practice within the four recognized advanced practice nursing roles. The focus of graduate nursing program focus for care of the adult population has been broadened to include gerontology. The change toward increasing graduate program breadth and focus to a lifespan adult/gerontology population will result in the need for analysis and restructuring of advanced practice programs in order to incorporate gerontologic content. The purpose of this article is to describe a process for developing or revitalizing meaningful learning outcomes as an integral component in program revision and evaluation for advanced practice programs incorporating gerontologic content. Learning outcomes will be included with examples and definitions from the beginning basis of role-specific selected adult gerontology competencies through data collection and analysis for program improvement. PMID- 27964820 TI - T Cell Exhaustion in Glioblastoma: Intricacies of Immune Checkpoints. AB - Glioblastoma is an aggressive and incurable primary brain tumor. While the blockade of immune checkpoints leads to reversal of T cell exhaustion in many cancers, the efficacy of this therapy in glioblastoma requires further consideration of the brain microenvironment beyond T cell activity. Neural cells are crucially dependent on glucose for survival, and tumor cells rabidly consume glucose; the glucose-deprived microenvironment further elevates immune checkpoint molecules to benefit tumor growth and exacerbate T cell exhaustion. We review here how immune checkpoints drive exhaustion in T cells while favoring tumor metabolism, and discuss how glucose competition in the unique CNS milieu is an important consideration to improve the outcomes of immune checkpoint blockade in glioblastoma. PMID- 27964821 TI - Mortality in childhood tuberculosis: has there been progress? PMID- 27964823 TI - The importance of electrophysiological assessment of myoclonus. PMID- 27964822 TI - Mortality in children diagnosed with tuberculosis: a systematic review and meta analysis. AB - BACKGROUND: Case fatality ratios in children with tuberculosis are poorly understood-particularly those among children with HIV and children not receiving tuberculosis treatment. We did a systematic review of published work to identify studies of population-representative samples of paediatric (ie, <15 years) tuberculosis cases. METHODS: We searched PubMed and Embase for reports published in English, French, Portuguese, or Spanish before Aug 12, 2016, that included terms related to tuberculosis, children, mortality, and population representativeness. We also reviewed our own files and reference lists of articles identified by this search. We screened titles and abstracts for inclusion, excluding studies in which outcomes were unknown for 10% or more of the children and publications detailing non-representative samples. We used random-effects meta-analysis to produce pooled estimates of case fatality ratios from the included studies, which we divided into three eras: the pre-treatment era (ie, studies before 1946), the middle era (1946-80), and the recent era (after 1980). We stratified our analyses by whether or not children received tuberculosis treatment, age (0-4 years, 5-14 years), and HIV status. FINDINGS: We identified 31 papers comprising 35 datasets representing 82 436 children with tuberculosis disease, of whom 9274 died. Among children with tuberculosis included in studies in the pre-treatment era, the pooled case fatality ratio was 21.9% (95% CI 18.1-26.4) overall. The pooled case fatality ratio was significantly higher in children aged 0-4 years (43.6%, 95% CI 36.8-50.6) than in those aged 5-14 years (14.9%, 11.5-19.1). In studies in the recent era, when most children had tuberculosis treatment, the pooled case fatality ratio was 0.9% (95% CI 0.5-1.6). US surveillance data suggest that the case fatality ratio is substantially higher in children with HIV receiving treatment for tuberculosis (especially without antiretroviral therapy) than in those without HIV. INTERPRETATION: Without adequate treatment, children with tuberculosis, especially those younger than 5 years, are at high risk of death. Children with HIV have an increased mortality risk, even when receiving tuberculosis treatment. FUNDING: US National Institutes of Health, Janssen Global Public Health. PMID- 27964824 TI - Pain in amyotrophic lateral sclerosis. AB - Pain is a largely neglected symptom in patients with amyotrophic lateral sclerosis (ALS) although it is reported by most of these patients. It occurs at all stages of the disease and can be an onset symptom preceding motor dysfunction. Pain is correlated with a deterioration in patients' quality of life and increased prevalence of depression. In the later stages of ALS, pain can be severe enough to require increased use of sedative and analgesic drugs, and is among the events that predict clinical deterioration and death. The site of pain depends on the pain type or underlying mechanism (eg, painful cramps, nociceptive pain, or neuropathic pain). Given the multifactorial nature of pain in patients with ALS, different treatments have been suggested, ranging from non-steroidal anti-inflammatory drugs, drugs for neuropathic pain, opioids, and cannabinoids, to physical therapy strategies and preventive assistive devices. Further understanding of the pathophysiology is crucial to drive assessment in clinical trials of therapeutic strategies targeted at specific mechanisms and studies of individualised therapies. PMID- 27964825 TI - Carbon dioxide laser treatment of penile intraepithelial neoplasia. AB - INTRODUCTION & OBJECTIVE: The non-invasive nature of penile intraepithelial neoplasia (PeIN) allows for curative penile sparing therapy and is recommended, in their guidelines, by the European Association of Urology (EAU). Treatment options include topical chemotherapy, immunotherapy, laser treatment, photodynamic therapy and surgical excision. Our primary aim was to evaluate the outcome of carbon dioxide (CO2) laser treatment of penile intraepithelial neoplasia. METHODS: A retrospective review of 47 patients who underwent CO2 laser ablation of PeIN, from May 2008 to June 2015, in our tertiary referral centre was performed. All patients underwent acetic acid mapping and had their lesions ablated with a Lumenis Shaplan CO2 laser device. Patients had regular follow up and further suspicious areas underwent re-biopsy. RESULTS: Forty-seven men had primary PeIN. After laser treatment, 8 men (17%) had a recurrence and the average time to recurrence was 19.4 months. Seven of the eight patients with recurrences, pathologically had further PeIN and one patient developed G1 pT1 disease. These patients underwent further laser treatment, glans resurfacing or local excision. No patients required penectomy. The average length of follow-up was 29 months (rg: 1-76). Penile cancer-specific survival was 100% and overall survival 98%. No patients required re-admission or developed other long-term complications, such as meatal stenosis from their treatment. CONCLUSION: Carbon dioxide laser treatment for penile intra-epithelial neoplasia is effective due to its 100% response rate, low progression rate and lower recurrence rate compared with topical agents. The laser has minimal morbidity with cosmetically acceptable outcomes compared to more invasive resurfacing surgeries. PMID- 27964826 TI - Therapeutic potentials of umbilical cord-derived mesenchymal stromal cells for ischemic-type biliary lesions following liver transplantation. AB - BACKGROUND AIMS: Ischemic-type biliary lesions are severe, graft-threatening complications after orthotopic liver transplantation, and a novel and efficient therapeutic strategy is urgently needed. Due to the immunosuppressive and regenerative properties, mesenchymal stromal cells (MSCs) could be an interesting candidate. METHODS: We initiated safety and efficacy of human umbilical cord derived MSC (UC-MSC) transfusions for patients with ischemic-type biliary lesions after liver transplantation. From January 2013 to June 2014, 12 ischemic-type biliary lesions patients were recruited as the MSCs group in this phase I, prospective, single-center clinical study. Patients in this group received six doses of UC-MSCs (about 1.0 * 106 MSCs per kilogram body weight through peripheral intravenous infusion). The traditional therapeutic protocol was applied during October 2003 to December 2012 in 70 ischemic-type biliary lesions patients who were treated as the control group. Liver function tests, the need for interventional therapies and graft survival rate were chosen to evaluate the therapeutic efficacy of MSC treatment. Adverse events were closely monitored up to 2 years after MSC transfusions. RESULTS: No significant MSC-related adverse events were observed during the trial. Compared with baseline, the levels of total bilirubin, gamma-glutamyl transferase and alkaline phosphatase were decreased after UC-MSC treatment at week 20 and week 48. Interventional therapies were performed in 64.3% (45/70) of patients in the control group and 33.3% (4/12) of patients in the MSCs groups. MSC therapy significantly decreased the need for interventional therapies (P = 0.046). The 1- and 2-year graft survival rates were higher in the MSCs group (100% and 83.3%, respectively) than in the control group (72.9% and 68.6%, respectively). CONCLUSIONS: The UC-MSC transfusions are clinically safe and short-term favorable, which may become a novel treatment for patients with ischemic-type biliary lesions after liver transplantation. PMID- 27964828 TI - Commentary to "Fetal megacystis: A systematic review". PMID- 27964827 TI - Asthma and Risk of Appendicitis in Children: A Population-Based Case-Control Study. AB - OBJECTIVE: To assess whether asthma is associated with risk of appendicitis in children. METHODS: We used a population-based case-control study design using a comprehensive medical record review and predetermined criteria for appendicitis and asthma. All children (age younger than 18 years of age) who resided in Olmsted County, Minnesota, and developed appendicitis between 2006 and 2012 were matched to controls (1:1) with regard to birthday, gender, registration date, and index date. Asthma status was ascertained using predetermined criteria. Active (current) asthma was defined as the presence of asthma symptoms or asthma-related events (eg, medication use, clinic visits, emergency department, or hospitalization) within 1 year before the index date. Inactive asthma was defined as subjects without these events. A conditional logistic regression model was used. RESULTS: Among the 309 appendicitis cases identified, when stratified according to asthma status, active asthma was associated with significantly increased risk of appendicitis compared with inactive asthma (odds ratio [OR] = 2.48; 95% confidence interval [CI], 1.22-5.03) and to no asthma (OR = 1.88; 95% CI, 1.07-3.27; overall P = .035). When controlling for potential confounders such as gender, age, and smoking status, active asthma was associated with a higher odds of developing appendicitis compared with nonasthmatic patients (adjusted OR = 1.75; 95% CI, 0.99-3.11) whereas inactive asthma was not (overall P = .049). Tobacco smoke exposure within 3 months was associated with an increased risk of appendicitis (adjusted OR = 1.66; 95% CI, 1.02-2.69). Among asthma medications, leukotriene receptor antagonists reduced the risk of appendicitis (OR = 0.18; 95% CI, 0.04-0.74). CONCLUSIONS: Active asthma might be an unrecognized risk factor for appendicitis in children whereas a history of inactive asthma does not pose such risk. Further investigation exploring the underlying mechanisms is warranted. PMID- 27964829 TI - The role of voiding cystourethrography in asymptomatic unilateral isolated ureteropelvic junction obstruction: A retrospective study. AB - INTRODUCTION: The presence of concomitant vesicoureteric reflux (VUR) and ureteropelvic junction obstruction (UPJO) is uncommon. Nevertheless, the reported VUR coexisting with asymptomatic unilateral isolated hydronephrosis (AUIH) requiring pyeloplasty for correction of UPJO was of low grade and mostly resolved during conservative follow-up. Therefore, VCUG may be not indicated in these children except if voiding symptoms, urinary tract infection (UTI), dilated ureters, or bladder and ureteric abnormalities are suspected. OBJECTIVES: The aim was to evaluate the need for VCUG in infants <1 year old with AUIH for whom a dismembered pyeloplasty was indicated for correction of UPJO. METHODS: Ninety-six children <1 year old with pyeloplasty carried out from January 2012 to March 2014 were retrospectively included. Children with voiding symptoms or dilated ureter, duplex system, fused kidneys, bilateral dilatation, or any bladder abnormality on ultrasound were excluded. Anderson-Hynes pyeloplasty was performed through a flank incision. Preoperative VCUG was analyzed in relation to outcome and any UTI during follow-up. The Student t test, Mann-Whitney U test, or Fisher exact test were used to compare variables. RESULTS: Five children had concomitant VUR with UPJO. Most of the children were circumcised during the first postnatal week. The remaining few children were circumcised at the time of pyeloplasty. Side, grade of detected VUR, and complications (18.75%) (postoperative or during follow-up) are presented in the Table. Outcomes in children with and without VUR were not different. Dismembered pyeloplasty was successful in children with VUR and with no complications except for non-febrile UTI in one child only. Ureters were still not dilated at the last follow-up. DISCUSSION: The required imaging in infants with AUIH is still a subject of debate. As we expected, there was a low incidence of associated VUR in the present study. They were of low grade without any complications during follow-up and without affecting the outcome. The present study has its limitations, including the retrospective nature and short follow up. However, as at least 2 years of follow-up were documented without any harm or ureteric dilation, VUR will mostly resolve. The present study is strengthened by inclusion of infants only. CONCLUSIONS: Our data suggest that VCUG is not indicated in infants with AUIH requiring pyeloplasty for correction of UPJO. VCUG will not affect the treatment decision, operative outcome, or postoperative complications. VCUG may be indicated in case of suspected voiding symptoms, UTI, dilated ureters, or bladder and ureteric abnormalities. PMID- 27964830 TI - Developing procedure-specific consent forms in plastic surgery: Lessons learnt. PMID- 27964831 TI - Oculogyric crises: Etiology, pathophysiology and therapeutic approaches. AB - Oculogyric crisis (OGC) describes the clinical phenomenon of sustained dystonic, conjugate and typically upward deviation of the eyes lasting from seconds to hours. It was initially observed in patients with postencephalitic parkinsonism, but since then a number of conditions have been associated with OGC. These include drug-induced reactions, hereditary and sporadic movement disorders, and focal brain lesions. Here, we systematically review the literature and discuss the spectrum of disorders associated with OGC in order to aid clinicians place this rare but distinctive clinical sign into the appropriate diagnostic context. We also provide a brief synthesis of putative pathophysiological mechanisms, as well as therapeutic recommendations based on the literature and our own experience. PMID- 27964832 TI - Role of the VPS35 D620N mutation in Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder involving the loss of dopaminergic neurons in the brain. Following the discovery of the PD-causing D620N mutation in the VPS35 (Vacuolar sorting protein 35) gene, dysfunction in the subcellular retromer complex has been strongly implicated in pathogenesis of PD. Although the function and dysfunction of the retromer has been a focus of study for some time, the role of this complex in the development of PD is not fully understood. Investigating cellular alterations that occur when the retromer is rendered dysfunctional, such as when the D620N disease-causing mutation is introduced into various model systems, shows that endosomal processing defects are major contributors to the disease phenotype. Altered trafficking of retromer cargo molecules, reduced cellular survival and altered processing of alpha synuclein have all been observed in the presence of the D620N mutation. In addition, interactions between the retromer and the protein products of other familial Parkinsonism-related genes, has made the retromer a prime target of research in PD. This review gives an overview of the changes in retromer function, identified thus far, that may contribute to the neurodegeneration observed in PD. PMID- 27964833 TI - Commentary: Integrating Social Determinants, Family Involvement, and Mental Health in Pediatric Primary Care. PMID- 27964834 TI - Variability of sweat chloride - A never ending story. PMID- 27964835 TI - Identification of metabolites associated with water stress responses in Solanum tuberosum L. clones. AB - Water deficiency has become a major issue for modern agriculture as its effects on crop yields and tuber quality have become more pronounced. Potato genotypes more tolerant to water shortages have been identified through assessment of yield and dry matter. In the present study, a combination of metabolite profiling and physiological/agronomical measurements has been used to explore complex system level responses to non-lethal water restriction. The metabolites identified were associated with physiological responses in three different plant tissues (leaf, root and tuber) of five different potato genotypes varying in susceptibility/tolerance to drought. This approach explored the potential of metabolite profiling as a tool to unravel sectors of metabolism that react to stress conditions and could mirror the changes in the plant physiology. The metabolite results showed different responses of the three plant tissues to the water deficit, resulting either in different levels of the metabolites detected or different metabolites expressed. The leaf material displayed the most changes to drought as reported in literature. The results highlighted genotype-specific signatures to water restriction over all three plant tissues suggesting that the genetics can predominate over the environmental conditions. This will have important implications for future breeding approaches. PMID- 27964836 TI - Non-heme dioxygenases in tumor hypoxia: They're all bound with the same fate. AB - Tumor tissues are known to harbor hypoxic areas. The hypoxic microenvironment promotes angiogenesis. Hypoxic tumor cells also manifest genome instability. DNA damage repair pathways, such as double-strand break repair, mismatch repair and base excision repair are known to be altered during hypoxia. This review is focused on the non-heme Fe(II) and 2-oxoglutarate-dependent dioxygenases which are involved in repair of DNA alkylation adducts. Activities of these DNA repair enzymes are completely oxygen-dependent and little information is available about inhibition of these enzymes during hypoxia. While impairment of function of non heme dioxygenase during tumor hypoxia has been implicated in different studies, the possible outcomes with respect to mutagenesis and genomic instability are explored here. PMID- 27964838 TI - Sitagliptin plus basal insulin: simplifying in-hospital diabetes treatment? PMID- 27964837 TI - Efficacy of sitagliptin for the hospital management of general medicine and surgery patients with type 2 diabetes (Sita-Hospital): a multicentre, prospective, open-label, non-inferiority randomised trial. AB - BACKGROUND: The role of incretin-based drugs in the treatment of patients with type 2 diabetes admitted to hospital has not been extensively assessed. In this study, we compared the safety and efficacy of a dipeptidyl peptidase-4 inhibitor (sitagliptin) plus basal insulin with a basal-bolus insulin regimen for the management of patients with type 2 diabetes in general medicine and surgery in hospitals. METHODS: We did a multicentre, prospective, open-label, non inferiority randomised clinical trial (Sita-Hospital) in five hospitals in the USA, enrolling patients aged 18-80 years with type 2 diabetes and a random blood glucose concentration of 7.8-22.2 mmol/L who were being treated with diet or oral antidiabetic drugs or had a total daily insulin dose of 0.6 units per kg or less, admitted to general medicine and surgery services. We randomly assigned patients (1:1) to receive either sitagliptin plus basal glargine once daily (the sitagliptin-basal group) or a basal-bolus regimen with glargine once daily and rapid-acting insulin lispro or aspart before meals (the basal-bolus group) during the hospital stay. All other antidiabetic drugs were discontinued on admission. The randomisation was achieved by computer-generated tables with block stratification according to randomisation blood glucose concentrations (ie, higher or lower than 11.1 mmol/L). The primary endpoint of the trial was non inferiority in mean differences between groups in their daily blood glucose concentrations during the first 10 days of therapy (point-of-care measurements; non-inferiority was deemed a difference <1 mmol/L). The safety endpoints included hypoglycaemia and uncontrolled hyperglycaemia leading to treatment failure. All participants who received at least one dose of study drug were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT01845831. FINDINGS: Between Aug 23, 2013, and July 27, 2015, we recruited 279 patients, and randomly assigned 277 to treatment; 138 to sitagliptin-basal and 139 to basal bolus. The length of stay in hospital was similar for both groups (median 4 days [IQR 3-8] vs 4 [3-8] days, p=0.54). The mean daily blood glucose concentration in the sitagliptin-basal group (9.5 mmol/L [SD 2.7]) was not inferior to that in the basal-bolus group 9.4 mmol/L [2.7]) with a mean blood glucose difference of 0.1 mmol/L (95% CI -0.6 to 0.7). No deaths occurred in this trial. Treatment failure occurred in 22 patients (16%) in the sitagliptin-basal group versus 26 (19%) in the basal-bolus group (p=0.54). Hypoglycaemia occurred in 13 patients (9%) in the sitagliptin-basal group and in 17 (12%) in the basal-bolus group (p=0.45). No differences in hospital complications were noted between groups. Seven patients (5%) developed acute kidney injury in the sitagliptin-basal group and six (4%) in the basal-bolus group. One patient (0.7%) developed acute pancreatitis (in the basal-bolus group). INTERPRETATION: The trial met the non-inferiority threshold for the primary endpoint, because there was no significant difference between groups in mean daily blood glucose concentrations. Treatment with sitagliptin plus basal insulin is as effective and safe as, and a convenient alternative to, the labour-intensive basal-bolus insulin regimen for the management of hyperglycaemia in patients with type 2 diabetes admitted to general medicine and surgery services in hospital in the non-intensive-care setting. FUNDING: Merck. PMID- 27964840 TI - Induced pluripotent stem cells: An unlimited source of organs for transplantation. AB - Organ production outside the human body could address the shortage of organs for transplantation. However, in vitro organ production is still a faraway perspective, particularly because of the difficulty in establishing an effective vascularization. A new emerging technology proposes to use carrier animals for the development of human organs. In this approach, induced pluripotent stem cells (iPSC) are injected in animal embryos to produce chimeric animals that contain autologous human organs. PMID- 27964839 TI - Post-traumatic balance disorder. AB - The causes of balance disorder are many and various, and the subjective syndrome of cranial trauma patients is diagnosed by elimination. Progress in otoneurologic functional exploration and brain imaging, however, now generally allow this functional complaint to be given an objective basis. In recent years, new diagnoses have improved recognition of such pathologies in the appraisal of corporal injury for compensation purposes. The present article seeks to detail etiology and, by a review of the literature, to determine factors liable to influence management and appraisal in particular. PMID- 27964841 TI - Infections in Cardiac Implantable Electronic Devices: Diagnosis and Management in a Referral Center. AB - INTRODUCTION AND OBJECTIVES: Infections in cardiac implantable electronic devices are increasing due to the expansion of the indications of these devices. The management of some aspects is controversial. Here, we report our broad experience. METHODS: Between 1985 and 2015, 325 infections (196 local and 129 systemic) were registered; 28.5% of them were referred from other centers: 229 pacemakers, 69 implantable cardioverter-defibrillators, and 27 patients with cardiac resynchronization therapy. The follow-up was at least 1 year after hospital discharge. RESULTS: Percutaneous traction (PCT) was the most frequent procedure (n=280) in local (n=166) and systemic infections (n=114), with complete extraction of the system in 82.5% of the patients, clinical success in 89%, and few complications (2 deaths attributable to the technique). Overall mortality was 1% in local infections and 8% in systemic infections. After 212 complete PCT, a new device was placed in 209: of these, a contralateral system was implanted in the same procedure in 152 (73%) and in a second procedure in 57, with no differences in relapses (2 in the 1-stage procedure, and 1 in the 2-stage procedure). CONCLUSIONS: Percutaneous traction in experienced hands has good results with very few complications. It is possible to perform contralateral implantation of the new device on the same day without increasing the risk of relapse. PMID- 27964842 TI - Live birth rates are satisfactory following multiple IVF treatment cycles in poor prognosis patients. AB - This seven-year retrospective study analysed the live birth rate (LBR) for women undergoing IVF treatment with various antral follicle counts (AFC). The LBR decreased with lower AFC ratings, and in 290 treatment cycles for women in the poorest AFC category, <=4 follicles (group E), the LBR was the lowest at 10.7%. The pregnancy loss rate (PLR) significantly increased with poorer AFC categories, from 21.8% in AFC group A (>=20 follicles), to 54.4% in AFC group E (p<0.0001). This trend was repeated with advancing age, from 21.6% for younger women (<35years), to 32.9, 48.5 and 100% for ages 35-39, 40-44 and >=45 years, respectively (p<0.0001). However, LBR within the specific AFC group E cohort was also age-dependent and decreased significantly from 30.0% for <35 years old, to 13.3, 3.9 and 0% for patients aged 35-39, 40-44 and >=45 years, respectively. Most, importantly, LBR rates within these age groups were not dependent on the number of IVF attempts (1st, 2nd, 3rd or >=4 cycles), which indicated that cycle number should not be the primary deciding factor for cessation of IVF treatment in responding women <45years old. PMID- 27964844 TI - TILs in metastatic breast cancer-no surprises, but more questions. PMID- 27964843 TI - Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study. AB - BACKGROUND: High quantities of tumour-infiltrating lymphocytes (TILs) in primary HER2-positive breast cancer are associated with improved prognosis and response to therapy. We aimed to investigate the prognostic role of host antitumour immunity as represented by baseline quantities of TILs in patients with advanced HER2-positive breast cancer treated with either pertuzumab or placebo in addition to trastuzumab and docetaxel. METHODS: CLEOPATRA was a randomised phase 3 study comparing the addition of either pertuzumab or placebo to first-line therapy with trastuzumab and docetaxel for patients with locally recurrent, unresectable, or metastatic HER2-positive breast cancer. We assessed the quantity of stromal TILs in prospectively collected tumour samples and investigated their association with progression-free survival, overall survival, clinicopathological characteristics, and pertuzumab treatment. We estimated hazard ratios (HR) and 95% CIs with multivariate Cox regression models fitting stromal TILs as a continuous variable (per 10% increment). The CLEOPATRA trial is registered with ClinicalTrials.gov, number NCT00567190. FINDINGS: Tumour samples from 678 (84%) of 808 participants were evaluable for TILs, including 519 (77%) archival samples, 155 (23%) freshly obtained samples (collected 45 days or fewer before randomisation), and four samples of unknown archival status. Median follow-up was 50 months (IQR 41-54) for progression-free survival and 51 months (IQR 46-57) for overall survival. 519 progression-free survival events occurred and 358 patients died. The median TIL value was 10% (IQR 5-30). Freshly obtained tumour samples had significantly lower TIL values than did archival samples (10.00% [95% CI 5.00-20.00] vs 15.00% [5.00 35.00]; p=0.00036). We detected no significant association between TIL values and progression-free survival (adjusted HR 0.95, 95% CI 0.90-1.00, p=0.063). However, for overall survival, each 10% increase in stromal TILs was significantly associated with longer overall survival (adjusted HR 0.89, 95% CI 0.83-0.96, p=0.0014). The treatment effect of pertuzumab did not differ significantly by stromal TIL value for either progression-free survival (pinteraction=0.23) or overall survival (pinteraction=0.21). INTERPRETATION: In patients with advanced HER2-positive breast cancer treated with docetaxel, trastuzumab, and pertuzumab or placebo, higher TIL values are significantly associated with improved overall survival, suggesting that the effect of antitumour immunity extends to the advanced setting. Future clinical studies in this cancer subtype should consider TILs as a stratification factor and investigate whether therapies that can augment immunity could potentially further improve survival. FUNDING: F Hoffmann La Roche-Genentech and the Breast Cancer Research Foundation. PMID- 27964845 TI - Intratympanic steroid injection and hyperbaric oxygen therapy for the treatment of refractory sudden hearing loss. AB - INTRODUCTION: Controversy surrounds the use of salvage therapies to treat sudden sensorineural hearing loss (SSNHL), with no consensus on recommendations. While several studies have demonstrated the effectiveness of intratympanic administration of steroids (ITS) and hyperbaric oxygen (HBO) treatment, few have compared the efficacy of ITS and HBO therapy in patients with refractory SSNHL. OBJECTIVE: We evaluated the efficiency of ITS and HBO therapy in patients with refractory SSNHL. METHODS: Patients who did not adequately benefit from systemic treatment were evaluated retrospectively. Refractory patients were defined as those who gained less than 20dB in hearing after initial treatment. All refractory patients were informed about salvage therapy options: ITS or HBO therapy, the advantages and disadvantages of which were explained briefly. ITS involved 4mg/mL dexamethasone administered through a 25 gauge needle. Patients underwent HBO therapy in a hyperbaric chamber where they breathed 100% oxygen for 120min at 2.5 atmospheric pressure. The hearing levels of both groups were evaluated before the salvage therapy and at 3 months after treatment. Improvements in hearing were evaluated according to the Furahashi criteria. We also compared the two therapies in terms of speech discrimination scores (SDSs) and the recovery of all frequencies. RESULTS: The salvage therapies generated similar results. Changes in pure tone averages and SDSs were similar for ITS and HBO therapy (p=0.364 and p=0.113). Comparison of SDSs and hearing thresholds at all frequencies showed similar levels of improvement. CONCLUSION: ITS and HBO therapy produced similar improvements in SSNHL patients, but the sample size was too small to draw definitive conclusions. Further randomized controlled studies are needed to identify the best therapy for patients with refractory sudden hearing loss. PMID- 27964846 TI - Corrigendum to "Giardia and Cryptosporidium spp. dissemination during wastewatertreatment and comparative detection via immunofluorescence assay (IFA), nested polymerase chain reaction (nested PCR) and loopmediated isothermal amplification (LAMP)" [Acta Trop. 158 (2016) 43-51]. PMID- 27964847 TI - Added value of diffusion-weighted magnetic resonance imaging for the diagnosis of perianal fistula. AB - PURPOSE: To evaluate the added value of diffusion-weighted (DWI) magnetic resonance imaging (MRI) by comparison with T2-weighted images alone in the diagnosis of perianal fistula. MATERIAL AND METHODS: MRI examinations of 123 patients (97 men, 26 women; mean age, 41.9 years) with suspected perianal fistula were retrospectively evaluated by two radiologists. Fat-suppressed T2-weighted fast spin echo images, DWI (b values, 0 and 1000s/mm2) and fat-suppressed gadolinium chelate-enhanced T1-weighted images were evaluated for each patient by using a four-point scale. Confidence scores and sensitivities were calculated for T2-weighted images alone, the combination of DWI and T2-weighted images and the combination of gadolinium chelate-enhanced T1-weighted images and T2-weighted images. The combination of gadolinium chelate-enhanced and T2-weighted images was used as reference standard. RESULTS: Perianal fistulas were present in 92/123 patients (74.8%). An almost perfect interobserver agreement was found for T2 weighted images (kappa=0.868), the combination of gadolinium chelate-enhanced T1 weighted images and T2-weighted images (kappa=0.96) and the combination of DWI and T2-weighted images (kappa=0.90). The confidence scores for the diagnosis of perianal fistula for the combination of gadolinium chelate-enhanced T1-weighted images and T2-weighted images were greater than those of T2-weighted images alone for observer 1 (P<0.001) and observer 2 (P=0.009). The confidence scores of the combination of DWI and T2-weighted images were greater than those of T2-weighted images alone for observer 1 (P<0.001) and observer 2 (P=0.032). Sensitivity and specificity of the combination of DWI and T2-weighted images were greater than those of T2-weighted images alone for both observers. CONCLUSION: DWI has a significant added value compared to T2-weighted imaging alone in the diagnosis of perianal fistula. PMID- 27964848 TI - Comments regarding: Nanda A, Krishnan S, Kaur H, Koli D, Manak K, Verma M, Gill S. Correction of microstomia in an edentulous patient. J Prosthet Dent 2016;115:137-40. PMID- 27964849 TI - Can nocturnal use of implant-retained overdenture improve cardiorespiratory stability of a patient with obstructive sleep apnea? A clinical report. AB - Few studies have evaluated the interaction between conventional complete dentures (CCD) and the respiratory system and the authors are unaware of any that evaluated the interaction between implant-retained overdentures (IROs) and the respiratory system. This clinical report documented the effects of wearing an IRO on the cardiorespiratory stability of an edentulous patient with obstructive sleep apnea (OSA). A 64-year-old woman was referred to the department of otolaryngology because of daytime sleepiness and morning headaches. The patient refused polysomnographic evaluation because of claustrophobia. Overnight pulse oximetry (PO) was performed to detect cardiorespiratory stability during sleep, and the oxygen desaturation index (ODI) of the patient was found to be 20.9. A mandibular advancement device (MAD) was fabricated; however, the patient did not comply with the treatment and stopped using the MAD because of intraoral discomfort. Therefore, the patient started to wear the conventional complete dentures (CCDs) nocturnally to prevent upper airway collapses. Despite the significant drop in ODI score to 12.6, because of displacement, the mandibular denture was converted to an IRO. The PO tests performed after another 6 months revealed an ODI score of 7.8. Wearing CCDs might improve respiratory stability of patients with edentulism during sleep; however, more favorable results could be obtained with IROs. PMID- 27964851 TI - Is epicutaneous immunotherapy only skin deep? PMID- 27964850 TI - Response to "Risk factors for developing prediabetes". PMID- 27964852 TI - Increasing Fruit and Vegetable Intake among Children and Youth through Gardening Based Interventions: A Systematic Review. AB - Although there are numerous health benefits associated with eating fruit and vegetables (F/V), few children are consuming recommended amounts. Gardening interventions have been implemented in various settings in an effort to increase children's F/V consumption by expanding knowledge, exposure, and preferences for a variety of F/V. The purpose of this review was to identify the effectiveness of gardening interventions that have been implemented to increase F/V consumption among children. A systematic review was conducted using four electronic databases: Web of Science, PubMed, Scopus, and the Cumulative Index to Nursing and Allied Health Literature. English language studies conducted in developed countries between January 2005 and October 2015 were included in this review. Included studies measured F/V consumption among children aged 2 to 15 years before and after implementation of a gardening intervention in a school, community, or afterschool setting. All study designs were included in this review. A total of 891 articles were identified through database searching and cross-referencing. After removing duplicates, 650 articles remained and were screened using inclusion and exclusion criteria. Twenty-seven full-text articles were analyzed and 14 articles were included in this review. Of the 14 articles reviewed, 10 articles found statistically significant increases in fruit or vegetable consumption among participants after implementation of a gardening intervention. However, many studies were limited by the use of convenience samples, small sample sizes, and self-reported measurements of F/V consumption. Although the evidence is mixed and fraught with limitations, most studies suggest a small but positive influence of gardening interventions on children's F/V intake. Future studies that include control groups, randomized designs, and assessments of F/V consumption over at least 1 year are needed to advance the literature on this topic. PMID- 27964853 TI - Seeing the doctor without fear: www.doctortea.org for the desensitization for medical visits in Autism Spectrum Disorders. AB - INTRODUCTION: Doctor Tea is an online website designed to facilitate medical visits for those with autism spectrum disorder and other disabilities. People diagnosed with autism not only have greater medical needs than the general population, but also have particular characteristics that are often not accommodated by medical services. This lack of medical accommodation often creates a very complicated, and sometimes traumatic experience, when visiting medical facilities. Individuals with autism have great difficulty understanding social situations and contexts, such as medical tests or consultations, as well as difficulty in tolerating new situations and atypical sensory thresholds. Doctor Tea aims to reduce anxiety before medical consultations and procedures from a safe and well-known environment (school, home, etc.). MATERIAL AND METHOD: The website, www.doctortea.org, provides information and materials (videos, cartoon, 3D animations, pictogram sequences, etc.) about the most frequent medical procedures and practices for patients with autism. The website also offers information to the doctors and families of patients with autism about the most common medical problems associated with autism. RESULTS: A total of 17,199 different users visited the website during 2015, with a total of 23,348 online visitors from more than 70 different countries since the website's release in November 2014. CONCLUSIONS: The familiarisation with the medical procedures and its environment appears to decrease the anxiety in patients with disabilities during medical visits, as well as optimising the effectiveness of their medical visits and tests. PMID- 27964854 TI - Spontaneous Esophageal Dissection. PMID- 27964855 TI - A Case of Brachiocephalic Fistula Steal and the Emergency Physician's Approach to Hemodialysis Arteriovenous Fistula Complications. AB - BACKGROUND: Chronic kidney disease is common in the United States, with many patients maintained on hemodialysis (HD). The process of HD requires vascular access through an arteriovenous (AV) fistula, AV graft, or central venous catheter. Today, as a result of the National Kidney Foundation's "Fistula First" initiative, nearly 55% of HD patients utilize an AV fistula. As there is significant morbidity and mortality associated with fistula placement and recurrent fistula cannulation, emergency physicians must be equipped to recognize and treat fistula complications. OBJECTIVE: To detail a case study of vascular insufficiency (vascular steal) presenting to an emergency department (ED) and provide an evidence-based approach to the emergency assessment and management of HD AV fistula complications. DISCUSSION: A 66-year-old man presented to the ED with left upper extremity pain, paresthesias, and loss of grip strength of 1-week duration 15 days after placement of left upper extremity brachiocephalic fistula. He was diagnosed with dialysis access-associated steal syndrome and taken to the operating room for revision. Patients with HD fistulas may experience several complications, including vascular insufficiency, hemorrhage, infection, stenosis, thrombosis, aneurysms, or pseudoaneurysms. Emergency physicians must be able to identify these complications and deliver timely treatment. CONCLUSIONS: A comprehensive understanding of the appropriate management of AV fistula complications is paramount for the emergency physician. Early recognition and treatment of vascular insufficiency resulting from fistula creation, fistula hemorrhage, fistula infection, stenosis, thrombosis, and aneurysms or pseudoaneurysms is vital to reducing the morbidity and mortality associated with HD. PMID- 27964856 TI - Ingestion of microplastics by natural zooplankton groups in the northern South China Sea. AB - The ingestion of microplastics by five natural zooplankton groups in the northern South China Sea was studied for the first time and two types of sampling nets (505MUm and 160MUm in mesh size) were compared. The microplastics were detected in zooplankton sampled from 16 stations, with the fibrous microplastics accounting for the largest proportion (70%). The main component of the found microplastics was polyester. The average length of the microplastics was 125MUm and 167MUm for Nets I and II, respectively. The encounter rates of microplastics/zooplankton increased with trophic levels. The average encounter rate of microplastics/zooplankton was 5%, 15%, 34%, 49%, and 120% for Net I, and 8%, 21%, 47%, 60%, and 143% for Net II for copepods, chaetognaths, jellyfish, shrimp, and fish larvae, respectively. The average abundance of microplastics that were ingested by zooplankton was 4.1pieces/m3 for Net I and 131.5pieces/m3 for Net II. PMID- 27964857 TI - [Toxicology screening in paediatrics. Authors reply]. PMID- 27964858 TI - Eat Well Keep Active: Qualitative findings from a feasibility and acceptability study of a brief midwife led intervention to facilitate healthful dietary and physical activity behaviours in pregnant women. AB - BACKGROUND: overweight and obesity in the pregnant population is increasing and this is a public health concern. Many women have difficulty in following the recommendation to maintain a healthy diet and to keep active, indeed some identify pregnancy as the start of their concern with being overweight. OBJECTIVE: to assess the feasibility and acceptability of the 'Eat Well Keep Active' intervention programme designed to promote healthy eating and physical activity in pregnant women. This brief midwife led intervention was based upon the Self Determination Theory (SDT) framework and utilised Motivational Interviewing and individualised goal setting. DESIGN: this was a prospective qualitative study to explore women's views on the acceptability and perceived efficacy of the 'Eat Well Keep Active' programme obtained through one-to-one interviews 6 weeks after the delivery of the intervention. Data were also analysed to assess fidelity of the intervention to the psychological constructs of SDT; autonomy, competence and relatedness. SETTING: Wales, UK. PARTICIPANTS: pregnant women suitable for Midwife Led Care and therefore deemed to be 'low risk' were recruited from a large maternity unit in South Wales (n=20). FINDINGS: the results indicated that the 'Eat Well Keep Active' intervention programme was well received by participants who reported that it positively influenced their health behaviours. There was clear evidence of the intervention supporting the three SDT psychological needs. KEY CONCLUSIONS: The Eat Well Keep Active intervention was designed to be incorporated into existing antenatal provision and findings from this study have demonstrated its acceptability. The brief midwife led intervention based on SDT was found to be acceptable by the participants who embraced the opportunity to discuss and explore their lifestyle behaviours with a midwife. IMPLICATIONS FOR PRACTICE: theoretically designed interventions that can facilitate women to pursue a healthy lifestyle during pregnancy are lacking and the 'Eat Well Keep Active' programme has the potential to address this. Further research is needed in order to assess the acceptability of the intervention to midwives and other groups of pregnant women prior to assessing its efficacy in changing and maintaining healthful behaviours. PMID- 27964860 TI - Timing of light exposure and activity in adults with delayed sleep-wake phase disorder. AB - OBJECTIVE: To characterize the patterns of light exposure and physical activity level and assess their relationship with sleep quality and depressive symptoms in adults with delayed sleep-wake phase disorder (DSWPD). METHODS: 42 DSWPD (22 female, mean age 34.5 y) and 26 (+/-4 years) age-and-sex-matched controls (12 female, mean age 33.4 y) underwent seven days of light and activity monitoring. RESULTS: Individuals with DSWPD had significantly delayed bed times and wake times, but similar sleep duration compared to controls. Subjective sleep quality (Pittsburgh Sleep Quality Index (PSQI)) was poorer in DSWPDs compared to controls. Those with DSWPD had significantly more activity and light exposure late at night (2:00-4:00) and significantly less activity and light exposure in the morning (8:00-11:00). Total 24 h levels of light and activity were not significantly different between DSWPD and controls. However, the DSWPD group had significantly more light exposure than controls 22 h after waking, during their sleep period. Later light exposure correlated with higher depression scores [Beck Depression Index (BDI)] and poorer sleep quality (PSQI). CONCLUSIONS: The light exposure patterns observed in DSWPD likely contribute to and perpetuate the chronically delayed sleep and wake phase in these patients. In addition, increased light exposure during the sleep period may also contribute to the poor sleep quality and mood disorders that are common in these individuals. PMID- 27964859 TI - Large-scale genome-wide scans do not support petaloid toenail as a Mendelian trait. PMID- 27964861 TI - Pain, opioids, and sleep: implications for restless legs syndrome treatment. AB - Opioid receptor agonists are known to relieve restless legs syndrome (RLS) symptoms, including both sensory and motor events, as well as improving sleep. The mechanisms of action of opioids in RLS are still a matter of speculation. The mechanisms by which endogenous opioids contribute to the pathophysiology of this polygenetic disorder, in which there are a number of variants, including developmental factors, remains unknown. A summary of the cellular mode of action of morphine and its (partial) antagonist naloxone via alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) receptors and the involvement of dendritic spine activation is described. By targeting pain and its consequences, opioids are the first-line treatment in many diseases and conditions with both acute and chronic pain and have thus been used in both acute and chronic pain conditions over the last 40 years. Addiction, dependence, and tolerability of opioids show a wide variability interindividually, as the response to opioids is influenced by a complex combination of genetic, molecular, and phenotypic factors. Although several trials have now addressed opioid treatment in RLS, hyperalgesia as a complication of long-term opioid treatment, or opioid-opioid interaction have not received much attention so far. Therapeutic opioids may act not only on opioid receptors but also via histamine or N-methyl-d-aspartate (NMDA) receptors. In patients with RLS, one of the few studies investigating opioid bindings found that possible brain regions involved in the severity of RLS symptoms are similar to those known to be involved in chronic pain, such as the medial pain system (medial thalamus, amygdala, caudate nucleus, anterior cingulate gyrus, insular cortex, and orbitofrontal cortex). The results of this diprenorphine positron emission tomography study suggested that the more severe the RLS, the greater the release of endogenous opioids. Since 1993, when the first small controlled study was performed with oxycodone in RLS, opioids have been considered an efficacious off-label therapy in patients with severe RLS. A recent trial has proved the efficacy of a combination of prolonged release oxycodone/naloxone in patients with severe RLS as second-line therapy, with a mean dosage of 10/5 mg twice daily (mean difference of International Restless Legs Syndrome Study Group Rating Scale (IRLS) score between groups at 12 weeks: 8.15), and has now been licensed as the first opioid therapy in Europe. The current results from both short- and long-term trials and studies with opioids encourage optimism in alleviating RLS symptoms in patients with severe RLS, or possibly during or after augmentation. PMID- 27964862 TI - Deep brain stimulation (DBS) for severe restless legs syndrome: therapeutic and physiologic considerations. PMID- 27964863 TI - Vitamin D status of male OSAS patients improved after long-term CPAP treatment mainly in obese subjects. AB - OBJECTIVE: The aim of this study was to evaluate the effect of one-year useful continuous positive airway pressure (CPAP) treatment on serum vitamin D levels in middle-aged men affected by obstructive sleep apnea syndrome (OSAS). METHODS: This is a secondary investigation related to a previously published observational study about the effect of short-term CPAP therapy on serum vitamin D levels in severe OSAS (Apnea-Hypopnea Index - AHI- >30/h) patients. In the present study, we included patients participating to the previous investigation who repeated serum vitamin D assessment after one year of useful CPAP treatment, and compared to control a group of OSAS patients with scarce compliance to CPAP treatment. OSAS patients with beneficial use of CPAP treatment were distributed in obese (Body Mass Index - BMI >=30) and non-obese (BMI < 30). Moreover, the mean change between baseline and one-year follow-up (Delta) of serum vitamin D levels was correlated with demographic, polygraphic and clinical data throughout a multiple regression analysis. RESULTS: We documented the significant increase of serum vitamin D levels after one year of CPAP treatment in the OSAS group (n = 39, p < 0.001) and in both subgroups of obese (n = 23, p < 0.01) and non-obese (n = 16, p < 0.01) OSAS patients. Conversely, OSAS patients with a scarce compliance to CPAP therapy did not change serum vitamin D levels after one year (n = 10, p > 0.05). OSAS patients with beneficial CPAP treatment showed higher vitamin D serum levels after one year and a more frequent shift from insufficient to sufficient vitamin D status compared to OSAS patients not adequately using CPAP treatment. In particular, the obese OSAS patients subgroup shifted from insufficient (<=20 ng/mL) to sufficient (>20 ng/mL) vitamin D status after CPAP therapy more than the non-obese OSAS patients subgroup (p < 0.05). We observed higher Delta of vitamin D serum levels, Epworth Sleepiness Scale score, and AHI in obese compared to non-obese OSAS patients. Finally, BMI obtained at baseline positively correlated with Delta of vitamin D serum levels. DISCUSSION: This study documented that long-term CPAP treatment is a viable therapeutic choice for correcting both sleep apnea condition and vitamin D deficiency in middle-aged male OSAS patients. Significantly, this effect was more evident in obese subjects and possibly represents a valid therapeutic strategy to ensure sufficient vitamin D levels in these patients, which frequently show a deficient vitamin D status. PMID- 27964864 TI - Eichhornia crassipes: Agro-waster for a novel thermostable laccase production by Pycnoporus sanguineus SYBC-L1. AB - The aim of this study was to explore the utilization of an intractable waster of Eichhornia crassipes in laccase production by Pycnoporus sanguineus SYBC-L1. E. crassipes as the sole carbon and nitrogen source was confirmed to produce laccase (7.26 U/g dry substrate). The fermentation medium for the maximum enzyme production was optimized and the laccase was then purified and characterized. The optimized culture medium was 25.1% E. crassipes, 13.9% sawdust, 1.5 mM CuSO4, 40 MUM gallic acid, 65% moisture content and initial pH 6.0. A maximum laccase activity of 32.02 U/g dry substrate was detected at 9th day, which was 4.5-fold compared to the initial medium. The molecular mass of the purified Lac-S was 58.4 kDa. The optimum activity of Lac-S for DMP was at pH 3.0 and 70 degrees C. Lac-S showed not only high catalytic activities at low temperature, but also good stabilities toward pH and temperature. The residual catalytic activities of Lac-S were 30%, 40% and 50% at 0 degrees C, 10 degrees C and 20 degrees C, and the half lives at 50 degrees C, 60 degrees C and 70 degrees C were 21.7, 9.7 and 1.5 h, respectively. The results provide a significant basis for E. crassipes further utilization and Lac-S specific application in harsh industry. PMID- 27964865 TI - Gastrointestinal stromal tumours (GISTs): A descriptive study on 29 cases. AB - BACKGROUND AND STUDY AIM: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract, originating from Cajal cells in different sites of the digestive tract. The aim of the study is to report on epidemiological, clinical, histological, and therapeutic characteristics of GISTs. PATIENTS AND METHODS: A retrospective descriptive study of 29 cases of GIST in gastroenterology and general surgery departments of Mohamed Tahar Maamouri Hospital (Nabeul, Tunisia) was conducted from January 2005 to March 2012. RESULTS: Among the 29 patients, there were 18 males (62%) and 11 females (38%) with a median age of 63 years (range, 30-96years). The main symptoms were abdominal pain (40%) and weight loss (28%). The tumour was revealed by a complication in 5 cases (17%). Six patients (20.7%) had metastatic lesions. The most common sites were the stomach (41.4%) and the small intestine (17.3%). The median tumour size was 9.5cm (range, 1-30cm). Spindle cell tumours were the main histological type (62%). KIT was positive in the majority of cases (75%). Twenty-one patients with primary disease (72%) underwent a surgical resection. Imatinib was prescribed in 7 patients (24%). Sunitinib malate was indicated in 3 patients who had tumour progression under imatinib. Median survival was 17 months (range, 1-69months). Ten patients died. CONCLUSION: The management of GISTs has considerably evolved during the last years. Surgical resection, which remains the mainstay of treatment, was indicated in the majority of patients. Imatinib treatment has not improved overall survival in metastatic and/or inoperable cases. PMID- 27964866 TI - Radioimmunotherapy of lymphoma: an underestimated therapy option. PMID- 27964868 TI - Compulsory drug detention centres: time to question their continued use? PMID- 27964867 TI - Consolidation anti-CD22 fractionated radioimmunotherapy with 90Y-epratuzumab tetraxetan following R-CHOP in elderly patients with diffuse large B-cell lymphoma: a prospective, single group, phase 2 trial. AB - BACKGROUND: Radioimmunotherapy represents a potential option as consolidation after chemoimmunotherapy in patients with diffuse large B-cell lymphoma who are not candidates for transplantation. We aimed to assess activity and toxicity of fractionated radioimmunotherapy using anti-CD22 90Y-epratuzumab tetraxetan as consolidation after front-line induction chemoimmunotherapy in untreated elderly patients with diffuse large B-cell lymphoma. METHODS: We did a prospective, single-group, phase 2 trial at 28 hospitals in France, with patients recruited from 17 hospitals. Eligible patients were aged 60-80 years with bulky stage 2-3 or stage 3-4 CD20-positive diffuse large B-cell lymphoma, previously untreated, and not eligible for transplantation. Patients received six cycles of R-CHOP (rituximab [375 mg/m2], cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], and vincristine [1.4 mg/m2, up to 2 mg] all on day 1, and prednisone [40 mg/m2] daily for 5 days), administered every 14 days. 6-8 weeks after R-CHOP, responders received two doses of 15 mCi/m2 (555 MBq/m2) 90Y-epratuzumab tetraxetan administered 1 week apart. The primary endpoint was 2 year event-free survival in all registered eligible patients who received at least 1 day of study treatment; the safety analysis was done in the same population. This trial is registered with ClinicalTrials.gov, number NCT00906841. FINDINGS: Between Oct 22, 2008, and Dec 16, 2010, we recruited 75 patients, of whom four (5%) were excluded after central pathology review; hence, 71 (95%) patients were included in the analysis. All patients started induction treatment; 57 (80%) received radioimmunotherapy. With a median follow-up of 37 months (IQR 30-44), the estimated 2 year event-free survival was 75% (95% CI 63-84). Radioimmunotherapy toxicity consisted of grade 3 4 thrombocytopenia in 48 (84%) of 57 patients and neutropenia in 45 (79%) of 57 patients. One patient developed myelodysplastic syndrome 28 months after receiving radioimmunotherapy and one patient developed acute myeloid leukaemia 5 months after receiving radioimmunotherapy. INTERPRETATION: Fractionated radioimmunotherapy with 90Y-epratuzumab tetraxetan might be appropriate for response consolidation after induction chemotherapy in older patients with advanced diffuse large B-cell lymphoma, but further comparative studies are needed. FUNDING: Immunomedics, Amgen, Canceropole Grand Ouest, the GOELAMS/LYSA group and the French National Agency for Research (Investissements d'Avenir). PMID- 27964870 TI - High frequency stimulation of the infralimbic cortex induces morphological changes in rat hippocampal neurons. AB - BACKGROUND: Although a significant subset of patients with major depressive disorder (MDD) fail to respond to medical or behavioural therapy, deep brain stimulation (DBS) applied to the subgenual cingulate cortex (SCC; sg25) has been shown to reduce depressive symptoms in a subset of patients. This area receives projections from neurons in the CA1 region and subiculum of the hippocampus (HC), a brain region implicated in the pathobiology and treatment of MDD. OBJECTIVE: To assess whether high frequency stimulation (HFS) of the infralimbic cortex is associated with changes in cellular morphology in the HC. METHODS: Rats were subjected to either infralimbic HFS or sham-stimulation. Measures of cellular morphology, including dendritic length and complexity, were assessed in pyramidal neurons in the CA1 region of the HC by means of the Golgi-Cox histological stain. RESULTS: Dendritic length (p = 0.013) and number of branch points (p = 0.004) were significantly increased across the entire dendritic tree in animals subjected to HFS. Subsequent Scholl analysis revealed that for dendritic length these effects were localized to the region between 80 and 160 MUm from the soma (p < 0.001 for either 40 MUm interval) in the basal dendritic tree, while branch point number was predominantly increased between 120 and 160 MUm from the soma (p < 0.001) in the apical dendritic tree. CONCLUSIONS: High-frequency stimulation of the infralimbic cortex increases the complexity of apical dendrites and the length of basal dendritic trees of pyramidal neurons located in the CA1 hippocampal subfield relative to sham-stimulated animals. PMID- 27964869 TI - Relapse to opioid use in opioid-dependent individuals released from compulsory drug detention centres compared with those from voluntary methadone treatment centres in Malaysia: a two-arm, prospective observational study. AB - BACKGROUND: Detention of people who use drugs into compulsory drug detention centres (CDDCs) is common throughout East and Southeast Asia. Evidence-based pharmacological therapies for treating substance use disorders, such as opioid agonist treatments with methadone, are generally unavailable in these settings. We used a unique opportunity where CDDCs coexisted with voluntary drug treatment centres (VTCs) providing methadone in Malaysia to compare the timing and occurrence of opioid relapse (measured using urine drug testing) in individuals transitioning from CDDCs versus methadone maintenance in VTCs. METHODS: We did a parallel, two-arm, prospective observational study of opioid-dependent individuals aged 18 years and older who were treated in Malaysia in the Klang Valley in two settings: CDDCs and VTCs. We used sequential sampling to recruit individuals. Assessed individuals in CDDCs were required to participate in services such as counselling sessions and manual labour. Assessed individuals in VTCs could voluntarily access many of the components available in CDDCs, in addition to methadone therapy. We undertook urinary drug tests and behavioural interviews to assess individuals at baseline and at 1, 3, 6, 9, and 12 months post-release. The primary outcome was time to opioid relapse post-release in the community confirmed by urinary drug testing in individuals who had undergone baseline interviewing and at least one urine drug test (our analytic sample). Relapse rates between the groups were compared using time-to-event methods. This study is registered at ClinicalTrials.gov (NCT02698098). FINDINGS: Between July 17, 2012, and August 21, 2014, we screened 168 CDDC attendees and 113 VTC inpatients; of these, 89 from CDDCs and 95 from VTCs were included in our analytic sample. The baseline characteristics of the two groups were similar. In unadjusted analyses, CDDC participants had significantly more rapid relapse to opioid use post-release compared with VTC participants (median time to relapse 31 days [IQR 26-32] vs 352 days [256-unestimable], log rank test, p<0.0001). VTC participants had an 84% (95% CI 75-90) decreased risk of opioid relapse after adjustment for control variables and inverse propensity of treatment weights. Time-varying effect modelling revealed the largest hazard ratio reduction, at 91% (95% CI 83-96), occurs during the first 50 days in the community. INTERPRETATION: Opioid-dependent individuals in CDDCs are significantly more likely to relapse to opioid use after release, and sooner, than those treated with evidence-based treatments such as methadone, suggesting that CDDCs have no role in the treatment of opioid-use disorders. FUNDING: The World Bank Group, Doris Duke Charitable Foundation, National Institute on Drug Abuse, Australian National Health & Medical Research Council, National Institute of Mental Health, and the University of Malaya-Malaysian Ministry of Higher Education High Impact Research Grant. PMID- 27964871 TI - Differential effects of cannabis dependence on cortical inhibition in patients with schizophrenia and non-psychiatric controls. AB - BACKGROUND: Cannabis is the most commonly used illicit substance among patients with schizophrenia. Cannabis exacerbates psychotic symptoms and leads to poor functional outcomes. Dysfunctional cortical inhibition has been implicated in the pathophysiology of schizophrenia; however, the effects of cannabis on this mechanism have been relatively unexamined. The goal of this study was to index cortical inhibition from the motor cortex among 4 groups: schizophrenia patients and non-psychiatric controls dependent on cannabis as well as cannabis-free schizophrenia patients and non-psychiatric controls. METHODS: In this cross sectional study, GABA-mediated cortical inhibition was index with single- and paired-pulse transcranial magnetic stimulation (TMS) paradigms to the left motor cortex in 12 cannabis dependent and 11 cannabis-free schizophrenia patients, and in 10 cannabis dependent and 13 cannabis-free controls. RESULTS: Cannabis dependent patients with schizophrenia displayed greater short-interval cortical inhibition (SICI) compared to cannabis-free schizophrenia patients (p = 0.029), while cannabis-dependent controls displayed reduced SICI compared to cannabis free controls (p = 0.004). SICI did not differ between cannabis dependent patients and cannabis-free controls, or between dependent schizophrenia patients compared to dependent controls. No significant differences were found for long interval cortical inhibition (LICI) or intra-cortical facilitation (ICF) receptor function, suggesting a selective effect on SICI. CONCLUSION: These findings suggest that cannabis dependence may have selective and differing effects on SICI in schizophrenia patients compared to controls, which may provide insight into the pathophysiology of co-morbid cannabis dependence in schizophrenia. PMID- 27964872 TI - Potential beneficial effects of high frequency rTMS to enhance visual function in bilateral visual cortex stroke: Case report. PMID- 27964873 TI - CT image quality assessment by a Channelized Hotelling Observer (CHO): Application to protocol optimization. AB - In this work we investigate the feasibility of employing a Channelized Hotelling model Observer (CHO) in a CT protocol optimization program with the aim at assuring that the scanners are working at their own best with regard to the quality of images and patient exposure. Although the benefit of using model observers in the clinical protocol optimization is evident, in the practice it is still to be investigated what are the pitfalls associated with this method. With this concern we focused on a clinical protocol for oncology of the abdomen. For the implementation of CHO, we designed a new phantom with the aim of minimizing the number of acquired images. After tuning the model according to a restricted data set, we applied it to the evaluation of a large data set of images obtained with different reconstruction algorithms and acquired on different scanners. Results were very encouraging about the usefulness of CHO for the mentioned purposes. For the first time, at our knowledge, the applicability of CHO was demonstrated for images reconstructed with both filtered back projection (FBP) and iterative (IR) algorithms on the same scanner as well as for images from different scanners, though produced by the same manufacturer. Instead it turned out that CHO was not applicable for the same purposes over images from another manufacturer. PMID- 27964874 TI - Differences in fatty degeneration of rotator cuff muscles at different sites, as quantified by T2 mapping. AB - BACKGROUND: Fatty degeneration of the cuff muscles is usually evaluated at the Y view in oblique sagittal images. It was recently proposed that muscle shift after repair may influence the fatty degeneration values, and the evaluation of the muscles at a more medial site was recommended. However, the differences in muscle quality in accord with measurement sites have been unclear. Here we evaluated differences in fatty degeneration of the rotator cuff muscles measured quantitatively at different sites, using T2 mapping. METHODS: We assessed 702 shoulders of 675 patients (335 males, 340 females; mean age, 62 years) who underwent MRI including T2 mapping. There were 345 shoulders without rotator cuff tears and 357 shoulders with tears: partial tear = 103 shoulders; small = 63; medium = 94; large = 71; massive = 26. T2 values of the supraspinatus and infraspinatus muscles were measured on the Y-view and on the image that was 15 mm medial to the Y-view. RESULTS: The T2 values at the medial site increased with the tear extent, as did those on the Y-view. There were no significant differences in supraspinatus T2 values between those on the Y-view and at the medial site in all tear size groups except medium and large tears (p = 0.008 and p < 0.001, respectively). There were also no significant differences in infraspinatus T2 values between the two sites in all tear size groups except large tears (p = 0.002). However, the differences were relatively small (2.4-5.6 ms), which were within the standard deviations of the measurements. CONCLUSIONS: The T2 values of the supraspinatus and infraspinatus muscles on the Y-view and at 15 mm medial to it were almost identical, with the exception of small differences in the case of larger tears. PMID- 27964875 TI - Characteristics of spinopelvic alignment in Parkinson's disease: Comparison with adult spinal deformity. AB - PURPOSE: The characteristics and pathogenesis of spinopelvic alignment in Parkinsons's disease (PD) patients-including differences compared to non-PD subjects and their relationships with the severity of PD-have not been clarified. The aim of this study was to investigate the characteristics of spinopelvic alignment in patients with PD. METHODS: Forty-eight PD patients complaining of chronic low back pain were included (PD group). The PD condition, determined using the Hoehn and Yahr (H&Y) stage and Unified Parkinson Disease Rating Scale (UPDRS) score; radiographic spinopelvic alignment; lumbar range of motion (ROM); and low back pain-related quality of life assessments were evaluated. Fifty age- and sex-matched patients with adult spinal deformities were included as controls (ASD group). RESULTS: The spinopelvic alignments of the PD/ASD groups demonstrated sagittal vertical axes of 120.9/106.3 mm and pelvic incidences of 49.7/52.9 degrees , with no significant differences. Conversely, there were significant differences in the thoracic kyphosis (TK; 27.6/16.7 degrees ), lumbar lordosis (-22.7/-7.9 degrees ), and pelvic tilt (25.3/34.4 degrees ) (all, p < 0.05). With regard to correlations with the PD condition, the H&Y stage demonstrated significant correlations with the sagittal vertical axis, thoracolumbar kyphosis, and lumbar ROM (all, p < 0.05), and the UPDRS score tended to correlate with the TK and thoracolumbar kyphosis (both, p < 0.01). CONCLUSION: Characteristic spinal conditions in PD exist, with progressed PD condition causing stooped posture with increased thoracic or thoracolumbar kyphosis and decreased lumbar ROM; moreover, global sagittal malalignment progresses without sufficient compensatory mechanisms such as loss of TK and pelvic retroversion. PMID- 27964877 TI - Corrigendum to "Calcipotriol and betamethasone dipropionate exert additive inhibitory effects on the cytokine expression of inflammatory dendritic cell-Th17 cell axis in psoriasis" [J. Dermatol. Sci. 81 (2016) 153-164]. PMID- 27964876 TI - A Calibrated Method of Massage Therapy Decreases Systolic Blood Pressure Concomitant With Changes in Heart Rate Variability in Male Rats. AB - OBJECTIVE: The purpose of this study was to develop a method for applying calibrated manual massage pressures by using commonly available, inexpensive sphygmomanometer parts and validate the use of this approach as a quantitative method of applying massage therapy to rodents. METHODS: Massage pressures were monitored by using a modified neonatal blood pressure (BP) cuff attached to an aneroid gauge. Lightly anesthetized rats were stroked on the ventral abdomen for 5 minutes at pressures of 20 mm Hg and 40 mm Hg. Blood pressure was monitored noninvasively for 20 minutes following massage therapy at 5-minute intervals. Interexaminer reliability was assessed by applying 20 mm Hg and 40 mm Hg pressures to a digital scale in the presence or absence of the pressure gauge. RESULTS: With the use of this method, we observed good interexaminer reliability, with intraclass coefficients of 0.989 versus 0.624 in blinded controls. In Long Evans rats, systolic BP dropped by an average of 9.86% +/- 0.27% following application of 40 mm Hg massage pressure. Similar effects were seen following 20 mm Hg pressure (6.52% +/- 1.7%), although latency to effect was greater than at 40 mm Hg. Sprague-Dawley rats behaved similarly to Long-Evans rats. Low frequency/high-frequency ratio, a widely-used index of autonomic tone in cardiovascular regulation, showed a significant increase within 5 minutes after 40 mm Hg massage pressure was applied. CONCLUSIONS: The calibrated massage method was shown to be a reproducible method for applying massage pressures in rodents and lowering BP. PMID- 27964878 TI - Changes in T cell and B cell composition in discoid lupus erythematosus skin at different stages. PMID- 27964880 TI - Role of GPx4 in human vascular endothelial cells, and the compensatory activity of brown rice on GPx4 ablation condition. AB - Oxidative stress is implicated in the pathologies of vascular endothelial cells. However, the importance of specific antioxidant enzymes in vascular endothelial cells is not fully understood. The purpose of this study was to elucidate the importance of Glutathione peroxidase 4 (GPx4), and the involvement of ferroptosis on cell death induced by GPx4 loss in human vascular endothelial cells. In addition, we examined the compensatory activity of brown rice on GPx4 ablation condition. Human umbilical vein endothelial cells were transfected with GPx4 or scramble control siRNA. GPx4 knockdown caused the increase in the levels of lipid oxidation, and induced cytotoxicity. On the other hand, alpha-tocopherol (vitamin E) and extract of brown rice, ameliorated lipid peroxidation, cytotoxicity, and delay of proliferation induced by GPx4 knockdown. Furthermore, ferrostatin-1, inhibitor of ferroptosis, also prevented cytotoxicity and delay of proliferation. In conclusion, our data demonstrated that GPx4 is an essential antioxidant enzyme for protecting lipid peroxidation, and is a regulator of ferroptosis in vascular endothelial cells. Furthermore, vitamin E rich food, such as brown rice, can compensate for GPx4 loss by protecting cells against lipid peroxidation. PMID- 27964879 TI - Activation of Langerhans cells promotes the inflammation in imiquimod-induced psoriasis-like dermatitis. AB - BACKGROUND: Langerhans cells (LCs) are epidermis-resident dendritic cells that sense and mediate stimuli from skin and outside world, and participate in various skin diseases, playing either pro-inflammatory or regulatory roles. However, the exact function of LCs in the pathogenesis of psoriasis remains unclear, and the conclusions of previous studies are controversial. OBJECTIVES: To explore the role of LCs in mouse model of imiquimod (IMQ)-induced psoriasis-like dermatitis using langerin-diphtheria toxin A (DTA) mice that are constitutively deficient in LCs. METHODS: IMQ (Aldara) was painted on the skin of mice to produce psoriasis like dermatitis, and inflammation was evaluated by gross ear thickness, histopathology, flow cytometry and cytokine production. Bone marrow transplantation and fluorescein isothiocyanate tracing were applied to access the migration of LCs. RESULTS: The severity of IMQ-induced dermatitis in langerin-DTA mice was significantly lower than that of wild-type mice, as evidenced by decreased level of ear thickness, inflammatory cell infiltration (gammadelta T cells and neutrophils) and inflammatory cytokine expression (IL-17, IL-22, IL-23 and tumor necrosis factor-alpha). After application with IMQ, LCs expanded in epidermis and showed increased expression of CD80 and CD86, and migrated to draining lymph node within 48h. LCs in the lymph node 48h after application with IMQ expressed increased level of CD80, CD86, CD40 and CC chemokine receptor 7. CONCLUSION: LCs were activated upon application with IMQ, and promoted the inflammatory responses in psoriasis-like dermatitis. PMID- 27964881 TI - Bivalent SIRT1 inhibitors. AB - In the current study, bivalent compounds 1-17 constructed by covalently linking the E-amino group of lysine in a tripeptidic scaffold to a functionality via a linker were prepared and examined for their inhibitory potencies against SIRT1, a prototypical member of the beta-nicotinamide adenine dinucleotide (beta-NAD+) dependent sirtuin family of protein Nepsilon-acyl-lysine deacylases. A few of them were found to be stronger SIRT1 inhibitors than the NE-acetyl-lysine containing monovalent counterparts 18 and 19. As exemplified with compounds 6 and 18, a bivalent SIRT1 inhibitor could exhibit a greater degree of inhibitory selectivity among SIRT1/2/3 than the corresponding monovalent counterpart. This study has laid a foundation for the future development of superior bivalent inhibitors against the (patho)physiologically and therapeutically important sirtuin family of deacylase enzymes. PMID- 27964882 TI - Identification and validation of small molecule modulators of the NusB-NusE interaction. AB - Formation of highly possessive antitermination complexes is crucial for the efficient transcription of stable RNA in all bacteria. A key step in the formation of these complexes is the protein-protein interaction (PPI) between N utilisation substances (Nus) B and E and thus this PPI offers a novel target for a new antibiotic class. A pharmacophore developed via a secondary structure epitope approach was utilised to perform an in silico screen of the mini Maybridge library (56,000 compounds) which identified 25 hits of which five compounds were synthetically tractable leads. Here we report the synthesis of these five leads and their biological evaluation as potential inhibitors of the NusB-NusE PPI. Two chemically diverse scaffolds were identified to be low micro molar potent PPI inhibitors, with compound (4,6-bis(2',4',3.4 tetramethoxyphenyl))pyrimidine-2-sulphonamido-N-4-acetamide 1 and N,N'-[1,4 butanediylbis(oxy-4,1-phenylene)]bis(N-ethyl)urea 3 exhibiting IC50 values of 6.1MUM and 19.8MUM, respectively. These inhibitors were also shown to be moderate inhibitors of Gram-positive Bacillus subtilis and Gram-negative Escherichia coli growth. PMID- 27964883 TI - Novel benzothiazine-piperazine derivatives by peptide-coupling as potential anti proliferative agents. AB - In an attempt to develop potential and selective anti-proliferative agents, a series of novel benzothiazine-piperazine derivatives 8a-i and 10a-g were synthesized by coupling of 2H-1,4-benzothiazin-3(4H)-one with various amines 7a-i and 9a-g in excellent yields and evaluated for their in vitro anti-proliferative activity against four cancer cell lines, HeLa (cervical), MIAPACA (pancreatic), MDA-MB-231 (breast) and IMR32 (neuroblastoma). In vitro inhibitory activity indicated that compounds 8a, 8d, 8g, 10a, 10b, 10e, 10f were found to be good anti-proliferative agents. Among them the derivatives 8g, 10e and 10f were found to be the most active members exhibiting remarkable growth inhibitory activity. Molecular docking was undertaken to investigate the probable binding mode and key active site interactions in HDAC8 and EHMT2 proteins. The docking results are complementary to the experimental results. PMID- 27964884 TI - Abridged geriatric assessment is a better predictor of overall survival than the Karnofsky Performance Scale and Physical Performance Test in elderly patients with cancer. AB - OBJECTIVES: Comprehensive geriatric assessment (CGA) is a complex and interdisciplinary approach to evaluate the health status of elderly patients. The Karnofsky Performance Scale (KPS) and Physical Performance Test (PPT) are less time-consuming tools that measure functional status. This study was designed to assess and compare abridged geriatric assessment (GA), KPS and PPT as predictive tools of mortality in elderly patients with cancer. MATERIALS AND METHODS: This prospective interventional study included all individuals aged >70years who were diagnosed with cancer during the study period. Subjects were interviewed directly using a procedure that included a clinical test and a questionnaire composed of the KPS, PPT and abridged GCA. Overall survival (OS) was the primary endpoint. The log rank test was used to compare survival curves, and Cox's regression model (forward procedure) was used for multivariate survival analysis. RESULTS: One hundred patients were included in this study. Abridged GA was the only tool found to predict mortality [median OS for unfit patients (at least two impairments) 467days vs 1030days for fit patients; p=0.04]. Patients defined as fit by mean PPT score (>20) had worse median OS (560 vs 721days); however, this difference was not significant (p=0.488 on log rank). Although median OS did not differ significantly between patients with low (<=80) and high (>80) KPS scores (467 and 795days, respectively; p=0.09), survival curves diverged after nearly 120days of follow-up. Visual and hearing impairments were the only components of abridged GA of prognostic value. CONCLUSION: Neither KPS nor PPT were shown to predict mortality in elderly patients with cancer whereas abridged GA was predictive. This study suggests a possible role for visual and hearing assessment as screening for patients requiring CGA. PMID- 27964885 TI - Membrane protein trafficking in Drosophila photoreceptor cells. AB - Membrane protein trafficking occurs throughout the lifetime of neurons and includes the initial protein synthesis and anterograde transport to the plasma membrane as well as internalization, degradation, and recycling of plasma membrane proteins. Defects in protein trafficking can result in neuronal degeneration and underlie blinding diseases such as retinitis pigmentosa as well as other neuronal disorders. Drosophila photoreceptor cells have emerged as a model system for identifying the components and mechanisms involved in membrane protein trafficking in neurons. Here we summarize the current knowledge about trafficking of three Drosophila phototransduction proteins, the visual pigment rhodopsin and the two light-activated ion channels TRP (transient receptor potential) and TRPL (TRP-like). Despite some common requirements shared by rhodopsin and TRP, details in the trafficking of these proteins differ considerably, suggesting the existence of several trafficking pathways for these photoreceptor proteins. PMID- 27964886 TI - Implementation of a vaccine screening program at an independent community pharmacy. AB - OBJECTIVES: To implement a comprehensive vaccine screening program and to identify best practices in workflow for a vaccine screening program. SETTING: Five independent community pharmacy locations with a common owner. PRACTICE DESCRIPTION: Moose Pharmacy is an independent family owned and operated pharmacy in rural North Carolina. Moose Pharmacy has 5 dispensing pharmacy locations that fill from 750 to 2800 prescriptions weekly. Each pharmacy regularly uses clinical pharmacists and pharmacy residents to provide comprehensive patient care. PRACTICE INNOVATION: A vaccine screening tool and documentation form were developed by the authors based on recommendations from the Centers for Disease Control and Prevention for immunizations that may be pharmacist administered by protocol in North Carolina. INTERVENTIONS: A pharmacy team member used the screening tool to identify vaccination opportunities in the patient population. Patients 18 years of age or older who entered the pharmacy workflow process were eligible for screening. EVALUATION: If pharmacy staff identified needed vaccinations for a patient, a pharmacist evaluated the screening and recommended immunization(s) to the patient. If the recommendation was accepted, the vaccine was administered. If the patient declined vaccination, a brief reason was designated from a predefined selection of choices. RESULTS: During the 30-day study period, 631 screenings were performed. Pharmacy technicians and pharmacists performed 95.4% and 4.6% of screenings, respectively. Of completed screenings, 81.5% were completed at data entry, 13.9% at fill station, 4.1% at prescription verification, and 0.5% during a clinical consultation. As a result of this study the following vaccines were administered: influenza (n = 11), pneumococcal conjugate (n = 5), pneumococcal polysaccharide (n = 1), Tdap (n = 5), and zoster (n = 6). CONCLUSION: A comprehensive vaccine screening tool was successfully used by pharmacy technicians and pharmacists at data entry and fill station during the traditional workflow at an independent community pharmacy. PMID- 27964887 TI - Developing a dashboard for benchmarking the productivity of a medication therapy management program. AB - OBJECTIVES: To describe a method for internal benchmarking of medication therapy management (MTM) pharmacist activities. SETTING: Multisite MTM pharmacist practices within an integrated health care system. PRACTICE DESCRIPTION: MTM pharmacists are located within primary care clinics and provide medication management through collaborative practice. MTM pharmacist activity is grouped into 3 categories: direct patient care, nonvisit patient care, and professional activities. PRACTICE INNOVATION: MTM pharmacist activities were tracked with the use of the computer-based application Pharmacist Ambulatory Resource Management System (PhARMS) over a 12-month period to measure growth during a time of expansion. RESULTS: A total of 81% of MTM pharmacist time was recorded. A total of 1655.1 hours (41%) was nonvisit patient care, 1185.2 hours (29%) was direct patient care, and 1190.4 hours (30%) was professional activities. The number of patient visits per month increased during the study period. There were 1496 direct patient care encounters documented. Of those, 1051 (70.2%) were face-to face visits, 257 (17.2%) were by telephone, and 188 (12.6%) were chart reviews. Nonvisit patient care and professional activities also increased during the period. IMPACT: PhARMS reported MTM pharmacist activities and captured nonvisit patient care work not tracked elsewhere. Internal benchmarking data proved to be useful for justifying increases in MTM pharmacist personnel resources. Reviewing data helped to identify best practices from high-performing sites. Limitations include potential for self-reporting bias and lack of patient outcomes data. CONCLUSION: Implementing PhARMS facilitated internal benchmarking of patient care and nonpatient care activities in a regional MTM program. PMID- 27964888 TI - A consistent professional brand for pharmacy-the need and a path forward. AB - OBJECTIVE: The authors draw on their broad experiences in the profession to put forth their assessment of the critical need for all elements of the pharmacy profession to agree upon its core services, and to deliver those services in all pharmacies. And also the need to promote the value of those services to patients, payers, and other providers. SUMMARY: Since the advent of pharmaceutical care, the profession has changed its curricula and its regulations to reflect the value of direct patient care. For many reasons, the practice has not been unified in delivering these services-lack of definition of what constitutes the service, principally. This has led to the "tower of babel" that exists because of the many names given to these patient-care services by various professional organizations, colleges, payers, and government agencies. Lack of inclusion in benefit design with value-based compensation is also recognized as an important barrier for a pharmacist wishing to provide direct patient-care services. CONCLUSION: The authors believe this issue to be critical for the profession, and appeal to JCPP and its member organizations to provide leadership to the various pharmacy associations and colleges to put immediate energy and resources into the definitions, labels, and branding of pharmacy practice. This leadership is essential if the profession's organizations and colleges are to promote the whole of practice and payment for the entirety of services pharmacists provide. PMID- 27964889 TI - Letter to the editor: A retrospective study of EGF and ofloxacin drops in the healing of human large traumatic eardrum perforation. PMID- 27964890 TI - Chemoenzymatic synthesis of fluorogenic phospholipids and evaluation in assays of phospholipases A, C and D. AB - Phospholipases are ubiquitous in nature and the target of significant research aiming at both their physiological roles and technical applications in e.g. the food industry. In the search for sensitive and selective phospholipase assays, we have focused on synthetic FRET (Forster resonance energy transfer) substrates. This has led to the development of a facile, easily scalable and low cost synthesis of fluorogenic phospholipids featuring the dansyl/dabcyl fluorophore/quencher-pair on the fatty acid omega-position and on the phosphatidylethanolamine head group, respectively. Hence, the two substrates lyso (dansyl-FA)-GPE-dabcyl (6) and (dansyl-FA)2-GPE-dabcyl (7) were synthesized by a chemoenzymatic strategy, in which preparation of (6) further included a novel selective enzymatic esterification step. As proof of concept, activity of a handful of phospholipases, one from each of the PLA1, PLA2, PLC and PLD classes, were assayed using substrates (6) and (7), and the kinetic parameter kcat/KM was determined. The PLA1 (Lecitase UltraTM) was found to be highly active on both substrates, whereas the PLD (from white cabbage) had no activity, presumably due to steric effects associated with the dabcyl-functionalization of the head group. It was further substantiated that the substrates are specific towards phospholipase activity as the tested lipase (LipolaseTM) showed close to zero activity. PMID- 27964891 TI - Formation of hybrid bilayers on silanized thin-film Ti electrode. AB - Phospholipid bilayer membranes are essential elements of living organisms as they form boundaries between the intracellular cytoplasm and the extracellular environment, as well as organelles. In this work we report on our attempts to assemble artificial phospholipid bilayer model membranes on Ti surface. To provide hydrophobic cushion for phospholipids, the surface of a thin-film Ti electrode was initially functionalized with trichloro(octadecyl)silane (OTS). Increased hydrophobicity of the solid support allowed vesicle fusion and the formation of a hybrid 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer, as probed by the electrochemical impedance spectroscopy (EIS), contact angle measurements (CA) also by the Fourier transform-infrared (FT-IR) spectroscopy, spectroscopic ellipsometry (SE) and atomic force microscopy (AFM). Our study demonstrates the applicability of thin-film Ti electrodes for the formation of hybrid bilayer membranes. These membranes allow functional reconstitution of the pore-forming toxins and provide a bioanalytical platform for the detection of the activity of the cholesterol-dependent cytolysins. PMID- 27964893 TI - Dermatological cancer screening: Evaluation of a new community pharmacy service. AB - BACKGROUND: Skin cancer accounts for one third of all cancers. Prognosis is inversely related to identification stage. OBJECTIVES: To describe a novel service, mole scans, performed in community pharmacy, the findings from the first 3.5 years it was in place, and to explore patient acceptability of the service. METHODS: Norwegian Boots' pharmacies offer a mole scanning service in cooperation with ScreenCancer. Scans are undertaken within pharmacy consultation rooms. Image interpretation is undertaken remotely by a specialist. Number and result of scans performed from 2010 to 2014 are reported. A satisfaction questionnaire was returned by 10% of participants. RESULTS: A total of 25836 scans were performed on 15777 individuals. Of these, 83.6% had normal scans, 1% had melanoma, and 15.4% had another skin condition. In 2014 the service identified 4.1% of melanoma cases registered in the Norwegian Cancer Registry. Most responders (88%) would use a similar service again. Nearly all (99%) felt the pharmacy was a suitable venue, and 95% would recommend the service to others. In total, 99% of respondents scored their overall satisfaction as "good" or higher. CONCLUSIONS: This approach was acceptable among participants who provided feedback. Providing mole scanning through pharmacies enables individuals to obtain a rapid check of moles causing concern, in an acceptable environment with a high level of satisfaction. PMID- 27964892 TI - Prognostic Value of Baseline Neutrophil-to-Lymphocyte Ratio in Metastatic Urothelial Carcinoma Patients Treated With First-line Chemotherapy: A Large Multicenter Study. AB - BACKGROUND: A high neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation and is associated with poor survival in localized or metastatic cancer. This study assessed the prognostic value of NLR after first-line chemotherapy (CT) in patients with metastatic urothelial carcinoma (mUC). PATIENTS AND METHODS: Two hundred eighty consecutive patients treated with first line platinum-based CT at 4 centers in France and Turkey between 2002 and 2014 were included. The association of NLR and Memorial Sloan Kettering Cancer Center (MSKCC) scores with overall survival (OS) and progression-free survival (PFS) was determined by univariate Cox models. RESULTS: Median OS was 10.6 months (follow up, 42.8 months). In univariate analysis, high NLR was associated with worse OS (hazard ratio [HR] for death = 1.36; 95% confidence interval [CI], 1.23-1.51; P < .0001); the result was similar after adjustment for MSKCC prognostic group (HR = 1.28; 95% CI, 1.14-1.43; P < .0001). Low NLR was associated with longer PFS (HR = 1.18; 95% CI, 1.05-1.33; P < .005). When NLR was divided in terciles, OS in the lowest tercile (NLR 0.6-2.78) was 12.4 to 16.6 (median, 13.4) months versus 5.3 to 9.9 (median, 7.3) months in the highest tercile (NLR 4.70-48.9) (P = .001). Similar trends were observed for PFS (5.6-8.9 [median, 7.6] months vs. 3.1-5.7 [median, 4.8] months) in patients with NLR values in the lowest versus highest tercile, respectively (P = .021). CONCLUSION: High pre-CT NLR was an independent prognostic factor for poor OS and PFS in mUC patients. The prognostic value of NLR, as either a continuous or categorical variable, compared favorably with MSKCC score but was easier to assess and monitor. PMID- 27964894 TI - Corneal biomechanical metrics of healthy Chinese adults using Corvis ST. AB - PURPOSE: To evaluate the corneal biomechanical metrics by Corvis ST (CST) in healthy Chinese adults. METHODS: This cross-sectional study used CST to measure intraocular pressure (IOP), central corneal thickness (CCT), and corneal biomechanical parameters, including time, velocity, length, deformation amplitude at the first (A1T, A1V, A1L, A1DA) and second applanation (A2T, A2V, A2L, A2DA), time, radius curvature and deformation amplitude at highest concavity (HCT, HCR, HCDA) and peak distance (PD). RESULTS: A total of 158 healthy adults (158 eyes) were included in the final analysis. No significant differences were observed between male and female for any biomechanical parameters (All P>0.05). With increasing age, a significant trend of increase was detected among A1V, A1DA, A2T, A2DA, and HCDA (All P<0.05). The A1T decreased significantly with increasing age (P<0.001). The cluster analysis using Pearson coefficient divided the CST parameters into 5 sub-clusters, where IOP, A1T, A2V had strongest relation. The multivariable linear regression analyses demonstrated that age was independently associated with A1DA, A2DA, and HCDA. The IOP was positively associated with A1T, A2V, and HCR, while negatively with A1V, A2T, HCT, PD, and HCDA. The CCT was positively correlated with A1L, A1DA, A2L, A2V, or HCR. CONCLUSIONS: CST provided informative corneal biomechanical measurements in this Chinese population. Most corneal biomechanical parameters were associated with IOP, and several parameters were influenced by age or CCT, suggesting adjustment of these factors was needed before interpretations of CST outputs. PMID- 27964895 TI - Spin-locking of half-integer quadrupolar nuclei in NMR of solids: The far off resonance case. AB - Spin-locking of spin I=3/2 and I=5/2 nuclei in the presence of large resonance offsets has been studied using both approximate and exact theoretical approaches and, in the case of I=3/2, experimentally. We show the variety of coherences and population states produced in a far off-resonance spin-locking NMR experiment (one consisting solely of a spin-locking pulse) and how these vary with the radiofrequency field strength and offset frequency. Under magic angle spinning (MAS) conditions and in the "adiabatic limit", these spin-locked states acquire a time dependence. We discuss the rotor-driven interconversion of the spin-locked states, using an exact density matrix approach to confirm the results of the approximate model. Using conventional and multiple-quantum filtered spin-locking 23Na (I=3/2) NMR experiments under both static and MAS conditions, we confirm the results of the theoretical calculations, demonstrating the applicability of the approximate theoretical model to the far off-resonance case. This simplified model includes only the effects of the initial rapid dephasing of coherences that occurs at the start of the spin-locking period and its success in reproducing both experimental and exact simulation data indicates that it is this dephasing that is the dominant phenomenon in NMR spin-locking of quadrupolar nuclei, as we have previously found for the on-resonance and near-resonance cases. Potentially, far off-resonance spin-locking of quadrupolar nuclei could be of interest in experiments such as cross polarisation as a consequence of the spin-locking pulse being applied to a better defined initial state (the thermal equilibrium bulk magnetisation aligned along the z-axis) than can be created in a powdered solid with a selective radiofrequency pulse, where the effect of the pulse depends on the orientation of the individual crystallites. PMID- 27964896 TI - Assessment of relationship on excess arsenic intake from drinking water and cognitive impairment in adults and elders in arsenicosis areas. AB - In this study, the relationships between high water arsenic exposure and cognitive impairment were investigated. A total of 483 residents aged 40 or older were randomly recruited and were divided into four groups according to the concentrations of arsenic in their water. Consumption levels (x-+/-sd) of drinking water arsenic for normal, mild, moderate, and high exposure groups were 4+/-2MUg/L, 25+/-11MUg/L, 73+/-15MUg/L, and 183+/-88MUg/L, respectively. The average scores (x-+/-sd) of the Chinese version Mini-Mental State Examination (MMSE) for females in each group were 21.49+/-3.14, 19.04+/-5.87, 16.18+/-8.14, and 15.82+/-7.78, and the average scores (x-+/-sd) for males were 24.50+/-3.97, 23.16+/-4.45, 21.00+/-6.57, and 18.92+/-7.99, respectively. Significant differences among the average scores of MMSE for males or females in the four groups were found (p<0.05). The prevalence of cognitive impairment for females in each group was 10.86%, 29.63%, 53.48%, and 55.29%, and the prevalence of cognitive impairment for males was 10.71%, 12.00%, 35.71%, and 50.89%, respectively. Significant differences between all groups were observed (p<0.05). In the multivariable regress model, high water was closely associated with the MMSE score (Standardized Coefficient=-0.021) and cognitive impairment (arsenic ?100 MUg/L PR4/1=4.01). The findings of our research suggested a significant positive relationship between arsenic exposure from drinking water and cognitive impairment. PMID- 27964897 TI - Algal toxicity of the alternative disinfectants performic acid (PFA), peracetic acid (PAA), chlorine dioxide (ClO2) and their by-products hydrogen peroxide (H2O2) and chlorite (ClO2-). AB - Environmental effect evaluation of disinfection of combined sewer overflow events with alternative chemical disinfectants requires that the environmental toxicity of the disinfectants and the main by-products of their use are known. Many disinfectants degrade quickly in water which should be included in the evaluation of both their toxicity as determined in standardized tests and their possible negative effect in the water environment. Here we evaluated according to the standardized ISO 8692 test the toxicity towards the green microalgae, Pseudokirchneriella subcapitata, of three disinfectants: performic acid (PFA), peracetic acid (PAA) and chlorine dioxide (ClO2) as well as two by-products of their use: hydrogen peroxide (H2O2) and chlorite. All of the five chemicals investigated showed clear toxicity to the algae with well-defined dose response curves. The EC50 values ranged from 0.16 to 2.9mg/L based on nominal concentrations leading to the labeling of the chemicals as either toxic or very toxic. The five investigated chemicals decreased in toxicity in the order chlorine dioxide, performic acid, peracetic acid, chlorite and hydrogen peroxide. The stability of the chemicals increased in the same order as the toxicity decrease. This indicates that even though ClO2 has the highest environmental hazard potential, it may still be suitable as an alternative disinfectant due to its rapid degradation in water. PMID- 27964899 TI - Reversed Palmaris Longus Muscle Causing Volar Forearm Pain and Ulnar Nerve Paresthesia. AB - A case of volar forearm pain associated with ulnar nerve paresthesia caused by a reversed palmaris longus muscle is described. The patient, an otherwise healthy 46-year-old male laborer, presented after a previous unsuccessful forearm fasciotomy for complaints of exercise exacerbated pain affecting the volar forearm associated with paresthesia in the ulnar nerve distribution. A second decompressive fasciotomy was performed revealing an anomalous "reversed" palmaris longus, with the muscle belly located distally. Resection of the anomalous muscle was performed with full relief of pain and sensory symptoms. PMID- 27964898 TI - Sorafenib for the Treatment of Advanced Hepatocellular Cancer - a UK Audit. AB - AIMS: Sorafenib is the current standard treatment for advanced hepatocellular carcinoma. We carried out a national audit of UK patients treated with sorafenib as standard-of-care and those treated with systemic therapy in first-line trials. MATERIALS AND METHODS: Sorafenib-treated and trial-treated patients were identified via the Cancer Drugs Fund and local databases. Data were collected retrospectively from medical records according to a standard case report form. The primary outcome measure was overall survival, estimated by the Kaplan-Meier method. RESULTS: Data were obtained for 448 sorafenib-treated patients from 15 hospitals. The median age was 68 years (range 17-89) and 75% had performance status <= 1. At baseline, 77% were Child-Pugh A and 16.1% Child-Pugh B; 38% were albumin-bilirubin grade 1 (ALBI-1) and 48% ALBI-2; 23% were Barcelona Clinic Liver Classification B (BCLC-B) and 72% BCLC-C. The median time on sorafenib was 3.6 months, with a mean daily dose of 590 mg. The median overall survival for 448 evaluable sorafenib-treated patients was 8.5 months. There were significant differences in overall survival comparing Child-Pugh A versus Child-Pugh B (9.5 versus 4.6 months), ALBI-1 versus ALBI-2 (12.9 versus 5.9 months) and BCLC-B versus BCLC-C (13.0 versus 8.3 months). For trial-treated patients (n=109), the median overall survival was 8.1 months and this was not significantly different from the sorafenib-treated patients. CONCLUSION: For Child-Pugh A patients with good performance status, survival outcomes were similar to those reported in global randomised controlled trials. Patients with ALBI grade > 1, Child-Pugh B or poor performance status seem to derive limited benefit from sorafenib treatment. PMID- 27964900 TI - Zone II Flexor Tendon Repairs in the United States: Trends in Current Management. AB - PURPOSE: The repair of zone II flexor tendon injuries is an evolving topic in hand surgery with current literature suggesting the use of a 4-strand repair; 3-0 or 4-0 braided, nonabsorbable sutures; and an epitendinous repair. It was hypothesized that variability would exist within the hand surgeon community in treatment of zone II flexor tendon repairs in surgical material used, surgical technique, and postoperative rehabilitation protocol. METHODS: An online single answer multiple-choice survey was distributed to the American Society for Surgery of the Hand members' database. Surgeons were asked questions about demographics, surgical technique, suture type, common complications, postoperative management, and the factor that plays the largest role in guiding their surgical preferences. Responses were compared with current medical evidence. RESULTS: A total of 410 individuals responded to the survey. In regards to technique, the majority of surgeons reported using a 4-strand repair; with 3-0 or 4-0 core braided, nonabsorbable sutures; and performing an epitendinous repair. Only 20% of surgeons surveyed reported ever using wide-awake local anesthesia, no tourniquet and postoperative protocols were split between early active and early passive rehabilitation. Senior surgeons (>= 15 years in practice) were more likely than their colleagues to use a 2-strand repair and a passive rehabilitation protocol. CONCLUSIONS: This study demonstrates that the majority of respondents are performing zone II flexor tendon repairs in accordance with the best currently available evidence, although there is variability with respect to suture material, surgical technique, and rehabilitation protocols. CLINICAL RELEVANCE: There is still a need for high-quality studies on surgical technique and rehabilitation protocols. PMID- 27964901 TI - Magnetic Resonance Imaging to Visualize Disintegration of Oral Formulations. AB - This article demonstrates that magnetic resonance imaging can visualize the disintegration of a variety of paracetamol containing oral formulations in an in vitro setting and in vivo in the human stomach. The different formulations had unique disintegration profiles which could be imaged both in vitro and in vivo. No special formulation approaches or other contrast agents were required. These data demonstrate the potential for further use of magnetic resonance imaging to investigate and understand the disintegration behavior of different formulation types in vivo, and could potentially be used as a teaching tool in pharmaceutical and medical curricula. PMID- 27964902 TI - Optimization of a DPI Inhaler: A Computational Approach. AB - Alternate geometries of a commercial dry powder inhaler (DPI, i.e., Turbuhaler; AstraZeneca, London, UK) are proposed based on the simulation results obtained from a fluid and particle dynamic computational model, previously developed by Milenkovic et al. The alternate DPI geometries are constructed by simple alterations to components of the commercial inhaler device leading to smoother flow patterns in regions where significant particle-wall collisions occur. The modified DPIs are investigated under the same conditions of the original studies of Milenkovic et al. for a wide range of inhalation flow rates (i.e., 30-70 L/min). Based on the computational results in terms of total particle deposition and fine particle fraction, the modified DPIs were improved over the original design of the commercial device. PMID- 27964903 TI - Coronary Catheterization and Percutaneous Interventions After Transcatheter Aortic Valve Implantation. AB - Coronary artery disease (CAD) is often present in patients with severe aortic valve stenosis candidates to transcatheter aortic valve implantation (TAVI). Mild CAD may also worsen and need treatment years after TAVI. The implantation of a transcatheter valve may interfere with the capability of reengaging the coronary arteries. We prospectively assessed the feasibility of performing coronary angiography (CA), fractional flow reserve, and, where indicated, percutaneous coronary intervention after valve implantation in a consecutive series of patients with CAD undergoing TAVI. Valve type and size were decided according to accurate computed tomography scan and angiographic measurement of the aortic root structures. We analyzed 66 consecutive patients undergoing TAVI, 41 with balloon expandable, and 25 with self-expandable transcatheter valves. Right and left coronary catheterization (132 vessels) was successful in all cases except in 1 left coronary artery after a high implantation of a self-expandable valve (unsuccess rate, 1 in 50 vessels). In 6 of 132 vessels (4%), CA was initially nonselective, but after positioning the 0.014" intracoronary guidewire, selective injections were obtained in all these cases. Percutaneous coronary intervention was performed successfully in 19 coronary vessels (17 patients) as indicated by fractional flow reserve measurements. In conclusion, catheterization of the coronary ostia after transfemoral TAVI with balloon or self-expandable valves is safe and feasible in almost all cases. Accurate imaging of the aortic root and procedural planning may help to avoid too high implantation of supra-annular self expandable valves to obviate difficulties in accessing coronary ostia. Use of intracoronary guidewires facilitates selective CA in cases with difficult access. PMID- 27964904 TI - Immediate and 12-Month Outcomes of Ischemic Versus Nonischemic Functional Mitral Regurgitation in Patients Treated With MitraClip (from the 2011 to 2012 Pilot Sentinel Registry of Percutaneous Edge-To-Edge Mitral Valve Repair of the European Society of Cardiology). AB - In literature, there are limited data comparing ischemic mitral regurgitation (I MR) versus nonischemic MR regarding outcomes after percutaneous "edge-to-edge" repair. We aimed to describe the early and 12-month results after MitraClip device implantation regarding the 2 etiologies. From January 2011 to December 2012, the Transcatheter Valve Treatment Sentinel Pilot Registry included 452 patients with MR who underwent MitraClip procedure in 25 centers across Europe. The prevalent etiology was I-MR (235 patients, 52.0%). I-MR group had a significantly higher proportion of men (74.9 vs 59.9%, p <0.001) and surgical risk (logistic EuroSCORE 24.8 +/- 18.2 vs 18.8 +/- 16.3, p <0.001). Acute procedural success was high (96%) and similar between groups (p = 0.48). Patients with I-MR required a higher, albeit not significant, number of clips to reduce MR (p = 0.08). Inhospital mortality was low (2.0%) without significant differences between etiologies. The estimated 1-year mortality and rehospitalization rates were 15.0% and 25.8%, respectively, without significant differences between groups. Paired echocardiographic data showed a persistent improvement of MR at 1 year in both etiologies. Despite a significant overall reverse atrial remodeling after clip, there were no significant changes in left ventricular volumes. In conclusion, this large independent cohort showed that percutaneous "edge-to-edge" therapy was associated with early- and long-term improvement of MR severity and functional condition both in patients with I-MR and nonischemic MR. There were no significant differences between the 2 etiologies regarding survival and freedom from rehospitalization due to heart failure at the 1-year follow-up. PMID- 27964905 TI - ACR appropriateness criteria: Permanent source brachytherapy for prostate cancer. AB - PURPOSE: To provide updated American College of Radiology (ACR) appropriateness criteria for transrectal ultrasound-guided transperineal interstitial permanent source brachytherapy. METHODS AND MATERIALS: The ACR appropriateness criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. RESULTS: Permanent prostate brachytherapy (PPB) is a treatment option for appropriately selected patients with localized prostate cancer with low to very high risk disease. PPB monotherapy remains an appropriate and effective curative treatment for low-risk prostate cancer patients demonstrating excellent long-term cancer control and acceptable morbidity. PPB monotherapy can be considered for select intermediate risk patients with multiparametric MRI useful in evaluation of such patients. High-risk patients treated with PPB should receive supplemental external beam radiotherapy (EBRT) along with androgen deprivation. Similarly, patients with involved pelvic lymph nodes may also be considered for such combined treatment but reported long-term outcomes are limited. Computed tomography-based postimplant dosimetry completed within 60 days of PPB is essential for quality assurance. PPB may be considered for treatment of local recurrence after EBRT but is associated with an increased risk of toxicity. CONCLUSIONS: Updated appropriateness criteria for patient evaluation, selection, treatment, and postimplant dosimetry are given. These criteria are intended to be advisory only with the final responsibility for patient care residing with the treating clinicians. PMID- 27964906 TI - Results of multiparametric transrectal ultrasound-based focal high-dose-rate dose escalation combined with supplementary external beam irradiation in intermediate- and high-risk localized prostate cancer patients. AB - PURPOSE: Clinical results of a biologic information-based focused dose escalation combined with dose de-escalation for the whole organ in external beam radiotherapy + high-dose-rate brachytherapy (HDR-BT) boost application for localized prostate cancer in a consecutively treated patient cohort. METHODS AND MATERIALS: One hundred thirty patients were treated with external beam radiotherapy (50 Gy) complementary to two multiparametric transrectal ultrasound guided 15 Gy HDR-BT fractions. Real-time multiparametric transrectal ultrasound based biologic planning for high-dose-rate boost dose planning used the summation of gray scale and Doppler sonography imaging + biopsy information. Target subvolumes received HDR-BT dose escalation up to 60 Gy/fraction. Dose-volume histogram parameters, organ at risks doses, and toxicity results were investigated. RESULTS: The median followup was 4.3 years, the median age was 68.62 years, and the mean initial prostate-specific antigen was 18.69 ng/mL. Low , intermediate-, and high-risk constituted 69%, 21%, and 10% of the patients, respectively. The mean peripheral dose was 3.9 Gy per fraction. Prostate-specific antigen nadir was in 93% of the patients <=1 ng/mL. Quality parameters were as follows: D90: 6.58 Gy, V100: 30.36%, V150: 9.96%, V200: 3.16%, uD0.1: 7.34 Gy, uD2: 9.34 Gy, rD01: 10.56 Gy, and rD2: 8.32 Gy, respectively. We observed G1, G2, G3 urinary toxicity in 17/130, 11/130, and 2/130 patients, respectively. Rectal toxicity: G1 and G2 occurred in 19/130 and 2/130 patients with mean dose values G1: 8.2 Gy and G2: 8.76 Gy. Analysis of variance test resulted in no correlation between toxicities and any other investigated factors. CONCLUSIONS: Focused extreme dose escalation with low prostate mean peripheral dose results in excellent long-term outcome data and very high focal boost doses and is causing no enhancement in late treatment toxicity. PMID- 27964907 TI - Occurrence of Legionella in UK household showers. AB - Household water systems have been proposed as a source of sporadic, community acquired Legionnaires' disease. Showers represent a frequently used aerosol generating device in the domestic setting yet little is known about the occurrence of Legionella spp. in these systems. This study has investigated the prevalence of Legionella spp. by culture and qPCR in UK household showers. Ninety nine showers from 82 separate properties in the South of England were sampled. Clinically relevant Legionella spp. were isolated by culture in 8% of shower water samples representing 6% of households. Legionella pneumophila sg1 ST59 was isolated from two showers in one property and air sampling demonstrated its presence in the aerosol state. A further 31% of showers were positive by Legionella spp. qPCR. By multi-variable binomial regression modelling Legionella spp. qPCR positivity was associated with the age of the property (p=0.02), the age of the shower (p=0.01) and the frequency of use (p=0.09). The concentration of Legionella spp. detected by qPCR was shown to decrease with increased frequency of use (p=0.04) and more frequent showerhead cleaning (p=0.05). There was no association between Legionella spp. qPCR positivity and the cold water supply or the showerhead material (p=0.65 and p=0.71, respectively). Household showers may be important reservoirs of clinically significant Legionella and should be considered in source investigations. Simple public health advice may help to mitigate the risk of Legionella exposure in the domestic shower environment. PMID- 27964908 TI - Corrigendum to "Urinary biomarkers of exposure to 57 xenobiotics and its association with oxidative stress in a population in Jeddah, Saudi Arabia" [Environ. Res. 150 (2016) 573-581]. PMID- 27964909 TI - An Educational Intervention to Improve Nurses' Understanding of Pain in Children in Western India. AB - Accurate assessment of pain and its management is a challenging aspect of pediatric care. Nurses, usually the primary caregivers, showed inadequate knowledge and restrictive attitudes toward pain assessment. We evaluated an educational intervention to improve nurses' assessment of pain in a teaching hospital in India. A convenient sample of nurses working in the neonatal intensive care unit, pediatric ward, pediatric intensive care unit, and pediatric cardiac intensive care unit were included in the study. Workshops to improve understanding of pain, its assessment, and management strategies were conducted. A modified and consensually validated Knowledge and Attitudes Survey Regarding Pain questionnaire-2008 consisting of 25 true/false questions, eight multiple choice questions, and two case scenarios was administered before, immediately after, and 3 months after the workshops to evaluate impact of the intervention. Eighty-seven nurses participated. Mean (standard deviation) experience was 4.04 (5.9) years. Thirty-seven percent felt that they could assess pain without pain scales. About half (49.4%) of the nurses had not previously heard of pain scales, while 47.1% reported using a pain scale in their routine practice. Significant improvement was observed between pretest and post-test total scores (15.69 [2.94] vs. 17.51 [3.47], p < .001) as well as the pretest and retention score (15.69 [2.94] vs. 19.40 [4.6], p < .001). Albeit the study site and sampling frame may limit the reliability of the findings, the educational intervention was successful, and better retention test scores suggest a cascading effect. Pain assessment and management education of children should be incorporated in the nursing curriculum and should be reinforced in all pediatric units. PMID- 27964910 TI - The Process of Motivating Oneself to Resist Being Controlled by Chronic Pain: A Qualitative Study of Japanese Older People Living in the Community. AB - Perceptions and experiences of chronic pain in older adults have not been fully explored. This study aimed to explore experiences and perceptions of life with chronic pain among older Japanese adults in the community. The grounded theory approach was used to identify a process model of older people's perceptions and experiences of living with chronic pain. Twenty-four people were recruited via snowball sampling. Ten participants had suffered from pain for 30 years or more. Data were collected through semistructured, individual interviews. Responses were transcribed verbatim, coded, and clustered. Categories were integrated using the constant comparison method. A core category-motivating oneself to resist being controlled by chronic pain-emerged from the analysis of experiences among participants with chronic pain. Participants alternated between two phases: losing the self in pain (phase 1) and regaining the self in pain (phase 2). Flare up pain was commonly experienced, and immobility and suffering led older adults to adopt several strategies to live with their pain. In phase 2, older participants adopted several strategies, such as "letting sleeping dogs lie" and "cutting corners." Their perceptions of and behaviors toward pain were often influenced by perceptions of their aging bodies. Nurses need to be aware of these conditions among older people with chronic pain and adjust their activities individually according to patient perceptions of their physical conditions. PMID- 27964911 TI - Acute Pain Characteristics in Patients with and without Chronic Pain following Lower Extremity Injury. AB - Many patients with injuries to lower extremities report chronic pain. High pain intensity at time of admission for injury is a risk factor for chronic pain, but it is not clear whether specific acute pain patterns following injury influence the development of chronic pain. To examine the relationship between the pain trajectory, the mean pain score, and the frequency of pain documentation during the immediate hospitalization following injury, with the report of chronic pain. This was a descriptive, retrospective cohort study of adults admitted with lower extremity fractures to an academic urban trauma center. Participants, 6-45 months postinjury, rated their current pain, worst pain, and average pain over the last 3 months. Pain scores from hospitalization associated with the injury were obtained through a retrospective chart review. The pain trajectory, mean pain score, and frequency of pain documentation was compared between patients with and without chronic pain. A total of 129 patients were enrolled in this study and 78% reported chronic pain at the site of injury. The mean pain score (5.1 vs. 4.2) and first pain score (5.6 vs. 3.4) were higher for patients with chronic pain compared to patients with no chronic pain. Consistent with other studies, high pain intensity at time of injury was associated with chronic pain. The findings contribute valuable information about acute pain characteristics associated with chronic pain and provide insight into the importance of early and adequate acute pain treatment. PMID- 27964912 TI - The Effect of Upper Limb Massage on Infants' Venipuncture Pain. AB - The purpose of the study was to investigate the effect of upper limb massage on relieving pain among infants undergoing venipuncture in Hong Kong. This study was a crossover, double-blind, randomized controlled trial. Eighty infants at the neonatal intensive care unit were randomly assigned to 2 groups in different order to receive interventions. The massage first group (N = 40) received 2 minute massage before venipuncture on the first occasion then received usual care (control) on the second occasion, and vice versa in the massage second group (N = 40). The infants' behavior and physiological responses were recorded on two occasions: (1) right after the intervention and (2) during the first 30 seconds of venipuncture procedure. The mean pain scores (Premature Infant Pain Profile) were significantly lower in infants who received massage (massage first: 6.0 [standard deviation = 3.3]; massage second: 7.30 [standard deviation = 4.4]) versus control (massage first: 12.0 [standard deviation = 4.3]; massage second: 12.7 [standard deviation = 3.1]). The crude and adjusted generalized estimating equations model showed that the infants had significantly lower pain score when receiving massage as compared to receiving the control treatment, and there were no significant time and carryover effects: -6.03 (95% confidence interval: -7.67 to -4.38), p < .001 and -5.96 (95% confidence interval: -7.56 to -4.36), p < .001, respectively. Upper limb massage may be effective in decreasing infants' venipuncture pain perception. PMID- 27964913 TI - Evaluation of the leaching behavior of incineration bottom ash using seawater: A comparison with standard leaching tests. AB - Batch and column tests were conducted on untreated incineration bottom ash (IBA) samples from two incineration plants in Singapore, using seawater as the leachant. The main objective of this study was to investigate the change in the leaching behavior of certain elements (i.e. As, Cd, Cr, Cu, Ni, Pb, Sb, Se and Zn) when IBA comes into contact with seawater. Such an investigation using seawater as leachant was not commonly carried out when investigating leaching behavior in IBA. The leaching tests were then carried out on the same IBA samples using DI water, as a comparison. Lower level of leaching was observed for Pb and Zn when seawater was used as the leachant. Cr and Sb showed significant cumulative release at Liquid-to-Solids (L/S) ratio 5 in the seawater column leaching. The influence of Dissolved Organic Carbon (DOC) on Cu leaching seems to decrease after L/S 2 when using seawater in the column test. Although the leaching behavior of IBA was affected when seawater was used, for the column test, there was no significant difference during the initial release when compared to DI water. The initial L/S fractions collected were important as the low L/S ratios represent the pore water concentration and the maximum output in an actual application. The results from this study would be useful for the future study on using IBA in marine applications. PMID- 27964914 TI - Closed circuit recovery of copper, lead and iron from electronic waste with citrate solutions. AB - An integral closed circuit hydrometallurgical process is presented for base metal recovery from electronic waste. The leaching medium consists of a sodium citrate solution, from which base metals are retrieved by direct electrowinning, and the barren solution is recycled back to the leaching stage. This leaching electrowinning cycle was repeated four times. The redox properties of the fresh citrate solution, as well as the leach liquors, were characterized by cyclic voltammetry to determine adequate conditions for metal reduction, as well as to limit citrate degradation. The leaching efficiency of electronic waste, employing the same solution after four complete cycles was 71, 83 and 94% for copper, iron and lead, respectively, compared to the original leach with fresh citrate solution. PMID- 27964915 TI - Fisher-Wright model with deterministic seed bank and selection. AB - Seed banks are common characteristics to many plant species, which allow storage of genetic diversity in the soil as dormant seeds for various periods of time. We investigate an above-ground population following a Fisher-Wright model with selection coupled with a deterministic seed bank assuming the length of the seed bank is kept constant and the number of seeds is large. To assess the combined impact of seed banks and selection on genetic diversity, we derive a general diffusion model. The applied techniques outline a path of approximating a stochastic delay differential equation by an appropriately rescaled stochastic differential equation. We compute the equilibrium solution of the site-frequency spectrum and derive the times to fixation of an allele with and without selection. Finally, it is demonstrated that seed banks enhance the effect of selection onto the site-frequency spectrum while slowing down the time until the mutation-selection equilibrium is reached. PMID- 27964916 TI - Optimal arterial carbon dioxide tension following cardiac arrest: Let Goldilocks decide? PMID- 27964917 TI - Clinical Significance of Positron Emission Tomography in Subcentimeter Non-Small Cell Lung Cancer. AB - BACKGROUND: This study evaluated the clinical significance of maximum standardized uptake value (SUVmax) on positron emission tomography (PET) in patients with subcentimeter non-small cell lung cancer (NSCLC). METHODS: Between 2008 and 2014, 189 patients were investigated preoperatively by PET for c-N0 subcentimeter NSCLC, and SUVmax was reviewed. Pathologic invasiveness (PI) was defined as having at least one of the following factors: lymphatic invasion, vascular invasion, pleural invasion, or nodal metastasis. Survival rates were calculated by Kaplan-Meier estimation methods using the log-rank test. RESULTS: Mean SUVmax was 1.7 +/- 1.8 (range, 0.6 to 13.0), and the median was 1.0. PI was found in 28 (15%) patients with subcentimeter NSCLC. Multivariate analysis revealed that SUVmax was an independent significant clinical predictor of PI (p = 0.0251) and a prognostic factor of overall survival (OS) (p = 0.0485). A receiver operating characteristics curve elucidated the predictive cutoff value of PI as SUVmax = 2.0. The high-SUVmax group (SUVmax >2.0; n = 42) had significantly more radiologically pure-solid lesions (91% vs 14%; p < 0.0001) and postoperative nodal involvement (12% vs 0%; p < 0.0001) than the low-SUVmax group (SUVmax <=2.0; n = 147). The 5-year lung cancer-specific OS (LCS-OS) elucidated significant difference between the high-SUVmax and low-SUVmax arms of the study (LCS-OS: 92.3% vs 96.9%, respectively; p = 0.0054), and cancer recurrence was found exclusively in pure-solid subcentimeter NSCLC on thin-section computed tomography. In the high-SUVmax arm of the study, lobectomy was associated with better 3-year recurrence-free survival compared with sublobar resection despite the subcentimeter disease (88.3% vs 50.0%; p = 0.0453). CONCLUSIONS: SUVmax on PET reflected tumor invasiveness and had a great impact on the prognosis of subcentimeter NSCLC, especially when a tumor showed a pure-solid appearance on a thin-section computed tomography scan. PMID- 27964918 TI - Optimal Plasma Transfusion in Patients Undergoing Cardiac Operations With Massive Transfusion. AB - BACKGROUND: Observational studies suggest that transfusion of high ratios of fresh frozen plasma (FFP) to red blood cells (RBCs) reduces mortality in severe hemorrhage. There are no studies examining the impact of the FFP to RBC transfusion ratio on mortality in massively transfused patients undergoing cardiac operations. METHODS: A single-center retrospective cohort study was performed over an 8.5-year period. Massive transfusion was defined as at least 8 RBC units administered during the operation. Patients were classified as having received a high FFP/RBC ratio (greater than 1:1), a moderate ratio (between 1:1 and 1:2), or a low ratio (<1:2). Thirty-day survival was compared between groups using Kaplan-Meier analysis, and Cox proportional hazards modeling was used to identify variables associated with 30-day mortality. In-hospital mortality and postoperative morbidities were also compared between groups using regression analyses. RESULTS: Of 7,492 patients undergoing cardiac operations, 452 (6%) were massively transfused. Thirty-day mortality was 25.4% and in-hospital mortality was 30.6%. Patients with a high transfusion ratio had improved 30-day survival when compared with those with a low ratio (hazard ratio [HR] for death, 0.339; p = 0.002). High transfusion ratios were also associated with fewer reoperations for bleeding, less renal failure, more prolonged ventilation, and more atrial fibrillation compared with low ratios. CONCLUSIONS: A high transfusion ratio may improve survival in patients undergoing cardiac operations with massive intraoperative transfusion but may increase the risk for prolonged ventilation and atrial fibrillation. PMID- 27964919 TI - Clinical Outcomes of the David V Valve-Sparing Root Replacement Compared With Bioprosthetic Valve-Conduits for Aortic Root Aneurysms. AB - BACKGROUND: Valve-sparing root replacement (VSRR) is an established therapy for aortic root pathology. Limited insight exists when the results of VSRR are compared with those of conventional root replacement with use of a bioprosthetic composite conduit (BIO). This study compares the operative and midterm results of VSRR and BIO. METHODS: A retrospective review from 2002 to 2015 at a United States academic center identified 282 patients who underwent VSRR and 425 patients who underwent BIO. Propensity-score matching was performed based on 20 preoperative characteristics, and 123 matched pairs were identified. RESULTS: The mean age (VSRR 53.5 +/- 11.1, BIO 53.0 +/- 13.0; p = 0.74) and left ventricular ejection fraction (VSRR 54.5 +/- 9.2%, BIO 54.4 +/- 9.4%; p = 0.99) were equivalent in both groups. The incidence of bicuspid valves (VSRR 26.0%, BIO 27.6%; p = 0.77), Marfan syndrome (VSRR 6.5%, BIO 4.9%; p = 0.58), type A dissection (VSRR 13.0%, BIO 13.0%; p = 0.99), reoperation (VSRR 15.4%, BIO 20.3%; p = 0.32) and arch replacement (VSRR 60.2%, BIO 63.4%; p = 0.60) were similar between the groups. Operative mortality was 5.7% in VSRR and 0.8% in BIO (p = 0.07). There were no significant differences in postoperative renal failure (VSRR 0.8%, BIO 0.0%; p = 0.99) or stroke (VSRR 3.3%, BIO 0.8%; p = 0.37) between the groups. The 7-year survival (VSSR 82.4%, BIO 83.0%; p = 0.53), 7-year freedom from reoperation (VSRR 97.4%, BIO 95.8%; p = 0.48), and 7-year freedom from greater than moderate aortic insufficiency (AI) (VSRR 98.1%, BIO 100.0%; p = 0.47) were similar between groups. CONCLUSIONS: VSRR and BIO result in equivalent operative mortality and morbidity with similar midterm survival and valve durability. VSRR is an effective alternative to BIO for aortic root pathologic conditions; however, careful patient selection is paramount. PMID- 27964920 TI - Intraoperative Near-Infrared Fluorescence Imaging of Thymus in Preclinical Models. AB - BACKGROUND: There are currently no thymus-specific contrast agents for biomedical imaging. Thus, finding ectopic thymic tissue during certain operations is extremely difficult. The purpose of the present study was to determine if near infrared (NIR) fluorescence imaging could provide high sensitivity, real-time identification of thymic tissue during the operation. METHODS: After initial in vivo screening of a 315-compound NIR fluorophore library for thymic uptake, methylene blue and five different 700-nm emitting candidate molecules were injected into CD-1 mice for quantitation of the signal-to-background ratio as a function of kinetics and dosing. Results were confirmed in 35-kg Yorkshire pigs. Dual-channel NIR imaging was also performed using a variety of 800-nm emitting NIR fluorophores targeted to various tissues in the mediastinum and neck. RESULTS: The compound Oxazine 170 demonstrated the highest signal-to-background ratio (>=3) for thymic tissue relative to mediastinal fat, heart, lung, muscle, thyroid gland, and parathyroid gland, with peak signal-to-background ratio occurring 4 h after 1 intravenous injection of a human equivalent dose of approximately 7 mg. Simultaneous dual-channel NIR imaging permitted unambiguous identification of the thymus from surrounding tissues, such as endocrine glands and lymph nodes. CONCLUSIONS: In mouse and pig, NIR fluorescence imaging using Oxazine 170 permits high sensitivity, real-time identification of thymic tissue for surgical procedures requiring its resection or avoidance. The performance of Oxazine 170 for imaging human thymic tissue is currently not known. PMID- 27964921 TI - Esophagectomy Outcomes in the Endoscopic Mucosal Resection Era. AB - BACKGROUND: Endoscopic mucosal resection (EMR) and esophagectomy are treatment options for cT1 esophageal adenocarcinoma. Our aim was to study outcomes for patients undergoing EMR then esophagectomy. METHODS: We identified patients undergoing EMR and esophagectomy for cT1 esophageal adenocarcinoma over 10 years. EMR histology was used to predict nodal involvement with a risk-scoring tool. Patient demographics, surgical techniques, pathology, postoperative outcomes, and survival were recorded. RESULTS: Of 1,092 that esophagectomies were performed, 51 patients underwent EMR and esophagectomy for cT1 esophageal adenocarcinoma. The mean time between EMR and esophagectomy was 4 (SD,8.0) months. According to the risk-scoring tool based on EMR histology, 1 patient was low risk, 13 (25%) were at moderate risk, and 37 (73%) were at high risk for lymph node metastasis. The time between EMR and the surgical intervention was longer and more patients had multiple EMRs in the moderate-risk group (9 vs 1.4 months, p = 0.03) compared with the high-risk group (38% vs 11% patients, p = 0.04). Operative mortality was 4% and morbidity was 43%. Pneumonia occurred in 3 of 51 patients (6%), atrial fibrillation in 4 (8%), and clinical anastomotic leak in 6 (12%). Of the 51 patients, 14 (27%) were upstaged after esophagectomy. Nodal involvement was present in 3 of 13 moderate-risk patients (23%) and in 7 of 37 high-risk patients (19%). The 5-year survival was reduced in moderate-risk compared with high-risk patients (54% vs 84%, p = 0.04). CONCLUSIONS: Studying outcomes for cT1 esophageal adenocarcinoma is important. These patients can be divided into those undergoing EMR for staging before esophagectomy and those in whom esophagectomy is a salvage procedure after therapeutic EMRs. Care should be taken to avoid upstaging of patients in the latter group, and we recommend frequent restaging and surveillance to prevent undetected progression of disease. A low threshold for esophagectomy when EMR fails to control disease should be considered. PMID- 27964922 TI - Transcriptomic information from Pacific white shrimp (Litopenaeus vannamei) ovary and eyestalk, and expression patterns for genes putatively involved in the reproductive process. AB - The increased use of massive sequencing technologies has enabled the identification of several genes known to be involved in different mechanisms associated with reproduction that so far have only been studied in vertebrates and other model invertebrate species. In order to further investigate the genes involved in Litopenaeus vannamei reproduction, cDNA and SSH libraries derived from female eyestalk and gonad were produced, allowing the identification of expressed sequences tags (ESTs) that potentially have a role in the regulation of gonadal maturation. In the present study, different transcripts involved in reproduction were identified and a number of them were characterized as full length. These transcripts were evaluated in males and females in order to establish their tissue expression profiles during developmental stages (juvenile, subadult and adult), and in the case of females, their possible association with gonad maturation was assessed through expression analysis of vitellogenin. The results indicated that the expression of vitellogenin receptor (vtgr) and minichromosome maintenance (mcm) family members in the female gonad suggest an important role during previtellogenesis. Additionally, the expression profiles of genes such as famet, igfbp and gpcr in brain tissues suggest an interaction between the insulin/insulin-like growth factor signaling pathway (IIS) and methyl farnesoate (MF) biosynthesis for control of reproduction. Furthermore, the specific expression pattern of farnesoic acid O-methyltransferase suggests that final synthesis of MF is carried out in different target tissues, where it is regulated by esterase enzymes under a tissue-specific hormonal control. Finally, the presence of a vertebrate type steroid receptor in hepatopancreas and intestine besides being highly expressed in female gonads, suggest a role of that receptor during sexual maturation. PMID- 27964923 TI - Surgical excision without whole breast irradiation for complete resection of ductal carcinoma in situ identified using strict, unified criteria. AB - BACKGROUND: The definition of complete resection of ductal carcinoma in situ (DCIS) is difficult to standardize because of the high variety of surgical breast conserving procedures, specimen handling, and pathological examinations. Using strictly controlled criteria in a single institute, the present study aimed to determine the ipsilateral breast cancer rate when radiotherapy is omitted following complete resection of DCIS. METHODS: We retrospectively examined 363 consecutive DCIS patients who underwent breast-conserving surgery, and of these, 125 (34.4%) had complete resection according to the criteria. We finally included 103 patients who omitted radiotherapy. Ipsilateral and contralateral breast cancer events were assessed. RESULTS: The median follow-up period was 118 months. The incidences of ipsilateral and contralateral breast cancer and ipsilateral invasive breast cancer at 10 years were 10.8%, 9.1%, and 3.6%, respectively. No patient died of breast cancer. CONCLUSION: If complete resection of DCIS can be ensured, the annual incidence of ipsilateral breast cancer, even without irradiation, can be limited to approximately 1%, which equals the incidence of contralateral breast cancer. PMID- 27964924 TI - An institutional comparison of total abdominal colectomy and diverting loop ileostomy and colonic lavage in the treatment of severe, complicated Clostridium difficile infections. AB - BACKGROUND: Total abdominal colectomy (TAC) is the standard surgical treatment of Clostridium difficile infection (CDI). An alternative therapy, loop ileostomy and colonic lavage (IL), was described in 2011, but the results have never been validated. METHODS: Patients treated surgically for CDI between April 2011 and June 2015 were included. Bivariable analysis was used to compare 30-day mortality, 1-year mortality, CDI recurrence, colon preservation and ileostomy reversal. RESULTS: Ten IL patients and thirteen TAC patients were identified. 30 day mortality (30% vs 23%, p = 1.0) and 1-year mortality (40% vs 46%, p = 1.0) were similar. Four IL and three TAC patients (57% vs 30%, p = 0.35) experienced recurrent CDI. All six surviving IL patients had successful colon preservation; five underwent ileostomy reversal compared to three in the TAC group (83% vs 43%, p = 0.27). CONCLUSIONS: Although IL allowed colon preservation and return of intestinal continuity in most patients, IL did not decrease mortality or recurrent CDI when compared to TAC. PMID- 27964925 TI - Who really manages our patients' medications? A study of inner city adults over 40 years of age. AB - OBJECTIVES: Primarily to determine how many of our adult patients receive significant assistance from another individual with medication management. Secondarily, to determine if the number of prescribed medications can be predictors of whether the patient receives significant assistance with medication management. DESIGN: Cross-sectional survey study. SETTING: A level 3 patient centered medical home family practice clinic in an inner city university hospital in Brooklyn, New York. PARTICIPANTS: Patients 40 years of age and older coming for a regular clinic visit to see the primary care physician. INTERVENTION: Administering the survey to the patients was the intervention. MAIN OUTCOME MEASURES: The number of patients who receive significant assistance with any phase of medication management was the main outcome measure. RESULTS: Out of 143 patients surveyed, 61 patients (42.7%) received assistance with 1 or more phases of medication management; 38.5% (n = 55) of patients received help with phase 1 (ensuring that patients have medications at home). Of those 55 patients, 28 (50.9%) received help from family members, 22 (40%) received help from pharmacies, and 5 (9.1%) received help from home health aides or visiting nurses. Thirteen patients (9%) received help with phase 2 (arranging medications to help take them properly); 11 (84.6%) of them received help from family members. Twenty three patients (16.1%) received help with phase 3 (reminding patients to take medications or handing them to the patient); 17 (73.9%) out of 23 received help from family members. There was a statistically significant trend (Mann-Whitney 2 sided test: P <0.001) showing a direct relationship between the number of medications and the need for assistance with 1 or more phases of medication management. CONCLUSION: Many adult patients receive help with 1 or more phases of medication management. Family members are the major source of assistance with medication management. Pharmacies also play an important role in making certain that patients have medications at home. Patients with a higher number of medications are more likely to receive assistance from others. PMID- 27964926 TI - Retinoic acid receptor signalling directly regulates osteoblast and adipocyte differentiation from mesenchymal progenitor cells. AB - Low and high serum retinol levels are associated with increased fracture risk and poor bone health. We recently showed retinoic acid receptors (RARs) are negative regulators of osteoclastogenesis. Here we show RARs are also negative regulators of osteoblast and adipocyte differentiation. The pan-RAR agonist, all-trans retinoic acid (ATRA), directly inhibited differentiation and mineralisation of early osteoprogenitors and impaired the differentiation of more mature osteoblast populations. In contrast, the pan-RAR antagonist, IRX4310, accelerated differentiation of early osteoprogenitors. These effects predominantly occurred via RARgamma and were further enhanced by an RARalpha agonist or antagonist, respectively. RAR agonists similarly impaired adipogenesis in osteogenic cultures. RAR agonist treatment resulted in significant upregulation of the Wnt antagonist, Sfrp4. This accompanied reduced nuclear and cytosolic beta-catenin protein and reduced expression of the Wnt target gene Axin2, suggesting impaired Wnt/beta-catenin signalling. To determine the effect of RAR inhibition in post natal mice, IRX4310 was administered to male mice for 10 days and bones were assessed by uCT. No change to trabecular bone volume was observed, however, radial bone growth was impaired. These studies show RARs directly influence osteoblast and adipocyte formation from mesenchymal cells, and inhibition of RAR signalling in vivo impairs radial bone growth in post-natal mice. PMID- 27964928 TI - Absolute and relative reliability of isokinetic and isometric trunk strength testing using the IsoMed-2000 dynamometer. AB - OBJECTIVES: The present study aimed to assess the between day reliability of isokinetic and isometric peak torque (PT) during trunk measurement on an isokinetic device (IsoMed 2000). DESIGN: Test-retest-protocol on five separate days. PARTICIPANTS: Fifteen healthy sport students (8 female and 7 male) aged 21 to 26. MAIN OUTCOME MEASURES: PT was assessed in isometric back extension and flexion as well as right and left rotation. Isokinetic strength was captured at a speed of 60 degrees /s and 150 degrees /s for all tasks. RESULTS: For none of the assessed parameters a meaningful variation in PT during test days was observed. Relative reliability (ICC = 0.85-0.96) was excellent for all tasks. Estimates of absolute reliability as Coefficient of Variation (CoV) and Standard Error of Measurement (SEM in Nm/kg lean body mass) remained stable for isometric (6.9% < CoV < 9.4%; 0.15 < SEM < 0.23) and isokinetic mode (60 degrees /s: 3.7% < CoV < 8.6%; 0.08 < SEM < 0.24; 150 degrees /s: 6.9% < CoV < 12.4%; 0.10 < SEM < 0.31). In contrast, reliability between familiarization day and day 1 was lower (6.6% < CoV < 26.2%; 0.10 < SEM < 0.65). CONCLUSIONS: Trunk strength measurement in flexion and extension or trunk rotation in either isometric or isokinetic condition is highly reliable. Therefore, it seems possible to elucidate changes which are smaller than 10% due to intervention programs when a preceding familiarization condition was applied. PMID- 27964927 TI - Long noncoding RNA MALAT1 regulates renal tubular epithelial pyroptosis by modulated miR-23c targeting of ELAVL1 in diabetic nephropathy. AB - Diabetic nephropathy is a common kidney condition in patients with diabetes mellitus, which can result in renal failure. Pyroptosis, the process of pro inflammatory programmed cell death, plays an important role in the pathogenesis of this disease. Long non-coding RNA MALAT1 has also been shown to be involved in diabetic nephropathy. Here, we investigated the role of MALAT1 and the microRNA miR-23c and its target gene ELAVL1 in renal tubular epithelial cells. Our data demonstrated that MALAT1 expression was substantially increased but miR-23c was decreased in streptozotocin-induced diabetic rats and in high-glucose-treated HK 2 cells. Downregulation of MALAT1 or upregulation the expression of miR-23c inhibited pyroptosis in HK-2 cells. In an effort to understand the signaling mechanisms underlying the pro-pyroptotic properties of MALAT1 and the anti pyroptotic properties of miR-23c, we found that inhibiting the expression of MALAT1 downregulated the expression of ELAVL1, NLRP3, Caspase-1 and the pro inflammatory cytokine IL-1beta. These findings were replicated by upregulation of miR-23c. Moreover, luciferase assays showed that miR-23c, as a target of MALAT1, directly repressed ELAVL1 expression and then decreased the expression of its downstream protein NLRP3. The expression of MALAT1 antagonized the effect of miR 23c on the downregulation of its target ELAVL1 and inhibited hyperglycemia induced cell pyroptosis. This mechanism may contribute to a better understanding of diabetic nephropathy pathogenesis and facilitate the development of new therapeutic strategies for the treatment of this disease. PMID- 27964930 TI - Platelet Immunology in China: Research and Clinical Applications. AB - Immunization against human platelet alloantigens (HPAs) is associated with a number of clinical complications. The detection and identification of clinically relevant platelet antibodies are important for the diagnosis and management of patients affected with immune-mediated thrombocytopenias. Human platelet alloantigen frequencies and the characteristics of antiplatelet antibodies vary widely between ethnic groups. Since 2008, the importance of platelet immunology in the field of transfusion medicine has gained greater recognition by clinical laboratories in China. Laboratories in China have established and improved methods for platelet antibody detection and HPA genotyping techniques, which are used for the diagnosis of alloimmune platelet disorders in clinic and research environments. Research has revealed the frequencies of HPA alleles in different Chinese ethnic groups and compared the differences in HPA gene frequencies between the Chinese Han and other ethnic groups of the world. Production of anti CD36 isoantibodies is an important risk factor for immune-mediated thrombocytopenia in the Chinese population. Advances in research and clinical application of platelet immunology have significantly improved the clinical diagnosis, treatment including transfusion support, and prevention of alloimmune platelet disorders in the Chinese population. PMID- 27964931 TI - The effect of extended aging on the optical properties of different zirconia materials. AB - PURPOSE: The purpose of this study was to determine if the optical properties of zirconia and glass-ceramic (e.max) were affected by low-temperature degradation (aging). METHODS: Experiment samples were fabricated with seven zirconia brands (n=10): Zenostar, Zirlux, Katana, Bruxzir, DD-BioZX2, DD-cubeX2, NexxZr; and e.max were used as a control. This resulted in a total of 80 samples in the experiment. The L*, a* and b* were measured for each sample, and then the optical properties including translucency parameter (TP), contrast ratio (CR), and opalescence parameter (OP) were calculated. The samples were aged (20, 40, 60, 80, 100h), and the optical properties were calculated after each interval. RESULTS: Most zirconia brands had lower L*, higher a*, higher b* with increased aging, which visually corresponds to darker, redder, and more yellow. Aging also increased CR, lowered TP, and lowered OP. e.max was also affected by aging but still had the highest TP (23.9+/-2.8), L* (81.7+/-3.4), and lowest CR (0.41+/ 0.05) compared to any zirconia. The Zenostar had the closest TP (24.1+/-0.4), and L* (90.2+/-0.5) values to e.max before aging. However, after 100h of aging, the DD-cubeX2 was least effected and had the highest TP (22.2+/-0.6) and lowest CR (0.43+/-0.01) compared with other zirconia samples and highest OP (11.3+/-0.2) of all ceramic samples. CONCLUSIONS: The optical properties of zirconia and e.max materials were affected by aging with the effects increasing with time. The magnitude of change was affected by seven brands of dental zirconia. PMID- 27964929 TI - Do inferences about mortality rates and disparities vary by source of mortality information? AB - PURPOSE: Researchers who study mortality among survey participants have multiple options for obtaining information about which participants died (and when and how they died). Some use public record and commercial databases; others use the National Death Index; some use the Social Security Death Master File; and still others triangulate sources and use Internet searches and genealogic methods. We ask how inferences about mortality rates and disparities depend on the choice of source of mortality information. METHODS: Using data on a large, nationally representative cohort of people who were first interviewed as high school sophomores in 1980 and for whom we have extensive identifying information, we describe mortality rates and disparities through about age 50 using four separate sources of mortality data. We rely on cross-tabular and multivariate logistic regression models. RESULTS: These sources of mortality information often disagree about which of our panelists died by about age 50 and also about overall mortality rates. However, differences in mortality rates (i.e., by sex, race/ethnicity, education) are similar across of sources of mortality data. CONCLUSION: Researchers' source of mortality information affects estimates of overall mortality rates but not estimates of differential mortality by sex, race and/or ethnicity, or education. PMID- 27964933 TI - Molecularly imprinted polymer for glutathione by modified precipitation polymerization and its application to determination of glutathione in supplements. AB - Molecularly imprinted polymers (MIP) particles for glutathione (GSH) with a narrow particle size distribution were prepared by modified precipitation polymerization using methacrylic acid as a functional monomer, divinylbenzene as a crosslinker and water as a co-solvent. The particle diameters of the MIP and non-imprinted polymer (NIP) prepared under the optimum conditions were 3.81+/ 0.95 (average+/-standard deviation) and 3.39+/-1.22MUm, respectively. The retention and molecular-recognition properties of the prepared MIP were evaluated using a mixture of acetonitrile and water as a mobile phase in hydrophilic interaction chromatography. With an increase of acetonitrile content, the retention factor of GSH was increased on the MIP. In addition to shape recognition, hydrophilic interactions seem to work for the recognition of GSH on the MIP. The MIP had a specific molecular-recognition ability for GSH, while glutathione disulfide, l-Glu, l-Cys, Gly-Gly and l-Cys-Gly could not be retained or recognized on the MIP. The effect of column temperature revealed that the separation of GSH on the MIP was entropically driven. Binding experiments and Scatchard analyses revealed that one binding sites were formed on both the MIP and NIP, while the MIP gave higher affinity and capacity for GSH than the NIP. Furthermore, the MIP was successfully applied for determination of GSH in the supplements. PMID- 27964932 TI - Effects of different electrolytes for micro-arc oxidation on the bond strength between titanium and porcelain. AB - PURPOSE: The aim of this study is to investigate the effects of different electrolytes on the titanium-porcelain bond strength after micro-arc oxidation (MAO) treatment. METHODS: Three electrolytes at the same concentration were used as MAO reaction solutions: Na2SiO3, KF, and MgSiF6. Blasting treatment was chosen as a control. After MAO treatment in each electrolyte, the titanium-porcelain bond strengths were measured by the three-point bending test, as described in ISO 9693. The morphologies and elemental compositions of the MAO coating on the titanium substrate were evaluated by scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS). The interface between the titanium and porcelain was also observed by SEM and EDS. RESULTS: The MAO coatings created in different electrolytes exhibited completely different morphologies and compositions. The bond strengths of the Na2SiO3 and MgSiF6 groups were significantly higher than those of the other groups (p<0.05). Additionally, the titanium-porcelain interfaces were compact in the former two groups, whereas pores and cracks were visible at the interfaces in the other groups. CONCLUSIONS: These results indicate that MAO treatment with an appropriate electrolyte could be an effective method to increase the titanium-porcelain bonding strength. According to ISO 9693, titanium-porcelain restorations subjected to MAO treatment with an appropriate electrolyte could be appropriate for clinical use. PMID- 27964935 TI - Molecular and in silico analysis of a new plasmid-mediated AmpC beta-lactamase (CMH-2) in clinical isolates of Klebsiella pneumoniae. AB - Two Klebsiella strains isolated from urine samples were positive for blaAmpC by PCR and showed sequence similarity with CMH-1 (98.6%) after sequencing. It also shares 82% similarity with ACT-1, 85% with MIR-1 and 81% with the chromosomal AmpC gene of Enterobacter cloacae. This gene was associated with the plasmid of IncK type. It has an open reading frame of 381 amino acid with four amino acid substitutions at position D144A, C189R, Q192E, and A195T as compared to CMH-1. When expressed in E.coli DH5alpha and E.coli strain B, this beta-lactamase conferred resistance to cefotaxime, ceftriaxone and ceftazidime. In addition, both in vitro and in silico analysis revealed that this cephalosporinase was inhibited by cefepime and carbapenem group of drugs. Therefore, this new plasmid encoded AmpC type beta-lactamase gene was designated as CMH-2. PMID- 27964934 TI - Double-barrel coronary artery after subintimal stenting for chronic total occlusion. AB - A 70-year-old man with a medical history of hypertension, dyslipidemia, and diabetes was referred to our hospital for effort angina. Coronary angiography revealed chronic total occlusion (CTO) of the proximal right coronary artery (RCA) that had been collateralized by septal branches from the left anterior descending coronary artery, left circumflex coronary artery, and an antegrade bridge. Three everolimus-eluting stents (Xience-Alpine: 3.0 * 38 mm, 2.75 * 38 mm, and 2.5 * 38 mm; Abbott-Vascular Co., Abbott Park, IL, USA; Fig. 1D, indicated by yellow lines) were implanted with stent overlap. Post-procedural angiography showed double-barrel flow through the RCA. Repeat angiography after 10 months showed double-barrel flow through the RCA, the stented lumen, and the non-stented lumen. Optical coherence tomography (OCT) demonstrated subintimal stenting. OCT revealed that the entry point from the true lumen (TL) was the proximal segment of the RCA, and the re-entry point to the TL was the distal segment of the RCA. Additionally, OCT showed smooth and thin neointimal proliferation inside the deployed stent, and there was no evidence of an intraluminal thrombus. To the best of our knowledge, this is the first report describing a subintimal stenting of CTO lesion involved with double-barrel coronary artery with OCT assessment. PMID- 27964936 TI - Musicianship enhances ipsilateral and contralateral efferent gain control to the cochlea. AB - Human hearing sensitivity is easily compromised with overexposure to excessively loud sounds, leading to permanent hearing damage. Consequently, finding activities and/or experiential factors that distinguish "tender" from "tough" ears (i.e., acoustic vulnerability) would be important for identifying people at higher risk for hearing damage. To regulate sound transmission and protect the inner ear against acoustic trauma, the auditory system modulates gain control to the cochlea via biological feedback of the medial olivocochlear (MOC) efferents, a neuronal pathway linking the lower brainstem and cochlear outer hair cells. We hypothesized that a salient form of auditory experience shown to have pervasive neuroplastic benefits, namely musical training, might act to fortify hearing through tonic engagement of these reflexive pathways. By measuring MOC efferent feedback via otoacoustic emissions (cochlear emitted sounds), we show that dynamic ipsilateral and contralateral cochlear gain control is enhanced in musically-trained individuals. Across all participants, MOC strength was correlated with the years of listeners' training suggested that efferent gain control is experience dependent. Our data provide new evidence that intensive listening experience(s) (e.g., musicianship) can strengthen the ipsi/contralateral MOC efferent system and sound regulation to the inner ear. Implications for reducing acoustic vulnerability to damaging sounds are discussed. PMID- 27964938 TI - High-Dose Metformin May Increase the Concentration of Atorvastatin in the Liver by Inhibition of Multidrug Resistance-Associated Protein 2. AB - In this study, we evaluated the effect of coadministered metformin on the biliary excretion and liver concentration of atorvastatin. To investigate the inhibitory effect of metformin on biliary efflux transporters, the transport of atorvastatin in MDCKII-MDR1, BCRP, and MRP2 was evaluated. The effects of metformin on the steady state liver concentration and biliary excretion of atorvastatin and 2 hydroxyatorvastatin were evaluated in SDR and Mrp2-deficient EHBR. Metformin did not inhibit the transport of atorvastatin via BCRP and MDR1. However, metformin significantly inhibited the transport of atorvastatin and 2-hydroxyatorvastatin via MRP2 (apparent IC50 = 12 and 2 MUM). Coadministered metformin significantly increased the Kp,liver and Cliver (1.7- and 1.6-fold) and decreased the biliary clearance of atorvastatin (2.7-fold) in SDR, but it did not affect the plasma concentration and total clearance of atorvastatin. Similar effects by metformin were observed for 2-hydroxyatorvastatin. In addition, coadministered metformin did not have any effect in EHBR. Therefore, coadministered metformin increases the liver concentration of atorvastatin via inhibition of the Mrp2 in rats, without affecting the plasma concentration. This "silent interaction" by metformin in atorvastatin and metformin combination therapy may be related to the unnoticeable pharmacological synergism or unpredicted side effects of atorvastatin in the liver. PMID- 27964937 TI - Tinnitus with a normal audiogram: Relation to noise exposure but no evidence for cochlear synaptopathy. AB - In rodents, exposure to high-level noise can destroy synapses between inner hair cells and auditory nerve fibers, without causing hair cell loss or permanent threshold elevation. Such "cochlear synaptopathy" is associated with amplitude reductions in wave I of the auditory brainstem response (ABR) at moderate-to-high sound levels. Similar ABR results have been reported in humans with tinnitus and normal audiometric thresholds, leading to the suggestion that tinnitus in these cases might be a consequence of synaptopathy. However, the ABR is an indirect measure of synaptopathy and it is unclear whether the results in humans reflect the same mechanisms demonstrated in rodents. Measures of noise exposure were not obtained in the human studies, and high frequency audiometric loss may have impacted ABR amplitudes. To clarify the role of cochlear synaptopathy in tinnitus with a normal audiogram, we recorded ABRs, envelope following responses (EFRs), and noise exposure histories in young adults with tinnitus and matched controls. Tinnitus was associated with significantly greater lifetime noise exposure, despite close matching for age, sex, and audiometric thresholds up to 14 kHz. However, tinnitus was not associated with reduced ABR wave I amplitude, nor with significant effects on EFR measures of synaptopathy. These electrophysiological measures were also uncorrelated with lifetime noise exposure, providing no evidence of noise-induced synaptopathy in this cohort, despite a wide range of exposures. In young adults with normal audiograms, tinnitus may be related not to cochlear synaptopathy but to other effects of noise exposure. PMID- 27964939 TI - Shipping-Induced Aggregation in Therapeutic Antibodies: Utilization of a Scale Down Model to Assess Degradation in Monoclonal Antibodies. AB - It is vital to understand the impact of transportation on monoclonal antibody (mAb) product quality during drug product development. Fully representative real time shipment studies are resource intensive, so in this work, we studied laboratory agitation methods to mimic the effect of real-time shipment on aggregation, specifically subvisible particle formation. The agitation methods studied include a rotator, orbital shaker, vortexer, and shipping simulator vibration table. The simulator is able to predict the particle formation behavior during real-time shipment for a number of mAbs in vial and prefilled syringe configurations, with a correlation of about 90%, whereas the other methods of agitation were inconsistent. This study demonstrates that using a shipping simulator vibration table provides an opportunity for consistent and predictive development studies of shipping stress with minimal resource requirements during early- or late-stage drug product development. PMID- 27964940 TI - The Role of Physiologically Based Oral Absorption Modelling in Formulation Development Under a Quality by Design Paradigm. AB - Within the last decade, Quality by Design (QbD) has been getting increased attention in its implementation in the development of pharmaceutical drug products. Understanding of the impact of formulation composition and process on clinical performance is a centerpiece of QbD. Physiologically based pharmacokinetic modeling incorporating biorelevant dissolution and a systems parameter approach to gastrointestinal absorption has been gaining increased traction in the pharmaceutical industry as an important tool to guide early formulation development. Extension of the models to support QbD appears the next logical step. This commentary discusses the current status of use of these models in the pharmaceutical industry and the opportunities these models can offer in ensuring drug product quality moving forward, including the development of clinically relevant specifications. PMID- 27964942 TI - Allimacrosides A-E, new steroidal glycosides from Allium macrostemon Bunge. AB - A new pregnane-type steroidal glycoside (1), two new spirostane-type steroidal glycosides (2, 3), and two new furostane-type steroidal glycosides (4, 5), named allimacrosides A-E, together with four known compounds (6-9) were isolated from a 80% MeOH extract of Allium macrostemon Bunge. The identification and structural elucidation of these compounds were based on their 1D- and 2D-NMR spectra, and HR FAB-MS data analysis. The isolated compounds were tested for cytotoxicity against four human tumor cell lines in vitro using the sulforhodamine B bioassay. PMID- 27964941 TI - Testing continuum models of psychosis: No reduction in source monitoring ability in healthy individuals prone to auditory hallucinations. AB - People with schizophrenia who hallucinate show impairments in reality monitoring (the ability to distinguish internally generated information from information obtained from external sources) compared to non-hallucinating patients and healthy individuals. While this may be explained at least in part by an increased externalizing bias, it remains unclear whether this impairment is specific to reality monitoring, or whether it also reflects a general deficit in the monitoring of self-generated information (internal source monitoring). Much interest has focused recently on continuum models of psychosis which argue that hallucination-proneness is distributed in clinical and non-clinical groups, but few studies have directly investigated reality monitoring and internal source monitoring abilities in healthy individuals with a proneness to hallucinations. Two experiments are presented here: the first (N = 47, with participants selected for hallucination-proneness from a larger sample of 677 adults) found no evidence of an impairment or externalizing bias on a reality monitoring task in hallucination-prone individuals; the second (N = 124) found no evidence of atypical performance on an internal source monitoring task in hallucination-prone individuals. The significance of these findings is reviewed in light of the clinical evidence and the implications for models of hallucination generation discussed. PMID- 27964943 TI - Hormone therapy and lung cancer mortality in women: Systematic review and meta analysis. AB - The mortality of lung cancer presents a significant difference between the sexes. A role of hormone therapy (HT) in lung cancer mortality has been suggested, but the evidence is inconclusive. We sought to elucidate this issue with a meta analysis. We conducted a systematic literature search in both Pubmed and Embase. Studies that reported the association of HT and mortality of lung cancer cases were included. Pooled hazard ratio (HR) was computed as the effect size to reflect the association between HT and lung cancer mortality. In total, 11 studies were included in the meta-analysis. The pooled HR of HT in relation to lung cancer mortality was 0.97 (95% CI 0.83-1.12, I2=59.2%, p=0.006) in all studies disregarding study design, and it was 0.80 (95% CI: 0.69-0.92, I2=21.4%, p=0.278) in prospective cohort studies. Results of this meta-analysis were robust, and there was no indication of significant differences in association in small and large studies. We observed a protective role of HT use in lung cancer mortality in pooled prospective cohorts, but not in pooled retrospective cohorts and post hoc analyses of randomized controlled trials. Future studies that address smoking, type and time of HT, menopausal status, and histology are warranted. PMID- 27964944 TI - Resequencing three candidate genes discovers seven potentially deleterious variants susceptibility to major depressive disorder and suicide attempts in Chinese. AB - BACKGROUND: To date almost 200 genes were found to be associated with major depressive disorder (MDD) or suicide attempts (SA), but very few genes were reported for their molecular mechanisms. This study aimed to find out whether there were common or rare variants in three candidate genes altering the risk for MDD and SA in Chinese. METHODS: Three candidate genes (HOMER1, SLC6A4 and TEF) were chosen for resequencing analysis and association studies as they were reported to be involved in the etiology of MDD and SA. Following that, bioinformatics analyses were applied on those variants of interest. RESULTS: After resequencing analysis and alignment for the amplicons, a total of 34 common or rare variants were found in the randomly selected 36 Hong Kong Chinese patients with both MDD and SA. Among those, seven variants show potentially deleterious features. Rs60029191 and a rare variant located in regulatory region of the HOMER1 gene may affect the promoter activities through interacting with predicted transcription factors. Two missense mutations existed in the SLC6A4 coding regions were firstly reported in Hong Kong Chinese MDD and SA patients, and both of them could affect the transport efficiency of SLC6A4 to serotonin. Moreover, a common variant rs6354 located in the untranslated region of this gene may affect the expression level or exonic splicing of serotonin transporter. In addition, both of a most studied polymorphism rs738499 and a low-frequency variant in the promoter region of the TEF gene were found to be located in potential transcription factor binding sites, which may let the two variants be able to influence the promoter activities of the gene. CONCLUSIONS: This study elucidated the potentially molecular mechanisms of the three candidate genes altering the risk for MDD and SA. These findings implied that not only common variants but rare variants could make contributions to the genetic susceptibility to MDD and SA in Chinese. PMID- 27964945 TI - Arpeggio: A Web Server for Calculating and Visualising Interatomic Interactions in Protein Structures. AB - Interactions between proteins and their ligands, such as small molecules, other proteins, and DNA, depend on specific interatomic interactions that can be classified on the basis of atom type and distance and angle constraints. Visualisation of these interactions provides insights into the nature of molecular recognition events and has practical uses in guiding drug design and understanding the structural and functional impacts of mutations. We present Arpeggio, a web server for calculating interactions within and between proteins and protein, DNA, or small-molecule ligands, including van der Waals', ionic, carbonyl, metal, hydrophobic, and halogen bond contacts, and hydrogen bonds and specific atom-aromatic ring (cation-pi, donor-pi, halogen-pi, and carbon-pi) and aromatic ring-aromatic ring (pi-pi) interactions, within user-submitted macromolecule structures. PyMOL session files can be downloaded, allowing high quality publication images of the interactions to be generated. Arpeggio is implemented in Python and available as a user-friendly web interface at http://structure.bioc.cam.ac.uk/arpeggio/ and as a downloadable package at https://bitbucket.org/harryjubb/arpeggio. PMID- 27964946 TI - Predicting the Effect of Amino Acid Single-Point Mutations on Protein Stability Large-Scale Validation of MD-Based Relative Free Energy Calculations. AB - The stability of folded proteins is critical to their biological function and for the efficacy of protein therapeutics. Predicting the energetic effects of protein mutations can improve our fundamental understanding of structural biology, the molecular basis of diseases, and possible routes to addressing those diseases with biological drugs. Identifying the effect of single amino acid point mutations on the thermodynamic equilibrium between the folded and unfolded states of a protein can pinpoint residues of critical importance that should be avoided in the process of improving other properties (affinity, solubility, viscosity, etc.) and suggest changes at other positions for increasing stability in protein engineering. Multiple computational tools have been developed for in silico predictions of protein stability in recent years, ranging from sequence-based empirical approaches to rigorous physics-based free energy methods. In this work, we show that FEP+, which is a free energy perturbation method based on all-atom molecular dynamics simulations, can provide accurate thermal stability predictions for a wide range of biologically relevant systems. Significantly, the FEP+ approach, while originally developed for relative binding free energies of small molecules to proteins and not specifically fitted for protein stability calculations, performs well compared to other methods that were fitted specifically to predict protein stability. Here, we present the broadest validation of a rigorous free energy-based approach applied to protein stability reported to date: 700+ single-point mutations spanning 10 different protein targets. Across the entire data set, we correctly classify the mutations as stabilizing or destabilizing in 84% of the cases, and obtain statistically significant predictions as compared with experiment [average error of ~1.6kcal/mol and coefficient of determination (R2) of 0.40]. This study demonstrates, for the first time in a large-scale validation, that rigorous free energy calculations can be used to predict changes in protein stability from point mutations without parameterization or system-specific customization, although further improvements should be possible with additional sampling and a better representation of the unfolded state of the protein. Here, we describe the FEP+ method as applied to protein stability calculations, summarize the large scale retrospective validation results, and discuss limitations of the method, along with future directions for further improvements. PMID- 27964947 TI - The New Federal School Nutrition Standards and Meal Patterns: Early Evidence Examining the Influence on Student Dietary Behavior and the School Food Environment. PMID- 27964949 TI - Vitamin D and the lung. AB - Vitamin D metabolism is complex and its deficiency has proven to be deleterious in bone health, and to have significant effects on the immune and cardiovascular systems. Vitamin D has also been associated with pulmonary diseases outcomes. This review will focus on vitamin D metabolism, and studies performed mostly in children with asthma or Cystic Fibrosis. PMID- 27964948 TI - Diagnostics in Children and Adolescents with Suspected or Confirmed Pulmonary Hypertension. AB - We provide a practical approach on the initial assessment and diagnostic work-up of children and adolescents with pulmonary hypertension (PH). Transthoracic echocardiography (TTE) often serves as initial study tool before invasive cardiac catheterization. Misinterpretation of TTE variables may lead to missed or delayed diagnosis with devastating consequences, or unnecessary invasive diagnostics that have inherited risks. In addition to clinical and biochemical markers, serial examination of patients with PH using a standardized TTE approach, determining conventional and novel echocardiographic variables, may allow early diagnosis and treatment in paediatric PH. Cardiac magnetic resonance imaging and computed tomography represent important non-invasive imaging modalities, that together with TTE may enable comprehensive assessment of ventricular function and pulmonary hemodynamics. Invasive assessment of haemodynamics (ventricular, pulmonary) and testing of acute vasoreactivity in the catheterization laboratory is still the gold standard for the diagnosis of PH and pulmonary hypertensive vascular disease (PHVD) in children and for the initiation of specific PH therapy. We suggest the regular assessment of prognostic TTE variables as part of a standardized approach for initial diagnosis of children with PH. Overreliance on any single TTE variable should be avoided as it detracts from the overall diagnostic potential of a standardized TTE examination for PH. PMID- 27964950 TI - Question 11: How should Allergic Bronchopulmonary Aspergillosis [ABPA] be managed in Cystic Fibrosis? PMID- 27964951 TI - Topical cystic fibrosis transmembrane conductance regulator gene replacement for cystic fibrosis-related lung disease. PMID- 27964952 TI - Docking simulations between drugs and HLA molecules associated with idiosyncratic drug toxicity. AB - Idiosyncratic drug toxicities (IDTs) caused by certain drugs are a significant cause of morbidity and mortality for patients. As IDTs are not normally detected even during clinical trials, it is difficult to foresee the risk during the early stage of drug development. Prediction of potential IDTs at the earliest possible opportunity is highly desirable. The strong associations between a particular IDT and a specific human leukocyte antigen (HLA) have been reported and the recent study has disclosed that the direct interaction between a drug in question and the HLA molecule triggers the onset of IDT. Since computational method, especially docking simulation, is applicable to prediction of the binding mode and affinity between the molecules involved in the interaction, it can be used to understand the molecular mechanism of this specific type of drug toxicity. The aim of this review is firstly to outline the methodologies used for docking simulation between drug and HLA molecules. Secondary, an overview of studies on docking simulations between IDT-inducing drugs and the corresponding HLA molecules is given. The results demonstrate that docking simulations are promising to predict the molecular mechanisms of HLA-associated IDTs and point out the causative compounds derived from the relevant drug molecules. PMID- 27964954 TI - RAP-eL: rheumatoid arthritis e-learning for physiotherapists. PMID- 27964953 TI - Blood-to-retina transport of riboflavin via RFVTs at the inner blood-retinal barrier. AB - Riboflavin (vitamin B2) supply to the retina across the inner blood-retinal barrier (BRB) was investigated. In rats, the apparent influx permeability clearance of [3H]riboflavin (62.8 MUL/(min.g retina)) was much higher than that of a non-permeable paracellular marker, suggesting the facilitative influx transport of riboflavin across the BRB. The retinal uptake index (RUI) of [3H]riboflavin was 59.0%, and significantly reduced by flavin adenine dinucleotide (FAD), but not by l-ascorbic acid, suggesting the substrate specificity of riboflavin transport. TR-iBRB2 cells, an in vitro model of the inner BRB, showed a temperature- and concentration-dependent [3H]riboflavin uptake with a Km of 113 nM, suggesting that the influx transport of riboflavin across the inner BRB involves a carrier-mediated process. [3H]Riboflavin uptake by TR-iBRB2 cells was slightly altered by Na+- and Cl--free buffers, suggesting that riboflavin transport at the inner BRB is preferentially Na+- and Cl- independent. [3H]Riboflavin uptake by TR-iBRB2 cells was significantly reduced by riboflavin analogues while the uptake remained unchanged by other vitamins. The function and inhibition profile suggested the involvement of riboflavin transporters (SLC52A/RFVT) in riboflavin transport at the inner BRB, and this is supported by expression and knockdown analysis of rRFVT2 (Slc52a2) and rRFVT3 (Slc52a3) in TR-iBRB2 cells. PMID- 27964955 TI - Anterior cruciate ligament. PMID- 27964956 TI - Daily rehabilitation improves physical function at 6 months, but not hospital length of stay, in patients with acute respiratory failure [synopsis]. PMID- 27964957 TI - Three weeks of parent-administered physiotherapy for very preterm infants improves motor performance at 37 weeks more than usual care [synopsis]. PMID- 27964958 TI - High-intensity acute hospital physiotherapy for patients with hip fracture may improve functional independence and can reduce hospital length of stay [synopsis]. PMID- 27964959 TI - Exercise therapy may be as effective as arthroscopic partial menisectomy in treating degenerative meniscal tears [commentary]. PMID- 27964960 TI - Exercise therapy may be as effective as arthroscopic partial meniscectomy in treating degenerative meniscal tears [synopsis]. PMID- 27964961 TI - Daily rehabilitation improves physical function at 6 months, but not hospital length of stay, in patients with acute respiratory failure [commentary]. PMID- 27964962 TI - Improving community ambulation after hip fracture: protocol for a randomised, controlled trial. AB - INTRODUCTION: After a hip fracture in older persons, significant disability often remains; dependency in functional activities commonly persists beyond 3 months after surgery. Endurance, dynamic balance, quadriceps strength, and function are compromised, and contribute to an inability to walk independently in the community. In the United States, people aged 65 years and older are eligible to receive Medicare funding for physiotherapy for a limited time after a hip fracture. A goal of outpatient physiotherapy is independent and safe household ambulation 2 to 3 months after surgery. Current Medicare-reimbursed post-hip fracture rehabilitation fails to return many patients to pre-fracture levels of function. Interventions delivered in the home after usual hip fracture physiotherapy has ended could promote higher levels of functional independence in these frail and older adult patients. PRIMARY OBJECTIVE: To evaluate the effect of a specific multi-component physiotherapy intervention (PUSH), compared with a non-specific multi-component control physiotherapy intervention (PULSE), on the ability to ambulate independently in the community 16 weeks after randomisation. DESIGN: Parallel, two-group randomised multicentre trial of 210 older adults with a hip fracture assessed at baseline and 16 weeks after randomisation, and at 40 weeks after randomisation for a subset of approximately 150 participants. PARTICIPANTS AND SETTING: A total of 210 hip fracture patients are being enrolled at three clinical sites and randomised up to 26 weeks after admission. Study inclusion criteria are: closed, non-pathologic, minimal trauma hip fracture with surgical fixation; aged >= 60 years at the time of randomisation; community residing at the time of fracture and randomisation; ambulating without human assistance 2 months prior to fracture; and being unable to walk at least 300 m in 6minutes at baseline. Participants are ineligible if the interventions are deemed to be unsafe or unfeasible, or if the participant has low potential to benefit from the interventions. INTERVENTIONS: Participants are randomly assigned to one of two multi-component treatment groups: PUSH or PULSE. PUSH is based on aerobic conditioning, specificity of training, and muscle overload, while PULSE includes transcutaneous electrical nerve stimulation, flexibility activities, and active range of motion exercises. Participants in both groups receive 32 visits in their place of residence from a study physiotherapist (two visits per week on non consecutive days for 16 weeks). The physiotherapists' adherence to the treatment protocol, and the participants' receipt of the prescribed activities are assessed. Participants also receive counselling from a registered dietician and vitamin D, calcium and multivitamin supplements during the 16-week intervention period. MEASUREMENTS: The primary outcome (community ambulation) is the ability to walk 300 m or more in 6minutes, as assessed by the 6-minute walk test, at 16 weeks after randomisation. Other measures at 16 and 40 weeks include cost effectiveness, endurance, dynamic balance, walking speed, quadriceps strength, lower extremity function, activities of daily living, balance confidence, quality of life, physical activity, depressive symptoms, increase of >= 50 m in distance walked in 6minutes, cognitive status, and nutritional status. ANALYSIS: Analyses for all aims will be performed according to the intention-to-treat paradigm. Except for testing of the primary hypothesis, all statistical tests will be two sided and not adjusted for multiple comparisons. The test of the primary hypothesis (comparing groups on the proportion who are community ambulators at 16 weeks after randomisation) will be based on a one-sided 0.025-level hypothesis test using a procedure consisting of four interim analyses and one final analysis with critical values chosen by a Hwang-Shih-Decani alpha-spending function. Analyses will be performed to test group differences on other outcome measures and to examine the differential impact of PUSH relative to PULSE in subgroups defined by pre-selected participant characteristics. Generalised estimating equations will be used to explore possible delayed or sustained effects in a subset of participants by comparing the difference between PUSH and PULSE in the proportion of community ambulators at 16 weeks with the difference at 40 weeks. DISCUSSION: This multicentre randomised study will be the first to test whether a home-based multi-component physiotherapy intervention targeting specific precursors of community ambulation (PUSH) is more likely to lead to community ambulation than a home-based non-specific multi-component physiotherapy intervention (PULSE) in older adults after hip fracture. The study will also estimate the potential economic value of the interventions. PMID- 27964963 TI - High-intensity acute hospital physiotherapy for patients with hip fracture may improve functional independence and can reduce hospital length of stay [commentary]. PMID- 27964964 TI - The Fugl-Meyer Upper Extremity Scale. PMID- 27964965 TI - Neurodynamic treatment improves leg pain, back pain, function and global perceived effect at 4 weeks in patients with chronic nerve-related leg pain. PMID- 27964966 TI - Three weeks of parent-administered physiotherapy for very preterm infants improves motor performance at 37 weeks more than usual care [commentary]. PMID- 27964967 TI - Expression and signaling of NGF in the healthy and injured retina. AB - This review summarizes the present knowledge concerning the retinal localization of the nerve growth factor (NGF), its precursor proNGF, and the receptors TrkA and p75NTR in the developing and mature rodent retina. We further discuss the changes in the expression of NGF and the receptors in experimental models of retinal disorders and diseases like inherited retinitis pigmentosa, retinal detachment, glaucoma, and diabetic retinopathy. Since proNGF is now recognized as a bioactive signaling molecule which induces cell death through p75NTR activation, the role of proNGF in the induction of retinal cell loss under neurodegenerative conditions is also highlighted. In addition, we present the evidences for a potential therapeutic intervention with NGF for the treatment of retinal neurodegenerative diseases. Different strategies have been developed and experimentally tested in mice and rats in order to reduce cell loss and Muller cell gliosis, e.g., increasing the availability of endogenous NGF, administration of exogenous NGF, activation of TrkA, and inhibition of p75NTR. Here, we discuss the several lines of evidence supporting a protective effect of NGF on retinal cell loss, with specific emphasis on photoreceptor and retinal ganglion cell degeneration. A better understanding of the mechanisms underlying the effects of NGF and proNGF in the modulation of neurodegeneration and gliosis in the retina will help to develop efficient therapeutic strategies for various retinal diseases. PMID- 27964968 TI - Convergent Validity of the Patient-Reported Outcomes Measurement Information System's Physical Function Computerized Adaptive Test for the Knee and Shoulder Injury Sports Medicine Patient Population. AB - PURPOSE: To evaluate the convergent validity, precision, and completion times for the Physical Function Computerized Adaptive Test (PF-CAT) in a sports medicine patient population relative to standard measures of knee and shoulder function. METHODS: We reviewed all patient visits from April through September 2014 with either knee or shoulder complaints from a university-based sports medicine clinic, during which PF-CAT, Single Assessment Numerical Evaluation (SANE), Simple Shoulder Test (SST), and American Shoulder and Elbow Surgeons (ASES) outcome scores for shoulder patients and PF-CAT, SANE, and International Knee Documentation Committee (IKDC) scores for knee patients were obtained, with an initial visit or one follow-up visit included in the study. Spearman correlation was used to evaluate pairwise agreement among scores. The McNemar chi2 test was used to evaluate a difference in the number of times floor and ceiling values occurred. Wilcoxon signed rank tests were used to compare differences in completion times. RESULTS: In total, 415 shoulder and 450 knee clinical evaluations qualified for inclusion in the study. A high correlation was found between IKDC and PF-CAT scores (r = 0.75, P < .0001), and a moderately high correlation was found between PF-CAT and both SST (r = 0.68, P < .0001) and ASES (r = 0.63, P < .0001) scores. Maximum differences in the sum of floor-ceiling values versus the PF-CAT were 15% for the SST (P < .0001), 2.5% for the ASES (ceiling only, P = .0133), and 5.8% for the shoulder SANE (floor P = .0012, ceiling P = .0269). The PF-CAT had values of 0.4% for the shoulder and 0.6% for the knee. Zero percent of IKDC scores but 6.9% of knee SANE scores hit floor or ceiling values (floor P = .0019, ceiling P = .0007). The PF-CAT median completion time was lower at 55 seconds versus 268 seconds for the IKDC assessment (P < .0001), whereas shoulder patients' times were 61, 139, and 116 seconds for the PF CAT, SST, and ASES evaluation, respectively (P < .0001). CONCLUSIONS: The PF-CAT showed a high correlation with IKDC scores and a moderately high correlation with ASES and SST outcomes. The PF-CAT takes significantly less time to complete and exhibits improved or similar floor and ceiling effects in comparison to IKDC, SST, and ASES scores. The PF-CAT can be used in evaluating sports medicine knee and shoulder patients. LEVEL OF EVIDENCE: Level III, cross-sectional study. PMID- 27964969 TI - Anterolateral Ligament and Iliotibial Band Control of Rotational Stability in the Anterior Cruciate Ligament-Intact Knee: Defined by Tibiofemoral Compartment Translations and Rotations. AB - PURPOSE: To determine the stabilizing effect of the anterolateral ligament (ALL) and iliotibial band (ITB) in resisting internal tibial rotation limits and anterior subluxations of the tibiofemoral compartments in anterior cruciate ligament (ACL)-intact knees during anterior drawer, internal rotation, and under 2 different 4-degree-of-freedom pivot-shift conditions. METHODS: A 6-degree-of freedom robotic simulator tested 19 fresh-frozen cadaver specimens with 3 testing conditions: intact, ALL- or ITB-sectioned (random), and both ALL and ITB sectioned. Anterior translation of the medial and lateral compartments and internal tibial rotation were measured under 100 N anterior drawer, 5 Nm internal rotation, and 2 pivot-shift conditions. Statistical equivalence was defined as P < .05. RESULTS: Sectioning the ALL alone had no effect on lateral compartment translation or internal rotation under any loading condition (equivalent P < .05). After ITB sectioning alone, small increases in internal rotation were found under 5 Nm internal rotation at 60 degrees (3.0 degrees [90% confidence interval 1.9-4.1]; P = .99) and 90 degrees (2.2 degrees [90% confidence interval 1.5-2.9]; P = .84) flexion. After both ALL and ITB were sectioned, increases in internal rotation of 1.7 degrees , 4.5 degrees , and 3.9 degrees occurred at 25 degrees , 60 degrees , and 90 degrees flexion, respectively (P > .05). Small increases in pivot-shift internal rotation (Group 1: 2.0 degrees [90% confidence interval 1.4-2.6]; P = .52) and lateral compartment translation occurred (Group 1: 0.9 mm [90% confidence interval 0.7-1.1]; P < .001). CONCLUSIONS: Sectioning the ALL does not lead to an increase in tibiofemoral compartment subluxations in the pivot-shift test with an intact ACL. Accordingly the ALL would not represent a primary restraint to pivot-shift subluxations. ALL sectioning alone does not lead to an increase in internal rotation motion limits, however sectioning both the ALL and ITB did produce small increases in rotation limits at higher flexion angles which would likely not be clinically detectable. CLINICAL RELEVANCE: A deficiency to both the ALL and ITB during in vitro simulated pivot-shift tests and internal rotation tests results in small, clinically undetectable changes in knee kinematics in the majority of knees assuming intact ACL function. PMID- 27964970 TI - Reply to Barroso-Sousa R et al. PMID- 27964971 TI - Outbreak of G2P[4] rotavirus gastroenteritis in a retirement community, Brazil, 2015: An important public health risk? AB - The present study described a group A rotavirus (RVA) outbreak in an age-care facility in Brazil, using epidemiologic and molecular diagnostic methods. A descriptive clinical, epidemiological and environmental investigation was conducted. Stool samples were collected and screened for RVA, Norovirus (NoV), Enteric Adenovirus 40/41 (AdV 40/41) and Astrovirus (AstV) using ELISA, RT-PCR, qRT-PCR, electron microscopy and sequencing methods. Outbreak occurred during 26th-29th October, 2015; 28 individuals affected (22 residents; 6 staff). The attack rate was 25.9% and 8.5% among residents (median-age: 85.5 years) and staff (median-age: 28 years), respectively. Female staff was identified as the index case. RVA G2P[4] genotype was detected in 87.5% (7/8). Genetic analysis demonstrated that the outbreak involved one single strain, suggesting a common source infection. RVA should be considered during outbreaks investigations in residential facilities, and raise the question if the current licensed RVA vaccines for children could also be helpful for the elderly. PMID- 27964973 TI - More than meets the eye. PMID- 27964974 TI - Can we kill 2 birds with 1 stone? PMID- 27964972 TI - Why older adults may decline offers of post-acute care services: A qualitative descriptive study. AB - The most common post-acute care (PAC) services available to patients after hospital discharge include home care, skilled nursing facilities, nursing homes, inpatient rehabilitation, and hospice. Patients who need PAC and receive services have better outcomes, however almost one-third of those offered services decline. Little research exists on PAC decision-making and why patients may decline services. This qualitative descriptive study explored the responses of thirty older adults to the question: "Can you, from the patient point of view, tell me why someone would not want post hospital care?" Three themes emerged. Participants may decline due to 1) previous negative experiences with PAC, or 2) a preference to be home. Some participants stated, "I'd be there" and would not decline services. Participants also discussed 3) why other patients might decline PAC which included patients' past experiences, lack of understanding/preconceived ideas, and preferences. Clinical implications include assessing patients' knowledge and experience before providing recommendations. PMID- 27964976 TI - Discussion. PMID- 27964975 TI - Midterm, multicenter clinical and hemodynamic results for the Trifecta aortic pericardial valve. AB - OBJECTIVE: To evaluate the midterm hemodynamic performance and clinical outcomes of the Trifecta aortic pericardial valve. METHODS: In a multicenter, prospective, nonrandomized, follow-up study, 710 patients underwent surgical implantation of a pericardial stented aortic prosthesis (Trifecta valve; St Jude Medical, St. Paul, Minn). The valve is constructed from bovine pericardium mounted externally onto a titanium stent. Subjects were followed on an annual basis over 6 years. RESULTS: Operations were performed from 2007 to 2009, and mean age was 72.4 +/- 9.3 years; 471 of 710 (66.3%) were men. Preoperatively, 361 of 710 (50.8%) of patients were in New York Heart Association class III or IV, and at 6 years postoperatively, 92 of 96 (95.8%) were New York Heart Association class I or II. Six years postoperatively, average mean gradient across all valve sizes was 11.0 mm Hg, and the average effective orifice area index was 0.80 cm2/m2. The proportion of patients without moderate-to-severe valvular regurgitation at 6 years was 95.2% (80/84). Six years postoperatively, freedom from valve-related mortality, nonstructural dysfunction, and paravalvular leak were 98.3%, 98.6%, and 98.9%, respectively, and freedom from reoperation due to structural valve deterioration was 97.3% (95% confidence limits, 98.6-94.7). CONCLUSION: These midterm results demonstrate that the Trifecta valve is a safe and effective valve substitute with excellent hemodynamic performance and durability that is maintained through the 6 year follow-up period. PMID- 27964977 TI - Evidence and resident physician duty hours: Should scientific experiments be more suspect than universal implementation of an untested practice? PMID- 27964978 TI - The matrix reloaded: Which pill to take to attenuate thoracic aortic aneurysm development? PMID- 27964979 TI - Thinking, fast and slow. PMID- 27964980 TI - Incidence of sternal wound infection after tracheostomy in patients undergoing cardiac surgery: A systematic review and meta-analysis. AB - PURPOSE: This systematic review and meta-analysis was performed to determine whether timing or type of tracheostomy was associated with superficial or deep sternal wound infections after cardiac surgery. METHODS: All studies reporting the incidence of sternal wound infection after tracheostomy in patients undergoing cardiac surgery were collected and analyzed. Subgroup analyses determined a priori included timing of tracheostomy and type of procedure (open vs percutaneous). All analyses used the random effects model. A meta-regression analysis was performed on the proportion of sternal wound infection and number of days between tracheostomy and initial cardiac surgery. RESULTS: A total of 13 studies met inclusion criteria. The incidence of sternal wound infection across all studies reported was 7% (95% confidence interval [CI], 4-10). The percutaneous tracheostomy group had a sternal wound infection proportion of 3% (95% CI, 1-8), and the open tracheostomy group had a sternal wound infection proportion of 9% (95% CI, 5-14). The incidence of sternal wound infection with early (<14 days) (7%; 95% CI, 3-11) versus late (>=14 days) (7%; 95% CI, 4-10) tracheostomy was similar. Meta-regression demonstrated no significant relationship between incidence of sternal wound infection and number of days between tracheostomy and initial cardiac surgery (R2 = 6.13%, P = .72). Reported secondary outcomes included 30-day and 1-year mortality, which were high at 23% (95% CI, 19-28) and 63% (95% CI, 43-80), respectively. CONCLUSIONS: The incidence of sternal wound infection after tracheostomy in patients undergoing cardiac surgery remains high at 7% (95% CI, 4-10). Open or percutaneous tracheostomy after cardiac surgery is a feasible option because the incidence of sternal wound infection and short-term mortality are comparable. Moreover, the timing of tracheostomy (early or late) had comparable rates of sternal wound infection and short-term mortality. PMID- 27964982 TI - Useful information, but still more open questions than answers. PMID- 27964981 TI - Aortic root surgery with circulatory arrest: Predictors of prolonged postoperative hospital stay. AB - OBJECTIVE: Little is known about the outcomes of aortic root operations that involve inducing hypothermic circulatory arrest for relatively extensive proximal aortic surgery. We attempted to identify predictors of postoperative hospital length of stay (LOS) and factors that affect postoperative recovery. METHODS: During 2006-2014, 247 of 265 patients (93.2%) with disease extending into the aortic arch survived aortic root operations (206 elective, 41 urgent/emergent) in which hypothermic circulatory arrest with moderate hypothermia was used. Stepwise multivariate regression analysis was performed to identify predictors of LOS (as a continuous variable) and prolonged LOS (defined as LOS >9 days, the median for the cohort). By this definition, 111 patients (45%) had prolonged LOS and 136 (55%) did not. RESULTS: Preoperative factors that independently predicted longer LOS in the entire cohort included age (P = .0014), redo sternotomy (P = .0047), and intraoperative packed red blood cell (PRBC) transfusion (P = .0007). Redo sternotomy and intraoperative PRBC transfusion also predicted longer LOS in 3 subgroup analyses: one of elective cases, one from which total arch replacement procedures were excluded, and one limited to patients who were discharged home. Age predicted longer LOS in the non-total arch (hemiarch) replacement patients. Ventilator support >48 hours (P < .0001) was associated with longer LOS. Elective aortic valve-sparing root replacement predicted a shorter LOS than valve replacement in multivariate regression analysis (P = .028). CONCLUSIONS: In patients undergoing aortic root surgery with hypothermic circulatory arrest for disease extending into the aortic arch, reducing intraoperative PRBC transfusion except when absolutely necessary may reduce postoperative LOS and expedite recovery. Performing aortic valve-sparing root replacement, when feasible, may also reduce LOS. PMID- 27964983 TI - Discussion. PMID- 27964984 TI - Did near-infrared spectroscopy leave us in the dark? PMID- 27964985 TI - The American Association for Thoracic Surgery 2016 ethics forum: Preoperative disclosure: In all honesty, my results.... PMID- 27964986 TI - Ventricular assist device thrombosis: Mind your P's &Q's-Pumps, patients, and pills. PMID- 27964987 TI - Analysis of the contaminants released from municipal solid waste landfill site: A case study. AB - Release and transport of leachate from municipal solid waste landfills pose a potential hazard to both surrounding ecosystems and human populations. In the present study, soil, groundwater, and surface water samples were collected from the periphery of a municipal solid waste landfill (located at Ranital of Jabalpur, Madhya Pradesh, India) for laboratory analysis to understand the release of contaminants. The landfill does not receive any solid wastes for dumping now as the same is under a landfill closure plan. Groundwater and soil samples were collected from the bore holes of 15m deep drilled along the periphery of the landfill and the surface water samples were collected from the existing surface water courses near the landfill. The landfill had neither any bottom liner nor any leachate collection and treatment system. Thus the leachate generated from the landfills finds paths into the groundwater and surrounding surface water courses. Concentrations of various physico-chemical parameters including some toxic metals (in collected groundwater, soil, and surface water samples) and microbiological parameters (in surface water samples) were determined. The analyzed data were integrated into ArcGIS environment and the spatial distribution of the metals and other physic- chemical parameter across the landfill was extrapolated to observe the distribution. The statistical analysis and spatial variations indicated the leaching of metals from the landfill to the groundwater aquifer system. The study will help the readers and the municipal engineers to understand the release of contaminants from landfills for better management of municipal solid wastes. PMID- 27964988 TI - Uptake and bioaccumulation of PCDD/Fs in earthworms after in situ and in vitro exposure to soil from a contaminated sawmill site. AB - Uptake of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) was studied in earthworms collected from a sawmill site in Sweden with severe PCDD/Fs contamination (the hot spot concentration was 690,000ng TEQWHO2005/kg d.w.) in order to investigate the transfer of PCDD/Fs from the site to the biota. PCDD/Fs concentrations in the collected earthworms were compared to PCDD/Fs concentrations in laboratory exposed earthworms (Eisenia fetida), which were exposed to contaminated soils from the sawmill site for 34days. All analyses were performed by high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS). PCDD/Fs concentrations in the earthworms ranged from 290 to 520,000pg/g (f.w.). The main congeners found in both soils and earthworms were OCDF, 1234678-HpCDF, OCDD and 1234678-HpCDD. The study showed that the PCDD/Fs in the soil were biovailable to the earthworms and the PCDD/Fs concentrations in the soils correlated with the concentrations in the earthworms. Earthworm samples from soil with lower concentration had higher bioaccumulation factors than samples from soils with high concentration of contamination. Thus, a less contaminated soil could yield higher concentrations in earthworms compared to a higher contaminated soil. Assuming that when assessing risks with PCDD/F contaminated soil, a combination of chemical analysis of soil PCDD/Fs concentrations and bioavailability should be employed for a more comprehensive risk assessment. PMID- 27964989 TI - Heavy metals in the mallard Anas platyrhynchos from eastern Austria. AB - A total of 77 specimens of the mallard Anas platyrhynchos were sampled from the eastern part of Austria before the ban on lead gun shot for hunting water fowl. Samples of muscle and liver were analyzed for their content of Cr, Cu, Zn, Ag, Cd, Hg and Pb using atomic absorption spectrometry. In addition the Hg content of feather samples from this aquatic bird species was evaluated. Results generally show higher concentrations of the metals in the liver compared to muscle; for mercury the concentrations were feathers>liver>muscle. Elevated, in some cases critical concentrations of Cr, Cu, Cd, Hg and Pb were measured. Levels of Ag were recorded for the first time for this species from Europe, providing basic information for future evaluation of this upcoming pollutant in aquatic environments. PMID- 27964990 TI - Biochar total surface area and total pore volume determined by N2 and CO2 physisorption are strongly influenced by degassing temperature. AB - The surface area and pore volume of carbonaceous materials, which are commonly determined by N2 and/or CO2 gas-physisorption, are important parameters when describing environmental processes such as adsorption. Their measurement requires prior degassing of samples, which can change the nature of the material. Current guidelines for biochar characterization recommend different degassing temperatures. To investigate how degassing temperatures affect gas-physisorption we systematically degassed a range of materials (four biochars, carbon nanotubes, and Al2O3 reference material) at different temperatures (105, 150, 200, 250 and 300 degrees C; for >=14h each). Degassing temperatures had no effect on Al2O3 or carbon nanotubes but the measured surface areas and pore volumes of biochars increased by up to 300% with degassing temperature. An equation is presented for predicting surface area obtained at different degassing temperatures. Elemental analysis and results from sorption batch experiments suggest that surface area and pore volume may increase as biochar components volatilize during degassing. Our results showed that degassing temperatures change material properties and influence gas-physisorption measurements, and therefore need to be standardized. These results may also apply to the characterization of other complex materials, including carbon nanotubes coated with natural organic matter and fouled activated carbon. PMID- 27964991 TI - Mitochondria and mitochondria-induced signalling molecules as longevity determinants. AB - An intense cross talk between mitochondria and nucleus continuously informs the cell about the functional state of these crucial organelles and elicits an effective stress response that strenghtens the cell, promoting its survival. Interestingly, this effect can spread also in a non-cell autonomous fashion to distal tissues by means of soluble factors. This stress response is responsible of a consistent lifespan increase in many animal models, while in humans there is still a lack of knowledge. This review summarises the available data on the involvement of mitochondria in longevity focusing in particular on this signalling activity and the consequent stress response that is elicited, and proposes the idea that, similarly to animal models, humans may benefit from this response in terms of delayed aging and longevity. PMID- 27964992 TI - Oxidative stress and pro-inflammatory cytokines may act as one of the signals for regulating microRNAs expression in Alzheimer's disease. AB - Oxidative stress and chronic inflammation are one of the earliest defects that initiate and promote Alzheimer's disease (AD). Studies showed that expressions of microRNAs were upregulated or downregulated in AD. Therefore, these biochemical defects may influence the levels of microRNAs. The up-regulated microRNAs cause neurodegeneration by: (a) decreasing the levels of a nuclear transcriptional factor-2 (Nrf2), (b) reducing the levels of alpha-secretase ADM10; and (c) reducing the levels of phosphatases. The down-regulated microRNAs cause neurodegeneration by: (a) increasing the levels of beta-secretase, (b) increasing the levels of tau kinase; (c) elevating the levels of tau proteins; (d) increasing the levels of APP; and (e) increasing the levels of nuclear factor kappaB (NF-kB). Antioxidants protect neurons by reducing oxidative stress and chronic inflammation. Therefore, they may also influence the levels of microRNAs. This review briefly describes the studies on changes in the expressions of microRNAs in the pathogenesis of AD. It proposes a hypothesis that free radicals and pro-inflammatory cytokines act as one of the signals that upregulate or downregulate the levels of microRNAs by influencing their transcription, processing or stability leading to neurodegeneration in AD. Antioxidants that reduce oxidative stress and pro-inflammatory cytokines also regulate the levels of microRNAs. PMID- 27964993 TI - Laminin is instructive and calmodulin dependent kinase II is non-permissive for the formation of complex aggregates of acetylcholine receptors on myotubes in culture. AB - Previous work has shown that myotubes cultured on laminin-coated substrates form complex aggregates of synaptic proteins that are similar in shape and composition to neuromuscular junctions (NMJs). Here we show that laminin instructs the location of complex aggregates which form only on the lower surface when laminin is coated onto culture dishes but over the entire cell when laminin is added in solution. Silencing of myotubes by agents that block electrical activity (tetrodotoxin, verapamil) or by inhibitors of calmodulin dependent kinase (CaMKII) render the myotube permissive for the formation of complex aggregates. Treatment with laminin alone will facilitate the formation of complex aggregates hours later when myotubes are made permissive by inhibiting CaMKII. The AChR agonist carbachol disperses pre formed aggregates suggesting that non permissiveness may involve active dispersal of AChRs. The permissive period requires ongoing protein synthesis. The latter may reflect a requirement for rapsyn, which turns over rapidly, and is necessary for aggregation. Consistent with this geldanamycin, an agent that increases rapsyn turnover disrupts complex aggregates. Agrin is well known to induce small clusters of AChRs but does not induce complex aggregates even though aggregate formation requires MuSK, a receptor tyrosine kinase activated by agrin. Dystroglycan (DG) is the major laminin receptor mediating complex aggregate formation with some contribution from beta1 integrins. In addition, there is a pool of CaMKII associated with DG. We discuss how these permissive and instructive mechanisms bear on NMJ formation in vivo. PMID- 27964994 TI - Magnetic resonance spectroscopy and brain volumetry in mild cognitive impairment. A prospective study. AB - OBJECTIVE: To assess the accuracy of magnetic resonance spectroscopy (1H-MRS) and brain volumetry in mild cognitive impairment (MCI) to predict conversion to probable Alzheimer's disease (AD). METHODS: Forty-eight patients fulfilling the criteria of amnestic MCI who underwent a conventional magnetic resonance imaging (MRI) followed by MRS, and T1-3D on 1.5 Tesla MR unit. At baseline the patients underwent neuropsychological examination. 1H-MRS of the brain was carried out by exploring the left medial occipital lobe and ventral posterior cingulated cortex (vPCC) using the LCModel software. A high resolution T1-3D sequence was acquired to carry out the volumetric measurement. A cortical and subcortical parcellation strategy was used to obtain the volumes of each area within the brain. The patients were followed up to detect conversion to probable AD. RESULTS: After a 3 year follow-up, 15 (31.2%) patients converted to AD. The myo-inositol in the occipital cortex and glutamate+glutamine (Glx) in the posterior cingulate cortex predicted conversion to probable AD at 46.1% sensitivity and 90.6% specificity. The positive predictive value was 66.7%, and the negative predictive value was 80.6%, with an overall cross-validated classification accuracy of 77.8%. The volume of the third ventricle, the total white matter and entorhinal cortex predict conversion to probable AD at 46.7% sensitivity and 90.9% specificity. The positive predictive value was 70%, and the negative predictive value was 78.9%, with an overall cross-validated classification accuracy of 77.1%. Combining volumetric measures in addition to the MRS measures the prediction to probable AD has a 38.5% sensitivity and 87.5% specificity, with a positive predictive value of 55.6%, a negative predictive value of 77.8% and an overall accuracy of 73.3%. CONCLUSION: Either MRS or brain volumetric measures are markers separately of cognitive decline and may serve as a noninvasive tool to monitor cognitive changes and progression to dementia in patients with amnestic MCI, but the results do not support the routine use in the clinical settings. PMID- 27964995 TI - Synthesis and optimization of novel alpha-phenylglycinamides as selective TRPM8 antagonists. AB - Transient receptor potential melastatin 8 (TRPM8) is activated by innocuous cold and chemical substances, and antagonists of this channel have been considered to be effective for pain and urinary diseases. N-(3-aminopropyl)-2-{[(3 methylphenyl)methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride (AMTB), a TRPM8 antagonist, was proposed to be effective for overactive bladder and painful bladder syndrome; however, there is a potential risk of low blood pressure. We report herein the synthesis and structure-activity relationships of novel phenylglycine derivatives that led to the identification of KPR-2579 (20l), a TRPM8 selective antagonist. KPR-2579 reduced the number of icilin-induced wet-dog shakes and rhythmic bladder contraction in rats, with no negative cardiovascular effects at the effective dose. PMID- 27964996 TI - alpha-Pyrone derivatives, tetra/hexahydroxanthones, and cyclodepsipeptides from two freshwater fungi. AB - Eighteen (1-18) and seven (1, 4, 6-8, 17 and 18) compounds were isolated from organic extracts of axenic cultures of two freshwater fungi Clohesyomyces sp. and Clohesyomyces aquaticus (Dothideomycetes, Ascomycota), respectively. Compounds 1 12 belong to the alpha-pyrone class of natural products, compounds 13 and 14 were tetrahydroxanthones, compounds 15 and 16 were hexahydroxanthones, while compounds 17 and 18 were cyclodepsipeptides. The structures were elucidated using a set of spectroscopic and spectrometric techniques. The absolute configurations of compounds 2, 3, 6, and 7 were assigned via a modified Mosher's ester method using 1H NMR data. The relative configurations of compounds 14-16 were determined through NOE data. Compounds 1, 2, 6, 8, 13, 14, and 15 were found to inhibit the essential enzyme bacterial peptidyl-tRNA hydrolase (Pth1), with (13; secalonic acid A) being the most potent. Compounds 1 and 4-18 were also evaluated for antimicrobial activity against an array of bacteria and fungi but were found to be inactive. PMID- 27964997 TI - Clinical study for pancreatic fistula after distal pancreatectomy with mesh reinforcement. AB - BACKGROUND: The purpose of this cohort study was to determine whether distal pancreatectomy with mesh reinforcement can reduce postoperative pancreatic fistula (POPF) rates compared with bare stapler. METHODS: In total, 51 patients underwent stapled distal pancreatectomy. Out of these, 22 patients (no mesh group) underwent distal pancreatectomy with bare stapler and 29 patients (mesh group) underwent distal pancreatectomy with mesh reinforced stapler. The risk factor for clinically relevant POPF (grades B and C) after distal pancreatectomy was also evaluated. RESULTS: Clinical characteristics were almost similar in both the groups. The days of the mean hospital stay and drainage tube insertion in the mesh group were significantly fewer than those in the no mesh group. The mean level of amylase in the discharge fluid in the mesh group was also significantly lower than that the in no mesh group. The rate of clinically relevant POPF (grades B and C ) in the mesh group was significantly lower than that in the no mesh group (p=0.016). Univariate analyses of risk factors for POPF (grades B and C) revealed that only mesh reinforcement was associated with POPF (grades B and C). Moreover, on multivariate analyses of POPF risk factors with p value<0.2 in univariate analyses by logistic regression, mesh reinforcement was regarded as a significant factor for POPF(grades B and C). CONCLUSIONS: The distal pancreatectomy with mesh reinforced stapler was thought to be favorable for the prevention of clinically relevant POPF (grades B and C). PMID- 27964998 TI - Vaccines for porcine epidemic diarrhea virus and other swine coronaviruses. AB - The recent introduction of the porcine epidemic diarrhea virus (PEDV) into the North American swine herd has highlighted again the need for effective vaccines for swine coronaviruses. While vaccines for transmissible gastroenteritis virus (TGEV) have been available to producers around the world for a long time, effective vaccines for PEDV and deltacoronaviruses were only recently developed or are still in development. Here, we review existing vaccine technologies for swine coronaviruses and highlight promising technologies which may help to control these important viruses in the future. PMID- 27964999 TI - Turnip Yellow Mosaic Virus P69 Interacts with and Suppresses GLK Transcription Factors to Cause Pale-Green Symptoms in Arabidopsis. PMID- 27965000 TI - TAL Effectors Drive Transcription Bidirectionally in Plants. AB - TAL effectors delivered by phytopathogenic Xanthomonas species are DNA-sequence specific transcriptional activators of host susceptibility genes and sometimes resistance genes. The modularity of DNA recognition by TAL effectors makes them important also as tools for gene targeting and genome editing. Effector binding elements (EBEs) recognized by native TAL effectors in plants have been identified only on the forward strand of target promoters. Here, we demonstrate that TAL effectors can drive plant transcription from EBEs on either strand and in both directions. Furthermore, we show that a native TAL effector from Xanthomonas oryzae pv. oryzicola drives expression of a target with an EBE on each strand of its promoter. By inserting that promoter and derivatives between two reporter genes oriented head to head, we show that the TAL effector drives expression from either EBE in the respective orientations, and that activity at the reverse strand EBE also potentiates forward transcription driven by activity at the forward-strand EBE. Our results reveal new modes of action for TAL effectors, suggesting the possibility of yet unrecognized targets important in plant disease, expanding the search space for off-targets of custom TAL effectors, and highlighting the potential of TAL effectors for probing fundamental aspects of plant transcription. PMID- 27965001 TI - Calcifying nested stromal-epithelial tumor (CNSET) of the liver in Beckwith Wiedemann syndrome. AB - Calcifying nested stromal-epithelial tumor (CNSET) is a rare neoplasm. In the 31 reported cases, CNSET is predominantly found in young girls and women. Beckwith Wiedemann syndrome (BWS) (OMIM #130650) is an overgrowth syndrome with an increased risk to develop cancer. Associations have been seen between BWS and embryonal tumors, especially Wilms tumor, hepatoblastoma, and adrenocortical carcinoma. Here we report on a female patient with BWS who presented with CNSET. Two other cases with the same association have been reported, with our case representing the third such reported in the literature. Although we recognize a potential reporting bias we speculate that CNSET may represent an unrecognized addition to the spectrum of BWS tumorigenesis. PMID- 27965003 TI - Psychosis and biological markers. PMID- 27965002 TI - Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study. AB - BACKGROUND: Psychosis is a common presenting feature in antibody-mediated encephalitis, for which prompt recognition and treatment usually leads to remission. We aimed to investigate whether people with circumscribed schizophrenia-like illnesses have such antibodies-especially antibodies against the N-methyl-D-aspartate receptor (NMDAR)-more commonly than do healthy controls. METHODS: We recruited patients aged 14-35 years presenting to any of 35 mental health services sites across England with first-episode psychosis, less than 6 weeks of treatment with antipsychotic medication, and a score of 4 or more on at least one selected Positive and Negative Syndrome Scale (PANSS) item. Patients and controls provided venous blood samples. We completed standardised symptom rating scales (PANSS, ACE-III, GAF) at baseline, and tested serum samples for antibodies against NMDAR, LGI1, CASPR2, the GABAA receptor, and the AMPA receptor using live cell-based assays. Treating clinicians assessed outcomes of ICD diagnosis and functioning (GAF) at 6 months. We included healthy controls from the general population, recruited as part of another study in Cambridge, UK. FINDINGS: Between Feb 1, 2013, and Aug 31, 2014, we enrolled 228 patients with first-episode psychosis and 105 healthy controls. 20 (9%) of 228 patients had serum antibodies against one or more of the neuronal cell surface antibodies compared with four (4%) of 105 controls (unadjusted odds ratio 2.4, 95% CI 0.8 7.3). These associations remained non-significant when adjusted for current cigarette smoking, alcohol consumption, and illicit drug use. Seven (3%) patients had NMDAR antibodies compared with no controls (p=0.0204). The other antibodies did not differ between groups. Antibody-positive patients had lower PANSS positive, PANSS total, and catatonia scores than did antibody-negative patients. Patients had comparable scores on other PANSS items, ACE-III, and GAF at baseline, with no difference in outcomes at 6 months. INTERPRETATION: Some patients with first-episode psychosis had antibodies against NMDAR that might be relevant to their illness, but did not differ from patients without NMDAR antibodies in clinical characteristics. Our study suggests that the only way to detect patients with these potentially pathogenic antibodies is to screen all patients with first-episode psychosis at first presentation. FUNDING: Medical Research Council. PMID- 27965004 TI - The comparative in vitro assessment of e-cigarette and cigarette smoke aerosols using the gammaH2AX assay and applied dose measurements. AB - DNA damage can be caused by a variety of external and internal factors and together with cellular responses, can establish genomic instability through multiple pathways. DNA damage therefore, is considered to play an important role in the aetiology and early stages of carcinogenesis. The DNA-damage inducing potential of tobacco smoke aerosols in vitro has been extensively investigated; however, the ability of e-cigarette aerosols to induce DNA damage has not been extensively investigated. E-cigarette use has grown globally in recent years and the health implications of long term e-cigarette use are still unclear. Therefore, this study has assessed the induction of double-strand DNA damage in vitro using human lung epithelial cells to e-cigarette aerosols from two different product variants (a "cigalike" and a closed "modular" system) and cigarette smoke. A Vitrocell(r) VC 10 aerosol exposure system was used to generate and dilute cigarette smoke and e-cigarette aerosols, which were delivered to human bronchial epithelial cells (BEAS-2Bs) housed at the air-liquid interface (ALI) for up to 120min exposure (diluting airflow, 0.25-1L/min). Following exposure, cells were immediately fixed, incubated with primary (0.1% gammaH2AX antibody in PBS) and secondary antibodies (DyLightTM 549 conjugated goat anti-mouse IgG) containing Hoechst dye DNA staining solution (0.2% secondary antibody and 0.01% Hoechst in PBS), and finally screened using the Cellomics Arrayscan VTI platform. The results from this study demonstrate a clear DNA damage-induced dose response with increasing smoke concentrations up to cytotoxic levels. In contrast, e-cigarette aerosols from two product variants did not induce DNA damage at equivalent to or greater than doses of cigarette smoke aerosol. In this study dosimetry approaches were used to contextualize exposure, define exposure conditions and facilitate comparisons between cigarette smoke and e-cigarette aerosols. Quartz crystal microbalance (QCM) technology and quantified nicotine delivery were both assessed at the exposure interface. Nicotine was eluted from the QCM surface to give a quantifiable measure of exposure to support deposited mass. Dose measured as deposited mass (MUg/cm2) and nicotine (ng/mL) demonstrated that in vitro e-cigarette exposures were conducted at doses up to 12 28 fold to that of cigarette smoke and demonstrated a consistent negative finding. PMID- 27965005 TI - Wearable Sensor-Based Biofeedback Training for Balance and Gait in Parkinson Disease: A Pilot Randomized Controlled Trial. AB - OBJECTIVES: To analyze the feasibility and efficacy of a novel system (Gamepad [GAMing Experience in PArkinson's Disease]) for biofeedback rehabilitation of balance and gait in Parkinson disease (PD). DESIGN: Randomized controlled trial. SETTING: Clinical rehabilitation gym. PARTICIPANTS: Subjects with PD (N=42) were randomized into experimental and physiotherapy without biofeedback groups. INTERVENTIONS: Both groups underwent 20 sessions of training for balance and gait. The experimental group performed tailored functional tasks using Gamepad. The system, based on wearable inertial sensors, provided users with real-time visual and acoustic feedback about their movement during the exercises. The physiotherapy group underwent individually structured physiotherapy without feedback. MAIN OUTCOME MEASURES: Assessments were performed by a blinded examiner preintervention, postintervention, and at 1-month follow-up. Primary outcomes were the Berg Balance Scale (BBS) and 10-m walk test (10MWT). Secondary outcomes included instrumental stabilometric indexes and the Tele-healthcare Satisfaction Questionnaire. RESULTS: Gamepad was well accepted by participants. Statistically significant between-group differences in BBS scores suggested better balance performances of the experimental group compared with the physiotherapy without biofeedback group both posttraining (experimental group-physiotherapy without biofeedback group: mean, 2.3+/-3.4 points; P=.047) and at follow-up (experimental group-physiotherapy without biofeedback group: mean, 2.7+/-3.3 points; P=.018). Posttraining stabilometric indexes showed that mediolateral body sway during upright stance was significantly reduced in the experimental group compared with the physiotherapy without biofeedback group (experimental group-physiotherapy without biofeedback group: -1.6+/-1.5mm; P=.003). No significant between-group differences were found in the other outcomes. CONCLUSIONS: Gamepad-based training was feasible and superior to physiotherapy without feedback in improving BBS performance and retaining it for 1 month. After training, 10MWT data were comparable between groups. Further development of the system is warranted to allow the autonomous use of Gamepad outside clinical settings, to enhance gait improvements, and to increase transfer of training effects to real-life contexts. PMID- 27965006 TI - Effects of Overground Locomotor Training on Walking Performance in Chronic Cervical Motor Incomplete Spinal Cord Injury: A Pilot Study. AB - OBJECTIVE: To determine the effects of a novel overground locomotor training program on walking performance in people with chronic cervical motor incomplete spinal cord injury (iSCI). DESIGN: Before-after pilot study. SETTING: Human performance research laboratory. PARTICIPANTS: Adults (N=6, age >18y) with chronic cervical iSCI with American Spinal Injury Association Impairment Scale grades C and D. INTERVENTIONS: Overground locomotor training included two 90 minute sessions per week for 12 to 15 weeks. Training sessions alternated between uniplanar and multiplanar stepping patterns. Each session was comprised of 5 segments: joint mobility, volitional muscle activation, task isolation, task integration, and activity rehearsal. MAIN OUTCOME MEASURES: Overground walking speed, oxygen consumption (Vo2), and carbon dioxide production (Vco2). RESULTS: Overground locomotor training increased overground walking speed (.36+/-.20 vs .51+/-.24 m/s, P<.001, d=.68). Significant decreases in Vo2 (6.6+/-1.3 vs 5.7+/ 1.4mL.kg.min, P=.038, d=.67) and Vco2 (753.1+/-125.5 vs 670.7+/-120.3mL/min, P=.036, d=.67) during self-selected constant work rate treadmill walking were also noted after training. CONCLUSIONS: The overground locomotor training program used in this pilot study is feasible and improved both overground walking speed and walking economy in a small sample of people with chronic cervical iSCI. Future studies are necessary to establish the efficacy of this overground locomotor training program and to differentiate among potential mechanisms contributing to enhanced walking performance in people with iSCI after overground locomotor training. PMID- 27965007 TI - Effects of Chin-Down Maneuver on the Parameters of Swallowing Function After Esophagectomy With 3-Field Lymphadenectomy Examined by Videofluoroscopy. AB - OBJECTIVES: To determine the effect of the chin-down maneuver after esophagectomy with 3-field lymphadenectomy (3FL) on pharyngeal residue, upper esophageal sphincter (UES) opening, and laryngeal closure. DESIGN: Prospective data were collected from a pharyngeal videofluoroscopic swallowing study. SETTING: Dysphagia clinics. PARTICIPANTS: Patients selected according to the inclusion criteria (N=14; mean age, 65.9y) from a total of 43 patients who underwent esophagectomy with 3FL from May to December 2014 were enrolled. INTERVENTIONS: Videofluoroscopy was conducted in head-neutral and chin-down positions to measure the pharyngeal constriction ratio (PCR), amount of residue in the vallecula and pyriform sinus after the first swallow, UES opening diameter, duration of UES opening, and duration of laryngeal vestibule closure. MAIN OUTCOME MEASURES: The aforementioned parameters were compared statistically between the head-neutral and chin-down positions. RESULTS: In comparison with the neutral group, the PCR and residue in the pyriform sinus were significantly smaller in the chin-down group (P<.01). However, the residue in the vallecula did not differ significantly from that of the neutral group (P=.44). The UES opening diameter, duration of UES opening, and duration of laryngeal vestibule closure were all significantly larger in the chin-down group than in the neutral group (P<.05). CONCLUSIONS: This study demonstrates that use of the chin-down maneuver after esophagectomy with 3FL can help expedite swallowing by strengthening pharyngeal constriction, widening the UES, and enhancing laryngeal closure. PMID- 27965008 TI - Association Between 7 Days Per Week Rehabilitation and Functional Recovery of Patients With Acute Stroke: A Retrospective Cohort Study Based on the Japan Rehabilitation Database. AB - OBJECTIVE: To test the hypothesis that functional outcome of patients with stroke who receive 7d/wk of rehabilitation is generally better than that of similar patients who undergo 5 or 6d/wk of rehabilitation. DESIGN: Retrospective cohort study. SETTING: Acute hospitals. PARTICIPANTS: From the Japan Rehabilitation Database, which includes data on 8033 patients with acute stroke collected between January 2005 and December 2013, we included 3072 patients with stroke who were admitted to the acute hospitals and received 7d/wk of rehabilitation. INTERVENTION: Seven days per week of rehabilitation was defined as rehabilitation therapy administrated by a physical or occupational therapist on every weekday, Saturday, and Sunday. MAIN OUTCOME MEASURE: Favorable functional independence in daily living, defined as a modified Rankin Scale score of 0 to 2 at the time of discharge. RESULTS: A total of 1075 (35.0%) patients received 7d/wk of rehabilitation. Univariate analysis demonstrated a significant difference in favorable functional recovery between the 7d/wk rehabilitation group and non 7d/wk rehabilitation group (43.3% vs 37.6%, respectively; P=.002). Multivariate logistic regression analysis using the generalized estimating equations method showed that 7d/wk of rehabilitation was independently associated with favorable functional recovery. CONCLUSIONS: Our cohort analysis demonstrated that 7d/wk of rehabilitation in early rehabilitation for patients with acute stroke can lead to functional recovery. PMID- 27965009 TI - Dual reductive/oxidative electrochemistry/liquid chromatography/mass spectrometry: Towards peptide and protein modification, separation and identification. AB - A new hyphenated technique based on on-line dual (oxidative and reductive) electrochemistry coupled to liquid chromatography and high resolution electrospray mass spectrometry is presented. Two liquid streams are combined, with one containing a disulfide, which is reduced to the respective thiol in an electrochemical cell based on a titanium working electrode. The other stream contains phenol, which is electrochemically activated to benzoquinone on a boron doped diamond working electrode. Upon combination of the two streams, a Michael addition takes places, leading to the covalent coupling of thiol to quinone. In continuous flow, the reaction mixture is transferred into an injection valve and the products are separated by reversed phase liquid chromatography and detected by electrospray-high resolution mass spectrometry. Proof of concept is demonstrated for low molecular mass disulfides and peptides, but further optimization will be required in future work to achieve efficient protein labelling. PMID- 27965010 TI - A novel CMOS image sensor system for quantitative loop-mediated isothermal amplification assays to detect food-borne pathogens. AB - Loop-mediated isothermal amplification (LAMP) is considered as one of the alternatives to the conventional PCR and it is an inexpensive portable diagnostic system with minimal power consumption. The present work describes the application of LAMP in real-time photon detection and quantitative analysis of nucleic acids integrated with a disposable complementary-metal-oxide semiconductor (CMOS) image sensor. This novel system works as an amplification-coupled detection platform, relying on a CMOS image sensor, with the aid of a computerized circuitry controller for the temperature and light sources. The CMOS image sensor captures the light which is passing through the sensor surface and converts into digital units using an analog-to-digital converter (ADC). This new system monitors the real-time photon variation, caused by the color changes during amplification. Escherichia coli O157 was used as a proof-of-concept target for quantitative analysis, and compared with the results for Staphylococcus aureus and Salmonella enterica to confirm the efficiency of the system. The system detected various DNA concentrations of E. coli O157 in a short time (45min), with a detection limit of 10fg/MUL. The low-cost, simple, and compact design, with low power consumption, represents a significant advance in the development of a portable, sensitive, user-friendly, real-time, and quantitative analytic tools for point-of-care diagnosis. PMID- 27965011 TI - Agrobacterium tumefaciens-mediated transformation as an efficient tool for insertional mutagenesis of Cercospora zeae-maydis. AB - An efficient Agrobacterium tumefaciens-mediated transformation (ATMT) approach was developed for the plant pathogenic fungus, Cercospora zeae-maydis, which is the causative agent of gray leaf spot in maize. The transformation was evaluated with five parameters to test the efficiencies of transformation. Results showed that spore germination time, co-cultivation temperature and time were the significant influencing factors in all parameters. Randomly selected transformants were confirmed and the transformants were found to be mitotically stable, with single-copy T-DNA integration in the genome. T-DNA flanking sequences were cloned by thermal asymmetric interlaced PCR. Thus, the ATMT approach is an efficient tool for insertional mutagenesis of C. zeae-maydis. PMID- 27965012 TI - Patterns of Failure After Surgery for Non-Small-cell Lung Cancer Invading the Chest Wall. AB - INTRODUCTION: The patterns of failure after resection of non-small-cell lung cancer (NSCLC) invading the chest wall are not well documented, and the role of adjuvant radiation therapy (RT) is unclear, prompting the present analysis. MATERIALS AND METHODS: The present institutional review board-approved study evaluated patients who had undergone surgery from 1995 to 2014 for localized NSCLC invading the chest wall. Patients with superior sulcus tumors were excluded. The clinical outcomes were estimated using the Kaplan-Meier method and compared using a log-rank test. The prognostic factors were assessed using a multivariate analysis, and the patterns of failure were scored. RESULTS: Seventy four patients were evaluated. Most patients had undergone lobectomy or pneumonectomy (85%) with en bloc chest wall resection (80%) and had pathologically node negative findings (81%). The surgical margins were positive in 10 patients (14%) and most commonly involved the chest wall (7 of 10). Adjuvant treatment included RT in 21 (28%) and chemotherapy in 28 (38%). A total of 24 local recurrences developed. The chest wall was a component of local disease recurrence in 19 of 24 cases (79%). The local control rate at 5 years for the entire population was 60% (95% confidence interval, 46%-74%). The local control rate was 74% with adjuvant RT versus 55% without RT (P = .43). On multivariate analysis, only resection less than lobectomy or pneumonectomy was associated with worse local control. The overall survival rate was 38% with RT versus 34% without RT (P = .59). CONCLUSION: Positive surgical margins and local disease recurrence were common after resection of NSCLC invading the chest wall. The primary pattern of failure was local recurrence in the chest wall. Adjuvant RT was not associated with improved local control or survival. PMID- 27965014 TI - Exploring the Educational Value of Patient Feedback: A Qualitative Analysis of Pediatric Residents' Perspectives. PMID- 27965013 TI - Patients' Attitudes and Physicians' Perceptions Toward Maintenance Therapy for Advanced Non-Small-cell Lung Cancer: A Multicenter Italian Survey. AB - INTRODUCTION: Pemetrexed maintenance therapy (MT) after induction with platinum based chemotherapy has recently become a common treatment strategy for advanced nonsquamous non-small-cell lung cancer (NSCLC). However, the benefits of MT should be weighed with consideration of the patients' perceptions and preferences. The aim of the present study was to evaluate patients' attitudes toward MT and to describe physicians' awareness of their patients' inclinations. MATERIALS AND METHODS: We administered a 12-question anonymous survey and the Distress Thermometer Questionnaire to patients with advanced or recurrent nonsquamous NSCLC. The survey was also distributed to the referring physicians. RESULTS: From December 2014 to July 2015, 92 patients and 37 physicians were enrolled. All 92 patients completed the questionnaire at T0 (before starting chemotherapy) and 56.5% also did so at T1 (after completion of induction). The physicians completed the survey only at T0. Most patients had a positive attitude toward MT at both T0 (78.9%) and T1 (86.5%), and 100% of the physicians thought their patients would be in favor of MT. The physicians believed that their patients' attitudes toward MT would decrease proportionally with the reduction in the magnitude of the overall survival increase and expected benefits. The decrease expected by the physicians was much greater than that reported by the patients. This was especially true for an overall survival increase as small as 1 month (51.9% of patients accepting MT vs. 13.5% supposed by physicians) or when the only treatment benefit was radiologic tumor stabilization (69.3% of patients accepting MT vs. 37.8% supposed by physicians). CONCLUSION: NSCLC patients have a generally positive attitude toward MT, which is not directly proportional to the expected benefits and greater than the attitude expected by physicians. PMID- 27965015 TI - Using life cycle assessment and techno-economic analysis in a real options framework to inform the design of algal biofuel production facilities. AB - This study investigates the use of "real options analysis" (ROA) to quantify the value of greater product flexibility at algal biofuel production facilities. A deterministic optimization framework is integrated with a combined life cycle assessment/techno-economic analysis model and subjected to an ensemble of 30-year commodity price trajectories. Profits are maximized for two competing plant configurations: 1) one that sells lipid-extracted algae as animal feed only; and 2) one that can sell lipid-extracted algae as feed or use it to recover nutrients and energy, due to an up-front investment in anaerobic digestion/combined heat and power. Results show that added investment in plant flexibility does not result in an improvement in net present value, because current feed meal prices discourage use of lipid-extracted algae for nutrient and energy recovery. However, this study demonstrates that ROA provides many useful insights regarding plant design that cannot be captured via traditional techno-economic modeling. PMID- 27965016 TI - Cross-reactivity of monoclonal antibodies against CD4-1 and CD8alpha of ginbuna crucian carp with lymphocytes of zebrafish and other cyprinid species. AB - We have monoclonal antibodies (mAbs) against CD4-1 (6D1) and CD8alpha (2C3) in ginbuna crucian carp Carassius auratus langsdorfii. In our previous studies we showed that 2C3 mAb positive cells are the primary cell type showing specific cytotoxicity against allogeneic targets, suggesting that CD8alpha+ lymphocytes in ginbuna are equivalent to cytotoxic T lymphocytes (CTLs) in mammals. We further demonstrated the helper T cell function of 6D1 mAb positive cells by studying mixed leukocyte culture (MLC) and hapten/carrier effects. Here, we report that our mAbs cross-react with zebrafish lymphocytes. First, mAbs 6D1 and 2C3 recognized 7-11% of zebrafish lymphocytes that were ZAP-70 positive and had the typical morphology of lymphocytes. Second, to verify the cell types reacting with the 6D1 and 2C3 mAbs we examined the expression profiles of zebrafish lymphocyte surface markers in FACS-sorted lymphocytes from kidney. cd4-1 (cd8a) and tcrac but not iglc transcripts were detected in 6D1(2C3)+ lymphocytes, whereas cd4-1 (cd8a) transcripts were not found in 6D1 (2C3)- lymphocytes. Third, we further confirmed that 6D1 reacted with zebrafish CD4-1 but not CD4-2, and 2C3 recognized zebrafish CD8alpha expressed on HEK293T cells. Collectively, these findings suggest that 6D1+ and 2C3+ lymphocytes in zebrafish are equivalent to CD4+ and CD8alpha+ T lymphocytes in mammals, respectively. Furthermore, we found the cross reactivity of our 6D1 and 2C3 mAbs with other cyprinid species including goldfish, common carp and grass carp. PMID- 27965017 TI - Structure and functionalities of the human c-reactive protein compared to the zebrafish multigene family of c-reactive-like proteins. AB - Because of the recent discovery of multiple c-reactive protein (crp)-like genes in zebrafish (Danio rerio) with predicted heterogeneous phospholipid-binding amino acid sequences and heterogeneous transcript expression levels in viral survivors and adaptive-deficient mutants, zebrafish constitute an attractive new model for exploring the evolution of these protein's functions, including their possible participation in fish trained immunity. Circulating human CRP belongs to the short pentraxin family of oligomeric proteins that are characteristic of early acute-phase innate responses and is widely used as a clinical inflammation marker. In contrast to pentameric human CRP (pCRP), zebrafish CRPs are trimeric (tCRP); however monomeric CRP (mCRP) conformations may also be generated when associated with cellular membranes as occurs in humans. Compared to human CRP, zebrafish CRP-like proteins show homologous amino acid sequence stretches that are consistent with, although not yet demonstrated, cysteine-dependent redox switches, calcium-binding spots, phosphocholine-binding pockets, C1q-binding domains, regions interacting with immunoglobulin Fc receptors (FcR), unique mCRP epitopes, mCRP binding peptides to cholesterol-enriched rafts, protease target sites, and/or binding sites to monocyte, macrophage, neutrophils, platelets and/or endothelial cells. Amino acid variations among the zebrafish CRP-like multiprotein family and derived isoforms in these stretches suggest that functional heterogeneity best fits the wide variety of aquatic pathogens. As occurs in humans, phospholipid-tagged tCRP-like multiproteins might also influence local inflammation and induce innate immune responses; however, in addition, different zebrafish tCRP-like proteins and/or isoforms might fine tune new still unknown functions. The information reviewed here could be of value for future studies not only to comparative but also medical immunologists and/or fisheries sectors. This review also introduces some novel speculations for future studies. PMID- 27965019 TI - Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio are 2 new inflammatory markers associated with pulmonary involvement and disease activity in patients with dermatomyositis. AB - BACKGROUND: The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have emerged as useful biomarkers to predict systemic inflammation. However, there is no study to investigate the relationship between the biomarkers and dermatomyositis (DM). METHODS: Seventy-three newly diagnosed patients with DM and 147 healthy subjects were selected in this retrospective study. We divided the 73 DM patients into 2 groups: 55 without interstitial lung disease (ILD) and 18 with ILD. Complete clinical characteristics were extracted from the medical records of DM patients. The correlations between NLR, PLR, the clinical characteristics and the disease activity were analyzed. RESULTS: For DM patients without ILD, the NLR and PLR were significantly higher than those in the control group (both P<0.001). For DM patients with ILD, the NLR and PLR were higher than in DM patients without ILD (P=0.004 and P=0.026, respectively). The NLR was positively correlated with C-reactive protein (CRP) (r=0.543, P<0.001) and the erythrocyte sedimentation rate (ESR) (r=0.513, P=0.001). The global activity scores correlated positively and significantly with NLR, PLR, and CRP (r=0.486, P<0.001; r=0.240, P=0.041; and r=0.343, P=0.003, respectively). Based on the ROC curve, to predict DM patients with ILD, the best cut-off value of the NLR was 3.98 (sensitivity 88.9%, specificity 52.7%, AUC=0.727), and the best cutoff value of PLR was 221.69 (sensitivity 77.8%, specificity 69.1%, AUC=0.722). CONCLUSIONS: Both NLR and PLR exhibit favorable diagnostic performance in predicting pulmonary involvement and disease activity in patients with DM. We provide the optimal cut off values for DM patients with ILD that would maximize the diagnostic efficiency. PMID- 27965021 TI - Commentary to "Following Superficial Ablation for Associated Superficial Reflux and Primary Deep Axial Reflux, Can Variable Outcomes be Due to Deep Venous Valve Anomalies?" PMID- 27965020 TI - Pre-operative Simulation of the Appropriate C-arm Position Using Computed Tomography Post-processing Software Reduces Radiation and Contrast Medium Exposure During EVAR Procedures. AB - OBJECTIVE/BACKGROUND: The aim was to evaluate the feasibility and efficacy of a new method for pre-operative calculation of an appropriate C-arm position for iliac bifurcation visualisation during endovascular aortic repair (EVAR) procedures by using three dimensional computed tomography angiography (CTA) post processing software. METHODS: Post-processing software was used to simulate C-arm angulations in two dimensions (oblique, cranial/caudal) for appropriate visualisation of distal landing zones at the iliac bifurcation during EVAR. Retrospectively, 27 consecutive EVAR patients (25 men, mean +/- SD age 73 +/- 7 years) were identified; one group of patients (NEW; n = 12 [23 iliac bifurcations]) was compared after implementation of the new method with a group of patients who received a historic method (OLD; n = 15 [23 iliac bifurcations]), treated with EVAR before the method was applied. RESULTS: In the OLD group, a median of 2.0 (interquartile range [IQR] 1-3) digital subtraction angiography runs were needed per iliac bifurcation versus 1.0 (IQR 1-1) runs in the NEW group (p = .007). The median dose area products per iliac bifurcation were 11951 mGy*cm2 (IQR 7308-16663 mGy*cm2) for the NEW, and 39394 mGy*cm2 (IQR 19066-53702 mGy*cm2) for the OLD group, respectively (p = .001). The median volume of contrast per iliac bifurcation was 13.0 mL (IQR: 13-13 mL) in the NEW and 26 mL (IQR 13-39 mL) in the OLD group (p = .007). CONCLUSION: Pre-operative simulation of the appropriate C-arm angulation in two dimensions using dedicated computed tomography angiography post-processing software is feasible and significantly reduces radiation and contrast medium exposure. PMID- 27965022 TI - A Clinical and Economic Comparison of Rasburicase and Allopurinol in the Treatment of Patients With Clinical or Laboratory Tumor Lysis Syndrome. AB - BACKGROUND: The aim of the study was to compare reductions in uric acid (UA), length of stay (LOS), and hospitalization costs in patients with tumor lysis syndrome (TLS) treated with rasburicase or allopurinol. PATIENTS AND METHODS: This retrospective study of administrative data included hospitalized pediatric and adult patients who had clinical or laboratory TLS and received rasburicase or allopurinol. Each rasburicase-treated patient was propensity score-matched with 4 allopurinol-treated patients. Mean changes in UA within <= 2 days of treatment initiation were determined. Economic outcomes included mean number of days in the intensive care unit (ICU), total LOS, costs/hospitalization, and costs/percentage change in UA. RESULTS: Twenty-six rasburicase-treated patients were matched with 104 allopurinol-treated patients. Reduction in plasma UA was 5.3 mg/dL greater for patients treated with rasburicase than for patients treated with allopurinol (P < .0001). Length of ICU stay was 2.5 days less for patients treated with rasburicase than for patients treated with allopurinol (P < .0001), and total LOS was 5 days less for patients treated with rasburicase than for patients treated with allopurinol (P = .02). Total costs per patient were $20,038 lower for patients treated with rasburicase than for patients treated with allopurinol (P < .02). Cost per percentage UA reduction was also lower for patients treated with rasburicase versus patients treated with allopurinol ($3899 vs. $16,894; P < .001). CONCLUSION: In this analysis of TLS patients who received care in real world settings, rasburicase versus allopurinol was significantly more effective in treating hyperuricemia and was associated with significantly shorter ICU and overall hospital stays and lower total inpatient costs. PMID- 27965023 TI - Believability of Cigar Warning Labels Among Adolescents. AB - PURPOSE: Despite high rates of cigar use among youth, little information exists about how cigar warnings are received by youth. We examined believability of different cigar warning messages with different sources among adolescents in a national phone survey. METHODS: Adolescents (aged 13-17 years) in the US (N = 1,125; total response rate, 66%) were randomized to receive one of three health messages ("cigar smoking can cause cancers of the mouth and throat, even if you do not inhale," "cigar smoking can cause lung cancer and heart disease," and "cigars are not a safe alternative to cigarettes") and one of four warning sources (Food and Drug Administration, Surgeon General, Centers for Disease Control and Prevention, and no source). Believability was assessed with "how believable is this warning," and responses were dichotomized for "not at all or somewhat" versus "very." RESULTS: Weighted logistic regression results indicated that most youth found the cigar warnings very believable (60.5%). Messages about mouth and throat cancer (regardless of inhalation) and the safety of cigars in comparison to cigarettes were rated as significantly less believable than messages about lung cancer and heart disease related to cigars. There were no significant differences by source or other demographics. However, youth susceptible to using cigarettes were less likely to report the cigar warnings to be very believable. CONCLUSIONS: The messages of cigar warning labels are not viewed as equally believable among adolescents. Future studies should examine how youth process messages about health effects of cigars and the impact of different cigar warnings on youth experimentation with and use of cigars. PMID- 27965024 TI - A novel GLP-1 analog, a dimer of GLP-1 via covalent linkage by a lysine, prolongs the action of GLP-1 in the treatment of type 2 diabetes. AB - GLP-1 is an incretin hormone that can effectively lower blood glucose, however, the short time of biological activity and the side effect limit its therapeutic application. Many methods have been tried to optimize GLP-1 to extend its in vivo half-time, reduce its side effect and enhance its activity. Here we have chosen the idea to dimerize GLP-1 with a C-terminal lysine to form a new GLP-1 analog, DLG3312. We have explored the structure and the biological property of DLG3312, and the results indicated that DLG3312 not only remained the ability to activate the GLP-1R, but also strongly stimulated Min6 cell to secrete insulin. The in vivo bioactivities have been tested on two kinds of animal models, the STZ induced T2DM mice and the db/db mice, respectively. DLG3312 showed potent anti diabetic ability in glucose tolerance assay and single-dose administration of DLG3312 could lower blood glucose for at least 10 hours. Long-term treatment with DLG3312 can reduce fasted blood glucose, decrease water consumption and food intake and significantly reduce the HbA1c level by 1.80% and 2.37% on STZ induced T2DM mice and the db/db mice, respectively. We also compared DLG3312 with liraglutide to investigate its integrated control of the type 2 diabetes. The results indicated that DLG3312 almost has the same effect as liraglutide but with a much simpler preparation process. In conclusion, we, by using C-terminal lysine as a linker, have synthesized a novel GLP-1 analog, DLG3312. With simplified preparation and improved physiological characterizations, DLG3312 could be considered as a promising candidate for the type 2 diabetes therapy. PMID- 27965018 TI - High content analysis in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by the progressive loss of motor neurons. Neurons, astrocytes, oligodendrocytes and microglial cells all undergo pathological modifications in the onset and progression of ALS. A number of genes involved in the etiopathology of the disease have been identified, but a complete understanding of the molecular mechanisms of ALS has yet to be determined. Currently, people affected by ALS have a life expectancy of only two to five years from diagnosis. The search for a treatment has been slow and mostly unsuccessful, leaving patients in desperate need of better therapies. Until recently, most pre-clinical studies utilized the available ALS animal models. In the past years, the development of new protocols for isolation of patient cells and differentiation into relevant cell types has provided new tools to model ALS, potentially more relevant to the disease itself as they directly come from patients. The use of stem cells is showing promise to facilitate ALS research by expanding our understanding of the disease and help to identify potential new therapeutic targets and therapies to help patients. Advancements in high content analysis (HCA) have the power to contribute to move ALS research forward by combining automated image acquisition along with digital image analysis. With modern HCA machines it is possible, in a period of just a few hours, to observe changes in morphology and survival of cells, under the stimulation of hundreds, if not thousands of drugs and compounds. In this article, we will summarize the major molecular and cellular hallmarks of ALS, describe the advancements provided by the in vitro models developed in the last few years, and review the studies that have applied HCA to the ALS field to date. PMID- 27965025 TI - Cardiovascular outcomes in patients with intraventricular conduction blocks: A sixteen-year follow-up in a state-wide database. AB - BACKGROUND: To assess the adverse clinical effects of left anterior hemiblock alone or in combination with right bundle branch block and of complete left bundle branch block in comparison with isolated right bundle branch block and the relationship of these effects with altered mechanoelectric factors resulting in left ventricular dysfunction. METHODS: In a 16-year follow-up study using a statewide database, we studied the occurrence of mortal and morbid cardiovascular (CV) events among patients without apparent ischemic heart disease who had left anterior hemiblock (LAHB, n=4273, right bundle branch block (RBBB) with LAHB (BFBB, n=1857) and left bundle branch block (LBBB, n=9484 compared to isolated RBBB (n=25288). RESULTS: After adjustment for demographics, co-morbidities and insurance, LAHB was associated with a significant excess risk of all-cause death (HR 1.134, 95% CI 1.061-1.213, p=0.0002) and CV death (HR 1.329, 95% CI 1.174 1.501, p<0.0001). BFBB was associated with excess HF (HR 1.190, 95% CI 1.048 1.351, p<0.0071), all-cause death (HR 1.440, 95% CI 1.045-1.252, p=0.0036) and CV death (HR 1.210, 95% CI 1.020-1.436, p<0.0001). LBBB was associated with an excess risk of MR (HR 1.307, 95% CI 1.116-1.530, p<0.0009), HF 1.177, 95% CI1.097 1.263, p<0.0001) and CV death (HR 1.220, 95% CI 1.106-1.345, p<0.0001). CONCLUSIONS: In patients without apparent ischemic heart disease, the presence of LAHB alone or in combination with RBBB imparts increased risk of CV and all-cause death compared to isolated RBBB. BFBB is also associated with an increased risk of HF. PMID- 27965026 TI - Disentangling stimulus plausibility and contextual congruency: Electro physiological evidence for differential cognitive dynamics. AB - Expectancy mechanisms are routinely used by the cognitive system in stimulus processing and in anticipation of appropriate responses. Electrophysiology research has documented negative shifts of brain activity when expectancies are violated within a local stimulus context (e.g., reading an implausible word in a sentence) or more globally between consecutive stimuli (e.g., a narrative of images with an incongruent end). In this EEG study, we examine the interaction between expectancies operating at the level of stimulus plausibility and at more global level of contextual congruency to provide evidence for, or against, a disassociation of the underlying processing mechanisms. We asked participants to verify the congruency of pairs of cross-modal stimuli (a sentence and a scene), which varied in plausibility. ANOVAs on ERP amplitudes in selected windows of interest show that congruency violation has longer-lasting (from 100 to 500ms) and more widespread effects than plausibility violation (from 200 to 400ms). We also observed critical interactions between these factors, whereby incongruent and implausible pairs elicited stronger negative shifts than their congruent counterpart, both early on (100-200ms) and between 400-500ms. Our results suggest that the integration mechanisms are sensitive to both global and local effects of expectancy in a modality independent manner. Overall, we provide novel insights into the interdependence of expectancy during meaning integration of cross-modal stimuli in a verification task. PMID- 27965027 TI - A functional centromere lacking CentO sequences in a newly formed ring chromosome in rice. AB - An awned rice (Oryza sativa) plant carrying a tiny extra chromosome was discovered among the progeny of a telotrisomic line 2n+4L. Fluorescence in situ hybridization (FISH) using chromosome specific BAC clones revealed that this extra chromosome was a ring chromosome derived from part of the long arm of chromosome 4. So the aneuploidy plant was accordingly named as 2n+4L ring. We did not detect any CentO FISH signals on the ring chromosome, and found only the centromeric probe Centromeric Retrotransposon of Rice (CRR) was co-localized with the centromere-specific histone CENH3 as revealed by sequential FISH after immunodetection. The extra ring chromosome exhibited a unique segregation pattern during meiosis, including no pairing between the ring chromosome and normal chromosome 4 during prophase I and pre-separation of sister chromatids at anaphase I. PMID- 27965029 TI - Packaging Patients and Handing Them Over: Communication Context and Persuasion in the Emergency Department. AB - STUDY OBJECTIVE: Communication is commonly understood by health professional researchers to consist of relatively isolated exchanges of information. The social and organizational context is given limited credit. This article examines the significance of the environmental complexity of the emergency department (ED) in influencing communication strategies and makes the case for adopting a richer understanding of organizational communication. METHODS: This study draws on approximately 12 months (1,600 hours) of ethnographic observations, yielding approximately 4,500 interactions across 260 clinicians and staff in the EDs of 2 metropolitan public teaching hospitals in Sydney, Australia. RESULTS: The study identifies 5 communication competencies of increasing complexity that emergency clinicians need to accomplish. Furthermore, it identifies several factors hierarchy, formally imposed organizational boundaries and roles, power, and education-that contribute to the collective function of ensuring smooth patient transfer through and out of the ED. These factors are expressed by and shape external communication with clinicians from other hospital departments. CONCLUSION: This study shows that handoff of patients from the ED to other hospital departments is a complex communication process that involves more than a series of "checklistable" information exchanges. Clinicians must learn to use both negotiation and persuasion to achieve objectives. PMID- 27965028 TI - Two De Novo Mutations in an Autistic Child Who Had Previously Undergone Transplantation for Dilated Cardiomyopathy: The Importance of Keeping an Open Mind. AB - We report the finding of 2 de novo mutations in an 8-year-old boy with developmental delay and autism who underwent heart transplantation at 1 year of age for idiopathic dilated cardiomyopathy. We identified a de novo microdeletion at chromosome 2p16.3 involving the neurexin-1 (NRXN1) gene and a de novo pathologic variant (Pro838Leu) in the myosin heavy chain 7 (MYH7) gene. This case emphasizes the importance of comprehensive genetic evaluation in patients with cardiomyopathy, particularly if they have extracardiac abnormalities, and the necessity of interpreting variants with attention to the phenotype. A complete genetic diagnosis may require multiple testing modalities. PMID- 27965030 TI - Does This Patient With Chest Pain Have Acute Coronary Syndrome? PMID- 27965031 TI - In Patients With Cardiac Arrest, Does Amiodarone or Lidocaine Increase Meaningful Survival? PMID- 27965032 TI - Molecular insights into allosteric modulation of Class C G protein-coupled receptors. AB - Class C G protein-coupled receptors (GPCRs) recognise diverse extracellular stimuli and are highly tractable drug targets for a host of different psychiatric, neurological and metabolic disorders. Discovery efforts focussed on allosteric modulators for Class C GPCRs have been highly fruitful, with diverse chemotypes identified for multiple Class C members. Indeed, a positive allosteric modulator of the calcium-sensing receptor, cinacalcet, was one of the first GPCR allosteric ligands to enter the clinic. Despite this success, allosteric modulator discovery and development remains challenging. In particular, the prevalence of probe dependence and biased pharmacology (both agonism and modulation) adds considerable complexity. Recent studies have yielded new insights into the structural basis for allosteric interactions at Class C GPCRs. This information coupled with rigorous analytical approaches has increased our understanding of the rich molecular pharmacology and biology for Class C GPCRs. PMID- 27965033 TI - Medication management policy, practice and research in Australian residential aged care: Current and future directions. AB - Eight percent of Australians aged 65 years and over receive residential aged care each year. Residents are increasingly older, frailer and have complex care needs on entry to residential aged care. Up to 63% of Australian residents of aged care facilities take nine or more medications regularly. Together, these factors place residents at high risk of adverse drug events. This paper reviews medication related policies, practices and research in Australian residential aged care. Complex processes underpin prescribing, supply and administration of medications in aged care facilities. A broad range of policies and resources are available to assist health professionals, aged care facilities and residents to optimise medication management. These include national guiding principles, a standardised national medication chart, clinical medication reviews and facility accreditation standards. Recent Australian interventions have improved medication use in residential aged care facilities. Generating evidence for prescribing and deprescribing that is specific to residential aged care, health workforce reform, medication-related quality indicators and inter-professional education in aged care are important steps toward optimising medication use in this setting. PMID- 27965034 TI - The ins and outs of calcium signalling in lactation and involution: Implications for breast cancer treatment. AB - The mammary epithelium is highly responsive to hormonal and non-hormonal signalling cues for physiological growth, function and tissue remodelling. Whilst steroid hormones freely diffuse across the cell membrane to bind to intracellular hormone receptors, cell-impermeable ligands, including many peptide hormones, growth factors and cytokines, bind to receptors on the plasma membrane and relay their message via the specific activation of intracellular signal transduction pathways. A signalling pathway that is indispensable for decoding many extracellular signals into cellular responses is calcium (Ca2+). Changes in the expression of specific Ca2+ channels, pumps and binding proteins may therefore greatly alter the nature of the cellular response to various growth, morphogenetic and cell death stimuli. This review summarises changes in the expression, localisation and function of key Ca2+ channels and pumps in mammary epithelial cells during lactation and discusses how this altered Ca2+ handling may later expose these cells to targeted cell death during post-lactational involution. A greater understanding of the processes regulating the growth, death and regeneration of the mammary epithelium under physiological conditions may provide important insights into the proliferation and survival mechanisms underpinning malignant growth. The therapeutic manipulation of specific calcium signalling pathways in breast cancer cells to control aberrant cell proliferation and/or turnover represents an aim for the future. PMID- 27965035 TI - Experimental toxicology: Issues of statistics, experimental design, and replication. AB - The difficulty of replicating experiments has drawn considerable attention. Issues with replication occur for a variety of reasons ranging from experimental design to laboratory errors to inappropriate statistical analysis. Here we review a variety of guidelines for statistical analysis, design, and execution of experiments in toxicology. In general, replication can be improved by using hypothesis driven experiments with adequate sample sizes, randomization, and blind data collection techniques. PMID- 27965036 TI - Fast detection of Southern tomato virus by one-step transcription loop-mediated isothermal amplification (RT-LAMP). AB - Southern tomato virus (STV) is a double stranded RNA (dsRNA) virus belonging to genus Amalgavirus (family Amalgamaviridae) which has been detected in tomato plants showing stunting, fruit discoloration and size reduction. A one-step reverse-transcription loop-mediated isothermal amplification (RT-LAMP) assay was developed for the detection of STV in total RNA or sap extracts (obtained just by grinding in buffer) from STV-infected tomato plants by using a set of three primers pairs which were designed to the sequence of the STV putative coat protein. Amplification products were visualized by gel electrophoresis or direct staining of DNA. The sensitivity of RT-LAMP was identical to that of the conventional RT-PCR and less affected by the presence of polymerase inhibitors. STV was detected by RT-LAMP in different tomato tissues, i.e. leaves, roots, fruits and seeds. Also the virus was successfully detected by RT-LAMP from sap extracts obtained from field tomato plants whereas conventional RT-PCR did not. Results of this work show that RT-LAMP is a specific, rapid and cheap procedure to detect STV and it could be implemented on field surveys and sanitation programs. PMID- 27965037 TI - Portal vein thrombosis: The role of imaging in the clinical setting. AB - Portal vein thrombosis is an infrequent condition occurring in several different clinical scenarios. In the last years it has been increasingly recognised due to the broad use of radiological methods. In this review we underline the central role of imaging in diagnosing portal vein thrombosis, in clarifying its etiology, choosing the best therapeutic approach and screening possible complications. Special attention is given to the role of imaging to differentiate portal vein thrombosis from neoplastic invasion of the portal vein, and to new diagnostic methods available for clinical practice in this field. PMID- 27965038 TI - Increased anxiety but normal fear and safety learning in orexin-deficient mice. AB - The loss of orexin neurons in humans leads to the disease narcolepsy, characterized by daytime sleepiness and cataplexy. Recent data suggest that orexin is also involved in emotional processing. The goal of the present study was to evaluate fear and safety learning as well as unconditioned fear (anxiety) in orexin-deficient animals. Orexin-deficient mice are an established animal model used to investigate the neuropathology and potential treatments for narcolepsy. Here, we present novel data showing that orexin-deficient mice express increased anxiety in the open field, light-dark box test and carnivore odor-induced avoidance, but are normal in fear and safety learning. These findings suggest an important role of orexin in brain areas involved in anxiety. PMID- 27965040 TI - Hemodynamic shear stress stimulates migration and extravasation of tumor cells by elevating cellular oxidative level. AB - Cancer cells are shed into the blood stream and are exposed to hemodynamic shear stress during metastasis. It has been shown that shear stress can destroy circulating tumor cells (CTCs) both in vitro and in vivo. However, it remains unclear whether shear stress can modulate the properties and functions of tumor cells in a manner that might help CTCs to exit circulation. In this study, we established a microfluidic circulatory system to apply physiological fluid shear stress on breast cancer cells and demonstrated that an arterial level of shear stress significantly enhanced tumor cell migration in transwell and wound healing assays, and enhanced extravasation in a transendothelial assay. Circulatory treatment elevated the intracellular levels of reactive oxygen species (ROS), which is an early and indispensable event for activating the extracellular signal regulated kinases (ERK1/2). Subsequently, ERK1/2 activation promoted the migration of tumor cells and enhanced their extravasation. Finally, reducing cellular ROS production suppressed tumor cell extravasation in both a transendothelial assay and a zebrafish model. This new understanding of how fluid shear stress promotes tumor cell migration has important implications in cancer treatment and can help us to identify potential therapeutic targets for inhibiting tumor progression. PMID- 27965039 TI - Genetic predisposition to high anxiety- and depression-like behavior coincides with diminished DNA methylation in the adult rat amygdala. AB - Understanding biological mechanisms that shape vulnerability to emotional dysfunction is critical for elucidating the neurobiology of psychiatric illnesses like anxiety and depression. To elucidate molecular and epigenetic alterations in the brain that contribute to individual differences in emotionality, our laboratory utilized a rodent model of temperamental differences. Rats bred for low response to novelty (Low Responders, LRs) are inhibited in novel situations and display high anxiety, helplessness, and diminished sociability compared to High Novelty Responder (HR) rats. Our current transcriptome profiling experiment identified widespread gene expression differences in the amygdala of adult HR/LR rats; we hypothesize that HR/LR gene expression and downstream behavioral differences stem from distinct epigenetic (specifically DNA methylation) patterning in the HR/LR brain. Although we found similar levels of DNA methyltransferase proteins in the adult HR/LR amygdala, next-generation sequencing analysis of the methylome revealed 793 differentially methylated genomic sites between the groups. Most of the differentially methylated sites were hypermethylated in HR versus LR, so we next tested the hypothesis that enhancing DNA methylation in LRs would improve their anxiety/depression-like phenotype. We found that increasing DNA methylation in LRs (via increased dietary methyl donor content) improved their anxiety-like behavior and decreased their typically high levels of Forced Swim Test (FST) immobility; however, dietary methyl donor depletion exacerbated LRs' high FST immobility. These data are generally consistent with findings in depressed patients showing that treatment with DNA methylation-promoting agents improves depressive symptoms, and highlight epigenetic mechanisms that may contribute to individual differences in risk for emotional dysfunction. PMID- 27965041 TI - Trichodermin induces c-Jun N-terminal kinase-dependent apoptosis caused by mitotic arrest and DNA damage in human p53-mutated pancreatic cancer cells and xenografts. AB - Pancreatic cancer is an aggressive malignancy, which generally responds poorly to chemotherapy. In this study, trichodermin, an endophytic fungal metabolite from Nalanthamala psidii, was identified as a potent and selective antitumor agent in human pancreatic cancer. Trichodermin exhibited antiproliferative effects against pancreatic cancer cells, especially p53-mutated cells (MIA PaCa-2 and BxPC-3) rather than normal pancreatic epithelial cells. We found that trichodermin induced caspase-dependent and mitochondrial intrinsic apoptosis. Trichodermin also increased apoptosis through mitotic arrest by activating Cdc2/cyclin B1 complex activity. Moreover, trichodermin promoted the activation of c-Jun N terminal kinase (JNK), and inhibition of JNK by its inhibitor, shRNA, or siRNA significantly reversed trichodermin-mediated caspase-dependent apoptosis. Trichodermin triggered DNA damage stress to activate p53 function for executing apoptosis in p53-mutated cells. Importantly, we demonstrated that trichodermin with efficacy similar to gemcitabine, profoundly suppressed tumor growth through inducing intratumoral DNA damage and JNK activation in orthotopic pancreatic cancer model. Based on these findings, trichodermin is a potential therapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially the mutant p53 pancreatic cancer. PMID- 27965043 TI - At the interface of medicine and dentistry: shared decision-making using decision aids and clinical decision support tools. PMID- 27965042 TI - Do sanitary ceramic workers have a worse presentation of chest radiographs or pulmonary function tests than other ceramic workers? AB - BACKGROUND/PURPOSE: Silicosis remains the most prevalent occupational disease worldwide. There have been no specific studies focusing on the association between exposure settings at work and the clinical severity in silicosis patients. In this study, we describe and compare the clinical characteristics and silicosis-associated exposure history at work among workers from several types of ceramic production facilities in Taiwan. METHODS: We reviewed the medical records of 221 patients who were first diagnosed with silicosis at the Occupational Medicine Clinic of Northern Taiwan in 2012. For each patient, we collected data on demographic characteristics, smoking habits, working history, duration of exposure, and years on the first relevant job. We also retrieved clinical reports of the pulmonary function test and the baseline chest radiography used for silicosis staging. RESULTS: As compared to other ceramic workers, sanitary ceramic workers had a worse X-ray type (p=0.044), more advanced age (p<0.001), longer working duration (p=0.029), and a higher proportion of starting the first relevant job prior to the year 1975 (p=0.003). However, after adjusting for age, work duration, and an initial occupational exposure prior to 1975, sanitary ceramic workers showed a comparable risk for worse X-ray findings to other ceramic workers (adjusted odds ratio=1.18, p=0.704). Results of multivariable regression models on individual lung function parameter also suggested comparably impaired lung function tests between sanitary and other ceramic workers (p>0.05). CONCLUSION: In this study, we found that sanitary ceramic workers were at a similar risk to other ceramic workers for moderate to severe silicosis when older age and longer working duration were accounted for. PMID- 27965044 TI - Criteria for use of composite end points for competing risks-a systematic survey of the literature with recommendations. AB - BACKGROUND: Composite end points are frequently used in reports of clinical trials. One rationale for the use of composite end points is to account for competing risks. In the presence of competing risks, the event rate of a specific event depends on the rates of other competing events. One proposed solution is to include all important competing events in one composite end point. Clinical trialists require guidance regarding when this approach is appropriate. OBJECTIVES: To identify publications describing criteria for use of composite end points for competing risk and to offer guidance regarding when a composite end point is appropriate on the basis of competing risks. METHODS, DATA SOURCES, STUDY SELECTION AND DATA EXTRACTION: We searched MEDLINE, CINAHL, EMBASE, The Cochrane's Central & Systematic Review databases including the Health Technology Assessment database, and the Cochrane's Methodology register from inception to April 2015, and candidate textbooks, to identify all articles providing guidance on this issue. Eligible publications explicitly addressed the issue of a composite outcome to address competing risks. Two reviewers independently screened the titles and abstracts for full-text review; independently reviewed full-text publications; and abstracted specific criteria authors offered for use of composite end points to address competing risks. RESULTS: Of 63,645 titles and abstracts, 166 proved potentially relevant of which 43 publications were included in the final review. Most publications note competing risks as a reason for using composite end points without further elaboration. None of the articles or textbook chapters provide specific criteria for use of composite end points for competing risk. Some advocate using composite end points to avoid bias due to competing risks and others suggest that composite end points seldom or never be used for this purpose. We recommend using composite end points for competing risks only if the competing risk is plausible and if it occurs with sufficiently high frequency to influence the interpretation of the effect of intervention on the end point of interest. These criteria will seldom be met. Review of heart failure trials published in the New England Journal of Medicine revealed that many of them use the composite end point of death or hospitalization; none of the trials, however, satisfied our criteria. CONCLUSION: The existing literature fails to provide clear guidance regarding use of composite end point for competing risks. We recommend using composite end points for competing risks only if the competing risk is plausible and if it occurs sufficiently often. PMID- 27965045 TI - A Trial-Based Economic Evaluation Comparing Spinal Cord Stimulation With Best Medical Treatment in Painful Diabetic Peripheral Neuropathy. AB - : The objective was to perform an economic evaluation comparing spinal cord stimulation (SCS) in combination with best medical treatment (BMT) with BMT in painful diabetic peripheral neuropathy patients. Alongside a prospective 2-center randomized controlled trial, involving 36 painful diabetic peripheral neuropathy patients with severe lower limb pain not responding to conventional therapy, an economic evaluation was performed. Incremental cost-effectiveness ratios were based on: 1) societal costs and quality-adjusted life years (QALYs), and 2) direct health care costs and the number of successfully treated patients, respectively, both with a time horizon of 12 months. Bootstrap and secondary analyses were performed to address uncertainty. Total societal cost amounted to ?26,539.18 versus ?5,313.45 per patient in the SCS and BMT group, respectively. QALYs were .58 versus .36 and the number of successfully treated patients was 55% versus 7% for the SCS and BMT group, respectively. This resulted in incremental cost-effectiveness ratios of ?94,159.56 per QALY and ?34,518.85 per successfully treated patient, respectively. Bootstrap analyses showed that the probability of SCS being cost-effective ranges from 0 to 46% with willingness to pay threshold values ranging between ?20,000 and ?80,000 for a QALY. Secondary analyses showed that cost-effectiveness of SCS became more favorable after correcting for baseline cost imbalance between the 2 groups, extending the depreciation period of SCS material to 4 years, and extrapolation of the data up to 4 years. Although SCS was considerably more effective compared with BMT, the substantial initial investment that is required resulted in SCS not being cost-effective in the short term. Cost-effectiveness results were sensitive to baseline cost imbalances between the groups and the depreciation period of the SCS material. PERSPECTIVE: Painful diabetic peripheral neuropathy is a common complication of diabetes mellitus and the humanistic and economic burden is high. This article presents the cost-effectiveness of SCS in patients suffering from painful diabetic peripheral neuropathy from a societal and health care perspective with a time horizon of 12 months. PMID- 27965046 TI - Bone resorption, matrix metalloproteinases and caffeic acid phenethyl ester. PMID- 27965047 TI - Biomechanical comparison of orthogonal versus parallel double plating systems in intraarticular distal humerus fractures. AB - OBJECTIVES: In intraarticular distal humerus fractures, internal fixation with double plates is the gold standard treatment. However the optimal plate configuration is not clear in the literature. The aim of this study was to compare the biomechanical stability of the parallel and the orthogonal anatomical locking plating systems in intraarticular distal humerus fractures in artificial humerus models. METHODS: Intraarticular distal humerus fracture (AO13-C2) with 5 mm metaphyseal defect was created in sixteen artificial humeral models. Models were fixed with either orthogonal or parallel plating systems with locking screws (Acumed elbow plating systems). Both systems were tested for their stiffness with loads in axial compression, varus, valgus, anterior and posterior bending. Then plastic deformation after cyclic loading in posterior bending and load to failure in posterior bending were tested. The failure mechanisms of all the samples were observed. RESULTS: Stiffness values in every direction were not significantly different among the orthogonal and the parallel plating groups. There was no statistical difference between the two groups in plastic deformation values (0.31 mm-0.29 mm) and load to failure tests in posterior bending (372.4 N-379.7 N). In the orthogonal plating system most of the failures occurred due to the proximal shaft fracture, whereas in the parallel plating system failure occurred due to the shift of the most distal screw in proximal fragment. CONCLUSION: Our study showed that both plating systems had similar biomechanical stabilities when anatomic plates with distal locking screws were used in intraarticular distal humerus fractures in artificial humerus models. PMID- 27965048 TI - Isolation of Clostridium difficile from dogs with digestive disorders, including stable metronidazole-resistant strains. AB - The prevalence of Clostridium difficile in 107 dogs with diverse digestive disorders attended in a Spanish veterinary teaching hospital was assessed. The microorganism was isolated from 13 dogs (12.1%) of different disease groups. Isolates belonged to PCR ribotypes 078, 106, 154 and 430 (all of them toxigenic) and 110 (non-toxigenic), and were resistant to several antimicrobial drugs. Notably, seven isolates obtained from different dogs displayed stable resistance to metronidazole. The results of this study provide further evidence that dogs can act as a reservoir of C. difficile strains of epidemic ribotypes with resistance to multiple antibiotics. PMID- 27965049 TI - Clinical efficacy of Rong-Yang-Jyh-Gan-Tang on patients with chronic hepatitis C: A double-blinded randomized placebo-controlled crossover study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) has been widely used by the Chinese population for treatment of chronic hepatitis. However, the efficacy of TCM for patients with chronic hepatitis has not been confirmed, mostly due to the lack of available scientific parameters such as serum viral load to evaluate treatment response. AIM OF THE STUDY: We evaluated the efficacy of Rong-Yang-Jyh-Gan-Tang (RYJGT, composed of Long-Dan-Xie-Gan-Tang, Jia-Wei-Xia-Yao-San, Dan-Shen, and Hou-Po) on patients with chronic hepatitis C. MATERIALS AND METHODS: Thirty-six patients with chronic hepatitis C who had no response to or had contraindications to interferon-ribavirin therapy were randomly allocated to receive RYJGT 15g/day or placebo for 12 weeks. After a 2 week washout period, patients were crossed over to receive placebo or RYJGT for another 12 weeks. Evaluation parameters included liver biochemistries, serum HCVRNA, side effects of RYJGT/placebo, and TCM symptoms. RESULTS: Of the patients who had 12-week RYJGT treatment, 51.7% had decreased serum HCVRNA levels, whereas only 25.8% patients had decreased levels in the placebo group (p=0.036). TCM patterns of "Damp-Heat" and "Liver Qi Depression" had significantly improved after RYJGT treatment in comparison with the placebo. Logistic analyses showed that RYJGT treatment, and pre-treatment values of TCM symptoms of "Damp-Heat" and "Liver Qi Depression", were statistically significant factors in predicting the decrease in serum HCVRNA. CONCLUSION: Chronic hepatitis C patients who received a 12-week RYJGT treatment had significantly higher HCVRNA decrease ratio, and improved TCM symptoms of "Damp-Heat" and "Liver Qi Depression", than those who received the placebo. Our results require further larger scale clinical trials. PMID- 27965051 TI - Reduced allergic lung inflammation by root extracts from two species of Peucedanum through inhibition of Th2 cell activation. AB - ETHNOPHARMACOLOGICAL EVIDENCE: Peucedani Radix (PR), the root of Peucedanum praeruptorum Dunn (PPD) or Peucedanum decursivum (Miq.) Maxim. (PDM), has long been used in Korea to eliminate sputum, relieve cough, and reduce bronchus contraction. Furthermore, these therapeutic strategies are recognized as general and effective methods in western medicine as well as traditional Korean medicine. AIM OF THE STUDY: To determine and compare the anti-inflammatory effects of PPD extracts (PPDE) and PDM extracts (PDME) on allergic lung inflammation, using in vivo OVA-induced airway inflammation in mice and in vitro primary cell culture systems. MATERIALS AND METHODS: Eight-week-old female C57BL/6 mice were placed into four groups (n=4 per group): saline control, OVA-induced allergic lung inflammation with vehicle, or PPDE (200mg/kg) or PDME (200mg/kg) treatment. PR extracts (PRE) were administered from 1 week before 1st OVA sensitization to the day before sacrifice. Mice were sacrificed 18h after last OVA intra-nasal challenge followed by histological and biochemical analyses. RESULTS: Inflammatory phenotypes were alleviated with oral administration of PRE. PRE treatment decreased mucus production in airway epithelium, inflammatory cell number, eosinophilia, type 2 cytokines, and histamine in bronchoalveolar lavage fluid (BALF). Mice with PRE administration showed diminished activated CD4 T cell (CD4+CD25+ cell) and GATA-3 level in the lung. In addition, PRE treatment reduced Th2 cell activation in vitro, using Th2 polarization system. CONCLUSION: Our findings indicate that the anti-inflammatory effects of PRE arise from reduced Th2 cell activation and validate the clinical use of PR in traditional Korean medicine. PMID- 27965050 TI - The optimal dose of arsenic trioxide induced opposite efficacy in autophagy between K562 cells and their initiating cells to eradicate human myelogenous leukemia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Arsenic trioxide (As2O3), a main component of arsenolite which is a common traditional Chinese medicine (TCM) wildly used as a therapeutic agent for more than 2400 years in china, has been accepted as a standard treatment for the patients with acute promyelocytic leukemia (APL) based on the principle in TCM of "using a poison to fight against other poisons or malignancy illnesses". However, it remains unknown that which mechanism is actually responsible for the therapeutic effects against these blood malignancies. AIM OF THE STUDY: The purpose of this study was to explore the actual mechanism that ATO exerts its effects in K562 cells and their initiating cells (K562s). MATERIALS AND METHODS: K562s cells were separated and enriched for CD34+/CD38- cells using magnetic microbeads. Cell proliferation was determined by incorporation of BrdU. Cell apoptosis was evaluated by Annexin-V binding and PI uptake. Autophagy was estimated by acridine orange and immunofluorescence staining of LC3-B and p62. MC colonic formation was used to examine cell self renew. ROS generation inside living cells was measured by DCFH-DA. Cell differentiation was assessed by the benzidine staining. The SA-beta-gal assay was used to detect cell senescence. Protein expression was examined by western blotting and immunohistochemical staining. RESULTS: K562s cells were stronger in self-renew and resistance to ATO cytotoxicity and starvation-induced apoptosis than K562 cells. Unexpectedly, we found that ATO at a dose of 0.5MUM which had no effect on cell proliferation resulted in maximum suppression on self-renew in both cells and maximum starvation-induced apoptosis in K562s cells but minimum starvation-induced apoptosis in K562 cells. Next, we found that ATO no more than 0.5MUM selectively induced K562s cell differentiation indicated by benzidine staining, gamma-globin and CD235a expression. More importantly, we found that ATO no more than 0.5MUM led to opposite efficacy in autophagy between K562 and K562s cells, and the opposite autophagy could induced late-phase senescence in both cells. Finally, we used the optimal dose of ATO to eradicate leukemia cells and obtained a satisfied therapeutic outcomes in vivo. CONCLUSIONS: Our results suggest that the used dose of ATO may determine the fate of cell differentiation senescence or malignant transformation, and the optimal dose of ATO induced opposite efficacy in autophagy between K562 cells and their initiating cells and ultimately leads both cells to late-phase senescence. PMID- 27965052 TI - A traditional Chinese formula composed of Chuanxiong Rhizoma and Gastrodiae Rhizoma (Da Chuanxiong Formula) suppresses inflammatory response in LPS -induced RAW 264.7 cells through inhibition of NF-kappaB pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Da Chuanxiong Formula (DCXF) which origins from Jin Dynasty is a famous classical 2-herb Chinese medicinal prescription. It is composed of dried rhizomes of Ligusticum chuanxiong (Chuanxiong Rhizoma, CR) and Gastrodia elata (Gastrodiae Rhizoma, GR) at the ratio of 4:1 (w/w). It has been used to treat headache which is caused by wind pathogen and blood stasis for thousands of years in China. AIM OF STUDY: The present study was performed to investigate the anti-inflammatory effect of DCXF and elucidate its underlying molecular mechanisms using LPS-stimulated RAW 264.7 cells. MATERIALS AND METHODS: The anti-inflammatory effect of DCXF was evaluated using LPS-stimulated RAW 264.7 cells. Generation of nitric oxide (NO) and prostaglandin E2 (PGE2) were measured by the Griess colorimetric method and enzyme-linked immunosorbent assay (ELISA), respectively. The gene expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected by reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, the effect of DCXF on NF-kappaB activation was measured by western blot assay. RESULTS: Treatment with DCXF significantly suppressed the productions of NO and PGE2 through inhibitions of iNOS and COX-2 expressions in LPS-stimulated RAW 264.7 cells. DCXF significantly decreased IkappaBalpha phosphorylation, inhibited p65 expression and reduced p-p65 level. These results suggested the anti-inflammatory effect of DCXF was associated with the reduction of inflammatory mediators through inhibition of NF-kappaB pathway. CONCLUSIONS: These results indicated that DCXF inhibited inflammation in LPS stimulated RAW 264.7 cells through inactivation of NF-kappaB pathway. PMID- 27965053 TI - The spinal cord shows the way - How axons navigate intermediate targets. AB - Functional neural circuits depend on the establishment of specific connections between neurons and their target cells. To this end, many axons have to travel long distances to reach their target cells during development. Studies addressing the molecular mechanisms of axon guidance have to overcome the complexity of subpopulation-specific requirements with respect to pathways, guidance cues, and target recognition. Compared to the brain, the relatively simple structure of the spinal cord provides an advantage for experimental studies of axon guidance mechanisms. Therefore, the so far best understood model for axon guidance is the dI1 population of dorsal interneurons of the spinal cord. They extend their axons ventrally towards the floor plate. After midline crossing, they turn rostrally along the contralateral floor-plate border. Despite the fact that the trajectory of dI1 axons seems to be rather simple, the number of axon guidance molecules involved in the decisions taken by these axons is bewildering. Because guidance molecules and mechanisms are conserved throughout the developing nervous system, we can generalize what we have learned about the navigation of the floor plate as an intermediate target for commissural axons to the brain. PMID- 27965055 TI - In toto imaging of the migrating Zebrafish lateral line primordium at single cell resolution. AB - The zebrafish Posterior Lateral Line primordium (PLLp) has emerged as an important model system for studying many aspects of development, including cell migration, cell type specification and tissue morphogenesis. Despite this, basic aspects of PLLp biology remain incompletely understood. The PLLp is a group of approximately 140 cells which pioneers the formation of the Posterior Lateral Line (LL) system by migrating along the length of the embryo, periodically depositing clusters of epithelial cells, which will go on to form the mature sense organs of the lateral line, called neuromasts. The neuromasts are formed within the migrating PLLp as protoneuromasts: the first protoneuromast is formed close to the trailing end and additional protoneuromasts are formed sequentially, progressively closer to the leading edge of the migrating collective. We imaged the migration of PLL primordia and tracked every cell in the lateral line system over the course of migration. From this data set we unambiguously determined the lineage and fate of every cell deposited by the migrating PLLp. We show that, on average, proliferation across the entire PLLp is weakly patterned, with leading cells tending to divide more slowly than trailing cells. Neuromasts are formed sequentially by local expansion of existing cells along the length of the PLLp, not by self-renewing stem cell-like divisions of a restricted leading population that is highly proliferative. The fate of deposited cells, either within neuromasts or as interneuromast cells (in between deposited neuromasts) is not determined by any obvious stereotyped lineages. Instead, it is determined somewhat stochasitcailly, as a function of a cells distance from the center of a maturing protoneuromast. Together, our data provide a rigorous baseline for the behavior of the PLLp, which can be used to inform further study of this important model system. PMID- 27965056 TI - Porcupine-dependent Wnt signaling controls stromal proliferation and endometrial gland maintenance through the action of distinct WNTs. AB - Wnt signaling has been shown to be important in orchestrating proper development of the female reproductive tract. In the uterus, six members of the Wnt family are expressed in the neonatal endometrium and deletion of individual Wnt genes often leads to similar phenotypes, suggesting an interaction of these genes in uterine development and function. Furthermore, Wnts may have complementary functions, which could mask the identification of their individual functional role in single gene deletions. To circumvent this issue, we have generated a deletion of the Porcupine homolog within the female reproductive tract using progesterone receptor-Cre mice (PgrCre/+); preventing Wnt secretion from the producing cells. We show that Porcupine-dependent Wnt signaling, unlike previously reported, is dispensable for postnatal gland formation but is required for post-pubertal gland maintenance as well as for stromal cell proliferation. Furthermore, our results demonstrate that WNT7a is sufficient to restore post pubertal endometrial gland formation. Although WNT5a did not restore gland formation, it rescued stromal cell proliferation; up-regulating several secreted factors including Fgf10 and Ihh. Our results further elucidate the roles of Wnt signaling in uterine development and function as well as provide an ideal system to address individual Wnt functions in the uterus. PMID- 27965054 TI - ARID3A is required for mammalian placenta development. AB - Previous studies in the mouse indicated that ARID3A plays a critical role in the first cell fate decision required for generation of trophectoderm (TE). Here, we demonstrate that ARID3A is widely expressed during mouse and human placentation and essential for early embryonic viability. ARID3A localizes to trophoblast giant cells and other trophoblast-derived cell subtypes in the junctional and labyrinth zones of the placenta. Conventional Arid3a knockout embryos suffer restricted intrauterine growth with severe defects in placental structural organization. Arid3a null placentas show aberrant expression of subtype-specific markers as well as significant alteration in cytokines, chemokines and inflammatory response-related genes, including previously established markers of human placentation disorders. BMP4-mediated induction of trophoblast stem (TS) like cells from human induced pluripotent stem cells results in ARID3A up regulation and cytoplasmic to nuclear translocation. Overexpression of ARID3A in BMP4-mediated TS-like cells up-regulates TE markers, whereas pluripotency markers are down-regulated. Our results reveal an essential, conserved function for ARID3A in mammalian placental development through regulation of both intrinsic and extrinsic developmental programs. PMID- 27965057 TI - Visible light enhances the antimicrobial effect of some essential oils. AB - The photodisinfection is a topical, broad spectrum antimicrobial technology, targeting bacteria, virus, fungi, and protozoa effective for single cells as for biofilms. Natural molecules have been studied less than synthetic agents in the process but they are currently receiving great interest. Therefore, the aim of this study is to evaluate for the first time if non-coherent blue and red light enhances the antimicrobial activity of some essential oils when standard strains for antibiotic or fungicide tests are enlightened in vitro. Staphylococcus epidermidis, Pseudomonas aeruginosa and Candida albicans collection strains were irradiated with monochromatic visible light from light emitting diodes in the presence of 5% and 0.5% eucalyptus (Eucalyptus globulus), clove (Eugenia caryophyllata), and thyme (Thymus vulgaris) essential oils. Microbial levels were measured by plate count on culture media. In this preliminary report, the results differ according to the kind and concentration of antimicrobial oils, the wavelength of light, and the prokaryotic or eukaryotic microorganism. The results support the idea that mainly blue light enhances the innate antimicrobial activity of the essential oils, especially phenols, and could offer a very efficient and natural way to combat microorganisms in several industries and medical applications (cutaneous and oral infections, medical textiles, foodstuffs and fruit surface, etc.). PMID- 27965058 TI - Apathy and higher level of gait control in normal pressure hydrocephalus. AB - Apathy represents the most common behavioral disturbance in patients with suspicion of idiopathic normal pressure hydrocephalus (iNPH) and has a major impact on quality of life. However, its impact on gait -the hallmark motor disturbance of iNPH - has never been studied yet. This study aims to evaluate the impact of apathy on higher level of gait control in patients with suspicion of iNPH. Stride time variability (STV), a marker of higher level of gait control, was quantified during usual walking (single task) and during walking while performing simultaneously cognitive tasks (dual task) of counting and verbal fluency. Among 46 patients with suspicion of iNPH (77.6+/-6.7years; 34.8% women), 30 (65.2%) presented apathy (defined by a score>=14 on the Starkstein apathy scale). Backward counting induced more important worsening of STV (i.e. increasing STV) in apathetic compared to non-apathetic patients (14.8+/-25.1% versus 9.0+/-20.4%; p=0.005), while both groups presented similar executive functioning. These findings suggest that apathy contributes to gait disorders in iNPH. Apathy is easy to monitor and should be considered as a target symptom of treatment. PMID- 27965059 TI - Epigenetics of psoriatic disease: A systematic review and critical appraisal. AB - Psoriasis is an inflammatory disease of the skin that is sometimes accompanied by an auto-inflammatory arthritis called psoriatic arthritis (PsA). Psoriasis and PsA are multifactorial diseases that result from complex interactions of environmental and genetic risk factors. Epigenetic marks, which are labile chemical marks with diverse functions, form a layer of biological information that sits at the interface of genetics and the environment. Aberrant epigenetic regulation has been previously implicated in other rheumatological disorders. The purpose of this review is to summarize and critically evaluate the nascent literature on epigenetics in psoriasis and PsA. A systematic review yielded 52 primary articles after applying inclusion and exclusion criteria. Data were extracted using a standardized template and study quality assessed using a methodological quality checklist. Studies reflect a broad range of epigenetic sub disciplines, the most common being DNA methylation, followed by the parent of origin effect or genomic imprinting, expression or activity of epigenetic modifying enzymes, and histone modifications. Epidemiological studies demonstrating excessive paternal transmission provided the earliest evidence of epigenetic deregulation in psoriatic disease, however few studies have examined its molecular mechanisms. Methylation studies evolved rapidly from low resolution global to targeted analyses of known psoriatic disease susceptibility loci such as HLA-C*0602. The recent explosion of epigenome-wide association studies has provided us with novel insights into psoriasis pathogenesis, and the mechanism of action of UVB, methotrexate, and anti-TNF therapies, as well as molecular signatures of psoriasis that may have clinical relevance. Finally, recent studies of pharmacological inhibitors of epigenetic modifier enzymes demonstrate their potential applicability as novel treatment modalities for psoriasis. Challenges of epigenetics research in psoriasis and PsA were identified and future perspectives are discussed herein. PMID- 27965061 TI - CFTR nonsense mutations: Therapeutic benefits from clinically approved drugs? PMID- 27965060 TI - IgG4 autoantibodies against muscle-specific kinase undergo Fab-arm exchange in myasthenia gravis patients. AB - Autoimmunity mediated by IgG4 subclass autoantibodies is an expanding field of research. Due to their structural characteristics a key feature of IgG4 antibodies is the ability to exchange Fab-arms with other, unrelated, IgG4 molecules, making the IgG4 molecule potentially monovalent for the specific antigen. However, whether those disease-associated antigen-specific IgG4 are mono or divalent for their antigens is unknown. Myasthenia gravis (MG) with antibodies to muscle specific kinase (MuSK-MG) is a well-recognized disease in which the predominant pathogenic IgG4 antibody binds to extracellular epitopes on MuSK at the neuromuscular junction; this inhibits a pathway that clusters the acetylcholine (neurotransmitter) receptors and leads to failure of neuromuscular transmission. In vitro Fab-arm exchange-inducing conditions were applied to MuSK antibodies in sera, purified IgG4 and IgG1-3 sub-fractions. Solid-phase cross linking assays were established to determine the extent of pre-existing and inducible Fab-arm exchange. Functional effects of the resulting populations of IgG4 antibodies were determined by measuring inhibition of agrin-induced AChR clustering in C2C12 cells. To confirm the results, kappa/kappa, lambda/lambda and hybrid kappa/lambda IgG4s were isolated and tested for MuSK antibodies. At least fifty percent of patients had IgG4, but not IgG1-3, MuSK antibodies that could undergo Fab-arm exchange in vitro under reducing conditions. Also MuSK antibodies were found in vivo that were divalent (monospecific for MuSK). Fab-arm exchange with normal human IgG4 did not prevent the inhibitory effect of serum derived MuSK antibodies on AChR clustering in C2C12 mouse myotubes. The results suggest that a considerable proportion of MuSK IgG4 could already be Fab-arm exchanged in vivo. This was confirmed by isolating endogenous IgG4 MuSK antibodies containing both kappa and lambda light chains, i.e. hybrid IgG4 molecules. These new findings demonstrate that Fab-arm exchanged antibodies are pathogenic. PMID- 27965062 TI - Gel filtration of dilute human embryonic hemoglobins reveals basis for their increased oxygen binding. AB - This report establishes a correlation between two known properties of the human embryonic hemoglobins-- their weak subunit assemblies as demonstrated here by gel filtration at very dilute protein concentrations and their high oxygen affinities and reduced cooperativities reported previously by others but without a mechanistic basis. We demonstrate here that their high oxygen affinities are a consequence of their weak assemblies. Weak vs strong hemoglobin tetramers represent a regulatory mechanism to modulate oxygen binding capacity by altering the equilibrium between the various steps in the assembly process that can be described as an inverse allosteric effect. PMID- 27965063 TI - A novel method for immobilization of proteins via entrapment of magnetic nanoparticles through epoxy cross-linking. AB - A method for immobilization of functional proteins by chemical cross-linking of the protein of interest and uncoated iron oxide nanoparticles in the presence of Epichlorohydrin is described. As a result of the cross-linking, the proteins form a matrix in which the particles get entrapped. The optimum concentration of Epichlorohydrin that facilitates immobilization of protein without affecting the functional properties of the protein was determined. This method was used to immobilize several functional proteins and the development and functional activity of Protein A-magnetic nanoparticles (MNPs) is described here in detail. The Protein A-MNPs possess high binding capacity due to the increased surface area of uncoated nanoparticles and robust magnetic separation due to the absence of polymeric coating materials. Protein A-MNPs were successfully used for purification of antibodies and also for immunoprecipitation. We also immobilized enzymes such as horse radish peroxidase and esterase and found that by providing the optimum incubation time, temperature and protein to nanoparticle ratio, we can retain the activity and improve the stability of the enzyme. This study is the first demonstration that Epichlorohydrin can be used to entrap nanoparticles in a cross-linked matrix of protein without impairing the activity of immobilized protein. PMID- 27965064 TI - Solutions to decrease a systematic error related to AAPH addition in the fluorescence-based ORAC assay. AB - Oxygen radical absorbance capacity (ORAC) assay in 96-well multi-detection plate readers is a rapid method to determine total antioxidant capacity (TAC) in biological samples. A disadvantage of this method is that the antioxidant inhibition reaction does not start in all of the 96 wells at the same time due to technical limitations when dispensing the free radical-generating azo initiator 2,2'-azobis (2-methyl-propanimidamide) dihydrochloride (AAPH). The time delay between wells yields a systematic error that causes statistically significant differences in TAC determination of antioxidant solutions depending on their plate position. We propose two alternative solutions to avoid this AAPH-dependent error in ORAC assays. PMID- 27965065 TI - Recurrent themes in the history of the home use of electrical stimulation: Transcranial direct current stimulation (tDCS) and the medical battery (1870 1920). AB - BACKGROUND: In recent years, neuroscientists and ethicists have warned of the dangers of the unsupervised home use of transcranial direct current stimulation (tDCS), in which individuals stimulate their own brains with low levels of electricity for self-improvement purposes. Although the home use of tDCS is often referred to as a novel phenomenon, in reality the late nineteenth and early twentieth century saw a proliferation of electrical stimulation devices for home use. In particular, the use of an object known as the medical battery bears a number of striking similarities to the modern-day use of tDCS. OBJECTIVE: This article reviews a number of features thought to be unique to the present day home use of brain stimulation, with a particular focus on analogies between tDCS and the medical battery. METHODS: Archival research was conducted at the Bakken Museum and at the American Medical Association's Historical Health Fraud Archives. RESULTS: Many of the features characterizing the contemporary home use tDCS-a do-it-yourself (DIY) movement, anti-medical establishment themes, conflicts between lay and professional usage-are a repetition of themes that occurred a century ago with regard to the medical battery. A number of features, however, seem to be unique to the present, such as the dominant discourse about risk and safety, the division between cranial and non-cranial stimulation, and utilization for cognitive enhancement purposes. CONCLUSION(S): Viewed in the long duree, the contemporary use of electrical stimulation at home is not a novel phenomenon, but rather the latest wave in a series of ongoing attempts by lay individuals to utilize electricity for therapeutic purposes. PMID- 27965066 TI - Response to "Response to Hoy, 'Gender imbalance and brain stimulation conferences: We have a problem and it is everyone's problem'". PMID- 27965067 TI - Physiological and behavioral effects of beta-tACS on brain self-regulation in chronic stroke. AB - BACKGROUND: Unlike in healthy controls, sensorimotor beta-desynchronization (beta ERD) is compromised in stroke patients, i.e., the more severe the patient's motor impairment, the less beta-ERD. This, in turn, provides a target substrate for therapeutic brain self-regulation and neurofeedback. OBJECTIVE: Transcranial alternating current stimulation (tACS) has been shown to modulate brain oscillations during and after stimulation, and may thus facilitate brain self regulation during neurofeedback interventions. METHODS: Twenty severely impaired, chronic stroke patients performed kinesthetic motor-imagery while a brain-robot interface transformed beta-ERD (17-23 Hz) of the ipsilesional sensorimotor cortex into opening of the paralyzed hand by a robotic orthosis. In a parallel group design, beta-tACS (20 Hz, 1.1 mA peak-to-peak amplitude) was applied to the lesioned motor cortex either continuously (c-tACS) before or intermittently (i tACS) during the intervention. Physiological effects of beta-tACS were studied using electroencephalography. The patients' ability for brain self-regulation was captured by neurofeedback performance metrics. RESULTS: i-tACS - but not c-tACS - improved the classification accuracy of the neurofeedback intervention in comparison to baseline. This effect was mediated via the increased specificity of the classification, i.e., reduced variance of resting oscillations. Neither i tACS nor c-tACS had aftereffects following the stimulation period. CONCLUSION: beta-tACS may constitute an adjunct neuromodulation technique during neurofeedback-based interventions for stroke rehabilitation. PMID- 27965069 TI - The nuts and bolts of doing science. PMID- 27965068 TI - Personal Digital Assistant-Based Self-Work Sampling Study of Pediatric Interns Quantifies Workday and Educational Value. AB - OBJECTIVE: Optimizing clinical proficiency and education of residents has become more important with restricted residency duty hours. Our objective was to investigate how interns spend their time on inpatient rotations and the perceived educational value of workday activities. METHODS: We performed a descriptive self work sampling study using a personal digital assistant (PDA) to randomly query interns on inpatient rotations in real time regarding their activity and the perceived educational value of that activity on a 4-point Likert scale. RESULTS: A total of 31 interns participated on 88 workdays over a 5-month period, generating 2082 samples from which the average workday was modeled. Time spent using the electronic health record (EHR) accounted for 33% of intern time, communicating with the health care team 23%, educational activities 17%, and time with patients and families 12%. Time with patients and families was perceived to be the most educational part of clinical service. Time spent using the EHR was perceived as the least educational. Interns perceived clinical service as excellent or good 37% of the time, while planned educational activities were perceived as excellent or good 81% of the time. CONCLUSIONS: Interns spend the majority of their time using the EHR and communicating with the health care team. Interns perceive time spent in planned educational activities has more educational value than time spent in clinical service. The distribution of daily activities is discordant with the perceived educational value of those activities. PMID- 27965070 TI - Fluoroquinolones or macrolides in combination with beta-lactams in adult patients hospitalized with community acquired pneumonia: a systematic review and meta analysis. AB - OBJECTIVE: The best treatment option for hospitalized patients with community acquired pneumonia (CAP) has not been defined. The effectiveness of beta lactam/fluoroquinolone (BLFQ) versus beta-lactam/macrolide (BLM) combinations for the treatment of patients with CAP was evaluated. METHODS: PubMed, Scopus and the Cochrane Library were searched for observational cohort studies, non-randomized and randomized controlled trials providing data for patients with CAP receiving BLM or BLFQ. Mortality was the primary outcome. A meta-analysis was performed. MINORS and GRADE were used for data quality assessment. RESULTS: Seventeen studies (16 684 patients) were included. Randomized trials were not identified. A variety of beta-lactams, fluoroquinolones and macrolides were used within and between the studies. Mortality was reported at different time points. The available body of evidence had very low quality. In the analysis of unadjusted data, mortality with BLFQ was higher than with BLM (risk ratio 1.33, 95% CI 1.15 1.54, I2 28%). BLFQ was associated with higher mortality regardless of the study design, mortality recording time, study period and study BLM group mortality. BLFQ was associated with higher mortality in American but not European studies. No difference was observed in patients with bacteraemia and septic shock. In the meta-analysis of adjusted mortality data, a non-significant difference between the two regimens was observed (eight studies, adjusted risk ratio 1.26, 95% CI 0.95-1.67, I2 43%). CONCLUSION: In the absence of data from randomized controlled trials recommendations cannot be made for or against either of the studied regimens in this group of hospitalized patients with CAP. Well designed randomized controlled trials comparing the two regimens are warranted. PMID- 27965071 TI - A betulinic acid derivative SH479 inhibits collagen-induced arthritis by modulating T cell differentiation and cytokine balance. AB - The ideal therapeutic drug for rheumatoid arthritis (RA) should not only inhibit inflammation, but also prevent articular joint damage and particularly inhibit osteoclastogenesis. Betulinic acid (BA) is a natural pentacyclic triterpene that has displayed moderate anti-inflammatory and anti-osteoclastogenesis activities in various experimental systems, suggesting that BA or its derivatives could have an inhibitory effect on RA. In this study, we screened BA derivatives and found a heterocyclic ring-fused BA derivative, SH479, which had greater inhibitory effect than BA on Th17 differentiation. Moreover, we investigated the immune regulatory activity and potential therapeutic effects of SH479 in an experimental model of rheumatoid arthritis, the collagen-induced arthritis (CIA) mouse model. SH479 significantly inhibited Th1 and Th17 polarization, antigen-specific T cell proliferation and splenic lymphocyte-induced osteoclastogenesis. Furthermore, it diminished arthritis scores as well as bone destruction and cartilage depletion in the CIA mouse model. The protective effect of SH479 was accompanied by decreased levels of pro-inflammatory cytokines IL-17 and IFN-gamma, together with enhanced anti-inflammatory cytokine expression including IL-10 and IL-4, as well as elevated CD4+ Foxp3+ cell number. At the molecular level, our results indicated that SH479 alleviated CIA through regulation of CD4+ T cell subtypes by JAK-STAT pathways. In conclusion, this study demonstrates that SH479 has therapeutic potential for rheumatoid arthritis through an anti-inflammatory effect by shifting a pathogenic Th17/Th1 response to a Th2/Treg phenotype, and also through an additional articular bone protection effect. PMID- 27965072 TI - Rare Lesions of the Internal Auditory Canal. AB - BACKGROUND: Approximately 95% of tumors occurring within the internal auditory canal (IAC) are vestibular schwannomas. Many undergo stereotactic radiation without definitive tissue diagnosis. Rare IAC tumors are not all radiosensitive and are poorly described. METHODS: Between 1992 and 2015, 289 consecutive patients with IAC lesions operated on were reviewed retrospectively. RESULTS: Fifteen patients (5.2%) (16 operations) had unusual histologic findings, including nonvestibular schwannomas (2 facial schwannomas, 2 cochlear schwannomas, 2 intermedius schwannomas), 3 meningiomas, 3 cavernous hemangiomas, a mucosa-associated lymphoid tissue lymphoma, an arachnoid cyst, and a lipochoristoma. None of these rare tumors could be identified before surgery. Three operative approaches were used: the retrosigmoid approach, middle fossa subtemporal approach, or translabyrinthine approach. Few complications occurred, including facial nerve palsy, loss of hearing, and vestibular function. Five-year average follow-up revealed one patient with recurrence. CONCLUSIONS: Clinical examination and imaging alone were insufficient to correctly identify these tumors. Definitive pathologicdiagnosis should be strongly considered to help tailor treatment. PMID- 27965074 TI - Anterior Temporal Artery-to-Anterior Cerebral Artery Bypass: Anatomic Feasibility of a Novel Intracranial-Intracranial Revascularization Technique. AB - BACKGROUND: Complex aneurysms of the anterior cerebral artery (ACA) may require a bypass procedure as part of their surgical management. Most current bypass paradigms recommend technically demanding side-to-side anastomosis of pericallosal arteries or use of interposition grafts, which involve longer ischemia times. The purpose of this study is to assess the feasibility of an anterior temporal artery (ATA) to ACA end-to-side bypass. METHODS: Fourteen cadaveric specimens (17 ATAs) were prepared for surgical simulation. The cisternal course of the ATA was freed from perforating branches and arachnoid. The M3-M4 junction of the ATA was cut, and the artery was mobilized to the interhemispheric fissure. The feasibility of ATA bypass to the precommunicating and postcommunicating ACA was assessed in relation to the cisternal length and branching pattern of the middle cerebral artery. RESULTS: Successful anastomosis was feasible in 14 ATAs (82%). Three ATAs did not reach the ACA. These ATAs were branching distally and originated from the M3 (opercular) middle cerebral artery. In specimens where bypass was not feasible, the average cisternal length of the ATA was significantly shorter than the rest. CONCLUSIONS: ATA-ACA bypass is anatomically feasible and may be a useful alternative to other revascularization techniques in selected patients. It is technically simpler than A3-A3 in situ bypass. ATA-ACA bypass can be performed through the same pterional exposure used for the ACA aneurysms, sparing the patient an additional interhemispheric approach, required for the A3-A3 anastomosis. PMID- 27965073 TI - Outcomes of Endonasal and Lateral Approaches to Petroclival Meningiomas. AB - OBJECTIVE: Transpetrosal approaches for the treatment of petroclival meningiomas are often associated with substantial morbidity and long recovery. With the goal of early clinical improvement, we have used less invasive surgical approaches for petroclival meningiomas. METHODS: We retrospectively reviewed 32 patients with petroclival meningiomas. Eleven patients (34.4%) were managed with lateral approaches (retrosigmoid or far lateral approach), 17 (53.1%) with anterior midline approaches (endoscopic endonasal approach [EEA]), and 4 (12.5%) with a combination. RESULTS: The average Karnofsky Performance Score (KPS) at presentation was 73.8. The average postoperative KPS improved to 87.9 (P < 0.001) during short-term follow-up of 14 months (range, 1-42) and was significantly higher in primary tumors (P = 0.013), tumors <4 cm (P = 0.039), and tumors without vascular encasement (P = 0.002) but remained significant regardless of age, tumor size, or vascular encasement. The greatest benefit occurred with primary tumors, in young patients and in those who underwent nontotal resection (P < 0.001). EEA had a significantly greater potential for improved KPS (P = 0.002). Gross (n = 6) or near total (n = 9) resection was achieved in 15 of 32 cases (47%). Complications included new cranial nerve palsies affecting mainly the abducens nerve (18.7%). New lower cranial nerve palsies occurred in only 1 case (3.1%). Other complications included postoperative hydrocephalus (15.6%) and cerebrospinal fluid leak (28.1%). One patient died in the perioperative period (3.1%). CONCLUSIONS: In the short-term, less aggressive cranial base approaches, including retrosigmoid exposures and the recently introduced EEA, are effective alternatives to transpetrosal approaches for debulking petroclival meningiomas with significant early clinical improvement and limited major surgical complications. PMID- 27965077 TI - Endoscopic Treatment of a Third Ventricular Epidermoid Cyst. AB - Epidermoid cyst is a benign and congenital lesion of ectodermal origin. Traditionally, microsurgical techniques are used to treat these lesions, and their occurrence in the third ventricle is rare. Here, the authors report a case of epidermoid cyst in the third ventricle that presented with signs and symptoms of intracranial hypertension, which was treated safely and effectively using neuroendoscopic surgery. PMID- 27965075 TI - Diagnostic Value and Safety of Stereotactic Biopsy in Acquired Immune Deficiency Syndrome Patients with Intracranial Lesions: Systematic Review and Meta-Analysis. AB - OBJECTIVE: To evaluate the diagnostic value and safety of stereotactic biopsy in acquired immune deficiency syndrome (AIDS) patients with intracranial lesions via meta-analysis. METHODS: Relevant cohort studies were identified through a literature search in PubMed, Embase, and Ovid from 1985 to October 1, 2016. Appropriate studies were identified per search criteria. Systematic review and meta-analysis were used to assess the diagnostic success rate, changed management rate, clinical improvement rate, mortality rate, morbidity rate, hemorrhage rate, hemorrhage in morbidity rate, and final histologic diagnosis results. Study specific outcomes were combined per a random effects model. Outcomes were compared between the pre-highly active antiretroviral therapy (HAART) and post HAART groups. Correlations between outcomes were assessed via meta-regression analysis. RESULTS: A total of 19 cohort studies with 820 patients were included in this meta-analysis. The weighted proportions per the random effects model were 92.2% (95% confidence interval [CI; 89.3%-94.5%]) for diagnostic success rate, 5.1% (95% CI [2.5%-8.3%]) for morbidity, and 0.7% (95% CI [0%-1.9%]) for mortality. The most common procedure-related morbidity was hemorrhage at 3.3% (95% CI [1.1%-6.3%]). Hemorrhage in morbidity was 78.0% (95% CI [51.4%-97.4%]). Management changed and clinical improvement were 60.4% (95% CI [49.4%-71.0%]) and 34.0% (95% CI [22.2%-46.8%]), respectively. The 4 most common diagnoses were primary central nervous system lymphoma (27.8%; 95% CI [20.2%-36.1%]), progressive multifocal leukoencephalopathy (PML) (21.0%; 95% CI [14.3%-28.4%]), toxoplasma encephalitis (TE) (20.3%; 95% CI [14.3%-27.0%]), and human immunodeficiency virus (HIV) encephalitis (4.1%; 95% CI [1.4%-7.6%]). Multiple diagnoses rate was 1.2% (95% CI [0.0%-3.6%]). HIV encephalitis rate was significantly higher in the post-HAART group than the pre-HAART group (17.9% vs. 3.2%, respectively; P = 0.0024). CONCLUSIONS: Stereotactic biopsy is a safe and effective way of diagnosing intracranial lesions in patients with AIDS. It is helpful for the differential diagnosis and for choosing a suitable therapy. The 4 most common intracranial lesions in patients with AIDS are lymphoma, PML, TE, and HIV encephalitis. PMID- 27965076 TI - Magnetic Resonance Imaging Signal Characteristics of Medishield: Early Postoperative Profile in a Rabbit Interlaminotomy Model. AB - OBJECTIVE: Application of Medishield to the nerve root is common during spinal surgery to create a mechanical barrier from pain mediators and reduce scar formation. However, Medishield's signal characteristics on magnetic resonance imaging (MRI) have not yet been examined. METHODS: Microsurgical interlaminotomy was performed on 2 lower lumbar segments in 17 adult New Zealand white rabbits. After dural exposure, applications of 1 mL (autologous blood clot or Medishield) were randomized for each level. On postoperative days 1 through 3, various MRI sequences in 1.5T were performed including T1-weighted, T2-w, T1-gadolinium weighted, susceptibility-weighted and turbo inversion recovery magnitude (TIRM) sequence. Signaling characteristics were analyzed by 3 blinded observers. Inter rater agreement was calculated using Fleiss's kappa coefficient (kappa). Positive and negative likelihood ratios in detecting Medishield by MRI were determined. RESULTS: Of 24 MRIs performed, TIRM sequence identified Medishield with the highest likelihood ratio. Medishield's positive likelihood ratio was highest (5.8) on postoperative day 1 with interobserver agreement of 93% (kappa = 0.75); these rates declined to 2.5 and 1.4 on postoperative days 2 and 3 with interobserver agreements of 71% (kappa = 0.43) and 83% (kappa = 0.67), respectively. Medishield adherence was confirmed in each rabbit by histologic examinations. CONCLUSION: Understanding that radiologic detection of Medishield diminished over time as its signal characteristics became less distinguishable from a blood clot is essential in clinical practice. Medishield was detected on postoperative day 1 but not 2 days later after hemodynamic changes had occurred. These results may provide a guide for postoperative findings, such as differential diagnosis of hematoma. PMID- 27965078 TI - A High-Resolution Analysis on the Meteorological Influences on Spontaneous Intracerebral Hemorrhage Incidence. AB - OBJECTIVE: To investigate the influence of meteorological factors on the incidence of intracerebral hemorrhage (ICH). METHODS: We included 295 ICH admissions between 2005 and 2013. The hourly meteorological parameters considered were surface pressure, temperature, relative humidity, wind gusts, and precipitation. To minimize confounding effects of seasonality, data were analyzed with the following 3 complementary statistical approaches: 1) deviation of daily measure from the 10-year monthly mean at the day of ictus; 2) deviation from monthly average with respect to changes in daily measures between the day of ictus and 2 days before; and 3) evolution of daily measures from 5 days before to 5 days after the ICH occurred. For 1) and 2), the statistical significance of the results was determined with a Monte Carlo simulation combined with a resampling technique (1000*). RESULTS: Regarding all patients, no statistically significant and meteorologically meaningful signal could be found. With respect to subgroup analysis, ICH related to vascular pathologies occurred significantly more frequently at days with especially low relative humidity, whereas an opposite relation was present in patients with cerebral amyloid angiopathy. However, as absolute deviations were small, a strong functional effect is questionable. With respect to seasonal distribution, a greater incidence of ICH could be detected during the cold season, in line with previous reports. CONCLUSIONS: By using high quality meteorological data analyzed with a sophisticated and robust statistical method that minimizes the confounding effect of seasonality, no clearly identifiable meteorological influence for the ICH events considered can be found. PMID- 27965079 TI - Diversity of astrocyte potassium channels: An update. AB - Astrocyte K+ channels and the K+ currents they mediate dwarf all other transmembrane conductances in these cells. This defining feature of astrocytes and its functional implications have been investigated intensely over the past decades. Nonetheless, many aspects of astrocyte K+ handling and signaling remain incompletely understood. In this review, we provide an update on the diversity of K+ channels expressed by astrocytes and new functional implications. We focus on inwardly-rectifying K+ channels (particularly Kir4.1), two-pore K+ channels and voltage and Ca2+-dependent K+ channels. We further discuss new insights into the involvement of these K+ channels in K+ buffering, control of synaptic transmission, regulation of the vasculature and in diseases of the central nervous system. PMID- 27965080 TI - Influence of Platelet-rich Plasma on the immune response of human monocyte derived dendritic cells and macrophages stimulated with Aspergillus fumigatus. AB - Dendritic cells (DCs) and macrophages (MPhi) are critical for protection against pathogenic fungi including Aspergillus fumigatus. To analyze the role of platelets in the innate immune response, human DCs and MPhis were challenged with A. fumigatus in presence or absence of human platelet rich plasma (PRP). Gene expression analyses and functional investigations were performed. A systems biological approach was used for initial modelling of the DC - A. fumigatus interaction. DCs in a quiescent state together with different corresponding activation states were validated using gene expression data from DCs and MPhi stimulated with A. fumigatus. To characterize the influence of platelets on the immune response of DCs and MPhi to A. fumigatus, we experimentally quantified their cytokine secretion, phagocytic capacity, maturation, and metabolic activity with or without platelets. PRP in combination with A. fumigatus treatment resulted in the highest expression of the maturation markers CD80, CD83 and CD86 in DCs. Furthermore, PRP enhanced the capacity of macrophages and DCs to phagocytose A. fumigatus conidia. In parallel, PRP in combination with the innate immune cells significantly reduced the metabolic activity of the fungus. Interestingly, A. fumigatus and PRP stimulated MPhi showed a significantly reduced gene expression and secretion of IL6 while PRP only reduced the IL-6 secretion of A. fumigatus stimulated DCs. The in silico systems biological model correlated well with these experimental data. Different modules centrally involved in DC function became clearly apparent, including DC maturation, cytokine response and apoptosis pathways. Taken together, the ability of PRP to suppress IL-6 release of human DCs might prevent local excessive inflammatory hemorrhage, tissue infarction and necrosis in the human lung. PMID- 27965082 TI - Analysis of whole chloroplast genomes from the genera of the Clauseneae, the curry tribe (Rutaceae, Citrus family). AB - The Clauseneae (Aurantioideae, Rutaceae) is a tribe in the Citrus family that, although economically important as it contains the culinary and medicinally useful curry tree (Bergera koenigii), has been relatively understudied. Due to the recent significant taxonomic changes made to this tribe, a closer inspection of the genetic relationships among its genera has been warranted. Whole genome skimming was used to generate chloroplast genomes from six species, representing each of the four genera (Bergera, Clausena, Glycosmis, Micromelum) in the Clauseneae tribe plus one closely related outgroup (Merrillia), using the published plastome sequence of Citrus sinensis as a reference. Phylogenetically informative character (PIC) data were analyzed using a genome alignment of the seven species, and variability frequency among the species was recorded for each coding and non-coding region, with the regions of highest variability identified for future phylogenetic studies. Non-coding regions exhibited a higher percentage of variable characters as expected, and the phylogenetic markers ycf1, matK, rpoC2, ndhF, trnS-trnG spacer, and trnH-psbA spacer proved to be among the most variable regions. Other markers that are frequently used in phylogenetic studies, e.g. rps16, atpB-rbcL, rps4-trnT, and trnL-trnF, proved to be far less variable. Phylogenetic analyses of the aligned sequences were conducted using Bayesian inference (MrBayes) and Maximum Likelihood (RAxML), yielding highly supported divisions among the four genera. PMID- 27965081 TI - Improved sampling at the subspecies level solves a taxonomic dilemma - A case study of two enigmatic Chinese tit species (Aves, Passeriformes, Paridae, Poecile). AB - A recent full species-level phylogeny of tits, titmice and chickadees (Paridae) has placed the Chinese endemic black-bibbed tit (Poecile hypermelaenus) as the sister to the Palearctic willow tit (P. montanus). Because this sister-group relationship is in striking disagreement with the traditional affiliation of P. hypermelaenus close to the marsh tit (P. palustris) we tested this phylogenetic hypothesis in a multi-locus analysis with an extended taxon sampling including sixteen subspecies of willow tits and marsh tits. As a taxonomic reference we included type specimens in our analysis. The molecular genetic study was complemented with an analysis of biometric data obtained from museum specimens. Our phylogenetic reconstructions, including a comparison of all GenBank data available for our target species, clearly show that the genetic lineage previously identified as P. hypermelaenus actually refers to P. weigoldicus because sequences were identical to that of a syntype of this taxon. The close relationship of P. weigoldicus and P. montanus - despite large genetic distances between the two taxa - is in accordance with current taxonomy and systematics. In disagreement with the previous phylogenetic hypothesis but in accordance with most taxonomic authorities, all our P. hypermelaenus specimens fell in the sister clade of all western and eastern Palearctic P. palustris. Though shared haplotypes among the Chinese populations of the two latter species might indicate mitochondrial introgression in this part of the breeding range, further research is needed here due to the limitations of our own sampling. PMID- 27965084 TI - Cannabinoid modulation of zebrafish fear learning and its functional analysis investigated by c-Fos expression. AB - It has been shown that zebrafish fear learning proceeds in the same way as reported for rodents. However, in zebrafish fear learning it is possible to substitute the use of electric shocks as unconditioned stimulus and utilize the inborn fear responses to the alarm substance Schreckstoff, instead. The skin extract Schreckstoff elicits typical fear reactions such as preferred bottom dwelling, swimming in a tighter shoal, erratic movements and freezing. This natural fear behavior can be transferred from Schreckstoff to any other sensory stimulus by associative conditioning (fear learning). We presented Schreckstoff simultaneously with a red light stimulus and tested the effectiveness of fear learning during memory retrieval. The two brain regions known to be relevant for learning in zebrafish are the medial and the lateral pallium of the dorsal telencephalon, both containing rich expressions of the endocannabinoid receptor CB1. To test the influence of the zebrafish endocannabinoid system on fear acquisition learning, an experimental group of ten fish was pretreated with the CB1 receptor agonist THC (Delta9-tetrahydrocannabinol; 100nM for 1h). We found that CB1 activation significantly inhibited acquisition of fear learning, possibly by impairing stimulus encoding processes in pallial areas. This was supported by analyzes of c-Fos expression in the brains of experimental animals. Schreckstoff exposure during fear acquisition learning and memory retrieval during red light presentation increased the number of labelled cells in pallial structures, but in no other brain region investigated (e.g. striatum, thalamus, and habenula). THC administration before fear conditioning significantly decreased c-Fos expression in these structures to a level similar to the control group without Schreckstoff experience, suggesting that Schreckstoff induced fear learning requires brain circuits restricted mainly to pallial regions of the dorsal telencephalon. PMID- 27965083 TI - A molecular-dated phylogeny and biogeography of the monotypic legume genus Haplormosia, a missing African branch of the otherwise American-Australian Brongniartieae clade. AB - A comprehensively sampled reassessment of the molecular phylogeny of the genistoid legumes questions the traditional placement of Haplormosia, an African monotypic genus traditionally classified within tribe Sophoreae close to the Asian-American geographically disjunct genus Ormosia. Plastid matK sequences placed Haplormosia as sister to the American-Australian tribe Brongniartieae. Despite a superficial resemblance between Haplormosia and Ormosia, a re examination of the morphology of Haplormosia corroborates the new phylogenetic result. The reciprocally monophyletic deep divergence of the Haplormosia stem lineage from the remaining Brongniartieae is dated to ca. 52Mya, thus supporting a signature of an old single long-distance dispersal during the early Eocene. Conversely, we estimated a relatively recent long-distance dispersal rooted in the Early Miocene for the Australian Brongniartieae clade emerging from within a grade of American Brongniartieae. The Bayesian ancestral area reconstruction revealed the coming and going of neotropical ancestors during the diversification history of the Brongniartieae legumes in Africa and all over the Americas and Australia. PMID- 27965085 TI - The interaction of a Trypanosoma brucei KH-domain protein with a ribonuclease is implicated in ribosome processing. AB - Ribosomal RNA maturation is best understood in yeast. While substantial efforts have been made to explore parts of these essential pathways in animals, the similarities and uniquenesses of rRNA maturation factors in non-Opisthokonts remain largely unexplored. Eukaryotic ribosome synthesis requires the coordinated activities of hundreds of Assembly Factors (AFs) that transiently associate with pre-ribosomes, many of which are essential. Pno1 and Nob1 are two of six AFs that are required for the cytoplasmic maturation of the 20S pre-rRNA to 18S rRNA in yeast where it has been almost exclusively analyzed. Specifically, Nob1 ribonucleolytic activity generates the mature 3'-end of 18S rRNA. We identified putative Pno1 and Nob1 homologues in the protist Trypanosoma brucei, named TbPNO1 and TbNOB1, and set out to explore their rRNA maturation role further as they are both essential for normal growth. TbPNO1 is a nuclear protein with limited cytosolic localization relative to its yeast homologue. Like in yeast, it interacts directly with TbNOB1, with indications of associations with a larger AF containing complex. Interestingly, in the absence of TbPNO1, TbNOB1 exhibits non specific degradation activity on RNA substrates, and its cleavage activity becomes specific only in the presence of TbPNO1, suggesting that TbPNO1-TbNOB1 interaction is essential for regulation and site-specificity of TbNOB1 activity. These results highlight a conserved role of the TbPNO1-TbNOB1 complex in 18S rRNA maturation across eukaryotes; yet reveal a novel role of their interaction in regulation of TbNOB1 enzymatic activity. PMID- 27965086 TI - The effect of poly(ADP-ribosyl)ation inhibition on the porcine cumulus-oocyte complex during in vitro maturation. AB - Poly(ADP-ribosyl)ation (PARylation) plays important roles in DNA repair, apoptosis, transcriptional regulation, and cell death, and occurs via the activity of poly(ADP-ribose) polymerases (PARPs). Previous studies have shown that PARylation affects mouse and porcine pre-implantation development and participates in mechanisms of autophagy. However, there have not yet been reported the role of PARylation during in vitro maturation (IVM) of porcine oocytes. Thus, we investigated the effect of PARylation inhibition on this process; cumulus-oocyte complexes (COCs) were cultured with 3-aminobenzamide (3 ABA, PARP inhibitor) during porcine IVM. Full cumulus expansion was significantly reduced (10.34 +/- 1.23 [3-ABA] vs. 48.17 +/- 2.03% [control]), but nuclear maturation rates were not changed in the 3-ABA treatment group. Especially, we observed that cumulus cells were little expanded after 22 h in 3-ABA treated COCs. The mRNA expression levels of oocyte maturation- and cumulus expansion related genes were evaluated at 22 and 44 h. GDF9, BMP15, COX-2, and PTX3 expression were upregulated at 44 h, whereas the levels of HAS2 and TNFAIP6 were downregulated in the 3-ABA treated group. Furthermore, 3-ABA treatment significantly decreased the developmental rate (28.24 +/- 1.06 vs. 40.24 +/- 3.03%) and total cell number (41.12 +/- 2.10 vs. 50.38 +/- 2.27), but increased the total apoptotic index (6.44 +/- 0.81 vs. 3.08 +/- 0.51) in parthenogenetically activated embryos. In conclusion, these results showed that PARylation regulates cumulus expansion through the regulation of gene expression and affects developmental competence and quality in parthenogenetic embryos. PMID- 27965087 TI - SHIP, a novel factor to ameliorate extracellular matrix accumulation via suppressing PI3K/Akt/CTGF signaling in diabetic kidney disease. AB - Tubular interstitial extracellular matrix accumulation, which plays a key role in the pathogenesis and progression of diabetic kidney disease (DKD), is believed to be mediated by activation of PI3K/Akt signal pathway. However, it is still not clear whether SH2 domain-containing inositol 5'-phosphatase (SHIP), known as a negative regulator of PI3K/Akt pathway is also involved in extracellular matrix metabolism of diabetic kidney. In the present study, decreased SHIP and increased phospho-Akt (Ser 473, Thr 308) were found in renal tubular cells of diabetic mice accompanied by overexpression of connective tissue growth factor (CTGF) and extracellular matrix deposition versus normal mice. Again, high glucose attenuated SHIP expression in a time-dependent manner, concomitant with activation of PI3K/Akt signaling and extracellular matrix production in human renal proximal tubular epithelial cells (HK2) cultured in vitro, which was significantly prevented by transfection of M90-SHIP vector. Furthermore, in vivo delivery of rAd-INPP5D vector (SHIP expression vector) via intraperitoneal injection in diabetic mice increased SHIP expression by 3.36 times followed by 65.26%, 70.38% and 46.71% decreases of phospho-Akt (Ser 473), phospho-Akt (Thr 308) and CTGF expression versus diabetic mice receiving rAd-EGFP vector. Meanwhile, increased renal extracellular matrix accumulation of diabetic mice was also inhibited with intraperitoneal injection of rAd-INPP5D vector. These above data suggested that overexpression of SHIP might be a potent method to lessen renal extracellular matrix accumulation via inactivation of PI3K/Akt pathway and suppression of CTGF expression in DKD. PMID- 27965088 TI - Lanthionine ketimine ester promotes locomotor recovery after spinal cord injury by reducing neuroinflammation and promoting axon growth. AB - The mammalian central nervous system (CNS) has limited regenerative ability after injury, largely due to scar formation and axonal growth inhibitors. Experimental suppression of neuroinflammation encourages recovery from spinal cord injury (SCI), yet practical means for pharmacologically treating SCI have remained elusive. Lanthionine ketimine (LK) is a natural brain sulfur amino acid metabolite with demonstrated anti-neuroinflammatory and neurotrophic activities. LK and its synthetic brain-penetrating ethyl ester (LKE) promote growth factor dependent neurite extension in cultured cell and suppress microglial activation in animal models of neurodegeneration. Thus far however, LKE has not been explored as a potential therapy for SCI. The present study investigated the hypothesis that systemic LKE could improve motor functional recovery after SCI in a mouse model. Intraperitoneal administration of LKE (100 mg/kg/d) after near complete transect of spinal cord at the T7 level significantly improved motor function over a 4-week time course. Vehicle-treated mice, in contrast, demonstrated negligible functional recovery. In terms of histology, LKE treatment reduced pro-neuroinflammatory microglia/macrophage activation evidenced by quantitative Iba1 labeling and shifted the microglial phenotype toward a more neurotrophic M2 character evidenced by changes in the M2 marker arginase-1. This was correlated with less dense scar formation and more extensive axonal regrowth across the transection site demonstrated by 5-hydroxytryptamine (5HT) immunolabeling of raphespinal tract axons. These data provide evidence that LKE or similar compounds have potential therapeutic value for recovery after certain forms of SCI. PMID- 27965089 TI - Background norepinephrine primes astrocytic calcium responses to subsequent norepinephrine stimuli in the cerebral cortex. AB - Norepinephrine (NE) levels in the cerebral cortex are regulated in two modes; the brain state is correlated with slow changes in background NE concentration, while salient stimuli induce transient NE spikes. Previous studies have revealed their diverse neuromodulatory actions; however, the modulatory role of NE on astrocytic activity has been poorly characterized thus far. In this study, we evaluated the modulatory action of background NE on astrocytic responses to subsequent stimuli, using two-photon calcium imaging of acute murine cortical brain slices. We find that subthreshold background NE significantly augments calcium responses to subsequent pulsed NE stimulation in astrocytes. This priming effect is independent of neuronal activity and is mediated by the activation of beta adrenoceptors and the downstream cAMP pathway. These results indicate that background NE primes astrocytes for subsequent calcium responses to NE stimulation and suggest a novel gliomodulatory role for brain state-dependent background NE in the cerebral cortex. PMID- 27965090 TI - Overexpression of miR-183/-96/-182 triggers neuronal cell fate in Human Retinal Pigment Epithelial (hRPE) cells in culture. AB - miR-183 cluster, composed of miR-183/-96/-182 genes, is highly expressed in the adult retina, particularly in photoreceptors. It involves in development, maturation and normal function of neuroretina. Ectopic overexpression of miR-183/ 96/-182 genes was performed to assess reprogramming of hRPE cells. They were amplified from genomic DNA and cloned independently or in tandem configuration into pAAV.MCS vector. hRPE cells were then transfected with the recombinant constructs. Real-Time PCR was performed to measure the expression levels of miR 183/-96/-182 and that of several retina-specific neuronal genes such as OTX2, NRL, PDC and DCT. The transfected cells also were immunocytochemically examined for retina-specific neuronal markers, including Rhodopsin, red opsin, CRX, Thy1, CD73, recoverin and PKCalpha, to determine the cellular fate of the transfected hRPE cells. Data showed that upon miR-183/-96/-182 overexpression in hRPE cultures, the expression of neuronal genes including OTX2, NRL, PDC and DCT was also upregulated. Moreover, miR-183 cluster-treated hRPE cells were immunoreactive for neuronal markers such as Rhodopsin, red opsin, CRX and Thy1. Both transcriptional and translational upregulation of neuronal genes in miR-183 cluster-treated hRPE cells suggests that in vitro overexpression of miR-183 cluster could trigger reprogramming of hRPE cells to retinal neuron fate. PMID- 27965091 TI - beta1,6 GlcNAc branches-modified protein tyrosine phosphatase alpha enhances its stability and promotes focal adhesion formation in MCF-7 cells. AB - Receptor-like protein tyrosine phosphatase alpha (RPTPalpha or PTPalpha), a type I transmembrane glycoprotein with complex N-glycans, executes multifunction roles on cell behaviors. However, its effect on tumorigenesis and metastasis remains controversial. In this study, PTPalpha is identified as a novel substrate of N Acetylglucosaminyltransferase V (GnT-V). Immunofluorescence results showed that addition of beta1,6 GlcNAc branches on PTPalpha enhanced PTPalpha's cytomembrane assemble in GnT-V-MCF-7 compared with Mock-MCF-7 (MCF7 cells transfected with the vector pcDNA3). Then we found the alleviating degradation of PTPalpha was observed in GnT-V-MCF-7 while PTPalpha in Mock-MCF-7 was prone to quick degradation. Increased cell-surface retention subsequently enhanced PTPalpha's catalytic activity on the dephosphorylation of Src kinase at Tyr529 and promoted focal adhesion formation and mature. Therefore, our findings could provide an insight into the molecular mechanism of how GnT-V promoted cell migration, suggesting that PTPalpha could be one of factors regulating promote migration of breast cancer cell. PMID- 27965092 TI - Toll-like receptor 4 signaling is required for clusterin-induced tumor necrosis factor-alpha secretion in macrophage. AB - Clusterin is a secretory glycoprotein that is up-regulated in areas of inflammation and under increased levels of oxidative stress. Previously, we demonstrated that clusterin activates NF-kappaB, and up-regulates the expression of MMP-9 and TNF-alpha. In this research, we extend our previous findings by reporting that such clusterin-induced macrophage response is mediated via TLR4 signaling. Specifically, we found that TNF-alpha induced by clusterin was significantly abrogated by pretreatment of TLR4-signaling inhibitors and anti TLR4 neutralizing antibody. Additionally, a primary culture of macrophages derived from TLR4-signal defective and knockout mice were unresponsive to clusterin, resulting in no TNF-alpha secretion, whereas macrophages carrying wild type TLR4 responded to clusterin and induced TNF-alpha. Moreover, clusterin increased NF-kappaB promoter activity in HEK-Blue hTLR4 cells, but not in HEK Blue Null2 cells. To confirm that clusterin elicits TLR4 signal transduction, recombinant clusterin was generated and purified from cell culture. Interestingly, we found that the recombinant clusterin with C-terminal HA-tag induces TNF-alpha secretion at a significantly lower level compared to an intact form of clusterin without C-terminal HA-tag. Removal of HA-tag from the recombinant clusterin restored its activity, suggesting that C-terminal HA-tag partially masks the domain involved in TLR4 signaling. Furthermore, clusterin enhanced TLR4 mobilization into lipid raft of plasma membrane, and TNF-alpha and MMP-9 secretion stimulated by clusterin was diminished by pretreatment with methyl-beta-cyclodextrin (MbetaCD), which was used to disrupt lipid raft. In conclusion, clusterin-induced TNF-alpha and MMP-9 up-regulation is most likely mediated via TLR4 recruitment into lipid rafts, and these data describe a novel role of clusterin as an endogenous regulator for TLR4 signaling. PMID- 27965098 TI - Protective effects of hydroxytyrosol on gentamicin induced nephrotoxicity in mice. AB - BACKGROUND: Gentamicin (GM) is an effective and common antibiotic against severe gram-negative infections. However, its nephrotoxic action has limited the extent of its use. The aim of this study was to investigate the protective effects of hydroxytyrosol (HT) on gentamicin induced nephrotoxicity in mice. METHODS: Male mice (n = 27) were randomly assigned to three groups: (1) Sham, (2) GM (100 mg/kg for 7 days) (3) GM + HT (2 mg/kg BW; gastric gavages, for 7 days). 24-h urine samples were collected on day 8 and then animal were anesthetized. The blood and kidney tissue samples were collected. RESULTS: Gentamicin led to increase in plasma BUN and creatinine, fractional excretion of sodium and potassium and decrease in creatinine clearance and urine flow rate. SOD and GSH levels were reduced and MDA was increased in the GM group compared with the sham group. In GM + HT group, plasma BUN and creatinine, fractional excretion of Na, creatinine clearance and urine flow rate were decreased in contrast to GM group. Increase in SOD and GSH activity and decrease in MDA compared to GM group were seen. CONCLUSIONS: Findings suggest that HT partly protected the kidneys from gentamicin induced nephrotoxicity and it is partly due to antioxidant effect of HT. PMID- 27965102 TI - Psychogenic non-epileptic seizures: The daunting mimicker. PMID- 27965100 TI - The novel extremely psychrophilic luciferase from Metridia longa: Properties of a high-purity protein produced in insect cells. AB - The bright bioluminescence of copepod Metridia longa is conditioned by a small secreted coelenterazine-dependent luciferase (MLuc). To date, three isoforms of MLuc differing in length, sequences, and some properties were cloned and successfully applied as high sensitive bioluminescent reporters. In this work, we report cloning of a novel group of genes from M. longa encoding extremely psychrophilic isoforms of MLuc (MLuc2-type). The novel isoforms share only ~54 64% of protein sequence identity with the previously cloned isoforms and, consequently, are the product of a separate group of paralogous genes. The MLuc2 isoform with consensus sequence was produced as a natively folded protein using baculovirus/insect cell expression system, purified, and characterized. The MLuc2 displays a very high bioluminescent activity and high thermostability similar to those of the previously characterized M. longa luciferase isoform MLuc7. However, in contrast to MLuc7 revealing the highest activity at 12-17 degrees C and 0.5 M NaCl, the bioluminescence optima of MLuc2 isoforms are at ~5 degrees C and 1 M NaCl. The MLuc2 adaptation to cold is also accompanied by decrease of melting temperature and affinity to substrate suggesting a more conformational flexibility of a protein structure. The luciferase isoforms with different temperature optima may provide adaptability of the M. longa bioluminescence to the changes of water temperature during diurnal vertical migrations. PMID- 27965093 TI - Reversible aggregation of HIV-1 Gag proteins mediated by nucleic acids. AB - HIV-1 Gag protein is the major structural protein for the assembly of virion particles. Although studies have been carried out using partially purified Gag proteins to investigate the mechanisms of viral particle assembly, the outcomes of an assembly reaction remain controversial. Here we have developed an improved procedure for purification of several untagged retroviral Gag proteins from E. coli to more than 95% purity and characterized Gag assembly in solution. We found that HIV-1 Gag proteins can undergo nucleic acid-dependent aggregation with several unexpected features: (1) they form spherical particles that are as large as microns in diameter; (2) the size of the aggregates vary with the molar ratio between nucleic acids and proteins, with the average size of these particles reaching maximal at a molar ratio of 1:2 between nucleic acids and proteins; and (3) these particles can be efficiently disassembled simply upon addition of excess nucleic acids into the solution, suggesting the presence of an ordered assembly. Single-stranded DNA oligos that are 10 nucleotides or shorter do not support the formation of these particles. Furthermore, the matrix domain of the Gag protein dramatically facilitates the formation of these aggregates. These studies uncover a previously uncharacterized pathway of HIV Gag assembly in vitro, and have implications for HIV-1 Gag assembly and pathogenesis in vivo. PMID- 27965094 TI - Isoform-specific regulation of osteogenic factors by polypeptide N Acetylgalactosaminyltransferases 1 and 4. AB - The family of UDP-GalNAc polypeptide: N-Acetylgalactosaminlytransfersases (ppGalNAcTs) catalyzes the initial step of O-linked protein glycosylation. Mucin type O-glycoproteins are abundant in the bone and may play an important role in osteogenesis. Herein, we examined the effects of ppGalNAc-T isoforms on osteogenesis of MC3T3-E1 pre-osteoblasts. We found that ppGalNAc-T1 and -T4 isoforms were highly expressed during osteogenesis of MC3T3-E1 and their knockdown by short hairpin RNA (shRNA) decreased osteoblast formation and bone mineralization. Knockdown of ppGalNAc-T1 or -T4 decreased mRNA and protein levels of bone sialoprotein (BSP). Knockdown of ppGalNAc-T1decreased mRNA levels of osteocalcin (OC), osteoprotegerin (OPG). Knockdown ofppGalNAc-T4 isoform decreased mRNA levels of OC, OPG and vitamin D receptor (VDR). While knockdown of T1 or T4 isoforms did not change the expression of osteopontin (OPN), COLLI, receptor activator for nuclear factor-kappaB ligand (RANKL) and transforming growth factor-beta (TGF-beta). Our results demonstrated that the ppGalNAc-T4 was highly expressed in MC3T3-E1 cells during osteogenesis for the first time. We also found that ppGalNAc-T1 and -T4 affected the expression of different osteogenic factors, suggesting distinct roles ppGalNAc-T isoformsplay in regulating osteogenesis in vitro. PMID- 27965095 TI - BmNHR96 participate BV entry of BmN-SWU1 cells via affecting the cellular cholesterol level. AB - B.mori nucleopolyhedrovirus (BmNPV), which produces BV and ODV two virion phenotypes in its life cycle, caused the amount of economic loss in sericulture. But the mechanism of its infection was still unclear. In this study we characterized B.mori nuclear hormone receptor 96 (BmNHR96) as a NHR96 family member, which was localized in the nucleus. We also found BmNHR96 over-expression could enhance the entry of BV as well as cellular cholesterol level. Furthermore, we validated that BmNHR96 increased membrane fusion mediated by GP64, which could probably promote BV-infection. In summary, our study suggested that BmNHR96 plays an important role in BV infection and this function probably actualized by affecting cellular cholesterol level, and our results provided insights to the mechanisms of BV-infection of B.mori. PMID- 27965096 TI - Deregulation of RUNX2 by miR-320a deficiency impairs steroidogenesis in cumulus granulosa cells from polycystic ovary syndrome (PCOS) patients. AB - Deregulation of epigenetic modification by microRNAs (miRNAs) contributes to the development of estrogen deficiency, a hallmark of the multigenic endocrine disorder polycystic ovary syndrome (PCOS), but its etiology remains unclear. Previous study has pointed to a tight association between miR-320a expression and oocyte development in human follicular fluid. Given that the bi-directional communication existing between cumulus cells (CCs) and follicular fluid is essential for ovarian steroidogenesis and CCs are the main site where estrogen is finally synthesized, it is intriguing to know whether miR-320a have any regulatory roles in this unique cell. Here we report that miR-320a expression is significantly down-regulated in primary CCs from PCOS patients and this down regulation promotes estrogen deficiency in CCs. From a mechanistic standpoint, IGF1 regulates miR-320a expression in CCs, and miR-320a could potentiate the steroidogenesis in CCs through modulation of CYP11A1 and CYP19A1 expression, by directly targeting 3'untranslated region (3'UTR) of the osteogenic transcription factor RUNX2. Overall, our results strongly suggest that deregulation of miR 320a/RUNX2/CYP11A1 (CYP19A1) cascade plays an important role in the development of estrogen deficiency in human CCs. Testing patients for miR-320a/RUNX2 expression ratios may provide more accurate diagnostic information and could influence the recommended course of treatment for PCOS. PMID- 27965106 TI - Dietary intake of phosphorus flame retardants (PFRs) using Swedish food market basket estimations. AB - The occurrence of eight phosphorus flame retardants (PFRs) was investigated in 53 composite food samples from 12 food categories, collected in 2015 for a Swedish food market basket study. 2-ethylhexyl diphenyl phosphate (EHDPHP), detected in most food categories, had the highest median concentrations (9 ng/g ww, pastries). It was followed by triphenyl phosphate (TPHP) (2.6 ng/g ww, fats/oils), tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) (1.0 ng/g ww, fats/oils), tris(2-chloroethyl) phosphate (TCEP) (1.0 ng/g ww, fats/oils), and tris(1-chloro-2-propyl) phosphate (TCIPP) (0.80 ng/g ww, pastries). Tris(2 ethylhexyl) phosphate (TEHP), tri-n-butyl phosphate (TNBP), and tris(2 butoxyethyl) phosphate (TBOEP) were not detected in the analyzed food samples. The major contributor to the total dietary intake was EHDPHP (57%), and the food categories which contributed the most to the total intake of PFRs were processed food, such as cereals (26%), pastries (10%), sugar/sweets (11%), and beverages (17%). The daily per capita intake of PFRs (TCEP, TPHP, EHDPHP, TDCIPP, TCIPP) from food ranged from 406 to 3266 ng/day (or 6-49 ng/kg bw/day), lower than the health-based reference doses. This is the first study reporting PFR intakes from other food categories than fish (here accounting for 3%). Our results suggest that the estimated human dietary exposure to PFRs may be equally important to the ingestion of dust. PMID- 27965097 TI - BRAF-mutated cells activate GCN2-mediated integrated stress response as a cytoprotective mechanism in response to vemurafenib. AB - In BRAF-mutated melanoma cells, the BRAF inhibitor, vemurafenib, induces phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) and subsequent induction of activating transcription factor 4 (ATF4), the central regulation node of the integrated stress response (ISR). While the ISR supports cellular adaptation to various stresses, the role of vemurafenib-triggered ISR has not been fully characterized. Here, we showed that in response to vemurafenib, BRAF mutated melanoma and colorectal cancer cells rapidly induced the ISR as a cytoprotective mechanism through activation of general control nonderepressible 2 (GCN2), an eIF2alpha kinase sensing amino acid levels. The vemurafenib-triggered ISR, an event independent of downstream MEK inhibition, was specifically prevented by silencing GCN2, but not other eIF2alpha kinases, including protein kinase-like endoplasmic reticulum kinase, which transmits endoplasmic reticulum (ER) stress. Consistently, the ER stress gatekeeper, GRP78, was not induced by vemurafenib. Interestingly, ATF4 silencing by siRNA rendered BRAF-mutated melanoma cells sensitive to vemurafenib. Thus, the GCN2-mediated ISR can promote cellular adaptation to vemurafenib-induced stress, providing an insight into the development of drug resistance. PMID- 27965108 TI - Crystal structure of Pla l 1 reveals both structural similarity and allergenic divergence within the Ole e 1-like protein family. PMID- 27965099 TI - Glucagon-like peptide-1 inhibits the receptor for advanced glycation endproducts to prevent podocyte apoptosis induced by advanced oxidative protein products. AB - OBJECTIVE: To investigate whether and how glucagon-like peptide-1 (GLP-1) can protect podocytes from apoptosis induced by advanced oxidative protein products (AOPPs). METHODS: Murine podocytes were stimulated with 200 MUg/ml AOPP for 48 h in the presence or absence of GLP-1. Cell viability was assessed using the cell counting kit-8 assay. Podocyte apoptosis was detected by flow cytometry and Hoechst 33258 staining. Superoxide radical production was assayed using lucigenin enhanced chemiluminescence, and Western blotting was used to measure expression of RAGE, NADPH oxidase subunits p47phox and gp91phox, as well as apoptosis associated proteins p53, Bax, Bcl-2 and caspase-3. RESULTS: Incubating podocytes with AOPPs reduced cell viability, triggered changes in cell morphology and promoted apoptosis. GLP-1 partially inhibited AOPP-induced apoptosis, O2- overproduction, and AOPP-induced expression of RAGE. GLP-1 inhibited expression of p47phox and gp91phox in AOPP-treated podocytes, and it attenuated AOPP-induced expression of p53, Bax and cleaved caspase-3, whereas it restored expression of Bcl-2. CONCLUSION: GLP-1 partially inhibits AOPP-induced apoptosis in podocytes, perhaps by interfering with the AOPP-RAGE axis, decreasing oxidative stress and inhibiting the downstream p53/Bax/caspase-3 apoptotic pathway. GLP-1 may be a useful anti-apoptotic agent for early intervention in diabetic nephropathy. PMID- 27965103 TI - Biological Databases for Hematology Research. AB - With the advances of genome-wide sequencing technologies and bioinformatics approaches, a large number of datasets of normal and malignant erythropoiesis have been generated and made public to researchers around the world. Collection and integration of these datasets greatly facilitate basic research and clinical diagnosis and treatment of blood disorders. Here we provide a brief introduction of the most popular omics data resources of normal and malignant hematopoiesis, including some integrated web tools, to help users get better equipped to perform common analyses. We hope this review will promote the awareness and facilitate the usage of public database resources in the hematology research. PMID- 27965101 TI - Skeletal muscle PI3K p110beta regulates expression of AMP-activated protein kinase. AB - Skeletal muscle metabolic homeostasis is maintained through numerous biochemical and physiological processes. Two principal molecular regulators of skeletal muscle metabolism include AMP-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase (PI3K); however, PI3K exists as multiple isoforms, and specific metabolic actions of each isoform have not yet been fully elucidated in skeletal muscle. Given this lack of knowledge, we performed a series of experiments to define the extent to which PI3K p110beta mediated expression and (or) activation of AMPK in skeletal muscle. To determine the effect of p110beta inhibition on AMPK expression and phosphorylation in cultured cells, C2C12 myoblasts were treated with a pharmacological inhibitor of p110beta (TGX-221), siRNA against p110beta, or overexpression of kinase-dead p110beta. Expression and phosphorylation of AMPK were unaffected in myoblasts treated with TGX-221 or expressing kinase-dead p110beta. However, expressions of total and phosphorylated AMPK at T172 were reduced in myoblasts treated with p110beta siRNA. When normalized to expression of total AMPK, phosphorylation of AMPK S485/491 was elevated in p110beta-deficient myoblasts. Similar results were observed in tibialis anterior muscle from mice with conditional deletion of p110beta (p110beta-mKO mice). Analysis of AMPK transcript expression revealed decreased expression of Prkaa2 in p110beta-deficient myoblasts and in p110beta-mKO muscle. Loss of p110beta had no effect on oligomycin-stimulated phosphorylation of AMPK or phosphorylated Acetyl-CoA carboxylase (ACC), although oligomycin-induced AMPK and ACC phosphorylation were increased in p110beta-deficient myoblasts compared to oligomycin-stimulated control myoblasts when normalized to levels of total AMPK or ACC. Overall, these results suggest that p110beta positively regulates expression of AMPK in cultured myoblasts and in skeletal muscle in vivo; moreover, despite the reduced abundance of AMPK in p110beta-deficient myoblasts, loss of p110beta does not appear to impair AMPK activation following stimulus. These findings thus reveal a novel role for p110beta in mediating skeletal muscle metabolic signaling. PMID- 27965109 TI - Combined immunodeficiency with severe inflammation and allergy caused by ARPC1B deficiency. PMID- 27965107 TI - Molecular evidence on the protective effect of ellagic acid on phosalone-induced senescence in rat embryonic fibroblast cells. AB - Salient evidence testifies the link between organophosphorus (OPs) exposure and the formation of free radical oxidants; and it is well accepted that free radicals are one of the basic concerns of senescence. To show the oxidative features of phosalone (PLN) as a key member of OPs, to induce senescence in rat embryonic fibroblast (REF) cells and to demonstrate the beneficial effects of the known antioxidant ellagic acid (EA) in diminishing the PLN-induced toxic effects, the levels of cell viability, oxidative stress markers, inflammatory cytokines, telomerase activity, and the expression of the genes related to senescence were investigated. Our results lend support to the hypothesis that PLN enhances the entire premature senescence parameters of REF cells. This accounts for the mechanistic approval of the role of OPs in induction of senescence in rat fibroblasts. Moreover, incorporation of EA diminished PLN toxicity mainly through suppression of p38 and p53 at gene and protein levels, and tempered the inflammation factors (TNF-alpha, IL-1beta, IL-6 and NF-kappaB), which further affected cell division. Analysis of cell cycle showed that the percentage of G0/G1 arrest, in REF cells treated by EA was elevated as compared to control and PLN treated cells. PMID- 27965104 TI - Identification of Risk Pathways and Functional Modules for Coronary Artery Disease Based on Genome-wide SNP Data. AB - Coronary artery disease (CAD) is a complex human disease, involving multiple genes and their nonlinear interactions, which often act in a modular fashion. Genome-wide single nucleotide polymorphism (SNP) profiling provides an effective technique to unravel these underlying genetic interplays or their functional involvements for CAD. This study aimed to identify the susceptible pathways and modules for CAD based on SNP omics. First, the Wellcome Trust Case Control Consortium (WTCCC) SNP datasets of CAD and control samples were used to assess the joint effect of multiple genetic variants at the pathway level, using logistic kernel machine regression model. Then, an expanded genetic network was constructed by integrating statistical gene-gene interactions involved in these susceptible pathways with their protein-protein interaction (PPI) knowledge. Finally, risk functional modules were identified by decomposition of the network. Of 276 KEGG pathways analyzed, 6 pathways were found to have a significant effect on CAD. Other than glycerolipid metabolism, glycosaminoglycan biosynthesis, and cardiac muscle contraction pathways, three pathways related to other diseases were also revealed, including Alzheimer's disease, non-alcoholic fatty liver disease, and Huntington's disease. A genetic epistatic network of 95 genes was further constructed using the abovementioned integrative approach. Of 10 functional modules derived from the network, 6 have been annotated to phospholipase C activity and cell adhesion molecule binding, which also have known functional involvement in Alzheimer's disease. These findings indicate an overlap of the underlying molecular mechanisms between CAD and Alzheimer's disease, thus providing new insights into the molecular basis for CAD and its molecular relationships with other diseases. PMID- 27965105 TI - Factors Associated with Sequelae of Campylobacter and Non-typhoidal Salmonella Infections: A Systematic Review. AB - Despite the significant global burden of gastroenteritis and resulting sequelae, there is limited evidence on risk factors for sequelae development. We updated and extended previous systematic reviews by assessing the role of antibiotics, proton pump inhibitors (PPI) and symptom severity in the development of sequelae following campylobacteriosis and salmonellosis. We searched four databases, including PubMed, from 1 January 2011 to 29 April 2016. Observational studies reporting sequelae of reactive arthritis (ReA), Reiter's syndrome (RS), irritable bowel syndrome (IBS) and Guillain-Barre syndrome (GBS) following gastroenteritis were included. The primary outcome was incidence of sequelae of interest amongst cases of campylobacteriosis and salmonellosis. A narrative synthesis was conducted where heterogeneity was high. Of the 55 articles included, incidence of ReA (n=37), RS (n=5), IBS (n=12) and GBS (n=9) were reported following campylobacteriosis and salmonellosis. A pooled summary for each sequela was not estimated due to high level of heterogeneity across studies (I2>90%). PPI usage and symptoms were sparsely reported. Three out of seven studies found a statistically significant association between antibiotics usage and development of ReA. Additional primary studies investigating risk modifying factors in sequelae of GI infections are required to enable targeted interventions. PMID- 27965110 TI - Alterations in B-cell subsets in pediatric patients with early atopic dermatitis. AB - BACKGROUND: B cells undergo maturation and class-switching in response to antigen exposure and T-cell help. Early B-cell differentiation has not been defined in patients with early-onset atopic dermatitis (AD). OBJECTIVE: We sought to define the frequency of B-cell subsets associated with progressive B-cell maturation and IgE class-switching. METHODS: We studied 27 children and 34 adults with moderate to-severe AD (mean SCORAD score, 55 and 65, respectively) and age-matched control subjects (15 children and 27 adults). IgD/CD27 and CD24/CD38 core gating systems and an 11-color flow cytometric panel were used to determine the frequencies of circulating B-cell subsets. Serum total and allergen-specific IgE (sIgE) levels were measured by using ImmunoCAP. RESULTS: Compared with adults, children showed T-cell predominance in the skin. Circulating CD19+CD20+ B-cell counts were lower in patients with pediatric AD than in control subjects (24% vs 33%, P = .04), whereas CD3+ T-cell counts were higher (62% vs 52%, P = .05). A decreased B cell/T-cell lymphocyte ratio with age was observed only in pediatric control subjects (r = -0.48, P = .07). In pediatric patients with AD, a positive correlation was observed between B-cell/T-cell ratio and nonswitched memory B cell counts (r = 0.42, P = .03). Higher frequencies of positive sIgE levels were seen in pediatric patients with AD (P < .0001). Diverse sIgE levels correlated with SCORAD scores and age of pediatric patients with AD (P < .01). Positive correlations were observed between activated B-cell and memory T-cell counts (P < .02). In patients with AD, IgE sensitization to most allergens clustered with age, TH1, TH2, total IgE levels, and B-cell memory subsets. CONCLUSIONS: Peripheral B and T cells are altered in pediatric patients with early AD, but T cells predominate in skin lesions. PMID- 27965111 TI - Sialylated Fetuin-A as a candidate predictive biomarker for successful grass pollen allergen immunotherapy. AB - BACKGROUND: Eligibility to immunotherapy is based on the determination of IgE reactivity to a specific allergen by means of skin prick or in vitro testing. Biomarkers predicting the likelihood of clinical improvement during immunotherapy would significantly improve patient selection. METHODS: Proteins were differentially assessed by using 2-dimensional differential gel electrophoresis and label-free mass spectrometry in pretreatment sera obtained from clinical responders and nonresponders within a cohort of 82 patients with grass pollen allergy receiving sublingual immunotherapy or placebo. Functional studies of Fetuin-A (FetA) were conducted by using gene silencing in a mouse asthma model, human dendritic cell in vitro stimulation assays, and surface plasmon resonance. RESULTS: Analysis by using quantitative proteomics of pretreatment sera from patients with grass pollen allergy reveals that high levels of O-glycosylated sialylated FetA isoforms are found in patients exhibiting a strong decrease in rhinoconjunctivitis symptoms after sublingual immunotherapy. Although FetA is involved in numerous inflammatory conditions, its potential role in allergy is unknown. In vivo silencing of the FETUA gene in BALB/c mice results in a dramatic upregulation of airway hyperresponsiveness, lung resistance, and TH2 responses after allergic sensitization to ovalbumin. Both sialylated and nonsialytated FetA bind to LPS, but only the former synergizes with LPS and grass pollen or mite allergens to enhance the Toll-like receptor 4-mediated proallergic properties of human dendritic cells. CONCLUSIONS: As a reflection of the patient's inflammatory status, pretreatment levels of sialylated FetA in the blood are indicative of the likelihood of clinical responses during grass pollen immunotherapy. PMID- 27965112 TI - Proteolytic processing of the Saccharomyces cerevisiae cell wall protein Scw4 regulates its activity and influences its covalent binding to glucan. AB - Yeast cell wall contains a number of proteins that are either non-covalently (Scw proteins), or covalently (Ccw-proteins) bound to beta-1,3-glucan, the latter either through GPI-anchors and beta-1,6-glucan, or by alkali labile ester linkages between gamma-carboxyl groups of glutamic acid and hydroxyl groups of glucoses (Pir-proteins). It was shown that a part of Scw4, previously identified among the non-covalently bound cell wall proteins, was covalently attached to wall polysaccharides by a so far unknown alkali sensitive linkage. Thus Scw4 could be released from cell walls by treatments with hot SDS, mild alkali, or beta-1,3-glucanases, respectively. It was further shown that non-covalently bound Scw4 (SDS released) underwent the Kex2 proteolytic processing. In this paper it was demonstrated that Scw4 was also processed by yapsins at a position 9 amino acids downstream of the Kex2 cleavage site. Scw4 cleaved at the yapsin site had a markedly lower potential for covalent attachment to glucan. The overproduction of the fully processed form of Scw4 lead to high mortality, particularly in the stationary phase of growth, and to markedly increased cell size. On the other hand, the overproduction of Scw4 processed only by Kex2 or not processed at all had no apparent change in mortality indicating that only the smallest, completely mature form of Scw4 had the activity leading to observed phenotype changes. PMID- 27965116 TI - Introduction of novel 3D-printed superficial applicators for high-dose-rate skin brachytherapy. AB - PURPOSE: Custom-made surface mold applicators often allow more flexibility when carrying out skin brachytherapy, particularly for small treatment areas with high surface obliquity. They can, however, be difficult to manufacture, particularly if there is a lack of experience in superficial high-dose-rate brachytherapy techniques or with limited resources. METHODS AND MATERIALS: We present a novel method of manufacturing superficial brachytherapy applicators utilizing three dimensional (3D)-printing techniques. We describe the treatment planning process and the process of applicator manufacture. RESULTS: The treatment planning process, with the introduction of a pre-plan, allows for an "ideal" catheter arrangement within an applicator to be determined, exploiting varying catheter orientations, heights, and curvatures if required. The pre-plan arrangement is then 3D printed to the exact specifications of the pre-plan applicator design. This results in improved target volume coverage and improved sparing of organs at risk. CONCLUSIONS: Using a pre-plan technique for ideal catheter placement followed by automated 3D-printed applicator manufacture has greatly improved the entire process of superficial high-dose-rate brachytherapy treatment. We are able to design and manufacture flexible, well-fitting, superior quality applicators resulting in a more efficient and improved patient pathway and patient experience. PMID- 27965118 TI - Comparison of computed tomography and magnetic resonance imaging in cervical cancer brachytherapy: A systematic review. AB - PURPOSE: The aim of this overview was to assess the accuracy of computed tomography (CT)-based imaging technology and to compare it with magnetic resonance imaging (MRI) for the treatment planning of high-dose rate brachytherapy in cervical cancer. METHODS AND MATERIALS: A systematic search in PubMed, Embase, and the Cochrane Central was performed to identify clinical studies involving brachytherapy of cervical cancer and published before February 1, 2016. Outcomes of interest were geometric dimensions, dose parameters, and clinical results. RESULTS: After screening 675 articles, 13 clinical studies involving 465 patients were included for critical appraisal; 10 studies compared CT with MRI and three compared hybrid (CT/MRI based) with MRI only-based imaging technologies. The geometric dimensions of the high-risk clinical target volume (HR-CTV), dose parameters, and clinical outcomes were reported in 11, 10, and 1 studies, respectively. CONCLUSIONS: Among those geometric parameters of HR-CTV, width was significantly overestimated on CT compared with MRI. Height might be underestimated, and thickness was comparable. The dose parameters for HR-CTV were lower on CT only-based technique compared with MRI-based one. It is proposed that at least one pre- or at brachytherapy MRI is required to assess the tumor extension. With the help of MRI information, CT contouring will be much more accurate in cervical cancer brachytherapy. PMID- 27965115 TI - Npa3/ScGpn1 carboxy-terminal tail is dispensable for cell viability and RNA polymerase II nuclear targeting but critical for microtubule stability and function. AB - Genetic deletion of the essential GTPase Gpn1 or replacement of the endogenous gene by partial loss of function mutants in yeast is associated with multiple cellular phenotypes, including in all cases a marked cytoplasmic retention of RNA polymerase II (RNAPII). Global inhibition of RNAPII-mediated transcription due to malfunction of Gpn1 precludes the identification and study of other cellular function(s) for this GTPase. In contrast to the single Gpn protein present in Archaea, eukaryotic Gpn1 possesses an extension of approximately 100 amino acids at the C-terminal end of the GTPase domain. To determine the importance of this C terminal extension in Saccharomyces cerevisiae Gpn1, we generated yeast strains expressing either C-terminal truncated (gpn1DeltaC) or full-length ScGpn1. We found that ScGpn1DeltaC was retained in the cell nucleus, an event physiologically relevant as gpn1DeltaC cells contained a higher nuclear fraction of the RNAPII CTD phosphatase Rtr1. gpn1DeltaC cells displayed an increased size, a delay in mitosis exit, and an increased sensitivity to the microtubule polymerization inhibitor benomyl at the cell proliferation level and two cellular events that depend on microtubule function: RNAPII nuclear targeting and vacuole integrity. These phenotypes were not caused by inhibition of RNAPII, as in gpn1DeltaC cells RNAPII nuclear targeting and transcriptional activity were unaffected. These data, combined with our description here of a genetic interaction between GPN1 and BIK1, a microtubule plus-end tracking protein with a mitotic function, strongly suggest that the ScGpn1 C-terminal tail plays a critical role in microtubule dynamics and mitotic progression in an RNAPII independent manner. PMID- 27965124 TI - Comment on "Laparoscopic Myomectomy of a Symptomatic Uterine Leiomyoma in a 15 Year-Old Adolescent". PMID- 27965121 TI - The application of microbeads to microfluidic systems for enhanced detection and purification of biomolecules. AB - This paper describes microbead-based microfluidic systems. Several aspects of bead assays in microfluidics make them advantageous for bioassays in simple microchannels, including enhanced surface-to-volume ratio, improved molecular recognition reaction efficiency, and the wide range of surface functionalization available with commercial microbeads. Two-level SU-8 molds are used to fabricate PDMS microchannels that can hydrodynamically trap different types of microbeads, with characteristic dimensions of tens of microns. The use of these microbead based microfluidic systems in the biosensing of antibodies, toxins and nucleic acids, as well as in antibody purification will be presented and discussed in this paper. PMID- 27965122 TI - Assembling a Functional Clitoris and Vulva from a Pseudo-Penis: A Surgical Technique for an Adult Woman with Congenital Adrenal Hyperplasia. AB - BACKGROUND: Congenital adrenal hyperplasia (CAH) is associated with a genital deformation that might cause a negative body image. The genital ambiguity is generally "corrected" surgically during early infancy. The advantage is a psychological benefit. The disadvantages are multiple surgical procedures and the loss of orgasm. CASE: A 22-year-old woman with CAH consulted for genital reconstructive surgery. She had a pseudopenis of 4 cm and could achieve an orgasm by masturbating. During surgery, the penis was dismantled and with the preserved glans penis and the corpora cavernosa, a clitoris and vestibules were constructed, respectively. On the basis of the anamneses during the follow-up, she had a functional vagina and could still achieve orgasms. SUMMARY AND CONCLUSION: Genital correction surgery for CAH at an older age was easier, could be done in 1 step, and enabled the preservation of orgasm. PMID- 27965113 TI - Dissecting the molecular mechanisms that impair stress granule formation in aging cells. AB - Aging affects numerous aspects of cell biology, but the senescence-associated changes in the stress response are only beginning to emerge. To obtain mechanistic insights into these events, we examined the formation of canonical and non-canonical stress granules (SGs) in the cytoplasm. SG generation is a key event after exposure to physiological or environmental stressors. It requires the SG-nucleating proteins G3BP1 and TIA-1/TIAR and stress-related signaling events. To analyze SG formation, we used two independent models of somatic cell aging. In both model systems, cellular senescence impaired the assembly of two SG classes: (i) it compromised the formation of canonical SGs, and (ii) skewed the production of non-canonical SGs. We dissected the mechanisms underlying these senescence dependent changes in granule biogenesis and identified several specific targets that were modulated by aging. Thus, we demonstrate a depletion of G3BP1 and TIA 1/TIAR in senescent cells and show that the loss of G3BP1 contributed to impaired SG formation. We further reveal that aging reduced Sp1 levels; this transcription factor regulated G3BP1 and TIA-1/TIAR abundance. The assembly of canonical SGs relies on the phosphorylation of translation initiation factor eIF2alpha. We show that senescence can cause eIF2alpha hyperphosphorylation. CReP is a subunit of protein phosphatase 1 and critical to reverse the stress-dependent phosphorylation of eIF2alpha. We demonstrate that the loss of CReP correlated with the aging-related hyperphosphorylation of eIF2alpha. Together, we have identified significant changes in the stress response of aging cells and provide mechanistic insights. Based on our work, we propose that the decline in SG formation can provide a new biomarker to evaluate cellular aging. PMID- 27965126 TI - Structure-activity relationships on the study of beta-galactosidase folding/unfolding due to interactions with immobilization additives: Triton X-100 and ethanol. AB - Improving the enzyme stability is a challenge for allowing their practical application. The surfactants are stabilizing agents, however, there are still questions about their influence on enzyme properties. The structure activity/stability relationship for beta-galactosidase from Bacillus circulans is studied here by Circular Dichroism and activity measurements, as a function of temperature and pH. The tendency of preserving the beta-sheet and alpha-helix structures at temperatures below 65 degrees C and different pH is the result of the balance between the large- and short-range effects, respecting to the active site. This information is fundamental for explaining the structural changes of this enzyme in the presence of Triton X-100 surfactant and ethanol. The enzyme thermal stabilization in the presence of this surfactant responds to the rearrangement of the secondary structure for having optimal activity/stability. The effect of ethanol is more related with changes in the dielectric properties of the aqueous solution than with protein structural transformations. These results contribute to understand the effects of surfactant-enzyme interactions on the enzyme behavior, from the structural point of view and to rationalize the surfactant-based stabilizing strategies for beta-galactosidades. PMID- 27965119 TI - Ultrasound registration: A review. AB - This article is a review of registration algorithms for use between ultrasound images (monomodal image-based ultrasound registration). Ultrasound is safe, inexpensive, and real-time, providing many advantages for clinical and scientific use on both humans and animals, but ultrasound images are also notoriously noisy and subject to several unique artifacts/distortions. This paper introduces the topic and unique aspects of ultrasound-to-ultrasound image registration, providing a broad introduction and summary of the literature and the field. Both theoretical and practical aspects are introduced. The first half of the paper is theoretical, organized according to the basic components of a registration framework, namely preprocessing, image-similarity metrics, optimizers, etc. It further subdivides these methods between those suitable for elastic (non-rigid) vs. inelastic (matrix) transforms. The second half of the paper is organized by anatomy and is practical in nature, presenting and discussing the complete published systems that have been validated for registration in specific anatomic regions. PMID- 27965123 TI - Lymphoblastic Lymphoma Presenting as Bilateral Ovarian Mass in an Adolescent Girl. AB - BACKGROUND: Lymphomas rarely involve the genital tract and non-Hodgkin lymphoma (NHL) presenting as ovarian tumor is rare. Precursor B-cell lymphoblastic lymphoma arising from the ovary is extremely rare and to our knowledge, only 5 cases have been reported in the literature. CASE: A 15-year-old girl presented with bilateral ovarian masses, which, on biopsy proved to be precursor B-cell lymphoblastic lymphoma. She was treated with a Berlin-Frankfurt-Munster 90 protocol and she is alive in complete remission for more than 10 years. SUMMARY AND CONCLUSION: NHL of the ovary should also be considered as a differential diagnosis in adolescent and young adults with ovarian masses. Attempt to make a preoperative diagnosis is crucial because ovarian NHL responds well to chemotherapy and has a good prognosis. PMID- 27965120 TI - Electrochemical immunosensor for tumor necrosis factor-alpha detection in undiluted serum. AB - An immunosensor for the sensitive detection and estimation of tumor necrosis factor-alpha (TNF-alpha) in undiluted serum has been developed via an electrochemical enzyme-linked immunosorbent assay (ELISA) process. Electrochemical sensing was performed using a TNF-alpha specific monoclonal antibody modified self-assembled monolayer of dithiobis(succinimidyl propionate) on a comb-shaped gold electrode microarray. After anti-TNF-alpha antibody binding, unreacted active groups of DTSP were blocked using ethanol amine (EA) and nonspecific binding was prevented using phosphate buffer based starting block T20 (SB). Sensitive and disposable SB-EA-anti-TNF-alpha/DTSP/Au electrodes were exposed to solutions with different TNF-alpha concentrations for 20min in undiluted serum. Conversion of 4-aminophenyl phosphate to 4-aminophenol and its electrochemical oxidation was utilized for indirect estimation of TNF-alpha. Results for SB-anti-TNF-alpha/DTSP/Au electrodes indicate that the sensors can be used for the sensitive estimation of TNF-alpha in undiluted serum in the range 500pg/ml to 100ng/ml with a detection limit of 60pg/ml and sensitivity of 0.46 (ng/ml)-1. Negligible interference from serum and other biomarker proteins was observed. The described electrochemical ELISA is much faster than conventional ELISA and can be applied for sensing of a range of analytes in real patient samples. PMID- 27965127 TI - The preparation and characterization of chitin and chitosan under large-scale submerged fermentation level using shrimp by-products as substrate. AB - The crustacean shells of crabs and shrimps produces quantities of by-products, leading to seriously environmental pollution and human health problems during industrial processing, yet they turned into high-value useful products, such as chitin and chitosan. To prepare them under large-scale submerged fermentation level, shrimp shell powders (SSPs) was fermented by successive three-step fermentation of Serratia marcescens B742, Lactobacillus plantarum ATCC 8014 and Rhizopus japonicus M193 to extract chitin and chitosan based on previously optimal conditions. Moreover, the key parameters was investigated to monitor the changes of resulted products during fermentation process. The results showed that the yield of prepared chitin and chitosan reached 21.35 and 13.11% with the recovery rate of 74.67 and 63.42%, respectively. The degree of deacetylation (DDA) and molecular mass (MM) of produced chitosan were 81.23% and 512.06kDa, respectively. The obtained chitin and chitosan was characterized using Fourier transform infrared spectrometer (FT-IR) and X-ray diffraction (XRD) analysis. The established microbial fermentation method can be applied for the industrial large scale production of chitin and chitosan, while the use of chemical reagents was significantly reduced. PMID- 27965125 TI - Structure-function relationship of a bio-pesticidal trypsin/chymotrypsin inhibitor from winged bean. AB - Protease inhibitors are essential bio-molecules that serve as a model system for the study of protein structure and protease-protease inhibitor interaction. We here report a bi-functional serine protease inhibitor from winged bean (WBCTI) that completely retains its inhibitory property against trypsin and chymotrypsin even after heating at 70 degrees C. Detailed circular dichroism and fluorescence studies at different temperatures, 30-90 degrees C, have been performed to understand the reason behind thermal stability of the protein. On the basis of our results it appears that WBCTI maintains its canonical structure up to 70 degrees C. Above that the heat induced conformational change becomes irreversible which causes aggregation followed by precipitation of the protein. Moreover, the activity and stability of the secondary structure are found to decrease drastically in presence of dithiothreitol indicating that the protein acquires additional stability for the occurrence of two disulfide bonds. In addition to the structural characterization, an important property of WBCTI against the polyphagous pest Helicoverpa armigera has been explored in present study. WBCTI has showed reasonable inhibition of the mid-gut proteases of H. armigera. In artificial feeding trial through addition of WBCTI in diet resulted in significant growth retardation, delayed pupae formation and higher mortality of H. armigera larvae. PMID- 27965114 TI - Myogenic differentiation depends on the interplay of Grb2 and N-WASP. AB - Myogenesis requires a well-coordinated withdrawal from cell cycle, morphological changes and cell fusion mediated by actin cytoskeleton. Grb2 is an adaptor protein whose central SH2 domain binds to phosphorylated tyrosine residues of activated receptors and activates intracellular signaling pathway, while its N terminal and C-terminal SH3 domains bind to proline rich proteins such as N-WASP (Neural-Wiskott Aldrich Syndrome Protein). We found that the expression of Grb2 was increased at the beginning of differentiation and remained constant during differentiation in C2C12 myoblasts. Knocking down endogenous Grb2 expression caused a significant increase in the fusion index and expression of MyHC, a terminal differentiation marker when compared with the control. Over expression of Grb2 in C2C12 (C2C12Grb2-Myc) reduced myotube formation and expression of MyHC. Similarly over expression of Grb2P49L-Myc (N-terminal SH3 domain mutant) or Grb2R86K-Myc (SH2 domain mutant) inhibited myogenic differentiation of C2C12 cells. However, the expression of Grb2P206L-Myc (C-terminal SH3 domain mutant) did not inhibit myotube formation and expression of MyHC. This suggests that the C-terminal SH3 domain of Grb2 is critical for the inhibition of myogenic differentiation. The C2C12Grb2-Myc cells have reduced phalloidin staining at late stages of differentiation. Expression of N-WASP in C2C12Grb2-Myc cells rescued the myogenic defect and increased phalloidin staining (increased F-actin) in these cells. Thus our results suggest that Grb2 is a negative regulator of myogenesis and reduces myogenic differentiation by inhibiting actin polymerization/remodeling through its C-terminal SH3 domain. PMID- 27965117 TI - High-dose-rate brachytherapy monotherapy without androgen deprivation therapy for intermediate-risk prostate cancer. AB - PURPOSE: Outcomes using high-dose-rate (HDR) brachytherapy monotherapy (without androgen deprivation therapy or external beam radiation therapy) for National Comprehensive Cancer Network-defined intermediate-risk (IR) patients are limited. We report our long-term data using HDR monotherapy for this patient population. METHODS AND MATERIALS: One-hundred ninety IR prostate cancer patients were treated 1996-2013 with HDR monotherapy. Biochemical prostate-specific antigen (PSA) failure was per the Phoenix definition. Acute and late genitourinary and gastrointestinal toxicities were graded according to Common Toxicity Criteria of Adverse Events, version 4. Kaplan-Meier (KM) biochemical progression-free survival (BPFS), cause-specific survival, and overall survival rates were calculated. Univariate analyses were performed to determine relationships with BPFS. The median patient age was 66 years (43-90), and the median initial PSA was 7.4 ng/mL. The Gleason score was <=6 in 26%, 3 + 4 in 62%, and 4 + 3 in 12%. The median treatment BED1.5 was 254 Gy; 83% of patients were treated with a dose of 7.25 Gy * six fractions delivered in two separate implants. RESULTS: With a median follow-up of 6.2 years, KM BPFS at 5/8 years was 97%/90%, cause-specific survival at 8 years was 100%, and overall survival at 5/8 years was 93%/88%. Late genitourinary toxicities were 36.3% Grade 1, 18.9% Grade 2, and 3.7% Grade 3. Late gastrointestinal toxicities were 6.3% Grade 1, 1.1% Grade 2, and no Grade >=3. Of the patients with no sexual dysfunction before treatment, 68% maintained potency. Age, initial PSA, T stage, Gleason score, prostate volume, and percent positive cores did not correlate with BPFS. Stratifying by favorable vs. unfavorable IR groups did not affect BPFS. CONCLUSIONS: HDR brachytherapy monotherapy represents a safe and highly effective treatment for IR prostate cancer patients with long-term follow-up. PMID- 27965130 TI - Approaches for grouping of pesticides into cumulative assessment groups for risk assessment of pesticide residues in food. AB - The European Food Safety Authority (EFSA) is developing approaches to cumulative risk assessment of pesticides by assigning individual pesticides to cumulative assessment groups (CAGs). For assignment to CAGs, EFSA recommended to rely on adverse effects on the specific target system. Contractors to EFSA have proposed to allocate individual pesticides into CAGs relying on NOAELs for effects on target organs. This manuscript evaluates the assignments by applying EFSAs criteria to the CAGs "Toxicity to the nervous system" and "Toxicity to the thyroid hormone system (gland or hormones)". Assignment to the CAG "Toxicity to the nervous system" based, for example, on neurochemical effects like choline esterase inhibition is well supported, whereas assignment to the CAG "Toxicity to the thyroid hormone system (gland or hormones)" has been based in the examined case studies on non-reproducible effects seen in single studies or on observations that are not adverse. Therefore, a more detailed effects evaluation is required to assign a pesticide to a CAG for a target organ where many confounders regarding effects are present. Relative potency factors in cumulative risk assessment should be based on benchmark doses from studies in one species with identical study design and human relevance of effects on specific target organs should be analyzed to define minimal margins of exposure. PMID- 27965133 TI - Abdominal Wall Reconstruction with Concomitant Ostomy-Associated Hernia Repair: Outcomes and Propensity Score Analysis. AB - BACKGROUND: The optimal strategy for abdominal wall reconstruction in the presence of a stomal-site hernia is unclear. We hypothesized that the rate of ventral hernia recurrence in patients undergoing a combined ventral hernia repair and stomal-site herniorraphy would not differ clinically from the ventral hernia recurrence rate in patients undergoing an isolated ventral hernia repair. We also hypothesized that bridged ventral hernia repairs result in worse outcomes compared with reinforced repairs, regardless of stomal hernia. STUDY DESIGN: We retrospectively reviewed prospectively collected data from consecutive abdominal wall reconstructions performed with acellular dermal matrix (ADM) at a single center between 2000 and 2015. We compared patients who underwent a ventral hernia repair alone (AWR) and those who underwent both a ventral hernia repair and ostomy-associated herniorraphy (AWR+O). We conducted a propensity score matched analysis to compare the outcomes between the 2 groups. Multivariable Cox proportional hazards and logistic regression models were used to study associations between potential predictive or protective reconstructive strategies and surgical outcomes. RESULTS: We included 499 patients (median follow-up 27.2 months; interquartile range [IQR] 12.4 to 46.6 months), 118 AWR+O and 381 AWR. After propensity score matching, 91 pairs were obtained. Ventral hernia recurrence was not statistically associated with ostomy-associated herniorraphy (adjusted hazard ratio [HR] 0.7; 95% CI 0.3 to 1.5; p = 0.34). However, the AWR+O group experienced a significantly higher percentage of surgical site occurrences (34.1%) than the AWR group (18.7%; adjusted odds ratio 2.3; 95% CI 1.4 to 3.7; p < 0.001). In the AWR group, there were significantly fewer ventral hernia recurrences when the repair was reinforced compared with bridged (5.3% vs 38.5%; p < 0.001). CONCLUSIONS: There was no statistically significant difference in ventral hernia recurrence between the AWR and AWR+O groups. Bridging was associated with an increased rate of hernia recurrence and should be avoided if possible. PMID- 27965129 TI - Comparative subcutaneous repeated toxicity study of enoxaparin products in rats. AB - Enoxaparin is a low-molecular-weight heparin widely used for the prevention and treatment of thromboembolism. With the development of several enoxaparin biosimilars, real medical concerns about their safety and efficacy have been raised. This repeated dose toxicity study consists of preclinical toxicological evaluation of a biosimilar biological version of enoxaparin, the drug product "Enoxa", compared to the enoxaparin reference drug product, "Lovenox". Eighty white Wistar rats were treated with "Enoxa" versus the reference product, using subcutaneous therapeutic and toxic doses, varying from 3.5 to 100 mg/kg/day. Dose levels were adjusted and ultimately fixed at 3.5 and 20 mg/kg/day as therapeutic and toxic doses, respectively. A sodium chloride solution (0.9%) was used as the control, and the comparative study was conducted over periods of 14 and 28 days. Comparable effects were observed with few adverse effects at the administration dose of 20 mg/kg/day, for both enoxaparin biosimilar and reference products. Interestingly, mortality started only at high doses of 40 mg/kg/day and reached 25% at 100 mg/kg/day for both products. These results, as part of the recommended biosimilarity monitoring, demonstrated comparable toxicity profiles of "Enoxa" and "Lovenox" products in rats. Continuing investigation of biosimilarity on humans to confirm safety and efficacy is suggested. PMID- 27965131 TI - Patient-Reported Outcomes Measurement Information System (PROMIS) Use in Surgical Care: A Scoping Study. AB - BACKGROUND: Surgeons recognize the importance of patient reported outcomes in the evaluation of health care. Documenting health related quality of life (HRQOL) can enhance surgical quality improvement efforts. Systematic documentation of HRQOL began in 1963. Currently, multiple varied and unstandardized instruments make it difficult to compare quality of life measures across studies. The NIH developed the Patient Reported Outcomes Measurement Information System (PROMIS) to provide a standardized assessment designed to complement traditional outcomes measures. STUDY DESIGN: We used systematic scoping methodology to investigate the characteristics of PROMIS use in studies assessing quality of life measures as surgical outcomes. RESULTS: A systematic search of PubMed revealed 21 publications describing the use of PROMIS to assess surgical outcomes. The 121 study publications reported observations on 2,561 patients. Twenty-nine percent of patients had injuries, 33% had neoplasms, and 38% included other patients having neither injuries nor neoplasms. General surgery/gynecology/plastic surgery had 8 publications, orthopaedic surgery had 9 publications, and neurosurgery had 4 publications. Most studies included additional measures. There were 25 instruments used in addition to PROMIS. CONCLUSIONS: This study revealed that PROMIS performed efficiently, accurately, and reliably in assessing patient reported HRQOL in multidisciplinary surgical publications. PMID- 27965128 TI - Anti-angiogenic potential of trypsin inhibitor purified from Cucumis melo seeds: Homology modeling and molecular docking perspective. AB - Melons have a good source of protease inhibitors. Its fruit and seeds have been used as a traditional medicine. However, its effects on angiogenesis and mechanism of its action remain elusive. Herein trypsin inhibitor from aqueous extract of C. melo seeds (TICMS) was purified. Its effects on different steps of angiogenesis were evaluated. Also, we examined its effects on migration and angiogenesis of endothelial cells. Three dimensional model of TICMS protein was accurately built in which TICMS docked to alphaVbeta3 integrin and VEGFR1. Electrophoresis analysis of the purified protein revealed a single band with a molecular mass of about 3kDa. Treatment with TICMS at six doses resulted in a significant decrease of endothelial cell proliferation with an IC50 value of about 20MUg/ml. Tubulogenesis assay revealed that a dose dependent anti angiogenic activity of TICMS (5-40MUg/ml). Also, TICMS had inhibitory effects on VEGF, MMP-2 and MMP-9 secretion. Our docking result speculated that TICMS could bind to the cleft between the alphaVbeta3 integrin and it able to decrease the activity of this receptor. The TICMS was also able to interact with VEGFR1 receptor, but with low probability. Based on our study, TICMS could be used as a specific angiogenesis inhibitor. PMID- 27965132 TI - Low-Volume vs High-Volume Centers and Management of Fournier's Gangrene in Washington State. AB - BACKGROUND: Fournier's gangrene (FG) is a life-threatening infection affecting the perineum and genitals. Complex patient management often necessitates transfer to tertiary centers. We aimed to characterize hospital transfer patterns and assess morbidity among patients with FG in Washington State. STUDY DESIGN: The Washington State Comprehensive Hospital Abstract Reporting System includes claims from all hospital discharges in Washington. We identified patients with FG between 2007 and 2013, based on diagnosis and treatment codes. Analyses were stratified by center volume (low-volume centers [LVCs] or high-volume centers [HVCs]), and transfer status. Variables of interest included number of debridements, septic shock, acute renal failure, acute respiratory failure, length of hospitalization, and death. RESULTS: We identified 165 FG patients. Only 1 HVC treated more than 2 FG patients per year. Overall mortality was 6.7%. Most patients (57%) were treated entirely at LVCs; 87% of patients treated at the HVC were transferred from an LVC. High-volume center-treated patients had similar baseline comorbidities (p = 0.77) and similar mortality (p = 0.87), despite higher rates of septic shock (p < 0.01) and respiratory failure (p = 0.01) compared with LVC patients. Among HVC-transferred patients, immediate compared with delayed transfer was associated with fewer debridements (p < 0.01), lower rates of septic shock (p = 0.05), and acute renal failure (p = 0.04). CONCLUSIONS: Patients treated at the HVC were more acutely ill, yet mortality was similar compared with patients treated solely at LVCs, suggesting a benefit to transfer of high acuity patients. Immediate vs delayed transfer may benefit FG health outcomes; however, this may also reflect greater disease acuity of patients with delayed transfer status. PMID- 27965135 TI - Effective targeting of gemcitabine to pancreatic cancer through PEG-cored Flt-1 antibody-conjugated dendrimers. AB - Tumor-targeted delivery of anticancer drugs using dendrimers has been recognized as a promising strategy to increase efficiency and reduce adverse effects of chemotherapy. Herein, we developed a dendrimer-based drug delivery system targeting Flt-1 (a receptor for vascular endothelial growth factors (VEGF)) receptor to improve therapeutic efficacy of gemcitabine in pancreatic cancer. Synthesized polyethylene glycol (PEG)-cored PAMAM dendrimers, which bear anionic carboxylic acid groups on the surface were modified with PEG chains, which were then conjugated with Flt-1 antibody. Following structural and chemical characterization studies, gemcitabine HCl-dendrimer inclusion complexes were successfully prepared. These complexes were efficiently engulfed by Flt-1 expressing pancreatic cancer cells, which enhanced the cytotoxicity of gemcitabine. Moreover, pancreatic tumors established in mice were highly targeted by PEG-cored Flt-1 antibody-conjugated dendrimers and increased accumulation of these gemcitabine-loaded complexes exhibited satisfactory in vivo anti-cancer efficacy. In conclusion, dendrimer-based targeted delivery of chemotherapeutics may serve as a promising approach for the treatment of malignancies such as pancreatic cancer that do not benefit from conventional chemotherapy. PMID- 27965141 TI - In vivo two-photon imaging reveals a role of progesterone in reducing axonal dieback after spinal cord injury in mice. AB - Progesterone (PG) as a neuroprotective reagent has been used for the treatment of spinal cord injury (SCI) in experimental animal models. However, its effect and mechanism on axonal dieback at the early stage of SCI remain unclear. Here, we investigate the dynamics of injured axons and the effect of PG on the axonal dieback, glial response, and behavioral recovery in a mouse model of SCI. Two photon intravital imaging combined with a simplified imaging window chamber were used to image axons in hemisected spinal cords over a period of 3 days. Repeated imaging showed that axonal dieback distance in mice treated with PG after SCI was significantly reduced than that in mice treated with vehicle after SCI (P < 0.05) at the time point of 24 h, 48 h, and 72 h after SCI. The densities of astrocytes and microglia in the SCI-vehicle treated group were significantly higher than those in mice treated with PG after SCI (P < 0.05). Real time polymerase chain reaction assay indicated that administration of PG after SCI down-regulated the expression of pro-inflammatory cytokines MCP-1, NOS2, and IL-1beta (P < 0.05). PG treatment also improved the behavioral performance post injury. These findings suggested that PG exerted a neuroprotective effect by attenuating axonal dieback, reducing the accumulation of astrocytes and microglia and inhibiting the release of pro-inflammatory cytokines. PMID- 27965137 TI - Osteoarthritis year in review 2016: imaging. AB - PURPOSE: The current narrative review covers original research related to imaging in osteoarthritis (OA) in humans published in English between April 1st 2015 and March 31st 2016, in peer reviewed journals available in Medline via PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). METHODS: Relevant studies in humans, subjectively decided by the authors, contributing significantly to the OA imaging field, were selected from an extensive Medline search using the terms "Osteoarthritis" in combination with "MRI", "Imaging", "Radiography", "X-rays", "Ultrasound", "Computed tomography", "Nuclear medicine", "PET-CT", "PET-MRI", "Scintigraphy", "SPECT". Publications were sorted according to relevance for the OA imaging research community with an emphasis on high impact special interest journals using the software for systematic reviews www.covidence.org. RESULTS: An overview of newly published studies compared to studies reported previous years is presented, followed by a review of selected imaging studies of primarily knee, hip and hand OA focussing on (1) results for detection of OA and OA-related pathology (2) studies dealing with treatments and (3) studies focussing on prognosis of disease progression or joint replacement. A record high number of 1420 articles were published, among others, of new technologies and tools for improved morphological and pathophysiological understanding of OA-related changes in joints. Also, imaging data were presented of monitoring treatment effect and prognosis of OA progression, primarily using established radiographic, magnetic resonance imaging (MRI), and ultrasound (US) methods. CONCLUSION: Imaging continues to play an important role in OA research, where several exciting new technologies and computer aided analysis methods are emerging to complement the conventional imaging approaches. PMID- 27965142 TI - Duane syndrome with prominent oculo-auricular phenomenon. AB - Duane syndrome is a congenital cranial dysinnervation disorder involving absent or anomalous innervation of the lateral and medial rectus muscles that is sometimes associated with other manifestations of dysinnervation. We describe a patient with right esotropic Duane syndrome with a long-standing retroauricular tugging sensation in right gaze who was noted to have prominent ipsilateral oculo auricular phenomenon, representing either abnormal enhancement of existing innervation or an uncommon dysinnervation. After successful strabismus surgery the tugging sensation improved but the phenomenon could still be elicited. PMID- 27965136 TI - Activity-dependent proteolytic cleavage of cell adhesion molecules regulates excitatory synaptic development and function. AB - Activity-dependent remodeling of neuronal connections is critical to nervous system development and function. These processes rely on the ability of synapses to detect neuronal activity and translate it into the appropriate molecular signals. One way to convert neuronal activity into downstream signaling is the proteolytic cleavage of cell adhesion molecules (CAMs). Here we review studies demonstrating the mechanisms by which proteolytic processing of CAMs direct the structural and functional remodeling of excitatory glutamatergic synapses during development and plasticity. Specifically, we examine how extracellular proteolytic cleavage of CAMs switches on or off molecular signals to 1) permit, drive, or restrict synaptic maturation during development and 2) strengthen or weaken synapses during adult plasticity. We will also examine emerging studies linking improper activity-dependent proteolytic processing of CAMs to neurological disorders such as schizophrenia, brain tumors, and Alzheimer's disease. Together these findings suggest that the regulation of activity dependent proteolytic cleavage of CAMs is vital to proper brain development and lifelong function. PMID- 27965143 TI - Anticholinergic activity in the nervous system: Consequences for visuomotor function. AB - Acetylcholine is present in the peripheral and central nervous system, where it is involved in a number of fundamental physiological and biochemical processes. In particular, interaction with muscarinic receptors can cause adverse effects such as dry mouth, drowsiness, mydriasis and cognitive dysfunction. Despite the knowledge that exists regarding these common side-effects, little is known about how anticholinergic medications influence central motor processes and fine motor control in healthy individuals. This paper reviews critical visuomotor processes that operate in healthy individuals, and how controlling these motor processes are influenced by medications that interfere with central cholinergic neurotransmission. An overview of receptor function and neurotransmitter interaction following the ingestion or administration of anticholinergics is provided, before exploring how visuomotor performance is affected by anticholinergic medications. In particular, this review will focus on the effects that anticholinergic medications have on fixation stability, saccadic eye movements, smooth pursuit eye movements, and general pupil dynamics. PMID- 27965139 TI - Physiological exercise loading suppresses post-traumatic osteoarthritis progression via an increase in bone morphogenetic proteins expression in an experimental rat knee model. AB - OBJECTIVE: To evaluate the dose-response relationship of exercise loading in the cartilage-subchondral bone (SB) unit in surgically-induced post-traumatic osteoarthritis (PTOA) of the knee. DESIGN: Destabilized medial meniscus (DMM) surgery was performed on the right knee of 12-week-old male Wistar rats, and sham surgery was performed on the contralateral knee. Four weeks after the surgery, the animals were subjected to moderate (12 m/min) or intense (21 m/min) treadmill exercises for 30 min/day, 5 days/week for 4 weeks. PTOA development in articular cartilage and SB was examined using histological and immunohistochemical analyses, micro-computed tomography (micro-CT) analysis, and biomechanical testing at 8 weeks after surgery. Gremlin-1 was injected to determine the role of bone morphogenetic protein (BMP) signaling on PTOA development following moderate exercise. RESULTS: Moderate exercise increased BMP-2, BMP-4, BMP-6, BMP receptor 2, pSmad-5, and inhibitor of DNA binding protein-1 expression in the superficial zone chondrocytes and suppressed cartilage degeneration, osteophyte growth, SB damage, and osteoclast-mediated SB resorption. However, intense exercise had little effect on BMP expression and even caused progression of these osteoarthritis (OA) changes. Gremlin-1 injection following moderate exercise caused progression of the PTOA development down to the level of the non-exercise DMM-operated knee. CONCLUSIONS: Exercise regulated cartilage-SB PTOA development in DMM-operated knees in a dose-dependent manner. Our findings shed light on the important role of BMP expression in superficial zone chondrocytes in attenuation of PTOA development following physiological exercise loading. Further studies to support a mechanism by which BMPs would be beneficial in preventing PTOA progression are warranted. PMID- 27965144 TI - Mapping of Schistosoma mansoni in the Nile Delta, Egypt: Assessment of the prevalence by the circulating cathodic antigen urine assay. AB - In line with WHO recommendations on elimination of schistosomiasis, accurate identification of all areas of residual transmission is a key step to design and implement measures aimed at interrupting transmission in low-endemic settings. To this purpose, we assessed the prevalence of active S. mansoni infection in five pilot governorates in the Nile Delta of Egypt by examining schoolchildren (6-15 years) using the Urine-Circulating Cathodic Antigen (Urine-CCA) cassette test; we also carried out the standard Kato-Katz (KK) thick smear, the monitoring and evaluation tool employed by Egypt's national schistosomiasis control programme. Prevalence rates determined by the Urine-CCA test for all governorates were higher than those determined by KK (p<0.01). Of 35 districts surveyed in the five governorates, S. mansoni infection was detected in 19 districts (54.3%) using KK, and in 31 districts (88.6%) by Urine-CCA (chi2=9.94; P=0.0016). S. mansoni infections were detected by Urine-CCA, but not by KK in 12 districts (34.3%), and infection was not detected by either of the two diagnostic methods in four districts in Qalyubia governorate. Males and higher age-groups have significantly higher Urine-CCA prevalence rates. Based on the findings of the current S. mansoni mapping exercise, authorities of the Ministry of Health and Population (MoHP) adopted a new elimination strategy by readjusting thresholds for mass treatment with praziquantel and targeting all transmission areas. MoHP is now planning to remap in all other endemic governorates using Urine-CCA with the aim of identifying all areas of transmission where the elimination strategy should be applied. PMID- 27965140 TI - Multimodality scoring of chondral injuries in the equine fetlock joint ex vivo. AB - OBJECTIVE: We investigate the potential of a prototype multimodality arthroscope, combining ultrasound, optical coherence tomography (OCT) and arthroscopic indentation device, for assessing cartilage lesions, and compare the reliability of this approach with conventional arthroscopic scoring ex vivo. DESIGN: Areas of interest (AIs, N = 43) were selected from equine fetlock joints (N = 5). Blind coded AIs were independently scored by two equine surgeons employing International Cartilage Repair Society (ICRS) scoring system via conventional arthroscope and multimodality arthroscope, in which high-frequency ultrasound and OCT catheters were attached to an arthroscopic indentation device. In addition, cartilage stiffness was measured with the indentation device, and lesions in OCT images scored using custom-made automated software. Measurements and scorings were performed twice in two separate rounds. Finally, the scores were compared to histological ICRS scores. RESULTS: OCT and arthroscopic examinations showed the highest average agreements (55.2%) between the scoring by surgeons and histology scores, whereas ultrasound had the lowest (50.6%). Average intraobserver agreements of surgeons and interobserver agreements between rounds were, respectively, for conventional arthroscope (68.6%, 69.8%), ultrasound (68.6%, 68.6%), OCT (65.1%, 61.7%) and automated software (65.1%, 59.3%). CONCLUSIONS: OCT imaging supplemented with the automated software provided the most reliable lesion scoring. However, limited penetration depth of light limits the clinical potential of OCT in assessing human cartilage thickness; thus, the combination of OCT and ultrasound could be optimal for reliable diagnostics. Present findings suggest imaging and quantitatively analyzing the entire articular surface to eliminate surgeon-related variation in the selection of the most severe lesion to be scored. PMID- 27965134 TI - National Rise of Primary Pancreatic Carcinoid Tumors: Comparison to Functional and Nonfunctional Pancreatic Neuroendocrine Tumors. AB - BACKGROUND: New guidelines recommend differentiating between carcinoid and pancreatic neuroendocrine tumors (PNETs) during clinical trials. However, little is known about the behavior and incidence of primary pancreatic carcinoid tumors. STUDY DESIGN: We performed a retrospective cohort study using the National Cancer Data Base (NCDB) to identify adults with primary PNETs diagnosed between 2004 and 2013. The Kaplan-Meier method was used to evaluate overall survival, and multivariate Cox proportional hazards model was used to assess the hazard of death in resected patients. RESULTS: Of 10,752 patients, 12.7% were diagnosed with carcinoid tumors, 84.7% with nonfunctional and 2.6% with functional PNETs. Although the number of functional PNETs has remained relatively constant over time, rates of nonfunctional and carcinoid tumors have risen dramatically. Only 36 (5.7%) carcinoid tumors were diagnosed in 2004; this increased to 497 (27.7%) in 2013. Overall survival was significantly longer for carcinoid compared with functional and nonfunctional tumors (log-rank p < 0.0001), with 5-year survival rates of 63.1%, 58.3%, and 52.6%, respectively. For patients having resection, overall survival further improved for carcinoid tumors relative to functional (log-rank p = 0.0011) and nonfunctional (log-rank p < 0.0001) tumors, but the survival difference between functional and nonfunctional tumors disappeared (log rank p = 0.4579); 5-year survival rates were 89.2%, 76.6%, and 78.7%, respectively. On multivariate Cox regression of the resected cohort, mortality was significantly higher for patients with functional (hazard ratio [HR] 1.81) and nonfunctional (HR 1.40) PNETs compared with carcinoid tumors. CONCLUSIONS: Primary pancreatic carcinoid tumors are increasingly being diagnosed. Differentiating PNET subtypes plays an important role in prognostication. Resection remains a critical component of care. PMID- 27965145 TI - Assessment of individual and household malaria risk factors among women in a South African village. AB - There is need to understand how various malaria risk factors interact at the individual, household and community levels, as well as wider contexts, in order to guide the design and implementation of effective and more comprehensive control strategies. Using a cross-sectional approach, this study investigated various malaria risk factors among residents of Mgedula Village, a malaria endemic community located in Jozini Local Municipality, UMkhanyakude District, South Africa from May to August 2014. Data from 121 randomly sampled women were collected using close-ended questionnaires. The women were aged between 18 and 40 years; and had been residents in the study area for five years or more. A multivariable logistic regression model was used to measure the association between a history of malaria infection in the previous 12 months and various potential risk factors. The results showed that practicing animal husbandry (OR 20), residing in household structures that had not been sprayed (OR 16.7) and cross-border movement (OR 14.3) were greatly associated with malaria infection. Other factors that were significantly associated with this infection included illiteracy (OR 9.1), having a largely populated household (OR 6.1) and low income (OR 1.65). Individuals with a history of malaria infection were less likely to lack basic malaria-related knowledge (OR 0.58), to have negative attitude towards malaria (OR 0.29) and also to have poor malaria practices (OR 0.3). There was no association between a malaria episode and residing at a long distance from the health facility. Indoor residual spraying indicated a notable reduction of malaria risk at the community level. However, other socio-economic, geographical and socio-demographic factors interacted at different levels to increase this risk among different individuals and households. To achieve malaria elimination by the year 2018, these aspects should be considered when developing and implementing elimination strategies at the individual, household and community levels, among high-risk populations. PMID- 27965153 TI - Covalent inhibition of carboxylesterase-2 by sofosbuvir and its effect on the hydrolytic activation of tenofovir disoproxil. PMID- 27965147 TI - Murine survival of infection with Francisella novicida and protection against secondary challenge is critically dependent on B lymphocytes. AB - Respiratory infection of mice with Francisella novicida has recently been used as a model for the highly virulent human pathogen Francisella tularensis. Similar to F. tularensis, even small doses of F. novicida administered by respiratory routes are lethal for inbred laboratory mice. This feature obviously limits study of infection-induced immunity. Parenteral sublethal infections of mice with F. novicida are feasible, but the resulting immune responses are incompletely characterized. Here we use parenteral intradermal (i.d.) and intraperitoneal (i.p.) F. novicida infections of C57BL/6J mice to determine the role of B cells in controlling primary and secondary F. novicida infections. Despite developing comparable levels of F. novicida-primed T cells, B cell knockout mice were much more susceptible to both primary i.d. infection and secondary i.p. challenge than wild type (normal) C57BL/6J mice. Transfer of F. novicida-immune sera to either wild type C57BL/6J mice or to B cell knockout mice did not appreciably impact survival of subsequent lethal F. novicida challenge. However, F. novicida-immune mice that were depleted of T cells after priming but just before challenge survived and cleared secondary i.p. F. novicida challenge. Collectively these results indicate that B cells, if not serum antibodies, play a major role in controlling F. novicida infections in mice. PMID- 27965150 TI - Genome analysis of canine astroviruses reveals genetic heterogeneity and suggests possible inter-species transmission. AB - Canine astrovirus RNA was detected in the stools of 17/63 (26.9%) samples, using either a broadly reactive consensus RT-PCR for astroviruses or random RT-PCR coupled with massive deep sequencing. The complete or nearly complete genome sequence of five canine astroviruses was reconstructed that allowed mapping the genome organization and to investigate the genetic diversity of these viruses. The genome was about 6.6kb in length and contained three open reading frames (ORFs) flanked by a 5' UTR, and a 3' UTR plus a poly-A tail. ORF1a and ORF1b overlapped by 43 nucleotides while the ORF2 overlapped by 8 nucleotides with the 3' end of ORF1b. Upon genome comparison, four strains (HUN/2012/2, HUN/2012/6, HUN/2012/115, and HUN/2012/135) were more related genetically to each other and to UK canine astroviruses (88-96% nt identity), whilst strain HUN/2012/126 was more divergent (75-76% nt identity). In the ORF1b and ORF2, strains HUN/2012/2, HUN/2012/6, and HUN/2012/135 were related genetically to other canine astroviruses identified formerly in Europe and China, whereas strain HUN/2012/126 was related genetically to a divergent canine astrovirus strain, ITA/2010/Zoid. For one canine astrovirus, HUN/2012/8, only a 3.2kb portion of the genome, at the 3' end, could be determined. Interestingly, this strain possessed unique genetic signatures (including a longer ORF1b/ORF2 overlap and a longer 3'UTR) and it was divergent in both ORF1b and ORF2 from all other canine astroviruses, with the highest nucleotide sequence identity (68% and 63%, respectively) to a mink astrovirus, thus suggesting a possible event of interspecies transmission. The genetic heterogeneity of canine astroviruses may pose a challenge for the diagnostics and for future prophylaxis strategies. PMID- 27965148 TI - An in vitro skin sensitization assay termed EpiSensA for broad sets of chemicals including lipophilic chemicals and pre/pro-haptens. AB - To evaluate chemicals (e.g. lipophilic chemicals, pre/pro-haptens) that are difficult to correctly evaluate using in vitro skin sensitization tests (e.g. DPRA, KeratinoSens or h-CLAT), we developed a novel in vitro test termed "Epidermal Sensitization Assay: EpiSensA" that uses reconstructed human epidermis. This assay is based on the induction of multiple marker genes (ATF3, IL-8, DNAJB4 and GCLM) related to two keratinocyte responses (inflammatory or cytoprotective) in the induction of skin sensitization. Here, we first confirmed the mechanistic relevance of these marker genes by focusing on key molecules that regulate keratinocyte responses in vivo (P2X7 for inflammatory and Nrf2 for cytoprotective responses). The up-regulation of ATF3 and IL-8, or DNAJB4 and GCLM induced by the representative sensitizer 2,4-dinitrochlorobenzene in human keratinocytes was significantly suppressed by a P2X7 specific antagonist KN-62, or by Nrf2 siRNA, respectively, which supported mechanistic relevance of marker genes. Moreover, the EpiSensA had sensitivity, specificity and accuracy of 93%, 100% and 93% for 29 lipophilic chemicals (logKow>=3.5), and of 96%, 75% and 88% for 43 hydrophilic chemicals including 11 pre/pro-haptens, compared with the LLNA. These results suggested that the EpiSensA could be a mechanism-based test applicable to broad sets of chemicals including lipophilic chemicals and pre/pro haptens. PMID- 27965152 TI - Beneficial and detrimental spore-formers: a world of diversity. PMID- 27965151 TI - Riptortus pedestris and Burkholderia symbiont: an ideal model system for insect microbe symbiotic associations. AB - A number of insects establish symbiotic associations with beneficial microorganisms in various manners. The bean bug Riptortus pedestris and allied stink bugs possess an environmentally acquired Burkholderia symbiont in their midgut crypts. Unlike other insect endosymbionts, the Burkholderia symbiont is easily culturable and genetically manipulatable outside the host. In conjunction with the experimental advantages of the host insect, the Riptortus-Burkholderia symbiosis is an ideal model system for elucidating the molecular bases underpinning insect-microbe symbioses, which opens a new window in the research field of insect symbiosis. This review summarizes current knowledge of this system and discusses future perspectives. PMID- 27965138 TI - The STR/ort mouse model of spontaneous osteoarthritis - an update. AB - Osteoarthritis is a degenerative joint disease and a world-wide healthcare burden. Characterized by cartilage degradation, subchondral bone thickening and osteophyte formation, osteoarthritis inflicts much pain and suffering, for which there are currently no disease-modifying treatments available. Mouse models of osteoarthritis are proving critical in advancing our understanding of the underpinning molecular mechanisms. The STR/ort mouse is a well-recognized model which develops a natural form of osteoarthritis very similar to the human disease. In this Review we discuss the use of the STR/ort mouse in understanding this multifactorial disease with an emphasis on recent advances in its genetics and its bone, endochondral and immune phenotypes. PMID- 27965146 TI - Movement-related beta oscillations show high intra-individual reliability. AB - Oscillatory activity in the beta frequency range (15-30Hz) recorded from human sensorimotor cortex is of increasing interest as a putative biomarker of motor system function and dysfunction. Despite its increasing use in basic and clinical research, surprisingly little is known about the test-retest reliability of spectral power and peak frequency measures of beta oscillatory signals from sensorimotor cortex. Establishing that these beta measures are stable over time in healthy populations is a necessary precursor to their use in the clinic. Here, we used scalp electroencephalography (EEG) to evaluate intra-individual reliability of beta-band oscillations over six sessions, focusing on changes in beta activity during movement (Movement-Related Beta Desynchronization, MRBD) and after movement termination (Post-Movement Beta Rebound, PMBR). Subjects performed visually-cued unimanual wrist flexion and extension. We assessed Intraclass Correlation Coefficients (ICC) and between-session correlations for spectral power and peak frequency measures of movement-related and resting beta activity. Movement-related and resting beta power from both sensorimotor cortices was highly reliable across sessions. Resting beta power yielded highest reliability (average ICC=0.903), followed by MRBD (average ICC=0.886) and PMBR (average ICC=0.663). Notably, peak frequency measures yielded lower ICC values compared to the assessment of spectral power, particularly for movement-related beta activity (ICC=0.386-0.402). Our data highlight that power measures of movement-related beta oscillations are highly reliable, while corresponding peak frequency measures show greater intra-individual variability across sessions. Importantly, our finding that beta power estimates show high intra-individual reliability over time serves to validate the notion that these measures reflect meaningful individual differences that can be utilised in basic research and clinical studies. PMID- 27965154 TI - Dysfunction of hepatic regulatory T cells in experimental sclerosing cholangitis is related to IL-12 signaling. AB - BACKGROUND & AIMS: Reduced numbers of regulatory T cells (Treg) have been reported in patients with primary sclerosing cholangitis (PSC); therefore, Treg expansion might serve as a therapeutic approach. Here, we explored whether treatment with IL-2/IL-2 monoclonal antibody complex (IL-2/IL-2Ab complex) could provide in vivo Treg expansion and treatment of experimental sclerosing cholangitis. METHODS: Treg were expanded by repeated injection of IL-2/IL-2Ab complex in mouse models of cholangitis (Mdr2-/-, DDC) or colitis (dextran sulfate sodium [DSS]) as control. In vitro suppressive capacity and gene expression were analyzed in isolated hepatic and splenic Treg. RESULTS: In vivo expansion resulted in a 5-fold increase in hepatic Treg, which localized within the inflamed portal tracts. However, although Treg expansion was associated with reduced pro-inflammatory IL-17 and increased anti-inflammatory IL-10 production by hepatic lymphocytes, the severity of cholangitis was not reduced. In contrast, DSS-induced colitis could be improved by Treg expansion, suggesting a selectively reduced functionality of intrahepatic Treg. Indeed, hepatic Treg manifested reduced Foxp3 expression and reduced suppressive capacity compared to splenic Treg. Hepatic Treg dysfunction could be linked to increased IL-12 signaling due to an upregulation of the IL-12 receptor. Accordingly, IL-12 receptor beta 2 knockout mice (IL-12rb2-/-) were able to maintain hepatic Treg functionality. CONCLUSIONS: Hepatic Treg expanded in vivo failed to improve the course of cholangitis, which was related to the effects of hepatic IL-12 on Treg. Therefore, neutralization of IL-12 should be considered as part of treatment strategies targeting Treg in sclerosing cholangitis. LAY SUMMARY: Primary sclerosing cholangitis (PSC) is associated with a paucity of regulatory T cells (Treg) that have a particular ability to control immune responses; therefore, in vivo expansion of Treg might serve as a treatment of cholangitis. However, in a mouse model of PSC, we show that Treg enrichment in the liver was not sufficient to provide effective control of cholangitis, as the suppressive functionality of hepatic Treg was significantly limited by IL-12 signals. Thus, neutralization of IL-12 should be considered as part of treatment strategies to improve the efficacy of Treg-based treatments for liver diseases. Data accession number: GSE 87898. PMID- 27965149 TI - Involvement of Brd4 in different steps of the papillomavirus life cycle. AB - Bromodomain-containing protein 4 (Brd4) is a cellular chromatin-binding factor and transcriptional regulator that recruits sequence-specific transcription factors and chromatin modulators to control target gene transcription. Papillomaviruses (PVs) have evolved to hijack Brd4's activity in order to create a facilitating environment for the viral life cycle. Brd4, in association with the major viral regulatory protein E2, is involved in multiple steps of the PV life cycle including replication initiation, viral gene transcription, and viral genome segregation and maintenance. Phosphorylation of Brd4, regulated by casein kinase II (CK2) and protein phosphatase 2A (PP2A), is critical for viral gene transcription as well as E1- and E2-dependent origin replication. Thus, pharmacological agents regulating Brd4 phosphorylation and inhibitors blocking phospho-Brd4 functions are promising candidates for therapeutic intervention in treating human papillomavirus (HPV) infections as well as associated disease. PMID- 27965155 TI - Stem cell-derived hepatocytes: A promising novel tool to study hepatitis B virus infection. PMID- 27965157 TI - Patients with hepatocellular carcinoma: Your address matters! PMID- 27965159 TI - Advancing hepatitis B virus entry inhibitors. PMID- 27965158 TI - Sofosbuvir and ribavirin for genotype 2 HCV infected patients with cirrhosis: A real life experience. AB - BACKGROUND & AIMS: Sofosbuvir (SOF) and weight-based ribarivin (RBV) represented until recently the standard of care in hepatitis C virus (HCV) genotype (GT)2 patients. In registration studies 12-16weeks duration were associated with a 90% sustained virological response at 12weeks (SVR12). Real life cohorts showed lower SVR12 rates. METHODS: SVR12 rates attained in an Italian real life cohort and possible benefits of a duration extended up to 20weeks was investigated in HCV GT2 patients with cirrhosis. The role of 2k/1b chimeras as potential predictor of treatment failure was also analysed. RESULTS: Overall, 291 HCV GT2 infected patients with bridging fibrosis or cirrhosis were evaluated. Median age was 68years (18-87); 163 were treatment naive. Of 168 cirrhotic patients, 149 had Child-Pugh score A and 19 B, 50 platelets count <100,000/mm3 and 62 albumin <3.5g/dl. SVR12 were 95.53% overall, with 99.15% in non-cirrhotic patients and 93.06% in cirrhotic patients. In patients who completed treatment, SVR rates for cirrhotic patients resulted in 94.51%, and 94.94% after 16 or 20weeks respectively. Predictors of SVR were low platelet count and esophageal varices (OR 7.2; 95% CI 1.67-31.25; p=0.0022 and OR 0.1; 95% CI 0.01-0.72; p=0.0079, respectively). Anemia was mild in 12.4%, moderate in 3.4%, and severe in 2.4% of cases. Anemia was slightly more frequent among longer duration but not associated with treatment discontinuations. No 2k/1b strains or genotypes different from those at baseline were identified at relapse. CONCLUSIONS: In GT2 cirrhotic patients, SOF/RBV for 16 or 20weeks is associated with real life SVR12 rates of 95%. LAY SUMMARY: A duration of treatment of 16-20weeks was recommended for treatment of HCV GT2 patients using the combination of sofosbuvir and ribavirin. Real life experiences, where patients received 12weeks of treatment regardless of the severity of liver disease, suggested that response rates are lower than expected, in particular in patients with liver cirrhosis. A misleading genotyping of a 2k/1b strain as GT2 was also hypothesized as a further explanation for less effectiveness. We demonstrated that using the recommended extended duration in patients with more severe disease 95% of patients with severe liver disease including cirrhosis can be cured and that 2k/1b strain plays only a secondary role in specific countries like Germany. Although this combination has been recently replaced by sofosbuvir and velpatasvir fixed dose combination as the standard of care for treating HCV GT2 patients, our findings may inform physicians from countries where the new regimen is not yet available. PMID- 27965163 TI - Montanide IMS 1312 VG adjuvant enhances the efficacy of immersion vaccine of inactivated viral hemorrhagic septicemia virus (VHSV) in olive flounder, Paralichthys olivaceus. AB - Vaccination by immersion is suitable for mass vaccination of small size fish. However, no viral vaccine has been developed for immersion applications, because of low efficacy. In this study, we evaluated the efficacy and safety of immersion vaccine against viral hemorrhagic septicemia (VHS) containing Montanide IMS 1312 VG adjuvant in olive flounder (Paralichthys olivaceus). Healthy fish were vaccinated by an immersion method with a heat-inactivated FP-VHS2010-1 strain of VHS virus (VHSV) in combination with Montanide IMS 1312 VG for 5 min at 20 +/- 2 degrees C. The control group was vaccinated with sterile PBS. No toxicity of immersion vaccine with Montanide IMS 1312 VG adjuvant was observed by hematological and histopathological analysis. Immersion vaccine with adjuvant enhanced gene expression of immune-associated genes, i.e., genes encoding interleukin (IL)-1beta, IL-6, IL-8, and Toll-like receptor (TLR) 3. Relative percent survival (RPS) of fish was measured on weeks 4 and 8 post vaccination. In fish vaccinated with adjuvant, RPS was significantly higher than that of fish vaccinated without adjuvant. The results of the present study provide evidence that the VHSV immersion vaccine with Montanide IMS 1312 VG induces protective immunity in olive flounder against VHS. PMID- 27965161 TI - Molecular similarity considerations in the licensing of orphan drugs. AB - The large costs associated with modern drug discovery mean that governments and regulatory bodies need to provide economic incentives to promote the development of orphan drugs (i.e., medicinal products that are designed to treat rare disease that affect only small numbers of patients). Under European Union (EU) legislation, a medicine can only be authorised for treating a specific rare disease if it is not similar to other orphan drugs already authorised for that particular disease. Here, we discuss the use of 2D fingerprints to calculate the Tanimoto similarity between potential and existing orphan drugs for the same disease, and present logistic regression models correlating these computed similarities with the judgements of human experts. PMID- 27965162 TI - Transcriptome profiling of developing spleen tissue and discovery of immune related genes in grass carp (Ctenopharyngodon idella). AB - Grass carp Ctenopharyngodon idella is an important freshwater aquaculture species. However, studies regarding transcriptomic profiling of developing spleen tissue in the grass carp are lacking. Here, the transcriptome sequencing from the spleen tissue of one-year-old (cis1) and three-year-old (cis3) grass carp was performed using Illumina paired-end sequencing technology. The de novo assemblies yielded 48,970 unigenes with average lengths of 1264.51 bp from the two libraries. The assembled unigenes were evaluated and functionally annotated by comparing with sequences in major public databases including Nr, COG, Swiss-Prot, KEGG, Pfam and GO. Comparative analysis of expression levels revealed that a total of 38,254 unigenes were expressed in both the cis1 and cis3 libraries, while 4356 unigenes were expressed only in the cis1 library, and 3312 unigenes were expressed only in the cis3 library. Meanwhile, 1782 unigenes (including 903 down-regulated and 879 up-regulated unigenes) were differentially expressed between the two developmental stages of the grass carp spleen. Based on GO and KEGG enrichment analysis, these differentially expressed genes widely participated in the regulation of immunity and response in the grass carp. Moreover, the main components of six immune-related pathways were identified, including complement and coagulation cascades, Toll-like receptor signaling, B cell receptor signaling, T-cell receptor signaling, antigen processing and presentation, and chemokine signaling. Finally, two identified transcripts including TLR 8 and complement component C8 were validated for reliability by RT PCR. Collectively, the results obtained in this study will provide a basis for the study of molecular mechanisms in grass carp spleen development. PMID- 27965156 TI - Fibrin(ogen) drives repair after acetaminophen-induced liver injury via leukocyte alphaMbeta2 integrin-dependent upregulation of Mmp12. AB - BACKGROUND & AIMS: Acetaminophen (APAP)-induced liver injury is coupled with activation of the blood coagulation cascade and fibrin(ogen) accumulation within APAP-injured livers of experimental mice. We sought to define the role of fibrin(ogen) deposition in APAP-induced liver injury and repair. METHODS: Wild type, fibrinogen-deficient mice, mutant mice with fibrin(ogen) incapable of binding leukocyte alphaMbeta2 integrin (Fibgamma390-396A mice) and matrix metalloproteinase 12 (Mmp12)-deficient mice were fasted, injected with 300mg/kg APAP i.p. and evaluated at a range of time-points. Plasma and liver tissue were analyzed. Rescue of Fibgamma390-396A mice was carried out with exogenous Mmp12. To examine the effect of the allosteric leukocyte integrin alphaMbeta2 activator leukadherin-1 (LA-1), APAP-treated mice were injected with LA-1. RESULTS: In wild type mice, APAP overdose increased intrahepatic levels of high molecular weight cross-linked fibrin(ogen). Anticoagulation reduced early APAP hepatotoxicity (6h), but increased hepatic injury at 24h, implying a protective role for coagulation at the onset of repair. Complete fibrin(ogen) deficiency delayed liver repair after APAP overdose, evidenced by a reduction of proliferating hepatocytes (24h) and unresolved hepatocellular necrosis (48 and 72h). Fibgamma390-396A mice had decreased hepatocyte proliferation and increased multiple indices of liver injury, suggesting a mechanism related to fibrin(ogen) leukocyte interaction. Induction of Mmp12, was dramatically reduced in APAP treated Fibgamma390-396A mice. Mice lacking Mmp12 displayed exacerbated APAP induced liver injury, resembling Fibgamma390-396A mice. In contrast, administration of LA-1 enhanced hepatic Mmp12 mRNA and reduced necrosis in APAP treated mice. Further, administration of recombinant Mmp12 protein to APAP treated Fibgamma390-396A mice restored hepatocyte proliferation. CONCLUSIONS: These studies highlight a novel pathway of liver repair after APAP overdose, mediated by fibrin(ogen)-alphaMbeta2 integrin engagement, and demonstrate a protective role of Mmp12 expression after APAP overdose. LAY SUMMARY: Acetaminophen overdose leads to activation of coagulation cascade and deposition of high molecular weight cross-linked fibrin(ogen) species in the liver. Fibrin(ogen) is required for stimulating liver repair after acetaminophen overdose. The mechanism whereby fibrin(ogen) drives liver repair after acetaminophen overdose requires engagement of leukocyte alphaMbeta2 integrin and subsequent induction of matrix metalloproteinase 12. PMID- 27965168 TI - A specific spectral signature of serum and plasma-derived extracellular vesicles for cancer screening. AB - In cancer, extracellular vesicles (EV) contribute to tumor progression by regulating local and systemic effects. Being released into body fluids, EV may be used in nanomedicine as a valuable source for diagnostic biomarkers. In this work, infrared and Raman spectroscopy were used for comprehensive comparative analysis of cancer versus non-cancer EV and patient screening. Two different EV fractions enriched in exosomes and microvesicles were isolated by differential centrifugation from serum and plasma of cancer and non-cancer patients and from serum and plasma of a healthy donor. The EV fractions were then subjected to drop coating deposition and drying on calcium fluoride substrates. Reduction of alpha helix-rich proteins and enhancement of beta-sheet-rich proteins as a cancer specific blood EV signature was determined, and subsequently this feature was applied for a pilot study aiming to detect prostate cancer in a test cohort of patients with high-grade prostate carcinoma and benign hypoplasia. PMID- 27965164 TI - Glucose enhances tilapia against Edwardsiella tarda infection through metabolome reprogramming. AB - We have recently reported that the survival of tilapia, Oreochromis niloticus, during Edwardsiella tarda infection is tightly associated with their metabolome, where the survived O. niloticus has distinct metabolomic profile to dying O. niloticus. Glucose is the key metabolite to distinguish the survival- and dying metabolome. More importantly, exogenous administration of glucose to the fish greatly enhances their survival for the infection, indicating the functional roles of glucose in metabolome repurposing, known as reprogramming metabolomics. However, the underlying information for the reprogramming is not yet available. Here, GC/MS based metabolomics is used to understand the mechanisms by which how exogenous glucose elevates O. niloticus, anti-infectious ability to E. tarda. Results showed that exogenous glucose promotes stearic acid and palmitic acid biosynthesis but attenuates TCA cycle to potentiate O. niloticus against bacterial infection, which is confirmed by the fact that exogenous stearic acid increases immune protection in O. niloticus against E. tarda infection in a manner of Mx protein. These results indicate that exogenous glucose reprograms O. niloticus anti-infective metabolome that characterizes elevation of stearic acid and palmitic acid and attenuation of the TCA cycle. Therefore, our results proposed a novel mechanism that glucose promotes unsaturated fatty acid biosynthesis to cope with infection, thereby highlighting a potential way of enhancing fish immunity in aquaculture. PMID- 27965165 TI - Suspected cases of cholangiocarcinoma seen in reference hospitals in Lao People's Democratic Republic. AB - Cholangiocarcinoma (CCA) poses a significant public health problem in Southeast Asia, with chronic Opisthorchis viverrini infection being the main risk factor. Epidemiological data on CCA is not available for Lao People Democratic Republic (Lao PDR), though there is a high prevalence of O. viverrini infection in the country. A hospital record-based retrospective study was carried out in six referral hospitals (four in the capital city, one in Savannakhet, one in Pakse) to assess the number of suspected CCA cases admitted between January 2006 and December 2010. In total, we identified 274 patients with liver lesions suggesting CCA, as diagnosed by ultrasound and CT scan. Male gender and age 50years and above were main characteristics of those identified. The majority were admitted to hospitals in the central (58.0%) and southern (29.6%) parts of Lao PDR. Abdominal pain (48.5%) and jaundice (14.2%) were the main symptoms leading to hospitalisation. Some 267 (97.4%) patients had dilated bile ducts; 40 (74.1%) had gallstone or intrahepatic stone, and 33 (12.0%) had a parasitologically confirmed O. viverrini infection. This study provides the first estimated numbers of suspected CCA cases admitted to selected hospitals in Lao PDR. Definitive diagnosis of CCA was not possible. Therefore, case diagnosis and registration of suspected CCA cases are warranted to gather evidence for a national burden estimate of CCA, to develop large-scale studies and adequate preventive and curative health services. A cancer registry would be a most useful tool. PMID- 27965170 TI - Atomic scale modeling of iron-doped biphasic calcium phosphate bioceramics. AB - : Biphasic calcium phosphates (BCPs) are bioceramics composed of hydroxyapatite (HAp, Ca10(PO4)6(OH)2) and beta-Tricalcium Phosphate (beta-TCP, Ca3(PO4)2). Because their chemical and mineral composition closely resembles that of the mineral component of bone, they are potentially interesting candidates for bone repair surgery, and doping can advantageously be used to improve their biological behavior. However, it is important to describe the doping mechanism of BCP thoroughly in order to be able to master its synthesis and then to fully appraise the benefit of the doping process. In the present paper we describe the ferric doping mechanism: the crystallographic description of our samples, sintered at between 500 degrees C and 1100 degrees C, was provided by Rietveld analyses on X ray powder diffraction, and the results were confirmed using X-ray absorption spectroscopy and 57Fe Mossbauer spectrometry. The mechanism is temperature dependent, like the previously reported zinc doping mechanism. Doping was performed on the HAp phase, at high temperature only, by an insertion mechanism. The Fe3+ interstitial site is located in the HAp hexagonal channel, shifted from its centre to form a triangular three-fold coordination. At lower temperatures, the Fe3+ are located at the centre of the channel, forming linear two-fold coordinated O-Fe-O entities. The knowledge of the doping mechanism is a prerequisite for a correct synthesis of the targeted bioceramic with the adapted (Ca+Fe)/P ratio, and so to be able to correctly predict its potential iron release or magnetic properties. STATEMENT OF SIGNIFICANCE: Biphasic calcium phosphates (BCPs) are bioceramics composed of hydroxyapatite (HAp, Ca10(PO4)6(OH)2) and beta-Tricalium Phosphate (beta-TCP, Ca3(PO4)2). Because their chemical and mineral composition closely resembles that of the mineral component of bone, they are potentially interesting candidates for bone repair surgery. Doping can advantageously be used to improve their biological behaviors and/or magnetic properties; however, it is important to describe the doping mechanism of BCP thoroughly in order to fully appraise the benefit of the doping process. The present paper scrutinizes in detail the incorporation of ferric cation in order to correctly interpret the behavior of the iron-doped bioceramic in biological fluid. The temperature dependent mechanism has been fully described for the first time. And it clearly appears that temperature can be used to design the doping according to desired medical application: blood compatibility, remineralization, bactericidal or magnetic response. PMID- 27965171 TI - Human placenta hydrogel reduces scarring in a rat model of cardiac ischemia and enhances cardiomyocyte and stem cell cultures. AB - INTRODUCTION: Xenogeneic extracellular matrix (ECM) hydrogels have shown promise in remediating cardiac ischemia damage in animal models, yet analogous human ECM hydrogels have not been well development. An original human placenta-derived hydrogel (hpECM) preparation was thus generated for assessment in cardiomyocyte cell culture and therapeutic cardiac injection applications. METHODS AND RESULTS: Hybrid orbitrap-quadrupole mass spectrometry and ELISAs showed hpECM to be rich in collagens, basement membrane proteins, and regenerative growth factors (e.g. VEGF-B, HGF). Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes synchronized and electrically coupled on hpECM faster than on conventional cell culture environments, as validated by intracellular calcium measurements. In vivo, injections using biotin-labeled hpECM confirmed its spatially discrete localization to the myocardium proximal to the injection site. hpECM was injected into rat myocardium following an acute myocardium infarction induced by left anterior descending artery ligation. Compared to sham treated animals, which exhibited aberrant electrical activity and larger myocardial scars, hpECM injected rat hearts showed a significant reduction in scar volume along with normal electrical activity of the surviving tissue, as determined by optical mapping. CONCLUSION: Placental matrix and growth factors can be extracted as a hydrogel that effectively supports cardiomyocytes in vitro, and in vivo reduces scar formation while maintaining electrophysiological activity when injected into ischemic myocardium. STATEMENT OF SIGNIFICANCE: This is the first report of an original extracellular matrix hydrogel preparation isolated from human placentas (hpECM). hpECM is rich in collagens, laminin, fibronectin, glycoproteins, and growth factors, including known pro-regenerative, pro-angiogenic, anti-scarring, anti-inflammatory, and stem cell-recruiting factors. hpECM supports the culture of cardiomyocytes, stem cells and blood vessels assembly from endothelial cells. In a rat model of myocardial infarction, hpECM injections were safely deliverable to the ischemic myocardium. hpECM injections repaired the myocardium, resulting in a significant reduction in infarct size, more viable myocardium, and a normal electrophysiological contraction profile. hpECM thus has potential in therapeutic cardiovascular applications, in cellular therapies (as a delivery vehicle), and is a promising biomaterial for advancing basic cell-based research and regenerative medicine applications. PMID- 27965169 TI - Investigating appearance and regulation of the MXR phenotype in early embryo stages of the Mediterranean mussel (Mytilus galloprovincialis). AB - Multixenobiotic resistance (MXR) efflux transporters constitute a broad-spectrum physiological defense system allowing marine bivalves to cope with environmental challenges. There is, however, scarce information on the type and role that different MXR transporters may have in embryos, which represent the most sensitive stages of bivalves to environmental stress. In this study regulation of MXR-related transporters was investigated in early developmental stages of the Mediterranean mussel (Mytilus galloprovincialis). In vitro fertilization experiments using gametes from naturally-spawning broodstocks were performed to follow embryo development from fertilized eggs (30min post fertilization, pf) to fully developed D-shape veligers (48hpf). Quantitative PCR analyses indicated that ABCB and ABCC transcripts encoding the MXR-related transporters P glycoproteins (P-gp) and Multidrug resistance proteins (Mrp), respectively, were expressed soon after 30minpf, with ABCC being more expressed than ABCB. Copy numbers of both transcripts were increased in trochophorae and D-veligers. MXR efflux activity assessed using the fluorescent substrate rhodamine 123 and selective P-gp or Mrp inhibitors showed that the P-gp mediated efflux was detected only in D-veligers, while a significant Mrp mediated efflux was detected soon after 30minpf and remained almost unchanged in trochophorae and D-veligers. MXR modulation by propranolol and carbamazepine showed that the pharmaceuticals may act as transcriptional regulators and substrates. Results reported lead to hypothesize that while P-gp aids in xenobiotic efflux performing a prominent protective role, Mrp could be a dual-functioning transporter performing both protective and physiological functions in mussel development. PMID- 27965167 TI - Nanoparticle passage through porcine jejunal mucus: Microfluidics and rheology. AB - A micro-slide chamber was used to screen and rank sixteen functionalized fluorescent silica nanoparticles (SiNP) of different sizes (10, 50, 100 and 200 nm) and surface coatings (aminated, carboxylated, methyl-PEG1000ylated, and methyl-PEG2000ylated) according to their capacity to permeate porcine jejunal mucus. Variables investigated were influence of particle size, surface charge and methyl-PEGylation. The anionic SiNP showed higher transport through mucus whereas the cationic SiNP exhibited higher binding with lower transport. A size dependence in transport was identified - 10 and 50 nm anionic (uncoated or methyl PEGylated) SiNP showed higher transport compared to the larger 100 and 200 nm SiNP. The cationic SiNP of all sizes interacted with the mucus, making it more viscous and less capable of swelling. In contrast, the anionic SiNP (uncoated or methyl-PEGylated) caused minimal changes in the viscoelasticity of mucus. The data provide insights into mucus-NP interactions and suggest a rationale for designing oral nanomedicines with improved mucopermeability. PMID- 27965173 TI - clickECM: Development of a cell-derived extracellular matrix with azide functionalities. AB - : In vitro cultured cells produce a complex extracellular matrix (ECM) that remains intact after decellularization. The biological complexity derived from the variety of distinct ECM molecules makes these matrices ideal candidates for biomaterials. Biomaterials with the ability to guide cell function are a topic of high interest in biomaterial development. However, these matrices lack specific addressable functional groups, which are often required for their use as a biomaterial. Due to the biological complexity of the cell-derived ECM, it is a challenge to incorporate such functional groups without affecting the integrity of the biomolecules within the ECM. The azide-alkyne cycloaddition (click reaction, Huisgen-reaction) is an efficient and specific ligation reaction that is known to be biocompatible when strained alkynes are used to avoid the use of copper (I) as a catalyst. In our work, the ubiquitous modification of a fibroblast cell-derived ECM with azides was achieved through metabolic oligosaccharide engineering by adding the azide-modified monosaccharide Ac4GalNAz (1,3,4,6-tetra-O-acetyl-N-azidoacetylgalactosamine) to the cell culture medium. The resulting azide-modified network remained intact after removing the cells by lysis and the molecular structure of the ECM proteins was unimpaired after a gentle homogenization process. The biological composition was characterized in order to show that the functionalization does not impair the complexity and integrity of the ECM. The azides within this "clickECM" could be accessed by small molecules (such as an alkyne-modified fluorophore) or by surface-bound cyclooctynes to achieve a covalent coating with clickECM. STATEMENT OF SIGNIFICANCE: The clickECM was produced by the incorporation of azide functionalized sugar analogues into the extracellular glycans of fibroblast cell cultures by metabolic oligosaccharide engineering. By introducing these azide groups into the glycan structures, we enabled this cell-derived ECM for bioorthogonal click reactions. Click chemistry provides extremely specific reactions with high efficiency, high selectivity, and high reaction yields. We could show that the azide functionalities within the clickECM are chemically accessible. Based on our here described clickECM technique it will be possible to create and investigate new clickECM materials with tunable bioactive properties and additional functionalities, which offers a promising approach for basic and applied research in the field of biomaterial science, biomedical applications, and tissue engineering. PMID- 27965172 TI - Molecular weight specific impact of soluble and immobilized hyaluronan on CD44 expressing melanoma cells in 3D collagen matrices. AB - : Hyaluronan (HA) and its principal receptor CD44 are known to be involved in regulating tumor cell dissemination and metastasis. The direct correlation of CD44-HA interaction on proliferation and invasion of tumor cells in dependence on the molecular weight and the presentation form of HA is not fully understood because of lack of appropriate matrix models. To address this issue, we reconstituted 3D collagen (Coll I) matrices and functionalized them with HA of molecular weight of 30-50kDa (low molecular weight; LMW-HA) and 500-750kDa (high molecular weight; HMW-HA). A post-modification strategy was applied to covalently immobilize HA to reconstituted fibrillar Coll I matrices, resulting in a non altered Coll I network microstructure and stable immobilization over days. Functionalized Coll I matrices were characterized regarding topological and mechanical characteristics as well as HA amount using confocal laser scanning microscopy, colloidal probe force spectroscopy and quantitative Alcian blue assay, respectively. To elucidate HA dependent tumor cell behavior, BRO melanoma cell lines with and without CD44 receptor expression were used for in vitro cell experiments. We demonstrated that only soluble LMW-HA promoted cell proliferation in a CD44 dependent manner, while HMW-HA and immobilized LMW-HA did not. Furthermore, an enhanced cell invasion was found only for immobilized LMW-HA. Both findings correlated with a very strong and specific adhesive interaction of LMW-HA and CD44+ cells quantified in single cell adhesion measurements using soft colloidal force spectroscopy. Overall, our results introduce an in vitro biomaterials model allowing to test presentation mode and molecular weight specificity of HA in a 3D fibrillar matrix thus mimicking important in vivo features of tumor microenvironments. STATEMENT OF SIGNIFICANCE: Molecular weight and presentation form (bound vs. soluble) of hyaluronan (HA) are intensively discussed as key regulators in tumor progression and inflammation. We introduce 3D fibrillar collagen matrices with defined microstructure and stiffness allowing the presentation of specific molecular weight forms of HA in soluble and bound manner. Mimicking in that way important in vivo features of tumor microenvironments, we found that only low molecular weight HA (LMW-HA) in soluble form promoted proliferation of a melanoma cell line (BRO), while it enhanced cell invasion in bound form. The molecular weight specificity of LMW-HA was verified to be CD44 receptor dependent and was correlated to adhesive ligand-receptor interactions in quantitative colloidal force spectroscopy at single cell level. PMID- 27965166 TI - Construction and evaluation of pH-sensitive immunoliposomes for enhanced delivery of anticancer drug to ErbB2 over-expressing breast cancer cells. AB - 1,5-Dihexadecyl N,N-diglutamyl-lysyl-L-glutamate (GGLG) liposomes were previously developed to enhance drug delivery efficiency in tumor cells owing to its pH responsive properties. Herein, we report the modification of GGLG liposomes by conjugating a Fab' fragment of an ErbB2 antibody to the terminus of PEG (polyethylene glycol)-lipid (Fab'-GGLG liposomes). The conjugation of Fab' fragments did not affect the antibody activity, drug (doxorubicin, DOX) encapsulation efficiency, stability during storage or pH-sensitivity. However, the binding affinity of Fab'-GGLG liposomes was enhanced to ErbB2-overexpressing HCC1954 cells specifically, and the cell association increased 10-fold in comparison to GGLG liposomes. Consequently, intracellular DOX delivery was enhanced, with an increased cytotoxicity in HCC1954 cells (i.e., IC50 of 1.17 and 3.08 MUg/mL for Fab'-GGLG-DOX and GGLG-DOX liposomes, respectively). Further, a significantly enhanced tumor growth inhibition was obtained in an ErbB2 overexpressing breast cancer-bearing mouse model. Therefore, a potent anticancer drug delivery system was constructed by the immunological modification of pH sensitive liposomes. PMID- 27965160 TI - Hormonal and systemic regulation of sclerostin. AB - The Wnt/beta-catenin signaling pathway plays an essential role in osteoblast biology. Sclerostin is a soluble antagonist of Wnt/beta-catenin signaling secreted primarily by osteocytes. Current evidence indicates that sclerostin likely functions as a local/paracrine regulator of bone metabolism rather than as an endocrine hormone. Nonetheless, circulating sclerostin levels in humans often reflect changes in the bone microenvironment, although there may be exceptions to this observation. Using existing assays, circulating sclerostin levels have been shown to be altered in response to both hormonal stimuli and across a variety of normal physiological and pathophysiological conditions. In both rodents and humans, parathyroid hormone provided either intermittently or continuously suppresses sclerostin levels. Likewise, most evidence from both human and animal studies supports a suppressive effect of estrogen on sclerostin levels. Efforts to examine non-hormonal/systemic regulation of sclerostin have in general shown less consistent findings or have provided associations rather than direct interventional information, with the exception of mechanosensory studies which have consistently demonstrated increased sclerostin levels with skeletal unloading, and conversely decreases in sclerostin with enhanced skeletal loading. Herein, we will review the existent literature on both hormonal and non hormonal/systemic factors which have been studied for their impact on sclerostin regulation. PMID- 27965175 TI - The other-race effect in children from a multiracial population: A cross-cultural comparison. AB - The role of experience with other-race faces in the development of the other-race effect was investigated through a cross-cultural comparison between 5- and 6-year olds and 13- and 14-year-olds raised in a monoracial (British White, n=83) population and a multiracial (Malaysian Chinese, n=68) population. British White children showed an other-race effect to three other-race faces (Chinese, Malay, and African Black) that was stable across age. Malaysian Chinese children showed a recognition deficit for less experienced faces (African Black) but showed a recognition advantage for faces of which they have direct or indirect experience. Interestingly, younger (Malaysian Chinese) children showed no other-race effect for female faces such that they can recognize all female faces regardless of race. These findings point to the importance of early race and gender experiences in reorganizing the face representation to accommodate changes in experience across development. PMID- 27965174 TI - Measurement and structural invariance of the US version of the Birth Satisfaction Scale-Revised (BSS-R) in a large sample. AB - BACKGROUND: The 10-item Birth Satisfaction Scale-Revised (BSS-R) is being increasingly used internationally. The use of the measure and the concept has gathered traction in the United States following the development of a US version of the tool. A limitation of previous studies of the measurement characteristics of the BSS-R is modest sample size. Unplanned pregnancy is recognised as being associated with a range of negative birth outcomes, but the relationship to birth satisfaction has received little attention, despite the importance of birth satisfaction to a range of postnatal outcomes. AIM: The current investigation sought to evaluate the measurement characteristics of the BSS-R in a large postpartum sample. METHODS: Multiple Groups Confirmatory Factor Analysis (MGCFA) was used to evaluate a series of measurement and structural models of the BSS-R to evaluate fundamental invariance characteristics using planned/unplanned pregnancy status to differentiate groups. FINDINGS: Complete data from N=2116 women revealed that the US version of the BSS-R offers an excellent fit to data and demonstrates full measurement and structural invariance. Little difference was observed between women on the basis of planned/unplanned pregnancy stratification on measures of birth satisfaction. DISCUSSION: The established relationship between unplanned pregnancy and negative perinatal outcomes was not found to extend to birth satisfaction in the current study. The BSS-R demonstrated exemplary measurement and structural invariance characteristics. CONCLUSION: The current study strongly supports the use of the US version of the BSS-R to compare birth satisfaction across different groups of women with theoretical and measurement confidence. PMID- 27965178 TI - Study of novel anticancer 4-thiazolidinone derivatives. AB - 4-Thiazolidinones are a known class of prospective drug-like molecules, especially in the design of new anticancer agents. Two of the most prominent subtypes of these compounds are 5-ene-2-amino(amino)-4-thiazolidinones and thiopyrano[2,3-d]thiazoles. The latter are considered to be cyclic mimetics of biologically active 5-ene-4-thiazolidinones with similar pharmacological profiles. Therefore, the aim of this study was to evaluate the impact of 4 thiazolidinone-based compounds on cytotoxicity, the apoptotic process, and metabolism in the human squamous carcinoma (SCC-15) cell line. The SCC-15 cells were cultured in phenol red-free DMEM/F12 medium supplemented with 10% FBS, hydrocortisone, and exposed to rising concentrations (1 nM-100 MUM) of the studied compounds for 6, 24 and 48 h. Afterwards, reactive oxygen species (ROS) formation, cell viability, caspase-3 activity, and cell metabolism were measured. The obtained results showed that all of the studied compounds in a wide range of concentrations (1 nM-100 MUM) increased DCF fluorescence which suggests a stimulation of ROS production. Nevertheless, these new compounds showed cytotoxic and proapoptotic properties only at high (10-100 MUM) concentrations. Our studies are the first to be carried out on these compounds and require further investigation to clarify the mechanism of action of their anticancer potential. PMID- 27965181 TI - Stimulation of the bilateral anterior nuclei of the thalamus in the treatment of refractory epilepsy: two cases of subcortical band heterotopia. AB - Subcortical band heterotopia is a neuronal migration disorder that may cause refractory epilepsy. In these patients, resective surgery has yielded inadequate results. Deep brain stimulation of the anterior nuclei of the thalamus has been used for the treatment of refractory epilepsy with good results. We describe the first two patients with subcortical band heterotopia who were submitted to deep brain stimulation of the anterior nuclei of the thalamus, with evaluation of seizure outcome after 12 and 18 months of follow-up. At these times, both showed a >50% decrease in seizure frequency and an increase in seizure freedom. Both patients had a depressive syndrome after surgery that responded fully to anti depressive medication in one patient and partly in the other. In both, deep brain stimulation of the anterior nuclei of the thalamus was associated with good seizure outcome. This procedure can therefore be considered in the treatment of patients with subcortical band heterotopia and refractory epilepsy. Depression may be a transient adverse event of the surgery or stimulation, however, its aetiology is probably multifactorial. PMID- 27965176 TI - Effect of Acetabular Component Positioning on Functional Outcomes in Primary Total Hip Arthroplasty. AB - BACKGROUND: Acetabular component positioning is crucial to a successful total hip arthroplasty (THA). This study evaluated the effect of absolute acetabular component position as well as acetabular position relative to bony anatomy on patient-reported functional outcomes after primary THA. METHODS: Primary, press fit, hemispherical metal-on-polyethylene THA performed between 2003 and 2011 were analyzed. Western Ontario and McMaster Osteoarthritis Index (WOMAC), Harris Hip Score (HHS), Short Form-12 scores, and radiographs between 2 and 3 years after the index procedure were assessed. RESULTS: Of the 1241 primary THA included, the mean abduction and anteversion angles were 44.4 +/- 6.94 and 21.7 +/- 11.9 degrees, respectively. The mean anterior and lateral overhang were 1.9 +/- 3.6 and 2.5 +/- 3.4 mm, respectively. There was no correlation between functional outcomes and acetabular inclination. A weak positive correlation between anteversion and HHS (P < .001) and WOMAC (P = .02) scores was found. For relative position, anterior overhang of the acetabular component beyond the bone resulted in inferior Short Form-12 physical function (P = .001), HHS (P = .004), and WOMAC (P < .001) scores compared to those with bony coverage. Mean HHS pain score was 41.20 +/- 5.69 in patients with lateral overhang and 41.97 +/- 5.04 in those who had bony coverage of the lateral edge of the acetabular component (P = .02). CONCLUSION: The tribology and biomechanics of acetabular component position have been extensively studied without examination of how it affects patient function. Although statistical significance was seen, clinical outcome scores were not sensitive enough to show a clinically significant effect of the absolute or relative position of the acetabular component. PMID- 27965182 TI - Drug treatment strategies for epilepsy revisited: starting early or late? One drug or several drugs? AB - There are two popular strategies for current drug treatment of epilepsy; starting early may be better and polytherapy conveys advantages over monotherapy. This review briefly examines if the historical record is much of a guide to determine the clinical value of these two strategies. Great clinical scientists of the 19th and early 20th century, such as Sir William Gowers, and William Aldren Turner, offered vivid single case studies and showed early results of seizure remission in groups of subjects. The historical record offered, however, no evidence of clear clinical benefits for early treatment and polytherapy. Combination treatment was thought to be useful in only some cases. In agreement, current evidence shows no clear clinical benefit of starting treatment early, except perhaps in severe epilepsy. Polytherapy is clinically useful in a subgroup of subjects, but despite being a standard treatment strategy for over one hundred years, it has been poorly studied. In fact, there is no compelling experimental or clinical evidence for a difference in seizure outcome between monotherapy and polytherapy. This surprising finding should prompt a re-appraisal regarding the need to test both strategies separately for the licensing of new antiepileptic drugs. PMID- 27965187 TI - The implementation of public health interventions in Africa: a neglected strategic theme. AB - Organizing effective public health interventions is required to improve population health and reduce social inequalities in health. However, measuring their effectiveness is not enough; we must also understand how these interventions are implemented and what role is played by the context and the social actors. Today, it seems that the importance of studying intervention implementation by public health actors (stakeholders, policy makers, donors, and researchers) has not yet been sufficiently considered. In this Tribune, we wish to draw the attention of the public health community, including that interested in interventions in Africa, to the need to analyze their implementation in depth. We must produce empirical and theoretical knowledge about implementation but also train students and young researchers more effectively in this scientific approach, which, although indispensable, has been ignored too long. PMID- 27965179 TI - Brown fat thermogenesis: Stability of developmental programming and transient effects of temperature and gut microbiota in adults. AB - Evidence from animal studies continues to document the effectiveness of brown fat based thermogenesis in stimulating energy expenditure to reduce obesity. Evidence shows that the number of brown adipocytes in white fat is determined by developmental mechanisms, not the environment. The large variability in the capacity for brown fat thermogenesis comes from genetic variability in developmental mechanisms extent in the animal. This genetic variability ultimately drives the capacity for induction of the brown adipocyte phenotype in response to environmental signals in adult animals. We highlight recent studies that suggest a role for gut microbiota in the regulation of brown fat thermogenesis that is based, in part, upon the observation that bile acids can effectively induce thermogenesis by interscapular brown fat at thermoneutrality. PMID- 27965185 TI - Risk factors for low birth weight in Lubumbashi, Democratic Republic of the Congo. AB - The aim of this study was to identify the risk factors associated with low birth weight (LBW) in the city of Lubumbashi (DR Congo). This case-control study of singleton births took place from July to December 2014 in 3 referral maternity units in Lubumbashi. The mothers' social and demographic characteristics and medical and obstetric history, especially during this pregnancy, as well as the newborns' sex were compared between the case group (< 2500 g) and the control group. The usual statistics and logistic regression were used to analyze the results. The significance level was set at P < 0.05. We observed that a low educational level (OR adjusted = 2.5 [1.5-4.0]), employment (OR adjusted = 2.0 [1.3-3.1]), lack of prenatal care (OR adjusted = 2.5 [1.5-4.2]), maternal anemia (OR adjusted = 7.6 [2.3-24.8]), malaria during the pregnancy (OR adjusted = 1.5 [1.0-2.3]), urogenital infections during pregnancy (OR adjusted = 1.6 [1.1-2.5]), gestational hypertension (OR adjusted = 2.7 [1.5-4.9]), and maternal malnutrition (OR adjusted = 8.3 [2.4-28.5]) were all significantly associated with LBW. This study shows that some maternal demographic, medical, and obstetric factors influence the birth of LBW infants. Because some of these factors can be addressed and treated, the reduction of neonatal morbidity and mortality associated with LBW requires improving the health care system in our city, including its accessibility. PMID- 27965183 TI - Dosing strategies for antiepileptic drugs: from a standard dose for all to individualised treatment by implementation of therapeutic drug monitoring. AB - This review focuses on the evolution of approaches to dosing of antiepileptic drugs (AEDs) in clinical practice through history. There has been a shift in the view of treatment of epilepsy, from "one dose fits all patients" in the early days to individualisation of treatment. Over the past 50 years, our knowledge of pharmacological variability of AEDs has markedly increased through implementation of therapeutic drug monitoring (TDM). The use of TDM has demonstrated extensive pharmacokinetic variability for AEDs and a need to individualise the treatment for an optimal outcome. Factors that contribute to pharmacokinetic variability include external factors (including food and comedication), physiological factors (gender, age, and pregnancy), pathological conditions (organ dysfunction), and genetic factors (polymorphisms in metabolising enzymes). Patient groups of children, pregnant women, and the elderly, in whom the most extensive pharmacokinetic changes occur, need special attention and close follow-up of treatment. Patients with complicated and changing combination treatments are also vulnerable. Therapeutic drug monitoring may be particularly helpful in such situations. There are also challenges regarding the use and misuse of therapeutic drug monitoring, such as the use of drug monitoring without a clear indication, misinterpretation of the reference range, and erroneous sampling times. PMID- 27965186 TI - Impact of sevelamer hydrochloride on serum magnesium concentrations in hemodialysis patients. AB - Serum Mg levels are elevated in patients with renal insufficiency: harmful effects of hypomagnesemia have been reported in patients receiving hemodialysis (HD). In this cross-sectional study, which included 86 HD patients (male : female = 56:30, age 68 +/- 12 years), we examined the clinical factors associated with serum Mg levels, with a focus on sevelamer, a phosphate binder widely used to control the hyperphosphatemia of HD patients. The mean serum Mg concentration among our patients was 2.48 +/- 0.37 mg/dL (1.02 +/- 0.15 mmol/L). Sevelamer was administered to 67 patients (77.9%) at a mean dose of 1.98 +/- 1.64 g/day. Sex, diabetes mellitus, cardiovascular disease, anuria, and drugs other than sevelamer were not associated with serum Mg levels. HD duration, serum calcium, albumin, high-density lipoprotein cholesterol, normalized protein catabolic rate (nPCR), creatinine generation rate, and sevelamer dose correlated positively with serum Mg levels, whereas a negative correlation was observed for age and high sensitivity C-reactive protein. A stepwise multiple regression analysis revealed that age, nPCR, and the dose of sevelamer were independently associated with serum Mg levels. Sevelamer and Mg have been reported to exhibit similar effects, such as an anti-inflammatory effect, inhibition of cardiovascular calcification, and decreased mortality. Therefore, the pleiotropic effects of sevelamer may be partly attributable to the increase in serum Mg levels caused by the drug itself. PMID- 27965184 TI - Delayed cutaneous hypersensitivity reactions to iodinated contrast media. PMID- 27965189 TI - Magnesium, C-reactive protein, and cortisol in drug-naive patients with short illness-duration, first episode major depressive disorder: possible immunomodulatory role for magnesium. AB - Plasma magnesium concentration alterations, hypercortisolaemia, and systemic inflammation are observed in major depressive disorder (MDD). This exploratory study examined whether, and to what extent, plasma magnesium is related to C reactive protein (CRP) levels and cortisolaemia in MDD. The concentrations of plasma magnesium, salivary CRP, and baseline plasma cortisol were studied in 20, treatment-naive MDD patients with short-illness-duration, first affective episodes and 20 matched controls. Depressed patients showed a basal score higher than 20 on the Hamilton Rating Scale for Depression (HAMD-17). Significantly higher magnesium (p = 0.016) and baseline cortisol (p = 0.01) concentrations were observed in MDD as compared to controls. No significant difference in CRP concentrations between the MDD and control groups was observed. A significant negative correlation was seen between magnesium and CRP in MDD (p<0.01), whereas no correlation was found in controls. A significant positive correlation was found between cortisol and CRP, both in MDD subjects (p = 0.008) and controls (p = 0.004). No significant correlations were observed between magnesium and cortisol levels. The study supports data for hypercortisolaemia in MDD, but provides no evidence of primary hypomagnesaemia or elevated CRP levels in drug naive MDD patients with short-illness-duration. The study supports the hypothesis linking hypercortisolaemia to systemic inflammation, with hypermagnesaemia exerting an immunomodulatory action at early stages of the disease. PMID- 27965188 TI - Psoriasis vulgaris in a hepatitis B virus carrier successfully treated with secukinumab and entecavir combination therapy. PMID- 27965180 TI - A randomized controlled trial of a community health worker intervention in a population of patients with multiple chronic diseases: Study design and protocol. AB - : Upstream interventions - e.g. housing programs and community health worker interventions- address socioeconomic and behavioral factors that influence health outcomes across diseases. Studying these types of interventions in clinical trials raises a methodological challenge: how should researchers measure the effect of an upstream intervention in a sample of patients with different diseases? This paper addresses this question using an illustrative protocol of a randomized controlled trial of collaborative-goal setting versus goal-setting plus community health worker support among patients multiple chronic diseases: diabetes, obesity, hypertension and tobacco dependence. At study enrollment, patients met with their primary care providers to select one of their chronic diseases to focus on during the study, and to collaboratively set a goal for that disease. Patients randomly assigned to a community health worker also received six months of support to address socioeconomic and behavioral barriers to chronic disease control. The primary hypothesis was that there would be differences in patients' selected chronic disease control as measured by HbA1c, body mass index, systolic blood pressure and cigarettes per day, between the goal-setting alone and community health worker support arms. To test this hypothesis, we will conduct a stratum specific multivariate analysis of variance which allows all patients (regardless of their selected chronic disease) to be included in a single model for the primary outcome. Population health researchers can use this approach to measure clinical outcomes across diseases. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01900470. PMID- 27965177 TI - A rare presentation of type II myocardial infarction mimicking Takotsubo cardiomyopathy. PMID- 27965193 TI - William Perry Kirkwood Calwell. PMID- 27965192 TI - Humanising healthcare. PMID- 27965190 TI - Creating Live Interactions to Mitigate Barriers (CLIMB): A Mobile Intervention to Improve Social Functioning in People With Chronic Psychotic Disorders. AB - BACKGROUND: Numerous psychosocial interventions for individuals with chronic psychotic disorders (CPD) have shown positive effects on social cognitive and functional outcome measures. However, access to and engagement with these interventions remains limited. This is partly because these interventions require specially trained therapists, are not available in all clinical settings, and have a high scheduling burden for participants, usually requiring a commitment of several weeks. Delivering interventions remotely via mobile devices may facilitate access, improve scheduling flexibility, and decrease participant burden, thus improving adherence to intervention requirements. To address these needs, we designed the Creating Live Interactions to Mitigate Barriers (CLIMB) digital intervention, which aims to enhance social functioning in people with CPD. CLIMB consists of two treatment components: a computerized social cognition training (SCT) program and optimized remote group therapy (ORGT). ORGT is an innovative treatment that combines remote group therapy with group texting (short message service, SMS). OBJECTIVES: The objectives of this single-arm study were to investigate the feasibility of delivering 6 weeks of CLIMB to people with CPD and explore the initial effects on outcomes. METHODS: Participants were recruited, screened and enrolled via the Internet, and delivered assessments and interventions remotely using provided tablets (iPads). Participants were asked to complete 18 hours of SCT and to attend 6 remote group therapy sessions. To assess feasibility, adherence to study procedures, attrition rates, engagement metrics, and acceptability of the intervention were evaluated. Changes on measures of social cognition, quality of life, and symptoms were also explored. RESULTS: In total, 27 participants were enrolled over 12 months. Remote assessments were completed successfully on 96% (26/27) of the enrolled participants. Retention in the 6-week trial was 78% (21/27). Of all the iPads used, 95% (22/23) were returned undamaged at the end of the intervention. Participants on average attended 84% of the group therapy sessions, completed a median of 9.5 hours of SCT, and posted a median of 5.2 messages per week on the group text chat. Participants rated CLIMB in the medium range in usability, acceptability, enjoyment, and perceived benefit. Participants showed significant improvements in emotion identification abilities for prosodic happiness (P=.001), prosodic happiness intensity (P=.04), and facial anger (P=.04), with large within-group effect sizes (d=.60 to d=.86). Trend-level improvements were observed on aspects of quality of life (P values less than .09). No improvements were observed for symptoms. CONCLUSIONS: It is feasible and acceptable to remotely deliver an intervention aimed at enhancing social functioning in people with CPD using mobile devices. This approach may represent a scalable method to increase treatment access and adherence. Our pilot data also demonstrate within-group gains in some aspects of social cognition after 6 weeks of CLIMB. Future randomized controlled studies in larger samples should evaluate the extent to which CLIMB significantly improves social cognition, symptoms, and quality of life in CPD. PMID- 27965201 TI - Paediatrician is denied permission to appeal against manslaughter conviction. PMID- 27965195 TI - Fake penicillin, The Third Man, and Operation Claptrap. PMID- 27965191 TI - Association Between Physician Online Rating and Quality of Care. AB - BACKGROUND: Patients are increasingly using physician review websites to find "a good doctor." However, to our knowledge, no prior study has examined the relationship between online rating and an accepted measure of quality. OBJECTIVE: The purpose of this study was to assess the association between online physician rating and an accepted measure of quality: 30-day risk-adjusted mortality rate following coronary artery bypass graft (CABG) surgery. METHODS: In the US states of California, Massachusetts, New Jersey, New York, and Pennsylvania-which together account for over one-quarter of the US population-risk-adjusted mortality rates are publicly reported for all cardiac surgeons. From these reports, we recorded the 30-day mortality rate following isolated CABG surgery for each surgeon practicing in these 5 states. For each surgeon listed in the state reports, we then conducted Internet-based searches to determine his or her online rating(s). We then assessed the relationship between physician online rating and risk-adjusted mortality rate. RESULTS: Of the 614 surgeons listed in the state reports, we found 96.1% (590/614) to be rated online. The average online rating was 4.4 out of 5, and 78.7% (483/614) of the online ratings were 4 or higher. The median number of reviews used to formulate each rating was 4 (range 1-89), and 32.70% (503/1538) of the ratings were based on 2 or fewer reviews. Overall, there was no correlation between surgeon online rating and risk adjusted mortality rate (P=.13). Risk-adjusted mortality rates were similar for surgeons across categories of average online rating (P>.05), and surgeon average online rating was similar across quartiles of surgeon risk-adjusted mortality rate (P>.05). CONCLUSIONS: In this study of cardiac surgeons practicing in the 5 US states that publicly report outcomes, we found no correlation between online rating and risk-adjusted mortality rates. Patients using online rating websites to guide their choice of physician should recognize that these ratings may not reflect actual quality of care as defined by accepted metrics. PMID- 27965194 TI - Sustained enjoyment of life and mortality at older ages: analysis of the English Longitudinal Study of Ageing. AB - OBJECTIVE: To test whether the number of reports of enjoyment of life over a four year period is quantitatively associated with all cause mortality, and with death from cardiovascular disease and from other causes. DESIGN AND SETTING: Longitudinal observational population study using the English Longitudinal Study of Ageing (ELSA), a nationally representative sample of older men and women living in England. PARTICIPANTS: 9365 men and women aged 50 years or older (mean 63, standard deviation 9.3) at recruitment. MAIN OUTCOME MEASURES: Time to death, based on mortality between the third phase of data collection (wave 3 in 2006) and March 2013 (up to seven years). RESULTS: Subjective wellbeing with measures of enjoyment of life were assessed in 2002 (wave 1), 2004 (wave 2), and 2006 (wave 3). 2264 (24%) respondents reported no enjoyment of life on any assessment, with 1833 (20%) reporting high enjoyment on one report of high enjoyment of life, 2063 (22%) on two reports, and 3205 (34%) on all three occasions. 1310 deaths were recorded during follow-up. Mortality was inversely associated with the number of occasions on which participants reported high enjoyment of life. Compared with the no high enjoyment group, the hazard ratio for all cause mortality was 0.83 (95% confidence interval 0.70 to 0.99) for two reports of enjoyment of life, and 0.76 (0.64 to 0.89) for three reports, after adjustment for demographic factors, baseline health, mobility impairment, and depressive symptoms. The same association was observed after deaths occurring within two years of the third enjoyment measure were excluded (0.90 (0.85 to 0.95) for every additional report of enjoyment), and in the complete case analysis (0.90 (0.83 to 0.96)). CONCLUSIONS: This is an observational study, so causal conclusions cannot be drawn. Nonetheless, the results add a new dimension to understanding the significance of subjective wellbeing for health outcomes by documenting the importance of sustained wellbeing over time. PMID- 27965199 TI - Exploring the physiological and physical effects of acupuncture using ultrasound. PMID- 27965202 TI - Denis Dewhurst Hilton. PMID- 27965197 TI - Protein kinase C is involved with upstream signaling of methyl farnesoate for photoperiod-dependent sex determination in the water flea Daphnia pulex. AB - Sex determination of Daphnia pulex is decided by environmental conditions. We established a suitable experimental system for this study using D. pulex WTN6 strain, in which the sex of the offspring can be controlled by photoperiod. Long day conditions induced females and short-day conditions induced males. Using this system, we previously found that methy farnesoate (MF), which is a putative innate juvenile hormone molecule in daphnids, is necessary for male sex determination and that protein kinase C (PKC) is a candidate factor of male sex determiner. In this study, we demonstrated that a PKC inhibitor [bisindolylmaleimide IV (BIM)] application strongly suppressed male offspring induction in the short-day condition. Moreover, co-treatment of BIM with MF revealed that PKC signaling acts upstream of MF signaling for male sex determination. This is the first experimental evidence that PKC is involved in the male sex determination process associated with methyl farnesoate signaling in daphnid species. PMID- 27965210 TI - War games and diagnostic errors. PMID- 27965208 TI - Eric William Taylor. PMID- 27965198 TI - Sniffing out significant "Pee values": genome wide association study of asparagus anosmia. AB - OBJECTIVE: To determine the inherited factors associated with the ability to smell asparagus metabolites in urine. DESIGN: Genome wide association study. SETTING: Nurses' Health Study and Health Professionals Follow-up Study cohorts. PARTICIPANTS: 6909 men and women of European-American descent with available genetic data from genome wide association studies. MAIN OUTCOME MEASURE: Participants were characterized as asparagus smellers if they strongly agreed with the prompt "after eating asparagus, you notice a strong characteristic odor in your urine," and anosmic if otherwise. We calculated per-allele estimates of asparagus anosmia for about nine million single nucleotide polymorphisms using logistic regression. P values <5*10-8 were considered as genome wide significant. RESULTS: 58.0% of men (n=1449/2500) and 61.5% of women (n=2712/4409) had anosmia. 871 single nucleotide polymorphisms reached genome wide significance for asparagus anosmia, all in a region on chromosome 1 (1q44: 248139851-248595299) containing multiple genes in the olfactory receptor 2 (OR2) family. Conditional analyses revealed three independent markers associated with asparagus anosmia: rs13373863, rs71538191, and rs6689553. CONCLUSION: A large proportion of people have asparagus anosmia. Genetic variation near multiple olfactory receptor genes is associated with the ability of an individual to smell the metabolites of asparagus in urine. Future replication studies are necessary before considering targeted therapies to help anosmic people discover what they are missing. PMID- 27965213 TI - Cochrane systematic review highlights the importance of lactulose in the management of hepatic encephalopathy. PMID- 27965215 TI - The Gatekeeper and the Wizard: the Gatekeeper goes digital. PMID- 27965204 TI - Effects of paternal obesity on growth and adiposity of male rat offspring. AB - Emerging evidence suggests that paternal obesity plays an important role in offspring health. Our previous work using a rodent model of diet-induced paternal obesity showed that female offspring from high-fat diet (HFD)-fed fathers develop glucose intolerance due to impairment of pancreatic insulin secretion. Here, we focused on the health outcomes of male offspring from HFD-fed fathers. Male Sprague-Dawley rats (3 wk old) were fed control (CD-F0) or HFD (HFD-F0) for 12 wk before mating with control-fed females. Male offspring were fed control diets for up to 8 wk or 6 mo. Although male offspring from HFD-F0 did not develop any obvious glucose metabolism defects in this study, surprisingly, a growth deficit phenotype was observed from birth to 6 mo of age. Male offspring from HFD-F0 had reduced birth weight compared with CD-F0, followed by reduced postweaning growth from 9 wk of age. This resulted in 10% reduction in body weight at 6 mo with significantly smaller fat pads and skeletal muscles. Reduced circulating levels of growth hormone (GH) and IGF-I were detected at 8 wk and 6 mo, respectively. Expression of adipogenesis markers was decreased in adipose tissue of HFD-F0 offspring at 8 wk and 6 mo, and expression of growth markers was decreased in muscle of HFD-F0 offspring at 8 wk. We propose that the reduced GH secretion at 8 wk of age altered the growth of male offspring from HFD-F0, resulting in smaller animals from 9 wk to 6 mo of age. Furthermore, increased muscle triglyceride content and expression of lipogenic genes were observed in HFD-F0 offspring, potentially increasing their metabolic risk. PMID- 27965214 TI - John David Elliott Edwards. PMID- 27965212 TI - Letter to the Editor re 'Characteristics of breakthrough cancer pain and its influence on quality of life in an international cohort of patients with cancer (BMJ Support Palliat Care 2016;6:344-52)'. PMID- 27965211 TI - Gotta catch'em all! Pokemon GO and physical activity among young adults: difference in differences study. AB - OBJECTIVE: To estimate the effect of playing Pokemon GO on the number of steps taken daily up to six weeks after installation of the game. DESIGN: Cohort study using online survey data. PARTICIPANTS: Survey participants of Amazon Mechanical Turk (n=1182) residing in the United States, aged 18 to 35 years and using iPhone 6 series smartphones. MAIN OUTCOME MEASURES: Number of daily steps taken each of the four weeks before and six weeks after installation of Pokemon GO, automatically recorded in the "Health" application of the iPhone 6 series smartphones and reported by the participants. A difference in difference regression model was used to estimate the change in daily steps in players of Pokemon GO compared with non-players. RESULTS: 560 (47.4%) of the survey participants reported playing Pokemon GO and walked on average 4256 steps (SD 2697) each day in the four weeks before installation of the game. The difference in difference analysis showed that the daily average steps for Pokemon GO players during the first week of installation increased by 955 additional steps (95% confidence interval 697 to 1213), and then this increase gradually attenuated over the subsequent five weeks. By the sixth week after installation, the number of daily steps had gone back to pre-installation levels. No significant effect modification of Pokemon GO was found by sex, age, race group, bodyweight status, urbanity, or walkability of the area of residence. CONCLUSIONS: Pokemon GO was associated with an increase in the daily number of steps after installation of the game. The association was, however, moderate and no longer observed after six weeks. PMID- 27965203 TI - Myostatin propeptide mutation of the hypermuscular Compact mice decreases the formation of myostatin and improves insulin sensitivity. AB - The TGFbeta family member myostatin (growth/differentiation factor-8) is a negative regulator of skeletal muscle growth. The hypermuscular Compact mice carry the 12-bp Mstn(Cmpt-dl1Abc) deletion in the sequence encoding the propeptide region of the precursor promyostatin, and additional modifier genes of the Compact genetic background contribute to determine the full expression of the phenotype. In this study, by using mice strains carrying mutant or wild-type myostatin alleles with the Compact genetic background and nonmutant myostatin with the wild-type background, we studied separately the effect of the Mstn(Cmpt dl1Abc) mutation or the Compact genetic background on morphology, metabolism, and signaling. We show that both the Compact myostatin mutation and Compact genetic background account for determination of skeletal muscle size. Despite the increased musculature of Compacts, the absolute size of heart and kidney is not influenced by myostatin mutation; however, the Compact genetic background increases them. Both Compact myostatin and genetic background exhibit systemic metabolic effects. The Compact mutation decreases adiposity and improves whole body glucose uptake, insulin sensitivity, and 18FDG uptake of skeletal muscle and white adipose tissue, whereas the Compact genetic background has the opposite effect. Importantly, the mutation does not prevent the formation of mature myostatin; however, a decrease in myostatin level was observed, leading to altered activation of Smad2, Smad1/5/8, and Akt, and an increased level of p AS160, a Rab-GTPase-activating protein responsible for GLUT4 translocation. Based on our analysis, the Compact genetic background strengthens the effect of myostatin mutation on muscle mass, but those can compensate for each other when systemic metabolic effects are compared. PMID- 27965217 TI - Nonsurgical Facial Rejuvenation Procedures in Patients Under 50 Prior to Undergoing Facelift: Habits, Costs, and Results. AB - Background: Facial rejuvenation in patients younger than 50 years of age has experienced an unprecedented growth with multimodality nonsurgical and less invasive rhytidectomy techniques. Objectives: To analyze the nonsurgical treatment habits of patients prior to undergoing rhytidectomy at <50 years of age. Methods: Retrospective study to enlist patients who underwent primary rhytidectomy at age <50 years between January 1, 2003 and December 31, 2013 by the senior author (AAJ) to complete a survey. Results: One hundred and fifty seven patients were surveyed. Patients had nonsurgical rejuvenation starting at an average age of 37 years and rhytidectomy at an average age of 44 years. Thirty two percent of responders had injectable treatments prior to their facelift, reporting a mean of 7 rounds of injectable treatments prior to pursuing rhytidectomy. Sixteen percent of responders had laser skin resurfacing undergoing 4 separate treatments prior to rhytidectomy, and 10% had energy-based facial tightening treatments one time prior to their rhytidectomy. Average expenditure on nonsurgical treatments prior to rhytidectomy was $7000 cumulatively. Fifty nine percent of patients who went on to rhytidectomy did not report regret over this cost expenditure. Patients reported that they appeared 4 years younger after nonsurgical intervention, and 8 years younger after their facelift, a statistically significant difference (P = .048). Conclusions: Patients undergoing rhytidectomy <50 years old begin less invasive facial rejuvenation treatments at an even earlier age. The majority of these patients did not regret the costs associated with noninvasive treatments, even though they saw that rhytidectomy provided a greater rejuvenation effect. Rhytidectomy surgeons should incorporate nonsurgical techniques into their practice to best serve the needs of the modern aging face patient. PMID- 27965218 TI - Managing the Difficult Soft Tissue Envelope in Facial and Rhinoplasty Surgery. AB - BACKGROUND: The nasal soft tissue envelope affects the final rhinoplasty result, and can limit the expected improvement. Currently, no dependable and objective test exists to measure the thickness of the nasal skin and underlying soft tissue. OBJECTIVES: This paper presents a simple, yet reliable method to determine the thickness of the soft tissue envelope. An algorithm is presented for treatment of the dermis and/or soft tissue apart from surgery of the underlying osseocartilaginous structures. METHODS: Seventy-five patients presenting for primary rhinoplasty underwent visual and ultrasound assessment of their nasal soft tissue envelope. At preoperative evaluation, the Obagi "skin pinch test" was used to assess the thickness of the nasolabial fold and whether or not the skin was oily. Patients were classified based on the pinch thickness. At time of surgery prior to injection of local anesthesia, ultrasonic assessment was done at the nasolabial fold, keystone junction, supratip, and tip to measure the thickness of the nasal dermis and underlying soft tissue. RESULTS: Patients determined to have thin, normal, and thick skin by the "skin pinch test" were found to have a nasolabial fold dermal thickness with an average of 0.7 mm (0.4 1.2 mm), 1.1 mm (0.8-1.8 mm), and 1.4 mm (0.7-2.0 mm). Patients determined to have thin, normal, and thick skin were found to have a dermal thickness at the keystone junction with an average of 0.3 mm (0.2-0.4 mm), 0.5 mm (0.3-1.1 mm), and 0.9 mm (0.6-1.2 mm), respectively. This difference in thickness also translated to the supratip and tip areas measured. However, all areas were also affected by the oiliness of the skin. Soft tissue thickness (SMAS and muscle) underlying the dermis was variable. Patients of non-Caucasian background were more likely to have a thicker soft tissue layer. CONCLUSIONS: The "skin pinch test" is an easy and reliable way for the surgeon to evaluate the thickness of the nasal soft tissue envelope. The rhinoplasty surgeon can make decisions pre- and postoperatively to treat patients with difficult soft tissue envelopes. LEVEL OF EVIDENCE 4. PMID- 27965216 TI - Gillian Mary Hunt. PMID- 27965219 TI - Effects of platelet-rich plasma and triamcinolone acetonide on interleukin-1beta stimulated human rotator cuff-derived cells. AB - OBJECTIVES: Triamcinolone acetonide (TA) is widely used for the treatment of rotator cuff injury because of its anti-inflammatory properties. However, TA can also produce deleterious effects such as tendon degeneration or rupture. These harmful effects could be prevented by the addition of platelet-rich plasma (PRP), however, the anti-inflammatory and anti-degenerative effects of the combined use of TA and PRP have not yet been made clear. The objective of this study was to determine how the combination of TA and PRP might influence the inflammation and degeneration of the rotator cuff by examining rotator cuff-derived cells induced by interleukin (IL)-1beta. METHODS: Rotator cuff-derived cells were seeded under inflammatory stimulation conditions (with serum-free medium with 1 ng/ml IL-1beta for three hours), and then cultured in different media: serum-free (control group), serum-free + TA (0.1mg/ml) (TA group), serum-free + 10% PRP (PRP group), and serum-free + TA (0.1mg/ml) + 10% PRP (TA+PRP group). Cell morphology, cell viability, and expression of inflammatory and degenerative mediators were assessed. RESULTS: Exposure to TA significantly decreased cell viability and changed the cell morphology; these effects were prevented by the simultaneous administration of PRP. Compared with the control group, expression levels of inflammatory genes and reactive oxygen species production were reduced in the TA, PRP, and TA+PRP groups. PRP significantly decreased the expression levels of degenerative marker genes. CONCLUSIONS: The combination of TA plus PRP exerts anti-inflammatory and anti-degenerative effects on rotator cuff-derived cells stimulated by IL-1beta. This combination has the potential to relieve the symptoms of rotator cuff injury.Cite this article: T. Muto, T. Kokubu, Y. Mifune, A. Inui, R. Sakata, Y. Harada, F. Takase, M. Kurosaka. Effects of platelet-rich plasma and triamcinolone acetonide on interleukin-1beta-stimulated human rotator cuff-derived cells. Bone Joint Res 2016;5:602-609. DOI: 10.1302/2046 3758.512.2000582. PMID- 27965206 TI - Prior lactation reduces future diabetic risk through sustained postweaning effects on insulin sensitivity. AB - Breastfeeding for >=12 mo is recommended for optimal infant nutrition but may hold maternal benefits as well. Indeed, lactation has been associated with lower long-term risk of diabetes in the mother, but the mechanism by which it imparts sustained postweaning effects on glucose tolerance remains unclear. In this context, we postulated that lactation could potentially induce postweaning beneficial effects on glucose tolerance by modifying the natural history of insulin sensitivity and/or pancreatic beta-cell function over time. Thus, in this study, we evaluated the relationships between duration of lactation [<=3 mo (n = 70), 3-12 mo (n = 140), and >=12 mo (n = 120)] and trajectories of insulin sensitivity/resistance, beta-cell function, and glycemia over the first 3 yr postpartum in a cohort of 330 women comprising the full spectrum of glucose tolerance in pregnancy, who underwent serial metabolic characterization, including oral glucose tolerance tests, at 3 mo, 1 yr, and 3 yr postpartum. The prevalence of dysglycemia (pre-diabetes/diabetes) at 3 yr postpartum was lower in women who breastfed for >=12 mo (12.5%) than in those who breastfed for <=3 mo (21.4%) or for 3-12 mo (25.7%)(overall P = 0.028). On logistic regression analysis, lactation for >=12 mo independently predicted a lower likelihood of prediabetes/diabetes at 3 yr postpartum (OR = 0.37, 95% CI 0.18-0.78, P = 0.009). Notably, lactation for >=12 mo predicted lesser worsening of insulin sensitivity/resistance (P < 0.0001), fasting glucose (P < 0.0001), and 2-h glucose (P = 0.011) over 3 yr compared with lactation <=3 mo but no differences in beta-cell function (P >= 0.37). It has thus emerged that adherence to current breastfeeding recommendations reduces future diabetic risk through sustained postweaning effects on insulin sensitivity/resistance but not beta-cell function. PMID- 27965205 TI - Postnatal treatment with metyrapone attenuates the effects of diet-induced obesity in female rats exposed to early-life stress. AB - Experimental studies in rodents have shown that females are more susceptible to exhibiting fat expansion and metabolic disease compared with males in several models of fetal programming. This study tested the hypothesis that female rat pups exposed to maternal separation (MatSep), a model of early-life stress, display an exacerbated response to diet-induced obesity compared with male rats. Also, we tested whether the postnatal treatment with metyrapone (MTP), a corticosterone synthase inhibitor, would attenuate this phenotype. MatSep was performed in WKY offspring by separation from the dam (3 h/day, postnatal days 2 14). Upon weaning, male and female rats were placed on a normal (ND; 18% kcal fat) or high-fat diet (HFD; 60% kcal fat). Nondisturbed littermates served as controls. In male rats, no diet-induced differences in body weight (BW), glucose tolerance, and fat tissue weight and morphology were found between MatSep and control male rats. However, female MatSep rats displayed increased BW gain, fat pad weights, and glucose intolerance compared with control rats (P < 0.05). Also, HFD increased plasma corticosterone (196 +/- 51 vs. 79 +/- 18 pg/ml, P < 0.05) and leptin levels (1.8 +/- 0.4 vs. 1.3 +/- 0.1 ng/ml, P < 0.05) in female MatSep compared with control rats, whereas insulin and adiponectin levels were similar between groups. Female control and MatSep offspring were treated with MTP (50 ug/g ip) 30 min before the daily separation. MTP treatment significantly attenuated diet-induced obesity risk factors, including elevated adiposity, hyperleptinemia, and glucose intolerance. These findings show that exposure to stress hormones during early life could be a key event to enhance diet-induced obesity and metabolic disease in female rats. Thus, pharmacological and/or behavioral inflection of the stress levels is a potential therapeutic approach for prevention of early life stress-enhanced obesity and metabolic disease. PMID- 27965196 TI - Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. AB - Despite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n = 873; 87%); the remainder received reduced-intensity conditioning regimens (n = 125; 13%). Bone marrow was the predominant stem cell source (n = 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Event-free survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after 2006 (HR, 0.95; P = .013). Twenty-three patients experienced graft failure, and 70 patients (7%) died, with the most common cause of death being infection. The excellent outcome of a cohort transplanted over the course of 3 decades confirms the role of HLA-identical sibling transplantation for children and adults with SCD. PMID- 27965221 TI - The Second Time Around. PMID- 27965209 TI - Effectiveness of Chlorthalidone Plus Amiloride for the Prevention of Hypertension: The PREVER-Prevention Randomized Clinical Trial. AB - BACKGROUND: Prehypertension is associated with higher cardiovascular risk, target organ damage, and incidence of hypertension. The Prevention of Hypertension in Patients with PreHypertension (PREVER-Prevention) trial aimed to evaluate the efficacy and safety of a low-dose diuretic for the prevention of hypertension and end-organ damage. METHODS AND RESULTS: This randomized, parallel, double-blind, placebo-controlled trial was conducted in 21 Brazilian academic medical centers. Participants with prehypertension who were aged 30 to 70 years and who did not reach optimal blood pressure after 3 months of lifestyle intervention were randomized to a chlorthalidone/amiloride combination pill or placebo and were evaluated every 3 months during 18 months of treatment. The primary outcome was incidence of hypertension. Development or worsening of microalbuminuria, new onset diabetes mellitus, and reduction of left ventricular mass were secondary outcomes. Participant characteristics were evenly distributed by trial arms. The incidence of hypertension was significantly lower in 372 study participants allocated to diuretics compared with 358 allocated to placebo (hazard ratio 0.56, 95% CI 0.38-0.82), resulting in a cumulative incidence of 11.7% in the diuretic arm versus 19.5% in the placebo arm (P=0.004). Adverse events; levels of blood glucose, glycosylated hemoglobin, creatinine, and microalbuminuria; and incidence of diabetes mellitus were no different between the 2 arms. Left ventricular mass assessed through Sokolow-Lyon voltage and voltage-duration product decreased to a greater extent in participants allocated to diuretic therapy compared with placebo (P=0.02). CONCLUSIONS: A combination of low-dose chlorthalidone and amiloride effectively reduces the risk of incident hypertension and beneficially affects left ventricular mass in patients with prehypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov, www.ensaiosclinicos.gov. Unique identifiers: NCT00970931, RBR-74rr6s. PMID- 27965225 TI - Evidence-Based Review and Discussion Points. PMID- 27965224 TI - Feasibility and Effectiveness of a Delirium Prevention Bundle in Critically Ill Patients. AB - BACKGROUND: Strategies for preventing delirium include early identification and avoiding or modifying patient, environmental, and iatrogenic factors. Minimal research exists on a prescriptive delirium prevention bundle that details elements or strategies for each bundle component. Even less research has been focused on nurse-driven interventions or components. OBJECTIVE: To evaluate the effectiveness of a delirium prevention bundle in decreasing delirium incidence in 2 medical-surgical intensive care units in a large Texas medical center. METHODS: Researchers used the Confusion Assessment Method for the Intensive Care Unit to assess delirium incidence by using a controlled interventional cohort design with 447 delirium-negative critically ill patients. Bundle components consist of sedation cessation, pain management, sensory stimulation, early mobilization, and sleep promotion. RESULTS: The intervention, analyzed by using a logistic regression model, reduced the odds of delirium by 78% (odds ratio, 0.22; P = .001). CONCLUSIONS: The delirium prevention bundle was effective in reducing the incidence of delirium in critically ill medical-surgical patients. Further validation studies are under way. PMID- 27965226 TI - Preventing Delirium in Critically Ill Patients. PMID- 27965220 TI - The use of rats and mice as animal models in ex vivo bone growth and development studies. AB - In vivo animal experimentation has been one of the cornerstones of biological and biomedical research, particularly in the field of clinical medicine and pharmaceuticals. The conventional in vivo model system is invariably associated with high production costs and strict ethical considerations. These limitations led to the evolution of an ex vivo model system which partially or completely surmounted some of the constraints faced in an in vivo model system. The ex vivo rodent bone culture system has been used to elucidate the understanding of skeletal physiology and pathophysiology for more than 90 years. This review attempts to provide a brief summary of the historical evolution of the rodent bone culture system with emphasis on the strengths and limitations of the model. It encompasses the frequency of use of rats and mice for ex vivo bone studies, nutritional requirements in ex vivo bone growth and emerging developments and technologies. This compilation of information could assist researchers in the field of regenerative medicine and bone tissue engineering towards a better understanding of skeletal growth and development for application in general clinical medicine.Cite this article: A. A. Abubakar, M. M. Noordin, T. I. Azmi, U. Kaka, M. Y. Loqman. The use of rats and mice as animal models in ex vivo bone growth and development studies. Bone Joint Res 2016;5:610-618. DOI: 10.1302/2046 3758.512.BJR-2016-0102.R2. PMID- 27965228 TI - Safety of Continuous Peripheral Infusion of 3% Sodium Chloride Solution in Neurocritical Care Patients. AB - BACKGROUND: Numerous drug information resources recommend that continuous intravenous 3% sodium chloride solution be administered via a central catheter. OBJECTIVES: To evaluate the incidence of infusion-related reactions and electrolyte abnormalities in neurocritical care patients treated with continuous intravenous infusion of 3% sodium chloride solution via a peripheral catheter. METHODS: Data on patients treated with continuous intravenous infusion of 3% sodium chloride solution at 2 academic medical centers were evaluated retrospectively to determine the administration site. Electronic notes on catheter status were reviewed to determine the occurrence of infusion-related reactions. Prespecified thresholds were used to assess electrolyte abnormalities. RESULTS: Of 213 patients who had peripheral continuous intravenous infusions of 3% sodium chloride solution, 15 (7%) had infusion-related reactions. Administration was changed to a central catheter in 56 patients (26.3%), but only 5 changes were due to an infusion-related reaction. Most (157 patients, 73.7%) received their entire treatment peripherally, for a median duration of 44 hours, 3 minutes. The most common electrolyte abnormalities were hyperchloremia in 49.3% and hypokalemia in 46.9% of patients. CONCLUSION: Current recommendations that a central catheter is required for continuous intravenous infusion of 3% sodium chloride solution should be reevaluated. Only a few patients who had peripheral infusions had infusion-related reactions. Electrolyte abnormalities occurred frequently with peripheral infusion, but the clinical importance of the abnormalities remains unclear. PMID- 27965223 TI - Feasibility of a Mindfulness-Based Intervention for Surgical Intensive Care Unit Personnel. AB - BACKGROUND: Surgical intensive care unit personnel are exposed to catastrophic situations as they care for seriously injured or ill patients. Few interventions have been developed to reduce the negative effects of work stress in this environment. OBJECTIVE: This pilot study evaluated the feasibility of a workplace intervention for increasing resilience to stress. The intervention was implemented within the unique constraints characteristic of surgical intensive care units. METHODS: Participants were randomly assigned to an intervention or control group. The mindfulness-based intervention included meditation, mild yoga movement, and music and was conducted in a group format 1 hour a week for 8 weeks in a surgical intensive care unit during work hours. Assessments were performed 1 week before and 1 week after the intervention. RESULTS: The intervention was well received, with a 97% overall retention rate and 100% retention in the intervention group. Work satisfaction, measured with the Utrecht Work Engagement Scale, increased significantly in the intervention group with no change in the control group. Negative correlations were found between the vigor subscale scores of the Utrecht Work Engagement Scale and scores for emotional exhaustion on the Maslach Burnout Inventory and scores for burnout on the Professional Quality of Life scale. Participants rated recognizing their stress response as a main benefit of the intervention. CONCLUSION: Workplace group interventions aimed at decreasing the negative effects of stress can be applied within hospital intensive care units. Despite many constraints, attendance at weekly sessions was high. Institutional support was critical for implementation of this program. PMID- 27965230 TI - Tobacco-Cessation Interventions and Attributes of Individual and Organizational Excellence in Acute Care. AB - BACKGROUND: Despite years of reducing tobacco use, few studies describe to what extent evidence-based tobacco-cessation interventions are a standard of acute and critical care nursing practice using the US Public Health Service 5 A's framework: ask, advise, assess, assist, and arrange. OBJECTIVES: To identify relationships between the 5 A's framework, attributes of individual and organizational excellence, and intention to integrate tobacco-cessation interventions as a standard of daily practice among nurses. METHODS: Nurses attending the American Association of Critical-Care Nurses National Teaching Institute were invited to complete a 21-item survey. Data were gathered in Boston, Orlando, and Chicago in a 3-year period. Descriptive statistics and logistic regression were used for data analysis. RESULTS: Among 1773 completed surveys, nurses from organizations with standing orders for tobacco dependence were 5 times more likely to have high confidence in their 5 A's skills (odds ratio, 5.037; 95% CI, 3.429-7.400; P < .001) and 3.4 times more likely to have high intentions to integrate tobacco cessation into their daily practice (odds ratio, 3.421; 95% CI, 1.765-6.628; P < .001). Nurses with certifications were more likely to want to learn how to integrate tobacco-cessation interventions (odds ratio, 1.676; 95% CI, 0.990-2.836; P = .05). CONCLUSIONS: Opportunities abound to create strategies leveraging attributes of nursing and organizational excellence to promote evidence-based approaches to improve health outcomes in acutely and critically ill tobacco-dependent populations. PMID- 27965232 TI - Critical Care Nurses' Reasons for Poor Attendance at a Continuous Professional Development Program. AB - BACKGROUND: Society demands competent and safe health care, which obligates professionals to deliver quality patient care using current knowledge and skills. Participation in continuous professional development programs is a way to ensure quality nursing care. Despite the importance of continuous professional development, however, critical care nurse practitioners' attendance rates at these programs is low. OBJECTIVE: To explore critical care nurses' reasons for their unsatisfactory attendance at a continuous professional development program. METHODS: A nominal group technique was used as a consensus method to involve the critical care nurses and provide them the opportunity to reflect on their experiences and challenges related to the current continuous professional development program for the critical care units. Participants were 14 critical care nurses from 3 critical care units in 1 private hospital. RESULTS: The consensus was that the central theme relating to the unsatisfactory attendance at the continuous professional development program was attitude. In order of importance, the 4 contributing priorities influencing attitude were communication, continuous professional development, time constraints, and financial implications. CONCLUSION: Attitude relating to attending a continuous professional development program can be changed if critical care nurses are aware of the program's importance and are involved in the planning and implementation of a program that focuses on the nurses' individual learning needs. PMID- 27965227 TI - Effects of Ambulation and Nondependent Transfers on Vital Signs in Patients Receiving Norepinephrine. AB - PURPOSE: To assess the safety of mobilizing patients receiving low-dose norepinephrine (0.05 MUg/kg per min) by examining mean arterial pressure and heart rate before and after activity with parameters set by the physician. BACKGROUND: Norepinephrine is a peripheral vasoconstrictor administered for acute hypotension. During activity, blood flows to the periphery to supply muscles with oxygen, which may oppose the norepinephrine vasoconstriction. The safety of mobilizing patients receiving norepinephrine is unclear. METHODS: Heart rate, mean arterial pressure, norepinephrine dose, and activity performed were extracted retrospectively from charts of 47 cardiothoracic surgery patients during the first patient transfer to chair or ambulation with norepinephrine infusing. Mean arterial pressure and heart rate were compared before and after physical therapy (paired t tests). Differences among norepinephrine doses and physical activity levels were evaluated (Kruskal-Wallis test). RESULTS: Forty-one of the 47 patients (87%) tolerated the activity within safe ranges of vital signs. The change in patients' mean arterial pressure from before to after activity was not significant (P = .16), but a significant increase in heart rate occurred after activity (P < .001). A Kruskal-Wallis test showed no significant difference in the norepinephrine dose and activity level (chi2 = 6.34, P = .17). No instances of cardiopulmonary or respiratory arrest occurred during any physical therapy sessions. CONCLUSIONS: Infusion of low-dose norepinephrine should not be considered an automatic reason to keep patients on bed rest. PMID- 27965234 TI - A Rare Disease With Cardiac Involvement. PMID- 27965233 TI - Research in Review: Advancing Critical Care Practice. AB - Research published in 2016 identified strategies to enhance acute and critical care, initiated discussions on professional roles and responsibilities, clarified complex care issues, and led to robust debate. Some of this important work addressed strategies to prevent delirium and pressure ulcers, considerations for pain management within the context of the opioid abuse crisis, strategies to guide fluid resuscitation in patients with sepsis and heart failure, and ways to enhance care for family members of intensive care patients. The new sepsis definitions highlight the importance of detecting and providing care to patients with sepsis outside of critical care areas. Chimeric antigen receptor T-cell therapy is an example of the advancement of research in genomics and personalized medicine and of the need to understand the care implications of these therapies. Other research topics include interprofessional collaboration and shared decision making as well as nurses' role in family conferences. Resources such as policies related to medical futility and inappropriate care and the American Association of Critical-Care Nurses' healthy work environment standards may inform conversations and provide strategies to address these complex issues. PMID- 27965237 TI - Evidence of correlated evolution and adaptive differentiation of stem and leaf functional traits in the herbaceous genus, Helianthus. AB - PREMISE OF THE STUDY: Patterns of plant stem traits are expected to align with a "fast-slow" plant economic spectrum across taxa. Although broad patterns support such tradeoffs in field studies, tests of hypothesized correlated trait evolution and adaptive differentiation are more robust when taxa relatedness and environment are taken into consideration. Here we test for correlated evolution of stem and leaf traits and their adaptive differentiation across environments in the herbaceous genus, Helianthus. METHODS: Stem and leaf traits of 14 species of Helianthus (28 populations) were assessed in a common garden greenhouse study. Phylogenetically independent contrasts were used to test for evidence of correlated evolution of stem hydraulic and biomechanical properties, correlated evolution of stem and leaf traits, and adaptive differentiation associated with source habitat environments. KEY RESULTS: Among stem traits, there was evidence for correlated evolution of some hydraulic and biomechanical properties, supporting an expected tradeoff between stem theoretical hydraulic efficiency and resistance to bending stress. Population differentiation for suites of stem and leaf traits was found to be consistent with a "fast-slow" resource-use axis for traits related to water transport and use. Associations of population traits with source habitat characteristics supported repeated evolution of a resource acquisitive "drought-escape" strategy in arid environments. CONCLUSIONS: This study provides evidence of correlated evolution of stem and leaf traits consistent with the fast-slow spectrum of trait combinations related to water transport and use along the stem-to-leaf pathway. Correlations of traits with source habitat characteristics further indicate that the correlated evolution is associated, at least in part, with adaptive differentiation of Helianthus populations among native habitats differing in climate. PMID- 27965231 TI - Prehospital Delay, Precipitants of Admission, and Length of Stay in Patients With Exacerbation of Heart Failure. AB - BACKGROUND: Factors that precipitate hospitalization for exacerbation of heart failure provide targets for intervention to prevent hospitalizations. OBJECTIVES: To describe demographic, clinical, behavioral, and psychosocial factors that precipitate admission for exacerbation of heart failure and assess the relationships between precipitating factors and delay before hospitalization, and between delay time and length of hospital stay. METHODS: All admissions in 12 full months to a tertiary medical center were reviewed if the patient had a discharge code related to heart failure. Data on confirmed admissions for exacerbation of heart failure were included in the study. Electronic and paper medical records were reviewed to identify how long it took patients to seek care after they became aware of signs and symptoms, factors that precipitated exacerbation, and discharge details. RESULTS: Exacerbation of heart failure was confirmed in 482 patients. Dyspnea was the most common symptom (92.5% of patients), and 20.3% of patients waited until they were severely dyspneic before seeking treatment. The most common precipitating factor was poor medication adherence. Delay times from symptom awareness to seeking treatment were shorter in patients who had a recent change in medicine for heart failure, renal failure, or poor medication adherence and longer in patients with depressive symptoms and hypertension. CONCLUSIONS: Depressive symptoms, recent change in heart failure medicine, renal failure, poor medication adherence, and hypertension are risk factors for hospitalizations for exacerbation of heart failure. PMID- 27965239 TI - Clonal integration increases relative competitive ability in an invasive aquatic plant. AB - PREMISE OF THE STUDY: Physiological integration between connected ramets is well known to increase performance of clonal plant species. However, no direct evidence appears to exist that integration can increase the ability of clonal species to compete with other species within mixed communities. We tested this hypothesis using two floating, invasive, aquatic species in which fragmentation and thus extent of integration-is likely to vary between habitats and times. METHODS: Individual ramets of Pistia stratiotes and Eichhornia crassipes were grown in monoculture or in mixture, and new stolons bearing new offspring were severed or left intact. After 6 wk, the numbers of offspring and second generation (2 degrees ) offspring produced by each original ramet, or parent, were counted; and the final dry mass of each parent, its stolons, its offspring, and its 2 degrees offspring were measured. KEY RESULTS: Fragmentation decreased the relative competitive ability of Pistia, but not that of Eichhornia. This was mainly because Pistia accumulated ~30% less dry mass of offspring when fragmented and grown with Eichhornia than in other treatments. Offspring of Pistia were smaller than those of Eichhornia in all treatments. CONCLUSIONS: Our results show that clonal integration can increase competitive ability in some clonal species. In this case, integration appeared to enable the small offspring of Pistia to compete more effectively with the large offspring of Eichhornia. Lower rates of fragmentation may select for production of more numerous, smaller vegetative offspring in clonal species. PMID- 27965229 TI - Risk Factors for Bacteremia in Patients With Urinary Catheter-Associated Bacteriuria. AB - BACKGROUND: Catheter-associated bacteriuria is complicated by secondary bacteremia in 0.4% to 4.0% of cases. The directly attributable mortality rate is 12.7%. OBJECTIVE: To identify risk factors for bacteremia associated with catheter-associated bacteriuria. METHODS: Data were acquired from a large electronic clinical and administrative database of consecutive adult inpatient admissions to 2 acute care hospitals during a 7-year period. Data on patients with catheter-associated bacteriuria and bacteremia were compared with data on control patients with catheter-associated bacteriuria and no bacteremia, matched for date of admission plus or minus 30 days. Urine and blood cultures positive for the same pathogen within 7 days were used to define catheter-associated bacteriuria and bacteremia. Multivariable conditional logistic regression was used to determine independent risk factors for bacteremia. RESULTS: The sample consisted of 158 cases and 474 controls. Independent predictors of bacteremia were male sex (odds ratio, 2.76), treatment with immunosuppressants (odds ratio, 1.68), urinary tract procedure (odds ratio, 2.70), and catheter that remained in place after bacteriuria developed (odds ratio, 2.75). Patients with enterococcal bacteriuria were half as likely to become bacteremic as were patients with other urinary pathogens (odds ratio, 0.46). Odds of secondary bacteremia increased 2% per additional day of hospital stay (95% CI, 1.01-1.04) and decreased 1% with each additional year of age (95% CI, 0.97-0.99). CONCLUSIONS: The results add new information about increased risk for bacteremia among patients with catheters remaining in place after catheter-associated bacteriuria and confirm evidence for previously identified risk factors. PMID- 27965236 TI - Outcomes of Emergency Medical Patients Admitted to an Intermediate Care Unit With Detailed Admission Guidelines. AB - BACKGROUND: An important, but not well characterized, population receiving intermediate care is that of medical patients admitted directly from the emergency department. OBJECTIVE: To characterize emergency medical patients and their outcomes when admitted to an intermediate care unit with clearly defined admission guidelines. METHODS: Demographic data, admitting diagnoses, illness severity, comorbid conditions, lengths of stay, and hospital mortality were characterized for all emergency medical patients admitted directly to an intermediate care unit from July through December 2012. RESULTS: A total of 317 unique patients were admitted (mean age, 54 [SD, 16] years). Most patients were admitted with respiratory (26.5%) or cardiac (17.0%) syndromes. The mean (SD) Acute Physiology and Chronic Health Evaluation score version II, Simplified Acute Physiology Score version II, and Charlson Comorbidity Index were 15.6 (6.5), 20.7 (11.8), and 2.7 (2.3), respectively. Severity of illness and length of stay were significantly different for patients who required intensive care within 24 hours of admission (n = 16) or later (n = 25), patients who continued with inter mediate care for more than 24 hours (n = 247), and patients who were downgraded or discharged in less than 24 hours (n = 29). Overall hospital mortality was 4.4% (14 deaths). CONCLUSIONS: Emergency medical patients with moderate severity of illness and comorbidity can be admitted to an intermediate level of care with relatively infrequent transfer to intensive care and relatively low mortality. PMID- 27965240 TI - Functional trait values, not trait plasticity, drive the invasiveness of Rosa sp. in response to light availability. AB - PREMISE OF THE STUDY: Functional trait plasticity in resource capture traits has been suggested as an underlying mechanism promoting invasive species establishment and spread. Earlier studies on this mechanism treat invasiveness as a discrete characteristic (i.e., invasive vs. noninvasive) and do not consider the potential impacts of evolutionary history. In the present study, we used a continuous measure of invasiveness and a phylogenetic framework to quantify the relationship between functional trait expression, plasticity, and invasiveness in Rosa. METHODS: In a manipulative greenhouse experiment, we evaluated how light availability affects functional traits and their plasticity in Rosa sp. and the out-group species, Potentilla recta, which vary in their invasiveness. KEY RESULTS: Across functional traits, we found no significant relationship between plasticity and invasiveness. However, more invasive roses demonstrated an ability to produce a more branched plant architecture, promoting optimal light capture. Invasiveness also was linked with lower photosynthetic and stomatal conductance rates, leading to increased water-use efficiency (WUE) in more invasive roses. CONCLUSIONS: Our results suggest that functional trait values, rather than plasticity, promote invasive rose success, counter to earlier predictions about the role of plasticity in invasiveness. Furthermore, our study indicates that invasive roses demonstrate key functional traits, such as increased WUE, to promote their success in the high-light, edge habitats they commonly invade. PMID- 27965238 TI - Vertical stratification of the foliar fungal community in the world's tallest trees. AB - PREMISE OF THE STUDY: The aboveground tissues of plants host numerous, ecologically important fungi, yet patterns in the spatial distribution of these fungi remain little known. Forest canopies in particular are vast reservoirs of fungal diversity, but intracrown variation in fungal communities has rarely been explored. Knowledge of how fungi are distributed throughout tree crowns will contribute to our understanding of interactions between fungi and their host trees and is a first step toward investigating drivers of community assembly for plant-associated fungi. Here we describe spatial patterns in fungal diversity within crowns of the world's tallest trees, coast redwoods (Sequoia sempervirens). METHODS: We took a culture-independent approach, using the Illumina MiSeq platform, to characterize the fungal assemblage at multiple heights within the crown across the geographical range of the coast redwood. KEY RESULTS: Within each tree surveyed, we uncovered evidence for vertical stratification in the fungal community; different portions of the tree crown harbored different assemblages of fungi. We also report between-tree variation in the fungal community within redwoods. CONCLUSIONS: Our results suggest the potential for vertical stratification of fungal communities in the crowns of other tall tree species and should prompt future study of the factors giving rise to this stratification. PMID- 27965241 TI - Oh, the places you'll go! Understanding the evolutionary interplay between dispersal and habitat adaptation as a driver of plant distributions. PMID- 27965242 TI - Genome-wide genotyping-by-sequencing data provide a high-resolution view of wild Helianthus diversity, genetic structure, and interspecies gene flow. AB - PREMISE: Wild sunflowers harbor considerable genetic diversity and are a major resource for improvement of the cultivated sunflower, Helianthus annuus. The Helianthus genus is also well known for its propensity for gene flow between taxa. METHODS: We surveyed genomic diversity of 292 samples of wild Helianthus from 22 taxa that are cross-compatible with the cultivar using genotyping by sequencing. With these data, we derived a high-resolution phylogeny of the taxa, interrogated genome-wide levels of diversity, explored H. annuus population structure, and identified localized gene flow between H. annuus and its close relatives. KEY RESULTS: Our phylogenomic analyses confirmed a number of previously established interspecific relationships and indicated for the first time that a newly described annual sunflower, H. winteri, is nested within H. annuus. Principal component analyses showed that H. annuus has geographic population structure with most notable subpopulations occurring in California and Texas. While gene flow was identified between H. annuus and H. bolanderi in California and between H. annuus and H. argophyllus in Texas, this genetic exchange does not appear to drive observed patterns of H. annuus population structure. CONCLUSIONS: Wild H. annuus remains an excellent resource for cultivated sunflower breeding effort because of its diversity and the ease with which it can be crossed with cultivated H. annuus. Cases of interspecific gene flow such as those documented here also indicate wild H. annuus can act as a bridge to capture alleles from other wild taxa; continued breeding efforts with it may therefore reap the largest rewards. PMID- 27965244 TI - NHS approach to investigating patient deaths is poor, says regulator. PMID- 27965243 TI - Biotic and abiotic factors associated with altitudinal variation in plant traits and herbivory in a dominant oak species. AB - PREMISE OF THE STUDY: It is generally thought that herbivore pressure is higher at lower elevations where climate is warmer and less seasonal, and that this has led to higher levels of plant defense investment at low elevations. However, the generality of this expectation has been called into question by recent studies. METHODS: We tested for altitudinal gradients in insect leaf damage, plant defenses (phenolic compounds), and nutritional traits (phosphorus and nitrogen) in leaves of the long-lived tree Quercus robur, and further investigated the abiotic factors associated with such gradients. We sampled 20 populations of Q. robur distributed along an altitudinal gradient spanning 35-869 m above sea level, which covered most of the altitudinal range of this species and varied substantially in abiotic conditions, plant traits, and herbivory. KEY RESULTS: Univariate regressions showed that leaf herbivory, phenolics, and phosphorus increased toward higher elevations, whereas leaf nitrogen did not vary with altitude. Multiple regression analyses indicated that temperature was the single most important factor associated with herbivory and appears to be strongly associated with altitudinal variation in damage. Leaf phenolics were also correlated with herbivory, but in a manner that suggests these chemical defenses do not underlie altitudinal variation in damage. In addition, we found that variation in leaf traits (phenolics and nutrients) was in turn associated with both climatic and soil variables. CONCLUSIONS: Overall, these findings suggest that altitudinal gradients in herbivory and defenses in Q. robur are uncoupled and that elevational variation in herbivory and plant traits responds mainly to abiotic factors. PMID- 27965245 TI - Colette Denise Gina Le Doux. PMID- 27965246 TI - Association of sleep duration with rheumatoid arthritis in Korean adults: analysis of seven years of aggregated data from the Korea National Health and Nutrition Examination Survey (KNHANES). AB - OBJECTIVES: To investigate the association between rheumatoid arthritis (RA) and self-reported sleep duration. SETTING: The present study analysed 7 years of aggregated cross-sectional data (2007-2013) from the Korea National Health and Nutrition Examination Surveys (KNHANES). PARTICIPANTS: A total of 37 979 individuals were selected for the analyses. INTERVENTIONS: RA. PRIMARY AND SECONDARY OUTCOME MEASURES: Sleep duration. RESULTS: After adjusting for confounding factors, the odds of short-duration sleepers (<=6 hours/day) and long duration sleepers (>=9 hours/day) for RA were 1.23-fold (95% CI 1.101 to 1.51) and 1.27-fold (95% CI 0.85 to 1.88) higher, respectively, than those for persons with sleep duration of 7-8 hours/day. A subgroup analysis according to the extent of pain in RA revealed that the strong relationship between RA and sleep disturbances was observed in those with high pain from RA (OR: 1.28 CI 1.04 to 1.58). CONCLUSIONS: Individuals with RA may be at a higher risk for sleep disturbances compared with individuals without RA. Therefore, the provision of comprehensive care for patients with RA by healthcare professionals should include assessments of sleep duration and patients with RA should be encouraged to report sleep problems. PMID- 27965247 TI - Can commonly prescribed drugs be repurposed for the prevention or treatment of Alzheimer's and other neurodegenerative diseases? Protocol for an observational cohort study in the UK Clinical Practice Research Datalink. AB - INTRODUCTION: Current treatments for Alzheimer's and other neurodegenerative diseases have only limited effectiveness meaning that there is an urgent need for new medications that could influence disease incidence and progression. We will investigate the potential of a selection of commonly prescribed drugs, as a more efficient and cost-effective method of identifying new drugs for the prevention or treatment of Alzheimer's disease, non-Alzheimer's disease dementias, Parkinson's disease and amyotrophic lateral sclerosis. Our research will focus on drugs used for the treatment of hypertension, hypercholesterolaemia and type 2 diabetes, all of which have previously been identified as potentially cerebroprotective and have variable levels of preclinical evidence that suggest they may have beneficial effects for various aspects of dementia pathology. METHODS AND ANALYSIS: We will conduct a hypothesis testing observational cohort study using data from the Clinical Practice Research Datalink (CPRD). Our analysis will consider four statistical methods, which have different approaches for modelling confounding. These are multivariable adjusted Cox regression; propensity matched regression; instrumental variable analysis and marginal structural models. We will also use an intention-to-treat analysis, whereby we will define all exposures based on the first prescription observed in the database so that the target parameter is comparable to that estimated by a randomised controlled trial. ETHICS AND DISSEMINATION: This protocol has been approved by the CPRD's Independent Scientific Advisory Committee (ISAC). We will publish the results of the study as open-access peer-reviewed publications and disseminate findings through national and international conferences as are appropriate. PMID- 27965249 TI - Prevalence of type 2 diabetes mellitus in women of childbearing age in Africa during 2000-2016: protocol of a systematic review and meta-analysis. AB - INTRODUCTION: African women of childbearing age are increasingly being exposed to risk factors for type 2 diabetes mellitus (T2DM), most particularly obesity. A differentiating feature of diabetes in women of childbearing age is that the disease may affect the mother and the developing fetus. Apart from mapping the extent of the problem, understanding the prevalence of T2DM in African women of childbearing age can help to galvanise targeted interventions for reducing the burden of T2DM. This is a protocol for a systematic review aiming to assess the prevalence of and risk factors for T2DM in women of childbearing age (15-49 years) in Africa. METHODS AND ANALYSES: We will carry out a comprehensive literature search among a number of databases, using appropriate adaptations of the African search filter to identify diabetes prevalence studies, published from 2000 to 2016, among African women of childbearing age (15-49 years) according to the WHO definition. Full copies of articles identified through searches and considered to meet the inclusion criteria will be obtained for data extraction and synthesis. The analysis of the primary outcome (prevalent diabetes) will include two steps: (1) identification of data sources and documenting estimates and (2) application of the random-effects meta-analysis model to aggregate prevalence estimates and account for between-study variability in calculating the overall pooled estimates and 95% CI for diabetes prevalence. We will assess heterogeneity and publication bias using established methods. This systematic review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol (PRISMA-P) 2015. ETHICS AND DISSEMINATION: Ethical approval is not required for this study, given that this is a protocol for a systematic review, which utilises published data. The findings of this study will be widely disseminated through peer reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: CRD42015027635. PMID- 27965250 TI - Is frequent attendance of longer duration related to less transient episodes of care? A retrospective analysis of transient and chronic episodes of care. AB - OBJECTIVES: Frequent attenders (FAs) suffer more and consult general practitioners (GPs) more often for chronic physical and psychiatric illnesses, social difficulties and distress than non-FAs. However, it is unclear to what extent FAs present transient episodes of care (TECs) compared with non-FAs. DESIGN: Retrospective analysis of all episodes of care (ECs) in 15 116 consultations in 1 year. Reasons for encounter (RFEs) linked to patients' problem lists were defined as chronic ECs (CECs), other episodes as TECs. SETTING: 1 Dutch urban primary healthcare centre served by 5 GPs. PARTICIPANTS: All 5712 adult patients were enlisted between 2007 and 2009. FAs were patients whose attendance rate ranked within the top decile of their sex and age group in at least one of the years between 2007 and 2009. OUTCOME MEASURES: Number of RFEs linked to TECs/CECs for non-FAs and 1-year (1yFAs), 2-year (2yFAs) and 3-year FAs (3yFAs), and the adjusted effect of frequent attendance of different duration on the number of TECs. RESULTS: The average number of RFEs linked to TECs (non-FAs 1.4; 3yFAs 7.3) and to CECs (non-FAs 0.9; 3yFAs 6.2) increased substantially with the duration of frequent attendance. The ratio of TECs to all ECs differed little for FAs (52-54%) and non-FAs (64%). Compared with non-FAs, the adjusted additional number of TECs was 3.4 (95% CI 3.2 to 3.7, 1yFAs), 6.6 (95% CI 6.1 to 7.0, 2yFAs) and 9.4 (95% CI 8.8 to 10.1, 3yFAs). CONCLUSIONS: FAs present more TECs and CECs with longer duration of frequent attendance. The constant ratio of TECs might be a sign of a low threshold for FAs to consult their GP. The large numbers of TECs in FAs might be associated with their high level of anxiety and low mastery. The consultation pattern of FAs may best be characterised by describing both TECs and CECs. PMID- 27965248 TI - Gender disparities in red blood cell transfusion in elective surgery: a post hoc multicentre cohort study. AB - OBJECTIVES: A post hoc gender comparison of transfusion-related modifiable risk factors among patients undergoing elective surgery. SETTINGS: 23 Austrian centres randomly selected and stratified by region and level of care. PARTICIPANTS: We consecutively enrolled in total 6530 patients (3465 women and 3065 men); 1491 underwent coronary artery bypass graft (CABG) surgery, 2570 primary unilateral total hip replacement (THR) and 2469 primary unilateral total knee replacement (TKR). MAIN OUTCOME MEASURES: Primary outcome measures were the number of allogeneic and autologous red blood cell (RBC) units transfused (postoperative day 5 included) and differences in intraoperative and postoperative transfusion rate between men and women. Secondary outcomes included perioperative blood loss in transfused and non-transfused patients, volume of RBCs transfused, perioperative haemoglobin values and circulating red blood volume on postoperative day 5. RESULTS: In all surgical groups, the transfusion rate was significantly higher in women than in men (CABG 81 vs 49%, THR 46 vs 24% and TKR 37 vs 23%). In transfused patients, the absolute blood loss was higher among men in all surgical categories while the relative blood loss was higher among women in the CABG group (52.8 vs 47.8%) but comparable in orthopaedic surgery. The relative RBC volume transfused was significantly higher among women in all categories (CABG 40.0 vs 22.3; TKR 25.2 vs 20.2; THR 26.4 vs 20.8%). On postoperative day 5, the relative haemoglobin values and the relative circulating RBC volume were higher in women in all surgical categories. CONCLUSIONS: The higher transfusion rate and volume in women when compared with men in elective surgery can be explained by clinicians applying the same absolute transfusion thresholds irrespective of a patient's gender. This, together with the common use of a liberal transfusion strategy, leads to further overtransfusion in women. PMID- 27965251 TI - Women's reasons for participation in a clinical trial for menstrual pain: a qualitative study. AB - OBJECTIVES: The aim of the study was to explore women's motivations for participating in a clinical trial and to evaluate how financial compensation impacts women's explanations for participation. DESIGN, SETTING AND PARTICIPANTS: Semistructured interviews were conducted face to face or by telephone with 25 of 220 women who participated in a pragmatic randomised trial for app-administered self-care acupressure for dysmenorrhoea (AKUD). Of these 25 women, 10 had entered AKUD knowing they would receive a financial compensation of ?30. A purposive sampling strategy was used. RESULTS: Women had a long history of seeking help and were unsatisfied with the options available, namely painkillers and oral contraceptives. While interviewees were open to painkillers, they were uneasy about taking them on a monthly basis. The AKUD trial offered the possibility to find an alternative solution. A second reason for participation was the desire to add a new treatment to routine medical care, for which the interviewees considered randomised trials a prerequisite. The financial incentive was a subsidiary motivation in the interviewees' narratives. CONCLUSIONS: Our results contribute to the ongoing discussion of the impact of financial compensation on research participants' assessment of risk. The interviewed women considered all research participants able to make their own choices regarding trial participation, even in the face of financial compensation or payment of study participants. Furthermore, the importance of clinical trials providing new treatments that could change medical practice might be an overlooked reason for trial participation and could be used in future recruitment strategies. PMID- 27965253 TI - Assessment of a web-based Guided Self-Determination intervention for adults with type 2 diabetes in general practice: a study protocol. AB - INTRODUCTION: Self-management is deemed the cornerstone in overall diabetes management. Web-based self-management interventions have potential to support adults with type 2 diabetes (T2DM) in managing their disease. Owing to somewhat ambiguous results of such interventions, interventions should be theory-based and incorporate well-defined counselling methods and techniques for behavioural change. This study is designed to assess the effectiveness of a theory-driven web based Guided Self-Determination (GSD) intervention among adults with T2DM in general practice to improve diabetes self-management behaviours and glycosylated haemoglobin (HbA1c). METHODS AND ANALYSIS: A complex intervention design based on the framework of the UK Medical Research Council is employed as a guide for developing the intervention, assessing its feasibility and evaluating its effectiveness. The study consists of three phases: (1) the modelling phase adapting the original GSD programme for adults with T2DM, using a qualitative design, (2) feasibility assessment of the adapted intervention on the web, employing qualitative and quantitative methods and (3) evaluating the effectiveness of the intervention on diabetes self-management behaviours and HbA1c, using a quasi-experimental design. The first phase, which is completed, and the second phase, which is underway, will provide important information about the development of the intervention and its acceptability, whereas the third phase will assess the effectiveness of this systematically developed intervention. ETHICS AND DISSEMINATION: The Norwegian Regional Committee for Medical and Health Research Ethics (REK west number 2015/60) has approved the study design. Patients recruited in the different phases will fill out an informed consent form prior to inclusion and will be guaranteed anonymity and the right to withdraw from the study at any time. The results of the study will be published in peer-reviewed journals, electronically and in print, and presented at research conferences. TRIAL REGISTRATION NUMBER: NCT02575599. PMID- 27965252 TI - Changes in the prevalence of breast feeding in preterm infants discharged from neonatal units: a register study over 10 years. AB - OBJECTIVE: There are indications that the prevalence of exclusively breastfed preterm infants is decreasing in Sweden. The objective was to investigate trends in exclusive breast feeding at discharge from Swedish neonatal units and associated factors in preterm infants. DESIGN, SETTING AND PARTICIPANTS: This is a register study with data from the Swedish Neonatal Quality Register. Data from 29 445 preterm infants (gestational age (GA) <37 weeks) who were born during the period 2004-2013 were retrieved. Data included maternal, perinatal and neonatal characteristics. Data were analysed for the whole population as well as for 3 GA groups. RESULTS: From 2004 to 2013, the prevalence of exclusive breast feeding decreased, in extremely preterm (GA 22-27 weeks) from 55% to 16%, in very preterm (GA 28-31 weeks) from 41% to 34% and in moderately preterm infants (GA 32-36 weeks) from 64% to 49%. The decline was statistically significant (p<0.001) in all 3 GA groups. This decline remained significant when adjustments were made for factors negatively associated with exclusive breast feeding and which became more prevalent during the study period, that is, small for GA (all groups) and maternal mental illness (very preterm and moderately preterm infants). CONCLUSIONS: In the past 10 years, Sweden has experienced a lower rate of exclusive breast feeding in preterm infants, especially in extremely preterm infants. The factors analysed in this study explain only a small proportion of this decline. The decline in exclusive breast feeding at discharge from neonatal units raises concern and present challenges to the units to support and promote breast feeding. PMID- 27965254 TI - Retrospective cohort study of usage patterns of epidural injections for spinal pain in the US fee-for-service Medicare population from 2000 to 2014. AB - OBJECTIVE: To assess the usage patterns of epidural injections for chronic spinal pain in the fee-for-service (FFS) Medicare population from 2000 to 2014 in the USA. DESIGN: A retrospective cohort. METHODS: The descriptive analysis of the administrative database from Centers for Medicare and Medicaid Services (CMS) Physician/Supplier Procedure Summary (PSPS) master data from 2000 to 2014 was performed. The guidance from Strengthening the Reporting of Observational studies in Epidemiology (STROBE) was applied. Analysis included multiple variables based on the procedures, specialties and geography. RESULTS: Overall epidural injections increased 99% per 100 000 Medicare beneficiaries with an annual increase of 5% from 2000 to 2014. Lumbar interlaminar and caudal epidural injections constituted 36.2% of all epidural injections, with an overall decrease of 2% and an annual decrease of 0.2% per 100 000 Medicare beneficiaries. However, lumbosacral transforaminal epidural injections increased 609% with an annual increase of 15% from 2000 to 2014 per 100 000 Medicare population. CONCLUSIONS: Usage of epidural injections increased from 2000 to 2014, with a decline thereafter. However, an escalating growth has been seen for lumbosacral transforaminal epidural injections despite numerous reports of complications and regulations to curb the usage of transforaminal epidural injections. PMID- 27965255 TI - Psychometric evaluation of the Holden Communication Scale (HCS) for persons with dementia. AB - OBJECTIVE: To investigate the psychometric properties of the Holden Communication Scale (HCS) and the association between scores on HCS and cognitive function among persons with dementia. METHOD: Internal consistency was assessed by the Cronbach's alpha coefficient and inter-item correlations. Test-retest was carried out to test the instrument's stability. An exploratory factor analysis with the principal components extraction method and oblimin rotation was performed to evaluate construct validity. Pearson's correlation coefficients were calculated to explore associations between the scores on the HCS and cognitive function. RESULTS: A total of 128 persons with moderate-to-severe cognitive impairment (mean Mini-Mental State Examination (MMSE) score 8.9 (SD 7.0)) participated. The mean age was 85.2 (SD 7.2) and 101 of the participants were women. The Cronbach's alpha of the HCS was 0.94 and test-retest reliability was r=0.71. The corrected item-total correlation ranged from 0.63 to 0.79 and factor analysis showed a 1 factor structure of the HCS, which explained 63% of the variance. However, a forced 3-factor structure explained 76% of the variance. The correlation between cognitive function as measured by the MMSE and ability to communicate as measured with HCS was found to be moderate for those with an MMSE score of 0-10 (-0.61) and low for persons with an MMSE score of 11-20 (-0.06). CONCLUSIONS: The HCS is a reliable and valid scale for assessing communication ability in persons with moderate and severe cognitive impairment, and might have a 1-factor or 3-factor structure. PMID- 27965256 TI - Traditional Chinese acupuncture versus minimal acupuncture for mild-to-moderate knee osteoarthritis: a protocol for a randomised, controlled pilot trial. AB - INTRODUCTION: Knee osteoarthritis (KOA) is one of the most common musculoskeletal disorders. Acupuncture is a popular form of complementary medicine for musculoskeletal conditions, although the evidence is inconclusive. Our objective is to evaluate the efficacy of traditional Chinese acupuncture for pain relief and function improvement in mild-to-moderate knee osteoarthritis (TCAKOA) participants. METHODS/ANALYSIS: 42 patients will be recruited who have been diagnosed with mild-to-moderate KOA and randomly allocated in equal proportions to traditional Chinese acupuncture or minimal acupuncture. They will receive acupuncture for 24 sessions over 8 weeks. The primary end point is success rate, which will be calculated according to a change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index pain and function scores at 8 weeks. Secondary end points include pain and function measurement, global change, the quality of life and the use of non-steroidal anti-inflammatory drugs (Celebrex, Pfizer) at 8, 16 and 26 weeks. ETHICS AND DISSEMINATION: Ethical approval of this study has been granted by the Research Ethical Committee of Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University (permission number: 2016BL-010-02). Written informed consent will be obtained from all participants. Outcomes of the trial will be disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN14016893; Pre-results. PMID- 27965257 TI - Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study. AB - OBJECTIVE: To evaluate the effect of secukinumab, an interleukin-17A inhibitor, on clinical signs and symptoms and radiographic changes through 2 years in patients with ankylosing spondylitis (AS). METHODS: In the phase III MEASURE 1 study, patients were randomised to receive intravenous secukinumab 10 mg/kg (at baseline, week 2 and week 4) followed by subcutaneous secukinumab 150 mg (intravenous 150 mg; n=125) or 75 mg (intravenous 75 mg; n=124) every four weeks, or matched placebo (n=122). Placebo-treated patients were re-randomised to subcutaneous secukinumab 150 or 75 mg from week 16. Clinical efficacy assessments included Assessment of SpondyloArthritis international Society 20 (ASAS20) response rates through week 104. Radiographic changes at week 104 were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). RESULTS: 97 (77.6%) and 103 (83.1%) patients in the intravenous 150 mg and intravenous 75 mg groups, respectively, completed week 104. In the full analysis set (intent-to treat), ASAS20 response rates at week 104 were 73.7% and 68.0% in the intravenous 150 mg and intravenous 75 mg groups, respectively. Among patients with evaluable X-rays who were originally randomised to secukinumab (n=168), mean change in mSASSS from baseline to week 104 was 0.30+/-2.53. Serious adverse events were reported in 12.2% and 13.4% of patients in the 150 mg and 75 mg groups, respectively. CONCLUSIONS: Secukinumab improved AS signs and symptoms through 2 years of therapy, with no unexpected safety findings. Data from this study suggest a low mean progression of spinal radiographic changes, which will need to be confirmed in longer-term controlled studies. TRIAL REGISTRATION NUMBER: NCT01358175. PMID- 27965258 TI - A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis). AB - OBJECTIVES: Inflammasomes are multiprotein complexes that sense pathogens and trigger biological mechanisms to control infection. Nucleotide-binding oligomerisation domain-like receptor (NLR) containing a PYRIN domain 1 (NLRP1), NLRP3 and NLRC4 plays a key role in this innate immune system by directly assembling in inflammasomes and regulating inflammation. Mutations in NLRP3 and NLRC4 are linked to hereditary autoinflammatory diseases, whereas polymorphisms in NLRP1 are associated with autoimmune disorders such as vitiligo and rheumatoid arthritis. Whether human NLRP1 mutation is associated with autoinflammation remains to be determined. METHODS: To search for novel genes involved in systemic juvenile idiopathic arthritis, we performed homozygosity mapping and exome sequencing to identify causative genes. Immunoassays were performed with blood samples from patients. RESULTS: We identified a novel disease in three patients from two unrelated families presenting diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Molecular screening revealed a non-synonymous homozygous mutation in NLRP1 (c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin. The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome. CONCLUSIONS: We demonstrate the responsibility of human NLRP1 in a novel autoinflammatory disorder that we propose to call NAIAD for NLRP1-associated autoinflammation with arthritis and dyskeratosis. This disease could be a novel autoimmuno-inflammatory disease combining autoinflammatory and autoimmune features. Our data, combined with that in the literature, highlight the pleomorphic role of NLRP1 in inflammation and immunity. TRIAL REGISTRATION NUMBER: NCT02067962; Results. PMID- 27965261 TI - Very early endothelial cell loss after penetrating keratoplasty with organ cultured corneas. AB - AIMS: After keratoplasty, postoperative endothelial cell loss is calculated between the eye bank endothelial cell density (ebECD) and the postoperative specular microscopy (SM). To elucidate the very early cell loss, always described after penetrating keratoplasty (PK), we designed two complementary studies. METHODS: (1) Clinical prospective study of 90 consecutive PKs (keratoconus, Fuchs' corneal dystrophy, lattice dystrophy, bullous keratopathy) with organ cultured corneas and postoperative follow-up by SM at day 5 (D5), D15, month 1 (M1) and M3. This series provided a quantification of the difference between ebECD performed 2 days before graft and very early postoperative ECD. (2) Ten pairs of corneas with comparable ebECD in both corneas and same organ-culture (OC) duration were randomised: one cornea was grafted, and, at the same time, the viable ECD (vECD) of the other was measured after labelling with Hoechst/ethidium/calcein-AM. The relationship between vECD and very early postoperative ECD was studied. RESULTS: vECD at the time of graft did not differ from ECD 5 days after PK, with a difference of 39 (-356; 355) cells/mm2 (median (10 degrees ; 90 degrees percentile, p=0.799)), whereas a significant difference of 755 (359; 1146) cells/mm2, corresponding to 28% (95% CI 26 to 30) of cells, was measured between ebECD and ECD 5 days after PK (p<0.001). CONCLUSIONS: In OC, ebECD provided to surgeons significantly overestimate the number of viable ECs grafted to patients. The absence of difference between the vECD at D0 and ECD at D5 indicates that the very early endothelial cell loss is almost negligible in recipients. PMID- 27965260 TI - CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis. AB - OBJECTIVES: While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/CCR5 chemokine axes in OA pathogenesis. METHODS: Ccl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains. RESULTS: Mice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA. CONCLUSIONS: Our findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA. PMID- 27965264 TI - Surge in Philanthropy Fuels Cancer Research. AB - Philanthropy could lead to faster cures by funding riskier research-projects more likely to fail but with potentially high impact-and promoting better teamwork among researchers. However, researchers and fundraisers say that it should augment, not replace, government funding. PMID- 27965263 TI - Primary intravenous chemotherapy for group D retinoblastoma: a 13-year retrospective analysis. AB - BACKGROUND: Eye salvage rate for group D retinoblastoma using intravenous chemotherapy (IVC) as a primary modality is <50%. To report on 13 years' experience with the use of primary IVC for group D retinoblastoma. METHODS: A retrospective analysis of 64 group D eyes (52 patients) treated with primary IVC, from 2002 to 2014. RESULTS: The median age at presentation was 11.0 months (mean: 18.6, range: 0.6-144.0), 35 (67%) patients had bilateral disease, 38 (73%) germline disease and 8 (15%) cases were familial. In addition to IVC, patients received a median number of three treatments (mean: 6, range: 0-24), including thermotherapy/cryotherapy, plaque radiotherapy, intra-ophthalmic artery chemotherapy (IAC) and/or intravitreous chemotherapy. External beam radiotherapy (EBRT) was used in five eyes, all of which were eventually enucleated. In a median follow-up time of 55 months (mean: 64, range: 14-156), 63% of eyes were salvaged. By the Kaplan-Meier survival analysis, globe salvage rate was 83%, 70%, 59% and 45% at 1, 3, 5 and 10 years, respectively. There were no cases of metastatic spread from intraocular retinoblastoma and no deaths. IVC-related adverse events included febrile neutropenia in 21 (40%) patients and anaphylactic reaction to carboplatin in 2 (4%), all conservatively resolved. Of the patients receiving IAC, third and sixth nerve palsies were documented in two (10%) and one (5%) eyes, respectively. CONCLUSIONS: Primary IVC for group D eyes, with adjuvant treatments as required, was found to be a safe and efficient approach, achieving 63% eye salvage rate, no metastatic spread from intraocular retinoblastoma and no deaths. IAC has now replaced EBRT as a successful salvage treatment. PMID- 27965262 TI - The United Kingdom Diabetic Retinopathy Electronic Medical Record Users Group, Report 1: baseline characteristics and visual acuity outcomes in eyes treated with intravitreal injections of ranibizumab for diabetic macular oedema. AB - AIMS: To describe baseline characteristics and visual outcome for eyes treated with ranibizumab for diabetic macular oedema (DMO) from a multicentre database. METHODS: Structured clinical data were anonymised and extracted from an electronic medical record from 19 participating UK centres: age at first injection, ETDRS visual acuity (VA), number of injections, ETDRS diabetic retinopathy (DR) and maculopathy grade at baseline and visits. The main outcomes were change in mean VA from baseline, number of injections and clinic visits and characteristics affecting VA change and DR grade. RESULTS: Data from 12 989 clinic visits was collated from baseline and follow-up for 3103 eyes. Mean age at first treatment was 66 years. Mean VA (letters) for eyes followed at least 2 years was 51.1 (SD=19.3) at baseline, 54.2 (SD: 18.6) and 52.5 (SD: 19.4) at 1 and 2 years, respectively. Mean visual gain was five letters. The proportion of eyes with VA of 72 letters or better was 25% (baseline) and 33% (1 year) for treatment naive eyes. Eyes followed for at least 6 months received a mean of 3.3 injections over a mean of 6.9 outpatient visits in 1 year. CONCLUSIONS: In a large cohort of eyes with DMO treated with ranibizumab injections in the UK, 33% of patients achieved better than or equal to 6/12 in the treated eye at 12 months compared with 25% at baseline. The mean visual gain was five letters. Eyes with excellent VA at baseline maintain good vision at 18 months. PMID- 27965259 TI - Standardisation of labial salivary gland histopathology in clinical trials in primary Sjogren's syndrome. AB - Labial salivary gland (LSG) biopsy is used in the classification of primary Sjogren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0-10 scale) and comments. Criteria for agreement were a mean score >=6/10 and 75% of respondents scoring >=6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus. PMID- 27965265 TI - New Ways of Approaching Indoor Residual Spraying for Malaria. PMID- 27965266 TI - Indoor Residual Spraying Delivery Models to Prevent Malaria: Comparison of Community- and District-Based Approaches in Ethiopia. AB - BACKGROUND: Indoor residual spraying (IRS) for malaria prevention has traditionally been implemented in Ethiopia by the district health office with technical and operational inputs from regional, zonal, and central health offices. The United States President's Malaria Initiative (PMI) in collaboration with the Government of Ethiopia tested the effectiveness and efficiency of integrating IRS into the government-funded community-based rural health services program. METHODS: Between 2012 and 2014, PMI conducted a mixed-methods study in 11 districts of Oromia region to compare district-based IRS (DB IRS) and community-based IRS (CB IRS) models. In the DB IRS model, each district included 2 centrally located operational sites where spray teams camped during the IRS campaign and from which they traveled to the villages to conduct spraying. In the CB IRS model, spray team members were hired from the communities in which they operated, thus eliminating the need for transport and camping facilities. The study team evaluated spray coverage, the quality of spraying, compliance with environmental and safety standards, and cost and performance efficiency. RESULTS: The average number of eligible structures found and sprayed in the CB IRS districts increased by 19.6% and 20.3%, respectively, between 2012 (before CB IRS) and 2013 (during CB IRS). Between 2013 and 2014, the numbers increased by about 14%. In contrast, in the DB IRS districts the number of eligible structures found increased by only 8.1% between 2012 and 2013 and by 0.4% between 2013 and 2014. The quality of CB IRS operations was good and comparable to that in the DB IRS model, according to wall bioassay tests. Some compliance issues in the first year of CB IRS implementation were corrected in the second year, bringing compliance up to the level of the DB IRS model. The CB IRS model had, on average, higher amortized costs per district than the DB IRS model but lower unit costs per structure sprayed and per person protected because the community-based model found and sprayed more structures. CONCLUSION: Established community-based service delivery systems can be adapted to include a seasonal IRS campaign alongside the community-based health workers' routine activities to improve performance efficiency. Further modifications of the community-based IRS model may reduce the total cost of the intervention and increase its financial sustainability. PMID- 27965267 TI - Evidence-based medicine: a persisting desire under fire. AB - Healthcare infrastructure and medical schools in Syria have been greatly compromised by military conflict and humanitarian disaster. Medical students and healthcare professionals reached out for remote learning opportunities. Surprisingly, they desired a curriculum in evidence-based medicine. We report on a curriculum that was delivered to 126 learners using an online remote delivery platform. This experience demonstrates the feasibility of this approach in disaster-stricken areas and underscores the importance of evidence-based medicine even under such conditions. PMID- 27965268 TI - In critically ill patients with acute kidney injury stage 2, early initiation of renal replacement therapy is associated with reduced 90-day mortality compared to delayed initiation. PMID- 27965269 TI - Safety and efficacy of the subdermal etonogestrel contraceptive implant Implanon(r). PMID- 27965270 TI - Immune checkpoint blockade can synergize with radiation therapy, even in tumors resistant to checkpoint monotherapy. PMID- 27965272 TI - Batoid locomotion: effects of speed on pectoral fin deformation in the little skate, Leucoraja erinacea. AB - Most batoids have a unique swimming mode in which thrust is generated by either oscillating or undulating expanded pectoral fins that form a disc. Only one previous study of the freshwater stingray has quantified three-dimensional motions of the wing, and no comparable data are available for marine batoid species that may differ considerably in their mode of locomotion. Here, we investigate three-dimensional kinematics of the pectoral wing of the little skate, Leucoraja erinacea, swimming steadily at two speeds [1 and 2 body lengths (BL) s-1]. We measured the motion of nine points in three dimensions during wing oscillation and determined that there are significant differences in movement amplitude among wing locations, as well as significant differences as speed increases in body angle, wing beat frequency and speed of the traveling wave on the wing. In addition, we analyzed differences in wing curvature with swimming speed. At 1 BL s-1, the pectoral wing is convex in shape during the downstroke along the medio-lateral fin midline, but at 2 BL s-1 the pectoral fin at this location cups into the flow, indicating active curvature control and fin stiffening. Wing kinematics of the little skate differed considerably from previous work on the freshwater stingray, which does not show active cupping of the whole fin on the downstroke. PMID- 27965273 TI - The Significance of Deaf Identity for Psychological Well-Being. PMID- 27965271 TI - Different mechanisms of Na+ uptake and ammonia excretion by the gill and yolk sac epithelium of early life stage rainbow trout. AB - In rainbow trout, the dominant site of Na+ uptake (JNa,in) and ammonia excretion (Jamm) shifts from the skin to the gills over development. Post-hatch (PH; 7 days post-hatch) larvae utilize the yolk sac skin for physiological exchange, whereas by complete yolk sac absorption (CYA; 30 days post-hatch), the gill is the dominant site. At the gills, JNa,in and Jamm occur via loose Na+/NH4+ exchange, but this exchange has not been examined in the skin of larval trout. Based on previous work, we hypothesized that, contrary to the gill model, JNa,in by the yolk sac skin of PH trout occurs independently of Jamm Following a 12 h exposure to high environmental ammonia (HEA; 0.5 mmol l-1 NH4HCO3; 600 umol l-1 Na+; pH 8), Jamm by the gills of CYA trout and the yolk sac skin of PH larvae, which were isolated using divided chambers, increased significantly. However, this was coupled to an increase in JNa,in across the gills only, supporting our hypothesis. Moreover, gene expression of proteins involved in JNa,in [Na+/H+ exchanger-2 (NHE2) and H+-ATPase] increased in response to HEA only in the CYA gills. We further identified expression of the apical Rhesus (Rh) proteins Rhcg2 in putative pavement cells and Rhcg1 (co-localized with apical NHE2 and NHE3b and Na+/K+-ATPase) in putative peanut lectin agglutinin-positive (PNA+) ionocytes in gill sections. Similar Na+/K+-ATPase-positive cells expressing Rhcg1 and NHE3b, but not NHE2, were identified in the yolk sac epithelium. Overall, our findings suggest that the mechanisms of JNa,in and Jamm by the dominant exchange epithelium at two distinct stages of early development are fundamentally different. PMID- 27965275 TI - Gastric Strongyloidiasis: Report of 2 Cases and Brief Review of the Literature. AB - Strongyloides stercoralis is an intestinal nematode with a complicated lifecycle and auto-infection. In healthy individuals, this parasite usually does not cause any symptoms. But in immunocompromised patients, the symptoms vary from abdominal pain and discomfort to sepsis and death.Gastric infection and involvement by this nematode are rare and uncommon. Here we report 2 cases of Strongyloides stercoralis hyperinfection that were discovered in gastric biopsies in 2 immunocompromised patients. A gastric biopsy was taken for each patient and both showed cross sections of adult worms, eggs, and rhabditiform larvae of S. stercoralis embedded within gastric crypts. This short report describes these 2 immunocompromised patients with disseminated infection by S. strecoralis with gastric involvement with emphasis on recognition of the histological findings in gastric biopsies. PMID- 27965274 TI - Rapid Production of Virus Protein Microarray Using Protein Microarray Fabrication through Gene Synthesis (PAGES). AB - The high genetic variability of RNA viruses is a significant factor limiting the discovery of effective biomarkers, the development of vaccines, and characterizations of the immune response during infection. Protein microarrays have been shown to be a powerful method in biomarker discovery and the identification of novel protein-protein interaction networks, suggesting that this technique could also be very useful in studies of infectious RNA viruses. However, to date, the amount of genetic material required to produce protein arrays, as well as the time- and labor-intensive procedures typically needed, have limited their more widespread application. Here, we introduce a method, protein microarray fabrication through gene synthesis (PAGES), for the rapid and efficient construction of protein microarrays particularly for RNA viruses. Using dengue virus as an example, we first identify consensus sequences from 3,604 different strains and then fabricate complete proteomic microarrays that are unique for each consensus sequence. To demonstrate their applicability, we show that these microarrays can differentiate sera from patients infected by dengue virus, related pathogens, or from uninfected patients. We anticipate that the microarray and expression library constructed in this study will find immediate use in further studies of dengue virus and that, more generally, PAGES will become a widely applied method in the clinical characterization of RNA viruses. PMID- 27965278 TI - Regression of advanced neuroendocrine tumors among patients receiving placebo. PMID- 27965277 TI - Treatment of metastatic pancreatic neuroendocrine tumors: relevance of ENETS 2016 guidelines. AB - The choice of first-line treatment for metastatic pancreatic neuroendocrine tumors (mP-NET) is mainly based on prognostic factors. ENETS-2016 guidelines stratified treatment according to 3 groups: Group 1, patients in whom all lesions could be removed; Group 2, patients with Ki67 <10%, low tumor burden, no symptoms and stable disease, for whom a watch-and-wait strategy or somatostatin analogs are proposed; Group 3, symptomatic patients or with Ki67 >10% or significant tumor burden or progressive disease, for whom a systemic chemotherapy is proposed. This retrospective study aimed to determine patient distribution, characteristics and outcome among these 3 groups. Patients with mP-NET diagnosis from 2004 to 2016 were categorized into the three groups. Prognosis was calculated using the Kaplan-Meier method. All treatments were recorded, and consistency with ENETS guidelines was explored. 104 patients were analyzed: 64% synchronous mP-NET, 80% grade 2 tumors and median overall survival (OS) of 104 (95% CI: 65-143) months. There were 15 patients in ENETS Group 1, 16 in Group 2 and 73 in Group 3. Median OS was not reached in Groups 1 and 2 and was 64 months (35-93) in Group 3. High liver tumor volume, high-grade tumor and progressive disease were associated with worse OS in multivariate analysis. The first-line treatment was in accordance with guidelines in 82%. 77% percent of deceased patients received less than 4 lines of treatment. Most patients are in Group 3 and do not receive all available treatments. Thus, trials are warranted to improve first-line chemotherapy. Alternative treatments may be considered for less aggressive disease. PMID- 27965276 TI - Thyroid nodules and cancer management guidelines: comparisons and controversies. AB - Thyroid cancer is an increasingly prevalent malignancy throughout the world. Management guidelines for both thyroid nodules and thyroid cancer have been published and updated by a number of societies internationally. All of these guidelines recognize this increasing incidence, particularly of small papillary thyroid cancers, due in part to improved technology enabling early or even 'over' diagnosis. Recent advances in molecular imaging and molecular methods have been developed to better characterize thyroid nodules, and a number of studies that have clarified risk stratification systems that can be modified over time allow for individualization of diagnosis, initial treatment, and subsequent follow-up strategies. Advances in surgical approaches and new treatments for patients with the most aggressive forms of thyroid cancer have all influenced management guidelines. Despite substantial similarities, there also are important differences between recent guidelines for some of the common clinical scenarios encountered by physicians in clinical practice. In the present manuscript, we will highlight similarities and differences between several of the most recently published guidelines focused on key areas of importance to clinical care and controversy. These are key areas for future research to strengthen the data to support future guideline recommendations. PMID- 27965281 TI - Influence of potassium-competitive acid blocker on the gut microbiome of Helicobacter pylori-negative healthy individuals. PMID- 27965279 TI - Sex differences in prodromal symptoms in acute coronary syndrome in patients aged 55 years or younger. AB - BACKGROUND: Studies suggest that young women are at highest risk for failing to recognise early symptoms of acute coronary syndrome (ACS). OBJECTIVES: To examine sex differences in prodromal symptoms occurring days and weeks prior to the acute presentation of ACS. We also examined health-seeking behaviours and prehospital management in young patients. METHODS: Prospective cross-sectional analysis of 1145 patients (368 women) hospitalised for ACS, aged <=55 years, from the GENdEr and Sex DetermInantS of Cardiovascular Disease: From Bench to Beyond Premature Acute Coronary SYndrome cohort study (January 2009-April 2013). Prodromal symptoms were determined using the McSweeney Acute and Prodromal Myocardial Infarction Symptom questionnaire. Health-seeking behaviour and prehospital care were determined by questionnaires. RESULTS: The median age was 49 years. The prevalence of prodromal symptoms was high and more women reported symptoms than men (85% vs 72%, p<0.0001). Symptoms were similar between sexes and included unusual fatigue, sleep disturbances, anxiety and arm weakness/discomfort. Chest pain was less common in both sexes (24%). Women were more likely to seek care (49% vs 42%, p=0.04). Among those who sought care, women were more likely to use an ambulance for their ACS compared with men (52% vs 39%). Cardiovascular risk reduction therapy use was low (<=40%) in all patients and less than half perceived their care provider suspected a cardiac source. CONCLUSIONS: Prior to ACS, women were more likely to experience prodromal symptoms and seek medical attention than men. Prehospital care was generally similar between sexes but demonstrated underutilisation of risk-reduction therapies in at-risk young adults. PMID- 27965280 TI - Longitudinal systolic strain, cardiac function improvement, and survival following treatment of light-chain (AL) cardiac amyloidosis. AB - Aims: To determine whether echocardiographic longitudinal systolic strain (LS) parameters identify short-term improvement following chemotherapy for light-chain (AL) cardiac amyloidosis (CA). Among patients with CA, standard echocardiographic measures are commonly unchanged at 1 year following successful chemotherapy, despite observed reductions in cardiac biomarkers. Methods and results: We retrospectively identified 61 patients with AL-CA treated with high-dose melphalan or bortezomib-based regimens. Patients were classified by hematologic response at 1 year into two groups: complete response (CR; n = 18, or 30%) or non CR (non-CR; n = 43, or 70%), and followed for 20 months. Serum free light chains (FLC), B-type natriuretic peptide (BNP), troponin I (TnI), and echocardiography including LS, were acquired at baseline and 1 year. Seven patients died (11.5%), all in the non-CR group (P < 0.01). At 1 year, while reductions were observed in BNP (44% CR, 18% non-CR) and FLC (94% CR, 73% non-CR), both P < 0.05 from baseline, there were no differences in wall thickness, EF, or diastolic function in either group. LS improved only in the CR group with notable improvement in apical to basal strain ratio (P < 0.05). Strain improvement and BNP reduction were correlated (R = 0.6, P < 0.01). Baseline global LS < -10.2% was associated with survival and proved superior to BNP and TnI. The addition of global LS to biomarkers identified the patients at highest risk of mortality. Conclusion: These data suggest that LS is a sensitive measure of pre-treatment cardiac functional impairment in AL-CA, can predict survival over and above that of cardiac biomarkers, and detect early cardiac functional improvement following chemotherapy. PMID- 27965282 TI - Thinking out of the Gut: a case of obscure lower GI bleeding. AB - CLINICAL PRESENTATION: A middle-aged man was admitted for episodes of fresh per rectal bleeding, which were not associated with defecation. He was recently investigated for macrocytic anaemia in the outpatient haematology clinic. Examination of the perineum revealed grade 1 internal haemorrhoids with no signs of bleeding.Initial laboratory tests revealed macrocytic anaemia (haemoglobin 10.5 g/dL, normal 12.9-17.0 g/dL; mean corpuscular haemoglobin 95.3 fL, normal 80.0-95.0 fL). Peripheral blood film showing blasts, dysplastic neutrophils, nucleated red blood cells and hypogranular platelets.The patient underwent a sigmoidoscopy and rubber band ligation of the internal haemorrhoids after persistent fresh per-rectal bleeding. The bleeding persisted with the development of hypotension and a significant drop of haemoglobin to 4.8 g/dL requiring blood transfusions and intensive care monitoring. Repeated endoscopy, including intubation of the terminal ileum, revealed uncomplicated right-sided diverticulosis. CT mesenteric angiography performed during an episode of significant bleeding revealed extravasation of contrast in the ileum, but mesenteric angiography was unsuccessful, possibly due to a temporary cessation of bleeding. Bleeding subsequently recurred and in light of the persistent bleeding with no clear source and with a total of 12 units of packed cell transfused, exploratory laparotomy, on-table enteroscopy (figure 1) with small bowel resection was performed. Histopathological examination of the specimen was performed (figures 2 4).gutjnl;66/12/2068/GUTJNL2016313252F1F1GUTJNL2016313252F1Figure 1Multiple ileal lesions with stigmata of recent bleed.gutjnl;66/12/2068/GUTJNL2016313252F2F2GUTJNL2016313252F2Figure 2Area of ulceration associated with atypical mononuclear infiltrate.gutjnl;66/12/2068/GUTJNL2016313252F3F3GUTJNL2016313252F3Figure 3Atypical mononuclear infiltrate composed of cells with enlarged, irregular nuclei containing variably prominent nucleoli.gutjnl;66/12/2068/GUTJNL2016313252F4F4GUTJNL2016313252F4Figure 4Atypical cells displayed cytoplasmic expression of myeloperoxidase. QUESTION: What is the diagnosis? PMID- 27965284 TI - Development of a Microscopic Colitis Disease Activity Index: a prospective cohort study. AB - OBJECTIVE: Microscopic colitis (MC) is a common cause of chronic diarrhoea, often with additional symptoms. No validated instruments exist to assess disease activity in MC, making it difficult to compare efficacy of treatments between clinical trials. We aimed to identify clinical features that independently predicted disease severity and create a Microscopic Colitis Disease Activity Index (MCDAI). DESIGN: Patients with MC were prospectively administered a survey assessing their GI symptoms and the IBD Questionnaire (IBDQ). A single investigator also scored a physician global assessment (PGA) of disease severity on a 10-point scale. Multiple linear regression identified which symptoms best predicted the PGA. These symptoms were then combined in a weighted formula to create the MCDAI. The relationship between MCDAI and the IBDQ was investigated. RESULTS: Of the 175 patients enrolled, 13 (7.4%) did not complete the survey. The remaining 162 had a median age of 66 years (range, 57-73) and 74% were female. Several clinical features were independently associated with PGA (number of unformed stools daily, presence of nocturnal stools, abdominal pain, weight loss, faecal urgency and faecal incontinence). These parameters were combined to create the MCDAI, which strongly predicted the PGA (R2=0.80). A 1-unit decrease in disease activity (DeltaMCDAI) was associated with a 9-unit increase in quality of life (DeltaIBDQ). CONCLUSIONS: The MCDAI strongly predicted the PGA and correlated with a validated measure of quality of life. Several symptoms in addition to diarrhoea are associated with disease severity in MC. PMID- 27965283 TI - ZEB1-induced tumourigenesis requires senescence inhibition via activation of DKK1/mutant p53/Mdm2/CtBP and repression of macroH2A1. AB - OBJECTIVE: Understand the role of ZEB1 in the tumour initiation and progression beyond inducing an epithelial-to-mesenchymal transition. DESIGN: Expression of the transcription factor ZEB1 associates with a worse prognosis in most cancers, including colorectal carcinomas (CRCs). The study uses survival analysis, in vivo mouse transgenic and xenograft models, gene expression arrays, immunostaining and gene and protein regulation assays. RESULTS: The poorer survival determined by ZEB1 in CRCs depended on simultaneous high levels of the Wnt antagonist DKK1, whose expression was transcriptionally activated by ZEB1. In cancer cells with mutant TP53, ZEB1 blocked the formation of senescence-associated heterochromatin foci at the onset of senescence by triggering a new regulatory cascade that involves the subsequent activation of DKK1, mutant p53, Mdm2 and CtBP to ultimately repress macroH2A1 (H2AFY). In a transgenic mouse model of colon cancer, partial downregulation of Zeb1 was sufficient to induce H2afy and to trigger in vivo tumour senescence, thus resulting in reduced tumour load and improved survival. The capacity of ZEB1 to induce tumourigenesis in a xenograft mouse model requires the repression of H2AFY by ZEB1. Lastly, the worst survival effect of ZEB1 in patients with CRC ultimately depends on low expression of H2AFY and of senescence-associated genes. CONCLUSIONS: The tumourigenic capacity of ZEB1 depends on its inhibition of cancer cell senescence through the activation of a herein identified new molecular pathway. These results set ZEB1 as a potential target in therapeutic strategies aimed at inducing senescence. PMID- 27965285 TI - Impact of Computed Tomography Perfusion Imaging on the Response to Tenecteplase in Ischemic Stroke: Analysis of 2 Randomized Controlled Trials. AB - BACKGROUND: We pooled 2 clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke, 1 that demonstrated superiority of tenecteplase and the other that showed no difference between the treatments in patient clinical outcomes. We tested the hypotheses that reperfusion therapy with tenecteplase would be superior to alteplase in improving functional outcomes in the group of patients with target mismatch as identified with advanced imaging. METHODS: We investigated whether tenecteplase-treated patients had a different 24 hour reduction in the National Institutes of Health Stroke Scale and a favorable odds ratio of a modified Rankin scale score of 0 to 1 versus 2 to 6 compared with alteplase-treated patients using linear regression to generate odds ratios. Imaging outcomes included rates of vessel recanalization and infarct growth at 24 hours and occurrence of large parenchymal hematoma. Baseline computed tomography perfusion was analyzed to assess whether patients met the target mismatch criteria (absolute mismatch volume >15 mL, mismatch ratio >1.8, baseline ischemic core <70 mL, and volume of severely hypoperfused tissue <100 mL). Patients meeting target mismatch criteria were analyzed as a subgroup to identify whether they had different treatment responses from the pooled group. RESULTS: Of 146 pooled patients, 71 received alteplase and 75 received tenecteplase. Tenecteplase treated patients had greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 7; alteplase, 2; P=0.018) and less parenchymal hematoma (2 of 75 versus 10 of 71; P=0.02). The pooled group did not show improved patient outcomes when treated with tenecteplase (modified Rankin scale score 0-1: odds ratio, 1.77; 95% confidence interval, 0.89-3.51; P=0.102) compared with alteplase therapy. However, in patients with target mismatch (33 tenecteplase, 35 alteplase), treatment with tenecteplase was associated with greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 6; alteplase, 1; P<0.001) and better late independent recovery (modified Rankin scale score 0-1: odds ratio, 2.33; 95% confidence interval, 1.13-5.94; P=0.032) than those treated with alteplase. CONCLUSIONS: Tenecteplase may offer an improved efficacy and safety profile compared with alteplase, benefits possibly exaggerated in patients with baseline computed tomography perfusion-defined target mismatch. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01472926. URL: https://www.anzctr.org.au. Unique identifier: ACTRN12608000466347. PMID- 27965286 TI - Identifying and Creating the Next Generation of Community-Based Cancer Prevention Studies: Summary of a National Cancer Institute Think Tank. AB - In late 2015, the NCI Division of Cancer Prevention convened cancer prevention research experts and stakeholders to discuss the current state of cancer prevention research, identify key prevention research priorities for the NCI, and identify studies that could be conducted within the NCI Community Oncology Research Program. Goals included identifying cancer prevention research opportunities offering the highest return on investment, exploring the concept of precision prevention and what is needed to advance this area of research, and identifying possible targets for prevention. Four study populations were considered for cancer prevention research: healthy people, those at increased risk for a specific cancer, people with preneoplastic lesions, and children, adolescents, and young adults. Priorities that emerged include screening (e.g., surveillance intervals, tomosynthesis vs. digital mammography), a pre-cancer genome atlas (PreTCGA), HPV vaccines, immunoprevention of noninfectious origins, and overdiagnosis. Challenges exist, as the priority list is ambitious and potentially expensive. Clinical trials need to be carefully designed to include and maximize prospective tissue collection. Exploring existing cofunding mechanisms will likely be necessary. Finally, relationships with a new generation of physician specialists will need to be cultivated to reach the target populations. Cancer Prev Res; 10(2); 99-107. (c)2016 AACR. PMID- 27965288 TI - Identifying High-Risk Women for Endometrial Cancer Prevention Strategies: Proposal of an Endometrial Cancer Risk Prediction Model. AB - Already the fourth most common cancer in women in the developed world, the incidence of endometrial cancer is increasing rapidly, in line with the increasing prevalence of obesity. Relatively few studies have been undertaken of risk-reducing interventions aimed at limiting the impact of the disease on both individuals and the health service. Those that have been performed have demonstrated only modest results due to their application in relatively unselected populations. A validated risk prediction model is therefore urgently required to identify individuals at particularly high risk of endometrial cancer who may benefit from targeted primary prevention strategies and to guide trial eligibility. On the basis of a systematic review of the literature, the evidence for inclusion of measures of obesity, reproduction, insulin resistance, and genetic risk in such a model is discussed, and the strength of association between these risk factors and endometrial cancer is used to guide the development of a pragmatic risk prediction scoring system that could be implemented in the general population. Provisional cutoff values are described pending refinement of the model and external validation in large prospective cohorts. Potential risk-reducing interventions are suggested, highlighting the need for future studies in this area if the increasing tide of endometrial cancer is to be stemmed. Cancer Prev Res; 10(1); 1-13. (c)2016 AACR. PMID- 27965287 TI - Clinical Challenges Associated with Universal Screening for Lynch Syndrome Associated Endometrial Cancer. AB - Universal testing for Lynch syndrome is now a routine component of the diagnostic work-up of endometrial cancer patients. The purpose of this study was to identify prospectively the barriers to universal screening based on a tissue testing approach [microsatellite instability (MSI) analysis, IHC for DNA mismatch repair proteins, and MLH1 methylation analysis]. Endometrial carcinoma patients (n = 213) prospectively underwent microsatellite instability and IHC testing for expression of DNA mismatch repair (MMR) proteins. Patients with low (MSI-L) or high (MSI-H) levels of tumor MSI or immunohistochemical loss of MLH1 (and absent MLH1 methylation), MSH2, MSH6, or PMS2 were referred to a genetic counselor for consideration of germline testing. Six discordances (3.1% of tested cases) between IHC and MSI were identified. Half of these exhibited heterogeneous immunohistochemical loss of MLH1/PMS2 and were microsatellite stable (MSS). Of the remaining cases, one was MSS with immunohistochemical loss of MSH6, one was MSS with immunohistochemical loss of MLH1/PMS2 and absent MLH1 promoter methylation, and one was MSI-H with intact expression of DNA MMR proteins. Four patients had MSI-L tumors with intact immunohistochemical protein expression; the clinical significance of MSI-L in endometrial cancer is unclear. Eight patients did not have germline mutations despite tissue testing suggesting Lynch syndrome. Including cases with insufficient tissue for testing and patients declining tissue or germline testing, we encountered significant barriers to universal screening in 13.6% of screened patients (29/213) that preclude designation of a tumor as sporadic or hereditary. Cancer Prev Res; 10(2); 108-15. (c)2016 AACR. PMID- 27965290 TI - Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators. AB - Transcription factors (TFs) are key mediators that propagate extracellular and intracellular signals through to changes in gene expression profiles. However, the rules by which promoters decode the amount of active TF into target gene expression are not well understood. To determine the mapping between promoter DNA sequence, TF concentration, and gene expression output, we have conducted in budding yeast a large-scale measurement of the activity of thousands of designed promoters at six different levels of TF. We observe that maximum promoter activity is determined by TF concentration and not by the number of binding sites. Surprisingly, the addition of an activator site often reduces expression. A thermodynamic model that incorporates competition between neighboring binding sites for a local pool of TF molecules explains this behavior and accurately predicts both absolute expression and the amount by which addition of a site increases or reduces expression. Taken together, our findings support a model in which neighboring binding sites interact competitively when TF is limiting but otherwise act additively. PMID- 27965289 TI - Large-scale reduction of the Bacillus subtilis genome: consequences for the transcriptional network, resource allocation, and metabolism. AB - Understanding cellular life requires a comprehensive knowledge of the essential cellular functions, the components involved, and their interactions. Minimized genomes are an important tool to gain this knowledge. We have constructed strains of the model bacterium, Bacillus subtilis, whose genomes have been reduced by ~36%. These strains are fully viable, and their growth rates in complex medium are comparable to those of wild type strains. An in-depth multi-omics analysis of the genome reduced strains revealed how the deletions affect the transcription regulatory network of the cell, translation resource allocation, and metabolism. A comparison of gene counts and resource allocation demonstrates drastic differences in the two parameters, with 50% of the genes using as little as 10% of translation capacity, whereas the 6% essential genes require 57% of the translation resources. Taken together, the results are a valuable resource on gene dispensability in B. subtilis, and they suggest the roads to further genome reduction to approach the final aim of a minimal cell in which all functions are understood. PMID- 27965291 TI - Comparative analyses of super-enhancers reveal conserved elements in vertebrate genomes. AB - Super-enhancers (SEs) are key transcriptional drivers of cellular, developmental, and disease states in mammals, yet the conservational and regulatory features of these enhancer elements in nonmammalian vertebrates are unknown. To define SEs in zebrafish and enable sequence and functional comparisons to mouse and human SEs, we used genome-wide histone H3 lysine 27 acetylation (H3K27ac) occupancy as a primary SE delineator. Our study determined the set of SEs in pluripotent state cells and adult zebrafish tissues and revealed both similarities and differences between zebrafish and mammalian SEs. Although the total number of SEs was proportional to the genome size, the genomic distribution of zebrafish SEs differed from that of the mammalian SEs. Despite the evolutionary distance separating zebrafish and mammals and the low overall SE sequence conservation, ~42% of zebrafish SEs were located in close proximity to orthologs that also were associated with SEs in mouse and human. Compared to their nonassociated counterparts, higher sequence conservation was revealed for those SEs that have maintained orthologous gene associations. Functional dissection of two of these SEs identified conserved sequence elements and tissue-specific expression patterns, while chromatin accessibility analyses predicted transcription factors governing the function of pluripotent state zebrafish SEs. Our zebrafish annotations and comparative studies show the extent of SE usage and their conservation across vertebrates, permitting future gene regulatory studies in several tissues. PMID- 27965293 TI - Reconstructing genetic history of Siberian and Northeastern European populations. AB - Siberia and Northwestern Russia are home to over 40 culturally and linguistically diverse indigenous ethnic groups, yet genetic variation and histories of peoples from this region are largely uncharacterized. We present deep whole-genome sequencing data (~38*) from 28 individuals belonging to 14 distinct indigenous populations from that region. We combined these data sets with additional 32 modern-day and 46 ancient human genomes to reconstruct genetic histories of several indigenous Northern Eurasian populations. We found that Siberian and East Asian populations shared 38% of their ancestry with a 45,000-yr-old Ust'-Ishim individual who was previously believed to have no modern-day descendants. Western Siberians trace 57% of their ancestry to ancient North Eurasians, represented by the 24,000-yr-old Siberian Mal'ta boy MA-1. Eastern Siberian populations formed a distinct sublineage that separated from other East Asian populations ~10,000 yr ago. In addition, we uncovered admixtures between Siberians and Eastern European hunter-gatherers from Samara, Karelia, Hungary, and Sweden (from 8000-6600 yr ago); Yamnaya people (5300-4700 yr ago); and modern-day Northeastern Europeans. Our results provide new insights into genetic histories of Siberian and Northeastern European populations and evidence of ancient gene flow from Siberia into Europe. PMID- 27965294 TI - Cancer Survival Disparities Between First Nation and Non-Aboriginal Adults in Canada: Follow-up of the 1991 Census Mortality Cohort. AB - BACKGROUND: The burden of cancer among indigenous people in Canada has been understudied due to a lack of ethnic identifiers in cancer registries. We compared cancer survival among First Nations to that among non-Aboriginal adults in Canada in the first national study of its kind to date. METHODS: A population based cohort of approximately 2 million respondents to the 1991 Canadian Long Form Census was followed for cancer diagnoses and deaths using probabilistic linkage to cancer and death registries until 2009. Excess mortality rate ratios (EMRR) and 5-year age-standardized relative survival rates were calculated for 15 cancers using age, sex, ethnicity, and calendar-time-specific life tables derived from the cohort at large. RESULTS: First Nations diagnosed with cancers of the colon and rectum, lung and bronchus, breast, prostate, oral cavity and pharynx, cervix, ovary, or with non-Hodgkin lymphoma and leukemia all had significantly poorer 5-year survival than their non-Aboriginal peers. For colorectal cancer, a significant disparity was only present between 2001 and 2009 (EMRR: 1.52; 95% CI, 1.28-1.80). For prostate cancer, a significant disparity was only present between 1992 and 2000 (EMRR: 2.76; 95% CI, 1.81-4.21). Adjusting for income and rurality had little impact on the EMRRs. CONCLUSIONS: Compared with non-Aboriginals, First Nations people had poorer survival for 14 of 15 of the most common cancers, and disparities could not be explained by income and rurality. IMPACT: The results of this study can serve as a benchmark for monitoring progress toward narrowing the gap in survival. Cancer Epidemiol Biomarkers Prev; 26(1); 145-51. (c)2016 AACR. PMID- 27965292 TI - Engineered LINE-1 retrotransposition in nondividing human neurons. AB - Half the human genome is made of transposable elements (TEs), whose ongoing activity continues to impact our genome. LINE-1 (or L1) is an autonomous non-LTR retrotransposon in the human genome, comprising 17% of its genomic mass and containing an average of 80-100 active L1s per average genome that provide a source of inter-individual variation. New LINE-1 insertions are thought to accumulate mostly during human embryogenesis. Surprisingly, the activity of L1s can further impact the somatic human brain genome. However, it is currently unknown whether L1 can retrotranspose in other somatic healthy tissues or if L1 mobilization is restricted to neuronal precursor cells (NPCs) in the human brain. Here, we took advantage of an engineered L1 retrotransposition assay to analyze L1 mobilization rates in human mesenchymal (MSCs) and hematopoietic (HSCs) somatic stem cells. Notably, we have observed that L1 expression and engineered retrotransposition is much lower in both MSCs and HSCs when compared to NPCs. Remarkably, we have further demonstrated for the first time that engineered L1s can retrotranspose efficiently in mature nondividing neuronal cells. Thus, these findings suggest that the degree of somatic mosaicism and the impact of L1 retrotransposition in the human brain is likely much higher than previously thought. PMID- 27965295 TI - DNA Methylation-Derived Neutrophil-to-Lymphocyte Ratio: An Epigenetic Tool to Explore Cancer Inflammation and Outcomes. AB - Background: The peripheral blood neutrophil-to-lymphocyte ratio (NLR) is a cytologic marker of both inflammation and poor outcomes in patients with cancer. DNA methylation is a key element of the epigenetic program defining different leukocyte subtypes and may provide an alternative to cytology in assessing leukocyte profiles. Our aim was to create a bioinformatic tool to estimate NLR using DNA methylation, and to assess its diagnostic and prognostic performance in human populations.Methods: We developed a DNA methylation-derived NLR (mdNLR) index based on normal isolated leukocyte methylation libraries and established cell-mixture deconvolution algorithms. The method was applied to cancer case control studies of the bladder, head and neck, ovary, and breast, as well as publicly available data on cancer-free subjects.Results: Across cancer studies, mdNLR scores were either elevated in cases relative to controls, or associated with increased hazard of death. High mdNLR values (>5) were strong indicators of poor survival. In addition, mdNLR scores were elevated in males, in nonHispanic white versus Hispanic ethnicity, and increased with age. We also observed a significant interaction between cigarette smoking history and mdNLR on cancer survival.Conclusions: These results mean that our current understanding of mature leukocyte methylomes is sufficient to allow researchers and clinicians to apply epigenetically based analyses of NLR in clinical and epidemiologic studies of cancer risk and survival.Impact: As cytologic measurements of NLR are not always possible (i.e., archival blood), mdNLR, which is computed from DNA methylation signatures alone, has the potential to expand the scope of epigenome-wide association studies. Cancer Epidemiol Biomarkers Prev; 26(3); 328-38. (c)2016 AACR. PMID- 27965297 TI - Clinical Impact of Suboptimal Stenting and Residual Intrastent Plaque/Thrombus Protrusion in Patients With Acute Coronary Syndrome: The CLI-OPCI ACS Substudy (Centro per la Lotta Contro L'Infarto-Optimization of Percutaneous Coronary Intervention in Acute Coronary Syndrome). AB - BACKGROUND: Clinical consequences of optical coherence tomographic (OCT) high definition visualization of plaque/stent structures in acute patients remain undefined. In this retrospective substudy, we assessed the prognostic impact of postprocedural culprit lesion OCT findings in patients with acute coronary syndrome undergoing percutaneous coronary intervention. METHODS AND RESULTS: In the CLI-OPCI (Centro per la Lotta Contro L'Infarto-Optimization of Percutaneous Coronary Intervention) database collecting cases from 5 independent OCT experienced centers, we retrospectively analyzed postprocedural OCT findings in acute coronary syndrome patients and explored its possible impact (specifically that of residual intrastent plaque/thrombus protrusion) on outcome. From 2009 to 2013, 507 patients (588 lesions) were evaluated. Patients experiencing device oriented cardiovascular events showed more frequently the features of suboptimal stent implantation defined as the presence of significant residual intrastent plaque/thrombus protrusion (hazard ratio [HR], 2.35; P<0.01), in-stent minimum lumen area (MLA) <4.5 mm2 (HR, 2.72; P<0.01), dissection >200 um at distal stent edge (HR, 3.84; P<0.01), and reference lumen area <4.5 mm2 at either distal (HR, 6.07; P<0.001) or proximal (HR, 8.50; P<0.001) stent edges. Postprocedural OCT assessment of treated culprit lesion revealed at least one of these parameters in 55.2% of cases, with an associated increased risk of device-oriented cardiovascular events during follow-up (17.9% versus 4.8%; P<0.001). Both the presence of at least one of these parameters (HR, 3.69; P=0.002) and the residual intrastent plaque/thrombus protrusion (HR, 2.83; P=0.008) were confirmed as independent predictors of device-oriented cardiovascular events. CONCLUSIONS: In this retrospective study of acute coronary syndrome patients undergoing percutaneous coronary intervention, a composite of OCT-defined suboptimal stent implantation characteristics at the culprit lesion and residual intrastent plaque/thrombus protrusion was associated with adverse outcome. PMID- 27965298 TI - Right Ventricular Outflow Tract Stenting in Tetralogy of Fallot Infants With Risk Factors for Early Primary Repair. AB - BACKGROUND: Tetralogy of Fallot with cyanosis requiring surgical repair in early infancy reflects poor anatomy and is associated with more clinical instability and longer hospitalization than those who can be electively repaired later. We bridged symptomatic infants with risk factors for early primary repair by right ventricular outflow tract stenting (stent). METHODS AND RESULTS: Four groups of tetralogy of Fallot with confluent central pulmonary arteries were studied: stent group (n=42), primary repair (aged <3 months) with pulmonary stenosis (early-PS group; n=44), primary repair (aged <3 months) with pulmonary atresia (early-PA group; n=49), and primary repair between 3 and 11 months of age (surg>3mo group; n=45). Stent patients had the smallest pulmonary arteries with a median (95% credible intervals) Nakata index (mm2/m2) of 79 (66-85) compared with the early PA 139 (129-154), early-PS 136 (121-153), and surg>3mo 167 (153-200) groups. Only stent infants required unifocalization of aortopulmonary collaterals (17%). Stent and early-PA infants had younger age and lower weight than early-PS infants. Stent infants had the most multiple comorbidities. Stenting allowed deferral of complete surgical repair to an age (6 months), weight (6.3 [5.8-7.0] kg), and Nakata index (147 [132-165]) similar to the low-risk surg>3mo group. The 3 early treatment groups had similar intensive care unit/hospital stays and high reintervention rates in the first 12 months after repair, compared with the surg>3mo group. CONCLUSIONS: Right ventricular outflow tract stenting of symptomatic tetralogy of Fallot with poor anatomy (small pulmonary arteries) and adverse factors (multiple comorbidities, low weight) relieves cyanosis and defers surgical repair. This allowed pulmonary arterial and somatic growth with clinical results comparable to early surgical repair in more favorable patients. PMID- 27965296 TI - INNOVATION Study (Impact of Immediate Stent Implantation Versus Deferred Stent Implantation on Infarct Size and Microvascular Perfusion in Patients With ST Segment-Elevation Myocardial Infarction). AB - BACKGROUND: The aim of this study was to assess whether deferred stenting (DS) reduces infarct size and microvascular obstruction (MVO) compared with immediate stenting (IS) in primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. METHODS AND RESULTS: From February 2013 to August 2015, 114 patients (mean age: 69 years) were randomized into the following 2 groups: DS with an intention to stent 3 to 7 days later or IS after primary reperfusion in 2 centers. The primary and secondary end points were infarct size and the incidence of MVO, respectively, assessed by cardiac magnetic resonance imaging at 30 days after primary reperfusion. The median time to the second procedure in the DS was 72.8 hours. Six patients in the DS group were crossed over to the IS group because of progression of dissection or safety concerns after randomization. In the intention-to-treat analysis, DS did not significantly reduce infarct size (15.0% versus 19.4%; P=0.112) and the incidence of MVO (42.6% versus 57.4%; P=0.196), compared with IS. However, in anterior wall myocardial infarction, infarct size (16.1% versus 22.7%; P=0.017) and the incidence of MVO (43.8% versus 70.3%; P=0.047) were significantly reduced in the DS group. There was no urgent revascularization event during deferral period. CONCLUSIONS: A routine DS did not significantly reduce infarct size and MVO compared with IS, although it was safe. The beneficial effect of DS in patients with anterior myocardial infarction should be confirmed by larger randomized studies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02324348. PMID- 27965299 TI - Right Ventricular Outflow Tract Stenting: The Ideal Palliative Option in the Management of High-Risk Cyanotic Infants With Tetralogy of Fallot? PMID- 27965300 TI - Very Early ART and Persistent Inflammation in Treated HIV. PMID- 27965301 TI - High Rates of Anal High-Grade Squamous Intraepithelial Lesions in HIV-Infected Women Who Do Not Meet Screening Guidelines. AB - BACKGROUND: Human immunodeficiency virus (HIV)-infected women have a higher burden of anal high-grade squamous intraepithelial lesions (HSIL) and anal cancer (AC) compared with HIV-uninfected women. Guidelines for AC screening in this population are heterogeneous. Here we report outcomes and risk factors for anal HSIL following implementation of universal AC screening offered to all HIV infected women. METHODS: Data from women who underwent AC screening with anal cytology from April 2009 to July 2014 were analyzed. Routine clinical data included anal and cervical cytology, demographic/behavioral data, and high resolution anoscopy (HRA) results. We evaluated the association of cytology with HRA results, and predictors of HSIL pathology, and compared rates of HSIL pathology among women meeting screening guidelines to those who did not. RESULTS: Seven hundred forty-five HIV-infected women were screened with anal cytology. Thirty-nine percent had abnormal anal cytology on initial screen and 15% on secondary screen; 208 women underwent HRA following abnormal anal cytology. HSIL was found in 26% and 18% of anal biopsies following initial and secondary screening, respectively. One woman had AC. Cigarette smoking more than doubled HSIL risk. Among women who underwent AC screening despite not meeting existing guideline criteria, 21% and 10%, respectively, were found to have HSIL on biopsy. Neither meeting criteria for screening nor history of receptive anal sex was significantly associated with HSIL. CONCLUSIONS: Anal HSIL is common in HIV infected women. Substantial numbers of HSIL would have been missed by strictly adhering to existing AC screening guidelines. These results support routine screening of all HIV-infected women regardless of human papillomavirus history or sexual practices. PMID- 27965302 TI - Proton Pump Inhibitor Use Is Associated With Extended-Spectrum beta-Lactamase Producing Enterobacteriaceae Rectal Carriage at Hospital Admission: A Cross Sectional Study. AB - In this cross-sectional study, 8.5% of patients using proton pump inhibitors (PPIs) were rectal carriers of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E), compared with 2.9% of non-PPI users. In multivariable analysis, PPI use was independently associated with ESBL-E rectal carriage at hospital admission (adjusted odds ratio, 3.89; 95% confidence interval, 1.65 - 9.19). PMID- 27965303 TI - The MYB107 Transcription Factor Positively Regulates Suberin Biosynthesis. AB - Suberin, a lipophilic polymer deposited in the outer integument of the Arabidopsis (Arabidopsis thaliana) seed coat, represents an essential sealing component controlling water and solute movement and protecting seed from pathogenic infection. Although many genes responsible for suberin synthesis are identified, the regulatory components controlling its biosynthesis have not been definitively determined. Here, we show that the Arabidopsis MYB107 transcription factor acts as a positive regulator controlling suberin biosynthetic gene expression in the seed coat. MYB107 coexpresses with suberin biosynthetic genes in a temporal manner during seed development. Disrupting MYB107 particularly suppresses the expression of genes involved in suberin but not cutin biosynthesis, lowers seed coat suberin accumulation, alters suberin lamellar structure, and consequently renders higher seed coat permeability and susceptibility to abiotic stresses. Furthermore, MYB107 directly binds to the promoters of suberin biosynthetic genes, verifying its primary role in regulating their expression. Identifying MYB107 as a positive regulator for seed coat suberin synthesis offers a basis for discovering the potential transcriptional network behind one of the most abundant lipid-based polymers in nature. PMID- 27965304 TI - Targeted Degradation of Proteins Localized in Subcellular Compartments by Hybrid Small Molecules. AB - Development of novel small molecules that selectively degrade pathogenic proteins would provide an important advance in targeted therapy. Recently, we have devised a series of hybrid small molecules named SNIPER (specific and nongenetic IAP dependent protein ERaser) that induces the degradation of target proteins via the ubiquitin-proteasome system. To understand the localization of proteins that can be targeted by this protein knockdown technology, we examined whether SNIPER molecules are able to induce degradation of cellular retinoic acid binding protein II (CRABP-II) proteins localized in subcellular compartments of cells. CRABP-II is genetically fused with subcellular localization signals, and they are expressed in the cells. SNIPER(CRABP) with different IAP-ligands, SNIPER(CRABP)-4 with bestatin and SNIPER(CRABP)-11 with MV1 compound, induce the proteasomal degradation of wild-type (WT), cytosolic, nuclear, and membrane-localized CRABP II proteins, whereas only SNIPER(CRABP)-11 displayed degradation activity toward the mitochondrial CRABP-II protein. The small interfering RNA-mediated silencing of cIAP1 expression attenuated the knockdown activity of SNIPER(CRABP) against WT and cytosolic CRABP-II proteins, indicating that cIAP1 is the E3 ligase responsible for degradation of these proteins. Against membrane-localized CRABP II protein, cIAP1 is also a primary E3 ligase in the cells, but another E3 ligase distinct from cIAP2 and X-linked inhibitor of apoptosis protein (XIAP) could also be involved in the SNIPER(CRABP)-11-induced degradation. However, for the degradation of nuclear and mitochondrial CRABP-II proteins, E3 ligases other than cIAP1, cIAP2, and XIAP play a role in the SNIPER-mediated protein knockdown. These results indicate that SNIPER can target cytosolic, nuclear, membrane localized, and mitochondrial proteins for degradation, but the responsible E3 ligase is different, depending on the localization of the target protein. PMID- 27965305 TI - Bone Marrow Cell Trafficking Analyzed by 89Zr-oxine Positron Emission Tomography in a Murine Transplantation Model. AB - Purpose: The success of hematopoietic stem cell transplantation (HSCT) depends on donor cell homing to the bone marrow. However, there is no reliable method of noninvasively monitoring the kinetics and distribution of transferred cells. Using zirconium-89 (89Zr)-oxine cell labeling combined with PET imaging, we sought to visualize and quantify donor cell homing in a mouse bone marrow transplantation model.Experimental Design: The effect of 89Zr-oxine labeling on bone marrow cell viability and differentiation was evaluated in vitro89Zr-labeled bone marrow cells (2 * 107 cells, 16.6 kBq/106 cells) were transferred intravenously, and serial microPET images were obtained (n = 5). The effect of a CXCR4 inhibitor, plerixafor (5 mg/kg) and G-CSF (2.5 MUg) on bone marrow homing and mobilization were examined (n = 4). Engraftment of the transferred 89Zr labeled cells was evaluated (n = 3).Results:89Zr-oxine-labeled bone marrow cells showed delayed proliferation, but differentiated normally. Transferred bone marrow cells rapidly migrated to the bone marrow, spleen, and liver (n = 5). Approximately 36% of donor cells homed to the bone marrow within 4 hours, irrespective of prior bone marrow ablation. Inhibition of CXCR4 by plerixafor alone or with G-CSF significantly blocked the bone marrow homing (P < 0.0001, vs. nontreated, at 2 hours), confirming a crucial role of the CXCR4-CXCL12 system. Mobilization of approximately 0.64% of pretransplanted bone marrow cells induced a 3.8-fold increase of circulating bone marrow cells. 89Zr-labeled donor cells engrafted as well as nonlabeled cells.Conclusions:89Zr-oxine PET imaging reveals rapid bone marrow homing of transferred bone marrow cells without impairment of their stem cell functions, and thus, could provide useful information for optimizing HSCT. Clin Cancer Res; 23(11); 2759-68. (c)2016 AACR. PMID- 27965306 TI - Dendritic Cell Vaccination Enhances Immune Responses and Induces Regression of HER2pos DCIS Independent of Route: Results of Randomized Selection Design Trial. AB - Purpose: Vaccination with HER2 peptide-pulsed DC1s stimulates a HER2-specific T cell response. This randomized trial aimed to establish safety and evaluate immune and clinical responses to vaccination via intralesional (IL), intranodal (IN), or both intralesional and intranodal (ILN) injection.Experimental Design: Fifty-four HER2pos patients [42 pure ductal carcinoma in situ (DCIS), 12 early invasive breast cancer (IBC)] were enrolled in a neoadjuvant HER2 peptide-pulsed DC1 vaccine trial. Patients were randomized to IL (n = 19), IN (n = 19), or ILN (n = 16) injection. Immune responses were measured in peripheral blood and sentinel lymph nodes by ELISPOT or in vitro sensitization assay. Pathologic response was assessed in resected surgical specimens.Results: Vaccination by all injection routes was well tolerated. There was no significant difference in immune response rates by vaccination route (IL 84.2% vs. IN 89.5% vs. ILN 66.7%; P = 0.30). The pathologic complete response (pCR) rate was higher in DCIS patients compared with IBC patients (28.6% vs. 8.3%). DCIS patients who achieved pCR (n = 12) and who did not achieve pCR (n = 30) had similar peripheral blood anti-HER2 immune responses. All patients who achieved pCR had an anti-HER2 CD4 immune response in the sentinel lymph node, and the quantified response was higher by response repertoire (P = 0.03) and cumulative response (P = 0.04).Conclusions: Anti-HER2 DC1 vaccination is a safe and immunogenic treatment to induce tumor-specific T-cell responses in HER2pos patients; immune and clinical responses were similar independent of vaccination route. The immune response in the sentinel lymph nodes, rather than in the peripheral blood, may serve as an endpoint more reflective of antitumor activity. Clin Cancer Res; 23(12); 2961-71. (c)2016 AACR. PMID- 27965307 TI - Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting. AB - Purpose: While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model.Experimental Design: In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors.Results: ACTIV therapy induced durable complete remission of a variety of Her2+ tumors, some in excess of 150 mm2, in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFNgamma. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient.Conclusions: This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues. Clin Cancer Res; 23(10); 2478-90. (c)2016 AACR. PMID- 27965308 TI - Involvement of c-Fos in the Promotion of Cancer Stem-like Cell Properties in Head and Neck Squamous Cell Carcinoma. AB - Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although improvements in surgical techniques, chemotherapy and radiation delivery, and supportive care have improved quality of life for patients with HNSCC, regional and distant recurrence remain common. Recent evidence suggests that cancer stem-like cells (CSC) play a significant role in recurrence and chemoresistance. We previously observed that c-Fos was highly upregulated in the HNSCC sphere-forming cells. Consequences of c-Fos upregulation for the biology of HNSCC-CSCs are poorly understood. In this study, we investigated the role of c-Fos in renewal of stemness of HNSCC and tumor growth.Experimental Design and Results: We generated stable HNSCC cell lines ectopically expressing the c-Fos gene. Exogenous expression of c-Fos in nontumorigenic MDA1386Tu cells makes these cells tumorigenic in nude mice. Furthermore, subcutaneous transplantation of c-Fos-overexpressing Cal27 cells (tumorigenic) into immunocompromised mice enhanced tumor growth as compared with parental cells. Mechanistic investigations demonstrated that c-Fos overexpression enhanced the epithelial-mesenchymal transition (EMT) state and expression of CSC markers (Nanog, c-Myc, Sox2, and Notch1). Ectopic expression of c-Fos in HNSCC cells also displays increased sphere formation. We further observed that overexpression of c-Fos increased the expression of pERK and cyclin D1 in HNSCC cells.Conclusions: Together, our results strongly suggest a novel role of c-Fos as a regulator of EMT and cancer stem cell reprogramming in HNSCC cells, which may hold potential as a CSC-directed therapeutic approach to improve HNSCC treatment. Clin Cancer Res; 23(12); 3120-8. (c)2016 AACR. PMID- 27965310 TI - Rare cause of back pain: Staphylococcus aureus vertebral osteomyelitis complicated by recurrent epidural abscess and severe sepsis. AB - An epidural abscess represents a rare acute medical emergency, with a reported incidence of 2.5/10 000 hospital admissions annually. The clinical features include fever, spinal pain, radiating nerve root pain and leg weakness. When sepsis is present, prompt recognition is required to initiate appropriate antimicrobial therapy and surgical decompression. We present the case of a man aged 68 years presenting to the emergency department with a 3-day history of fever, low back, right hip and leg pain. He was hypoxic, tachycardic and hypotensive. He required intubation and ventilation. An MRI spine confirmed a posterior epidural abscess from T12 to L4. Blood cultures revealed Staphylococcus aureus He started treatment with linezolid and underwent incision and drainage. He remained septic and 8 days later, a repeat MRI spine showed a peripherally enhancing posterior epidural collection from L2/L3 to L4/L5, consistent with a recurrent epidural abscess. Further drainage was performed. He developed bilateral knee pain requiring washout. His right knee synovial biopsy cultured S. aureus He continued treatment with linezolid for 6 weeks until his C reactive protein was 0.8 ng/L. He started neurorehabilitation. 10 weeks later, he became feverish with lumbar spine tenderness. An MRI spine showed discitis of the L5/S1 endplate. A CT-guided biopsy confirmed discitis and osteomyelitis. Histology was positive for S. aureus and he started treatment with oral linezolid. After 19 days, he was discharged with 1 week of oral linezolid 600 mg 2 times per day, followed by 1 further week of oral clindamycin 600 mg 4 times daily. This case report reinforces the importance of maintaining a high clinical suspicion, with a prompt diagnosis and combined medical and surgical treatment to prevent adverse outcomes in this patient cohort. With spinal surgical services centralised, physicians may not encounter this clinical diagnosis more often in day-to-day hospital medical practice. The unique aspect of this case is the persistence and then the recurrence (despite 6 weeks of antimicrobial therapy and a second debridement) of S. aureus infection. Furthermore, the paucity of clinical recommendations and the controversy regarding the adequate duration of antimicrobial therapy are notable features of this case. PMID- 27965311 TI - Accurate diagnosis of iliac vein thrombosis in pregnancy with magnetic resonance direct thrombus imaging (MRDTI). AB - A pregnant woman aged 29 years, G1P0 at 21 weeks of gestation of a dichorionic diamniotic twin, presented with suspected deep vein thrombosis (DVT) of the left leg. Repeated (compression) ultrasonography was not diagnostic for DVT but showed reduced flow over the left external iliac vein, common femoral vein and superficial femoral vein. In pursue of a definite diagnosis, magnetic resonance direct thrombus imaging was performed showing a clear high signal in the left common iliac vein which is diagnostic for acute thrombosis in this venous segment. Phase contrast venography supported this diagnosis, showing no flow in the left common iliac vein. Treatment with anticoagulants was started. 6 months after the diagnosis, the patient is doing well and does not report signs of post thrombotic syndrome. PMID- 27965309 TI - Selective Targeting of Myeloid-Derived Suppressor Cells in Cancer Patients Using DS-8273a, an Agonistic TRAIL-R2 Antibody. AB - Purpose: Myeloid-derived suppressor cells (MDSC) are one of the major contributors to immune suppression in cancer. We recently have demonstrated in preclinical study that MDSCs are sensitive to TRAIL receptor 2 (TRAIL-R2) agonist. The goal of this study was to clinically test the hypothesis that targeting TRAIL-R2 can selectively eliminate MDSCs.Experimental Design: The TRAIL R2 agonistic antibody (DS-8273a) has been tested in 16 patients with advanced cancers enrolled in a phase I trial. The antibody (24 mg/kg) was administered intravenously once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated.Results: The treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Treatment with DS-8273a resulted in reduction of the elevated numbers of MDSCs in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSCs rebounded back to the pretreatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells. Decrease in MDSCs inversely correlated with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSCs in 50% of the patients who were able to provide pre- and on-treatment biopsies.Conclusions: Targeting TRAIL-R2 resulted in elimination of different populations of MDSCs without affecting mature myeloid or lymphoid cells. These data support the use of this antibody in combination immmunotherapy of cancer. Clin Cancer Res; 23(12); 2942-50. (c)2016 AACR. PMID- 27965312 TI - Hyponatraemia-induced rhabdomyolysis complicated by anuric acute kidney injury: a renal replacement conundrum. AB - Hyponatraemia-induced rhabdomyolysis is a rare, but reported phenomenon, particularly in patients with chronic schizophrenia on depot antipsychotics prone to psychogenic polydipsia. To the best of our knowledge, there are no reported cases of hyponatraemia-induced rhabdomyolysis complicated by oligo-anuric acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT). The initiation of CRRT is complicated in severe hyponatraemia, predominantly due to the need to avoid rapid changes in tonicity associated with rapid changes in sodium. We report a case of severe hyponatraemia (104 mmol/L) complicated by oligo-anuric rhabdomyolysis-induced AKI and our management of the renal prescription. PMID- 27965313 TI - Know thy unknowns: why we need to widen our view on endocrine disruptors. PMID- 27965315 TI - Public pensions and unmet medical need among older people: cross-national analysis of 16 European countries, 2004-2010. AB - BACKGROUND: Since the onset of the Great Recession in Europe, unmet need for medical care has been increasing, especially in persons aged 65 or older. It is possible that public pensions buffer access to healthcare in older persons during times of economic crisis, but to our knowledge, this has not been tested empirically in Europe. METHODS: We integrated panel data on 16 European countries for years 2004-2010 with indicators of public pension, unemployment insurance and sickness insurance entitlement from the Comparative Welfare Entitlements Dataset and unmet need (due to cost) prevalence rates from EuroStat 2014 edition. Using country-level fixed-effects regression models, we evaluate whether greater public pension entitlement, which helps reduce old-age poverty, reduces the prevalence of unmet medical need in older persons and whether it reduces inequalities in unmet medical need across the income distribution. RESULTS: We found that each 1 unit increase in public pension entitlement is associated with a 1.11 percentage point decline in unmet medical need due to cost among over 65s (95% CI -0.55 to 1.66). This association is strongest for the lowest income quintile (1.65 percentage points, 95% CI -1.19 to -2.10). Importantly, we found consistent evidence that out-of-pocket payments were linked with greater unmet needs, but that this association was mitigated by greater public pension entitlement (beta= 1.21 percentage points, 95% CI -0.37 to -2.06). CONCLUSIONS: Greater public pension entitlement plays a crucial role in reducing inequalities in unmet medical need among older persons, especially in healthcare systems which rely heavily on out-of-pocket payments. PMID- 27965314 TI - How voter turnout varies between different chronic conditions? A population-based register study. AB - BACKGROUND: While poor self-rated health is known to decrease an individual's propensity to vote, disaggregation of the components of health on turnout has thus far received only little attention. This study deepens on the understanding of such relationships by examining the association between chronic diseases and voting. METHODS: The study uses an individual-level register-based data set that contains an 11% random sample of the entire electorate in the 1999 Finnish parliamentary elections. With information on hospital discharge diagnoses and reimbursements for drugs prescribed, we identify persons with chronic hospital treated diseases (coronary heart disease, chronic obstructive pulmonary disease (COPD) and asthma, depression, cancer, psychotic mental disease, diabetes, cerebrovascular disease, rheumatic disease, epilepsy, arthrosis, alcoholism, dementia, atherosclerosis, Parkinson's disease, other degenerative brain diseases, multiple sclerosis and kidney disease). RESULTS: After adjusting for gender, age, education, occupational class, income, partnership status, cohabitation with underaged children and hospitalisation during Election Day, neurodegenerative brain diseases had the strongest negative relationship with voting (dementia OR=0.20, 95% CI 0.18 to 0.22; others up to OR=0.70). Alcoholism (OR=0.66) and mental disorders also had a negative association (depression OR=0.91; psychotic mental disease OR=0.79), whereas cancer and COPD/asthma had a positive association (both OR=1.05). Having more than one condition at a time further decreased voting probability. CONCLUSIONS: By showing how different health conditions are related to voter turnout, this study provides essential information for identifying gaps in the potential for political participation and for further inquiries aiming to develop models that explain the link between health and voting probability. PMID- 27965316 TI - Association of perceived ethnic discrimination with general and abdominal obesity in ethnic minority groups: the HELIUS study. AB - BACKGROUND: Discrimination is associated with obesity, but this may differ according to the type of obesity and ethnic group. This study examines the association of perceived ethnic discrimination (PED) with general and abdominal obesity in 5 ethnic minority groups. METHODS: We used cross-sectional data from the HELIUS study, collected from 2011 to 2015. The study sample included 2297 Ghanaians, 4110 African Surinamese, 3021 South-Asian Surinamese, 3562 Turks and 3868 Moroccans aged 18-70 years residing in Amsterdam, the Netherlands. Body mass index (BMI) was used as a measure for general obesity, and waist circumference (WC) for abdominal obesity. PED was measured using the Everyday Discrimination Scale. We used linear regression models adjusted for sociodemographics, psychosocial stressors and health behaviours. In additional analysis, we used standardised variables to compare the strength of the associations. RESULTS: In adjusted models, PED was significantly, positively associated with BMI in the South-Asian Surinamese (beta coefficient 0.338; 95% CI 0.106 to 0.570), African Surinamese (0.394; 0.171 to 0.618) and Turks (0.269; 0.027 to 0.510). For WC, a similar pattern was seen: positive associations in the South-Asian Surinamese (0.759; 0.166 to 1.353), African Surinamese (0.833; 0.278 to 1.388) and Turks (0.870; 0.299 to 1.440). When stratified by sex, we found positive associations in Surinamese women, Turkish men and Moroccan men. The strength of the associations with BMI and WC was comparable in the groups. Among the Ghanaians, no significant associations were observed. CONCLUSIONS: Ethnic and sex variations are observed in the association of PED with both general and abdominal obesity. Further research on psychosocial buffers and underlying biological mechanisms might help in understanding these variations. PMID- 27965317 TI - Cell-Specific Computational Modeling of the PIM Pathway in Acute Myeloid Leukemia. AB - Personalized therapy is a major goal of modern oncology, as patient responses vary greatly even within a histologically defined cancer subtype. This is especially true in acute myeloid leukemia (AML), which exhibits striking heterogeneity in molecular segmentation. When calibrated to cell-specific data, executable network models can reveal subtle differences in signaling that help explain differences in drug response. Furthermore, they can suggest drug combinations to increase efficacy and combat acquired resistance. Here, we experimentally tested dynamic proteomic changes and phenotypic responses in diverse AML cell lines treated with pan-PIM kinase inhibitor and fms-related tyrosine kinase 3 (FLT3) inhibitor as single agents and in combination. We constructed cell-specific executable models of the signaling axis, connecting genetic aberrations in FLT3, tyrosine kinase 2 (TYK2), platelet-derived growth factor receptor alpha (PDGFRA), and fibroblast growth factor receptor 1 (FGFR1) to cell proliferation and apoptosis via the PIM and PI3K kinases. The models capture key differences in signaling that later enabled them to accurately predict the unique proteomic changes and phenotypic responses of each cell line. Furthermore, using cell-specific models, we tailored combination therapies to individual cell lines and successfully validated their efficacy experimentally. Specifically, we showed that cells mildly responsive to PIM inhibition exhibited increased sensitivity in combination with PIK3CA inhibition. We also used the model to infer the origin of PIM resistance engineered through prolonged drug treatment of MOLM16 cell lines and successfully validated experimentally our prediction that this resistance can be overcome with AKT1/2 inhibition. Cancer Res; 77(4); 827-38. (c)2016 AACR. PMID- 27965318 TI - Mapping and ablation of anteroseptal atrial tachycardia in patients with congenitally corrected transposition of the great arteries: implication of pulmonary sinus cusps. AB - Aims: We sought to investigate focal atrial tachycardias (ATs) in patients with congenitally corrected transposition of the great arteries (ccTGA). Methods and results: We identified three cases of focal ATs with ccTGA from 2007 to 2015. The clinical findings, electrocardiography, electrophysiological features, and ablation were reported. All three cases had {S,L,L}-type ccTGA. The AT P waves shared the following features: narrow in width, positive in leads I and aVL, and negative/positive in lead V1. All ATs had focal activation pattern with early activation at the anteroseptal area, and further mapping demonstrated earliest atrial activation (EAA) inside the pulmonary sinus cusps (PSCs), especially the right PSC. In Cases 1 and 2, double potentials were recorded at the EAA sites. Conduction delay between the two potentials during atrial extrastimulus was observed. After successful ablation, the second potential during sinus rhythm was further delayed in Case 1 and was eliminated in Case 2. However, only one potential was recorded in Case 3. All three cases were successfully managed by ablating the sites with EAA, which preceded the P-wave onset by 60, 80, and 42 ms, respectively. During ablation, no junctional rhythm was observed. Incomplete left bundle branch block was induced during mapping in Case 1, but no other complications occurred. All patients were free from tachycardia during follow-up periods of 36, 7, and 5 months, respectively. Conclusion: Anteroseptal AT in patients with ccTGA could be eliminated by ablation inside the PSC. PMID- 27965319 TI - High prevalence of early repolarization in the paediatric relatives of sudden arrhythmic death syndrome victims and in normal controls. AB - Aims: Elevation of the ECG J-point in the inferior and lateral leads (early repolarization) has been described in survivors of ventricular fibrillation (VF) arrest and occurs in adult first-degree relatives of sudden cardiac death (SCD) probands at a frequency significantly greater than in controls, raising the possibility that this could represent an independent risk factor in the aetiology of SCD. However, data on early repolarization in the paediatric population are lacking. This study aimed to assess the prevalence of early repolarization in paediatric first-degree relatives of sudden arrhythmic death syndrome (SADS) victims. Methods and results: Paediatric relatives (aged <18 years) of SADS probands referred to the Inherited Arrhythmia Clinic at Great Ormond Street Hospital had their initial screening ECG reviewed for evidence of J-point elevation. J-point elevation was defined as QRS-ST slurring or a discrete notch in two or more inferior (II, III, aVF) or lateral (I, aVL, V4, V5, V6) leads with the change beginning >1 mV from baseline. The ECGs of 77 consecutive paediatric first-degree relatives of SADS victims from 46 families were reviewed by two assessors. J-point elevation was present in 24 patients (31%) of this patient group compared with the reported prevalence of 5-13% in the published general paediatric population (P = 0.02) and that of 19% in the internal control group (P = 0.07). Subgroup analysis according to J-point elevation and ST segment morphologies showed a significantly higher prevalence of inferior early repolarization 0.1-0.2 mV in the study group compared with controls (75 vs. 38%; P = 0.02). Conclusion: Inferolateral J-point elevation occurs in a substantial proportion of paediatric first-degree relatives of SADS probands with a similar prevalence to that described in adults. This suggests that early repolarization could be an important inherited trait when evaluating relatives of SADS victims. However, prospective follow-up of this group of children is important to establish the implication of this finding in future risk stratification, given the apparently high prevalence in normal individuals. PMID- 27965320 TI - Staphylococcus aureus, phagocyte NADPH oxidase and chronic granulomatous disease. AB - Dysfunction of phagocytes is a relevant risk factor for staphylococcal infection. The most common hereditary phagocyte dysfunction is chronic granulomatous disease (CGD), characterized by impaired generation of reactive oxygen species (ROS) due to loss of function mutations within the phagocyte NADPH oxidase NOX2. Phagocytes ROS generation is fundamental to eliminate pathogens and to regulate the inflammatory response to infection. CGD is characterized by recurrent and severe bacterial and fungal infections, with Staphylococcus aureus as the most frequent pathogen, and skin and lung abscesses as the most common clinical entities. Staphylococcus aureus infection may occur in virtually any human host, presumably because of the many virulence factors of the bacterium. However, in the presence of functional NOX2, staphylococcal infections remain rare and are mainly linked to breaches of the skin barrier. In contrast, in patients with CGD, S. aureus readily survives and frequently causes clinically apparent disease. Astonishingly, little is known why S. aureus, which possesses a wide range of antioxidant enzymes (e.g. catalase, SOD), is particularly sensitive to control through NOX2. In this review, we will evaluate the discovery of CGD and our present knowledge of the role of NOX2 in S. aureus infection. PMID- 27965321 TI - Suppressing P16Ink4a and P14ARF pathways overcomes apoptosis in individualized human embryonic stem cells. AB - Dissociation-induced apoptosis is a striking phenomenon in human embryonic stem cells (hESCs), but not in naive mouse ESCs. Rho-associated kinase-dependent actin myosin hyperactivation is an underlying mechanism that triggers apoptosis in dissociated hESCs; however, in this study, we show that the Ink4A-ARF-mediated senescence pathway is another mechanism to cause apoptosis in individualized hESCs. We show that P16INK4A and P14ARF are immediately induced in hESCs upon dissociation, but not in mouse ESCs. Overexpression of BMI1, a suppressor for Ink4A-ARF, greatly promotes survival and cloning efficiency of individualized hESCs mechanistically via direct binding the H3K27me3-marked Ink4A-ARF locus. Forced expression of BMI1 in hESCs does not reduce the actin-myosin activation that is triggered by dissociation, which indicates it is an independent pathway for hESC survival. Furthermore, dual inhibition of both Ink4A-ARF and actin myosin hyperactivation enables successful passaging of hESCs via gelatin, a nonbioactive matrix. In sum, we provide an additional mechanism that underlies cell death in individualized hESCs that might help to fully understand the differential cell characteristics between naive and primed ESCs.-Wang, W., Zhu, Y., Huang, K., Shan, Y., Du, J., Dong, X., Ma, P., Wu, P., Zhang, J., Huang, W., Zhang, T., Liao, B., Yao, D., Pan, G., Liu, J. Suppressing P16Ink4a and P14ARF pathways overcomes apoptosis in individualized human embryonic stem cells. PMID- 27965323 TI - Conversation with Ian McWhinney. PMID- 27965324 TI - ? PMID- 27965325 TI - Family physician-based care of patients with serious mental illness: Using a case managed approach. PMID- 27965322 TI - Superficial cells are self-renewing chondrocyte progenitors, which form the articular cartilage in juvenile mice. AB - Articular cartilage has little regenerative capacity. Recently, genetic lineage tracing experiments have revealed chondrocyte progenitors at the articular surface. We further characterized these progenitors by using in vivo genetic approaches. Histone H2B-green fluorescent protein retention revealed that superficial cells divide more slowly than underlying articular chondrocytes. Clonal genetic tracing combined with immunohistochemistry revealed that superficial cells renew their number by symmetric division, express mesenchymal stem cell markers, and generate chondrocytes via both asymmetric and symmetric differentiation. Quantitative analysis of cellular kinetics, in combination with phosphotungstic acid-enhanced micro-computed tomography, showed that superficial cells generate chondrocytes and contribute to the growth and reshaping of articular cartilage. Furthermore, we found that cartilage renewal occurs as the progeny of superficial cells fully replace fetal chondrocytes during early postnatal life. Thus, superficial cells are self-renewing progenitors that are capable of maintaining their own population and fulfilling criteria of unipotent adult stem cells. Furthermore, the progeny of these cells reconstitute adult articular cartilage de novo, entirely substituting fetal chondrocytes.-Li, L., Newton, P. T., Bouderlique, T., Sejnohova, M., Zikmund, T., Kozhemyakina, E., Xie, M., Krivanek, J., Kaiser, J., Qian, H., Dyachuk, V., Lassar, A. B., Warman, M. L., Barenius, B., Adameyko, I., Chagin, A. S. Superficial cells are self renewing chondrocyte progenitors, which form the articular cartilage in juvenile mice. PMID- 27965326 TI - Mental disorders, risks, and disability: Primary care needs a novel approach. PMID- 27965327 TI - Telehealth and patient-doctor relationships in rural and remote communities. PMID- 27965329 TI - ? PMID- 27965328 TI - The perils and the promise of proximity: Dr Ian McWhinney Lecture, 2016. PMID- 27965330 TI - Approach to risk identification in undifferentiated mental disorders. AB - OBJECTIVE: To provide primary care physicians with a novel approach to risk identification and related clinical decision making in the management of undifferentiated mental disorders. SOURCES OF INFORMATION: We conducted a review of the literature in PubMed, CINAHL, PsycINFO, and Google Scholar using the search terms diagnostic uncertainty, diagnosis, risk identification, risk assessment/methods, risk, risk factors, risk management/methods, cognitive biases and psychiatry, decision making, mental disorders/diagnosis, clinical competence, evidence-based medicine, interviews as topic, psychiatry/education, psychiatry/methods, documentation/methods, forensic psychiatry/education, forensic psychiatry/methods, mental disorders/classification, mental disorders/psychology, violence/prevention and control, and violence/psychology. MAIN MESSAGE: Mental disorders are a large component of practice in primary care and often present in an undifferentiated manner, remaining so for prolonged periods. The challenging search for a diagnosis can divert attention from risk identification, as diagnosis is commonly presumed to be necessary before treatment can begin. This might inadvertently contribute to preventable adverse events. Focusing on salient aspects of the patient presentation related to risk should be prioritized. This article presents a novel approach to organizing patient information to assist risk identification and decision making in the management of patients with undifferentiated mental disorders. CONCLUSION: A structured approach can help physicians to manage the clinical uncertainty common to risk identification in patients with mental disorders and cope with the common anxiety and cognitive biases that affect priorities in risk-related decision making. By focusing on risk, functional impairments, and related symptoms using a novel framework, physicians can meet their patients' immediate needs while continuing the search for diagnostic clarity and long-term treatment. PMID- 27965331 TI - Understanding attention deficit hyperactivity disorder as a continuum. AB - OBJECTIVE: To review research findings that consider whether attention deficit hyperactivity disorder (ADHD) is a discrete entity or whether it is more consistent with an extreme end-of-trait distribution in the population and to then grapple with the potential clinical implications. QUALITY OF EVIDENCE: Peer reviewed publications in the past 5 years, drawing from diverse fields (taxonomy, epidemiology, genetics, neurobiology, and neuropsychology), were identified through searches in MEDLINE and PsycINFO. MAIN MESSAGE: Accumulating research findings are most consistent with a predominately dimensional rather than a qualitatively distinct existence for ADHD. This does not negate the clinical needs of those who have substantial ADHD symptom clusters, nor the risks that such symptoms entail. However, the lack of discontinuity in the distribution of such traits in the population creates great uncertainty as to what thresholds should prompt explicit intervention. CONCLUSION: The implications of this pattern of findings might include the need to de-emphasize categorical conceptualizations of ADHD, produce evidence to better inform risk-benefit ratios of interventions along a spectrum of symptom and functional severity, and more coherently triage and arrange service delivery on the basis of symptom and functional severity rather than artificial diagnostic categorizations. PMID- 27965332 TI - ? PMID- 27965333 TI - Nebulized epinephrine for young children with bronchiolitis. AB - QUESTION: Every winter I see infants with flulike symptoms and wheezing. I frequently diagnose them with bronchiolitis based on their presenting symptoms. Would it be prudent to send those infants to the nearest emergency department for treatment with nebulized epinephrine? ANSWER: Nebulized epinephrine should not be routinely used in infants with bronchiolitis. It is an option to consider in those with severe symptoms. If it is given and there are no signs of improvement, further doses are discouraged. Ongoing studies of epinephrine combined with other agents (eg, hypertonic saline, oral dexamethasone) are needed to confirm their benefit. PMID- 27965334 TI - Spontaneous coronary artery dissection: Case report and review of the literature. PMID- 27965335 TI - What works best for nongenital warts? PMID- 27965336 TI - Just a pinch: Technique for skin tag removal in sensitive areas. PMID- 27965337 TI - Aiming at the right things: Reflections on public health care, community, and social accountability. PMID- 27965340 TI - CFPC welcomes its 2016-2017 President, Dr David White. PMID- 27965341 TI - ? PMID- 27965342 TI - ? PMID- 27965343 TI - News from the Foundation. PMID- 27965344 TI - ? PMID- 27965345 TI - ? PMID- 27965346 TI - ? PMID- 27965347 TI - ? PMID- 27965348 TI - Peer-support writing group in a community family medicine teaching unit: Facilitating professional development. AB - PROBLEM ADDRESSED: Aspiring physician writers need an environment that promotes self-reflection and can help them improve their skills and confidence in writing. OBJECTIVE OF PROGRAM: To create a peer-support writing group for physicians in the Markham-Stouffville community in Ontario to promote professional development by encouraging self-reflection and fostering the concept of physician as writer. PROGRAM DESCRIPTION: The program, designed based on a literature review and a needs assessment, was conducted in 3 sessions over 6 months. Participants included an emergency physician, 4 family physicians, and 3 residents. Four to 8 participants per session shared their projects with guest physician authors. Eight pieces of written work were brought to the sessions, 3 of which were edited. A mixed quantitative and qualitative evaluation model was used with preprogram and postprogram questionnaires and a focus group. CONCLUSION: This program promoted professional development by increasing participants' frequency of self-reflection and improving their proficiency in writing. Successful elements of this program include creating a supportive group environment and having a physician-writer expert facilitate the peer-feedback sessions. Similar programs can be useful in postgraduate education or continuing professional development. PMID- 27965349 TI - Patient safety principles in family medicine residency accreditation standards and curriculum objectives: Implications for primary care. AB - OBJECTIVE: To conduct a thematic analysis of the College of Family Physicians of Canada's (CFPC's) Red Book accreditation standards and the Triple C Competency based Curriculum objectives with respect to patient safety principles. DESIGN: Thematic content analysis of the CFPC's Red Book accreditation standards and the Triple C curriculum. SETTING: Canada. MAIN OUTCOME MEASURES: Coding frequency of the patient safety principles (ie, patient engagement; respectful, transparent relationships; complex systems; a just and trusting culture; responsibility and accountability for actions; and continuous learning and improvement) found in the analyzed CFPC documents. RESULTS: Within the analyzed CFPC documents, the most commonly found patient safety principle was patient engagement (n = 51 coding references); the least commonly found patient safety principles were a just and trusting culture (n = 5 coding references) and complex systems (n = 5 coding references). Other patient safety principles that were uncommon included responsibility and accountability for actions (n = 7 coding references) and continuous learning and improvement (n = 12 coding references). CONCLUSION: Explicit inclusion of patient safety content such as the use of patient safety principles is needed for residency training programs across Canada to ensure the full spectrum of care is addressed, from community-based care to acute hospital based care. This will ensure a patient safety culture can be cultivated from residency and sustained into primary care practice. PMID- 27965351 TI - Extended family medicine training: Measuring training flows at a time of substantial pedagogic change. AB - OBJECTIVE: To examine trends in family medicine training at a time when substantial pedagogic change is under way, focusing on factors that relate to extended family medicine training. DESIGN: Aggregate-level secondary data analysis based on the Canadian Post-MD Education Registry. SETTING: Canada. PARTICIPANTS: All Canadian citizens and permanent residents who were registered in postgraduate family medicine training programs within Canadian faculties of medicine from 1995 to 2013. MAIN OUTCOME MEASURES: Number and proportion of family medicine residents exiting 2-year and extended (third-year and above) family medicine training programs, as well as the types and numbers of extended training programs offered in 2015. RESULTS: The proportion of family medicine trainees pursuing extended training almost doubled during the study period, going from 10.9% in 1995 to 21.1% in 2013. Men and Canadian medical graduates were more likely to take extended family medicine training. Among the 5 most recent family medicine exit cohorts (from 2009 to 2013), 25.9% of men completed extended training programs compared with 18.3% of women, and 23.1% of Canadian medical graduates completed extended training compared with 13.6% of international medical graduates. Family medicine programs vary substantially with respect to the proportion of their trainees who undertake extended training, ranging from a low of 12.3% to a high of 35.1% among trainees exiting from 2011 to 2013. CONCLUSION: New initiatives, such as the Triple C Competency-based Curriculum, CanMEDS-Family Medicine, and Certificates of Added Competence, have emerged as part of family medicine education and credentialing. In acknowledgment of the potential effect of these initiatives, it is important that future research examine how pedagogic change and, in particular, extended training shapes the care family physicians offer their patients. As part of that research it will be important to measure the breadth and uptake of extended family medicine training programs. PMID- 27965350 TI - Measuring the patient experience in primary care: Comparing e-mail and waiting room survey delivery in a family health team. AB - OBJECTIVE: To compare the characteristics and responses of patients completing a patient experience survey accessed online after e-mail notification or delivered in the waiting room using tablet computers. DESIGN: Cross-sectional comparison of 2 methods of delivering a patient experience survey. SETTING: A large family health team in Toronto, Ont. PARTICIPANTS: Family practice patients aged 18 or older who completed an e-mail survey between January and June 2014 (N = 587) or who completed the survey in the waiting room in July and August 2014 (N = 592). MAIN OUTCOME MEASURES: Comparison of respondent demographic characteristics and responses to questions related to access and patient-centredness. RESULTS: Patients responding to the e-mail survey were more likely to live in higher income neighbourhoods (P = .0002), be between the ages of 35 and 64 (P = .0147), and be female (P = .0434) compared with those responding to the waiting room survey; there were no significant differences related to self-rated health. The differences in neighbourhood income were noted despite minimal differences between patients with and without e-mail addresses included in their medical records. There were few differences in responses to the survey questions between the 2 survey methods and any differences were explained by the underlying differences in patient demographic characteristics. CONCLUSION: Our findings suggest that respondent demographic characteristics might differ depending on the method of survey delivery, and these differences might affect survey responses. Methods of delivering patient experience surveys that require electronic literacy might underrepresent patients living in low-income neighbourhoods. Practices should consider evaluating for nonresponse bias and adjusting for patient demographic characteristics when interpreting survey results. Further research is needed to understand how primary care practices can optimize electronic survey delivery methods to survey a representative sample of patients. PMID- 27965352 TI - Burden of common mental disorders in a community health centre sample. AB - OBJECTIVE: To examine the rates of common mental disorders (CMDs) such as depression, anxiety, posttraumatic stress disorder (PTSD), and alcohol use in an urban community health care centre (CHC) serving vulnerable immigrant and ethnoracial communities in order to improve knowledge on the rates of CMDs specific to these groups accessing primary care settings. DESIGN: English or Spanish, self-administered, tablet-based survey known as the Interactive Computer Assisted Client Assessment Survey (iCCAS). SETTING: Access Alliance Multicultural Health and Community Services CHC in Toronto, Ont. PARTICIPANTS: Adult patients waiting to see a clinician. MAIN OUTCOME MEASURES: The iCCAS screened for depression (using the PHQ-9 [Patient Health Questionnaire]), anxiety (using the GAD-7 [Generalized Anxiety Disorder 7-item scale]), PTSD (using the PC-PTSD [Primary Care PTSD Screen]), and alcohol dependency (using the CAGE questionnaire); those with an existing diagnosis and active treatment for one of these conditions were not asked to complete that condition-specific screening scale. An exit survey measured demographic characteristics and relevant indicators. RESULTS: A response rate of 78.6% was achieved. The iCCAS survey was completed by 75 patients (26 men and 49 women) with a mean age of 36.5 years. Almost all were first-generation immigrants: 32.0% originated from Latin America, 28.0% from South Asia, and 17.3% from Africa or the Middle East. Major depression was found among 44.0% of participants (11 with diagnosis and treatment, 22 with a score of 10 or greater on the PHQ-9). Generalized anxiety disorder was present in 26.7% of participants (7 with diagnosis and treatment, 13 with a score of 10 or greater on the GAD-7 scale). Posttraumatic stress disorder was detected in 37.3% of participants (7 with diagnosis and treatment, 21 with a score of 3 or greater on the PC-PTSD tool). Alcohol dependency was found among 10.7% of participants (1 with diagnosis and treatment, 7 with a score of 2 or greater on the CAGE questionnaire). CONCLUSION: The high rates of probable depression, generalized anxiety, and PTSD that were found in the studied population suggest a need for systematic assessment of CMDs in CHCs, as well as training and resources to increase readiness to handle identified cases. PMID- 27965353 TI - ? PMID- 27965354 TI - Complementary and alternative medicine: Do physicians believe they can meet the requirements of the College des medecins du Quebec? AB - OBJECTIVE: To determine whether medical training prepares FPs to meet the requirements of the College des medecins du Quebec for their role in advising patients on the use of complementary and alternative medicine (CAM). DESIGN: Secondary analysis of survey results. SETTING: Quebec. PARTICIPANTS: Family physicians and GPs in active practice. MAIN OUTCOME MEASURES: Perceptions of the role of the physician as an advisor on CAM; level of comfort responding to questions and advising patients on CAM; frequency with which patients ask their physicians about CAM; personal position on CAM; and desire for training on CAM. RESULTS: The response rate was 19.5% (195 respondents of 1000) and the sample appears to be representative of the target population. Most respondents (85.8%) reported being asked about CAM several times a month. A similar proportion (86.7%) believed it was their role to advise patients on CAM. However, of this group, only 33.1% reported being able to do so. There is an association between an urban practice and knowledge of the advisory role of physicians. More than three-quarters of respondents expressed interest in receiving additional training on CAM. CONCLUSION: There is a gap between the training that Quebec physicians receive on CAM and their need to meet legal and ethical obligations designed to protect the public where CAM products and therapies are concerned. One solution might be more thorough training on CAM to help physicians meet the College des medecins du Quebec requirements. PMID- 27965356 TI - Structure of the Lipid Nanodisc-reconstituted Vacuolar ATPase Proton Channel: DEFINITION OF THE INTERACTION OF ROTOR AND STATOR AND IMPLICATIONS FOR ENZYME REGULATION BY REVERSIBLE DISSOCIATION. AB - Eukaryotic vacuolar H+-ATPase (V-ATPase) is a multisubunit enzyme complex that acidifies subcellular organelles and the extracellular space. V-ATPase consists of soluble V1-ATPase and membrane-integral Vo proton channel sectors. To investigate the mechanism of V-ATPase regulation by reversible disassembly, we recently determined a cryo-EM reconstruction of yeast Vo The structure indicated that, when V1 is released from Vo, the N-terminal cytoplasmic domain of subunit a (aNT) changes conformation to bind rotor subunit d However, insufficient resolution precluded a precise definition of the aNT-d interface. Here we reconstituted Vo into lipid nanodiscs for single-particle EM. 3D reconstructions calculated at ~15-A resolution revealed two sites of contact between aNT and d that are mediated by highly conserved charged residues. Alanine mutagenesis of some of these residues disrupted the aNT-d interaction, as shown by isothermal titration calorimetry and gel filtration of recombinant subunits. A recent cryo EM study of holo V-ATPase revealed three major conformations corresponding to three rotational states of the central rotor of the enzyme. Comparison of the three V-ATPase conformations with the structure of nanodisc-bound Vo revealed that Vo is halted in rotational state 3. Combined with our prior work that showed autoinhibited V1-ATPase to be arrested in state 2, we propose a model in which the conformational mismatch between free V1 and Vo functions to prevent unintended reassembly of holo V-ATPase when activity is not needed. PMID- 27965357 TI - Activin/Smad2-induced Histone H3 Lys-27 Trimethylation (H3K27me3) Reduction Is Crucial to Initiate Mesendoderm Differentiation of Human Embryonic Stem Cells. AB - Differentiation of human embryonic stem cells into mesendoderm (ME) is directed by extrinsic signals and intrinsic epigenetic modifications. However, the dynamics of these epigenetic modifications and the mechanisms by which extrinsic signals regulate the epigenetic modifications during the initiation of ME differentiation remain elusive. In this study, we report that levels of histone H3 Lys-27 trimethylation (H3K27me3) decrease during ME initiation, which is essential for subsequent differentiation induced by the combined effects of activin and Wnt signaling. Furthermore, we demonstrate that activin mediates the H3K27me3 decrease via the Smad2-mediated reduction of EZH2 protein level. Our results suggest a two-step process of ME initiation: first, epigenetic priming via removal of H3K27me3 marks and, second, transcription activation. Our findings demonstrate a critical role of H3K27me3 priming and a direct interaction between extrinsic signals and epigenetic modifications during ME initiation. PMID- 27965358 TI - Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals. AB - Dithiocarbamates (DTCs) are important industrial chemicals used extensively as pesticides and in a variety of therapeutic applications. However, they have also been associated with neurotoxic effects and in particular with the development of Parkinson-like neuropathy. Although different pathways and enzymes (such as ubiquitin ligases or the proteasome) have been identified as potential targets of DTCs in the brain, the molecular mechanisms underlying their neurotoxicity remain poorly understood. There is increasing evidence that alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. Interestingly, recent studies with N,N-diethyldithiocarbamate suggest that brain glycogen phosphorylase (bGP) and glycogen metabolism could be altered by DTCs. Here, we provide molecular and mechanistic evidence that bGP is a target of DTCs. To examine this system, we first tested thiram, a DTC pesticide known to display neurotoxic effects, observing that it can react rapidly with bGP and readily inhibits its glycogenolytic activity (kinact = 1.4 * 105 m-1 s-1). Using cysteine chemical labeling, mass spectrometry, and site-directed mutagenesis approaches, we show that thiram (and certain of its metabolites) alters the activity of bGP through the formation of an intramolecular disulfide bond (Cys318-Cys326), known to act as a redox switch that precludes the allosteric activation of bGP by AMP. Given the key role of glycogen metabolism in brain functions and neurodegeneration, impairment of the glycogenolytic activity of bGP by DTCs such as thiram may be a new mechanism by which certain DTCs exert their neurotoxic effects. PMID- 27965360 TI - Screening Guidelines for Venous Thromboembolism Risk in Hospitalized Children Have Low Sensitivity for Central Venous Catheter-Associated Thrombosis. AB - OBJECTIVES: Local pediatric screening guidelines for venous thromboembolism (VTE) are developed from incomplete pediatric data and extrapolated from adult data in which immobility is a major risk factor. We hypothesized that screening guidelines centered on immobility are inadequate for identifying children at risk of central venous catheter (CVC)-associated VTE. METHODS: This retrospective case control (4:1) study at an academic, quaternary-level, free-standing children's hospital applied screening guidelines for VTE risk to all cases of VTE from July 2012 to April 2014. Cases and controls were classified as "at risk" or "not at risk" of VTE by guideline criteria. These guidelines assessed VTE risk factors, including CVC, as reported in the pediatric literature. RESULTS: VTE prevalence was 0.5 per 100 admissions. Sixty-nine of 114 patients with radiographically confirmed VTE were classified as being "at risk" by the guidelines, with a sensitivity of 61%, specificity of 90.8%, a positive predictive value of 2.4%, and negative predictive value of 99.8%. There was no difference in screening guidelines sensitivity for identifying CVC-associated VTE versus non-CVC associated VTE. Half of the 45 patients with VTE who were not captured as being "at risk" did not have decreased mobility, the entry point to the algorithm, and 80% of these patients had a CVC. CONCLUSIONS: Screening guidelines have low sensitivity for identifying hospitalized children at increased risk of both CVC associated and other VTE events. Decreased mobility is not a requirement for CVC associated VTE. Risk factors extrapolated from adult data are insufficient for identifying children at risk of VTE. PMID- 27965359 TI - Activation of the Stress Response Kinase JNK (c-Jun N-terminal Kinase) Attenuates Insulin Action in Retina through a p70S6K1-dependent Mechanism. AB - Despite recent advances in therapeutics, diabetic retinopathy remains a leading cause of vision impairment. Improvement in the treatment of diabetic retinopathy requires a better understanding of the molecular mechanisms that cause neurovascular complications, particularly in type 2 diabetes. Recent studies demonstrate that rodents fed a high fat diet exhibit retinal dysfunction concomitant with attenuated Akt phosphorylation. The purpose of the present study was to evaluate the impact of a high fat/high sucrose diet on retinal insulin signaling and evaluate the mechanism(s) responsible for the changes. Mice fed a high fat/sucrose diet exhibited attenuated Akt phosphorylation in the retina as compared with mice fed normal chow. Retinas of mice fed a high fat/sucrose diet also exhibited elevated levels of activated JNK as well as enhanced p70S6K1 autoinhibitory domain phosphorylation. In cells, JNK activation enhanced p70S6K1 phosphorylation and mTORC1-dependent activation of the kinase, as evidenced by enhanced phosphorylation of key substrates. Rictor phosphorylation by p70S6K1 was specifically enhanced by the addition of phosphomimetic mutations in the autoinhibitory domain and was more sensitive to inhibition of the kinase as compared with rpS6. Notably, rictor and IRS-1 phosphorylation by p70S6K1 attenuate insulin action through a negative feedback pathway. Indeed, p70S6K1 inhibition prevented the repressive effect of JNK activation on insulin action in retinas. Overall, the results identify the JNK/S6K1 axis as a key molecular mechanism whereby a high fat/sucrose diet impairs insulin action in retina. PMID- 27965361 TI - Effect of preceding medications on resuscitation outcome of out-of-hospital cardiac arrest. AB - As evidence regarding the impact of preceding medications on resuscitation outcomes has been inconsistent, this study aimed to analyze the association between preceding medications and resuscitation outcomes in patients experiencing out-of-hospital cardiac arrest (OHCA). This retrospective study included patients with OHCA presenting to a tertiary care hospital by emergency medical service (EMS) between January 2006 and June 2011. Using the Utstein template, data were collected from EMS and hospital medical records for prehospital care, in-hospital care, and medications which were taken continuously for at least 2 weeks preceding OHCA. Primary outcome was the proportion of patients with a survived event. Multivariable logistic regression analyses were performed to evaluate the predictors of survived events. Among the 1381 included patients with OHCA, 552 (40.0%) patients achieved sustained return of spontaneous circulation and 463 (33.5%) patients survived after resuscitation, 96 (7.0%) patients survived until discharge, and 20 (1.4%) patients had a favorable neurological outcome at discharge. The multivariable analyses revealed that use of statins preceding OHCA was independently associated with a greater probability of a survived events (OR=2.09, 95% CI 1.08 to 4.03, p=0.028).Use of digoxin was adversely associated with survived events (OR=0.39, 95% CI 0.16 to 0.90, p=0.028) in patients with OHCA. The continuous use of statins preceding OHCA was positively associated with survived events, while use of digoxin was adversely related. It deserves more attention on medications preceding OHCA because of their potential effect on resuscitation outcomes. PMID- 27965362 TI - Transport and homeostasis of potassium and phosphate: limiting factors for sustainable crop production. AB - Potassium (K) and phosphate (Pi) are both macronutrients essential for plant growth and crop production, but the unrenewable resources of phosphorus rock and potash have become limiting factors for food security. One critical measure to help solve this problem is to improve nutrient use efficiency (NUE) in plants by understanding and engineering genetic networks for ion uptake, translocation, and storage. Plants have evolved multiple systems to adapt to various nutrient conditions for growth and production. Within the NUE networks, transport proteins and their regulators are the primary players for maintaining nutrient homeostasis and could be utilized to engineer high NUE traits in crop plants. A large number of publications have detailed K+ and Pi transport proteins in plants over the past three decades. Meanwhile, the discovery and validation of their regulatory mechanisms are fast-track topics for research. Here, we provide an overview of K+ and Pi transport proteins and their regulatory mechanisms, which participate in the uptake, translocation, storage, and recycling of these nutrients in plants. PMID- 27965363 TI - Regulation of vascular cell division. AB - Vascular tissue, comprising xylem and phloem, is responsible for the transport of water and nutrients throughout the plant body. Such tissue is continually produced from stable populations of stem cells, specifically the procambium during primary growth and the cambium during secondary growth. As the majority of plant biomass is produced by the cambium, there is an obvious demand for an understanding of the genetic mechanisms that control the rate of vascular cell division. Moreover, wood is an industrially important product of the cambium, and research is beginning to uncover similar mechanisms in trees such as poplar. This review focuses upon recent work that has identified the major molecular pathways that regulate procambial and cambial activity. PMID- 27965365 TI - Novel tools for quantifying secondary growth. AB - Secondary growth occurs in dicotyledons and gymnosperms, and results in an increased girth of plant organs. It is driven primarily by the vascular cambium, which produces thousands of cells throughout the life of several plant species. For instance, even in the small herbaceous model plant Arabidopsis, manual quantification of this massive process is impractical. Here, we provide a comprehensive overview of current methods used to measure radial growth. We discuss the issues and problematics related to its quantification. We highlight recent advances and tools developed for automated cellular phenotyping and its future applications. PMID- 27965368 TI - Environmental and hormonal control of cambial stem cell dynamics. AB - Perennial trees have the amazing ability to adjust their growth rate to both adverse and favorable seasonally reoccurring environmental conditions over hundreds of years. In trunks and stems, the basis for the tuning of seasonal growth rate is the regulation of cambial stem cell activity. Cambial stem cell quiescence and dormancy protect the tree from potential physiological and genomic damage caused by adverse growing conditions and may permit a long lifespan. Cambial dormancy and longevity are both aspects of a tree's life for which the study of cambial stem cell behavior in the annual model plant Arabidopsis is inadequate. Recent functional analyses of hormone perception and catabolism mutants in Populus indicate that shoot-derived long-range signals, as well as local cues, steer cambial activity. Auxin is central to the regulation of cambial activity and probably also maintenance. Emerging genome editing and phenotyping technologies will enable the identification of down-stream targets of hormonal action and facilitate the genetic dissection of complex traits of cambial biology. PMID- 27965369 TI - Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder. AB - Although the physiologic role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of beta3-adrenergic receptors (beta3ARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel beta3AR agonist vibegron (MK-4618, KRP 114V) and explored mechanistic interactions of beta3AR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full beta3AR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys. The relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antagonist, compared with coadministration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a beta3AR agonist and tolterodine in contrast to simple additivity with darifenacin. To determine expression in rhesus bladder, we employed a novel beta3AR agonist probe, [3H]MRL 037, that selectively labels beta3 receptors in both urothelium and detrusor smooth muscle. Vibegron administration caused a dose-dependent increase in circulating glycerol and fatty acid levels in rhesus and rat in vivo, suggesting these circulating lipids can be surrogate biomarkers. The translation of our observation to the clinic has yet to be determined, but the combination of beta3AR agonists with M2/M3 antimuscarinics has the potential to redefine the standard of care for the pharmacological treatment of overactive bladder. PMID- 27965370 TI - Genetic characterization of a mouse line with primary aldosteronism. AB - In an attempt to define novel genetic loci involved in the pathophysiology of primary aldosteronism, a mutagenesis screen after treatment with the alkylating agent N-ethyl-N-nitrosourea was established for the parameter aldosterone. One of the generated mouse lines with hyperaldosteronism was phenotypically and genetically characterized. This mouse line had high aldosterone levels but normal creatinine and urea values. The steroidogenic enzyme expression levels in the adrenal gland did not differ significantly among phenotypically affected and unaffected mice. Upon exome sequencing, point mutations were identified in seven candidate genes (Sspo, Dguok, Hoxaas2, Clstn3, Atm, Tipin and Mapk6). Subsequently, animals were stratified into wild-type and mutated groups according to their genotype for each of these candidate genes. A correlation of their genotypes with the respective aldosterone, aldosterone-to-renin ratio (ARR), urea and creatinine values as well as steroidogenic enzyme expression levels was performed. Aldosterone values were significantly higher in animals carrying mutations in four different genes (Sspo, Dguok, Hoxaas2 and Clstn3) and associated statistically significant adrenal Cyp11b2 overexpression as well as increased ARR was present only in mice with Sspo mutation. In contrast, mutations of the remaining candidate genes (Atm, Tipin and Mapk6) were associated with lower aldosterone values and lower Hsd3b6 expression levels. In summary, these data demonstrate association between the genes Sspo, Dguok, Hoxaas2 and Clstn3 and hyperaldosteronism. Final proofs for the causative nature of the mutations have to come from knock-out and knock-in experiments. PMID- 27965371 TI - Metabolic signaling functions of ER-mitochondria contact sites: role in metabolic diseases. AB - Beyond the maintenance of cellular homeostasis and the determination of cell fate, ER-mitochondria contact sites, defined as mitochondria-associated membranes (MAM), start to emerge as an important signaling hub that integrates nutrient and hormonal stimuli and adapts cellular metabolism. Here, we summarize the established structural and functional features of MAM and mainly focus on the latest breakthroughs highlighting a crucial role of organelle crosstalk in the control of metabolic homeostasis. Lastly, we discuss recent studies that have revealed the importance of MAM in not only metabolic diseases but also in other pathologies with disrupted metabolism, shedding light on potential common molecular mechanisms and leading hopefully to novel treatment strategies. PMID- 27965372 TI - 2016 Jack Kenney Award for Outstanding Service. PMID- 27965367 TI - Stem development through vascular tissues: EPFL-ERECTA family signaling that bounces in and out of phloem. AB - Plant cells communicate with each other using a variety of signaling molecules. Recent studies have revealed that various types of secreted peptides, as well as phytohormones known since long ago, mediate cell-cell communication in diverse contexts of plant life. These peptides affect cellular activities, such as proliferation and cell fate decisions, through their perception by cell surface receptors located on the plasma membrane of target cells. ERECTA (ER), an Arabidopsis thaliana receptor kinase gene, was first identified as a stem growth regulator, and since then an increasing number of studies have shown that ER is involved in a wide range of developmental and physiological processes. In particular, molecular functions of ER have been extensively studied in stomatal patterning. Furthermore, the importance of ER signaling in vascular tissues of inflorescence stems, especially in phloem cells, has recently been highlighted. In this review article, first we briefly summarize the history of ER research including studies on stomatal development, then introduce ER functions in vascular tissues, and discuss its interactions with phytohormones and other receptor kinase signaling pathways. Future questions and challenges will also be addressed. PMID- 27965374 TI - Albuminuria is associated with a higher prevalence of depression in a population based cohort study: the Maastricht Study. AB - Background: Depression is common in individuals with chronic kidney disease (CKD). However, data on the association of albuminuria, which together with reduced estimated glomerular filtration rate (eGFR) defines CKD, with depression are scarce and conflicting. In addition, it is not clear when in the course from normal kidney function to CKD the association with depression appears. Methods: We examined the cross-sectional associations of albuminuria and eGFR with depressive symptoms and depressive episodes in 2872 and 3083 40- to 75-year-old individuals, respectively, who completed the baseline survey of an ongoing population-based cohort study conducted in the southern part of The Netherlands between November 2010 and September 2013. Urinary albumin excretion (UAE) was the average UAE in two 24-h urine collections and eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration equation based on creatinine and cystatin C. Depressive symptoms were assessed with the 9-item Patient Health Questionnaire (PHQ-9) and the presence of a minor or major depressive episode was assessed with the MINI-International Neuropsychiatric Interview. Results: In total, 5.4% had a minor or major depressive episode. UAE was <15 mg/24 h in 81.2%, 15-<30 mg/24 h in 10.3% and >=30 mg/24 h in 8.6%. In a multivariable logistic regression analysis adjusted for potential confounders, and with UAE <15 mg/24 h as reference category, the odds ratio for a minor or major depressive episode was 2.13 [95% confidence interval (CI) 1.36-3.36] for UAE 15-<30 mg/24 h and 1.81 (95% CI 1.10-2.98) for UAE >=30 mg/24 h. The average eGFR was 88.2 +/- 14.7 mL/min/1.73 m2. eGFR was not associated with the presence of a minor or major depressive episode. Results were similar when we assessed associations with depressive symptoms or clinically relevant depressive symptoms (PHQ-9 score >=10). Conclusions: Albuminuria was associated with depressive symptoms and depressive episodes, even at levels of UAE that do not fulfil the CKD criteria. Future longitudinal studies should examine the direction of this association and whether albuminuria could serve as a biomarker to identify individuals at risk of depression. PMID- 27965375 TI - Recessive progressive symmetric erythrokeratoderma results from a homozygous loss of-function mutation of KRT83 and is allelic with dominant monilethrix. AB - BACKGROUND: Progressive symmetric erythrokeratoderma (PSEK) is a rare skin disorder characterised by symmetrically distributed demarcated hyperkeratotic plaques, often with associated palmoplantar hyperkeratosis, with new plaques appearing over time. Most cases are inherited in an autosomal dominant manner, although a few cases exhibit apparent autosomal recessive inheritance. OBJECTIVE: To identify the gene underlying autosomal recessive PSEK in a large Pakistani kindred. METHODS: We first carried out autozygosity mapping using microsatellite markers in candidate regions of the genome. We then carried out exome sequencing of five family members, autozygosity mapping and mutation analysis using the exome data and verification by Sanger sequencing. RESULTS: Autozygosity mapping and exome sequencing identified a homozygous frameshift deletion (c.811delA; p.Ser271fs) in KRT83, which co-segregated with the PSEK phenotype in the family and which is expected to abolish keratin 83, a type II keratin of hair and skin. CONCLUSIONS: At least some cases of PSEK result from loss-of-function mutations in KRT83. Heterozygous missense substitutions in KRT83 have been implicated in autosomal dominant monilethrix, a rare hair disorder. Our findings indicate that at least some cases of autosomal recessive PSEK and autosomal dominant monilethrix are allelic, respectively resulting from loss-of-function and missense mutations in the KRT83 gene. Together, these findings indicate that different types of mutations in KRT83 can result in quite different skin and hair phenotypes. PMID- 27965376 TI - The Timetree of Prokaryotes: New Insights into Their Evolution and Speciation. AB - The increasing size of timetrees in recent years has led to a focus on diversification analyses to better understand patterns of macroevolution. Thus far, nearly all studies have been conducted with eukaryotes primarily because phylogenies have been more difficult to reconstruct and calibrate to geologic time in prokaryotes. Here, we have estimated a timetree of 11,784 'species' of prokaryotes and explored their pattern of diversification. We used data from the small subunit ribosomal RNA along with an evolutionary framework from previous multi-gene studies to produce three alternative timetrees. For each timetree we surprisingly found a constant net diversification rate derived from an exponential increase of lineages and showing no evidence of saturation (rate decline), the same pattern found previously in eukaryotes. The implication is that prokaryote diversification as a whole is the result of the random splitting of lineages and is neither limited by existing diversity (filled niches) nor responsive in any major way to environmental changes. PMID- 27965377 TI - Twenty-year Follow-up of Kangaroo Mother Care Versus Traditional Care. AB - BACKGROUND AND OBJECTIVES: Kangaroo mother care (KMC) is a multifaceted intervention for preterm and low birth weight infants and their parents. Short- and mid-term benefits of KMC on survival, neurodevelopment, breastfeeding, and the quality of mother-infant bonding were documented in a randomized controlled trial (RCT) conducted in Colombia from 1993 to 1996. The aim of the present study was to evaluate the persistence of these results in young adulthood. METHODS: From 2012 to 2014, a total of 494 (69%) of the 716 participants of the original RCT known to be alive were identified; 441 (62% of the participants in the original RCT) were re-enrolled, and results for the 264 participants weighing <=1800 g at birth were analyzed. The KMC and control groups were compared for health status and neurologic, cognitive, and social functioning with the use of neuroimaging, neurophysiological, and behavioral tests. RESULTS: The effects of KMC at 1 year on IQ and home environment were still present 20 years later in the most fragile individuals, and KMC parents were more protective and nurturing, reflected by reduced school absenteeism and reduced hyperactivity, aggressiveness, externalization, and socio-deviant conduct of young adults. Neuroimaging showed larger volume of the left caudate nucleus in the KMC group. CONCLUSIONS: This study indicates that KMC had significant, long-lasting social and behavioral protective effects 20 years after the intervention. Coverage with this efficient and scientifically based health care intervention should be extended to the 18 million infants born each year who are candidates for the method. PMID- 27965379 TI - Kangaroo Mother Care 20 Years Later: Connecting Infants and Families. PMID- 27965378 TI - Improving Mental Health Access for Low-Income Children and Families in the Primary Care Setting. AB - Poverty is a common experience for many children and families in the United States. Children <18 years old are disproportionately affected by poverty, making up 33% of all people in poverty. Living in a poor or low-income household has been linked to poor health and increased risk for mental health problems in both children and adults that can persist across the life span. Despite their high need for mental health services, children and families living in poverty are least likely to be connected with high-quality mental health care. Pediatric primary care providers are in a unique position to take a leading role in addressing disparities in access to mental health care, because many low-income families come to them first to address mental health concerns. In this report, we discuss the impact of poverty on mental health, barriers to care, and integrated behavioral health care models that show promise in improving access and outcomes for children and families residing in the contexts of poverty. We also offer practice recommendations, relevant to providers in the primary care setting, that can help improve access to mental health care in this population. PMID- 27965380 TI - Trends in Weight-for-Length Among Infants in WIC From 2000 to 2014. AB - OBJECTIVES: To describe the prevalence and secular trends of high weight-for length among infants (ages, 3-23 months) in the biennial US Department of Agriculture Women, Infants, and Children Program and Participants Characteristic (WIC-PC) Survey from 2000 through 2014 (n = 16 927 120). METHODS: Weight-for length was considered to be "high" if it was >=2 SDs above the sex- and age specific median in the World Health Organization growth standards. Poisson regression was used to calculate adjusted prevalence ratios. RESULTS: The overall prevalence of high weight-for-length increased from 13.4% in 2000 to 14.5% in 2004, remained constant until 2010, and then decreased by >2 percentage points (to 12.3%) through 2014. The prevalence of high weight-for-length was associated with sex (higher among boys), race-ethnicity (highest among American Indians/Alaskan Natives), and with both age (positive) and family income (inverse). The secular trends, however, were fairly similar within categories of these variables. From 2010 to 2014, the prevalence of high weight-for-length decreased in 40 states and 3 (of 5) US territories, with the largest decreases seen in Puerto Rico (-9 percentage points) and Kentucky (-7 percentage points), and the largest increase (+2 percentage points) seen in West Virginia. CONCLUSIONS: Although the current results cannot be considered representative of infants in the populations, the prevalence of a high weight-for-length has decreased among infants in WIC-PC since 2010. These decreases were similar across categories of most characteristics, but there were substantial differences across jurisdictions, possibly reflecting differences in policy and local programs that target maternal and infant health. PMID- 27965382 TI - Predictors for venous sinus stent retreatment in patients with idiopathic intracranial hypertension. AB - BACKGROUND: Venous sinus stenting for dural sinus stenoses is an emerging alternative to cerebrospinal fluid diversion in cases of medically refractory idiopathic intracranial hypertension. Juxta-stent 're-stenoses' have been reported and managed alternatively with ventricular shunting or stent revision. Identification of factors that might predispose patients to recurrent narrowing may help to select or exclude patients with idiopathic intracranial hypertension for venous sinus stenting. METHODS: We retrospectively reviewed a prospectively maintained database spanning December 2011 to May 2015 of all patients with idiopathic intracranial hypertension who were screened for possible venous sinus stenting, including only patients who received a stent, noting symptomatic improvements, changes in opening lumbar puncture pressure, demographic characteristics, and any subsequent intervention after stent placement. Fisher's exact test and logistic regression were used to test each of seven potential predictors for retreatment. RESULTS: There were eight revisions in 31 patients (25.8%). Among Caucasians, 8.0% required a revision compared with 100% of African Americans (p<0.001). The c-index for race was 0.857. Body mass index (BMI) was also a significant predictor of revision (p=0.031): among class III obese patients the revision rate was 46.2% compared with 16.7% among class I and II obese patients and 0% among overweight to normal weight patients. CONCLUSIONS: BMI was a significant predictor of revision, suggesting that higher BMI may have a higher risk of revision. The small number of African-Americans in the study makes interpretation of the practical significance of the revision rate in these patients uncertain. None of the other studied factors was statistically significant. PMID- 27965381 TI - Opercular Index Score: a CT angiography-based predictor of capillary robustness and neurological outcomes in the endovascular management of acute ischemic stroke. AB - BACKGROUND: Many CT angiography (CTA) collateral scoring systems are either subjective or complex and time consuming. OBJECTIVE: To evaluate the correlation between a CTA collateral scoring system-the Opercular Index Score (OIS)-with neurological outcomes at 90 days following endovascular treatment for acute ischemic stroke (AIS) secondary to large vessel occlusion. METHODS: Fifty-five patients with AIS due to distal internal carotid artery, M1, or proximal M2 occlusions who underwent endovascular treatment were included. OIS was retrospectively calculated from CTA images, reconstructed from CT perfusion imaging, as the ratio of opacified M3 opercular branches in the Sylvian fissure on the unaffected side to those on the stroke side and dichotomized into favorable (OIS<=2) and poor (OIS>2). The ability of OIS to predict good neurological outcomes (modified Rankin Scale score <=2 at 90 days) was assessed using sensitivity, specificity, and area under the curve (AUC) with receiver operating characteristic analysis. RESULTS: Thirty-five patients had a favorable OIS and 20 patients had a poor OIS. Patients with favorable OIS had an 80.0% (n=28) rate of good neurological outcomes compared with 15.0% (n=3) of patients with a poor OIS (p<0.0001). On multivariate logistic regression analysis adjusting for baseline National Institutes of Health Stroke Scale score, OIS, and device used, favorable OIS was the only variable independently associated with good neurological outcome (OR=17.2, 95% CI 3.8 to 104.3) and demonstrated a sensitivity of 90.3% and specificity of 70.8% with an AUC of 0.822. CONCLUSIONS: OIS is a simple and practical non-invasive scoring system that can be used to predict collateral robustness and good neurological outcome among patients with AIS undergoing endovascular treatment. PMID- 27965383 TI - Defects in CD4+ T cell LFA-1 integrin-dependent adhesion and proliferation protect Cd47-/- mice from EAE. AB - CD47 is known to play an important role in CD4+ T cell homeostasis. We recently reported a reduction in mice deficient in the Cd47 gene (Cd47-/-) CD4+ T cell adhesion and transendothelial migration (TEM) in vivo and in vitro as a result of impaired expression of high-affinity forms of LFA-1 and VLA-4 integrins. A prior study concluded that Cd47-/- mice were resistant to experimental autoimmune encephalomyelitis (EAE) as a result of complete failure in CD4+ T cell activation after myelin oligodendrocyte glycoprotein peptide 35-55 aa (MOG35-55) immunization. As the prior EAE study was published before our report, authors could not have accounted for defects in T cell integrin function as a mechanism to protect Cd47-/- in EAE. Thus, we hypothesized that failure of T cell activation involved defects in LFA-1 and VLA-4 integrins. We confirmed that Cd47 /- mice were resistant to MOG35-55-induced EAE. Our data, however, supported a different mechanism that was not a result of failure of CD4+ T cell activation. Instead, we found that CD4+ T cells in MOG35-55-immunized Cd47-/- mice were activated, but clonal expansion contracted within 72 h after immunization. We used TCR crosslinking and mitogen activation in vitro to investigate the underlying mechanism. We found that naive Cd47-/- CD4+ T cells exhibited a premature block in proliferation and survival because of impaired activation of LFA-1, despite effective TCR-induced activation. These results identify CD47 as an important regulator of LFA-1 and VLA-4 integrin-adhesive functions in T cell proliferation, as well as recruitment, and clarify the roles played by CD47 in MOG35-55-induced EAE. PMID- 27965384 TI - Signal transducer and activator of transcription 3 (Stat3) regulates host defense and protects mice against herpes simplex virus-1 (HSV-1) infection. AB - Signal transducer and activator of transcription 3 (STAT3) mediates cellular responses to multiple cytokines, governs gene expression, and regulates the development and activation of immune cells. STAT3 also modulates reactivation of latent herpes simplex virus-1 (HSV-1) in ganglia. However, it is unclear how STAT3 regulates the innate immune response during the early phase of HSV-1 lytic infection. Many cell types critical for the innate immunity are derived from the myeloid lineage. Therefore, in this study, we used myeloid-specific Stat3 knockout mice to investigate the role of STAT3 in the innate immune response against HSV-1. Our results demonstrate that Stat3 knockout bone marrow-derived macrophages (BMMs) expressed decreased levels of interferon-alpha (IFN-alpha) and interferon-stimulated genes (ISGs) upon HSV-1 infection. In vivo, knockout mice were more susceptible to HSV-1, as marked by higher viral loads and more significant weight loss. Splenic expression of IFN-alpha and ISGs was reduced in the absence of STAT3, indicating that STAT3 is required for optimal type I interferon response to HSV-1. Expression of TNF-alpha and IL-12, cytokines that have been shown to limit HSV-1 replication and pathogenesis, was also significantly lower in knockout mice. Interestingly, Stat3 knockout mice failed to expand the CD8+ conventional DC (cDC) population upon HSV-1 infection, and this was accompanied by impaired NK and CD8 T cell activation. Collectively, our data demonstrate that myeloid-specific Stat3 deletion causes defects in multiple aspects of the immune system and that STAT3 has a protective role at the early stage of systemic HSV-1 infection. PMID- 27965385 TI - Frontline Science: HMGB1 induces neutrophil dysfunction in experimental sepsis and in patients who survive septic shock. AB - Sepsis is accompanied by the initial activation of proinflammatory pathways and long-lasting immunosuppression that appears to contribute to late-occurring mortality. Although high-mobility group box 1 (HMGB1) is involved in many aspects of inflammation, its role in sepsis-induced immune suppression remains unclear. In this study, we examined HMGB1's contribution to neutrophil NADPH oxidase activity dysfunction and associated neutrophil-dependent bacterial clearance in mice subjected to sepsis and in patients who survive septic shock. Using a murine model of polymicrobial septic peritonitis, we demonstrated that treatment with anti-HMGB1 Ab significantly diminished sepsis-induced dysfunction of neutrophil NADPH oxidase activity. In a subsequent set of experiments, we found that blocking HMGB1 preserved the ability of neutrophils from patients recovering from septic shock to activate NADPH oxidase. Taken together, our data suggest that HMGB1 accumulation in the late phase of sepsis plays a specific role in the development of postsepsis immunosuppression and specifically affects neutrophil dependent antibacterial defense mechanisms. Thus, blocking HMGB1 may be a promising therapeutic intervention to diminish the adverse effects of sepsis induced immunosuppression. PMID- 27965386 TI - Active-site MMP-selective antibody inhibitors discovered from convex paratope synthetic libraries. AB - Proteases are frequent pharmacological targets, and their inhibitors are valuable drugs in multiple pathologies. The catalytic mechanism and the active-site fold, however, are largely conserved among the protease classes, making the development of the selective inhibitors exceedingly challenging. In our departure from the conventional strategies, we reviewed the structure of known camelid inhibitory antibodies, which block enzyme activities via their unusually long, convex-shaped paratopes. We synthesized the human Fab antibody library (over 1.25 * 109 individual variants) that carried the extended, 23- to 27-residue, complementarity-determining region (CDR)-H3 segments. As a proof of principle, we used the catalytic domain of matrix metalloproteinase-14 (MMP-14), a promalignant protease and a drug target in cancer, as bait. In our screens, we identified 20 binders, of which 14 performed as potent and selective inhibitors of MMP-14 rather than as broad-specificity antagonists. Specifically, Fab 3A2 bound to MMP 14 in the vicinity of the active pocket with a high 4.8 nM affinity and was similarly efficient (9.7 nM) in inhibiting the protease cleavage activity. We suggest that the convex paratope antibody libraries described here could be readily generalized to facilitate the design of the antibody inhibitors to many additional enzymes. PMID- 27965387 TI - PMS1T, producing phased small-interfering RNAs, regulates photoperiod-sensitive male sterility in rice. AB - Phased small-interfering RNAs (phasiRNAs) are a special class of small RNAs, which are generated in 21- or 24-nt intervals from transcripts of precursor RNAs. Although phasiRNAs have been found in a range of organisms, their biological functions in plants have yet to be uncovered. Here we show that phasiRNAs generated by the photopheriod-sensetive genic male sterility 1 (Pms1) locus were associated with photoperiod-sensitive male sterility (PSMS) in rice, a germplasm that started the two-line hybrid rice breeding. The Pms1 locus encodes a long noncoding RNA PMS1T that was preferentially expressed in young panicles. PMS1T was targeted by miR2118 to produce 21-nt phasiRNAs that preferentially accumulated in the PSMS line under long-day conditions. A single nucleotide polymorphism in PMS1T nearby the miR2118 recognition site was critical for fertility change, likely leading to differential accumulation of the phasiRNAs. This result suggested possible roles of phasiRNAs in reproductive development of rice, demonstrating the potential importance of this RNA class as regulators in biological processes. PMID- 27965388 TI - TIFA as a crucial mediator for NLRP3 inflammasome. AB - Toll-like receptor-mediated NF-kappaB activation is a major innate immune reaction of vascular endothelial cells (ECs) in response to prooxidative and proinflammatory stimuli. We identified that TNF-alpha receptor-associated factor interacting protein with a forkhead-associated domain (TIFA) is a regulator of priming (signal 1) and activating (signal 2) signals of nucleotide oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome in ECs. Oxidative and inflammatory stresses such as atheroprone flow and hyperlipidemia induce and activate TIFA in vitro and in vivo. For the priming of signal 1, sterol regulatory element-binding protein 2 transactivates TIFA, which in turn induces NF-kappaB activation and augments the transcription of NLRP3 inflammasome components. For the activation of signal 2, Akt is involved in TIFA Thr9 phosphorylation, which is essential for TIFA-TIFA homophilic oligomerization. Thr9 phosphorylation-dependent TIFA oligomerization facilitates the higher-order assembly of NLRP3 inflammasome, as indicated by the interaction between TIFA and caspase-1 in the activated ECs. Our results suggest that TIFA is a crucial mediator in the endothelial innate immune response by potentiating and amplifying NLRP3 inflammasome via augmenting signals 1 and 2. PMID- 27965389 TI - Conservation of coevolving protein interfaces bridges prokaryote-eukaryote homologies in the twilight zone. AB - Protein-protein interactions are fundamental for the proper functioning of the cell. As a result, protein interaction surfaces are subject to strong evolutionary constraints. Recent developments have shown that residue coevolution provides accurate predictions of heterodimeric protein interfaces from sequence information. So far these approaches have been limited to the analysis of families of prokaryotic complexes for which large multiple sequence alignments of homologous sequences can be compiled. We explore the hypothesis that coevolution points to structurally conserved contacts at protein-protein interfaces, which can be reliably projected to homologous complexes with distantly related sequences. We introduce a domain-centered protocol to study the interplay between residue coevolution and structural conservation of protein-protein interfaces. We show that sequence-based coevolutionary analysis systematically identifies residue contacts at prokaryotic interfaces that are structurally conserved at the interface of their eukaryotic counterparts. In turn, this allows the prediction of conserved contacts at eukaryotic protein-protein interfaces with high confidence using solely mutational patterns extracted from prokaryotic genomes. Even in the context of high divergence in sequence (the twilight zone), where standard homology modeling of protein complexes is unreliable, our approach provides sequence-based accurate information about specific details of protein interactions at the residue level. Selected examples of the application of prokaryotic coevolutionary analysis to the prediction of eukaryotic interfaces further illustrate the potential of this approach. PMID- 27965390 TI - DNA methylation in the gene body influences MeCP2-mediated gene repression. AB - Rett syndrome is a severe neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein gene (MECP2). MeCP2 is a methyl-cytosine binding protein that is proposed to function as a transcriptional repressor. However, multiple gene expression studies comparing wild-type and MeCP2-deficient neurons have failed to identify gene expression changes consistent with loss of a classical transcriptional repressor. Recent work suggests that one function of MeCP2 in neurons is to temper the expression of the longest genes in the genome by binding to methylated CA dinucleotides (mCA) within transcribed regions of these genes. Here we explore the mechanism of mCA and MeCP2 in fine tuning the expression of long genes. We find that mCA is not only highly enriched within the body of genes normally repressed by MeCP2, but also enriched within extended megabase-scale regions surrounding MeCP2-repressed genes. Whereas enrichment of mCA exists in a broad region around these genes, mCA together with mCG within gene bodies appears to be the primary driver of gene repression by MeCP2. Disruption of methylation at CA sites within the brain results in depletion of MeCP2 across genes that normally contain a high density of gene-body mCA. We further find that the degree of gene repression by MeCP2 is proportional to the total number of methylated cytosine MeCP2 binding sites across the body of a gene. These findings suggest a model in which MeCP2 tunes gene expression in neurons by binding within the transcribed regions of genes to impede the elongation of RNA polymerase. PMID- 27965392 TI - Is there a pathway for N2O production from hydroxylamine oxidoreductase in ammonia-oxidizing bacteria? PMID- 27965391 TI - Reducing future fears by suppressing the brain mechanisms underlying episodic simulation. AB - Imagining future events conveys adaptive benefits, yet recurrent simulations of feared situations may help to maintain anxiety. In two studies, we tested the hypothesis that people can attenuate future fears by suppressing anticipatory simulations of dreaded events. Participants repeatedly imagined upsetting episodes that they feared might happen to them and suppressed imaginings of other such events. Suppressing imagination engaged the right dorsolateral prefrontal cortex, which modulated activation in the hippocampus and in the ventromedial prefrontal cortex (vmPFC). Consistent with the role of the vmPFC in providing access to details that are typical for an event, stronger inhibition of this region was associated with greater forgetting of such details. Suppression further hindered participants' ability to later freely envision suppressed episodes. Critically, it also reduced feelings of apprehensiveness about the feared scenario, and individuals who were particularly successful at down regulating fears were also less trait-anxious. Attenuating apprehensiveness by suppressing simulations of feared events may thus be an effective coping strategy, suggesting that a deficiency in this mechanism could contribute to the development of anxiety. PMID- 27965393 TI - Twist of generalized skyrmions and spin vortices in a polariton superfluid. AB - We study the spin vortices and skyrmions coherently imprinted into an exciton polariton condensate on a planar semiconductor microcavity. We demonstrate that the presence of a polarization anisotropy can induce a complex dynamics of these structured topologies, leading to the twist of their circuitation on the Poincare sphere of polarizations. The theoretical description of the results carries the concept of generalized quantum vortices in two-component superfluids, which are conformal with polarization loops around an arbitrary axis in the pseudospin space. PMID- 27965395 TI - Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. AB - BACKGROUND: Cerebellar ataxias are the result of diverse disease processes that can be genetic or acquired. Establishing a diagnosis requires a methodical approach with expert clinical evaluation and investigations. We describe the causes of ataxia in 1500 patients with cerebellar ataxia. METHODS: All patients were referred to the Sheffield Ataxia Centre, UK, and underwent extensive investigations, including, where appropriate genetic testing using next generation sequencing (NGS). Patients were followed up on a 6-monthly basis for reassessment and further investigations if indicated. RESULTS: A total of 1500 patients were assessed over 20 years. Twenty per cent had a family history, the remaining having sporadic ataxia. The commonest cause of sporadic ataxia was gluten ataxia (25%). A genetic cause was identified in 156 (13%) of sporadic cases with other causes being alcohol excess (12%) and cerebellar variant of multiple system atrophy (11%). Using NGS, positive results were obtained in 32% of 146 patients tested. The commonest ataxia identified was EA2. A genetic diagnosis was achieved in 57% of all familial ataxias. The commonest genetic ataxias were Friedreich's ataxia (22%), SCA6 (14%), EA2 (13%), SPG7 (10%) and mitochondrial disease (10%). The diagnostic yield following attendance at the Sheffield Ataxia Centre was 63%. CONCLUSIONS: Immune-mediated ataxias are common. Advances in genetic testing have significantly improved the diagnostic yield of patients suspected of having a genetic ataxia. Making a diagnosis of the cause of ataxia is essential due to potential therapeutic interventions for immune and some genetic ataxias. PMID- 27965396 TI - The tough body at the epicentre of amyotrophic lateral sclerosis. PMID- 27965394 TI - Perspectives on the role of mobility, behavior, and time scales in the spread of diseases. AB - The dynamics, control, and evolution of communicable and vector-borne diseases are intimately connected to the joint dynamics of epidemiological, behavioral, and mobility processes that operate across multiple spatial, temporal, and organizational scales. The identification of a theoretical explanatory framework that accounts for the pattern regularity exhibited by a large number of host parasite systems, including those sustained by host-vector epidemiological dynamics, is but one of the challenges facing the coevolving fields of computational, evolutionary, and theoretical epidemiology. Host-parasite epidemiological patterns, including epidemic outbreaks and endemic recurrent dynamics, are characteristic to well-identified regions of the world; the result of processes and constraints such as strain competition, host and vector mobility, and population structure operating over multiple scales in response to recurrent disturbances (like El Nino) and climatological and environmental perturbations over thousands of years. It is therefore important to identify and quantify the processes responsible for observed epidemiological macroscopic patterns: the result of individual interactions in changing social and ecological landscapes. In this perspective, we touch on some of the issues calling for the identification of an encompassing theoretical explanatory framework by identifying some of the limitations of existing theory, in the context of particular epidemiological systems. Fostering the reenergizing of research that aims at disentangling the role of epidemiological and socioeconomic forces on disease dynamics, better understood as complex adaptive systems, is a key aim of this perspective. PMID- 27965397 TI - REM sleep behaviour disorder: prodromal and mechanistic insights for Parkinson's disease. AB - Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterised by complex motor enactment of dreams and is a potential prodromal marker of Parkinson's disease (PD). Of note, patients with PD observed during RBD episodes exhibit improved motor function, relative to baseline states during wake periods. Here, we review recent epidemiological and mechanistic findings supporting the prodromal value of RBD for PD, incorporating clinical and electrophysiological studies. Explanations for the improved motor function during RBD episodes are evaluated in light of recent publications. In addition, we present preliminary findings describing changes in the activity of the basal ganglia across the sleep wake cycle that contribute to our understanding of RBD. PMID- 27965398 TI - Computational flow cytometry reveals that cryopreservation induces spermptosis but subpopulations of spermatozoa may experience capacitation-like changes. AB - The reduced lifespan of cryopreserved spermatozoa in the mare reproductive tract has been attributed to both capacitative and apoptotic changes. However, there is a lack of studies investigating both phenomena simultaneously. In order to improve our knowledge in this particular point, we studied in raw and frozen thawed samples apoptotic and capacitative markers using a wide battery of test based in flow cytometry. Apoptotic markers evaluated were caspase 3 activity, externalization of phosphatidylserine (PS), and mitochondrial membrane potential. Markers of changes resembling capacitation were membrane fluidity, tyrosine phosphorylation, and intracellular sodium. Conventional and computational flow cytometry using nonlinear dimensionally reduction techniques (t-distributed stochastic neighbor embedding (t-SNE)) and automatic classification of cellular expression by nonlinear stochastic embedding (ACCENSE) were used. Most of the changes induced by cryopreservation were apoptotic, with increase in caspase 3 activation (P < 0.01), PS translocation to the outer membrane (P < 0.001), loss of mitochondrial membrane potential (P < 0.05), and increase in intracellular Na+ (P < 0.01). Average values of markers of capacitative changes were not affected by cryopreservation; however, the analysis of the phenotype of individual spermatozoa using computational flow cytometry revealed the presence of subpopulations of spermatozoa experiencing capacitative changes. For the first time advanced computational techniques were applied to the analysis of spermatozoa, and these techniques were able to disclose relevant information of the ejaculate that remained hidden using conventional flow cytometry. PMID- 27965400 TI - Decreased levels of sRAGE in follicular fluid from patients with PCOS. AB - This study aimed to explore the association between soluble receptor for advanced glycation end products (sRAGE) levels in follicular fluid and the number of oocytes retrieved and to evaluate the effect of sRAGE on vascular endothelial growth factor (VEGF) in granulosa cells in patients with polycystic ovarian syndrome (PCOS). Two sets of experiments were performed in this study. In part one, sRAGE and VEGF protein levels in follicular fluid samples from 39 patients with PCOS and 35 non-PCOS patients were measured by ELISA. In part two, ovarian granulosa cells were isolated from an additional 10 patients with PCOS and cultured. VEGF and SP1 mRNA and protein levels, as well as pAKT levels, were detected by real-time PCR and Western blotting after cultured cells were treated with different concentrations of sRAGE. Compared with the non-PCOS patients, patients with PCOS had lower sRAGE levels in follicular fluid. Multi-adjusted regression analysis showed that high sRAGE levels in follicular fluid predicted a lower Gn dose, more oocytes retrieved, and a better IVF outcome in the non-PCOS group. Logistic regression analysis showed that higher sRAGE levels predicted favorably IVF outcomes in the non-PCOS group. Multi-adjusted regression analysis also showed that high sRAGE levels in follicular fluid predicted a lower Gn dose in the PCOS group. Treating granulosa cells isolated from patients with PCOS with recombinant sRAGE decreased VEGF and SP1 mRNA and protein expression and pAKT levels in a dose-dependent manner. PMID- 27965401 TI - Bovine piRNA-like RNAs are associated with both transposable elements and mRNAs. AB - PIWI proteins and their associated piRNAs have been the focus of intensive research in the past decade; therefore, their participation in the maintenance of genomic integrity during spermatogenesis has been well established. Recent studies have suggested important roles for the PIWI/piRNA system outside of gametogenesis, based on the presence of piRNAs and PIWI proteins in several somatic tissues, cancers, and the early embryo. Here, we investigated the small RNA complement present in bovine gonads, gametes, and embryos through next generation sequencing. A distinct piRNA population was present in the testis as expected. However, we also found a large population of slightly shorter, 24-27 nt piRNA-like RNA (pilRNAs) in pools of oocytes and zygotes. These oocyte and embryo pilRNAs exhibited many of the canonical characteristics of piRNAs including a 1U bias, the presence of a 'ping-pong' signature, genomic clustering, and transposable element targeting. Some of the major transposons targeted by oocyte and zygote pilRNA were from the LINE RTE and ERV1 classes. We also identified pools of pilRNA potentially derived from, or targeted at, specific mRNA sequences. We compared the frequency of these gene-associated pilRNAs to the fold change in the expression of respective mRNAs from two previously reported transcriptome datasets. We observed significant negative correlations between the number of pilRNAs targeting mRNAs, and their fold change in expression between the 4-8 cell and 8-16 cell stages. Together, these results represent one of the first characterizations of the PIWI/piRNA pathway in the translational bovine model, and in the novel context of embryogenesis. PMID- 27965399 TI - Selenium-Binding Protein 1 (SBP1) autoantibodies in ovarian disorders and ovarian cancer. AB - Infertility is a risk factor for ovarian cancer (OvCa). The goal was to determine if antibodies to selenium-binding protein 1 (SBP1), an autoantibody we identified in patients with premature ovarian failure (POF), occurs in both infertility and OvCa patients, and thus could be associated with preneoplasia. Anti-SBP1 was measured by immunoassay against recombinant SBP1, in sera from OvCa (n = 41), infertility (n = 92) and control (n = 87) patients. Infertility causes were POF, unexplained, irregular ovulation or endometriosis. The percent of anti-SBP1 positive sera was higher in POF (P = 0.02), irregular ovulation (P = 0.001), unexplained causes (P = 0.02), late (III-IV)-stage OvCa (P = 0.02) but was not significant in endometriosis, benign ovarian tumors/cysts, early stage (I-II) OvCa or uterine cancer compared to healthy controls. Anti-SBP1 was significantly higher in women with serous (P = 0.04) but not non-serous (P = 0.33) OvCa compared to controls. Also, we determined if anti-SBP1 was associated with CA125 or anti-TP53, markers often studied in OvCa. Anti-TP53 and CA125 were measured by established immunoassays. The ability of anti-SBP1 alone to discriminate infertility or OvCa from controls or when combined with anti-TP53 and CA125, to identify OvCa was evaluated by comparing the area under the curve (AUC) in ROC analysis. Anti-SBP1 alone discriminated infertility (AUC = 0.7; P = 0.001) or OvCa (AUC = 0.67; P = 0.03) from controls. The sensitivity and specificity of OvCa identification was increased by combining CA125, anti-TP53 and anti-SBP1 (AUC = 0.96). Therefore, anti-SBP1 occurs in infertile women with POF, ovulatory disturbances or unexplained infertility and in serous OvCa. This suggests an autoimmune process is associated with the development of serous OvCa. PMID- 27965402 TI - Respiratory symptoms in people living with HIV and the effect of antiretroviral therapy: a systematic review and meta-analysis. AB - BACKGROUND: Antiretroviral therapy (ART) has significantly altered the pattern of acute and chronic HIV-related disease. However, it is not clear what this means in terms of respiratory symptoms. We sought to investigate the association between HIV status and respiratory symptoms and how these have changed with the availability of ART. METHODS: We searched Cochrane, Medline and Embase databases for studies published between 1946 and August 2015 comparing the prevalence of respiratory symptoms in populations with and without HIV infection. We undertook random effects meta-analysis of the main symptoms reported. We studied heterogeneity and completed sensitivity analyses and funnel plots. RESULTS: From 5788 unique references identified, 24 papers provided relevant data: 18 documented the prevalence of cough and 11 examined the prevalence of breathlessness among other symptoms reported. Compared with the HIV negative, people living with HIV (PLWH) were more likely to have respiratory symptoms with pooled ORs for the prevalence of cough of 3.05 (95% CI 2.24 to 4.16) in resource limited populations without access to ART; 2.18 (1.56 to 3.18) in resource-rich populations without access to ART and 1.11 (0.99 to 1.24) in resource-rich populations with access to ART. In resource-rich settings, although the availability of ART was associated with a reduction in the difference between HIV positive and HIV-negative individuals, PLWH were more likely to report breathlessness, OR 1.39 (95% CI 1.11 to 1.73). CONCLUSIONS: Respiratory symptoms are more common in PLWH than controls. This association persists although at a reduced level in populations with access to ART. PMID- 27965403 TI - Innate and Learned Olfactory Responses in a Wild Population of the Egg Parasitoid Trichogramma (Hymenoptera: Trichogrammatidae). AB - Parasitoid insects face the fundamental problem of finding a suitable host in environments filled with competing stimuli. Many are deft sensors of olfactory cues emitted by other insects and the plants they live on, and use these cues to find hosts. Using olfactory cues from host-plants is effective because plants release volatile organic compounds (VOCs), in response to herbivory or oviposition, that contain information about the presence of hosts. However, plant produced cues can also be misleading because they are influenced by a variety of stimuli (abiotic variation, infection and multiple sources of induction via herbivory or oviposition). Flexible behavior is one strategy that parasitoids may use to cope with variation in olfactory cues. We examine the innate and learned responses of a natural population of wasp egg parasitoids (Trichogramma deion and Trichogramma sathon) using a series of laboratory and field Y-olfactometer experiments. Wasps typically attack eggs of the hawkmoth Manduca sexta and Manduca quinquemaculata on native Datura wrightii plants in the southwestern United States. We show that Trichogramma wasps responded innately to VOCs produced by D. wrightii and could distinguish plants recently attacked by M. sexta from non-attacked plants. Furthermore, adult Trichogramma wasps were able to learn components of the VOC blend given off by D. wrightii, though they did not learn during exposure as pupae. By further exploring the behavioral ecology of a natural population of Trichogramma, we gain greater insight into how egg parasitoids function in tri-trophic systems. PMID- 27965404 TI - Targeted genome editing in a quail cell line using a customized CRISPR/Cas9 system. AB - Soon after RNA-guided Cas9 (CRISPR-associated protein 9) endonuclease opened a new era of targeted genome editing, the CRISPR/Cas9 platform began to be extensively used to modify genes in various types of cells and organisms. However, successful CRISPR/Cas9-mediated insertion/deletion (indel) mutation remains to be demonstrated in avian cell lines. The objective of this study was to design a poultry-specific CRISPR/Cas9 system to efficiently introduce targeted deletion mutation in chromosomes of the quail muscle clone 7 (QM7) cell line using a customized quail CRISPR vector. In this study, two avian-specific promoters, quail 7SK (q7SK) promoter and CBh promoter, the hybrid form of cytomegalovirus and chicken beta-actin promoters, were cloned into a CRISPR vector for the expression of guide RNA and Cas9 protein, respectively. Then, guide RNA, which was designed to target 20-base pair (bp) nucleotides in the quail melanophilin (MLPH) locus, was ligated to the modified CRISPR vector and transfected to QM7 cells. Our results showed multiple indel mutations in the quail MLPH locus in nearly half of the alleles being tested, suggesting the high efficiency of the system for targeted gene modification. The new CRISPR vector developed from this study has the potential application to generate knockout avian cell lines and knockout poultry. PMID- 27965405 TI - Critical limits for the control points for halal poultry slaughter. AB - This study proposes critical limits (CL) for control points for halal slaughter (CPHS). Previously, 6 control points (CP) were determined, and CL for these 6 CPHS are suggested based on: 1) a literature survey for the CL for CP 1 (poultry breeding, rearing, and poultry feed) and CP 2 (welfare of poultry during transportation and lairage); 2) a field survey of slaughter plants in Kuantan (Malaysia) for CP 3 (immobilization), CP 4 (slaughter), CP 5 (time for full bleed out), and CP 6 (washing and packaging); and 3) controlled experiments to refine the CL for CP 3, 4, and 5. The CL for CP 1 focused on stress reduction during rearing and use of substances that could compromise poultry meat wholesomeness. The CL for CP 2 emphasizes humane best-practices for handling poultry during lairage. The CL for CP 3 suggests a gap of 5 s between 2 shackles if only one shackler is employed and shackling times of <1 min for live chickens. In countries permitting water-bath electrical stunning of halal poultry, the stunning current needed to induce unconsciousness must be defined for the breed and bird size but not cause any chicken deaths. The CL for CP 4 mandates the recitation of the tasmiyah (the invocation), which if done for every chicken, will require >=5 s between stunning and neck cutting. The CL for CP 4 also includes information about the slaughter knife. In CP 5 the recommended minimum time between neck cutting and scalding is 9.5 min. Finally, the CL for CP 6 emphasizes good supply chain hygiene and zero adulteration from haram species and substances. PMID- 27965406 TI - Effects of In Ovo feeding of dextrin-iodinated casein in broilers: I. Hatch weights and early growth performance. AB - This study was conducted to determine the effect of in ovo feeding of dextrin (Dext) and iodinated casein (IC) on hatch and early growth in broilers. Three experiments were conducted at a commercial hatchery using a commercial InovojectTM system with treatments occurring in conjunction with vaccination at transfer from incubator to hatcher units (18.5 to 19 d embryonic development). In all 3 experiments, approximately 15,000 eggs (2,500 eggs per group) were treated and transferred to a single hatcher unit. Treatments in Exp. 1 consisted of buffered saline solution alone (Control, Cont) or a dextrin solution (Dext, 18% maltodextrin, 10% potato starch dextrin) containing zero, 80, 240, 720, or 2,160 MUg IC/mL. The results of this initial experiment indicated that broiler chicks at hatch that received 240 and 720 MUg IC/mL in Dext were heavier (P < 0.05) compared to the other treatment groups; there were no differences in hatchability between groups. Based on these findings, subsequent studies used treatments of zero, 240, and 480 MUg/mL IC in Dext or Cont. In Exp. 2, hatch weights in all treatment groups were higher (P < 0.05) compared to those receiving Cont. In Exp. 3, chicks given Dext alone or 240 and 480 MUg/mL in saline weighed less at hatch compared to the other treatment groups. However, chicks provided Dext alone in Exp. 3 had less weight loss after a 24-hour holding period compared to the other groups. All treatment groups exhibited greater weight gain from one to 10 d compared to the Cont group. The results indicate that in ovo feeding of broiler embryos with Dext containing 240 and 480 MUg IC/mL may have beneficial effects on broiler hatch weights and early growth rate. PMID- 27965407 TI - Effect of in ovo feeding of dextrin-iodinated casein in broilers: II. Hatch window and growth performance. AB - Studies were conducted using a commercial InovojectTM system to determine effects of in ovo feeding of dextrin and iodinated casein (IC) on hatch and posthatch growth in broilers. At ~18.5 d embryonic development, eggs were treated with 0, 240, or 480 MUg IC/mL in saline (Cont, IC240, and IC480) or dextrin (Dext, DextIC240 and DextIC480). The Dext solution consisted of 18% maltodextrin and 10% potato starch dextrin; saline was the vehicle used by the company for in ovo vaccination. The volume for all in ovo treatments was 50 MUL/injection. Eggs in Experiment 1 were transferred to a commercial hatcher unit whereas eggs in Experiments 2 and 3 were transferred to a research hatcher unit to assess effects of treatments on timing of hatch. At hatch, chicks were randomly selected and placed in floor pens and grown to 6 wk. In Experiment 1, there were no differences in hatch weights, but broilers provided Dext IC240 in ovo were heavier (P < 0.05) at 6 wk compared to other treatments with the exception of the Dext IC240 group. In Experiment 2, hatch weights were heavier (P < 0.05) in chicks receiving IC240 and DexIC480 treatments compared to Controls. At 6 wk, broilers in all treatments were heavier (P < 0.05) than Cont with the exception of IC480. In Experiment 3, hatch was stimulated by IC240 (in saline), but was delayed by Dext IC240. Serum analysis of beta-hydroxybutyrate (MUM/mL), as an indicator of ketone accumulation from fat metabolism of chicks held in chick boxes for 24 h posthatch (to simulate delay in placement after hatch), indicated that chicks in the IC240 group (that hatched earlier) had higher blood ketones compared to chicks that received Dext or DextIC240 in ovo (that hatched later). We conclude dextrin and iodinated casein (240 MUg/mL) provided in ovo (~18.5 d of embryonic development) has the potential to improve chick quality and posthatch body weight by delaying or narrowing hatch window. PMID- 27965409 TI - Variability in amino acid digestibility and metabolizable energy of corn studied in cecectomized laying hens1. AB - To optimize the use of corn grain in diets for laying hens, differences in amino acid (AA) digestibility and metabolizable energy among different corn samples should be considered in feed formulation. The present study investigated the variability of AA digestibility and AMEn concentration of 20 corn samples in cecectomized laying hens. Corn grains were characterized based on their physical properties (thousand seed weight, test weight, grain density, and extract viscoelasticity), chemical composition (proximate nutrients, AA, minerals, and inositol phosphates), gross energy concentration, and in vitro solubility of nitrogen to study any relationship with AA digestibility or AMEn. The animal study comprised 4 Latin squares (6 * 6) distributed between 2 subsequent runs. Cecectomized LSL-Classic hens were individually housed in metabolism cages and fed either a basal diet containing 500 g/kg cornstarch or one of 20 corn diets, each replacing the cornstarch with one corn batch, for 8 days. During the last 4 d, feed intake was recorded and excreta were collected quantitatively. A linear regression approach was used to calculate AA digestibility of the corn. The digestibility of all AA differed significantly between the 20 corn batches, including Lys (digestibility range 64 to 85%), Met (86 to 94%), Thr (72 to 89%), and Trp (21 to 88%). The AMEn of the corn batches ranged between 15.7 and 17.1 MJ/kg DM. However, consistent correlations between AA digestibility or AMEn and the physical and chemical characteristics of the grains were not detected. Equations to predict AA digestibility or AMEn based on the grain's physical and chemical characteristics were calculated by multiple linear regressions. The explanatory power (adjusted R2;) of prediction equations was below 0.6 for the majority of AA and AMEn, and, thus, was not sufficiently precise for practical use. Possible explanations for the variation in AA digestibility and AMEn beyond the determined characteristics are discussed. In conclusion, AA digestibility and AMEn of corn grain is high in laying hens, but varies among different corn samples, with physical and chemical characteristics not suitable for explaining these variations. PMID- 27965408 TI - Prenatal betaine exposure modulates hypothalamic expression of cholesterol metabolic genes in cockerels through modifications of DNA methylation. AB - Cholesterol is essential for neuronal development and brain function. Previously we reported that in ovo administration of betaine modulates hepatic cholesterol metabolism in the chicken, yet it remains unknown whether maternal betaine affects the cholesterol content and the expression of cholesterol metabolic genes in chicken hypothalamus. In this study, eggs were injected with saline or betaine at 2.5 mg/egg, and the hatchlings were raised under the same condition until 64 d of age. Maternal betaine significantly (P = 0.05) increased the body weight and suppressed aggressive behavior of 64-day-old cockerels, in association with significantly (P < 0.05) up-regulated expression of 5-HTR1A receptor in the hypothalamus. Concurrently, betaine in ovo significantly increased (P < 0.05) the hypothalamic content of total cholesterol and cholesterol ester, which coincided with significantly up-regulated (P < 0.05) hypothalamic expression of cholesterol biosynthetic genes, such as sterol-regulatory element binding protein 2 and 3 hydroxy-3-methyl-glutaryl-CoA reductase as well as acetyl-CoA cholesterol acyltransferase 1, which converts free cholesterol to cholesterol ester for storage. In contrast, low density lipoprotein receptor, which mediates the cholesterol uptake, was significantly down-regulated (P < 0.05). In ovo betaine administration significantly enhanced the expression of betaine-homocysteine methyltransferase and DNA methyltransferase 1 (P < 0.05), which was associated with alterations of CpG methylation on the promoter of modified cholesterol metabolic genes. These results indicate that maternal betaine modulates hypothalamic cholesterol metabolism in cockerels through modifying DNA methylation on the promoter of cholesterol metabolic genes. PMID- 27965410 TI - Associations among gait score, production data, abattoir registrations, and postmortem tibia measurements in broiler chickens. AB - Lameness and impaired walking ability in rapidly growing meat-type broiler chickens are major welfare issues that cause economic losses. This study analyzed the prevalence of impaired walking and its associations with production data, abattoir registrations, and postmortem tibia measurements in Norwegian broiler chickens. Gait score (GS) was used to assess walking ability in 59 different commercial broiler flocks (Ross 308) close to the slaughter d, 5,900 broilers in total, in 3 different geographical regions. In each flock, 100 arbitrary broilers were gait scored and 10 random broilers were culled to harvest tibias. Abattoir registrations on flock level were collected after slaughter. A total of 24.6% of the broilers had moderate to severe gait impairment. The broilers were sampled in 2 stages, first slaughterhouse/region, and then owner/flock. The final models showed that impaired gait is associated with first-week mortality (P < 0.05), region (P < 0.001), height of tibias mid-shaft (P < 0.05), and calcium content in the tibia ash (P < 0.05), and negatively associated with DOA (P < 0.05). The prevalence of impaired gait indicates that this is a common problem in the broiler industry in Norway, although the mean slaughter age is only 31 d and the maximum allowed animal density is relatively low. Impaired walking ability could not be predicted by the welfare indicators footpad lesion score, total on-farm mortality, and decreasing DOA prevalence. Further studies are needed to explore the relationship between first-week mortality and gait score. PMID- 27965411 TI - The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is a neutrophil-dominant disorder with no effective pharmacological therapies. While the cyclin-dependent kinase inhibitor AT7519 induces neutrophil apoptosis to promote inflammation resolution in preclinical models of lung inflammation, its potential efficacy in ARDS has not been examined. Untreated peripheral blood sepsis-related ARDS neutrophils demonstrated prolonged survival after 20 hours in vitro culture. AT7519 was able to override this phenotype to induce apoptosis in ARDS neutrophils with reduced expression of the pro-survival protein Mcl-1. We demonstrate the first pharmacological compound to induce neutrophil apoptosis in sepsis-related ARDS, highlighting cyclin-dependent kinase inhibitors as potential novel therapeutic agents. PMID- 27965413 TI - k-SLAM: accurate and ultra-fast taxonomic classification and gene identification for large metagenomic data sets. AB - k-SLAM is a highly efficient algorithm for the characterization of metagenomic data. Unlike other ultra-fast metagenomic classifiers, full sequence alignment is performed allowing for gene identification and variant calling in addition to accurate taxonomic classification. A k-mer based method provides greater taxonomic accuracy than other classifiers and a three orders of magnitude speed increase over alignment based approaches. The use of alignments to find variants and genes along with their taxonomic origins enables novel strains to be characterized. k-SLAM's speed allows a full taxonomic classification and gene identification to be tractable on modern large data sets. A pseudo-assembly method is used to increase classification accuracy by up to 40% for species which have high sequence homology within their genus. PMID- 27965412 TI - RMI1 and TOP3alpha limit meiotic CO formation through their C-terminal domains. AB - At meiosis, hundreds of programmed DNA double-strand breaks (DSBs) form and are repaired by homologous recombination. From this large number of DSBs, only a subset yields crossovers (COs), with a minimum of one CO per chromosome pair. All DSBs must be repaired and every recombination intermediate must be resolved to avoid subsequent entanglement and chromosome breakage. The conserved BLM TOP3alpha-RMI1 (BTR) complex acts on early and late meiotic recombination intermediates to both limit CO outcome and promote chromosome integrity. In Arabidopsis, the BLM homologues RECQ4A and RECQ4B act redundantly to prevent meiotic extra COs, but recombination intermediates are fully resolved in their absence. In contrast, TOP3alpha is needed for both processes. Here we show through the characterization of specific mutants that RMI1 is a major anti-CO factor, in addition to being essential to prevent chromosome breakage and entanglement. Further, our findings suggest a specific role of the C-terminal domains of RMI1 and TOP3alpha, that respectively contain an Oligo Binding domain (OB2) and ZINC finger motifs, in preventing extra-CO. We propose that these domains of TOP3alpha and RMI1 define a sub-domain of the BTR complex which is dispensable for the resolution of recombination intermediates but crucial to limit extra-COs. PMID- 27965414 TI - Overlapping roles for PARP1 and PARP2 in the recruitment of endogenous XRCC1 and PNKP into oxidized chromatin. AB - A critical step of DNA single-strand break repair is the rapid recruitment of the scaffold protein XRCC1 that interacts with, stabilizes and stimulates multiple enzymatic components of the repair process. XRCC1 recruitment is promoted by PARP1, an enzyme that is activated following DNA damage and synthesizes ADP ribose polymers that XRCC1 binds directly. However, cells possess two other DNA strand break-induced PARP enzymes, PARP2 and PARP3, for which the roles are unclear. To address their involvement in the recruitment of endogenous XRCC1 into oxidized chromatin we have established 'isogenic' human diploid cells in which PARP1 and/or PARP2, or PARP3 are deleted. Surprisingly, we show that either PARP1 or PARP2 are sufficient for near-normal XRCC1 recruitment at oxidative single strand breaks (SSBs) as indicated by the requirement for loss of both proteins to greatly reduce or ablate XRCC1 chromatin binding following H2O2 treatment. Similar results were observed for PNKP; an XRCC1 protein partner important for repair of oxidative SSBs. Notably, concentrations of PARP inhibitor >1000-fold higher than the IC50 were required to ablate both ADP-ribosylation and XRCC1 chromatin binding following H2O2 treatment. These results demonstrate that very low levels of ADP-ribosylation, synthesized by either PARP1 or PARP2, are sufficient for XRCC1 recruitment following oxidative stress. PMID- 27965415 TI - DisProt 7.0: a major update of the database of disordered proteins. PMID- 27965416 TI - A patient feedback reporting tool for OpenNotes: implications for patient clinician safety and quality partnerships. AB - BACKGROUND: OpenNotes, a national movement inviting patients to read their clinicians' notes online, may enhance safety through patient-reported documentation errors. OBJECTIVE: To test an OpenNotes patient reporting tool focused on safety concerns. METHODS: We invited 6225 patients through a patient portal to provide note feedback in a quality improvement pilot between August 2014 and 2015. A link at the end of the note led to a 9-question survey. Patient Relations personnel vetted responses, shared safety concerns with providers and documented whether changes were made. RESULTS: 2736/6225(44%) of patients read notes; among these, 1 in 12 patients used the tool, submitting 260 reports. Nearly all (96%) respondents reported understanding the note. Patients and care partners documented potential safety concerns in 23% of reports; 2% did not understand the care plan and 21% reported possible mistakes, including medications, existing health problems, something important missing from the note or current symptoms. Among these, 64% were definite or possible safety concerns on clinician review, and 57% of cases confirmed with patients resulted in a change to the record or care. The feedback tool exceeded the reporting rate of our ambulatory online clinician adverse event reporting system several-fold. After a year, 99% of patients and care partners found the tool valuable, 97% wanted it to continue, 98% reported unchanged or improved relationships with their clinician, and none of the providers in the small pilot reported worsening workflow or relationships with patients. CONCLUSIONS: Patients and care partners reported potential safety concerns in about one-quarter of reports, often resulting in a change to the record or care. Early data from an OpenNotes patient reporting tool may help engage patients as safety partners without apparent negative consequences for clinician workflow or patient-clinician relationships. PMID- 27965417 TI - Why diets fail: a hypothesis for discussion. AB - Weight regulation depends on the difference between weights of absorbed and metabolised carbon and excretion of the end products of metabolism, calories and carbon dioxide, which can be independently and variably excreted. Calories can be variably excreted as heat by vasoconstriction or vasodilation and carbon dioxide can be excreted variably as exhaled carbon dioxide (the major route of carbon excretion). Unless there are changes in ventilatory carbon excretion, 'metabolism,' 'genetic factors,' 'hormones' or 'exercise' do not provide complete explanatory mechanisms for weight changes, obesity and failure of diets. Low sensitivity of respiratory centres to carbon dioxide may cause overweight and dietary failures after initial weight loss. PMID- 27965418 TI - Non-gut microbiota as a source of bioactive hydrogen. PMID- 27965419 TI - Downbeat nystagmus. PMID- 27965420 TI - Microalbuminuria in Subjects With COPD: Relationship to the New Version of Global Initiative for Chronic Obstructive Lung Disease Staging. AB - BACKGROUND: Microalbuminuria, used as a marker of endothelial dysfunction, is a predictor of mortality for any reason and of cardiovascular events. Recent research on the management of COPD has focused more on comorbidities, including cardiovascular events. The objective of this study was to investigate the incidence of microalbuminuria and whether it is associated with physiological and clinical features in a subject group that was classified in line with the new version of the Global Initiative for Chronic Obstructive Lung Disease stages. METHODS: The study included 105 stable subjects with mild to very severe COPD. The urinary albumin/creatinine ratio was calculated using a previously defined formula. The presence of microalbuminuria was accepted as a urinary albumin/creatinine ratio >=20 in males and >=30 in females. RESULTS: Urinary albumin/creatinine ratios were significantly higher in subjects grouped as having more symptoms and high future risk than in those with fewer symptoms and low future risk. In addition, significant differences were observed when the subjects were grouped based on PaO2 (<=65 mm Hg vs >65 mm Hg), PaCO2 (<=41 mm Hg vs >41 mm Hg), arterial oxygen saturation (<=92% vs >92%), and median split C-reactive protein (<=4.6 mg/L vs >4.6 mg/L). Pearson correlation analysis revealed that the urinary albumin/creatinine ratio was significantly inversely correlated with percent-of-predicted FEV1 (r = -0.56, P = .001), percent-of-predicted SaO2 (r = 0.48, P = .001), and PaO2 (r = 0.60, P = .001). A positive correlation was also found between urinary albumin/creatinine ratio and COPD assessment test scores (r = 0.53, P = .001). CONCLUSIONS: The results of this study indicate a strong relationship between microalbuminuria and cardiovascular events in subjects with COPD, particularly in subjects with more symptoms and high future risk. Therefore, microalbuminuria should be regularly monitored in this subgroup of subjects with COPD for risk of cardiovascular morbidity or mortality. PMID- 27965421 TI - ICU Clinicians Underestimate Breathing Discomfort in Ventilated Subjects. AB - BACKGROUND: Breathing discomfort (dyspnea) during mechanical ventilation in the ICU may contribute to patient distress and complicate care. Assessment of nonverbal cues may allow caregivers to estimate patient breathing discomfort. This study assesses the accuracy of those caregiver estimates. METHODS: Thirty subjects were identified from ventilated, hemodynamically stable patients in the special care unit of Maine Medical Center. Those with impaired neurological function or too unstable to waken were excluded. Subjects provided a subjective score of breathing discomfort (0-10 using a modified Borg scale) during daily wake-up from sedation (sedation-agitation score of 3 or 4). Clinicians (physicians, respiratory therapists, and nurses) then provided a blinded estimate of subject breathing discomfort (0-10) through observation of the subject and inspection of ventilator parameters alone. Subject scores and caregiver estimates were compared. RESULTS: All subjects reported breathing discomfort with median score (interquartile range) of 4 (3-4). Caregiver estimates of breathing discomfort were significantly lower than subject scores (2 [0-3]), and the discrepancy was seen in all professions (physicians 1 point lower [0-2], P = .02; respiratory therapists 1 point lower [0-2], P = .01; nurses 2 points lower [1-3], P < .001). There was a positive correlation between subject breathing discomfort and degree of underestimation (ie, the degree of underestimation increased as the subject scores rose). The 3 most commonly used cues were subjects' facial expression, use of accessory muscles, and nasal flaring. CONCLUSIONS: Significant breathing discomfort is prevalent in mechanically ventilated ICU patients and is underestimated by caregivers, regardless of profession. The increasing disparity in caregiver estimate as breathing discomfort rises may expose patients to levels of dyspnea that promote anxiety and fear. This study demonstrates the need for further development and standardization of methods to assess dyspnea in nonverbal patients. PMID- 27965422 TI - Circulating ACE2 activity correlates with cardiovascular disease development. AB - It was shown recently that angiotensin-converting enzyme activity is limited by endogenous inhibition in vivo, highlighting the importance of angiotensin II (ACE2) elimination. The potential contribution of the ACE2 to cardiovascular disease progression was addressed. Serum ACE2 activities were measured in different clinical states (healthy, n=45; hypertensive, n=239; heart failure (HF) with reduced ejection fraction (HFrEF) n=141 and HF with preserved ejection fraction (HFpEF) n=47). ACE2 activity was significantly higher in hypertensive patients (24.8+/-0.8 U/ml) than that in healthy volunteers (16.2+/-0.8 U/ml, p=0.01). ACE2 activity further increased in HFrEF patients (43.9+/-2.1 U/ml, p=0.001) but not in HFpEF patients (24.6+/-1.9 U/ml) when compared with hypertensive patients. Serum ACE2 activity negatively correlated with left ventricular systolic function in HFrEF, but not in hypertensive, HFpEF or healthy populations. Serum ACE2 activity had a fair diagnostic value to differentiate HFpEF from HFrEF patients in this study. Serum ACE2 activity correlates with cardiovascular disease development: it increases when hypertension develops and further increases when the cardiovascular disease further progresses to systolic dysfunction, suggesting that ACE2 metabolism plays a role in these processes. In contrast, serum ACE2 activity does not change when hypertension progresses to HFpEF, suggesting a different pathomechanism for HFpEF, and proposing a biomarker based identification of these HF forms. PMID- 27965423 TI - Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC. AB - ACDC (arterial calcification due to deficiency of CD73) is an autosomal recessive disease resulting from loss-of-function mutations in NT5E, which encodes CD73, a 5'-ectonucleotidase that converts extracellular adenosine monophosphate to adenosine. ACDC patients display progressive calcification of lower extremity arteries, causing limb ischemia. Tissue-nonspecific alkaline phosphatase (TNAP), which converts pyrophosphate (PPi) to inorganic phosphate (Pi), and extracellular purine metabolism play important roles in other inherited forms of vascular calcification. Compared to cells from healthy subjects, induced pluripotent stem cell-derived mesenchymal stromal cells (iMSCs) from ACDC patients displayed accelerated calcification and increased TNAP activity when cultured under conditions that promote osteogenesis. TNAP activity generated adenosine in iMSCs derived from ACDC patients but not in iMSCs from control subjects, which have CD73. In response to osteogenic stimulation, ACDC patient-derived iMSCs had decreased amounts of the TNAP substrate PPi, an inhibitor of extracellular matrix calcification, and exhibited increased activation of AKT, mechanistic target of rapamycin (mTOR), and the 70-kDa ribosomal protein S6 kinase (p70S6K), a pathway that promotes calcification. In vivo, teratomas derived from ACDC patient cells showed extensive calcification and increased TNAP activity. Treating mice bearing these teratomas with an A2b adenosine receptor agonist, the mTOR inhibitor rapamycin, or the bisphosphonate etidronate reduced calcification. These results show that an increase of TNAP activity in ACDC contributes to ectopic calcification by disrupting the extracellular balance of PPi and Pi and identify potential therapeutic targets for ACDC. PMID- 27965427 TI - Editor's Correspondence. PMID- 27965426 TI - Mitotic phosphotyrosine network analysis reveals that tyrosine phosphorylation regulates Polo-like kinase 1 (PLK1). AB - Tyrosine phosphorylation is closely associated with cell proliferation. During the cell cycle, serine and threonine phosphorylation plays the leading role, and such phosphorylation events are most dynamic during the mitotic phase of the cell cycle. However, mitotic phosphotyrosine is not well characterized. Although a few functionally-relevant mitotic phosphotyrosine sites have been characterized, evidence suggests that this modification may be more prevalent than previously appreciated. Here, we examined tyrosine phosphorylation in mitotic human cells including those on spindle-associated proteins.? Database mining confirmed ~2000 mitotic phosphotyrosine sites, and network analysis revealed a number of subnetworks that were enriched in tyrosine-phosphorylated proteins, including components of the kinetochore or spindle and SRC family kinases. We identified Polo-like kinase 1 (PLK1), a major signaling hub in the spindle subnetwork, as phosphorylated at the conserved Tyr217 in the kinase domain. Substitution of Tyr217 with a phosphomimetic residue eliminated PLK1 activity in vitro and in cells. Further analysis showed that Tyr217 phosphorylation reduced the phosphorylation of Thr210 in the activation loop, a phosphorylation event necessary for PLK1 activity. Our data indicate that mitotic tyrosine phosphorylation regulated a key serine/threonine kinase hub in mitotic cells and suggested that spatially separating tyrosine phosphorylation events can reveal previously unrecognized regulatory events and complexes associated with specific structures of the cell cycle. PMID- 27965424 TI - Chemoattractant concentration-dependent tuning of ERK signaling dynamics in migrating neutrophils. AB - The directed migration (chemotaxis) of neutrophils toward the bacterial peptide N formyl-Met-Leu-Phe (fMLP) is a crucial process in immune defense against invading bacteria. While navigating through a gradient of increasing concentrations of fMLP, neutrophils and neutrophil-like HL-60 cells switch from exhibiting directional migration at low fMLP concentrations to exhibiting circuitous migration at high fMLP concentrations. The extracellular signal-regulated kinase (ERK) pathway is implicated in balancing this fMLP concentration-dependent switch in migration modes. We investigated the role and regulation of ERK signaling through single-cell analysis of neutrophil migration in response to different fMLP concentrations over time. We found that ERK exhibited gradated, rather than all-or-none, responses to fMLP concentration. Maximal ERK activation occurred in response to about 100 nM fMLP, and ERK inactivation was promoted by p38. Furthermore, we found that directional migration of neutrophils reached a maximal extent at about 100 nM fMLP and that ERK, but not p38, was required for neutrophil migration. Thus, our data suggest that, in chemotactic neutrophils responding to fMLP, ERK displays gradated activation and p38-dependent inhibition and that these ERK dynamics promote neutrophil migration. PMID- 27965425 TI - Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine. AB - Although the molecular mechanism is not clear, the clinically tested drug ketamine has rapid antidepressant action that does not require the multiple weeks of treatment needed for other antidepressant drugs to have an effect. We showed that ketamine potentiated Schaffer collateral-CA1 cell excitatory synaptic transmission in hippocampal slice preparations from rodents and enhanced the phosphorylation of the GluA1 subunit on Ser845 of the AMPA-type glutamate receptor in the hippocampal area CA1. These effects persisted when gamma aminobutyric acid (GABA) receptors were pharmacologically blocked. Ketamine reduced behavioral despair in wild-type mice but had no effect in GluA1 S845A knock-in mutant mice. Presynaptic (CA3 pyramidal cell), but not postsynaptic (CA1 pyramidal cell), deletion of N-methyl-d-aspartate (NMDA)-type glutamate receptors eliminated the ketamine-induced enhancement of excitatory synaptic transmission in hippocampal slices and the antidepressant actions of ketamine in mice. The synaptic and behavioral actions of ketamine were completely occluded by inhibition or deletion of the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1). Our results implicate presynaptic NMDA receptor inhibition followed by reduced activity of presynaptic HCN1 channels, which would result in an increase in glutamate release and postsynaptic glutamate receptor activity, as a mechanism of ketamine action. These data provide a mechanism for changes in synaptic activity that could explain the fast-acting antidepressant effects of this drug. PMID- 27965428 TI - Discharge Disposition After Stroke in Patients With Liver Disease. AB - BACKGROUND AND PURPOSE: Liver disease is associated with both hemorrhagic and thrombotic processes, including an elevated risk of intracranial hemorrhage. We sought to assess the relationship between liver disease and outcomes after stroke, as measured by discharge disposition. METHODS: Using administrative claims data, we identified a cohort of patients hospitalized with stroke in California, Florida, and New York from 2005 to 2013. The predictor variable was liver disease. All diagnoses were defined using validated diagnosis codes. Ordinal logistic regression was used to analyze the association between liver disease and worsening discharge disposition: home, nursing/rehabilitation facility, or death. Secondarily, multiple logistic regression was used to analyze the association between liver disease and in-hospital mortality. Models were adjusted for demographics, vascular risk factors, and comorbidities. RESULTS: We identified 121 428 patients with intracerebral hemorrhage and 703 918 with ischemic stroke. Liver disease was documented in 13 584 patients (1.7%). Liver disease was associated with worse discharge disposition after both intracerebral hemorrhage (global odds ratio, 1.28; 95% confidence interval, 1.19-1.38) and ischemic stroke (odds ratio, 1.23; 95% confidence interval, 1.17-1.29). Similarly, liver disease was associated with in-hospital death after both intracerebral hemorrhage (odds ratio, 1.33; 95% confidence interval, 1.23-1.44) and ischemic stroke (odds ratio, 1.60; 95% confidence interval, 1.51-1.71). CONCLUSIONS: Liver disease was associated with worse hospital discharge disposition and in-hospital mortality after stroke, suggesting worse functional outcomes. PMID- 27965432 TI - Science and Culture: Looking at a shared sky, through the lens of art. PMID- 27965429 TI - Age-Period-Cohort Analysis of Stroke Mortality in China: Data From the Global Burden of Disease Study 2013. AB - BACKGROUND AND PURPOSE: Stroke has been the leading cause of death in China. The aim of this study is to assess the long-term trends of stroke mortality in China between 1994 and 2013. METHODS: The mortality data were obtained from the GBD 2013 (Global Burden of Disease Study 2013) and were analyzed with the age-period cohort framework. RESULTS: We found that the net drift was -2.665% (95% confidence interval, -2.854% to -2.474%) per year for men and -4.064% (95% confidence interval, -4.279% to -3.849%) per year for women, and the local drift values were below 0 in all age groups (P<0.05 for all) in both sexes during the period of 1994 to 2013. In the same birth cohort, the risk of death from stroke rose exponentially with age for both sexes after controlling for period deviations. The estimated period and cohort relative risks were found in similar monotonic downward patterns (significantly with P<0.05 for all) for both sexes, with more quickly decreasing for women than for men during the whole period (significantly with P<0.05 for both). CONCLUSIONS: The decreased mortality rates of stroke in China are likely to be related to improvements in medical care and techniques, spectacular economic growth and fast urbanization, and better early life nutrition conditions of Chinese people. Besides, better education and better awareness of stroke-related knowledge in successive generations could also probably play a role. PMID- 27965430 TI - Timing of Percutaneous Endoscopic Gastrostomy for Acute Ischemic Stroke: An Observational Study From the US Nationwide Inpatient Sample. AB - BACKGROUND AND PURPOSE: Stroke guidelines recommend time-limited trials of nasogastric feeding prior to percutaneous endoscopic gastrostomy (PEG) tube placement. We sought to describe timing of PEG placement and identify factors associated with early PEG for acute ischemic stroke. METHODS: We designed a retrospective observational study to examine time to PEG for ischemic stroke admissions in the Nationwide Inpatient Sample, 2001 to 2011. We defined early PEG placement as 1 to 7 days from admission. Using multivariable regression analysis, we identified the effects of patient and hospital characteristics on PEG timing. RESULTS: We identified 34 623 admissions receiving a PEG from 2001 to 2011, 53% of which received the PEG 1 to 7 days from admission. Among hospitals placing >=10 PEG tubes, median time to PEG for individual hospitals ranged from 3 days to over 3 weeks (interquartile range 6-8.5 days). Older adult age groups were associated with early PEG (>=85 years versus 18-54 years: adjusted odds ratio 1.68, 95% confidence interval 1.50-1.87). Those receiving a PEG and tracheostomy were more likely to receive the PEG beyond 7 days, and these patients were more often younger compared with PEG only recipients. Those admitted to high-volume hospitals were more likely to receive their PEG early (>=350 versus <150 hospitalizations; adjusted odds ratio 1.26, 95% confidence interval 1.17-1.35). CONCLUSIONS: More than half of the PEG recipients received their surgical feeding tube within 7 days of admission. The oldest old, who may benefit most from time limited trials of nasogastric feeding for >=2 to 3 weeks, were most likely to receive a PEG within 7 days. PMID- 27965433 TI - Core Concept: Prebiotics gain prominence but remain poorly defined. PMID- 27965435 TI - Can we predict the outcome for people with patellofemoral pain? A systematic review on prognostic factors and treatment effect modifiers. AB - BACKGROUND: Patellofemoral pain (PFP) is a multifactorial and often persistent knee condition. One strategy to enhance patient outcomes is using clinically assessable patient characteristics to predict the outcome and match a specific treatment to an individual. AIM: A systematic review was conducted to determine which baseline patient characteristics were (1) associated with patient outcome (prognosis); or (2) modified patient outcome from a specific treatment (treatment effect modifiers). METHODS: 6 electronic databases were searched (July 2016) for studies evaluating the association between those with PFP, their characteristics and outcome. All studies were appraised using the Epidemiological Appraisal Instrument. Studies that aimed to identify treatment effect modifiers underwent a checklist for methodological quality. RESULTS: The 24 included studies evaluated 180 participant characteristics. 12 studies investigated prognosis, and 12 studies investigated potential treatment effect modifiers. Important methodological limitations were identified. Some prognostic studies used a retrospective design. Studies aiming to identify treatment effect modifiers often analysed too many variables for the limiting sample size and typically failed to use a control or comparator treatment group. 16 factors were reported to be associated with a poor outcome, with longer duration of symptoms the most reported (>4 months). Preliminary evidence suggests increased midfoot mobility may predict those who have a successful outcome to foot orthoses. CONCLUSIONS: Current evidence can identify those with increased risk of a poor outcome, but methodological limitations make it difficult to predict the outcome after one specific treatment compared with another. Adequately designed randomised trials are needed to identify treatment effect modifiers. PMID- 27965436 TI - An interview with Doug Melton. AB - Doug Melton is Xander University Professor at Harvard University, co-director of the Harvard Stem Cell Institute and a Howard Hughes Medical Institute Investigator. His lab investigates the development of the pancreas, and uses insights from this process to direct the production of insulin-producing beta cells from stem cells. We met Doug at the 2016 Society for Developmental Biology International Society of Differentiation (SDB-ISD) joint meeting in Boston, USA, where he gave the Jean Brachet Lecture. PMID- 27965437 TI - Fox transcription factors: from development to disease. AB - Forkhead box (Fox) transcription factors are evolutionarily conserved in organisms ranging from yeast to humans. They regulate diverse biological processes both during development and throughout adult life. Mutations in many Fox genes are associated with human disease and, as such, various animal models have been generated to study the function of these transcription factors in mechanistic detail. In many cases, the absence of even a single Fox transcription factor is lethal. In this Primer, we provide an overview of the Fox family, highlighting several key Fox transcription factor families that are important for mammalian development. PMID- 27965441 TI - Correction: Mice humanised for the EGF receptor display hypomorphic phenotypes in skin, bone and heart. PMID- 27965438 TI - The many faces of hematopoietic stem cell heterogeneity. AB - Not all hematopoietic stem cells (HSCs) are alike. They differ in their physical characteristics such as cell cycle status and cell surface marker phenotype, they respond to different extrinsic signals, and they have different lineage outputs following transplantation. The growing body of evidence that supports heterogeneity within HSCs, which constitute the most robust cell fraction at the foundation of the adult hematopoietic system, is currently of great interest and raises questions as to why HSC subtypes exist, how they are generated and whether HSC heterogeneity affects leukemogenesis or treatment options. This Review provides a developmental overview of HSC subtypes during embryonic, fetal and adult stages of hematopoiesis and discusses the possible origins and consequences of HSC heterogeneity. PMID- 27965440 TI - CFAP157 is a murine downstream effector of FOXJ1 that is specifically required for flagellum morphogenesis and sperm motility. AB - Motile cilia move extracellular fluids or mediate cellular motility. Their function is essential for embryonic development, adult tissue homeostasis and reproduction throughout vertebrates. FOXJ1 is a key transcription factor for the formation of motile cilia but its downstream genetic programme is only partially understood. Here, we characterise a novel FOXJ1 target, Cfap157, that is specifically expressed in motile ciliated tissues in mouse and Xenopus in a FOXJ1 dependent manner. CFAP157 protein localises to basal bodies and interacts with tubulin and the centrosomal protein CEP350. Cfap157 knockout mice appear normal but homozygous males are infertile. Spermatozoa display impaired motility and a novel phenotype: Cfap157-deficient sperm exhibit axonemal loops, supernumerary axonemal profiles with ectopic accessory structures, excess cytoplasm and clustered mitochondria in the midpiece regions, and defective axonemes along the flagella. Our study thus demonstrates an essential sperm-specific function for CFAP157 and suggests that this novel FOXJ1 effector is part of a mechanism that acts during spermiogenesis to suppress the formation of supernumerary axonemes and ensures a correct ultrastructure. PMID- 27965439 TI - Transcriptional regulation of intermediate progenitor cell generation during hippocampal development. AB - During forebrain development, radial glia generate neurons through the production of intermediate progenitor cells (IPCs). The production of IPCs is a central tenet underlying the generation of the appropriate number of cortical neurons, but the transcriptional logic underpinning this process remains poorly defined. Here, we examined IPC production using mice lacking the transcription factor nuclear factor I/X (Nfix). We show that Nfix deficiency delays IPC production and prolongs the neurogenic window, resulting in an increased number of neurons in the postnatal forebrain. Loss of additional Nfi alleles (Nfib) resulted in a severe delay in IPC generation while, conversely, overexpression of NFIX led to precocious IPC generation. Mechanistically, analyses of microarray and ChIP-seq datasets, coupled with the investigation of spindle orientation during radial glial cell division, revealed that NFIX promotes the generation of IPCs via the transcriptional upregulation of inscuteable (Insc). These data thereby provide novel insights into the mechanisms controlling the timely transition of radial glia into IPCs during forebrain development. PMID- 27965446 TI - Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells. AB - : The cytokine gamma interferon (IFN-gamma) induces cell-autonomous immunity to combat infections with intracellular pathogens, such as the bacterium Chlamydia trachomatis The present study demonstrates that IFN-gamma-primed human cells ubiquitinate and eliminate intracellular Chlamydia-containing vacuoles, so-called inclusions. We previously described how IFN-gamma-inducible immunity-related GTPases (IRGs) employ ubiquitin systems to mark inclusions for destruction in mouse cells and, furthermore, showed that the rodent pathogen Chlamydia muridarum blocks ubiquitination of its inclusions by interfering with mouse IRG function. Here, we report that ubiquitination of inclusions in human cells is independent of IRG and thus distinct from the murine pathway. We show that C. muridarum is susceptible to inclusion ubiquitination in human cells, while the closely related human pathogen C. trachomatis is resistant. C. muridarum, but not C. trachomatis, inclusions attract several markers of cell-autonomous immunity, including the ubiquitin-binding protein p62, the ubiquitin-like protein LC3, and guanylate binding protein 1. Consequently, we find that IFN-gamma priming of human epithelial cells triggers the elimination of C. muridarum, but not C. trachomatis, inclusions. This newly described defense pathway is independent of indole-2,3-dioxygenase, a known IFN-gamma-inducible anti-Chlamydia resistance factor. Collectively, our observations indicate that C. trachomatis evolved mechanisms to avoid a human-specific, ubiquitin-mediated response as part of its unique adaptation to its human host. IMPORTANCE: Chlamydia trachomatis is the leading cause of sexually transmitted bacterial infections and responsible for significant morbidity, including pelvic inflammatory disease, infertility, and ectopic pregnancies in women. As an obligate intracellular pathogen, C. trachomatis is in perpetual conflict with cell-intrinsic defense programs executed by its human host. Our study defines a novel anti-Chlamydia host resistance pathway active in human epithelial cells. This defense program promotes the deposition of the small antimicrobial protein ubiquitin on vacuoles containing Chlamydia We show that this ubiquitin-based resistance pathway of human cells is highly effective against a Chlamydia species adapted to rodents but ineffective against human-adapted C. trachomatis This observation indicates that C. trachomatis evolved strategies to avoid entrapment within ubiquitin labeled vacuoles as part of its adaptation to the human innate immune system. PMID- 27965451 TI - Erratum for Lauber et al., Identification of a New Lipoprotein Export Signal in Gram-Negative Bacteria. PMID- 27965449 TI - Probiotic Diversity Enhances Rhizosphere Microbiome Function and Plant Disease Suppression. AB - : Bacterial communities associated with plant roots play an important role in the suppression of soil-borne pathogens, and multispecies probiotic consortia may enhance disease suppression efficacy. Here we introduced defined Pseudomonas species consortia into naturally complex microbial communities and measured the importance of Pseudomonas community diversity for their survival and the suppression of the bacterial plant pathogen Ralstonia solanacearum in the tomato rhizosphere microbiome. The survival of introduced Pseudomonas consortia increased with increasing diversity. Further, high Pseudomonas diversity reduced pathogen density in the rhizosphere and decreased the disease incidence due to both intensified resource competition and interference with the pathogen. These results provide novel mechanistic insights into elevated pathogen suppression by diverse probiotic consortia in naturally diverse plant rhizospheres. Ecologically based community assembly rules could thus play a key role in engineering functionally reliable microbiome applications. IMPORTANCE: The increasing demand for food supply requires more-efficient control of plant diseases. The use of probiotics, i.e., naturally occurring bacterial antagonists and competitors that suppress pathogens, has recently reemerged as a promising alternative to agrochemical use. It is, however, still unclear how many and which strains we should choose for constructing effective probiotic consortia. Here we present a general ecological framework for assembling effective probiotic communities based on in vitro characterization of community functioning. Specifically, we show that increasing the diversity of probiotic consortia enhances community survival in the naturally diverse rhizosphere microbiome, leading to increased pathogen suppression via intensified resource competition and interference with the pathogen. We propose that these ecological guidelines can be put to the test in microbiome engineering more widely in the future. PMID- 27965450 TI - Functional Characterization of Pneumocystis carinii Inositol Transporter 1. AB - : Fungi in the genus Pneumocystis live in the lungs of mammals, where they can cause a fatal pneumonia (PCP [Pneumocystis pneumonia]) in hosts with compromised immune systems. The absence of a continuous in vitro culture system for any species of Pneumocystis has led to limited understanding of these fungi, especially for the discovery of new therapies. We recently reported that Pneumocystis carinii, Pneumocystis murina, and most significantly, Pneumocystis jirovecii lack both enzymes necessary for myo-inositol biosynthesis but contain genes with homologies to fungal myo-inositol transporters. Since myo-inositol is essential for eukaryotic viability, the primary transporter, ITR1, was functionally and structurally characterized in P. carinii The predicted structure of P. carinii ITR1 (PcITR1) contained 12 transmembrane alpha-helices with intracellular C and N termini, consistent with other inositol transporters. The apparent Km was 0.94 +/- 0.08 (mean +/- standard deviation), suggesting that myo inositol transport in P. carinii is likely through a low-affinity, highly selective transport system, as no other sugars or inositol stereoisomers were significant competitive inhibitors. Glucose transport was shown to use a different transport system. The myo-inositol transport was distinct from mammalian transporters, as it was not sodium dependent and was cytochalasin B resistant. Inositol transport in these fungi offers an attractive new drug target because of the reliance of the fungi on its transport, clear differences between the mammalian and fungal transporters, and the ability of the host to both synthesize and transport this critical nutrient, predicting low toxicity of potential inhibitors to the fungal transporter. IMPORTANCE: myo-Inositol is a sugarlike nutrient that is essential for life in most organisms. Humans and microbes alike can obtain it by making it, which involves only 2 enzymes, by taking it from the environment by a transport process, or by recycling it from other cellular constituents. Inspection of the genomes of the pathogenic fungi of the genus Pneumocystis showed that these pneumonia-causing parasites could not make myo-inositol, as they lacked the 2 enzymes. Instead, we found evidence of inositol transporters, which would import the sugar from the lungs where the fungi reside. In the present report, we characterized the transport of myo inositol in the fungus and found that the transporter was highly selective for myo-inositol and did not transport any other molecules. The transport was distinct from that in mammalian cells, and since mammals can both make and transport myo-inositol, while Pneumocystis fungi must transport it, this process offers a potential new drug target. PMID- 27965447 TI - The Antiviral Mechanism of an Influenza A Virus Nucleoprotein-Specific Single Domain Antibody Fragment. AB - : Alpaca-derived single-domain antibody fragments (VHHs) that target the influenza A virus nucleoprotein (NP) can protect cells from infection when expressed in the cytosol. We found that one such VHH, alphaNP-VHH1, exhibits antiviral activity similar to that of Mx proteins by blocking nuclear import of incoming viral ribonucleoproteins (vRNPs) and viral transcription and replication in the nucleus. We determined a 3.2-A crystal structure of alphaNP-VHH1 in complex with influenza A virus NP. The VHH binds to a nonconserved region on the body domain of NP, which has been associated with binding to host factors and serves as a determinant of host range. Several of the NP/VHH interface residues determine sensitivity of NP to antiviral Mx GTPases. The structure of the NP/alphaNP-VHH1 complex affords a plausible explanation for the inhibitory properties of the VHH and suggests a rationale for the antiviral properties of Mx proteins. Such knowledge can be leveraged for much-needed novel antiviral strategies. IMPORTANCE: Influenza virus strains can rapidly escape from protection afforded by seasonal vaccines or acquire resistance to available drugs. Additional ways to interfere with the virus life cycle are therefore urgently needed. The influenza virus nucleoprotein is one promising target for antiviral interventions. We have previously isolated alpaca-derived single-domain antibody fragments (VHHs) that protect cells from influenza virus infection if expressed intracellularly. We show here that one such VHH exhibits antiviral activities similar to those of proteins of the cellular antiviral defense (Mx proteins). We determined the three-dimensional structure of this VHH in complex with the influenza virus nucleoprotein and identified the interaction site, which overlaps regions that determine sensitivity of the virus to Mx proteins. Our data define a new vulnerability of influenza virus, help us to better understand the cellular antiviral mechanisms, and provide a well-characterized tool to further study them. PMID- 27965448 TI - The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection. AB - : ADP-ribosylation is a common posttranslational modification that may have antiviral properties and impact innate immunity. To regulate this activity, macrodomain proteins enzymatically remove covalently attached ADP-ribose from protein targets. All members of the Coronavirinae, a subfamily of positive-sense RNA viruses, contain a highly conserved macrodomain within nonstructural protein 3 (nsp3). However, its function or targets during infection remain unknown. We identified several macrodomain mutations that greatly reduced nsp3's de-ADP ribosylation activity in vitro Next, we created recombinant severe acute respiratory syndrome coronavirus (SARS-CoV) strains with these mutations. These mutations led to virus attenuation and a modest reduction of viral loads in infected mice, despite normal replication in cell culture. Further, macrodomain mutant virus elicited an early, enhanced interferon (IFN), interferon-stimulated gene (ISG), and proinflammatory cytokine response in mice and in a human bronchial epithelial cell line. Using a coinfection assay, we found that inclusion of mutant virus in the inoculum protected mice from an otherwise lethal SARS-CoV infection without reducing virus loads, indicating that the changes in innate immune response were physiologically significant. In conclusion, we have established a novel function for the SARS-CoV macrodomain that implicates ADP ribose in the regulation of the innate immune response and helps to demonstrate why this domain is conserved in CoVs. IMPORTANCE: The macrodomain is a ubiquitous structural domain that removes ADP-ribose from proteins, reversing the activity of ADP-ribosyltransferases. All coronaviruses contain a macrodomain, suggesting that ADP-ribosylation impacts coronavirus infection. However, its function during infection remains unknown. Here, we found that the macrodomain is an important virulence factor for a highly pathogenic human CoV, SARS-CoV. Viruses with macrodomain mutations that abrogate its ability to remove ADP-ribose from protein were unable to cause lethal disease in mice. Importantly, the SARS-CoV macrodomain suppressed the innate immune response during infection. Our data suggest that an early innate immune response can protect mice from lethal disease. Understanding the mechanism used by this enzyme to promote disease will open up novel avenues for coronavirus therapies and give further insight into the role of macrodomains in viral pathogenesis. PMID- 27965452 TI - Bystander Host Cell Killing Effects of Clostridium perfringens Enterotoxin. AB - : Clostridium perfringens enterotoxin (CPE) binds to claudin receptors, e.g., claudin-4, and then forms a pore that triggers cell death. Pure cultures of host cells that do not express claudin receptors, e.g., fibroblasts, are unaffected by pathophysiologically relevant CPE concentrations in vitro However, both CPE insensitive and CPE-sensitive host cells are present in vivo Therefore, this study tested whether CPE treatment might affect fibroblasts when cocultured with CPE-sensitive claudin-4 fibroblast transfectants or Caco-2 cells. Under these conditions, immunofluorescence microscopy detected increased death of fibroblasts. This cytotoxic effect involved release of a toxic factor from the dying CPE-sensitive cells, since it could be reproduced using culture supernatants from CPE-treated sensitive cells. Supernatants from CPE-treated sensitive cells, particularly Caco-2 cells, were found to contain high levels of membrane vesicles, often containing a CPE species. However, most cytotoxic activity remained in those supernatants even after membrane vesicle depletion, and CPE was not detected in fibroblasts treated with supernatants from CPE treated sensitive cells. Instead, characterization studies suggest that a major cytotoxic factor present in supernatants from CPE-treated sensitive cells may be a 10- to 30-kDa host serine protease or require the action of that host serine protease. Induction of caspase-3-mediated apoptosis was found to be important for triggering release of the cytotoxic factor(s) from CPE-treated sensitive host cells. Furthermore, the cytotoxic factor(s) in these supernatants was shown to induce a caspase-3-mediated killing of fibroblasts. This bystander killing effect due to release of cytotoxic factors from CPE-treated sensitive cells could contribute to CPE-mediated disease. IMPORTANCE: In susceptible host cells, Clostridium perfringens enterotoxin (CPE) binds to claudin receptors and then forms pores that result in cell death. Using cocultures of CPE receptor expressing sensitive cells mixed with CPE-insensitive cells lacking receptors for this toxin, the current study determined that CPE-treated sensitive cells release soluble cytotoxic factors, one of which may be a 10- to 30-kDa serine protease, to cause apoptotic death of cells that are themselves CPE insensitive. These findings suggest a novel bystander killing mechanism by which a pore-forming toxin may extend its damage to affect cells not directly responsive to that toxin. If confirmed to occur in vivo by future studies, this bystander killing effect may have significance during CPE-mediated disease and could impact the translational use of CPE for purposes such as cancer therapy. PMID- 27965453 TI - Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5. AB - : Leukocidin ED (LukED) is a bicomponent pore-forming toxin produced by Staphylococcus aureus that lyses host cells by targeting the chemokine receptors CC chemokine receptor type 5 (CCR5), CXCR1, CXCR2, and DARC. In addition to its role as a receptor for LukED, CCR5 is the major coreceptor for primary isolates of human immunodeficiency virus type 1 (HIV-1) and has been extensively studied. To compare how LukED and HIV-1 target CCR5, we analyzed their respective abilities to use CCR5/CCR2b chimeras to mediate cytotoxicity and virus entry. These analyses showed that the second and third extracellular loops (ECL) of CCR5 are necessary and sufficient for LukED to target the receptor and promote cell lysis. In contrast, the second ECL of CCR5 is necessary but not sufficient for HIV-1 infectivity. The analysis of CCR5 point mutations showed that glycine-163 is critical for HIV-1 infectivity, while arginine-274 and aspartic acid-276 are critical for LukED cytotoxicity. Point mutations in ECL2 diminished both HIV-1 infectivity and LukED cytotoxicity. Treatment of cells with LukED did not interfere with CCR5-tropic HIV-1 infectivity, demonstrating that LukED and the viral envelope glycoprotein use nonoverlapping sites on CCR5. Analysis of point mutations in LukE showed that amino acids 64 to 69 in the rim domain are required for CCR5 targeting and cytotoxicity. Taking the results together, this study identified the molecular basis by which LukED targets CCR5, highlighting the divergent molecular interactions evolved by HIV-1 and LukED to interact with CCR5. IMPORTANCE: The bicomponent pore-forming toxins are thought to play a vital role in the success of Staphylococcus aureus as a mammalian pathogen. One of the leukocidins, LukED, is necessary and sufficient for lethality in mice. At the molecular level, LukED causes cell lysis through binding to specific cellular receptors. CCR5 is one of the receptors targeted by LukED and is the major coreceptor for CCR5-tropic HIV-1. While the molecular interaction of CCR5 and HIV 1 is well characterized, the means by which LukED interacts with CCR5 is less clear. In this study, we demonstrated that receptor specificity is conferred through unique interactions between key domains on CCR5 and LukE. Although HIV-1 and LukED target the same receptor, our data demonstrated that they interact with CCR5 differently, highlighting the molecular complexity of host-pathogen interactions. PMID- 27965454 TI - Mycosins of the Mycobacterial Type VII ESX Secretion System: the Glue That Holds the Party Together. AB - Since their discovery as important determinants of virulence and growth, the type VII ESX secretion systems (ESX-1 to ESX-5) of slow-growing pathogenic mycobacteria have been the focus of intense scrutiny. Genetic studies have been instrumental in identifying the core components and substrates of these molecular secretion machines and have helped uncover the multifunctional properties of some of them. For instance, the mycosin MycP1 of ESX-1, a membrane-associated subtilisin-like serine protease, was shown to have dual functions: the entire protein is essential for ESX-1 function, but only the serine protease regulates secretion activity. MycP5 of ESX-5, on the other hand, is required for ESX-5 secretion activity, but the function of its predicted serine protease remains unknown. Recently, van Winden and colleagues (mBio 7:e01471-16, 2016, http://dx.doi.org/10.1128/mBio.01471-16) reported compelling evidence that MycP1 and MycP5 serve to stabilize the interactions of core ESX-1 and ESX-5 components, respectively, thus explaining how they facilitate the secretion activities of their associated systems. PMID- 27965455 TI - Staphylococcus aureus and Influenza A Virus: Partners in Coinfection. AB - Nasal carriage of Staphylococcus aureus is a significant risk factor for secondary staphylococcal pneumonia in influenza A virus (IAV)-infected hosts. However, little research has been undertaken to define the environmental and physiological changes that cause S. aureus to shift from commensal to pathogenic organism in this setting. The ability of virus-driven danger signals to cause S. aureus to transition from commensalism to pulmonary infection was explored in a recent study by Reddinger et al. R. M. Reddinger, N. R. Luke-Marshall, A. P. Hakansson, and A. A. Campagnari, mBio 7(6):e01235-16, 2016, http://dx.doi.org/10.1128/mBio.01235-16 The authors report that physiological host changes, including febrile temperature and a combination of host stress response signals, caused S. aureus biofilms to disperse from the nasal environment and cause active pulmonary infection. This commentary discusses the new finding in light of the current understanding of the mechanisms behind staphylococcal coinfection with IAV. In addition, it considers the mechanisms behind staphylococcal dispersal in this model. Overall, the study indicates that interkingdom signaling may occur following IAV infection and this likely contributes to sensitizing the IAV-infected host to secondary staphylococcal pneumonia. PMID- 27965456 TI - Comprehensive Genome Analysis of Carbapenemase-Producing Enterobacter spp.: New Insights into Phylogeny, Population Structure, and Resistance Mechanisms. AB - : Knowledge regarding the genomic structure of Enterobacter spp., the second most prevalent carbapenemase-producing Enterobacteriaceae, remains limited. Here we sequenced 97 clinical Enterobacter species isolates that were both carbapenem susceptible and resistant from various geographic regions to decipher the molecular origins of carbapenem resistance and to understand the changing phylogeny of these emerging and drug-resistant pathogens. Of the carbapenem resistant isolates, 30 possessed blaKPC-2, 40 had blaKPC-3, 2 had blaKPC-4, and 2 had blaNDM-1 Twenty-three isolates were carbapenem susceptible. Six genomes were sequenced to completion, and their sizes ranged from 4.6 to 5.1 Mbp. Phylogenomic analysis placed 96 of these genomes, 351 additional Enterobacter genomes downloaded from NCBI GenBank, and six newly sequenced type strains into 19 phylogenomic groups-18 groups (A to R) in the Enterobacter cloacae complex and Enterobacter aerogenes Diverse mechanisms underlying the molecular evolutionary trajectory of these drug-resistant Enterobacter spp. were revealed, including the acquisition of an antibiotic resistance plasmid, followed by clonal spread, horizontal transfer of blaKPC-harboring plasmids between different phylogenomic groups, and repeated transposition of the blaKPC gene among different plasmid backbones. Group A, which comprises multilocus sequence type 171 (ST171), was the most commonly identified (23% of isolates). Genomic analysis showed that ST171 isolates evolved from a common ancestor and formed two different major clusters; each acquiring unique blaKPC-harboring plasmids, followed by clonal expansion. The data presented here represent the first comprehensive study of phylogenomic interrogation and the relationship between antibiotic resistance and plasmid discrimination among carbapenem-resistant Enterobacter spp., demonstrating the genetic diversity and complexity of the molecular mechanisms driving antibiotic resistance in this genus. IMPORTANCE: Enterobacter spp., especially carbapenemase producing Enterobacter spp., have emerged as a clinically significant cause of nosocomial infections. However, only limited information is available on the distribution of carbapenem resistance across this genus. Augmenting this problem is an erroneous identification of Enterobacter strains because of ambiguous typing methods and imprecise taxonomy. In this study, we used a whole-genome based comparative phylogenetic approach to (i) revisit and redefine the genus Enterobacter and (ii) unravel the emergence and evolution of the Klebsiella pneumoniae carbapenemase-harboring Enterobacter spp. Using genomic analysis of 447 sequenced strains, we developed an improved understanding of the species designations within this complex genus and identified the diverse mechanisms driving the molecular evolution of carbapenem resistance. The findings in this study provide a solid genomic framework that will serve as an important resource in the future development of molecular diagnostics and in supporting drug discovery programs. PMID- 27965457 TI - Induction of hypoxia and necrosis in multicellular tumor spheroids is associated with resistance to chemotherapy treatment. AB - Culture of cancerous cells in standard monolayer conditions poorly mirrors growth in three-dimensional architectures typically observed in a wide majority of cancers of different histological origin. Multicellular tumor spheroid (MCTS) culture models were developed to mimic these features. However, in vivo tumor growth is also characterized by the presence of ischemic and necrotic areas generated by oxygenation gradients and differential access to nutrients. Hypoxia and necrosis play key roles in tumor progression and resistance to treatment. To provide in vitro models recapitulating these events in highly controlled and standardized conditions, we have generated colorectal cancer (CRC) cell spheroids of different sizes and analyzed their gene expression profiles and sensitivity to treatment with 5FU, currently used in therapeutic protocols. Here we identify three MCTS stages, corresponding to defined spheroid sizes, characterized by normoxia, hypoxia, and hypoxia plus necrosis, respectively. Importantly, we show that MCTS including both hypoxic and necrotic areas most closely mimic gene expression profiles of in vivo-developing tumors and display the highest resistance to 5FU. Taken together, our data indicate that MCTS may mimic in vitro generation of ischemic and necrotic areas in highly standardized and controlled conditions, thereby qualifying as relevant models for drug screening purposes. PMID- 27965458 TI - Association between the HOTAIR polymorphisms and cancer risk: an updated meta analysis. AB - PURPOSE: LncRNA HOTAIR plays an important role in many cancer. Several studies have shown that some HOTAIR SNPs might be associated with tumor risk in case control studies, but the results are inconsistent and inconclusive. Therefore, it is necessary to better evaluate association between the HOTAIR SNPs and the risk of cancer. RESULTS: rs920778, rs7958904 and rs874945 but not rs4759314 and rs1899663 loci were significantly related to cancer risk, among of which rs920778 and rs874945 increased and rs7958904 decreased cancer risk, respectively. Moreover, rs920778 is significantly susceptible in both Asian population and digestive cancer risks. MATERIALS AND METHODS: Data were collected from PubMed, Embase and Web of Science. A total of 11 case-control studies were selected for the quantitative analysis. Software Stata (Version 12) was used to calculate Odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the strength of the associations. Subgroup analysis, sensitivity analysis, and publication bias were also performed. Five HOTAIR SNPs were finally enrolled in the study. CONCLUSIONS: HOTAIR SNP rs920778, rs7958904 and rs874945 are susceptible to cancer risk. SNP rs920778 is also a useful risk factor in evaluation of Asian population and digestive cancer. In addition, the cancer risk SNP rs874945 is first reported in the meta-analysis. PMID- 27965459 TI - Integrated analyses for genetic markers of polycystic ovary syndrome with 9 case control studies of gene expression profiles. AB - Due to genetic heterogeneity and variable diagnostic criteria, genetic studies of polycystic ovary syndrome are particularly challenging. Furthermore, lack of sufficiently large cohorts limits the identification of susceptibility genes contributing to polycystic ovary syndrome. Here, we carried out a systematic search of studies deposited in the Gene Expression Omnibus database through August 31, 2016. The present analyses included studies with: 1) patients with polycystic ovary syndrome and normal controls, 2) gene expression profiling of messenger RNA, and 3) sufficient data for our analysis. Ultimately, a total of 9 studies with 13 datasets met the inclusion criteria and were performed for the subsequent integrated analyses. Through comprehensive analyses, there were 13 genetic factors overlapped in all datasets and identified as significant specific genes for polycystic ovary syndrome. After quality control assessment, there were six datasets remained. Further gene ontology enrichment and pathway analyses suggested that differentially expressed genes mainly enriched in oocyte pathways. These findings provide potential molecular markers for diagnosis and prognosis of polycystic ovary syndrome, and need in-depth studies on the exact function and mechanism in polycystic ovary syndrome. PMID- 27965462 TI - LEF1 reduces tumor progression and induces myodifferentiation in a subset of rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and show characteristics of skeletal muscle differentiation. The two major RMS subtypes in children are alveolar (ARMS) and embryonal RMS (ERMS). We demonstrate that approximately 50% of ARMS and ERMS overexpress the LEF1/TCF transcription factor LEF1 when compared to normal skeletal muscle and that LEF1 can restrain aggressiveness especially of ARMS cells. LEF1 knockdown experiments in cell lines reveal that depending on the cellular context, LEF1 can induce pro-apoptotic signals. LEF1 can also suppress proliferation, migration and invasiveness of RMS cells both in vitro and in vivo. Furthermore, LEF1 can induce myodifferentiation of the tumor cells. This may involve regulation of other LEF1/TCF factors i.e. TCF1, whereas beta-catenin activity plays a subordinate role. Together these data suggest that LEF1 rather has tumor suppressive functions and attenuates aggressiveness in a subset of RMS. PMID- 27965460 TI - Opposing roles of KIT and ABL1 in the therapeutic response of gastrointestinal stromal tumor (GIST) cells to imatinib mesylate. AB - Most gastrointestinal stromal tumors (GISTs) are caused by activating mutations of the KIT receptor tyrosine kinase. The small molecule inhibitor imatinib mesylate was initially developed to target the ABL1 kinase, which is constitutively activated through chromosomal translocation in BCR-ABL1-positive chronic myeloid leukemia. Because of cross-reactivity of imatinib against the KIT kinase, the drug is also successfully used for the treatment of GIST. Although inhibition of KIT clearly has a major role in the therapeutic response of GIST to imatinib, the contribution of concomitant inhibition of ABL in this context has never been explored. We show here that ABL1 is expressed in the majority of GISTs, including human GIST cell lines. Using siRNA-mediated knockdown, we demonstrate that depletion of KIT in conjunction with ABL1 - hence mimicking imatinib treatment - leads to reduced apoptosis induction and attenuated inhibition of cellular proliferation when compared to depletion of KIT alone. These results are explained by an increased activity of the AKT survival kinase, which is mediated by the cyclin-dependent kinase CDK2, likely through direct phosphorylation. Our results highlight that distinct inhibitory properties of targeted agents can impede antitumor effects and hence provide insights for rational drug development. Novel KIT-targeted agents to treat GIST should therefore comprise an increased specificity for KIT while at the same time displaying a reduced ability to inhibit ABL1. PMID- 27965461 TI - KRAS mutant colorectal cancer gene signatures identified angiotensin II receptor blockers as potential therapies. AB - Colorectal cancer (CRC) is a life-threatening disease with high prevalence and mortality worldwide. The KRAS oncogene is mutated in approximately 40% of CRCs. While antibody based EGFR inhibitors (cetuximab and panitumumab) represent a major treatment strategy for advanced KRAS wild type (KRAS-WT) CRCs, there still remains no effective therapeutic course for advanced KRAS mutant (KRAS-MT) CRC patients.In this study, we employed a novel and comprehensive approach of gene expression connectivity mapping (GECM) to identify candidate compounds to target KRAS-MT tumors. We first created a combined KRAS-MT gene signature with 248 ranked significant genes using 677 CRC clinical samples. A series of 248 sub signatures was then created containing an increasing number of the top ranked genes. As an input to GECM analysis, each sub-signature was translated into a statistically significant therapeutic drugs list, which was finally combined to obtain a single list of significant drugs.We identify four antihypertensive angiotensin II receptor blockers (ARBs) within the top 30 significant drugs indicating that these drugs have a mechanism of action that can alter the KRAS-MT CRC oncogenic signaling. A hypergeometric test (p-value = 6.57 * 10-6) confirmed that ARBs are significantly enriched in our results. These findings support the hypothesis that ARB antihypertensive drugs may directly block KRAS signaling resulting in improvement in patient outcome or, through a reversion to a KRAS wild-type phenotype, improve the response to anti-EGFR treatment. Antihypertensive angiotensin II receptor blockers are therefore worth further investigation as potential therapeutic candidates in this difficult category of advanced colorectal cancers. PMID- 27965463 TI - Ameloblastoma RNA profiling uncovers a distinct non-coding RNA signature. AB - Ameloblastoma of the jaws remains the top difficult to treat odontogenic tumour and has a high recurrence rate. New evidence suggests that non-coding RNAs (ncRNAs) play a critical role in tumourgenesis and prognosis of cancer. However, ameloblastoma ncRNA expression data is lacking. Here we present the first report of ameloblastoma ncRNA signatures. A total of 95 ameloblastoma cases and a global array transcriptome technology covering > 285.000 full-length transcripts were used in this two-step analysis. The analysis first identified in a test cohort 31 upregulated ameloblastoma-associated ncRNAs accompanied by signalling pathways of cancer, spliceosome, mRNA surveillance and Wnt. Further validation in an independent cohort points out the long non-coding (lncRNAs) and small nucleolar RNA (snoRNAs): LINC340, SNORD116-25, SNORA11, SNORA21, SNORA47 and SNORA65 as a distinct ncRNA signature of ameloblastoma. Importantly, the presence of these ncRNAs was independent of BRAF-V600E and SMO-L412F mutations, histology type or tumour location, but was positively correlated with the tumour size. Taken together, this study shows a systematic investigation of ncRNA expression of ameloblastoma, and illuminates new diagnostic and therapeutic targets for this invasive odontogenic tumour. PMID- 27965464 TI - High expression of Snail and NF-kappaB predicts poor survival in Chinese hepatocellular carcinoma patients. AB - In this study, we explored the roles of Snail and NF-kappaB in hepatocellular carcinoma (HCC). Samples of HCC tumor tissue were collected from 83 Chinese HCC patients. Snail and NF-kappaB expression was then examined based on immunohistochemical staining, and the relations between Snail and NF-kappaB expression and the clinical characteristics of the patients were assessed using Cox model analysis. Snail and NF-kappaB were both expressed in HCC tissue, and their levels were strongly correlated. In addition, levels of both Snail and NF kappaB expression were negatively related to tumor differentiation, which was an independent factor predictive of survival in HCC patients. Snail and NF-kappaB may thus be useful markers of tumor differentiation and survival in HCC, and may also be useful for guiding treatment and exploring molecular mechanisms. PMID- 27965465 TI - Decreased Galphaq expression in T cells correlates with enhanced cytokine production and disease activity in systemic lupus erythematosus. AB - Aberrant T cell immune responses appear central to the development of systemic lupus erythematosus (SLE). We previously reported that Galphaq, the alpha subunit of Gq, regulates T and B cell immune responses, promoting autoimmunity. To address whether Galphaq contributes to the pathogenesis of SLE, Galphaq mRNA expression was studied using real time-PCR in PBMCs and T cells from SLE patients as well as age- and sex-matched healthy controls. Our results showed that Galphaq mRNA expression was decreased in PBMCs and T cells from SLE patients compared to healthy individuals. Correlation analyses showed that Galphaq expression in T cells from SLE patients was associated with disease severity (as per SLE Disease Activity Index), the presence of lupus nephritis, and expression of Th1, Th2 and Th17 cytokines. In keeping with clinical results, T-helper cell subsets (Th1, Th2 and Th17) were over-represented in Galphaq knockout mice. In addition, Galphaq expression in SLE T cells was negatively correlated with the expression of Bcl-2, an anti-apoptotic gene, and positively correlated with the expression of Bax, a pro-apoptotic gene. These data suggest that reduced Galphaq levels in T cells may promote enhanced and prolonged T cell activation, contributing to the clinical manifestations of SLE. PMID- 27965468 TI - HabibTM 4X-assisted resection versus clamp-crush resection for hepatocellular carcinoma: a propensity-matching study. AB - Long term outcome of ablation-assisted hepatic resection is unclear for hepatocellular carcinoma (HCC) patients. This study was scheduled to compare the outcome of Habib 4X ablation assisted resection (Habib group) with clamp-crush resection (CC group) for HCC. In this study, we retrospectively enrolled 81 patients from the Habib group and 103 patients from the CC group. Oncologic outcomes were analyzed using a propensity score matching (PSM) method. Compared with the CC group, the Habib group had higher levels of gamma-glutamyltransferase (P=0.044) and albumin (P=0.001), larger tumor sizes (P=0.007), shorter operation times (P=0.001), less blood loss (P=0.005), and less blood transfusions (P=0.038). There were no significant differences in complications (P=0.310), recurrence-free survival rates (RFS, P=0.112), or overall survival rates (OS, P=0.203) between the two groups. For the 67 patient pairs selected from the PSM analysis, the Habib group had better RFS and OS (P=0.033 and P=0.014, respectively). A Cox proportional hazards analysis revealed that Habib-assisted resection was an independent factor for RFS and OS (P=0.008 and P=0.016, respectively). Furthermore, for the 42 patients with central and large tumors, the Habib group had better RFS and OS than the CC group (P=0.035 and P=0.038, respectively). However, the differences of RFS and OS (P=0.117 and P=0.126, respectively) were not significant among 92 patients with peripheral or small tumors. Hence, HabibTM 4X-assisted resection is safe and provides better survival for HCC patients, particularly those with central and large tumors. PMID- 27965467 TI - MicroRNA expressing profiles in A53T mutant alpha-synuclein transgenic mice and Parkinsonian. AB - alpha-synuclein gene mutations can cause alpha-synuclein protein aggregation in the midbrain of Parkinson's disease (PD) patients. MicroRNAs (miRNAs) play a key role in the metabolism of alpha-synuclein but the mechanism involved in synucleinopathy remains unclear. In this study, we investigated the miRNA profiles in A53T-alpha-synuclein transgenic mice and analyzed the candidate miRNAs in the cerebrospinal fluid (CSF) of PD patients. The 12-month A53T transgenic mouse displayed hyperactive movement and anxiolytic-like behaviors with alpha-synuclein aggregation in midbrain. A total of 317,759 total and 289,207 unique small RNA sequences in the midbrain of mice were identified by high-throughput deep sequencing. We found 644 miRNAs were significantly changed in the transgenic mice. Based on the conserved characteristic of miRNAs, we selected 11 candidates from the 40 remarkably expressed miRNAs and explored their expression in 44 CSF samples collected from PD patients. The results revealed that 11 microRNAs were differently expressed in CSF, emphatically as miR-144-5p, miR-200a-3p and miR-542-3p, which were dramatically up-regulated in both A53T transgenic mice and PD patients, and had a helpful accuracy for the PD prediction. The ordered logistic regression analysis showed that the severity of PD has strong correlation with an up-expression of miR-144-5p, miR-200a-3p and miR-542-3p in CSF. Taken together, our data suggested that miRNAs in CSF, such as miR-144-5p, miR-200a-3p and miR-542-3p, may be useful to the PD diagnosis as potential biomarkers. PMID- 27965469 TI - The role of tumor microenvironment in therapeutic resistance. AB - Cancer cells undergo unlimited progression and survival owing to activation of oncogenes. However, support of the tumor microenvironment is essential to the formation of clinically relevant tumors. Recent evidence indicates that the tumor microenvironment is a critical regulator of immune escape, progression, and distant metastasis of cancer. Moreover, the tumor microenvironment is known to be involved in acquired resistance of tumors to various therapies. Despite significant advances in chemotherapy and radiotherapy, occurrence of therapeutic resistance leads to reduced efficacy. This review highlights myeloid cells, cancer-associated fibroblasts, and mesenchymal stem cells consisting of the tumor microenvironment, as well as the relevant signaling pathways that eventually render cancer cells to be therapeutically resistant. PMID- 27965470 TI - Aberrant expression of lncRNAs and mRNAs in patients with intracranial aneurysm. AB - Intracranial aneurysm (IA) is pathological dilatations of the cerebral artery and rupture of IAs can cause subarachnoid hemorrhage, which has a high ratio of fatality and morbidity. However, the pathogenesis of IAs remains unknown. We performed long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in IA tissues and superficial temporal arteries (STAs). A total of 4129 differentially expressed lncRNAs and 2926 differentially expressed mRNAs were obtained from the microarrays (P < 0.05). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that up regulated mRNAs were enriched in immune response, inflammatory response, regulation of immune response and lysosome, et al; while the down-regulated mRNAs were enriched in muscle contraction, smooth muscle contraction, cGMP-PKG signaling pathway and vascular smooth muscle contraction, et al. The lncRNA-mRNA co-expression networks were represented in immune response, inflammatory response, muscle contraction and vascular smooth muscle contraction. These findings may gain insight in the pathogenesis of IAs and provide clues to find key roles for IA patients. PMID- 27965471 TI - Critical role of SP thymocyte motility in regulation of thymic output in neonatal Aire-/- mice. AB - Autoimmune regulator (Aire) is essential in the perinatal period to prevent the multiorgan autoimmunity. Here we show that Aire-regulated single positive thymocyte trafficking in neonatal period is critical for thymic egress. Reduced thymic emigration was found in Aire-/- mice during neonatal period, leading to enhanced homeostatic expansion of peripheral T cells as early as 2 weeks of age. In neonatal Aire-/- mice, thymic expression of CCR7 ligands were dramatically reduced, resulting in decreased thymocyte motility and thymocyte emigration. This reduction of thymic egress in Aire-/- mice was alleviated beyond 3 weeks of age by an early upregulation of S1P1 signaling. As the numbers and quality of thymic emigrants are essential for the establishment and maintenance of peripheral tolerance, the reduced thymic emigration during neonatal period may deteriorate autoimmunity caused by the emigration of autoreactive T cells. PMID- 27965472 TI - Quantitative assessment of Zirconium-89 labeled cetuximab using PET/CT imaging in patients with advanced head and neck cancer: a theragnostic approach. AB - Biomarkers predicting treatment response to the monoclonal antibody cetuximab in locally advanced head and neck squamous cell carcinomas (LAHNSCC) are lacking. We hypothesize that tumor accessibility is an important factor in treatment success of the EGFR targeting drug. We quantified uptake of cetuximab labeled with Zirconium-89 (89Zr) using PET/CT imaging.Seventeen patients with stage III-IV LAHNSCC received a loading dose unlabeled cetuximab, followed by 10 mg 54.5+/-9.6 MBq 89Zr-cetuximab. PET/CT images were acquired either 3 and 6 or 4 and 7 days post-injection. 89Zr-cetuximab uptake was quantified using standardized uptake value (SUV) and tumor-to-background ratio (TBR), and correlated to EGFR immunohistochemistry. TBR was compared between scan days to determine optimal timing.Uptake of 89Zr-cetuximab varied between patients (day 6-7: SUVpeak range 2.5-6.2). TBR increased significantly (49+/-28%, p < 0.01) between first (1.1+/ 0.3) and second scan (1.7+/-0.6). Between groups with a low and high EGFR expression a significant difference in SUVmean (2.1 versus 3.0) and SUVpeak (3.2 versus 4.7) was found, however, not in TBR. Data is available at www.cancerdata.org (DOI: 10.17195/candat.2016.11.1).In conclusion, 89Zr-cetuximab PET imaging shows large inter-patient variety in LAHNSCC and provides additional information over FDG-PET and EGFR expression. Validation of the predictive value is recommended with scans acquired 6-7 days post-injection. PMID- 27965473 TI - Diagnostic Value of Endoscopic Ultrasonography in Symptomatic Patients with High and Intermediate Probabilities of Common Bile Duct Stones and a Negative Computed Tomography Scan. AB - Background/Aims: When computed tomography (CT) does not indicate choledocholithiasis in highly suspicious patients, there is no definite consensus on the subsequent modality. Endoscopic ultrasonography (EUS) indicates fewer procedure-related complications than endoscopic retrograde cholangiopancreatography (ERCP) and has a lower cost than magnetic resonance cholangiopancreatography. Therefore, we aimed to investigate the diagnostic value of EUS in patients with suspected choledocholithiasis and negative CT findings. Methods: Between March 2008 and November 2014, we retrospectively evaluated 200 patients with negative CT findings and high or intermediate probabilities of choledocholithiasis. All patients initially underwent EUS followed by ERCP as a confirmatory criterion standard. The primary outcome in these patients was the accuracy of EUS in the detection of choledocholithiasis. The secondary outcome was the clinical prediction of common bile duct (CBD) stones in this group. Results: EUS indicated choledocholithiasis in 165 of the 200 patients, and ERCP confirmed choledocholithiasis in 161 patients (80.5%). The accuracy of EUS in the detection of choledocholithiasis was 94.0% (sensitivity, 97.5%; specificity, 79.5%; positive predictive value, 95.2%; negative predictive value, 88.6%). A multivariate analysis demonstrated that choledocholithiasis was strongly predicted by EUS detection of choledocholithiasis, an age >55 years and a clinical diagnosis of cholangitis. Conclusions: An EUS-first approach is recommended for patients with suspected CBD stones and negative CT findings. PMID- 27965474 TI - Acai Berries Inhibit Colon Tumorigenesis in Azoxymethane/Dextran Sulfate Sodium Treated Mice. AB - Background/Aims: The aim of this study was to investigate the protective effect of acai against azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colorectal cancer development. Methods: The effect of acai on tumorigenesis was assessed by evaluating tumor incidence, multiplicity and invasiveness in the mouse colon. The levels of myeloperoxidase (MPO) and proinflammatory cytokines (tumor necrosis factor alpha [TNF-alpha], interleukin [IL]-1beta, and IL-6) were measured via enzyme-linked immunosorbent assay. Protein levels of cyclooxygenase 2 (COX-2), proliferating cell nuclear antigen (PCNA), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated death promoter (Bad) and cleaved-caspase-3 were assessed by immunoblotting. Results: Administration of pellets containing 5% acai powder reduced the incidences of both colonic adenoma and cancer (adenoma, 23.1% vs 76.9%, respectively, p=0.006; cancer, 15.4% vs 76.9%, respectively, p=0.002). In the acai-treated mice, the MPO, TNF-alpha, IL-1beta and IL-6 levels in the colon were significantly down-regulated. Acai inhibited PCNA and Bcl-2 expression and increased Bad and cleaved-caspase-3 expression. In vitro studies demonstrated that acai treatment reduced lipopolysaccharide-induced expression of TNF-alpha, IL-1beta, IL-6 and COX-2 in murine macrophage RAW 264.7 cells. Conclusions: Acai demonstrated protective effects against AOM/DSS-induced colon carcinogenesis, which suggests that the intake of acai may be beneficial for the prevention of human colon cancer. PMID- 27965476 TI - Positive Glucose Breath Tests in Patients with Hysterectomy, Gastrectomy, and Cholecystectomy. AB - Background/Aims: This study aimed to investigate the prevalence and characteristics of small intestinal bacterial overgrowth (SIBO) in patients undergoing abdominal surgeries, such as gastrectomy, cholecystectomy, and hysterectomy. Methods: One hundred seventy-one patients with surgery (50 hysterectomy, 14 gastrectomy, and 107 cholecystectomy), 665 patients with functional gastrointestinal disease (FGID) and 30 healthy controls undergoing a hydrogen (H2)-methane (CH4) glucose breath test (GBT) were reviewed. Results: GBT positivity (+) was significantly different among the surgical patients (43.9%), FGID patients (31.9%), and controls (13.3%) (p<0.01). With respect to the patients, 65 (38.0%), four (2.3%), and six (3.5%) surgical patients and 150 (22.6%), 30 (4.5%), and 32 (4.8%) FGID patients were in the GBT (H2)+, (CH4)+ and (mixed)+ groups, respectively (p<0.01). The gastrectomy group had a significantly increased preference in GBT+ (71.4% vs 42.0% or 41.1%, respectively) and GBT (H2)+ (64.3% vs 32.0% or 37.4%, respectively) compared with the hysterectomy or cholecystectomy groups (p<0.01). During GBT, the total H2 was significantly increased in the gastrectomy group compared with the other groups. Conclusions: SIBO producing H2 is common in abdominal surgical patients. Different features for GBT+ may be a result of the types of abdominal surgery. PMID- 27965475 TI - Magnetic Resonance Elastography and Diffusion Weighted Imaging in the Evaluation of Hepatic Fibrosis in Chronic Hepatitis B. AB - Background/Aims: Comparison of the accuracy of magnetic resonance elastography (MRE) and diffusion weighted imaging (DWI) for the diagnosis of liver fibrosis in patients with chronic hepatitis B (CHB). Methods: In this retrospective analysis, we investigated 63 patients with CHB and liver fibrosis. DWI was performed with both breath-hold (DWI-BH) and free-breathing (DWI-FB) sequences (b=0, 500). The mean liver stiffness and apparent diffusion coefficient (ADC) were calculated by drawing regions of interest maps. Fibrosis staging according to the METAVIR system was independently performed by an experienced pathologist. A receiver operating curve (ROC) analysis was conducted to determine the accuracy of MRE, DWI-BH and DWI-FB in the detection and stratification of liver fibrosis. The performance of the detection of significant fibrosis (>=F2), advanced fibrosis (>=F3), and cirrhosis (F4) was also evaluated by comparing areas under the ROC. Results: There was a moderate and significantly negative correlation between the ADC values and liver stiffness. The accuracies for the detection of >=F2/>=F3/F4 stage fibrosis with DWI-FB, DWI-BH and MRE were 0.84/0.76/0.72, 0.72/0.83/0.79 and 0.99/0.99/0.98, respectively. The performance of MRE was significantly better than DWI-FB and DWI-BH. There were no significant differences between the performance of DWI-FB and DWI-BH. Conclusions: MRE is more accurate than DWI for the detection and stratification of liver fibrosis in CHB. PMID- 27965477 TI - Impact of Obesity on a Chinese Population with Erosive Esophagitis and Barrett's Esophagus. AB - Background/Aims: The aim of this study was to investigate the associations between obesity and erosive esophagitis (EE) or Barrett's esophagus (BE) in a Chinese population. Methods: Data from subjects were retrospectively collected from 2006 to 2009. Individuals with BE were identified and age- and sex-matched at a 1:2 ratio with normal esophagocardial junction and EE patients. The subjects were stratified into two groups: the normal weight group and overweight/ obesity group (body mass index >=25 mg/m2) or the normal waist group and abdominal obesity group (waist circumference >=90 cm for men and >=80 cm for women). Results: Overall, 45%, 72%, and 52% were overweight/obese and 23%, 65%, and 18% had abdominal obesity in the normal, EE, and BE groups, respectively. Positive associations were identified between EE and overweight/obesity (odds ratio [OR], 3.14; 95% confidence interval [CI], 1.75 to 5.66) and abdominal obesity (OR, 6.22; 95% CI, 3.34 to 11.57); however, the associations were nonsignificant between BE and overweight/obesity (OR, 1.32; 95% CI, 0.67 to 2.61) or abdominal obesity (OR, 0.73; 95% CI, 0.31 to 1.73). Female BE patients had a significantly increased rate of being overweight/obese. Conclusions: Obesity is a contributing factor in EE. The association of BE and obesity was not significant, with the exception of female BE cases. PMID- 27965479 TI - Role of Dental Profession in Oral Cancer Prevention and Diagnosis. AB - The incidence of oral cancer is increasing worldwide. Malignant neoplasms of the mouth and pharynx have been rated as the 10th most common cancer in men and 7th in women, though geographical variations exist.1Generally, in a society, oral cancer is not properly understood. The sign and symptoms are frequently overlooked in the initial stages when it is responsive to treat. PMID- 27965466 TI - Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis. AB - Virally induced liver cancer usually evolves over long periods of time in the context of a strongly oxidative microenvironment, characterized by chronic liver inflammation and regeneration processes. They ultimately lead to oncogenic mutations in many cellular signaling cascades that drive cell growth and proliferation. Oxidative stress, induced by hepatitis viruses, therefore is one of the factors that drives the neoplastic transformation process in the liver. This review summarizes current knowledge on oxidative stress and oxidative stress responses induced by human hepatitis B and C viruses. It focuses on the molecular mechanisms by which these viruses activate cellular enzymes/systems that generate or scavenge reactive oxygen species (ROS) and control cellular redox homeostasis. The impact of an altered cellular redox homeostasis on the initiation and establishment of chronic viral infection, as well as on the course and outcome of liver fibrosis and hepatocarcinogenesis will be discussed The review neither discusses reactive nitrogen species, although their metabolism is interferes with that of ROS, nor antioxidants as potential therapeutic remedies against viral infections, both subjects meriting an independent review. PMID- 27965480 TI - Catalogue of Interactive Learning Objectives to improve an Integrated Medical and Dental Curriculum. AB - INTRODUCTION: Online learning media are increasingly being incorporated into medical and dental education. However, the coordination between obligatory and facultative teaching domains still remains unsatisfying. The Catalogue of Interactive Learning Objectives of the University Clinic of Mainz (ILKUM), aims to offer knowledge transfer for students while being mindful of their individual qualifications. Its hierarchical structure is designed according to the Association for Dental Education in Europe (ADEE) levels of competence. MATERIALS AND METHODS: The ILKUM was designed to establish a stronger interconnection between already existing and prospective learning strategies. All contents are linked to the current lectures as well as to e-learning modules, e.g., clinical case studies and OR videos. Students can conduct self-examinations regarding specific learning objectives. Since 2007, ILKUM has been developed and analyzed regarding its acceptance among dental students. RESULTS: These improved e learning techniques foster time and location-independent access to study materials and allow an estimation of the knowledge achieved by students. Surveys of our students clearly show a large demand for upgrading ILKUM content (89%; n = 172) with integrated self-testing (89%; n = 174). In parallel to the advancement of our e-learning offering, a portion of internet-based learning is constantly rising among students. CONCLUSION: The broad acceptance and demand for the development of ILKUM show its potential. Moreover, ILKUM grants fast, topic oriented querying of learning content without time and locale limitations as well as direct determination of the individually needed knowledge conditions. CLINICAL SIGNIFICANCE: The long-term goal of the ILKUM project is to be a sustainable, important additional modality of teaching and training for dental and medical students. PMID- 27965478 TI - Efficacy of Capecitabine Plus Oxaliplatin Combination Chemotherapy for Advanced Pancreatic Cancer after Failure of First-Line Gemcitabine-Based Therapy. AB - Background/Aims: Second-line chemotherapy in patients with advanced pancreatic ductal adenocarcinoma (PDAC) that progresses following gemcitabine-based treatment has not been established. This study aimed to investigate the efficacy and safety of second-line combination chemotherapy with capecitabine and oxaliplatin (XELOX) in these patients. Methods: Between August 2011 and May 2014, all patients who received at least one cycle of XELOX (capecitabine, 1,000 mg/m2 twice daily for 14 days; oxaliplatin, 130 mg/m2 on day 1 of a 3-week cycle) combination chemotherapy for unresectable or recurrent PDAC were retrospectively recruited. The response was evaluated every 9 weeks, and the tumor response rate, progression-free survival and overall survival, and adverse events were assessed. Results: Sixty-two patients were included; seven patients (11.3%) had a partial tumor response, and 20 patients (32.3%) had stable disease. The median progression-free and overall survival were 88 days (range, 35.1 to 140.9 days) and 158 days (range, 118.1 to 197.9 days), respectively. Patients who remained stable longer with frontline therapy (>=120 days) exhibited significantly longer progression-free and overall survival. The most common grade 3 to 4 adverse events in patients were vomiting (8.1%) and anorexia (6.5%). There was one treatment-related mortality caused by severe neutropenia and typhlitis. Conclusions: Second-line XELOX combination chemotherapy demonstrated an acceptable response and survival rate in patients with advanced PDAC who had failed gemcitabine-based chemotherapy. PMID- 27965483 TI - Surface Hardness of Dental Composite Resin Restorations in Response to Preventive Agents. AB - INTRODUCTION: To assess the impact of using preventive mouthwash agents on the surface hardness of various resins composites. MATERIALS AND METHODS: Hundred specimens were prepared from five types of composite resin material in a Teflon mold. Five specimens from each type of restorative materials (Herculite XRV Ultra, Estelite Sigma Quick, Z Hermack, Versa Comp Sultan, and Empress Direct IPS) were evaluated posttreatment with immersion in four types of preventive mouthwashes gels and rinses - group 1: Flocare gel (0.4% stannous fluoride), group 2: Pascal gel (topical APF fluoride), group 3: Pro-relief mouthwash (Na fluoride), and group 4: Plax Soin mouthwash (Na fluoride) - at 37 degrees C in a dark glass container at 24, 48, and 72 hours. Surface hardness measurement was made for each tested material. Statistically, we analyzed the mean values with one-way analysis of variance (ANOVA) and Tukey's test, with significance level of p < 0.05. RESULTS: All composite resin materials showed decrease in their surface hardness with the time elapsed (24, 48, and 72 hours) postimmersion in the preventive mouthwashes and gels except the Herculite XRV Ultra and Versa Comp Sultan materials. Flocare gel group showed increase in the surface hardness after 48 hours of immersion than the other periods and in Estelite Sigma Quick after 72 hours. There was significant differences in all materials tested with the immersion in the preventive mouthwashes and gels, such as Flocare gel (0.4% stannous fluoride), Pro-relief mouthwash (Na fluoride), and Plax Soin mouthwash (Na fluoride) except Pascal gel (topical APF fluoride) (p > 0.05), at time intervals mentioned earlier (p < 0.05). CONCLUSION: The effect of preventive mouthwashes and gels on resin composite materials was decreased surface hardness with the time elapse of immersion for all materials except the Flocare gel group, which contains 0.4% stannous fluoride as a preventive ingredient increases the surface hardness after 48 h for Herculite XRV Ultra and Versa Comp Sultan and Estelite Sigma Quick after 72 hours. CLINICAL SIGNIFICANCE: The preventive agents in the form of mouthwash and gel are used to prevent oral diseases that affect the surface hardness of composite resin, and this leads to occlusion, color stability, and surface roughness. PMID- 27965482 TI - Comparative Evaluation of Antibacterial Effect of Dental Luting Cements on Streptococcus mutans and Lactobacillus acidophilus: An In vitro Study. AB - INTRODUCTION: This study aimed at evaluating and comparing the antibacterial activity of six types of dental luting cements on Streptococcus mutans and Lactobacillus acidophilus using the agar diffusion test (ADT) and the direct contact test (DCT). The antibacterial activity in ADT was measured based on the diameter of the zone of inhibition formed, whereas in DCT the density of the bacterial suspension was measured. The lower the density of the suspension, the more antibacterial activity the cement possesses. MATERIALS AND METHODS: Agar diffusion test was carried out on the bacteria. After an incubation period of 24 hours, the plates were checked for the presence of zone of inhibition. In DCT the cement was mixed and applied. Once the cement was set, bacterial suspension and brain-heart infusion medium was poured and incubated for 24 hours. After 24 hours, the plate was placed in the enzyme-linked immunosorbent assay plate reader, which measured the optical density of the fluid. The first set of data was recorded approximately 1 hour after incubation. Overall, three sets of data were recorded. Additional experiments were performed on set test materials that were allowed to age for 24 hours, 1 week, 1, 3, and 6 months. RESULTS: When using ADT only two cements zinc oxide eugenol (ZOE) and zinc polycarboxylate (ZPC) cement showed antibacterial activity against the test organisms. When using DCT, all cements showed some amount of antibacterial activity. Zinc oxide eugenol and ZPC cement showed highest amount of antibacterial activity against S. mutans and L. acidophilus respectively. CONCLUSION: Within the limitations of study, ZOE cement and ZPC cement were most effective against the tested microorganisms followed by the newer resin cement. The glass ionomer cement was the weakest of all. CLINICAL SIGNIFICANCE: Patients with high caries index can be treated more effectively using the abovementioned cements. PMID- 27965481 TI - Marginal Fit Metal-Ceramic and In-Ceram Single Crown Cement retained in Implant supported Abutments. AB - INTRODUCTION: This study evaluated the cervical fit of cemented metal-ceramic and In-Ceram implant-supported crowns, before and after the cementing procedure. MATERIALS AND METHODS: Twenty crowns cemented on implant abutments are divided into two groups (n = 10): Group 1 -cemented metal-ceramic crowns and group 2 - cemented In-Ceram crowns. The marginal adaptations before and after cementation were evaluated in a comparison microscope with an error of 1 MUm. All crowns were cemented with zinc phosphate cement. RESULTS: The cervical misalignment of cemented crowns before cementation (52.65 +/- 11.83 and 85.73 +/- 14.06 MUm) was lower than that after cementation (66.80 +/- 15.86 and 89.36 +/- 22.66 MUm). CONCLUSION: The cementing procedure interferes with the marginal fit of cemented crowns on implant abutments, with the prosthesis having better adaptation before cementation. Cemented metal-ceramic crowns exhibited better cervical adaptation than In-Ceram crowns cemented before and after the cementing procedure. CLINICAL SIGNIFICANCE: The maintenance of gum health and the longevity of prosthetic restorations are closely related to the restoration's marginal integrity. PMID- 27965484 TI - Influence of Dentin Deproteinization on Bonding Degradation: 1-year Results. AB - INTRODUCTION: The decalcification protocol of dentin surface with sodium hypochlorite removes the exposed collagen fibrils and could improve the longevity of the bonding interface. This study evaluated the influence of collagen removal with 10% sodium hypochlorite (10% NaOCl) on the longitudinal shear bond strength (SBS) of adhesives to dentin. MATERIALS AND METHODS: Seventy-two extracted human molars were sectioned and the buccal and lingual surfaces were flattened and acid etched with 37% phosphoric acid for 15 seconds. The specimens were divided into six groups (n = 12 teeth - 24 sections), according to adhesive and collagen removal protocol: group 1: UNO Dentastic; group 2: Prime and Bond NT; group 3: Single Bond; group 4: 10% NaOCl + UNO Dentastic; group 5: 10% NaOCl + Prime and Bond NT; group 6: 10% NaOCl + Single Bond. Composite Z100 buildup was prepared, and the SBS test was assessed after 24 hours and 1 year. Data were submitted to three-way analysis of variance (ANOVA) and Tukey tests (p < 0.05). RESULTS: The mean values (MPa) were for 24 hours: G1: 22.45B; G2: 7.90DE; G3: 12.56CD; G4: 19.85BC; G5: 33.73A; G6: 20.77B; and for 1 year: G1: 2.43E; G2: 2.26E; G3: 4.3DE; G4: 18.79BC; G5: 26.49AB; G6: 22.73B. CONCLUSION: Dentin deproteinization treatment with 10% NaOCI influenced the SBS compared with conventional treatment. The negative influence on SBS detected for conventional groups at 1-year interval was not detected for deproteinized groups. CLINICAL RELEVANCE: The longevity of hybrid layer is critical due to the hydrolysis process at the adhesive interface over time. The use of 10% NaOCl deproteinization protocol might improve the longevity of bonding in adhesive restorations. PMID- 27965485 TI - Effect of Intracanal Cryotherapy and Negative Irrigation Technique on Postendodontic Pain. AB - AIM: To evaluate the effect of intracanal cryotherapy with negative pressure irrigation (EndoVac) on postendodontic pain after vital single-visit root canal treatment (RCT). MATERIALS AND METHODS: A total of 75 single-rooted teeth with single root canal were treated endodontically. After root canal preparation with Protaper Universal rotary system and irrigation, teeth were divided randomly into three groups (n = 25) according to additional irrigation protocol as follows: Group I: No additional irrigation was applied (control); group II: A 20 mL of room temperature saline was irrigated during 5 minutes using EndoVac, and group III: A 20 mL of 2 to 4 degrees C cold saline was irrigated during 5 minutes using EndoVac. Pain levels were assessed by visual analog scale (VAS) and verbal evaluation of pain questionnaire after 6, 12, 24, 48 hours, and 7 days of canal obturation. The data were then analyzed using Statistical Package for the Social Sciences (SPSS) 13.0 using Kruskal-Wallis and Mann-Whitney U tests at p-value of 0.05. RESULTS: The results showed that pain levels were high in groups I and II after 6 hours that decreased with time to almost diminish after 1 week, and on the other hand, group III showed no pain among different monitoring periods. Also pain levels in groups II were lower compared with group I after only 6 hours, with significance p < 0.05. CONCLUSION: Postendodontic pain presented with highest values after 6 hours of treatment and reduced to almost nil after 1 week. Intracanal cryotherapy eliminated postendodontic pain clinically. Negative pressure reduced postendodontic pain after 6 hours of treatment. CLINICAL SIGNIFICANCE: The outcome of this study indicates that the use of intracanal cryotherapy technique with negative pressure irrigation eliminates postendodontic pain after single-visit RCTs. PMID- 27965487 TI - Accuracy of Three Shade-matching Devices in Replicating the Shade of Metal Ceramic Restorations: An in vitro Study. AB - INTRODUCTION: In restorative dentistry, the clinician commonly encounters the challenge of replicating the color of natural teeth due to the subjectivity of perceptual evaluation. Recent advances in photography and computing have resulted in the widespread use of the digital camera for color imaging. These instruments can be used effectively for shade matching and communication to yield predictable results. MATERIALS AND METHODS: The study sample consisted of 20 freshly extracted noncarious premolars. The Commission Internationale de l'Eclairage (CIE) L*a*b* values of the tooth were obtained through a spectrophotometer, digital camera, and digital camera with a polarizer. Shade selection was carried out using VITA 3D Master and calculating the Euclidian distance. The fabricated metal ceramic crowns were then evaluated to check the shade replication by comparing the CIE L*a*b* values of the crowns with the reference shade tab images. RESULTS: The three-way analysis of variance (ANOVA) and comparative analysis using Bonferroni test reveals that the difference in the mean L*a* values between spectrophotometer and polarization dental imaging modality (PDIM) was insignificant. The difference in the mean L*a*b* of spectrophotometer and digital camera was statistically significant. The mean DeltaE for metal ceramic crowns and shade tabs was 4.2 that was greater than the clinically acceptable level (3.2). CONCLUSION: A statistically significant correlation was found to exist between the spectrophotometer and PDIM for all CIE L*, a*, and b* color coordinates. CLINICAL SIGNIFICANCE: The present study was undertaken to assess the shade-matching ability of three shade-matching devices, such as spectrophotometer, digital camera, and PDIM, in the accuracy of replication of metal ceramic restorations. PMID- 27965486 TI - Comparison of Shear Bond Strength and Microleakage of Various Bulk-fill Bioactive Dentin substitutes: An in vitro Study. AB - INTRODUCTION: Various bulk-fill materials depending on their composition, viscosity, and flow ability have different physical and mechanical properties. The aim of this in vitro study was to determine and compare the shear bond strength and microleakage properties of activa restorative with other bulk-fill restorative materials surefil (SDR), Biodentine, ever X posterior. MATERIALS AND METHODS: Forty permanent premolars were selected for shear bond strength, and 20 permanent premolars were selected with class II cavities on mesial and distal side for microleakage. Universal testing device was used to assess the shear bond strength. Microleakage was checked using dye penetration method under a stereomicroscope. Mean and standard deviation values were calculated from the recorded values. Intergroup comparison was done by one-way analysis of variance (ANOVA) followed by pairwise comparison using Tukey honestly significant difference (HSD) post hoc test. RESULTS: The mean shear bond strength was highest for SDR surefil followed by Ever X posterior, Bioactive restorative, and Biodentine respectively. In this study, SDR (surefil) showed better shear bond strength and better microleakage properties compared with the other test materials (F = 186.7157, p < 0.05). CONCLUSION: The result of this study showed that flowable and fiber-reinforced composites have better shear bond strength and microleakage properties. CLINICAL SIGNIFICANCE: Flowable bulk-fill composite resins can be used as dentin substitutes because of its superior properties. PMID- 27965488 TI - Rebamipide to Manage Stomatopyrosis in Oral Submucous Fibrosis. AB - INTRODUCTION: Oral submucous fibrosis (OSF) causes progressive debilitating symptoms, such as oral burning sensation (stomatopyrosis) and limited mouth opening. The standard of care (SOC) protocol includes habit cessation, intralesional steroid and hyaluronidase injections, and mouth opening exercises. The objective of the study was to evaluate efficacy of rebamipide in alleviating burning sensation of the oral mucosa in OSF in comparison with SOC intralesional steroid injections. MATERIALS AND METHODS: Twenty OSF patients were divided into two groups [rebamipide (100 mg TID for 21 days) and betamethasone (4 mg/mL biweekly for 4 weeks)] of 10 each by random sampling. Burning sensation was assessed every week for 1 month. Burning sensation scores were analyzed using repeated measures analysis of variance (ANOVA) and paired t-test. RESULTS: Change in burning sensation score was significant (p < 0.05) in the first four visits. However, score between the 4th and 5th visit was not statistically significant (p > 0.05). CONCLUSION: Our study has shown that rebamipide can be considered as an effective modality to manage burning sensation in patients suffering from OSF. CLINICAL SIGNIFICANCE: Considering stomatopyrosis and trismus as a major cause for inability to eat in OSF, use of newer adjunctive modalities, such as rebamipide will ease patients suffering and also encourage them to consume food. PMID- 27965489 TI - Effect of Audioanalgesia in 6- to 12-year-old Children during Dental Treatment Procedure. AB - INTRODUCTION: To evaluate the effect of audioanalgesia in 6- to 12-year-old children during dental treatment procedure. MATERIALS AND METHODS: A total of 40 children were selected and divided into two groups, study group - with audioanalgesia and control group - without audioanalgesia. The value of their pain was evaluated using Venham's pain rating scale. Data were compared using one sample t-test using Statistical Package for the Social Sciences (SPSS) (Inc.; Chicago, IL, USA), version 17.0. RESULTS: The difference in the control group and study group was statistically significant (p < 0.05). CONCLUSION: The method of distraction using audioanalgesia instills better positive dental attitude in children and decreases their pain perception. CLINICAL SIGNIFICANCE: Playing or hearing music during dental procedure significantly alters the perception of pain in 6- to 12-year-old children. PMID- 27965490 TI - Comparison of the Solubility of Conventional Luting Cements with that of the Polyacid Modified Composite Luting Cement and Resin-modified Glass lonomer Cement. AB - INTRODUCTION: This study was planned to find the solubility of the conventional luting cements in comparison with that of the polyacid-modified composite luting cement and recently introduced resin-modified glass ionomer cement (RMGIC) with exposure to water at early stages of mixing. MATERIALS AND METHODS: An in vitro study of the solubility of the following five commercially available luting cements, viz., glass ionomer cement (GIC) (Fuji I, GC), zinc phosphate (Elite 100, GC), polyacid-modified resin cement (PMCR) (Principle, Dentsply), polycarboxylate cement (PC) (Poly - F, Dentsply), RMGIC (Vitremer, 3M), was conducted. For each of these groups of cements, three resin holders were prepared containing two circular cavities of 5 mm diameter and 2 mm depth. All the cements to be studied were mixed in 30 seconds and then placed in the prepared cavities in the resin cement holder for 30 seconds. RESULTS: From all of the observed luting cements, PMCR cement had shown the lowest mean loss of substance at all immersion times and RMGIC showed the highest mean loss of substanceat all immersion times in water from 2 to 8 minutes. The solubility of cements decreased by 38% for GIC, 33% for ZnPO4, 50% for PMCR, 29% for PC, and 17% for RMGIC. CONCLUSION: The PMCR cement (Principle-Dentsply) had shown lowest solubility to water at the given time intervals of immersion. This was followed by PC, zinc phosphate, and GIC to various time intervals of immersion. PMID- 27965491 TI - In vitro Comparative Evaluation of Various Restorative Materials used for restoring Class III Cavities in Deciduous Anterior Teeth: A Clinical Study. AB - INTRODUCTION: Beauty standards in today's modernized world scenario are formed by well-aligned and well-designed bright white teeth. One of the major reasons behind patients reporting to dental clinics is pain. Caries in the anterior primary teeth forms one of the major concerns from a restorative point of view. Very few studies are quoted in literature which stresses on the follow-up of anterior restorations in primary teeth. Hence, we evaluated and compared the efficacy of composite resin and resin-modified glass ionomer cement (RGIC) for class III restorations in primary anterior teeth. MATERIALS AND METHODS: The present study was conducted in the pediatric dental wing and included a total of 80 patients aged 3 to 51/2 years who reported with the chief complaint of carious lesions in the primary anterior teeth. Patients having minimal of a pair of similar appearing small carious lesions on the same proximal surfaces of the deciduous maxillary incisors were included for the study. All the patients were randomly divided into two groups: One in which RGIC restoration was done and other in which composite restoration was done. Cavity preparation was done and filling of the cavity with the restorative materials was carried out. Assessment of the restorations was done at 4, 8, and 12 months time following criteria given by Ryge et al. All the results were analyzed by Statistical Package for the Social Sciences (SPSS) software. Mann-Whitney test and one-way analysis of variance (ANOVA) were used to evaluate the level of significance; p value less than 0.05 was considered as significant. RESULTS: For composite and RGIC restorations, the mean score for anatomic shape was 1.21 and 1.10 respectively. While comparing the clinical parameters, nonsignificant results were obtained between composite and RGIC restorative materials at 4-, 8-, and 12-month interval. On comparing the clinical parameters for individual restorative materials at different time intervals, statistically significant results were obtained only for anatomical shape and form. CONCLUSION: Both RGIC and composite resin restorative materials showed acceptable clinical outcomes after 12 months of follow-up in deciduous anterior teeth. In restoring class III restorations in primary anterior teeth, both the restorative materials showed similar outcome. CLINICAL SIGNIFICANCE: Keywords: Composite, Marginal, Resin-modified glass ionomer cement. PMID- 27965492 TI - Antibacterial Activity of Two Chemomechanical Caries Removal Gels on Carious Dentin of Primary Teeth: An in vitro Study. AB - INTRODUCTION: Chemomechanical caries removal (CMCR) is an effective method of caries removal especially for primary teeth as they cause less discomfort when compared with conventional caries removal. The most significant thing about caries removal is the elimination of cariogenic bacteria. This study compares the antibacterial activity of two CMCR gels. MATERIALS AND METHODS: A total of 40 primary molar teeth with carious dentin were split along the long axis in a laboratory. Total viable count (TVC) was taken for the teeth before splitting as a measure of colony-forming units per milliliter (CFU/mL). Each half was treated with either Carisolv or Carie-Care CMCR gels. Clean dentin samples were evaluated for Streptococcus mutans (SM) and Lactobacillus acidophilus (LB) after removal of carious tissue using the caries removal gels using serial dilutions and incubating on specific agar plates. RESULTS: The results showed significant reduction in mean TVC after use of both the CMCR gels. Both gels reduced the CFU/mL of SM and LB to a significant level (p < 0.05). However, there was no significant difference between the antibacterial activities of the two CMCR gels. CONCLUSION: The CMCR gels (Carisolv and Carie-Care) significantly reduced the residual TVC as well as SM and LB in carious primary dentin. Both CMCR gels had a similar antibacterial activity on the carious dentin of primary teeth. CLINICAL SIGNIFICANCE: The CMCR gels tested have a significant antibacterial activity and can be effectively used for elimination of caries-causing bacteria in primary teeth. PMID- 27965493 TI - New Single-bottle Ceramic Primer: 6-month Case Report and Laboratory Performance. AB - INTRODUCTION: This article presents a 6-month case report and an in vitro evaluation of the performance of the new self-etching glass-ceramic monobond etch and prime (MEP) when applied in a lithium disilicate (LD). The MEP contains in the same bottle, along with acid conditioner and silanes. This simplifies the bonding procedures by reducing not only the number of steps, but also the working time. A 42-year-old female patient sought for esthetic treatment, and the main complaint was the darkened appearance of the upper lateral incisor. The esthetic treatment includes dental bleaching and gingivectomy, all-ceramic zirco-nia crowns, and all-ceramic crown and laminate veneer LD. After 6 months of esthetic treatment, marginal staining, gap, or chip fracturing damaging margins after sharp explorer in the margins was not observed. Furthermore, the inferior etching pattern of MEP was compared with traditional hydrofluoric acid (HF) conditioning. The microshear bond strength to the intaglio surface of LD was statistically similar when HF was compared with MEP. This new self-etching glass-ceramic showed good in vitro and 6 months clinical results in this case report. Future long-term clinical studies with more clinical case need to be done to confirm the performance of the use of this new conditioner. CLINICAL SIGNIFICANCE: The use of a new self-etching glass-ceramic showed a good in vitro and 6 months clinical results. This new product can be an easy, simple, and alternative approach for esthetics bonding procedure. PMID- 27965494 TI - Multidisciplinary Management of Candidates for Maxillary Sinus Augmentation by a Surgeon and ENT Specialist. AB - Maxillary sinus augmentation has been shown to be a predictable treatment option for placing dental implants in areas of posterior maxilla with lack of sufficient residual alveolar bone height.1 The transalveolar (crestal) and the lateral window are the main techniques for the maxillary sinus augmentation with the goal of creating a space beneath the Schneiderian membrane in which to place various grafting materials in order to increase alveolar bone height. PMID- 27965495 TI - Use of the Tooth Coronal Pulp Index for Recognition of the Pubertal Growth Period. AB - AIM: The present study aimed to investigate the association between the tooth coronal index (TCI) and the pubertal growth stages (PGS) for children and adolescents. MATERIALS AND METHODS: A cross-sectional study was performed using retrospectively collected panoramic and hand-wrist radiographs of 262 individuals (125 males, 137 females). The coronal height (CH) and the coronal pulp cavity height (CPCH) of the left mandibular teeth were measured. Then the TCI for which was calculated according to Ikeda et al (1985). The estimated TCI for individuals with the following PGS after Fishman (1987) are: SMI 4 (S), SMI 5 (DP3 cap), SMI 6 (MP3 cap) and SMI 7 (Mp5 cap). The associations between the TCI and the PGS were investigated by correlation coefficient of Spearman's rho, and the validity values for the PGS were computed. RESULTS: Significant correlations were noted between the simple TCI values for premolars and molars and the PGS, and the highest correlation was for the summed TCI for both first and second molars. Utilizing the validity values of the summed TCI for both first and second mandibular molars, the PGS can be predicted as follows: S stage when TCI is 49.17 or lesser, DP3cap stage when TCI is 43.52 or lesser, MP3cap stage when TCI is 36.73 or lesser, and Mp5cap stage when TCI is 26.84 or lesser. CONCLUSION: The TCI values declined along with the maturational process in children and adolescents. The TCI for both first and second molars was the best predictor of the PGS. CLINICAL SIGNIFICANCE: Panoramic photographs can be beneficial for prediction of the skeletal maturity and treatment planning without resorting to hand-wrist radiographs. PMID- 27965496 TI - Socket Preservation using Enzyme-treated Equine Bone Granules and an Equine Collagen Matrix: A Case Report with Histological and Histomorphometrical Assessment. AB - AIM: To histologically assess the effectiveness of a socket-preservation technique using enzyme-treated equine bone granules as a bone-graft material in combination with an equine collagen matrix as a scaffold for soft-tissue regeneration. BACKGROUND: Enzyme-treated equine bone granules and equine collagen matrix recently have been developed to help overcome alveolar bone deficiencies that develop in the wake of edentulism. CASE REPORT: The patient had one mandibular molar extracted and the socket grafted with equine bone granules. The graft was covered with the equine collagen matrix, placed in a double layer. No flap was prepared, and the gingival margins were stabilized with a single stitch, leaving the matrix partially exposed and the site to heal by secondary intention. The adjacent molar was extracted 1 month later, and that socket was left to heal by secondary intention without any further treatment. Three months after each surgery, an implant was placed and a biopsy was collected. The two biopsies underwent histological processing and qualitative evaluation. Histomorphometric analysis was also performed to calculate the percentage of newly formed bone (NFB) in the two cores. Healing at both sites was uneventful, and no inflammation or other adverse reactions were observed in the samples. Soft-tissue healing by secondary intention appeared to occur faster at the grafted site. The corresponding core showed a marked separation between soft and hard tissue that was not observed in the core from the nongrafted site, where soft-tissue hypertrophy could be observed. Newly formed bone at the grafted and nongrafted sites was not significantly different (27.2 +/- 7.1 and 29.4 +/- 6.2% respectively, p = 0.45). CONCLUSION: The surgical technique employed in this case appeared to facilitate postextraction soft-tissue healing by second intention and simplify soft-tissue management. CLINICAL SIGNIFICANCE: Using a collagen-based matrix to cover a postextraction grafted site may facilitate second intention soft-tissue healing and proper soft-tissue growth. PMID- 27965497 TI - Intended and Achieved Torque of Implant Abutment's Screw using Manual Wrenches in Simulated Clinical Setting. AB - OBJECTIVE: To measure the difference between the intended torque and the achieved torque by the operator using the spring-style mechanical torque-limiting device (MTLD). MATERIALS AND METHODS: Inexperienced and experienced clinicians used one spring-type MTLD to torque two abutment screws of each anterior and posterior implants, which were attached to two digital torque meters through a jaw model. The jaw model was part of a preclinical bench manikin attached to a dental chair. The intended torque value was 35 N cm (recommended by manufacturer) and the technique of torquing was observed for all the participants (instantaneous and repeated). The mean torque value was calculated for each subject for the anterior and posterior implants independently; t-test was used to compare between the intended and achieved torque values and to compare between the experienced and inexperienced clinicians (p <= 0.05). RESULTS: Thirty-seven clinicians participated, with an overall mean torque value of 34.30 N cm. The mean torque value of the achieved torque (34.30 +/- 4.13 N cm) was statistically significantly less than the intended torque (p = 0.041). The male clinicians produced more statistically significantly accurate torque value (34.54 +/- 3.78 N cm) than the female clinicians (p = 0.034), and the experienced clinicians produced more accurate torque values (34.9 +/- 5.13 N cm) than the inexperienced clinicians (p = 0.048). CONCLUSION: Within the limitation of this study, the use of MTLDs did not always produce consistent torque values and the technique by which the operators use the MTLD might affect the torque value. PMID- 27965499 TI - Micromovement Evaluation of Original and Compatible Abutments at the Implant abutment Interface. AB - INTRODUCTION: Use of compatible abutments may increase micromovements between the abutments, and the inner part of the implant may increase the stress on marginal bone level. Also micromovement will change the volume of the inner space of the implant-abutment complex. The resulting pumping effect can transport even initially immobile microorganisms from the exterior to the interior and vice versa. OBJECTIVES: The purpose of the study was to evaluate the mechanical comportment of OsseoSpeedTM Tx implants connected with original and compatible abutments in vitro under simulated clinical loading conditions. MATERIALS AND METHODS: A total of 15 OsseoSpeedTM TX implants (4 * 11 mm) were used and divided into three groups (n = 5). Three types of abutments were used in the study; group I: Five original Ti DesignTM abutments, group II: Five NateaTM abutments, and group III: ImplanetTM abutments. Abutments used in groups II and III were all compatible with Astra Tech Implant SystemTM. Implants were embedded into resin. Simulating the human masticatory cycle, the axial force vector was increased up to a defined maximum (25, 50, 75, 100, 125, 150, 175, and 200 N) and inclined 30 degrees to the implant axis. A radiograph amplifier was used to convert the X ray projection into a picture. The visual evaluation of the frames and the provided X-ray videos were evaluated for an existing microgap in width and length between the implant and the abutment. RESULTS: An initial width gap was observed in groups II and III in four of the five samples with an average of 6.5 and 5 MUm respectively. When the axial forces reach 75 N, only groups II and III demonstrated a gap width of 5.2 +/- 3.63 and 4.8 +/- 3.03 MUm, and a gap length of 5.2 +/- 3.63 and 94 +/- 125.3 MUm respectively. At 200 N, group I showed a gap width of 8.4 +/- 1.67 MUm and a gap length of 187.6 +/- 43.6 MUm, while groups II and III showed a gap width of 12.4 +/- 3.29 and 22.8 +/- 5.76 MUm, and a gap length of 387.2 +/- 84.36 and 641.2 +/- 122.6 MUm respectively. CONCLUSION: Within the limitations of this study and under the parameters used and from the resulting data collected, we can presume that the use of compatible components leads to significant micromovement when compared with the use of original ones. CLINICAL SIGNIFICANCE: The use of compatible prosthetic components with original implants showed significant micromovements when compared with the use of abutment and implant from the same manufacturer. Clinically, the micromovements when associated with leakage leads to bone loss around the neck of the implant and later to peri-implantitis. PMID- 27965498 TI - Shaping Ability of ProTaper Next, WaveOne, and Reciproc in Simulated Root Canals. AB - INTRODUCTION: The study aimed to compare the shaping and preservation of the original curvature of simulated curved root canals using the following instruments: Reciproc (Rcp), WaveOne (Wo), and the ProTaper Next system (Ptn). MATERIALS AND METHODS: A total of 45 resin blocks with simulated curved root canals were divided into three groups (n = 15), prepared using the Rcp (R25), Wo (25/0.8), and Ptn (X2) instruments. Standardized photographs were taken before and after canal instrumentation. After the superimposition of the images, the amount of resin removed from the curvature's inner and outer walls was measured at six apical levels, at intervals of 1 mm. The canals' angles of curvature before and after instrumentation were subtracted. RESULTS: There were no significant differences between the instruments in terms of the total amount of resin removed of the inner or outer walls of the apical curvature (p > 0.05). The Rcp instruments provided the best resin removed ratios between the walls. The means of the change in angle were as follows: Wo = 2.15 degrees , Ptn = 0.92 degrees , and Rcp = 0.21 degrees . WaveOne caused significantly higher deviations than Rcp. CONCLUSION: All of the instruments demonstrated a tendency to straighten the simulated root canal. Instruments that use rotary movement achieved an effect similar to that of the reciprocating instruments in relation to change in angle. CLINICAL SIGNIFICANCE: Deviations from the original shape of the root canal could have a negative impact on the quality of a filling and consequently on the success of the endodontic treatment. PMID- 27965500 TI - Effect of Intraoral Aging on Debris Accumulation and Friction of First Molar Tubes. AB - AIM: The aim of this article was to evaluate the impact of intraoral aging and site specificity on debris accumulation and friction in molar tubes after intraoral use. MATERIALS AND METHODS: A total of 80 intraorally used first molar convertible tubes were provided by 20 orthodontic adolescent patients after 6 months of treatment. The specimens were divided into eight groups (n = 10) according to the mouth quadrant and the type of examination [four groups of ten tubes for scanning electron microscope (SEM) and four groups of ten tubes for friction test]. Scanning electron microscope examination was performed after opening the convertible caps and friction test was executed using a 0.019'' * 0.025'' stainless steel wire, which was inserted in the tubes belonging to each group. The Mann-Whitney test, analysis of variance (ANOVA), and Bonferroni tests were performed for statistical analysis at 0.01 level of significance. RESULTS: There was a significant increase in the amount of debris and frictional force after 6 months of intraoral exposure (p < 0.0001). Debris scores were higher (10% increase) on the upper tubes when compared with the lower ones, with no statistical difference. Mean frictional force ranged from 0.22 to 0.26 N according to the mouth quadrant, but the difference between groups was also not significant. CONCLUSION: After 6 months of intraoral exposure, there was a significant increase in the amount of debris in the first molar tube slots, leading to significantly higher frictional forces during sliding mechanics. The influence of site specificity on the amount of debris and on frictional forces of the first molar tubes could not be demonstrated. CLINICAL SIGNIFICANCE: Molar tubes should be cleaned, before and during sliding mechanics, in order to minimize friction. PMID- 27965501 TI - Effect of Surface Treatments on the Bond Strength to Turkom-Cera All-ceramic Material. AB - AIM: The aim of this study was to evaluate the effect of surface treatments on shear bond strength (SBS) of Turkom-Cera (Turkom-Ceramic (M) Sdn. Bhd., Puchong, Malaysia) all-ceramic material cemented with resin cement Panavia-F (Kuraray Medical Inc., Okayama, Japan). MATERIALS AND METHODS: Forty Turkom-Cera ceramic disks (10 mm * 3 mm) were prepared and randomly divided into four groups. The disks were wet ground to 1000-grit and subjected to four surface treatments: (1) No treatment (Control), (2) sandblasting, (3) silane application, and (4) sandblasting + silane. The four groups of 10 specimens each were bonded with Panavia-F resin cement according to manufacturer's recommendations. The SBS was determined using the universal testing machine (Instron) at 0.5 mm/min crosshead speed. Failure modes were recorded and a qualitative micromorphologic examination of different surface treatments was performed. The data were analyzed using the one-way analysis of variance (ANOVA) and Tukey honestly significant difference (HSD) tests. RESULTS: The SBS of the control, sandblasting, silane, and sandblasting + silane groups were: 10.8 +/- 1.5, 16.4 +/- 3.4, 16.2 +/- 2.5, and 19.1 +/- 2.4 MPa respectively. According to the Tukey HSD test, only the mean SBS of the control group was significantly different from the other three groups. There was no significant difference between sandblasting, silane, and sandblasting + silane groups. CONCLUSION: In this study, the three surface treatments used improved the bond strength of resin cement to Turkom-Cera disks. CLINICAL SIGNIFICANCE: The surface treatments used in this study appeared to be suitable methods for the cementation of glass infiltrated all-ceramic restorations. PMID- 27965502 TI - Study of Caries Prevalence among Miswak and Non-Miswak Users: A Prospective Study. AB - INTRODUCTION: Various types of oral hygiene measures have been practiced by different populations around the world, as there is difference in the oral hygiene products including toothpicks and toothpowders. Miswak or tooth cleaning stick, for mechanical tooth cleaning, can be traced back at least to pre-Islamic times. Currently, many of the world populations still use chewing sticks as the single method for tooth brushing. The present study was done to study the incidence and prevalence of caries among Miswak and non-Miswak users. MATERIALS AND METHODS: The study was done consisting of 120 cases and 120 control group (60 boys and 60 girls in each group) from the secondary school. The materials used were light, explorer, mirror, gloves, upper and lower teeth models, Miswak, and common toothbrush. After the recording of the primary data, Miswak was given to case group and the students were trained to use it on the teeth models. After 2 years, the examination of the teeth was done using the same method as before start of the study and by the same investigators. All the data were recorded, tabulated, and analyzed with the help of Statistical Package for the Social Sciences (SPSS) statistics version 17 using Student's t-test. RESULTS: From the 240 participants, only 211 had continued the study for the total period of time. Out of these, 111 were from the study group and 100 from the control group. On comparison of the decayed-missing-filled (DMF) index scores of the study and control groups, before and after completion of the study, had also shown that the caries index was increased and the difference was found to be statistically significant. CONCLUSION: From the study, it can be concluded that the study group using Miswak had less number of caries incidence than the control group of non Miswak. CLINICAL SIGNIFICANCE: Miswak can be used as teeth cleaning aid in day-to day life as it can reduce the caries incidence. PMID- 27965503 TI - A Case-control Study for the Assessment of Correlation of Denture-related Sores and Oral Cancer Risk. AB - INTRODUCTION: Oral cancer is one of the most common cancers in the world. Although multifactorial, the exact pathogenesis of oral cancer is still unclear. Apart from tobacco chewing and smoking, chronic long-term irritation by ill fitting denture is also said to be an important risk factor for the development of oral cancer. Literature quotes some amount of evidence that correlates long term denture irritation as a risk factor for the development of oral cancer. Hence, we analyzed the correlation of denture-related sores as a risk factor for the development of oral cancer. MATERIALS AND METHODS: The present case-control study included 140 newly diagnosed oral cancer cases and 140 patients as the control healthy group. One-hour questionnaire was framed and was conducted to the control group and the study group by 10 experienced interviewers who were trained for such type of analysis. Assessment of the patients' socioeconomic status, cigarette smoking habit, alcohol drinking habit, and oral health status was done and compared on the two study groups. Logistic regression models along with multivariate models were used for the assessment of the results. RESULTS: In the control group and the cancer patient group, total of 140 new cancer cases and 140 subjects were included. Out of 140 patients in the cancer group, 16 were nonsmokers, while 110 smoked cigarette in the cancer patient group. As far as alcohol consumption is concerned, 42 patients in the control group and 102 patients in the oral cancer group were chronic heavy drinkers. Fried food intake was high in both the groups. Significant correlation was obtained while comparing the heavy smokers, heavy alcohol consumers, and oral health status in both the study groups. CONCLUSION: Our results favor the hypothesis that positive correlation exists between oral cancer risk and recurrent denture sores. CLINICAL SIGNIFICANCE: People wearing denture prosthesis should be periodically visualized for identification of any mucosal alteration or changes at the earliest. PMID- 27965504 TI - Assessment of Myeloperoxidase and Nitric Levels around Dental Implants and Natural Teeth as a Marker of Inflammation: A Comparative Study. AB - INTRODUCTION: Dental implants form the mainstay of dental treatment involving rehabilitation of missing teeth. One of the major concerns for the clinicians doing dental implants is the postsurgical failure of dental implants. Success of dental implants is dependent upon the skills of the surgeon and the amount and quality of the bone remaining at the edentulous area where dental implant has to be placed. Myeloperoxidase (MPO) and nitrites are few of the enzymes and molecules which are said to be altered in inflammation. However, their exact role in the inflammatory processes around natural tooth and dental implant is still unclear. Hence we comparatively evaluated the levels of MPO and nitrites in the areas around the dental implants and natural teeth. MATERIALS AND METHODS: The present study comprises 42 patients who underwent prosthetic rehabilitation by dental implants from 2011 to 2014. Depth of probing value (DP), score of plaque index (SPI), gingival index (GI), and index of gingival bleeding time (GBT) were evaluated for the assessment of the periimplant soft tissue changes. Assessment of inflammation around the dental implant surface and around natural tooth was done based on the readings of these parameters. For the measurement of the MPO levels, spectrophotometric MPO assay was used. All the results were analyzed by Statistical Package for the Social Sciences (SPSS) software. RESULTS: The mean plaque index values were 1.56 and 0.97 in periodontitis cases of natural teeth and inflamed cases of dental implants respectively. While comparing mean plaque index, mean probing depth, and mean gingival bleeding index in between the two groups, significant difference was obtained. Mean MPO concentration in periodontitis and gingivitis cases in natural teeth were 0.683 and 0.875 U/MUL, while in inflamed dental implant cases, the mean value was 0.622 U/MUL. While comparing the total MPO levels, total nitrite levels, and total nitrite concentration in between two study groups, significant difference was obtained. On comparing the healthy and periodontitis cases in natural teeth, significant difference was obtained. CONCLUSION: In the inflammatory processes occurring around dental implant and natural teeth, MPO and NO make some amount of significant contribution. CLINICAL SIGNIFICANCE: The present study enforces on the role of MPO and nitrite as diagnostic and prognostic marker. PMID- 27965505 TI - Apical Extrusion of Intracanal Bacteria following use of Two Engine-driven Instrumentation Techniques: An in vitro Study. AB - AIM: The aim of the present study was to compare in vitro the amount of debris extruded apically from extracted teeth, using Twisted files and ProTaper rotary during two different instrumentation systems. MATERIALS AND METHODS: Forty-five human single-rooted mandibular premolar teeth were randomly divided into three groups and contaminated with Enterococcus faecalis. The teeth in experimental groups were instrumented until reaching the working length with ProTaper rotary instruments and Twisted files with XSmart and XSmart Dual groups. Debris extruded from the apical foramen was collected into glass vials and the amount of bacteria was calculated. The data obtained were analyzed using Kruskal-Wallis one-way analysis of variance and Mann-Whitney U tests, with p = 0.05 as the level for statistical significance. RESULTS: The XSmart Dual group extruded comparatively lesser bacteria compared to the XSmart group. Lesser amount of bacterial extrusion was seen when Twisted files were used compared to the ProTaper files (p < 0.05). CONCLUSION: Under the circumstances of this in vitro study, it can be concluded that all instrumentation techniques produced measurable apical extrusion of debris. So, it is upon the practitioner to decide which system best fits their individual needs and their level of skill and experience that will provide the best possible endodontic care for our patients. CLINICAL SIGNIFICANCE: The newer instrument designs, including noncutting tips, different cross sections, radial lands, and variable tapers, are better for the clinicians to improve working safety, to reduce the working time, and to create a greater flare within the preparations. PMID- 27965506 TI - A Clinicopathologic Study of Oral Changes in Gastroesophageal Reflux Disease, Gastritis, and Ulcerative Colitis. AB - OBJECTIVES: The aim and objectives of this study are to identify oral changes in certain gastrointestinal (GI) diseases, namely gastroesophageal reflux disease (GERD), ulcerative colitis, gastritis, and to evaluate these oral symptoms as indicators for assessing GI disorders. MATERIALS AND METHODS: In this study, the oral manifestations of various GI disorders were assessed in a varying age group of 250 patients in Government Stanley Medical College and Hospital, Chennai. Out of 250 patients, 142 were affected by GERD, 99 were affected by gastritis, and 9 patients were affected by ulcerative colitis. Of these patients, 177 were males and 73 were females. RESULTS: Evaluation of patients with gastritis revealed that 66.7% affected with gingivitis, 19.2% with dental erosion on the palatal and lingual aspects of maxillary and mandibular teeth predominantly in the anterior region, 10.1% with periodontitis, 2% with gingival erythema. Among the patients with GERD, 44% of the cases showed dental erosion, 25.5% periodontitis, 9.9% gingivitis, 5.7% gingival erythema, 2.8% palatal erythema, 2.1% gingival ulcers, glossitis 2%, 1.4% floor of the mouth erythema, and 0.7% erythema of the tongue. Patients with ulcerative colitis showed 44.4% of gingival erythema, 33.3% of dental erosions, and 22.2% of gingival ulcers and periodontitis. CONCLUSION: In our study of 250 patients, oral manifestations were observed in 88% of the patients. Both soft tissue and hard tissue changes were evident. There was a high correlation between various GI disease and dental erosion, erythema at various sites of the oral cavity, oral ulcers, gingivitis, periodontitis, and glossitis. Careful evaluation of oral cavity may unveil many GI disorders and help the patient by providing early diagnosis, which further facilitates the prognosis. PMID- 27965507 TI - Reinforcing Heat-cured Poly-methyl-methacrylate Resins using Fibers of Glass, Polyaramid, and Nylon: An in vitro Study. AB - INTRODUCTION: As civilization has progressed, there has been continued refinement of materials available for dental practice. The applications of resins have been extended to increased practical uses in numerous areas of prosthetic and restorative dentistry. Certain significant alterations in the technique of manipulation and nature of the dental product have influenced the range of application in dentistry. The present study was done to measure and compare the fracture strength of heat polymerized poly-methyl-methacrylate (PMMA) resin reinforced with fibers of glass, polyaramid, and nylon. MATERIALS AND METHODS: The present study was conducted in vitro on 40 PMMA denture base resin specimens. Specimens were divided into four subgroups with ten specimens each and tested for transverse strength using universal testing machine. RESULTS: In group I, the transverse strength mean value was 67.82 MPa. In group II, the transverse strength mean value was 59.47 MPa. In group III, the transverse strength mean value was 66.87 MPa, while in group IV, the transverse strength mean value was 66.47 MPa. CONCLUSION: Incorporation of 4% weight glass fibers in loose form significantly increased the transverse strength of denture base PMMA, while 4% of polyaramid fiber in random distribution significantly increased the transverse strength of denture base PMMA. PMID- 27965508 TI - Evaluation of Osseointegration in Implants using Digital Orthopantomogram and Cone Beam Computed Tomography. AB - INTRODUCTION: Accurate assessment of osseointegration in dental implants requires precise radiographic visualization of pathologic conditions as well as anatomical structures. The present study aimed to evaluate the formation of bony tissue (osseointegration) using digital orthopantomogram (OPG) and cone beam computed tomography (CBCT) immediately after implant insertion (within 7 days) and 3 months postinsertion. MATERIALS AND METHODS: Twenty single-implant sites on mandi bular posterior regions were selected on patients irrespective of their gender. Both digital OPG and CBCT were done within a week and again after 3 months of implant insertion surgery, using the same exposure parameters. RESULTS: Three of the 20 implants were submerged and were excluded as the crestal bone height could not be measured. The participants were recalled for radiographic measurements after 3 months of implant placement. On an average, there was 0.03 mm of osseointegration at the apical portion after 3 months of implant insertion on digital OPG; 0.04 mm of osseointegration at the crestal bone height after 3 months on digital OPG; and 0.01 mm of osseointegration at the apical portion after 3 months on CBCT. No change or <=0.02 mm of osseointegration at crestal bone height after 3 months on CBCT. CONCLUSION: Both digital OPG and CBCT are significant for the assessment of osseointegration in implants, and hence, endow definite benefit for accurate assessment in terms of the success of the implant placement. CLINICAL SIGNIFICANCE: However, CBCT is a better mode of evaluating dental implants but one should keep in mind that radiographic examination must be conducted to the benefit of the patient by application of the lowest achievable dose. PMID- 27965509 TI - A Rare Case of Labial Myiasis caused by Dermatobia hominis. AB - INTRODUCTION: The aim of this article is to present a rare case of myiasis caused by Dermatobia hominis. Myiasis is a disease caused by invasion of tissues of animals and humans by larval stages of dipterous (2-winged) flies. There are few reports of oral myiasis in the literature, mostly related to Cochliomyia hominivorax larvae. We present a case of a 53-year-old man with painful swelling of the left lower lip that was confirmed to be myiasis caused by D. hominis. Though more common in tropical and subtropical regions of North and South America, myiasis should be considered in the differential diagnosis of subcutaneous masses among residents or travelers in endemic areas. PMID- 27965510 TI - The effect of high-dose steroid treatment used for the treatment of acute demyelinating diseases on endothelial and cardiac functions. AB - OBJECTIVE: The cardiovascular effects of short-term high-dose steroid treatment (pulse steroid treatment) have not yet been clarified. We examined the short- and long-term effects of pulse steroid treatment in demyelinating diseases on endothelial and cardiac functions. METHODS: In this prospective study, we included 35 patients (20 females and 15 males; mean age, 32.8+/-9.3 years) who were not treated with steroids and who were previously diagnosed with multiple sclerosis or neuromyelitis optica. Patients were evaluated before, 1 week after, and 3 months after the steroid treatment. Brachial artery flow-mediated relaxation and cardiac systolic/diastolic function were evaluated using echocardiography to assess physical examination results, carotid intima-media thickness, and endothelial function. RESULTS: There was no difference between biochemical values, systolic function, left ventricular dimensions, and carotid intima-media thicknesses in the three evaluation periods. There were significant increases in the body mass index, body weight, and systolic/diastolic blood pressure measurements at 1 week and 3 months after treatment (p<0.001). There was a significant decrease in brachial artery flow-mediated relaxation at 1 week and 3 months (1 versus 2, p=0.042; 1 versus 3, p=0.003). In Doppler measurements at 1 week and 3 months, there was an increase in mitral A velocity, IVRT, and EDT values and a decrease in the E/A ratio in line with diastolic dysfunction. CONCLUSION: Pulse steroid therapy used for demyelinating diseases deteriorated endothelial and left ventricular diastolic functions in the early and late periods. Future studies are needed to evaluate the development of cardiovascular mortality and morbidity in patients receiving this type of treatment. PMID- 27965511 TI - Assessment of atrial conduction times in prediabetic patients with coronary artery disease. AB - OBJECTIVE: Prediabetes is a dysglycemic state and is associated with subtle myocardial injury and dysfunction. We evaluated atrial conduction times (ACTs) and atrial electromechanical delays (EMDs) in prediabetic patients with coronary artery disease (CAD). METHODS: In the present study, we recruited 128 consecutive patient candidates (40 euglycemic, 48 prediabetic, and 40 diabetic patients) for coronary artery bypass grafting. ACTs were measured using tissue Doppler imaging (TDI). The time intervals between the beginning of the P wave in the surface electrocardiogram and the peak of the a' wave in TDI (PA) in the septal and lateral mitral annuli and the lateral tricuspid annulus were measured and termed as "septal PA," "lateral PA," and "right ventricular (RV) PA," respectively. The differences between lateral and septal PA, septal and RV PA, and lateral and RV PA were termed as "left intra-atrial EMD," "right intra-atrial EMD," and "inter atrial EMD" respectively. RESULTS: Septal PA, lateral PA, RV PA, left and right intra-atrial EMDs, and inter-atrial EMD were not statistically different between these three groups. Furthermore, multivariable linear regression models, adjusted for potential confounders, showed that glycemic state was not associated with ACTs, left and right intra-atrial EMDs, and inter-atrial EMD. CONCLUSION: There were no significant differences between the euglycemic, prediabetic, and diabetic patients with CAD regarding ACTs and atrial EMDs. PMID- 27965513 TI - Barrett oesophagus: Risk stratification using Cytosponge. PMID- 27965514 TI - Therapy: Sterile faecal transfer for C. difficile infection. PMID- 27965512 TI - In-Depth Analysis on Influencing Factors of Adjacent Segment Degeneration After Cervical Fusion. AB - BACKGROUND To explore the related influencing factors of adjacent segment degeneration (ASD) after cervical discectomy and fusion (ACDF). MATERIAL AND METHODS A retrospective analysis of 263 patients who underwent ACDF was carried out. Cervical x-ray and magnetic resonance imaging (MRI) were required before operation, after operation, and at the last follow-up. General information and some radiographic parameters of all patients were measured and recorded. According to the imaging data, patients were put into one of two groups: non-ASD group and ASD group. The differences between the two groups were compared by t test and chi2-test, and the related influencing factors of ASD were analyzed by logistic regression. RESULTS In all, 138 patients had imaging ASD. Comparing the age, the postoperative cervical arc chord distance (po-CACD), and the plate to disc distance (PDD) of the two groups, differences were statistically significant (p<0.05). The gender, the fusion segment number, the pre-CACD, the pre-and-po CACD, the preoperative cervical spinal canal ratio, and the upper and lower disc height (DH) showed no statistical difference between the two groups (p>0.05). The results of logistic regression analysis showed that there were significant correlations in the following characteristics: age, postoperative po-CACD, and the PDD (p<0.05). Of all these characteristics, the correlation of age was the highest (R=1.820). CONCLUSIONS Age, po-CACD, and PDD were risk factors for ASD after ACDF. The older the operation age, the worse the recovery was of postoperative physiological curvature of cervical spine, and a PDD < 5 mm was more likely to lead to ASD. PMID- 27965515 TI - IBD: Ustekinumab therapy for Crohn's disease. PMID- 27965516 TI - New aminoglycoside-modifying enzymes APH(3')-VIII and APH(3')-IX in Acinetobacter rudis and Acinetobacter gerneri. AB - Analysis of whole-genome sequences of 133 strains of Acinetobacter detected two genes for new types of aminoglycoside 3'-O-phosphotransferase [APH(3')], type VIII in Acinetobacter rudis and IX in A. gerneri. The enzymes were related to each other (49% identity) and to APH(3')-VI (61% and 51% identity, respectively), which is intrinsic to A. guillouiae. The cloned genes conferred kanamycin and amikacin resistance to Escherichia coli but were cryptic or expressed at low levels in the original hosts. The chromosomal location of both genes and the genetic events for acquisition of an ancestral aphA gene by A. rudis and A. gerneri, and loss by A. bereziniae were supported by the molecular phylogenetic tree of these genes. These data confirm that nonpathogenic susceptible bacterial species can be considered as potential reservoirs of resistance genes. PMID- 27965517 TI - Laser-enhanced high-intensity focused ultrasound heating in an in vivo small animal model. AB - The enhanced heating effect during the combination of high-intensity focused ultrasound (HIFU) and low-optical-fluence laser illumination was investigated by using an in vivo murine animal model. The thighs of murine animals were synergistically irradiated by HIFU and pulsed nano-second laser light. The temperature increases in the target region were measured by a thermocouple under different HIFU pressures, which were 6.2, 7.9, and 9.8 MPa, in combination with 20 mJ/cm2 laser exposures at 532 nm wavelength. In comparison with conventional laser therapies, the laser fluence used here is at least one order of magnitude lower. The results showed that laser illumination could enhance temperature during HIFU applications. Additionally, cavitation activity was enhanced when laser and HIFU irradiation were concurrently used. Further, a theoretical simulation showed that the inertial cavitation threshold was indeed decreased when laser and HIFU irradiation were utilized concurrently. PMID- 27965518 TI - Non-invasive activation of optogenetic actuators. AB - The manipulation of genetically targeted neurons with light (optogenetics) continues to provide unprecedented avenues into studying the function of the mammalian brain. However, potential translation into the clinical arena faces a number of significant hurdles, foremost among them the need for insertion of optical fibers into the brain to deliver light to opsins expressed on neuronal membranes. In order to overcome these hardware-related problems, we have developed an alternative strategy for delivering light to opsins which does not involve fiber implants. Rather, the light is produced by a protein, luciferase, which oxidizes intravenously applied substrate, thereby emitting bioluminescence. In proof-of-principle studies employing a fusion protein of a light-generating luciferase to a light-sensing opsin (luminopsin), we showed that light emitted by Gaussia luciferase is indeed able to activate channelrhodopsin, allowing modulation of neuronal activity when expressed in cultured neurons. Here we assessed applicability of the concept in vivo in mice expressing luminopsins from viral vectors and from genetically engineered transgenes. The experiments demonstrate that intravenously applied substrate reaches neurons in the brain, causing the luciferase to produce bioluminescence which can be imaged in vivo, and that activation of channelrhodopsin by bioluminescence is sufficient to affect behavior. Further developments of such technology based on combining optogenetics with bioluminescence - i.e. combining light-sensing molecules with biologically produced light through luciferases - should bring optogenetics closer to clinical applications. PMID- 27965520 TI - Reassessing the Role of the Active TGF-beta1 as a Biomarker in Systemic Sclerosis: Association of Serum Levels with Clinical Manifestations. AB - Objective. To determine active TGF-beta1 (aTGF-beta1) levels in serum, skin, and peripheral blood mononuclear cell (PBMC) culture supernatants and to understand their associations with clinical parameters in systemic sclerosis (SSc) patients. Methods. We evaluated serum samples from 56 SSc patients and 24 healthy controls (HC). In 20 SSc patients, we quantified spontaneous or anti-CD3/CD28 stimulated production of aTGF-beta1 by PBMC. The aTGF-beta1 levels were measured by ELISA. Skin biopsies were obtained from 13 SSc patients and six HC, and TGFB1 expression was analyzed by RT-PCR. Results. TGF-beta1 serum levels were significantly higher in SSc patients than in HC (p < 0.0001). Patients with increased TGF-beta1 serum levels were more likely to have diffuse subset (p = 0.02), digital ulcers (p = 0.02), lung fibrosis (p < 0.0001), positive antitopoisomerase I (p = 0.03), and higher modified Rodnan score (p = 0.046). Most of our culture supernatant samples had undetectable levels of TGF-beta1. No significant difference in TGFB1 expression was observed in the SSc skin compared with HC skin. Conclusion. Raised active TGF-beta1 serum levels and their association with clinical manifestations in scleroderma patients suggest that this cytokine could be a marker of fibrotic and vascular involvement in SSc. PMID- 27965519 TI - Biomarkers Discovery for Colorectal Cancer: A Review on Tumor Endothelial Markers as Perspective Candidates. AB - Colorectal cancer (CRC) is the third most common cancer in the world. The early detection of CRC, during the promotion/progression stages, is an enormous challenge for a successful outcome and remains a fundamental problem in clinical approach. Despite the continuous advancement in diagnostic and therapeutic methods, there is a need for discovery of sensitive and specific, noninvasive biomarkers. Tumor endothelial markers (TEMs) are associated with tumor-specific angiogenesis and are potentially useful to discriminate between tumor and normal endothelium. The most promising TEMs for oncogenic signaling in CRC appeared to be the TEM1, TEM5, TEM7, and TEM8. Overexpression of TEMs especially TEM1, TEM7, and TEM8 in colorectal tumor tissue compared to healthy tissue suggests their role in tumor blood vessels formation. Thus TEMs appear to be perspective candidates for early detection, monitoring, and treatment of CRC patients. This review provides an update on recent data on tumor endothelial markers and their possible use as biomarkers for screening, diagnosis, and therapy of colorectal cancer patients. PMID- 27965522 TI - Corrigendum to "Sphingolipids as Mediators in the Crosstalk between Microbiota and Intestinal Cells: Implications for Inflammatory Bowel Disease". AB - [This corrects the article DOI: 10.1155/2016/9890141.]. PMID- 27965521 TI - Lymphocyte Antigen 75 Polymorphisms Are Associated with Disease Susceptibility and Phenotype in Japanese Patients with Inflammatory Bowel Disease. AB - Recent genome-wide association studies have rapidly improved our understanding of the molecular pathways leading to inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC). Although several reports have demonstrated that gene single nucleotide polymorphisms (SNPs) are associated with susceptibility to IBD, its precise genetic factors have not been fully clarified. Here, we performed an association analysis between lymphocyte antigen 75 (LY75) genetic variations and IBD susceptibility or phenotype. SNPs were genotyped in 51 CD patients, 94 UC patients, and 269 healthy controls of Japanese ethnicity. We detected a significant relationship with CD susceptibility for the rs16822581 LY75 SNP (P = 0.045). One haplotype (GT, P = 0.042) was also associated with CD susceptibility, while another carrying the opposite SNP (CA) was linked to an absence of surgical history for CD. Our findings confirm that LY75 is involved in CD susceptibility and may play a role in disease activity in the Japanese population. PMID- 27965523 TI - A Prospective Multicenter Registry of Patients Undergoing Hysteroscopic Morcellation of Uterine Polyps and Myomas. AB - Background: Hysteroscopic morcellation removes uterine pathology under direct visualization with continuous real-time tissue fragment removal. Objective: The aim of this study was to explore the feasibility of hysteroscopic morcellation across a diverse set of facilities, including both surgical and office-based settings. Design: This was a prospective, single-arm, multicenter registry development (Canadian Task Force classification II-3). Materials and Methods: Thirty-four U.S. obstetrics and gynecology facilities enrolled subjects into the registry. Inclusion criteria were women ages 18-65 with indications for hysteroscopic myomectomy and/or polypectomy who were treated with the MyoSure(r) Hysteroscopic Tissue Removal System (Hologic Inc., Marlborough, MA). Intrauterine lesion type/size and removal parameters, adverse events (AEs), and physician satisfaction ratings were recorded. Results: A total of 559 pathologies (187 fibroids; 372 polyps) were removed from 278 registered subjects (mean age: 43.9 +/- 9.0 years), with 250 procedures (89.9%) performed in an ambulatory surgery center or hospital outpatient setting and 28 (10.1%) in a gynecologic office setting. Most patients (n = 206, 74.1%) were treated for abnormal uterine bleeding, and 42 (15.1%) were treated for infertility. Mean fibroid diameter was 2.2 +/- 1.2 cm. Mean polyp diameter was 1.3 +/- 1.0 cm. Overall mean percentage of pathology removed was 95.4% (polyps 99.3%, fibroids 86.8%). Five AEs included four incidents of blunt cervical trauma and a single postoperative case of pedal edema; all were considered mild and resolved spontaneously. Postprocedure surveys indicated that 95% of reporting physicians were "satisfied" or "highly satisfied" with device performance. Conclusions: Hysteroscopic morcellation of intrauterine pathology was accomplished safely with a high degree of physician satisfaction in 278 patients treated in diverse healthcare settings that are reflective of general community practice in the United States. (J GYNECOL SURG 32:318). PMID- 27965525 TI - Facile Synthesis, Characterization, and Cytotoxic Activity of Europium-Doped Nanohydroxyapatite. AB - The objective of this study was to synthetize europium-doped nanohydroxyapatite using a simple aqueous precipitation method and, thereafter, characterize and impregnate selected samples with 5-fluorouracil in order to explore the properties and the releasing capacity of this material. The nanohydroxyapatite was doped with 3, 5, 10, and 20 wt% of europium. The obtained samples were characterized after they were dried at 80 degrees C and hydrothermal treated at 120 degrees C by 2 hours. The samples were analyzed by transmission electron microscopy, X-ray diffraction analysis, Fourier transform infrared spectroscopy, and photoluminescence. Also, impregnation and release of 5-fluorouracil were assessed in PBS. The toxicity effects of all samples were studied using viability assays on human fibroblasts cells (HGF-1) in vitro. The sizes of the crystallites were about 10-70 nm with irregular morphology and present the phase corresponding to the JCPDS card 9-0432 for hydroxyapatite. The results of the toxicity experiments indicated that doped and undoped powders are biocompatible with fibroblasts cells. Hydroxyapatite samples doped with 5% of europium and loaded with 5-fluorouracil release almost 7 mg/L of the drug after 60 minutes in PBS and decrease the viability of HeLa cells after 24 hours. PMID- 27965524 TI - Healthcare Providers' Knowledge and Current Practice of Pain Assessment and Management: How Much Progress Have We Made? AB - Context. Despite improvement in pain management and availability of clinical treatment guidelines, patients in Jordan are still suffering from pain. Negative consequences of undertreated pain are being recognized as a reason for further illnesses and poor quality of life. Healthcare providers (HCPs) are responsible for relieving pain of their patients. Objective. To evaluate the knowledge and attitudes of HCPs toward pain management in Jordan. Methods. A 16-item questionnaire with agree or disagree options was given to 662 HCPs in seven hospitals in Jordan who volunteered to participate in the study. Following data collection, the responses were coded and entered into SPSS. Results. There was a statistically significant difference (p < 0.004) in percentage scores between physicians (36%) and pharmacists (36%) versus nurses (24%). The level of knowledge was the best among physicians, followed by pharmacists specifically in the area of cancer pain management. Nurses scored the lowest for knowledge of pain assessment and management among HCPs. However, HCPs overall scores indicated insufficient knowledge specifically in relation to pain assessment and management among children. PMID- 27965526 TI - Fracture Resistance of K3 Nickel-Titanium Files Made from Different Thermal Treatments. AB - The purpose of this study was to compare fracture resistances of K3 nickel titanium files made from different thermal treatments. K3 (SybronEndo, Orange, CA), K3XF (SybronEndo), and experimentally heat treated K3 (K3H) were used. For the cyclic fatigue test, the samples were rotated with up-and-down motion in the artificial canal with the curvature of 60 degrees until the fracture occurred. The number of cycles to fracture (NCF) was measured. For the torsional fracture test, the samples were tightly bound and rotated until the fracture occurred. Elastic modulus (EM), ultimate torsional strength (UTS), and angle of rotation to fracture (ARF) were measured. The results were statistically analyzed by one-way ANOVA. The NCF of K3H was higher than those of K3 and K3XF (P < 0.05). The EM of K3XF and K3H was lower than that of K3 (P < 0.05). There was no significant difference in UTS. The ARF of K3XF was higher than that of K3 (P < 0.05). K3XF and K3H showed more flexibility than K3. The maximum torsional angle of K3XF was higher than that of K3, but there was no significant difference on the UTS in all three groups. PMID- 27965527 TI - Lexical Specification of Prosodic Information in Swedish: Evidence from Mismatch Negativity. AB - Like that of many other Germanic languages, the stress system of Swedish has mainly undergone phonological analysis. Recently, however, researchers have begun to recognize the central role of morphology in these systems. Similar to the lexical specification of tonal accent, the Swedish stress system is claimed to be morphologically determined and morphemes are thus categorized as prosodically specified and prosodically unspecified. Prosodically specified morphemes bear stress information as part of their lexical representations and are classified as tonic (i.e., lexically stressed), pretonic and posttonic, whereas prosodically unspecified morphemes receive stress through a phonological rule that is right edge oriented, but is sensitive to prosodic specification at that edge. The presence of prosodic specification is inferred from vowel quality and vowel quantity; if stress moves elsewhere, vowel quality and quantity change radically in phonologically stressed morphemes, whereas traces of stress remain in lexically stressed morphemes. The present study is the first to investigate whether stress is a lexical property of Swedish morphemes by comparing mismatch negativity (MMN) responses to vowel quality and quantity changes in phonologically stressed and lexically stressed words. In a passive oddball paradigm, 15 native speakers of Swedish were presented with standards and deviants, which differed from the standards in formant frequency and duration. Given that vowel quality and quantity changes are associated with morphological derivations only in phonologically stressed words, MMN responses are expected to be greater in phonologically stressed words than in lexically stressed words that lack such an association. The results indicated that the processing differences between phonologically and lexically stressed words were reflected in the amplitude and topography of MMN responses. Confirming the expectation, MMN amplitude was greater for the phonologically stressed word than for the lexically stressed word and showed a more widespread topographic distribution. The brain did not only detect vowel quality and quantity changes but also used them to activate memory traces associated with derivations. The present study therefore implies that morphology is directly involved in the Swedish stress system and that changes in phonological shape due to stress shift cue upcoming stress and potential addition of a morpheme. PMID- 27965530 TI - The Effect of Physical Therapy Treatment in Patients with Subjective Tinnitus: A Systematic Review. AB - Background: Tinnitus is a very common symptom that often causes distress and decreases the patient's quality of life. Apart from the well-known causes, tinnitus can in some cases be elicited by dysfunctions of the cervical spine or the temporomandibular joint (TMJ). To date however, it is unclear whether alleviation of these dysfunctions, by physical therapy treatment, also decreases the tinnitus complaints. Such physical therapy could be an interesting treatment option for patients that are now often left without treatment. Objectives: The aim of this review was to investigate the current evidence regarding physical therapy treatment in patients with tinnitus. Data sources: The online databases Pubmed, Web of Science, Cochrane, and Embase were searched up to March 2016. Two independent reviewers conducted the data extraction and methodological quality assessment. Study eligibility criteria: Only randomized controlled trials and quasi-experimental trials were included in the review. Studies had to be written in English, French, Dutch, or German. Participants and interventions: The included studies investigated the effect of physical therapy treatment modalities on tinnitus severity in patients suffering from subjective tinnitus. Results: Six studies were included in this review, four investigating cervical spine treatment and two investigating TMJ treatment. These studies show positive effects of cervical spine treatment (manipulations, exercises, triggerpoint treatment) on tinnitus severity. Additionally, decrease in tinnitus severity and intensity was demonstrated after TMJ treatment, following splints, occlusal adjustments as well as jaw exercises. Limitations: The risk of bias in the included studies was high, mainly due to lack of randomization, lack of blinding of subjects, therapists, and/or investigators. Additionally, risk of bias is present due to incomplete presentation of the data and selective reporting. A major issue of the reviewed papers is the heterogeneity of the included study populations, treatments and outcome measures, which inhibit data pooling and meta-analysis. Conclusions: Despite the methodological issues in the included studies and the consequent low quality evidence, it is noteworthy that all included studies show positive treatment effects. Before recommendations can be made, these results need to be confirmed in larger, high quality studies, using unambiguous inclusion criteria, state-of-the-art treatment, and high quality outcome measures. PMID- 27965529 TI - s-SMOOTH: Sparsity and Smoothness Enhanced EEG Brain Tomography. AB - EEG source imaging enables us to reconstruct current density in the brain from the electrical measurements with excellent temporal resolution (~ ms). The corresponding EEG inverse problem is an ill-posed one that has infinitely many solutions. This is due to the fact that the number of EEG sensors is usually much smaller than that of the potential dipole locations, as well as noise contamination in the recorded signals. To obtain a unique solution, regularizations can be incorporated to impose additional constraints on the solution. An appropriate choice of regularization is critically important for the reconstruction accuracy of a brain image. In this paper, we propose a novel Sparsity and SMOOthness enhanced brain TomograpHy (s-SMOOTH) method to improve the reconstruction accuracy by integrating two recently proposed regularization techniques: Total Generalized Variation (TGV) regularization and l1-2 regularization. TGV is able to preserve the source edge and recover the spatial distribution of the source intensity with high accuracy. Compared to the relevant total variation (TV) regularization, TGV enhances the smoothness of the image and reduces staircasing artifacts. The traditional TGV defined on a 2D image has been widely used in the image processing field. In order to handle 3D EEG source images, we propose a voxel-based Total Generalized Variation (vTGV) regularization that extends the definition of second-order TGV from 2D planar images to 3D irregular surfaces such as cortex surface. In addition, the l1-2 regularization is utilized to promote sparsity on the current density itself. We demonstrate that l1-2 regularization is able to enhance sparsity and accelerate computations than l1 regularization. The proposed model is solved by an efficient and robust algorithm based on the difference of convex functions algorithm (DCA) and the alternating direction method of multipliers (ADMM). Numerical experiments using synthetic data demonstrate the advantages of the proposed method over other state-of-the-art methods in terms of total reconstruction accuracy, localization accuracy and focalization degree. The application to the source localization of event-related potential data further demonstrates the performance of the proposed method in real-world scenarios. PMID- 27965531 TI - Fatty Acid Biosynthesis Inhibition Increases Reduction Potential in Neuronal Cells under Hypoxia. AB - Recently, we have reported a novel neuronal specific pathway for adaptation to hypoxia through increased fatty acid (FA) biosynthesis followed by esterification into lipids. However, the biological role of this pathway under hypoxia remains to be elucidated. In the presented study, we have tested our hypothesis that activation of FA synthesis maintains reduction potential and reduces lactoacidosis in neuronal cells under hypoxia. To address this hypothesis, we measured the effect of FA synthesis inhibition on [Formula: see text]/NAD+ and [Formula: see text]/NADP+ ratios, and lactic acid levels in neuronal SH-SY5Y cells exposed to normoxic and hypoxic conditions. FA synthesis inhibitors, TOFA (inhibits Acetyl-CoA carboxylase) and cerulenin (inhibits FA synthase), increased [Formula: see text]/NAD+ and [Formula: see text]/NADP+ ratios under hypoxia. Further, FA synthesis inhibition increased lactic acid under both normoxic and hypoxic conditions, and caused cytotoxicity under hypoxia but not normoxia. These results indicate that FA may serve as hydrogen acceptors under hypoxia, thus supporting oxidation reactions including anaerobic glycolysis. These findings may help to identify a radically different approach to attenuate hypoxia related pathophysiology in the nervous system including stroke. PMID- 27965532 TI - The Neuropeptide 26RFa (QRFP) and Its Role in the Regulation of Energy Homeostasis: A Mini-Review. AB - This mini-review deals with the neuropeptide 26RFa (or QRFP) which is a member of the RFamide peptide family discovered simultaneously by three groups in 2003. 26RFa (or its N-extended form 43RFa) was subsequently shown to be the endogenous ligand of the human orphan receptor GPR103. In the brain, 26RFa and GPR103mRNA are primarily expressed in hypothalamic nuclei involved in the control of feeding behavior, and at the periphery, the neuropeptide and its receptor are present in abundance in the gut and the pancreatic islets, suggesting that 26RFa is involved in the regulation of energy metabolism. Indeed, 26RFa stimulates food intake when injected centrally, and its orexigenic effect is even more pronounced in obese animals. The expression of 26RFa is up-regulated in the hypothalamus of obese animals, supporting that the 26RFa/GPR103 system may play a role in the development and/or maintenance of the obese status. Recent data indicate that 26RFa is also involved in the regulation of glucose homeostasis. 26RFa reduces glucose-induced hyperglycemia, increases insulin sensitivity and insulinemia. Furthermore, an oral ingestion of glucose strongly stimulates 26RFa release by the gut, indicating that 26RFa is a novel incretin. Finally, 26RFa is able to prevent pancreatic beta cell death and apoptosis. This brief overview reveals that 26RFa is a key neuropeptide in the regulation of energy metabolism. Further fields of research are suggested including the pathophysiological implication of the 26RFa/GPR103 system. PMID- 27965533 TI - Impact of Transcranial Direct Current Stimulation (tDCS) on Neuronal Functions. AB - Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, modulates neuronal excitability by the application of a small electrical current. The low cost and ease of the technique has driven interest in potential clinical applications. However, outcomes are highly sensitive to stimulation parameters, leading to difficulty maximizing the technique's effectiveness. Although reversing the polarity of stimulation often causes opposite effects, this is not always the case. Effective clinical application will require an understanding of how tDCS works; how it modulates a neuron; how it affects the local network; and how it alters inter-network signaling. We have summarized what is known regarding the mechanisms of tDCS from sub-cellular processing to circuit level communication with a particular focus on what can be learned from the polarity specificity of the effects. PMID- 27965534 TI - Inhibition of Histone Deacetylase 3 (HDAC3) Mediates Ischemic Preconditioning and Protects Cortical Neurons against Ischemia in Rats. AB - Brain ischemic preconditioning (PC) provides vital insights into the endogenous protection against stroke. Genomic and epigenetic responses to PC condition the brain into a state of ischemic tolerance. Notably, PC induces the elevation of histone acetylation, consistent with evidence that histone deacetylase (HDAC) inhibitors protect the brain from ischemic injury. However, less is known about the specific roles of HDACs in this process. HDAC3 has been implicated in several neurodegenerative conditions. Deletion of HDAC3 confers protection against neurotoxicity and neuronal injury. Here, we hypothesized that inhibition of HDAC3 may contribute to the neuronal survival elicited by PC. To address this notion, PC and transient middle cerebral artery occlusion (MCAO) were conducted in Sprague-Dawley rats. Additionally, primary cultured cortical neurons were used to identify the modulators and effectors of HDAC3 involved in PC. We found that nuclear localization of HDAC3 was significantly reduced following PC in vivo and in vitro. Treatment with the HDAC3-specific inhibitor, RGFP966, mimicked the neuroprotective effects of PC 24 h and 7 days after MCAO, causing a reduced infarct volume and less Fluoro-Jade C staining. Improved functional outcomes were observed in the neurological score and rotarod test. We further showed that attenuated recruitment of HDAC3 to promoter regions following PC potentiates transcriptional initiation of genes including Hspa1a, Bcl2l1, and Prdx2, which may underlie the mechanism of protection. In addition, PC-activated calpains were implicated in the cleavage of HDAC3. Pretreatment with calpeptin blockaded the attenuated nuclear distribution of HDAC3 and the protective effect of PC in vivo. Collectively, these results demonstrate that the inhibition of HDAC3 preconditions the brain against ischemic insults, indicating a new approach to evoke endogenous protection against stroke. PMID- 27965528 TI - The Neuroendocrine Regulation of Food Intake in Fish: A Review of Current Knowledge. AB - Fish are the most diversified group of vertebrates and, although progress has been made in the past years, only relatively few fish species have been examined to date, with regards to the endocrine regulation of feeding in fish. In fish, as in mammals, feeding behavior is ultimately regulated by central effectors within feeding centers of the brain, which receive and process information from endocrine signals from both brain and peripheral tissues. Although basic endocrine mechanisms regulating feeding appear to be conserved among vertebrates, major physiological differences between fish and mammals and the diversity of fish, in particular in regard to feeding habits, digestive tract anatomy and physiology, suggest the existence of fish- and species-specific regulating mechanisms. This review provides an overview of hormones known to regulate food intake in fish, emphasizing on major hormones and the main fish groups studied to date. PMID- 27965535 TI - Sensory Input-Dependent Changes in Glutamatergic Neurotransmission- Related Genes and Proteins in the Adult Rat Trigeminal Ganglion. AB - Experience-dependent plasticity induces lasting changes in the structure of synapses, dendrites, and axons at both molecular and anatomical levels. Whilst relatively well studied in the cortex, little is known about the molecular changes underlying experience-dependent plasticity at peripheral levels of the sensory pathways. Given the importance of glutamatergic neurotransmission in the somatosensory system and its involvement in plasticity, in the present study, we investigated gene and protein expression of glutamate receptor subunits and associated molecules in the trigeminal ganglion (TG) of young adult rats. Microarray analysis of naive rat TG revealed significant differences in the expression of genes, coding for various glutamate receptor subunits and proteins involved in clustering and stabilization of AMPA receptors, between left and right ganglion. Long-term exposure to sensory-enriched environment increased this left-right asymmetry in gene expression. Conversely, unilateral whisker trimming on the right side almost eliminated the mentioned asymmetries. The above manipulations also induced side-specific changes in the protein levels of glutamate receptor subunits. Our results show that sustained changes in sensory input induce modifications in glutamatergic transmission-related gene expression in the TG, thus supporting a role for this early sensory-processing node in experience-dependent plasticity. PMID- 27965536 TI - A Tribute to Peter H Seeburg (1944-2016): A Founding Father of Molecular Neurobiology. PMID- 27965538 TI - Lack of Cdkl5 Disrupts the Organization of Excitatory and Inhibitory Synapses and Parvalbumin Interneurons in the Primary Visual Cortex. AB - Cyclin-dependent kinase-like 5 (CDKL5) mutations are found in severe neurodevelopmental disorders, including the Hanefeld variant of Rett syndrome (RTT; CDKL5 disorder). CDKL5 loss-of-function murine models recapitulate pathological signs of the human disease, such as visual attention deficits and reduced visual acuity. Here we investigated the cellular and synaptic substrates of visual defects by studying the organization of the primary visual cortex (V1) of Cdkl5-/y mice. We found a severe reduction of c-Fos expression in V1 of Cdkl5 /y mutants, suggesting circuit hypoactivity. Glutamatergic presynaptic structures were increased, but postsynaptic PSD-95 and Homer were significantly downregulated in CDKL5 mutants. Interneurons expressing parvalbumin, but not other types of interneuron, had a higher density in mutant V1, and were hyperconnected with pyramidal neurons. Finally, the developmental trajectory of pavalbumin-containing cells was also affected in Cdkl5-/y mice, as revealed by fainter appearance perineuronal nets at the closure of the critical period (CP). The present data reveal an overall disruption of V1 cellular and synaptic organization that may cause a shift in the excitation/inhibition balance likely to underlie the visual deficits characteristic of CDKL5 disorder. Moreover, ablation of CDKL5 is likely to tamper with the mechanisms underlying experience dependent refinement of cortical circuits during the CP of development. PMID- 27965537 TI - Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus. AB - The physiological role of amyloid precursor protein (APP) has been extensively investigated in the rodent hippocampus. Evidence suggests that APP plays a role in synaptic plasticity, dendritic and spine morphogenesis, neuroprotection and-at the behavioral level-hippocampus-dependent forms of learning and memory. Intriguingly, however, studies focusing on the role of APP in synaptic plasticity have reported diverging results and considerable differences in effect size between the dentate gyrus (DG) and area CA1 of the mouse hippocampus. We speculated that regional differences in APP expression could underlie these discrepancies and studied the expression of APP in both regions using immunostaining, in situ hybridization (ISH), and laser microdissection (LMD) in combination with quantitative reverse transcription polymerase chain reaction (RT qPCR) and western blotting. In sum, our results show that APP is approximately 1.7-fold higher expressed in pyramidal cells of Ammon's horn than in granule cells of the DG. This regional difference in APP expression may explain why loss of-function approaches using APP-deficient mice revealed a role for APP in Hebbian plasticity in area CA1, whereas this could not be shown in the DG of the same APP mutants. PMID- 27965540 TI - Rifampicin Attenuated Global Cerebral Ischemia Injury via Activating the Nuclear Factor Erythroid 2-Related Factor Pathway. AB - Background: Recent studies have found that rifampicin has neuroprotective properties in neurodegenerative diseases. However, the exact mechanisms of action remain unclear. The nuclear factor erythroid 2-related factor 2 (Nrf2) has been considered a potential target for neuroprotection. In this study, we examined whether rifampicin exhibits beneficial effects mediated by the Nrf2 pathway after global cerebral ischemia (GCI). Methods: Rats were randomly assigned to four groups that included a sham group and three treatment groups with global ischemia reperfusion [control, rifampicin, and rifampicin plus brusatol (an inhibitor of Nrf2)]. Rats were subjected to transient GCI induced by bilateral common carotid artery occlusion for 20 min with systemic hypotension by blood withdrawal. The Morris water maze test was performed for neurobehavioral testing, whereas the pathological changes were investigated using HE and TUNEL staining. The protein expression of Nrf2, hemeoxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) in the hippocampus were analyzed by Western blotting. The immunofluorescence staining was used to determine the distribution of Nrf2. Results: Rifampicin treatment significantly improved spatial learning ability compared with the control group, which was consistent with the pathological changes. In addition, rifampicin significantly elevated the nuclear expression of Nrf2, Nrf2 downstream anti oxidant protein, HO-1 compared with the control group, and it simultaneously downregulated the expression of COX-2 in the hippocampus on day 3 after ischemia reperfusion. Interestingly, the forenamed effects of rifampicin were abolished by pretreatment with brusatol, a specific inhibitor of Nrf2 activation. Conclusions: Rifampicin exerts neuroprotective effects against global cerebral ischemia, which may be attributed to activation of the Nrf2 pathway. PMID- 27965539 TI - Sevoflurane Post-conditioning Enhanced Hippocampal Neuron Resistance to Global Cerebral Ischemia Induced by Cardiac Arrest in Rats through PI3K/Akt Survival Pathway. AB - The purpose of this current study was to evaluate whether improvement of mitochondrial dysfunction was involved in the therapeutic effect of sevoflurane post-conditioning in global cerebral ischemia after cardiac arrest (CA) via the PI3K/Akt pathway. In the first experiment, animals were randomly divided into three groups: a sham group, a CA group, a CA+sevoflurane post-conditioning group (CA+SE). Sevoflurane post-conditioning was achieved by administration of 2.5% sevoflurane for 30 min after resuscitation. Sevoflurane post-conditioning has a significant neuroprotective effect by increasing survival rates and reducing neuronal apoptosis. Additionally, the gene and protein expression of PGC-1alpha, NRF-1, and TFAM, the master regulators of mitochondrial biogenesis, were up regulated in the CA+SE group, when compared to the CA group. Similarly, in contrast to the CA group, mitochondria-specific antioxidant enzymes, including heat-shock protein 60 (HSP60), peroxiredoxin 3 (Prx3), and thioredoxin 2 (Trx2) were also increased in the CA+SE group. Finally, administration of sevoflurane ameliorated mitochondrial reactive oxygen species (ROS) formation and maintained mitochondrial integrity. In the second experiment, we investigated the relationship between the PI3K/Akt pathway and mitochondrial biogenesis and mitochondria-specific antioxidant enzymes in sevoflurane-induced neuroprotection. The selective PI3K inhibitor wortmannin not only eliminated the beneficial biochemical processes of sevoflurane by reducing the level of mitochondrial biogenesis-related proteins and aggravating mitochondrial integrity, but also reversed the elevation of mitochondria-specific antioxidant enzymes induced by sevoflurane. Therefore, our data suggested that sevoflurane post-conditioning provides neuroprotection via improving mitochondrial biogenesis and integrity, as well as increasing mitochondria-specific antioxidant enzymes by a mechanism involving the PI3K/Akt pathway. PMID- 27965541 TI - Modulation of Oligodendrocyte Differentiation by Mechanotransduction. AB - Oligodendrocytes (OLs) are responsible for the myelination of axons in the central nervous system (CNS). The differentiation of OLs encompasses several stages, through which cells undergo dramatic biochemical and morphological changes. OL differentiation is modulated by soluble factors (SFs)-such as growth factors and hormones-, known to be essential for each maturation stage. Besides SFs, insoluble factors such as extracellular matrix (ECM) proteins and other microenvironmental elements also play a pivotal role during OL differentiation. Recently, a growing number of studies were published concerning the effect of biophysical properties of the extracellular milieu on OL differentiation and myelination, showing the importance of ECM stiffness and topography, strain forces and spatial constraints. For instance, it was shown in vitro that OL differentiation and maturation is enhanced by substrates within the reported range of stiffness of the brain and that this effect is potentiated by the presence of merosin, whereas the myelination process is influenced by the diameter of axonal-like fibers. In this mini review article, we will discuss the effect of mechanical cues during OL differentiation and the possible molecular mechanisms involved in such regulation. PMID- 27965543 TI - Controllable Pulse Parameter TMS and TMS-EEG As Novel Approaches to Improve Neural Targeting with rTMS in Human Cerebral Cortex. PMID- 27965542 TI - Releasing the Cortical Brake by Non-Invasive Electromagnetic Stimulation? rTMS Induces LTD of GABAergic Neurotransmission. AB - Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive brain stimulation technique which modulates cortical excitability beyond the stimulation period. However, despite its clinical use rTMS-based therapies which prevent or reduce disabilities in a functionally significant and sustained manner are scarce. It remains unclear how rTMS-mediated changes in cortical excitability, which are not task- or input-specific, exert beneficial effects in some healthy subjects and patients. While experimental evidence exists that repetitive magnetic stimulation (rMS) is linked to the induction of long-term potentiation (LTP) of excitatory neurotransmission, less attention has been dedicated to rTMS-induced structural, functional and molecular adaptations at inhibitory synapses. In this review article we provide a concise overview on basic neuroscience research, which reveals an important role of local disinhibitory networks in promoting associative learning and memory. These studies suggest that a reduction in inhibitory neurotransmission facilitates the expression of associative plasticity in cortical networks under physiological conditions. Hence, it is interesting to speculate that rTMS may act by decreasing GABAergic neurotransmission onto cortical principal neurons. Indeed, evidence has been provided that rTMS is capable of modulating inhibitory networks. Consistent with this suggestion recent basic science work discloses that a 10 Hz rTMS protocol reduces GABAergic synaptic strength on principal neurons. These findings support a model in which rTMS-induced long-term depression (LTD) of GABAergic synaptic strength mediates changes in excitation/inhibition-balance of cortical networks, which may in turn facilitate (or restore) the ability of stimulated networks to express input- and task-specific associative synaptic plasticity. PMID- 27965545 TI - Cellular and Subcellular Localization of the RGS7/Gbeta5/R7BP Complex in the Cerebellar Cortex. AB - A member of regulator of G-protein signaling family, RGS7, is an essential modulator of signaling through GABAB receptors. RGS7 functions as a macromolecular complex with type 5 G protein beta (Gbeta5) and R7 binding protein (R7BP) to control the localization and function of the resultant heterotrimeric complexes. Here, we used co-immunoprecipitation, in situ hybridization, histoblot and immunohistochemical techniques at the light and electron microscopic level to advance understanding of RGS7-Gbeta5-R7BP complexes in the central nervous system, focusing on distinct neuronal populations in the cerebellar cortex. Histoblot analysis showed that RGS7, Gbeta5 and R7BP proteins were widely expressed in the brain, with mostly an overlapping pattern and showing a high expression level in the molecular layer of the cerebellar cortex. Co immunoprecipitation experiments established that the RGS7/Gbeta5 forms complexes with R7BP in the cerebellum. At the cellular level, RGS7 and R7BP mRNAs were expressed at the highest level in Purkinje cells (PCs) and Golgi cells, and at low levels in granule cells. Immunohistochemistry confirmed that labeling for RGS7, Gbeta5 and R7BP were present in the three neuronal populations and concentrated in dendrites and spines. At the electron microscopic level, immunolabeling for RGS7, Gbeta5 and R7BP proteins was found both at postsynaptic and presynaptic sites and showed similar distribution patterns. Immunoreactivity for the three proteins was mostly localized along the extrasynaptic plasma membrane of dendritic shafts and spines of PCs and to a lesser extent, in axon terminals (AT) establishing excitatory synapses. Quantitative analysis of immunogold particles for RGS7, Gbeta5 and R7BP revealed that they are non uniformly distributed along the surface of PCs, and show enrichment around excitatory synapses on dendritic spines. We further report that deletion of R7BP in mice reduced the targeting of both RGS7 and Gbeta5 to the plasma membrane. Altogether, these data support the existence of macromolecular complexes composed of RGS7-Gbeta5-R7BP in PCs. The location at post- and pre-synaptic sites in PCs spines-parallel fiber synapses suggests their involvement in the modulation of glutamatergic neurotransmission in the cerebellar cortex. PMID- 27965546 TI - Spatial and Temporal Distribution of Dopaminergic Neurons during Development in Zebrafish. AB - As one of the model organisms of Parkinson's disease (PD) research, the zebrafish has its advantages, such as the 87% homology with human genome and transparent embryos which make it possible to observe the development of dopaminergic neurons in real time. However, there is no midbrain dopaminergic system in zebrafish when compared with mammals, and the location and projection of the dopaminergic neurons are seldom reported. In this study, Vmat2:GFP transgenic zebrafish was used to observe the development and distribution of dopaminergic neurons in real time. We found that diencephalons (DC) 2 and DC4 neuronal populations were detected at 24 h post fertilization (hpf). All DC neuronal populations as well as those in locus coeruleus (LC), raphe nuclei (Ra) and telencephalon were detected at 48 hpf. Axons were detected at 72 hpf. At 96 hpf, all the neuronal populations were detected. For the first time we reported axons from the posterior tubercle (PT) of ventral DC projected to subpallium in vivo. However, when compared with results from whole mount tyrosine hydroxylase (TH) immunofluorescence staining in wild type (WT) zebrafish, we found that DC2 and DC4 neuronal populations were mainly dopaminergic, while DC1, DC3, DC5 and DC6 might not. Neurons in pretectum (Pr) and telencephalon were mainly dopaminergic, while neurons in LC and Ra might be noradrenergic. Our study makes some corrections and modifications on the development, localization and distribution of zebrafish dopaminergic neurons, and provides some experimental evidences for the construction of the zebrafish PD model. PMID- 27965544 TI - An Exploratory Study of Spectroscopic Glutamatergic Correlates of Cortical Excitability in Depressed Adolescents. AB - Introduction: Transcranial magnetic stimulation (TMS) research has suggested dysfunction in cortical glutamatergic systems in adolescent depression, while proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated deficits in concentrations of glutamatergic metabolites in depressed individuals in several cortical regions, including the anterior cingulate cortex (ACC). However, few studies have combined TMS and MRS methods to examine relationships between glutamatergic neurochemistry and excitatory and inhibitory neural functions, and none have utilized TMS-MRS methodology in clinical populations or in youth. This exploratory study aimed to examine relationships between TMS measures of cortical excitability and inhibition and concentrations of glutamatergic metabolites as measured by 1H-MRS in depressed adolescents. Methods: Twenty-four adolescents (aged 11-18 years) with depressive symptoms underwent TMS testing, which included measures of the resting motor threshold (RMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Fourteen participants from the same sample also completed 1H-MRS in a 3 T MRI scanner after TMS testing. Glutamate + glutamine (Glx) concentrations were measured in medial ACC and left primary motor cortex voxels with a TE-optimized PRESS sequence. Metabolite concentrations were corrected for cerebrospinal fluid (CSF) after tissue segmentation. Pearson product-moment and Spearman rank-order correlations were calculated to assess relationships between TMS measures and [Glx]. Results: In the left primary motor cortex voxel, [Glx] had a significant positive correlation with the RMT. In the medial ACC voxel, [Glx] had significant positive correlations with ICF at the 10 ms and 20-ms interstimulus intervals (ISIs). Conclusion: These preliminary data implicate glutamate in cortical excitatory processes measured by TMS. Limitations included small sample size, lack of healthy control comparators, possible age- and sex-related effects, and observational nature of the study. Further research aimed at examining the relationship between glutamatergic metabolite concentrations measured through MRS and the excitatory and inhibitory physiology measured through TMS is warranted. Combined TMS-MRS methods show promise for future investigations of the pathophysiology of depression in adults as well as in children and adolescents. PMID- 27965547 TI - Regular Cycles of Forward and Backward Signal Propagation in Prefrontal Cortex and in Consciousness. AB - This paper addresses two fundamental questions: (1) Is it possible to develop mathematical neural network models which can explain and replicate the way in which higher-order capabilities like intelligence, consciousness, optimization, and prediction emerge from the process of learning (Werbos, 1994, 2016a; National Science Foundation, 2008)? and (2) How can we use and test such models in a practical way, to track, to analyze and to model high-frequency (>= 500 hz) many channel data from recording the brain, just as econometrics sometimes uses models grounded in the theory of efficient markets to track real-world time-series data (Werbos, 1990)? This paper first reviews some of the prior work addressing question (1), and then reports new work performed in MATLAB analyzing spike sorted and burst-sorted data on the prefrontal cortex from the Buzsaki lab (Fujisawa et al., 2008, 2015) which is consistent with a regular clock cycle of about 153.4 ms and with regular alternation between a forward pass of network calculations and a backwards pass, as in the general form of the backpropagation algorithm which one of us first developed in the period 1968-1974 (Werbos, 1994, 2006; Anderson and Rosenfeld, 1998). In business and finance, it is well known that adjustments for cycles of the year are essential to accurate prediction of time-series data (Box and Jenkins, 1970); in a similar way, methods for identifying and using regular clock cycles offer large new opportunities in neural time-series analysis. This paper demonstrates a few initial footprints on the large "continent" of this type of neural time-series analysis, and discusses a few of the many further possibilities opened up by this new approach to "decoding" the neural code (Heller et al., 1995). PMID- 27965549 TI - Analyzing the User Behavior toward Electronic Commerce Stimuli. AB - Based on the Stimulus-Organism-Response paradigm this research analyzes the main differences between the effects of two types of web technologies: Verbal web technology (i.e., navigational structure as utilitarian stimulus) versus non verbal web technology (music and presentation of products as hedonic stimuli). Specific webmosphere stimuli have not been examined yet as separate variables and their impact on internal and behavioral responses seems unknown. Therefore, the objective of this research consists in analyzing the impact of these web technologies -which constitute the web atmosphere or webmosphere of a website- on shopping human behavior (i.e., users' internal states -affective, cognitive, and satisfaction- and behavioral responses - approach responses, and real shopping outcomes-) within the retail online store created by computer, taking into account some mediator variables (i.e., involvement, atmospheric responsiveness, and perceived risk). A 2 ("free" versus "hierarchical" navigational structure) * 2 ("on" versus "off" music) * 2 ("moving" versus "static" images) between subjects computer experimental design is used to test empirically this research. In addition, an integrated methodology was developed allowing the simulation, tracking and recording of virtual user behavior within an online shopping environment. As main conclusion, this study suggests that the positive responses of online consumers might increase when they are allowed to freely navigate the online stores and their experience is enriched by animate gifts and music background. The effect caused by mediator variables modifies relatively the final shopping human behavior. PMID- 27965548 TI - Methodological Problems on the Way to Integrative Human Neuroscience. AB - Neuroscience is a multidisciplinary effort to understand the structures and functions of the brain and brain-mind relations. This effort results in an increasing amount of data, generated by sophisticated technologies. However, these data enhance our descriptive knowledge, rather than improve our understanding of brain functions. This is caused by methodological gaps both within and between subdisciplines constituting neuroscience, and the atomistic approach that limits the study of macro- and mesoscopic issues. Whole-brain measurement technologies do not resolve these issues, but rather aggravate them by the complexity problem. The present article is devoted to methodological and epistemic problems that obstruct the development of human neuroscience. We neither discuss ontological questions (e.g., the nature of the mind) nor review data, except when it is necessary to demonstrate a methodological issue. As regards intradisciplinary methodological problems, we concentrate on those within neurobiology (e.g., the gap between electrical and chemical approaches to neurophysiological processes) and psychology (missing theoretical concepts). As regards interdisciplinary problems, we suggest that core disciplines of neuroscience can be integrated using systemic concepts that also entail human environment relations. We emphasize the necessity of a meta-discussion that should entail a closer cooperation with philosophy as a discipline of systematic reflection. The atomistic reduction should be complemented by the explicit consideration of the embodiedness of the brain and the embeddedness of humans. The discussion is aimed at the development of an explicit methodology of integrative human neuroscience, which will not only link different fields and levels, but also help in understanding clinical phenomena. PMID- 27965550 TI - Social Support Modulates Stress-Related Gene Expression in Various Brain Regions of Piglets. AB - The presence of an affiliative conspecific may alleviate an individual's stress response in threatening conditions. However, the mechanisms and neural circuitry underlying the process of social buffering have not yet been elucidated. Using the domestic pig as an animal model, we examined the effect of a 4-h maternal and littermate deprivation on stress hormones and on mRNA expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11beta hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2 and the immediate early gene c-fos in various brain regions of 7-, 21- and 35-day old piglets. The deprivation occurred either alone or with a familiar or unfamiliar age-matched piglet. Compared to piglets deprived alone, the presence of a conspecific animal significantly reduced free plasma cortisol concentrations and altered the MR/GR balance and 11beta-HSD2 and c-fos mRNA expression in the prefrontal cortex (PFC), amygdala and hypothalamus, but not in the hippocampus. The alterations in brain mRNA expression were particularly found in 21- or 35-day old piglets, which may reflect the species-specific postnatal ontogeny of the investigated brain regions. The buffering effects of social support were most pronounced in the amygdala, indicating its significance both for the assessment of social conspecifics as biologically relevant stimuli and for the processing of emotional states. In conclusion, the present findings provide further evidence for the importance of the cortico-limbic network underlying the abilities of individuals to cope with social stress and strongly emphasize the benefits of social partners in livestock with respect to positive welfare and health. PMID- 27965551 TI - Implications of Social Support as a Self-Control Resource. AB - Self-control is an intricate component of decision making and effectively managing day-to-day life. Failing to maintain adequate self-control can have negative effects on many desired goals and social experiences. As such, understanding how different facets of the human experience may affect self control is an important undertaking. One area that is yet unclear is the possible relationships between social support and self-control. Research suggests that social support can be an effective resource in reducing stress and promoting health and well-being. Research has also indicated that stress can be a limiting factor on self-control. In contrast, few studies have focused on social support as a potential resource for self-control. The goal of this mini-review article is to explore the intersections between self-control and social support and encourage integration of these two relatively independent areas of research. This review will help provide a broader understanding of self-control resources and how we can better understand the relationships between social well-being and our ability to monitor and utilize our capacity to maintain self-control. PMID- 27965552 TI - Dietary Intake of Nutrients and Lifestyle Affect the Risk of Mild Cognitive Impairment in the Chinese Elderly Population: A Cross-Sectional Study. AB - Mild cognitive impairment (MCI) is a pre-clinical stage of Alzheimer's disease afflicting a large number of the elderly throughout the world. However, modifiable risk factors for the onset and progression of MCI remain unclear. A cross-sectional study was performed to explore whether and how daily dietary nutrients intake and lifestyle impacted the risk of MCI in the Chinese elderly. We examined 2,892 elderly subjects, including 768 MCI patients and 2,124 subjects with normal cognition in three different Provinces of China. Dietary intake of nutrients were collected by using a 33-item food frequency questionnaire and calculated based on the Chinese Food Composition database. The MCI patients were first screened by Montreal Cognitive Assessment and then diagnosed by medical neurologists. Multivariate logistic regression and exploratory factor analyses were applied to identify and rank the risk factors. Three dietary nutrient intake combination patterns were identified as the major protective factors of MCI, with eigenvalues of 14.11, 2.26, and 1.51 and adjusted odds ratios (OR) of 0.77, 0.81, and 0.83 (P < 0.05), respectively. The most protective combination was featured with eight vitamins and six minerals, and OR for the third and fourth quartiles of these nutrients intake ranged from 0.48 to 0.74 (P < 0.05). Carotenoids, vitamin C, and vitamin B6 exhibited the highest protective factor loadings of 0.97, 0.95, and 0.92 (P < 0.05), respectively. Education, computer use, reading, and drinking represented the most protective lifestyle factors (OR = 0.25 to 0.85, P < 0.05), whereas smoking and peripheral vascular diseases were associated with higher (OR = 1.40 and 1.76, P < 0.05) risk of MCI. Adequate dietary intake of monounsaturated fatty acids and cholesterol were significantly associated with decreased risk of MCI. In conclusion, adequate or enhanced intake of micronutrients seemed to lower the risk of MCI in the Chinese elderly. In addition, improving education and lifestyle such as reading, computer use and moderate drinking might also help to decrease the risk of MCI. PMID- 27965553 TI - The Effects of Transcranial Direct Current Stimulation (tDCS) on Multitasking Throughput Capacity. AB - Background: Multitasking has become an integral attribute associated with military operations within the past several decades. As the amount of information that needs to be processed during these high level multitasking environments exceeds the human operators' capabilities, the information throughput capacity reaches an asymptotic limit. At this point, the human operator can no longer effectively process and respond to the incoming information resulting in a plateau or decline in performance. The objective of the study was to evaluate the efficacy of a non-invasive brain stimulation technique known as transcranial direct current stimulation (tDCS) applied to a scalp location over the left dorsolateral prefrontal cortex (lDLPFC) to improve information processing capabilities during a multitasking environment. Methods: The study consisted of 20 participants from Wright-Patterson Air Force Base (16 male and 4 female) with an average age of 31.1 (SD = 4.5). Participants were randomly assigned into two groups, each consisting of eight males and two females. Group one received 2 mA of anodal tDCS and group two received sham tDCS over the lDLPFC on their testing day. Results: The findings indicate that anodal tDCS significantly improves the participants' information processing capability resulting in improved performance compared to sham tDCS. For example, the multitasking throughput capacity for the sham tDCS group plateaued near 1.0 bits/s at the higher baud input (2.0 bits/s) whereas the anodal tDCS group plateaued near 1.3 bits/s. Conclusion: The findings provided new evidence that tDCS has the ability to augment and enhance multitasking capability in a human operator. Future research should be conducted to determine the longevity of the enhancement of transcranial direct current stimulation on multitasking performance, which has yet to be accomplished. PMID- 27965554 TI - Benefits and Limitations of Computer Gesture Therapy for the Rehabilitation of Severe Aphasia. AB - Aphasia intervention has made increasing use of technology in recent years. The evidence base, which is largely limited to the investigation of spoken language outcomes, indicates positive treatment effects for people with mild to moderate levels of aphasia. Outcomes for those with severe aphasia, however, are less well documented and - where reported - present less consistent gains for measures of spoken output. This study investigates the effects of a purpose-built gesture therapy technology for people with severe aphasia: GeST+. Study outcomes show significant improvement in gesture production abilities for adults with severe aphasia following computer intervention. They indicate no transfer of effects into naming gains or interactive gesture. Outcomes offer encouraging results for computer therapy methods within this hitherto under-researched population but indicate a need for further refinement of interventions in order to maximize persistence of effects and generalization into everyday communication. PMID- 27965555 TI - Virtual Embodiment of White People in a Black Virtual Body Leads to a Sustained Reduction in Their Implicit Racial Bias. AB - Virtual reality can be used to visually substitute a person's body by a life sized virtual one. Such embodiment results in a perceptual illusion of body ownership over the virtual body (VB). Previous research has shown that the form of the VB can influence implicit attitudes. In particular, embodying White people in a Black virtual body is associated with an immediate decrease in their implicit racial bias against Black people. We tested whether the reduction in implicit bias lasts for at least 1 week and whether it is enhanced by multiple exposures. Two experiments were carried out with a total of 90 female participants where the virtual body was either Black or White. Participants were required to follow a virtual Tai Chi teacher who was either Asian or European Caucasian. Each participant had 1, 2, or 3 exposures separated by days. Implicit racial bias was measured 1 week before their first exposure and 1 week after their last. The results show that implicit bias decreased more for those with the Black virtual body than the White. There was also some evidence of a general decrease in bias independently of body type for which possible explanations are put forward. PMID- 27965556 TI - Toward a Molecular Profile of Self-Representation. AB - Feeling embodiment over our body or body part has a major role in the understanding of the self and control of self-actions. Even though it is crucial in our daily life, embodiment is not an homogenous phenotype across population, as quantified by implicit and explicit measures (i.e., neuroimaging or self reports). Studies have shown differences in neuropathological conditions compared to healthy controls, but also across healthy individuals. We discuss examples of self-perception differences, and the molecular origin of embodiment, focusing on clinical cases, during the first and second section. We then discuss two important questions in this molecular-to-embodiment relationship: (i) which are the molecular levels (and their associated techniques) that can be relevant to embodiment, and (ii) which are the most adequate experiments to correlate molecular profiles and embodiment quantification across individuals. Potential answers for both questions will be outlined during the third and fourth sections, respectively, in order to design a framework to study the molecular profile of body embodiment. PMID- 27965558 TI - Visualization of Whole-Night Sleep EEG From 2-Channel Mobile Recording Device Reveals Distinct Deep Sleep Stages with Differential Electrodermal Activity. AB - Brain activity during sleep is a powerful marker of overall health, but sleep lab testing is prohibitively expensive and only indicated for major sleep disorders. This report demonstrates that mobile 2-channel in-home electroencephalogram (EEG) recording devices provided sufficient information to detect and visualize sleep EEG. Displaying whole-night sleep EEG in a spectral display allowed for quick assessment of general sleep stability, cycle lengths, stage lengths, dominant frequencies and other indices of sleep quality. By visualizing spectral data down to 0.1 Hz, a differentiation emerged between slow-wave sleep with dominant frequency between 0.1-1 Hz or 1-3 Hz, but rarely both. Thus, we present here the new designations, Hi and Lo Deep sleep, according to the frequency range with dominant power. Simultaneously recorded electrodermal activity (EDA) was primarily associated with Lo Deep and very rarely with Hi Deep or any other stage. Therefore, Hi and Lo Deep sleep appear to be physiologically distinct states that may serve unique functions during sleep. We developed an algorithm to classify five stages (Awake, Light, Hi Deep, Lo Deep and rapid eye movement (REM)) using a Hidden Markov Model (HMM), model fitting with the expectation maximization (EM) algorithm, and estimation of the most likely sleep state sequence by the Viterbi algorithm. The resulting automatically generated sleep hypnogram can help clinicians interpret the spectral display and help researchers computationally quantify sleep stages across participants. In conclusion, this study demonstrates the feasibility of in-home sleep EEG collection, a rapid and informative sleep report format, and novel deep sleep designations accounting for spectral and physiological differences. PMID- 27965557 TI - The Multivariate Temporal Response Function (mTRF) Toolbox: A MATLAB Toolbox for Relating Neural Signals to Continuous Stimuli. AB - Understanding how brains process sensory signals in natural environments is one of the key goals of twenty-first century neuroscience. While brain imaging and invasive electrophysiology will play key roles in this endeavor, there is also an important role to be played by noninvasive, macroscopic techniques with high temporal resolution such as electro- and magnetoencephalography. But challenges exist in determining how best to analyze such complex, time-varying neural responses to complex, time-varying and multivariate natural sensory stimuli. There has been a long history of applying system identification techniques to relate the firing activity of neurons to complex sensory stimuli and such techniques are now seeing increased application to EEG and MEG data. One particular example involves fitting a filter-often referred to as a temporal response function-that describes a mapping between some feature(s) of a sensory stimulus and the neural response. Here, we first briefly review the history of these system identification approaches and describe a specific technique for deriving temporal response functions known as regularized linear regression. We then introduce a new open-source toolbox for performing this analysis. We describe how it can be used to derive (multivariate) temporal response functions describing a mapping between stimulus and response in both directions. We also explain the importance of regularizing the analysis and how this regularization can be optimized for a particular dataset. We then outline specifically how the toolbox implements these analyses and provide several examples of the types of results that the toolbox can produce. Finally, we consider some of the limitations of the toolbox and opportunities for future development and application. PMID- 27965559 TI - Effect of Position- and Velocity-Dependent Forces on Reaching Movements at Different Speeds. AB - The speed of voluntary movements is determined by the conflicting needs of maximizing accuracy and minimizing mechanical effort. Dynamic perturbations, e.g., force fields, may be used to manipulate movements in order to investigate these mechanisms. Here, we focus on how the presence of position- and velocity dependent force fields affects the relation between speed and accuracy during hand reaching movements. Participants were instructed to perform reaching movements under visual control in two directions, corresponding to either low or high arm inertia. The subjects were required to maintain four different movement durations (very slow, slow, fast, very fast). The experimental protocol included three phases: (i) familiarization-the robot generated no force; (ii) force field the robot generated a force; and (iii) after-effect-again, no force. Participants were randomly assigned to four groups, depending on the type of force that was applied during the "force field" phase. The robot was programmed to generate position-dependent forces-with positive (K+) or negative stiffness (K-)-or velocity-dependent forces, with either positive (B+) or negative viscosity (B-). We focused on path curvature, smoothness, and endpoint error; in the latter we distinguished between bias and variability components. Movements in the high inertia direction are smoother and less curved; smoothness also increases with movement speed. Endpoint bias and variability are greater in, respectively, the high and low inertia directions. A robust dependence on movement speed was only observed in the longitudinal components of both bias and variability. The strongest and more consistent effects of perturbation were observed with negative viscosity (B-), which resulted in increased variability during force field adaptation and in a reduction of the endpoint bias, which was retained in the subsequent after-effect phase. These findings confirm that training with negative viscosity produces lasting effects in movement accuracy at all speeds. PMID- 27965561 TI - Elderly Fallers Enhance Dynamic Stability Through Anticipatory Postural Adjustments during a Choice Stepping Reaction Time. AB - In the case of disequilibrium, the capacity to step quickly is critical to avoid falling in elderly. This capacity can be simply assessed through the choice stepping reaction time test (CSRT), where elderly fallers (F) take longer to step than elderly non-fallers (NF). However, the reasons why elderly F elongate their stepping time remain unclear. The purpose of this study is to assess the characteristics of anticipated postural adjustments (APA) that elderly F develop in a stepping context and their consequences on the dynamic stability. Forty-four community-dwelling elderly subjects (20 F and 24 NF) performed a CSRT where kinematics and ground reaction forces were collected. Variables were analyzed using two-way repeated measures ANOVAs. Results for F compared to NF showed that stepping time is elongated, due to a longer APA phase. During APA, they seem to use two distinct balance strategies, depending on the axis: in the anteroposterior direction, we measured a smaller backward movement and slower peak velocity of the center of pressure (CoP); in the mediolateral direction, the CoP movement was similar in amplitude and peak velocity between groups but lasted longer. The biomechanical consequence of both strategies was an increased margin of stability (MoS) at foot-off, in the respective direction. By elongating their APA, elderly F use a safer balance strategy that prioritizes dynamic stability conditions instead of the objective of the task. Such a choice in balance strategy probably comes from muscular limitations and/or a higher fear of falling and paradoxically indicates an increased risk of fall. PMID- 27965562 TI - Sluggishness of Early-Stage Face Processing (N170) Is Correlated with Negative and General Psychiatric Symptoms in Schizophrenia. AB - Patients with schizophrenia consistently exhibit abnormalities in the N170 event related potential (ERP) component evoked by images of faces. However, the relationship between these face-specific N170 abnormalities in patients with schizophrenia and the clinical characteristics of this disorder has not been elucidated. Here, ERP recordings were conducted for patients with schizophrenia and healthy controls. The amplitude and latency of the N170 component were recorded while participants passively viewed face and non-face (table) images to explore the correlation between face-specific processing and clinical characteristics in schizophrenia. The results provided evidence for a face specific N170 latency delay in patients with schizophrenia. The N170 latency in patients with schizophrenia was significantly longer than that in healthy controls when images of faces were presented in both upright and inverted orientations. Importantly, the face-related N170 latencies of the left temporo occipital electrodes (P7 and PO7) were positively correlated with both negative and general psychiatric symptoms in these patients. The N170 amplitudes were weaker in patients than in controls for inverted images of both faces and non faces (tables), with a left-hemisphere dominance. The face inversion effect (FIE), meaning the difference in N170 amplitude between upright and inverted faces, was absent in patients with schizophrenia, suggesting an abnormality of holistic face processing. Together, these results revealed a marked symptom relevant neural delay associated with face-specific processing in patients with schizophrenia, providing additional evidence to support the demyelination hypothesis of schizophrenia. PMID- 27965564 TI - Distorted Low-Level Visual Features Affect Saliency-Based Visual Attention. PMID- 27965563 TI - Functional Connectivity Reveals Which Language the "Control Regions" Control during Bilingual Production. AB - Bilingual studies have revealed critical roles for the dorsal anterior cingulate cortex (dACC) and the left caudate nucleus (Lcaudate) in controlling language processing, but how these regions manage activation of a bilingual's two languages remains an open question. We addressed this question by identifying the functional connectivity (FC) of these control regions during a picture-naming task by bimodal bilinguals who were fluent in both a spoken and a signed language. To quantify language control processes, we measured the FC of the dACC and Lcaudate with a region specific to each language modality: left superior temporal gyrus (LSTG) for speech and left pre/postcentral gyrus (LPCG) for sign. Picture-naming occurred in either a single- or dual-language context. The results showed that in a single-language context, the dACC exhibited increased FC with the target language region, but not with the non-target language region. During the dual-language context when both languages were alternately the target language, the dACC showed strong FC to the LPCG, the region specific to the less proficient (signed) language. By contrast, the Lcaudate revealed a strong connectivity to the LPCG in the single-language context and to the LSTG (the region specific to spoken language) in the dual-language context. Our findings suggest that the dACC monitors and supports the processing of the target language, and that the Lcaudate controls the selection of the less accessible language. The results support the hypothesis that language control processes adapt to task demands that vary due to different interactional contexts. PMID- 27965560 TI - Ketamine: 50 Years of Modulating the Mind. AB - Ketamine was introduced into clinical practice in the 1960s and continues to be both clinically useful and scientifically fascinating. With considerably diverse molecular targets and neurophysiological properties, ketamine's effects on the central nervous system remain incompletely understood. Investigators have leveraged the unique characteristics of ketamine to explore the invariant, fundamental mechanisms of anesthetic action. Emerging evidence indicates that ketamine-mediated anesthesia may occur via disruption of corticocortical information transfer in a frontal-to-parietal ("top down") distribution. This proposed mechanism of general anesthesia has since been demonstrated with anesthetics in other pharmacological classes as well. Ketamine remains invaluable to the fields of anesthesiology and critical care medicine, in large part due to its ability to maintain cardiorespiratory stability while providing effective sedation and analgesia. Furthermore, there may be an emerging role for ketamine in treatment of refractory depression and Post-Traumatic Stress Disorder. In this article, we review the history of ketamine, its pharmacology, putative mechanisms of action and current clinical applications. PMID- 27965566 TI - On Shapley Ratings in Brain Networks. AB - We consider the problem of computing the influence of a neuronal structure in a brain network. Abraham et al. (2006) computed this influence by using the Shapley value of a coalitional game corresponding to a directed network as a rating. Kotter et al. (2007) applied this rating to large-scale brain networks, in particular to the macaque visual cortex and the macaque prefrontal cortex. Our aim is to improve upon the above technique by measuring the importance of subgroups of neuronal structures in a different way. This new modeling technique not only leads to a more intuitive coalitional game, but also allows for specifying the relative influence of neuronal structures and a direct extension to a setting with missing information on the existence of certain connections. PMID- 27965565 TI - Memory-Efficient Analysis of Dense Functional Connectomes. AB - The functioning of the human brain relies on the interplay and integration of numerous individual units within a complex network. To identify network configurations characteristic of specific cognitive tasks or mental illnesses, functional connectomes can be constructed based on the assessment of synchronous fMRI activity at separate brain sites, and then analyzed using graph-theoretical concepts. In most previous studies, relatively coarse parcellations of the brain were used to define regions as graphical nodes. Such parcellated connectomes are highly dependent on parcellation quality because regional and functional boundaries need to be relatively consistent for the results to be interpretable. In contrast, dense connectomes are not subject to this limitation, since the parcellation inherent to the data is used to define graphical nodes, also allowing for a more detailed spatial mapping of connectivity patterns. However, dense connectomes are associated with considerable computational demands in terms of both time and memory requirements. The memory required to explicitly store dense connectomes in main memory can render their analysis infeasible, especially when considering high-resolution data or analyses across multiple subjects or conditions. Here, we present an object-based matrix representation that achieves a very low memory footprint by computing matrix elements on demand instead of explicitly storing them. In doing so, memory required for a dense connectome is reduced to the amount needed to store the underlying time series data. Based on theoretical considerations and benchmarks, different matrix object implementations and additional programs (based on available Matlab functions and Matlab-based third-party software) are compared with regard to their computational efficiency. The matrix implementation based on on-demand computations has very low memory requirements, thus enabling analyses that would be otherwise infeasible to conduct due to insufficient memory. An open source software package containing the created programs is available for download. PMID- 27965567 TI - Biomechanical Reconstruction Using the Tacit Learning System: Intuitive Control of Prosthetic Hand Rotation. AB - Background: For mechanically reconstructing human biomechanical function, intuitive proportional control, and robustness to unexpected situations are required. Particularly, creating a functional hand prosthesis is a typical challenge in the reconstruction of lost biomechanical function. Nevertheless, currently available control algorithms are in the development phase. The most advanced algorithms for controlling multifunctional prosthesis are machine learning and pattern recognition of myoelectric signals. Despite the increase in computational speed, these methods cannot avoid the requirement of user consciousness and classified separation errors. "Tacit Learning System" is a simple but novel adaptive control strategy that can self-adapt its posture to environment changes. We introduced the strategy in the prosthesis rotation control to achieve compensatory reduction, as well as evaluated the system and its effects on the user. Methods: We conducted a non-randomized study involving eight prosthesis users to perform a bar relocation task with/without Tacit Learning System support. Hand piece and body motions were recorded continuously with goniometers, videos, and a motion-capture system. Findings: Reduction in the participants' upper extremity rotatory compensation motion was monitored during the relocation task in all participants. The estimated profile of total body energy consumption improved in five out of six participants. Interpretation: Our system rapidly accomplished nearly natural motion without unexpected errors. The Tacit Learning System not only adapts human motions but also enhances the human ability to adapt to the system quickly, while the system amplifies compensation generated by the residual limb. The concept can be extended to various situations for reconstructing lost functions that can be compensated. PMID- 27965568 TI - Regularized Linear Discriminant Analysis of EEG Features in Dementia Patients. AB - The present study explores if EEG spectral parameters can discriminate between healthy elderly controls (HC), Alzheimer's disease (AD) and vascular dementia (VaD) using. We considered EEG data recorded during normal clinical routine with 114 healthy controls (HC), 114 AD, and 114 VaD patients. The spectral features extracted from the EEG were the absolute delta power, decay from lower to higher frequencies, amplitude, center and dispersion of the alpha power and baseline power of the entire frequency spectrum. For discrimination, we submitted these EEG features to regularized linear discriminant analysis algorithm with a 10-fold cross-validation. To check the consistency of the results obtained by our classifiers, we applied bootstrap statistics. Four binary classifiers were used to discriminate HC from AD, HC from VaD, AD from VaD, and HC from dementia patients (AD or VaD). For each model, we measured the discrimination performance using the area under curve (AUC) and the accuracy of the cross-validation (cv ACC). We applied this procedure using two different sets of predictors. The first set considered all the features extracted from the 22 channels. For the second set of features, we automatically rejected features poorly correlated with their labels. Fairly good results were obtained when discriminating HC from dementia patients with AD or VaD (AUC = 0.84). We also obtained AUC = 0.74 for discrimination of AD from HC, AUC = 0.77 for discrimination of VaD from HC, and finally AUC = 0.61 for discrimination of AD from VaD. Our models were able to separate HC from dementia patients, and also and to discriminate AD from VaD above chance. Our results suggest that these features may be relevant for the clinical assessment of patients with dementia. PMID- 27965569 TI - Cognitive Intervention As an Early Non-pharmacological Strategy in Alzheimer's Disease: A Translational Perspective. PMID- 27965571 TI - Increase of EEG Spectral Theta Power Indicates Higher Risk of the Development of Severe Cognitive Decline in Parkinson's Disease after 3 Years. AB - Objective: We investigated quantitative electroencephalography (qEEG) and clinical parameters as potential risk factors of severe cognitive decline in Parkinson's disease. Methods: We prospectively investigated 37 patients with Parkinson's disease at baseline and follow-up (after 3 years). Patients had no severe cognitive impairment at baseline. We used a summary score of cognitive tests as the outcome at follow-up. At baseline we assessed motor, cognitive, and psychiatric factors; qEEG variables [global relative median power (GRMP) spectra] were obtained by a fully automated processing of high-resolution EEG (256 channels). We used linear regression models with calculation of the explained variance to evaluate the relation of baseline parameters with cognitive deterioration. Results: The following baseline parameters significantly predicted severe cognitive decline: GRMP theta (4-8 Hz), cognitive task performance in executive functions and working memory. Conclusions: Combination of neurocognitive tests and qEEG improves identification of patients with higher risk of cognitive decline in PD. PMID- 27965570 TI - Combining Exergame Training with Omega-3 Fatty Acid Supplementation: Protocol for a Randomized Controlled Study Assessing the Effect on Neuronal Structure/Function in the Elderly Brain. AB - A common problem in the older population is the risk of falling and related injury, immobility, and reduced survival. Age-related neuronal changes, e.g., decline in gray-and white-matter, affect neuronal, cognitive, and motor functioning. The improvement of these factors might decrease fall events in elderly. Studies showed that administration of video game-based physical exercise, a so-called exergame, or omega-3 fatty acid (FA) may improve motor and/or cognitive functioning through neuronal changes in the brain of older adults. The aim of this study is to assess the effects of a combination of exergame training with omega-3 FA supplementation on the elderly brain. We hypothesize that an intervention using a combination approach differently affects on the neuronal structure and function of the elderly's brain as compared to the sole administration of exergame training. The study is a parallel, double blinded, randomized controlled trial lasting 26 weeks. Sixty autonomous living, non-smoking, and right-handed healthy older (>65 years) adults who live independently or in a senior residency are included, randomized, and allocated to one of two study groups. The experimental group receives a daily amount of 13.5 ml fish oil (including 2.9 g of omega-3 FA), whereas the control group receives a daily amount of 13.5 ml olive oil for 26 weeks. After 16 weeks, both groups start with an exergame training program three times per week. Measurements are performed on three time-points by treatment blinded investigators: pre intervention measurements, blood sample after 16 week, and post-intervention measurements. The main outcomes are motor evoked potentials of the right M. tibialis anterior (transcranial magnetic stimulation) and response-related potentials (electroencephalography) during a cognitive test. For secondary outcomes, reaction time during cognitive tests and spatio-temporal parameters during gait performance are measured. Statistics will include effect sizes and a 2 * 2-ANOVA with normally distributed data or the non-parametric equivalent for data not fulfilling normal distribution. The randomized controlled study is the first to investigate the effectiveness of exergame training combined with omega-3 FA in counteracting age- and behavioral-dependent neuronal changes in the brain. This study has been registered in the Swiss National Clinical Trials (SNCTP000001623) and the ISRCTN (ISRCTN12084831) Portals. PMID- 27965572 TI - Voice Pitch Elicited Frequency Following Response in Chinese Elderlies. AB - Background: Perceptual and electrophysiological studies have found reduced speech discrimination in quiet and noisy environment, delayed neural timing, decreased neural synchrony, and decreased temporal processing ability in elderlies, even those with normal hearing. However, recent studies have also demonstrated that language experience and auditory training enhance the temporal dynamics of sound encoding in the auditory brainstem response (ABR). The purpose of this study was to explore the pitch processing ability at the brainstem level in an aging population that has a tonal language background. Method: Mandarin speaking younger (n = 12) and older (n = 12) adults were recruited for this study. All participants had normal audiometric test results and normal suprathreshold click evoked ABR. To record frequency following responses (FFRs) elicited by Mandarin lexical tones, two Mandarin Chinese syllables with different fundamental frequency pitch contours (Flat Tone and Falling Tone) were presented at 70 dB SPL. Fundamental frequencies (f0) of both the stimulus and the responses were extracted and compared to individual brainstem responses. Two indices were used to examine different aspects of pitch processing ability at the brainstem level: Pitch Strength and Pitch Correlation. Results: Lexical tone elicited FFR were overall weaker in the older adult group compared to their younger adult counterpart. Measured by Pitch Strength and Pitch Correlation, statistically significant group differences were only found when the tone with a falling f0 (Falling Tone) were used as the stimulus. Conclusion: Results of this study demonstrated that in a tonal language speaking population, pitch processing ability at the brainstem level of older adults are not as strong and robust as their younger counterparts. Findings of this study are consistent with previous reports on brainstem responses of older adults whose native language is English. On the other hand, lexical tone elicited FFRs have been shown to correlate with the length of language exposure. Older adults' degraded responses in our study may also be due to that, the Mandarin speaking older adults' long term exposure somewhat counteracted the negative impact on aging and helped maintain, or at least reduced, the degradation rate in their temporal processing capacity at the brainstem level. PMID- 27965573 TI - 7,8-Dihydroxyflavone Ameliorates Cognitive Impairment by Inhibiting Expression of Tau Pathology in ApoE-Knockout Mice. AB - 7,8-Dihydroxyflavone (7,8-DHF), a tyrosine kinase B agonist that mimics the neuroprotective properties of brain-derived neurotrophic factor, which can not efficiently deliver into the brain, has been reported to be useful in ameliorating cognitive impairment in many diseases. Researches have indicated that apolipoprotein E-knockout (ApoE-KO) mouse was associated with cognitive alteration via various mechanisms. Our present study investigated the possible mechanisms of cognitive impairment of ApoE-KO mouse fed with western type diet and the protective effects of 7,8-DHF in improving spatial learning and memory in ApoE-KO mouse. Five-weeks-old ApoE-KO mice and C57BL/6 mice were chronically treated with 7,8-DHF (with a dosage of 5 mg/kg) or vehicles orally for 25 weeks, and then subjected to Morris water maze at the age of 30 weeks to evaluate the cognitive performances. Afterward, histology analysis and western blotting were performed. Spatial learning and memory deficits were observed in ApoE-KO mice, which were consistent with higher expression of active-asparaginyl endopeptidase (active-AEP) as well as AEP-derived truncated tau N368 compared with normal group. In addition to that, long-term treatment of 7,8-DHF dramatically ameliorated cognitive decline in ApoE-KO mice, accompanied by the activation in phosphorylated protein kinase B (Akt)/glycogen synthase kinase-3beta (GSK-3beta) pathway and down-regulated expression of tau S396 and PHF-tau (phosphorylated tau at ser396 and ser404 epitope). These findings suggested that cognitive impairment of ApoE-KO mouse might associate with tau pathology and 7,8-DHF could activate AKT and then phosphorylate its downstream molecule to inhibit expression of abnormal tau, meanwhile, 7,8-DHF could reduce the expression of active-AEP and then inhibit production of truncated tau N368. PMID- 27965574 TI - Neurofilaments in CSF As Diagnostic Biomarkers in Motor Neuron Disease: A Meta Analysis. AB - Objective: Neurofilaments in CSF are promising biomarkers which might help in the diagnosis of motor neuron disease (MND). We aim to assess the diagnostic value of neurofilaments in CSF for MND. Methods: Pubmed, Emabase, and Web of Science were searched for relevant studies systematically. Articles in English that evaluated the utility of neurofilaments in CSF in the diagnosis of MND were included. Data were extracted by two independent investigators. Diagnostic indexes for neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) were calculated separately. Stata 12.0 software with a bivariate mixed effects model was used to summarize the diagnostic indexes from eligible studies. Results: Five studies on NFL and eight studies on pNFH met inclusion criteria. For NFL, the pooled sensitivity and specificity were 81% (95% confidence interval [CI], 72-88%) and 85% (95% CI, 76-91%), respectively; the positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 5.5 (95% CI, 3.1-9.8) and 0.22 (95% CI, 0.14-0.35), respectively; the summary diagnostic odds ratio (DOR) was 25 (95% CI, 9-70), and the area under summary receiver operator characteristic curve (AUC) was 0.90 (95% CI, 0.87-0.92). For pNFH, the pooled sensitivity, specificity, PLR and NLR were 85% (95% CI, 80-88%), 85% (95% CI, 77 90%), 5.5 (95% CI, 3.6-8.4), and 0.18 (95% CI, 0.13-0.25), respectively; the DOR was 30 (95% CI, 16-58), and the AUC was 0.91 (95% CI, 0.88-0.93). Conclusion: Neurofilaments in CSF have a high value in the diagnosis of MND, though the optimal cutoff value remains to be further investigated. PMID- 27965577 TI - Expected Impacts of Connected Multimodal Imaging in Precision Oncology. PMID- 27965575 TI - San-Huang-Xie-Xin-Tang Constituents Exert Drug-Drug Interaction of Mutual Reinforcement at Both Pharmacodynamics and Pharmacokinetic Level: A Review. AB - Inflammatory disorders underlie varieties of human diseases. San-Huang-Xie-xin Tang (SHXXT), composed with Rhizoma Rhei (Rheum palmatum L.), Rhizoma Coptidis (Coptis chinensis Franch), and Radix Scutellaria (Scutellaria baicalensis Georgi), is a famous formula which has been widely used in the fight against inflammatory abnormalities. Mutual reinforcement is one of the basic theories of traditional Chinese medicine. Here this article reviewed and analyzed the recent research on (1) How the main constituents of SHXXT impact on inflammation associated signaling pathway molecules. (2) The interaction between the main constituents and efflux pumps or intestinal transporters. The goal of this work was to, (1) Provide evidence to support the theory of mutual reinforcement. (2) Clarify the key targets of SHXXT and suggest which targets need further investigation. (3) Give advice for the clinical use of SHXXT to elevated the absorption of main constituents and eventually promote oral bioavailability. We search literatures in scientific databases with key words of "each main SHXXT constituent," in combination with "each main inflammatory pathway target molecule" or each main intestinal transporter, respectively. We report the effect of five main constituents on target molecules which lies in three main inflammatory signaling pathways, we as well investigate the interaction between constituents and intestinal transporter. We conclude, (1) The synergistic effect of constituents at both levels confirm the mutual reinforcement theory of TCM as it is proven in this work. (2) The effect of main constituents on downstream targets in nuclear need more further investigation. (3) Drug elevating the absorption of rhein, berberine and baicalein can be employed to promote oral bioavailability of SHXXT. PMID- 27965578 TI - Computational Models of Reactive Oxygen Species as Metabolic Byproducts and Signal-Transduction Modulators. AB - Reactive oxygen species (ROS) are widely involved in intracellular signaling and human pathologies, but their precise roles have been difficult to enumerate and integrate holistically. The context- and dose-dependent intracellular effects of ROS can lead to contradictory experimental results and confounded interpretations. For example, lower levels of ROS promote cell signaling and proliferation, whereas abundant ROS cause overwhelming damage to biomolecules and cellular apoptosis or senescence. These complexities raise the question of whether the many facets of ROS biology can be joined under a common mechanistic framework using computational modeling. Here, we take inventory of some current models for ROS production or ROS regulation of signaling pathways. Several models captured non-intuitive observations or made predictions that were later verified by experiment. There remains a need for systems-level analyses that jointly incorporate ROS production, handling, and modulation of multiple signal transduction cascades. PMID- 27965579 TI - In vitro Anti-viral Activity of Psoraleae Semen Water Extract against Influenza A Viruses. AB - Influenza causes respiratory infections and poses health risks to humans and animals; its effects are complicated by increasing resistance to existing anti influenza viral agents. Therefore, novel therapeutic approaches against influenza virus infection are required. Psoraleae semen has been widely used in traditional medicine in Korea, Taiwan, China, and Japan for treating and preventing various diseases. In this study, we examined the anti-viral activities and mechanism of action of the water extract of Psoraleae semen (WPS) using RAW 264.7 and MDCK cells. We found that pre- and post-treatment with 100 MUg/mL WPS markedly inhibited influenza A virus replication as assessed using a green fluorescent protein reporter virus, reduced viral protein expression (NS-1, PA, HA, PB-1, M1, and M2), and inhibited NA and HA activities. Mechanism studies revealed that WPS induced type I interferon cytokine secretion and subsequent stimulation of an anti-viral state in RAW 264.7 cells. Further, WPS exerted inhibitory effects on neuraminidase in influenza virus strains H1N1 and H3N2. Meanwhile, WPS exhibited inhibitory effects on hemagglutination in H3N2 but not in H1N1. Based on these results, WPS serves as an immunomodulator and inhibitor of influenza hemagglutinin and neuraminidase. Our results suggest that WPS is a promising source of novel anti-influenza drug candidates. PMID- 27965576 TI - Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development. AB - We have recently generated a novel medulloblastoma (MB) mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+/ /Tis21KO ). Its main phenotype is a defect of migration of the cerebellar granule precursor cells (GCPs). By genomic analysis of GCPs in vivo, we identified as drug target and major responsible of this defect the down-regulation of the promigratory chemokine Cxcl3. Consequently, the GCPs remain longer in the cerebellum proliferative area, and the MB frequency is enhanced. Here, we further analyzed the genes deregulated in a Tis21-dependent manner (Patched1+/-/Tis21 wild-type vs. Ptch1+/-/Tis21 knockout), among which are a number of down regulated tumor inhibitors and up-regulated tumor facilitators, focusing on pathways potentially involved in the tumorigenesis and on putative new drug targets. The data analysis using bioinformatic tools revealed: (i) a link between the Shh signaling and the Tis21-dependent impairment of the GCPs migration, through a Shh-dependent deregulation of the clathrin-mediated chemotaxis operating in the primary cilium through the Cxcl3-Cxcr2 axis; (ii) a possible lineage shift of Shh-type GCPs toward retinal precursor phenotype, i.e., the neural cell type involved in group 3 MB; (iii) the identification of a subset of putative drug targets for MB, involved, among the others, in the regulation of Hippo signaling and centrosome assembly. Finally, our findings define also the role of Tis21 in the regulation of gene expression, through epigenetic and RNA processing mechanisms, influencing the fate of the GCPs. PMID- 27965580 TI - OSU-2S/Sorafenib Synergistic Antitumor Combination against Hepatocellular Carcinoma: The Role of PKCdelta/p53. AB - Background: Sorafenib (Nexavar(r)) is an FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, the low efficacy and adverse effects at high doses limit the clinical application of sorafenib and strongly recommend its combination with other agents aiming at ameliorating its drawbacks. OSU-2S, a PKCdelta activator, was selected as a potential candidate anticancer agent to be combined with sorafenib to promote the anti-cancer activity through synergistic interaction. Methods: The antitumor effects of sorafenib, OSU-2S and their combination were assessed by MTT assay, caspase activation, Western blotting, migration/invasion assays in four different HCC cell lines. The synergistic interactions were determined by Calcusyn analysis. PKCdelta knockdown was used to elucidate the role of PKCdelta activation as a mechanism for the synergy. The knockdown/over-expression of p53 was used to explain the differential sensitivity of HCC cell lines to sorafenib and/or OSU-2S. Results: OSU-2S synergistically enhanced the anti-proliferative effects of sorafenib in the four used HCC cell lines with combination indices <1. This effect was accompanied by parallel increases in caspase 3/7 activity, PARP cleavage, PKCdelta activation and inhibition of HCC cell migration/invasion. In addition, PKCdelta knockdown abolished the synergy between sorafenib and OSU-2S. Furthermore, p53 restoration in Hep3B cells through the over-expression rendered them more sensitive to both agents while p53 knockdown from HepG2 cells increased their resistance to both agents. Conclusion: OSU-2S augments the anti proliferative effect of sorafenib in HCC cell lines, in part, through the activation of PKCdelta. The p53 status in HCC cells predicts their sensitivity toward both sorafenib and OSU-2S. The proposed combination represents a therapeutically relevant approach that can lead to a new HCC therapeutic protocol. PMID- 27965581 TI - Triptolide Upregulates Myocardial Forkhead Helix Transcription Factor p3 Expression and Attenuates Cardiac Hypertrophy. AB - The forkhead/winged helix transcription factor (Fox) p3 can regulate the expression of various genes, and it has been reported that the transfer of Foxp3 positive T cells could ameliorate cardiac hypertrophy and fibrosis. Triptolide (TP) can elevate the expression of Foxp3, but its effects on cardiac hypertrophy remain unclear. In the present study, neonatal rat ventricular myocytes (NRVM) were isolated and stimulated with angiotensin II (1 MUmol/L) to induce hypertrophic response. The expression of Foxp3 in NRVM was observed by using immunofluorescence assay. Fifty mice were randomly divided into five groups and received vehicle (control), isoproterenol (Iso, 5 mg/kg, s.c.), one of three doses of TP (10, 30, or 90 MUg/kg, i.p.) for 14 days, respectively. The pathological morphology changes were observed after Hematoxylin and eosin, lectin and Masson's trichrome staining. The levels of serum brain natriuretic peptide (BNP) and troponin I were determined by enzyme-linked immunosorbent assay and chemiluminescence, respectively. The mRNA and protein expressions of alpha- myosin heavy chain (MHC), beta-MHC and Foxp3 were determined using real-time PCR and immunohistochemistry, respectively. It was shown that TP (1, 3, 10 MUg/L) treatment significantly decreased cell size, mRNA and protein expression of beta MHC, and upregulated Foxp3 expression in NRVM. TP also decreased heart weight index, left ventricular weight index and, improved myocardial injury and fibrosis; and decreased the cross-scetional area of the myocardium, serum cardiac troponin and BNP. Additionally, TP markedly reduced the mRNA and protein expression of myocardial beta-MHC and elevated the mRNA and protein expression of alpha-MHC and Foxp3 in a dose-dependent manner. In conclusion, TP can effectively ameliorate myocardial damage and inhibit cardiac hypertrophy, which is at least partly related to the elevation of Foxp3 expression in cardiomyocytes. PMID- 27965584 TI - More Severe Insomnia Complaints in People with Stronger Long-Range Temporal Correlations in Wake Resting-State EEG. AB - The complaints of people suffering from Insomnia Disorder (ID) concern both sleep and daytime functioning. However, little is known about wake brain temporal dynamics in people with ID. We therefore assessed possible alterations in Long Range Temporal Correlations (LRTC) in the amplitude fluctuations of band-filtered oscillations in electroencephalography (EEG) recordings. We investigated whether LRTC differ between cases with ID and matched controls. Within both groups, we moreover investigated whether individual differences in subjective insomnia complaints are associated with LRTC. Resting-state high-density EEG (256-channel) was recorded in 52 participants with ID and 43 age- and sex-matched controls, during Eyes Open (EO) and Eyes Closed (EC). Detrended fluctuation analysis was applied to the amplitude envelope of band-filtered EEG oscillations (theta, alpha, sigma, beta-1, beta-2) to obtain the Hurst exponents (H), as measures of LRTC. Participants rated their subjective insomnia complaints using the Insomnia Severity Index (ISI). Through general linear models, we evaluated whether H, aggregated across electrodes and frequencies, differed between cases and controls, or showed within-group associations with individual differences in ISI. Additionally, we characterized the spatio-spectral profiles of group differences and associations using non-parametric statistics. H did not differ between cases with ID and controls in any of the frequency bands, neither during EO nor EC. During EO, however, within-group associations between H and ISI indicated that individuals who experienced worse sleep quality had stronger LRTC. Spatio spectral profiles indicated that the associations held most prominently for the amplitude fluctuations of parietal theta oscillations within the ID group, and of centro-frontal beta-1 oscillations in controls. While people suffering from insomnia experience substantially worse sleep quality than controls, their brain dynamics express similar strength of LRTC. In each group, however, individuals experiencing worse sleep quality tend to have stronger LRTC during eyes open wakefulness, in a spatio-spectral range specific for each group. Taken together, the findings indicate that subjective insomnia complaints involve distinct dynamical processes in people with ID and controls. The findings are in agreement with recent reports on decreasing LRTC with sleep depth, and with the hypothesis that sleep balances brain excitability. PMID- 27965585 TI - A Mouse Intra-Intestinal Infusion Model and its Application to the Study of Nanoparticle Distribution. AB - The oral route is the most preferable one when it comes to drug administration. Different animal models have been used to characterize the fate of potential medicines upon oral delivery but fail to clarify specific events occurring at localized sites of the gastrointestinal tract, particularly at the small intestine. We developed a new mouse intra-intestinal infusion model that enabled the direct administration of substances (such as drugs or nanoparticle drug carriers) in the small intestine through an implanted catheter, which can be maintained for prolonged periods of time. The location of catheter insertion can be previously determined as more proximal or distal, allowing to test specific portions of the intestine. Since the model is presumably able to maintain normal physiological characteristics, namely the mucus coating of the intestinal wall, it allowed studying the distribution of different nanoparticles upon localized intra-intestinal administration. The hereby proposed mouse model has the potential to be useful in other types of studies, namely in clarifying localized processes occurring at specific sites of the intestine. PMID- 27965582 TI - Annotation of the Asian Citrus Psyllid Genome Reveals a Reduced Innate Immune System. AB - Citrus production worldwide is currently facing significant losses due to citrus greening disease, also known as Huanglongbing. The citrus greening bacteria, Candidatus Liberibacter asiaticus (CLas), is a persistent propagative pathogen transmitted by the Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Liviidae). Hemipterans characterized to date lack a number of insect immune genes, including those associated with the Imd pathway targeting Gram-negative bacteria. The D. citri draft genome was used to characterize the immune defense genes present in D. citri. Predicted mRNAs identified by screening the published D. citri annotated draft genome were manually searched using a custom database of immune genes from previously annotated insect genomes. Toll and JAK/STAT pathways, general defense genes Dual oxidase, Nitric oxide synthase, prophenoloxidase, and cellular immune defense genes were present in D. citri. In contrast, D. citri lacked genes for the Imd pathway, most antimicrobial peptides, 1,3-beta-glucan recognition proteins (GNBPs), and complete peptidoglycan recognition proteins. These data suggest that D. citri has a reduced immune capability similar to that observed in A. pisum, P. humanus, and R. prolixus. The absence of immune system genes from the D. citri genome may facilitate CLas infections, and is possibly compensated for by their relationship with their microbial endosymbionts. PMID- 27965583 TI - Fatty Acid Regulation of Voltage- and Ligand-Gated Ion Channel Function. AB - Free fatty acids (FFA) are essential components of the cell, where they play a key role in lipid and carbohydrate metabolism, and most particularly in cell membranes, where they are central actors in shaping the physicochemical properties of the lipid bilayer and the cellular adaptation to the environment. FFA are continuously being produced and degraded, and a feedback regulatory function has been attributed to their turnover. The massive increase observed under some pathological conditions, especially in brain, has been interpreted as a protective mechanism possibly operative on ion channels, which in some cases is of stimulatory nature and in other cases inhibitory. Here we discuss the correlation between the structure of FFA and their ability to modulate protein function, evaluating the influence of saturation/unsaturation, number of double bonds, and cis vs. trans isomerism. We further focus on the mechanisms of FFA modulation operating on voltage-gated and ligand-gated ion channel function, contrasting the still conflicting evidence on direct vs. indirect mechanisms of action. PMID- 27965586 TI - The Antioxidant Peroxiredoxin 6 (Prdx6) Exhibits Different Profiles in the Livers of Seawater- and Fresh Water-Acclimated Milkfish, Chanos chanos, upon Hypothermal Challenge. AB - A tropical species, the euryhaline milkfish (Chanos chanos), is a crucial economic species in Southeast Asia and is intolerant of water temperature below 12 degrees C. Large numbers of milkfish die during cold periods in winter. Hypothermal environments usually increase oxidative stress in teleosts, and the liver is the major organ for anti-oxidative responses in the body. Peroxiredoxin 6 (Prdx6) in mammals is a multi-functional enzyme and acts as both glutathione peroxidase, phospholipase A2 and acyl-transferase for maintenance of redox status and prevention of cell membrane peroxidation. Prdx6 can protect cells from oxidant-induced membrane damage by translocating the Prdx6 protein from the cytosol to the membrane. Upon cold stress, Ccprdx6 transcript levels were up regulated after 24 h and 96 h in livers of fresh water (FW)- and seawater (SW) acclimated milkfish, respectively. In the hypothermal FW group, the Prdx6 protein was up-regulated in the cytosol of hepatocytes with a similar role as glutathione peroxidase to reduce oxidative stress upon hypothermal challenge. Conversely, in hypothermal SW milkfish, total Prdx6 protein was down-regulated. However, cytosolic Prdx6 protein was translocated to the membrane, using the ability of phospholipase A2 to stabilize the membrane redox state. Moreover, H2O2 content was increased in FW-acclimated milkfish livers upon hypothermal challenge. Ex vivo H2O2 treatment of milkfish livers also induced Ccprdx6 transcriptional expression, which provided more evidence of the antioxidant role of milkfish Prdx6. Taken together, upon hypothermal challenge, greater oxidative stress in livers of FW-acclimated milkfish rather than SW-acclimated individuals led to different profiles of hepatic CcPrdx6 expression between the FW and SW group. The results indicated that CcPrdx6 played the role of antioxidant with different mechanisms, i.e., binding to reactive oxygen species and stabilizing membrane fluidity, in livers of hypothermal FW and SW milkfish, respectively. PMID- 27965587 TI - Exploring the Mechanisms of Exercise-Induced Hypoalgesia Using Somatosensory and Laser Evoked Potentials. AB - Exercise-induced hypoalgesia is well described, but the underlying mechanisms are unclear. The aim of this study was to examine the effect of exercise on somatosensory evoked potentials, laser evoked potentials, pressure pain thresholds and heat pain thresholds. These were recorded before and after 3-min of isometric elbow flexion exercise at 40% of the participant's maximal voluntary force, or an equivalent period of rest. Exercise-induced hypoalgesia was confirmed in two experiments (Experiment 1-SEPs; Experiment 2-LEPs) by increased pressure pain thresholds at biceps brachii (24.3 and 20.6% increase in Experiment 1 and 2, respectively; both d > 0.84 and p < 0.001) and first dorsal interosseous (18.8 and 21.5% increase in Experiment 1 and 2, respectively; both d > 0.57 and p < 0.001). In contrast, heat pain thresholds were not significantly different after exercise (forearm: 10.8% increase, d = 0.35, p = 0.10; hand: 3.6% increase, d = 0.06, p = 0.74). Contrasting effects of exercise on the amplitude of laser evoked potentials (14.6% decrease, d = -0.42, p = 0.004) and somatosensory evoked potentials (10.9% increase, d = -0.02, p = 1) were also observed, while an equivalent period of rest showed similar habituation (laser evoked potential: 7.3% decrease, d = -0.25, p = 0.14; somatosensory evoked potential: 20.7% decrease, d = -0.32, p = 0.006). The differential response of pressure pain thresholds and heat pain thresholds to exercise is consistent with relative insensitivity of thermal nociception to the acute hypoalgesic effects of exercise. Conflicting effects of exercise on somatosensory evoked potentials and laser evoked potentials were observed. This may reflect non-nociceptive contributions to the somatosensory evoked potential, but could also indicate that peripheral nociceptors contribute to exercise-induced hypoalgesia. PMID- 27965588 TI - Unilateral Eccentric Contraction of the Plantarflexors Leads to Bilateral Alterations in Leg Dexterity. AB - Eccentric contractions can affect musculotendon mechanical properties and disrupt muscle proprioception, but their behavioral consequences are poorly understood. We tested whether repeated eccentric contractions of plantarflexor muscles of one leg affected the dexterity of either leg. Twenty healthy male subjects (27.3 +/- 4.0 yrs) compressed a compliant and slender spring prone to buckling with each isolated leg. The maximal instability they could control (i.e., the maximal average sustained compression force, or lower extremity dexterity force, LEDforce) quantified the dexterity of each leg. We found that eccentric contractions did not affect LEDforce, but reduced force variability (LEDSD). Surprisingly, LEDforce increased in the non-exposed, contralateral leg. These effects were specific to exposure to eccentric contractions because an effort matched exposure to walking did not affect leg dexterity. In the exposed leg, eccentric contractions (i) reduced voluntary error corrections during spring compressions (i.e., reduced 0.5-4 Hz power of LEDforce); (ii) did not change spinal excitability (i.e., unaffected H-reflexes); and (iii) changed the structure of the neural drive to the alpha-motoneuron pool (i.e., reduced EMG power within the 4-8 Hz physiological tremor band). These results suggest that repeated eccentric contractions alter the feedback control for dexterity in the exposed leg by reducing muscle spindle sensitivity. Moreover, the unexpected improvement in LEDforce in the non-exposed contralateral leg was likely a consequence of crossed-effects on its spinal and supraspinal feedback control. We discuss the implications of these bilateral effects of unilateral eccentric contractions, their effect on spinal and supraspinal control of dynamic foot ground interactions, and their potential to facilitate rehabilitation from musculoskeletal and neuromotor impairments. PMID- 27965589 TI - M-currents (Kv7.2-7.3/KCNQ2-KCNQ3) Are Responsible for Dysfunctional Autonomic Control in Hypertensive Rats. AB - : Autonomic dysfunctions play important roles in hypertension, heart failure and arrhythmia, often with a detrimental and fatal effect. The present study analyzed if these dysfunctions involved M-channels (members of the Kv7/KNCQ family) in spontaneously hypertensive rats (SHR). Cardiac output and heart rate (HR) were recorded by a flow probe on the ascending aorta in anesthetized SHR and normotensive rats (WKY), and blood pressure (BP) by a femoral artery catheter. Total peripheral vascular resistance (TPR) was calculated. XE-991 (Kv7.1-7.4 inhibitor) reduced resting HR in WKY but only after reserpine in SHR. XE-991 increased TPR and BP baseline in both strains. Retigabine (Kv7.2-7.5-opener) reduced HR, TPR and BP, also after reserpine. Depolarization induced by 3,4 diaminopyridine (3,4-DAP), a voltage-sensitive K+ channel (Kv) inhibitor, activated release of both acetylcholine and norepinephrine, thus activating an initial, cholinergic bradycardia in SHR, followed by sustained, norepinephrine dependant tachycardia in both strains. XE-991 augmented the initial 3,4-DAP induced bradycardia and eliminated the late tachycardia in SHR, but not in WKY. The increased bradycardia was eliminated by hexamethonium and methoctramine (M2muscarinic receptor antagonist) but not reserpine. Retigabine eliminated the increased bradycardia observed in reserpinized SHR. XE-991 also increased 3,4-DAP stimulated catecholamine release, but not after hexamethonium or reserpine. CONCLUSIONS: M-currents hampered parasympathetic ganglion excitation and, through that, vagal control of HR, in SHR but not WKY. M-currents also opposed catecholamine release in SHR but not in WKY. M-currents represented a vasodilatory component in resting TPR-control, with no strain-related difference detected. Excessive M-currents may represent the underlying cause of autonomic dysfunctions in hypertension. PMID- 27965590 TI - Electrode Position and Current Amplitude Modulate Impulsivity after Subthalamic Stimulation in Parkinsons Disease-A Computational Study. AB - Background: Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) is highly effective in alleviating motor symptoms of Parkinson's disease (PD) which are not optimally controlled by dopamine replacement therapy. Clinical studies and reports suggest that STN-DBS may result in increased impulsivity and de novo impulse control disorders (ICD). Objective/Hypothesis: We aimed to compare performance on a decision making task, the Iowa Gambling Task (IGT), in healthy conditions (HC), untreated and medically-treated PD conditions with and without STN stimulation. We hypothesized that the position of electrode and stimulation current modulate impulsivity after STN-DBS. Methods: We built a computational spiking network model of basal ganglia (BG) and compared the model's STN output with STN activity in PD. Reinforcement learning methodology was applied to simulate IGT performance under various conditions of dopaminergic and STN stimulation where IGT total and bin scores were compared among various conditions. Results: The computational model reproduced neural activity observed in normal and PD conditions. Untreated and medically-treated PD conditions had lower total IGT scores (higher impulsivity) compared to HC (P < 0.0001). The electrode position that happens to selectively stimulate the part of the STN corresponding to an advantageous panel on IGT resulted in de-selection of that panel and worsening of performance (P < 0.0001). Supratherapeutic stimulation amplitudes also worsened IGT performance (P < 0.001). Conclusion(s): In our computational model, STN stimulation led to impulsive decision making in IGT in PD condition. Electrode position and stimulation current influenced impulsivity which may explain the variable effects of STN-DBS reported in patients. PMID- 27965591 TI - Pre-dive Whole-Body Vibration Better Reduces Decompression-Induced Vascular Gas Emboli than Oxygenation or a Combination of Both. AB - Purpose: Since non-provocative dive profiles are no guarantor of protection against decompression sickness, novel means including pre-dive "preconditioning" interventions, are proposed for its prevention. This study investigated and compared the effect of pre-dive oxygenation, pre-dive whole body vibration or a combination of both on post-dive bubble formation. Methods: Six healthy volunteers performed 6 no-decompression dives each, to a depth of 33 mfw for 20 min (3 control dives without preconditioning and 1 of each preconditioning protocol) with a minimum interval of 1 week between each dive. Post-dive bubbles were counted in the precordium by two-dimensional echocardiography, 30 and 90 min after the dive, with and without knee flexing. Each diver served as his own control. Results: Vascular gas emboli (VGE) were systematically observed before and after knee flexing at each post-dive measurement. Compared to the control dives, we observed a decrease in VGE count of 23.8 +/- 7.4% after oxygen breathing (p < 0.05), 84.1 +/- 5.6% after vibration (p < 0.001), and 55.1 +/- 9.6% after vibration combined with oxygen (p < 0.001). The difference between all preconditioning methods was statistically significant. Conclusions: The precise mechanism that induces the decrease in post-dive VGE and thus makes the diver more resistant to decompression stress is still not known. However, it seems that a pre-dive mechanical reduction of existing gas nuclei might best explain the beneficial effects of this strategy. The apparent non-synergic effect of oxygen and vibration has probably to be understood because of different mechanisms involved. PMID- 27965592 TI - Fatigue Induced by Physical and Mental Exertion Increases Perception of Effort and Impairs Subsequent Endurance Performance. AB - Endurance performance involves the prolonged maintenance of constant or self regulated power/velocity or torque/force. While the impact of numerous determinants of endurance performance has been previously reviewed, the impact of fatigue on subsequent endurance performance still needs to be documented. This review aims to present the impact of fatigue induced by physical or mental exertion on subsequent endurance performance. For the purpose of this review, endurance performance refers to performance during whole-body or single-joint endurance exercise soliciting mainly the aerobic energy system. First, the impact of physical and mental exertion on force production capacity is presented, with specific emphasize on the fact that solely physical exertion and not mental exertion induces a decrease in force production capacity of the working muscles. Then, the negative impact of fatigue induced by physical exertion and mental exertion on subsequent endurance performance is highlighted based on experimental data. Perception of effort being identified as the variable altered by both prior physical exertion and mental exertion, future studies should investigate the underlying mechanisms increasing perception of effort overtime and in presence of fatigue during endurance exercise. Perception of effort should be considered not only as marker of exercise intensity, but also as a factor limiting endurance performance. Therefore, using a psychophysiological approach to explain the regulation of endurance performance would allow a better understanding of the interaction between physiological and psychological phenomena known to impact endurance performance. PMID- 27965593 TI - The Cu, Zn Superoxide Dismutase: Not Only a Dismutase Enzyme. AB - The Cu,Zn superoxide dismutase (SOD1) is an ubiquitary cytosolic dimeric carbohydrate free molecule, belonging to a family of isoenzymes involved in the scavenger of superoxide anions. This effect certainly represents the main and well known function ascribed to this enzyme. Here we highlight new aspects of SOD1 physiology that point out some inedited effects of this enzyme in addition to the canonic role of oxygen radical enzymatic dismutation. In the last two decades our research group produced many data obtained in in vitro studies performed in many cellular lines, mainly neuroblastoma SK-N-BE cells, indicating that this enzyme is secreted either constitutively or after depolarization induced by high extracellular K+ concentration. In addition, we gave many experimental evidences showing that SOD1 is able to stimulate, through muscarinic M1 receptor, pathways involving ERK1/2, and AKT activation. These effects are accompanied with an intracellular calcium increase. In the last part of this review we describe researches that link deficient extracellular secretion of mutant SOD1G93A to its intracellular accumulation and toxicity in NSC-34 cells. Alternatively, SOD1G93A toxicity has been attributed to a decrease of Km for H2O2 with consequent OH radical formation. Interestingly, this last inedited effect of SOD1G93A could represent a gain of function that could be involved in the pathogenesis of familial Amyotrophic Lateral Sclerosis (fALS). PMID- 27965595 TI - Cutting a Long Intron Short: Recursive Splicing and Its Implications. AB - Over time eukaryotic genomes have evolved to host genes carrying multiple exons separated by increasingly larger intronic, mostly non-protein-coding, sequences. Initially, little attention was paid to these intronic sequences, as they were considered not to contain regulatory information. However, advances in molecular biology, sequencing, and computational tools uncovered that numerous segments within these genomic elements do contribute to the regulation of gene expression. Introns are differentially removed in a cell type-specific manner to produce a range of alternatively-spliced transcripts, and many span tens to hundreds of kilobases. Recent work in human and fruitfly tissues revealed that long introns are extensively processed cotranscriptionally and in a stepwise manner, before their two flanking exons are spliced together. This process, called "recursive splicing," often involves non-canonical splicing elements positioned deep within introns, and different mechanisms for its deployment have been proposed. Still, the very existence and widespread nature of recursive splicing offers a new regulatory layer in the transcript maturation pathway, which may also have implications in human disease. PMID- 27965594 TI - Lack of Adrenomedullin Results in Microbiota Changes and Aggravates Azoxymethane and Dextran Sulfate Sodium-Induced Colitis in Mice. AB - The link between intestinal inflammation, microbiota, and colorectal cancer is intriguing and the potential underlying mechanisms remain unknown. Here we evaluate the influence of adrenomedullin (AM) in microbiota composition and its impact on colitis with an inducible knockout (KO) mouse model for AM. Microbiota composition was analyzed in KO and wild type (WT) mice by massive sequencing. Colitis was induced in mice by administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS) in the drinking water. Colitis was evaluated using a clinical symptoms index, histopathological analyses, and qRT-PCR. Abrogation of the adm gene in the whole body was confirmed by PCR and qRT-PCR. KO mice exhibit significant changes in colonic microbiota: higher proportion of delta Proteobacteria class; of Coriobacteriales order; and of other families and genera was observed in KO feces. Meanwhile these mice had a lower proportion of beneficial bacteria, such as Lactobacillus gasseri and Bifidobacterium choerinum. TLR4 gene expression was higher (p < 0.05) in KO animals. AM deficient mice treated with DSS exhibited a significantly worse colitis with profound weight loss, severe diarrhea, rectal bleeding, colonic inflammation, edema, infiltration, crypt destruction, and higher levels of pro-inflammatory cytokines. No changes were observed in the expression levels of adhesion molecules. In conclusion, we have shown that lack of AM leads to changes in gut microbiota population and in a worsening of colitis conditions, suggesting that endogenous AM is a protective mediator in this pathology. PMID- 27965596 TI - Noise Decomposition Principle in a Coherent Feed-Forward Transcriptional Regulatory Loop. AB - Coherent feed-forward loops exist extensively in realistic biological regulatory systems, and are common signaling motifs. Here, we study the characteristics and the propagation mechanism of the output noise in a coherent feed-forward transcriptional regulatory loop that can be divided into a main road and branch. Using the linear noise approximation, we derive analytical formulae for the total noise of the full loop, the noise of the branch, and the noise of the main road, which are verified by the Gillespie algorithm. Importantly, we find that (i) compared with the branch motif or the main road motif, the full motif can effectively attenuate the output noise level; (ii) there is a transition point of system state such that the noise of the main road is dominated when the underlying system is below this point, whereas the noise of the branch is dominated when the system is beyond the point. The entire analysis reveals the mechanism of how the noise is generated and propagated in a simple yet representative signaling module. PMID- 27965597 TI - Transcranial Direct Current Stimulation Effects on Athletes' Cognitive Performance: An Exploratory Proof of Concept Trial. AB - Among the 2016 Olympic and Paralympic Games' unforgettable moments, one could not overlook performances by Phelps and Bolt, which challenge old premises about the maximum extension of individual supremacism in ultracompetitive modalities and the doping scandals. Different media channels resonated these two trends, with an unseen rise on discussions about traits and practices that may set ultrahigh performance athletes apart from the more ordinary ones. Yet, some key issues remain undebated. This paper aims to add to this debate, with a proof of concept trial, which investigates whether transcranial direct current stimulation (tDCS) may serve as an aid for professional athletes. Ten professional athletes of three different modalities (judo, N = 4 athletes, swimming, N = 3 athletes, and rhythmic gymnastics, N = 3 athletes) received anodal stimulation (2 mA) for 20 min on the left dorsolateral prefrontal cortex for ten consecutive weekdays. We observed a positive effect of tDCS in their cognitive performance, including a significant improvement in alternated, sustained, and divided attention and in memory scores. We also observed a decrease in Beck Depression Inventory scores (4.50 points) in this non-clinical population. These preliminary results suggest that tDCS sessions may translate into competitive advantages for professional athletes and recommend the deepening of the discussion on its ethical use in sports, which is ultimately tied to the wider debate around the risks and opportunities that neuromodulation brings to the table. PMID- 27965598 TI - Defining Precision Medicine Approaches to Autism Spectrum Disorders: Concepts and Challenges. AB - The tremendous clinical and etiological variability between individuals with autism spectrum disorder (ASD) has made precision medicine the most promising treatment approach. It aims to combine new pathophysiologically based treatments with objective tests (stratification biomarkers) to predict which treatment may be beneficial for a particular person. Here we discuss significant advances and current challenges for this approach: rare monogenic forms of ASD have provided a major breakthrough for the identification of treatment targets by providing a means to trace causal links from a gene to specific molecular alterations and biological pathways. To estimate whether treatment targets thus identified may be useful for larger patient groups we need a better understanding of whether different etiologies (i.e., genetic and environmental risk factors acting at different critical time points) lead to convergent or divergent molecular mechanisms, and how they map onto differences in circuit-level brain and cognitive development, and behavioral symptom profiles. Several recently failed clinical trials with syndromic forms of ASD provide valuable insights into conceptual and methodological issues linked to limitations in the translatability from animal models to humans, placebo effects, and a need for mechanistically plausible, objective outcome measures. To identify stratification biomarkers that enrich participant selection in clinical trials, large-scale multi-modal longitudinal observational studies are underway. Addressing these different factors in the next generation of research studies requires a translatable developmental perspective and multidisciplinary, collaborative efforts, with a commitment to sharing protocols and data, to increase transparency and reproducibility. PMID- 27965599 TI - Computational Psychiatry and Psychometrics Based on Non-Conscious Stimuli Input and Pupil Response Output. PMID- 27965601 TI - Toward a Principled Sampling Theory for Quasi-Orders. AB - Quasi-orders, that is, reflexive and transitive binary relations, have numerous applications. In educational theories, the dependencies of mastery among the problems of a test can be modeled by quasi-orders. Methods such as item tree or Boolean analysis that mine for quasi-orders in empirical data are sensitive to the underlying quasi-order structure. These data mining techniques have to be compared based on extensive simulation studies, with unbiased samples of randomly generated quasi-orders at their basis. In this paper, we develop techniques that can provide the required quasi-order samples. We introduce a discrete doubly inductive procedure for incrementally constructing the set of all quasi-orders on a finite item set. A randomization of this deterministic procedure allows us to generate representative samples of random quasi-orders. With an outer level inductive algorithm, we consider the uniform random extensions of the trace quasi orders to higher dimension. This is combined with an inner level inductive algorithm to correct the extensions that violate the transitivity property. The inner level correction step entails sampling biases. We propose three algorithms for bias correction and investigate them in simulation. It is evident that, on even up to 50 items, the new algorithms create close to representative quasi order samples within acceptable computing time. Hence, the principled approach is a significant improvement to existing methods that are used to draw quasi-orders uniformly at random but cannot cope with reasonably large item sets. PMID- 27965600 TI - False Memories for Affective Information in Schizophrenia. AB - Studies have shown a direct link between memory for emotionally salient experiences and false memories. In particular, emotionally arousing material of negative and positive valence enhanced reality monitoring compared to neutral material since emotional stimuli can be encoded with more contextual details and thereby facilitate the distinction between presented and imagined stimuli. Individuals with schizophrenia appear to be impaired in both reality monitoring and memory for emotional experiences. However, the relationship between the emotionality of the to-be-remembered material and false memory occurrence has not yet been studied. In this study, 24 patients and 24 healthy adults completed a false memory task with everyday episodes composed of 12 photographs that depicted positive, negative, or neutral outcomes. Results showed how patients with schizophrenia made a higher number of false memories than normal controls (p < 0.05) when remembering episodes with positive or negative outcomes. The effect of valence was apparent in the patient group. For example, it did not affect the production causal false memories (p > 0.05) resulting from erroneous inferences but did interact with plausible, script consistent errors in patients (i.e., neutral episodes yielded a higher degree of errors than positive and negative episodes). Affective information reduces the probability of generating causal errors in healthy adults but not in patients suggesting that emotional memory impairments may contribute to deficits in reality monitoring in schizophrenia when affective information is involved. PMID- 27965603 TI - Understanding Risk-taking Behavior in Bullies, Victims, and Bully Victims Using Cognitive- and Emotion-Focused Approaches. AB - Bullying and risky behavior are two common problems among adolescents and can strongly affect a youth's overall functioning when both coexist. Some studies suggest that bullying in adolescence may promote risky behavior as a coping strategy to deal with victimization related stress. Other studies consider bullying as an outcome of high-risk behavior. Despite the association between the two is well-established, no study has examined the risk-taking patterns among bullying groups (i.e., bully, victim, and bully victim). This study attempted to elucidate the potential relationships between bullying and risk-taking by addressing the two models: a cognitive-focused model and an emotion-focused model of risk taking, and to clarify how adolescents' characteristics in risk taking associate with bullying outcomes. Method: 136 Chinese adolescents (Mean Age = 14.5, M = 65, F = 71) were recruited and grouped according to bullying identity: Bully (n = 27), Victim (n = 20), Bully victim (n = 37) and Control (n = 52). Cognitive Appraisal of Risky Events (CARE) questionnaire was used to measure participants' expectancies about the risks, benefits and involvement associated with risky activities. Cambridge Gambling Task (CGT) was administered to capture the emotion-laden process in risk taking. Results: Cognitively, Bully was associated with an overestimation of risk while Victim was associated with an underestimation of risk and overrated benefit. Bully victim exhibited a unique pattern with an overestimation of benefit and risk. All study groups projected higher involvement in risky behavior. Behaviorally, both Bully and Bully victim were associated with high risk modulation whereas Victim was associated with impulsive decision-making. Interestingly, compared with bully, bully victim had significantly higher bullying scores, suggesting a wider range and more frequent bullying activities. In conclusion, Bully maybe a group of adolescents that is vigilant in situational deliberation and risk modulation while Victims with high impulsivity, are more likely to place themselves in risky situations. Bully victims presented the combined pattern of the two pure groups and associated with the highest risk-taking propensity. Better picture of risk taking pattern associated with different groups was illustrated, allowing better matching for future prevention and intervention program for distinct bullying individuals. PMID- 27965602 TI - A New Semi-automated Method for Assessing Avian Acoustic Networks Reveals that Juvenile and Adult Zebra Finches Have Separate Calling Networks. AB - Social networks are often inferred from spatial associations, but other parameters like acoustic communication are likely to play a central role in within group interactions. However, it is currently difficult to determine which individual initiates vocalizations, or who responds to whom. To this aim, we designed a method that allows analyzing group vocal network while controlling for spatial networks, by positioning each group member in equidistant individual cages and analyzing continuous vocal interactions semi-automatically. We applied this method to two types of zebra finch groups, composed of either two adult females and two juveniles, or four young adults (juveniles from the first groups). Young often co-occur in the same social group as adults but are likely to have a different social role, which may be reflected in their vocal interactions. Therefore, we tested the hypothesis that the social structure of the group influences the parameters of the group vocal network. We found that groups including juveniles presented periods with higher level of activity than groups composed of young adults. Using two types of analyses (Markov analysis and cross-correlation), we showed that juveniles as well as adults were more likely to respond to individuals of their own age-class (i.e. to call one after another, in terms of turn-taking, and within a short time-window, in terms of time delay). When juveniles turned into adulthood, they showed adult characteristics of vocal patterns. Together our results suggest that vocal behavior changes during ontogeny, and individuals are more strongly connected with individuals of the same age-class within acoustic networks. PMID- 27965604 TI - The N400 Effect during Speaker-Switch-Towards a Conversational Approach of Measuring Neural Correlates of Language. AB - Language occurs naturally in conversations. However, the study of the neural underpinnings of language has mainly taken place in single individuals using controlled language material. The interactive elements of a conversation (e.g., turn-taking) are often not part of neurolinguistic setups. The prime reason is the difficulty to combine open unrestricted conversations with the requirements of neuroimaging. It is necessary to find a trade-off between the naturalness of a conversation and the restrictions imposed by neuroscientific methods to allow for ecologically more valid studies. Here, we make an attempt to study the effects of a conversational element, namely turn-taking, on linguistic neural correlates, specifically the N400 effect. We focus on the physiological aspect of turn taking, the speaker-switch, and its effect on the detectability of the N400 effect. The N400 event-related potential reflects expectation violations in a semantic context; the N400 effect describes the difference of the N400 amplitude between semantically expected and unexpected items. Sentences with semantically congruent and incongruent final words were presented in two turn-taking modes: (1) reading aloud first part of the sentence and listening to speaker-switch for the final word, and (2) listening to first part of the sentence and speaker switch for the final word. A significant N400 effect was found for both turn taking modes, which was not influenced by the mode itself. However, the mode significantly affected the P200, which was increased for the reading aloud mode compared to the listening mode. Our results show that an N400 effect can be detected during a speaker-switch. Speech articulation (reading aloud) before the analyzed sentence fragment did also not impede the N400 effect detection for the final word. The speaker-switch, however, seems to influence earlier components of the electroencephalogram, related to processing of salient stimuli. We conclude that the N400 can effectively be used to study neural correlates of language in conversational approaches including speaker-switches. PMID- 27965605 TI - Differences in Knowledge, Stress, Sensation Seeking, and Locus of Control Linked to Dietary Adherence in Hemodialysis Patients. AB - Patients with chronic kidney disease (CKD) often require regular hemodialysis (HD) to prolong life. However, between HD sessions, patients have to restrict their diets carefully to avoid excess accumulation of potassium, phosphate, sodium, and fluid, which their diseased kidneys can no longer regulate. Failure to adhere to their renal dietary regimes can be fatal; nevertheless, non adherence is common, and yet little is known about the psychological variables that might predict this dietary behavior. Thus, this study aimed to assess whether dietary adherence might be affected by a variety of psychological factors including stress, personality, and health locus of control, as well as dietary knowledge, in chronic HD patients. Fifty-one patients (30 men; age range 25-85) who had undergone HD for at least 3 months and had been asked to restrict at least one of potassium, phosphate or fluid, were recruited from a hospital renal unit. Measures of adherence to each of potassium, phosphate, and fluid were derived from standard criteria for these physiological indices in renal patients. Knowledge of food/drink sources of these dietary factors, and their medical implications in relation to HD and CKD were assessed by a bespoke questionnaire. Psychological factors including stress, personality and health locus of control beliefs were measured by standardized questionnaires. Having to restrict a particular nutrient was associated with better knowledge of both food sources and medical complications for that nutrient; however, greater dietary knowledge was not linked to adherence, and knowledge of medical complications tended to be associated with poorer adherence to potassium and phosphate levels. Adherence to these two nutrient requirements was also associated with lower reported stress in the past week. Adherence was associated with differences in locus of control: these differences varied across indices although there was a tendency to believe in external loci. For potassium, phosphate, and fluid restriction, adherers were less likely to be sensation seekers but did not differ from non-adherers on impulsivity, anxiety sensitivity, or hopelessness. In conclusion, the links between dietary adherence and stress, locus of control and personality suggests that screening for such psychological factors may assist in managing adherence in HD patients. PMID- 27965607 TI - Impaired Spatial Category Representations in Williams Syndrome; an Investigation of the Mechanistic Contributions of Non-verbal Cognition and Spatial Language Performance. AB - The aims of this study were to: provide a precise characterisation of spatial category representations in Williams syndrome (WS); to determine the nature of the mechanistic contributions from spatial language performance and non-verbal cognition to spatial category representations in WS; and to explore the stability of spatial category representations in WS using error analysis. Spatial category representation was assessed across nine spatial categories (In, On, Under, In Front, Behind, Above, Below, Left, and Right) using an odd-one-out task. The performance of individuals with WS (N = 24; 12;00 years;months to 30;07 years;months) was compared to data from typically developing children aged four to 7 years (N = 75), published in Farran and Atkinson (2016). The WS group performed at the level of typical 4- and 5-year-olds. Despite this low level of ability, they demonstrated typical variation in their representation of easier to harder spatial categories, in line with the spatial category representation model (Farran and Atkinson, 2016). Error analysis of broad category understanding (i.e., category understanding which includes non-prototypical category members), however, showed that errors reflected fewer guess responses than expected by chance in the WS group only, which could suggest strategic responding in this group. Developmental trajectory analyses demonstrated a significant contributing influence of both non-verbal mental age and spatial language ability in the TD group. For the WS group, non-verbal mental age significantly contributed to spatial category representations, whilst the contributing influence of spatial language ability was marginally significant. With reference to level of ability, spatial category representations in the WS group were consistently lower than would be expected for non-verbal mental age, but on a par with their (low) spatial language mental age. Spatial category representations in WS are discussed with reference to their contribution to the hallmark deficit in spatial construction and drawing abilities in WS. PMID- 27965606 TI - Take the Money and Run: Psychopathic Behavior in the Trust Game. AB - We study the association among different sources of individual differences such as personality, cognitive ability and risk attitudes with trust and reciprocate behavior in an incentivized experimental binary trust game in a sample of 220 (138 females) undergraduate students. The game involves two players, player 1 (P1) and player 2 (P2). In the first stage, P1 decides whether to trust and let P2 decide, or to secure an egalitarian payoff for both players. If P1 trusts P2, the latter can choose between a symmetric payoff that is double than the secure alternative discarded by P1, and an asymmetric payoff in which P2 earns more than in any other case but makes P1 worse off. Before the main experiment, we obtained participants' scores for Abstract Reasoning (AR), risk attitudes, basic personality characteristics, and specific traits such as psychopathy and impulsivity. During the main experiment, we measured Heart Rate (HR) and ElectroDermal Activity (EDA) variation to account for emotional arousal caused by the decision and feedback processes. Our main findings indicate that, on one hand, P1 trust behavior associates to positive emotionality and, specifically, to the extraversion's warmth facet. In addition, the impulsivity facet of positive urgency also favors trust behavior. No relation to trusting behavior was found for either other major personality aspects or risk attitudes. The physiological results show that participants scoring high in psychopathy exhibit increased EDA and reduced evoked HR deceleration at the moment in which they are asked to decide whether or not to trust. Regarding P2, we find that AR ability and mainly low disagreeable disinhibition favor reciprocal behavior. Specifically, lack of reciprocity significantly relates with a psychopathic, highly disinhibited and impulsive personality. Thus, the present study suggests that personality characteristics would play a significant role in different behaviors underlying cooperation, with extraversion/positive emotionality being more relevant for initiating cooperation, and low disagreeable disinhibition for maintaining it. PMID- 27965608 TI - Commentary: The Relationship between Sleep Complaints, Depression, and Executive Functions on Older Adults. PMID- 27965609 TI - Polish Translation and Validation of the Tinnitus Handicap Inventory and the Tinnitus Functional Index. AB - Objective: The need for validated measures enabling clinicians to classify tinnitus patients according to the severity of tinnitus and screen the progress of therapies in our country led us to translate into Polish and to validate two tinnitus questionnaires, namely the Tinnitus Handicap Inventory (THI) and the Tinnitus Functional Index (TFI). Design: The original English versions of the questionnaires were translated into Polish and translated back to English by three independent translators. These versions were then finalized by the authors into a Polish THI (THI-Pl) and a Polish TFI (TFI-Pl). Participants from three laryngological centers in Poland anonymously answered the THI-Pl (N = 98) and the TFI-Pl (N = 108) in addition to the Polish versions of the Center for Epidemiologic Studies Depression Scale as a measure of self-perceived level of depression, and the Satisfaction With Life Scale to assess self-perceived quality of life. Both were used to determine discriminant validity. Two Visual Analog Scales were used to measure tinnitus annoyance and tinnitus loudness in order to determine convergent validity. Results: Similar to the original version of the THI, the THI-Pl showed a high internal consistency (Cronbach's alpha = 0.93). The exploratory factor analysis revealed that the questionnaire has a three-factorial structure that does not correspond to the original division for functional, catastrophic, and emotional subscales. Convergent and discriminant validities were confirmed. The TFI-Pl showed high internal consistency (Cronbach's alpha = 0.96) with the reliability ranging from 0.82 to 0.95 for its different subscales. Factor analysis confirmed an eight-factorial structure with factors assigning all items to appropriate subscales reported in the original version of the questionnaire. Discriminant and convergent validities were also confirmed for the TFI-Pl. Conclusion: We translated and validated the Polish versions of the THI and the TFI to make them suitable for clinical use in Poland. PMID- 27965610 TI - Identification of Socio-demographic and Psychological Factors Affecting Women's Propensity to Breastfeed: An Italian Cohort. AB - Background: Exclusive breastfeeding until 6 months postpartum is a World Health Organization objective and benefits have been demonstrated for both mother and infant. It is important to clarify which factors influence breastfeeding intentions. Our objective was to assess and identify socio-demographic and psychological factors associated with breastfeeding intention in a sample of pregnant Italian women. Materials and Methods: This prospective study included 160 pregnant women. The following psychological constructs were measured using standardized questionnaires: anxiety, prenatal attachment, adult attachment, personality traits, and intention to breastfeed. Socio-demographic data were also collected using a self-report questionnaire. Assessment took place after the 20th gestational week. Results: Self-employment, age and feeding received as an infant were significantly related to breastfeeding intention. Regarding psychological factors, we also found that Neuroticism was negatively associated with mother's breastfeeding intentions. Relationships between psychological constructs and breastfeeding attitude were examined and represented within a graphical modeling framework. Conclusion: It may be possible to identify women that are less inclined to breastfeed early on in pregnancy. This may aid healthcare staff to pay particular attention to women who show certain socio-demographic and psychological characteristics, so as to fulfill more focused programs. PMID- 27965611 TI - Personalized Behavioral Feedback for Online Gamblers: A Real World Empirical Study. AB - Responsible gambling tools (e.g., limit-setting tools, pop-up messages, and personalized feedback) have become increasingly popular as a way of facilitating players to gamble in a more responsible manner. However, relatively few studies have evaluated whether such tools actually work. The present study examined whether the use of three types of information (i.e., personalized feedback, normative feedback, and/or a recommendation) could enable players to gamble more responsibly as assessed using three measures of gambling behavior, i.e., theoretical loss (TL), amount of money wagered, and gross gaming revenue (GGR) (i.e., net win/loss). By manipulating the three forms of information, data from six different groups of players were analyzed. The participant sample drawn from the population were those that had played at least one game for money on the Norsk Tipping online platform (Instaspill) during April 2015. A total of 17,452 players were randomly selected from 69,631 players that fulfilled the selection criteria. Of these, 5,528 players participated in the experiment. Gambling activity among the control group (who received no personalized feedback, normative feedback or no recommendation) was also compared with the other five groups that received information of some kind (personalized feedback, normative feedback and/or a recommendation). Compared to the control group, all groups that received some kind of messaging significantly reduced their gambling behavior as assessed by TL, amount of money wagered, and GGR. The results support the hypothesis that personalized behavioral feedback can enable behavioral change in gambling but that normative feedback does not appear change behavior significantly more than personalized feedback. PMID- 27965612 TI - Can Psychological Expectation Models Be Adapted for Placebo Research? AB - Placebo responses contribute substantially to the effect and clinical outcome of medical treatments. Patients' expectations have been identified as one of the major mechanisms contributing to placebo effects. However, to date a general theoretical framework to better understand how patient expectations interact with features of medical treatment has not been developed. In this paper we outline an expectation model that can be used as framework for experimental studies on both placebo and nocebo mechanisms. This model is based on psychological concepts of expectation development, expectation maintenance, and expectation change within the typical paradigms used in placebo research. This theoretical framework reflects the dynamic aspects of the interaction between expectations and medical treatment, and offers a platform to combine psychological and neurophysiological research activities. Moreover, this model can be used to identify important future research questions. For example, we argue that the dynamic processes of expectation maintenance vs. expectation changes are not sufficiently addressed in current research on placebo mechanisms. Therefore, the question about how to change and optimize patients' expectations prior to treatment should be a special focus of future clinical research. PMID- 27965613 TI - Need for Closure Moderates the Break in the Message Effect. AB - Cutting the message into smaller portions is a common practice in the media. Typically such messages consist of a headline followed by a story elaboration. In a series of studies Dolinski and Kofta (2001) have shown that such a break in the message increases the effect of the information provided in the headline over that of a story which actually contained information inconsistent with that headline. A possible explanation of this effect, based on the concept of the need for cognitive closure, is presented in the article. The experiment shows that break-in-the-message effect is found mainly for participants with high need for closure but not for those with low such need. PMID- 27965614 TI - Stimulus Threat and Exposure Context Modulate the Effect of Mere Exposure on Approach Behaviors. AB - Mere-exposure (ME) research has found that initially neutral objects made familiar are preferred relative to novel objects. Recent work extends these preference judgments into the behavioral domain by illustrating that mere exposure prompts approach-oriented behavior toward familiar stimuli. However, no investigations have examined the effect of mere exposure on approach-oriented behavior toward threatening stimuli. The current work examines this issue and also explores how exposure context interacts with stimulus threat to influence behavioral tendencies. In two experiments participants were presented with both mere-exposed and novel stimuli and approach speed was assessed. In the first experiment, when stimulus threat was presented in a homogeneous format (i.e., participants viewed exclusively neutral or threatening stimuli), ME potentiated approach behaviors for both neutral and threatening stimuli. However, in the second experiment, in which stimulus threat was presented in a heterogeneous fashion (i.e., participants viewed both neutral and threatening stimuli), mere exposure facilitated approach only for initially neutral stimuli. These results suggest that ME effects on approach behaviors are highly context sensitive and depend on both stimulus valence and exposure context. Further implications of these findings for the ME literature are discussed. PMID- 27965615 TI - Parenting Capacity Assessment for the Court in a Multifamily Group Setting. AB - Parenting capacity assessment in court evaluations is a particularly complex task, given that it is necessary to consider the vast array of distinct and interrelated aspects and abilities which represent parenting, as well as the elevated number of contextual levels that influence parenting quality. The perspective we want to introduce regards the potentiality of the multifamily group as the elective observational setting in parenting capacity assessment. PMID- 27965616 TI - Contact with Nature and Children's Restorative Experiences: An Eye to the Future. AB - This article offers an overview of what has been done until now on restorative research with children and opens up new inquires for future research. Most of the work has studied children's exposure to nature and the restorative benefits this contact provides, focusing on the renewal of children's psychological resources. The paper begins with an introduction to children's current tendency toward an alienation from the natural world and sets out the objectives of the article. It is followed by four main sections. The first two sections report on what we already know in this research area, distinguishing between children with normal mental capabilities and those suffering from attention-deficit hyperactivity disorder (ADHD). The findings gathered in these sections suggest that children's contact with nature improves their mood and their cognitive functioning, increases their social interactions and reduces ADHD symptoms. The next section describes five suggestions for future research: (1) the need for considering the relational dynamics between the child and the environment in restoration research, and the concept of constrained restoration; (2) the possibility of restorative needs arising from understimulation; (3) the importance of considering children's social context for restoration; (4) the relationship between restoration and pro-social and pro-environmental behaviors; and (5) children's restorative environments other than nature. We close by making some final remarks about the importance of restoring daily depleted resources for children's healthy functioning. PMID- 27965617 TI - Response: Commentary: Greater Emotional Gain from Giving in Older Adults: Age Related Positivity Bias in Charitable Giving. PMID- 27965618 TI - The System Justification Conundrum: Re-Examining the Cognitive Dissonance Basis for System Justification. PMID- 27965619 TI - Dynamic Changes in Spectral and Spatial Signatures of High Frequency Oscillations in Rat Hippocampi during Epileptogenesis in Acute and Chronic Stages. AB - OBJECTIVE: To analyze spectral and spatial signatures of high frequency oscillations (HFOs), which include ripples and fast ripples (FRs, >200 Hz) by quantitatively assessing average and peak spectral power in a rat model of different stages of epileptogenesis. METHODS: The lithium-pilocarpine model of temporal lobe epilepsy was used. The acute phase of epilepsy was assessed by recording intracranial electroencephalography (EEG) activity for 1 day after status epilepticus (SE). The chronic phase of epilepsy, including spontaneous recurrent seizures (SRSs), was assessed by recording EEG activity for 28 days after SE. Average and peak spectral power of five frequency bands of EEG signals in CA1, CA3, and DG regions of the hippocampus were analyzed with wavelet and digital filter. RESULTS: FRs occurred in the hippocampus in the animal model. Significant dynamic changes in the spectral power of FRS were identified in CA1 and CA3. The average spectral power of ripples increased at 20 min before SE (p < 0.05), peaked at 10 min before diazepam injection. It decreased at 10 min after diazepam (p < 0.05) and returned to baseline after 1 h. The average spectral power of FRs increased at 30 min before SE (p < 0.05) and peaked at 10 min before diazepam. It decreased at 10 min after diazepam (p < 0.05) and returned to baseline at 2 h after injection. The dynamic changes were similar between average and peak spectral power of FRs. Average and peak spectral power of both ripples and FRs in the chronic phase showed a gradual downward trend compared with normal rats 14 days after SE. SIGNIFICANCE: The spectral power of HFOs may be utilized to distinguish between normal and pathologic HFOs. Ictal average and peak spectral power of FRs were two parameters for predicting acute epileptic seizures, which could be used as a new quantitative biomarker and early warning marker of seizure. Changes in interictal HFOs power in the hippocampus at the chronic stage may be not related to seizure occurrence. PMID- 27965620 TI - A Method for Whole Brain Ex Vivo Magnetic Resonance Imaging with Minimal Susceptibility Artifacts. AB - Magnetic resonance imaging (MRI) is a non-destructive technique that is capable of localizing pathologies and assessing other anatomical features (e.g., tissue volume, microstructure, and white matter connectivity) in postmortem, ex vivo human brains. However, when brains are removed from the skull and cerebrospinal fluid (i.e., their normal in vivo magnetic environment), air bubbles and air tissue interfaces typically cause magnetic susceptibility artifacts that severely degrade the quality of ex vivo MRI data. In this report, we describe a relatively simple and cost-effective experimental setup for acquiring artifact-free ex vivo brain images using a clinical MRI system with standard hardware. In particular, we outline the necessary steps, from collecting an ex vivo human brain to the MRI scanner setup, and have also described changing the formalin (as might be necessary in longitudinal postmortem studies). Finally, we share some representative ex vivo MRI images that have been acquired using the proposed setup in order to demonstrate the efficacy of this approach. We hope that this protocol will provide both clinicians and researchers with a straight-forward and cost-effective solution for acquiring ex vivo MRI data from whole postmortem human brains. PMID- 27965621 TI - Upper Trunk Brachial Plexus Palsy Following Chiropractic Manipulation. AB - INTRODUCTION: Upper trunk brachial plexus palsy can result from high-energy trauma and has never been reported following spinal manipulation. BACKGROUND: The case is presented of a patient who developed an acute brachial plexus upper trunk palsy following spinal manipulative therapy. DISCUSSION: Discussion is made on the incidence of complications following manipulation and recommendations to prospectively capture all serious complications. CONCLUDING REMARKS: Risks exist with spinal manipulative therapy. Neurological injury can occur. Risk assessment and re-examination should occur at every visit. Large rigorous prospective studies are required to identify the true incidence of serious complications resulting from manipulative therapy and the benefit:risk ratio. PMID- 27965622 TI - Laryngeal Sensitivity in Patients with Amyotrophic Lateral Sclerosis. AB - Recent studies have shown the involvement of the sensory nervous system in patients with amyotrophic lateral sclerosis (ALS). The aim of our study was to investigate the correlation between the laryngeal sensitivity deficit and the type of ALS onset (bulbar or spinal) in a large series of 114 consecutive ALS patients. Participants were subdivided into two groups, bulbar and spinal ALS, according to the clinical onset of disease and submitted to a clinical and instrumental evaluation of swallowing, including a fiber-optic endoscopic evaluation of swallowing with sensory testing. Dysphagia severity was scored using the Penetration-Aspiration Scale (PAS) and the Pooling score (P-score). In addition, three patients with laryngeal sensitivity deficit were submitted to a laryngeal biopsy to assess the status of the sensory innervation. All patients showed a normal glottal closure during phonation and volitional cough. Fifty-six subjects (49%), 14 spinal- and 42 bulbar-onset ALS, showed dysphagia at the first clinical observation (PAS score >1; P-score >5). Dysphagia resulted more frequently in bulbar-onset ALS (P < 0.01). Thirty-eight (33%) patients had a sensory deficit of the larynx. The sensory deficit of the larynx was significantly more frequent in bulbar-onset ALS (P < 0.01). The sensory deficit of the larynx among dysphagic patients was also significantly more frequent in bulbar-onset ALS (P = 0.02). Several abnormalities were found in all three subjects who underwent a laryngeal biopsy: in one patient, no intraepidermal fiber was found; in the other two, the fibers showed morphological changes. Our observations are important to consider for assessment and management of dysphagia in patients with ALS. PMID- 27965623 TI - Transcranial Alternating Current Stimulation: A Potential Risk for Genetic Generalized Epilepsy Patients (Study Case). AB - Transcranial alternating current stimulation (tACS) is a re-emergent neuromodulation technique that consists in the external application of oscillating electrical currents that induces changes in cortical excitability. We present the case of a 16-year-old female with pharmaco-resistant juvenile myoclonic epilepsy to 3 antiepileptic's drugs characterized by 4 myoclonic and 20 absence seizures monthly. She received tACS at 1 mA at 3 Hz pulse train during 60 min over Fp1-Fp2 (10-20 EEG international system position) during 4 consecutive days using an EndeavorTM IOM Systems device(r) (Natus Medical Incorporated, Middleton, WI, USA). At the 1-month follow-up, she reported a 75% increase in seizures frequency (only myoclonic and tonic-clonic events) and developed a 24-h myoclonic status epilepticus that resolved with oral clonazepam and intravenous valproate. At the 2-month follow-up, the patient reported a 15-day seizure-free period. PMID- 27965624 TI - RU486 Mitigates Hippocampal Pathology Following Status Epilepticus. AB - Status epilepticus (SE) induces rapid hyper-activation of the hypothalamo pituitary-adrenocortical (HPA) axis. HPA axis hyperactivity results in excess exposure to high levels of circulating glucocorticoids, which are associated with neurotoxicity and depression-like behavior. These observations have led to the hypothesis that HPA axis dysfunction may exacerbate SE-induced brain injury. To test this hypothesis, we used the mouse pilocarpine model of epilepsy to determine whether use of the glucocorticoid receptor antagonist RU486 can attenuate hippocampal pathology following SE. Excess glucocorticoid secretion was evident 1 day after SE in the mice, preceding the development of spontaneous seizures (which can take weeks to develop). RU486 treatment blocked the SE associated elevation of glucocorticoid levels in pilocarpine-treated mice. RU486 treatment also mitigated the development of hippocampal pathologies induced by SE, reducing loss of hilar mossy cells and limiting pathological cell proliferation in the dentate hilus. Mossy cell loss and accumulation of ectopic hilar cells are positively correlated with epilepsy severity, suggesting that early treatment with glucocorticoid antagonists could have anti-epileptogenic effects. PMID- 27965625 TI - Editorial: Sound, Music, and Movement in Parkinson's Disease. PMID- 27965626 TI - High Prevalence of Gut Microbiota Colonization with Broad-Spectrum Cephalosporin Resistant Enterobacteriaceae in a Tunisian Intensive Care Unit. AB - Healthcare-associated infections due to cefotaxime-resistant (CTX-R) Enterobacteriaceae have become a major public health threat, especially in intensive care units (ICUs). Often acquired nosocomially, CTX-R Enterobacteriaceae can be introduced initially by patients at admission. This study aimed to determine the prevalence and genetic characteristics of CTX-R Enterobacteriaceae-intestinal carriage in ICU patients, to evaluate the rate of acquisition of these organisms during hospitalization, and to explore some of the associated risk factors for both carriage and acquisition. Between December 2014 and February 2015, the 63 patients admitted in the ICU of Charles Nicolle hospital were screened for rectal CTX-R Enterobacteriaceae colonization at admission and once weekly thereafter to identify acquisition. CTX-R Enterobacteriaceae fecal carriage rate was 20.63% (13/63) at admission. Among the 50 non-carriers, 35 were resampled during their hospitalization and the acquisition rate was 42.85% (15/35). Overall, 35 CTX-R Enterobacteriaceae isolates were collected from 28 patients (25 Klebsiella pneumoniae, seven Escherichia coli, and three Enterobacter cloacae strains). Seven patients were simultaneously colonized with two CTX-R Enterobacteriaceae isolates. CTX-M-15 was detected in most of the CTX-R Enterobacteriaceae isolates (30/35, 88.23%). Three strains co-produced CMY-4 and 22 strains were carbapenem-resistant and co produced a carbapenemase [OXA-48 (n = 13) or NDM-1 (n = 6)]. Molecular typing of K. pneumoniae strains, revealed eight Pulsed field gel electrophoresis (PFGE) patterns and four sequence types (ST) [ST101, ST147, ST429, and ST336]. However, E. coli isolates were genetically unrelated and belonged to A (n = 2), B1 (n = 2) and B2 (n = 3) phylogenetic groups and to ST131 (two strains), ST572 (two strains), ST615 (one strain) and ST617 (one strain). Five colonized patients were infected by CTX-R Enterobacteriaceae (four with the same strain identified from their rectal swab and one with a different strain). Whether imported or acquired during the stay in the ICU, colonization by CTX-R Enterobacteriaceae is a major risk factor for the occurrence of serious nosocomial infections. Their systematic screening in fecal carriage is mandatory to prevent the spread of these multidrug resistant bacteria. PMID- 27965627 TI - Bacteriophage WO Can Mediate Horizontal Gene Transfer in Endosymbiotic Wolbachia Genomes. AB - Phage-mediated horizontal gene transfer (HGT) is common in free-living bacteria, and many transferred genes can play a significant role in their new bacterial hosts. However, there are few reports concerning phage-mediated HGT in endosymbionts (obligate intracellular bacteria within animal or plant hosts), such as Wolbachia. The Wolbachia-infecting temperate phage WO can actively shift among Wolbachia genomes and has the potential to mediate HGT between Wolbachia strains. In the present study, we extend previous findings by validating that the phage WO can mediate transfer of non-phage genes. To do so, we utilized bioinformatic, phylogenetic, and molecular analyses based on all sequenced Wolbachia and phage WO genomes. Our results show that the phage WO can mediate HGT between Wolbachia strains, regardless of whether the transferred genes originate from Wolbachia or other unrelated bacteria. PMID- 27965629 TI - How to Sustainably Feed a Microbe: Strategies for Biological Production of Carbon Based Commodities with Renewable Electricity. AB - As interest and application of renewable energy grows, strategies are needed to align the asynchronous supply and demand. Microbial metabolisms are a potentially sustainable mechanism for transforming renewable electrical energy into biocommodities that are easily stored and transported. Acetogens and methanogens can reduce carbon dioxide to organic products including methane, acetic acid, and ethanol. The library of biocommodities is expanded when engineered metabolisms of acetogens are included. Typically, electrochemical systems are employed to integrate renewable energy sources with biological systems for production of carbon-based commodities. Within these systems, there are three prevailing mechanisms for delivering electrons to microorganisms for the conversion of carbon dioxide to reduce organic compounds: (1) electrons can be delivered to microorganisms via H2 produced separately in a electrolyzer, (2) H2 produced at a cathode can convey electrons to microorganisms supported on the cathode surface, and (3) a cathode can directly feed electrons to microorganisms. Each of these strategies has advantages and disadvantages that must be considered in designing full-scale processes. This review considers the evolving understanding of each of these approaches and the state of design for advancing these strategies toward viability. PMID- 27965628 TI - Evidence of Increased Antibiotic Resistance in Phylogenetically-Diverse Aeromonas Isolates from Semi-Intensive Fish Ponds Treated with Antibiotics. AB - The genus Aeromonas is ubiquitous in aquatic environments encompassing a broad range of fish and human pathogens. Aeromonas strains are known for their enhanced capacity to acquire and exchange antibiotic resistance genes and therefore, are frequently targeted as indicator bacteria for monitoring antimicrobial resistance in aquatic environments. This study evaluated temporal trends in Aeromonas diversity and antibiotic resistance in two adjacent semi-intensive aquaculture facilities to ascertain the effects of antibiotic treatment on antimicrobial resistance. In the first facility, sulfadiazine-trimethoprim was added prophylactically to fingerling stocks and water column-associated Aeromonas were monitored periodically over an 11-month fish fattening cycle to assess temporal dynamics in taxonomy and antibiotic resistance. In the second facility, Aeromonas were isolated from fish skin ulcers sampled over a 3-year period and from pond water samples to assess associations between pathogenic strains to those in the water column. A total of 1200 Aeromonas isolates were initially screened for sulfadiazine resistance and further screened against five additional antimicrobials. In both facilities, strong correlations were observed between sulfadiazine resistance and trimethoprim and tetracycline resistances, whereas correlations between sulfadiazine resistance and ceftriaxone, gentamicin, and chloramphenicol resistances were low. Multidrug resistant strains as well as sul1, tetA, and intI1 gene-harboring strains were significantly higher in profiles sampled during the fish cycle than those isolated prior to stocking and these genes were extremely abundant in the pathogenic strains. Five phylogenetically distinct Aeromonas clusters were identified using partial rpoD gene sequence analysis. Interestingly, prior to fingerling stocking the diversity of water column strains was high, and representatives from all five clusters were identified, including an A. salmonicida cluster that harbored all characterized fish skin ulcer samples. Subsequent to stocking, diversity was much lower and most water column isolates in both facilities segregated into an A. veronii associated cluster. This study demonstrated a strong correlation between aquaculture, Aeromonas diversity and antibiotic resistance. It provides strong evidence for linkage between prophylactic and systemic use of antibiotics in aquaculture and the propagation of antibiotic resistance. PMID- 27965631 TI - Long-Term Application of Bioorganic Fertilizers Improved Soil Biochemical Properties and Microbial Communities of an Apple Orchard Soil. AB - Soil biochemical properties and microbial communities are usually considered as important indicators of soil health because of their association with plant nutrition. In this study, we investigated the impact of long-term application of bioorganic fertilizer (BOF) on soil biochemical properties and microbial communities in the apple orchard soil of the Loess Plateau. The experiment included three treatments: (1) control without fertilization (CK); (2) chemical fertilizer application (CF); and (3) bioorganic fertilizer application (BOF). The high throughput sequencing was used to examine the bacterial and fungal communities in apple orchard soil. The results showed that the BOF treatment significantly increased the apple yield during the experimental time (2009-2015). The application of BOF significantly increased the activities of catalase and invertase compared to those in CK and CF treatments. The high throughput sequencing data showed that the application of BOF changed the microbial community composition of all soil depths considered (0-20 cm, 20-40 cm, and 40-60 cm), e.g., the relative abundance of bio-control bacteria (Xanthomonadales, Lysobacter, Pseudomonas, and Bacillus), Proteobacteria, Bacteroidetes, Ohtaekwangia, Ilyonectria, and Lecanicillium was increased while that of Acidobacteria, Chloroflexi, Gp4, Gp6 and Sphaerobacter was decreased. The increase in apple yield after the application of BOF might be due to increase in organic matter, total nitrogen and catalase and invertase activities of soil and change in the bacterial community composition by enriching Bacillus, Pseudomonas, Lysobacter, and Ohtaekwangia. These results further enhance the understanding on how BOFs alter soil microbial community composition to stimulate soil productivity. PMID- 27965632 TI - Primer Sets Developed for Functional Genes Reveal Shifts in Functionality of Fungal Community in Soils. AB - Phylogenetic diversity of soil microbes is a hot topic at the moment. However, the molecular tools for the assessment of functional diversity in the fungal community are less developed than tools based on genes encoding the ribosomal operon. Here 20 sets of primers targeting genes involved mainly in carbon cycling were designed and/or validated and the functioning of soil fungal communities along a chronosequence of land abandonment from agriculture was evaluated using them. We hypothesized that changes in fungal community structure during secondary succession would lead to difference in the types of genes present in soils and that these changes would be directional. We expected an increase in genes involved in degradation of recalcitrant organic matter in time since agriculture. Out of the investigated genes, the richness of the genes related to carbon cycling was significantly higher in fields abandoned for longer time. The composition of six of the genes analyzed revealed significant differences between fields abandoned for shorter and longer time. However, all genes revealed significant variance over the fields studied, and this could be related to other parameters than the time since agriculture such as pH, organic matter, and the amount of available nitrogen. Contrary to our initial hypothesis, the genes significantly different between fields were not related to the decomposition of more recalcitrant matter but rather involved in degradation of cellulose and hemicellulose. PMID- 27965630 TI - Evaluation of Machine Learning and Rules-Based Approaches for Predicting Antimicrobial Resistance Profiles in Gram-negative Bacilli from Whole Genome Sequence Data. AB - The time-to-result for culture-based microorganism recovery and phenotypic antimicrobial susceptibility testing necessitates initial use of empiric (frequently broad-spectrum) antimicrobial therapy. If the empiric therapy is not optimal, this can lead to adverse patient outcomes and contribute to increasing antibiotic resistance in pathogens. New, more rapid technologies are emerging to meet this need. Many of these are based on identifying resistance genes, rather than directly assaying resistance phenotypes, and thus require interpretation to translate the genotype into treatment recommendations. These interpretations, like other parts of clinical diagnostic workflows, are likely to be increasingly automated in the future. We set out to evaluate the two major approaches that could be amenable to automation pipelines: rules-based methods and machine learning methods. The rules-based algorithm makes predictions based upon current, curated knowledge of Enterobacteriaceae resistance genes. The machine-learning algorithm predicts resistance and susceptibility based on a model built from a training set of variably resistant isolates. As our test set, we used whole genome sequence data from 78 clinical Enterobacteriaceae isolates, previously identified to represent a variety of phenotypes, from fully-susceptible to pan resistant strains for the antibiotics tested. We tested three antibiotic resistance determinant databases for their utility in identifying the complete resistome for each isolate. The predictions of the rules-based and machine learning algorithms for these isolates were compared to results of phenotype based diagnostics. The rules based and machine-learning predictions achieved agreement with standard-of-care phenotypic diagnostics of 89.0 and 90.3%, respectively, across twelve antibiotic agents from six major antibiotic classes. Several sources of disagreement between the algorithms were identified. Novel variants of known resistance factors and incomplete genome assembly confounded the rules-based algorithm, resulting in predictions based on gene family, rather than on knowledge of the specific variant found. Low-frequency resistance caused errors in the machine-learning algorithm because those genes were not seen or seen infrequently in the test set. We also identified an example of variability in the phenotype-based results that led to disagreement with both genotype-based methods. Genotype-based antimicrobial susceptibility testing shows great promise as a diagnostic tool, and we outline specific research goals to further refine this methodology. PMID- 27965634 TI - Structural Elucidation and Molecular Docking of a Novel Antibiotic Compound from Cyanobacterium Nostoc sp. MGL001. AB - Cyanobacteria are rich source of array of bioactive compounds. The present study reports a novel antibacterial bioactive compound purified from cyanobacterium Nostoc sp. MGL001 using various chromatographic techniques viz. thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). Further characterization was done using electrospray ionization mass spectroscopy (ESIMS) and nuclear magnetic resonance (NMR) and predicted structure of bioactive compound was 9-Ethyliminomethyl-12-(morpholin - 4 - ylmethoxy) -5, 8, 13, 16 tetraaza-hexacene - 2, 3 dicarboxylic acid (EMTAHDCA). Structure of EMTAHDCA clearly indicated that it is a novel compound that was not reported in literature or natural product database. The compound exhibited growth inhibiting effects mainly against the gram negative bacterial strains and produced maximum zone of inhibition at 150 MUg/mL concentration. The compound was evaluated through in silico studies for its ability to bind 30S ribosomal fragment (PDB ID: 1YRJ, 1MWL, 1J7T, and 1LC4) and OmpF porin protein (4GCP, 4GCQ, and 4GCS) which are the common targets of various antibiotic drugs. Comparative molecular docking study revealed that EMTAHDCA has strong binding affinity for these selected targets in comparison to a number of most commonly used antibiotics. The ability of EMTAHDCA to bind the active sites on the proteins and 30S ribosomal fragments where the antibiotic drugs generally bind indicated that it is functionally similar to the commercially available drugs. PMID- 27965633 TI - Initiation of Chromosomal Replication in Predatory Bacterium Bdellovibrio bacteriovorus. AB - Bdellovibrio bacteriovorus is a small Gram-negative predatory bacterium that attacks other Gram-negative bacteria, including many animal, human, and plant pathogens. This bacterium exhibits a peculiar biphasic life cycle during which two different types of cells are produced: non-replicating highly motile cells (the free-living phase) and replicating cells (the intracellular-growth phase). The process of chromosomal replication in B. bacteriovorus must therefore be temporally and spatially regulated to ensure that it is coordinated with cell differentiation and cell cycle progression. Recently, B. bacteriovorus has received considerable research interest due to its intriguing life cycle and great potential as a prospective antimicrobial agent. Although, we know that chromosomal replication in bacteria is mainly regulated at the initiation step, no data exists about this process in B. bacteriovorus. We report the first characterization of key elements of initiation of chromosomal replication - DnaA protein and oriC region from the predatory bacterium, B. bacteriovorus. In vitro studies using different approaches demonstrate that the B. bacteriovorus oriC (BdoriC) is specifically bound and unwound by the DnaA protein. Sequence comparison of the DnaA-binding sites enabled us to propose a consensus sequence for the B. bacteriovorus DnaA box [5'-NN(A/T)TCCACA-3']. Surprisingly, in vitro analysis revealed that BdoriC is also bound and unwound by the host DnaA proteins (relatively distantly related from B. bacteriovorus). We compared the architecture of the DnaA-oriC complexes (orisomes) in homologous (oriC and DnaA from B. bacteriovorus) and heterologous (BdoriC and DnaA from prey, Escherichia coli or Pseudomonas aeruginosa) systems. This work provides important new entry points toward improving our understanding of the initiation of chromosomal replication in this predatory bacterium. PMID- 27965635 TI - Photoinactivation Using Visible Light Plus Water-Filtered Infrared-A (vis+wIRA) and Chlorine e6 (Ce6) Eradicates Planktonic Periodontal Pathogens and Subgingival Biofilms. AB - Alternative treatment methods for pathogens and microbial biofilms are required due to the widespread rise in antibiotic resistance. Antimicrobial photodynamic therapy (aPDT) has recently gained attention as a novel method to eradicate pathogens. The aim of this study was to evaluate the antimicrobial effects of a novel aPDT method using visible light (vis) and water infiltrated infrared A (wIRA) in combination with chlorine e6 (Ce6) against different periodontal pathogens in planktonic form and within in situ subgingival oral biofilms. Eight different periodontal pathogens were exposed to aPDT using vis+wIRA and 100 MUg/ml Ce6 in planktonic culture. Additionally, pooled subgingival dental biofilm was also treated by aPDT and the number of viable cells determined as colony forming units (CFU). Live/dead staining was used in combination with confocal laser scanning microscopy to visualize and quantify antimicrobial effects within the biofilm samples. Untreated negative controls as well as 0.2% chlorhexidine treated positive controls were used. All eight tested periodontal pathogens including Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Eikenella corrodens, Actinomyces odontolyticus, Fusobacterium nucleatum, Parvimonas micra, Slackia exigua, and Atopobium rimae and the aPDT-treated subgingival biofilm were eliminated over the ranges of 3.43-8.34 and 3.91-4.28 log10 CFU in the log10 scale, respectively. Thus, aPDT showed bactericidal effects on the representative pathogens as well as on the in situ subgingival biofilm. The live/dead staining also revealed a significant reduction (33.45%) of active cells within the aPDT-treated subgingival biofilm. Taking the favorable tissue healing effects of vis+wIRA into consideration, the significant antimicrobial effects revealed in this study highlight the potential of aPDT using this light source in combination with Ce6 as an adjunctive method to treat periodontitis as well as periimplantitis. The present results encourage also the evaluation of this method for the treatment of caries and apical periodontitis. PMID- 27965636 TI - Multiple and Variable NHEJ-Like Genes Are Involved in Resistance to DNA Damage in Streptomyces ambofaciens. AB - Non-homologous end-joining (NHEJ) is a double strand break (DSB) repair pathway which does not require any homologous template and can ligate two DNA ends together. The basic bacterial NHEJ machinery involves two partners: the Ku protein, a DNA end binding protein for DSB recognition and the multifunctional LigD protein composed a ligase, a nuclease and a polymerase domain, for end processing and ligation of the broken ends. In silico analyses performed in the 38 sequenced genomes of Streptomyces species revealed the existence of a large panel of NHEJ-like genes. Indeed, ku genes or ligD domain homologues are scattered throughout the genome in multiple copies and can be distinguished in two categories: the "core" NHEJ gene set constituted of conserved loci and the "variable" NHEJ gene set constituted of NHEJ-like genes present in only a part of the species. In Streptomyces ambofaciens ATCC23877, not only the deletion of "core" genes but also that of "variable" genes led to an increased sensitivity to DNA damage induced by electron beam irradiation. Multiple mutants of ku, ligase or polymerase encoding genes showed an aggravated phenotype compared to single mutants. Biochemical assays revealed the ability of Ku-like proteins to protect and to stimulate ligation of DNA ends. RT-qPCR and GFP fusion experiments suggested that ku-like genes show a growth phase dependent expression profile consistent with their involvement in DNA repair during spores formation and/or germination. PMID- 27965638 TI - Functional Characterization of Triclosan-Resistant Enoyl-acyl-carrier Protein Reductase (FabV) in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is extremely resistant to triclosan. Previous studies have shown that P. aeruginosa encodes a triclosan-resistant enoyl-acyl-carrier protein reductase (ENR), FabV, and that deletion of fabV causes P. aeruginosa to be extremely sensitive to triclosan. In this report, we complemented a P. aeruginosa fabV deletion strain with several triclosan-resistant ENR encoding genes, including Vibrio cholerae fabV, Bacillus subtilis fabL and Enterococcus faecalis fabK. All complemented strains restored triclosan resistance to the level of the wild-type strain, which confirmed that triclosan-resistant ENR allows P. aeruginosa to be extremely resistant to triclosan. Moreover, fabV exhibits pleiotropic effects. Deletion of fabV led P. aeruginosa to show attenuated swarming motility, decreased rhamnolipid, pyoverdine and acyl-homoserine lactones (AHLs) production. Complementation of the fabV mutant with any one ENR encoding gene could restore these features to some extent, in comparison with the wild type strain. Furthermore, we found that addition of exogenous AHLs could restore the fabV mutant strain to swarm on semisolid plates and to produce more virulence factors than the fabV mutant strain. These findings indicate that deletion of fabV reduced the activity of ENR in P. aeruginosa, decreased fatty acid synthesis, and subsequently depressed the production of AHLs and other virulence factors, which finally may led to a reduction in the pathogenicity of P. aeruginosa. Therefore, fabV should be an ideal target for the control of P. aeruginosa infectivity. PMID- 27965637 TI - Genome Sequencing of Sulfolobus sp. A20 from Costa Rica and Comparative Analyses of the Putative Pathways of Carbon, Nitrogen, and Sulfur Metabolism in Various Sulfolobus Strains. AB - The genome of Sulfolobus sp. A20 isolated from a hot spring in Costa Rica was sequenced. This circular genome of the strain is 2,688,317 bp in size and 34.8% in G+C content, and contains 2591 open reading frames (ORFs). Strain A20 shares ~95.6% identity at the 16S rRNA gene sequence level and <30% DNA-DNA hybridization (DDH) values with the most closely related known Sulfolobus species (i.e., Sulfolobus islandicus and Sulfolobus solfataricus), suggesting that it represents a novel Sulfolobus species. Comparison of the genome of strain A20 with those of the type strains of S. solfataricus, Sulfolobus acidocaldarius, S. islandicus, and Sulfolobus tokodaii, which were isolated from geographically separated areas, identified 1801 genes conserved among all Sulfolobus species analyzed (core genes). Comparative genome analyses show that central carbon metabolism in Sulfolobus is highly conserved, and enzymes involved in the Entner Doudoroff pathway, the tricarboxylic acid cycle and the CO2 fixation pathways are predominantly encoded by the core genes. All Sulfolobus species encode genes required for the conversion of ammonium into glutamate/glutamine. Some Sulfolobus strains have gained the ability to utilize additional nitrogen source such as nitrate (i.e., S. islandicus strain REY15A, LAL14/1, M14.25, and M16.27) or urea (i.e., S. islandicus HEV10/4, S. tokodaii strain7, and S. metallicus DSM 6482). The strategies for sulfur metabolism are most diverse and least understood. S. tokodaii encodes sulfur oxygenase/reductase (SOR), whereas both S. islandicus and S. solfataricus contain genes for sulfur reductase (SRE). However, neither SOR nor SRE genes exist in the genome of strain A20, raising the possibility that an unknown pathway for the utilization of elemental sulfur may be present in the strain. The ability of Sulfolobus to utilize nitrate or sulfur is encoded by a gene cluster flanked by IS elements or their remnants. These clusters appear to have become fixed at a specific genomic site in some strains and lost in other strains during the course of evolution. The versatility in nitrogen and sulfur metabolism may represent adaptation of Sulfolobus to thriving in different habitats. PMID- 27965640 TI - RNAseq Analysis of Endornavirus-Infected vs. Endornavirus-Free Common Bean (Phaseolus vulgaris) Cultivar Black Turtle Soup. PMID- 27965639 TI - Antibacterial Compounds-Macrolactin Alters the Soil Bacterial Community and Abundance of the Gene Encoding PKS. AB - Macrolactin produced by many soil microbes has been shown to be an efficient antibacterial agent against many bacterial pathogens. However, studies examining the effect of macrolactin on both the soil bacterial community and the intrinsic bacterial species that harbor genes responsible for the production of this antibiotic have not been conducted so far. In this study, a mixture of macrolactin was isolated from the liquid culture of Bacillus amyloliquefaciens NJN-6, and applied to the soil once a week for four weeks. 16S rRNA Illumina MiSeq sequencing showed that continuous application of macrolactin reduced the alpha-diversity of the soil bacterial community and thereby changed the relative abundance of microbes at both the phylum and genus level. The relative abundance of Proteobacteria and Firmicutes was significantly increased along with a significant decrease in the relative abundance of Acidobacteria. However, the application of macrolactins had an insignificant effect on the total numbers of bacteria. Further, the native gene responsible for the production of macrolactin, the gene encoding polyketide synthase was reduced in copy number after the application of macrolactin. The results of this study suggested that a bactericide from a microbial source could decrease the diversity of the soil bacterial community and change the bacterial community structure. Moreover, the populations of the intrinsic bacterial species which harbor genes responsible for macrolactin production were inhibited when the external source antibiotic was applied. PMID- 27965641 TI - The Current Status of the Soybean-Soybean Mosaic Virus (SMV) Pathosystem. AB - Soybean mosaic virus (SMV) is one of the most devastating pathogens that cost huge economic losses in soybean production worldwide. Due to the duplicated genome, clustered and highly homologous nature of R genes, as well as recalcitrant to transformation, soybean disease resistance studies is largely lagging compared with other diploid crops. In this review, we focus on the major advances that have been made in identifying both the virulence/avirulence factors of SMV and mapping of SMV resistant genes in soybean. In addition, we review the progress in dissecting the SMV resistant signaling pathways in soybean, with a special focus on the studies using virus-induced gene silencing. The soybean genome has been fully sequenced, and the increasingly saturated SNP markers have been identified. With these resources available together with the newly developed genome editing tools, and more efficient soybean transformation system, cloning SMV resistant genes, and ultimately generating cultivars with a broader spectrum resistance to SMV are becoming more realistic than ever. PMID- 27965643 TI - The Minor Flagellin of Campylobacter jejuni (FlaB) Confers Defensive Properties against Bacteriophage Infection. AB - A screen of bacteriophages infecting a panel of Campylobacter jejuni PT14 gene knock-out mutants identified a role for the minor flagellin encoded by the flaB gene, in the defense of the host against CP8unalikevirus bacteriophage CP_F1 infection. Inactivation of the flaB gene resulted in an increase in the susceptibility of PT14 cultures to infection by CP_F1 and an increase in bacteriophage yields. Infection of wild type PT14 with CP_F1 produces turbid plaques in bacterial lawns, from which 78% of the resistant isolates recovered exhibit either attenuation or complete loss of motility. CP_F1 produces clear plaques on the flaB mutant with no regrowth in the lysis zones. Complementation of the mutant restored overgrowth and the development of resistance at the expense of motility. Further analyses revealed an increase in bacteriophage adsorption constant of nearly 2-fold and burst-size 3-fold, relative to the wild type. Motility analysis showed no major reduction in swarming motility in the flaB mutant. Thus, we propose a new role for FlaB in the defense of campylobacters against bacteriophage infection. PMID- 27965642 TI - Detection of Inter-Lineage Natural Recombination in Avian Paramyxovirus Serotype 1 Using Simplified Deep Sequencing Platform. AB - Newcastle disease virus (NDV) is a prototype member of avian paramyxovirus serotype 1 (APMV-1), which causes severe and contagious disease in the commercial poultry and wild birds. Despite extensive vaccination programs and other control measures, the disease remains endemic around the globe especially in Asia, Africa, and the Middle East. Being a single serotype, genotype II based vaccines remained most acceptable means of immunization. However, the evidence is emerging on failures of vaccines mainly due to evolving nature of the virus and higher genetic gaps between vaccine and field strains of APMV-1. Most of the epidemiological and genetic characterizations of APMVs are based on conventional methods, which are prone to mask the diverse population of viruses in complex samples. In this study, we report the application of a simple, robust, and less resource-demanding methodology for the whole genome sequencing of NDV, using next generation sequencing (NGS) on the Illumina MiSeq platform. Using this platform, we sequenced full genomes of five virulent Malaysian NDV strains collected during 2004-2013. All isolates clustered within highly prevalent lineage 5 (specifically in lineage 5a); however, a significantly greater genetic divergence was observed in isolates collected from 2004 to 2011. Interestingly, genetic characterization of one isolate collected in 2013 (IBS025/13) shown natural recombination between lineage 2 and lineage 5. In the event of recombination, the isolate (IBS025/13) carried nucleocapsid protein consist of 55-1801 nucleotides (nts) and near complete phosphoprotein (1804-3254 nts) genes of lineage 2 whereas surface glycoproteins (fusion, hemagglutinin-neuraminidase) and large polymerase of lineage 5. Additionally, the recombinant virus has a genome size of 15,186 nts which is characteristics for the old genotypes I-IV isolated from 1930 to 1960. Taken together, we report the occurrence of a natural recombination in circulating strains of NDV in commercial poultry using NGS methodology. These findings will not only highlight the potential of RNA viruses to evolve but also to consider the application of NGS in revealing the genetic diversity of these viruses in clinical materials. Factors that drive these evolutionary events and subsequent impact of these divergences on clinical outcome of the disease warrant future investigations. PMID- 27965644 TI - Molecular Detection and Characterization of Zoonotic and Veterinary Pathogens in Ticks from Northeastern China. AB - Tick-borne diseases are considered as emerging infectious diseases in humans and animals in China. In this study, Ixodes persulcatus (n = 1699), Haemaphysalis concinna (n = 412), Haemaphysalis longicornis (n = 390), Dermacentor nuttalli (n = 253), and Dermacentor silvarum (n = 204) ticks were collected by flagging from northeastern China, and detected for infection with Anaplasma, Ehrlichia, Babesia, and Hepatozoon spp. by using nested polymerase chain reaction assays and sequencing analysis. Anaplasma phagocytophilum was detected in all tick species, i.e., I. persulcatus (9.4%), H. longicornis (1.9%), H. concinna (6.5%), D. nuttalli (1.7%), and D. silvarum (2.3%); Anaplasma bovis was detected in H. longicornis (0.3%) and H. concinna (0.2%); Ehrlichia muris was detected in I. persulcatus (2.5%) and H. concinna (0.2%); Candidatus Neoehrlichia mikurensis was only detected in I. persulcatus (0.4%). The Ehrlichia variant (GenBank access number KU921424), closely related to Ehrlichia ewingii, was found in H. longicornis (0.8%) and H. concinna (0.2%). I. persulcatus was infected with Babesia venatorum (1.2%), Babesia microti (0.6%), and Babesia divergens (0.6%). Additionally, four Babesia sequence variants (GenBank access numbers 862303 862306) were detected in I. persulcatus, H. longicornis, and H. concinna, which belonged to the clusters formed by the parasites of dogs, sheep, and cattle (B. gibsoni, B. motasi, and B. crassa). Two Hepatozoon spp. (GenBank access numbers KX016028 and KX016029) associated with hepatozoonosis in Japanese martens were found in the collected ticks (0.1-3.1%). These findings showed the genetic variability of Anaplasma, Ehrlichia, Babesia, and Hepatozoon spp. circulating in ticks in northeastern China, highlighting the necessity for further research of these tick-associated pathogens and their role in human and animal diseases. PMID- 27965646 TI - Synthesis of Sphingolipids Impacts Survival of Porphyromonas gingivalis and the Presentation of Surface Polysaccharides. AB - Bacteria alter the biophysical properties of their membrane lipids in response to environmental cues, such as shifts in pH or temperature. In essence, lipid composition determines membrane structure, which in turn influences many basic functions, such as transport, secretion, and signaling. Like other members of the phylum Bacteroidetes, the oral anaerobe Porphyromonas gingivalis possesses the ability to synthesize a variety of novel membrane lipids, including species of dihydroceramides that are distinct, yet similar in structure to sphingolipids produced by the human host. The role of dihydroceramides in the physiology and pathogenic potential of the human microbiota is only beginning to be explored; yet there is increasing data indicating that these lipids play a role in human diseases, such as periodontitis and multiple sclerosis. Here, we report on the identification of a gene (PG1780) in the chromosome of P. gingivalis strain W83 encoding a putative serine palmitoyltransferase, the enzyme that catalyzes the first step in sphingolipid biosynthesis. While we were able to detect dihydroceramides in whole lipid extracts of P. gingivalis cells as well as crude preparations of outer membrane vesicles, sphingolipids were absent in the PG1780 mutant strain. Moreover, we show that the synthesis of sphingolipids plays an essential role in the long-term survival of the organism as well as its resistance to oxidative stress. Further, a PG1780 mutant displayed much lower activity of cell-associated arginine and lysine gingipains, yet slightly higher activity in the corresponding culture supernates, which we hypothesize is due to altered membrane properties and anchoring of these proteases to the cell surface. In addition, we determined that sphingolipid production is critical to the presentation of surface polysaccharides, with the mutant strain displaying less K antigen capsule and more anionic polysaccharide (APS). Overall, we have discovered that, in addition to their role in pathogenicity, the synthesis of sphingolipids is critical to the cellular homeostasis and persistence of this important dental pathogen. PMID- 27965645 TI - Glucose Induces ECF Sigma Factor Genes, sigX and sigM, Independent of Cognate Anti-sigma Factors through Acetylation of CshA in Bacillus subtilis. AB - Extracytoplasmic function (ECF) sigma factors have roles related to cell envelope and/or cell membrane functions, in addition to other cellular functions. Without cell-surface stresses, ECF sigma factors are sequestered by the cognate anti sigma factor, leading to inactivation and the resultant repression of regulons due to the inhibition of transcription of their own genes. Bacillus subtilis has seven ECF sigma factors including sigmaX and sigmaM that transcribe their own structural genes. Here, we report that glucose addition to the medium induced sigX and sigM transcription independent of their anti-sigma factors. This induction was dependent on an intracellular acetyl-CoA pool. Transposon mutagenesis searching for the mutants showing no induction of sigX and sigM revealed that the cshA gene encoding DEAD-box RNA helicase is required for gene induction. Global analysis of the acetylome in B. subtilis showed CshA has two acetylated lysine residues. We found that in a cshA mutant with acetylation abolishing K to R exchange mutations, glucose induction of sigX and sigM was abolished and that glucose addition stimulated acetylation of CshA in the wild type strain. Thus, we present a model wherein glucose addition results in a larger acetyl-CoA pool, probably leading to increased levels of acetylated CshA. CshA is known to associate with RNA polymerase (RNAP), and thus RNAP with acetylated CshA could stimulate the autoregulation of sigX and sigM. This is a unique model showing a functional link between nutritional signals and the basal transcription machinery. PMID- 27965647 TI - Microbial Communities of Lycaenid Butterflies Do Not Correlate with Larval Diet. AB - Herbivores possess many counteradaptations to plant defenses, and a growing body of research describes the role of symbiotic gut bacteria in mediating herbivorous diets among insects. However, persistent bacterial symbioses have not been found in Lepidoptera, despite the fact that perhaps 99% of the species in this order are herbivorous. We surveyed bacterial communities in the guts of larvae from 31 species of lycaenid butterflies whose caterpillars had diets ranging from obligate carnivory to strict herbivory. Contrary to our expectations, we found that the bacterial communities of carnivorous and herbivorous caterpillars do not differ in richness, diversity, or composition. Many of the observed bacterial genera are commonly found in soil and plant surfaces, and we detected known homopteran endosymbionts in the guts of homopterophagous species, suggesting that larvae acquire gut bacteria from their food and environment. These results indicate that lycaenid butterflies do not rely on specific bacterial symbioses to mediate their diverse diets, and provide further evidence of taxonomically depauperate bacterial communities among Lepidoptera. PMID- 27965648 TI - Surveillance of Diarrheagenic Escherichia coli Strains Isolated from Diarrhea Cases from Children, Adults and Elderly at Northwest of Mexico. AB - Diarrheagenic Escherichia coli (DEC) strains are a main cause of gastrointestinal disease in developing countries. In this study we report the epidemiologic surveillance in a 4-year period (January 2011 to December 2014) of DEC strains causing acute diarrhea throughout the Sinaloa State, Mexico. DEC strains were isolated from outpatients of all ages with acute diarrhea (N = 1,037). Specific DEC pathotypes were identified by PCR-amplification of genes encoding virulence factors. The adhesion phenotype and antibiotic resistance were also investigated. DEC strains were detected in 23.3% (242/1037) of cases. The most frequently DEC strain isolated was EAEC [(12.2%), 126/242] followed by EPEC [(5.1%), 53/242], ETEC [(4.3%), 43/242] DAEC [(1.4%), 15/242], STEC [(0.3%), 3/242], and EIEC [(0.2%), 2/242]. EHEC strains were not detected. Overall DEC strains were more prevalent in children <=2 years of age with EPEC strains the most common of DEC pathotypes. While ~65% of EAEC strains were classified as typical variant based on the aggregative adherence to in vitro cultures of HEp-2 cells, a high proportion of EPEC strains was classified as atypical strains. EAEC, EPEC, ETEC, and DAEC strains were distributed in the north, central and south regions of Sinaloa state. Among all DEC strains, >90% were resistant to at least one commonly prescribed antibiotic. Strains were commonly resistant to first-line antibiotics such as tetracycline, ampicillin, and sulfamethoxazole-trimethoprim. Furthermore, more than 80% of DEC isolates were multi-drug resistant and EPEC and DAEC were the categories with major proportion of this feature. In conclusion, in nearly one out of four cases of acute diarrhea in Northwestern Mexico a multi drug resistant DEC strain was isolated, in these cases EAEC was the most prevalent (52%) pathotype. PMID- 27965649 TI - The 12 Gastrointestinal Pathogens Spectrum of Acute Infectious Diarrhea in a Sentinel Hospital, Shenzhen, China. AB - Acute infectious gastroenteritis is one of the most common diseases among all ages, particularly in developing countries. The pathogen spectrum may differ among different regions and seasons. To investigate the etiology of acute diarrhea in Shenzhen, a prospective study was conducted from August 2014 to September 2015. Stools from 412 patients with diarrhea (286 of whom were adults) including the general epidemiological information of the patients were collected. The 19 pathogens were detected by conventional culture method or multiplex PCR assay, which included five viruses (rotavirus, adenovirus, sapovirus, norovirus, and astrovirus), 11 bacterial pathogens (Salmonella, Campylobacter jejuni, Shigella, Listeria monocytogenes, Vibrio parahaemolyticus, Vibrio cholera, Enterohemorrhagic (EHEC), enteropathogenic (EPEC), enteroinvasive (EIEC), enterotoxigenic (ETEC); and enteroaggregative Escherichia coli (EAEC)) and three parasites (Entamoeba histolytica, Giardia lamblia, and Cryptosporidium parvum). A potential pathogen and coinfection was found in 41.5 and 7.0% of cases, respectively. The bacterial infection was the dominant cause of diarrhea (32.3%), and the three most frequently identified organisms were Salmonella (12.1%), ETEC (8.0%), and Campylobacter jejuni (4.9%). Salmonella enteritidis was the leading serotype of Salmonella sp. Norovirus (8.3%) and sapovirus (2.2%) were the most common viral pathogens, followed by adenovirus (1.5%) and rotavirus (1.2%). No EHEC, L. monocytogenes, V. cholera, Shigella, and parasites were found. The single most important causes of diarrhea were Salmonella spp. and Campylobacter jejuni, which points toward the need for testing and surveillance for these pathogens in this region. PMID- 27965650 TI - An Integrative Genomic Island Affects the Adaptations of the Piezophilic Hyperthermophilic Archaeon Pyrococcus yayanosii to High Temperature and High Hydrostatic Pressure. AB - Deep-sea hydrothermal vent environments are characterized by high hydrostatic pressure and sharp temperature and chemical gradients. Horizontal gene transfer is thought to play an important role in the microbial adaptation to such an extreme environment. In this study, a 21.4-kb DNA fragment was identified as a genomic island, designated PYG1, in the genomic sequence of the piezophilic hyperthermophile Pyrococcus yayanosii. According to the sequence alignment and functional annotation, the genes in PYG1 could tentatively be divided into five modules, with functions related to mobility, DNA repair, metabolic processes and the toxin-antitoxin system. Integrase can mediate the site-specific integration and excision of PYG1 in the chromosome of P. yayanosii A1. Gene replacement of PYG1 with a SimR cassette was successful. The growth of the mutant strain DeltaPYG1 was compared with its parent strain P. yayanosii A2 under various stress conditions, including different pH, salinity, temperature, and hydrostatic pressure. The DeltaPYG1 mutant strain showed reduced growth when grown at 100 degrees C, while the biomass of DeltaPYG1 increased significantly when cultured at 80 MPa. Differential expression of the genes in module III of PYG1 was observed under different temperature and pressure conditions. This study demonstrates the first example of an archaeal integrative genomic island that could affect the adaptation of the hyperthermophilic piezophile P. yayanosii to high temperature and high hydrostatic pressure. PMID- 27965651 TI - Interaction between Nitrogen and Phosphate Stress Responses in Sinorhizobium meliloti. AB - Bacteria have developed various stress response pathways to improve their assimilation and allocation of limited nutrients, such as nitrogen and phosphate. While both the nitrogen stress response (NSR) and phosphate stress response (PSR) have been studied individually, there are few experiments reported that characterize effects of multiple stresses on one or more pathways in Sinorhizobium meliloti, a facultatively symbiotic, nitrogen-fixing bacteria. The PII proteins, GlnB and GlnK, regulate the NSR activity, but analysis of global transcription changes in a PII deficient mutant suggest that the S. meliloti PII proteins may also regulate the PSR. PII double deletion mutants grow very slowly and pseudoreversion of the slow growth phenotype is common. To understand this phenomenon better, transposon mutants were isolated that had a faster growing phenotype. One mutation was in phoB, the response regulator for a two component regulatory system that is important in the PSR. phoB::Tn5 mutants had different phenotypes in the wild type compared to a PII deficient background. This led to the hypothesis that phosphate stress affects the NSR and conversely, that nitrogen stress affects the PSR. Our results show that phosphate availability affects glutamine synthetase activity and expression, which are often used as indicators of NSR activity, but that nitrogen availability did not affect alkaline phosphatase activity and expression, which are indicators of PSR activity. We conclude that the NSR is co-regulated by nitrogen and phosphate, whereas the PSR does not appear to be co-regulated by nitrogen in addition to its known phosphate regulation. PMID- 27965652 TI - Identification and Characterization of Novel Compounds Blocking Shiga Toxin Expression in Escherichia coli O157:H7. AB - Infections caused by Shiga toxin (Stx)-producing E. coli strains constitute a health problem, as they are problematic to treat. Stx production is a key virulence factor associated with the pathogenicity of enterohaemorrhagic E. coli (EHEC) and can result in the development of haemolytic uremic syndrome in infected patients. The genes encoding Stx are located on temperate lysogenic phages integrated into the bacterial chromosome and expression of the toxin is generally coupled to phage induction through the SOS response. We aimed to find new compounds capable of blocking expression of Stx type 2 (Stx2) as this subtype of Stx is more strongly associated with human disease. High-throughput screening of a small-molecule library identified a lead compound that reduced Stx2 expression in a dose-dependent manner. We show that the optimized compound interferes with the SOS response by directly affecting the activity and oligomerization of RecA, thus limiting phage activation and Stx2 expression. Our work suggests that RecA is highly susceptible to inhibition and that targeting this protein is a viable approach to limiting production of Stx2 by EHEC. This type of approach has the potential to limit production and transfer of other phage induced and transduced determinants. PMID- 27965653 TI - ESBL-Producing Escherichia coli from Cows Suffering Mastitis in China Contain Clinical Class 1 Integrons with CTX-M Linked to ISCR1. AB - The prevalence of pathogenic multi-drug resistant (MDR) extended-spectrum beta lactamase (ESBL)-producing Escherichia coli is rapidly increasing, becoming a global concern. In a veterinary context, ESBL-producing E. coli are mostly reported in poultry and pigs. Here, we report on the prevalence and characterize ESBL-producing E. coli isolated from diverse dairy farms in China. Overall, 36 (23.53%) out of 153 E. coli isolates from mastitic milk samples (n = 1252) were confirmed as ESBL-producers by double-disc synergy testing and PCR. Nucleotide analysis of PCR amplicons revealed that blaCTX-M was the predominant ESBL gene detected in 28 (77.78%) isolates, with blaCTX-M-15 being the major (78.57%) allele encoding for ESBLs. Also, 20 (55.56%) and 6 (16.67%) of the ESBL isolates were carrying blaTEM and blaSHV genes, respectively, in singlet or in combination. The majority of these isolates belonged to phylo-group A (69.44%) and D (16.67%). Strikingly, all these isolates were found to be MDR showing high resistance to cephalosporins including the fourth generation cefepime and common non beta-lactams. Additionally, class 1 integrons (intI1) were found in 30 (83.33%) isolates. Analysis of the class 1 integrons variable regions indicated that they were carrying up to five different gene cassettes conferring resistance to various drugs with a predominant combination of dfrA17-aadA5 genes in tandem, conferring resistance to aminoglycosides and trimethoprim. However, no ESBL encoding genes were found in the cassettes. Interestingly, 22 (66.11%) of the ESBL isolates were also carrying insertion sequence common region 1 (ISCR1) which was found to be associated with most of the CTX-M genes. Altogether, the current study reports on the high prevalence of ESBL-positive E. coli, particularly CTX-M 15, carrying clinical class 1 integrons and ISCR1 elements are likely indicative of their rapid and wider dissemination, posing threats to veterinary and public health. To the best of our knowledge, this is the first comprehensive study to report on the alarming high occurrence of ESBL-producing E. coli from mastitic cows in China. PMID- 27965655 TI - Repression of Rgg But Not Upregulation of LacD.1 in emm1-type covS Mutant Mediates the SpeB Repression in Group A Streptococcus. AB - CovR/CovS is an important two-component regulatory system in human pathogen group A Streptococcus (GAS). Epidemiological studies have shown that inactivation of the sensor kinase CovS is correlated with invasive clinical manifestations. The phosphorylation level of response regulator CovR decreases dramatically in the absence of CovS, resulting in the derepression of virulence factor expression and an increase in bacterial invasiveness. Streptococcal pyrogenic exotoxin B (SpeB) is a cysteine protease and is negatively regulated by CovR; however, the expression of SpeB is almost completely repressed in the covS mutant. The present study found that in the emm1-type A20 strain, non-phosphorylated CovR acts as a transcriptional repressor for SpeB-positive regulator Rgg. In addition, the expression of Rgg-negative regulator LacD.1 is upregulated in the covS mutant. These results suggest that inactivation of Rgg in the covS mutant would directly mediate speB repression. The current study showed that overexpression of rgg but not inactivation of lacD.1 in the covS mutant partially restores speB expression, indicating that only rgg repression, but not lacD.1 upregulation, contributes to the speB repression in the covS mutant. PMID- 27965657 TI - Editorial: Biofilms from a Food Microbiology Perspective: Structures, Functions, and Control Strategies. PMID- 27965654 TI - The Neuro-endocrinological Role of Microbial Glutamate and GABA Signaling. AB - Gut microbiota provides the host with multiple functions (e.g., by contributing to food digestion, vitamin supplementation, and defense against pathogenic strains) and interacts with the host organism through both direct contact (e.g., through surface antigens) and soluble molecules, which are produced by the microbial metabolism. The existence of the so-called gut-brain axis of bi directional communication between the gastrointestinal tract and the central nervous system (CNS) also supports a communication pathway between the gut microbiota and neural circuits of the host, including the CNS. An increasing body of evidence has shown that gut microbiota is able to modulate gut and brain functions, including the mood, cognitive functions, and behavior of humans. Nonetheless, given the extreme complexity of this communication network, its comprehension is still at its early stage. The present contribution will attempt to provide a state-of-the art description of the mechanisms by which gut microbiota can affect the gut-brain axis and the multiple cellular and molecular communication circuits (i.e., neural, immune, and humoral). In this context, special attention will be paid to the microbial strains that produce bioactive compounds and display ascertained or potential probiotic activity. Several neuroactive molecules (e.g., catecholamines, histamine, serotonin, and trace amines) will be considered, with special focus on Glu and GABA circuits, receptors, and signaling. From the basic science viewpoint, "microbial endocrinology" deals with those theories in which neurochemicals, produced by both multicellular organisms and prokaryotes (e.g., serotonin, GABA, glutamate), are considered as a common shared language that enables interkingdom communication. With regards to its application, research in this area opens the way toward the possibility of the future use of neuroactive molecule-producing probiotics as therapeutic agents for the treatment of neurogastroenteric and/or psychiatric disorders. PMID- 27965658 TI - A Bioengineered Nisin Derivative, M21A, in Combination with Food Grade Additives Eradicates Biofilms of Listeria monocytogenes. AB - The burden of foodborne disease has large economic and social consequences worldwide. Despite strict regulations, a number of pathogens persist within the food environment, which is greatly contributed to by a build-up of resistance mechanisms and also through the formation of biofilms. Biofilms have been shown to be highly resistant to a number of antimicrobials and can be extremely difficult to remove once they are established. In parallel, the growing concern of consumers regarding the use of chemically derived antimicrobials within food has led to a drive toward more natural products. As a consequence, the use of naturally derived antimicrobials has become of particular interest. In this study we investigated the efficacy of nisin A and its bioengineered derivative M21A in combination with food grade additives to treat biofilms of a representative foodborne disease isolate of Listeria monocytogenes. Investigations revealed the enhanced antimicrobial effects, in liquid culture, of M21A in combination with citric acid or cinnamaldehyde over its wild type nisin A counterpart. Subsequently, an investigation was conducted into the effects of these combinations on an established biofilm of the same strain. Nisin M21A (0.1 MUg/ml) alone or in combination with cinnamaldehyde (35 MUg/ml) or citric acid (175 MUg/ml) performed significantly better than combinations involving nisin A. All combinations of M21A with either citric acid or cinnamaldehyde eradicated the L. monocytogenes biofilm (in relation to a non-biofilm control). We conclude that M21A in combination with available food additives could further enhance the antimicrobial treatment of biofilms within the food industry, simply by substituting nisin A with M21A in current commercial products such as Nisaplin(r) (Danisco, DuPont). PMID- 27965656 TI - Identification of a Chemoreceptor in Pseudomonas aeruginosa That Specifically Mediates Chemotaxis Toward alpha-Ketoglutarate. AB - Pseudomonas aeruginosa is an ubiquitous pathogen able to infect humans, animals, and plants. Chemotaxis was found to be associated with the virulence of this and other pathogens. Although established as a model for chemotaxis research, the majority of the 26 P. aeruginosa chemoreceptors remain functionally un-annotated. We report here the identification of PA5072 (named McpK) as chemoreceptor for alpha-ketoglutarate (alphaKG). High-throughput thermal shift assays and isothermal titration calorimetry studies (ITC) of the recombinant McpK ligand binding domain (LBD) showed that it recognizes exclusively alpha-ketoglutarate. The ITC analysis indicated that the ligand bound with positive cooperativity (Kd1 = 301 MUM, Kd2 = 81 MUM). McpK is predicted to possess a helical bimodular (HBM) type of LBD and this and other studies suggest that this domain type may be associated with the recognition of organic acids. Analytical ultracentrifugation (AUC) studies revealed that McpK-LBD is present in monomer-dimer equilibrium. Alpha-KG binding stabilized the dimer and dimer self-dissociation constants of 55 MUM and 5.9 MUM were derived for ligand-free and alphaKG-bound forms of McpK-LBD, respectively. Ligand-induced LBD dimer stabilization has been observed for other HBM domain containing receptors and may correspond to a general mechanism of this protein family. Quantitative capillary chemotaxis assays demonstrated that P. aeruginosa showed chemotaxis to a broad range of alphaKG concentrations with maximal responses at 500 MUM. Deletion of the mcpK gene reduced chemotaxis over the entire concentration range to close to background levels and wild type like chemotaxis was recovered following complementation. Real-time PCR studies indicated that the presence of alphaKG does not modulate mcpK expression. Since alphaKG is present in plant root exudates it was investigated whether the deletion of mcpK altered maize root colonization. However, no significant changes with respect to the wild type strain were observed. The existence of a chemoreceptor specific for alphaKG may be due to its central metabolic role as well as to its function as signaling molecule. This work expands the range of known chemoreceptor types and underlines the important physiological role of chemotaxis toward tricarboxylic acid cycle intermediates. PMID- 27965659 TI - Evolution and Phylogeny of Large DNA Viruses, Mimiviridae and Phycodnaviridae Including Newly Characterized Heterosigma akashiwo Virus. AB - Nucleocytoplasmic DNA viruses are a large group of viruses that harbor double stranded DNA genomes with sizes of several 100 kbp, challenging the traditional concept of viruses as small, simple 'organisms at the edge of life.' The most intriguing questions about them may be their origin and evolution, which have yielded the variety we see today. Specifically, the phyletic relationship between two giant dsDNA virus families that are presumed to be close, Mimiviridae, which infect Acanthamoeba, and Phycodnaviridae, which infect algae, is still obscure and needs to be clarified by in-depth analysis. Here, we studied Mimiviridae Phycodnaviridae phylogeny including the newly identified Heterosigma akashiwo virus strain HaV53. Gene-to-gene comparison of HaV53 with other giant dsDNA viruses showed that only a small proportion of HaV53 genes show similarities with the others, revealing its uniqueness among Phycodnaviridae. Phylogenetic/genomic analysis of Phycodnaviridae including HaV53 revealed that the family can be classified into four distinctive subfamilies, namely, Megaviridae (Mimivirus like), Chlorovirus-type, and Coccolitho/Phaeovirus-type groups, and HaV53 independent of the other three groups. Several orthologs found in specific subfamilies while absent from the others were identified, providing potential family marker genes. Finally, reconstruction of the evolutionary history of Phycodnaviridae and Mimiviridae revealed that these viruses are descended from a common ancestor with a small set of genes and reached their current diversity by differentially acquiring gene sets during the course of evolution. Our study illustrates the phylogeny and evolution of Mimiviridae-Phycodnaviridae and proposes classifications that better represent phyletic relationships among the family members. PMID- 27965660 TI - Reflections on HLA Epitope-Based Matching for Transplantation. AB - HLA antibodies are primary causes of transplant rejection; they recognize epitopes that can be structurally defined by eplets. There are many reviews about HLA epitope-based matching in transplantation. This article describes some personal reflections about epitopes including a historical perspective of HLA typing at the antigen and allele levels, the repertoires of antibody-verified HLA epitopes, the use of HLAMatchmaker in determining the specificities of antibodies tested in different assays, and, finally, possible strategies to control HLA antibody responses. PMID- 27965661 TI - Clinical Evaluation of Humira(r) Biosimilar ONS-3010 in Healthy Volunteers: Focus on Pharmacokinetics and Pharmacodynamics. AB - ONS-3010 is being developed by Oncobiologics Inc. (Cranbury, NJ, USA) as a biosimilar of Humira(r). This randomized, double blind, single-center phase I study (EudraCT registration # 2013-003551-38) was performed to demonstrate pharmacokinetic (PK) biosimilarity between two reference products (Humira(r) EU and US) and ONS-3010 in healthy volunteers, and to compare the safety and immunogenicity profiles. In addition, the intended pharmacological activity was assessed and compared by application of a whole blood challenge. Hundred ninety eight healthy volunteers received a single 40 mg subcutaneous dose of ONS-3010, Humira(r) EU, or US. The pharmacodynamic effects were assessed by lipopolysaccharide (LPS)/aluminum hydroxide whole blood challenges (n = 36; n = 12 per treatment arm; male:female, 1:1). Equivalence was demonstrated on the PK endpoints (AUC0-inf, Cmax, and AUC0-last) based on bounds of 80-125% for the ratio of the geometric means (ONS-3010/Humira(r)). The immunogenicity profiles were comparable between treatment groups, and there were no indications for differences in routine safety parameters. Administration of adalimumab resulted in the observation of dramatically reduced tumor necrosis factor-alpha (TNFalpha) levels upon stimulation with LPS/aluminum hydroxide (>99%), with no differences between the three treatment groups in terms of magnitude or duration. Adalimumab also resulted in a reduction of LPS/aluminum hydroxide-induced interleukin (IL)-8 release (maximally 30%), suggested to have a causal relationship with the anti TNFalpha treatment. LPS/aluminum hydroxide-induced release of IL-1beta and IL-6 was not inhibited by anti-TNFalpha treatment. Taken together, these data are promising for the further clinical development of ONS-3010, demonstrate the relevance of the LPS/aluminum challenge to monitor Humira(r) effects, and emphasize the value of whole blood challenges for monitoring of proximal drug effects in healthy volunteers, and potentially in the target population. PMID- 27965663 TI - Alteration in the Gut Microbiota Provokes Susceptibility to Tuberculosis. AB - The microbiota that resides in the gastrointestinal tract provides essential health benefits to the host. In particular, they regulate immune homeostasis. Recently, several evidences indicate that alteration in the gut microbial community can cause infectious and non-infectious diseases. Tuberculosis (TB) is the most devastating disease, inflicting mortality and morbidity. It remains unexplored, whether changes in the gut microbiota can provoke or prevent TB. In the current study, we have demonstrated the antibiotics driven changes in the gut microbial composition and their impact on the survival of Mycobacterium tuberculosis (Mtb) in the lungs, liver, and spleen of infected mice, compared to those with intact microbiota. Interestingly, dysbiosis of microbes showed significant increase in the bacterial burden in lungs and dissemination of Mtb to spleen and liver. Furthermore, elevation in the number of Tregs and decline in the pool of IFN-gamma- and TNF-alpha-releasing CD4 T cells was noticed. Interestingly, fecal transplantation in the gut microbiota disrupted animals exhibited improved Th1 immunity and lesser Tregs population. Importantly, these animals displayed reduced severity to Mtb infection. This study for the first time demonstrated the novel role of gut microbes in the susceptibility to TB and its prevention by microbial implants. In future, microbial therapies may help in treating patients suffering from TB. PMID- 27965662 TI - Visceral Leishmaniasis Patients Display Altered Composition and Maturity of Neutrophils as well as Impaired Neutrophil Effector Functions. AB - Immunologically, active visceral leishmaniasis (VL) is characterized by profound immunosuppression, severe systemic inflammatory responses, and an impaired capacity to control parasite replication. Neutrophils are highly versatile cells, which play a crucial role in the induction as well as the resolution of inflammation, the control of pathogen replication, and the regulation of immune responses. Neutrophil functions have been investigated in human cutaneous leishmaniasis; however, their role in human VL is poorly understood. In the present study we evaluated the activation status and effector functions of neutrophils in patients with active VL and after successful anti-leishmanial treatment. Our results show that neutrophils are highly activated and have degranulated; high levels of arginase, myeloperoxidase, and elastase, all contained in neutrophils' granules, were found in the plasma of VL patients. In addition, we show that a large proportion of these cells are immature. We also analyzed effector functions of neutrophils that are essential for pathogen clearance and show that neutrophils have an impaired capacity to release neutrophil extracellular traps, produce reactive oxygen species, and phagocytose bacterial particles, but not Leishmania parasites. Our results suggest that impaired effector functions, increased activation, and immaturity of neutrophils play a key role in the pathogenesis of VL. PMID- 27965664 TI - Transfusion as an Inflammation Hit: Knowns and Unknowns. AB - Transfusion of blood cell components is frequent in the therapeutic arsenal; it is globally safe or even very safe. At present, residual clinical manifestations are principally inflammatory in nature. If some rare clinical hazards manifest as acute inflammation symptoms of various origin, most of them linked with conflicting and undesirable biological material accompanying the therapeutic component (infectious pathogen, pathogenic antibody, unwanted antigen, or allergen), the general feature is subtler and less visible, and essentially consists of alloimmunization or febrile non-hemolytic transfusion reaction. The present essay aims to present updates in hematology and immunology that help understand how, when, and why subclinical inflammation underlies alloimmunization and circumstances characteristic of red blood cells and - even more frequently - platelets that contribute inflammatory mediators. Modern transfusion medicine makes sustained efforts to limit such inflammatory hazards; efforts can be successful only if one has a clear view of each element's role. PMID- 27965665 TI - Deoxycholic Acid Triggers NLRP3 Inflammasome Activation and Aggravates DSS Induced Colitis in Mice. AB - A westernized high-fat diet (HFD) is associated with the development of inflammatory bowel disease (IBD). High-level fecal deoxycholic acid (DCA) caused by HFD contributes to the colonic inflammatory injury of IBD; however, the mechanism concerning the initiation of inflammatory response by DCA remains unclear. In this study, we sought to investigate the role and mechanism of DCA in the induction of inflammation via promoting NLRP3 inflammasome activation. Here, we, for the first time, showed that DCA dose-dependently induced NLRP3 inflammasome activation and highly pro-inflammatory cytokine-IL-1beta production in macrophages. Mechanistically, DCA-triggered NLRP3 inflammasome activation by promoting cathepsin B release at least partially through sphingosine-1-phosphate receptor 2. Colorectal instillation of DCA significantly increased mature IL 1beta level in colonic tissue and exacerbated DSS-induced colitis, while in vivo blockage of NLRP3 inflammasome or macrophage depletion dramatically reduced the mature IL-1beta production and ameliorated the aggravated inflammatory injury imposed by DCA. Thus, our findings show that high-level fecal DCA may serve as an endogenous danger signal to activate NLRP3 inflammasome and contribute to HFD related colonic inflammation. NLRP3 inflammasome may represent a new potential therapeutical target for treatment of IBD. PMID- 27965668 TI - Biomarker Tools to Design Clinical Vaccines Determined from a Study of Annual Listeriosis Incidence in Northern Spain. AB - Two regions of northern Spain, Gipuzkoa, and Cantabria present high annual incidence of listeriosis (1.86 and 1.71 cases per 100,000 inhabitants, respectively). We report that the high annual incidences are a consequence of infection with highly virulent Listeria monocytogenes isolates linked to fatal outcomes in elderly patients with cancer. In addition, listeriosis patients with cancer present low IL-17A/IL-6 ratios and significantly reduced levels of anti GAPDH1-22 antibodies, identified as two novel biomarkers of poor prognosis. Analysis of these biomarkers may aid in reducing the incidence of listeriosis. Moreover, GAPDH1-22-activated monocyte-derived dendritic cells of listeriosis patients with cancer seem useful tools to prepare clinical vaccines as they produce mainly Th1 cytokines. PMID- 27965669 TI - Complement Regulator FHR-3 Is Elevated either Locally or Systemically in a Selection of Autoimmune Diseases. AB - The human complement factor H-related protein-3 (FHR-3) is a soluble regulator of the complement system. Homozygous cfhr3/1 deletion is a genetic risk factor for the autoimmune form of atypical hemolytic-uremic syndrome (aHUS), while also found to be protective in age-related macular degeneration (AMD). The precise function of FHR-3 remains to be fully characterized. We generated four mouse monoclonal antibodies (mAbs) for FHR-3 (RETC) without cross-reactivity to the complement factor H (FH)-family. These antibodies detected FHR-3 from human serum with a mean concentration of 1 MUg/mL. FHR-3 levels in patients were significantly increased in sera from systemic lupus erythematosus, rheumatoid arthritis, and polymyalgia rheumatica but remained almost unchanged in samples from AMD or aHUS patients. Moreover, by immunostaining of an aged human donor retina, we discovered a local FHR-3 production by microglia/macrophages. The mAb RETC-2 modulated FHR-3 binding to C3b but not the binding of FHR-3 to heparin. Interestingly, FHR-3 competed with FH for binding C3b and the mAb RETC-2 reduced the interaction of FHR-3 and C3b, resulting in increased FH binding. Our results unveil a previously unknown systemic involvement of FHR-3 in rheumatoid diseases and a putative local role of FHR-3 mediated by microglia/macrophages in the damaged retina. We conclude that the local FHR-3/FH equilibrium in AMD is a potential therapeutic target, which can be modulated by our specific mAb RETC-2. PMID- 27965666 TI - Critical Roles of Kupffer Cells in the Pathogenesis of Alcoholic Liver Disease: From Basic Science to Clinical Trials. AB - Alcoholic liver disease (ALD) encompasses a spectrum of liver injury ranging from steatosis to steatohepatitis, fibrosis, and finally cirrhosis. Accumulating evidences have demonstrated that Kupffer cells (KCs) play critical roles in the pathogenesis of both chronic and acute ALD. It has become clear that alcohol exposure can result in increased hepatic translocation of gut-sourced endotoxin/lipopolysaccharide, which is a strong M1 polarization inducer of KCs. The activated KCs then produce a large amount of reactive oxygen species (ROS), pro-inflammatory cytokines, and chemokines, which finally lead to liver injury. The critical roles of KCs and related inflammatory cascade in the pathogenesis of ALD make it a promising target in pharmaceutical drug developments for ALD treatment. Several drugs (such as rifaximin, pentoxifylline, and infliximab) have been evaluated or are under evaluation for ALD treatment in randomized clinical trials. Furthermore, screening pharmacological regulators for KCs toward M2 polarization may provide additional therapeutic agents. The combination of these potentially therapeutic drugs with hepatoprotective agents (such as zinc, melatonin, and silymarin) may bring encouraging results. PMID- 27965670 TI - Activated IL-1RI Signaling Pathway Induces Th17 Cell Differentiation via Interferon Regulatory Factor 4 Signaling in Patients with Relapsing-Remitting Multiple Sclerosis. AB - IL-1beta plays a crucial role in the differentiation of human Th17 cells. We report here that IL-1RI expression is significantly increased in both naive and memory CD4+ T cells derived from relapsing-remitting multiple sclerosis (RR MS) patients in comparison to healthy controls. Interleukin 1 receptor (IL-1R)I expression is upregulated in the in vitro-differentiated Th17 cells from RR MS patients in comparison to the Th1 and Th2 cell subsets, indicating the role of IL 1R signaling in the Th17 cell differentiation in RR MS. When IL-1RI gene expression was silenced using siRNA, human naive CD4+ T cells cultured in the presence of Th17-polarizing cytokines had a significantly decreased expression of interleukin regulatory factor 4 (IRF4), RORc, IL-17A, IL-17F, IL-21, IL-22, and IL-23R genes, confirming that IL-1RI signaling induces Th17 cell differentiation. Since IL-1R gene expression silencing inhibited IRF4 expression and Th17 differentiation, and IRF4 gene expression silencing inhibited Th17 cell differentiation, our results indicate that IL-1RI induces human Th17 cell differentiation in an IRF4-dependant manner. Our study has identified that IL-1RI mediated signaling pathway is constitutively activated, leading to an increased Th17 cell differentiation in IRF4-dependent manner in patients with RR MS. PMID- 27965667 TI - Danger Signals and Graft-versus-host Disease: Current Understanding and Future Perspectives. AB - Graft-versus-host response after allogeneic hematopoietic stem cell transplantation (allo-HCT) represents one of the most intense inflammatory responses observed in humans. Host conditioning facilitates engraftment of donor cells, but the tissue injury caused from it primes the critical first steps in the development of acute graft-versus-host disease (GVHD). Tissue injuries release pro-inflammatory cytokines (such as TNF-alpha, IL-1beta, and IL-6) through widespread stimulation of pattern recognition receptors (PRRs) by the release of danger stimuli, such as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). DAMPs and PAMPs function as potent stimulators for host and donor-derived antigen presenting cells (APCs) that in turn activate and amplify the responses of alloreactive donor T cells. Emerging data also point towards a role for suppression of DAMP induced inflammation by the APCs and donor T cells in mitigating GVHD severity. In this review, we summarize the current understanding on the role of danger stimuli, such as the DAMPs and PAMPs, in GVHD. PMID- 27965672 TI - Hereditary Angioedema as a Metabolic Liver Disorder: Novel Therapeutic Options and Prospects for Cure. AB - Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by mutations of the SERPING1 or the Factor 12 genes. It is potentially fatal, particularly if not identified at an early stage. Apart from androgens, which are contraindicated in children and in pregnant women, a range of effective, albeit very expensive treatments have recently become available for HAE patients. The cost of these new treatments is beyond the reach of most developing countries. At this time, there is no cure for the disorder. In spite of mutations of the SERPING1 gene, autoimmunity and infections are not prominent features of the condition. Here, we present the argument that HAE should be viewed primarily as a metabolic liver disorder. This conceptual paradigm shift will stimulate basic research and may facilitate new therapeutic approaches to HAE outlined in this paper. We suggest several novel potential treatment options for HAE from the perspectives of clinical immunology, molecular biology, and liver transplantation. Many of these offer the prospect of curing the disorder. The effectiveness of these options is rapidly improving in many cases, and their risks are decreasing. Given the very high costs of treating HAE, some of these curative options may become feasible in the next decade. PMID- 27965671 TI - Neuron-Microglia Interactions in Mental Health Disorders: "For Better, and For Worse". AB - Persistent cognitive and behavioral symptoms that characterize many mental health disorders arise from impaired neuroplasticity in several key corticolimbic brain regions. Recent evidence suggests that reciprocal neuron-microglia interactions shape neuroplasticity during physiological conditions, implicating microglia in the neurobiology of mental health disorders. Neuron-microglia interactions are modulated by several molecular and cellular pathways, and dysregulation of these pathways often have neurobiological consequences, including aberrant neuronal responses and microglia activation. Impaired neuron-microglia interactions are implicated in mental health disorders because rodent stress models lead to concomitant neuronal dystrophy and alterations in microglia morphology and function. In this context, functional changes in microglia may be indicative of an immune state termed parainflammation in which tissue-resident macrophages (i.e., microglia) respond to malfunctioning cells by initiating modest inflammation in an attempt to restore homeostasis. Thus, aberrant neuronal activity and release of damage-associated signals during repeated stress exposure may contribute to functional changes in microglia and resultant parainflammation. Furthermore, accumulating evidence shows that uncoupling neuron-microglia interactions may contribute to altered neuroplasticity and associated anxiety- or depressive-like behaviors. Additional work shows that microglia have varied phenotypes in specific brain regions, which may underlie divergent neuroplasticity observed in corticolimbic structures following stress exposure. These findings indicate that neuron-microglia interactions are critical mediators of the interface between adaptive, homeostatic neuronal function and the neurobiology of mental health disorders. PMID- 27965673 TI - The Role of Lymphatic Endothelial Cells in Liver Injury and Tumor Development. AB - Lymphatics and lymphatic endothelial cells (LECs) possess multiple immunological functions besides affecting immune cell migration, such as inhibiting T cell proliferation and antigen presentation by dendritic cells. Moreover, they control the trans-endothelial transport of multiple molecules and antigens. Emerging evidence suggest their active involvements in immunregulation, tumor, and metastases formation. In the liver, increased lymphangiogenesis, specifically at the portal area has been associated with multiple liver diseases in particular primary biliary cirrhosis, idiopathic portal hypertension, and liver malignancies. Nevertheless, the exact role and contribution of LECs to liver diseases are poorly understood. The review summarizes the current understanding of LECs in liver diseases. PMID- 27965674 TI - Molecular and Cellular Characterization of Human CD8 T Suppressor Cells. AB - Bidirectional interactions between dendritic cells and Ag-experienced T cells initiate either a tolerogenic or immunogenic pathway. The outcome of these interactions is of crucial importance in malignancy, transplantation, and autoimmune diseases. Blockade of costimulation results in the induction of T helper cell anergy and subsequent differentiation of antigen-specific CD8+ T suppressor/regulatory cells (Ts). Ts, primed in the presence of inhibitory signals, exert their inhibitory function in an antigen-specific manner, a feature with tremendous clinical potential. In transplantation or autoimmunity, antigen specific Ts can enforce tolerance to auto- or allo-antigens, while otherwise leaving the immune response to pathogens uninhibited. Alternatively, blockade of inhibitory receptors results in the generation of cytolytic CD8+ T cells, which is vital toward defense against tumors and viral diseases. Because CD8+ T cells are MHC Class I restricted, they are able to recognize HLA-bound antigenic peptides presented not only by APC but also on parenchymal cells, thus eliciting or suppressing auto- or allo-immune reactions. PMID- 27965675 TI - iNKT Cells in Secondary Progressive Multiple Sclerosis Patients Display Pro inflammatory Profiles. AB - BACKGROUND: Multiple sclerosis (MS), an autoimmune disease with neurodegeneration and inflammation is characterized by several alterations of different T cell subsets. However, few data exist on the role of iNKT lymphocytes. OBJECTIVE: To identify possible changes in the phenotype of iNKT cells in patients with different clinical forms of MS and find alterations in their polyfunctionality [i.e., ability to produce simultaneously up to four cytokines such as IL-17, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and IL-4]. METHODS: We studied a total of 165 patients, 91 with a relapsing-remitting form [RR; 31 were treated with interferon (IFN)1a-beta, 25 with natalizumab (NAT), 29 with glatiramer acetate; 17 were newly diagnosed RR without treatment, 19 not-active RR without treatment]. Forty-four patients had a progressive MS: 20 primary progressive (PP) and 24 secondary progressive (SP). A total of 55 age- and sex matched subjects represented healthy controls (CTR). Among fresh peripheral blood mononuclear cells, iNKT cells were identified by flow cytometry. Moreover, the capability of iNKT cells to produce different cytokines (IL-17, TNF-alpha, IFN gamma, and IL-4) after in vitro stimulation were evaluated in 18 RR (11 treated with NAT and 7 with IFN), 4 PP, 6 SP, and 16 CTR. RESULTS: No main differences were found in iNKT cell phenotype among MS patients with different MS forms or during different treatments. However, the polyfunctional response of iNKT cells showed Th1 and Th17 profiles. This was well evident in patients with SP form, who are characterized by high levels of inflammation and neurodegeneration, and exhibited a sustained increase in the production of Th17 cytokines. Patients treated with NAT displayed lower levels of iNKT cells producing IL-17, TNF-alpha, and IFN-gamma. CONCLUSION: Our data suggest that the progressive phase of the disease is characterized by permanent iNKT activation and a skewing towards an inflammatory phenotype. Compared to other treatments, NAT was able to modulate iNKT cell function. PMID- 27965676 TI - Tissue-Specific Transcriptome and Hormonal Regulation of Pollinated and Parthenocarpic Fig (Ficus carica L.) Fruit Suggest that Fruit Ripening Is Coordinated by the Reproductive Part of the Syconium. AB - In the unconventional climacteric fig (Ficus carica) fruit, pollinated and parthenocarpic fruit of the same genotype exhibit different ripening characteristics. Integrative comparative analyses of tissue-specific transcript and of hormone levels during fruit repining from pollinated vs. parthenocarpic fig fruit were employed to unravel the similarities and differences in their regulatory processes during fruit repining. Assembling tissue-specific transcripts into 147,000 transcripts with 53,000 annotated genes provided new insights into the spatial distribution of many classes of regulatory and structural genes, including those related to color, taste and aroma, storage, protein degradation, seeds and embryos, chlorophyll, and hormones. Comparison of the pollinated and parthenocarpic tissues during fruit ripening showed differential gene expression, especially in the fruit inflorescence. The distinct physiological green phase II and ripening phase III differed significantly in their gene-transcript patterns in both pulp and inflorescence tissues. Gas chromatographic analysis of whole fruits enabled the first determination of ripening-related hormone levels from pollinated and non-pollinated figs. Ethylene and auxin both increased during fruit ripening, irrespective of pollination, whereas no production of active gibberellins or cytokinins was found in parthenocarpic or pollinated ripening fruit. Tissue-specific transcriptome revealed apparent different metabolic gene patterns for ethylene, auxin and ABA in pollinated vs. parthenocarpic fruit, mostly in the fruit inflorescence. Our results demonstrate that the production of abscisic acid (ABA), non-active ABA-GE conjugate and non-active indoleacetic acid (IAA)-Asp conjugate in pollinated fruits is much higher than in parthenocarpic fruits. We suggest that fruit ripening is coordinated by the reproductive part of the syconium and the differences in ABA production between pollinated and parthenocarpic fig fruit might be the key to their different ripening characteristics. PMID- 27965678 TI - Expression Profiles and DNA-Binding Affinity of Five ERF Genes in Bunches of Vitis vinifera cv. Cardinal Treated with High Levels of CO2 at Low Temperature. AB - Ethylene response factors (ERFs) play an important role in plants by regulating defense response through interaction with various stress pathways. After harvest, table grapes (Vitis vinifera L.) are subject to a range of problems associated with postharvest storage at 0 degrees C, such as fungal attack, water loss and rachis browning. The application of a 3-day high CO2 treatment maintained fruit quality and activated the induction of transcription factors belonging to different families such as ERF. In this paper, we have isolated five VviERFs from table grapes cv. Cardinal, whose deduced amino acid sequence contained the conserved apetalous (AP2)/ERF domain. The phylogeny and putative conserved motifs in VviERFs were analyzed and compared with those previously reported in Vitis. VviERFs-c gene expression was studied by quantitative real-time RT-PCR in the different tissues of bunches stored at low temperature and treated with high levels of CO2. The results showed that in most of the tissues analyzed, VviERFs-c gene expression was induced by the storage under normal atmosphere although the application of high levels of CO2 caused a greater increase in the VviERFs-c transcript accumulation. The promoter regions of two PRs (pathogenesis related proteins), Vcchit1b and Vcgns1, were obtained and the in silico analysis revealed the presence of a cis-acting ethylene response element (GCC box). In addition, expression of these two PR genes was analyzed in the pulp and rachis of CO2 treated and non-treated table grapes stored at 0 degrees C and results showed significant correlations with VviERF2-c and VviERF6L7-c gene expression in rachis, and between VviERF11-c and Vcchit1b in pulp. Finally by using electro mobility shift assays, we denoted differences in binding of VviERFs to the GCC sequences present in the promoters of both PRs, with VviERF6L7-c being the only member which did not bind to any tested probe. Overall, our results suggest that the beneficial effect of high CO2 treatment maintaining table grape quality seems to be mediated by the regulation of ERFs and in particular VviERF2-c might play an important role by modulating the expression of PR genes. PMID- 27965677 TI - Nitric Oxide Overproduction in Tomato shr Mutant Shifts Metabolic Profiles and Suppresses Fruit Growth and Ripening. AB - Nitric oxide (NO) plays a pivotal role in growth and disease resistance in plants. It also acts as a secondary messenger in signaling pathways for several plant hormones. Despite its clear role in regulating plant development, its role in fruit development is not known. In an earlier study, we described a short root (shr) mutant of tomato, whose phenotype results from hyperaccumulation of NO. The molecular mapping localized shr locus in 2.5 Mb region of chromosome 9. The shr mutant showed sluggish growth, with smaller leaves, flowers and was less fertile than wild type. The shr mutant also showed reduced fruit size and slower ripening of the fruits post-mature green stage to the red ripe stage. Comparison of the metabolite profiles of shr fruits with wild-type fruits during ripening revealed a significant shift in the patterns. In shr fruits intermediates of the tricarboxylic acid (TCA) cycle were differentially regulated than WT indicating NO affected the regulation of TCA cycle. The accumulation of several amino acids, particularly tyrosine, was higher, whereas most fatty acids were downregulated in shr fruits. Among the plant hormones at one or more stages of ripening, ethylene, Indole-3-acetic acid and Indole-3-butyric acid increased in shr, whereas abscisic acid declined. Our analyses indicate that the retardation of fruit growth and ripening in shr mutant likely results from the influence of NO on central carbon metabolism and endogenous phytohormones levels. PMID- 27965680 TI - Molecular Cloning, Characterization, and Expression of MiSOC1: A Homolog of the Flowering Gene SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 from Mango (Mangifera indica L). AB - MADS-box transcription factor plays a crucial role in plant development, especially controlling the formation and development of floral organs. Mango (Mangifera indica L) is an economically important fruit crop, but its molecular control of flowering is largely unknown. To better understand the molecular basis of flowering regulation in mango, we isolated and characterized the MiSOC1, a putative mango orthologs for the Arabidopsis SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1/AGAMOUS-LIKE 20 (SOC1/AGL20) with homology-based cloning and RACE. The full-length cDNA (GenBank accession No.: KP404094) is 945 bp in length including a 74 bp long 5' UTR and a 189 bp long 3' UTR and the open reading frame was 733 bps, encoding 223 amino acids with molecular weight 25.6 kD. Both sequence alignment and phylogenetic analysis all indicated that deduced protein contained a conservative MADS-box and semi-conservative K domain and belonged to the SOC1/TM3 subfamily of the MADS-box family. Quantitative real-time PCR was performed to investigate the expression profiles of MiSOC1 gene in different tissues/organs including root, stem, leaves, flower bud, and flower. The result indicated MiSOC1 was widely expressed at different levels in both vegetative and reproductive tissues/organs with the highest expression level in the stems' leaves and inflorescences, low expression in roots and flowers. The expression of MiSOC1 in different flower developmental stages was different while same tissue specific pattern among different varieties. In addition, MiSOC1 gene expression was affect by ethephon while high concentration ethephon inhibit the expression of MiSOC1. Overexpression of MiSOC1 resulted in early flowering in Arabidopsis. In conclusion, these results suggest that MiSOC1 may act as induce flower function in mango. PMID- 27965679 TI - Linking Dynamic Phenotyping with Metabolite Analysis to Study Natural Variation in Drought Responses of Brachypodium distachyon. AB - Drought is an important environmental stress limiting the productivity of major crops worldwide. Understanding drought tolerance and possible mechanisms for improving drought resistance is therefore a prerequisite to develop drought tolerant crops that produce significant yields with reduced amounts of water. Brachypodium distachyon (Brachypodium) is a key model species for cereals, forage grasses, and energy grasses. In this study, initial screening of a Brachypodium germplasm collection consisting of 138 different ecotypes exposed to progressive drought, highlighted the natural variation in morphology, biomass accumulation, and responses to drought stress. A core set of ten ecotypes, classified as being either tolerant, susceptible or intermediate, in response to drought stress, were exposed to mild or severe (respectively, 15 and 0% soil water content) drought stress and phenomic parameters linked to growth and color changes were assessed. When exposed to severe drought stress, phenotypic data and metabolite profiling combined with multivariate analysis revealed a remarkable consistency in separating the selected ecotypes into their different pre-defined drought tolerance groups. Increases in several metabolites, including for the phytohormones jasmonic acid and salicylic acid, and TCA-cycle intermediates, were positively correlated with biomass yield and with reduced yellow pixel counts; suggestive of delayed senescence, both key target traits for crop improvement to drought stress. While metabolite analysis also separated ecotypes into the distinct tolerance groupings after exposure to mild drought stress, similar analysis of the phenotypic data failed to do so, confirming the value of metabolomics to investigate early responses to drought stress. The results highlight the potential of combining the analyses of phenotypic and metabolic responses to identify key mechanisms and markers associated with drought tolerance in both the Brachypodium model plant as well as agronomically important crops. PMID- 27965681 TI - Contrasting Susceptibilities to Flavescence Doree in Vitis vinifera, Rootstocks and Wild Vitis Species. AB - Flavescence doree (FD) is a quarantine disease of grapevine, involving interactions between the plants, leafhopper vectors, and FD phytoplasma. Characterizing the susceptibility of vine varieties could limit disease propagation. After extensive surveys in vineyards, we showed that Cabernet Sauvignon (CS) is highly susceptible, with a high proportion of symptomatic branches and phytoplasma titers, in contrast to Merlot (M). Localized insect transmissions and grafting showed that phytoplasma circulate in the whole plant in the CS cultivar, but in M they are restricted to the transmission point. Insect-mediated transmission under high confinement mimicking natural conditions confirmed these phenotypes and allowed the classification of 28 Vitis accessions into three distinct categories, according to the percentage of infected plants and their phytoplasma titers. Reduced symptoms, low phytoplasma titers, and low percentages of infected plants were found to be associated in the Vitis vinifera cultivars tested. Interestingly, the low susceptibility of M was observed for one of its parents, i.e., Magdeleine Noire des Charentes. Rootstocks and their Vitis parents, although having high percentages of infected plants and intermediate to high phytoplasma titers, shared a symptomless response. This is troubling, because rootstocks can constitute a silent reservoir of contamination in mother plants or when they grow wild nearby vineyards. Altogether, data suggest distribution of genetic traits within the Vitis genus involved in insect-mediated phytoplasma transmission, multiplication, circulation, and symptom development. PMID- 27965683 TI - Bradyrhizobium Inoculants Enhance Grain Yields of Soybean and Cowpea in Northern Ghana. AB - This study evaluated the symbiotic effectiveness and economic evaluation of Rhizobium inoculants with the objective of recommending the most effective inoculant strain for soybean and cowpea production in Northern Ghana. Field experiments were established in three locations using randomized complete block design with five blocks. A total of four treatments (Legumefix, Biofix, 100 kg N ha-1 and uninoculated control for soybean and BR 3267, BR 3262, 100 kg N ha-1 and uninoculated control for cowpea) were applied. At Nyankpala, inoculation of soybean with Legumefix and Biofix led to significant (P < 0.05) increases in nodule number (90-118%), nodule dry weight (>two-folds), and grain yield (12-19%) relative to the control. The Biofix effect on soybean grain yield was 1.5-fold of Legumefix. Similarly, inoculation of cowpea with BR 3262 and BR 3267 significantly (P < 0.05) increased nodule number (41-68%), nodule dry weight (45 65%), and grain yield (11-38%) relative to the control. Strain BR 3267 performed consistently (>two-folds) better than BR 3262 on grain yield. At Nyagli, there was no significant effect of inoculation on cowpea. Wilks lambda values (0.067, 0.039; P = 0.00) indicated that 93.3 and 96.1% of the variations observed in soybean and cowpea, respectively, were due to the applied inoculants. Biofix and BR 3267 were economically profitable with VCR ratio of 8.7 and 4.6, respectively. Based on grain yield and economic returns observed, Biofix and BR 3267 can be recommended in Nyankpala for inoculation of soybean and cowpea, respectively. PMID- 27965682 TI - Stable Epigenetic Variants Selected from an Induced Hypomethylated Fragaria vesca Population. AB - Epigenetic inheritance was transmitted through selection over five generations of extreme early, but not late flowering time phenotypic lines in Fragaria vesca. Epigenetic variation was initially artificially induced using the DNA demethylation reagent 5-azacytidine (5-azaC). It is the first report to explore epigenetic variant selection and phenotypic trait inheritance in strawberry. Transmission frequency of these traits was determined across generations. The early flowering (EF4) and late stolon (LS) phenotypic traits were successfully transmitted across five and three generations through meiosis, respectively. Stable mitotic transmission of the early flowering phenotype was also demonstrated using clonal daughters derived from the 4th Generation (S4) mother plant. In order to further explore the DNA methylation patterns underlying the early flowering trait, the standard MSAP method using isoschizomers Hpa II/Msp I, and newly modified MSAP method using isoschizomers Tfi I/Pfe I which detected DNA methylation at CG, CHG, CHH sites were used in two early flowering lines, EF lines 1 (P2) and EF lines 2 (P3), and control lines (P1). A significant reduction in the number of fully-methylated bands was detected in P2 and P3 when compared to P1 using the novel MSAP method. In the standard MSAP, the symmetric CG and CHG methylation was maintained over generations in the early flowering lines based on the clustering in P2 and P3, the novel MSAP approach revealed the asymmetric CHH methylation pattern was not maintained over generations. This study provides evidence of stable selection of phenotypic traits, particularly early flowering through both meiosis and mitosis, which is meaningful to both breeding programs and commercial horticulture. The maintenance in CG and CHG methylation over generations suggests the early flowering phenotype might be related to DNA methylation alterations at the CG or CHG sites. Finally, this work provides a new approach for studying the role of epigenetics on complex quantitative trait improvement in strawberry, as well as providing a tool to expand phenotypic diversity and expedite potential new horticulture cultivar releases through either seed or vegetative propagation. PMID- 27965684 TI - Single R Gene Introgression Lines for Accurate Dissection of the Brassica - Leptosphaeria Pathosystem. AB - Seven blackleg resistance (R) genes (Rlm1, Rlm2, Rlm3, Rlm4, LepR1, LepR2 & LepR3) were each introgressed into a common susceptible B. napus doubled-haploid (DH) line through reciprocal back-crossing, producing single-R gene introgression lines (ILs) for use in the pathological and molecular study of Brassica Leptosphaeria interactions. The genomic positions of the R genes were defined through molecular mapping and analysis with transgenic L. maculans isolates was used to confirm the identity of the introgressed genes where possible. Using L. maculans isolates of contrasting avirulence gene (Avr) profiles, we preformed extensive differential pathology for phenotypic comparison of the ILs to other B. napus varieties, demonstrating the ILs can provide for the accurate assessment of Avr-R gene interactions by avoiding non-Avr dependant alterations to resistance responses which can occur in some commonly used B. napus varieties. Whole-genome SNP-based assessment allowed us to define the donor parent introgressions in each IL and provide a strong basis for comparative molecular dissection of the pathosystem. PMID- 27965685 TI - Nitrogen Source and Rate Management Improve Maize Productivity of Smallholders under Semiarid Climates. AB - Nitrogen is one of the most important factor affecting maize (Zea mays L.) yield and income of smallholders under semiarid climates. Field experiments were conducted to investigate the impact of different N-fertilizer sources [urea, calcium ammonium nitrate (CAN), and ammonium sulfate (AS)] and rates (50, 100, 150, and 200 kg ha-1) on umber of rows ear-1 (NOR ear-1), number of seeds row-1 (NOS row-1), number of seeds ear-1 (NOS ear-1), number of ears per 100 plants (NOEP 100 plants-1), grain yield plant-1, stover yield (kg ha-1), and shelling percentage (%) of maize genotypes "Local cultivars (Azam and Jalal) vs. hybrid (Pioneer-3025)." The experiment was conducted at the Agronomy Research Farm of the University of Agriculture Peshawar during summers of 2008 (year one) and 2010 (year two). The results revealed that the N treated (rest) plots (the average of all the experimental plots treated with N) had produced higher yield and yield components, and shelling percentage over N-control plots (plots where N was not applied). Application of nitrogen at the higher rate increased yield and yield components in maize (200 > 150 > 100 > 50 kg N ha-1). Application of AS and CAN had more beneficial impact on yield and yield components of maize as compared to urea (AS > CAN > urea). Hybrid maize (P-3025) produced significantly higher yield and yield components as well as higher shelling percentage than the two local cultivars (P-3025 > Jalal = Azam). Application of ammonium sulfate at the rate of 200 kg N ha-1 to hybrid maize was found most beneficial in terms of higher productivity and grower's income in the study area. For the two local cultivars, application of 150 kg N ha-1 was found more beneficial over 120 kg N ha-1 (recommended N rate) in terms of greater productivity and growers income. PMID- 27965687 TI - Editorial: How Can Secretomics Help Unravel the Secrets of Plant-Microbe Interactions? PMID- 27965686 TI - Ca2+/Cation Antiporters (CaCA): Identification, Characterization and Expression Profiling in Bread Wheat (Triticum aestivum L.). AB - The Ca2+/cation antiporters (CaCA) superfamily proteins play vital function in Ca2+ ion homeostasis, which is an important event during development and defense response. Molecular characterization of these proteins has been performed in certain plants, but they are still not characterized in Triticum aestivum (bread wheat). Herein, we identified 34 TaCaCA superfamily proteins, which were classified into TaCAX, TaCCX, TaNCL, and TaMHX protein families based on their structural organization and evolutionary relation with earlier reported proteins. Since the T. aestivum comprises an allohexaploid genome, TaCaCA genes were derived from each A, B, and D subgenome and homeologous chromosome (HC), except chromosome-group 1. Majority of genes were derived from more than one HCs in each family that were considered as homeologous genes (HGs) due to their high similarity with each other. These HGs showed comparable gene and protein structures in terms of exon/intron organization and domain architecture. Majority of TaCaCA proteins comprised two Na_Ca_ex domains. However, TaNCLs consisted of an additional EF-hand domain with calcium binding motifs. Each TaCaCA protein family consisted of about 10 transmembrane and two alpha-repeat regions with specifically conserved signature motifs except TaNCL, which had single alpha repeat. Variable expression of most of the TaCaCA genes during various developmental stages suggested their specified role in development. However, constitutively high expression of a few genes like TaCAX1-A and TaNCL1-B indicated their role throughout the plant growth and development. The modulated expression of certain genes during biotic (fungal infections) and abiotic stresses (heat, drought, salt) suggested their role in stress response. Majority of TaCCX and TaNCL family genes were found highly affected during various abiotic stresses. However, the role of individual gene needs to be established. The present study unfolded the opportunity for detail functional characterization of TaCaCA proteins and their utilization in future crop improvement programs. PMID- 27965688 TI - Mutations in Rice yellow mottle virus Polyprotein P2a Involved in RYMV2 Gene Resistance Breakdown. AB - Rice yellow mottle virus (RYMV) is one of the major diseases of rice in Africa. The high resistance of the Oryza glaberrima Tog7291 accession involves a null allele of the RYMV2 gene, whose ortholog in Arabidopsis, CPR5, is a transmembrane nucleoporin involved in effector-triggered immunity. To optimize field deployment of the RYMV2 gene and improve its durability, which is often a weak point in varietal resistance, we analyzed its efficiency toward RYMV isolates representing the genetic diversity of the virus and the molecular basis of resistance breakdown. Tog7291 resistance efficiency was highly variable depending on the isolate used, with infection rates ranging from 0 to 98% of plants. Back inoculation experiments indicated that infection cases were not due to an incomplete resistance phenotype but to the emergence of resistance-breaking (RB) variants. Interestingly, the capacity of the virus to overcome Tog7291 resistance is associated with a polymorphism at amino-acid 49 of the VPg protein which also affects capacity to overcome the previously studied RYMV1 resistance gene. This polymorphism appeared to be a main determinant of the emergence of RB variants. It acts independently of the resistance gene and rather reflects inter-species adaptation with potential consequences for the durability of resistance. RB mutations were identified by full-length or partial sequencing of the RYMV genome in infected Tog7291 plants and were validated by directed mutagenesis of an infectious viral clone. We found that Tog7291 resistance breakdown involved mutations in the putative membrane anchor domain of the polyprotein P2a. Although the precise effect of these mutations on rice/RYMV interaction is still unknown, our results offer a new perspective for the understanding of RYMV2 mediated resistance mechanisms. Interestingly, in the susceptible IR64 variety, RB variants showed low infectivity and frequent reversion to the wild-type genotype, suggesting that Tog7291 resistance breakdown is associated with a major loss of viral fitness in normally susceptible O. sativa varieties. Despite the high frequency of resistance breakdown in controlled conditions, this loss of fitness is an encouraging element with regards to RYMV2 resistance durability. PMID- 27965689 TI - Setaria viridis as a Model System to Advance Millet Genetics and Genomics. AB - Millet is a common name for a group of polyphyletic, small-seeded cereal crops that include pearl, finger and foxtail millet. Millet species are an important source of calories for many societies, often in developing countries. Compared to major cereal crops such as rice and maize, millets are generally better adapted to dry and hot environments. Despite their food security value, the genetic architecture of agronomically important traits in millets, including both morphological traits and climate resilience remains poorly studied. These complex traits have been challenging to dissect in large part because of the lack of sufficient genetic tools and resources. In this article, we review the phylogenetic relationship among various millet species and discuss the value of a genetic model system for millet research. We propose that a broader adoption of green foxtail (Setaria viridis) as a model system for millets could greatly accelerate the pace of gene discovery in the millets, and summarize available and emerging resources in S. viridis and its domesticated relative S. italica. These resources have value in forward genetics, reverse genetics and high throughput phenotyping. We describe methods and strategies to best utilize these resources to facilitate the genetic dissection of complex traits. We envision that coupling cutting-edge technologies and the use of S. viridis for gene discovery will accelerate genetic research in millets in general. This will enable strategies and provide opportunities to increase productivity, especially in the semi-arid tropics of Asia and Africa where millets are staple food crops. PMID- 27965690 TI - Root-to-Shoot Hormonal Communication in Contrasting Rootstocks Suggests an Important Role for the Ethylene Precursor Aminocyclopropane-1-carboxylic Acid in Mediating Plant Growth under Low-Potassium Nutrition in Tomato. AB - Selection and breeding of rootstocks that can tolerate low K supply may increase crop productivity in low fertility soils and reduce fertilizer application. However, the underlying physiological traits are still largely unknown. In this study, 16 contrasting recombinant inbred lines (RILs) derived from a cross between domestic and wild tomato species (Solanum lycopersicum * Solanum pimpinellifolium) have been used to analyse traits related to the rootstock mediated induction of low (L, low shoot fresh weight) or high (H, high shoot fresh weight) vigor to a commercial F1 hybrid grown under control (6 mM, c) and low-K (1 mM, k). Based on hormonal and ionomic composition in the root xylem sap and the leaf nutritional status after long-term (7 weeks) exposure low-K supply, a model can be proposed to explain the rootstocks effects on shoot performance with the ethylene precursor aminocyclopropane-1-carboxylic acid (ACC) playing a pivotal negative role. The concentration of this hormone was higher in the low vigor Lc and Lk rootstocks under both conditions, increased in the sensitive HcLk plants under low-K while it was reduced in the high-vigor Hk ones. Low ACC levels would promote the transport of K vs. Na in the vigorous Hk grafted plants. Along with K, Ca, and S, micronutrient uptake and transport were also activated in the tolerant Hk combinations under low-K. Additionally, an interconversion of trans zeatin into trans-zeatin riboside would contribute to decrease ACC in the tolerant LcHk plants. The high vigor induced by the Hk plants can also be explained by an interaction of ACC with other hormones (cytokinins and salicylic, abscisic and jasmonic acids). Therefore, Hk rootstocks convert an elite tomato F1 cultivar into a (micro) nutrient-efficient phenotype, improving growth under reduced K fertilization. PMID- 27965691 TI - A Comprehensive and Effective Mass Spectrometry-Based Screening Strategy for Discovery and Identification of New Brassinosteroids from Rice Tissues. AB - The exploration and identification of new brassinosteroid (BR) compounds is critical to improve the biosynthetic research of BRs and expand the chemodiversity of active BRs. However, traditional methods are labor-intensive, time-consuming, and less sensitive. Here, we present a facile screening strategy for discovering and identifying novel BRs from plant tissues based on ultra performance liquid chromatography-mass spectrometry (UPLC-MS). A total of 14 potential BRs were discovered from only 1 g of rice tissues and structurally elucidated by following a MS-based clue, acquired through multiple reaction monitoring (MRM) data-dependent enhanced product ion (EPI) scan, high resolution MS, and MS survey-dependent MS/MS. One of the 14 candidates was identified as 6 deoxo-28-homotyphasterol, a brand new BR compound that is reported for the first time in the BRs biosynthesis pathway. Detailed comparison with reference standards and quantitative level analysis in rice BR mutants confirmed the availability of the other candidates. This effective, yet simple method provides an efficient way to find more and more chemically new BR biosynthetic intermediates in plants, which is significant for complementing the biosynthesis and metabolism network of BRs. This strategy may also be used to discover unknown compounds of other plant hormone species as well as their key metabolites. PMID- 27965693 TI - Comprehensive Analysis of Photosynthetic Characteristics and Quality Improvement of Purple Cabbage under Different Combinations of Monochromatic Light. AB - Light is essential for plant growth. Light intensity, photoperiod, and light quality all affect plant morphology and physiology. Compared to light intensity, photoperiod, little is known about the effects of different monochromatic lights on crop species. To investigate how different lighting conditions influence crops with heterogeneous colors in leaves, we examined photosynthetic characteristics and quality (regarding edibility and nutrition) of purple cabbage under different combinations of lights. Eight different treatments were applied including monochromic red (R), monochromic blue (B), monochromic yellow (Y), monochromic green (G), and the combination of red and blue (3/1, RB), red/blue/yellow (3/1/1, RBY), red/blue/green (3/1/1,RBG), and white light as the control. Our results indicate that RBY (3/1/1) treatment promotes the PSII activity of purple cabbage, resulting in improved light energy utilization. By contrast, both G and Y lights alone have inhibitory effect on the PSII activity of purple cabbage. In addition, RBY (3/1/1) significantly boosts the anthocyanin and flavonoids content compared with other treatments. Although we detected highest soluble protein and vitamin C content under B treatment (increased by 30.0 and 14.3% compared with the control, respectively), RBY (3/1/1) appeared to be the second-best lighting condition (with soluble protein and vitamin C content increased by 8.6 and 4.1%, respectively compared with the control). Thus we prove that the addition of yellow light to the traditional combination of red/blue lighting conditions is beneficial to synthesizing photosynthetic pigments and enables superior outcome of purple cabbage growth. Our results indicate that the growth and nutritional quality of purple cabbage are greatly enhanced under RBY (3/1/1) light, and suggest that strategical management of lighting conditions holds promise in maximizing the economic efficiency of plant production and food quality of vegetables grown in controlled environments. PMID- 27965694 TI - Insertions/Deletions-Associated Nucleotide Polymorphism in Arabidopsis thaliana. AB - Although high levels of within-species variation are commonly observed, a general mechanism for the origin of such variation is still lacking. Insertions and deletions (indels) are a widespread feature of genomes and we hypothesize that there might be an association between indels and patterns of nucleotide polymorphism. Here, we investigate flanking sequences around 18 indels (>100 bp) among a large number of accessions of the plant, Arabidopsis thaliana. We found two distinct haplotypes, i.e., a nucleotide dimorphism, present around each of these indels and dimorphic haplotypes always corresponded to the indel-present/ absent patterns. In addition, the peaks of nucleotide diversity between the two divergent alleles were closely associated with these indels. Thus, there exists a close association between indels and dimorphisms. Further analysis suggests that indel-associated substitutions could be an important component of genetic variation shaping nucleotide polymorphism in Arabidopsis. Finally, we suggest a mechanism by which indels might generate these highly divergent haplotypes. This study provides evidence that nucleotide dimorphisms, which are frequently regarded as evidence of frequency-dependent selection, could be explained simply by structural variation in the genome. PMID- 27965692 TI - New Insights on Plant Salt Tolerance Mechanisms and Their Potential Use for Breeding. AB - Soil salinization is a major threat to agriculture in arid and semi-arid regions, where water scarcity and inadequate drainage of irrigated lands severely reduce crop yield. Salt accumulation inhibits plant growth and reduces the ability to uptake water and nutrients, leading to osmotic or water-deficit stress. Salt is also causing injury of the young photosynthetic leaves and acceleration of their senescence, as the Na+ cation is toxic when accumulating in cell cytosol resulting in ionic imbalance and toxicity of transpiring leaves. To cope with salt stress, plants have evolved mainly two types of tolerance mechanisms based on either limiting the entry of salt by the roots, or controlling its concentration and distribution. Understanding the overall control of Na+ accumulation and functional studies of genes involved in transport processes, will provide a new opportunity to improve the salinity tolerance of plants relevant to food security in arid regions. A better understanding of these tolerance mechanisms can be used to breed crops with improved yield performance under salinity stress. Moreover, associations of cultures with nitrogen-fixing bacteria and arbuscular mycorrhizal fungi could serve as an alternative and sustainable strategy to increase crop yields in salt-affected fields. PMID- 27965696 TI - Modeling Rice Metabolism: From Elucidating Environmental Effects on Cellular Phenotype to Guiding Crop Improvement. AB - Crop productivity is severely limited by various biotic and abiotic stresses. Thus, it is highly needed to understand the underlying mechanisms of environmental stress response and tolerance in plants, which could be addressed by systems biology approach. To this end, high-throughput omics profiling and in silico modeling can be considered to explore the environmental effects on phenotypic states and metabolic behaviors of rice crops at the systems level. Especially, the advent of constraint-based metabolic reconstruction and analysis paves a way to characterize the plant cellular physiology under various stresses by combining the mathematical network models with multi-omics data. Rice metabolic networks have been reconstructed since 2013 and currently six such networks are available, where five are at genome-scale. Since their publication, these models have been utilized to systematically elucidate the rice abiotic stress responses and identify agronomic traits for crop improvement. In this review, we summarize the current status of the existing rice metabolic networks and models with their applications. Furthermore, we also highlight future directions of rice modeling studies, particularly stressing how these models can be used to contextualize the affluent multi-omics data that are readily available in the public domain. Overall, we envisage a number of studies in the future, exploiting the available metabolic models to enhance the yield and quality of rice and other food crops. PMID- 27965695 TI - Integration of Plant Defense Traits with Biological Control of Arthropod Pests: Challenges and Opportunities. AB - Crop plants exhibit a wide diversity of defensive traits and strategies to protect themselves from damage by herbivorous pests and disease. These defensive traits may be naturally occurring or artificially selected through crop breeding, including introduction via genetic engineering. While these traits can have obvious and direct impacts on herbivorous pests, many have profound effects on higher trophic levels, including the natural enemies of herbivores. Multi-trophic effects of host plant resistance have the potential to influence, both positively and negatively, biological control. Plant defense traits can influence both the numerical and functional responses of natural enemies; these interactions can be semiochemically, plant toxin-, plant nutrient-, and/or physically mediated. Case studies involving predators, parasitoids, and pathogens of crop pests will be presented and discussed. These diverse groups of natural enemies may respond differently to crop plant traits based on their own unique biology and the ecological niches they fill. Genetically modified crop plants that have been engineered to express transgenic products affecting herbivorous pests are an additional consideration. For the most part, transgenic plant incorporated protectant (PIP) traits are compatible with biological control due to their selective toxicity to targeted pests and relatively low non-target impacts, although transgenic crops may have indirect effects on higher trophic levels and arthropod communities mediated by lower host or prey number and/or quality. Host plant resistance and biological control are two of the key pillars of integrated pest management; their potential interactions, whether they are synergistic, complementary, or disruptive, are key in understanding and achieving sustainable and effective pest management. PMID- 27965698 TI - Analysis of Complete Chloroplast Genome Sequences Improves Phylogenetic Resolution in Paris (Melanthiaceae). AB - The genus Paris in the broad concept is an economically important group in the monocotyledonous family Melanthiaceae (tribe Parideae). The phylogeny of Paris was controversial in previous morphology-based classification and molecular phylogeny. Here, the complete cp genomes of eleven Paris taxa were sequenced, to better understand the evolutionary relationships among these plants and the mutation patterns in their chloroplast (cp) genomes. Comparative analyses indicated that the overall cp genome structure among the Paris taxa is quite similar. The triplication of trnI-CAU was found only in the cp genomes of P. quadrifolia and P. verticillata. Phylogenetic analyses based on the complete cp genomes did not resolve Paris as a monophyletic group, instead providing evidence supporting division of the twelve taxa into two segregate genera: Paris sensu strict and Daiswa. The sister relationship between Daiswa and Trillium was well supported. We recovered two fully supported lineages with divergent distribution in Daiswa; however, none of the previously recognized sections in Daiswa was resolved as monophyletic using plastome data, suggesting that the infrageneric relationships and biogeography of Daiswa species require further investigation. Ten highly divergent DNA regions, suitable for species identification, were detected among the 12 cp genomes. This study is the first successful attempt to provide well-supported evolutionary relationships in Paris based on phylogenomic analyses. The findings highlight the potential of the whole cp genomes for improving resolution in phylogeny as well as species identification in phylogenetically and taxonomically difficult plant genera. PMID- 27965699 TI - Genome-Wide Association Study for Plant Height and Grain Yield in Rice under Contrasting Moisture Regimes. AB - Drought is one of the vitally critical environmental stresses affecting both growth and yield potential in rice. Drought resistance is a complicated quantitative trait that is regulated by numerous small effect loci and hundreds of genes controlling various morphological and physiological responses to drought. For this study, 270 rice landraces and cultivars were analyzed for their drought resistance. This was done via determination of changes in plant height and grain yield under contrasting water regimes, followed by detailed identification of the underlying genetic architecture via genome-wide association study (GWAS). We controlled population structure by setting top two eigenvectors and combining kinship matrix for GWAS in this study. Eighteen, five, and six associated loci were identified for plant height, grain yield per plant, and drought resistant coefficient, respectively. Nine known functional genes were identified, including five for plant height (OsGA2ox3, OsGH3-2, sd-1, OsGNA1, and OsSAP11/OsDOG), two for grain yield per plant (OsCYP51G3 and OsRRMh) and two for drought resistant coefficient (OsPYL2 and OsGA2ox9), implying very reliable results. A previous study reported OsGNA1 to regulate root development, but this study reports additional controlling of both plant height and root length. Moreover, OsRLK5 is a new drought resistant candidate gene discovered in this study. OsRLK5 mutants showed faster water loss rates in detached leaves. This gene plays an important role in the positive regulation of yield-related traits under drought conditions. We furthermore discovered several new loci contributing to the three investigated traits (plant height, grain yield, and drought resistance). These associated loci and candidate genes significantly improve our knowledge of the genetic control of these traits in rice. In addition, many drought resistant cultivars screened in this study can be used as parental genotypes to improve drought resistance of rice by molecular breeding. PMID- 27965697 TI - Non-host Resistance Induced by the Xanthomonas Effector XopQ Is Widespread within the Genus Nicotiana and Functionally Depends on EDS1. AB - Most Gram-negative plant pathogenic bacteria translocate effector proteins (T3Es) directly into plant cells via a conserved type III secretion system, which is essential for pathogenicity in susceptible plants. In resistant plants, recognition of some T3Es is mediated by corresponding resistance (R) genes or R proteins and induces effector triggered immunity (ETI) that often results in programmed cell death reactions. The identification of R genes and understanding their evolution/distribution bears great potential for the generation of resistant crop plants. We focus on T3Es from Xanthomonas campestris pv. vesicatoria (Xcv), the causal agent of bacterial spot disease on pepper and tomato plants. Here, 86 Solanaceae lines mainly of the genus Nicotiana were screened for phenotypical reactions after Agrobacterium tumefaciens-mediated transient expression of 21 different Xcv effectors to (i) identify new plant lines for T3E characterization, (ii) analyze conservation/evolution of putative R genes and (iii) identify promising plant lines as repertoire for R gene isolation. The effectors provoked different reactions on closely related plant lines indicative of a high variability and evolution rate of potential R genes. In some cases, putative R genes were conserved within a plant species but not within superordinate phylogenetical units. Interestingly, the effector XopQ was recognized by several Nicotiana spp. lines, and Xcv infection assays revealed that XopQ is a host range determinant in many Nicotiana species. Non-host resistance against Xcv and XopQ recognition in N. benthamiana required EDS1, strongly suggesting the presence of a TIR domain-containing XopQ-specific R protein in these plant lines. XopQ is a conserved effector among most xanthomonads, pointing out the XopQ-recognizing RxopQ as candidate for targeted crop improvement. PMID- 27965701 TI - Cuticular Wax Accumulation Is Associated with Drought Tolerance in Wheat Near Isogenic Lines. AB - Previous studies have shown that wheat grain yield is seriously affected by drought stress, and leaf cuticular wax is reportedly associated with drought tolerance. However, most studies have focused on cuticular wax biosynthesis and model species. The effects of cuticular wax on wheat drought tolerance have rarely been studied. The aims of the current study were to study the effects of leaf cuticular wax on wheat grain yield under drought stress using the above mentioned wheat NILs and to discuss the possible physiological mechanism of cuticular wax on high grain yield under drought stress. Compared to water irrigated (WI) conditions, the cuticular wax content (CWC) in glaucous and non glaucous NILs under drought-stress (DS) conditions both increased; mean increase values were 151.1 and 114.4%, respectively, which was corroborated by scanning electronic microscopy images of large wax particles loaded on the surfaces of flag leaves. The average yield of glaucous NILs was higher than that of non glaucous NILs under DS conditions in 2014 and 2015; mean values were 7368.37 kg.ha-1 and 7103.51 kg.ha-1. This suggested that glaucous NILs were more drought tolerant than non-glaucous NILs (P = 0.05), which was supported by the findings of drought tolerance indices TOL and SSI in both years, the relatively high water potential and relative water content, and the low ELWL. Furthermore, the photosynthesis rate (Pn ) of glaucous and non-glaucous wheat NILs under DS conditions decreased by 7.5 and 9.8%, respectively; however, glaucous NILs still had higher mean values of Pn than those of non-glaucous NILs, which perhaps resulted in the higher yield of glaucous NILs. This could be explained by the fact that glaucous NILs had a smaller Fv/Fm reduction, a smaller PI reduction and a greater ABS/RC increase than non-glaucous NILs under DS conditions. This is the first report to show that wheat cuticular wax accumulation is associated with drought tolerance. Moreover, the leaf CWC can be an effective selection criterion in the development of drought-tolerant wheat cultivars. PMID- 27965700 TI - Genome-Wide Analysis of the Aquaporin Gene Family in Chickpea (Cicer arietinum L.). AB - Aquaporins (AQPs) are essential membrane proteins that play critical role in the transport of water and many other solutes across cell membranes. In this study, a comprehensive genome-wide analysis identified 40 AQP genes in chickpea (Cicer arietinum L.). A complete overview of the chickpea AQP (CaAQP) gene family is presented, including their chromosomal locations, gene structure, phylogeny, gene duplication, conserved functional motifs, gene expression, and conserved promoter motifs. To understand AQP's evolution, a comparative analysis of chickpea AQPs with AQP orthologs from soybean, Medicago, common bean, and Arabidopsis was performed. The chickpea AQP genes were found on all of the chickpea chromosomes, except chromosome 7, with a maximum of six genes on chromosome 6, and a minimum of one gene on chromosome 5. Gene duplication analysis indicated that the expansion of chickpea AQP gene family might have been due to segmental and tandem duplications. CaAQPs were grouped into four subfamilies including 15 NOD26-like intrinsic proteins (NIPs), 13 tonoplast intrinsic proteins (TIPs), eight plasma membrane intrinsic proteins (PIPs), and four small basic intrinsic proteins (SIPs) based on sequence similarities and phylogenetic position. Gene structure analysis revealed a highly conserved exon-intron pattern within CaAQP subfamilies supporting the CaAQP family classification. Functional prediction based on conserved Ar/R selectivity filters, Froger's residues, and specificity determining positions suggested wide differences in substrate specificity among the subfamilies of CaAQPs. Expression analysis of the AQP genes indicated that some of the genes are tissue-specific, whereas few other AQP genes showed differential expression in response to biotic and abiotic stresses. Promoter profiling of CaAQP genes for conserved cis-acting regulatory elements revealed enrichment of cis-elements involved in circadian control, light response, defense and stress responsiveness reflecting their varying pattern of gene expression and potential involvement in biotic and abiotic stress responses. The current study presents the first detailed genome-wide analysis of the AQP gene family in chickpea and provides valuable information for further functional analysis to infer the role of AQP in the adaptation of chickpea in diverse environmental conditions. PMID- 27965703 TI - New Communities on Eucalypts Grown Outside Australia. AB - The expansion of eucalypt forestry worldwide has been accompanied by accidental and deliberate introductions of Australian insects associated with eucalypts. Local insect species have also colonized introduced eucalypts in many regions. This situation provides a unique opportunity to observe the development of new insect communities across trophic levels. Here the history of Australian invaders and native colonizers on eucalypts outside Australia is reviewed from the perspective of herbivore guilds: leaf chewers, sap suckers, wood borers, gall formers, termites. Historical patterns of invasion are identified across these guilds. Very few species of Australian leaf chewers, wood borers or termites have become widespread but these guilds are proportionately high in native colonizers. In contrast, sap suckers have multiple invasive species globally with relatively fewer native colonizers. The gall former guild also has several invasive species but so far includes no native colonizers, perhaps due to their tendency to have highly specific host plant associations. Natural enemies of Australian invaders are also members of new eucalypt insect communities, partly through planned biological control programs, but the rate of accidental introductions at higher trophic levels is increasing steadily. At the same time, local natural enemies enter eucalypt communities either to form new associations with Australian invaders or to follow native colonizers into this new habitat. Australian sap suckers have attracted far more new associations than other guilds so far. Native leaf chewers have often been followed by their local natural enemies into eucalypt communities, particularly in Brazil. Generally there are fewer records relating to local natural enemies and their role in new eucalypt communities. The complexity of new eucalypt communities outside Australia is expected to increase in future. PMID- 27965702 TI - The Eucalyptus Tonoplast Intrinsic Protein (TIP) Gene Subfamily: Genomic Organization, Structural Features, and Expression Profiles. AB - Plant aquaporins are water channels implicated in various physiological processes, including growth, development and adaptation to stress. In this study, the Tonoplast Intrinsic Protein (TIP) gene subfamily of Eucalyptus, an economically important woody species, was investigated and characterized. A genome-wide survey of the Eucalyptus grandis genome revealed the presence of eleven putative TIP genes (referred as EgTIP), which were individually assigned by phylogeny to each of the classical TIP1-5 groups. Homology modeling confirmed the presence of the two highly conserved NPA (Asn-Pro-Ala) motifs in the identified EgTIPs. Residue variations in the corresponding selectivity filters, that might reflect differences in EgTIP substrate specificity, were observed. All EgTIP genes, except EgTIP5.1, were transcribed and the majority of them showed organ/tissue-enriched expression. Inspection of the EgTIP promoters revealed the presence of common cis-regulatory elements implicated in abiotic stress and hormone responses pointing to an involvement of the identified genes in abiotic stress responses. In line with these observations, additional gene expression profiling demonstrated increased expression under polyethylene glycol-imposed osmotic stress. Overall, the results obtained suggest that these novel EgTIPs might be functionally implicated in eucalyptus adaptation to stress. PMID- 27965704 TI - Magnesium Alleviates Adverse Effects of Lead on Growth, Photosynthesis, and Ultrastructural Alterations of Torreya grandis Seedlings. AB - Magnesium (Mg2+) has been shown to reduce the physiological and biochemical stress in plants caused by heavy metals. To date our understanding of how Mg2+ ameliorates the adverse effects of heavy metals in plants is scarce. The potential effect of Mg2+ on lead (Pb2+) toxicity in plants has not yet been studied. This study was designed to clarify the mechanism of Mg2+-induced alleviation of lead (Pb2+) toxicity. Torreya grandis (T. grandis) seedlings were grown in substrate contaminated with 0, 700 and 1400 mg Pb2+ per kg-1 and with or without the addition of 1040 mg kg-1 Mg2+. Growth parameters, concentrations of Pb2+ and Mg2+ in the plants' shoots and roots, photosynthetic pigment, gas exchange parameters, the maximum quantum efficiency (Fv/Fm), root oxidative activity, ultrastructure of chloroplasts and root growth were determined to analyze the effect of different Pb2+ concentrations on the seedlings as well as the potential ameliorating effect of Mg2+ on the Pb2+ induced toxicity. All measurements were tested by a one-way ANOVA for the effects of treatments. The growth of T. grandis seedlings cultivated in soils treated with 1400 mg kg-1 Pb2+ was significantly reduced compared with that of plants cultivated in soils treated with 0 or 700 mg kg-1 Pb2+. The addition of 1040 mg kg-1 Mg2+ improved the growth of the Pb2+-stressed seedlings, which was accompanied by increased chlorophyll content, the net photosynthetic rate and Fv/Fm, and enhanced chloroplasts development. In addition, the application of Mg2+ induced plants to accumulate five times higher concentrations of Pb2+ in the roots and to absorb and translocate four times higher concentrations of Mg2+ to the shoots than those without Mg2+ application. Furthermore, Mg2+ addition increased root growth and oxidative activity, and protected the root ultrastructure. To the best of our knowledge, our study is the first report on the mechanism of Mg2+-induced alleviation of Pb2+ toxicity. The generated results may have important implications for understanding the physiological interactions between heavy metals and plants, and for successful management of T. grandis plantations grown on soils contaminated with Pb2+. PMID- 27965706 TI - Beneficial Roles of Melatonin on Redox Regulation of Photosynthetic Electron Transport and Synthesis of D1 Protein in Tomato Seedlings under Salt Stress. AB - Melatonin is important in the protection of plants suffering various forms of abiotic stress. The molecular mechanisms underlying the melatonin-mediated protection of their photosynthetic machinery are not completely resolved. This study investigates the effects of exogenous melatonin applications on salt induced damage to the light reaction components of the photosynthetic machinery of tomato seedlings. The results showed that melatonin pretreatments can help maintain growth and net photosynthetic rate (PN) under salt stress conditions. Pretreatment with melatonin increased the effective quantum yield of photosystem II (PhiPSII), the photochemical quenching coefficient (qP) and the proportion of PSII centers that are "open" (qL) under saline conditions. In this way, damage to the photosynthetic electron transport chain (PET) in photosystem II (PSII) was mitigated. In addition, melatonin pretreatment facilitated the repair of PSII by maintaining the availability of D1 protein that was otherwise reduced by salinity. The ROS levels and the gene expressions of the chloroplast TRXs and PRXs were also investigated. Salt stress resulted in increased levels of reactive oxygen species (ROS), which were mitigated by melatonin. In tomato leaves under salt stress, the expressions of PRXs and TRXf declined but the expressions of TRXm1/4 and TRXm2 increased. Melatonin pretreatment promoted the expression of TRXf and the abundances of TRXf and TRXm gene products but had no effects on the expressions of PRXs. In summary, melatonin improves the photosynthetic activities of tomato seedlings under salt stress. The mechanism could be that: (1) Melatonin controls ROS levels and prevents damaging elevations of ROS caused by salt stress. (2) Melatonin facilitates the recovery of PET and D1 protein synthesis, thus enhancing the tolerance of photosynthetic activities to salinity. (3) Melatonin induces the expression of TRXf and regulates the abundance of TRXf and TRXm gene products, which may facilitate repair of the light reaction parts of the photosynthetic machinery. PMID- 27965707 TI - Efficient Breeding by Genomic Mating. AB - Selection in breeding programs can be done by using phenotypes (phenotypic selection), pedigree relationship (breeding value selection) or molecular markers (marker assisted selection or genomic selection). All these methods are based on truncation selection, focusing on the best performance of parents before mating. In this article we proposed an approach to breeding, named genomic mating, which focuses on mating instead of truncation selection. Genomic mating uses information in a similar fashion to genomic selection but includes information on complementation of parents to be mated. Following the efficiency frontier surface, genomic mating uses concepts of estimated breeding values, risk (usefulness) and coefficient of ancestry to optimize mating between parents. We used a genetic algorithm to find solutions to this optimization problem and the results from our simulations comparing genomic selection, phenotypic selection and the mating approach indicate that current approach for breeding complex traits is more favorable than phenotypic and genomic selection. Genomic mating is similar to genomic selection in terms of estimating marker effects, but in genomic mating the genetic information and the estimated marker effects are used to decide which genotypes should be crossed to obtain the next breeding population. PMID- 27965705 TI - Characterization and Genetic Analysis of Rice Mutant crr1 Exhibiting Compromised Non-host Resistance to Puccinia striiformis f. sp. tritici (Pst). AB - Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most devastating diseases of wheat in China. Rapid change to virulence following release of resistant cultivars necessitates ongoing discovery and exploitation of new resistance resources. Considerable effort has been directed at non-host resistance (NHR) which is believed to be durable. In the present study we identified rice mutant crr1 (compromised resistance to rust 1) that exhibited compromised NHR to Pst. Compared with wild type rice variety Nipponbare, crr1 mutant displayed a threefold increase in penetration rate by Pst, and enhanced hyphal growth. The pathogen also developed haustoria in crr1 mesophyll cells, but failed to sporulate. The response to the adapted rice pathogen Magnaporthe oryzae was unchanged in crr1 relative to the wild type. Several defense-related genes involved in the SA- and JA-mediated defense pathways response and in phytoalexin synthesis (such as OsPR1a, OsLOX1, and OsCPS4) were more rapidly and strongly induced in infected crr1 leaves than in the wild type, suggesting that other layers of defense are still in effect. Genetic analysis and mapping located the mutant loci at a region between markers ID14 and RM25792, which cover about 290 kb genome sequence on chromosome 10. Further fine mapping and cloning of the locus should provide further insights into NHR to rust fungi in rice, and may reveal new strategies for improving rust resistance in wheat. PMID- 27965708 TI - n-Gram-Based Text Compression. AB - We propose an efficient method for compressing Vietnamese text using n-gram dictionaries. It has a significant compression ratio in comparison with those of state-of-the-art methods on the same dataset. Given a text, first, the proposed method splits it into n-grams and then encodes them based on n-gram dictionaries. In the encoding phase, we use a sliding window with a size that ranges from bigram to five grams to obtain the best encoding stream. Each n-gram is encoded by two to four bytes accordingly based on its corresponding n-gram dictionary. We collected 2.5 GB text corpus from some Vietnamese news agencies to build n-gram dictionaries from unigram to five grams and achieve dictionaries with a size of 12 GB in total. In order to evaluate our method, we collected a testing set of 10 different text files with different sizes. The experimental results indicate that our method achieves compression ratio around 90% and outperforms state-of-the-art methods. PMID- 27965710 TI - New Biofunctional Loading of Natural Antimicrobial Agent in Biodegradable Polymeric Films for Biomedical Applications. AB - The study focuses on the development of novel Aloe vera based polymeric composite films and antimicrobial suture coatings. Polyvinyl alcohol (PVA), a synthetic biocompatible and biodegradable polymer, was combined with Aloe vera, a natural herb used for soothing burning effects and cosmetic purposes. The properties of these two materials were combined together to get additional benefits such as wound healing and prevention of surgical site infections. PVA and Aloe vera were mixed in a fixed quantity to produce polymer based films. The films were screened for antibacterial and antifungal activity against bacterial (E. coli, P. aeruginosa) and fungal strains (Aspergillus flavus and Aspergillus tubingensis) screened. Aloe vera based PVA films showed antimicrobial activity against all the strains; the lowest Aloe vera concentration (5%) showed the highest activity against all the strains. In vitro degradation and release profile of these films was also evaluated. The coating for sutures was prepared, in vitro antibacterial tests of these coated sutures were carried out, and later on in vivo studies of these coated sutures were also performed. The results showed that sutures coated with Aloe vera/PVA coating solution have antibacterial effects and thus have the potential to be used in the prevention of surgical site infections and Aloe vera/PVA based films have the potential to be used for wound healing purposes. PMID- 27965709 TI - Pattern and Distribution of Colorectal Cancer in Tanzania: A Retrospective Chart Audit at Two National Hospitals. AB - Background. Colorectal cancer (CRC) is a growing public health concern with increasing rates in countries with previously known low incidence. This study determined pattern and distribution of CRC in Tanzania and identified hot spots in case distribution. Methods. A retrospective chart audit reviewed hospital registers and patient files from two national institutions. Descriptive statistics, Chi square (chi2) tests, and regression analyses were employed and augmented by data visualization to display risk variable differences. Results. CRC cases increased sixfold in the last decade in Tanzania. There was a 1.5% decrease in incidences levels of rectal cancer and 2% increase for colon cancer every year from 2005 to 2015. Nearly half of patients listed Dar es Salaam as their primary residence. CRC was equally distributed between males (50.06%) and females (49.94%), although gender likelihood of diagnosis type (i.e., rectal or colon) was significantly different (P = 0.027). More than 60% of patients were between 40 and 69 years. Conclusions. Age (P = 0.0183) and time (P = 0.004) but not gender (P = 0.0864) were significantly associated with rectal cancer in a retrospective study in Tanzania. Gender (P = 0.0405), age (P = 0.0015), and time (P = 0.0075) were all significantly associated with colon cancer in this study. This retrospective study found that colon cancer is more prevalent among males at a relatively younger age than rectal cancer. Further, our study showed that although more patients were diagnosed with rectal cancer, the trend has shown that colon cancer is increasing at a faster rate. PMID- 27965711 TI - The Buried Bumper Syndrome: External Bumper Extraction after Radial Mini Incisions and Replacement through an Adjacent Tract. AB - Although considered as a safe method to provide long-term nutritional support, percutaneous endoscopic gastrostomy (PEG) may be complicated by a buried bumper syndrome (BBS), a life-threatening condition. Removal of the PEG tube with its buried bumper and reinsertion of a new PEG tube is often necessary. Since its description in 1988, less than 50 cases of BBS managed by external extraction of the buried bumper have been reported. We report a case of buried bumper that was removed by external traction without the need for endoscopic or laparoscopic treatment but with the need of two radial millimeter skin incisions after abdominal CT study and finally immediate PEG replacement but through an adjacent site. PMID- 27965712 TI - Targeted Inhibition of the miR-199a/214 Cluster by CRISPR Interference Augments the Tumor Tropism of Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells under Hypoxic Condition. AB - The human induced pluripotent stem cell (hiPSC) provides a breakthrough approach that helps overcoming ethical and allergenic challenges posed in application of neural stem cells (NSCs) in targeted cancer gene therapy. However, the tumor tropic capacity of hiPSC-derived NSCs (hiPS-NSCs) still has much room to improve. Here we attempted to promote the tumor tropism of hiPS-NSCs by manipulating the activity of endogenous miR-199a/214 cluster that is involved in regulation of hypoxia-stimulated cell migration. We first developed a baculovirus-delivered CRISPR interference (CRISPRi) system that sterically blocked the E-box element in the promoter of the miR-199a/214 cluster with an RNA-guided catalytically dead Cas9 (dCas9). We then applied this CRISPRi system to hiPS-NSCs and successfully suppressed the expression of miR-199a-5p, miR-199a-3p, and miR-214 in the microRNA gene cluster. Meanwhile, the expression levels of their targets related to regulation of hypoxia-stimulated cell migration, such as HIF1A, MET, and MAPK1, were upregulated. Further migration assays demonstrated that the targeted inhibition of the miR-199a/214 cluster significantly enhanced the tumor tropism of hiPS-NSCs both in vitro and in vivo. These findings suggest a novel application of CRISPRi in NSC-based tumor-targeted gene therapy. PMID- 27965714 TI - Doppler ultrasound in kidney diseases: a key parameter in clinical long-term follow-up. AB - Doppler ultrasound has been extensively used in detecting reno-vascular diseases, showing to be a non-invasive, safe, low cost and repeatable tool. The Renal Resistive Index (RRI) [(peak systolic velocity - end diastolic velocity)/peak systolic velocity] is a semi-quantitative index derived by Doppler evaluation of renal vascular bed. Normally RRI is in the range of 0.47-0.70, it increases with aging and, usually, it shows a difference between the two kidneys less than 5-8 %. RRI is an important prognostic marker in chronic kidney diseases (CKD), both in diabetic and non-diabetic kidney diseases, because, in longitudinal prospective studies, it significantly correlated with hemodynamic (ABPM, SBP, DBP, pulse pressure) and histopathological parameters (glomerular sclerosis, arteriolosclerosis, interstitial fibrosis/tubular atrophy, interstitial infiltration). In acute kidney injury (AKI) RI is a valid tool in differentiating between pre-renal and renal failure and in predicting renal response to vaso active agents. In addition a RRI >0.74 can predict the onset of AKI in septic patients. Renal Resistive Index is a useful marker in allograft diseases because it has been widely showed a correlation with histological lesions during worsening of renal function, both in acute rejection and in chronic allograft nephropathy. Recent studies suggest its role in the risk of new onset diabetes after transplantation and it could be one of the parameters to evaluate to shift or withdrawal immunological and/or hypertensive therapy. PMID- 27965713 TI - Short-Term Efficacy of Pudilan Keyanning Toothpaste in Treatment of Minor Recurrent Aphthous Ulcers. AB - Aim. To examine the potential of Pudilan Keyanning toothpaste (PKT) to treat minor aphthous ulcers (MiAU). Method. A double-blind clinical trial was conducted in which 80 volunteers were randomly assigned to the PKT group (N = 40) or the control group (N = 40). The control group used a placebo toothpaste containing no Pudilan extract. At baseline, after 3 days, and after 6 days the following parameters were recorded for the target ulcers: healing rate, healing period, pain (visual analogue scale, VAS), areas of the target ulcerated lesions, degree of exudation, and hyperemia. Results. At the end of the study, the healing rate in the PKT group was 80%, compared to 50% in the control group (p < 0.05). At day 6, the VAS scores, ulcer area, degree of exudation, and hyperemia were significantly different between the two groups, with better performance observed in the PKT group (p < 0.05). Conclusion. PKT toothpaste appears to promote effective healing of MiAU. PMID- 27965715 TI - Speed of sound in rubber-based materials for ultrasonic phantoms. AB - PURPOSE: In this work we provide measurements of speed of sound (SoS) and acoustic impedance (Z) of some doped/non-doped rubber-based materials dedicated to the development of ultrasound phantoms. These data are expected to be useful for speeding-up the preparation of multi-organ phantoms which show similar echogenicity to real tissues. METHODS: Different silicones (Ecoflex, Dragon-Skin Medium) and polyurethane rubbers with different liquid (glycerol, commercial detergent, N-propanol) and solid (aluminum oxide, graphene, steel, silicon powder) inclusions were prepared. SoS of materials under investigation was measured in an experimental setup and Z was obtained by multiplying the density and the SoS of each material. Finally, an anatomically realistic liver phantom has been fabricated selecting some of the tested materials. RESULTS: SoS and Z evaluation for different rubber materials and formulations are reported. The presence of liquid additives appears to increase the SoS, while solid inclusions generally reduce the SoS. The ultrasound images of realized custom fabricated heterogeneous liver phantom and a real liver show remarkable similarities. CONCLUSIONS: The development of new materials' formulations and the knowledge of acoustic properties, such as speed of sound and acoustic impedance, could improve and speed-up the development of phantoms for simulations of ultrasound medical procedures. PMID- 27965716 TI - Localized cervical pain: advantages and limits of ultrasound evaluation. AB - PURPOSE: Cervical pain is very frequent in the general population. In clinical practice, plain X-ray and, in selected cases, computed tomography or magnetic resonance imaging, are performed. However, the feasibility and utility of ultrasound examination have been poorly investigated. Aim of the present study was to evaluate whether ultrasound could be useful in the diagnosis of localized cervical pain. METHODS: Subjects suffering from posterior cervical pain without irradiation to surrounding tissues were enrolled. After clinical and functional evaluation (demographic and anthropometric data, VAS at rest and during neck movements, symptoms duration, and characteristics of pain onset [atraumatic or traumatic]), an ultrasound exam of the cervical spine was performed according to standard protocols. RESULTS: The anatomic structures of the neck district were visualized in 124/127 enrolled patients and pathological features were observed in 58. Significant ultrasound differences were registered between the patients with traumatic and atraumatic onset of neck pain. In the first group, articular effusion, capsular bulging, disalignment and avulsion of the articular apex were observed, whereas in the latter cortical irregularities, osteophytosis, and articular ankylosis were prevalent. CONCLUSIONS: Ultrasound examination can be used as diagnostic tool in the evaluation of selected patients suffering from localized cervical pain, particularly in cases of pain due to traumatic injuries. PMID- 27965717 TI - Evaluation of the human blood entropy production: a new thermodynamic approach. AB - In this paper, we follow the thermodynamic theory with internal variables of Kluitenberg evaluating the entropy production of red blood cell in saline solution and whole blood, respectively, when they are subjected to an ultrasound wave. From a thermodynamic point of view, blood is an open system; so to fully represent the entropy variation as function of frequency perturbation we employ phenomenological coefficients which allow us to qualitatively discriminate among classes of phenomena which cannot be observed in any other way. Therefore, a correlation between these coefficients and quantities experimentally measurable allows to a deeper knowledge of biological phenomena. PMID- 27965718 TI - Limiting overdiagnosis of low-risk prostate cancer through an evaluation of the predictive value of transrectal and power Doppler ultrasonography. AB - PURPOSE: Overdiagnosis induced by prostate cancer screening makes necessary a better selection of candidate patients for prostate biopsy. The objective of our study is to assess the probability of having a high- or low-risk lesion that could require active surveillance (AS) after biopsies and a normal or abnormal examination, including transrectal and power Doppler ultrasonography (TRUS-PDS). METHODS: Four hundred and twenty-nine consecutive patients with a PSA level <10 ng/ml and a normal digital rectal examination (DRE) had guided biopsies in a prospective study. We used D'Amico's criteria to assess the risk of a biological recurrence and Dall'Era's criteria to assess possible AS. The TRUS-PDS was considered positive if one biopsy was positive in the same sextant as the suspect image. RESULTS: One hundred and seventy-seven out of 429 (41 %) T1c cancers were diagnosed; 131 out of 177 (74 %) could be qualified as low risk, and 119 out of 177 (67 %) could require AS. The TRUS-PDS was normal in 285 of 429 patients (66 %). With a normal TRUS-PDS, the probability of not having cancer with a high or intermediate risk was 96 % (negative predictive value). With an abnormal TRUS PDS, the probability of having a positive biopsy was 59 %, and the probability of having a significant cancer was 30 %, according to the Dall'Era criteria. When TRUS-PDS was normal, these probabilities significantly decreased to 32 and 5 %, respectively (p < 0.01). CONCLUSIONS: Patients with a PSA level <10 ng/ml, a normal DRE, and a normal TRUS-PDS have a less than 5 % risk of high- or intermediate-risk cancer. PMID- 27965720 TI - An unusual cause of lumbar pain after physical exercise: Caval vein duplicity and its detection by ultrasound. AB - This paper deals with two recent cases of Inferior Caval Vein (IVC) duplicity, congenital anomaly often but not always asymptomatic that should be considered in the differential diagnosis of flank pain when other more common disorders have been excluded. Here are described the clinical and surgical significance together with the typical sonographic findings useful for the diagnosis of IVC duplicity. Particular attention is given to a peculiar and easily repeatable sonographic aspect associated with IVC duplicity, not previously reported in Literature and that we called the "Neptune's sign". PMID- 27965719 TI - What is the role of contrast-enhanced ultrasound in the evaluation of the endoleak of aortic endoprostheses? A comparison between CEUS and CT on a widespread scale. AB - OBJECTIVE: To evaluate the accuracy of contrast-enhanced ultrasound (CEUS) in comparison to CT angiography (CTA) to identify and classify endoleaks following abdominal aortic aneurism repair with endoprosthesis. MATERIALS AND METHODS: A retrospective analysis of 181 patients treated with EVAR, from September 2009 to September 2014, was performed. Patients were evaluated with CEUS, CTA and angiography in the cases requiring treatment. Sac diameter, sac integrity, identification and classification of endoleaks were taken into consideration. Sensitivity, specificity, accuracy and negative predictive values were considered for each modality of endoleak identification. RESULTS: Forty-two endoleaks (23.2%; type II: 39 cases, type III: 3 cases) were documented. Sensitivity and specificity of CEUS and CT were, respectively, 97.6 and 90.5, 100 and 100%. In two cases, CEUS was able to better classify endoleaks compared to CT. CONCLUSIONS: CEUS accuracy to identify endoleaks following EVAR is similar to CT. CEUS should be considered as an effective modality for the long-term surveillance of EVAR because of its capability to correctly classify endoleaks with no ionizing radiation exposure. PMID- 27965722 TI - Usefulness of ultrasound imaging in overhydrated nephropathic patients. PMID- 27965721 TI - Killian-Jamieson diverticulum: real-time sonographic findings. AB - Killian-Jamieson diverticulum (KJD) is a pharyngoesophageal diverticulum that can be observed during a neck ultrasound examination. Because of its position, it is frequently misinterpreted as a thyroid nodule. We present a case of an incidental finding of KJD, where changes in shape during dynamic scanning led to the correct diagnosis, preventing from invasive procedures such as fine needle aspiration. PMID- 27965723 TI - Prevalence of polycystic ovary morphology in a region of South Italy. PMID- 27965725 TI - Clinical characteristics of childhood cancer in emergency room in a tertiary hospital in Pakistan. PMID- 27965724 TI - Enterogenous infection of Candida albicans in immunocompromised rats under severe acute pancreatitis. AB - BACKGROUND: Opportunistic infection of Candida albicans (C. albicans) has become a serious problem in immunocompromised patients. The study aimed to explore the mechanism of enterogenous infection of C. albicans in immunocompromised rats under severe acute pancreatitis (SAP). METHODS: Sprague Dawley (SD) rats (n=100) were randomly assigned into 5 groups as the following: blank group, cyclophosphamide+ceftriaxone+SAP group, cyclophosphamide+ceftriaxone group, cyclophosphamide+SAP group, and cyclophosphamide group. The rats were sacrificed at 5 and 10 days, and their jejunum, colon, mesenteric lymph nodes, pancreas, intestinal content, and blood were quickly collected to detect C. albicans. A region of the 25S rRNA gene was chosen and amplified by polymerase chain reaction (PCR) to differentiate C. albicans genotypes. The amplified products were further sequenced and compared to judge their homology. RESULTS: Compared with the Cyclophosphamide group, the combination of immunosuppressants and broad-spectrum antibiotics significantly increased the colonization of C. albicans in intestine in 5 and 10 days. Pure SAP stress did not increase the opportunistic infection of C. albicans. The PCR products of C. albicans isolates all belonged to the genotype A family, and sequence alignment showed that the amplified fragments were homologous. CONCLUSION: The damage of immune system and broad-spectrum antimicrobial agents are important risk factors for opportunistic fungal infection. Intestinal tract is an important source for genotype-A C. albicans to translocate and invade into bloodstream. PMID- 27965726 TI - When gastroenteritis isn't: a case report of a 20-year-old male with Boerhaave's syndrome complicated by intra-abdomimal hemorrhage. PMID- 27965727 TI - Emergency department diagnosis of a concealed pleurocutaneous fistula in a 78 year-old man using point-of-care ultrasound. PMID- 27965728 TI - Stroke due to Bonzai use: two patients. PMID- 27965729 TI - A novel method for fabricating engineered structures with branched micro-channel using hollow hydrogel fibers. AB - Vascularization plays a crucial role in the regeneration of different damaged or diseased tissues and organs. Vascularized networks bring sufficient nutrients and oxygen to implants and receptors. However, the fabrication of engineered structures with branched micro-channels (ESBM) is still the main technological barrier. To address this problem, this paper introduced a novel method for fabricating ESBM; the manufacturability and feasibility of this method was investigated. A triaxial nozzle with automatic cleaning function was mounted on a homemade 3D bioprinter to coaxially extrude sodium alginate (NaAlg) and calcium chloride (CaCl2) to form the hollow hydrogel fibers. With the incompleteness of cross-linking and proper trimming, ESBM could be produced rapidly. Different concentrations of NaAlg and CaCl2 were used to produce ESBM, and mechanical property tests were conducted to confirm the optimal material concentration for making the branched structures. Cell media could be injected into the branched channel, which showed a good perfusion. Fibroblasts were able to maintain high viability after being cultured for a few days, which verified the non cytotoxicity of the gelation and fabrication process. Thus, hollow hydrogel fibers were proved to be a potential method for fabricating micro-channels for vascularization. PMID- 27965730 TI - A microfluidic method and custom model for continuous, non-intrusive biofilm viscosity measurements under different nutrient conditions. AB - Straight, low-aspect ratio micro flow cells are used to support biofilm attachment and preferential accumulation at the short side-wall, which progressively reduces the effective channel width. The biofilm shifts downstream at measurable velocities under the imposed force from the constant laminar co flowing nutrient stream. The dynamic behaviour of the biofilm viscosity is modeled semi-analytically, based on experimental measurements of biofilm dimensions and velocity as inputs. The technique advances the study of biofilm mechanical properties by strongly limiting biases related to non-Newtonian biofilm properties (e.g., shear dependent viscosity) with excellent time resolution. To demonstrate the proof of principle, young Pseudomonas sp. biofilms were analyzed under different nutrient concentrations and constant micro-flow conditions. The striking results show that large initial differences in biofilm viscosities grown under different nutrient concentrations become nearly identical in less than one day, followed by a continuous thickening process. The technique verifies that in 50 h from inoculation to early maturation stages, biofilm viscosity could grow by over 2 orders of magnitude. The approach opens the way for detailed studies of mechanical properties under a wide variety of physiochemical conditions, such as ionic strength, temperature, and shear stress. PMID- 27965731 TI - Dynamic simulations show repeated narrowing maximizes DNA linearization in elastomeric nanochannels. AB - This paper uses computer simulations to reveal unprecedented details about linearization of deoxyribonucleic acid (DNA) inside dynamic nanochannels that can be repeatedly widened and narrowed. We first analyze the effect of rate of channel narrowing on DNA linearization dynamics. Quick (~0.1 s) narrowing of nanoscale channels results in rapid overstretching of the semi-flexible chain followed by a slower (~0.1-10 s) relaxation to an equilibrium extension. Two phenomena that induce linearization during channel narrowing, namely, elongational-flow and confinement, occur simultaneously, regardless of narrowing speed. Interestingly, although elongational flow is a minimum at the mid-point of the channel and increases towards the two ends, neither the linearization dynamics nor the degree of DNA extension varies significantly with the center-of mass of the polymer projected on the channel axis. We also noticed that there was a significant difference in time to reach the equilibrium length, as well as the degree of DNA linearization at short times, depending on the initial conformation of the biopolymer. Based on these observations, we tested a novel linearization protocol where the channels are narrowed and widened repeatedly, allowing DNA to explore multiple conformations. Repeated narrowing and widening, something uniquely enabled by the elastomeric nanochannels, significantly decrease the time to reach the equilibrium-level of stretch when performed within periods comparable to the chain relaxation time and more effectively untangle chains into more linearized biopolymers. PMID- 27965734 TI - The Effect of Macrocyclic Lactones-Ivermectin Exposure on Egg Hatching and Larval Development of Caenorhabditis elegans. AB - To date, the ivermectin resistance in nematode parasites has been reported and many studies are carried out to determine the causes of this problem. A free living Caenorhabditis elegans is used as a model system for this study to investigate the response of C. elegans to ivermectin exposure by using larval development assay. Worms were exposed to ivermectin at concentration from 1 ng/mL to 10 ng/mL and dimethyl sulphoxide (DMSO) as a control. The developments of the worms were monitored for 24, 48, 72, and 96 hours until the worms become adults. Results indicated that worms' growth began to be affected by ivermectin at a concentration of 5 ng/mL, while at the concentration of 6, 7, 8, 9, and 10 ng/mL, the growth of worms were inhibited compared to control worms. Further study of the protein expression in C. elegans should be done to investigate the up regulated and down-regulated proteins involve in ivermectin resistance. PMID- 27965732 TI - Phytochemical Composition, Antioxidant Activity, and the Effect of the Aqueous Extract of Coffee (Coffea arabica L.) Bean Residual Press Cake on the Skin Wound Healing. AB - The world coffee consumption has been growing for its appreciated taste and its beneficial effects on health. The residual biomass of coffee, originated in the food industry after oil extraction from coffee beans, called coffee beans residual press cake, has attracted interest as a source of compounds with antioxidant activity. This study investigated the chemical composition of aqueous extracts of coffee beans residual press cake (AE), their antioxidant activity, and the effect of topical application on the skin wound healing, in animal model, of hydrogels containing the AE, chlorogenic acid (CGA), allantoin (positive control), and carbopol (negative control). The treatments' performance was compared by measuring the reduction of the wound area, with superior result (p < 0.05) for the green coffee AE (78.20%) with respect to roasted coffee AE (53.71%), allantoin (70.83%), and carbopol (23.56%). CGA hydrogels reduced significantly the wound area size on the inflammatory phase, which may be associated with the well known antioxidant and anti-inflammatory actions of that compound. The topic use of the coffee AE studied improved the skin wound healing and points to an interesting biotechnological application of the coffee bean residual press cake. PMID- 27965735 TI - Environment and Host Affects Arbuscular Mycorrhiza Fungi (AMF) Population. AB - The association of arbuscular mycorrhiza fungi (AMF) and roots undoubtedly gives positive advantages to the host plant. However, heavily fertilised soil such as in oil palm plantation, inhibit the growth of mycorrhiza. Thus, the aim of this research is to distinguish and quantify the availability of AMF population and propagules at different sites of an oil palm plantation by Most Probable Number (MPN) assay. In addition, root infection method was employed to observe host compatibility through the propagation of AMF using two different types of hosts, monocotyledon (Echinochloa cruss-galli) and dicotyledon (Vigna radiata). Three different locations at an oil palm plantation were chosen for sampling. Each location was represented by a distinctive soil series, and were further divided into two sites, that is canopy and midway area. Midway site had a greater population of AMF compared to canopy. The result showed that different environments affect the availability of AMF in the soil. Higher number of AMF infection observed in monocotyledon host suggests that the fibrous root system provide a better association with mycorrhiza. PMID- 27965733 TI - Calcium Oxalate Induces Renal Injury through Calcium-Sensing Receptor. AB - Objective. To investigate whether calcium-sensing receptor (CaSR) plays a role in calcium-oxalate-induced renal injury. Materials and Methods. HK-2 cells and rats were treated with calcium oxalate (CaOx) crystals with or without pretreatment with the CaSR-specific agonist gadolinium chloride (GdCl3) or the CaSR-specific antagonist NPS2390. Changes in oxidative stress (OS) in HK-2 cells and rat kidneys were assessed. In addition, CaSR, extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal protein kinase (JNK), and p38 expression was determined. Further, crystal adhesion assay was performed in vitro, and the serum urea and creatinine levels and crystal deposition in the kidneys were also examined. Results. CaOx increased CaSR, ERK, JNK, and p38 protein expression and OS in vitro and in vivo. These deleterious changes were further enhanced upon pretreatment with the CaSR agonist GdCl3 but were attenuated by the specific CaSR inhibitor NPS2390 compared with CaOx treatment alone. Pretreatment with GdCl3 further increased in vitro and in vivo crystal adhesion and renal hypofunction. In contrast, pretreatment with NPS2390 decreased in vitro and in vivo crystal adhesion and renal hypofunction. Conclusions. CaOx-induced renal injury is related to CaSR-mediated OS and increased mitogen-activated protein kinase (MAPK) signaling, which subsequently leads to CaOx crystal adhesion. PMID- 27965736 TI - Early Studies on Protoplast Isolation of Ludisia discolor, A Wild Orchid. AB - The terrestrial Ludisia discolor, also referred to as the jewel orchid is prized for the quality of its leaves. L. discolor is known as a medicinal herb and is touted for its heat- and pathogen-resisting qualities. L. discolor is valuable in the production of both flavonoids and anthocyanins, antioxidants that are exalted in the health industry. Plant cell cultures have emerged as alternative sources of anthocyanin production. Plant protoplast cultures are used frequently in transient gene expression studies and in the establishment of callus and cell suspension cultures. Benefits of plant protoplast system include similarity to cells found in plant tissues, reproduction under controlled conditions, and prevention of masking of stress responses to previous handling techniques. A study was conducted to assess the amenability of the stem and leaves of L. discolor to protoplast isolation. The stem and leaf segments were weighed, sliced into thin layers, immersed in a digestion medium, washed and then cultured onto a recovery medium. Results indicated that the production of plant protoplasts from L. discolor may be viewed as an alternative in the generation of cell cultures and ultimately in the production of anthocyanins from the cell cultures. PMID- 27965738 TI - Zooplankton Composition and Abundance as Indicators of Eutrophication in Two Small Man-made Lakes. AB - The distribution and abundance of zooplankton species of Harapan and Aman Lakes were investigated in relation to physical parameters and chlorophyll-a content. Both lakes were characterised by the occurrence of algal bloom problem. The composition of zooplankton was collected at monthly intervals from November 2013 to February 2014. The total number of taxa in Harapan and Aman Lakes were 23 and 27, respectively. Rotifera was the highest abundance group represent 64% of the total species recorded followed by Copepoda (29%) and Cladocera (7%). Three dominant zooplankton that been recorded in both the lakes are Brachionus forficula, Brachionus nilsoni, and Trichocerca sp. High abundance of these species indicates that the lakes are eutrophic water bodies. Overall, zooplankton species distribution and abundance in the study sites are influenced by various environmental factors such as water transparency and chlorophyll-a content. PMID- 27965737 TI - Effect of Salinity on Embryo and Larval Development of Oyster Crassostrea iredalei. AB - The effects of salinity on the embryonic and larvae stage of Crassostrea iredalei were investigated. Fertilised eggs and one day old D-larvae were subjected to salinities ranging from 0 to 30 ppt at temperature of 30+/-2 degrees C. At salinity lower than 10 ppt, 100% mortality was observed. For embryo development, the highest survival was observed at salinity 25 ppt with 80.9+/-2.2% survival with no significant difference compared to 15 and 30 ppt. Shell height and length were both greatest at salinity 30 ppt. Throughout the 11 days culture, the highest larval survival occurred at salinity 15 ppt with no significant difference compared to all other salinities except 10 ppt. Larval shell sizes showed no significant differences between salinities, except for 10 ppt. Optimum culture condition for larvae growth are salinities ranging from 15 to 30 ppt whereby the larval of this species can tolerate wider range of salinity compared to other oyster species and thus, making it a competitive species to be cultured. PMID- 27965739 TI - Coastal Macroinvertebrate Study in Penang Island, Malaysia. AB - Land reclamation in Penang began two decades ago and is still rampant with large reclamation projects planned to be executed in the near future. The present study provides the first information on effects of land reclamation in Penang towards the coastal macroinvertebrates. This study assessed the abundance, diversity, and evenness of coastal invertebrates assumed to be the foremost affected when land is reclaimed. Three kinds of areas were focused on: reclaimed, unclaimed (adjacent to reclaimed), and undisturbed. A total of 53 species of macroinvertebrates from 10 classes (Gastropoda, Bivalvia, Polychaeta, Malacostraca, Maxillopoda, Echinoidea, Polyplacophora, Branchiopoda, Scaphopoda, and Holothuroidea) were sampled. Reclaimed areas were moderately rich in species averaging 11 species compared to 7 species in adjacent and 14 in undisturbed areas. Species richness was the highest in Teluk Aling (an undisturbed area) with 22 species, and was the lowest in Gurney Drive (an adjacent area) with 2 species. The average species diversity and evenness on reclaimed land was the lowest with values of 1.9974 and 0.5787, respectively. The diversity was higher by 5.07% in adjacent areas and by 22.92% in undisturbed areas compared to reclaimed areas. Species evenness was 29.75% higher in unreclaimed areas and 17.87% higher in undisturbed areas compared to reclaimed areas. Land reclamation reduces species diversity and evenness, and to a lesser extent, species richness. PMID- 27965740 TI - The Effects of Salinity on the Filtration Rates of Juvenile Tropical Oyster Crassostrea iredalei. AB - A small scale laboratory study was conducted to determine the effects of salinity ranging from 15, 20, 25, 30, 35, 40, and 45 ppt on the filtration rates of juvenile oyster Crassostrea iredalei with 25 ppt as the control. Three juvenile oysters (shell weight: 1.04 +/- 0.12 g; shell length: 1.9 +/- 0.2 cm; shell height: 1.9 +/- 0.1 cm) were used to test the filtration rates in each salinity over the course of 8 hours. The hourly filtration rates were determined from the exponential decrease in algal (Chaetoceros calcitrans) concentration as a function of time. The oyster in 35 ppt salinity produced the highest overall filtration rate (FR2) with 134.06 +/- 15.66 mL-1 hr-1 oyster-1 and the lowest overall filtration rate (FR2) occurred in oyster exposed to 15 ppt and 45 ppt with 31.30 +/- 6.90 mL-1 hr-1 oyster-1 and 32.11 +/- 7.68 mL-1 hr-1 oyster-1 respectively throughout the 8 hours. The result from this study can be useful for optimum oyster culturing and the oysters can be employed as a natural biofilter in marine polyculture farming. PMID- 27965741 TI - Three New Records of Gammarid Amphipod in Songkhla Lake, Thailand. AB - Songkhla Lake is known as the most popular area for gammarid amphipod studies in the Gulf of Thailand. The first gammarid amphipod study was investigated in 1925 by Chilton. After that, there are various studies including diversity, ecology, and biology. In this study, gammarid amphipod in Songkhla Lake were collected from year 2010 to 2014. In this study, three newly recorded amphipods had been reported namely Hyale dollfusi Chevreux, 1911, Grandidierella megnae (Giles, 1888), and Hourstonius japonica (Hirayama, 1983) which had not been previously reported from the Thai waters. The gammarid amphipods had been catalogued. Their characteristics had been described and illustrated. All specimens were deposited at Princess Maha Chakri Sirindhorn Natural History Museum, Prince of Songkla University, Thailand. PMID- 27965742 TI - Preliminary Assessment on Autecological Studies of Beardless Barb, Cyclocheilichthys apogon (Valenciennes, 1842) from Muda Reservoir of Kedah, Malaysia. AB - Like many other countries, reservoirs in Malaysia are primarily built for various functions such as hydroelectric power generation, drinking water supply, flood mitigation and irrigation for agricultural purposes. Artisanal fisheries activities were also performed in these reservoirs. The freshwater fish are a requisite source of protein for the rural population. Consequently, the fish resources in reservoirs should be carefully maintained at sustainable level. Present study elucidates the preliminary assessment on autecological studies of beardless barb, Cyclocheilichthys apogon as a model of fish biota in Muda Reservoir. This research investigates the growth pattern of C. apogon using length-weight relationship and their condition factor. A total of 307 specimens were captured using cast net for six consecutive months from March 2014 until August 2014. The growth coefficient (b) from the length-weight equation (W = aLb ) for male and female of C. apogon were 3.150 and 3.185, respectively, indicating positive allometric growth. The condition factor values of male and female of C. apogon were 1.023 +/- 0.111 and 1.026 +/- 0.100, respectively, suggesting that C. apogon is in good condition in Muda Reservoir. The paucity of research on the autecological study in the Muda Reservoir contributes to the main reason of performing this research. The findings will serve as baseline information of this species in Muda Reservoir, as well as for comparative study in the future. PMID- 27965743 TI - The Abundance and Spatial Distribution of Soft Sediment Communities in Tanjung Bungah, Malaysia: A Preliminary Study. AB - Benthic faunal communities are important components in the intertidal zones. The diversity and abundance of the benthic communities are subjected to different natural and anthropogenic disturbances. The study was conducted as one off sampling on 6th November 2013 (1) to investigate the abundance and distribution of soft sediment communities in relation to environmental variables and (2) investigate the changes of population structure and diversity using spatial scales of 1 m, 10 m, and 100 m. Results indicated a total of 110 individuals of macrobenthos consisting of 7 different groups (Annelida, Bivalvia, Crustacea, Gastropoda, Nematoda, Nemertea, Polychaeta) and 4 different groups of meiobenthos (Copepoda, Nematoda, Ostracoda, Polychaeta) consisting 920 individuals were recorded. Dissolved oxygen played the most significant role in affecting the distribution of soft sediment communities while ammonia concentrations only affected marcobenthic organisms. However, sediment grain size did not show significant correlation (p>0.05) on soft sediment communities. Hence, understanding how different properties of benthos respond to changes in environmental variables is crucial in determining how the impacts on the sediment are tolerated by the benthic organisms. PMID- 27965744 TI - Checklist of Fishes at Selected Rivers around Bukit Merah Reservoir, Perak, Malaysia. AB - A study was conducted at five selected rivers around Bukit Merah Reservoir, Perak, Malaysia for eight weeks in order to determine the fish diversity and distribution. A total of 28 species comprised of 9 families were identified. The study depicted that there were significant changes to the fish composition when compared to previous study which had captured 36 species due to different areas covered and different types of sampling gear used between both studies. PMID- 27965745 TI - The Identification of Octocorals from the Northern Region of Straits of Malacca. AB - Coral reefs in the northern region of the Straits of Malacca have a diverse group of octocorals growing on its bed. The octocorals identified in this study are from islands along the Straits. In this study, 23 specimens were identified, belonging to 4 sub-orders, which have been subdivided into 8 families. From these 8 families, 15 different genera have been identified. The identification process for this research was conducted based on five important keys; the external form and colouration, polyps or colonial and fundamental structure of colonies, monomorphic or dimorphic, the arrangement of polyps, and the arrangement of sclerites. PMID- 27965747 TI - Biodiversity of Mushrooms in Conservative Forest in Dansai District of Loei Province, Thailand. AB - Dansai District is located in Loei Province, Northeast Thailand, rich in natural resources and composes of many kinds of forests, such as evergreen forests and mixed-deciduous forests. The objectives of the study are to determine the diversity of mushrooms and investigate the values of the forest influencing the community way of life and exploration of problems and guidelines for developing the forest along with sufficiency economy theory. The study includes compilation of data from past studies, semi-structured interview with the local communities and discussion with focus group. The survey was done once a month during the rainy season from May to August in 2012 and 2013. The results of the survey revealed 56 species belonging to 26 families, 38 genera. A total of 52 mushroom species belong to Basidiomycota, while 4 species belong to Ascomycota. The community forest remains fertile due to the conservation effort by the community leaders and a group of villagers. A community forestry board were set up to conserve the forest and proposed to the government at Dansai Vocational Community College to officially declare the forest as a formal community forest. The conservation management relied upon the kinship relations, seniority, and religious belief along with the enforcing authorities. If an encroacher is found, he would be fined according to the regulations and defamed publicly. However, encroachment still exists. In general, community forest is valuable and directly affected the villagers' ways of life in which they could generate income from the forest, particularly reducing the daily expenses and promoting their socio cultural perspective. PMID- 27965746 TI - The Effects of Light and Height of Building in Attracting Paederus fuscipes Curtis to Disperse towards Human Residential Areas. AB - Paederus fuscipes Curtis is a nocturnal insect. The attractiveness of artificial light sources from residential premises eventually causes the risk of severe dermatitis effect, once Paederus is in contact with human skin. The objective of this study is to investigate whether the light and height factors of residential buildings and its' association to rice cultivation phases are primary reasons for P. fuscipes's mass dispersal into human residential areas. The study site was located in residential premises that were built adjacent to rice field areas (~ 32-60 m and 164 m) north of the rice field located in Teluk Air Tawar, mainland of Pulau Pinang. Overall, both light sources and rice cultivation phases caused a significant effect for P. fuscipes beetles dispersal flight to invade human settlements. More P. fuscipes were captured near the bright light source with the highest number of beetles found during harvesting stage. Whereas, significantly higher number of P. fuscipes were captured at level 2 and 3 compared to ground and level 1 of the apartment building and P. fuscipes was also found significantly affected by the rice cultivation phases at different elevation levels. This indicates that bright light sources and higher elevation levels are the main factors in attracting P. fuscipes beetles to disperse and causes infestations in residential areas. This finding could create awareness among the public on P. fuscipes dispersal pattern. PMID- 27965748 TI - Assessment of Temperature Effects on Early Larval Development Survival of Hatchery-reared Tropical Oyster, Crassostrea iredalei. AB - The influence of the cool and warm temperatures on early life development and survival of tropical oyster, Crassostrea iredalei was studied. D-hinged larvae (day 1 larvae) were reared to three different temperatures (20 degrees C, 27 degrees C, and 34 degrees C) for nine days. Oyster larvae reared in temperature 27 degrees C, acted as control (ambient temperature). The highest survival rate occurred when the larvae were reared in 20 degrees C and 27 degrees C. Larvae reared at 34 degrees C exhibited reduced survival but increase in the growth rate. The growth rate in larvae reared in high temperature (34 degrees C) was significantly higher compared to larvae reared in 20 degrees C and 27 degrees C (p<0.05). The results from the present study indicated that tropical oyster larvae, C. iredalei had faster growth rate at the high temperature (34 degrees C). However, the larval survival was decreasing according to days. There is no significant difference in the larval growth and survival in lower temperature (20 degrees C) and control condition (27 degrees C). PMID- 27965749 TI - Oviposition Habitat Selection of Dengue Vectors, Aedes aegypti and Aedes albopictus in Response to Fish Predator. AB - To understand the effects of fish predator's kairomones on Aedes mosquitoes' oviposition, we established an experiment using gravid Aedes females. Kairomones concentrations were established using Hampala macrolepidota. One individual fish was placed inside containers with varying water levels (1 L, 5 L, and 10 L of water). The fish were kept in the containers for 24 hours and were removed immediately at the start of each trial in order to have the kairomones remnants. Twenty gravid adult females of Aedes aegypti and Aedes albopictus were allowed to lay eggs on oviposition site with various treatments: (1) control without any kairomones; (2) kairomone remnant in 1 L of water; (3) kairomone remnant in 5 L of water; and (4) kairomone remnant in 10 L of water. There are significant differences between the numbers of eggs laid by both Aedes species for each different treatment (F = 9.131, df = 16, p<0.001). However, fewer eggs were laid by Ae. albopictus compared to Ae. aegypti in the presence of kairomone remnants. This suggested that Ae. albopictus are significantly affected by the kairomones itself and have ability to detect the residual kairomone presence from H. macrolepidota. PMID- 27965750 TI - Establishment and Analysis of the 3-dimensional (3D) Spheroids Generated from the Nasopharyngeal Carcinoma Cell Line HK1. AB - Spheroids have been shown to recapitulate the tumour in vivo with properties such as the tumour microenvironment, concentration gradients, and tumour phenotype. As such, it can serve as a platform for determining the growth and invasion behaviour pattern of the cancer cells as well as be utilised for drug sensitivity assays; capable of exhibiting results that are closer to what is observed in vivo compared to two-dimensional (2D) cell culture assays. This study focused on establishing a three-dimensional (3D) cell culture model using the Nasopharyngeal Carcinoma (NPC) cell line, HK1 and analysing its growth and invasion phenotypes. The spheroids will also serve as a model to elucidate their sensitivity to the chemotherapeutic drug, Flavopiridol. The liquid overlay method was employed to generate the spheroids which was embedded in bovine collagen I matrix for growth and invasion phenotypes observation. The HK1 cells formed compact spheroids within 72 hours. Our observation from the 3 days experiments revealed that the spheroids gradually grew and invaded into the collagen matrix, showing that the HK1 spheroids are capable of growth and invasion. Progressing from these experiments, the HK1 spheroids were employed to perform a drug sensitivity assay using the chemotherapeutic drug, Flavopiridol. The drug had a dose-dependent inhibition on spheroid growth and invasion. PMID- 27965751 TI - Effect of Soybean Flour on Physico-chemical, Functional, and Rheological Properties of Composite Flour from Rice, Sweet Potato, and Potato. AB - Three composite flours were prepared by combining rice flour, potato starch, sweet potato flour, soybean flour, and xanthan gum in the ratio of 30: 15: 50: 4.5: 0.5; 30: 15: 45: 9.5: 0.5; and 30: 15: 40: 14.5: 0.5, were analysed for selected physical, chemical, functional, and rheological properties. Fat, protein, ash, and crude fibre content were found to increase with increase in the ratio of soybean flour and decrease in the ratio of sweet potato flour in the mixture. The composite flours were not significantly different in water and oil absorption capacity, swelling power, and baking expansion. There was a tendency for the relative viscosities of the composite flours to increase significantly with increasing proportion of the soybean flour and decreasing proportion of sweet potato flour in the mixture. Pasting viscosity measurements of the composite flours gave maximum (peak) viscosity values ranging from 582.00-668.67 cP. The pasting analysis results indicated increased level of setback and final viscosity, pasting temperature, setback and stability ratio while peak viscosity decreased with increasing proportion of soybean flour and decreasing proportion of sweet potato flour in the mixture. PMID- 27965752 TI - Ascorbate Peroxidase Activity of Aranda Broga Blue Orchid Protocorm-like Bodies (PLBs) In Response to PVS2 Cryopreservation Method. AB - Throughout the cryopreservation process, plants were exposed to a series of abiotic stresses such as desiccation and osmotic pressure due to highly concentrated vitrification solution. Abiotic stress stimulates the production of reactive oxygen species (ROS) which include hydrogen peroxide, superoxide radicals, and singlet oxygen. Higher production of ROS may lead to oxidative stress which contributes to the major injuries in cryopreserved explants. Antioxidant enzymes in plant such as ascorbate peroxidase (APX) can protect plants from cell damage by scavenging the free radicals. This study was determined based on APX enzyme activity of Aranda Broga Blue orchid's protocorm like bodies (PLBs) in response to PVS2 (Plant Vitrification Solution 2) cryopreservation treatments at different stages. PLBs that were precultured at 0.25 M sucrose for 3 days were subjected to vitrification cryopreservation method. Results obtained showed that the highest APX activity was achieved at PVS2 cryoprotectant treatment prior liquid nitrogen (LN) storage. This phenomenon indicating that accumulation of osmotic and dehydrating stress throughout the cryopreservation treatment resulted in oxidative burst which in turn leads to higher APX activity in order to control the excess production of ROS. To conclude, PVS2 treatment was revealed as the most detrimental step throughout cryopreservation treatment. Thus, this research also suggested that exogenous antioxidant such as ascorbic acid can be added throughout cryopreservation procedure especially at PVS2 treatment in the future experiments to aid in regrowth of cryopreserved explants by reducing oxidative stress. PMID- 27965753 TI - Cloning and Expression of a Subfamily 1.4 Lipase from Bacillus licheniformis IBRL CHS2. AB - We report on the cloning of the lipase gene from Bacillus licheniformis IBRL-CHS2 and the expression of the recombinant lipase. DNA sequencing analysis of the cloned lipase gene showed that it shares 99% identity with the lipase gene from B. licheniformis ATCC 14580 and belongs to subfamily 1.4 of true lipases based on amino acid sequence alignment of various Bacillus lipases. The 612 bp lipase gene was then cloned into the pET-15b(+) expression vector and the construct was transformed into E. coli BL21 (DE3) for bulk expression of the lipase. Expression was analysed by SDS-PAGE where the lipase was found to have a molecular weight of about 23 kDa. PMID- 27965754 TI - Psychrophilic Lipase from Arctic Bacterium. AB - A lipase producer psychrophilic microorganism isolated from Arctic sample was studied. The genomic DNA of the isolate was extracted using modified CTAB method. Identification of the isolate by morphological and 16S rRNA sequence analysis revealed that the isolate is closely related to Arthrobacter gangotriensis (97% similarity). A. gangotriensis was determined as positive lipase producer based on the plate screening using specific and sensitive plate assay of Rhodamine B. The PCR result using Arthrobacter sp.'s full lipase gene sequence as the template primers emphasised a possible lipase gene at 900 bp band size. The gene is further cloned in a suitable vector system for expression of lipase. PMID- 27965755 TI - Screening of Potential Free Radicals Scavenger and Antibacterial Activities of Purwoceng (Pimpinella alpina Molk). AB - Purwoceng (Pimpinella alpina Molk) is a traditional medicinal plant used for its aphrodisiac values. This plant was originated Dieng Plateu, Central Java, Indonesia. Purwoceng has been reported to contain steroid, flavonoids, glycoside, saponins, tannins, and phenolic. Based on secondary metabolite compounds of Purwoceng herbs, a research need to be done to determine the other potential free radicals scavenger and antibacterial activities of Purwoceng. The objectives of this research are to screen the potential free radicals scavenger activity of in vitro using DPPH (1,1 diphenyl-2-picryl-hydrazil) radicals and NO* (nitric oxide) radicals, and antibacterial activity of Purwoceng. The extraction is done by a maceration method with petroleum ether, ethyl acetate, and ethanol solvent, respectively. Free radicals scavenger test was performed using DPPH radicals and NO* radicals, while antibacterial activity screening was performed using agar diffusion test. The results showed that ethyl acetate extract of Purwoceng has free radical scavenger activity with IC50 53.07 ppm lower than butylated hydroxytoluene. Ethyl acetate extract and ethanol extract of Purwoceng have antibacterial activity against Staphyloccus aureus, Escherichia coli, and MG42 bacterial isolate. PMID- 27965757 TI - Exercise-induced bronchoconstriction: new evidence in pathogenesis, diagnosis and treatment. AB - The acute airway narrowing that occurs as a result of exercise is defined exercise-induced bronchoconstriction (EIB). Most recent guidelines recommend distinguishing EIB with underlying clinical asthma (EIBA) from the occurrence of bronchial obstruction in subjects without other symptoms and signs of asthma (EIBwA). EIB has been in fact reported in up to 90 % of asthmatic patients, reflecting the level of disease control, but it may develop even in subjects without clinical asthma, particularly in children, athletes, patients with atopy or rhinitis and following respiratory infections. Both EIBA and EIBwA have peculiar pathogenic mechanisms, diagnostic criteria and responses to treatment and prevention. The use of biomarkers, proteomic approaches and innovative technological procedures will hopefully contribute to better define peculiar phenotypes and to clarify the role of EIB as risk factor for the development of asthma, as well as an occupational disease. PMID- 27965758 TI - The patient with rhinitis in the pharmacy. A cross-sectional study in real life. AB - BACKGROUND: In the practical management of allergic rhinitis (AR), pharmacists are usually the first-line contact, also because some medications are available as over the counter. Therefore, pharmacists may represent an important resource, in mediating the interaction between patients and physicians. We evaluated the clinical/demographic characteristics of patients with respiratory allergies who consulted their pharmacists as first-line contact. A patient-oriented questionnaire was developed by a scientific committee including pharmacists, GPs, allergists, pulmonologists and ENT specialists. METHODS: The questionnaire consisted of items covering the general aspects of AR. Allergic Rhinitis and its Impact on Asthma guidelines were assumed as reference for diagnosis and therapy. The questionnaire was distributed to pharmacies, and pharmacists were asked to deliver the questionnaire to all patients referring for nasal symptoms. RESULTS: 30 pharmacies were involved during the pollen season 2011, and 410 patients (55 % male) participated. The most frequent complaints were 20 rhinitis (49 %) and conjunctivitis (29 %), followed by lower respiratory symptoms (cough and/or dyspnea). Isolated conjunctival symptoms were present in only 22 % of patients. Among patients with lower respiratory symptoms, cough was the most frequent, variously associated with upper respiratory symptoms or overt dyspnea. Dyspnea alone was present in 16 % of patients. 39 % of patients had no physician-based diagnosis. Oral antihistamines were the most used self-medication, followed by intranasal decongestants. 30 % of respondents had used alternative medicines. CONCLUSION: According to these data, AR is still considered a trivial disease, frequently self-managed, with over the counter medications, not in line with guidelines. A physician-based diagnosis is present in about 60 % of patients. PMID- 27965759 TI - Asthma research and practice: a new journey begins. PMID- 27965756 TI - Asthma and obesity: mechanisms and clinical implications. AB - Obesity is the most common asthma co-morbidity; it has been associated with increased risk for asthma exacerbations, worse respiratory symptoms and poor control. The exact mechanisms remain elusive and are probably multifactorial, stemming from mechanical alterations of the airways and lung parenchyma, to systemic and airway inflammatory and metabolic dysregulation that adversely influences lung function and or response to therapy. However, the fact that not every obese asthmatic is equally affected by weight gain highlights the many challenges and complexities in understanding this association. The factors that determine susceptibility may not depend on being obese alone, but rather the interactions with other phenotypical characteristics, such as age of asthma onset, gender and race to name a few. Inability to account for asthma phenotypes that are differentially affected by increasing body mass index (BMI) may contribute to the lack of consistent results across studies. This review will provide a succinct summary of obesity-related mechanisms and the clinical impact on asthma including highlights on recent progress. PMID- 27965761 TI - Psychological aspects in asthma: do psychological factors affect asthma management? AB - Despite the regular treatment with inhaled corticosteroids (ICS) or ICS plus long acting beta2-agonists, permits to control de majority of asthmatics, a significant proportion of patients does not respond to this treatment. This review was aimed to explore the role of psychological factors associated to the unsuccessful fulfilment of optimal levels of asthma control, especially in patients suffering from severe asthma. The results of a Medline search were 5510 articles addressed to different psychological key concepts, constructs and variables. This review will highlight how some selected psychological factors may have a burden on asthma management. Evidences are now available about the link between asthma (in terms of severity and control), some psychological aspects (subjective perception, alexithymia, coping style) and mental health (anxiety, depression). Taking into account this most probably bidirectional influence, a screening of mental symptoms and psychological aspects related to asthma, could lead to plan appropriate interventions to better control asthma and to improve the patient's well-being. PMID- 27965760 TI - Allergen immunotherapy in asthma; what is new? AB - The use and role of allergen immunotherapy (AIT) in asthma is still a matter of debate, and no definite recommendation about this is made in guidelines, both for the subcutaneous and sublingual routes. This is essentially due to the fact that most controlled randomised trials were not specifically designed for asthma, and that objective measures of pulmonary function were only occasionally considered. Nonetheless, in many trials, favourable results in asthma (symptoms, medication usage, bronchial reactivity) were consistently reported. There are also several meta analyses in favour of AIT, although their validity is limited by a relevant methodological heterogeneity. In addition to the crude clinical effect, a disease modifying action of AIT (prevention of asthma onset and long-lasting effects) have been reported. The safety is an important aspect to consider in asthma. Fatalities were rare: in Europe no fatality was reported in the last three decades, as in the United States in the last 4 years. Based on previous surveys, and common sense, uncontrolled asthma is still recognized as the most important risk factor for severe adverse events. On the contrary, there is no evidence that AIT can worsen or induce asthma. According to the available evidence, AIT can be safely used as add-on treatment when asthma is associated with rhinitis (a frequent condition), provided that asthma is adequately controlled by pharmacotherapy. AIT cannot be recommended or suggested as single therapy. When asthma is the unique manifestation of respiratory allergy, its use should be evaluated case by case. PMID- 27965762 TI - Allergic rhinitis: the "Ghost Diagnosis" in patients with asthma. AB - Allergic rhinitis (AR) is a common comorbidity of asthma that contributes to asthma severity. Although over 80 % of asthmatics have AR, the condition is frequently underdiagnosed in subjects with asthma. AR itself is also a highly prevalent condition, affecting 10-30 % of adults and up to 40 % of children. AR has been associated with both increased risk of asthma development and asthma severity. The exact mechanisms underlying these relationships have yet to be fully elucidated, but evidence supports a role for allergen sensitization. Compared to those with asthma alone, patients with comorbid AR and asthma have greater use of health care resources, including visits to the general practitioner, emergency department and hospitalizations. Pharmacological treatment of AR reduces this health care burden. Immunotherapy for AR improves both asthma and rhinitis symptoms in addition to preventing future allergen sensitizations and asthma development. Appropriate recognition, diagnosis and treatment of AR can significantly reduce asthma morbidity and improve quality of life. PMID- 27965763 TI - Vocal cord dysfunction: a review. AB - Vocal cord dysfunction (VCD) is a term that refers to inappropriate adduction of the vocal cords during inhalation and sometimes exhalation. It is a functional disorder that serves as an important mimicker of asthma. Vocal cord dysfunction can be difficult to treat as the condition is often underappreciated and misdiagnosed in clinical practice. Recognition of vocal cord dysfunction in patients with asthma-type symptoms is essential since missing this diagnosis can be a barrier to adequately treating patients with uncontrolled respiratory symptoms. Although symptoms often mimic asthma, the two conditions have certain distinct clinical features and demonstrate specific findings on diagnostic studies, which can serve to differentiate the two conditions. Moreover, management of vocal cord dysfunction should be directed at minimizing known triggers and initiating speech therapy, thereby minimizing use of unnecessary asthma medications. This review article describes key clinical features, important physical exam findings and commonly reported triggers in patients with vocal cord dysfunction. Additionally, this article discusses useful diagnostic studies to identify patients with vocal cord dysfunction and current management options for such patients. PMID- 27965765 TI - "Asthma can take over your life but having the right support makes that easier to deal with." Informing research priorities by exploring the barriers and facilitators to asthma control: a qualitative analysis of survey data. AB - BACKGROUND: Involving patients and the public in research prioritisation is important. Cochrane Airways works with authors to produce systematic reviews of evidence related to chronic airways disease. Cochrane Airways has undertaken activities to identify research priorities, including workshops with stakeholders and consultation with experts. We present the findings of an online survey, designed to align our work with the priorities of people affected by asthma. METHODS: We promoted a survey comprising open-ended questions via social media to people affected by asthma. We compiled the free-text responses and conducted an exploratory thematic analysis to identify important barriers and facilitators to asthma control. We triangulated findings with other research prioritisation activities to produce new review questions. RESULTS: We received 57 survey responses. Eight main themes emerged, most encompassing both facilitators and barriers: attitudes and knowledge; financial costs; environmental factors and triggers; healthcare systems; lifestyle factors; medication; self-care; and support. Barriers were more frequently mentioned than facilitators and many related to healthcare systems. CONCLUSIONS: These findings offer valuable insights into the challenges faced by individuals affected by asthma in the UK, and possibly further afield. We developed a list of priority reviews based on what was said by people in this survey and at a workshop. This demonstrates the real impact that people affected by asthma have on the research agenda of Cochrane Airways. Over the next 2-3 years we will produce reviews that address some of these questions hopefully leading to health benefits. PMID- 27965764 TI - Genetic and epigenetic studies of FOXP3 in asthma and allergy. AB - Multiple factors interact to trigger allergic diseases, including individual genetic background and factors related to the environment such as exposure to allergens, air pollution and respiratory infections. The FOXP3 transcription factor is constitutively expressed in CD4+CD25+FOXP3+ regulatory T cells (Tregs) and is critical for the maintenance of immune homeostasis. For example, FOXP3 is responsible for the suppression of the Th2 response following exposure to allergens. Studies have shown that expression of the FOXP3 gene is reduced in patients with asthma and allergies compared to healthy controls. Therefore, the impairment of FOXP3 function caused by genetic polymorphisms and/or epigenetic mechanisms may be involved in the etiology of asthma and other allergic diseases. This review discusses some aspects of the role of FOXP3 in the development of asthma and allergy, with a particular emphasis on genetic and epigenetic factors. PMID- 27965767 TI - Sickle cell disease: wheeze or asthma? AB - Sickle cell disease (SCD) is the most common life-limiting genetic disease among African Americans, affecting more than 100,000 people in the United States. Respiratory disorders in patients with sickle cell disease have been associated with increased morbidity and mortality. Associations between asthma and pain, acute chest syndrome (ACS), and even death have long been reported. More recently wheezing, even in the absence of an asthma diagnosis, has gained attention as a possible marker of SCD severity. Several challenges exist with regards to making the diagnosis of asthma in patients with SCD, including the high prevalence of wheezing, evidence of airway obstruction on pulmonary function testing, and/or airway hyperresponsiveness among patients with SCD. These features often occur in isolation, in the absence of other clinical criteria necessary for an asthma diagnosis. In this review we will summarize: 1) Our current understanding of the epidemiology of asthma, wheezing, airway obstruction, and airway responsiveness among patients with SCD; 2) The evidence supporting associations with SCD morbidity; 3) Our understanding of the pathophysiology of airway inflammation in SCD; 4) Current approaches to diagnosis and management of asthma in SCD; and 5) Future directions. PMID- 27965768 TI - The WEB-based Asthma Control: an intriguing connection or a dangerous hazard? AB - Globally, an estimated 300 million people have asthma, presenting a considerable and increasing burden of disease for healthcare systems, families, and patients themselves. Despite two decades of guidelines, asthma seems to remain not optimally controlled in a substantial proportion of people. The achievement of asthma control is the result of the interaction among different variables concerning the disease pattern and patients' and physicians' knowledge and behavior. It is well known that adherence to treatment increases in parallel to patient education. There is now a growing interest in the use of digital information technologies to promote asthma control and improve outcomes. Mobile health, or mHealth, refers to mobile devices, medical sensors, and communication technologies that can enhance chronic disease care and monitoring. Aim of this review was to evaluate the web resources nowadays available and to analyze the published studies about the web-based instruments used to improve asthma knowledge, control asthma outcomes. In general, studies revealed that the technology is well accepted. Interactive asthma technology may be, in addition, of help in reaching populations difficult to reach, such as inner city populations. The number of tools and apps available continues to increase, and agencies such as the FDA, become involved in their regulation, thus the mHealth landscape will continue to evolve. Although asthma tools and apps have great potential to improve care for asthma, the proof of data reproducibility, the demonstration of effectiveness, and the privacy issues still represent the major technical problems. PMID- 27965766 TI - Small airway dysfunction and bronchial asthma control : the state of the art. AB - According to national and international guidelines, achieving and maintaining asthma control is a major goal of disease management. In closely controlled clinical trials, good asthma control can be achieved , with the medical treatments currently available, in the majority of patients , but large population-based studies suggest that a significant proportion of patients in real-life setting experience suboptimal levels of asthma control and report lifestyle limitations with a considerable burden on quality of life. Poor treatment adherence and persistence, failure to use inhalers correctly, heterogeneity of asthma phenotypes and associated co-morbidities are the main contributing factors to poor disease control. Now, it is widely accepted that peripheral airway dysfunction , already present in patients with mild asthma, is a key contributor of worse control. The aim of this paper is to investigate the association between small-airways dysfunction and asthma symptoms/control. We therefore performed a PubMed search using keywords : small airways; asthma (limits applied: Humans, English language) and selected papers with a study population of asthmatic patients, reporting measurement of small-airways parameters and clinical symptoms/control. PMID- 27965769 TI - Higher serum levels of periostin and the risk of exacerbations in moderate asthmatics. AB - BACKGROUND: In asthma, exacerbations and poor disease control are linked to airway allergic inflammation. Serum periostin has been proposed as a systemic biomarker of eosinophilic inflammation. This pilot study aims at evaluating whether in patients with moderate asthma, higher baseline levels of serum periostin are associated with a greater risk of exacerbation. METHODS: Fifteen outpatients with moderate allergic asthma were recruited. Serum concentrations of periostin were assessed (ELISA) at baseline, and the frequency of asthma exacerbations was recorded during a one-year follow-up. RESULTS: Patients (M/F: 10/5, mean age of 47.6 +/- 11.0 years) had mean ACQ score of 5.5 +/- 4.2 and FEV1%pred of 81.9 +/- 21.7 %. Baseline serum levels of periostin did not correlate with lung function parameters, nor with the ACQ score (p >=0.05 for all analyses). Five subjects (33 % of the study group) reported one or more exacerbations during the following year. Baseline serum levels of periostin were significantly higher in subjects who experienced one or more exacerbations during the one year period of follow-up, compared with subjects with no exacerbations: median serum periostin level was 4047 ng/ml (range: 2231 to 4889 ng/ml) and 222 ng/ml (range 28.2 to 1631 ng/ml) respectively; p = 0.001. CONCLUSION: The findings of the present pilot study could form the basis for the design of larger studies aiming at developing strategies to identify asthmatic patients at risk for exacerbations. PMID- 27965770 TI - The geriatric asthma: pitfalls and challenges. AB - Historically, asthma has been envisioned as a disease of younger ages. This has led to the assumption that respiratory symptoms suggestive of asthma occurring in older ages are to be attributed to conditions other than asthma, mainly COPD. Old observational reports and new epidemiological studies confirm that asthma is as frequent in older as it is in younger populations. Nevertheless, under recognition, misdiagnosis and under-treatment are still relevant issues. The characterization of asthma in the aged suffers from the fact that there has been very little original research in this field. Indeed, geriatric asthma is often excluded from clinical trials because of age and comorbidities. The current review paper revises the areas that need to be elucidated, and highlights the gaps in the management of this condition. It follows that a multidimensional management is advocated for elderly asthmatics to evaluate the severity and establish the complexity of the disease. We suggest that the term "geriatric" asthma should be preferred to "senile" asthma, which is confined to the age related changes in the lung, or the more generic "asthma in the elderly", which is only descriptive of the prevalence in specific age groups. PMID- 27965771 TI - Asthma in the elderly patient. AB - Asthma affects a significant proportion of elderly patients, but unfortunately, it is responsible for a high asthma-related morbidity and mortality in this population. This may be related not only to the development of a more severe asthma phenotype compared to younger patients, with more marked airway obstruction and a more neutrophilic type of airway inflammation, but also to the presence of many co-morbid conditions. Furthermore, in older patients, asthma is often under-diagnosed, undertreated and poorly managed. Unfortunately, elderly patients have usually been excluded of clinical trials on asthma and there is an urgent need to perform more research on the optimal management of asthma in this population. PMID- 27965772 TI - Once-daily fluticasone furoate/vilanterol versus twice daily combination therapies in asthma-mixed treatment comparisons of clinical efficacy. AB - BACKGROUND: Fluticasone furoate (FF)/vilanterol (VI) is a once-daily inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) combination. FF/VI, 92/22mcg and 184/22mcg, are approved in Europe as maintenance therapy in persistent asthma. We report data from mixed treatment comparisons (MTC) of once daily FF/VI against established twice-daily ICS/LABA combination therapies on clinical efficacy outcomes. METHODS: Data from 31 parallel-group randomised controlled trials (RCTs) of ICS/LABA, of >=8 weeks' duration in patients aged >=12 years with asthma, identified by systematic review, were analysed using covariate-adjusted Bayesian hierarchical models for four efficacy outcomes (primary analysis). Lung function, assessed by change from baseline morning peak expiratory flow (PEF) (n = 18 studies) and forced expiratory volume in 1 s (FEV1) (n = 28), was the outcome of primary interest. Secondary objectives were assessment of relative efficacy in terms of exacerbation rates (n = 6) and health status (n = 7). Overall, 24 different treatment arms were included in the MTC; we report findings comparing FF/VI (92/22mcg and 184/22mcg) with fluticasone propionate/salmeterol (FP/SAL) (250/50mcg and 500/50mcg) and budesonide/formoterol (BUD/FORM) (320/9mcg and 640/18mcg). RESULTS: For PEF (margin = 12 l/min), FF/VI 92/22mcg demonstrated >=94 % probability and FF/VI 184/22mcg >99 % probability of non-inferiority to corresponding doses of both FP/SAL and BUD/FORM. For FEV1 (margin = 100 ml), FF/VI demonstrated >=98 % (92/22mcg) and >99 % (184/22mcg) probability of non-inferiority to both FP/SAL and BUD/FORM. Findings for exacerbations were inconclusive due to lack of data: FF/VI 92/22mcg demonstrated 74 % and 82 % probability of non-inferiority (margin = 10 %) to FP/SAL 250/50mcg and BUD/FORM 320/9mcg, respectively. For Asthma Quality of Life Questionnaire (AQLQ) score, FF/VI 92/22mcg demonstrated >99 % and 90 % probability of non-inferiority (margin = 0.25) to FP/SAL 250/50mcg and BUD/FORM 320/9mcg. Data were unavailable to assess non-inferiority of FF/VI 184/22mcg on exacerbations or AQLQ. CONCLUSIONS: Both strengths of once-daily FF/VI in asthma were comparable with corresponding doses of twice-daily FP/SAL and BUD/FORM in terms of lung function in this MTC analysis. FF/VI 92/22mcg was comparable with FP/SAL and BUD/FORM on AQLQ, but exacerbation results were inconclusive. Model limitations include disconnected treatment networks and variability across studies. Our data support previous RCT findings suggesting that the efficacy of once-daily FF/VI in improving lung function and health status in asthma is comparable with twice-daily ICS/LABAs. PMID- 27965773 TI - Treatment of asthma in young children: evidence-based recommendations. AB - : In the present review, we focus on evidence-based data for the use of inhaled corticosteroids (ICS), leukotriene receptor antagonist (LTRA), long-acting beta2 agonits (LABA) and oral corticosteroids (OCS), with a special emphasis on well performed randomized clinical trials (RCTs) and meta-analyses of such trials for the chronic management of asthma/wheeze in infants and preschoolers. RESULTS: Seven meta-analyses and 14 RCTs were reviewed. Daily ICS should be the preferred drug for infants/preschoolers with recurrent wheezing, especially in asthmatics. For those with moderate or severe episodes of EVW, the use of high intermittent ICS doses significantly reduce the use of OCS. There is no evidence of effect of intermittent ICS at low-moderate dose in preschoolers with mild EVW episodes. In preschoolers with asthma, there were no significant differences between daily vs. intermittent ICS in terms of asthma exacerbations with insufficient power to conclude to equivalence; however, for other asthma control outcomes, daily ICS works significantly better than intermittent ICS for older children. Daily ICS is superior to daily or intermittent LRTA for reducing symptoms, preventing exacerbations, and improving lung function. No RCTs testing combination therapy with ICS and LABA (or LTRA) were published in infant/preschoolers. Parent initiation of OCS at the first sign of symptoms is not effective in children with recurrent wheezing episode. In terms of ICS safety, growth suppression is dose and molecule-dependent but it's effect is not cumulative beyond the first year of therapy and may be associated with some catch-up growth while on or off therapy. Linear growth must be monitored as individual susceptibility to ICS drugs may vary considerably. PMID- 27965774 TI - CXC chemokine superfamily induced by Interferon-gamma in asthma: a cross sectional observational study. AB - BACKGROUND: Asthma is a disease encompassing a variety of contributing factors. Phenotyping of asthma based on the profile of accumulated granulocytes in the airways has been performed to explore the mediators involved in allergic bronchial inflammation. The aim of this study was to clarify the characteristics of the CXC chemokine superfamily induced by IFN-gamma, namely CXCR3 ligands, in the airways of patients with asthma stratified by the differential proportion of granulocytes in sputum. METHODS: Sputum was induced in 39 adult patients with asthma and 12 healthy subjects. Sputum samples were analyzed for total cell counts and differentials, and concentrations of IFN-gamma-inducible protein 10 kDa (IP-10, CXCL10), monokine induced by IFN-gamma (Mig, CXCL9), IFN-inducible T cell a chemoattractant (I-TAC, CXCL11), and IL-8 in the supernatants were assayed by ELISA. RESULTS: Sputum concentrations of IP-10, Mig, and IL-8 were significantly higher in asthma than in healthy subjects. IP-10, Mig, and IL-8 were significantly higher in the mixed granulocyte subtype (eosinophils >= 2 % and neutrophils >= 40 % in sputum) than in healthy subjects. Additionally, IP-1 0 was significantly higher in the mixed granulocyte subtype than in eosinophil predominant or neutrophil-predominant subtype (eosinophil percentage >= 2 % or neutrophil percentage >= 40 %). Mig and IL-8 were significantly higher in the mixed granulocyte subtype than in the paucigranulocyte subtype (eosinophils < 2 % and neutrophils < 40 % in sputum). I-TAC was not different between healthy subjects and asthmatics or granulocyte subtypes. All CXCR3 ligands were significantly associated with the composite of the eosinophil and neutrophil ratio in patients with asthma. Only Mig was significantly correlated with the total eosinophil and neutrophil ratio in patients with asthma on adjusted partial correlation analysis. Mig and IL-8 were significantly negatively correlated with forced expiratory volume in 1 s % predicted (% FEV1) in patients with asthma. CONCLUSIONS: CXCR3 ligands may serve as potent promoters in eosinophilic and neutrophilic airway inflammation in asthma. PMID- 27965776 TI - A qualitative evaluation of the implementation of guidelines and a support tool for asthma management in primary care. AB - BACKGROUND: Asthma management in Australia is suboptimal. The "Guidelines for provision of a Pharmacist Only medicine: short acting beta agonists" (SABA guidelines) and a novel West Australian "Asthma Action Plan card" (AAP card) were concurrently developed to improve asthma management. The aim of this qualitative research was to evaluate the collaborative, multidisciplinary and multifaceted implementation of these asthma resources and identify the lessons learnt to inform future initiatives. METHODS: Feedback was sought about the implementation of the SABA guidelines and the AAP card using focus groups with key stakeholders including pharmacists (*2), pharmacy assistants, asthma educators, general practitioners, practice nurses and people with asthma (patients). Audio recordings were transcribed verbatim. Data were analysed thematically using constant comparison. The common themes identified from the focus groups were categorised according to a taxonomy of barriers including barriers related to knowledge, attitudes and behaviour. RESULTS: Seven focus group sessions were held with 57 participants. Knowledge barriers were identified included a lack of awareness and lack of familiarity of the resources. There was a significant lack of awareness of the AAP card where passive implementation methods had been utilised. Pharmacists had good awareness of the SABA guidelines but pharmacy assistants were unaware of the guidelines despite significant involvement in the sale of SABAs. Environmental barriers included time and workflow issues and the role of the pharmacy assistant in the organisation workflows of the pharmacy. The attitudes and behaviours of health professionals and patients with asthma were discordant and this undermined optimal asthma management. Suggestions to improve asthma management included the use of legislation, the use of electronic resources integrated into workflows and training pharmacists or practice nurses to provide patients with written asthma action plans. CONCLUSIONS: Greater consideration needs to be given to implementation of resources to improve awareness and overcome barriers to utilisation. Attitudes and behaviours of both health professionals and patients with asthma need to be addressed. Interventions directed toward health professionals should focus on skills needs related to achieving improved communication and patient behaviour change. PMID- 27965775 TI - Child maltreatment and pediatric asthma: a review of the literature. AB - BACKGROUND: Child maltreatment is a common problem with known adverse consequences, yet its contributions to the development and course of pediatric asthma are only poorly understood. MAIN: This review first describes possible pathways connecting child maltreatment to pediatric asthma, including aspects of the physical home environment, health behaviors and disease management, and psychological consequences of child maltreatment. We subsequently review existing studies, which generally report an association between maltreatment experiences and asthma outcomes in childhood. However, this literature is in its early stages; there are only a handful studies, most of them rely on self-reports of both child maltreatment and asthma history, and none have investigated the physiological underpinnings of this association. Taken together, however, the studies are suggestive of child maltreatment playing a role in pediatric asthma incidence and expression that should be explored further. CONCLUSION: Existing data are sparse and do not allow for specific conclusions. However, the data are suggestive of child maltreatment influencing asthma risk and morbidity long before the adult years. Future research should focus on understanding how child maltreatment contributes to asthma disease risk and progression in this highly vulnerable population. PMID- 27965777 TI - Potential of molecular based diagnostics and its impact on allergen immunotherapy. AB - Molecular based in vitro technologies greatly changed the diagnostic approaches in allergy. At present, sensitization profiles can be dissected according to IgE subsets, which are specific for genuine or cross-reacting components and potentially dangerous or virtually harmless components. The identification of IgE in components with specific characteristics has a direct impact on the accuracy of the diagnosis (indeed, it is possible at present to not only identify the allergen derived from a given allergen source but also the family of molecules to which the patient is sensitized), on the prognosis of the patient's allergy, and on the prevention activities to be implemented. More interestingly, during the last few years, and thanks to the tools of molecular diagnostics, the indications for Allergen Immunotherapy (AIT) have also be modified, and novel strategies for the selection of the allergens to be administered have been better defined. Indeed, protocols indicating how Molecular Based Diagnosis (MBD) can be used to identify the best AIT approach have been recently published. In this review, the rationale for the use of MBD tools is discussed, and the recent strategies for the choice of allergens to be used in AIT are reported. PMID- 27965778 TI - The management of asthmatic smokers. AB - Asthma is still a major public health problem in most countries; new strategies to better control this disease are necessary. Such strategies must include predisposing factors. One of these factors is smoking and a significant fraction of asthmatics are smokers. However, clinical trials studying new drugs or newer therapeutic regimens for asthma generally exclude smokers. Therefore, there is a lack of specific information about the treatment of asthma in smokers. The asthmatic smoker is a special phenotype with important therapeutic and prognostic clinical implications. Any form of tobacco use, especially cigarette smoking, plays an important role in this disease. Asthmatic smokers are prone to several negative outcomes. Smoking cessation results in an improvement of symptoms and pulmonary functioning. Counselling and first-line medications for smoking cessation (nicotine replacement therapy, bupropion and varenicline) significantly increase quitting rates. The role of electronic cigarettes in this group of patients has only begun to be studied. The treatment of asthmatics that smoke has characteristics that need must be well understood by clinicians, especially the poor response to corticosteroids. This condition is not universal and physicians should always consider its inclusion in the treatment of these patients. The association of inhaled corticosteroids (ICS) plus a long-acting beta2 adrenegic (LABA) by smoking asthmatics results in more pronounced improvement in several asthma outcomes compared with the use of corticosteroid alone. Inhaled corticosteroids in extra-fine particles associated with LABA may be a new perspective of treatment. Also the use of leukotriene antagonists may become another therapeutic alternative. The purpose of this narrative review is to discuss the challenges faced by clinicians to control asthma in smokers and to present methods of coping with smoking treatment and avoiding relapses. PMID- 27965781 TI - Preacutionary labelling of cross-reactive foods: The case of rapeseed. AB - Food allergic individuals are exposed to unnecessary dietary restrictions due to precautionary food allergy labelling (PFAL). Two forms of PFAL exist: type I identifies the possible presence of allergenic contaminaion in foods ('may content...'), type II indicates as potentially dangerous ingredients or contaminants that do no belong to official list of food allergens. PFAL type II is based on the fear of cross-reactivity with foods belonging to that list. PFAL type II is less known, but may be tempting for the legal offices of food companies, for clinicians in a 'defensive medicine' key, and even for legislators. We identify here a case of PFAL type II, allergy to rapeseed (belonging to the family of Brassicaceae). Increasingly used for their nutritional and nutraceutic value in asthma prevention, rapeseed has been indicated by regulatory authorities in Canada and Europe as potential cross reactor with mustard. In this review, we provide the elements for a risk assessment of cross-reactivity of rapeseed/mustard allergy in the general population both clinically and from the point of view of the molecular allergy. Three findings emerge: 1. Allergic reactions to rapeseed are exceptional 2. The allergens identified in rapeseed and mustard are similar, but not identical 3. Reactions to rapeseed have never been described in mustard-allergic patients. On the ground of existing evidence, a precautionary labeling for rapeseed as potentially dangerous for patients allergic to mustard is not justified. In the interest of patients with multiple food allergy, PFAL type II must be avoided. PMID- 27965779 TI - Asthma phenotypes: the intriguing selective intervention with Montelukast. AB - Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation and a variable course associated with various underlying mechanisms that can differ between individuals. Patients with asthma can therefore exhibit different phenotypes, a term used to define the observable characteristics of an organism resulting from the interaction between its genetic makeup and the environment. The heterogeneity of asthma has received a large amount of attention in the last few years in order to better tailor treatment according to the different clinical and biological phenotypes of the disease. Specific asthma phenotypes may require an approach to treatment sometimes different from that recommended by current guidelines, so a personalized approach to asthma pharmacotherapy is recommended. Growing evidence suggests that leukotrienes play an important role in the pathogenesis of bronchial asthma. The mechanisms of action of leukotriene-receptor antagonists theoretically predict a good response in some asthma "phenotypes".In this article we have performed an analysis of the recent literature (controlled clinical trials and real-life studies) about a possible selective intervention with Montelukast in specific asthma phenotypes. PMID- 27965782 TI - A cluster-randomized controlled knowledge translation feasibility study in Alberta community pharmacies using the PARiHS framework: study protocol. AB - BACKGROUND: Despite evidence of benefit for pharmacist involvement in chronic disease management, the provision of these services in community pharmacy has been suboptimal. The Promoting Action on Research Implementation in Health Services (PARiHS) framework suggests that for knowledge translation to be effective, there must be evidence of benefit, a context conducive to implementation, and facilitation to support uptake. We hypothesize that while the evidence and context components of this framework are satisfied, that uptake into practice has been insufficient because of a lack of facilitation. This protocol describes the rationale and methods of a feasibility study to test a facilitated pharmacy practice intervention based on the PARiHS framework, to assist community pharmacists in increasing the number of formal and documented medication management services completed for patients with diabetes, dyslipidemia, and hypertension. METHODS: A cluster-randomized before-after design will compare ten pharmacies from within a single organization, with the unit of randomization being the pharmacy. Pharmacies will be randomized to facilitated intervention based on the PARiHS framework or usual practice. The Alberta Context Tool will be used to establish the context of practice in each pharmacy. Pharmacies randomized to the intervention will receive task-focused facilitation from an external facilitator, with the goal of developing alternative team processes to allow the greater provision of medication management services for patients with diabetes, hypertension, and dyslipidemia. The primary outcome will be a process evaluation of the needs of community pharmacies to provide more clinical services, the acceptability and uptake of modifications made, and the willingness of pharmacies to participate. Secondary outcomes will include the change in the number of formal and documented medication management services in the aforementioned chronic conditions provided 6 months before, versus after, the intervention between the two groups, and identification of feasible quantitative outcomes for evaluating the effect of the intervention on patient care outcomes. RESULTS: To date, the study has identified and enrolled the ten pharmacies required and initiated the intervention process. CONCLUSION: This study will be the first to examine the role of facilitation in pharmacy practice, with the goal of scalable and sustainable practice change. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02191111. PMID- 27965780 TI - Manifesto on small airway involvement and management in asthma and chronic obstructive pulmonary disease: an Interasma (Global Asthma Association - GAA) and World Allergy Organization (WAO) document endorsed by Allergic Rhinitis and its Impact on Asthma (ARIA) and Global Allergy and Asthma European Network (GA2LEN). AB - Evidence that enables us to identify, assess, and access the small airways in asthma and chronic obstructive pulmonary disease (COPD) has led INTERASMA (Global Asthma Association) and WAO to take a position on the role of the small airways in these diseases. Starting from an extensive literature review, both organizations developed, discussed, and approved the manifesto, which was subsequently approved and endorsed by the chairs of ARIA and GA2LEN. The manifesto describes the evidence gathered to date and defines and proposes issues on small airway involvement and management in asthma and COPD with the aim of challenging assumptions, fostering commitment, and bringing about change. The small airways (defined as those with an internal diameter <2 mm) are involved in the pathogenesis of asthma and COPD and are the major determinant of airflow obstruction in these diseases. Various tests are available for the assessment of the small airways, and their results must be integrated to confirm a diagnosis of small airway dysfunction. In asthma and COPD, the small airways play a key role in attempts to achieve disease control and better outcomes. Small-particle inhaled formulations (defined as those that, owing to their size [usually <2 MUm], ensure more extensive deposition in the lung periphery than large molecules) have proved beneficial in patients with asthma and COPD, especially those in whom small airway involvement is predominant. Functional and biological tools capable of accurately assessing the lung periphery and more intensive use of currently available tools are necessary. In patients with suspected COPD or asthma, small airway involvement must be assessed using currently available tools. In patients with subotpimal disease control and/or functional or biological signs of disease activity, the role of small airway involvement should be assessed and treatment tailored. Therefore, the choice between large- and small-particle inhaled formulations must reflect the physician's considerations of disease features, phenotype, and response to previous therapy. This article is being co-published in Asthma Research and Practice and the World Allergy Organization Journal. PMID- 27965783 TI - A cluster randomised feasibility trial evaluating six-month nutritional interventions in the treatment of malnutrition in care home-dwelling adults: recruitment, data collection and protocol. AB - BACKGROUND: Protein energy malnutrition predisposes individuals to disease, delays recovery from illness and reduces quality of life. Care home residents are especially vulnerable, with an estimated 30%-42% at risk. There is no internationally agreed protocol for the nutritional treatment of malnutrition in the care home setting. Widely used techniques include food-based intervention and/or the use of prescribed oral nutritional supplements, but a trial comparing the efficacy of interventions is necessary. In order to define outcomes and optimise the design for an adequately powered, low risk of bias cluster randomised controlled trial, a feasibility trial with 6-month intervention is being run, to assess protocol procedures, recruitment and retention rates, consent processes and resident and staff acceptability. METHODS: Trial recruitment began in September 2013 and concluded in December 2013. Six privately run care homes in Solihull, England, were selected to establish feasibility within different care home types. Residents with or at risk of malnutrition with no existing dietetic intervention in place were considered for receipt of the allocated intervention. Randomisation took place at the care home level, using a computer-generated random number list to allocate each home to either a dietetic intervention arm (food-based or prescribed supplements) or the standard care arm, continued for 6 months. Dietetic intervention aimed to increase daily calorie intake by 600 kcal and protein by 20-25 g. RESULTS: The primary outcomes will be trial feasibility and acceptability of trial design and allocated interventions. A range of outcome assessments and data collection tools will be evaluated for feasibility, including change in nutrient intake, anthropometric parameters and patient-centric measures, such as quality of life and self-perceived appetite. CONCLUSIONS: The complexities inherent in care home research has resulted in the under representation of this population in research trials. The results of this feasibility trial will be used to inform the development and design of a future cluster randomised controlled trial to compare food-based intervention with prescribed oral nutritional supplements (ONS) in the treatment of malnutrition within the care home population. TRIAL REGISTRATION: Current Controlled Trials ISRCTN38047922. PMID- 27965786 TI - A pilot feasibility trial of alcohol screening and brief intervention in the police custody setting (ACCEPT): study protocol for a cluster randomised controlled trial. AB - BACKGROUND: There is evidence of an association between alcohol use and offending behaviour and around a quarter of police time is spent on alcohol-related incidents. Police custody, therefore, provides an important opportunity to intervene. This pilot trial aims to investigate whether a definitive evaluation of screening and brief interventions aimed at reducing risky drinking in arrestees is acceptable and feasible in the custody suite setting. METHODS: Screening will be carried out by trained detention officers or drug and alcohol workers in four police forces across two geographical areas (North East and South West England). Detention officers (or drug and alcohol workers) will be cluster randomised to one of three conditions: screening only (control group), screening followed immediately by 10 min of manualised brief structured advice delivered by the individual responsible for screening (intervention 1) or screening followed by 10 min of manualised brief structured advice delivered by the individual responsible for screening plus the offer of a subsequent 20-min session of behaviour change counselling delivered by a trained alcohol health worker (intervention 2). Participants will be arrestees aged 18+ who screen positive on the Alcohol Use Disorders Identification Test. Participants will be followed up at 6 and 12 months post-intervention. An embedded qualitative process evaluation will explore acceptability of alcohol screening and brief intervention to staff and arrestees as well as facilitators and barriers to the delivery of such approaches in this setting. RESULTS: Recruitment is currently underway and due to end May 2015. CONCLUSION: Results from this pilot trial will determine if a definitive evaluation is possible in the future and will provide stakeholder input to its design. TRIAL REGISTRATION: Reference number: ISRCTN89291046. PMID- 27965785 TI - A single-blind, pilot randomised trial of a weight management intervention for adults with intellectual disabilities and obesity: study protocol. AB - BACKGROUND: The prevalence of obesity in adults with intellectual disabilities has consistently been reported to be higher than the general population. Despite the negative impact of obesity on health, there is little evidence of the effectiveness of weight management interventions for adults with intellectual disabilities and obesity. Preliminary results from a single-stranded feasibility study of a multi-component weight management intervention specifically designed for adults with intellectual disabilities and obesity (TAKE 5) and that satisfied clinical recommendations reported that it was acceptable to adults with intellectual disabilities and their carers. This study aims to determine the feasibility of a full-scale clinical trial of TAKE 5. METHODS: This study will follow a pilot randomised trial design. Sixty-six obese participants (body mass index (BMI) >=30 kg/m2) will be randomly allocated to the TAKE 5 multi-component weight management intervention or a health education 'active' control intervention (Waist Winners Too (WWToo)). Both interventions will be delivered over a 12-month period. Participants' anthropometric measures (body weight, BMI, waist circumference, percentage body fat); indicators of activity (levels of physical activity and sedentary behaviour) and well-being will be measured at three time points: baseline, 6 and 12 months. The researcher collecting outcome measures will be blind to study group allocation. CONCLUSIONS: The data from this study will generate pilot data on the acceptability of randomisation, attrition rates and the estimates of patient-centred outcomes of TAKE 5, which will help inform future research and the development of a full-scale randomised clinical trial. TRIAL REGISTRATION: ISRCTN52903778. PMID- 27965787 TI - CanWalk: study protocol for a randomized feasibility trial of a walking intervention for people with recurrent or metastatic cancer. AB - BACKGROUND: Increasing numbers of people in the UK are living with recurrent or metastatic cancer, many of whom experience reduced quality of life resulting from the physical and psychosocial consequences of cancer and its treatment. While drug treatments are important at alleviating some symptoms, there is increasing evidence of the benefits of exercise in enhancing quality of life and health outcomes. Walking is an inexpensive and accessible form of exercise. To our knowledge, no studies have investigated whether a walking intervention is sufficient to enhance quality of life and alleviate symptoms in people with recurrent or metastatic cancer across a range of tumor types. This paper describes the CanWalk study protocol, which aims to assess the feasibility and acceptability of undertaking a randomized controlled trial of a community-based walking program to enhance quality of life and well-being in people with recurrent or metastatic cancer. METHODS: A mixed methods feasibility study includes an exploratory two-center randomized controlled trial and qualitative interviews. A minimum of 60 participants will be recruited from two London NHS Trusts and randomized 1:1 between the walking intervention and standard care using minimization. The walking intervention consists of the initial provision of written/online information followed by a short motivational interview. Participants are instructed to walk for 30 min on alternate days and attend an organized volunteer-led walk once a week. Half of all participants will be asked to use a pedometer. Postal questionnaires will be completed at baseline (pre randomization) and at 6, 12 and 24 weeks. A subsample of participants and stakeholders will be interviewed at the end of the study. RESULTS: Primary outcomes will be the acceptability and feasibility of the intervention and trial. A range of secondary outcome assessments needed to design a main study, including estimates of recruitment, adherence and variability in quality of life, will be evaluated. CONCLUSIONS: Data from this study will be used to refine the walking intervention, investigate the acceptability of the intervention and study design, and determine the most appropriate outcome measures thereby providing estimates of the factors needed to design the main study. TRIAL REGISTRATION: ISRCTN42072606. PMID- 27965788 TI - A randomised controlled feasibility trial of family and social network intervention for young people who misuse alcohol and drugs: study protocol (Y SBNT). AB - BACKGROUND: A growing body of research has identified family interventions to be effective in treating young people's substance use problems. However, despite this evidence, take-up of family-based approaches in the UK has been low. Key factors for this appear to include the resource-intensive nature of most family interventions which challenges implementation and delivery in many service settings and the cultural adaptation of approaches developed in the USA to a UK setting. This study aims to demonstrate the feasibility of recruiting young people to a specifically developed family- and wider social network-based intervention by testing an adapted version of adult social behaviour and network therapy (SBNT). METHODS: A pragmatic, randomised controlled, open feasibility trial delivered in two services for young people in the UK. Potential participants are aged 12-18 years referred for drug or alcohol problems to either service. The main purpose of this study is to demonstrate the feasibility of recruiting young people to a specifically developed family and social network based intervention. The feasibility and acceptability of this intervention will be measured by recruitment rates, treatment retention, follow-up rates and qualitative interviews. The feasibility of training staff from existing services to deliver this intervention will be explored. Using this opportunity to compare the effectiveness of the intervention against treatment as usual, Timeline Follow Back interviews will document the proportion of days on which the main problem substance was used in the preceding 90-day period at each assessment point. The economic component will examine the feasibility of conducting a full incremental cost-effectiveness analysis of the two treatments. The study will also explore and develop models of patient and public involvement which support the involvement of young people in a study of this nature. DISCUSSION: An earlier phase of work adapted social behaviour and network therapy (adult approach) to produce a purpose-designed youth version supported by a therapy manual and associated resources. This was achieved by consultation with young people with experience of services and professionals working in services for young people. This feasibility trial alongside ongoing consultations with young people will offer a meaningful understanding of processes of delivery and implementation. TRIAL REGISTRATION: ISRCTN93446265; Date ISRCTN assigned 31/05/2013. PMID- 27965789 TI - Lumbar transversus abdominis plane block: the role of local anesthetic volume and concentration-a pilot, prospective, randomized, controlled trial. AB - BACKGROUND: The lumbar transversus abdominis plane (TAP) block has become an optional part of multimodal analgesia following several abdominal surgeries. There remains a lack of consensus regarding the extent of dermatomal blockade following lumber TAP block, as well as the optimal local anesthetic volumes and concentrations. The objectives of this pilot trial were to assess the feasibility of conducting a similar full-scale trial and gather information on relevant clinical outcomes, namely whether greater local anesthetic volumes would lead to more cephalad dermatomal blockade. METHODS: The study was a prospective, double blinded pilot randomized controlled trial (RCT) with three arms, each representing different local anesthetic volumes: 20 ml 0.5% ropivacaine, 30 ml 0.33% ropivacaine, and 40 ml 0.25% ropivacaine. We planned to recruit 30 females undergoing total abdominal hysterectomy for non-malignant pathology, who would then receive bilateral ultrasound-guided midaxillary TAP blocks at the completion of surgery. Randomized patients would be followed for 48 h post-block and would receive multimodal analgesia. The primary outcomes were measurements of patient recruitment and safety, to inform the feasibility of a larger trial. The main secondary outcome was the clinically pertinent endpoint of dermatomal blockade, which was assessed by loss of sensation to ice and pinprick. RESULTS: Our target sample size was reached in 8 months, and the recruitment rate was 52% (31/60). A total of 58 TAP blocks were performed among 29 patients. All but one of the patients who received interventions were successfully followed and assessed up to 48 h. No patient safety-related adverse events were reported during the study period. The mean highest dermatome blocked in each group at any time point was T8. The 20 ml 0.5% ropivacaine group achieved a T9-L1 block that lasted for 48 h. The 30 ml 0.33% ropivacaine group had a sensory block from T9-L1 that regressed to T10-T12 between 24 and 48 h. The 40 ml 0.25% ropivacaine group reported an initial sensory block from T9-T12 that regressed by 24 h to include only the T12 dermatome. CONCLUSIONS: This pilot study demonstrated that the study design is feasible and safe to be carried to a full-scale RCT. The preliminary clinical findings showed that increasing the volume, while maintaining a constant dose, of local anesthetic does not appear to extend the height of dermatomal blockade following midaxillary TAP block. This finding needs to be confirmed in future studies. TRIAL REGISTRATION: ClinicalTrials.gov registration is: NCT01307215. PMID- 27965790 TI - NOURISH, Nutritional OUtcomes from a Randomised Investigation of Intradialytic oral nutritional Supplements in patients receiving Haemodialysis: a pilot randomised controlled trial. AB - BACKGROUND: The study was done to assess the feasibility of conducting a trial evaluating the use of an intradialytic oral nutritional supplement (ONS) on nutritional status. METHODS: The study design is a single centre, parallel group, external pilot randomised controlled trial (RCT). The setting was at a haemodialysis unit in Sheffield, UK. The aim was to recruit 30 trial participants to allow at least 12 evaluable patients per arm, but the actual study sample consisted of 10 adults with a body mass index (BMI) <=22 kg/m2, receiving thrice weekly haemodialysis. All participants received nutritional advice from a renal dietitian as per usual practice. The intervention included the provision of an intradialytic ONS. Feasibility outcomes included recruitment to time and retention of participants along with palatability of ONS. Secondary outcomes were clinical parameters to obtain variance and estimates of effect size to inform the sample size calculation for a definitive trial. RESULTS: Recruitment was undertaken for a fixed period of 6 weeks. Rates were lower than expected mainly due to ineligibility with only 7% of screened patients (19/265) being eligible and 4% (10/265) of these being recruited. Due to the small proportion of patients eligible for the trial, all haemodialysis patients at the specified unit were assessed for eligibility. Data completion rates were low for session questionnaires (23%). Sample sizes derived from variance in secondary outcome measure of handgrip strength and adjusted for a dropout rate of 20% indicate that 189 patients would be required for a definitive RCT, requiring 19 UK haemodialysis units to participate. CONCLUSIONS: A definitive RCT is feasible with some adaptation to exclusion criteria and methodology. The exclusion criteria could be adapted to include an increase in upper limit for BMI. The use of questionnaires at each dialysis session may not be feasible but the inclusion of appetite and supplement consumption data collection at the main assessments would provide similar outcome data. Quality of life assessment using SF-12 would be acceptable. TRIAL REGISTRATION: ISRCTN37431579. PMID- 27965791 TI - Pilot randomised controlled trial of protective socks against usual care to reduce skin tears in high risk people "STOPCUTS": study protocol. AB - BACKGROUND: Skin tears are traumatic injuries occurring mostly on the extremities due to shearing and friction forces that separate the epidermis and the dermis from underlying tissues. They are common and occur mostly in older adults and those taking medications that compromise skin integrity. Pretibial skin tears can develop into leg ulcers, which require lengthy, expensive treatment to heal. Traumatic injuries are the second most common type of wounds after pressure ulcers in care homes and are the commonest reason for older adults to require the attention of a community nurse. Common causes of skin tear injuries are bumping into furniture and other obstacles, using mobility aids, transfer to/from wheelchairs, getting in and out of bed and falls. No effective preventative measures currently exist but knee-length, protective socks are now available that contain impact-resistant Kevlar fibres (of the type used in stab-proof vests) and cushioning layers underneath. METHODS/DESIGN: In this pilot parallel group, randomised controlled trial, 90 people at risk of skin-tear injury will be randomised with equal allocation to receive the intervention or usual care. They will be recruited from care homes and from the community via general practices and a research volunteer database. Pilot outcomes include recruitment, eligibility, attrition, ascertainment of injuries and completion of outcome measures. Acceptability of the intervention and of study participation will be explored using semi-structured interviews. The proposed primary outcome for the future definitive trial is skin tear-free days. Secondary outcomes are skin tear severity, health status, specific skin-tears quality of life, capability and fear of falling, measured at baseline and the end of the study and in the event of a skin tear. DISCUSSION: The results of this study will be used to inform the development and design of a future randomised controlled trial to assess the effectiveness and cost-effectiveness of a unique and innovative approach to skin tear prevention. Approval was granted by the NRES - Cornwall and Plymouth Research Ethics Committee (13/SW/013). Dissemination will include publication of quantitative and qualitative findings, and experience of public involvement in peer-reviewed journals. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN96565376. PMID- 27965793 TI - Evaluating an online support package delivered within a disability unemployment service: study protocol for a randomised controlled feasibility study. AB - BACKGROUND: Mental health problems such as anxiety and depression are known to be higher in those who are unemployed. Cognitive behavioural therapy (CBT) is a recognised support for people with such problems and can improve the ability of people to get back to work. METHODS/DESIGN: Participants with symptoms of low mood will be recruited from the disability employment service, Remploy. Participants will receive either immediate or delayed access to an online CBT based life skills intervention, the "Living Life" package. The primary end point will be at 3 months when the delayed group will be offered the intervention. This feasibility study will test the trial design and assess recruitment, retention, acceptability and adherence, as well as providing efficacy data. DISCUSSION: The study will inform the design and sample size for a future full randomised controlled trial (RCT) which will be carried out to determine the effectiveness of the online package in improving mood and employment status. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10316077. PMID- 27965792 TI - Fracture in the Elderly Multidisciplinary Rehabilitation (FEMuR): study protocol for a phase II randomised feasibility study of a multidisciplinary rehabilitation package following hip fracture [ISRCTN22464643]. AB - BACKGROUND: Proximal femoral fracture is a common, major health problem in old age resulting in loss of functional independence and a high-cost burden on society, with estimated health and social care costs of L2.3 billion per year in the UK. Rehabilitation has the potential to maximise functional recovery and maintain independent living, but evidence of effectiveness is lacking. Usual rehabilitation care is delivered by a multi-disciplinary team in the hospital and in the community. An 'enhanced rehabilitation' intervention has been developed consisting of a workbook, goal-setting diary and extra therapy sessions, designed to improve self-efficacy and increase the amount and quality of the practice of physical exercise and activities of daily living. METHODS/DESIGN: This paper describes the design of a phase II study comprising an anonymous cohort of all proximal femoral fracture patients admitted to the three acute hospitals in Betsi Cadwaladr University Health Board over a 6-month period with a randomised feasibility study comparing the enhanced rehabilitation intervention with usual care. These will assess the feasibility of a future definitive randomised controlled trial and concurrent economic evaluation in terms of recruitment, retention, outcome measure completion, compliance with the intervention and fidelity of delivery, health service use data, willingness to be randomised and effect size for a future sample size calculation. Focus groups will provide qualitative data to contribute to the assessment of the acceptability of the intervention amongst patients, carers and rehabilitation professionals and the feasibility of delivering the planned intervention. The primary outcome measure is function assessed by the Barthel Index. Secondary outcomes measure the ability to perform activities of daily living, anxiety and depression, potential mediators of outcomes such as hip pain, self-efficacy and fear of falling, health utility, health service use, objectively assessed physical function and adverse events. Participants' preference for rehabilitation services will be assessed in a discrete choice experiment. DISCUSSION: Phase II studies are an opportunity to not only assess the feasibility of trial methods but also to compare different methods of outcome measurement and novel methods of obtaining health service use data from routinely collected patient information. TRIAL REGISTRATION: Current Controlled Trials ISRCTN22464643, UKCRN16677. PMID- 27965795 TI - Investigating the collection and assessment of patient-reported outcome data amongst unplanned surgical hospital admissions: a feasibility study. AB - BACKGROUND: Randomised controlled trials (RCTs) in surgery can be challenging to conduct, and trials in the emergency surgical setting when patients have unplanned hospital admissions are particularly difficult. One area of challenge is capturing baseline patient-reported outcome (PRO) data. This study examined the feasibility and optimal methods for the collection of baseline and follow-up PRO data in the setting of unplanned surgical hospital admissions. METHODS: Clinically stable adult patients with unplanned admissions through the day and night under the care of general surgeons at two acute NHS trusts were approached during working week days and asked to complete validated PRO measures (European Quality of Life-5 Dimension, Short Form-12, and Gastrointestinal Quality of Life Index) on admission and 6 weeks following discharge. Feasibility of PRO data collection was determined by the proportions of admitted patients eligible and recruited and by questionnaire-response rates at baseline and follow up. Reasons for non-recruitment and non-completion of questionnaires were sought and recorded. RESULTS: There were 276 admissions, of whom 235 (85.1 %) were eligible. Reasons for ineligibility were the following: age under 18 years old (n = 5, 1.8 %), non-surgical presenting complaint (n = 6, 2.2 %) and clinical instability (n = 30, 10.9 %). One hundred and sixty-six patients (70.6 %) were recruited (98 female, 59.0 %); median age 53, range 19-100). Common reasons for non-recruitment included patients being discharged home before approached by researchers (n = 29, 12.3 %) or declining participation because they felt unwell (n = 15, 6.4 %). The most common reason for admission to the hospital was abdominal pain (n = 120, 72.3 % recruited patients), of whom 50 (30.1 %) required operative intervention. Baseline PRO data was obtained from 153 patients (93.3 %), and 74 (48.4 %) returned follow-up questionnaires. CONCLUSIONS: Collection of baseline PRO data amongst unplanned admissions in general surgery is feasible. Methods for optimising retention and follow up are needed. PMID- 27965794 TI - Experiences of recruiting to a pilot trial of Cardiac Rehabilitation In patients with Bowel cancer (CRIB) with an embedded process evaluation: lessons learned to improve recruitment. AB - BACKGROUND: Recruitment to randomised controlled trials (RCTs) is a perennial problem. Calls have been made for trialists to make recruitment performance publicly available. This article presents our experience of recruiting to a pilot RCT of cardiac rehabilitation for patients with bowel cancer with an embedded process evaluation. METHODS: Recruitment took place at three UK hospitals. Recruitment figures were based on the following: i) estimated number of patient admissions, ii) number of patients likely to meet inclusion criteria from clinician input and iii) recruitment rates in previous studies. The following recruitment procedure was used:Nurse assessed patients for eligibility.Patients signed a screening form indicating interest in and agreement to be approached by a researcher about the study.An appointment was made at which the patient signed a consent form and was randomised to the intervention or control group. Information about all patients considered for the study and subsequently included or excluded at each stage of the recruitment process and reasons given were recorded. RESULTS: There were variations in the time taken to award Research Management approval to run the study at the three sites (45-359 days). Sixty-two percent of the original recruitment estimate was reached. The main reason for under-recruitment was due to over-estimation of the number of patient admissions; other reasons were i) not assessing all patients for eligibility, ii) not completing a screening form for eligible patients and iii) patients who signed a screening form being lost to the study before consenting and randomisation. CONCLUSIONS: Pilot trials should not simply aim to improve recruitment estimates but should also identify factors likely to influence recruitment performance in a future trial and inform the development of that trial's recruitment strategies. Pilot trials are a crucial part of RCT design. Nevertheless, pilot trials are likely to be small scale, involving only a small number of sites, and contextual differences between sites are likely to impact recruitment performance in any future trial. This means that ongoing monitoring and evaluation in trials are likely to be required. TRIAL REGISTRATION: ISRCTN63510637; UKCRN id 14092. PMID- 27965797 TI - Feasibility of a laboratory-based accelerometer calibration protocol for children with intellectual disabilities. AB - BACKGROUND: Accelerometry has not been calibrated for the estimation of physical activity in children with intellectual disabilities (ID), raising questions regarding the validity of interpreting accelerometer data in this population. Various protocols and criterion measures have been used in calibration studies involving typically developing (TD) children; however, the suitability of these activities and measures for children with ID is unknown. Therefore, this study aimed to test the feasibility of a laboratory-based calibration protocol for children with ID. Specifically, the feasibility of activities, measurements, and recruitment was investigated. METHODS: Five children with mild to moderate ID (10.20 +/- .98 years) and a comparative sample of five TD children (12.40 +/- .01 years) participated in this study. Participants performed a free-living and treadmill-based activity protocol during two laboratory-based sessions. Activities were performed for 5 min and ranged from sedentary to vigorous intensity. Treadmill activities ranged from 3 to 8 km/h, and free-living activities included watching a DVD, passing a football, and jumping jacks. Resting energy expenditure was measured, and a graded exercise test was used to assess cardiorespiratory fitness. Breath-by-breath respiratory gas exchange and accelerometry were continually measured during all activities. Feasibility was assessed using observations, activity completion rates, and respiratory data. RESULTS: All TD participants and one participant with ID completed the protocol. The physical demands of the treadmill activities affected the completion rate for participants with ID. No participant met the maximal criteria for the graded exercise test or attained a steady state during the resting measurements. Limitations were identified with the usability of respiratory gas exchange equipment and the validity of measurements. The school-based recruitment strategy was not effective, with a participation rate of 6 %. A significant (z = 13.21, p < .0001) difference in the relationship of [Formula: see text] and accelerometry was identified between ID and TD participants. CONCLUSIONS: Due to issues with the usability and validity of breath-by-breath respiratory gas exchange and recruitment, a laboratory-based calibration protocol is currently not feasible for children with ID. An alternative field-based protocol with a non-invasive criterion measure should be considered for future studies. PMID- 27965796 TI - Exploring the Determinants of Suicidal Behavior: Conventional and Emergent Risk (DISCOVER): a feasibility study. AB - BACKGROUND: Suicidal behavior is a growing public health concern resulting in morbidity and premature death. Although certain factors such as age, sex, and psychiatric disorders have been consistently reported to be associated with suicidal behavior, other factors including biological markers, diet, and physical activity may also influence suicidal behavior. The purpose of this pilot study was to evaluate the feasibility of conducting a full-scale study to identify the conventional and novel risk factors of suicidal behavior in individuals who made a recent suicide attempt. METHODS: This pilot study was a case-control study of participants with recent (within 1 month of admission) suicide attempts admitted to hospital and compared to two control groups: 1) psychiatric inpatient participants without a history of suicide attempts and 2) community-based controls. We collected information on demographic variables, circumstances of suicide attempts (for cases), medical and psychiatric diagnoses, behavioral patterns, physical measurements, and social factors. Blood and urine samples were also collected for biological markers. Feasibility outcomes are as follows: 1) 50 % of all eligible cases will consent to participate, 2) 50 cases and 100 controls per year can be recruited, and 3) at least 80 % of the participants will provide blood samples for DNA and biological markers. RESULTS: We recruited 179 participants in total; 51 cases, 57 psychiatric controls without suicide attempt, and 71 non-psychiatric controls in Hamilton, Ontario. Recruitment rate was 70 % (213/304), and we obtained urine and blood specimens from 90 % (191/213) of participants. Questionnaire completion rates were high, and data quality was very good with few data-related queries to resolve. We learned that cases tended to be hospitalized for long periods of time and the suicide attempt occurred more than a month ago in many of the cases; therefore, we expanded our inclusion criterion related to timing of suicide attempt to 3 months instead of 1 month. CONCLUSIONS: The study procedures needed certain modifications including extending the time between suicide attempt and date of recruitment, and more detailed questionnaires related to diet were necessary while other questionnaires such as social support needed to be shortened. Overall, this study showed that it is feasible to conduct a larger-scale study. PMID- 27965798 TI - Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial PROSPECT: protocol for a feasibility randomized pilot trial. AB - BACKGROUND: Probiotics are defined as live microorganisms that may confer health benefits when ingested. Meta-analysis of probiotic trials suggests a 25 % lower ventilator-associated pneumonia (VAP) and 18 % lower infection rates overall when administered to patients in the intensive care unit (ICU). However, prior trials are small, largely single center, and at high risk of bias. Before a large rigorous trial is launched, testing whether probiotics confer benefit, harm, or have no impact, a pilot trial is needed. The aim of the PROSPECT Pilot Trial is to determine the feasibility of performing a larger trial in mechanically ventilated critically ill patients investigating Lactobacillus rhamnosus GG. A priori, we determined that the feasibility of the larger trial would be based on timely recruitment, high protocol adherence, minimal contamination, and an acceptable VAP rate. METHODS/DESIGN: Patients >=18 years old in the ICU who are anticipated to receive mechanical ventilation for >=72 hours will be included. Patients are excluded if they are at increased risk of probiotic-associated infection, have strict enteral medication contraindications, are pregnant, previously enrolled in a related trial, or are receiving palliative care. Following informed consent, patients are randomized in variable unspecified block sizes in a fixed 1:1 ratio, stratified by ICU, and medical, surgical, or trauma admitting diagnosis. Patients receive 1 * 1010 colony forming units of L. rhamnosus GG (Culturelle, Locin Industries Ltd) or an identical placebo suspended in tap water administered twice daily via nasogastric tube in the ICU. Clinical and research staff, patients, and families are blinded. DISCUSSION: The primary outcomes for this pilot trial are the following: (1) recruitment success, (2) >=90 % protocol adherence, (3) <=5 % contamination, and (4) ~10 % VAP rate. Additional clinical outcomes are VAP, other infections, diarrhea (total, antibiotic associated, and Clostridium difficile), ICU and hospital length of stay, and mortality. The morbidity, mortality, and cost of VAP underscore the need for cost-effective prophylactic interventions. The PROSPECT Pilot Trial is the initial step toward rigorously evaluating whether probiotics decrease nosocomial infections, have no effect, or actually cause infections in critically ill patients. TRIAL REGISTRATION: ClinicalTrials.gov. NCT01782755. PMID- 27965799 TI - Measuring the implementation of a group-based Lifestyle-integrated Functional Exercise (Mi-LiFE) intervention delivered in primary care for older adults aged 75 years or older: a pilot feasibility study protocol. AB - BACKGROUND: Declines in function and quality of life, and an increased risk of cardiovascular events, falls, and fractures occur with aging and may be amenable to exercise intervention. Primary care is an ideal setting for identifying older adults in need of exercise intervention. However, a cost-effective, generalizable model of chronic disease management using exercise in a real-world setting remains elusive. Our objective is to measure the feasibility, potential effectiveness, and implementation of an evidence-based Lifestyle-integrated Functional strength and balance Exercise (LiFE) intervention adapted as a group based format (Mi-LiFE) for primary care to promote increased physical activity levels in older adults aged 75 years or older. We hypothesize that the intervention will be feasible without modification if >=30 individuals are recruited over 6 months, >=75 % of our sample is retained, and >=50 % of our sample complete exercises >=3 days per week. METHODS/DESIGN: A pre-post pilot study design will be used to evaluate feasibility, potential effectiveness, and implementation outcomes over a 6-month period in physically inactive older adults >=75 years recruited from a local family health team practice. The reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework will be applied to evaluate the public health effects of the intervention including outcomes both at the individual and organizational levels. A physical therapist will teach participants how to integrate strength and balance activities into their daily lives over one individual and four group-based sessions, and two phone calls. Assessments will be completed at baseline and 6 months. Feasibility outcomes include recruitment over 6 months, retention at follow-up, and adherence measured by activity diaries. Change in patient-centered and implementation outcomes that will be evaluated include physical activity levels using accelerometers and International Physical Activity Questionnaire, physical performance using short physical performance battery, quality of life using EQ5D questionnaire, falls and harms using daily calendar diaries and self-report, fidelity using descriptive feedback, barriers and facilitators to implementation using thematic content analysis, and process outcomes. DISCUSSION: The feasibility and implementation of the Mi-LiFE intervention in primary care for older adults will be evaluated, as well as the effects of the intervention on secondary outcomes. If the intervention appears feasible, we will use the resultant information to design a larger trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCTO2266225. PMID- 27965800 TI - Protocol for a pilot randomised controlled trial of an intervention to increase the use of traffic light food labelling in UK shoppers (the FLICC trial). AB - BACKGROUND: Traffic light labelling of foods-a system that incorporates a colour coded assessment of the level of total fat, saturated fat, sugar and salt on the front of packaged foods-has been recommended by the UK Government and is currently in use or being phased in by many UK manufacturers and retailers. This paper describes a protocol for a pilot randomised controlled trial of an intervention designed to increase the use of traffic light labelling during real life food purchase decisions. METHODS/DESIGN: The objectives of this two-arm randomised controlled pilot trial are to assess recruitment, retention and data completion rates, to generate potential effect size estimates to inform sample size calculations for the main trial and to assess the feasibility of conducting such a trial. Participants will be recruited by email from a loyalty card database of a UK supermarket chain. Eligible participants will be over 18 and regular shoppers who frequently purchase ready meals or pizzas. The intervention is informed by a review of previous interventions encouraging the use of nutrition labelling and the broader behaviour change literature. It is designed to impact on mechanisms affecting belief and behavioural intention formation as well as those associated with planning and goal setting and the adoption and maintenance of the behaviour of interest, namely traffic light label use during purchases of ready meals and pizzas. Data will be collected using electronic sales data via supermarket loyalty cards and web-based questionnaires and will be used to estimate the effect of the intervention on the nutrition profile of purchased ready meals and pizzas and the behavioural mechanisms associated with label use. Data collection will take place over 48 weeks. A process evaluation including semi-structured interviews and web analytics will be conducted to assess feasibility of a full trial. DISCUSSION: The design of the pilot trial allows for efficient recruitment and data collection. The intervention could be generalised to a wider population if shown to be feasible in the main trial. TRIAL REGISTRATION: ISRCTN: ISRCTN19316955. PMID- 27965801 TI - Evaluation and treatment of low and anxious mood in Chinese-speaking international students studying in Scotland: study protocol of a pilot randomised controlled trial. AB - BACKGROUND: Low mood is a common mental health problem affecting up to 121 million people worldwide and is common in students, particularly international students. Cognitive behavioural therapy (CBT) is known to be effective as a treatment for low mood and anxiety when delivered one to one by an expert practitioner, however this can be expensive and many services have waiting lists and delayed access. A range of additional ways of increasing access to services includes the offer of online courses such as computerised CBT as a possible additional pathway for care. This project aims to test the feasibility of a pilot randomised controlled trial of an online CBT-based life skills course with Chinese-speaking international students experiencing low mood and anxiety. METHODS/DESIGN: Chinese-speaking international students with symptoms of low mood and/or anxiety will be recruited from the University of Glasgow, Scotland. Participants will be remotely randomised to receive either immediate access (IA) or delayed access (DA) to a guided/supported online CBT-based life skills package, the "Living Life" package (Chinese version). Participants will be randomly assigned to IA or DA to the intervention. The primary end point will be at 3 months when the delayed group will be offered the intervention. Levels of depression, anxiety, social functioning and satisfaction will be assessed. DISCUSSION: This pilot study will test the trial design, ability to recruit, gather completed questionnaires, test drop-out rates and investigate completion and acceptability of the package. The study aims to reduce uncertainties about the delivery of a future substantive study and will also inform a sample size calculation for that subsequent substantive randomised controlled trial (RCT) which will be carried out to determine the effectiveness of the online package in improving low mood and anxiety in the Chinese-speaking student population. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30816908. PMID- 27965802 TI - Prescribed computer games in addition to occlusion versus standard occlusion treatment for childhood amblyopia: a pilot randomised controlled trial. AB - BACKGROUND: Amblyopia ("lazy eye") is the commonest vision deficit in children. If not fully corrected by glasses, amblyopia is treated by patching or blurring the better-seeing eye. Compliance with patching is often poor. Computer-based activities are increasingly topical, both as an adjunct to standard treatment and as a platform for novel treatments. Acceptability by families has not been explored, and feasibility of a randomised controlled trial (RCT) using computer games in terms of recruitment and treatment acceptability is uncertain. METHODS: We carried out a pilot RCT to test whether computer-based activities are acceptable and accessible to families and to test trial methods such as recruitment and retention rates, randomisation, trial-specific data collection tools and analysis. The trial had three arms: standard near activity advice, Eye Five, a package developed for children with amblyopia, and an off-the-shelf handheld games console with pre-installed games. We enrolled 60 children age 3-8 years with moderate or severe amblyopia after completion of optical treatment. RESULTS: This trial was registered as UKCRN-ID 11074. Pre-screening of 3600 medical notes identified 189 potentially eligible children, of whom 60 remained eligible after optical treatment, and were enrolled between April 2012 and March 2013. One participant was randomised twice and withdrawn from the study. Of the 58 remaining, 37 were boys. The mean (SD) age was 4.6 (1.7) years. Thirty-seven had moderate and 21 severe amblyopia. Three participants were withdrawn at week 6, and in total, four were lost to follow-up at week 12. Most children and parents/carers found the study procedures, i.e. occlusion treatment, usage of the allocated near activity and completion of a study diary, easy. The prescribed cumulative dose of near activity was 84 h at 12 weeks. Reported near activity usage numbers were close to prescribed numbers in moderate amblyopes (94 % of prescribed) but markedly less in severe amblyopes (64 %). Reported occlusion usage at 12 weeks was 90 % of prescribed dose for moderate and 33 % for severe amblyopes. CONCLUSIONS: Computer-based games and activities appear acceptable to families as part of their child's amblyopia treatment. Trial methods were appropriate and accepted by families. PMID- 27965803 TI - Facilitating return to work through early specialist health-based interventions (FRESH): protocol for a feasibility randomised controlled trial. AB - BACKGROUND: Over one million people sustain traumatic brain injury each year in the UK and more than 10 % of these are moderate or severe injuries, resulting in cognitive and psychological problems that affect the ability to work. Returning to work is a primary rehabilitation goal but fewer than half of traumatic brain injury survivors achieve this. Work is a recognised health service outcome, yet UK service provision varies widely and there is little robust evidence to inform rehabilitation practice. A single-centre cohort comparison suggested better work outcomes may be achieved through early occupational therapy targeted at job retention. This study aims to determine whether this intervention can be delivered in three new trauma centres and to conduct a feasibility, randomised controlled trial to determine whether its effects and cost effectiveness can be measured to inform a definitive trial. METHODS/DESIGN: Mixed methods study, including feasibility randomised controlled trial, embedded qualitative studies and feasibility economic evaluation will recruit 102 people with traumatic brain injury and their nominated carers from three English UK National Health Service (NHS) trauma centres. Participants will be randomised to receive either usual NHS rehabilitation or usual rehabilitation plus early specialist traumatic brain injury vocational rehabilitation delivered by an occupational therapist. The primary objective is to assess the feasibility of conducting a definitive trial; secondary objectives include measurement of protocol integrity (inclusion/exclusion criteria, intervention adherence, reasons for non-adherence) recruitment rate, the proportion of eligible patients recruited, reasons for non recruitment, spectrum of TBI severity, proportion of and reasons for loss to follow-up, completeness of data collection, gains in face-to-face Vs postal data collection and the most appropriate methods of measuring primary outcomes (return to work, retention) to determine the sample size for a larger trial. DISCUSSION: To our knowledge, this is the first feasibility randomised controlled trial of a vocational rehabilitation health intervention specific to traumatic brain injury. The results will inform the design of a definitive trial. TRIAL REGISTRATION: The trial is registered ISRCTN Number 38581822. PMID- 27965804 TI - Rhythmic cued motor imagery and walking in people with multiple sclerosis: a randomised controlled feasibility study. AB - BACKGROUND: Novel physiotherapy approaches such as motor imagery and rhythmic auditory stimulation have been shown to improve walking in people with multiple sclerosis (MS). Rhythmic cued motor imagery was used in this study, whose objectives were to evaluate the feasibility of a larger randomised controlled trial (RCT) in people with MS and to obtain information on walking. METHODS: Thirty adult people with MS who scored 1.5-4.5 on the Expanded Disability Status Scale were recruited at the MS Clinic Innsbruck, Austria. Participants were randomly allocated to one of three groups, all receiving usual care: 17 min of motor imagery, six times per week, for 4 weeks, with music (A) or metronome cues (B) and (C) controls. Primary outcomes were recruitment rates, retention, compliance, adverse events and fatigue (Modified Fatigue Impact Scale). Secondary outcomes were walking speed (Timed 25-Foot Walk) and walking distance (6-Minute Walk Test). RESULTS: We achieved our recruitment target by recruiting 12 participants per month, a mean eligibility rate of 40.1 % (95 % confidence interval (CI) 35.8, 44.6 %) out of 2500 MS Centre patients, mean consent rate of 15.9 % (95 % CI 11.3, 21.7 %) plus 54.5 % (95 % CI 47.4, 61.4 %) of eligible patients who expressed their interest to participate. Retention of 100 %, no adverse events, good compliance, high acceptability of the interventions and no worsening of fatigue confirmed feasibility. The mean improvement in walking speed in both groups A and B was -0.9 s (95 % CI -1.3, -0.5), and mean worsening in group C was 0.4 s (95 % CI -0.3, 1.1). The mean improvement in walking distance in group A was 68.1 m (95 % CI 51.4, 84.7) and in group B 92.9 m (95 % CI 55.2, 130.5), and mean worsening in group C was -9.4 m (95 % CI -35.6, 16.9). CONCLUSIONS: Results from our study showed that a full-scale RCT is feasible to investigate the effects of rhythmic cued motor imagery on walking in people with MS, with no changes to the interventions and assessments. Based on the walking improvements, a total sample size of 138 participants was calculated. Stratified blocked randomisation, allocation concealment and blinding will be used in the main study. TRIAL REGISTRATION: ISRCTN: ISRCTN67054113. PMID- 27965805 TI - A pilot cluster randomised controlled trial to investigate the addition of direct access to physiotherapy to usual GP-led primary care for adults with musculoskeletal pain: the STEMS pilot trial protocol (ISRCTN23378642). AB - BACKGROUND: Musculoskeletal problems are common, accounting for up to 30 % of general practitioner (GP) consultations and are a major cause of chronic disability worldwide. Demand for health care for musculoskeletal conditions is likely to continue to rise given the ageing population and the increasing impact of these common painful conditions. Physiotherapists are well equipped to deliver evidence-based management for these conditions. Direct access allows patients to access physiotherapy without seeing their GP or another referring practitioner first; however, for most patients in the UK, access to National Health Service physiotherapy is controlled through GP referral. METHODS/DESIGN: The aim of this pilot, pragmatic, cluster trial is to assess the feasibility of a future large trial to compare the clinical and cost-effectiveness of the additional offer of direct access to physiotherapy versus continuing with usual GP-led primary care alone for adults with common musculoskeletal problems. The pilot will focus on process outcomes to assess feasibility, although performance of the likely outcomes of a main trial will also be assessed. This is a two-arm parallel, cluster RCT where GP practices are the units of randomisation (the clusters), yet data are collected from individual patients with musculoskeletal problems (the participants). A direct access service will be set up in the participating physiotherapy service to provide the option of direct access to patients of the intervention arm practices. Inclusion criteria are broad to reflect the 'real world' operation of an NHS physiotherapy direct access service for patients with musculoskeletal pain. Data collection will be through patient self-reported questionnaires at baseline, 2, 6 and 12 months and medical record review. DISCUSSION: No previous trials have been conducted into direct access to physiotherapy for patients with musculoskeletal problems. The strengths of the STEMS pilot trial are its size, the length of follow-up, and collection of process, clinical and cost outcomes to fully inform a future main trial to meet calls to provide robust trial evidence of the impact on clinical outcomes, work loss and costs to provide clinicians and service funders with the high quality trial data they need to guide decisions on the best models of care. TRIAL REGISTRATION: The STEMS pilot trial is registered at Current Controlled Trials: ISRCTN23378642. PMID- 27965807 TI - Nail bed INJury Assessment Pilot (NINJA-P) study: should the nail plate be replaced or discarded after nail bed repair in children? Study protocol for a pilot randomised controlled trial. AB - BACKGROUND: Nail bed injuries account for the majority of paediatric hand trauma cases. Despite their frequency, controversy remains regarding their treatment. The accepted teaching is to remove the fingernail, repair the underlying nail bed with fine sutures and replace the nail under the nail fold. A recent study by Miranda et al. (Plast Reconst Surg. 129(2):394e-396e, 2012) suggests that replacing the nail is associated with increased complications, in particular post operative infection. Nail bed INJury Assessment Pilot (NINJA-P) is an external pilot study for a large pragmatic, multicentre, randomised, controlled study (NINJA) to assess whether the nail should be replaced or discarded after nail bed repair in children under the age of 16. METHODS/DESIGN: NINJA-P is a randomised pilot study. The participants are patients below 16 years of age who require surgical repair of the nail bed. Eligible patients will be randomised to receive one of two possible interventions. Group 1 will have the nail replaced after nail bed repair, and group 2 will have the nail discarded. The clinical outcome measures include the presence of post-operative complications at 2 weeks and 30 days, the cosmetic appearance of the nail at 4 months and the level of pain experienced by the child at their first dressings change at 2 weeks. In order to inform the design of the main NINJA trial, the following feasibility data will also be recorded: the number of potentially eligible children and the proportion which agree to take part in the study, the proportion of children who received the allocated treatment and reasons for any non-compliance and the proportion of participants with a valid response at each follow-up point. Neither the patient, family members nor treating physicians will be blinded. A replaced nail can take several weeks to fall off once a new nail has grown out. The cosmetic appearance of the nail at 4 months will be assessed by a blinded assessor. DISCUSSION: The NINJA-P pilot study will inform the design and execution of the NINJA trial, which will assess whether the nail should be replaced or discarded after nail bed repair in children under 16. It will provide randomised comparative evidence for the treatment of this common injury. TRIAL REGISTRATION: First participant randomised: 21/04/2015, UKCRN Portfolio ID: 18516, ISRCTN16571591. PMID- 27965806 TI - DIgital Alcohol Management ON Demand (DIAMOND) feasibility randomised controlled trial of a web-based intervention to reduce alcohol consumption in people with hazardous and harmful use versus a face-to-face intervention: protocol. AB - BACKGROUND: "Hazardous and harmful" drinkers make up approximately 23 % of the adult population in England. However, only around 10 % of these people access specialist care, such as face-to-face extended brief treatment in community alcohol services. This may be due to stigma, difficulty accessing services during working hours, a shortage of trained counsellors and limited provision of services in many places. Web-based alcohol treatment programmes may overcome these barriers and may better suit people who are reluctant or unable to attend face-to-face services, but there is a gap in the evidence base for the acceptability, effectiveness and cost-effectiveness of these programmes compared with treatment as usual (TAU) in community alcohol services. This study aims investigate the feasibility of all parts of a randomised controlled trial (RCT) of a psychologically informed web-based alcohol treatment programme called Healthy Living for People who use Alcohol (HeLP-Alcohol) versus TAU in community alcohol services, e.g. recruitment and retention, online data collection methods, and the use and acceptability of the intervention to participants. METHODS: A feasibility RCT delivered in north London community alcohol services, comparing HeLP-Alcohol with TAU. Potential participants are aged >=18 years referred or self-referred for hazardous and harmful use of alcohol, without co-morbidities or other complex problems. The main purpose of this study is to demonstrate the feasibility of recruiting participants to the study and will test online methods for collecting baseline demographic and outcome questionnaire data, randomising participants and collecting 3-month follow-up data. The acceptability of this intervention will be measured by recruitment and retention rates, automated log in data collection and an online service satisfaction questionnaire. The feasibility of using tailored text message, email or phone prompt to maintain engagement with the intervention will also be explored. Results of the study will inform a definitive Phase 3 RCT. RESULTS: Recruitment started on 26 September 2014 and will run for 1 year. CONCLUSION: The proposed trial will provide data to inform a fully powered non-inferiority effectiveness and cost-effectiveness RCT comparing HeLP-Alcohol with TAU. TRIAL REGISTRATION: ISRCTN31789096. PMID- 27965808 TI - Feasibility and preliminary efficacy of a physical activity counseling intervention using Fitbit in people with knee osteoarthritis: the TRACK-OA study protocol. AB - BACKGROUND: Physical activity (PA) reduces pain and improves functioning in people with knee osteoarthritis (OA), but few people with the condition meet recommended PA guidelines. Successful intervention strategies to increase PA include goal setting, action planning, self-monitoring, and follow-up feedback from a healthcare professional. Recently developed consumer wearable activity trackers allow users to set activity goals, self-monitor daily goal-progress, and provide feedback on goal attainment. It is hypothesized that a multi-component physiotherapist-led intervention that includes a short (40-min) education module, guided goal-setting and action planning, the use of a wristband activity tracker, and weekly follow-up phone calls will lead to increased PA outcomes. METHODS/DESIGN: Thirty-six participants will be recruited from the community for a two-group pilot randomized controlled trial with a stepped-wedge design using an intention-to-treat analysis. Computer-generated block randomization will be performed using varying block sizes and a 1:1 allocation ratio. The 4-week intervention will be delivered immediately (immediate-intervention group) or after a 5-week delay (delayed-intervention group). Outcome measures of pain and disability (Knee Injury and OA Outcome Score), disease self-management ability (Partners in Health Scale), and objective bouted moderate-to-vigorous PA and sedentary time (BodyMedia SenseWear Mini Armband) will be collected at baseline (week 0) and two follow-ups (weeks 5 and 10), for a total study duration of 11 weeks. Feasibility data relating to process, resource, management, and scientific elements of the trial will be collected. Outcome measure and feasibility data will be summarized, and an estimate of intervention efficacy will be obtained by regression model with planned comparisons. The trial began recruiting in February 2015. To date, 34 subjects have been recruited. DISCUSSION: This study will evaluate the feasibility and preliminary efficacy of a novel intervention to promote PA in people living with knee OA. The results will provide valuable information to inform a larger randomized trial to assess intervention effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02313506 (registration date 8 December 2014). First participant randomized 20 February 2015. PMID- 27965809 TI - Glycerin suppositories used prophylactically in premature infants (SUPP) trial: a study protocol for a pilot randomized controlled trial. AB - BACKGROUND: Feeding is a significant challenge for premature infants in the neonatal intensive care unit (NICU). These patients are often treated with glycerin suppositories to stimulate the passage of meconium and prevent feeding intolerance. Unfortunately, the evidence for this practice is inconclusive. METHODS/DESIGN: This protocol is for an external pilot study that will assess the feasibility of a superiority, placebo-controlled, parallel-design, multicenter randomized controlled trial. Participants are premature infants treated in a level 3 NICU with a gestational age 24 to 32 weeks and/or birth weight of 500 to 1500 g. Thirty participants will be recruited as part of this external pilot study. Participants will be randomized to glycerin suppository (250 mg) or placebo starting 48 to 72 h after birth and continuing once daily until meconium evacuation is complete or for a maximum of 12 days. The placebo consists of a 250 mg glycerin suppository placed in the diaper rather than the rectum. Study treatments are administered by the charge nurse on duty who is not otherwise involved in patient care. All other clinicians and research personnel will remain blinded. Outcomes for the pilot study are percentage of eligible participants randomized, percentage of infants reaching full enteral feeds, cost, and treatment-related adverse events (rectal bleeding, rectal perforation, and anal fissure). DISCUSSION: This external pilot study will assess the feasibility of a multicenter randomized controlled trial of glycerin suppositories in premature infants. The subsequent multicenter trial will have sufficient power to determine whether this treatment strategy is associated with decreased time to full enteral feeds. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02153606. PMID- 27965810 TI - Maximising the impact of qualitative research in feasibility studies for randomised controlled trials: guidance for researchers. AB - Feasibility studies are increasingly undertaken in preparation for randomised controlled trials in order to explore uncertainties and enable trialists to optimise the intervention or the conduct of the trial. Qualitative research can be used to examine and address key uncertainties prior to a full trial. We present guidance that researchers, research funders and reviewers may wish to consider when assessing or undertaking qualitative research within feasibility studies for randomised controlled trials. The guidance consists of 16 items within five domains: research questions, data collection, analysis, teamwork and reporting. Appropriate and well conducted qualitative research can make an important contribution to feasibility studies for randomised controlled trials. This guidance may help researchers to consider the full range of contributions that qualitative research can make in relation to their particular trial. The guidance may also help researchers and others to reflect on the utility of such qualitative research in practice, so that trial teams can decide when and how best to use these approaches in future studies. PMID- 27965811 TI - Protocol for a pragmatic randomised controlled trial to evaluate effects of a brief intervention for emergency department attendees who present with moderate or high levels of non-specific psychological distress: a pilot study. AB - BACKGROUND: Screening and brief intervention in the emergency department (ED) has almost exclusively focused on individuals with alcohol-use problems. The early detection of mental health problems before problems become severe will enable early intervention and support which may improve health and prevent further deterioration. The main aim of this pilot study is to provide evidence of the acceptance of a telephone intervention aimed at ED attendees with moderate or high psychological distress. This will be determined by recruitment rates, retention rates and participant satisfaction with the intervention. Secondary outcomes include whether socio-demographic variables have an impact on retention rates, and whether the intervention had any impact on psychological distress. METHODS/DESIGN: This study will be a single-site pragmatic randomised controlled pilot study. Consenting ED attendees will be screened with the Kessler Psychological Distress Scales (K10). There will be three arms to the study: a moderate/high psychological distress group with or without intervention, and a low psychological distress group. Those with severe psychological distress will be excluded. All included participants will be followed-up at 1, 3, 6 and 12 months post-recruitment. Retention rates will be determined by successful completion of surveys at the follow-up time-points. Psychological distress will be measured by the K10 at all follow-up time-points. DISCUSSION: This study will provide information regarding the potential for screening and recruitment at an opportunistic hospital presentation. It will provide data for a future larger study with regard to participants accepting to be included in this study. Participant acceptability will be measured in terms of recruitment rates and retention rates measured by successful follow-ups over the following 12 months post-recruitment. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12614000031662. Registered 10/01/2014. PMID- 27965812 TI - Online intervention, 'MePlusMe', supporting mood, wellbeing, study skills, and everyday functioning in students in higher education: a protocol for a feasibility study. AB - BACKGROUND: Psychological and study skill difficulties faced by students in higher education can lead to poor academic performance, sub-optimal mental health, reduced study satisfaction, and drop out from study. At the same time, higher education institutions' support services are costly, oversubscribed, and struggle to meet demand whilst facing budget reductions. The purpose of the proposed study is to evaluate the acceptability of a new online intervention, MePlusMe, aimed at students in higher education facing mild to moderate psychological and/or study skill difficulties. The study will also assess the feasibility of proposed recruitment and outcome assessment protocols for a future trial of effectiveness. The system supports self-management strategies alongside ongoing monitoring facilitated by a messaging service, as well as featuring a built-in community of student users. It is based on current clinical guidelines for the management of common mental health problems, together with best practice from the educational field. METHODS/DESIGN: Two hundred and forty two students will be recruited to a within-subjects, repeated measures study conducted over 8 weeks. Self-report measures of depression and anxiety symptoms, mental wellbeing, academic self-efficacy, and everyday functioning will be collected at baseline, and then at 2, 4, and 8 weeks. During this period, students will have access to the intervention system. UK higher education institutions Bournemouth University and University of Warwick will participate in the study. Data on student satisfaction and engagement will also be collected. Study findings will help to determine the most appropriate primary outcome and the required sample size for a future trial. DISCUSSION: This study will evaluate the acceptability of an online intervention system for students facing psychological and/or study skill difficulties and will test recruitment procedures and outcome measures for a future trial of effectiveness. The system is designed to be implemented as a stand-alone service or a service complementary to student support services, which is accessible to the majority of students and effective in improving student experience at higher education institutions. PMID- 27965813 TI - Timed walk as primary outcome measure of treatment response in clinical trials for HTLV-1-associated myelopathy: a feasibility study. AB - BACKGROUND: To advance the treatment of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), randomised controlled therapeutic studies with appropriate and sensitive outcomes are reuired. One candidate outcome is the 10 metre walk test (10MWT), a patient-centred, simple and functional measure. To calculate sample size based on 10MWT as the primary outcome, variability within and between subjects must be known. METHODS: Data on 10MWT from 76 patients with HAM/TSP were prospectively collected from four specialist centres in Brazil, Japan, USA and UK. Data, collected at two time points, 6 months apart, were log transformed and subjected to analysis of covariance. RESULTS: Baseline mean (standard deviation = SD), median 10MWT were 23.5 (18.9), 16.3 s/10 m and at 6 months 24.9 (23.9), 16.4 s/10 m. The mean (SD) % increase in walk time was 5.74 % (28.2 %). After logarithmic transformation, the linear correlation between baseline and 24 weeks 10MWT was r = 0.938. Using these data, it was determined that a randomised controlled trial with 30 participants per group would have 90 % power to detect a 19 % decrease or a 23 % increase in 10MWT. CONCLUSIONS: The intra-patient variability of 10MWT is relatively small in HAM/TSP over 6 months. 10MWT is a feasible outcome measure for a clinical trial in HAM/TSP. To our knowledge, this is the first ever recommendation for the sample size required for trials in HAM/TSP patients. PMID- 27965814 TI - A new era for intervention development studies. AB - This editorial introduces a new special series on intervention development in the on-line open access journal Pilot and Feasibility Studies. An intervention development study reports the rationale, decision-making processes, methods and findings which occur between the idea or inception of an intervention until it is ready for formal feasibility, pilot or efficacy testing prior to a full trial or evaluation. This editorial begins to explore some of the challenges associated with this early research stage. It commences a debate about how to produce novel interventions which are fit for purpose and which solve important health and social care problems. By transparently reporting more intervention development studies, scientific rigour will be improved and everyone can learn from the experiences of others. PMID- 27965815 TI - The person-based approach to enhancing the acceptability and feasibility of interventions. AB - BACKGROUND: This paper provides three illustrations of how the "person-based approach" can be used to assess and enhance the acceptability and feasibility of an intervention during the early stages of development and evaluation. The person based approach involves using mixed methods research to systematically investigate the beliefs, attitudes, needs and situation of the people who will be using the intervention. The in-depth understanding of users' perspectives derived from this research then enables intervention developers to design or modify the intervention to make it more relevant, persuasive, accessible and engaging. METHODS: The first illustration describes how relevant beliefs and attitudes of people with asthma were identified from the existing qualitative and quantitative literature and then used to create guiding principles to inform the design of a web-based intervention to improve quality of life. The second illustration describes how qualitative "think-aloud" interviews and patient and public involvement (PPI) input are used to improve the acceptability of a booklet for people with asthma. In the third illustration, iterative think-aloud methods are used to create a more accurate and accessible activity planner for people with diabetes. RESULTS: In the first illustration of the person-based approach, we present the guiding principles we developed to summarise key design issues/objectives and key intervention features to address them. The second illustration provides evidence from interviews that positive, non-medical messages and images were preferred in booklet materials for people with asthma. The third illustration demonstrates that people with diabetes found it difficult to complete an online activity planner accurately, resulting in incorrect personalised advice being given prior to appropriate modification of the planner. CONCLUSIONS: The person-based approach to intervention development can complement theory- and evidence-based development and participant input into intervention design, offering a systematic process for systematically investigating and incorporating the views of a wide range of users. PMID- 27965816 TI - Exploring the feasibility and synergistic value of the One Health approach in clinical research: protocol for a prospective observational study of diagnostic pathways in human and canine patients with suspected urinary tract infection. AB - BACKGROUND: The One Health approach is emerging in response to the development of bacterial resistance. To the best of our knowledge, the possibility to use this approach in a clinical context has not yet been explored. Thus, in this paper, we report the procedures to implement a prospective observational study of diagnostic pathways in human and canine patients with suspected urinary tract infection as a means to assess the feasibility and synergistic value of setting up One Health clinical research projects and interventions. METHODS/DESIGN: A prospective observational study will compare different diagnostic pathways (i.e., 16 possible combinations of diagnostic tools) to gold standard in human and veterinary primary care practice in Denmark. Fifty primary care practices and 100 veterinary clinics will each consecutively include 20 human patients or 8-10 dogs, respectively. Data will be collected at practice and patient level comprising (a) information about the organization of the practice and access to different diagnostic tools, (b) information about clinical history, diagnostic path and treatment during the index consultation, (c) information about severity of symptoms during the 7-10 days following inclusion, and (d) urine culture (type of microorganism and susceptibility test). The feasibility and synergistic value of conducting future research, and/or designing common interventions, will be assessed by evaluating the comparability of human primary care and veterinary primary care with respect to study implementation and study results. DISCUSSION: Results from this study will give an insight into the feasibility and synergistic value of setting-up One Health research projects in a clinical context. This is crucial if we are to embrace the One Health approach, as a legitimate strategy to implement common interventions aimed at influencing the diagnostic process in human and canine patients in order to decrease inappropriate use of antibiotics. TRIAL REGISTRATION: The study in humans has been registered in ClinicalTrials.gov NCT02249273. PMID- 27965818 TI - Reducing dementia risk by targeting modifiable risk factors in mid-life: study protocol for the Innovative Midlife Intervention for Dementia Deterrence (In MINDD) randomised controlled feasibility trial. AB - BACKGROUND: Dementia prevalence is increasing as populations live longer, with no cure and the costs of caring exceeding many other conditions. There is increasing evidence for modifiable risk factors which, if addressed in mid-life, can reduce the risk of developing dementia in later life. These include physical inactivity, low cognitive activity, mid-life obesity, high blood pressure, and high cholesterol. This study aims to assess the acceptability and feasibility and impact of giving those in mid-life, aged between 40 and 60 years, an individualised dementia risk modification score and profile and access to personalised on-line health information and goal setting in order to support the behaviour change required to reduce such dementia risk. A secondary aim is to understand participants' and practitioners' views of dementia prevention and explore the acceptability and integration of the Innovative Midlife Intervention for Dementia Deterrence (In-MINDD) intervention into daily life and routine practice. METHODS/DESIGN: In-MINDD is a multi-centre, primary care-based, single blinded randomised controlled feasibility trial currently being conducted in four European countries (France, Ireland, the Netherlands and the UK). Participants are being recruited from participating general practices. Inclusion criteria will include age between 40 and 60 years; at least one modifiable risk factor for dementia risk (including diabetes, hypertension, obesity, renal dysfunction, current smoker, raised cholesterol, coronary heart disease, current or previous history of depression, self-reported sedentary lifestyle, and self-reported low cognitive activity) access to the Internet. Primary outcome measure will be a change in dementia risk modification score over the timescale of the trial (6 months). A qualitative process evaluation will interview a sample of participants and practitioners about their views on the acceptability and feasibility of the trial and the links between modifiable risk factors and dementia prevention. This work will be underpinned by Normalisation Process Theory. DISCUSSION: This study will explore the feasibility and acceptability of a risk profiler and on-line support environment to help individuals in mid-life assess their risk of developing dementia in later life and to take steps to alleviate that risk by tackling health-related behaviour change. Testing the intervention in a robust and theoretically informed manner will inform the development of a future, full scale randomised controlled trial. TRIAL REGISTRATION: ISRCTN Registry: ISRCTN 98553005 (DOI: 10.1186/ISRCTN98553005). PMID- 27965817 TI - A pragmatic pilot randomized trial to investigate the effectiveness of behavioural activation group therapy in reducing depressive symptoms and improving quality of life in patients with depression: the BRAVE pilot trial protocol. AB - BACKGROUND: Depression is a common disorder with a lifetime prevalence of 16 %. Despite the availability of several treatment options for depression, many patients do not respond to treatment and develop chronic illness associated with several secondary comorbidities. Behavioural activation (BA) is a simple therapy that has the potential for improving symptoms of depression and quality of life in patients with depression. The effectiveness of BA has not, however, been tested in a group format for patients with moderate to severe depression attending a specialized mood disorders tertiary care setting. Group format has the advantage of treating more patients at the same time especially in resource limited settings. The primary objective of this pilot study is to test the feasibility of a main trial by assessing the recruitment and retention rates, average group size, completion of data and resources needed and receive the participants' feedback on the intervention. The secondary objective is to explore the change in mood and quality of life measures in adults with depression receiving BA. METHODS/DESIGN: Using a pragmatic pilot randomized controlled trial design, we will test the feasibility of a large trial to assess the effectiveness of BA added to usual care compared to a depression support group with usual care. Participants will be randomized after obtaining informed written consent to one of two study arms. Face-to-face group therapy will be provided in a hospital setting by trained therapists. Intervention and control groups will be seen twice weekly for 10 weeks and then once weekly for further 8 weeks. Participants will be completing mood symptom scales, quality of life questionnaires and anthropometric measures and provide blood samples for future analysis of biomarkers of response to treatment. During the pilot study we will also solicit participants' feedback and experience regarding the number, frequency and contents of the sessions as well as to explore participant perceptions of barriers or benefits associated with the BA program. DISCUSSION: The pilot study will help to inform a larger trial and assist in modifying the intervention based on patients' feedback. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT02045771. Hamilton Integrated Research Ethics Board (HiREB) number: 14-042. PMID- 27965819 TI - Impact of bottle size on in-home consumption of sugar-sweetened beverages: protocol for a feasibility and acceptability study. AB - BACKGROUND: Intake of free sugars in the population exceeds recommendations, with the largest source in the diet being sugar-sweetened beverages (SSBs). SSB consumption is linked to adverse health consequences and contributes to health inequalities, given greater consumption amongst the most deprived. One possible intervention is to reduce the available sizes of SSB packaging but there is an absence of evidence that this would reduce consumption. Based on evidence from studies targeting food consumption that people consume less when exposed to smaller package sizes, we hypothesise that presenting SSBs in smaller containers reduces consumption. We are planning a crossover randomised controlled trial to assess the impact of presenting a fixed volume of SSB in different bottle sizes on consumption at home. To reduce the uncertainties related to this trial, we propose a preliminary study to assess the feasibility and acceptability of the recruitment, allocation, measurement, retention and intervention procedures. METHODS/DESIGN: Households which purchase at least 2 l of regular cola drinks per week and live in Cambridgeshire, UK will have a set amount of a cola SSB (based on their typical weekly purchasing of cola) delivered to their homes each week by the research team. This total amount of cola will be packaged into bottles of one of four sizes: (i) 1500 ml, (ii) 1000 ml, (iii) 500 ml or (iv) 250 ml. A crossover design will be used in which households will each receive all four of the week-long interventions (the four different bottle sizes) over time, randomised in their order of presentation. Approximately 100 eligible households will be approached to assess the proportion interested in actively participating in the study. Of those interested, 16 will be invited to continue participation. DISCUSSION: The findings will inform the procedures for a crossover randomised controlled trial assessing the impact of presenting a fixed volume of SSB in different bottle sizes on consumption at home. The findings from such a trial are expected to provide the best estimate to date of the effect of container size on beverage consumption and inform ongoing scientific and policy discussions about the effectiveness of this intervention at reducing population intake of free sugars in beverages. TRIAL REGISTRATION: ISRCTN14964130. PMID- 27965820 TI - Journeying through Dementia, a community-based self-management intervention for people aged 65 years and over: a feasibility study to inform a future trial. AB - BACKGROUND: A study to determine the feasibility of conducting a future population-based trial into a self-management intervention for community-living adults with early stage dementia included evaluation of intervention content and modes of delivery, staffing requirements, recruitment methods and the utility and usability of patient reported outcomes. METHODS: Participants identified through memory clinics in one city took part in an intervention called 'Journeying through Dementia'. The 12-week programme incorporating four individual sessions with one of the facilitators encourages participants to engage in discussion and activities related to health and well-being positioning them as the expert enabling long-term behavioural change. Participants (n = 10) and their nominated carers (n = 7) were all asked to complete selected outcomes at baseline, 8 weeks (participants only) and post intervention and invited to comment on their usability. All participants and carers were qualitatively interviewed before intervention delivery about their expectations and participants; nominated carers and facilitators were all interviewed after cessation about their experiences. RESULTS: The manualised intervention and modes of delivery proved acceptable to participants and carers. Reported benefits included increased confidence and self efficacy, engagement in new or lapsed activities and re-engagement in fun and friendships. People with dementia and carers were able to self-complete all outcome measures, but time required to complete the measures is a key factor. Strategies for recruitment need to include direct contact within 24-48 h post invitation to the study. Analysis of data on the primary outcome did not reveal any trends. Facilitators found the training and support to be appropriate and helpful. CONCLUSIONS: The tailored intervention reportedly met the needs of all participants. The study confirmed the need for careful identification and application of patient-reported outcome measures. Outcomes to measure some dimensions of reported benefit are not available. TRIAL REGISTRATION: Current Controlled Trials ISRCTN67209155. PMID- 27965821 TI - A feasibility study of a Family Focused Treatment for Adolescents with Bipolar Disorder-the FAB study. AB - BACKGROUND: The aim of this study is to examine the feasibility of a future definitive randomised controlled trial of Family Focused Treatment for Adolescents UK (FFT-A UK) in the management of early-onset bipolar disorder (EOBD) (under 18 years). The FFT-A has been evaluated in the USA to augment the pharmacological treatment of adolescents with bipolar disorder (BD). The FFT-A UK has been condensed to 16 sessions over approximately 6 months to be utilised within the UK National Health Service. Research from the USA suggests that families experience high levels of distress, stress, burden and family disharmony when living with a young person who has BD. The FFT-A UK is a family-based approach designed to increase understanding of BD (psycho-education), improve communication and increase ability to problem-solve. METHODS/DESIGN: The trial will examine the feasibility of a randomised, parallel group, non-blinded design and the procedures of a subsequent definitive trial. Thirty-three young people with BD and their families will be recruited. Participants will complete measures at baseline, on completion of the 6-month treatment and again after a further 6 months. The self-report measures include the Warwick Edinburgh Mental Well-being Scale, The McMaster Family Assessment Device (FAD), Conflict Behaviour Questionnaire aka 'Interaction Behaviour Questionnaire', EuroQuol EQ-5D-3L and EQ 5D-Y. Primary outcomes will be rates of eligibility, recruitment and retention, estimates of the variability in the self-report measures and assessment of the intervention delivery in the study population. Participants' qualitative views on the measures and intervention will be sought to confirm the acceptability of intervention and study design. The health economics component will establish how cost-effectiveness will be assessed in a future definitive trial. DISCUSSION: The study will produce a full trial protocol and amendments to the FFT-A UK to inform a well-designed multi-centre randomised controlled trial (RCT) as an adjunct to pharmacotherapy in the management of EOBD. TRIAL REGISTRATION: Current Controlled Trials ISRCTN59769322. PMID- 27965822 TI - Lessons from a pilot and feasibility randomised trial in depression (Blood pressure Rapid Intensive Lowering And Normal Treatment for Mood and cognition in persistent depression (BRILiANT mood study)). AB - BACKGROUND: The blood pressure rapid intensive lowering and normal treatment for mood and cognition in persistent depression (BRILiANT mood study) was devised as a pilot study to investigate the feasibility and safety of intensive blood pressure lowering as treatment for persistent mood and cognitive symptoms in older adults with major depressive disorder and to assess the availability of this population for recruitment. In addition, the relationship between reduced blood pressure and the change in cerebral blood flow and mood was to be investigated. METHODS: A single centre pilot randomised controlled trial (RCT), with two parallel groups of intensive or normal treatment for hypertension, recruiting from primary and secondary care and newspaper advert, with an aim of recruiting 66 participants, was observed in this study. At the end of the recruitment period, in order to explore the reasons for failure to recruit to target, surveys were developed and issued to those involved in recruitment. RESULTS: Recruitment rates were lower than expected which led to the study being expanded to further areas and opened to self-referral via advertisement. However, because of better management of hypertension due to changes in the UK Quality and Outcomes Framework guidelines for blood pressure treatment, few eligible patients were identified and the study closed at the end of the recruitment period, with 13 participants consenting, but 12 failing screening resulting in one recruited participant. CONCLUSIONS: Overall, the BRILiANT mood study was found not to be feasible, and results suggest that the expected patient population no longer exists. To overcome such recruitment difficulties, a prompt commencement of a study after funding so no relevant care changes occur might help prevent similar problems in future studies. In addition, self-referral, in this case via advertisement in papers, may be a useful tool to increase response rate. When recruiting in primary care, direct access to primary care databases, in a secure and anonymised way, may enable more effective screening. Ultimately, the BRILiANT mood study was shown not to be feasible; this was a useful conclusion from this pilot study. TRIAL REGISTRATION: ISRCTN 64524251; UKCRN Portfolio No: 13284. PMID- 27965823 TI - Feasibility of a stepped wedge cluster RCT and concurrent observational sub-study to evaluate the effects of modified ward night lighting on inpatient fall rates and sleep quality: a protocol for a pilot trial. AB - BACKGROUND: Falls among hospitalised patients impose a considerable burden on health systems globally and prevention is a priority. Some patient-level interventions have been effective in reducing falls, but others have not. An alternative and promising approach to reducing inpatient falls is through the modification of the hospital physical environment and the night lighting of hospital wards is a leading candidate for investigation. In this pilot trial, we will determine the feasibility of conducting a main trial to evaluate the effects of modified night lighting on inpatient ward level fall rates. We will test also the feasibility of collecting novel forms of patient level data through a concurrent observational sub-study. METHODS/DESIGN: A stepped wedge, cluster randomised controlled trial will be conducted in six inpatient wards over 14 months in a metropolitan teaching hospital in Brisbane (Australia). The intervention will consist of supplementary night lighting installed across all patient rooms within study wards. The planned placement of luminaires, configurations and spectral characteristics are based on prior published research and pre-trial testing and modification. We will collect data on rates of falls on study wards (falls per 1000 patient days), the proportion of patients who fall once or more, and average length of stay. We will recruit two patients per ward per month to a concurrent observational sub-study aimed at understanding potential impacts on a range of patient sleep and mobility behaviour. The effect on the environment will be monitored with sensors to detect variation in light levels and night-time room activity. We will also collect data on possible patient-level confounders including demographics, pre-admission sleep quality, reported vision, hearing impairment and functional status. DISCUSSION: This pragmatic pilot trial will assess the feasibility of conducting a main trial to investigate the effects of modified night lighting on inpatient fall rates using several new methods previously untested in the context of environmental modifications and patient safety. Pilot data collected through both parts of the trial will be utilised to inform sample size calculations, trial design and final data collection methods for a subsequent main trial. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Register (ANZCTR): ACTRN12614000615684 (cluster RCT) and ACTRN12614000616673 (observational sub-study). Date Registered: 10 June 2014 (both studies). Protocol version: 1.2 (Dated: 01 June 2014) Anticipated completion: September 2015 Role of Trial Sponsor: The named sponsor for this investigator-initiated trial was the Director of the Royal Brisbane and Women's Hospital (RBWH) Safety and Quality Unit (Therese Lee, Phone: +61 7 3646 8111). The principal investigators, SC and MA, are employed by the RBWH Safety and Quality Unit. The trial sponsor has no involvement in any aspects of study design, conduct or decision to submit the report for publication. AM and MD are employed by other departments in the same organisation. PMID- 27965825 TI - Aminoaciduria in the prediction of ifosfamide-induced tubulopathy after childhood cancer: a feasibility study. AB - BACKGROUND: Ifosfamide, an alkylating agent used widely in the treatment of childhood malignancy, can cause many side effects including a proximal tubulopathy. Studies suggest that aminoaciduria is seen most commonly of all the biochemical abnormalities of ifosfamide-induced tubulopathy. A recent systematic review has found a paucity of data regarding the value of early markers indicating clinically significant tubulopathy. We undertook a pilot study to determine the feasibility of examining whether patients can be risk-stratified on the basis of aminoaciduria for the development of future significant ifosfamide induced tubulopathy, to allow the evolution of appropriate follow-up strategies. We also aimed to define accrual rates, costs and clinical demands for a future larger study. METHODS: This observational study recruited 21 patients from the Leeds Paediatric Oncology service. The medical notes of each patient were reviewed for demographic and clinical data. Simultaneous samples of blood and urine were obtained. RESULTS: The investigations in the feasibility study were acceptable to patients and were minimally demanding on both clinical and laboratory staff. Financially, the cost per patient was minimal. This study was not powered to detect significant associations with TmP/GFR (ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate), growth and electrolyte supplementation. However, all patients with minimal aminoaciduria (<=2 elevated urinary amino acids) had normal TmP/GFR and no need for electrolyte supplementation. CONCLUSIONS: This pilot study has shown that a larger study is feasible and may provide clinically useful data to change current practice. This should aim to establish whether the number of abnormal amino acids or the degree of abnormality is most significant in predicting clinically significant proximal tubulopathy. PMID- 27965824 TI - Participants' perspectives on mindfulness-based cognitive therapy for inflammatory bowel disease: a qualitative study nested within a pilot randomised controlled trial. AB - BACKGROUND: Mindfulness-based interventions have shown to improve depression and anxiety symptoms as well as quality of life in patients with inflammatory bowel disease (IBD). However, little is known about the experiences of this group of patients participating in mindfulness interventions. This paper sets out to explore the perspectives of patients with IBD recruited to a pilot randomised controlled trial (RCT) of mindfulness-based cognitive therapy (MBCT) about the intervention. METHODS: In a qualitative study nested within a parallel two-arm pilot RCT of mindfulness-based cognitive therapy for patients with IBD, two focus group interviews (using the same schedule) and a free text postal survey were conducted. Data from both were analysed using thematic analysis. Data and investigator triangulation was performed to enhance confidence in the ensuing findings. Forty-four patients with IBD were recruited to the pilot RCT from gastroenterology outpatient clinics from two Scottish NHS boards. Eighteen of these patients (ten from mindfulness intervention and eight from control group) also completed a postal survey and participated in two focus groups after completing post intervention assessments. RESULTS: The major themes that emerged from the data were the following: perceived benefits of MBCT for IBD, barriers to attending MBCT and expectations about MBCT. Participants identified MBCT as a therapeutic, educational and an inclusive process as key benefits of the intervention. Key barriers included time and travel constraints. CONCLUSIONS: This qualitative study has demonstrated the acceptability of MBCT in a group of patients with IBD. Participants saw MBCT as a therapeutic and educational initiative that transformed their relationship with the illness. The inclusive process and shared experience of MBCT alleviated the sense of social isolation commonly associated with IBD. However, time commitment and travel were recognised as a barrier to MBCT which could potentially influence the degree of therapeutic gain from MBCT for some participants. PMID- 27965826 TI - The SABRTooth feasibility trial protocol: a study to determine the feasibility and acceptability of conducting a phase III randomised controlled trial comparing stereotactic ablative radiotherapy (SABR) with surgery in patients with peripheral stage I non-small cell lung cancer (NSCLC) considered to be at higher risk of complications from surgical resection. AB - BACKGROUND: Stage I non-small cell lung cancer (NSCLC) is potentially curable, and surgery is considered to be the standard of care for patients with good performance status and minimal co-morbidity. However, a significant proportion of patients with stage I NSCLC have a poorer performance status and significant medical co-morbidity that make them at higher risk of morbidity and mortality from surgery. Stereotactic ablative radiotherapy (SABR), which uses modern radiotherapeutic techniques to deliver large doses of radiation, has shown superiority over conventional radiotherapy in terms of local control and toxicity and is a standard of care for patients with stage I NSCLC who are at too high risk for surgery. However, it is not known whether surgery or SABR is the most effective in patients with stage I NSCLC who are suitable for surgery but are less fit and at higher risk surgical complications. Previous randomised studies have failed to recruit in this setting, and therefore, a feasibility study is required to see whether a full randomised control trial would be possible. METHODS/DESIGN: SABRTooth is a UK-based, multi-centre, open-label, two-group individually (1:1) randomised controlled feasibility study in patients with peripheral stage I NSCLC considered to be at higher risk from surgical resection. The study will assess the feasibility of conducting a definitive large-scale phase III trial. The primary objective is to assess recruitment rates to provide evidence that, when scaled up, recruitment to a large phase III trial would be possible; the target recruitment being 54 patients in total, over a 21-month period. There are multiple secondary and exploratory objectives designed to explore the optimum recruitment and data collection strategies to help optimise the design of a future phase III trial. DISCUSSION: To know whether SABR is a better, equivalent or inferior alternative to surgery for higher risk patients is a key question in lung cancer. Other studies comparing SABR to surgery have closed early due to poor recruitment, and therefore, the SABRTooth feasibility study has been designed around the UK National Health Service (NHS) cancer pathway incorporating many design features in order to maximise recruitment for a future definitive phase III trial. TRIAL REGISTRATION: controlled-trials.com ISRCTN13029788. PMID- 27965827 TI - A feasibility study comparing UK older adult mental health inpatient wards which use protected engagement time with other wards which do not: study protocol. AB - BACKGROUND: Protected engagement time (PET) is a concept of managing staff time on mental health inpatient wards with the aim of increasing staff and patient interaction. Despite apparent widespread use of PET, there remains a dearth of evidence as to how it is implemented and whether it carries benefits for staff or patients. This protocol describes a study which is being carried out on mental health wards caring for older adults (aged over 65) in England. The study shares a large proportion of the procedures, measures and study team membership of a recently completed investigation of the impact of PET in adult acute mental health wards. The study aims to identify prevalence and components of PET to construct a model for the intervention, in addition to testing the feasibility of the measures and procedures in preparation for a randomised trial. METHODS/DESIGN: The study comprises four modules and uses a mixed methods approach. Module 1 involves mapping all inpatient wards in England which provide care for older adults, including those with dementia, ascertaining how many of these provide PET and in what way. Module 2 uses a prospective cohort method to compare five older adult mental health wards that use PET with five that do not across three National Health Service (NHS) Foundation Trust sites. The comparison comprises questionnaires, observation tools and routinely collected clinical service data and combines validated measures with questions developed specifically for the study. Module 3 entails an in-depth case study evaluation of three of the participating PET wards (one from each NHS Trust site) using semi structured interviews with patients, carers and staff. Module 4 describes the development of a model and fidelity scale for PET using the information derived from the other modules with a working group of patients, carers and staff. DISCUSSION: This is a feasibility study to test the application of the measures and methods in inpatient wards for older adults and develop a draft model for the intervention. The next stage will prospectively involve testing of the model and fidelity scale in randomised conditions to provide evidence for the effectiveness of PET as an intervention. TRIAL REGISTRATION: ISRCTN31919196. PMID- 27965828 TI - 'Moving on and feeling good': a feasibility study to explore the lifestyle behaviours of young adults with intellectual disabilities as they transition from school to adulthood-a study protocol. AB - BACKGROUND: The transition from adolescence to adulthood is a 'high-risk' period for weight gain in the general population. There is speculation that this may also be a risk period for adults with intellectual disabilities; however, there has been no research which has monitored change in health indicators. Since adults with intellectual disabilities have higher rates of obesity and engage in more sedentary behaviour and less physical activity than the general population, there is a need to understand more about the lifestyle behaviours of this population during the transition to adulthood. This protocol paper will provide details of the moving on and feeling good feasibility study, designed for young people with intellectual disabilities. METHODS/DESIGN: A multi-point recruitment strategy will be used to recruit 30 participants with a mild-moderate level of intellectual disability. The aim of the feasibility study is to examine the feasibility of recruitment, participant retention and the measurement of relevant health behaviour outcomes. The study will assess the feasibility of monitoring weight, diet and physical activity levels in adolescents over a 12-month transitional period from school to adult life. This mixed method study will provide insight into the lives of young people with intellectual disabilities and will examine the use of Walker et al.'s social-ecological approach to promote self-determination specific to lifestyle behaviours, during this transition period. Baseline data will be collected during the final year of school, with follow-up data collection at 6 and 12 months. Anthropometric (weight, height, waist and hip circumference), objective physical activity measures (7-day accelerometer wear) and dietary and choice measures will be collected at each time point to assess the feasibility of measuring diet patterns, food frequency, physical activity and BMI. Furthermore, ten participants will be selected for short semi-structured scoping interviews at baseline and 12-month follow-up, to gain information on psychological, social and environmental factors which might affect behaviour change. DISCUSSION: The outcomes from the feasibility study will aid the development and piloting of a sufficiently powered randomised controlled trial. This would allow us to evaluate the effectiveness and sustainability of a lifestyle behaviour intervention, over a 5-year transition period. PMID- 27965829 TI - The challenge of mothers learning about secondhand smoke (MLASS): a quasi experimental, mixed methods feasibility study. AB - BACKGROUND: Exposure to secondhand smoke (SHS) in the antenatal and postnatal period is associated with a detrimental health impact to the foetus and newborn baby and is recognised as a preventable public health challenge. The aim of the mother's learning about secondhand smoke (MLASS) study was to test the feasibility of delivering and evaluating the effectiveness of a smoke-free homes (SFH) health education intervention in the antenatal and postnatal period to reduce foetal and newborn exposure to SHS. METHODS: Pregnant women aged 17-40 years old who attended their first community-based antenatal appointment in Leeds, UK, were eligible to participate if they currently smoked, or if they were non-smokers but lived in a household where someone else smoked, or had regular visitors to the home who smoked. A SFH health education intervention was delivered at four time points by community midwives and health visitors. Outcome measures included self-reported level of household smoking restrictions and SHS exposure in pregnant women who did not smoke during pregnancy and in the newborn baby, measured by salivary and urine cotinine levels, respectively. We planned to conduct focus group discussions with participants and health professionals. A post hoc survey of pregnant women was conducted at the recruitment site. RESULTS: Eight pregnant women were recruited over a 6-month recruitment period. Of the 65 eligible pregnant women approached, 57 (88 %) declined to participate in the study. The majority declined to participate due to lack of interest in the study. In the post hoc survey, the majority of pregnant women reported that they were already implementing household smoking restrictions to reduce SHS; only a small number had no household smoking restrictions. CONCLUSIONS: The post hoc survey identified women who could benefit from a SFH intervention; therefore, future studies should consider what SFH means to pregnant women and may wish to target those not currently implementing household smoking restrictions. Future recruitment strategies in studies of an SFH intervention in the context of maternity service pressures needs careful consideration; this includes the capacity to undertake the research, the recruitment setting, the criteria for individuals requiring the intervention, and individuals' willingness to engage with such research. PMID- 27965830 TI - Western medical acupuncture in a group setting for knee osteoarthritis: results of a pilot randomised controlled trial. AB - BACKGROUND: Evidence suggests acupuncture may be effective for treating the symptoms of knee osteoarthritis. Offering this in a group setting may offer cost savings. The aim of this study was to establish the feasibility of a definitive trial to assess the clinical and cost-effectiveness of Western medical acupuncture given in groups, or given individually, for adults with severe knee pain attributable to osteoarthritis. METHODS: A pilot randomised controlled trial (RCT) was conducted. Participants were recruited from seven general practices in Plymouth, Devon. Acupuncture was provided, at a dosage that increased up to and including electroacupuncture if no pain relief was reported, by one experienced acupuncturist in a community clinic. Potentially eligible adults aged at least 45 years with knee osteoarthritis were identified from practice registers, screened and randomised to either: (1) standardised advice and exercise booklet alone ('standard'); (2) booklet plus group acupuncture ('group'); and (3) booklet plus individual acupuncture ('individual'). Both acupuncture arms received up to ten treatments over 12 weeks. Recruitment, retention and data completion rates were recorded, and participants completed questionnaires on acceptability. We collected pain, stiffness and function data (using the Western Ontario McMaster Universities Osteoarthritis Index; WOMAC) and general health (EQ-5D) and economic measures at baseline and 14 weeks post-randomisation. RESULTS: We screened 149 people and randomised 60 (40 %), 20 per arm. The overall 14 week follow-up rate was 77 %, but only 70 % in the 'standard' group; 4.1 % of data points were missing. The study was acceptable to participants. Changes in WOMAC pain score (intention to treat complete case analysis) from baseline to 14 week follow-up were: 'standard', 0.4 (95 % confidence interval (CI) -1.4, 2.2, n = 14); 'group' 3.2 (95 % CI -5.1, -1.4, n = 17); 'individual' -2.4 (95 % CI -4.1, -0.7, n = 15). CONCLUSIONS: A definitive three-arm trial is feasible. Further follow-up reminders, minimum data collection and incentives should be considered to improve participant retention in the follow-up processes in the standardised advice and exercise booklet arm. TRIAL REGISTRATION: ISRCTN05305406. PMID- 27965832 TI - Assessing the feasibility of evaluating and delivering a physical activity intervention for pre-school children: a pilot randomised controlled trial. AB - BACKGROUND: Few evidence-based physical activity interventions for pre-school children are available. This two-armed pilot cluster randomised controlled trial aimed to evaluate the feasibility of conducting a full-scale trial and of delivering an outdoor physical activity intervention for pre-school children. METHODS: School was the unit of randomisation, and follow-up occurred at 10 and 52 weeks. Trial feasibility was assessed by recruitment, retention and completion rates of primary (daily moderate-to-vigorous physical activity (MVPA)) and secondary (anthropometric, quality of life, self-efficacy) outcomes. Potential effectiveness was assessed for the primary outcome using a linear regression model comparing MVPA between trial arms adjusting for clustering by school. Feasibility of delivering the intervention was assessed by intervention fidelity and attendance. Semi-structured interviews with parents, intervention facilitators, and head teachers explored acceptability and capability to deliver the intervention as well as acceptability of the study design. RESULTS: Recruitment rates were 37 % of schools (n = 10 schools) and 48 % of pre-school children (n = 164 children). Retention of children to the trial at 52 weeks was 83.5 %. Thirty-nine percent of children had valid primary outcome accelerometer data at baseline and 52 weeks. Response rates for secondary outcome measures ranged from 52 to 88 % at 10 weeks and 59 to 80 % at 52 weeks. The mean difference in daily MVPA between trial arms at 52 weeks was 0.4, 95 % CI 16.3 to 17.0; p = 0.96. Fidelity of intervention implementation was 81 %. Intervention attendance was higher (82 %) during the summer initiation phase compared to autumn/spring initiation (50 %). Parents, facilitators and head teachers found the intervention acceptable and beneficial. CONCLUSIONS: Recruitment and retention rates suggest a trial in this outdoor setting with this population was feasible but is weather sensitive. However, strategies to increase accelerometer wear-time would need to be implemented for reliable primary outcome data to be obtained. There was high implementation fidelity by facilitators, and the intervention was seen as acceptable and deliverable. However, attendance was low and preliminary data showed no evidence of intervention effectiveness. A revised intervention, building on the successful elements of this pilot alongside adapting implementation strategies to improve attendance, should therefore be considered. TRIAL REGISTRATION: Trial registry name and number: Current Controlled Trials, ISRCTN54165860. Date of registration: 4 September 2012. PMID- 27965833 TI - Protocol for a feasibility study of a self-help cognitive behavioural therapy resource for the reduction of dental anxiety in young people. AB - BACKGROUND: Childhood dental anxiety is very common, with 10-20 % of children and young people reporting high levels of dental anxiety. It is distressing and has a negative impact on the quality of life of young people and their parents as well as being associated with poor oral health. Affected individuals may develop a lifelong reliance on general anaesthetic or sedation for necessary dental treatment thus requiring the support of specialist dental services. Children and young people with dental anxiety therefore require additional clinical time and can be costly to treat in the long term. The reduction of dental anxiety through the use of effective psychological techniques is, therefore, of high importance. However, there is a lack of high-quality research investigating the impact of cognitive behavioural therapy (CBT) approaches when applied to young people's dental anxiety. METHODS/DESIGN: The first part of the study will develop a profile of dentally anxious young people using a prospective questionnaire sent to a consecutive sample of 100 young people referred to the Paediatric Dentistry Department, Charles Clifford Dental Hospital, in Sheffield. The second part will involve interviewing a purposive sample of 15-20 dental team members on their perceptions of a CBT self-help resource for dental anxiety, their opinions on whether they might use such a resource with patients, and their willingness to recruit participants to a future randomised controlled trial (RCT) to evaluate the resource. The third part of the study will investigate the most appropriate outcome measures to include in a trial, the acceptability of the resource, and retention and completion rates of treatment with a sample of 60 dentally anxious young people using the CBT resource. DISCUSSION: This study will provide information on the profile of dentally anxious young people who could potentially be helped by a guided self-help CBT resource. It will gain the perceptions of dental care team members of guided self-help CBT for dental anxiety in young people and their willingness to recruit participants to a trial. Acceptability of the resource to participants and retention and completion rates will also be investigated to inform a future RCT. PMID- 27965834 TI - Do fetuses move their lips to the sound that they hear? An observational feasibility study on auditory stimulation in the womb. AB - BACKGROUND: We investigate in this feasibility study whether specific lip movements increase prenatally when hearing a particular sound. We hypothesised that fetuses would produce more mouth movements resembling those required to make the sound stimulus they heard (i.e. mouth stretch) compared with a no-sound control group who heard no specific auditory stimuli. Secondly, we predicted that fetuses hearing the sound would produce a similar number of mouth movements unrelated to the sound heard (i.e. lip pucker) as the no-sound group of fetuses. METHODS: In an observational feasibility study, 17 fetuses were scanned twice at 32 and 36 weeks of gestation, and two different types of mouth movements were recorded. Three fetuses received an auditory stimulus, and 14 did not. A generalised mixed effects log-linear model was used to determine statistical significance. RESULTS: Fetuses in the sound group performed one specific mouth movement (mouth stretch) significantly more frequently than fetuses in the no sound group. A significant interaction between group and gestational age indicates that there was differential change in this specific movement as age increases (X2 = 7.58 on 1 df, p = 0.006), with the no-sound group showing a decline of 76 % between 32 weeks and 36 weeks (p < 0.001), whereas the sound group showed no significant change over time (p = 0.41). There was no significant difference between the sound group and no-sound group in the frequency of lip puckering-the second, unrelated mouth movement (p = 0.35). CONCLUSIONS: These results suggest that a sound stimulus is associated with an increase in specific, rather than general, mouth movements. The results are informative for the development of infant speech and potentially could also lead to a diagnostic test for deafness in utero. More research is needed to replicate this research with a randomised design and with a range of different auditory stimuli which would be produced with different mouth movements, such as "o" which would be seen as pursed lips. PMID- 27965836 TI - Feasibility study of a clinical decision support system for the management of multimorbid seniors in primary care: study protocol. AB - BACKGROUND: Care for seniors is complex because patients often have more than one disease, one medication, and one physician. It is a key challenge for primary care physicians to structure the various aspects of each patient's care, to integrate each patient's preferences, and to maintain a long-term overview. This article describes the design for the development and feasibility testing of the clinical decision support system (CDSS) eCare*Seniors(c) which is electronic health record (EHR)-based allowing for a long-term, comprehensive, evidence based, and patient preference-oriented management of multimorbid seniors. METHODS/DESIGN: This mixed-methods study is designed in three steps. First, focus groups and practice observations will be conducted to develop criteria for software design from a physicians' and practice assistants' perspective. Second, based on these criteria, a CDSS prototype will be developed. Third, the prototype's feasibility will be tested by five primary care practices in the care of 30 multimorbid seniors. Primary outcome is the usability of the software measured by the validated system usability scale (SUS) after 3 months. Secondary outcomes are the (a) willingness to routinely use the CDSS, (b) degree of utilization of the CDSS, (c) acceptance of the CDSS, (d) willingness of the physicians to purchase the CDSS, and (e) willingness of the practice assistants to use the CDSS in the long term. These outcomes will be measured using semi structured interviews and software usage data. If the SUS score reaches >=70 %, feasibility testing will be judged successful. Otherwise, the CDSS prototype will be refined according to the users' needs and retested by the physicians and practice assistants until it is fully adapted to their requirements and reaches a usability score >=70 %. DISCUSSION: The study will support the development of a CDSS which is primary care-defined, user-friendly, easy-to-comprehend, workflow oriented, and comprehensive. The software will assist physicians and practices in their long-term, individualized care for multimorbid seniors. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00008777. PMID- 27965835 TI - Protocol-based management of older adults with hip fractures in Delhi, India: a feasibility study. AB - BACKGROUND: Worldwide hip fractures are projected to increase from 1.7 million in 1990 to 6.3 million in 2050. In India, conservative estimates suggest an annual incidence of 600,000 osteoporotic hip fractures and this is expected to increase significantly due to ageing and increase life expectancy. Protocol-based 'care pathways' for the management of adults, over 60 years of age, with hip fractures in high-income countries has resulted in decreased mortality rates, early hospital discharge, improved quality of life and reduction in healthcare costs. The study objectives are to determine appropriateness, acceptability and feasibility of adopting best-practice guideline or protocol-based care for the management of hip fractures among older adults in India. The study will also identify barriers and facilitators in recruiting patients and retention till the agreed follow-up period. METHODS: This will be a mixed-methods prospective cohort study. The quantitative data collection will involve recruitment of consecutive patients aged >50 years with an X-ray-confirmed hip fracture admitted in four tertiary care hospitals in Delhi, India, over a 2-month period. The quantitative data will be collected at three points: from patients at admission to hospital, from medical records at discharge and by telephone interviews with patients at 30 days post hip fracture. Qualitative data collection will involve key informant interviews, conducted with clinical leads and focus group discussions, conducted with groups of healthcare providers and patients and/or their carers. COM-B theoretical framework (capability, opportunity, motivation and behaviour) will be used to explore healthcare providers' behaviour in order to facilitate development and implementation of appropriate integrated care pathway for management of older adults with hip fractures in India. DISCUSSION: The proposed study will identify gaps in best practice in the management of older people with hip fractures in tertiary care hospitals in Delhi and document barriers and facilitators to the implementation of protocol-based care through recording the contextual realities of the health systems and care-seeking behaviours. Insights into these factors will be used to facilitate the development of protocol-based management of older people with hip fractures that is appropriate, context specific and acceptable by stakeholders in a low- and middle-income country setting, such as India. PMID- 27965837 TI - Optimisation of complex health interventions prior to a randomised controlled trial: a scoping review of strategies used. AB - BACKGROUND: Many complex intervention trials fail to show an intervention effect. Although this may be due to genuine ineffectiveness, it may also be the result of sub-optimal intervention design, implementation failure or a combination of these. Given current financial constraints and the pressure to reduce waste and increase value in health services research, pre-trial strategies are needed to reduce the likelihood of design or implementation failure and to maximise the intervention's potential for effectiveness. In this scoping review, we aimed to identify and synthesise the available evidence relating to the strategies and methods used to 'optimise' complex interventions at the pre-trial stage. METHODS: We searched MEDLINE, CINAHL, AMED, PsycINFO and ProQuest Nursing & Allied Health Source for papers published between January 2000 and March 2015. We included intervention development and optimisation studies that explored potential intervention weaknesses and limitations before moving to a definitive randomised controlled trial (RCT). Two reviewers independently applied selection criteria and systematically extracted information relating to the following: study characteristics; intervention under development; framework used to guide the development process; areas of focus of the optimisation process, methods used and outcomes of the optimisation process. Data were tabulated and summarised in a narrative format. RESULTS: We screened 3968 titles and 231 abstracts for eligibility. Eighty-nine full-text papers were retrieved; 27 studies met our selection criteria. Optimisation strategies were used for a range of reasons: to explore the feasibility and acceptability of the intervention to patients and healthcare professionals; to estimate the effectiveness and cost-effectiveness of different combinations of intervention components; and to identify potential barriers to implementation. Methods varied widely across studies, from interviews and focus groups to economic modelling and probability analysis. CONCLUSIONS: The review identifies a range of optimisation strategies currently used. Although a preliminary classification of these strategies can be proposed, a series of questions remain as to which methods to use for different interventions and how to determine when the intervention is ready or 'optimised enough' to be tested in a RCT. Future research should explore potential answers to the questions raised, to guide researchers in the development and evaluation of more effective interventions. PMID- 27965838 TI - Immediate tumor resection in patients with locally advanced gastroesophageal adenocarcinoma with nonresponse to chemotherapy after 4 weeks of treatment versus resection after completion of chemotherapy (OPTITREAT trial, DRKS00004668): study protocol for a randomized controlled pilot trial. AB - BACKGROUND: Neoadjuvant chemotherapy is a standard of care for patients with adenocarcinoma of the esophagus and stomach in Europe, but still only 20-40 % respond to therapy and the critical issue; how to treat nonresponding patients is still unclear. So far, there is no randomized trial evaluating the impact of early termination of neoadjuvant chemotherapy and immediate tumor resection in nonresponding patients with locally advanced gastroesophageal cancer on postoperative outcome. With this exploratory pilot trial, we want to get first estimates about the effect of discontinuation of chemotherapy with the aim to plan and conduct a further definitive trial. METHODS/DESIGN: OPTITREAT is designed as a single-center, randomized controlled pilot trial with two parallel study groups. Four weeks after starting neoadjuvant chemotherapy in all patients, clinical response will be assessed by endoscopy and endosonographic ultrasound. Then, nonresponding patients (n = 84) will be randomized in a 1:1 ratio to intervention group with stopping chemotherapy and immediate tumor resection or control group with completion of chemotherapy before surgery. Outcome measures are overall survival, R0 resection rate, perioperative morbidity and mortality, histopathological response, and quality of life. Statistical analysis will be based on the intention-to-treat population. Due to the study design as an explorative pilot trial, no formal sample size calculation was performed. The planned total sample size of 120 patients is considered ethical and large enough to show the feasibility and safety of the concept. First data on differences between the study groups in the defined endpoints will also be generated. DISCUSSION: Individualized therapy is of utmost interest in the treatment of locally advanced gastroesophageal adenocarcinoma as less than half of the patients show objective response to current chemotherapy regimens. The findings of the OPTITREAT trial will help to get first data about clinical response evaluation followed by immediate tumor resection in nonresponding patients after 4 weeks of neoadjuvant chemotherapy. Based on the results of this pilot study, a future confirmatory trial will be planned to prove efficacy and evaluate significance. TRIAL REGISTRATION: German Clinical Trial Register number: DRKS00004668. PMID- 27965839 TI - Cognitive behavioural therapy for psychopathology in relatives of missing persons: study protocol for a pilot randomised controlled trial. AB - BACKGROUND: It is hypothesized that the grieving process of relatives of missing persons is complicated by having to deal with uncertainty about the fate of their loved one. We developed a cognitive behavioural therapy (CBT) with mindfulness that focuses on dealing with this uncertainty. In this article, we elucidate the rationale of a pilot randomised controlled trial (RCT) for testing the feasibility and potential effectiveness of this CBT for reducing symptoms of psychopathology in relatives of missing persons. METHODS: A pilot RCT comparing participants of the CBT condition (n = 15) with waiting list controls (n = 15) will be executed. Individuals suffering from psychopathology related to the long term disappearance of a loved one are eligible to participate. The treatment consists of eight individual sessions. Questionnaires tapping psychological constructs will be administered before, during, and after the treatment. The feasibility of the treatment will be evaluated using descriptive statistics (e.g., attrition rate). The primary analysis consists of a within-group analysis of changes in mean scores of persistent complex bereavement disorder from baseline to immediately post-treatment and follow-up (12 and 24 weeks post treatment). DISCUSSION: A significant number of people experience the disappearance of a loved one. Surprisingly, an RCT to evaluate a treatment for psychopathology among relatives of missing persons has never been conducted. Knowledge about treatment effects is needed to improve treatment options for those in need of help. The strengths of this study are the development of a tailored treatment for relatives of missing persons and the use of a pilot design before exposing a large sample to a treatment that has yet to be evaluated. Future research could benefit from the results of this study. TRIAL REGISTRATION: NTR4732 (The Netherlands National Trial Register (NTR)). PMID- 27965840 TI - A collaborative process for developing a weight management toolkit for general practitioners in Australia-an intervention development study using the Knowledge To Action framework. AB - BACKGROUND: Obesity is commonly seen in the Australian general practice population; however, few resources are specifically targeted at GPs working with these patients. The National Health and Medical Research Council (Australia) guideline for managing patients who are overweight and obese supports the involvement of a regular health professional. As 85 % of the population visit a GP annually, resources to support GPs working with this patient population are needed. This study describes the collaborative process used to develop an obesity management programme based on current Australian guidelines for GPs and their patients to be used in primary care. The Knowledge To Action framework was applied to develop a weight management toolkit for GPs based on current Australian guidelines. This draft was then reviewed by clinical GPs, GP registrars, consumer representatives and allied health professionals using focus groups and interviews. The participants gave feedback on the content, layout and acceptability of the documents. The feedback from the stakeholder groups was evaluated, and changes were incorporated into the final documents. A graphic designer was contracted to assist with the layout to improve useability and attractiveness of the documents. RESULTS: A total of 38 participants gave feedback on the draft weight management programme, and the research team amalgamated their responses to further improve the documents. The general response from GPs and consumer representatives was positive with most conveying their wish to try the programme themselves. CONCLUSIONS: "The Change Program" is a practical tool for Australian GPs to use with their patients who are overweight or obese. It was developed in collaboration with GPs, allied health professionals and consumer stakeholders based on current Australian guidelines. It is currently being piloted in five general practices. PMID- 27965841 TI - Behavioral activation group therapy for reducing depressive symptoms and improving quality of life: a feasibility study. AB - BACKGROUND: Depression is associated with a loss of productivity and noticeable personal, social, and economic decline; it affects more than 350 million people worldwide. Behavioral activation (BA), derived from cognitive behavioral therapy, has drawn increasingly more interest as a means of treatment for major depressive disorder due to its relative cost-effectiveness and efficacy. In this study, we disseminate findings from a feasibility study evaluating barriers to implementing a group BA program for major depressive disorder. The purpose of this feasibility study is to assess both patient and clinician perceptions on components of a group-based behavioral activation (BA) program. In particular, this feasibility study provides in-depth evaluation of the acceptability of BA prior to the design and implementation of a randomized trial to investigate BA effectiveness. Findings from this study directly informed decisions regarding the design and implementation of BA during the pilot trial. Specific components of BA were assessed and modified based on the results of this study. METHODS: This qualitative study was completed through the Mood Disorders Program at St. Joseph's Healthcare Hamilton. The authors of this study used data from two focus group sessions, one consisting of an interdisciplinary group of clinicians working in the Mood Disorders Program, and the other of registered outpatients of the Mood Disorders Program with a confirmed clinical diagnosis of depression. The benefits of offering this program in a group format, mainly social skill development opportunities and the use of technology such as activity tracking device, smart phones, and tablets during the therapy sessions, are a major focus of both the clinician and patient groups. Both groups emphasized the importance of offering sustainable activation. RESULTS: Differences in opinions existed between staff and patient groups regarding the use of technology in the program, though ultimately it was agreed upon that technology could be useful as a therapeutic aid. All participants agreed that behavioral activation was essential to the development of positive habits and routines necessary for recovery from depression. Patients agreed the program looked sustainable and stressed the potential benefit for improving depressive symptoms. CONCLUSIONS: Discussions from clinician and patient-centered focus groups directly informed decisions regarding the design and implementation of BA during the pilot trial. Specific components of BA were assessed and modified based on the results of this study. These findings provide insight for clinicians providing behavioral activation programming, and will serve as a framework for the development of the Out of the Blues program, a group-based BA program to be piloted in the Mood Disorders Program at St. Joseph's Healthcare Hamilton. TRIAL REGISTRATION: Clinical Trials registration number NCT02045771. PMID- 27965842 TI - A head and neck cancer intervention for use in survivorship clinics: a protocol for a feasibility study. AB - BACKGROUND: Head and neck cancer survivors commonly experience severe long-term toxicities, late-occurring symptoms, and significant risks of the second primary malignancy and comorbid illnesses. With multiple simultaneous health issues, these complex cancer survivors often do not receive comprehensive health care that addresses their needs. A tool is needed to streamline and standardize comprehensive care for this cohort. METHODS/DESIGN: We designed the Head and Neck Survivorship Tool: Assessment and Recommendations (HN-STAR) to address health care challenges for head and neck cancer survivors. HN-STAR is an electronic platform that aims to simplify the provision of personalized care in cancer survivorship clinics. It uses an algorithmic approach to integrate patient reported outcomes, clinical details, and evidence-based guidelines to standardize comprehensive care provided in routine survivorship visits. It has four integrated components: (1) a simplified treatment summary, which pulls treatment details from a clinical database or can be completed manually using a streamlined form; (2) an online self-assessment for patients to report their own symptoms; (3) an interactive discussion guide presenting all relevant information to the provider during the clinic visit; and (4) a survivorship care plan generated at the end of each visit that reflects decisions made during the visit. By using a modifiable electronic platform, HN-STAR provides a method for incorporating survivorship care plans into clinical practice and for disseminating evidence on symptom management and preventive care. This is a study to assess the feasibility of a future multi-site, randomized clinical trial of HN-STAR. We will enroll head and neck cancer survivors who are followed in one of two nurse practitioner-led survivorship clinics. We will implement HN-STAR for one routine survivorship visits. We will assess (1) usability and feasibility outcomes of HN-STAR from the perspective of key stakeholders and (2) the planned outcomes intended for the larger trial. We will collect usability and feasibility data from online surveys of survivors and their providers. Our findings will inform whether it is feasible to advance HN-STAR to trial. If so, we will adapt HN-STAR and the study design of the trial in response to feedback from survivors and providers. The long-term goal is to determine if such an intervention will lead to improved and simplified comprehensive survivorship care. DISCUSSION: This feasibility study will evaluate implementation of HN-STAR into clinical practice in terms of usability, practicality, and clinical flow in two distinct clinical settings. This study will also provide critical baseline data to characterize this vulnerable population. Findings from this study will inform a multicenter randomized trial of HN-STAR, aimed at standardizing and streamlining the delivery of evidence guided comprehensive care for head and neck cancer survivors. Ultimately, if found effective, the modular structure of HN-STAR could permit its expansion to survivors of other complex cancers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02571673. PMID- 27965844 TI - Methods and processes for development of a CONSORT extension for reporting pilot randomized controlled trials. AB - BACKGROUND: Feasibility and pilot studies are essential components of planning or preparing for a larger randomized controlled trial (RCT). They are intended to provide useful information about the feasibility of the main RCT-with the goal of reducing uncertainty and thereby increasing the chance of successfully conducting the main RCT. However, research has shown that there are serious inadequacies in the reporting of pilot and feasibility studies. Reasons for this include a lack of explicit publication policies for pilot and feasibility studies in many journals, unclear definitions of what constitutes a pilot or feasibility RCT/study, and a lack of clarity in the objectives and methodological focus. All these suggest that there is an urgent need for new guidelines for reporting pilot and feasibility studies. OBJECTIVES: The aim of this paper is to describe the methods and processes in our development of an extension to the Consolidated Standards of Reporting Trials (CONSORT) Statement for reporting pilot and feasibility RCTs, that are executed in preparation for a future, more definitive RCT. METHODS/DESIGN: There were five overlapping parts to the project: (i) the project launch-which involved establishing a working group and conducting a review of the literature; (ii) stakeholder engagement-which entailed consultation with the CONSORT group, journal editors and publishers, the clinical trials community, and funders; (iii) a Delphi process-used to assess the agreement of experts on initial definitions and to generate a reporting checklist for pilot RCTs, based on the 2010 CONSORT statement extension applicable to reporting pilot studies; (iv) a consensus meeting-to discuss, add, remove, or modify checklist items, with input from experts in the field; and (v) write-up and implementation which included a guideline document which gives an explanation and elaboration (E&E) and which will provide advice for each item, together with examples of good reporting practice. This final part also included a plan for dissemination and publication of the guideline. CONCLUSIONS: We anticipate that implementation of our guideline will improve the reporting completeness, transparency, and quality of pilot RCTs, and hence benefit several constituencies, including authors of journal manuscripts, funding agencies, educators, researchers, and end-users. PMID- 27965843 TI - The Aging, Community and Health Research Unit-Community Partnership Program for older adults with type 2 diabetes and multiple chronic conditions: a feasibility study. AB - BACKGROUND: Few studies have examined the effectiveness of community-based self management interventions in older adults with type 2 diabetes mellitus (T2DM) and multiple chronic conditions (MCC). The objectives of this study were to examine the feasibility of implementation in practice (primary) and the feasibility of study methods and potential effectiveness (secondary) of the Aging, Community and Health-Community Partnership Program, a new 6-month interprofessional, nurse-led program to promote diabetes self-management in older adults (>65 years) with T2DM and MCC. METHODS: This study used a prospective one-group pre-test/post-test design. Participants were recruited from a specialized diabetes clinic. They received a median of three in-home/clinic visits by certified diabetes educators (CDEs) and attended a median of three group wellness sessions provided by the CDEs in partnership with a community-based seniors' association. The primary outcome was the feasibility of the program (acceptability, fidelity, implementation barriers/facilitators). Secondary outcomes included the feasibility of the study methods (recruitment/retention rates and procedures, eligibility criteria, data collection and analysis methods) and potential effectiveness of the program based on 6-month changes in self-reported outcomes including self-management behavior (diet, exercise, self-monitoring), health status (quality of life, mental health), and costs of service use. Analysis of feasibility outcomes was primarily based on descriptive statistics. The potential effectiveness of the program was explored using different tests, with the results expressed using descriptive statistics and effect estimates (95 % confidence intervals). RESULTS: In total, 45 (88 %) of 51 eligible persons consented to participate. Of these, 37 (82 %) completed the 6-month follow-up. Participants and providers viewed the program as acceptable and feasible. Participants had a higher SF-12 physical component summary score at 6 months compared with baseline (mean score difference 3.0, 95 % CI 0.2-5.8). Median costs for diabetes care increased over 6 months (reflecting inclusion of program costs), while other service costs either decreased or remained unchanged. CONCLUSIONS: This study offers preliminary evidence that the program was feasible to deliver and acceptable to participants and providers. Initial results suggest that the program may improve physical functioning. A randomized controlled trial is feasible, with some adaptations to the program and study methods that were identified from this feasibility study. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01880476. PMID- 27965845 TI - Wildcat wellness coaching feasibility trial: protocol for home-based health behavior mentoring in girls. AB - BACKGROUND: Childhood obesity is a major public health problem, with one third of America's children classified as either overweight or obese. Obesity prevention and health promotion programs using components such as wellness coaching and home based interventions have shown promise, but there is a lack of published research evaluating the impact of a combined home-based and wellness coaching intervention for obesity prevention and health promotion in young girls. The main objective of this study is to test the feasibility of such an intervention on metrics related to recruitment, intervention delivery, and health-related outcome assessments. The secondary outcome is to evaluate the possibility of change in health-related psychosocial, behavioral, and biomedical outcomes in our sample of participants. METHODS/DESIGN: Forty girls who are overweight or obese (aged 8-13 years) will be recruited from a Midwestern college town. Participants will be recruited through posted flyers, newspaper advertisements, email, and social media. The volunteer convenience sample of girls will be randomized to one of two home-based wellness coaching interventions: a general health education condition or a healthy eating physical activity skills condition. Trained female wellness coaches will conduct weekly hour-long home visits for 12 consecutive weeks. Assessments will occur at baseline, post-intervention (3 months after baseline), and follow-up (6 months after baseline) and will include height, weight, waist circumference, body composition, pulmonary function, blood pressure, systemic inflammation, physical activity (Actical accelerometer), and self-reported survey measures (relevant to fruit and vegetable consumption, physical activity, and quality of life). DISCUSSION: This study will evaluate the feasibility of home-based wellness coaching interventions for overweight and obese girls and secondarily assess the preliminary impact on health-related psychosocial, behavioral, and biomedical outcomes. Results will provide information regarding the feasibility of this new model for use in girls as an approach to reduce the burden of overweight and obesity toward the prevention of chronic disease. TRIAL REGISTRATION: NCT01845480. PMID- 27965846 TI - A feasibility study of implementing grip strength measurement into routine hospital practice (GRImP): study protocol. AB - BACKGROUND: Handgrip strength is a non-invasive marker of muscle strength, and low grip strength in hospital inpatients is associated with poor healthcare outcomes including longer length of stay, increased functional limitations, and mortality. Measuring grip strength is simple and inexpensive. However, grip strength measurement is not routinely used in clinical practice. The aim of this study is to evaluate the feasibility of implementing grip strength measurement into routine clinical practice. METHODS/DESIGN: This feasibility study is a mixed methods design combining qualitative, quantitative, and economic elements and is based on the acute medical wards for older people in one hospital. The study consists of three phases: phase 1 will define current baseline practice for the identification of inpatients at high risk of poor healthcare outcomes, their nutrition, and mobility care through interviews and focus groups with staff as well as a review of patients' clinical records. Phase 2 will focus on the feasibility of developing and implementing a training programme using Normalisation Process Theory to enable nursing and medical staff to measure and interpret grip strength values. Following the training, grip strength will be measured routinely for older patients as part of admission procedures with the use of a care plan for those with low grip strength. Finally, phase 3 will evaluate the acceptability of grip strength measurement, its adoption, coverage, and basic costs using interviews and focus groups with staff and patients, and re examination of clinical records. DISCUSSION: The results of this study will inform the translation of grip strength measurement from a research tool into clinical practice to improve the identification of older inpatients at risk of poor healthcare outcomes. TRIAL REGISTRATION: Clinicaltrials.gov NCTO2447445. PMID- 27965847 TI - Acceptability and proof of concept of internet-delivered treatment for depression, anxiety, and stress in university students: protocol for an open feasibility trial. AB - BACKGROUND: In recent years, university counseling and mental health services have reported an increase in the number of clients seeking services and in yearly visits. This trend has been observed at many universities, indicating that behavioral and mental health issues pose significant problems for many college students. The aim of this study is to assess the acceptability and proof of concept of internet-delivered treatment for depression, anxiety, and stress for university students. METHODS/DESIGN: The study is an open feasibility trial of the SilverCloud programs for depression (Space from Depression), anxiety (Space from Anxiety), and stress (Space from Stress). All three are 8-module internet delivered CBT (iCBT) intervention programs. Participants are assigned a supporter who provides weekly feedback on progress and exercises. Participants will complete the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7 (GAD-7), and stress subscale of the Depression, Anxiety, Stress Scale-21 (DASS 21) as the outcome measures for the depression, anxiety, and stress interventions, respectively. Other outcomes include measures of acceptability of, and satisfaction, with the intervention. Data will be collected at baseline, 8 weeks and 3-month follow-up. DISCUSSION: It is anticipated that the study will inform the researchers and service personnel of the programs' potential to reduce depression, anxiety, and stress in a student population as well as the protocols to be employed in a future trial. In addition, it will provide insight into students' engagement with the programs, their user experience, and their satisfaction with the online delivery format. PMID- 27965848 TI - A feasibility study incorporating a pilot randomised controlled trial of oral feeding plus pre-treatment gastrostomy tube versus oral feeding plus as-needed nasogastric tube feeding in patients undergoing chemoradiation for head and neck cancer (TUBE trial): study protocol. AB - BACKGROUND: There are 7000 new cases of head and neck squamous cell cancers (HNSCC) treated by the NHS each year. Stage III and IV HNSCC can be treated non surgically by radio therapy (RT) or chemoradiation therapy (CRT). CRT can affect eating and drinking through a range of side effects with 90 % of patients undergoing this treatment requiring nutritional support via gastrostomy (G) or nasogastric (NG) tube feeding. Long-term dysphagia following CRT is a primary concern for patients. The effect of enteral feeding routes on swallowing function is not well understood, and the two feeding methods have, to date, not been compared to assess which leads to a better patient outcome. The purpose of this study is to explore the feasibility of conducting a randomised controlled trial (RCT) comparing these two options with particular emphasis on patient willingness to be randomised and clinician willingness to approach eligible patients. METHODS/DESIGN: This is a mixed methods multicentre study to establish the feasibility of a randomised controlled trial comparing oral feeding plus pre treatment gastrostomy versus oral feeding plus as required nasogastric tube feeding in patients with HNSCC. A total of 60 participants will be randomised to the two arms of the study (1:1 ratio). The primary outcome of feasibility is a composite of recruitment (willingness to randomise and be randomised) and retention. A qualitative process evaluation investigating patient, family and friends and staff experiences of trial participation will also be conducted alongside an economic modelling exercise to synthesise available evidence and provide estimates of cost-effectiveness and value of information. Participants will be assessed at baseline (pre-randomisation), during CRT weekly, 3 months and 6 months. DISCUSSION: Clinicians are in equipoise over the enteral feeding options for patients being treated with CRT. Swallowing outcomes have been identified as a top priority for patients following treatment and this trial would inform a future larger scale RCT in this area to inform best practice. TRIAL REGISTRATION: ISRCTN48569216. PMID- 27965850 TI - Increasing support for the next generation of clinical trials leaders. AB - The National Institute for Health Research (NIHR) has identified a gap in the number of people it funds who are on a pathway to become future leaders of clinical trials, compared to how much the NIHR invests in clinical trials. In order to support the clinical trials of tomorrow, it is vital that the right people are supported now to lead these trials. To address this issue, NIHR organised a workshop with key stakeholders to understand the barriers to embarking on a clinical trials career and explore initiatives to increase capacity and capability in clinical trials. The output from the workshop was a set of recommendations which NIHR is now considering to shape future support. PMID- 27965849 TI - Impact of sit-stand desks at work on energy expenditure and sedentary time: protocol for a feasibility study. AB - BACKGROUND: Prolonged sitting, an independent risk factor for disease development and premature mortality, is increasing in prevalence in high- and middle-income countries, with no signs of abating. Adults in such countries spend the largest proportion of their day in sedentary behaviour, most of which is accumulated at work. One promising method for reducing workplace sitting is the use of sit-stand desks. However, key uncertainties remain about this intervention, related to the quality of existing studies and a lack of focus on key outcomes, including energy expenditure. We are planning a randomised controlled trial to assess the impact of sit-stand desks at work on energy expenditure and sitting time in the short and longer term. To reduce the uncertainties related to the design of this trial, we propose a preliminary study to assess the feasibility and acceptability of the recruitment, allocation, measurement, retention and intervention procedures. METHODS: Five hundred office-based employees from two companies in Cambridge, UK, will complete a survey to assess their interest in participating in a trial on the use of sit-stand desks at work. The workspaces of 100 of those interested in participating will be assessed for sit-stand desk installation suitability, and 20 participants will be randomised to either the use of sit-stand desks at work for 3 months or a waiting list control group. Energy expenditure and sitting time, measured via Actiheart and activPAL monitors, respectively, as well as cardio-metabolic and anthropometric outcomes and other outcomes relating to health and work performance, will be assessed in 10 randomly selected participants. All participants will also be interviewed about their experience of using the desks and participating in the study. DISCUSSION: The findings are expected to inform the design of a trial assessing the impact of sit-stand desks at work on short and longer term workplace sitting, taking into account their impact on energy expenditure and the extent to which their use has compensation effects outside the workplace. The findings from such a trial are expected to inform discussions regarding the potential of sit-stand desks at work to alleviate the harm to cardio-metabolic health arising from prolonged sitting. TRIAL REGISTRATION: ISRCTN44827407. PMID- 27965851 TI - Prioritising wheelchair services for children: a pilot discrete choice experiment to understand how child wheelchair users and their parents prioritise different attributes of wheelchair services. AB - BACKGROUND: Approximately 95 million children worldwide are disabled; 10 % use a wheelchair. In the UK, an estimated 770,000 children are disabled. National Health Service Wheelchair Services are the largest provider of wheelchairs in the UK; however, recent reports have highlighted issues with these services. This study explores the use of discrete choice experiment methods to inform wheelchair service provision for disabled children based on service user preferences. The aim was to explore how disabled children and their parents prioritise different attributes of wheelchair services. The secondary aims were to compare priorities between parents and disabled children and to explore marginal rate of substitution for incremental changes in attributes. METHODS: Discrete choice experiments are a method of attribute-based stated preference valuation used by health economists to understand how individuals prioritise different attributes of healthcare services and treatments. We conducted the first pilot discrete choice experiment to explore how disabled children (aged 11 to 18) and their parents prioritise different attributes of hypothetical wheelchair services. Eleven disabled children (aged 11 to 18) and 30 parents of disabled children completed eight pairwise choice tasks based on five service attributes: wheelchair assessment, cost contribution, training, delivery time and frequency of review. Data were analysed using conditional logistic regression. For each pairwise choice, the participants were asked to choose which service scenario (A or B) they preferred. RESULTS: Comprehensiveness of wheelchair assessment and wheelchair delivery time significantly (P < 0.05) affected service preferences of children (beta-coefficients = 1.43 [95 % bootstrapped CI = 1.42 to 2.08] and 0.92 [95 % bootstrapped CI = -1.41 to -0.84], respectively) and parents (beta coefficients = 1.53 [95 % bootstrapped CI = 1.45 to 2.16] and -1.37 [95 % bootstrapped CI = -1.99 to -1.31], respectively). Parents were willing to contribute more financially to receive preferred services, although this was non significant. CONCLUSIONS: Both samples placed the greatest importance on holistic wheelchair assessments encompassing more than health. The National Health Service should consider using discrete choice experiment methods to examine wheelchair service preferences of disabled children (aged 11 and over) and their parents on a wider scale; however, care must be taken to ensure that this method is used appropriately. PMID- 27965852 TI - Testing the feasibility of a knowledge translation intervention designed to improve chiropractic care for adults with neck pain disorders: study protocol for a pilot cluster-randomized controlled trial. AB - BACKGROUND: Neck pain in adults is common and a leading cause of physical disability. Recently, a guideline was developed for the management of non specific neck pain (NSNP) with an aim to improve the quality of the delivery of chiropractic care. One key guideline recommendation is to undertake multimodal care for patients with NSNP. The aim of this pilot study is to determine the feasibility of implementing a multifaceted knowledge translation intervention by promoting the use of multimodal care by chiropractors managing patients with NSNP. METHODS/DESIGN: The design is a cluster-randomized controlled pilot and feasibility trial. Chiropractors in private practice in Canada will be approached to participate in the study. Thirty consenting chiropractors will be randomized to receive either a theory-based educational intervention in the experimental group or simply a printed copy of the guideline in the control group. Each chiropractor will recruit five neck pain patients (a total of 150 patients) into the study. Development of the multifaceted intervention was informed by the results of a related qualitative study based on the Theoretical Domains Framework and consists of a series of three webinars, two online case scenarios, a self management video on Brief Action Planning, and a printed copy of the practice guideline. Primary feasibility outcomes for both chiropractors and patients include rates of (1) recruitment, (2) retention, and (3) adherence to the intervention. A checklist of proxy measures embedded within patient encounter forms will be used to assess chiropractors' compliance with guideline recommendations (e.g. exercise and self-care prescriptions) at study onset and at 3 months. Secondary outcomes include scores of behavioural constructs (level of knowledge and self-efficacy) for recommended multimodal care. Clinical outcomes include pain intensity and neck pain-specific disability. Analyses from this study will focus on generating point estimates and corresponding 95 % confidence intervals for parameters of a priori interest (recruitment, retention, adherence, pain intensity, Neck Disability Index). DISCUSSION: Results of this study will inform the design of a larger cluster-randomized controlled trial aimed at evaluating the effectiveness of the theory-based tailored intervention and increasing the use of multimodal care by chiropractors managing patients with NSNP. TRIAL REGISTRATION: https://clinicaltrials.gov/, NCT02483091. PMID- 27965853 TI - Feasibility and acceptability of a nursing intervention with family caregiver on self-care among heart failure patients: a randomized pilot trial. AB - BACKGROUND: Self-care practices in heart failure (HF) contribute to quality of life, symptom stabilization, and extended life expectancy. However, adherence to practices such as liquid and salt restriction or symptom monitoring require high motivation on a daily basis. The aim was to assess the feasibility, acceptability, and potential effectiveness of a nursing intervention with family caregivers, aimed at improving self-care practice of HF patients. METHODS: This pilot study involved 32 HF patient-caregiver dyads (16/group) randomized to an experimental (EG) or control group (CG). The intervention, based on the Self Determination Theory, was designed to enhance patients' autonomy and motivation in self-care practices, by involving their caregivers' support. Five encounters were planned with the EG dyads-two face-to-face during hospitalization and three by telephone after discharge. The feasibility of delivering the protocol was evaluated as well as the acceptability of the intervention. The potential effectiveness of the intervention was assessed based on patient outcomes, including general self-care management and self-care specific to HF, perceived competence to manage HF, autonomous motivation (A-motivation, external extrinsic motivation, internal extrinsic motivation, and intrinsic motivation), and perceived support from the caregiver. Caregiver outcomes included level of support provided to the patient. RESULTS: Despite recruitment challenges, the intervention was feasible, with 12 of the 16 dyads receiving all 5 encounters delivered per protocol. The 4 other dyads received the two hospital encounters, but at least 1 of the 3 post-discharge planned telephone encounters was not feasible because the patients had been re-hospitalized or was deceased. Participant's satisfaction with the intervention was high. Outcomes favoring the EG include self-care specific to HF, internal extrinsic motivation, intrinsic motivation, and caregiver's feeling that they provide a higher level of support. CONCLUSIONS: Caregiver involvement was found to be both a feasible and acceptable means of supporting self-care practice in HF patients. This approach presents a potential avenue for enhancing patients' efforts in this regard. However, this pilot study offers preliminary findings only, which need to be replicated in a phase 3 clinical trial. PMID- 27965854 TI - The effect of an enriched environment on activity levels in people with stroke in an acute stroke unit: protocol for a before-after pilot study. AB - BACKGROUND: Clinical practice guidelines advocate engaging stroke survivors in as much activity as possible early after stroke. One approach found to increase activity levels during inpatient rehabilitation incorporated an enriched environment (EE), whereby physical, cognitive, and social activity was enhanced. The effect of an EE in an acute stroke unit (ASU) has yet not been explored. METHODS/DESIGN: We will perform a prospective non-randomized before-after intervention study. The primary aim is to determine if an EE can increase physical, social, and cognitive activity levels of people with stroke in an ASU compared to usual care. Secondary aims are to determine if fewer secondary complications and improved functional outcomes occur within an EE. We will recruit 30 people with stroke to the usual care block and subsequently 30 to the EE block. Participants will be recruited within 24-72 h after onset of stroke, and each block is estimated to last for 12 weeks. In the usual care block current management and rehabilitation within an ASU will occur. In the EE block, the ASU environment will be adapted to promote greater physical, social, and cognitive activity. Three months after the EE block, another 30 participants will be recruited to determine sustainability of this intervention. The primary outcome is change in activity levels measured using behavioral mapping over 12 h (7.30 am to 7.30 pm) across two weekdays and one weekend day within the first 10 days of admission. Secondary outcomes include functional outcome measures, adverse and serious adverse events, stroke survivor, and clinical staff experience. DISCUSSION: There is a need for effective interventions that starts directly in the ASU. The EE is an innovative intervention that could increase activity levels in stroke survivors across all domains and promote early recovery of stroke survivors in the acute setting. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry, ANZCTN12614000679684. PMID- 27965855 TI - Optimising self-care support for people with heart failure and their caregivers: development of the Rehabilitation Enablement in Chronic Heart Failure (REACH-HF) intervention using intervention mapping. AB - BACKGROUND: We aimed to establish the support needs of people with heart failure and their caregivers and develop an intervention to improve their health-related quality of life. METHODS: We used intervention mapping to guide the development of our intervention. We identified "targets for change" by synthesising research evidence and international guidelines and consulting with patients, caregivers and health service providers. We then used behaviour change theory, expert opinion and a taxonomy of behaviour change techniques, to identify barriers to and facilitators of change and to match intervention strategies to each target. A patient and public involvement group helped to identify patient and caregiver needs, refine the intervention objectives and strategies and deliver training to the intervention facilitators. A feasibility study (ISRCTN25032672) involving 23 patients, 12 caregivers and seven trained facilitators at four sites assessed the feasibility and acceptability of the intervention and quality of delivery and generated ideas to help refine the intervention. RESULTS: The Rehabilitation Enablement in Chronic Heart Failure (REACH-HF) intervention is a comprehensive self-care support programme comprising the "Heart Failure Manual", a choice of two exercise programmes for patients, a "Family and Friends Resource" for caregivers, a "Progress Tracker" tool and a facilitator training course. The main targets for change are engaging in exercise training, monitoring for symptom deterioration, managing stress and anxiety, managing medications and understanding heart failure. Secondary targets include managing low mood and smoking cessation. The intervention is facilitated by trained healthcare professionals with specialist cardiac experience over 12 weeks, via home and telephone contacts. The feasibility study found high levels of satisfaction and engagement with the intervention from facilitators, patients and caregivers. Intervention fidelity analysis and stakeholder feedback suggested that there was room for improvement in several areas, especially in terms of addressing caregivers' needs. The REACH-HF materials were revised accordingly. CONCLUSIONS: We have developed a comprehensive, evidence-informed, theoretically driven self care and rehabilitation intervention that is grounded in the needs of patients and caregivers. A randomised controlled trial is underway to assess the effectiveness and cost-effectiveness of the REACH-HF intervention in people with heart failure and their caregivers. PMID- 27965856 TI - Ketamine for depression relapse prevention following electroconvulsive therapy: protocol for a randomised pilot trial (the KEEP-WELL trial). AB - BACKGROUND: Major depressive disorder is a common debilitating illness that is the second leading contributor to the global burden of disease. Unfortunately, about 30 % of patients do not respond to adequate trials of antidepressants and/or psychotherapies. About 45-60 % of such treatment-resistant patients will remit with electroconvulsive therapy (ECT). However, relapse rates are high following ECT-38 % after 6 months. There is a need for better relapse prevention strategies. One possibility is to use ketamine, a competitive glutamate receptor antagonist used for anaesthesia. A recent paradigm shift in treating depression and understanding its biology has been the finding that ketamine has a robust, rapid-onset, though short-lived, antidepressant effect that is possibly mediated through neuroplastic effects. However, ketamine has not previously been reported on for relapse prevention. METHODS/DESIGN: The main objective of this study is to conduct a randomised controlled pilot trial (n = 40) of a 4-week course of once weekly ketamine infusions for relapse prevention following ECT for depression to assess trial procedures that will inform a future definitive trial. Participants with unipolar depression will be recruited prior to commencing ECT and be assessed weekly during the ECT course using the primary clinical outcome, the 24 item Hamilton Rating Scale for Depression (HRSD-24). Those who meet standard response criteria will be invited, on completing ECT, to be randomised in a 1:1 ratio to a course of four once-weekly infusions of ketamine or an active comparator midazolam, which mimics some of the effects of ketamine and may improve blinding over inactive placebo. Participants will be followed up over 6 months using the HRSD-24 to assess for relapse. DISCUSSION: This is the first registered trial (NCT02414932, https://clinicaltrials.gov/ct2/show/NCT02414932) of ketamine for depression relapse prevention, an important possible use of this agent. The primary focus of the pilot trial is on feasibility. However, a 95 % confidence interval will be determined for the difference between ketamine and midazolam groups in 6-month relapse rates to help inform a future definitive trial. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT02414932 Secondary Identifying numbers: EudraCT number: 2014-000339-18 Sponsors' Reference, Sponsor: St. Patrick's Mental Health Services: 05/14 Research Ethics Committee Reference, Joint REC of St James' and Tallaght Hospitals, Dublin: 2014-08-19. PMID- 27965858 TI - Development and feasibility of a Swallowing intervention Package (SiP) for patients receiving radiotherapy treatment for head and neck cancer-the SiP study protocol. AB - BACKGROUND: Head and neck cancer (HNC) is the sixth most common cancer worldwide, and the functional, psychological and social consequences of HNC cancer and its treatment can be severe and chronic. Dysphagia (swallowing problems) affects up to two thirds of patients undergoing combined chemoradiotherapy. Recent reviews suggest that prophylactic swallowing exercises may improve a range of short- and long-term outcomes; however, the importance of psychological and behavioural factors on adherence to swallowing exercises has not been adequately studied. This study aims to develop and test the feasibility of a Swallowing intervention Package (SiP) designed in partnership with patients, speech and language therapists (SLTs) and other members of the head and neck multi-disciplinary team (MDT), for patients undergoing chemoradiotherapy (CRT) or radiotherapy (RT) for head and neck cancer. METHODS/DESIGN: This feasibility study uses quantitative and qualitative research methods, within a quasi-experimental design, to assess whether patients will tolerate and adhere to the SiP intervention, which aspects of the intervention can be implemented and which cannot, whether treatment fidelity can be achieved across different contexts, whether study processes and outcome measures will be feasible and acceptable and to what extent the intervention is likely to have an impact on swallowing dysfunction and quality of life. Patients are being recruited from five sites in Scotland and England (three interventions and two usual care). The SLT based in the relevant intervention centre teaches the exercise programme and provides supporting materials. A combination of patient-reported outcome measures (PROMs), adherence measures and clinical swallowing assessments are used prior to intervention (baseline), at the end of treatment, 3 and 6 months post-treatment. DISCUSSION: This collaborative study has taken a unique approach to the development of a patient-centred and evidence-based swallowing intervention. The introduction of an e-SiP app provides an exploration of the use of technology in delivering this intervention. The study provides an opportunity to examine the feasibility of delivering and participating in a supported swallowing intervention across several different NHS sites and will provide the evidence needed to refine intervention and study processes for a future trial. TRIAL REGISTRATION: NCRI portfolio, 18192 & 20259. PMID- 27965857 TI - Culturally-adapted Family Intervention (CaFI) for African-Caribbeans diagnosed with schizophrenia and their families: a feasibility study protocol of implementation and acceptability. AB - BACKGROUND: African-Caribbeans in the UK have the highest schizophrenia incidence and greatest inequity in access to mental health services of all ethnic groups. The National Institute for Health and Care Excellence (NICE) highlights this crisis in care and urgent need to improve evidence-based mental healthcare, experiences of services and outcomes for this group. Family intervention (FI) is clinically and cost-effective for the management of schizophrenia but it is rarely offered. Evidence for FI with minority ethnic groups generally, and African-Caribbeans in particular, is lacking. This study aims to test the feasibility and acceptability of delivering Culturally-adapted Family Intervention (CaFI) to African-Caribbean service users diagnosed with schizophrenia. METHODS/DESIGN: This is a feasibility cohort design study. Over a 12-month intervention period, 30 service users and their families, recruited from hospital and community settings, will receive ten one-hourly sessions of CaFI. Where biological families are absent, access to the intervention will be optimised through 'family support members'; trusted individuals nominated by service users or study volunteers. We shall collect data on eligibility, uptake, retention and attrition and assess the utility and feasibility of collecting various outcome measures including readmission, service engagement, working alliance, clinical symptoms and functioning, perceived criticism, psychosis knowledge, familial stress and economic costs. Measures will be collected at baseline, post-intervention and at 3-month follow-up using validated questionnaires and standardised interviews. Admission rates and change in care management will be rated by independent case note examination. Variability in the measures will inform sample size estimates for a future trial. Independent raters will assess fidelity to the intervention in 10 % of sessions. Feedback at the end of each session along with thematically-analysed qualitative interviews will examine CaFI's acceptability to service users, families and healthcare professionals. DISCUSSION: This innovative response to inequalities in mental healthcare experienced by African-Caribbeans diagnosed with schizophrenia might improve engagement in services, access to evidence-based interventions and clinical outcomes. Successful implementation of CaFI in this group could pave the way for better engagement and provision across marginalised groups and therefore has potentially important implications for commissioning and service delivery in ethnically diverse populations. This study will demonstrate whether the approach is feasible and acceptable and can be implemented with fidelity in different settings. PMID- 27965859 TI - The iBRA (implant breast reconstruction evaluation) study: protocol for a prospective multi-centre cohort study to inform the feasibility, design and conduct of a pragmatic randomised clinical trial comparing new techniques of implant-based breast reconstruction. AB - BACKGROUND: Implant-based breast reconstruction (IBBR) is the most commonly performed reconstructive procedure in the UK. The introduction of techniques to augment the subpectoral pocket has revolutionised the procedure, but there is a lack of high-quality outcome data to describe the safety or effectiveness of these techniques. Randomised controlled trials (RCTs) are the best way of comparing treatments, but surgical RCTs are challenging. The iBRA (implant breast reconstruction evaluation) study aims to determine the feasibility, design and conduct of a pragmatic RCT to examine the effectiveness of approaches to IBBR. METHODS/DESIGN: The iBRA study is a trainee-led research collaborative project with four phases:Phase 1 - a national practice questionnaire (NPQ) to survey current practicePhase 2 - a multi-centre prospective cohort study of patients undergoing IBBR to evaluate the clinical and patient-reported outcomesPhase 3- an IBBR-RCT acceptability survey and qualitative work to explore patients' and surgeons' views of proposed trial designs and candidate outcomes.Phase 4 - phases 1 to 3 will inform the design and conduct of the future RCT All centres offering IBBR will be encouraged to participate by the breast and plastic surgical professional associations (Association of Breast Surgery and British Association of Plastic Reconstructive and Aesthetic Surgeons). Data collected will inform the feasibility of undertaking an RCT by defining current practice and exploring issues surrounding recruitment, selection of comparator arms, choice of primary outcome, sample size, selection criteria, trial conduct, methods of data collection and feasibility of using the trainee collaborative model to recruit patients and collect data. DISCUSSION: The preliminary work undertaken within the iBRA study will determine the feasibility, design and conduct of a definitive RCT in IBBR. It will work with the trainee collaborative to build capacity by creating an infrastructure of research-active breast and plastic surgeons which will facilitate future high-quality research that will ultimately improve outcomes for all women seeking reconstructive surgery. TRIAL REGISTRATION: ISRCTN37664281. PMID- 27965860 TI - Behavioural activation written self-help to improve mood, wellbeing and quality of life in people with dementia supported by informal carers (PROMOTE): a study protocol for a single-arm feasibility study. AB - BACKGROUND: Increases in life expectancy have resulted in a global rise in dementia prevalence. Dementia is associated with poor wellbeing, low quality of life and increased incidence of mental health difficulties such as low mood or depression. However, currently, there is limited access to evidence-based psychological interventions for people with dementia experiencing low mood and poor wellbeing. Behavioural activation-based self-help, supported by informal carers and guided by mental health professionals, may represent an effective and acceptable solution. METHODS/DESIGN: The present study is a phase II (feasibility) single-arm trial informed by the Medical Research Council complex interventions research methods framework. Up to 50 dementia participant/informal carer dyads will be recruited from a variety of settings including primary care, dementia-specific health settings and community outreach. People living with dementia will receive behavioural activation-based self-help and be supported by their informal carer who has received training in the skills required to support the self-help approach. In turn, during the use of the intervention, the informal carer will be guided by mental health professionals to help them work through the materials and problem solve any difficulties. Consistent with the objectives of feasibility studies, outcomes relating to recruitment from different settings, employment of different recruitment methods, attrition, data collection procedures, clinical delivery and acceptability of the intervention will be examined. Clinical outcomes for people with dementia (symptoms of depression and quality of life) and informal carers (symptoms of depression and anxiety, carer burden and quality of life) will be measured pre-treatment and at 3 months post treatment allocation. DISCUSSION: This study will examine the feasibility and acceptability of a novel behavioural activation-based self-help intervention designed to promote wellbeing and improve low mood in people living with dementia, alongside methodological and procedural uncertainties associated with research-related procedures. As determined by pre-specified progression criteria, if research procedures and the new intervention demonstrate feasibility and acceptability, results will then be used to inform the design of a pilot randomised controlled trial (RCT) to specifically examine remaining methodological uncertainties associated with recruitment into a randomised controlled design. TRIAL REGISTRATION: Current Controlled Trials ISRCTN42017211. PMID- 27965861 TI - EXercise to prevent AnthrCycline-based Cardio-Toxicity (EXACT) in individuals with breast or hematological cancers: a feasibility study protocol. AB - BACKGROUND: Anthracyclines (AC), widely used and effective anticancer agents, are known to induce both acute and chronic declines in cardiovascular health, ranging in severity from asymptomatic, subclinical dysfunction to substantial cardiomyopathy leading to congestive heart failure and death. There is substantial evidence that physical activity, higher levels of cardiorespiratory fitness, and exercise therapy can help prevent cardiovascular disease. Moreover, animal studies have shown that exercise performed concomitantly with AC treatment may attenuate early cardiac damage that results from AC exposure. Our primary objective is to assess the feasibility of a 12-week aerobic exercise training (AET) program in patients receiving AC-based chemotherapy. METHODS/DESIGN: This is a prospective, single-arm (pre-post-test design), feasibility study of a supervised 12-week progressive, light-to-moderate to moderate-to-vigorous intensity AET program for patients (18-65 years) receiving AC chemotherapeutic treatment for a primary/non-recurrent breast cancer or hematological malignancy. Both feasibility (e.g., participant recruitment, program adherence, safety) and intervention outcome (e.g., biological markers of cardiotoxicity, aerobic capacity, quality of life) measures will be collected. The AET program will include two, 45-min community-based exercise sessions (treadmill or cycle) per week for a total of 12 weeks. All exercise sessions will be supervised by trained exercise specialists. DISCUSSION: Data from the EXACT study will be evaluated to determine the need to refine patient recruitment methods and general acceptability of the AET program. Preliminary data on the effects of the AET intervention on pertinent cardiac and health outcomes will also be evaluated and used to inform future studies in terms of the most appropriate outcome measure(s) to adopt and sample size estimation. TRIAL REGISTRATION: ClinicalTrails.gov, NCT02471053. PMID- 27965862 TI - Behavioural Activation Therapy for Depression after Stroke (BEADS): a study protocol for a feasibility randomised controlled pilot trial of a psychological intervention for post-stroke depression. AB - BACKGROUND: There is currently insufficient evidence for the clinical and cost effectiveness of psychological therapies for treating post-stroke depression. METHODS/DESIGN: BEADS is a parallel group feasibility multicentre randomised controlled trial with nested qualitative research and economic evaluation. The aim is to evaluate the feasibility of undertaking a full trial comparing behavioural activation (BA) to usual stroke care for 4 months for patients with post-stroke depression. We aim to recruit 72 patients with post-stroke depression over 12 months at three centres, with patients identified from the National Health Service (NHS) community and acute services and from the voluntary sector. They will be randomly allocated to receive behavioural activation in addition to usual care or usual care alone. Outcomes will be measured at 6 months after randomisation for both participants and their carers, to determine their effectiveness. The primary clinical outcome measure for the full trial will be the Patient Health Questionnaire-9 (PHQ-9). Rates of consent, recruitment and follow-up by centre and randomised group will be reported. The acceptability of the intervention to patients, their carers and therapists will also be assessed using qualitative interviews. The economic evaluation will be undertaken from the National Health Service and personal social service perspective, with a supplementary analysis from the societal perspective. A value of information analysis will be completed to identify the areas in which future research will be most valuable. DISCUSSION: The feasibility outcomes from this trial will provide the data needed to inform the design of a definitive multicentre randomised controlled trial evaluating the clinical and cost-effectiveness of behavioural activation for treating post-stroke depression. TRIAL REGISTRATION: Current controlled trials ISRCTN12715175. PMID- 27965863 TI - A theory-informed approach to developing visually mediated interventions to change behaviour using an asthma and physical activity intervention exemplar. AB - BACKGROUND: Visualisation techniques are used in a range of healthcare interventions. However, these frequently lack a coherent rationale or clear theoretical basis. This lack of definition and explicit targeting of the underlying mechanisms may impede the success of and evaluation of the intervention. We describe the theoretical development, deployment, and pilot evaluation, of a complex visually mediated behavioural intervention. The exemplar intervention focused on increasing physical activity among young people with asthma. We employed an explicit five-stage development model, which was actively supported by a consultative user group. The developmental stages involved establishing the theoretical basis, establishing a narrative structure, visual rendering, checking interpretation, and pilot testing. We conducted in-depth interviews and focus groups during early development and checking, followed by an online experiment for pilot testing. A total of 91 individuals, including young people with asthma, parents, teachers, and health professionals, were involved in development and testing. RESULTS: Our final intervention consisted of two components: (1) an interactive 3D computer animation to create intentions and (2) an action plan and volitional help sheet to promote the translation of intentions to behaviour. Theory was mediated throughout by visual and audio forms. The intervention was regarded as highly acceptable, engaging, and meaningful by all stakeholders. The perceived impact on asthma understanding and intentions was reported positively, with most individuals saying that the 3D computer animation had either clarified a range of issues or made them more real. Our five-stage model underpinned by extensive consultation worked well and is presented as a framework to support explicit decision-making for others developing theory informed visually mediated interventions. CONCLUSIONS: We have demonstrated the ability to develop theory-based visually mediated behavioural interventions. However, attention needs to be paid to the potential ambiguity associated with images and thus the concept of visual literacy among patients. Our revised model may be helpful as a guide to aid development, acceptability, and ultimately effectiveness. PMID- 27965864 TI - A brief CBT intervention for depersonalisation/derealisation in psychosis: study protocol for a feasibility randomised controlled trial. AB - BACKGROUND: Depersonalisation is the experience of being detached or disconnected from one's experience. Studies suggest that clinically significant levels of depersonalisation are common in individuals who have psychotic symptoms and are associated with increased impairment. However, to date, there have been no studies that have investigated an intervention designed to target clinically significant depersonalisation in such patient groups. This study aims to determine the feasibility and acceptability of a brief intervention targeting clinically significant depersonalisation in those who also have current psychotic symptoms. METHODS/DESIGN: The feasibility of delivering six sessions of cognitive behavioural therapy for depersonalisation in psychosis patients will be evaluated using a single-blinded randomised controlled trial with a treatment as usual control condition. Participants will be assessed at baseline and then randomised to either the treatment or control arm. Participants randomised to the treatment arm will be offered six sessions of individual cognitive behavioural therapy delivered over a maximum of 10 weeks. Therapy will focus on an individualised shared formulation of depersonalisation experiences and behavioural, cognitive, emotional regulation and thinking process strategies to decrease distress associated with depersonalisation. Participants will be assessed again at a 10 week (post-randomisation) follow-up assessment. The primary outcomes of interest will be those assessing the feasibility and acceptability of the intervention including rates of referral, eligibility and acceptance to participate; attendance at therapy sessions and completion of homework tasks; satisfaction with the intervention; maintenance of blinding; and therapist competence. Secondary outcomes will be data on clinical outcome measures of depersonalisation and positive symptoms of psychosis, anxiety, depression and post-traumatic stress. DISCUSSION: This study will determine the feasibility of delivering six sessions of cognitive behavioural therapy for individuals with current psychotic symptoms who also experience clinically significant levels of depersonalisation. The results will provide information to inform a larger randomised trial to assess intervention efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02427542. PMID- 27965865 TI - Cultural adaptation of a children's weight management programme for Bangladeshi and Pakistani families in the UK: a cluster-randomised feasibility study protocol. AB - BACKGROUND: Group-based children's weight management programmes are widely available in the UK and evidence shows that these are effective in the short term. No programmes have been specifically developed to meet the cultural requirements of UK minority ethnic communities. South Asian children are a high risk group for obesity and its consequences; therefore, the study aim is to adapt an existing weight management programme for children aged 4-11 years and their families to ensure cultural relevance to Pakistani and Bangladeshi communities, and undertake a feasibility study of the adapted programme. METHODS/DESIGN: Pakistani and Bangladeshi families of overweight children who have been offered the existing children's weight management programme in Birmingham, UK, will be invited to interviews and focus groups to explore their experiences and views of the programme. These data, together with existing literature and service provider information, will inform adaptation of the programme to be more culturally relevant to these families. The feasibility study will employ a cluster randomised design, and will assess success of programme adaptation and feasibility of programme delivery. Planned programmes will be randomised to be delivered as the adapted programme (intervention) or the standard programme (comparator) with a 2:1 ratio. The primary outcome will be the proportion of Pakistani and Bangladeshi families completing the adapted programme. To assess recruitment, retention and data collection methods to inform a future trial, we aim to recruit 80 participants. A range of assessments will be undertaken with participants pre-, post- and 6-months post-intervention. DISCUSSION: This study addresses the identified need to provide children's weight management programmes that are suitable for minority ethnic communities. Whilst the focus of the intervention adaptation is on Pakistani and Bangladeshi communities, the programme will be developed to be flexibly delivered to meet the cultural needs of communities of all ethnic compositions. The feasibility study will directly compare the adapted and existing weight management programmes, and will enable a comprehensive evaluation of the success of the adaptation. Essential information will also be gathered to inform the design and sample size calculation of a future trial to evaluate intervention effectiveness. TRIAL REGISTRATION: ISRCTN81798055, registered: 13/05/2014. PMID- 27965866 TI - Progesterone supplementation for HIV-positive pregnant women on protease inhibitor-based antiretroviral regimens (the ProSPAR study): a study protocol for a pilot randomized controlled trial. AB - BACKGROUND: In Canada, the majority of HIV-positive pregnant women receive combination antiretroviral therapy that includes a ritonavir-boosted protease inhibitor to prevent mother-to-child HIV transmission. However, protease inhibitor-based combination antiretroviral therapy has been associated with increased rates of preterm, low birth weight, and small for gestational age births. Our previous experimental findings demonstrate that protease inhibitor use during pregnancy is associated with decreased progesterone levels that correlate with fetal growth, and that progesterone supplementation can improve protease inhibitor-induced fetal growth restriction. We hypothesize that HIV positive pregnant women who receive protease inhibitor-based combination therapy may also benefit from progesterone supplementation during pregnancy. METHODS/DESIGN: In order to test this hypothesis, we have designed an open-label, multi-centre, randomized controlled (parallel group) pilot trial. The initial goal of this trial is to test feasibility and acceptability of our intervention. Forty HIV-positive pregnant women who are either on, or intending to start or switch to a boosted protease inhibitor-based combination antiretroviral regimen will be enrolled from six sites across Ontario, Canada. Twenty-five women will be randomized to self-administer natural progesterone (Prometrium, 200 mg) vaginally every night starting between gestational week 16 and 24 until week 36, and 15 women will be randomized to no intervention. While the participants and treating physicians will not be blinded, the laboratory personnel performing the biochemical and morphological evaluations will be blinded to ensure unbiased evaluation. The primary outcome of the pilot study is the feasibility of enrolment as measured by the recruitment rate and patient-reported reasons to decline participation. Secondary outcomes in participants include safety, acceptability, and adherence to progesterone supplementation. DISCUSSION: Given the safety of intravaginal progesterone and its current use in the general obstetrical population to prevent recurrent preterm delivery, this pilot study will provide data to determine the feasibility of a larger randomized controlled trial to assess the impact of this intervention on improving neonatal health in the context of HIV-positive pregnancies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02400021. PMID- 27965867 TI - Repetitive arm functional tasks after stroke (RAFTAS): a pilot randomised controlled trial. AB - BACKGROUND: Repetitive functional task practise (RFTP) is a promising treatment to improve upper limb recovery following stroke. We report the findings of a study to determine the feasibility of a multi-centre randomised controlled trial to evaluate this intervention. METHODS: A pilot randomised controlled trial recruited patients with new reduced upper limb function within 14 days of acute stroke from three stroke units. Participants were randomised to receive a four week upper limb RFTP therapy programme consisting of goal setting, independent activity practise, and twice weekly therapy reviews in addition to usual post stroke rehabilitation, or usual post stroke rehabilitation. The recruitment rate; adherence to the RFTP therapy programme; usual post stroke rehabilitation received; attrition rate; data quality; success of outcome assessor blinding; adverse events; and the views of study participants and therapists about the intervention were recorded. RESULTS: Fifty five eligible patients were identified, 4-6 % of patients screened at each site. Twenty four patients participated in the pilot study. Two study sites met the recruitment target of 1 2 participants per month. The median number of face to face therapy sessions received was 6 [IQR 3-8]. The median number of daily repetitions of activities recorded was 80 [IQR 39-80]. Data about usual post stroke rehabilitation were available for 18/24 (75 %). Outcome data were available for 22/24 (92 %) at one month and 20/24 (83 %) at three months. Outcome assessors were unblinded to participant group allocation for 11/22 (50 %) at one month and 6/20 (30 %) at three months. Four adverse events were considered serious as they resulted in hospitalisation. None were related to study treatment. Feedback from patients and therapists about the RFTP programme was mainly positive. CONCLUSIONS: A multi centre randomised controlled trial to evaluate an upper limb RFTP therapy programme provided early after stroke is feasible and acceptable to patients and therapists, but there are issues which need to be addressed when designing a Phase III study. A Phase III study will need to monitor and report not only recruitment and attrition but also adherence to the intervention, usual post stroke rehabilitation received, and outcome assessor blinding. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) 58527251. PMID- 27965868 TI - The feasibility and acceptability of trial procedures for a pragmatic randomised controlled trial of a structured physical activity intervention for people diagnosed with colorectal cancer: findings from a pilot trial of cardiac rehabilitation versus usual care (no rehabilitation) with an embedded qualitative study. AB - BACKGROUND: Pilot and feasibility work is conducted to evaluate the operational feasibility and acceptability of the intervention itself and the feasibility and acceptability of a trials' protocol design. The Cardiac Rehabilitation In Bowel cancer (CRIB) study was a pilot randomised controlled trial (RCT) of cardiac rehabilitation versus usual care (no rehabilitation) for post-surgical colorectal cancer patients. A key aim of the pilot trial was to test the feasibility and acceptability of the protocol design. METHODS: A pilot RCT with embedded qualitative work was conducted in three sites. Participants were randomly allocated to cardiac rehabilitation or usual care groups. Outcomes used to assess the feasibility and acceptability of key trial parameters were screening, eligibility, consent, randomisation, adverse events, retention, completion, missing data, and intervention adherence rates. Colorectal patients' and clinicians' perceptions and experiences of the main trial procedures were explored by interview. RESULTS: Quantitative study. Three sites were involved. Screening, eligibility, consent, and retention rates were 79 % (156/198), 67 % (133/198), 31 % (41/133), and 93 % (38/41), respectively. Questionnaire completion rates were 97.5 % (40/41), 75 % (31/41), and 61 % (25/41) at baseline, follow-up 1, and follow-up 2, respectively. Sixty-nine percent (40) of accelerometer datasets were collected from participants; 31 % (20) were removed for not meeting wear-time validation. Qualitative study: Thirty-eight patients and eight clinicians participated. Key themes were benefits for people with colorectal cancer attending cardiac rehabilitation, barriers for people with colorectal cancer attending cardiac rehabilitation, generic versus disease specific rehabilitation, key concerns about including people with cancer in cardiac rehabilitation, and barriers to involvement in a study about cardiac rehabilitation. CONCLUSIONS: The study highlights where threats to internal and external validity are likely to arise in any future studies of similar structured physical activity interventions for colorectal cancer patients using similar methods being conducted in similar contexts. This study shows that there is likely to be potential recruitment bias and potential imprecision due to sub optimal completion of outcome measures, missing data, and sub-optimal intervention adherence. Hence, strategies to manage these risks should be developed to stack the odds in favour of conducting successful future trials. TRIAL REGISTRATION: ISRCTN63510637. PMID- 27965869 TI - Feasibility and acceptance of exercise recommendations (10,000 steps a day) within routine German health check (Check-Up 35/GOA29)-study protocol. AB - BACKGROUND: Benefits of exercise to prevent non-communicable diseases are well documented. Limited data exists to promote physical activity in healthy but sedentary and/or overweight people. Brief interventions within routine German health checks may be an effective way to reach these patients. METHODS/DESIGN: The quasi-experimental, multi-center prospective feasibility study is designed for general practices in Cologne (intervention group) and Dusseldorf (control group), up to 20 per region. Eight to 10 inactive and/or overweight patients per practice will be recruited for a total of 300. General practitioners and at least one of their nurses for the intervention group will be trained in motivational interviewing and familiarized with low-threshold recommendations for exercise (activities of daily life (ADL), target of 10,000 steps/day) and additional tools (pedometers, activity diaries). Participants in the control group will only receive general advice (150 min of exercise/week). The primary aims are to evaluate the feasibility of this intervention and to determine whether it is possible to reach a mean increase of 1000 steps/day in the target group within 6 months. Secondary objectives focus on the number of patients who reach a target of 10,000 steps/day and their improvements in quality of life and decrease in body mass index, waist circumference, and blood pressure. DISCUSSION: The study will assess whether it is feasible to run brief interventions within the GP setting can promote an active lifestyle in overweight and/or inactive patients. PMID- 27965870 TI - Protecting children from secondhand smoke: a mixed-methods feasibility study of a novel smoke-free home intervention. AB - BACKGROUND: Globally, 40 % of children under 14 years are regularly exposed to secondhand smoke (SHS), typically in their homes. There is limited evidence of the effectiveness of interventions to reduce children's SHS exposure, and so the aim of this study was to test the feasibility and acceptability of a novel intervention to help parents and carers (caregivers) to reduce their children's exposure to SHS at home. METHODS: A novel multi-component intervention to support caregivers to reduce their children's SHS exposure at home was tested in a two phase feasibility study. The 12-week intensive intervention delivered in the home consisted of three components: behavioural support, nicotine replacement therapy (NRT) for temporary abstinence and feedback on levels of SHS exposure in the form of children's salivary cotinine (phase 1) or home air quality (PM2.5) (phase 2). Participants were caregivers who smoked inside their homes and had at least one child under the age of 5 years living with them the majority of the time. Mixed methods were used to explore the acceptability and feasibility of the intervention as well as processes, particularly around recruitment and retention, for an exploratory efficacy trial. RESULTS: Twelve caregivers completed the study, all received personalised feedback on SHS exposure and behavioural support to help them to make their homes smoke-free and the majority at least tried NRT. Saliva cotinine results were variable in phase 1, and therefore, measures of PM2.5 were used for feedback in phase 2. Behavioural support was well received with personalised feedback reported as being the key motivator for initiating and maintaining behaviour change. CONCLUSIONS: Recruiting disadvantaged caregivers was labour intensive, but once recruited, this novel intervention was both feasible and acceptable in supporting caregivers to reduce their children's exposure to SHS at home. It is appropriate to test the efficacy of this novel intervention in an exploratory randomised controlled trial. TRIAL REGISTRATION: This is not applicable for the current study; however, a registered exploratory randomised controlled trial linked to this manuscript is currently ongoing (ISRCTN81701383). PMID- 27965871 TI - Using Specialist Screening Practitioners (SSPs) to increase uptake of the Bowel Scope (Flexible Sigmoidoscopy) Screening Programme: a study protocol for a feasibility single-stage phase II trial. AB - BACKGROUND: The NHS Bowel Scope Screening (BSS) programme offers men and women aged 55 years a once-only flexible sigmoidoscopy (FS), a test that can help reduce colorectal cancer (CRC) incidence and mortality. However, the benefits of BSS are contingent on uptake. This National Institute for Health Research-funded single-stage phase II trial will test the feasibility of using patient navigation (PN), an intervention that offers support to patients to overcome barriers to healthcare, to increase BSS uptake within a socially deprived area of England. METHODS/DESIGN: All individuals invited for BSS at South Tyneside NHS Foundation Trust during the 6-month recruitment period will be invited to take part in the study. Consenting participants will be randomised to receive PN or usual care in a 2:1 ratio. PN involves non-attenders receiving a phone call from a Specialist Screening Practitioner (SSP) who will elicit reasons for non-attendance and offer educational, practical, and emotional support as needed. If requested by the patient, another appointment for BSS will then be arranged. We anticipate 30 % of participants will be non-attenders. Using A'Hern single-stage design, with 20 % significance level and 80 % power, at least 35 participants who receive PN need to subsequently attend for PN to be considered worthy of further investigation in a definitive trial. The primary outcome measure will be the number of participants in the PN group who re-book and attend their BSS appointment. A qualitative analysis of the PN transcripts, and interviews with the SSPs, will also be conducted, alongside a quantitative analysis of completed patient reported experience questionnaires. An economic analysis will calculate the costs of delivering PN. DISCUSSION: This feasibility study will be instrumental in deciding whether to conduct the first definitive trial of PN in BSS in England. If PN is subsequently shown to be cost-effective at increasing uptake of BSS, NHS policies could be modified to implement PN as a standard service. The results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number, ISRCTN13314752. PMID- 27965872 TI - The safety climate in primary care (SAP-C) study: study protocol for a randomised controlled feasibility study. AB - BACKGROUND: Research on patient safety has focused largely on secondary care settings, and there is a dearth of knowledge relating to safety culture or climate, and safety climate improvement strategies, in the context of primary care. This is problematic given the high rates of usage of primary care services and the myriad of opportunities for clinical errors daily. The current research programme aimed to assess the effectiveness of an intervention derived from the Scottish Patient Safety Programme in Primary Care. The intervention consists of safety climate measurement and feedback and patient chart audit using the trigger review method. The purpose of this paper is to describe the background to this research and to present the methodology of this feasibility study in preparation for a future definitive RCT. METHODS: The SAP-C study is a feasibility study employing a randomised controlled pretest-posttest design that will be conducted in 10 general practices in the Republic of Ireland and Northern Ireland. Five practices will receive the safety climate intervention over a 9-month period. The five practices in the control group will continue care as usual but will complete the GP-SafeQuest safety climate questionnaire at baseline (month 1) and at the terminus of the intervention (month 9). The outcomes of the study include process evaluation metrics (i.e. rates of participant recruitment and retention, rates of completion of safety climate measures, qualitative data regarding participants' perceptions of the intervention's potential efficacy, acceptability, and sustainability), patient safety culture in intervention and control group practices at posttest, and instances of undetected patient harm identified through patient chart audit using the trigger review method. DISCUSSION: The planned study investigates an intervention to improve safety climate in Irish primary care settings. The resulting data may inform our knowledge of the frequency of undetected patient safety incidents in primary care, may contribute to improved patient safety practices in primary care settings, and may inform future research on patient safety improvement initiatives. PMID- 27965873 TI - Using mobile health technology to improve behavioral skill implementation through homework in evidence-based parenting intervention for disruptive behavior disorders in youth: study protocol for intervention development and evaluation. AB - BACKGROUND: Disruptive behavior disorders (DBDs) (oppositional defiant disorder (ODD) and conduct disorder (CD)) are prevalent, costly, and oftentimes chronic psychiatric disorders of childhood. Evidence-based interventions that focus on assisting parents to utilize effective skills to modify children's problematic behaviors are first-line interventions for the treatment of DBDs. Although efficacious, the effects of these interventions are often attenuated by poor implementation of the skills learned during treatment by parents, often referred to as between-session homework. The multiple family group (MFG) model is an evidence-based, skills-based intervention model for the treatment of DBDs in school-age youth residing in urban, socio-economically disadvantaged communities. While data suggest benefits of MFG on DBD behaviors, similar to other skill-based interventions, the effects of MFG are mitigated by the poor homework implementation, despite considerable efforts to support parents in homework implementation. This paper focuses on the study protocol for the development and preliminary evaluation of a theory-based, smartphone mobile health (mHealth) application (My MFG) to support homework implementation by parents participating in MFG. METHODS/DESIGN: This paper describes a study design proposal that begins with a theoretical model, uses iterative design processes to develop My MFG to support homework implementation in MFG through a series of pilot studies, and a small-scale pilot randomised controlled trial to determine if the intervention can demonstrate change (preliminary efficacy) of My MFG in outpatient mental health settings in socioeconomically disadvantaged communities. DISCUSSION: This preliminary study aims to understand the implementation of mHealth methods to improve the effectiveness of evidence-based interventions in routine outpatient mental health care settings for youth with disruptive behavior and their families. Developing methods to augment the benefits of evidence-based interventions, such as MFG, where homework implementation is an essential mediator of treatment benefits is critical to full adoption/implementation of these intervention in routine practice settings and maximizing benefits for youth with DBDs and their families. TRIAL REGISTRATION: ClinicalTrials.gov NCT01917838. PMID- 27965874 TI - Can a mindfulness-informed intervention reduce aggressive behaviour in people with intellectual disabilities? Protocol for a feasibility study. AB - BACKGROUND: Approximately 10-20 % of adults with intellectual disabilities engage in challenging behaviours such as aggression, destructiveness, and self-injury, which are often accompanied by feelings of anger. The inability to manage anger can reduce quality of life. For example, aggression is a strong predictor of out of-area placements and is a risk variable for abuse. Recent research suggests that mindfulness-based therapies (specifically, Singh's Soles of the Feet meditation) can help people with intellectual disabilities manage angry emotions, with resultant reductions in challenging behaviour. However, previous research has been single-case design studies, and no group studies have been published with people with intellectual disabilities and aggressive behaviour. METHODS/DESIGN: For this feasibility study, a UK protocol will be developed for use by health professionals within National Health Service (NHS) Intellectual Disability (ID) teams, based upon Singh's Soles of the Feet manual. Twenty adults with intellectual disabilities and identified problems with anger control will be recruited and six sessions will be delivered by a trained ID clinician. The study will monitor participant's aggressive behaviour, health-related quality of life, anxiety, depression, and use of support services (medication, hospital appointments etc.). These will be measured at three time points: (1) Baseline (within 2 weeks prior to the first session of the intervention), (2) 2 months post-baseline, and (3) 6 months post-baseline. Qualitative interviews will be conducted with participants, their carers, and the therapists who delivered the intervention. In order to help design an economic evaluation alongside a future full trial, we will cost the intervention and test the acceptability and validity of health economics measures to record resource use and health-related quality of life outcomes. DISCUSSION: The data from this study will inform the feasibility of the project protocol and intervention, which will help develop future research and to determine whether a larger, randomised controlled trial with concurrent economic evaluation is feasible. TRIAL REGISTRATION: UKCERN: 16743. PMID- 27965875 TI - Measuring prefrontal cortical activity during dual task walking in patients with Parkinson's disease: feasibility of using a new portable fNIRS device. AB - BACKGROUND: Many patients with Parkinson's disease (PD) have difficulties in performing a second task during walking (i.e., dual task walking). Functional near-infrared spectroscopy (fNIRS) is a promising approach to study the presumed contribution of dysfunction within the prefrontal cortex (PFC) to such difficulties. In this pilot study, we examined the feasibility of using a new portable and wireless fNIRS device to measure PFC activity during different dual task walking protocols in PD. Specifically, we tested whether PD patients were able to perform the protocol and whether we were able to measure the typical fNIRS signal of neuronal activity. METHODS: We included 14 PD patients (age 71.2 +/- 5.4 years, Hoehn and Yahr stage II/III). The protocol consisted of five repetitions of three conditions: walking while (i) counting forwards, (ii) serially subtracting, and (iii) reciting digit spans. Ability to complete this protocol, perceived exertion, burden of the fNIRS devices, and concentrations of oxygenated (O2Hb) and deoxygenated (HHb) hemoglobin from the left and right PFC were measured. RESULTS: Two participants were unable to complete the protocol due to fatigue and mobility safety concerns. The remaining 12 participants experienced no burden from the two fNIRS devices and completed the protocol with ease. Bilateral PFC O2Hb concentrations increased during walking while serially subtracting (left PFC 0.46 MUmol/L, 95 % confidence interval (CI) 0.12-0.81, right PFC 0.49 MUmol/L, 95 % CI 0.14-0.84) and reciting digit spans (left PFC 0.36 MUmol/L, 95 % CI 0.03-0.70, right PFC 0.44 MUmol/L, 95 % CI 0.09-0.78) when compared to rest. HHb concentrations did not differ between the walking tasks and rest. CONCLUSIONS: These findings suggest that a new wireless fNIRS device is a feasible measure of PFC activity in PD during dual task walking. Future studies should reduce the level of noise and inter-individual variability to enable measuring differences in PFC activity between different dual walking conditions and across health states. PMID- 27965876 TI - Implementing resilience engineering for healthcare quality improvement using the CARE model: a feasibility study protocol. AB - BACKGROUND: Resilience engineering (RE) is an emerging perspective on safety in complex adaptive systems that emphasises how outcomes emerge from the complexity of the clinical environment. Complexity creates the need for flexible adaptation to achieve outcomes. RE focuses on understanding the nature of adaptations, learning from success and increasing adaptive capacity. Although the philosophy is clear, progress in applying the ideas to quality improvement has been slow. The aim of this study is to test the feasibility of translating RE concepts into practical methods to improve quality by designing, implementing and evaluating interventions based on RE theory. The CARE model operationalises the key concepts and their relationships to guide the empirical investigation. METHODS: The settings are the Emergency Department and the Older Person's Unit in a large London teaching hospital. Phases 1 and 2 of our work, leading to the development of interventions to improve the quality of care, are described in this paper. Ethical approval has been granted for these phases. Phase 1 will use ethnographic methods, including observation of work practices and interviews with staff, to understand adaptations and outcomes. The findings will be used to collaboratively design, with clinical staff in interactive design workshops, interventions to improve the quality of care. The evaluation phase will be designed and submitted for ethical approval when the outcomes of phases 1 and 2 are known. DISCUSSION: Study outcomes will be knowledge about the feasibility of applying RE to improve quality, the development of RE theory and a validated model of resilience in clinical work which can be used to guide other applications. Tools, methods and practical guidance for practitioners will also be produced, as well as specific knowledge of the potential effectiveness of the implemented interventions in emergency and older people's care. Further studies to test the application of RE at a larger scale will be required, including studies of other healthcare settings, organisational contexts and different interventions. PMID- 27965877 TI - Survivors of intensive care with type 2 diabetes and the effect of shared care follow-up clinics: study protocol for the SWEET-AS randomised controlled feasibility study. AB - BACKGROUND: Many patients who survive the intensive care unit (ICU) experience long-term complications such as peripheral neuropathy and nephropathy which represent a major source of morbidity and affect quality of life adversely. Similar pathophysiological processes occur frequently in ambulant patients with diabetes mellitus who have never been critically ill. Some 25 % of all adult ICU patients have diabetes, and it is plausible that ICU survivors with co-existing diabetes are at heightened risk of sequelae from their critical illness. ICU follow-up clinics are being progressively implemented based on the concept that interventions provided in these clinics will alleviate the burdens of survivorship. However, there is only limited information about their outcomes. The few existing studies have utilised the expertise of healthcare professionals primarily trained in intensive care and evaluated heterogenous cohorts. A shared care model with an intensivist- and diabetologist-led clinic for ICU survivors with type 2 diabetes represents a novel targeted approach that has not been evaluated previously. Prior to undertaking any definitive study, it is essential to establish the feasibility of this intervention. METHODS: This will be a prospective, randomised, parallel, open-label feasibility study. Eligible patients will be approached before ICU discharge and randomised to the intervention (attending a shared care follow-up clinic 1 month after hospital discharge) or standard care. At each clinic visit, patients will be assessed independently by both an intensivist and a diabetologist who will provide screening and targeted interventions. Six months after discharge, all patients will be assessed by blinded assessors for glycated haemoglobin, peripheral neuropathy, cardiovascular autonomic neuropathy, nephropathy, quality of life, frailty, employment and healthcare utilisation. The primary outcome of this study will be the recruitment and retention at 6 months of all eligible patients. DISCUSSION: This study will provide preliminary data about the potential effects of critical illness on chronic glucose metabolism, the prevalence of microvascular complications, and the impact on healthcare utilisation and quality of life in intensive care survivors with type 2 diabetes. If feasibility is established and point estimates are indicative of benefit, funding will be sought for a larger, multi-centre study. TRIAL REGISTRATION: ANZCTR ACTRN12616000206426. PMID- 27965878 TI - Revie ?: the influence of a life review intervention including a positive, patient-centered approach towards enhancing the personal dignity of patients with advanced cancer-a study protocol for a feasibility study using a mixed method investigation. AB - BACKGROUND: It is generally recognized that existential concerns must be addressed to promote the dignity of patients with advanced cancer. A number of interventions have been developed in this regard, such as dignity therapy and other life review interventions (LRI). However, so far, none have focused on a positive approach or evaluated its effects on dignity and personal growth. This study aims to explore the feasibility of Revie ?, a life review intervention comprising a positive, patient-centered approach, and to determine potential changes of patients' sense of dignity, posttraumatic growth, and satisfaction with life. METHODS: A mixed method study will be performed, which includes specialized nurses and 40 patients with advanced cancer in an ambulatory and in patient setting of a Swiss university hospital. Quantitative methods involve a single group, pre- and post-intervention, and outcome measurements include the Patient Dignity Inventory, the Posttraumatic Growth Inventory, and the Satisfaction with Life Scale. Feasibility data relating to process, resource, and scientific elements of the trial will also be collected. A semi-directed interview will be used to collect qualitative data about the process and the participants' experiences of the intervention. In this way, enhanced quantitative qualitative evidence can be drawn from outcome measures as well as individual, contextualized personal views, to help inform researchers about the plausibility of this complex intervention before testing its effectiveness in a subsequent full trial. DISCUSSION: Patient dignity is a goal of quality end-of-life care. To our knowledge, this is the first trial to evaluate the role of a life review intervention that is focused on personal growth and on changes relating to the experience of having cancer. This study will evaluate the feasibility of a novel intervention, Revie ?, which we hope will contribute to promote the dignity, personal growth, and overall life satisfaction of patients with advanced cancer. TRIAL REGISTRATION: ISRCTN, ISRCTN12497093. PMID- 27965880 TI - Lifestyle change in the cancer setting using 'the teachable moment': protocol for a proof-of-concept pilot in a urology service. AB - BACKGROUND: Previous research has shown diagnosis or screening for cancer may be a 'teachable moment' for prevention through lifestyle change. Previous trials have been successful but have been delivered via national programmes targeting patients being screened for colorectal cancer. This manuscript reports the protocol for a proof-of-concept study to assess the feasibility and acceptability of a lifestyle change service targeting men suspected or diagnosed with cancer of the prostate in a secondary care cancer service within the UK. METHODS: Lifestyle change will be promoted through integration of a lifestyle change service in a urology department in one NHS Board. The service is delivered by a Health Psychologist and uses motivational interviewing and behavioural change techniques to motivate and support patients to consider and address topics such as increasing physical activity and a healthy diet, smoking cessation, alcohol reduction and weight loss. A service evaluation will assess feasibility and acceptability via a patient experience survey, a survey exploring staff knowledge, attitudes and practice, pre- and post-intervention lifestyle behaviour survey and an audit of routine patient database. DISCUSSION: This pilot will assess the viability of using cancer testing and diagnosis as a teachable moment for lifestyle change in a unique population (i.e. men with suspected cancer of the prostate). If successful, this approach offers potential for preventative services to enhance routine and person-centred clinical cancer care provided within secondary care settings. PMID- 27965881 TI - Development and feasibility testing of an intervention to support active lifestyles in youths with type 1 diabetes-the ActivPals programme: a study protocol. AB - BACKGROUND: The global incidence of type 1 diabetes is rising, and youths with type 1 diabetes continue to suffer poorer health than peers without diabetes. Evidence suggests youths with type 1 diabetes have physical activity (PA) levels well below the recommendations for health and have high levels of sedentary behaviour. An active lifestyle is therefore recommended to improve health. There is limited research showing effective lifestyle behaviour change in this population; therefore, an evidence gap exists between the need to promote physical activity in type 1 diabetes care and lack of understanding on how to do this. This protocol paper describes a feasibility and pilot study of the ActivPals programme-an intervention to support active lifestyles in youths with type 1 diabetes. METHODS/DESIGN: Key intervention components have been identified from preliminary work (individual and family focus, peer mentoring, technology integration and improved communication and understanding) and are being developed into a pragmatic randomised controlled trial (RCT) supported by recruitment pathways. A steering group of health care professionals and managers will refine the intervention to patient needs. A pilot trial is providing data on intervention implementation, acceptability and feasibility. Twenty youths with type 1 diabetes are being recruited and randomised into an intervention or control group. Physical activity is being measured objectively using the Actigraph GT3X+ monitor at baseline and 1-month follow-up. Contextual factors associated with intervention delivery are being explored. DISCUSSION: This study will contribute to the development of evidence-based, user-informed and pragmatic interventions leading to healthier lifestyles in youths with type 1 diabetes. PMID- 27965879 TI - CONSORT 2010 statement: extension to randomised pilot and feasibility trials. AB - The Consolidated Standards of Reporting Trials (CONSORT) statement is a guideline designed to improve the transparency and quality of the reporting of randomised controlled trials (RCTs). In this article we present an extension to that statement for randomised pilot and feasibility trials conducted in advance of a future definitive RCT. The checklist applies to any randomised study in which a future definitive RCT, or part of it, is conducted on a smaller scale, regardless of its design (eg, cluster, factorial, crossover) or the terms used by authors to describe the study (eg, pilot, feasibility, trial, study). The extension does not directly apply to internal pilot studies built into the design of a main trial, non-randomised pilot and feasibility studies, or phase II studies, but these studies all have some similarities to randomised pilot and feasibility studies and so many of the principles might also apply. The development of the extension was motivated by the growing number of studies described as feasibility or pilot studies and by research that has identified weaknesses in their reporting and conduct. We followed recommended good practice to develop the extension, including carrying out a Delphi survey, holding a consensus meeting and research team meetings, and piloting the checklist. The aims and objectives of pilot and feasibility randomised studies differ from those of other randomised trials. Consequently, although much of the information to be reported in these trials is similar to those in randomised controlled trials (RCTs) assessing effectiveness and efficacy, there are some key differences in the type of information and in the appropriate interpretation of standard CONSORT reporting items. We have retained some of the original CONSORT statement items, but most have been adapted, some removed, and new items added. The new items cover how participants were identified and consent obtained; if applicable, the prespecified criteria used to judge whether or how to proceed with a future definitive RCT; if relevant, other important unintended consequences; implications for progression from pilot to future definitive RCT, including any proposed amendments; and ethical approval or approval by a research review committee confirmed with a reference number. This article includes the 26 item checklist, a separate checklist for the abstract, a template for a CONSORT flowchart for these studies, and an explanation of the changes made and supporting examples. We believe that routine use of this proposed extension to the CONSORT statement will result in improvements in the reporting of pilot trials. Editor's note: In order to encourage its wide dissemination this article is freely accessible on the BMJ and Pilot and Feasibility Studies journal websites. PMID- 27965883 TI - Update to a protocol for a feasibility cluster randomised controlled trial of a peer-led school-based intervention to increase the physical activity of adolescent girls (PLAN-A). AB - BACKGROUND: Physical activity levels are low amongst adolescent girls, and this population faces specific barriers to being active. Peer influences on health behaviours are important in adolescence, and peer-led interventions might hold promise to change behaviour. This paper describes the protocol for a feasibility cluster randomised controlled trial of Peer-Led physical Activity iNtervention for Adolescent girls (PLAN-A), a peer-led intervention aimed at increasing adolescent girls' physical activity levels. In addition, this paper describes an update that has been made to the protocol for the PLAN-A feasibility cluster randomised controlled trial. METHODS/DESIGN: A two-arm cluster randomised feasibility trial will be conducted in six secondary schools (intervention n = 4; control n = 2) with year 8 (12-13 years old) girls. The intervention will operate at a year group level and consist of year 8 girls nominating influential peers within their year group to become peer supporters. Approximately 15% of the cohort will receive 3 days of training about physical activity and interpersonal communication skills. Peer supporters will then informally diffuse messages about physical activity amongst their friends for 10 weeks. Data will be collected at baseline (time 0 (T0)), immediately after the intervention (time 1 (T1)) and 12 months after baseline measures (time 2 (T2)). In this feasibility trial, the primary interest is in the recruitment of schools and participants (both year 8 girls and peer supporters), delivery and receipt of the intervention, data provision rates and identifying the cost categories for future economic analysis. Physical activity will be assessed using 7-day accelerometry, with the likely primary outcome in a fully powered trial being daily minutes of moderate-to vigorous physical activity. Participants will also complete psychosocial questionnaires at each time point: assessing motivation, self-esteem and peer physical activity norms. Data analysis will be largely descriptive and focus on recruitment, attendance and data provision rates. The findings will inform the sample size required for a definitive trial. A detailed process evaluation using qualitative and quantitative methods will be conducted with a variety of stakeholders (i.e. pupils, parents, teachers and peer-supporter trainers) to identify areas of success and necessary improvements prior to proceeding to a definitive trial. DISCUSSION: The study will provide the information necessary to design a fully powered trial should PLAN-A demonstrate evidence of promise. This paper describes an update to the protocol for the PLAN-A feasibility cluster randomised controlled trial related to the data-linkage component. TRIAL REGISTRATION: ISRCTN12543546. PMID- 27965882 TI - Trial of Optimal Personalised Care After Treatment for Gynaecological cancer (TOPCAT-G): a study protocol for a randomised feasibility trial. AB - BACKGROUND: Gynaecological cancers are diagnosed in over 1000 women in Wales every year. We estimate that this is costing the National Health Service (NHS) in excess of L1 million per annum for routine follow-up appointments alone. Follow up care is not evidence-based, and there are no definitive guidelines from The National Institute for Health and Care Excellence (NICE) for the type of follow up that should be delivered. Standard care is to provide a regular medical review of the patient in a hospital-based outpatient clinic for a minimum of 5 years. This study is to evaluate the feasibility of a proposed alternative where the patients are delivered a specialist nurse-led telephone intervention known as Optimal Personalised Care After Treatment for Gynaecological cancer (OPCAT-G), which comprised of a protocol-based patient education, patient empowerment and structured needs assessment. METHODS: The study will recruit female patients who have completed treatment for cervical, endometrial, epithelial ovarian or vulval cancer within the previous 3 months in Betsi Cadwaladr University Health Board (BCUHB) in North Wales. Following recruitment, participants will be randomised to one of two arms in the trial (standard care or OPCAT-G intervention). The primary outcomes for the trial are patient recruitment and attrition rates, and the secondary outcomes are quality of life, health status and capability, using the EORTC QLQ-C30, EQ-5D-3L and ICECAP-A measures. Additionally, a client service receipt inventory (CSRI) will be collected in order to pilot an economic evaluation. DISCUSSION: The results from this feasibility study will be used to inform a fully powered randomised controlled trial to evaluate the difference between standard care and the OPCAT-G intervention. TRIAL REGISTRATION: ISRCTN45565436. PMID- 27965884 TI - Investigating the differential impact of school and community-based integrated control programmes for soil-transmitted helminths in Timor-Leste: the (S)WASH-D for Worms pilot study protocol. AB - BACKGROUND: Water, sanitation and hygiene (WASH) interventions represent an important component of soil-transmitted helminth (STH) infection control, alongside the administration of anthelmintic drugs, which are generally targeted to school-aged children. Recent modelling studies have suggested that STH control programmes should be broadened to include all age groups across the community. We describe the protocol for a pilot study investigating the impact of school-versus community-based delivery of integrated WASH and deworming programmes on STH infections in school-aged children in Timor-Leste. METHODS: The (S)WASH-D for Worms pilot is a two-arm, non-randomised cluster intervention study. The aims are to determine feasibility and acceptability of the intervention and study procedures and to establish proof of principle for the hypothesis that STH control programmes directed to the entire community will lead to greater reductions in STH infections in children than programmes directed only to school aged children. Of the six participating communities, three receive a school-based integrated WASH and deworming programme and three additionally receive a community-based integrated WASH and deworming programme. The primary outcomes are the proportions of eligible children who enrol in the study and participate in the data collection, and outcomes relating to WASH and deworming programme completion, coverage, and use. Secondary outcomes are the cumulative incidence and mean intensity of STH infection in school-aged children at 6-month follow-up, mean haemoglobin concentration and several anthropometric indices. Results will inform the design of a cluster-randomised controlled trial (RCT). DISCUSSION: This pilot study is being conducted in preparation for a cluster-RCT investigating the differential impact of school- and community-based integrated STH control programmes on STH infections in school-aged children. It aims to establish feasibility and proof of principle, while results of the subsequent RCT could have significant implications for global STH control policy. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615001012561. PMID- 27965885 TI - Evaluation of the effectiveness of music therapy in improving the quality of life of palliative care patients: a randomised controlled pilot and feasibility study. AB - BACKGROUND: Music therapy is frequently used as a palliative therapy. In consonance with the goals of palliative care, the primary aim of music therapy is to improve people's quality of life by addressing their psychological needs and facilitating communication. To date, primarily because of a paucity of robust research, the evidence for music therapy's effectiveness on patient reported outcomes is positive but weak. This pilot and feasibility study will test procedures, outcomes and validated tools; estimate recruitment and attrition rates; and calculate the sample size required for a phase III randomised trial to evaluate the effectiveness of music therapy in improving the quality of life of palliative care patients. METHODS: A pilot randomised controlled trial supplemented with qualitative methods. The quantitative data collection will involve recruitment of >52 patients from an inpatient Marie Curie hospice setting over a 12-month period. Eligibility criteria include all patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 03- indicating they are medically fit to engage with music therapy and an Abbreviated Mental Test (AMT) score of >=7 indicating they are capable of providing meaningful informed consent and accurate responses to outcome measures. Baseline data collection will include the McGill Quality of Life Questionnaire (MQOL); medical and socio-demographic data will be undertaken before randomisation to an intervention or control group. Participants in the intervention arm will be offered two 30-45 min sessions of music therapy per week for three consecutive weeks, in addition to care as usual. Participants in the control arm will receive care as usual. Follow-up measures will be administered in 1, 3 and 5 weeks. Qualitative data collection will involve focus group and individual interviews with HCPs and carers. DISCUSSION: This study will ensure a firm methodological grounding for the development of a robust phase III randomised trial of music therapy for improving quality of life in palliative care patients. By undertaking the pilot and feasibility trial under normal clinical conditions in a hospice setting, the trial will result in reliable procedures to overcome some of the difficulties in designing music therapy RCTs for palliative care settings. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02791048. PMID- 27965886 TI - Assessing the feasibility of injectable growth-promoting therapy in Crohn's disease. AB - BACKGROUND: Despite optimal therapy, many children with Crohn's disease (CD) experience growth retardation. The objectives of the study are to assess the feasibility of a randomised control trial (RCT) of injectable forms of growth promoting therapy and to survey the attitudes of children with CD and their parents to it. METHODS: A feasibility study was carried out to determine study arms, sample size and numbers of eligible patients. A face-to-face questionnaire surveyed willingness to consent to future participation in the RCT. Eligibility to the survey was any child under 18 (with their parent/guardian) with CD whose height standard deviation score (HtSDS) was <=+1. Of 118 questionnaires, 94 (80%) were returned (48 by children and 46 by parents). RESULTS: The median age of the patients in the survey was 14.3 years (range 7.0 to 17.7), and 35 (73%) were male. Their median HtSDS was -1.2 (-3.01, 0.23), and it was lower than the median mid-parental HtSDS of -0.6 (-3.1, 1.4). We analysed the willingness of the children whose HtSDS <-1 to take part in the proposed RCT, being those most likely to require treatment. Overall, 18 (47%) children and 17 (46%) parents were willing. This increased to 61% of children who were slightly concerned about their height and 100% (4/4) of those very concerned. A common reason for not taking part in the RCT was fear of injections (44%); 111 children are required for randomisation into three study arms from nine centres. CONCLUSIONS: Almost half of children and parents surveyed would take part in an RCT of growth promoting therapy. Allaying fears about injections may result in higher recruitment rates. PMID- 27965888 TI - The curious case of an internal pilot in a multicentre randomised trial-time for a rethink? AB - Multicentre randomised trials are complex projects with many operational uncertainties. The embedding of a formal check upon study progress and viability at a pre-specified time point (sometimes referred to as an 'internal pilot') is becoming increasingly common within multicentre pragmatic randomised trials. However, it is worth considering this practice. We argue that most, if not all, multicentre trials have reassessment of the recruitment strategy and study processes whilst the study is running. Additionally, we propose discontinuation of the 'internal/external pilot study' terminology. Instead, we suggest for an alternative taxonomy along with greater recognition of the process of refinement which routinely occurs in trials and transparent reporting of it. PMID- 27965887 TI - Evaluating acupuncture and standard care for pregnant women with back pain: the EASE Back pilot randomised controlled trial (ISRCTN49955124). AB - BACKGROUND: Low back pain (LBP) and pelvic girdle pain (PGP) during pregnancy are common and often accepted as a 'normal' part of pregnancy. Many women receive little in the way of treatment, and yet pain interferes with sleep, daily activities and work and leads to increasing requests for induction of labour or elective caesarean section. The aim of this study was to assess the feasibility of a full RCT evaluating the benefit of acupuncture for pregnancy-related back pain. METHODS: This study is a single-centre, three-arm pilot RCT in one large maternity unit and associated antenatal and physiotherapy clinics. Women were eligible if they had pregnancy-related LBP with or without PGP. Exclusions included a history of miscarriage, high risk of early labour or pre-eclampsia, PGP only and previous acupuncture. Interventions were standard care (SC): a self management booklet with physiotherapy if needed. SC+TA: the booklet and physiotherapy comprising true (penetrating) acupuncture, advice and exercise. SC+NPA: the booklet and physiotherapy comprising non-penetrating acupuncture, advice and exercise. Remote telephone randomisation used a 1:1:1 allocation ratio stratified by gestational weeks. Three measures of pain/function were compared to inform the primary outcome measure in a full RCT: the Pelvic Girdle Questionnaire (PGQ), Oswestry Disability Index (ODI) and 11-point 0-10 numerical rating scale for pain. Analysis focused on process evaluation of recruitment, retention, descriptive information on outcomes, adherence to treatment, occurrence of adverse events and impact of physiotherapist training. RESULTS: One hundred twenty-five women were randomised (45% of those eligible) between April and October 2013; 73% (n = 91) provided 8-week follow-up data. Three of six recruitment methods accounted for 82% of total uptake: screening questionnaire at the 20-week scan, community midwives issuing study cards, and self-referral following local awareness initiatives. Physiotherapists' self-confidence on managing pregnancy-related LBP improved post training. The PGQ is suitable as the primary outcome in a full trial. The average number of treatment sessions in both SC+TA and SC+NPA was six (in line with treatment protocols). No serious adverse events attributable to the trial treatments were reported. CONCLUSIONS: A full RCT is feasible and would provide evidence about the effectiveness of acupuncture and inform treatment choices for women with pregnancy-related LBP. TRIAL REGISTRATION: ISRCTN49955124. PMID- 27965889 TI - Elevated Plasma Endothelin-1 Levels in Normal Tension Glaucoma and Primary Open Angle Glaucoma: A Meta-Analysis. AB - Purpose. The aim of this meta-analysis was to clarify the association between the plasma endothelin-1 level and the risks of normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG). Methods. Relevant publications were collected from three databases including PubMed, EMBASE, and the Web of Science through December 31, 2015. In this study, the terms "(endothelin OR ET) AND glaucoma" were searched. Review Manager 5.2 was used to process the data. Results. Seven studies (212 cases, 164 controls) were included for the NTG analysis. The mean plasma endothelin-1 level in the NTG subjects was 0.60 pg/mL (p = 0.02, 95% CI: 0.17-1.04) higher than that of the healthy controls. Six studies (160 cases, 174 controls) were included for the POAG analysis, and the endothelin-1 level was 0.63 pg/mL (p = 0.007, 95% CI: 0.12-1.15) higher in the POAG subjects than in the healthy controls. Additionally, two studies influenced the meta-analysis results regarding the association of plasma endothelin-1 with POAG by sensitivity analysis, and the probability of publication bias was low. Conclusions. The observation that NTG and POAG subjects showed significantly elevated endothelin-1 plasma concentrations suggests that a higher plasma level of endothelin-1 might increase the risk of NTG and POAG development. PMID- 27965890 TI - Effects of V4c-ICL Implantation on Myopic Patients' Vision-Related Daily Activities. AB - The new type implantable Collamer lens with a central hole (V4c-ICL) is widely used to treat myopia. However, halos occur in some patients after surgery. The aim is to evaluate the effect of V4c-ICL implantation on vision-related daily activities. This retrospective study included 42 patients. Uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), intraocular pressure (IOP), endothelial cell density (ECD), and vault were recorded and vision-related daily activities were evaluated at 3 months after operation. The average spherical equivalent was -0.12 +/- 0.33 D at 3 months after operation. UCVA equal to or better than preoperative BCVA occurred in 98% of eyes. The average BCVA at 3 months after operation was -0.03 +/- 0.07 LogMAR, which was significantly better than preoperative BCVA (0.08 +/- 0.10 LogMAR) (P = 0.029). Apart from one patient (2.4%) who had difficulty reading computer screens, all patients had satisfactory or very satisfactory results. During the early postoperation, halos occurred in 23 patients (54.8%). However there were no significant differences in the scores of visual functions between patients with and without halos (P > 0.05). Patients were very satisfied with their vision-related daily activities at 3 months after operation. The central hole of V4c-ICL does not affect patients' vision-related daily activities. PMID- 27965891 TI - The Outcome of Endoscopic Transethmosphenoid Optic Canal Decompression for Indirect Traumatic Optic Neuropathy with No-Light-Perception. AB - Purpose. To present the safety and effect of endoscopic transethmosphenoid optic canal decompression (ETOCD) for indirect traumatic optic neuropathy (ITON) patients with no-light-perception (NLP). Methods. A retrospective study performed on 96 patients (96 eyes) with NLP after ITON between June 1, 2010, and June 1, 2015, who underwent ETOCD, was reviewed. Visual outcome before and after treatment was taken into comparison. Results. The overall visual acuity improvement rate after surgery was 46.9%. The improvement rates of visual acuity of patients who received treatment within 3 days of injury, 3-7 days after injury, and later than 7 days were 63.6%, 42.9%, and 35.7%, respectively. Statistically significant difference was detected between the effective rates of within-3-day group and later-than-7-day group (chi2 = 5.772, P = 0.016). The effective rate of atrophy group and nonatrophy group was 25.0% and 51.3%, respectively. The effective rate was significantly higher in nonatrophy group (chi2 = 4.417, P = 0.036). Conclusion. For patients suffering from ITON with NLP, time to medical treatment within 3 days is an influential factor for visual prognosis. Optic nerve atrophy is an important predictor for visual prognosis. Treatment should still be recommended even for cases of delayed presentation to hospital. PMID- 27965892 TI - Risk Factors and Symptoms of Meibomian Gland Loss in a Healthy Population. AB - Purpose. The aim of this study was to investigate the relationships between MGL and ocular symptoms, several systemic conditions, and key markers of ocular surface health. Methods. We included into the study 91 healthy volunteers between the ages of 20 and 77 years. We analyzed meibomian gland morphology, function, and lid margin alterations. We correlated our findings with self-reported ocular symptoms, systemic medical history, lifestyle factors, and tear film abnormalities. Results. We observed that a high ocular surface disease index, a history of either chalazion or hordeolum, experience of puffy eyelids upon waking, and foreign body sensation all appeared to be predictors of an abnormal meiboscore after adjusting for age and sex (p = 0.0007; p = 0.001; p = 0.02; p = 0.001, resp.). Multivariate logistic regression model including age and sex showed that there were three independent predictors of abnormal meiboscore: older age (OR = 1.03, 95% CI = 1.01-1.04 per year, p = 0.006), postmenopausal hormone therapy (OR = 4.98, 95% CI = 1.52-16.30, p = 0.007), and the use of antiallergy drugs (OR = 5.85, 95% CI = 2.18-15.72, p = 0.0004). Conclusion. Our findings extend current knowledge on the pathophysiology of MGL. PMID- 27965893 TI - The Hypertension of Hemophilia Is Not Explained by the Usual Cardiovascular Risk Factors: Results of a Cohort Study. AB - Background. The etiology of the high prevalence of hypertension among patients with hemophilia (PWH) remains unknown. Methods. We compared 469 PWH in the United States with males from the National Health and Nutrition Examination Survey (NHANES) to determine whether differences in cardiovascular risk factors can account for the hypertension in hemophilia. Results. Median systolic and diastolic BP were higher in PWH than NHANES (P < 0.001) for subjects not taking antihypertensives. Those taking antihypertensives showed similar differences. Differences in both systolic and diastolic BP were especially marked among adults <30 years old. Differences between PWH and NHANES persisted after adjusting for age and risk factors (body mass index, renal function, cholesterol, smoking, diabetes, Hepatitis C, and race). Conclusions. Systolic and diastolic BP are higher in PWH than in the general male population and especially among PWH < 30 years old. The usual cardiovascular risk factors do not account for the etiology of the higher prevalence of hypertension in hemophilia. New investigations into the missing link between hemophilia and hypertension should include age of onset of hypertension and hemophilia-specific morbidities such as the role of inflammatory joint disease. PMID- 27965894 TI - Bariatric Surgery, Polycystic Ovary Syndrome, and Infertility. AB - Background. Polycystic ovary syndrome (PCOS) is the commonest cause of female infertility. Visceral obesity and insulin resistance are key pathophysiological mechanisms behind PCOS. Women suffering from this syndrome and infertility often seek bariatric surgery hoping that they would be able to conceive postoperatively. Objective. At present, there is no consensus on the role of bariatric surgery in the management of PCOS-associated infertility within the medical community, making it difficult to give specific advice to these women, so a review of the literature was necessary. Results. A detailed review of the literature was performed. Only 6 manuscripts were relevant and contained quantitative data. They demonstrated that bariatric surgery results in postoperative conception rates varying from 33% to 100%. Surgery is also associated with amelioration of menstrual irregularities, hormonal abnormalities, and hirsutism that are associated with PCOS. These studies were retrospective and only had a small number of participants with infertility. Conclusions. Bariatric surgery has been shown to conclusively improve life expectancy, quality of life, and comorbidities like type 2 diabetes and obstructive sleep apnea. However, further research is required to identify whether weight loss surgery results in significant improvement in fertility of women with PCOS and to investigate which operation has the best results. PMID- 27965896 TI - Comment on "Gender-Based Differences and Barriers in Skin Protection Behaviors in Melanoma Survivors". PMID- 27965895 TI - Role of B Cell Development Marker CD10 in Cancer Progression and Prognosis. AB - The human CD10 antigen is a single pass, type II transmembrane, 100 kD cell surface glycoprotein belonging to peptidase M13 family. Identified in common acute lymphoblastic leukemia as a cancer specific antigen, CD10 is a cell surface ectoenzyme widely expressed on different types of cells. Earlier, it was used only as a cell surface marker to identify and differentiate between haematological malignancies. Later, reported to be present in various malignancies, it is thought to play significant role in cancer development and progression. Regulated expression of CD10 is necessary for angiogenesis and so forth. However its expression level is found to be deregulated in different cancers. In some cancers, it acts as tumor suppressor and inhibits tumor progression whereas in others it has tumor promoting tendency. However, its role in tumorigenesis remains unclear. This review summarises structural features, functions, and probable role of CD10 in cancer development. PMID- 27965897 TI - Targeted Delivery of Glucan Particle Encapsulated Gallium Nanoparticles Inhibits HIV Growth in Human Macrophages. AB - Glucan particles (GPs) are hollow, porous 3-5 MUm microspheres derived from the cell walls of Baker's yeast (Saccharomyces cerevisiae). The 1,3-beta-glucan outer shell provides for receptor-mediated uptake by phagocytic cells expressing beta glucan receptors. GPs have been used for macrophage-targeted delivery of a wide range of payloads (DNA, siRNA, protein, small molecules, and nanoparticles) encapsulated inside the hollow GPs or bound to the surface of chemically derivatized GPs. Gallium nanoparticles have been proposed as an inhibitory agent against HIV infection. Here, macrophage targeting of gallium using GPs provides for more efficient delivery of gallium and inhibition of HIV infection in macrophages compared to free gallium nanoparticles. PMID- 27965898 TI - NLRP3 Is Expressed in the Spiral Ganglion Neurons and Associated with Both Syndromic and Nonsyndromic Sensorineural Deafness. AB - Nonsyndromic deafness is genetically heterogeneous but phenotypically similar among many cases. Though a variety of targeted next-generation sequencing (NGS) panels has been recently developed to facilitate genetic screening of nonsyndromic deafness, some syndromic deafness genes outside the panels may lead to clinical phenotypes similar to nonsyndromic deafness. In this study, we performed comprehensive genetic screening in a dominant family in which the proband was initially diagnosed with nonsyndromic deafness. No pathogenic mutation was identified by targeted NGS in 72 nonsyndromic and another 72 syndromic deafness genes. Whole exome sequencing, however, identified a p.E313K mutation in NLRP3, a gene reported to cause syndromic deafness Muckle-Wells Syndrome (MWS) but not included in any targeted NGS panels for deafness in previous reports. Follow-up clinical evaluation revealed only minor inflammatory symptoms in addition to deafness in six of the nine affected members, while the rest, three affected members, including the proband had no obvious MWS-related inflammatory symptoms. Immunostaining of the mouse cochlea showed a strong expression of NLRP3 in the spiral ganglion neurons. Our results suggested that NLRP3 may have specific function in the spiral ganglion neurons and can be associated with both syndromic and nonsyndromic sensorineural deafness. PMID- 27965900 TI - Treatment of a Developmental Groove and Supernumerary Root Using Guided Tissue Regeneration Technique. AB - Introduction. The radicular groove is a developmental groove which is usually found on the palatal or lateral aspects of the maxillary incisor teeth. The present case is a maxillary lateral incisor with a small second root and a deep radicular groove. The developmental groove caused a combined periodontal endodontic lesion. Methods. Case was managed using a combined treatment procedure involving nonsurgical root canal therapy and surgical periodontal treatment. After completion of root canal treatment, guided tissue regeneration (GTR) was carried out using decalcified freeze dried bone allograft (DFDBA) and a bioabsorbable collagenous membrane. Tooth also was splinted for two months. Results. After 12 months the tooth was asymptomatic. The periapical radiolucency disappeared and probing depth did not exceed 3 mm. Conclusion. Combined treatment procedure involving nonsurgical root canal therapy and surgical periodontal regenerative treatment can be a predictable technique in treating combined endodontic-periodontal lesions caused by radicular groove. PMID- 27965899 TI - The Role of the Cognitive Control System in Recovery from Bilingual Aphasia: A Multiple Single-Case fMRI Study. AB - Aphasia in bilingual patients is a therapeutic challenge since both languages can be impacted by the same lesion. Language control has been suggested to play an important role in the recovery of first (L1) and second (L2) language in bilingual aphasia following stroke. To test this hypothesis, we collected behavioral measures of language production (general aphasia evaluation and picture naming) in each language and language control (linguistic and nonlinguistic switching tasks), as well as fMRI during a naming task at one and four months following stroke in five bilingual patients suffering from poststroke aphasia. We further applied dynamic causal modelling (DCM) analyses to the connections between language and control brain areas. Three patients showed parallel recovery in language production, one patient improved in L1, and one improved in L2 only. Language-control functions improved in two patients. Consistent with the dynamic view of language recovery, DCM analyses showed a higher connectedness between language and control areas in the language with the better recovery. Moreover, similar degrees of connectedness between language and control areas were found in the patients who recovered in both languages. Our data suggest that engagement of the interconnected language-control network is crucial in the recovery of languages. PMID- 27965901 TI - Autogenous Tooth Fragment Adhesive Reattachment for a Complicated Crown Root Fracture: Two Interdisciplinary Case Reports. AB - Trauma of anterior teeth is quite a common occurrence in both children and adults. Various degrees of trauma leading to fracture may affect teeth in different ways depending on the age of the patient and extent of fracture and other factors that will be discussed. Guidelines have been given as to how each of these situations should be treated. In the past, often more aggressive restorations were performed to restore fractured teeth. However improved and more efficient adhesion may affect the type of treatment we decide to carry out, leading to more conservative therapies through an increased preservation of tooth structures. PMID- 27965902 TI - Tuberculosis and Migration: A Challenge for Medical Staff and Public Health. AB - A high number of asylum seekers enter Switzerland every year. They often originate from countries with a high TB prevalence. Our patient from Somalia presented with 2 lipoma-like tumors with pain on palpation on his left chest wall but no symptoms including coughing, fever, night-sweats, or loss of weight. CT scan then showed diffuse infiltrations of his lung and multiple abscesses on his left chest wall. Therefore contagious tuberculosis (TB) was suspected and the patient was put in isolation. In the follow-up the diagnosis of open TB was proofed with bronchial secretion and EBUS-guided biopsy that showed acid-fast rods. This particular case shows how difficult the identification of patients with open TB can be, especially if there are no respiratory or systemic symptoms. Therefore awareness of possible infectious disease is paramount for ED Doctors treating patients from countries with high prevalence. Early and strict isolation measures can help to reduce risk of contagion among staff and patients. PMID- 27965903 TI - Atypical Aortoesophageal Fistula with Atypical and Delayed Presentation and Negative Imaging Studies. AB - A 59-year-old man with past medical history of thoracic aortic aneurysm treated with thoracic endovascular aortic repair presented with melena for 2 weeks. Initial EGD did not reveal the source of bleeding and showed normal esophagus; abdominal arteriogram did not reveal a fistulous communication and initial CTA showed normal position of the aortic graft stent without endoleak. The sixth EGD revealed a submucosal tumor-like projection in the upper esophagus and stigmata of recent bleeding. Another thoracic endovascular aortic repair with stent was placed over the old graft for presumed aortoesophageal fistula. Poststent upper gastrointestinal series with contrast showed extravasation of the contrast from the esophagus and CTA showed fistulous tract between aorta and esophagus. The patient refused definitive surgical repair despite having infected aortic graft; jejunostomy tube was placed and life-long suppressive antibiotic treatment was given and the patient is doing well at 2-year follow-up. PMID- 27965904 TI - Rituximab-Associated Inflammatory Progressive Multifocal Leukoencephalopathy. AB - Progressive multifocal leukoencephalopathy (PML) is a rare disease of the immunosuppression that results from neurotropic invasion of the JC virus which leads to demyelination of oligodendrocytes. Immune reconstitution inflammatory syndrome (IRIS), on the other hand, is a condition of inflammation that develops as the immune system reconstitutes. This case report describes a case of a 35 year-old HIV-negative male who presented with three weeks of right lower extremity paresthesias as well as right upper extremity apraxia. He was diagnosed with PML complicated by IRIS secondary to Rituximab, which he had completed four months prior to presentation. Despite the condition's poor prognosis, the patient recovered with only minor deficits. PMID- 27965907 TI - A Rare Tumor in the Cervical Sympathetic Trunk: Ganglioneuroblastoma. AB - Ganglioneuroblastoma is a rare tumor with moderate malignancy, which is composed of mature ganglion cells and seen in sympathetic ganglia and adrenal medulla. The diagnosis is possible after cytological and immunohistochemical studies following a needle biopsy or surgical excision. There is no consensus regarding the need for chemo- or radiotherapy after surgery. In this case report, clinical behavior and diagnosis and treatment of the rare tumor cervical ganglioneuroblastoma were discussed. PMID- 27965906 TI - Could Elastography Be Used in the Prediction of Morbidly Adherent Placentation? AB - Morbidly adherent placentation (MAP) is a condition in which the placenta is abnormally attached to the uterine myometrium. MAP is a complication of pregnancy that can cause significant morbidity to the mother and fetus and therefore early diagnosis is crucial in its management and prevention of adverse outcomes. Ultrasonography remains the primary diagnostic tool for MAP, with magnetic resonance imaging (MRI) serving as a secondary diagnostic modality. Elastography is a relatively new concept in ultrasound based imaging, which has found application in several fields of medicine, including obstetrics, primarily for evaluation of the firmness of cervical tissue in a preterm labour setting. We report a case on a patient who was diagnosed with placenta increta on ultrasound, aided by elastography and her subsequent management with an en bloc hysterectomy. PMID- 27965905 TI - Stroke as the Sole Manifestation of Takayasu Arteritis in a 15-Year-Old Boy with Latent Tuberculosis. AB - Introduction. Takayasu arteritis is a rare disease affecting the aorta and its main branches, causing arterial claudication and end-organ ischemia, including stroke. The etiology is unknown but is believed to be autoimmune. An association between Takayasu arteritis and tuberculosis has been suggested, but the possible relation is unclear. Case Presentation. A 15-year-old Somali boy was diagnosed with latent tuberculosis. He had a lesion in the right lung, and both the tuberculin skin test by the Mantoux method and Quantiferon GOLD test turned out positive. After he suffered a cerebral infarct in the right hemisphere, childhood Takayasu arteritis was diagnosed. The diagnosis was based on diagnostic imaging showing a high-grade stenosis of the origin of the right common carotid artery, an occluded common carotid artery on the left side, a circumferential thickening of the vessel walls in the right and left common carotid artery, and laboratory findings with elevated C-reactive protein. Conclusion. Takayasu arteritis is an uncommon cause of stroke. It should however be kept in mind as a cause of cerebrovascular disease, especially in the young. PMID- 27965908 TI - A Previously Undescribed Presentation of Mixed Adenoneuroendocrine Carcinoma. AB - We report a case of mixed adenoneuroendocrine carcinoma (MANEC) of stomach with tubular adenoma and well-differentiated neuroendocrine tumor (WD-NET) in the primary tumor in the stomach giving rise to biphenotypic regional nodal metastases. A 35-year-old woman with abdominal pain was found to have a 1.8-cm gastric lesion, diagnosed as WD-NET (intermediate grade) on the biopsy. The resection specimen contained residual WD-NET; there was also a gastric adenoma adjacent to the NET and nodal metastasis with both adeno- and neuroendocrine components. The tumor was classified as MANEC. Of note, the entire gastric tissue was submitted and multiple deeper levels of the adenomatous lesion were examined; no adenocarcinoma was present in the primary lesion. While association of gastric adenoma with neuroendocrine neoplasm is rare, presence of biphenotypic metastasis originating from such a lesion is highly unusual and to the best of our knowledge has not been reported. PMID- 27965909 TI - Hemorrhagic Lacrimation and Epistaxis in Acute Hemorrhagic Edema of Infancy. AB - Acute hemorrhagic edema of infancy is an uncommon benign cutaneous vasculitis. Despite its worrisome presentation, it carries good prognosis with rarely reported systemic involvement. Management of these cases has been an area of debate with majority of physicians adopting conservative modalities. We report a case that presented with classic triad of rash, low grade fever, and peripheral edema along with two rarely reported manifestations in literature: hemorrhagic lacrimation and epistaxis. PMID- 27965910 TI - Teppanyaki/Hibachi Pneumonitis: An Exotic Cause of Exogenous Lipoid Pneumonia. AB - Exogenous lipoid pneumonia (ELP) is a rare type of inflammatory lung disease caused by aspiration and/or inhalation of fatty substances and characterized by a chronic foreign body-type reaction to intra-alveolar lipid deposits. The usual clinical presentation occurs with insidious onset of nonspecific respiratory symptoms and radiographic findings that can mimic other pulmonary diseases. Diagnosis of ELP is often missed or delayed as it requires a high index of suspicion and familiarity with the constellation of appropriate history and radiologic and pathologic features. We herein report a case of occupational exposure to tabletop "Teppanyaki" entertainment cooking as a cause of ELP, confirmed by surgical lung biopsies in a 63-year-old Asian woman who worked as a Hibachi-Teppanyaki chef for 25 years. PMID- 27965911 TI - Occipital Hypometabolism on FDG PET/CT Scan in a Child with Hodgkin's Lymphoma. AB - It is known that Fluorodeoxyglucose (FDG) Positron Emission/Computed Tomography (PET/CT) images may be helpful for evaluation of brain function in newborns. Here we described the fluorine-18 [18-F] FDG PET/CT imaging findings of encephalomalacia due to perinatal asphyxia in a child with refractory Hodgkin's Lymphoma (HL) who underwent PET/CT scan to stage the primary disease. Prominent hypometabolism was incidentally detected in the occipital regions bilaterally apart from the FDG uptakes in the malign lymphatic infiltrations. This case highlights the potential coexistence of a malignancy and a functional brain disorder. PMID- 27965912 TI - Impact of Lifestyle Intervention on HDL-Induced eNOS Activation and Cholesterol Efflux Capacity in Obese Adolescent. AB - Background. Endothelial dysfunction occurs in obese children and adolescent and is regarded as a key step in the development of atherosclerosis. Important components for the development of endothelial dysfunction are reduced activity of endothelial nitric oxide synthase (eNOS) and an increase in cholesterol deposition in the vessel wall, due to reduced reverse cholesterol transport (RCT) activity. High density lipoprotein (HDL) exhibits antiatherosclerotic properties including modulation of eNOS activity and cholesterol efflux capacity. Lifestyle intervention programs can modify endothelial dysfunction in obese adolescents, but their impact on HDL-mediated eNOS activation and RCT is unknown so far. Methods. Obese adolescents (15 +/- 1 years, BMI > 35 kg/m2) where randomized either to an intervention group (IG, n = 8; restricted diet and exercise) or to a usual care group (UC, n = 8). At the beginning and after 10 months of treatment HDL-mediated eNOS phosphorylation and cholesterol efflux capacity were evaluated. Results. Ten months of treatment resulted in a substantial weight loss (-31%), an improvement of endothelial function, and an increase in HDL-mediated eNOS-Ser1177 phosphorylation and RCT. A correlation between change in eNOS-Ser1177 phosphorylation or RCT and change in endothelial function was noted. Conclusion. A structured lifestyle intervention program improves antiatherosclerotic HDL functions, thereby positively influencing endothelial function. PMID- 27965913 TI - Blood Plasma of Patients with Parkinson's Disease Increases Alpha-Synuclein Aggregation and Neurotoxicity. AB - A pathological hallmark of Parkinson's disease (PD) is formation of Lewy bodies in neurons of the brain. This has been attributed to the spread of alpha synuclein (alpha-syn) aggregates, which involves release of alpha-syn from a neuron and its reuptake by a neighboring neuron. We found that treatment with plasma from PD patients induced more alpha-syn phosphorylation and oligomerization than plasma from normal subjects (NS). Compared with NS plasma, PD plasma added to primary neuron cultures caused more cell death in the presence of extracellular alpha-syn. This was supported by the observations that phosphorylated alpha-syn oligomers entered neurons, rapidly increased accumulated thioflavin S-positive inclusions, and induced a series of metabolic changes that included activation of polo-like kinase 2, inhibition of glucocerebrosidase and protein phosphatase 2A, and reduction of ceramide levels, all of which have been shown to promote alpha-syn phosphorylation and aggregation. We also analyzed neurotoxicity of alpha-syn oligomers relative to plasma from different patients. Neurotoxicity was not related to age or gender of the patients. However, neurotoxicity was positively correlated with H&Y staging score. The modification in the plasma may promote spreading of alpha-syn aggregates via an alternative pathway and accelerate progression of PD. PMID- 27965914 TI - Computational Model-Based Analysis of Strategies to Enhance Scaffold Vascularization. AB - Stable and extensive blood vessel networks are required for cell function and survival in engineered tissues. A number of different strategies are currently being investigated to enhance biomaterial vascularization with screening primarily through extensive in vitro and in vivo experiments. In this article, we describe an agent-based model (ABM) developed to evaluate various strategies in silico, including design of optimal biomaterial structure, delivery of angiogenic factors, and application of prevascularized biomaterials. The model predictions are evaluated using experimental data. The ABM developed provides insight into different strategies currently applied for scaffold vascularization and will enable researchers to rapidly screen new hypotheses and explore alternative strategies for enhancing vascularization. PMID- 27965915 TI - Mixed Fibronectin-Derived Peptides Conjugated to a Chitosan Matrix Effectively Promotes Biological Activities through Integrins, alpha4beta1, alpha5beta1, alphavbeta3, and Syndecan. AB - Mimicking the biological function of the extracellular matrix is an approach to developing cell adhesive biomaterials. The RGD peptide, derived from fibronectin (Fn), mainly binds to integrin alphavbeta3 and has been widely used as a cell adhesive peptide on various biomaterials. However, cell adhesion to Fn is thought to be mediated by several integrin subtypes and syndecans. In this study, we synthesized an RGD-containing peptide (FIB1) and four integrin alpha4beta1 binding-related motif-containing peptides (LDV, IDAPS, KLDAPT, and PRARI) and constructed peptide-chitosan matrices. The FIB1-chitosan matrix promoted human dermal fibroblast (HDF) attachment, and the C-terminal elongated PRARI (ePRARI-C) conjugated chitosan matrix significantly promoted HDF attachment through integrin alpha4beta1 and syndecan binding. Next, we constructed a mixed ePRARI-C- and FIB1 chitosan matrix to develop a Fn mimetic biomaterial. The mixed ePRARI-C/FIB1 chitosan matrix promoted significantly better cell attachment and neurite outgrowth compared to those of either ePRARI-C- or FIB1-chitosan matrices. HDF adhesion to the ePRARI-C/FIB1-chitosan matrix was mediated by integrin, alpha4beta1, alpha5beta1, and alphavbeta3, similar to HDF adhesion to Fn. These data suggest that an ePRARI-C/FIB1-chitosan matrix can be used as a tool to analyze the multiple functions of Fn and can serve as a Fn-mimetic biomaterial. PMID- 27965917 TI - The Value and Limitations of Guidelines, Expert Consensus, and Registries on the Management of Patients with Thoracic Aortic Disease. AB - Doctors are often faced with difficult decisions and uncertainty when patients need a certain treatment. They routinely rely on the scientific literature, in addition to their knowledge, experience, and patient preferences. Clinical practice guidelines are created with the intention of facilitating decision making. They may offer concise instructions for the diagnosis, management (medical or surgical treatments), and prevention of specific diseases or conditions. All information included in the final version are the result of a systematic review of scientific articles and an assessment of the benefits and costs of alternative care options. The final document attempts to meet the needs of most patients in most circumstances and clinicians, aware of these recommendations, should always make individualized treatment decisions. In this review, we attempted to define the intent and applicability of clinical practice guidelines, expert consensus documents, and registry studies, focusing on the management of patients with thoracic aortic disease. PMID- 27965916 TI - In Vivo Flow Cytometry of Circulating Tumor-Associated Exosomes. AB - Circulating tumor cells (CTCs) demonstrated the potential as prognostic markers of metastatic development. However, the incurable metastasis can already be developed at the time of initial diagnosis with the existing CTC assays. Alternatively, tumor-associated particles (CTPs) including exosomes can be a more valuable prognostic marker because they can be released from the primary tumor long before CTCs and in larger amount. However, little progress has been made in high sensitivity detection of CTPs, especially in vivo. We show here that in vivo integrated photoacoustic (PA) and fluorescence flow cytometry (PAFFC) platform can provide the detection of melanoma and breast-cancer-associated single CTPs with endogenously expressed melanin and genetically engineered proteins or exogenous dyes as PA and fluorescent contrast agents. The two-beam, time-of-light PAFFC can measure the sizes of CTCs and CTPs and identify bulk and rolling CTCs and CTC clusters, with no influence on blood flow instability. This technique revealed a higher concentration of CTPs than CTCs at an early cancer stage. Because a single tumor cell can release many CTPs and in vivo PAFFC can examine the whole blood volume, PAFFC diagnostic platform has the potential to dramatically improve (up to 105-fold) the sensitivity of cancer diagnosis. PMID- 27965918 TI - Minimally Invasive Cardiac Surgery versus Conventional Median Sternotomy for Atrial Septal Defect Closure. AB - BACKGROUND: Median sternotomy is the standard approach for atrial septal defect (ASD) closure. However, minimally invasive cardiac surgery (MICS) has been introduced at many centers in adult/grown-up congenital heart patients. We retrospectively reviewed the results of right anterolateral thoracotomy compared with conventional median sternotomy (CMS) for ASD closure at Seoul National University Hospital. METHODS: We retrospectively analyzed 60 adult patients who underwent isolated ASD closure from January 2004 to December 2013 (42 in the CMS group, 18 in the MICS group). Preoperative, operative, and postoperative data were collected and compared between the 2 groups. RESULTS: The MICS group was younger (44.6 years vs. 32.4 years, p=0.002) and included more females (66.7% vs. 94.4%, p=0.025) than the CMS group. Operation time (188.4 minutes vs. 286.7 minutes, p<0.001), cardiopulmonary bypass time (72.7 minutes vs. 125.8 minutes, p<0.001), and aortic cross-clamp time (25.5 minutes vs. 45.6 minutes, p<0.001) were significantly longer in the MICS group. However, there were no significant differences in morbidity and mortality between groups. Only chest tube drainage in the first 24 hours (627.1 mL vs. 306.1 mL, p<0.001) exhibited a significant difference. CONCLUSION: MICS via right anterolateral thoracotomy is an alternative choice for ASD closure. The results demonstrated similar morbidity and mortality between groups, and favored MICS in chest tube drainage in the first 24 hours. PMID- 27965919 TI - Results of Protocol-based Perioperative Management in Off-Pump Coronary Artery Bypass Grafting for Patients with Non-dialysis-dependent Chronic Kidney Disease. AB - BACKGROUND: Recent studies have demonstrated the benefits of off-pump coronary bypass grafting over the on-pump technique in patients with chronic kidney disease (CKD). To further reduce the risk of acute kidney injury and the need for renal replacement therapy, even in patients undergoing off-pump coronary artery bypass grafting, we adopted protocol-based perioperative management for patients with CKD. METHODS: From December 2012 to March 2015, 265 patients underwent isolated off-pump coronary artery bypass grafting. To analyze renal function in a stable condition, we excluded 12 dialysis-dependent end stage renal failure and 10 emergency or urgent cases. Among the remaining 243 patients, 208 patients had normal kidney function (normal group), and 35 patients had CKD (CKD group). Minimizing contrast exposure, ensuring adequate hydration, using strict drug dosage adjustment, and optimizing hemodynamic status were key elements of the protocol for the CKD group. RESULTS: The risk of acute kidney injury was about *3 higher in the CKD group than in the normal group (p=0.01). Estimated glomerular filtration rates and serum creatinine levels deteriorated until the third postoperative day in the CKD group. However, by adopting protocol-based perioperative management, this transient renal dysfunction recovered to preoperative levels by the fifth postoperative day without requiring renal replacement therapy in all cases. CONCLUSION: Off-pump coronary bypass surgery combined with this protocol-based perioperative management strategy in patients with non-dialysis-dependent CKD could mostly be performed without renal replacement therapy. PMID- 27965920 TI - Blunt Traumatic Cardiac Rupture: Single-Institution Experiences over 14 Years. AB - BACKGROUND: Blunt traumatic cardiac rupture is rare. However, such cardiac ruptures carry a high mortality rate. This study reviews our experience treating blunt traumatic cardiac rupture. METHODS: This retrospective study included 21 patients who experienced blunt traumatic cardiac rupture from 1999 to 2015. Every patient underwent surgery. Several variables were compared between survivors and fatalities. RESULTS: Sixteen of the 21 patients survived, and 5 (24%) died. No instances of intraoperative mortality occurred. The most common cause of injury was a traffic accident (81%). The right atrium was the most common location of injury (43%). Ten of the 21 patients were suspected to have cardiac tamponade. Significant differences were found in preoperative creatine kinase-myocardial band (CK-MB) levels (p=0.042) and platelet counts (p= 0.004) between the survivors and fatalities. The patients who died had higher preoperative Glasgow Coma Scale scores (p=0.007), worse Trauma and Injury Severity Scores (p=0.007), and higher Injury Severity Scores (p=0.004) than those who survived. CONCLUSION: We found that elevated CK-MB levels, a low platelet count, and multi-organ traumatic injury were prognostic factors predicting poor outcomes of blunt cardiac rupture. If a patient with blunt traumatic cardiac rupture has these factors, clinicians should be especially attentive and respond promptly in order to save the patient's life. PMID- 27965922 TI - Pulmonary Metastasectomy in Adult Patients with Synovial Sarcoma: A Single-Center Experience. AB - BACKGROUND: This study assessed the efficacy of pulmonary metastasectomy for synovial sarcoma in adult patients. METHODS: Fifty patients, diagnosed with pulmonary metastasis from June 1990 to August 2010, were reviewed retrospectively. Twenty-eight patients underwent complete pulmonary metastasectomy, and their survival was evaluated. Age, sex, time to metastatic progression, laterality, number of tumors, size of largest nodule, and number of metastasectomies were analyzed as potential prognostic factors. RESULTS: In all, 29 patients underwent at least one pulmonary metastasectomy, and 51 resections were performed. One intraoperative mortality occurred, and the 5-year survival rate was 58.4%. Bilateral metastases and early metastatic progression were associated with poor survival in multivariate analyses. CONCLUSION: Surgical resection can be a good option for treating pulmonary metastasis in patients with synovial sarcoma. Repeated resection was feasible with low mortality and morbidity. PMID- 27965921 TI - Clinical Implication of Aortic Wall Biopsy in Aortic Valve Disease with Bicuspid Valve Pathology. AB - BACKGROUND: Although unique aortic pathology related to bicuspid aortic valve (BAV) has been previously reported, clinical implications of BAV to aortopathy risk have yet to be investigated. We looked for potential differences in matrix protein expressions in the aortic wall in BAV patients. METHODS: Aorta specimens were obtained from 31 patients: BAV group (n=27), tricuspid aortic valve (TAV) group (n=4). The BAV group was categorized into three subgroups: left coronary sinus-right coronary sinus (R+L group; n=13, 42%), right coronary sinus-non coronary sinus (R+N group; n=8, 26%), and anteroposterior (AP group; n=6, 19%). We analyzed the expression of endothelial nitric oxide synthase (eNOS), matrix metalloproteinase (MMP)-9, and tissue inhibitor of matrix metalloproteinase (TIMP)-2. RESULTS: Based on the mean value of the control group, BAV group showed decreased expression of eNOS in 72.7% of patients, increased MMP-9 in 82.3%, and decreased TIMP in 79.2%. There was a higher tendency for aortopathy in the BAV group: eNOS (BAV:TAV)= 53%+/-7%:57%+/-11%, MMP-9 (BAV:TAV)=48%+/-10%:38%+/-1%. The AP group showed lower expression of eNOS than the fusion (R+L, R+N) group did; 48%+/-5% vs. 55%+/-7% (p=0.081). CONCLUSION: Not all patients with BAV had expression of aortopathy; however, for patients who had a suspicious form of bicuspid valve, aortic wall biopsy could be valuable to signify the presence of aortopathy. PMID- 27965923 TI - Surgical Outcomes of Pneumatic Compression Using Carbon Dioxide Gas in Thoracoscopic Diaphragmatic Plication. AB - BACKGROUND: Surgical correction needs to be considered when diaphragm eventration leads to impaired ventilation and respiratory muscle fatigue. Plication to sufficiently tense the diaphragm by VATS is not as easy to achieve as plication by open surgery. We used pneumatic compression with carbon dioxide (CO2) gas in thoracoscopic diaphragmatic plication and evaluated feasibility and efficacy. METHODS: Eleven patients underwent thoracoscopic diaphragmatic plication between January 2008 and December 2013 in Pusan National University Hospital. Medical records were retrospectively reviewed, and compared between the group using CO2 gas and group without using CO2 gas, for operative time, plication technique, duration of hospital stay, postoperative chest tube drainage, pulmonary spirometry, dyspnea score pre- and postoperation, and postoperative recurrence. RESULTS: The improvement of forced expiratory volume at 1 second in the group using CO2 gas and the group not using CO2 gas was 22.46+/-11.27 and 21.08+/-5.39 (p=0.84). The improvement of forced vital capacity 3 months after surgery was 16.74+/-10.18 (with CO2) and 15.6+/-0.89 (without CO2) (p=0.03). During follow-up (17+/-17 months), there was no dehiscence in plication site and relapse. No complications or hospital mortalities occurred. CONCLUSION: Thoracoscopic plication under single lung ventilation using CO2 insufflation could be an effective, safe option to flatten the diaphragm. PMID- 27965924 TI - Combined Bilateral Lung Transplantation and Off-Pump Coronary Artery Bypass. AB - Coronary artery disease has historically been a contraindication to lung transplantation. We report a successful combined bilateral lung transplantation and off-pump coronary artery bypass in a 62-year-old man. The patient had a progressive decline in lung function due to idiopathic pulmonary fibrosis and a history of severe occlusive coronary artery disease. PMID- 27965925 TI - Non-Anastomotic Rupture of a Woven Dacron Graft in the Descending Thoracic Aorta Treated with Endovascular Stent Grafting. AB - The intrinsic structural failure of a Dacron graft resulting from the loss of structural integrity of the graft fabric can cause late graft complications. Late non-anastomotic rupture has traditionally been treated surgically via open thoracotomy. We report a case of the successful use of thoracic endovascular repair to treat a Dacron graft rupture in the descending aorta. The rupture occurred 20 years after the graft had been placed. Two stent grafts were placed at the proximal portion of the surgical graft, covering almost its entire length. PMID- 27965927 TI - Catastrophic Bronchial Spasm Due to a Severe Anaphylactic Reaction to Protamine. AB - Fatal anaphylactic reactions to protamine sulfate during cardiac surgery are very rare. We report a case of catastrophic bronchial spasm due to an anaphylactic reaction to protamine. The patient was managed successfully using a bronchodilator, steroid treatment, and extracorporeal membrane oxygenation. PMID- 27965926 TI - Non-Tuberculous Mycobacterium Induced Pseudoaneurysm of the Common Carotid Artery. AB - An 81-year-old male patient presented with complaint of a pulsating neck mass. The patient had a previous history of cervical lymphadenopathy by non-tuberculous mycobacterium infection. Rapid growth of the mass on admission and contrast enhanced computed tomography of the neck resulted in a diagnosis of non tuberculous mycobacterium induced pseudoaneurysm. The patient underwent emergency open repair of the pseudoaneurysm. Pseudoaneurysm of the common carotid artery is regularly reported, but here we report a rare case of non-tuberculous mycobacterium induced pseudoaneurysm of the common carotid artery. PMID- 27965928 TI - Elevated Carbohydrate Antigen 19-9 Level in a Patient with Horseshoe Type Pulmonary Sequestration. AB - Elevated carbohydrate antigen (CA) 19-9 can indicate malignancies of the gastrointestinal, pancreatic, and biliary tracts, and be found in a pulmonary sequestration. A 30-year-old man visited Seoul National University Bundang Hospital due to elevated CA 19-9 levels, representing pulmonary sequestration of the bilateral lower lobes, which were connected with each other. We performed left lower lobectomy and division of the systemic arteries. After operation, CA 19-9 levels decreased to normal range, even though a small amount of sequestrated lung remained in the right lower lobe. It is not uncommon that presence of pulmonary sequestration might elevate serum CA 19-9 levels; however, horseshoe type bilateral pulmonary sequestration is very rare. PMID- 27965930 TI - A Case of Severe Thoracoabdominal Impalement by a Steel Bar. AB - A 53-year-old man arrived at the trauma center with a steel bar penetrating from the epigastrium to the right scapula. He was hypotensive and hypoxic, and immediate resuscitation and basic evaluation were performed. An emergency operation was performed due to an unstable hemodynamic state. Multiple injuries were confirmed in the right lower lobe, posterior chest wall, diaphragm, and liver lateral segment. Right lower lobectomy and liver lateral sectionectomy were performed following removal of the bar. The patient recovered without additional hemorrhage after the surgery, and was transferred to a rehabilitation institution with periodic follow-up. PMID- 27965931 TI - Simple Anastomotic Techniques for Coronary Artery Bypass Surgery in Patients with Small Coronary Arteries or a Marked Size Discrepancy Between the Coronary Artery and Graft. AB - Different suture techniques have been used for anastomosis in coronary artery bypass graft surgery. Bypass surgery may be difficult for patients who have small coronary arteries or marked size discrepancies between target coronary arteries and grafts. For proximal and distal anastomoses, three continuous stitches are first placed in the heel and toe of the small coronary arteries; for sequential anastomosis, an interrupted eight-stitch technique is used. We applied these anastomotic suture techniques in patients requiring coronary artery bypass graft surgery, achieving an early angiographic patency rate of 100%. PMID- 27965929 TI - Successful Management of Delayed Esophageal Rupture with T-Tube Drainage Using Video-Assisted Thoracoscopic Surgery. AB - Spontaneous perforation of the esophagus after forceful vomiting is known as Boerhaave syndrome, a rare and life-threatening condition associated with a high rate of mortality. The management of Boerhaave syndrome is challenging, especially when diagnosed late. Herein, we report the successful management of late-diagnosed Boerhaave syndrome with T-tube drainage in a 55-year-old man. The patient was transferred to our institution 8 days after the onset of symptoms, successfully managed by placing a T-tube, and was discharged on postoperative day 46 without complications. PMID- 27965932 TI - Valve-Sparing Root Replacement: Aortic Root Remodeling with External Subvalvular Ring Annuloplasty. AB - The original valve-sparing procedures for aortic root aneurysms were remodeling and reimplantation of the aortic root. The remodeling technique provides more physiologic movement of the cusps within 3 reconstructed neo-sinuses, thus preserving root expansibility through the interleaflet triangles. However, the durability of remodeling has been a matter of concern due to the high rate of aortic insufficiency when annular dilation is not addressed. Therefore, a modified approach was developed, combining a physiologic remodeling of the root with a subvalvular annuloplasty. This case report highlights the first case of successful aortic root remodeling with external subvalvular ring annuloplasty in Korea. PMID- 27965933 TI - Colorectal Choriocarcinoma in a Patient with Probable Lynch Syndrome. AB - BACKGROUND: Personalized therapy of colorectal cancer is influenced by morphological, molecular, and host-related factors. Here, we report the comprehensive clinicopathological and molecular analysis of an extra-gestational colorectal choriocarcinoma in a patient with probable Lynch syndrome. CASE PRESENTATION: A 61-year-old female with history of gastric cancer at age 36 presented with a transmurally invasive tumor of the right hemicolon and liver metastasis. A right hemicolectomy was performed. Histopathological analysis showed a mixed trophoblastic and syncytiotrophoblastic differentiation, consistent with choriocarcinoma. Disease progression was rapid under oxaliplatin, capecitabine, irinotecan, and bevacizumab. Molecular phenotyping identified loss of mismatch-repair protein immunostaining for PMS2, microsatellite instability, a lack of MLH1 promoter methylation, and lack of BRAF mutation suggestive of Lynch syndrome. Targeted next-generation sequencing revealed an ataxia telangiectasia mutated (p.P604S) missense mutation. A bleomycin, etoposide, and cisplatin treatment protocol targeting germ cell neoplasia lead to disease remission and prolonged survival of 34 months. CONCLUSION: Comprehensive immunohistochemical and genetic testing is essential to identify uncommon cancers possibly related to Lynch syndrome. For rare tumors, personalized therapeutic approaches should take both molecular and morphological information into account. PMID- 27965934 TI - Editorial: Glycosylation Changes in Cancer: An Innovative Frontier at the Interface of Cancer and Glycobiology. PMID- 27965935 TI - Clinical and Genomic Analysis of Liver Abscess-Causing Klebsiella pneumoniae Identifies New Liver Abscess-Associated Virulence Genes. AB - Hypervirulent variants of Klebsiella pneumoniae (hvKp) that cause invasive community-acquired pyogenic liver abscess (PLA) have emerged globally. Little is known about the virulence determinants associated with hvKp, except for the virulence genes rmpA/A2 and siderophores (iroBCD/iucABCD) carried by the pK2044 like large virulence plasmid. Here, we collected most recent clinical isolates of hvKp from PLA samples in China, and performed clinical, molecular, and genomic sequencing analyses. We found that 90.9% (40/44) of the pathogens causing PLA were K. pneumoniae. Among the 40 LA-Kp, K1 (62.5%), and K2 (17.5%) were the dominant serotypes, and ST23 (47.5%) was the major sequence type. S1-PFGE analyses demonstrated that although 77.5% (31/40) of the LA-Kp isolates harbored a single large virulence plasmid varied in size, 5 (12.5%) isolates had no plasmid and 4 (10%) had two or three plasmids. Whole genome sequencing and comparative analysis of 3 LA-Kp and 3 non-LA-Kp identified 133 genes present only in LA-Kp. Further, large scale screening of the 133 genes in 45 LA-Kp and 103 non LA-Kp genome sequences from public databases identified 30 genes that were highly associated with LA-Kp, including iroBCD, iucABCD and rmpA/A2 and 21 new genes. Then, these 21 new genes were analyzed in 40 LA-Kp and 86 non-LA-Kp clinical isolates collected in this study by PCR, showing that new genes were present 80 100% among LA-Kp isolates while 2-11% in K. pneumoniae isolates from sputum and urine. Several of the 21 genes have been proposed as virulence factors in other bacteria, such as the gene encoding SAM-dependent methyltransferase and pagO which protects bacteria from phagocytosis. Taken together, these genes are likely new virulence factors contributing to the hypervirulence phenotype of hvKp, and may deepen our understanding of virulence mechanism of hvKp. PMID- 27965937 TI - HHEX: A Crosstalker between HCMV Infection and Proliferation of VSMCs. AB - Objective: The study was designed to evaluate the role of Human cytomegalovirus (HCMV) infection on homebox (HOX) gene expression and the effects of overexpression of HOX genes on proliferation and apoptosis of vascular smooth muscle cells (VSMCs). Methods: Viral infection was verified by observation of cytopathic effects through inverted microscopy, viral particles by electron microscopy and HCMV IE gene amplification by RT-PCR. cDNA profiling technology was used to screen expression of HOX genes after HCMV infection in VSMCs. Abnormal expression of Haematopoietically-expressed homeobox (HHEX) was selected to construct over-expressed vector and transfected into VSMCs. The effects of over expression of HHEX on cell proliferation and apoptosis of VSMCs were assayed by flow cytometry. Apoptosis and proliferation-associated genes were also assayed by RT-PCR. Results: Multiple HOX gene expression levels had obvious changes after HCMV infection, among which expression of HHEX gene increased obviously at 24, 48, and 72 h after infection. Over expression of HHEX can promote VSMCs proliferation by promoting G0/G1 phase cells into S phase and inhibit VSMCs apoptosis. HHEX inhibited the expression of apoptosis-associated caspase 2 and caspase3 and promoted the expression of cell cycle-related genes such as CDK2 and CDK6, CyclinB2 and CyclinD2. Conclusion: HHEX over expression induced by HCMV infection closely associated with vascular proliferative diseases. PMID- 27965938 TI - Different Use of Cell Surface Glycosaminoglycans As Adherence Receptors to Corneal Cells by Gram Positive and Gram Negative Pathogens. AB - The epithelium of the cornea is continuously exposed to pathogens, and adhesion to epithelial cells is regarded as an essential first step in bacterial pathogenesis. In this article, the involvement of glycosaminoglycans in the adhesion of various pathogenic bacteria to corneal epithelial cells is analyzed. All microorganisms use glycosaminoglycans as receptors, but arranged in different patterns depending on the Gram-type of the bacterium. The heparan sulfate chains of syndecans are the main receptors, though other molecular species also seem to be involved, particularly in Gram-negative bacteria. Adherence is inhibited differentially by peptides, including heparin binding sequences, indicating the participation of various groups of Gram-positive, and -negative adhesins. The length of the saccharides produces a major effect, and low molecular weight chains inhibit the binding of Gram-negative microorganisms but increase the adherence of Gram-positives. Pathogen adhesion appears to occur preferentially through sulfated domains, and is very dependent on N- and 6-O-sulfation of the glucosamine residue and, to a lesser extent, 2-O sulfation of uronic acid. These data show the differential use of corneal receptors, which could facilitate the development of new anti-infective strategies. PMID- 27965936 TI - Pseudomonas aeruginosa Airway Infection Recruits and Modulates Neutrophilic Myeloid-Derived Suppressor Cells. AB - Pseudomonas aeruginosa is an opportunistic pathogen that causes infections mainly in patients with cystic fibrosis (CF) lung disease. Despite innate and adaptive immune responses upon infection, P. aeruginosa is capable of efficiently escaping host defenses, but the underlying immune mechanisms remain poorly understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that are functionally characterized by their potential to suppress T- and natural killer (NK)-cell responses. Here we demonstrate, using an airway in vivo infection model, that P. aeruginosa recruits and activates neutrophilic MDSCs, which functionally suppress T-cell responses. We further show that the CF gene defect (CF transmembrane conductance regulator, CFTR) modulates the functionality, but not the recruitment or generation of neutrophilic MDSCs. Collectively, we define a mechanism by which P. aeruginosa airway infection undermines host immunity by modulating neutrophilic MDSCs in vivo. PMID- 27965939 TI - Association of Serum Osteocalcin with Insulin Resistance and Coronary Atherosclerosis. AB - BACKGROUND: To determine the associations between serum osteocalcin level and insulin resistance, coronary atherosclerosis by using dual-source coronary computed tomography angiography. METHODS: A total of 98 subjects (24 men and 74 women) were selected for this retrospective cross-sectional study who voluntarily visited a health examination center for routine health check-up including the blood test for serum osteocalcin level and coronary computed tomography angiography. Multiple regression analysis was used to determine which variables were independently related to osteocalcin levels and coronary atherosclerosis. RESULTS: Stepwise multiple regression analysis adjusted for age, sex, menopausal status, body mass index, serum alkaline phosphatase, serum calcium and phosphate showed that osteocalcin negatively correlated with serum glucose (beta=-0.145, P=0.001) and homeostasis model assessment of insulin resistance (HOMA-IR) index (beta=-1.794, P=0.027) independently. The age, serum glucose, smoking status but not osteocalcin level were independent risk factors for coronary atherosclerosis by use of multiple logistic regression analysis after controlling for other variables. CONCLUSIONS: Serum osteocalcin level was inversely associated with fasting glucose level and insulin resistance measured by HOMA-IR, suggesting that osteocalcin is important for glucose metabolism. However, in this study, no significant difference was observed in the serum osteocalcin level according to the presence of coronary atherosclerotic plaques. PMID- 27965941 TI - Health-related Quality of Life in Accordance with Fracture History and Comorbidities in Korean Patients with Osteoporosis. AB - BACKGROUND: The purpose of this study was to explore health-related quality of life (HRQOL) among Korean patients with osteoporosis and to measure the impact of fractures and comorbidity on their quality of life (QOL) using the Korean National Health and Nutrition Examination Survey (KNHANES) data with a nationwide representativeness. METHODS: This study was based on 4-year-data obtained from the KNHANES 2008 to 2011. Osteoporosis was diagnosed in 2,078 survey participants according to their bone mineral density measurements using dual energy X-ray absorptiometry. According to the World Health Organization study group, T-scores at or above -1.0 are considered normal, those between -1.0 and -2.5 as osteopenia, and those at or below -2.5 as osteoporosis The EuroQol five dimensional questionnaire (EQ-5D) index score was used to assess the QOL. RESULTS: Of 2,078 patients diagnosed with osteoporosis, fractures were found to occur at 11.02%. Wrist fracture was the most frequent, affecting 4.52% of the patients, with a significantly different prevalence among men and women (P<0.001). The overall EQ-5D index score was 0.84+/-0.01 among patients with osteoporosis. With the exception of cancer, the EQ-5D index score were significantly lower for those having osteoarthritis, rheumatoid arthritis, hypertension, diabetes, chronic obstructive pulmonary disease and cardiovascular events compared to those without the related diseases. CONCLUSIONS: We found that low health utility was associated with previous spine fracture and comorbidities in patients with osteoporosis. In particular, the number of fracture experiences greatly deteriorated the HRQOL in patients with osteoporosis. Thus, prevention of secondary fractures and chronic care model for comorbidities should be a priority for osteoporosis management in order to improve HRQOL. PMID- 27965942 TI - Attenuation of RANKL-induced Osteoclast Formation via p38-mediated NFATc1 Signaling Pathways by Extract of Euphorbia Lathyris L. AB - BACKGROUND: Osteoclasts are the only cell type capable of breaking down bone matrix, and its excessive activation is responsible for the development of bone destructive diseases. Euphorbia lathyris L. (ELL) is an herbal plant that belongs to the Euphorbiaceae family. This study investigated the effects of the methanol extract of the aerial part of ELL on receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast formation and signaling pathways. METHODS: Osteoclasts were formed by co-culturing mouse bone marrow with osteoblasts or by culturing mouse bone marrow-derived macrophages (BMMs) with macrophage colony stimulating factor (M-CSF) and RANKL. Bone resorption assays were performed using dentine slices. The expression level of mRNA was analyzed by real-time polymerase chain reaction (PCR) or reverse transcription (RT)-PCR. Western blotting assays were performed to detect the expression or activation level of proteins. RESULTS: ELL inhibited RANKL-induced osteoclast formation without cytotoxicity. Furthermore, the RANKL-stimulated bone resorption was diminished by ELL. Mechanistically, ELL blocked the RANKL-triggered p38 mitogen-activated protein kinase (MAPK) phosphorylation, which resulted in the suppression of the expression of c-Fos and nuclear factor of activated T cells (NFATc1). In osteoblasts, ELL had little effect on the mRNA expression of RANKL and osteoprotegerin (OPG). CONCLUSIONS: The present data suggest that ELL has an inhibitory effect on osteoclast differentiation and function via downregulation of the p38/c-Fos/NFATc1 signaling pathways. Thus, ELL could be useful for the treatment of bone diseases associated with excessive bone resorption. PMID- 27965940 TI - Coronary Calcification Is Reversely Related with Bone and Hair Calcium: The Relationship among Different Calcium Pools in Body. AB - BACKGROUND: With aging, calcium efflux from bone is increased with age-related bone loss, and it can reduce bone mineral density (BMD). On the contrary, age related calcium adoption into arterial wall progressively stiffens blood vessels. Theses process insinuates shift of calcium among different pools in body. However, their relationships have not been elucidated yet. So we investigated the correlation among calcium contents in different body pools, such as hair, bone, and blood vessels in women. METHODS: We analyzed 50 females retrospectively who measured Agatston coronary artery calcium score (CACS), BMD, and hair calcium concentration at a regular health check-up in a university hospital. CACS was achieved by coronary multidetector computed tomography, BMD was measured by dual energy X-ray absorptiometry in the lumbar spine and femur, and hair calcium level was checked by hair tissue mineral analysis. RESULTS: CACS inversely correlated with BMD (r=-0.280, P=0.049 with lumbar vertebrae 1-4, r=-0.310, P=0.028 with femur neck, r=-0.333, P=0.018 with femur total) and hair calcium concentration (r=-0.352, P=0.012). CONCLUSIONS: CACS has negative correlation with BMD and hair calcium level in women. Different body calcium pools such as bone, hair and blood vessel significantly correlated each other. PMID- 27965943 TI - Bone Mineral Density and Fatty Degeneration of Thigh Muscles Measured by Computed Tomography in Hip Fracture Patients. AB - BACKGROUND: Recently, as an independent fracture factor from Bone mineral density (BMD), muscle weakness due to the fatty degeneration of thigh muscles have been attracting attentions as causes of hip fracture. The purpose of this study is to investigate the correlation between the body composition and BMD and fatty degeneration of thigh muscles of the female patients over 65 years old with osteoporotic hip fracture. METHODS: This study was conducted with 178 female osteoporotic hip fracture patients. Total hip BMD was measured using dual energy X-ray absorptiometry. Cross-sectional area (CSA), cross-sectional muscle area (CSmA), muscle attenuation coefficient (MAC), and intramuscular adipose tissue (IMAT) of gluteus maximus, hip abductors, quadriceps and hamstring muscle were measured with computed tomography. Normalized IMAT (nIMAT) was calculated by dividing the fat area in the muscle into the size of each muscle. The correlation between each measurement is examined then the differences between the intertrochanteric fracture group and the femoral neck fracture group were analyzed. RESULTS: CSmA and MAC of quadriceps were the largest and nIMAT was the lowest. CSA and CSmA of the four muscles showed a statistically significant positive correlation with weight, height, body mass index (BMI), and BMD. MAC of 2 gluteal muscles was positively correlated with weight, BMI and BMD. nIMAT of all four muscles was positively correlation with weight and BMI but nIMAT of 2 mid-thigh muscles was positively correlation with BMD. CONCLUSIONS: Muscle size and fatty degeneration in the thigh muscles were most positively correlated with the body weight. BMD was positively correlation with CSA and CSmA of all thigh muscles, and MAC of 2 gluteal muscles and fatty degeneration of 2 mid-thigh muscles. There was no statistically significant difference in the size of the femoral muscle and the degree of fatty degeneration between the two fracture groups. PMID- 27965944 TI - Relationship between Heavy Metal Exposure and Bone Mineral Density in Korean Adult. AB - BACKGROUND: Exposure to heavy metals from environmental and industrial sources remains a concern of serious public health risk. This study was conducted to analysis the relationship between heavy metal concentrations and bone density. METHODS: This study used data from a nation-based sample of Koreans (n=2,429) from 2008 to 2011 Korea National Health and Nutrition Examination Survey. We were obtained heavy metals (lead, mercury and cadmium), socioeconomic and demographic factors and bone mineral density (BMD) measured by T-score. RESULTS: Menopausal women, current smoker or the frequent alcohol drinking, low educational level and low family income were greater in the osteopenia or osteoporosis groups than normal group, and were associated with an increased blood heavy metal concentration levels. The highest quartile group in blood lead had a 1.47 times (95% confidence interval [CI] 1.16-1.87) risk of osteopenia or osteoporosis. In case of blood cadmium, the risk for osteopenia or osteoporosis increased 2.1 times (95% CI 1.64-2.68). CONCLUSIONS: We observed a significant association between blood heavy metals (lead and cadmium) levels and low BMD. Our findings suggest that heavy metal exposure may be a risk factor for osteoporosis. PMID- 27965945 TI - Replication of Caucasian Loci Associated with Osteoporosis-related Traits in East Asians. AB - BACKGROUND: Most reported genome-wide association studies (GWAS) seeking to identify the loci of osteoporosis-related traits have involved Caucasian populations. We aimed to identify the single nucleotide polymorphisms (SNPs) of osteoporosis-related traits among East Asian populations from the bone mineral density (BMD)-related loci of an earlier GWAS meta-analysis. METHODS: A total of 95 SNPs, identified at the discovery stage of the largest GWAS meta-analysis of BMD, were tested to determine associations with osteoporosis-related traits (BMD, osteoporosis, or fracture) in Korean subjects (n=1,269). The identified SNPs of osteoporosis-related traits in Korean subjects were included in the replication analysis using Chinese (n=2,327) and Japanese (n=768) cohorts. RESULTS: A total of 17 SNPs were associated with low BMD in Korean subjects. Specifically, 9, 6, 9, and 5 SNPs were associated with the presence of osteoporosis, non-vertebral fractures, vertebral fractures, and any fracture, respectively. Collectively, 35 of the 95 SNPs (36.8%) were associated with one or more osteoporosis-related trait in Korean subjects. Of the 35 SNPs, 19 SNPs (54.3%) were also associated with one or more osteoporosis-related traits in East Asian populations. Twelve SNPs were associated with low BMD in the Chinese and Japanese cohorts. Specifically, 3, 4, and 2 SNPs were associated with the presence of hip fractures, vertebral fractures, and any fracture, respectively. CONCLUSIONS: Our results identified the common SNPs of osteoporosis-related traits in both Caucasian and East Asian populations. These SNPs should be further investigated to assess whether they are true genetic markers of osteoporosis. PMID- 27965946 TI - Prevalence of Sarcopenia Adjusted Body Mass Index in the Korean Woman Based on the Korean National Health and Nutritional Examination Surveys. AB - BACKGROUND: The purpose of this study was to determine cut-off point of appendicular skeletal muscle mass (ASM) adjusted body mass index (BMI) for sarcopenia in the Korean women and evaluate the prevalence of sarcopenia in postmenopausal women. METHODS: This study was based on the data obtained from 2008 to 2011 Korean National Health and Nutrition Examination Survey (KNHANES) IV and V. A whole body dual energy X-ray absorptiometry (DXA) scan and measurement of BMI were performed on individuals of >=10 years old. Five thousand, two hundred and fifteen women older than 50 years were included in the study. ASM was obtained by adding the muscle masses of the four limbs. To determine the young reference group, mean and standard deviation of ASM and ASM/BMI by ages was measured. We calculated the prevalence rate of sarcopenia by each age group according to the cut-off point based on ASM and ASM/BMI. RESULTS: In determining the cut-off values related ASM/BMI, using the value that is two standard deviations below mean values for young reference group (20's and 30's) thus recommends 0.50 m2 in women. The overall prevalence among women older than 50 years was 15.6%. Among women older than 65 years prevalence of sarcopenia was 22.9%. CONCLUSIONS: The prevalence of sarcopenia among Korean women obtained in this study is within the proper range of value to research about sarcopenia. Furthermore, using 0.50 m2 as the cut-off value can help compare various studies about sarcopenia in Korea. PMID- 27965947 TI - Commentary: Blood Eosinophilia Is Associated with Unfavorable Hospitalization Outcomes in Children with Bronchiolitis. PMID- 27965948 TI - Do Self- and Proxy Reports of Cognitive Problems Reflect Intellectual Functioning in Children and Adolescents with Congenital Heart Defects? AB - AIM: Children with congenital heart defects (CHD) who suffer from cognitive impairments and school difficulties need to be identified as early as possible in order to set appropriate interventions in place that may enhance the school situation and quality of life for these children. Identifying children and adolescents at risk for cognitive difficulties requires specific screening tools. This study assessed such a tool - Pediatric Quality of Life Inventory Cardiac Module subscale: Cognitive Problems - to investigate whether proxy reported and self-reported cognitive problems were associated with measured intellectual functioning in children and adolescents with CHD treated with surgery or by catheter interventions. METHOD: The sample consisted of 184 children/adolescents aged 3, 5, 9, and 15 years. The severity of the CHD diagnoses was categorized into three groups (mild, moderate, or severe) for all age groups. For all the age groups, we collected proxy ratings of cognitive problems, and for the 5-, 9-, and 15-year-olds, we also collected self-reported cognitive problems. Intellectual functioning was measured with the Wechsler intelligence scales. The control variables were socioeconomic status and severity of diagnosis. RESULTS: A strong association was found between the parent's ratings of cognitive problems and the children's and adolescents' results on the Wechsler scales. This association was present for all ages, including the 3-year-olds. As for the self-reports, an association was only found between the 15-year-olds self-report of cognitive problems and their results on the Wechsler scales. CONCLUSION: To identify children with cognitive problems as early as at the age of 3 years, parent-rated Pediatrics Quality of Life subscale: Cognitive Problems can be used as a screening tool. For 15-year-olds, the self-report ratings can be used as a screening tool. We also suggest a cutoff score of 80 for both the 15-year olds as well as the proxy reports. If the score falls below 80 the child should be formally evaluated using standardized cognitive test. PMID- 27965949 TI - A Novel Prototype Neonatal Resuscitator That Controls Tidal Volume and Ventilation Rate: A Comparative Study of Mask Ventilation in a Newborn Manikin. AB - The objective of this randomized controlled manikin trial was to examine tidal volume (VT) delivery and ventilation rate during mask positive pressure ventilation (PPV) with five different devices, including a volume-controlled prototype Next StepTM device for neonatal resuscitation. We hypothesized that VT and rate would be closest to target with the Next StepTM. Twenty-five Neonatal Resuscitation Program providers provided mask PPV to a newborn manikin (simulated weight 1 kg) in a randomized order with a self-inflating bag (SIB), a disposable T-piece, a non-disposable T-piece, a stand-alone resuscitation system T-piece, and the Next StepTM. All T-pieces used a peak inflation pressure of 20 cmH2O and a positive end-expiratory pressure of 5 cmH2O. The participants were instructed to deliver a 5 mL/kg VT (rate 40-60/min) for 1 min with each device and each of three test lungs with increasing compliance of 0.5, 1.0, and 2.0 mL/cmH2O. VT and ventilation rate were compared between devices and compliance levels (linear mixed model). All devices, except the Next StepTM delivered a too high VT, up to sixfold the target at the 2.0-mL/cmH2O compliance. The Next StepTM VT was 26% lower than the target in the low compliance. The ventilation rate was within target with the Next StepTM and SIB, and slightly lower with the T-pieces. In conclusion, routinely used newborn resuscitators over delivered VT, whereas the Next StepTM under delivered in the low compliant test lung. The SIB had higher VT and rate than the T-pieces. More research is needed on volume-controlled delivery room ventilation. PMID- 27965951 TI - Person- and People-Centered Integrated Health Care for Alcohol Dependence - Whether It Is Real in the Present Moment. AB - Alcohol continues to occupy a leading position in Europe as a popular substance of abuse. According to WHO sources together with cigarette smoking and obesity, alcohol is a major cause of preventable diseases. Harmful use of alcohol is one of the main factors contributing to premature deaths and disability and has a major impact on public health. The consequences of alcohol use on human health are enormous. Additionally, alcohol use can have harmful effects that do not directly affect person who consumes alcohol (e.g., fetal alcohol syndrome violations that are related to alcohol use, etc.). It is well known that the harmful effects and consequences of alcohol use (e.g., acute and chronic illness, injuries in fights, at the workplace, in traffic, violent behavior, and death) create a great burden for the economic development of society. Persons who have been diagnosed with alcoholism and currently drinking have a less chance to achieve a life insurance cover. On the contrary, recovering alcoholic with a significant abstinent period can get a good life insurance quote. The abstinence of a year or 2 is usually enough for a person to get an average price of life insurance. Furthermore, new consequent relapses could also be considered as potential aggravating factor to accomplish this kind of financial benefits. So far, the research (and interventions) focused on the effects on the population level, such as the increase in taxes, advertising bans, and the implementation of laws that prevent the use of alcohol in traffic. However, it seems that the problem may be viewed at the individual level. The models of the treatment should be designed according to the needs of the individual. These models should incorporate not only the reduction of alcohol intake but also the path to abstinence. The plan should take into account the different (individual) needs for treatment, with regard to the degree of alcohol dependence and health status and also include the needs of the family, community, and broader society. PMID- 27965952 TI - Rising Health Expenditure Due to Non-Communicable Diseases in India: An Outlook. AB - With ongoing demographic transition, epidemiological transition has been emerged as a growing concern in India. The share of non-communicable disease in total disease burden has increased from 31% in 1990 to 45% in 2010. This paper seeks to explore the health scenario of India in the wake of the growing pace of non communicable diseases such as diabetes and hypertension among Indian population using data from health and morbidity survey of the National Sample Survey Organisation (2004) and notifies about the resource needed to tackle this growing health risk. Given the share of private players (70%) in Indian health system, results indicate a higher private expenditure, mostly out-of-pocket expense, on account of non-communicable diseases. A timely look into the matter may tackle a more dreadful situation in near future. PMID- 27965950 TI - Preterm Birth during Influenza Season Is Associated with Adverse Outcome in Very Low Birth Weight Infants. AB - OBJECTIVE: We investigated the relationship between influenza seasonality and outcome of very low birth weight infants (VLBWI) in a large observational cohort study of the German Neonatal Network. MATERIALS AND METHODS: Within the observational period (July 2009 until December 2014), five influenza seasons occurred (mean duration: 97 days, range: 48-131 days). We stratified VLBWI (n = 10,187) according to date of birth into three categories: (1) before influenza season, (2) during influenza season, and (3) 3 months after the end of the respective season. Outcomes were assessed in univariate and logistic regression analyses. In a subgroup of infants (n = 1497), the number of respiratory infections during the first 24 months of life was assessed. RESULTS: VLBWI born during influenza season carried a higher risk for clinical sepsis (31.0 vs. 28.2%; p = 0.014) and periventricular leukomalacia (PVL, 3.7 vs. 2.5%, p = 0.004). In a multivariate logistic regression model, birth during influenza season was associated with PVL [odds ratio (OR) 1.47 (1.11-1.95), p = 0.007] and clinical sepsis [OR 1.13 (1.01-1.27), p = 0.036], independent of known risk factors, i.e., gestational age, multiple birth, gender, and small for gestational age. The risk for bronchopulmonary dysplasia was not influenced by influenza seasonality. In the small subgroup with information on 24 months follow-up (n = 1497), an increased incidence of common cold and bronchitis episodes was noted in infants born during influenza season. CONCLUSION: Our observational data indicate that preterm birth during influenza season is associated with PVL and sepsis. These are novel aspects that deserve further investigations to address underlying causes and to include virus surveillance. PMID- 27965953 TI - Metabolic Engineering of Pseudomonas putida KT2440 for the Production of para Hydroxy Benzoic Acid. AB - para-Hydroxy benzoic acid (PHBA) is the key component for preparing parabens, a common preservatives in food, drugs, and personal care products, as well as high performance bioplastics such as liquid crystal polymers. Pseudomonas putida KT2440 was engineered to produce PHBA from glucose via the shikimate pathway intermediate chorismate. To obtain the PHBA production strain, chorismate lyase UbiC from Escherichia coli and a feedback resistant 3-deoxy-d-arabino heptulosonate-7-phosphate synthase encoded by gene aroGD146N were overexpressed individually and simultaneously. In addition, genes related to product degradation (pobA) or competing for the precursor chorismate (pheA and trpE) were deleted from the genome. To further improve PHBA production, the glucose metabolism repressor hexR was knocked out in order to increase erythrose 4 phosphate and NADPH supply. The best strain achieved a maximum titer of 1.73 g L 1 and a carbon yield of 18.1% (C-mol C-mol-1) in a non-optimized fed-batch fermentation. This is to date the highest PHBA concentration produced by P. putida using a chorismate lyase. PMID- 27965954 TI - Potential of an Exploitation of Acid-Tolerant Antimicrobial Microorganisms Evolving Enzyme Systems for the Utilization of Dairy By-products and Lignocellulosic Biomass to Lactic Acid. PMID- 27965955 TI - WNT/beta-Catenin Signaling in Vertebrate Eye Development. AB - The vertebrate eye is a highly specialized sensory organ, which is derived from the anterior neural plate, head surface ectoderm, and neural crest-derived mesenchyme. The single central eye field, generated from the anterior neural plate, divides to give rise to the optic vesicle, which evaginates toward the head surface ectoderm. Subsequently, the surface ectoderm, in conjunction with the optic vesicle invaginates to form the lens vesicle and double-layered optic cup, respectively. This complex process is controlled by transcription factors and several intracellular and extracellular signaling pathways including WNT/beta catenin signaling. This signaling pathway plays an essential role in multiple developmental processes and has a profound effect on cell proliferation and cell fate determination. During eye development, the activity of WNT/beta-catenin signaling is tightly controlled. Faulty regulation of WNT/beta-catenin signaling results in multiple ocular malformations due to defects in the process of cell fate determination and differentiation. This mini-review summarizes recent findings on the role of WNT/beta-catenin signaling in eye development. Whilst this mini-review focuses on loss-of-function and gain-of-function mutants of WNT/beta-catenin signaling components, it also highlights some important aspects of beta-catenin-independent WNT signaling in the eye development at later stages. PMID- 27965956 TI - Diacylglycerol Kinases: Shaping Diacylglycerol and Phosphatidic Acid Gradients to Control Cell Polarity. AB - Diacylglycerol kinases (DGKs) terminate diacylglycerol (DAG) signaling and promote phosphatidic acid (PA) production. Isoform specific regulation of DGKs activity and localization allows DGKs to shape the DAG and PA gradients. The capacity of DGKs to constrain the areas of DAG signaling is exemplified by their role in defining the contact interface between T cells and antigen presenting cells: the immune synapse. Upon T cell receptor engagement, both DGK alpha and zeta metabolize DAG at the immune synapse thus constraining DAG signaling. Interestingly, their activity and localization are not fully redundant because DGKzeta activity metabolizes the bulk of DAG in the cell, whereas DGKalpha limits the DAG signaling area localizing specifically at the periphery of the immune synapse. When DGKs terminate DAG signaling, the local PA production defines a new signaling domain, where PA recruits and activates a second wave of effector proteins. The best-characterized example is the role of DGKs in protrusion elongation and cell migration. Indeed, upon growth factor stimulation, several DGK isoforms, such as alpha, zeta, and gamma, are recruited and activated at the plasma membrane. Here, local PA production controls cell migration by finely modulating cytoskeletal remodeling and integrin recycling. Interestingly, DGK produced PA also controls the localization and activity of key players in cell polarity such as aPKC, Par3, and integrin beta1. Thus, T cell polarization and directional migration may be just two instances of the general contribution of DGKs to the definition of cell polarity by local specification of membrane identity signaling. PMID- 27965957 TI - 22q11 Deletion Syndrome and Urogenital Manifestations: A Clinicopathological Case Report. AB - BACKGROUND: Deletion in the chromosomal region 22q11 results from the abnormal development of the third and fourth pharyngeal pouches during embryonic life and presents an expansive phenotype with more than 180 clinical features described that involve every organ and system. HISTORY AND SIGNS: A 23-year-old African woman presented for the first trimester echography, which revealed an isolated anechoic structure suggesting a ureteral dilatation. The suspicion of a malposition of great arteries in the second trimester indicated an amniocentesis leading to a diagnosis of 22q11 deletion. OUTCOME: At 32 weeks, the patient was admitted for premature rupture of membranes and gave birth 2 weeks later to a male newborn who presented a respiratory distress syndrome and probably died secondary to a tracheal stenosis. Necropsy revealed typical clinical features of 22q11 deletion associated with left renal agenesis, hypospadias, and penile hypoplasia. CONCLUSION: We report a case of 22q11 deletion syndrome with typical clinical features associated with urogenital manifestations suspected at the first trimester ultrasound. PMID- 27965959 TI - A Novel Antithrombotic Mechanism Mediated by the Receptors of the Kallikrein/Kinin and Renin-Angiotensin Systems. AB - The contact activation (CAS) and kallikrein/kinin (KKS) systems regulate thrombosis risk in two ways. First, the CAS influences contact activation-induced factor XI activation and thrombin formation through the hemostatic cascade. Second, prekallikrein (PK) and bradykinin of the KKS regulate expression of three vessel wall G-protein-coupled receptors, the bradykinin B2 receptor (B2R), angiotensin receptor 2, and Mas to influence prostacyclin formation. The degree of intravascular prostacyclin formation inversely regulates intravascular thrombosis risk. A 1.5- to 2-fold increase in prostacyclin, as seen in PK deficiency, increases vessel wall Sirt1 and KLF4 to downregulate vessel wall tissue factor which alone is sufficient to lengthen induced thrombosis times. A twofold to threefold increase in prostacyclin, as seen the B2R-deficient mouse, delays thrombosis and produces a selective platelet function defect of reduced GPVI activation and platelet spreading. Regulation of CAS and KKS protein expression has a profound influence on thrombosis-generating mechanisms in the intravascular compartment. PMID- 27965961 TI - Focus on Alectinib and Competitor Compounds for Second-Line Therapy in ALK Rearranged NSCLC. AB - The management of anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) exemplifies the potential of a precision medicine approach to cancer care. The ALK inhibitor crizotinib has led to improved outcomes in the first- and second-line setting; however, toxicities, intracranial activity, and acquired resistance necessitated the advent of later generation ALK inhibitors. A large portion of acquired resistance to ALK inhibitors is caused by secondary mutations in the ALK kinase domain. Alectinib is a second-generation ALK inhibitor capable of overcoming multiple crizotinib-resistant ALK mutations and has demonstrated improved outcomes after crizotinib failure. Favorable toxicity profile and improved intracranial activity have spurred ongoing front-line trials and comparisons to other ALK inhibitors. However, important questions regarding comparability to competitor compounds, acquired alectinib resistance, and ALK inhibitor sequencing remain. Here, we review the key clinical data supporting alectinib in the second-line therapy of ALK+ NSCLC and provide context in comparison to other ALK inhibitors in development. PMID- 27965962 TI - Caffeine Consumption and General Health in Secondary School Children: A Cross sectional and Longitudinal Analysis. AB - Although caffeine is sometimes associated with beneficial effects in adults, the substance may be dangerous if intake is too high. This concern is particularly relevant in regards to children and adolescents, as consumption of energy drinks may be particularly high in such populations. For this reason, the current study examined data from the Cornish Academies Project to determine whether caffeine intake in secondary school children was related to responses to a single-item measure of general health. Two cross-sections of data were available: questionnaires were completed by 2030 at baseline, by 2307 at 6-month follow-up, and by 1660 at both time-points. Relationships were, therefore, explored both cross-sectionally and longitudinally. High caffeine consumption (i.e., 1000 mg/week) was associated with low general health in both cross-sections of data, and analyses of individual caffeine sources suggested that the effects related specifically to cola and energy drinks. However, after controlling for additional aspects of diet, demography, and lifestyle, total weekly intake only remained significantly associated with general health at the latter time-point. Further to this, null findings from cross-lag and change-score analyses suggest that caffeine and general health were unlikely to be causally linked in this sample. However, due to methodological limitations, such as the two cross-sections of data being collected only 6 months apart, it is suggested that further longitudinal and intervention studies are required in order for firm conclusions to be drawn. PMID- 27965960 TI - Activation of Coagulation and Fibrinolysis in Acute Respiratory Distress Syndrome: A Prospective Pilot Study. AB - INTRODUCTION: Coagulation and fibrinolysis remain sparsely addressed with regards to acute respiratory distress syndrome (ARDS). We hypothesized that ARDS development might be associated with changes in plasma coagulation and fibrinolysis. Our aim was to investigate the relationships between ARDS diagnosis and plasma concentrations of tissue factor (TF), tissue plasminogen activator (t PA), and plasminogen activator inhibitor-1 (PAI-1) in mechanically ventilated patients at increased risk of developing ARDS. MATERIALS AND METHODS: We performed an ethically approved prospective observational pilot study. Inclusion criteria were patients with PaO2/FiO2 < 300 mmHg admitted to the intensive care unit (ICU) for mechanical ventilation for 24 h, or more, because of one or more disease conditions associated with increased risk of developing ARDS. Exclusion criteria were age below 18 years; cardiac disease. We sampled plasma prospectively and compared patients who developed ARDS with those who did not using descriptive statistics and chi-square analysis of baseline demographical and clinical data. We also analyzed plasma concentrations of TF, t-PA, and PAI-1 at inclusion (T0) and on third (T3) and seventh day (T7) of the ICU stay with non parametric statistics inclusive their sensitivity and specificity associated with the development of ARDS using receiver operating characteristic curve analysis. Statistical significance: p < 0.05. RESULTS: Of 24 patients at risk, 6 developed mild ARDS and 4 of each moderate or severe ARDS, respectively, 3 +/- 2 (mean +/- SD) days after inclusion. Median plasma concentrations of TF and PAI-1 were significantly higher at T7 in patients with ARDS, as compared to non-ARDS. Simultaneously, we found moderate correlations between plasma concentrations of TF and PAI-1, TF and PaO2/FiO2, and positive end-expiratory pressure and TF. TF plasma concentration was associated with ARDS with 71% sensitivity and 100% specificity, a cut off level of 145 pg/ml and AUC 0.78, p = 0.02. PAI-1 displayed 64% sensitivity and 100% specificity with a cut off concentration of 117.5 pg/ml and AUC 0.77, p = 0.02. t-PA did not change significantly during the observation time. CONCLUSION: This pilot study showed that increased plasma concentrations of TF and PAI-1 might support ARDS diagnoses in mechanically ventilated patients after 7 days in ICU. PMID- 27965963 TI - Transforming Beef By-products into Valuable Ingredients: Which Spell/Recipe to Use? AB - Satisfying the increasing global demand for protein results in challenges from a supply perspective. Increased use of animal proteins, through greater use of meat by-products, could form part of the solution, subject to consumer acceptance. This research investigates consumer evaluations of food products that incorporate ingredients derived from offals that have been produced through a range of food processing technologies. Using focus groups incorporating product stimuli representing various combinations of offals, processing, and carrier products, the research finds that the physical state and perceived naturalness of the ingredients influences acceptance. It also highlights the impact of life experiences, linked to demographic characteristics, on interpretations and evaluations of products and processes. Ideational influences, i.e., knowledge of the nature or origin of the substance, are reasons for rejecting some concepts, with misalignment between nature of processing and the product resulting in rejection of others. Lack of perceived necessity also results in rejection. Alignment of ingredients with existing culinary practices and routines, communication of potential sensory, or other benefits as well as naturalness are factors likely to promote acceptance, and generate repeat purchase, in some consumer segments. Trust in oversight that the products are safe is a prerequisite for acceptance in all cases. These findings have implications for pathways to increase sustainability of beef production and consumption through increased use of beef by-products. PMID- 27965964 TI - Pulmonary Perfusion and Ventilation during Cardiopulmonary Bypass Are Not Associated with Improved Postoperative Outcomes after Cardiac Surgery. AB - OBJECTIVES: Clinical trials of either pulmonary perfusion or ventilation during cardiopulmonary bypass (CBP) are equivocal. We hypothesized that to achieve significant improvement in outcomes both interventions had to be concurrent. DESIGN: Retrospective case-control study. SETTINGS: Major academic tertiary referral medical center. PARTICIPANTS: Two hundred seventy-four consecutive patients who underwent open heart surgery with CBP 2009-2013. INTERVENTIONS: The outcomes of 86 patients who received pulmonary perfusion and ventilation during CBP were retrospectively compared to the control group of 188 patients. MEASUREMENTS AND MAIN RESULTS: Respiratory complications rates were similar in both groups (33.7 vs. 33.5%), as were the rates of postoperative pneumonia (4.7 vs. 4.3%), pleural effusions (13.9 vs. 12.2%), and re-intubations (9.3 vs. 9.1%). Rates of adverse postoperative cardiac events including ventricular tachycardia (9.3 vs. 8.5%) and atrial fibrillation (33.7 vs. 28.2%) were equivalent in both groups. Incidence of sepsis (8.1 vs. 5.3%), postoperative stroke (2.3 vs. 2.1%), acute kidney injury (2.3 vs. 3.7%), and renal failure (5.8 vs. 3.7%) was likewise comparable. Despite similar transfusion requirements, coagulopathy (12.8 vs. 5.3%, p = 0.031) and the need for mediastinal re-exploration (17.4 vs. 9.6%, p = 0.0633) were observed more frequently in the pulmonary perfusion and ventilation group, but the difference did not reach the statistical significance. Intensive care unit (ICU) and hospital stays, and the ICU readmission rates (7.0 vs. 8.0%) were similar in both groups. CONCLUSION: Simultaneous pulmonary perfusion and ventilation during CBP were not associated with improved clinical outcomes. PMID- 27965965 TI - Cell-Based Veterinary Pharmaceuticals - Basic Legal Parameters Set by the Veterinary Pharmaceutical Law and the Genetic Engineering Law of the European Union. AB - Cell-based therapies have been in use in veterinary medicine for years. However, the legal requirement of manufacturing, placing on the market and use of cell based veterinary pharmaceuticals are not as well developed as the respective requirements of chemical pharmaceuticals. Cell-based veterinary pharmaceuticals are medicinal products in the sense of the pharmaceutical law of the European Union (EU). For that reason, such medicinal products principally require official approval for their manufacture and an official marketing authorization for their placement on the market before being used by the veterinarian. The manufacture, placing on the market, and use of cell-based veterinary pharmaceuticals without manufacturing approval and marketing authorization is permitted only in certain exceptional cases determined by EU and individual Member State law. Violations of this requirement may have consequences for the respective veterinarian under criminal law and under the code of professional conduct in the respective Member State. The regular use of cell-based veterinary pharmaceuticals within the scope of a therapeutic emergency as well as the import of such veterinary pharmaceuticals from non-European countries for use in the EU are currently out of the question in the EU because of a lack of legal bases. Here, we review the general legal requirement of manufacturing, placing on the market, and use of cell-based veterinary pharmaceuticals within the EU and point out different implementations of EU law within the different Member States. PMID- 27965967 TI - Physiological and Behavioral Responses of Dairy Cattle to the Introduction of Robot Scrapers. AB - Autonomous mobile robot scrapers are increasingly used in order to clean the floors on dairy farms. Given the complexity of robot scraper operation, stress may occur in cows due to unpredictability of the situation. Experiencing stress can impair animal welfare and, in the long term, the health and milk production of the cows. Therefore, this study addressed potential stress responses of dairy cattle to the robot scraper after introducing the autonomous mobile machine. Thirty-six cows in total were studied on three different farms to explore possible modifications in cardiac function, behavior, and adrenocortical activity. The research protocol on each farm consisted of four experimental periods including one baseline measurement without robot scraper operation followed by three test measurements, in which cows interacted with the robotic cleaning system. Interbeat intervals were recorded in order to calculate the heart rate variability (HRV) parameter RMSSD; behavior was observed to determine time budgets; and fecal samples were collected for analysis of the cortisol metabolites concentration. A statistical analysis was carried out using linear mixed-effects models. HRV decline immediately after the introduction of the robot scraper and modified behavior in the subsequent experimental periods indicated a stress response. The cortisol metabolites concentration remained constant. It is hypothesized that after the initial phase of decrease, HRV stabilized through the behavioral adjustments of the cows in the second part of the study. Persistent alterations in behavior gave rise to the assumption that the animals' habituation process to the robot scraper was not yet completed. In summary, the present study illustrated that the cows showed minor signs of disturbance toward the robotic cleaning system. Thus, our findings suggest that dairy cattle can largely adjust their behavior to avoid aversive effects on animal welfare. Additional research can provide further insight into the development of the animal-machine interaction beyond the initial phase of robot scraper operation considered in this study. PMID- 27965966 TI - Challenges of Generating and Maintaining Protective Vaccine-Induced Immune Responses for Foot-and-Mouth Disease Virus in Pigs. AB - Vaccination can play a central role in the control of outbreaks of foot-and-mouth disease (FMD) by reducing both the impact of clinical disease and the extent of virus transmission between susceptible animals. Recent incursions of exotic FMD virus lineages into several East Asian countries have highlighted the difficulties of generating and maintaining an adequate immune response in vaccinated pigs. Factors that impact vaccine performance include (i) the potency, antigenic payload, and formulation of a vaccine; (ii) the antigenic match between the vaccine and the heterologous circulating field strain; and (iii) the regime (timing, frequency, and herd-level coverage) used to administer the vaccine. This review collates data from studies that have evaluated the performance of foot-and mouth disease virus vaccines at the individual and population level in pigs and identifies research priorities that could provide new insights to improve vaccination in the future. PMID- 27965969 TI - Early Decision Indicators for Foot-and-Mouth Disease Outbreaks in Non-Endemic Countries. AB - Disease managers face many challenges when deciding on the most effective control strategy to manage an outbreak of foot-and-mouth disease (FMD). Decisions have to be made under conditions of uncertainty and where the situation is continually evolving. In addition, resources for control are often limited. A modeling study was carried out to identify characteristics measurable during the early phase of a FMD outbreak that might be useful as predictors of the total number of infected places, outbreak duration, and the total area under control (AUC). The study involved two modeling platforms in two countries (Australia and New Zealand) and encompassed a large number of incursion scenarios. Linear regression, classification and regression tree, and boosted regression tree analyses were used to quantify the predictive value of a set of parameters on three outcome variables of interest: the total number of infected places, outbreak duration, and the total AUC. The number of infected premises (IPs), number of pending culls, AUC, estimated dissemination ratio, and cattle density around the index herd at days 7, 14, and 21 following first detection were associated with each of the outcome variables. Regression models for the size of the AUC had the highest predictive value (R2 = 0.51-0.9) followed by the number of IPs (R2 = 0.3-0.75) and outbreak duration (R2 = 0.28-0.57). Predictability improved at later time points in the outbreak. Predictive regression models using various cut-points at day 14 to define small and large outbreaks had positive predictive values of 0.85 0.98 and negative predictive values of 0.52-0.91, with 79-97% of outbreaks correctly classified. On the strict assumption that each of the simulation models used in this study provide a realistic indication of the spread of FMD in animal populations. Our conclusion is that relatively simple metrics available early in a control program can be used to indicate the likely magnitude of an FMD outbreak under Australian and New Zealand conditions. PMID- 27965968 TI - A Review of Pain Assessment in Pigs. AB - There is a moral obligation to minimize pain in pigs used for human benefit. In livestock production, pigs experience pain caused by management procedures, e.g., castration and tail docking, injuries from fighting or poor housing conditions, "management diseases" like mastitis or streptococcal meningitis, and at parturition. Pigs used in biomedical research undergo procedures that are regarded as painful in humans, but do not receive similar levels of analgesia, and pet pigs also experience potentially painful conditions. In all contexts, accurate pain assessment is a prerequisite in (a) the estimation of the welfare consequences of noxious interventions and (b) the development of more effective pain mitigation strategies. This narrative review identifies the sources of pain in pigs, discusses the various assessment measures currently available, and proposes directions for future investigation. PMID- 27965971 TI - Profiling of the Predicted Circular RNAs in Ductal In Situ and Invasive Breast Cancer: A Pilot Study. AB - The recent advantage obtained by next generation sequencing allows a depth investigation of a new "old" kind of noncoding transcript, the circular RNAs. Circular RNAs are nontranslated RNAs, typically nonpolyadenylated, with a resistance to exonucleases that gives them the ability to be more stable than the common linear RNA isoforms. We used a bioinformatic detection tool (CIRCexplorer) to research predictive circRNAs from the next generation sequenced data of five samples of ductal in situ carcinoma (DCIS) and matched adjacent invasive ductal carcinoma (IDC). Furthermore, we also investigated the circular RNAs expressed in MCF7, an invasive breast ductal carcinoma cell line. We described the genomic context of the predicted circular RNAs and we address the hypothetical possible functional roles. This study showed a perspective of a panel of predictive circRNAs identified and the function that circRNAs could exert. PMID- 27965970 TI - Relevance of Indirect Transmission for Wildlife Disease Surveillance. AB - Epidemiological models of infectious diseases are essential tools in support of risk assessment, surveillance design, and contingency planning in public and animal health. Direct pathogen transmission from host to host is an essential process of each host-pathogen system and respective epidemiological modeling concepts. It is widely accepted that numerous diseases involve indirect transmission (IT) through pathogens shed by infectious hosts to their environment. However, epidemiological models largely do not represent pathogen persistence outside the host explicitly. We hypothesize that this simplification might bias management-related model predictions for disease agents that can persist outside their host for a certain time span. We adapted an individual based, spatially explicit epidemiological model that can mimic both transmission processes. One version explicitly simulated indirect pathogen transmission through a contaminated environment. The second version simulated direct host-to host transmission only. We aligned the model variants by the transmission potential per infectious host (i.e., basic reproductive number R0) and the spatial transmission kernel of the infection to allow unbiased comparison of predictions. The quantitative model results are provided for the example of surveillance plans for early detection of foot-and-mouth disease in wild boar, a social host. We applied systematic sampling strategies on the serological status of randomly selected host individuals in both models. We compared between the model variants the time to detection and the area affected prior to detection, measures that strongly influence mitigation costs. Moreover, the ideal sampling strategy to detect the infection in a given time frame was compared between both models. We found the simplified, direct transmission model to underestimate necessary sample size by up to one order of magnitude but to overestimate the area put under control measures. Thus, the model predictions underestimated surveillance efforts but overestimated mitigation costs. We discuss parameterization of IT models and related knowledge gaps. We conclude that the explicit incorporation of IT mechanisms in epidemiological modeling may reward by adapting surveillance and mitigation efforts. PMID- 27965972 TI - A Hybrid Signal Processing of RR Intervals from QTc Variation Searching Arrhythmia and Improving Heart Rate Variability Assessment in Acute Large Artery Ischemic Stroke. AB - Sudden death caused by abnormal QTc and atrial fibrillation (AF) has been reported in stroke. Heart rate variability (HRV) is reduced with missing beats of RRI during arrhythmic episode and abnormal QTc variation during acute stroke. In this study, we develop a hybrid signal processing by Pan Tompkins QRS detection and Kalman filter estimator for meaningful missing beats and searching AF with prolonged QTc. We use this hybrid model to investigate RRIs of Lead II ECG in thirty acute stroke patients with long QTc and AF (LQTc-AF) and normal QTc without AF (NQTc-nonAF) and then assess them by HRV. In LQTc-AF Kalman, higher mean heart rate with lower mean RRIs compared to NQTc-nonAF Kalman was characterized. LQTc-AF Kalman showed significant increase in SDNN, HF, SD2, SD2/SD1, and sample entropy. SDNN and HF associated with high RMSSD, pNN50, and SD1 reflect predominant parasympathetic drive for sympathovagal balance in LQTc AF Kalman. Greater SD2, SD2/SD1, and sample entropy indicate more scatter of Poincare plot. Compared with conventional Labchart, fractal scaling exponent of alpha1 (DFA) is higher in LQTc-AF Kalman. Remarkable complexity with parasympathetic drive in LQTc-AF Kalman suggests an influence of missing beats during stroke. PMID- 27965973 TI - Piloting Psychology Annual Reviews as a Method of Measuring Psychological Distress and Quality of Life in Paediatric Renal Transplant Patients. AB - Psychosocial distress and poorer quality of life after renal transplantation are common in children and young people. This has implications for medication adherence and survival. Posttransplant psychology annual reviews were introduced in one Paediatric Renal Service in the UK as a means of measuring psychological distress and quality of life, as well as facilitating identification of patients and parents/carers who would benefit from psychological intervention. The process of completing posttransplant psychology annual reviews is discussed within this paper. The posttransplant psychology annual review appointments identified patients experiencing depression and/or anxiety and problems in quality of life. These assessments have led to appropriate referrals to, and engagement with, the renal psychology service as well as with community tier 3 child and adolescent mental health services. The posttransplant psychology annual review will continue to be completed at this UK site and discussions will be undertaken with other paediatric renal transplant services to consider whether these could be introduced at a national level to facilitate collection of longitudinal data regarding long-term psychosocial impact of paediatric renal transplantation and its effect on quality of life. PMID- 27965974 TI - Outcomes of Recurrent Acute Otitis Media in Children Treated for Dental Malocclusion: A Preliminary Report. AB - Aim. To investigate the role of dental malocclusion treatment in the outcomes of Recurrent Acute Otitis Media (RAOM). Materials and Methods. The clinical outcome (number of acute recurrences in 12 months) of 61 consecutive children treated medically for RAOM was analysed. Children underwent an odontostomatologic evaluation, a fiberoptic endoscopy, and skin-prick tests. Results. 32 children (group A) were diagnosed with dental malocclusion and treated with a mandibular repositioning plate. Dental malocclusion was ruled out in the other 29 patients with RAOM, and they were used as controls (group B). The two groups were homogeneous in terms of sex, exposure to RAOM risk factors, skin test results, and adenoid hypertrophy, while age was significantly higher in group A. Age, sex, exposure to RAOM risk factors, adenoid hypertrophy, and skin test results were not associated with RAOM outcome. Children in group A treated for dental malocclusion were strongly associated with a lower number of acute episode recurrences at both univariate (p < 0.0001) and multivariate analysis (p = 0.001). Conclusions. RAOM showed better outcomes in children with dental malocclusion wearing a mandibular repositioning device. Dental malocclusion in children with RAOM may play a role in the pathogenesis of Eustachian tube dysfunction. PMID- 27965975 TI - Comparison of Extended-Spectrum beta-Lactamase-Producing Escherichia coli Isolates from Drinking Well Water and Pit Latrine Wastewater in a Rural Area of China. AB - The present study was conducted to gain insights into the occurrence and characteristics of extended-spectrum beta-lactamase- (ESBL-) producing Escherichia coli (E. coli) from drinking well water in the rural area of Laiwu, China, and to explore the role of the nearby pit latrine as a contamination source. ESBL-producing E. coli from wells were compared with isolates from pit latrines in the vicinity. The results showed that ESBL-producing E. coli isolates, with the same antibiotic resistance profiles, ESBL genes, phylogenetic group, plasmid replicon types, and enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) fingerprints, were isolated from well water and the nearby pit latrine in the same courtyard. Therefore, ESBL producing E. coli in the pit latrine may be a likely contributor to the presence of ESBL-producing E. coli in rural well water. PMID- 27965976 TI - Identification of ITGA2B and ITGB3 Single-Nucleotide Polymorphisms and Their Influences on the Platelet Function. AB - The aim of the study was to investigate ITGA2B and ITGB3 genetic polymorphisms and to evaluate the variability in the platelet function in healthy Chinese subjects. The genetic sequence of the entire coding region of the ITGA2B and ITGB3 genes was investigated. Adenosine diphosphate-induced platelet aggregation, glycoprotein IIb/IIIa content, bleeding time, and coagulation indexes were detected. Thirteen variants in the ITGA2B locus and 29 variants in the ITGB3 locus were identified in the Chinese population. The rs1009312 and rs2015049 were associated with the mean platelet volume. The rs70940817 was significantly correlated with the prothrombin time. The rs70940817 and rs112188890 were related with the activated partial thromboplastin time, and ITGB3 rs4642 was correlated with the thrombin time and fibrinogen. The minor alleles of rs56197296 and rs5919 were associated with decreased ADP-induced platelet aggregation, and rs55827077 was related with decreased GPIIb/IIIa per platelet. The rs1009312, rs2015049, rs3760364, rs567581451, rs7208170, and rs117052258 were related with bleeding time. Further studies are needed to explore the clinical importance of ITGA2B and ITGB3 SNPs in the platelet function. PMID- 27965977 TI - Lack of Association between Genetic Polymorphisms of JAK-STAT Signaling Pathway Genes and Acute Anterior Uveitis in Han Chinese. AB - Purpose. This study aimed to investigate the association between single nucleotide polymorphisms (SNPs) of JAK-STAT signaling pathway genes and acute anterior uveitis (AAU) with or without ankylosing spondylitis (AS) in the Han Chinese population. Methods. Eleven SNPs of the JAK1, JAK2, STAT1, IRF1, and NOS2 genes were analyzed in 443 AAU patients with AS, 486 AAU patients without AS, and 714 healthy controls. Genotyping was performed by PCR-RFLP assay or TaqMan(r) probe assay. The Chi-squared (chi2) test and multivariate logistic regression analysis were used to compare the distributions of alleles and genotypes between patients and controls. P values were adjusted using Bonferroni correction. Results. We did not observe significant differences in the genotype and allele frequencies of any SNP between AAU patients with or without AS and healthy controls. Stratification analyses by gender and HLA-B27 status showed a boundary significant association between two SNPs (rs10975003 and rs10758669) in JAK2 and AAU (P = 0.052 and P = 0.053, resp.). Conclusions. Our results indicated that genetic polymorphisms of the JAK-STAT signaling pathway genes may not be associated with AAU in the Han Chinese population. PMID- 27965978 TI - Rebamipide, an Amino Acid Analog of 2(1H)-Quinolinone, Inhibits the Formation of Human Osteoclasts. AB - Objectives. Drug repositioning or drug reprofiling (DR) has recently been growing in importance. DR has a significant advantage over traditional drug development because the repositioned drug has already passed toxicity tests; its safety is known, and the risk of adverse toxicology is reduced. In the current study, we investigated the role of rebamipide, a mucosa-protecting agent, with recently reported anti-inflammatory function, in human osteoclastogenesis. Methods. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence of M-CSF and sRANKL. Osteoclast formation was evaluated by immunohistological staining for CD51/61 (vitronectin receptors). Osteoclast formation, in the presence or absence of rebamipide (0, 1, and 3 mM), was observed by time-lapse photography and actin ring formation. The number of absorption sites and area of absorption were calculated using OsteologicTM plates. Pit formation was studied by 3D-SEM. Results. Rebamipide inhibited human osteoclast formation at 3 mM, a pharmacological concentration, and inhibited resorbing activity dose-dependently. Rebamipide induced the degradation of actin rings in mature osteoclasts. This mechanism may involve inhibiting the osteoclast fusion pathway through reducing the expression of DC-specific transmembrane protein (DC-STAMP). Conclusions. The present study suggests that rebamipide would be useful as a novel agent for osteoporosis and rheumatoid arthritis. PMID- 27965979 TI - Effect of Low-Pressurized Perfusion with Different Concentration of Elastase on the Aneurysm Formation Rate in the Abdominal Aortic Aneurysm Model in Rabbits. AB - Establishing an animal model of abdominal aortic aneurysm (AAA) is the key to study the pathogenesis and the pathophysiological features of AAAs. We investigated the effects of low-pressurized perfusion with different concentrations of elastase on aneurysm formation rate in the AAA model. Fifty male New Zealand white rabbits were randomly divided into A, B, C, D, and E groups. 10 MUL of normal saline was perfused into the abdominal aorta in group A and 1 U/mL, 10 U/mL, 100 U/mL, or 200 U/mL of elastase was, respectively, perfused for the other four groups. All the animals were perfused for 7 min. Doppler ultrasound examinations of the abdominal aorta were performed before surgery and on day 14 after surgery. The rabbits were sacrificed and the perfused segment of the abdominal aorta was observed visually and after staining. The aneurysm formation rate of group A, group B, group C, group D, and group E was, respectively, 0%, 0%, 33.3%, 102.5-146.8%, and 241.5-255.2%. The survival rate of five groups was 90%, 90%, 90%, 90%, and 40%, respectively. So, we concluded that low-pressurized perfusion with 100 U/mL of elastase can effectively establish AAAs in rabbits with a high aneurysm formation rate. PMID- 27965982 TI - hsa-miR-376c-3p Regulates Gastric Tumor Growth Both In Vitro and In Vivo. AB - Background. In recent studies, aberrant expression of various microRNAs (miRNAs) is reported to be associated with gastric cancer metastasis. Method. Overexpression construct and inhibitor of hsa-miR-376c-3p were expressed in human gastric adenocarcinoma cell line SGC-7901. The expression level of tumor related genes was detected by qPCR, western blot, and immunostaining. Cell apoptosis was determined by flow cytometry. Xenograft of SGC-7901 cells was used to elucidate the function of hsa-miR-376c-3p in gastric tumor growth in vivo. Result. Expression of hsa-miR-376c-3p was detected in SGC-7901 cells. Downregulation of hsa-miR-376c-3p increased the expression level of BCL-2 and decreased the expression of smad4 and BAD. On the contrary, overexpression of hsa-miR-376c-3p increased the expression of BAD and smad4, while it led to the decreasing expression level of BCL-2. Overexpression of hsa-miR-376c-3p also promoted cell apoptosis in vitro and inhibited gastric tumor growth in vivo. Furthermore, the expression of BCL-2 was higher and expression of smad4 and BAD was lower in tumor tissue than the tissue adjacent to tumor from gastric cancer patients. Conclusion. This study demonstrated that hsa-miR-376c-3p plays an important role in the inhibition of gastric tumor growth and tumor related gene expression both in vitro and in vivo. PMID- 27965980 TI - In Vitro Protective Effects of Lycium barbarum Berries Cultivated in Umbria (Italy) on Human Hepatocellular Carcinoma Cells. AB - Lycium barbarum is a famous plant in the traditional Chinese medicine. The plant is known to have health-promoting bioactive components. The properties of Lycium barbarum berries cultivated in Umbria (Italy) and their effect on human hepatocellular carcinoma cells (HepG2) have been investigated in this work. The obtained results demonstrated that the Lycium barbarum berries from Umbria region display high antioxidant properties evaluated by total phenolic content and ORAC method, on hydrophilic and lipophilic fractions. Moreover, on HepG2 cell line Lycium barbarum berries extract did not change cell viability analyzed by MTT and Trypan blue exclusion assay and did not induce genotoxic effect analyzed by comet assay. Furthermore, it was demonstrated, for the first time, that the berries extract showed a protective effect on DNA damage, expressed as antigenotoxic activity in vitro. Finally, Lycium barbarum berries extract was able to modulate the expression of genes involved in oxidative stress, proliferation, apoptosis, and cancer. In particular, downexpression of genes involved in tumor migration and invasion (CCL5), in increased risk of metastasis and antiapoptotic signal (DUSP1), and in carcinogenesis (GPx-3 and PTGS1), together with overexpression of tumor suppressor gene (MT3), suggested that Umbrian Lycium barbarum berries could play a protective role against hepatocellular carcinoma. PMID- 27965981 TI - Silkworm Sericin: Properties and Biomedical Applications. AB - Silk sericin is a natural polymer produced by silkworm, Bombyx mori, which surrounds and keeps together two fibroin filaments in silk thread used in the cocoon. The recovery and reuse of sericin usually discarded by the textile industry not only minimizes environmental issues but also has a high scientific and commercial value. The physicochemical properties of the molecule are responsible for numerous applications in biomedicine and are influenced by the extraction method and silkworm lineage, which can lead to variations in molecular weight and amino acid concentration of sericin. The presence of highly hydrophobic amino acids and its antioxidant potential make it possible for sericin to be applied in the food and cosmetic industry. The moisturizing power allows indications as a therapeutic agent for wound healing, stimulating cell proliferation, protection against ultraviolet radiation, and formulating creams and shampoos. The antioxidant activity associated with low digestibility of sericin that expands the application in the medical field, such as antitumour, antimicrobial and anti-inflammatory agent, anticoagulant, acts in colon health, improving constipation and protects the body from obesity through improved plasma lipid profile. In addition, the properties of sericin allow its application as a culture medium and cryopreservation, in tissue engineering and for drug delivery, demonstrating its effective use, as an important biomaterial. PMID- 27965983 TI - Xanthine Oxidase Activity in Type 2 Diabetes Mellitus Patients with and without Diabetic Peripheral Neuropathy. AB - This study investigated the relationship between serum xanthine oxidase (XOD) activity and the occurrence of diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients. Serum XOD activity, ischemia-modified albumin (IMA), uric acid (UA), albumin, glycated hemoglobin (HbA1c), advanced glycation end products (AGE), total free thiols, atherogenic index of plasma (AIP), and body mass index (BMI) were measured in 80 T2DM patients (29 with and 51 without DPN), and 30 nondiabetic control subjects. Duration of diabetes, hypertension, medication, and microalbuminuria was recorded. Serum XOD activities in controls, non-DPN, and DPN were 5.7 +/- 2.4 U/L, 20.3 +/- 8.6 U/L, and 27.5 +/- 10.6 U/L (p < 0.01), respectively. XOD activity was directly correlated to IMA, UA, BMI, HbA1c, and AGE, while inversely correlated to serum total free thiols. A multivariable logistic regression model, which included duration of diabetes, hypertension, AIP, HbA1c, UA, and XOD activity, revealed HbA1c [OR = 1.03 (1.00 1.05); p = 0.034] and XOD activity [OR = 1.07 (1.00-1.14); p = 0.036] as independent predictors of DPN. Serum XOD activity was well correlated to several other risk factors. These results indicate the role of XOD in the development of DPN among T2DM patients. PMID- 27965984 TI - IL-6 Promotes Islet beta-Cell Dysfunction in Rat Collagen-Induced Arthritis. AB - The aim of this study was to explore the possible mechanism of rheumatoid arthritis- (RA-) related abnormal glucose metabolism. The model of collagen induced arthritis (CIA) was established by intradermal injection of type II collagen into Wistar rats; complete Freund's adjuvant injections were used as the control group. Fasting plasma glucose (FBG) was measured by the glucose oxidase method. Fasting insulin (FIns) and the expressions of IL-6 were detected by ELISA. Islet caspase-3 was examined by immunohistochemistry. On day 17 after immunization, FBG of the CIA group showed an elevated FBG value compared with the control group. Meanwhile, the FIns of group CIA was lower when compared with the control group. Interestingly, the inflammatory cytokine IL-6 expression was significantly increased when compared with the control group. As expected, the abnormal glucose metabolism was accompanied by the increased IL-6 expression. Furthermore, in line with the upregulated IL-6 expression, the apoptosis related enzyme caspase-3 was also markedly increased. These data showed that the elevated FBG in CIA may be associated with the reduced FIns level secondary to the overapoptosis of pancreas islet cells induced by IL-6. PMID- 27965985 TI - Erratum to "Hyperglycemia Induces Toll-Like Receptor-2 and -4 Expression and Activity in Human Microvascular Retinal Endothelial Cells: Implications for Diabetic Retinopathy". AB - [This corrects the article DOI: 10.1155/2014/790902.]. PMID- 27965987 TI - Assessment of Natural Radioactivity Levels and Radiation Hazards in Agricultural and Virgin Soil in the State of Kedah, North of Malaysia. AB - The activity concentrations of naturally occurring radionuclides 226Ra, 232Th, and 40K were determined in 30 agricultural and virgin soil samples randomly collected from Kedah, north of Malaysia, at a fertile soil depth of 0-30 cm. Gamma-ray spectrometry was applied using high-purity germanium (HPGe) gamma-ray detector and a PC-based MCA. The mean radioactivity concentrations of 226Ra, 232Th, and 40K were found to be 102.08 +/- 3.96, 133.96 +/- 2.92, and 325.87 +/- 9.83 Bq kg-1, respectively, in agricultural soils and 65.24 +/- 2.00, 83.39 +/- 2.27, and 136.98 +/- 9.76 Bq kg-1, respectively, in virgin soils. The radioactivity concentrations in agricultural soils are higher than those in virgin soils and compared with those reported in other countries. The mean values of radium equivalent activity (Raeq), absorbed dose rates D (nGy h-1), annual effective dose equivalent, and external hazard index (Hex) are 458.785 Bq kg-1, 141.62 nGy h-1, and 0.169 mSv y-1, respectively, in agricultural soils and 214.293 Bq kg-1, 87.47 nGy h-1, and 0.106 mSv y-1, respectively, in virgin soils, with average Hex of 0.525. Results were discussed and compared with those reported in similar studies and with internationally recommended values. PMID- 27965988 TI - Single molecule based SNP detection using designed DNA carriers and solid-state nanopores. AB - Single nucleotide polymorphisms (SNPs) play a crucial role as molecular markers in medical and diagnostic application. We demonstrate a nanopore based method for SNP detection at the single molecule level. Designed DNA carriers are used to distinguish DNA strands containing only one single base difference and follow strand displacement kinetics. PMID- 27965986 TI - Donor Cell Composition and Reactivity Predict Risk of Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation. AB - Background. Graft-versus-host disease (GVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). We designed a functional assay for assessment of individual risk for acute GVHD. Study Design and Methods. Blood samples were collected from patients and donors before HSCT. Two groups of seven patients each were selected, one in which individuals developed acute GVHD grades II-IV and one in which none showed any clinical signs of GVHD. Peripheral blood mononuclear cells (PBMCs) isolated from donors were incubated in mixed lymphocyte cultures (MLCs) with recipient PBMCs. The cells were characterized by flow cytometry before and after MLC. Results. Samples from donors in the GVHD group contained significantly lower frequencies of naive gammadelta T-cells and T-cells expressing NK-cell markers CD56 and CD94. Donor samples in this group also exhibited lower frequencies of naive CD95+ T-cells compared to controls. After MLC, there were dissimilarities in the CD4/CD8 T-cell ratio and frequency of CD69+ T-cells between the two patient groups, with the non GVHD group showing higher frequencies of CD8+ and CD69+ T-cells. Conclusion. We conclude that a thorough flow cytometric analysis of donor cells for phenotype and allogeneic reactivity may be of value when assessing pretransplant risk for severe acute GVHD. PMID- 27965989 TI - Human carnitine biosynthesis proceeds via (2S,3S)-3-hydroxy-Nepsilon trimethyllysine. AB - Nepsilon-Trimethyllysine hydroxylase (TMLH) catalyses the first step in mammalian biosynthesis of carnitine, which plays a crucial role in fatty acid metabolism. The stereochemistry of the 3-hydroxy-Nepsilon-trimethyllysine product of TMLH has not been defined. We report enzymatic and asymmetric synthetic studies, which define the product of TMLH catalysis as (2S,3S)-3-hydroxy-Nepsilon trimethyllysine. PMID- 27965990 TI - An unusual photoconductive property of polyiodide and enhancement by catenating with 3-thiophenemethylamine salt. AB - During our investigation of perovskite solar cell materials, we serendipitously discovered an unusual photoconductive property of polyiodide, which can be enhanced greatly through the interaction of in situ-formed polyiodide and 3 thiophenemethylamine salt. This communication examined the photoconductive properties of polyiodide with and without adding different aromatic methylamine compounds. MATPI2 exhibits a high photoconductivity and short response time. The enhanced photoelectric conversion efficiencies are attributed to the strong interaction of polyiodide and the 3-thiophenemethylamine salt. PMID- 27965991 TI - Correlation ion mobility spectrometry. AB - Using a linearly swept chirp function to modulate a Bradbury-Nielsen (BN) ion gate and application of a common signal processing technique (cross-correlation), we outline a method for obtaining high resolution IMS-MS spectra with ion gate duty cycles approaching 50%. Correlation IMS (CIMS) offers advantages over current multiplexing approaches in IMS-MS, which include the Hadamard and Fourier transforms, by minimizing transform artifacts while maintaining high ion throughput. Although cross-correlation techniques have been utilized previously in the field of IMS, to the best of our knowledge, this approach has not been utilized to obtain spectrum that resembles traditional IMS spectrum with resolving powers approaching the theoretical limit. This new approach relies on a linear sweep, which is a swept frequency signal, commonly utilized in different applications because of its compatibility with the fast Fourier transform (FFT). However, unlike spectra derived from Fourier transformation, CIMS yields data sampling rates that are not dependent upon terminal frequency and takes advantage of several factors unique to IMS operation; the non-linear response of ions at relatively low gate pulse widths, fluctuations in intensity, and peak profiles resembling the input gate pulse vector observed especially noted at low gating frequencies. PMID- 27965992 TI - Full- and reduced-dimensionality instanton calculations of the tunnelling splitting in the formic acid dimer. AB - The ring-polymer instanton approach is applied to compute the ground-state tunnelling splitting of four isotopomers of the formic acid dimer using the accurate PES of Qu and Bowman [Phys. Chem. Chem. Phys., 2016, 18, 24835]. As well as performing the calculations in full dimensionality, we apply a reduced dimensionality approach to study how the results converge as successively more degrees of freedom are included. The instanton approximation compares well to exact quantum results where they are available but shows that nearly all the modes are required to quantitatively obtain the tunnelling splitting. The full dimensional instanton calculation reproduces the experimental results, with an error of only about 20 percent. PMID- 27965994 TI - Happy New Year from ChemComm - still the right place to make an impact! AB - Happy New Year from ChemComm to all our readers, authors and reviewers! We share with you some of our highlights from the last year, and in particular how we aim to support the most outstanding emerging investigators. PMID- 27965993 TI - Characterization of a PEGylated protein therapeutic by ion exchange chromatography with on-line detection by native ESI MS and MS/MS. AB - Detailed profiling of both enzymatic (e.g., glycosylation) and non-enzymatic (e.g., oxidation and deamidation) post-translational modifications (PTMs) is frequently required for the quality assessment of protein-based drugs. Challenging as it is, this task is further complicated for the so-called second generation biopharmaceuticals, which also contain "designer PTMs" introduced to either enhance their pharmacokinetic profiles (e.g., PEGylated proteins) or endow them with therapeutic activity (e.g., protein-drug conjugates). Such modifications of protein covalent structure can dramatically increase structural heterogeneity, making the very notion of "molecular mass" meaningless, as ions representing different glycoforms of a PEGylated protein may have nearly identical distributions of ionic current as a function of m/z, making their contributions to the mass spectrum impossible to distinguish. In this work we demonstrate that a combination of ion exchange chromatography (IXC) with on-line detection by electrospray ionization mass spectrometry (ESI MS) and methods of ion manipulation in the gas phase (limited charge reduction and collision-induced dissociation) allows meaningful structural information to be obtained on a structurally heterogeneous sample of PEGylated interferon beta-1a. IXC profiling of the protein sample gives rise to a convoluted chromatogram with several partially resolved peaks which can represent both deamidation and different glycosylation patterns within the protein, as well as varying extent of PEGylation. Thus, profiling the protein with on-line IXC/ESI/MS/MS allows it to be characterized by providing information on three different types of PTMs (designer, enzymatic and non-enzymatic) within a single protein therapeutic. PMID- 27965995 TI - A circumflex coronary artery-to-right atrial fistula in a 10-month-old child. AB - A coronary fistula (CF) is a rare congenital cardiac anomaly in which there is a connection between the coronary artery and a cardiac chamber or a great vessel. In the paediatric population, a CF is usually asymptomatic. While the circumflex coronary artery (Cx) is the least common source of a CF, the right heart chambers are the most common location of drainage. Herein, we present a symptomatic 10 month-old boy with an atrial septal defect (ASD) in whom we incidentally detected a CF, which stemmed from the Cx and drained to the right atrium. Because the patient was symptomatic and his small size was not appropriate for percutaneous closure of the ASD, surgical closure of the ASD and CF was performed. PMID- 27965996 TI - Measuring publication impact, and publishing and funding models. PMID- 27965997 TI - The importance of perseverance, pilot studies and the search for effective adjuvant therapies in the management of tuberculous pericarditis. PMID- 27965998 TI - A prospective investigation into the effect of colchicine on tuberculous pericarditis. AB - INTRODUCTION: Tuberculous (TB) pericarditis carries significant mortality and morbidity rates, not only during the primary infection, but also as part of the granulomatous scar-forming fibrocalcific constrictive pericarditis so commonly associated with this disease. Numerous therapies have previously been investigated as adjuvant strategies in the prevention of pericardial constriction. Colchicine is well described in the treatment of various aetiologies of pericarditis. The aim of this research was to investigate the merit for the use of colchicine in the management of tuberculous pericarditis, specifically to prevent constrictive pericarditis. METHODS: This pilot study was designed as a prospective, double-blinded, randomised, control cohort study and was conducted at a secondary level hospital in the Northern Cape of South Africa between August 2013 and December 2015. Patients with a probable or definite diagnosis of TB pericarditis were included (n = 33). Study participants with pericardial effusions amenable to pericardiocentesis underwent aspiration until dryness. All patients were treated with standard TB treatment and corticosteroids in accordance with the South African Tuberculosis Treatment Guidelines. Patients were randomised to an intervention and control group using a web-based computer system that ensured assignment concealment. The intervention group received colchicine 1.0 mg per day for six weeks and the control group received a placebo for the same period. Patients were followed up with serial echocardiography for 16 weeks. The primary outcome assessed was the development of pericardial constriction. Upon completion of the research period, the blinding was unveiled and data were presented for statistical analysis. RESULTS: TB pericarditis was found exclusively in HIV-positive individuals. The incidence of pericardial constriction in our cohort was 23.8%. No demonstrable benefit with the use of colchicine was found in terms of prevention of pericardial constriction (p = 0.88, relative risk 1.07, 95% CI: 0.46-2.46). Interestingly, pericardiocentesis appeared to decrease the incidence of pericardial constriction. CONCLUSION: Based on this research, the use of colchicine in TB pericarditis cannot be advised. Adjuvant therapy in the prevention of pericardial constriction is still being investigated and routine pericardiocentesis may prove to be beneficial in this regard. PMID- 27965999 TI - Uncontrolled hypertension among patients managed in primary healthcare facilities in Kinshasa, Democratic Republic of the Congo. AB - BACKGROUND: Uncontrolled hypertension remains an important issue in daily clinical practice worldwide. Although the majority of patients are treated in primary care, most of the data on blood pressure control originate from population-based studies or secondary healthcare. OBJECTIVE: The aim of this study was to evaluate the frequency of uncontrolled hypertension and associated risk factors among hypertensive patients followed at primary care facilities in Kinshasa, the capital city of Democratic Republic of the Congo. METHODS: A sample of 298 hypertensive patients seen at primary healthcare facilities, 90 men and 208 women, aged >= 18 years, were consecutively included in this cross-sectional study. The majority (66%) was receiving monotherapy, and diuretics (43%) were the most used drugs. According to 2007 European Society of Hypertension/European Society of Cardiology hypertension guidelines, uncontrolled hypertension was defined as blood pressure >= 140/90 or >= 130/80 mmHg (diabetes or chronic kidney disease). Logistic regression analysis was used to identify the determinants of uncontrolled hypertension. RESULTS: Uncontrolled hypertension was observed in 231 patients (77.5%), 72 men and 159 women. Uncontrolled systolic blood pressure (SBP) was more frequent than uncontrolled diastolic blood pressure (DBP) and increased significantly with advancing age (p = 0.002). The proportion of uncontrolled SBP and DBP was significantly higher in patients with renal failure (p = 0.01) and those with high (p = 0.03) to very high (p = 0.02) absolute cardiovascular risk. The metabolic syndrome (OR 2.40; 95% CI 1.01-5.74; p = 0.04) emerged as the main risk factor associated with uncontrolled hypertension. CONCLUSION: Uncontrolled hypertension was common in this case series and was associated with factors related to lifestyle and diet, which interact with blood pressure control. PMID- 27966000 TI - The differential effects of FTY720 on functional recovery and infarct size following myocardial ischaemia/reperfusion. AB - AIM: The aim of this study was to evaluate the effects of the sphingosine analogue, FTY720 (Fingolimod), on the outcomes of myocardial ischaemia/reperfusion (I/R) injury. METHODS: Two concentrations of FTY720 (1 or 2.5 uM were administered either prior to (PreFTY), or following (PostFTY) 20 minutes' global (GI) or 35 minutes' regional ischaemia (RI) in the isolated, perfused, working rat heart. Functional recovery during reperfusion was assessed following both models of ischaemia, while infarct size (IFS) was determined following RI. RESULTS: FTY720 at 1 uM exerted no effect on functional recovery, while 2.5 uM significantly impaired aortic output (AO) recovery when administered prior to GI (% recovery: control: 33.88 +/- 6.12% vs PreFTY: 0%, n = 6-10; p < 0.001), as well as before and after RI ( % recovery: control: 27.86 +/- 13.22% vs PreFTY: 0.62% ; p < 0.05; and PostFTY: 2.08%; p = 0.0585, n = 6). FTY720 at 1 uM administered during reperfusion reduced IFS (% of area at risk (AAR): control: 39.89 +/- 3.93% vs PostFTY: 26.56 +/- 4.32%, n = 6-8; p < 0.05), while 2.5 uM FTY720 reduced IFS irrespective of the time of administration ( % of AAR: control: 39.89 +/- 3.93% vs PreFTY: 29.97 +/- 1.03% ; and PostFTY: 30.45 +/- 2.16%, n = 6; p < 0.05). CONCLUSION: FTY720 exerted divergent outcomes on function and tissue survival depending on the concentration administered, as well as the timing of administration. PMID- 27966002 TI - European Society of Cardiology congress update, Rome, 27-31 August 2016. PMID- 27966001 TI - Cortisol:brain-derived neurotrophic factor ratio associated with silent ischaemia in a black male cohort: the SA BPA study. AB - AIM: Emotional distress has been associated with cardiovascular disease (CVD) in Africans. Cortisol and brain-derived neurotrophic factor (BDNF), as markers of emotional distress, increase cardiometabolic risk. We therefore aimed to investigate associations between cardiometabolic risk markers and the cortisol-to BDNF ratio (cortisol:BDNF). METHODS: A cross-sectional study included a bi-ethnic gender cohort (n = 406) aged 44.7 +/- 9.52 years. Ambulatory blood pressure (ABPM), ECG, fasting serum cortisol and BDNF levels and cardiometabolic risk markers were obtained. RESULTS: Africans had increased incidence of hyperglycaemia and 24-hour silent ischaemic events, and elevated 24-hour blood pressure (BP) and cortisol:BDNF ratios compared to Caucasians. Forward stepwise linear regression analysis underscored a similar trend with associations between hyperglycaemia, 24-hour BP [Adj R2 0.21-0.29; beta 0.23 (0.1-0.4); p = 0.01], silent ischaemia [Adj R2 0.22; beta 0.40 (0.2-0.6); p < 0.01] and cortisol:BDNF levels in Africans, mostly in the men. CONCLUSION: Attenuated cortisol levels in this group may be indicative of emotional distress and if chronic, drive the cortisol:BDNF ratio to desensitise BDNF. Desensitised cortisol:BDNF may sustain cardiometabolic risk and induce neurodegeneration in African men via silent ischaemia. Compensatory increases in blood pressure to increase perfusion and maintain homeostasis may increase coronary artery disease risk. PMID- 27966003 TI - SASCI/SCTSSA joint consensus statement and guidelines on transcatheter aortic valve implantation (TAVI) in South Africa. PMID- 27966004 TI - Management of cardiovascular disease in aging persons with haemophilia. AB - With the aging of the haemophilia population, age related comorbidities become more and more a medical issue. Managing haemophilia patients with cardiovascular disease is a difficult task for many haemophilia-treating physicians. Over the years, insights on prevalence, risk factors and management of cardiovascular disease in haemophilia have improved substantially. It is now recognised that many risk factors, such as hypertension and overweight, occur quite frequently in patients with haemophilia. Several new insights in anticoagulation management of atrial fibrillation and coronary ischaemia in haemophilia have been suggested. This review provides an general overview of the current knowledge of these topics in literature. PMID- 27965958 TI - A Dormant Microbial Component in the Development of Preeclampsia. AB - Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused. We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is, in fact, microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of "preeclampsia" that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills the Bradford Hill criteria for ascribing a disease to an environmental cause and suggests a number of treatments, some of which have, in fact, been shown to be successful. PE was classically referred to as endotoxemia or toxemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one. PMID- 27966007 TI - ? PMID- 27966006 TI - Medical Record Keeping in the Summer Camp Setting. AB - BACKGROUND: Approximately one fifth of school-aged children spend a significant portion of their year at residential summer camp, and a growing number have chronic medical conditions. Camp health records are essential for safe, efficient care and for transitions between camp and home providers, yet little research exists regarding these systems. OBJECTIVE: To survey residential summer camps for children to determine how camps create, store, and use camper health records. To raise awareness in the informatics community of the issues experienced by health providers working in a special pediatric care setting. METHODS: We designed a web based electronic survey concerning medical recordkeeping and healthcare practices at summer camps. 953 camps accredited by the American Camp Association received the survey. Responses were consolidated and evaluated for trends and conclusions. RESULTS: Of 953 camps contacted, 298 (31%) responded to the survey. Among respondents, 49.3% stated that there was no computer available at the health center, and 14.8% of camps stated that there was not any computer available to health staff at all. 41.1% of camps stated that internet access was not available. The most common complaints concerning recordkeeping practices were time burden, adequate completion, and consistency. CONCLUSIONS: Summer camps in the United States make efforts to appropriately document healthcare given to campers, but inconsistency and inefficiency may be barriers to staff productivity, staff satisfaction, and quality of care. Survey responses suggest that the current methods used by camps to document healthcare cause limitations in consistency, efficiency, and communications between providers, camp staff, and parents. As of 2012, survey respondents articulated need for a standard software to document summer camp healthcare practices that accounts for camp-specific needs. Improvement may be achieved if documentation software offers the networking capability, simplicity, pediatrics-specific features, and avoidance of technical jargon. PMID- 27966005 TI - ePrescribing: Reducing Costs through In-Class Therapeutic Interchange. AB - INTRODUCTION: Spending on pharmaceuticals in the US reached $373.9 billion in 2014. Therapeutic interchange offers potential medication cost savings by replacing a prescribed drug for an equally efficacious therapeutic alternative. METHODS: Hard-stop therapeutic interchange recommendation alerts were developed for four medication classes (HMG-CoA reductase inhibitors, serotonin receptor agonists, intranasal steroid sprays, and proton-pump inhibitors) in an electronic prescription-writing tool for outpatient prescriptions. Using prescription data from January 2012 to June 2015, the Compliance Ratio (CR) was calculated by dividing the number of prescriptions with recommended therapeutic interchange medications by the number of prescriptions with non-recommended medications to measure effectiveness. To explore potential cost savings, prescription data and medication costs were analyzed for the 45,000 Vanderbilt Employee Health Plan members. RESULTS: For all medication classes, significant improvements were demonstrated - the CR improved (proton-pump inhibitors 2.8 to 5.32, nasal steroids 2.44 to 8.16, statins 2.06 to 5.51, and serotonin receptor agonists 0.8 to 1.52). Quarterly savings through the four therapeutic interchange interventions combined exceeded $200,000 with an estimated annual savings for the health plan of $800,000, or more than $17 per member. CONCLUSION: A therapeutic interchange clinical decision support tool at the point of prescribing resulted in increased compliance with recommendations for outpatient prescriptions while producing substantial cost savings to the Vanderbilt Employee Health Plan - $17.77 per member per year. Therapeutic interchange rules require rational targeting, appropriate governance, and vigilant content updates. PMID- 27966010 TI - [Computer games for prevention of delirium?] PMID- 27966008 TI - [Mechanobiology of fracture healing part 1 : Principles]. AB - It is undisputed that the stability of fracture fixation influences the fracture healing process; however, up until now the mechanical conditions which guide bone healing were unknown and it was therefore not possible to optimize the design of fracture fixation devices. This article presents how the stability of fracture fixation, interfragmentary movement and interfragmentary tissue strain depend on each other and how the mechanical environment influences the cellular processes in the healing tissue. A tissue transformation hypothesis is presented which was developed taking into consideration the results of animal experimental studies, cellular biomechanical investigations and numerical methods. This tissue differentiation hypothesis allows the prediction of bone healing by intramembranous and endochondral bone formation as a function of the local mechanical environment in the fracture healing zone. This allows the possibility for selection of a fracture fixation stability to achieve high-quality bone healing. PMID- 27966011 TI - [Factors which influence the position towards euthanasia : Results of a representative survey among older people in Germany]. AB - BACKGROUND: Until now older adults have not been a target group for surveys regarding their personal attitudes towards euthanasia, although they are closest to chronic illness and death. OBJECTIVE: To determine the attitudes of older adults towards euthanasia and controversial topics in the context of illness, euthanasia and care (e. g. palliative care) on the basis of a representative sample. MATERIAL AND METHODS: The study was based on a postal survey of a representative random sample of the population aged 65 years and older (n = 3500) from a city in southern Germany using a standardized questionnaire. RESULTS: A total of 1068 persons completed the questionnaire (response rate 30.5%). Assisted death was supported by 74.2% of the respondants and assisted suicide by 80.4%. According to multiple logistic regression analysis the support decreased with increasing strength of religious faith and a non-German country of origin. Of the participants 53.3% were worried about being a burden to their family, especially people with a limited state of health. People who shared this concern showed significantly more support for both types of euthanasia. More than 40% feared that people with severe and incurable illnesses would be more likely to be forced into a premature death (slippery slope argument). This concern was associated with a decreasing support of euthanasia. CONCLUSION: The results indicate that the strong approval of the legalization of assisted death and assisted suicide by older people is motivated not only by their desire for a self-determined death but also by fears and concerns. The findings have important implications for counseling, palliative care and treatment. PMID- 27966009 TI - [Interventions for promoting physical activity in nursing homes : Systematic review of the effectiveness of universal prevention]. AB - BACKGROUND: Among residents of nursing homes, physical activity might be beneficial in maintaining health-related quality of life because impairment is caused in particular by functional decline. The aim is the evaluation of the effectiveness of universal preventive interventions directed at increasing physical activity on activities of daily living in nursing home residents. MATERIAL AND METHODS: Relevant studies were identified through database searching in MEDLINE, the Cochrane library, EMBASE, CINAHL, PsycINFO and PEDro. Two review authors independently selected articles, assessed the risk of bias and extracted data. Results were combined in random effects meta-analyses. RESULTS: By including 14 primary studies, nursing home residents participating in physical activities showed a statistically significant greater physical functioning compared to controls (standardized mean difference [SMD] = 0.48, 95% confidence interval [95% CI] 0.26-0.71, p < 0.0001). Subgroup analyses suggest that especially nursing home residents with severe physical and cognitive impairment might benefit from participation in physical activities. Results after non training periods substantiate the necessity of a sustained implementation. Due to the high risk of bias in included studies, the results must be interpreted with caution. CONCLUSION: Physical activity for nursing home residents can be effective. Considering the low-quality evidence, performance of high-quality studies is essential in order to verify the statistical results. PMID- 27966012 TI - [Surface replacement of proximal interphalangeal joints using CapFlex-PIP]. AB - OBJECTIVE OF SURGERY: The cementless implantation of the surface replacement CapFlex-PIP enables pain relief, preservation of motion, improves lateral stability and corrects axis deviation in proximal interphalangeal (PIP) joints of patients with primary and secondary PIP osteoarthritis. INDICATIONS: Painful PIP joints as a result of degenerative or posttraumatic osteoarthritis with restriction of motion. Secondary inflammatory destruction of PIP joints in rheumatoid arthritis with low inflammatory activity and good bone conditions. CONTRAINDICATIONS: Destruction of PIP joints with severe bone loss, osseous defects and chronic joint luxation. Joint destruction induced by florid or subacute bacterial arthritis. Skin infections. SURGICAL TECHNIQUE: Dorsal or palmar incision over the affected PIP joint while sparing the peritendinous tissue. Exposure of the proximal phalangeal head and meticulous bone resection. Precontouring of the bone bed for proximal prosthesis. Insertion of the trial prosthesis. Exposure of the distal base and resection in the correct axis. Determination of distal prosthesis size and height of the polyethylene inlay. Insertion of the trial prosthesis without bone protrusion. After clinical and radiological control, implantation of the final prosthesis. FOLLOW-UP: Long finger splint, palmar flexor support splint for 2-3 weeks with active mobilization. Then active free mobilization with a twin bandage. After 6 weeks radiological check and free functional mobilization. RESULTS: The active range of motion of 50 patients increased from 43.4 degrees before surgery to 55.9 degrees after 1 year with concomitant pain relief (6.5 to 2.2). In one case revision surgery was required due to traumatic rupture of the radial collateral ligament and four secondary tenolyses were performed. PMID- 27966013 TI - Choice of marker for assessment of RV dysfunction in acute pulmonary embolism : NT-proBNP, pulmonary artery systolic pressure, mean arterial pressure, or blood pressure index. AB - BACKGROUND: We aimed to examine the value of NT-proBNP, pulmonary artery systolic pressure (PASP), blood pressure index (BPI), and mean arterial pressure (MAP) in the determination of right ventricular dysfunction (RVD) in patients with acute pulmonary embolism (APE). PATIENTS AND METHODS: A total of 547 patients diagnosed with APE were included in the study. Demographic characteristics and comorbid conditions of patients were recorded in patient files. For blood pressure measurement, a calibrated digital blood pressure monitor was used at regular intervals. Blood samples were taken from patients at the time of admission for hemogram, biochemical, and hemostasis blood tests. Echocardiography was performed on all patients to detect RVD and evaluate pulmonary artery pressure. RESULTS: PASP (p < 0.001), MAP (p < 0.001), diastolic blood pressure (p < 0.001), D-dimer (p = 0.001), NT-proBNP (p = 0.001), white blood cell (p < 0.001), and platelet (p = 0.001) counts were higher in APE patients with RVD compared with those without RVD, whereas the mean BPI level (p < 0.001) was lower. BPI had a negative correlation with PASP, NT-proBNP, platelet count, and triglyceride levels in patients with RVD. In regression analysis, BPI and PASP were found to be independent predictors of RVD. In receiver operating characteristic curve analysis, BPI (AUC +/- SE = 0.975 +/- 0.006; p < 0.001) was found to be the best predictor of RVD with a higher sensitivity (92.8%) and specificity (100%). CONCLUSION: We found that BPI had a better diagnostic discrimination for RVD compared with PASP and NT-proBNP. PMID- 27966014 TI - [Data on palliative care in Germany : Which data sources are available and what do they tell?] AB - Palliative care is more and more in the focus of politics and the public. Although provision and utilization of palliative care have increased considerably in recent years, there is still a great need for palliative services and a comprehensive supply has not yet been achieved. Reliable and continually available data are indispensable to describe developments in Germany, to identify existing gaps in palliative care provision, and to assess the impact of relevant policies. In this article, we present a systematic outline of publicly available data sources on palliative care in Germany and point out their potentials and limitations. We show that mainly data on palliative care provision are available. Data on utilization are basically limited to inpatient and specialized outpatient palliative care ("spezialisierte ambulante Palliativversorgung", SAPV). Periodical analyses of routine data, e. g. from statutory health insurances or from the Association of Statutory Health Insurance Physicians, would be helpful to fill these data gaps. Monitoring the sociodemographic characteristics of users of palliative care could also be of major interest. Another important indicator is the place of death. The difference between the places where people die and where they wish to die indicates that there is a continuous need to strengthen outpatient structures of palliative care. PMID- 27966017 TI - SEI-forming electrolyte additives for lithium-ion batteries: development and benchmarking of computational approaches. AB - SEI-forming additives play an important role in lithium-ion batteries, and the key to improving battery functionality is to determine if, how, and when these additives are reduced. Here, we tested a number of computational approaches and methods to determine the best way to predict and describe the properties of the additives. A wide selection of factors were evaluated, including the influences of the solvent and lithium cation as well as the DFT functional and basis set used. An optimized computational methodology was employed to assess the usefulness of different descriptors. PMID- 27966016 TI - Austrian recommendations for the management of primary myelofibrosis, post polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis: an expert statement. AB - The entity "myelofibrosis" represents a subgroup of the Philadelphia chromosome negative myeloproliferative neoplasms. It comprises primary myelofibrosis, post polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. This heterogeneous disease is characterized by clonal myeloproliferation, dysregulated kinase signalling and the abnormal expression of several proinflammatory cytokines. Clinically, patients present with symptoms related to thrombocytosis/leukocytosis, anemia and/or progressive splenomegaly. Mutations in Janus kinase 2, an enzyme that is essential for the normal development of erythrocytes, granulocytes, and platelets, notably the V617F mutation, have been identified in approximately 60% of patients with primary myelofibrosis. Recent molecular advances have not only elucidated critical pathways in the pathogenesis of the disease, but also contributed to a more precise assessment of a patient's individual risk. While allogeneic stem cell transplantation remains the only curative treatment, the natural course of the disease and the patient's survival and quality of life may be improved by new treatments, notably ruxolitinib, the first Janus kinase 1/2 inhibitor approved for the management of myelofibrosis. Additional treatment options are being explored. PMID- 27966015 TI - Oral shedding of human herpesviruses in patients undergoing radiotherapy/chemotherapy treatment for head and neck squamous cell carcinoma. AB - OBJECTIVE: Opportunistic infections may affect the oral mucosa of patients undergoing radio/chemotherapy through exacerbation of oral mucositis. The aim of this study is to evaluate the oral shedding of all eight human herpesviruses and its possible association with oral mucositis. MATERIALS AND METHODS: In this prospective cohort study, we analyzed oral rinse samples, collected weekly, from 20 patients during radiotherapy treatment. Serologic status to HSV1 and HSV2, EBV, CMV, and VZV in three different periods was performed by ELISA assay. PCR and enzymatic digestion was performed to detect HSV1, HSV2, EBV, CMV, VZV, HHV6, HHV7, and HHV8. Oral mucositis was evaluated according to the WHO criteria. RESULTS: Oral shedding of EBV, HHV6, and HHV7 was observed in all weeks of radiotherapy. Considering the episodes of shedding, the highest frequency was found in patients with EBV excretion (55.0%). No virus reactivation was observed by serological analysis. EBV oral shedding frequency was significantly higher than that of other viruses and showing a positive correlation with oral mucositis grade >=2. CONCLUSIONS: There was a positive correlation between EBV oral shedding and oral mucositis grade >=2, particularly after 3 weeks of radiotherapy, a period in which the severity of mucositis was statistically higher. These findings allow us to infer that the local inflammatory environment in mucositis grade >=2 is more favorable for EBV replication. CLINICAL RELEVANCE: Mucositis is a frequent and important side effect of radio/chemotherapy treatment. Understanding the possible participation of viruses in the mechanism of this condition is important to develop strategies for treatment and prevention. PMID- 27966018 TI - Identification of lead BAY60-7550 analogues as potential inhibitors that utilize the hydrophobic groove in PDE2A: a molecular dynamics simulation study. AB - The phosphodiesterase (PDE) family of proteins are important regulators of signal transduction, which they achieve by controlling the secondary messengers cyclic AMP (cAMP) and cyclic GMP (cGMP). cAMP and cGMP are involved in many critical intracellular processes such as gene transcription, kinase activation, signal transduction in learning and memory, and channel function as secondary messengers. The involvement of PDEs in neuronal communication has made them important therapeutic targets. Considering the recent discovery that PDE2A inhibition can improve cognitive functioning, a combined molecular dynamics simulation and scoring and docking study was carried out to identify selective inhibitors of PDE2A that specifically interact with the recently discovered hydrophobic groove in PDE2A. Using the X-ray crystal structure of PDE2A (from PDB ID: 4HTX), we investigated the binding modes of a range of promising inhibitors based on the known PDE2A inhibitor BAY60-7550 to PDE2A. Graphical abstract The lead molecule showing highest MMPBSA binding energy with 2D and 3D binding pose in hydrophobic groove. PMID- 27966019 TI - Fear of clowns in hospitalized children: prospective experience. AB - : Medical clowns (MC) have become an integral part of the pediatric staff of hospital wards. While several studies have demonstrated the huge benefits of MC, there are almost no data regarding fear of clowns, a known phenomenon that means an irrational fear of clowns. In the current study, we sought to examine the prevalence of fear of clowns in pediatrics wards, and to characterize the affected children. The clinical work of three certified MCs was prospectively assessed. Every child with fear of clowns was noted, data were retrieved from the medical records, and the parents/child completed a specific questionnaire with a research assistant. Fear of clowns was defined as crying, anxiety response or effort to avoid contact with the MCs in small children, while in older children, it was determined if the child either reported fear of MCs or made actions to avoid clowns' intervention. A total of 1160 children participated in the study. All were hospitalized in the department of pediatrics or the pediatric emergency medicine department at Carmel Medical Center, and were exposed to a MC intervention session. Of the 1160 children, 14 children experienced fear of clowns (1.2%). The average age of children who experienced fear of clowns was 3.5 years (range 1-15). Interestingly, most of the children demonstrating fear of clowns were girls (12 out of 14, 85.7%). We found no association between fear of clowns and specific diagnosis, fever, clinical appearance, religion, or ethnicity. CONCLUSION: The prevalence of fear of clowns in the general pediatric hospitalized population was 1.2%, with a significant predominance of girls (85.7%). Children who experienced significant fear of clowns also experienced significant fear of encountering or thinking about a MC visit. Fear of clowns can affect children at any age (range 1-15), any ethnicity, religion, or degree of illness. Further large scale studies are required to better understand this unique phenomenon of fear of clowns. What is Known: * Fear of clowns is a phenomenon known for more than several decades and related to the increased use of clowns as negative characters in horror movies and TV shows. * The increased use of medical clowns in hospital wards and corridors increases the significance of defining and characterizing this phenomenon in hospital wards. What is New: * The study is novel by giving new data related to the extent of fear of clowns in pediatrics wards and giving demographic characteristic of children experiencing fear of clowns. PMID- 27966020 TI - Application of Western blot analysis for the diagnosis of Encephalitozoon cuniculi infection in rabbits: example of a quantitative approach. AB - Diagnosis of Encephalitozoon cuniculi infection in rabbits remains a major veterinary issue. ELISA or immunofluorescence assays are the current reference standards of serological tests. However, these conventional techniques suffer from a lack of accuracy for distinguishing active from past infections, as a positive serostatus is common in clinically normal rabbits. In this study, we assessed the diagnostic performance of Western blot (WB) to detect both anti-E. cuniculi immunoglobulin G (IgG) and immunoglobulin M (IgM) in comparison with ELISA and to address the intensity of the immune response through a quantitative approach. Positive WB results were highly correlated with the E. cuniculi-related diseased status (P < 0.0001). Although it was more labor intensive and less standardized, quantitative WB provided detailed comparable analysis regarding the humoral response and diagnostic performance similar to ELISA testing with statistically higher sensitivity (88.4 vs. 76.1% for IgG detection and 84.3 vs. 70.4% for IgM, P < 0.01). Several specific WB bands were shown to be significantly associated with concomitant clinical signs, like the one located at 50 kDa (OR = 8.2, [2.4-27.7], P = 0.0008) for IgG and (OR = 27.9, [4.2-187.9], P = 0.0006) for IgM. Therefore, the quantitative WB may have application in veterinary diagnostic laboratories to increase the accuracy of the clinical diagnosis of E. cuniculi infection. In addition, this tool may help to further understand the development and function of the humoral immune response to this infectious agent. PMID- 27966021 TI - Short hydration regimen with magnesium supplementation prevents cisplatin-induced nephrotoxicity in lung cancer: a retrospective analysis. AB - PURPOSE: The purpose of this study was to evaluate renal function in lung cancer patients who were administered cisplatin with continuous higher-volume hydration (CH) or a short hydration (SH) regimen. METHODS: We retrospectively evaluated patients with lung cancer who were treated with chemotherapy regimens including >50 mg/m2 of cisplatin between August 2007 and March 2015. Between August 2007 and December 2012, patients received a continuous higher-volume hydration regimen without magnesium (Mg) supplementation (CH group), and after May 2013, patients received a short hydration regimen with Mg supplementation (SH group). To evaluate the factors influencing serum creatinine (SCr) increase during the first course of cisplatin chemotherapy, univariate and multivariate logistic regression analyses were conducted. RESULTS: A total of 122 patients were evaluated, 62 patients in the CH group and 60 patients in the SH group. Grade 1 (National Cancer Institute Common Toxicity Criteria for Adverse Events; version 4.0) or higher SCr increases were more frequently observed in the CH group than in the SH group after the first cycle (P = 0.01, Fisher's exact test) and for all cycles (P = 0.03). Multivariate analysis revealed that short hydration (odds ratio (OR), 0.30; 95% confidence internal (CI) (0.11-0.75), P = 0.01) and estimated creatinine clearance (eCcr) of >=70 mL/min (OR, 0.25; 95% CI (0.088-0.69), P = 0.008) were associated with a significantly reduced risk for cisplatin-induced grade 1 or higher SCr increase. CONCLUSION: Our study suggested that a short hydration method with Mg supplementation and eCcr of >=70 mL/min reduced the risk of cisplatin-induced nephrotoxicity. PMID- 27966022 TI - Prevalence and predictors of posttraumatic stress symptoms in parents of children with ongoing treatment for cancer in South China: a multi-centered cross sectional study. AB - PURPOSE: Parents of children with ongoing cancer treatment are exposed to risks of developing posttraumatic stress symptoms (PTSS), but little is known about the prevalence and predictors of PTSS among Chinese parents of children with cancer. This study aimed to examine the predictors of PTSS, and explored the correlation of depression, resilience, and family functions with severe PTSS. METHODS: This cross-sectional survey was conducted from May 2014 to September 2015 among the parents of cancer children treated in four general hospitals in South China. PTSS in the parents were measured using post-traumatic stress checklist-civilian version (PCL-C). Multiple regression analyses were performed to evaluate the predictive values of depression, resilience, family functioning, and the demographic variables for severe PTSS. RESULTS: A total of 279 parents (192 mothers and 87 fathers) participated in the survey. Severe PTSS, as defined by a PCL-C score >=50, were reported in 32.97% (n = 92) of the total participants, 26.44% (23/87) in the fathers and 35.94% (69/192) in the mothers. The level of PTSS was positively correlated with depression (r = 0.782, P < 0.01) and a poor general family function (r = 0.325, P < 0.01) and negatively correlated with resilience (r = -0.236, P < 0.01). Multivariate analyses indicated that depression, general family function, gender, and education level were significant predictive factors of severe PTSS in the overall parents, accounting for 64.2% of the variance in the prediction of PTSS (R 2 = 0.642, F = 122.602, P = 0.000). For the mothers, depression and family function accounted for 66.5% of the variance in the prediction of PTSS (R 2 = 0.665, F = 187.451, P = 0.000); for the fathers, depression and educational level accounted for 58.8% of the variance in the prediction of PTSS (R 2 = 0.588, F = 59.829, P = 0.000). CONCLUSION: Parents, especially the mothers, of children with ongoing treatment for cancer are at risk of developing PTSS. Supportive psychological interventions to attenuate the negative emotions of the parents and improve their family functions are important means to promote their natural protective mechanisms to cope with the stressful events. PMID- 27966023 TI - Bismuth adjuvant ameliorates adverse effects of high-dose chemotherapy in patients with multiple myeloma and malignant lymphoma undergoing autologous stem cell transplantation: a randomised, double-blind, prospective pilot study. AB - PURPOSE: High-dose chemotherapy prior to autologous stem cell transplantation (ASCT) leads to adverse effects including mucositis, neutropenia and bacteremia. To reduce the toxicity, we treated myeloma and lymphoma patients with peroral bismuth as an adjuvant to chemotherapy to convey cytoprotection in non-malignant cells. METHODS: This trial was a prospective, randomised, double-blind, placebo controlled pilot study of hematological inpatients (n = 50) receiving bismuth or placebo tablets, in order to identify any potential superiority of bismuth on toxicity from chemotherapy. RESULTS: We show for the first time that bismuth significantly reduces grade 2 stomatitis, febrile neutropenia and infections caused by melphalan in multiple myeloma, where adverse effects also were significantly linked to gender. In lymphoma patients, bismuth significantly reduces diarrhoea relative to placebo. Also, lymphoma patients' adverse effects were linked to gender. For the first time, bismuth is demonstrated as a safe strategy against chemotherapy's toxicity without interfering with intentional anti-cancer efficiency. Also, we show how gender significantly influences various adverse effects and response to treatment in both multiple myeloma and malignant lymphomas. CONCLUSION: These results may impact clinical prevention of chemotherapy's cytotoxicity in certain patient groups, and also, this study may direct further attention towards the impact of gender during the course and treatment outcome of malignant disorders. PMID- 27966024 TI - Comparing the symptom experience of cancer patients and non-cancer patients. AB - PURPOSE: Symptom burden is an established concept in oncology encompassing the presence and severity of symptoms experienced by cancer patients. Few studies have examined differences in symptom burden between cancer patients and non cancer patients. This study seeks to examine the differences in symptom burden between cancer patients (CP) and non-cancer patients (NCP) in order to better understand symptom burden in both populations. METHODS: Two groups of patients completed the Memorial Symptom Assessment Scale: 301 patients from a general medical clinic and 558 cancer patients from a cancer tumor registry. Participants provided demographic information-age, race/ethnicity, and sex and completed the Memorial Symptom Assessment Scale. Medical comorbidity was also measured. RESULTS: Most symptoms were more common in CP, except for pain, which was more prevalent in the NCP (45% of CP vs. 54% of NCP, p < .05). There was no difference in prevalence for the following symptoms: dry mouth, mouth sores, feeling nervous, worry, cough, and dizziness. The CP had greater mean MSAS Total scores (0.53 vs. 0.43, p < .01), number of symptoms (9.11 vs. 6.13, p < .01), and psychological subscale scores (0.77 vs. 0.64, p < .05). There was no difference by group in the physical nor the GDI subscale scores. CONCLUSION: The results of this study support the perception that cancer patients have greater symptom burden. There were some unexpected results, particularly in terms of pain, which was more common in NCP and other symptoms that were experienced equally in both patient populations. PMID- 27966025 TI - Fear of recurrence or progression as a link between somatic symptoms and perceived stress among cancer survivors. AB - PURPOSE: Many cancer survivors report experiencing somatic symptoms as well as elevated stress. Theoretical models have suggested that physical symptoms generate subjective stress via fears of recurrence or progression. To date, this indirect effect has not been established empirically. This study aimed to provide preliminary evidence as to whether fear of recurrence or progression is an intermediary between somatic symptom severity and perceived stress among heterogeneous cancer survivors. METHODS: Adult cancer survivors (N = 67; median 2.4 years since diagnosis; 34% male) presenting at a hospital survivorship clinic completed measures assessing somatic symptom severity (Patient Health Questionnaire-15 (PHQ-15)), perceived stress (four-item Perceived Stress Scale (PSS-4)), and fear of recurrence or progression (Assessment of Survivor Concerns (ASC)). Interrelatedness among variables was assessed using Pearson correlations. Indirect effects were modeled using 5000-iteration bootstrapping. RESULTS: Survivors endorsed a range of somatic symptom severity (29% minimal, 39% low, 18% medium, and 14% high). Somatic symptoms, perceived stress, and fear of recurrence or progression were all significantly positively correlated (rs 0.29 to 0.47). Controlling for time since diagnosis, there was a significant indirect effect of somatic symptom severity on stress via fear of recurrence or progression [B = 0.06, SE = 0.04 (95% CI 0.01-0.16)]. The model accounted for more than one third of the variance in perceived stress [R 2 = 0.35, F(3,54) = 9.59, p < 0.001]. CONCLUSIONS: Survivors with greater somatic symptoms tended to report higher levels of stress, due in part to elevated fears of recurrence or progression. Our findings support concerns about recurrence or progression as a mechanism underlying stress states in cancer survivors. Efforts to assist survivors with stress management should teach strategies for managing cancer-related uncertainties stemming from somatic symptoms. PMID- 27966028 TI - Abstracts 2017 Society of Skeletal Radiology Annual Scientific Meeting. PMID- 27966026 TI - Retrospective study of unplanned hospital admission for metastatic cancer patients visiting the emergency department. AB - PURPOSE: The purpose of the study was to identify factors that predict unplanned admission for metastatic cancer patients visiting the emergency department (ED). METHODS: Patients visiting the ED of a general hospital from April 2012 to March 2013 were investigated retrospectively. Data including demographics, vital signs, and laboratory measurements were collected from a chart review for each patient. Factors related to emergency admission were identified by univariate and multivariate analyses. RESULTS: A total of 15,716 individuals visiting the ED during the study period included 1244 (7.9%) patients with cancer. Among the 491 cancer patients with metastasis, univariate analysis revealed that emergency admission was significantly associated with an age of >=76 years; an altered mental status; fever (>=38 degrees C); a blood oxygen saturation of <90%; a white blood cell (WBC) count of <=2000 or >=10,000/MUL; hypoalbuminemia (<=2.5 g/dL); and elevated levels of aspartate aminotransferase (>=100 IU/L), blood urea nitrogen (>=25 mg/dL), and C-reactive protein (CRP, >=10 mg/dL). Multivariate analysis identified age, an altered mental status, hypoxemia, an abnormal WBC count, and elevated CRP as putative independent predictive factors for emergency admission. The number of these five factors present was also correlated with 30 day mortality (c-statistic = 0.72). CONCLUSIONS: Age, unconsciousness, hypoxemia, an abnormal WBC count, and elevated CRP were found to be associated with emergency admission and 30-day mortality for metastatic cancer patients. Prospective validation of a predictive scoring system based on these findings is warranted. PMID- 27966027 TI - Combined thalamic and subthalamic deep brain stimulation for tremor-dominant Parkinson's disease. AB - Deep brain stimulation (DBS) in the thalamic ventral intermediate (Vim) or the subthalamic nucleus (STN) reportedly improves medication-refractory Parkinson's disease (PD) tremor. However, little is known about the potential synergic effects of combined Vim and STN DBS. We describe a 79-year-old man with medication-refractory tremor-dominant PD. Bilateral Vim DBS electrode implantation produced insufficient improvement. Therefore, the patient underwent additional unilateral left-sided STN DBS. Whereas Vim or STN stimulation alone led to partial improvement, persisting tremor resolution occurred after simultaneous stimulation. The combination of both targets may have a synergic effect and is an alternative option in suitable cases. PMID- 27966029 TI - Chondroblastoma of the thoracic spine: a rare location. Case report with radiologic-pathologic correlation. AB - Chondroblastoma is a rare benign cartilage neoplasm that arises from the appendicular skeleton in the vast majority of the cases (80%). Chondroblastoma of the spine is an even more rare condition (30 cases reported), and vertebral chondroblastomas, unlike chondroblastomas of the extremities, present with the appearance of an aggressive tumor on CT and MR imaging and occur at least a decade later. Even though vertebral chondroblastomas are very uncommon tumors, they should nonetheless be included in the differential diagnosis when encountered with an aggressive vertebral mass, and a histological confirmation should be performed. We present a case of chondroblastoma of the thoracic spine of a 27-year-old female for which detailed radiologic-pathologic correlation was obtained. PMID- 27966031 TI - Bilateral bony fusion around the supraspinatus muscle inducing muscle hypoplasia and shoulder pain. AB - We describe the case of a 30-year-old man who developed chronic bilateral shoulder pain that relapsed and remitted over the course of 1 year. The patient was diagnosed with congenital shoulder fusion anomalies. The right shoulder showed anomalous accessory articulation between the distal third of the clavicle and the acromion along with normal articulation of the shoulder on CT. At the left shoulder, bony fusions were present between the distal portion of the clavicle, the acromion, and the coracoid process, and between the coracoid process, upper portion of the glenoid, and upper body of the scapula, which formed a bony canal and was responsible for hypoplasia of the supraspinatus muscle on CT and MRI. To our knowledge, this is the first description of such congenital shoulder anomalies with extreme bony fusion and is an illustrative example of how imaging may be used to differentiate fusion from other congenital abnormalities of the shoulder to aid diagnosis. PMID- 27966032 TI - [Transcorneal electrical stimulation in primary open angle glaucoma]. AB - Recently, reports have been published on the effectiveness of electrical stimulation in patients and experimental animal models with neurodegenerative ocular diseases. Our study included 14 patients with primary open angle glaucoma (POAG), who were randomized into one of three groups with 0% (sham, n = 5), 66% (n = 5) or 150% (n = 4) of their individual electrical phosphene thresholds. Patients were treated with transcorneal electrical stimulation (TES) for 30 min once a week for 6 consecutive weeks. Outcome measures of our study were the detection of possible adverse events and efficacy of TES using DTL electrodes in subjective and objective parameters of visual function under treatment. TES was tolerated well and no serious adverse events were registered relating to the treatment. One single adverse event was registered as appearance of an optic disc hemorrhage of a sham-stimulated eye. In summary, one significant increase of intra-ocular pressure in the 66% group was observed in comparison to the sham group (p = 0.04), without significant differences compared to the 150% group (both sham vs. 150% group and 66% vs. 150% group). This difference (mean difference compared to baseline of -2.33 mm Hg for the sham group and +0.97 mm Hg for the 66% group; REML) was not clinical meaningful. All other findings, including results of the visual field, were not statistically significant different between groups. It was shown that TES using DTL electrodes did not trigger adverse or serious adverse events in the stimulated groups in patients with POAG. Patients with POAG should currently receive TES only under study conditions. PMID- 27966033 TI - [Arch-shaped retinal appearance of a previously healthy women]. PMID- 27966034 TI - Population pharmacokinetics of meropenem in elderly patients: dosing simulations based on renal function. AB - OBJECTIVES: The aim of this study was to evaluate different dosage regimens of meropenem in elderly patients in relation with renal function using a population pharmacokinetic (popPK) model. METHODS: The data of 178 elderly patients treated with meropenem was collected from different sources. A popPK model was developed by using NONMEM(r) and the influence of different covariates on meropenem CL and V1 was observed. Monte Carlo dosing simulations were performed at steady state to observe the % T > MIC for targets of 40, 60 and 80% of dosage intervals at different levels of creatinine clearance (CLCR). RESULTS: The data was described by a two-compartment model and the values of parameter estimates for CL, V1, Q and V2 were 5.27 L/h, 17.2 L, 9.92 L/h and 10.6 L, respectively. The CLCR, body weight and centre had a significant influence on meropenem CL while no direct influence of age was observed. Extended infusions had pharmacokinetic and pharmacodynamic (PK/PD) breakpoint one dilution greater than corresponding short infusion regimens for each target of % T > MIC. CONCLUSION: Meropenem CL was significantly lower in the elderly compared to CL reported in younger patients due to the reduced renal function. An extended infusion of 1000 mg q8h can be considered for empirical treatment of infections in elderly patients when CLCR is <= 50 mL/min. A continuous infusion of 3000 mg daily dose is preferred if CLCR > 50 mL/min. However, a higher daily dose of meropenem would be required for resistant strains (MIC >8 mg/L) of bacteria if CLCR is >100 mL/min. PMID- 27966035 TI - Network meta-analysis as a tool for improving the effectiveness assessment of biosimilars based on both direct and indirect evidence: application to infliximab in rheumatoid arthritis. PMID- 27966036 TI - The Underlying Ecological Processes of Gut Microbiota Among Cohabitating Retarded, Overgrown and Normal Shrimp. AB - Increasing evidence of tight links among the gut microbiota, obesity, and host health has emerged, but knowledge of the ecological processes that shape the variation in microbial assemblages across growth rates remains elusive. Moreover, inadequately control for differences in factors that profoundly affect the gut microbial community, hampers evaluation of the gut microbiota roles in regulating growth rates. To address this gap, we evaluated the composition and ecological processes of the gut bacterial community in cohabitating retarded, overgrown, and normal shrimps from identically managed ponds. Gut bacterial community structures were distinct (P = 0.0006) among the shrimp categories. Using a structural equation modeling (SEM), we found that changes in the gut bacterial community were positively related to digestive activities, which subsequently affected shrimp growth rate. This association was further supported by intensified interspecies interaction and enriched lineages with high nutrient intake efficiencies in overgrown shrimps. However, the less phylogenetic clustering of gut microbiota in overgrown and retarded subjects may offer empty niches for pathogens invasion, as evidenced by higher abundances of predicted functional pathways involved in disease infection. Given no differences in biotic and abiotic factors among the cohabitating shrimps, we speculated that the distinct gut community assembly could be attributed to random colonization in larval shrimp (e.g., priority effects) and that an altered microbiota could be a causative factor in overgrowth or retardation in shrimp. To our knowledge, this is the first study to provide an integrated overview of the direct roles of gut microbiota in shaping shrimp growth rate and the underlying ecological mechanisms. PMID- 27966038 TI - GM-CSF treatment is not effective in congenital neutropenia patients due to its inability to activate NAMPT signaling. AB - Severe congenital neutropenia (CN) is a bone marrow failure syndrome characterized by an absolute neutrophil count (ANC) below 500 cells/MUL and recurrent, life-threatening bacterial infections. Treatment with granulocyte colony-stimulating factor (G-CSF) increases the ANC in the majority of CN patients. In contrary, granulocyte-monocyte colony-stimulating factor (GM-CSF) fails to increase neutrophil numbers in CN patients in vitro and in vivo, suggesting specific defects in signaling pathways downstream of GM-CSF receptor. Recently, we detected that G-CSF induces granulopoiesis in CN patients by hyperactivation of nicotinamide phosphoribosyl transferase (NAMPT)/Sirtuin 1 signaling in myeloid cells. Here, we demonstrated that, in contrast to G-CSF, GM CSF failed to induce NAMPT-dependent granulopoiesis in CN patients. We further identified NAMPT signaling as an essential downstream effector of the GM-CSF pathway in myelopoiesis. PMID- 27966037 TI - Microbiology Meets Archaeology: Soil Microbial Communities Reveal Different Human Activities at Archaic Monte Iato (Sixth Century BC). AB - Microbial ecology has been recognized as useful in archaeological studies. At Archaic Monte Iato in Western Sicily, a native (indigenous) building was discovered. The objective of this study was the first examination of soil microbial communities related to this building. Soil samples were collected from archaeological layers at a ritual deposit (food waste disposal) in the main room and above the fireplace in the annex. Microbial soil characterization included abundance (cellular phospholipid fatty acids (PLFA), viable bacterial counts), activity (physiological profiles, enzyme activities of viable bacteria), diversity, and community structure (bacterial and fungal Illumina amplicon sequencing, identification of viable bacteria). PLFA-derived microbial abundance was lower in soils from the fireplace than in soils from the deposit; the opposite was observed with culturable bacteria. Microbial communities in soils from the fireplace had a higher ability to metabolize carboxylic and acetic acids, while those in soils from the deposit metabolized preferentially carbohydrates. The lower deposit layer was characterized by higher total microbial and bacterial abundance and bacterial richness and by a different carbohydrate metabolization profile compared to the upper deposit layer. Microbial community structures in the fireplace were similar and could be distinguished from those in the two deposit layers, which had different microbial communities. Our data confirmed our hypothesis that human consumption habits left traces on microbiota in the archaeological evidence; therefore, microbiological residues as part of the so-called ecofacts are, like artifacts, key indicators of consumer behavior in the past. PMID- 27966039 TI - Magnetic resonance tissue phase mapping demonstrates altered left ventricular diastolic function in children with chronic kidney disease. AB - BACKGROUND: Echocardiographic examinations have revealed functional cardiac abnormalities in children with chronic kidney disease. OBJECTIVE: To assess the feasibility of MRI tissue phase mapping in children and to assess regional left ventricular wall movements in children with chronic kidney disease. MATERIALS AND METHODS: Twenty pediatric patients with chronic kidney disease (before or after renal transplantation) and 12 healthy controls underwent tissue phase mapping (TPM) to quantify regional left ventricular function through myocardial long (Vz) and short-axis (Vr) velocities at all 3 levels of the left ventricle. RESULTS: Patients and controls (age: 8 years-20 years) were matched for age, height, weight, gender and heart rate. Patients had higher systolic blood pressure. No patient had left ventricular hypertrophy on MRI or diastolic dysfunction on echocardiography. Fifteen patients underwent tissue Doppler echocardiography, with normal z-scores for mitral early diastolic (VE), late diastolic (VA) and peak systolic (VS) velocities. Throughout all left ventricular levels, peak diastolic Vz and Vr (cm/s) were reduced in patients: Vzbase -10.6 +/- 1.9 vs. 13.4 +/- 2.0 (P < 0.0003), Vzmid -7.8 +/- 1.6 vs. -11 +/- 1.5 (P < 0.0001), Vzapex -3.8 +/- 1.6 vs. -5.3 +/- 1.6 (P = 0.01), Vrbase -4.2 +/- 0.8 vs. -4.9 +/- 0.7 (P = 0.01), Vrmid -4.7 +/- 0.7 vs. -5.4 +/- 0.7 (P = 0.01), Vrapex -4.7 +/- 1.4 vs. -5.6 +/- 1.1 (P = 0.05). CONCLUSION: Tissue phase mapping is feasible in children and adolescents. Children with chronic kidney disease show significantly reduced peak diastolic long- and short-axis left ventricular wall velocities, reflecting impaired early diastolic filling. Thus, tissue phase mapping detects chronic kidney disease-related functional myocardial changes before overt left ventricular hypertrophy or echocardiographic diastolic dysfunction occurs. PMID- 27966040 TI - Diagnostic performance of calcification-suppressed coronary CT angiography using rapid kilovolt-switching dual-energy CT. AB - OBJECTIVES: Multi-detector-row computed tomography angiography (MDCTA) plays an important role in the assessment of patients with suspected coronary artery disease. However, MDCTA tends to overestimate stenosis in calcified coronary artery lesions. The aim of our study was to evaluate the diagnostic performance of calcification-suppressed material density (MD) images produced by using a single-detector single-source dual-energy computed tomography (ssDECT). METHODS: We enrolled 67 patients with suspected or known coronary artery disease who underwent ssDECT with rapid kilovolt-switching (80 and 140 kVp). Coronary artery stenosis was evaluated on the basis of MD images and virtual monochromatic (VM) images. The diagnostic performance of the two methods for detecting coronary artery disease was compared with that of invasive coronary angiography as a reference standard. RESULTS: We evaluated 239 calcified segments. In all the segments, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for detecting significant stenosis were respectively 88%, 88%, 75%, 95% and 88% for the MD images, 91%, 71%, 56%, 95% and 77% for the VM images. PPV was significantly higher on the MD images than on the VM images (P < 0.0001). CONCLUSIONS: Calcification-suppressed MD images improved PPV and diagnostic performance for calcified coronary artery lesions. KEY POINTS: * Computed tomography angiography tends to overestimate stenosis in calcified coronary artery. * Dual-energy CT enables us to suppress calcification of coronary artery lesions. * Calcification-suppressed material density imaging reduces false-positive diagnosis of calcified lesion. PMID- 27966041 TI - Glutamate-glutamine and GABA in brain of normal aged and patients with cognitive impairment. AB - OBJECTIVES: To explore the changes of glutamate-glutamine (Glx) and gamma aminobutyric acid (GABA) in the brain in normal old age and cognitive impairment using magnetic resonance spectroscopy (MRS). METHODS: Seventeen normal young controls (NYC), 15 normal elderly controls (NEC), 21 patients with mild cognitive impairment (MCI) and 17 with Alzheimer disease (AD) patients were included in this study. Glx and GABA+ levels in the anterior cingulate cortex (ACC) and right hippocampus (rHP) were measured by using a MEGA-PRESS sequence. Glx/Cr and GABA+/Cr ratios were compared between NYC and NEC and between the three elderly groups using analysis of covariance (ANCOVA); the tissue fractions of voxels were used as covariates. The relationships between metabolite ratios and cognitive performance were analysed using Spearman correlation coefficients. RESULTS: For NEC and NYC groups, Glx/Cr and GABA+/Cr ratios were lower in NEC in ACC and rHP. For the three elderly groups, Glx/Cr ratio was lower in AD in ACC compared to NEC and MCI; Glx/Cr ratio was lower in AD in rHP compared to NEC. There was no significant decrease for GABA+/Cr ratio. CONCLUSIONS: Glx and GABA levels may decrease simultaneously in normal aged, and Glx level decreased predominantly in AD, and it is helpful in the early diagnosis of AD. KEY POINTS: * Glx and GABA levels may decrease simultaneously in normal aged. * Glx level may decrease predominantly in Alzheimer disease. * The balance in excitatory-inhibitory systems may be broken in AD. * Decreased Glx level may be helpful in early diagnosis of AD. PMID- 27966042 TI - Fertility after uterine artery embolization for symptomatic multiple fibroids with no other infertility factors. AB - OBJECTIVES: To evaluate the fertility of women eligible for surgical multiple myomectomy, but who carefully elected a fertility-sparing uterine artery embolization (UAE). METHODS: Non-comparative open-label trial, on women <=40 years, presenting with multiple symptomatic fibroids (at least 3, >=3 cm), immediate pregnancy wish, and no associated infertility factor. Women had a bilateral limited UAE using tris-acryl gelatin microspheres >=500 MUm. Fertility, ovarian reserve, uterus and fibroid sizes, and quality of life questionnaires (UFS-QoL) were prospectively followed. RESULTS: Fifteen patients, aged 34.8 years (95%CI 32.2-37.5, median 36.0, q1-q3 29.4-39.5) were included from November 2008 to May 2012. During the year following UAE, 9 women actively attempting to conceive experienced 5 live-births (intention-to-treat fertility rate 33.3%, 95%CI 11.8%-61.6%). Markers of ovarian reserve remained stable. The symptoms score was reduced by 66% (95%CI 48%-85%) and the quality of life score was improved by 112% (95%CI 21%-204%). Uterine volume was reduced by 38% (95%CI 24% 52%). Women were followed for 43.1 months (95%CI 32.4-53.9), 10 live-births occurred in 8 patients, and 5 patients required secondary surgeries for fibroids. CONCLUSION: Women without associated infertility factors demonstrated an encouraging capacity to deliver after UAE. Further randomized controlled trials comparing UAE and myomectomy are warranted. KEY POINTS: * Women without infertility factors showed an encouraging delivery rate after UAE. * For women choosing UAE over abdominal myomectomy, childbearing may not be impaired. * Data are insufficient to definitively recommend UAE as comparable to myomectomy. * Further randomized trials comparing fertility after UAE or myomectomy are warranted. PMID- 27966043 TI - Radiation dose reduction using 100-kVp and a sinogram-affirmed iterative reconstruction algorithm in adolescent head CT: Impact on grey-white matter contrast and image noise. AB - OBJECTIVES: To retrospectively evaluate the image quality and radiation dose of 100-kVp scans with sinogram-affirmed iterative reconstruction (IR) for unenhanced head CT in adolescents. METHODS: Sixty-nine patients aged 12-17 years underwent head CT under 120- (n = 34) or 100-kVp (n = 35) protocols. The 120-kVp images were reconstructed with filtered back-projection (FBP), 100-kVp images with FBP (100-kVp-F) and sinogram-affirmed IR (100-kVp-S). We compared the effective dose (ED), grey-white matter (GM-WM) contrast, image noise, and contrast-to-noise ratio (CNR) between protocols in supratentorial (ST) and posterior fossa (PS). We also assessed GM-WM contrast, image noise, sharpness, artifacts, and overall image quality on a four-point scale. RESULTS: ED was 46% lower with 100- than 120 kVp (p < 0.001). GM-WM contrast was higher, and image noise was lower, on 100-kVp S than 120-kVp at ST (p < 0.001). CNR of 100-kVp-S was higher than of 120-kVp (p < 0.001). GM-WM contrast of 100-kVp-S was subjectively rated as better than of 120-kVp (p < 0.001). There were no significant differences in the other criteria between 100-kVp-S and 120-kVp (p = 0.072-0.966). CONCLUSIONS: The 100-kVp with sinogram-affirmed IR facilitated dramatic radiation reduction and better GM-WM contrast without increasing image noise in adolescent head CT. KEY POINTS: * 100 kVp head CT provides 46% radiation dose reduction compared with 120-kVp. * 100 kVp scanning improves subjective and objective GM-WM contrast. * Sinogram affirmed IR decreases head CT image noise, especially in supratentorial region. * 100-kVp protocol with sinogram-affirmed IR is suited for adolescent head CT. PMID- 27966044 TI - Gd-EOB-DTPA-enhanced MRI for monitoring future liver remnant function after portal vein embolization and extended hemihepatectomy: A prospective trial. AB - OBJECTIVES: To evaluate changes in liver function after right portal vein embolization (PVE) and extended right hemihepatectomy using gadolinium ethoxybenzyl-DTPA-enhanced (Gd-EOB-DTPA) MRI. METHODS: In this prospective trial, 37 patients undergoing PVE were examined before and 14 and 28 days after PVE and 10 days after extended hemihepatectomy using Gd-EOB-DTPA-enhanced MRI. Lobar volume, kinetic growth rate (KGR), relative enhancement (RE) as well as hepatocellular uptake index (HUI) and fat signal fraction (FSF) were calculated for each lobe. RESULTS: RE of the left liver lobe (LLL) was steadily increasing after PVE and decreased to 0.48 +/- 0.19 10 days after surgery, which is significantly lower than 14 days and 28 days post PVE (P < 0.05). KGR was 14.06 +/- 9.82%/week for the period from PVE to 14 days after PVE. HUI of the LLL increased steadily after PVE and was significantly higher at both 14 and 28 days after PVE compared to pre PVE (P < 0.05). HUI of the residual liver after surgery was lower than before. CONCLUSIONS: Gd-EOB-DTPA-enhanced MRI may be used to monitor the functional increase in the FLR after PVE and to depict the intraoperative liver injury leading to a decrease in liver remnant function. KEY POINTS: * The most significant FLR volume increase happens within the first 14 days. * No MRI parameter was able to predict the success of FLR growth. * Our data suggest an early resection about 14 days after PVE. * Routine Gd-EOB-DTPA enhanced MRI might be suitable to replace ICG-test. PMID- 27966045 TI - Inter-rater variability of visual interpretation and comparison with quantitative evaluation of 11C-PiB PET amyloid images of the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) multicenter study. AB - PURPOSE: The aim of this study was to assess the inter-rater variability of the visual interpretation of 11C-PiB PET images regarding the positivity/negativity of amyloid deposition that were obtained in a multicenter clinical research project, Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI). The results of visual interpretation were also compared with a semi-automatic quantitative analysis using mean cortical standardized uptake value ratio to the cerebellar cortex (mcSUVR). METHODS: A total of 162 11C-PiB PET scans, including 45 mild Alzheimer's disease, 60 mild cognitive impairment, and 57 normal cognitive control cases that had been acquired as J-ADNI baseline scans were analyzed. Based on visual interpretation by three independent raters followed by consensus read, each case was classified into positive, equivocal, and negative deposition (ternary criteria) and further dichotomized by merging the former two (binary criteria). RESULTS: Complete agreement of visual interpretation by the three raters was observed for 91.3% of the cases (Cohen kappa = 0.88 on average) in ternary criteria and for 92.3% (kappa = 0.89) in binary criteria. Cases that were interpreted as visually positive in the consensus read showed significantly higher mcSUVR than those visually negative (2.21 +/- 0.37 vs. 1.27 +/- 0.09, p < 0.001), and positive or negative decision by visual interpretation was dichotomized by a cut-off value of mcSUVR = 1.5. Significant positive/negative associations were observed between mcSUVR and the number of raters who evaluated as positive (rho = 0.87, p < 0.0001) and negative (rho = -0.85, p < 0.0001) interpretation. Cases of disagreement among raters showed generally low mcSUVR. CONCLUSIONS: Inter-rater agreement was almost perfect in 11C-PiB PET scans. Positive or negative decision by visual interpretation was dichotomized by a cut off value of mcSUVR = 1.5. As some cases of disagreement among raters tended to show low mcSUVR, referring to quantitative method may facilitate correct diagnosis when evaluating images of low amyloid deposition. PMID- 27966046 TI - Differentiated Thyroid Cancer lymph-node relapse. Role of adjuvant radioactive iodine therapy after lymphadenectomy. AB - PURPOSE: Our purpose as to evaluate the impact of adjuvant radioactive iodine therapy (RAI) on prognosis, as assessed by progression-free survival (PFS) and overall survival (OS), in patients affected by differentiated thyroid carcinoma (DTC) lymph-node relapse and previously treated with lymphadenectomy. METHODS: We retrospectively evaluated DTC patients treated with lymph-node dissection for disease relapse. All patients had previously undergone total thyroidectomy and radioiodine remnant ablation (RRA). We used clinical and histological data obtained during follow-up to assess response and outcome. By means of univariate and multivariate time-to-event analyses, we assessed the impact of RAI on outcome (PFS and OS) and the prognostic role of thyroglobulin (Tg) levels under suppression with levothyroxine (Tg-on) measured 1-3 months after lymphadenectomy and of other risk factors. RESULTS: We evaluated 113 patients (age at diagnosis: median 41 years, interquartile range: 31-59), 64 of whom were treated with RAI. Over a median follow-up time of 5.7 years, 27 patients showed disease progression and 13 died. Kaplan-Meier PFS and OS curves showed that age on diagnosis, tumor histology, tumor size, DTC aggressive variant, and Tg-on were associated with prognosis. Patients with Tg-on >=1 ng/ml treated with RAI showed a better PFS (Log-rank pp 0.001) and OS (p = 0.005) than untreated patients, while no effect of RAI was observed in patients with Tg-on <1 ng/ml. Multivariate models showed that age, Tg-on (>=1 vs. < 1 ng/ml, HR: 18.2, 95% CI: 5.09-64.8, p = 0.001) and RAI (Yes vs. No, HR: 0.36,95%CI: 0.15-0. 9, p = 0.02) remained the only independent factors associated with PFS, but only age and Tg-on remained significantly associated with OS (HR: 8.31, 95%CI:1.56-44.3, p = 0.01). Nonetheless, patients treated with RAI showed a lower risk of mortality (HR: 0.34, 95%CI: 0.1-1.15 p = 0.08) than untreated patients. CONCLUSIONS: RAI after lymphadenectomy for DTC relapse is significantly associated with better PFS only in patients with Tg-on >=1 ng/ml. PMID- 27966047 TI - Natural products from filamentous fungi and production by heterologous expression. AB - Filamentous fungi represent an incredibly rich and rather overlooked reservoir of natural products, which often show potent bioactivity and find applications in different fields. Increasing the naturally low yields of bioactive metabolites within their host producers can be problematic, and yield improvement is further hampered by such fungi often being genetic intractable or having demanding culturing conditions. Additionally, total synthesis does not always represent a cost-effective approach for producing bioactive fungal-inspired metabolites, especially when pursuing assembly of compounds with complex chemistry. This review aims at providing insights into heterologous production of secondary metabolites from filamentous fungi, which has been established as a potent system for the biosynthesis of bioactive compounds. Numerous advantages are associated with this technique, such as the availability of tools that allow enhanced production yields and directing biosynthesis towards analogues of the naturally occurring metabolite. Furthermore, a choice of hosts is available for heterologous expression, going from model unicellular organisms to well characterised filamentous fungi, which has also been shown to allow the study of biosynthesis of complex secondary metabolites. Looking to the future, fungi are likely to continue to play a substantial role as sources of new pharmaceuticals and agrochemicals-either as producers of novel natural products or indeed as platforms to generate new compounds through synthetic biology. PMID- 27966049 TI - The sigma54-dependent two-component system regulating sulfur oxidization (Sox) system in Acidithiobacillus caldus and some chemolithotrophic bacteria. AB - The sulfur oxidization (Sox) system is the central sulfur oxidization pathway of phototrophic and chemotrophic sulfur-oxidizing bacteria. Regulation and function of the Sox system in the chemotrophic Paracoccus pantotrophus has been elucidated; however, to date, no information is available on the regulation of this system in the chemolithotrophic Acidithiobacillus caldus, which is widely utilized in bioleaching. We described the novel tspSR-sox-like clusters in A. caldus and other chemolithotrophic sulfur-oxidizing bacteria containing Sox systems. The highly homologous sigma54-dependent two-component signaling system (TspS/R), upstream of the sox operons in these novel clusters, was identified by phylogenetic analyses. A typical sigma54-dependent promoter, P1, was identified upstream of soxX-I in the sox-I cluster of A. caldus MTH-04. The transcriptional start site (G) and the -12/-24 regions (GC/GG) of P1 were determined by rapid amplification of cDNA ends (5'RACE), and the upstream activator sequences (UASs; TGTCCCAAATGGGACA) were confirmed by electrophoretic mobility shift assays (EMSAs) in vitro and by UAS-probe-plasmids assays in vivo. Sequence analysis of promoter regions in tspSR-sox-like clusters revealed that there were similar sigma54 dependent promoters upstream of the soxX genes. Based on our results, we proposed a TspSR-mediated signal transduction and transcriptional regulation pathway for the Sox system in A. caldus. The regulation of sigma54-dependent two-component systems (TCSs) for Sox pathways were explained for the first time in A. caldus, A. thiooxidans, T. tepidarius, and T. denitrificans, indicating the significance of modulating the sulfur oxidization in these chemolithotrophic sulfur oxidizers. PMID- 27966050 TI - Erratum to: Microarray (phylochip) analysis of freshwater pathogens at several sites along the Northern German coast transecting both estuarine and freshwaters. PMID- 27966048 TI - Discovery and characterization of an F420-dependent glucose-6-phosphate dehydrogenase (Rh-FGD1) from Rhodococcus jostii RHA1. AB - Cofactor F420, a 5-deazaflavin involved in obligatory hydride transfer, is widely distributed among archaeal methanogens and actinomycetes. Owing to the low redox potential of the cofactor, F420-dependent enzymes play a pivotal role in central catabolic pathways and xenobiotic degradation processes in these organisms. A physiologically essential deazaflavoenzyme is the F420-dependent glucose-6 phosphate dehydrogenase (FGD), which catalyzes the reaction F420 + glucose-6 phosphate -> F420H2 + 6-phospho-gluconolactone. Thereby, FGDs generate the reduced F420 cofactor required for numerous F420H2-dependent reductases, involved e.g., in the bioreductive activation of the antitubercular prodrugs pretomanid and delamanid. We report here the identification, production, and characterization of three FGDs from Rhodococcus jostii RHA1 (Rh-FGDs), being the first experimental evidence of F420-dependent enzymes in this bacterium. The crystal structure of Rh-FGD1 has also been determined at 1.5 A resolution, showing a high similarity with FGD from Mycobacterium tuberculosis (Mtb) (Mtb FGD1). The cofactor-binding pocket and active-site catalytic residues are largely conserved in Rh-FGD1 compared with Mtb-FGD1, except for an extremely flexible insertion region capping the active site at the C-terminal end of the TIM-barrel, which also markedly differs from other structurally related proteins. The role of the three positively charged residues (Lys197, Lys258, and Arg282) constituting the binding site of the substrate phosphate moiety was experimentally corroborated by means of mutagenesis study. The biochemical and structural data presented here provide the first step towards tailoring Rh-FGD1 into a more economical biocatalyst, e.g., an F420-dependent glucose dehydrogenase that requires a cheaper cosubstrate and can better match the demands for the growing applications of F420H2-dependent reductases in industry and bioremediation. PMID- 27966051 TI - Transoral laser microsurgery versus radiotherapy for T1 glottic carcinoma: a systematic review and meta-analysis. AB - Transoral laser microsurgery (TLM) and radiotherapy (RT) are both accepted treatment modalities for glottic cancer. The objective of the study was to assess the oncologic outcomes and life quality of TLM in comparison with RT for T1 glottic carcinoma. We searched Medline/PubMed, Web of knowledge, EMBASE, the Cochrane Library, the Wiley online library, Springer, Google, China National Knowledge Infrastructure (CNKI), etc. We screened the literature, assessed the quality of the studies, and extracted the relevant data through the establishment of inclusion and exclusion criteria. Meta-analysis was done using the Cochrane collaboration' s RevMan 5.0 for data analysis. A total of 11 studies were included in this meta-analysis. The laryngeal preservation for patients undergoing TLM was significantly better than that for RT (P < 0.00). The laser surgery significantly improved the overall survival of patients with T1 glottic carcinoma (P = 0.04). No statistically significant differences were found between TLM and RT regarding the local control (P = 0.91). The funnel plot demonstrates no apparent publication bias in the overall survival and laryngeal preservation comparison. Our meta-analysis suggested that laser surgery was a preferred method than radiotherapy with respect to significantly better overall survival and laryngeal preservation. But the local control was not significant different. Further prospective randomized controlled studies will be needed. PMID- 27966053 TI - Erratum to: Picosecond lasers for tattoo removal: a systematic review. PMID- 27966052 TI - The efficacy and safety of 2-MUm continuous laser in the treatment of high-risk patients with benign prostatic hyperplasia. AB - Two-micrometer laser resection of prostate-tangerine technique dissects whole prostatic lobes off the surgical capsular, similar to peeling a tangerine. The present study aimed to evaluate the safety and efficacy of 2-MUm continuous laser vaporization in the treatment of high-risk patients with benign prostatic hyperplasia (BPH) during the 24-month follow-up. The study included 248 patients with moderate to severe lower urinary tract symptoms who underwent 2-MUm continuous laser vaporization of the prostate. All patients were accompanied with different degree comorbidities and 94 patients were taking oral anticoagulants. BPH was successfully treated with 2-MUm continuous laser vaporization in all patients. Mean pre-operative prostate volume was 76 +/- 25.3 ml and mean operative time was 49.8 +/- 16.5 min. There were no major complications intra operatively or postoperatively, and no blood transfusions were needed. About 20 patients (8.1%) needed bladder irrigation postoperatively. Average catheterization time was 2.0 +/- 1.8 days (range 1-5 days). Four patients required reoperation due to enlarged prostates from residual adenoma. At 3-, 6-, 12-, and 24-month follow-ups, maximum urinary flow rates (Qmax) increased from 6.9 +/- 1.7 to 19.1 +/- 4.2, 19.5 +/- 4.6, 19.4 +/- 4.6, and 19.5 +/- 4.1 ml/s, respectively. Mean International Prostate Symptom Scores (IPSS) decreased from 27.6 +/- 5.1 (pre-operation) to 9.2 +/- 2.6, 7.12 +/- 1.42, 6.18 +/- 1.32, and 6.25 +/- 1.30 at 3-, 6-, 12-, and 24-month post-operation, respectively. Two micrometer continuous laser vaporization is a safe and effective surgical endoscopic technique associated with low complication rate in BPH patients at high risk and those on anticoagulation therapy who have severe LUTS caused by BPH. PMID- 27966054 TI - Lifestyle Risk Factors for Breast Cancer in BRCA1/2-Mutation Carriers Around Childbearing Age. AB - BRCA1/2-mutation carriers are at high risk of breast cancer (BC) and ovarian cancer. Physical inactivity, overweight (body mass index >=25, BMI), smoking, and alcohol consumption are jointly responsible for about 1 in 4 postmenopausal BC cases in the general population. Limited evidence suggests physical activity also increases BC risk in BRCA1/2-mutation carriers. Women who have children often reduce physical activity and have weight gain, which increases BC risk. We assessed aforementioned lifestyle factors in a cohort of 268 BRCA1/2-mutation carriers around childbearing age (born between 1968 and 1983, median age 33 years, range 21-44). Furthermore, we evaluated the effect of having children on physical inactivity and overweight. Carriers were asked about lifestyle 4-6 weeks after genetic diagnosis at the Familial Cancer Clinic Nijmegen. Physical inactivity was defined as sports activity fewer than once a week. Carriers were categorized according to the age of their youngest child (no children, age 0-3 years and >=4 years). In total, 48% of carriers were physically inactive, 41% were overweight, 27% smoked, and 70% consumed alcohol (3% >=8 beverages/week). Physical inactivity was 4-5 times more likely in carriers with children. Overweight was not associated with having children. Carriers with children are a subgroup that may specifically benefit from lifestyle support to reduce BC risk. PMID- 27966056 TI - Lessons from the Rise-and Fall?-of VA Healthcare. PMID- 27966055 TI - Severity of individual obstruction events is gender dependent in sleep apnea. AB - PURPOSE: In obstructive sleep apnea (OSA), severity of individual obstruction events is connected to increased mortality rate and it can be significantly different in patients with similar apnea-hypopnea index (AHI). However, possible gender-dependent variation in severity of obstruction events in different OSA categories is unknown. We investigated whether the severity of obstruction events differs between genders with similar AHI and if this difference varies between OSA categories. METHODS: Polygraphic recordings of 2057 consecutive patients with suspected OSA were reanalyzed and those with AHI >=5/h were included for further analysis (n male = 893 and n female = 197). Statistical significance of differences in AHI, apnea index, hypopnea index, oxygen desaturation index, obstruction severity parameter, and severity of individual obstruction events between genders were evaluated using the Mann-Whitney U (MWU) test as well as the general linear model (GLM) univariate analysis adjusted for age, BMI, smoking, daytime sleepiness, snoring, and heart failure. RESULTS: Apneas were 16.9 and 19.6% longer (MWU p <= 0.015, GLM p <= 0.036) and desaturation areas were 15.4 and 23.7% larger (MWU p <= 0.024, GLM p <= 0.053) in males compared to females with moderate and severe OSA, respectively. In contrast, hypopneas were 9.1% shorter (MWU p = 0.001, GLM p <= 0.001) and desaturation areas were 6.0% smaller (MWU p = 0.114, GLM p = 0.025) in men with mild OSA. The apnea index was 433.3 and 313.1% higher (MWU p <= 0.001, GLM p <= 0.043) and the hypopnea index was 12.2 and 17.8% lower (MWU p <= 0.001, GLM p = 0.002, p = 0.083) in males with mild and moderate OSA, respectively. CONCLUSION: As severity of individual obstruction events was significantly different in males and females, the overall severity of OSA may not be similar despite the similarity in AHI. PMID- 27966057 TI - Suitability of the National Health Care Surveys to Examine Behavioral Health Services Associated with Polycystic Ovary Syndrome. AB - The National Institutes of Health, Office of Disease Prevention, has described polycystic ovary syndrome (PCOS) as a major public health problem for women in the USA. This study examines the suitability of the National Health Care Surveys, collected by the Centers for Disease Control and Prevention, to understand patient demographics and behavioral health services associated with PCOS-related medical visits. Data were from the 2005-2010 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey. PCOS-related medical visits were identified using the International Classification of Diseases, 9th Revision, Clinical Modification code 256.4. Items on mental health and health education ordered or provided did not meet the National Center for Health Statistics criteria necessary to produce reliable national estimates (i.e., at least 30 unweighted records and a relative standard error <30%). Findings underscore the need to strengthen national surveillance to further understand behavioral health care for patients with PCOS. PMID- 27966059 TI - The Role of the Curator in Modern Hospitals: A Transcontinental Perspective. AB - This paper explores the role of the curator in hospitals. The arts play a significant role in every society; however, recent studies indicate a neglect of the aesthetic environment of healthcare. This international study explores the complex role of the curator in modern hospitals. Semi-structured interviews were conducted with ten arts specialists in hospitals across five countries and three continents for a qualitative, phenomenological study. Five themes arose from the data: (1) Patient involvement and influence on the arts programme in hospital (2) Understanding the role of the curator in hospital (3) Influences on arts programming in hospital (4) Types of arts programmes (5) Limitations to effective curation in hospital. Recommendations arising from the research included recognition of the specialised role of the curator in hospitals; building positive links with clinical staff to effect positive hospital arts programmes and increasing formal involvement of patients in arts planning in hospital. Hospital curation can be a vibrant arena for arts development, and the role of the hospital curator is a ground-breaking specialist role that can bring benefits to hospital life. The role of curator in hospital deserves to be supported and developed by both the arts and health sectors. PMID- 27966058 TI - Surgical Considerations in the Treatment of Small Bowel Crohn's Disease. AB - Surgery remains a cornerstone of the management of Crohn's disease (CD). Despite the rise of biologic therapy, most CD patients require surgery for penetrating, obstructing, or malignant complications. Optimal surgical therapy requires sophisticated operative judgment and medical optimization. Intraoperatively, surgeons must balance treatment of CD complications against bowel preservation and functional outcome. This demands mastery of multiple techniques for anastomosis and strictureplasty, accurate assessment of bowel integrity for margin minimization, and a comprehensive skillset for navigating adhesions and altered anatomy, controlling thickened mesentery, and safely managing the hostile abdomen. Outside of the operating room, a multi-disciplinary team is critical for pre-operative optimization, patient support, and medical management. Postoperatively, prevention and surveillance of recurrence remain a matter of research and debate, and medical options include older drugs with limited efficacy and tolerability versus biologic agents with greater effect sizes and shorter track records. The evidence base for current management is limited by the inherent challenges of studying a chronic disease marked by heterogeneity and recurrence, but also by a lack of prospective trials incorporating both medical and surgical therapies. PMID- 27966060 TI - Components of a mammalian protein disaggregation/refolding machine are targeted to nuclear speckles following thermal stress in differentiated human neuronal cells. AB - Heat shock proteins (Hsps) are a set of highly conserved proteins involved in cellular repair and protective mechanisms. They counter protein misfolding and aggregation that are characteristic features of neurodegenerative diseases. Hsps act co-operatively in disaggregation/refolding machines that assemble at sites of protein misfolding and aggregation. Members of the DNAJ (Hsp40) family act as "holdases" that detect and bind misfolded proteins, while members of the HSPA (Hsp70) family act as "foldases" that refold proteins to biologically active states. HSPH1 (Hsp105alpha) is an important additional member of the mammalian disaggregation/refolding machine that acts as a disaggregase to promote the dissociation of aggregated proteins. Components of a disaggregation/refolding machine were targeted to nuclear speckles after thermal stress in differentiated human neuronal SH-SY5Y cells, namely: HSPA1A (Hsp70-1), DNAJB1 (Hsp40-1), DNAJA1 (Hsp40-4), and HSPH1 (Hsp105alpha). Nuclear speckles are rich in RNA splicing factors, and heat shock disrupts RNA splicing which recovers after stressful stimuli. Interestingly, constitutively expressed HSPA8 (Hsc70) was also targeted to nuclear speckles after heat shock with elements of a disaggregation/refolding machine. Hence, neurons have the potential to rapidly assemble a disaggregation/refolding machine after cellular stress using constitutively expressed Hsc70 without the time lag needed for synthesis of stress-inducible Hsp70. Constitutive Hsc70 is abundant in neurons in the mammalian brain and has been proposed to play a role in pre-protecting neurons from cellular stress. PMID- 27966061 TI - UBL/BAG-domain co-chaperones cause cellular stress upon overexpression through constitutive activation of Hsf1. AB - As a result of exposure to stress conditions, mutations, or defects during synthesis, cellular proteins are prone to misfold. To cope with such partially denatured proteins, cells mount a regulated transcriptional response involving the Hsf1 transcription factor, which drives the synthesis of molecular chaperones and other stress-relieving proteins. Here, we show that the fission yeast Schizosaccharomyces pombe orthologues of human BAG-1, Bag101, and Bag102, are Hsp70 co-chaperones that associate with 26S proteasomes. Only a subgroup of Hsp70 type chaperones, including Ssa1, Ssa2, and Sks2, binds Bag101 and Bag102 and key residues in the Hsp70 ATPase domains, required for interaction with Bag101 and Bag102, were identified. In humans, BAG-1 overexpression is typically observed in cancers. Overexpression of bag101 and bag102 in fission yeast leads to a strong growth defect caused by triggering Hsp70 to release and activate the Hsf1 transcription factor. Accordingly, the bag101-linked growth defect is alleviated in strains containing a reduced amount of Hsf1 but aggravated in hsp70 deletion strains. In conclusion, we propose that the fission yeast UBL/BAG proteins release Hsf1 from Hsp70, leading to constitutive Hsf1 activation and growth defects. PMID- 27966062 TI - Diversity of mitochondrial DNA in three Arabian horse strains. AB - Arabian horse registries classify Arabian horses based on their dam lineages into five main strains. To test the maternal origin of Syrian Arabian horses, 192 horses representing the three major strains Saglawi, Kahlawi, and Hamdani were sequenced for 353 bp of their mitochondrial displacement loop (D-loop) region. Sequencing revealed 28 haplotypes comprising 38 sequence variations. The haplotype diversity values were 0.95, 0.91, and 0.90 in Kahlawi, Hamdani, and Saglawi strains, respectively. The pair-wise population differentiation estimates (Fst) between strains were low, ranging between 0.098 and 0.205. The haplotype diversity and the pair-wise population differentiation estimates (Fst) between strains showed high diversity within individuals of each strain and low variation between the three strains. Mitochondrial haplotypes scattered all over the neighbor-joining tree without clear separation of the three strains. In the median-joining network, the Syrian horses were grouped into seven major haplogroups. These results suggest that more than five ancestors exist that share common maternal haplotypes with other horse breeds. PMID- 27966063 TI - Effects of Neighborhood Walkability on Physical Activity and Sedentary Behavior Long-Term Post-Bariatric Surgery. AB - : ?: Chronic inactivity and weight regain are serious health concerns following bariatric surgery. Neighborhood walkability is associated with higher physical activity and lower obesity rates in normal weight populations. PURPOSE: Explore the influence of neighborhood walkability on physical activity and sedentarism among long-term post-bariatric surgery patients. METHODS: Fifty-eight adults aged 50.5 +/- 9.1 years, with a BMI of 34.6 +/- 9.7 kg/m2 having undergone surgery 9.8 +/- 3.15 years earlier participated in this study. Participants were asked to wear an ActivPALTM tri-axial accelerometer attached to their mid-thigh for 7 consecutive days, 24 hours/day. The sample was separated into those that live in Car-Dependent (n = 23), Somewhat Walkable (n = 14), Very Walkable (n = 16), and Walker's Paradise (n = 5) neighborhoods as defined using Walk Score(r). ANCOVA was performed comparing Walk Score(r) categories on steps and sedentary time controlling for age and sex. RESULTS: Neighborhood walkability did not influence either daily steps (F (3, 54) = 0.921, p = 0.437) or sedentary time (F (3, 54) = 0.465, p = 0.708), Car-Dependent (6359 +/- 2712 steps, 9.54 +/- 2.46 hrs), Somewhat Walkable (6563 +/- 2989 steps, 9.07 +/- 2.70 hrs), Very Walkable (5261 +/- 2255 steps, 9.97 +/- 2.06 hrs), and Walker's Paradise (6901 +/- 1877 steps, 10.14 +/- 0.815 hrs). CONCLUSION: Walkability does not appear to affect sedentary time or physical activity long-term post-surgery. As the built-environment does not seem to influence activity, sedentarism, or obesity as it does with a normal weight population, work needs to be done to tailor physical activity programming after bariatric surgery. PMID- 27966064 TI - Plasma Ghrelin Levels and Weight Regain After Roux-en-Y Gastric Bypass Surgery. AB - PURPOSE: Ghrelin is a gut hormone that induces hunger, gastric acid secretion, and gastrointestinal motility. A number of studies have previously demonstrated a possible correlation between a decrease in ghrelin level and weight loss after Roux-en-Y gastric bypass (RYGB). This study aimed to assess if there was a relationship between ghrelin level and weight regain after RYGB nadir weight had been achieved. MATERIALS AND METHODS: Sixty-three consecutive RYGB patients who were referred for an upper endoscopy were enrolled. Weight and responses to the 21-item Three-Factor Eating Questionnaire (TFEQ-R21) were collected. Ghrelin levels were measured. Upper endoscopy was performed to evaluate pouch length and stoma diameter. Multivariate linear regression was performed to assess an association between ghrelin level, TFEQ-R21 score, pouch length, stoma diameter, and percentage of weight regained. RESULTS: Subjects were 47 +/- 10 years old and had a BMI of 38 +/- 7.7 kg/m2. Out of 63 patients, 76 % had weight regain (gaining of >=20 % of maximal weight lost after the RYGB) and 24 % did not. Average pouch length was 44 +/- 13 mm, stoma diameter 20 +/- 6.6 mm, and ghrelin levels 125 +/- 99 ng/ml. Ghrelin level was not associated with weight regain (beta = 0.17, p = 0.2). GJ stoma diameter was associated with weight regain (beta = 0.39, p < 0.01) and the uncontrolled eating domain of the TFEQ-R21 (beta = 0.45, p < 0.01). CONCLUSION: Ghrelin levels do not appear to correlate with weight change after RYGB nadir weight has been achieved. A dilated GJ stoma diameter is a risk factor for weight regain and uncontrolled eating behavior after RYGB. PMID- 27966065 TI - Conversion of an Open Salmon's Technique to a Laparoscopic Gastric Bypass. AB - BACKGROUND: There are a growing number of patients who require revisional bariatric surgery due to the failure of their primary procedures. The aim of this video is to present a laparoscopic revisional procedure for dysphagia and gastroesophageal reflux disease (GERD) after an uncommonly performed bariatric surgery, Salmon's technique, consisting of a vertical banded gastroplasty and a horizontal stomach stapling with a Roux-en-Y bypass. METHODS: A 42-year-old obese male, with a history of dyslipidemia and a current body mass index (BMI) of 33, presented with severe dysphagia to solids and frequent spitting 10 years after the primary bariatric surgery (Salmon's procedure) with a BMI of 43. Endoscopy revealed a hiatal hernia. The endoscope passed down without difficulty to the antrum-duodenum and to efferent loop of the small bowel, demonstrating the presence of a fistula in the horizontal stapling of the stomach. Helicobacter pylori was negative. Esophageal transit showed the contrast passing adequately through the esophagogastric junction. Esophageal manometry revealed a hypotensive lower esophageal sphincter (mean pressure of 8 mmHg) and an ineffective peristalsis (40% of waves with normal amplitude and duration). Esophageal pHmetry showed severe GERD with a DeMeester score of 88.5 and a pH less than four, 18.7% of the total time. The patient was on PPIs at the time of symptom evaluation, but stopped the treatment before the performance of the pH study. Laparoscopic conversion to a Roux-en-Y gastric bypass was successfully performed. An extensive adhesiolysis was needed. The esophageal hiatus was dissected and the stomach was partially descended to reduce the hiatal hernia. A subsequent hiatal closure was performed. The efferent loop of the small bowel was freed from the gastric pouch. The new gastric pouch was performed stapling superiorly to the gastric ring and medially to the vertical gastroplasty. The new gastrojejunal anastomosis was performed using a mechanical linear stapler, in an antecolic fashion, and checked for leaks using methylene blue dye. RESULTS: The procedure took 300 min and no intraoperative complications occurred. The patient had an uneventful postoperative course, with a hospital stay of 4 days. One month after the revisional surgery, the patient presented with a stenosis of the gastrojejunal anastomosis, which was successfully solved after two endoscopic dilations. A year and a half after revisional surgery, the patient is completely asymptomatic, has a BMI of 29, and dyslipidemia as the only comorbidity. CONCLUSIONS: Salmon's technique is an uncommon bariatric procedure. Revisional surgery might be needed in case of late complications, like dysphagia and reflux, as it was the case in our patient. In addition, a fistula in the previous horizontal partitioning of the stomach was present. Laparoscopic conversion from Salmon's technique to a gastric bypass was decided. This procedure was successful in solving patient's symptoms and resulted in an increased weight lost. Laparoscopic revisional surgery after an open Salmon's technique is a complex procedure with an increased risk of complications. Our patient developed an anastomotic stenosis 1 month after surgery, probably due to the use of the same gauge as in non-fibrotic tissues. PMID- 27966066 TI - Effects of Bariatric Surgery on Liver Function Tests in Patients with Nonalcoholic Fatty Liver Disease. AB - OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) affects over 80% of obese patients and is fueled by the metabolic syndrome. Weight loss is strongly advocated as a central treatment for NAFLD and has been shown to induce histological improvement. We aimed to define the patterns of improvement in NAFLD with weight loss and determine target weight goals for NAFLD resolution. METHODS: A prospective study of 84 morbidly obese patients with NAFLD undergoing bariatric surgery was conducted. Intraoperative liver biopsies were taken. Monthly follow up, including blood tests and measurements, was performed. We monitored improvements in NAFLD by monthly alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) levels over 1 year. RESULTS: There was rapid improvement in ALT, particularly in the first 6 months following surgery, with statistically significant reduction in ALT at 2 months (35 vs 27 IU/L, p < 0.001). In multivariate analysis, there were significantly increased odds of ALT normalization after a %TBWL of 10-15% (odds ratio 2.49, p = 0.005). The odds of resolution increased with increasing weight loss. Triglyceride levels (odds ratio 0.59, p = 0.021) and baseline NAFLD activity score (odds ratio 0.28, p < 0.001) were also significantly related to ALT normalization. Improvements in ALT occurred prior to metabolic improvement and well before traditional ideal weight goals were reached. CONCLUSION: Improvements in NAFLD occurred rapidly after bariatric surgery and were closely related to weight loss and metabolic factors. A 10-15% reduction in body weight is an appropriate target to achieve substantial improvement in ALT levels. TRIAL REGISTRATION NUMBER: Australian Clinical Trials Registry (ACTRN12610000049077). PMID- 27966067 TI - Cathepsin B Improves beta-Amyloidosis and Learning and Memory in Models of Alzheimer's Disease. AB - Amyloid-beta (Abeta) precursor protein (APP) metabolism engages neuronal endolysosomal pathways for Abeta processing and secretion. In Alzheimer's disease (AD), dysregulation of APP leads to excess Abeta and neuronal dysfunction; suggesting that neuronal APP/Abeta trafficking can be targeted for therapeutic gain. Cathepsin B (CatB) is a lysosomal cysteine protease that can lower Abeta levels. However, whether CatB-modulation of Abeta improves learning and memory function deficits in AD is not known. To this end, progenitor neurons were infected with recombinant adenovirus expressing CatB and recovered cell lysates subjected to proteomic analyses. The results demonstrated Lamp1 deregulation and linkages between CatB and the neuronal phagosome network. Hippocampal injections of adeno-associated virus expressing CatB reduced Abeta levels, increased Lamp1 and improved learning and memory. The findings were associated with the emergence of c-fos + cells. The results support the idea that CatB can speed Abeta metabolism through lysosomal pathways and as such reduce AD-associated memory deficits. PMID- 27966068 TI - Body mass does not impact the clinical response to intravenous abatacept in patients with rheumatoid arthritis. Analysis from the "pan-European registry collaboration for abatacept (PANABA). AB - Some evidences suggest that obesity impairs the effectiveness of TNF inhibitors. We examined the impact of body mass index (BMI) on the clinical effectiveness of abatacept in rheumatoid arthritis (RA) patients. This is a pooled analysis of 10 prospective cohorts of RA patients. All patients with available BMI were included in this study. The primary endpoint was drug retention of abatacept in the different BMI categories. Multivariable Cox regression was used to estimate hazard ratios (HRs) for drug discontinuation. A secondary endpoint was EULAR/LUNDEX response rates at 6/12 months. Of the 2015 RA patients initiating therapy with IV abatacept, 380 (18.9%) were classified as obese. Obese patients had more functional disability, and were less often RF positive. The median abatacept retention time was 1.91 years for obese RA patients compared to 2.12 years for non-obese patients (p = 0.15). The risk of abatacept discontinuation was not significantly different for overweight (HR 1.03 (95% CI 0.89-1.19)), or for obese (HR 1.08 (95% CI 0.89-1.30)) compared to normal-weight patients. Rheumatoid factor positivity reduced the risk of abatacept discontinuation (HR 0.83 (95% CI 0.72-0.95)), while previous biologic therapy was positively associated with drug interruption (HRs increasing from 1.68 to 2.16 with the line of treatments). Obese and non-obese patients attained similar rates of EULAR/LUNDEX clinical response at 6/12 months. Drug retention and clinical response rates to abatacept do not seem to be decreased by obesity in RA patients. PMID- 27966069 TI - ImmunoPET Imaging of Murine CD4+ T Cells Using Anti-CD4 Cys-Diabody: Effects of Protein Dose on T Cell Function and Imaging. AB - PURPOSE: Molecular imaging of CD4+ T cells throughout the body has implications for monitoring autoimmune disease and immunotherapy of cancer. Given the key role of these cells in regulating immunity, it is important to develop a biologically inert probe. GK1.5 cys-diabody (cDb), a previously developed anti-mouse CD4 antibody fragment, was tested at different doses to assess its effects on positron emission tomography (PET) imaging and CD4+ T cell viability, proliferation, CD4 expression, and function. PROCEDURES: The effect of protein dose on image contrast (lymphoid tissue-to-muscle ratio) was assessed by administering different amounts of 89Zr-labeled GK1.5 cDb to mice followed by PET imaging and ex vivo biodistribution analysis. To assess impact of GK1.5 cDb on T cell biology, GK1.5 cDb was incubated with T cells in vitro or administered intravenously to C57BL/6 mice at multiple protein doses. CD4 expression and T cell proliferation were analyzed with flow cytometry and cytokines were assayed. RESULTS: For immunoPET imaging, the lowest protein dose of 2 MUg of 89Zr-labeled GK1.5 cDb resulted in significantly higher % injected dose/g in inguinal lymph nodes (ILN) and spleen compared to the 12-MUg protein dose. In vivo administration of GK1.5 cDb at the high dose of 40 MUg caused a transient decrease in CD4 expression in spleen, blood, lymph nodes, and thymus, which recovered within 3 days postinjection; this effect was reduced, although not abrogated, when 2 MUg was administered. Proliferation was inhibited in vivo in ILN but not the spleen by injection of 40 MUg GK1.5 cDb. Concentrations of GK1.5 cDb in excess of 25 nM significantly inhibited CD4+ T cell proliferation and interferon-gamma production in vitro. Overall, using low-dose GK1.5 cDb minimized biological effects on CD4+ T cells. CONCLUSIONS: Low-dose GK1.5 cDb yields high contrast immunoPET images with minimal effects on T cell biology in vitro and in vivo and may be a useful tool for investigating CD4+ T cells in the context of preclinical disease models. Future approaches to minimizing biological effects may include the creation of monovalent fragments or selecting anti-CD4 antibodies which target alternative epitopes. PMID- 27966070 TI - African swine fever outbreak on a medium-sized farm in Uganda: biosecurity breaches and within-farm virus contamination. AB - In Uganda, a low-income country in east Africa, African swine fever (ASF) is endemic with yearly outbreaks. In the prevailing smallholder subsistence farming systems, farm biosecurity is largely non-existent. Outbreaks of ASF, particularly in smallholder farms, often go unreported, creating significant epidemiological knowledge gaps. The continuous circulation of ASF in smallholder settings also creates biosecurity challenges for larger farms. In this study, an on-going outbreak of ASF in an endemic area was investigated on farm level, including analyses of on-farm environmental virus contamination. The study was carried out on a medium-sized pig farm with 35 adult pigs and 103 piglets or growers at the onset of the outbreak. Within 3 months, all pigs had died or were slaughtered. The study included interviews with farm representatives as well as biological and environmental sampling. ASF was confirmed by the presence of ASF virus (ASFV) genomic material in biological (blood, serum) and environmental (soil, water, feed, manure) samples by real-time PCR. The ASFV-positive biological samples confirmed the clinical assessment and were consistent with known virus characteristics. Most environmental samples were found to be positive. Assessment of farm biosecurity, interviews, and the results from the biological and environmental samples revealed that breaches and non-compliance with biosecurity protocols most likely led to the introduction and within-farm spread of the virus. The information derived from this study provides valuable insight regarding the implementation of biosecurity measures, particularly in endemic areas. PMID- 27966071 TI - Structure and dynamics of high- and low-density water molecules in the liquid and supercooled regimes. AB - By combining the local structure index with potential energy minimisations we study the local environment of the water molecules for a couple of water models, TIP5P-Ew and SPC/E, in order to characterise low- and high-density "species". Both models show a similar behaviour within the supercooled regime, with two clearly distinguishable populations of unstructured and structured molecules, the fraction of the latter increasing with supercooling. Additionally, for TIP5P-Ew, we find that the structured component vanishes quickly at the normal liquid regime (above the melting temperature). Thus, while SPC/E provides a fraction of structured molecules similar to that found in X-ray experiments, we show that TIP5P-Ew underestimates such value. Moreover, unlike SPC/E, we demonstrate that TIP5P-Ew does not follow the linear dependence of the logarithm of the structured fraction with inverse temperature, as predicted by the two-order parameter model. Finally, we link structure to dynamics by showing that there exists a strong correlation between structural fluctuation and dynamics in the supercooled state with spatial correlations in both static and dynamic quantities. PMID- 27966072 TI - Nanostructural determination of a lipid bilayer tethered to a gold substrate. AB - Tethered lipid bilayer membranes (tBLM) are planar membranes composed of free lipids and molecules tethered to a solid planar substrate providing a useful model of biological membranes for a wide range of biophysical studies and biotechnological applications. The properties of the tBLM depend on the free lipids and on the chemistry of the tethering molecules. We present a nanoscale characterization of a tBLM composed of deuterated 1,2-dimyristoyl-sn-glycero-3 phosphocholine (d-DMPC) free lipids, benzyl disulfide undecaethylene glycol phytanol (DLP) tethering molecules, and benzyl disulfiide tetraethylene glycol polar spacer molecules (PSM) used to control the areal density of tethering molecules through coadsorption. The use of selected isotopic substitution provides a way to distinguish the conformation and location of the tethered lipids from the free lipids and to elucidate how the two components influence the structure of the tBLM. These findings provide useful information to optimise the insertion of transmembrane proteins into the tethered bilayer system. PMID- 27966073 TI - Microorganism billiards in closed plane curves. AB - Recent experiments have shown that many species of microorganisms leave a solid surface at a fixed angle determined by steric interactions and near-field hydrodynamics. This angle is completely independent of the incoming angle. For several collisions in a closed body this determines a unique type of billiard system, an aspecular billiard in which the outgoing angle is fixed for all collisions. We analyze such a system using numerical simulation of this billiard for varying tables and outgoing angles, and also utilize the theory of one dimensional maps and wavefront dynamics. When applicable we cite results from and compare our system to similar billiard systems in the literature. We focus on examples from three broad classes: the ellipse, the Bunimovich billiards, and the Sinai billiards. The effect of a noisy outgoing angle is also discussed. PMID- 27966074 TI - Brain-Defective Insulin Signaling Is Associated to Late Cognitive Impairment in Post-Septic Mice. AB - Sepsis survivors frequently develop late cognitive impairment. Because little is known on the mechanisms of post-septic memory deficits, there are no current effective approaches to prevent or treat such symptoms. Here, we subjected mice to severe sepsis induced by cecal ligation and puncture (CLP) and evaluated the sepsis-surviving animals in the open field, novel object recognition (NOR), and step-down inhibitory avoidance (IA) task at different times after surgery. Post septic mice (30 days post-surgery) failed in the NOR and IA tests but exhibited normal performance when re-evaluated 45 days after surgery. Cognitive impairment in post-septic mice was accompanied by reduced hippocampal levels of proteins involved in synaptic plasticity, including synaptophysin, cAMP response element binding protein (CREB), CREB phosphorylated at serine residue 133 (CREBpSer133), and GluA1 phosphorylated at serine residue 845 (GluA1pSer845). Expression of tumor necrosis factor alpha (TNF-alpha) was increased and brain insulin signaling was disrupted, as indicated by increased hippocampal IRS-1 phosphorylation at serine 636 (IRS-1pSer636) and decreased phosphorylation of IRS-1 at tyrosine 465 (IRS-1pTyr465), in the hippocampus 30 days after CLP. Phosphorylation of Akt at serine 473 (AktpSer473) and of GSK3 at serine 9 (GSK3betapSer9) were also decreased in hippocampi of post-septic animals, further indicating that brain insulin signaling is disrupted by sepsis. We then treated post-septic mice with liraglutide, a GLP-1 receptor agonist with insulinotropic activity, or TDZD-8, a GSK3beta inhibitor, which rescued NOR memory. In conclusion, these results establish that hippocampal inflammation and disrupted insulin signaling are induced by sepsis and are linked to late memory impairment in sepsis survivors. PMID- 27966075 TI - Protective Effect of Curcumin by Modulating BDNF/DARPP32/CREB in Arsenic-Induced Alterations in Dopaminergic Signaling in Rat Corpus Striatum. AB - Earlier, protective role of curcumin in arsenic-induced dopamine (DA)-D2 receptor dysfunctions in corpus striatum has been demonstrated by us. In continuation to that, the present study is focused to decipher the molecular mechanisms associated with alterations in dopaminergic signaling on arsenic exposure in corpus striatum and assess the protective efficacy of curcumin. Exposure to arsenic (20 mg/kg, body weight p.o. for 28 days) in rats resulted to decrease the expression of presynaptic proteins-tyrosine hydroxylase and VMAT2 while no effect was observed on the expression of DAT in comparison to controls. A significant decrease in the expression of DA-D2 receptors associated with alterations in the expression of PKA, pDARPP32 (Thr 34), and PP1 alpha was clearly evident on arsenic exposure. Expression of BDNF and pGSK3beta in corpus striatum was found decreased in arsenic-exposed rats. Simultaneous treatment with curcumin (100 mg/kg, body weight p.o. for 28 days) resulted to protect arsenic-induced alterations in the expression of DA-D2 receptors, PKA, pDARPP32, pCREB, and pPP1alpha. Neuroprotective efficacy of curcumin can possibly be attributed to its antioxidant potential which significantly protected arsenic-induced mitochondrial dysfunctions by modulating the ROS generation and apoptosis. Modulation in the expression of BDNF and pGSK3beta in corpus striatum by curcumin exhibits the importance of neuronal survival pathway in arsenic-induced dopaminergic dysfunctions. Interestingly, curcumin was also found to protect arsenic-induced ultrastructural changes in corpus striatum. The results exhibit that curcumin modulates BDNF/DARPP32/CREB in arsenic-induced alterations in dopaminergic signaling in rat corpus striatum. PMID- 27966076 TI - The Level of Testosterone, Vitamin D, and Irregular Menstruation More Important than Omega-3 in Non-Symptomatic Women Will Define the Fate of Multiple Scleroses in Future. AB - Multiple sclerosis is one of the most salient degenerative disorders of CNS with dysregulated immune process that resulted in axonal damage and demyelination. In the present investigation, the serum level of testosterone was assessed in women who were struggling with multiple sclerosis (MS). Also, the level of omega-3, vitamin D, and the irregular menstruation in women 5 years before the onset MS symptoms were surveyed. Although the levels of omega-3 and vitamin D in women MS patients were non-significant and significantly less than the healthy ones, they were significantly less in the whole population of MS patients. However, the MS patients more experienced more irregular menstruation some years before the onset of MS with the low level of testosterone. Based on the presented findings, it might be said that the vitamin D intake has significant protective role in women and men MS patients unlike the omega-3 that had significant protective role just in men. However, vitamin D metabolism encoding genes of CYP27B1 and CYP24A1 and predicting MS risk gene of HLA-DRB1*15:01 define its fate as well. Besides, vitamin D intake, through the proliferation decrement of pro-inflammatory cells, decreases of pro-inflammatory markers (IL-6, TNF-alpha, INF-gamma) and auto immune pathways have potential role in recovery of irregular menstruation in women with the low level of testosterone as a red warning factor of MS development. The low level of testosterone and vitamin D consumption increase the neural damage and pro-inflammatory pathways in MS patients, and the difference among the investigations is related to the long-standing history of MS that influences severity of damage to the neural cells and biomolecules and complicate its recovery. PMID- 27966077 TI - Prolyl Oligopeptidase Regulates Dopamine Transporter Phosphorylation in the Nigrostriatal Pathway of Mouse. AB - Alpha-synuclein is the main component of Lewy bodies, a histopathological finding of Parkinson's disease. Prolyl oligopeptidase (PREP) is a serine protease that binds to alpha-synuclein and accelerates its aggregation in vitro. PREP enzyme inhibitors have been shown to block the alpha-synuclein aggregation process in vitro and in cellular models, and also to enhance the clearance of alpha synuclein aggregates in transgenic mouse models. Moreover, PREP inhibitors have induced alterations in dopamine and metabolite levels, and dopamine transporter immunoreactivity in the nigrostriatal tissue. In this study, we characterized the role of PREP in the nigrostriatal dopaminergic and GABAergic systems of wild-type C57Bl/6 and PREP knockout mice, and the effects of PREP overexpression on these systems. Extracellular concentrations of dopamine and protein levels of phosphorylated dopamine transporter were increased and dopamine reuptake was decreased in the striatum of PREP knockout mice, suggesting increased internalization of dopamine transporter from the presynaptic membrane. Furthermore, PREP overexpression increased the level of dopamine transporters in the nigrostriatal tissue but decreased phosphorylated dopamine transporters in the striatum in wild-type mice. Our results suggest that PREP regulates the function of dopamine transporter, possibly by controlling the phosphorylation and transport of dopamine transporter into the striatum or synaptic membrane. PMID- 27966078 TI - Analysis of piRNA-Like Small Non-coding RNAs Present in Axons of Adult Sensory Neurons. AB - Small non-coding RNAs (sncRNAs) have been shown to play pivotal roles in spatiotemporal-specific gene regulation that is linked to many different biological functions. PIWI-interacting RNAs (piRNAs), typically 25-34-nucleotide long, are originally identified and thought to be restricted in germline cells. However, recent studies suggest that piRNAs associate with neuronal PIWI proteins, contributing to neuronal development and function. Here, we identify a cohort of piRNA-like sncRNAs (piLRNAs) in rat sciatic nerve axoplasm and directly contrast temporal changes of piLRNA levels in the nerve following injury, as compared with those in an uninjured nerve using deep sequencing. We find that 32 of a total of 53 annotated piLRNAs show significant changes in their levels in the regenerating nerve, suggesting that individual axonal piLRNAs may play important regulatory roles in local messenger RNA (mRNA) translation during regeneration. Bioinformatics and biochemical analyses show that these piLRNAs carry characteristic features of mammalian piRNAs, including sizes, a sequence bias for uracil at the 5'-end and a 2'-O-methylation at the 3'-end. Their axonal expression is directly visualized by fluorescence in situ hybridization in cultured dorsal root ganglion neurons as well as immunoprecipitation with MIWI. Further, depletion of MIWI protein using RNAi from cultured sensory neurons increases axon growth rates, decreases axon retraction after injury, and increases axon regrowth after injury. All these data suggest more general roles for MIWI/piLRNA pathway that could confer a unique advantage for coordinately altering the population of proteins generated in growth cones and axons of neurons by targeting mRNA cohorts. PMID- 27966079 TI - Anti-Apoptotic Effect of IGF1 on Schwann Exposed to Hyperglycemia is Mediated by Neuritin, a Novel Neurotrophic Factor. AB - The aim of the present study is to explore the effects of exogenous insulin-like growth factor-1 (IGF1) on hyperglycemia-induced apoptosis of Schwann cells via neuritin-mediated pathway. Neuritin was identified with immunohistochemistry. Exogenous IGF1 was used to prevent possible changes in neuritin expression and apoptosis of Schwann cells isolated from rat sciatic nerves and cultured in high glucose media. Neuritin silencing or overexpressing lentivirus transfection of Schwann cells was conducted. Expressions of neuritin at levels of transcription or translation were measured using quantitative PCR or Western blot. Caspase-3 and caspase-9 fluorometric assays were performed. Bcl-2 and Bax were assayed using Western blotting. Apoptosis of Schwann cells was measured using FACS analysis and TUNEL assay. A pathway of IGF1 action in relation to neuritin was explored. Neuritin and Bcl-2 protein were localized in Schwann cells of rats' sciatic nerves. In vitro, apoptosis increased with downregulated neuritin expression, which was prevented by exogenous IGF1 treatment in contrast to without, in Schwann cells isolated from rat sciatic nerve and cultured in high glucose and serum-free media. A phosphatidylinositol-3-kinase (PI3K) inhibitor treatment blocked the action of IGF1. The inhibitor did not affect the apoptosis rate that decreased obviously after neuritin was overexpressed in Schwann cells. The apoptosis rate increased drastically after neuritin was silenced, and the resultant apoptosis was suppressed by a caspase inhibitor treatment but not affected by exogenous IGF1. The activities of caspase-3 and caspase-9 changed positively with apoptosis. An anti-apoptotic protein (Bcl-2) not Bax increased or decreased in neuritin-overexpressed or neuritin-silenced Schwann cells, respectively. Bcl-2-selective inhibitor blocked the anti-apoptotic effect of neuritin. IGF1 or neuritin was not found to affect glucose levels in media during the experiment. The anti-apoptotic effect of IGF1 on Schwann cells inflicted by hyperglycemia is mediated at least by neuritin, a novel neurotrophic factor, through PI3K and Bcl-2. PMID- 27966082 TI - Change detection for Lake Burullus, Egypt using remote sensing and GIS approaches. AB - Lake Burullus is the second largest natural coastal lake in Egypt. It has an economic importance for fish yield. However, several anthropogenic activities such as industrial, agriculture, and reclamation activities lead to a deterioration of its water quality and a decrease of the water body area of the lake. This study aims to detect the spatiotemporal changes of Lake Burullus in the period 1972-2015 using 12 Landsat {(1,3-MSS), (4,5-TM), and (7-ETM+)} imageries and water indices approach. To extract water feature from imageries, the Normalized Difference Water Index (NDWI) and the Water Ratio Index (WRI) were applied. The NDWI was applied to the MSS imageries. For other TM and ETM+ imageries, the WRI was applied. Obtained results show a significant decrease in the water area of the Lake Burullus, where it lost about (49%) of its surface area during the period from the year 1972 to the year 2015. A rapid decrease in the lake surface area was noticed through the period from 1972 to 1984. A prediction model was built depending on the calculated water area of the lake. Finally, the multi-temporal maps of the lake surface area are overlaid to produce a map for the changes of the lake surface area using Geographic Information System (GIS). PMID- 27966080 TI - Photocatalytic behaviour of WO3/TiO2-N for diclofenac degradation using simulated solar radiation as an activation source. AB - In this study, the photocatalytic removal of an emerging contaminant, diclofenac (DCF) sodium, was performed using the nitrogen-doped WO3/TiO2-coupled oxide catalyst (WO3/TiO2-N). The catalyst synthesis was accomplished by a sol-gel method using tetrabutyl orthotitanate (C16H36O4Ti), ammonium p-tungstate [(NH4)10H2W12O42.4H2O] and ammonium nitrate (NH4NO3) as the nitrogen source. For comparison, TiO2 and WO3/TiO2 were also prepared under similar conditions. Analysis by X-ray diffraction (XRD), N2 adsorption-desorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM), diffuse reflectance UV Vis spectroscopy (DRS) and X-ray photoelectron spectroscopy (XPS) were conducted to characterize the synthesized materials. The photocatalytic efficiency of the semiconductors was determined in a batch reactor irradiated with simulated solar light. Residual and mineralized DCF were quantified by high-performance liquid chromatography, total organic carbon analysis and ion exchange chromatography. The results indicated that the tungsten atoms were dispersed on the surface of TiO2 as WO3. The partial substitution of oxygen by nitrogen atoms into the lattice of TiO2 was an important factor to improve the photocatalytic efficiency of WO3/TiO2. Therefore, the best photocatalytic activity was obtained with the WO3/TiO2-N0.18 catalyst, reaching 100% DCF transformation at 250 kJ m-2 and complete mineralization at 400 kJ m-2 of solar-accumulated energy. PMID- 27966081 TI - Vectorization of agrochemicals: amino acid carriers are more efficient than sugar carriers to translocate phenylpyrrole conjugates in the Ricinus system. AB - Producing quality food in sufficient quantity while using less agrochemical inputs will be one of the great challenges of the twenty-first century. One way of achieving this goal is to greatly reduce the doses of plant protection compounds by improving the targeting of pests to eradicate. Therefore, we developed a vectorization strategy to confer phloem mobility to fenpiclonil, a contact fungicide from the phenylpyrrole family used as a model molecule. It consists in coupling the antifungal compound to an amino acid or a sugar, so that the resulting conjugates are handled by active nutrient transport systems. The method of click chemistry was used to synthesize three conjugates combining fenpiclonil to glucose or glutamic acid with a spacer containing a triazole ring. Systemicity tests with the Ricinus model have shown that the amino acid promoiety was clearly more favorable to phloem mobility than that of glucose. In addition, the transport of the amino acid conjugate is carrier mediated since the derivative of the L series was about five times more concentrated in the phloem sap than its counterpart of the D series. The systemicity of the L-derivative is pH dependent and almost completely inhibited by the protonophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP). These data suggest that the phloem transport of the L-derivative is governed by a stereospecific amino acid carrier system energized by the proton motive force. PMID- 27966083 TI - The causal link among militarization, economic growth, CO2 emission, and energy consumption. AB - This paper examines the long-run and the causal relationship among CO2 emissions, militarization, economic growth, and energy consumption for USA for the period 1960-2013. Using the bound test approach to cointegration, a short-run as well as a long-run relationship among the variables with a positive and a statistically significant relationship between CO2 emissions and militarization was found. To determine the causal link, MWALD and Rao's F tests were applied. According to Rao's F tests, the evidence of a unidirectional causality running from militarization to CO2 emissions, from energy consumption to CO2 emissions, and from militarization to energy consumption all without a feedback was found. Further, the results determined that 26% of the forecast-error variance of CO2 emissions was explained by the forecast error variance of militarization and 60% by energy consumption. PMID- 27966084 TI - Effects of dietary inclusion level of a mixture of probiotic cultures and enzymes on broiler chickens immunity response. AB - The current study was conducted to analyse the effect of a mixture of probiotic cultures and enzymes (Probio Enzyme, XVET GmbH, Germany) on the immune response and weight of central lymphoid organs and liver in broilers. A total of 270 male chickens were randomly divided into nine groups, with three replicates of 10 birds each. Treatment groups were fed for either 22 or 42 days with different levels of Probio Enzyme 250, 500, 750 and 1000 g/ton, whereas the control group fed a basal diet without Probio Enzyme. To analyse the effects of dietary supplementation on broilers humoral immune response, the antibodies titres for avian influenza (AI) and Newcastle disease virus (NDV) and to the sheep red blood cells (SRBC) challenge were assayed in birds from each experimental unit, along with the assessment of the weight of the main lymphoid organs and liver. The addition of the Probio Enzyme mixture did not significantly affect the titres of the antibodies against AI and NDV at day 42, despite the wide individual variation observed specially on the antibody titres at day 33. Treatments affected the production of IgG after the second challenge with SRBC (P = 0.003), which was transposed to the correspondent total Ig titres (P = 0.044). Conversely, a lower birds' body weight (BW) was found in the majority of treated groups compared to control (P = 0.031). The spleen was the only lymphoid organ showing differences in the absolute and relative weight (P = 0.003 and P = 0.001, respectively). No differences were found in thymus and Bursa of Fabricius weights. In conclusion, broilers treated with Probio Enzyme showed a satisfactory immune response compared with control, despite the wide variation found after the first vaccine challenge against AI. Moreover, the probiotic mixture dose and duration modulated differently the immune response and the spleen weight, unaffecting the central lymphoid organs weight. PMID- 27966085 TI - Biogenic synthesis of silver nanoparticle by using secondary metabolites from Pseudomonas aeruginosa DM1 and its anti-algal effect on Chlorella vulgaris and Chlorella pyrenoidosa. AB - Biogenic synthesis of silver nanoparticles (AgNPs) using extracellular metabolites from the bacterium Pseudomonas aeruginosa DM1 offers an eco-friendly and sustainable way of metal nanoparticle synthesis. The present work highlights the biotransformation of silver nitrate solution into AgNP, mediated by extracellular secondary metabolite pyoverdine, a siderophore produced by P. aeruginosa. The bioreduction of silver ions into AgNPs by using pyoverdine was recorded in terms of Fourier transform infrared spectroscopy (FTIR) analysis and color change in the reaction mixture (AgNO3 + pyoverdine) from pale yellow to dark brown with absorption maxima at 415 nm. The results of X-ray diffraction (XRD) analysis of AgNPs showed its crystalline face-centered cubic structure. The scanning electron microscopy (SEM) and transmission electron microscopy (TEM) pictures of AgNPs showed spherical morphology of AgNP in the range of 45-100 nm, with tendency of agglomerations. The energy-dispersive X-ray (EDX) analysis of particles provided strong signal of elemental silver with few minor peaks of other impurities. The present approach offers a unique in vitro method of metal nanoparticle synthesis by exogenously produced bacterial secondary metabolites, where direct contact between the toxic metal and biological resource material can be avoided. The biologically synthesized AgNPs are found to have anti-algal effects against two species of Chlorella (Chlorella vulgaris and Chlorella pyenoidosa), as indicated by zone of growth inhibition on algal culture plates. Further results exhibit concentration-dependent progressive inhibition of chlorophyll content in the algal cells by AgNPs, confirming the algicidal effect of AgNPs. PMID- 27966087 TI - Signaling pathways underlying the antidepressant-like effect of inosine in mice. AB - Inosine is a purine nucleoside formed by the breakdown of adenosine that elicits an antidepressant-like effect in mice through activation of adenosine A1 and A2A receptors. However, the signaling pathways underlying this effect are largely unknown. To address this issue, the present study investigated the influence of extracellular-regulated protein kinase (ERK)1/2, Ca2+/calmoduline-dependent protein kinase (CaMKII), protein kinase A (PKA), phosphoinositide 3-kinase (PI3K)/Akt, and glycogen synthase kinase 3beta (GSK-3beta) modulation in the antiimmobility effect of inosine in the tail suspension test (TST) in mice. In addition, we attempted to verify if inosine treatment was capable of altering the immunocontent and phosphorylation of the transcription factor cyclic adenosine monophosphatate (cAMP) response-binding element protein (CREB) in mouse prefrontal cortex and hippocampus. Intracerebroventricular administration of U0126 (5 MUg/mouse, MEK1/2 inhibitor), KN-62 (1 MUg/mouse, CaMKII inhibitor), H 89 (1 MUg/mouse, PKA inhibitor), and wortmannin (0.1 MUg/mouse, PI3K inhibitor) prevented the antiimmobility effect of inosine (10 mg/kg, intraperitoneal (i.p.)) in the TST. Also, administration of a sub-effective dose of inosine (0.1 mg/kg, i.p.) in combination with a sub-effective dose of AR-A014418 (0.001 MUg/mouse, GSK-3beta inhibitor) induced a synergic antidepressant-like effect. None of the treatments altered locomotor activity of mice. Moreover, 24 h after a single administration of inosine (10 mg/kg, i.p.), CREB phosphorylation was increased in the hippocampus. Our findings provided new evidence that the antidepressant-like effect of inosine in the TST involves the activation of PKA, PI3K/Akt, ERK1/2, and CaMKII and the inhibition of GSK-3beta. These results contribute to the comprehension of the mechanisms underlying the purinergic system modulation and indicate the intracellular signaling pathways involved in the antidepressant-like effect of inosine in a preclinical test of depression. PMID- 27966090 TI - Multiresidue Screening of Veterinary Drugs in Meat, Milk, Egg, and Fish Using Liquid Chromatography Coupled with Ion Trap Time-of-Flight Mass Spectrometry. AB - New approaches to veterinary drug screening based on liquid chromatography-mass spectrometry (LC-MS/MS) and time-of-flight mass spectrometry (ToF/MS) are rapid and have high selectivity and sensitivity. In this study, we developed a multiresidue method for screening over 100 veterinary drug residues using ion trap (IT)-ToF/MS. The screened compounds comprised major drug classes used in veterinary practice, representing the following: amphenicols, anthelmintics, benzimidazoles, beta-lactams, coccidiostats, ionophores, macrolides, non steroidal anti-inflammatory drugs, quinolones, sulfonamides, tetracyclines, and tranquilizers. The method was developed based on chromatographic retention time, specific accurate mass, isotope distribution, and fragment data. Each compound was validated at three levels, and the mass accuracy, accuracy, and repeatability were calculated. All parameters showed acceptable values and conformed to the Commission Decision 2002/657/EC criteria. This screening method can simultaneously analyze over 100 veterinary drugs in meat, milk, eggs, and fish in a single analytical run. PMID- 27966089 TI - Correlation of Conformational Changes and Protein Degradation with Loss of Lysozyme Activity Due to Chlorine Dioxide Treatment. AB - Chlorine dioxide (ClO2) is a potent oxidizing agent used for the treatment of drinking water and decontamination of facilities and equipment. The purpose of this research is to elucidate the manner in which ClO2 destroys proteins by studying the effects of ClO2 on lysozyme. The degree of enzyme activity lost can be correlated to the treatment time and levels of the ClO2 used. Lysozyme activity was drastically reduced to 45.3% of original enzyme activity when exposed to 4.3 mM ClO2 in the sample after 3 h. Almost all activities were lost in 3 h after exposure to higher ClO2 concentrations of up to 16.8 and 21.9 mM. Changes in protein conformation and amount as a result of ClO2 treatment were determined using the Raman spectroscopy and gel electrophoresis. Raman shifts and the alteration of spectral features observed in the ClO2-treated lysozyme samples are associated with loss of the alpha-helix secondary structure, tertiary structure, and disulfide bond. Progressive degradation of the denatured lysozyme by increasing levels of chlorine dioxide was also observed in gel electrophoresis. Hence, ClO2 can effectively cause protein denaturation and degradation resulting in loss of enzyme activity. PMID- 27966091 TI - The Journal and Social Media. PMID- 27966088 TI - Drug Distribution Part 2. Predicting Volume of Distribution from Plasma Protein Binding and Membrane Partitioning. AB - PURPOSE: Volume of distribution is an important pharmacokinetic parameter in the distribution and half-life of a drug. Protein binding and lipid partitioning together determine drug distribution. METHODS: Here we present a simple relationship that estimates the volume of distribution with the fraction of drug unbound in both plasma and microsomes. Model equations are based upon a two compartment system and the experimental fractions unbound in plasma and microsomes represent binding to plasma proteins and cellular lipids, respectively. RESULTS: The protein and lipid binding components were parameterized using a dataset containing human in vitro and in vivo parameters for 63 drugs. The resulting equation explains ~84% of the variance in the log of the volume of distribution with an average fold-error of 1.6, with 3 outliers. CONCLUSIONS: These results suggest that Vss can be predicted for most drugs from plasma protein binding and microsomal partitioning. PMID- 27966086 TI - Procedures of determining organic trace compounds in municipal sewage sludge-a review. AB - Sewage sludge is the largest by-product generated during the wastewater treatment process. Since large amounts of sludge are being produced, different ways of disposal have been introduced. One tempting option is to use it as fertilizer in agricultural fields due to its high contents of inorganic nutrients. This, however, can be limited by the amount of trace contaminants in the sewage sludge, containing a variety of microbiological pollutants and pathogens but also inorganic and organic contaminants. The bioavailability and the effects of trace contaminants on the microorganisms of soil are still largely unknown as well as their mixture effects. Therefore, there is a need to analyze the sludge to test its suitability before further use. In this article, a variety of sampling, pretreatment, extraction, and analysis methods have been reviewed. Additionally, different organic trace compounds often found in the sewage sludge and their methods of analysis have been compiled. In addition to traditional Soxhlet extraction, the most common extraction methods of organic contaminants in sludge include ultrasonic extraction (USE), supercritical fluid extraction (SFE), microwave-assisted extraction (MAE), and pressurized liquid extraction (PLE) followed by instrumental analysis based on gas or liquid chromatography and mass spectrometry. PMID- 27966092 TI - Attitudes of Patients and Relatives Toward Disability and Treatment in Malignant MCA Infarction. AB - BACKGROUND: Attitudes among patients and relatives toward the degree of acceptable disability and the importance of aphasia are critical in deciding on decompressive hemicraniectomy (DHC) in malignant middle cerebral artery infarction (MMI). However, most MMI patients are not able to communicate their will. Furthermore, attitudes of healthy individuals and relatives may not correspond to those of stroke patients. METHODS: This is a multicenter survey among 355 patients and 199 relatives during treatment for acute minor or moderate severe ischemic stroke in Germany. Questions address the acceptance of disability, importance of aphasia, and the preferred treatment in the hypothetical case of future MMI. RESULTS: mRS scores of 2 or better were considered acceptable by the majority of all respondents (72.9-88.1%). A mRS of 3, 4, and 5 was considered acceptable by 56.0, 24.5, and 6.8%, respectively. Except for a mRS of 1, relatives indicated each grade of disability significantly more often acceptable than patients. Differences regarding acceptable disability and treatment decision were depending on family status, housing situation, need of care, and disability. The presence of aphasia was considered important for treatment decision by both patients (46.5%) and relatives (39.2%). Older respondents more often refrained from DHC (p < 0.001). CONCLUSION: In Germany, there is substantial heterogeneity in patients and relatives regarding acceptable disability, aphasia, and treatment decision in the hypothetical case of MMI. Relatives significantly overestimate the degree of disability that is acceptable to stroke patients. Further studies are warranted to determine whether differences in attitudes impact on the decision to undergo DHC. PMID- 27966093 TI - Spatial Fuzzy C Means and Expectation Maximization Algorithms with Bias Correction for Segmentation of MR Brain Images. AB - The Fuzzy C Means (FCM) and Expectation Maximization (EM) algorithms are the most prevalent methods for automatic segmentation of MR brain images into three classes Gray Matter (GM), White Matter (WM) and Cerebrospinal Fluid (CSF). The major difficulties associated with these conventional methods for MR brain image segmentation are the Intensity Non-uniformity (INU) and noise. In this paper, EM and FCM with spatial information and bias correction are proposed to overcome these effects. The spatial information is incorporated by convolving the posterior probability during E-Step of the EM algorithm with mean filter. Also, a method of pixel re-labeling is included to improve the segmentation accuracy. The proposed method is validated by extensive experiments on both simulated and real brain images from standard database. Quantitative and qualitative results depict that the method is superior to the conventional methods by around 25% and over the state-of-the art method by 8%. PMID- 27966094 TI - Therapeutic Hypothermia for Birth Asphyxia in Neonates. AB - India contributes to the highest neonatal mortality globally. Birth asphyxia is one of the leading causes of neonatal mortality in India. A large number of neonates who suffer from birth asphyxia progress to Hypoxic Ischemic Encephalopathy (HIE). The risk of a neonate progressing to severe form of HIE is many times higher in the low and middle income countries (LMICs) with ill developed health infrastructure. Till date LMICs have had a low institutional delivery rate, poor regionalization of care, lack of adequate transport facilities and ill equipped neonatal intensive care facilities. This has lead to a tremendous burden on the health care systems with a cohort of developmentally challenged neonates surviving into adulthood. Recently, Therapeutic Hypothermia (TH) has emerged as an evidence based intervention to reduce mortality and neurodevelopmental disability associated with asphyxia induced encephalopathy. TH has become the gold standard in the management of such cases in the western world. Extension of this knowledge to the LMICs and countries like India require a better understanding of the unique sociocultural issues associated with asphyxial brain injury in neonates. The high incidence of sepsis and presence of economic constraints make this problem more complex in such countries. The current review has tried to address these issues and looked at the basics of this complex topic from the perspective of a general pediatrician. PMID- 27966095 TI - [Determinants of social participation and social inclusion of people with severe mental illness]. AB - BACKGROUND: Individuals with mental disorders are known to be socially excluded so that improving social inclusion has become a major goal of healthcare provision. However, empirical research on specific determinants of social inclusion is rather scarce. METHODS: A cross-sectional survey of adults with a severe mental illness (n =70) was conducted using a measure of participation and social inclusion for individuals with a chronic mental disorder (F-INK). Univariate and multivariate regression analyses were conducted to identify determinants of social participation and social inclusion. RESULTS: Social participation increased with the number of friends and was, independently thereof, higher in adults living independently than in adults living in supported housing arrangements. The level of social inclusion was higher in those cohabitating and increased with duration of illness. CONCLUSION: Findings on social participation indicate the need for a re-organization of community-based supported housing arrangements, and, with respect to existing settings, an amendment of present conditions. To promote social inclusion, measures to prime a feeling of ongoing social affiliation should be taken during the first years of psychiatric illness. PMID- 27966097 TI - [Report of the 23rd annual meeting of the Working Group Kidney Transplantation of the German Society of Urology in Homburg (Saar)]. PMID- 27966096 TI - Psychiatric emergencies of minors with and without migration background. AB - BACKGROUND: The conditions of children and adolescents with migration background receiving emergency psychiatric care in Europe are not well known. Migrants usually attend regular psychiatric care less frequently than the autochthonous population. We therefore speculated that, being undertreated, they would be overrepresented among psychiatric emergency care patients. METHODS: We retrospectively analyzed the records of 1093 minors aged 4-18 years treated during a period of three years at the psychiatric emergency outpatient clinic of the Department of Child and Adolescent Psychiatry at the Medical University of Vienna. RESULTS: More minors with migration background than natives consulted our emergency clinic. Most frequent reasons for referral were suicide attempts by Turkish patients, acute stress disorder in Serbian/Croatian/Bosnian and in Austrian patients. Psychiatric diagnoses like eating and personality disorders were mostly diagnosed in natives. We found gender specific differences between the groups. CONCLUSIONS: The reasons for these differences possibly relate to deficits of adequate mental health-care in Austria, to intercultural and intrafamiliar conflicts related to acculturation distress in the migrant population. Prospective longitudinal studies focusing on the utilization of mental health care by the migrant children and the impact of the migration background on their mental health are needed for improving adequate culture sensitive mental-health care for this population. PMID- 27966100 TI - Erratum: Chapter 35 The Effects of Passive Cycling Exercise for 20 min on Cardiorespiratory Dynamics in Healthy Men. PMID- 27966098 TI - Selective Transgenic Expression of Mutant Ubiquitin in Purkinje Cell Stripes in the Cerebellum. AB - The ubiquitin-proteasome system (UPS) is one of the major mechanisms for protein breakdown in cells, targeting proteins for degradation by enzymatically conjugating them to ubiquitin molecules. Intracellular accumulation of ubiquitin B+1 (UBB+1), a frameshift mutant of ubiquitin-B, is indicative of a dysfunctional UPS and has been implicated in several disorders, including neurodegenerative disease. UBB+1-expressing transgenic mice display widespread labeling for UBB+1 in brain and exhibit behavioral deficits. Here, we show that UBB+1 is specifically expressed in a subset of parasagittal stripes of Purkinje cells in the cerebellar cortex of a UBB+1-expressing mouse model. This expression pattern is reminiscent of that of the constitutively expressed Purkinje cell antigen HSP25, a small heat shock protein with neuroprotective properties. PMID- 27966101 TI - Measuring Perceived Educational Impact of a Resident-Led Research Newsletter. AB - OBJECTIVE: To determine the perceived educational impact of a resident-led psychiatry research newsletter ('Research Watch') on the psychiatry residents at the authors' residency program. METHODS: An anonymous, voluntary paper questionnaire was distributed to all psychiatry residents at the program. The survey inquired about the degree of exposure (quantified as 'exposure index') and contribution to the newsletter. A set of questions asked residents to estimate how much of the improvement they attributed to the influence of the newsletter, rating the attribution between 0 and 100%, in the areas of interest in scholarly activities/research, knowledge of current psychiatric research, and participation in scholarly activities/research. The survey also inquired if the newsletter had any impact on their clinical practice. RESULTS: Of 29 residents in the program who received the survey, 27 (93%) responded. The percentage of residents reporting perceived non-zero impact of the newsletter on specific areas of improvement was as follows: interest in scholarly activities/research (44%), knowledge of current psychiatric research (48%), participation in scholarly activities/research (40%), and clinical practice (40%). Exposure index significantly and positively correlated with self-reported percentage attribution for knowledge (correlation coefficient 0.422, p value 0.028) and self-reported impact on clinical practice (correlation coefficient 0.660, p value 0.000), and degree of contribution significantly and positively correlated with self-reported percentage attribution for knowledge (correlation coefficient 0.488, p value 0.010). CONCLUSIONS: A resident-led research newsletter can have a positive perceived impact on the residents' interest, knowledge, and participation in research, as well as a positive perceived impact on clinical practice. PMID- 27966099 TI - Small molecules as therapeutic agents for inborn errors of metabolism. AB - Most inborn errors of metabolism (IEM) remain without effective treatment mainly due to the incapacity of conventional therapeutic approaches to target the neurological symptomatology and to ameliorate the multisystemic involvement frequently observed in these patients. However, in recent years, the therapeutic use of small molecules has emerged as a promising approach for treating this heterogeneous group of disorders. In this review, we focus on the use of therapeutically active small molecules to treat IEM, including readthrough agents, pharmacological chaperones, proteostasis regulators, substrate inhibitors, and autophagy inducers. The small molecules reviewed herein act at different cellular levels, and this knowledge provides new tools to set up innovative treatment approaches for particular IEM. We review the molecular mechanism underlying therapeutic properties of small molecules, methodologies used to screen for these compounds, and their applicability in preclinical and clinical practice. PMID- 27966102 TI - Behavioral and neural correlates of disrupted orienting attention in posttraumatic stress disorder. AB - Prior work has revealed that posttraumatic stress disorder (PTSD) is associated with altered (a) attentional performance and (b) resting-state functional connectivity (rsFC) in brain networks linked to attention. Here, we sought to characterize and link these behavioral and brain-based alterations in the context of Posner and Peterson's tripartite model of attention. Male military veterans with PTSD (N = 49; all deployed to Iraq or Afghanistan) and healthy age-and gender-matched community controls (N = 26) completed the Attention Network Task. A subset of these individuals (36 PTSD and 21 controls) also underwent functional magnetic resonance imaging (fMRI) to assess rsFC. The behavioral measures revealed that the PTSD group was impaired at disengaging spatial attention, relative to the control group. FMRI measures further revealed that, relative to the control group, the PTSD group exhibited greater rsFC between the salience network and (a) the default mode network, (b) the dorsal attention network, and (c) the ventral attention network. Moreover, problems with disengaging spatial attention increased the rsFC between the networks above in the control group, but not in the PTSD group. The present findings link PTSD to both altered orienting of spatial attention and altered relationships between spatial orienting and functional connectivity involving the salience network. Interventions that target orienting and disengaging spatial attention may be a new avenue for PTSD research. PMID- 27966103 TI - The drift diffusion model as the choice rule in reinforcement learning. AB - Current reinforcement-learning models often assume simplified decision processes that do not fully reflect the dynamic complexities of choice processes. Conversely, sequential-sampling models of decision making account for both choice accuracy and response time, but assume that decisions are based on static decision values. To combine these two computational models of decision making and learning, we implemented reinforcement-learning models in which the drift diffusion model describes the choice process, thereby capturing both within- and across-trial dynamics. To exemplify the utility of this approach, we quantitatively fit data from a common reinforcement-learning paradigm using hierarchical Bayesian parameter estimation, and compared model variants to determine whether they could capture the effects of stimulant medication in adult patients with attention-deficit hyperactivity disorder (ADHD). The model with the best relative fit provided a good description of the learning process, choices, and response times. A parameter recovery experiment showed that the hierarchical Bayesian modeling approach enabled accurate estimation of the model parameters. The model approach described here, using simultaneous estimation of reinforcement learning and drift diffusion model parameters, shows promise for revealing new insights into the cognitive and neural mechanisms of learning and decision making, as well as the alteration of such processes in clinical groups. PMID- 27966104 TI - The impact of the new National Bone Health Alliance (NBHA) diagnostic criteria on the prevalence of osteoporosis in the USA. AB - : We evaluated the prevalence of osteoporosis using the osteoporosis diagnostic criteria developed by the National Bone Health Alliance (NBHA), which includes qualified fractures, FRAX score in addition to bone mineral density (BMD). The expanded definition increases the prevalence compared to BMD alone definitions; however, it may better identify those at elevated fracture risk. PURPOSE: The purpose of this paper is to estimate the prevalence of osteoporosis in US adults >=50 years using the NBHA osteoporosis diagnostic criteria. METHODS: Utilizing 2005-2008 data of the National Health and Nutrition Examination Survey (NHANES), we identified participants with osteoporosis with any one of the following: (1) femoral neck or lumbar spine T-score <= -2.5; (2) low trauma hip fracture irrespective of BMD or clinical vertebral, proximal humerus, pelvis, or distal forearm fracture with a T-score >-2.5 <-1.0; or (3) FRAX score at the National Osteoporosis Foundation intervention thresholds (>=3% for hip fracture or >=20% for major osteoporotic fracture). We estimated the prevalence overall and by gender and age. RESULTS: Our sample included 1948 (54.3%) men and 1639 (45.7%) women. Approximately 12% were 80+ years and 21% were from racial/ethnic minority groups. We estimated that 16.0% (0.8) of men and 29.9% (1.0) of women 50+ years have osteoporosis. The prevalence increases with age to 46.3% in men and 77.1% in women 80+ years. The combination of FRAX score and fractures was the largest contributing factor defining osteoporosis in men (70-79, 88.1%; 80+, 80.1%), whereas T-score was the largest contributing factor in women (70-79, 49.2%; 80+, 43.5%). CONCLUSIONS: We found that 16% of men and 29.9% of women 50+ have osteoporosis based on the NBHA diagnostic criteria. Although the expanded definition increases the prevalence compared to BMD alone-based definitions, it may better identify those at elevated fracture risk in order to reduce the burden of fractures in older adults. PMID- 27966106 TI - Retreatment with teriparatide: our experience in three patients with severe secondary osteoporosis. AB - Teriparatide is a drug for the treatment of osteoporosis which is licensed for use for up to 24 months. There is little experience with retreatment. The aim of this study was to evaluate, in three patients with severe secondary osteoporosis, the response to a second cycle of teriparatide regarding bone mineral density (BMD) and osteocalcin. Case 1 : A 62-year-old woman with multiple vertebral fractures has received corticoids for a long time. After starting teriparatide, her BMD and osteocalcin increased. She then received ibandronate for 3 years but her BMD declined. After a second treatment with teriparatide, her BMD increased again (18%). Case 2 : A 60-year-old woman with severe osteoporosis in lumbar spine (LS) (T-score - 4.5) had received corticoids for a long time and had celiac disease. After starting teriparatide, her BMD improved by 11.7%. She then received zoledronic acid for 15 months, but bone density decreased, so she was retreated with teriparatide. BMD had a slightly higher increase than after the first cycle (12.6%). Case 3 : A 60-year-old woman consulted for osteoporosis (LS T-score - 5.3), several fractures, and hyperthyroidism. She started teriparatide with improvement in BMD (39%). After 24 months, she received ibandronate for 1 year, but as her BMD declined, she was retreated with teriparatide. BMD showed an increase of 15%. The indication of a second cycle of treatment with teriparatide in three patients was effective in increasing BMD. Additional studies are needed to further identify the benefits and safety of retreatment with teriparatide. PMID- 27966105 TI - Habitual levels of higher, but not medium or low, impact physical activity are positively related to lower limb bone strength in older women: findings from a population-based study using accelerometers to classify impact magnitude. AB - : This study assessed the effect of accelerometry-measured higher impacts resulting from habitual weight-bearing activity on lower limb bone strength in older women. Despite higher impacts being experienced rarely in this population based cohort, positive associations were observed between higher vertical impacts and lower limb bone size and strength. INTRODUCTION: We investigated whether the benefit of habitual weight-bearing physical activity (PA) for lower limb bone strength in older women is explained by exposure to higher impacts, as previously suggested by observations in younger individuals. METHODS: Four hundred and eight women from the Cohort for Skeletal Health in Bristol and Avon (COSHIBA), mean 76.8 years, wore tri-axial accelerometers at the waist for a mean of 5.4 days. Y axis peaks were categorised, using previously identified cutoffs, as low (0.5-1.0 g), medium (1.0-1.5 g), and higher (>=1.5 g) impacts. Mid and distal peripheral quantitative computed tomography scans of the tibia and radius were performed, as were hip and lumbar spine Dual X-ray Absorptiometry (DXA) scans. Regressions between (log transformed) number of low, medium and high impacts, and bone outcomes were adjusted for artefact error grade, age, height, fat and lean mass and impacts in other bands. RESULTS: Eight thousand eight hundred and nine (4047, 16,882) low impacts were observed during the measurement week, 345 (99, 764) medium impacts and 42 (17, 106) higher impacts (median with 25th and 75th quartiles). Higher vertical impacts were positively associated with lower limb bone strength as reflected by cross-sectional moment of inertia (CSMI) of the tibia [0.042 (0.012, 0.072) p = 0.01] and hip [0.067 (0.001, 0.133) p = 0.045] (beta coefficients show standard deviations change per doubling in impacts, with 95 % confidence interval). Higher impacts were positively associated with tibial periosteal circumference (PC) [0.015 (0.003, 0.027) p = 0.02], but unrelated to hip BMD. Equivalent positive associations were not seen for low or medium impacts. CONCLUSIONS: Despite their rarity, habitual levels of higher impacts were positively associated with lower limb bone size and strength, whereas equivalent relationships were not seen for low or medium impacts. PMID- 27966107 TI - The Middle East Respiratory Syndrome Coronavirus - A Continuing Risk to Global Health Security. AB - Two new zoonotic coronaviruses causing disease in humans (Zumla et al. 2015a; Hui and Zumla 2015; Peiris et al. 2003; Yu et al. 2014) have been the focus of international attention for the past 14 years due to their epidemic potential; (1) The Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) (Peiris et al. 2003) first discovered in China in 2001 caused a major global epidemic of the Severe Acute Respiratory Syndrome (SARS). (2) The Middle East respiratory syndrome coronavirus (MERS-CoV) is a new corona virus isolated for the first time in a patients who died of severe lower respiratory tract infection in Jeddah (Saudi Arabia) in June 2012 (Zaki et al. 2012). The disease has been named Middle East Respiratory Syndrome (MERS) and it has remained on the radar of global public health authorities because of recurrent nosocomial and community outbreaks, and its association with severe disease and high mortality rates (Assiri et al. 2013a; Al-Abdallat et al. 2014; Memish et al. 2013a; Oboho et al. 2015; The WHO MERS-CoV Research Group 2013; Cotten et al. 2013a; Assiri et al. 2013b; Memish et al. 2013b; Azhar et al. 2014; Kim et al. 2015; Wang et al. 2015; Hui et al. 2015a). Cases of MERS have been reported from all continents and have been linked with travel to the Middle East (Hui et al. 2015a; WHO 2015c). The World Health Organization (WHO) have held nine meetings of the Emergency Committee (EC) convened by the Director-General under the International Health Regulations (IHR 2005) regarding MERS-CoV (WHO 2015c). There is wishful anticipation in the political and scientific communities that MERS-CoV like SARS CoV will disappear with time. However it's been nearly 4 years since the first discovery of MERS-CoV, and MERS cases continue to be reported throughout the year from the Middle East (WHO 2015c). There is a large MERS-CoV camel reservoir, and there is no specific treatment or vaccine (Zumla et al. 2015a). With 10 million people visiting Saudi Arabia every year for Umrah and/or Hajj, the potential risk of global spread is ever present (Memish et al. 2014a; McCloskey et al. 2014; Al Tawfiq et al. 2014a). PMID- 27966108 TI - Membrane Fusion and Infection of the Influenza Hemagglutinin. AB - The influenza virus is a major health concern associated with an estimated 5000 to 30,000 deaths every year (Reed et al. 2015) and a significant economic impact with the development of treatments, vaccinations and research (Molinari et al. 2007). The entirety of the influenza genome is comprised of only eleven coding genes. An enormous degree of variation in non-conserved regions leads to significant challenges in the development of inclusive inhibitors for treatment. The fusion peptide domain of the influenza A hemagglutinin (HA) is a promising candidate for treatment since it is one of the most highly conserved sequences in the influenza genome (Heiny et al. 2007), and it is vital to the viral life cycle. Hemagglutinin is a class I viral fusion protein that catalyzes the membrane fusion process during cellular entry and infection. Impediment of the hemagglutinin's function, either through incomplete post-translational processing (Klenk et al. 1975; Lazarowitz and Choppin 1975) or through mutations (Cross et al. 2001), leads to non-infective virus particles. This review will investigate current research on the role of hemagglutinin in the virus life cycle, its structural biology and mechanism as well as the central role of the hemagglutinin fusion peptide (HAfp) to influenza membrane fusion and infection. PMID- 27966110 TI - Antibiotic Treatment of Hospitalized Patients with Pneumonia Complicated by Clostridium Difficile Infection. AB - Clostridium difficile infection (CDI) is one of the most common gastrointestinal complication after antimicrobial treatment. It is estimated that CDI after pneumonia treatment is connected with a higher mortality than other causes of hospitalization. The aim of the study was to assess the relationship between the kind of antibiotic used for pneumonia treatment and mortality from post-pneumonia CDI. We addressed the issue by examining retrospectively the records of 217 patients who met the diagnostic criteria of CDI. Ninety four of those patients (43.3 %) came down with CDI infection after pneumonia treatment. Fifty of the 94 patients went through severe or severe and complicated CDI. The distribution of antecedent antibiotic treatment of pneumonia in these 50 patients was as follows: ceftriaxone in 14 (28 %) cases, amoxicillin with clavulanate in 9 (18 %), ciprofloxacin in 8 (16.0 %), clarithromycin in 7 (14 %), and cefuroxime and imipenem in 6 (12 %) each. The findings revealed a borderline enhancement in the proportion of deaths due to CDI in the ceftriaxone group compared with the ciprofloxacin, cefuroxime, and imipenem groups. The corollary is that ceftriaxone should be shunned in pneumonia treatment. The study demonstrates an association between the use of a specific antibiotic for pneumonia treatment and post pneumonia mortality in patients who developed CDI. PMID- 27966109 TI - Renal Ultrasound (and Doppler Sonography) in Hypertension: An Update. AB - Ultrasound (US) allows the non-invasive evaluation of morphological changes of kidney structure (by means of B-Mode) and patterns of renal and extrarenal vascularization (by means of color-Doppler and contrast-enhanced US). In hypertensive subjects it offers a relevant contribution to the diagnosis of early renal damage, acute or chronic nephropathies and nephrovascular disease. However, morphological changes are often detected late and non-specific and in recent years evidence has increased regarding the clinical relevance of renal resistive index (RRI) for the study of vascular and renal parenchymal renal abnormalities. RRI is measured by Doppler sonography in an intrarenal artery, as the difference between the peak systolic and end-diastolic blood velocities divided by the peak systolic velocity. At first RRI was proved to be a marker of renal disease onset and progression; later the influence of systemic vascular properties on RRI was shown and authors claimed its use as an independent predictor of cardiovascular risk rather than of renal damage. Indeed, renal vascular resistance is only one of several renal (vascular compliance, interstitial and venous pressure), and extrarenal (heart rate, pulse pressure) determinants that concur to determine RRI individual values but not the most important one. The clinical relevance of RRI measurement as a surrogate endpoint of specific renal damage or/and as surrogate endpoint of atherosclerotic diffuse vascular damage is still debated.To summarize, from the literature: (a) In hypertensives with normal renal function and no albuminuria, especially in younger people, RRI is an early marker of renal damage that is especially useful when hypertension and diabetes concur in the same subjects. In these subjects RRI could improve current clinical scores used to stratify early renal damage. In older subjects RRI increases in accordance with the increase in systemic vascular stiffness and, because of this close relationship, RRI is also a marker of systemic atherosclerotic burden and the role of renal determinants can weaken. The clinical relevance was not specifically investigated. (b) In transplant kidney and in chronic renal disease high (>0.80) RRI values can independently predict renal failure. The recent claim that systemic (pulse pressure) rather than renal hemodynamic determinants sustain this predictive role of RRI, does not significantly reduce this predictive role of RRI. (c) Doppler ultrasound allows diagnosis and grading of renal stenosis in both fibromuscolar dysplastic and atherosclerotic diseases. Moreover, by RRI assay Doppler ultrasound can indirectly measure the hemodynamic impact of renal artery stenosis on the homolateral kidney, by virtue of the stenosis-related decrease in pulse pressure. However, in elderly subjects with atherosclerotic renal artery stenosis coexisting renal diseases can independently increase RRI by the augmentation in renal vascular stiffness and tubulo-interstitial pressure and hidden changes due to renal artery stenosis. PMID- 27966111 TI - Concha Bullosa in Paleoanthropological Material. AB - Concha bullosa is a variant of the sinonasal anatomy in which the middle nasal turbinate contains pneumatized cells, which leads to turbinate enlargement. The reason for concha bullosa formation is unclear, but the variant is seen in up to half the modern population and it may predispose to paranasal sinusitis. The variant has hitherto featured little in paleopathology. Therefore, in the present study we seek to determine the presence of concha bullosa, with the coexisting hypertrophy of the middle turbinate and signs of sinusitis or other pathology of the paranasal complex, in a population living in Tomersdorf-Toporow in the Upper Lausatia, a historical region in Germany and Poland, presently Zgorzelec County in the Lower Silesian voivodeship, at the turn of the nineteenth and twentieth century. The material consisted of 32 skeletons (24 males, 8 females). The gender, age, and stress indicators and the presence of pathological signs were assessed, followed by CT of the skulls. We found 2 skulls (6.3 %) with concha bullosa. In one case septal nasal deviation was present. We conclude that the incidence of concha bullosa could be lower in the past times than at present. Wider research is necessary to settle whether concha bullosa is indeed a rare respiratory paleopathology or a missed, and thus underreported observation. PMID- 27966112 TI - ? PMID- 27966113 TI - ? PMID- 27966114 TI - ? PMID- 27966116 TI - ? PMID- 27966115 TI - ? PMID- 27966117 TI - ? PMID- 27966118 TI - ? PMID- 27966119 TI - ? PMID- 27966120 TI - [Blood pressure targets for antihypertensive treatment - Consent with ongoing discussion]. PMID- 27966121 TI - ? PMID- 27966122 TI - [Current diagnosis and therapy of achalasia]. PMID- 27966123 TI - ? PMID- 27966125 TI - [Foot and ankle tumors: a closure look at indistinct masses of the foot and ankle]. PMID- 27966124 TI - [Ciguatera: a multifaceted and puzzling disorder]. PMID- 27966126 TI - [Calluses, corns and others - beware of the self-treatment!] PMID- 27966128 TI - ? PMID- 27966129 TI - ? PMID- 27966127 TI - [Update lesser foot problems]. PMID- 27966130 TI - ? PMID- 27966132 TI - ? PMID- 27966131 TI - ? PMID- 27966133 TI - ? PMID- 27966134 TI - ? PMID- 27966135 TI - ? PMID- 27966136 TI - ? PMID- 27966137 TI - ? PMID- 27966139 TI - ? PMID- 27966140 TI - ? PMID- 27966138 TI - ? PMID- 27966142 TI - ? PMID- 27966141 TI - ? PMID- 27966143 TI - ? PMID- 27966144 TI - ? PMID- 27966145 TI - ? PMID- 27966146 TI - ? PMID- 27966147 TI - ? PMID- 27966150 TI - ? PMID- 27966148 TI - ? PMID- 27966149 TI - ? PMID- 27966151 TI - ? PMID- 27966153 TI - ? PMID- 27966152 TI - ? PMID- 27966154 TI - ? PMID- 27966155 TI - ? PMID- 27966156 TI - ? PMID- 27966157 TI - ? PMID- 27966158 TI - ? PMID- 27966160 TI - ? PMID- 27966159 TI - ? PMID- 27966162 TI - ? PMID- 27966161 TI - ? PMID- 27966164 TI - ? PMID- 27966163 TI - ? PMID- 27966165 TI - ? PMID- 27966167 TI - ? PMID- 27966168 TI - [Non-substance-elated addictive disorders: prevention and intervention strategies]. PMID- 27966169 TI - In ovo sexing of chicken eggs by fluorescence spectroscopy. AB - Culling of day-old male chicks in production of laying hen strains involves several millions of animals every year worldwide and is ethically controversial. In an attempt to provide an alternative, optical spectroscopy was investigated to determine nondestructively in ovo the sex of early embryos of the domestic chicken. The extraembryonic blood circulation system was accessed by producing a window in the egg shell and the flowing blood was illuminated with a near infrared laser. The strong fluorescence and the weak Raman signals were acquired and spectroscopically analyzed between 800 and 1000 nm. The increase of fluorescence intensity between 3.5 and 11.5 days of incubation was found to be in agreement with the erythropoietic stages, thus enabling to identify hemoglobin as fluorescence source. Sex-related differences in the fluorescence spectrum were found at day 3.5, and principal component (PC) analysis showed that the blood of males was characterized by a specific fluorescence band located at ~910 nm. Supervised classification of the PC scores enabled the determination of the sex of 380 eggs at day 3.5 of incubation with a correct rate up to 93% by combining the information derived from both fluorescence and Raman scattering. Graphical abstract The fluorescence of blood obtained in ovo by illumination of embryonic vessels with a IR laser displays spectral differences that can be employed for sexing of eggs in early stage of incubation, before onset of embryo sensitivity and without hindering its development into a healthy chick. PMID- 27966170 TI - A comparison of sample preparation strategies for biological tissues and subsequent trace element analysis using LA-ICP-MS. AB - Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) is one of the most commonly applied methods for lateral trace element distribution analysis in medical studies. Many improvements of the technique regarding quantification and achievable lateral resolution have been achieved in the last years. Nevertheless, sample preparation is also of major importance and the optimal sample preparation strategy still has not been defined. While conventional histology knows a number of sample pre-treatment strategies, little is known about the effect of these approaches on the lateral distributions of elements and/or their quantities in tissues. The technique of formalin fixation and paraffin embedding (FFPE) has emerged as the gold standard in tissue preparation. However, the potential use for elemental distribution studies is questionable due to a large number of sample preparation steps. In this work, LA-ICP-MS was used to examine the applicability of the FFPE sample preparation approach for elemental distribution studies. Qualitative elemental distributions as well as quantitative concentrations in cryo-cut tissues as well as FFPE samples were compared. Results showed that some metals (especially Na and K) are severely affected by the FFPE process, whereas others (e.g., Mn, Ni) are less influenced. Based on these results, a general recommendation can be given: FFPE samples are completely unsuitable for the analysis of alkaline metals. When analyzing transition metals, FFPE samples can give comparable results to snap-frozen tissues. Graphical abstract Sample preparation strategies for biological tissues are compared with regard to the elemental distributions and average trace element concentrations. PMID- 27966171 TI - Detection of lead nanoparticles in game meat by single particle ICP-MS following use of lead-containing bullets. AB - This study investigated whether game meat may contain nanoparticles of lead from ammunition. Lead nanoparticles in the range 40 to 750 nm were detected by ICP-MS in single particle mode in game shot with lead-containing bullets. The median diameter of the detected nanoparticles was around 60 nm. The particle mass concentration ranged from 290 to 340 ng/g meat and the particle number concentrations from 27 to 50 million particles/g meat. The size limit of detection strongly depended on the level of dissolved lead and was in the range of 40 to 80 nm. In game meat sampled more than 10 cm away from the wound channel, no lead particles with a diameter larger than 40 nm were detected. In addition to dissolved lead in meat that originated from particulates, the presence of lead nano particles in game meat represents a hitherto unattended source of lead with a largely unknown toxicological impact to humans. Graphical Abstract Detection of lead nanoparticles in game meat by single particle ICP-MS following use of leadcontaining bullets. PMID- 27966172 TI - Characterization of Lipid A Variants by Energy-Resolved Mass Spectrometry: Impact of Acyl Chains. AB - Lipid A molecules consist of a diglucosamine sugar core with a number of appended acyl chains that vary in their length and connectivity. Because of the challenging nature of characterizing these molecules and differentiating between isomeric species, an energy-resolved MS/MS strategy was undertaken to track the fragmentation trends and map genealogies of product ions originating from consecutive cleavages of acyl chains. Generalizations were developed based on the number and locations of the primary and secondary acyl chains as well as variations in preferential cleavages arising from the location of the phosphate groups. Secondary acyl chain cleavage occurs most readily for lipid A species at the 3' position, followed by primary acyl chain fragmentation at both the 3' and 3 positions. In the instances of bisphosphorylated lipid A variants, phosphate loss occurs readily in conjunction with the most favorable primary and secondary acyl chain cleavages. Graphical Abstract ?. PMID- 27966173 TI - Development of a Magnetic Microbead Affinity Selection Screen (MagMASS) Using Mass Spectrometry for Ligands to the Retinoid X Receptor-alpha. AB - To overcome limiting factors in mass spectrometry-based screening methods such as automation while still facilitating the screening of complex mixtures such as botanical extracts, magnetic microbead affinity selection screening (MagMASS) was developed. The screening process involves immobilization of a target protein on a magnetic microbead using a variety of possible chemistries, incubation with mixtures of molecules containing possible ligands, a washing step that removes non-bound compounds while a magnetic field retains the beads in the microtiter well, and an organic solvent release step followed by LC-MS analysis. Using retinoid X receptor-alpha (RXRalpha) as an example, which is a nuclear receptor and target for anti-inflammation therapy as well as cancer treatment and prevention, a MagMASS assay was developed and compared with an existing screening assay, pulsed ultrafiltration (PUF)-MS. Optimization of MagMASS involved evaluation of multiple protein constructs and several magnetic bead immobilization chemistries. The full-length RXRalpha construct immobilized with amylose beads provided optimum results. Additional enhancements of MagMASS were the application of 96-well plates to enable automation, use of UHPLC instead of HPLC for faster MS analyses, and application of metabolomics software for faster, automated data analysis. Performance of MagMASS was demonstrated using mixtures of synthetic compounds and known ligands spiked into botanical extracts. Graphical Abstract ?. PMID- 27966174 TI - High Mass Ion Detection with Charge Detector Coupled to Rectilinear Ion Trap Mass Spectrometer. AB - Conventional linear ion trap mass analyzers (LIT-MS) provide high ion capacity and show their MS n ability; however, the detection of high mass ions is still challenging because LIT-MS with secondary electron detectors (SED) cannot detect high mass ions. To detect high mass ions, we coupled a charge detector (CD) to a rectilinear ion trap mass spectrometer (RIT-MS). Immunoglobulin G ions (m/z ~150,000) are measured successfully with controlled ion kinetic energy. In addition, when mass-to-charge (m/z) ratios of singly charged ions exceed 10 kTh, the detection efficiency of CD is found to be greater than that of SED. The CD can be coupled to LIT-MS to extend the detection mass range and provide the potential to perform MS n of high mass ions inside the ion trap. Graphical Abstract ?. PMID- 27966175 TI - pH Effects on Electrospray Ionization Efficiency. AB - Electrospray ionization efficiency is known to be affected by mobile phase composition. In this paper, a detailed study of analyte ionization efficiency dependence on mobile phase pH is presented. The pH effect was studied on 28 compounds with different chemical properties. Neither pK a nor solution phase ionization degree by itself was observed to be sufficient at describing how aqueous phase pH affects the ionization efficiency of the analyte. Therefore, the analyte behavior was related to various physicochemical properties via linear discriminant analyses. Distinction between pH-dependent and pH-independent compounds was achieved using two parameters: number of potential charge centers and hydrogen bonding acceptor capacity (in the case of 80% acetonitrile) or polarity of neutral form of analyte and pK a (in the case of 20% acetonitrile). It was also observed that decreasing pH may increase ionization efficiency of a compound by more than two orders of magnitude. Graphical Abstract ?. PMID- 27966176 TI - Design of Magnetic Polymeric Particles as a Stimulus-Responsive System for Gastric Antimicrobial Therapy. AB - The treatment of peptic ulcers induced by H. pylori remains challenging due to the deep mucous layer location of bacteria preventing antimicrobial drug access. The present work aimed to design and evaluate in vitro dual responsive (both pH and magnetic field-sensitive) polymeric magnetic particles loaded with amoxicillin as a smart drug carrier for deep mucous layer penetration and in situ drug release. Magnetite particles were produced by the co-precipitation method and subsequently coated with the Eudragit(r)S100 and amoxicillin by using the spray-drying technique. The physicochemical characterization of the obtained particles was carried out by optical and scanning electron microscopy, X-ray powder diffraction, Fourier transform infrared spectroscopy, nitrogen adsorption/desorption isotherms, and vibrating sample magnetometry. Additionally, drug release tests and antibacterial activity tests were evaluated in vitro. Microparticles presented 17.2 +/- 0.4 MUm in size and their final composition was 4.3 +/- 1.5% of amoxicillin, 87.0 +/- 2.3% of Eudragit, and 9.0 +/- 0.3% of magnetite. They were both pH and magnetic field responsive while presenting antimicrobial activity. On one side, magnetic field responsiveness of particles is expected to prompt them to reach bacterium niche in deep mucous layer by means of magnetic forces. On the other side, pH responsiveness is expected to enable drug release in the neutral pH of the deep mucous layer, preventing undesired delivery in the acidic gastric lumen. Smart microparticles were designed presenting both pH and magnetic field responsiveness as well as antimicrobial activity. These may be promising assets for peptic ulcer treatment. PMID- 27966177 TI - Biocompatible Phospholipid-Based Mixed Micelles for Tamoxifen Delivery: Promising Evidences from In - Vitro Anticancer Activity and Dermatokinetic Studies. AB - Tamoxifen (TAM) is frequently prescribed for the management breast cancer, but is associated with the challenges like compromised aqueous solubility and poor bioavailability to the target site. It was envisioned to develop phospholipid based mixed micelles to explore the promises offered by the biocompatible carriers. Various compositions were prepared, employing soya lecithin, polysorbate 80, sodium chloride/dextrose, and water, by self-assembled technique. The formulations were characterized for micromeritics and evaluated for in vitro drug release, hemolysis study, dermatokinetic studies on rodents, and cytotoxicity on MCF-7 cell lines. Cellular uptake of the system was also studied using confocal laser scanning microscopy. The selected composition was of sub micron range (28.81 +/- 2.1 nm), with spherical morphology. During in-vitro studies, the mixed micelles offered controlled drug release than that of conventional gel. Cytotoxicity was significantly enhanced and IC50 value was reduced that of the naive drug. The bioavailability in epidermis and dermis skin layers was enhanced approx. fivefold and threefold, respectively. The developed nanosystem not only enhanced the efficacy of the drug but also maintained the integrity of skin, as revealed by histological studies. The developed TAM nanocarrier possesses potential promises for safe and better delivery of TAM. PMID- 27966178 TI - Long-term efficacy and safety of tension free vaginal tape in a historic cohort of 463 women with stress urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: We report retrospective data on the long-term safety and efficacy of the retropubic midurethral sling (MUS) in a large series of women with stress urinary incontinence. METHODS: In all, 517 patients were treated during the period January 2005 to June 2012 at a single centre in France. The Urinary Symptoms Profile score was used to identify women who were subjectively cured or improved or in whom treatment had failed. The rates of peroperative, and early (<30 days) and late postoperative complications were recorded. RESULTS: A total of 463 patients were evaluable at a mean (+/-SD) follow-up of 71 +/- 23 months. At the last follow-up, 344 patients (74.3 %) demonstrated subjective cure, 55 (11.9 %) were improved and 64 (13.8 %) had treatment failure. Bladder perforations occurred in 33 patients (7.1 %); however, this had no effect on cure rate. In the early postoperative period, temporary intermittent self catheterization was required in 10 patients (2.2 %) due to voiding difficulties. The most frequent long-term postoperative complication was de novo urge incontinence that was reported by 59 patients (12.7 %); seven patients (1.5 %) needed tape excision due to voiding difficulties and six (1.3 %) needed tape removal due to erosion or chronic pain. CONCLUSIONS: The retropubic MUS was shown to be durable at a mean follow-up of 71 +/- 23 months, with a high success/improvement rate and no serious long-term tape-induced adverse effects. PMID- 27966179 TI - [Endoprostheses in geriatric traumatology]. AB - BACKGROUND: Geriatric traumatology is increasing in importance due to the demographic transition. In cases of fractures close to large joints it is questionable whether primary joint replacement is advantageous compared to joint preserving internal fixation. OBJECTIVE: The aim of this study was to describe the importance of prosthetic joint replacement in the treatment of geriatric patients suffering from frequent periarticular fractures in comparison to osteosynthetic joint reconstruction and conservative methods. MATERIAL AND METHODS: A selective search of the literature was carried out to identify studies and recommendations concerned with primary arthroplasty of fractures in the region of the various joints (hip, shoulder, elbow and knee). RESULTS: The importance of primary arthroplasty in geriatric traumatology differs greatly between the various joints. Implantation of a prosthesis has now become the gold standard for displaced fractures of the femoral neck. In addition, reverse shoulder arthroplasty has become an established alternative option to osteosynthesis in the treatment of complex proximal humeral fractures. Due to a lack of large studies definitive recommendations cannot yet be given for fractures around the elbow and the knee. Nowadays, joint replacement for these fractures is recommended only if reconstruction of the joint surface is not possible. CONCLUSION: The importance of primary joint replacement for geriatric fractures will probably increase in the future. Further studies with larger patient numbers must be conducted to achieve more confidence in decision making between joint replacement and internal fixation especially for shoulder, elbow and knee joints. PMID- 27966181 TI - Longstanding Eosinophilia in a Case of Late Diagnosis Chronic Granulomatous Disease. PMID- 27966180 TI - [Endoprostheses in the elderly : Biomaterials, implant selection and fixation technique]. AB - The replacement of hip and knee joints is one of the greatest success stories in orthopedics. Due to continuous improvement of biomaterials and implant design, patient-associated problems are now mostly multifactorial and only rarely caused by the implant. Abrasion was significantly reduced by the introduction of highly cross-linked polyethylene (PE), antioxidant stabilized PE, new ceramics and the development of ceramic and protective surfaces. It is assumed that further reduction of frictional resistance will not lead to a significantly better clinical result: however, the problem of periprosthetic infections and implant related incompatibility is still unsolved and remains challenging for biomaterial research. For the knee joint PE will be irreplaceable for joint articulation even in the future due to the contact situation. Mobile bearings and fixed bearings are two established successful philosophies, which have shown comparably good clinical results. For the hip joint, it is forecasted that ceramic-on-ceramic will be the system of the future if the correct positioning and mounting of the components can be solved so that the problems, such as development of noise and breakage can be reduced to a minimum. An in-depth understanding and detailed knowledge of the biomaterials by the surgeon can prevent implant-related problems. For elderly patients it is assumed that the economic burden on the public healthcare system will have the strongest impact on implant selection. PMID- 27966182 TI - Erratum to: Trends in Media Reports of Celebrities' Breast Cancer Treatment Decisions. PMID- 27966185 TI - Safety and efficacy of transseptal puncture guided by real-time fusion of echocardiography and fluoroscopy. AB - AIMS: Visual guidance through echocardiography and fluoroscopy is crucial for a successful transseptal puncture (TSP) in a prespecified region of the fossa ovalis. The novel EchoNavigator system Release II (EchoNav II, Philips Healthcare, Andover, Massachusetts, USA) enables the real-time fusion of fluoroscopic and echocardiographic images. We evaluated this new imaging method in respect to safety and efficacy of TSP during MitraClip implantation and left atrial appendage closure. METHODS: Forty-four patients before (-EchoNav) and 44 patients after (+EchoNav) the introduction of real-time fusion were included in our retrospective, single-centre study. The primary endpoint was the occurrence of adverse events due to TSP. Secondary endpoints were successful puncture at the prespecified region and time until TSP (min). RESULTS: In both groups TSP was performed successfully in the prespecified region and no adverse events occurred during or due to the accomplishment of TSP. Time until TSP was significantly reduced in the +EchoNav group in comparison with the EchoNav group (18.48 +/- 5.62 min vs. 23.20 +/- 9.61 min, p = 0.006). CONCLUSIONS: Real-time fusion of echocardiography and fluoroscopy proved to be as safe and successful as standard best practice for TSP. Moreover, efficacy was improved through significant reduction of time until TSP. PMID- 27966186 TI - Adult cor triatriatum sinistrum: a rare cause of ischaemic stroke. PMID- 27966184 TI - 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: comments from the Dutch ACS working group. AB - On behalf of the Dutch ACS working group, we discuss multiple recommendations which have been implemented in the 2015 ESC guidelines for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST segment elevation. PMID- 27966183 TI - Electro-acupuncture at Acupoint ST36 Ameliorates Inflammation and Regulates Th1/Th2 Balance in Delayed-Type Hypersensitivity. AB - Increasing evidence indicates anti-allergic and anti-inflammatory effects of electro-acupuncture (EA) therapy. However, its underlying mechanism on delayed type hypersensitivity (DTH), a classic allergic inflammatory disease, still remains unclear. In this study, we aimed to explore the immunomodulatory mechanism of EA intervention in a mouse model of ovalbumin (OVA)-induced DTH. Mice were randomly divided into four groups: Control, OVA-DTH, DTH + EA, DTH + Sham. "Zusanli" acupoint (ST36) was used for DTH + EA, whereas a non-acupoint (localized 5 mm below the "Zusanli" acupoint) was selected for DTH + Sham. Footpad thickness was checked, and the infiltration of inflammatory cells was estimated by hematoxylin and eosin staining. Levels of IgG and IgE in serum of different groups and inflammatory cytokines in the supernatants from homogenized footpads, including IFN-gamma, TNF-alpha, IL-4, and IL-5, were determined by ELISA. Cell proliferation of spleen lymphocytes was assayed by 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT). The frequency of CD4+IFN gamma+ and CD4+IL-4+ T cells was analyzed with flow cytometry. In addition, the mRNA and protein expression of T-bet and GATA-3 were evaluated by real-time PCR and Western blotting, respectively. Our data showed EA treatment at acupoint ST36 relieved the pathological progression of DTH responses via reduction in footpad swelling, infiltration of inflammatory cells, levels of IgG and IgE as well as decreased production of IFN-gamma and TNF-alpha in homogenized footpad tissue. Moreover, detailed studies were performed revealing that EA attenuated the percentage of CD4+IFN-gamma+ T cells and prevented Th cells differentiation into Th1 cells, and this results from inhibiting secretion of IFN-gamma and suppressing expression of T-bet, an IFN-gamma transcription factor. The results indicated that EA treatment improved Th1-mediated allergic skin inflammation via restoring Th1/Th2 balance by curbing Th1 differentiation. These findings suggested that EA at acupoint ST36 might be a useful and promising therapeutic for allergic inflammatory as well as Th1-mediated inflammation response. PMID- 27966187 TI - Three-dimensional image fusion guidance of percutaneous pulmonary valve implantation to reduce radiation exposure and contrast dose: A comparison with traditional two-dimensional and three-dimensional rotational angiographic guidance. AB - INTRODUCTION: Three-dimensional rotational angiography (3DRA) has been used in the guidance of various transcatheter therapies including percutaneous pulmonary valve implantation (PPVI). The most recently available 3D image fusion software (VesselNavigator, Philips) extends this technology to use pre-registered computed tomography or magnetic resonance imaging datasets, promising reductions in contrast and radiation exposure along with shorter procedural times. METHODS: In this retrospective review, patients were assigned to three groups according to the mode of imaging guidance: two-dimensional angiography (2DA), 3DRA and VesselNavigator (VN) assisted valve implantation. Patient characteristics and catheterisation data were reviewed with a focus on contrast and radiation exposure, fluoroscopy, and procedural times. RESULTS: Between July 2012 and June 2016, 21 patients underwent PPVI: 8 with 2D guidance, 6 patients with 3DRA and most recently 7 patients with VN assistance. Patents in the VN group received significantly less absolute and weight indexed contrast when compared with those with 2DA or 3DRA guided PPVI. Patients in the 2DA group received a significantly higher total dose area product radiation dose and air kerma in comparison with patients with 3DRA and VN guided intervention. Application of VN resulted in the shortest fluoroscopy time, although not statistically significant, and a significantly shorter study time when compared with 2DA. CONCLUSIONS: Utilisation of pre-intervention image manipulation with VesselNavigator for 3D guidance of PPVI results in a reduction in contrast and radiation exposure and study time as compared with traditional 2D guidance, and contrast usage as compared with 3DRA. PMID- 27966188 TI - No fire in the belly: SPECT diagnosis of ruptured abdominal aortic aneurysm. PMID- 27966190 TI - HPLC-MS Analysis of Lichen-Derived Metabolites in the Life Stages of Crambidia cephalica (Grote & Robinson). AB - Tiger moths (Lepidoptera: Erebidae: Arctiinae: Arctiini) are notable for their specialized associations with hosts that produce toxic secondary compounds, and are thus an ideal study system for understanding insect-plant interactions and the evolution of antipredatory defense. Likewise, their sister lineage (Arctiinae: Lithosiini) has been documented feeding on algae and lichens, and is known to sequester lichen-derived secondary compounds from the larval to adult stages. Prevalence of lichenivory in this early radiation (ca. 3000 species) may provide clues to the phylogenetic basis for storied chemical sequestration within all tiger moths. Despite the evolutionary significance of this trait, we lack a basic understanding of the extent of lichenivory among lithosiines, and the distribution of sequestered chemicals among life stages. The dynamics of chemical sequestration throughout the lifecycle for the lichen moth Crambidia cephalica were investigated by testing the hypothesis that lichen-derived metabolites are unequally distributed among life stages, and that laboratory-reared C. cephalica have less metabolite diversity than wild-caught individuals. Crambidia cephalica was reared on Physcia, and analyzed using high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). Several putative lichen-derived metabolites were detected across three life stages, i.e., larval, pupal, and adult, and differences among life stages and lichen host were observed. These results provide evidence that multiple lichen-derived metabolites are sequestered by C. cephalica; some metabolites are retained through adulthood, and others are lost or modified in earlier life stages. The presence of differing lichen-derived metabolites across life stages may indicate functional properties of the metabolites for C. cephalica with regards to chemical protection from antagonists, and other physiological processes. PMID- 27966191 TI - Climatic implications on variations of Qehan Lake in the arid regions of Inner Mongolia during the recent five decades. AB - The Qehan Lake Basin (QLB) and its system of lakes are located in a marginal monsoon zone and are extremely sensitive to global climate change. In this paper, using aerial photographs from different periods, in addition to MSS, TM, and ETM images, and combining these with regional topographic maps, we analyze lake area changes from 1958 to 2010 and the relation between Qehan Lake (QL) and climate variability. Our results indicate that there was a relatively high lake level in 1959, when the area and volume of the lake were 118.9 km2 and 151.9 * 106 m3, respectively, but this level was subject to a shrinking trend until 2010, when the lake area was only 28.1 km2, and the water volume was 41.1 * 106 m3. West Qehan Lake (WQL) has experienced severe water shrinkage and lake level fluctuation. In 1958, WQL was 80.2 km2 in area and 124.1 * 106 m3 in volume. However, due to a rapid decrease in precipitation and increases in both temperature and evaporation, it began to dry up in 2002. The WQL Water area decreased by 1.82 km2/a, and the lake level declined by 7 m during 1958-2002, so it became an ephemeral lake. PMID- 27966189 TI - Conceptualising engagement with digital behaviour change interventions: a systematic review using principles from critical interpretive synthesis. AB - "Engagement" with digital behaviour change interventions (DBCIs) is considered important for their effectiveness. Evaluating engagement is therefore a priority; however, a shared understanding of how to usefully conceptualise engagement is lacking. This review aimed to synthesise literature on engagement to identify key conceptualisations and to develop an integrative conceptual framework involving potential direct and indirect influences on engagement and relationships between engagement and intervention effectiveness. Four electronic databases (Ovid MEDLINE, PsycINFO, ISI Web of Knowledge, ScienceDirect) were searched in November 2015. We identified 117 articles that met the inclusion criteria: studies employing experimental or non-experimental designs with adult participants explicitly or implicitly referring to engagement with DBCIs, digital games or technology. Data were synthesised using principles from critical interpretive synthesis. Engagement with DBCIs is conceptualised in terms of both experiential and behavioural aspects. A conceptual framework is proposed in which engagement with a DBCI is influenced by the DBCI itself (content and delivery), the context (the setting in which the DBCI is used and the population using it) and the behaviour that the DBCI is targeting. The context and "mechanisms of action" may moderate the influence of the DBCI on engagement. Engagement, in turn, moderates the influence of the DBCI on those mechanisms of action. In the research literature, engagement with DBCIs has been conceptualised in terms of both experience and behaviour and sits within a complex system involving the DBCI, the context of use, the mechanisms of action of the DBCI and the target behaviour. PMID- 27966193 TI - Optimization of Methods Verifying Volunteers' Ability to Provide Hospice Care. AB - The subject of the presented work was an attempt at optimization of the methods used for verification of the candidates for medical voluntary workers in a hospice and decreasing the danger of a negative influence of an incompetent volunteer on a person in a terminal stage of a disease and his or her relatives. The study was carried out in St. Lazarus Hospice in Krakow, Poland, and included 154 adult participants in four consecutive editions of "A course for volunteers - a guardian of the sick" organized by the hospice. In order to improve the recruitment of these workers, the hitherto methods of selection (an interview with the coordinator of volunteering and no less than 50% of attendance in classes of a preparatory course for volunteers") were expanded by additional instruments-the tests whose usefulness was examined in practice. Knowledge of candidates was tested with the use of a written examination which consisted of four open questions and an MCQ test comprising 31 questions. Practical abilities were checked by the Objective Structured Clinical Examination (OSCE). A reference point for the results of these tests was a hidden standardized long-term observation carried out during the subsequent work of the volunteers in the stationary ward in the hospice using the Amsterdam Attitude and Communication Scale (AACS). Among the tests used, the greatest value (confirmed by a quantitative and qualitative analysis) in predicting how a given person would cope with practical tasks and in contact with the sick and their relatives had a practical test of the OSCE type. PMID- 27966192 TI - How Does a Shared Decision-Making (SDM) Intervention for Oncologists Affect Participation Style and Preference Matching in Patients with Breast and Colon Cancer? AB - : The aims of this study are to assess patients' preferred and perceived decision making roles and preference matching in a sample of German breast and colon cancer patients and to investigate how a shared decision-making (SDM) intervention for oncologists influences patients' preferred and perceived decision-making roles and the attainment of preference matches. This study is a post hoc analysis of a randomised controlled trial (RCT) on the effects of an SDM intervention. The SDM intervention was a 12-h SDM training program for physicians in combination with decision board use. For this study, we analysed a subgroup of 107 breast and colon cancer patients faced with serious treatment decisions who provided data on specific questionnaires with regard to their preferred and perceived decision-making roles (passive, SDM or active). Patients filled in questionnaires immediately following a decision-relevant consultation (t1) with their oncologist. Eleven of these patients' 27 treating oncologists had received the SDM intervention within the RCT. A majority of cancer patients (60%) preferred SDM. A match between preferred and perceived decision-making roles was reached for 72% of patients. The patients treated by SDM-trained physicians perceived greater autonomy in their decision making (p < 0.05) with more patients perceiving SDM or an active role, but their preference matching was not influenced. A SDM intervention for oncologists boosted patient autonomy but did not improve preference matching. This highlights the already well-known reluctance of physicians to engage in explicit role clarification. TRIAL REGISTRATION: German Clinical Trials Register DRKS00000539; Funding Source: German Cancer Aid. PMID- 27966194 TI - Responsiveness of a Brief Measure of Lung Cancer Screening Knowledge. AB - Our aim was to examine the responsiveness of a lung cancer screening brief knowledge measure (LCS-12). Eligible participants were aged 55-80 years, current smokers or had quit within 15 years, and English speaking. They completed a baseline pretest survey, viewed a lung cancer screening video-based patient decision aid, and then filled out a follow-up posttest survey. We performed a paired samples t-test, calculated effect size, and calculated absolute and relative percent improvement for each item. Participants (n = 30) were primarily White (63%) with less than a college degree (63%), and half were female (50%). Mean age was 61.5 years (standard deviation [SD] = 4.67) and average smoking history was 30.4 pack-years (range = 4.6-90.0). Mean score on the 12-item measure increased from 47.3% correct on the pretest to 80.3% correct on the posttest (mean pretest score = 5.67 vs. mean posttest score = 9.63; mean score difference = 3.97, SD = 2.87, 95% CI = 2.90, 5.04). Total knowledge scores improved significantly and were responsive to the decision aid intervention (paired samples t-test = 7.57, p < .001; Cohen's effect size = 1.59; standard response mean [SRM] = 1.38). All individual items were responsive, yet two items had lower absolute responsiveness than the others (item 8: "Without screening, is lung cancer often found at a later stage when cure is less likely?" pretest correct = 83.3% vs. posttest = 96.7%, responsiveness = 13.4%; and item 10: "Can a CT scan find lung disease that is not cancer?" pretest correct = 80.0% vs. posttest = 93.3%, responsiveness = 13.3%). The LCS-12 knowledge measure may be a useful outcome measure of shared decision making for lung cancer screening. PMID- 27966195 TI - Beyond bronchitis: a review of the congenital and acquired abnormalities of the bronchus. AB - Anomalies of the bronchus can be both congenital and acquired. Several different congenital aberrations of the bronchial anatomy are commonly encountered including tracheal bronchus, accessory cardiac bronchus, and bronchial agenesis/aplasia/hypoplasia. In addition, Williams-Campbell syndrome and cystic fibrosis are two other congenital conditions that result in bronchial pathology. Acquired pathology affecting the bronchi can typically be divided into three broad categories of bronchial disease: bronchial wall thickening, dilatation/bronchiectasis, and obstruction/stenosis. Bronchial wall thickening is the common final response of the airways to irritants, which cause the bronchi to become swollen and inflamed. Bronchiectasis/bronchial dilatation can develop in response to many aetiologies, including acquired conditions such as infection, pulmonary fibrosis, recurrent or chronic aspiration, as well as because of congenital conditions such as cystic fibrosis. The causes of obstruction and stenosis are varied and include foreign body aspiration, acute aspiration, tracheobronchomalacia, excessive dynamic airway collapse, neoplasm, granulomatous disease, broncholithiasis, and asthma. Knowledge of normal bronchial anatomy and its congenital variants is essential for any practicing radiologist. It is the role of the radiologist to identify common imaging patterns associated with the various categories of bronchial disease and provide the ordering clinician a useful differential diagnosis tailored to the patient's clinical history and imaging findings. Teaching Points * Bronchial disorders are both congenital and acquired in aetiology.* Bronchial disease can be divided by imaging appearance: wall thickening, dilatation, or obstruction.* Bronchial wall thickening is the common final response of the airways to irritants.* Imaging patterns must be recognised and the differential diagnosis tailored for patient management. PMID- 27966197 TI - Ruptured Aneurysms of Collateral Vessels in Adult Onset Moyamoya Disease with Hemorrhagic Presentation. AB - PURPOSE: Strategies for treating intracranial aneurysms of collateral vessels in adult onset moyamoya disease (MMD) remain unclear, because overall case numbers are limited and data on long-term outcomes are lacking. The aim of this study was to assess clinical and anatomic outcomes of such aneurysms in adult MMD sufferers who present with hemorrhage. METHODS: Of the 77 adult patients consecutively enrolled between January 2003 and December 2014 in the MMD registry at a single institution, those presenting with hemorrhage and followed for >12 months were studied. Aneurysms involving collateral vessels at sites of hemorrhage were considered culprit lesions. RESULTS: Aneurysms of collateral vessels in 19 patients (19/77, 24.7%) were confirmed as ruptured by conventional angiography. In five of these patients, obliterative endovascular embolization was successfully performed. The other 14 patients were managed conservatively due to lesion inaccessibility, and follow-up imaging studies (13 available) confirmed later disappearance of aneurysms in 12 patients (92.3%). In the aneurysm group (n = 19), re-bleeding occurred in 8 patients (42.1%) during follow-up (mean 67.4 +/- 38.9 months). The re-bleeding involved contralateral hemispheres in 6 patients (75.0%), and all re-bleeding events occurred >6 months after initial hemorrhage. In the other 58 subjects without aneurysms 13 (22.4%) also suffered re-bleeding (mean follow-up 71.9 +/- 46.3 months). CONCLUSION: Although endovascular interventions are appropriate for ruptured aneurysms of collateral arteries in MMD, conservative treatment can be a viable alternative for technically inaccessible lesions. PMID- 27966196 TI - MicroRNAs 33, 122, and 208: a potential novel targets in the treatment of obesity, diabetes, and heart-related diseases. AB - Despite decades of research, obesity and diabetes remain major health problems in the USA and worldwide. Among the many complications associated with diabetes is an increased risk of cardiovascular diseases, including myocardial infarction and heart failure. Recently, microRNAs have emerged as important players in heart disease and energy regulation. However, little work has investigated the role of microRNAs in cardiac energy regulation. Both human and animal studies have reported a significant increase in circulating free fatty acids and triacylglycerol, increased cardiac reliance on fatty acid oxidation, and subsequent decrease in glucose oxidation which all contributes to insulin resistance and lipotoxicity seen in obesity and diabetes. Importantly, MED13 was initially identified as a negative regulator of lipid accumulation in Drosophilia. Various metabolic genes were downregulated in MED13 transgenic heart, including sterol regulatory element-binding protein. Moreover, miR-33 and miR-122 have recently revealed as key regulators of lipid metabolism. In this review, we will focus on the role of microRNAs in regulation of cardiac and total body energy metabolism. We will also discuss the pharmacological and non pharmacological interventions that target microRNAs for the treatment of obesity and diabetes. PMID- 27966199 TI - Review of John Cartwright's Evolution and Human Behaviour: Darwinian Perspectives on the Human Condition : (London: Palgrave Macmillan, 2016). PMID- 27966198 TI - Contribution of real-time PCR to Plasmodium species identification and to clinical decisions: a nationwide study in a non-endemic setting. AB - Treatment choice for patients with malaria in Israeli hospitals is based on microscopy and rapid diagnostic tests (RDTs). Here, we demonstrate the cumulative value of real-time polymerase chain reaction (PCR) in optimizing the treatment of malaria. Between January 2009 and December 2015, 451 samples from 357 patients were tested in our laboratory using a real-time PCR assay. Hospital laboratory results (without real-time PCR) were compared to those obtained in our laboratory. A total of 307 patients had a malaria-positive laboratory finding in the hospital. Out of those, 288 were confirmed positive and 19 negative using real-time PCR. Two negative hospital results were found to be positive by real time PCR. More specifically, of 153 cases positive for Plasmodium falciparum by real-time PCR, only 138 (90%) had been correctly identified at the hospitals. Similarly, 66 (67%) of 99 cases positive for P. vivax, 2 (11%) of 18 cases positive for P. ovale, and 3 (30%) of 10 cases positive for P. malariae had been correctly identified. Of 10 cases of mixed infection, only one had been identified as such at the hospital. Thus, real-time PCR was required for correct identification in 81 (28%) out of 290 positive cases. In 52 (18%) of those, there was an erroneous categorization of relapsing versus non-relapsing parasites. In a nationwide study, we found that the use of real-time PCR is definitely beneficial and may change the decision regarding the choice of treatment. PMID- 27966201 TI - The demographics and diving behaviour of DAN Asia-Pacific members with and without pre-existing medical conditions. AB - INTRODUCTION: This report examines Diver Alert Network Asia-Pacific (DAN AP) members with and without cardiac or respiratory conditions, diabetes or hypertension and compares their demographics, health and diving activities. METHODOLOGY: Two online cross-sectional surveys of DAN AP members were conducted. The first sought information from 833 divers who applied for membership between July 2009 and August 2013 and who had declared the targeted medical conditions. The second, conducted between December 2014 and April 2015, was sent to 9,927 current members with known email addresses. The groups were compared for age, gender, body mass index, fitness, smoking and diving qualifications, history, currency and practices. RESULTS: Of 343 (41%) respondents to the first survey, 267 (32%) provided sufficient information for inclusion. Of 1,786 (18%) respondents to the second survey, 1,437 (15%) had no targeted medical condition and were included in the analysis. Those with medical conditions were on average 4.7 years older (P < 0.001); more overweight or obese (68% versus 57%, P = 0.001); took more medications (57% vs. 29%, P < 0.001), smoked less (4% vs. 7%, P = 0.02) and did less repetitive diving (median 75 vs 90, P < 0.001). Other diving demographics were similar. CONCLUSIONS: A substantial number of people are diving with medical conditions and there is a need to better understand the associated risks. Divers need to be well-educated about the potential impact such conditions may have on diving safety and should monitor their health status, especially as they age. PMID- 27966202 TI - Provisional report on diving-related fatalities in Australian waters in 2011. AB - INTRODUCTION: An individual case review of diving-related deaths reported as occurring in Australia in 2011 was conducted as part of the DAN Asia-Pacific dive fatality reporting project. METHOD: The case studies were compiled using reports from witnesses, the police and coroners. In each case, the particular circumstances of the accident and, where available, details from the post-mortem examination are provided. A chain of events analysis was conducted for each case. RESULTS: In total, there were 30 reported fatalities (10 more than in 2010). These included 15 snorkel/breath-hold divers, 14 scuba divers and one diver using surface-supplied breathing apparatus. Twenty-four victims were males. The mean age of snorkelling victims was 49.6 (range 23-75) years and compressed gas divers 42.2 (range 23-55) years. Cardiac-related issues were thought to have been the disabling injury in the deaths of at least seven snorkel divers and five scuba divers. Immersion pulmonary oedema was implicated in at least one death; and three fatalities resulted from attacks by marine animals. Two novices died while under instruction/supervision after separation from their instructor in poor visibility. CONCLUSIONS: Pre-existing medical conditions, separation and inadequate supervision and seafood collection in areas frequented by marine predators were once again features in several deaths in this series. PMID- 27966203 TI - Estimating the risk of a scuba diving fatality in Australia. AB - INTRODUCTION: There are few data available on which to estimate the risk of death for Australian divers. This report estimates the risk of a scuba diving fatality for Australian residents, international tourists diving in Queensland, and clients of a large Victorian dive operator. METHODOLOGY: Numerators for the estimates were obtained from the Divers Alert Network Asia-Pacific dive fatality database. Denominators were derived from three sources: Participation in Exercise, Recreation and Sport Surveys, 2001-2010 (Australian resident diving activity data); Tourism Research Australia surveys of international visitors to Queensland 2006-2014 and a dive operator in Victoria 2007-2014. Annual fatality rates (AFR) and 95% confidence intervals (95% CI) were calculated using an exact binomial test. RESULTS: Estimated AFRs were: 0.48 (0.37-0.59) deaths per 100,000 dives, or 8.73 (6.85-10.96) deaths per 100,000 divers for Australian residents; 0.12 (0.05-0.25) deaths per 100,000 dives, or 0.46 (0.20-0.91) deaths per 100,000 divers for international visitors to Queensland; and 1.64 (0.20-5.93) deaths per 100,000 dives for the dive operator in Victoria. On a per diver basis, Australian residents are estimated to be almost twenty times more likely to die whilst scuba diving than are international visitors to Queensland, or to lower than fourfold on a per dive basis. On a per dive basis, divers in Victoria are fourteen times more likely to die than are Queensland international tourists. CONCLUSIONS: Although some of the estimates are based on potentially unreliable denominator data extrapolated from surveys, the diving fatality rates in Australia appear to vary by State, being considerably lower in Queensland than in Victoria. These estimates are similar to or lower than comparable overseas estimates, although reliability of all such measurements varies with study size and accuracy of the data available. PMID- 27966204 TI - The influence of pressure changes on the retentive force and coronal microleakage of different types of posts in endodontically treated teeth during simulated dives. AB - OBJECTIVES: We assessed the influence of a simulated diving environment on the interfacial microleakage and retentive forces of different post types in root canal-filled teeth. MATERIALS AND METHODS: One-hundred-and-twenty extracted, single-rooted teeth were endodontically treated and were randomly divided into three groups according to the post and cement used: ER Post/Harvard cement (Titanium), CeraPost/DentinBuild Evo (Zirconia), DT Light Post/Calibra (FRC). Each group was randomly divided into two equal subgroups, a control group, and an experimental group, subjected to simulated dives to 456 kPa in a diving chamber. For 10 specimens of each subgroup the pull-out strength and the coronal microleakage were measured. RESULTS: Significant differences in the linear coronal penetration were observed between the Titanium and FRC groups (experimental group P <= 0.001; control group P = 0.02). Diving simulation had no significant impact on the microleakage for the three post types. The FRC groups showed significantly higher retentive strength values compared to the Titanium and Zirconia groups before and after simulated diving. The pull-out strength of the titanium experimental group was significantly less than the control group (P = 0.008). CONCLUSIONS: Following root canal treatment the combination of fibre reinforced posts and resin cement should be preferred for patients requiring retention for tooth restorations using posts that are likely to be exposed to hyperbaric conditions. PMID- 27966205 TI - Increasing the probability of surviving loss of consciousness underwater when using a rebreather. AB - Re-circulating underwater breathing apparatus (rebreathers) have become increasingly popular amongst sport divers. In comparison to open-circuit scuba, rebreathers are complex life support equipment that incorporates many inherent failure modes and potential for human error. This individually or in combination can lead to an inappropriate breathing gas. Analysis of rebreather diving incidents suggests that inappropriate breathing gas is the most prevalent disabling agent. This can result in spontaneous loss of consciousness (LoC), water aspiration and drowning. Protecting the airway by maintaining the diver/rebreather oral interface may delay water aspiration following LoC underwater; the possibility of a successful rescue is, thus, increased. One means of protecting the airway following LoC underwater is the use of a full-face mask (FFM). However, such masks are complex and expensive; therefore, they have not been widely adopted by the sport diving community. An alternative to the FFM used extensively throughout the global military diving community is the mouthpiece retaining strap (MRS). A recent study documented 54 LoC events in military rebreather diving with only three consequent drownings; all divers were reported to be using a MRS. Even allowing for the concomitant use of a tethered diving partner system in most cases, the low number of fatalities in this large series is circumstantially supportive of the efficacy of the MRS. Despite drowning featuring as a final common pathway in the vast majority of rebreather fatalities, the MRS has not been widely adopted by the sport rebreather diving community. PMID- 27966206 TI - Middle ear barotrauma causing transient facial nerve paralysis after scuba diving. AB - Middle ear barotrauma is a well known entity with typical injury occurring when diving or ascending in a commercial jetliner. Patients often present with symptoms of acute onset otalgia, hearing loss and sometimes haemotympanum (with or without tympanic membrane perforation). On rare occasions, facial nerve paralysis can occur when the tympanic segment of the facial nerve is dehiscent within the middle ear. We present a case of spontaneously resolving facial nerve palsy associated with middle ear barotrauma following a brief, shallow dive. Prompt and astute diagnosis leads to proper management with simple myringotomy and can prevent unnecessary testing and other misguided treatments. PMID- 27966207 TI - Partial retraction of Lawrence CHD, Chen IYD. The effect of scuba diving on airflow obstruction in divers with asthma. Diving and Hyperbaric Medicine. 2016 March;46(1):11-14. AB - Consistent with the Committee on Publication Ethics guidelines, we the above authors are initiating a partial retraction of our paper: Lawrence CHD, Chen IYD. The effect of scuba diving on airflow obstruction in divers with asthma. Diving and Hyperbaric Medicine. 2016 March;46(1):11-14. We wish to make the following statement: "Following independent statistical review of our paper we would like to withdraw the following: all subgroup statistical analysis including Table 1 and the statement "* P < 0.05, non-asthmatic controls vs Group A3 asthmatics" in the legend of Figure 2; the discussion statement: "We hope that these data will provide practitioners assessing and risk stratifying people with asthma prior to diving with a modest evidence basis on which to advise them of their relative risk of airflow obstruction compared to the normal population." The reason for this is that, following publication, it was identified that the scientific method for comparing between groups was inappropriate for the study design. We are extremely disappointed that our statistical method for calculating significance when comparing groups was inadequate but equally grateful to the journal editors and readers for their input in rectifying this and maintaining scientific integrity. We would like to make absolutely clear that at no point did we seek to mislead or misguide the journal or any other group. We have learnt a valuable lesson in study design and the limitations of statistics. The observational data as published looking at airflow obstruction in divers with asthma in real-world conditions remain valid and in the context of diving and asthma still have value in addition to what is already in the scientific domain. We hope that this can serve as a foundation for future studies in this field". PMID- 27966208 TI - Puerarin and zinc additively prevent mandibular bone loss through inhibiting osteoclastogenesis in ovariectomized rats. AB - Puerarin and zinc play a key role in preventing osteoporotic-related bone loss. Previous research on puerarin or zinc mainly focused on the anti-osteoporotic effects of long bone. However, it is obscure for puerarin or zinc to prevent mandibular osteoporosis. Here, we explore the effects on additive coadministration of puerarin and zinc on preventing mandibular bone loss in ovariectomized rats, and evaluate the underlying mechanisms ex vivo. Rats were ovariectomized and administrated puerarin, zinc or both. After 12 weeks, bone mineral density (BMD) and histomorphometry of mandibles were measured by micro CT. The mechanical properties were determined using a three-point bending test. Then, osteogenic differentiation of primary bone marrow stromal cells (BMSCs) and osteoclastogenesis of bone marrow mononuclear were performed ex vivo. The culture supernatant and serum level of bone biochemical markers including osteoprotegerin (OPG), osteopontin (OPN), receptor activator of nuclear factor (NF)-kappaB ligand (RANKL), and tartrate-resistant acid phosphatase (TRAP) were detected by ELISA. Culture supernatant and serum levels of calcium were measured using a Plasma Emission Spectrometer. One-way ANOVA was used for statistical analyses. The results showed that administration of puerarin plus zinc prevented the decrease in mandibular BMD and bone morphometrical parameters more effectively than single use of puerarin or zinc (p<0.05), which was similar to the biomechanical tests (p<0.05). Furthermore, puerarin and zinc additively up-regulated OPG, OPN protein levels, Ca ion level and down-regulated RANKL, TRAP protein levels. In conclusion, puerarin and zinc additively prevent mandibular bone loss through inhibiting osteoclastogenesis in ovariectomized rats, which will shed more light on the potential use of puerarin and zinc in the prevention/treatment of oral bone loss clinically. PMID- 27966209 TI - Doxycycline down-regulates matrix metalloproteinase expression and inhibits NF kappaB signaling in LPS-induced PC3 cells. AB - INTRODUCTION: Matrix metalloproteinase enzymes (MMPs) play important role in inflammation, malignant cell proliferation, invasion and angiogenesis by mediating extracellular matrix degradation. Doxycycline, a synthetic tetracycline, behaves as a MMP inhibitor at a subantimicrobial dose and inhibits tumor cell proliferation, invasion and angiogenesis. The aberrant activity of nuclear factor kappa B (NF-kappaB) causes activation of MMPs and thereby proliferation and invasion of cancer cells. The aim of this study was to investigate the effects of doxycycline on the expression of MMPs in lipopolysaccharide (LPS)-induced PC3 human prostate cancer cells and the possible role of NF-kappaB signaling. MATERIAL AND METHODS: PC3 cells were incubated with LPS (0.5 MUg/mL) for 24 h in the presence or absence of doxycycline (5 MUg/mL). The effects of LPS and doxycycline on the expressions of MMP-2, MMP-8, MMP-9, MMP 10, NF-kappaB/p65, IkappaB-alpha, p-IkappaB-alpha, IKK-beta were examined by Western blotting and immunohistochemistry in PC3 cells. Furthermore, relative proteinase activities of MMP-2 and MMP-9 were determined by gelatin zymography. RESULTS: LPS increased expression and activity of MMP-9 and expression of MMP-8, MMP-10, NF-kappaB /p65, p-IkappaB-alpha, IKK-beta and doxycycline down-regulated its effects with the exception of MMP-10 expression. The expression of MMP-2 and IkappaB-alpha was affected by neither LPS nor doxycycline. CONCLUSIONS: Our findings indicate that doxycycline inhibits the expression of various MMPs and NF kappaB signaling may play a role in the regulation of MMPs expression in LPS induced PC3 human prostate cancer cells. PMID- 27966210 TI - Ghrelin-immunoreactive cells in the gastrointestinal tract of hypertensive rats. AB - INTRODUCTION: Ghrelin, an appetite-stimulating hormone secreted by the endocrine cells of the gastrointestinal (GI) tract, has recently been shown to affect the function of the cardiovascular system. This study aimed to assess the number and morphology of ghrelin-immunopositive (GhrIP) cells in the gastrointestinal tract of rats at different developmental phases of experimentally evoked renovascular hypertension. MATERIAL AND METHODS: The study involved 40 rats divided into two groups: control (C; n = 20) and rats with experimentally induced hypertension (EH; n = 20). The Goldblatt model of two-kidneys, one clip (2K1C) was used to induce hypertension. Renovascular hypertension was maintained for either 3 (EH1 group; n = 10) or 42 (EH2 group; n = 10) days. Paraffin sections from the cardia, corpus and pylorus of the stomach, as well as from the duodenum, jejunum, ileum and colon were processed for peroxidase immunohistochemistry. RESULTS: The number of GhrIP cells was significantly higher in the cardia and corpus of the stomach as well as the duodenum and jejunum of hypertensive rats compared to that found in the control animals. CONCLUSIONS: The increased number of GhrIP cells in the rat gastrointestinal tract after partial unilateral ligation of the renal artery suggests that renovascular hypertension may affect ghrelin secretion, which can contribute to the development of cardiovascular complications. PMID- 27966211 TI - Detection of pantothenic acid-immunoreactive neurons in the rat lateral septal nucleus by a newly developed antibody. AB - INTRODUCTION: The available immunohistochemical techniques have documented restricted distribution of vitamins in the mammalian brain. The aim of the study was to develop a highly specific antiserum directed against pantothenic acid to explore the presence of this vitamin in the mammalian brain. MATERIAL AND METHODS: According to ELISA tests, the anti-pantothenic acid antiserum used showed a good affinity (10-8 M) and specificity. The antiserum was raised in rabbits. Using an indirect immunoperoxidase technique, the mapping of pantothenic acid-immunoreactive structures was carried out in the rat brain. RESULTS: Pantothenic acid-immunoreactive perikarya were exclusively found in the intermediate part of the lateral septal nucleus. These cells were generally small, round, fusiform or pyramidal and showed 2-3 long (50-100 MUm) immunoreactive dendrites. Any immunoreactive axons containing pantothenic acid were detected. CONCLUSIONS: The very restricted anatomical distribution of the pantothenic acid suggests that this vitamin could be involved in some specific neurophysiological mechanisms. PMID- 27966212 TI - Factors stimulating riboflavin produced by Lactobacillus plantarum CRL 725 grown in a semi-defined medium. AB - Riboflavin (vitamin B2 ) is one of the B-group water-soluble vitamins and is essential for energy metabolism of the cell. The aim of this study was to determine factors that affect riboflavin production by Lactobacillus (L.) plantarum CRL 725 grown in a semi defined medium and evaluate the expression of its rib genes. The factors found to enhance riboflavin production in this medium were incubation at 30 degrees C, and the addition of specific medium constituents, such as casamino acids (10 g L-1 ), guanosine (0.04 g L-1 ), and sucrose as carbon source (20 g L-1 ). In these conditions, higher riboflavin concentrations were directly associated with significant increases in the expression of ribA, ribB, and ribC genes. The culture conditions defined in this work and its application to a roseoflavin resistant mutant of L. plantarum allowed for a sixfold increase in riboflavin concentrations in our semi-defined medium which were also significantly higher than those obtained previously using the same strain to ferment soymilk. These conditions should thus be evaluated to increase vitamin production in fermented foods. PMID- 27966213 TI - Occult upper gastrointestinal mucosal abnormalities in critically ill patients. AB - BACKGROUND: The objectives of this study were to estimate the frequency of occult upper gastrointestinal abnormalities, presence of gastric acid as a contributing factor, and associations with clinical outcomes. METHODS: Data were extracted for study participants at a single centre who had an endoscopy performed purely for research purposes and in whom treating physicians were not suspecting gastrointestinal bleeding. Endoscopic data were independently adjudicated by two gastroenterologists who rated the likelihood that observed pathological abnormalities were related to gastric acid secretion using a 3-point ordinal scale (unlikely, possible or probable). RESULTS: Endoscopy reports were extracted for 74 patients [age 52 (37, 65) years] undergoing endoscopy on day 5 [3, 9] of ICU admission. Abnormalities were found in 25 (34%) subjects: gastritis/erosions in 10 (14%), nasogastric tube trauma in 8 (11%), oesophagitis in 4 (5%) and non bleeding duodenal ulceration in 3 (4%). The contribution of acid secretion to observed pathology was rated 'probable' in six subjects (rater #1) and five subjects (rater #2). Prior to endoscopy, 39 (53%) patients were receiving acid suppressive therapy. The use of acid-suppressive therapy was not associated with the presence of an endoscopic abnormality (present 15/25 (60%) vs. absent 24/49 (49%); P = 0.46). Haemoglobin concentrations, packed red cells transfused and mortality were not associated with mucosal abnormalities (P = 0.83, P > 0.9 and P > 0.9 respectively). CONCLUSIONS: Occult mucosal abnormalities were observed in one-third of subjects. The presence of mucosal abnormalities appeared to be independent of prior acid-suppressive therapy and was not associated with reduced haemoglobin concentrations, increased transfusion requirements, or mortality. PMID- 27966215 TI - Behavioural responses of Ixodes ricinus nymphs to carbon dioxide and rodent odour. AB - Many haematophagous ectoparasites use carbon dioxide (CO2 ) and host odour to detect and locate their hosts. The tick Ixodes ricinus (Linnaeus) (Ixodida: Ixodidae) walks only small distances and quests in vegetation until it encounters a host. The differential effects of CO2 and host odour on the host-finding behaviour of I. ricinus have, however, never been clarified and hence represent the subject of this study. The effects of CO2 and odour from bank voles on the activation and attraction of I. ricinus nymphs were analysed in a Y-tube olfactometer. Carbon dioxide evoked a response in the absence and presence of host odour, but did not attract nymphs. Host odour, however, did not evoke a response but did attract nymphs in the absence and presence of CO2 . The current results show that CO2 is an activator, but not an attractant, and that host odour is an attractant, but not an activator, of I. ricinus nymphs, and provide ecological insights into the host-finding behaviour of I. ricinus. PMID- 27966216 TI - The Gross Motor Function Classification System Family Report Questionnaire: reliability between special-education teachers and caregivers. AB - AIM: The aim of this study was to investigate the reliability of the Thai Gross Motor Function Classification System Family Report Questionnaire (GMFCS-FR) and the possibility of special-education teachers and caregivers in the community using this system in children with cerebral palsy (CP). METHOD: The reliability was examined by two teachers and two caregivers who classified 21 children with CP aged 2 to 12 years. A GMFCS-FR workshop was organized for raters. The teachers and caregivers classified the mobility of 362 children. The rater reliability was analysed using the weighted kappa coefficient. The possibility of using the GMFCS FR is reported. The reliability of using the GMFCS-FR in the community was analysed by the intraclass correlation coefficient. RESULTS: The intrarater reliability ranged from 0.91 to 1.00. The interrater reliability between teachers was 0.85 (95% confidence interval [CI] 0.69-0.97) and between caregivers was 0.84 (95% CI 0.70-0.97). Ninety-seven percent of raters used the Thai GMFCS-FR correctly. The overall intraclass correlation coefficient between raters was 0.90 (95% CI 0.88-0.92). INTERPRETATION: The Thai GMFCS-FR is a reliable system for classifying the motor function of young children with CP by teachers and caregivers in the community. PMID- 27966217 TI - Do different data analytic approaches generate discrepant findings when measuring mother-infant HPA axis attunement? AB - Attunement between mothers and infants in their hypothalamic-pituitary-adrenal (HPA) axis responsiveness to acute stressors is thought to benefit the child's emerging physiological and behavioral self-regulation, as well as their socioemotional development. However, there is no universally accepted definition of attunement in the literature, which appears to have resulted in inconsistent statistical analyses for determining its presence or absence, and contributed to discrepant results. We used a series of data analytic approaches, some previously used in the attunement literature and others not, to evaluate the attunement between 182 women and their 1-year-old infants in their HPA axis responsivity to acute stress. Cortisol was measured in saliva samples taken from mothers and infants before and twice after a naturalistic laboratory stressor (infant arm restraint). The results of the data analytic approaches were mixed, with some analyses suggesting attunement while others did not. The strengths and weaknesses of each statistical approach are discussed, and an analysis using a cross-lagged model that considered both time and interactions between mother and infant appeared the most appropriate. Greater consensus in the field about the conceptualization and analysis of physiological attunement would be valuable in order to advance our understanding of this phenomenon. PMID- 27966218 TI - Mental health nurses' perceptions of patient safety culture in psychiatric settings. AB - BACKGROUND: Mental health nurses have a crucial role in preventing medical incidents and in promoting safety culture because they provide and coordinate most of patients' care. Therefore, they are able to enhance patients' outcomes and reduce nurses' injuries. AIMS: The aims of this study were to assess the perception of mental health nurses about patients' safety culture and to detect the factors which may affect patients' safety culture at psychiatric hospitals. METHODS: A predictive correlational design was employed to collect data about patient safety culture and safety outcomes from 224 mental health nurses working in psychiatric hospitals using Hospital Survey on Patient Safety Culture. RESULTS: Positive scores to patients' safety culture dimensions ranged between 13.4% and 81.2%. Two-thirds of mental health nurses perceived safety as excellent/very good, 20.5% perceived it as acceptable and 10.8% perceived it as poor/failing. Overall perception of safety correlated significantly with four dimensions and explained 32.6% of the variance. Frequency of events reported correlated significantly with six dimensions and explained 23.1% of the variance. CONCLUSION: Of the 12 dimensions of patients' safety culture, only one was strong, six within acceptable range and five were weak and need improvement. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Healthcare managers and policy-makers should encourage educational interventions and help to establish a reporting system that focus on improving systems, not on blaming individuals and encourage open communication among mental healthcare workers. PMID- 27966219 TI - Oncofertility program implementation increases access to fertility preservation options and assisted reproductive procedures for breast cancer patients. AB - BACKGROUND AND OBJECTIVES: Breast cancer treatment can cause premature ovarian failure, yet the majority of young cancer patients do not receive adequate education about treatment effects before initiating chemotherapy. We studied the impact of an oncofertility program on access to fertility preservation. METHODS: An oncofertility program was initiated to foster collaboration between oncologists and reproductive endocrinologists, and to help increase access to fertility preservation. Documented conversations about fertility concerns, specialist referrals, appointments, and fertility preservation procedures were compared between breast cancer patients from 2004 to 2006, before oncofertility program initiation, and 2007-2012, after program initiation. The study included women <45, stages 0-III, diagnosed before (n = 278) and after (n = 515) program initiation. RESULTS: Demographics for the cohorts were similar. Fertility discussions (P < 0.0001), patients interested in maintaining fertility at diagnosis (P = 0.0041), referrals to reproductive endocrinologists (P < 0.0001), appointments (P < 0.0001), and fertility preservation procedures (P < 0.0183) increased significantly after programmatic implementation. CONCLUSIONS: An oncofertility program increased discussions about fertility preservation and access to assisted reproductive procedures. This program positively impacted compliance with national guidelines advising reproductive-age cancer patients to be offered fertility preservation counseling as an initial component of the multidisciplinary care plan. J. Surg. Oncol. 2017;115:116-121. (c) 2016 Wiley Periodicals, Inc. PMID- 27966221 TI - Determination of the microbial community features of Haemaphysalis flava in different developmental stages by high-throughput sequencing. AB - In this study, we analyzed the in vivo microbial community structure and diversity differences of Haemaphysalis flava (H. flava) in four developmental stages (egg, larva, nymph, and adult) to determine which bacterial genera could be propagated through transovarial transmission and transmitted by transstadial transmission during different developmental stages of H. flava. Paired-end sequencing of the V3 region of the 16S ribosomal DNA (16S rDNA) of H. flava in four developmental stage samples was conducted using the Illumina MiSeq sequencing platform. The following operational taxonomic units (OTUs) of H. flava were obtained during the four developmental stages: 89 of egg, 111 of larva, 104 of nymph, and 106 of female adult tick. Sixty-four of these OTUs had high similarity in the four developmental stages of H. flava. Eight bacterial genera had the highest abundances in all developmental stages, namely, Rickettsia, Coxiella, Pseudomonas, Ehrlichia, Escherichia, Acinetobacter, Citrobacter, and Cupriavidus. The nymph had the highest abundance of Coxiella, and the female adult tick had the highest abundance of Rickettsia. Staphylococcus and Wolbachia were detected in all developmental stages except the egg. PMID- 27966220 TI - Semi-automated delineation of breast cancer tumors and subsequent materialization using three-dimensional printing (rapid prototyping). AB - OBJECTIVE: Three-dimensional (3D) printing has become widely available, and a few cases of its use in clinical practice have been described. The aim of this study was to explore facilities for the semi-automated delineation of breast cancer tumors and to assess the feasibility of 3D printing of breast cancer tumors. METHODS: In a case series of five patients, different 3D imaging methods-magnetic resonance imaging (MRI), digital breast tomosynthesis (DBT), and 3D ultrasound were used to capture 3D data for breast cancer tumors. The volumes of the breast tumors were calculated to assess the comparability of the breast tumor models, and the MRI information was used to render models on a commercially available 3D printer to materialize the tumors. RESULTS: The tumor volumes calculated from the different 3D methods appeared to be comparable. Tumor models with volumes between 325 mm3 and 7,770 mm3 were printed and compared with the models rendered from MRI. The materialization of the tumors reflected the computer models of them. CONCLUSION: 3D printing (rapid prototyping) appears to be feasible. Scenarios for the clinical use of the technology might include presenting the model to the surgeon to provide a better understanding of the tumor's spatial characteristics in the breast, in order to improve decision-making in relation to neoadjuvant chemotherapy or surgical approaches. J. Surg. Oncol. 2017;115:238-242. (c) 2016 Wiley Periodicals, Inc. PMID- 27966222 TI - Older peoples' perspectives on time spent alone. AB - BACKGROUND: Large amounts of time spent alone by older people have been associated with loneliness and poor mental and physical health. There is a paucity of research, however, that examines time alone from an occupational perspective. In this exploratory study we explored the perspectives of older people on their time spent alone. METHODS: A qualitative descriptive study design was selected. With the aim of maximising variation, five participants were recruited from retirement villages and seven participants who lived independently in the community. Participants recorded time spent alone in a time diary for three days as priming for a semi-structured in-depth interview. Transcripts were analysed thematically. RESULTS: Three key themes were identified: 'it is a matter of getting some balance'; 'keeping busy'; and 'the nights are the worst'. The study highlights the importance older people place on the need to manage time alone so that it is a positive and nourishing experience and to avoid experiencing extended periods of boredom potentially leading to loneliness. Older people utilise occupations to keep busy and achieve an individually acceptable level of time alone. CONCLUSION: Enabling older people to balance time spent alone by addressing barriers to participation in the community in addition to finding engaging occupations to occupy time has the potential to prevent boredom, loneliness and improve wellbeing. PMID- 27966223 TI - Prevalence of Sleep Disturbances and Their Associations With Demographic and Clinical Characteristics and Quality of Life in Older Adults in Macao. AB - PURPOSE: To examine the prevalence of sleep disturbances (difficulty initiating sleep [DIS], difficulty maintaining sleep [DMS], and early morning awakening [EMA]), their socio-demographic and clinical correlates, and quality of life (QOL) in older adults in Macao. DESIGN AND METHODS: Four hundred fifty-one subjects were interviewed using standardized instruments. FINDINGS: The prevalence of at least one type of sleep disturbance was 38.1%; the figures of DIS, DMS, and EMA were 18.6, 31.3, and 23.9%, respectively. Female sex and depressive symptoms were independently associated with more frequent sleep disturbances. Sleep disturbances were independently associated with lower physical QOL. PRACTICE IMPLICATIONS: Sleep disturbances are common in older adults in Macao. Appropriate strategies should be implemented to prevent and treat sleep disturbances and concerted attempts should be made to improve access to treatment. PMID- 27966224 TI - The development of a culturally appropriate school based intervention for Australian Aboriginal children living in remote communities: A formative evaluation of the Alert Program(r) intervention. AB - BACKGROUND/AIM: Although previous research has demonstrated the benefits of targeting self-regulation in non-Aboriginal children, it is unclear whether such programs would be effective for Aboriginal children attending school in remote communities. Some of these children have been diagnosed with a fetal alcohol spectrum disorder (FASD) impairing their ability to self-regulate. The aim of this article is to describe a three phase formative process to develop and pilot a curriculum version of the Alert Program(r) , a promising intervention for improving self-regulation that could be used in remote community schools. This modified version of the program will be subsequently tested in a cluster randomised controlled trial. METHODS: A mixed methods approach was used. RESULTS: Modifications to the Alert Program(r) , its delivery and evaluation were made after community and stakeholder consultation facilitated by a senior Aboriginal community researcher. Changes to lesson plans and program resources were made to reflect the remote community context, classroom environment and the challenging behaviours of children. Standardised study outcome measures were modified by removing several questions that had little relevance to the lives of children in remote communities. Program training for school staff was reduced in length to reduce staff burden. CONCLUSIONS: This study identified aspects of the Alert Program(r) training, delivery and measures for evaluation that need modification before their use in assessing the efficacy of the Alert Program(r) in remote Aboriginal community primary schools. PMID- 27966225 TI - Parasympathetic withdrawal increases heart rate after 2 weeks at 3454 m altitude. AB - KEY POINTS: Heart rate is increased in chronic hypoxia and we tested whether this is the result of increased sympathetic nervous activity, reduced parasympathetic nervous activity, or a non-autonomic mechanism. In seven lowlanders, heart rate was measured at sea level and after 2 weeks at high altitude after individual and combined pharmacological inhibition of sympathetic and/or parasympathetic control of the heart. Inhibition of parasympathetic control of the heart alone or in combination with inhibition of sympathetic control abolished the high altitude induced increase in heart rate. Inhibition of sympathetic control of the heart alone did not prevent the high altitude-induced increase in heart rate. These results indicate that a reduced parasympathetic nervous activity is the main mechanism underlying the elevated heart rate in chronic hypoxia. ABSTRACT: Chronic hypoxia increases resting heart rate (HR), but the underlying mechanism remains incompletely understood. We investigated the relative contributions of the sympathetic and parasympathetic nervous systems, along with potential non autonomic mechanisms, by individual and combined pharmacological inhibition of muscarinic and/or beta-adrenergic receptors. In seven healthy lowlanders, resting HR was determined at sea level (SL) and after 15-18 days of exposure to 3454 m high altitude (HA) without drug intervention (control, CONT) as well as after intravenous administration of either propranolol (PROP), or glycopyrrolate (GLYC), or PROP and GLYC in combination (PROP+GLYC). Circulating noradrenaline concentration increased from 0.9 +/- 0.4 nmol l-1 at SL to 2.7 +/- 1.5 nmol l-1 at HA (P = 0.03). The effect of HA on HR depended on the type of autonomic inhibition (P = 0.006). Specifically, HR was increased at HA from 64 +/- 10 to 74 +/- 12 beats min-1 during the CONT treatment (P = 0.007) and from 52 +/- 4 to 59 +/- 5 beats min-1 during the PROP treatment (P < 0.001). In contrast, HR was similar between SL and HA during the GLYC treatment (110 +/- 7 and 112 +/- 5 beats min-1 , P = 0.28) and PROP+GLYC treatment (83 +/- 5 and 85 +/- 5 beats min 1 , P = 0.25). Our results identify a reduction in cardiac parasympathetic activity as the primary mechanism underlying the elevated HR associated with 2 weeks of exposure to hypoxia. Unexpectedly, the sympathoactivation at HA that was evidenced by increased circulating noradrenaline concentration had little effect on HR, potentially reflecting down-regulation of cardiac beta-adrenergic receptor function in chronic hypoxia. These effects of chronic hypoxia on autonomic control of the heart may concern not only HA dwellers, but also patients with disorders that are associated with hypoxaemia. PMID- 27966226 TI - Achieving Uniform Monolayer Transition Metal Dichalcogenides Film on Silicon Wafer via Silanization Treatment: A Typical Study on WS2. AB - A silanization reaction is employed to improve the dispersion of precursors on a silicon wafer for a large-size uniform transition metal dichalcogenide (TMD) film synthesis and to achieve a highly crystalline monolayer WS2 film up to 1 cm2 . The novel strategy is also verified for the synthesis of WSe2 and MoS2 uniform films, suggesting universality for TMD film fabrication. PMID- 27966228 TI - Abstracts of the 16th Annual Congress of the French Speaking Society of Transplantation, Liege, Belgium, 6-9 December 2016. PMID- 27966229 TI - Superior Bifunctional Liquid Fuel Oxidation and Oxygen Reduction Electrocatalysis Enabled by PtNiPd Core-Shell Nanowires. AB - An ultrathin PtNi NWs mediated strategy to form PtNiPd core-shell NWs is constructed. The combination of 1D structure, high-index bounded surface, and unique core-shell structure with high activity of the PtNi shell results in superior performance toward both the liquid fuel oxidation reactions and oxygen reduction reaction. PMID- 27966227 TI - Tacrolimus dose requirements in paediatric renal allograft recipients are characterized by a biphasic course determined by age and bone maturation. AB - AIMS: Despite longstanding recognition of significant age-dependent differences in drug disposition during childhood, the exact course and the underlying mechanisms are not known. Our aim was to determine the course and determinants of individual relative dose requirements, during long-term follow-up in children on tacrolimus. METHODS: This was a cohort study in a tertiary hospital with standardized annual pharmacokinetic (PK) follow-up (AUC0-12hr ) in recipients of a renal allograft (<=19 years), between 1998 and 2015. In addition, the presence of relevant pharmacogenetic variants was determined. The evolution of dose corrected exposure was evaluated using mixed models. RESULTS: A total of 184 PK visits by 43 children were included in the study (median age: 14.6). AUC0-12h corrected for dose per kg demonstrated a biphasic course: annual increase 4.4% (CI: 0.3-8.7%) until +/-14 years of age, followed by 13.4% increase (CI 8.7 18.3%). Moreover, exposure corrected for dose per m2 proved stable until 14 years (+0.8% annually; CI: -3.0 to +4.8%), followed by a steep increase >=14 years (+11%; CI: 7.0-16.0%). Analysis according to bone maturation instead of age demonstrated a similar course with a distinct divergence at TW2: 800 (P = 0.01). Genetic variation in CYP3A4, CYP3A5, and CYP3A7 was associated with altered dose requirements, independent of age. CONCLUSIONS: Children exhibit a biphasic course in tacrolimus disposition characterized by a high and stable drug clearance until a specific phase in pubertal development (TW2: 800 at age: +/-14 years), followed by an important decline in relative dose requirements thereafter. Pharmacogenetic variation demonstrated an age/puberty independent effect. We suggest a critical reappraisal of current paediatric dosing algorithms for tacrolimus and drugs with a similar disposition. PMID- 27966230 TI - Method development and validation: quantitation of telmisartan bulk drug and its tablet formulation by 1 H NMR spectroscopy. AB - The quantitative NMR (qNMR) spectroscopy is nowadays a new tool for the determination of pharmaceutical potent biologically active molecules in bulk drug and its tablet formulation than the other analytical techniques. Herein, qNMR method was developed for an anti-hypertensive drug, telmisartan in bulk drug and its tablet formulation. The precise method was developed by using malononitrile as an internal standard. The methylene signal of telmisartan appeared at delta = 5.46 ppm (singlet) relative to the signal of malononitrile at delta = 3.59 ppm (singlet) in CDCl3 , as an NMR solvent. The development and validation of the method were carried out as per International Conference on Harmonization guidelines. The method was found to be linear (r2 = 0.9999) for 0.5 to 3.5 mg/ml in the drug concentration range. The relative standard deviation for accuracy and precession was not more than 2.0%. The sensitivity of the method was carried out by limit of detection and a limit of quantification, at 0.05 and 0.2 mg/ml, respectively, concentration. The robustness of the method was studied by changing parameters as well as different solvent manufacturer company. The result shows that method was accurately developed for quantification of telmisartan in pharmaceutical dosage form. The developed method by 1 H NMR spectroscopy is comparatively easy and more precise with respect to the other analytical tools. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27966231 TI - Assessing a surrogate predictive value: a causal inference approach. AB - Several methods have been developed for the evaluation of surrogate endpoints within the causal-inference and meta-analytic paradigms. In both paradigms, much effort has been made to assess the capacity of the surrogate to predict the causal treatment effect on the true endpoint. In the present work, the so-called surrogate predictive function (SPF) is introduced for that purpose, using potential outcomes. The relationship between the SPF and the individual causal association, a new metric of surrogacy recently proposed in the literature, is studied in detail. It is shown that the SPF, in conjunction with the individual causal association, can offer an appealing quantification of the surrogate predictive value. However, neither the distribution of the potential outcomes nor the SPF are identifiable from the data. These identifiability issues are tackled using a two-step procedure. In the first step, the region of the parametric space of the distribution of the potential outcomes, compatible with the data at hand, is geometrically characterized. Further, in a second step, a Monte Carlo approach is used to study the behavior of the SPF on the previous region. The method is illustrated using data from a clinical trial involving schizophrenic patients and a newly developed and user friendly R package Surrogate is provided to carry out the validation exercise. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27966232 TI - DFT calculations as a powerful tool for ESR spin trapping experiments. AB - A combined electron spin resonance (ESR) and density functional theory study has been carried out to obtain deeper insight in the reaction mechanism of the photorearrangement of 3-hydroxyindolic nitrones. Also, in this case, the combination of these techniques constitutes a powerful tool when discriminating between different reaction pathways. In particular, density functional theory calculations played an important role for unraveling the overlapping of signals coming from different species in the ESR spin trapping experiments. In the present study, the computed energies and the corresponding ESR parameters of each possible isomer hypothesized have been considered, taking also into account their different possibilities of intramolecular H-bond formation. However, the results obtained indicate that the possibility of intramolecular H-bonding did not play a determinant role in this case. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27966234 TI - Complete 1 H and 13 C NMR assignments of an uncommon 2,3-dihydroxynaphthoquinone isolated from Cordia multispicata (Cham.). PMID- 27966233 TI - The synthesis of [1-14 C]2-(1H-tetrazol-5-yl)acetic acid. AB - Tetrazoles are a common heterocyclic functionality in many biologically active molecules. [1-14 C]2-(1H-Tetrazol-5-yl)acetic acid was required as an intermediate in the synthesis of a development candidate as part of a discovery phase program to complete metabolic profiling studies. [1-14 C]2-(1H-Tetrazol-5 yl)acetic acid was prepared in 4 steps overall and in 3 radiochemical steps from K14 CN in an overall 32% radiochemical yield. PMID- 27966235 TI - Toward Multispectral Imaging with Colloidal Metasurface Pixels. AB - Multispectral colloidal metasurfaces are fabricated that exhibit greater than 85% absorption and ~100 nm linewidths by patterning film-coupled nanocubes in pixels using a fusion of bottom-up and top-down fabrication techniques over wafer-scale areas. With this technique, the authors realize a multispectral pixel array consisting of six resonances between 580 and 1125 nm and reconstruct an RGB image with 9261 color combinations. PMID- 27966236 TI - In vitro evaluation of concentration, labeling effectiveness and stability for 131 I-labeled radioimmunoassay ligand using real-time detection technology. AB - Radioimmunoassay belongs to the analytical method enabling highly specific and sensitive quantification of molecules. The verification of the real-time radioimmunoassay technology usefulness for ligand-quality characteristics evaluation such as concentration, influence of radiolabeling on binding affinity and stability was estimated. The anti-epidermal growth factor receptor antibody 131 I-cetuximab was employed as the ligand antibody. The concentration of 131 I cetuximab was derived from the shape of binding curves coming from the ligand receptor interaction. The binding curves also allowed the estimation of 131 I cetuximab binding affinity for different radiolabeling procedures (incubation times 1, 5, and 10 minutes) in stability testing up to 96 hours at 4 degrees C. The stability testing also included comparative analysis by size exclusion high performance liquid chromatography. The assessment of cetuximab concentrations using real-time method showed acceptable accordance between real and calculated values. The real-time method revealed that 1-minute radiolabeling proved to be the optimal incubation time for direct radioiodination of cetuximab. Stability testing showed the significant change in radioligand affinity by one order at the longest incubation times (72 and 96 hours). Characterization of stability and binding behavior of radiolabeled monoclonal antibodies by the verified real-time method before use in other assays may be employed to eliminate variability and suboptimal antibody performance. PMID- 27966238 TI - Mechanisms and possible controls of the in utero Zika virus infection: Where is the Holy Grail? AB - Zika virus infection (ZVI) is a great concern for human health because it frequently causes fetal anomalies. Little is known about pathophysiology of ZVI because it has been regarded as a mild, no life-threatening infection. However, the latest endemic in South and Central America took attention of perinatologists, microbiologists, and pathologists. Both in vivo and in vitro studies suggest neurotropic nature of Zika virus but do not clarify viral kinetics during vertical transmissions. In this review, we focus on the clinical and microbiological natures ZVI for pregnant women especially how placental barriers are broken down. PMID- 27966237 TI - Assessment of pharmacokinetic interaction between rilotumumab and epirubicin, cisplatin and capecitabine (ECX) in a Phase 3 study in gastric cancer. AB - AIMS: Rilotumumab is a fully human monoclonal antibody investigated for the treatment of MET-positive gastric cancer. The aim of this study was to evaluate the potential pharmacokinetic (PK)-based drug-drug interaction (DDI) between rilotumumab and epirubicin (E), cisplatin(C) and capecitabine (X). METHODS: This was a Phase 3 double-blind, placebo-controlled study, in which rilotumumab, epirubicin and cisplatin were administered intravenously at 15 mg kg-1 , 50 mg m 2 , and 60 mg m-2 Q3W, respectively, while capecitabine was given orally at 625 mg m-2 twice daily. Rilotumumab PK samples were taken at pre-dose and at the end of-infusion from all patients in cycles 1, 3, 5 and 7. ECX PK samples were taken in cycle 3 from patients who participated in the intensive PK assessment. ECX PK was assessed by non-compartmental (NCA) analyses and PK parameters were compared between two arms. Rilotumumab PK was assessed by comparing the observed rilotumumab serum concentrations with model-predicted concentrations using a population PK model developed from previous Phase 1 and Phase 2 studies. RESULTS: The study enrolled 609 patients. ECX plasma concentrations in the presence and absence of rilotumumab were similar, as demonstrated by the geometric mean ratios for Cmax and AUC, which were close to 1.0, suggesting ECX PK was not affected by co-administration of rilotumumab. The observed rilotumumab serum concentrations were similar to the values predicted by population PK modelling on the basis of a prediction-corrected visual predictive check, indicating rilotumumab exposure was not affected by co-administration of ECX. CONCLUSIONS: The results suggest lack of PK-based DDI between rilotumumab and ECX. PMID- 27966239 TI - Evaluation of clinical coding data to determine causes of critical bleeding in patients receiving massive transfusion: a bi-national, multicentre, cross sectional study. AB - OBJECTIVES: To evaluate the use of routinely collected data to determine the cause(s) of critical bleeding in patients who receive massive transfusion (MT). BACKGROUND: Routinely collected data are increasingly being used to describe and evaluate transfusion practice. MATERIALS/METHODS: Chart reviews were undertaken on 10 randomly selected MT patients at 48 hospitals across Australia and New Zealand to determine the cause(s) of critical bleeding. Diagnosis-related group (DRG) and International Classification of Diseases (ICD) codes were extracted separately and used to assign each patient a cause of critical bleeding. These were compared against chart review using percentage agreement and kappa statistics. RESULTS: A total of 427 MT patients were included with complete ICD and DRG data for 427 (100%) and 396 (93%), respectively. Good overall agreement was found between chart review and ICD codes (78.3%; kappa = 0.74, 95% CI 0.70 0.79) and only fair overall agreement with DRG (51%; kappa = 0.45, 95% CI 0.40 0.50). Both ICD and DRG were sensitive and accurate for classifying obstetric haemorrhage patients (98% sensitivity and kappa > 0.94). However, compared with the ICD algorithm, DRGs were less sensitive and accurate in classifying bleeding as a result of gastrointestinal haemorrhage (74% vs 8%; kappa = 0.75 vs 0.1), trauma (92% vs 62%; kappa = 0.78 vs 0.67), cardiac (80% vs 57%; kappa = 0.79 vs 0.60) and vascular surgery (64% vs 56%; kappa = 0.69 vs 0.65). CONCLUSION: Algorithms using ICD codes can determine the cause of critical bleeding in patients requiring MT with good to excellent agreement with clinical history. DRG are less suitable to determine critical bleeding causes. PMID- 27966240 TI - Information needs of the Chinese community affected by cancer: A systematic review. AB - OBJECTIVE: The information needs of patients and carers from culturally and linguistically diverse backgrounds, including from the Chinese community, are not well understood, and there has been no previous synthesis of the literature. We conducted a systematic review of the information needs of the Chinese community affected by cancer. METHODS: Database, reference list, and author searches were conducted to identify studies reporting information needs of the Chinese community affected by cancer. Data synthesis was undertaken to define categories of information needs. RESULTS: Initial searches yielded 2558 articles. Out of the 40 full-text articles reviewed, 26 met all the eligibility criteria. Cancer specific, treatment, and prognosis information were the most frequently reported information needs across the cancer care continuum. Similarly, this information was the most commonly reported information needs across different health systems, migration statuses, and Chinese cultural values. Though less frequent, information needs related to interpersonal/social, financial/legal, and body image/sexuality were also raised. Thirteen studies quantified the prevalence of unmet needs, and the most frequently reported unmet needs were related to health system and information, followed by psychological, patient care and support, physical daily living, and sexuality needs. Language and cultural factors were identified in all studies involving Chinese migrants living in English-speaking countries. CONCLUSIONS: Failing to meet the information needs of the Chinese community members affected by cancer increases the risk for poor cancer outcomes. Potential interventions such as translated resources, bilingual advocates, an online information portal, and communication aids can be helpful in addressing the unmet needs for this community. PMID- 27966242 TI - A critical commentary on management science in relation to reforms after institutional National Health Service failures. AB - AIM(S): A discussion paper on the United Kingdom (UK) National Health Service (NHS) market reforms. BACKGROUND: NHS market reforms reliance on management science methods introduced a fundamental shift in measuring care for commissioning. EVALUATION: A number of key reports are discussed in relation to NHS market reforms and management science. KEY ISSUES: NHS market reforms were influenced through a close alliance between policy makers, the department of health, free market think tanks and management consultancies. The timing of reforms coincided with reports on NHS failings and the evolution of measurement methods to focus on finance. CONCLUSIONS: The balance in favour of measurement practises is of concern. Management science methods are criticised in the Francis Report yet promoted as the solution to some of the key findings; why may be explained by the close alliance. IMPLICATIONS FOR NURSING MANAGEMENT: A return to principles of management involving consensus, trust and involvement to promote quality care and use management science methods to this end. PMID- 27966241 TI - Clinical analysis of hyperkalemic renal tubular acidosis caused by calcineurin inhibitors in solid organ transplant recipients. AB - WHAT IS KNOWN AND OBJECTIVE: Calcineurin inhibitor (CNI)-based immunosuppressive regimen is widely used for preventing rejection in solid organ transplantation. Hyperkalemic renal tubular acidosis (RTA) caused by CNI is uncommon and potentially underappreciated. We reported four such cases to increase awareness of this risk and to provide recommendations for its management based on our experience. CASE SUMMARY: Four middle-aged males underwent solid organ transplant (two kidneys, one liver, one heart) and were treated with CNI-based immunosuppressive regimen (one cyclosporine A, three tacrolimus). On post operative day 13-35, hyperkalemic hyperchloremic non-gap metabolic acidosis developed. All patients had relatively preserved renal function, normal urine output and plasma aldosterone level. Reduction in CNI dosage was partly effective; the patient on cyclosporine A was treated with fludrocortisone, and two others temporarily switched to sirolimus (SRL). WHAT IS NEW AND CONCLUSION: We should alert for CNI-induced hyperkalemic RTA in transplant recipients. By CNI dosage reduction or adding low dose fludrocortisone, or temporarily switching to SRL, the prognosis of CNI-induced hyperkalemic RTA is favourable. PMID- 27966243 TI - pH Control on the Sequential Uptake and Release of Organic Cations by Cucurbit[7]uril. AB - Cucurbit[7]uril (CB7) is a macrocycle with the ability to form the most stable supramolecular complexes in water ever reported for an artificial receptor. Its use for the design of advanced functional materials is, however, very limited because there is no example of a fully reversible CB7 based supramolecular complex enabling repetitious dissociation/association controlled by external stimuli. We report the synthesis of a new ferrocene amino acid that forms with CB7 a 1:1 inclusion complex that is stable in submicromolar concentration at low pH but dissociates at high pH. This reversible process was used for the sequential uptake and release of bispyridinium and antraquinone guests by CB7, which is controlled by adjusting the pH of the solution. PMID- 27966244 TI - RhII -Catalyzed beta-C(sp2 )-H Alkylation of Enol Ethers, Enamides and Enecarbamates with alpha-Diazo Dicarbonyl Compounds. AB - A RhII -catalyzed method for intermolecular alkylation of the beta-C(sp2 )-H bond of enol ethers, enamides, and enecarbamates with alpha-diazo-1,3-dicarbonyl compounds is reported. The products are formed in up to 99 % yield and can be readily derivatized under a variety of conditions. By utilizing a combination of experimental and computational studies, the presumptive addition-elimination reaction mechanism was investigated and found to proceed under thermodynamic control at higher temperature. The acquired fundamental knowledge was translated into a strategic reaction design and yielded the first example of the beta-C-H functionalizations of acyclic enol ethers using alpha-diazo-1,3-dicarbonyl compounds. PMID- 27966245 TI - Gaining Insight Into Reactivity Differences Between Malonic Acid Half Thioesters (MAHT) and Malonic Acid Half Oxyesters (MAHO). AB - An efficient two-step synthesis of structurally and functionally diverse thiophenol- and (cyclo)alkyl-derived malonic acid half thioesters (MAHTs) and phenol-derived malonic acid half oxyesters (MAHOs) has been achieved using cheap, readily available and easily handled starting materials. The synthesis of the MAHTs and MAHOs (the majority of which have not been previously reported) is readily scalable to afford gram quantities of product. In a hydrogen->deuterium exchange, an interesting stereoelectronic effect was observed when different aryl groups were incorporated. Significant changes in the rates of hydrogen->deuterium exchange and levels of isotope incorporation were observed. By way of example, using [2 H]methanol and 4-bromophenol-derived MAHO afforded only 14 % [2 H] incorporation (9 min, k=31) whereas the corresponding 4-bromothiophenol-derived MAHT afforded 97 % [2 H]-incorporation (9 min, k=208). In a benchmark procedure and comprehensive DFT study, 54 ester and thioester configurations and conformations were characterized. In the MAHT series, a sulfur-containing molecular orbital provides a path for increased delocalisation of electron density into the enol that is unavailable in MAHOs. This facilitates keto-enol tautomerisation and consequently enhances the rate and percentage of hydrogen >deuterium exchange. PMID- 27966246 TI - Commentary on "The Evolutionary Origin of Female Orgasm" by M. Pavlicev and G. Wagner, 2016, J. Exp. Zool. (Mol. Dev. Evol.) 326(6):326-337. AB - Evidence is presented as an alternative to the authors' claims that in the course of evolution, a link between orgasm and ovulation has been lost in women, that evolutionary changes in clitoral anatomy underlie this loss, and that women's orgasm plays no significant role in reproduction. PMID- 27966247 TI - Can twice weekly hemodialysis expand patient access under resource constraints? AB - The convention of prescribing hemodialysis on a thrice weekly schedule began empirically when it seemed that this frequency was convenient and likely to treat symptoms for a majority of patients. Later, when urea was identified as the main target and marker of clearance, studies supported the prevailing notion that thrice weekly dialysis provided appropriate clearance of urea. Today, national guidelines on hemodialysis from most countries recommend patients receive at least thrice weekly therapy. However, resource constraints in low- and middle income countries (LMIC) have resulted in a substantial proportion of patients using less frequent hemodialysis in these settings. Observational studies of patients on twice weekly dialysis show that twice weekly therapy has noninferior survival rates compared with thrice weekly therapy. In fact, models of urea clearance also show that twice weekly therapy can meet urea clearance "targets" if patients have significant residual function or if they follow a protein restricted diet, as may be common in LMIC. Greater reliance on twice weekly therapy, at least at the start of hemodialysis, therefore has potential to reduce health care costs and increase access to renal replacement therapy in low resource settings; however, randomized control trials are needed to better understand long-term outcomes of twice versus thrice weekly therapy. PMID- 27966249 TI - Cost-effectiveness of elbasvir/grazoprevir use in treatment-naive and treatment experienced patients with hepatitis C virus genotype 1 infection and chronic kidney disease in the United States. AB - Among patients with chronic kidney disease (CKD) in the United States, HCV infection causes significant morbidity and mortality and results in substantial healthcare costs. A once-daily oral regimen of elbasvir/grazoprevir (EBR/GZR) for 12 weeks was found to be a safe and efficacious treatment for HCV in patients with CKD. We evaluated the cost-effectiveness of EBR/GZR in treatment-naive and treatment-experienced CKD patients compared with no treatment (NoTx) and pegylated interferon plus ribavirin (peg-IFN/RBV) using a computer-based model of the natural history of chronic HCV genotype 1 infection, CKD and liver disease. Data on baseline characteristics of the simulated patients were obtained from NHANES, 2000-2010. Model inputs were estimated from published studies. Cost of treatment with EBR/GZR and peg-INF/RBV were based on wholesale acquisition cost. All costs were from a third-party payer perspective and were expressed in 2015 U.S. dollars. We estimated lifetime incidence of liver-related complications, liver transplantation, kidney transplantation, end-stage live disease mortality and end-stage renal disease mortality; lifetime quality-adjusted life years (QALY); and incremental cost-utility ratios (ICUR). The model predicted that EBR/GZR will significantly reduce the incidence of liver-related complications and prolong life in patients with chronic HCV genotype 1 infection and CKD compared with NoTx or use of peg-IFN/RBV. EBR/GZR-based regimens resulted in higher average remaining QALYs and higher costs (11.5716, $191 242) compared with NoTx (8.9199, $156 236) or peg-INF/RBV (10.2857, $186 701). Peg-IFN/RBV is not cost-effective, and the ICUR of EBR/GZR compared with NoTx was $13 200/QALY. Treatment of a patient on haemodialysis with EBR/GZR resulted in a higher ICUR ($217 000/QALY). Assuming a threshold of $100 000 per QALY gained for cost effectiveness, use of elbasvir/grazoprevir to treat an average patient with CKD can be considered cost-effective in the United States. PMID- 27966248 TI - Misspecification of at-risk periods and distributional assumptions in estimating COPD exacerbation rates: The resultant bias in treatment effect estimation. AB - In trials comparing the rate of chronic obstructive pulmonary disease exacerbation between treatment arms, the rate is typically calculated on the basis of the whole of each patient's follow-up period. However, the true time a patient is at risk should exclude periods in which an exacerbation episode is occurring, because a patient cannot be at risk of another exacerbation episode until recovered. We used data from two chronic obstructive pulmonary disease randomized controlled trials and compared treatment effect estimates and confidence intervals when using two different definitions of the at-risk period. Using a simulation study we examined the bias in the estimated treatment effect and the coverage of the confidence interval, using these two definitions of the at-risk period. We investigated how the sample size required for a given power changes on the basis of the definition of at-risk period used. Our results showed that treatment efficacy is underestimated when the at-risk period does not take account of exacerbation duration, and the power to detect a statistically significant result is slightly diminished. Correspondingly, using the correct at risk period, some modest savings in required sample size can be achieved. Using the proposed at-risk period that excludes recovery times requires formal definitions of the beginning and end of an exacerbation episode, and we recommend these be always predefined in a trial protocol. PMID- 27966250 TI - Continuous soil carbon storage of old permanent pastures in Amazonia. AB - Amazonian forests continuously accumulate carbon (C) in biomass and in soil, representing a carbon sink of 0.42-0.65 GtC yr-1 . In recent decades, more than 15% of Amazonian forests have been converted into pastures, resulting in net C emissions (~200 tC ha-1 ) due to biomass burning and litter mineralization in the first years after deforestation. However, little is known about the capacity of tropical pastures to restore a C sink. Our study shows in French Amazonia that the C storage observed in native forest can be partly restored in old (>=24 year) tropical pastures managed with a low stocking rate (+/-1 LSU ha-1 ) and without the use of fire since their establishment. A unique combination of a large chronosequence study and eddy covariance measurements showed that pastures stored between -1.27 +/- 0.37 and -5.31 +/- 2.08 tC ha-1 yr-1 while the nearby native forest stored -3.31 +/- 0.44 tC ha-1 yr-1 . This carbon is mainly sequestered in the humus of deep soil layers (20-100 cm), whereas no C storage was observed in the 0- to 20-cm layer. C storage in C4 tropical pasture is associated with the installation and development of C3 species, which increase either the input of N to the ecosystem or the C:N ratio of soil organic matter. Efforts to curb deforestation remain an obvious priority to preserve forest C stocks and biodiversity. However, our results show that if sustainable management is applied in tropical pastures coming from deforestation (avoiding fires and overgrazing, using a grazing rotation plan and a mixture of C3 and C4 species), they can ensure a continuous C storage, thereby adding to the current C sink of Amazonian forests. PMID- 27966251 TI - Identification and conservation of gene loss events of Hox gene clusters in the marine medaka (Oryzias melastigma). AB - In this study, the identification of the whole Hox gene clusters (46 Hox genes) in the marine medaka Oryzias melastigma was investigated using genome assembly and RNA-seq information. Moreover, the gene loss events of Hox gene clusters, which may occur during fish evolution, were examined for a better understanding of the evolutionary status of the gene lost events of the Hox gene cluster across fish species, particularly in the genus Oryzias. PMID- 27966252 TI - Field Effect Enhanced Hydrogen Evolution Reaction of MoS2 Nanosheets. AB - Hydrogen evolution reaction performance of MoS2 can be enhanced through electric field-facilitated electron transport. The best catalytic performance of a MoS2 nanosheet can achieve an overpotential of 38 mV (100 mA cm-2 ) at gate voltage of 5 V, the strategy of utilizing the electric field can be used in other semiconductor materials to improve their electrochemical catalysis for future relevant research. PMID- 27966254 TI - Diverse ontogenies of reciprocal and prosocial behavior: cooperative development in Fiji and the United States. AB - Contingent reciprocity is an important foundation of human cooperation, but we know little about how reciprocal behavior develops across diverse societies, nor about how the development of reciprocal behavior is related to the development of prosocial behavior more broadly. Three- to 16-year-old children were presented with the opportunity to control the allocation of real food rewards in a binary choice cooperative dilemma. Within dyads children alternated making choices across multiple trials, and reciprocal behavior emerged in three diverse populations (rural Fijian villages, and urban communities in both Fiji and the United States) by age 7-8. There was more societal variation in prosocial behavior than in reciprocal behavior, and there were more substantial differences between Fijians and Americans than between rural and urban populations. This suggests that the development of prosocial behavior is not driven entirely by the development of reciprocity, and differences in prosocial behavior across rural Fijians and urban Americans may not be due only to differences across rural and urban populations. PMID- 27966253 TI - Treatment of a soft tissue calcification in a patient receiving peritoneal dialysis. AB - Chronic Kidney Disease patients suffer from Mineral and Bone Disorder (CKD-MBD) leading to increased vascular and soft-tissue calcification. The prevalence of soft tissue calcification in dialysis patients is not well described, and most cases describe such calcifications in hemodialysis patients. We describe a case of a massive soft tissue calcification in the right gluteal region in a peritoneal dialysis patient. The patient had severe pain and were disabled. The treatment was converted to an intensive hemodialysis regimen with a minimal calcium load and high dose of cinacalcet. During the treatment, the calcification diminished rapidly from a diameter of 26.6 to 2.9 cm, and the patient symptoms were relieved, leaving the patient with no pain or restriction in mobilization. PMID- 27966255 TI - Liquid chromatography quadrupole time-of-flight mass spectrometry identification and determination of tri- and hexaaryl chloro imidazoles in sewage sludge. AB - The identification and further quantification of 2-chloro-triarylimidazole (o-Cl TAI) and its dimer (o-DCl-HABI) in sludge from a sewage treatment plant (STP) is reported for the first time. Liquid chromatography (LC) quadrupole time-of-flight (QTOF) mass spectrometry (MS) was used as analytical technique during screening and determination steps. Pollutants were identified following a post-run search strategy, applying the chlorine mass filter, and characterized by their accurate MS and product ion scan spectra. Finally, their identities were confirmed with authentic standards. The species (o-Cl-TAI) has been rated as potentially genotoxic and carcinogenic for mice and rats. Effects of sample preparation in the stability and the extraction efficiency of both compounds are discussed. Under final conditions, they were extracted from freeze-dried samples (0.5 g of sludge or biosolids dispersed with 2 g of C18 and packed into a polypropylene syringe) with 20 ml of methanol, which also flowed through a clean-up layer of Florisil and PSA sorbents (0.5 g each). This method attained quantitative extraction yields and limits of quantification between 4 and 10 ng/g. The pollutants o-Cl-TAI and o-DCl-HABI were ubiquitous in sludge and biosolids obtained in consecutive years from the investigated STP. Their concentrations varied from 0.02 to more than 13 MUg/g (freeze-dried sample). Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27966256 TI - Modification and intercalation of layered zirconium phosphates: a solid-state NMR monitoring. AB - Several layered zirconium phosphates treated with Zr(IV) ions, modified by monomethoxy-polyethyleneglycol-monophosphate and intercalated with doxorubicin hydrochloride have been studied by solid-state MAS NMR techniques. The organic components of the phosphates have been characterized by the 13 C{1 H} CP MAS NMR spectra compared with those of initial compounds. The multinuclear NMR monitoring has provided to establish structure and covalent attachment of organic/inorganic moieties to the surface and interlayer spaces of the phosphates. The MAS NMR experiments including kinetics of proton-phosphorus cross polarization have resulted in an unusual structure of zirconium phosphate 6 combining decoration of the phosphate surface by polymer units and their partial intercalation into the interlayer space. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27966257 TI - Twenty-five year outcomes following composite graft aortic root replacement. AB - BACKGROUND: Operative choices for aortic root disease include traditional root replacement with a composite valved graft as well as various valve-sparing and root repair procedures. OBJECTIVES: To report our experience with traditional composite graft aortic root replacement by a single surgeon over a 25-year period in 449 patients, focusing on long-term survival and freedom from late reoperation and adverse events. METHODS: The coronary button technique was used in all patients. Mean age was 56.1 +/- 14.0 years (range 14-87) with 83% males (373/449). Valve prosthesis was mechanical in 343 (76%) and bioprosthetic in 106 (24%). A modified Cabrol procedure (Dacron coronary graft) was employed in 10% (45/449) and concomitant coronary artery bypass graft in 10.9% (49/449). There were 15.8% (71/449) urgent/emergent and 8.2% (37/449) redo procedures. Survival follow-up was 100%. Mean follow-up was 7.0 +/- 5.1 years (range 0.1-24.8). RESULTS: Operative mortality occurred in 14 patients (3.1%) and was 2.2% (9/418) in non-dissection and 1.9% (7/361) in elective first-time operations. Stroke and re-exploration for bleeding occurred in nine (2.0%) and 20 (4.5%) patients, respectively. Major late events included bleeding in 2.5% (11/435) and thromboembolism in 1.1% (5/435). At 5, 10, and 20 years, freedom from major events and reoperations on the root were 97.8, 95.4, and 94.39%, and 99.0, 99.0, and 97.9%, respectively. Survival in patients aged <60 years was 92.0, 90.1, and 79.8% at five, 10, and 20 years versus 88.4, 67.9, and 42.6% in patients aged >=60 years (p = 0.001). Compared with age- and gender-matched controls, survival was not significantly different (p = 0.20). CONCLUSIONS: Composite graft aortic root replacement is associated with low operative risk, excellent long-term survival, and low incidence of reoperation and late events. PMID- 27966259 TI - Estimands-new statistical principle or the emperor's new clothes? PMID- 27966258 TI - Promoting resuscitation of viable but nonculturable cells of Vibrio harveyi by a resuscitation-promoting factor-like protein YeaZ. AB - AIMS: To demonstrate the resuscitation-promoting activities of recombinant YeaZ from Vibrio harveyi SF-1. METHODS AND RESULTS: The gene of resuscitation promoting factor YeaZ was cloned from genomic DNA of V. harveyi SF-1. The gene was expressed in Escherichia coli, and the expressed protein was purified by Ni2+ -affinity chromatography. A yeaZ mutant was constructed by using the suicide plasmid pNQ705 with homologous recombination. Disruption of yeaZ did not affect cell growth significantly in 2216 E broth at 28 degrees C. The wild-type and mutant viable but nonculturable (VBNC) cells could be resuscitated by temperature upshift method. In addition, the recombinant YeaZ increased the culturable counts from 1.27 * 104 CFU per ml and 1.99 * 104 CFU per ml to 2.88 * 105 CFU per ml and 4.59 * 105 CFU per ml, respectively. After the VBNC cells of wild-type and mutant cells were maintained at 4 degrees C for 120 days, no resuscitation was obtained by temperature upshift method, but addition of the recombinant YeaZ promoted the resuscitation of the wild-type and mutant cells, with the culturable cell counts of 1.13 * 103 and 1.44 * 103 CFU per ml, respectively. Disruption of yeaZ decreased the virulence of V. harveyi in zebrafish. The lethal dose 50% of the yeaZ null mutant was more than 10-fold higher than that of the wild-type cells. CONCLUSIONS: The recombinant YeaZ could efficiently promote resuscitation of the wild-type and mutant cells of V. harveyi from VBNC to culturable state. The protein also promoted resuscitation of the VBNC wild-type and mutant cells, which were maintained at 4 degrees C for 120 days and not recovered by temperature upshift method. Disruption of yeaZ decreased the virulence of V. harveyi in zebrafish. SIGNIFICANCE AND IMPACT OF THE STUDY: Here, we show clear evidence of a resuscitation-promoting factor YeaZ of V. harveyi and the roles in resuscitation of the VBNC cells and its pathogenicity. PMID- 27966260 TI - Statistical inferences for data from studies conducted with an aggregated multivariate outcome-dependent sample design. AB - Outcome-dependent sampling (ODS) scheme is a cost-effective sampling scheme where one observes the exposure with a probability that depends on the outcome. The well-known such design is the case-control design for binary response, the case cohort design for the failure time data, and the general ODS design for a continuous response. While substantial work has been carried out for the univariate response case, statistical inference and design for the ODS with multivariate cases remain under-developed. Motivated by the need in biological studies for taking the advantage of the available responses for subjects in a cluster, we propose a multivariate outcome-dependent sampling (multivariate-ODS) design that is based on a general selection of the continuous responses within a cluster. The proposed inference procedure for the multivariate-ODS design is semiparametric where all the underlying distributions of covariates are modeled nonparametrically using the empirical likelihood methods. We show that the proposed estimator is consistent and developed the asymptotically normality properties. Simulation studies show that the proposed estimator is more efficient than the estimator obtained using only the simple-random-sample portion of the multivariate-ODS or the estimator from a simple random sample with the same sample size. The multivariate-ODS design together with the proposed estimator provides an approach to further improve study efficiency for a given fixed study budget. We illustrate the proposed design and estimator with an analysis of association of polychlorinated biphenyl exposure to hearing loss in children born to the Collaborative Perinatal Study. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27966261 TI - A Bifunctional Amino Acid Enables Both Covalent Chemical Capture and Isolation of in Vivo Protein-Protein Interactions. AB - In vivo covalent chemical capture by using photoactivatable unnatural amino acids (UAAs) is a powerful tool for the identification of transient protein-protein interactions (PPIs) in their native environment. However, the isolation and characterization of the crosslinked complexes can be challenging. Here, we report the first in vivo incorporation of the bifunctional UAA BPKyne for the capture and direct labeling of crosslinked protein complexes through post-crosslinking functionalization of a bioorthogonal alkyne handle. Using the prototypical yeast transcriptional activator Gal4, we demonstrate that BPKyne is incorporated at the same level as the commonly used photoactivatable UAA pBpa and effectively captures the Gal4-Gal80 transcriptional complex. Post-crosslinking, the Gal4 Gal80 adduct was directly labeled by treatment of the alkyne handle with a biotin azide probe; this enabled facile isolation and visualization of the crosslinked adduct from whole-cell lysate. This bifunctional amino acid extends the utility of the benzophenone crosslinker and expands our toolbox of chemical probes for mapping PPIs in their native cellular environment. PMID- 27966262 TI - N-glycoprotein surfaceome of human induced pluripotent stem cell derived hepatic endoderm. AB - Using cell surface capture technology, the cell surface N-glycoproteome of human induced pluripotent stem cell derived hepatic endoderm cells was assessed. Altogether, 395 cell surface N-glycoproteins were identified, represented by 1273 N-glycopeptides. This study identified N-glycoproteins that are not predicted to be localized to the cell surface and provides experimental data that assist in resolving ambiguous or incorrectly annotated transmembrane topology annotations. In a proof-of-concept analysis, combining these data with other cell surface proteome datasets is useful for identifying potentially cell type and lineage restricted markers and drug targets to advance the use of stem cell technologies for mechanistic developmental studies, disease modeling, drug discovery, and regenerative medicine. PMID- 27966263 TI - Molecular- and microarray-based analysis of diversity among resting and osteogenically induced porcine mesenchymal stromal cells of several tissue origin. AB - Mesenchymal stromal cells (MSCs) play a pivotal role in modern therapeutic approaches in bone-healing disorders. Although bone marrow-derived MSCs are most frequently used, the knowledge that many other adult tissues represent promising sources for potent MSCs has gained acceptance. In the present study, the osteogenic differentiation potential of porcine skin fibroblasts (FBs), as well as bone marrow- (BMSCs), adipose tissue- (ASCs) and dental pulp-derived stromal cells (DSCs) were evaluated. However, additional application of BMP-2 significantly elevated the delayed osteogenic differentiation capacity of ASC and FB cultures, and in DSC cultures the supplementation of platelet-rich plasma increased osteogenic differentiation potential to a comparable level of the good differentiable BMSCs. Furthermore, microarray gene expression performed in an exemplary manner for ASCs and BMSCs revealed that ASCs and BMSCs use different gene expression patterns for osteogenic differentiation under standard media conditions, as diverse MSCs are imprinted dependent from their tissue niche. However, after increasing the differentiation potential of ASCs to a comparable level as shown in BMSCs, a small subset of identical key molecules was used to differentiate in the osteogenic lineage. Until now, the importance of identified genes seems to be underestimated for osteogenic differentiation. Apparently, the regulation of transmembrane protein 229A, interleukin-33 and the fibroblast growth factor receptor-2 in the early phase of osteogenic differentiation is needed for optimum results. Based on these results, bone regeneration strategies of MSCs have to be adjusted, and in vivo studies on the osteogenic capacities of the different types of MCSs are warranted. Copyright (c) 2016 The Authors Tissue Engineering and Regenerative Medicine published by John Wiley & Sons, Ltd. PMID- 27966264 TI - PD1 and PDL1 expression in primary central nervous system diffuse large B-cell lymphoma are frequent and expression of PD1 predicts poor survival. AB - Primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is a rare and aggressive type of diffuse large B-cell lymphoma (DLBCL) whit poorly understood pathogenesis. Finding biomarkers associated with patient survival may be important for understanding its physiopathology and to develop new therapeutic approaches. We investigated 32 PCNS-DLBCL from immunocompetent patients for BCL2, CMYC, LMO2, and P53 expression and for cytogenetic aberrations of BCL2, BCL6, and MYC genes, all known for their prognostic value in systemic DLBCL (s-DLBCL). We analyzed PD1 and PDL1 protein expression in both tumor infiltrating lymphocytes (TILs) and tumor cells. Finally, we searched for correlation between biological data and clinical course. The PCNS-DLBCL expressed BCL2, CMYC, LMO2, and P53 at similar frequency than s-DLBCL but without significant prognostic on survival. None cases harbored aberrations involving BCL2 and MYC gene whereas BCL6 abnormalities were present in 20.7% of cases but without value on survival. Expression of PD1 in TILs and PDL1 in tumor cells was observed at higher rates than in s-DLBCL (58% and 37%, respectively). The PD1 expression in TILs correlated with PDL1 expression in tumor cells (P = .001). Presence of PD1 positive TILs was associated with poorer overall survival (P = .011). Patients with PDL1 overexpression tended to better response to chemotherapy (P = .23). In conclusion PCNS-DLBCL pathogenesis differs from s-DLBCL without prognostic value of the phenotypic and cytogenetic parameters known for their pejorative impact in the latter. The PD1/PDL1 pathway plays a strong role in PCNS-DLBCL and represents an attractive target for this aggressive lymphoma. PMID- 27966265 TI - Molecular-Level Design of Hierarchically Porous Carbons Codoped with Nitrogen and Phosphorus Capable of In Situ Self-Activation for Sustainable Energy Systems. AB - Hierarchically porous carbons are attracting tremendous attention in sustainable energy systems, such as lithium ion battery (LIB) and fuel cell, due to their excellent transport properties that arise from the high surface area and rich porosity. The state-of-the-art approaches for synthesizing hierarchically porous carbons normally require chemical- and/or template-assisted activation techniques, which is complicate, time consuming, and not feasible for large scale production. Here, a molecular-level design principle toward large-scale synthesis of nitrogen and phosphorus codoped hierarchically porous carbon (NPHPC) through an in situ self-activation process is proposed. The material is fabricated based on the direct pyrolysis of a well-designed polymer, melamine polyphosphate, which is capable of in situ self-activation to generate large specific surface area (1479 m2 g-1 ) and hierarchical pores in the final NPHPC. As an anode material for LIB, NPHPC delivers a high reversible capacity of 1073 mAh g-1 and an excellent cyclic stability for 300 cycles with negligible capacity decay. The peculiar structural properties and synergistic effect of N and P codopants also enable NPHPC a promising electrocatalyst for oxygen reduction reaction, a key cathodic reaction process of many energy conversion devices (for example, fuel cells and metal air batteries). Electrochemical measurements show NPHPC a comparable electrocatalytic performance to commercial Pt/C catalyst (onset potential of 0.88 V vs reversible hydrogen electrode in alkaline medium) with excellent stability (89.8% retention after 20 000 s continuous operation) and superior methanol tolerance. PMID- 27966266 TI - Full-thickness oesophageal regeneration in pig using a polyurethane mucosal cell seeded graft. AB - Malignant oesophageal pathology typically requires resection of a portion of oesophagus. The aim of this study was to investigate attachment and growth of swine oesophageal mucosal cells on electrospun synthetic nanofibre matrices of varying chemistries and to determine whether a mucosal-seeded graft, in a swine animal model, could induce regeneration. Swine mucosal oesophageal cells were isolated and seeded them onto five different matrix materials. Matrix samples were cultured for up to 14 days, after which matrices were analysed for cell attachment. Attachment varied for each of the matrix materials tested, with the most rigid showing the lowest levels of attachment. Importantly, sections of these matrices illustrated that multiple layers of mucosal cells formed, mimicking endogenous oesophageal structure. A tdTomato reporter line (mucosaltdt cells) was created to enable cell tracking. As polyurethane matrix was found optimal through in vitro testing, a graft was prepared using mucosaltdt cells, along with an unseeded control, and implanted into swine for determination of oesophageal regeneration. Mucosal seeded polyurethane grafts initiated full thickness regeneration of the oesophagus, including epithelial, submucosal, and skeletal muscle layers which were highly vascularized. Interestingly, an unseeded graft showed similar regeneration, indicating that the role of cells in the process of oesophageal regeneration is still unclear. The electrospun polyurethane matrix does appear suitable for multilayered cellular attachment and growth of oesophageal mucosal cells, and implantation of polyurethane grafts initiated full thickness regeneration of the oesophagus, indicating potential for oesophageal reconstruction in humans. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27966267 TI - Peptide Optical waveguides. AB - Small-scale optical devices, designed and fabricated onto one dielectric substrate, create integrated optical chip like their microelectronic analogues. These photonic circuits, based on diverse physical phenomena such as light-matter interaction, propagation of electromagnetic waves in a thin dielectric material, nonlinear and electro-optical effects, allow transmission, distribution, modulation, and processing of optical signals in optical communication systems, chemical and biological sensors, and more. The key component of these optical circuits providing both optical processing and photonic interconnections is light waveguides. Optical confinement and transmitting of the optical waves inside the waveguide material are possible due to the higher refractive index of the waveguides in comparison with their surroundings. In this work, we propose a novel field of bionanophotonics based on a new concept of optical waveguiding in synthetic elongated peptide nanostructures composed of ordered peptide dipole biomolecules. New technology of controllable deposition of peptide optical waveguiding structures by nanofountain pen technique is developed. Experimental studies of refractive index, optical transparency, and linear and nonlinear waveguiding in out-of-plane and in-plane diphenylalanine peptide nanotubes have been conducted. Optical waveguiding phenomena in peptide structures are simulated by the finite difference time domain method. The advantages of this new class of bio-optical waveguides are high refractive index contrast, wide spectral range of optical transparency, large optical nonlinearity, and electro-optical effect, making them promising for new applications in integrated multifunctional photonic circuits. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27966268 TI - Ophthalmological findings in children with encephalitis. AB - PURPOSE: To evaluate ophthalmological abnormalities in children with acute encephalitis. METHODS: Thirty-six children included in a hospital-based prospectively and consecutively collected cohort of children with acute encephalitis were investigated for ophthalmological abnormalities. The investigation included clinical ophthalmological examination, fundus photography, neuro-ophthalmological examinations as well as visual and stereo acuity. Results on laboratory examinations, clinical findings, neuroimaging and electroencephalography registrations were recorded for all children. RESULTS: The median age was 4.0 years (Interquartile Range 1.9-9.8). The aetiology was identified in 74% of cases. Three of 36 patients were found to have abnormal ophthalmological findings related to the encephalitis. Transient sixth nerve palsy was seen in a 15-year-old child and transient visual impairment was seen in a 3.5-year-old child. Bilateral miosis and ptosis, i.e. autonomic nerve system symptoms, were seen in an 11-month-old child, with herpes simplex 1 and N-methyl d-aspartate receptor antibody encephalitis. All three children recovered and improved their ophthalmological function with time. CONCLUSION: Only 3 of 36 children were found to have ophthalmological abnormalities due to encephalitis and they all improved with time. Thus, ophthalmological consultation does not seem to fit in a screening programme for childhood encephalitis but should be considered in selected cases. PMID- 27966269 TI - The effect of blue-blocking and neutral intraocular lenses on circadian photoentrainment and sleep one year after cataract surgery. AB - PURPOSE: To compare the long-term effect on circadian photoentrainment and sleep in patients implanted with neutral and blue-blocking intraocular lenses 1 year after cataract surgery. METHODS: Randomized, controlled trial involving 67 patients with age-related cataract. Intervention was cataract surgery with implantation of either a neutral or a blue-blocking intraocular lens (IOL). Main outcome was activation of the intrinsically photosensitive retinal ganglion cells (ipRGC) measured by chromatic pupillometry. The circadian rhythm was analysed by 24-hr melatonin profiles and actigraphy; the latter was also used to determine objective sleep quality. The Pittsburgh Sleep Quality Index determined subjective sleep quality. RESULTS: One year after surgery, peak melatonin concentration was 3.3 pg/ml (95% CI, 2-5.5) corresponding to 50% lower for the participants allocated to blue-blocking IOLs compared with participants allocated to neutral IOLs. Compared with preoperative levels, the ipRGC response had increased by 13.7% (95% confidence interval [CI], 3.2-22.6) 1 year after surgery. Objective sleep quality was also improved as the time of wakefulness after sleep onset had improved by 5 min (95% CI, 1-10) for the entire population while sleep efficiency had increased by two percentage points (95% CI, 0.42-3.65) although exclusively, for the participants allocated to blue-blocking IOLs. CONCLUSION: Blue-blocking IOLs increased sleep efficiency but lowered nocturnal melatonin secretion compared with neutral IOLs. Cataract surgery improved the response of ipRGCs and sleep quality. However, the effect of cataract surgery on sleep quality may be unrelated to circadian photoentrainment. PMID- 27966270 TI - Comparison of targeted proteomics approaches for detecting and quantifying proteins derived from human cancer tissues. AB - Targeted mass spectrometry-based proteomics approaches enable the simultaneous and reproducible quantification of multiple protein analytes across numerous conditions in biology and clinical studies. These approaches involve e.g. selected reaction monitoring (SRM) typically conducted on a triple quadrupole mass spectrometer, its high-resolution variant named pseudo-SRM (p-SRM), carried out in a quadrupole coupled with an TOF analyzer (qTOF), and "sequential window acquisition of all theoretical spectra" (SWATH). Here we compared these methods in terms of signal-to-noise ratio (S/N), coefficient of variance (CV), fold change (FC), limit of detection and quantitation (LOD, LOQ). We have shown the highest S/N for p-SRM mode, followed by SRM and SWATH, demonstrating a trade-off between sensitivity and level of multiplexing for SRM, p-SRM, and SWATH. SRM was more sensitive than p-SRM based on determining their LOD and LOQ. Although SWATH has the worst S/N, it enables peptide multiplexing with post-acquisition definition of the targets, leading to better proteome coverage. FC between breast tumors of different clinical-pathological characteristics were highly correlated (R2 >0.97) across three methods and consistent with the previous study on 96 tumor tissues. Our technical note presented here, therefore, confirmed that outputs of all the three methods were biologically relevant and highly applicable to cancer research. PMID- 27966272 TI - Pd-Catalyzed, Ligand-Enabled Stereoselective 1,2-Iodine(III) Shift/1,1 Carboxyalkynylation of Alkynylbenziodoxoles. AB - A PdII -catalyzed 2:1 coupling reaction of alkynylbenziodoxole with carboxylic acid to afford (alk-1-en-3-ynyl)benziodoxole, which is efficiently promoted by an octahydrophenazine ligand, is reported. The reaction involves a Pd-assisted 1,2 iodine(III) shift of the alkynylbenziodoxole followed by stereoselective introduction of carboxy and alkynyl groups (the latter originating from another molecule of the alkynylbenziodoxole) into the 1-position of the transient Pd vinylidene species. The product of this 1,1-carboxyalkynylation reaction serves as a new functionalized enyne-type building block for further synthetic transformations. PMID- 27966271 TI - Do evidence-based guidelines change clinical practice patterns? AB - In 2013, the Danish Health and Medicines Authorities published a National Clinical Guideline on the treatment of age-related cataracts. The guideline provided evidence-based recommendations on the indication for cataract surgery, cataract surgery in patients with age-related macular degeneration, on the use of toric intraocular lenses (IOLs) to correct preoperative corneal astigmatism, the use of intracameral and topical antibiotics to prevent endophthalmitis, choice of anti-inflammatory medication to control postoperative inflammation and prevent cystoid macular oedema, the use of immediate sequential bilateral cataract surgery and on the postoperative check-up of patients. A questionnaire was sent to all members of the Danish Ophthalmological Society before and after publication of the guideline. The responses showed that the guideline had changed practice patterns so that surgeons were more likely to prescribe non-steroidal anti-inflammatory eye drops and to not prescribe topical antibiotic eye drops after the guideline was published. Other parameters, most notably the use of toric IOLs and use of postoperative examinations were more guided by reimbursement standards than by evidence-based medicine. Thus, evidence-based guidelines do change practice patterns unless they are counteracted by the reimbursement system. PMID- 27966273 TI - So you want to publish your research in the Journal of Thrombosis and Haemostasis? PMID- 27966275 TI - Unstructured play for anxiety in pediatric inpatient care. AB - PURPOSE: The purpose of this study was to examine the effects of unstructured play activities on the anxiety levels of hospitalized children. METHODS: A nonequivalent control group pretest posttest design was employed for this study. The sample included children (N = 165) ages 4-7 years admitted to a large pediatric referral center in the United Arab Emirates. The control group (n = 84) received usual care, while the experimental group (n = 81) engaged in age appropriate unstructured play activities using disposable games and toys. Parents and siblings, if present, were encouraged to participate. Research assistants conducted the play activities twice a day, with 30-min morning and evening sessions. Anxiety was measured at baseline and at the end of days 2 and 3 with a translated form of the Short-State-Trait Anxiety Inventory for Children. RESULTS: Anxiety scores in both groups were similar at baseline and decreased significantly over the 3 days. Compared with the control group, anxiety scores in the intervention group were significantly lower on day 2 (12.7 +/- 2.3 vs. 10.7 +/- 2.5, p = .003) and day 3 (10.6 +/- 2.2 vs. 9.47 +/- 2.4, p < .001). The greatest decrease occurred in the percentage of children in the experimental group with medium-level anxiety scores: baseline (n = 61, 75%), day 2 (n = 24, 30%), and day 3 (n = 0, 0%). CONCLUSIONS: This simple, low-cost play intervention implemented by nurses resulted in statistically and clinically significant decreases in the anxiety levels of children in an acute inpatient setting. PMID- 27966276 TI - Autonomic Tone Activity Before the Onset of Atrial Fibrillation. AB - INTRODUCTION: The autonomic nervous system has been proven to play a major role in the onset of atrial fibrillation (AF), along with a predisposing substrate and a specific trigger event usually consisting of a premature supraventricular ectopic beat (SVEB). By means of heart rate variability (HRV) analysis, we investigated the activity of the autonomic nervous system before SVEBs nontriggering and triggering AF. METHODS AND RESULTS: We evaluated 28 patients with at least 1 episode of sustained AF (>30 seconds) recorded during 24-hour Holter monitorings. We performed HRV analysis during the hour preceding 35 AF onsets and compared these results with the HRV values before nontriggering SVEBs with similar prematurity. According to the low frequency (LF)/high frequency (HF) ratio in the 5 minutes before the onset, AF episodes were classified as either vagal (LF/HF ratio <1.5) or adrenergic (LF/HF ratio >=1.5).Vagal episodes (16) showed a decrease in LF (from 50.81 +/- 1.67 to 32.73 +/- 3.54) and an increase in HF (from 36.00 +/- 2.30 to 54.7 +/- 3.69) throughout the hour preceding the onset. Adrenergic episodes (19) had opposite changes in LF (from 55.4 +/- 4.95 to 67.51 +/- 5.24) and HF (from 33.78 +/- 5.82 to 27.96 +/- 3.51) during the same period. No similar trends were observed before the selected nontriggering SVEBs. CONCLUSION: Only SVEBs occurring during a phase of hyperactivity of one of the 2 branches of the autonomic nervous system are able to trigger episodes of AF. PMID- 27966274 TI - Cell Proliferation Pattern and Twist Expression in an Aplacophoran Mollusk Argue Against Segmented Ancestry of Mollusca. AB - The study of aplacophoran mollusks (i.e., Solenogastres or Neomeniomorpha and Caudofoveata or Chaetodermomorpha) has traditionally been regarded as crucial for reconstructing the morphology of the last common ancestor of the Mollusca. Since their proposed close relatives, the Polyplacophora, show a distinct seriality in certain organ systems, the aplacophorans are also in the focus of attention with regard to the question of a potential segmented ancestry of mollusks. To contribute to this question, we investigated cell proliferation patterns and the expression of the twist ortholog during larval development in solenogasters. In advanced to late larvae, during the outgrowth of the trunk, a pair of longitudinal bands of proliferating cells is found subepithelially in a lateral to ventrolateral position. These bands elongate during subsequent development as the trunk grows longer. Likewise, expression of twist occurs in two laterally positioned, subepithelial longitudinal stripes in advanced larvae. Both, the pattern of proliferating cells and the expression domain of twist demonstrate the existence of extensive and long-lived mesodermal bands in a worm-shaped aculiferan, a situation which is similar to annelids but in stark contrast to conchiferans, where the mesodermal bands are usually rudimentary and ephemeral. Yet, in contrast to annelids, neither the bands of proliferating cells nor the twist expression domain show a separation into distinct serial subunits, which clearly argues against a segmented ancestry of mollusks. Furthermore, the lack of twist expression during the development of the ventromedian muscle argues against homology of a ventromedian longitudinal muscle in protostomes with the notochord of chordates. PMID- 27966277 TI - The luminescent properties and crystal structure of Sr(1.5-x)-(1.5y) Mg0.5 SiO4 :xEu2+ ,yCe3+ blue phosphor synthesized by co-precipitation method. AB - In order to improve the luminescent performance of silicate blue phosphors, Sr(1.5-x)-(1.5y) Mg0.5 SiO4 :xEu2+ ,yCe3+ phosphors were synthesized using one step calcination of a precursor prepared by chemical co-precipitation. The crystal structure and luminescent properties of the phosphors were analyzed using X-ray diffraction and fluorescence spectrophotometry, respectively. Because the activated ions (Eu2+ ) can occupy two different types of sites (Sr1 and Sr2 ), the emission spectrum of Eu2+ excited at 350 nm contains two single bands (EM1 and EM2 ) in the wavelength range 400-550 nm, centered at 463 nm, and the emission intensity first increases and then decreases with increasing concentrations of Eu2+ ions. Co-doping of Ce3+ ions can greatly enhance the emission intensity of Eu2+ by transferring its excitation energy to Eu2+ . Because of concentration quenching, a higher substitution concentration of Ce3+ can lead to a decrease in the intensity. Meanwhile, the quantum efficiency of the phosphor is improved after doping with Ce3+ , and a blue shift phenomenon is observed in the CIE chromaticity diagram. The results indicate that Sr(1.5-x) (1.5y) Mg0.5 SiO4 :xEu2+ ,yCe3+ can be used as a potential new blue phosphor for white light-emitting diodes. PMID- 27966278 TI - Computational resources and tools for antimicrobial peptides. AB - Antimicrobial peptides (AMPs), as evolutionarily conserved components of innate immune system, protect against pathogens including bacteria, fungi, viruses, and parasites. In general, AMPs are relatively small peptides (<10 kDa) with cationic nature and amphipathic structure and have modes of action different from traditional antibiotics. Up to now, there are more than 19 000 AMPs that have been reported, including those isolated from nature sources or by synthesis. They have been considered to be promising substitutes of conventional antibiotics in the quest to address the increasing occurrence of antibiotic resistance. However, most AMPs have modest direct antimicrobial activity, and their mechanisms of action, as well as their structure-activity relationships, are still poorly understood. Computational strategies are invaluable assets to provide insight into the activity of AMPs and thus exploit their potential as a new generation of antimicrobials. This article reviews the advances of AMP databases and computational tools for the prediction and design of new active AMPs. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27966279 TI - Training and transfer effects of response inhibition training in children and adults. AB - Response inhibition is crucial for mental and physical health but studies assessing the trainability of this type of inhibition are rare. Thirty-nine children aged 10-12 years and 46 adults aged 18-24 years were assigned to an adaptive go/no-go inhibition training condition or an active control condition. Transfer of training effects to performance on tasks assessing response inhibition, interference control, working memory updating, task-switching, and non-verbal fluid intelligence were assessed during 3- and 6-month follow-up sessions and/or an immediate post-training session. Significant training improvements and positive transfer effects to a similar response inhibition task with other stimuli were observed for both children and adults. Reliable albeit short-lived transfer effects were only found for the children, specifically to working memory updating and task switching. These results suggest some potential for response-inhibition training programs to enhance aspects of cognitive functioning in children but not adults. PMID- 27966280 TI - Diminished ability to identify facial emotional expressions in children with disorganized attachment representations. AB - The development of children's ability to identify facial emotional expressions has long been suggested to be experience dependent, with parental caregiving as an important influencing factor. This study attempts to further this knowledge by examining disorganization of the attachment system as a potential psychological mechanism behind aberrant caregiving experiences and deviations in the ability to identify facial emotional expressions. Typically developing children (N = 105, 49.5% boys) aged 6-7 years (M = 6 years 8 months, SD = 1.8 months) completed an attachment representation task and an emotion identification task, and parents rated children's negative emotionality. The results showed a generally diminished ability in disorganized children to identify facial emotional expressions, but no response biases. Disorganized attachment was also related to higher levels of negative emotionality, but discrimination of emotional expressions did not moderate or mediate this relation. Our novel findings relate disorganized attachment to deviations in emotion identification, and therefore suggest that disorganization of the attachment system may constitute a psychological mechanism linking aberrant caregiving experiences to deviations in children's ability to identify facial emotional expressions. Our findings further suggest that deviations in emotion identification in disorganized children, in the absence of maltreatment, may manifest in a generally diminished ability to identify emotional expressions, rather than in specific response biases. PMID- 27966282 TI - Enzyme from an Uncultivated Sponge Bacterium Catalyzes S-Methylation in a Ribosomal Peptide. AB - Amino acid modifications are essential for the structural diversity and bioactivity of ribosomally synthesized and post-translationally modified peptide natural products (RiPPs). A particularly large and virtually untapped pool of unusual RiPPs and associated modifying enzymes is provided by uncultivated bacteria. An example is the chemically rich sponge symbiont "Candidatus Entotheonella factor", which produces the hypermodified polytheonamides of the poorly studied proteusin RiPP family. In addition to the polytheonamide genes, "E. factor" contains several further additional RiPP clusters of unknown function. Here we provide insights into one of these cryptic proteusin pathways by identifying an enzyme (PtyS) that catalyzes the S-methylation of cysteine residues. S-methylcysteine is rare in natural peptides and proteins, and the enzymatic activity was previously unknown for RiPPs, thus adding a new modification to the ribosomal peptide toolbox. PMID- 27966283 TI - Motivational Value of the Female Orgasm for Reproductive Success. PMID- 27966284 TI - Increased ventilatory response to exercise in symptomatic and asymptomatic LMNA mutation carriers: a follow-up study. AB - BACKGROUND: LMNA mutations are an important cause of cardiomyopathy often leading to cardiac arrhythmias, heart failure and even heart transplantation. An increasing number of asymptomatic mutation carriers are identified, as family members of the index patients are screened. Our aim was to study the disease progression in asymptomatic LMNA mutation carriers and in patients with symptomatic cardiolaminopathy by repeated spiroergometric testing in a prospective clinical follow-up study. METHODS AND RESULTS: We studied 26 LMNA mutation carriers once a year during 5 years up to 6 times by spiroergometry, clinical assessment, laboratory tests and echocardiography. The 23 control subjects underwent clinical assessment and spiroergometry once. Twelve of the mutation carriers were asymptomatic, and 14 had some clinical manifestations of the mutation ranging from clinically relevant rhythm disturbances to DCM and heart failure. Compared to controls, the symptomatic carriers showed a higher slope of the ventilatory equivalent for CO2 (VE/VCO2 slope) and a lower fraction of end-tidal CO2 (FetCO2 ). The asymptomatic mutation carriers also showed an increased ventilatory response to exercise during the follow-up as indicated by increased VE/VCO2 slope and decreased FetCO2 . CONCLUSIONS: The study suggests that an increased ventilatory response during exercise might reveal a preclinical manifestation of DCM in LMNA mutation carriers. PMID- 27966285 TI - Drug screening in 3D in vitro tumor models: overcoming current pitfalls of efficacy read-outs. AB - There is cumulating evidence that in vitro 3D tumor models with increased physiological relevance can improve the predictive value of pre-clinical research and ultimately contribute to achieve decisions earlier during the development of cancer-targeted therapies. Due to the role of tumor microenvironment in the response of tumor cells to therapeutics, the incorporation of different elements of the tumor niche on cell model design is expected to contribute to the establishment of more predictive in vitro tumor models. This review is focused on the several challenges and adjustments that the field of oncology research is facing to translate these advanced tumor cells models to drug discovery, taking advantage of the progress on culture technologies, imaging platforms, high throughput and automated systems. The choice of 3D cell model, the experimental design, choice of read-outs and interpretation of data obtained from 3D cell models are critical aspects when considering their implementation in drug discovery. In this review, we foresee some of these aspects and depict the potential directions of pre-clinical oncology drug discovery towards improved prediction of drug efficacy. PMID- 27966286 TI - Biocatalytic Reduction of HMF to 2,5-Bis(hydroxymethyl)furan by HMF-Tolerant Whole Cells. AB - Catalytic upgrading of 5-hydroxymethylfurfural (HMF), an important biobased platform chemical for high-value products, is currently of great interest. In this work, a new highly HMFtolerant yeast strain-Meyerozyma guilliermondii SC1103 was isolated, and biocatalytic reduction of HMF to 2,5-bis(hydroxymethyl)furan (BHMF) using its resting cells was reported. Cosubstrates exerted a significant effect on the catalytic activity and selectivity of microbial cells as well as their HMF-tolerant levels whereas the nitrogen source and mineral salts had no effects. In addition, M. guilliermondii SC1103 cells exhibited good catalytic performances within the range of pH 4.0-10.0. The yeast was highly tolerant to both HMF (up to 110 mm) and BHMF (up to 200 mm). In addition, 100 mm HMF could be selectively reduced to BHMF within 12 h by its resting cells in the presence of 100 mm glucose (as cosubstrate), with a yield of 86 % and selectivity of >99 %. The production of 191 mm of BHMF was realized within 24.5 h by using a fed-batch strategy, with a productivity of approximately 24 g L-1 per day. In addition, this new biocatalytic approach was applied for the reduction of furfural and 5 methylfurfural, affording the corresponding furfuryl alcohols with yields of 83 and 89 %, respectively. PMID- 27966288 TI - An analysis of incidental and symptomatic pulmonary embolism (PE) in medical oncology patients. AB - AIM: To determine the incidence of symptomatic versus incidental pulmonary embolism (PE) in oncology patients, characterize the nature and extent of incidental PE and the factors contributing to diagnosis. METHODS: Specialized web search engine was used to identify oncology patients with positive imaging studies for PE. PE identified at staging CT scans were classified as incidental PEs, whereas PE diagnosed by CTPA/VQ scan were classified as symptomatic PEs. RESULTS: A total of 111 patients with PE were identified over the period of three years. Of these, 67 (60%) patients had symptomatic whereas 44 (40%) patients had incidental PE. Most PEs were segmental and non-occlusive irrespective of the type of PE or stage of the disease. Incidence of PE was equal with/without chemotherapy. Platinum-based chemotherapy was more commonly associated with PE. Most patients received anticoagulation irrespective of type of PE. CONCLUSION: Forty percent of the diagnosed PEs were incidental, more common in the metastatic group. This may be due to the increased frequency of staging scans performed in patients with metastatic disease, as well as the inherent disease biology of metastatic compared with localized disease. Further prospective analysis of survival by PE subtype and optimal length of anticoagulation in incidental PE is warranted. PMID- 27966287 TI - Transoral laser microsurgery versus radiation therapy in the management of T1 and T2 laryngeal glottic carcinoma: which modality is cost-effective within the UK? AB - OBJECTIVES: To identify the most cost-effective treatment strategy in patients with early stage (T1 and T2) cancers of the laryngeal glottis. DESIGN: A Markov decision model populated using data from updated systematic reviews and meta analyses, with attributable costs from NHS sources. Data on local control and mortality were obtained from updates of existing systematic reviews conducted for the NICE guideline on cancer of the upper aerodigestive tract. Procedure costs were sourced from NHS reference costs 2013/14 by applying tariffs associated with the appropriate health resource group code SETTING: The UK National Health Service. POPULATION: Patients with early stage (T1 and T2) cancers of the laryngeal glottis. INTERVENTIONS: Transoral laser microsurgery (TLM) and radiation therapy (RT). MAIN OUTCOME MEASURES: Total costs, incremental costs and quality adjusted life years (QALYs) over a 10-year time horizon. RESULTS: Radiation therapy as the initial treatment strategy was found to be more expensive (L2654 versus L623) and less effective (QALY reduction of 0.141 and 0.04 in T1a and T1b-T2 laryngeal cancers, respectively) than TLM. The dominance of TLM for T1a cancers was unchanged in most scenarios modelled in sensitivity analysis. For T1b-T2 laryngeal cancers, the result changed in numerous scenarios. In probabilistic sensitivity analysis, TLM was found to have a 71% and 58% probability of being cost-effective in T1a and T1b-T2 laryngeal cancers, respectively. CONCLUSIONS: Transoral laser microsurgery is a cost-effective strategy to adopt in the management of T1a laryngeal cancers. Uncertainty remains over the optimal strategy to adopt in T1b-T2 laryngeal cancers. PMID- 27966290 TI - Chemical and Photochemical Water Oxidation Mediated by an Efficient Single-Site Ruthenium Catalyst. AB - Water oxidation is a fundamental step in artificial photosynthesis for solar fuels production. In this study, we report a single-site Ru-based water oxidation catalyst, housing a dicarboxylate-benzimidazole ligand, that mediates both chemical and light-driven oxidation of water efficiently under neutral conditions. The importance of the incorporation of the negatively charged ligand framework is manifested in the low redox potentials of the developed complex, which allows water oxidation to be driven by the mild one-electron oxidant [Ru(bpy)3 ]3+ (bpy=2,2'-bipyridine). Furthermore, combined experimental and DFT studies provide insight into the mechanistic details of the catalytic cycle. PMID- 27966289 TI - An epidemiological study of avian influenza A (H5) virus in nomadic ducks and their raising practices in northeastern Bangladesh, 2011-2012. AB - BACKGROUND: In Bangladesh, nomadic duck flocks are groups of domestic ducks reared for egg production that are moved to access feeding sites beyond their owners' village boundaries and are housed overnight in portable enclosures in scavenging areas. The objectives of this study were to measure the prevalence of influenza A virus RNA and H5-specific antibodies in nomadic ducks and to characterize nomadic duck raising practices in northeastern Bangladesh. METHODS: We tested duck egg yolk specimens by competitive ELISA to detect antibodies against avian influenza A (H5) and environmental fecal samples by real-time reverse-transcription polymerase chain reaction (rRT-PCR) to detect influenza A virus RNA and H5 subtype. RESULTS: The median age of the ducks was 24 months (range: 8-36 months) and the median flock size was 300 ducks (range: 105-1100). Of 1860 egg yolk samples, 556 (30%, 95% confidence interval (CI): 28-32) were positive for antibodies against H5 and 58 flocks (94%) had at least one egg with H5-specific antibodies. Of 496 fecal samples, 121 (24%, 95% CI: 22-29) had detectable influenza A RNA. Thirty-three flocks (53%) had at least one fecal sample positive for influenza A RNA. CONCLUSIONS: Nomadic ducks in Bangladesh are commonly infected with avian influenza A (H5) virus and may serve as a bridging host for transmission of avian influenza A (H5) virus or other avian influenza A viruses subtypes between wild waterfowl, backyard poultry, and humans in Bangladesh. PMID- 27966291 TI - Estimated Time to Complete Direct Nursing Interventions Using the Nursing Interventions Classification (NIC) at Eight Hospitals in South Korea. AB - BACKGROUND: Without data on the average time for performing nursing interventions, it is not possible to identify the cost-effective nursing practices, nurse staffing levels, and skill mix that are associated with improved patient outcomes, nor can reimbursement rates be accurately determined. PURPOSE: The purpose of this study was to estimate the time needed to perform direct nursing interventions in Korea using the Nursing Interventions Classification (NIC) system, and then compare the findings with time estimates made by U.S. nurses. METHODS: Data were collected from 721 registered nurses working in eight hospitals in South Korea. Each nurse was asked to choose the 30 most frequently used direct nursing interventions from a list of 433 from the Korean version of the NIC and to estimate the time needed to perform their selections. The U.S. data from the second edition of NIC were used for comparative purposes. RESULTS: Among the 92 nursing interventions studied, the majority were in the physiological domain, with 46 (50%) in Physiological: Basic and 25 (27%) in Physiological: Complex. In Korea, the intervention reported as taking the shortest time was Tube Care: Umbilical Line, while the intervention reported as taking the longest time was Bowel Irrigation. Comparisons of the time to perform interventions in the two countries indicated that only 38 (41.3%) interventions are performed in 15 min or less in both countries. Of the remainder, six interventions showed considerable variation in time to perform between the two countries. CONCLUSION AND IMPLICATION: Findings from the study will provide fundamental data for calculating the cost of nursing interventions, which is critical for the establishment of reimbursement rates for interventions provided. PMID- 27966292 TI - Out-of-pocket medical costs and third-party healthcare costs for children with Down syndrome. AB - Prior analyses have estimated the lifetime total societal costs of a person with Down syndrome (DS); however, no studies capture the expected medical costs that patients with DS can expect to incur during childhood. The study utilized the OptumHealth Reporting and Insights administrative claims database from 1999 to 2013. Children with a diagnosis of DS were identified, and their time was divided into clinically relevant age categories. Patients with DS in each age category were matched to controls without chromosomal conditions. Out-of-pocket medical costs and third-party expenditures were compared between the patient-age cohorts with DS and matched controls. Patients with DS had significantly higher mean annual out-of-pocket costs than their matched controls within each age and cost category. Total annual incremental out-of-pocket costs associated with DS were highest among individuals from birth to age 1 ($1,907, P < 0.001). The main drivers of the incremental out-of-pocket costs associated with DS were inpatient costs in the 1st year of life ($925, P < 0.001) and outpatient costs in later years (ranging $183-$623, all P < 0.001). Overall, patients with DS incurred incremental out-of-pocket medical costs of $18,248 between birth and age 18 years; third-party payers incurred incremental costs of $230,043 during the same period. Across all age categories, mean total out-of-pocket annual costs were greater for individuals with DS than those of matched controls. On average, parents of children with DS pay an additional $84 per month for out-of-pocket medical expenses when costs are amortized over 18 years. (c) 2016 Wiley Periodicals, Inc. PMID- 27966293 TI - Behcet syndrome: the vascular cluster. AB - Although skin-mucosa lesions are common in almost all patients with Behcet syndrome (BS), clinical properties may differ from one patient to another. Within BS, there are subsets with different organ involvement and hence probably different pathological pathways. These subsets can be described as a) solo skin mucosa disease with no major organ involvement, b) eye disease, c) seronegative spondyloarthropathy-like disease (arthritis, enthesopathy, and folliculitis), d) Crohn-like disease, and finally the topic of this chapter: e) vascular disease. In the vascular disease subset, not surprisingly, several types of vascular involvement may be observed in the same individual. These subsets may make up the total clinical picture all at the same time or step by step with each relapse. Significant correlations exist between cerebral vascular thrombosis and pulmonary artery involvement, intracardiac thrombi and pulmonary artery involvement, Budd Chiari syndrome, and inferior vena cava syndrome. Lower extremity vein thrombosis is often present in these associations and even precedes them. The recognition of these clusters is not only important in diagnosis and management but also in basic science, including genetic studies. PMID- 27966294 TI - The association of vaspin rs2236242 and leptin rs7799039 polymorphism with metabolic syndrome in Egyptian women. AB - BACKGROUND/AIM: Genetic predisposition is implicated in the etiology of metabolic syndrome. This study aimed to investigate the1397645907association of vaspin rs2236242 and leptin rs7799039 polymorphisms with their serum levels and with the risk of developing metabolic syndrome in Egyptian women. MATERIALS AND METHODS: This case control study included 100 Egyptian women with metabolic syndrome and 100 without metabolic syndrome. The genotypes of vaspin rs2236242 and leptin rs7799039 were detected by a methodology based on PCR-RFLP. Serum vaspin and leptin levels were determined by ELISA. RESULTS: The metabolic syndrome group was associated with higher serum vaspin and leptin levels when compared to the nonmetabolic syndrome group. The AA genotype of leptin rs7799039 was associated with metabolic syndrome and with higher serum leptin levels, while the different genotypes of vaspin rs2236242 were not associated with metabolic syndrome or different serum vaspin levels. CONCLUSION: The AA genotype of leptin rs7799039 was associated with metabolic syndrome and higher serum leptin levels . Serum leptin and vaspin can be used as diagnostic markers of metabolic syndrome. PMID- 27966295 TI - The impact of calcineurin inhibitors and mammalian target of rapamycininhibitors on anxiety and depression scores in kidney transplant patients. AB - BACKGROUND/AIM: Depression and anxiety are prevalent symptoms in kidney transplant patients. We aimed to evaluate the frequency and the severity of depression and anxiety symptoms in kidney transplant recipients using the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). The data were compared between the patients on CNI-based and mTORi-based maintenance immunosuppressive regimens. MATERIALS AND METHODS: A total of 94 kidney transplant patients were enrolled in the study after exclusion of the patients already taking neuropsychiatric medications or unwilling to participate in the study. Participants were asked to self-report the inventories. RESULTS: Analysis of data showed that 62 (66%) recipients had BDI scores that indicated depression. The patients on CNI-based regimens (n = 74) had increased total BDI scores compared those on mTORi-based regimens [18 (8.75-28) vs. 6 (5.25-14.25), respectively, P < 0.001]. Regarding BAI scores, 79 patients (84%) had prominent anxiety symptoms. The patients on CNI-based regimens had significantly increased total BAI scores compared to those on mTORi-based regimens [21 (13-30.50) vs. 10.50 (8.25-14.75), respectively, P < 0.001]. CONCLUSION: Our results identified fewer side effects of mTORi-based maintenance immunosuppressive regimens regarding depression and anxiety symptoms compared to CNI-based regimens in kidney transplant patients. PMID- 27966296 TI - Interlukine-17 and TGF-beta levels in patients with acute brucellosisbefore and after treatment. AB - BACKGROUND/AIM: T-helper cell type 1 (Th1)/Th2 cytokine balance is involved in the resistance or susceptibility to Brucella infection. The analysis of cytokine levels is valuable to determine the role of the immune system in Brucella prognosis. The aim of this study was to investigate the levels of serum interleukin-17 (IL-17) and transforming growth factor beta (TGF-beta) and their alterations with treatment in patients with acute brucellosis. MATERIALS AND METHODS: TGF-beta was tested in 33 acute brucellosis patients and 19 controls and IL-17 was analyzed in 40 patients and 12 controls. Cytokine levels were tested in controls and patients before and after treatment by ELISA. RESULTS: TGF-beta levels were significantly lower in brucellosis cases compared to controls. At the end of the treatment, the serum levels of this cytokine had increased, but there was no significant difference between this cytokine level before and after treatment. The IL-17 level was significantly higher in the brucellosis group compared to controls and its value decreased in patients at the end of treatment without any significant difference. CONCLUSION: This study indicated that TGF beta was lower and IL-17 was higher in brucellosis cases and, after treatment, the serum level of TGF-beta increased and that of IL-17 decreased in these patients. PMID- 27966297 TI - The role of apelin in the assessment of response to chemotherapyand prognosis in stage 4 nonsmall cell lung cancer. AB - BACKGROUND/AIM: Prediction of response to chemotherapy and prognosis bears clinical significance in patients with lung cancer. The aim of the study was to examine the association between apelin expression in tumor tissues and overall survival, progression-free survival, chemoresistance, and treatment response in stage 4 nonsmall cell lung cancer (NSCLC) patients undergoing chemotherapy. MATERIALS AND METHODS: A total of 81 patients who received chemotherapy due to a biopsy-documented diagnosis of NSCLC between 2004 and 2011 were retrospectively studied. Bronchoscopic biopsy samples were examined immunohistochemically. RESULTS: Of the overall study population (n = 81), the mean age was 59.0 +/- 9.2 years; 83% (n = 67) were male and 17% (n = 14) were female. All patients received chemotherapy. A total of 30 patients (37%) had no apelin positivity, while 21 (30%) had 1 +, 20 (25%) had 2 +, and 10 (12%) had 3 + apelin positivity. We detected no association between apelin positivity and overall survival, 6-month survival, or 1-year survival rates (P = 0.05, 0.74, and 0.63). Patients with apelin expression as compared to those without it had shorter overall survival (P = 0.05). CONCLUSION: Our results suggest that apelin, an angiogenic factor, does not seem to provide significant prognostic information in this patient group. PMID- 27966298 TI - Differentiated thyroid cancer in patients with prolactinoma. AB - BACKGROUND/AIM: Increasing evidence is available about the role of prolactin in the development of various cancers. The purpose of this study is to evaluate the frequency of thyroid cancer in patients with prolactinoma followed at a single site. MATERIALS AND METHODS: The medical records of 182 patients diagnosed with prolactinoma were reviewed retrospectively. Serum prolactin, antithyroglobulin, antithyroid peroxidase antibody, thyroid-stimulating hormone, free T4, and free T3 values and pituitary gland magnetic resonance imaging and thyroid ultrasound reports were evaluated. RESULTS: Forty-five (39.5%) patients were found to have a thyroid nodule (13 solitary, 32 multiple). Ten patients were administered a thyroidectomy, and differentiated thyroid cancer (DTC) was detected in 6 of these patients (6/114, 5.3%). One patient had lung metastasis. The control group consisted of 113 individuals (101 females, 12 males with a mean age of 32.1 +/- 9.1). In the ultrasound reports, 28 of these individuals (24.8%) had a thyroid nodule (5 solitary, 23 multiple), and one individual (1/113, 0.8%) had DTC. CONCLUSION: When compared to the control group, thyroid volume and thyroid nodularity were significantly higher in patients with prolactinoma (P < 0.001, P = 0.018, respectively); however, no statistically significant difference existed for the incidence of thyroid cancer (P = 0.196). PMID- 27966300 TI - Relationship between gestational transient thyrotoxicosis and vitamin D. AB - BACKGROUND/AIM: Gestational transient thyrotoxicosis (GTT) is a transient, mild hyperthyroidism that occurs early in pregnancy and is due to human chorionic gonadotropin. There is no clear information about why only some pregnant women develop GTT. Previous papers stated that vitamin D plays a role in thyroid functions. We aimed to evaluate the relationship between vitamin D and GTT. MATERIALS AND METHODS: Fifty-three patients diagnosed with GTT at the 6th to 10th weeks of gestation were included in the study (GTT group). Thirty-five pregnant women with normal thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) levels served as a control group. Vitamin D, TSH, fT3, and fT4 levels were followed during entire the pregnancy. RESULTS: TSH levels had been normalized at the 20th week of gestation in all patients with GTT (mean TSH: 0.56 +/- 0.2 MUIU/mL). Vitamin D levels were significantly lower in the GTT group than the controls (11.1 +/- 7.7 and 16.5 +/- 0.5 ng/mL, respectively; P = 0.008). CONCLUSION: Pregnant women who are diagnosed with GTT should be evaluated for possible vitamin D deficiency. PMID- 27966299 TI - Cognitive impairment one year after ischemic stroke: predictorsand dynamics of significant determinants. AB - BACKGROUND/AIM: Evidence suggests that the risk for dementia increases after stroke. This study investigated the dynamics of the neurological and cognitive status of patients with no baseline dementia over a 1-year period after ischemic stroke. MATERIALS AND METHODS: We examined 47 ischemic stroke patients admitted within 48 h of ictus. Their neurological and cognitive statuses, blood biochemical parameters, and microalbuminuria levels were prospectively evaluated over a 1-year period post-stroke. RESULTS: A more severe neurological deficit was found in the cognitively impaired patients (P = 0.003). The NIHSS score over a 1 year follow-up period improved only in patients with normal cognition (P = 0.000). Time-varying dynamics of the MMSE score were observed in both patient groups (P = 0.000). Age (R = 0.000), education (R = 0.004), sex (R = 0.041), history of diabetes (R = 0.045), and serum high sensitive C-reactive protein (hs CRP) on admission (R = 0.003) were significant determinants of cognitive decline 1 year after a stroke. The albumin-to-creatinine ratio was high during the whole follow-up period in the cognitively impaired group after adjusting for sex and age (P = 0.010). Binary logistic regression showed that hs-CRP (R = 0.013) and age (R = 0.010) were independent predictors of patients' cognitive status 1 year after stroke. CONCLUSION: The level of inflammatory markers could be considered as an additional criterion of long-term cognitive impairment. PMID- 27966301 TI - Colistin efficacy in the treatment of multidrug-resistant and extremelydrug resistant gram-negative bacterial infections. AB - BACKGROUND/AIM: Colistin is used as a salvage therapy for multidrug-resistant and extremely drug-resistant gram-negative bacterial infections. Our aim was to evaluate colistin efficiency and toxicity in the treatment of these resistant gram-negative bacterial infections. MATERIALS AND METHODS: This is a retrospective study carried out in a tertiary care hospital during 2011-2013. Study data were collected from the medical records and consultations of the infectious diseases clinic. RESULTS: The study group included 158 patients with nosocomial infections and 136 (86.1%) of them were hospitalized in the ICU. Respiratory tract infections were the most commonly observed ones (n = 103, 65.2%). The most frequently isolated microorganism was Acinetobacter baumannii (72.2%). A total of 98 (62.0%) patients had clinical cure. There was no statistically significant difference between monotherapy (n = 3/6, 50.0%) and combination therapies (n = 95/152, 62.5%) according to clinical response. Underlying ultimately fatal disease, previous renal disease, and total parenteral nutrition were independent risk factors for poor clinical response. Nephrotoxicity developed in 80 (50.6%) patients and clinical cure was statistically unrelated with nephrotoxicity. CONCLUSION: Colistin may be used as an effective agent for multidrug-resistant and extremely drug-resistant gram negative bacterial infections with close monitoring of renal functions, especially for older and critically ill patients. PMID- 27966302 TI - Cost analysis and evaluation of nosocomial infections in intensive care units. AB - BACKGROUND/AIM: The purpose of this study was to evaluate nosocomial infections occurring in our hospital intensive care units (ICUs) and the risk factors for these, and to determine the effect of these infections on mortality and cost. MATERIALS AND METHODS: This retrospective study was performed via infection control committee surveillance data, ICU records, and information processing data between 1 January and 31 December 2013 at the Kanuni Education and Research Hospital. RESULTS: A total of 309 nosocomial infections were observed in 205 out of 566 patients. The density of nosocomial infections was 25.4 in 1000 patient days. Hospitalization was prolonged, and APACHE II and Charlson comorbidity scores were high in patients developing nosocomial infections (P < 0.001). Of the patients diagnosed with a nosocomial infection, 170 died. Infections were determined as the cause of death in 62 (36.5%) of the nonsurviving patients with a nosocomial infection. Acinetobacter baumannii was identified in 46 (74.2%) of the patients that died from nosocomial infections. The mean cost in patients developing a nosocomial infection was 15,229.30 Turkish lira (TL), compared to 9648.00 TL in patients without a nosocomial infection (P = 0.002). CONCLUSION: Regular infection control education sessions need to be held and the number of nurses needs to be increased in order to be able to reduce this high mortality, morbidity, and cost. PMID- 27966303 TI - Examination of factors affecting women's barrier perception to participate in breast cancer screenings in a region affiliated with a family health center in Turkey. AB - BACKGROUND/AIM: This study was conducted in order to determine the factors related to women's barrier perception to participate in breast cancer screenings in a region affiliated with a family health center. MATERIALS AND METHODS: The study was a cross-sectional study. The sample group of the study consisted of 300 women. Descriptive statistics, t test, and Mann-Whitney U test were performed for the analysis of the data. RESULTS: Breast self-examination (BSE) and mammography barrier perception mean score of those who were illiterate in terms of educational status, and BSE and mammography barrier perception mean score of those who were single in terms of marital status were determined to be significantly higher (P < 0.05). No significant difference was found between BSE and mammography barrier perception mean scores of those who had no health insurance and lived in a district or a village (P > 0.05). CONCLUSION: Demographic factors as well as factors such as women's knowledge on early diagnosis of breast cancer and previous experiences in participation in early diagnosis behaviors of breast cancer could affect the barrier perception. PMID- 27966304 TI - Chronic liver diseases and iron: a concise review with emphasis on hypotransferrinemia and hypohepcidinemia. AB - Iron studies in chronic liver diseases (CLDs) have a long history. Currently we can mention certainties, uncertainties, and hopes related to this topic. It is certain that iron metabolism problems and hepatic siderosis are frequent in CLDs and they get more frequent as CLD progresses, but true iron overload is rare. There are conflicting literature data on the mechanism of siderosis, the role of iron in CLD pathogenesis, and the potential benefits of iron removal. We may hope that pharmacological approaches targeting iron metabolism disorders of CLD will be actively evaluated in the future. In this review, we aimed to present a general outlook of this extensively studied topic. PMID- 27966305 TI - Efficacy of mitomycin-C and infliximab in reducing adhesionand fibrosis following strabismus surgery. AB - BACKGROUND/AIM: The present study aimed to investigate the efficacy of mitomycin C (MMC) and infliximab (INF) in reducing adhesion and fibrosis following strabismus surgery. MATERIALS AND METHODS: Forty eyes of 20 albino rabbits were separated into MMC and INF groups. Right and left eyes of rabbits were assigned to the drug and control groups, respectively. The superior rectus muscle was disinserted, the drug was administered to the surgical area for 5 min in the drug eyes (MMC 0.2 mg/mL or INF 5 mg/mL), and physiological saline was administered to the control eyes. Surgical areas were rinsed with 10 mL of physiological saline. The disinserted muscle was then sutured to the same area using 6.0 Vicryl. The rabbits were sacrificed after 4 weeks for histopathological examination. RESULTS: Significant reduction was observed in fibrosis in the INF group as compared to the control group (P = 0.005). Although adhesion formation in the drug eyes reduced in the MMC and INF groups as compared to the control group, the difference was not significant (P = 0.280 and P = 0.579, respectively). CONCLUSION: This study demonstrated the fibrosis-preventing efficacy of IFN; thus, it can be a good option in reducing fibrosis in strabismus surgery. PMID- 27966306 TI - The efficacy of oral ribavirin on clinical and laboratory parameters inCrimean Congo hemorrhagic fever: an observational study from Turkey. AB - BACKGROUND/AIM: In this observational study, the effects of oral ribavirin on clinical and laboratory parameters and blood products use in patients with Crimean-Congo hemorrhagic fever (CCHF) were evaluated. MATERIALS AND METHODS: CCHF patients (n = 100) who were hospitalized between 2007 and 2010 were included. Oral ribavirin was administered to 56 patients with symptom duration less than 5 days. Forty-four patients did not receive ribavirin (control group). The patients that received ribavirin in the first 3 days following the initiation of symptoms were designated as Group 1 (n = 29) and the others were designated as Group 2. RESULTS: Ribavirin-treated and untreated groups were similar in terms of demographic and most clinical characteristics. Leukocyte and platelet counts were lower in the ribavirin group than in the control group, but values of prothrombin time, activated partial thromboplastin time, aspartate aminotransferase, creatinine phosphokinase, and lactate dehydrogenase were higher (P = 0.011, P = 0.015, P = 0.001, P = 0.001, P = 0.021, P = 0.019, P = 0.004, respectively). Platelet concentrates use was greater in the ribavirin group (P = 0.01). CONCLUSION: No positive effects of oral ribavirin on blood products use or clinical or laboratory parameters of CCHF patients were observed. Moreover, no difference was shown between early and late initiation of ribavirin. PMID- 27966307 TI - The effects of sebum configuration on Demodex spp. density. AB - BACKGROUND/AIM: Demodex spp. are ectoparasites living in the pilosebaceous units, which feed on the host's sebum and cellular proteins. The protective barrier of the skin consists of sebum secretion, moisture, and the acid mantle. In this study, we aimed to determine the effects of skin sebum, moisture, pH levels, and sebum configuration on Demodex spp. density. MATERIALS AND METHODS: Forty-five patients who had demodicosis were enrolled in the study group, while the control group consisted of 40 subjects without demodicosis. Body fat percentage, serum triglyceride and cholesterol levels, skin sebum, moisture, and pH levels were measured. Demodex spp. density was determined with a standardized skin surface biopsy. Sebum samples were taken from the forehead and a high-performance thin layer chromatography (HPTLC) method was performed on these samples. Subsequently, densitometric analyses were applied to the HPTLC plates. RESULTS: Demodex spp. were found on the cheeks and lived in an alkali environment. Skin sebum and moisture levels were low in all groups. The skin pH levels and cholesterol ester in the sebum configuration were determined to be significantly higher in the group with demodicosis. CONCLUSION: We suggest that Demodex spp. may use cholesterol ester in the sebum as nutriment. In other words, cholesterol ester may be a suitable growth medium for the proliferation of Demodex spp. PMID- 27966308 TI - Serum procalcitonin and C-reactive protein kinetics as indicators of treatmentoutcome in hospitalized patients with community-acquired pneumonia. AB - BACKGROUND/AIM: There has been growing interest in the use of serum procalcitonin (PCT) and C-reactive protein (CRP) in patients with community-acquired pneumonia (CAP). The aim of this study was to investigate whether an assessment of fever, leukocyte count, and serum CRP and PCT levels on admission and during follow-up (day 3) provides any information about the clinical outcome in hospitalized patients with CAP. MATERIALS AND METHODS: Patients with a diagnosis of CAP who were admitted to and followed at four university hospitals were evaluated retrospectively using the Turkish Thoracic Society Pneumonia Database. RESULTS: A total of 103 hospitalized CAP patients (57 males, mean age: 61.5 +/- 16.7 years) were enrolled in the study. Treatment failure (TF) was observed in 20 patients (19.4%). Pneumonia Severity Index scores, serum CRP levels, and PCT levels on admission were significantly higher in the TF group. There were significant decreases in CRP and PCT levels between admission day and day 3 in the treatment success group. CONCLUSION: In patients with CAP, the body temperature and leukocyte count on admission do not predict outcome. Monitoring levels of CRP and PCT may be useful as a predictor of treatment outcome. PMID- 27966309 TI - Comparison of ultrasonographic and laboratory findings of acute cholecystitis between elderly and nonelderly patients. AB - BACKGROUND/AIM: The incidence of acute cholecystitis (AC) increases with age, and aging is also one of the poor prognostic factors. Aging is related to altered physiology, so diseases may show different characteristics in elderly patients. We aimed to investigate the differences between the main characteristic features of AC in elderly and nonelderly patients. MATERIALS AND METHODS: In this retrospective study, patients who had a diagnosis of AC were included and divided into two groups of people aged <65 years or >65 years. Laboratory and ultrasonographic findings related to AC were compared statistically between elderly and nonelderly patients. RESULTS: The data of 305 patients diagnosed with AC were recorded. Patients in the nonelderly group were more likely to be female, but in elderly patients the sex distribution was similar. There were no significant differences with respect to liver function tests and ultrasonographic findings at the time of admission between the elderly and nonelderly groups. However, the elderly group had a significantly higher rate of patients with an elevated white blood cell count and higher C-reactive protein values than the nonelderly group. CONCLUSION: Aging is related to altered immunologic and pathophysiologic processes. Thus, age and baseline comorbidities influence overall mortality rates. Efforts should be made to understand disease mechanisms and minimize avoidable harms. PMID- 27966310 TI - Lung transplantation in Turkey: lessons from surgeons and pulmonologists. AB - BACKGROUND/AIM: In order to actualize an efficient lung transplantation program, it is necessary to determine priorities and set up strategies. This study aimed to estimate the present situation in Turkey by determining the level of interest and knowledge of pulmonologists and thoracic surgeons regarding lung transplantation. MATERIALS AND METHODS: A questionnaire was prepared to establish the level of interest and knowledge of physicians on lung transplantation. It was sent to 2131 pulmonologists and thoracic surgeons, and 130 physicians completed the questionnaire. RESULTS: Of the 130 physicians who responded, 42 were thoracic surgeons and 88 were pulmonologists. There was no significant difference between the two groups regarding the availability of lung transplantation at their hospitals. The rates of correct answers to the questions and responses supporting the transplant initiative were higher in the thoracic surgeon group than in the pulmonologist group. CONCLUSION: The establishment of a successful system for lung transplantation in Turkey requires an increase in interest, knowledge, and dedication of physicians, coupled with adequate and continuous training. There also needs to be sufficient equipment and financing in addition to disciplined multidisciplinary teams and cooperation. This survey shows there is still much work to be done to achieve success in lung transplantation in Turkey. PMID- 27966311 TI - The increasing incidence of esophageal squamous cell carcinoma in women in Turkey. AB - BACKGROUND/AIM: This study assessed the trend changes in the histological types of esophageal cancer in a 25-year period in eastern Turkey. MATERIALS AND METHODS: We searched all cases of esophageal cancer from 1990 to 2015 according to their histological diagnosis and sex, grouping the patients in 5-year time periods to evaluate time trends. RESULTS: We identified 1462 cases of esophageal cancer. In terms of patient make-up, 742 were male and 720 were female. In general, 75.86% of the patients had squamous cell carcinoma (SCC), 19.56% of the patients had adenocarcinoma (ADC), and the remaining 4.58% patients were found to have other histopathologic disorders. While the SCC to ADC ratio was 1.76 between 1990 and 1994, this rate increased to 8.73 between 2010 and 2014; during these periods, the male to female ratio decreased from 1.43 to 0.86. Between these two periods, statistically significant changes were observed of SCC and the number of female patients (P < 0.001, P = 0.008, respectively). CONCLUSION: While the incidence of esophagus ADC and the number of male patients increased recently in Western countries, the number of female patients and SCC cases increased in our region in the last 25 years. PMID- 27966312 TI - The common genetic variants of toll-like receptor and susceptibilityto adenoid hypertrophy: a hospital-based cohort study. AB - BACKGROUND/AIM: Adenoid hypertrophy (AH) is one of the most frequent pediatric disorders. The aim of this study was to investigate the effects of TLR2-R753Q, TLR4-T399I, and TLR4-D299G polymorphisms in children with AH. MATERIALS AND METHODS: The variants of the TLR gene were determined by restriction fragment length polymorphism (PCR-RFLP) analysis in 60 patients with AH and in 50 healthy children. Data were analyzed with SNPStats and multifactor dimensionality reduction (MDR) software. RESULTS: We found that the presence of the G allele, the AG+GG and AG genotypes at TLR4-D299G, and the GGT haplotype were associated with AH in children (P = 0.013, P = 0.02, P = 0.038, and P = 0.001, respectively). On the contrary, no association was found between TLR2-R753Q and predisposition to AH. The CT genotype at TLR4-T399I showed a sex-specific association with AH, occurring only in boys with allergies (P = 0.0048). In addition, MDR analysis indicated a strong synergy between TLR gene markers contributing to AH. Allergic children with the diplotypes that included minor alleles of TLR4-D299G or TLR4-T399I had about a 4-fold increased risk for AH. CONCLUSION: Common genetic variants of the gene encoding the TLR4 protein may have differential effects on AH and the presence of sex-specific allergy. PMID- 27966313 TI - Neurological outcome after cardiac arrest: a prospective study of the predictive ability of prognostic biomarkers neuron-specific enolase, glial fibrillary acidic protein, S-100B, and procalcitonin. AB - BACKGROUND/AIM: Factors affecting neurological outcome and the usefulness of neuron-specific enolase (NSE), S-100B, glial fibrillary acidic protein (GFAP), and procalcitonin (PCT) in predicting neurological outcomes were assessed in patients who survived at least 24 h after cardiopulmonary resuscitation (CPR). MATERIALS AND METHODS: Thirty successfully resuscitated cardiac arrest patients were included in this prospective clinical study. The initial cardiac arrest rhythm, duration of CPR, return of spontaneous circulation time, administered doses of adrenaline, base excess, blood sugar, and hemodynamic parameters were recorded. Patients with Glasgow Outcome Scale (GOS) scores of 1-3 were defined as Group I and patients with GOS scores of 4-5 were defined as Group II. Serum NSE, GFAP, S-100B, and PCT levels were compared between the two groups shortly after CPR (hour 0) and at hours 12 and 24 of the postresuscitation period. RESULTS: Serum S-100B was significantly higher (P = 0.009) in Group II immediately after CPR. Serum S-100B and NSE after CPR at hours 0, 12, and 24 were significantly lower in patients who survived to hospital discharge. Serum PCT at hours 12 and 24 and serum S-100B after CPR at 0, 12, and 24 h reached 94.7% sensitivity. Serum NSE, GFAP, S-100B, and PCT specificities were lower than 50%. CONCLUSION: In predicting neurological outcomes, serum S-100B has high sensitivity and low specificity immediately after CPR. PMID- 27966314 TI - Factors affecting treatment success in community-acquired pneumonia. AB - BACKGROUND/AIM: Treatment failure in hospitalized patients with community acquired pneumonia is a major cause of mortality. The aim of this study was to evaluate the factors affecting treatment success in community-acquired pneumonia. MATERIALS AND METHODS: A total of 537 patients (mean age: 66.1 +/- 15.8 years, 365 males) registered to the Turkish Thoracic Society Pneumonia Database were analyzed. Of these, clinical improvement or cure, defined as treatment success, was achieved in 477, whereas 60 patients had treatment failure and/or died. RESULTS: Lower numbers of neutrophils (5989.9 +/- 6237.3 vs. 8495.6 +/- 7279.5/mm3), higher blood urea levels (66.1 +/- 42.1 vs. 51.2 +/- 38.2 mg/dL), higher Pneumonia Severity Index (PSI) scores (123.3 +/- 42.6 vs. 96.3 +/- 32.9), higher CURB-65 scores (2.7 +/- 1.2 vs. 2.2 +/- 0.9), lower PaO2/FiO2 ratios (216.3 +/- 86.8 vs. 269.9 +/- 65.6), and the presence of multilobar (33.3% vs. 16.4%) and bilateral (41.7% vs. 18.9%) radiologic infiltrates were related to treatment failure. The PSI score and PaO2/FiO2 ratio were independent parameters affecting treatment results in multivariate linear regression analysis (P < 0.001). CONCLUSION: The risk of treatment failure is high in patients with severe pneumonia and with respiratory failure. Effective treatment and close monitoring are required for these cases. PMID- 27966315 TI - The relationship of mean platelet volume with retinopathy in type 2 diabetes mellitus. AB - BACKGROUND/AIM: Patients with diabetes mellitus have an increased risk of developing micro- and macrovascular complications. Retinopathy is one of the most important complications of diabetes whose pathophysiological cause has not yet been determined. One candidate may be platelet volume. In this study we aimed to investigate the association between mean platelet volume and diabetic retinopathy. MATERIALS AND METHODS: Mean platelet volume levels were investigated in type 2 diabetic patients with and without retinopathy, and in healthy participants. After reclassifying our diabetics in terms of the presence or absence of hypertension and hyperlipidemia, we compared their mean platelet volumes. We then checked to see if the mean platelet volume correlated with hemoglobin A1c and body mass index. RESULTS: The mean platelet volume levels were higher in all diabetic patients, and they were highest in diabetics with retinopathy. The mean platelet volume levels were not different in diabetic patients with and without hypertension or hyperlipidemia. Moreover, the mean platelet volume levels did not correlate with hemoglobin A1c or body mass index. CONCLUSION: We think that platelets may play a role in diabetic retinopathy. We can also say that, in diabetic patients, hypertension, hyperlipemia, obesity, and control of diabetes were not related to mean platelet volume. PMID- 27966316 TI - Evaluation of cutaneous anthrax cases during an outbreak in the east region of Turkey. AB - BACKGROUND/AIM: Anthrax is a zoonotic infection caused by Bacillus anthracis. We aimed to retrospectively evaluate cutaneous anthrax cases that occurred during an outbreak in eastern Turkey (Hakkari-Yuksekova), where people mostly earn their living from animal husbandry. MATERIALS AND METHODS: Forty-six cutaneous anthrax patients that were admitted to the hospital during a very short duration of 3 months (June-August 2011) were evaluated. RESULTS: Out of 46 patients, 27 (52%) were women and 19 (48%) were men. The mean age was 37 +/- 13 years. The distribution of occupations was 1 butcher, 1 cook, 5 farmers, 27 housewives, 11 shepherds, and 1 teacher. Multiple lesions were seen in 7 patients (15%) and the rest of the patients had only 1 lesion. We observed significant clinical differences among the cases and noted which particular symptoms were associated with the various skin lesions. We treated our patients with intramuscular procaine penicillin or oral ciprofloxacin/doxycycline. CONCLUSION: Anthrax is an important health problem that can cause lethal outbreaks. Therefore, one should think about anthrax when faced with a patient with history of animal contact that has a painless ulcer with edema and/or vesicles, especially in endemic countries like Turkey. PMID- 27966317 TI - Health-related quality of life of pediatric renal transplant recipientsand their parents: the role of associated factors and clinical counseling. AB - BACKGROUND/AIM: This study evaluates the health-related quality of life (HRQoL) of pediatric renal transplant recipients and their parents and investigates the effects of clinical, socioeconomic, and psychological factors as well as continuous counseling on the HRQoL. MATERIALS AND METHODS: Patients aged 8-17 years (mean: 14.9 +/- 2.9) were enrolled. Clinical and demographic data were noted. The Beck Depression Inventory (BDI), Rosenberg Self-Esteem Scale (RSES), and Turkish version of the Kinder Lebensqualitat Fragebogen (KINDL) questionnaire for children and the BDI, RSES, parent-proxy version of KINDL, and Short-Form 36 (SF-36) for parents were applied (step 1). Following a 1-year counseling program, the tests were repeated (step 2). RESULTS: Child-self and parent-proxy KINDL scores were optimal with no difference between periods (for child-self and parent proxy scores, P > 0.05). Parent SF-36 scores indicated optimal results. Parent RSES scores decreased in step 2 (P < 0.05). The BDI scores were higher in parents than children in both periods (P < 0.05 for step 1 and P < 0.01 for step 2). Higher creatinine levels, lower monthly income, and urological comorbidities modified the HRQoL negatively in step 1. CONCLUSION: Continuous education with psychosocial counseling carries importance in improving HRQoL in the posttransplant period. PMID- 27966318 TI - Should antibiotics be administered after endoscopic mucosalresection in patients with colon polyps? AB - BACKGROUND/AIM: Endoscopic mucosal resection (EMR) is widely used for treating gastrointestinal polypoid lesions. However, it is currently unclear whether antibiotic administration is necessary after EMR of colon polyps to prevent infection. We aimed to assess whether antibiotic administration is essential in such conditions. MATERIALS AND METHODS: In total, 115 patients with colon polyps were randomly assigned to 3 groups based on the treatment given after EMR: Group A, no antibiotics treatment after EMR (n = 38); Group B, administration of levofloxacin after EMR (n = 38); and Group C, administration of ceftazidime after EMR (n = 39). RESULTS: The colon polyps were completely removed by EMR in all cases without any serious complications. Although infection developed in 2 cases in Group A, it was resolved via levofloxacin injection over 3 days; infection did not develop in any cases in Group B and C. The postoperative infection rate was not significantly different among Groups A, B, and C. After 6 months, we noted that the wound surface had properly healed and there was no relapse of colon polyps in any patients. CONCLUSION: The use of antibiotics after EMR of colon polyps to prevent infection did not affect the prognosis of patients. PMID- 27966319 TI - The frequency of buccopalpebral reflex in Parkinson disease. AB - BACKGROUND/AIM: This study aimed to define the frequency of a primitive reflex, the buccopalpebral reflex (BPR), and its association with the clinical situation in patients with Parkinson disease. MATERIALS AND METHODS: Between May 2010 and May 2011, 222 patients, 115 with Parkinson disease and 107 patients without any sign of neurodegenerative disease, were included in the study. All included patients were examined for BPR and snout reflex and were also evaluated with the Mini Mental State Examination. All patients with Parkinson disease were classified with the Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr Score to determine their clinical severity. RESULTS: Sixteen patients with Parkinson disease (13.9%) had a BPR (+) and 4 patients in the control group (3.7%) (P < 0.001). The UPDRS score, UPDRS daily life activities score, and UPDRS motor system score were all higher in the group with BPR (+). All patients with a BPR also had a positive snout reflex. CONCLUSION: BPR is more frequent in patients with Parkinson disease than in patients without a neurodegenerative disease. PMID- 27966320 TI - The effect of cotinine concentrations in seminal plasma and follicular fluid on the pregnancy outcomes of couples undergoing assisted reproductive techniques. AB - BACKGROUND/AIM: This study determined the effects of cotinine concentrations in follicular fluid (FF) and seminal plasma (SP) on the pregnancy outcome of couples using assisted reproductive techniques (ARTs). MATERIALS AND METHODS: This study was conducted as a case-control study. A total of 217 couples were included in the study. Among these couples, there were nonsmokers (66 women and 40 men), passive smokers (106 women and 54 men), and active smokers (45 women and 123 men). Demographic and smoking data were collected by questionnaire at the onset of treatment. FF and SP samples were obtained from the couples on the day of oocyte retrieval. RESULTS: The cotinine concentrations in the FF and SP of nonsmokers were significantly lower than they were in the other groups (P = 0.001). The difference in cotinine concentrations detected in FF between women with positive pregnancy test results and women with negative pregnancy test results was statistically insignificant. It was also determined that the percentage of clinical pregnancy was lower in nonsmoker women than in passive smoker or smoker women (P > 0.05). CONCLUSION: Although we found there was no significant difference in the pregnancy outcome between nonsmoker and passive smoker or smoker women, smoking cessation should be an integral part of ARTs. PMID- 27966321 TI - Determination of genotypic varieties and genotyping of multiple drug-resistant tuberculosis by the RFLP and spoligotyping methods. AB - BACKGROUND/AIM: The purpose of the present study was to determine the distribution and epidemiological features of mycobacteria with molecular methods. MATERIALS AND METHODS: Fifty-five culture-positive samples were analyzed by polymerase chain reaction-restriction enzyme length polymorphism (PCR-RFLP) at species level, and their molecular typing was performed with spoligotyping. The IS6110 region and the locus of gene coding for Hsp65 were amplified. RFLP profiles were obtained by cutting the Hsp65 region with the Hae III and BstE II (Eco91I) enzymes. Spoligotyping was carried out by commercial kit. The H37Rv strain was used as the control. RESULTS: All samples showed the same cutting pattern with the H37Rv strain. The RFLP profiles of 9 strains identified as "mycobacteria other than tuberculosis" were compatible with the M. tuberculosis complex. Spoligotyping of 55 isolates detected 13 different genetic profiles. The Beijing genotype was not detected. One isolate was described as an orphan strain according to the SpolDB4 database. The most frequently detected family was T1 with 32 strains (64%), followed by 9 isolates (18%) belonging to the LAM7 TUR family. CONCLUSION: PCR-RFLP is a specific, rapid, and effective method in routine diagnosis of mycobacteria. Spoligotyping is an ideal method in the determination of genotypic varieties of mycobacteria. PMID- 27966322 TI - Determination of reference range with the indirect method of the 25 hydroxyvitaminD3 test in the Balikesir region, Turkey. AB - BACKGROUND/AIM: The aim of this study is to determine the reference ranges of 25 hydroxyvitamin D3 (25(OH)vitD3) by an indirect method using data obtained from patients over the course of 3 years. MATERIALS AND METHODS: The 25(OH)vitD3 test results of the patients who applied to the medical biochemistry laboratory of Balikesir State Hospital between the years of 2010 and 2014 were analyzed. Patient data were retrospectively taken from the laboratory information system. The 25(OH)vitD3 levels of patients were examined after exclusion of outliers. Patients were divided into subgroups according to season, sex, and age. The central 95% reference intervals were calculated using a nonparametric method. RESULTS: Calculated reference intervals showed lower values than the recommended reference values of the manufacturer. In our study, 25(OH)vitD3 test results obtained for the reference values were 6.43-30.0 ng/mL for the percentile range of 2.5-97.5. For 25(OH)vitD3, the determined reference interval for our data was significantly different from the data provided by the manufacturer. CONCLUSION: This work should also be carried out in a healthy population. Data obtained from this study can be combined with the reference range determination studies for other regions in Turkey, and therefore it can contribute to the determination of the reference ranges of the Turkish community. This study is important for verification of the reference range recommended by the manufacturer. PMID- 27966323 TI - Genotypic analysis of Escherichia coli strains that cause urosepsis in the Aegean region. AB - BACKGROUND/AIM: The aim of this study was to characterize strains genotypically, to determine their phylogenetic relationships, to investigate the presence of the papG gene, and to compare their antibiotic susceptibility test results. MATERIALS AND METHODS: Seventy pathogenic E. coli strains were isolated from both urine and blood cultures of patients with the preliminary diagnosis of urosepsis who were referred to the Ege University Faculty of Medicine, Bacteriology Laboratory of Medical Microbiology Department in Izmir. All of these strains were examined for the papG gene and phylogenetic groups with the multiplex polymerase chain reaction technique. Pulsed-field gel electrophoresis and multilocus sequence typing (MLST) were used for epidemiologic analysis. RESULTS: Phylogenetically, it was found that 16 belonged to group B2, 31 belonged to group D, 15 belonged to group A, and 7 belonged to group B1. One strain was not identified as belonging to a group. papG genes were found in 26 of 70 E. coli strains. Thirty urosepsis pathogenic E. coli strains were analyzed with MLST. Twenty-two strains were identified as new STs. CONCLUSION: These findings are extremely important for Turkey and these new 22 strains should be investigated in more detail because they are new and have the potential to lead to infections. PMID- 27966324 TI - The effect of pneumoperitoneum on intravascular fibrinolytic activity in rats. AB - BACKGROUND/AIM: Venous stasis during pneumoperitoneum in laparoscopic surgery is closely related to fibrin synthesis and deposition. The etiologic factors underlying fibrinolysis or hypercoagulability are not clearly defined. This study aimed to determine the effects of pneumoperitoneum time and pressure on coagulation cascade and the fibrinolytic pathway. MATERIALS AND METHODS: After the pneumoperitoneum model was established in rats, PAI-1, tPA, TAFI, D-dimer, and fibrinogen activities were evaluated in different time periods under different pressures in groups including 6 rats. Group 1 did not undergo any procedure. Group 2 received 8 mmHg of pressure for 30 min, Group III 8 mmHg for 60 min, Group IV 12 mmHg for 30 min, and Group V 12 mmHg for 60 min. RESULTS: D dimer levels had a tendency to decrease with increasing intraabdominal pressures. In both low and high pressure groups, fibrinogen had a tendency to increase with exposure time. There was no statistically significant difference among the study groups in terms of fibrinogen, D-dimer, and PAI-1. The levels of TAFI were significantly decreased with increasing pressure regardless of the exposure time. CONCLUSION: Pneumoperitoneum of the coagulation system can be changed by duration of time and pressure. PMID- 27966325 TI - The protective effects of hydrogen on HO-1 expression in the brainafter focal cerebral ischemia reperfusion in rats. AB - BACKGROUND/AIM: The aim of this study was to investigate whether a hydrogen administration can produce neuroprotective effects after brain ischemia reperfusion in rats. MATERIALS AND METHODS: A brain ischemia reperfusion injury was induced by a 2-h left middle cerebral artery occlusion (MCAO) using an intraluminal filament, followed by 46 h of reperfusion. A hydrogen-rich saline (1 mL/kg body weight i.p.) was administered at the beginning of reperfusion. Saline (1 mL/kg)-treated animals were used as the control. Sham-operated animals were also used. Subsequently, 48 h after the MCAO, histological alternations, heme oxygenase-1 (HO-1) expression, and levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in the cerebral cortex and the hippocampus were examined. RESULTS: Hydrogen significantly alleviated brain tissue histological damage, promoted HO-1 expression, upregulated levels of SOD, and decreased the levels of MDA in brain tissue after the ischemia reperfusion injury. CONCLUSION: The results suggest that the neuroprotective effects of hydrogen may be mediated by promoting HO-1 expression and attenuated the oxidative injury. PMID- 27966327 TI - Effect of methylprednisolone injection on interleukin-4 and interferon-gamma expression following hepatitis B vaccination in mice. AB - BACKGROUND/AIM: The prevalence of hepatitis B infection is high worldwide with liver cirrhosis and hepatocellular carcinoma as important complications. Immunosuppression, especially from corticosteroids, is often cited as a cause of poor immune response and there is documented evidence of irrational administration of glucocorticoids to children and adults. Decreased expression of interleukin-4 and interferon-gamma is an indication of poor humoral and cellular immune responses, respectively. Therefore, we decided to find out if methylprednisolone injection decreases interleukin-4 and interferon-gamma expression following hepatitis B vaccination in mice. MATERIALS AND METHODS: Mice were randomly divided into 2 groups. Daily intramuscular injections of methylprednisolone (15 mg/kg) were given to the test group while water for injection (0.1 mL) was given to the control group for 30 days. On day 6 all mice were given 2 MUg of hepatitis B vaccine and they received a booster dose on day 27. On day 34, blood samples were collected and analyzed for interleukin-4 and interferon-gamma titers. RESULTS: There was positive interleukin-4 and interferon gamma response in all groups but the differences in titers were not statistically significant. CONCLUSION: At the dosages and length of exposure used in this study, methylprednisolone injection did not significantly inhibit interleukin-4 and interferon-gamma expression following immunization against hepatitis B virus in mice. PMID- 27966326 TI - An assessment of adherence to asthma medication guidelines: findingsfrom a tertiary care center in the state of Penang, Malaysia. AB - BACKGROUND/AIM: Multiple asthma guidelines have been developed to reduce asthma mortality, morbidity, and cost associated with asthma worldwide. In Malaysia, within this context, it is relatively unknown to what extent doctors adhere to the asthma guidelines. This study aimed to assess guideline adherence and calculate the cost of adhered and nonadhered prescriptions by medical doctors in a public tertiary health care facility. MATERIALS AND METHODS: A cross-sectional study was carried out at Hospital Pulau Pinang, Malaysia. One hundred and eighty patients, a total of 30 patients per doctor, were enrolled to assess guideline adherence. The patients were followed for a second visit to assess their lung function. The costs of adhered and nonadhered prescriptions were calculated. RESULTS: One hundred and forty-three patients (79%) received guideline (Global Initiative for Asthma 2011)-adhering pharmacotherapy. In the majority of patients (n = 133, 73.9%) asthma control was classified as partially controlled. There was no significant association observed between patient asthma control and patient demographics; however, there was a significant difference (P < 0.001) between lung function values from the first and second visits. The cost of adhered prescription was higher (70.1 Malaysian ringgit) than that of nonadhered prescription (13.74 Malaysian ringgit). CONCLUSION: Fair levels of guideline adherence were observed. Emphasis should be placed on identifying appropriate cost-effective medication regimens based on patient asthma control and constant feedback from patients. PMID- 27966328 TI - Adulthood behavioral and neurodevelopmental effects of being raised byan ambivalent mother in rats: what does not kill you makes you stronger. AB - BACKGROUND/AIM: This study aimed to investigate the effects of early adverse life events and being raised by an ambivalent mother on rats. MATERIALS AND METHODS: The rats were separated into four groups: 1) the control group (n = 12), which was raised under standard care; 2) the early handling (EH) group, which was raised using an EH model (n = 16); 3) the early deprivation (ED) group, which was raised using an ED model (n = 13), and 4) the ambivalent mother (AM) group, which spent 3 h/day with a "fake mother" (n = 17). When they became adults, their anxiety levels, depressive-like behaviors, and memory functions were measured using the elevated plus maze test, the forced swim test, and the novel object recognition test, respectively. Their neurodevelopment was evaluated by measuring the brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex, the dentate gyrus, and the cerebellum via ELISA. RESULTS: The rats in the ED and AM groups exhibited less anxiety and depressive-like behavior than those in the control and EH groups, particularly in females. There was no significant difference between the groups in memory function or brain BDNF levels. CONCLUSION: Severe and ambivalent early adverse life events may decrease anxiety and depressive-like behavior in adult rats. PMID- 27966329 TI - Effect of resveratrol on resistin and apelin gene expressions in adipose tissue of diabetic rats. AB - BACKGROUND/AIM: Adipose tissue plays a major role in glucose homeostasis. Dietary antioxidants such as resveratrol (RSV) may offer some protection against the early stage of diabetes mellitus and the development of complications. The present study investigated the effects of RSV on biochemical parameters and resistin and apelin gene expressions in adipose tissue of rats with type 2 diabetes. MATERIALS AND METHODS: Diabetes was induced using a single dose of streptozotocin + nicotinamide. Three groups of diabetic rats were treated with different doses of RSV (1, 5, and 10 mg/kg body weight per day). Oxidative status, serum biochemical parameters, insulin, and HOMA index were measured. Finally, resistin and apelin gene expressions were determined in rats' adipose tissue using RT- PCR (qRT-PCR). RESULTS: A significant reduction in serum glucose level was observed in rats treated with 5 and 10 mg/kg per day RSV compared with the diabetic control. Resistin expression in adipose tissue was reduced in RSV treated groups, while no significant changes were observed in apelin expression. CONCLUSION: The results showed that RSV improves insulin sensitivity due to a simultaneous decrease in blood glucose and an increase in insulin. We concluded that RSV has potential hypoglycemic effect, probably by increasing insulin levels and changing the expression of resistin. PMID- 27966330 TI - Therapeutic effects of intralipid and medialipid emulsionsin a rat model of verapamil toxicity. AB - BACKGROUND/AIM: Lipid emulsions are promising as a potential new therapy for severe verapamil overdose. Our purpose is to draw attention to the choice of solution by investigating the efficacy of intralipid 20% or medialipid 20% in verapamil overdose. MATERIALS AND METHODS: Eighteen adult Sprague Dawley rats were randomly divided into three groups: control (saline; Group C), intralipid 20% (Group I), and medialipid 20% (Group M). Rats were anesthetized with ketamine. Blood gas analysis, baseline heart rate (HRb), and mean arterial pressure (MAPb) were evaluated. Verapamil at 2.5 mg kg-1 min-1 was infused until the HRb and MAPb decreased by 50% and the times to HR0 and MAP0 were recorded. Treatment solutions of the groups were administered as 12.4 mL kg-1 in 5 min. RESULTS: While HR did not show a difference, MAP showed statistically significant differences among the groups. Intralipid 20% was more efficient than the other two treatments at an early stage; however, as the administration time progressed, medialipid 20% also turned out to be more efficient than the control treatment. CONCLUSION: Our findings indicate that in a toxicity model of rats produced with verapamil, intralipid 20% and medialipid 20% solutions partially eliminate cardiac-depressant effects and increase the survival rate. PMID- 27966331 TI - Boswellia serrata gum resin aqueous extract upregulatesBDNF but not CREB expression in adult male rat hippocampus. AB - BACKGROUND/AIM: Boswellia from the family Burseraceae has been proposed for prevention of amnesia; however, the molecular mechanism by which it affects memory is not clear. To reveal the potential molecular mechanism, the effects of boswellia on the expression of two memory related genes, CREB and BDNF, were investigated. MATERIALS AND METHODS: Twenty-one male rats were randomly divided into 3 groups (n = 7): the control group received distilled water and the treatment groups received two doses of aqueous extract of Boswellia serrata gum resin (boswellia) (50 and 100 mg/kg) every day for 4 weeks. The animals were tested by the Morris water maze (MWM) and their hippocampus was isolated. Expression of CREB and BDNF genes was analyzed by Q-RT-PCR. RESULTS: The MWM test showed improvement in spatial learning and memory in both treatment groups. Gene expression analysis revealed a significant increase in BDNF but not CREB expression in rats treated with both 50 and 100 mg/kg doses in comparison with the control group. CONCLUSION: Although boswellia exerts its effects on memory formation at least partly by affecting the expression of BDNF, the results imply that boswellia probably affects memory via another BDNF-related pathway than the BDNF-CREB-BDNF cycle. PMID- 27966332 TI - Analysis of diabetes-related cerebellar changes in streptozotocin-induced diabetic rats. AB - BACKGROUND/AIM: Diabetic peripheral neuropathy has been extensively studied and reported, but the number of studies that have investigated diabetes-related changes in the central nervous system are limited, with even fewer studies on the cerebellum. The aim of this experimental study was to perform a histologic analysis of the diabetes-related changes in the cerebellums of diabetic rats. MATERIALS AND METHODS: Twenty Sprague Dawley rats weighing between 200 and 220 g were included in the study. Diabetes was induced in 14 of these rats by a single intraperitoneal injection of 65 mg/kg streptozotocin dissolved in saline, while 6 animals constituted the control group. The induction of diabetes was confirmed by measuring the blood glucose levels in the tail blood with a glucometer. Levels equal to or above 200 mg/dL were considered diabetic. Induction of diabetes failed in 3 animals, who were then excluded from the study. RESULTS: Light and electron microscopic studies revealed that the neurons and glial cells in the diabetic group had degenerative changes, irregularities and disruption in the myelin sheath, disintegration in the presynaptic vesicles, engorged axon terminals, perivascular and mitochondrial swelling, mitochondrial structural changes, and fragmentation of the neurofilaments. CONCLUSION: Ultrastructural alterations are observed in the diabetic rat cerebellum. PMID- 27966333 TI - Effects of crocin on experimental obesity and type-2 diabetes. AB - BACKGROUND/AIM: The aim of this study is to scrutinize the effects of crocin on obesity and type-2 diabetes, with an approach that takes oxidative stress and inflammatory parameters into account. MATERIALS AND METHODS: The experimental obesity model was created by utilizing a 10-week-long high-fat diet (HFD). An experimental type-2 diabetes model was created by injecting multiple low-dose streptozocin (STZ) injections into rats that were fed with the HFD. The treatment groups were administered a daily crocin dose of 150 mg/kg for 6 weeks via gavage. RESULTS: Findings of the study demonstrated that crocin could be effective in relieving the symptoms of obesity and diabetes (hyperinsulinemia, hyperleptinemia, insulin resistance, and weight gain). It was determined that crocin lowered the plasma TNF-alpha and IL-1beta levels and the pancreas tissue TNF-alpha and IFN-gamma levels, which were increased due to diabetes, and reduced the inflammation in diabetic rats. Similarly, it was found that oxidative stress, which increased due to the progress of diabetes, was reduced in crocin treatment group. CONCLUSION: Crocin could contribute to the development of phytotherapeutic approaches in the treatment of obesity, diabetes, and diabesity (obesity-induced diabetes), which is promising as the abovementioned incidences have increased considerably in today's world. PMID- 27966334 TI - Study of mouse induced pluripotent stem cell transplantation intoWistar albino rat cochleae after hair cell damage. AB - BACKGROUND/AIM: As the regeneration capacity of hair cells is limited, inner ear stem cell therapies hold promise. Effects of mouse induced pluripotent stem cells (IPSCs) on Wistar albino rats (WARs) with hearing impairment were investigated. MATERIALS AND METHODS: Thirty-five adult WARs with normal hearing were divided into 4 groups. Excluding the study group (n = 15), the other three groups served as control groups for ototoxicity and IPSC injection models. IPSC injections were performed via cochleostomy after a retroauricular approach. Auditory functions were evaluated with auditory brainstem responses (ABRs) before and after the injections. After a final hearing assessment the WARs were sacrificed and cochleae were extracted to see the biologic behavior of IPSCs in the inner ear by light microscopy and immunohistochemistry. RESULTS: There were no significant differences in the click-ABR thresholds in the study group after IPSC transplantation. The mean hearing threshold in the study group after ototoxic agent injection was 53.2 dB (10-90 dB). There was no significant difference between groups (P > 0.05) and no differentiated stem cells were observed immunohistochemically. CONCLUSION: Transplanted IPSCs did not show a therapeutic effect in this trial. We discuss potential pitfalls and factors affecting the therapeutic effect. PMID- 27966335 TI - Radiation dose to breasts from a cardiac computed tomography angiographyscanogram can be reduced by switching tube position. AB - BACKGROUND/AIM: In a computed tomography (CT) examination, scanogram images are used to determine the range of the area to be imaged before scanning. The importance of scanogram image exposure has increased since total examination radiation has decreased due to technological advancements. The purpose of this study was to determine and compare radiation doses delivered to patients while the tube was in anterior-posterior (AP) and posterior-anterior (PA) positions during a CT angiography scanogram. MATERIALS AND METHODS: The radiation doses absorbed by the breast tissue of 55 female patients who underwent cardiac dual source computed tomography (DSCT) angiography were determined using thermoluminescent dosimeters (TLD-100, Harshaw, MA, USA). Four patients were excluded from the study for various reasons. RESULTS: Radiation doses absorbed by the breasts were significantly lower when the tube position was switched during the scanogram. The absorbed doses, calculated from scanogram exposures, were 520 +/- 50 MUSv for the AP projection and 410 +/- 45 MUSv for the PA projection. Total skin doses from the DSCT examinations were 18.9 +/- 2.3 mSv. CONCLUSION: We attributed the approximately 20% lower doses to the position of the scanogram tube, which was in the PA position. PMID- 27966336 TI - Anticyclic citrullinated peptide antibody in rheumatoid arthritis:a cross sectional study in Iran. AB - BACKGROUND/AIM: Studies have shown that anticyclic citrullinated peptide antibody (anti-CCP) titers can be useful in the diagnosis of rheumatoid arthritis (RA). We evaluate the association between anti-CCP antibody titers and the demographic, clinical, and laboratory characteristics of RA patients. Moreover, we explore whether there is any relation between joint destruction and demographic and clinical characteristics of RA patients. MATERIALS AND METHODS: One hundred and four RA patients with positive anti-CCP titers were compared to 104 RA patients with negative anti-CCP titers. The activity of RA was evaluated using the Disease Activity Score 28 (DAS28). Joint destruction was assessed in the subjects by X rays of the wrists. Blood samples were collected for assessment of anti-CCP, rheumatoid factor (RF), and erythrocyte sedimentation rate. RESULTS: Forty-eight (23.0%) males and 160 (76.9%) females were included in this study. RF, DAS28, and joint destruction were significantly different between patients with and without anti-CCP (P < 0.0001). DAS28, duration of disease, hospitalizations, and occupation differed significantly between patients with and without joint destruction (P < 0.0001). CONCLUSION: This study indicates that anti-CCP is correlated with a high disease activity index and more joint destruction in RA patients and it may be used as a prognostic factor for RA. PMID- 27966337 TI - The incidence of pressure ulcer in patients on mechanical ventilation andeffects of selected risk factors on pressure ulcer development. AB - BACKGROUND/AIM: This study aimed to determine the incidence of pressure ulcers in patients on mechanical ventilation and selected risk factors likely to play a role in pressure ulcer development. MATERIALS AND METHODS: The study included 110 patients recruited from an anesthesia critical care unit of a university hospital. Data were collected with a demographic and clinical characteristics form. The form was composed of questions about demographic characteristics and clinical features including diagnosis, duration of mechanical ventilation, general well-being, oxygenation, perfusion, and skin condition. RESULTS: The incidence of pressure ulcer was 15.5%. Duration of mechanical ventilation was longer and the body mass index was higher in patients developing pressure ulcers than in those without pressure ulcers. Additionally, 90.11% of patients with pressure ulcers had edema and 82.35% of patients with pressure ulcers received vasopressin. The patients with pressure ulcers had higher PH levels, lower PaO2 levels, higher PCO2 levels, lower SaO2 levels, and higher urine output. CONCLUSION: It can be recommended that nurses and other health professionals should be aware of factors playing a role in pressure ulcer development and should be able to conduct appropriate interventions to prevent pressure ulcers. PMID- 27966338 TI - The clinical and laboratory characteristics, treatments, and outcomes of patients with Brucella epididymo-orchitis (BEO) compared to those without BEO. AB - BACKGROUND/AIM: We aim to describe the clinical and laboratory characteristics, treatment, and outcomes of 21 patients with Brucella epididymo-orchitis (BEO) from Eskisehir Yunus Emre State Hospital, Turkey. MATERIALS AND METHODS: A total of 21 patients with BEO who were diagnosed and followed in the Infectious Diseases Clinic between June 2001 and June 2013 were evaluated retrospectively. RESULTS: One hundred and twenty-eight of 192 patients evaluated throughout the study were male and BEO was determined in 21 (16.4%) patients. A total of 18 (85.7%) patients had a titer of b1:160 in standard agglutination test (STA). Three patients with STA '160 were diagnosed by blood culture. When all the male patients were evaluated in terms of demographic, clinical, and laboratory findings, animal contact, rural living, and subacute clinical type were statistically significantly higher in the group that developed epididymo orchitis. None of the patients underwent surgery after medical treatment, but due to a delay in diagnosis of brucellosis, orchiectomy was performed in 1 patient with the suspicion of tumor. CONCLUSION: In endemic countries like Turkey, BEO should be considered in the differential diagnosis of epididymo-orchitis. In uncomplicated patients, medical treatment is adequate for BEO. PMID- 27966339 TI - An investigation on the prevalence and efficiency of immunochromatographic testing in suspected malarial patients of Rawalpindi and Islamabad, Pakistan. AB - BACKGROUND/AIM: The prevalences of Plasmodium falciparum and Plasmodium vivax are increasing rapidly in Pakistan, but recent data on the epidemiology of malaria are not properly reported with scarce diagnostic methods for quick diagnosis. This study was designed to determine the current prevalence and distribution of Plasmodium species in the vicinity of Rawalpindi and Islamabad and report on the validity of the immunochromatographic test (ICT) in diagnosing malarial infections. MATERIALS AND METHODS: A total of 1500 blood samples obtained from a local hospital were screened during the course of this study via microscopic examination and ICT. RESULTS: It was seen that malaria was highly endemic in this region. Both P. vivax and P. falciparum were prevalent in all age groups with high seasonal variations, showing a summer peak for P. vivax and a winter peak for P. falciparum. In a comparative study of the diagnostic methods it was observed that the ICT is 95% sensitive and 100% specific for both P. falciparum and P. vivax, while microscopic study was 100% sensitive and 96.8% specific. CONCLUSION: Epidemiological study of the malarial parasites showed that majority of the patients were from Rawalpindi as compared to Islamabad and that P. vivax was the dominant cause of malarial infection. PMID- 27966340 TI - Al(2)O(3) Surface Complexation for Photocatalytic Organic Transformations. AB - The use of sunlight to drive organic reactions constitutes a green and sustainable strategy for organic synthesis. Herein, we discovered that the earth abundant aluminum oxide (Al2O3) though paradigmatically known to be an insulator could induce an immense increase in the selective photo-oxidation of different benzyl alcohols in the presence of a large variety of dyes and O2. This unique phenomenon is based on the surface complexation of benzyl alcohol (BnOH) with the Bronsted base sites on Al2O3, which reduces its oxidation potential and causes an upshift in its HOMO for electron abstraction by the dye. The surface complexation of O2 with Al2O3 also activates the adsorbed O2 for receiving electrons from the photoexcited dyes. This discovery brings forth a new understanding on utilizing surface complexation mechanisms between the reactants and earth abundant materials to effectively achieve a wider range of photoredox reactions. PMID- 27966341 TI - Urinary Polycyclic Aromatic Hydrocarbon Metabolites and Human Semen Quality in China. AB - Toxicological studies have demonstrated that polycyclic aromatic hydrocarbons (PAHs) exposure impairs male reproductive health. However, the epidemiological evidence is limited and discordant. Our goal was to investigate the relationship between PAH exposures and human semen quality. We analyzed 12 urinary metabolites of PAHs from 933 men who sought semen quality analysis in an infertility clinic in Wuhan, China. Associations with semen quality were assessed using a multivariable linear regression. Restricted cubic splines were used to explore the dose-response relationships between urinary metabolites of PAHs and semen quality. We observed inverse associations between urinary 1-hydroxynaphthalene (1 OHNa) and sperm count, sperm concentration, and percentage of normal morphology (all p for trends <0.05) as well as between urinary ?OHNa (sum of 1-OHNa and 2 OHNa) and sperm concentration (p for trend =0.04). Additionally, we found inverse associations between urinary 9-hydroxyphenanthrene (9-OHPh) and semen volume and sperm straight-line velocity (both p for trends <0.05) as well as between urinary ?OHPh (sum of 1-, 2-, 3-, 4-, and 9-OHPh) and sperm count (p for trend =0.04). These dose-response relationships were further confirmed in the curves of the restricted cubic splines. Our data suggest that exposure to naphthalene and phenanthrene is related to decreased semen quality. Our results contribute to the growing body of evidence regarding the widespread exposure to PAHs and the detriment to male reproductive function. PMID- 27966342 TI - A Turn-On Fluorescent Sensor for Selective and Sensitive Detection of Alkaline Phosphatase Activity with Gold Nanoclusters Based on Inner Filter Effect. AB - In this work, a novel approach for simple and sensitive determination of alkaline phosphatase (ALP) is developed on the basis of an inner filter effect of p nitrophenylphosphate (PNPP) on the fluorescence of gold nanoclusters (AuNCs). AuNCs with a high quantum yield of 12% were synthesized by one-pot strategy and were directly applied as fluorescent substance. When AuNCs were mixed with PNPP, the fluorescence of the AuNCs was remarkably quenched or was decreased via the inner filter effect since the absorption spectrum of PNPP overlaps well with the excitation spectrum of the AuNCs. While in the presence of ALP, PNPP was catalytically hydrolyzed into p-nitrophenol, which has different absorption characteristics from those of PNPP, resulting in the recovery of the AuNCs fluorescence. Thus, a novel "turn-on" fluorescent sensor for detecting ALP was established with a detection limit as low as 0.002 U/L (signal-to-noise ratio of 3). The turn-on fluorescent sensor exhibits many merits such as high sensitivity, excellent selectivity, and high signal output because of the low background signals. In addition, the developed sensing method was successfully applied to investigate ALP inhibitors and ALP determination in serum samples. A good linear relationship was obtained in the range from 0.02 to 50 U/L, and satisfactory recoveries at four spiking levels of ALP ranged from 95% to 106% with precision below 5%. The very simple sensing approach proposed here should promote the development of fluorescence turn-on chemosensors for chemo/biodetection. PMID- 27966344 TI - Strength and Performance Enhancement of Bonded Joints by Spatial Tailoring of Adhesive Compliance via 3D Printing. AB - Adhesive bonding continues to emerge as a preferred route for joining materials with broad applications including advanced structures, microelectronics, biomedical systems, and consumer goods. Here, we study the mechanics of deformation and failure of tensile-loaded single-lap joints with a compliance tailored adhesive. Tailoring of the adhesive compliance redistributes stresses and strains to reduce both shear and peel concentrations at the ends of the adhesive that determine failure of the joint. Utilizing 3D printing, the modulus of the adhesive is spatially varied along the bondlength. Experimental strength testing, including optical strain mapping, reveals that the strain redistribution results in a greater than 100% increase in strength and toughness concomitant with a 50% increase in strain-to-break while maintaining joint stiffness. The tailoring demonstrated here is immediately realizable in a broad array of 3D printing applications, and the level of performance enhancement suggests that compliance tailoring of the adhesive is a generalizable route for achieving superior performance of joints in other applications, such as advanced structural composites. PMID- 27966343 TI - Biosynthetic Origin of the Ether Ring in Platensimycin. AB - Platensimycin (PTM) and platencin (PTN) are highly functionalized bacterial diterpenoid natural products that target bacterial and mammalian fatty acid synthases. PTM and PTN feature varying diterpene-derived ketolides that are linked to the same 3-amino-2,4-dihydroxybenzoic acid moiety. As a result, PTM is a selective inhibitor for FabF/FabB, while PTN is a dual inhibitor of FabF/FabB and FabH. We previously determined that the PTM cassette, consisting of five genes found in the ptm, but not ptn, gene cluster, partitions the biosynthesis of the PTM and PTN diterpene-derived ketolides. We now report investigation of the PTM cassette through the construction of diterpene production systems in E. coli and genetic manipulation in the PTM-PTN dual overproducer Streptomyces platensis SB12029, revealing two genes, ptmT3 and ptmO5, that are responsible for the biosynthetic divergence between the PTM and PTN diterpene-derived ketolides. PtmT3, a type I diterpene synthase, was determined to be a (16R)-ent-kauran-16-ol synthase, the first of its kind found in bacteria. PtmO5, a cytochrome P450 monooxygenase, is proposed to catalyze the formation of the characteristic 11S,16S-ether ring found in PTM. Inactivation of ptmO5 in SB12029 afforded the DeltaptmO5 mutant SB12036 that accumulated nine PTM and PTN congeners, seven of which were new, including seven 11-deoxy-16R-hydroxy-PTM congeners. The two fully processed PTM analogues showed antibacterial activities, albeit lower than that of PTM, indicating that the ether ring, or minimally the stereochemistry of the hydroxyl group at C-16, is crucial for the activity of PTM. PMID- 27966345 TI - Doping Versatile n-Type Organic Semiconductors via Room Temperature Solution Processable Anionic Dopants. AB - In this study, we describe a facile solution-processing method to effectively dope versatile n-type organic semiconductors, including fullerene, n-type small molecules, and graphene by commercially available ammonium and phosphonium salts via in situ anion-induced electron transfer. In addition to the Lewis basicity of anions, we unveiled that the ionic binding strength between the cation and anion of the salts is also crucial in modulating the electron transfer strength of the dopants to affect the resulting doping efficiency. Furthermore, combined with the rational design of n-type molecules, an n-doped organic semiconductor is demonstrated to be thermally and environmentally stable. This finding provides a simple and generally applicable method to make highly efficient n-doped conductors which complements the well-established p-doped organics such as PEDOT:PSS for organic electronic applications. PMID- 27966346 TI - Dynamics of Uncrystallized Water, Ice, and Hydrated Protein in Partially Crystallized Gelatin-Water Mixtures Studied by Broadband Dielectric Spectroscopy. AB - The glass transition of partially crystallized gelatin-water mixtures was investigated using broadband dielectric spectroscopy (BDS) over a wide range of frequencies (10 mHz to 10 MHz), temperatures (113-298 K), and concentrations (10 45 wt %). Three dielectric relaxation processes (processes I, II, and III) were clearly observed. Processes I, II, and III originate from uncrystallized water (UCW) in the hydration shells of gelatin, ice, and hydrated gelatin, respectively. A dynamic crossover, called the Arrhenius to non-Arrhenius transition of UCW, was observed at the glass transition temperature of the relaxation process of hydrated gelatin for all mixtures. The amount of UCW increases with increasing gelatin content. However, above 35 wt % gelatin, the amount of UCW became more dependent on the gelatin concentration. This increase in UCW causes a decrease in the glass transition temperature of the cooperative motion of gelatin and UCW, which appears to result from a change in the aggregation structure of gelatin in the mixture at a gelatin concentration of approximately 35 wt %. The temperature dependence of the relaxation time of process II has nearly the same activation energy as pure ice made by slow crystallization of ice Ih. This implies that process II originates from the dynamics of slowly crystallized ice Ih. PMID- 27966348 TI - Theoretical Study of Nickel-Catalyzed Selective Alkenylation of Pyridine: Reaction Mechanism and Crucial Roles of Lewis Acid and Ligands in Determining the Selectivity. AB - Selective alkenylation of pyridine is challenging in synthetic organic chemistry due to the poor reactivity and regioselectivity of the aromatic ring. We theoretically investigated Ni-catalyzed selective alkenylation of pyridine with DFT. The first step is coordination of the pyridine-AlMe3 adduct with the active species Ni(0)(NHC)(C2H2) 1 in an eta2-fashion to form an intermediate Int1. After the isomerization of Int1, the oxidative addition of the C-H bond of pyridine across the nickel-acetylene moiety occurs via a transition state TS2 to form a Ni(II)(NHC) pyridyl vinyl intermediate Int3. This oxidative addition is rate determining. The next step is C-C bond formation between pyridyl and vinyl groups leading to the formation of vinyl-pyridine (P1). One of the points at issue in this type of functionalization is how to control the regioselectivity. With the use of Ni(NHC)/AlMe3 catalyst, the C4- and C3-alkenylated products (DeltaG degrees ? = 17.4 and 21.5 kcal mol-1, respectively) are formed preferably to the C2 one (DeltaG degrees ? = 22.0 kcal mol-1). The higher selectivity of the C4 alkenylation over the C3 and the C2 ones is attributed to the small steric repulsion between NHC and AlMe3 in the C4-alkenylation. Interestingly, with Ni(P(i-Pr)3)/AlMe3 catalyst, the C2-alkenylation occurs more easily than the C3 and C4 ones. This regioselectivity arises from the smaller steric repulsion induced by P(i-Pr)3 than by bulky NHC. It is notable that AlMe3 accelerates the alkenylation by inducing the strong CT from Ni to pyridine-AlMe3. In the absence of AlMe3, pyridine strongly coordinates with the Ni atom through the N atom, which increases Gibbs activation energy (DeltaG degrees ? = ~27 kcal mol-1) of the C-H bond activation. In other words, AlMe3 plays two important roles, acceleration of the reaction and enhancement of the regioselectivity for the C4 alkenylation. PMID- 27966349 TI - Advances in Understanding the Molecular Structures and Functionalities of Biodegradable Zein-Based Materials Using Spectroscopic Techniques: A Review. AB - Zein's amphiphilic properties, film forming capability, and biodegradability make it a highly demanded polymer for fabrication of packaging materials, production of drug carrier nanoparticles, scaffolds in tissue engineering, and formation of biodegradable platforms for biosensors including microfluidic devices. Zein properties can be improved by chemical modifications, which are often analyzed with spectroscopic techniques. However, there is not a consensus on the structure of zein. For this reason, in this Review the aim is to compile the recent studies conducted on zein-based products and compare them under five main spectroscopic techniques: Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, circular dichroism (CD), X-ray diffraction (XRD) and atomic force microscopy (AFM). This Review serves as a library of recent zein studies and helps readers to have a better perception of contradictions in the literature to take their studies one step further. PMID- 27966347 TI - Stimulated Raman Scattering: From Bulk to Nano. AB - Stimulated Raman scattering (SRS) describes a family of techniques first discovered and developed in the 1960s. Whereas the nascent history of the technique is parallel to that of laser light sources, recent advances have spurred a resurgence in its use and development that has spanned across scientific fields and spatial scales. SRS is a nonlinear technique that probes the same vibrational modes of molecules that are seen in spontaneous Raman scattering. While spontaneous Raman scattering is an incoherent technique, SRS is a coherent process, and this fact provides several advantages over conventional Raman techniques, among which are much stronger signals and the ability to time resolve the vibrational motions. Technological improvements in pulse generation and detection strategies have allowed SRS to probe increasingly smaller volumes and shorter time scales. This has enabled SRS research to move from its original domain, of probing bulk media, to imaging biological tissues and single cells at the micro scale, and, ultimately, to characterizing samples with subdiffraction resolution at the nanoscale. In this Review, we give an overview of the history of the technique, outline its basic properties, and present historical and current uses at multiple length scales to underline the utility of SRS to the molecular sciences. PMID- 27966350 TI - Acid-Base Properties of a Freebase Form of a Quadruply Ring-Fused Porphyrin Stepwise Protonation Induced by Rigid Ring-Fused Structure. AB - We report herein unique stepwise protonation at inner imino-nitrogen atoms of a freebase derivative of a quadruply fused porphyrin (H2QFP), which has been newly synthesized. H2QFP has been revealed to have the two inner NH protons on the two nonfused pyrroles by X-ray diffraction analysis and 1H NMR spectroscopy. The first protonation at one of the two imino-nitrogen atoms of the fused pyrroles smoothly proceeds with trifluoroacetic acid (TFA) in CH2Cl2 and the equilibrium constant (K1) of the protonation has been determined to be (1.3 +/- 0.1) * 105 M 1. In contrast, the second protonation at the other imino-nitrogen atom is hard to occur unless a large excess amount of TFA is used, as reflected on a much smaller equilibrium constant, K2 = 7.3 +/- 0.3 M-1. The stepwise protonation is ascribed to the structural rigidity caused by the ring fusion and the resultant steric repulsion among inner NH atoms of the diprotonated form. Electrochemical studies have revealed that protonation at the pyrrole nitrogen atoms caused positive shifts of the reduction potentials of the QFP derivatives. In addition, the ESR spectrum of the electrochemically one-electron-reduced monoprotonated QFP derivative showed well-resolved hyperfine splitting to represent its unsymmetrical electronic structure due to the monoprotonation. PMID- 27966351 TI - Fluorescent Biosensor for Phosphate Determination Based on Immobilized Polyfluorene-Liposomal Nanoparticles Coupled with Alkaline Phosphatase. AB - This work describes the development of a novel fluorescent biosensor based on the inhibition of alkaline phosphatase (ALP). The biosensor is composed of the enzyme ALP and the conjugated cationic polyfluorene HTMA-PFP. The working principle of the biosensor is based on the fluorescence quenching of this polyelectrolyte by p nitrophenol (PNP), a product of the hydrolysis reaction of p-nitrophenyl phosphate (PNPP) catalyzed by ALP. Because HTMA-PFP forms unstable aggregates in buffer, with low fluorescence efficiency, previous stabilization of the polyelectrolyte was required before the development of the biosensor. HTMA-PFP was stabilized through its interaction with lipid vesicles to obtain stable blue emitting nanoparticles (NPs). Fluorescent NPs were characterized, and the ability to be quenched by PNP was evaluated. These nanoparticles were coupled to ALP and entrapped in a sol-gel matrix to produce a biosensor that can serve as a screening platform to identify ALP inhibitors. The components of the biosensor were examined before and after sol-gel entrapment, and the biosensor was optimized to allow the determination of phosphate ion in aqueous medium. PMID- 27966352 TI - Synthesis of Benzyltributylstannanes by the Reaction of N-Tosylhydrazones with Bu3SnH. AB - An efficient stannylation process with N-tosylhydrazones or directly with carbonyl compounds has been developed. A series of functionalized benzyl- and alkyltributylstannanes can be synthesized in moderate to good yields under transition-metal-free conditions. Tandem transformations involving stannylation/Stille cross-coupling reaction have been carried out without purification of the benzyltributylstannane intermediates to afford a series of diarylmethane derivatives. PMID- 27966353 TI - Protonation-Dependent Structural Heterogeneity in the Chromophore Binding Site of Cyanobacterial Phytochrome Cph1. AB - Phytochromes are biological red/far-red light sensors found in many organisms. Photoisomerization of the linear methine-bridged tetrapyrrole triggers transient proton translocation events in the chromophore binding pocket (CBP) leading to major conformational changes of the protein matrix that are in turn associated with signaling. By combining pH-dependent resonance Raman and UV-visible absorption spectroscopy, we analyzed protonation-dependent equilibria in the CBP of Cph1 involving the proposed Pr-I and Pr-II substates that prevail below and above pH 7.5, respectively. The protonation pattern and vibrational properties of these states were further characterized by means of hybrid quantum mechanics/molecular mechanics calculations. From this combined experimental theoretical study, we were able to identify His260 as the key residue controlling pH-dependent equilibria. This residue is not only responsible for the conformational heterogeneity of CBP in the Pr state of prokaryotic phytochromes, discussed extensively in the past, but it constitutes the sink and source of protons in the proton release/uptake mechanism involving the tetrapyrrole chromophore which finally leads to the formation of the Pfr state. Thus, this work provides valuable information that may guide further experiments toward the understanding of the specific role of protons in controlling structure and function of phytochromes in general. PMID- 27966354 TI - Non-Heme Iron Loading Capacities of Anchovy (Engraulis japonicus) Meat Fractions under Simulated Gastrointestinal Digestion. AB - A ferric oxyhydroxide nanoparticle (FeONP)-mediated mechanism has been suggested recently for anchovy (Engraulis japonicus) meat (AM) enhancement of non-heme iron absorption. The current paper fractionates AM biomass into protein (70.67%), lipid (20.98%), and carbohydrate (i.e., glycogen and mucopolysaccharide, 1.07%) and evaluates their capacities in templating the formation of FeONPs under simulated gastrointestinal digestion. Results show that their iron-loading capacities (mg/g) follow the ascending order glycogen (2.43 +/- 0.65), protein (20.16 +/- 0.56), AM (28.19 +/- 0.86), lipid (33.60 +/- 1.12), and mucopolysaccharide (541.33 +/- 32.33). Protein and lipid act in synergy to contribute the overwhelming majority (about 90%) of AM's iron-loading capacity. l alpha-Phosphatidylcholine and l-alpha-lysophosphatidylcholine are the predominant iron-loading fractions in the lipid digest. Dynamic light scattering and transmission electron microscopy exhibit coating of inorganic cores of the formed FeONPs with peptides or phospholipid-based mixed micelles. Overall, protein and phospholipid are key players in the nanoparticle-mediated "meat factor" mechanism. PMID- 27966355 TI - Accurate Three States Model for Amino Acids with Two Chemically Coupled Titrating Sites in Explicit Solvent Atomistic Constant pH Simulations and pK(a) Calculations. AB - Correct protonation of titratable groups in biomolecules is crucial for their accurate description by molecular dynamics simulations. In the context of constant pH simulations, an additional protonation degree of freedom is introduced for each titratable site, allowing the protonation state to change dynamically with changing structure or electrostatics. Here, we extend previous approaches for an accurate description of chemically coupled titrating sites. A second reaction coordinate is used to switch between two tautomeric states of an amino acid with chemically coupled titratable sites, such as aspartate (Asp), glutamate (Glu), and histidine (His). To this aim, we test a scheme involving three protonation states. To facilitate charge neutrality as required for periodic boundary conditions and Particle Mesh Ewald (PME) electrostatics, titration of each respective amino acid is coupled to a "water" molecule that is charged in the opposite direction. Additionally, a force field modification for Amber99sb is introduced and tested for the description of carboxyl group protonation. Our three states model is tested by titration simulations of Asp, Glu, and His, yielding a good agreement, reproducing the correct geometry of the groups in their different protonation forms. We further show that the ion concentration change due to the neutralizing "water" molecules does not significantly affect the protonation free energies of the titratable groups, suggesting that the three states model provides a good description of biomolecular dynamics at constant pH. PMID- 27966356 TI - DACHPt-Loaded Unimolecular Micelles Based on Hydrophilic Dendritic Block Copolymers for Enhanced Therapy of Lung Cancer. AB - Combining sufficient stability during circulation and desirable drug release is still a great challenge for the clinical applications of nanocarriers. To satisfy this demand, we developed a novel unimolecular micelle (UM) to deliver the antitumor agent 1,2-diaminocyclohexane-platinum(II) (DACHPt) for enhanced therapy of lung cancer. This DACHPt-loaded UM (UM/DACHPt) was formed through chelate complexation between DACHPt and a hydrophilic and biodegradable dendritic block copolymer poly(amidoamine)-polyglutamic acid-b-polyethylene glycol (PAM-PGlu-b PEG), which was composed of generation 3 PAMAM (PAMAM-G3), polyglutamic acid, and long-circulating polymer PEG. This UM/DACHPt displayed robust stability and would effectively inhibit the undesired release under physiological condition, thus exhibiting much longer in vivo half-life than diblock copolymer micelles. With significant in vitro cell cytotoxicity to A549 lung cancer cells, this UM/DACHPt demonstrated efficient antitumor efficacy on an A549 xenograft tumor model with negligible tissue cytotocxity. Therefore, this UM/DACHPt provides a promising new strategy for lung cancer therapy. PMID- 27966357 TI - Coupled Nitrification-Denitrification Caused by Suspended Sediment (SPS) in Rivers: Importance of SPS Size and Composition. AB - Suspended sediment (SPS) is ubiquitous in rivers, and SPS with different particle sizes and compositions may affect coupled nitrification-denitrification (CND) occurring on SPS significantly. However, there is no related research report. In this work, 15N isotope tracer technique was adopted to explore the CND in systems containing SPS (8 g L-1 and 1 g L-1) collected from the Yellow River with various particle sizes, including <2, 2-20, 20-50, 50-100, and 100-200 MUm. The results showed that the CND occurred on SPS and the CND rate was negatively related to particle size; both nitrification and denitrification rate constants increased with decreasing SPS particle size. For instance, SPS (8 g L-1) with a particle size below 2 MUm had the highest 15N2 emission rate of 1.15 mg-N/(m3.d), which was 2.9 times that of 100-200 MUm. This is because SPS with a smaller particle size had a larger specific surface area and a higher organic carbon content, which is beneficial for bacteria growth. Both the nitrifying and denitrifying bacteria population were positively correlated with CND rate (p < 0.05). Different from the 15N2 production, 15N2O emission rate did not decrease with increasing SPS particle size. For the system containing 8 g L-1 SPS, 15N2O emission rate reached the highest of 1.05 MUg-N/(m3.d) in the 50-100 MUm SPS system, which was 17.5 times that of 100-200 MUm. Similar results could be found from the system with 1 g L-1 SPS. This is due to the fact that the oxygen concentration at the SPS-water interface increased with SPS particle size, and the oxygen conditions might be most suitable for the production of N2O in the 50 100 MUm system. This study suggests that SPS size and composition play an important role in nitrogen cycle of river systems, especially for the production of N2O. PMID- 27966358 TI - Exploring the Photophysical and Photochemical Properties of N-(Thioalkyl) saccharins as an Alternative Route to the Synthesis of Tricyclic Sultams. AB - Photocyclization of N-(thioalkyl)-saccharin was carried out to obtain different polycyclic sultams in good yields. These photoreactions were efficient under inert atmosphere and acetone triplet-sensitized conditions indicating that the triplet excited state is directly involved in the formation of annulated products. The presence of molecular oxygen changes product distribution, and only photo-oxygenation products (sulfoxides and sulfones) were found. This result is especially valuable since, by simple changing from nitrogen- to oxygen-saturated solvent conditions, the reaction outcome can be tuned from cyclized to sulfur oxidation products. Additionally, steady-state photolysis, electrochemistry, and laser time-resolved spectroscopic studies confirmed that these reactions mainly proceeded by intramolecular electron transfer (ET) between the triplet excited saccharin moiety and sulfur atom. PMID- 27966359 TI - Deliquescence Relative Humidities of Organic and Inorganic Salts Important in the Atmosphere. AB - The deliquescence relative humidities (DRH) as a function of temperature have been determined for several salts of atmospheric importance using humidity controlled thermogravimetric analysis (HTGA): sodium hydrogen oxalate monohydrate (NaHC2O4.H2O), sodium oxalate (Na2C2O4), sodium ammonium sulfate dihydrate (NaNH4SO4.2H2O, lecontite), sodium hydrogen malonate monohydrate (NaHC3H2O4.H2O), sodium malonate monohydrate (Na2C3H2O4.H2O), and ammonium hydrogen malonate (NH4HC3H2O4). The temperature-dependent onset DRH values (where a dry mixture begins to take up water) were also determined for mixtures of ammonium sulfate with malonic acid, and ammonium sulfate with sodium oxalates and sodium malonates, respectively. We demonstrate that the onset DRH is independent of the ratio of solids in the mixture. In general, onset DRH values were always lower than the pure component DRH values. PMID- 27966360 TI - Extension of the Slipids Force Field to Polyunsaturated Lipids. AB - The all-atomic force field Slipids (Stockholm Lipids) for lipid bilayers simulations has been extended to polyunsaturated lipids. Following the strategy adopted in the development of previous versions of the Slipids force field, the parametrization was essentially based on high-level ab initio calculations. Atomic charges and torsion angles related to polyunsaturated lipid tails were parametrized using structures of dienes molecules. The new parameters of the force field were validated in simulations of bilayers composed of seven polyunsaturated lipids. An overall good agreement was found with available experimental data on the areas per lipids, volumetric properties of bilayers, deuterium order parameters, and scattering form factors. Furthermore, simulations of bilayers consisting of highly polyunsaturated lipids and cholesterol molecules have been carried out. The majority of cholesterol molecules were found in a position parallel to bilayer normal with the hydroxyl group directed to the membrane surface, while a small fraction of cholesterol was found in the bilayer center parallel to the membrane plane. Furthermore, a tendency of cholesterol molecules to form chain-like clusters in polyunsaturated bilayers was qualitatively observed. PMID- 27966361 TI - Identification of Short Hydrophobic Cell-Penetrating Peptides for Cytosolic Peptide Delivery by Rational Design. AB - Cell-penetrating peptides (CPPs) enhance the cellular uptake of membrane impermeable molecules. Most CPPs are highly cationic, potentially increasing the risk of toxic side effects and leading to accumulation in organs such as the liver. As a consequence, there is an unmet need for less cationic CPPs. However, design principles for effective CPPs are still missing. Here, we demonstrate a design principle based on a classification of peptides according to accumulated side-chain polarity and hydrophobicity. We show that in comparison to randomly selected peptides, CPPs cover a distinct parameter space. We designed peptides of only six to nine amino acids with a maximum of three positive charges covering this property space. All peptides were tested for cellular uptake and subcellular distribution. Following an initial round of screening we enriched the collection with short and hydrophobic peptides and introduced d-amino acid substitutions and lactam bridges which increased cell uptake, in particular for long-term incubation. Using a GFP complementation assay, for the most active peptides we demonstrate cytosolic delivery of a biologically active cargo peptide. PMID- 27966362 TI - Ion Pathways in the Na+/K+-ATPase. AB - Na+/K+-ATPase (NKA) is an essential cation pump protein responsible for the maintenance of the sodium and potassium gradients across the plasma membrane. Recently published high-resolution structures revealed amino acids forming the cation binding sites (CBS) in the transmembrane domain and variable position of the domains in the cytoplasmic headpiece. Here we report molecular dynamic simulations of the human NKA alpha1beta1 isoform embedded into DOPC bilayer. We have analyzed the NKA conformational changes in the presence of Na+- or K+ cations in the CBS, for various combinations of the cytoplasmic ligands, and the two major enzyme conformations in the 100 ns runs (more than 2.5 MUs of simulations in total). We identified two novel cytoplasmic pathways along the pairs of transmembrane helices TM3/TM7 or TM6/TM9 that allow hydration of the CBS or transport of cations from/to the bulk. These findings can provide a structural explanation for previous mutagenesis studies, where mutation of residues that are distal from the CBS resulted in the alteration of the enzyme affinity to the transported cations or change in the enzyme activity. PMID- 27966363 TI - Bayesian Model Averaging for Ensemble-Based Estimates of Solvation-Free Energies. AB - This paper applies the Bayesian Model Averaging statistical ensemble technique to estimate small molecule solvation free energies. There is a wide range of methods available for predicting solvation free energies, ranging from empirical statistical models to ab initio quantum mechanical approaches. Each of these methods is based on a set of conceptual assumptions that can affect predictive accuracy and transferability. Using an iterative statistical process, we have selected and combined solvation energy estimates using an ensemble of 17 diverse methods from the fourth Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) blind prediction study to form a single, aggregated solvation energy estimate. Methods that possess minimal or redundant information are pruned from the ensemble and the evaluation process repeats until aggregate predictive performance can no longer be improved. We show that this process results in a final aggregate estimate that outperforms all individual methods by reducing estimate errors by as much as 91% to 1.2 kcal mol-1 accuracy. This work provides a new approach for accurate solvation free energy prediction and lays the foundation for future work on aggregate models that can balance computational cost with prediction accuracy. PMID- 27966364 TI - Temperature-Induced Lattice Relaxation of Perovskite Crystal Enhances Optoelectronic Properties and Solar Cell Performance. AB - Hybrid organic-inorganic perovskite crystals have recently become one of the most important classes of photoactive materials in the solar cell and optoelectronic communities. Albeit improvements have focused on state-of-the-art technology including various fabrication methods, device architectures, and surface passivation, progress is yet to be made in understanding the actual operational temperature on the electronic properties and the device performances. Therefore, the substantial effect of temperature on the optoelectronic properties, charge separation, charge recombination dynamics, and photoconversion efficiency are explored. The results clearly demonstrated a significant enhancement in the carrier mobility, photocurrent, charge carrier lifetime, and solar cell performance in the 60 +/- 5 degrees C temperature range. In this temperature range, perovskite crystal exhibits a highly symmetrical relaxed cubic structure with well-aligned domains that are perpendicular to a principal axis, thereby remarkably improving the device operation. This finding provides a new key variable component and paves the way toward using perovskite crystals in highly efficient photovoltaic cells. PMID- 27966366 TI - Metabolic Phenotype of Obesity in a Saudi Population. AB - Metabolic phenotyping of obese populations can shed light on understanding environmental interactions underpinning obesogenesis. Obesity and its comorbidities are a major health and socioeconomic concern globally and are highly prevalent in the Middle East. We employed nuclear magnetic resonance spectroscopy to characterize the metabolic signature of urine and blood plasma for a cohort of obese (n = 50) compared to non-obese (n = 48) Saudi participants. The urinary metabolic phenotype of obesity was characterized by higher concentrations of N-acetyl glycoprotein fragments, bile acids, lysine, and methylamines and lower concentrations of tricarboxylic acid cycle intermediates, glycine, and gut microbial metabolites. The plasma metabolic phenotype of obesity was dominated by sugars, branched chain amino acids, and lipids, particularly unsaturated lipids, with lower levels of plasma phosphorylcholine and HDL. Serum hepatic enzymes, triglycerides, and cholesterol mapped to specific metabolic phenotypes, potentially indicating the dysregulation of multiple distinct obesity related pathways. Differences between urine and plasma phenotypes of obesity for this Saudi population and that reported for Caucasian individuals indicate population disparities in pathways relating to ketogenesis (more apparent in the Saudi obese population), dysregulated liver function, and the gut microbiome. Mapping population-specific metabolic perturbations may hold promise in establishing population differences relevant to disease risk and stratification of individuals with respect to discovery of new therapeutic targets. PMID- 27966367 TI - Novel SiO2/H2Ti2O5.H2O-Nanochain Composite with High UV-Visible Photocatalytic Activity for Supertransparent Multifunctional Thin Films. AB - In the current work, a peroxo titanium complex (PTC) solution was used as a novel water-soluble precursor to fabricate H2Ti2O5.H2O and the SiO2/H2Ti2O5.H2O nanochain composite at low temperature (90-100 degrees C). The average width of H2Ti2O5.H2O nanochains is 4.5 +/- 1.5 nm. Under full-spectrum irradiation, the Si/Ti-nanochain composite showed good UV-visible light absorption and excellent photocatalytic activity, which is 2.8 times that of P25. In the composite, SiO2 not only contributes to the formation of nanochains and improves the catalytic performance of H2Ti2O5.H2O but also reduces the refractive index of the complex. When coated on transparent organic substrates, the composite thin film exhibited excellent antireflective (as high as 99.3% on PC and 98.9% on PMMA) and self cleaning properties. Pencil hardness, washing, and tape adhesion tests showed favorable adhesion-to-substrate and mechanical robustness of thin films, which make them extremely attractive for applications as highly transparent and self cleaning thin films on lenses, photovoltaic cells, and windows of high-rise buildings. PMID- 27966365 TI - Proteomic Analysis of Primary Human Airway Epithelial Cells Exposed to the Respiratory Toxicant Diacetyl. AB - Occupational exposures to the diketone flavoring agent, diacetyl, have been associated with bronchiolitis obliterans, a rare condition of airway fibrosis. Model studies in rodents have suggested that the airway epithelium is a major site of diacetyl toxicity, but the effects of diacetyl exposure upon the human airway epithelium are poorly characterized. Here we performed quantitative LC MS/MS-based proteomics to study the effects of repeated diacetyl vapor exposures on 3D organotypic cultures of human primary tracheobronchial epithelial cells. Using a label-free approach, we quantified approximately 3400 proteins and 5700 phosphopeptides in cell lysates across four independent donors. Altered expression of proteins and phosphopeptides were suggestive of loss of cilia and increased squamous differentiation in diacetyl-exposed cells. These phenomena were confirmed by immunofluorescence staining of culture cross sections. Hyperphosphorylation and cross-linking of basal cell keratins were also observed in diacetyl-treated cells, and we used parallel reaction monitoring to confidently localize and quantify previously uncharacterized sites of phosphorylation in keratin 6. Collectively, these data identify numerous molecular changes in the epithelium that may be important to the pathogenesis of flavoring-induced bronchiolitis obliterans. More generally, this study highlights the utility of quantitative proteomics for the study of in vitro models of airway injury and disease. PMID- 27966368 TI - Perfectionistic concerns predict increases in adolescents' anxiety symptoms: a three-wave longitudinal study. AB - BACKGROUND AND OBJECTIVES: Although perfectionism has been proposed to be a risk factor for the development of anxiety, research on perfectionism and anxiety symptoms in adolescents is scarce and inconclusive. The aim of the present study was to investigate whether the two higher-order dimensions of perfectionism - perfectionistic strivings and perfectionistic concerns - predict the development and maintenance of anxiety symptoms. An additional aim of the present study was to examine potential reciprocal effects of anxiety symptoms predicting increases in perfectionism. DESIGN: The study used a longitudinal design with three waves spaced 4-5 months apart. METHODS: A non-clinical sample of 489 adolescents aged 12-19 years completed a paper-and-pencil questionnaire. RESULTS: As expected, results showed a positive effect from perfectionistic concerns to anxiety symptoms, but the effect was restricted to middle-to-late adolescents (16-19 years old): Perfectionistic concerns predicted longitudinal increases in adolescents' anxiety symptoms, whereas perfectionistic strivings did not. Furthermore, anxiety symptoms did not predict increases in perfectionism. CONCLUSIONS: Implications for the understanding of the relationship between perfectionism and anxiety symptoms are discussed. PMID- 27966369 TI - The theory of agency and breastfeeding. AB - OBJECTIVE: In this paper, we apply psychological agency theory to women's interviews of their breastfeeding experiences to understand the role of agency in relation to breastfeeding initiation, maintenance and duration. DESIGN: Qualitative, video interviews were collected from 49 women in the UK from a wide range of ethnic, religious, educational and employment backgrounds about their breastfeeding experiences. We undertook secondary analysis of the data focusing on their accounts of vulnerability and agency. FINDINGS: Women's agency was impacted by a variety of factors including their own vulnerability, knowledge, expectations and experience, the feeding environment and the support of health professionals in sharing decision-making and dealing with uncertainty. CONCLUSION: Health professionals as co-agents with women are well positioned to maintain, enhance or restore women's sense of agency. Breastfeeding goals should be included in women's birth plans. Training related to agency, continuity of care, and staffing and workload management supported by national breastfeeding policies could improve breastfeeding rates and experiences. PMID- 27966370 TI - Investigation of the role of flocculation conditions in recuperative thickening on dewatering performance and biogas production. AB - There is considerable interest in recuperative thickening (RT), the recycling of partially digested solids in an anaerobic digester outlet stream back into the incoming feed, as a 'high-performance' process to increase biogas production, increase system capacity, and improve biosolids stabilization. While polymer flocculation is commonly used in full-scale RT operations, no studies have investigated the effect of flocculation conditions on RT process performance. Our goal was to investigate the effect of polymer type and dosage conditions on dewatering performance and biogas production in a lab-scale RT system. The type of polymer flocculant significantly affected dewatering performance. For example, the 440 LH polymer (low molecular weight (MW) polyacrylamide) demonstrated lower capillary suction time (CST) and filtrate total suspended solids (TSS) values than the C-6267 polymer (high MW polyacrylamide). An examination of the dewatering performance of RT digesters with different polymers found a strong correlation between CST and filtrate TSS. The type of polymer flocculant had no significant effect on biogas productivity or composition; the methane content was greater than 60% in good agreement with typical results. The optimization of the polymer flocculation conditions is a critical task for which the lab-scale RT system used in this work is ideally suited. PMID- 27966371 TI - Engineering of microcomplex of artemether and lumefantrine for effective drug treatment in malaria. AB - The objective of the present work was to engineer and characterize stable citric acid cross-linked microcomplex of the inclusion complexes of artemether with beta cyclodextrin and Kollidon VA 64(r) with lumefantrine to release the drugs in controlled manner for effective combinational drug treatment in malaria. The microcomplex had a hydrodynamic diameter of 1047 +/- 147 nm with surface charge of -19.7 +/- 0.5 mV. The microcomplex showed high encapsulation efficiencies 85.6 +/- 1.78% for artemether and 91.16 +/- 2.21% for lumefantrine due to the lipophilic nature of drugs. In-vitro and in-vivo drug release studies showed the controlled release of artemether and lumefantrine for a period of 24 h. PMID- 27966372 TI - Increased first-trimester nuchal translucency associated with a dicentric chromosome and 9q34.3 microdeletion syndrome. AB - We present prenatal diagnosis and chromosomal microarray analysis (CMA) of 9q34.3 microdeletion in a foetus with an increased nuchal translucency (NT). Conventional G-banding analysis showed a de novo translocation: 45, XX, dic (9;13)(q34;p13). CMA revealed a 3.6 Mb 9q34.3 microdeletion encompassing an OMIM gene of EHMT1 consistent with the diagnosis of Kleefstra syndrome and 9q subtelomeric deletion syndrome. We suggest an application of CMA at prenatal diagnosis in pregnancies with increased NT and an apparent balanced translocation on conventional karyotype. PMID- 27966374 TI - Journal of Wound Care Supplement. Edited abstracts from: Advances in wound management - A European Wound Management Association/Journal of Wound Care Conference, to be held in Madrid on 26-28 April, 1998. AB - Leg ulcers; Pressure sores; Diabetic foot disease; Dressings; Pressure relieving/reducing supports; Wound infection and microbiology; Wound assessment; New techniques in wound treatment; Quality of life and the patient's perspective; Financial issues. PMID- 27966373 TI - Potential hypoglycaemic activity phenolic glycosides from Moringa oleifera seeds. AB - Moringa oleifera seed has remarkable curative effects on reducing blood pressure, blood sugar and enhancing human immunity. In this study, one novel phenolic glycoside (1) together with four known compounds 2-5 were isolated from the macroporous resin adsorption extract of M. oleifera seeds, and the compound 3 was reported for the first time from this plant. The structure of the new crystalline compound was determined on the basis of spectroscopic analyses including mass spectrometry, 1D and 2D NMR experiments. The hypoglycaemic activity of isolated compounds was investigated with HepG2 cell and STZ-induced mice. It was found that compound 1, 4 and 5 could promote the glucose consumption of insulin resistance cells and reduce blood glucose levels of STZ-induced mice. This study concludes that compound 1, 4 and 5 may be developed as new and safe hypoglycaemic drugs. PMID- 27966375 TI - Controlled biosynthesis of silver nanoparticles using nitrate reductase enzyme induction of filamentous fungus and their antibacterial evaluation. AB - The controlled synthesis of silver nanoparticles (AgNPs) using cell-free filtrate of Fusarium oxysporum fungus was investigated. The effect of fungal incubation period on nanoparticle formation and nitrate reductase enzyme activity was studied using UV-visible spectroscopy and Harley assay, respectively. The highest AgNP formation was observed in the cell-free filtrate of biomass harvested at the early stationary phase where the NR enzyme activity is the maximum. Mixing of the cell-free filtrates of fungal cultures obtained at 23, 28, and 33 degrees C with silver nitrate solution confirms the higher productivity of AgNP biosynthesis using the cell-free filtrate of fungus incubated at 28 degrees C. The effect of some factors such as carbon and nitrate sources and light in fungal incubation period on nitrate reductase induction and AgNP formation was also evaluated. In conclusion, increasing nitrate and carbon sources and presence of light induced NR enzyme and produced AgNPs with smaller size, higher monodispersity, and productivity. Results revealed that the presence of ammonium prevents the NR enzyme secretion and causes to the lower productivity of AgNPs. PMID- 27966376 TI - Production of 17-O-demethyl-geldanamycin, a cytotoxic ansamycin polyketide, by Streptomyces hygroscopicus DEM20745. AB - The actinomycete DEM20745, collected from non-rhizosphere soil adjacent to Paraserianthes falactaria trees (Cangkringan, Indonesia), is an efficient producer of the anticancer ansamycin polyketide 17-O-demethyl-geldanamycin (17-O DMG), a biosynthetic precursor of the Hsp90 inhibitor geldanamycin (GDM). In DEM20745, 17-O-DMG is the major ansamycin product observed reaching a maximum titre of 17 mg/L in the fermentation broth. 17-O-DMG has the potential to be a key starting material for the semi-synthesis of GDM analogues for use in anticancer therapy. Thus, this preferential biosynthesis of 17-O-DMG facilitates easy access to this important molecule and provides further insight in the biosynthesis of the geldanamycins. PMID- 27966377 TI - Acute myeloid leukemia: a retrospective claims analysis of resource utilization and expenditures for newly diagnosed patients from first-line induction to remission and relapse. AB - OBJECTIVE: The objective of this study was to estimate resource utilization and expenditures for patients with acute myeloid leukemia (AML) in a real-world claims database. RESEARCH DESIGN AND METHODS: AML patients were identified in MarketScan claims databases between 1 January 2009 and 31 January 2015. Patients had a minimum of two AML diagnosis codes, hospitalization within 14 days after initial diagnosis, and >=6 months of enrollment before initial diagnosis. Patients were monitored from first-line induction to a record of remission. A subset had a record of a second treatment period, defined as time from relapse to remission. Patient demographics, AML risk factors, and comorbidities were recorded. Descriptive analysis of utilization and expenditures (in 2014 $US) were reported for each cohort. RESULTS: The inclusion criteria were met in 1597 patients (mean age, 58.4 years; 51.0% male). Ninety percent of patients had >=1 risk factor for AML. Mean (SD) healthcare expenditures for patients from first line induction to remission (n = 681) were $208,857 ($152,090). Of the 157 who had a record of relapse, 70 had a record of a second remission. Expenditures for these patients (n = 70) from relapse to remission were $142,569 ($208,307); 60% were admitted to a hospital for a mean of 18.5 hospital days, and 20% had >=1 emergency room visit. CONCLUSIONS: Although this claims-based analysis is limited by a lack of generalizability to noninsured populations and potential underreporting of certain events and diagnoses, we found that treating AML patients poses a significant healthcare burden, during both first-line induction and relapse. With people living longer, the number of cases of AML is expected to increase in the future. PMID- 27966378 TI - Compression Bandaging: Selection and Evidence. AB - The use of effective compression has been shown to heal venous leg ulcers1 and prevent their recurrence2 whereas inappropriate compression may lead to skin damage and, in extreme cases, amputation3. It is therefore important to differentiate between appropriate and inappropriate compression. Compression is palliative rather than curative, and hence needs to be worn for as long as the patient's venous disease is present: in most cases this means a lifetime. Compression should be applied only after a clinician with appropriate training has excluded the possibility of arterial disease. PMID- 27966379 TI - Information for Patients and Carers. AB - It Is essential for nurses to develop their skills in the education of patients with leg ulcers. No ulcer will be healed, or prevented, unless the patient co operates with, and participates in, the treatment. Full compliance is more likely if the patient understands what is being done, and why. Teaching patients the self-help skills which they should practise for the rest of their lives to promote healing and prevent ulcer recurrence requires patience, skill and an understanding of the individual's personal circumstances1. PMID- 27966380 TI - Leg Ulcer Clinics. AB - The Crown report on nurse prescribing estimates that the treatment of leg ulcers costs the NHS L300-L600 million per year1. The bulk of this expenditure falls on the community nurses who care for these patients2. PMID- 27966381 TI - Investigations for Assessment. AB - One of the most important aspects of leg ulcer management is to establish the causal pathology. Unless the correct diagnosis is established treatment is, at best, likely to be unsuccessful but could be harmful1. For example, inappropriate use of compression bandaging can cause significant skin necrosis1,2. Equally, failure to use adequate compression when treating venous ulceration has been shown to delay healing3 significantly. It is therefore important that the patient is fully assessed and a structured history obtained4,5. This should determine which investigations will be required. PMID- 27966382 TI - Graduated Compression Hosiery. AB - Graduated compression hosiery is used for several clinical conditions related to venous insufficiency and lymphoedema. In the management of venous ulceration, graduated compression hosiery is regarded as an essential component of prevention of ulcer recurrence. Occasionally it is used for ulcer healing. It is also used prophylactically in the prevention of deep vein thrombosis1. PMID- 27966383 TI - Managing Leg Ulcers. AB - Thorough, systematic and accurate assessment of the patient, identification of the underlying cause of ulcer and any local problems at the wound site are prerequisites to planning appropriate care and to preventing avoidable delays in healing1. On the following pages two decision-making algorithms are illustrated; one for use in differential diagnosis (Figure 1), the other (Figure 2) for choosing appropriate treatment regimens for venous leg ulcers2. PMID- 27966384 TI - Secondary erythrocytosis caused by hemoglobin Tak/beta0-thalassaemia disease during pregnancy: A case report. PMID- 27966385 TI - One new lignan derivative from the Combretum alfredii Hance. AB - One new lignan derivative 2,3-dimethyl-4-(4-methoxyphenyl)-6,7 dihydroxynaphthalene (1), together with five known compounds (2-6), were isolated from ethanol extract of the branches and leaves of Combretum alfredii Hance collected in Hainan Province, China. Their structures were elucidated by the detailed analysis of comprehensive spectroscopic data. Compounds 1, 2, 5 and 6 were isolated from the genus of Combretum for the first time. All compounds were evaluated for their antibacterial activities. Compounds 1 and 2 showed significant antibacterial activities against six pathogenic bacteria. PMID- 27966386 TI - More on the thrombocytopenia of the non-alcoholic fatty liver disease. AB - BACKGROUND: Using only serologic determinations, we have previously found that thrombocytopenia presents in less than one half of patients with non-alcoholic fatty liver disease (NAFLD). MATERIAL AND METHODS: Employing a more accurate method to define the presence of NAFLD, serologic determinations (Fibromax(r)) coupled with liver transient elastography (TE/Fibroscan(r)), we have prospectively studied a group of 211 individuals with a suspicion of a liver disease. RESULTS: NAFLD was identified in 81 individuals. In 48 persons another causes of liver damage were identified and discarded from further analysis. A subset of 33 patients with NAFLD without liver fibrosis or cirrhosis was analyzed. In eight of them (24%), thrombocytopenia (less than 150 * 109/l platelets) was identified. The presence of thrombocytopenia in this subset of persons was associated with overweight, was usually mild, above 50 * 109/l, was not associated to mucocutaneous bleeding and did not require treatment. CONCLUSIONS: NAFLD should be considered as a cause of mild thrombocytopenia. Our initial observation has been confirmed and defined more precisely. Additional studies are needed to further define more features of the thrombocytopenia of NAFLD, as well as its mechanisms. PMID- 27966387 TI - Latency to vaginal mesh exposure with mesh placed abdominally versus vaginally in pelvic floor surgery: A retrospective comparative study. AB - The primary aim was to compare the difference in time to mesh exposure between mesh placed abdominally versus vaginally. This is a retrospective comparative study of patients presented with vaginal mesh exposure between January 2001 and July 2012. This study compares patients who had undergone vaginally placed mesh procedures to those who had had abdominally placed mesh. Kaplan-Meier survival analysis was used to measure the time to mesh exposure. There were 68 patients with mesh exposure in our cohort. Thirty eight patients had undergone vaginal placement of mesh and 30 patients had abdominal mesh. There was a statistically significant difference in time to mesh exposure between abdominal and vaginal meshes (p<=.0001). Mean time to vaginal mesh exposure with abdominal mesh was 59.8 months (95%CI 46.2-73.3) compared to 23 months (95%CI 15.9-30.2) for vaginal mesh. When controlling for age, BMI and surgeon at index surgery, the Hazard Ratio for mesh exposure in our Cox Regression model was 0.53 (95%CI 0.39-0.71) (p <=.0001). The mean time to vaginal mesh exposure after abdominal mesh was longer compared to the time to exposure with vaginally placed mesh (60 versus 23 months, p <=.0001). These results support the evolving evidence that mesh exposures can occur many years distant from the procedure and warrant some level of surveillance or provision of warning signs by the providers who perform procedures with mesh. PMID- 27966388 TI - Municipal wastewater biological nutrient removal driven by the fermentation liquid of dairy wastewater. AB - : Carbon substrate is required by biological nutrient removal (BNR) microorganism, but it is usually insufficient in the influent of many municipal wastewater treatment plants. In this study the use of ethanol-enriched fermentation liquid, which was derived from dairy wastewater, as the preferred carbon substrate of BNR was reported. First, the application of dairy wastewater and food processing wastewater and their fermentation liquid as the carbon substrate of BNR was compared in the short-term tests. The fermented wastewater showed higher BNR performance than the unfermented one, and the fermentation liquid of dairy wastewater (FL-DW), which was obtained under pH 8 and fermentation time of 6 day, exhibited the highest phosphorus (95.5%) and total nitrogen (97.6%) removal efficiencies due to its high ethanol content (57.9%). Then, the long-term performance of FL-DW acting as the carbon substrate of BNR was compared with that of acetate and ethanol, and the FL-DW showed the greatest phosphorus and total nitrogen removal. Further investigation showed that the use of FL-DW caused the highest polyhydroxyalkanoates (PHAs) synthesis in BNR microbial cells, and more PHAs were used for phosphorus uptake and denitrification rather than glycogen synthesis and microbial growth. The FL-DW can be used as a preferred carbon substrate for BNR microbes. ABBREVIATIONS: AB: aerobic end sludge active biomass; BNR: biological nutrient removal; DW: dairy wastewater; FL-DW: fermentation liquid of dairy wastewater; FPW: food processing wastewater; FL-FPW: fermentation liquid of food processing wastewater; PHAs: polyhydroxyalkanoates; PHB: poly-3-hydroxybutyrate; PHV: poly-3-hydroxyvalerate; PH2MV: poly-3-hydroxy-2- methylvalerate; PAOs: phosphorus accumulating organisms; SBR: sequencing batch reactor; SOP: soluble ortho-phosphorus; TN: total nitrogen; TSS: total suspended solids; VSS: volatile suspended solids; VFAs: volatile fatty acids; WWTPs: wastewater treatment plants. PMID- 27966389 TI - Effect of gradual-increasing aeration mode in an aerobic tank on nutrients' removal and functional microbial communities. AB - Different aeration rates and modes in an aerobic tank of an anaerobic/anoxic/aerobic (A2O) process were investigated to reveal their influence on nitrogen and phosphorus removal efficiency. Meanwhile, Illumina high throughput sequencing of partial 16S rRNA gene of bacteria was conducted to monitor the abundance and composition of microbial communities. The results showed that higher aeration rate led to better nutrients' removal efficiency. The gradual-increasing aeration mode along the wastewater stream enhanced the contaminants' removal and the system achieved chemical oxygen demand, [Formula: see text]-N, total nitrogen (TN) removal rates of 72%, 96% and 51%, respectively. However, the gradual-decreasing or uniform aeration modes resulted in inefficient removal of TN, especially the ammonia due to low DO in the end parts of A2O. Microbial community analysis indicated that denitrifying phosphorus-accumulating bacteria Acinetobacter spp. were the most dominant groups under the gradual increasing aeration mode in all tanks of the A2O bioreactor. Moreover, the members of genera Clostridium, Thauera and Dechloromonas also largely existed in the system. The gradual-increasing aeration mode and cooperation of different groups of bacteria made the system stable and high-performance. PMID- 27966390 TI - Adsorption isotherm, kinetic and mechanism of expanded graphite for sulfadiazine antibiotics removal from aqueous solutions. AB - The adsorption of sulfadiazine from water by expanded graphite (EG), a low cost and environmental-friendly adsorbent, was investigated. Several adsorption parameters (including the initial sulfadiazine concentration, contact time, pH of solution, ionic strength and temperature) were studied. Results of equilibrium experiments indicated that adsorption of sulfadiazine onto EG were better described by the Langmuir and Tempkin models than by the Freundlich model. The maximum adsorption capacity is calculated to be 16.586 mg/g at 298 K. The kinetic data were analyzed by pseudo-first-order, pseudo-second-order and intraparticle models. The results indicated that the adsorption process followed pseudo-second order kinetics and may be controlled by two steps. Moreover, the pH significantly influenced the adsorption process, with the relatively high adsorption capacity at pH 2-10. The electrostatic and hydrophobic interactions are manifested to be two main mechanisms for sulfadiazine adsorption of EG. Meanwhile, the ionic concentration of Cl- slightly impacted the removal of sulfadiazine. Results of thermodynamics analysis showed spontaneous and exothermic nature of sulfadiazine adsorption on EG. In addition, regeneration experiments imply that the saturated EG could be reused for sulfadiazine removal by immersing sodium hydroxide. PMID- 27966391 TI - Resident characteristics to evaluate during recruitment and interview: a Delphi study. AB - BACKGROUND AND OBJECTIVES: The recruitment and interview process for medical residency programmes is a time- and resource-intensive effort. There is very little research to guide programmes when evaluating residency candidates. This study represents one step in identifying candidate characteristics to assess during the recruitment and interview process. METHODS: Sixteen expert interviewers from 14 family medicine residency programmes in North Carolina participated in a three-round Delphi study to build consensus around a ranked list of successful resident candidate characteristics. An interrater reliability analysis produced average pair-wise agreement and Krippendorff's Alpha coefficients. RESULTS: Clinical skills, medical knowledge, interpersonal and communication skills, critical thinking, and professional and ethical behaviour were the highest ranked characteristics. Average pair-wise agreement for rounds two and three were 6.30 and 11.04%, respectively. CONCLUSIONS: Residency programmes may benefit from using an empirically studied list of characteristics to evaluate candidate applications and interviews. Future research should include national surveys of expert interviewers from a variety of residency programmes and a longitudinal study to correlate interview evaluations using the ranked list with measures of residency success. PMID- 27966392 TI - Changes in cytokines, leptin, and IGF-1 levels in overtrained athletes during a prolonged recovery phase: A case-control study. AB - We investigated how cytokines are implicated with overtraining syndrome (OTS) in athletes during a prolonged period of recovery. Plasma IL-6, IL-10, TNF-alpha, IL 1beta, adipokine leptin, and insulin like growth factor-1 (IGF-1) concentrations were measured in overtrained (OA: 5 men, 2 women) and healthy control athletes (CA: 5 men, 5 women) before and after exercise to volitional exhaustion. Measurements were conducted at baseline and after 6 and 12 months. Inflammatory cytokines did not differ between groups at rest. However, resting leptin concentration was lower in OA than CA at every measurement (P < 0.050) but was not affected by acute exercise. Although IL-6 and TNF-alpha concentrations increased with exercise in both groups (P < 0.050), pro-inflammatory IL-1beta concentration increased only in OA (P < 0.050) and anti-inflammatory IL-10 was greater in CA (P < 0.001). In OA, exercise-related IL-6 and TNF-alpha induction was enhanced during the follow-up (P < 0.050). IGF-1 decreased with exercise in OA (P < 0.050); however, no differences in resting IGF-1 were observed. In conclusion, low leptin level at rest and a pro-inflammatory cytokine response to acute exercise may reflect a chronic maladaptation state in overtrained athletes. In contrast, the accentuation of IL-6 and TNF-alpha responses to acute exercise seemed to associate with the progression of recovery from overtraining. PMID- 27966393 TI - Letters. AB - ODOUR-ABSORBING DRESSINGS: 1 ODOUR-ABSORBING DRESSINGS: 2 SUB-BANDAGE PRESSURE MEASUREMENT CONTROLLING BLEEDING IN FRAGILE FUNGATING TUMOURS PREVENTING HYPERTROPHIC SCARRING AND KELOIDS. PMID- 27966394 TI - From the Journals. AB - NURSES' KNOWLEDGE AND PRESSURE SORE TREATMENT POPLITEAL VEIN REFLUX. PMID- 27966395 TI - Understanding compression therapy. AB - The selection and application of safe and effective compression therapy requires a basic understanding of how compression achieves its clinical effects and how to identify patients who might benefit from it and those in whom it is a contraindication. PMID- 27966398 TI - Eradicating Bacterial Biofilms with Natural Products and Their Inspired Analogues that Operate Through Unique Mechanisms. AB - Bacterial biofilms are surface-attached communities of slow- or non-replicating bacterial cells that display high levels of tolerance toward conventional antibiotic therapies. It is important to know that our entire arsenal of conventional antibiotics originated from screens used to identify inhibitors of bacterial growth, so it should be little surprise that our arsenal of growth inhibiting agents have little effect on persistent biofilms. Despite this current state, a diverse collection of natural products and their related or inspired synthetic analogues are emerging that have the ability to kill persistent bacterial biofilms and persister cells in stationary cultures. Unlike conventional antibiotics that hit bacterial targets critical for rapidly-dividing bacteria (i.e., cell wall machinery, bacterial ribosomes), biofilm-eradicating agents operate through unique growth-independent mechanisms. These naturally occurring agents continue to inspire discovery efforts aimed at effectively treating chronic and recurring bacterial infections due to persistent bacterial biofilms. PMID- 27966397 TI - Constituents from stem barks of Luehea ochrophylla Mart and evaluation of their antiparasitic, antimicrobial, and antioxidant activities. AB - Luehea species are found in almost all Central and South American countries. The present work describes the phytochemical study, isolation, and structural characterisation of friedelin, beta-friedelinol, lupeol, pseudotaraxasterol, beta sitosterol, betulinic acid, taraxasterol, (-)-epicatechin, beta-sitosterol-3-O beta-d-glucopyranoside, and (+)-epicatechin-(4beta->8)-epicatechin from stem barks of Luehea ochrophylla Mart. The structural identification of the isolated compounds was mainly performed by NMR analyses and comparison with the data from literature. These compounds were isolated for the first time in the genus Luehea, except beta-sitosterol glucopyranoside, (-)-epicatechin, and lupeol. Hexane extract (HE) and dichloromethane (DF) and ethyl acetate (AF) fractions exhibited antiparasitic activity against amastigote (intracellular) and trypomastigote culture forms of Trypanosoma cruzi. The ethanol extract (EE), DF, and ethanol fraction (EF) exhibited considerable antifungal activity against Candida albicans. Moreover, extracts and fractions exhibited significant percentage of capture free radicals of 2,2-diphenyl-picrylhydrazyl (DPPH) when compared to the standard of ascorbic acid. PMID- 27966399 TI - Editorial: Beyond Pills and Needles: Delivering on New Promise. PMID- 27966400 TI - Editorial: Overview on microRNAs in Cancer Development and Virus Infection. PMID- 27966401 TI - [Treatment of neglect, an attention disorder]. AB - - Neglect occurs in 30-50% of patients in the subacute phase post-stroke. Patients with neglect ignore one side of their body or one part of the space around them. - Treatment of neglect is important, as patients with neglect recover more slowly and are less independent compared to patients without neglect.- Visual scanning training is currently recommended in the guidelines as a treatment. The focus of this intensive treatment is on compensation, not on recovery. Scientific evidence for its effectiveness is scarce. - Other treatments, such as prism adaptation, limb activation training and brain stimulation are being investigated. However, the available evidence for their effectiveness is insufficient as yet. - In addition to neuropsychological tests, outcome measures at the level of functioning in daily life should be included in studies regarding the treatment of neglect.- New research is increasingly focusing on combining different treatments, which should ultimately be adapted for each patient individually. PMID- 27966402 TI - [Colorectal cancer surgery in the oldest Dutch patients: retrospective analysis of two national databases covering 2011 and 2012]. AB - OBJECTIVE: Adequate decision-making concerning elderly patients with colorectal cancer requires accurate information regarding the risks of treatment. We analysed the post-operative outcomes and survival following colorectal resections in the oldest old patients (>= 85 years old). DESIGN: Retrospective study. METHOD: We analysed the data from 2011 and 2012 of all patients with colorectal carcinoma, stage I-III, from two national databases, namely the Dutch Surgical Colorectal Audit registry (DSCA) and the Netherlands Cancer Registry (NKR). RESULTS: The study included over 1200 elderly patients. The postoperative complication rate was 41%. The frequency of cardiopulmonary complications rose rapidly with age, from 11% in those < 70 years to 38% in those aged > 85 years. The postoperative 30-day mortality rate was 10% for the oldest old patients, whereas it was 14% after three months, 24% after one year and 36% after two years. After correction for expected mortality in the general population, excess mortality for the oldest old was 12% in the first year and 3% in the second year. CONCLUSION: For patients aged >= 85 years who undergo surgical resection for colorectal carcinoma, high rates of cardiopulmonary complications and excess mortality in the first year after surgery are observed. We propose that these data could be analysed together with information regarding individual patients' health status, to enable optimisation of future decision-making regarding potential surgical intervention in elderly patients. PMID- 27966403 TI - [A 9-year-old boy with 'pinpoint pain' caused by pyomyositis]. AB - BACKGROUND: Pyomyositis is a rare bacterial infection of striated muscle, usually caused by Staphylococcus aureus. CASE DESCRIPTION: A healthy 9-year-old boy was referred to us because of pain in the hip and fever. We noticed he could point to the pain with one finger; this is referred to as 'pinpoint pain'. An MRI indicated a diagnosis of pyomyositis of the iliacus muscle and piriformis. The infection was caused by S. aureus. The boy recovered completely and swiftly with antibiotic therapy. CONCLUSION: This specific type of pyomyositis in the hip is rare, especially in children. Being able to localise the pain with one finger is a typical characteristic of this condition. MRI is the investigation of first choice to confirm this diagnosis. PMID- 27966404 TI - [Ischemic stroke in young women]. AB - - In virtually all age groups, the incidence of ischemic stroke is higher in men. However, in women aged between 25-49 years the prevalence is higher than in men. Female-specific risk factors and disorders may explain this peak.- Pregnancy and the post-partum period are associated with physiological changes which can increase blood coagulation. Complications during pregnancy may also increase the risk of ischaemic stroke.- Migraine with aura and antiphospholipid syndrome are disorders which are also associated with an increased risk of ischaemic stroke. These disorders are more common in women compared to men. Furthermore, hormonal contraceptives containing oestrogen are also identified to increase the incidence of ischaemic stroke.- The acute treatment and secondary prevention of ischaemic stroke in young women is identical to that in elderly stroke patients, be it men or women, although thrombolysis and platelet aggregation inhibition in pregnant women should be approached with care.- Clinical outcomes after stroke for women under the age of 50 are worse compared to age-matched men. PMID- 27966405 TI - [Overweight, obesity and life expectancy: do people with a high BMI live longer?] AB - - The relationship between BMI and relative mortality risk is J- or U-shaped; both a low and a high BMI are related to increased risk of mortality.- When analyses are restricted to healthy individuals who are non-smokers and are followed up for a long time, the relative mortality risk is already increased at a BMI of 25 kg/m2 and increases further with increasing BMI.- There are people with obesity who do not have significant cardiovascular risk factors, but even so they are at increased risk of cardiovascular disease compared to people who are not overweight and lack risk factors.- People with severe illnesses often experience weight loss and - at the same time - are at increased risk of premature death, and therefore it appears that overweightness is associated with a favourable prognosis.- The observation that overweight and obese people are not linked to increased mortality can largely be explained by methodological sources of bias. PMID- 27966406 TI - [Randomized trial of a lifestyle program in obese infertile women]. AB - OBJECTIVE: Small intervention studies suggest that modest weight loss increases the chance of conception and may improve perinatal outcome, but large randomized controlled trials (RCT) are lacking. Our objective was to investigate the effects of a lifestyle intervention in obese infertile women in a multicenter RCT. DESIGN: We randomly assigned infertile women with body mass index >= 29 k/m2 to a six-month lifestyle intervention preceding infertility treatment or to prompt infertility treatment. The primary outcome was the vaginal birth of a healthy singleton at term within 2 years of randomization. RESULTS: Between June 2009 June 2102 we randomly allocated 577 women to one of two treatment strategies: 290 to lifestyle intervention preceding infertility treatment (intervention group) and 287 to prompt infertility treatment (control group). Three women withdrew informed consent, leaving 289 and 285 women for analysis. Discontinuation rate during the lifestyle intervention was 22%. Mean weight loss in the intervention group was 4.4 kg and in the control group 1.1 kg ( p < 0.001); the primary outcome occurred in 76 women (27%) in the intervention group versus 100 (35%) in the control group (RR: 0.77, 95% CI 0.60 to 0.99). The number of natural conceptions leading to ongoing pregnancies was 73 (26%) versus 46 (16%) (RR: 1.6, 95% CI 1.2 to 2.2). Maternal pregnancy-related and labor-related complications and neonatal complications were comparable. CONCLUSION: In obese infertile women lifestyle intervention preceding infertility treatment did not result in better rates of vaginal birth of healthy singletons at term as compared to prompt infertility treatment. PMID- 27966407 TI - Diffuse Symmetric Cerebral Calcifications: An Emerging Clinical Pivot. PMID- 27966408 TI - REPRODUCTIVE AND CHILD HEALTH SERVICES AND DEMOGRAPHIC CHANGE IN THE DISTRICTS OF UTTAR PRADESH, 2002-13 - CORRIGENDUM. PMID- 27966410 TI - ? PMID- 27966409 TI - The Men's Safer Sex project: intervention development and feasibility randomised controlled trial of an interactive digital intervention to increase condom use in men. AB - BACKGROUND: This report details the development of the Men's Safer Sex website and the results of a feasibility randomised controlled trial (RCT), health economic assessment and qualitative evaluation. OBJECTIVES: (1) Develop the Men's Safer Sex website to address barriers to condom use; (2) determine the best design for an online RCT; (3) inform the methods for collecting and analysing health economic data; (4) assess the Sexual Quality of Life (SQoL) questionnaire and European Quality of Life-5 Dimensions, three-level version (EQ-5D-3L) to calculate quality-adjusted life-years (QALYs); and (5) explore clinic staff and men's views of online research methodology. METHODS: (1) Website development: we combined evidence from research literature and the views of experts (n = 18) and male clinic users (n = 43); (2) feasibility RCT: 159 heterosexually active men were recruited from three sexual health clinics and were randomised by computer to the Men's Safer Sex website plus usual care (n = 84) or usual clinic care only (n = 75). Men were invited to complete online questionnaires at 3, 6, 9 and 12 months, and sexually transmitted infection (STI) diagnoses were recorded from clinic notes at 12 months; (3) health economic evaluation: we investigated the impact of using different questionnaires to calculate utilities and QALYs (the EQ 5D-3L and SQoL questionnaire), and compared different methods to collect resource use; and (4) qualitative evaluation: thematic analysis of interviews with 11 male trial participants and nine clinic staff, as well as free-text comments from online outcome questionnaires. RESULTS: (1) Software errors and clinic Wi-Fi access presented significant challenges. Response rates for online questionnaires were poor but improved with larger vouchers (from 36% with L10 to 50% with L30). Clinical records were located for 94% of participants for STI diagnoses. There were no group differences in condomless sex with female partners [incidence rate ratio (IRR) 1.01, 95% confidence interval (CI) 0.52 to 1.96]. New STI diagnoses were recorded for 8.8% (7/80) of the intervention group and 13.0% (9/69) of the control group (IRR 0.75, 95% CI 0.29 to 1.89). (2) Health-care resource data were more complete using patient files than questionnaires. The probability that the intervention is cost-effective is sensitive to the source of data used and whether or not data on intended pregnancies are included. (3) The pilot RCT fitted well around clinical activities but 37% of the intervention group did not see the Men's Safer Sex website and technical problems were frustrating. Men's views of the Men's Safer Sex website and research procedures were largely positive. CONCLUSIONS: It would be feasible to conduct a large-scale RCT using clinic STI diagnoses as a primary outcome; however, technical errors and a poor response rate limited the collection of online self-reported outcomes. The next steps are (1) to optimise software for online trials, (2) to find the best ways to integrate digital health promotion with clinical services, (3) to develop more precise methods for collecting resource use data and (4) to work out how to overcome barriers to digital intervention testing and implementation in the NHS. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18649610. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 91. See the NIHR Journals Library website for further project information. PMID- 27966411 TI - [The effect of Christmas joy on the mood among medical doctors - a randomized, blinded intervention study]. AB - INTRODUCTION: Each December Santa's elves spread Christmas joy (JN). Laughter and humour may influence health and stress level. No other study has investigated the effect of JN on the good spirit (DGH) among healthcare professionals. MATERIAL AND METHODS: We performed a single-centre blinded intervention study with crossover at three hospital departments. JN intervention of three days was randomized. Median +/- standard deviation was given. The level of significance was p < 0.05. RESULTS: During a four-week period, we made 24 observations (response rate 67). The laugh index increased from 0.02 in November to 0.03 in December (without JN) and further to 0.05 with JN. At one department, the rise was significant. At a department without morning coffee, the DGH level raised after JN intervention corresponding to the level at the departments with morning coffee before JN intervention. CONCLUSION: Christmas atmosphere tended to increase DGH at the morning conferences. JN tended to have an additive effect. JN exposure may be beneficial. FUNDING: The study did not receive any funding. TRIAL REGISTRATION: The trial was not registered and was kept secret for the participants in accordance with the tradition of Santa's elves. PMID- 27966412 TI - [Head injuries in Duckburg in 1959 and 2009]. AB - Comic books have been a part of popular culture through generations. Debates concerning their graphic depictions of violence have been ongoing for nearly as long. Our aim was to examine if the violence in "Donald Duck & Co." (a weekly published Danish comic book), illustrated through the number of head injuries, increased in the period from 1959 to 2009. The comic book vintages from the years 1959 and 2009 were read, and the number of head injuries noted. The head injuries were characterized by severity, in part by a modified Glasgow Coma Scale and in part by a newly developed Comic Book Coma Scale. The number of head injuries were equal in the examined years, however, the number of head injuries per page decreased from 1/10 pages to 1/20 pages. Donald Duck sustained a better part of the injuries increasing from 17% in 1959 to 33% in 2009. The study indicates that we, with peace of mind, can read a comic book while the rest of the family takes care of the dishes at Christmas. PMID- 27966413 TI - [Orthopaedics' megalomania - myth or mobbing?] AB - INTRODUCTION: It is a general impression in the world of medicine that orthopaedic surgeons differ from doctors of other specialities in terms of intellect and self-confidence. The purpose of this study was to evaluate the self confidence of orthopaedics. MATERIALS AND METHODS: We asked doctors from 30 different specialities to fill out a questionnaire. In addition to this, the participating orthopaedics were asked to rate their self-perceived surgical skills. RESULTS: In all, 120 orthopaedics and 416 non-orthopaedic doctors completed the questionnaire. There was no difference in GSE scores between orthopaedics and other doctors (p = 0.58). 98% of young orthopaedics estimated that their surgical talent was average or above average when compared with their colleagues on the same level of education. 72% believed that they were "equally talented", "more talented", or "far more talented" than their colleagues on a higher level of education. 76% believed that when assisting a senior surgeon the patients would "sometimes" (60%), "often" (14%) or "always" (2%) be better off if they were the ones performing the operation. More orthopaedics than non orthopaedics believed that their speciality was regarded as one of the least important specialities in the world of medicine (p = 0.001). CONCLUSION: Orthopaedic surgeons in general are not more self-confident than other doctors or the average population, but young orthopaedic surgeons have a very high level of confidence in their own operation skills. FUNDING: none. TRIAL REGISTRATION: none. PMID- 27966414 TI - [Design of artificial foetor flatus based on bacterial volatile compounds]. AB - INTRODUCTION: Excessive flatulence can be a huge social problem. The purpose of this study was to design artificial flatus from bacterial volatile compounds to stimulate research into neutralizing measures. MATERIAL AND METHODS: Anaerobic bacteria, representing a broad spectrum, from a recognized international culture collection were included. The strains were incubated in an anaerobic jar. After 24 hours the lid was removed, and the odour was evaluated by a specialist in clinical microbiology. RESULTS: Four different anaerobic strains were chosen for further studies based on their individual odours. In total, seven different combinations of two or three strains were tested. The combination of Bacteroides fragilis ATCC 25285, Clostridium difficile ATCC 700057 and Fusobacterium necrophorum ATCC 25286 was chosen as it had a suitably foul odour. CONCLUSION: It is possible to design artificial flatus from bacterial volatile compounds. The method is easy and inexpensive and can stimulate further research into neutralizing measures. TRIAL REGISTRATION: none. FUNDING: none. PMID- 27966415 TI - [The sick songs]. AB - Popular music is ubiquitous, and musicians and songwriters have similar experiences with disease as other people. The aim of this review was to analyze popular songs' content of descriptions of diseases. The most frequently occurring symptom was fever, mostly a metaphor for lovesickness or sexual orgasm. The most frequent and complete descriptions of diseases were in respiratory and psychiatric ailments. In conclusion, popular songs may provide valuable descriptions of symptoms and disease of educational importance to doctors. PMID- 27966416 TI - [The effect on mold formation when leaving the first slice in situ in white sliced bread]. AB - INTRODUCTION: To study the effect on mold formation when leaving the first slice in situ in white sliced bread (WSB). MATERIAL AND METHODS: We randomized 20 bags of WSB from a single production batch to either have the first slice removed or left in situ and compared mold formation and dryness on day ten. We removed two slices of bread from each bag daily and used blinded outcome assessors. RESULTS: We found mold in seven vs. six bags in the groups (p = 1.00). Results on dryness were inconsistent. The study may have been underpowered. CONCLUSION: Leaving the end slice in situ may not affect mold formation in WSB. PMID- 27966417 TI - [Medical speciality, belief in Santa and the risk of divorce]. AB - INTRODUCTION: Christmas is a unique time for family occasions - unfortunately the number of divorces increase in the months after Christmas. In this study, we examined the relationship between medical speciality, length of relationship, risk of divorce and if belief in Santa impacted on these outcomes. MATERIAL AND METHODS: A questionnaire was developed from the lived experiences of the authors and distributed to doctors of any speciality through links (SurveyXact) in emails, text messages and Facebook from June 28 2016 to August 1 2016. Multivariate regression models were used to analyze the results. RESULTS: A total of 1,100 completed questionnaires were included in the analyses. The divorce rate among respondents was 12%. Compared to the speciality "general practice" all other specialities had higher divorce rates. The highest risk of divorce was reported by physicians specialized in psychiatry (odds ratio 2.13 (95% confidence interval: 1.03-4.43)). Belief in Santa was associated with a slightly increased risk of divorce in all medical specialities, with the exception of psychiatry. General practitioners also exhibited the longest duration of relationships compared to peers in other medical specialities. CONCLUSION: Being a general practitioner was associated with a low risk of divorce and significantly longer relationships than in other medical specialities. Belief in Santa in regard to divorce only seemed to be beneficial for psychiatrists. So please participate in the joy of Christmas but do not rely on Santa - go shop your own presents for the family. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 27966418 TI - [Foreign objects in the urethra]. AB - Foreign objects in the urethra are rare. Most cases are often caused by self mutilating behaviour, in which the patient inserts an object into the urethra. Usually this is performed in a sexual context, and many different objects have been used. This case report presents a patient who used a 4 cm bullet-looking metal object for sexual pleasure. Cystoscopy revealed an object deep in the urethra, penetrating through the urethral mucosa. The object was removed endoscopically. At follow-up the patient experienced no sequelae, although infections, urethral stricture or fistula may occur in these cases. PMID- 27966420 TI - [Work-related stress urticaria]. AB - A medical doctor occasionally experienced itching papular exanthema during work hours. Careful history taking and a diary of symptoms demonstrated an association between the urticaria and stressful work situations. Urticaria can have many triggers, and stress is among the well-known triggers. The usual treatment of urticaria consists of avoiding triggers and, if necessary, antihistamines. Whereas it might be difficult to follow these recommendations in the case of work related urticaria, the disorder may be perceived as a reminder of work situations which are going awry. PMID- 27966419 TI - [A 87-year-old woman was run down by a hit-and-run driver and cured of malignant lymphoma]. AB - A 87-year-old woman was run down by a hit-and-run driver while riding her bicycle. An acute computed tomography (CT) showed no fractures or internal bleedings but revealed an asymptomatic tumour in the colon transversum. During operation, a diffuse large B-cell lymphoma was resected. Subsequent positron emission tomography/CT and bone marrow examination revealed no dissemination. No chemotherapy or radiation therapy was given. The patient was seen in the outpatient clinic every six months, and after two and a half year she is still in complete remission with a normal haemoglobin level. PMID- 27966421 TI - [Acute mackerel-induced sleep in a young researcher]. AB - Sleeping disorders are common and they are associated with substantial psychological and physical strain in those affected. We report a case of sudden onset of deep sleep in a 29-year-old Danish woman just after intake of mackerel in tomato sauce. There were no abnormal findings in the physical examination and no suspicion of underlying neurological disease. We hypothesize that the observed association between mackerel intake and deep sleep is causal and we suggest that more research is conducted in order to establish the potential of mackerel in treatment of sleeping disorders. PMID- 27966422 TI - [Rhabdomyolysis after lifting IKEA bags in a man using sertraline]. AB - We present a case of a 28-year-old male, using sertraline, who experienced progressive oedema in both upper extremities after having lifted two IKEA bags weighing 20 kg each from his car up to the third floor. Blood creatine kinase (CK) level was measured 5,260 U/l, and the patient was admitted for oral rehydration with the diagnosis rhabdomyolysis. The MRI showed swelling in the triceps muscles and latissimus dorsi muscles resulting in compression of the brachial vein. We discuss the pathomechanism behind the increased CK level and the swelling, and the possible effect sertraline may have had on the development of rhabdomyolysis. PMID- 27966423 TI - [The field of technologies for diabetes treatment]. AB - The field of diabetes technologies is growing exponentially. In this article we provide an overview of technologies for blood glucose monitoring and insulin administration along with computer programmes for data download and visualization currently available in Denmark. In addition, we summarize evidence of technology effects as well as local treatment guidelines and reimbursement rules. PMID- 27966424 TI - [Diagnosis and treatment of chronic thromboembolic pulmonary hypertension in Denmark]. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is an important differential diagnosis in patients with unexplained dyspnoea. CTEPH is under recognized and carries a poor prognosis without treatment. Surgical pulmonary endarterectomy is the preferred treatment for the majority of patients. Advances in surgical and anaesthetic techniques and post-operative intensive treatment have reduced perioperative morbidity and mortality. Pulmonary endarterectomy results in major improvement of haemodynamics and clinical status and offers excellent long-term survival. It is most often a curative treatment. The surgical treatment of CTEPH in Denmark is centralized at Aarhus University Hospital. Pulmonary vasodilators and pulmonary balloon angioplasty are supplementary treatment options in this patient group. PMID- 27966425 TI - [Lactic acidosis in a 24-year-old woman with status asthmaticus]. AB - A 24-year-old woman with asthma presented with symptoms of upper airway infection and tachypnoea and wheezes. She had a history of admissions to intensive care units (ICU) due to respiratory insufficiency. The initial lactate concentration was 2.1 mmol/l. The treatment consisted of inhaled and intravenous beta 2 agonists. Hereafter, the lactate concentration rose to 9.8 mmol/l, and the patient was admitted to the ICU due to severe asthma exacerbation. The elevation of lactate concentration cleared after discontinuation of beta 2 agonist therapy. Although lactic acidosis is a rare side effect to beta 2 agonist treatment, it is important to recog-nize it when present. PMID- 27966426 TI - [Lamotrigine-induced pneumonitis]. AB - A 28-year-old woman diagnosed with schizophrenia was admitted to hospital due to progressing dyspnoea for months. At admission, she was oxygen-dependent, and a high-resolution computed tomography revealed ground glass opacities. She had no obvious exposures besides having been treated with lamotrigine for several years. A psychiatrist doubted the diagnosis, and the lamotrigine treatment was tapered. After some months, she became clinically stable without further need of oxygen. Lamotrigine can cause pneumonitis, and this side effect should be suspected in patients who are being treated with lamotrigine and presenting with progressive dyspnoea. Crucial treatment is to remove the exposure. PMID- 27966427 TI - Patterns of diagnostic marker assessment in adult diffuse glioma: a survey of the European Confederation of Neuropathological Societies (Euro-CNS). AB - The 2016 update of the WHO classification has introduced an integrated diagnostic approach that incorporates both tumor morphology and molecular information. This conceptual change has far-reaching implications, especially for neuropathologists who are in the forefront of translating molecular markers to routine diagnostic use. Adult diffuse glioma is a prototypic example for a group of tumors that underwent substantial regrouping, and it represents a major workload for surgical neuropathologists. Hence, we conducted a survey among members of the European Confederation of Neuropathological Societies (Euro-CNS) in order to assess 1) the extent to which molecular markers have already been incorporated in glioma diagnoses, 2) which molecular techniques are in daily use, and 3) to set a baseline for future surveys in this field. Based on 130 responses from participants across 40 nations neuropathologists uniformly rate molecular marker testing as highly relevant and already incorporate molecular information in their diagnostic assessments. At the same time however, the survey documents substantial differences in access to crucial biomarkers and molecular techniques across geographic regions and within individual countries. Concerns are raised concerning the validity of test assays with MGMT, 1p19q, and ATRX; being perceived as most problematic. Neuropathologists advocate the need for international harmonization of standards and consensus guidelines, and the majority is willing to actively engage in interlaboratory trials aiming at quality control (Figure 1).?. PMID- 27966428 TI - Clinical Neuropathology image 1-2017: incidental schwannoma of the posterior root. PMID- 27966429 TI - Fine-tuning of Notch signaling sets the boundary of the organ of Corti and establishes sensory cell fates. AB - The signals that induce the organ of Corti and define its boundaries in the cochlea are poorly understood. We show that two Notch modifiers, Lfng and Mfng, are transiently expressed precisely at the neural boundary of the organ of Corti. Cre-Lox fate mapping shows this region gives rise to inner hair cells and their associated inner phalangeal cells. Mutation of Lfng and Mfng disrupts this boundary, producing unexpected duplications of inner hair cells and inner phalangeal cells. This phenotype is mimicked by other mouse mutants or pharmacological treatments that lower but not abolish Notch signaling. However, strong disruption of Notch signaling causes a very different result, generating many ectopic hair cells at the expense of inner phalangeal cells. Our results show that Notch signaling is finely calibrated in the cochlea to produce precisely tuned levels of signaling that first set the boundary of the organ of Corti and later regulate hair cell development. PMID- 27966430 TI - Multiple alleles at a single locus control seed dormancy in Swedish Arabidopsis. AB - Seed dormancy is a complex life history trait that determines the timing of germination and is crucial for local adaptation. Genetic studies of dormancy are challenging, because the trait is highly plastic and strongly influenced by the maternal environment. Using a combination of statistical and experimental approaches, we show that multiple alleles at the previously identified dormancy locus DELAY OF GERMINATION1 jointly explain as much as 57% of the variation observed in Swedish Arabidopsis thaliana, but give rise to spurious associations that seriously mislead genome-wide association studies unless modeled correctly. Field experiments confirm that the major alleles affect germination as well as survival under natural conditions, and demonstrate that locally adaptive traits can sometimes be dissected genetically. PMID- 27966431 TI - Adjuvant S-1 chemotherapy after curative resection of gastric cancer in Chinese patients: assessment of treatment tolerability and associated risk factors. AB - INTRODUCTION: The use of adjuvant chemotherapy with S-1 (tegafur, gimeracil, and oteracil potassium) has been shown to improve the outcome of patients with gastric cancer. There are limited data on the tolerability of S-1 in Chinese patients. In this multicentre retrospective study, we assessed the toxicity profile in local patients. METHODS: Patients with stage II-IIIC gastric adenocarcinoma who had undergone curative resection and who had received S-1 adjuvant chemotherapy were included in the study. Patient demographics, tumour characteristics, chemotherapy records, as well as biochemical, haematological, and other toxicity profiles were extracted from medical charts. Potential factors associated with grade 2-4 toxicities were identified. RESULTS: Adjuvant S-1 was administered to 30 patients. Overall, 19 (63%) patients completed eight cycles. The most common grade 3-4 adverse events included neutropaenia (10%), anaemia (6.7%), septic episode (16.7%), diarrhoea (6.7%), hyperbilirubinaemia (6.7%), and syncope (6.7%). Dose reductions were made in 22 (73.3%) patients and 12 (40.0%) patients had dose delays. Univariate analyses showed that patients who underwent total gastrectomy were more likely to experience adverse haematological events (P=0.034). Patients with nodal involvement were more likely to report adverse non haematological events (P=0.031). Patients with a history of regular alcohol intake were more likely to have earlier treatment withdrawal (P=0.044). Lower body weight (P=0.007) and lower body surface area (P=0.017) were associated with dose interruptions. CONCLUSIONS: The tolerability of adjuvant S-1 in our patient population was similar to that in other Asian patient populations. The awareness of S-1-related toxicities and increasing knowledge of potential associated factors may enable optimisation of S-1 therapy. PMID- 27966432 TI - The pattern of cervical smear abnormalities in marginalised women in Hong Kong. AB - INTRODUCTION: "Ripple Action" and "WE Stand" are projects co-organised by the Hong Kong Women Doctors Association. The two projects organise free cervical screening for low-income women, new immigrants from Mainland China, and ethnic minority women. The objective of this study was to analyse the pattern of cervical smear abnormalities in these marginalised women. METHODS: The study group consisted of 1189 marginalised women who participated in a free cervical screening campaign, including 324 low-income local Chinese, 540 new immigrants from Mainland China, and 325 ethnic minority women. The comparison group consisted of 1141 local Chinese who attended a well women clinic. The prevalence of cervical smear abnormalities was compared using Chi squared test. RESULTS: In the study group, 42.6% of women had never had a cervical smear. Compared with the comparison group, they had a significantly higher prevalence of cervical smear abnormalities (13.7% vs 1.4%; P<0.001), including atypical smear (10.8% vs 0.5%; P<0.001), low-grade lesion (1.8% vs 0.8%; P=0.036), and high-grade lesion (1.1% vs 0.1%; P=0.002). Logistic regression analysis showed that the strongest predictors for abnormal cervical smear were being South Asian (odds ratio=11.859; 95% confidence interval, 4.635-30.341), South-East Asian (6.484; 3.192-13.171), or new immigrant from Mainland China (6.253; 2.463-15.877). CONCLUSIONS: Marginalised women had a significantly higher prevalence of cervical smear abnormality than the general population and almost half had never had a cervical smear before. Outreach strategies are needed to enrol this population into screening programmes. PMID- 27966433 TI - Operative outcome of Hong Kong centenarians with hip fracture. AB - INTRODUCTION: International clinical guidelines recommend early surgical treatment for geriatric patients with hip fracture. There are, however, few data concerning the operative outcome of centenarians. This study aimed to report the epidemiology of hip fracture and postoperative mortality rate, and to discuss whether operation is justified in centenarians in Hong Kong. METHODS: This observational study was carried out in all public hospitals of Hong Kong. All patients aged 100 years or above who underwent hip fracture surgery in any public hospital between 1 January 2010 and 31 December 2013 were included. Their postoperative mean and median survival time was recorded. RESULTS: Of 114 centenarians, 96 (84%) were female. The age of patients ranged from 100 to 109 years, with the largest number (44%) aged 100 years. The follow-up interval ranged from 5 to 1619 days (median, 412 days; interquartile range, 683 days). The 1-month, 6-month, and 1-year mortalities were 8%, 25%, and 37%, respectively. By Kaplan-Meier analysis, the postoperative mean survival was 2 years 2 months (95% confidence interval, 680-936 days) and the median survival time was 2 years (interquartile range, 1234 days). CONCLUSION: The 1-year mortality among Hong Kong centenarians with hip fracture was 37%, which is lower than the 41.1% in the general centenarian population in Japan. The median survival time after hip fracture surgery was 2 years, suggesting that surgery even at an extreme age is worthwhile to maintain quality of life. Extreme age should not be a barrier to operative treatment. PMID- 27966434 TI - Clindamycin-induced acute generalised exanthematous pustulosis: five cases and a review of the literature. AB - Acute generalised exanthematous pustulosis (AGEP) is a rare but serious cutaneous adverse drug reaction, often related to antibiotics such as beta-lactams or macrolides. However, it is rarely associated with clindamycin which belongs to the lincosamide antibiotics. The Netherlands Pharmacovigilance Centre Lareb received five reports of AGEP associated with the use of clindamycin. We present these five cases and provide support for this association from the Lareb database, the database of the WHO Collaborating Centre for International Drug Monitoring (VigibaseTM), the database of the European Medicine Agency (Eudravigilance), and from a mini review of the literature. PMID- 27966435 TI - Screening for complications after pregnancy-related disorders; don't restrict to gestational diabetes. PMID- 27966436 TI - Investigating screening for diabetes in women with a history of gestational diabetes. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is encountered more frequently in women with a history of gestational diabetes (GD). Screening for T2DM after pregnancy is, therefore, recommended every >= 1-3 years in this population. Early detection could allow for timely intervention strategies, especially in women of childbearing age. Data on adherence to diabetes screening recommendations and the prevalence of T2DM in this population are not available in the Dutch population. AIM: To investigate the T2DM screening rate and evaluate the risk of T2DM in the five-year period following GD pregnancy. METHODS: Single-centre survey in 85 women diagnosed with GD in 2010, using electronic medical records. Primary care physicians were asked to complete a survey regarding the screening frequency and the onset of T2DM in the five-year period following the GD pregnancy. RESULTS: On average 33% underwent yearly screening. The screening rate, however, went up to 61.2% after primary care physicians were requested to screen this population in 2015. Of the women who were screened, 10 (19.2%) developed T2DM within five years after GD. CONCLUSION: Current screening recommendations are poorly met, leading to missed, or delayed diagnosis of T2DM in our population. T2DM is a frequently occurring long-term complication in those who were screened in the five-year period after delivery. Optimising awareness amongst health care professionals of GD as a risk factor for T2DM is warranted and strategies to improve surveillance are necessary. PMID- 27966437 TI - Physician consensus on preventability and predictability of readmissions based on standard case scenarios. AB - BACKGROUND: Policy makers struggle with unplanned readmissions as a quality indicator since integrating preventability in such indicators is difficult. Most studies on the preventability of readmissions questioned physicians whether they consider a given readmission to be preventable, from which conclusions on factors predicting preventable readmissions were derived. There is no literature on the interobserver agreement of physician judgement. AIM: To assess the degree of agreement among physicians regarding predictability and preventability of medical readmissions. DESIGN: An online survey based on eight real-life case scenarios was distributed to European physicians. METHODS: Physicians were requested to rate from the first four (index admission) scenarios whether they expected these patients to be readmitted within 30 days (the predictability). The remaining four cases, describing a readmission, were used to assess the preventability. The main outcome was the degree of agreement among physicians determined using the intra class correlation coefficient (ICC). RESULTS: 526 European medical physicians completed the survey. Most physicians had internal medicine as primary specialism. The median years of clinical experience was 11. ICC for predictability of readmission was 0.67 (moderate to good) and ICC for preventability of readmission was 0.13 (poor). CONCLUSION: There was moderate to good agreement among physicians on the predictability of readmissions while agreement on preventability was poor. This study indicates that assessing preventability of readmissions based solely on the judgement of physicians is far from perfect. Current literature on the preventability of readmissions and conclusions derived on the basis of physician opinion should be interpreted with caution. PMID- 27966438 TI - Never ignore extremely elevated D-dimer levels: they are specific for serious illness. AB - BACKGROUND: D-dimer is routinely measured as part of the clinical diagnosis algorithms for venous thromboembolism (VTE). In these algorithms, low D- dimer cut-off values are used to generate a dichotomous test result that is sensitive, but very non-specific for VTE. A consequence of any test dichotomisation is loss of information that is hidden in the continuous spectrum of results. For D-dimer, the information conveyed by extremely elevated results may be particularly relevant. Our aim was to assess the differential diagnosis of extremely elevated D-dimer levels in a hospital setting. METHODS: Retrospective cohort study of patients > 18 years with an extremely elevated (> 5000 MUg/l; > 10x cut-off to exclude VTE) D-dimer test result. Electronic medical records were reviewed for diagnoses. RESULTS: A total of 759 extremely elevated D-dimer results were identified. After exclusion of 120 duplicate cases, 53 patients undergoing cardiopulmonary resuscitation, and 5 cases without diagnostic information, 581 cases were analysed. Their D-dimer ranged between 5030 and 239,000 MUg/l, with a mean of 17,598 MUg/l (SD 22,972 MUg/l). Altogether, 89% of these patients had a diagnosis of VTE, sepsis and/or cancer. The prevalence was highest for pulmonary embolism (183 patients; 32%), followed by cancer (168 patients; 29%), sepsis (142 patients; 24%), trauma/surgery (142 patients; 24%), and deep vein thrombosis (73 patients; 13%). CONCLUSION: Although D-dimer testing has a reputation for being very non-specific, an extremely elevated D-dimer is uniquely associated with severe disease, mainly including VTE, sepsis and/or cancer. These results suggest that, even if sharply elevated D-dimers are a seemingly solitary finding, clinical suspicion of severe underlying disease should be maintained. PMID- 27966439 TI - Ganciclovir-induced ataxia and encephalopathy. AB - BACKGROUND: Ganciclovir can be used to treat a primary cytomegalovirus (CMV) infection, however it can cause side effects. CASE DESCRIPTION: We describe a 60 year-old immunocompromised woman with a primary CMV infection who was treated with ganciclovir. She developed an encephalopathy which resolved after discontinuation of ganciclovir. CONCLUSION: A reversible encephalopathy as a side effect of ganciclovir. PMID- 27966440 TI - Actinomycosis of the abdominal wall after cholecystectomy: transferral theory. AB - Abdominal actinomycosis is a rare disease caused by Gram-positive anaerobic Actinomyces bacteria. Here, we present a patient with an intrauterine contraceptive device who developed a long lasting and unexplained recurrent, painful abdominal swelling a few months after a laparoscopic cholecystectomy. PMID- 27966441 TI - A novel mutation in mitochondrial DNA in a patient with diabetes, deafness and proteinuria. AB - Maternally inherited deafness and diabetes (MIDD) is characterised by a defect in insulin secretion and bilateral hearing impairment. The m.3243A>G mutation is the most reported in mitochondrial DNA (mtDNA) causing MIDD, although other, rare, mtDNA point mutations have also been mentioned. We report on a 28-year-old Caucasian woman with a history of diabetes, kidney disease, deafness, diarrhoea, myopathy and fatigue. The diagnosis of mitochondrial disease was made in this patient, which resulted from a novel 09155A>G mutation in the mtDNA. As far as we know, this mutation has never been described before as causing MIDD. PMID- 27966442 TI - A black umbilicus in a patient with a decompensated liver cirrhosis. PMID- 27966443 TI - Answer to Photo Quiz: A black umbilicus in a patient with a decompensated liver cirrhosis. PMID- 27966445 TI - Antimetastatic effects of cordycepin mediated by the inhibition of mitochondrial activity and estrogen-related receptor alpha in human ovarian carcinoma cells. AB - Cordycepin (3'-deoxyadenosine) is a compound for antitumor, which has been found to exert antiangiogenic, antimetastatic, and antiproliferative effects, as well as inducing apoptosis. However, the association between cancer metastasis and mitochondrial activity in cordycepin-treated ovarian carcinoma cells remains unclear. The 50 and 100 MUM of cordycepin inhibits mitochondrial fusion and induces mitochondrial fission, respectively. These suggested that cordycepin showed the down-regulation of mitochondrial function and limitation of energy production. Because of activation of mitochondria and generation of energy are needed in cancer cell migration/invasion. After 24 h treatment, cordycepin suppresses epithelial-mesenchymal transition and migration in ovarian carcinoma cells through inhibiting estrogen-related receptor (ERR)-alpha. The ERRalpha is a co-transcription factor for gene expressions associated with mitochondrial fusion. Our results indicate that cordycepin suppresses metastasis and migration of ovarian carcinoma cells via inhibiting mitochondrial activity in non-toxic concentrations, and cordycepin has potential benefits in ovarian cancer therapy. PMID- 27966444 TI - Construction of differential mRNA-lncRNA crosstalk networks based on ceRNA hypothesis uncover key roles of lncRNAs implicated in esophageal squamous cell carcinoma. AB - Increasing evidence has indicated that lncRNAs acting as competing endogenous RNAs (ceRNAs) play crucial roles in tumorigenesis, metastasis and diagnosis of cancer. However, the function of lncRNAs as ceRNAs involved in esophageal squamous cell carcinoma (ESCC) is still largely unknown. In this study, clinical implications of two intrinsic subtypes of ESCC were identified based on expression profiles of lncRNA and mRNA. ESCC subtype-specific differential co expression networks between mRNAs and lncRNAs were constructed to reveal dynamic changes of their crosstalks mediated by miRNAs during tumorigenesis. Several well known cancer-associated lncRNAs as the hubs of the two networks were firstly proposed in ESCC. Based on the ceRNA mechanism, we illustrated that the"loss" of miR-186-mediated PVT1-mRNA and miR-26b-mediated LINC00240-mRNA crosstalks were related to the two ESCC subtypes respectively. In addition, crosstalks between LINC00152 and EGFR, LINC00240 and LOX gene family were identified, which were associated with the function of "response to wounding" and "extracellular matrix receptor interaction". Furthermore, functional cooperation of multiple lncRNAs was discovered in the two differential mRNA-lncRNA crosstalk networks. These together systematically uncovered the roles of lncRNAs as ceRNAs implicated in ESCC. PMID- 27966446 TI - VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers. AB - We have investigated the role of vascular-endothelial (VE)-cadherin in melanoma and breast cancer metastasis. We found that VE-cadherin is expressed in highly aggressive melanoma and breast cancer cell lines. Remarkably, inactivation of VE cadherin triggered a significant loss of malignant traits (proliferation, adhesion, invasion and transendothelial migration) in melanoma and breast cancer cells. These effects, except transendothelial migration, were induced by the VE cadherin RGD motifs. Co-immunoprecipitation experiments demonstrated an interaction between VE-cadherin and alpha2beta1 integrin, with the RGD motifs found to directly affect beta1 integrin activation. VE-cadherin-mediated integrin signaling occurred through specific activation of SRC, ERK and JNK, including AKT in melanoma. Knocking down VE-cadherin suppressed lung colonization capacity of melanoma or breast cancer cells inoculated in mice, while pre-incubation with VE cadherin RGD peptides promoted lung metastasis for both cancer types. Finally, an in silico study revealed the association of high VE-cadherin expression with poor survival in a subset of melanoma patients and breast cancer patients showing low CD34 expression. These findings support a general role for VE-cadherin and other RGD cadherins as critical regulators of lung and liver metastasis in multiple solid tumours. These results pave the way for cadherin-specific RGD targeted therapies to control disseminated metastasis in multiple cancers. PMID- 27966447 TI - A four gene signature predictive of recurrent prostate cancer. AB - Prostate cancer is the most common form of non-dermatological cancer among US men, with an increasing incidence due to the aging population. Patients diagnosed with clinically localized disease identified as intermediate or high-risk are often treated by radical prostatectomy. Approximately 33% of these patients will suffer recurrence after surgery. Identifying patients likely to experience recurrence after radical prostatectomy would lead to improved clinical outcomes, as these patients could receive adjuvant radiotherapy. Here, we report a new tool for prediction of prostate cancer recurrence based on the expression pattern of a small set of cooperation response genes (CRGs). CRGs are a group of genes downstream of cooperating oncogenic mutations previously identified in a colon cancer model that are critical to the cancer phenotype. We show that systemic dysregulation of CRGs is also found in prostate cancer, including a 4-gene signature (HBEGF, HOXC13, IGFBP2, and SATB1) capable of differentiating recurrent from non-recurrent prostate cancer. To develop a suitable diagnostic tool to predict disease outcomes in individual patients, multiple algorithms and data handling strategies were evaluated on a training set using leave-one-out cross validation (LOOCV). The best-performing algorithm, when used in combination with a predictive nomogram based on clinical staging, predicted recurrent and non recurrent disease outcomes in a blinded validation set with 83% accuracy, outperforming previous methods. Disease-free survival times between the cohort of prostate cancers predicted to recur and predicted not to recur differed significantly (p = 1.38x10-6). Therefore, this test allows us to accurately identify prostate cancer patients likely to experience future recurrent disease immediately following removal of the primary tumor. PMID- 27966448 TI - Differential expression of peroxiredoxin 3 in laryngeal squamous cell carcinoma. AB - Peroxiredoxin (PRDX) proteins are involved in carcinogenesis. PRDX3, which is predominantly localized in mitochondria and up-regulated in several human cancers, seems to confer increased treatment resistance and aggressive phenotypes. This study examined the expression profile of PRDX3 and its possible clinical value in laryngeal squamous cell carcinoma (LSCC). The expression of PRDX3 in LSCC samples was confirmed by Western blotting and further analyzed by immunohistochemistry in LSCC samples of different clinical pathological stages. The results showed that up-regulated expression of PRDX3 was observed in LSCC and associated with poor differentiation (P < 0.01), primary tumor location, N category and tumor stage (P < 0.05). Knockdown of PRDX3 in the Hep-2 laryngeal carcinoma epithelial cell line significantly enhanced Hep-2 cells' apoptosis and inhibited their proliferation and migration. Taken together, our results suggest that PRDX3 has substantial clinical impact on the progression of LSCC and shed new light on the role of PRDX3 in treatment resistance and aggressive phenotypes in LSCC. PMID- 27966449 TI - Association between FGFR2 (rs2981582, rs2420946 and rs2981578) polymorphism and breast cancer susceptibility: a meta-analysis. AB - The association between fibroblast growth factor receptor 2 (FGFR2) polymorphism and breast cancer (BC) susceptibility remains inconclusive. The purpose of this systematic review was to evaluate the relationship between FGFR2 (rs2981582, rs2420946 and rs2981578) polymorphism and BC risk. PubMed, Web of science and the Cochrane Library databases were searched before October 11, 2015 to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of associations. Sensitivity and subgroup analyses were conducted. Thirty-five studies published from 2007 to 2015 were included in this meta-analysis. The pooled results showed that there was significant association between all the 3 variants and BC risk in any genetic model. Subgroup analysis was performed on rs2981582 and rs2420946 by ethnicity and Source of controls, the effects remained in Asians, Caucasians, population-based and hospital-based groups. We did not carryout subgroup analysis on rs2981578 for the variant included only 3 articles. This meta-analysis of case-control studies provides strong evidence that FGFR2 (rs2981582, rs2420946 and rs2981578) polymorphisms were significantly associated with the BC risk. For rs2981582 and rs2420946, the association remained significant in Asians, Caucasians, general populations and hospital populations. However, further large scale multicenter epidemiological studies are warranted to confirm this finding and the molecular mechanism for the association need to be elucidated further. PMID- 27966450 TI - Upregulated NNT-AS1, a long noncoding RNA, contributes to proliferation and migration of colorectal cancer cells in vitro and in vivo. AB - The expression patterns of the long non-coding RNA Nicotinamide Nucleotide Transhydrogenase-antisense RNA1 (NNT-AS1) have not been investigated in the context of cancer. In this study, we aim to investigate the NNT-AS1 expression level in colorectal cancer (CRC) patients and its potential roles in tumor biology. We measured the expression of NNT-AS1 in 70 paired tumor tissues and adjacent normal tissues. NNT-AS1 was expressed higher in tumor tissues than that in adjacent noncancer tissues, and higher expression of NNT-AS1 was significantly correlated with lymph node metastasis (Yes vs. No, P=0.004), TNM stage (I/II vs. III/IV, P=0.004), vessel invasion (Yes vs. No, P=0.002) and differentiation (well and moderate vs. poor, P=0.008). Multivariate analyses revealed that NNT-AS1 expression was an independent predictor of overall survival (P=0.0174) and progression free survival (P=0.0132) for CRC. Knockdown of NNT-AS1 using small interfering RNA (siRNA) significantly impaired CRC cell proliferation, migration and invasion in vitro and silencing NNT-AS1 also suppressed tumor growth and metastasis in nude mice. The western blot experiments revealed that silencing NNT AS1 inhibited epithelial-mesenchymal transition (EMT) and inactivated MAPK/Erk signaling pathway in CRC cell lines. In conclusion, our studies implied that NNT AS1 may involve in the development and progression of CRC via its regulation of cell proliferation, migration, and invasion by NNT-AS1-mediated activating of MAPK/Erk signaling pathway and EMT. NNT-AS1 may be a useful diagnostic and prognostic biomarker and a potential therapeutic target in CRC patients. PMID- 27966451 TI - FGFR4 polymorphic alleles modulate mitochondrial respiration: A novel target for somatostatin analog action in pituitary tumors. AB - We reported that a single nucleotide polymorphism (SNP) at codon 388 of the fibroblast growth factor receptor 4 (FGFR4-Gly388Arg) can result in distinct proteins that alter pituitary cell growth and function. Here, we examined the differential properties of the available therapeutic somatostatin analogs, octreotide and pasireotide, in pituitary tumor cells expressing the different FGFR4 isoforms. Consistent with their enhanced growth properties, FGFR4-R388 expressing cells show higher mitochondrial STAT3 serine phosphorylation driving basal and maximal oxygen consumption rate (OCR) than pituitary cells expressing the more common FGFR4-G388 isoform. While both somatostatin analogs reduce the OCR in FGFR4-G388 cells, pasireotide was more effective in decreasing OCR in cells expressing the variant FGFR4-R388 isoform. Down-regulation of somatostatin receptor 5 (SSTR5) abrogated the effect of pasireotide, demonstrating its involvement in mediating this action. The effects on OCR were recapitulated by introducing a constitutively active serine STAT3 but not by a tyrosine-active mutant. Moreover, pharmacologic inhibition demonstrated the role for the phosphatase PP2A in mediating the dephosphorylation of STAT3-S727 by pasireotide. Our data indicate that FGFR4 polymorphic isoforms mediate signaling that yields mitochondrial therapeutic targets of relevance to the actions of different somatostatin analogs. PMID- 27966452 TI - Toxicity assessment of hydrogen peroxide on Toll-like receptor system, apoptosis, and mitochondrial respiration in piglets and IPEC-J2 cells. AB - In this study, expressions of toll-like receptors (TLRs) and apoptosis-related genes in piglets and mitochondrial respiration in intestinal porcine epithelial cells were investigated after hydrogen peroxide (H2O2) exposure. The in vivo results showed that H2O2 influenced intestinal expressions of TLRs and apoptosis related genes. H2O2 treatment (5% and 10%) downregulated uncoupling protein 2 (UCP2) expression in the duodenum (P < 0.05), while low dosage of H2O2 significantly increased UCP2 expression in the jejunum (P < 0.05). In IPEC-J2 cells, H2O2 inhibited cell proliferation (P < 0.05) and caused mitochondrial dysfunction via reducing maximal respiration, spare respiratory, non mitochondrial respiratory, and ATP production (P < 0.05). However, 50 uM H2O2 significantly enhanced mitochondrial proton leak (P < 0.05). In conclusion, H2O2 affected intestinal TLRs system, apoptosis related genes, and mitochondrial dysfunction in vivo and in vitro models. Meanwhile, low dosage of H2O2 might exhibit a feedback regulatory mechanism against oxidative injury via increasing UCP2 expression and mitochondrial proton leak. PMID- 27966453 TI - Oncolytic virus synergizes with Smac mimetic compounds to induce rhabdomyosarcoma cell death in a syngeneic murine model. AB - Rhabdomyosarcoma (RMS), a neoplasm characterized by undifferentiated myoblasts, is the most common soft tissue tumour in children. Therapeutic resistance is common in RMS and is often caused by acquired defects in the cellular apoptotic program. Smac mimetic compounds (SMCs) are a novel class of inhibitor of apoptosis (IAP) antagonists that are currently under clinical development as cancer therapeutics. We previously reported that cIAP1 is overexpressed in human primary RMS tumours and in patient-derived RMS cell lines where it drives resistance to apoptosis. In this study, we investigated whether inflammatory cytokine production triggered by activators of innate immunity synergizes with LCL161 to induce bystander killing of RMS cells in vitro and in vivo. Indeed, we show that innate immune stimuli (oncolytic virus (VSVDelta51-GFP), interferon gamma (IFNgamma), and tumour necrosis factor-like weak inducer of apoptosis (TWEAK)) combine with SMCs in vitro to reduce cell viability in the Kym-1 RMS cancer cell line. Other human RMS cell lines (RH36, RH41, RD, RH18, RH28, and RH30) and the murine RMS cell line 76-9 are resistant to treatment with LCL161 alone or in combination with immune stimulants in in vitro cell viability assays. In contrast, we report that the combination of LCL161 and VSVDelta51-GFP reduces tumour volume and prolongs survival in a 76-9 syngeneic murine model. Our results support further exploration of the combined use of IAP antagonists and innate immune stimuli as a therapeutic approach for RMS cancers. PMID- 27966454 TI - Deregulation of miR-183 promotes melanoma development via lncRNA MALAT1 regulation and ITGB1 signal activation. AB - Dysregulation of miR-183 has been recently elucidated in several carcinomas. However, the expression patterns and mechanisms of miR-183 involved in malignant melanoma remain unidentified. Here, we found down-regulation of miR-183 in melanoma tissues and cells. Decreased level of miR-183 was relevant to poor overall survival, while miR-183 up-regulation resulted in a marked suppression of cell growth in vitro and in vivo. We further found that the expression and function of miR-183 were suppressed by MALAT1. Integrin beta1 (ITGB1) was then speculated and confirmed as a direct target of miR-183. We also illustrated that MALAT1 may function as a sponge competitive endogenous RNA (ceRNA) for miR-183, and thus regulate the molecular expression of ITGB1. Collectively, we found a new signaling pathway promoting melanoma development by MALAT1-miR-183-ITGB1 axis, which may be clinically valuable as new targets for malignant melanoma therapy. PMID- 27966455 TI - A multidisciplinary team care approach improves outcomes in high-risk pediatric neuroblastoma patients. AB - We assessed the impact of a multidisciplinary team care program on treatment outcomes in neuroblastoma patients. Newly diagnosed neuroblastoma patients received treatment under the Taiwan Pediatric Oncology Group (TPOG) N2002 protocol at the National Taiwan University Hospital beginning in 2002. A multidisciplinary team care approach that included nurse-led case management for patients treated under this protocol began in January 2010. Fifty-eight neuroblastoma patients, including 29 treated between 2002 and 2009 (Group 1) and 29 treated between 2010 and 2014 (Group 2), were enrolled in the study. The 5 year overall survival (OS) and event-free survival (EFS) rates for all 58 patients were 59% and 54.7%, respectively. Group 2 patients, who were treated after implementation of the multidisciplinary team care program, had better 3 year EFS (P = 0.046), but not OS (P = 0.16), rates than Group 1 patients. In a multivariate analysis, implementation of the multidisciplinary team approach was the only significant independent prognostic factor for neuroblastoma patients. In further subgroup analyses, the multidisciplinary team approach improved EFS, but not OS, in patients with stage 4 disease, those in the high-risk group, and those with non-MYCN amplified tumors. These data indicate a multidisciplinary team care approach improved survival outcomes in high-risk neuroblastoma patients. However, further investigation will be required to evaluate the long-term effects of this approach over longer follow-up periods. PMID- 27966456 TI - Ablating all three retinoblastoma family members in mouse lung leads to neuroendocrine tumor formation. AB - Lung cancer is a deadly disease with increasing cases diagnosed worldwide and still a very poor prognosis. While mutations in the retinoblastoma (RB1) tumor suppressor have been reported in lung cancer, mainly in small cell lung carcinoma, the tumor suppressive role of its relatives p107 and p130 is still a matter of debate. To begin to investigate the role of these two Rb family proteins in lung tumorigenesis, we have generated a conditional triple knockout mouse model (TKO) in which the three Rb family members can be inactivated in adult mice. We found that ablation of all three family members in the lung of mice induces tumorlets, benign neuroendocrine tumors that are remarkably similar to their human counterparts. Upon chemical carcinogenesis, DHPN and urethane accelerate tumor development; the TKO model displays increased sensitivity to DHPN, and urethane increases malignancy of tumors. All the tumors developing in TKO mice (spontaneous and chemically induced) have neuroendocrine features but do not progress to fully malignant tumors. Thus, loss of Rb and its family members confers partial tumor susceptibility in neuroendocrine lineages in the lungs of mice. Our data also imply the requirement of other oncogenic signaling pathways to achieve full transformation in neuroendocrine lung lesions mutant for the Rb family. PMID- 27966457 TI - Meta-prediction of MTHFR gene polymorphism-mutations, air pollution, and risks of leukemia among world populations. AB - The major objective of this study was to examine the association between Methylenetetrahydrofolate Reductase (MTHFR) polymorphisms and the risk of various types of leukemias across the lifespans of children and adults by using the meta predictive techniques. The secondary objective was to examine the interactions among epigenetic risk factors (including air pollution), MTHFR polymorphisms, and the risks of developing leukemia. We completed a comprehensive search of 6 databases to find 54 studies (10,033 leukemia cases and 15,835 controls) for MTHFR 677, and 43 studies (8,868 cases and 14,301 controls) for MTHFR 1298, published from 1999 to 2014. The results revealed that, in European populations; childhood populations; children from Europe, East Asia, and America; and children with acute lymphocytic leukemia (ALL), MTHFR 677 polymorphisms (both TT and CT types together and individually) are protective, while CC wildtype was leukemogenic. In addition, MTHFR 1298 polymorphisms were protective against ALL and acute myeloid leukemia in European children, and in chronic myeloid leukemia in all adults worldwide and American adults. Air pollution played a role in the increased polymorphisms of MTHFR 677 genotypes in childhood leukemia. PMID- 27966458 TI - GABARAPL1 suppresses metastasis by counteracting PI3K/Akt pathway in prostate cancer. AB - Metastasis remains the primary cause of prostate cancer (CaP)-related death. Using a genome wide shRNA screen, we identified GABARAPL1 as a potential CaP metastasis suppressor. GABARAPL1 mRNA levels inversely correlate with the invasive potential of a panel of human CaP cell lines. Lower mRNA levels correlate with higher Gleason scores in clinical CaP tumor samples. Moreover, Kaplan-Meier curves analysis showed that GABARAPL1 down-regulation in cancer tissues is associated with decreased disease-free survival in CaP patients. Knockdown of GABARAPL1 in human LNCaP cells results in increased invasion in vitro and lymph node metastasis in vivo. Vice versa, ectopic expression of GABARAPL1 decreases the invasiveness of CWR22Rv1 cells. Our previous in vitro shRNA screening identified FOXO4, a PI3K/Akt-inactivating downstream target, as a potential CaP metastasis suppressor. We show here that silencing FOXOs leads to reduced GABARAPL1 expression and enhanced invasion in LNCaP cells. Transfection of constitutively-activated Akt (myr-Akt) increased the invasion of LNCaP cells, which is associated with the inactivation of FOXOs and decreased GABARAPL1 expression. Indeed, forced expression of GABARAPL1 reversed the increased invasiveness of LNCaP/myr-Akt cells. Finally, immunohistochemistry analysis shows that Akt phosphorylation is negatively correlated with GABARAPL1 expression in human CaP tissues. Taken together, our data indicate that the suppression of FOXOs-GABARAPL1 signaling by Akt is an important mechanism for CaP progression and metastasis. PMID- 27966461 TI - Effect of nanocavities on Ge nanoclustering and out-diffusion in SiO2. AB - Germanium nanocrystals (Ge-ncs) were synthesized by implantation of Ge+ ions into the fused silica, followed by a thermal annealing at 1000 degrees C. High resolution transmission electron microscopy was employed to characterize both the morphology of the formed Ge-ncs and the evolution of their depth-distribution as a function of annealing durations. The formation of nanocavities in the vicinity of nanocrystal/SiO2 interface is evidenced, as well as their influence on the release of the compressive stress exerted on Ge-ncs by surrounding SiO2. Some Ge ncs are found inside nanocavities, and can move into the implanted layer through a nanocavity-assisted diffusion mechanism. This finding sheds light on a new process that can explain the non-uniformity of the Ge-nanocrystal spatial distribution. PMID- 27966460 TI - Potent CD4+ T cell-associated antitumor memory responses induced by trifunctional bispecific antibodies in combination with immune checkpoint inhibition. AB - Combinatorial approaches of immunotherapy hold great promise for the treatment of malignant disease. Here, we examined the potential of combining an immune checkpoint inhibitor and trifunctional bispecific antibodies (trAbs) in a preclinical melanoma mouse model using surrogate antibodies of Ipilimumab and Catumaxomab, both of which have already been approved for clinical use. The specific binding arms of trAbs redirect T cells to tumor cells and trigger direct cytotoxicity, while the Fc region activates accessory cells eventually giving rise to a long-lasting immunologic memory. We show here that T cells redirected to tumor cells by trAbs strongly upregulate CTLA-4 expression in vitro and in vivo. This suggested that blocking of CTLA-4 in combination with trAb treatment enhances T-cell activation in a tumor-selective manner. However, when mice were challenged with melanoma cells and subsequently treated with antibodies, there was only a moderate beneficial effect of the combinatorial approach in vivo with regard to direct tumor destruction in comparison to trAb therapy alone. By contrast, a significantly improved vaccination effect was obtained by CTLA-4 blocking during trAb-dependent immunization. This resulted in enhanced rejection of melanoma cells given after pre-immunization. The improved immunologic memory induced by the combinatorial approach correlated with an increased humoral antitumor response as measured in the sera and an expansion of CD4+ memory T cells found in the spleens. PMID- 27966459 TI - The transcription levels and prognostic values of seven proteasome alpha subunits in human cancers. AB - Proteasome alpha subunits (PSMAs) have been shown to participate in the malignant progression of human cancers. However, the expression patterns and prognostic values of individual PSMAs remain elusive in most cancers. In the present study, we investigated the mRNA expression levels of seven PSMAs in different kinds of cancers using Oncomine and The Cancer Genome Atlas (TCGA) databases. The prognostic significance of PSMAs was also determined by Kaplan-Meier Plotter and PrognScan databases. Combined with Oncomine and TCGA, the mRNA expression levels of PSMA1-7 were significantly upregulated in breast, lung, gastric, bladder and head and neck cancer compared with normal tissues. Moreover, only PSMA6 and PSMA5 were not overexpressed in colorectal and kidney cancer, respectively. In survival analyses based on Kaplan-Meier Plotter, PSMA1-7 showed significant prognostic values in breast, lung and gastric cancer. Furthermore, potential correlations between PSMAs and survival outcomes were also observed in ovarian cancer, colorectal cancer and melanoma by Kaplan-Meier Plotter and PrognScan. These data indicated that PSMAs might serve as novel biomarkers and potential therapeutic targets for multiple human cancers. However, further studies are needed to explore the detailed biological functions and molecular mechanisms involved in tumor progression. PMID- 27966463 TI - Growth of wurtzite Al x Ga1-x P nanowire shells and characterization by Raman spectroscopy. AB - The phonon energies of AlGaP in wurtzite crystal structure are generally not known, as opposed to their zincblende counterparts, because AlGaP crystallizes in zincblende phase in bulk and thin films structures. However, in nanowires AlGaP can be grown in wurtzite crystal structure. In this work we have grown wurtzite GaP/AlGaP/GaP core-shell nanowires by use of MOVPE. After developing suitable growth conditions, the Al composition was determined by STEM-EDX measurements and the wurtzite AlGaP phonon energies by Raman spectroscopy. Raman measurements show a peak shift with increasing Al composition in the AlGaP shell. We find that the phonon energies for wurtzite AlGaP are slightly lower than for zincblende AlGaP. Our results can be used to determine the Al composition in wurtzite AlGaP by Raman scattering. PMID- 27966462 TI - Radio frequency-mediated local thermotherapy for destruction of pancreatic tumors using Ni-Au core-shell nanowires. AB - We present a novel method of radio frequency (RF)-mediated thermotherapy in tumors by remotely heating nickel (Ni)-gold (Au) core-shell nanowires (CSNWs). Ectopic pancreatic tumors were developed in nude mice to evaluate the thermotherapeutic effects on tumor progression. Tumor ablation was produced by RF mediated thermotherapy via activation of the paramagnetic properties of the Ni-Au CSNWs. Histopathology demonstrated that heat generated by RF irradiation caused significant cellular death with pyknotic nuclei and nuclear fragmentation dispersed throughout the tumors. These preliminary results suggest that thermotherapy ablation induced via RF activation of nanowires provides a potential alternative therapy for cancer treatment. PMID- 27966464 TI - Graphene-loaded tin oxide nanofibers: optimization and sensing performance. AB - We investigated the gas sensing characteristics of graphene nanosheet (NS)-loaded SnO2 nanofibers (NFs) that were synthesized by a low-cost facile electrospinning process. The sensing performance was characterized as a function of the graphene content with various gases such as C6H6, C7H8, CO, CO2, and H2S. The loading of graphene NSs significantly improved the gas sensing performances of SnO2 NFs. The optimal amount of graphene NSs was found to be 0.5 wt%. We proposed a sensing mechanism for the enhanced sensing performance based on the chemical sensitization of graphene NSs and the charge transfer through the heterointerfaces between graphene NSs and SnO2 nanograins. The results show that graphene NS-loaded SnO2 NFs are a promising sensing material system that can detect hazardous gaseous species. PMID- 27966465 TI - Polarization-driven self-organization of silver nanoparticles in 1D and 2D subwavelength gratings for plasmonic photocatalysis. AB - One of the main challenges in plasmonics is to conceive large-scale, low-cost techniques suitable for the fabrication of metal nanoparticle patterns showing precise spatial organization. Here, we introduce a simple method based on continuous-wave laser illumination to induce the self-organization of silver nanoparticles within high-index thin films. We show that highly regular and homogeneous nanoparticle gratings can be produced on large areas using laser controlled self-organization processes. This very versatile technique can provide 1D and 2D patterns at a subwavelength scale with tunable features. It does not need any stabilization or expensive devices, such as those required by optical or electron lithography, and is rapid to implement. Accurate in-plane and in-depth characterizations provide valuable information to explain the mechanisms that lead to pattern formation and especially how 2D self-organization can fall into place with successive laser scans. The regular and homogeneous 2D self organization of metallic NPs with a single laser scan is also reported for the first time in this article. As the reported nanostructures are embedded in porous TiO2, we also theoretically explore the interesting potential of organization on the photocatalytic activity of Ag-NP-containing TiO2 porous films, which is one of the most promising materials for self-cleaning or remediation applications. Realistic electromagnetic simulations demonstrate that the periodic organization of silver nanoparticles can increase the light intensity within the film more than ten times that produced with randomly distributed nanoparticles, leading as expected to enhanced photocatalytic efficiency. PMID- 27966466 TI - Real-time path-integral approach for dissipative quantum dot-cavity quantum electrodynamics: impure dephasing-induced effects. AB - A dissipative quantum dot (QD)-cavity system, where the QD is initially prepared in the excited state with no photon in the cavity, coupled to a longitudinal acoustic (LA) phonon reservoir is studied using a numerically exact real-time path-integral approach. Three distinct dynamical regimes of weak (WC), strong (SC), and coherent coupling (CC) are discussed and more accurate conditions identifying them are presented. Our results show that to have the CC regime, which is characterized by clear vacuum Rabi oscillation (VRO), vacuum Rabi splitting (VRS) should be larger than the sum of the widths of the corresponding peaks. In order to distinguish between contributions of population decay and impure dephasing, induced by LA phonon bath and the dissipations, we propose a two-part phenomenological expression, corresponding to the population decay and impure dephasing, which fits the QD-cavity decay curves perfectly and is used to calculate the corresponding spectra. We demonstrate that the effective population decay rate (the emission rate) increases from the carrier recombination rate to a maximum value, which is the mean of the QD and cavity dissipation rates, with QD cavity coupling strength. To study the role of the effective impure dephasing rate on the width of the central peak of the spectra we introduce a quantity that can also be applied in determining the distinct coupling regimes. This quantity enables us to identify the onset of the SC regime as the point where the impure dephasing term begins to contribute to the central band of the spectrum significantly, as a result of the existence of VRO with a very small frequency (unclear VRO) at the corresponding decay curve. Its contribution to the width of the central peak increases with the coupling strength up to the onset of the CC regime, then reduces as a result of the appearance of sidebands in the spectra, which originates from clear VRO. The effective population decay and impure dephasing rate contribute solely to the width-of the central and sideband peaks of the triplet spectra respectively-only beyond a very large coupling strength which is the same across the considered temperature range. For higher temperatures, the maximum achievable emission rate can be obtained at larger coupling strengths. PMID- 27966467 TI - Effect of body aerodynamics on the dynamic flight stability of the hawkmoth Manduca sexta. AB - This study explores the effects of the body aerodynamics on the dynamic flight stability of an insect at various different forward flight speeds. The insect model, whose morphological parameters are based on measurement data from the hawkmoth Manduca sexta, is treated as an open-loop six-degree-of-freedom dynamic system. The aerodynamic forces and moments acting on the insect are computed by an aerodynamic model that combines the unsteady panel method and the extended unsteady vortex-lattice method. The aerodynamic model is then coupled to a multi body dynamic code to solve the system of motion equations. First, the trimmed flight conditions of insect models with and without consideration of the body aerodynamics are obtained using a trim search algorithm. Subsequently, the effects of the body aerodynamics on the dynamic flight stability are analysed through modal structures, i.e., eigenvalues and eigenvectors in this case, which are based on linearized equations of motion. The solutions from the nonlinear and linearized equations of motion due to gust disturbances are obtained, and the effects of the body aerodynamics are also investigated through these solutions. The results showed the important effect of the body aerodynamics at high-speed forward flight (in this paper at 4.0 and 5.0 m s-1) and the movement trends of eigenvalues when the body aerodynamics is included. PMID- 27966468 TI - Understanding thermal transport in asymmetric layer hexagonal boron nitride heterostructure. AB - In this work, thermal transport at the junction of an asymmetric layer hexagonal boron-nitride (h-BN) heterostructure is explored using a non-equilibrium molecular dynamics method. A thermal contact resistance of 3.6 * 10-11 K . m2 W-1 is characterized at a temperature of 300 K with heat flux from the trilayer to monolayer regions. The mismatch in the flexural phonon modes revealed by power spectra analysis provides the driving force for the calculated thermal resistance. A high thermal rectification efficiency of 360% is calculated at the layer junction surpassing that of graphene. Several modulators, i.e. the system temperature, contact pressure and lateral dimensions, are applied to manipulate the thermal conductance and rectification across the interfaces. The predicted thermal rectification sustains positive correlations with temperature and phonon propagation lengths with little change to the coupling strength. PMID- 27966469 TI - EPR investigation of pure and Co-doped ZnO oriented nanocrystals. AB - Pure and cobalt-doped zinc oxide aligned nanorods have been grown by the low temperature (90 degrees C) aqueous chemical method on amorphous ZnO seed layer, deposited on a sapphire substrate. High crystallinity of these objects is demonstrated by the electron paramagnetic resonance investigation at liquid helium temperature. The successful incorporation of Co2+ ions in substitution of Zn2+ ones in the ZnO matrix has also been confirmed. A drastic reduction of intrinsic ZnO nanorods core defects is observed in the Co-doped samples, which enhances the structural quality of the NRs. The quantification of substitutional Co2+ ions in the ZnO matrix is achieved by comparison with a reference sample. The findings in this study indicate the potential of using the low-temperature aqueous chemical approach for synthesizing material for spintronics applications. PMID- 27966470 TI - Interfacial double layer mediated electrochemical growth of thin-walled platinum nanotubes. AB - This work demonstrates that thin-walled platinum nanotubes can be readily synthesized by controlling the interfacial double layer in alumina nanochannels. The gradient distribution of ions in nanochannels enables the creation of Pt nanotubes with walls as thin as 5 nm at the top end when using a solution containing polyvinylpyrrolidone (PVP) and chloroplatinic acid (H2PtCl6) under the influence of an electric potential in nanochannels. The highly efficient formation of thin-walled Pt nanotubes is a result of the concentration gradient of [Formula: see text] and a thick double layer, which was caused by the low concentration of Pt precursors and the enhanced surface charge density induced by protonated PVP steric adsorption. This well-controlled synthesis reveals that the interfacial double layer is a useful tool to tailor the structure of nanomaterials in a nanoscale space, and holds promise in the construction of more complex functional nanostructures. PMID- 27966471 TI - Gas sensing at the nanoscale: engineering SWCNT-ITO nano-heterojunctions for the selective detection of NH3 and NO2 target molecules. AB - The gas response of single-wall carbon nanotubes (SWCNT) functionalized with indium tin oxide (ITO) nanoparticles (NP) has been studied at room temperature and an enhanced sensitivity to ammonia and nitrogen dioxide is demonstrated. The higher sensitivity in the functionalized sample is related to the creation of nano-heterojunctions at the interface between SWCNT bundles and ITO NP. Furthermore, the different response of the two devices upon NO2 exposure provides a way to enhance also the selectivity. This behavior is rationalized by considering a gas sensing mechanism based on the build-up of space-charge layers at the junctions. Finally, full recovery of the signal after exposure to NO2 is achieved by UV irradiation for the functionalized sample, where the ITO NP can play a role to hinder the poisoning effects on SWCNT due to NO2 chemisorption. PMID- 27966472 TI - Inductively-coupled-plasma-induced electret enhancement for triboelectric nanogenerators. AB - Polyethylene terephthalate (PET) films' electret property was significantly enhanced after being treated with inductively coupled plasma (ICP). Based on this modified material, the triboelectric nanogenerators' (TENGs) transferred charges remained at 68.6% of the initial value after 400 000 cycles of contact-separation process, which was about three times that of the untreated samples. PMID- 27966474 TI - Site- and phase-selective x-ray absorption spectroscopy based on phase-retrieval calculation. AB - Understanding the chemical state of a particular element with multiple crystallographic sites and/or phases is essential to unlocking the origin of material properties. To this end, resonant x-ray diffraction spectroscopy (RXDS) achieved through a combination of x-ray diffraction (XRD) and x-ray absorption spectroscopy (XAS) techniques can allow for the measurement of diffraction anomalous fine structure (DAFS). This is expected to provide a peerless tool for electronic/local structural analyses of materials with complicated structures thanks to its capability to extract spectroscopic information about a given element at each crystallographic site and/or phase. At present, one of the major challenges for the practical application of RXDS is the rigorous determination of resonant terms from observed DAFS, as this requires somehow determining the phase change in the elastic scattering around the absorption edge from the scattering intensity. This is widely known in the field of XRD as the phase problem. The present review describes the basics of this problem, including the relevant background and theory for DAFS and a guide to a newly-developed phase-retrieval method based on the logarithmic dispersion relation that makes it possible to analyze DAFS without suffering from the intrinsic ambiguities of conventional iterative-fitting. Several matters relating to data collection and correction of RXDS are also covered, with a final emphasis on the great potential of powder sample-based RXDS (P-RXDS) to be used in various applications relevant to practical materials, including antisite-defect-type electrode materials for lithium-ion batteries. PMID- 27966475 TI - Ionic Hamiltonians for transition metal atoms: effective exchange coupling and Kondo temperature. AB - An ionic Hamiltonian for describing the interaction between a metal and a d-shell transition metal atom having an orbital singlet state is introduced and its properties analyzed using the Schrieffer-Wolf transformation (exchange coupling) and the poor man's scaling method (Kondo temperature). We find that the effective exchange coupling between the metal and the atom has an antiferromagnetic or a ferromagnetic interaction depending on the kind of atomic fluctuations, either [Formula: see text] or [Formula: see text], associated with the metal-atom coupling. We present a general scheme for all those processes and calculate, for the antiferromagnetic interaction, the corresponding Kondo-temperature. PMID- 27966473 TI - Optical properties of biomimetic probes engineered from erythrocytes. AB - Light-activated theranostic materials offer a potential platform for optical imaging and phototherapeutic applications. We have engineered constructs derived from erythrocytes, which can be doped with the FDA-approved near infrared (NIR) chromophore, indocyanine green (ICG). We refer to these constructs as NIR erythrocyte-mimicking transducers (NETs). Herein, we investigated the effects of changing the NETs mean diameter from micron- (~4 MUm) to nano- (~90 nm) scale, and the ICG concentration utilized in the fabrication of NETs from 5 to 20 MUM on the resulting absorption and scattering characteristics of the NETs. Our approach consisted of integrating sphere-based measurements of light transmittance and reflectance, and subsequent utilization of these measurements in an inverse adding-doubling algorithm to estimate the absorption (MU a) and reduced scattering (MU s') coefficients of these NETs. For a given NETs diameter, values of MU a increased over the approximate spectral band of 630-860 nm with increasing ICG concentration. Micron-sized NETs produced the highest peak value of MU a when using ICG concentrations of 10 and 20 MUM, and showed increased values of MU s' as compared to nano-sized NETs. Spectral profiles of MU s' for these NETs showed a trend consistent with Mie scattering behavior for spherical objects. For all NETs investigated, changing the ICG concentration minimally affected the scattering characteristics. A Monte Carlo-based model of light distribution showed that the presence of these NETs enhanced the fluence levels within simulated blood vessels. These results provide important data towards determining the appropriate light dosimetry parameters for an intended light based biomedical application of NETs. PMID- 27966476 TI - Charge-separation enhancement in inverted polymer solar cells by molecular-level triple heterojunction: NiO-np:P3HT:PCBM. AB - Hole collection and transport are crucial physical processes in bulk heterojunction (BHJ) solar cells, which represent major bottlenecks due to their limitations in power conversion efficiency (PCE). Hence, a more efficient alternative is needed to accept and transport holes to the collection electrode in BHJ solar cells. Here, we bring both electron and hole collection centres close to the point of exciton generation by infiltrating P3HT poly(3 hexylthiophene):PCBM ([6,6]-phenyl-C61-butyric acid methyl ester) blend into a highly porous interconnected p-type NiO-nanoparticle (NiO-np) network, through solvent-assisted grafting. In this study, a hybrid polymer solar cell is demonstrated with a P3HT:PCBM:NiO-np triple-heterojunction active layer which showed greatly improved rectification behaviour, long electron lifetime and generated higher PCE of 4% under AM 1.5 solar illumination with a 75% increase in PCE with respect to the P3HT:PCBM device. The optimum NiO-np amount and active layer thickness were found to be 2% and 250 nm, respectively. PMID- 27966477 TI - Application of metal nanowire networks on hydrogenated amorphous silicon thin film solar cells. AB - We demonstrate the application of metal nanowire (NW) networks as a transparent electrode on hydrogenated amorphous Si (a-Si:H) solar cells. We first systematically investigate the optical performances of the metal NW networks on a Si:H solar cells in different electrode configurations through numerical simulations to fully understand the mechanisms to guide the experiments. The theoretically optimized configuration is discovered to be metal NWs sandwiched between a 40 nm indium tin oxide (ITO) layer and a 20 nm ITO layer. The overall performances of the solar cells integrated with the metal NW networks are experimentally studied. It has been found the experimentally best performing NW integrated solar cell deviates from the theoretically predicated design due to the performance degradation induced by the fabrication complicity. A 6.7% efficiency enhancement was achieved for the solar cell with metal NW network integrated on top of a 60 nm thick ITO layer compared to the cell with only the ITO layer due to enhanced electrical conductivity by the metal NW network. PMID- 27966478 TI - Porosimetry and packing morphology of vertically-aligned carbon nanotube arrays via impedance spectroscopy. AB - Vertically aligned one-dimensional nanostructure arrays are promising in many applications such as electrochemical systems, solar cells, and electronics, taking advantage of high surface area per unit volume, nanometer length scale packing, and alignment leading to high conductivity. However, many devices need to optimize arrays for device performance by selecting an appropriate morphology. Developing a simple, non-invasive tool for understanding the role of pore volume distribution and interspacing would aid in the optimization of nanostructure morphologies in electrodes. In this work, we combined electrochemical impedance spectroscopy (EIS) with capacitance measurements and porous electrode theory to conduct in situ porosimetry of vertically-aligned carbon nanotubes (VA CNTs) non-destructively. We utilized the EIS measurements with a pore size distribution model to quantify the average and dispersion of inter-CNT spacing (Gamma), stochastically, in carpets that were mechanically densified from 1.7 * 1010 tubes/cm2 to 4.5 * 1011 tubes/cm2. Our analysis predicts that the inter-CNT spacing ranges from over 100 +/- 50 nm in sparse carpets to sub 10 +/- 5 nm in packed carpets. Our results suggest that waviness of CNTs leads to variations in the inter-CNT spacing, which can be significant in sparse carpets. This methodology can be used to predict the performance of many nanostructured devices, including supercapacitors, batteries, solar cells, and semiconductor electronics. PMID- 27966479 TI - The Nobel Prize for understanding autophagy, a cellular mechanism of waste disposal that keeps us healthy. PMID- 27966480 TI - Triphala, a formulation of traditional Ayurvedic medicine, shows protective effect against X-radiation in HeLa cells. AB - Ayurveda is a holistic medical system of traditional medicine, and Triphala is one of the most popular formulations in Ayurveda. Triphala is composed of three kinds of herb, Terminalia chebula, Terminalia bellirica, and Emblica officinalis. Since Triphala is shown to exhibit a protective activity against ionizing radiation in mice, we investigated its activity in HeLa cells. We found that Triphala showed the protective effects against X-radiation and bleomycin, both of which generate DNA strand breaks, in HeLa cells. Further, Triphala efficiently eliminated reactive oxygen species (ROS) in HeLa cells. Thus, the antioxidant activity of Triphala would likely play a role in its protective actions against X radiation and bleomycin because both agents damage DNA through the generation of ROS. These observations suggested that the radioprotective activity of Triphala can be, at least partly, studied with the cells cultured in vitro. The simple bioassay system with human cultured cells would facilitate the understanding of the molecular basis for the beneficial effects of Triphala. PMID- 27966481 TI - Engineering and introduction of de novo disulphide bridges in organophosphorus hydrolase enzyme for thermostability improvement. AB - The organophosphorus hydrolase (OPH) has been used to degrade organophosphorus chemicals, as one of the most frequently used decontamination methods. Under chemical and thermal denaturing conditions, the enzyme has been shown to unfold. To utilize this enzyme in various applications, the thermal stability is of importance. The engineering of de novo disulphide bridges has been explored as a means to increase the thermal stability of enzymes in the rational method of protein engineering. In this study, Disulphide by Design software, homology modelling and molecular dynamics simulations were used to select appropriate amino acid pairs for the introduction of disulphide bridge to improve protein thermostability. The thermostability of the wild-type and three selected mutant enzymes were evaluated by half-life, delta G inactivation (DeltaGi) and structural studies (fluorescence and far-UV CD analysis). Data analysis showed that half-life of A204C/T234C and T128C/E153C mutants were increased up to 4 and 24 min, respectively; however, for the G74C/A78C mutant, the half-life was decreased up to 9 min. For the T128C/E124C mutant, both thermal stability and Catalytic efficiency (kcat) were also increased. The half-life and DeltaGi results were correlated to the obtained information from structural studies by circular dichroism (CD) spectrometry and extrinsic fluorescence experiments; as rigidity increased in A204C/T2234C and T128C/E153C mutants, half-life and DeltaGi also increased. For G74C/A78C mutant, these parameters decreased due to its higher flexibility. The results were submitted a strong evidence for the possibility to improve the thermostability of OPH enzyme by introducing a disulphide bridge after bioinformatics design, even though this design would not be always successful. PMID- 27966482 TI - Characterization of a DUF820 family protein Alr3200 of the cyanobacterium Anabaena sp. strain PCC7120. AB - The hypothetical protein 'Alr3200' of Anabaena sp. strain PCC7120 is highly conserved among cyanobacterial species. It is a member of the DUF820 (Domain of Unknown Function) protein family, and is predicted to have a DNase domain. Biochemical analysis revealed a Mg(II)-dependent DNase activity for Alr3200 with a specific activity of 8.62x104 Kunitz Units (KU) mg -1 protein. Circular dichroism analysis predicted Alr3200 to have approximately 40 percent beta strands and approximately 9 percent alpha-helical structures. Anabaena PCC7120 inherently expressed Alr3200 at very low levels, and its overexpression had no significant effect on growth of Anabaena under control conditions. However, Analr3200+, the recombinant Anabaena strain overexpressing Alr3200, exhibited zero survival upon exposure to 6 kGy of gamma-radiation, which is the LD50 for wild type Anabaena PCC7120 as well as the vector control recombinant strain, AnpAM. Comparative analysis of the two recombinant Anabaena strains suggested that it is not the accumulated Alr3200 per se, but its possible interactions with the radiation-induced unidentified DNA repair proteins of Anabaena, which hampers DNA repair resulting in radiosensitivity. PMID- 27966483 TI - Quaternary ammonium salt N-(dodecyloxycarboxymethyl)-N,N,N-trimethyl ammonium chloride induced alterations in Saccharomyces cerevisiae physiology. AB - We investigated the influence of the quaternary ammonium salt (QAS) called IM (N (dodecyloxycarboxymethyl)- N,N,N-trimethyl ammonium chloride) on yeast cells of the parental strain and the IM-resistant mutant (EO25 IMR) growth. The phenotype of this mutant was pleiotropic. The IMR mutant exhibited resistance to ethanol, osmotic shock and oxidative stress, as well as increased sensitivity to UV. Moreover, it was noted that mutant EO25 appears to have an increased resistance to clotrimazole, ketoconazole, fluconazole, nystatin and cycloheximide. It also tolerated growth in the presence of crystal violet, DTT and metals (selenium, tin, arsenic). It was shown that the presence of IM decreased ergosterol level in mutant plasma membrane and increased its unsaturation. These results indicate changes in the cell lipid composition. Western blot analysis showed the induction of Pma1 level by IM. RT-PCR revealed an increased PMA1 expression after IM treatment. PMID- 27966484 TI - Genetic and biochemical evidences reveal novel insights into the mechanism underlying Saccharomyces cerevisiae Sae2-mediated abrogation of DNA replication stress. AB - In Saccharomyces cerevisiae, the Mre11-Rad50-Xrs2 (MRX) protein complex plays pivotal roles in double-strand break (DSB) repair, replication stress and telomere length maintenance. Another protein linked to DSB repair is Sae2, which regulates MRX persistence at DSBs. However, very little is known about its role in DNA replication stress and repair. Here, we reveal a crucial role for Sae2 in DNA replication stress. We show that different mutant alleles of SAE2 cause hypersensitivity to genotoxic agents, and when combined with Deltamre11 or nuclease-defective mre11 mutant alleles, the double mutants are considerably more sensitive suggesting that the sae2 mutations synergize with mre11 mutations. Biochemical studies demonstrate that Sae2 exists as a dimer in solution, associates preferentially with single-stranded and branched DNA structures, exhibits structure-specific endonuclease activity and cleaves these substrates from the 5' end. Furthermore, we show that the nuclease activity is indeed intrinsic to Sae2. Interestingly, sae2G270D protein possesses DNA-binding activity, but lacks detectable nuclease activity. Altogether, our data suggest a direct role for Sae2 nuclease activity in processing of the DNA structures that arise during replication and DNA damage and provide insights into the mechanism underlying Mre11-Sae2-mediated abrogation of replication stressrelated defects in S. cerevisiae. PMID- 27966485 TI - Metabolic alterations derived from absence of Two-Pore Channel 1 at cardiac level. AB - Two-pore channels (TPCs or TPCNs) are novel voltage-gated ion channels that have been postulated to act as Ca2+ and/or Na+ channels expressed exclusively in acidic organelles such as endosomes and lysosomes. TPCNs participate in the regulation of diverse biological processes and recently have been proposed to be involved in the pathophysiology of metabolic disorders such as obesity, fatty liver disease and type 2 diabetes mellitus. Due to the importance of these pathologies in the development of cardiovascular diseases, we aimed to study the possible role of two-pore channel 1 (TPCN1) in the regulation of cardiac metabolism. To explore the cardiac function of TPCN1, we developed proteomic approaches as 2-DE-MALDI-MS and LC-MALDI-MS in the cardiac left ventricle of TPCN1 KO and WT mice, and found alterations in several proteins implicated in glucose and fatty acid metabolism in TPCN1 KO vs. WT mice. The results confirmed the altered expression of HFABP, a key fatty acid transport protein, and of enolase and PGK1, the key enzymes in the glycolytic process. Finally, in vitro experiments performed in neonatal rat cardiomyocytes, in which TPCN1 was silenced using siRNAs, confirmed that the downregulation of TPCN1 gene expression increased 2-deoxy-D-[3H]-glucose uptake and GLUT4 mobilization into cell peripherals in cardiac cells. Our results are the first to suggest a potential role for TPCNs in cardiac metabolism regulation. PMID- 27966486 TI - Selective serotonin reuptake inhibitor sertraline inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells. AB - We examined the effects of the selective serotonin reuptake inhibitor (SSRI) sertraline on voltage-dependent K+ (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells using the voltage-clamp technique. Sertraline decreased the Kv channel current in a dose-dependent manner, with an IC50 value of 0.18 mu M and a slope value (Hill coefficient) of 0.61. Although the application of 1 mu M sertraline did not affect the steady-state activation curves, sertraline caused a significant, negative shift in the inactivation curves. Pretreatment with another SSRI, paroxetine, had no significant effect on Kv currents and did not alter the inhibitory effects of sertraline on Kv currents. From these results, we concluded that sertraline dose-dependently inhibited Kv currents independently of serotonin reuptake inhibition by shifting inactivation curves to a more negative potential. PMID- 27966488 TI - Long non-coding RNA HOTAIR regulates proliferation and invasion via activating Notch signalling pathway in retinoblastoma. AB - Retinoblastoma is the most frequently occurring tumour in the eyes in early childhood. Novel targets that are important for the diagnosis or treatment of retinoblastoma could be valuable in increasing the survival rate of patients affected by this disease. Long non-coding RNAs (lncRNAs) are a recently discovered type of RNAs with no proteincoding function; yet it has become increasingly clear that lncRNAs are responsible for important gene regulatory functions in various diseases. In this study, the expression of lncRNA HOTAIR was measured by qRT-PCR, and HOTAIR expression was found to be significantly upregulated in human retinoblastomas tissues as compared with that in paracancerous tissues. Knockdown of HOTAIR restricted the proliferation and invasion of the more invasive retinoblastoma Y79 cells, and led to G0/G1 arrest, possibly through inhibiting phospho-RB1, RB1 and CCNE. Furthermore, we found that the Notch signalling pathway was activated abnormally in retinoblastoma cell lines, while knockdown of HOTAIR attenuated the endogenous Notch signalling pathway in vitro and in vivo. In addition, knockdown of HOTAIR could inhibit the tumour progression in a xenograft model of retinoblastoma. In summary, our findings indicate that HOTAIR may play important roles in retinoblastoma progression via Notch pathway. HOTAIR has the potential to enhance the development of novel targeted diagnostic and therapeutic approaches for retinoblastoma. PMID- 27966487 TI - Expressions of visual pigments and synaptic proteins in neonatal chick retina exposed to light of variable photoperiods. AB - Light causes damage to the retina, which is one of the supposed factors for age related macular degeneration in human. Some animal species show drastic retinal changes when exposed to intense light (e.g. albino rats). Although birds have a pigmented retina, few reports indicated its susceptibility to light damage. To know how light influences a cone-dominated retina (as is the case with human), we examined the effects of moderate light intensity on the retina of white Leghorn chicks (Gallus g. domesticus). The newly hatched chicks were initially acclimatized at 500 lux for 7 days in 12 h light: 12 h dark cycles (12L:12D). From posthatch day (PH) 8 until PH 30, they were exposed to 2000 lux at 12L:12D, 18L:6D (prolonged light) and 24L:0D (constant light) conditions. The retinas were processed for transmission electron microscopy and the level of expressions of rhodopsin, S- and L/M cone opsins, and synaptic proteins (Synaptophysin and PSD 95) were determined by immunohistochemistry and Western blotting. Rearing in 24L:0D condition caused disorganization of photoreceptor outer segments. Consequently, there were significantly decreased expressions of opsins and synaptic proteins, compared to those seen in 12L:12D and 18L:6D conditions. Also, there were ultrastructural changes in outer and inner plexiform layer (OPL, IPL) of the retinas exposed to 24L:0D condition. Our data indicate that the cone dominated chick retina is affected in constant light condition, with changes (decreased) in opsin levels. Also, photoreceptor alterations lead to an overall decrease in synaptic protein expressions in OPL and IPL and death of degenerated axonal processes in IPL. PMID- 27966489 TI - Reserpine requires the D2-type receptor, dop-3, and the exoribonuclease, eri-1, to extend the lifespan in C. elegans. AB - Lifespan extension is an all systems encompassing event. Involvement of reduced insulin/IGF1 signalling is well worked out, first in the model organism Caenorhbaditis elegans followed by other systems including humans. But the role of neuronal component in lifespan extension is not well understood due to the refractory nature of neurons to small RNA interference (sRNAi) in C. elegans. Earlier, we have demonstrated that an antihypertensive drug, reserpine, extends lifespan through modulation of neurotransmitter release, especially, acetylcholine, in C. elegans. Intriguingly, the reserpine mediated lifespan extension (RMLE) does not happen through the known longevity pathways. Here, we report that the D2-type dopamine receptor (DOP-3), which acts through the inhibitory Gprotein coupled (G alpha i) pathway mediated signalling is partly required for RMLE. In the dop-3 loss of function mutant RMLE is shortened. DOP-3 acts through Galphao (goa-1). One of the downstream targets of G protein signalling is the transcription factor, jun-1. MRP-1, an ATP binding cassette transporter, belonging to the multidrug resistance protein family is one of the genes turned on by JUN-1. RMLE is shortened in dop-3-->goa-1-->jun1-->mrp-1 loss of function mutants, elucidating the contribution of dop-3 signalling. The dop-3 receptor system is known to inhibit acetylcholine release. This suggests dopamine receptor, dop-3 could be contributing to the modulation of acetylcholine release by reserpine. ERI-1 is a 3'-5' exoribonuclease, one of the negative regulators of sRNAi, whose loss of function makes neurons amenable to siRNA. In the absence of eri-1, RMLE is shortened. In the dop-3 loss-of-function background, lack of eri-1 completely abolishes RMLE. This suggests that dop-3 and eri-1 act in independent parallel pathways for RMLE and these two pathways are essential and sufficient for the longevity enhancement by reserpine in C. elegans. PMID- 27966491 TI - A lateralized functional auditory network is involved in anuran sexual selection. AB - Right ear advantage (REA) exists in many land vertebrates in which the right ear and left hemisphere preferentially process conspecific acoustic stimuli such as those related to sexual selection. Although ecological and neural mechanisms for sexual selection have been widely studied, the brain networks involved are still poorly understood. In this study we used multi-channel electroencephalographic data in combination with Granger causal connectivity analysis to demonstrate, for the first time, that auditory neural network interconnecting the left and right midbrain and forebrain function asymmetrically in the Emei music frog (Babina daunchina), an anuran species which exhibits REA. The results showed the network was lateralized. Ascending connections between the mesencephalon and telencephalon were stronger in the left side while descending ones were stronger in the right, which matched with the REA in this species and implied that inhibition from the forebrainmay induce REA partly. Connections from the telencephalon to ipsilateral mesencephalon in response to white noise were the highest in the non-reproductive stage while those to advertisement calls were the highest in reproductive stage, implying the attention resources and living strategy shift when entered the reproductive season. Finally, these connection changes were sexually dimorphic, revealing sex differences in reproductive roles. PMID- 27966490 TI - Ayurvedic Amalaki Rasayana promotes improved stress tolerance and thus has anti aging effects in Drosophila melanogaster. AB - Amalaki Rasayana (AR) is a common Ayurvedic herbal formulation of Phyllanthus emblica fruits and some other ingredients, and is used for general good health and healthy aging. We reported it to improve life history traits and to suppress neurodegeneration as well as induced apoptosis in Drosophila. The present study examines responses of Drosophila reared on AR-supplemented food to crowding, thermal or oxidative stresses. Wild-type larvae/flies reared on AR-supplemented food survived the various cell stresses much better than those reared on control food. AR-fed mutant park13 or DJ-1 beta Delta93 (Parkinson's disease model) larvae/flies, however, showed only partial or no protection, respectively, against paraquat-induced oxidative stress, indicating essentiality of DJ-1 beta for AR-mediated oxidative stress tolerance. AR feeding reduced the accumulation of reactive oxygen species (ROS) and lipid peroxidation even in aged (35-day-old) wild-type flies while enhancing superoxide dismutase (SOD) activity. We show that while Hsp70 or Hsp83 expression under normal or stress conditions was not affected by AR feeding, Hsp27 levels were elevated in AR-fed wild-type control as well as heat-shocked larvae. Therefore, besides the known anti-oxidant activity of Phyllanthus emblica fruits, dietary AR also enhances cellular levels of Hsp27. Our in vivo study on a model organism shows that AR feeding significantly improves tolerance to a variety of cell stresses through reduced ROS and lipid peroxidation on the one hand, and enhanced SOD activity and Hsp27 on the other. The resulting better homeostasis improves life span and quality of organism's life. PMID- 27966493 TI - PluriPred: AWeb server for predicting proteins involved in pluripotent network. AB - Pluripotency is a unique property of stem cells that allows them to differentiate into all types of adult cells or maintain the self-renewal property. PluriPred predicts whether a protein is involved in pluripotency from primary protein sequence using manually curated pluripotent proteins as training datasets. Machine learning techniques (MLTs) such as Support Vector Machine (SVM), Naive Base (NB), Random Forest (RF), and sequence alignment technique BLAST were used in our study. The combination of SVM and PSI-BLAST was our proposed best model, which obtained a sensitivity of 77.40 percent, specificity of 79.72 percent, accuracy of 79.2 percent, and area under the ROC curve was 0.82 using 5-fold cross-validation. Furthermore, PluriPred gives the confidence of the prediction from training dataset's SVM score distribution and p-value from BLAST. We validated our proposed model with the other existing highthroughput studies using blind/independent datasets. Using PluriPred, 233 novel core and 323 novel extended core pluripotent proteins from mouse proteome, and 167 novel core and 385 extended core pluripotent proteins from human proteome, were predicted with high confidence. The Web application of PluriPred is available from bicresources. jcbose.ac.in/ssaha4/pluripred/. Many pluripotent genes/proteins take part in protein-protein networks associated with stem cell, cancer, and developmental biology, and we believe that PluriPred will help in these research. PMID- 27966492 TI - Functional analyses of Populus euphratica brassinosteroid biosynthesis enzyme genes DWF4 (PeDWF4) and CPD (PeCPD) in the regulation of growth and development of Arabidopsis thaliana. AB - DWF4 and CPD are key brassinosteroids (BRs) biosynthesis enzyme genes. To explore the function of Populus euphratica DWF4 (PeDWF4) and CPD (PeCPD), Arabidopsis thaliana transgenic lines (TLs) expressing PeDWF4, PeCPD or PeDWF4 plus PeCPD, namely PeDWF4-TL, PeCPD-TL and PeCP/DW-TL, were characterized. Compared with wild type (WT), the changes of both PeDWF4-TL and PeCPD-TL in plant heights, silique and hypocotyls lengths and seed yields were similar, but in bolting time and stem diameters, they were opposite. PeCP/DW-TL was more in plant heights and the lengths of primary root, silique, and fruit stalk, but less in silique numbers and seed yields than either PeDWF4-TL or PeCPD-TL. PeDWF4 and PeCPD specially expressed in PeDWF4-TL or PeCPDTL, and the transcription level of PeDWF4 was higher than that of PeCPD. In PeCP/DW-TL, their expressions were all relatively reduced. Additionally, the expression of PeDWF4 and PeCPD differentially made the expression levels of AtDWF4, AtCPD, AtBR6OX2, AtFLC, AtTCP1 and AtGA5 change in the TLs. The total BRs contents were PeDWF4-TL greater than PeCP/DW-TL greater than WT greater than PeCPD-TL. These results imply that PeDWF4 is functionally not exactly the same as PeCPD and there may be a synergistic and antagonistic effects in physiology between both of them in the regulation of plant growth and development. PMID- 27966494 TI - Brain-derived neurotrophic factor and early-life stress: Multifaceted interplay. AB - The brain-derived neurotrophic factor (BDNF) is a key regulator of neural development and plasticity. Longterm changes in the BDNF pathway are associated with childhood adversity and adult depression symptoms. Initially, stress-induced decreases in the BDNF pathway were found in some studies, but subsequent reports indicated the relationship between stress and BDNF to be much more complex, and the concept was significantly revised. In the present mini-review, we focus on the structure and regulation of the Bbnf gene as well as on the stress-BDNF interactions under early-life adverse conditions. PMID- 27966497 TI - Global health issues related to cleft lip and palate: Prevention and treatment need to team together. PMID- 27966498 TI - Smartphone application in tobacco cessation services. PMID- 27966496 TI - Recent excitements in protein NMR: Large proteins and biologically relevant dynamics. AB - The advent of Transverse Relaxation Optimized SpectroscopY (TROSY) and perdeuteration allowed biomolecular NMR spectroscopists to overcome the size limitation barrier (approx. 20 kDa) in de novo structure determination of proteins. The utility of these techniques was immediately demonstrated on large proteins and protein complexes (e.g. GroELGroES, ClpP protease, Hsp90-p53, 20S proteasome, etc.). Further, recent methodological developments such as Residual Dipolar Couplings and Paramagnetic Relaxation Enhancement allowed accurate measurement of long-range structural restraints. Additionally, Carr-Purcell Meiboom-Gill (CPMG), rotating frame relaxation experiments (R1(rho)) and saturation transfer experiments (CEST and DEST) created never-before accessibility to the (mu)s-ms timescale dynamic parameters that led to the deeper understanding of biological processes. Meanwhile, the excitement in the field continued with a series of developments in the fast data acquisition methods allowing rapid structural studies on less stable proteins. This review aims to discuss important developments in the field of biomolecular NMR spectroscopy in the recent past, i.e., in the post TROSY era. These developments not only gave access to the structural studies of large protein assemblies, but also revolutionized tools in the arsenal of today's biomolecular NMR and point to a bright future of biomolecular NMR spectroscopy. PMID- 27966499 TI - Foramen magnum as a tool for sexual dimorphism: A cone beam computed tomography study. AB - BACKGROUND AND OBJECTIVES: (1) To evaluate dimensions of the foramen magnum (FM) among males and females and to establish its role in sexual dimorphism using cone beam computed tomography (CBCT). (2) To evaluate sagittal diameter, transverse diameter, area, and circumference of FM among males and females. MATERIALS AND METHODS: Two hundred and eighty CBCT scans (140 males and 140 females; age range, 20-80 years) were selected for this study. The sagittal diameter, transverse diameter, area, and circumference of FM were measured, and data were subjected to discriminant analysis for the evaluation of sexual dimorphism. RESULTS: The area of FM was the best discriminant parameter which is used to study the sexual dimorphism with an overall accuracy of 72%. INTERPRETATION AND CONCLUSIONS: It can be concluded that the reconstructed CBCT image provides valuable measurements for the FM and could be used for sexing even when other methods are inconclusive. PMID- 27966501 TI - Determination of normal maxillary transverse dimension by using intercanine width and interpalatal first molar width. AB - BACKGROUND: Malocclusion in the vertical and sagittal planes is easy to observe whereas it is difficult to diagnose malocclusion in the transverse plane. There are yet no criteria defining a normal transverse occlusion. AIM: The aim of this study was to identify a ratio that defines a normal transverse occlusion. STUDY DESIGN: This was a retrospective study. MATERIALS AND METHODS: A total sample of 151 maxillary dental models (M = 55, F = 96) in the age range of 12-16 years were randomly selected, with 73 models in control group and 78 in the study group. All the models were mixed up and given to an operator for the measurement of intercanine width (ICW) and inter-palatal molar width (IPMW). STATISTICAL ANALYSIS USED: The data were statistically analyzed using SPSS software version 16.0. Chi-square test was performed to test the statistical significance difference between the groups at p <= 0.05. RESULTS: Nearly 98.60% of normal arches were found to have an IPMW to ICW ratio of 1:1 +/- 0.05. On further analysis, it was found that when IPMW >=37.45 mm, then the case may be considered to have normal arches, and if the ratio between IPMW to ICW is 1.15:1 +/- 0.05 or more and IPMW is <34.92 mm, then the case may be identified as deficient arch. CONCLUSION: The IPMW-to-ICW ratio can be used to differentiate deficient and normal arches. This hypothesis (Banker's hypothesis) is an easy and noninvasive method, using only two parameters, developed to help clinicians in identifying normal transverse dimension. PMID- 27966500 TI - Quantitative analysis of tumor-associated tissue eosinophilia in different histological grades of oral squamous cell carcinoma. AB - BACKGROUND AND OBJECTIVES: Oral squamous cell carcinoma (OSCC) is the 8 th most common aggressive epithelial malignant neoplasm worldwide today. The eosinophil may be a "multifaceted cell" that can be associated with wound-healing processes, as well as to tissue damage which has increased the speculations around tumor associated tissue eosinophilia in malignant tumors. The aim of this study was to detect the role and quantitative analysis of tumor-associated tissue eosinophils in different histological grades of OSCC. MATERIALS AND METHODS: A retrospective study was carried out in sixty cases of histopathologically graded OSCCs. Tissue sections of 4 MU thickness were made from paraffin-embedded tissue blocks and were stained with hematoxylin and eosin. Eosinophils were counted under randomly selected twenty high-power (*40) fields. Data were subjected to statistical analysis using ANOVA test. RESULTS: Higher mean eosinophils were recorded in well differentiated squamous cell carcinoma (WDSCC) followed by moderately differentiated squamous cell carcinoma (MDSCC) and poorly differentiated squamous cell carcinoma (PDSCC) groups, respectively. The difference in mean eosinophils was found to be statistically significant between WDSCC and MDSCC (P < 0.001), as well as between WDSCC and PDSCC (P < 0.001). CONCLUSION: Tumor-associated tissue eosinophil count is higher in WDSCC as compared to moderate and PDSCC. PMID- 27966502 TI - Evaluation of sexual dimorphism in maxillary and mandibular canine using mesiodistal, labiolingual dimensions, and crown height. AB - CONTEXT: Gender estimation is one of the most important parameters in forensic identification. Teeth being the central component of the masticatory apparatus of the skull is a good source of material for civil and medico-legal purpose. Gender estimation using dental features is primarily based on the comparison of tooth dimensions in male and female. AIMS: To analyze the presence of sexual dimorphism in maxillary and mandibular canine using mesiodistal (MD), labiolingual (LL), and height of crown. SUBJECTS AND METHODS: A total number of 100 subjects (50 males and 50 females) were included in the study between the age group of 20 and 25 years. Dimensions (MD, LL, height of crown) of maxillary and mandibular canine were recorded with a digital vernier calliper. STATISTICAL ANALYSIS USED: The data obtained is subjected to statistical analysis using Student's t-test and intra-reliability test. RESULTS: The present study revealed that male shows larger mean dimensions of teeth than female. Out of all the four canines, right maxillary canine shows highly consistent results for sexual dimorphism. Hence, by drawing the conclusion, it can be stated that right maxillary canine can be used as an adjunct along with other procedures for gender estimation. CONCLUSION: The findings support the usefulness of employing odontometric analysis of the canine teeth in gender estimation. It is an easy, reproducible, and objective method. PMID- 27966495 TI - Heterochromatin and the molecular mechanisms of 'parent-of-origin' effects in animals. AB - Twenty five years ago it was proposed that conserved components of constitutive heterochromatin assemble heterochromatinlike complexes in euchromatin and this could provide a general mechanism for regulating heritable (cell-to-cell) changes in gene expressibility. As a special case, differences in the assembly of heterochromatin-like complexes on homologous chromosomes might also regulate the parent-of-origin-dependent gene expression observed in placental mammals. Here, the progress made in the intervening period with emphasis on the role of heterochromatin and heterochromatin-like complexes in parent-of-origin effects in animals is reviewed. PMID- 27966503 TI - Clinical efficacy of four interventions in the reduction of dentinal hypersensitivity: A 2-month study. AB - BACKGROUND AND AIM: Dentinal hypersensitivity is a relatively common problem experienced in clinical dental practice and is characterized by short, sharp pain in response to stimuli such as tactile, thermal, evaporative, osmotic, or chemical. Several agents and treatment modalities have been used in the treatment of this condition. This study was conducted to compare the efficacy of four commercially available toothpastes in the reduction of dentinal hypersensitivity (DH), based on the hypothesis that calcium sodium phosphosilicate (CSPS) group had a better efficacy of the four. SETTINGS AND DESIGN: This study design was a prospective, single-blind, randomized, parallel clinical design. SUBJECTS AND METHODS: A total of 160 cases (93 males and 67 females; aged 20-60 years) were randomly divided into four groups: Group 1 - toothpaste containing 5% potassium nitrate; Group 2 - toothpaste containing 5% CSPS (NovaMin); Group 3 - toothpaste containing 10% strontium chloride; and Group 4 - a herbal formulation. The patients' DH scores for tactile, thermal, and evaporative stimuli were recorded on a visual analog scale at baseline, 2 weeks, 1 month, and 2 months. STATISTICAL ANALYSIS USED: The data were analyzed with Wilcoxon signed-rank test, Kruskal Wallis test, and Mann-Whitney U-test (P < 0.05). RESULTS: The four desensitizing kinds of toothpaste containing different active agents were effective in relieving dentinal hypersensitivity. However, CSPS group showed a better clinical response at the end of 2 months. CONCLUSIONS: The CSPS group showed a better reduction in the symptoms of DH. PMID- 27966504 TI - Evaluation of efficacy of photodynamic therapy as an adjunct to nonsurgical periodontal therapy in treatment of chronic periodontitis patients: A clinico microbiological study. AB - BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) is a local noninvasive treatment modality without side effects caused by antibiotics. The aim of this study was to evaluate the efficacy of adjunctive use of PDT with scaling and root planing as compared with SRP alone in the treatment of chronic periodontitis. SUBJECTS AND METHODS: Twenty participants with chronic periodontitis having probing pocket depths (PDs) of >=5 mm were selected for the study. Patients were randomly divided into control group and test group with ten patients in each group. Full-mouth SRP was performed in both the groups, followed by PDT in test group. Assessment of plaque index (PI), gingival index (GI), PD, and clinical attachment level (CAL) was done at baseline and after 3 months. Microbiological assessment of Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola was done by polymerase chain reaction (PCR) at baseline and 3 months after the therapy. RESULTS: There was a significant reduction in PI, GI, PD, CAL, and microbiologic parameters in test group, following SRP and PDT, when compared with SRP alone in control group. CONCLUSION: PDT in conjunction with SRP has shown additional improvement in periodontal parameters when compared to SRP alone and has a beneficial effect in chronic periodontitis patients. PMID- 27966505 TI - Effect of nightguard vital bleaching gel on the color stability of provisional restorative materials. AB - PURPOSE: To assess the hypothesis that there was no difference in effect of 10% and 15% tooth bleaching agents on color stability of materials used for provisional fixed dental prosthesis. METHODOLOGY: Fifteen samples from two materials used for provisional fixed dental prosthesis: methacrylate-based and composite-based materials and 15 preformed polycarbonate crowns soaked in bleaching gel or distilled water. Spectrophotometer recorded color of specimens at baseline, after 3, 7, and 14 days. Data were statistically analyzed using two factor ANOVA test to compare the color stability of tested materials. RESULTS: Methyl-based provisional material exhibited statistically higher color change when exposed to 10% and 15% bleaching gel (delta EFNx01: 9.0 and 11.1, respectively) as compared to distilled water (delta EFNx01: 2.9). Delta EFNx01 of composite-based material specimens exposed to distilled water was statistically higher (6.3) than specimens exposed to 10% and 15% bleaching gel (1.5 and 1.1, respectively). Polycarbonate crowns showed a statistically lower color change when exposed to 15% (0.9) than to 10% bleaching gel (5.1) or distilled water (5.5). CONCLUSIONS: Composite-based provisional material showed highest color stability when exposed to vital tooth bleaching gel, whereas methacrylate-based material was the least color stable. Polycarbonate crowns were more color stable when exposed to 15% bleaching gel as opposed to 10% bleaching gel. PMID- 27966506 TI - Versatility of nasolabial flaps for the management of severe trismus in oral submucous fibrosis. AB - BACKGROUND: Oral submucous fibrosis (OSMF) is a chronic insidious disease affecting any part of the oral cavity and sometimes the pharynx. It is a collagen related disorder predominantly associated with tobacco/areca nut chewing habit and characterized by progressive hyalinization of the submucosa. Prevalence of OSMF is 2.01%, and malignant transformation rate of 2.3%-7.6% has been reported in the literature. Measures such as forcing the mouth open and cutting the fibrotic bands have resulted in more fibrosis and disability. AIM: Various surgical treatment modalities have been advocated in the surgical management of OSMF with variable results. This retrospective study evaluates the efficacy of nasolabial flap in the surgical treatment of OSMF. MATERIALS AND METHODS: Retrospective analysis of 42 patients who underwent surgical management of OSMF with mouth opening <20 mm by nasolabial flap at authors center from 2000 to 2015. Only the cases diagnosed as advanced OSMF based on long-standing positive history of habits (chewing tobacco, betel nut, etc.), clinical and histopathological examination. OSMF due to other causes such as nutritional deficiency, immunological diseases, and systemic illness with medically compromised patients were excluded from the study. Inferiorly based nasolabial flaps were raised in the supramuscular plane and transferred intraorally through a transbuccal tunnel. RESULTS: The study groups consist of 42 cases of clinical and histopathologically proven cases of OSMF treated by nasolabial flap. Out of 42 cases, 39 (92.85%) were males and 3 (7.15%) were females which showed a male predominance and the ratio was 13:1. The mean (standard deviation [SD]) preoperative mouth opening was 14.60 mm (3.06). After release of fibrotic bands, a mean forced intraoperative mouth opening of 36.27 (2.11) mm was achieved. The mean (SD) postoperative mouth opening was 33.05 mm (2.40) at the end of 2-year follow-up. The mean (SD) increase in mouth opening after surgical management at the end of 2-year follow up is 18.46 mm (1.89). Sixteen out of 42 patients' histopathological report turned out to be dysplastic. The mean (SD) follow-up was 2.79 years (1.08). There was no incidence of infection in the transferred flap and the recipient site in all cases except one case with malignant transformation. All flaps healed without evidence of infection, dehiscence, or necrosis. Results were assessed by comparing the pre- and post-operative maximum mouth opening. CONCLUSION: The nasolabial flap is a versatile flap, which can be successfully used in the reconstruction of defects created after the release of fibrotic bands in OSMF. The versatility of the nasolabial flap has been attributed to its reliable vascularity derived from numerous vessels in the vicinity. Major advantage is the ease of elevation, proximity to the defect, suitable size for coverage of defect, minimal swallowing and speech difficulties, and a relatively cosmetic result as scar is in natural crease. All the cases treated for OSMF using bilateral nasolabial flaps showed adequate mouth opening at 2-year follow-up postoperatively, recommending its use. PMID- 27966507 TI - The effect of pre-etching with 37% orthophosphoric acid on the shear bond strength of orthodontic brackets bonded using self-etching primer-adhesive system. AB - OBJECTIVES: The purpose of this study was to compare the effect of pre-etching with 37% orthophosphoric acid on the shear bond strength (SBS) of orthodontic brackets bonded using self-etching primer (SEP). MATERIALS AND METHODS: Two hundred freshly extracted human premolars were divided randomly into two groups based on pre-etching with 37% orthophosphoric acid: Group 1 (control, n = 50) without pre-etching and Group 2 (experimental, n = 150) with pre-etching. Group 2 was further divided into three sub groups 2a, 2b, and 2c with 50 teeth each and was first pre-etched with 37% orthophosphoric acid for 10, 30, and 60 s, respectively. Brackets were bonded on the teeth in both the groups using SEP and light cure adhesive. The SBS were determined using universal testing machine. The comparison of SBS was done using one-way analysis of variance and Tukey's honest significant difference test. RESULTS: The SBS of experimental Group 2 was significantly higher than the control Group 1 (p < 0.0001). Further, the SBS of Group 2a was highest, followed by Group 2b and 2c (p < 0.0001). CONCLUSION: It was found that pre-etching for 10 s prior to application of SEP-adhesive system increases the SBS of orthodontic brackets. PMID- 27966508 TI - Comparative evaluation of platelet-rich fibrin and autogenous bone graft for the treatment of infrabony defects in chronic periodontitis: Clinical, radiological, and surgical reentry. AB - CONTEXT: Both intraoral autogenous bone grafting (ABG) and platelet-rich fibrin (PRF) offer a useful treatment modality for periodontal regeneration of intrabony defects (IBDs). However, predictable regeneration in patients with severe attachment loss is a challenge to the practitioners. AIM: The aim of this study was to compare the clinical efficacy of PRF with ABG for the treatment of IBDs in chronic periodontitis. SETTINGS AND DESIGN: This is a randomized controlled trial. MATERIALS AND METHODS: Twenty chronic periodontitis patients with IBDs were randomly treated by PRF or ABG. Probing pocket depth (PPD), relative attachment level (RAL), surgical reentry bone fill, and radiographic bone fill (RBF) were recorded at baseline, 3, 6, and 9 months postsurgery, respectively. STATISTICAL ANALYSIS: Student's t-test was used for continuous variables. All means were expressed as mean +/- standard deviation and proportions were expressed in percentage. The level of significance was set at P < 0.05. RESULTS: Both PRF and ABG sites produced a significant improvement from baseline to 9 months for all the parameters. However, there was no significant difference between the two treatment modalities in the reduction of PPD and RAL gain at 9 months. In addition, ABG showed significantly greater RBF (30.34%) as compared to PRF (20.22%). Similar findings were supported by surgical reentry, where a surgical reentry of 65.31% at ABG sites and 43.64% at PRF sites was seen. CONCLUSION: Both ABG and PRF can be used predictably to reconstruct lost periodontal structures as indicated by PPD reduction and RAL gain. However, in terms of osseous defect fill, ABG yields more definitive outcome than PRF. PMID- 27966509 TI - The effect of oil pulling with rice bran oil, sesame oil, and chlorhexidine mouth rinsing on halitosis among pregnant women: A comparative interventional study. AB - CONTEXT: Rice bran oil, owing to its potential antioxidant benefits, could be an effective and novel alternative to sesame oil for oil pulling. As it is safe and a growingly popular edible oil, it may be acceptable during pregnancy, especially in the Indian context where women may be hesitant to use chemical plaque control methods for preventing halitosis. AIMS: The present study was conducted to compare the effects of oil pulling with rice bran oil, oil pulling with sesame oil, and oil pulling with chlorhexidine mouth rinsing on reducing halitosis among pregnant women. SETTINGS AND DESIGN: Thirty pregnant women who attended the Gynecology Outpatient Department (OPD) of Muslim Medical Hospital, Haran Khana Road, Pani Gate, Vadodara, Gujarat, India, were recruited in the present randomized double-blind interventional study. SUBJECTS AND METHODS: Eligible pregnant women individuals who gave consent for the study were randomly allocated to receive the interventions under investigation. Halitosis was measured at baseline and after 14 days of intervention using TANITA breath checker HC-212M BL. STATISTICAL ANALYSIS USED: Data entry was done in Microsoft Excel 2007, and statistical analysis was performed using SPSS version 17. Wilcoxon signed rank tests were used to interpret the differences in baseline and postintervention halitosis levels. One-way ANOVA was done to compare the mean reduction in halitosis scores of the three intervention groups. RESULTS: There was a statistically significant reduction in the grades of halitosis at baseline and 14 days after intervention for all the three groups. There was no statistically significant difference between chlorhexidine mouth rinsing, oil pulling with sesame oil, and oil pulling with rice bran oil in halitosis reduction. CONCLUSIONS: Rice bran oil when used in oil pulling was effective in reducing halitosis. It performed comparably and marginally superior to other agents tested in the study when change in halitosis postintervention was considered. PMID- 27966510 TI - Evaluation of frictional resistance and surface characteristics after immersion of orthodontic brackets and wire in different chemical solutions: A comparative in vitrostudy. AB - AIM: To evaluate the changes of static and kinetic frictional forces between the brackets and wires following exposure to a soft drink, acidic food ingredient, and acidulated fluoride prophylactic agents. MATERIALS AND METHODS: Two types of Roth prescription mandibular incisor brackets were used: 3M Unitek Victory stainless steel (SS) brackets (n = 40) and Transcend 6000 polycrystalline alumina (PCA) brackets (n = 40) as well as eighty 0.019 * 0.025" dimension ortho technology SS wires of 50 mm length each. Subsequently, brackets tied with SS wires divided into eight subgroups (n = 10) and were immersed in vinegar (pH = 3.5 +/- 0.5), Pepsi (r) (pH = 2.46), Colgate Phos-Flur mouth rinse (pH = 5.1), and artificial saliva (control group pH = 7) for 24 h. Changes in surface morphology under scanning electron microscope *1000, surface roughness (Ra) with surface profilometer (single bracket and single wire from each subgroup), and frictional resistance using universal testing machine were evaluated. RESULTS: Highest mean (standard deviation) static frictional force of 2.65 (0.25) N was recorded in Pepsi (r) followed by 2.57 (0.25) N, 2.40 (0.22) N, and 2.36 (0.17) N for Vinegar, Colgate Phos-Flur mouth rinse, and artificial saliva groups, respectively. In a similar order, lesser mean kinetic frictional forces obtained. PCA brackets revealed more surface deterioration and higher frictional force values than SS brackets. A significant positive correlation was observed between frictional forces and bracket slot roughness (r = 0.861 and 0.802, respectively, for static and kinetic frictional forces, p < 0.001 for both) and wire roughness (r = 0.243 and 0.242, respectively, for static and kinetic frictional forces, p < 0.05 for both). CONCLUSIONS: Findings may have long-term implications when acidic food substances are used during fixed orthodontic treatment. Further, in vivo studies are required to analyze the clinical effect of acidic mediums in the oral environment during orthodontic treatment. PMID- 27966511 TI - Comparative evaluation of application of different fluoride varnishes on artificial early enamel lesion: An in vitro study. AB - INTRODUCTION: In an attempt to manage noncavitated carious lesions noninvasively through remineralization, a range of novel fluoride varnishes with additional remineralizing agents have been made available for clinical application. AIM AND OBJECTIVES: The aim of this study was to compare and evaluate the remineralization potential of three commercially available varnishes on artificial enamel lesions. MATERIALS AND METHODS: This in vitro study involves eighty intact enamel specimens prepared from premolars extracted for orthodontic purposes. After specimen preparation, the eighty samples were divided randomly into two groups (n = 40) for measurement of baseline surface Vickers microhardness and baseline calcium/phosphorus ratio (% weight) through EDAX testing. Thereafter, the specimens were subjected to demineralization for 96 h to induce initial enamel lesions and the measurements were repeated. Following demineralization, each of the two groups was divided randomly into four subgroups (n = 10) from which one was used as the control group and the others three were allotted to each of the three test varnishes. After varnish application, all the specimens were subjected to a pH cycling regimen that included alternative demineralization (3 h) and remineralization (21 h) daily, for 5 consecutive days. The Vickers microhardness and EDAX measurements were then repeated. RESULTS: One way ANOVA and post hoc Tukey's tests were conducted for multiple group comparison. All the three commercially available varnishes were capable of remineralizing initial enamel lesions that were induced artificially. No difference was noted in the remineralizing efficacy of the varnishes despite their different compositions. MI VarnishTM (casein phosphopeptide-amorphous calcium phosphate fluoride varnish) showed slightly better recovery in surface microhardness as compared to the other two varnishes. CONCLUSION: All the varnishes used in this in vitro study are capable of reversing early enamel lesions. PMID- 27966512 TI - Evaluating the efficacy of denture cleansing materials in removal of tea and turmeric stains: An in vitro study. AB - CONTEXT: Extrinsic staining of acrylic resin dentures could be a major esthetic problem for denture wearers. Tea, coffee, cola, turmeric, and tobacco often cause extrinsic staining of dentures. AIM: To evaluate the efficacy of various denture cleansing materials in the removal of tea and turmeric stains and to compare the efficacy of those denture cleansers with each other in the removal of tea and turmeric stains. MATERIALS AND METHODS: Heat-cured acrylic resin specimens were stained using tea and turmeric solutions. The spectrophotometer was used to determine the reflectance values of the samples and to evaluate the efficacy of various denture cleansing materials in removal of tea and turmeric stains. Three denture cleansers, namely, sodium hypochlorite, Safe plus, and Clinsodent were used in the study. Water was used as a control. STATISTICAL ANALYSIS USED: ANOVA test and post hoc Tukey's test were used to determine the statistical difference between the groups. RESULT: A statistically significant difference was found (p <= 0.05) between the different denture cleansing materials used. Products containing sodium perborate along with trisodium phosphate had the highest stain removing capability. CONCLUSION: It was found that all the denture cleansing materials used in the study were effective in removing tea and turmeric stains. Products containing sodium perborate along with trisodium phosphate had a comparatively greater stain removal capability than products containing sodium perborate along with sodium bicarbonate followed by products containing sodium hypochlorite followed by water (control). PMID- 27966513 TI - Comparative evaluation of sutures coated with triclosan and chlorhexidine for oral biofilm inhibition potential and antimicrobial activity against periodontal pathogens: An in vitro study. AB - BACKGROUND: Surgical site plaque accumulation is one of the challenging problems leading to unfavorable healing. The antibacterial sutures can be used to reduce or inhibit plaque formation. Presently there is no study comparing efficacy of sutures coated with triclosan and chlorhexidine in terms of oral biofilm inhibition and antimicrobial property against periodontal pathogens. AIM: The aim of present study was to evaluate the antibacterial efficacy and oral biofilm inhibition around chlorhexidine and triclosan coated polyglactin sutures in comparison to uncoated sutures. MATERIALS AND METHOD: Equal segments of chlorhexidine and triclosan coated polyglactin sutures (3-0) were incubated at 370 degrees C in saliva collected from 10 chronic periodontitis patients for 7 days. Plain uncoated suture served as control. Biofilm formation was analyzed with Confocal Laser-Scanning Microscopy (CLSM) and Scanning Electron Microscopy (SEM). Quantitative assessment was done using Colony Forming Units (CFU/mL).The antibacterial efficacy of the sutures was tested against specific periodontal pathogens (S.mutans, F.nucleatum, A.actinomycetomcomitans, P.intermedia, P.gingivalis) using agar diffusion method. CLSM and SEM were not subjected to statistical analysis. ANOVA test was used for colony forming units and agar diffusion test. (P < 0.05) Results: CLSM and SEM showed substantial biofilm inhibition around chlorhexidine-coated sutures followed by triclosan-coated when compared to plain uncoated suture. The antibacterial coated sutures showed statistically significant difference in CFUs/ml and zone of inhibition compared to plain uncoated sutures. Among coated sutures, chlorhexidine-coated sutures showed better results. CONCLUSION: The antibacterial coated sutures have a promising potential in preventing the colonization of periodontal pathogens around it thereby inhibiting biofilm formation. PMID- 27966514 TI - Prevalence of impacted permanent mandibular second molars in South Indian population: A cross-sectional study. AB - AIMS: The aim of this study is to retrospectively determine the prevalence of impacted second molars and associated dental and radiographic findings in South Indian population. SETTINGS AND DESIGN: Cross-sectional design. MATERIALS AND METHODS: Dental records of 4976 patients depending on the selection criteria from various dental clinics in South India were retrospectively analyzed in this study. All selected radiographs and records were examined by the two authors. The angle of impacted second molars was also recorded on panoramic radiographs. Data were tabulated and analyzed. RESULTS: The prevalence of impacted second mandibular molars was found to be 0.16%. In seven cases, the impaction was unilateral with three on the left and four on the right, and in one case, it was bilateral. The prevalence was found to be more in females than males. The angle of impaction was found to range from 19 degrees to 80 degrees . CONCLUSIONS: Although the prevalence of impacted second molars is low, it is crucial to diagnose early for optimal treatment. PMID- 27966515 TI - Prevalence of idiopathic osteosclerosis in an Iranian population. AB - AIM: Idiopathic osteosclerosis (IO) is a localized radiopacity with no associated pain, bony expansion, symptom, or known etiology. The aim of this study was to assess its frequency and distribution according to its location and patient's age and gender and internal structure using panoramic radiography. SUBJECTS AND METHODS: In this retrospective study, 3975 panoramic radiographs (PRs) were used. Radiopaque regions which had no certain relationship to any known sources of hard tissue production were accepted as IO and characteristics such as shape, location, internal structure, and personal information were investigated. STATISTICAL ANALYSIS USED: The obtained data were evaluated using SPSS software and Chi-square test. RESULTS: IO was found in 113 (2.84%) out of 3975 patients. The most frequent site was the posterior region of mandible. There was no significant difference in the incidence of IO between genders (P = 0.766). CONCLUSION: IO is an asymptomatic radiopaque mass commonly seen in PR, which was found mostly in the first molar region of mandible. Furthermore, its maximum frequency was in the second decade. PMID- 27966516 TI - Prevalence of dental caries and treatment needs among school going children of Chandigarh. AB - INTRODUCTION: Dental caries is the most common chronic disease of childhood that interferes with normal nutrition intake, speech, and daily routine activities. Dental caries is a lifetime disease, and the highest priority risk group is school children. AIM: To assess the prevalence of dental caries and treatment needs among school going children of Chandigarh. MATERIALS AND METHODS: A cross sectional study was done among school going children of Chandigarh in the age group of 3-17 years. The subjects were selected from four randomly selected schools. All the children from the selected schools were examined. A total of 4493 subjects formed the sample size. Dentition status was assessed using dft index by Gruebbel for primary dentition and DMFT index by Klein, Palmer, Knutson for permanent dentition, respectively. Chi-square test was used to find an association between the study variables. Independent t-test and one-way ANOVA were used to compare the mean difference. RESULTS: Among the 4493 study subjects, caries prevalence was found to be 47.3%. Mean dft and DMFT score of the population was 1.06 +/- 1.995 and 0.41 +/- 1.022, respectively. When analyzing the treatment needs among various age groups 42.6% of the study subjects required oral prophylaxis and 45% required restorative procedures. CONCLUSION: Based on the findings, it can be concluded that high prevalence of caries was found in primary dentition than permanent dentition and most of the decayed teeth were untreated. This study emphasize the need for treating dental caries at its earliest possible stage and parents should be made aware of caries preventive measures for their children. PMID- 27966517 TI - Characterization of an eye prosthesis using monopoly syrup. AB - The eye is a vital organ and an important component of facial expression. Loss of an eye has a crippling effect on the psychology of the patient. Maxillofacial prostheses restore and replace stomatognathic and associated facial structures with artificial substitutes. The objectives of eye prosthesis is to improve the patient esthetics, restore and maintain the health of the remaining associated structures, consequently provide physical and mental well-being. The primary purpose of an ocular prosthesis is to maintain the volume of eye socket and create the illusion of a healthy eye and surrounding tissue. A custom ocular prosthesis is a good option when reconstruction is done by plastic surgery, and osseointegrated implants are either not possible or not desired. A case of a custom-made ocular acrylic prosthesis is presented with acceptable fit, good retention, and esthetics. PMID- 27966518 TI - Impact of highly active antiretroviral therapy in the development and remission of oral plasmablastic lymphoma. AB - Plasmablastic lymphoma (PBL) represents a rare type of non-Hodgkin lymphoma associated with human immunodeficiency virus (HIV) infection. The impact of highly active antiretroviral therapy (HAART) in this tumor is poorly known due to its small incidence. This study reports a case of a 33-year-old HIV-positive woman who was referred to the Stomatology Department complaining about a painful gingival growth and cervical nodule both with 20 days of evolution. The lesions appeared 7 months after the patient stopped HAART. The final diagnosis was PBL. After resuming HAART for 45 days, the gingival lesion presented complete remission. The patient continued with HAART alongside chemotherapy. At 24 months follow-up, the patient was stable. The dental surgeon plays an essential role in orientation and retention in care of HIV patients once the adherence of HAART seems to play an important role in PBL development and response to treatment. PMID- 27966519 TI - Combretastatin A4 Regulates Proliferation, Migration, Invasion, and Apoptosis of Thyroid Cancer Cells via PI3K/Akt Signaling Pathway. AB - BACKGROUND Combretastatin A4 (CA4) is a potential therapeutic candidate for a variety of human cancer treatments. However, the inhibitive effects of CA4 on thyroid cancer cells are still not well-clarified. This study aimed to investigate the potential effect of CA4 on thyroid cancer cells, as well as underlying mechanism. MATERIAL AND METHODS Human thyroid papillary carcinoma cell line TPC1 was pre-treated with 5 concentrations of CA4 (0, 1, 2, 5, or 10 MUM) for 2 h. Cell proliferation was determined by 3-(4, 5-dimethyl-2- thiazolyl)-2, 5 diphenyl -2-H-tetrazolium bromide (MTT) assay. Cell migration and invasion were detected by a modified Boyden chamber assay. Moreover, cell apoptosis was detected by terminal deoxynucleotidyl (TUNEL) staining assay and flow cytometry method. Western blot analysis was performed to determine the expression changes of epithelial-mesenchymal transition (EMT)-related proteins and phosphatidylinositol-3-kinase/serine/threonine kinase (PI3K/Akt) signaling pathway proteins. RESULTS CA4 significantly inhibited the cell proliferation, migration, and invasion, and significantly promoted cell apoptosis in a dose dependent manner compared with the control group. The EMT-related protein levels of N-Cadherin, Vimentin, Snail1, Slug, Twist1, and ZEB1 were significantly decreased by CA4, while E-cadherin had no significant difference compared with the control group. Moreover, PI3K/Akt signaling pathway protein levels of p-PI3K and p-Akt were significantly decreased, whereas PI3K and Akt had no significant differences compared with the control group. CONCLUSIONS CA4 can inhibit proliferation, migration, and invasion and promote apoptosis of TPC1 cells. These effects might be through the PI3K/Akt signaling pathway. CA4 may be a potential therapeutic target for the treatment of thyroid cancer. PMID- 27966521 TI - A reconstruction algorithm for compressive quantum tomography using various measurement sets. AB - Compressed sensing (CS) has been verified that it offers a significant performance improvement for large quantum systems comparing with the conventional quantum tomography approaches, because it reduces the number of measurements from O(d2) to O(rd log(d)) in particular for quantum states that are fairly pure. Yet few algorithms have been proposed for quantum state tomography using CS specifically, let alone basis analysis for various measurement sets in quantum CS. To fill this gap, in this paper an efficient and robust state reconstruction algorithm based on compressive sensing is developed. By leveraging the fixed point equation approach to avoid the matrix inverse operation, we propose a fixed point alternating direction method algorithm for compressive quantum state estimation that can handle both normal errors and large outliers in the optimization process. In addition, properties of five practical measurement bases (including the Pauli basis) are analyzed in terms of their coherences and reconstruction performances, which provides theoretical instructions for the selection of measurement settings in the quantum state estimation. The numerical experiments show that the proposed algorithm has much less calculating time, higher reconstruction accuracy and is more robust to outlier noises than many existing state reconstruction algorithms. PMID- 27966522 TI - Corrigendum: Molecular characterization of a family 5 glycoside hydrolase suggests an induced-fit enzymatic mechanism. PMID- 27966520 TI - Impact of cuticle photoluminescence on the color morphism of a male damselfly Ischnura senegalensis (Rambur, 1842). AB - In this study the damselfly Ischnura senegalensis (Rambur, 1842) was first found to produce strong photoluminescence (PL) emissions from various colored-body portions, such as the eighth abdominal segment of the tail. The colors of the colored-body portions can be enhanced or modified by the PL emissions for assistance in reducing intrasexual and male harassment, and improving mature mating and conspecific identity. Therefore, the PL emissions that contribute to the color modification and coloration are involved in the cuticle evolution of the damselflies. The micro-PL confocal images verify that the PL emissions can strongly influence the surface colors of the cuticle, and demonstrate why the damselfly Ischnura senegalensis is called a bluetail. PMID- 27966525 TI - Corrigendum: Structural Stability and Deformation of Solvated Sm@C2(42)-C90 under High Pressure. PMID- 27966524 TI - Directional interlayer spin-valley transfer in two-dimensional heterostructures. AB - Van der Waals heterostructures formed by two different monolayer semiconductors have emerged as a promising platform for new optoelectronic and spin/valleytronic applications. In addition to its atomically thin nature, a two-dimensional semiconductor heterostructure is distinct from its three-dimensional counterparts due to the unique coupled spin-valley physics of its constituent monolayers. Here, we report the direct observation that an optically generated spin-valley polarization in one monolayer can be transferred between layers of a two dimensional MoSe2-WSe2 heterostructure. Using non-degenerate optical circular dichroism spectroscopy, we show that charge transfer between two monolayers conserves spin-valley polarization and is only weakly dependent on the twist angle between layers. Our work points to a new spin-valley pumping scheme in nanoscale devices, provides a fundamental understanding of spin-valley transfer across the two-dimensional interface, and shows the potential use of two dimensional semiconductors as a spin-valley generator in two-dimensional spin/valleytronic devices for storing and processing information. PMID- 27966523 TI - Functional screening for anti-CMV biologics identifies a broadly neutralizing epitope of an essential envelope protein. AB - The prototypic beta-herpesvirus human cytomegalovirus (CMV) establishes life-long persistence within its human host. The CMV envelope consists of various protein complexes that enable wide viral tropism. More specifically, the glycoprotein complex gH/gL/gO (gH-trimer) is required for infection of all cell types, while the gH/gL/UL128/130/131a (gH-pentamer) complex imparts specificity in infecting epithelial, endothelial and myeloid cells. Here we utilize state-of-the-art robotics and a high-throughput neutralization assay to screen and identify monoclonal antibodies (mAbs) targeting the gH glycoproteins that display broad spectrum properties to inhibit virus infection and dissemination. Subsequent biochemical characterization reveals that the mAbs bind to gH-trimer and gH pentamer complexes and identify the antibodies' epitope as an 'antigenic hot spot' critical for virus entry. The mAbs inhibit CMV infection at a post attachment step by interacting with a highly conserved central alpha helix-rich domain. The platform described here provides the framework for development of effective CMV biologics and vaccine design strategies. PMID- 27966528 TI - Continuous-variable quantum computing on encrypted data. AB - The ability to perform computations on encrypted data is a powerful tool for protecting a client's privacy, especially in today's era of cloud and distributed computing. In terms of privacy, the best solutions that classical techniques can achieve are unfortunately not unconditionally secure in the sense that they are dependent on a hacker's computational power. Here we theoretically investigate, and experimentally demonstrate with Gaussian displacement and squeezing operations, a quantum solution that achieves the security of a user's privacy using the practical technology of continuous variables. We demonstrate losses of up to 10 km both ways between the client and the server and show that security can still be achieved. Our approach offers a number of practical benefits (from a quantum perspective) that could one day allow the potential widespread adoption of this quantum technology in future cloud-based computing networks. PMID- 27966526 TI - Osteoblasts secrete Cxcl9 to regulate angiogenesis in bone. AB - Communication between osteoblasts and endothelial cells (ECs) is essential for bone turnover, but the molecular mechanisms of such communication are not well defined. Here we identify Cxcl9 as an angiostatic factor secreted by osteoblasts in the bone marrow microenvironment. We show that Cxcl9 produced by osteoblasts interacts with vascular endothelial growth factor and prevents its binding to ECs and osteoblasts, thus abrogating angiogenesis and osteogenesis both in mouse bone and in vitro. The mechanistic target of rapamycin complex 1 activates Cxcl9 expression by transcriptional upregulation of STAT1 and increases binding of STAT1 to the Cxcl9 promoter in osteoblasts. These findings reveal the essential role of osteoblast-produced Cxcl9 in angiogenesis and osteogenesis in bone, and Cxcl9 can be targeted to elevate bone angiogenesis and prevent bone loss-related diseases. PMID- 27966527 TI - Five colour variants of bright luminescent protein for real-time multicolour bioimaging. AB - Luminescence imaging has gained attention as a promising bio-imaging modality in situations where fluorescence imaging cannot be applied. However, wider application to multicolour and dynamic imaging is limited by the lack of bright luminescent proteins with emissions across the visible spectrum. Here we report five new spectral variants of the bright luminescent protein, enhanced Nano lantern (eNL), made by concatenation of the brightest luciferase, NanoLuc, with various colour hues of fluorescent proteins. eNLs allow five-colour live-cell imaging, as well as detection of single protein complexes and even single molecules. We also develop an eNL-based Ca2+ indicator with a 500% signal change, which can image spontaneous Ca2+ dynamics in cardiomyocyte and neural cell models. These eNL probes facilitate not only multicolour imaging in living cells but also sensitive imaging of a wide repertoire of proteins, even at very low expression levels. PMID- 27966529 TI - Bandgap renormalization and work function tuning in MoSe2/hBN/Ru(0001) heterostructures. AB - The van der Waals interaction in vertical heterostructures made of two dimensional (2D) materials relaxes the requirement of lattice matching, therefore enabling great design flexibility to tailor novel 2D electronic systems. Here we report the successful growth of MoSe2 on single-layer hexagonal boron nitride (hBN) on the Ru(0001) substrate using molecular beam epitaxy. Using scanning tunnelling microscopy and spectroscopy, we found that the quasi-particle bandgap of MoSe2 on hBN/Ru is about 0.25 eV smaller than those on graphene or graphite substrates. We attribute this result to the strong interaction between hBN/Ru, which causes residual metallic screening from the substrate. In addition, the electronic structure and the work function of MoSe2 are modulated electrostatically with an amplitude of ~0.13 eV. Most interestingly, this electrostatic modulation is spatially in phase with the Moire pattern of hBN on Ru(0001) whose surface also exhibits a work function modulation of the same amplitude. PMID- 27966530 TI - Dense GeV electron-positron pairs generated by lasers in near-critical-density plasmas. AB - Pair production can be triggered by high-intensity lasers via the Breit-Wheeler process. However, the straightforward laser-laser colliding for copious numbers of pair creation requires light intensities several orders of magnitude higher than possible with the ongoing laser facilities. Despite the numerous proposed approaches, creating high-energy-density pair plasmas in laboratories is still challenging. Here we present an all-optical scheme for overdense pair production by two counter-propagating lasers irradiating near-critical-density plasmas at only ~1022 W cm-2. In this scheme, bright gamma-rays are generated by radiation trapped electrons oscillating in the laser fields. The dense gamma-photons then collide with the focused counter-propagating lasers to initiate the multi-photon Breit-Wheeler process. Particle-in-cell simulations indicate that one may generate a high-yield (1.05 * 1011) overdense (4 * 1022 cm-3) GeV positron beam using 10 PW scale lasers. Such a bright pair source has many practical applications and could be basis for future compact high-luminosity electron positron colliders. PMID- 27966531 TI - Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. AB - Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen-Lysyl oxidase-like 2 (Loxl2)-is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF beta2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-beta2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF. PMID- 27966532 TI - Integrative modelling of tumour DNA methylation quantifies the contribution of metabolism. AB - Altered DNA methylation is common in cancer and often considered an early event in tumorigenesis. However, the sources of heterogeneity of DNA methylation among tumours remain poorly defined. Here we capitalize on the availability of multi platform data on thousands of human tumours to build integrative models of DNA methylation. We quantify the contribution of clinical and molecular factors in explaining intertumoral variability in DNA methylation. We show that the levels of a set of metabolic genes involved in the methionine cycle is predictive of several features of DNA methylation in tumours, including the methylation of cancer genes. Finally, we demonstrate that patients whose DNA methylation can be predicted from the methionine cycle exhibited improved survival over cases where this regulation is disrupted. This study represents a comprehensive analysis of the determinants of methylation and demonstrates the surprisingly large interaction between metabolism and DNA methylation variation. Together, our results quantify links between tumour metabolism and epigenetics and outline clinical implications. PMID- 27966533 TI - TOC1-PIF4 interaction mediates the circadian gating of thermoresponsive growth in Arabidopsis. AB - Arabidopsis adapts to elevated temperature by promoting stem elongation and hyponastic growth through a temperature-responsive transcription factor PIF4. Here we show that the evening-expressed clock component TOC1 interacts with and inactivates PIF4, thereby suppressing thermoresponsive growth in the evening. We find that the expression of PIF4 target genes show circadian rhythms of thermosensitivity, with minimum responsiveness in the evening when TOC1 level is high. Loss of function of TOC1 and its close homologue PRR5 restores thermosensitivity in the evening, whereas TOC1 overexpression causes thermo insensitivity, demonstrating that TOC1 mediates the evening-specific inhibition of thermoresponses. We further show that PIF4 is required for thermoadaptation mediated by moderately elevated temperature. Our results demonstrate that the interaction between TOC1 and PIF4 mediates the circadian gating of thermoresponsive growth, which may serve to increase fitness by matching thermoresponsiveness with the day-night cycles of fluctuating temperature and light conditions. PMID- 27966534 TI - Evaluating the convergence between eddy-covariance and biometric methods for assessing carbon budgets of forests. AB - The eddy-covariance (EC) micro-meteorological technique and the ecology-based biometric methods (BM) are the primary methodologies to quantify CO2 exchange between terrestrial ecosystems and the atmosphere (net ecosystem production, NEP) and its two components, ecosystem respiration and gross primary production. Here we show that EC and BM provide different estimates of NEP, but comparable ecosystem respiration and gross primary production for forest ecosystems globally. Discrepancies between methods are not related to environmental or stand variables, but are consistently more pronounced for boreal forests where carbon fluxes are smaller. BM estimates are prone to underestimation of net primary production and overestimation of leaf respiration. EC biases are not apparent across sites, suggesting the effectiveness of standard post-processing procedures. Our results increase confidence in EC, show in which conditions EC and BM estimates can be integrated, and which methodological aspects can improve the convergence between EC and BM. PMID- 27966535 TI - Estimating parent-specific QTL effects through cumulating linked identity-by state SNP effects in multiparental populations. AB - The emergence of multiparental mapping populations enabled plant geneticists to gain deeper insights into the genetic architecture of major agronomic traits and to map quantitative trait loci (QTLs) controlling the expression of these traits. Although the investigated mapping populations are similar, one open question is whether genotype data should be modelled as identical by state (IBS) or identical by descent (IBD). Whereas IBS simply makes use of raw genotype scores to distinguish alleles, IBD data are derived from parental offspring information. We report on comparing IBS and IBD by applying two multiple regression models on four traits studied in the barley nested association mapping (NAM) population HEB 25. We observed that modelling parent-specific IBD genotypes produced a lower number of significant QTLs with increased prediction abilities compared with modelling IBS genotypes. However, at lower trait heritabilities the IBS model produced higher prediction abilities. We developed a method to estimate multiallelic QTL effects in multiparental populations from simple biallelic IBS data. This method is based on cumulating IBS-derived single-nucleotide polymorphism (SNP) effect estimates in a defined genetic region surrounding a QTL. Comparing the resulting parent-specific QTL effects with those obtained from IBD approaches revealed high accordance that could be confirmed through simulations. The method turned out to be also applicable to a barley multiparent advanced generation inter-cross (MAGIC) population. The 'cumulation method' represents a universal approach to differentiate parent-specific QTL effects in multiparental populations, even if no IBD information is available. In future, the method could further benefit from the availability of much denser SNP maps. PMID- 27966536 TI - Adaptive microwave impedance memory effect in a ferromagnetic insulator. AB - Adaptive electronics, which are often referred to as memristive systems as they often rely on a memristor (memory resistor), are an emerging technology inspired by adaptive biological systems. Dissipative systems may provide a proper platform to implement an adaptive system due to its inherent adaptive property that parameters describing the system are optimized to maximize the entropy production for a given environment. Here, we report that a non-volatile and reversible adaptive microwave impedance memory device can be realized through the adaptive property of the dissipative structure of the driven ferromagnetic system. Like the memristive device, the microwave impedance of the device is modulated as a function of excitation microwave passing through the device. This kind of new device may not only helpful to implement adaptive information processing technologies, but also may be useful to investigate and understand the underlying mechanism of spontaneous formation of complex and ordered structures. PMID- 27966537 TI - High-throughput computational design of cathode coatings for Li-ion batteries. AB - Cathode degradation is a key factor that limits the lifetime of Li-ion batteries. To identify functional coatings that can suppress this degradation, we present a high-throughput density functional theory based framework which consists of reaction models that describe thermodynamic and electrochemical stabilities, and acid-scavenging capabilities of materials. Screening more than 130,000 oxygen bearing materials, we suggest physical and hydrofluoric-acid barrier coatings such as WO3, LiAl5O8 and ZrP2O7 and hydrofluoric-acid scavengers such as Sc2O3, Li2CaGeO4, LiBO2, Li3NbO4, Mg3(BO3)2 and Li2MgSiO4. Using a design strategy to find the thermodynamically optimal coatings for a cathode, we further present optimal hydrofluoric-acid scavengers such as Li2SrSiO4, Li2CaSiO4 and CaIn2O4 for the layered LiCoO2, and Li2GeO3, Li4NiTeO6 and Li2MnO3 for the spinel LiMn2O4 cathodes. These coating materials have the potential to prolong the cycle-life of Li-ion batteries and surpass the performance of common coatings based on conventional materials such as Al2O3, ZnO, MgO or ZrO2. PMID- 27966538 TI - NQO1 inhibits proteasome-mediated degradation of HIF-1alpha. AB - Overexpression of NQO1 is associated with poor prognosis in human cancers including breast, colon, cervix, lung and pancreas. Yet, the molecular mechanisms underlying the pro-tumorigenic capacities of NQO1 have not been fully elucidated. Here we show a previously undescribed function for NQO1 in stabilizing HIF 1alpha, a master transcription factor of oxygen homeostasis that has been implicated in the survival, proliferation and malignant progression of cancers. We demonstrate that NQO1 directly binds to the oxygen-dependent domain of HIF 1alpha and inhibits the proteasome-mediated degradation of HIF-1alpha by preventing PHDs from interacting with HIF-1alpha. NQO1 knockdown in human colorectal and breast cancer cell lines suppresses HIF-1 signalling and tumour growth. Consistent with this pro-tumorigenic function for NQO1, high NQO1 expression levels correlate with increased HIF-1alpha expression and poor colorectal cancer patient survival. These results collectively reveal a function of NQO1 in the oxygen-sensing mechanism that regulates HIF-1alpha stability in cancers. PMID- 27966540 TI - Selective and low temperature transition metal intercalation in layered tellurides. AB - Layered materials embrace rich intercalation reactions to accommodate high concentrations of foreign species within their structures, and find many applications spanning from energy storage, ion exchange to secondary batteries. Light alkali metals are generally most easily intercalated due to their light mass, high charge/volume ratio and in many cases strong reducing properties. An evolving area of materials chemistry, however, is to capture metals selectively, which is of technological and environmental significance but rather unexplored. Here we show that the layered telluride T2PTe2 (T=Ti, Zr) displays exclusive insertion of transition metals (for example, Cd, Zn) as opposed to alkali cations, with tetrahedral coordination preference to tellurium. Interestingly, the intercalation reactions proceed in solid state and at surprisingly low temperatures (for example, 80 degrees C for cadmium in Ti2PTe2). The current method of controlling selectivity provides opportunities in the search for new materials for various applications that used to be possible only in a liquid. PMID- 27966539 TI - Parallel Metabolomic Profiling of Cerebrospinal Fluid and Serum for Identifying Biomarkers of Injury Severity after Acute Human Spinal Cord Injury. AB - Suffering an acute spinal cord injury (SCI) can result in catastrophic physical and emotional loss. Efforts to translate novel therapies in acute clinical trials are impeded by the SCI community's singular dependence upon functional outcome measures. Therefore, a compelling rationale exists to establish neurochemical biomarkers for the objective classification of injury severity. In this study, CSF and serum samples were obtained at 3 time points (~24, 48, and 72 hours post injury) from 30 acute SCI patients (10 AIS A, 12 AIS B, and 8 AIS C). A differential chemical isotope labeling liquid chromatography mass spectrometry (CIL LC-MS) with a universal metabolome standard (UMS) was applied to the metabolomic profiling of these samples. This method provided enhanced detection of the amine- and phenol-containing submetabolome. Metabolic pathway analysis revealed dysregulations in arginine-proline metabolism following SCI. Six CSF metabolites were identified as potential biomarkers of baseline injury severity, and good classification performance (AUC > 0.869) was achieved by using combinations of these metabolites in pair-wise comparisons of AIS A, B and C patients. Using the UMS strategy, the current data set can be expanded to a larger cohort for biomarker validation, as well as discovering biomarkers for predicting neurologic outcome. PMID- 27966541 TI - Prevalence, birth incidence, and penetrance of von Hippel-Lindau disease (vHL) in Denmark. AB - Von Hippel-Lindau disease (vHL) is a rare hereditary tumour predisposition with multiorgan involvement that is not always easily recognized. The disease is reported to be almost fully penetrant at age 60 years. Previous estimates of vHL prevalence and incidence are all regional and vary widely. Most are >20 years old and prone to selection bias because of inclusion of only clinically affected vHL patients who were diagnosed before genetic testing was available. In an unselected cohort of all known Danish carriers of a disease-causing VHL variant, we assessed vHL penetrance on a national basis. We further used national health registers to identify individuals who fulfilled the clinical diagnostic vHL criteria based on their registered diagnostic codes, but had not been diagnosed with vHL. We also assessed the medical histories of first-degree relatives to identify familial cases. This study gives the first national estimates of vHL prevalence (1 in 46 900 individuals) and birth incidence (1 in 27 300 live births). vHL has been underdiagnosed in Denmark, and as many as 25% of the overall vHL cohort (diagnosed+undiagnosed patients) have a missed diagnosis in spite of fulfilling the international diagnostic criteria. We found an overall penetrance of 87% at age 60 years. When considering only vHL patients who have not attended surveillance, 20% will still be asymptomatic at age 60 years. This should be considered in the context of genetic counselling, especially when assessing the risk of vHL in asymptomatic adult first-degree relatives who are often not genetically tested. PMID- 27966542 TI - Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology. AB - SIK1 syndrome is a newly described developmental epilepsy disorder caused by heterozygous mutations in the salt-inducible kinase SIK1. To better understand the pathophysiology of SIK1 syndrome, we studied the effects of SIK1 pathogenic sequence variations in human neurons. Primary human fetal cortical neurons were transfected with a lentiviral vector to overexpress wild-type and mutant SIK1 protein. We evaluated the transcriptional activity of known downstream gene targets in neurons expressing mutant SIK1 compared with wild type. We then assayed neuronal morphology by measuring neurite length, number and branching. Truncating SIK1 sequence variations were associated with abnormal MEF2C transcriptional activity and decreased MEF2C protein levels. Epilepsy-causing SIK1 sequence variations were associated with significantly decreased expression of ARC (activity-regulated cytoskeletal-associated) and other synaptic activity response element genes. Assay of mRNA levels for other MEF2C target genes NR4A1 (Nur77) and NRG1, found significantly, decreased the expression of these genes as well. The missense p.(Pro287Thr) SIK1 sequence variation was associated with abnormal neuronal morphology, with significant decreases in mean neurite length, mean number of neurites and a significant increase in proximal branches compared with wild type. Epilepsy-causing SIK1 sequence variations resulted in abnormalities in the MEF2C-ARC pathway of neuronal development and synapse activity response. This work provides the first insights into the mechanisms of pathogenesis in SIK1 syndrome, and extends the ARX-MEF2C pathway in the pathogenesis of developmental epilepsy. PMID- 27966543 TI - Limb girdle myasthenia with digenic RAPSN and a novel disease gene AK9 mutations. AB - Though dysfunction of neuromuscular junction (NMJ) is associated with congenital myasthenic syndrome (CMS), the proteins involved in neuromuscular transmission have not been completely identified. In this study, we aimed to identify a novel CMS gene in a consanguineous family with limb-girdle type CMS. Homozygosity mapping of the novel CMS gene was performed using high-density single-nucleotide polymorphism microarrays. The variants in CMS gene were identified by whole-exome sequencing (WES) and Sanger sequencing. A 20 MB-region of homozygosity (ROH) was mapped on chromosome 6q15-21. This was the only ROH that present in all clinically affected siblings and absent in all clinically unaffected siblings. WES showed a novel variant of AK9 gene located in this ROH. This variant was a start-gain mutation and introduced a cryptic 5'-UTR signal in intron 5 of the AK9 gene. The normal splicing signal would be interfered by the cryptic translation signal leading to defective splicing. Another 25 MB-ROH was found on chromosome 11p13-q12 in all siblings. WES showed a homozygous RAPSN pathogenic variant in this ROH. Since RAPSN-associated limb-girdle type CMS was only manifested in AK9 homozygous variant carriers, the disease phenotype was of digenic inheritance, and was determined by the novel disease modifier AK9 which provides NTPs for N glycosylation. This is the first time that this specific genotype-phenotype correlation is reported. Importantly, the AK9-associated nucleotide deficiency may replete by dietary supplements. Since AK9 is a disease modifier, enhancing N glycosylation by increasing dietary nucleotides may be a new therapeutic option for CMS patients. PMID- 27966544 TI - A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome. AB - Nager syndrome is a rare preaxial acrofacial dysostosis that is caused by heterozygous loss-of-function variants in SF3B4. This gene encodes for a protein required for the assembly of spliceosomal complexes, being a master gene for splicing regulation. The main clinical features of Nager syndrome include facial mandibular and preaxial limb malformations, with normal cognitive functioning. Most Nager patients are sporadic, but few familial cases with a highly variable phenotype have been reported. In this work, we report a novel synonymous variant within exon 3 of the SF3B4 gene in a family with three members affected by Nager syndrome. No pathogenic variants have been detected in other 24 genes associated with syndromes characterized by mandibulo-facial anomalies. The pathogenicity of the mutation was demonstrated through a hybrid minigene assay, which confirmed an aberrant splicing with the creation of a cryptic splice site, and showed that this allele is hypomorphic. Our findings emphasize the importance to perform functional analyses to assess the possible consequences of synonymous variants and confirmed that hybrid minigenes represent an effective tool to evaluate the effects of variants on splicing, particularly when RNA is not available. PMID- 27966545 TI - The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs. AB - SeSAME/EAST syndrome is a multisystemic disorder in humans, characterised by seizures, sensorineural deafness, ataxia, developmental delay and electrolyte imbalance. It is exclusively caused by homozygous or compound heterozygous variations in the KCNJ10 gene. Here we describe a similar syndrome in two families belonging to the Malinois dog breed, based on clinical, neurological, electrodiagnostic and histopathological examination. Genetic analysis detected a novel pathogenic KCNJ10 c.986T>C (p.(Leu329Pro)) variant that is inherited in an autosomal recessive way. This variant has an allele frequency of 2.9% in the Belgian Malinois population, but is not found in closely related dog breeds or in dog breeds where similar symptoms have been already described. The canine phenotype is remarkably similar to humans, including ataxia and seizures. In addition, in half of the dogs clinical and electrophysiological signs of neuromyotonia were observed. Because there is currently no cure and treatment is nonspecific and unsatisfactory, this canine translational model could be used for further elucidating the genotype/phenotype correlation of this monogenic multisystem disorder and as an excellent intermediate step for drug safety testing and efficacy evaluations before initiating human studies. PMID- 27966546 TI - Noninvasive Electroencephalogram Based Control of a Robotic Arm for Reach and Grasp Tasks. AB - Brain-computer interface (BCI) technologies aim to provide a bridge between the human brain and external devices. Prior research using non-invasive BCI to control virtual objects, such as computer cursors and virtual helicopters, and real-world objects, such as wheelchairs and quadcopters, has demonstrated the promise of BCI technologies. However, controlling a robotic arm to complete reach and-grasp tasks efficiently using non-invasive BCI has yet to be shown. In this study, we found that a group of 13 human subjects could willingly modulate brain activity to control a robotic arm with high accuracy for performing tasks requiring multiple degrees of freedom by combination of two sequential low dimensional controls. Subjects were able to effectively control reaching of the robotic arm through modulation of their brain rhythms within the span of only a few training sessions and maintained the ability to control the robotic arm over multiple months. Our results demonstrate the viability of human operation of prosthetic limbs using non-invasive BCI technology. PMID- 27966547 TI - Evaluating structure selection in the hydrothermal growth of FeS2 pyrite and marcasite. AB - While the ab initio prediction of the properties of solids and their optimization towards new proposed materials is becoming established, little predictive theory exists as to which metastable materials can be made and how, impeding their experimental realization. Here we propose a quasi-thermodynamic framework for predicting the hydrothermal synthetic accessibility of metastable materials and apply this model to understanding the phase selection between the pyrite and marcasite polymorphs of FeS2. We demonstrate that phase selection in this system can be explained by the surface stability of the two phases as a function of ambient pH within nano-size regimes relevant to nucleation. This result suggests that a first-principles understanding of nano-size phase stability in realistic synthesis environments can serve to explain or predict the synthetic accessibility of structural polymorphs, providing a guideline to experimental synthesis via efficient computational materials design. PMID- 27966548 TI - Hetero-type dual photoanodes for unbiased solar water splitting with extended light harvesting. AB - Metal oxide semiconductors are promising photoelectrode materials for solar water splitting due to their robustness in aqueous solutions and low cost. Yet, their solar-to-hydrogen conversion efficiencies are still not high enough for practical applications. Here we present a strategy to enhance the efficiency of metal oxides, hetero-type dual photoelectrodes, in which two photoanodes of different bandgaps are connected in parallel for extended light harvesting. Thus, a photoelectrochemical device made of modified BiVO4 and alpha-Fe2O3 as dual photoanodes utilizes visible light up to 610 nm for water splitting, and shows stable photocurrents of 7.0+/-0.2 mA cm-2 at 1.23 VRHE under 1 sun irradiation. A tandem cell composed with the dual photoanodes-silicon solar cell demonstrates unbiased water splitting efficiency of 7.7%. These results and concept represent a significant step forward en route to the goal of >10% efficiency required for practical solar hydrogen production. PMID- 27966549 TI - Angular dependent anisotropic terahertz response of vertically aligned multi walled carbon nanotube arrays with spatial dispersion. AB - Spatial dispersion effect of aligned carbon nanotubes (CNTs) in the terahertz (THz) region has significance for both theoretical and applied consideration due to the unique intrinsically anisotropic physical properties of CNTs. Herein, we report the angular dependent reflection of p-polarized THz wave from vertically aligned multi-walled CNT arrays in both experiment and theory. The spectra indicate that the reflection depends on the film thickness of vertically aligned CNTs, the incident angle, and the frequency. The calculation model is based on the spatial dispersion effect of aligned CNTs and performed with effective impedance method and the Maxwell-Garnett approximation. The results fit well with the experiment when the thickness of CNT film is thin, which reveals a coherent superposition mechanism of the CNT surface reflection and CNTs/Si interface reflection. For thick CNT films, the CNTs/Si interface response determines the reflection at small incident angles, while the CNTs surface effect dominates at large incident angles. This work investigates the spatial dispersion effect of vertically aligned CNT arrays in the THz region, and paves a way for potential anisotropic THz applications based on CNTs with oblique incidence requirements. PMID- 27966550 TI - Vaccination for Mycobacterium tuberculosis infection: reprogramming CD4 T-cell homing into the lung. AB - Development of effective tuberculosis vaccines is hampered by insufficient understanding of protective immunity. Here, Woodworth et al.1 show secondary effector CD4 T cells generated after Mtb challenge of H56/CAF01 vaccinated mice display superior lung homing compared with primary effectors. Vaccination generates large populations of parenchymal lung effector cells by inducing CXCR3+KLRG1- cells that continuously migrate from lymph nodes to lung, and limiting the generation of non-protective CX3CR1+KLRG1+ intravascular effectors, providing insight vaccine-mediated protection against tuberculosis. PMID- 27966552 TI - Contraction of intestinal effector T cells by retinoic acid-induced purinergic receptor P2X7. AB - The intestinal environment harbors a large number of activated T cells, which are potentially inflammatory. To prevent inflammatory responses, intestinal T cells are controlled by various tolerogenic mechanisms, including T-cell apoptosis. We investigated the expression mechanism and function of the purinergic receptor P2X7 in contraction of intestinal CD4+ effector T cells. We found that P2X7 upregulation on CD4+ effector T cells is induced by retinoic acid through retinoic acid receptor alpha binding to an intragenic enhancer region of the P2rx7 gene. P2X7 is highly expressed by most intestinal alphabeta and gammadelta T cells, including T-helper type 1 (Th1) and Th17 cells. The intestinal effector T cells are effectively deleted by P2X7 activation-dependent apoptosis. Moreover, P2X7 activation suppressed T-cell-induced colitis in Rag1-/- mice. The data from vitamin A-deficient and P2rx7-/- mice indicate that the retinoic acid-P2X7 pathway is important in preventing aberrant buildup of activated T cells. We conclude that retinoic acid controls intestinal effector T-cell populations by inducing P2X7 expression. These findings have important ramifications in preventing inflammatory diseases in the intestine. PMID- 27966551 TI - The respiratory tract microbiome and lung inflammation: a two-way street. AB - The lungs are not sterile or free from bacteria; rather, they harbor a distinct microbiome whose composition is driven by different ecological rules than for the gastrointestinal tract. During disease, there is often a shift in community composition towards Gammaproteobacteria, the bacterial class that contains many common lung-associated gram-negative "pathogens." Numerous byproducts of host inflammation are growth factors for these bacteria. The extracellular nutrient supply for bacteria in the lungs, which is severely limited during health, markedly increases due to the presence of mucus and vascular permeability. While Gammaproteobacteria benefit from airway inflammation, they also encode molecular components that promote inflammation, potentially creating a cyclical inflammatory mechanism. In contrast, Prevotella species that are routinely acquired via microaspiration from the oral cavity may participate in immunologic homeostasis of the airways.vAreas of future research include determining for specific lung diseases (1) whether an altered lung microbiome initiates disease pathogenesis, promotes chronic inflammation, or is merely a marker of injury and inflammation, (2) whether the lung microbiome can be manipulated therapeutically to change disease progression, (3) what molecules (metabolites) generated during an inflammatory response promote cross-kingdom signaling, and (4) how the lung "ecosystem" collapses during pneumonia, to be dominated by a single pathogen. PMID- 27966554 TI - IL-36 receptor deletion attenuates lung injury and decreases mortality in murine influenza pneumonia. AB - Influenza virus causes a respiratory disease in humans that can progress to lung injury with fatal outcome. The interleukin (IL)-36 cytokines are newly described IL-1 family cytokines that promote inflammatory responses via binding to the IL 36 receptor (IL-36R). The mechanism of expression and the role of IL-36 cytokines are poorly understood. Here, we investigated the role of IL-36 cytokines in modulating the innate inflammatory response during influenza virus-induced pneumonia in mice. The intranasal administration of influenza virus upregulated IL-36alpha mRNA and protein production in the lungs. In vitro, influenza virus mediated IL-36alpha but not IL-36gamma is induced and secreted from alveolar epithelial cells (AECs) through both a caspase-1 and caspase-3/7 dependent pathway. IL-36alpha was detected in microparticles shed from AECs and promoted the production of pro-inflammatory cytokines and chemokines in respiratory cells. IL-36R-deficient mice were protected from influenza virus-induced lung injury and mortality. Decreased mortality was associated with significantly reduced early accumulation of neutrophils and monocytes/macrophages, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines, and permeability of the alveolar-epithelial barrier in despite impaired viral clearance. Taken together, these data indicate that IL-36 ligands exacerbate lung injury during influenza virus infection. PMID- 27966553 TI - Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. AB - Intestinal IgA, which is regulated by gut microbiota, has a crucial role in maintenance of intestinal homeostasis and in protecting the intestines from inflammation. However, the means by which microbiota promotes intestinal IgA responses remain unclear. Emerging evidence suggests that the host can sense gut bacterial metabolites in addition to pathogen-associated molecular patterns and that recognition of these small molecules influences host immune response in the intestines and beyond. We reported here that microbiota metabolite short-chain fatty acid acetate promoted intestinal IgA responses, which was mediated by "metabolite-sensing" GPR43. GPR43-/- mice demonstrated lower levels of intestinal IgA and IgA+ gut bacteria compared with those in wild type (WT) mice. Feeding WT but not GPR43-/- mice acetate but not butyrate promoted intestinal IgA response independent of T cells. Acetate promoted B-cell IgA class switching and IgA production in vitro in the presence of WT but not GPR43-/- dendritic cells (DCs). Mechanistically, acetate-induced DC expression of Aldh1a2, which converts Vitamin A into its metabolite retinoic acid (RA). Moreover, blockade of RA signaling inhibited the acetate induction of B-cell IgA production. Our studies thus identified a new pathway by which microbiota promotes intestinal IgA response through its metabolites. PMID- 27966556 TI - MV140, a sublingual polyvalent bacterial preparation to treat recurrent urinary tract infections, licenses human dendritic cells for generating Th1, Th17, and IL 10 responses via Syk and MyD88. AB - Recurrent urinary tract infections (RUTIs) are one of the most common bacterial infectious diseases, especially in women. Antibiotics remain the mainstay of treatment, but their overuse is associated with antibiotic-resistant infections and deleterious effects in the microbiota. Therefore, alternative approaches are fully demanded. Sublingual immunization with MV140 (Uromune), a polyvalent bacterial preparation (PBP) of whole heat-inactivated bacteria, demonstrated clinical efficacy for the treatment of RUTIs, but the involved immunological mechanisms remain unknown. Herein, we demonstrated that MV140 endorses human dendritic cells (DCs) with the capacity to generate Th1/Th17 and IL-10-producing T cells by mechanisms depending on spleen tyrosine kinase (Syk)- and myeloid differentiation primary response gene 88 (MyD88)-mediated pathways. MV140-induced activation of nuclear factor kappaB (NF-kappaB) and p38 in human DCs is essential for the generated Th1/Th17 and IL-10 immune responses whereas c-Jun N-terminal Kinase (JNK) and extracellular-signal regulated kinase (ERK) contribute to Th1 and IL-10 responses, respectively. Sublingual immunization of BALB/c mice with MV140 also induces potent systemic Th1/Th17 and IL-10 responses in vivo. We uncover immunological mechanisms underlying the way of action of MV140, which might well also contribute to understand the rational use of specific PBPs in other clinical conditions with potential high risk of recurrent infections. PMID- 27966557 TI - Broadly neutralizing antibodies suppress post-transcytosis HIV-1 infectivity. AB - Broadly neutralizing antibodies (bNAbs) offer promising opportunities for preventing HIV-1 infection in humans. Immunoprophylaxis with potent bNAbs efficiently protects non-human primates from mucosal transmission even after repeated challenges. However, the precise mechanisms of bNAb-mediated viral inhibition in mucosal tissues are currently unknown. Here, we show that immunoglobulin (Ig)G and IgA bNAbs do not interfere with the endocytic transport of HIV-1 across epithelial cells, a process referred to as transcytosis. Instead, both viruses and antibodies are translocated to the basal pole of epithelial cells, possibly in the form of an immune complex. Importantly, as opposed to free virions, viral particles bound by bNAbs are no longer infectious after transepithelial transit. Post-transcytosis neutralization activity of bNAbs displays comparable inhibitory concentrations as those measured in classical neutralization assays. Thus, bNAbs do not block the transport of incoming HIV-1 viruses across the mucosal epithelium but rather neutralize the transcytosed virions, highlighting their efficient prophylactic and protective activity in vivo. PMID- 27966559 TI - Corrigendum to "Targeted Delivery of C/EBPalpha -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo". PMID- 27966558 TI - Gene Therapy for Epidermolysis Bullosa: Sticky Business. PMID- 27966555 TI - Reversal of TREM-1 ectodomain shedding and improved bacterial clearance by intranasal metalloproteinase inhibitors. AB - Triggering receptor expressed on myeloid cells-1 (TREM-1) is expressed on neutrophils and monocyte/macrophages and amplifies Toll-like receptor-mediated inflammation during infection. TREM-1 also exists in an antagonistic soluble form (sTREM-1) that has been used as a peripheral biomarker in sepsis, though the mechanisms of its release are not entirely clear. The requirement of TREM-1 in single microbial infections is controversial, with some studies showing a protective role and others a contribution to immunopathology. Furthermore, the role of membrane-bound and sTREM-1 in polygenic infections is currently unknown. In a mouse co-infection model where preceding viral infection greatly enhances bacteria co-infection, we now determine a mechanisms for the striking increase in sTREM-1 and the loss of TREM-1 on surface of neutrophils. We identified a matrix metalloproteinase (MMP)-9 cleavage site in TREM-1 and that the increase of MMP-9 in bronchoalveolar lavage fluid mirrors sTREM-1 release. In vitro studies with neutrophils and MMP-9 and the reduction of sTREM-1 in vivo after MMP-9 inhibition verifies that this enzyme cleaves TREM-1. Intriguingly, MMP-9 inhibition significantly reduces bacterial load and ensuing immunopathology in a co infection model. This highlights MMP-9 inhibition as a potential therapeutic via blocking cleavage of TREM-1. PMID- 27966563 TI - Corrigendum to "A Self-restricted CRISPR System to Reduce Off-target Effects". PMID- 27966562 TI - One Size Fits All?: Ethical Considerations for Examining Efficacy in First-in Human Pluripotent Stem Cell Studies. PMID- 27966564 TI - Habitual dietary phosphorus intake and urinary excretion in chronic kidney disease patients: a 3-day observational study. AB - Hyperphosphatemia in chronic kidney disease (CKD) is associated with vascular calcification, cardiovascular morbidity and mortality. The aim of this study was to estimate the daily dietary phosphorus intake compared with recommendations in CKD patients and to evaluate the reproducibility of the 24-h urinary phosphorus excretion. Twenty CKD patients stage 3-4 from the outpatient clinic, collected 24 h urine and kept dietary records for 3 consecutive days. The mean daily phosphorus intake was 1367+/-499, 1642+/-815 and 1426+/-706 mg/day, respectively (P=0.57). The mean urinary phosphorus excretion was 914+/-465, 954+/-414 and 994+/-479 mg/day, respectively (P=0.21). In this population of CKD patients stage 3-4 the daily phosphorus intake was above the recommended. Twenty-four-hour urinary phosphorus excretion was reproducible and the data indicate that a single 24-h urine collection is sufficient to estimate the individual phosphorus excretion. PMID- 27966566 TI - It is not how much you crave but what you do with it that counts: behavioural responses to food craving during weight management. AB - BACKGROUND/OBJECTIVES: The relationship between food craving and dieting is mixed and uncertain, with little evidence during active weight management. Accordingly, the frequency and nature of food cravings were investigated in people attending a commercial weight management programme. SUBJECTS/METHODS: An online survey was completed by 2932 participants (97% female, mean age=43.0 years, mean body mass index=31.6 kg/m2). Assessments included the Control of Eating Questionnaire, measuring the frequency, intensity, specificity and behaviour following food cravings. Others included body weight, dietary restraint, perceived success of dieting and mood. Forty-two per cent of the sample completed a second survey 7 weeks later. RESULTS: Cross-sectional analysis showed those currently dieting to lose weight (55% of sample) had significantly fewer, less intense and more resisted food cravings than those watching what they ate so as not to gain weight (35% of sample). Cravings were fewer for chocolate and other sweet foods. Longitudinally, food cravings decreased over the period of weight loss (2.0 kg). Fewer foods were craved and the cravings were less intense, easier to resist and to control. Eating in response to food cravings was a significant predictor of weight change. CONCLUSIONS: People with obesity and recent experience of resisting eating in response to food cravings lost more weight over the next 7 weeks. Feeling in control of eating was also associated with greater weight loss. This suggests it is the behaviour that follows food cravings rather than simply their frequency or intensity that contributes to successful weight management. This has implications for interventions to help address food cravings. PMID- 27966565 TI - The acute effects of inulin and resistant starch on postprandial serum short chain fatty acids and second-meal glycemic response in lean and overweight humans. AB - BACKGROUND/OBJECTIVES: Colonic fermentation of dietary fiber to short-chain fatty acids (SCFA) may protect against obesity and diabetes, but excess production of colonic SCFA has been implicated in the promotion of obesity. We aimed to compare the effects of two fermentable fibers on postprandial SCFA and second-meal glycemic response in healthy overweight or obese (OWO) vs lean (LN) participants. SUBJECTS/METHODS: Using a randomized crossover design, 13 OWO and 12 LN overnight fasted participants were studied for 6 h on three separate days after consuming 300 ml water containing 75 g glucose (GLU) as control or with 24 g inulin (IN) or 28 g resistant starch (RS). A standard lunch was served 4 h after the test drink. RESULTS: Within the entire group, compared with control, IN significantly increased serum SCFA (P<0.001) but had no effect on free-fatty acids (FFA) or second-meal glucose and insulin responses. In contrast, RS had no significant effect on SCFA but reduced FFA rebound (P<0.001) and second-meal glucose (P=0.002) and insulin responses (P=0.024). OWO had similar postprandial serum SCFA and glucose concentrations but significantly greater insulin and FFA than LN. However, the effects of IN and RS on SCFA, glucose, insulin and FFA responses were similar in LN and OWO. CONCLUSIONS: RS has favorable second-meal effects, likely related to changes in FFA rather than SCFA concentrations. However, a longer study may be needed to demonstrate an effect of RS on SCFA. We found no evidence that acute increases in SCFA after IN reduce glycemic responses in humans, and we were unable to detect a significant difference in SCFA responses between OWO vs LN subjects. PMID- 27966567 TI - Improved and more effective algorithms to screen for nutrient deficiencies after bariatric surgery. AB - BACKGROUND/OBJECTIVES: Most bariatric guidelines recommend frequent lab monitoring of patients to detect nutrient and vitamin deficiencies as early as possible. The aim of this study was to optimize the cost effectiveness of the nutrient panel, by developing an algorithm, which detects nutrient deficiencies at lower costs. SUBJECTS/METHODS: In this retrospective study, 2055 patients who had undergone Laparoscopic Roux-Y Gastric Bypass (LRYGB) and Laparoscopic Sleeve Gastrectomy (LSG) surgery at Catharina Hospital Eindhoven between January 2009 and December 2013 were included. Perioperative biochemical measurements (7 days before and 127 days after surgery) and measurements >549 days before surgery were excluded. For analysis, the most recent preoperative and postoperative measurements were selected for each biochemical parameter separately. First, the amount of moderate and severe deficiencies were calculated. Second, we investigated whether each variable (vitamins A, B1, B6, B12, D, folate, ferritin, zinc and magnesium) could predict the presence of deficiency. RESULTS: In total, 561 (LRYGB) and 831 (LSG) patients had at least preoperative and postoperative values of vitamin A, B1, B6, B12, D, folate, ferritin, zinc or magnesium. The algorithm reduces vitamin D, B12, B6, B1 and ferritin examinations by 15, 11, 28, 28 and 38%, respectively, without missing clinically relevant deficiencies. The corresponding potential cost savings was 14%. CONCLUSIONS: This study identified substantial cost savings in laboratory test for both LRYGB and LSG procedures. The potential cost reduction of 14% might even be increased to 42% when less frequent moderate deficiencies are not screened anymore, whereas >99.0 of moderate deficiencies will be detected. PMID- 27966568 TI - Eating at restaurants, at work or at home. Is there a difference? A study among adults of 11 European countries in the context of the HECTOR* project. AB - BACKGROUND/OBJECTIVES: To compare macronutrient intakes out of home-by location to those at home and to investigate differences in total daily intakes between individuals consuming more than half of their daily energy out of home and those eating only at home. SUBJECTS/METHODS: Data collected through 24-h recalls or diaries among 23 766 European adults. Participants were grouped as 'non substantial', 'intermediate' and 'very substantial out-of-home' eaters based on energy intake out of home. Mean macronutrient intakes were estimated at home and out of home (overall, at restaurants, at work). Study/cohort-specific mean differences in total intakes between the 'very substantial out-of-home' and the 'at-home' eaters were estimated through linear regression and pooled estimates were derived. RESULTS: At restaurants, men consumed 29% of their energy as fat, 15% as protein, 45% as carbohydrates and 11% as alcohol. Among women, fat contributed 33% of energy intake at restaurants, protein 16%, carbohydrates 45% and alcohol 6%. When eating at work, both sexes reported 30% of energy from fat and 55% from carbohydrates. Intakes at home were higher in fat and lower in carbohydrates and alcohol. Total daily intakes of the 'very substantial out-of home' eaters were generally similar to those of individuals eating only at home, apart from lower carbohydrate and higher alcohol intakes among individuals eating at restaurants. CONCLUSIONS: In a large population of adults from 11 European countries, eating at work was generally similar to eating at home. Alcoholic drinks were the primary contributors of higher daily energy intakes among individuals eating substantially at restaurants. PMID- 27966569 TI - DASH dietary pattern and chronic kidney disease in elderly Korean adults. AB - BACKGROUND/OBJECTIVES: Dietary patterns are linked to risk and outcomes in chronic kidney disease (CKD). Dietary intake varies by race, region and age. The relationship between a Dietary Approaches to Stop Hypertension (DASH) diet and CKD in elderly Koreans is unclear. SUBJECTS/METHODS: We conducted cross-sectional analyses of 2408 community-dwelling elderly participants from the Korean National Health and Nutrition Examination Survey (2011-2012). DASH dietary patterns for six nutrients (protein, fiber, calcium, potassium, total fat and sodium) were collected by 24 h recall. DASH-US (based on the US recommendations) and DASH-KQ (Korean quartile) scores were generated by summing the scores for the six nutrients. Multivariate logistic regression analysis was used to calculate odds ratio (OR) for the association between a DASH diet and CKD. RESULTS: Mean subject age was 72.4+/-5.1 years, 13.9% had CKD and 23.8% had diabetes. Protein, fiber, calcium and potassium intake was lower in CKD than non-CKD participants. In multivariate logistic regression analysis adjusted for age, sex, body mass index, comorbid conditions and other factors, a high DASH score was associated with a low odds for CKD based on DASH-US (OR=0.78, 95% confidence interval (CI), 0.65 0.94, P=0.009) and DASH-KQ (OR=0.95, 95% CI, 0.91-0.99, P=0.022). In six nutrients of DASH diet, high fiber intake showed a low odds for CKD in the DASH KQ model (P for trend=0.010). CONCLUSIONS: Our findings suggest that higher adherence to a DASH diet and higher fiber intake are associated with lower odds of CKD in elderly Koreans. These results should be corroborated through longitudinal studies of the association between a DASH diet and high-fiber diet on the risk of developing CKD. PMID- 27966570 TI - Passive and active roles of fat-free mass in the control of energy intake and body composition regulation. AB - While putative feedback signals arising from adipose tissue are commonly assumed to provide the molecular links between the body's long-term energy requirements and energy intake, the available evidence suggests that the lean body or fat-free mass (FFM) also plays a role in the drive to eat. A distinction must, however, be made between a 'passive' role of FFM in driving energy intake, which is likely to be mediated by 'energy-sensing' mechanisms that translate FFM-induced energy requirements to energy intake, and a more 'active' role of FFM in the drive to eat through feedback signaling between FFM deficit and energy intake. Consequently, a loss of FFM that results from dieting or sedentarity should be viewed as a risk factor for weight regain and increased fatness not only because of the impact of the FFM deficit in lowering the maintenance energy requirement but also because of the body's attempt to restore FFM by overeating-a phenomenon referred to as 'collateral fattening'. A better understanding of these passive and active roles of FFM in the control of energy intake will necessitate the elucidation of peripheral signals and energy-sensing mechanisms that drive hunger and appetite, with implications for both obesity prevention and its management. PMID- 27966571 TI - Vitamin D and serum leptin: a systematic review and meta-analysis of observational studies and randomized controlled trials. AB - We aimed to investigate the potential association between vitamin D and serum leptin levels by pooling together the results from observational studies and clinical trials. A systematic literature search of PubMed, Scopus and Google Scholar was conducted up to March 2015. The analysis of observational studies was conducted on six papers that reported nine correlation coefficients using Fisher's Z and its standard error. Then, effect sizes of eligible trials were pooled using random-effects models (the DerSimonian-Laird estimator). Results of observational studies showed an inverse association between leptin and 25 hydroxyvitamin D (25(OH)D) (Fisher's Z=-0.93, 95% CI: -0.95, -0.91). After combining trials, pooled mean difference (PMD) for 25(OH)D was 24.06 ng/ml (95% CI, 17.27-30.85; P<0.001) with significant heterogeneity among studies (P<0.001; I2=89.1%). Raising 25(OH)D was associated with significant increase in leptin level (PMD=4.60 ng/ml, 95% CI, 0.55-8.66, P=0.026) with significant heterogeneity (P<0.001; I2=96.4%). Population with diabetes (PMD: 13.63 ng/ml), age younger than 50 years (PMD: 1.884 ng/ml), doses less than 1000 IU/day (PMD: 1.53 ng/ml), duration less than 24 weeks (PMD: 14.668 ng/ml) and baseline 25(OH)D <50 nmol/l (PMD: 13.483 ng/ml) were sources of heterogeneity. Current evidence indicates that inverse association between leptin level and 25(OH)D concentration was observed in observational studies, which was not demonstrated in intervention studies with high heterogeneity. Clearly, there is a need for properly designed and large prospective dose-response trials with long-term follow-up to assess the sources of heterogeneity. PMID- 27966573 TI - The association of change in physical activity and body weight in the regulation of total energy expenditure. AB - BACKGROUND/OBJECTIVES: The limited success in addressing the current obesity epidemic reflects the insufficient understanding of the regulation of energy balance. The present study examines the longitudinal association of body weight with physical activity (PA), total daily energy expenditure (TDEE) and total daily energy intake (TDEI). SUBJECTS/METHODS: A total of 195 adults (52% male) between 21 and 35 years of age with no intention for weight loss were followed over a 2-year period. Body weight, fat mass and fat-free mass were measured every 3 months. Participants were stratified into three groups based on change in body weight using a 5% cutpoint. TDEE and time spent in different PA intensities were determined via a multisensor device at each measurement time. TDEI was calculated based on change in body composition and TDEE. RESULTS: At 2-year follow-up, 57% of the participants maintained weight, 14% lost weight and 29% gained weight. Average weight change was -6.9+/-3.4 and 7.1+/-3.6 kg in the weight-loss and weight-gain groups, respectively. Average TDEE and TDEI did not change significantly in any weight change group (P>0.16). Moderate-to-vigorous PA, however, increased significantly in the weight-loss group (35+/-49 min/day; P<0.01) and decreased in the weight-gain group (-35+/-46 min/day; P<0.01). CONCLUSIONS: Results of this observational study indicate an inverse association between body weight and PA to maintain a stable TDEE and allow for a stable TDEI over time. Sufficient PA levels, therefore, are an important contributor to weight loss maintenance. PMID- 27966572 TI - Genetic ancestry in relation to the metabolic response to a US versus traditional Mexican diet: a randomized crossover feeding trial among women of Mexican descent. AB - BACKGROUND/OBJECTIVES: Certain populations with a large proportion of indigenous American (IA) genetic ancestry may be evolutionarily adapted to traditional diets high in legumes and complex carbohydrates, and may have a detrimental metabolic response to US diets high in refined carbohydrates and added sugars. We tested whether IA ancestry modified the metabolic response to a US versus traditional Mexican diet in a controlled dietary intervention. SUBJECTS/METHODS: First and second generation Mexican immigrant women (n=53) completed a randomized crossover feeding trial testing the effects of a US versus traditional Mexican diet. The metabolic response to the diets was measured by fasting serum concentrations of glucose, insulin, insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3), adiponectin, C-reactive protein, interleukin-6 and computed homeostasis model assessment for insulin resistance (HOMAIR). Blood collected at baseline was used for genotyping, and estimation of African, European and IA ancestries with the use of 214 ancestry informative markers. RESULTS: The genetic ancestral background was 56% IA, 38% European and 6% African. Women in the highest IA ancestry tertile (>62%) were shorter in height, less educated and less acculturated to the US lifestyle, and tended to have higher waist-to-hip ratio compared with women in the middle and lowest IA ancestry tertiles, respectively. Compared with the US diet, the traditional Mexican diet tended to reduce glucose, insulin, IGF-1, IGFBP-3 and HOMAIR among women in the middle IA ancestry group (IA ancestry ?45-62%), whereas having no effect on biomarkers related to inflammation. CONCLUSIONS: We observed modest interactions between IA ancestry and the metabolic response to a US versus traditional Mexican diet among Mexican immigrant women. PMID- 27966575 TI - Clinical impact of vitamin D treatment in cystic fibrosis: a pilot randomized, controlled trial. AB - BACKGROUND/OBJECTIVES: Vitamin D insufficiency in cystic fibrosis is common. Vitamin D3 is currently preferred over D2. We aimed to study the efficacy of vitamin D2 and D3 at increasing serum 25-hydroxyvitamin D (s25OHD) concentrations and their effect on respiratory health in cystic fibrosis. SUBJECTS/METHODS: Sixteen CF patients were randomized to receive vitamin D2 or D3 or to serve as controls. The starting dose of 5000 IU (<16 years old) or 7143 IU/day (?16 years old) was further individually adjusted. Three months of intervention were followed by two of washout (ClinicalTrials.gov NCT01321905). RESULTS: To increase s25OHD, the mean daily dose of vitamin D2 and D3 had to be increased up to 15650 and 8184 IU, respectively. The combined group of vitamin D2 and D3 treated patients decreased plasma IL-8 (P<0.05). Patients provided vitamin D3 improved FVC at the end of the trial (P<0.05). Change in s25OHD was positively correlated with changes in the adult Quality-of-Life respiratory score at the end of supplementation (P=0.006, r=0.90), and with changes in FEV1 (P=0.042, r=0.62) and FVC (P=0.036, r=0.63) at one month of washout. CONCLUSIONS: Vitamin D supplementation may contribute to reduced inflammation and improved lung function in CF. PMID- 27966574 TI - Acute increases in serum colonic short-chain fatty acids elicited by inulin do not increase GLP-1 or PYY responses but may reduce ghrelin in lean and overweight humans. AB - BACKGROUND: Colonic fermentation of dietary fibre to short-chain fatty acids (SCFA) influences appetite hormone secretion in animals, but SCFA production is excessive in obese animals. This suggests there may be resistance to the effect of SCFA on appetite hormones in obesity. OBJECTIVES: To determine the effects of inulin (IN) and resistant starch (RS) on postprandial SCFA, and gut hormone (glucagon-like peptide (GLP-1), peptide-tyrosine-tyrosine (PYY) and ghrelin) responses in healthy overweight/obese (OWO) vs lean (LN) humans. SUBJECTS/METHODS: Overnight-fasted participants (13 OWO and 12 LN) consumed 300 ml water containing 75 g glucose (GLU) as control or 75 g GLU plus 24 g IN, or 28.2 g RS using a randomised, single-blind, cross-over design. Blood for appetite hormones and SCFA was collected at intervals over 6 h. A standard lunch was served 4 h after the test drink. RESULTS: Relative to GLU, IN, but not RS, significantly increased SCFA areas under the curve (AUC) from 4-6 h (AUC4-6). Neither IN nor RS affected GLP-1 or PYY-AUC4-6. Although neither IN nor RS reduced ghrelin-AUC4-6 compared with GLU, ghrelin at 6 h after IN was significantly lower than that after GLU (P<0.05). After IN, relative to GLU, the changes in SCFA-AUC4-6 were negatively related to the changes in ghrelin-AUC4-6 (P=0.017). SCFA and hormone responses did not differ significantly between LN and OWO. CONCLUSIONS: Acute increases in colonic SCFA do not affect GLP-1 or PYY responses in LN or OWO subjects, but may reduce ghrelin. The results do not support the hypothesis that SCFA acutely stimulate PYY and GLP-1 secretion; however, a longer adaptation to increased colonic fermentation or a larger sample size may yield different results. PMID- 27966576 TI - Physics-driven Spatiotemporal Regularization for High-dimensional Predictive Modeling: A Novel Approach to Solve the Inverse ECG Problem. AB - This paper presents a novel physics-driven spatiotemporal regularization (STRE) method for high-dimensional predictive modeling in complex healthcare systems. This model not only captures the physics-based interrelationship between time varying explanatory and response variables that are distributed in the space, but also addresses the spatial and temporal regularizations to improve the prediction performance. The STRE model is implemented to predict the time-varying distribution of electric potentials on the heart surface based on the electrocardiogram (ECG) data from the distributed sensor network placed on the body surface. The model performance is evaluated and validated in both a simulated two-sphere geometry and a realistic torso-heart geometry. Experimental results show that the STRE model significantly outperforms other regularization models that are widely used in current practice such as Tikhonov zero-order, Tikhonov first-order and L1 first-order regularization methods. PMID- 27966577 TI - Salivary and pellicle proteome: A datamining analysis. AB - We aimed to comprehensively compare two compartmented oral proteomes, the salivary and the dental pellicle proteome. Systematic review and datamining was used to obtain the physico-chemical, structural, functional and interactional properties of 1,515 salivary and 60 identified pellicle proteins. Salivary and pellicle proteins did not differ significantly in their aliphatic index, hydrophaty, instability index, or isoelectric point. Pellicle proteins were significantly more charged at low and high pH and were significantly smaller (10 20 kDa) than salivary proteins. Protein structure and solvent accessible molecular surface did not differ significantly. Proteins of the pellicle were more phosphorylated and glycosylated than salivary proteins. Ion binding and enzymatic activities also differed significantly. Protein-protein-ligand interaction networks relied on few key proteins. The identified differences between salivary and pellicle proteins could guide proteome compartmentalization and result in specialized functionality. Key proteins could be potential targets for diagnostic or therapeutic application. PMID- 27966578 TI - Urinary KIM-1: a novel biomarker for evaluation of occupational exposure to lead. AB - Chronic occult lead poisoning often develops ensuing occupational lead exposure. Early diagnosis of lead poisoning is critical for timely discontinuation of lead exposure and for prognosis. This study explored the value of urinary kidney injury molecule-1 (KIM-1) in diagnosing renal injury induced by lead at an early stage. We retrospectively analyzed 92 workers exposed to occupational lead and demonstrated a better correlation ship between blood lead levels and urine excretion of KIM-1 than other traditional renal injury biomarkers following creatinine adjustment. Receiver operating characteristic curve analysis of the ability of diverse biomarkers for predicting kidney injury in lead-exposed workers demonstrated that the order of predicting accuracy of the studied biomarkers is as follows: urinary KIM-1-to-creatinine ratio > urinary N-acetyl beta-(D)-glucosaminidase-to-creatinine ratio > urinary beta2-microglobulin-to creatinine ratio > urinary alpha1-microglobulin-to-creatinine ratio, with the Youden index being 16.59 ng/g, 14.01 U/g, 0.15 mg/g, and 4.63 mg/g, respectively. Collectively, our findings suggest that short-period occupational lead exposure may cause injury of renal tubules. Urinary excretion of KIM-1 correlates with blood lead levels better than other traditional renal injury biomarkers, including N-acetyl-beta-(D)-glucosaminidase, alpha1-microglobulin, and beta2 microglobulin. Longitudinal surveillance of urinary KIM-1 may aid for early diagnosis of renal tubular injury in workers with occupational lead exposure. PMID- 27966579 TI - Phenotypic plasticity in sex pheromone production in Bicyclus anynana butterflies. AB - Phenotypic plasticity refers to the environmental control of phenotypes. Cues experienced during development (developmental plasticity) or during adulthood (acclimatization) can both affect adult phenotypes. Phenotypic plasticity has been described in many traits but examples of developmental plasticity in physiological traits, in particular, remain scarce. We examined developmental plasticity and acclimatization in pheromone production in the butterfly Bicyclus anynana in response to rearing temperature. B. anynana lives in the African tropics where warm rearing temperatures of the wet season produce active males that court and females that choose, whereas cooler temperatures of the dry season lead to choosy less active males and courting females. We hypothesized that if male pheromone production is costly, it should be reduced in the dry season form. After describing the ultrastructure of pheromone producing cells, we showed that dry season males produced significantly less sex pheromones than wet season males, partly due to acclimatization and partly due to developmental plasticity. Variation in levels of one of the compounds is associated with differential regulation of a pheromone biosynthetic enzyme gene. This plasticity might be an adaptation to minimize pheromone production costs during the stressful dry season. PMID- 27966581 TI - A Novel Information-Theoretic Approach for Variable Clustering and Predictive Modeling Using Dirichlet Process Mixtures. AB - In the era of big data, there are increasing interests on clustering variables for the minimization of data redundancy and the maximization of variable relevancy. Existing clustering methods, however, depend on nontrivial assumptions about the data structure. Note that nonlinear interdependence among variables poses significant challenges on the traditional framework of predictive modeling. In the present work, we reformulate the problem of variable clustering from an information theoretic perspective that does not require the assumption of data structure for the identification of nonlinear interdependence among variables. Specifically, we propose the use of mutual information to characterize and measure nonlinear correlation structures among variables. Further, we develop Dirichlet process (DP) models to cluster variables based on the mutual information measures among variables. Finally, orthonormalized variables in each cluster are integrated with group elastic-net model to improve the performance of predictive modeling. Both simulation and real-world case studies showed that the proposed methodology not only effectively reveals the nonlinear interdependence structures among variables but also outperforms traditional variable clustering algorithms such as hierarchical clustering. PMID- 27966580 TI - Microarray analysis of long noncoding RNA and mRNA expression profiles in human macrophages infected with Mycobacterium tuberculosis. AB - Macrophages play a crucial role in the control and elimination of invading Mycobacterium tuberculosis (Mtb), and also serve as the major residence for Mtb. However, the interaction between macrophages and Mtb remains to be clearly determined. Although long noncoding RNAs (lncRNAs) have emerged as key regulators in many biological processes, their roles in anti-mycobacterial responses of macrophages remain to be elucidated. Here, we applied microarray analysis to examine lncRNA and mRNA expression profiles in human primary macrophages after 72 h of infection with H37Ra or H37Rv. Our results revealed that many lncRNAs were differentially expressed in macrophages after H37Ra or H37Rv infection, indicating a possible role for lncRNAs in immune responses induced by Mtb infection and providing important cues for further functional studies. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analysis of the differentially expressed mRNAs showed the potential functions and pathways related to the pathogenesis of Mtb infection. Finally, two lncRNAs, MIR3945HG V1 and MIR3945HG V2, were identified as novel candidate diagnostic markers for tuberculosis. Our results provide novel insight into the mechanisms of the pivotal Mtb-macrophage interactions, and reveal potential targets for diagnostics and the treatment of tuberculosis. PMID- 27966583 TI - The effect of standardized food intake on the association between BMI and 1H-NMR metabolites. AB - Multiple studies have shown that levels of 1H-NMR metabolites are associated with disease and risk factors of disease such as BMI. While most previous investigations have been performed in fasting samples, meta-analysis often includes both cohorts with fasting and non-fasting blood samples. In the present study comprising 153 participants (mean age 63 years; mean BMI 27 kg/m2) we analyzed the effect of a standardized liquid meal (SLM) on metabolite levels and how the SLM influenced the association between metabolites and BMI. We observed that many metabolites, including glycolysis related metabolites, multiple amino acids, LDL diameter, VLDL and HDL lipid concentration changed within 35 minutes after a standardized liquid meal (SLM), similarly for all individuals. Remarkable, however, is that the correlations of metabolite levels with BMI remained highly similar before and after the SLM. Hence, as exemplified with the disease risk factor BMI, our results suggest that the applicability of 1H-NMR metabolites as disease biomarkers depends on the standardization of the fasting status rather than on the fasting status itself. Future studies are required to investigate the dependency of metabolite biomarkers for other disease risk factors on the fasting status. PMID- 27966582 TI - Electroacupuncture enhances rehabilitation through miR-181b targeting PirB after ischemic stroke. AB - Recent studies have demonstrated microRNAs (miRNAs) and proteins are beneficial to axon regeneration, which may be involved in Electroacupuncture (EA) therapy against stroke. In this study, we aimed to determine the pivotal role of PirB in EA-produced rehabilitation against ischemic stroke; and to screen and investigate the potential miRNAs directly regulating PirB expression. The results showed EA treatment enhanced axon regeneration and new projections from the corticospinal tract at 28 d after cerebral ischemic reperfusion injury of rats. Then, we found EA decreased pirb mRNA and PirB protein expression in the penumbra within 28 days after reperfusion. The reduction of PirB expression facilitated neurite outgrowth after oxygen-glucose deprivation injury. The miRNA microarray showed the level of twenty kinds of miRNAs changed in the penumbra after EA administration. The bioinformatics study and luciferase assay verified miR-181b directly regulated pirb mRNA expression. EA increased miR-181b levels in the penumbras, and improved neurobehavioral function rehabilitation through miR-181b direct targeting of pirb mRNA to regulate the expression of PirB, RhoA and GAP43. In conclusion, we provide the first evidence that EA enhances rehabilitation against stroke by regulating epigenetic changes to directly act on its targets, such as the miR 181b/PirB/RhoA/GAP43 axis, which is a novel mechanism of EA therapy. PMID- 27966585 TI - Ultrafast laser induced local magnetization dynamics in Heusler compounds. AB - The overarching goal of the field of femtomagnetism is to control, via laser light, the magnetic structure of matter on a femtosecond time scale. The temporal limits to the light-magnetism interaction are governed by the fact that the electron spin interacts indirectly with light, with current studies showing a laser induced global loss in the magnetic moment on a time scale of the order of a few 100 s of femtoseconds. In this work, by means of ab-initio calculations, we show that more complex magnetic materials - we use the example of the Heusler and half-Heusler alloys - allow for purely optical excitations to cause a significant change in the local moments on the order of 5 fs. This, being purely optical in nature, represents the ultimate mechanism for the short time scale manipulation of spins. Furthermore, we demonstrate that qualitative behaviour of this rich magnetic response to laser light can be deduced from the ground-state spectrum, thus providing a route to tailoring the response of some complex magnetic materials, like the Heuslers, to laser light by the well established methods for material design from ground-state calculations. PMID- 27966584 TI - Ebselen Preserves Tissue-Engineered Cell Sheets and their Stem Cells in Hypothermic Conditions. AB - Clinical trials have been performed using autologous tissue-engineered epithelial cell sheets for corneal regenerative medicine. To improve stem cell-based therapy for convenient clinical practice, new techniques are required for preserving reconstructed tissues and their stem/progenitor cells until they are ready for use. In the present study, we screened potential preservative agents and developed a novel medium for preserving the cell sheets and their stem/progenitor cells; the effects were evaluated with a luciferase-based viability assay. Nrf2 activators, specifically ebselen, could maintain high ATP levels during preservation. Ebselen also showed a strong influence on maintenance of the viability, morphology, and stem cell function of the cell sheets preserved under hypothermia by protecting them from reactive oxygen species-induced damage. Furthermore, ebselen drastically improved the preservation performance of human cornea tissues and their stem cells. Therefore, ebselen shows good potential as a useful preservation agent in regenerative medicine as well as in cornea transplantation. PMID- 27966586 TI - Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia. AB - Observational studies have established a strong association between matrix metalloproteinase-9 (MMP-9) and ventricular arrhythmia. However, whether MMP-9 has a causal link to ventricular arrhythmia, as well as the underlying mechanism, remains unclear. Here, we investigated the mechanistic involvement of myocardial MMP-9 in the pathophysiology of ventricular arrhythmia. Increased levels of myocardial MMP-9 are linked to ventricular arrhythmia attacks after angiotensin II (Ang II) treatment. MMP-9-deficient mice were protected from ventricular arrhythmia. Increased expressions of protein kinase A (PKA) and ryanodine receptor phosphorylation at serine 2808 (pS2808) were correlated with inducible ventricular arrhythmia. MMP-9 deficiency consistently prevented PKA and pS2808 increases after Ang II treatment and reduced ventricular arrhythmia. Calcium dynamics were examined via confocal imaging in isolated murine cardiomyocytes. MMP-9 inhibition prevents calcium leakage from the sarcoplasmic reticulum and reduces arrhythmia-like irregular calcium transients via protein kinase A and ryanodine receptor phosphorylation. Human induced pluripotent stem cell-derived cardiomyocytes similarly show that MMP-9 inhibition prevents abnormal calcium leakage. Myocardial MMP-9 inhibition prevents ventricular arrhythmia through pleiotropic effects, including the modulation of calcium homeostasis and reduced calcium leakage. PMID- 27966588 TI - Sympathetic neurons are a powerful driver of myocyte function in cardiovascular disease. AB - Many therapeutic interventions in disease states of heightened cardiac sympathetic activity are targeted to the myocytes. However, emerging clinical data highlights a dominant role in disease progression by the neurons themselves. Here we describe a novel experimental model of the peripheral neuro-cardiac axis to study the neuron's ability to drive a myocyte cAMP phenotype. We employed a co culture of neonatal ventricular myocytes and sympathetic stellate neurons from normal (WKY) and pro-hypertensive (SHR) rats that are sympathetically hyper responsive and measured nicotine evoked cAMP responses in the myocytes using a fourth generation FRET cAMP sensor. We demonstrated the dominant role of neurons in driving the myocyte beta-adrenergic phenotype, where SHR cultures elicited heightened myocyte cAMP responses during neural activation. Moreover, cross culturing healthy neurons onto diseased myocytes rescued the diseased cAMP response of the myocyte. Conversely, healthy myocytes developed a diseased cAMP response if diseased neurons were introduced. Our results provide evidence for a dominant role played by the neuron in driving the adrenergic phenotype seen in cardiovascular disease. We also highlight the potential of using healthy neurons to turn down the gain of neurotransmission, akin to a smart pre-synaptic beta blocker. PMID- 27966587 TI - Differential protein expression in metallothionein protection from depleted uranium-induced nephrotoxicity. AB - The purpose of this study was to investigate the underlying mechanism of metallothionein (MT) protection from depleted uranium (DU) using a proteomics approach to search for a DU toxicity-differential protein. MT-/- and MT+/+ mice were administrated with a single dose of DU (10 mg/kg, i.p.) or equal volume of saline. After 4 days, protein changes in kidney tissues were evaluated using a proteomics approach. A total of 13 differentially expressed proteins were identified using two-dimensional electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The validating results showed that the expression of aminoacylase-3 (ACY-3) and the mitochondrial ethylmalonic encephalopathy 1 (ETHE1) decreased significantly after DU exposure; in addition, the reduction in MT-/- mice was more significant than that in MT+/+ mice. The results also showed that exogenous ETHE1 or ACY-3 could increase the survival rate of human embryonic kidney 293 (HEK293) cells after DU exposure. A specific siRNA of ETHE1 significantly increased cell apoptosis rates after DU exposure, whereas exogenous ETHE1 significantly decreased cell apoptosis rates. In summary, ACY-3 and ETHE1 might involve in protection roles of MT. ETHE1 could be a new sensitive molecular target of DU-induced cell apoptosis. PMID- 27966589 TI - High Vimentin Expression Associated with Lymph Node Metastasis and Predicated a Poor Prognosis in Oral Squamous Cell Carcinoma. AB - Oral squamous cell carcinoma (OSCC) is a common public health problem worldwide with poor prognosis, which is largely due to lymph node metastasis and recurrence. Identification of specific molecular markers of OSCC with lymph node metastasis would be very important for early and specific diagnosis. In this study, we screened for the potential prognosis markers via unbiased transcriptomic microarray analysis in paired two OSCC cell lines, a lymph node metastatic HN12 cell line and a low metastatic parental HN4 cell line. The results showed that vimentin, with 87-fold increase of expression, was on the top of all upregulated genes in metastatic HN12 cells compared to non-metastatic HN4 cells. Treatment of non-metastatic HN4 cells with TGF-beta1 induced epithelial to mesenchymal transition (EMT), with increased vimentin expression as well as enhanced migration activity. Consistently, knockdown of vimentin via siRNA resulted in suppressed invasion and migration activities of HN12 cells, suggesting an essential role of vimentin in EMT-related functions of OSCC cells. Finally, immunohistochemical (IHC) staining analysis showed that high vimentin expression was strongly associated with high lymph node metastases (p < 0.05), and poor overall survival (p < 0.05) in OSCC patients. Thus, high vimentin expression is strongly associated with increased metastatic potential, and may serve as a prediction marker for poor prognosis in OSCC patients. PMID- 27966591 TI - Ringing phenomenon in chaotic microcavity for high-speed ultra-sensitive sensing. AB - The ringing phenomenon in whispering-gallery-mode (WGM) microcavities has demonstrated its great potential for highly-sensitive and high-speed sensing. However, traditional symmetric WGM microcavities have suffered from an extremely low coupling efficiency via free-space coupling because the emission of symmetric WGMs is non-directional. Here we report a new approach for high-speed ultra sensitive sensing using the ringing phenomenon in a chaotic regime. By breaking the rotational symmetry of a WGM microcavity and introducing chaotic behaviors, we show that the ringing phenomenon in chaotic WGM microcavities extends over both the positive and the negative frequency detune, allowing the ringing phenomenon to interact with analytes over a much broader bandwidth with a reduced dead time. Because the coupling of the chaotic microcavity is directional, it produces a significantly higher signal output, which improves its sensitivity without the need of a fiber coupler. PMID- 27966590 TI - Gait patterns associated with thyroid function: The Rotterdam Study. AB - Gait is an important health indicator and poor gait is strongly associated with disability and risk of falls. Thyroid dysfunction is suggested as a potential determinant of gait deterioration, but this has not been explored in a population based study. We therefore investigated the association of thyroid function with gait patterns in 2645 participants from the Rotterdam Study with data available on TSH (thyroid-stimulating hormone), FT4 (free thyroxine) and gait, without known thyroid disease or dementia. The primary outcome was Global gait (standardized Z-score), while secondary outcomes included gait domains (Rhythm, Variability, Phases, Pace, Base of support, Tandem, Turning) and velocity. Gait was assessed by electronic walkway. Multivariable regression models revealed an inverted U-shaped association of TSH (p < 0.001), but no association of FT4 concentrations with Global gait (p = 0.2). TSH levels were positively associated with Base of support (p = 0.01) and followed an inverted U-shaped curve with Tandem (p = 0.002) and velocity (p = 0.02). Clinical and subclinical hypothyroidism were associated with worse Global gait than euthyroidism (beta = 0.61; CI = -1.03, -0.18; p = 0.004 and beta = -0.13; CI = -0.26, -0.00; p = 0.04, respectively). In euthyroid participants, higher thyroid function was associated with worse gait patterns. In conclusion, both low and high thyroid function are associated with alterations in Global gait, Tandem, Base of support and velocity. PMID- 27966592 TI - Detecting the existence of gene flow between Spanish and North African goats through a coalescent approach. AB - Human-driven migrations are one of the main processes shaping the genetic diversity and population structure of domestic species. However, their magnitude and direction have been rarely analysed in a statistical framework. We aimed to estimate the impact of migration on the population structure of Spanish and African goats. To achieve this goal, we analysed a dataset of 1,472 individuals typed with 23 microsatellites. Population structure of African and Spanish goats was moderate (mean FST = 0.07), with the exception of the Canarian and South African breeds that displayed a significant differentiation when compared to goats from North Africa and Nigeria. Measurement of gene flow with Migrate-n and IMa coalescent genealogy samplers supported the existence of a bidirectional gene flow between African and Spanish goats. Moreover, IMa estimates of the effective number of migrants were remarkably lower than those calculated with Migrate-n and classical approaches. Such discrepancies suggest that recent divergence, rather than extensive gene flow, is the main cause of the weak population structure observed in caprine breeds. PMID- 27966594 TI - Meteorite Impact-Induced Rapid NH3 Production on Early Earth: Ab Initio Molecular Dynamics Simulation. AB - NH3 is an essential molecule as a nitrogen source for prebiotic amino acid syntheses such as the Strecker reaction. Previous shock experiments demonstrated that meteorite impacts on ancient oceans would have provided a considerable amount of NH3 from atmospheric N2 and oceanic H2O through reduction by meteoritic iron. However, specific production mechanisms remain unclear, and impact velocities employed in the experiments were substantially lower than typical impact velocities of meteorites on the early Earth. Here, to investigate the issues from the atomistic viewpoint, we performed multi-scale shock technique based ab initio molecular dynamics simulations. The results revealed a rapid production of NH3 within several picoseconds after the shock, indicating that shocks with greater impact velocities would provide further increase in the yield of NH3. Meanwhile, the picosecond-order production makes one expect that the important nitrogen source precursors of amino acids were obtained immediately after the impact. It was also observed that the reduction of N2 proceeded according to an associative mechanism, rather than a dissociative mechanism as in the Haber-Bosch process. PMID- 27966593 TI - Subtype-specific structural constraints in the evolution of influenza A virus hemagglutinin genes. AB - The influenza A virus genome consists of eight RNA segments. RNA structures within these segments and complementary (cRNA) and protein-coding mRNAs may play a role in virus replication. Here, conserved putative secondary structures that impose significant evolutionary constraints on the gene segment encoding the surface glycoprotein hemagglutinin (HA) were investigated using available sequence data on tens of thousands of virus strains. Structural constraints were identified by analysis of covariations of nucleotides suggested to be paired by structure prediction algorithms. The significance of covariations was estimated by mutual information calculations and tracing multiple covariation events during virus evolution. Covariation patterns demonstrated that structured domains in HA RNAs were mostly subtype-specific, whereas some structures were conserved in several subtypes. The influence of RNA folding on virus replication was studied by plaque assays of mutant viruses with disrupted structures. The results suggest that over the whole length of the HA segment there are local structured domains which contribute to the virus fitness but individually are not essential for the virus. Existence of subtype-specific structured regions in the segments of the influenza A virus genome is apparently an important factor in virus evolution and reassortment of its genes. PMID- 27966595 TI - Highly intense monocycle terahertz vortex generation by utilizing a Tsurupica spiral phase plate. AB - Optical vortex, possessing an annular intensity profile and an orbital angular momentum (characterized by an integer termed a topological charge) associated with a helical wavefront, has attracted great attention for diverse applications due to its unique properties. In particular for terahertz (THz) frequency range, several approaches for THz vortex generation, including molded phase plates consisting of metal slit antennas, achromatic polarization elements and binary diffractive optical elements, have been recently proposed, however, they are typically designed for a specific frequency. Here, we demonstrate highly intense broadband monocycle vortex generation near 0.6 THz by utilizing a polymeric Tsurupica spiral phase plate in combination with tilted-pulse-front optical rectification in a prism-cut LiNbO3 crystal. A maximum peak power of 2.3 MW was obtained for THz vortex output with an expected topological charge of 1.15. Furthermore, we applied the highly intense THz vortex beam for studying unique nonlinear behaviors in bilayer graphene towards the development of nonlinear super-resolution THz microscopy and imaging system. PMID- 27966596 TI - Supersymmetrical bounding of asymmetric states and quantum phase transitions by anti-crossing of symmetric states. AB - Von Neumann and Wigner theorized the bounding and anti-crossing of eigenstates. Experiments have demonstrated that owing to anti-crossing and similar radiation rates, the graphene-like resonance of inhomogeneously strained photonic eigenstates can generate a pseudomagnetic field, bandgaps and Landau levels, whereas exponential or dissimilar rates induce non-Hermicity. Here, we experimentally demonstrate higher-order supersymmetry and quantum phase transitions by resonance between similar one-dimensional lattices. The lattices consisted of inhomogeneous strain-like phases of triangular solitons. The resonance created two-dimensional, inhomogeneously deformed photonic graphene. All parent eigenstates were annihilated. Eigenstates of mildly strained solitons were annihilated at similar rates through one tail and generated Hermitian bounded eigenstates. The strongly strained solitons with positive phase defects were annihilated at exponential rates through one tail, which bounded eigenstates through non-Hermitianally generated exceptional points. Supersymmetry was evident, with preservation of the shapes and relative phase differences of the parent solitons. Localizations of energies generated from annihilations of mildly and strongly strained soliton eigenstates were responsible for geometrical (Berry) and topological phase transitions, respectively. Both contributed to generating a quantum Zeno phase, whereas only strong twists generated topological (Anderson) localization. Anti-bunching-like condensation was also observed. PMID- 27966598 TI - Electric-field-induced interferometric resonance of a one-dimensional spin-orbit coupled electron. AB - The efficient control of electron spins is of crucial importance for spintronics, quantum metrology, and quantum information processing. We theoretically formulate an electric mechanism to probe the electron spin dynamics, by focusing on a one dimensional spin-orbit-coupled nanowire quantum dot. Owing to the existence of spin-orbit coupling and a pulsed electric field, different spin-orbit states are shown to interfere with each other, generating intriguing interference-resonant patterns. We also reveal that an in-plane magnetic field does not affect the interval of any neighboring resonant peaks, but contributes a weak shift of each peak, which is sensitive to the direction of the magnetic field. We find that this proposed external-field-controlled scheme should be regarded as a new type of quantum-dot-based interferometry. This interferometry has potential applications in precise measurements of relevant experimental parameters, such as the Rashba and Dresselhaus spin-orbit-coupling strengths, as well as the Lande factor. PMID- 27966597 TI - Association between sleep duration and cardiac structure in youths at risk for metabolic syndrome. AB - The evidence for a link between sleep duration and cardiovascular risk is accumulating in youths, but no study has yet investigated the relationship between sleep duration and change of cardiac structure. In this study, we recruited 559 youths aged 14-28 years from the cohort of Beijing Child and Adolescent Metabolic Syndrome Study. Questionnaire, color Doppler echocardiography, oral glucose tolerance test and blood biomarkers analyses were performed. We found that sleep duration was negatively correlated with body mass index, waist circumstance, and HbA1c (all P < 0.05), but not with adiponectin and leptin. Meanwhile, participants with shorter sleep duration (<=7 h) had larger interventricular septal diastolic thickness, left ventricular (LV) end-diastolic diameter, LV posterior wall thickness, LV mass (LVM), and LV mass index (LVMI), compared to participants in 7-9 h/night or >9 h/night group. Findings remained significant after adjustment for the major confounding factors (P < 0.05). Multivariate regression modeling revealed that each additional hour of sleep was associated with smaller LVM (beta: -3.483, P < 0.0001) and LVMI (beta: -0.815, P < 0.0001). Our findings suggest that short sleep has a possible direct effect on cardiac remodeling, occurring already at young ages. PMID- 27966599 TI - Transcriptional analysis of degenerate strain Clostridium beijerinckii DG-8052 reveals a pleiotropic response to CaCO3-associated recovery of solvent production. AB - Degenerate Clostridium beijerinckii strain (DG-8052) can be partially recovered by supplementing CaCO3 to fermentation media. Genome resequencing of DG-8052 showed no general regulator mutated. This study focused on transcriptional analysis of DG-8052 and its response to CaCO3 treatment via microarray. The expressions of 5168 genes capturing 98.6% of C. beijerinckii NCIMB 8052 genome were examed. The results revealed that with addition of CaCO3 565 and 916 genes were significantly up-regulated, and 704 and 1044 genes significantly down regulated at acidogenic and solventogenic phase of DG-8052, respectively. These genes are primarily responsible for glycolysis to solvent/acid production (poR, pfo), solventogensis (buk, ctf, aldh, adh, bcd) and sporulation (spo0A, sigE, sigma-70, bofA), cell motility and division (ftsA, ftsK, ftsY, ftsH, ftsE, mreB, mreC, mreD, rodA), and molecular chaperones (grpE, dnaK, dnaJ, hsp20, hsp90), etc. The functions of some altered genes in DG-8052, totalling 5.7% at acidogenisis and 8.0% at sovlentogenisis, remain unknown. The response of the degenerate strain to CaCO3 was suggested significantly pleiotropic. This study reveals the multitude of regulatory function that CaCO3 has in clostridia and provides detailed insights into degeneration mechanisms at gene regulation level. It also enables us to develop effective strategies to prevent strain degeneration in future. PMID- 27966601 TI - Development of a computer-aided design software for dental splint in orthognathic surgery. AB - In the orthognathic surgery, dental splints are important and necessary to help the surgeon reposition the maxilla or mandible. However, the traditional methods of manual design of dental splints are difficult and time-consuming. The research on computer-aided design software for dental splints is rarely reported. Our purpose is to develop a novel special software named EasySplint to design the dental splints conveniently and efficiently. The design can be divided into two steps, which are the generation of initial splint base and the Boolean operation between it and the maxilla-mandibular model. The initial splint base is formed by ruled surfaces reconstructed using the manually picked points. Then, a method to accomplish Boolean operation based on the distance filed of two meshes is proposed. The interference elimination can be conducted on the basis of marching cubes algorithm and Boolean operation. The accuracy of the dental splint can be guaranteed since the original mesh is utilized to form the result surface. Using EasySplint, the dental splints can be designed in about 10 minutes and saved as a stereo lithography (STL) file for 3D printing in clinical applications. Three phantom experiments were conducted and the efficiency of our method was demonstrated. PMID- 27966600 TI - Gene network analysis identifies rumen epithelial cell proliferation, differentiation and metabolic pathways perturbed by diet and correlated with methane production. AB - Ruminants obtain nutrients from microbial fermentation of plant material, primarily in their rumen, a multilayered forestomach. How the different layers of the rumen wall respond to diet and influence microbial fermentation, and how these process are regulated, is not well understood. Gene expression correlation networks were constructed from full thickness rumen wall transcriptomes of 24 sheep fed two different amounts and qualities of a forage and measured for methane production. The network contained two major negatively correlated gene sub-networks predominantly representing the epithelial and muscle layers of the rumen wall. Within the epithelium sub-network gene clusters representing lipid/oxo-acid metabolism, general metabolism and proliferating and differentiating cells were identified. The expression of cell cycle and metabolic genes was positively correlated with dry matter intake, ruminal short chain fatty acid concentrations and methane production. A weak correlation between lipid/oxo acid metabolism genes and methane yield was observed. Feed consumption level explained the majority of gene expression variation, particularly for the cell cycle genes. Many known stratified epithelium transcription factors had significantly enriched targets in the epithelial gene clusters. The expression patterns of the transcription factors and their targets in proliferating and differentiating skin is mirrored in the rumen, suggesting conservation of regulatory systems. PMID- 27966602 TI - Validated methodology for quantifying infestation levels of dreissenid mussels in environmental DNA (eDNA) samples. AB - The zebra mussel (Dreissena polymorpha Pallas, 1771) and the quagga mussel (D. rostriformis Deshayes, 1838) are successful invasive bivalves with substantial ecological and economic impacts in freshwater systems once they become established. Since their eradication is extremely difficult, their detection at an early stage is crucial to prevent spread. In this study, we optimized and validated a qPCR detection method based on the histone H2B gene to quantify combined infestation levels of zebra and quagga mussels in environmental DNA samples. Our results show specific dreissenid DNA present in filtered water samples for which microscopic diagnostic identification for larvae failed. Monitoring a large number of locations for invasive dreissenid species based on a highly specific environmental DNA qPCR assay may prove to be an essential tool for management and control plans focused on prevention of establishment of dreissenid mussels in new locations. PMID- 27966603 TI - Combination of dynamic transformation and dynamic recrystallization for realizing ultrafine-grained steels with superior mechanical properties. AB - Dynamic recrystallization (DRX) is an important grain refinement mechanism to fabricate steels with high strength and high ductility (toughness). The conventional DRX mechanism has reached the limitation of refining grains to several microns even though employing high-strain deformation. Here we show a DRX phenomenon occurring in the dynamically transformed (DT) ferrite, by which the required strain for the operation of DRX and the formation of ultrafine grains is significantly reduced. The DRX of DT ferrite shows an unconventional temperature dependence, which suggests an optimal condition for grain refinement. We further show that new strategies for ultra grain refinement can be evoked by combining DT and DRX mechanisms, based on which fully ultrafine microstructures having a mean grain size down to 0.35 microns can be obtained without high-strain deformation and exhibit superior mechanical properties. This study will open the door to achieving optimal grain refinement to nanoscale in a variety of steels requiring no high-strain deformation in practical industrial application. PMID- 27966605 TI - Organic Redox Species in Aqueous Flow Batteries: Redox Potentials, Chemical Stability and Solubility. AB - Organic molecules are currently investigated as redox species for aqueous low cost redox flow batteries (RFBs). The envisioned features of using organic redox species are low cost and increased flexibility with respect to tailoring redox potential and solubility from molecular engineering of side groups on the organic redox-active species. In this paper 33, mainly quinone-based, compounds are studied experimentially in terms of pH dependent redox potential, solubility and stability, combined with single cell battery RFB tests on selected redox pairs. Data shows that both the solubility and redox potential are determined by the position of the side groups and only to a small extent by the number of side groups. Additionally, the chemical stability and possible degradation mechanisms leading to capacity loss over time are discussed. The main challenge for the development of all-organic RFBs is to identify a redox pair for the positive side with sufficiently high stability and redox potential that enables battery cell potentials above 1 V. PMID- 27966604 TI - Endogenous programmed death ligand-1 restrains the development and onset of Sjogren's syndrome in non-obese diabetic mice. AB - Programmed death-ligand 1 (PD-L1) down-modulates various immune responses by engaging the co-inhibitory receptor programmed death-1. Expression of PD-L1 and programmed death-1 is elevated in the salivary glands of patients with Sjogren's syndrome (SS). The objective of this study is to define the role of endogenous PD L1 in SS pathogenesis in non-obese diabetic (NOD) mouse model of this disease. We inhibited endogenous PD-L1 function by intraperitoneal administration of a blocking antibody to 6 week-old female NOD/ShiLtJ mice repeatedly during a 9-day period. PD-L1 blockade accelerated leukocyte infiltration and caspase-3 activation in the submandibular gland (SMG), production of antinuclear and anti M3 muscarinic acetylcholine receptor (M3R) autoantibodies and impairment of saliva secretion, indicative of accelerated development and onset of SS. The effect of PD-L1 blockade was associated with increased T- and B cells and T helper 1 cytokine IFN-gamma in the SMG. Local administration of exogenous IFN gamma to the SMG led to impaired salivary secretion accompanied by down regulation of aquaporin 5 and an increase in anti-M3R autoantibodies. Conversely, neutralization of IFN-gamma markedly improved salivary secretion and aquaporin 5 expression in anti-PD-L1-treated NOD/ShiLtJ mice. Hence, endogenous PD-L1 hinders the development and onset of SS in NOD mice, in part by suppressing IFN-gamma production. PMID- 27966606 TI - Enhanced Lithium Storage in Hierarchically Porous Carbon Derived from Waste Tea Leaves. AB - In this study, highly nanoporous carbon (HCl-TW-Car) was successfully synthesized using a facile procedure combining acid treatment with a carbonization process that uses waste tea leaves from spent tea bags as raw materials. The acid treatment not only promotes the efficient removal of unnecessary inorganic impurities but also increases the product porosity to enable synthesis of hierarchically porous carbon materials with various micro-, meso-, and macropores. When used as an anode material for lithium-ion batteries, HCl-TW-Car demonstrated a much higher discharge capacity than is theoretically possible using graphite [479 mAh g-1 after the 200th cycle at a rate of 0.2C (1C = 372 mA g-1)] and exhibited greater rate capabilities compared with those of carbonated products from tea waste without acid treatment. It was shown that the good electrochemical properties of HCl-TW-Car can be ascribed to large Brunauer-Emmett Teller (BET) surface area, well-formed hierarchical pores, and the prevention of unexpected electrochemical reactions from the reduction of metallic atoms. PMID- 27966607 TI - Host cell surfaces induce a Type IV pili-dependent alteration of bacterial swimming. AB - For most pathogenic bacteria, flagellar motility is recognized as a virulence factor. Here, we analysed the swimming behaviour of bacteria close to eukaryotic cellular surfaces, using the major opportunistic pathogen Pseudomonas aeruginosa as a model. We delineated three classes of swimming trajectories on both cellular surfaces and glass that could be differentiated by their speeds and local curvatures, resulting from different levels of hydrodynamic interactions with the surface. Segmentation of the trajectories into linear and curved sections or pause allowed us to precisely describe the corresponding swimming patterns near the two surfaces. We concluded that (i) the trajectory classes were of same nature on cells and glass, however the trajectory distribution was strikingly different between surface types, (ii) on cell monolayers, a larger fraction of bacteria adopted a swimming mode with stronger bacteria-surface interaction mostly dependent upon Type IV pili. Thus, bacteria swim near boundaries with diverse patterns and importantly, Type IV pili differentially influence swimming near cellular and abiotic surfaces. PMID- 27966608 TI - Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma. AB - Osteosarcoma is the most common primary bone tumor, with metastatic disease responsible for most treatment failure and patient death. A forward genetic screen utilizing Sleeping Beauty mutagenesis in mice previously identified potential genetic drivers of osteosarcoma metastasis, including Slit-Robo GTPase Activating Protein 2 (Srgap2). This study evaluates the potential role of SRGAP2 in metastases-associated properties of osteosarcoma cell lines through Srgap2 knockout via the CRISPR/Cas9 nuclease system and conditional overexpression in the murine osteosarcoma cell lines K12 and K7M2. Proliferation, migration, and anchorage independent growth were evaluated. RNA sequencing and immunohistochemistry of human osteosarcoma tissue samples were used to further evaluate the potential role of the Slit-Robo pathway in osteosarcoma. The effects of Srgap2 expression modulation in the murine OS cell lines support the hypothesis that SRGAP2 may have a role as a suppressor of metastases in osteosarcoma. Additionally, SRGAP2 and other genes in the Slit-Robo pathway have altered transcript levels in a subset of mouse and human osteosarcoma, and SRGAP2 protein expression is reduced or absent in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in osteosarcoma metastasis, with loss of SRGAP2 potentially contributing to a more aggressive phenotype. PMID- 27966609 TI - Symbiont-derived sphingolipids modulate mucosal homeostasis and B cells in teleost fish. AB - Symbiotic bacteria and mucosal immunoglobulins have co-evolved for millions of years in vertebrate animals. Symbiotic bacteria products are known to modulate different aspects of the host immune system. We recently reported that Flectobacillus major is a predominant species that lives in the gill and skin mucosal surfaces of rainbow trout (Oncorhynchus mykiss). F. major is known to produce sphingolipids of a unique molecular structure. Here we propose a role for F. major and its sphingolipids in the regulation of B cell populations in rainbow trout, as well as an essential role for sphingolipids in trout mucosal homeostasis. We found that F. major-specific IgT titers are confined to the gill and skin mucus, whereas F. major-specific IgM titers are only detected in serum. Live F. major cells are able to stimulate sustained IgT expression and secretion in gills. F. major sphingolipids modulate the growth of trout total skin and gill symbiotic bacteria. In vivo systemic administration of F. major sphingolipids changes the proportion of IgT+ to IgM+ B cells in trout HK. These results demonstrate the key role of the symbiont F. major and its sphingolipids in mucosal homeostasis via the modulation of mucosal and systemic Igs and B cells. PMID- 27966611 TI - Identification of Development-Related Genes in the Ovaries of Adult Harmonia axyridis (Pallas) Lady Beetles Using a Time- Series Analysis by RNA-seq. AB - Adults of the lady beetle species Harmonia axyridis (Pallas) are bred artificially en masse for classic biological control, which requires egg-laying by the H. axyridis ovary. Development-related genes may impact the growth of the H. axyridis adult ovary but have not been reported. Here, we used integrative time-series RNA-seq analysis of the ovary in H. axyridis adults to detect development-related genes. A total of 28,558 unigenes were functionally annotated using seven types of databases to obtain an annotated unigene database for ovaries in H. axyridis adults. We also analysed differentially expressed genes (DEGs) between samples. Based on a combination of the results of this bioinformatics analysis with literature reports and gene expression level changes in four different stages, we focused on the development of oocyte reproductive stem cell and yolk formation process and identified 26 genes with high similarity to development-related genes. 20 DEGs were randomly chosen for quantitative real time PCR (qRT-PCR) to validate the accuracy of the RNA-seq results. This study establishes a robust pipeline for the discovery of key genes using high throughput sequencing and the identification of a class of development-related genes for characterization. PMID- 27966610 TI - Molecular mechanism: the human dopamine transporter histidine 547 regulates basal and HIV-1 Tat protein-inhibited dopamine transport. AB - Abnormal dopaminergic transmission has been implicated as a risk determinant of HIV-1-associated neurocognitive disorders. HIV-1 Tat protein increases synaptic dopamine (DA) levels by directly inhibiting DA transporter (DAT) activity, ultimately leading to dopaminergic neuron damage. Through integrated computational modeling prediction and experimental validation, we identified that histidine547 on human DAT (hDAT) is critical for regulation of basal DA uptake and Tat-induced inhibition of DA transport. Compared to wild type hDAT (WT hDAT), mutation of histidine547 (H547A) displayed a 196% increase in DA uptake. Other substitutions of histidine547 showed that DA uptake was not altered in H547R but decreased by 99% in H547P and 60% in H547D, respectively. These mutants did not alter DAT surface expression or surface DAT binding sites. H547 mutants attenuated Tat-induced inhibition of DA transport observed in WT hDAT. H547A displays a differential sensitivity to PMA- or BIM-induced activation or inhibition of DAT function relative to WT hDAT, indicating a change in basal PKC activity in H547A. These findings demonstrate that histidine547 on hDAT plays a crucial role in stabilizing basal DA transport and Tat-DAT interaction. This study provides mechanistic insights into identifying targets on DAT for Tat binding and improving DAT-mediated dysfunction of DA transmission. PMID- 27966612 TI - Sex differences in number processing: Differential systems for subtraction and multiplication were confirmed in men, but not in women. AB - Neuroimaging studies suggest segregated neuronal systems underlying number magnitude processing (e.g. subtraction) and arithmetic fact retrieval (e.g. multiplication). While number magnitude processing is thought to rely on the intraparietal sulcus (IPS) bilaterally, arithmetic fact retrieval is thought to rely on the left angular gyrus (AG). However, evidence from brain damaged patients and brain stimulation challenges this view and suggests considerable overlap between the systems underlying number magnitude processing and arithmetic fact retrieval. This study investigates, whether sex differences in number processing can account for these conflicting findings. A subtraction and a multiplication task were administered to 40 men and 34 women in their luteal phase during functional MRI. Replicating previous studies in men, we found the IPS to be more strongly activated during subtraction than multiplication, and the AG to be more strongly activated during multiplication than subtraction. However, no differences between the two tasks were observed in women. PMID- 27966613 TI - Spreading to localized targets in complex networks. AB - As an important type of dynamics on complex networks, spreading is widely used to model many real processes such as the epidemic contagion and information propagation. One of the most significant research questions in spreading is to rank the spreading ability of nodes in the network. To this end, substantial effort has been made and a variety of effective methods have been proposed. These methods usually define the spreading ability of a node as the number of finally infected nodes given that the spreading is initialized from the node. However, in many real cases such as advertising and news propagation, the spreading only aims to cover a specific group of nodes. Therefore, it is necessary to study the spreading ability of nodes towards localized targets in complex networks. In this paper, we propose a reversed local path algorithm for this problem. Simulation results show that our method outperforms the existing methods in identifying the influential nodes with respect to these localized targets. Moreover, the influential spreaders identified by our method can effectively avoid infecting the non-target nodes in the spreading process. PMID- 27966616 TI - Bell's Nonlocality Can be Detected by the Violation of Einstein-Podolsky-Rosen Steering Inequality. AB - Recently quantum nonlocality has been classified into three distinct types: quantum entanglement, Einstein-Podolsky-Rosen steering, and Bell's nonlocality. Among which, Bell's nonlocality is the strongest type. Bell's nonlocality for quantum states is usually detected by violation of some Bell's inequalities, such as Clause-Horne-Shimony-Holt inequality for two qubits. Steering is a manifestation of nonlocality intermediate between entanglement and Bell's nonlocality. This peculiar feature has led to a curious quantum phenomenon, the one-way Einstein-Podolsky-Rosen steering. The one-way steering was an important open question presented in 2007, and positively answered in 2014 by Bowles et al., who presented a simple class of one-way steerable states in a two-qubit system with at least thirteen projective measurements. The inspiring result for the first time theoretically confirms quantum nonlocality can be fundamentally asymmetric. Here, we propose another curious quantum phenomenon: Bell nonlocal states can be constructed from some steerable states. This novel finding not only offers a distinctive way to study Bell's nonlocality without Bell's inequality but with steering inequality, but also may avoid locality loophole in Bell's tests and make Bell's nonlocality easier for demonstration. Furthermore, a nine setting steering inequality has also been presented for developing more efficient one-way steering and detecting some Bell nonlocal states. PMID- 27966615 TI - The hepatic and skeletal muscle ovine metabolomes as affected by weight loss: a study in three sheep breeds using NMR-metabolomics. AB - Sheep are a valuable resource for meat and wool production. During the dry summer, pastures are scarce and animals face Seasonal Weight Loss (SWL), which decreases production yields. The study of breeds tolerant to SWL is important to understand the physiological mechanisms of tolerance to nutritional scarcity, and define breeding strategies. Merino, Damara and Dorper sheep breeds have been described as having different levels of tolerance to SWL. In this work, we assess their liver and muscle metabolomes, and compare the responses to feed restriction. Ram lambs from each breed were divided into growth and feed restricted groups, over 42 days. Tissue metabolomes were assessed by 1H-NMR. The Dorper restricted group showed few changes in both tissues, suggesting higher tolerance to nutritional scarcity. The Merinos exhibited more differences between treatment groups. Major differences were related to fat and protein mobilization, and antioxidant activity. Between the Damara groups, the main differences were observed in amino acid composition in muscle and in energy-related pathways in the liver. Integration of present results and previous data on the same animals support the hypothesis that, Dorper and Damara breeds are more tolerant to SWL conditions and thus, more suitable breeds for harsh environmental conditions. PMID- 27966614 TI - Imbalanced positive selection maintains the functional divergence of duplicated DIHYDROKAEMPFEROL 4-REDUCTASE genes. AB - Gene duplication could be beneficial by functional division but might increase the risk of genetic load. The dynamics of duplicated paralogs number could involve recombination, positive selection, and functional divergence. Duplication of DIHYDROFLAVONOL 4-REDUCTASE (DFR) has been reported in several organisms and may have been retained by escape from adaptive conflict (EAC). In this study, we screened the angiosperm DFR gene focusing on a diversified genus Scutellaria to investigate how these duplicated genes are retained. We deduced that gene duplication involved multiple independent events in angiosperms, but the duplication of DFR was before the divergence of Scutellaria. Asymmetric positive selective pressures resulted in different evolutionary rates between the duplicates. Different numbers of regulatory elements, differential codon usages, radical amino acid changes, and differential gene expressions provide evidences of functional divergence between the two DFR duplicates in Scutellaria, implying adaptive subfunctionalization between duplicates. The discovery of pseudogenes accompanying a reduced replacement rate in one DFR paralogous gene suggested possibly leading to "loss of function" due to dosage imbalance after the transient adaptive subfunctionalization in the early stage of duplication. Notwithstanding, episodic gene duplication and functional divergence may be relevant to the diversification of ecological function of DFR gene in Scutellaria. PMID- 27966618 TI - Restoration of clipped seismic waveforms using projection onto convex sets method. AB - The seismic waveforms would be clipped when the amplitude exceeds the upper-limit dynamic range of seismometer. Clipped waveforms are typically assumed not useful and seldom used in waveform-based research. Here, we assume the clipped components of the waveform share the same frequency content with the un-clipped components. We leverage this similarity to convert clipped waveforms to true waveforms by iteratively reconstructing the frequency spectrum using the projection onto convex sets method. Using artificially clipped data we find that statistically the restoration error is ~1% and ~5% when clipped at 70% and 40% peak amplitude, respectively. We verify our method using real data recorded at co located seismometers that have different gain controls, one set to record large amplitudes on scale and the other set to record low amplitudes on scale. Using our restoration method we recover 87 out of 93 clipped broadband records from the 2013 Mw6.6 Lushan earthquake. Estimating that we recover 20 clipped waveforms for each M5.0+ earthquake, so for the ~1,500 M5.0+ events that occur each year we could restore ~30,000 clipped waveforms each year, which would greatly enhance useable waveform data archives. These restored waveform data would also improve the azimuthal station coverage and spatial footprint. PMID- 27966617 TI - Multivalent pIX phage display selects for distinct and improved antibody properties. AB - Phage display screening readily allows for the identification of a multitude of antibody specificities, but to identify optimal lead candidates remains a challenge. Here, we direct the antibody-capsid fusion away from the signal sequence-dependent secretory SEC pathway in E. coli by utilizing the intrinsic signal sequence-independent property of pIX to obtain virion integration. This approach was combined with the use of an engineered helper phage known to improve antibody pIX display and retrieval. By direct comparison with pIII display, we demonstrate that antibody display using this pIX system translates into substantially improved retrieval of desired specificities with favorable biophysical properties in de novo selection. We show that the effect was due to less E. coli host toxicity during phage propagation conferred by the lack of a signal sequence. This pIX combinatorial display platform provides a generic alternative route for obtaining good binders with high stability and may thus find broad applicability. PMID- 27966621 TI - Exceptionally omnidirectional broadband light harvesting scheme for multi junction concentrator solar cells achieved via ZnO nanoneedles. AB - GaInP/GaAs/Ge triple-junction concentrator solar cells with significant efficiency enhancement were demonstrated with antireflective ZnO nanoneedles. The novel nanostructure was attained with a Zn(NO3)2-based solution containing vitamin C. Under one sun AM 1.5G solar spectrum, conversion efficiency of the triple-junction device was improved by 23.7% via broadband improvement in short circuit currents of 3 sub-cells after the coverage by the nanoneedles with a graded refractive index profile. The efficiency enhancement further went up to 45.8% at 100 suns. The performance boost through the nanoneedles also became increasingly pronounced in the conditions of high incident angles and the cloudy weather, e.g. 220.0% of efficiency enhancement was observed at the incident angle of 60 degrees . These results were attributed to the exceptional broadband omnidirectionality of the antireflective nanoneedles. PMID- 27966619 TI - NLRP3 inflammasome has a protective effect against oxazolone-induced colitis: a possible role in ulcerative colitis. AB - The inflammasomes induce maturation of pro-interleukin-1beta (IL-1beta) and pro IL-18. We investigated roles of the NLRP3 inflammasome in the pathogenesis of ulcerative colitis (UC). After induction of oxazolone-induced colitis, a mouse UC model, colonic tissues were assayed for inflammatory mediators. Histological studies were performed on inflamed colonic tissue from mice and UC patients. Histological severity of murine colitis peaked on day 1, accompanied by an increase in the expression of Th2 cytokines including IL-4 and IL-13. Oxazolone treatment stimulated maturation of pro-caspase-1 and pro-IL-1beta, while it reduced IL-18 expression. Either exogenous IL-1beta or IL-18 ameliorated the colitis with or without reduction in Th2 cytokine expression, respectively. Induction of colitis decreased MUC2 expression, which was reversed by administration of IL-18, but not IL-1beta. Compared to wild-type mice, NLRP3-/- mice exhibited higher sensitivity to oxazolone treatment with enhancement of Th2 cytokine expression and reduction of mature IL-1beta and IL-18 production; this phenotype was rescued by exogenous IL-1beta or IL-18. Immunofluorescent studies revealed positive correlation of NLRP3 expression with disease severity in UC patients, and localization of the inflammasome-associated molecules in macrophages. The NLRP3 inflammasome-derived IL-1beta and IL-18 may play a protective role against UC through different mechanisms. PMID- 27966622 TI - Harman Measurements for Thermoelectric Materials and Modules under Non-Adiabatic Conditions. AB - Accuracy of the Harman measurement largely depends on the heat transfer between the sample and its surroundings, so-called parasitic thermal effects (PTEs). Similar to the material evaluations, measuring thermoelectric modules (TEMs) is also affected by the PTEs especially when measuring under atmospheric condition. Here, we study the correction methods for the Harman measurements with systematically varied samples (both bulk materials and TEMs) at various conditions. Among several PTEs, the heat transfer via electric wires is critical. Thus, we estimate the thermal conductance of the electric wires, and correct the measured properties for a certain sample shape and measuring temperature. The PTEs are responsible for the underestimation of the TEM properties especially under atmospheric conditions (10-35%). This study will be useful to accurately characterize the thermoelectric properties of materials and modules. PMID- 27966620 TI - Reduced activation in isometric muscle action after lengthening contractions is not accompanied by reduced performance fatigability. AB - After active lengthening contractions, a given amount of force can be maintained with less muscle activation compared to pure isometric contractions at the same muscle length and intensity. This increase in neuromuscular efficiency is associated with mechanisms of stretch-induced residual force enhancement. We hypothesized that stretch-related increase in neuromuscular efficiency reduces fatigability of a muscle during submaximal contractions. 13 subjects performed 60 s isometric knee extensions at 60% of maximum voluntary contraction (MVC) with and without prior stretch (60 degrees /s, 20 degrees ). Each 60 s trial was preceded and followed by neuromuscular tests consisting of MVCs, voluntary activation (VA) and resting twitches (RT), and there was 4 h rest between sets. We found a significant (p = 0.036) 10% reduction of quadriceps net-EMG after lengthening compared to pure isometric trials. However, increase in neuromuscular efficiency did not influence the development of fatigue. Albeit we found severe reduction of MVC (30%), RT (30%) and VA (5%) after fatiguing trials, there were no differences between conditions with and without lengthening. As the number of subjects showing no activation reduction increased with increasing contraction time, intensity may have been too strenuous in both types of contractions, such that a distinction between different states of fatigue was not possible anymore. PMID- 27966623 TI - Hybrid microscaffold-based 3D bioprinting of multi-cellular constructs with high compressive strength: A new biofabrication strategy. AB - A hybrid 3D bioprinting approach using porous microscaffolds and extrusion-based printing method is presented. Bioink constitutes of cell-laden poly(D,L-lactic-co glycolic acid) (PLGA) porous microspheres with thin encapsulation of agarose collagen composite hydrogel (AC hydrogel). Highly porous microspheres enable cells to adhere and proliferate before printing. Meanwhile, AC hydrogel allows a smooth delivery of cell-laden microspheres (CLMs), with immediate gelation of construct upon printing on cold build platform. Collagen fibrils were formed in the AC hydrogel during culture at body temperature, improving the cell affinity and spreading compared to pure agarose hydrogel. Cells were proven to proliferate in the bioink and the bioprinted construct. High cell viability up to 14 days was observed. The compressive strength of the bioink is more than 100 times superior to those of pure AC hydrogel. A potential alternative in tissue engineering of tissue replacements and biological models is made possible by combining the advantages of the conventional solid scaffolds with the new 3D bioprinting technology. PMID- 27966624 TI - Transportation dynamics on coupled networks with limited bandwidth. AB - The communication networks in real world often couple with each other to save costs, which results in any network does not have a stand-alone function and efficiency. To investigate this, in this paper we propose a transportation model on two coupled networks with bandwidth sharing. We find that the free-flow state and the congestion state can coexist in the two coupled networks, and the free flow path and congestion path can coexist in each network. Considering three bandwidth-sharing mechanisms, random, assortative and disassortative couplings, we also find that the transportation capacity of the network only depends on the coupling mechanism, and the fraction of coupled links only affects the performance of the system in the congestion state, such as the traveling time. In addition, with assortative coupling, the transportation capacity of the system will decrease significantly. However, the disassortative coupling has little influence on the transportation capacity of the system, which provides a good strategy to save bandwidth. Furthermore, a theoretical method is developed to obtain the bandwidth usage of each link, based on which we can obtain the congestion transition point exactly. PMID- 27966625 TI - The Spatial Relationship of Malignant and Benign Breast Lesions with Respect to the Fat-Gland Interface on Magnetic Resonance Imaging. AB - The fat-gland interface in the breast is noteworthy in that major vessels and lymphatic channels supplying the breast are located there; however, the relationship between breast lesion formation and the fat-gland interface is poorly understood. Here we evaluate the location of malignant and benign breast lesions with respect to the fat-gland interface in 881 women 50 years of age and younger, utilizing MR imaging. We find that most breast lesions are located in or near the interface in qualitative (89.7%) and quantitative (90.0%, 1 cm within the interface) analyses. This propensity for the fat-gland interface is not accounted for by breast anatomy, whereby 12.3% and 55.7% of breast volume is within 2 mm and 1 cm of the interface, respectively. Malignant lesions were located in or near the interface in significantly higher proportions than benign lesions in qualitative (94.3% vs. 67.3%, P < 0.001) and quantitative (49.7% vs. 34.5%, P < 0.001, 2 mm within the interface) analyses. This phenomenon may reflect a biological importance of the fat-gland interface in breast cancer development and progression. PMID- 27966626 TI - PD-L1+MDSCs are increased in HCC patients and induced by soluble factor in the tumor microenvironment. AB - Myeloid-derived suppressor cells (MDSCs) could have important roles in immune regulation, and MDSCs can be induced in patients with various malignant tumors. The immune-suppressive functions of MDSCs in hepatocellular carcinoma (HCC) patients have not been clarified. Therefore, we tried to analyze the biological significance of MDSCs in HCC patients. We quantified PD-L1+MDSCs of HCC patients in various conditions by using multi-color flow cytometry analysis. PBMCs from HCC patients contained significantly higher percentages of PD-L1+MDSCs in comparison to those from healthy subjects (p < 0.001). The percentages of PD L1+MDSCs were reduced by curative treatment for HCC (p < 0.05), and the percentages of PD-L1+MDSCs before treatment were inversely correlated with disease-free survival time. After we cocultivated PBMCs and several liver cancer cell lines in a transwell coculture system, the percentages of PD-L1+MDSCs were significantly increased compared with control (p < 0.05). The expression of M-CSF and VEGFA was higher in the cell lines that strongly induced PD-L1+MDSCs. Peripheral blood from HCC patients had significantly higher percentages of PD L1+MDSCs in comparison to those of healthy subjects, and the percentages of PD L1+MDSCs were reduced by HCC treatment, suggesting that we might use PD-L1+MDSCs as a new biomarker of HCC. PMID- 27966627 TI - Design and evaluation of primers targeting genes encoding NO-forming nitrite reductases: implications for ecological inference of denitrifying communities. AB - The detection of NO-forming nitrite reductase genes (nir) has become the standard when studying denitrifying communities in the environment, despite well-known amplification biases in available primers. We review the performance of 35 published and 121 newly designed primers targeting the nirS and nirK genes, against sequences from complete genomes and 47 metagenomes from three major habitats where denitrification is important. There were no optimal universal primer pairs for either gene, although published primers targeting nirS displayed up to 75% coverage. The alternative is clade-specific primers, which show a trade off between coverage and specificity. The test against metagenomic datasets showed a distinct performance of primers across habitats. The implications of clade-specific nir primers choice and their performance for ecological inference when used for quantitative estimates and in sequenced-based community ecology studies are discussed and our phylogenomic primer evaluation can be used as a reference along with their environmental specificity as a guide for primer selection. Based on our results, we also propose a general framework for primer evaluation that emphasizes the testing of coverage and phylogenetic range using full-length sequences from complete genomes, as well as accounting for environmental range using metagenomes. This framework serves as a guideline to simplify primer performance comparisons while explicitly addressing the limitations and biases of the primers evaluated. PMID- 27966629 TI - Pt-Bi decorated nanoporous gold for high performance direct glucose fuel cell. AB - Binary PtBi decorated nanoporous gold (NPG-PtBi) electrocatalyst is specially designed and prepared for the anode in direct glucose fuel cells (DGFCs). By using electroless and electrochemical plating methods, a dense Pt layer and scattered Bi particles are sequentially coated on NPG. A simple DGFC with NPG PtBi as anode and commercial Pt/C as cathode is constructed and operated to study the effect of operating temperatures and concentrations of glucose and NaOH. With an anode noble metal loading of only 0.45 mg cm-2 (Au 0.3 mg and Pt 0.15 mg), an open circuit voltage (OCV) of 0.9 V is obtained with a maximum power density of 8 mW cm-2. Furthermore, the maximum gravimetric power density of NPG-PtBi is 18 mW mg-1, about 4.5 times higher than that of commercial Pt/C. PMID- 27966628 TI - Genes essential for the morphogenesis of the Shiga toxin 2-transducing phage from Escherichia coli O157:H7. AB - Shiga toxin 2 (Stx2), one of the most important virulence factors of enterohaemorrhagic Escherichia coli (EHEC), is encoded by phages. These phages (Stx2 phages) are often called lambda-like. However, most Stx2 phages are short tailed, thus belonging to the family Podoviridae, and the functions of many genes, especially those in the late region, are unknown. In this study, we performed a systematic genetic and morphological analysis of genes with unknown functions in Sp5, the Stx2 phage from EHEC O157:H7 strain Sakai. We identified nine essential genes, which, together with the terminase genes, determine Sp5 morphogenesis. Four of these genes most likely encoded portal, major capsid, scaffolding and tail fiber proteins. Although exact roles/functions of the other five genes are unknown, one was involved in head formation and four were required for tail formation. One of the four tail genes encoded an unusually large protein of 2,793 amino-acid residues. Two genes that are likely required to maintain the lysogenic state were also identified. Because the late regions of Stx2 phages from various origins are highly conserved, the present study provides an important basis for better understanding the biology of this unique and medically important group of bacteriophages. PMID- 27966630 TI - Arsenic resistance strategy in Pantoea sp. IMH: Organization, function and evolution of ars genes. AB - Pantoea sp. IMH is the only bacterium found in genus Pantoea with a high As resistance capacity, but its molecular mechanism is unknown. Herein, the organization, function, and evolution of ars genes in IMH are studied starting with analysis of the whole genome. Two ars systems - ars1 (arsR1B1C1H1) and ars2 (arsR2B2C2H2) - with low sequence homology and two arsC-like genes, were found in the IMH genome. Both ars1 and ars2 are involved in the As resistance, where ars1 is the major contributor at 15 degrees C and ars2 at 30 degrees C. The difference in the behavior of these two ars systems is attributed to the disparate activities of their arsR promoters at different temperatures. Sequence analysis based on concatenated ArsRBC indicates that ars1 and ars2 clusters may be acquired from Franconibacter helveticus LMG23732 and Serratia marcescens (plasmid R478), respectively, by horizontal gene transfer (HGT). Nevertheless, two arsC-like genes, probably arising from the duplication of arsC, do not contribute to the As resistance. Our results indicate that Pantoea sp. IMH acquired two different As resistance genetic systems by HGT, allowing the colonization of changing ecosystems, and highlighting the flexible adaptation of microorganisms to resist As. PMID- 27966631 TI - Water photolysis effect on the long-term stability of a fiber optic hydrogen sensor with Pt/WO3. AB - One of the technological challenges for hydrogen sensors is long-term stability and reliability. In this article, the UV-light irradiation was introduced into the hydrogen sensing process based on water photolysis effect of Pt/WO3. Ascribing to that, fiber optic hydrogen sensor with Pt/WO3 nanosheets as the sensing element was demonstrated with significantly improved performance of stability. Under UV irradiation, the hydrogen sensor exhibits higher sensitivity and resolution together with a smaller error range than that without UV irradiation. The enhanced performance could be attributed to the effective decomposition of water produced in the hydrogen sensing process due to the water photolysis effect of Pt/WO3. The influence of the water on stability was evaluated using experimental results, and the UV irradiation to remove water was analysed by theoretical and FT-IR spectra. This work provides new strategy of UV light irradiation to promote the long-term stability of hydrogen sensor using Pt/WO3 as the sensing element. PMID- 27966633 TI - Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations. AB - Congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for 90 95% of CAH cases. In this work we performed an extensive survey of mutations and SNPs modifying the coding sequence of the CYP21A2 gene. Using bioinformatic tools and two plausible CYP21A2 structures as templates, we initially classified all known mutants (n = 343) according to their putative functional impacts, which were either reported in the literature or inferred from structural models. We then performed a detailed analysis on the subset of mutations believed to exclusively impact protein stability. For those mutants, the predicted stability was calculated and correlated with the variant's expected activity. A high concordance was obtained when comparing our predictions with available in vitro residual activities and/or the patient's phenotype. The predicted stability and derived activity of all reported mutations and SNPs lacking functional assays (n = 108) were assessed. As expected, most of the SNPs (52/76) showed no biological implications. Moreover, this approach was applied to evaluate the putative synergy that could emerge when two mutations occurred in cis. In addition, we propose a putative pathogenic effect of five novel mutations, p.L107Q, p.L122R, p.R132H, p.P335L and p.H466fs, found in 21-hydroxylase deficient patients of our cohort. PMID- 27966632 TI - Surfactin inducing mitochondria-dependent ROS to activate MAPKs, NF-kappaB and inflammasomes in macrophages for adjuvant activity. AB - Surfactin, a natural lipopeptide, can be used both as parenteral and non parenteral adjuvant for eliciting immune response. However, the mechanisms that confer its adjuvant properties have not been fully explored. By staining with NHS Rhodamine B labeled surfactin and Mito-Tracker Green, we found surfactin could penetrate into macrophages to bind with mitochondria, following induce ROS that could be inhibited by mitochondria-dependent ROS inhibitor. ROS enhanced p38 MAPK and JNK expression, as well their phorsphorylation, following activated NF-kappaB nuclear translocation in macrophages that was obviously inhibited by mitochondria dependent ROS inhibitor. However, inhibition of ROS production only weakened p38 MAPK and JNK expression, but not their phosphorylation in macrophages. As a result, surfaction could activate NF-kappaB to release TNF-alpha by the mitochondria-dependent ROS signalling pathway. ROS also induced macrophages apoptosis to release endogenous danger signals, following activated inflammasomes of NLRP1, NLRP3, IPAF and AIM2 in vitro and only NLRP1 in vivo, as well caspase-1 and IL-1 in macrophages, which were significantly inhibited by pre-treatment with ROS inhibitors. Collectively, surfactin as a kind of non-pathogen-associated molecular patterns, modulates host innate immunity by multiple signalling pathways, including induction of mitochondria-dependent ROS, activating MAPKs and NF-kappaB, and inducing cell apoptosis to realease endogenous danger signals for activation of inflammasomes. PMID- 27966634 TI - The impact of zinc oxide nanoparticles on the bacterial microbiome of activated sludge systems. AB - The expected growth in nanomaterial applications could result in increased amounts of nanoparticles entering municipal sewer systems, eventually ending up in wastewater treatment plants and therefore negatively affecting microbial populations and biological nutrient removal. The aim of this study was to ascertain the impact of zinc oxide nanoparticles (nZnO) on the bacterial microbiome of an activated sludge system. A metagenomic approach combined with the latest generation Illumina MiSeq platform and RDP pipeline tools were used to identify and classify the bacterial microbiome of the sludge. Results revealed a drastic decrease in the number of operational taxonomic units (OTUs) from 27 737 recovered in the nZnO-free sample to 23 743, 17 733, and 13 324 OTUs in wastewater samples exposed to various concentrations of nZnO (5, 10 and 100 mg/L nZnO, respectively). These represented 12 phyla, 21 classes, 30 orders, 54 families and 51 genera, completely identified at each taxonomic level in the control samples; 7-15-25-28-20 for wastewater samples exposed to 5 mg/L nZnO; 9 15-24-31-23 for those exposed to 10 mg/L and 7-11-19-26-17 for those exposed 100 mg/L nZnO. A large number of sequences could not be assigned to specific taxa, suggesting a possibility of novel species to be discovered. PMID- 27966636 TI - Epidemiology of two human protoparvoviruses, bufavirus and tusavirus. AB - Two human parvoviruses were recently discovered by metagenomics in Africa, bufavirus (BuV) in 2012 and tusavirus (TuV) in 2014. These viruses have been studied exclusively by PCR in stool and detected only in patients with diarrhoea, although at low prevalence. Three genotypes of BuV have been identified. We detected, by in-house EIA, BuV1-3 IgG antibodies in 7/228 children (3.1%) and 10/180 adults (5.6%), whereas TuV IgG was found in one child (0.4%). All children and 91% of the adults were Finnish, yet interestingly 3/6 adults of Indian origin were BuV-IgG positive. By competition EIA, no cross-reactivity between the BuVs was detected, indicating that the BuV genotypes represent distinct serotypes. Furthermore, we analysed by BuV qPCR stool and nasal swab samples from 955 children with gastroenteritis, respiratory illness, or both, and found BuV DNA in three stools (0.3%) and for the first time in a nasal swab (0.1%). This is the first study documenting the presence of BuV and TuV antibodies in humans. Although the seroprevalences of both viruses were low in Finland, our results indicate that BuV infections might be widespread in Asia. The BuV-specific humoral immune responses appeared to be strong and long-lasting, pointing to systemic infection in humans. PMID- 27966635 TI - Boosting Adaptive Immunity: A New Role for PAFR Antagonists. AB - We have previously shown that the Platelet-Activating Factor Receptor (PAFR) engagement in murine macrophages and dendritic cells (DCs) promotes a tolerogenic phenotype reversed by PAFR-antagonists treatment in vitro. Here, we investigated whether a PAFR antagonist would modulate the immune response in vivo. Mice were subcutaneously injected with OVA or OVA with PAFR-antagonist WEB2170 on days 0 and 7. On day 14, OVA-specific IgG2a and IgG1 were measured in the serum. The presence of WEB2170 during immunization significantly increased IgG2a without affecting IgG1 levels. When WEB2170 was added to OVA in complete Freund's adjuvant, enhanced IgG2a but not IgG1 production was also observed, and CD4+ FoxP3+ T cell frequency in the spleen was reduced compared to mice immunized without the antagonist. Similar results were observed in PAFR-deficient mice, along with increased Tbet mRNA expression in the spleen. Additionally, bone marrow-derived DCs loaded with OVA were transferred into naive mice and their splenocytes were co-cultured with fresh OVA-loaded DCs. CD4+ T cell proliferation was higher in the group transferred with DCs treated with the PAFR-antagonist. We propose that the activation of PAFR by ligands present in the site of immunization is able to fine-tune the adaptive immune response. PMID- 27966638 TI - Cumulative release characteristics of controlled-release nitrogen and potassium fertilizers and their effects on soil fertility, and cotton growth. AB - To investigate the interacting effects of polymer coated urea (PCU) and polymer coated potassium chloride (PCPC) on cotton growth, an experiment was conducted with containerized plants in 2014 and 2015. There were two kinds of nitrogen fertilizer, PCU and urea, which were combined with PCPC at three application rates (40, 80 and 120 kg ha-1). The kinds of nitrogen fertilizer formed the main plot, while individual rates of PCPC were the subplots. The results suggested N and K release patterns for PCU and PCPC in the soil were closely matched to the N and K requirements by cotton. Soil inorganic nitrogen contents significantly increased by using PCU instead of urea, and the same trend was observed with soil available potassium contents, which also had increased rates. Meanwhile, the number of bolls and lint yields of cotton in the PCU treatments were 4.9-35.3% and 2.9-40.7% higher than from urea treatments. Lint yields also increased by 9.1 12.7% with PCPC80 and PCPC120 treatments compared with PCPC40 treatment at the same nitrogen type. Hence, application of PCU combined with 80 kg ha-1 of PCPC fertilizer on cotton increased the yields and fertilizer use efficiencies in addition to improving fiber quality and delaying leaf senescence. PMID- 27966639 TI - Microwave-assisted cross-linking of milk proteins induced by microbial transglutaminase. AB - We investigated the combined effects of microbial transglutaminase (MTGase, 7.0 units/mL) and microwave irradiation (MI) on the polymerization of milk proteins at 30 degrees C for 3 h. The addition of MTGase caused the milk proteins to become polymerized, which resulted in the formation of components with a higher molecular-weight (>130 kDa). SDS-PAGE analysis revealed reductions in the protein content of beta-lactoglobulin (beta-LG), alphaS-casein (alphaS-CN), kappa-casein (kappa-CN) and beta-casein (beta-CN) to 50.4 +/- 2.9, 33.5 +/- 3.0, 4.2 +/- 0.5 and 1.2 +/- 0.1%, respectively. The use of MTGase in conjunction MI with led to a 3-fold increase in the rate of milk protein polymerization, compared to a sample that contained MTGase but did not undergo MI. Results of two-dimensional gel electrophoresis (2-DE) indicated that kappa-CN, beta-CN, a fraction of serum albumin (SA), beta-LG, alpha-lactalbumin (alpha-LA), alphas1-casein (alphas1-CN), and alphas2-casein (alphas2-CN) were polymerized in the milk, following incubation with MTGase and MI at 30 degrees C for 1 h. Based on this result, the combined use of MTGase and MI appears to be a better way to polymerize milk proteins. PMID- 27966637 TI - Particles from the Echinococcus granulosus laminated layer inhibit IL-4 and growth factor-driven Akt phosphorylation and proliferative responses in macrophages. AB - Proliferation of macrophages is a hallmark of inflammation in many type 2 settings including helminth infections. The cellular expansion is driven by the type 2 cytokine interleukin-4 (IL-4), as well as by M-CSF, which also controls homeostatic levels of tissue resident macrophages. Cystic echinococcosis, caused by the tissue-dwelling larval stage of the cestode Echinococcus granulosus, is characterised by normally subdued local inflammation. Infiltrating host cells make contact only with the acellular protective coat of the parasite, called laminated layer, particles of which can be ingested by phagocytic cells. Here we report that a particulate preparation from this layer (pLL) strongly inhibits the proliferation of macrophages in response to IL-4 or M-CSF. In addition, pLL also inhibits IL-4-driven up-regulation of Relm-alpha, without similarly affecting Chitinase-like 3 (Chil3/Ym1). IL-4-driven cell proliferation and up-regulation of Relm-alpha are both known to depend on the phosphatidylinositol (PI3K)/Akt pathway, which is dispensable for induction of Chil3/Ym1. Exposure to pLL in vitro inhibited Akt activation in response to proliferative stimuli, providing a potential mechanism for its activities. Our results suggest that the E. granulosus laminated layer exerts some of its anti-inflammatory properties through inhibition of PI3K/Akt activation and consequent limitation of macrophage proliferation. PMID- 27966640 TI - Trans-generational desensitization and within-generational resensitization of a sucrose-best neuron in the polyphagous herbivore Helicoverpa armigera (Lepidoptera: Noctuidae). AB - Dietary exposure of insects to a feeding deterrent substance for hours to days can induce habituation and concomitant desensitization of the response of peripheral gustatory neurons to such a substance. In the present study, larvae of the herbivore Helicoverpa armigera were fed on diets containing either a high, medium or low concentration of sucrose, a major feeding stimulant. The responsiveness of the sucrose-best neuron in the lateral sensilla styloconica on the galea was quantified. Results showed the response of the sucrose-best neuron exposed to high-sucrose diets decreased gradually over successive generations, resulting in complete desensitization in the 5th and subsequent generations. However, the sensitivity was completely restored in the ninth generation after neonate larvae were exposed to low-sucrose diet. These findings demonstrate phenotypic plasticity and exclude inadvertent artificial selection for low sensitivity to sucrose. No significant changes were found in the sensitivity of caterpillars which experienced low- or medium-sucrose diets over the same generations. Such desensitization versus re-sensitization did not generalise to the phagosimulant myo-inositol-sensitive neuron or the feeding deterrent sensitive neuron. Our results demonstrate that under conditions of high sucrose availability trans-generational desensitization of a neuron sensitive to this feeding stimulant becomes more pronounced whereas re-sensitization occurs within one generation. PMID- 27966641 TI - Resilin microjoints: a smart design strategy to avoid failure in dragonfly wings. AB - Dragonflies are fast and manoeuvrable fliers and this ability is reflected in their unique wing morphology. Due to the specific lightweight structure, with the crossing veins joined by rubber-like resilin patches, wings possess strong deformability but can resist high forces and large deformations during aerial collisions. The computational results demonstrate the strong influence of resilin containing vein joints on the stress distribution within the wing. The presence of flexible resilin in the contact region of the veins prevents excessive bending of the cross veins and significantly reduces the stress concentration in the joint. PMID- 27966643 TI - Simulated effects of nitrogen saturation on the global carbon budget using the IBIS model. AB - Over the past 100 years, human activity has greatly changed the rate of atmospheric N (nitrogen) deposition in terrestrial ecosystems, resulting in N saturation in some regions of the world. The contribution of N saturation to the global carbon budget remains uncertain due to the complicated nature of C-N (carbon-nitrogen) interactions and diverse geography. Although N deposition is included in most terrestrial ecosystem models, the effect of N saturation is frequently overlooked. In this study, the IBIS (Integrated BIosphere Simulator) was used to simulate the global-scale effects of N saturation during the period 1961-2009. The results of this model indicate that N saturation reduced global NPP (Net Primary Productivity) and NEP (Net Ecosystem Productivity) by 0.26 and 0.03 Pg C yr-1, respectively. The negative effects of N saturation on carbon sequestration occurred primarily in temperate forests and grasslands. In response to elevated CO2 levels, global N turnover slowed due to increased biomass growth, resulting in a decline in soil mineral N. These changes in N cycling reduced the impact of N saturation on the global carbon budget. However, elevated N deposition in certain regions may further alter N saturation and C-N coupling. PMID- 27966642 TI - Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation. AB - The objective of the present study was to assess the effect of elevating epoxygenated fatty acids on retinal vascular inflammation. To stimulate inflammation we utilized TNFalpha, a potent pro-inflammatory mediator that is elevated in the serum and vitreous of diabetic patients. In TNFalpha-stimulated primary human retinal microvascular endothelial cells, total levels of epoxyeicosatrienoic acids (EETs), but not epoxydocosapentaenoic acids (EDPs), were significantly decreased. Exogenous addition of 11,12-EET or 19,20-EDP when combined with 12-(3-adamantane-1-yl-ureido)-dodecanoic acid (AUDA), an inhibitor of epoxide hydrolysis, inhibited VCAM-1 and ICAM-1 expression and protein levels; conversely the diol product of 19,20-EDP hydrolysis, 19,20-DHDP, induced VCAM1 and ICAM1 expression. 11,12-EET and 19,20-EDP also inhibited leukocyte adherence to human retinal microvascular endothelial cell monolayers and leukostasis in an acute mouse model of retinal inflammation. Our results indicate that this inhibition may be mediated through an indirect effect on NFkappaB activation. This is the first study demonstrating a direct comparison of EET and EDP on vascular inflammatory endpoints, and we have confirmed a comparable efficacy from each isomer, suggesting a similar mechanism of action. Taken together, these data establish that epoxygenated fatty acid elevation will inhibit early pathology related to TNFalpha-induced inflammation in retinal vascular diseases. PMID- 27966644 TI - Restoration of foveal photoreceptors after intravitreal ranibizumab injections for diabetic macular edema. AB - Anti-vascular endothelial growth factor drugs are the first-line treatment for diabetic macular edema (DME), although the mechanism of the visual acuity (VA) improvement remains largely unknown. The association between photoreceptor damage and visual impairment encouraged us to retrospectively investigate the changes in the foveal photoreceptors in the external limiting membrane (ELM) and ellipsoid zone (EZ) on spectral-domain optical coherence tomography (SD-OCT) images in 62 eyes with DME treated with intravitreal ranibizumab (IVR) injections. The transverse lengths of the disrupted EZ and ELM were shortened significantly (P < 0.001 and P = 0.044, respectively) at 12 months. The qualitative investigation also showed restoration of the EZ and ELM lines on SD-OCT images. The EZ at 12 months lengthened in 34 of 38 eyes with discontinuous EZ and was preserved in 16 of 21 eyes with complete EZ at baseline. VA improvement was positively correlated with shortening of the disrupted EZ at 12 months (rho = 0.463, P < 0.001), whereas the decrease in central subfield thickness was associated with neither VA improvement nor changes in EZ status (rho = 0.215, P = 0.093 and (rho = 0.209, P = 0.103, respectively). These data suggested that photoreceptor restoration contributes to VA improvement after pro re nata treatment with IVR injections for DME independent of resolved retinal thickening. PMID- 27966646 TI - Insulin-induced Effects on the Subcellular Localization of AKT1, AKT2 and AS160 in Rat Skeletal Muscle. AB - AKT1 and AKT2, the AKT isoforms that are highly expressed in skeletal muscle, have distinct and overlapping functions, with AKT2 more important for insulin stimulated glucose metabolism. In adipocytes, AKT2 versus AKT1 has greater susceptibility for insulin-mediated redistribution from cytosolic to membrane localization, and insulin also causes subcellular redistribution of AKT Substrate of 160 kDa (AS160), an AKT2 substrate and crucial mediator of insulin-stimulated glucose transport. Although skeletal muscle is the major tissue for insulin mediated glucose disposal, little is known about AKT1, AKT2 or AS160 subcellular localization in skeletal muscle. The major aim of this study was to determine insulin's effects on the subcellular localization and phosphorylation of AKT1, AKT2 and AS160 in skeletal muscle. Rat skeletal muscles were incubated ex vivo +/ insulin, and differential centrifugation was used to isolate cytosolic and membrane fractions. The results revealed that: 1) insulin increased muscle membrane localization of AKT2, but not AKT1; 2) insulin increased AKT2 phosphorylation in the cytosol and membrane fractions; 3) insulin increased AS160 localization to the cytosol and membranes; and 4) insulin increased AS160 phosphorylation in the cytosol, but not membranes. These results demonstrate distinctive insulin effects on the subcellular redistribution of AKT2 and its substrate AS160 in skeletal muscle. PMID- 27966645 TI - Divergent topological architecture of the default mode network as a pretreatment predictor of early antidepressant response in major depressive disorder. AB - Identifying a robust pretreatment neuroimaging marker would be helpful for the selection of an optimal therapy for major depressive disorder (MDD). We recruited 82 MDD patients [n = 42 treatment-responsive depression (RD) and n = 40 non responding depression (NRD)] and 50 healthy controls (HC) for this study. Based on the thresholded partial correlation matrices of 58 specific brain regions, a graph theory approach was applied to analyse the topological properties. When compared to HC, both RD and NRD patients exhibited a lower nodal degree (Dnodal) in the left anterior cingulate gyrus; as for RD, the Dnodal of the left superior medial orbitofrontal gyrus was significantly reduced, but the right inferior orbitofrontal gyrus was increased (all P < 0.017, FDR corrected). Moreover, the nodal degree in the right dorsolateral superior frontal cortex (SFGdor) was significantly lower in RD than in NRD. Receiver operating characteristic curve analysis demonstrated that the lambda and nodal degree in the right SFGdor exhibited a good ability to distinguish nonresponding patients from responsive patients, which could serve as a specific maker to predict an early response to antidepressants. The disrupted topological configurations in the present study extend the understanding of pretreatment neuroimaging predictors for antidepressant medication. PMID- 27966648 TI - Anesthesia and brain sensory processing: impact on neuronal responses in a female songbird. AB - Whether anesthesia impacts brain sensory processing is a highly debated and important issue. There is a general agreement that anesthesia tends to diminish neuronal activity, but its potential impact on neuronal "tuning" is still an open question. Here we show, based on electrophysiological recordings in the primary auditory area of a female songbird, that anesthesia induces neuronal responses towards biologically irrelevant sounds and prevents the seasonal neuronal tuning towards functionally relevant species-specific song elements. PMID- 27966649 TI - Ecology and biogeography of megafauna and macrofauna at the first known deep-sea hydrothermal vents on the ultraslow-spreading Southwest Indian Ridge. AB - The Southwest Indian Ridge is the longest section of very slow to ultraslow spreading seafloor in the global mid-ocean ridge system, but the biogeography and ecology of its hydrothermal vent fauna are previously unknown. We collected 21 macro- and megafaunal taxa during the first Remotely Operated Vehicle dives to the Longqi vent field at 37 degrees 47'S 49 degrees 39'E, depth 2800 m. Six species are not yet known from other vents, while six other species are known from the Central Indian Ridge, and morphological and molecular analyses show that two further polychaete species are shared with vents beyond the Indian Ocean. Multivariate analysis of vent fauna across three oceans places Longqi in an Indian Ocean province of vent biogeography. Faunal zonation with increasing distance from vents is dominated by the gastropods Chrysomallon squamiferum and Gigantopelta aegis, mussel Bathymodiolus marisindicus, and Neolepas sp. stalked barnacle. Other taxa occur at lower abundance, in some cases contrasting with abundances at other vent fields, and delta13C and delta15N isotope values of species analysed from Longqi are similar to those of shared or related species elsewhere. This study provides baseline ecological observations prior to mineral exploration activities licensed at Longqi by the United Nations. PMID- 27966647 TI - DkXTH8, a novel xyloglucan endotransglucosylase/hydrolase in persimmon, alters cell wall structure and promotes leaf senescence and fruit postharvest softening. AB - Fruit softening is mainly associated with cell wall structural modifications, and members of the xyloglucan endotransglucosylase/hydrolase (XTH) family are key enzymes involved in cleaving and re-joining xyloglucan in the cell wall. In this work, we isolated a new XTH gene, DkXTH8, from persimmon fruit. Transcriptional profiling revealed that DkXTH8 peaked during dramatic fruit softening, and expression of DkXTH8 was stimulated by propylene and abscisic acid but suppressed by gibberellic acid and 1-MCP. Transient expression assays in onion epidermal cells indicated direct localization of DkXTH8 to the cell wall via its signal peptide. When expressed in vitro, the recombinant DkXTH8 protein exhibited strict xyloglucan endotransglycosylase activity, whereas no xyloglucan endohydrolase activity was observed. Furthermore, overexpression of DkXTH8 resulted in increased leaf senescence coupled with higher electrolyte leakage in Arabidopsis and faster fruit ripening and softening rates in tomato. Most importantly, transgenic plants overexpressing DkXTH8 displayed more irregular and twisted cells due to cell wall restructuring, resulting in wider interstitial spaces with less compact cells. We suggest that DkXTH8 expression causes cells to be easily destroyed, increases membrane permeability and cell peroxidation, and accelerates leaf senescence and fruit softening in transgenic plants. PMID- 27966650 TI - A novel chemiluminescence sensor for sensitive detection of cholesterol based on the peroxidase-like activity of copper nanoclusters. AB - A sensitive and selective chemiluminescence (CL) sensor based on the peroxidase like activity of copper nanoclusters was established for the detection of cholesterol. Copper nanoclusters catalyse the CL reaction between luminol and H2O2. Because H2O2 is the oxidative product of cholesterol in the presence of cholesterol oxidase, the oxidation of cholesterol can be quantitatively converted to a CL response by combining the two reactions. The proposed method is simple and can be completed in a few minutes with high sensitivity. Under the optimal conditions, the CL intensity was proportional to the concentration of cholesterol over a wide range of 0.05-10 mM, with a detection limit of 1.5 MUM. Furthermore, the method was successfully applied to determine cholesterol in milk powder and human serum with satisfactory accuracy and precision. This method expands the applications of nano-mimic enzymes in the field of CL-based sensors. PMID- 27966651 TI - Heterogeneous shedding of influenza by human subjects and its implications for epidemiology and control. AB - Heterogeneity of infectiousness is an important feature of the spread of many infections, with implications for disease dynamics and control, but its relevance to human influenza virus is still unclear. For a transmission event to occur, an infected individual needs to release infectious particles via respiratory symptoms. Key factors to take into account are virus dynamics, particle release in relation to respiratory symptoms, the amount of virus shed and, importantly, how these vary between infected individuals. A quantitative understanding of the process of influenza transmission is relevant to designing effective mitigation measures. Here we develop an influenza infection dynamics model fitted to virological, systemic and respiratory symptoms to investigate how within-host dynamics relates to infectiousness. We show that influenza virus shedding is highly heterogeneous between subjects. From analysis of data on experimental infections, we find that a small proportion (<20%) of influenza infected individuals are responsible for the production of 95% of infectious particles. Our work supports targeting mitigation measures at most infectious subjects to efficiently reduce transmission. The effectiveness of public health interventions targeted at highly infectious individuals would depend on accurate identification of these subjects and on how quickly control measures can be applied. PMID- 27966652 TI - Effectiveness and Safety of Transcatheter Patent Foramen Ovale Closure for Migraine (EASTFORM) Trial. AB - We evaluated the safety and effectiveness of transcatheter patent foramen ovale (PFO) closure for the treatment of migraine in a Chinese population. This non randomized clinical trial enrolled 258 consecutive substantial or severe migraineurs with a right-to-left shunt (RLS) (grade II-IV) and grouped subjects according to their election or refusal of PFO closure. Migraine was diagnosed according to the International Classification of Headache Disorders III-beta and evaluated using the Headache Impact Test-6 (HIT-6). In total, 241 participants (125 in the transcatheter closure group and 116 in the control group) were included in the study. In general, the PFO closure procedure was found to be safe. At 1 month after closure, 76.1% of patients returned for c-TCD evaluation; of these, 85.7% were downgraded to negative status or a grade-I shunt. Residual shunts and placebo effects were thought to resolve by 12 months post-procedure, when migraine impact was reported to decrease by 73.6%. Transcatheter PFO closure was demonstrated to be effective for the treatment of migraine by comparing HIT-6 scores between the transcatheter closure and control groups (p < 0.001). Our results suggest that transcatheter PFO closure is a safe and effective approach for the treatment of migraine in the Chinese population, especially in females with constant RLS. Clinical trial no. NCT02127294 (registered on April 29, 2014). PMID- 27966653 TI - The accessory proteins REEP5 and REEP6 refine CXCR1-mediated cellular responses and lung cancer progression. AB - Some G-protein-coupled receptors have been reported to require accessory proteins with specificity for proper functional expression. In this study, we found that CXCR1 interacted with REEP5 and REEP6, but CXCR2 did not. Overexpression of REEP5 and REEP6 enhanced IL-8-stimulated cellular responses through CXCR1, whereas depletion of the proteins led to the downregulation of the responses. Although REEPs enhanced the expression of a subset of GPCRs, in the absence of REEP5 and REEP6, CXCR1 was expressed in the plasma membrane, but receptor internalization and intracellular clustering of beta-arrestin2 following IL-8 treatment were impaired, suggesting that REEP5 and REEP6 might be involved in the ligand stimulated endocytosis of CXCR1 rather than membrane expression, which resulted in strong cellular responses. In A549 lung cancer cells, which endogenously express CXCR1, the depletion of REEP5 and REEP6 significantly reduced growth and invasion by downregulating IL-8-stimulated ERK phosphorylation, actin polymerization and the expression of genes related to metastasis. Furthermore, an in vivo xenograft model showed that proliferation and metastasis of A549 cells lacking REEP5 and REEP6 were markedly decreased compared to the control group. Thus, REEP5 and REEP6 could be novel regulators of G-protein-coupled receptor signaling whose functional mechanisms differ from other accessory proteins. PMID- 27966654 TI - Comparative Proteomics Reveals that Phosphorylation of beta Carbonic Anhydrase 1 Might be Important for Adaptation to Drought Stress in Brassica napus. AB - Little is known about the mechanism of drought tolerance in rapeseed (Brassica napus L.). In this study, different morphological and physiological responses to drought stress were studied in three rapeseed cultivars. For the cultivar 2AF009 with high drought tolerance, comparative proteomic analyses were conducted to determine the molecular mechanism behind. Approximately 138 differentially abundant proteins (DAPs) and 1232 phosphoproteins containing 4469 phosphopeptides were identified. Furthermore, 337 phosphoproteins containing 547 phosphorylation sites demonstrated significant changes. These drought-responsive DAPs and phosphoproteins were mainly involved in signal transduction, photosynthesis, and glutathione-ascorbate metabolism. Notably, 9 DAPs were also identified as drought responsive phosphoproteins, especially beta carbonic anhydrase 1 (betaCA1), which was represented by eight distinct protein spots with different abundant levels during drought stress. Tyr207 phosphorylated site of betaCA1 was down-regulated at the phosphorylation level during drought stress, which was also located in the substrate-binding active region of three-dimensional (3D) structure. Moreover, drought stress inhibited CA activity. We concluded that Tyr207 was the most likely phosphorylation target affecting the enzyme activity, and phosphorylation of betaCA1 might be important for the response to drought stress in rapeseed. The study provided a new clue for the drought tolerance mechanism in B.napus. PMID- 27966655 TI - The 5'UTR variant of ERCC5 fails to influence outcomes in ovarian and lung cancer patients undergoing treatment with platinum-based drugs. AB - The common polymorphic variant in the 5' untranslated region of the excision repair cross-complementation group 5 (ERCC5) gene was described to generate an upstream open reading frame that regulates both the basal ERCC5 expression and its ability to be synthesized following DNA damage. This variant was reported to affect response to platinum therapy in a cohort of patients with pediatric ependymoma. The role of this variant was investigated in two cohorts of cancer patients, specifically in non-small-cell lung cancer (NSCLC) patients (N = 137) and in epithelial ovarian carcinoma (EOC) patients (N = 240), treated in first line with platinum-based compounds. Differently from what reported for pediatric ependymoma, the analysis of the polymorphism in NSCLC patients cohort was not able to detect any difference among patients harboring different genotypes both in progression free survival (HR = 0.93; 95%CI 0.64-1.33; p-value = 0.678) and overall survival (HR = 0.90; 95%CI 0.62-1.33; p-value = 0.625). These data were corroborated in a EOC patients cohort, where similar progression free survival (HR = 0.91; 95% CI 0.67-1.24; p-value = 0.561) and overall survival (HR = 0.98; 95% CI 0.71-1.35; p-value = 0.912) were found for the different genotypes. These data, obtained in appropriately sized populations, indicate that the effect of this ERCC5 polymorphism is likely to be relevant only in specific tumors. PMID- 27966656 TI - Neonatal repetitive pain in rats leads to impaired spatial learning and dysregulated hypothalamic-pituitary-adrenal axis function in later life. AB - Preterm birth is a major health issue. As part of their life-saving care, most preterm infants require hospitalization and are inevitably exposed to repetitive skin-breaking procedures. The long-term effects of neonatal repetitive pain on cognitive and emotional behaviors involving hypothalamic-pituitary-adrenal (HPA) axis function in young and adult rats are unknown. From P8 to P85, mechanical hypersensitivity of the bilateral hindpaws was observed in the Needle group (P < 0.001). Compared with the Tactile group, the Needle group took longer to find the platform on P30 than on P29 (P = 0.03), with a decreased number of original platform site crossings during the probe trial of the Morris water maze test (P = 0.026). Moreover, the Needle group spent more time and took longer distances in the central area than the Tactile group in the Open-field test, both in prepubertal and adult rats (P < 0.05). The HPA axis function in the Needle group differed from the Tactile group (P < 0.05), with decreased stress responsiveness in prepuberty and puberty (P < 0.05) and increased stress responsiveness in adulthood (P < 0.05). This study indicates that repetitive pain that occurs during a critical period may cause severe consequences, with behavioral and neuroendocrine disturbances developing through prepuberty to adult life. PMID- 27966657 TI - Modeling quorum sensing trade-offs between bacterial cell density and system extension from open boundaries. AB - Bacterial communities undergo collective behavioural switches upon producing and sensing diffusible signal molecules; a mechanism referred to as Quorum Sensing (QS). Exemplarily, biofilm organic matrices are built concertedly by bacteria in several environments. QS scope in bacterial ecology has been debated for over 20 years. Different perspectives counterpose the role of density reporter for populations to that of local environment diffusivity probe for individual cells. Here we devise a model system where tubes of different heights contain matrix embedded producers and sensors. These tubes allow non-limiting signal diffusion from one open end, thereby showing that population spatial extension away from an open boundary can be a main critical factor in QS. Experimental data, successfully recapitulated by a comprehensive mathematical model, demonstrate how tube height can overtake the role of producer density in triggering sensor activation. The biotic degradation of the signal is found to play a major role and to be species-specific and entirely feedback-independent. PMID- 27966658 TI - Occurrence investigation of perfluorinated compounds in surface water from East Lake (Wuhan, China) upon rapid and selective magnetic solid-phase extraction. AB - Using a novel magnetic nanocomposite as adsorbent, a convenient and effective magnetic solid-phase extraction (MSPE) procedure was established for selective separation and concentration of nine perfluorinated compounds (PFCs) in surface water sample. Then an ultra high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) system was employed for detection of PFCs. Good linearity of the developed analytical method was in the range of 0.5-100 ng L-1 with R2 > 0.9917, and the limits of detection (LODs) ranged from 0.029 to 0.099 ng L-1. At three fortified concentrations of 0.5, 5 and 50 ng L-1, the spiked recoveries of PFCs were in the range of 90.05-106.67% with RSDs < 12.62% (n = 3). The proposed analytical method was applied for determination of PFCs in surface water from East Lake (Wuhan, China). The total concentrations of nine PFCs ranged from 30.12 to 125.35 ng L-1, with perfluorooctane sulfonate and perfluoroctanoic acid as the most prevalent PFCs, and the greatest concentrations of PFCs were observed in Niuchao lakelet. The concentrations of the PFCs (C >= 11) were mostly less than the limits of quantification (LOQs), attributed to the possibility that the more hydrophobic long-chain PFCs are potential to accumulate in sediment and aquatic biota. PMID- 27966659 TI - The functional architecture of mother-infant communication, and the development of infant social expressiveness in the first two months. AB - By two-three months, infants show active social expressions during face-to-face interactions. These interactions are important, as they provide the foundation for later emotional regulation and cognition, but little is known about how infant social expressiveness develops. We considered two different accounts. One emphasizes the contingency of parental responsiveness, regardless of its form; the other, the functional architecture account, emphasizes the preparedness of both infants and parents to respond in specific ways to particular forms of behaviour in their partner. We videotaped mother-infant interactions from one to nine weeks, and analysed them with a micro-analytic coding scheme. Infant social expressiveness increased through the nine-week period, particularly after 3 weeks. This development was unrelated to the extent of maternal contingent responsiveness, even to infant social expressions. By contrast, specific forms of response that mothers used preferentially for infant social expressions mirroring, marking with a smile- predicted the increase in these infant behaviours over time. These results support a functional architecture account of the perceptual and behavioural predispositions of infants and parents that allow young infants to capitalize on relatively limited exposure to specific parental behaviours, in order to develop important social capacities. PMID- 27966660 TI - New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps. AB - A comprehensive identification of sphingoid bases and ceramides in wild Cordyceps was performed by integrating a sequential chromatographic enrichment procedure and an UHPLC-ultrahigh definition-Q-TOF-MS based sphingolipidomic approach. A total of 43 sphingoid bases and 303 ceramides were identified from wild Cordyceps, including 12 new sphingoid base analogues and 159 new ceramide analogues based on high-resolution MS and MS/MS data, isotope distribution, matching with the comprehensive personal sphingolipid database, confirmation by sphingolipid standards and chromatographic retention time rule. The immunosuppressive bioassay results demonstrated that Cordyceps sphingoid base fraction exhibits more potent immunosuppressive activity than ceramide fraction, elucidating the immunosuppressive ingredients of wild Cordyceps. This study represented the most comprehensive identification of sphingoid bases and ceramides from a natural source. The findings of this study provided an insight into therapeutic application of wild Cordyceps. PMID- 27966662 TI - Magnetic Phases of Sputter Deposited Thin-Film Erbium. AB - We present a detailed structural and magnetic characterization of sputter deposited thin film erbium, determined by x-ray diffraction, transport measurements, magnetometry and neutron diffraction. This provides information on the onset and change of the magnetic state as a function of temperature and applied magnetic field. Many of the features of bulk material are reproduced. Also of interest is the identification of a conical magnetic state which repeats with a wavevector parallel to the c axis tauc = 4/17 in units of the reciprocal lattice parameter c*, which is a state not observed in any other thin film or bulk measurements. The data from the various techniques are combined to construct magnetic field, temperature (H, T)-phase diagrams for the 200 nm-thick Er sample that serves as a foundation for future exploitation of this complex magnetic thin film system. PMID- 27966661 TI - Variation in the TAS2R31 bitter taste receptor gene relates to liking for the nonnutritive sweetener Acesulfame-K among children and adults. AB - The nonnutritive sweetener (NNS) acesulfame potassium (Ace-K) elicits a bitter off-taste that varies among adults due to polymorphisms in a bitter taste receptor gene. Whether polymorphisms affect liking for Ace-K by children, who live in different sensory worlds, is unknown. We examined hedonic response to Ace K among children compared to adults, and whether response was related to common variants of the TAS2R31 bitter taste receptor gene and to NNS intake. Children (N = 48) and their mothers (N = 34) rated liking of Ace-K, and mothers reported whether they or their children ever consume NNSs via questionnaire. Participants were genotyped for TAS2R31 variant sites associated with adult perception of Ace K (R35W, L162M, A227V, and V240I). Regardless of age, more participants with 1 or no copies than with 2 copies of the TAS2R31 WMVI haplotype liked Ace-K (p = 0.01). NNS-sweetened products were consumed by 50% and 15% of mothers and children, respectively, with no association between intake and TAS2R31. The TAS2R31 WMVI haplotype was partly responsible for children's hedonic response to Ace-K, highlighting a potential role for inborn differences in vulnerability to overconsumption of Ace-K-containing products. Currently available methods to measure NNS intake yield crude estimates at best, suggesting self-reports are not reflective of actual intake. PMID- 27966663 TI - Synthesis of Mesoporous alpha-Fe2O3 Nanoparticles by Non-ionic Soft Template and Their Applications to Heavy Oil Upgrading. AB - This paper reports the synthetic route of 3-D network shape alpha-Fe2O3 from aqueous solutions of iron precursor using a non-ionic polymeric soft-template, Pluronic P123. During the synthesis of alpha-Fe2O3, particle sizes, crystal phases and morphologies were significantly influenced by pH, concentrations of precursor and template. The unique shape of worm-like hematite was obtained only when a starting solution was prepared by a weakly basic pH condition and a very specific composition of constituents. The synthesized nanocrystal at this condition had a narrow pore size distribution and high surface area compared to the bulk alpha-Fe2O3 or the one synthesized from lower pH conditions. The hydrocracking performance was tested over the synthesized iron oxide catalysts with different morphologies. The worm-like shape of iron oxide showed a superior performance, including overall yield of liquid fuel product and coke formation, over the hydrocracking of heavy petroleum oil. PMID- 27966664 TI - Maternal/fetal metabolomes appear to mediate the impact of arsenic exposure on birth weight: A pilot study. AB - Arsenic exposure has been associated with low birth weight. However, the underlying mechanisms are not well understood. Alterations to metabolites may act as causal mediators of the effect of arsenic exposure on low birth weight. This pilot study aimed to explore the role of metabolites in mediating the association of arsenic exposure on infant birth weight. Study samples were selected from a well-established prospectively enrolled cohort in Bangladesh comprising 35 newborns and a subset of 20 matched mothers. Metabolomics profiling was performed on 35 cord blood samples and 20 maternal peripheral blood samples collected during the second trimester of pregnancy. Inorganic arsenic (iAs) exposure was evaluated via cord blood samples and maternal toenail samples collected during the first trimester. Multiple linear regression and mediation analyses were used to explore the relationship between iAs exposure, metabolite alterations, and low birth weight. Cord blood arsenic level was correlated with elevated levels of 17 methylstearate, laurate (12:0) and 4-vinylphenol sulfate along with lower birth weight. Prenatal maternal toenail iAs level was associated with two peripheral blood metabolites (butyrylqlycine and tartarate), which likely contributed to higher cord blood iAs levels both independently and interactively. Findings of this pilot study indicate that both intrauterine and maternal peripheral blood metabolites appear to influence the toxic effect of inorganic arsenic exposure on low birth weight. PMID- 27966665 TI - Estimation of personal exposure to asbestos of brake repair workers. AB - Exposure assessments are key tools to conduct epidemiological studies. Since 2010, 28 riveters from 18 brake repair shops with different characteristics and workloads were sampled for asbestos exposure in Bogota, Colombia. Short-term personal samples collected during manipulation activities of brake products, and personal samples collected during non-manipulation activities were used to calculate 103 8-h TWA PCM-equivalent personal asbestos concentrations. The aims of this study are to identify exposure determinant variables associated with the 8-h TWA personal asbestos concentrations among brake mechanics, and propose different models to estimate potential asbestos exposure of brake mechanics in an 8-h work-shift. Longitudinal-based multivariate linear regression models were used to determine the association between personal asbestos concentrations in a work-shift with different variables related to work tasks and workload of the mechanics, and some characteristics of the shops. Monte Carlo simulations were used to estimate the 8-h TWA PCM-Eq personal asbestos concentration in work shifts that had manipulations of brake products or cleaning activities of the manipulation area, using the results of the sampling campaigns. The simulations proposed could be applied for both current and retrospective studies to determine personal asbestos exposures of brake mechanics, without the need of sampling campaigns or historical data of air asbestos concentrations. PMID- 27966666 TI - Measurement error in mobile source air pollution exposure estimates due to residential mobility during pregnancy. AB - Prenatal air pollution exposure is frequently estimated using maternal residential location at the time of delivery as a proxy for residence during pregnancy. We describe residential mobility during pregnancy among 19,951 children from the Kaiser Air Pollution and Pediatric Asthma Study, quantify measurement error in spatially resolved estimates of prenatal exposure to mobile source fine particulate matter (PM2.5) due to ignoring this mobility, and simulate the impact of this error on estimates of epidemiologic associations. Two exposure estimates were compared, one calculated using complete residential histories during pregnancy (weighted average based on time spent at each address) and the second calculated using only residence at birth. Estimates were computed using annual averages of primary PM2.5 from traffic emissions modeled using a Research LINE-source dispersion model for near-surface releases (RLINE) at 250 m resolution. In this cohort, 18.6% of children were born to mothers who moved at least once during pregnancy. Mobile source PM2.5 exposure estimates calculated using complete residential histories during pregnancy and only residence at birth were highly correlated (rS>0.9). Simulations indicated that ignoring residential mobility resulted in modest bias of epidemiologic associations toward the null, but varied by maternal characteristics and prenatal exposure windows of interest (ranging from -2% to -10% bias). PMID- 27966667 TI - Arsenic levels in cutaneous appendicular organs are correlated with digitally evaluated hyperpigmented skin of the forehead but not the sole in Bangladesh residents. AB - There has been no report showing the effect of arsenic level on digitized skin pigmentation level, a typical diagnostic marker for arsenicosis. Correlations among history of drinking well water, arsenic levels in hair and toenails, and digitalized skin pigmentation levels (L*-value) in sunlight-exposed (forehead) and unexposed (sole) skin areas digitally evaluated by using a reflectance spectrophotometer were examined in 150 residents of Bangladesh. Univariate analysis showed that arsenic levels in hair and toenails of subjects with a history of drinking well water were 10.6-fold and 7.1-fold higher, respectively, than those in subjects without a history of drinking well water. The mean L* value of foreheads, but not that of soles, in subjects with a history of drinking well water was 1.15-fold lower (more pigmented) than that in subjects without a history of drinking well water. Significant correlations were found between duration of drinking well water and arsenic concentrations in hair (r=0.63; P<0.01) and toenails (r=0.60; P<0.01). Multivariate analysis showed that the arsenic levels in hair and toenails and the duration of drinking well water were strongly correlated with the digitized pigmented level of the forehead but not that of the sole. An increase in the duration of drinking well water may increase hyperpigmentation in the forehead, but not that in the sole, through an increased arsenic level in the human body as shown in cutaneous appendicular organs (hair and toenails). PMID- 27966669 TI - Asthma diagnosis in a child and cessation of smoking in the child's home: the PIAMA birth cohort. AB - Second hand smoke (SHS) exposure is associated with increased incidence and severity of childhood asthma. We investigated whether, in turn, asthma diagnosis in a child is associated with cessation of smoking exposure in the child's home. In the PIAMA birth cohort (n=3963), parents reported on smoking in their home and on asthma diagnosis in their child, annually from birth to 8 years. We used generalized estimating equations to assess the association between asthma diagnosis in a child and cessation of smoking in the child's home. Among children with residential SHS exposure, smoking stopped in 23.7% of the homes of children with newly diagnosed asthma as compared with 16.2% of the homes of children without asthma diagnosis (P=0.014). For children with an asthma diagnosis, the relative risk of smoking cessation in their home was 1.36 (one-sided 95% confidence interval: 1.09, inf.) and changed little after adjustment for maternal education, parental allergy and child's age. In most smokers' households (76.3%), smoking continued when the child got an asthma diagnosis. Nevertheless, an asthma diagnosis in the child increased the probability of a smoke-free home for the child and its parents and siblings. Cross-sectional associations between SHS exposure and asthma may underestimate true associations, because exposure may have been reduced following diagnosis of the disease. PMID- 27966668 TI - Predictors of polycyclic aromatic hydrocarbon exposure and internal dose in inner city Baltimore children. AB - Polycyclic aromatic hydrocarbons (PAHs), the by-products of incomplete combustion of organic materials, are commonly found on particulate matter (PM) and have been associated with the development of asthma and asthma exacerbation in urban populations. We examined time spent in the home and outdoors as predictors of exposures to airborne PAHs and measured urinary 1-hydroxypyrene-glucuronide (1 OHPG) as internal dose of PAHs in 118 children aged 5-12 years from Baltimore, MD. During weeklong periods (Saturday-Saturday) in each of four seasons: daily activities were assessed using questionnaires, indoor air nicotine and PM concentrations were monitored, and urine specimens were collected on Tuesday (day 3) and Saturday (day 7) for measurement of 1-OHPG. Time spent in non-smoking homes was associated with significantly decreased 1-OHPG concentration in urine (beta=-0.045, 95% CI (-0.076, -0.013)), and secondhand smoke (SHS) exposures modified these associations, with higher urinary 1-OHPG concentrations in children spending time in smoking homes than non-smoking homes (P-value for interaction=0.012). Time spent outdoors was associated with increased urinary 1 OHPG concentrations (beta=0.097, 95% CI (0.037, 0.157)) in boys only. Our results suggest that SHS and ambient (outdoor) air pollution contribute to internal dose of PAHs in inner city children. PMID- 27966670 TI - Pyrethroid insecticides and their environmental degradates in repeated duplicate diet solid food samples of 50 adults. AB - Previous research has reported concurrent levels of pyrethroid insecticides and their environmental degradates in foods. These data raise concerns about using these same pyrethroid degradates found in the diet as urinary biomarkers of exposures in humans. The primary objective was to quantify levels of selected pyrethroids and their environmental degradates in duplicate-diet solid food samples of 50 adults over a six-week monitoring period. The study was conducted at the US EPA's Human Studies Facility in North Carolina and at participants' residences in 2009-2011. Participants collected duplicate-diet solid food samples on days 1 and 2 during weeks 1, 2, and 6 of the monitoring period. These samples were collected over three consecutive time periods each sampling day. A total of 782 food samples were homogenized and analyzed by LC/MS/MS for seven pyrethroids (bifenthrin, lambda-cyhalothrin, cyfluthrin, cypermethrin, cis-deltamethrin, esfenvalerate, and cis/trans-permethrin) and six pyrethroid degradates. Results showed that 49% and 2% of all the samples contained at least one target pyrethroid or pyrethroid degradate, respectively. Cis/trans-permethrin (20%) and bifenthrin (20%) were the most frequently detected pyrethroids. The results suggest that the pyrethroid degradates were likely not present in sufficient levels in the diet to substantially impact the adults' urinary biomarker concentrations. PMID- 27966671 TI - A Critical Role for Toxoplasma gondii Vacuolar Protein Sorting VPS9 in Secretory Organelle Biogenesis and Host Infection. AB - Accurate sorting of proteins to the three types of parasite-specific secretory organelles namely rhoptry, microneme and dense granule in Toxoplasma gondii is crucial for successful host cell invasion by this obligate intracellular parasite. Despite its tiny body architecture and limited trafficking machinery, T. gondii relies heavily on transport of vesicles containing proteins, lipids and important virulence-like factors that are delivered to these secretory organelles. However, our understanding on how trafficking of vesicles operates in the parasite is still limited. Here, we show that the T. gondii vacuolar protein sorting 9 (TgVps9), has guanine nucleotide exchange factor (GEF) activity towards Rab5a and is crucial for sorting of proteins destined to secretory organelles. Our results illuminate features of TgVps9 protein as a key trafficking facilitator that regulates protein maturation, secretory organelle formation and secretion, thereby ensuring a primary role in host infection by T. gondii. PMID- 27966674 TI - Correction: Prospective pilot study of fully covered self-expandable metal stents for refractory benign pancreatic duct strictures: long-term outcomes. AB - [This corrects the article DOI: 10.1055/s-0042-115934.]. PMID- 27966672 TI - Biology of archaea from a novel family Cuniculiplasmataceae (Thermoplasmata) ubiquitous in hyperacidic environments. AB - The order Thermoplasmatales (Euryarchaeota) is represented by the most acidophilic organisms known so far that are poorly amenable to cultivation. Earlier culture-independent studies in Iron Mountain (California) pointed at an abundant archaeal group, dubbed 'G-plasma'. We examined the genomes and physiology of two cultured representatives of a Family Cuniculiplasmataceae, recently isolated from acidic (pH 1-1.5) sites in Spain and UK that are 16S rRNA gene sequence-identical with 'G-plasma'. Organisms had largest genomes among Thermoplasmatales (1.87-1.94 Mbp), that shared 98.7-98.8% average nucleotide identities between themselves and 'G-plasma' and exhibited a high genome conservation even within their genomic islands, despite their remote geographical localisations. Facultatively anaerobic heterotrophs, they possess an ancestral form of A-type terminal oxygen reductase from a distinct parental clade. The lack of complete pathways for biosynthesis of histidine, valine, leucine, isoleucine, lysine and proline pre-determines the reliance on external sources of amino acids and hence the lifestyle of these organisms as scavengers of proteinaceous compounds from surrounding microbial community members. In contrast to earlier metagenomics-based assumptions, isolates were S-layer-deficient, non-motile, non methylotrophic and devoid of iron-oxidation despite the abundance of methylotrophy substrates and ferrous iron in situ, which underlines the essentiality of experimental validation of bioinformatic predictions. PMID- 27966673 TI - Spatial distribution of planktonic bacterial and archaeal communities in the upper section of the tidal reach in Yangtze River. AB - Bacterioplankton and archaeaplankton communities play key roles in the biogeochemical processes of water, and they may be affected by many factors. In this study, we used high-throughput 16S rRNA gene sequencing to profile planktonic bacterial and archaeal community compositions in the upper section of the tidal reach in Yangtze River. We found that the predominant bacterial phyla in this river section were Proteobacteria, Firmicutes, and Actinobacteria, whereas the predominant archaeal classes were Halobacteria, Methanomicrobia, and unclassified Euryarchaeota. Additionally, the bacterial and archaeal community compositions, richnesses, functional profiles, and ordinations were affected by the spatial heterogeneity related to the concentration changes of sulphate or nitrate. Notably, the bacterial community was more sensitive than the archaeal community to changes in the spatial characteristics of this river section. These findings provide important insights into the distributions of bacterial and archaeal communities in natural water habitats. PMID- 27966676 TI - Petechial haemorrhage of the face. PMID- 27966675 TI - Protocol for a feasibility cluster randomised controlled trial of a peer-led school-based intervention to increase the physical activity of adolescent girls (PLAN-A). AB - BACKGROUND: Physical activity levels are low amongst adolescent girls, and this population faces specific barriers to being active. Peer influences on health behaviours are important in adolescence and peer-led interventions might hold promise to change behaviour. This paper describes the protocol for a feasibility cluster randomised controlled trial of Peer-Led physical Activity iNtervention for Adolescent girls (PLAN-A), a peer-led intervention aimed at increasing adolescent girls' physical activity levels. METHODS/DESIGN: A two-arm cluster randomised feasibility trial will be conducted in six secondary schools (intervention n = 4; control n = 2) with year 8 (12-13 years old) girls. The intervention will operate at a year group level and consist of year 8 girls nominating influential peers within their year group to become peer-supporters. Approximately 15 % of the cohort will receive 3 days of training about physical activity and interpersonal communication skills. Peer-supporters will then informally diffuse messages about physical activity amongst their friends for 10 weeks. Data will be collected at baseline (time 0 (T0)), immediately after the intervention (time 1 (T1)) and 12 months after baseline measures (time 2 (T2)). In this feasibility trial, the primary interest is in the recruitment of schools and participants (both year 8 girls and peer-supporters), delivery and receipt of the intervention, data provision rates and identifying the cost categories for future economic analysis. Physical activity will be assessed using 7-day accelerometry, with the likely primary outcome in a fully-powered trial being daily minutes of moderate-to-vigorous physical activity. Participants will also complete psychosocial questionnaires at each time point: assessing motivation, self-esteem and peer physical activity norms. Data analysis will be largely descriptive and focus on recruitment, attendance and data provision rates. The findings will inform the sample size required for a definitive trial. A detailed process evaluation using qualitative and quantitative methods will be conducted with a variety of stakeholders (i.e. pupils, parents, teachers and peer-supporter trainers) to identify areas of success and necessary improvements prior to proceeding to a definitive trial. DISCUSSION: This paper describes the protocol for the PLAN-A feasibility cluster randomised controlled trial which will provide the information necessary to design a fully-powered trial should PLAN-A demonstrate evidence of promise. TRIAL REGISTRATION: ISRCTN12543546. PMID- 27966677 TI - The discharge summary as a medium for teaching and learning PMID- 27966678 TI - A biotinylated piperazine-rhodol derivative: a 'turn-on' probe for nitroreductase triggered hypoxia imaging. AB - We developed a nitroreductase responsive theranostic probe 1; it comprises biotinylated rhodol in conjunction with p-nitrobenzyl functionality. The probe 1 showed a remarkable fluorescence 'turn-on' signal in the presence of nitroreductase under physiological conditions. The probe is considerably stable within a wide biological pH range (6-8) and also is very sensitive toward a reducing micro-environment e.g. liver microsome. Further, it enables providing cellular and in vivo nematode images in a reducing microenvironment. PMID- 27966679 TI - Development of a full micro-scale spatially offset Raman spectroscopy prototype as a portable analytical tool. AB - We present, for the first time, a portable full micro-Spatially Offset Raman Spectroscopy (micro-SORS) prototype permitting the in situ analysis of thin, highly turbid stratified layers at depths not accessible to conventional Raman microscopy. The technique is suitable for the characterisation of painted layers in panels, canvases and mural paintings, painted statues and decorated objects in cultural heritage or stratified polymers, and biological, catalytic and forensics samples where invasive analysis is undesirable or impossible to perform. The new device is characterised conceptually in polymer and paint layer systems. The provision of portability with full micro-SORS delivers subsurface micro-SORS capability unlocking the non-invasive and non-destructive potential of micro-SORS at its most effective form permitting it to be applied to large and non-portable objects in situ without recourse to removing micro-fragments for laboratory analysis on benchtop Raman microscopes. PMID- 27966680 TI - Developing high-performance small molecule organic solar cells via a large planar structure and an electron-withdrawing central unit. AB - We designed and synthesized a new small molecule donor material named DR3TBDD using an electron-withdrawing unit BDD as the central building block. A PCE of 9.53% with a high Voc of around 1 V was achieved. PMID- 27966682 TI - Beyond the electrostatic model: the significant roles of orbital interaction and the dispersion effect in aqueous-pi systems. AB - The electrostatic model, which is widely used to explain pi-involved interactions, gives an intuitive picture of these intermolecular interactions and has successfully predicted many phenomena in recent decades. Still, this simple model faces problems in certain cases and it has come under fire in previous studies on pi-pi stacking interactions. Here, employing ab initio calculations, we have identified several counter examples in aqueous-pi systems which cannot be explained adequately using the classical electrostatic model, and revealed the underlying reason. We find strong intermolecular orbital interactions in both aqueous-pi hydrogen bond and lone-pair-pi interactions, and thus extend the previously proposed new model for pi-pi stacking to aqueous-pi systems: while the electrostatic attraction and dispersion effects are the main driving forces pulling the monomers together, Pauli repulsion plays a role in keeping them apart. Interestingly, the molecular orbitals on the concerned monomers exhibit a weak bonding nature at the equilibrium distance. PMID- 27966681 TI - Bottom-up proteomics analysis of the secretome of murine islets of Langerhans in elevated glucose levels. AB - Glucotoxicity is a causative agent of type-2 diabetes, where high glucose levels damage the islets of Langerhans resulting in oxidative damage and endoplasmic reticulum stress. We evaluated the secretomes of healthy CD-1 murine islets. Three experimental conditions were investigated in biological triplicate: a control incubated with 11 mM glucose, 1-day incubation with 25 mM glucose, and 2 day incubation with 25 mM glucose. An SDS-based, filter-aided sample preparation protocol was used to prepare secretomes for analysis. A total of 428 protein groups were identified across the nine samples. Each condition generated between 328-349 protein IDs and intracondition protein overlap was between 66-90% for the biological triplicates. 232 protein groups were identified in all three conditions with 184 quantified at least once in each condition. Significant expression changes were observed for proteins associated with the unfolded protein response, such as proteases, chaperones, and elongation factors, as well as proteins associated with peptide hormone processing and small molecule metabolism. PMID- 27966683 TI - Reaching the ideal glass transition by aging polymer films. AB - Searching for the ideal glass transition, we exploit the ability of glassy polymer films to explore low energy states in remarkably short time scales. We use 30 nm thick polystyrene (PS) films, which in the supercooled state basically display the bulk polymer equilibrium thermodynamics and dynamics. We show that in the glassy state, this system exhibits two mechanisms of equilibrium recovery. The faster one, active well below the kinetic glass transition temperature (Tg), allows massive enthalpy recovery. This implies that the 'fictive' temperature (Tf) reaches values as low as the predicted Kauzmann temperature (TK) for PS. Once the thermodynamic state corresponding to Tf = TK is reached, no further decrease of enthalpy is observed. This is interpreted as a signature of the ideal glass transition. PMID- 27966684 TI - Anti-Stokes shift luminescent materials for bio-applications. AB - Anti-Stokes shift luminescence is a special optical process, which converts long wavelength excitation to short-wavelength emission. This unique ability is especially helpful for bio-applications, because the longer-wavelength light source, usually referring to near infrared light, has a larger penetration depth offering a longer working distance for in vivo applications. The anti-Stokes shift luminescence signal can also be distinguished from the auto-fluorescence of biological tissues, thus reducing background interference during bioimaging. Herein, we summarize recent advances in anti-Stokes shift luminescent materials, including lanthanide and triplet-triplet-annihilation-based upconversion nanomaterials, and newly improved hot-band absorption-based luminescent materials. We focus on the synthetic strategies, optical optimization and biological applications as well as present comparative discussions on the luminescence mechanisms and characteristics of these three types of luminescent materials. PMID- 27966685 TI - On the ionophoric selectivity of nonactin and related macrotetrolide derivatives. AB - Nonactin and its analogs constitute a central class of macrocycles with an antibiotic activity closely related to their selective ionophoric behavior. In this study, we apply experimental and computational methods to revisit the specificity of cation binding and transport by three nactin variants differing in structural properties, such as the position of the ester linkages, the nature of the side groups, or the flexibility of the backbone. On the one hand, electrospray ionization mass spectrometry and infrared spectroscopy are employed to expose the selectivity of the liquid-liquid (water-chloroform) extraction of alkali cations by nonactin and to demonstrate that the cation complexes are partially hydrated in the organic phase. Furthermore, laser desorption mass spectrometry is employed to determine the intrinsic cation affinities of nonactin under solvent-free conditions. On the other hand, density functional theory calculations are performed to characterize the conformations of the alkali cation complexes of the three nactins, and to assess the role of intermolecular and solvent interactions in determining their relative stability. Depending on the structure of the macrocycle, the cation complexes adopt either a cage-like conformation or a tweezer-like conformation. The computations show that the partial hydration of those different conformations in the organic phase, determine the distinct cation extraction selectivities that are observed experimentally. PMID- 27966687 TI - A simply triggered peptide-based hydrogel as an injectable nanocarrier of tanshinone IIA and tanshinones. AB - An easily self-assembled and gelated octa-peptide FHFDFHFD was chosen as a novel drug delivery system (DDS) for both tanshinone IIA and total tanshinone extract. The DDS showed increased loading capacity, sustained drug release and better anticancer capability. Our research proved that a hydrogel DDS of other traditional Chinese medicines is possible. PMID- 27966686 TI - A microchip electrophoresis-based fluorescence signal amplification strategy for highly sensitive detection of biomolecules. AB - We have developed a microchip electrophoresis (MCE)-based fluorescence signal amplification strategy as a universal MCE method for the detection of trace biomolecules. This strategy exhibits high sensitivity and specificity for target molecules, and has been applied for the detection of interferon-gamma (IFN-gamma) in human plasma with satisfactory results. PMID- 27966688 TI - Functional polyoxometalates from solvothermal reactions of VOSO4 with tripodal alkoxides - a study on the reactivity of different "tris" derivatives. AB - We report a study on the structure directing effects of functional groups and counterions. The aim was to find a facile and high yielding synthetic procedure to obtain polyoxometalate (POM) building blocks for post-functionalisation. Therefore, solvothermal reactions of VOSO4 with various tris(hydroxymethyl)methane derivatives in alkaline methanolic solutions were investigated. In doing so, new POM fragments were isolated and characterised. The binding modes of the functionalised tripodal alkoxides turned out to be surprisingly different. PMID- 27966689 TI - Screening out unfeasible hypothetical zeolite structures via the closest non adjacent OO pairs. AB - To boost function-led discovery of new zeolites with desired pores and properties, millions of hypothetical zeolite structures have been predicted via various computational approaches. It is now well accepted that most of these predicted structures are experimentally unrealisable under conventional synthetic conditions. Many structure evaluation criteria have been proposed to screen out unfeasible structures, among which the framework density-framework energy correlation criterion and the local interatomic distances criteria are the most frequently used. However, many hypothetical structures passing these criteria have been found unfeasible because of the existence of highly distorted framework rings. Here, we propose a new set of structure evaluation criteria to screen out such unfeasible structures. After optimising all existing zeolite structures as silica polymorphs, we find that the closest non-adjacent OO distances in existing zeolite rings generally show a normal distribution. By comparing the closest non adjacent OO distances between existing and hypothetical zeolite structures, we are able to screen out many unfeasible hypothetical zeolite structures with distorted rings that are deemed feasible according to previous structure evaluation methods. PMID- 27966690 TI - Interfacial assembly structures and nanotribological properties of saccharic acids. AB - Saccharides have been recognized as potential bio-lubricants because of their good hydration ability. However, the interfacial structures of saccharides and their derivatives are rarely studied and the molecular details of interaction mechanisms have not been well understood. In this paper, the supramolecular assembly structures of saccharic acids (including galactaric acid and lactobionic acid), mediated by hydrogen bonds O-HN and O-HO, were successfully constructed on a highly oriented pyrolytic graphite (HOPG) surface by introducing pyridine modulators and were explicitly revealed by using scanning tunneling microscopy (STM). Furthermore, friction forces were measured in the saccharic acid/pyridine co-assembled system by atomic force microscopy (AFM), revealing a larger value than a pristine saccharic acid system, which could be attributed to the stronger tip-assembled molecule interactions that lead to the higher potential energy barrier needed to overcome. The effort on saccharide-related supramolecular self assembly and nanotribological behavior could provide a novel and promising pathway to explore the interaction mechanisms underlying friction and reveal the structure-property relationship at the molecular level. PMID- 27966691 TI - A hybrid method using the widely-used WIEN2k and VASP codes to calculate the complete set of XAS/EELS edges in a hundred-atoms system. AB - Most of the recent developments in EELS modelling has been focused on getting a better agreement with measurements. Less work however has been dedicated to bringing EELS calculations to larger structures that can more realistically describe actual systems. The purpose of this paper is to present a hybrid approach well adapted to calculating the whole set of localised EELS core-loss edges (at the XAS level of theory) on larger systems using only standard tools, namely the WIEN2k and VASP codes. We illustrate the usefulness of this method by applying it to a set of amorphous silicon structures in order to explain the flattening of the silicon L2,3 EELS edge peak at the onset. We show that the peak flattening is actually caused by the collective contribution of each of the atoms to the average spectrum, as opposed to a flattening occurring on each individual spectrum. This method allowed us to reduce the execution time by a factor of 3 compared to a usual-carefully optimised-WIEN2k calculation. It provided even greater speed-ups on more complex systems (interfaces, ~300 atoms) that will be presented in a future paper. This method is suited to calculate all the localized edges of all the atoms of a structure in a single calculation for light atoms as long as the core-hole effects can be neglected. PMID- 27966692 TI - An immobilized symmetrical bis-(NHC) palladium complex as a highly efficient and recyclable Suzuki-Miyaura catalyst in aerobic aqueous media. AB - A bis-N-heterocyclic carbene (NHC) functionalized with chloropropyltriethoxysilane over silica was used to synthesize a well-defined immobilized palladium complex. This complex is a suitable and easily retrievable catalyst for Suzuki-Miyaura cross-coupling reactions under mild aqueous conditions. Excellent yields and conversions were obtained with low palladium loadings (down to 0.03 mol% Pd). The catalyst can be reused up to six cycles without the loss of its activity. The catalytic role of the NHC complex of palladium during coupling between bromobenzene and phenylboronic acid was investigated theoretically. The oxidative addition step is predicted to be endothermic in agreement with the experimental conditions. PMID- 27966693 TI - Energetics and structural characterization of the "DFG-flip" conformational transition of B-RAF kinase: a SITS molecular dynamics study. AB - B-RAF protein kinase is a promising target to treat malignant melanoma. The kinase activity of B-RAF is regulated by a "DFG-flip" conformational transition between functional DFG-in and DFG-out states. The difficulty in resolving the activation loop in crystal structures and the even greater difficulty in experimentally capturing high-energy-level transient structures render elusive the molecular mechanism of the B-RAF functional conformational transition. Here, a homology modeling technique and an enhanced sampling molecular dynamics simulation were used to identify and energetically characterize the conformational transition pathway of B-RAF on a multi-dimensional free-energy landscape. The results reveal that the conformational transition is a two-state transition, with the evaluated free-energy barrier comparable to those of other kinds of kinases as reported in the previous literature. Hydrophobic interactions between activation loop and neighboring segments are suggested to dominate the conformational transition and determine the free-energy barrier. The detailed analysis of hydrophobic interactions involved in the conformational transition may show a suitable pathway for the development of the B-RAF inhibitor. PMID- 27966694 TI - Observation of partial reduction of manganese in the lithium rich layered oxides, 0.4Li2MnO3-0.6LiNi1/3Co1/3Mn1/3O2, during the first charge. AB - Lithium-rich layered oxides show promise as high-energy harvesting materials due to their large capacities. However, questions remain regarding the large irreversible loss in capacities for the first charge-discharge cycle due to oxygen removal in lattices related to layered Li2MnO3. Herein we present detailed studies on Li-rich Mn-based layered oxides of 0.4Li2MnO3-0.6LiNi1/3Co1/3Mn1/3O2 (Li-rich NCM) electrochemically activated between 2.5 V and 4.3 or 4.7 V vs. Li+/Li. Electron energy loss spectroscopy (EELS) and X-ray absorption spectroscopy (XAS) revealed unusual manganese reduction after the first charge up to a high voltage of 4.7 V. Moreover, the electronic structure did not fully recover to the original pristine of Mn4+ state after discharge. Interestingly, these phenomena were not limited to a single particle, but were observed across the entire electrode. High-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) images and electron dispersive spectra (EDS) also showed a dramatic decline in oxygen content with highly porous morphologies, associated with oxygen vacancy formation following oxidation of O2- ions to O2. Our analysis suggests that an unstable manganese valence state with severe defects due to oxygen vacancies may lead to large irreversible capacity loss during the first charge-discharge cycle of Li-rich layered oxides. PMID- 27966695 TI - The role of arsenic in the hydrolysis and DNA metalation processes in an arsenous acid-platinum(ii) anticancer complex. AB - Platinum(ii)-based molecules are the most commonly used anticancer drugs in the chemotherapeutic treatment of tumours but possess serious side effects and some cancer types exhibit resistance with respect to these compounds (e.g. cisplatin). For these reasons, the research of new compounds that can bypass this limitation is in continuous development. Recently, mixed Pt(ii)-As(iii) systems have been synthesized and tested as potential anticancer agents. The mechanism of action of these kinds of drugs is unclear. Since in other platinum(ii) containing drugs, hydrolysis plays an important role in the activation of the compound before it reaches DNA, we have explored the aquation process using density functional theory (DFT), focusing our attention on the arsenoplatin complex, [Pt(MU NHC(CH3)O)2ClAs(OH)2]. As DNA is believed to be the cellular target for Pt anticancer drugs, the metalation mechanism of DNA purine bases has been also investigated. Also for this new drug it appears that guanine is the preferred site with respect to adenine as with other platinum-containing compounds. A comparison with cisplatin is performed in order to highlight the contribution of arsenic in the anticancer activity of this new proposed anticancer agent. PMID- 27966696 TI - Controlling photophysics of styrylnaphthalimides through TICT, fluorescence and E,Z-photoisomerization interplay. AB - The photophysical properties of naphthalimide dyes NI1-3 with electron releasing 4-methoxy- (NI1), 3,4-dimethoxystyryl- (NI2) and dimethylaminostyryl (NI3) groups are examined in a variety of protic and aprotic solvents. All compounds demonstrate positive solvatochromism in the steady-state absorption and fluorescence spectra. The analysis of the dependence of the Stokes shift on the polarity of the solvent using the Lippert-Mataga equation allowed us to determine the change in the dipole moment upon excitation. The obtained data correspond to the formation of highly polar charge transfer states. Based on the transient absorption spectra and time-resolved fluorescence measurements, the presence of two different emissive states was definitely proved. The primarily formed planar Local Excited (LE) state dominates in non-polar solvents like cyclohexane and toluene where it relaxes mostly through fluorescence and E,Z-isomerisation pathways. In polar solvents, an alternative relaxation channel emerges that consists of twisting around single bond between styryl and naphthalimide fragments, which leads to the formation of a Twisted Intramolecular Charge Transfer (TICT) state. The factors affecting the fluorescence of TICT states are discussed. The observed spectral effects are rationalized using quantum-chemical calculations, X-ray data and NMR spectroscopy. PMID- 27966697 TI - A non-chiral lithium aluminate reagent for the determination of enantiomeric excess of chiral alcohols. AB - Here we illustrate a new method for the rapid determination of ee's of chiral alcohols using the thermally-stable, non-chiral lithium aluminate reagent [EtAl(6 Me-2-py)3Li] (1). In situ reaction of the alcohols with 1 produces robust dimers in solution, present as diastereomeric pairs (SS/RR and RS) with distinct resonances in their 1H and 7Li NMR spectra. The ee can be calculated simply from integration of the 1H and/or 7Li NMR spectra. PMID- 27966698 TI - Size-dependent hardness of five-fold twin structured Ag nanowires. AB - In this study, the size dependent hardness of silver nanowires with a five-fold twin structure was examined using nanoindentation. As the diameter of the nanowires is reduced, the five-fold twin boundaries restrict the dislocation motion, and therefore a size dependent plasticity is expected for these uniquely structured nanowires. The polyol reduction method with modifications was used to synthesize silver nanowires with different diameters in the range of 70 nm to 144 nm. The nanoindentation experiments were performed on silver nanowires deposited on a stiff MgO substrate, and the resulting h, P, and S data were analyzed using the analytical double contact model for nanowire indentation. The hardness of the nanowires determined using the double contact model showed an increase in the hardness with reduction in the diameter of the nanowires, as expected due to the presence of the twin boundaries. The hardness values determined using the analytical double contact model compared favorably to the hardness values calculated from the contact areas that were extracted from finite element method simulations of an elastic indentation into the silver nanowires on the MgO substrate. PMID- 27966699 TI - Electronic structures and transport properties of a MoS2-NbS2 nanoribbon lateral heterostructure. AB - Lateral heterostructures built from an armchair MoS2 nanoribbon (AMoS2NR) and an armchair NbS2 nanoribbon (ANbS2NR) were studied based on first-principles calculations and a non-equilibrium Green's function method. It is found that the work function of the AMoS2NR shows substantial oscillation with increasing nanoribbon width, which is different from the work functions of other kinds of nanoribbons. The AMoS2NR-ANbS2NR lateral heterostructure exhibits an anomalous transport gap that is much larger than the bandgap of the AMoS2NR. As a result, a field effect transistor with AMoS2NR as the channel and ANbS2NRs as electrodes has high on-off ratios of 106-107 and a tiny leakage current of the order of 10-8 MUA. These results suggest that lateral metal-semiconductor heterostructures of transition metal dichalcogenides may have potential applications in nanodevices with low energy consumption. PMID- 27966700 TI - Development of molecularly imprinted polymers specific for blood antigens for application in antibody-free blood typing. AB - A novel approach in antibody-free blood typing based on molecularly imprinted polymeric nanoparticles is described. PMID- 27966703 TI - Synthesis of oxindole from acetanilide via Ir(iii)-catalyzed C-H carbenoid functionalization. AB - Herein we disclose the first report on the synthesis of oxindole derivatives from acetanilide via Ir(iii)-catalyzed intermolecular C-H functionalization with diazotized Meldrum's acid. A broad range of substituted anilides were found to react smoothly under the Ir(iii)-catalytic system to afford the corresponding N protected oxindoles. The N-protecting groups, such as Ac, Bz or Piv, can be easily removed to furnish the oxindole. Various synthetic applications of the synthesized oxindole were also demonstrated. PMID- 27966701 TI - Synthesis and cellular activity of stereochemically-pure 2'-O-(2-methoxyethyl) phosphorothioate oligonucleotides. AB - Stereochemically-pure 2'-O-(2-methoxyethyl)-phosphorothioate (PS-MOE) oligonucleotides were synthesized from new chiral oxazaphospholidine-containing nucleosides. Thermal stability studies showed that the incorporation of Rp-PS linkages increased RNA-binding affinity. In cells, a full Rp-PS-MOE splice switching oligonucleotide targeting part of the ferrochelatase gene was more potent than its Sp-PS counterpart, but of similar potency to the stereorandom PS parent sequence. PMID- 27966702 TI - A novel aggregation-induced emission enhancement triggered by the assembly of a chiral gelator: from non-emissive nanofibers to emissive micro-loops. AB - In this study, a novel aggregation-induced emission (AIE) enhancement triggered by the self-assembly of chiral gelator is described. Tuning of molecular chirality in situ triggers different assemblies of superstructures exhibiting fluorescence. This novel AIE material can constitute an emerging library of chiral supramolecules for turn-on fluorescent sensors. It will also help in better understanding the effects of chiral factors on the photophysical process. PMID- 27966704 TI - The intrinsic stabilities and structures of alkali metal cationized guanine quadruplexes. AB - The structures and stabilities of self-assembled guanine quadruplexes, M(9eG)8+ (M = Na, K, Rb, Cs; 9eG = 9-ethylguanine), have been studied in the gas phase by blackbody infrared radiative dissociation to determine the difference in the stabilizing effect of the alkali metal cations. The order of stabilities to decomposition was determined to be K+ > Rb+ > Cs+ ? Na+, which is consistent with the observation of K+ being the ion of choice in guanine quadruplexes in nucleic acids. In the gas phase, the sodiated quadruplex was found to lose one 9eG at a time, whereas the quadruplexes of the heavier cations lost a neutral guanine tetrad. Vibrational spectroscopy on the gas-phase quadruplex ions was consistent with the structures in which the metal cations were sandwiched between two guanine tetrads. Electronic structure calculations are also used to compare with the observed stabilities and vibrational spectra. PMID- 27966705 TI - Nanomolar affinity protein trans-splicing monitored in real-time by fluorophore quencher pairs. AB - High background originating from non-reacted, 'always-on' fluorescent probes remains a key unsolved problem in life science since washing procedures are not easily applicable. Covalent labeling approaches with simultaneous activation of fluorescence are advantageous to increase sensitivity and to reduce background signal. Here, we combined high-affinity protein trans-splicing with fluorophore/quencher pairs for online detection of covalent N-terminal 'traceless' protein labeling under physiological conditions in cellular environments. Substantial fluorescence enhancement at nanomolar probe concentrations was achieved. PMID- 27966706 TI - Mixed valence copper-sulfur clusters of highest nuclearity: a Cu8 wheel and a Cu16 nanoball. AB - Fully spin delocalized mixed valence copper-sulfur clusters, 1 and 2, supported by MU4-sulfido and NSthiol donor ligands are synthesized and characterized. Wheel shaped 1 consists of Cu2S2 units. The unprecedented nanoball 2 can be described as S@Cu4(tetrahedron)@O6(octahedron)@Cu12S12(cage) consisting of both Cu2S2 and (MU4-S)Cu4 units. The Cu2S2 and (MU4-S)Cu4 units resemble biological CuA and CuZ sites respectively. PMID- 27966707 TI - Mesoporous stilbene-based lanthanide metal organic frameworks: synthesis, photoluminescence and radioluminescence characteristics. AB - Ultra large pore isostructural metal organic frameworks (MOFs) which exhibit both photoluminescence and scintillation properties, were synthesized from trans-4,4' stilbenedicarboxylic acid (H2L) and trivalent lanthanide (Ln) metal salts under solvothermal conditions (Ln = Er3+ (1) and Tm3+ (2)). This new class of mesoporous materials is a non-interpenetrating network that features ultra-large diamond shaped pores of dimensions with approximate cross-sectional dimensions of 28 A * 12 A. The fully deprotonated ligand, L, is isolated and rigidified as it serves as the organic linker component of the MOF structure. Its low density unit cells possess asymmetric units with two crystallographically independent Ln3+ ions in seven coordinate arrangements. A distinct feature of the structure is the bis-bidentate carboxylate groups. They serve as a ligand that coordinates two Ln(iii) ions while each L connects four Ln(iii) ions yielding an exceptionally large diamond-shaped rectangular network. The structure exhibits ligand-based photoluminescence with increased lifetime compared to free stilbene molecules on exposure to UV radiation, and also exhibits strong scintillation characteristics, comprising of both prompt and delayed radioluminescence features, on exposure to ionizing radiation. PMID- 27966708 TI - meso-Acetoxymethyl BODIPY dyes for photodynamic therapy: improved photostability of singlet oxygen photosensitizers. AB - We report two BODIPY based photosensitizers (Br2BOAc and I2BOAc) featuring an acetoxymethyl substituent at the meso-position. These photosensitizers show improved photostability against singlet oxygen, when compared to a BODIPY photosensitizer lacking the acetoxymethyl group. Both compounds were evaluated for photodynamic therapy against HeLa cells and photodynamic inactivation against E. coli bacteria. We show that the compounds readily embed in the lipid membranes of HeLa cervical cancer cells and efficiently induced light-dependent apoptosis at nanomolar concentration. Also, both compounds showed a substantial degree of photoinactivation of E. coli bacteria when used at low micromolar concentrations. PMID- 27966709 TI - Diglycolamide-functionalized poly(propylene imine) diaminobutane dendrimers for sequestration of trivalent f-elements: synthesis, extraction and complexation. AB - Three diglycolamide-functionalized poly(propylene imine) diaminobutane dendrimers, viz., zero generation (LI), first generation (LII), and second generation (LIII), were synthesized and evaluated for their complexation ability towards trivalent actinides and lanthanides. The distribution coefficient (D) of Am3+ with 1.0 mmol L-1 ligand in 3 M HNO3 follows the order: 0.1 (LI) < 42 (LII) < 110 (LIII). Slope analysis indicated the stoichiometry of the extracted complexes as: 1 : 2 (M : L) for LI and 1 : 2 (M : L) for both LII and LIII. A complexation study of a representative lanthanide (Eu3+) with the three ligands by absorption spectroscopy and luminescence spectroscopy confirmed the formation of the above stoichiometry. The stability constants (log beta) for the ML complexes of Eu3+ with the three ligands were determined to be 5.2 +/- 0.03, 5.3 +/- 0.01, and 5.4 +/- 0.02 for LI, LII, and LIII, respectively. The identical log beta values (within experimental error) for all the ligands indicate that the complexation is not affected by the branching of the ligands. The metal/ligand complex formation was explained with the help of spectroscopic data. PMID- 27966710 TI - Unexpected alkane elimination from cationic group 13 dialkyls in a reaction with a macrocyclic polyamine. AB - A macrocyclic polyamine 1,4,7-trimethyl-1,4,7,10-tetraazacyclododecane, (Me3TACD)H formed thermally stable adducts with MMe3 (M = Al, In). The reactions with cationic dialkyls [MR2]+ directly provided cationic monoalkyls [(Me3TACD)MR]+ under RH elimination. Reactions between [Li(Me3TACD)]2 and Me2MCl gave chloro-bridged heterobimetallic adducts. PMID- 27966712 TI - A novel and sensitive chemosensor based on a KMnO4-rhodamine B-CdS quantum dot chemiluminescence system for meropenem detection. AB - A sensitive and simple flow injection chemiluminescence (CL) system was constructed for the determination of meropenem, in which the CL intensity of the KMnO4-rhodamine B (Rh B) reaction was enhanced in the presence of CdS quantum dots (QDs). A CL resonance energy transfer (CRET) occurs between CdS QDs as a donor and Rh B as an energy acceptor. Based on the strong specific quenching effect of meropenem on the CL intensity, a novel chemosensor for meropenem sensing was developed. Under the optimized conditions, the quenched CL emission intensity was proportional to the concentration of meropenem in the range of 0.002-10.0 mg L-1 with a detection limit (3sigma) of 0.8 MUg L-1 Moreover, the feasibility of the induced CL system was studied via the meropenem determination in environmental water samples. PMID- 27966711 TI - Development of a point-of-care diagnostic for influenza detection with antiviral treatment effectiveness indication. AB - Currently, diagnosis of influenza is performed either through tedious polymerase chain reaction (PCR) or through rapid antigen detection assays. The rapid antigen detection assays available today are highly specific but not very sensitive, and most importantly, lack the ability to show if the strain of influenza detected is susceptible to antiviral agents, such as Tamiflu and Relenza. The ability to rapidly determine if a patient has an infectious disease and what type of treatment the infection will respond to, would significantly reduce the treatment decision time, shorten the impact of symptoms, and minimize transfer to others. In this study, a novel, point-of-care style MUPAD (microfluidic paper-based diagnostic) for influenza has been developed with the ability to determine antiviral susceptibility of the strain for treatment decision. The assay exploits the enzymatic activity of surface proteins present on all influenza strains, and potential false positive responses can be mitigated. A sample can be added to the device, distributed to 4 different reagent zones, and development of the enzymatic substrate under different buffer conditions takes place on bottom of the device. Analysis can be performed by eye or through a colorimetric image analysis smartphone application. PMID- 27966713 TI - High intrinsic catalytic activity of two-dimensional boron monolayers for the hydrogen evolution reaction. AB - Two-dimensional (2D) boron monolayers have been successfully synthesized on a silver substrate very recently. Their potential application is thus of great significance. In this work, we explore the possibility of boron monolayers (BMs) as electrocatalysts for the hydrogen evolution reaction (HER) by first-principles methods. Our calculations show that BMs are active catalysts for HER with nearly zero free energy of hydrogen adsorption, metallic conductivity and plenty of active sites in the basal plane. The effect of the substrate on HER activity is further assessed. It is found that the substrate has a positive effect on the HER performance caused by the competitive effect of mismatch strain and charge transfer. The in-depth understanding of the structure dependent HER activity is also provided. PMID- 27966714 TI - Transition metal catalysis-a unique road map in the stereoselective synthesis of 1,3-polyols. AB - The present review summarizes recent diverse reactions employed in the formation of 1,3-polyols providing an overview of the mechanistic pathway and the enantioselectivity obtained, in terms of the properties of transition metals directly involved in the catalytic transformations and their interaction with various ligands. PMID- 27966716 TI - Synthesis and structural characterization of homochiral 2D coordination polymers of zinc and copper with conformationally flexible ditopic imidazolium-based dicarboxylate ligands. AB - Different novel coordination polymers containing zinc, 1-4, and copper, 5-8, metals, connected via chiral imidazolium-based dicarboxylate ligands, [LR]-, were isolated by reaction between zinc acetate or copper acetate and enantiomerically pure HLR compounds. They were characterised and structurally identified by X-ray diffraction methods (single crystal and powder). These compounds are two dimensional homochiral coordination polymers, [M(LR)2]n, in which the metal ions are coordinated by the two carboxylate groups of [LR]- anions in a general bridging monodentate MU2-kappa1-O1,kappa1-O3 fashion that afforded tetrahedral metal coordination environments for zinc, 1-4, and square planar for copper, 5-8, complexes. In all the compounds the 3D supramolecular architecture is constructed by non-covalent interactions between the hydrophobic parts (R groups) of the homochiral 2D coordination polymers and, in some cases, by weak C-HO non classical hydrogen bonds that provided, in general, a dense crystal packing. DFT calculations on the [LR]- anions confirmed their conformational flexibility as ditopic linkers and this fact makes possible the formation of different coordination polymers for four-coordinated metal centers. Preliminary studies on the Zn-catalyzed synthesis of chiral alpha-aminophosphonates were carried out and, unfortunately, no enantioselectivity was observed in these reactions. PMID- 27966715 TI - pH-Responsive magnetic metal-organic framework nanocomposites for selective capture and release of glycoproteins. AB - Novel magnetic metal-organic framework nanocomposites with 1,4 phenylenebisboronic acid as both an organic ligand and a functional molecule are proposed for the first time as a new type of intelligent nanomaterial to selectively capture and release glycoproteins via pH-stimulus-response, and would be of great potential for use in bio-separation. PMID- 27966717 TI - Ag2S nanoparticle-decorated MoS2 for enhanced electrocatalytic and photoelectrocatalytic activity in water splitting. AB - In this article, a novel Ag2S nanoparticle-decorated MoS2 composite (A@M) was synthesized through a facile in situ growth of the monoclinic crystallographic Ag2S on MoS2 nanosheets. The A@M composite was used as a catalyst in water splitting which exhibits higher electrocatalytic and photoelectrocatalytic activity than the respective pure MoS2 and Ag2S counterparts. Experimental results indicate that the as-prepared A@M composite with an optimal Ag2S/MoS2 molar ratio of 16.30% (16%A@M) shows the best catalytic performance with low overpotentials (110 mV for Voc, 190 mV for onset overpotential, 208 mV for the current density of 20 mA cm-2), a small Tafel slope (42 mV dec-1), and a high photocurrent (82 MUA cm-2 under an applied potential of 0.4 V). The enhanced electrocatalytic activity is associated with the improved electrical conductivity resulting from the stretched MoS2 nanosheets and the enriched active sites due to the decorated Ag2S particles. The formation of a type II heterojunction structure at the interface between Ag2S and MoS2 facilitates the separation of photogenerated charge carriers, and thus is responsible for the enhanced photoelectrocatalytic activity and photocatalytic H2 production rate (628 MUmol h 1 g-1). This work suggests a promising choice to overcome the intrinsic drawbacks of MoS2 nanostructures for the application in hydrogen evolution. PMID- 27966718 TI - Green-light ionization of 3-aminoperylene in SDS micelles-a promising access to hydrated electrons despite a myth debunked. AB - Using an improved methodology, we have carefully reinvestigated the title reaction by laser flash photolysis and disproved an earlier study (J. K. Thomas and P. Piciulo, J. Am. Chem. Soc., 1978, 100, 3239), which claimed this green light ionization to be monophotonic, the only instance of such a scenario ever reported for a stable compound. We show it to be biphotonic instead, in accordance with thermodynamic considerations, and present a photokinetic model that accurately represents the intensity dependences throughout the whole excitation range in the green (532 nm) and the near UV (355 nm), up to near quantitative electron release in the latter case. A major artifact deceptively similar to a chemical decay arises from an SDS-related laser-induced turbidity but can be eliminated by difference experiments or careful selection of excitation intensities and temporal windows. The ionization step is not accompanied by side processes, and affords an extremely long-lived (0.35 s) radical cation remaining solubilized. The micelles completely block attacks of hydrated electrons or hydroxyl radicals on the starting material and its radical cation but allow a post-ionization regeneration by high concentrations of the hydrophilic ascorbate monoanion. PMID- 27966719 TI - Physical and chemical properties of Cu(i) compounds with O and/or H. AB - The electronic structure and chemical bonding of Cu(i) compounds with O and/or H are investigated using ab initio calculations based on density functional theory. A hybrid functional PBE0 is employed, which accurately reproduces an experimental band gap of cuprite Cu2O. Cuprous hydroxide CuOH (cuprice) is found to be an indirect band gap semiconductor. Depending on the bond network configuration of CuOH, its band gap is found to vary between 2.73 eV and 3.03 eV. The presence of hydrogen in CuOH has little effect on the character of Cu-O bonds, as compared to Cu2O, but lowers the energy levels of the occupied states upon O-H bond formation. The bonding charge density and electron localization function calculations reveal that a closed-shell Cu-Cu interaction takes place in Cu2O and CuOH between the neighbouring Cu cations belonging to different bond networks. Besides, three structures of cuprous hydride CuH are investigated. We find that the halite structure of CuH can be stabilized at high pressure (above 32 GPa) while wurtzite is the most stable structure of CuH at ambient pressure. The H-H interaction contributes to the dynamical stabilization of the halite structure. The wurtzite and sphalerite structures of CuH are predicted to be semiconducting with small band gaps, while the halite structure is calculated to be metallic. PMID- 27966720 TI - Chewing bread: impact on alpha-amylase secretion and oral digestion. AB - During chewing, saliva helps in preparing the food bolus by agglomerating the formed particles, and it initiates enzymatic food breakdown. However, limited information is actually available on the adaptation of saliva composition during the oral processing of complex foods, especially for foods that are sensitive to salivary enzymes. We addressed this question in the context of starch-based products and salivary alpha-amylase. The objectives were two-fold: (1) to determine if salivary alpha-amylase secretion can be modulated by the bread type and (2) to evaluate the contribution of the oral phase in bread enzymatic breakdown. Mouthfuls of three different wheat breads (industrial, artisan and whole-meal breads) were chewed by twelve subjects. Saliva samples were collected at rest and at different times corresponding to 33, 66 and 100% of the individual's chewing sequence. Alpha-amylase activity and total protein content were determined for all saliva samples that were collected. Additionally, the salivary maltose concentration was measured as a marker of bread enzymatic digestion. Boluses were collected at the swallowing time to evaluate the saliva uptake. Chewing industrial bread induced higher saliva uptake than the other breads despite a similar chewing duration. The evolution of salivary amylase activity tended to depend on the type of bread and was highly influenced by a large degree of inter- and intra-subject variability. The protein and maltose concentration steadily increased during chewing as a result of bread breakdown. The salivary protein concentration was mainly affected by the release of the water-soluble proteins of the bread. The salivary maltose concentration was found to be significantly lower for the whole-meal bread. When considering the weight of the mouthful, enzymatic breakdown was found to be most efficient for the breads ranking from industrial > artisan > whole-meal. PMID- 27966721 TI - Integrated discovery of FOXO1-DNA stabilizers from marine natural products to restore chemosensitivity to anti-EGFR-based therapy for metastatic lung cancer. AB - The transcription factor forkhead box O1 (FOXO1) negatively regulates activated EGFR signaling by turning on the gene expression of tumor suppressor Kruppel-like factor 6. Here, we propose that the chemosensitivity to anti-EGFR-based lung cancer therapy can be restored by stabilization of the FOXO1-DNA complex architecture using small-molecule marine natural medicines. A synthetic protocol that integrates computational ligand-protein-DNA binding analysis and an experimental fluorescence binding assay was applied against a large library of structurally diverse, drug-like marine natural products to discover novel stabilizers of DNA-bound FOXO1 conformation. The screening utilized chemical similarity analysis to exclude structurally redundant compounds, and then carried out high-throughput molecular docking and computational binding analysis to identify potential marine natural product candidates. Consequently, eight commercially available hits were selected and tested in vitro, from which four marine natural product compounds (tanzawaic acid D, hymenidin, cribrostatin 6 and barbamide) were found to have high or moderate potency to selectively bind to the FOXO1 DNA-binding domain (DBD) in the presence of its cognate DNA partner. Atomistic molecular dynamics (MD) simulations revealed that the identified stabilizers do not directly interact with DNA; instead, they can effectively stabilize the free FOXO1 DBD domain in the DNA-bound conformation and thus promote the binding of FOXO1 to DNA. PMID- 27966722 TI - Effects of liquid oil vs. oleogel co-ingested with a carbohydrate-rich meal on human blood triglycerides, glucose, insulin and appetite. AB - We examined the differences in how coconut oil in a liquid or oleogel form affects blood triglycerides, glucose, insulin, and appetite when co-ingested with a carbohydrate-rich meal. This was a randomised, controlled, crossover study where eligible participants attended a screening visit where baseline demographics were measured. On test days, participants arrived at the laboratory after an overnight fast of 10 hours. Upon arrival, cannulation of the antecubital vein was performed and fasting capillary blood glucose, plasma insulin and triglyceride levels, and appetite sensations were measured. Following that, orange juice and rice porridge alone (control), or with 22.25 g of coconut oil (CO) or 25 g of coconut oleogel (CG) (22.25 g coconut oil + 2.75 g ethylcellulose to form an oleogel) was consumed. Subsequently, capillary blood glucose and plasma insulin and triglyceride levels were measured at fixed intervals for 6 hours. Appetite sensations were also measured using visual analog scales every 30 minutes. Sixteen healthy young adult males completed the study (age = 27 +/- 6 years, weight = 65.5 +/- 5.5 kg, BMI = 21.9 +/- 1.7 kg m-2). After test meals, glucose, insulin, triglycerides and appetite sensations changed significantly (time effects, p < 0.001). Significant time * treatment effects were found only in postprandial glucose (p = 0.015) and triglyceride (p = 0.001) changes. CO reduced the peak of the glucose response, and increased the incremental area under the curve for postprandial triglycerides. CG produced outcomes comparable to those of the control treatment. Appetite sensations did not differ between all treatments. The gelling of coconut oil with ethylcellulose into an oleogel form reversed its effects on postprandial glucose and triglycerides. PMID- 27966723 TI - Twisting the ethano-Troger's base: the bisamide. AB - The typically planar amide when incorporated into bicyclic systems can undergo a significant distortion from planarity resulting in physical properties and reactivity that deviate from classical amide behaviour. Herein, we report a succinct protocol that utilises potassium permanganate to selectively alpha oxygenate the benzylic position of ethano-Troger's base derivatives to yield a new class of twisted bisamides. Additionally, we report the first synthesis of an ethano-Troger's base derivative bearing substituents in the positions ortho to the nitrogen atoms. PMID- 27966724 TI - The protective effects of Cichorium glandulosum seed and cynarin against cyclophosphamide and its metabolite acrolein-induced hepatotoxicity in vivo and in vitro. AB - Cyclophosphamide (CP) is a widely utilized chemotherapy drug. CP and its metabolite, acrolein, could induce hepatotoxicity. In this study, Cichorium glandulosum seed (CGS) effectively mitigated CP-induced hepatotoxicity in mice. Protection of cynarin, the major compound of CGS, against acrolein cytotoxicity in HepG2 cells was studied. Pretreatment with cynarin could improve cell survival against acrolein cytotoxicity. Cynarin restored the balance of glutathione (GSH) and reactive oxygen species (ROS), and inhibited mitochondrial depolarization. The kinetics of Nrf2 expression in cytosolic and nuclear fractions were observed after acrolein exposure. Intracellular Nrf2 expression was triggered within 6 h of exposure but did not translocate to the nucleus. Cynarin pretreatment ameliorated the expression and activity of GSH S-transferase and triggered Nrf2 nuclear translocation. In conclusion, treatment with CGS and cynarin protects liver injury against CP and acrolein hepatotoxicity via improvement of GSH activity and activation of the Nrf2 pathway. PMID- 27966725 TI - Tuning the iron redox state inside a microporous porphyrinic metal organic framework. AB - Two new 3D porphyrin-based metal organic frameworks were obtained by solvothermally reacting iron(iii) chloride, a free base (5,10,15,20-tetrakis[4 (2,3,4,5-tetrazolyl)phenyl]porphyrin) (H2TTPP) and either pyrazine or 1,4 diazabicyclo[2.2.2]octane (DABCO). Both MOFs displayed a 3-D open framework of the fry topology, where the inorganic building unit is a chain of corner-sharing FeN4O2 octahedra and the porphyrinic linker is metallated with iron during the reaction course, with the N-donor base bridging the iron of the porphyrinic cores. Through thorough structural and spectroscopic analyses of the pyrazine containing material the chemical formula [FeIIpzTTP(FeDMF1-xFeOHx)]n was inferred (x >= 0.25). Whereas the already reported carboxylate analogue is built up from a pure iron(iii) inorganic chain, here spectroscopic and structural studies evidenced a mixed valence iron(ii/iii) state, evidencing that, in agreement with the HSAB theory, the substitution of a carboxylate function by a tetrazolate one allows redox tuning. Finally, both materials feature one-dimensional channels of ca. 8 * 12 A within the structures with permanent microporosity. PMID- 27966727 TI - A direct cross-coupling reaction of electron-deficient alkenes using an oxidizing directing group. AB - An oxidant-free cross-coupling reaction of electron-deficient alkenes using an inexpensive ruthenium catalyst is reported. With the assistance of the oxidizing directing group CONH(OMe), this protocol provides a mild, straightforward and efficient method for the preparation of valuable 1,3-butadiene skeletons with excellent Z,E selectivities. PMID- 27966726 TI - Broccoli sprouts in analgesia - preclinical in vivo studies. AB - BACKGROUND: Broccoli is a rich source of health-promoting glucosinolates, phenolic compounds, minerals and vitamins, which might have potential to alleviate pain. AIM: To explore the antinociceptive effects of a broccoli sprout aqueous extract (BSE) in experimental models of pain and an opioid mechanism. MATERIALS AND METHODS: the BSE was administered to mice and rats that were subjected to the writhing and formalin tests, respectively. Gastric damage or sedative-like response, as adverse effects observed in anti-inflammatory non steroidal and opioid analgesic drugs, respectively, were also explored. RESULTS: Antinociception, but not sedative or gastric injury response, was observed in a significant and dose-dependent manner with the BSE (50-500 mg kg-1, i.p. and 500 2000 mg kg-1, p.o.) in comparison to the control group; these effects resembled those observed with the analgesic tramadol (30 mg kg-1, i.p.) in writhing and formalin assessments. Blockage of opioid receptors by naloxone (1 mg kg-1, i.p.) produced partial inhibition of the antinociceptive effect of the BSE in both assays. CONCLUSION: This study gives evidence of the potential activity of broccoli sprouts in pain therapy. PMID- 27966728 TI - Structure investigations of group 13 organometallic carboxylates. AB - The octet-compliant group 13 organometallics with highly polarized bonds in the metal coordination sphere exhibit a significant tendency to maximize their coordination number through the formation of adducts with a wide range of neutral donor ligands or by self-association to give aggregates containing tetrahedral and higher coordinated aluminium centres, and even in some cases molecular complexes equilibrate with ionic species of different coordination numbers of the metal centre. This work provides a comprehensive overview of the structural chemistry landscape of the group 13 carboxylates. Aside from a more systematic approach to the general structural chemistry of the title compounds, the structure investigations of [R2M(MU-O2CPh)]2-type benzoate complexes (where M = B, Al and Ga) and their Lewis acid-base adducts [(R2M)(MU-O2CPh)(py-Me)] are reported. DFT calculations were also performed to obtain a more in-depth understanding of both the changes in the bonding of group 13 organometallic carboxylate adducts with a pyridine ligand. PMID- 27966729 TI - Hyperbranched polymer as an acceptor for polymer solar cells. AB - For the first time, a hyperbranched polymer acceptor, HP-PDI, was designed, synthesized and applied in polymer solar cells (PSCs). Devices based on HP-PDI showed a power conversion efficiency of 2.15%, which is 14 times higher than that of devices based on the small molecular acceptor SM-PDI. The hyperbranched structure can effectively suppress the aggregation of PDI molecules preventing them from forming large domains. Our preliminary results have demonstrated that high efficiency PSCs could be achieved by using a hyperbranched polymer acceptor. PMID- 27966730 TI - A novel octa-nuclear 32-membered zirconocene macrocycle based on the aromatic selenite. AB - A novel macrocyclic zirconocene(iv) aromatic selenite [(CpZr)8L16].2(Cp4Zr2(MU O)Cl2) (complex 1) (Cp = cyclopentadienyl anion; L = 4-fluorobenzeneseleninic acid) was prepared by the reaction of bis(cyclopentadienyl)zirconium dichloride with 4-fluorobenzeneseleninic acid and characterized by elemental analysis, infrared spectroscopy, 1H, 13C NMR spectroscopy, ESI-MS, XRD and X-ray diffraction. The structure analysis shows that complex 1 is a centrosymmetric 32 membered macrocycle containing an eight-nuclear zirconocene. In this complex, the 4-fluorobenzeneseleninic acid ligands adopt bidentate mode in coordinating to zirconium, which play a bridging role in the formation of a macrocycle. The title compound is a rare example of aromatic selenic acid-based zirconocene derivatives. Furthermore, the preliminary in vitro anti-tumor activity of complex 1 has also been studied toward breast cancer cell lines (MDA-MB-231) and human cervix cell lines (HeLa). The results indicate that complex 1 shows higher activity compared with the ligand and bis(cyclopentadienyl)zirconium dichloride. PMID- 27966731 TI - Arabinoxylan hydrolyzates as immunomodulators in Caco-2 and HT-29 colon cancer cell lines. AB - The use of plant derived polysaccharides as health promoters has gained immense interest in the past few years. Arabinoxylan (AX) is the predominant non-starch polysaccharide in cereals and grasses including wheat. The current research aimed to investigate the structure-function relationship of arabinoxylan hydrolyzates (AXH), obtained by the enzymatic hydrolysis of AX using xylanase and arabinofuranosidase as immunomodulators in two colon cancer cell lines: Caco-2 and HT-29. Fine structural details had a strong correlation with the immunological properties of the wheat AXH. As a general trend, as the presence of arabinose substitution increased in the AXH, the production of proinflammatory cytokines, IL-8 and TNF-alpha, decreased in both cell lines. Thus, AXH with a higher degree of arabinose substitution might be better adept in lowering inflammation in colon cancer cells. PMID- 27966732 TI - A de novo 2q35-q36.1 deletion incorporating IHH in a Chinese boy (47,XYY) with syndactyly, type III Waardenburg syndrome, and congenital heart disease. AB - Reports of terminal and interstitial deletions of the long arm of chromosome 2 are rare in the literature. Here, we present a case report concerning a Chinese boy with a 47,XYY karyotype and a de novo deletion comprising approximately 5 Mb between 2q35 and q36.1, along with syndactyly, type III Waardenburg syndrome, and congenital heart disease. High-resolution chromosome analysis to detect copy number variations was carried out using an Affymetrix microarray platform, and the genes affected by the patient's deletion, including IHH, were determined. However, no copy number changes were observed in his healthy parents. The present case exhibited novel syndactyly features, broadening the spectrum of clinical findings observed in individuals with 2q interstitial deletions. Our data, together with previous observations, suggest that IHH haploinsufficiency is the principal pathogenic factor in the syndactyly phenotype in this study, and that different types of variations at the IHH locus may cause divergent disease phenotypes. This is the first report of the involvement of IHH haploinsufficiency in syndactyly phenotype. PMID- 27966733 TI - RETRACTION of articles with common plagiarism. PMID- 27966734 TI - Comparative analysis of shell color variety and genetic structure among five high quality freshwater pearl mussel populations. AB - Four Hyriopsis cumingii populations, a breeding population (BP), a cultured population (FP), two wild populations from Poyang Lake (PY) and Dongting Lake (DT), and an H. schlegelii population were collected (JX), and the first filial generations (F1) were bred synchronously. The shell nacre polymorphisms, population genetic diversity, and genetic structures of the F1 of each population were analyzed and compared using CIELAB colorimetric measurements and microsatellite markers. The color parameters of the shell nacre (L*, a*, dE*) in the BP were significantly different from those in the FP, PY, and JX populations (P < 0.05), whereas the shell nacre color did not differ significantly between the left and right sides of the shells within the same population (P > 0.05). The BP had relatively darker nacre at the posterior end of the shell, and the color parameters (L*, a*, b*, and dE*) differed significantly from those at the front end (P < 0.05). The five populations showed relatively high levels of genetic diversity (HO = 0.733-0.829). The genetic distance between the H. cumingii populations and H. schlegelii was the greatest, whereas that within the H. cumingii populations and between the FP and the PY population was the smallest. All the individuals tested in this study were optimally grouped into four theoretical populations. In conclusion, the BP was significantly different from the base populations of PY and DT in terms of genetic background and phenotypic parameters of shell nacre color, with potential for further genetic improvement. PMID- 27966735 TI - Genetic polymorphisms in extracellular superoxide dismutase Leu53Leu, Arg213Gly, and Ala40Thr and susceptibility to type 2 diabetes mellitus. AB - The most common type of endocrine disease is type 2 diabetes mellitus (T2DM); genetic factors contribute to the development to T2DM. In this study, we investigated the role of the Leu53Leu, Arg213Gly, and Ala40Thr polymorphisms in extracellular superoxide dismutase (EC-SOD) gene in the development of T2DM in a Chinese population. DNA was extracted from peripheral blood samples obtained from 256 T2DM patients and 324 control subjects recruited from our hospital between January 2013 and March 2015. DNA was genotyped by polymerase chain reaction restriction fragment length polymorphism. The obtained data was then statistically analyzed. The chi-square test revealed a statistically significant difference in the genotype frequencies of EC-SOD Ala40Thr (chi2 = 13.26, P = 0.001) between the patients and controls. Unconditional regression analysis indicated that the GA and AA genotypes of EC-SOD Ala40Thr were associated with an increased risk of T2DM compared to the GG genotype {adjusted odds ratio (OR) [95% confidence interval (CI)] = 1.46 (1.01-2.11) and 2.67 (1.48-4.85), respectively}. In the dominant model, the GA+AA genotype of EC-SOD Ala40Thr was correlated with a higher risk of T2DM, in comparison with the GG genotype (OR = 1.64, 95%CI = 1.16-2.33). In the recessive model, AA of EC-SOD Ala40Thr showed a 2.19-fold higher risk of developing T2DM than the GG+GA genotype. In conclusion, people with the Ala40Thr polymorphism in EC-SOD are at a higher risk of developing T2DM; therefore, this may be utilized as a biomarker for early screening of T2DM in a Chinese population. PMID- 27966736 TI - Identification and characterization of the 14-3-3 gene family in switchgrass. AB - Members of the 14-3-3 family of proteins are conserved regulatory proteins that are widely found in eukaryotes and play crucial roles in diverse physiological processes, including responses to different stresses. Although genome-wide analysis of 14-3-3 proteins has been performed in a few plant species, it has not been performed in switchgrass. In this study, we identified 21 switchgrass 14-3-3 proteins (designated PvGF14a to PvGF14u) and examined genes for improved stress tolerance in this species. A phylogenetic tree was constructed to demonstrate that PvGF14 proteins can be divided into six groups, and that PvGF14 proteins belonging to each class exhibit similar gene structure. A phylogenetic analysis of PvGF14 proteins among switchgrass, Arabidopsis, and rice was conducted. Ten PvGF14 proteins were found to be orthologous to several abiotic stresses, and these were particularly responsive proteins in Arabidopsis and rice. Tissue specific expression profiles showed that PvGF14a, PvGF14k, PvGF14l, and PvGF14m may play significant roles in the regulation of lignin metabolism, and that PvGF14r may participate in flower development. Taken together, these data suggest that PvGF14 proteins may be involved in various biosynthesis. PMID- 27966737 TI - MYBA2 gene involved in anthocyanin and flavonol biosynthesis pathways in grapevine. AB - MYBA2 transcription factor (Myb-related gene) affects the coloring in grapevine berry and plays an important role in the biosynthesis of anthocyanin. The MYBA2 gene was cloned from Vitis vinifera L. cv. Cabernet Sauvignon and polyclonal antibodies for VvmybA2 were prepared. The VvmybA2 gene expression patterns were observed in seven tissues (the leaf, stem, flower, bud, root, berry, and tendril) and during the berry development stage at transcriptional and translational levels, respectively. The results indicated that the expression of VvmybA2 was approximately 11-fold higher in the berry than that in the other six tissues, and increased rapidly from 60 days after full bloom reaching a maximum on day 80. Furthermore, both the anthocyanin content and UDP-glucose:flavonoid-3-O glucosyltransferase (UFGT) gene expression levels increased rapidly 60 days after full bloom. Moreover, correlation analysis indicated that the transcriptional and translational expression levels of the VvmybA2 gene were significantly positively correlated with not only UFGT and DFR genes but also with the anthocyanin content during berry development. These results suggested that VvmybA2 could not only regulate the transcription of both UFGT and DFR but also is involved in the expression of the UFGT gene associated with color determination in grape berries. PMID- 27966738 TI - Fine mapping and candidate gene analysis of Brtri1, a gene controlling trichome development in Chinese cabbage (Brassica rapa L. ssp pekinensis). AB - Trichomes are derived from the epidermis and constitute an ideal system for studying cell division in plants. Here, a Chinese cabbage doubled haploid (DH) line (FT) without trichomes was crossed with another DH line (PurDH-1) with trichomes to develop an F2 population for fine mapping of trichome control genes. Genetic analysis showed that the trichome phenotype was controlled by a single dominant gene, Brtri1. Using 1226 glabrous individuals in the F2 segregation population, Brtri1 was localized to a 16.84 kb region between markers Pur6-31 and Pur6-39 on chromosome A06. One of the four complete open reading frames within the mapping region, Bra025311, encodes a MYB transcription factor and is highly homologous to the trichome regulatory gene GL1 in Arabidopsis thaliana. It was thus regarded as a candidate gene for Brtri1. Comparative sequencing showed a 5 bp deletion in the third exon of Bra025311 in FT, resulting in a frame-shift mutation. No expression of Bra025311 was detected in FT. A co-dominant indel marker close to this mutation site was developed for marker-assisted selection in Chinese cabbage breeding. PMID- 27966739 TI - Parameters of a dynamic mechanistic model of cattle growth retain enough biological interpretation for genotype-to-phenotype mapping. AB - This study aimed to investigate the predictability of a phenotype when using a dynamic model of cattle growth. Genotypic and phenotypic information on Nellore (Bos indicus) cattle were used in a genome-wide association analysis designed to contrast the biological interpretation of core parameters [conversion efficiency of metabolizable energy to net energy for gain (kg) and adjusted final shrunk body weight (AFSBW)] to their associated genomic regions and nearby quantitative trait loci (QTLs). Single nucleotide polymorphisms (SNPs) were used to develop prediction equations for kg and AFSBW, which enter the model for simulative prediction purposes. QTLs and genes, one related to mature body weight and another to growth efficiency, are consistent with the model equations. Significantly associated SNPs were used to compute parameters, which yielded reasonable model outcomes when compared with regular parameter computations. Our results provide evidence of the biological validity of using such parameters as component traits of higher phenotypes and the possibility of using genomic data for genotype-to-parameter mapping. PMID- 27966740 TI - Hypoxia facilitates epithelial-mesenchymal transition-mediated rectal cancer progress. AB - Rectal cancer is a commonly observed tumor in clinics, and epithelial-mesenchymal transition (EMT) is very important for tumor invasion and metastasis. We established a rectal cancer HCT-116 cell hypoxia model and detected cell proliferation, invasion, and EMT-related protein expression in this model, aiming to analyze the effect of hypoxia on rectal cancer cell EMT. Rectal cancer cell line HCT-116 was cultured in normoxic, hypoxic, or anaerobic environment, and hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA expression was detected in the cells by real-time PCR. Cell proliferation was tested by MTT assay; cell invasion was determined by transwell assay, and HIF-1alpha, epithelial-cadherin, and Snail protein levels were evaluated by western blot analysis. HIF-1alpha mRNA level significantly increased in the anaerobic group compared to that in the normoxic and hypoxic groups (P < 0.05). HCT-116 cell proliferation in the anaerobic group was obviously higher than that in the other two groups, with the hypoxic group showing stronger proliferative ability than the normoxic group (P < 0.05). Compared to the normoxic group, the HCT-116 cells demonstrated enhanced cell invasion and migration in hypoxic and anaerobic groups. HIF-1alpha and Snail expressions were upregulated, whereas epithelial-cadherin expression had declined in the hypoxic and anaerobic groups, compared to those in the normal control (P < 0.05). Therefore, hypoxia promoted rectal cancer cell progress by increasing HIF 1alpha to induce EMT. PMID- 27966741 TI - Genetic characteristics of non-Hodgkin lymphoma in ethnic Uighur people, and their clinical significance. AB - The incidence of non-Hodgkin lymphoma (NHL) in China is increasing and is attracting attention as a topic of research. The percentage of NHL cases in ethnic Uighur people is also gradually increasing. We therefore recruited Uighur people with NHL to investigate the correlation between genetic alternations and clinical/pathological features in an attempt to determine their clinical significance. A total of 60 NHL patients were recruited from our hospital for a microscopic examination of their tumor cell morphology. Further analysis of chromosome karyotypes revealed the relationship between genetic alternations and clinical/pathological features. Microscopic examination revealed increased numbers of tumor cells with altered morphology. The recruited patients all exhibited abnormal karyotypes. Chromosomal breakages were detected at 14q32, 18q21, 6q21-25, +3, +, +18, and short tandem repeat 17 (str17) in 18.3, 25, 25, 18.3, 15, and 21.7% of patients, respectively. Karyotype change was not related to age, gender, performance status score, or pathological type (P > 0.05), but was correlated with clinical stage, average lactate dehydrogenase (LDH) level, extra-lymphatic metastasis, median survival time, and efficacy of radio- or chemotherapy (P < 0.05). Independent risk factors for genetic change in Uighur NHL patients included clinical stage, average LDH level, extra-lymphatic metastasis, median survival time, and efficacy of radio- or chemotherapy (P < 0.05). Uighur NHL patients exhibited genetic changes including t(14:18), 6q21-25, +3, +7, +18, and str17. Clinical stage, average LDH level, extra-lymphatic metastasis, median survival time, and efficacy of radio- or chemotherapy were all independent risk factors for NHL. PMID- 27966742 TI - Genetic association between ACTN3 polymorphism and risk of non-acute ankle sprain. AB - In this study, we investigated the association between ACTN3 R577X polymorphism and non-acute ankle sprain by measuring the allele frequency and genotype distribution of ACTN3 in a Chinese Han population. We recruited 100 patients with non-acute ankle sprain and 100 healthy controls with no history of ankle injuries. Mass spectrometric analysis of single nucleotide polymorphism was used to analyze the genotype and allele frequencies of ACTN3. Results showed that the genotype frequency of RR in patients was 12.0%, which was significantly lower than that of the controls (24.0%) (OR = 1.7; 95%CI = 1.5-2.7; P = 0.001). The frequency distribution of the R allele in patients and controls were 68.5 and 56.7%, respectively (P = 0.002). Moreover, frequency of the RR genotype exhibited a downward linear trend with increased incidences of ankle sprain. Our results suggest that ACTN3 R577X polymorphism is associated with non-acute ankle sprain in the Chinese Han population. PMID- 27966743 TI - Reproductive outcome of male carriers of chromosomal abnormalities: multidisciplinary approach for genetic counseling and its implications. AB - Chromosomal abnormality is the most common genetic cause of infertility. Infertility, as a psychological problem, has received an increasing amount of attention. Psychological interventions have been shown to have beneficial effects on infertile patients with chromosomal abnormalities. The present study explored reproductive outcome of male carriers of chromosomal abnormalities, who accepted genetic counseling and psychological support. Cytogenetic analysis was performed using cultured peripheral blood lymphocytes and G-banding. The detection rate of chromosomal abnormalities was 10.3% in pre-pregnancy counseled males, with polymorphisms being most common, followed by 47,XXY and balanced translocation. Follow-up of 170 carriers with normozoospermia, after 3 years, showed that 94.7% of the cases resulted in live births. In the carriers of polymorphisms, balanced translocation, inv(9), Robertsonian translocation, inversion, and 47,XYY, live birth rates were 96.8, 85.7, 100, 83.3, 75, and 100%, respectively. Follow-up of 54 carriers with oligozoospermia or azoospermia, after 3 years, showed that 14.8% of the cases resulted in live births. In the carriers of 47,XXY with severe oligozoospermia or azoospermia, 80 or 5.9% of the cases resulted in live births, respectively. Therefore, timely psychological support would be beneficial and multidisciplinary approach should be preferentially considered for the management of individuals with chromosomal abnormalities. PMID- 27966744 TI - Absence of toxicity and genotoxicity in an extract of Rubus coriifolius. AB - Rubus coriifolius Focke is a wild plant from the Rosaceae family. It grows in both Guatemala and Mexico. The polar extract of the aerial parts of this plant has antibacterial, anti-inflammatory, and anti-protozoal activities. These properties may explain the traditional use of this plant. In vivo and in vitro assays were used to assess the genotoxic and toxic effects of an ethanol extract of the aerial parts of R. coriifolius. Three groups of rats were orally administered the R. coriifolius extract diluted in ethanol (5%) at doses of 1.89 mg/kg body weight (low dose), 4.72 mg/kg body weight (medium dose), and 9.44 mg/kg body weight (high dose) for 3 weeks. Genotoxic/cytotoxic effects induced by the R. coriifolius ethanol extract were evaluated in vivo by a micronuclei (MN) test in rat's bone marrow cells and in vitro by MN and sister chromatid exchange (SCE) in human lymphocyte cultures. In vivo genotoxicity analyses revealed that the average number of micronucleated polychromatic erythrocytes and the polychromatic erythrocyte/red blood cell ratio at all doses were not significantly different from those of the negative control. In vitro genotoxicity analyses showed that MN, SCE, and proliferative index frequencies in a human lymphocyte cell culture were not significantly different from those of the negative control. These results demonstrate that the ethanol extract of R. coriifolius aerial parts is not toxic or mutagenic (in vitro and in vivo) and does not affect cell proliferation at the concentrations analyzed. PMID- 27966745 TI - Myostatin mRNA expression and its association with body weight and carcass traits in Yunnan Wuding chicken. AB - Myostatin (MSTN) is expressed in the myotome and developing skeletal muscles, and acts to regulate the number of muscle fibers. Wuding chicken large body, developed muscle, high disease resistance, and tender, delicious meat, and are not selected for fast growth. Broiler chickens (Avian broiler) are selected for fast growth and have a large body size and high muscle mass. Here, 240 one-day old chickens (120 Wuding chickens and 120 broilers) were examined. Twenty chickens from each breed were sacrificed at days 1, 30, 60, 90, 120, and 150. Breast and leg muscle samples were collected within 20 min of sacrifice to investigate the effects of MSTN gene expression on growth performance and carcass traits. Body weight, carcass traits, and skeletal muscle mass in Wuding chickens were significantly (P < 0.05) lower than those in broiler chickens at all time points. Breast muscle MSTN mRNA was lower in Wuding chickens than in broilers before day 30 (P < 0.05). After day 30, breast muscle MSTN expression was higher in Wuding chicken than in broilers (P < 0.05). Leg muscle MSTN mRNA expression was higher in Wuding chicken than in broilers at all ages except for day 60 (P < 0.05). Correlation analysis revealed that breast muscle MSTN expression has a greater effect in slow growing Wuding chickens than in the fast growing broilers. In contract, leg muscle MSTN mRNA level has a greater effect in broilers than in Wuding chickens. MSTN regulates growth performance and carcass traits in chickens. PMID- 27966746 TI - Polymorphisms in the leptin gene promoter in Brazilian beef herds. AB - Brazil is the world's largest producer of beef cattle; however, the quality of its herds needs to be improved. The use of molecular markers as auxiliary tools in selecting animals for reproduction with high pattern for beef production would significantly improve the quality of the final beef product in Brazil. The leptin gene has been demonstrated to be an excellent candidate gene for bovine breeding. The objective of this study was to sequence and compare the leptin gene promoter of Brazil's important cattle breeds in order to identify polymorphisms in it. Blood samples of the Nellore, Guzerat, Tabapua, and Senepol breeds were collected for genomic DNA extraction. The genomic DNA was used as a template for polymerase chain reaction (PCR) to amplify a 1575-bp fragment, which in turn was sequenced, aligned, and compared between animals of different breeds. Twenty-three single nucleotide polymorphic sites, including transitions and transversions, were detected at positions -1457, -1452, -1446, -1397, -1392, -1361, -1238, -963,-901, -578, -516, -483, -478, -470, -432, -430, -292, -282, -272, -211, -202, -170, and -147. Additionally, two insertion sites at positions -680 and -416 and two deletion sites at positions -1255 and -1059 were detected. As the promoter region of the leptin gene has been demonstrated to vary among breeds, these variations must be tested for their use as potential molecular markers for artificial selection of animals for enhanced beef production in different systems of bovine production in Brazil. PMID- 27966747 TI - Effects of low temperature on photosynthetic characteristics in the super-high yield hybrid rice 'Liangyoupeijiu' at the seedling stage. AB - To elucidate the resistance of high-yield hybrid rice (Oryza sativa L.) at the seedling stage to low temperature, photosynthetic characteristics, such as membrane lipid peroxidation, fatty acid composition, and chloroplast ultrastructure, were investigated in a newly developed super-hybrid rice ('Liangyoupeijiu') and a traditional chill-sensitive hybrid rice ('Shanyou63'), with 20 degrees C as the control condition and 10 degrees C as the low temperature treatment. Chlorophyll content, oxygen consumption by photosystem I, and oxygen production by photosystem II in the thylakoid membrane mainly decreased under the low-temperature treatment. The malondialdehyde content of 'Liangyoupeijiu' decreased slightly, while increases in membrane lipid peroxidation were greater in 10 degrees C-treated than in 25 degrees C-treated 'Shanyou63' seedlings. The index of unsaturated fatty acids increased in the two cultivars, particularly in 'Liangyoupeijiu'. No severe chloroplast ultrastructure damage was observed under cold stress, but the number of osmiophilic granules in 'Shanyou63' increased rapidly. The results indicate that compared to 'Shanyou63', 'Liangyoupeijiu' is more chill-resistant at the seedling stage. PMID- 27966748 TI - Effect of selective serotonin reuptake inhibitors on expression of 5-HT1AR and neurotransmitters in rats with vascular dementia. AB - 5-hydroxytryptamine receptor 1A (5-HT1AR) is closely associated with cognitive functions. Selective serotonin reuptake inhibitors (SSRIs) can protect individuals from brain damage following ischemia/hypoxia. To investigate the function of SSRIs in vascular dementia (VD), we established a rat model of VD, and observed the effect of SSRIs on the expression of 5-HT1AR mRNA and neurotransmitters. Male SD rats (6 months) were randomly assigned into sham, model, and SSRI groups (N = 30). VD was achieved by permanent ligation of the bilateral common carotid artery. Escitalopram, a highly selective 5-HT reabsorption inhibitor, was ip injected into the rats for three consecutive weeks. The Morris water-maze was used to test learning and memory. H&E staining for neuronal injury was conducted on cortical and hippocampal tissues. HPLC was used to determine the levels of dopamine (DA), 5-HT, and norepinephrine (NE). RT PCR was used to determine expression of 5-HT1AR mRNA. As compared to control rats, model animals demonstrated elongated escape latency, lower platform crossing times, and significant injuries to hippocampal CA1 neurons. This was accompanied by reductions in DA, 5-HT, and NE levels in hippocampal tissues, as well as reduced cortical 5-HT and decreased 5-HT1AR mRNA expression (P < 0.05). Escitalopram treatments reduced escape latency, elevated platform crossing times, improved CA1 neuronal damage, increased DA and 5-HT levels in hippocampal and cortical neurons, as well as elevated expression of 5-HT1AR mRNA (P < 0.05). Therefore, SSRIs may improve cognitive dysfunction of VD rats, possibly by stimulating expression of neurotransmitters and protecting neurons. PMID- 27966749 TI - Prognostic significance of tumor-associated macrophage infiltration in gastric cancer: a meta-analysis. AB - Tumor-associated macrophages (TAMs), which play a crucial role in the tumor microenvironment, can be divided into M1 and M2 phenotypes, these phenotypes may exert opposite effects on the prognoses of patients with gastric cancer (GC). The association between TAMs and GC is contentious. Thus, a meta-analysis of 12 studies (incorporating 1388 patients) retrieved from the Cochrane Library, PubMed, and Embase databases was conducted in order to evaluate the relationship between TAMs and GC prognosis. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled to explore the effect of these cells on survival of GC patients. Our results implied that high total TAM infiltration levels correspond to worse overall survival (OS) in patients with GC (HR = 1.70, 95%CI = 1.39-2.09; P < 0.001), and a similar result was observed in relation to M2 macrophage infiltration (HR = 1.71, 95%CI = 1.19-2.45; P = 0.004). In contrast, elevated M1 macrophage density in GC patients was associated with better OS (HR = 0.46, 95%CI = 0.33-0.65; P < 0.001). This meta-analysis showed that the numbers of infiltrating M2 macrophages and total TAMs might be negative prognostic factors for patients with GC, while M1 macrophage infiltration may be associated with a favorable survival rate. PMID- 27966750 TI - Acidic and basic fibroblast growth factor expression levels in cervical cancer and their effects on tumor cell proliferation. AB - Fibroblast growth factors (FGFs) play important roles in angiogenesis, wound healing, embryonic development, and endocrine signaling pathways. Increasingly, recent studies have reported aberrant FGF expression in various malignancies. However, the involvement of FGFs in cervical carcinoma pathogenesis remains unclear. We aimed to investigate expression of acidic (aFGF) and basic FGF (bFGF) in patients with this disease, and assess their effects on cervical cancer cell proliferation. Twenty cervical cancer patients and 10 cervical intraepithelial neoplasia (CIN) patients were recruited, and 10 cancer-free individuals were included as controls. Reverse transcription-polymerase chain reaction and western blotting were employed to detect FGF mRNA and protein levels, respectively. Furthermore, HeLa cells were treated with FGFs and subjected to thiazolyl blue tetrazolium bromide assays to quantify proliferation. Compared with CIN and normal cervical tissues, aFGF and bFGF mRNA and protein levels were significantly elevated in cervical carcinomas (P < 0.05). CIN tissues exhibited higher expression of these FGFs than normal tissues (P < 0.05). Moreover, their mRNA levels were increased in advanced cancer stages (P < 0.05), although no significant difference was detected between tumors of different differentiation grades in this regard (P > 0.05). HeLa cell proliferation increased in an aFGF- and bFGF-dose-dependent manner (P < 0.05), the latter exerting a more potent proliferative influence, with its effect peaking at 75 ng/mL. aFGF and bFGF were highly expressed in cervical cancer tissues and their levels positively correlated with clinical stage. Both facilitate proliferation of cervical carcinoma cells and are implicated in cancer pathogenesis and progression. PMID- 27966751 TI - Identification of the CAD gene from Eucalyptus urophylla GLU4 and its functional analysis in transgenic tobacco. AB - Cinnamyl alcohol dehydrogenase (CAD) catalyzes the final step in lignin biosynthesis. The genus Eucalyptus belongs to the family Myrtaceae, which is the main cultivated species in China. Eucalyptus urophylla GLU4 (GLU4) is widely grown in Guangxi. It is preferred for pulping because of its excellent cellulose content and fiber length. Based on GLU4 and CAD gene expression, a Eucalyptus variety low in lignin content should be obtained using transgenic technology, which could reduce the cost of pulp and improve the pulping rate, and have favorable prospects for application. However, the role and function of CAD in GLU4 is still unclear. In the present study, EuCAD was cloned from GLU4 and identified using bioinformatic tools. Subsequently, in order to evaluate its impact on lignin synthesis, a full-length EuCAD RNAi vector was constructed, and transgenic tobacco was obtained via Agrobacterium-mediated transformation. A significant decrease in CAD expression and lignin content in transgenic tobacco demonstrated a key role for EuCAD in lignin biosynthesis and established a regulatory role for RNAi. In our study, the direct molecular basis of EuCAD expression was determined, and the potential regulatory effects of this RNAi vector on lignin biosynthesis in E. urophylla GLU4 were demonstrated. Our results provide a theoretical basis for the study of lignin biosynthesis in Eucalyptus. PMID- 27966752 TI - DNase concentration assay to obtain DNA-free RNA from sugarcane leaves. AB - The success of gene expression studies, protein synthesis, and construction of cDNA libraries directly depends on the purity and integrity of the RNA used in these tests, as even minor amounts of contaminant DNA (<1%) can produce a false positive amplification signal in quantitative real-time PCR. For RNA contaminated with genomic DNA, an essential step in the studies on gene expression is the treatment of the RNA samples with DNase. This study was conducted to test three different concentrations of DNase I (0.02, 0.04, and 0.06 MUL/ng of RNA), which were chosen based on the results of the RNA sample quantifications and as indicated by the manufacturer, to digest genomic DNA present in the RNA samples extracted from sugarcane leaves with the ConcertTM Plant RNA Reagent. The results showed that all three concentrations of DNase significantly reduced DNA concentrations. However, RNA was also degraded on DNase I treatment. In addition, the amount of DNA present in the RNA samples after purification with DNase I was sufficient for its amplification in the tests conducted with conventional PCR. Furthermore, the condition of RNA samples obtained after the treatments allowed for real-time PCR. Therefore, we concluded that 0.02 MUL DNase I was the ideal concentration for sugarcane RNA purification, as higher concentrations do not increase the efficiency of the genomic DNA digestion in RNA samples and only make the purification process more expensive. This study provides important information on the effect of high concentrations of DNase I and complements previous studies that have so far tested only the DNase concentration recommended by the manufacturer. PMID- 27966753 TI - Polymorphism of starch pathway genes in cassava. AB - The distribution and frequency of single nucleotide polymorphisms (SNPs) can help to understand changes associated with characteristics of interest. We aimed to evaluate nucleotide diversity in six genes involved in starch biosynthesis in cassava using a panel of 96 unrelated accessions. The genes were sequenced, aligned, and used to obtain values for nucleotide diversity (pi), segregating sites (theta), Tajima's D test, and neighbor-joining (NJ) clustering. On average, one SNP per 147 and 171 bp was identified in exon and intron regions, respectively. Thirteen heterozygous loci were found. Three of seven SNPs in the exon region resulted in non-synonymous replacement or four synonymous substitutions. However, no associations were noted between SNPs and root dry matter content. The parameter pi ranged from 0.0001 (granule bound starch synthase I) to 0.0033 (alpha-amylase), averaging 0.0011, while theta ranged from 0.00014 (starch branching enzyme) to 0.00584 (starch synthase I), averaging 0.002353. The theta diversity value was typically double that of the pi. Results of the D test did not suggest any evidence of deviance of neutrality in these genes. Among the evaluated accession, 82/96 were clustered using the NJ method but without a clear separation of the root dry-matter content, root pulp coloration, and classification of the cyanogenic compound content. High variation in genes of the starch biosynthetic pathway can be used to identify associations with the functional properties of starch for the use of polymorphisms for selection purposes. PMID- 27966754 TI - Translocation breakpoints of chromosome 4 in male carriers: clinical features and implications for genetic counseling. AB - Cytogenetic analysis remains a powerful and cost-effective technology, and has wide applicability in genetic counseling for infertile males. Chromosomal rearrangements are thought to be one of the major genetic factors that influence male infertility. Some carriers with balanced reciprocal translocation have been identified as having oligozoospermia or azoospermia, and there is an association between balanced translocation and recurrent abortion. Researchers have reported the involvement of chromosome 4 translocations in male factor infertility and recurrent miscarriages. A translocation breakpoint might interrupt the structure of an important gene, and it is associated with reproductive failure. However, the clinical characteristics of the breakpoints in chromosome 4 translocations have not been studied. Here, we report the breakpoints in chromosome 4 translocation and the clinical features presented in carriers to enable informed genetic counseling of these patients. Of 82 patients with balanced reciprocal translocations, 14 were carriers of the chromosome 4 translocation: four presented with pregestational infertility (clinical manifestations: oligozoospermia, severe oligozoospermia, or azoospermia), whereas 10 presented with gestational infertility (able to conceive but with a tendency to miscarry). The breakpoint at 4q12 was associated with pregestational infertility, whereas the breakpoints at 4q13, 4q21, 4q25, and 4q32 were associated with gestational infertility. However, the breakpoint at 4q35 was associated with both pregestational and gestational infertility. Chromosome 4 translocation carriers with pregestational or gestational infertility should be counseled on chromosomal breakpoints and the different technologies available to assist reproduction. PMID- 27966755 TI - Identification of quantitative trait loci for mineral elements in grains and grass powder of barley. AB - Mineral elements in barley (Hordeum vulgare) play an important physiological role in global human health. In this study, quantitative trait loci (QTLs) for concentration of nine mineral elements in barley grain and grass powder were detected in a population of 193 recombinant inbred lines of the barley cross Ziguangmangluoerling x Schooner and the parents. We observed large genetic variation contributing to element concentrations in both grains and grass powder. The mean K, Ca, and Fe concentrations in grass powder were 6.67, 12.00, and 4.58 times that of regenerating barley grains. In grains, 17 QTLs that accounted for 6.36-64.08% of the phenotypic variation in Zn, Mg, Ca, K, Na, Mn, Fe, and P concentrations were identified. In grass powder, seven QTLs were identified; these accounted for 6.03-21.86% of the variation in Ca, Zn, Mg, K, Fe, and Cu concentrations. These QTLs affecting elements in grain and grass powder are so far unreported in barley. To our knowledge, QTLs with pleiotropic effects for three elements were also identified for the first time in barley. The qK1/qMg1/qCa1 region between markers Bmag0211 and GBMS0014 on chromosome 1H was shown to have large additive effects for Mg, Ca, and K concentrations in grains. These additive effects indicated that the high element (Mg, Ca, Zn, Mn, and K) alleles were contributed by Ziguangmangluoerling. These results will further our understanding of the genetic basis of mineral elements and help us develop markers linked with mineral elements for marker-assisted selection breeding in barley. PMID- 27966756 TI - Karyotype asymmetry in Cynodon Rich. (Poaceae) accessions. AB - Cynodon is a genus of plants with forage potential that has attracted the interest of breeders. These species have high morphological variability in a large number of varieties and cytotypes, hampering identification. This study aimed to determine the karyotype asymmetry index among accessions of Cynodon to discriminate between them. Karyotype symmetry was based on three estimates, which were compared. The basic number for the genus is x = 9. The results of the chromosome count and DNA quantification, respectively, were as follows: two diploid accessions (2n = 2x = 18 and 1.08 +/- 0.094 to 1.17 +/- 0.036 pg DNA and +/- standard deviation), one triploid accession (2n = 3x = 27 and 1.63 +/- 0.017 pg DNA), four tetraploid accessions (2n = 4x = 36 and 1.88 +/- 0.069 to 2.10 +/- 0.07 pg DNA), and one pentaploid accession (2n = 5x = 45 and 2.55 +/- 0.098 pg DNA). C. incompletus var. hirsutus had the longest total length of the haploid lot (29.05 um), with chromosomes that ranged from 1.7 to 6.2 um in length. On the basis of the karyotype asymmetry indices, the accessions were divided into two groups: 1) C. dactylon var. dactylon, C. transvaalensis, C. dactylon var. polevansii, three accessions of Cynodon sp, and C. nlemfuensis; and 2) C. incompletus var. hirsutus. This is the first description of tetraploidy in C. transvaalensis. The karyotypic data facilitated a determination of the degree of proximity between the accessions. PMID- 27966757 TI - Equine chorionic gonadotropin influence on sheep oocyte in vitro maturation, apoptosis, and follicle-stimulating hormone receptor and luteinizing hormone receptor expression. AB - We assessed the effects of equine chorionic gonadotropin (eCG) on oocyte in vitro maturation (IVM), apoptosis, and follicle-stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR), and gonadotropin-releasing hormone receptor (GnRHR) expression and mRNA levels. Cumulus-oocyte complexes (COCs) were recovered from sheep ovaries and pooled in groups, before being cultured in IVM media containing varying eCG concentrations. Maturation and apoptosis rates were then calculated. Expression of FSHR, LHR, and GnRHR mRNA in oocytes was measured using quantitative reverse transcription polymerase chain reaction. Protein levels were ascertained by western blotting. Matured oocytes displayed and released an intact first polar body. Sheep oocyte maturation rates gradually increased as eCG concentration was raised from 0 to 20 ug/mL. Apoptosis rates of eCG-treated oocytes were lower than those of the control group, and were lowest using 20 ug/mL eCG. FSHR, LHR, and GnRHR mRNA expression increased (P < 0.01, P < 0.05, and P < 0.05, respectively, compared to 0 ug/mL eCG) with eCG concentration, being highest following exposure to 20 ug/mL. FSHR and GnRHR protein levels were significantly higher in oocytes administered 20 ug/mL eCG compared with those matured in the absence of eCG. eCG dose positively correlated with FSHR, LHR, and GnRHR mRNA and protein expression. In conclusion, eCG enhances maturation and decreases apoptosis of oocytes undergoing IVM, and heightens FSHR, LHR, and GnRHR expression. Such increased expression may facilitate oocyte IVM. These findings contribute to our understanding of the mechanisms of underlying hormonal control of sheep oocyte IVM, advancing ovine reproductive methods. PMID- 27966758 TI - Molecular phylogenetic and dating analysis of pierid butterfly species using complete mitochondrial genomes. AB - Pieridae is a butterfly family whose evolutionary history is poorly understood. Due to the difficulties in identifying morphological synapomorphies within the group and the scarcity of the fossil records, only a few studies on higher phylogeny of Pieridae have been reported to date. In this study, we describe the complete mitochondrial genomes of four pierid butterfly species (Aporia martineti, Aporia hippia, Aporia bieti, and Mesapia peloria), in order to better characterize the pierid butterfly mitogenomes and perform the phylogenetic analyses using all available mitogenomic sequence data (13PCGs, rRNAs, and tRNAs) from the 18 pierid butterfly species comprising the three main subfamilies (Dismorphiinae, Coliadinae and Pierinae). Our analysis shows that the four new mitogenomes share similar features with other known pierid mitogenomes in gene order and organization. Phylogenetic analyses by maximum likelihood and Bayesian inference show that the pierid higher-level relationship is: Dismorphiinae + (Coliadinae + Pierinae), which corroborates the results of some previous molecular and morphological studies. However, we found that the Hebomoia and Anthocharis make a sister group, supporting the traditional tribe Anthocharidini; in addition, the Mesapia peloria was shown to be clustered within the Aporia group, suggesting that the genus Mesapia should be reduced to the taxonomic status of subgenus. Our molecular dating analysis indicates that the family Pieridae began to diverge during the Late Cretaceous about 92 million years ago (mya), while the subfamily Pierinae diverged from the Coliadinae at about 86 mya (Late Cretaceous). PMID- 27966760 TI - Association analysis of IGF-I gene expression with growth and reproductive traits in Jinghai yellow chickens. AB - The insulin-like growth factor, IGF-I, plays an important role in the development of growth and reproductive traits. Single-strand conformation polymorphism analysis was used to detect and analyze polymorphisms and expression profiles of the IGF-I gene and its association with growth and reproductive traits of Jinghai yellow chickens. A point mutation g.295T>C was detected in the IGF-I gene with three genotypes CC, CT, and TT. The CT and TT genotypes were found to be significantly (P < 0.05) superior to the CC genotype in 8-, 10-, 12-, 14-, and 16 week-age weight of chickens (for growth traits) and in body weight at first egg laying (for reproductive traits). Comparison of the expression level between males and females showed similarity in their expression curves, with females showing relatively higher IGF-I expression than males in all studied tissues. A similar IGF-I expression pattern was observed in the breast and leg muscles of both males and females, with the leg muscle showing relative higher IGF-I expression than the breast muscle. Our results indicate that, g.295T>C mutation in the IGF-I gene affects certain growth and reproductive traits, and it could be used to provide a theoretical basis as well as marker-assisted selection to upgrade the development of Jinghai yellow chickens in future. PMID- 27966759 TI - Analysis of genetic diversity of a native population of Myrcia lundiana Kiaersk. plants using ISSR markers. AB - Myrcia lundiana Kiaersk. is a tree of the family Myrtaceae found in tropical and subtropical areas of the southern hemisphere that produces essential oil. The aim of this study was to characterize the genetic diversity of M. lundiana plants from a native population of Parque Nacional de Itabaiana, using inter-simple sequence repeat molecular markers. Thirty-five primers were tested, 20 of which were polymorphic, resulting in 135 polymorphic and informative bands. Results of the cluster analysis, obtained using the unweighted pair group method with arithmetic mean, grouped plants into three clusters: Cluster I - MLU001, MLU002, MLU003, MLU004, MLU005, MLU006, MLU018, MLU019, MLU020, MLU021, MLU022; MLU008, MLU011, MLU012, MLU014, MLU015, MLU017, MLU026, and MLU028; Cluster II - MLU007, MLU009, MLU010, MLU013, and MLU016; and Cluster III - MLU023, MLU024, MLU025, and MLU027. Jaccard similarity coefficients for pair-wise comparisons of plants ranged between 0.15 and 0.87. MLU014 and MLU015 presented low genetic diversity, with a similarity index of 0.87. Conversely, MLU007 and MLU019 presented high diversity, with a similarity index of 0.15. According to the structure analysis, three distinct clusters were formed. Genetic diversity of M. lundiana plants was intermediate, and expansion of its genetic diversity is necessary. MLU026 and MLU028 are the most suitable for selection in breeding programs, since they clearly represent all of the diversity present in these plants. Moreover, these results provide important information on the existing genetic variability, highlighting the importance of Parque Nacional de Itabaiana for the conservation of this species. PMID- 27966761 TI - Genetic divergence and admixture of ancestral genome groups in the sugarcane variety 'RB867515' (Saccharum spp). AB - We analyzed 80 plants of the sugarcane (Saccharum spp) variety 'RB867515' in order to investigate its diversity and genetic structure at the molecular level. Four simple sequence repeat (SSR) loci (UGSM51, SMC1237, SEGMS1069, and UGSM38) and five expressed sequence tag (EST)-SSR loci (ESTA68, ESTB92, ESTB145, ESTC66, and ESTC84) were used as molecular markers. The polymorphic loci rate was 66.6%. A total of 17 alleles and an average of 1.88 alleles/locus were detected. The number of alleles in the EST-SSR loci was lower than the number of alleles in the SSRs of non-expressed loci. The mean observed heterozygosity among the nine SSR loci was 0.3291. Genetic structure analysis showed that 'RB867515' contains alleles from three ancestral groups (K = 3), but there is little admixing of alleles in the same plant (from 0.8 to 17.3%); only 1.88% of the plants shared alleles from two or three groups. ESTB92, ESTC84, and UGSM38 were monomorphic, but there was evidence of polymorphism in ESTA68, ESTB145, ESTC66, UGSM51, SMC1237, and SEGMS1069, indicating that 'RB867515' has variability at the molecular level and the potential to be used as a parent in breeding programs. The molecular variability observed in 'RB867515' indicates that the clone terminology that is used to identify this cultivar is inconsistent with the original meaning of "clone", which is defined as a sample of genetically identical plants. PMID- 27966762 TI - CASE-REPORT Low-level trisomy 14 mosaicism in a male newborn with ectrodactyly. AB - Complete trisomy 14 mosaicism is a rare chromosome disorder and was first reported in 1970. We describe a case of a male neonate who presented complete trisomy 14 mosaicism in only 4% of the cells from peripheral blood. A nineteen day-old male neonate was born as result of the second pregnancy. The infant was delivered by cesarean section due to gestational hypertension and chronic fetal distress. The length of the term pregnancy was 37 weeks, the birth weight was 3.105 g, the length was 48 cm, and the head circumference was 35.5 cm. The baby remained hospitalized for 19 days in the neonatal intensive care unit due to respiratory distress syndrome and congenital malformations. Physical examination revealed a toned and normal activity, followed by phenotypic changes such as a broader forehead, formation of a cleft palate, hypertelorism, low-set ears, bilateral cryptorchidism, absence of the second toe of the left foot (ectrodactyly), and fusion of third and fourth toes in the right foot (bilateral syndactyly). Cytogenetic analysis was performed on peripheral blood cultures after hospitalization in the neonatal intensive care unit. Analysis of 200 G banded metaphases showed that 192 (96%) had normal karyotype 46,XY and only 8 (4%) presented trisomy 47,XY,+14. It was not possible to perform cytogenetic analysis on the patient's parents. Our patient represents the first case of trisomy 14 disorder to present ectrodactyly. PMID- 27966763 TI - Combining ability of S3 progenies for key agronomic traits in popcorn: comparison of testers in top-crosses. AB - The successful development of hybrid cultivars depends on the reliability of estimated combining ability of the parent lines. The objectives of this study were to assess the combining ability of partially inbred S3 families of popcorn derived from the open-pollinated variety UENF 14, via top-crosses with four testers, and to compare the testers for their ability to discriminate the S3 progenies. The experiment was conducted in the 2015/2016 crop season, in an incomplete-block (Lattice) design with three replications. The following agronomic traits were evaluated: average plant height, grain yield (GY), popping expansion (PE), and expanded popcorn volume per hectare. The top-cross hybrid, originating from the BRS-Angela vs S3 progeny 10 combination, was indicated as promising, showing high values for specific combining ability for GY and PE. For the S3 progenies that showed high and positive GCA values for GY and PE, the continuity of the breeding program is recommended, with the advance of self pollination generations. Fasoulas' differentiation index discriminated the BRS Angela tester as the most suitable for identifying the superior progenies. PMID- 27966764 TI - Closer to a polio-free Eastern Mediterranean Region. PMID- 27966765 TI - Validation of Persian version of WHOQOL-HIV BREF questionnaire in Islamic Republic of Iran. AB - The aim of this cross-sectional study was to validate the first Persian version of the WHOQOL-HIV BREF questionnaire. The study sample comprised 61 patients regularly attending the outpatient infectious disease clinic consultation centre for patients with behavioural disorders in 2013-2014. The internal consistency, content related validity and reliability of WHOQOL-HIV BREF were evaluated. Content validity was quantified using the content validity ratio (CVR) according the to Lawshe formula. CVR > 0.51 and mean judgment > 2 were significant at P = 0.05. The Cronbach alpha score was > 0.7 for each domain and = 0.87 for the whole scale, indicating good reliability. Item-to-total correlation coefficient between each item and its respective domain was 0.39-0.87. The correlation between each domain and overall QOL was excellent. This study demonstrates that the Persian version of WHOQOL-HIV BREF is a valid and reliable tool for evaluation of QOL in HIV-infected patients. PMID- 27966766 TI - Effect of anti-smoking advertisements on Turkish adolescents. AB - The aim of the present study was to determine the perception of 10 anti-smoking advertisements in 1434 Turkish adolescents. We used the Effectiveness of the Anti smoking Advertisements Scale, which included 6 items for each advertisement; each item was assessed on a 5-point Likert-type scale. Multiple logistic regression analysis was used to determine the factors associated with the impact of the advertisements. All the advertisements were more effective for adolescents who had never smoked compared to ex-smokers and current smokers. We also noted that, regardless of age, smoking status decreased the effectiveness of all the advertisements. Previous studies have shown that smokers have a negative attitude towards anti-smoking messages. In the present study, the most effective advertisements among adolescents were those with "Sponge and tar", "Smoking harms in every breath" and "Children want to grow". In conclusion, although anti smoking campaigns are targeted towards adults, they also have a strong influence on adolescents. The main target population for advertisements should be individuals aged < 15 years who have not yet started smoking. PMID- 27966767 TI - The impact of media and advertising of food on the eating behaviour of adolescent girls in Jeddah, Saudi Arabia. AB - This study aims to detect differences in eating behaviours demonstrated by adolescent girls in Jeddah Saudi Arabia, according to the influence of the media through TV advertisements. A cross-sectional survey was conducted of 1519 girls from 20 schools in Jeddah. Survey questions included information regarding media advertising and its effect on eating behaviour. Bivariate analyses were performed to define differences in eating behaviour according to media influence and Chi square analyses to detect significant relationships. The results indicated a significant correlation between dessert consumption and advertising exposure (P = 0.035). Adolescent girls exposed to such advertising were more likely to consume dessert [n=299 (48.5%)], to shop for food [n=316 (50.7%)], and had attempted to lose weight [n=373 (59.5%)]. The results emphasize the role and obligation of decision-makers to protect young consumers through increased legislation and control of media content (particularly food advertisements) targeting young people. PMID- 27966768 TI - Prevalence and correlates of metabolic syndrome in pre-crisis Syria: call for current relief efforts. AB - This study aimed to assess the prevalence, components and correlates of metabolic syndrome (MetS) in adults in pre-crisis Aleppo, Syrian Arab Republic. We used a population-based, 2-stage cluster sampling method in a population of 557 men and 611 women, randomly selected from 83 residential neighbourhoods including many rural settlers. Sociodemographic and lifestyle characteristics, comorbidity, anthropometry and biochemical indices were measured. Prevalence of MetS was estimated at 39.6%, with comparable rates in men and women. Hypertension was the most prevalent component (56.6%), followed by central obesity (51.4%). Among women, education (12 years) was inversely associated with risk of MetS, while family history of obesity and diabetes was associated with an increased risk. The high prevalence of MetS and its components emphasizes the burden of cardiovascular diseases among adults in pre-crisis Aleppo. A system of surveillance and management for cardiovascular diseases needs to be incorporated into the current humanitarian response. PMID- 27966769 TI - Trends in outpatient cataract surgery in the Islamic Republic of Iran, 2006-2010. AB - This study aimed to determine the trends in outpatient cataract surgery and its determinants in the Islamic Republic of Iran between 2006 and 2010. In this cross sectional study, 106 cataract surgery centres were selected in all provinces by multistage randomized cluster sampling. The number of centres in each province was determined from the number of cataract operations and the number of patient charts examined in each centre was proportionate to the number of cataract operations in that centre. The prevalence of outpatient surgery increased from 46.0% (95% CI, 35.3-56.8) in 2006 to 51.4% (95% CI, 40.2-62.7) in 2010 (P = 0.549). Patients stayed in hospital for more than one night after 10.5% (95% CI, 6.9-14.1) of operations. Use of phacoemulsification and topical anaesthesia increased the prevalence of outpatient surgery and decreased intraoperative complications. Although outpatient cataract surgery increased by 11.7%, use of methods such as phacoemulsification is not widespread, and more attention should be paid to the barriers to outpatient cataract surgery in the Islamic Republic of Iran. PMID- 27966770 TI - The status of serum vitamin D in the population of the United Arab Emirates. AB - Research exploring the status of serum vitamin D levels in the populations of countries bordering the Arabian Gulf shows a high prevalence of vitamin D deficiency/insufficiency. These reports were usually drawn from small samples unlikely to be representative of the population. We explored serum vitamin D level in a large sample (7924) of patients who were given a blood test to check their vitamin D status on their first consultation at a day surgery hospital in Dubai. The overall mean level of 25(OH) D was ~ 20 ng/mL Deficiency was found among all age groups, in both sexes and in both local and non-local populations: overall 85.4% were vitamin D deficient, 12.5% showed insufficient serum vitamin D level, and only 2.1% had an appropriate level. In the multivariate model, serum vitamin D concentrations were positively correlated with male sex, local population and the 17-31 years age group. PMID- 27966771 TI - Association between body mass index, diet and dental caries in Grade 6 boys in Medina, Saudi Arabia. AB - The prevalence of obesity is increasing in Saudi Arabia and although caries is associated with obesity, this association has not been investigated in Medina. This study aimed to determine the association between dental caries, body mass index (BMI) and dietary habits of 12-year-old boys from four geographically distinct schools in Medina. Mean BMI was 22.17 kg/m2 (+/- 5.15); 41% had normal BMI, 25% were overweight and 30% were obese. The mean Decayed, Missing and Filled Teeth (DMFT) score was 1.46 (+/- 2.04). Those in the normal BMI range had a significantly higher prevalence of caries (57%) and DMFT score (1.92) compared with the overweight and obese groups (P < 0.05). These differences remained significant after controlling for possible confounders via linear regression. Mean BMI was significantly lower in boys with severe compared with mild or no caries. Normal and underweight participants had an almost 2 times greater risk of developing caries compared with their overweight and obese counterparts. The children had poor dietary habits and there were no significant associations between dietary variables and caries. PMID- 27966772 TI - Essential public health functions: the experience of the Eastern Mediterranean Region. PMID- 27966773 TI - The growing threat of antibiotic resistance in the Eastern Mediterranean Region - what does it take to control it? PMID- 27966774 TI - Primary oral health care: a missing link in public health in Pakistan. AB - In Pakistan, the limited availability of oral health care and the high level of unmet oral health care needs are well documented. The recorded prevalence of dental caries is 50-70% and that of oral cancer is among the highest in the world. Although oral health care has been declared to be part of the primary health care system, oral health disparities between rich and poor, and emerging problems of access to and use of appropriate care have never been addressed, reflecting a lack of awareness among both patients and health system decisionmakers. Oral cancer screening and atraumatic restorative treatment for tooth decay could be included in a basic package of oral care that does not require qualified dental surgeons. This article develops an argument, based on literature review and an analysis of the health system in Pakistan, for how a basic oral health programme could be an accessible, affordable and acceptable component of the primary health care system. PMID- 27966775 TI - MiR-101-3p Regulates the Viability of Lung Squamous Carcinoma Cells via Targeting EZH2. AB - The aim of this study was to investigate the effects of miR-101-3p on the viability, migration, invasion, and mitosis of lung squamous carcinoma cells by inhibiting EZH2. In this study, RT-qPCR was used to detect the expression of miR 101-3p and EZH2 in both tissues and cells at RNA level. The dual luciferase reporter gene system was used to determine whether there was targeting relationship between miR-101-3p and EZH2-3'UTR. Western Blot was used to detect the expression of EZH2 as well as the proliferation and invasion related proteins. The CCK-8 assay, Transwell invasion assay, wound healing assay and flow cytometry were conducted to test the cell viability, invasion, migration and apoptosis. The results of RT-qPCR and Western blot showed that miR-101-3p was low expressed and EZH2 was overexpressed in lung squamous cell carcinoma tissues and cells. Meanwhile the Western blot confirmed the effects of EZH2 expression on the proliferation and invasion of carcinoma cells. The results of luciferase assay and RT-qPCR showed that miR-101-3p had a negative regulation effect on EZH2. The CCK-8 assay, Transwell invasion assay, wound healing assay and flow cytometry results showed that the inhibition of EZH2 or the up-regulation of miR-101-3p inhibited the viability, migration, invasion and cell cycle but promoted cell apoptosis of lung squamous cell carcinoma. MiR-101-3p could inhibit the viability, migration, invasion, and cell cycle of lung squamous carcinoma cells by inhibiting the EZH2. J. Cell. Biochem. 118: 3142-3149, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27966776 TI - Tumor Necrosis Factor-alpha Increases Claudin-1, 4, and 7 Expression in Tubular Cells: Role in Permeability Changes. AB - Tumor necrosis factor-alpha (TNFalpha), is a pathogenic cytokine in kidney disease that alters expression of claudins in tubular cells. Previously we showed that in LLC-PK1 cells TNFalpha caused a biphasic change in transepithelial resistance (TER) consisting of an early drop and recovery, followed by a late increase. However, the underlying mechanisms and the role of specific claudins in the TER effect remained incompletely understood. Here we sought to define how TNFalpha affects claudins 1, 4, and 7 in tubular cells and to correlate their changes with the TER effect. We show that TNFalpha elevates total and surface levels of Cldn-1, 4, and 7, and increases their mRNA expression through the ERK and JNK pathways. Further, JNK is also important for TNFalpha-induced changes in claudin-2 expression. Continuous monitoring of TER using Electric cell-substrate impedance sensing (ECIS) reveals that the two phases of the TNFalpha effect are differently regulated. Specifically, inhibition of the ERK or JNK pathways prevent the late TER increase, but not the early TER effect. Silencing experiments also show that Cldn-1 is necessary for the early TNFalpha-induced TER change, while all three claudins appear to contribute to the late TER increase. In summary, we define a central role for ERK and JNK in TNFalpha-induced altered claudin expression and barrier tightening. Together, our current and previous works show that the TNFalpha-induced early TER effect requires claudin-1, while claudin-2 decrease is a significant mediator of the late TER increase, and elevation in claudin-1, 4, and 7 contribute to a smaller extent. J. Cell. Physiol. 232: 2210-2220, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27966777 TI - Fostering the educational value of candidate evaluation. AB - Approaches to fostering the educational value of candidate evaluation are presented, in view of the plethora of intra-psychic challenges that combine with many other complexities of learning to work as an analyst. Four integrally interrelated practices have been found to address sensitivities inherent in candidates' experience of training in general, and being evaluated in particular. When applied in concert, the institute's evaluative process not only becomes more considered, but also better promotes a psychoanalytic attitude and minimizes the intrusion of evaluators' personal responses. The first is defining and employing in synergy criteria for clinical immersion based on demonstration of the development and deepening of an analytic process, as well as the development of psychoanalytic competencies. The second is mandating institute-wide application of guidelines for assessment of progression/graduation that are clearly explicated to all candidates and faculty. The third is transparent and timely communication between candidates and their supervisors and progression advisors regarding progress essential to a sense of collaboration. Fourth the progression review process must be systematic and in-depth, with built-in consultative relationships serving as checks and balances on personal elements. The implementation and educational impact of these practices are considered in the case of one candidate. PMID- 27966778 TI - Anti-Atherosclerotic Effects of Vitamins D and E in Suppression of Atherogenesis. AB - Atherosclerosis is a progressive and multifactorial disease which occurs under the influence of various risk factors including endothelial dysfunction (ED), oxidative stress, and low-density lipoprotein (LDL) oxidation. In contract to the initial hypotheses on the usefulness of vitamin E supplementation for cardiovascular disease prevention, large outcome trials showed consumption of vitamin E has no obvious effect on cardiovascular disease and, in some cases, it may even increase the rate of mortality. This seemingly unexpected finding may be due to the opposite effects of vitamin E compounds. Vitamin E is a group of compounds which have different and even opposing effects, yet in most of the studies, the exact consumed component of vitamin E is not determined. It appears that the combined consumption of gamma-tocopherol, vitamin C, D, and tetrahydrobiopterin (BH4) may be extremely effective in both preventing atherogenesis and suppressing plaque development. In this regard, one of main issues is effect of vitamins E and D deficiency on microRNAs network in atherosclerosis. Various studies have indicated that miRNAs have key roles in atherosclerosis pathogenesis. The deficiency of vitamins E and D could provide a deregulation for miRNAs network and these events could lead to progression of atherosclerosis. Here, we highlighted a variety of mechanisms involve in the progression of atherosclerosis and effects of vitamins D and E on these mechanisms. Moreover, we summarized miRNAs involve in atherosclerosis and their regulation by vitamins E and D deficiency. J. Cell. Physiol. 232: 2968-2976, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27966779 TI - Serum Levels of TIMP-3, LIPC, IER3, and SLC16A8 in CFH-Negative AMD Cases. AB - AMD is a complex eye disease predominantly occurring in aged population. Till now about 53 genetic loci have been found to be associated with the AMD pathology. AMD pathogenesis is being increasingly known to progress through mechanisms independent of the CFH mediated pathway. Therefore, our aim for current study was to examine the genes by analyzing their expression levels in AMD. We recruited about 50 AMD and same number of age matched controls. We analyzed the CFH duplication and deletion by multiplex ligation probe amplification (MLPA) and found no duplication and deletion in CFH gene in AMD patients. We also estimated the IER-3, SLC16A8, LIPC, and TIMP-3 expression levels in both CFH-negative AMD cases (i.e. no duplication and deletion in CFH gene) besides examining these in AMD and controls. We found that the expression level of LIPC, SLC16A8, and TIMP-3 was significantly associated with AMD pathology in both groups (LIPC: P = 0.008, SLC16A8: P < 0.001, TIMP-3: P < 0.001, respectively). However, we did not find any significant difference in IER-3 levels in AMD and controls. Therefore, the evidence from current study, suggests that AMD pathology may be mediated through mechanistic pathways linked to other genetic loci. J. Cell. Biochem. 118: 2087 2095, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27966780 TI - Annual Research Review: An expanded account of information-processing mechanisms in risk for child and adolescent anxiety and depression. AB - BACKGROUND: Anxiety and depression occurring during childhood and adolescence are common and costly. While early-emerging anxiety and depression can arise through a complex interplay of 'distal' factors such as genetic and environmental influences, temperamental characteristics and brain circuitry, the more proximal mechanisms that transfer risks on symptoms are poorly delineated. Information processing biases, which differentiate youth with and without anxiety and/or depression, could act as proximal mechanisms that mediate more distal risks on symptoms. This article reviews the literature on information-processing biases, their associations with anxiety and depression symptoms in youth and with other distal risk factors, to provide direction for further research. METHODS: Based on strategic searches of the literature, we consider how youth with and without anxiety and/or depression vary in how they deploy attention to social-affective stimuli, discriminate between threat and safety cues, retain memories of negative events and appraise ambiguous information. We discuss how these information processing biases are similarly or differentially expressed on anxiety and depression and whether these biases are linked to genetic and environmental factors, temperamental characteristics and patterns of brain circuitry functioning implicated in anxiety and depression. FINDINGS: Biases in attention and appraisal characterise both youth anxiety and depression but with some differences in how these are expressed for each symptom type. Difficulties in threat-safety cue discrimination characterise anxiety and are understudied in depression, while biases in the retrieval of negative and overgeneral memories have been observed in depression but are understudied in anxiety. Information processing biases have been studied in relation to some distal factors but not systematically, so relationships remain inconclusive. CONCLUSIONS: Biases in attention, threat-safety cue discrimination, memory and appraisal may characterise anxiety and/or depression risk. We discuss future research directions that can more systematically test whether these biases act as proximal mechanisms that mediate other distal risk factors. PMID- 27966781 TI - Coexisting geriatric anxiety and depressive disorders may increase the risk of ischemic heart disease mortality-a nationwide longitudinal cohort study. AB - OBJECTIVES: In the elderly, the risk of mortality because of physical illnesses related to anxiety disorders varies with potential confounding influences, including comorbidity with depressive disorders. Our study aimed to explore (i) whether anxiety disorders increase the risk of mortality in the elderly, and (ii) whether the risk of mortality mediated by anxiety and depressive disorders differs between physical illnesses. METHODS: Our longitudinal cohort study included subjects aged over 60 years from the National Health Insurance Research Database. One thousand and eighty-six subjects with anxiety disorders and 50 554 control subjects without anxiety disorders were included. Propensity score matched cohorts were analyzed. Rate ratios (RRs) were calculated for the risk of mortality associated with different physical illnesses with comorbidities of either anxiety disorders only or both anxiety and depressive disorders. RESULTS: The risk of mortality in patients with anxiety disorders was significantly higher than controls, and was even higher when subjects had both anxiety and depressive disorder comorbidities. Furthermore, the co-occurrence of anxiety and depressive disorders increased the risk of mortality in elderly patients with ischemic heart diseases (RR = 1.60; 95% CI: 1.14-2.24). CONCLUSIONS: Coexisting anxiety and depressive disorders could increase the risk of mortality in elderly patients with ischemic heart diseases. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27966782 TI - Impact of Cryopreservation on Caprine Fetal Adnexa Derived Stem Cells and Its Evaluation for Growth Kinetics, Phenotypic Characterization, and Wound Healing Potential in Xenogenic Rat Model. AB - This study was conducted to know the impact of cryopreservation on caprine fetal adnexa derived mesenchymal stem cells (MSCs) on the basic stem cell characteristics. Gravid caprine uteri (2-3 months) were collected from local abattoir to derive (amniotic fluid [cAF], amniotic sac [cAS], Wharton's jelly [cWJ], and cord blood [cCB]) MSCs and expanded in vitro. Cells were cryopreserved at 3rd passage (P3) using 10% DMSO. Post-thaw viability and cellular properties were assessed. Cells were expanded to determine growth kinetics, tri-lineage differentiation, localization, and molecular expression of MSCs and pluripotency markers; thereafter, these cells were transplanted in the full-thickness (2 * 2cm2 ) rat skin wound to determine their wound healing potential. The post-thaw (pt) growth kinetics study suggested that cWJ MSCs expanded more rapidly with faster population doubling time (PDT) than that of other fetal adnexa MSCs. The relative mRNA expression of surface antigens (CD73, CD90, and CD 105) and pluripotency markers (Oct4, KLF, and cMyc) was higher in cWJ MSCs in comparison to cAS, cAF, and cCB MSCs post-thaw. The percent wound contraction on 7th day was more than 50% for all the MSC-treated groups (pre and post-thaw), against 39.55% in the control group. On day 28th, 99% and more wound contraction was observed in cAF, cAF-pt, cAS-pt, cWJ, cWJ-pt, and cCB, MSCs with better scores for epithelization, neovascularization, and collagen characteristics at a non significant level. It is concluded that these MSCs could be successfully cryopreserved without altering their stemness and wound healing properties. J. Cell. Physiol. 232: 2186-2200, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27966784 TI - Hybrid implementation model of community-partnered early intervention for toddlers with autism: a randomized trial. AB - BACKGROUND: Interventions found to be effective in research settings are often not as effective when implemented in community settings. Considering children with autism, studies have rarely examined the efficacy of laboratory-tested interventions on child outcomes in community settings using randomized controlled designs. METHODS: One hundred and thirteen children with autism enrolled in public early intervention classrooms in low resource neighborhoods were randomized to Joint Attention, Symbolic Play, Engagement, and Regulation (JASPER) intervention or treatment as usual waitlist for 10 weeks with 1-month follow-up. RESULTS: Teaching assistants delivered JASPER at adequate fidelity. Children randomized to JASPER demonstrated significant gains over treatment as usual in core developmental outcomes of joint engagement, joint attention, and play skills that were maintained at follow-up. CONCLUSIONS: Supervised teaching assistants delivered JASPER intervention with a range of toddlers with autism leading to significant gains in developmental outcomes. PMID- 27966785 TI - AMERICAN INDIAN AND ALASKA NATIVE BOYS: EARLY CHILDHOOD RISK AND RESILIENCE AMIDST CONTEXT AND CULTURE. AB - American Indian and Alaska Native (AIAN) adolescent and adult men experience a range of health disparities relative to their non-AIAN counterparts and AIAN women. Given the relatively limited literature on early development in tribal contexts, however, indicators of risk during early childhood specific to AIAN boys are not well-known. The current article reviews sources of strength and challenge within AIAN communities for AIAN children in general, including cultural beliefs and practices that support development, and contextual challenges related to socioeconomic and health disparities and historical trauma affecting the AIAN population as a whole. The research literature on early development is reviewed, highlighting what this literature reveals about early gender differences. The article concludes with calls to action on behalf of AIAN boys that align with each of the five tiers of R. Frieden's (2010) Public Health Pyramid. PMID- 27966786 TI - Fibroblast Growth Factor 21 (FGF21) Promotes Formation of Aerobic Myofibers via the FGF21-SIRT1-AMPK-PGC1alpha Pathway. AB - Fibroblast growth factor 21(FGF21) is a pivotal regulator of energy metabolism, which is currently being assessed as a potential drug target for the treatment of insulin-resistant conditions. However, the cellular mechanisms by which FGF21 affects myogenesis remain unclear. In this study, we explored the function of FGF21 in myogenesis both in vitro and in vivo. Our experiments showed for the first time that FGF21 promotes myoblast differentiation and serves as a switch of molecular transformation from anaerobic myofibers to aerobic myofibers via the FGF21-SIRT1-AMPK-PGC1alpha axis. Furthermore, we employed the Dual-Luciferase Reporter Assay System and Electrophoretic Mobility Shift Assay (EMSA) and demonstrated that MYOD, a major myogenic transcription factor, binds directly to the promoter region of Fgf21, leading to the activation of Fgf21 expression in mouse C2C12 myoblasts. Our study revealed a novel mechanism of myogenesis and muscle fiber transformation and indicated that FGF21 serves as a vital regulator of muscle development and important contributor to the pathogenesis of myopathy. J. Cell. Physiol. 232: 1893-1906, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27966787 TI - Mesenchyme Homeobox 2 Enhances Migration of Endothelial Colony Forming Cells Exposed to Intrauterine Diabetes Mellitus. AB - Diabetes mellitus (DM) during pregnancy has long-lasting implications for the fetus, including cardiovascular morbidity. Previously, we showed that endothelial colony forming cells (ECFCs) from DM human pregnancies have decreased vasculogenic potential. Here, we evaluate whether the molecular mechanism responsible for this phenotype involves the transcription factor, Mesenchyme Homeobox 2 (MEOX2). In human umbilical vein endothelial cells, MEOX2 upregulates cyclin-dependent kinase inhibitor expression, resulting in increased senescence and decreased proliferation. We hypothesized that dysregulated MEOX2 expression in neonatal ECFCs from DM pregnancies decreases network formation through increased senescence and altered cell cycle progression. Our studies show that nuclear MEOX2 is increased in ECFCs from DM pregnancies. To determine if MEOX2 is sufficient and/or required to induce impaired network formation, MEOX2 was overexpressed and depleted in ECFCs from control and DM pregnancies, respectively. Surprisingly, MEOX2 overexpression in control ECFCs resulted in increased network formation, altered cell cycle progression, and increased senescence. In contrast, MEOX2 knockdown in ECFCs from DM pregnancies led to decreased network formation, while cell cycle progression and senescence were unaffected. Importantly, migration studies demonstrated that MEOX2 overexpression increased migration, while MEOX2 knockdown decreased migration. Taken together, these data suggest that altered migration may be mediating the impaired vasculogenesis of ECFCs from DM pregnancies. While initially believed to be maladaptive, these data suggest that MEOX2 may serve a protective role, enabling increased vessel formation despite exposure to a DM intrauterine environment. J. Cell. Physiol. 232: 1885-1892, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27966783 TI - The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy. AB - Skeletal muscle atrophy is the consequence of protein degradation exceeding protein synthesis. This arises for a multitude of reasons including the unloading of muscle during microgravity, post-surgery bedrest, immobilization of a limb after injury, and overall disuse of the musculature. The development of therapies prior to skeletal muscle atrophy settings to diminish protein degradation is scarce. Mitochondrial dysfunction is associated with skeletal muscle atrophy and contributes to the induction of protein degradation and cell apoptosis through increased levels of ROS observed with the loss of organelle function. ROS binds mtDNA, leading to its degradation and decreasing functionality. Mitochondrial transcription factor A (TFAM) will bind and coat mtDNA, protecting it from ROS and degradation while increasing mitochondrial function. Exercise stimulates cell signaling pathways that converge on and increase PGC-1alpha, a well-known activator of the transcription of TFAM and mitochondrial biogenesis. Therefore, in the present review we are proposing, separately, exercise and TFAM treatments prior to atrophic settings (muscle unloading or disuse) alleviate skeletal muscle atrophy through enhanced mitochondrial adaptations and function. Additionally, we hypothesize the combination of exercise and TFAM leads to a synergistic effect in targeting mitochondrial function to prevent skeletal muscle atrophy. J. Cell. Physiol. 232: 2348-2358, 2017. (c) 2016 The Authors. Journal of Cellular Physiology Published by (c) 2016 Wiley Periodicals, Inc. PMID- 27966788 TI - Notch Signaling Participates in TGF-beta-Induced SOST Expression Under Intermittent Compressive Stress. AB - Notch signaling is regulated by mechanical stimuli in various cell types. It has previously been reported that intermittent compressive stimuli enhanced sclerostin (SOST) expression in human periodontal ligament cells (hPDLs) by regulating transforming growth factor-beta (TGF-beta) expression. The aim of the present study was to determine the involvement of Notch signaling in the TGF-beta induced SOST expression in hPDLs. Cells were treated with intermittent compressive stress in a computer-controlled apparatus for 24 h. The mRNA and protein expression of the cells were determined by real-time polymerase chain reaction and Western blot analysis, respectively. In some experiments, the target signaling pathway was impeded by the addition of a TGF-beta receptor kinase inhibitor (SB431542) or a gamma-secretase inhibitor (DAPT). The results demonstrated that hPDLs under intermittent compressive stress exhibited significantly higher NOTCH2, NOTCH3, HES1, and HEY1 mRNA expression compared with control, indicating that mechanical stress induced Notch signaling. DAPT pretreatment markedly reduced the intermittent stress-induced SOST expression. The expression of NOTCH2, NOTCH3, HES1, and HEY1 mRNA under compressive stress was significantly reduced after pretreatment with SB431542, coinciding with a reduction in SOST expression. Recombinant human TGF-beta1 enhanced SOST, Notch receptor, and target gene expression in hPDLs. Further, DAPT treatment attenuated rhTGF-beta1-induced SOST expression. In summary, intermittent compressive stress regulates Notch receptor and target gene expression via the TGF-beta signaling pathway. In addition, Notch signaling participates in TGF-beta-induced SOST expression in hPDLs. J. Cell. Physiol. 232: 2221-2230, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27966789 TI - The Black dentist workforce in the United States. AB - OBJECTIVES: The purpose of this paper is to describe the Black dentist workforce, the practice patterns of providers, and their contributions to oral health care for minority and underserved patients. METHODS: A national sample survey of underrepresented minority dentists was conducted in 2012 and received a 32.6 percent response rate for self-reported Black dentists. Data were weighted for selection and response bias to be nationally representative. Descriptive and multivariable statistics were computed to provide a workforce profile of Black dentists. National comparisons are provided from published data. RESULTS: Among all Black dentists (weighted n = 6,254), 76.6 percent self-identify as African American, 13.2 percent as African, and 10.3 percent as Afro-Caribbean. The largest share of Black dentists are male, married, heterosexual, born in the United States and raised in a medium to large city. One third of Black dentists were the first in their family to graduate from college. Black dentists report higher average educational debt than all dental students, with graduates from International Dentist Programs having the greatest debt. Traditional practices (i.e., private practices) dominate, with 67.1 percent of Black dentists starting out in this setting and 73.5 percent currently in the setting. Black dentists care for a disproportionate share of Black patients, with an average patient mix that is 44.9 percent Black. Two in five Black dentists reported their patient pool is made up of more than 50 percent Black patients. CONCLUSIONS: The underrepresentation for Black dentists is extraordinary, and the Black dentists that are in practice are shouldering a disproportionate share of dental care for minority and underserved communities. PMID- 27966790 TI - Combinations of 1,8-cineol and oseltamivir for the treatment of influenza virus A (H3N2) infection in mice. AB - It is need for development of new means against influenza virus due to the lack of efficacy of available therapeutic strategies. In previous research, 1,8-cineol exert its inhibition of nuclear factor (NF)-kappaB, the main regulator of cytokine and chemokine production in influenza, and anti-inflammatory activity. These fact supports and helps establish the hypothesis that 1,8-cineol may have synergism with an antiviral on influenza virus infection. The combined effect of 1,8-cineol with oseltamivir in a mouse type A influenza virus (Victoria/3/75,H3N2) model were examined. We initially tested combinations of 1,8 cineol (30, 60, and 120 mg/kg/day) and oseltamivir (0.1, 0.2, and 0.4 mg/kg/day). In addition, the 0.4 mg/kg/day of oseltamivir combined with 120 mg/kg of 1,8 cineol was selected for further combination studies. Oseltamivir was 30%, 40%, and 60% protective at 0.1, 0.2, and 0.4 mg/kg/d. Combinations of 1,8-cineol (30, 60, and 120 mg/kg/d) and oseltamivir (0.1, 0.2, and 0.4 mg/kg/d) increased the number of survivors and mean survival time (MST) following combination treatment was greater than monotherapy alone. Three dimensional analysis of drug interactions using the MacSynergy method showed a strong synergistic effect of these drug combinations. Survival, MST, lung parameters (lung index, viral titers, and pathology), and cytokines (IL-10, TNF-alpha, IL-1beta, and IFN-gamma) expression in lung demonstrated the high effectiveness of the combination. Combined treatment was associated with longer MST and more reduced cytokine levels than oseltamivir alone. These data demonstrate that combinations of 1,8 cineol and oseltamivir have synergistic effect against influenza A virus (H3N2) infection. PMID- 27966791 TI - Separase: Function Beyond Cohesion Cleavage and an Emerging Oncogene. AB - Proper and timely segregation of genetic endowment is necessary for survival and perpetuation of every species. Mis-segregation of chromosomes and resulting aneuploidy leads to genetic instability, which can jeopardize the survival of an individual or population as a whole. Abnormality with segregation of genetic contents has been associated with several medical consequences including cancer, sterility, mental retardation, spontaneous abortion, miscarriages, and other birth related defects. Separase, by irreversible cleavage of cohesin complex subunit, paves the way for metaphase/anaphase transition during the cell cycle. Both over or reduced expression and altered level of separase have been associated with several medical consequences including cancer, as a result separase now emerges as an important oncogene and potential molecular target for medical intervenes. Recently, separase is also found to be essential in separation and duplication of centrioles. Here, I review the role of separase in mitosis, meiosis, non-canonical roles of separase, separase regulation, as a regulator of centriole disengagement, nonproteolytic roles, diverse substrates, structural insights, and association of separase with cancer. At the ends, I proposed a model which showed that separase is active throughout the cell cycle and there is a mere increase in separase activity during metaphase contrary to the common believes that separase is inactive throughout cell cycle except for metaphase. J. Cell. Biochem. 118: 1283-1299, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27966792 TI - Children's use of decomposition strategies mediates the visuospatial memory and arithmetic accuracy relation. AB - This study examined the mediating role of children's use of decomposition strategies in the relation between visuospatial memory (VSM) and arithmetic accuracy. Children (N = 78; Age M = 9.36) completed assessments of VSM, arithmetic strategies, and arithmetic accuracy. Consistent with previous findings, VSM predicted arithmetic accuracy in children. Extending previous findings, the current study showed that the relation between VSM and arithmetic performance was mediated by the frequency of children's use of decomposition strategies. Identifying the role of arithmetic strategies in this relation has implications for increasing the math performance of children with lower VSM. Statement of contribution What is already known on this subject? The link between children's visuospatial working memory and arithmetic accuracy is well documented. Frequency of decomposition strategy use is positively related to children's arithmetic accuracy. Children's spatial skill positively predicts the frequency with which they use decomposition. What does this study add? Short-term visuospatial memory (VSM) positively relates to the frequency of children's decomposition use. Decomposition use mediates the relation between short-term VSM and arithmetic accuracy. Children with limited short-term VSM may struggle to use decomposition, decreasing accuracy. PMID- 27966793 TI - Alcohol Fuels Hepatitis C Virus Propensity for Infection in ISGylation/Proteasome Dependent Manner. PMID- 27966794 TI - Diagnostic and Therapeutic Potential of Exosomes in Cancer: The Beginning of a New Tale? AB - Exosomes have emerged as one of the main players in intercellular communication. These small nano-sized particles have many roles in various physiological pathways in normal and abnormal cells. Exosomes can carry various cargos such as proteins, mRNAs, and miRNAs to recipient cells. Uptake of exosomes and their cargo can induce and/or inhibit different cellular and molecular pathways that lead to the alteration of cell behavior. Multiple lines of evidence have indicated that exosomes released from cancer cells can effect development of cancer in different stages. These particles and their cargo could regulate different processes such as tumor growth, metastasis, drug resistance, angiogenesis, and immune system functioning. It has been observed that exosomes can be used as potential diagnostic biomarkers in various cancer types. Moreover, some studies have used these particles as biological vehicles for delivery of various drugs such as doxorubicin, siRNAs, and miRNAs. Here, we summarized the findings on the role of exosomes in different pathological processes involved in cancer. Moreover, application of these particles as diagnostic and therapeutic biomarkers in different types of cancers is discussed. J. Cell. Physiol. 232: 3251-3260, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27966795 TI - The so-called death drive, an indispensable force for any subjective life. AB - The psychoanalytic movement has difficulty in overcoming the malaise bequeathed by what Freud wanted to call the 'death drive'. This term remains doubly problematic: first because the indispensable antagonist of Eros-binding cannot be reduced to a particular drive; and secondly because this Anteros plays a vital role in subjectivization. The Freudian idea of the 'death drive' has in addition the drawback of confusing dissociative thrust (unbinding) with the aggressive component of libidinal cathexis. Now it is precisely the lack of articulation between them that leads to deconstructing it. For it is constantly observed that in the psychic register aggression is much more fixing than unbinding. The essential role of Anteros/unbinding in the process of subjectivization can be illustrated through several key operations in subjective development: sublimatory activity and its renunciation of pleasure-discharge, the work of mourning opposed to melancholic fixation, the intricating-unbinding parental function, and finally the psychoanalytic treatment and its work of analysis. This means we should cease to anathematize the dynamic component of unbinding as 'of death' and seek to explain the concept of subjectivization better. PMID- 27966797 TI - Quantitative Predictions of Shape-Memory Effects in Polymers. AB - Unique shape-memory transitions manifested by directional extension and subsequent retraction in polymers are attributed to stored conformational entropy. This behavior is quantified in terms of stored (DeltaS S ) entropic energy density, the maximum strain (epsilonmax ), and stress (sigmaSF at epsilonmax ). This concept allows quantitative assessments of the shape-memory effect (SME) and can be utilized in any material that exhibits a glass-transition temperature (T g ) and a rubbery plateau. PMID- 27966796 TI - Identification of MSX1 and DCLK1 as mRNA Biomarkers for Colorectal Cancer Detection Through DNA Methylation Information. AB - Colorectal cancer is the second most deadly malignancy in the United States. However, the currently screening options had their limitation. Novel biomarkers for colorectal cancer detections are necessary to reduce the mortality. The clinical information, mRNA expression levels and DNA methylation information of colorectal cancer were downloaded from TCGA. The patients were separated into training group and testing group based on their platforms for DNA methylation. Beta values of DNA methylation from tumor tissues and normal tissues were utilized to figure out the position that were differentially methylated. The expression levels of mRNA of thirteen genes, whose CpG islands were differentially methylated, were extracted from the RNA-Seq results from TCGA. The probabilities whether the mRNA was differentially expressed between tumor and normal samples were calculated using Student's t-test. Logistic regression and decision tree were built for cancer detection and their performances were evaluated by the area under the curve (AUC). Twenty-four genomic locations were differentially methylated, which could be mapped to eleven genes. Nine out of eleven genes had differentially expressed mRNA levels, which were used to build the model for cancer detection. The final detection models consisting of mRNA expression levels of these nine genes had great performances on both training group and testing group. The model that constructed in this study suggested MSX1 and DCLK1 might be used in colorectal cancer detection or as target of cancer therapies. J. Cell. Physiol. 232: 1879-1884, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27966798 TI - Chiral Superstructure Mesophases of Achiral Bent-Shaped Molecules - Hierarchical Chirality Amplification and Physical Properties. AB - Chiral mesophases in achiral bent-shaped molecules have attracted particular attention since their discovery in the middle 1990s, not only because of their homochirality and polarity, but also due to their unique physical/physicochemical properties. Here, the most intriguing results in the studies of such symmetry broken states, mainly helical-nanofilament (HNF) and dark-conglomerate (DC) phases, are reviewed. Firstly, basic information on the typical appearance and optical activity in these phases is introduced. In the following section, the formation of mesoscopic chiral superstructures in the HNF and DC phases is discussed in terms of hierarchical chirality. Nanoscale phase segregation in mixture systems and gelation ability in the HNF phase are also described. In addition, some other related chiral phases of bent-shaped molecules are shown. Recent attempts to control such mesoscopic chiral structure and the alignment/confinement of HNFs are also discussed, along with several examples of their fascinating advanced physical properties, i.e. huge enhancement of circular dichroism, electro- and photo-tunable optical activities, chirality-induced nonlinear optics (second-harmonic-generation circular difference and electrogyration effect), enhanced hydrophobicity through the dual-scale surface morphological modulation, and photoconductivity in the HNF/fullerene binary system. Future prospects from basic science and application viewpoints are also indicated in the concluding section. PMID- 27966799 TI - Infant Attachment and Maternal Sensitivity in the Arab Minority in Israel. AB - This study is the first to examine infant-mother attachment in the Arab culture. Eighty-five Arab 1-year-old infants from Israel were observed in the strange situation, and maternal sensitivity was assessed from home observations. Supporting attachment theory's normativity hypothesis, no differences were found between the Arab-Israeli attachment distribution and Jewish-Israeli, Western, and non-Western distributions when examined at the two-way secure versus insecure level, although a few differences emerged when examined at the four-way ABCD level. Supporting the sensitivity hypothesis, mothers of secure infants were more sensitive than those of insecure infants but only in the case of Christian (and not Muslim) mothers. The findings provide support to attachment theory's generalizability but raise questions regarding the assessment of maternal sensitivity cross-culturally. PMID- 27966800 TI - Individual Differences in Children's Corepresentation of Self and Other in Joint Action. AB - Previous research has shown that children aged 4-5 years, but not 2-3 years, show adult-like interference from a partner when performing a joint task (Milward, Kita, & Apperly, 2014). This raises questions about the cognitive skills involved in the development of such "corepresentation (CR)" of a partner (Sebanz, Knoblich, & Prinz, 2003). Here, individual differences data from one hundred and thirteen 4- to 5-year-olds showed theory of mind (ToM) and inhibitory control (IC) as predictors of ability to avoid CR interference, suggesting that children with better ToM abilities are more likely to succeed in decoupling self and other representations in a joint task, while better IC is likely to help children avoid interference from a partner's response when selecting their own response on the task. PMID- 27966801 TI - Case study: Analysis of a traumatized hemophiliac boy. AB - The author presents a case study of a hemophiliac boy in four-times-a-week analysis from the age of four to six and a half years. An extensive narrative of various phases of the analysis including the termination provides the reader access to the material for discussion of therapeutic action. Her analytic technique is based on a developmental point of view and illustrates the use of limits, play, and interpretation based on countertransference. She understands the boy's symptoms of preferring to be a girl, asking to cut his penis off, and wishing to die as defenses against the fear of castration, which in his case is aggravated by the actual threat of repeated medical interventions, and by the underlying fear of a lack of body composition. An unusual feature of the case is the illustration of the symptom, the analysis, and the recovery of the male self, captured in a complex collage that was made over the course of the relatively short analysis. PMID- 27966802 TI - Zika virus: A new threat to human reproduction. AB - Zika virus (ZIKV) was first isolated in 1947 in a rhesus monkey from the Zika forest of Uganda. Until 2007, only 14 human cases were reported. The first large human outbreak occurred in 2007 (Yap Island, Federated States of Micronesia, Pacific) followed by French Polynesia in 2013 and Brazil in 2015. The virus is mainly transmitted through Aedes mosquito bites, but sexual and post-transfusion transmissions have been reported. Symptoms include low-grade fever, maculopapular rash, conjunctivitis, myalgia, arthralgia, and asthenia. During the recent outbreaks in French Polynesia and Brazil, ZIKV infection has been associated with two major complications: microcephaly and Guillain-Barre syndrome. Since fetal infection includes other birth defects, congenital Zika syndrome has been used to define in utero infection. The majority of sexual transmission occurred from a symptomatic male to a female, but female-to-male and male-to-male transmission have been reported. Asymptomatic male-to-female transmission has also been described. Importantly, ZIKV RNA can persist at least 6 months in semen. The male urogenital tract may therefore act as a reservoir for the virus. ZIKV RNA was detected in a cervical swab of a patient 3 days after presenting the classic symptoms suggesting a potential tropism for the female genital tract. Long lasting presence of ZIKV RNA might not indicate that the individual is infectious but makes recommendation for couples potentially exposed to the virus and willing to conceive difficult. It will also be important to determine whether genital ZIKV infection might have a deleterious effect on male and female fertility. PMID- 27966804 TI - Rhodium(I)-Catalyzed Intermolecular Aza-[4+3] Cycloaddition of Vinyl Aziridines and Dienes: Atom-Economical Synthesis of Enantiomerically Enriched Functionalized Azepines. AB - A new synthetic application of vinyl aziridines as N-containing three-atom components in a rhodium-catalyzed [4+3] cycloaddition reaction is described. The reaction proceeds well with various silyl dienol ethers and vinyl aziridines, and enables the efficient synthesis of highly functionalized azepines in an enantioselective manner with net inversion of absolute configuration. The salient features of the transformation include the use of readily available substrates, high selectivity, and mild reaction conditions, as well as the versatile functionalization of the products. PMID- 27966803 TI - Yield of screening echocardiograms during pediatric follow-up in survivors treated with anthracyclines and cardiotoxic radiation. AB - BACKGROUND: Guidelines published by the Children's Oncology Group recommend screening echocardiograms for childhood cancer survivors exposed to anthracyclines and/or cardiotoxic radiation. This study aims to assess risk factors for cardiac late effects while evaluating the overall yield of screening echocardiograms. PROCEDURE: Demographics, exposures, and echocardiogram results were abstracted from the medical records of survivors diagnosed at <= 21 years old and >= 2 years off therapy who were exposed to anthracyclines and/or potentially cardiotoxic radiotherapy. Descriptive statistics and logistic regressions were performed and the yield of screening echocardiograms was calculated. RESULTS: Of 853 patients, 1,728 screening echocardiograms were performed, and 37 patients had an abnormal echocardiogram (overall yield 2.1%). Yields were only somewhat higher in more frequently screened patients. Risk factors for an abnormal result included anthracycline dose of >=300 mg/m2 (adjusted odds ratio [aOR] 3.1; 95% confidence interval [CI]: 1.3-7.2; P < 0.01) with a synergist relationship in patients who also received radiation doses >=30 Gy (aOR 7.0; 95% CI: 1.6-31.9; P = 0.01), as well as autologous bone marrow transplant (OR 3.3; 95% CI: 1.3-8.5; P = 0.01). Sex, race, age at diagnosis, and cyclophosphamide exposure were not statistically significant risk factors, and no patient receiving <100 mg/m2 anthracycline dose without concomitant radiation had an abnormal echocardiogram. CONCLUSIONS: Dose-dependent and synergist anthracycline and cardiotoxic radiotherapy risks for developing cardiomyopathy were confirmed. However, previously identified risk factors including female sex, black race, and early age at diagnosis were not replicated in this cohort. The yields showed weak correlation across frequency categories. Echocardiographic screening recommendations for low-risk pediatric patients may warrant re evaluation. PMID- 27966805 TI - Successful treatment of mature B-cell lymphoma with rituximab-based chemotherapy in a patient with Bloom syndrome. AB - This report presents a case of Bloom syndrome (BS) in a consanguineous Saudi family. The patient, an 11-year-old male with mature B-cell lymphoma, had minimal therapeutic response and significant dose-limiting toxicity with standard chemotherapy treatment. He later responded successfully to a rituximab-based chemotherapy protocol. This case highlights that the rituximab-based chemotherapy protocol is an effective and safe treatment alternative for mature B-cell lymphoma in patients with BS. Further trials are warranted to investigate this modality of treatment. PMID- 27966806 TI - Efficiency of uterine fluid cytology in the diagnosis of subclinical endometritis in the water buffalo (Bubalus bubalis). AB - This study compared endometrial cytology vis-a-vis uterine fluid cytology for assessment of uterine health in clinically normal and subclinical endometritis (SE)-affected buffaloes. Uterine fluid samples and endometrial samples were collected from the buffaloes (n = 38) at oestrus using blue sheath and cytobrush, respectively. The smears were stained with Field stain for 3 minutes, and a minimum of 400 cells were counted in each smear for determination of the percentage of polymorphonuclear (PMN) leucocyte. The incidence of subclinical endometritis, based on the cytobrush cytology, was 23.08%. The correlation between cytobrush cytology with uterine fluid cytology was positive and significant (r = .37; p = .02). The ratio of PMN leucocyte in cytobrush cytology to uterine fluid cytology was 1:2.4. ROC analysis revealed that the threshold value of 6.16% PMN leucocyte in uterine fluid cytology showed a diagnostic sensitivity and specificity of 100% in differentiating normal from SE-affected buffaloes. In conclusion, collection of uterine fluid was easier compared to collection of endometrial samples using cytobrush and the percentage of PMN leucocyte in uterine fluid cytology can be used as a tool for diagnosis of subclinical endometritis in buffaloes. PMID- 27966807 TI - Seed-Mediated Growth of Colloidal Metal Nanocrystals. AB - Seed-mediated growth is a powerful and versatile approach for the synthesis of colloidal metal nanocrystals. The vast allure of this approach mainly stems from the staggering degree of control one can achieve over the size, shape, composition, and structure of nanocrystals. These parameters not only control the properties of nanocrystals but also determine their relevance to, and performance in, various applications. The ingenuity and artistry inherent to seed-mediated growth offer extensive promise, enhancing a number of existing applications and opening the door to new developments. This Review demonstrates how the diversity of metal nanocrystals can be expanded with endless opportunities by using seeds with well-defined and controllable internal structures in conjunction with a proper combination of capping agent and reduction kinetics. New capabilities and future directions are also highlighted. PMID- 27966808 TI - Porous TiO2 Nanotubes with Spatially Separated Platinum and CoOx Cocatalysts Produced by Atomic Layer Deposition for Photocatalytic Hydrogen Production. AB - Efficient separation of photogenerated electrons and holes, and associated surface reactions, is a crucial aspect of efficient semiconductor photocatalytic systems employed for photocatalytic hydrogen production. A new CoOx /TiO2 /Pt photocatalyst produced by template-assisted atomic layer deposition is reported for photocatalytic hydrogen production on Pt and CoOx dual cocatalysts. Pt nanoclusters acting as electron collectors and active sites for the reduction reaction are deposited on the inner surface of porous TiO2 nanotubes, while CoOx nanoclusters acting as hole collectors and active sites for oxidation reaction are deposited on the outer surface of porous TiO2 nanotubes. A CoOx /TiO2 /Pt photocatalyst, comprising ultra-low concentrations of noble Pt (0.046 wt %) and CoOx (0.019 wt %) deposited simultaneously with one atomic layer deposition cycle, achieves remarkably high photocatalytic efficiency (275.9 MUmol h-1 ), which is nearly five times as high as that of pristine TiO2 nanotubes (56.5 MUmol h-1 ). The highly dispersed Pt and CoOx nanoclusters, porous structure of TiO2 nanotubes with large specific surface area, and the synergetic effect of the spatially separated Pt and CoOx dual cocatalysts contribute to the excellent photocatalytic activity. PMID- 27966809 TI - Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia. AB - BACKGROUND: Carboxypeptidase G2 (CPDG2 ) can be used as rescue treatment in cases of delayed methotrexate elimination (DME) and Mtx-induced nephrotoxicity. PROCEDURE: Between July 2008 and December 2014, all children (1.0-17.9 years) in the Nordic countries diagnosed with Philadelphia chromosome negative acute lymphoblastic leukemia (ALL) were treated according to the Nordic Organization for Pediatric Hematology and Oncology (NOPHO) ALL 2008 protocol, including administration of six to eight high-dose (5 g/m2 /24 hr) Mtx (HDMtx) courses. The protocol includes recommendations for CPDG2 administration in cases of DME (clinicaltrials.gov NCT01305655). RESULTS: Forty-seven of the 1,286 children (3.6%) received CPDG2 during 50 HDMtx courses at a median dose of 50 IU/kg. In 49% of the cases, CPDG2 was used during the first HDMtx course. Within a median of 6 hr from CPDG2 administration, the Mtx concentration decreased by 75% when measured with immune-based methods, and by 100% when measured with high performance liquid chromatography. The median time from the start of Mtx infusion to plasma levels <= 0.2 MUM was 228 hr (range: 48-438). The maximum increase in plasma creatinine was 375% (range: 100-1,310). Creatinine peaked after a median of 48 hr (range: 36-86). Mtx elimination time was shorter in patients with body surface area < 1 m2 (median 198.5 vs. 257 hr; P = 0.004) and was inversely correlated to the maximum creatinine increase (209 vs. 258 hr; P = 0.034). All patients normalized their renal function as measured with s-creatinine. CONCLUSIONS: CPDG2 administration is highly effective as rescue in case of delayed Mtx clearance. Subsequent HDMtx courses could be administered without events in most of the patients. PMID- 27966811 TI - Widely Controllable Syngas Production by a Dye-Sensitized TiO2 Hybrid System with ReI and CoIII Catalysts under Visible-Light Irradiation. AB - Visible-light irradiation of a ternary hybrid catalyst prepared by grafting a dye, an H2 evolving CoIII catalyst and a CO-producing ReI catalyst on TiO2 have been found to produce both H2 and CO (syngas) in CO2 -saturated N,N-dimethyl formamide (DMF)/water solution containing a 0.1 m sacrificial electron donor. The H2 /CO ratios are effectively controlled by changing either the water content of the solvent or the molar ratio of the ReI and CoIII catalysts ranging from 1:2 to 15:1. The controlled syngas formation is discussed in terms of competitive electron flow from TiO2 to each of the CO2 -reduction and hydrogen-evolving sites depending on the efficiencies of the two catalytic reaction cycles under given reaction conditions. PMID- 27966813 TI - Hypervalent Iodine(III)-Mediated Oxidative Fluorination of Alkylsilanes by Fluoride Ions. AB - The first example of a hypervalent iodine(III)-mediated oxidative fluorination of alkylsilanes by fluoride ions without the use of transition metals is demonstrated. This reaction is operationally simple, scalable, and proceeds under mild reaction conditions. Mechanistic studies suggest the involvement of a single electron transfer resulting from the interaction of an organopentafluorosilicate and aryliodonium difluoride, which were generated in situ from the corresponding alkylsilane and iodosobenzene, respectively, in the presence of fluoride ions. PMID- 27966812 TI - HCV/HBV coinfection: The dark side of DAAs treatment? PMID- 27966810 TI - Discovery of a PCAF Bromodomain Chemical Probe. AB - The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(-)-norephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L 45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use. PMID- 27966814 TI - Bidirectional Photomodulation of Surface Tension in Langmuir Films. AB - Switching systems operating in a cooperative manner capable of converting light energy into mechanical motion are of great interest for optical devices, data storage, nanoscale energy converters and molecular sensing. Herein, photoswitchable monolayers were formed at the air-water interface from either a pure bis(thiaxanthylidene)-based photoswitchable amphiphile or from a mixture of the photoswitchable amphiphile with a conventional lipid dipalmitoylphosphatidylcholine (DPPC). Efficient photoisomerization of the anti folded to syn-folded geometry of the amphiphile's central core induces changes in the surface pressure in either direction, depending on the initial molecular density. Additionally, the switching behavior can be regulated in the presence of DPPC, which influences the packing of the molecules, thereby controlling the transformation upon irradiation. Bis(thiaxanthylidene)-based photoswitchable monolayers provide a promising system to explore cooperativity and amplification of motion. PMID- 27966816 TI - A Four-Component Reaction Strategy for Pyrimidine Carboxamide Synthesis. AB - Demonstrated herein is a highly effective 3 starting materials-4 component reaction (3SM-4CR) strategy for the synthesis of pyrimidine carboxamides from amidines, styrene, and N,N-dimethylformamide (DMF) by a palladium-catalyzed oxidative process. This transformation represents the first example of employing DMF as a dual synthon, a one-carbon-atom synthon and amide synthon, and was proven by isotope-labeling experiments. Additionally, the combination of C-H bond functionalization and cross-dehydrogenative coupling processes affords four chemical bond formations. This sequential 3SM-4CR strategy features inexpensive, readily available starting materials, green oxidants, as well as atom and step economy. It leads to the preparation of pyrimidine carboxamides and has potential applications in the pharmaceutical industry. PMID- 27966815 TI - Zika virus infection of Hofbauer cells. AB - Recent studies have linked antenatal infection with Zika virus (ZIKV) with major adverse fetal and neonatal outcomes, including microcephaly. There is a growing consensus for the existence of a congenital Zika syndrome (CZS). Previous studies have indicated that non-placental macrophages play a key role in the replication of dengue virus (DENV), a closely related flavivirus. As the placenta provides the conduit for vertical transmission of certain viruses, and placental Hofbauer cells (HBCs) are fetal-placental macrophages located adjacent to fetal capillaries, it is not surprising that several recent studies have examined infection of HBCs by ZIKV. In this review, we describe congenital abnormalities associated with ZIKV infection, the role of HBCs in the placental response to infection, and evidence for the susceptibility of HBCs to ZIKV infection. We conclude that HBCs may contribute to the spread of ZIKV in placenta and promote vertical transmission of ZIKV, ultimately compromising fetal and neonatal development and function. Current evidence strongly suggests that further studies are warranted to dissect the specific molecular mechanism through which ZIKV infects HBCs and its potential impact on the development of CZS. PMID- 27966818 TI - Benzo-Fused Double [7]Carbohelicene: Synthesis, Structures, and Physicochemical Properties. AB - A benzo-fused double [7]carbohelicene (D7H) was synthesized through a regioselective cyclodehydrogenation of a tetranaphthyl-p-terphenyl-based precursor. The twisted (D7H-1) and anti-folded (D7H-2) conformers of D7H were separated by recrystallization, and their double helicene structures with overlapping terminal benzene rings were unambiguously elucidated by X-ray crystallography. A record-high isomerization barrier (46.0 kcal mol-1 ) in double helicenes was estimated based on density functional theory (DFT) calculation, which resulted in the excellent conformational stability of D7H. The physicochemical properties of D7H-1 and D7H-2 were investigated by UV/Vis absorption spectroscopy and cyclic voltammetry, displaying the variation of electronic structure upon conformational changes. The optical resolution of the racemic D7H-1 was carried out by chiral HPLC, offering enantiopure D7H-1-(P,P) and D7H-1-(M,M), which were further characterized by circular dichroism spectroscopy. PMID- 27966817 TI - Mimicking Nacre by Ice Templating. AB - Ice-T loves nacre: An ice-templating approach resulted in a series of high performance lamellar composites. This novel bioinspired approach opens up new opportunities for the preparation of bulk composite materials with tunable nano- and microscopic structures and various constituents. PMID- 27966819 TI - Micromechanics of Amorphous Metal/Polymer Hybrid Structures with 3D Cellular Architectures: Size Effects, Buckling Behavior, and Energy Absorption Capability. AB - By designing advantageous cellular geometries and combining the material size effects at the nanometer scale, lightweight hybrid microarchitectured materials with tailored structural properties are achieved. Prior studies reported the mechanical properties of high strength cellular ceramic composites, obtained by atomic layer deposition. However, few studies have examined the properties of similar structures with metal coatings. To determine the mechanical performance of polymer cellular structures reinforced with a metal coating, 3D laser lithography and electroless deposition of an amorphous layer of nickel-boron (NiB) is used for the first time to produce metal/polymer hybrid structures. In this work, the mechanical response of microarchitectured structures is investigated with an emphasis on the effects of the architecture and the amorphous NiB thickness on their deformation mechanisms and energy absorption capability. Microcompression experiments show an enhancement of the mechanical properties with the NiB thickness, suggesting that the deformation mechanism and the buckling behavior are controlled by the brittle-to-ductile transition in the NiB layer. In addition, the energy absorption properties demonstrate the possibility of tuning the energy absorption efficiency with adequate designs. These findings suggest that microarchitectured metal/polymer hybrid structures are effective in producing materials with unique property combinations. PMID- 27966820 TI - Overexpression of TEAD4 in atypical teratoid/rhabdoid tumor: New insight to the pathophysiology of an aggressive brain tumor. AB - BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor that occurs mainly in early childhood. Although most of the tumors are characterized by inactivating mutations of the tumor suppressor gene, SMARCB1, the biological basis of its tumorigenesis and aggressiveness is still unknown. PROCEDURE: We performed high-throughput copy number variation analysis of primary cell lines generated from primary and relapsed tumors from one of our patients to identify new genes involved in AT/RT biology. The expression of the identified gene was validated in 29 AT/RT samples by gene expression profiling, quantitative real-time polymerase chain reaction, and immunohistochemistry (IHC). Furthermore, we investigated the function of this gene by mutating it in rhabdoid tumor cells. RESULTS: TEAD4 amplification was detected in the primary cell lines and its overexpression was confirmed at mRNA and protein levels in an independent cohort of AT/RT samples. TEAD4's co-activator, YAP1, and the downstream targets, MYC and CCND1, were also found to be upregulated in AT/RT when compared to medulloblastoma. IHC showed TEAD4 and YAP1 overexpression in all samples. Cell proliferation and migration were significantly reduced in TEAD4-mutated cells. CONCLUSIONS: We report the overexpression of TEAD4 in AT/RT, which is a key component of Hippo pathway. Recent reports revealed that dysregulation of the Hippo pathway is implicated in tumorigenesis and poor prognosis of several human cancers. Our results suggest that TEAD4 plays a role in the pathophysiology of AT/RT, which represents a new insight into the biology of this aggressive tumor. PMID- 27966821 TI - Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria. AB - Sialuria is a rare autosomal dominant disorder of mammalian metabolism, caused by defective feedback inhibition of the UDP-N-acetylglucosamine-2-epimerase N acetylmannosamine kinase (GNE), the key enzyme of sialic acid biosynthesis. Sialuria is characterized by overproduction of free sialic acid in the cell cytoplasm. Patients exhibit vastly increased urinary excretion of sialic acid and show differently pronounced developmental delays. The physiopathology of sialuria is not well understood. Here we established a transgenic mouse line that expresses GNE containing the sialuria mutation R263L, in order to investigate the influence of an altered sialic acid concentration on the organism. The transgenic mice that expressed the mutated RNA excreted up to 400 times more N acetylneuraminic acid than wild-type mice. Additionally, we found higher sialic acid concentration in the brain cytoplasm. Analyzing the (poly)sialylation of neural cell adhesion molecule (NCAM) revealed increased polysialylation in brains of transgenic mice compared to wild-type. However, we found only minor changes in membrane-bound sialylation in various organs but, surprisingly, a significant increase in surface sialylation on leukocytes. Our results suggest that the intracellular sialic acid concentration regulates polysialylation on NCAM in vivo; this could play a role in the manifestation of the developmental delays in sialuria patients. PMID- 27966822 TI - Orthogonal Cysteine Protection Enables Homogeneous Multi-Drug Antibody-Drug Conjugates. AB - A strategy for the preparation of homogeneous antibody-drug conjugates (ADCs) containing multiple payloads has been developed. This approach utilizes sequential unmasking of cysteine residues with orthogonal protection to enable site-specific conjugation of each drug. In addition, because the approach utilizes conjugation to native antibody cysteine residues, it is widely applicable and enables high drug loading for improved ADC potency. To highlight the benefits of ADC dual drug delivery, this strategy was applied to the preparation of ADCs containing two classes of auristatin drug-linkers that have differing physiochemical properties and exert complementary anti-cancer activities. Dual-auristatin ADCs imparted activity in cell line and xenograft models that are refractory to ADCs comprised of the individual auristatin components. This work presents a facile method for construction of potent dual drug ADCs and demonstrates how delivery of multiple cytotoxic warheads can lead to improved ADC activities. Lastly, we anticipate that the conditions utilized herein for orthogonal cysteine unmasking are not restricted to ADCs and can be broadly utilized for site-specific protein modification. PMID- 27966823 TI - Oxytocin receptors in dioestrous and anoestrous canine uteri. AB - The aim of the study was to localize oxytocin receptors (OTR) and measure mRNA expression of OTR in the canine uterus with and without the influence of progesterone. Uterine samples were taken from nine anoestrous and eight dioestrous bitches during ovariohysterectomy. Histological changes were evaluated in haematoxylin and eosin (HE)-stained samples. Purified polyclonal antibody for OTR was used in immunohistochemistry to localize receptors in uterine layers. Relative mRNA concentration of OTR was evaluated with real-time PCR from full thickness uterine samples taken from the middle horn and the body. Myometrial smooth muscle cells, endometrial luminal epithelium (LE) and deep and superficial glandular epithelium were positively stained for oxytocin receptors in non pregnant animals. No significant difference in staining intensity was detected between uterine middle horn and body. However, the staining intensity of LE was significantly higher in dioestrous than in anoestrous uteri (p < .05). Leucocytes and endothelium of blood vessels were also positively stained for OTR. Real-time PCR showed no significant differences in OTR mRNA expression between the middle horn and the body of the uterus, or between anoestrous and dioestrous uterus. No correlation was noted between OTR mRNA expression and blood progesterone concentration. In conclusion, despite the apparent inactivity, the uterus of the non-pregnant bitch expresses OTR. The distribution or relative expression of OTR does not differ between uterine horn and body in dioestrus or anoestrus except in LE. LE may have more oxytocin-dependent activity during dioestrus than anoestrus. PMID- 27966824 TI - Ultraclean and Direct Transfer of a Wafer-Scale MoS2 Thin Film onto a Plastic Substrate. AB - An ultraclean method to directly transfer a large-area MoS2 film from the original growth substrate to a flexible substrate by using epoxy glue is developed. The transferred film is observed to be free of wrinkles and cracks and to be as smooth as the film synthesized on the original substrate. PMID- 27966825 TI - Passivation of Black Phosphorus via Self-Assembled Organic Monolayers by van der Waals Epitaxy. AB - An effective passivation approach to protect black phosphorus (BP) from degradation based on multi-scale simulations is proposed. The self-assembly of perylene-3,4,9,10-tetracarboxylic dianhydride monolayers via van der Waals epitaxy on BP does not break the original electronic properties of BP. The passivation layer thickness is only 2 nm. This study opens up a new pathway toward fine passivation of BP. PMID- 27966826 TI - Nanoreinforced Hydrogels for Tissue Engineering: Biomaterials that are Compatible with Load-Bearing and Electroactive Tissues. AB - Given their highly porous nature and excellent water retention, hydrogel-based biomaterials can mimic critical properties of the native cellular environment. However, their potential to emulate the electromechanical milieu of native tissues or conform well with the curved topology of human organs needs to be further explored to address a broad range of physiological demands of the body. In this regard, the incorporation of nanomaterials within hydrogels has shown great promise, as a simple one-step approach, to generate multifunctional scaffolds with previously unattainable biological, mechanical, and electrical properties. Here, recent advances in the fabrication and application of nanocomposite hydrogels in tissue engineering applications are described, with specific attention toward skeletal and electroactive tissues, such as cardiac, nerve, bone, cartilage, and skeletal muscle. Additionally, some potential uses of nanoreinforced hydrogels within the emerging disciplines of cyborganics, bionics, and soft biorobotics are highlighted. PMID- 27966828 TI - The onset of puberty in Cameroon Dwarf goats kept as pets in northwestern Croatia. AB - The aim of this study was to determine onset of puberty in Cameroon Dwarf goats (CDGs) kept as pets in northwestern Croatia by determining progesterone (PGS) and insulin-like growth factor-I (IGF-I) levels in the blood by RIA methods. The first cyclic ovarian activity was estimated according to hormone profiles as determined in CDG in a moderate climate environment. Sixteen female CDG kids were kept in stables with access to pasture which provided space for exercise. The goat kids born in winter (December-January-February), spring (March-April-May), summer (June-July-August) and autumn (September-October-November) were assigned into four groups according to the season of the year of birth (n = 4 in each group). At 75 days of age at the initiation of the study, they weighed between 3.2 and 5.1 kg (4.24 +/- 0.53 kg). The onset of ovulatory activity was determined by PGS and IGF-I serum concentrations every 10 days starting from 75 days to 155 days of age. The onset of puberty in CDG kids occurred on average at 141.15 +/- 2.66 days of age, but varied depending on the season of birth. All CDG kids born during summer were in heat by 155 days of age. In the other groups (kids born in autumn, winter or spring), one goat in each group was not in heat. Changes in blood serum PGS and IGF-I concentrations during prepubertal and pubertal periods could aid in the evaluation of reproductive status and determination of the onset of puberty in CDG during all seasons of the year in a moderate climate region. PMID- 27966829 TI - Paediatric eye injuries in Finland - Helsinki eye trauma study. AB - PURPOSE: To determine the current population-based epidemiology, treatment, use of resources and outcomes of children's eye injuries in Finland. METHODS: The study included all new patients, 16 years of age or under, with ocular or orbital traumas taken into care to the Helsinki University Eye Hospital (population base 1.5 million people) in 1 year. The follow-up period was 3 months. RESULTS: Two hundred and two children's eye injuries were treated. The eye injury incidence was 5.2-8.3 per 10 000 per year, including all minor and major eye traumas. Eye injury most likely occurred at the junior high school age (13-16 years). Thirty three percentage of accidents took place at home and 24% at school or in day care. The most common causes were sports equipment (15%), contact with human body (12%) and superficial foreign bodies (11%). Excluding minor injuries, contusion was the most common diagnosis (n = 60, 30%). Eighty-seven percentage of contusion patients were estimated to need lifelong follow-up due to elevated glaucoma risk. Nine percentage of all patients had a permanent disability. Guns, fireworks, tools and pellet guns were relatively the most dangerous objects. Pellet guns caused 6% of eye injuries, 36% of them causing permanent impairment. The number of outpatient visits was altogether 443, inpatient days were 49, and 60 children had major surgeries. CONCLUSIONS: Use of protective eyewear would have prevented or diminished eye traumas caused by pellet gun, floorball, most of the firework and in many superficial foreign body. The use of pellet guns and protective eyewear should be more supervised. Fireworks and tools are not suitable toys for children. PMID- 27966830 TI - Homocysteine and risk of age-related macular degeneration: a systematic review and meta-analysis. AB - There is still no agreement on total plasma homocysteine (tHcy) role in age related macular degeneration (AMD), the leading cause of new blindness in industrialized countries. We performed a systematic review and meta-analysis of the published data on the correlation between tHcy and AMD. MEDLINE/PubMed and ISI Web of Sciences searches were performed according to MOOSE guidelines. Case control studies were eligible for inclusion. Participants and controls were AMD patients and subjects without AMD. The main outcome measure was wet AMD. Homocysteine level was the main exposure variable. Data were pooled using a random-effects model. Twelve case-control studies were identified: 10 assessed wet AMD, four dry AMD, one early AMD, one late AMD, and one any AMD. As for wet AMD, there was a total of 453 cases and 514 controls. Mean tHcy was on average 1.1 MUmol/l (95% confidence interval [CI] = 0.96-1.25) greater in wet AMD cases, but there was evidence of extreme between-study heterogeneity (p < 0.001, I2 = 91.8%). In a model homogenous for age, including six wet AMD studies (214 cases, 274 controls), mean tHcy was on average 0.58 MUmol/l (95% CI = 0.35-0.73) greater in the case group, a not statistically significant result (p = 0.144) associated with moderate heterogeneity (I2 = 39.2%). Our meta-analysis indicates that there is some weak evidence that increased tHcy might be associated with wet AMD; however, this result should be interpreted cautiously, because of a marked between-study heterogeneity and the possible effect of publication bias. Future studies, preferably of cohort design, are necessary before any firm conclusions on the putative role of increased tHcy on AMD can be drawn. PMID- 27966831 TI - Prevalence of posterior vitreous detachment in glaucoma patients and controls. AB - PURPOSE: To evaluate the impact of oxidative stress - present in glaucoma - on the vitreous. We therefore compare the presence of early and late stages of posterior vitreous detachment (PVD) between patients with glaucoma and controls. METHODS: The vitreous state was evaluated by the combination of optical coherence tomography and ultrasound. The main outcome was the vitreous state classified into 'no PVD', 'initial PVD' and 'advanced PVD'. RESULTS: We evaluated the vitreous state in 48 patients with glaucoma (age: mean 66.5 +/- 11.9 years; visual field deviation: mean 10.4 +/- 6.8 dB) and compared the results with 101 previously investigated controls (age: mean 73.6 +/- 9.3 years). After one-to-one matching on age and sex, ordinal logistic regression revealed that patients with glaucoma were significantly more likely to exhibit advanced PVD stages compared to non-glaucoma patients (OR 2.60, 95% confidence interval: 1.06-6.36, p = 0.037). CONCLUSION: Our results suggest that the presence or absence of PVD might be a valuable hint for diagnosing glaucoma - however, further research is needed to determine whether PVD can be used to supplement current glaucoma screening guidelines. PMID- 27966832 TI - Design of Block Copolymer Micellar Aggregates for Co-Delivery of Enzyme and Anticancer Prodrug. AB - Traditional enzyme-prodrug therapy (EPT) is a two-step strategy, which has many serious deficiencies, so having a one-step EPT treatment becomes a problem of immediate interest. This study aims to achieve an effective co-delivery of horseradish peroxidase (HRP) as a kind of enzyme for prodrug activation and ethyl 3-indoleacetate (EIA) as anticancer prodrug. A ternary block copolymer PEG PAsp(AED)-CA consisting of poly(ethylene glycol) (PEG), reduction-sensitive poly (N-(2,2'-dithiobis(ethylamine)) aspartamide) PAsp(AED), and cholic acid (CA) was synthesized and assembled into spherical micelles which encapsulated EIA in its hydrophobic core and HRP in a reduction-sensitive interlayer. TEM photographs show that the polymer micelle is around 40 nm, and the cell survival rate test shows that the EIA/HRP polymer micelle is highly lethal to human lung adenocarcinoma cells. Thus, co-delivery of EIA and HRP demonstrates great potential in cancer therapy, offering a structurally simple and highly tunable platform for the synchronous delivery of enzymes and prodrugs in EPT. PMID- 27966834 TI - Outcomes of scleral buckling using chandelier endoillumination. AB - PURPOSE: To report the results and complications of scleral buckling for the treatment of rhegmatogenous retinal detachment (RRD) using 25-gauge chandelier endoillumination. METHODS: A total of 61 patients (61 eyes) with RRD were treated with scleral buckling. For the sclera buckling procedure, a 25-gauge chandelier was inserted through the pars plana for intra-ocular illumination, and retinal tears were identified and treated with episcleral cryotherapy under surgical microscope. On postoperative days 1, 3 and 7, the intra-ocular pressure was measured by a non-contact tonometer. On postoperative months 1 and 3, ultrasound biomicroscopy was used to examine the pars plana incision. RESULTS: In the surgical procedure, there was no lenticular or retinal damage due to the chandelier insertion. There was no conjunctival bleb formation at pars plana incision and no incidence of endophthalmitis after surgery. The mean intra-ocular pressure was 15.74 +/- 2.98, 15.83 +/- 2.76 and 16.14 +/- 2.52 mmHg on postoperative days 1, 3 and 7, respectively. The one-time retinal reattachment rate was 93.4%. No visible vitreous incarceration was found in the incision of the pars plana. CONCLUSION: There was no complication found due to the chandelier insertion in early postoperative period. Chandelier endoillumination is a feasible method for retinal visualization under surgical microscope during scleral buckling. PMID- 27966835 TI - The Epidemiology and Characteristics of Q fever and Co-infections with Scrub Typhus, Murine Typhus or Leptospirosis in Taiwan: A Nationwide Database Study. AB - Q fever (QF) is a worldwide zoonosis associated with outbreaks. Only a few nationwide studies regarding the surveillance and epidemiology of human QF have been reported. Although QF is endemic in Taiwan, a nationwide database investigation of the epidemiology and characteristics of QF and its associations with scrub typhus (ST), murine typhus (MT) and leptospirosis (LS) has never been reported. We analysed nationwide databases of suspected QF, ST, MT and LS cases from October 2007 to December 2014 obtained from the Centers for Disease Control, Taiwan. A total of 468 (4.2%) QF cases were identified among 11 109 suspected QF cases. QF cases were mainly distributed in the southern and Kaohsiung-Pingtung regions but rarely in the eastern region. Compared to non-QF cases, QF cases had significantly higher percentages of males (88.7 versus 66.2%) and high-risk occupations (farming, animal husbandry or veterinary medicine) (16.2 versus 10.5%). But the percentages of specific animal contact, including cattle (0.6 versus 0.8%) and goats (0.9 versus 1.0%), were low in both. The majority of suspected QF cases (89.4%) were simultaneously suspected with ST, MT or LS, and the combinations of suspected diseases differed between regions. The number of suspected QF cases from the eastern region decreased since 2009, which was not observed in other regions. A total of 1420 (12.8%) cases had confirmed diseases, including QF (453, 4.1%), QF+ST (7, 0.06%), QF+MT (4, 0.04%), QF+LS (4, 0.04%), MT (186, 1.7%), ST (545, 4.9%), ST+LS (11, 0.1%) and LS (210, 1.9%). Compared to cases of unknown disease, QF cases had larger percentages of high-risk occupations (16.2 versus 9.6%) but similar histories of animal contact (29.8 versus 25.1%). QF is an endemic disease in southern Taiwan. It is difficult to differentiate QF from ST, MT or LS only by high-risk occupations and history of animal contact, and co-infection of QF with these diseases should be considered. PMID- 27966833 TI - Stable Transmission of Borrelia burgdorferi Sensu Stricto on the Outer Banks of North Carolina. AB - The spirochaete (Borrelia burgdorferi) associated with Lyme disease was detected in questing ticks and rodents during a period of 18 years, 1991-2009, at five locations on the Outer Banks of North Carolina. The black-legged tick (Ixodes scapularis) was collected at varied intervals between 1991 and 2009 and examined for B. burgdorferi. The white-footed mouse (Peromyscus leucopus), house mouse (Mus musculus) marsh rice rat (Oryzomys palustris), marsh rabbit (Sylvilagus palustris), eastern cottontail (Sylvilagus floridanus) and six-lined racerunner (Cnemidophorus sexlineatus) were live-trapped, and their tissues cultured to isolate spirochaetes. Borrelia burgdorferi isolates were obtained from questing adult I. scapularis and engorged I. scapularis removed from P. leucopus, O. palustris and S. floridanus. The prevalence of B. burgdorferi infection was variable at different times and sites ranging from 7 to 14% of examined questing I. scapularis. Mitochondrial (16S) rRNA gene phylogenetic analysis from 65 adult I. scapularis identified 12 haplotypes in two major clades. Nine haplotypes were associated with northern/Midwestern I. scapularis populations and three with southern I. scapularis populations. Sixteen isolates obtained from tick hosts in 2005 were confirmed to be B. burgdorferi by amplifying and sequencing of 16S rRNA and 5S-23S intergenic spacer fragments. The sequences had 98-99% identity to B. burgdorferi sensu stricto strains B31, JD1 and M11p. Taken together, these studies indicate that B. burgdorferi sensu stricto is endemic in questing I. scapularis and mammalian tick hosts on the Outer Banks of North Carolina. PMID- 27966837 TI - Authors reply to: toric intraocular lens implantation in children with developmental cataract and preexisting corneal astigmatism by Ram et al. PMID- 27966836 TI - Physical activity in relation to development and progression of myopia - a systematic review. AB - On a global scale, myopia is one of the most common causes of visual impairment. Given the increasing prevalence of myopia, it is vital to understand the pathogenesis and to identify potential interventions. Some studies have described physical activity as a potential correlation for myopia. The objective of this study was to make a systematic review regarding the correlation between physical activity and myopia. A total of 263 papers were identified in a systematic database search of PubMed/Medline and Embase. Five steps of screening removed studies of a low evidence quality and animal studies. Studies included had refractive error and physical activity (as measured by questionnaires, accelerometers and cycle ergometers) as separate, well-defined outcomes. Nine studies (six cross-sectional, two cohorts and one case-control study) with a total of 17 634 subjects were included. Six studies demonstrated a reverse association between physical activity and myopia. Three studies supported this, but also attributed the results to time spent outdoors and not physical activity per se. One cross-sectional study found no relation. We could not identify trends among the papers regarding the type of studies, population sizes, ethnicity or age of study subjects. A consistent relationship between more physical activity and less myopia was observed. No evidence of physical activity as an independent risk factor for myopia was seen. Evidence suggests that time outdoors remain the most important factor. Future studies should include objective measurements of physical activity to determine a potential independent effect. Distinction between physical activity and outdoor exposure remains important. PMID- 27966838 TI - Translaminar pressure in Caucasian normal tension glaucoma patients. AB - PURPOSE: The aim of this study was to examine the translaminar pressure difference (TLP) in Caucasian patients with normal tension glaucoma (NTG) and its possible impact onto the pathogenesis of NTG. METHODS: Retrospective analysis of medical records of patients with open-angle glaucoma (OAG) in the period from 2005 to 2015 from the Ophthalmology Department, Cantonal Hospital Aarau, Switzerland. A total of 67 eyes of 38 patients (mean age 68.6 +/- 11.3 years, 21 women and 17 men) fulfilled the diagnostic criteria of progressive NTG and underwent lumbar puncture (LP) during computer-assisted cisternography (CT - cisternography). The intraocular pressure (IOP) and lumbar cerebrospinal fluid pressure (CSF-p) were analysed and the TLP calculated. The TLP was compared with the mean defect (MD) of visual fields. Statistical analysis was performed with the one and two-tailed paired and unpaired t-test and the non-parametric Spearman correlation test. RESULTS: The mean lumbar opening CSF-p measured 11.6 +/- 3.7 mmHg. The mean IOP in the right eye measured 14.7 +/- 2.4 mmHg, in the left eye 14.7 +/- 2.5 mmHg. The calculated mean TLP was 3.0 +/- 4.2 mmHg in the right and 3.3 +/- 4.3 mmHg in the left eye. There was no significant correlation between TLP and the MD of visual fields in both eyes. CONCLUSIONS: This study did not confirm either a lower lumbar CSF-p or increased TLP compared to previous retrospective and prospective studies. As cerebrospinal fluid (CSF) flow is not homogenous throughout all CSF spaces and CSF-p and IOP fluctuate, the current view on TLP needs modifications to improve its validity. PMID- 27966842 TI - Biotechnology Journal 2016 Cover Gallery. PMID- 27966840 TI - Elevated iron status and risk of gestational diabetes mellitus: A systematic review and meta-analysis. AB - The aim of this systematic review and meta-analysis of observational studies was to assess the relationship between elevated iron status, measured as hemoglobin and ferritin levels, and the risk of gestational diabetes mellitus (GDM). The present study was recorded in PROSPERO (2013:CRD42013005717). The selected studies were identified through a systematic review of scientific literature published in The Cochrane Library and PubMed/MEDLINE databases from their inception until March 10, 2016, in addition to citation tracking and hand searches. The search strategy of original articles combined several terms for hemoglobin, ferritin, pregnancy, and GDM. OR and 95% CI of the selected studies were used to identify associations between hemoglobin and/or ferritin levels with the risk of GDM. Summary estimates were calculated by combining inverse-variance using fixed-effects model. 2468 abstracts were initially found during the search. Of these, 11 with hemoglobin and/or ferritin data were selected for the meta analyses. We observed that high hemoglobin (OR = 1.52; 95% CI: 1.23-1.88), as well as ferritin (OR = 2.09; 95% CI: 1.48-2.96) levels were linked to an increased risk of GDM. Low heterogeneity was observed in hemoglobin (I2 = 33.3%, P = 0.151) and ferritin (I2 = 0.7%, P = 0.418) meta-analyses, respectively. Publication bias was not appreciated. High hemoglobin or ferritin levels increase the risk of GDM by more than 50% and more than double, respectively, in the first and third trimester. Therefore, determining of hemoglobin or ferritin concentration in early pregnancy might be a useful tool for recognizing pregnant women at risk of GDM. PMID- 27966839 TI - Household food insecurity in Mexico is associated with the co-occurrence of overweight and anemia among women of reproductive age, but not female adolescents. AB - We aimed to determine the association between household food insecurity (HFI) and the co-occurrence of overweight and anemia among women of reproductive age in the Mexican population. We analyzed data on 4,039 nonpregnant female adolescents (15 19 years) and 10,760 nonpregnant adult women of reproductive age (20-49 years) from the 2012 National Health and Nutrition Survey of Mexico. The survey uses a two-stage sampling design, stratified by rural and urban regions. The Latin American and Caribbean Food Security Scale was used to assess HFI. We assessed overweight and obesity in women based on World Health Organization classifications for body mass index, and BMI-for-age Z-scores for female adolescents, and defined anemia as an altitude-adjusted hemoglobin (Hb) concentration < 120 g/L based on measurement of capillary Hb concentrations. In multiple logistic regression models adjusting for potential confounding covariates, HFI was not associated with the co-occurrence of anemia and overweight among female adolescents. The adjusted odds of women of reproductive age from mildly and moderately food-insecure households, respectively, experiencing concurrent anemia and overweight were 48% (OR: 1.48; 95% CI: 1.15, 1.91) and 49% (OR: 1.49; 95% CI: 1.08, 2.06) higher than among women from food secure households. Severe HFI was not associated with concurrent overweight and anemia among female adolescents or women. HFI may be a shared mechanism for dual forms of malnutrition within the same individual, simultaneously contributing to overconsumption and dietary inadequacy. PMID- 27966843 TI - Editorial: ECAB focus issue: Engineered catalysts, robust, cost-effective and integrated bioprocesses and high-throughput screening. AB - How can technology and industrial biotechnology contribute to a more bio-based economy? At the 3rd European Congress of Applied Biotechnology (ECAB3) in Nice in 2015, relevant topics and technologies and their contribution to sustainability were presented and discussed. In this issue of Biotechnology Journal, five special articles are selected from this conference, highlighting processes and technologies envisaging the development of engineered catalysts, robust bioprocesses, as well as high-throughput screening methods for process development. PMID- 27966844 TI - Intellectual property rights, standards and data exchange in systems biology: Reflections from the IP Expert Meeting at the University of Luxembourg, 8-9 October 2015, ERASysAPP - ERA-Net for Systems Biology Applications. AB - Intellectual property rights (IPRs) have become a key concern for researchers and industry in basically all high-tech sectors. IPRs regularly figure prominently in scientific journals and at scientific conferences and lead to dedicated workshops to increase the awareness and "IPR savviness" of scientists. In 2015, Biotechnology Journal published a report from an expert meeting on "Synthetic Biology & Intellectual Property Rights" organized by the Danish Agency for Science, Technology and Innovation sponsored by the European Research Area Network (ERA-Net) in Synthetic Biology (ERASynBio), in which we provided a number of recommendations for a variety of stakeholders [1]. The current article offers some deeper reflections about the interface between IPRs, standards and data exchange in systems biology (SysBio) resulting from an Expert Meeting funded by another ERA-Net, ERASysAPP. The meeting brought together experts and stakeholders (e.g. scientists, company representatives, officials from public funding organizations) in SysBio from different European countries. Despite the different profiles of the stakeholders at the meeting and the variety of interests, many concerns and opinions were shared. In case particular views were expressed by a specific type of stakeholder, this will be explicitly mentioned in the text. In this article, we explore a number of particularly relevant issues that were discussed at the meeting and offer some recommendations. SysBio involves the study of biological systems at a so-called systems level. This is not a new concept in the life sciences - many former approaches in physiology, enzymology and other scientific disciplines have already taken a systemic view of selected biological subjects. Yet, SysBio has gained strong interest within the past 10 to 15 years. One predominant reason and a critical prerequisite for this success story being that the relevant scientific methodologies and research tools have become far more powerful and accurate. Remarkable technical progress allows scientists to generate, collect, display and analyse quantitative and qualitative data on biological processes and activities in much greater volumes, velocity, variety and veracity. The skilful integration of multiple heterogeneous data sets allows scientists to model and predict biological processes. SysBio's interdisciplinary nature requires data, models and other research assets to be formatted and described in standard ways to enable exchange and reuse of high quality data [2]. This allows a more effective utilisation of the enormous potential that rests in "big data" analysis. Finally, SysBio is often closely linked to or provides the foundation for Synthetic Biology (SynBio). Standardization and data exchange in SysBio may result in challenges and opportunities related to IPRs. The aim of this article is to raise awareness on these issues within the SysBio scientific community and to stimulate exploration of different strategies for dealing with IPRs in order to optimize access to and use of valuable research results. PMID- 27966846 TI - Taenia solium: WHO endemicity map update. PMID- 27966847 TI - Aggregation-Induced Energy Transfer of Conjugated Polymer Materials for ATP Sensing. AB - Water-soluble conjugated polymers are attractive fluorescent materials for applications in chemical and biological sensing. The molecular wire effect of such polymers amplifies changes in the fluorescence signal, which can be used for detecting various analytes with high sensitivity. In this work, we report an efficient ratiometric fluorescent probe based on a water-soluble conjugated polymer that showed high sensitivity and selectivity toward adenosine 5' triphosphate (ATP). The macromolecular probe consisted of a polyfluorene backbone doped with 5 mol % 1,4-dithienylbenzothiadiazole (DBT) modified by bis imidazolium and oligo(ethylene glycol) moieties. Solutions of the polymer emitted purple fluorescence, which changed to red upon addition of ATP molecules. The addition of ATP caused the polymer to aggregate, which enhanced fluorescence resonance energy transfer efficiency from the fluorene segments to DBT units, leading to an increase in red emission. The ratio of the fluorescence at these different wavelengths (I655/I423) showed a strong dependence on the ATP concentration. PF-DBT-BIMEG also exhibited high selectivity for ATP sensing over other representative anions and discriminated it from adenosine 5'-diphosphate (ADP) and adenosine 5'-monophosphate (AMP). This can be explained by the much stronger electrostatic interactions between the polymer and ATP than the interactions between the polymer and ADP or AMP, as confirmed through molecular dynamics simulations. PMID- 27966848 TI - Phenomenal Ultraviolet Photoresponsivity and Detectivity of Graphene Dots Immobilized on Zinc Oxide Nanorods. AB - A combination of dimensionally reduced graphene quantum dots (GQDs) having edge effects and the vertically aligned ZnO nanorods shows highly selective visible blind ultraviolet (UV) sensing. The GQD immobilized ZnO nanorod heterostructure shows remarkable responsivity of ~6.62 * 104 A/W and detectivity of ~1.78 * 1015 Jones under 365 nm (10 MUW) incident light and 2 V bias potential with high stability of at least 5 cycles, fast response time of 2.14 s, and recovery time of 0.91 s. The grain boundary assisted electron transport across GQDs was calculated from the normalized absorption below bandgap. The highest UV responsivity and detectivity were found to be proportional to the lowest trap state density at the grain boundaries (Qt) and minimum grain boundary potential (Eb). For the best GQD, Qt and Eb were found to be ~4 * 1013 cm-2 and 0.4 meV, respectively. The phenomenal performance of ZnO-GQD heterostructure is attributed to the efficient immobilization of GQDs on ZnO nanorods and the idea of employing GQDs as photosensitizers than solely as electron transporting medium. The efficiency of GQDs is superior to carbon quantum dots (CQDs) containing minimal graphitic domains, and graphene oxide (GO) or reduced graphene oxide (rGO) having larger dimensions preventing their immobilization on ZnO nanorods. PMID- 27966849 TI - Ruthenium/Graphene-like Layered Carbon Composite as an Efficient Hydrogen Evolution Reaction Electrocatalyst. AB - Efficient water splitting through electrocatalysis has been studied extensively in modern energy devices, while the development of catalysts with activity and stability comparable to those of Pt is still a great challenge. In this work, we successfully developed a facile route to synthesize graphene-like layered carbon (GLC) from a layered silicate template. The obtained GLC has layered structure similar to that of the template and can be used as support to load ultrasmall Ru nanoparticles on it in supercritical water. The specific structure and surface properties of GLC enable Ru nanoparticles to disperse highly uniformly on it even at a large loading amount (62 wt %). When the novel Ru/GLC was used as catalyst on a glass carbon electrode for hydrogen evolution reaction (HER) in a 0.5 M H2SO4 solution, it exhibits an extremely low onset potential of only 3 mV and a small Tafel slope of 46 mV/decade. The outstanding performance proved that Ru/GLC is highly active catalyst for HER, comparable with transition-metal dichalcogenides or selenides. As the price of ruthenium is much lower than platinum, our study shows that Ru/GLC might be a promising candidate as an HER catalyst in future energy applications. PMID- 27966850 TI - Natural Materials Assembled, Biodegradable, and Transparent Paper-Based Electret Nanogenerator. AB - Developing eco-friendly and low-cost electronics is an effective strategy to address the electronic waste issue. In this study, transparent cellulose nanopaper (T-paper) and polylactic acid (PLA) electret were used to construct a biodegradable and transparent paper-based electret nanogenerator. The nanogenerator could be assembled with paper products to form a self-powered smart packaging system without impairing the appearance, due to the high transparency and desirable output performance. Furthermore, the self-degradation property in the natural soil of the nanogenerator is demonstrated, indicating that the nanogenerator is recycled and will not pollute the environment. We anticipate that this study will provide new insights to develop eco-friendly power source and paper-based electronics. PMID- 27966851 TI - Fabrication of Surface Protein-Imprinted Biofuel Cell for Sensitive Self-Powered Glycoprotein Detection. AB - Glycoproteins are important biomarkers and therapeutic targets in clinical diagnostics. The conventional analytical methods for glycoprotein are usually faced with some challenges, such as the complex pretreatment of samples, poor availability, and limited stability of antibody, making them not suitable for point-of-care and on-site application. Herein, we demonstrate a novel miniaturized biofuel cells (BFCs)-based self-powered nanosensor for the specific and sensitive determination of glycoproteins in complex samples through the combination of boronate-affinity molecularly imprinted polymer (MIP) and the boronate affinity functionalized biliroxidase-carbon nanotube nanocomposites. The above MIP and the nanocomposites act as both signal probe and biocatalyst at the cathode. The as-obtained self-powered MIP-BFC-based biosensor can detect horseradish peroxidase (a type of glycoprotein) with a wide linear range of 1 ng/mL to 10 MUg/mL and a very low detection limit of 1 ng/mL. Especially, it shows high tolerance for different interferences (e.g., sugars and other glycoproteins) and can even measure the alpha-fetoprotein level in serum samples. Moreover, it exhibits significant advantages over the conventional assays in terms of cost efficiency, stability, and speed, especially inexpensive instrument needed. Our novel approach for construction of the sensor paves a simple and economical way to fabricate portable devices for point-of-care and on-site application. PMID- 27966852 TI - Balancing Osmotic Pressure of Electrolytes for Nanoporous Membrane Vanadium Redox Flow Battery with a Draw Solute. AB - Vanadium redox flow batteries with nanoporous membranes (VRFBNM) have been demonstrated to be good energy storage devices. Yet the capacity decay due to permeation of vanadium and water makes their commercialization very difficult. Inspired by the forward osmosis (FO) mechanism, the VRFBNM battery capacity decrease was alleviated by adding a soluble draw solute (e.g., 2-methylimidazole) into the catholyte, which can counterbalance the osmotic pressure between the positive and negative half-cell. No change of the electrolyte volume has been observed after VRFBNM being operated for 55 h, revealing that the permeation of water and vanadium ions was effectively limited. Consequently, the Coulombic efficiency (CE) of nanoporous TiO2 vanadium redox flow battery (VRFB) was enhanced from 93.5% to 95.3%, meanwhile, its capacity decay was significantly suppressed from 60.7% to 27.5% upon the addition of soluble draw solute. Moreover, the energy capacity of the VRFBNM was noticeably improved from 297.0 to 406.4 mAh remarkably. These results indicate balancing the osmotic pressure via the addition of draw solute can restrict pressure-dependent vanadium permeation and it can be established as a promising method for up-scaling VRFBNM application. PMID- 27966853 TI - Exploration of Ca0.5Ti2(PO4)3@carbon Nanocomposite as the High-Rate Negative Electrode for Na-Ion Batteries. AB - Exploring suitable electrode materials with high specific capacity and high-rate capability is a challenging goal for the development of Na-ion batteries. Here, we report a NASICON-structured compound, Ca0.5Ti2(PO4)3, with respect to its synthesis and electrochemical properties. The electrode is found to enable fast Na+ ion diffusion owing to the rich crystallographic vacancies, affording a reversible capacity of 264 mA h g-1 between 3.0 and 0.01 V. In particular, the hybrid Ca0.5Ti2(PO4)3@carbon exhibits remarkable rate performance with a discharge capacity of nearly 45 mA h g-1 at a current density of 20 A g-1, which is attributed to the pseudocapacitive effect. PMID- 27966854 TI - Nanoparticle-Directed Metal-Organic Framework/Porous Organic Polymer Monolithic Supports for Flow-Based Applications. AB - A two-step nanoparticle-directed route for the preparation of macroporous polymer monoliths for which the pore surface is covered with a metal-organic framework (MOF) coating has been developed to facilitate the use of MOFs in flow-based applications. The flow-through monolithic matrix was prepared in a column format from a polymerization mixture containing ZnO-nanoparticles. These nanoparticles embedded in the precursor monolith were converted to MOF coatings via the dissolution-precipitation equilibrium after filling the pores of the monolith with a solution of the organic linker. Pore surface coverage with the microporous zeolitic imidazolate framework ZIF-8 resulted in an increase in surface area from 72 to 273 m2 g-1. Monolithic polymer containing ZIF-8 coating was implemented as a microreactor catalyzing the Knoevenagel condensation reaction and also in extraction column format enabling the preconcentration of trace levels of toxic chlorophenols in environmental waters. Our approach can be readily adapted to other polymers and MOFs thus enabling development of systems for flow-based MOF applications. PMID- 27966855 TI - MOF-Derived Noble Metal Free Catalysts for Electrochemical Water Splitting. AB - Noble metal free electrocatalysts for water splitting are key to low-cost, sustainable hydrogen production. In this work, we demonstrate that metal-organic frameworks (MOFs) can be controllably converted into catalysts for the oxygen evolution reaction (OER) or the hydrogen evolution reaction (HER). The OER catalyst is composed of FeNi alloy nanoparticles encapsulated in N-doped carbon nanotubes, which is obtained by thermal decomposition of a trimetallic (Zn2+, Fe2+, and Ni2+) zeolitic imidazolate framework (ZIF). It reaches 10 mA cm-2 at the overpotential of 300 mV with a low Tafel slope of 47.7 mV dec-1. The HER catalyst consists of Ni nanoparticles coated with a thin layer of N-doped carbon. It is obtained by thermal decomposition of a Ni-MOF in NH3. It shows low overpotential of only 77 mV at 20 mA cm-2 with low Tafel slope of 68 mV dec-1. The above noble metal free OER and HER electrocatalysts are applied in an alkaline electrolyzer driven by a commercial polycrystalline solar cell. It achieves electrolysis efficiency of 64.4% at 65 mA cm-2 under sun irradiation of 50 mW cm-2. This practical application shows the promising prospect of low-cost and high-efficiency sustainable hydrogen production from combination of solar cells with high-performance noble metal free electrocatalysts. PMID- 27966856 TI - Enhancing Electrode Performance by Exsolved Nanoparticles: A Superior Cobalt-Free Perovskite Electrocatalyst for Solid Oxide Fuel Cells. AB - The successful development of low-cost, durable electrocatalysts for oxygen reduction reaction (ORR) at intermediate temperatures is critical for broad commercialization of solid oxide fuel cells. Here, we report our findings in design, fabrication, and characterization of a cobalt-free SrFe0.85Ti0.1Ni0.05O3 delta cathode decorated with NiO nanoparticles. Exsolved from and well bonded to the parent electrode under well-controlled conditions, the NiO nanoparticles uniformly distributed on the surface of the parent electrode greatly enhance cathode performance, demonstrating ORR activity better than that of the benchmark cobalt-based Ba0.5Sr0.5Co0.8Fe0.2O3-delta. Further, a process for regeneration of the NiO nanoparticles was also developed to mitigate potential performance degradation due to coarsening of NiO particles under practical operating conditions. As a general approach, this exsolution-dissolution of electrocatalytically active nanoparticles on an electrode surface may be applicable to the development of other high-performance cobalt-free cathodes for fuel cells and other electrochemical systems. PMID- 27966858 TI - Rhenium-Based Molecular Trap as an Evanescent Wave Infrared Chemical Sensing Medium for the Selective Determination of Amines in Air. AB - An evanescent wave infrared chemical sensor was developed to selectively detect volatile amines with heterocyclic or phenyl ring. To achieve this goal, a rhenium based metallacycle with a "molecular-trap" structure was designed and synthesized as host molecules to selectively trap amines with heterocyclic or phenyl ring through Re-amine and pi-pi interactions. To explore the trapping properties of the material, a synthesized Re-based molecular trap was treated on an IR sensing element, and wide varieties of volatile organic compounds (VOCs) were examined to establish the selectivity for detection of amines. Based on the observed IR intensities, the Re-based molecular trap favors interaction with amines as evidenced by the variation of absorption bands of the Re molecular trap. With extra pi-pi interaction force, molecules, such as pyridine and benzylamine, could be detected. After optimization of the parameters for IR sensing, a rapid response in the detection of pyridine was observed, and the linear ranges were generally up to 10 mg/L with a detection limit around 5.7 MUg/L. In the presence of other VOCs, the recoveries in detection of pyridine were all close to 100%. PMID- 27966857 TI - A Review of the Fundamental Principles and Applications of Solution Blow Spinning. AB - Solution blow spinning (SBS) is a technique that can be used to deposit fibers in situ at low cost for a variety of applications, which include biomedical materials and flexible electronics. This review is intended to provide an overview of the basic principles and applications of SBS. We first describe a method for creating a spinnable polymer solution and stable polymer solution jet by manipulating parameters such as polymer concentration and gas pressure. This method is based on fundamental insights, theoretical models, and empirical studies. We then discuss the unique bundled morphology and mechanical properties of fiber mats produced by SBS, and how they compare with electrospun fiber mats. Applications of SBS in biomedical engineering are highlighted, showing enhanced cell infiltration and proliferation versus electrospun fiber scaffolds and in situ deposition of biodegradable polymers. We also discuss the impact of SBS in applications involving textiles and electronics, including ceramic fibers and conductive composite materials. Strategies for future research are presented that take advantage of direct and rapid polymer deposition via cost-effective methods. PMID- 27966859 TI - ALD TiO2-Coated Flower-like MoS2 Nanosheets on Carbon Cloth as Sodium Ion Battery Anode with Enhanced Cycling Stability and Rate Capability. AB - We report the fabrication of 3D flower-like MoS2 nanosheets arrays on carbon cloth as a binder-free anode for sodium ion battery. Ultrathin and conformal TiO2 layers are used to modify the surface of MoS2 by atomic layer deposition. The electrochemical performance measurements demonstrate that the ALD TiO2 layer can improve the cycling stability and rate capability of MoS2. The MoS2 nanosheets with 0.5-nm TiO2 coating electrode show the highest initial discharge capacity of 1392 mA h g-1 at 200 mA g-1, which is increased by 53% compared with that of bare MoS2. After 150 cycles, the capacity retention rate of the TiO2-coated MoS2 achieves 75.8% of its second cycle's capacity at 200 mA h g-1 in contrast to that of 59% of pure MoS2. Furthermore, the mechanism behind the experimental results is revealed by ex situ scanning electron microscope (SEM), X-ray powder diffraction (XRD), and electrochemical impedance spectroscopy (EIS) characterizations, which confirms that the ultrathin TiO2 modifications can prevent the structural degradation and the formation of SEI film of MoS2 electrode. PMID- 27966860 TI - The Effect of Interfacial Dipoles on the Metal-Double Interlayers-Semiconductor Structure and Their Application in Contact Resistivity Reduction. AB - We demonstrate the contact resistance reduction for III-V semiconductor-based electrical and optical devices using the interfacial dipole effect of ultrathin double interlayers in a metal-interlayers-semiconductor (M-I-S) structure. An M-I S structure blocks metal-induced gap states (MIGS) to a sufficient degree to alleviate Fermi level pinning caused by MIGS, resulting in contact resistance reduction. In addition, the ZnO/TiO2 interlayers of an M-I-S structure induce an interfacial dipole effect that produces Schottky barrier height (PhiB) reduction, which reduces the specific contact resistivity (rhoc) of the metal/n-type III-V semiconductor contact. As a result, the Ti/ZnO(0.5 nm)/TiO2(0.5 nm)/n-GaAs metal double interlayers-semiconductor (M-DI-S) structure achieved a rhoc of 2.51 * 10 5 Omega.cm2, which exhibited an ~42 000* reduction and an ~40* reduction compared to the Ti/n-GaAs metal-semiconductor (M-S) contact and the Ti/TiO2(0.5 nm)/n-GaAs M-I-S structure, respectively. The interfacial dipole at the ZnO/TiO2 interface was determined to be approximately -0.104 eV, which induced a decrease in the effective work function of Ti and, therefore, reduced PhiB. X-ray photoelectron spectroscopy analysis of the M-DI-S structure also confirmed the existence of the interfacial dipole. On the basis of these results, the M-DI-S structure offers a promising nonalloyed Ohmic contact scheme for the development of III-V semiconductor-based applications. PMID- 27966861 TI - Ultrasensitive GSH-Responsive Ditelluride-Containing Poly(ether-urethane) Nanoparticles for Controlled Drug Release. AB - A novel ultrasensitive redox-responsive system for the controlled release of doxorubicin (DOX) was fabricated by ditelluride-containing poly(ether-urethane) copolymers. In this study, the ditelluride group was introduced for the first time into water-soluble copolymers used for drug delivery. Doxorubicin loaded in the copolymer nanoparticles can be released in a controlled manner through the cleavage of ditelluride bonds by glutathione (GSH). The ditelluride-containing poly(ether-urethane) nanoparticles were demonstrated to be biocompatible as drug delivery vehicles, therefore opening a new avenue in drug delivery systems for chemotherapy. Furthermore, the in vitro and in vivo studies revealed that the DOX loaded ditelluride-containing poly(ether-urethane) nanoparticles exhibited efficient uptake in cancer cells, specific tumor targeting and antitumor activity, indicating their excellent potential as novel nanocarriers for drug delivery and cancer therapy. PMID- 27966862 TI - Controlling Microstructure-Transport Interplay in Highly Phase-Separated Perfluorosulfonated Aromatic Multiblock Ionomers via Molecular Architecture Design. AB - Proton-conducting multiblock polysulfones bearing perfluorosulfonic acid side chains were designed to encode nanoscale phase-separation, well-defined hydrophilic/hydrophobic interfaces, and optimized transport properties. Herein, we show that the superacid side chains yield highly ordered morphologies that can be tailored by best compromising ion-exchange capacity and block lengths. The obtained microstructures were extensively characterized by small-angle neutron scattering (SANS) over an extended range of hydration. Peculiar swelling behaviors were evidenced at two different scales and attributed to the dilution of locally flat polymer particles. We evidence the direct correlation between the quality of interfaces, the topology and connectivity of ionic nanodomains, the block superstructure long-range organization, and the transport properties. In particular, we found that the proton conductivity linearly depends on the microscopic expansion of both ionic and block domains. These findings indicate that neat nanoscale phase-separation and block-induced long-range connectivity can be optimized by designing aromatic ionomers with controlled architectures to improve the performances of polymer electrolyte membranes. PMID- 27966864 TI - Role of Intrinsic Ion Accumulation in the Photocurrent and Photocapacitive Responses of MAPbBr3 Photodetectors. AB - We studied steady state and transient photocurrents in thin film and single crystal devices of MAPbBr3, a prototype organic-inorganic hybrid perovskite. We found that the devices' capacitance is abnormally large, which originates from accumulation of large densities of Pb2+ and Br- in the active perovskite layer. Under applied bias, these ions are driven toward the opposite electrodes leading to space-charge fields close to the metal/perovskite interfaces. The ion accumulation, in turn, causes photocurrent reversal polarity that depends on the history of the applied bias and excitation photon energy with respect to the optical gap. Furthermore, the large capacitive response dominates the transient photocurrent and, therefore, obscures the weaker contribution from the photocarriers' drift. We show that these properties depend on the ambient conditions in which the measurements are performed. Understanding these phenomena may lead to better control over the stability of perovskite photodetectors for visible light. PMID- 27966865 TI - Enhanced ZT of InxCo4Sb12-InSb Nanocomposites Fabricated by Hydrothermal Synthesis Combined with Solid-Vapor Reaction: A Signature of Phonon-Glass and Electron-Crystal Materials. AB - A rapid route of synthesizing pristine Co4Sb12 at relatively low temperature was previously developed. However, filling the voids using the same procedure is not successful. We develop a new route to fabricate In-filled cobalt skutterudites with InSb nanoinclusions InxCo4Sb12-(InSb)y via solid-vapor reaction between hydrothermally synthesized Co4Sb12 powder and the indium chunk. The nanocomposites are characterized using powder X-ray diffraction, field-emission scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy, and inductively coupled plasma mass spectrometry (ICP-MS). With the success of partial filling of In into the voids and InSb nanoinclusions, the power factor of the InxCo4Sb12-(InSb)y nanocomposites is significantly enhanced, and the thermal conductivity is lowered as compared with the pristine Co4Sb12. As a result, ZT with its highest value of 1.0 is attained for the hierarchical structured In0.04Co4Sb12-(InSb)0.05 nanocomposite at 575 K. The attained ZT value is among the highest ever reported value at T <= 575 K for In filled cobalt skutterudites. PMID- 27966863 TI - MT1-MMP Responsive Doxorubicin Conjugated Poly(lactic-co-glycolic Acid)/Poly(styrene-alt-maleic Anhydride) Core/Shell Microparticles for Intrahepatic Arterial Chemotherapy of Hepatic Cancer. AB - In this study, we demonstrated that the MT1-MMP-responsive peptide (sequence: GPLPLRSWGLK) and doxorubicin-conjugated poly(lactic-co-glycolic acid/poly(styrene alt-maleic anhydride) core/shell microparticles (PLGA/pSMA MPs) can be applied for intrahepatic arterial injection for hepatocellular carcinoma (HCC). PLGA/pSMA MPs were prepared with a capillary-focused microfluidic device. The particle size, observed by scanning electron microscopy (SEM), was around 22 +/- 3 MUm. MT1-MMP-responsive peptide and doxorubicin (DOX) were chemically conjugated with pSMA segments on the shell of MPs to form a PLGA/pSMA-peptide-DOX complex, resulting in high encapsulation efficiency (91.1%) and loading content (2.9%). DOX was released from PLGA/pSMA-peptide-DOX MPs in a pH-dependent manner (~25% at pH 5.4 and ~8% at pH 7.4) and accumulated significantly in an MT1-MMP overexpressing Hep3B cell line. An in vivo intrahepatic injection study showed localization of MPs on the hepatic vessels and hepatic lobes up to 24 h after the injection without any shunting to the lung. Moreover, MPs efficiently inhibited tumor growth of Hep3B hepatic tumor xenografted mouse models. We expect that PLGA/pSMA-peptide-DOX MPs can be utilized as an effective intrahepatic drug delivery system for the treatment of HCC. PMID- 27966866 TI - Grafted Polymethylhydrosiloxane on Hierarchically Porous Silica Monoliths: A New Path to Monolith-Supported Palladium Nanoparticles for Continuous Flow Catalysis Applications. AB - Polymethylhydrosiloxane has been grafted on the surface of a hierarchically porous silica monolith using a facile catalytic reaction between Si-H and silanol to anchor the polymer. This easy methodology leads to the functionalization of the surface of a silica monolith, where a large amount of free Si-H bonds remain available for reducing metal ions in solution. Palladium nanoparticles of 15 nm have been synthesized homogeneously inside the mesopores of the monolith without any stabilizers, using a flow of a solution containing Pd2+. This monolith was used as column-type fixed bed catalyst for continuous flow hydrogenation of styrene and selective hydrogenation of 3-hexyn-1-ol, in each case without a significant decrease of the catalytic activity after several hours or days. Conversion, selectivity, and stereoselectivity of the alkyne hydrogenation can be tuned by flow rates of hydrogen and the substrate solution, leading to high productivity (1.57 mol g(Pd)-1 h-1) of the corresponding cis-alkene. PMID- 27966867 TI - Propelled Transnuclear Gene Transport Achieved through Intracellularly Redox Responsive and Acidity-Accelerative Decomposition of Supramolecular Florescence Quenchable Vectors. AB - Intracellularly biotriggered decomposition of gene vectors is generally thought to benefit transfection. However, the bioresponsiveness is far from satisfactory, and the exact role of biodecomposition in the transfection process remains unclear to date. To overcome the challenges, highly rapid bioresponse of vectors has to be achieved so as to greatly amplify the intracellular deviation compared with the noncontrolled pattern. To this end, a supramolecular polyrotaxane has been elaborately designed by integrating reversible dynamics of supramolecular assembly and chemically labile bonds, in order to effectively propel intracellular decomposition. Inside tumor cells, the redox-responsive bulk dissociation of the supramolecular vector readily took place and was further accelerated by the lysosomal-acidity-triggered terminal decomposition. Both the in vitro and in vivo experiments have demonstrated that this supramolecule could mediate considerably more rapid gene accumulation in nuclei than the nonresponsive controls including PEI25K, the gold standard of nonviral vectors. Along with the structural decomposition, the supramolecule simultaneously underwent the transition of fluorescence quenching, favoring the evaluation over the bioresponsiveness inside cells. Based on the resulting data, it is suggested that the biotriggered volume expansion of supramolecule/DNA complexes may be the major factor accounting for that dramatically accelerated transnuclear gene transport during cellular mitosis, thus affecting the transfection. This study offers an understanding of the intracellular gene transport from a new viewpoint. PMID- 27966868 TI - Single-Phase Photo-Cross-Linkable Bioinspired Adhesive for Precise Control of Adhesion Strength. AB - A bioinspired, modular terpolymer adhesive, poly(N-methacryloyl-3,4-dihydroxyl-l phenylalanine-co-9-(acryloyloxy)butyl anthracene-9-carboxylate-co-acrylic acid), has been synthesized containing three different functionalities: a photo-cross linking segment, a wet interfacial adhesion segment, and a water-soluble segment. The synthesized adhesive polymer is the first example of a single-phase, photo cross-linkable adhesive which does not require additional photoinitiator or other cross-linking agents. The terpolymer demonstrates strong adhesion when it swells in water and/or ethanol. The terpolymer is composed of three repeating units: N methacryloyl-3,4-dihydroxyl-l-phenylalanine (MDOPA), which has been known to generate strong adhesion under wet conditions, poly(acrylic acid), which has been known to increase water solubility of polymers, and a photo-cross-linking segment consisting of an anthracene-based monomer used for enhancement of cohesion properties via UV irradiation (352 nm). A photomediated [4 + 4] cycloaddition reaction of anthracene results in the cross-linking of individual polymer chains after interfacial adhesion between substrates and adhesive polymers. Chemically, the covalent photo-cross-linking was confirmed by UV-vis, 1H NMR, and gel permeation chromatography (GPC). The cross-linking-fortified cohesion of the adhesive polymer network yields strengthened cohesion properties of the bulk material. The photoreaction was conveniently controlled via the duration of UV irradiation. The adhesion properties of new adhesives were characterized by lap shear strength on transparent Mylar film and glasses after the adhesive was swollen in biologically friendly solvents including water and ethanol. The adhesion strength (J/m2) was enhanced by 850% under 352 nm UV-irradiation. Multiple application variables were tested to determine the optimal conditions, such as solvent, concentration, polymer composition, and substrate. The best adhesion properties were obtained from a 1:1 weight ratio of polymer:solvent in water on a Mylar film surface. As a single-phase system, the synthesized terpolymer is very convenient to use, and its adhesion strength can be easily modified by UV light. Additionally, the terpolymer's high water compatibility makes it ideally suited for application in the biomedical field. PMID- 27966869 TI - Electrochemical Behavior of Anode-Respiring Bacteria on Doped Carbon Electrodes. AB - Cultivating anodic respiring bacteria (ARB) on anodes doped with metal-enhanced biological growth and affected higher electocatalytic activity (ECA). The anode doped with calcium sulfide (CaS) proved more favorable for ARB than the magnetite (Fe3O4) or iron(II) sulfide (FeS). Average anodic current densities of 8.4 Am2- (Fe3O4), 11.1 Am2- (FeS), and 22.0 Am2- (CaS) were achieved as compared to that of nondoped carbon (5.1 A m-2). Thus, CaS-doped graphite represents a promising anode material which is suitable for highly efficient bioelectrochemical systems (BES). Electrochemical evaluation during turnover and starvation using simple cycle voltammetry (CV) and derivative cycle voltammetry (DCV) indicated several extracellular electron transfer (EET) pathways characterized with lower potentials for biofilms. However, despite the high affinity of bacteria to iron, their lower ECA was kinetically attributed to the accumulation of self-produced mediators on iron-doped anodes. PMID- 27966870 TI - Confined Formation of Ultrathin ZnO Nanorods/Reduced Graphene Oxide Mesoporous Nanocomposites for High-Performance Room-Temperature NO2 Sensors. AB - Here we demonstrate high-performance room-temperature NO2 sensors based on ultrathin ZnO nanorods/reduced graphene oxide (rGO) mesoporous nanocomposites. Ultrathin ZnO nanorods were loaded on rGO nanosheets by a facile two-step additive-free solution synthesis involving anchored seeding followed by oriented growth. The ZnO nanorod diameters were simply controlled by the seed diameters associated with the spatial confinement effects of graphene oxide (GO) nanosheets. Compared to the solely ZnO nanorods and rGO-based sensors, the optimal sensor based on ultrathin ZnO nanorods/rGO nanocomposites exhibited higher sensitivity and quicker p-type response to parts per million level of NO2 at room temperature, and the sensitivity to 1 ppm of NO2 was 119% with the response and recovery time being 75 and 132 s. Moreover, the sensor exhibited full reversibility, excellent selectivity, and a low detection limit (50 ppb) to NO2 at room temperature. In addition to the high transport capability of rGO as well as excellent NO2 adsorption ability derived from ultrathin ZnO nanorods and mesoporous structures, the superior sensing performance of the nanocomposites was attributed to the synergetic effect of ZnO and rGO, which was realized by the electron transfer across the ZnO-rGO interfaces through band energy alignment. PMID- 27966871 TI - ZnO-Decorated Carbon Nanotube Hybrids as Fillers Leading to Reversible Nonlinear I-V Behavior of Polymer Composites for Device Protection. AB - Overvoltage protection is becoming increasingly important because of miniaturization and multifunctionality of electronic devices. Flexible, easily processable materials with nonlinear and reversible I-V behavior are highly desired. In this study, hybrid nanoparticles of ZnO-decorated carbon nanotubes (CNT-ZnO) were synthesized via a sol-gel hydrothermal process employed in an epoxy matrix to prepare composites. Microstructure analysis demonstrated that ZnO nanoparticles were well-bonded to the surface of CNT. The CNT-ZnO/epoxy composites exhibited nonlinear I-V behavior under increasingly applied voltage with a nonlinear coefficient of 5.01 (10 wt % filler loading). More importantly, the composites possessed excellent reversibility from dielectric to conductor and vise versa in the recycling of increase and decrease of applied electric field, in contrast to the poor recoverability of pure CNT-filled epoxy. The mechanism of the nonlinear I-V behavior and reversibility was investigated and discussed. A simple circuit was fabricated, which verified well the protection function of the CNT-ZnO/polymer composites. PMID- 27966872 TI - In Situ Multitechnical Investigation into Capacity Fading of High-Voltage LiNi0.5Co0.2Mn0.3O2. AB - LiNi0.5Co0.2Mn0.3O2 positive electrode materials of lithium ion battery can release a discharge capacity larger than 200 mAh/g at high potential (>4.30 V). However, its inevitable capacity fading, which is greatly related to the structural evolution, reduces the cycling performance. The origin of this capacity fading is investigated by coupled in situ XRD-PITT-EIS. A new phase of NiMn2O4 is discovered on the surface of the LiNi0.5Co0.2Mn0.3O2 upon charging to high voltage, which blocks Li+ diffusion pathways. Theoretical calculations predict the formation of cubic NiMn2O4. Moreover, corrosion, cracks, and microstress appear to increase the difficulty of Li+ transportation, which are attributed to the protection degradation of the interfacial film on the positive electrode material at high voltage. After 50 electrochemical cycles, the increase in degree of crystal defects by low-angle grain boundary, evidenced through HR TEM, leads to poor Li+ kinetics, which in turn causes capacity loss. The in situ XRD-PITT-EIS technique can bring multiperspective insights into fading mechanism of the high-voltage positive electrode materials and provide a solution to control or suppress the problem on the basis of structural, kinetic, and electrochemical interfacial understandings. PMID- 27966873 TI - Cell Growth on ("Janus") Density Gradients of Bifunctional Zeolite L Crystals. AB - Nanoparticle density gradients on surfaces have attracted interest as two dimensional material surfaces that can mimic the complex nano-/microstructure of the native extracellular matrix, including its chemical and physical gradients, and can therefore be used to systematically study cell-material interactions. In this respect, we report the preparation of density gradients made of bifunctional zeolite L crystals on glass surfaces and the effects of the density gradient and biopolymer functionalization of zeolite L crystals on cell adhesion. We also describe how we created "Janus" density gradient surfaces by gradually depositing two different types of zeolite L crystals that were functionalized and loaded with different chemical groups and guest molecules onto the two distinct sides of the same glass substrate. Our results show that more cells adhered on the density gradient of biopolymer-coated zeolites than on uncoated ones. The number of adhered cells increased up to a certain surface coverage of the glass by the zeolite L crystals, but then it decreased beyond the zeolite density at which a higher surface coverage decreased fibroblast cell adhesion and spreading. Additionally, cell experiments showed that cells gradually internalized the guest molecule-loaded zeolite L crystals from the underlying density gradient containing bifunctional zeolite L crystals. PMID- 27966874 TI - Nitrogen-Doped Carbon Fiber Paper by Active Screen Plasma Nitriding and Its Microwave Heating Properties. AB - In this paper, active screen plasma nitriding (ASPN) treatment was performed on polyacrylonitrile carbon fiber papers. Electric resistivity and microwave loss factor of carbon fiber were described to establish the relationship between processing parameters and fiber's ability to absorb microwaves. The surface processing effect of carbon fiber could be characterized by dynamic thermal mechanical analyzer testing on composites made of carbon fiber. When the process temperature was at 175 degrees C, it was conducive to obtaining good performance of dynamical mechanical properties. The treatment provided a way to change microwave heating properties of carbon fiber paper by performing different treatment conditions, such as temperature and time parameters. Atomic force microscope, scanning electron microscope, and X-ray photoelectron spectroscopy analysis showed that, during the course of ASPN treatment on carbon fiber paper, nitrogen group was introduced and silicon group was removed. The treatment of nitrogen-doped carbon fiber paper represented an alternative promising candidate for microwave curing materials used in repairing and heating technology, furthermore, an efficient dielectric layer material for radar-absorbing structure composite in metamaterial technology. PMID- 27966875 TI - Multifunctional Polymeric Platform of Magnetic Ferrite Colloidal Superparticles for Luminescence, Imaging, and Hyperthermia Applications. AB - Adequately designed multiresponsive water-soluble graft copolymers were used to serve as a multifunctional polymeric platform for the encapsulation and transfer in aqueous media of hydrophobic magnetic nanoparticles (MNPs). The backbone of the graft copolymers was composed of hydrophilic sodium methacrylate units, hydrophobic dodecyl methacrylate units, and luminescent quinoline-based units, while either the homopolymer poly(N-isopropylacrylamide) or a poly(N,N dimethylacrylamide-co-N-isopropylacrylamide) copolymer was used as thermosensitive pendent side chains. The polymeric platform forms micellar-type assemblies in aqueous solution, and exhibits pH-responsive luminescent properties and a lower critical solution temperature behavior in water. Depending on the design of the side chains, the cloud point temperatures were determined at 38 and 42 degrees C, close or slightly above body temperature (37 degrees C). Above the critical micelle concentration (CMC), both graft copolymers can effectively stabilize in aqueous media as magnetic colloidal superparticles (MSPs), oleylamine-coated MnFe2O4 MNPs, as well as 1:1 mixture of oleylamine-coated MnFe2O4 and CoFe2O4 MNPs. When CoFe2O4 particles were mixed with MnFeO4 in equal amounts, the specific loss power increased significantly, while an opposite trend was observed in the magnetic resonance imaging (MRI) studies, probably due to the anisotropy of cobalt. As a consequence, fine-tuning of the chemical structure of the copolymers and the composition of the MSPs can lead to materials that are able to act simultaneously as luminescent, hyperthermia, and contrast MRI agents. PMID- 27966876 TI - Solubility-Dependent NiMoO4 Nanoarchitectures: Direct Correlation between Rationally Designed Structure and Electrochemical Pseudokinetics. AB - Tailoring the binary metal oxide along with developing new synthetic methods for controlling resultant nanostructures in a predictive way is an essential requirement for achieving the further improved electrochemical performance of pseudocapacitors. Here, through a rational design of the supersaturation-mediated driving force for hydrothermal nucleation and crystal growth, we successfully obtain one-dimensional (1-D) nickel molybdenum oxide (NiMoO4) nanostructures with controlled aspect ratios. The morphology of the 1-D NiMoO4 nanostructures can be tuned from a low to a high aspect ratio (over a range of diameter sizes from 80 to 800 nm). Such a controllable structure provides a platform for understanding the electrochemical relationships in terms of fast relaxation times and improved ion-diffusion coefficients. We show that the 1-D NiMoO4 electrode with a high aspect ratio (HAR) exhibits a much higher specific capacitance of 1335 F g-1 at a current density of 1 A g-1 compared to the other electrodes with a relatively low aspect ratio, which is due to the unique physical and chemical structure being suitable for electrochemical kinetics. We further demonstrate that an asymmetric supercapacitor consisting of the tailored HAR-NiMoO4 electrode can achieve an energy density of 40.7 Wh kg-1 and a power density of 16 kW kg-1. PMID- 27966877 TI - Functionalization of the Polymeric Surface with Bioceramic Nanoparticles via a Novel, Nonthermal Dip Coating Method. AB - The only nonthermal method of depositing a bioceramic-based coating on polymeric substrates is by incubation in liquid, e.g., simulated body fluid to form an apatite-like layer. The drawbacks of this method include the long processing time, the production of low scratch resistant coating, and an end product that does not resemble the intended bioceramic composition. Techniques, such as plasma spraying and magnetron sputtering, involving high processing temperature are unsuitable for polymers, e.g., PMMA. Here, we introduce a nonthermal coating method to immobilize hydroxyapatite (HAp) and TiO2 nanoparticles on PMMA via a simple and fast dip coating method. Cavities that formed on the PMMA, induced by chloroform, appeared to trap the nanoparticles which accumulated to form layers of bioceramic coating only after 60 s. The resulting coating was hydrophilic and highly resistant to delamination. In the context of our research and to address the current clinical need, we demonstrate that the HAp-coated PMMA, which is intended to be used as a visual optic of a corneal prosthetic device, improves its bonding and biointegration with collagen, the main component of a corneal stroma. The HAp-coated PMMA resulted in better adhesion with the collagen than untreated PMMA in artificial tear fluid over 28 days. Human corneal stromal fibroblasts showed better attachment, viability, and proliferation rate on the HAp-coated PMMA than on untreated PMMA. This coating method is an innovative solution to immobilize various bioceramic nanoparticles on polymers and may be used in other biomedical implants. PMID- 27966878 TI - Vertically Aligned FeOOH/NiFe Layered Double Hydroxides Electrode for Highly Efficient Oxygen Evolution Reaction. AB - Employing a low-cost and highly efficient electrocatalyst to replace Ir-based catalysts for oxygen evolution reaction (OER) has drawn increasing interest in renewable energy storage. In this work, a vertically aligned FeOOH/NiFe layered double hydroxides (LDHs) nanosheets supported on Ni foam (VA FeOOH/NiFe LDHs-NF) is prepared as a highly effective OER electrode in alkaline electrolyte. The VA FeOOH/NiFe LDHs-NF represents nanosheet arrays on nickel foam with some interspace among them. The vertically aligned and interlayer-structured architecture is binder-free and contributes to facile strain relaxation, relieving the exfoliation of the catalysts layer caused by the oxygen evolution process. The as-prepared electrode shows current densities of 10 and 500 mA cm-2 at overpotentials of 208 and 288 mV, and good stability in a half-cell electrolyzer. Besides, the alkaline polymer electrolyte water electrolyzer (APEWE) with this electrode showed 1.71 V at 200 mA cm-2, and 2.041 V at 500 mA cm-2, exhibiting the corresponding energy efficiency of 86.0% and 72.0% (based on the lower heating value of hydrogen), which is better than the typical commercial alkaline water electrolyzer. PMID- 27966881 TI - Low-Cost Paper Electrode Fabricated by Direct Writing with Silver Nanoparticle Based Ink for Detection of Hydrogen Peroxide in Wastewater. AB - A simple, low cost and user-friendly method for the fabrication of paper electrode (PE) using silver nanoparticles capped with octylamine (AgNPs-OA) is reported for detection of hydrogen peroxide (H2O2) in wastewater samples. The PE was prepared by direct writing onto the photo paper using a ball-point pen filled with nanoink (10 wt % of AgNPs-OA in chloroform). The prepared electrode was sintered at 100 degrees C for 1 h to make it conductive. The PE/AgNPs-OA was used as a working electrode in cyclic voltammetry (CV) for the detection of H2O2. The PE/AgNPs-OA exhibited a wide linear calibration range from 1.7 MUM to 30 mM for the determination of H2O2 with a low limit of detection, 0.5 MUM. The good recovery percentage (95.2-96.2%) and interference study for determination of H2O2 in wastewater samples demonstrated the selectivity of the method from the complex sample matrices. The PE/AgNPs-OA electrode is found to be economic, facile and user-friendly for multiple analyses (n = 60) of H2O2 in CV compared to other commercially available electrodes and custom-made modified electrodes. PMID- 27966879 TI - Single-Molecule FRET Measurements in Additive-Enriched Aqueous Solutions. AB - The addition of high amounts of chemical denaturants, salts, viscosity enhancers or macro-molecular crowding agents has an impact on the physical properties of buffer solutions. Among others, the (microscopic) viscosity, the refractive index, the dielectric constant, and the ionic strength can be affected. Here, we systematically evaluate the importance of solvent characteristics with respect to single-molecule FRET (smFRET) data. First, we present a confocal based method for the determination of fluorescence quantum yields to facilitate a fast characterization of smFRET-samples at sub-nM-concentrations. As a case study, we analyze smFRET data of structurally rigid, double-stranded DNA-oligonucleotides in aqueous buffer and in buffers with specific amounts of glycerol, guanidine hydrochloride (GdnHCl), and sodium chloride (NaCl) added. We show that the calculation of interdye distances, without taking into account solvent-induced spectral and photophysical changes of the labels, leads to deviations of up to 4 A from the real interdye distances. Additionally, we demonstrate that electrostatic dye-dye repulsions are negligible for the interdye distance regime considered here (>50 A). Finally, we use our approach to validate the further compaction of the already unfolded state of phosphoglycerate kinase (PGK) with decreasing denaturant concentrations, a mechanism known as coil-globule transition. PMID- 27966880 TI - Enhanced Photocatalytic Performance Depending on Morphology of Bismuth Vanadate Thin Film Synthesized by Pulsed Laser Deposition. AB - We have fabricated high quality bismuth vanadate (BiVO4) polycrystalline thin films as photoanodes by pulsed laser deposition (PLD) without a postannealing process. The structure of the grown films is the photocatalytically active phase of scheelite-monoclinic BiVO4 which was obtained by X-ray diffraction (XRD) analysis. The change of surface morphology for the BIVO4 thin films depending on growth temperature during synthesis has been observed by scanning electron microscopy (SEM), and its influence on water splitting performance was investigated. The current density of the BiVO4 film grown on a glass substrate covered with fluorine-doped tin oxide (FTO) at 230 degrees C was as high as 3.0 mA/cm2 at 1.23 V versus the potential of the reversible hydrogen electrode (VRHE) under AM 1.5G illumination, which is the highest value so far in previously reported BiVO4 films grown by physical vapor deposition (PVD) methods. We expect that doping of transition metal or decoration of oxygen evolution catalyst (OEC) in our BiVO4 film might further enhance the performance. PMID- 27966882 TI - Metal-Organic Coordination Polymer to Prepare Density Controllable and High Nitrogen-Doped Content Carbon/Graphene for High Performance Supercapacitors. AB - Design and preparation of carbon-based electrode material with high nitrogen doping ratio and appropriate density attract much interest for supercapacitors in practical application. Herein, three porous carbon/graphene (NCGCu, NCGFe, and NCGZn) with high doping ratio of nitrogen have been prepared via directly pyrolysis of graphene oxide (GO)/metal-organic coordination polymer (MOCP) composites, which were formed by reacting 4,4'-bipyridine (BPD) with CuCl2, FeCl3, and ZnCl2, respectively. As-prepared NCGCu, NCGFe and NCGZn showed high nitrogen doping ratio of 10.68, 12.99, and 11.21 at. %; and high density of 1.52, 0.84, and 1.15 g cm-3, respectively. When as-prepared samples were used as supercapacitor electrodes, NCGCu, NCGFe and NCGZn exhibited high gravimetric specific capacitances of 369, 298.5, 309.5 F g-1, corresponding to high volumetric specific capacitances of 560.9, 250.7, 355.9 F cm-3 at a current density of 0.5 A g-1, as well as good cycling stability, nearly 100% of the capacitance retained after 1000 cycles even at a large current density of 10 A g 1. It is expected that the provided novel strategy can be used to develop electrode materials in high performance energy conversion/storage devices. PMID- 27966883 TI - PEGylated Au@Pt Nanodendrites as Novel Theranostic Agents for Computed Tomography Imaging and Photothermal/Radiation Synergistic Therapy. AB - The integration of photothermal therapy (PTT) with radiation therapy (RT) in a single nanoscale platform is believed to have considerable potential for cancer therapy. In this work, the rationally designed PEGylated Au@Pt nanodendrites (NDs) have been developed as a novel X-ray computed tomography (CT) and PTT/RT enhanced theranostic agent for cancer therapy. The absorption of Au@Pt NDs was turned to the near-infrared region with the growth of Pt nanobranches and thus enhances the efficacy of PTT. Furthermore, because of the high atomic number (high Z) of Au as well as Pt, Au@Pt NDs significantly enhanced lethal effects of RT by inducing a highly localized radiation dose within cancer cells. More importantly, the combination of Au@Pt ND-enhanced RT with PTT suppressed cancer cell growth more efficiently than that RT or PTT alone did, indicating a synergistic effect. Meanwhile, the Au@Pt NDs also possess significant CT imaging signal enhancement that has the potential to guide PTT/RT for cancers. The integrated strategy significantly improved CT and PTT/RT of cancer cells with mild laser and radiation. Because of these advantages, Au@Pt NDs have become appealing and effective agents for cancer theranostic. PMID- 27966884 TI - Ligand Binding in the Extracellular Vestibule of the Neurotransmitter Transporter Homologue LeuT. AB - The human monoamine transporters (MATs) facilitate the reuptake of monoamine neurotransmitters from the synaptic cleft. MATs are linked to a number of neurological diseases and are the targets of both therapeutic and illicit drugs. Until recently, no high-resolution structures of the human MATs existed, and therefore, studies of this transporter family have relied on investigations of the homologues bacterial transporters such as the leucine transporter LeuT, which has been crystallized in several conformational states. A two-substrate transport mechanism has been suggested for this transporter family, which entails that high affinity binding of a second substrate in an extracellular site is necessary for the substrate in the central binding site to be transported. Compelling evidence for this mechanism has been presented, however, a number of equally compelling accounts suggest that the transporters function through a mechanism involving only a single substrate and a single high-affinity site. To shed light on this apparent contradiction, we have performed extensive molecular dynamics simulations of LeuT in the outward-occluded conformation with either one or two substrates bound to the transporter. We have also calculated the substrate binding affinity in each of the two proposed binding sites through rigorous free energy simulations. Results show that substrate binding is unstable in the extracellular vestibule and the substrate binding affinity within the suggested extracellular site is very low (0.2 and 3.3 M for the two dominant binding modes) compared to the central substrate binding site (14 nM). This suggests that for LeuT in the outward-occluded conformation only a single high-affinity substrate binding site exists. PMID- 27966886 TI - Nanoparticle Based on Poly(Ionic Liquid) as an Efficient Solid Immobilization Catalyst for Aldol Reaction and Multicomponent Reaction in Water. AB - An environmentally friendly nanoparticle-supported catalyst was successfully prepared via in situ ionic complexation between imidazolium-based polymer ionic liquid (PIL) and poly(l-prolinamide-co-MAA). The physical and chemical properties of the obtained nanoparticles were characterized by TEM, FTIR, XPS, and static water contact angle experiments. The surface properties of the nanoparticle were found to significantly affect the catalytic performance. The nanoparticle with PIL outer facilitated the adsorption of reaction substrate in it. As a result, the catalytic system catalyzed the asymmetric Aldol reaction and multicomponent reaction in pure water efficiently. The catalytic system was able to be reused and recycled five times, and with no discernible loss in catalytic activity and enantioselectivity. These findings suggest that nanoparticles based on PIL may provide a new approach for preparing high performance supported catalysts for organic reactions in water. This technology also addresses issues associated with mass transfer in pure water reactions. PMID- 27966887 TI - Well-Defined Multivalent Ligands for Hepatocytes Targeting via Asialoglycoprotein Receptor. AB - Targeted delivery of therapeutic agents to hepatocytes is a particularly attractive strategy for the treatment of hepatocellular carcinoma and other liver diseases. The asialoglycoprotein receptor (ASGP-R) is abundantly expressed on hepatocytes and minimally found on extra-hepatic cells, making it an ideal entry gateway for hepatocyte-targeted therapy. Numerous multivalent ligands have been developed to target ASGP-R, among which well-defined multivalent ligands display especially high binding affinity to the receptor. Recently, several gene delivery systems based on such ligands for ASGP-R showed encouraging clinical results, drawing increasing interest in the scientific community and eventually promoting the improvement of current treatment for liver diseases. Here, we review ASGP-R targeting with a special emphasis on well-defined systems and properties such as the linker's length, hydrophilic-hydrophobic balance of the linker, and the spatial geometry of the scaffold. The present manuscript provides important guidelines for the design of multivalent ligands for ASGP-R. PMID- 27966885 TI - High-Fat-Diet-Induced Deficits in Dopamine Terminal Function Are Reversed by Restoring Insulin Signaling. AB - Systemically released insulin crosses the blood-brain barrier and binds to insulin receptors on several neural cell types, including dopaminergic neurons. Insulin has been shown to decrease dopamine neuron firing in the ventral tegmental area (VTA), but potentiate release and reuptake at dopamine terminals in the nucleus accumbens (NAc). Here we show that prolonged consumption of a high fat diet blocks insulin's effects in the NAc, but insulin's effects are restored by inhibiting protein tyrosine phosphatase 1B, which supports insulin receptor signaling. Mice fed a high fat diet (60% kcals from fat) displayed significantly higher fasting blood glucose 160 mg/dL, compared to 101 mg/dL for control-diet fed mice, and high-fat-diet-fed mice showed reduced blood glucose clearance after an intraperitoneal glucose tolerance test. Using fast scan cyclic voltammetry to measure electrically evoked dopamine in brain slices containing the NAc core, high-fat-diet-fed mice exhibited slower dopamine reuptake compared to control diet-fed mice (2.2 +/- 0.1 and 2.67 +/- 0.15 MUM/s, respectively). Moreover, glucose clearance rate was negatively correlated with Vmax. Insulin (10 nM to 1 MUM) dose dependently increased reuptake rates in control-diet-fed mice compared with in the high-fat-diet group; however, the small molecule insulin receptor sensitizing agent, TCS 401 (300 nM), restored reuptake in high-fat-diet-fed mice to control-diet levels, and a small molecule inhibitor of the insulin receptor, BMS 536924 (300 nM), attenuated reuptake, similar to high-fat-diet-fed mice. These data show that a high-fat diet impairs dopamine reuptake by attenuating insulin signaling at dopamine terminals. PMID- 27966888 TI - DNA-Catalytically Active Gold Nanoparticle Conjugates-Based Colorimetric Multidimensional Sensor Array for Protein Discrimination. AB - A series of single-strand oligonucleotides functionalized catalytically active gold nanoparticle (AuNPs) as nonspecific receptors have been designed to build a protein sensing array. We take advantage of the correlation between the catalytic activity and the exposed surface area of AuNPs, i.e., DNA-proteins interactions mask the surface area of AuNPs, leading to poor catalytic performance of AuNPs. As the number of DNA-bound proteins increases, the surfaces of AuNPs become more masked; thus, the time of 4- nitrophenol/NaBH4 reaction for color change (yellow > colorless) of the solution increases. Taking advantage of three nonspecific SH labeled DNA sequences (A15, C15, and T15) as array sensing elements and the color change time (CCT) of the solution as signal readout, colorimetric response patterns can be obtained on the array and identified via linear discriminant analysis (LDA). Eleven proteins have been completely distinguished with 100% accuracy with the naked eye at the 30 nM level. Remarkably, two similar proteins (bovine serum albumin and human serum albumin), two different proteins (bovine serum albumin and concanavalin) at the same concentration, and the mixtures of the two proteins with different molar ratios have been discriminated with 100%. The practicability of this sensor array is further validated by high accuracy (100%) identification of 11 proteins in human serum samples. PMID- 27966889 TI - Cellular Assays for Ferredoxins: A Strategy for Understanding Electron Flow through Protein Carriers That Link Metabolic Pathways. AB - The ferredoxin (Fd) protein family is a structurally diverse group of iron-sulfur proteins that function as electron carriers, linking biochemical pathways important for energy transduction, nutrient assimilation, and primary metabolism. While considerable biochemical information about individual Fd protein electron carriers and their reactions has been acquired, we cannot yet anticipate the proportion of electrons shuttled between different Fd-partner proteins within cells using biochemical parameters that govern electron flow, such as holo-Fd concentration, midpoint potential (driving force), molecular interactions (affinity and kinetics), conformational changes (allostery), and off-pathway electron leakage (chemical oxidation). Herein, we describe functional and structural gaps in our Fd knowledge within the context of a sequence similarity network and phylogenetic tree, and we propose a strategy for improving our understanding of Fd sequence-function relationships. We suggest comparing the functions of divergent Fds within cells whose growth, or other measurable output, requires electron transfer between defined electron donor and acceptor proteins. By comparing Fd-mediated electron transfer with biochemical parameters that govern electron flow, we posit that models that anticipate energy flow across Fd interactomes can be built. This approach is expected to transform our ability to anticipate Fd control over electron flow in cellular settings, an obstacle to the construction of synthetic electron transfer pathways and rational optimization of existing energy-conserving pathways. PMID- 27966890 TI - A Novel Approach for Gene Expression Optimization through Native Promoter and 5' UTR Combinations Based on RNA-seq, Ribo-seq, and TSS-seq of Streptomyces coelicolor. AB - Streptomycetes are Gram-positive mycelial bacteria, which synthesize a wide range of natural products including over two-thirds of the currently available antibiotics. However, metabolic engineering in Streptomyces species to overproduce a vast of natural products are hampered by a limited number of genetic tools. Here, two promoters and four 5' UTR sequences showing constant strengths were selected based upon multiomics data sets from Streptomyces coelicolor M145, including RNA-seq, Ribo-seq, and TSS-seq, for controllable transcription and translation. A total eight sets of promoter/5' UTR combinations, with minimal interferences of promoters on translation, were constructed using the transcription start site information, and evaluated with the GusA system. Expression of GusA could be controlled to various strengths in three different media, in a range of 0.03- to 2.4-fold, compared to that of the control, ermE*P/Shine-Dalgarno sequence. This method was applied to engineer three previously reported promoters to enhance gene expressions. The expressions of ActII-ORF4 and MetK were also tuned for actinorhodin overproductions in S. coelicolor as examples. In summary, we provide a novel approach and tool for optimizations of gene expressions in Streptomyces coelicolor. PMID- 27966892 TI - Rotational Dynamics and Heating of Trapped Nanovaterite Particles. AB - We synthesize, optically trap, and rotate individual nanovaterite crystals with a mean particle radius of 423 nm. Rotation rates of up to 4.9 kHz in heavy water are recorded. Laser-induced heating due to residual absorption of the nanovaterite particle results in the superlinear behavior of the rotation rate as a function of trap power. A finite element method based on the Navier-Stokes model for the system allows us to determine the residual optical absorption coefficient for a trapped nanovaterite particle. This is further confirmed by the theoretical model. Our data show that the translational Stokes drag force and rotational Stokes drag torque need to be modified with appropriate correction factors to account for the power dissipated by the nanoparticle. PMID- 27966891 TI - Combining Sense and Nonsense Codon Reassignment for Site-Selective Protein Modification with Unnatural Amino Acids. AB - Incorporation of unnatural amino acids (uAAs) via codon reassignment is a powerful approach for introducing novel chemical and biological properties to synthesized polypeptides. However, the site-selective incorporation of multiple uAAs into polypeptides is hampered by the limited number of reassignable nonsense codons. This challenge is addressed in the current work by developing Escherichia coli in vitro translation system depleted of specific endogenous tRNAs. The translational activity in this system is dependent on the addition of synthetic tRNAs for the chosen sense codon. This allows site-selective uAA incorporation via addition of tRNAs pre- or cotranslationally charged with uAA. We demonstrate the utility of this system by incorporating the BODIPY fluorophore into the unique AGG codon of the calmodulin(CaM) open reading frame using in vitro precharged BODIPY-tRNACysCCU. The deacylated tRNACysCCU is a poor substrate for Cysteinyl-tRNA synthetase, which ensures low background incorporation of Cys into the chosen codon. Simultaneously, p-azidophenylalanine mediated amber-codon suppression and its post-translational conjugation to tetramethylrhodamine dibenzocyclooctyne (TAMRA-DIBO) were performed on the same polypeptide. This simple and robust approach takes advantage of the compatibility of BODIPY fluorophore with the translational machinery and thus requires only one post translational derivatization step to introduce two fluorescent labels. Using this approach, we obtained CaM nearly homogeneously labeled with two FRET-forming fluorophores. Single molecule FRET analysis revealed dramatic changes in the conformation of the CaM probe upon its exposure to Ca2+ or a chelating agent. The presented approach is applicable to other sense codons and can be directly transferred to eukaryotic cell-free systems. PMID- 27966894 TI - Microrheological Coagulation Assay Exploiting Micromechanical Resonators. AB - Rheological measurements in biological liquids yield insights into homeostasis and provide information on important molecular processes that affect fluidity. We present a fully automated cantilever-based method for highly precise and sensitive measurements of microliter sample volumes of human blood plasma coagulation (0.009 cP for viscosity range 0.5-3 cP and 0.0012 g/cm3 for density range 0.9-1.1 g/cm3). Microcantilever arrays are driven by a piezoelectric element, and resonance frequencies and quality factors of sensors that change over time are evaluated. A highly accurate approximation of the hydrodynamic function is introduced that correlates resonance frequency and quality factor of cantilever beams immersed in a fluid to the viscosity and density of that fluid. The theoretical model was validated using glycerol reference solutions. We present a surface functionalization protocol that allows minimization of unspecific protein adsorption onto cantilevers. Adsorption leads to measurement distortions and incorrect estimation of the fluid parameters (viscosity and density). Two hydrophilic terminated self-assembled monolayers (SAMs) sensor surfaces are compared to a hydrophobic terminated SAM coating. As expected, the hydrophobic modified surfaces induced the highest mass adsorption and could promote conformational changes of the proteins and subsequent abnormal biological activity. Finally, the activated partial thromboplastin time (aPTT) coagulation assay was performed, and the viscosity, density, and coagulation rate of human blood plasma were measured along with the standard coagulation time. The method could extend and improve current coagulation testing. PMID- 27966895 TI - Design and Tailoring of the 3D Macroporous Hydrous RuO2 Hierarchical Architectures with a Hard-Template Method for High-Performance Supercapacitors. AB - In this work, RuO2 honeycomb networks (RHCs) and hollow spherical structures (RHSs) were rationally designed and synthesized with modified-SiO2 as a sacrificial template via two hydrothermal approaches. At a high current density of 20 A g-1, the two hierarchical porous RuO2.xH2O frameworks showed the specific capacitance as high as 628 and 597 F g-1; this is about 80% and 75% of the capacitance retention of 0.5 A g-1 for RHCs and RHSs, respectively. Even after 4000 cycles at 5 A g-1, the RHCs and RHSs can still remain at 86% and 91% of their initial specific capacitances, respectively. These two hierarchical frameworks have a well-defined pathway that benefits for the transmission/diffusion of electrolyte and surface redox reactions. As a result, they exhibit good supercapacitor performance in both acid (H2SO4) and alkaline (KOH) electrolytes. As compared to RuO2 bulk structure and similar RuO2 counterpart reported in pseudocapacitors, the two hierarchical porous RuO2.xH2O frameworks have better energy storage capabilities, high-rate performance, and excellent cycling stability. PMID- 27966893 TI - Enhancing PET Signal at Target Tissue in Vivo: Dendritic and Multimeric Tris(hydroxypyridinone) Conjugates for Molecular Imaging of alphavbeta3 Integrin Expression with Gallium-68. AB - Tris(hydroxypyridinone) chelators conjugated to peptides can rapidly complex the positron-emitting isotope gallium-68 (68Ga) under mild conditions, and the resulting radiotracers can delineate peptide receptor expression at sites of diseased tissue in vivo. We have synthesized a dendritic bifunctional chelator containing nine 1,6-dimethyl-3-hydroxypyridin-4-one groups (SCN-HP9) that can coordinate up to three Ga3+ ions. This derivative has been conjugated to a trimeric peptide (RGD3) containing three peptide groups that target the alphavbeta3 integrin receptor. The resulting dendritic compound, HP9-RGD3, can be radiolabeled in 97% radiochemical yield at a 3-fold higher specific activity than its homologues HP3-RGD and HP3-RGD3 that contain only a single metal binding site. PET scanning and biodistribution studies show that [68Ga(HP9-RGD3)] demonstrates higher receptor-mediated tumor uptake in animals bearing U87MG tumors that overexpress alphavbeta3 integrin than [68Ga(HP3-RGD)] and [68Ga(HP3 RGD3)]. However, concomitant nontarget organ retention of [68Ga(HP9-RGD3)] results in low tumor to nontarget organ contrast in PET images. On the other hand, the trimeric peptide homologue containing a single tris(hydroxypyridinone) chelator, [68Ga(HP3-RGD3)], clears nontarget organs and exhibits receptor mediated uptake in mice bearing tumors and in mice with induced rheumatoid arthritis. PET imaging with [68Ga(HP3-RGD3)] enables clear delineation of alphavbeta3 integrin receptor expression in vivo. PMID- 27966896 TI - Glioma-Targeted Drug Delivery Enabled by a Multifunctional Peptide. AB - The rapid proliferation of glioma relies on vigorous angiogenesis for the supply of essential nutrients; thus, a radical method of antiglioma therapy should include blocking tumor neovasculature formation. A phage display selected heptapeptide, the glioma-initiating cell peptide GICP, was previously reported as a ligand of VAV3 protein (a Rho GTPase guanine nucleotide exchange factor), which is overexpressed on glioma cells and tumor neovasculature. Therefore, GICP holds potential for the multifunctional targeting of glioma (tumor cells and neovasculature). We developed GICP-modified micelle-based paclitaxel delivery systems for antiglioma therapy in vitro and in vivo. GICP and GICP-modified PEG PLA micelles (GICP-PEG-PLA) could be significantly taken up by U87MG cells, a human cell line derived from malignant gliomas and human umbilical vein endothelial cells (HUVECs). Furthermore, GICP-PEG-PLA micelles demonstrated enhanced penetration in a tumor spheroid model in vitro in comparison to unmodified micelles. In vivo, DiR-loaded GICP-PEG-PLA micelles exhibited superior accumulation in the tumor region by targeting neovasculature and glioma cells in nude mice bearing subcutaneous glioma. When loaded with paclitaxel, GICP-PEG-PLA micelles could more effectively suppress tumor growth and neovasculature formation than unmodified micelles in vivo. Our results indicated that GICP could serve as a promising multifunctional ligand for glioma targeting. PMID- 27966897 TI - Integrating MS1 and MS2 Scans in High-Resolution Parallel Reaction Monitoring Assays for Targeted Metabolite Quantification and Dynamic 13C-Labeling Metabolism Analysis. AB - Quantification of targeted metabolites, especially trace metabolites and structural isomers, in complex biological materials is an ongoing challenge for metabolomics. Initially developed for proteomic analysis, the parallel reaction monitoring (PRM) technique exploiting high-resolution MS2 fragment ion data has shown high promise for targeted metabolite quantification. Notably, MS1 ion intensity data acquired independently as part of each PRM scan cycle are often underutilized in the PRM assay. In this study, we developed an MS1/MS2-combined PRM workflow for quantification of central carbon metabolism intermediates, amino acids and shikimate pathway-related metabolites on an orthogonal QqTOF system. Concentration curve assessment revealed that exploiting both MS1 and MS2 scans in PRM analysis afforded higher sensitivity, wider dynamic range and better reproducibility than relying on either scan mode for quantification. Furthermore, Skyline was incorporated into our workflow to process the MS1/MS2 ion intensity data, and eliminate noisy signals and transitions with interferences. This integrated MS1/MS2 PRM approach was applied to targeted metabolite quantification in engineered E. coli strains for understanding of metabolic pathway modulation. In addition, this new approach, when first implemented in a dynamic 13C-labeling experiment, showed its unique advantage in capturing and correcting isotopomer labeling curves to facilitate nonstationary 13C-labeling metabolism analysis. PMID- 27966898 TI - Amorphous ZnO Quantum Dot/Mesoporous Carbon Bubble Composites for a High Performance Lithium-Ion Battery Anode. AB - Due to its high theoretical capacity (978 mA h g-1), natural abundance, environmental friendliness, and low cost, zinc oxide is regarded as one of the most promising anode materials for lithium-ion batteries (LIBs). A lot of research has been done in the past few years on this topic. However, hardly any research on amorphous ZnO for LIB anodes has been reported despite the fact that the amorphous type could have superior electrochemical performance due to its isotropic nature, abundant active sites, better buffer effect, and different electrochemical reaction details. In this work, we develop a simple route to prepare an amorphous ZnO quantum dot (QDs)/mesoporous carbon bubble composite. The composite consists of two parts: mesoporous carbon bubbles as a flexible skeleton and monodisperse amorphous zinc oxide QDs (smaller than 3 nm) encapsulated in an amorphous carbon matrix as a continuous coating tightly anchored on the surface of mesoporous carbon bubbles. With the benefits of abundant active sites, amorphous nature, high specific surface area, buffer effect, hierarchical pores, stable interconnected conductive network, and multidimensional electron transport pathways, the amorphous ZnO QD/mesoporous carbon bubble composite delivers a high reversible capacity of nearly 930 mA h g 1 (at current density of 100 mA g-1) with almost 90% retention for 85 cycles and possesses a good rate performance. This work opens the possibility to fabricate high-performance electrode materials for LIBs, especially for amorphous metal oxide-based materials. PMID- 27966899 TI - Extracellular Osmotic Stress Reduces the Vesicle Size while Keeping a Constant Neurotransmitter Concentration. AB - Secretory cells respond to hypertonic stress by cell shrinking, which causes a reduction in exocytosis activity and the amount of signaling molecules released from single exocytosis events. These changes in exocytosis have been suggested to result from alterations in biophysical properties of cell cytoplasm and plasma membrane, based on the assumption that osmotic stress does not affect the secretory vesicle content and size prior to exocytosis. To further investigate whether vesicles in secretory cells are affected by the osmolality of the extracellular environment, we used intracellular electrochemical cytometry together with transmission electron microscopy imaging to quantify and determine the catecholamine concentration of dense core vesicles in situ before and after cell exposure to osmotic stress. In addition, single cell amperometry recordings of exocytosis at chromaffin cells were used to monitor the effect on exocytosis activity and quantal release when cells were exposed to osmotic stress. Here we show that hypertonic stress hampers exocytosis secretion after the first pool of readily releasable vesicles have been fused and that extracellular osmotic stress causes catecholamine filled vesicles to shrink, mainly by reducing the volume of the halo solution surrounding the protein matrix in dense core vesicles. In addition, the vesicles demonstrate the ability to perform adjustments in neurotransmitter content during shrinking, and intracellular amperometry measurements in situ suggest that vesicles reduce the catecholamine content to maintain a constant concentration within the vesicle compartment. Hence, the secretory vesicles in the cell cytoplasm are highly affected and respond to extracellular osmotic stress, which gives a new perspective to the cause of reduction in quantal size by these vesicles when undergoing exocytosis. PMID- 27966900 TI - Development of a Desalination Membrane Bioinspired by Mangrove Roots for Spontaneous Filtration of Sodium Ions. AB - The shortage of available fresh water is one of the global issues presently faced by humanity. To determine a solution to this problem, the survival strategies of plants have been examined. In this study, a nature-inspired membrane with a highly charged surface is proposed as an effective membrane for the filtration of saline water. To mimic the desalination characteristics of mangrove roots, a macroporous membrane based on polyethylene terephthalate is treated with polyelectrolytes using a layer-by-layer deposition method. The fabricated membrane surface has a highly negative charged zeta-potential value of -97.5 +/- 4.3 mV, similar to that of the first layer of mangrove roots. Desalination of saline water using this membrane shows a high salt retention rate of 96.5%. The highly charged surface of the membrane may induce a relatively thick and stable ion depletion zone in front of the membrane. As a result, most co-ions are repelled from the membrane surface, and counterions are also rejected by virtue of their electroneutrality. The water permeability is found to be 7.60-7.69 L/m2.h, which is 10 times higher than that of the reverse osmosis desalination method. This nature-inspired filtration membrane exhibits steady desalination performance over 72 h of operation, successfully demonstrating the stable filtration of saline water. This nature-inspired membrane is applicable to the design of a small-scale, portable, and energy-free desalination device for use in third-world countries or small villages. PMID- 27966902 TI - Impacts of Acidification and Potential Recovery on the Expected Value of Recreational Fisheries in Adirondack Lakes (USA). AB - We estimated the potential economic value of recreational fisheries in lakes altered by acid pollution in the Adirondack Mountains (USA). We found that the expected value of recreational fisheries has been diminished because of acid deposition but may improve as lakes recover from acidification under low emissions scenarios combined with fish stocking. Fishery value increased with lake pH, from a low of $4.41 angler day-1 in lakes with pH < 4.5, to a high of $38.40 angler day-1 in lakes with pH > 6.5 that were stocked with trout species. Stocking increased the expected fishery value by an average of $11.50 angler day 1 across the entire pH range of the lakes studied. Simulating the future long term trajectory of a subset of lakes, we found that pH and expected fishery value increased over time in all future emissions scenarios. Differences in estimated value among pollution reduction scenarios were small (<$1 angler day-1) compared to fish stocking scenarios (>$4 angler day-1). Our work provides a basis for assessing the costs and benefits of emissions reductions and management efforts that can hasten recovery of the economic and cultural benefits of ecosystems degraded by chronic pollution. PMID- 27966901 TI - Multiplexed Post-Experimental Monoisotopic Mass Refinement (mPE-MMR) to Increase Sensitivity and Accuracy in Peptide Identifications from Tandem Mass Spectra of Cofragmentation. AB - Mass spectrometry (MS)-based proteomics, which uses high-resolution hybrid mass spectrometers such as the quadrupole-orbitrap mass spectrometer, can yield tens of thousands of tandem mass (MS/MS) spectra of high resolution during a routine bottom-up experiment. Despite being a fundamental and key step in MS-based proteomics, the accurate determination and assignment of precursor monoisotopic masses to the MS/MS spectra remains difficult. The difficulties stem from imperfect isotopic envelopes of precursor ions, inaccurate charge states for precursor ions, and cofragmentation. We describe a composite method of utilizing MS data to assign accurate monoisotopic masses to MS/MS spectra, including those subject to cofragmentation. The method, "multiplexed post-experiment monoisotopic mass refinement" (mPE-MMR), consists of the following: multiplexing of precursor masses to assign multiple monoisotopic masses of cofragmented peptides to the corresponding multiplexed MS/MS spectra, multiplexing of charge states to assign correct charges to the precursor ions of MS/MS spectra with no charge information, and mass correction for inaccurate monoisotopic peak picking. When combined with MS-GF+, a database search algorithm based on fragment mass difference, mPE-MMR effectively increases both sensitivity and accuracy in peptide identification from complex high-throughput proteomics data compared to conventional methods. PMID- 27966903 TI - Critical Role of the Sorting Polymer in Carbon Nanotube-Based Minority Carrier Devices. AB - A prerequisite for carbon nanotube-based optoelectronic devices is the ability to sort them into a pure semiconductor phase. One of the most common sorting routes is enabled through using specific wrapping polymers. Here we show that subtle changes in the polymer structure can have a dramatic influence on the figures of merit of a carbon nanotube-based photovoltaic device. By comparing two commonly used polyfluorenes (PFO and PFO-BPy) for wrapping (7,5) and (6,5) chirality SWCNTs, we demonstrate that they have contrasting effects on the device efficiency. We attribute this to the differences in their ability to efficiently transfer charge. Although PFO may act as an efficient interfacial layer at the anode, PFO-BPy, having the additional pyridine side groups, forms a high resistance layer degrading the device efficiency. By comparing PFO|C60 and C60 only devices, we found that presence of a PFO layer at low optical densities resulted in the increase of all three solar cell parameters, giving nearly an order of magnitude higher efficiency over that of C60-only devices. In addition, with a relatively higher contribution to photocurrent from the PFO-C60 interface, an open circuit voltage of 0.55 V was obtained for PFO-(7,5)-C60 devices. On the other hand, PFO-BPy does not affect the open circuit voltage but drastically reduces the short circuit current density. These results indicate that the charge transport properties and energy levels of the sorting polymers have to be taken into account to fully understand their effect on carbon nanotube-based solar cells. PMID- 27966904 TI - The Low Barrier Hydrogen Bond in the Photoactive Yellow Protein: A Vacuum Artifact Absent in the Crystal and Solution. AB - There has been considerable debate on the existence of a low-barrier hydrogen bond (LBHB) in the photoactive yellow protein (PYP). The debate was initially triggered by the neutron diffraction study of Yamaguchi et al. ( Proc. Natl. Acad. Sci., U. S. A. , 2009 , 106 , 440 - 444 ) who suggested a model in which a neutral Arg52 residue triggers the formation of the LBHB in PYP. Here, we present an alternative model that is consistent within the error margins of the Yamaguchi structure factors. The model explains an increased hydrogen bond length without nuclear quantum effects and for a protonated Arg52. We tested both models by calculations under crystal, solution, and vacuum conditions. Contrary to the common assumption in the field, we found that a single PYP in vacuum does not provide an accurate description of the crystal conditions but instead introduces strong artifacts, which favor a LBHB and a large 1H NMR chemical shift. Our model of the crystal environment was found to stabilize the two Arg52 hydrogen bonds and crystal water positions for the protonated Arg52 residue in free MD simulations and predicted an Arg52 pKa upshift with respect to PYP in solution. The crystal and solution environments resulted in almost identical 1H chemical shifts that agree with NMR solution data. We also calculated the effect of the Arg52 protonation state on the LBHB in 3D nuclear equilibrium density calculations. Only the charged crystal structure in vacuum supports a LBHB if Arg52 is neutral in PYP at the previously reported level of theory ( J. Am. Chem. Soc. , 2014 , 136 , 3542 - 3552 ). We attribute the anomalies in the interpretation of the neutron data to a shift of the potential minimum, which does not involve nuclear quantum effects and is transferable beyond the Yamaguchi structure. PMID- 27966905 TI - Development of a Particulate Mass Measurement System for Quantification of Ambient Reactive Mercury. AB - The Teledyne Advanced Pollution Instrumentation (TAPI) model 602 BetaPlus particulate system provides nondestructive analysis of particulate matter (PM2.5) mass concentration. This instrument was used to determine if measurements made with cation exchange membranes (CEM) were comparable to standard methods, the beta attenuation method at two locations in Reno, NV and an environmental beta attenuation method and gravimetric method at Great Basin National Park, NV. TAPI PM2.5 CEM measurements were statistically similar to the other three PM2.5 methods. Once this was established, the second objective, a destructive method for measurement of reactive mercury (RM = gaseous oxidized and particulate bound Hg), was tested. Samples collected at 16.7 L per min (Lpm) for 24 h on CEM from the TAPI were compared to those measured by the University of Nevada, Reno Reactive Mercury Active System (UNRRMAS, 1 Lpm) CEM and a Tekran 2537/1130/1135 system (7 Lpm). Given the use of CEM in the TAPI and UNRRMAS, we hypothesized that both should collect RM. Due to the high flow rate and different inlets, TAPI data were systematically lower than the UNRRMAS. Correlation between RM concentrations demonstrated that the TAPI may be used to estimate 24 h resolution RM concentrations in Nevada. PMID- 27966907 TI - Ultrafast Interfacial Self-Assembly of 2D Transition Metal Dichalcogenides Monolayer Films and Their Vertical and In-Plane Heterostructures. AB - Cost effective scalable method for uniform film formation is highly demanded for the emerging applications of 2D transition metal dichalcogenides (TMDs). We demonstrate a reliable and fast interfacial self-assembly of TMD thin films and their heterostructures. Large-area 2D TMD monolayer films are assembled at air water interface in a few minutes by simple addition of ethyl acetate (EA) onto dilute aqueous dispersions of TMDs. Assembled TMD films can be directly transferred onto arbitrary nonplanar and flexible substrates. Precise thickness controllability of TMD thin films, which is essential for thickness-dependent applications, can be readily obtained by the number of film stacking. Most importantly, complex structures such as laterally assembled 2D heterostructures of TMDs can be assembled from mixture solution dispersions of two or more different TMDs. This unusually fast interfacial self-assembly could open up a novel applications of 2D TMD materials with precise tunability of layer number and film structures. PMID- 27966906 TI - Overcoming Tamoxifen Resistance of Human Breast Cancer by Targeted Gene Silencing Using Multifunctional pRNA Nanoparticles. AB - Most breast cancers express estrogen receptor (ER) alpha, and the antiestrogen drug tamoxifen has been widely used for their treatment. Unfortunately, up to half of all ERalpha-positive tumors have intrinsic or acquired endocrine therapy resistance. Our recent studies revealed that the ER coactivator Mediator Subunit 1 (MED1) plays a critical role in tamoxifen resistance through cross-talk with HER2. Herein, we assembled a three-way junction (3-WJ) pRNA-HER2apt-siMED1 nanoparticle to target HER2-overexpressing human breast cancer via an HER2 RNA aptamer to silence MED1 expression. We found that these ultracompact RNA nanoparticles are very stable under RNase A, serum, and 8 M urea conditions. These nanoparticles specifically bound to HER2-overexpressing breast cancer cells, efficiently depleted MED1 expression, and significantly decreased ERalpha mediated gene transcription, whereas point mutations of the HER2 RNA aptamer on these nanoparticles abolished such functions. The RNA nanoparticles not only reduced the growth, metastasis, and mammosphere formation of the HER2 overexpressing breast cancer cells but also sensitized them to tamoxifen treatment. These biosafe nanoparticles efficiently targeted and penetrated into HER2-overexpressing tumors after systemic administration in orthotopic xenograft mouse models. In addition to their ability to greatly inhibit tumor growth and metastasis, these nanoparticles also led to a dramatic reduction in the stem cell content of breast tumors when combined with tamoxifen treatment in vivo. Overall, we have generated multifunctional RNA nanoparticles that specifically targeted HER2-overexpressing human breast cancer, silenced MED1, and overcame tamoxifen resistance. PMID- 27966908 TI - High-NOx Photooxidation of n-Dodecane: Temperature Dependence of SOA Formation. AB - The temperature and concentration dependence of secondary organic aerosol (SOA) yields has been investigated for the first time for the photooxidation of n dodecane (C12H26) in the presence of NOx in the CESAM chamber (French acronym for "Chamber for Atmospheric Multiphase Experimental Simulation"). Experiments were performed with and without seed aerosol between 283 and 304.5 K. In order to quantify the SOA yields, a new parametrization is proposed to account for organic vapor loss to the chamber walls. Deposition processes were found to impact the aerosol yields by a factor from 1.3 to 1.8 between the lowest and the highest value. As with other photooxidation systems, experiments performed without seed and at low concentration of oxidant showed a lower SOA yield than other seeded experiments. Temperature did not significantly influence SOA formation in this study. This unforeseen behavior indicates that the SOA is dominated by sufficiently low volatility products for which a change in their partitioning due to temperature would not significantly affect the condensed quantities. PMID- 27966909 TI - Assessing the Suitability of Multiple Dispersion and Land Use Regression Models for Urban Traffic-Related Ultrafine Particles. AB - Comparative evaluations are needed to assess the suitability of near-road air pollution models for traffic-related ultrafine particle number concentration (PNC). Our goal was to evaluate the ability of dispersion (CALINE4, AERMOD, R LINE, and QUIC) and regression models to predict PNC in a residential neighborhood (Somerville) and an urban center (Chinatown) near highways in and near Boston, Massachusetts. PNC was measured in each area, and models were compared to each other and measurements for hot (>18 degrees C) and cold (<10 degrees C) hours with wind directions parallel to and perpendicular downwind from highways. In Somerville, correlation and error statistics were typically acceptable, and all models predicted concentration gradients extending ~100 m from the highway. In contrast, in Chinatown, PNC trends differed among models, and predictions were poorly correlated with measurements likely due to effects of street canyons and nonhighway particle sources. Our results demonstrate the importance of selecting PNC models that align with study area characteristics (e.g., dominant sources and building geometry). We applied widely available models to typical urban study areas; therefore, our results should be generalizable to models of hourly averaged PNC in similar urban areas. PMID- 27966910 TI - A Novel Technique for Determining the Adsorption Capacity and Breakthrough Time of Adsorbents Using a Noncontact High-Resolution Microwave Resonator Sensor. AB - A newly developed noncontact high-resolution real-time microwave sensor was used to determine the breakthrough time and adsorption capacity of adsorbents/adsorbates with different dielectric properties. The sensor is a microwave microstrip planar resonator with an enhanced quality factor using a regenerative feedback loop operating at 1.4 GHz and an adjustable quality factor of 200-200000. Beaded activated carbon (BAC, microwave-absorbing) and a polymeric adsorbent (V503, microwave transparent) were completely loaded with 1,2,4 trimethylbenzene (nonpolar) or 2-butoxyethanol (polar). During adsorption, variations in the dielectric properties of the adsorbents were monitored using two microwave parameters; quality factor and resonant frequency. Those parameters were related to adsorption breakthrough time and capacity. Adsorption tests were completed at select relative pressures (0.03, 0.1, 0.2, 0.4, and 0.6) of adsorbates in the influent stream. For all experiments, the difference between the breakthrough time (t5%) and the settling time of the quality factor variation (time that the quality factor was 0.95 of its final value) was <5%. Additionally, a linear relationship between the final value of the resonant frequency shift and adsorption capacity was observed. The proposed noncontact sensor can be used to determine the breakthrough time and adsorption capacity. PMID- 27966911 TI - Modulating Paratropicity Strength in Diareno-Fused Antiaromatics. AB - Understanding and controlling the electronic structure of molecules is crucial when designing and optimizing new organic semiconductor materials. We report the regioselective synthesis of eight pi-expanded diarenoindacene analogues based on the indeno[1,2-b]fluorene framework along with the computational investigation of an array of diareno-fused antiaromatic compounds possessing s-indacene, pentalene, or cyclobutadiene cores. Analysis of the experimental and computationally derived optoelectronic properties uncovered a linear correlation between the bond order of the fused arene bond and the paratropicity strength of the antiaromatic unit. The Ered1 for the pentalene and indacene core molecules correlates well with their calculated NICSpiZZ values. The findings of this study can be used to predict the properties of, and thus rationally design, new diareno fused antiaromatic molecules for use as organic semiconductors. PMID- 27966913 TI - Functional Characterization of a Novel Amidase Involved in Biotransformation of Triclocarban and its Dehalogenated Congeners in Ochrobactrum sp. TCC-2. AB - Haloaromatic antimicrobial triclocarban (3,4,4'-trichlorocarbanilide, TCC) is a refractory contaminant which is frequently detected in various aquatic and sediment environments globally. However, few TCC-degrading communities or pure cultures have been documented, and functional enzymes involved in TCC biodegradation hitherto have not yet been characterized. In this study, a bacterial strain, Ochrobactrum sp. TCC-2, capable of degrading TCC under both aerobic and anaerobic conditions was isolated from a sediment sample. A novel amidase gene (tccA), responsible for the hydrolysis of the two amide bonds of TCC and its dehalogenated congeners 4,4'-dichlorocarbanilide (DCC) and carbanilide (NCC) to more biodegradable chloroaniline or aniline products, was cloned and characterized. TccA shares low amino acid sequence identity (27 to 38%) with other biochemically characterized amidases and contains the conserved catalytic triad (Ser-Ser-Lys) of the amidase signature enzyme family. TccA was stable over a pH range of 5.0 to 10.0 and at temperatures lower than 60 degrees C, and it was constitutively expressed in strain TCC-2. In contrast to the halogenated TCC and DCC, the nonchlorinated NCC was the preferred substrate for TccA. TccA also had hydrolysis activity to a broad spectrum of amide bonds in herbicides, insecticides, and chemical intermediates. The constitutive expression and broad substrate spectrum of TccA suggested strain TCC-2 may be potentially useful for bioremediation applications. PMID- 27966914 TI - Identification and Characterization of Ana o 3 Modifications on Arginine-111 Residue in Heated Cashew Nuts. AB - Raw and roasted cashew nut extracts were evaluated for protein modifications by mass spectrometry. Independent modifications on the Arg-111 residue of Ana o 3 were observed in roasted but not raw cashew nuts. The mass changes of 72.0064 or 53.9529 Da are consistent with the formation of carboxyethyl and hydroimidazolone modifications at the Arg-111 residue. These same modifications were observed in Ana o 3 purified from roasted but not raw cashew nuts, albeit at a relatively low occurrence. Circular dichroism indicated that Ana o 3 purified from raw and roasted cashew nuts had similar secondary structure, and dynamic light scattering analysis indicated there was no observable difference in particle size. The stability of Ana o 3 purified from raw and roasted cashew nuts to trypsin was similar in the absence of or following treatment with a reducing agent. Only minor differences in IgE binding to Ana o 3 were observed by ELISA among a cohort of cashew-allergic patient sera. PMID- 27966912 TI - Allostery and Hysteresis Are Coupled in Human UDP-Glucose Dehydrogenase. AB - Human UDP-glucose dehydrogenase (hUGDH) is regulated by an atypical allosteric mechanism in which the feedback inhibitor UDP-xylose (UDP-Xyl) competes with the substrate for the active site. Binding of UDP-Xyl triggers the T131-loop/alpha6 allosteric switch, which converts the hexameric structure of hUGDH into an inactive, horseshoe-shaped complex (EOmega). This allosteric transition buries residue A136 in the protein core to produce a subunit interface that favors the EOmega structure. Here we use a methionine substitution to prevent the burial of A136 and trap the T131-loop/alpha6 switch in the active conformation. We show that hUGDHA136M does not exhibit substrate cooperativity, which is strong evidence that the methionine substitution prevents the formation of the low-UDP Glc-affinity EOmega state. In addition, the inhibitor affinity of hUGDHA136M is reduced 14-fold, which most likely represents the Ki for competitive inhibition in the absence of the allosteric transition to the higher-affinity EOmega state. hUGDH also displays a lag in progress curves, which is caused by a slow, substrate-induced isomerization that activates the enzyme. Stopped-flow analysis shows that hUGDHA136M does not exhibit hysteresis, which suggests that the T131 loop/alpha6 switch is the source of the slow isomerization. This interpretation is supported by the 2.05 A resolution crystal structure of hUGDHA136M, which shows that the A136M substitution has stabilized the active conformation of the T131-loop/alpha6 allosteric switch. This work shows that the T131-loop/alpha6 allosteric switch couples allostery and hysteresis in hUGDH. PMID- 27966916 TI - Injectable and 3D Bioprinted Polysaccharide Hydrogels: From Cartilage to Osteochondral Tissue Engineering. AB - Biomechanical performance of functional cartilage is executed by the exclusive anisotropic composition and spatially varying intricate architecture in articulating ends of diarthrodial joint. Osteochondral tissue constituting the articulating ends comprise superfical soft cartilage over hard subchondral bone sandwiching interfacial soft-hard tissue. The shock-absorbent, lubricating property of cartilage and mechanical stability of subchondral bone regions are rendered by extended chemical structure of glycosaminoglycans and mineral deposition, respectively. Extracellular matrix glycosaminoglycans analogous polysaccharides are major class of hydrogels investigated for restoration of functional cartilage. Recently, injectable hydrogels have gained momentum as it offers patient compliance, tunable mechanical properties, cell deliverability, and facile administration at physiological condition with long-term functionality and hyaline cartilage construction. Interestingly, facile modifiable functional groups in carbohydrate polymers impart tailorability of desired physicochemical properties and versatile injectable chemistry for the development of highly potent biomimetic in situ forming scaffold. The scaffold design strategies have also evolved from single component to bi- or multilayered and graded constructs with osteogenic properties for deep subchondral regeneration. This review highlights the significance of polysaccharide structure-based functions in engineering cartilage tissue, injectable chemistries, strategies for combining analogous matrices with cells/stem cells and biomolecules and multicomponent approaches for osteochondral mimetic constructs. Further, the rheology and precise spatiotemporal positioning of cells in hydrogel bioink for rapid prototyping of complex three-dimensional anisotropic cartilage have also been discussed. PMID- 27966915 TI - Hydrophobic Ligand Entry and Exit Pathways of the CB1 Cannabinoid Receptor. AB - It has been reported that some hydrophobic ligands of G-protein-coupled receptors access the receptor's binding site from the membrane rather than from bulk water. In order to identify the most probable ligand entrance pathway into the CB1 receptor, we performed several steered molecular dynamics (SMD) simulations of two CB1 agonists, THC and anandamide, pulling them from the receptor's binding site with constant velocity. The four main directions of ligand pulling were probed: between helices TM4 and TM5, between TM5 and TM6, between TM7 and TM1/TM2, and toward the bulk water. The smallest forces were measured during pulling between TM7 and TM1/TM2. We also performed supervised molecular dynamics (SuMD) simulations for both anandamide and THC entering the CB1 receptor's binding site and found the same pathway as in the pulling simulations. The residues F1742.61 and F1772.64 (both on the TM2 helix) are involved in the gating mechanism and, by forming pi-pi interactions with ligand molecules, facilitated the ligand orientation required for passage. Using SuMD we also found an alternative binding site for THC. The results of mutagenesis studies evidencing that residues F1742.61 and F1772.64 are important for CB1 ligand binding are in agreement with our observations. PMID- 27966917 TI - Regioselective Thiocarbonylation of Vinyl Arenes. AB - A palladium-catalyzed thiocarbonylation of styrene derivatives is reported for the first time. The combination of thiols as nucleophiles and a bidentate ligand ensures a unique reaction outcome with high regioselectivity toward the more valuable branched isomer and new reactivity. The ambient reaction conditions (temperature, catalyst loading) and the use of a CO surrogate render this transformation a useful method for the synthesis of thioesters from available feedstock. Various functional groups on arene and thiol substituents are tolerated by the system. Notably, challenging ortho-substituted styrenes are converted with unprecedentedly high regioselectivity. PMID- 27966918 TI - Oxidative Entry into the Illicium Sesquiterpenes: Enantiospecific Synthesis of (+)-Pseudoanisatin. AB - Illicium sesquiterpenes have been the subject of numerous synthetic efforts due to their ornate and highly oxidized structures as well as significant biological activities. Herein we report the first chemical synthesis of (+)-pseudoanisatin from the abundant feedstock chemical cedrol (~$50 USD/kg) in 12 steps using extensive site-selective C(sp3)-H bond functionalization. Significantly, this work represents a novel oxidative strategic template for future approaches to these natural products and their analogs. PMID- 27966919 TI - Fluorescent pH-Sensing Probe Based on Biorefinery Wood Lignosulfonate and Its Application in Human Cancer Cell Bioimaging. AB - A water-soluble, ratiometric fluorescent pH probe, L-SRhB, was synthesized via grafting spirolactam Rhodamine B (SRhB) to lignosulfonate (LS). As the ring opening product of L-SRhB, FL-SRhB was also prepared. The pH-response experiment indicated that L-SRhB showed a rapid response to pH changes from 4.60 to 6.20 with a pKa of 5.35, which indicated that L-SRhB has the potential for pH detection of acidic organelle. In addition, the two probes were internalized successfully by living cells through the endocytosis pathway and could distinguish normal cells from cancer cells by different cell staining rates. In addition, L-SRhB showed obvious cytotoxicity to cancer cells, whereas it was nontoxic to normal cells in the same condition. L-SRhB might have potential in cancer therapy. L-SRhB might be a promising ratiometric fluorescent pH sensor and bioimaging dye for the recognition of cancer cells. The results also provided a new perspective to the high-value utilization of lignin. PMID- 27966920 TI - Halogen-Assisted Piezochromic Supramolecular Assemblies for Versatile Haptic Memory. AB - Sensory memory is capable of recording information and giving feedback based on external stimuli. Haptic memory in particular can retain the sensation of the interaction between the human body and the environment and help humans to describe the physical quantities in their environment and manipulate objects in daily activities. Although sensitive and accurate tactile sensors have been produced on optical and electronic devices, their rigorous operation and equipment requirements seriously limit their further applicability. In addition, their poor retainability after the removal of external stimuli also warrants further improvements. Thus, haptic memory materials, having simple structures and high sensitivity, are highly desired. Herein, we successfully developed two piezochromic assemblies assisted by halogen bonding for haptic memory. The halogen bond not only contributes to the fabrication of the network and enhances integrative stability but also broadens the natural piezofluorescent range, thus promoting sensory sensitivity. Moreover, the colorimetric change of the assemblies could be well-retained after the stimulus was removed. Upon mild heating treatment, the piezochromic response could be recovered to its original state, confirming the recyclability of this haptic memory material for use in practical applications. The present work enriches the library of piezochromic materials with enhanced performance for haptic memory. PMID- 27966921 TI - Na2B6O9F2: A Fluoroborate with Short Cutoff Edge and Deep-Ultraviolet Birefringent Property Prepared by an Open High-Temperature Solution Method. AB - As important materials in modulating the polarization of light, birefringent crystals have attracted considerable attention and played crucial roles in the field of optical communication and the laser industry. Limited by the transparency range, few birefringent crystals can be used in the deep-ultraviolet (DUV) region, except for alpha-BaB2O4 (alpha-BBO). However, the application of alpha-BBO in the DUV range is restricted by the relatively high cutoff edge and low transmittance rate below 200 nm. In this paper, we design and synthesize a new fluoroborate, Na2B6O9F2, by introducing fluorine into borate system. It possesses a short cutoff edge of 169 nm and birefringence larger than 0.080 at 589.3 nm. The Na2B6O9F2 crystals with sizes up to 3.0 mm * 1.5 mm * 0.2 mm have been grown with good quality by a high-temperature solution method in the open system. First-principles calculations were carried out to understand the optical properties. PMID- 27966922 TI - Recent Advances in the Preparation and Application of Allylboron Species in Organic Synthesis. AB - In this Perspective we will highlight the most important recent breakthroughs in selective allylboron chemistry (both the synthesis and application of these species). In addition we will provide an outlook toward the future of this promising subfield of organic synthesis. PMID- 27966923 TI - Nonoccupational Exposure to Pyrethroids and Risk of Coronary Heart Disease in the Chinese Population. AB - Pyrethroids and the metabolites have been frequently observed in the environment. Animal data suggests that pyrethroids can induce adverse effect on the cardiovascular system but there are no human studies examining pyrethoids exposure as a risk for coronary heart disease (CHD). We analyzed three nonspecific pyrethroids metabolites in urine and studied the association with CHD risk. A total of 72 CHD patients and 136 healthy subjects were recruited in Shanxi province in China from 2013 to 2014 by matching age and gender. The median concentrations of urinary cis-CDDA (cis-3-(2,2-dichlorovinyl)-2,2-dimethyl cyclopropane carboxylic acid), trans-CDDA (trans-3-(2,2-dichlorovinyl)-2,2 dimethyl cyclopropane carboxylic acid) and 3-PBA (3-phenoxybenzoic acid) among healthy subjects were 1.03, 0.42, 0.74 MUg/L respectively, while the median concentrations of the three metabolites among CHD patients were 1.93, 1.07, 1.09 MUg/L respectively, significantly higher than healthy subjects. Upper tertile of urinary pyrethroid metabolites were associated with an increased risk of CHD compared with the lowest tertile (cis-CDDA: ORT3vsT1 = 6.86, 95% CI: 2.76-17.06, p-trend = 0.000; trans-CDDA: ORT3vsT1 = 6.94; 95% CI: 2.80-17.19; p-trend =0.000; 3-PBA: ORT3vsT1 = 3.62; 95% CI: 1.48-8.88; p-trend = 0.009; total pyrethroid metabolites: ORT3vsT1 = 4.55; 95% CI: 1.80-11.54; p-trend = 0.002). This study provides information on pyrethroids exposure in China and reveals a possible positive association between pyrethroids exposure and the risk of coronary heart disease. PMID- 27966924 TI - Isophlorinoids: The Antiaromatic Congeners of Porphyrinoids. AB - Ever since the discovery of the porphyrin ring in "pigments of life", such as chlorophyll and hemoglobin, it has become a prime synthetic target for optoelectronic properties and in the design of metal complexes. During one such early expedition on the synthesis of porphyrin, Woodward proposed that condensing pyrrole with an aldehyde under acidic conditions yields the "precursor" porphyrinogen macrocycle. Its four-electron oxidation leads to the "transitory" 20pi isophlorin, which undergoes subsequent two-electron oxidation to form the 18pi "porphyrin". Due to its fleeting lifetime, it has been a synthetic challenge to stabilize the tetrapyrrolic isophlorin. This macrocycle symbolizes the antiaromatic character of a porphyrin-like macrocycle. In addition, the pyrrole NH also plays a key role in the proton-coupled, two-electron oxidation of isophlorin to the aromatic porphyrin. However, a major aspect of its unstable nature was attributed to its antiaromatic character, which is understood to destabilize the macrocycle upon conjugation. Antiaromaticity in general has not gained significant attention mainly due to the lack of stable 4npi systems. In this regard, a stable isophlorin and its derivatives provide a glimmering hope to peek into the world of antiaromatic systems. This review will focus on the attempted synthesis of antiaromatic isophlorin ever since its conception. Based on recent synthetic advances, the chemistry of isophlorins can be expected to blossom into expanded derivatives of this antiaromatic macrocycle. Along with the synthetic details, the structural, electronic, and redox properties of isophlorin and its expanded derivatives will be elaborated. PMID- 27966925 TI - Efficient Extracellular Expression of Metalloprotease for Z-Aspartame Synthesis. AB - Metalloprotease PT121 and its mutant Y114S (Tyr114 was substituted to Ser) are effective catalysts for the synthesis of Z-aspartame (Z-APM). This study presents the selection of a suitable signal peptide for improving expression and extracellular secretion of proteases PT121 and Y114S by Escherichia coli. Co inducers containing IPTG and arabinose were used to promote protease production and cell growth. Under optimal conditions, the expression levels of PT121 and Y114S reached >500 mg/L, and the extracellular activity of PT121/Y114S accounted for 87/82% of the total activity of proteases. Surprisingly, purer protein was obtained in the supernatant, because arabinose reduced cell membrane permeability, avoiding cell lysis. Comparison of Z-APM synthesis and caseinolysis between proteases PT121 and Y114S showed that mutant Y114S presented remarkably higher activity of Z-APM synthesis and considerably lower activity of caseinolysis. The significant difference in substrate specificity renders these enzymes promising biocatalysts. PMID- 27966926 TI - Two-Dimensional (C4H9NH3)2PbBr4 Perovskite Crystals for High-Performance Photodetector. AB - Two-dimensional (2D) layered hybrid perovskites of (RNH3)2PbX4 (R is an alkyl and X is a halide) have been recently synthesized and exhibited rich optical properties including fluorescence and exciton effects. However, few studies on transport and optoelectronic measurements of individual 2D perovskite crystals have been reported, presumably owing to the instability issue during electronic device fabrications. Here we report the first photodetector based on individual 2D (C4H9NH3)2PbBr4 perovskite crystals, built with the protection and top contact of graphene film. Both a high responsivity (~2100 A/W) and extremely low dark current (~10-10 A) are achieved with a design of interdigital graphene electrodes. Our study paves the way to build high-performance optoelectronic devices based on the emerging 2D single-crystal perovskite materials. PMID- 27966927 TI - Thermal Chemistry of Cp*W(NO)(CH2CMe3)(H)(L) Complexes (L = Lewis Base). AB - The complexes trans-Cp*W(NO)(CH2CMe3)(H)(L) (Cp* = eta5-C5Me5) result from the treatment of Cp*W(NO)(CH2CMe3)2 in n-pentane with H2 (~1 atm) in the presence of a Lewis base, L. The designation of a particular geometrical isomer as cis or trans indicates the relative positions of the alkyl and hydrido ligands in the base of a four-legged piano-stool molecular structure. The thermal behavior of these complexes is markedly dependent on the nature of L. Some of them can be isolated at ambient temperatures [e.g., L = P(OMe)3, P(OPh)3, or P(OCH2)3CMe]. Others undergo reductive elimination of CMe4 via trans to cis isomerization to generate the 16e reactive intermediates Cp*W(NO)(L). These intermediates can intramolecularly activate a C-H bond of L to form 18e cis complexes that may convert to the thermodynamically more stable trans isomers [e.g., Cp*W(NO)(PPh3) initially forms cis-Cp*W(NO)(H)(kappa2-PPh2C6H4) that upon being warmed in n pentane at 80 degrees C isomerizes to trans-Cp*W(NO)(H)(kappa2-PPh2C6H4)]. Alternatively, the Cp*W(NO)(L) intermediates can effect the intermolecular activation of a substrate R-H to form trans-Cp*W(NO)(R)(H)(L) complexes [e.g., L = P(OMe)3 or P(OCH2)3CMe; R-H = C6H6 or Me4Si] probably via their cis isomers. These latter activations are also accompanied by the formation of some Cp*W(NO)(L)2 disproportionation products. An added complication in the L = P(OMe)3 system is that thermolysis of trans-Cp*W(NO)(CH2CMe3)(H)(P(OMe)3) results in it undergoing an Arbuzov-like rearrangement and being converted mainly into [Cp*W(NO)(Me)(PO(OMe)2)]2, which exists as a mixture of two isomers. All new complexes have been characterized by conventional and spectroscopic methods, and the solid-state molecular structures of most of them have been established by single-crystal X-ray crystallographic analyses. PMID- 27966928 TI - Arsenic Incorporation in Pyrite at Ambient Temperature at Both Tetrahedral S-I and Octahedral FeII Sites: Evidence from EXAFS-DFT Analysis. AB - Pyrite is a ubiquitous mineral in reducing environments and is well-known to incorporate trace elements such as Co, Ni, Se, Au, and commonly As. Indeed, As bearing pyrite is observed in a wide variety of sedimentary environments, making it a major sink for this toxic metalloid. Based on the observation of natural hydrothermal pyrites, As-I is usually assigned to the occupation of tetrahedral S I sites, with the same oxidation state as in arsenopyrite (FeAsS), although rare occurrences of AsIII and AsII have been reported. However, the modes of As incorporation into pyrite during its crystallization under low-temperature diagenetic conditions have not yet been elucidated because arsenic acts as an inhibitor for pyrite nucleation at ambient temperature. Here, we provide evidence from X-ray absorption spectroscopy for AsII,III incorporation into pyrite at octahedral FeII sites and for As-I at tetrahedral S-I sites during crystallization at ambient temperature. Extended X-ray absorption fine structure (EXAFS) spectra of these As-bearing pyrites are explained by local structure models obtained using density functional theory (DFT), assuming incorporation of As at the Fe and S sites, as well as local clustering of arsenic. Such observations of As-I incorporation at ambient temperature can aid in the understanding of the early formation of authigenic arsenian pyrite in subsurface sediments. Moreover, evidence for substitution of AsII,III for Fe in our synthetic samples raises questions about both the possible occurrence and the geochemical reactivity of such As-bearing pyrites in low-temperature subsurface environments. PMID- 27966929 TI - Combined Docking and Quantum Chemical Study on CYP-Mediated Metabolism of Estrogens in Man. AB - Long-term exposure to estrogens seriously increases the incidence of various diseases including breast cancer. Experimental studies indicate that cytochrome P450 (CYP) enzymes catalyze the bioactivation of estrogens to catechols, which can exert their harmful effects via various routes. It has been shown that the 4 hydroxylation pathway of estrogens is the most malign, while 2-hydroxylation is considered a benign pathway. It is also known experimentally that with increasing unsaturation of ring B of estrogens the prevalence of the 4-hydroxylation pathway significantly increases. In this study, we used a combination of structural analysis, docking, and quantum chemical calculations at the B3LYP/6-311+G* level to investigate the factors that influence the regioselectivity of estrogen metabolism in man. We studied the structure of human estrogen metabolizing enzymes (CYP1A1, CYP1A2, CYP1B1, and CYP3A4) in complex with estrone using docking and investigated the susceptibility of estrone, equilin, and equilenin (which only differ in the unsaturation of ring B) to undergo 2- and 4 hydroxylation using several models of CYP enzymes (Compound I, methoxy, and phenoxy radical). We found that even the simplest models could account for the experimental difference between the 2- and 4- hydroxylation pathways and thus might be used for fast screening purposes. We also show that reactivity indices, specifically in this case the radical and nucleophilic condensed Fukui functions, also correctly predict the likeliness of estrogen derivatives to undergo 2- or 4 hydroxylation. PMID- 27966930 TI - Encapsulation of Pancreatic Lipase in Hydrogel Beads with Self-Regulating Internal pH Microenvironments: Retention of Lipase Activity after Exposure to Gastric Conditions. AB - Oral delivery of lipase is important for individuals with exocrine pancreatic insufficiency; however, lipase loses activity when exposed to the highly acidic gastric environment. In this study, pancreatic lipase was encapsulated in hydrogel beads fabricated from alginate (gel former), calcium chloride (cross linker), and magnesium hydroxide (buffer). Fluorescence confocal microscopy imaging was used to map the pH microclimate within the hydrogel beads under simulated gastrointestinal tract (GIT) conditions. The pH within buffer-free beads rapidly decreased when they moved from mouth (pH 6.3) to stomach (pH <4), leading to a loss of lipase activity in the small intestine. Conversely, the pH inside buffer-loaded beads remained close to neutral in the mouth (pH 7.33) and stomach (pH 7.39), leading to retention of lipase activity in the small intestine, as shown by pH-stat analysis of lipid digestion. The presence of the encapsulated buffer also reduced bead shrinkage under gastric conditions. PMID- 27966931 TI - Protein-Grafted Polymers Prepared Through a Site-Specific Conjugation by Microbial Transglutaminase for an Immunosorbent Assay. AB - Protein-polymer conjugates have been developed in many fields. Most hybrids are composed of one protein attached to one or several polymer chains. The other form of hybrid involves the construction of multiple proteins on one polymer chain, thereby facilitating protein assemblies that provide multivalent effects. Unfortunately, synthetic methods for production of these types of hybrids are limited and challenging because precise control of the conjugation sites is needed. Herein, a novel synthetic polymer that can enzymatically assemble multiple proteins was developed. Polyacrylamide grafted with multiple microbial transglutaminase (MTG)-recognizable peptide derivatives was synthesized, and MTG catalyzed site-specific conjugation of proteins with the polymer was achieved. The application for immunological biosensing was demonstrated using the assembly of a fusion protein composed of antibody-binding and enzyme moieties. This enzymatic method to synthesize a one-dimensional protein assembly on a synthetic polymer is versatile and can be expanded to a wide range of applications. PMID- 27966932 TI - Understanding the Influence of the Electronic Structure on the Crystal Structure of a TTF-PTM Radical Dyad. AB - The understanding of the crystal structure of organic compounds, and its relationship to their physical properties, have become essential to design new advanced molecular materials. In this context, we present a computational study devoted to rationalize the different crystal packing displayed by two closely related organic systems based on the TTF-PTM dyad (TTF = tetrathiafulvalene, PTM = polychlorotriphenylmethane) with almost the same molecular structure but a different electronic one. The radical species (1), with an enhanced electronic donor-acceptor character, exhibits a herringbone packing, whereas the nonradical protonated analogue (2) is organized forming dimers. The stability of the possible polymorphs is analyzed in terms of the cohesion energy of the unit cell, intermolecular interactions between pairs, and molecular flexibility of the dyad molecules. It is observed that the higher electron delocalization in radical compound 1 has a direct influence on the geometry of the molecule, which seems to dictate its preferential crystal structure. PMID- 27966933 TI - High-Affinity DNA Aptamer Generation Targeting von Willebrand Factor A1-Domain by Genetic Alphabet Expansion for Systematic Evolution of Ligands by Exponential Enrichment Using Two Types of Libraries Composed of Five Different Bases. AB - The novel evolutionary engineering method ExSELEX (genetic alphabet expansion for systematic evolution of ligands by exponential enrichment) provides high-affinity DNA aptamers that specifically bind to target molecules, by introducing an artificial hydrophobic base analogue as a fifth component into DNA aptamers. Here, we present a newer version of ExSELEX, using a library with completely randomized sequences consisting of five components: four natural bases and one unnatural hydrophobic base, 7-(2-thienyl)imidazo[4,5-b]pyridine (Ds). In contrast to the limited number of Ds-containing sequence combinations in our previous library, the increased complexity of the new randomized library could improve the success rates of high-affinity aptamer generation. To this end, we developed a sequencing method for each clone in the enriched library after several rounds of selection. Using the improved library, we generated a Ds-containing DNA aptamer targeting von Willebrand factor A1-domain (vWF) with significantly higher affinity (KD = 75 pM), relative to those generated by the initial version of ExSELEX, as well as that of the known DNA aptamer consisting of only the natural bases. In addition, the Ds-containing DNA aptamer was stabilized by introducing a mini-hairpin DNA resistant to nucleases, without any loss of affinity (KD = 61 pM). This new version is expected to consistently produce high-affinity DNA aptamers. PMID- 27966934 TI - Intramolecular Acylation of Unactivated Pyridines or Arenes via Multiple C-H Functionalizations: Synthesis of All Four Azafluorenones and Fluorenones. AB - An unprecedented intramolecular acylation of unactivated pyridines via multiple C(sp3/sp2)-H functionalizations of a methyl, hydroxymethyl, or aldehyde group has been developed providing a general access to all four azafluorenones. The application of this protocol is further demonstrated to the synthesis of azafluorenone related fused nitrogen heterocycles and fluorenones. In addition, design and synthesis of a novel fluorene based organic emitter for potential use in organic light emitting devices (OLEDs) is also reported. PMID- 27966936 TI - Origin of Blue-Green Emission in alpha-Zn2P2O7 and Local Structure of Ln3+ Ion in alpha-Zn2P2O7:Ln3+ (Ln = Sm, Eu): Time-Resolved Photoluminescence, EXAFS, and DFT Measurements. AB - Considering the fact that pyrophosphate-based hosts are in high demand for making highly efficient luminescence materials, we doped two visible lanthanide ions, viz. Sm3+ and Eu3+, in Zn2P2O7. Interestingly, it was oberved that pure Zn2P2O7 displayed blue-green dual emission on irradiation with ultraviolet light. Emission and lifetime spectroscopy shows the presence of defects in pyrophosphate samples which are responsible for such emission. DFT calculations clearly pinpointed that the electronic transitions between defect states located at just below the conduction band minimum (arises due to VO1+ and VO2+ defects) and valence band maximum, as well as impurity states situated in the band gap, can lead to dual emission in the blue-green region, as is also indicated by emission and lifetime spectra. X-ray absorption near edge spectroscopy (XANES) shows the stabilization of europium as well as samarium ion in the +3 oxidation state in alpha-Zn2P2O7. The fact that alpha-Zn2P2O7 has two different coordination numbers for zinc ions, i.e. five- and six-coordinate, the study of dopant ion distribution in this particular matrix will be an important step in realizing a highly efficient europium- and samarium-based red-emitting phosphor. Time resolved photoluminescence (TRPL) shows that both of these ions are heterogeneously distributed between five- and six-coordinated Zn2+ sites and it is the six-coordinated Zn2+ site which is the most favorable for lanthanide ion doping. Extended X-ray absorption fine structure (EXAFS) measurements also suggested that a six-coordinated zinc ion is the preferred site occupied by trivalent lanthanide ions, which is in complete agreement with TRPL results. It was observed that there is almost complete transfer of photon energy from Zn2P2O7 to Eu3+, whereas this transfer is inefficient and almost incomplete in case of Sm3+, which is indeed important information for the realization of pyrophosphate based tunable phosphors. PMID- 27966935 TI - Antimicrobial Oligophenalenone Dimers from the Soil Fungus Talaromyces stipitatus. AB - New polyketide-derived oligophenalenone dimers, 9a-epi-bacillisporin E (1) and bacillisporins F-H (2-5), along with the known bacillisporin A (6), were isolated from the fungus Talaromyces stipitatus. Their structures and absolute configurations were determined on the basis of spectroscopic analyses, electronic circular dichroism, and GIAO NMR shift calculation followed by DP4 analysis. The antimicrobial activity of these compounds was evaluated against a panel of human pathogenic bacteria. Among them, bacillisporin H (5) exhibited antimicrobial activity together with modest cytotoxicity against HeLa cells. PMID- 27966937 TI - Quantitative Assessment of Halogen Bonding Utilizing Vibrational Spectroscopy. AB - A total of 202 halogen-bonded complexes have been studied using a dual-level approach: omegaB97XD/aug-cc-pVTZ was used to determine geometries, natural bond order charges, charge transfer, dipole moments, electron and energy density distributions, vibrational frequencies, local stretching force constants, and relative bond strength orders n. The accuracy of these calculations was checked for a subset of complexes at the CCSD(T)/aug-cc-pVTZ level of theory. Apart from this, all binding energies were verified at the CCSD(T) level. A total of 10 different electronic effects have been identified that contribute to halogen bonding and explain the variation in its intrinsic strength. Strong halogen bonds are found for systems with three-center-four-electron (3c-4e) bonding such as chlorine donors in interaction with substituted phosphines. If halogen bonding is supported by hydrogen bonding, genuine 3c-4e bonding can be realized. Perfluorinated diiodobenzenes form relatively strong halogen bonds with alkylamines as they gain stability due to increased electrostatic interactions. PMID- 27966938 TI - Does Alkaline-Earth-Metal-Based Superalkali Exist? AB - A series of MkF2k-1+ (M = Mg, Ca; k = 2, 3) cations have been theoretically investigated to make a new attempt to design superalkali species. As expected, most of these cations were identified as pseudoalkali or even superalkali cations in view of their low electron affinities (EAs). The stability of these cationic clusters is indicated by considerable HOMO-LUMO gaps and positive dissociation energies. More intriguingly, these alkaline-earth-metal-based cations have advantages over alkali-metal-based superalkalis in two aspects: (1) they possess much larger binding energy values; (2) they can keep the chemical stability along with the increasing cluster size. Therefore, it is proposed here that the alkaline-earth-metal atoms could partner with halogens to construct stable cations of low EA value, which may add new candidates to the superalkali family. PMID- 27966939 TI - Mechanism of Single-Site Molecule-Like Catalytic Ethylene Dimerization in Ni-MFU 4l. AB - A recently developed metal-organic framework (MOF) catalyst for the dimerization of ethylene has a combination of selectivity and activity that surpasses that of commercial homogeneous catalysts, which have dominated this important industrial process for nearly 50 years. The uniform catalytic sites available in MOFs provide a unique opportunity to directly study reaction mechanisms in heterogeneous catalysts, a problem typically intractable due to the multiplicity of coordination environments found in many solid catalysts. In this work, we use a combination of isotopic labeling studies, mechanistic probes, and DFT calculations to demonstrate that Ni-MFU-4l operates via the Cossee-Arlman mechanism, which has also been implicated in homogeneous late transition metal catalysts. These studies demonstrate that metal nodes in MOFs mimic homogeneous catalysts not just functionally, but also mechanistically. They provide a blueprint for the development of advanced heterogeneous catalysts with similar degrees of tunability to their homogeneous counterparts. PMID- 27966940 TI - Electronic Polarization Effect of the Water Environment in Charge-Separated Donor Acceptor Systems: An Effective Fragment Potential Model Study. AB - The electronic polarization (POL) of the surrounding environment plays a crucial role in the energetics of charge-separated systems. Here, the mechanism of POL in charge-separated systems is studied using a combined quantum mechanical and effective fragment potential (QM/EFP) method. In particular, the POL effect caused by charge separation (CS) is investigated at the atomic level by decomposition into the POL at each polarizability point. The relevance of the electric field generated by the CS is analyzed in detail. The model systems investigated are Na+-Cl- and guanine-thymine solvated in water. The dominant part of the POL arises from solvent molecules close to the donor (D) and acceptor (A) units. At short D-A distances, the electric field shows both positive and negative interferences. The former case enhances the POL energy. At longer distances, the interference is weakened, and the local electric field determines the POL energy. PMID- 27966941 TI - Copper-Catalyzed Three-Component Coupling Reaction of Azoles, Se Powder, and Aryl Iodides. AB - A copper-catalyzed three-component coupling reaction of azoles, Se powder, and aryl iodide is described for the first time. This transformation provides a straightforward and facile pathway to synthesis 2-arylselanyl-azoles via a copper catalyzed double C-Se bonds formation process. This reaction is attractive and practical since the cheap copper catalyst is employed and it does not require ligands, proceeds in generally good yields, and has a broad range of functional groups tolerance. PMID- 27966942 TI - Mono- and Mixed-Valence Tetrathiafulvalene Semiconductors (TTF)BiI4 and (TTF)4BiI6 with 1D and 0D Bismuth-Iodide Networks. AB - Two new compounds containing tetrathiafulvalene (TTF) cations with extended and discrete anions based on Bi and I are reported. The compound (TTF)BiI4 comprises [BiI2I4/2]- chains of edge-shared octahedra that are interspersed with stacks of TTF+*. The compound (TTF)4BiI6 has mixed-valence stacks of TTF and TTF+* and discrete molecules of TTF+* separated by discrete [BiI6]-3 anions. The optical and electrical transport properties of these compounds are reported. Due to the mixed-valence stacks of TTF, (TTF)4BiI6 is the significantly better electrical conductor than (TTF)BiI4, despite the discrete nature of the inorganic moiety. PMID- 27966943 TI - Poly(vinyl alcohol) Hydrogels Reinforced with Nanocellulose for Ophthalmic Applications: General Characteristics and Optical Properties. AB - Globally, uncorrected refractive errors are one of the main causes of visual impairment, and contact lenses form an important part of modern day eye care and culture. Several hydrogels with varying physicochemical properties are in use to manufacture soft contact lenses. Hydrogels are generally too soft and reinforcement with appropriate materials is desirable to achieve high water content without compromising mechanical properties. In this study, we have developed a highly transparent macroporous hydrogel with water content >90%, by combining poly(vinyl alcohol) with nanocellulose. Furthermore, the results show that the composite hydrogel has refractive index close to that of water and very good UV-blocking properties. PMID- 27966944 TI - Formation, Oxidation, and Fate of the Breslow Intermediate in the N-Heterocyclic Carbene-Catalyzed Aerobic Oxidation of Aldehydes. AB - The reaction paths and intermediate structures related to the formation of the Breslow intermediate and its oxidation along the oxidative/oxygenative lanes have been studied from a mechanistic point of view, with the support of gas-phase and computational studies. The results confirm the occurrence of a single-electron transfer from the Breslow intermediate to the molecular oxygen with formation of a radical couple that recombines either as a peroxide anion 7' to afford the aldehyde-to-carboxylic acid product or as a hydroperoxy derivative 7" that evolved into an electrophilic acyl azolium, opening to the aldehyde-to-ester conversion. Steric factors enter into determining the different reactivity. All of the intermediates of both catalytic paths have been observed and characterized under mass spectrometric conditions. In particular, for the imidazoline catalyst, the (+)ESI-MS/(MS) detection of the genuine Breslow intermediate was made possible in virtue of its limited reactivity. Mechanistic aspects of the N heterocyclic carbenes catalyzed aerobic oxidation of aldehydes shares important similarities with that one of the recently revisited benzoin condensation. PMID- 27966945 TI - Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists. AB - A series of (E)-11-isonitrosostrychnine oxime ethers, 2-aminostrychnine, (strychnine-2-yl)propionamide, 18-oxostrychnine, and N-propylstrychnine bromide were synthesized and evaluated pharmacologically at human alpha1 and alpha1beta glycine receptors in a functional fluorescence-based and a whole-cell patch-clamp assay and in [3H]strychnine binding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime ethers were the most potent alpha1 and alpha1beta antagonists in the series, displaying IC50 values similar to those of strychnine at the two receptors. Docking experiments to the strychnine binding site of the crystal structure of the alpha3 glycine receptor indicated the same orientation of the strychnine core for all analogues. For the most potent oxime ethers, the ether substituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy group as a suitable attachment point for linking two strychnine pharmacophores by a polymethylene spacer and are, therefore, important for the design of bivalent ligands targeting glycine receptors. PMID- 27966946 TI - How Does the Alkyl Chain Length of an Ionic Liquid Influence Solute Rotation in the Presence of an Electrolyte? AB - Fluorescence anisotropies of a nonpolar solute, 9-phenylanthracene (9-PA), have been measured in 1-alkyl-3-methylimidazolium (alkyl = methyl, butyl, octyl, and dodecyl) bis(trifluoromethylsulfonyl)imides ([RMIM][Tf2N]) with varying amounts (0-0.3 mole fraction) of lithium bis(trifluoromethylsulfonyl)imide (LiTf2N). This study has been carried out to understand how the length of the alkyl chain and the concentration of the electrolyte influence the rotational diffusion of a nonpolar solute. It has been observed that the addition of an electrolyte to the ionic liquid increases the bulk viscosity of the system significantly, as the Li+ cations strongly coordinate with the [Tf2N] anions in the polar domains. The reorientation times of 9-PA have been analyzed with the aid of Stokes-Einstein Debye hydrodynamic (SED) theory, and they fall within the broad limits set by the hydrodynamic slip and stick boundary conditions. However, deviations from the SED theory have been noticed upon addition of LiTf2N, and the influence of the electrolyte is more pronounced in the case of ionic liquids with shorter alkyl chains. The observed trends have been rationalized in terms of electrolyte induced structural changes in these ionic liquids. PMID- 27966947 TI - Massively Parallel Implementation of Explicitly Correlated Coupled-Cluster Singles and Doubles Using TiledArray Framework. AB - A new distributed-memory massively parallel implementation of standard and explicitly correlated (F12) coupled-cluster singles and doubles (CCSD) with canonical O(N6) computational complexity is described. The implementation is based on the TiledArray tensor framework. Novel features of the implementation include (a) all data greater than O(N) is distributed in memory and (b) the mixed use of density fitting and integral-driven formulations that optionally allows to avoid storage of tensors with three and four unoccupied indices. Excellent strong scaling is demonstrated on a multicore shared-memory computer, a commodity distributed-memory computer, and a national-scale supercomputer. The performance on a shared-memory computer is competitive with the popular CCSD implementations in ORCA and Psi4. Moreover, the CCSD performance on a commodity-size cluster significantly improves on the state-of-the-art package NWChem. The large-scale parallel explicitly correlated coupled-cluster implementation makes routine accurate estimation of the coupled-cluster basis set limit for molecules with 20 or more atoms. Thus, it can provide valuable benchmarks for the merging reduced scaling coupled-cluster approaches. The new implementation allowed us to revisit the basis set limit for the CCSD contribution to the binding energy of pi-stacked uracil dimer, a challenging paradigm of pi-stacking interactions from the S66 benchmark database. The revised value for the CCSD correlation binding energy obtained with the help of quadruple-zeta CCSD computations, -8.30 +/- 0.02 kcal/mol, is significantly different from the S66 reference value, -8.50 kcal/mol, as well as other CBS limit estimates in the recent literature. PMID- 27966948 TI - Discovery of Novel, Highly Potent, and Selective Matrix Metalloproteinase (MMP) 13 Inhibitors with a 1,2,4-Triazol-3-yl Moiety as a Zinc Binding Group Using a Structure-Based Design Approach. AB - On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative 1 and triazole derivative 2 with matrix metalloproteinase (MMP)-13 catalytic domain, a novel series of fused pyrimidine compounds which possess a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed. Among the herein described and evaluated compounds, 31f exhibited excellent potency for MMP-13 (IC50 = 0.036 nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1, -2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-alpha converting enzyme (TACE). Furthermore, the inhibitor was shown to protect bovine nasal cartilage explants against degradation induced by interleukin-1 and oncostatin M. In this article, we report the discovery of extremely potent, highly selective, and orally bioavailable fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group as a novel ZBG for selective MMP-13 inhibition. PMID- 27966949 TI - Profiling Prediction of Kinase Inhibitors: Toward the Virtual Assay. AB - Kinome-wide screening would have the advantage of providing structure-activity relationships against hundreds of targets simultaneously. Here, we report the generation of ligand-based activity prediction models for over 280 kinases by employing Machine Learning methods on an extensive data set of proprietary bioactivity data combined with open data. High quality (AUC > 0.7) was achieved for ~200 kinases by (1) combining open with proprietary data, (2) choosing Random Forest over alternative tested Machine Learning methods, and (3) balancing the training data sets. Tests on left-out and external data indicate a high value for virtual screening projects. Importantly, the derived models are evenly distributed across the kinome tree, allowing reliable profiling prediction for all kinase branches. The prediction quality was further improved by employing experimental bioactivity fingerprints of a small kinase subset. Overall, the generated models can support various hit identification tasks, including virtual screening, compound repurposing, and the detection of potential off-targets. PMID- 27966950 TI - Diterpenoids of the Cassane Type from Caesalpinia decapetala. AB - Eighteen compounds, including eight new cassane-type furanoditerpenoids, 3beta hydroxyphanginin H (1), 3beta-acetoxyphanginin H (2), 7beta-acetoxyphanginin H (3), 7beta-hydroxyphanginin H (4), 4-epi-3beta-hydroxycaesalpinilinn (5), 4-epi 3beta-acetoxycaesalpinilinn (6), 20-acetoxytaepeenin D (7), and tomocin E (8), along with 10 known compounds (9-18) were isolated from the roots of Caesalpinia decapetala. Compounds 1-13 were isolated from C. decapetala for the first time. The new compounds with their absolute configurations were determined by extensive spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compounds 1, 4, 5, 7, and 11 exhibited inhibitory activities against the SW1990 human pancreatic cancer cell line with IC50 values ranging from 2.9 to 8.9 MUM. PMID- 27966951 TI - Unconventional O-H...C Hydrogen Bonding and Effects of Conformational Changes on Infrared Spectroscopy of o-Cresol in Solutions. AB - The unconventional O-H...C intramolecular hydrogen bonding and the effect of conformational changes on IR spectra of o-cresol in aqueous solutions were investigated by using molecular dynamics (MD) simulations, density functional theory (DFT), and experiments. A facial rotational isomerization between global minimum with trans conformation and the cis isomer is predicted to take place in gas phase with a low barrier of about 3.7 kcal/mol through a vertical-like transition state. Upon solvation in aqueous solution, the contents of energetically high-lying vertical and cis conformations of neutral o-cresol are increased to 19% and 57%, respectively, in comparison with those (vertical, 0%; cis, 27%) in vacuum. The IR spectra of aqueous solution are closely related to the relative population of the different conformations, especially for the cis conformation with hydroxyl group facing to alkyl group. The appearance of cis conformations and unconventional O-H...C intramolecular hydrogen bond (HB) caused the low-frequency shift in OH stretching vibration of the IR spectra, which was also correlated with cation-like charge distribution and the decrease in s component of oxygen hybridization orbital. However, the intermolecular HB between the o-cresol and surrounding water (o-cresol) molecules gave rise to more evident shifts in IR spectra than that caused by the intramolecular HB contributions in cis isomer. Further identification of intramolecular HB effect is performed through the comparison of spectrum changes that occurs on passing from aqueous solution to less interacting (carbon tetrachloride and cyclohexane) solvents. The absence of the intermolecular HB interaction between o-cresol and carbon tetrachloride (and cyclohexane) solvents leads to the weaker intensity and narrower width of OH stretching vibration region (around 3407 cm-1) in the IR spectra than that in aqueous solution. PMID- 27966952 TI - Total Synthesis and Biological Evaluation of Hybrubin A. AB - Here, we report the first total synthesis of hybrubin A, a bipyrrole tetramic acid alkaloid representing a new carbon framework derived from convergent (truncated red cluster and exogenous hbn cluster) biosynthetic pathways. A highly convergent synthesis was developed, employing 4-methoxy-1,5-dihydro-2H-pyrrol-2 one (13) as a single starting material to provide hybrubin A in three steps from 13 and 20.8% overall yield. As no biological activity was prescribed to hybrubin A except for a lack of cytotoxicity, we further profiled this unique alkaloid across panels of discrete molecular targets. Interestingly, hybrubin A was found to be a ligand for a variety of GPCRs with a propensity for potent binding across therapeutically relevant adenosine receptors (A1, A2a, and A3) as well as a potent activity at a kinase, FLT3. This pattern of biological activity is distinct from other related prodigiosin natural and unnatural products and is even more intriguing in the absence of cytotoxicity. PMID- 27966953 TI - Scalable, One-Pot, Microwave-Accelerated Tandem Synthesis of Unsymmetrical Urea Derivatives. AB - We report a facile, microwave-accelerated, one-pot tandem synthesis of unsymmetrical ureas via a Curtius rearrangement. In this method, one-pot microwave irradiation of commercially available (hetero)aromatic acids and amines in the presence of diphenylphosphoryl azide enabled extremely rapid (1-5 min) construction of an array of unsymmetrical ureas in good to excellent yields. We demonstrate the utility of our method in the efficient, gram-scale synthesis of key biologically active compounds targeting the cannabinoid 1 and alpha7 nicotinic acetylcholine receptors. PMID- 27966954 TI - Discovery of 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3 (trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-yl)oxy)benzamide (CHMFL ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding. AB - The discovery of a novel potent type II ABL/c-KIT dual kinase inhibitor compound 34 (CHMFL-ABL/KIT-155), which utilized a hydrogen bond formed by NH on the kinase backbone and carbonyl oxygen of 34 as a unique hinge binding, is described. 34 potently inhibited purified ABL (IC50: 46 nM) and c-KIT kinase (IC50: 75 nM) in the biochemical assays and displayed high selectivity (S Score (1) = 0.03) at the concentration of 1 MUM among 468 kinases/mutants in KINOMEscan assay. It exhibited strong antiproliferative activities against BCR-ABL/c-KIT driven CML/GISTs cancer cell lines through blockage of the BCR-ABL/c-KIT mediated signaling pathways, arresting cell cycle progression and induction of apoptosis. 34 possessed a good oral PK property and effectively suppressed the tumor progression in the K562 (CML) and GIST-T1 (GISTs) cells mediated xenograft mouse model. The distinct hinge-binding mode of 34 provided a novel pharmacophore for expanding the chemical structure diversity for the type II kinase inhibitors discovery. PMID- 27966955 TI - Physical Absorption of Green House Gases in Amines: The Influence of Functionality, Structure, and Cross-Interactions. AB - Monte Carlo simulations were performed in the isothermal-isobaric ensemble (NPT) to calculate the Henry constants of methane (CH4), nitrous oxide (N2O), and carbon dioxide (CO2) in pure H2O, amines, and alkanolamines using the classical Lorentz-Berthelot combining rules (L-B). The Henry constants of N2O and CO2 in water are highly overestimated and motivated us to propose a new set of unlike interactions. Contrarily, the Henry constant of N2O in MEA is underestimated by around 40%, and again, a new reoptimized cross unlike parameter is able to reproduce the constant to within 10%. An analysis is given of the relationship between the physical absorption of these gases and the chemical structure or functionality of 12 molecules including amines and alkanolamines using the anisotropic united atom intermolecular potential (AUA4). Finally, the solubility of N2O in an aqueous solution of monoethanolamine (MEA) at 30% (wt) was also studied. A Henry constant within 7% of the experimental value was found by using the reoptimized parameters along with L-B to account for the MEA + H2O unlike interactions. This very good agreement without additional adjustments for the MEA + H2O system may be attributed to the good excess properties predictions found in previous works for the binary mixture (MEA + H2O). However, further work, including additional alkanolamines in aqueous solutions at several concentrations, is required to verify this particular point. PMID- 27966957 TI - Gold-Catalyzed Stereoselective Synthesis of Bicyclic Lactams and Ketones from N Tosylynamidomethyl-Tethered Cyclohexenes. AB - Six-membered ring 3-enynamides underwent cycloisomerization in the presence of a catalytic amount of a gold(I) complex delivering mainly 4 azatricyclo[4.3.1.03,10]dec-2-ene derivatives and dibenz[cd,f]indole derivatives as the minor products under mild reaction conditions. Upon exposure to air, most aryl-substituted azatricycles led to bicyclic gamma-lactams, while the ortho tolyl- or alkyl-substituted azatricycles provided the corresponding bicyclic gamma-lactams after oxidation with osmium tetraoxide and N-methylmorpholine-N oxide. Under acidic conditions, the ortho-tolyl- or alkyl-substituted azatricycles were further transformed into 5-N-tosylaminomethyl-tethered bicyclo[4.2.0]octan-7-ones. The gold(I)-catalyzed tandem cycloisomerization/oxidation reaction also provided a new route for the synthesis of bridged bicyclic delta-lactams from six-membered ring 4-enynamides. The mild reaction conditions allowed the synthesis of a range of bicyclic gamma- and delta lactams and N-tosylaminomethyl-tethered bicyclo[4.2.0]octan-7-ones with high diastereoselectivities. PMID- 27966956 TI - A Potent, Selective, and Orally Bioavailable HCV NS5A Inhibitor for Treatment of Hepatitis C Virus: (S)-1-((R)-2-(Cyclopropanecarboxamido)-2-phenylacetyl)-N-(4 phenylthiazol-2-yl)pyrrolidine-2-carboxamide. AB - Starting from the initial lead 4-phenylthiazole 18, a modest HCV inhibitor (EC50 = 9440 nM), a series of structurally related thiazole derivatives has been identified as a novel chemical class of potent and selective HCV NS5A inhibitors. The introduction of a carboxamide group between the thiazole and pyrrolidine ring (42) of compound 18 resulted in a dramatic increase in activity (EC50 = 0.92 nM). However, 42 showed only moderate pharmacokinetic properties and limited oral bioavalability of 18.7% in rats. Further optimization of the substituents at the 4-position of the thiazole ring and pyrrolidine nitrogen of the lead compound 42 led to the identification of compound 57, a highly potent and selective NS5A inhibitor of HCV (EC50 = 4.6 nM), with greater therapeutic index (CC50/EC50 > 10000). Pharmacokinetic studies revealed that compound 57 had a superior oral exposure and desired bioavailability of 45% after oral administration in rats. PMID- 27966958 TI - Effects of Solvent Crystallization in Swollen net-Poly(ethyl acrylate) alpha Relaxation Dynamics. AB - The polymer alpha relaxation process for net-PEA gels swollen with nonpolar p xylene is studied by employing dielectric relaxation spectroscopy. The results present the in situ monitoring of the dielectric behavior of alpha relaxation process under p-xylene cold crystallization, isothermal crystallization as well as crystallization from quenching. For the partially crystallized systems, the results exhibit that the amount of p-xylene crystal phase has no remarkable effects on the time scale, being controlled mainly by the amount of the noncrystallized p-xylene (cpx= 0.11-0.15) gel phase. Surprisingly, the stretching exponent betaKWW obtains higher values in the isothermal crystallization process as the p-xylene crystallization is in progress and the reorganization of p-xylene through diffusion to crystallites approaches thermodynamic equilibrium. This directly indicates that any alpha process broadening is originated not solely from the amount of p-xylene crystallites and the induced heterogeneities, but from the presence of remarkable concentration fluctuations close to respective effective glass transition temperature, enhanced for higher solvent contents as well. Finally, the results suggest that the existence of p-xylene crystallites decrease significantly the dielectric strength of alpha process. The effective medium theory is applied to check whether this recorded reduction originates from the induced spatial heterogeneities (p-xylene crystallites) or from the immobilization in parts of polymer configurations. PMID- 27966959 TI - Syntheses of Combretastatins D-1, D-2, and D-4 via Ring Contraction by Flash Vacuum Pyrolysis. AB - We report the syntheses of combretastatins D-2 and D-4 as well as a formal synthesis of combretastatin D-1 by a conceptually new route harnessing a ring contracting flash vacuum pyrolytic extrusion of sulfur dioxide from the respective 16-membered sulfone precursors. Via flash vacuum pyrolysis, even metaparacyclophanes as small and strained as the hitherto unknown oxa[1.5]metaparacyclophane could be prepared as a side product en route to combretastatin D-2 by synchronous extrusion of SO2 and CO2. PMID- 27966960 TI - Numerical Estimation of the Pseudo-Jahn-Teller Effect Using Nonadiabatic Coupling Integrals in Monocyclic and Bicyclic Conjugated Molecules. AB - The pseudo-Jahn-Teller (pJT) effect in monocyclic and bicyclic conjugated molecules was investigated by using the state-averaged multiconfiguration self consistent field (MCSCF) method, together with the 6-31G(d,p) basis sets. Following the perturbation theory, the force constant along a normal mode Q is given by the sum of the classical force constant and the vibronic contribution (VC) resulting from the interaction of the ground state with excited states. The latter is given as the sum of individual contributions arising from vibronic interactions between the ground state and excited states. In the present work, each VC was calculated on the basis of nonadiabatic coupling (NAC) integrals. Furthermore, the classical force constant was estimated by taking advantage of the VC and the force constant obtained by vibrational analyses. For pentalene and heptalene, the present method seems to overestimate the VC in absolute value because of the small energy gap between the ground state and the lowest excited state. However, we are confident that the VC and the classical force constant for the other molecules are reasonable in magnitude in comparison with available literature information. Thus, it is proved that the present method is applicable and useful for numerical estimation of pJT effect. PMID- 27966962 TI - Peptide-Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology. AB - A thousand-fold affinity gain is achieved by introduction of a C-terminal boronic acid moiety into dipeptidic inhibitors of the Zika, West Nile, and dengue virus proteases. The resulting compounds have Ki values in the two-digit nanomolar range, are not cytotoxic, and inhibit virus replication. Structure-activity relationships and a high resolution X-ray cocrystal structure with West Nile virus protease provide a basis for the design of optimized covalent-reversible inhibitors aimed at emerging flaviviral pathogens. PMID- 27966963 TI - Carboxylate-Enhanced Rhodium(III)-Catalyzed Aryl C-H Alkylation with Conjugated Alkenes under Mild Conditions. AB - Rhodium(III)-catalyzed C-H bond functionalization for the synthesis of beta-aryl aldehydes and ketones from (hetero)aryl oximes, pyri(mi)dine, as well as pyrazoles and alpha,beta-unsaturated carbonyl compounds has been developed under exceedingly mild reaction conditions. Thus, the versatile rhodium(III) catalysis features high step- and atom-economy, oxidant-free reaction conditions, and broad substrate scope. PMID- 27966961 TI - Newly Designed Quinolinol Inhibitors Mitigate the Effects of Botulinum Neurotoxin A in Enzymatic, Cell-Based, and ex Vivo Assays. AB - Botulinum neurotoxin A (BoNT/A) is one of the most deadly toxins and is the etiological agent of the potentially fatal condition, botulism. Herein, we investigated 8-hydroxyquinoline (quinolin-8-ol) as a potential inhibitor scaffold for preventing the deadly neurochemical effects of the toxin. Quinolinols are known chelators that can disrupt the BoNT/A metalloprotease zinc-containing active site, thus impeding its proteolysis of the endogenous protein substrate, synaptosomal-associated protein 25 (SNAP-25). By use of this information, the structure-activity relationship (SAR) of the quinolinol-5-sulfonamide scaffold was explored through preparation of a crude sulfonamide library and evaluation of the library in a BoNT/A LC enzymatic assay. Potency optimization of the sulfonamide hit compounds was undertaken as informed by docking studies, granting a lead compound with a submicromolar Ki. These quinolinol analogues demonstrated inhibitory activity in a cell-based model for SNAP-25 cleavage and an ex vivo assay for BoNT/A-mediated muscle paralysis. PMID- 27966964 TI - Solvent Polarity Governs Ion Interactions and Transport in a Solvated Room Temperature Ionic Liquid. AB - We explore the influence of the solvent dipole moment on cation-anion interactions and transport in 1-butyl-3-methyl-imidazolium bis(trifluoromethylsulfonyl), [BMIM+][Tf2N-]. Free energy profiles derived from atomistic molecular dynamics (MD) simulations show a correlation of the cation anion separation and the equilibrium depth of the potential of mean force with the dipole moment of the solvent. Correlations of the ion diffusivity with the dipole moment and the concentration of the solvent were further demonstrated by classical MD simulations. Quasi-elastic neutron scattering experiments with deuterated solvents reveal a complex picture of nanophase separation into the ionic liquid-rich and solvent-rich phases. The experiment corroborates the trend of concentration- and dipole moment-dependent enhancement of ion mobility by the solvent, as suggested by the simulations. Despite the considerable structural complexity of ionic liquid-solvent mixtures, we can rationalize and generalize the trends governing ionic transport in these complex electrolytes. PMID- 27966965 TI - The Symmetric Exchange Reaction OH + H2O -> H2O + OH: Convergent Quantum Mechanical Predictions. AB - The symmetric hydrogen exchange reaction OH + H2O -> H2O + OH has been studied using the "gold standard" CCSD(T) method with the correlation-consistent basis sets up to aug-cc-pV5Z. The CCSDT and CCSDT(Q) methods were used for the final energic predictions. Two entrance complexes and two transition states on the H3O2 potential surface were located. The vibrational frequencies and the zero-point vibrational energies of these stationary points for the reaction are reported. The entrance complex H2O...HO is predicted to lie 3.7 kcal mol-1 below the separated reactants, whereas the second complex HOH...OH lies only 2.1 kcal mol-1 below the separated reactants. The classical barrier height for the title reaction is predicted to be 8.4 kcal mol-1, and the transition state between the two complexes is only slightly higher than the second complex. We estimate a reliability of +/-0.2 kcal mol-1 for these predictions. The capabilities of different density functional theory methods is also tested for this reaction. PMID- 27966966 TI - Doubly Vinylogous Aldol Reaction of Furoate Esters with Aldehydes and Ketones. AB - The use of bulky Lewis acids, aluminum tris(2,6-diphenylphenoxide) (ATPH) and aluminum tris(2,6-di-2-naphthylphenoxide) (ATNP), in the doubly vinylogous aldol reaction between methyl-5-methyl-2-furoate and aldehydes or ketones is described. These reactions proceed smoothly and in high yields with both enolizable and non enolizable substrates. This C-C bond-forming reaction enables a new bond construction for the synthesis of functionalized furans. PMID- 27966967 TI - Electrical Detection of Quantum Dot Hot Electrons Generated via a Mn2+-Enhanced Auger Process. AB - An all-solid-state quantum-dot-based photon-to-current conversion device is demonstrated that selectively detects the generation of hot electrons. Photoexcitation of Mn2+-doped CdS quantum dots embedded in the device is followed by efficient picosecond energy transfer to Mn2+ with a long-lived (millisecond) excited-state lifetime. Electrons injected into the QDs under applied bias then capture this energy via Auger de-excitation, generating hot electrons that possess sufficient energy to escape over a ZnS blocking layer, thereby producing current. This electrically detected hot-electron generation is correlated with a quench in the steady-state Mn2+ luminescence and the introduction of a new nonradiative excited-state decay process, consistent with electron-dopant Auger cross-relaxation. The device's efficiency at detecting hot-electron generation provides a model platform for the study of hot-electron ionization relevant to the development of novel photodetectors and alternative energy-conversion devices. PMID- 27966968 TI - Stability Analysis of Printed Liquid Elbows. AB - In this study, a theoretical model was developed to analyze the stability of liquid elbow patterns and validated by experiments. An exemplar system of ethylene glycol continuously deposited on polyethylene terephthalate (PET) was used to study the effects of printing parameters on bulge formation near the elbow corners. In the elbow region, because of the capillary pressure differences, liquids flowed into the concave elbow corner and formed bulges easily after being printed. However, the bulge formation disappeared when the elbow angle is >90 degrees . A simple model based on surface energy analysis was proposed to explain the bulging phenomenon and can successfully predict bulge sizes at steady state. A stability diagram was also calculated to map out the stable regimes. With the guidance of the stability diagram, stable elbow lines without any bulges can be printed with various angles by controlling the thickness of liquids. In summary, this stabilization strategy in this study is effective to maintain the fidelity of printed liquid patterns and provides useful guidelines for printed electronic applications. PMID- 27966970 TI - Anionic and Cationic Silver Nanoparticle Binding Restructures Net-Anionic PC/PG Monolayers with Saturated or Unsaturated Lipids. AB - We have examined the interactions between polymer-coated anionic (Ag-COOH) and cationic (Ag-NH) silver nanoparticles, and net-anionic lipid monolayers using dynamic surface pressure measurements. Monolayers composed of saturated or monounsaturated mixtures of anionic phosphatidylglycerol (PG) and zwitterionic phosphatidylcholine (PC) lipids (3:1 molar ratio) were used to determine how lipid packing and monolayer phase state influence the extent of nanoparticle binding and the monolayer response. Anionic Ag-COOH inserted into saturated dipalmitoyl-PC/PG (DPPC/DPPG) and dioleoyl-PC/PG (DOPC/DOPG) monolayers at a low initial surface pressure (10 mN m-1) and caused lipid condensation at high initial surface pressures (20 and 30 mN m-1). Hydrophobic interactions were responsible for insertion, while electrostatic and charge-dipole interactions with PCs were responsible for condensation. In contrast, cationic Ag-NH inserted only into saturated DPPC/DPPG monolayers and otherwise led to lipid condensation. For Ag-NH, adsorption was driven primarily by electrostatic interactions with PGs. Analysis of the subphase Ag and phosphorus concentrations confirmed that Ag NH had a higher degree binding compared to Ag-COOH, and that the monolayer response was not due to lipid extraction. PMID- 27966969 TI - Method for Accessing Nitrogen-Containing, B-Heteroaryl-Substituted 2,1 Borazaronaphthalenes. AB - The azaborine motif provides a mimic of aromatic systems through replacement of a C?C bond with a B-N bond. In particular, 2,1-borazaronaphthalenes, accessible through robust methods of synthesis and subsequent functionalization, afford an ideal platform to use for a variety of applications. However, the scope of substructures for this archetype has been limited by the lack of nitrogen containing heteroaryls that can be incorporated within them. In this study, modified reaction conditions were developed to provide access to a wider range of substructures. PMID- 27966971 TI - Analysis of the Interfacial Molecular Behavior of a Lubrication Film of n Dodecane Containing Stearic Acid under Lubricating Conditions by Sum Frequency Generation Spectroscopy. AB - The molecular behavior of n-dodecane with added stearic acid at a friction interface was studied using sum frequency generation (SFG) spectroscopy and a tribometer. In the case of n-dodecane with stearic acid, under dynamic conditions, a strong peak from the symmetric stretching vibrational mode of methylene, which was not observed under static conditions, appears. However, this strong methylene peak was not observed in the case of only n-dodecane. The SFG spectrum in the C-H stretching mode region of n-dodecane-d26 with stearic acid in the dynamic condition was analogous to that in the static condition. These results indicate that the interfacial structure of stearic acid does not change under sliding condition. The n-dodecane on a stearic acid adsorption film is highly aligned. Moreover, from the sliding direction dependence of the SFG measurements, the molecular orientation of n-dodecane was deduced: n-dodecane on stearic acid adsorption films orient parallel to the sliding direction. These results have shown that the stearic acid adsorption film behaves as solid-like, which has also been mentioned in previous studies. Further, our results revealed a new function of stearic acid: the stearic acid adsorption film induces the formation of a well-defined n-dodecane interfacial structure and forces the n dodecane molecules to orient along the sliding direction at the friction interface. PMID- 27966972 TI - Role of Organic Hydrocarbons in Atmospheric Ice Formation via Contact Freezing. AB - An optical ice microscope apparatus equipped with a sealed cooling stage and a CCD camera was used to examine contact freezing events between a water droplet and ice nucleating particles (INP) containing organic hydrocarbons including octacosane, squalane, and squalene. Sample viscosities were measured with a capillary viscometer and compositions were characterized using Fourier transfer infrared spectroscopy with horizontal attenuated total reflectance and Raman microspectroscopy. All of the samples proved to be moderately efficient ice nuclei that induced freezing between -23 and -26 degrees C, regardless of whether the INP was solid or liquid. At their ice nucleating temperatures, the viscosity of the liquid samples (squalane and squalene) was 0.6 P or greater. Oxidation increased the viscosity of squalene to over 1330 P, but decreased the viscosity of squalane to 0.07 P at room temperature. Most importantly, our results demonstrate that even moderately viscous liquids in contact with water droplets can act to catalyze freezing, plausibly by providing a flexible template which decreases the energy barrier to ice nucleation. The simple soccer ball model of nucleation theory was used to derive the probability of freezing and nucleation rate coefficients as a function of temperature for each type of INP. PMID- 27966973 TI - Temperature Induced Order-Disorder Transition in Solutions of Conjugated Polymers Probed by Optical Spectroscopy. AB - The aggregation of pi-conjugated materials significantly impacts the photophysics and performance of optoelectronic devices. Nevertheless, little is known about the laws governing aggregate formation of pi-conjugated materials from solution. In this Perspective, we compare, discuss, and summarize how aggregates form for three different types of compounds, that is, homopolymers, donor-acceptor type polymers, and low molecular weight compounds. To this end, we employ temperature dependent optical spectroscopy, which is a simple yet powerful tool to investigate aggregate formation. We show how optical spectra can be analyzed to identify distinct conformational states. We find aggregate formation to proceed the same in all these compounds by a coil-to-globule-like first-order phase transition. Notably, the chain expands before it collapses into a highly ordered dense state. The role of side chains and the impact of changes in environmental polarization are addressed. PMID- 27966974 TI - Structural Determination of (-)-SCH 64874 and Hirsutellomycin by Semisynthesis. AB - The structure of a C2-symmetric epidithiodiketopiperazine alkaloid, SCH 64874, was determined by semisynthesis. The relative stereochemistry of the beta-hydroxy carboxylic acid chain having three chiral centers was determined by comparison of the NMR data of the four possible diastereomeric beta-hydroxy carboxylic acid fragments with those of SCH 64874. Condensation of the (-)-deacetylaranotin core with two enantiomeric beta-hydroxy carboxylic acids revealed the relative stereochemistry of SCH 64874. The relative stereochemistry of the beta-keto carboxylic acid chain of the analogous alkaloid hirsutellomycin was determined in a stepwise manner. The C4'-C6' syn relationships were predicted by comparing the NMR data of the corresponding ester fragments with that of hirsutellomycin. The relative stereochemistry of the whole molecule, including the epimerizable C2' stereocenter, was determined by introduction of four possible side chains into the bisdethiodi(methylthio)deacetylaranotin core. We found that the stereochemistry of C2' converged with that of the thermodynamically stable form influenced by the core structure. PMID- 27966975 TI - Mutual Effects of Glycerol and Inorganic Salts on Their Hydration Abilities. AB - It is a tough challenge to understand the mutual interactions among various components in aqueous solutions of inorganic mixed with organic solutes. The hydration number, nh, and critical hydration number, ncr, determined by the measurements of glass transition of the solutions, in conjunction with tracing the change in local water structure, can provide some insights into the complicated interplays in such a mixture. Here, the nh and ncr for aqueous solutions of glycerol, various chlorides, and mixtures of glycerol with a chloride are determined. The ratio of ncr/nh measures 4 for glycerol and 1.7 for all the chlorides, and for mixtures of glycerol with all of the chlorides except ZnCl2, it falls within these two extremes. Glycerol content dependence of nh and ncr reveals a rich and interesting scenario of mutual effects therein, in particular, the glycerol's replacement and sharing of hydration water with salt. In the case of ZnCl2, at most, one hydration water molecule is replaced by glycerol, and the excess glycerol molecules continuously reduce the number of glycerol molecules that share hydration water with ZnCl2. Our results can help establish a pathway for the investigation of interactions among the organic and inorganic components in aqueous solutions, which is desirable for many applications. PMID- 27966976 TI - Interaction of B12F122- with All-cis 1,2,3,4,5,6 Hexafluorocyclohexane in the Gas Phase. AB - Clusters of all-cis 1,2,3,4,5,6-hexafluorocyclohexane and the dodecafluorododecaboron dianion, [C6F6H6]n[B12F12]2- (n = 0-4), are investigated in a combined experimental and computational study. DFT calculations and IRMPD spectra in the region of 800-2000 cm-1 indicate that C6H6F6 binds to open trigonal faces of B12F122- via a three-point interlocking binding motif. Calculated binding interactions reveal substantial contributions from C-H...F hydrogen bonding and binding energies that are among the strongest observed for a neutral-anion system. PMID- 27966977 TI - Quantitative Measurement of Ligand Exchange with Small-Molecule Ligands on Iron Oxide Nanoparticles via Radioanalytical Techniques. AB - Ligand exchange on the surface of hydrophobic iron oxide nanoparticles is a common method for controlling surface chemistry for a desired application. Furthermore, ligand exchange with small-molecule ligands may be necessary to obtain particles with a specific size or functionality. Understanding to what extent ligand exchange occurs and what factors affect it is important for the optimization of this critical procedure. However, quantifying the amount of exchange may be difficult because of the limitations of commonly used characterization techniques. Therefore, we utilized a radiotracer technique to track the exchange of a radiolabeled 14C-oleic acid ligand with hydrophilic small molecule ligands on the surface of iron oxide nanoparticles. Iron oxide nanoparticles functionalized with 14C-oleic acid were modified with small molecule ligands with terminal functional groups including catechols, phosphonates, sulfonates, thiols, carboxylic acids, and silanes. These moieties were selected because they represent the most commonly used ligands for this procedure. The effectiveness of these molecules was compared using both procedures widely found in the literature and using a standardized procedure. After ligand exchange, the nanoparticles were analyzed using liquid scintillation counting (LSC) and inductively coupled plasma-mass spectrometry. The labeled and unlabeled particles were further characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) to determine the particle size, hydrodynamic diameter, and zeta potential. The unlabeled particles were characterized via attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and vibrating sample magnetometry (VSM) to confirm the presence of the small molecules on the particles and verify the magnetic properties, respectively. Radioanalytical determination of 14C-oleic acid was used to calculate the total amount of oleic acid remaining on the surface of the particles after ligand exchange. The results revealed that the ligand-exchange reactions performed using widely cited procedures did not go to completion. Residual oleic acid remained on the particles after these reactions and the reactions using a standardized protocol. A comparison of the ligand-exchange procedures indicated that the binding moiety, multidenticity, reaction time, temperature, and presence of a catalyst impacted the extent of exchange. Quantification of the oleic acid remaining after ligand exchange revealed a binding hierarchy in which catechol-derived anchor groups displace the most oleic acid on the surface of the nanoparticles and the thiol group displaces the least amount of oleic acid. Thorough characterization of ligand exchange is required to develop nanoparticles suitable for their intended application. PMID- 27966978 TI - Quantitative Global Proteomics of Yeast PBP1 Deletion Mutants and Their Stress Responses Identifies Glucose Metabolism, Mitochondrial, and Stress Granule Changes. AB - The yeast protein PBP1 is implicated in very diverse pathways. Intriguingly, its deletion mitigates the toxicity of human neurodegeneration factors. Here, we performed label-free quantitative global proteomics to identify crucial downstream factors, either without stress or under cell stress conditions (heat and NaN3). Compared to the wildtype BY4741 strain, PBP1 deletion always triggered downregulation of the key bioenergetics enzyme KGD2 and the prion protein RNQ1 as well as upregulation of the leucine biosynthesis enzyme LEU1. Without stress, enrichment of stress response factors was consistently detected for both deletion mutants; upon stress, these factors were more pronounced. The selective analysis of components of stress granules and P-bodies revealed a prominent downregulation of GIS2. Our yeast data are in good agreement with a global proteomics and metabolomics publication that the PBP1 ortholog ATAXIN-2 (ATXN2) knockout (KO) in mouse results in mitochondrial deficits in leucine/fatty acid catabolism and bioenergetics, with an obesity phenotype. Furthermore, our data provide the completely novel insight that PBP1 mutations in stress periods involve GIS2, a plausible scenario in view of previous data that both PBP1 and GIS2 relocalize from ribosomes to stress granules, interact with poly(A)-binding protein in translation regulation and prevent mitochondrial precursor overaccumulation stress (mPOS). This may be relevant for human diseases like spinocerebellar ataxias, amyotrophic lateral sclerosis, and the metabolic syndrome. PMID- 27966979 TI - Modeling Flow Coating of Colloidal Dispersions in the Evaporative Regime: Prediction of Deposit Thickness. AB - We investigate flow coating processes, i.e., the formation of dry coatings starting from dilute complex fluids confined between a static blade and a moving substrate. In particular, we focus on the evaporative regime encountered at low substrate velocity, at which the coating flow is driven mainly by solvent evaporation in the liquid meniscus. In this regime, general arguments based on mass conservation show that the thickness of the dry film decreases as the substrate velocity increases, unlike the behavior in the well-known Landau-Levich regime. This work focuses on colloidal dispersions, which deserve special attention. Indeed, flow coating is expected to draw first a solvent-saturated film of densely packed colloids, which further dries fully when air invades the pores of the solid film. We first develop a model based on the transport equations for binary mixtures, which can describe this phenomenon continuously, using appropriate boundary conditions and a criterion to take into account pore emptying in the colloidal film. Extensive numerical simulations of the model then demonstrate two regimes for the deposit thickness as a function of the process parameters (substrate velocity, evaporation rate, bulk concentration, and particle size). We finally derive an analytical model based on simplified transport equations that can reproduce the output of our numerical simulations very well. This model can predict analytically the two observed asymptotic regimes and therefore unifies the models recently reported in the literature. PMID- 27966980 TI - Impact of Viscous Droplets on Superamphiphobic Surfaces. AB - The impact of a liquid droplet on a solid surface is one of the most common phenomena in nature and frequently encountered in numerous technological processes. Despite the significant progress on understanding the droplet impact phenomenon over the past century, the impact dynamics, especially the coupling effects between the properties of a liquid and surface wettability on the impact process, is still poorly understood. In this work, we experimentally investigated the impact of viscous droplets on superamphiphobic surfaces, with the viscosity of liquids ranging from 0.89 to 150 mPa s. We showed that an increase in liquid viscosity will slow down the impact process and cause bouncing droplets to rebound lower and fewer times. The critical impact velocity, above which droplets can rebound from the superamphiphobic surface, was found to linearly increase with the liquid viscosity. We also showed that the maximum spreading factor increases with Weber number or Reynolds number but decreases with the liquid viscosity. Scaling analyses based on energy conservation were carried out to explain these findings, and they were found to be in good agreement with our experimental results. PMID- 27966981 TI - Thermodynamic Analysis of Isomerization Equilibria of Chlorotoluenes and Dichlorobenzenes in a Biphasic Reaction Systems Containing Highly Acidic Chloroaluminate Melts. AB - Thermodynamics and kinetics of the isomerization of chlorotoluenes and dichlorobenzene to the technically desired meta-isomers have been studied in the presence of highly acidic chloroaluminate melts with alkali metal and organic imidazolium cations. Enthalpies of four isomerization processes in reacting systems of chlorotoluenes and dichlorobenzene were obtained from temperature dependencies of the corresponding equilibrium constants in the liquid phase. Experimental reaction enthalpies, enthalpies of vaporization, and absolute vapor pressures of chlorotoluenes and dichlorobenzene have been used for the validation of quantum-chemical methods to predict thermodynamic functions of the four reactions under study successfully. Values of the standard Gibbs energies of formation, standard enthalpies and entropies of formation of chlorotoluenes and dichlorobenzenes in the liquid and in the gas phase have been derived. These values allow optimization of liquid-liquid biphasic manufacturing technologies for halogen-substituted benzenes. PMID- 27966982 TI - Lipid and Peptide Diffusion in Bilayers: The Saffman-Delbruck Model and Periodic Boundary Conditions. AB - The periodic Saffman-Delbruck (PSD) model, an extension of the Saffman-Delbruck model developed to describe the effects of periodic boundary conditions on the diffusion constants of lipids and proteins obtained from simulation, is tested using the coarse-grained Martini and all-atom CHARMM36 (C36) force fields. Simulations of pure Martini dipalmitoylphosphatidylcholine (DPPC) bilayers and those with one embedded gramicidin A (gA) dimer or one gA monomer with sizes ranging from 512 to 2048 lipids support the PSD model. Underestimates of Dinfinity (the value of the diffusion constant for an infinite system) from the 512-lipid system are 35% for DPPC, 45% for the gA monomer, and 70% for the gA dimer. Simulations of all-atom DPPC and dioleoylphosphatidylcholine (DOPC) bilayers yield diffusion constants not far from experiment. However, the PSD model predicts that diffusion constants at the sizes of the simulation should underestimate experiment by approximately a factor of 3 for DPPC and 2 for DOPC. This likely implies a deficiency in the C36 force field. A Bayesian method for extrapolating diffusion constants of lipids and proteins in membranes obtained from simulation to infinite system size is provided. PMID- 27966984 TI - Evidence of Ultrafast Charge Transfer Driven by Coherent Lattice Vibrations. AB - We report evidence that intermolecular vibrations coherently drive charge transfer between the sites of a material on ultrafast time scales. Following a nonresonant stimulated Raman pump pulse that excites the organic material quinhydrone, we observe the initial appearance of oscillations due to intermolecular lattice vibrations and then the delayed appearance of a higher frequency oscillation that we assign to a totally symmetric intramolecular vibration. We use the coherent dynamics of the transient reflectivity signal to propose that coherence transfer drives excitation of this intramolecular vibration. Furthermore, we conclude that the dynamical frequency shift of the intramolecular vibration reports the formation of a quasi-stable charge-separated state on ultrafast time scales. We calculate model dynamics using the extended Hubbard Hamiltonian to explain coherence transfer due to vibrationally driven charge transfer. These results demonstrate that the coherent excitation of low frequency vibrations can drive charge transfer in the solid state and control material properties. PMID- 27966983 TI - Palladium-Catalyzed Cyclization-Heck Reaction of Allenamides: An Approach to 3 Methylene-5-phenyl-1,2,3,4-tetrahydropyridine Derivatives. AB - An efficient one-pot construction of functionalized 3-methylene-5-phenyl-1,2,3,4 tetrahydropyridine derivatives via palladium-catalyzed cyclization-Heck reaction of allenamides has been described. The 3-methylene-5-phenyl-1,2,3,4 tetrahydropyridine derivatives feature a nonconjugated diene, including one endo enamine and one exocyclic double bond, which could be used for further transformation. Both aryl and vinyl halides performed very well under the standard conditions, delivering the corresponding products efficiently. PMID- 27966985 TI - Synthesis of delta- and alpha-Carbolines via Nickel-Catalyzed [2 + 2 + 2] Cycloaddition of Functionalized Alkyne-Nitriles with Alkynes. AB - A new method for the synthesis of delta- and alpha-carbolines through Ni catalyzed [2 + 2 + 2] cycloaddition of ynamide-nitriles or alkyne-cyanamides with alkynes has been developed. The catalytic system of NiCl2(DME)/dppp/Zn with a low cost Ni(II)-precursor was first utilized in Ni-catalyzed [2 + 2 + 2] cycloaddition reactions, and the in situ generated Lewis acid may play an important role for the successful transformation. Not only internal alkynes but also terminal alkynes undergo the desired cycloaddition reactions efficiently to furnish the carboline derivatives with wide diversity and functional group tolerance. PMID- 27966986 TI - Enhanced Graphene Photodetector with Fractal Metasurface. AB - Graphene has been demonstrated to be a promising photodetection material because of its ultrabroadband optical absorption, compatibility with CMOS technology, and dynamic tunability in optical and electrical properties. However, being a single atomic layer thick, graphene has intrinsically small optical absorption, which hinders its incorporation with modern photodetecting systems. In this work, we propose a gold snowflake-like fractal metasurface design to realize broadband and polarization-insensitive plasmonic enhancement in graphene photodetector. We experimentally obtain an enhanced photovoltage from the fractal metasurface that is an order of magnitude greater than that generated at a plain gold-graphene edge and such an enhancement in the photovoltage sustains over the entire visible spectrum. We also observed a relatively constant photoresponse with respect to polarization angles of incident light, as a result of the combination of two orthogonally oriented concentric hexagonal fractal geometries in one metasurface. PMID- 27966987 TI - Room-Temperature Skyrmion Shift Device for Memory Application. AB - Magnetic skyrmions are intensively explored for potential applications in ultralow-energy data storage and computing. To create practical skyrmionic memory devices, it is necessary to electrically create and manipulate these topologically protected information carriers in thin films, thus realizing both writing and addressing functions. Although room-temperature skyrmions have been previously observed, fully electrically controllable skyrmionic memory devices, integrating both of these functions, have not been developed to date. Here, we demonstrate a room-temperature skyrmion shift memory device, where individual skyrmions are controllably generated and shifted using current-induced spin-orbit torques. Particularly, it is shown that one can select the device operation mode in between (i) writing new single skyrmions or (ii) shifting existing skyrmions by controlling the magnitude and duration of current pulses. Thus, we electrically realize both writing and addressing of a stream of skyrmions in the device. This prototype demonstration brings skyrmions closer to real-world computing applications. PMID- 27966989 TI - Morphological Evolution of Self-Assembled Structures Induced by the Molecular Architecture of Supra-Amphiphiles. AB - A series of telechelic supramolecular amphiphiles [POSS-Azo8@(beta-CD-PDMAEMA)1 >8] was accomplished by orthogonally coupling the multiarm host polymer beta cyclodextrin-poly(dimethylaminoethyl methacrylate) (beta-CD-PDMAEMA) with an octatelechelic guest molecule azobenzene modified-polyhedral oligomeric silsesquioxanes (POSS-Azo8) under different host-guest ratios. These telechelic supramolecular amphiphiles possess a rigid core and flexible corona. Increasing the multiarm host polymer coupled onto the rigid POSS core made the molecular architecture tend to be symmetrical and spherical. POSS-Azo8@[beta-CD-PDMAEMA]1 >8 could self-assemble into diverse morphologies evolving from spherical micelles, wormlike micelles, and branched aggregates to bowl-shaped vesicles. Distinct from the traditional linear amphiphilic polymers, we discovered that the self-assembly of POSS-Azo8@[beta-CD-PDMAEMA]1->8 was dominantly regulated by their molecular architectures instead of hydrophilicity, which has also been verified using computer simulation results. PMID- 27966988 TI - Docetaxel-Loaded PLGA Nanoparticles Improve Efficacy in Taxane-Resistant Triple Negative Breast Cancer. AB - Novel treatment strategies, including nanomedicine, are needed for improving management of triple-negative breast cancer. Patients with triple-negative breast cancer, when considered as a group, have a worse outcome after chemotherapy than patients with breast cancers of other subtypes, a finding that reflects the intrinsically adverse prognosis associated with the disease. The aim of this study was to improve the efficacy of docetaxel by incorporation into a novel nanoparticle platform for the treatment of taxane-resistant triple-negative breast cancer. Rod-shaped nanoparticles encapsulating docetaxel were fabricated using an imprint lithography based technique referred to as Particle Replication in Nonwetting Templates (PRINT). These rod-shaped PLGA-docetaxel nanoparticles were tested in the C3(1)-T-antigen (C3Tag) genetically engineered mouse model (GEMM) of breast cancer that represents the basal-like subtype of triple-negative breast cancer and is resistant to therapeutics from the taxane family. This GEMM recapitulates the genetics of the human disease and is reflective of patient outcome and, therefore, better represents the clinical impact of new therapeutics. Pharmacokinetic analysis showed that delivery of these PLGA docetaxel nanoparticles increased docetaxel circulation time and provided similar docetaxel exposure to tumor compared to the clinical formulation of docetaxel, Taxotere. These PLGA-docetaxel nanoparticles improved tumor growth inhibition and significantly increased median survival time. This study demonstrates the potential of nanotechnology to improve the therapeutic index of chemotherapies and rescue therapeutic efficacy to treat nonresponsive cancers. PMID- 27966991 TI - New Insights into Aldol Reactions of Methyl Isocyanoacetate Catalyzed by Heterogenized Homogeneous Catalysts. AB - The Hayashi-Ito aldol reaction of methyl isocyanoacetate (MI) and benzaldehydes, a classic homogeneous Au(I)-catalyzed reaction, was studied with heterogenized homogeneous catalysts. Among dendrimer encapsulated nanoparticles (NPs) of Au, Pd, Rh, or Pt loaded in mesoporous supports and the homogeneous analogues, the Au NPs led to the highest yield and highest diastereoselectivity of products in toluene at room temperature. The Au catalyst was stable and was recycled for at least six runs without substantial deactivation. Moreover, larger pore sizes of the support and the use of a hydrophobic solvent led to a high selectivity for the trans diastereomer of the product. The activation energy is sensitive to neither the size of Au NPs nor the support. A linear Hammett plot was obtained with a positive slope, suggesting an increased electron density on the carbonyl carbon atom in the rate-limiting step. IR studies revealed a strong interaction between MI and the gold catalyst, supporting the proposed mechanism, in which rate-limiting step involves an electrophilic attack of the aldehyde on the enolate formed from the deprotonated MI. PMID- 27966992 TI - UGT1A10 Is a High Activity and Important Extrahepatic Enzyme: Why Has Its Role in Intestinal Glucuronidation Been Frequently Underestimated? AB - The aim of this work was to highlight a considerable and broad problem in UGT1A10 activity assessment that has led to underestimation of its role in intestinal glucuronidation of drugs and other xenobiotics. The reason appears to be poor activity of the commercial UGT1A10 that is used by many laboratories, and here we have tested it by comparison with our recombinant His-tagged UGT1A10 (designated as UGT1A10-H), both expressed in insect cells. The glucuronidation rates of morphine, estradiol, estrone, SN-38, diclofenac, 4-methylumbelliferone, 7-amino-4 methylcoumarin, N-(3-carboxypropyl)-4-hydroxy-1,8-naphthalimide, and bavachinin were assayed. The results revealed that the activity of commercial UGT1A10 was low, very low, and in the cases of morphine, estrone, 7-methyl-4-aminocoumarin, and bavachinin it was below the detection limit. On the other hand, under the same conditions, UGT1A10-H exhibited high glucuronidation rates toward all these compounds. Moreover, using estradiol, morphine, and estrone, in the presence and absence of suitable inhibitors, nilotinib or atractylenolide I, it was demonstrated that UGT1A10-H, but not the commercial UGT1A10, provides a good tool to study the role of native UGT1A10 in the human intestine. The results also suggest that much of the data in the literature on UGT1A10 activity may have to be re-evaluated. PMID- 27966994 TI - Optical Nanoimaging of Hyperbolic Surface Polaritons at the Edges of van der Waals Materials. AB - Hyperbolic polaritons in van der Waals (vdW) materials recently attract a lot of attention, owing to their strong electromagnetic field confinement, ultraslow group velocities, and long lifetimes. Typically, volume-confined hyperbolic polaritons (HPs) are studied. Here we show the first near-field optical images of hyperbolic surface polaritons (HSPs), which are confined and guided at the edges of thin flakes of a vdW material. To that end, we applied scattering-type scanning near-field optical microscopy (s-SNOM) for launching and real-space nanoimaging of hyperbolic surface phonon polariton modes on a hexagonal boron nitride (h-BN) flake. Our imaging data reveal that the fundamental HSP mode exhibits a stronger field confinement (shorter wavelength), smaller group velocities, and nearly identical lifetimes, as compared to the fundamental HP mode of the same h-BN flake. Our experimental data, corroborated by theory, establish a solid basis for future studies and applications of HPs and HSPs in vdW materials. PMID- 27966995 TI - Regioselective O-Sulfonylation of N,N-Bis(2-hydroxyalkyl)tosylamides as a Synthetic Key Step to Enantiopure Morpholines. AB - The synthesis of enantiopure 2,6-disubstituted morpholines was realized through sequential ring opening of two different optically pure oxiranes by a tosylamide, under solid-liquid phase-transfer catalysis (SL-PTC) conditions, mono-O sulfonylation of the resulting tosylamido-2,2'-diol, and cyclization to the morpholine. The crucial step, the regioselective formation of the monosulfonate, was controlled by taking advantage of the different stereo, electronic, and coordination properties of the oxirane-derived side chains in the diol backbone. As an application of this protocol, a new morpholine-3-carboxamide was synthesized starting from threonine. PMID- 27966990 TI - Site-Specific N-Glycosylation of Endothelial Cell Receptor Tyrosine Kinase VEGFR 2. AB - Vascular endothelial growth factor receptor-2 (VEGFR-2) is an important receptor tyrosine kinase (RTK) that plays critical roles in both physiologic and pathologic angiogenesis. The extracellular domain of VEGFR-2 is composed of seven immunoglobulin-like domains, each with multiple potential N-glycosylation sites (sequons). N-glycosylation plays a central role in RTK ligand binding, trafficking, and stability. However, despite its importance, the functional role of N-glycosylation of VEGFR-2 remains poorly understood. The objectives of the present study were to characterize N-glycosylation sites in VEGFR-2 via enzymatic release of the glycans and concomitant incorporation of 18O into formerly N glycosylated sites followed by tandem mass spectrometry (MS/MS) analysis to determine N-glycosylation site occupancy and the site-specific N-glycan heterogeneity of VEGFR-2 glycopeptides. The data demonstrated that all seven VEGFR-2 immunoglobulin-like domains have at least one occupied N-glycosylation site. MS/MS analyses of glycopeptides and deamidated, deglycosylated (PNGase F treated) peptides from ectopically expressed VEGFR-2 in porcine aortic endothelial (PAE) cells identified N-glycans at the majority of the 17 potential N-glycosylation sites on VEGFR-2 in a site-specific manner. The data presented here provide direct evidence for site-specific, heterogeneous N-glycosylation and N-glycosylation site occupancy on VEGFR-2. The study has important implications for the therapeutic targeting of VEGFR-2, ligand binding, trafficking, and signaling. PMID- 27966993 TI - Ring-Opening 1,3-Halochalcogenation of Cyclopropane Dicarboxylates. AB - Donor-acceptor cyclopropanes with two geminal carboxylic esters are reacted with chalcogenyl chlorides and bromides to afford ring-opened products bearing the halogen atoms in the 1-position, adjacent to the donor, and the chalcogenyl residue in the 3-position next to the two acceptor groups. A variety of different donors (e.g., aryl, N, and O) are used. The stereospecificity of the reaction is demonstrated by using a chiral starting material. PMID- 27966996 TI - One-Pot Three-Component Synthesis of Enamine-Functionalized 1,2,3-Triazoles via Cu-Catalytic Azide-Alkyne Click (CuAAC) and Cu-Catalyzed Vinyl Nitrene Transfer Sequence. AB - A number of enamine-functionalized 1,2,3-triazole derivatives have been prepared via the Cu-catalyzed three-component reaction of terminal alkyne, azide, and 2H azirine. The reaction proceeds through insertion of vinyl nitrene into the C-Cu bond of the triazolyl-Cu species, providing an efficient and step- and atom economic approach to the enamine-bearing polysubstituted 1,2,3-triazoles. The resulting triazoles were easily transformed to trisubstituted pyrazoles in the presence of a Rh catalyst. PMID- 27966997 TI - Synthesis of 5,5'-Diarylimino Quinoidal 2,2'-Bithiazoles. AB - A Pd(0)-catalyzed double C-N coupling of 5,5'-dibromo-2,2'-bithiazoles with (het)arylamines and subsequent in situ Ag2O-mediated oxidation provides access to cross-conjugated quinoidal 5,5'-diarylimino-2,2'-bithiazoles in moderate to high yield. The highly colored quinoidal 2,2'-bithiazoles were studied by UV/vis spectroscopy, cyclic voltammetry and computational methods. PMID- 27966998 TI - Synthesis and Properties of Dithiocarbamate-Linked Acenes. AB - A small set of unsymmetrically substituted acene derivatives containing either aniline or dithiocarbamate moieties was synthesized. A stepwise, one-pot procedure was used to transform appropriate acenequinones to aniline-linked acenes in one step with moderate yields. A heretofore-unreported carbon disulfide activation process involving the formation of a trialkylammonium dithiocarbamate intermediate was found to be essential to convert these acene anilines to acene dithiocarbamates. The effects of the aniline and dithiocarbamate moieties on the photophysical properties of selected acene chromophores were assessed by UV/vis absorption and fluorescence spectroscopies. PMID- 27966999 TI - Vlasov simulations of thermal plasma waves with relativistic phase velocity in a Lorentz boosted frame. AB - For certain classes of relativistic plasma problems, performing numerical calculations in a Lorentz boosted frame can be even more advantageous for gridded momentum-space-time (e.g., Vlasov) problems than has been demonstrated for position space-time problems and result in a potential reduction in the number of calculations needed by a factor ~gamma_{b}^{6}. In this study, the Lorentz boosted frame technique was applied to the problem of warm wave-breaking limits of plasma waves with relativistic phase velocity. The numerical results are consistent with analytic conclusions. By appropriate normalization and for sufficiently warm plasma, the dynamics for the Vlasov equation in different Lorentz frames were found to be independent of gamma_{p}. PMID- 27967000 TI - Finite-size scaling analysis of a nonequilibrium phase transition in the naming game model. AB - We realize an extensive numerical study of the naming game model with a noise term which accounts for perturbations. This model displays a nonequilibrium phase transition between an absorbing ordered consensus state, which occurs for small noise, and a disordered phase with fragmented clusters characterized by heterogeneous memories, which emerges at strong noise levels. The nature of the phase transition is studied by means of a finite-size scaling analysis of the moments. We observe a scaling behavior typical of a discontinuous transition and we are able to estimate the thermodynamic limit. The scaling behavior of the clusters size seems also compatible with this kind of transition. PMID- 27967001 TI - Assembly of the most topologically regular two-dimensional micro and nanocrystals with spherical, conical, and tubular shapes. AB - We consider how to control the extension of curvature-induced defects in the hexagonal order covering different curved surfaces. In these frames we propose a physical mechanism for improving structures of two-dimensional spherical colloidal crystals (SCCs). For any SCC comprising of about 300 or less particles the mechanism transforms all extended topological defects (ETDs) in the hexagonal order into the point disclinations. Perfecting the structure is carried out by successive cycles of the particle implantation and subsequent relaxation of the crystal. The mechanism is potentially suitable for obtaining colloidosomes with better selective permeability. Our approach enables modeling the most topologically regular tubular and conical two-dimensional nanocrystals including various possible polymorphic forms of the HIV viral capsid. Different HIV-like shells with an arbitrary number of structural units (SUs) and desired geometrical parameters are easily formed. Faceting of the obtained structures is performed by minimizing the suggested elastic energy. PMID- 27967002 TI - Patterning in systems driven by nonlocal external forces. AB - This work focuses on systems displaying domain patterns resulting from competing external and internal dynamics. To this end, we introduce a Lyapunov functional capable of describing the steady states of systems subject to external forces, by adding nonlocal terms to the Landau Ginzburg free energy of the system. Thereby, we extend the existing methodology treating long-range order interactions, to the case of external nonlocal forces. By studying the quadratic term of this Lyapunov functional, we compute the phase diagram in the temperature versus external field and we determine all possible modulated phases (domain patterns) as a function of the external forces and the temperature. Finally, we investigate patterning in chemical reactive mixtures and binary mixtures under irradiation, and we show that the last case opens the path toward micro-structural engineering of materials. PMID- 27967003 TI - Suppressing escape events in maps of the unit interval with demographic noise. AB - We explore the properties of discrete-time stochastic processes with a bounded state space, whose deterministic limit is given by a map of the unit interval. We find that, in the mesoscopic description of the system, the large jumps between successive iterates of the process can result in probability leaking out of the unit interval, despite the fact that the noise is multiplicative and vanishes at the boundaries. By including higher-order terms in the mesoscopic expansion, we are able to capture the non-Gaussian nature of the noise distribution near the boundaries, but this does not preclude the possibility of a trajectory leaving the interval. We propose a number of prescriptions for treating these escape events, and we compare the results with those obtained for the metastable behavior of the microscopic model, where escape events are not possible. We find that, rather than truncating the noise distribution, censoring this distribution to prevent escape events leads to results which are more consistent with the microscopic model. The addition of higher moments to the noise distribution does not increase the accuracy of the final results, and it can be replaced by the simpler Gaussian noise. PMID- 27967005 TI - Erratum: Spatiotemporal bounded noises and transitions induced by them in solutions of the real Ginzburg-Landau model [Phys. Rev. E 86, 021118 (2012)]. AB - This corrects the article DOI: 10.1103/PhysRevE.86.021118. PMID- 27967006 TI - Robustness of controlling edge dynamics in complex networks against node failure. AB - The robustness of controlling complex networks is significant in network science. In this paper, we focus on evaluating and analyzing the robustness of controlling edge dynamics in complex networks against node failure. Using three categories of all nodes to quantify the robustness, we find that the percentages of the three types of nodes are mainly related to the degree distribution of networks. The simulation results of model networks and analytic calculations show that the sparse inhomogeneous networks, which emerge in many real complex networks, have strong control robustness from the point of the number of ordinary nodes, but the strong positive correlation between in and out degrees reduces the control robustness. Evaluation of real-world networks indicates that most of them have few or no critical nodes, that is, they do not need to increase driver nodes to maintain control for most of node failures. Then an adding circuit-link strategy is proposed to optimize the robustness of edge controllability. PMID- 27967004 TI - Robustness of persistent spiking to partial synchronization in a minimal model of synaptically driven self-sustained activity. AB - We study the behavior of a minimal model of synaptically sustained persistent activity that consists of two quadratic integrate-and-fire neurons mutually coupled via excitatory synapses. Importantly, each of the neurons is excitable, as opposed to an oscillator; hence when uncoupled it sits at a subthreshold rest state. When the constituent neurons are mutually coupled via sufficiently strong fast excitatory synapses, the system demonstrates bistability between a fixed point (quiescent background state) and a limit cycle (memory state with synaptically driven spiking activity). Previous work showed that this persistent activity can be stopped by an excitatory input that synchronizes the network. Here we analyzed how this persistent state reacts to partial synchronization. We considered three types of progressively more complex excitatory synaptic kernels: delta pulse, square, and exponential. The first two cases were treated analytically, and the latter case numerically. Using phase-plane methods, we characterized the shape of the region, such that all orbits starting within it correspond to infinite spike trains; this constitutes the persistent activity region. In the case of instant coupling, all such active orbits were neutrally stable; in the case of noninstant coupling, the activity region contained a unique stable limit cycle (so the activity region was the basin of attraction for the limit cycle). This limit cycle corresponded to purely antiphase spiking of two neurons. Increasing synchronization shifted the system toward the border of the activity region, eventually terminating spiking activity. We calculated three measures of robustness of the active state: width of the activity region in the phase plane, critical level of synchronization that can be tolerated by the persistent spiking activity, and speed of reconvergence to the limit cycle. Our analysis revealed that the self-sustained activity is more robust to synchronization when each individual neuron is closer to SNIC bifurcation (closer to being an intrinsic oscillator), the recurrent synaptic excitation is stronger, and the synaptic decay is slower, which is in agreement with the existing data on local circuits in the cortex that show sustained activity. PMID- 27967007 TI - Linear irreversible thermodynamics and Onsager reciprocity for information-driven engines. AB - In the recent progress in nonequilibrium thermodynamics, information has been recognized as a kind of thermodynamic resource that can drive thermodynamic current without any direct energy injection. In this paper, we establish the framework of linear irreversible thermodynamics for a broad class of autonomous information processing. In particular, we prove that the Onsager reciprocity holds true with information: The linear response matrix is well-defined and is shown symmetric with both of the information affinity and the conventional thermodynamic affinity. As an application, we derive a universal bound for the efficiency at maximum power for information-driven engines in the linear regime. Our result reveals the fundamental role of information flow in linear irreversible thermodynamics. PMID- 27967008 TI - Fragmentation and shear band formation by slow compression of brittle porous media. AB - Localized fragmentation is an important phenomenon associated with the formation of shear bands and faults in granular media. It can be studied by empirical observation, by laboratory experiment, or by numerical simulation. Here we investigate the spatial structure and statistics of fragmentation using discrete element simulations of the strain-controlled uniaxial compression of cylindrical samples of different finite size. As the system approaches failure, damage localizes in a narrow shear band or synthetic fault "gouge" containing a large number of poorly sorted noncohesive fragments on a broad bandwidth of scales, with properties similar to those of natural and experimental faults. We determine the position and orientation of the central fault plane, the width of the shear band, and the spatial and mass distribution of fragments. The relative width of the shear band decreases as a power law of the system size, and the probability distribution of the angle of the central fault plane converges to around 30 degrees, representing an internal coefficient of friction of 0.7 or so. The mass of fragments is power law distributed, with an exponent that does not depend on scale, and is near that inferred for experimental and natural fault gouges. The fragments are in general angular, with a clear self-affine geometry. The consistency of this model with experimental and field results confirms the critical roles of preexisting heterogeneity, elastic interactions, and finite system size to grain size ratio on the development of shear bands and faults in porous media. PMID- 27967009 TI - Monosized dripping mode of axisymmetric flow focusing. AB - We identify and analyze the perfectly regular dripping mode of flow focusing. This mode occurs within narrow intervals of injected flow rates and applied pressure drops and leads to homogeneous-size droplets with diameters similar to or smaller than that of the discharge orifice. The balance between the local acceleration of the fluid particle and the applied pressure drop yields the scaling law for the droplet diameter. This scaling law is validated experimentally with excellent accord. PMID- 27967010 TI - Thermal conductance of one-dimensional materials calculated with typical lattice models. AB - We show through calculations on typical lattice models that thermal conductance sigma can well describe the near-equilibrium thermal transport property of one dimensional materials of finite length, which presents a situation often met in the application of nanoscale devices. The sigma generally contains contributions from the material itself and those from the thermal reservoirs. The intrinsic sigma of the material, i.e., the one with the fewest external influences, can be efficiently calculated with the help of the "blackbody"-like nonreflective thermal reservoir, either through the nonequilibrium method or through the Green Kubo-type formula. sigma thus calculated would be helpful to guide the design of thermal management and heat control in nanoscale devices. PMID- 27967011 TI - Optimal counter-current exchange networks. AB - We present a general analysis of exchange devices linking their efficiency to the geometry of the exchange surface and supply network. For certain parameter ranges, we show that the optimal exchanger consists of densely packed pipes which can span a thin sheet of large area (an "active layer"), which may be crumpled into a fractal surface and supplied with a fractal network of pipes. We derive the efficiencies of such exchangers, showing the potential for significant gains compared to regular exchangers (where the active layer is flat), using parameters relevant to biological systems. PMID- 27967012 TI - How mesoscopic staircases condense to macroscopic barriers in confined plasma turbulence. AB - This Rapid Communication sets forth the mechanism by which mesoscale staircase structures condense to form macroscopic states of enhanced confinement. Density, vorticity, and turbulent potential enstrophy are the variables for this model. Formation of the staircase structures is due to inhomogeneous mixing of (generalized) potential vorticity (PV). Such mixing results in the local sharpening of density and vorticity gradients. When PV gradients steepen, the density staircase structure develops into a lattice of mesoscale "jumps" and "steps," which are, respectively, regions of local gradient steepening and flattening. The jumps then merge and migrate in radius, leading to the emergence of a new macroscale profile structure, so indicating that profile self organization is a global process, which may be described by a local, but nonlinear model. This work predicts and demonstrates how mesoscale condensation of staircases leads to global states of enhanced confinement. PMID- 27967013 TI - Pinning-depinning transition in a stochastic growth model for the evolution of cell colony fronts in a disordered medium. AB - We study a stochastic lattice model for cell colony growth, which takes into account proliferation, diffusion, and rotation of cells, in a culture medium with quenched disorder. The medium is composed of sites that inhibit any possible change in the internal state of the cells, representing the disorder, as well as by active medium sites that do not interfere with the cell dynamics. By means of Monte Carlo simulations we find that the velocity of the growing interface, which is taken as the order parameter of the model, strongly depends on the density of active medium sites (rho_{A}). In fact, the model presents a (continuous) second order pinning-depinning transition at a certain critical value of rho_{A}^{crit}, such as, for rho_{A}>rho_{A}^{crit}, the interface moves freely across the disordered medium, but for rho_{A}0), and then the rest state (A_{0}=0) reenters into the EC (A_{0}=1); eventually, it develops into complicated EC(A_{0}>1). The reversed bell-shaped behavior of A_{0}(V_{N}) is evidence of ISR. The present ISR may be explained by taking into account colored noise characterized by its intensity and correlation time. PMID- 27967019 TI - Slow passage through thresholds in quantum dot lasers. AB - A turn on of a quantum dot (QD) semiconductor laser simultaneously operating at the ground state (GS) and excited state (ES) is investigated both experimentally and theoretically. We find experimentally that the slow passage through the two successive laser thresholds may lead to significant delays in the GS and ES turn ons. The difference between the turn-on times is measured as a function of the pump rate of change E and reveals no clear power law. This has motivated a detailed analysis of rate equations appropriate for two-state lasing QD lasers. We find that the effective time of the GS turn on follows an E^{-1/2} power law provided that the rate of change is not too small. The effective time of the ES transition follows an E^{-1} power law, but its first order correction in ln(E) is numerically significant. The two turn ons result from different physical mechanisms. The delay of the GS transition strongly depends on the slow growth of the dot population, whereas the ES transition only depends on the time needed to leave a repellent steady state. PMID- 27967020 TI - Splitting nodes and linking channels: A method for assembling biocircuits from stochastic elementary units. AB - Akin to electric circuits, we construct biocircuits that are manipulated by cutting and assembling channels through which stochastic information flows. This diagrammatic manipulation allows us to create a method which constructs networks by joining building blocks selected so that (a) they cover only basic processes; (b) it is scalable to large networks; (c) the mean and variance-covariance from the Pauli master equation form a closed system; and (d) given the initial probability distribution, no special boundary conditions are necessary to solve the master equation. The method aims to help with both designing new synthetic signaling pathways and quantifying naturally existing regulatory networks. PMID- 27967021 TI - Nonuniqueness of local stress of three-body potentials in molecular simulations. AB - Microscopic stress fields are widely used in molecular simulations to understand mechanical behavior. Recently, decomposition methods of multibody forces to central force pairs between the interacting particles have been proposed. Here, we introduce a force center of a three-body potential and propose different force decompositions that also satisfy the conservation of translational and angular momentum. We compare the force decompositions by stress-distribution magnitude and discuss their difference in the stress profile of a bilayer membrane by using coarse-grained and atomistic molecular dynamics simulations. PMID- 27967022 TI - Locking induced by distance-dependent delay in neuronal networks. AB - In the present paper, the locking phenomenon induced by distance-dependent delay in ring structured neuronal networks is investigated, wherein each neuron is modeled by a FitzHugh-Nagumo neuron. Through increasing the element time delay, the different spatiotemporal patterns are observed. By calculating the interspike interval and its value that is divided by the delay of the nearest neurons, it is found that these patterns are actually the lockings between the period of spiking and the distance-dependent delay of the connected neurons. The lockings could also be revealed by the mean time lag of the neurons and in different connection topologies. Furthermore, the influences of the network size and the coupling strength are investigated, wherein the former seems to play a negligible role on these locking patterns; in contrast, too small coupling strengths will blur the boundaries of different patterns and too large ones may destroy the high ratio locking patterns. Finally, one may predict the locking order which determines the emergence order of the patterns in the networks. PMID- 27967023 TI - Properties of low-dimensional collective variables in the molecular dynamics of biopolymers. AB - The description of the dynamics of a complex, high-dimensional system in terms of a low-dimensional set of collective variables Y can be fruitful if the low dimensional representation satisfies a Langevin equation with drift and diffusion coefficients that depend only on Y. We present a computational scheme to evaluate whether a given collective variable provides a faithful low-dimensional representation of the dynamics of a high-dimensional system. The scheme is based on the framework of a finite-difference Langevin equation, similar to that used for molecular-dynamics simulations. This allows one to calculate the drift and diffusion coefficients in any point of the full-dimensional system. The width of the distribution of drift and diffusion coefficients in an ensemble of microscopic points at the same value of Y indicates to what extent the dynamics of Y is described by a simple Langevin equation. Using a simple protein model, we show that collective variables often used to describe biopolymers display a non negligible width both in the drift and in the diffusion coefficients. We also show that the associated effective force is compatible with the equilibrium free energy calculated from a microscopic sampling, but it results in markedly different dynamical properties. PMID- 27967024 TI - Relaxation of a simulated lipid bilayer vesicle compressed by an atomic force microscope. AB - Using coarse-grained molecular dynamics simulations, we study the relaxation of bilayer vesicles, uniaxially compressed by an atomic force microscope cantilever. The relaxation time exhibits a strong force dependence. Force-compression curves are very similar to recent experiments wherein giant unilamellar vesicles were compressed in a nearly identical manner. PMID- 27967025 TI - Effect of long-range interactions on the phase transition of Axelrod's model. AB - Axelrod's model with F=2 cultural features, where each feature can assume k states drawn from a Poisson distribution of parameter q, exhibits a continuous nonequilibrium phase transition in the square lattice. Here we use extensive Monte Carlo simulations and finite-size scaling to study the critical behavior of the order parameter rho, which is the fraction of sites that belong to the largest domain of an absorbing configuration averaged over many runs. We find that it vanishes as rho~(q_{c}^{0}-q)^{beta} with beta~0.25 at the critical point q_{c}^{0}~3.10 and that the exponent that measures the width of the critical region is nu^{0}~2.1. In addition, we find that introduction of long-range links by rewiring the nearest-neighbors links of the square lattice with probability p turns the transition discontinuous, with the critical point q_{c}^{p} increasing from 3.1 to 27.17, approximately, as p increases from 0 to 1. The sharpness of the threshold, as measured by the exponent nu^{p}~1 for p>0, increases with the square root of the number of nodes of the resulting small-world network. PMID- 27967027 TI - Dynamic multiscaling in magnetohydrodynamic turbulence. AB - We present a study of the multiscaling of time-dependent velocity and magnetic field structure functions in homogeneous, isotropic magnetohydrodynamic (MHD) turbulence in three dimensions. We generalize the formalism that has been developed for analogous studies of time-dependent structure functions in fluid turbulence to MHD. By carrying out detailed numerical studies of such time dependent structure functions in a shell model for three-dimensional MHD turbulence, we obtain both equal-time and dynamic scaling exponents. PMID- 27967026 TI - Phase behavior of a binary fluid mixture of quadrupolar molecules. AB - We propose a model molecule to investigate microscopic properties of a binary mixture with a closed-loop coexistence region. The molecule is comprised of a Lennard-Jones particle and a uniaxial quadrupole. Gibbs ensemble Monte Carlo simulations demonstrate that the high-density binary fluid of the molecules with the quadrupoles of the same magnitude but of the opposite signs can show closed loop immiscibility. We find that an increase in the magnitude of the quadrupoles causes a shrinkage of the coexistence region. Molecular dynamics simulations also reveal that aggregates with two types of molecules arranged alternatively are formed in the stable one-phase region both above and below the coexistence region. String structures are dominant below the lower critical solution temperature, while branched aggregates are observed above the upper critical solution temperature. We conclude that the anisotropic interaction between the quadrupoles of the opposite signs plays a crucial role in controlling these properties of the phase behavior. PMID- 27967028 TI - Laser propagation measurements in long-scale-length underdense plasmas relevant to magnetized liner inertial fusion. AB - We report experimental results and simulations showing efficient laser energy coupling into plasmas at conditions relevant to the magnetized liner inertial fusion (MagLIF) concept. In MagLIF, to limit convergence and increase the hydrodynamic stability of the implosion, the fuel must be efficiently preheated. To determine the efficiency and physics of preheating by a laser, an Ar plasma with n_{e}/n_{crit}~0.04 is irradiated by a multi-ns, multi-kJ, 0.35-MUm, phase plate-smoothed laser at spot-averaged intensities ranging from 1.0*10^{14} to 2.5*10^{14}W/cm^{2} and pulse widths from 2 to 10 ns. Time-resolved x-ray images of the laser-heated plasma are compared to two-dimensional radiation-hydrodynamic simulations that show agreement with the propagating emission front, a comparison that constrains laser energy deposition to the plasma. The experiments show that long-pulse, modest-intensity (I=1.5*10^{14}W/cm^{2}) beams can efficiently couple energy (~82% of the incident energy) to MagLIF-relevant long-length (9.5 mm) underdense plasmas. The demonstrated heating efficiency is significantly higher than is thought to have been achieved in early integrated MagLIF experiments [A. B. Sefkow et al., Phys. Plasmas 21, 072711 (2014)10.1063/1.4890298]. PMID- 27967029 TI - Work extraction and energy storage in the Dicke model. AB - We study work extraction from the Dicke model achieved using simple unitary cyclic transformations keeping into account both a nonoptimal unitary protocol and the energetic cost of creating the initial state. By analyzing the role of entanglement, we find that highly entangled states can be inefficient for energy storage when considering the energetic cost of creating the state. Such a surprising result holds notwithstanding the fact that the criticality of the model at hand can sensibly improve the extraction of work. While showing the advantages of using a many-body system for work extraction, our results demonstrate that entanglement is not necessarily advantageous for energy storage purposes, when nonoptimal processes are considered. Our work shows the importance of better understanding the complex interconnections between nonequilibrium thermodynamics of quantum systems and correlations among their subparts. PMID- 27967030 TI - Stochastic resonance subject to multiplicative and additive noise: The influence of potential asymmetries. AB - The influence of potential asymmetries on stochastic resonance (SR) subject to both multiplicative and additive noise is studied by using two-state theory, where three types of asymmetries are introduced in double-well potential by varying the depth, the width, and both the depth and the width of the left well alone. The characteristics of SR in the asymmetric cases are different from symmetric ones, where asymmetry has a strong influence on output signal-to-noise ratio (SNR) and optimal noise intensity. Even optimal noise intensity is also associated with the steepness of the potential-barrier wall, which is generally ignored. Moreover, the largest SNR in asymmetric SR is found to be relatively larger than the symmetric one, which also closely depends on noise intensity ratio. In addition, a moderate cross-correlation intensity between two noises is good for improving the output SNR. More interestingly, a double SR phenomenon is observed in certain cases for two correlated noises, whereas it disappears for two independent noises. The above clues are helpful in achieving weak signal detection under heavy background noise. PMID- 27967031 TI - Two-frequency forcing of droplet rebounds on a liquid bath. AB - Droplets can bounce indefinitely on a liquid bath vertically vibrated in a sinusoidal fashion. We here present experimental results that extend this observation to forcing signals composed of a combination of two commensurable frequencies. The Faraday and Goodridge thresholds are characterized. Then a number of vertical bouncing modes are reported, including walkers. The vertical motion can become chaotic, in which case the horizontal motion is an alternation of walk and stop. PMID- 27967032 TI - Shock wave in a one-dimensional granular chain under Hertz contact. AB - The shock wave in one-dimensional bead chain is studied numerically. When the shock wave arrives, the bead velocity oscillates around the piston velocity. It is found that the shock front is composed of several solitary waves and the limitation of the maximum bead velocity is 2 times the piston velocity in the limiting case where the initial overlap is zero. If the initial overlap is not zero, then the maximum bead velocity is less than 2 times the piston velocity but larger than the piston velocity. As the initial overlap increases from zero to the finite value, the shock velocity depends on not only the piston velocity but also the initial overlap. The crossover of the dependence of the shock velocity on the piston velocity from the zero initial prestress to the finite value is obtained in the present manuscript. It is an improvement of the results presented in Phys. Rev. Lett. 108, 058001 (2012)10.1103/PhysRevLett.108.058001. In other words, the dependence of the shock velocity on the parameters of the granular materials is given. PMID- 27967033 TI - Symmetry breaking in clogging for oppositely driven particles. AB - The clogging behavior of a symmetric binary mixture of colloidal particles that are driven in opposite directions through constrictions is explored by Brownian dynamics simulations and theory. A dynamical state with a spontaneously broken symmetry occurs where one species is flowing and the other is blocked for a long time, which can be tailored by the size of the constrictions. Moreover, we find self-organized oscillations in clogging and unclogging of the two species. Apart from statistical physics, our results are of relevance for fields like biology, chemistry, and crowd management, where ions, microparticles, pedestrians, or other particles are driven in opposite directions through constrictions. PMID- 27967034 TI - Irreversibility of the two-dimensional enstrophy cascade. AB - We study the time irreversibility of the direct cascade in two-dimensional turbulence by looking at the time derivative of the square vorticity along Lagrangian trajectories, a quantity called metenstrophy. By means of extensive direct numerical simulations we measure the time irreversibility from the asymmetry of the probability density function of the metenstrophy and we find that it increases with the Reynolds number of the cascade, similarly to what is found in three-dimensional turbulence. A detailed analysis of the different contributions to the enstrophy budget reveals a remarkable difference with respect to what is observed for the energy cascade, in particular the role of the statistics of the forcing to determine the degree of irreversibility. PMID- 27967035 TI - One-dimensional model and solutions for creeping gas flows in the approximation of uniform pressure. AB - A model, along with analytical and numerical solutions, is presented to describe a wide variety of one-dimensional slow flows of compressible heat-conductive fluids. The model is based on the approximation of uniform pressure valid for the flows, in which the sound propagation time is much shorter than the duration of any meaningful density variation in the system. The energy balance is described by the heat equation that is solved independently. This approach enables the explicit solution for the fluid velocity to be obtained. Interfacial and volumetric heat and mass sources as well as boundary motion are considered as possible sources of density variation in the fluid. A set of particular tasks is analyzed for different motion sources in planar, axial, and central symmetries in the quasistationary limit of heat conduction (i.e., for large Fourier number). The analytical solutions are in excellent agreement with corresponding numerical solutions of the whole system of the Navier-Stokes equations. This work deals with the ideal gas. The approach is also valid for other equations of state. PMID- 27967036 TI - Emergent interparticle interactions in thermal amorphous solids. AB - Amorphous media at finite temperatures, be them liquids, colloids, or glasses, are made of interacting particles that move chaotically due to thermal energy, continuously colliding and scattering off each other. When the average configuration in these systems relaxes only at long times, one can introduce effective interactions that keep the mean positions in mechanical equilibrium. We introduce a framework to determine the effective force laws that define an effective Hessian that can be employed to discuss stability properties and the density of states of the amorphous system. We exemplify the approach with a thermal glass of hard spheres; these experience zero forces when not in contact and infinite forces when they touch. Close to jamming we recapture the effective interactions that at temperature T depend on the gap h between spheres as T/h [C. Brito and M. Wyart, Europhys. Lett. 76, 149 (2006)EULEEJ0295 507510.1209/epl/i2006-10238-x]. For hard spheres at lower densities or for systems whose binary bare interactions are longer ranged (at any density), the emergent force laws include ternary, quaternary, and generally higher-order many body terms, leading to a temperature-dependent effective Hessian. PMID- 27967037 TI - Memory states in small arrays of Josephson junctions. AB - We study memory states of a circuit consisting of a small inductively coupled Josephson junction array and introduce basic (write, read, and reset) memory operations logics of the circuit. The presented memory operation paradigm is fundamentally different from conventional single quantum flux operation logics. We calculate stability diagrams of the zero-voltage states and outline memory states of the circuit. We also calculate access times and access energies for basic memory operations. PMID- 27967039 TI - Energetics of synchronization in coupled oscillators rotating on circular trajectories. AB - We derive a concise and general expression of the energy dissipation rate for coupled oscillators rotating on circular trajectories by unifying the nonequilibrium aspects with the nonlinear dynamics via stochastic thermodynamics. In the framework of phase oscillator models, it is known that the even and odd parts of the coupling function express the effect on collective and relative dynamics, respectively. We reveal that the odd part always decreases the dissipation upon synchronization, while the even part yields a characteristic square-root change of the dissipation near the bifurcation point whose sign depends on the specific system parameters. We apply our theory to hydrodynamically coupled Stokes spheres rotating on circular trajectories that can be interpreted as a simple model of synchronization of coupled oscillators in a biophysical system. We show that the coupled Stokes spheres gain the ability to do more work on the surrounding fluid as the degree of phase synchronization increases. PMID- 27967038 TI - Dynamics of disk pairs in a nematic liquid crystal. AB - We use a hybrid lattice Boltzmann method to study the behavior of sets of ferromagnetic colloidal disks in a nematic liquid crystal. When a weak rotating magnetic field acts on the system, the disks rotate following the magnetic field. This leads to a distortion in the liquid crystal that drives translational motion of the disks. If the concentration of disks is high, disks get locked together: a stable chain configuration is created, where each disk lays on the nearest neighbor. For intermediate concentrations of disks, a different behavior is observed. When disks are rotated by the magnetic field by more than 90^{?} from their initial orientation, the distortion in the liquid crystal leads to a simultaneous flip of both disks. The final disk positions depends only weakly on the initial configuration. Consecutive rotations of magnetic field push disks towards an equidistant configuration. Periodicity of the systems studied and analysis of the flipping motion of a single disk imply that one can use weak rotating magnetic fields to create stable crystal structures of disks. PMID- 27967040 TI - What Big Data tells: Sampling the social network by communication channels. AB - Big Data has become the primary source of understanding the structure and dynamics of the society at large scale. The network of social interactions can be considered as a multiplex, where each layer corresponds to one communication channel and the aggregate of all of them constitutes the entire social network. However, usually one has information only about one of the channels or even a part of it, which should be considered as a subset or sample of the whole. Here we introduce a model based on a natural bilateral communication channel selection mechanism, which for one channel leads to consistent changes in the network properties. For example, while it is expected that the degree distribution of the whole social network has a maximum at a value larger than one, we get a monotonically decreasing distribution as observed in empirical studies of single channel data. We also find that assortativity may occur or get strengthened due to the sampling method. We analyze the far-reaching consequences of our findings. PMID- 27967041 TI - Erratum: Frequency effects on the scale and behavior of acoustic streaming [Phys. Rev. E 89, 013203 (2014)]. AB - This corrects the article DOI: 10.1103/PhysRevE.89.013203. PMID- 27967043 TI - Equivalent-neighbor Potts models in two dimensions. AB - We investigate the two-dimensional q=3 and 4 Potts models with a variable interaction range by means of Monte Carlo simulations. We locate the phase transitions for several interaction ranges as expressed by the number z of equivalent neighbors. For not-too-large z, the transitions fit well in the universality classes of the short-range Potts models. However, at longer ranges, the transitions become discontinuous. For q=3 we locate a tricritical point separating the continuous and discontinuous transitions near z=80, and a critical fixed point between z=8 and 12. For q=4 the transition becomes discontinuous for z>16. The scaling behavior of the q=4 model with z=16 approximates that of the q=4 merged critical-tricritical fixed point predicted by the renormalization scenario. PMID- 27967042 TI - High-precision estimate of the hydrodynamic radius for self-avoiding walks. AB - The universal asymptotic amplitude ratio between the gyration radius and the hydrodynamic radius of self-avoiding walks is estimated by high-resolution Monte Carlo simulations. By studying chains of length of up to N=2^{25}~34*10^{6} monomers, we find that the ratio takes the value R_{G}/R_{H}=1.5803940(45), which is several orders of magnitude more accurate than the previous state of the art. This is facilitated by a sampling scheme which is quite general and which allows for the efficient estimation of averages of a large class of observables. The competing corrections to scaling for the hydrodynamic radius are clearly discernible. We also find improved estimates for other universal properties that measure the chain dimension. In particular, a method of analysis which eliminates the leading correction to scaling results in a highly accurate estimate for the Flory exponent of nu=0.58759700(40). PMID- 27967044 TI - Extreme-value statistics of fractional Brownian motion bridges. AB - Fractional Brownian motion is a self-affine, non-Markovian, and translationally invariant generalization of Brownian motion, depending on the Hurst exponent H. Here we investigate fractional Brownian motion where both the starting and the end point are zero, commonly referred to as bridge processes. Observables are the time t_{+} the process is positive, the maximum m it achieves, and the time t_{max} when this maximum is taken. Using a perturbative expansion around Brownian motion (H=1/2), we give the first-order result for the probability distribution of these three variables and the joint distribution of m and t_{max}. Our analytical results are tested and found to be in excellent agreement, with extensive numerical simulations for both H>1/2 and H<1/2. This precision is achieved by sampling processes with a free end point and then converting each realization to a bridge process, in generalization to what is usually done for Brownian motion. PMID- 27967045 TI - Thermodynamic geometry of minimum-dissipation driven barrier crossing. AB - We explore the thermodynamic geometry of a simple system that models the bistable dynamics of nucleic acid hairpins in single molecule force-extension experiments. Near equilibrium, optimal (minimum-dissipation) driving protocols are governed by a generalized linear response friction coefficient. Our analysis demonstrates that the friction coefficient of the driving protocols is sharply peaked at the interface between metastable regions, which leads to minimum-dissipation protocols that drive rapidly within a metastable basin, but then linger longest at the interface, giving thermal fluctuations maximal time to kick the system over the barrier. Intuitively, the same principle applies generically in free energy estimation (both in steered molecular dynamics simulations and in single molecule experiments), provides a design principle for the construction of thermodynamically efficient coupling between stochastic objects, and makes a prediction regarding the construction of evolved biomolecular motors. PMID- 27967046 TI - Interplay of Darrieus-Landau instability and weak turbulence in premixed flame propagation. AB - In this study we investigate, both numerically and experimentally, the interplay between the intrinsic Darrieus-Landau (DL) or hydrodynamic instability of a premixed flame and the moderately turbulent flow field in which the flame propagates. The objective is threefold: to establish, unambiguously, through a suitably defined marker, the presence or absence of DL-induced effects on the turbulent flame, to quantify the DL effects on the flame propagation and morphology and, finally, to asses whether such effects are mitigated or suppressed as the turbulence intensity is increased. The numerical simulations are based on a deficient reactant model which lends itself to a wealth of results from asymptotic theory, such as the determination of stability limits. The skewness of the flame curvature probability density function is identified as an unambiguous morphological marker for the presence or absence of DL effects in a turbulent environment. In addition, the turbulent propagation speed is shown to exhibit a distinct dual behavior whereby it is noticeably enhanced in the presence of DL instability while it is unchanged otherwise. Furthermore, increasing the turbulence intensity is found to be mitigating with respect to DL induced effects such as the mentioned dual behavior which disappears at higher intensities. Experimental propane and/or air Bunsen flames are also investigated, utilizing two distinct diameters, respectively, above and below the estimated DL cutoff wavelength. Curvature skewness is still clearly observed to act as a marker for DL instability while the turbulent propagation speed is concurrently enhanced in the presence of the instability. PMID- 27967047 TI - Spatial splay states and splay chimera states in coupled map lattices. AB - We study the existence and stability of splay states in the coupled sine circle map lattice system using analytic and numerical techniques. The splay states are observed for very low values of the nonlinearity parameter, i.e., for maps which deviate very slightly from the shift map case. We also observe that depending on the parameters of the system the splay state bifurcates to a mixed or chimera splay state consisting of a mixture of splay and synchronized states, together with kinks in the phases of some of the maps and then to a stable globally synchronized state. We show that these pure states and the mixed states are all temporally chaotic for our systems, and we explore the stability of these states to perturbations. Our studies may provide pointers to the behavior of systems in diverse application contexts such as Josephson junction arrays and chemical oscillations. PMID- 27967048 TI - Hydrodynamic interaction of swimming organisms in an inertial regime. AB - We numerically investigate the hydrodynamic interaction of swimming organisms at small to intermediate Reynolds number regimes, i.e., Re~O(0.1-100), where inertial effects are important. The hydrodynamic interaction of swimming organisms in this regime is significantly different from the Stokes regime for microorganisms, as well as the high Reynolds number flows for fish and birds, which involves strong flow separation and detached vortex structures. Using an archetypal swimmer model, called a "squirmer," we find that the inertial effects change the contact time and dispersion dynamics of a pair of pusher swimmers, and trigger hydrodynamic attraction for two pullers. These results are potentially important in investigating predator-prey interactions, sexual reproduction, and the encounter rate of marine organisms such as copepods, ctenophora, and larvae. PMID- 27967049 TI - Thermal fluctuations of an interface near a contact line. AB - The effect of thermal fluctuations near a contact line of a liquid interface partially wetting an impenetrable substrate is studied analytically and numerically. Promoting both the interface profile and the contact line position to random variables, we explore the equilibrium properties of the corresponding fluctuating contact line problem based on an interfacial Hamiltonian involving a "contact" binding potential. To facilitate an analytical treatment, we consider the case of a one-dimensional interface. The effective boundary condition at the contact line is determined by a dimensionless parameter that encodes the relative importance of thermal energy and substrate energy at the microscopic scale. We find that this parameter controls the transition from a partial wetting to a pseudopartial wetting state, the latter being characterized by a thin prewetting film of fixed thickness. In the partial wetting regime, instead, the profile typically approaches the substrate via an exponentially thinning prewetting film. We show that, independently of the physics at the microscopic scale, Young's angle is recovered sufficiently far from the substrate. The fluctuations of the interface and of the contact line give rise to an effective disjoining pressure, exponentially decreasing with height. Fluctuations therefore provide a regularization of the singular contact forces occurring in the corresponding deterministic problem. PMID- 27967051 TI - Solidification of supercooled water in the vicinity of a solid wall. AB - An experimental approach utilizing a Hele-Shaw cell for the investigation of the solidification of a supercooled liquid in contact with a solid wall is presented. The setup is based on an idea presented by Marin et al. [A. G. Marin et al., Phys. Rev. Lett. 113, 054301 (2014)PRLTAO0031 900710.1103/PhysRevLett.113.054301], who investigated the planar freezing of a sessile drop without supercooling. This apparatus overcomes optical distortions present when observing the freezing of sessile drops, arising due to reflections and refraction of light on the drop surface. The facility is used to investigate the freezing process of water drops, supercooled down to -20^{?}C, and to qualitatively demonstrate that the growth behavior is uninfluenced by the use of the Hele-Shaw cell. Different features during freezing, which are known for sessile water drops, are also observed with the Hele-Shaw cell. The growth morphology within the first phase of solidification is categorized according to the initial drop supercooling. Furthermore, freezing velocities within this phase are related to data available in the literature for the growth of single ice dendrites. PMID- 27967050 TI - Determining conduction patterns on a sparse electrode grid: Implications for the analysis of clinical arrhythmias. AB - We present a general method of utilizing bioelectric recordings from a spatially sparse electrode grid to compute a dynamic vector field describing the underlying propagation of electrical activity. This vector field, termed the wave-front flow field, permits quantitative analysis of the magnitude of rotational activity (vorticity) and focal activity (divergence) at each spatial point. We apply this method to signals recorded during arrhythmias in human atria and ventricles using a multipolar contact catheter and show that the flow fields correlate with corresponding activation maps. Further, regions of elevated vorticity and divergence correspond to sites identified as clinically significant rotors and focal sources where therapeutic intervention can be effective. These flow fields can provide quantitative insights into the dynamics of normal and abnormal conduction in humans and could potentially be used to enhance therapies for cardiac arrhythmias. PMID- 27967052 TI - Replica analysis for the duality of the portfolio optimization problem. AB - In the present paper, the primal-dual problem consisting of the investment risk minimization problem and the expected return maximization problem in the mean variance model is discussed using replica analysis. As a natural extension of the investment risk minimization problem under only a budget constraint that we analyzed in a previous study, we herein consider a primal-dual problem in which the investment risk minimization problem with budget and expected return constraints is regarded as the primal problem, and the expected return maximization problem with budget and investment risk constraints is regarded as the dual problem. With respect to these optimal problems, we analyze a quenched disordered system involving both of these optimization problems using the approach developed in statistical mechanical informatics and confirm that both optimal portfolios can possess the primal-dual structure. Finally, the results of numerical simulations are shown to validate the effectiveness of the proposed method. PMID- 27967053 TI - Ergostatting and thermostatting at a fixed point. AB - We propose an innovative type of ergostats and thermostats for molecular dynamics simulations. A general class of active particle swarm models is considered, where any specific total energy (alternatively any specific temperature) can be provided at a fixed point of the evolution of the swarm. We identify the extended system feedback force of the Nose-Hoover thermostat with the "internal energy" variable of active Brownian motion. PMID- 27967054 TI - Fast algorithm for a three-dimensional synthetic model of intermittent turbulence. AB - Synthetic turbulence models are useful tools that provide realistic representations of turbulence, necessary to test theoretical results, to serve as background fields in some numerical simulations, and to test analysis tools. Models of one-dimensional (1D) and 3D synthetic turbulence previously developed still required large computational resources. A "wavelet-based" model of synthetic turbulence, able to produce a field with tunable spectral law, intermittency, and anisotropy, is presented here. The rapid algorithm introduced, based on the classic p-model of intermittent turbulence, allows us to reach a broad spectral range using a modest computational effort. The model has been tested against the standard diagnostics for intermittent turbulence, i.e., the spectral analysis, the scale-dependent statistics of the field increments, and the multifractal analysis, all showing an excellent response. PMID- 27967055 TI - Publisher's Note: Breathers and rogue waves excited by all-magnonic spin-transfer torque [Phys. Rev. E 94, 042220 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevE.94.042220. PMID- 27967056 TI - Spatial instabilities in a cloud of cold atoms. AB - Cold atomic clouds have been shown to have some similarities with plasmas. Previous studies showed that such clouds exhibit instabilities induced by long range interactions. However, they did not describe the spatial properties of the dynamics. In this paper, we study experimentally the spatial nature of stochastic instabilities, and we find out that the dynamics is localized. Data are analyzed both in the spectral domain and in the spatial domain (principal component analysis). Both methods fail to describe the dynamics in terms of eigenmodes, showing that space and time are not separable. PMID- 27967058 TI - Penetration in bimodal, polydisperse granular material. AB - We investigate the impact penetration of spheres into granular media which are compositions of two discrete size ranges, thus creating a polydisperse bimodal material. We examine the penetration depth as a function of the composition (volume fractions of the respective sizes) and impact speed. Penetration depths were found to vary between delta=0.5D_{0} and delta=7D_{0}, which, for mono-modal media only, could be correlated in terms of the total drop height, H=h+delta, as in previous studies, by incorporating correction factors for the packing fraction. Bimodal data can only be collapsed by deriving a critical packing fraction for each mass fraction. The data for the mixed grains exhibit a surprising lubricating effect, which was most significant when the finest grains [d_{s}~O(30) MUm] were added to the larger particles [d_{l}~O(200-500) MUm], with a size ratio, epsilon=d_{l}/d_{s}, larger than 3 and mass fractions over 25%, despite the increased packing fraction. We postulate that the small grains get between the large grains and reduce their intergrain friction, only when their mass fraction is sufficiently large to prevent them from simply rattling in the voids between the large particles. This is supported by our experimental observations of the largest lubrication effect produced by adding small glass beads to a bed of large sand particles with rough surfaces. PMID- 27967057 TI - Stochastic disks that roll. AB - We study a model of rolling particles subject to stochastic fluctuations, which may be relevant in systems of nano- or microscale particles where rolling is an approximation for strong static friction. We consider the simplest possible nontrivial system: a linear polymer of three disks constrained to remain in contact and immersed in an equilibrium heat bath so the internal angle of the polymer changes due to stochastic fluctuations. We compare two cases: one where the disks can slide relative to each other and the other where they are constrained to roll, like gears. Starting from the Langevin equations with arbitrary linear velocity constraints, we use formal homogenization theory to derive the overdamped equations that describe the process in configuration space only. The resulting dynamics have the formal structure of a Brownian motion on a Riemannian or sub-Riemannian manifold, depending on if the velocity constraints are holonomic or nonholonomic. We use this to compute the trimer's equilibrium distribution with and without the rolling constraints. Surprisingly, the two distributions are different. We suggest two possible interpretations of this result: either (i) dry friction (or other dissipative, nonequilibrium forces) changes basic thermodynamic quantities like the free energy of a system, a statement that could be tested experimentally, or (ii) as a lesson in modeling rolling or friction more generally as a velocity constraint when stochastic fluctuations are present. In the latter case, we speculate there could be a "roughness" entropy whose inclusion as an effective force could compensate the constraint and preserve classical Boltzmann statistics. Regardless of the interpretation, our calculation shows the word "rolling" must be used with care when stochastic fluctuations are present. PMID- 27967059 TI - Influence of Xe and Kr impurities on x-ray yield from debris-free plasma x-ray sources with an Ar supersonic gas jet irradiated by femtosecond near-infrared wavelength laser pulses. AB - Many aspects of physical phenomena occurring when an intense laser pulse with subpicosecond duration and an intensity of 10^{18}-10^{19}W/cm^{2} heats an underdense plasma in a supersonic clustered gas jet are studied to determine the relative contribution of thermal and nonthermal processes to soft- and hard-x-ray emission from debris-free plasmas. Experiments were performed at the University of Nevada, Reno (UNR) Leopard laser operated with a 15-J, 350-fs pulse and different pulse contrasts (10^{7} or 10^{5}). The supersonic linear (elongated) nozzle generated Xe cluster-monomer gas jets as well as jets with Kr-Ar or Xe-Kr Ar mixtures with densities of 10^{18}-10^{19}cm^{-3}. Prior to laser heating experiments, all jets were probed with optical interferometry and Rayleigh scattering to measure jet density and cluster distribution parameters. The supersonic linear jet provides the capability to study the anisotropy of x-ray yield from laser plasma and also laser beam self-focusing in plasma, which leads to efficient x-ray generation. Plasma diagnostics included x-ray diodes, pinhole cameras, and spectrometers. Jet signatures of x-ray emission from pure Xe gas, as well as from a mixture with Ar and Kr, was found to be very different. The most intense x-ray emission in the 1-9 KeV spectral region was observed from gas mixtures rather than pure Xe. Also, this x-ray emission was strongly anisotropic with respect to the direction of laser beam polarization. Non-local thermodynamic equilibrium (Non-LTE) models have been implemented to analyze the x-ray spectra to determine the plasma temperature and election density. Evidence of electron beam generation in the supersonic jet plasma was found. The influence of the subpicosecond laser pulse contrast (a ratio between the laser peak intensity and pedestal pulse intensity) on the jets' x-ray emission characteristics is discussed. Surprisingly, it was found that the x-ray yield was not sensitive to the prepulse contrast ratio. PMID- 27967060 TI - Recovery of couplings and parameters of elements in networks of time-delay systems from time series. AB - We propose a method for the recovery of coupling architecture and the parameters of elements in networks consisting of coupled oscillators described by delay differential equations. For each oscillator in the network, we introduce an objective function characterizing the distance between the points of the reconstructed nonlinear function. The proposed method is based on the minimization of this objective function and the separation of the recovered coupling coefficients into significant and insignificant coefficients. The efficiency of the method is shown for chaotic time series generated by model equations of diffusively coupled time-delay systems and for experimental chaotic time series gained from coupled electronic oscillators with time-delayed feedback. PMID- 27967061 TI - Magnetic resonance imaging measurements evidence weak dispersion in homogeneous porous media. AB - We measure the dispersion coefficient through homogeneous bead or sand packings at different flow rates from direct magnetic resonance imaging (MRI) visualizations of the transport characteristics of a pulse of paramagnetic nanoparticles. Through two-dimensional imaging we observe homogeneous dispersion inside the sample, but we show that entrance effects may induce significant radial heterogeneities, which would affect the interpretation of the breakthrough curve. Another MRI approach then provides quantitative measurements of the evolution in time of the longitudinal particle distribution in the sample. These data can be analyzed to deduce the coefficient of dispersion independently of entrance effects. The values obtained for this "effective" dispersion coefficient are almost ten times lower than the commonly accepted values. PMID- 27967062 TI - Convex hulls of multiple random walks: A large-deviation study. AB - We study the polygons governing the convex hull of a point set created by the steps of n independent two-dimensional random walkers. Each such walk consists of T discrete time steps, where x and y increments are independent and identically distributed Gaussian. We analyze area A and perimeter L of the convex hulls. We obtain probability densities for these two quantities over a large range of the support by using a large-deviation approach allowing us to study densities below 10^{-900}. We find that the densities exhibit in the limit T->infinity a time independent scaling behavior as a function of A/T and L/sqrt[T], respectively. As in the case of one walker (n=1), the densities follow Gaussian distributions for L and sqrt[A], respectively. We also obtained the rate functions for the area and perimeter, rescaled with the scaling behavior of their maximum possible values, and found limiting functions for T->infinity, revealing that the densities follow the large-deviation principle. These rate functions can be described by a power law for n->infinity as found in the n=1 case. We also investigated the behavior of the averages as a function of the number of walks n and found good agreement with the predicted behavior. PMID- 27967063 TI - Elimination of numerical Cherenkov instability in flowing-plasma particle-in-cell simulations by using Galilean coordinates. AB - Particle-in-cell (PIC) simulations of relativistic flowing plasmas are of key interest to several fields of physics (including, e.g., laser-wakefield acceleration, when viewed in a Lorentz-boosted frame) but remain sometimes infeasible due to the well-known numerical Cherenkov instability (NCI). In this article, we show that, for a plasma drifting at a uniform relativistic velocity, the NCI can be eliminated by simply integrating the PIC equations in Galilean coordinates that follow the plasma (also sometimes known as comoving coordinates) within a spectral analytical framework. The elimination of the NCI is verified empirically and confirmed by a theoretical analysis of the instability. Moreover, it is shown that this method is applicable both to Cartesian geometry and to cylindrical geometry with azimuthal Fourier decomposition. PMID- 27967064 TI - Derivation of Hodgkin-Huxley equations for a Na^{+} channel from a master equation for coupled activation and inactivation. AB - The Na^{+} current in nerve and muscle membranes may be described in terms of the activation variable m(t) and the inactivation variable h(t), which are dependent on the transitions of S4 sensors of each of the Na^{+} channel domains DI to DIV. The time-dependence of the Na^{+} current and the rate equations satisfied by m(t) and h(t) may be derived from the solution to a master equation that describes the coupling between two or three activation sensors regulating the Na^{+} channel conductance and a two-stage inactivation process. If the inactivation rate from the closed or open states increases as the S4 sensors activate, a more general form of the Hodgkin-Huxley expression for the open-state probability may be derived where m(t) is dependent on both activation and inactivation processes. The voltage dependence of the rate functions for inactivation and recovery from inactivation are consistent with the empirically determined expressions and exhibit saturation for both depolarized and hyperpolarized clamp potentials. PMID- 27967065 TI - Phonon transport in a one-dimensional harmonic chain with long-range interaction and mass disorder. AB - Atomic mass and interatomic interaction are the two key quantities that significantly affect the heat conduction carried by phonons. Here, we study the effects of long-range (LR) interatomic interaction and mass disorder on the phonon transport in a one-dimensional harmonic chain with up to 10^{5} atoms. We find that while LR interaction reduces the transmission of low-frequency phonons, it enhances the transmission of high-frequency phonons by suppressing the localization effects caused by mass disorder. Therefore, LR interaction is able to boost heat conductance in the high-temperature regime or in the large size regime, where the high-frequency modes are important. PMID- 27967066 TI - Numerical investigation of initial condition effects on Rayleigh-Taylor instability with acceleration reversals. AB - The influence of initial conditions on miscible incompressible baroclinically driven Rayleigh-Taylor instability undergoing nonuniform acceleration is explored computationally using an implicit large eddy simulation (ILES) technique. We consider the particular case of evolution during multiple reversals of acceleration direction, where the flow is alternately statically stable or unstable. In the unstable phase, the flow is driven by the baroclinic release of potential energy, whereas in the stable phase, work is done against the density stratification with the energy exchange taking place by wavelike mechanisms. These dynamics are fundamentally different; here, we track the evolution of volume-averaged turbulent statistics that are most sensitive to changes in the distribution of spectral power and bandwidth of the initial conditions as the flow alternates between dynamical regimes due to acceleration reversal. PMID- 27967068 TI - Cooperativity at the glass transition: A perspective from facilitation on the analysis of relaxation in modulated calorimetry. AB - The glass transition region in nonconfined polymeric and low-molecular-weight supercooled liquids is probed by temperature-modulated calorimetry at a frequency of 3.3 mHz. From the distribution of relaxation times derived by analyzing the complex heat capacity, the number N_{alpha} of cooperatively rearranging units is estimated. This is done by resorting to a method in which cooperative motion is viewed as a result of a spontaneous regression of energy fluctuations. After a first, local, structural transition occurs, the energy threshold for the rearrangement of adjacent molecular units decreases progressively. This facilitation process is associated to a corresponding evolution of the density of states in a canonical representation and may be considered as a continuous spanning through different dynamic states toward a condition in which configurational constraints disappear. A good agreement is found with the N_{alpha} values obtained from the same calorimetric data within the framework of Donth's fluctuation theory. It is shown that, at variance from previous treatments, N_{alpha} can be estimated from just the relaxation function, without resorting to the knowledge of the configurational entropy. Examples point to a modest dependence of the N_{alpha} estimates on the experimental method used to derive the relaxation function. PMID- 27967067 TI - How long do particles spend in vortical regions in turbulent flows? AB - We obtain the probability distribution functions (PDFs) of the time that a Lagrangian tracer or a heavy inertial particle spends in vortical or strain dominated regions of a turbulent flow, by carrying out direct numerical simulations of such particles advected by statistically steady, homogeneous, and isotropic turbulence in the forced, three-dimensional, incompressible Navier Stokes equation. We use the two invariants, Q and R, of the velocity-gradient tensor to distinguish between vortical and strain-dominated regions of the flow and partition the Q-R plane into four different regions depending on the topology of the flow; out of these four regions two correspond to vorticity-dominated regions of the flow and two correspond to strain-dominated ones. We obtain Q and R along the trajectories of tracers and heavy inertial particles and find out the time t_{pers} for which they remain in one of the four regions of the Q-R plane. We find that the PDFs of t_{pers} display exponentially decaying tails for all four regions for tracers and heavy inertial particles. From these PDFs we extract characteristic time scales, which help us to quantify the time that such particles spend in vortical or strain-dominated regions of the flow. PMID- 27967069 TI - Systems-level approach to uncovering diffusive states and their transitions from single-particle trajectories. AB - The stochastic motions of a diffusing particle contain information concerning the particle's interactions with binding partners and with its local environment. However, an accurate determination of the underlying diffusive properties, beyond normal diffusion, has remained challenging when analyzing particle trajectories on an individual basis. Here, we introduce the maximum-likelihood estimator (MLE) for confined diffusion and fractional Brownian motion. We demonstrate that this MLE yields improved estimation over traditional mean-square displacement analyses. We also introduce a model selection scheme (that we call mleBIC) that classifies individual trajectories to a given diffusion mode. We demonstrate the statistical limitations of classification via mleBIC using simulated data. To overcome these limitations, we introduce a version of perturbation expectation maximization (pEMv2), which simultaneously analyzes a collection of particle trajectories to uncover the system of interactions that give rise to unique normal and/or non-normal diffusive states within the population. We test and evaluate the performance of pEMv2 on various sets of simulated particle trajectories, which transition among several modes of normal and non-normal diffusion, highlighting the key considerations for employing this analysis methodology. PMID- 27967070 TI - Anomalous structural transition of confined hard squares. AB - Structural transitions are examined in quasi-one-dimensional systems of freely rotating hard squares, which are confined between two parallel walls. We find two competing phases: one is a fluid where the squares have two sides parallel to the walls, while the second one is a solidlike structure with a zigzag arrangement of the squares. Using transfer matrix method we show that the configuration space consists of subspaces of fluidlike and solidlike phases, which are connected with low probability microstates of mixed structures. The existence of these connecting states makes the thermodynamic quantities continuous and precludes the possibility of a true phase transition. However, thermodynamic functions indicate strong tendency for the phase transition and our replica exchange Monte Carlo simulation study detects several important markers of the first order phase transition. The distinction of a phase transition from a structural change is practically impossible with simulations and experiments in such systems like the confined hard squares. PMID- 27967072 TI - Synchronization of coupled noisy oscillators: Coarse graining from continuous to discrete phases. AB - The theoretical description of synchronization phenomena often relies on coupled units of continuous time noisy Markov chains with a small number of states in each unit. It is frequently assumed, either explicitly or implicitly, that coupled discrete-state noisy Markov units can be used to model mathematically more complex coupled noisy continuous phase oscillators. In this work we explore conditions that justify this assumption by coarse graining continuous phase units. In particular, we determine the minimum number of states necessary to justify this correspondence for Kuramoto-like oscillators. PMID- 27967071 TI - Radiative transfer of acoustic waves in continuous complex media: Beyond the Helmholtz equation. AB - Heterogeneity can be accounted for by a random potential in the wave equation. For acoustic waves in a fluid with fluctuations of both density and compressibility (as well as for electromagnetic waves in a medium with fluctuation of both permittivity and permeability) the random potential entails a scalar and an operator contribution. For simplicity, the latter is usually overlooked in multiple scattering theory: whatever the type of waves, this simplification amounts to considering the Helmholtz equation with a sound speed c depending on position r. In this work, a radiative transfer equation is derived from the wave equation, in order to study energy transport through a multiple scattering medium. In particular, the influence of the operator term on various transport parameters is studied, based on the diagrammatic approach of multiple scattering. Analytical results are obtained for fundamental quantities of transport theory such as the transport mean-free path l^{*}, scattering phase function f, and anisotropy factor g. Discarding the operator term in the wave equation is shown to have a significant impact on f and g, yet limited to the low frequency regime, i.e., when the correlation length of the disorder l_{c} is smaller than or comparable to the wavelength lambda. More surprisingly, discarding the operator part has a significant impact on the transport mean-free path l^{*} whatever the frequency regime. When the scalar and operator terms have identical amplitudes, the discrepancy on the transport mean-free path is around 300% in the low-frequency regime, and still above 30% for l_{c}/lambda=10^{3} no matter how weak fluctuations of the disorder are. Analytical results are supported by numerical simulations of the wave equation and Monte Carlo simulations. PMID- 27967073 TI - Summation of the spectra of all partially resolved transition arrays in a supertransition array. AB - It is shown that the contributions of all partially resolved transition arrays (PRTAs) to the spectrum of a supertransition array (STA) may be summed by an efficient analytical method. The method is similar to the configurationally resolved super transition array method [G. Hazak and Y. Kurzweil, High Energy Density Phys. 8, 290 (2012)1574-181810.1016/j.hedp.2012.05.001] and avoids the Gaussianity assumption of the partially resolved super transition arrays method [B. G. Wilson, C. A. Iglesias, and M. H. Chen High Energy Density Phys. 14, 67 (2015)1574-181810.1016/j.hedp.2015.02.007], thus yielding an STA spectrum which is resolved down to the PRTA level. PMID- 27967074 TI - Tightening the uncertainty principle for stochastic currents. AB - We connect two recent advances in the stochastic analysis of nonequilibrium systems: the (loose) uncertainty principle for the currents, which states that statistical errors are bounded by thermodynamic dissipation, and the analysis of thermodynamic consistency of the currents in the light of symmetries. Employing the large deviation techniques presented by Gingrich et al. [Phys. Rev. Lett. 116, 120601 (2016)PRLTAO0031-900710.1103/PhysRevLett.116.120601] and Pietzonka, Barato, and Seifert [Phys. Rev. E 93, 052145 (2016)2470 004510.1103/PhysRevE.93.052145], we provide a short proof of the loose uncertainty principle, and prove a tighter uncertainty relation for a class of thermodynamically consistent currents J. Our bound involves a measure of partial entropy production, that we interpret as the least amount of entropy that a system sustaining current J can possibly produce, at a given steady state. We provide a complete mathematical discussion of quadratic bounds which allows one to determine which are optimal, and finally we argue that the relationship for the Fano factor of the entropy production rate varsigma/meansigma>=2 is the most significant realization of the loose bound. We base our analysis both on the formalism of diffusions, and of Markov jump processes in the light of Schnakenberg's cycle analysis. PMID- 27967075 TI - Epidemic spreading in random rectangular networks. AB - The use of network theory to model disease propagation on populations introduces important elements of reality to the classical epidemiological models. The use of random geometric graphs (RGGs) is one of such network models that allows for the consideration of spatial properties on disease propagation. In certain real-world scenarios-like in the analysis of a disease propagating through plants-the shape of the plots and fields where the host of the disease is located may play a fundamental role in the propagation dynamics. Here we consider a generalization of the RGG to account for the variation of the shape of the plots or fields where the hosts of a disease are allocated. We consider a disease propagation taking place on the nodes of a random rectangular graph and we consider a lower bound for the epidemic threshold of a susceptible-infected-susceptible model or a susceptible-infected-recovered model on these networks. Using extensive numerical simulations and based on our analytical results we conclude that (ceteris paribus) the elongation of the plot or field in which the nodes are distributed makes the network more resilient to the propagation of a disease due to the fact that the epidemic threshold increases with the elongation of the rectangle. These results agree with accumulated empirical evidence and simulation results about the propagation of diseases on plants in plots or fields of the same area and different shapes. PMID- 27967076 TI - Fractional kinetics emerging from ergodicity breaking in random media. AB - We present a modeling approach for diffusion in a complex medium characterized by a random length scale. The resulting stochastic process shows subdiffusion with a behavior in qualitative agreement with single-particle tracking experiments in living cells, such as ergodicity breaking, p variation, and aging. In particular, this approach recapitulates characteristic features previously described in part by the fractional Brownian motion and in part by the continuous-time random walk. Moreover, for a proper distribution of the length scale, a single parameter controls the ergodic-to-nonergodic transition and, remarkably, also drives the transition of the diffusion equation of the process from nonfractional to fractional, thus demonstrating that fractional kinetics emerges from ergodicity breaking. PMID- 27967077 TI - Noisy oscillator: Random mass and random damping. AB - The problem of a linear damped noisy oscillator is treated in the presence of two multiplicative sources of noise which imply a random mass and random damping. The additive noise and the noise in the damping are responsible for an influx of energy to the oscillator and its dissipation to the surrounding environment. A random mass implies that the surrounding molecules not only collide with the oscillator but may also adhere to it, thereby changing its mass. We present general formulas for the first two moments and address the question of mean and energetic stabilities. The phenomenon of stochastic resonance, i.e., the expansion due to the noise of a system response to an external periodic signal, is considered for separate and joint action of two sources of noise and their characteristics. PMID- 27967078 TI - Universality and dependence on initial conditions in the class of the nonlinear molecular beam epitaxy equation. AB - We report extensive numerical simulations of growth models belonging to the nonlinear molecular beam epitaxy (nMBE) class, on flat (fixed-size) and expanding substrates (ES). In both d=1+1 and 2+1, we find that growth regime height distributions (HDs), and spatial and temporal covariances are universal, but are dependent on the initial conditions, while the critical exponents are the same for flat and ES systems. Thus, the nMBE class does split into subclasses, as does the Kardar-Parisi-Zhang (KPZ) class. Applying the "KPZ ansatz" to nMBE models, we estimate the cumulants of the 1+1 HDs. Spatial covariance for the flat subclass is hallmarked by a minimum, which is not present in the ES one. Temporal correlations are shown to decay following well-known conjectures. PMID- 27967079 TI - Wave propagation in one-dimensional microscopic granular chains. AB - We employ noncontact optical techniques to generate and measure stress waves in uncompressed, one-dimensional microscopic granular chains, and support our experiments with discrete numerical simulations. We show that the wave propagation through dry particles (150 MUm radius) is highly nonlinear and it is significantly influenced by the presence of defects (e.g., surface roughness, interparticle gaps, and misalignment). We derive an analytical relation between the group velocity and gap size, and define bounds for the formation of highly nonlinear solitary waves as a function of gap size and axial misalignment. PMID- 27967080 TI - Field measurement analysis to validate lane-changing behavior in a cellular automaton model. AB - In the present study, we analyzed field measurement data obtained for a Japanese expressway and used it as a data set for the validation of microscopic simulation models. Consequently, in accordance with previous studies, we confirmed the common features depicted by the fundamental diagram (flux vs density relation) and lane-usage ratio vs density diagram. We found two things regarding lane changing behavior: (1) a lane change occurs asymmetrically, where a lane change from a slow to a fast lane differs from that from a fast to a slow lane; and (2) the so-called incentive criterion in the case of small gaps between the preceding vehicles in both slow and fast lanes refers to the velocities and /or the relative velocities with respect to the preceding vehicles, whereas that for relatively large gaps refers to the distances to the preceding vehicles is cast into the above incentive criterion in addition to the two factors mentioned above. PMID- 27967081 TI - Conservation laws and symmetries in stochastic thermodynamics. AB - Phenomenological nonequilibrium thermodynamics describes how fluxes of conserved quantities, such as matter, energy, and charge, flow from outer reservoirs across a system and how they irreversibly degrade from one form to another. Stochastic thermodynamics is formulated in terms of probability fluxes circulating in the system's configuration space. The consistency of the two frameworks is granted by the condition of local detailed balance, which specifies the amount of physical quantities exchanged with the reservoirs during single transitions between configurations. We demonstrate that the topology of the configuration space crucially determines the number of independent thermodynamic affinities (forces) that the reservoirs generate across the system and provides a general algorithm that produces the fundamental affinities and their conjugate currents contributing to the total dissipation, based on the interplay between macroscopic conservations laws for the currents and microscopic symmetries of the affinities. PMID- 27967082 TI - Effect of stress nonhomogeneity on the shear melting of a thin boundary lubrication layer. AB - We consider the dynamical properties of boundary lubrication in contact between two atomically smooth solid surfaces separated by an ultrathin layer of lubricant. In contrast to previous works on this topic, we explicitly consider the heterogeneity of tangential stresses, which arises in a contact of elastic bodies that are moved tangentially relative to each other. To describe phase transitions between structural states of the lubricant we use an approach based on the field theory of phase transitions. It is assumed that the lubricant layer, when stressed, can undergo a shear-melting transition of first or second order. While solutions for the homogeneous system can be easily obtained analytically, the kinetics of the phase transitions in the spatially heterogeneous system can only be studied numerically. In our numerical experiments melting of the lubricant layer starts from the outer boundary of contact and propagates to its center. The melting wave is followed by a wave of solidification. This process repeats itself periodically, following the stick-slip pattern that is characteristic of such systems. Depending on the thermodynamic and kinetic parameters of the model, different modes of sliding with almost complete or only partial intermediate solidification are possible. PMID- 27967083 TI - Time-dependent probability density function in cubic stochastic processes. AB - We report time-dependent probability density functions (PDFs) for a nonlinear stochastic process with a cubic force using analytical and computational studies. Analytically, a transition probability is formulated by using a path integral and is computed by the saddle-point solution (instanton method) and a new nonlinear transformation of time. The predicted PDF p(x,t) in general involves a time integral, and useful PDFs with explicit dependence on x and t are presented in certain limits (e.g., in the short and long time limits). Numerical simulations of the Fokker-Planck equation provide exact time evolution of the PDFs and confirm analytical predictions in the limit of weak noise. In particular, we show that transient PDFs behave drastically differently from the stationary PDFs in regard to the asymmetry (skewness) and kurtosis. Specifically, while stationary PDFs are symmetric with the kurtosis smaller than 3, transient PDFs are skewed with the kurtosis larger than 3; transient PDFs are much broader than stationary PDFs. We elucidate the effect of nonlinear interaction on the strong fluctuations and intermittency in the relaxation process. PMID- 27967084 TI - Network inference in the nonequilibrium steady state. AB - Nonequilibrium systems lack an explicit characterization of their steady state like the Boltzmann distribution for equilibrium systems. This has drastic consequences for the inference of the parameters of a model when its dynamics lacks detailed balance. Such nonequilibrium systems occur naturally in applications like neural networks and gene regulatory networks. Here, we focus on the paradigmatic asymmetric Ising model and show that we can learn its parameters from independent samples of the nonequilibrium steady state. We present both an exact inference algorithm and a computationally more efficient, approximate algorithm for weak interactions based on a systematic expansion around mean-field theory. Obtaining expressions for magnetizations and two- and three-point spin correlations, we establish that these observables are sufficient to infer the model parameters. Further, we discuss the symmetries characterizing the different orders of the expansion around the mean field and show how different types of dynamics can be distinguished on the basis of samples from the nonequilibrium steady state. PMID- 27967085 TI - Transitional subphases near the electric-field-induced phase transition to the ferroelectric phase in Se-containing chiral smectic liquid crystals observed by resonant x-ray scattering. AB - Resonant x-ray scattering experiments revealed transitional subphases near the electric-field-induced phase transition of a Se-containing chiral liquid crystal in a planar aligned cell geometry. In the lower-temperature range (Sm-C_{A}^{*} and three-layer periodicity Sm-C_{gamma}^{*} phases), the six-layer periodicity subphase appeared with increasing electric field during the field-induced transition from Sm-C_{gamma}^{*} to Sm-C^{*}. In the higher-temperature range [four-layer periodicity antiferroelectric (AF) phase], the peak positions of the three-layer satellites shifted to those of the four-layer satellites and then the satellites corresponding to the five- through seven-layer periodicity appeared in sequence. Near the AF to Sm-C_{alpha}^{*} phase transition temperature, the layer periodicity increased with applied field. The molecular configurations of the subphases near the field-induced transition are discussed based on the Ising, distorted clock, and perfect clock models. PMID- 27967086 TI - Compressing turbulence and sudden viscous dissipation with compression-dependent ionization state. AB - Turbulent plasma flow, amplified by rapid three-dimensional compression, can be suddenly dissipated under continuing compression. This effect relies on the sensitivity of the plasma viscosity to the temperature, MU~T^{5/2}. The plasma viscosity is also sensitive to the plasma ionization state. We show that the sudden dissipation phenomenon may be prevented when the plasma ionization state increases during compression, and we demonstrate the regime of net viscosity dependence on compression where sudden dissipation is guaranteed. Additionally, it is shown that, compared to cases with no ionization, ionization during compression is associated with larger increases in turbulent energy and can make the difference between growing and decreasing turbulent energy. PMID- 27967087 TI - Bias, belief, and consensus: Collective opinion formation on fluctuating networks. AB - With the advent of online networks, societies have become substantially more interconnected with individual members able to easily both maintain and modify their own social links. Here, we show that active network maintenance exposes agents to confirmation bias, the tendency to confirm one's beliefs, and we explore how this bias affects collective opinion formation. We introduce a model of binary opinion dynamics on a complex, fluctuating network with stochastic rewiring and we analyze these dynamics in the mean-field limit of large networks and fast link rewiring. We show that confirmation bias induces a segregation of individuals with different opinions and stabilizes the consensus state. We further show that bias can have an unusual, nonmonotonic effect on the time to consensus and this suggests a novel avenue for large-scale opinion manipulation. PMID- 27967088 TI - Generalized synchrony of coupled stochastic processes with multiplicative noise. AB - We study the effect of multiplicative noise in dynamical flows arising from the coupling of stochastic processes with intrinsic noise. Situations wherein such systems arise naturally are in chemical or biological oscillators that are coupled to each other in a drive-response configuration. Above a coupling threshold we find that there is a strong correlation between the drive and the response: This is a stochastic analog of the phenomenon of generalised synchronization. Since the dynamical fluctuations are large when there is intrinsic noise, it is necessary to employ measures that are sensitive to correlations between the variables of drive and the response, the permutation entropy, or the mutual information in order to detect the transition to generalized synchrony in such systems. PMID- 27967089 TI - Local momentum and heat fluxes in transient transport processes and inhomogeneous systems. AB - This work examines existing formalisms for the derivation of microscopic momentum and heat fluxes. Both analytical and simulation results are provided to show that the widely used flux formulas are not applicable to transient transport processes or highly inhomogeneous systems, e.g., materials with atomically sharp interfaces. A method is formulated for formally deriving microscopic momentum and heat fluxes through the integral representation of conservation laws. The resulting flux formulas are mathematically rigorous, fully consistent with the physical concepts of momentum and heat fluxes, and applicable to nonequilibrium transient processes in atomically inhomogeneous systems with general many-body forces. PMID- 27967090 TI - Metastability in an open quantum Ising model. AB - We apply a recently developed theory for metastability in open quantum systems to a one-dimensional dissipative quantum Ising model. Earlier results suggest this model features either a nonequilibrium phase transition or a smooth but sharp crossover, where the stationary state changes from paramagnetic to ferromagnetic, accompanied by strongly intermittent emission dynamics characteristic of first order coexistence between dynamical phases. We show that for a range of parameters close to this transition or crossover point the dynamics of the finite system displays pronounced metastability, i.e., the system relaxes first to long lived metastable states before eventual relaxation to the true stationary state. From the spectral properties of the quantum master operator we characterize the low-dimensional manifold of metastable states, which are shown to be probability mixtures of two, paramagnetic and ferromagnetic, metastable phases. We also show that for long times the dynamics can be approximated by a classical stochastic dynamics between the metastable phases that is directly related to the intermittent dynamics observed in quantum trajectories and thus the dynamical phases. PMID- 27967091 TI - Network model of human aging: Frailty limits and information measures. AB - Aging is associated with the accumulation of damage throughout a persons life. Individual health can be assessed by the Frailty Index (FI). The FI is calculated simply as the proportion f of accumulated age-related deficits relative to the total, leading to a theoretical maximum of f<=1. Observational studies have generally reported a much more stringent bound, with f<=f_{max}<1. The value of f_{max} in observational studies appears to be nonuniversal, but f_{max}~0.7 is often reported. A previously developed network model of individual aging was unable to recover f_{max}<1 while retaining the other observed phenomenology of increasing f and mortality rates with age. We have developed a computationally accelerated network model that also allows us to tune the scale-free network exponent alpha. The network exponent alpha significantly affects the growth of mortality rates with age. However, we are only able to recover f_{max} by also introducing a deficit sensitivity parameter 1-q, which is equivalent to a false negative rate q. Our value of q=0.3 is comparable to finite sensitivities of age related deficits with respect to mortality that are often reported in the literature. In light of nonzero q, we use mutual information I to provide a nonparametric measure of the predictive value of the FI with respect to individual mortality. We find that I is only modestly degraded by q<1, and this degradation is mitigated when increasing number of deficits are included in the FI. We also find that the information spectrum, i.e., the mutual information of individual deficits versus connectivity, has an approximately power-law dependence that depends on the network exponent alpha. Mutual information I is therefore a useful tool for characterizing the network topology of aging populations. PMID- 27967092 TI - Anisotropic invasion and its consequences in two-strategy evolutionary games on a square lattice. AB - We have studied invasion processes in two-strategy evolutionary games on a square lattice for imitation rule when the players interact with their nearest neighbors. Monte Carlo simulations are performed for systems where the pair interactions are composed of a unit strength coordination game when varying the strengths of the self-dependent and cross-dependent components at a fixed noise level. The visualization of strategy distributions has clearly indicated that circular homogeneous domains evolve into squares with an orientation dependent on the composition. This phenomenon is related to the anisotropy of invasion velocities along the interfaces separating the two homogeneous regions. The quantified invasion velocities indicate the existence of a parameter region in which the invasions are opposite for the horizontal (or vertical) and the tilted interfaces. In this parameter region faceted islands of both strategies shrink and the system evolves from a random initial state into the homogeneous state that first percolated. PMID- 27967093 TI - Enhanced diffusion in finite-size simulations of a fragile diatomic glass former. AB - Using molecular dynamics simulations we investigate the finite-size dependence of the dynamical properties of a diatomic supercooled liquid. The simplicity of the molecule permits us to access the microsecond time scale. We find that the relaxation time decreases simultaneously with the strength of cooperative motions when the size of the system decreases. While the decrease of the cooperative motions is in agreement with previous studies, the decrease of the relaxation time opposes what has been reported to date in monatomic glass formers and in silica. This result suggests the presence of different competing physical mechanisms in the relaxation process. For very small box sizes the relaxation times behavior reverses itself and increases strongly when the box size decreases, thus leading to a nonmonotonic behavior. This result is in qualitative agreement with defect and facilitation theories. PMID- 27967094 TI - Quantum signatures of charge flipping vortices in the Bose-Hubbard trimer. AB - In this work we study quantum signatures of charge flipping vortices, found in the classical discrete nonlinear Schrodinger trimer, by use of the Bose-Hubbard model. We are able to identify such signatures in the quantum energy eigenstates, for instance when comparing the site amplitudes of the classical charge flipping vortices with the probability distribution over different particle configurations. It is also discussed how to construct quantum states that correspond to the classical charge flipping vortices and which effects can lead to deviations between the classical and quantum dynamics. We also examine properties of certain coherent states: classical-like quantum states that can be used to derive the classical model. Several quantum signatures are identified when studying the dynamics of these coherent states, for example, when comparing the average number of particles on a site with the classical site amplitude, when comparing the quantum and classical currents and topological charge, and when studying the evolution of the quantum probability amplitudes. The flipping of the quantum currents are found to be an especially robust feature of these states. PMID- 27967095 TI - Spectral properties of the hierarchical product of graphs. AB - The hierarchical product of two graphs represents a natural way to build a larger graph out of two smaller graphs with less regular and therefore more heterogeneous structure than the Cartesian product. Here we study the eigenvalue spectrum of the adjacency matrix of the hierarchical product of two graphs. Introducing a coupling parameter describing the relative contribution of each of the two smaller graphs, we perform an asymptotic analysis for the full spectrum of eigenvalues of the adjacency matrix of the hierarchical product. Specifically, we derive the exact limit points for each eigenvalue in the limits of small and large coupling, as well as the leading-order relaxation to these values in terms of the eigenvalues and eigenvectors of the two smaller graphs. Given its central roll in the structural and dynamical properties of networks, we study in detail the Perron-Frobenius, or largest, eigenvalue. Finally, as an example application we use our theory to predict the epidemic threshold of the susceptible-infected susceptible model on a hierarchical product of two graphs. PMID- 27967096 TI - Thickness-dependent glass transition temperature and charge mobility in cross linked polyfluorene thin films. AB - We report thickness-dependent glass transition temperature (T_{g}) and charge mobility in cross-linked thin films made of conjugated polymer poly(9,9 dioctylfluorene-co-N-(4-butylphenyl)diphenylamine) (TFB). Monotonic T_{g} depressions with reducing film thickness in thermally and UV cross-linked TFB thin films supported on Si-SiOx substrates are observed through ellipsometry measurements, suggesting that a surface mobile layer with enhanced chain dynamics still exists in cross-linked TFB thin films, even with a high cross-linking percentage. Data fitting using a three-layer model shows that the T_{g} in the interface, bulk and surface layer both increases with increasing cross-linking, while the thickness of the interface and surface layer increases and reduces, respectively. Cross-linking of TFB thin film generates traps that hinder charge transport and consequently reduce charge mobility. The charge mobility converges in thick (>140 nm) and thin (<40 nm) TFB films but shows strong thickness dependence in between, reducing from 4.0*10^{-4}cm^{2}/Vs in a 180-nm film to 0.1*10^{-4}cm^{2}/Vs in a 20-nm thin film. PMID- 27967097 TI - Excited-state quantum phase transitions in the two-spin elliptic Gaudin model. AB - We study the integrability of the two-spin elliptic Gaudin model for arbitrary values of the Hamiltonian parameters. The limit of a very large spin coupled to a small one is well described by a semiclassical approximation with just one degree of freedom. Its spectrum is divided into bands that do not overlap if certain conditions are fulfilled. In spite of the fact that there are no quantum phase transitions in each of the band heads, the bands show excited-state quantum phase transitions separating a region in which the parity symmetry is broken from another region in which time-reversal symmetry is broken. We derive analytical expressions for the critical energies in the semiclassical approximation, and confirm the results by means of exact diagonalizations for large systems. PMID- 27967098 TI - Roles of mixing patterns in the network reconstruction. AB - Compressive sensing is an effective way to reconstruct the network structure. In this paper, we investigate the effect of the mixing patterns, measured by the assortative coefficient, on the performance of network reconstruction. First, we present a model to generate networks with different assortativity coefficients, then we reconstruct the network structure by using the compressive sensing method. The experimental results show that when the assortativity coefficient r=0.2, the accuracy of the network reconstruction reaches the maximum value, which suggests that the compressive sensing is more effective for uncovering the links of social networks. Moreover, the accuracy of the network reconstruction will be higher as the network size increases. PMID- 27967099 TI - Stochastic bifurcations in the nonlinear parallel Ising model. AB - We investigate the phase transitions of a nonlinear, parallel version of the Ising model, characterized by an antiferromagnetic linear coupling and ferromagnetic nonlinear one. This model arises in problems of opinion formation. The mean-field approximation shows chaotic oscillations, by changing the couplings or the connectivity. The spatial model shows bifurcations in the average magnetization, similar to that seen in the mean-field approximation, induced by the change of the topology, after rewiring short-range to long-range connection, as predicted by the small-world effect. These coherent periodic and chaotic oscillations of the magnetization reflect a certain degree of synchronization of the spins, induced by long-range couplings. Similar bifurcations may be induced in the randomly connected model by changing the couplings or the connectivity and also the dilution (degree of asynchronism) of the updating. We also examined the effects of inhomogeneity, mixing ferromagnetic and antiferromagnetic coupling, which induces an unexpected bifurcation diagram with a "bubbling" behavior, as also happens for dilution. PMID- 27967100 TI - Erosion and deposition in depth-averaged models of dense, dry, inclined, granular flows. AB - We derive expressions for the rates of erosion and deposition at the interface between a dense, dry, inclined granular flow and an erodible bed. In obtaining these, we assume that the interface between the flowing grains and the bed moves with the speed of a pressure wave in the flow, for deposition, or with the speed of a disturbance through the contacting particles in the bed, for erosion. We employ the expressions for the rates of erosion and deposition to show that after an abrupt change in the angle of inclination of the bed the characteristic time for the motion of the interface is much shorter than the characteristic time of the flow. This eliminates the need for introducing models of erosion and deposition rate in the mass balance; and the instantaneous value of the particle flux is the same function of the instantaneous value of the flow depth as in a steady, uniform flow. PMID- 27967101 TI - Direct numerical solution of the Lippmann-Schwinger equation in coordinate space without partial-wave decomposition. AB - Direct numerical solution of the coordinate-space integral-equation version of the two-particle Lippmann-Schwinger (LS) equation is considered without invoking the traditional partial-wave decomposition. The singular kernel of the three dimensional LS equation in coordinate space is regularized by a subtraction technique. The resulting nonsingular integral equation is then solved via the Nystrom method employing a direct-product quadrature rule for three variables. To reduce the computational burden of discretizing three variables, advantage is taken of the fact that, for central potentials, the azimuthal angle can be integrated out, leaving a two-variable reduced integral equation. A regularization method for the kernel of the two-variable integral equation is derived from the treatment of the singularity in the three-dimensional equation. A quadrature rule constructed as the direct product of single-variable quadrature rules for radial distance and polar angle is used to discretize the two-variable integral equation. These two- and three-variable methods are tested on the Hartree potential. The results show that the Nystrom method for the coordinate space LS equation compares favorably in terms of its ease of implementation and effectiveness with the Nystrom method for the momentum-space version of the LS equation. PMID- 27967102 TI - Formation of localized sand patterns downstream from a vertical cylinder under steady flows: Experimental and theoretical study. AB - The generation of localized, spatially periodic patterns on a sandy bottom is experimentally and theoretically studied. Tests are performed in a hydrodynamic flume where patterns are produced downstream from a vertical cylinder under a steady current. It is found that patterns appear as a result of a subcritical instability of the water-sand bottom interface. A dependence of the area shape occupied by the patterns on the flow velocity and the cylinder diameter is investigated. It is shown that the patterns' characteristics can be explained using the Swift-Hohenberg equation. Numerical simulations point out that for a correct description of the patterns, an additional term which takes into account the impact of vortices on the sandy bottom in the wake of a cylinder must be added in the Swift-Hohenberg equation. PMID- 27967103 TI - Efficiency and its bounds of minimally nonlinear irreversible heat engines at arbitrary power. AB - The efficiency for minimally nonlinear irreversible heat engines at any arbitrary power has been systematically evaluated, and general lower and upper efficiency bounds under the tight coupling condition for different operating regions have been proposed, which can be seen as the generalization of the bounds [eta_{C}/22. We have done numerical quenches starting from a random initial state (infinite temperature state) by putting spins parallel to their local fields until there is no further decrease of the energy and found that in zero field it always produces minima that have zero overlap with each other. For the m=2 and m=3 cases in the SK model the final energy reached in the quench is very close to the energy E_{c} at which the overlap of the states would acquire replica symmetry-breaking features. These minima have marginal stability and will have long-range correlations between them. In the SK limit we have analytically studied the density of states rho(lambda) of the Hessian matrix in the annealed approximation. Despite the fact that in the presence of a random field there are no continuous symmetries, the spectrum extends down to zero with the usual sqrt[lambda] form for the density of states for fields below the AT field. However, when the random field is larger than the AT field, there is a gap in the spectrum, which closes up as the AT field is approached. The VB model behaves differently and seems rather similar to studies of the three-dimensional Heisenberg spin glass in a random vector field. PMID- 27967115 TI - Mesoscopic kinetic basis of macroscopic chemical thermodynamics: A mathematical theory. AB - Gibbs' macroscopic chemical thermodynamics is one of the most important theories in chemistry. Generalizing it to mesoscaled nonequilibrium systems is essential to biophysics. The nonequilibrium stochastic thermodynamics of chemical reaction kinetics suggested a free energy balance equation dF^{(meso)}/dt=E_{in}-e_{p} in which the free energy input rate E_{in} and dissipation rate e_{p} are both non negative, and E_{in}<=e_{p}. We prove that in the macroscopic limit by merely allowing the molecular numbers to be infinite, the generalized mesoscopic free energy F^{(meso)} converges to phi^{ss}, the large deviation rate function for the stationary distributions. This generalized macroscopic free energy phi^{ss} now satisfies a balance equation dphi^{ss}(x)/dt=cmf(x)-sigma(x), in which x represents chemical concentration. The chemical motive force cmf(x) and entropy production rate sigma(x) are both non-negative, and cmf(x)<=sigma(x). The balance equation is valid generally in isothermal driven systems and is different from mechanical energy conservation and the first law; it is actually an unknown form of the second law. Consequences of the emergent thermodynamic quantities and equalities are further discussed. The emergent "law" is independent of underlying kinetic details. Our theory provides an example showing how a macroscopic law emerges from a level below. PMID- 27967117 TI - Publisher's Note: Critical wind speed at which trees break [Phys. Rev. E 93, 023001 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevE.93.023001. PMID- 27967116 TI - Characterization of multiple topological scales in multiplex networks through supra-Laplacian eigengaps. AB - Multilayer networks have been the subject of intense research during the past few years, as they represent better the interdependent nature of many real-world systems. Here, we address the question of describing the three different structural phases in which a multiplex network might exist. We show that each phase can be characterized by the presence of gaps in the spectrum of the supra Laplacian of the multiplex network. We therefore unveil the existence of different topological scales in the system, whose relation characterizes each phase. Moreover, by capitalizing on the coarse-grained representation that is given in terms of quotient graphs, we explain the mechanisms that produce those gaps as well as their dynamical consequences. PMID- 27967119 TI - Characterization of base roughness for granular chute flows. AB - Base roughness plays an important role in the dynamics of granular flows but is still poorly understood due to the difficulty of its quantification. For a bumpy base made of spheres, at least two factors should be considered in order to characterize its geometric roughness, namely, the size ratio of flow to base particles and the packing arrangement of base particles. In this paper, we propose an alternative definition of base roughness, R_{a}, as a function of both the size ratio and the distribution of base particles. This definition is generalized for random and regular packings of multilayered spheres. The range of possible values of R_{a} is presented, and optimal arrangements for maximizing base roughness are studied. Our definition is applied to granular chute flows in both two- and three-dimensional configurations, and is shown to successfully predict whether slip occurs at the base. A transition is observed from slip to nonslip conditions as R_{a} increases. Critical values of R_{a} are identified for the construction of a nonslip base at various angles of inclination. PMID- 27967118 TI - Vibration-induced coherence enhancement of the performance of a biological quantum heat engine. AB - Photosynthesis has been a long-standing research interest due to its fundamental importance. Recently, studies on photosynthesis processes also have inspired attention from a thermodynamical aspect when considering photosynthetic apparatuses as biological quantum heat engines. Quantum coherence is shown to play a crucial role in enhancing the performance of these quantum heat engines. Based on the experimentally reported structure, we propose a quantum heat engine model with a non-Markovian vibrational mode. We show that one can obtain a performance enhancement easily for a wide range of parameters in the presence of the vibrational mode. Our results provide insights into the photosynthetic processes and a design principle mimicking natural organisms. PMID- 27967120 TI - Information flow and causality as rigorous notions ab initio. AB - Information flow or information transfer the widely applicable general physics notion can be rigorously derived from first principles, rather than axiomatically proposed as an ansatz. Its logical association with causality is firmly rooted in the dynamical system that lies beneath. The principle of nil causality that reads, an event is not causal to another if the evolution of the latter is independent of the former, which transfer entropy analysis and Granger causality test fail to verify in many situations, turns out to be a proven theorem here. Established in this study are the information flows among the components of time discrete mappings and time-continuous dynamical systems, both deterministic and stochastic. They have been obtained explicitly in closed form, and put to applications with the benchmark systems such as the Kaplan-Yorke map, Rossler system, baker transformation, Henon map, and stochastic potential flow. Besides unraveling the causal relations as expected from the respective systems, some of the applications show that the information flow structure underlying a complex trajectory pattern could be tractable. For linear systems, the resulting remarkably concise formula asserts analytically that causation implies correlation, while correlation does not imply causation, providing a mathematical basis for the long-standing philosophical debate over causation versus correlation. PMID- 27967121 TI - Analysis of ionic conductance of carbon nanotubes. AB - We use space-charge (SC) theory (also called the capillary pore model) to describe the ionic conductance, G, of charged carbon nanotubes (CNTs). Based on the reversible adsorption of hydroxyl ions to CNT pore walls, we use a Langmuir isotherm for surface ionization and make calculations as a function of pore size, salt concentration c, and pH. Using realistic values for surface site density and pK, SC theory well describes published experimental data on the conductance of CNTs. At extremely low salt concentration, when the electric potential becomes uniform across the pore, and surface ionization is low, we derive the scaling G?sqrt[c], while for realistic salt concentrations, SC theory does not lead to a simple power law for G PMID- 27967123 TI - Head-on collision of dust acoustic solitons in a nonextensive plasma with variable size dust grains of arbitrary charge. AB - The head-on collision of two dust acoustic solitons (DASs) in a nonextensive plasma with positive or negative dust grains fluid including the effect of dust size distribution (DSD) is studied. The phase shifts for the two solitons due to the collision are derived by applying the extended Poincare-Lighthill-Kuo (PLK) method. The influences of the power law DSD and the nonextensivity of plasma particles on the characteristic properties of the head-on collision of DASs are analyzed. It is found that the phase shifts can vanish, only for the case of positive dust grains, for certain values and ranges of the dust grain radius and the entropic index of ions (q_{i}). Also, they undergo a cutoff in the range of q_{i}>1 for the subextensive distribution. A brief discussion of possible applications in laboratory and space plasmas is included. PMID- 27967122 TI - Sensitivity of small myosin II ensembles from different isoforms to mechanical load and ATP concentration. AB - Based on a detailed crossbridge model for individual myosin II motors, we systematically study the influence of mechanical load and adenosine triphosphate (ATP) concentration on small myosin II ensembles made from different isoforms. For skeletal and smooth muscle myosin II, which are often used in actomyosin gels that reconstitute cell contractility, fast forward movement is restricted to a small region of phase space with low mechanical load and high ATP concentration, which is also characterized by frequent ensemble detachment. At high load, these ensembles are stalled or move backwards, but forward motion can be restored by decreasing ATP concentration. In contrast, small ensembles of nonmuscle myosin II isoforms, which are found in the cytoskeleton of nonmuscle cells, are hardly affected by ATP concentration due to the slow kinetics of the bound states. For all isoforms, the thermodynamic efficiency of ensemble movement increases with decreasing ATP concentration, but this effect is weaker for the nonmuscle myosin II isoforms. PMID- 27967124 TI - Localized fluidization in granular materials: Theoretical and numerical study. AB - We present analytical and numerical results on localized fluidization within a granular layer subjected to a local injection of fluid. As the injection rate increases the three different regimes previously reported in the literature are recovered: homogeneous expansion of the bed, fluidized cavity in which fluidization starts developing above the injection area, and finally the chimney of fluidized grains when the fluidization zone reaches the free surface. The analytical approach is at the continuum scale, based on Darcy's law and Therzaghi's effective stress principle. It provides a good description of the phenomenon as long as the porosity of the granular assembly remains relatively homogeneous, i.e., for small injection rates. The numerical approach is at the particle scale based on the coupled discrete element method and a pore-scale finite volume method. It tackles the more heterogeneous situations which occur at larger injection rates. The results from both methods are in qualitative agreement with data published independently. A more quantitative agreement is achieved by the numerical model. A direct link is evidenced between the occurrence of the different regimes of fluidization and the injection aperture. While narrow apertures let the three different regimes be distinguished clearly, larger apertures tend to produce a single homogeneous fluidization regime. In the former case, it is found that the transition between the cavity regime and the chimney regime for an increasing injection rate coincides with a peak in the evolution of inlet pressure. Finally, the occurrence of the different regimes is defined in terms of the normalized flux and aperture. PMID- 27967125 TI - Critical phenomena in active matter. AB - We investigate the effect of self-propulsion on a mean-field order-disorder transition. Starting from a phi^{4} scalar field theory subject to an exponentially correlated noise, we exploit the unified colored-noise approximation to map the nonequilibrium active dynamics onto an effective equilibrium one. This allows us to follow the evolution of the second-order critical point as a function of the noise parameters: the correlation time tau and the noise strength D. Our results suggest that the universality class of the model remains unchanged. We also estimate the effect of Gaussian fluctuations on the mean-field approximation finding an Ornstein-Zernike-like expression for the static structure factor at long wavelengths. Finally, to assess the validity of our predictions, we compare the mean-field theoretical results with numerical simulations of active Lennard-Jones particles in two and three dimensions, finding good qualitative agreement at small tau values. PMID- 27967126 TI - Publisher's Note: Generalized Gaussian wave packet dynamics: Integrable and chaotic systems [Phys. Rev. E 93, 012213 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevE.93.012213. PMID- 27967127 TI - Hydrodynamic interactions in freely suspended liquid crystal films. AB - Hydrodynamic interactions play an important role in biological processes in cellular membranes, a large separation of length scales often allowing such membranes to be treated as continuous, two-dimensional (2D) fluids. We study experimentally and theoretically the hydrodynamic interaction of pairs of inclusions in two-dimensional, fluid smectic liquid crystal films suspended in air. Such smectic membranes are ideal systems for performing controlled experiments as they are mechanically stable, of highly uniform structure, and have well-defined, variable thickness, enabling experimental investigation of the crossover from 2D to 3D hydrodynamics. Our theoretical model generalizes the Levine-MacKintosh theory of point-force response functions and uses a boundary element approach to calculate the mobility matrix for inclusions of finite extent. We describe in detail the theoretical and computational approach previously outlined in Z. Qi et al., Phys. Rev. Lett. 113, 128304 (2014)PRLTAO0031-900710.1103/PhysRevLett.113.128304 and extend the method to study the mutual mobilities of inclusions with asymmetric shapes. The model predicts well the observed mutual mobilities of pairs of circular inclusions in films and the self-mobility of a circular inclusion in the vicinity of a linear boundary. PMID- 27967128 TI - Testing for causality in reconstructed state spaces by an optimized mixed prediction method. AB - In this study, a method of causality detection was designed to reveal coupling between dynamical systems represented by time series. The method is based on the predictions in reconstructed state spaces. The results of the proposed method were compared with outcomes of two other methods, the Granger VAR test of causality and the convergent cross-mapping. We used two types of test data. The first test example is a unidirectional connection of chaotic systems of Rossler and Lorenz type. The second one, the fishery model, is an example of two correlated observables without a causal relationship. The results showed that the proposed method of optimized mixed prediction was able to reveal the presence and the direction of coupling and distinguish causality from mere correlation as well. PMID- 27967129 TI - Erratum: Microstructure identification via detrended fluctuation analysis of ultrasound signals [Phys. Rev. E 87, 043304 (2013)]. AB - This corrects the article DOI: 10.1103/PhysRevE.87.043304. PMID- 27967130 TI - Fidelity of the diagonal ensemble signals the many-body localization transition. AB - In this work, we use exact matrix diagonalization to explore the many-body localization (MBL) transition in a random-field Heisenberg chain. We demonstrate that the fidelity and fidelity susceptibility can be utilized to characterize the interaction-driven many-body localization transition in this closed spin system which is in agreement with previous analytical and numerical results [S. Garnerone, N. T. Jacobson, S. Haas, and P. Zanardi, Phys. Rev. Lett. 102, 057205 (2009)PRLTAO0031-900710.1103/PhysRevLett.102.057205; P. Zanardi and N. Paunkovic, Phys. Rev. E 74, 031123 (2006)PLEEE81539-375510.1103/PhysRevE.74.031123]. In particular, instead of ground-state fidelity, we test the fidelity between two diagonal ensembles related by a small parameter perturbation deltah, it is special that here the parameter perturbation deltah_{i} for each site are random variables like h_{i}. It shows that fidelity of the diagonal ensemble develop a pronounced drop at the transition. We utilize fidelity to estimate the critical disorder strength h_{c} for different system size, we get h_{c}? [2.5,3.9] and get a power-law decay with an exponent of roughly -1.49(2) for system size N, and can extrapolate h_{c}^{inf} of the infinite system is about 2.07 which all agree with a recent work by Huse and Pal, in which the MBL transition in the same model was predicted to be hc [2,4]. We also estimate the scaling of maximum of averaged fidelity susceptibility as a function of system size N, it shows a power law increase with an exponent of about 5.05(1). PMID- 27967131 TI - Sequential motif profile of natural visibility graphs. AB - The concept of sequential visibility graph motifs-subgraphs appearing with characteristic frequencies in the visibility graphs associated to time series-has been advanced recently along with a theoretical framework to compute analytically the motif profiles associated to horizontal visibility graphs (HVGs). Here we develop a theory to compute the profile of sequential visibility graph motifs in the context of natural visibility graphs (VGs). This theory gives exact results for deterministic aperiodic processes with a smooth invariant density or stochastic processes that fulfill the Markov property and have a continuous marginal distribution. The framework also allows for a linear time numerical estimation in the case of empirical time series. A comparison between the HVG and the VG case (including evaluation of their robustness for short series polluted with measurement noise) is also presented. PMID- 27967132 TI - Isostable reduction of periodic orbits. AB - The well-established method of phase reduction neglects information about a limit cycle oscillator's approach towards its periodic orbit. Consequently, phase reduction suffers in practicality unless the magnitude of the Floquet multipliers of the underlying limit cycle are small in magnitude. By defining isostable coordinates of a periodic orbit, we present an augmentation to classical phase reduction which obviates this restriction on the Floquet multipliers. This framework allows for the study and understanding of periodic dynamics for which standard phase reduction alone is inadequate. Most notably, isostable reduction allows for a convenient and self-contained characterization of the dynamics near unstable periodic orbits. PMID- 27967133 TI - Boundary scheme for linear heterogeneous surface reactions in the lattice Boltzmann method. AB - A boundary scheme is proposed to treat the linear heterogeneous surface reaction (i.e., general Robin boundary condition) for the lattice Boltzmann method (LBM) in this study. The basic idea of the present scheme is to compute the scalar variable gradient in the boundary condition with the moment of the nonequilibrium distribution functions. The unknown distribution functions on the boundary can then be obtained on the basis of the given boundary condition. For a straight wall, where the lattice nodes are located on the boundaries, both the scalar variable and its gradient can be expressed in terms of the distribution functions at the boundary node, and the scheme is purely local. The scheme is also extended to problems with a curved wall, in which a linear extrapolation is employed to realize the exact boundary position. A common feature of the two schemes lies in the easy treatment of the heterogenous reactions in comparison with existing methods. A number of simulations are performed to test the accuracy of the schemes. The results show that for flat walls the scheme can achieve second-order accuracy, while for curved walls the order of the accuracy is between 1.0 and 1.5. PMID- 27967134 TI - Impact of time delays on oscillatory dynamics of interlinked positive and negative feedback loops. AB - Interlinking a positive feedback loop (PFL) with a negative feedback loop (NFL) constitutes a typical motif in genetic networks, performing various functions in cell signaling. How time delay in feedback regulation affects the dynamics of such systems still remains unclear. Here, we investigate three systems of interlinked PFL and NFL with time delays: a synthetic genetic oscillator, a three node circuit, and a simplified single-node model. The stability of steady states and the routes to oscillation in the single-node model are analyzed in detail. The amplitude and period of oscillations vary with a pointwise periodicity over a range of time delay. Larger-amplitude oscillations can be induced when the PFL has an appropriately long delay, in comparison with the PFL with no delay or short delay; this conclusion holds true for all the three systems. We unravel the underlying mechanism for the above effects via analytical derivation under a limiting condition. We also develop a stochastic algorithm for simulating a single reaction with two delays and show that robust oscillations can be maintained by the PFL with a properly long delay in the single-node system. This work presents an effective method for constructing robust large-amplitude oscillators and interprets why similar circuit architectures are engaged in timekeeping systems such as circadian clocks. PMID- 27967135 TI - Grid refinement for entropic lattice Boltzmann models. AB - We propose a multidomain grid refinement technique with extensions to entropic incompressible, thermal, and compressible lattice Boltzmann models. Its validity and accuracy are assessed by comparison to available direct numerical simulation and experiment for the simulation of isothermal, thermal, and viscous supersonic flow. In particular, we investigate the advantages of grid refinement for the setups of turbulent channel flow, flow past a sphere, Rayleigh-Benard convection, as well as the supersonic flow around an airfoil. Special attention is paid to analyzing the adaptive features of entropic lattice Boltzmann models for multigrid simulations. PMID- 27967136 TI - Anomalous dynamics and the choice of Poincare recurrence set. AB - We investigate the dependence of Poincare recurrence-time statistics on the choice of recurrence set by sampling the dynamics of two- and four-dimensional Hamiltonian maps. We derive a method that allows us to visualize the direct relation between the shape of a recurrence set and the values of its return probability distribution in arbitrary phase-space dimensions. Such a procedure, which is shown to be quite effective in the detection of tiny regions of regular motion, allows us to explain why similar recurrence sets have very different distributions and how to modify them in order to enhance their return probabilities. Applied to data, this enables us to understand the coexistence of extremely long, transient powerlike decays whose anomalous exponent depends on the chosen recurrence set. PMID- 27967137 TI - Athermal rheology of weakly attractive soft particles. AB - We study the rheology of a soft particulate system where the interparticle interactions are weakly attractive. Using extensive molecular dynamics simulations, we scan across a wide range of packing fractions (phi), attraction strengths (u), and imposed shear rates (gamma[over ]). In striking contrast to repulsive systems, we find that at small shear rates generically a fragile isostatic solid is formed even if we go to phi?phi_{J}. Further, with increasing shear rates, even at these low phi, nonmonotonic flow curves occur which lead to the formation of persistent shear bands in large enough systems. By tuning the damping parameter, we also show that inertia plays an important role in this process. Furthermore, we observe enhanced particle dynamics in the attraction dominated regime as well as a pronounced anisotropy of velocity and diffusion constant, which we take as precursors to the formation of shear bands. At low enough phi, we also observe structural changes via the interplay of low shear rates and attraction with the formation of microclusters and voids. Finally, we characterize the properties of the emergent shear bands, and thereby, we find surprisingly small mobility of these bands, leading to prohibitively long time scales and extensive history effects in ramping experiments. PMID- 27967138 TI - Rotationally induced fingering patterns in a two-dimensional heterogeneous porous medium. AB - Rotating fluid flows under two-dimensional homogeneous porous media conditions (or in a rotating Hele-Shaw cell) reveal the development of complex interfacial fingering patterns. These pattern-forming structures are characterized by the occurrence of finger competition events, finger pinch-off episodes, as well as by the production of satellite droplets. In this work, we use intensive numerical simulations to investigate how these fully nonlinear pattern growth phenomena are altered by the presence of permeability heterogeneities in the rotating porous medium. This is done by employing a diffuse-interface Darcy-Cahn-Hilliard description of the problem and considering a permeability field presenting a log Gaussian distribution, characterized by a variance s and a correlation length l. We study how the heterogeneity measures s and l couple to the governing hydrodynamic dimensionless parameters of the problem and introduce important changes on the pattern formation dynamics of the system. PMID- 27967139 TI - Pair potentials for warm dense matter and their application to x-ray Thomson scattering in aluminum and beryllium. AB - Ultrafast laser experiments yield increasingly reliable data on warm dense matter, but their interpretation requires theoretical models. We employ an efficient density functional neutral-pseudoatom hypernetted-chain (NPA-HNC) model with accuracy comparable to ab initio simulations and which provides first principles pseudopotentials and pair potentials for warm-dense matter. It avoids the use of (i) ad hoc core-repulsion models and (ii) "Yukawa screening" and (iii) need not assume ion-electron thermal equilibrium. Computations of the x-ray Thomson scattering (XRTS) spectra of aluminum and beryllium are compared with recent experiments and with density-functional-theory molecular-dynamics (DFT-MD) simulations. The NPA-HNC structure factors, compressibilities, phonons, and conductivities agree closely with DFT-MD results, while Yukawa screening gives misleading results. The analysis of the XRTS data for two of the experiments, using two-temperature quasi-equilibrium models, is supported by calculations of their temperature relaxation times. PMID- 27967140 TI - Cascaded lattice Boltzmann method with improved forcing scheme for large-density ratio multiphase flow at high Reynolds and Weber numbers. AB - A recently developed forcing scheme has allowed the pseudopotential multiphase lattice Boltzmann method to correctly reproduce coexistence curves, while expanding its range to lower surface tensions and arbitrarily high density ratios [Lycett-Brown and Luo, Phys. Rev. E 91, 023305 (2015)PLEEE81539 375510.1103/PhysRevE.91.023305]. Here, a third-order Chapman-Enskog analysis is used to extend this result from the single-relaxation-time collision operator, to a multiple-relaxation-time cascaded collision operator, whose additional relaxation rates allow a significant increase in stability. Numerical results confirm that the proposed scheme enables almost independent control of density ratio, surface tension, interface width, viscosity, and the additional relaxation rates of the cascaded collision operator. This allows simulation of large density ratio flows at simultaneously high Reynolds and Weber numbers, which is demonstrated through binary collisions of water droplets in air (with density ratio up to 1000, Reynolds number 6200 and Weber number 440). This model represents a significant improvement in multiphase flow simulation by the pseudopotential lattice Boltzmann method in which real-world parameters are finally achievable. PMID- 27967141 TI - Helical turbulent Prandtl number in the A model of passive vector advection. AB - Using the field theoretic renormalization group technique in the two-loop approximation, turbulent Prandtl numbers are obtained in the general A model of passive vector advected by fully developed turbulent velocity field with violation of spatial parity introduced via the continuous parameter rho ranging from rho=0 (no violation of spatial parity) to |rho|=1 (maximum violation of spatial parity). Values of A represent a continuously adjustable parameter which governs the interaction structure of the model. In nonhelical environments, we demonstrate that A is restricted to the interval -1.723<=A<=2.800 (rounded to 3 decimal places) in the two-loop order of the field theoretic model. However, when rho>0.749 (rounded to 3 decimal places), the restrictions may be removed, which means that presence of helicity exerts a stabilizing effect onto the possible stationary regimes of the system. Furthermore, three physically important cases A?{-1,0,1} are shown to lie deep within the allowed interval of A for all values of rho. For the model of the linearized Navier-Stokes equations (A=-1) up to date unknown helical values of the turbulent Prandtl number have been shown to equal 1 regardless of parity violation. Furthermore, we have shown that interaction parameter A exerts strong influence on advection-diffusion processes in turbulent environments with broken spatial parity. By varying A continuously, we explain high stability of the kinematic MHD model (A=1) against helical effects as a result of its proximity to the A=0.912 (rounded to 3 decimal places) case where helical effects are completely suppressed. Contrary, for the physically important A=0 model, we show that it lies deep within the interval of models where helical effects cause the turbulent Prandtl number to decrease with |rho|. We thus identify internal structure of interactions given by the parameter A, and not the vector character of the admixture itself being the dominant factor influencing diffusion-advection processes in the helical A model. PMID- 27967142 TI - Significant difference in the dynamics between strong and fragile glass formers. AB - Glass-forming liquids are often classified into strong glass formers with nearly Arrhenius behavior and fragile ones with super-Arrhenius behavior. We reveal a significant difference in the dynamics between these two types of glass formers through molecular dynamics simulations: In strong glass formers, the relaxation dynamics of density fluctuations is nondiffusive, whereas in fragile glass formers it exhibits diffusive behavior. We demonstrate that this distinction is a direct consequence of the fundamental difference in the underlying elementary relaxation process between these two dynamical classes of glass formers. For fragile glass formers, a density-exchange process proceeds the density relaxation, which takes place locally at the particle level in normal states but is increasingly cooperative and nonlocal as the temperature is lowered in supercooled states. On the other hand, in strong glass formers, such an exchange process is not necessary for density relaxation due to the presence of other local relaxation channels. Our finding provides a novel insight into Angell's classification scheme from a hydrodynamic perspective. PMID- 27967143 TI - Characterizing folding funnels with replica exchange Wang-Landau simulation of lattice proteins. AB - We have studied the folding of ribonuclease A by mapping it onto coarse-grained lattice protein models. With replica exchange Wang-Landau sampling, we calculated the free energy vs end-to-end distance as a function of temperature. A mapping to the famous hydrophobic-polar (HP) model shows a relatively shallow folding funnel and flat free energy minimum, reflecting the high degeneracy of the ground state. In contrast, extending the HP model with an additional "neutral" monomer type (i.e., a mapping to the three-letter H0P model) has a well developed, rough free energy funnel with a low degeneracy ground state. In both cases, folding funnels are asymmetric with temperature dependent shape. PMID- 27967145 TI - Temporal disorder does not forbid discontinuous absorbing phase transitions in low-dimensional systems. AB - Recent papers have shown that spatial (quenched) disorder can suppress discontinuous absorbing phase transitions. Conversely, the scenario for temporal disorder is still unknown. To shed some light in this direction, we investigate its effect in three different two-dimensional models which are known to exhibit discontinuous absorbing phase transitions. The temporal disorder is introduced by allowing the control parameter to be time dependent p->p(t), either varying as a uniform distribution with mean p[over -] and variance sigma or as a bimodal distribution, fluctuating between a value p and a value p_{l}?p. In contrast to spatial disorder, our numerical results strongly suggest that such uncorrelated temporal disorder does not forbid the existence of a discontinuous absorbing phase transition. We find that all cases are characterized by behaviors similar to their pure (without disorder) counterparts, including bistability around the coexistence point and common finite-size scaling behavior with the inverse of the system volume, as recently proposed [M. M. de Oliveira et al., Phys. Rev. E 92, 062126 (2015)PLEEE81539-375510.1103/PhysRevE.92.062126]. We also observe that temporal disorder does not induce temporal Griffiths phases around discontinuous phase transitions, at least not for d=2. PMID- 27967146 TI - Effect of chain stiffness and temperature on the dynamics and microstructure of crystallizable bead-spring polymer melts. AB - We contrast the dynamics in model unentangled polymer melts of chains of three different stiffnesses: flexible, intermediate, and rodlike. Flexible and rodlike chains, which readily solidify into close-packed crystals (respectively, with randomly oriented and nematically aligned chains), display simple melt dynamics with Arrhenius temperature dependence and a discontinuous change upon solidification. Intermediate-stiffness chains, however, are fragile glass-formers displaying Vogel-Fulcher dynamical arrest, despite the fact that they also possess a nematic-close-packed crystalline ground state. To connect this difference in dynamics to the differing microstructure of the melts, we examine how various measures of structure, including cluster-level metrics recently introduced in studies of colloidal systems, vary with chain stiffness and temperature. No clear static-structural cause of the dynamical arrest is found. However, we find that the intermediate-stiffness chains display qualitatively different dynamical heterogeneity. Specifically, their stringlike motion (cooperative rearrangement) is correlated along chain backbones in a way not found for either flexible or rodlike chains. This activated "crawling" motion is clearly associated with the dynamical arrest observed in these systems, and illustrates one way in which factors controlling the crystallization versus glass formation competition in polymers can depend nonmonotonically on chain stiffness. PMID- 27967144 TI - Random matrix theory for analyzing the brain functional network in attention deficit hyperactivity disorder. AB - Attention deficit hyperactivity disorder (ADHD) is the most common childhood neuropsychiatric disorder and affects approximately 6-7% of children worldwide. Here, we investigate the statistical properties of undirected and directed brain functional networks in ADHD patients based on random matrix theory (RMT), in which the undirected functional connectivity is constructed based on correlation coefficient and the directed functional connectivity is measured based on cross correlation coefficient and mutual information. We first analyze the functional connectivity and the eigenvalues of the brain functional network. We find that ADHD patients have increased undirected functional connectivity, reflecting a higher degree of linear dependence between regions, and increased directed functional connectivity, indicating stronger causality and more transmission of information among brain regions. More importantly, we explore the randomness of the undirected and directed functional networks using RMT. We find that for ADHD patients, the undirected functional network is more orderly than that for normal subjects, which indicates an abnormal increase in undirected functional connectivity. In addition, we find that the directed functional networks are more random, which reveals greater disorder in causality and more chaotic information flow among brain regions in ADHD patients. Our results not only further confirm the efficacy of RMT in characterizing the intrinsic properties of brain functional networks but also provide insights into the possibilities RMT offers for improving clinical diagnoses and treatment evaluations for ADHD patients. PMID- 27967147 TI - Mesoscale pattern formation of self-propelled rods with velocity reversal. AB - We study self-propelled particles with velocity reversal interacting by uniaxial (nematic) alignment within a coarse-grained hydrodynamic theory. Combining analytical and numerical continuation techniques, we show that the physics of this active system is essentially controlled by the reversal frequency. In particular, we find that elongated, high-density, ordered patterns, called bands, emerge via subcritical bifurcations from spatially homogeneous states. Our analysis reveals further that the interaction of bands is weakly attractive and, consequently, bands fuse upon collision in analogy with nonequilibrium nucleation processes. Moreover, we demonstrate that a renormalized positive line tension can be assigned to stable bands below a critical reversal rate, beyond which they are transversally unstable. In addition, we discuss the kinetic roughening of bands as well as their nonlinear dynamics close to the threshold of transversal instability. Altogether, the reduction of the multiparticle system onto the dynamics of bands provides a unified framework to understand the emergence and stability of nonequilibrium patterns in this self-propelled particle system. In this regard, our results constitute a proof of principle in favor of the hypothesis in microbiology that velocity reversal of gliding rod-shaped bacteria regulates the transitions between various self-organized patterns observed during the bacterial life cycle. PMID- 27967148 TI - Incomplete phase-space method to reveal time delay from scalar time series. AB - A computationally quick and conceptually simple method to recover time delay of the chaotic system from scalar time series is developed in this paper. We show that the orbits in the incomplete two-dimensional reconstructed phase-space will show local clustering phenomenon after the component reordering procedure proposed in this work. We find that information captured by the incomplete two dimensional reconstructed phase-space is related to the time delay tau_{0} present in the system, and will be transferred to the reordered component by the procedure of component reordering. We then propose the segmented mean variance (SMV) from the reordered component to identify the time delay tau_{0} of the system. The proposed SMV shows clear maximum when the embedding delay tau of the incomplete reconstruction matches the time delay tau_{0} of the chaotic system. Numerical data generated by a time-delay system based on the Mackey-Glass equation operating in the chaotic regime are used to illustrate the effectiveness of the proposed SMV. Experimental results show that the proposed SMV is robust to additive observational noise and is able to recover the time delay of the chaotic system even though the amount of data is relatively small and the feedback strength is weak. Moreover, the time complexity of the proposed method is quite low. PMID- 27967149 TI - Aging Wiener-Khinchin theorem and critical exponents of 1/f^{beta} noise. AB - The power spectrum of a stationary process may be calculated in terms of the autocorrelation function using the Wiener-Khinchin theorem. We here generalize the Wiener-Khinchin theorem for nonstationary processes and introduce a time dependent power spectrum where t_{m} is the measurement time. For processes with an aging autocorrelation function of the form =t^{Upsilon}phi_{EA}(tau/t), where phi_{EA}(x) is a nonanalytic function when x is small, we find aging 1/f^{beta} noise. Aging 1/f^{beta} noise is characterized by five critical exponents. We derive the relations between the scaled autocorrelation function and these exponents. We show that our definition of the time-dependent spectrum retains its interpretation as a density of Fourier modes and discuss the relation to the apparent infrared divergence of 1/f^{beta} noise. We illustrate our results for blinking-quantum-dot models, single-file diffusion, and Brownian motion in a logarithmic potential. PMID- 27967150 TI - Work, work fluctuations, and the work distribution in a thermal nonequilibrium steady state. AB - Long-ranged correlations generically exist in nonequilibrium fluid systems. In the case of a nonequilibrium steady state caused by a temperature gradient, the correlations are especially long-ranged and strong. The anomalous light scattering predicted to exist in these systems is well-confirmed by numerous experiments. Recently, the Casimir force or pressure due to these fluctuations or correlations has been discussed in great detail. In this paper, the notion of a Casimir work is introduced, and an alternative way to measure the nonequilibrium Casimir force is suggested. In particular, the nonequilibrium Casimir force is related to nonequilibrium heat, and not, as in equilibrium, to a volume derivative of an average energy. The nonequilibrium work fluctuations are determined and shown to be very anomalous compared to equilibrium work fluctuations. The nonequilibrium work distribution is also computed, and it is contrasted with work distributions in systems with short-range correlations. Again, there is a striking difference in the two cases. Formal theories of work and work distributions in nonequilibrium steady states are not explicit enough to illustrate any of these interesting features. PMID- 27967151 TI - Extended Vicsek fractals: Laplacian spectra and their applications. AB - Extended Vicsek fractals (EVF) are the structures constructed by introducing linear spacers into traditional Vicsek fractals. Here we study the Laplacian spectra of the EVF. In particularly, the recurrence relations for the Laplacian spectra allow us to obtain an analytic expression for the sum of all inverse nonvanishing Laplacian eigenvalues. This quantity characterizes the large-scale properties, such as the gyration radius of the polymeric structures, or the global mean-first passage time for the random walk processes. Introduction of the linear spacers leads to local heterogeneities, which reveal themselves, for example, in the dynamics of EVF under external forces. PMID- 27967152 TI - Emergent kinetic constraints, ergodicity breaking, and cooperative dynamics in noisy quantum systems. AB - Kinetically constrained spin systems play an important role in understanding key properties of the dynamics of slowly relaxing materials, such as glasses. Recent experimental studies have revealed that manifest kinetic constraints govern the evolution of strongly interacting gases of highly excited atoms in a noisy environment. Motivated by this development we explore which types of kinetically constrained dynamics can generally emerge in quantum spin systems subject to strong noise and show how, in this framework, constraints are accompanied by conservation laws. We discuss an experimentally realizable case of a lattice gas, where the interplay between those and the geometry of the lattice leads to collective behavior and time-scale separation even at infinite temperature. This is in contrast to models of glass-forming substances which typically rely on low temperatures and the consequent suppression of thermal activation. PMID- 27967153 TI - Excitation and suppression of chimera states by multiplexing. AB - We study excitation and suppression of chimera states in an ensemble of nonlocally coupled oscillators arranged in a framework of multiplex network. We consider the homogeneous network (all identical oscillators) with different parametric cases and interlayer heterogeneity by introducing parameter mismatch between the layers. We show the feasibility to suppress chimera states in the multiplex network via moderate interlayer interaction between a layer exhibiting chimera state and other layers which are in a coherent or incoherent state. On the contrary, for larger interlayer coupling, we observe the emergence of identical chimera states in both layers which we call an interlayer chimera state. We map the spatiotemporal behavior in a wide range of parameters, varying interlayer coupling strength and phase lag in two and three multiplexing layers. We also prove the emergence of interlayer chimera states in a multiplex network via evaluation of a continuous model. Furthermore, we consider the two-layered network of Hindmarsh-Rose neurons and reveal that in such a system multiplex interaction between layers is capable of exciting not only the synchronous interlayer chimera state but also nonidentical chimera patterns. PMID- 27967154 TI - Probability distribution of intersymbol distances in random symbolic sequences: Applications to improving detection of keywords in texts and of amino acid clustering in proteins. AB - Symbolic sequences have been extensively investigated in the past few years within the framework of statistical physics. Paradigmatic examples of such sequences are written texts, and deoxyribonucleic acid (DNA) and protein sequences. In these examples, the spatial distribution of a given symbol (a word, a DNA motif, an amino acid) is a key property usually related to the symbol importance in the sequence: The more uneven and far from random the symbol distribution, the higher the relevance of the symbol to the sequence. Thus, many techniques of analysis measure in some way the deviation of the symbol spatial distribution with respect to the random expectation. The problem is then to know the spatial distribution corresponding to randomness, which is typically considered to be either the geometric or the exponential distribution. However, these distributions are only valid for very large symbolic sequences and for many occurrences of the analyzed symbol. Here, we obtain analytically the exact, randomly expected spatial distribution valid for any sequence length and any symbol frequency, and we study its main properties. The knowledge of the distribution allows us to define a measure able to properly quantify the deviation from randomness of the symbol distribution, especially for short sequences and low symbol frequency. We apply the measure to the problem of keyword detection in written texts and to study amino acid clustering in protein sequences. In texts, we show how the results improve with respect to previous methods when short texts are analyzed. In proteins, which are typically short, we show how the measure quantifies unambiguously the amino acid clustering and characterize its spatial distribution. PMID- 27967155 TI - Viscoacoustic model for near-field ultrasonic levitation. AB - Ultrasonic near-field levitation allows for contactless support and transportation of an object over vibrating surface. We developed an accurate model predicting pressure distribution in the gap between the surface and levitating object. The formulation covers a wide range of the air flow regimes: from viscous squeezed flow dominating in small gap to acoustic wave propagation in larger gap. The paper explains derivation of the governing equations from the basic fluid dynamics. The nonreflective boundary conditions were developed to properly define air flow at the outlet. Comparing to direct computational fluid dynamics modeling our approach allows achieving good accuracy while keeping the computation cost low. Using the model we studied the levitation force as a function of gap distance. It was shown that there are three distinguished flow regimes: purely viscous, viscoacoustic, and acoustic. The regimes are defined by the balance of viscous and inertial forces. In the viscous regime the pressure in the gap is close to uniform while in the intermediate viscoacoustic and the acoustic regimes the pressure profile is wavy. The model was validated by a dedicated levitation experiment and compared to similar published results. PMID- 27967156 TI - Random holographic "large worlds" with emergent dimensions. AB - I propose a random network model governed by a Gaussian weight corresponding to Ising link antiferromagnetism as a model for emergent quantum space-time. In this model, discrete space is fundamental, not a regularization; its spectral dimension d_{s} is not a model input but is, rather, completely determined by the antiferromagnetic coupling constant. Perturbative terms suppressing triangles and favoring squares lead to locally Euclidean ground states that are Ricci flat "large worlds" with power-law extension. I then consider the quenched graphs of lowest energy for d_{s}=2 and d_{s}=3, and I show how quenching leads to the spontaneous emergence of embedding spaces of Hausdorff dimension d_{H}=4 and d_{H}=5, respectively. One of the additional, spontaneous dimensions can be interpreted as time, causality being an emergent property that arises in the large N limit (with N the number of vertices). For d_{s}=2, the quenched graphs constitute a discrete version of a 5D-space-filling surface with a number of fundamental degrees of freedom scaling like N^{2/5}, a graph version of the holographic principle. These holographic degrees of freedom can be identified with the squares of the quenched graphs, which, being triangle-free, are the fundamental area (or loop) quanta. PMID- 27967157 TI - Statistical mechanics of consciousness: Maximization of information content of network is associated with conscious awareness. AB - It is said that complexity lies between order and disorder. In the case of brain activity and physiology in general, complexity issues are being considered with increased emphasis. We sought to identify features of brain organization that are optimal for sensory processing, and that may guide the emergence of cognition and consciousness, by analyzing neurophysiological recordings in conscious and unconscious states. We find a surprisingly simple result: Normal wakeful states are characterized by the greatest number of possible configurations of interactions between brain networks, representing highest entropy values. Therefore, the information content is larger in the network associated to conscious states, suggesting that consciousness could be the result of an optimization of information processing. These findings help to guide in a more formal sense inquiry into how consciousness arises from the organization of matter. PMID- 27967158 TI - Finite-size corrections and scaling for the dimer model on the checkerboard lattice. AB - Lattice models are useful for understanding behaviors of interacting complex many body systems. The lattice dimer model has been proposed to study the adsorption of diatomic molecules on a substrate. Here we analyze the partition function of the dimer model on a 2M*2N checkerboard lattice wrapped on a torus and derive the exact asymptotic expansion of the logarithm of the partition function. We find that the internal energy at the critical point is equal to zero. We also derive the exact finite-size corrections for the free energy, the internal energy, and the specific heat. Using the exact partition function and finite-size corrections for the dimer model on a finite checkerboard lattice, we obtain finite-size scaling functions for the free energy, the internal energy, and the specific heat of the dimer model. We investigate the properties of the specific heat near the critical point and find that the specific-heat pseudocritical point coincides with the critical point of the thermodynamic limit, which means that the specific heat shift exponent lambda is equal to infinity. We have also considered the limit N->infinity for which we obtain the expansion of the free energy for the dimer model on the infinitely long cylinder. From a finite-size analysis we have found that two conformal field theories with the central charges c=1 for the height function description and c=-2 for the construction using a mapping of spanning trees can be used to describe the dimer model on the checkerboard lattice. PMID- 27967159 TI - Formation of high-order acoustic Bessel beams by spiral diffraction gratings. AB - The formation of high-order Bessel beams by a passive acoustic device consisting of an Archimedes' spiral diffraction grating is theoretically, numerically, and experimentally reported in this paper. These beams are propagation-invariant solutions of the Helmholtz equation and are characterized by an azimuthal variation of the phase along its annular spectrum producing an acoustic vortex in the near field. In our system, the scattering of plane acoustic waves by the spiral grating leads to the formation of the acoustic vortex with zero pressure on axis and the angular phase dislocations characterized by the spiral geometry. The order of the generated Bessel beam and, as a consequence, the size of the generated vortex can be fixed by the number of arms in the spiral diffraction grating. The obtained results allow for obtaining Bessel beams with controllable vorticity by a passive device, which has potential applications in low-cost acoustic tweezers and acoustic radiation force devices. PMID- 27967160 TI - Heat conduction in a chain of colliding particles with a stiff repulsive potential. AB - One-dimensional billiards, i.e., a chain of colliding particles with equal masses, is a well-known example of a completely integrable system. Billiards with different particle masses is generically not integrable, but it still exhibits divergence of a heat conduction coefficient (HCC) in the thermodynamic limit. Traditional billiards models imply instantaneous (zero-time) collisions between the particles. We relax this condition of instantaneous impact and consider heat transport in a chain of stiff colliding particles with the power-law potential of the nearest-neighbor interaction. The instantaneous collisions correspond to the limit of infinite power in the interaction potential; for finite powers, the interactions take nonzero time. This modification of the model leads to a profound physical consequence-the probability of multiple (in particular triple) particle collisions becomes nonzero. Contrary to the integrable billiards of equal particles, the modified model exhibits saturation of the heat conduction coefficient for a large system size. Moreover, the identification of scattering events with triple-particle collisions leads to a simple definition of the characteristic mean free path and a kinetic description of heat transport. This approach allows us to predict both the temperature and density dependencies for the HCC limit values. The latter dependence is quite counterintuitive-the HCC is inversely proportional to the particle density in the chain. Both predictions are confirmed by direct numerical simulations. PMID- 27967161 TI - Hybrid Monte Carlo and continuum modeling of electrolytes with concentration induced dielectric variations. AB - The distribution of ions near a charged surface is an important quantity in many biological and material processes, and has been therefore investigated intensively. However, few theoretical and simulation approaches have included the influence of concentration-induced variations in the local dielectric permittivity of an underlying electrolyte solution. Such local variations have long been observed and known to affect the properties of ionic solution in the bulk and around the charged surface. We propose a hybrid computational model that combines Monte Carlo simulations with continuum electrostatic modeling to investigate such properties. A key component in our hybrid model is a semianalytical formula for the ion-ion interaction energy in a dielectrically inhomogeneous environment. This formula is obtained by solving for the Green's function Poisson's equation with ionic-concentration-dependent dielectric permittivity using a harmonic interpolation method and spherical harmonic series. We also construct a self-consistent continuum model of electrostatics to describe the effect of ionic-concentration-dependent dielectric permittivity and the resulting self-energy contribution. With extensive numerical simulations, we verify the convergence of our hybrid simulation scheme, show the qualitatively different structures of ionic distribution due to the concentration-induced dielectric variations, and compare our simulation results with the self consistent continuum model. In particular, we study the differences between weakly and strongly charged surfaces and multivalencies of counterions. Our hybrid simulations conform particularly the depletion of ionic concentrations near a charged surface and also capture the charge inversion. We discuss several issues and possible further improvement of our approach for simulations of large charged systems. PMID- 27967162 TI - Laser propagation in dense magnetized plasma. AB - A right-hand circularly polarized electromagnetic wave can propagate in a sufficiently magnetized plasma of any density without encountering cutoff in the whistler mode. With the recent realization of tens-kilotesla magnetic fields, laser propagation in highly magnetized high-density plasmas has become of practical interest, especially for heating plasmas to high energy density and igniting fusion targets. In this paper, the whistler regime of laser-plasma interaction is discussed. It is shown by one- and two-dimensional particle-in cell simulations that moderately intense right-hand circularly polarized laser light can enter and propagate in high-density plasma and heat it efficiently because of the significantly reduced wave length and speed. PMID- 27967163 TI - Instability in reaction-superdiffusion systems. AB - We study the effect of superdiffusion on the instability in reaction-diffusion systems. It is shown that reaction-superdiffusion systems close to a Turing instability are equivalent to a time-dependent Ginzburg-Landau model and the corresponding free energy is introduced. This generalized free energy which depends on the superdiffusion exponent governs the stability, dynamics, and the fluctuations of reaction-superdiffusion systems near the Turing bifurcation. In addition, we show that for a general n-component reaction-superdiffusion system, a fractional complex Ginzburg-Landau equation emerges as the amplitude equation near a Hopf instability. Numerical simulations of this equation are carried out to illustrate the effect of superdiffusion on spatiotemporal patterns. Finally, the effect of superdiffusion on the instability in the Brusselator model, as a special case of reaction-diffusion systems, is studied. In general, superdiffusion introduces a new parameter that changes the behavior of the system near the instability. PMID- 27967164 TI - Phase transition of social learning collectives and the echo chamber. AB - We study a simple model for social learning agents in a restless multiarmed bandit. There are N agents, and the bandit has M good arms that change to bad with the probability q_{c}/N. If the agents do not know a good arm, they look for it by a random search (with the success probability q_{I}) or copy the information of other agents' good arms (with the success probability q_{O}) with probabilities 1-p or p, respectively. The distribution of the agents in M good arms obeys the Yule distribution with the power-law exponent 1+gamma in the limit N,M->infinity, and gamma=1+(1-p)q_{I}/pq_{O}. The system shows a phase transition at p_{c}=q_{I}/q_{I}+q_{o}. For pp_{c}), the variance of N_{1} per agent is finite (diverges as ?N^{2-gamma} with N). There is a threshold value N_{s} for the system size that scales as lnN_{s}?1/(gamma-1). The expected value of the number of the agents with a good arm N_{1} increases with p for N>N_{s}. For p>p_{c} and N1, which is referred to as the "echo chamber." PMID- 27967165 TI - Markov state modeling of sliding friction. AB - Markov state modeling (MSM) has recently emerged as one of the key techniques for the discovery of collective variables and the analysis of rare events in molecular simulations. In particular in biochemistry this approach is successfully exploited to find the metastable states of complex systems and their evolution in thermal equilibrium, including rare events, such as a protein undergoing folding. The physics of sliding friction and its atomistic simulations under external forces constitute a nonequilibrium field where relevant variables are in principle unknown and where a proper theory describing violent and rare events such as stick slip is still lacking. Here we show that MSM can be extended to the study of nonequilibrium phenomena and in particular friction. The approach is benchmarked on the Frenkel-Kontorova model, used here as a test system whose properties are well established. We demonstrate that the method allows the least prejudiced identification of a minimal basis of natural microscopic variables necessary for the description of the forced dynamics of sliding, through their probabilistic evolution. The steps necessary for the application to realistic frictional systems are highlighted. PMID- 27967166 TI - Publisher's Note: Imaging grain boundary grooves in hard-sphere colloidal bicrystals [Phys. Rev. E 94, 042604 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevE.94.042604. PMID- 27967167 TI - Optical wall dynamics induced by coexistence of monostable and bistable spatial regions. AB - When nonequilibrium extended homogeneous systems exhibit multistability, it leads to the presence of domain walls between the existing equilibria. Depending on the stability of the steady states, the dynamics differs. Here, we consider the interface dynamics in the case of a spatially inhomogeneous system, namely, an optical system where the control parameter is spatially Gaussian. Then interfaces connect the monostable and the bistable nonuniform states that are associated with two distinct spatial regions. The coexistence of these two regions of different stability induces relaxation dynamics and the propagation of a wall with a time-dependent speed. We emphasize analytically these two dynamical behaviors using a generic bistable model. Experimentally, an inhomogeneous Gaussian light beam traveling through either a dye-doped liquid crystal cell or a Kerr cavity depicts these behaviors, in agreement with the theoretical predictions. PMID- 27967168 TI - Linking dissipation-induced instabilities with nonmodal growth: The case of helical magnetorotational instability. AB - The helical magnetorotational instability is known to work for resistive rotational flows with comparably steep negative or extremely steep positive shear. The corresponding lower and upper Liu limits of the shear are continuously connected when some axial electrical current is allowed to flow through the rotating fluid. Using a local approximation we demonstrate that the magnetohydrodynamic behavior of this dissipation-induced instability is intimately connected with the nonmodal growth and the pseudospectrum of the underlying purely hydrodynamic problem. PMID- 27967169 TI - Inhomogeneous diffusion and ergodicity breaking induced by global memory effects. AB - We introduce a class of discrete random-walk model driven by global memory effects. At any time, the right-left transitions depend on the whole previous history of the walker, being defined by an urnlike memory mechanism. The characteristic function is calculated in an exact way, which allows us to demonstrate that the ensemble of realizations is ballistic. Asymptotically, each realization is equivalent to that of a biased Markovian diffusion process with transition rates that strongly differs from one trajectory to another. Using this "inhomogeneous diffusion" feature, the ergodic properties of the dynamics are analytically studied through the time-averaged moments. Even in the long-time regime, they remain random objects. While their average over realizations recovers the corresponding ensemble averages, departure between time and ensemble averages is explicitly shown through their probability densities. For the density of the second time-averaged moment, an ergodic limit and the limit of infinite lag times do not commutate. All these effects are induced by the memory effects. A generalized Einstein fluctuation-dissipation relation is also obtained for the time-averaged moments. PMID- 27967170 TI - Maximum caliber inference and the stochastic Ising model. AB - We investigate the maximum caliber variational principle as an inference algorithm used to predict dynamical properties of complex nonequilibrium, stationary, statistical systems in the presence of incomplete information. Specifically, we maximize the path entropy over discrete time step trajectories subject to normalization, stationarity, and detailed balance constraints together with a path-dependent dynamical information constraint reflecting a given average global behavior of the complex system. A general expression for the transition probability values associated with the stationary random Markov processes describing the nonequilibrium stationary system is computed. By virtue of our analysis, we uncover that a convenient choice of the dynamical information constraint together with a perturbative asymptotic expansion with respect to its corresponding Lagrange multiplier of the general expression for the transition probability leads to a formal overlap with the well-known Glauber hyperbolic tangent rule for the transition probability for the stochastic Ising model in the limit of very high temperatures of the heat reservoir. PMID- 27967171 TI - Limitations of discrete-time approaches to continuous-time contagion dynamics. AB - Continuous-time Markov process models of contagions are widely studied, not least because of their utility in predicting the evolution of real-world contagions and in formulating control measures. It is often the case, however, that discrete time approaches are employed to analyze such models or to simulate them numerically. In such cases, time is discretized into uniform steps and transition rates between states are replaced by transition probabilities. In this paper, we illustrate potential limitations to this approach. We show how discretizing time leads to a restriction on the values of the model parameters that can accurately be studied. We examine numerical simulation schemes employed in the literature, showing how synchronous-type updating schemes can bias discrete-time formalisms when compared against continuous-time formalisms. Event-based simulations, such as the Gillespie algorithm, are proposed as optimal simulation schemes both in terms of replicating the continuous-time process and computational speed. Finally, we show how discretizing time can affect the value of the epidemic threshold for large values of the infection rate and the recovery rate, even if the ratio between the former and the latter is small. PMID- 27967172 TI - Scaling relations in the diffusive infiltration in fractals. AB - In a recent work on fluid infiltration in a Hele-Shaw cell with the pore-block geometry of Sierpinski carpets (SCs), the area filled by the invading fluid was shown to scale as F~t^{n}, with n<1/2, thus providing a macroscopic realization of anomalous diffusion [Filipovitch et al., Water Resour. Res. 52, 5167 (2016)WRERAQ0043-139710.1002/2016WR018667]. The results agree with simulations of a diffusion equation with constant pressure at one of the borders of those fractals, but the exponent n is very different from the anomalous exponent nu=1/D_{W} of single-particle diffusion in the same fractals (D_{W} is the random walk dimension). Here we use a scaling approach to show that those exponents are related as n=nu(D_{F}-D_{B}), where D_{F} and D_{B} are the fractal dimensions of the bulk and the border from which diffusing particles come, respectively. This relation is supported by accurate numerical estimates in two SCs and in two generalized Menger sponges (MSs), in which we performed simulations of single particle random walks (RWs) with a rigid impermeable border and of a diffusive infiltration model in which that border is permanently filled with diffusing particles. This study includes one MS whose external border is also fractal. The exponent relation is also consistent with the recent simulational and experimental results on fluid infiltration in SCs, and explains the approximate quadratic dependence of n on D_{F} in these fractals. We also show that the mean square displacement of single-particle RWs has log-periodic oscillations, whose periods are similar for fractals with the same scaling factor in the generator (even with different embedding dimensions), which is consistent with the discrete scale invariance scenario. The roughness of a diffusion front defined in the infiltration problem also shows this type of oscillation, which is enhanced in fractals with narrow channels between large lacunas. PMID- 27967173 TI - Operator calculus for information field theory. AB - Signal inference problems with non-Gaussian posteriors can be hard to tackle. Through using the concept of Gibbs free energy these posteriors are rephrased as Gaussian posteriors for the price of computing various expectation values with respect to a Gaussian distribution. We present a way of translating these expectation values to a language of operators which is similar to that in quantum mechanics. This simplifies many calculations, for instance such as those involving log-normal priors. The operator calculus is illustrated by deriving a self-calibrating algorithm which is tested with mock data. PMID- 27967174 TI - Sound propagation through a rarefied gas in rectangular channels. AB - Sound propagation through a rarefied gas inside a two-dimensional cavity is investigated on the basis of the linearized Boltzmann equation, where one of the cavity walls oscillates harmonically in the direction normal to its own surface and is considered as a sound source. An analytical solution at high oscillation frequencies is obtained and detailed numerical results for a wide range of gas rarefaction are presented. The influence of both the aspect ratio of the cavity and the oscillation frequency on the average gas pressure exerted on the oscillating plate is studied. It is found that, at large values of the aspect ratio, the average pressure oscillates when the sound frequency varies, due to the sound resonance and antiresonance along the oscillation direction of the plate. However, at small values of the aspect ratio, the average pressure is a monotonically decreasing function of the sound frequency, which cannot be observed in the corresponding one-dimensional counterpart. This is explained by the sound interference in the direction parallel to the oscillating plate. The influence of both the cavity aspect ratio and oscillation frequency on the sound speed is also investigated: Again it is found that a different aspect ratio leads to the different behavior of the sound speed as a function of the oscillation frequency. PMID- 27967175 TI - Eigenvalue spectra of large correlated random matrices. AB - Using the diagrammatic method, we derive a set of self-consistent equations that describe eigenvalue distributions of large correlated asymmetric random matrices. The matrix elements can have different variances and be correlated with each other. The analytical results are confirmed by numerical simulations. The results have implications for the dynamics of neural and other biological networks where plasticity induces correlations in the connection strengths within the network. We find that the presence of correlations can have a major impact on network stability. PMID- 27967176 TI - Onsager coefficients for systems with periodic potentials. AB - We carry out the thermodynamic analysis of a Markovian stochastic engine, driven by a spatially and temporally periodic modulation in a d-dimensional space. We derive the analytic expressions for the Onsager coefficients characterizing the linear response regime for the isothermal transfer of one type of work (a driver) to another (a load), mediated by a stochastic time-periodic machine. As an illustration, we obtain the explicit results for a Markovian kangaroo process coupling two orthogonal directions and find extremely good agreement with numerical simulations. In addition, we obtain and discuss expressions for the entropy production, power, and efficiency for the kangaroo process. PMID- 27967177 TI - Experimental evidence of nonlinear mode coupling between spherical and nonspherical oscillations of microbubbles. AB - We report observations of strong nonlinear interactions between the spherical, translational, and shape oscillations of micrometer-size bubbles. This is achieved through high-speed recordings of single bubble dynamics driven by amplitude-modulated ultrasound. The features of mode coupling are highlighted through (i) the exponential growth of the parametrically excited mode (n=3) triggered by the spherical oscillations followed by a saturation due to energy transfer towards the translation and even modes, (ii) the excitation of modes well below their parametric pressure threshold, and (iii) clear modification of the breathing mode R(t). These results are compared to recent theories accounting for nonlinear mode coupling, providing predictions in agreement with the observed bubble dynamics. PMID- 27967178 TI - Finite-temperature quantum effects on confined charges. AB - A quantum system of N Coulomb charges confined within a harmonic trap is considered over a wide range of densities and temperatures. A recently described construction of an equivalent classical system is applied in order to exploit the rather complete classical description of harmonic confinement via liquid-state theory. Here, the effects of quantum mechanics on that representation are described with attention focused on the origin and nature of shell structure. The analysis extends from the classical strong Coulomb coupling conditions of dusty plasmas to the opposite limit of low temperatures and large densities characteristic of "warm, dense matter." PMID- 27967179 TI - Identifying ergodicity breaking for fractional anomalous diffusion: Criteria for minimal trajectory length. AB - In this paper, we study ergodic properties of alpha-stable autoregressive fractionally integrated moving average (ARFIMA) processes which form a large class of anomalous diffusions. A crucial practical question is how long trajectories one needs to observe in an experiment in order to claim that the analyzed data are ergodic or not. This will be solved by checking the asymptotic convergence to 0 of the empirical estimator F(n) for the dynamical functional D(n) defined as a Fourier transform of the n-lag increments of the ARFIMA process. Moreover, we introduce more flexible concept of the epsilon-ergodicity. PMID- 27967180 TI - Drag reductions and the air-water interface stability of superhydrophobic surfaces in rectangular channel flow. AB - Flow in a rectangular channel with superhydrophobic (SH) top and bottom walls was investigated experimentally. Different SH surfaces, including hierarchical structured surfaces and surfaces with different micropost sizes (width and spacing) but the same solid fraction, were fabricated and measured. Pressure loss and flow rate in the channel with SH top and bottom walls were measured, with Reynolds number changing from 700 to 4700, and the corresponding friction factor for the SH surface was calculated. The statuses of the air plastron on different SH surfaces were observed during the experiment. In our experiment, compared with the experiment for the smooth surface, drag reductions were observed for all SH surfaces, with the largest drag reduction of 42.2%. It was found that the hierarchy of the microstructure can increase the drag reduction by decreasing the solid fraction and enhancing the stability of the air-water interface. With a fixed solid fraction, the drag reduction decreases as the post size (width and spacing) increases, due to the increasing curvature and instability effects of the air-water interface. A correlation parameter between the contact angle hysteresis, the air-water interface stability, and the drag reduction of the SH surfaces was found. PMID- 27967181 TI - Interdependent lattice networks in high dimensions. AB - We study the mutual percolation of two interdependent lattice networks ranging from two to seven dimensions, denoted as D. We impose that the length (measured as chemical distance) of interdependency links connecting nodes in the two lattices be less than or equal to a certain value, r. For each value of D and r, we find the mutual percolation threshold, p_{c}[D,r], below which the system completely collapses through a cascade of failures following an initial destruction of a fraction (1-p) of the nodes in one of the lattices. We find that for each dimension, D<6, there is a value of r=r_{I}>1 such that for r>=r_{I} the cascading failures occur as a discontinuous first-order transition, while for rr_{I}, and for r>r_{max} the vulnerability starts to decrease as r->infinity. However, the decrease becomes less significant as D increases, and p_{c}[D,r_{max}] p_{c}[D,infinity] decreases exponentially with D. We also investigate the dependence of p_{c}[D,r] on the system size as well as how the nature of the transition changes as the number of lattice sites, N->infinity. PMID- 27967182 TI - Heat dissipation and information flow for delayed bistable Langevin systems near coherence resonance. AB - In this paper, stochastic thermodynamics of delayed bistable Langevin systems near coherence resonance is discussed. We calculate the heat dissipation rate and the information flow of a delayed bistable Langevin system under various noise intensities. Both the heat dissipation rate and the information flow are found to be bell-shaped functions of the noise intensity, which implies that coherence resonance manifests itself in the thermodynamic properties. PMID- 27967183 TI - Enantiodromic effective generators of a Markov jump process with Gallavotti-Cohen symmetry. AB - This paper deals with the properties of the stochastic generators of the effective (driven) processes associated with atypical values of transition dependent time-integrated currents with Gallavotti-Cohen symmetry in Markov jump processes. Exploiting the concept of biased ensemble of trajectories by introducing a biasing field s, we show that the stochastic generators of the effective processes associated with the biasing fields s and E-s are enantiodromic with respect to each other where E is the conjugated field to the current. We illustrate our findings by considering an exactly solvable creation annihilation process of classical particles with nearest-neighbor interactions defined on a one-dimensional lattice. PMID- 27967184 TI - Self-adjoint integral operator for bounded nonlocal transport. AB - An integral operator is developed to describe nonlocal transport in a one dimensional system bounded on both ends by material walls. The "jump" distributions associated with nonlocal transport are taken to be Levy alpha stable distributions, which become naturally truncated by the bounding walls. The truncation process results in the operator containing a self-consistent, convective inward transport term (pinch). The properties of the integral operator as functions of the Levy distribution parameter set [alpha,gamma] and the wall conductivity are presented. The integral operator continuously recovers the features of local transport when alpha=2. The self-adjoint formulation allows for an accurate description of spatial variation in the Levy parameters in the nonlocal system. Spatial variation in the Levy parameters is shown to result in internally generated flows. Examples of cold-pulse propagation in nonlocal systems illustrate the capabilities of the methodology. PMID- 27967185 TI - Effects of thin film and Stokes drift on the generation of vorticity by surface waves. AB - Recently a theoretical scheme explaining the vorticity generation by surface waves in liquids was developed [Phys. Rev. Lett. 116, 054501 (2016)PRLTAO0031 900710.1103/PhysRevLett.116.054501]. Here we study how a thin (monomolecular) film presented on the surface of liquid affects the generated vorticity. We demonstrate that the vorticity becomes parametrically larger than for the case of liquid with a free surface, and the parameter is the quality factor of surface waves up to numerical factor. We also discuss the PIV experimental scheme intended to observe the generated vorticity and find that Stokes drift influences the measured velocity field. Explicit expression for the vertical vorticity was obtained. PMID- 27967186 TI - Broadband and tunable one-dimensional strongly nonlinear acoustic metamaterials: Theoretical study. AB - This paper focuses on the dispersion properties and mechanism of the one dimensional strongly nonlinear acoustic metamaterials (NAMMs) based on the homotopy method. The local bifurcation mechanism, which is different from conventional local resonance, is found. It is demonstrated that the local period doubling bifurcation of multiple cells will induce chaotic bands in the NAMMs, which can significantly expand the bandwidth for wave suppression. The saddle node bifurcation leads the system state jumping to the chaotic branch. Furthermore, the amplitude-dependent dispersion properties enable NAMMs to manipulate elastic waves externally. Study of broadband tunable abilities reveals that stronger nonlinearity (larger nonlinear coefficient or higher amplitude) presents a broader nonlinear band gap and larger transmission loss. Moreover, with less attached mass, a low frequency and broadband are achievable simultaneously. This research may provide useful approaches for elastic wave control. PMID- 27967187 TI - Multispecies plasma expansion into vacuum: The role of secondary ions and suprathermal electrons. AB - The self-similar expansion of multispecies ion plasma is investigated by a two ion fluid model with adiabatic equation of state for each ionic species. Our aim is to elucidate the effect of secondary ions on a plasma expansion front, in combination with energetic (suprathermal) electrons in the background, modeled by a kappa-type distribution function. The plasma density, velocity, and electric field profile is investigated. It is shown that energetic electrons have a significant effect on the expansion front dynamics, essentially energizing the front, thus enhancing the ion acceleration mechanism. Different special cases are considered as regards the relative magnitude of the ion mass and/or charge state. PMID- 27967188 TI - Dynamics of large-scale quantities in Rayleigh-Benard convection. AB - In this paper we estimate the relative strengths of various terms of the Rayleigh Benard equations. Based on these estimates and scaling analysis, we derive a general formula for the large-scale velocity U or the Peclet number that is applicable for arbitrary Rayleigh number Ra and Prandtl number Pr. Our formula fits reasonably well with the earlier simulation and experimental results. Our analysis also shows that the wall-bounded convection has enhanced viscous force compared to free turbulence. We also demonstrate how correlations deviate the Nusselt number scaling from the theoretical prediction of Ra^{1/2} to the experimentally observed scaling of nearly Ra^{0.3}. PMID- 27967189 TI - Noise-driven interfaces and their macroscopic representation. AB - We study the macroscopic representation of noise-driven interfaces in stochastic interface growth models in (1+1) dimensions. The interface is characterized macroscopically by saturation, which represents the fluctuating sharp interface by a smoothly varying phase field with values between 0 and 1. We determine the one-point interface height statistics for the Edwards-Wilkinson (EW) and Kadar Paris-Zhang (KPZ) models in order to determine explicit deterministic equations for the phase saturation for each of them. While we obtain exact results for the EW model, we develop a Gaussian closure approximation for the KPZ model. We identify an interface compression term, which is related to mass transfer perpendicular to the growth direction, and a diffusion term that tends to increase the interface width. The interface compression rate depends on the mesoscopic mass transfer process along the interface and in this sense provides a relation between meso- and macroscopic interface dynamics. These results shed light on the relation between mesoscale and macroscale interface models, and provide a systematic framework for the upscaling of stochastic interface dynamics. PMID- 27967190 TI - Inducing self-organized criticality in a network toy model by neighborhood assortativity. AB - Complex networks are a recent type of framework used to study complex systems with many interacting elements, such as self-organized criticality (SOC). The network nodes' tendency to link to other nodes of similar type is characterized by assortative mixing. Real networks exhibit assortative mixing by vertex degree, however, typical random network models, such as the Erdos-Renyi or the Barabasi Albert model, show no assortative arrangements. In this paper we introduce the notion of neighborhood assortativity as the tendency of a node to belong to a community (its neighborhood) showing an average property similar to its own. Imposing neighborhood assortative mixing by degree in a network toy model, SOC dynamics can be found. These dynamics are driven only by the network topology. The long-range correlations resulting from criticality have been characterized by means of fluctuation analysis and show an anticorrelation in the node's activity. The model contains only one parameter and its statistics plots for different values of the parameter can be collapsed into a single curve. The simplicity of the model allows us to perform numerical simulations and also to study analytically the statistics for a specific value of the parameter, making use of the Markov chains. PMID- 27967191 TI - Electron heating in subpicosecond laser interaction with overdense and near critical plasmas. AB - In this work we investigate electron heating induced by intense laser interaction with micrometric flat solid foils in the context of laser-driven ion acceleration. We propose a simple law to predict the electron temperature in a wider range of laser parameters with respect to commonly used existing models. An extensive two-dimensional (2D) and 3D numerical campaign shows that electron heating is due to the combined actions of j*B and Brunel effect. Electron temperature can be well described with a simple function of pulse intensity and angle of incidence, with parameters dependent on pulse polarization. We then combine our model for the electron temperature with an existing model for laser ion acceleration, using recent experimental results as a benchmark. We also discuss an exploratory attempt to model electron temperature for multilayered foam-attached targets, which have been proven recently to be an attractive target concept for laser-driven ion acceleration. PMID- 27967192 TI - Unsteady turbulence cascades. AB - We have run a total of 311 direct numerical simulations (DNSs) of decaying three dimensional Navier-Stokes turbulence in a periodic box with values of the Taylor length-based Reynolds number up to about 300 and an energy spectrum with a wide wave-number range of close to -5/3 power-law dependence at the higher Reynolds numbers. On the basis of these runs, we have found a critical time when (i) the rate of change of the square of the integral length scale turns from increasing to decreasing, (ii) the ratio of interscale energy flux to high-pass filtered turbulence dissipation changes from decreasing to very slowly increasing in the inertial range, (iii) the signature of large-scale coherent structures disappears in the energy spectrum, and (iv) the scaling of the turbulence dissipation changes from the one recently discovered in DNSs of forced unsteady turbulence and in wind tunnel experiments of turbulent wakes and grid-generated turbulence to the classical scaling proposed by G. I. Taylor [Proc. R. Soc. London, Ser. A 151, 421 (1935)1364-502110.1098/rspa.1935.0158] and A. N. Kolmogorov [Dokl. Akad. Nauk SSSR 31, 538 (1941)]. Even though the customary theoretical basis for this Taylor-Kolmogorov scaling is a statistically stationary cascade where large-scale energy flux balances dissipation, this is not the case throughout the entire time range of integration in all our DNS runs. The recently discovered dissipation scaling can be reformulated physically as a situation in which the dissipation rates of the small and large scales evolve together. We advance two hypotheses that may form the basis of a theoretical approach to unsteady turbulence cascades in the presence of large-scale coherent structures. PMID- 27967193 TI - Equivalence of coupled networks and networks with multimodal frequency distributions: Conditions for the bimodal and trimodal case. AB - Populations of oscillators can display a variety of synchronization patterns depending on the oscillators' intrinsic coupling and the coupling between them. We consider two coupled symmetric (sub)populations with unimodal frequency distributions. If internal and external coupling strengths are identical, a change of variables transforms the system into a single population of oscillators whose natural frequencies are bimodally distributed. Otherwise an additional bifurcation parameter kappa enters the dynamics. By using the Ott-Antonsen ansatz, we rigorously prove that kappa does not lead to new bifurcations, but that a symmetric two-coupled-population network and a network with a symmetric bimodal frequency distribution are topologically equivalent. Seeking for generalizations, we further analyze a symmetric trimodal network vis-a-vis three coupled symmetric unimodal populations. Here, however, the equivalence with respect to stability, dynamics, and bifurcations of the two systems no longer holds. PMID- 27967194 TI - Efficient time-sampling method in Coulomb-corrected strong-field approximation. AB - One of the main goals of strong-field physics is to understand the complex structures formed in the momentum plane of the photoelectron. For this purpose, different semiclassical methods have been developed to seek an intuitive picture of the underlying mechanism. The most popular ones are the quantum trajectory Monte Carlo (QTMC) method and the Coulomb-corrected strong-field approximation (CCSFA), both of which take the classical action into consideration and can describe the interference effect. The CCSFA is more widely applicable in a large range of laser parameters due to its nonadiabatic nature in treating the initial tunneling dynamics. However, the CCSFA is much more time consuming than the QTMC method because of the numerical solution to the saddle-point equations. In the present work, we present a time-sampling method to overcome this disadvantage. Our method is as efficient as the fast QTMC method and as accurate as the original treatment in CCSFA. The performance of our method is verified by comparing the results of these methods with that of the exact solution to the time-dependent Schrodinger equation. PMID- 27967195 TI - High-temperature ratchets with sawtooth potentials. AB - The concept of the effective potential is suggested as an efficient instrument to get a uniform analytical description of stochastic high-temperature on-off flashing and rocking ratchets. The analytical representation for the average particle velocity, obtained within this technique, allows description of ratchets with sharp potentials (and potentials with jumps in particular). For sawtooth potentials, the explicit analytical expressions for the average velocity of on off flashing and rocking ratchets valid for arbitrary frequencies of potential energy fluctuations are derived; the difference in their high-frequency asymptotics is explored for the smooth and cusped profiles, and profiles with jumps. The origin of the difference as well as the appearance of the jump behavior in ratchet characteristics are interpreted in terms of self-similar universal solutions which give the continuous description of the effect. It is shown how the jump behavior in motor characteristics arises from the competition between the characteristic times of the system. PMID- 27967196 TI - Local discretization method for overdamped Brownian motion on a potential with multiple deep wells. AB - We present a general method for transforming the continuous diffusion equation describing overdamped Brownian motion on a time-independent potential with multiple deep wells to a discrete master equation. The method is based on an expansion in localized basis states of local metastable potentials that match the full potential in the region of each potential well. Unlike previous basis methods for discretizing Brownian motion on a potential, this approach is valid for periodic potentials with varying multiple deep wells per period and can also be applied to nonperiodic systems. We apply the method to a range of potentials and find that potential wells that are deep compared to five times the thermal energy can be associated with a discrete localized state while shallower wells are better incorporated into the local metastable potentials of neighboring deep potential wells. PMID- 27967197 TI - Large-scale dynamics of magnetic helicity. AB - In this paper we investigate the dynamics of magnetic helicity in magnetohydrodynamic (MHD) turbulent flows focusing at scales larger than the forcing scale. Our results show a nonlocal inverse cascade of magnetic helicity, which occurs directly from the forcing scale into the largest scales of the magnetic field. We also observe that no magnetic helicity and no energy is transferred to an intermediate range of scales sufficiently smaller than the container size and larger than the forcing scale. Thus, the statistical properties of this range of scales, which increases with scale separation, is shown to be described to a large extent by the zero flux solutions of the absolute statistical equilibrium theory exhibited by the truncated ideal MHD equations. PMID- 27967198 TI - Elephant random walks and their connection to Polya-type urns. AB - In this paper, we explain the connection between the elephant random walk (ERW) and an urn model a la Polya and derive functional limit theorems for the former. The ERW model was introduced in [Phys. Rev. E 70, 045101 (2004)10.1103/PhysRevE.70.045101] to study memory effects in a highly non Markovian setting. More specifically, the ERW is a one-dimensional discrete-time random walk with a complete memory of its past. The influence of the memory is measured in terms of a memory parameter p between zero and one. In the past years, a considerable effort has been undertaken to understand the large-scale behavior of the ERW, depending on the choice of p. Here, we use known results on urns to explicitly solve the ERW in all memory regimes. The method works as well for ERWs in higher dimensions and is widely applicable to related models. PMID- 27967199 TI - Equivalence between modularity optimization and maximum likelihood methods for community detection. AB - We demonstrate an equivalence between two widely used methods of community detection in networks, the method of modularity maximization and the method of maximum likelihood applied to the degree-corrected stochastic block model. Specifically, we show an exact equivalence between maximization of the generalized modularity that includes a resolution parameter and the special case of the block model known as the planted partition model, in which all communities in a network are assumed to have statistically similar properties. Among other things, this equivalence provides a mathematically principled derivation of the modularity function, clarifies the conditions and assumptions of its use, and gives an explicit formula for the optimal value of the resolution parameter. PMID- 27967200 TI - Suppressing membrane height fluctuations leads to a membrane-mediated interaction among proteins. AB - Membrane-induced interactions can play a significant role in the spatial distribution of membrane-bound proteins. We develop a model that combines a continuum description of lipid bilayers with a discrete particle model of proteins to probe the emerging structure of the combined membrane-protein system. Our model takes into account the membrane's elastic behavior, the steric repulsion between proteins, and the quenching of membrane shape fluctuations due to the presence of the proteins. We employ coupled Langevin equations to describe the dynamics of the system. We show that coupling to the membrane induces an attractive interaction among proteins, which may contribute to the clustering of proteins in biological membranes. We investigate the lateral protein diffusion and find that it is reduced due to transient fluctuations in membrane shape. PMID- 27967201 TI - Theoretical description of effective heat transfer between two viscously coupled beads. AB - We analytically study the role of nonconservative forces, namely viscous couplings, on the statistical properties of the energy flux between two Brownian particles kept at different temperatures. From the dynamical model describing the system, we identify an energy flow that satisfies a fluctuation theorem both in the stationary and in transient states. In particular, for the specific case of a linear nonconservative interaction, we derive an exact fluctuation theorem that holds for any measurement time in the transient regime, and which involves the energy flux alone. Moreover, in this regime the system presents an interesting asymmetry between the hot and cold particles. The theoretical predictions are in good agreement with the experimental results already presented in our previous article [Imparato et al., Phys. Rev. Lett. 116, 068301 (2016)PRLTAO0031 900710.1103/PhysRevLett.116.068301], where we investigated the thermodynamic properties of two Brownian particles, trapped with optical tweezers, interacting through a dissipative hydrodynamic coupling. PMID- 27967202 TI - Spectral functions with the density matrix renormalization group: Krylov-space approach for correction vectors. AB - Frequency-dependent correlations, such as the spectral function and the dynamical structure factor, help illustrate condensed matter experiments. Within the density matrix renormalization group (DMRG) framework, an accurate method for calculating spectral functions directly in frequency is the correction-vector method. The correction vector can be computed by solving a linear equation or by minimizing a functional. This paper proposes an alternative to calculate the correction vector: to use the Krylov-space approach. This paper then studies the accuracy and performance of the Krylov-space approach, when applied to the Heisenberg, the t-J, and the Hubbard models. The cases studied indicate that the Krylov-space approach can be more accurate and efficient than the conjugate gradient, and that the error of the former integrates best when a Krylov-space decomposition is also used for ground state DMRG. PMID- 27967203 TI - Peroral endoscopic myotomy for an achalasia patient with multiple esophageal diverticula. AB - Peoral endoscopic myotomy (POEM) has been proved to be safe and effective for treating achalasia, however the presence of esophageal diverticulum would increase the technical difficulty. In this letter, we firstly report a case regarding POEM for achalasia with concomitant multiple esophageal diverticulums. PMID- 27967204 TI - Matrix Metalloproteinase-1 Activation Contributes to Airway Smooth Muscle Growth and Asthma Severity. AB - RATIONALE: Matrix metalloproteinase-1 (MMP-1) and mast cells are present in the airways of people with asthma. OBJECTIVES: To investigate whether MMP-1 could be activated by mast cells and increase asthma severity. METHODS: Patients with stable asthma and healthy control subjects underwent spirometry, methacholine challenge, and bronchoscopy, and their airway smooth muscle cells were grown in culture. A second asthma group and control subjects had symptom scores, spirometry, and bronchoalveolar lavage before and after rhinovirus-induced asthma exacerbations. Extracellular matrix was prepared from decellularized airway smooth muscle cultures. MMP-1 protein and activity were assessed. MEASUREMENTS AND MAIN RESULTS: Airway smooth muscle cells generated pro-MMP-1, which was proteolytically activated by mast cell tryptase. Airway smooth muscle treated with activated mast cell supernatants produced extracellular matrix, which enhanced subsequent airway smooth muscle growth by 1.5-fold (P < 0.05), which was dependent on MMP-1 activation. In asthma, airway pro-MMP-1 was 5.4-fold higher than control subjects (P = 0.002). Mast cell numbers were associated with airway smooth muscle proliferation and MMP-1 protein associated with bronchial hyperresponsiveness. During exacerbations, MMP-1 activity increased and was associated with fall in FEV1 and worsening asthma symptoms. CONCLUSIONS: MMP-1 is activated by mast cell tryptase resulting in a proproliferative extracellular matrix. In asthma, mast cells are associated with airway smooth muscle growth, MMP-1 levels are associated with bronchial hyperresponsiveness, and MMP-1 activation are associated with exacerbation severity. Our findings suggest that airway smooth muscle/mast cell interactions contribute to asthma severity by transiently increasing MMP activation, airway smooth muscle growth, and airway responsiveness. PMID- 27967208 TI - Welcome to the 11th Volume of Biomarkers in Medicine. PMID- 27967207 TI - Care staff perceptions of a social robot called Paro and a look-alike Plush Toy: a descriptive qualitative approach. AB - OBJECTIVES: Social robots such as Paro, a therapeutic companion robot, have recently been introduced into dementia care as a means to reduce behavioural and psychological symptoms of dementia. The purpose of this study was to explore care staff perceptions of Paro and a look-alike non-robotic animal, including benefits and limitations in dementia care. METHODS: The study assumed a descriptive qualitative approach, nested within a large cluster-randomised controlled trial. We interviewed a subsample of 20 facility care staff, from nine long-term care facilities in Southeast Queensland, Australia. Thematic analysis of the data, which was inductive and data-driven, was undertaken with the assistance of the qualitative software, ATLAS.ti(r). RESULTS: The findings refer to four categories: increasing excitement for Paro and decreasing enthusiasm for Plush Toy; value and function of Paro; opportunities for engagement; and alternatives vs. robustness. CONCLUSION: Staff caring for people with dementia preferred Paro compared to a look-alike Plush Toy. Staff identified that Paro had the potential to improve quality of life for people with dementia, whereas the Plush Toy had limitations when compared to Paro. However, participants expressed concern that the cost of Paro could reduce opportunities for use within aged care. PMID- 27967206 TI - Silencing Med12 Gene Reduces Proliferation of Human Leiomyoma Cells Mediated via Wnt/beta-Catenin Signaling Pathway. AB - Uterine fibroids, or leiomyoma, are the most common benign tumors in women of reproductive age. In this work, the effect of silencing the mediator complex subunit 12 (Med12) gene in human uterine fibroid cells was evaluated. The role of Med12 in the modulation of Wnt/beta-catenin and cell proliferation-associated signaling was evaluated in human uterine fibroid cells. Med12 was silenced in the immortalized human uterine fibroid cell line (HuLM) using a lentivirus-based Med12 gene-specific RNA interference strategy. HuLM cells were infected with lentiviruses carrying Med12-specific short hairpin RNA (shRNA) sequences or a nonfunctional shRNA scrambled control with green fluorescence protein. Stable cells that expressed low levels of Med12 protein were characterized. Wnt/beta catenin signaling, sex steroid receptor signaling, cell cycle-associated, and fibrosis-associated proteins were measured. Med12 knockdown cells showed significantly (P < 0.05) reduced levels of Wnt4 and beta-catenin proteins as well as cell proliferation, as compared with scrambled control cells. Med12 knockdown cells also showed reduced levels of cell cycle-associated cyclin D1, Cdk1, and Cdk2 proteins as well as reduced activation of p-extracellular signal-regulated kinase, p-protein kinase B, and transforming growth factor (TGF)-beta signaling pathways as compared with scrambled control cells. Moreover, TGF-beta-regulated fibrosis-related proteins such as fibronectin, collagen type 1, and plasminogen activator inhibitor-1 were significantly (P < 0.05) reduced in Med12 knockdown cells as compared with scrambled control cells. Together, these results suggest that Med12 plays a key role in the regulation of HuLM cell proliferation through the modulation of Wnt/beta-catenin, cell cycle-associated, and fibrosis associated protein expression. PMID- 27967205 TI - Gestational Hyperandrogenism in Developmental Programming. AB - Androgen excess (hyperandrogenism) is a common endocrine disorder affecting women of reproductive age. The potential causes of androgen excess in women include polycystic ovary syndrome, congenital adrenal hyperplasia (CAH), adrenal tumors, and racial disparity among many others. During pregnancy, luteoma, placental aromatase deficiency, and fetal CAH are additional causes of gestational hyperandrogenism. The present report reviews the various phenotypes of hyperandrogenism during pregnancy and its origin, pathophysiology, and the effect of hyperandrogenism on the fetal developmental trajectory and offspring consequences. PMID- 27967210 TI - Relationship Between Falls and Complementary and Alternative Medicine Use Among Community-Dwelling Older Adults. AB - OBJECTIVES: The objective of this study was to examine the potential relationship between different forms of complementary and alternative medicine (CAM) use and falls among older adults in New York City (NYC). DESIGN: This cross-sectional study of data from the NYC Health Indicators Project survey used modified questionnaire items from several national surveys. SETTINGS: Participants were recruited from 56 senior centers located in the 5 boroughs of NYC. PARTICIPANTS: There were 1273 participants aged 60 years or older included in the final analysis. OUTCOME MEASURES: Of particular interest to the researchers was a dichotomous outcome variable for falls, indicating that an individual had experienced no falls during the past year or one or more falls. Also of interest in the analyses were five CAM therapy types: alternative medical systems, biologically based therapies, manipulative and body-based therapies, mind-body therapies, and movement therapies. RESULTS: Prevalence of falls in NYC was 26.8%, which is consistent with the national average. Prevalence of CAM use was 92%. Participants who had tried manipulative and body-based therapies were more likely to report falling in the past 12 months (odds ratio, 1.65; 95% confidence interval, 1.26-2.15), after adjustment for age and sex. This observed association may reflect older adults with chronic pain who are already at risk for falling and are seeking therapy for this pain. None of the other CAM types were significantly associated with falls. CONCLUSIONS: Because of the growing popularity of CAM use within this population, CAM practitioners should be included in falls prevention strategies. Particular attention should be taken to include practitioners who provide manipulative and body-based therapies (e.g., chiropractors, osteopaths, physical and massage therapists) because of the high risk for falls observed among individuals who use these therapies. PMID- 27967209 TI - Cluster of Differentiation 36 Deficiency Aggravates Macrophage Infiltration and Hepatic Inflammation by Upregulating Monocyte Chemotactic Protein-1 Expression of Hepatocytes Through Histone Deacetylase 2-Dependent Pathway. AB - AIMS: Cluster of differentiation 36 (CD36) is involved in the development of nonalcoholic steatohepatitis (NASH). Excess CD36 facilitates liver cells taking fatty acid and activates inflammatory signals to promote hepatic steatosis and inflammation. However, CD36 deficiency paradoxically promotes nonalcoholic fatty liver disease by unknown mechanisms. We explored the probable molecular mechanism of hepatic inflammation induced by CD36 deficiency. RESULTS: CD36 deletion in mice (CD36-/- mice) specifically increased monocyte chemotactic protein-1 (MCP-1) in hepatocytes, promoted macrophage migration to the liver, and aggravated hepatic inflammatory response and fibrosis. The nuclear expression of histone deacetylase 2 (HDAC2), which highly expresses in wild-type hepatocytes and has an inhibitory effect on acetyl histone 3 (H3), was reduced in CD36-deficient hepatocytes. Consequently, the level of acetyl H3 binding to MCP-1 promoters was increased in CD36-deficient hepatocytes, causing hepatic-specific MCP-1 transcriptional activation. Reduction of nuclear HDAC2 in both CD36-/- mice liver and cultured hepatocytes was due to reduction of intracellular reactive oxygen species (ROS) level, while supplement of low-concentration hydrogen peroxide (H2O2) overcame the suppression of HDAC2 caused by CD36 deficiency, decreasing MCP-1 gene transcription and microphage migration. INNOVATION: Our results provide first evidence that decreased ROS production by CD36 deletion was also harmful for livers. The fine balance of CD36 plays an important role in maintaining balances of hepatic ROS and nuclear HDAC2, which could be a potential new therapeutic strategy for the prevention of NASH development. CONCLUSION: CD36 deficiency promoted the development of NASH by facilitating the transcription of MCP-1 in hepatocytes due to the reduction of ROS and nuclear HDAC2. Antioxid. Redox Signal. 00, 000-000. PMID- 27967211 TI - Barriers to peer-reviewed journal article publication of abstracts presented at the 2006-2008 Association of Chiropractic Colleges Educational Conference and Research Agenda Conference Meetings. AB - OBJECTIVE: We investigated the self-reported barriers to publication for authors of abstracts presented at the most recent chiropractic scientific meetings for which publication rates are known, that is the 2006 to 2008 Association of Chiropractic Colleges Educational Conference and Research Agenda Conference (ACC/RAC) meetings. METHODS: A 4-question electronic survey was sent via email to 1 of the listed authors for each abstract not published as a full paper within 4 years of the 2006 to 2008 ACC/RAC meetings. Each author was asked to complete the survey for only 1 abstract. Taking into account authors who appeared on more than 1 abstract, a link to the electronic survey was emailed to 111 potential participants. RESULTS: Of 111 participants, 67 completed a survey for a return rate of 60%. Over 80% (55/67) of the respondents were chiropractors who were faculty members at educational institutions. Of the subjects, 30% (20/67) indicated that the meeting abstract had either been published after 2012 or still was in the publishing process. For those who had not submitted a manuscript for publication, the most frequently cited barriers to publishing were pursuit of publishing as a low priority followed by a lack of time to prepare a manuscript. CONCLUSION: The main barriers to publishing in this sample were that publishing had a low priority compared to other possible uses of the abstract author's time and a perceived lack of time to pursue the publication process. PMID- 27967212 TI - A prospective survey of chiropractic student experiences with pediatric care and variability of case mix while on clinical placement in Rarotonga. AB - OBJECTIVE: To compare chiropractic students' perceptions of preparedness for practice before and after a clinical placement in Rarotonga and to report demographics from these experiences. METHODS: The students completed deidentified pre- and postplacement surveys assessing pediatric practice preparedness. Students tallied the patient numbers, age, and chiropractic techniques used per visit for each day of clinic placement. On completion of the program, participating students (27/34, or 79% of the student cohort) did a postplacement survey on their perception of practice preparedness. Data were analyzed with the Spearman rho correlation, the Mann-Whitney U test, and regression analysis. RESULTS: There was an increase in perceived preparedness for pediatric practice, ranging from 24.1% of the student cohort at the start of the study to 82.1% following clinical placement in Rarotonga. The change in student preparedness to practice with children was positively correlated with the total number of children managed (rs = .05, p = .01) and the number of children managed who were under 10 years of age (rs = .60, p = .001). Multiple regression analysis demonstrated a medium positive effect for postprogram preparedness (F [4, 20] = 3.567, p = .024). CONCLUSION: Clinical outreach to Rarotonga provided a broad case mix of patients and a change in student perceptions of preparedness to practice with children, which was positively affected by the total number of children managed and the number of children managed who were under 10 years of age. PMID- 27967213 TI - Could NLRP3-Inflammasome Be a Cardiovascular Risk Biomarker in Acute Myocardial Infarction Patients? AB - Conventional cardiovascular risk factors (CVRFs) are accepted to identify asymptomatic individuals with high risk of acute myocardial infarction (AMI). However, AMI affects many patients previously classified at low risk. New biomarkers are needed to improve risk prediction. We propose to evaluate the NLRP3-inflammasome complex as a potential conventional cardiovascular risk (CVR) indicator in healthy males and post-AMI patients and compare both groups by known CVRFs. We included 109 men with no history of cardiovascular disease (controls) and 150 AMI patients attending a cardiac rehabilitation program. AMI patients had higher mean of body mass index (BMI) and waist circumference than the controls. However, high percentages of the controls had a high BMI and a waist circumference >95 cm. The controls also had higher systolic blood pressure (p > 0.001), total and low-density lipoprotein cholesterol, dietary nutrient, and calorific intake. Fuster BEWAT score (FBS) correlated more closely than Framingham risk score (FRS) with most CVRF, groups. However, only the FBS showed a correlation with inflammasome cytokine interleukin 1beta (IL-1beta). Several CVRFs were significantly better in AMI patients; however, this group also had higher mRNA expression of the inflammasome gene NLRP3 and lower expression of the autophagy gene MAP-LC3. The controls had high levels of CVRF, probably reflecting unhealthy lifestyle. FBS reflects the efficiency of strategies to induce lifestyle changes such as cardiac rehabilitation programs, and could provide a sensitive evaluation CVR. These results lead to the hypothesis that NLRP3 inflammasome and associated IL-1beta release have potential as CVR biomarkers, particularly in post-AMI patients with otherwise low risk scores. Antioxid. Redox Signal. 27, 269-275. PMID- 27967214 TI - Three new benzolactones from Lavandula angustifolia and their bioactivities. AB - Three new benzolactones (1-3), together with four known ones (4-7), were isolated from the whole herb of Lavandula angustifolia. Their structures were established on the basis of detailed spectroscopic analysis (1D- and 2D-NMR, HRESIMS, UV, and IR) and comparison with data reported in the literature. New compounds were evaluated for their anti-tobacco mosaic virus (TMV) activities and cytotoxic activities. The results revealed that compounds 1-3 showed obvious anti-TMV activities with inhibition rates of 26.9, 30.2, and 28.4%, which were at the same grade as positive control. Compounds 1-3 also showed weak inhibitory activities against some tested human tumor cell lines with IC50 values in the range of 32.1 7.6 MUM. PMID- 27967216 TI - Randomized Study of Ureteral Catheter vs Double-J Stent in Tubeless Minimally Invasive Percutaneous Nephrolithotomy Patients. AB - OBJECTIVE: To prospectively analyze and compare the outcomes of using externalized ureteral catheter (EUC) vs Double-J ureteral stent (DJ) in tubeless minimally invasive percutaneous nephrolithotomy (MPCNL). PATIENTS AND METHODS: A total of 109 patients underwent tubeless MPCNL in our institute and have been enrolled into this study. Fifty-six and 53 patients had EUC and DJ positioning at the conclusion of the procedure, respectively. The two approaches have been compared for operative time, intraoperative blood loss, postoperative visual analogue pain scale (VAS) score, analgesic requirement, stent-related symptoms, hospital stay, degree of vesicoureteral reflux (VUR) on the operative side, and complications according to the modified Clavien system. RESULTS: There were no statistically significant differences between the two groups regarding the mean operative times, mean VAS scores, analgesic requirements, mean hemoglobin drop, mean hospital stay, and overall complication rate. However, compared with DJ group, EUC group presented fewer postoperative stent-related symptoms and less occurrence of severe VUR (p < 0.05). CONCLUSION: Positioning EUC in tubeless MPCNL is a safe alternative to DJ in patients with renal or upper ureteral calculi. EUC provides several benefits: obviated the need of a second endoscopic procedure, reduced stent-related discomfort, and lowered the occurrence of severe VUR. PMID- 27967217 TI - Diet Polyphenol Curcumin Stimulates Hepatic Fgf21 Production and Restores Its Sensitivity in High-Fat-Diet-Fed Male Mice. AB - We found previously that short-term curcumin gavage stimulated mouse hepatic fibroblast growth factor 21 (Fgf21) expression. Here we conducted mechanistic exploration and investigated the potential pathophysiological relevance on this regulation. Fgf21 stimulation was observed at messenger RNA and protein levels in mice with daily curcumin gavage for 4 or 8 days and in primary hepatocytes with curcumin treatment. Using peroxisome proliferator-activated receptor alpha (PPARalpha) agonist and antagonist, along with luciferase reporter and chromatin immune-precipitation approaches, we determined that curcumin stimulates Fgf21 transcription in a mechanism involving PPARalpha activation. High-fat diet (HFD) feeding also increased mouse hepatic and serum Fgf21 levels, whereas dietary curcumin intervention attenuated these increases. We found that HFD feeding reduced hepatic expression levels of genes that encode FGFR1 and betaKlotho, PGC1alpha, and the targets of the PPARalpha-PGC1alpha axis, whereas concomitant curcumin intervention restored or partially restored their expression levels. Importantly, hepatocytes from HFD-fed mice showed a loss of response to FGF21 treatment on Erk phosphorylation and the expression of Egr1 and cFos; this response was restored in hepatocytes from HFD-fed mice with curcumin intervention. This investigation expanded our mechanistic understanding of the metabolic beneficial effects of dietary curcumin intervention involving the regulation of Fgf21 production and the attenuation of HFD-induced Fgf21 resistance. PMID- 27967215 TI - Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma. AB - RATIONALE: Phenotypic distinctions between severe asthma (SA) and nonsevere asthma (NONSA) may be confounded by differential adherence or incorrect use of corticosteroids. OBJECTIVES: To determine if there are persistent phenotypic distinctions between SA (as defined by 2014 American Thoracic Society/European Respiratory Society guidelines) and NONSA after intramuscular triamcinolone acetonide (TA), and to identify predictors of a corticosteroid response in these populations. METHODS: A total of 526 adults age 18 years and older (315 SA) and 188 children age 6 to less than 18 years (107 SA) in the NHLBI Severe Asthma Research Program III were characterized before and 3 weeks after TA. The primary outcome for corticosteroid response was defined as greater than or equal to 10 point improvement in percent predicted FEV1. MEASUREMENTS AND MAIN RESULTS: Adult asthma groups exhibited a small but significant mean FEV1% predicted improvement after TA (SA group mean difference, 3.4%; 95% confidence interval, 2.2-4.7%; P = 0.001), whereas children did not. Adult SA continued to manifest lower FEV1 and worse asthma control as compared with NONSA after TA. In children, after TA only prebronchodilator FEV1 distinguished SA from NONSA. A total of 21% of adults with SA and 20% of children with SA achieved greater than or equal to 10% improvement after TA. Baseline bronchodilator response and fractional exhaled nitric oxide had good sensitivity and specificity for predicting response in all groups except children with NONSA. CONCLUSIONS: One in five patients with SA exhibit greater than or equal to 10% improvement in FEV1 with parenteral corticosteroid. Those likely to respond had greater bronchodilator responsiveness and fractional exhaled nitric oxide levels. In adults, differences in airflow obstruction and symptoms between SA and NONSA persist after parenteral corticosteroids, suggesting a component of corticosteroid nonresponsive pathobiology in adults with SA that may differ in children. Clinical trial registered with www.clinicaltrials.gov (NCT 01606826). PMID- 27967219 TI - A SURVEY OF CLINICAL PRACTICE PATTERNS IN MANAGEMENT OF GRAVES DISEASE IN THE MIDDLE EAST AND NORTH AFRICA. AB - OBJECTIVE: Graves disease (GD) is commonly seen in endocrine clinical practice. The objective of this study was to evaluate the current diagnosis and management of patients with GD in the Middle East and North Africa (MENA). METHODS: An electronic survey on GD management was performed using an online questionnaire of a large pool of practicing physicians. Responses from 352 eligible and willing physicians were included in this study. They were mostly endocrinologists (157) and internal medicine physicians (116). RESULTS: In addition to serum thyroid stimulating hormone (TSH) and free thyroxine assays, most respondents would request serum antithyroid peroxidase antibody and TSH-receptor autoantibody (50% and 46%, respectively), whereas serum antithyroglobulin antibodies would be ordered by fewer respondents (36%). Thyroid ultra-sound would be requested by a high number of respondents (63.7%), while only a small percentage would order isotopic thyroid studies. Antithyroid drug (ATD) therapy was the preferred first line treatment (52.7%), followed by radio-iodine (RAI) treatment (36.8%), beta blockers alone (6.9%), thyroidectomy (3.2%), and no therapy (1.3%). When RAI treatment was selected in the presence of mild Graves orbitopathy and/or associated risk factors for its occurrence/exacerbation, steroid prophylaxis was frequently used. The preferred ATD in pregnancy was propylthiouracil in the first trimester and carbimazole in the second and third trimesters. On most issues, choices of the MENA physicians fell between European and American practices. CONCLUSION: Hybrid practices are seen in the MENA region, perhaps reflecting training and affiliations. Management approaches most suitable for patients in this region are needed. ABBREVIATIONS: ATD = antithyroid drug CBZ = carbimazole FT3 = free T3 FT4 = free T4 GD = Graves disease GO = Graves orbitopathy MENA = Middle East and North Africa MMI = methimazole RAI = radioactive iodine RAIU = RAI uptake T3 = tri-iodothyronine T4 = thyroxine TG Ab = antithyroglobulin antibodies TRAb = TSH-receptor autoantibody TSH = thyroid-stimulating hormone PTU = propylthiouracil TID = thrice daily UAE = United Arab Emirates US = ultrasound. PMID- 27967220 TI - GROWTH RATE OF PARAGANGLIOMAS RELATED TO GERMLINE MUTATIONS OF THE SDHX GENES. AB - OBJECTIVE: The purpose was to determine the growth rate of succinate dehydrogenase subunit (SDHx) gene-related paragangliomas based on computed tomography (CT) measurements. METHODS: Twenty-seven patients with SDHx mutations who underwent subsequent CT examinations were enrolled in the study. Tumors were classified as head and neck (HNP), thoracic, or abdominal/pelvic paragangliomas (PGLs). The percentage volume increase and volume doubling time were estimated. RESULTS: We analyzed 56 PGLs (21 with SDHD, 6 with SDHB mutations) in 27 patients (16 men, 11 women; mean age 37.7 years). The estimated median of the follow-up was 23 months. Twenty-two (39.3%) PGLs were located in the abdomen, 8 (14.3%) in the thorax, and 26 (46.4%) in the head and neck region. The median volume growth rate was estimated at 10.4% per year (interquartile range [IQR]: -1.3; 36.3). The volume doubling time was estimated as 7.01 (2.24;+infinity) years. By tumor site, the estimated medians of the annual volume growth rates were 13.6% (IQR:0.8 30.4) for HNP, -6.06% (IQR: -1.79;47.32) for thoracic PGLs, and 10.5% (IQR: 2.2;44.6) for abdominal PGLs. The volume doubling time was 5.44 years (2.61; 87.0) for HNP, 11.8 years (1.79;+infinity) for thoracic PGLs, and 6.94 years (1,88;+infinity) for abdominal PGLs. There was no significant difference in the volume growth rate according to tumor location or initial size (P>.7 and P = .07, respectively) or gene mutation type (SDHB vs. SDHD, P>.8). CONCLUSION: PGLs related to SDHx mutations are slowly growing tumors. There were no correlations between tumor location, growth rate or initial size over a 23-month follow-up period. ABBREVIATIONS: CT = computed tomography HNP = head and neck paraganglioma IQR = interquartile range PGL = paraganglioma PPGL = pheochromocytoma and paraganglioma SDH = succinate dehydrogenase. PMID- 27967221 TI - PRECISION MEDICINE, GLYCEMIC CONTROL, AND THE PROBLEMS OF IDENTIFYING FRIEND FROM FOE. PMID- 27967222 TI - Visual Vignette. PMID- 27967218 TI - Protein S-Bacillithiolation Functions in Thiol Protection and Redox Regulation of the Glyceraldehyde-3-Phosphate Dehydrogenase Gap in Staphylococcus aureus Under Hypochlorite Stress. AB - AIMS: Bacillithiol (BSH) is the major low-molecular-weight thiol of the human pathogen Staphylococcus aureus. In this study, we used OxICAT and Voronoi redox treemaps to quantify hypochlorite-sensitive protein thiols in S. aureus USA300 and analyzed the role of BSH in protein S-bacillithiolation. RESULTS: The OxICAT analyses enabled the quantification of 228 Cys residues in the redox proteome of S. aureus USA300. Hypochlorite stress resulted in >10% increased oxidation of 58 Cys residues (25.4%) in the thiol redox proteome. Among the highly oxidized sodium hypochlorite (NaOCl)-sensitive proteins are five S-bacillithiolated proteins (Gap, AldA, GuaB, RpmJ, and PpaC). The glyceraldehyde-3-phosphate (G3P) dehydrogenase Gap represents the most abundant S-bacillithiolated protein contributing 4% to the total Cys proteome. The active site Cys151 of Gap was very sensitive to overoxidation and irreversible inactivation by hydrogen peroxide (H2O2) or NaOCl in vitro. Treatment with H2O2 or NaOCl in the presence of BSH resulted in reversible Gap inactivation due to S-bacillithiolation, which could be regenerated by the bacilliredoxin Brx (SAUSA300_1321) in vitro. Molecular docking was used to model the S-bacillithiolated Gap active site, suggesting that formation of the BSH mixed disulfide does not require major structural changes. Conclusion and Innovation: Using OxICAT analyses, we identified 58 novel NaOCl sensitive proteins in the pathogen S. aureus that could play protective roles against the host immune defense and include the glycolytic Gap as major target for S-bacillithiolation. S-bacillithiolation of Gap did not require structural changes, but efficiently functions in redox regulation and protection of the active site against irreversible overoxidation in S. aureus. Antioxid. Redox Signal. 28, 410-430. PMID- 27967223 TI - Visual Vignette. PMID- 27967226 TI - USE OF A COMPUTER-GUIDED GLUCOSE MANAGEMENT SYSTEM TO IMPROVE GLYCEMIC CONTROL AND ADDRESS NATIONAL QUALITY MEASURES: A 7-YEAR, RETROSPECTIVE OBSERVATIONAL STUDY AT A TERTIARY CARE TEACHING HOSPITAL. AB - OBJECTIVE: Inpatient hyperglycemia, hypoglycemia, and glucose variability are associated with increased mortality. The use of an electronic glucose management system (eGMS) to guide intravenous (IV) insulin infusion has been found to significantly improve blood glucose (BG) control. This retrospective observational study evaluated the 7-year (January 2009-December 2015) impact of the EndoTool(r) eGMS in intensive and intermediate units at Vidant Medical Center, a 900-bed tertiary teaching hospital. METHODS: Patients assigned to eGMS had indications for IV insulin infusion, including uncontrolled diabetes, stress hyperglycemia, and/or postoperative BG levels >140 mg/dL. This study evaluated time required to achieve BG control (<180 mg/dL; <140 mg/dL for cardiovascular surgery patients); hypoglycemia incidence (<70 and <40 mg/dL); glucose variability (assessed by SD and coefficient of variation percentage [CV%]); excursions (BG levels >180 mg/dL after control attained); and the impact of eGMS on hospital-acquired condition (HAC)-8 rates. RESULTS: Data were available for all treated patients (492,078 BG readings from 16,850 patients). With eGMS, BG levels were brought to target within 1.5 to 2.3 hours (4.5 to 4.8 hours for cardiovascular patients). Minimal hypoglycemia was observed (BG values <70 mg/dL, 0.93%; <40 mg/dL, 0.03%), and analysis of variance of BG values <70 mg/dL showed significant reductions over time in hypoglycemia frequency, from 1.04% in 2009 to 0.46% in 2015 (P<.0001). The CV% per patient visit was 26.5 (+/-12.9)%, and 4% of patients experienced glucose excursions (defined as BG levels >180 mg/dL once control was attained). HAC-8 rates were reduced from 0.083 per 1,000 patients (2008) to 0.032 per 1,000 patients (2011). CONCLUSION: The use of eGMS resulted in rapid, effective control of inpatient BG levels, including significantly reduced hypoglycemia rates. ABBREVIATIONS: BG = blood glucose CMS = Centers for Medicare and Medicaid Services CV = coefficient of variation CV% = coefficient of variation percentage eGMS = electronic glucose management system GV = glycemic variability HAC = Hospital-Acquired Condition ICU = intensive care unit IU = intermediate unit IV = intravenous LOS = length of stay VMC = Vidant Medical Center. PMID- 27967225 TI - THE IMPACT OF CARDIOVASCULAR DRUGS ON GLYCEMIC CONTROL: A REVIEW. AB - OBJECTIVE: The prevalence of diabetes mellitus (DM) is steadily rising in the U.S., both in the general population and among those with cardiovascular disease (CVD). Understanding how to treat a patient with both conditions is becoming increasingly important. With multiple therapeutic options for CVD management, some medications will invariably impact glycemia in this group of patients. The concept of "DM-friendly" management of CVD is based on a treatment approach of selecting medications that do not impair glycemic control and provide equivalent cardioprotective effects. This article reviews the glycemic effects of various classes of medications commonly used to treat CVD. METHODS: Data sources were all PubMed- and Google Scholar-referenced articles in English-language peer-reviewed journals from 1980 through April 2016. Studies selected could include observational studies or prospective clinical trials. Prospective clinical trials included in this review focused on investigating the association of the medication of interest with glycemic outcomes. Meta-analyses and systematic reviews were also included. RESULTS: The data on glycemic effects were lacking for many of the medication classes and individual medications examined. However, in our review, certain beta-blockers and renin angiotensin aldosterone system inhibitors, and select calcium channel blockers were consistently shown to have favorable glycometabolic profiles when compared with other commonly used cardiovascular therapies. CONCLUSION: Several commonly prescribed medications for the treatment of CVD, such as certain beta-blockers and renin angiotensin aldosterone system inhibiting agents, are associated with favorable glycometabolic effects. As clinicians are more often faced with the challenge of treating patients with DM and concomitant CVD, consideration of how common cardiovascular medications may affect glycemia should be incorporated into the clinical decision making process. ABBREVIATIONS: A1C = hemoglobin A1C ACE = angiotensin-converting enzyme ARB = angiotensin II receptor blocker CCB = calcium channel blocker CI = confidence interval CVD = cardiovascular disease DM = diabetes mellitus MI = myocardial infarction RR = relative risk. PMID- 27967227 TI - SODIUM AND WATER IMBALANCE AFTER SELLAR, SUPRASELLAR, AND PARASELLAR SURGERY. AB - OBJECTIVE: To report the frequency of sodium and water disturbances (SWDs) in patients undergoing sellar, suprasellar, and parasellar surgery (SSPS). METHODS: We conducted a cross-sectional, retrospective study on 115 patients in the Aga Khan University Hospital after ethical approval. Patients were 16 years old or older undergoing pituitary or sellar surgeries. We collected data on basic sociodemographic characteristics and clinical indication for surgery. We noted laboratory values for serum electrolytes, plasma and urine osmolality, urine sodium, and 24-hour fluid balance from the immediate postoperative day until discharge and follow-up. We recorded medical management plans. We also recorded diabetes insipidus (DI), syndrome of inappropriate antidiuretic hormone (SIADH), cerebral salt wasting (CSW), triphasic response, and hyponatremia, according to the diagnostic definitions. Finally, we performed data analysis using Statistical Package for the Social Sciences, version 19.0. RESULTS: Of 115 patients, there were 61.7% males, mean age 42.3 +/- 13.86 years, 91.3% had pituitary adenoma (73.0% nonfunctioning), and 86.1% underwent transsphenoidal surgical approach. Transient DI occurred from days 1 to 6, peaking with 57.4% on day 2. Permanent DI and SIADH were rare. We did not note typical triphasic response or CSW in any of the patients. However, isolated hyponatremia occurred in 11%, and 20.9% had DI with hyponatremia. CONCLUSION: Transient DI is the most common postoperative SWD after SSPS. Hyponatremia occurred alone and following DI. This is the first study describing postoperative SWDs after different sellar surgeries in Pakistan. ABBREVIATIONS: ADH = antidiuretic hormone CSW = cerebral salt wasting DI = diabetes insipidus SIADH = syndrome of inappropriate antidiuretic hormone SSPS = sellar, suprasellar, and parasellar surgery SWD = sodium and water disturbance. PMID- 27967229 TI - ADIPOSITY-BASED CHRONIC DISEASE AS A NEW DIAGNOSTIC TERM: THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT. AB - : The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) have created a chronic care model, advanced diagnostic framework, clinical practice guidelines, and clinical practice algorithm for the comprehensive management of obesity. This coordinated effort is not solely based on body mass index as in previous models, but emphasizes a complications-centric approach that primarily determines therapeutic decisions and desired outcomes. Adiposity-Based Chronic Disease (ABCD) is a new diagnostic term for obesity that explicitly identifies a chronic disease, alludes to a precise pathophysiologic basis, and avoids the stigmata and confusion related to the differential use and multiple meanings of the term "obesity." Key elements to further the care of patients using this new ABCD term are: (1) positioning lifestyle medicine in the promotion of overall health, not only as the first algorithmic step, but as the central, pervasive action; (2) standardizing protocols that comprehensively and durably address weight loss and management of adiposity-based complications; (3) approaching patient care through contextualization (e.g., primordial prevention to decrease obesogenic environmental risk factors and transculturalization to adapt evidence-based recommendations for different ethnicities, cultures, and socio-economics); and lastly, (4) developing evidence-based strategies for successful implementation, monitoring, and optimization of patient care over time. This AACE/ACE blueprint extends current work and aspires to meaningfully improve both individual and population health by presenting a new ABCD term for medical diagnostic purposes, use in a complications-centric management and staging strategy, and precise reference to the obesity chronic disease state, divested from counterproductive stigmata and ambiguities found in the general public sphere. ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists ABCD = Adiposity-Based Chronic Disease ACE = American College of Endocrinology BMI = body mass index CPG = clinical practice guidelines HCP = health care professionals. PMID- 27967228 TI - SAFETY AND EFFICACY OF PERSONALIZED GLYCEMIC CONTROL IN CRITICALLY ILL PATIENTS: A 2-YEAR BEFORE AND AFTER INTERVENTIONAL TRIAL. AB - OBJECTIVE: To determine the safety and efficacy of a change in blood glucose (BG) control protocol from a single target to 2 targets based on diabetes mellitus (DM) status and glycated hemoglobin A1C (A1C) in a cohort of critically ill patients. METHODS: This investigation includes 1,979 patients admitted to a single intensive care unit (ICU) between September 16, 2013 and September 15, 2015. The BG target was 90 to 120 mg/dL in the PRE era and 80 to 140 mg/dL for patients without diabetes (NON) and with DM with A1C <7% and 110 to 160 mg/dL for DM with A1C >=7% (TIGHT and LOOSE protocols) in the POST era. The primary efficacy outcome was the observed:expected (O:E) mortality ratio. RESULTS: Among NON, the mean BG was slightly lower in the POST era: 118 (106-132) versus 115 (101-120) mg/dL (P = .0003). Among DM, the mean BG was 139 (123-160) mg/dL in the PRE era versus 136 (119-149) and 159 (138-171) mg/dL for TIGHT and LOOSE in the POST era (P = .0668 and .0001, respectively). Overall, 11.0% and 11.8% of patients had at least 1 BG level <70 mg/dL in the 2 eras (P = .68). The O:E mortality ratios for NON and DM for the PRE and POST eras were 0.75 versus 0.74 (P = .51) and 0.69 versus 0.52 (P<.001) respectively, and among DM with A1C >=7% were 0.74 versus 0.52 (P = .004). CONCLUSION: This hypothesis-generating investigation suggests the need for additional prospective interventional studies assessing the outcomes of patients randomized to personalized glucose targets. ABBREVIATIONS: APACHE = Acute Physiology and Chronic Health Evaluation A1C = glycated hemoglobin A1C BG = blood glucose CV = co-efficient of variation DM = diabetes mellitus ICU = intensive care unit LOS = length of stay NON = patients without DM O:E = observed: expected. PMID- 27967230 TI - PATHOPHYSIOLOGY AND MANAGEMENT OF HYPOGLYCEMIAIN END-STAGE RENAL DISEASE PATIENTS: A REVIEW. AB - OBJECTIVE: This review focuses on hypoglycemia in patients with end-stage renal disease (ESRD). It discusses the pathophysiology of glucose metabolism in the kidney, the impact of dialysis on glucose and insulin metabolism, and the challenges of glucose monitoring in ESRD. The clinical relevance of these changes is reviewed in relation to altered blood glucose targets and modification of antidiabetes therapy to prevent hypoglycemia. Based on current data and guidelines, recommendations for the outpatient and inpatient setting are provided for diabetes management in ESRD. METHODS: PubMed, OVID, and Google Scholar were searched to identify related articles through May 2016 using the following keywords: "glucose metabolism," "kidney," "diabetes," "hypoglycemia," "ESRD," and "insulin" in various combinations for this review. RESULTS: In ESRD, a combination of impaired insulin clearance, changes in glucose metabolism, and the dialysis process make patients vulnerable to low blood glucose levels. Hypoglycemia accounts for up to 3.6% of all ESRD-related admissions. At admission or during hospitalization, hypoglycemia in ESRD has a poor prognosis, with mortality rates reported at 30%. Several guidelines suggest a modified hemoglobin A1c (A1c) goal of 7 to 8.5% (53 to 69 mmol/mol) and an average blood glucose goal of 150 to 200 mg/dL. Noninsulin antidiabetes agents like dipeptidyl peptidase 4 inhibitors, repaglinide, and glipizide in appropriate doses and reduction of insulin doses up to 50% may help decrease hypoglycemia. CONCLUSION: Patients with ESRD are at high risk for hypoglycemia. Increased awareness by providers regarding these risks and appropriate diabetes regimen adjustments can help minimize hypoglycemic events. ABBREVIATIONS: ADA = antidiabetes agent BG = blood glucose CKD = chronic kidney disease DPP-4 = dipeptidyl peptidase 4 eGFR = estimated glomerular filtration rate ESRD = end-stage renal disease GFR = glomerular filtration rate HD = hemodialysis NPH = neutral protamine Hagedorn PD = peritoneal dialysis SA = short acting SU = sulfonylurea. PMID- 27967231 TI - LETTER TO THE EDITOR. PMID- 27967232 TI - THE RECOGNITION THAT GENDER IDENTITY IS BIOLOGICAL COMPLICATES SOME PREVIOUSLY SETTLED CLINICAL DECISION MAKING. PMID- 27967233 TI - New evidence for oxetorone toxicity. AB - CONTEXT: Oxetorone is a serotonin antagonist antimigraine drug but literature relating to its toxic properties is poor. The aim of this study is to describe the toxicological profile of oxetorone and to highlight any relationship between clinical and analytical findings. MATERIALS AND METHODS: This is a retrospective and observational study of cases exposure to oxetorone, reported to the Angers Poison and Toxicovigilance Centre between January 2002 and May 2016. Severity was assessed using the Poisoning Severity Score (PSS). Cases where data were incomplete, where oxetorone was deemed not accountable, where clinical signs were linked mainly to a co-ingested drug or where the plasma concentration of oxetorone was negative were all excluded. RESULTS: We included 43 cases of exposure, 31 of whom were suicide attempts. The assumed ingested dose (60-3600 mg) was correlated to severity (rs = 0.45, p = 0.01). Symptoms of moderate severity (PSS2 = drowsiness, hypertonia, myosis, convulsions, arterial hypotension, QRS widening, QTc prolongation) were observed following ingestion of more than 600 mg of oxetorone (median dose =1200 mg) and severe symptoms (PSS 3 = coma, convulsions, QTc prolongation, QRS widening, ventricular tachycardia, arterial hypotension, cardiogenic shock) were observed starting from 1800 mg (median dose =2700 mg). In four cases, a secondary worsening of symptoms 10-48 h following ingestion was observed. Plasma oxetorone was measured in four patients. Severe symptoms were observed in the event of a concentration over 0.3 mg/L and the highest measured serum oxetorone level was delayed by 20-48 h following the ingestion for two cases. CONCLUSIONS: Several clinical and paraclinical parameters strongly point towards membrane-stabilising properties of the molecule and the risk of a delayed occurrence of symptoms or a secondary worsening. PMID- 27967235 TI - 17beta-HSD Type 12-Like Is Responsible for Maturation-Inducing Hormone Synthesis During Oocyte Maturation in Masu Salmon. AB - The maturation-inducing hormone 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) was first identified in the amago salmon. Although carbonyl reductase-like 20beta hydroxysteroid dehydrogenase (CR/20beta-HSD) was reported to convert 17alpha hydroxyprogesterone (17OHP) to DHP in rainbow trout, we previously found that CR/20beta-HSD messenger RNA (mRNA) was not upregulated in stimulated granulosa cells from masu salmon, which suggested that DHP is synthesized by a different enzyme. Accordingly, the current study aimed to identify the specific 20beta hydroxysteroid dehydrogenase (20beta-HSD) responsible for DHP production by granulosa cells during final oocyte maturation in masu salmon. RNA sequencing was performed on granulosa layers that were isolated from ovarian follicles at 1 month before ovulation and incubated with or without forskolin, which was used to mimic luteinizing hormone, and ~12 million reads were obtained, which yielded 71,062 contigs of >100 bp. tBlastx analysis identified 1 contig (#f103496) as similar to 17beta-hydroxysteroid dehydrogenase type 12 (hsd17beta12); however, because the full-length #f103496 sequence was different from hsd17beta12, it was termed hsd17beta12-like (hsd17beta12l). We found that mammalian cells transfected with full-length hsd17beta12l exhibited considerable 20beta-HSD activity, as indicated by efficient conversion of exogenous 17OHP to DHP. In addition, we found that hsd17beta12l mRNA levels were consistently low in follicles during vitellogenic growth; however, the levels increased significantly during final oocyte maturation. The levels of hsd17beta12l mRNA were also considerably increased in granulosa layers in which 20beta-HSD activity was induced by salmon pituitary extract. Therefore, we suggest that hsd17beta12l, not CR/20beta-HSD, is the 20beta-HSD responsible for DHP production by granulosa cells in masu salmon during final oocyte maturation. PMID- 27967234 TI - Alternative Progenitor Lineages Regenerate the Adult Lung Depleted of Alveolar Epithelial Type 2 Cells. AB - An aberrant oxygen environment at birth increases the severity of respiratory viral infections later in life through poorly understood mechanisms. Here, we show that alveolar epithelial cell (AEC) 2 cells (AEC2s), progenitors for AEC1 cells, are depleted in adult mice exposed to neonatal hypoxia or hyperoxia. Airway cells expressing surfactant protein (SP)-C and ATP binding cassette subfamily A member 3, alveolar pod cells expressing keratin (KRT) 5, and pulmonary fibrosis were observed when these mice were infected with a sublethal dose of HKx31, H3N2 influenza A virus. This was not seen in infected siblings birthed into room air. Genetic lineage tracing studies in mice exposed to neonatal hypoxia or hyperoxia revealed pre-existing secretoglobin 1a1+ cells produced airway cells expressing SP-C and ATP binding cassette subfamily A member 3. Pre-existing Kr5+ progenitor cells produced squamous alveolar cells expressing receptor for advanced glycation endproducts, aquaporin 5, and T1alpha in alveoli devoid of AEC2s. They were not the source of KRT5+ alveolar pod cells. These oxygen-dependent changes in epithelial cell regeneration and fibrosis could be recapitulated by conditionally depleting AEC2s in mice using diphtheria A toxin and then infecting with influenza A virus. Likewise, airway cells expressing SP-C and alveolar cells expressing KRT5 were observed in human idiopathic pulmonary fibrosis. These findings suggest that alternative progenitor lineages are mobilized to regenerate the alveolar epithelium when AEC2s are severely injured or depleted by previous insults, such as an adverse oxygen environment at birth. Because these lineages regenerate AECs in spatially distinct compartments of a lung undergoing fibrosis, they may not be sufficient to prevent disease. PMID- 27967237 TI - Brain Reactivity and Selective Attention to Sleep-Related Words in Patients With Chronic Insomnia. AB - OBJECTIVE/BACKGROUND: Sleep-related attentional bias has been suggested to represent an important factor for the maintenance of chronic insomnia. However, little is known about potentially underlying psychological mechanisms such as threat or craving. As these are associated with distinguishable brain activation patterns, we performed a functional neuroimaging study. PARTICIPANTS/METHODS: Functional magnetic resonance imaging was used to investigate brain reactivity to sleep-related words in 20 patients with primary insomnia according to DSM-IV criteria and 35 good sleeper controls according to Research Diagnostic Criteria. In addition, an emotional Stroop task was performed in all participants outside the scanner to investigate sleep-related attentional bias. RESULTS: Contrary to the hypotheses, patients with chronic insomnia did not differ from good sleeper controls in terms of threat- or craving-related brain reactivity to sleep-related words. In addition, the emotional Stroop task did not reveal any significant group difference in sleep-related attentional bias. Exploratory analyses did not show any significant correlations between brain reactivity/selective attention to sleep-related words and questionnaire scores/PSG parameters. CONCLUSIONS: The results from the present study call into question that attentional bias to sleep related stimuli is a core feature of chronic insomnia. Future studies may use pictorial stimuli and larger sample sizes for investigating sleep-related information processing in insomnia. PMID- 27967238 TI - A Refill for the Brain Mineralocorticoid Receptor: The Benefit of Cortisol Add-On to Dexamethasone Therapy. AB - Some serious medical conditions require life-saving treatment with high doses of synthetic glucocorticoids such as dexamethasone. A substantial number of patients subjected to this treatment develops psychosis, mood disturbances, or sleep problems. A recent clinical trial demonstrated that dexamethasone therapy for young patients with acute lymphoblastic leukemia caused severe adverse psychological effects and sleep disturbances in about 30% of these patients. These side effects were ameliorated by coadministration of a low dose of the naturally occurring glucocorticoid hormone cortisol. This paradoxical finding was predicted by the idea that the synthetic glucocorticoid targets the glucocorticoid receptor, causing suppression of cortisol secretion and, thus, depletion of the brain mineralocorticoid receptor (MR) of its endogenous ligand. The refill of the unoccupied brain MR with physiological amounts of cortisol ameliorates the dexamethasone-induced psychological side effects. In the present report, we discuss the mechanistic underpinning of the MR refill concept in glucocorticoid therapy. PMID- 27967236 TI - PKA-RIIB Deficiency Induces Brown Fatlike Adipocytes in Inguinal WAT and Promotes Energy Expenditure in Male FVB/NJ Mice. AB - Obesity has become the most common metabolic disorder worldwide. Promoting brown adipose tissue (BAT) and beige adipose tissue formation, and therefore, a functional increase in energy expenditure, may counteract obesity. Mice lacking type IIbeta regulatory subunit of adenosine 3',5' cyclic monophosphate (cAMP) dependent protein kinase A (PKA-RIIB) display reduced adiposity and resistance to diet-induced obesity. PKA-RIIB, encoded by the Prkar2b gene, is most abundant in BAT and white adipose tissue (WAT) and in the brain. In this study, we show that mice lacking PKA-RIIB have increased energy expenditure, limited weight gain, and improved glucose metabolism. PKA-RIIB deficiency induces brownlike adipocyte in inguinal WAT (iWAT). PKA-RIIB deficiency also increases the expression of uncoupling protein 1 and other thermogenic genes in iWAT and primary preadipocytes from iWAT through a mechanism involving increased PKA activity, which is represented by increased phosphorylation of PKA substrate, cAMP response element binding protein, and P38 mitogen-activated protein kinase. Our study provides evidence for the role of PKA-RIIB deficiency in regulating thermogenesis in WAT, which may potentially have therapeutic implications for the treatment of obesity and related metabolic disorders. PMID- 27967240 TI - The Significance of the Prognostic Nutritional Index for All Stages of Pancreatic Cancer. AB - Nutritional status affects the prognosis of various tumors. The prognostic nutritional index (PNI) is the known predictor of postoperative outcome in resectable pancreatic cancer patients. This study aimed to validate the prognostic value of PNI in all stages of pancreatic cancer. We retrospectively reviewed 499 patients with pancreatic cancer who were diagnosed at Severance Hospital between January 2006 and December 2011. The PNI value was calculated as 10 * serum albumin (g/dL) + 0.005 * total lymphocyte count (/mm3) at initial diagnosis. The median patient age was 62 yr, and 289 were men. The study group comprised resectable disease (n = 121), locally advanced disease (n = 118), and metastatic disease (n = 260). Univariate and multivariate analysis revealed that PNI <= 49.5 at initial diagnosis, together with performance status, platelet count, and clinical stage, was significantly associated with overall survival (hazard ratio, 1.562; all P < 0.05). Patients with PNI <= 49.5 (n = 208) had shorter median overall survival compared to patients with high PNI (9.8 vs. 14.2 mo; log rank, P < 0.001). In clinical stage subgroup analysis, initial PNI <=49.5 independently predicted shorter overall survival, especially in resectable and metastatic disease (P = 0.041, P = 0.002, respectively). PMID- 27967239 TI - Lipid Osteoclastokines Regulate Breast Cancer Bone Metastasis. AB - Bone metastasis is a deadly consequence of cancers, in which osteoclast forms a vicious cycle with tumor cells. Bone metastasis attenuation by clinical usage of osteoclast inhibitors and in our osteopetrotic mouse genetic models with beta catenin constitutive activation or peroxisome proliferator-activated receptor gamma deficiency fully support the important role of osteoclast in driving the bone metastatic niche. However, the mechanisms for this "partnership in crime" are underexplored. Here we show that osteoclasts reprogram their lipid secretion to support cancer cells. Metabolomic profiling reveals elevated prometastatic arachidonic acid (AA) but reduced antimetastatic lysophosphatidylcholines (LPCs). This shift in lipid osteoclastokines synergistically stimulates tumor cell proliferation, migration, survival, and expression of prometastatic genes. Pharmacologically, combined treatment with LPCs and BW-755C, an inhibitor of AA signaling via blocking lipoxygenase and cyclooxygenase, impedes breast cancer bone metastasis. Our findings elucidate key paracrine mechanisms for the osteoclast-cancer vicious cycle and uncover important therapeutic targets for bone metastasis. PMID- 27967241 TI - Acute Myeloid Leukemia Targeting by Chimeric Antigen Receptor T Cells: Bridging the Gap from Preclinical Modeling to Human Studies. AB - Acute myeloid leukemia (AML) still represents an unmet clinical need for adult and pediatric high-risk patients, thus demanding advanced and personalized therapies. In this regard, different targeted immunotherapeutic approaches are available, ranging from naked monoclonal antibodies (mAb) to conjugated and multifunctional mAbs (i.e., BiTEs and DARTs). Recently, researchers have focused their attention on novel techniques of genetic manipulation specifically to redirect cytotoxic T cells endowed with chimeric antigen receptors (CARs) toward selected tumor associated antigens. So far, CAR T cells targeting the CD19 antigen expressed by B-cell origin hematological cancers have gained impressive clinical results, leading to the possibility of translating the CAR platform to treat other hematological malignancies such as AML. However, one of the main concerns in the field of AML CAR immunotherapy is the identification of an ideal target cell surface antigen, being highly expressed on tumor cells but minimally present on healthy tissues, together with the design of an anti-AML CAR appropriately balancing efficacy and safety profiles. The current review focuses mainly on AML target antigens and the related immunotherapeutic approaches developed so far, deeply dissecting methods of CAR T cell safety improvements, when designing novel CARs approaching human studies. PMID- 27967243 TI - Clostridium perfringens: a rare cause of spondylodiscitis case report and review of the literature. AB - Presented is a case of a 64-year old male with a unique and yet unreported case of a spondylodiscitis caused by Clostridium perfringens. Becoming symptomatic with massive neurological deficits. Computed tomography (CT) revealed typical signs of spondylodiscitis involving the vertebral body L5 with extensive vacuum phenomenon. PMID- 27967242 TI - Low-Dose Dihydrotestosterone Drives Metabolic Dysfunction via Cytosolic and Nuclear Hepatic Androgen Receptor Mechanisms. AB - Androgen excess in women is associated with metabolic dysfunction (e.g., obesity, hyperinsulinemia, insulin resistance, and increased risk of type 2 diabetes) and reproductive dysfunction (e.g., polycystic ovaries, amenorrhea, dysregulated gonadotropin release, and infertility). We sought to identify the effects of androgen excess on glucose metabolic dysfunction and the specific mechanisms of action by which androgens are inducing pathology. We developed a mouse model that displayed pathophysiological serum androgen levels with normal body mass/composition to ensure that the phenotypes were directly from androgens and not an indirect consequence of obesity. We performed reproductive tests, metabolic tests, and hormonal assays. Livers were isolated and examined via molecular, biochemical, and histological analysis. Additionally, a low-dose dihydrotestosterone (DHT) cell model using H2.35 mouse hepatocytes was developed to study androgen effects on hepatic insulin signaling. DHT mice demonstrated impaired estrous cyclicity; few corpora lutea in the ovaries; glucose, insulin, and pyruvate intolerance; and lowered hepatic insulin action. Mechanistically, DHT increased hepatic androgen-receptor binding to phosphoinositide-3-kinase (PI3K)-p85, resulting in dissociation of PI3K-p85 from PI3K-p110, leading to reduced PI3K activity and decreased p-AKT and, thus, lowered insulin action. DHT increased gluconeogenesis via direct transcriptional regulation of gluconeogenic enzymes and coactivators. The hepatocyte model recapitulated the in vivo findings. The DHT-induced hepatocyte insulin resistance was reversed by the androgen-receptor antagonist, flutamide. These findings present a phenotype (i.e., impaired glucose tolerance and disrupted glucose metabolism) in a lean hyperandrogenemia model (low-dose DHT) and data to support 2 molecular mechanisms that help drive androgen-induced impaired glucose metabolism. PMID- 27967245 TI - End of Volume. PMID- 27967244 TI - Analyzing Complex Treatment Effects in Nonrandomized Observational Studies: The Case of Retention of Students in Grade. AB - Should low-achieving students be promoted to the next grade or be retained (held back) in the prior grade? This special section presents a discussion of the application of marginal structural models to the challenging problem of estimating the effect of promotion versus retention in grade on math scores in elementary school. Vandecandelaere, De Fraine, Van Damme, and Vansteelandt provide a didactic presentation of the marginal structural modeling approach, noting retention is a time-varying treatment because promoted low-achieving students may be retained in a subsequent grade. Steiner, Park, and Kim's commentary presents a detailed analysis of the treatment effects being estimated in same-age versus same-grade comparisons from the perspective of the potential outcomes model. Reshetnyak, Cham, and Kim's commentary clarifies the conditions under which same-age versus same-grade comparisons might be preferred; they also identify methods of further improving the estimation of retention effects. In their rejoinder, Vandecandelaere and Vansteelandt discuss tradeoffs in comparing the promoted and retained groups and highlight sensitivity analysis as a method of probing the robustness of treatment effect estimates. Our hope is that this combined didactic presentation and critical evaluation will encourage researchers to add marginal structural models to their methodological toolkits. PMID- 27967246 TI - Idiopathic thoracic intravertebral spinal cord herniation. PMID- 27967247 TI - How are we improving the delivery to back of the eye? Advances and challenges of novel therapeutic approaches. AB - INTRODUCTION: Drug delivery to the back of the eye requires strategic approaches that guarantee the long-term therapeutic effect with patient compliance. Current treatments for posterior eye diseases suffer from significant challenges including frequent intraocular injections of anti-VEGF agents and related adverse effects in addition to the high cost of the therapy. Areas covered: Treatment challenges and promising drug delivery approaches for posterior segment eye diseases, such as age-related macular degeneration (AMD) are summarized. Advances in the development of several nanotechnology-based systems, including stimuli responsive approaches to enhance drug bioavailability and overcome existing barriers for effective ocular delivery are discussed. Stem cell transplantation and encapsulated cell technology (ECT) approaches to treat posterior eye diseases are elaborated. Expert opinion: There are several drug delivery systems demonstrating promising results. However, a better understanding of ocular barriers, disease pathophysiology, and drug clearance mechanisms is required for better therapeutic outcomes. The stem cell transplantation strategy and ECT approach provide positive results in AMD therapy, but there are a number of challenges that must be overcome for long-term efficiency. Ultimately, there are numerous multidimensional challenges to cure vision problems and a collaborative approach among scientists is required. PMID- 27967248 TI - Level of agreement between physical activity levels measured by ActiHeart and the International Physical Activity Questionnaire in persons with intellectual disability. AB - PURPOSE: The purpose of this study was to determine the level of agreement between objective physical activity (PA) (ActiHeart(r)) and subjective proxy respondent International Physical Activity Questionnaire-short version (IPAQ-S) data in adults with intellectual disabilities (IDs). METHOD: Fifty-eight participants wore ActiHeart(r) monitors for seven consecutive days. Caregivers of each participant completed the IPAQ-S on behalf of the participant. Total PA, time spent in light, moderate, and vigorous activity as well as time spent being sedentary were assessed by the IPAQ-S and the ActiHeart(r). Results were compared by means of correlation analyses. The level of agreement was presented with Bland Altman plots. RESULTS: Objective PA (ActiHeart(r)) was higher (225.57 +/- 91.96 min/week) than IPAQ-S PA reported by care-givers (177.06 +/- 309.17 min/week). Weak significant correlations were observed between the ActiHeart(r) and IPAQ-S instruments for sedentary behavior (r = 0.31; p = 0.04); no significant correlations for light (r= -0.04; p = 0.8), moderate (r= -0.07; p = 0.63), or vigorous PA (r= -0.2; p = 0.18) were found. Limited agreement between objectively determine PA (ActiHeart(r)) and IPAQ-S was found. CONCLUSION: IPAQ-S is inaccurate when determining PA in persons with ID as it significantly underestimates the true levels of PA in this cohort. Implications for Rehabilitation Persons with intellectual disability (ID) report insufficient physical activity for health benefits. Physical activity is often determined by means of subjective proxy reporting. Objective physical activity measurements by means of combined heart rate and accelerometer are necessary to determine accurate levels of physical activity in persons with ID. Exercise interventions should be based on objective physical activity measurements. PMID- 27967249 TI - Sunitinib in kidney cancer: 10 years of experience and development. AB - INTRODUCTION: Sunitinib is a multi-target, anti-angiogenic tyrosine kinase inhibitor and a key molecule in the treatment of metastatic renal cell carcinoma (mRCC). Since it first demonstrated its efficacy ten years ago, overall survival of mRCC has more than doubled, in part due to sunitinib. In most recent years, progress has been made in the comprehension of its mechanism of action and resistance. Areas Covered: In this article, clinical trials involving sunitinib in kidney cancer have been reviewed, defining its different indications in metastatic and localized RCC. The rationale of sunitinib's efficacy, preclinical trials, past-clinical trials and ongoing clinical trials are summarized. Dose and scheme base are discussed, as the recommended dosage is frequently not well tolerated. Combination therapies appear to be toxic. Novel immunotherapies are changing the landscape of mRCC treatment and challenging sunitinib. Special attention has been paid towards cancer cell biology and immunity involved in treatment response. Expert Commentary: Sunitinib's place in the therapeutic arsenal is being redefined with the arrival of major challengers. Dosage and scheduling of sunitinib remains a major challenge. PMID- 27967250 TI - Bitopic muscarinic agonists and antagonists and uses thereof: a patent evaluation of US20160136145A1. AB - INTRODUCTION: Bitopic M ligands, that is, ligands that interact both with the ortho- and allosteric binding sites of the M receptor subtypes, hold great potential as novel selective for muscarinic acetylcholine (M) ligands for several therapeutic applications. Areas covered: The patent application describes a set of compounds based on the neurotransmitter acetylcholine applying the Schulman model for M ligands comprising heterocyclic (often quaternary) amines and a benzene ring (often as benzoic acid esters) to act as bitopic ligands. The compounds claimed hold functional selectivity and are supposed to be therapeutically applied as neuromuscular blocking agents, in asthma as well as CNS diseases. In vitro evaluations of selected compounds supported bitopic binding and some degree of functional selectivity was observed - albeit no selectivity was observed in binding studies. Expert opinion: The quaternary amine structure of the compounds claimed will prohibit penetration into the CNS and their ester structure will lead to significant metabolic instability which will hamper therapeutic applications for many indications. Furthermore, high affinity and subtype selectivity with regard to binding affinity which is observed for bitopic and allosteric ligands in the current literature is not observed for the compounds described in the patent. PMID- 27967252 TI - Hyperleukocytosis and leukostasis: management of a medical emergency. AB - INTRODUCTION: Hyperleukocytosis is defined as a white blood cell count greater than 100,000/mL in patients affected by acute leukemia and often it is associated with increased morbidity and mortality, that can be up to 40% if unrecognized. Areas covered: Risk factors include younger age, myelomonocytic or monocytic/monoblastic morphology, microgranular variant of acute promyelocitic leukemia and T-cell ALL, and some cytogenetic abnormalities. Poor prognosis due to high early death rate secondary to leukostasis. The mechanisms at the origin of leukostasis are still poorly understood. The management of acute hyperleukocytosis and leukostasis involves supportive measures and reducing the number of circulating leukemic blast cells, with careful monitoring of fluid balance, control of uric acid production and control of urine pH to prevent tumour lysis syndrome. Expert commentary: Several studies have been performed to ameliorate the outcome of this setting of patients. The high number of leukocytes may cause 3 main complications: disseminated intravascular coagulation (DIC), tumor lysis syndrome (TLS), and leukostasis. Although hyperleukocytosis and tumour lysis syndrome are still a challenge for clinicians, a better prognosis for these conditions is emerging in the last years. PMID- 27967251 TI - Glycation & the RAGE axis: targeting signal transduction through DIAPH1. AB - INTRODUCTION: The consequences of chronic disease are vast and unremitting; hence, understanding the pathogenic mechanisms mediating such disorders holds promise to identify therapeutics and diminish the consequences. The ligands of the receptor for advanced glycation end products (RAGE) accumulate in chronic diseases, particularly those characterized by inflammation and metabolic dysfunction. Although first discovered and reported as a receptor for advanced glycation end products (AGEs), the expansion of the repertoire of RAGE ligands implicates the receptor in diverse milieus, such as autoimmunity, chronic inflammation, obesity, diabetes, and neurodegeneration. Areas covered: This review summarizes current knowledge regarding the ligand families of RAGE and data from human subjects and animal models on the role of the RAGE axis in chronic diseases. The recent discovery that the cytoplasmic domain of RAGE binds to the formin homology 1 (FH1) domain, DIAPH1, and that this interaction is essential for RAGE ligand-stimulated signal transduction, is discussed. Finally, we review therapeutic opportunities targeting the RAGE axis as a means to mitigate chronic diseases. Expert commentary: With the aging of the population and the epidemic of cardiometabolic disease, therapeutic strategies to target molecular pathways that contribute to the sequelae of these chronic diseases are urgently needed. In this review, we propose that the ligand/RAGE axis and its signaling nexus is a key factor in the pathogenesis of chronic disease and that therapeutic interruption of this pathway may improve quality and duration of life. PMID- 27967253 TI - Psychometric properties of the International Classification of Functioning, Disability and Health set for spinal cord injury nursing based on Rasch analysis. AB - OBJECTIVE: To examine the psychometric properties of the International Classification of Functioning, Disability and Health (ICF) set for spinal cord injury nursing (ICF-SCIN) using Rasch analysis. METHODS: A total of 140 spinal cord injury patients were recruited between December 2013 and March 2014 through convenience sampling. Nurses used the components body functions (BF), body structures (BS), and activities and participation (AP) of the ICF-SCIN to rate the patients' functioning. Rasch analysis was performed using RUMM 2030 software. RESULTS: In each component, categories were rescored from 01234 to 01112 because of reversed thresholds. Nine testlets were created to overcome local dependency. Four categories which fit to the Rasch model poorly were deleted. After modification, the components BF, BS, and AP showed good fit to the Rasch model with a Bonferroni-adjusted significant level (chi2 = 86.29, p = 0.006; chi2 = 22.44, p = 0.130; chi2 = 39.92, p = 0.159). The person separation indices (PSIs) for the three components were 0.80, 0.54, and 0.97, respectively. No differential item functioning (DIF) was detected across age, gender, or educational level. CONCLUSIONS: The fit properties of the ICF set were satisfactory after modifications. The ICF-SCIN has the potential as a nursing assessment instrument for measuring the functioning of patients with spinal cord injury. Implications for rehabilitation The International Classification of Functioning, Disability and Health (ICF) set for spinal cord injury nursing contains a group of categories which can reflect the functioning of spinal cord injury patients from the perspective of nurses. The components body functions (BF), body structures (BS), and activities and participation (AP) of the ICF set for spinal cord injury achieved the fit to the Rasch model through rescoring, generating testlets, and deleting categories with poor fit. The ICF set for spinal cord injury nursing (ICF-SCIN) has the potential to be used as a clinical nursing assessment tool in measuring the functioning of patients with spinal cord injury. PMID- 27967254 TI - Could EPO studies improve mood disorder treatment strategies? PMID- 27967256 TI - Direct lineage reprogramming: a useful addition to the blood cell research toolbox. PMID- 27967255 TI - Endocrine therapy in epithelial ovarian cancer. AB - INTRODUCTION: The estrogen receptor (ER) is expressed at high levels in many epithelial ovarian cancers (EOC) and represents a potential target for endocrine therapy. Both anti-estrogens and aromatase inhibitors have been evaluated in phase II clinical trials. Areas covered: We present an overview of the phase II and phase III trials of anti-estrogens (tamoxifen and fulvestrant) and aromatase inhibitors (letrozole, anastrazole and exemestane) undertaken in epithelial ovarian cancer identified through a Pubmed search. We describe predictive biomarkers that are being investigated to identify responsive cancers. Expert commentary: The efficacy of endocrine therapy in epithelial ovarian cancer is likely to be confined to histological subtypes with the highest ER expression while low grade serous ovarian cancer appears to be one subgroup with good sensitivity to these agents. The low toxicity profile of these agents is favourable although their use is unlicensed and the optimal setting undefined. Prospective clinical trials of endocrine agents in the early relapse and maintenance settings are urgently required to establish their definitive role in the management of epithelial ovarian cancer. PMID- 27967257 TI - Laparoscopic abdominal cerclage during pregnancy: Report on two cases using a McCartney tube. PMID- 27967258 TI - Vaginal lentigo in a postmenopausal patient: Report of a unique entity. PMID- 27967259 TI - Vinpocetine Inhibited the CpG Oligodeoxynucleotide-induced Immune Response in Plasmacytoid Dendritic Cells. AB - Plasmacytoid dendritic cells (pDCs) exert dual roles in immune responses through inducing inflammation and maintaining immune tolerance. A switch of pDC phenotype from pro-inflammation to tolerance has therapeutic promise in the treatment of autoimmune diseases. Vinpocetine, a vasoactive vinca alkaloid extracted from the periwinkle plant, has recently emerged as an immunomodulatory agent. In this study, we evaluated the effect of vinpocetine on phenotype of pDCs isolated from C57BL/6 mice and explored its possible mechanism. Our data showed that vinpocetine significantly downregulated the expression of CD40, CD80, and CD86 on pDCs and increased the expression of translocator protein (TSPO), the specific receptor of vinpocetine, in pDCs. Vinpocetine significantly inhibited the Toll like receptor 9 signaling pathway and reduced the secretion of related cytokines in pDCs through TSPO. Furthermore, viability of pDCs was significantly promoted by vinpocetine. These findings imply that vinpocetine serves as an immunomodulatory agent for pDCs and may be applied for the treatment of pDCs related autoimmune diseases. PMID- 27967260 TI - PCSK9 inhibitors in sepsis: a new potential indication? PMID- 27967261 TI - A conceptual framework for a long-term economic model for the treatment of attention-deficit/hyperactivity disorder. AB - BACKGROUND: Models incorporating long-term outcomes (LTOs) are not available to assess the health economic impact of attention-deficit/hyperactivity disorder (ADHD). OBJECTIVE: Develop a conceptual modelling framework capable of assessing long-term economic impact of ADHD therapies. METHODS: Literature was reviewed; a conceptual structure for the long-term model was outlined with attention to disease characteristics and potential impact of treatment strategies. RESULTS: The proposed model has four layers: i) multi-state short-term framework to differentiate between ADHD treatments; ii) multiple states being merged into three core health states associated with LTOs; iii) series of sub-models in which particular LTOs are depicted; iv) outcomes collected to be either used directly for economic analyses or translated into other relevant measures. CONCLUSIONS: This conceptual model provides a framework to assess relationships between short- and long-term outcomes of the disease and its treatment, and to estimate the economic impact of ADHD treatments throughout the course of the disease. PMID- 27967262 TI - DFD-01: a novel topical formulation of betamethasone dipropionate for the treatment of extensive psoriasis. AB - INTRODUCTION: Betamethasone dipropionate has been used for the topical treatment of psoriasis in multiple formulations. DFD-01 (SernivoTM, Promius Pharma LLC) is a new midpotent lotion formulation of betamethasone dipropionate 0.05% that has recently been approved for the treatment of mild to moderate psoriasis for up to 4 weeks. Areas covered: This review will critically appraise available clinical information on DFD-01. Phase 3 efficacy and safety results will be reviewed on head-to-head comparison of DFD-01 with a superpotent augmented betamethasone dipropionate 0.05% lotion. It is suggested that the formulation of DFD-01 has enabled this midpotent topical steroid to demonstrate equivalent efficacy to a superpotent steroid. Expert commentary: DFD-01's unique advantage is that this product has the efficacy of a higher potency steroid but with the safety profile of a mid-potency steroid based on VCA assays. This formulation also has aesthetic appeal, which may benefit compliance. PMID- 27967263 TI - Starvation Resulting From Inadequate Dietary Planning for a 50-Day Rowing Expedition. AB - : Meeting the energy demands of prolonged arduous expeditions and endurance sport may be a significant barrier to success. Expedition rowing is associated with high levels of body-mass loss, reflecting the challenge of meeting energy expenditure in this exacting environment. PURPOSE: To use the doubly labeled water (DLW) technique to calculate the total energy expenditure (TEE) and body composition changes of two 28-y-old healthy male athletes during a 50-d continuous and unsupported row around Great Britain. METHODS: A measured dose of DLW was taken at the start of 2 separate study periods (days 5-19 and 34-48) followed by sequential urine collection, which was analyzed on return to land. RESULTS: Mean TEE was 15.3 MJ/d: athlete 1, 16.4 MJ/d; athlete 2, 14.9 MJ/d. Athlete 1 lost 11.2 kg and athlete 2 lost 14.9 kg of body mass during the row. Average energy provision was 19.1 MJ per 24-h ration pack. CONCLUSIONS: These results highlight the difficulty of maintaining energy balance during expedition rowing. A starvation state was observed despite dietary provision in excess of estimated energy expenditure, indicating that nutritional strategy rather than caloric availability was at fault. The authors recommend that future expeditions prioritize thorough testing and the individualization of rations to ensure that they are both palatable and practical during the weeks to months at sea. PMID- 27967264 TI - Tamoxifen Attenuates Lipopolysaccharide/Galactosamine-induced Acute Liver Failure by Antagonizing Hepatic Inflammation and Apoptosis. AB - Bacterial lipopolysaccharide (LPS)-induced acute liver failure (ALF) is a common severe clinical syndrome in intensive care unit. No other methods are available for its prevention apart from supportive treatment and liver transplantation. Tamoxifen (TAM) was reported to attenuate ALF induced by excessive acetaminophen, while its effect on LPS-induced ALF remained unknown. For this, in the present study, we comprehensively assessed whether TAM can attenuate ALF induced by LPS/galactosamine (GaIN). Mice were given TAM once a day for three times. Twelve hours after the last treatment, mice were given LPS/GaIN (intraperitoneally [i.p.]). Survival, plasma transaminases, and histopathology were examined. Serum TNF-alpha and IL-1beta were analyzed by ELISA. Hepatic apoptosis was analyzed by TUNEL and caspase-3 Western blotting, respectively. Compared to the model group, ALF induced by LPS/GaIN was alleviated remarkably following TAM administration, as evidenced by the improvement of survival (87.5% vs. 37.5%), hepatic swell, moderate transaminases, slightly increased serum TNF-alpha, IL-1beta (P < 0.05), and moderate histopathology. In respect of apoptosis, severe hepatocellular apoptosis was reduced notably by TAM treatment confirmed by less TUNEL-positive hepatocytes and decreased caspase-3 cleavage. The results demonstrated that TAM could attenuate LPS/GaIN-induced ALF effectively, probably due to hepatic inflammation and apoptosis antagonism. Furthermore, it was the first report about the effect of TAM on LPS/GaIN-induced ALF. PMID- 27967265 TI - Local and Systemic Profiles of Inflammatory Cytokines in Carrageenan-induced Paw Inflammation in Rats. AB - OBJECTIVE: Carrageenan (CA)-induced edema has been described as highly reproducible model of acute inflammation. However, little is known about the cytokines attributed to the CA-induced inflammation. In this study, we aimed to investigate the local and systemic expression profiles of various inflammatory cytokines following the subplantar injection of CA in rats. METHODOLOGY: Acute inflammation was induced in male Wistar rats by subplantar injection of CA. Serum and paw tissue were examined for the level of 19 specific inflammatory cytokines using antibody array. Further, the CA-elicited level of key inflammatory cytokines, cytokine-induced neutrophil chemoattractant (CINC)-2, CINC-3, interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, were quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: Edema was peaked 3 h postinjection of CA in hind paw. Among 19 specific cytokines profiled using antibody array, CA significantly (p < 0.05) elicited the levels of CINC-2, CINC-3, IL-1beta, IL-6, beta-NGF, TNF-alpha, and VEGF in paw tissue and that of CINC-2 and CINC-3 in serum. Consistently, levels of CINC-2, CINC-3, IL-1beta, IL 6, and TNF-alpha in tissue and CINC-2 and CINC-3 in serum were upregulated in CA treated rats when compared to control, quantified by ELISA. CONCLUSIONS: This study corroborates the distinct pattern of inflammatory cytokines involved during CA-induced acute inflammation. Furthermore, data provide new evidence on elevated expression of rat CXC chemokines: CINC-2 and CINC-3 at the site of inflammation as well as their significant reflection in the circulation, thereby suggesting their frontline role in CA-induced acute inflammation. PMID- 27967266 TI - Therapeutic applications of the versatile fatty acid mimetic WY14643. AB - INTRODUCTION: WY14643 - also known as pirinixic acid - is a versatile fatty acid mimetic that was originally developed as lipid lowering agent without knowledge of its molecular target. Various later studies discovered somewhat promiscuous activity of the compound on several receptors and enzymes. Pirinixic acid though never having reached clinical use was subjected to many in vivo studies and exerted beneficial effects in a variety of disease models. Areas covered: Inventions claiming the use of WY14643 for numerous indications ranging from the originally intended application in metabolic dysbalances over cancer and inflammation to some rare syndromes have been evaluated. Expert opinion: It is rather unlikely that pirinixic acid will gain relevance in treatment of metabolic diseases for which it was originally developed because more efficient and selective alternatives are available. Instead, several other claimed activities of the compound e.g. in inflammation, neurodegeneration and cancer seem very promising. However, some of the underlying studies are biased and for some effects of pirinixic acid, the molecular target and mode of action remain to be identified. PMID- 27967267 TI - Recent advances in acetylcholinesterase Inhibitors and Reactivators: an update on the patent literature (2012-2015). AB - INTRODUCTION: Acetylcholinesterase (AChE) is the major enzyme that hydrolyzes acetylcholine, a key neurotransmitter for synaptic transmission, into acetic acid and choline. Mild inhibition of AChE has been shown to have therapeutic relevance in Alzheimer's disease (AD), myasthenia gravis, and glaucoma among others. In contrast, strong inhibition of AChE can lead to cholinergic poisoning. To combat this, AChE reactivators have to be developed to remove the offending AChE inhibitor, restoring acetylcholine levels to normal. Areas covered: This article covers recent advances in the development of acetylcholinesterase modulators, including both inhibitors of acetylcholinesterase for the efforts in development of new chemical entities for treatment of AD, as well as re-activators for resurrection of organophosphate bound acetylcholinesterase. Expert opinion: Over the past three years, research efforts have continued to identify novel small molecules as AChE inhibitors for both CNS and peripheral diseases. The more recent patent activity has focused on three AChE ligand design areas: derivatives of known AChE ligands, natural product based scaffolds and multifunctional ligands, all of which have produced some unique chemical matter with AChE inhibition activities in the mid picomolar to low micromolar ranges. New AChE inhibitors with polypharmacology or dual inhibitory activity have also emerged as highlighted by new AChE inhibitors with dual activity at L-type calcium channels, GSK-3, BACE1 and H3, although most only show low micromolar activity, thus further research is warranted. New small molecule reactivators of organophosphate inhibited AChE have also been disclosed, which focused on the design of neutral ligands with improved pharmaceutical properties and blood-brain barrier (BBB) penetration. Gratifyingly, some research in this area is moving away from the traditional quaternary pyridinium oximes AChE reactivators, while still employing the necessary reactivation group (oximes). However, selectivity over inhibition of native AChE enzyme, effectiveness of reactivation, broad-spectrum reactivation against multiple organophosphates and reactivation of aged-enzyme continue to be hurdles for this area of research. PMID- 27967268 TI - Association Between Energy Balance and Metabolic Hormone Suppression During Ultraendurance Exercise. AB - Ultraendurance athletes often accumulate an energy deficit when engaging in ultraendurance exercise, and on completion of the exercise, they exhibit endocrine changes that are reminiscent of starvation. However, it remains unclear whether these endocrine changes are a result of the exercise per se or secondary to the energy deficit and, more important, whether these changes can be attenuated by increased dietary intake. The goal of the study was to assess the relationship between changes in key metabolic hormones after ultraendurance exercise and measures of energy balance. Metabolic hormones, as well as energy intake and expenditure, were assessed in 14 well-trained male cyclists who completed a 1230-km ultraendurance cycling event. After completion of the event, serum testosterone (-67% +/- 18%), insulin-like growth factor-1 (IGF-1) (-45% +/- 8%), and leptin (-79% +/- 9%) were significantly suppressed (P < .001) and remained suppressed after a 12-h recovery period (P < .001). Changes in IGF-1 were positively correlated with energy balance over the course of the event (r = .65, P = .037), which ranged from an 11,859-kcal deficit to a 3593-kcal surplus. The marked suppression of testosterone, IGF-1, and leptin after ultraendurance exercise is comparable to changes occurring during acute starvation. The suppression of IGF-1, but not that of other metabolic hormones, was strongly associated with the magnitude of the energy deficit, indicating that athletes who attained a greater energy deficit exhibited a more pronounced drop in IGF-1. Future studies are needed to determine whether increased dietary intake can attenuate the endocrine response to ultraendurance exercise. PMID- 27967269 TI - Small-molecule inhibitors of hepatitis C virus (HCV) non-structural protein 5A (NS5A): a patent review (2010-2015). AB - INTRODUCTION: Non-structural 5A (NS5A) protein has achieved a considerable attention as an attractive target for the treatment of hepatitis C (HCV). A number of novel NS5A inhibitors have been reported to date. Several drugs having favorable ADME properties and mild side effects were launched into the pharmaceutical market. For instance, daclatasvir was launched in 2014, elbasvir is currently undergoing registration, ledipasvir was launched in 2014 as a fixed dose combination with sofosbuvir (NS5B inhibitor). Areas covered: Thomson integrity database and SciFinder database were used as a valuable source to collect the patents on small-molecule NS5A inhibitors. All the structures were ranked by the date of priority. Patent holder and antiviral activity for each scaffold claimed were summarized and presented in a convenient manner. A particular focus was placed on the best-in-class bis-pyrrolidine-containing NS5A inhibitors. Expert opinion: Several first generation NS5A inhibitors have recently progressed into advanced clinical trials and showed superior efficacy in reducing viral load in infected subjects. Therapy schemes of using these agents in combination with other established antiviral drugs with complementary mechanisms of action can address the emergence of resistance and poor therapeutic outcome frequently attributed to antiviral drugs. PMID- 27967270 TI - Effects of 4 Weeks of beta-Alanine Supplementation on Swim-Performance Parameters in Water Polo Players. AB - In water polo, several high-intensity efforts are performed, leading to the fatigue process due to accumulation of hydrogen ions, and thus beta-alanine supplementation could be an efficient strategy to increase the intramuscular acid buffer. Purpose To investigate whether 4 wk of beta-alanine supplementation enhances parameters related to water polo performance. Methods Twenty-two highly trained male water polo players of national level were randomly assigned to receive 28 d of either beta-alanine or a placebo (4.8 g/d of the supplement in the first 10 d and 6.4 g/d in the final 18 d). The participants performed 30-s maximal tethered swimming (30TS), 200-m swimming (P200m), and 30-s crossbar jumps (30CJ) before and after the supplementation period. Results The beta-alanine group presented significant increases in 30TS for mean force (P = .04; Delta = 30.5% +/- 40.4%) and integral of force (P = .05; Delta = 28.0% +/- 38.0%), as well as P200m (P = .05; Delta = -2.2% +/- 2.6%), while the placebo group did not significantly differ for mean force (P = .13; Delta = 24.1% +/- 33.7%), integral of force (P = .12; Delta = 24.3% +/- 35.1%), or P200m (P = .10; Delta = -1.6% +/- 3.8%). However, there was no significant group effect for any variable, and the magnitude-based-inference analysis showed unclear outcomes between groups (Cohen d +/- 95%CL mean force = 0.16 +/- 0.83, integral of force = 0.12 +/- 0.84, and P200m = 0.05 +/- 0.30). For 30CJ the results were similar, with improvements in both groups (placebo, Delta = 14.9% +/- 14.1%; beta-alanine, Delta = 16.9% +/- 18.5%) but with no significant interaction effect between groups and an unclear effect (0.14 +/- 0.75). Conclusion Four weeks of beta-alanine supplementation does not substantially improve performance of 30TS, P200m, or 30CJ in highly trained water polo athletes compared with a control group. PMID- 27967271 TI - Representations of workers with hearing loss in Canadian newspapers: a thematic analysis. AB - OBJECTIVE: Participation in the labour force with a hearing impairment presents a number of challenges. This study describes how Canadian newspapers represent workers with hearing loss. DESIGN: Taking a critical framing theory approach, thematic analysis was performed through coding relevant articles, abstracting and hierarchically categorising themes. STUDY SAMPLE: Seven English-language Canadian newspapers were searched for publications between 1995 and 2016. Twenty-six articles met our criteria: discussing paid workers with hearing loss who used English rather than sign language on the job and making reference to workers' competence. RESULTS: We identified a global theme, Focussing on a good worklife or focussing on a limited worklife, composed of three organising themes (1) Prominent individuals struggle, take action, and continue despite hearing loss, (2) Workers with hearing loss in the community create their best day themselves, and (3) Workers with hearing loss, as a generalised whole, are portrayed as either competent or limited. CONCLUSIONS: The dominant framing portrays individual workers as ingenious, determined, and successful. Negative framings were predominantly generalisations to these workers as a group. To generate more positive framings, professionals can build relationships with consumer groups and, when contacted by the media, direct journalists to interview workers with hearing loss. PMID- 27967273 TI - Eccentric-Overload Training in Team-Sport Functional Performance: Constant Bilateral Vertical Versus Variable Unilateral Multidirectional Movements. AB - PURPOSE: To analyze the effects of 2 different eccentric-overload training (EOT) programs, using a rotational conical pulley, on functional performance in team sport players. A traditional movement paradigm (ie, squat) including several sets of 1 bilateral and vertical movement was compared with a novel paradigm including a different exercise in each set of unilateral and multi-directional movements. METHODS: Forty-eight amateur or semiprofessional team-sport players were randomly assigned to an EOT program including either the same bilateral vertical (CBV, n = 24) movement (squat) or different unilateral multidirectional (VUMD, n = 24) movements. Training programs consisted of 6 sets of 1 exercise (CBV) or 1 set of 6 exercises (VUMD) * 6-10 repetitions with 3 min of passive recovery between sets and exercises, biweekly for 8 wk. Functional-performance assessment included several change-of-direction (COD) tests, a 25-m linear-sprint test, unilateral multidirectional jumping tests (ie, lateral, horizontal, and vertical), and a bilateral vertical-jump test. RESULTS: Within-group analysis showed substantial improvements in all tests in both groups, with VUMD showing more robust adaptations in pooled COD tests and lateral/horizontal jumping, whereas the opposite occurred in CBV respecting linear sprinting and vertical jumping. Between-groups analyses showed substantially better results in lateral jumps (ES = 0.21), left-leg horizontal jump (ES = 0.35), and 10-m COD with right leg (ES = 0.42) in VUMD than in CBV. In contrast, left-leg countermovement jump (ES = 0.26) was possibly better in CBV than in VUMD. CONCLUSIONS: Eight weeks of EOT induced substantial improvements in functional-performance tests, although the force vector application may play a key role to develop different and specific functional adaptations. PMID- 27967272 TI - Activity Profiles in International Women's Team Handball Using PlayerLoad. AB - : Team handball matches place diverse physical demands on players, which may result in fatigue and decreased activity levels. However, previous speed-based methods of quantifying player activity may not be sensitive for capturing short lasting team-handball-specific movements. PURPOSE: To examine activity profiles of a women's team handball team and individual player profiles, using inertial measurement units. METHODS: Match data were obtained from 1 women's national team in 9 international matches (N = 85 individual player samples), using the Catapult OptimEye S5. PlayerLoad/min was used as a measure of intensity in 5- and 10-min periods. Team profiles were presented as relative to the player's match means, and individual profiles were presented as relative to the mean of the 5-min periods with >60% field time. RESULTS: A high initial intensity was observed for team profiles and for players with >=2 consecutive periods of play. Substantial declines in PlayerLoad/min were observed throughout matches for the team and for players with several consecutive periods of field time. These trends were found for all positional categories. Intensity increased substantially in the final 5 min of the first half for team profiles. Activity levels were substantially lower in the 5 min after a player's most intense period and were partly restored in the subsequent 5-min period. DISCUSSION: Possible explanations for the observed declines in activity profiles for the team and individual players include fatigue, situational factors, and pacing. However, underlying mechanisms were not accounted for, and these assumptions are therefore based on previous team-sport studies. PMID- 27967274 TI - A New Method to Individualize Monitoring of Muscle Recovery in Athletes. AB - PURPOSE: Assessment of muscle recovery is essential for the daily fine-tuning of training load in competitive sports, but individual differences may limit the diagnostic accuracy of group-based reference ranges. This article reports an attempt to develop individualized reference ranges using a Bayesian approach comparable to that developed for the Athlete Biological Passport. METHODS: Urea and creatine kinase (CK) were selected as indicators of muscle recovery. For each parameter, prior distributions and repeated-measures SDs were characterized based on data of 883 squad athletes (1758 data points, 1-8 per athlete, years 2013 2015). Equations for the individualization procedure were adapted from previous material to allow for discrimination of 2 physiological states (recovered vs nonrecovered). Evaluation of classificatory performance was carried out using data from 5 consecutive weekly microcycles in 14 elite junior swimmers and triathletes. Blood samples were collected every Monday (recovered) and Friday according to the repetitive weekly training schedule over 5 wk. On the group level, changes in muscle recovery could be confirmed by significant differences in urea and CK and validated questionnaires. Group-based reference ranges were derived from that same data set to avoid overestimating the potential benefit of individualization. RESULTS: For CK, error rates were significantly lower with individualized classification (P vs group-based: test-pass error rate P = .008; test-fail error rate P < .001). For urea, numerical improvements in error rates failed to reach significance. CONCLUSIONS: Individualized reference ranges seem to be a promising tool to improve accuracy of monitoring muscle recovery. Investigating application to a larger panel of indicators is warranted. PMID- 27967275 TI - Velocity, Oxygen Uptake, and Metabolic Cost of Pull, Kick, and Whole-Body Swimming. AB - PURPOSE: The contributions of the limbs to velocity and metabolic parameters in front-crawl swimming at different intensities have not been identified considering both stroke and kick rate. Consequently, velocity, oxygen uptake (VO2), and metabolic cost of swimming with the whole body (swim), the upper limbs only (pull), and lower limbs only (kick) were compared with stroke and kick rate controlled. METHODS: Twenty elite swimmers completed six 200-m trials: 2 swim, 2 pull, and 2 kick. Swim trials were guided by underwater lights at paces equivalent to 65% +/- 3% and 78% +/- 3% of participants' 200-m-freestyle personal best pace; paces were described as low and moderate, respectively. In the pull and kick trials, swimmers aimed to match the stroke and kick rates, respectively, recorded during the swim trials. VO2 was measured continuously, with velocity and metabolic cost calculated for each 200-m effort. RESULTS: The velocity contribution of the upper limbs (mean +/- SD; low 63.9% +/- 6.2%, moderate 59.6% +/- 4.2%) was greater than that of the lower limbs to a large extent at both intensities (low ES = 4.40, moderate ES = 4.60). The VO2 used by the upper limbs differed between the intensities (low 55.5% +/- 6.9%, moderate 51.4% +/- 4.0%; ES = 0.74). The lower limbs were responsible for a greater percentage of the metabolic cost than the upper limbs at both intensities (low 56.1% +/- 9.5%, ES = 1.30; moderate 55.1% +/- 6.6%, ES = 1.55). CONCLUSIONS: Implementation of this testing protocol before and after a pull- or kick-training block will enable sport scientists to determine how the velocity contributions and/or metabolic cost of the upper- and lower-limb actions have responded to the training program. PMID- 27967276 TI - The Impact of an Assistive Pole, Seat Configuration, and Strength in Paralympic Seated Throwing. AB - PURPOSE: To quantify the influence of the assistive pole, seat configuration, and upper-body and trunk strength on seated-throwing performance in athletes with a spinal-cord injury (SCI). METHODS: Ten Paralympic athletes competing in wheelchair rugby, basketball, or athletics (seated throws) participated in 2 randomized sessions: seated throwing and strength tests. Participants threw a club from a custom-built throwing chair, with and without a pole. 3D kinematic data were collected (150 Hz) for both conditions using standardized and self selected seat configurations. Dominant and nondominant grip strength were measured using a dynamometer, and upper-body and trunk strength were measured using isometric contractions against a load cell. RESULTS: Seated throwing with an assistive pole resulted in significantly higher hand speed at release than throwing without a pole (pole = 6.0 +/- 1.5 m/s, no pole = 5.3 +/- 1.5 m/s; P = .02). There was no significant difference in hand speed at release between standardized and self-selected seating configurations during seated throwing with or without an assistive pole. Grip strength (r = .59-.77), push/pull synergy (r = .81-.84), and trunk-flexion (r = .50-.58) strength measures showed large and significant correlations with hand speed at release during seated throwing with and without an assistive pole. CONCLUSIONS: This study has demonstrated the importance of the pole for SCI athletes in seated throwing and defined the relationship between strength and seated-throwing performance, allowing us to better understand the activity of seated throws and provide measures for assessing strength that may be valid for evidence-based classification. PMID- 27967277 TI - The Research Doesn't Always Apply: Practical Solutions to Evidence-Based Training Load Monitoring in Elite Team Sports. AB - Research describing load-monitoring techniques for team sport is plentiful. Much of this research is conducted retrospectively and typically involves recreational or semielite teams. Load-monitoring research conducted on professional team sports is largely observational. Challenges exist for the practitioner in implementing peer-reviewed research into the applied setting. These challenges include match scheduling, player adherence, manager/coach buy-in, sport traditions, and staff availability. External-load monitoring often attracts questions surrounding technology reliability and validity, while internal-load monitoring makes some assumptions about player adherence, as well as having some uncertainty around the impact these measures have on player performance This commentary outlines examples of load-monitoring research, discusses the issues associated with the application of this research in an elite team-sport setting, and suggests practical adjustments to the existing research where necessary. PMID- 27967278 TI - Validity, Sensitivity, Reproducibility, and Robustness of the PowerTap, Stages, and Garmin Vector Power Meters in Comparison With the SRM Device. AB - : A large number of power meters have been produced on the market for nearly 20 y according to user requirements. PURPOSE: To determine the validity, sensitivity, reproducibility, and robustness of the PowerTap (PWT), Stages (STG), and Garmin Vector (VCT) power meters in comparison with the SRM device. METHODS: A national level male competitive cyclist completed 3 laboratory cycling tests: a submaximal incremental test, a submaximal 30-min continuous test, and a sprint test. Two additional tests were performed, the first on vibration exposures in the laboratory and the second in the field. RESULTS: The VCT provided a significantly lower 5-s power output (PO) during the sprint test with a low gear ratio than the SRM did (-36.9%). The STG PO was significantly lower than the SRM PO in the heavy exercise-intensity zone (zone 2, -5.1%) and the low part of the severe-intensity zone (zone 3, -4.9%). The VCT PO was significantly lower than the SRM PO only in zone 2 (-4.5%). The STG PO was significantly lower in standing position than in the seated position (-4.4%). The reproducibility of the PWT, STG, and VCT was similar to that of the SRM system. The STG and VCT PO were significantly decreased from a vibration frequency of 48 Hz and 52 Hz, respectively. CONCLUSIONS: The PWT, STG, and VCT systems appear to be reproducible, but the validity, sensitivity, and robustness of the STG and VCT systems should be treated with some caution according to the conditions of measurement. PMID- 27967279 TI - Accuracy of Jump-Mat Systems for Measuring Jump Height. AB - : Vertical-jump tests are commonly used to evaluate lower-limb power of athletes and nonathletes. Several types of equipment are available for this purpose. PURPOSE: To compare the error of measurement of 2 jump-mat systems (Chronojump Boscosystem and Globus Ergo Tester) with that of a motion-capture system as a criterion and to determine the modifying effect of foot length on jump height. METHODS: Thirty-one young adult men alternated 4 countermovement jumps with 4 squat jumps. Mean jump height and standard deviations representing technical error of measurement arising from each device and variability arising from the subjects themselves were estimated with a novel mixed model and evaluated via standardization and magnitude-based inference. RESULTS: The jump-mat systems produced nearly identical measures of jump height (differences in means and in technical errors of measurement <=1 mm). Countermovement and squat-jump height were both 13.6 cm higher with motion capture (90% confidence limits +/-0.3 cm), but this very large difference was reduced to small unclear differences when adjusted to a foot length of zero. Variability in countermovement and squat-jump height arising from the subjects was small (1.1 and 1.5 cm, respectively, 90% confidence limits +/-0.3 cm); technical error of motion capture was similar in magnitude (1.7 and 1.6 cm, +/-0.3 and +/-0.4 cm), and that of the jump mats was similar or smaller (1.2 and 0.3 cm, +/-0.5 and +/-0.9 cm). CONCLUSIONS: The jump mat systems provide trustworthy measurements for monitoring changes in jump height. Foot length can explain the substantially higher jump height observed with motion capture. PMID- 27967280 TI - The Unlikeliness of an Imminent Sub-2-Hour Marathon: Historical Trends of the Gender Gap in Running Events. AB - The aim of the current study was to analyze men's and women's world records across the full range of running disciplines to contextualize the recent debate about the possibility of a sub-2-h marathon. The average male-female gap is currently 11.2% +/- 1.0% for all running events. However, reducing the marathon time to below 2 h would produce a performance 12.9% (+1.7 SD) faster than the women's marathon record. This gap would be greater than all current world-record differences and would also require a reversal of medium- and long-term historical trends in the men's and women's record differences. We therefore conclude that based on historical trends and known differences between men's and women's performances, the current women's world record is not yet the equivalent of a sub 2-h marathon and, therefore, that an imminent sub-2-h marathon is implausible. PMID- 27967281 TI - Carbohydrate Mouth Rinsing: Improved Neuromuscular Performance During Isokinetic Fatiguing Exercise. AB - PURPOSE: To determine whether repeated carbohydrate (CHO) mouth rinsing would improve neuromuscular performance during high-intensity fatiguing contractions. METHODS: Eighteen young men (age 26.1 +/- 5.0 y, BMI 22.9 +/- 1.9) performed 3 maximal voluntary isometric contractions (MVICPRE). Immediately after, they completed 10-second mouth rinse with 6.4% maltodextrin solution (MAL), 7.1% glucose solution (GLU), water (W), artificially sweetened solution (PLA), or a control trial with no rinse (CON) in a crossover protocol. Subjects performed 5 sets of 30 isokinetic fatiguing contractions at 180 degrees /s, and an MVICPOST with their elbow flexors was performed after each mouth rinse. Mechanical and electromyographic (EMG) signals were recorded from the biceps brachii and parameters of interest analyzed. RESULTS: When rinsing the mouth with a solution containing CHO, independently of the sweetness, isokinetic performance was enhanced as shown by the greater total work achieved in comparison with CON. The decay of torque and mean fiber-conduction velocity (MFCV) recorded at the end of the fatiguing task was lower when rinsing the mouth with GLU than with CON. The torque recorded during the MVICPOST was greater with CHO with respect to CON, and this was associated to a lower decay of MFCV. CONCLUSIONS: CHO mouth rinse counteracts fatigue-induced decline in neuromuscular performance, supporting the notion that CHO rinse may activate positive afferent signals able to modify motor output. Repeated mouth rinsing with sweet and nonsweet CHO-containing solutions can improve neuromuscular performance during an isokinetic intermittent fatiguing task. PMID- 27967282 TI - The Effect of Whole-Body Vibration on Subsequent Sprint Performance in Well Trained Cyclists. AB - : Postactivation-potentiation exercise with added whole-body vibration (WBV) has been suggested as a potential way to acutely improve sprint performance. In cycling, there are many competitions and situations where sprinting abilities are important. PURPOSE: To investigate the effect of adding WBV to warm-up procedures on subsequent cycle sprint performance. METHODS: Eleven well-trained cyclists participated in the study. All cyclists performed a familiarization session before 2 separate test sessions in randomized order. Each session included a standardized warm-up followed by 1 of the following preconditioning exercises: 30 s of half-squats without WBV or 30 s of half-squats with WBV at 40 Hz. A 15-s Wingate sprint was performed 1 min after the preconditioning exercise. RESULTS: Performing preconditioning exercise with WBV at 40 Hz resulted in superior peak power output compared with preconditioning exercise without WBV (1413 +/- 257 W vs 1353 +/- 213 W, P = .04) and a tendency toward superior mean power output during a 15-second all-out sprint (850 +/- 119 W vs 828 +/- 101 W, P = .08). Effect sizes showed a moderate practical effect of WBV vs no WBV on both peak and mean power output. CONCLUSIONS: Preconditioning exercise performed with WBV at 40 Hz seems to have a positive effect on cycling sprint performance in young well trained cyclists. This suggests that athletes can incorporate body-loaded squats with WBV in preparations to specific sprint training to improve the quality of the sprint training and also to improve sprint performance in relevant competitions. PMID- 27967283 TI - Do Fast Bowlers Fatigue in Cricket? A Paradox Between Player Anecdotes and Quantitative Evidence. AB - The manifestations of fatigue during fast bowling in cricket were systematically evaluated using subjective reports by cricket experts and quantitative data published from scientific studies. Narratives by international players and team physiotherapists were sourced from the Internet using criteria for opinion-based evidence. Research articles were evaluated for high-level fast bowlers who delivered 5- to 12-over spells with at least 1 quantitative fatigue measure. Anecdotes indicate that a long-term loss of bowling speed, tiredness, mental fatigue, and soreness occur. Scientific research shows that ball-release speed, bowling accuracy, bowling action (technique), run-up speed, and leg-muscle power are generally well maintained during bowling simulations. However, bowlers displaying excessive shoulder counterrotation toward the end of a spell also show a fall in accuracy. A single notable study involving bowling on 2 successive days in the heat showed reduced ball-release speed (-4.4 km/h), run-up speed (-1.3 km/h), and accuracy. Moderate to high ratings of perceived exertion transpire with simulations and match play (6.5-7.5 Borg CR-10 scale). Changes of blood lactate, pH, glucose, and core temperature appear insufficient to impair muscle function, although several potential physiological fatigue factors have not been investigated. The limited empirical evidence for bowling-induced fatigue appears to oppose player viewpoints and indicates a paradox. However, this may not be the case since bowling simulations resemble the shorter formats of the game but not multiday (test match) cricket or the influence of an arduous season, and comments of tiredness, mental fatigue, and soreness signify phenomena different from what scientists measure as fatigue. PMID- 27967284 TI - Sled Towing: The Optimal Overload for Peak Power Production. AB - PURPOSE: The effects of different loads on kinematic and kinetic variables during sled towing were investigated with the aim to identify the optimal overload for this specific sprint training. METHODS: Thirteen male sprinters (100-m personal best: 10.91 +/- 0.14 s) performed 5 maximal trials over a 20-m distance in the following conditions: unloaded and with loads from 15% to 40% of the athlete's body mass (BM). In these calculations the sled mass and friction were taken into account. Contact and flight times, stride length, horizontal hip velocity (vh), and relative angles of hip, knee, and ankle (at touchdown and takeoff) were measured step by step. In addition, the horizontal force (Fh) and power (Ph) and maximal force (Fh0) and power (Ph0) were calculated. RESULTS: vh, flight time, and step length decreased while contact time increased with increasing load (P < .001). These variables changed significantly also as a function of the step number (P < .01), except between the 2 last steps. No differences were observed in Fh among loads, but Fh was larger in sled towing than in unloaded. Ph was unaffected by load up to +20%BM but decreased with larger loads. Fh0 and Ph0 were achieved at 20%BM. Up to 20%BM, no significant effects on joint angles were observed at touchdown and takeoff, while at loads >30%BM joint angles tended to decrease. CONCLUSION: The 20%BM condition represents the optimal overload for peak power production-at this load sprinters reach their highest power without significant changes in their running technique (eg, joint angles). PMID- 27967285 TI - Player-Tracking Technology: Half-Full or Half-Empty Glass? AB - With the ongoing development of microtechnology, player tracking has become one of the most important components of load monitoring in team sports. The 3 main objectives of player tracking are better understanding of practice (provide an objective, a posteriori evaluation of external load and locomotor demands of any given session or match), optimization of training-load patterns at the team level, and decision making on individual players' training programs to improve performance and prevent injuries (eg, top-up training vs unloading sequences, return to play progression). This paper discusses the basics of a simple tracking approach and the need to integrate multiple systems. The limitations of some of the most used variables in the field (including metabolic-power measures) are debated, and innovative and potentially new powerful variables are presented. The foundations of a successful player-monitoring system are probably laid on the pitch first, in the way practitioners collect their own tracking data, given the limitations of each variable, and how they report and use all this information, rather than in the technology and the variables per se. Overall, the decision to use any tracking technology or new variable should always be considered with a cost/benefit approach (ie, cost, ease of use, portability, manpower/ability to affect the training program). PMID- 27967286 TI - Hematologic and renal improvement of monoclonal immunoglobulin deposition disease after treatment with bortezomib-based regimens. AB - Monoclonal immunoglobulin deposition disease (MIDD) is characterized by non organized immunoglobulin-fragments along renal basement membranes with subsequent organ deterioration. Treatment is directed against the immunoglobulin-producing clone. We treated 18 MIDD patients with bortezomib-based regimens (12 received bortezomib-dexamethasone, 6 bortezomib-dexamethasone with cyclophosphamide). Eleven (61%) patients achieved a hematologic response, but only 6 (33.3%) reached to a complete (CR) or very good partial response (VGPR). Regarding renal outcomes 77.8 and 55.6% had >=30 and >=50% reduction of proteinuria, respectively, but 33.3% ended up in end-stage renal disease (ESRD). Among patients with CR or VGPR, median eGFR improvement was 7.7 ml/min/1.73 m2 and none progressed to ESRD, but no significant renal recovery was observed in patients achieving a partial response or less, with 50% progressing to dialysis. Pretreatment eGFR seems to influence renal prognosis. Bortezomib-based treatment is considered an effective approach in MIDD and reaching to a deep hematologic response (>=VGPR) conditionally controls further renal declining. PMID- 27967287 TI - Early Therapy Services Following Neonatal Intensive Care Unit Discharge. AB - AIMS: To (1) characterize early therapy services for preterm infants in the first two years of life, and (2) define factors related to accessing early therapy services. METHODS: Therapy utilization after discharge from the neonatal intensive care unit (NICU) was tracked in 57 infants born <=30 weeks gestation from 2007 to 2010. Participants returned for developmental testing at two years. Factors related to early therapy utilization were explored. RESULTS: Fifty-two (91%) infants received a referral for therapy at NICU discharge but only 44 (77%) received at least one type of therapy during the first two years of life. Infants who received early therapy services were more likely to have more days on ventilation (p =.005), have single mothers (p =.047), and exhibit abnormal neurobehavior at term equivalent age (p =.03). On average, infants first received occupational therapy at a mean age of 5.1 +/- 4.6 months with a median of 2.6 (1.3-9.0), physical therapy at a mean age of 4.3 +/- 4.1 months with a median of 3.7 (0.1-5.5), and speech-language pathology services at a mean age of 14.0 +/- 6.1 months with a median of 15.0 (11.3-17.7) months corrected age. Of the 13 children who did not receive any therapy in the first two years after NICU discharge, seven (53%) had a developmental delay at an age of two years. CONCLUSIONS: In spite of high referral rates for therapy services, there is a delay in therapy activation following NICU discharge, and some infants who warrant services do not obtain them. PMID- 27967289 TI - Red, Amber, or Green? Athlete Monitoring in Team Sport: The Need for Decision Support Systems. AB - Decision-support systems are used in team sport for a variety of purposes including evaluating individual performance and informing athlete selection. A particularly common form of decision support is the traffic-light system, where color coding is used to indicate a given status of an athlete with respect to performance or training availability. However, despite relatively widespread use, there remains a lack of standardization with respect to how traffic-light systems are operationalized. This paper addresses a range of pertinent issues for practitioners relating to the practice of traffic-light monitoring in team sports. Specifically, the types and formats of data incorporated in such systems are discussed, along with the various analysis approaches available. Considerations relating to the visualization and communication of results to key stakeholders in the team-sport environment are also presented. In order for the efficacy of traffic-light systems to be improved, future iterations should look to incorporate the recommendations made here. PMID- 27967288 TI - Kabat rehabilitation for Bell's palsy in the elderly. AB - CONCLUSIONS: This study has confirmed the importance of combining the physical rehabilitation to the steroid treatment for a better outcome from BP in all age groups, especially in the old HB grade V. OBJECTIVES: To investigate the role played by aging in the recovery rate from peripheral facial nerve palsy. METHOD: In the present study, subjects affected by peripheral facial nerve palsy, distributed by age, were randomly assigned to medical treatment, either alone or associated with Kabat physical rehabilitation. Rate and speed of recovery were assessed in the younger and older groups. All the patients were also asked to fill in a specific questionnaire (beta FAce scale). A series of non-parametric tests (McNemar Chi-square and Chi-square) have been applied to verify the hypothesis of dependence of the final recovery level from the variables age and rehabilitation. RESULTS: The results show that, when treated only by medical therapy, the HB V subjects showed no significant age difference in relation to the achievement of a HB Grade III (100% in the over 65, 80% in the under 65), whilst, in the HB IV subjects, the younger population showed a better recovery, with 89% of a good recovery (HB I or II). In the patients who received the combined protocol, a better recovery rate was found, both in HB IV and V subjects, and the younger population could reach a good recovery in 90% of HB V cases in respect to the older population (50%). PMID- 27967290 TI - Ecotropic viral integration site I regulates alpha1, 6-fucosyl transferase expression and blocks erythropoiesis in chronic myeloid leukemia. AB - Although BCR-ABL is the hallmark genetic abnormality of chronic myeloid leukemia (CML), secondary molecular events responsible for the evolution of the disease to blast crisis are yet to be deciphered. Taking into account the significant association of ecotropic viral integration site I (EVI1) in CML drug resistance, it is necessary to decipher the other roles played by EVI1 in CML disease progression. In this regard, we cross-hybridized three microarray datasets and deduced a set of 11 genes that seems to be regulated by EVI1 in CML. We observed a strong correlation between EVI1 and alpha1, 6-fucosyltransferase (FUT8) in the chronic phase of the disease and both of them were found to be up-regulated with the progression of the disease. Knockdown of EVI1 in a CML cell line not only down-regulated FUT8, but also rendered the cells towards erythroid differentiation. Our study shows the involvement of EVI1 and FUT8 axis in blocking erythropoiesis in CML. PMID- 27967292 TI - The role of p53 in myelodysplastic syndromes and acute myeloid leukemia: molecular aspects and clinical implications. AB - TP53 gene mutations occurring in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are associated with high-risk karyotypes including 17p abnormalities, monosomal and complex cytogenetics. TP53 mutations in these disorders portend rapid disease progression and resistance to conventional therapeutics. Notably, the size of the TP53 mutant clone as measured by mutation allele burden is directly linked to overall survival (OS) confirming the importance of p53 as a negative prognostic variable. In nucleolar stress-induced ribosomopathies, such as del(5q) MDS, disassociation of MDM2 and p53 results in p53 accumulation in erythroid precursors manifested as erythroid hypoplasia. P53 antagonism by lenalidomide or other therapeutics such as antisense oligonucleotides, repopulates erythroid precursors and enhances effective erythropoiesis. These findings demonstrate that p53 is an intriguing therapeutic target that is currently under investigation in MDS and AML. This study reviews molecular advances in understanding the role of p53 in MDS and AML, and explores potential therapeutic strategies in this era of personalized medicine. PMID- 27967293 TI - The Time Course of Perceptual Recovery Markers After Match Play in Division I-A College American Football. AB - PURPOSE: To investigate the recovery time course of customized wellness markers (sleep, soreness, energy, and overall wellness) in response to match play in American Division I-A college football players. METHODS: A retrospective research design was used. Wellness data were collected and analyzed for 2 American college football seasons. Perceptions of soreness, sleep, energy, and overall wellness were obtained for the day before each game (GD-1) and the days after each game (GD+2, GD+3, and GD+4). Standardized effect-size (ES) analyses +/- 90% confidence intervals were used to interpret the magnitude of the mean differences between all time points for the start, middle, and finish of the season, using the following qualitative descriptors: 0-0.19 trivial, 0.2-0.59 small, 0.6-1.19 moderate, 1.2-1.99 large, <2.0 very large. RESULTS: Overall wellness showed small ES reductions on GD+2 (d = 0.22 +/- 0.09, likely [94.8%]), GD+3 (d = 0.37 +/- 0.15, very likely), and GD+4 (d = 0.29 +/- 0.12, very likely) compared with GD-1. There were small ES reductions for soreness between GD-1 and GD+2, GD+3, and GD +4 (d = 0.21 +/- 0.09, likely, d = 0.29 +/- 0.12, very likely, and 0.30 +/- 0.12, very likely, respectively). Small ES reductions were also evident between GD-1 and GD+3 (d = 0.21 +/- 0.09, likely) for sleep. Feelings of energy showed small ESs on GD+3 (d = 0.27 +/- 0.11, very likely) and GD+4 (d = 0.22 +/- 0.09, likely) compared with GD-1. CONCLUSION: All wellness markers were likely to very likely worse on GD+3 and GD+4 than on GD-1. These findings show that perceptual wellness takes longer than 4 d to return to pregame levels and thus should be considered when prescribing training and/or recovery. PMID- 27967291 TI - Novel Hypoglycemia Phenotype in Congenital Hyperinsulinism Due to Dominant Mutations of Uncoupling Protein 2. AB - Context: The rarest genetic form of congenital hyperinsulinism (HI) has been associated with dominant inactivating mutations in uncoupling protein 2 (UCP2), a mitochondrial inner membrane carrier that modulates oxidation of glucose vs amino acids. Objective: To evaluate the frequency of UCP2 mutations in children with HI and phenotypic features of this form of HI. Design: We examined 211 children with diazoxide-responsive HI seen at The Children's Hospital of Philadelphia (CHOP) between 1997 and October 2016. Setting: CHOP Clinical and Translational Research Center. Results: Of 211 cases of diazoxide-responsive HI, we identified 5 unrelated children with UCP2 mutations (5 of 211; 2.4%). All 5 were diagnosed with HI before 6 months of age; diazoxide treatment was only partly effective in 3 of the 5. Among the 5 cases, 4 unique mutations (3 missense and 1 splicing) were identified. Three mutations were novel; 1 was previously reported. In vitro functional assays showed 30% to 75% decrease in UCP2 activity. Two of the children, when not taking diazoxide, developed hypoketotic-hypoglycemia after fasting 15 to 20 hours; a similar trend toward hypoglycemia after fasting 24 hours occurred in 4 adult carriers. In contrast, both children and 2 of the 4 carriers developed symptomatic hypoglycemia 4 hours following oral glucose. Unusual oscillating glucose and insulin responses to oral glucose were seen in both cases and carriers. Conclusions: These data indicate that dominant UCP2 mutations are a more important cause of HI than has been recognized and that affected individuals are markedly hypersensitive to glucose-induced hypoglycemia. PMID- 27967295 TI - A Mine of Information: Can Sports Analytics Provide Wisdom From Your Data? AB - This paper explores the notion that the availability and analysis of large data sets have the capacity to improve practice and change the nature of science in the sport and exercise setting. The increasing use of data and information technology in sport is giving rise to this change. Web sites hold large data repositories, and the development of wearable technology, mobile phone applications, and related instruments for monitoring physical activity, training, and competition provide large data sets of extensive and detailed measurements. Innovative approaches conceived to more fully exploit these large data sets could provide a basis for more objective evaluation of coaching strategies and new approaches to how science is conducted. An emerging discipline, sports analytics, could help overcome some of the challenges involved in obtaining knowledge and wisdom from these large data sets. Examples of where large data sets have been analyzed, to evaluate the career development of elite cyclists and to characterize and optimize the training load of well-trained runners, are discussed. Careful verification of large data sets is time consuming and imperative before useful conclusions can be drawn. Consequently, it is recommended that prospective studies be preferred over retrospective analyses of data. It is concluded that rigorous analysis of large data sets could enhance our knowledge in the sport and exercise sciences, inform competitive strategies, and allow innovative new research and findings. PMID- 27967296 TI - New JAG1 Mutation Causing Alagille Syndrome Presenting With Severe Hypercholesterolemia: Case Report With Emphasis on Genetics and Lipid Abnormalities. AB - Context: Alagille syndrome is a rare autosomal-dominant genetic disorder caused by defects in the Notch signaling pathway, which involves multiple organ systems. Bile duct paucity is the main characteristic feature of the disease, which often leads to cholestatic hypercholesterolemia. Case Description: We report the case of a male infant who had developed failure to thrive, jaundice, intermittent pruritus, and multiple diffuse symmetrical skin xanthomas at 1 year of age. He was diagnosed with pulmonary stenosis, butterfly vertebrae of T4, T6, and T8; horseshoe kidney, and embryotoxon in the left eye. Laboratory workup revealed severe hypercholesterolemia. Alagille syndrome was suspected and confirmed by genetic testing, which identified a previously undescribed frameshift pathogenic heterozygous variant in the JAG1 gene, p.Arg486Lysfs*5. Conclusions: Here, we report a unique case of a patient diagnosed with Alagille syndrome who was found to have a previously undescribed frameshift pathogenic mutation in the JAG1 gene and who presented with xanthomatosis and levels of hypercholesterolemia more than 2 times higher than those previously reported in the literature. We also provide a review of the different pathophysiologic mechanisms associated with the increase in serum cholesterol and low-density lipoprotein cholesterol concentrations seen in cholestatic liver disease in general and in Alagille syndrome in particular. PMID- 27967297 TI - Active surveillance as a therapeutic option for patients with low-risk prostate cancer according to the 2014 International Society of Urological Pathology grading system: a review. AB - Extended prostate-specific antigen screening and the tightly focused execution of biopsies have resulted in an increased rate of detection, and thereby increased interventional treatment, of prostate cancer (PCa). The potential overdiagnosis and overtreatment of PCa patients have repeatedly been criticized in national and international literature. Controlled monitoring of patients in the setting of active surveillance (AS) can prevent overtreatment and the needless impairment of quality of life. The prerequisite for this treatment strategy is the diagnosis of low-grade/risk PCa. Since 2005, the modified Gleason grading system has been used for the histological assessment of PCa. In 2014, the International Society of Urological Pathology recommended a new prognostic grading system with five grades analogous to the modified Gleason score. This review discusses the importance of pathological histological analysis of PCa, particularly in the face of recent amendments, and sheds light on the significance of the new grading system for the diagnosis of low-grade/risk PCa with regard to the therapeutic option of AS. PMID- 27967294 TI - Patterns of growth factor usage and febrile neutropenia among older patients with diffuse large B-cell non-Hodgkin lymphoma treated with CHOP or R-CHOP: the Intergroup experience (CALGB 9793; ECOG-SWOG 4494). AB - Patterns of myeloid growth factor (GF) usage and febrile neutropenia (FN) were examined in patients >60 years of age with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) enrolled on CALGB 9793/ECOG-SWOG 4494, receiving initial therapy with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab + CHOP (R-CHOP). Myeloid GFs were administered to 256/520 (49%) patients. Indications for use were: prevent dose reduction/dose delay (81%, 207/256); treat FN or non-febrile neutropenia (NFN) (19%, 48/256). One or more FN episodes occurred in 41% (212/520) of patients, with FN most often in cycle 1 (38% of episodes). In multivariate analysis, risk factors for FN included age >65 years (odds ratio (OR) = 2.6, 95% CI: [1.4, 4.9]) and anemia (hemoglobin <12 g/dl) (OR =2.2, 95% confidence intervals (CI): [1.4, 3.5]. Myeloid GF use was common in this older DLBCL population receiving CHOP-based therapy, as was FN, especially during cycle one. Risk factors predictive for FN should be used prospectively to identify patients for whom myeloid GFs are best utilized. PMID- 27967298 TI - Effects of Aquatic Intervention on Gross Motor Skills in Children with Cerebral Palsy: A Systematic Review. AB - AIMS: To review the literature on the effects of aquatic intervention on gross motor skills for children with cerebral palsy (CP). DATA SOURCES: Six databases were searched from inception to January 2016. REVIEW METHODS: Aquatic studies for children aged 1-21 years with any type or CP classification and at least one outcome measuring gross motor skills were included. Information was extracted on study design, outcomes, and aquatic program type, frequency, duration, and intensity. Quality was rated using the Centre of Evidence-Based Medicine: Levels of Evidence and the PEDro scale. RESULTS: Of the 11 studies which met inclusion criteria, only two used randomized control trial design, and the results were mixed. Quality of evidence was rated as moderate to high for only one study. Most studies used quasi-experimental designs and reported improvements in gross motor skills for within group analyses after aquatic programs were held for two to three times per week and lasting for 6-16 weeks. Participants were classified according to the Gross Motor Function Classification System (GMFCS) levels I-V, and were aged 3-21 years. Mild to no adverse reactions were reported. CONCLUSIONS: Evidence on aquatic interventions for ambulatory children with CP is limited. Aquatic exercise is feasible and adverse effects are minimal; however, dosing parameters are unclear. Further research is needed to determine aquatic intervention effectiveness and exercise dosing across age categories and GMFCS levels. PMID- 27967300 TI - Clinical Features and Management of Non-HIV-Related Lipodystrophy in Children: A Systematic Review. AB - Context: Lipodystrophy syndromes are characterized by generalized or partial absence of adipose tissue. Objective: We conducted a systematic review to synthesize data on clinical and metabolic features of lipodystrophy (age at onset, < 18 years). Data Source: Sources included Medline, Embase, Cochrane Library, Scopus and Non-Indexed Citations from inception through January 2016. Study Selection: Search terms included lipodystrophy, and age 0 to 18 years. Patients with unambiguous diagnosis of lipodystrophy were included. Lipodystrophy secondary to HIV treatment was excluded. Data Synthesis: We identified 1141 patients from 351 studies. Generalized fat loss involving face, neck, abdomen, thorax, and upper and lower limbs was explicitly reported in 65% to 93% of patients with congenital generalized lipodystrophy (CGL) and acquired generalized lipodystrophy (AGL). In familial partial lipodystrophy (FPL), fat loss occurred from upper and lower limbs, with sparing of face and neck. In acquired partial lipodystrophy (APL), upper limbs were involved while lower limbs were spared. Other features were prominent musculature, acromegaloid, acanthosis nigricans and hepatosplenomegaly. Diabetes mellitus was diagnosed in 48% (n = 222) of patients with CGL (mean age at onset, 5.3 years). Hypertriglyceridemia was observed in CGL, AGL and FPL. Multiple interventions were used, with most patients receiving >= 3 interventions and being >= 18 years of age at the initiation of interventions. Conclusions: To our knowledge, this is the largest reported pooled database describing lipodystrophy patients with age at onset < 18 years. We have suggested core and supportive clinical features and summarized data on available interventions, outcomes and mortality. PMID- 27967301 TI - Analysis of hematologic alterations, immune responses and metallothionein gene expression in Nile tilapia (Oreochromis niloticus) exposed to silver nanoparticles. AB - In this study, Nile tilapia (Oreochromis niloticus) fingerlings were used as a model to examine acute and chronic toxicity of silver nanoparticles (AgNP). Expression levels of metallothionein (MT) transcripts in fish exposed to 0, 1 or 100 mg AgNP/kg fish were investigated by quantitative real-time RT-PCR. The results showed MT expression levels were significantly decreased 0.3-0.7-fold in the liver and spleen of fish exposed to 1 or 100 mg AgNP/kg after 6-48 h. In contrast, during this period, MT mRNA expression levels were increased 2-3-fold in the head kidney of the fish exposed to either level of AgNP. Investigations of effects of AgNP on the fish immune responses and hematological parameters revealed that phagocytic activity, the amount of red blood cells (RBC) and the percent hematocrit (%Hct) in fish exposed to AgNP were decreased significantly 1 week after exposure, especially those exposed to 100 mg AgNP/kg. Fish immunized with Streptococcus agalactiae vaccine and simultaneously exposed to 100 mg AgNP/kg presented decreased antibody titers during the early phase. Lastly, a challenge test showed that vaccinated fish exposed to AgNP, regardless of concentration, remained protected against S. agalactiae infection, with a lower mortality (10-20%) compared to 70% in control fish. These findings indicated that expression patterns of the MT gene in the liver, spleen and head kidney at different timepoints could be used to assess acute and chronic exposure of Nile tilapia to AgNP. Additionally, changes in innate immune responses and hematological parameters in fish may prove useful for evaluation of AgNP toxicity. Data obtained in this study strongly support the use of Nile tilapia as an animal model to potentially serve as a bio-indicator of environment contamination caused by AgNP. PMID- 27967302 TI - Cutaneous exposure to clinically-relevant pigeon pea (Cajanus cajan) proteins promote TH2-dependent sensitization and IgE-mediated anaphylaxis in Balb/c mice. AB - Epicutaneous (EC) sensitization to food allergens may occur when the skin has been lightly damaged. The study here tested whether cutaneous exposure to pigeon pea protein(s) may cause allergic sensitization. BALB/c mice were either orally gavaged or epicutaneously sensitized by repeated application of pigeon pea crude protein extract (CPE) on undamaged areas of skin without any adjuvant; afterwards, both groups were orally challenged with the pigeon pea CPE. Anaphylactic symptoms along with measures of body temperature, MCPT-1, TSLP, pigeon pea-specific IgE and IgG1, myeloperoxidase (MPO) activity, TH2 cytokines, TH2 transcription factors (TFs) and filaggrin expression were determined. Mast cell staining, eosinophil levels and histopathological analysis of the skin and intestines were also performed. In the epicutaneously-sensitized mice, elevated levels of specific IgE and IgG1, as well as of MCPT-1, TSLP, TH2 cytokines and TFs, higher anaphylactic scores and histological changes in the skin and intestine were indicative of sensitization ability via both routes in the pigeon pea CPE-treated hosts. Elevated levels of mast cells were observed in both the skin and intestine; increased levels of eosinophils and MPO activity were noted only in the skin. Decreased levels of filaggrin in skin may have played a key role in the skin barrier dysfunction, increasing the chances of sensitization. Therefore, the experimental data support the hypothesis that in addition to oral exposure, skin exposure to food allergens can promote TH2-dependent sensitization, IgE-mediated anaphylaxis and intestinal changes after oral challenge. Based on this, an avoidance of cutaneous exposures to allergens might prevent development of food anaphylaxis. PMID- 27967306 TI - Oedema and its treatment. AB - Bandages have been applied to leg ulcers for centuries, but it is only comparatively recently that the relationship between oedema reduction and ulcer healing has been recognised. Oedema inhibits the microcirculation, preventing adequate perfusion and nutritional exchange1. PMID- 27967303 TI - Immune responses induced by diclofenac or carbamazepine in an oral exposure model using TNP-Ficoll as reporter antigen. AB - Immune-mediated drug hypersensitivity reactions (IDHR) may result from immuno sensitization to a drug-induced neo-antigen. They rarely occur in patients and are usually not predicted preclinically using standard toxicity studies. To assess the potential of a drug to induce T-cell sensitization, trinitrophenyl (TNP)-Ficoll was used here as a bystander antigen in animal experiments. TNP Ficoll will only elicit TNP-specific IgG antibodies in the presence of non cognate T-cell help. Therefore, the presence of TNP-specific IgG antibodies after co-injection of drug and TNP-Ficoll was indicative of T-cell sensitization potential. This TNP-Ficoll-approach was used here to characterize T-cell help induced by oral exposure to diclofenac (DF) or carbamazepine (CMZ). DF or CMZ was administered orally to BALB/c mice and after 3 w, the mice were challenged in a hind paw with TNP-Ficoll and a dose of the drug that by itself does only elicit a sub-optimal popliteal lymph node assay (PLNA) response. T-cell-dependent responses were then evaluated in paw-draining popliteal lymph nodes (PLN). Also, shortly after oral exposure, mesenteric lymph nodes (MLN) were excised for evaluation of local responses. Both drugs were able to increase PLN cellularity and TNP-specific IgG1 production after challenge. Both DF and CMZ stimulated CD4+ and CD8+ T-cells and caused shifts of the subsets toward an effector phenotype. DF, but not CMZ, appeared to stimulate interferon (IFN)-gamma production. Remarkably, depletion of CD8+, but not CD4+, T-cells reduced TNP-specific IgG1 production, and was more pronounced in CMZ- than in DF-exposed animals. Local responses in the MLN caused by DF or CMZ also showed shifts of CD4+ and CD8+ cells toward a memory phenotype. Together, the data indicate that oral exposure to CMZ and DF differentially induced neo-antigen-specific T-cell reactions in the PLNA. PMID- 27967308 TI - A Biallelic Mutation in the Homologous Recombination Repair Gene SPIDR Is Associated With Human Gonadal Dysgenesis. AB - Context: Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction, characterized by amenorrhea with elevated gonadotropin levels. The disorder presents as absence of normal progression of puberty. Objective: To elucidate the cause of ovarian dysfunction in a family with POI. Design: We performed whole-exome sequencing in 2 affected individuals. To evaluate whether DNA double-strand break (DSB) repair activities are altered in biallelic mutation carriers, we applied an enhanced green fluorescent protein based assay for the detection of specific DSB repair pathways in blood-derived cells. Setting: Diagnoses were made at the Pediatric Endocrine Clinic, Clalit Health Services, Sharon-Shomron District, Israel. Genetic counseling and sample collection were performed at the Pediatric Genetics Unit, Schneider Children's Medical Center Israel, Petah Tikva, Israel. Patients and Intervention: Two sisters born to consanguineous parents of Israeli Muslim Arab ancestry presented with a lack of normal progression of puberty, high gonadotropin levels, and hypoplastic or absent ovaries on ultrasound. Blood samples for DNA extraction were obtained from all family members. Main Outcome Measure: Exome analysis to elucidate the cause of POI in 2 affected sisters. Results: Analysis revealed a stop-gain homozygous mutation in the SPIDR gene (KIAA0146) c.839G>A, p.W280*. This mutation altered SPIDR activity in homologous recombination, resulting in the accumulation of 53BP1-labeled DSBs postionizing radiation and gammaH2AX labeled damage during unperturbed growth. Conclusions: SPIDR is important for ovarian function in humans. A biallelic mutation in this gene may be associated with ovarian dysgenesis in cases of autosomal recessive inheritance. PMID- 27967312 TI - A Retrospective Survival Study of Trabecular Tantalum Implants Immediately Placed in Posterior Extraction Sockets Using a Flapless Technique. AB - A retrospective review of patient records was conducted in a single private practice to evaluate the efficacy of immediately placing a novel implant design in posterior jaw locations using a flapless technique. Forty-two patients (22 males, 20 females) with a mean (SD) age of 60.2 (7.6) years (range = 31-68) presented with 1-2 nonrestorable molar (maxillary = 14; mandibular = 8) or premolar (maxillary = 20; mandibular = 1) teeth compromised by periodontal disease, endodontic failure, root resorption, root fracture, or severe caries. Most patients (78.6%) had moderate (66.7%) or severe (11.9%) periodontitis. Other comorbidities included smoking (14.3%) and controlled diabetes mellitus (11.9%). After atraumatic extraction, teeth were immediately replaced with a total of 44 trabecular tantalum implants (Trabecular Metal Implants, Zimmer Biomet Dental) (diameter = 3.7-4.7 mm; length = 10-13 mm). Sites requiring augmentation were treated with 3 types of small-particle (250-1000 MUm), mineralized, solvent dehydrated, allografts (Puros) based on location: cortical for crestal sinus grafts, cancellous for peri-implant voids in thick tissue biotypes, or cortical cancellous (70:30) mix for peri-implant voids in thin tissue biotypes. Cortical particulate was used when slower resorption would help maintain graft volume for esthetics or implant support. Grafts were covered with resorbable bovine pericardium membranes (CopiOs, Zimmer Biomet). Cumulative implant survival and success rates were 97.7%, respectively, with a mean (+/-SD) follow-up time of 25.0 +/- 12.1 months (range = 4-48). One asymptomatic implant failed to osseointegrate. Within the limitations of this study, implants achieved outcomes comparable to conventionally placed and restored single-tooth implants in anterior jaw locations. PMID- 27967316 TI - Adipogenic Impairment of Adipose Tissue-Derived Mesenchymal Stem Cells in Subjects With Metabolic Syndrome: Possible Protective Role of FGF2. AB - Context: The decreased expansion capacity of adipose tissue plays a crucial role in the onset of disorders associated with metabolic syndrome. Objective: The aim of this study was to examine the state of adipose tissue-derived mesenchymal stem cells (ASCs) from obese subjects with different metabolic profiles. Design: This was a 2-year study to enroll subjects who underwent bariatric surgery or cholecystectomy. Setting: University Hospital. Patients and Intervention: Patients who underwent either bariatric surgery (20 morbidly obese) or cholecystectomy (40 subjects) participated in the study. Main Outcome Measures: ASCs were obtained from both visceral and subcutaneous adipose tissue. Adipogenic, fibrotic gene expression was quantified by quantitative polymerase chain reaction; Smad7 and fibroblast growth factor 2 were quantified by western blotting and enzyme-linked immunosorbent assay, respectively. The susceptibility of ASCs to apoptosis, their population doubling time, and their clonogenic potential were evaluated. Results: The worsening metabolic profile of the patients was accompanied by a decrease in the intrinsic levels of adipogenic gene expression, reduced proliferation rate, clonogenic potential, and exportation of fibroblast growth factor 2 to the cell surface of the ASCs derived from both tissues. In addition, the ASCs from patients without metabolic syndrome showed differences in susceptibility to apoptosis and expression of TGFbeta-signaling inhibitory protein Smad7 with respect to the ASCs from patients with metabolic syndrome. Conclusion: Our results suggest that the decrease in adipogenic-gene mRNA and clonogenic potential, as well as the accumulation of fibrotic proteins with metabolic alterations, could be a relevant mechanism controlling the number and size of neogenerated adipocytes and involved in alteration of adipose-tissue expansion. PMID- 27967317 TI - The Longitudinal Relationship Between Cortisol Responses to Mental Stress and Leukocyte Telomere Attrition. AB - Context: Chronic psychological stress has been associated with shorter telomeres, but the underlying mechanisms are poorly understood. One possibility is that the neuroendocrine responses to stress exposure are involved. Objective: To test the hypothesis that greater cortisol responsivity to acute stressors predicts more rapid telomere attrition. Design: We measured salivary cortisol responses to 2 challenging behavioral tasks. Leukocyte telomere length was measured at the time of mental stress testing and 3 years later. Participants: We studied 411 initially healthy men and women aged 54 to 76 years. Main outcome measure: Leukocyte telomere length. Results: Cortisol responses to this protocol were small; we divided participants into cortisol responders (n = 156) and nonresponders (n = 255) using a criterion (>=20% increase in cortisol concentration) previously shown to predict increases in cardiovascular disease risk. There was no significant association between cortisol responsivity and baseline telomere length, although cortisol responders tended to have somewhat shorter telomeres (beta = -0.061; standard error, 0.049). But cortisol responders had shorter telomeres and more rapid telomere attrition than nonresponders on follow-up, after controlling statistically for age, sex, socioeconomic status, smoking, time of day of stress , and baseline telomere length (beta = -0.10; standard error, 0.046; P = 0.029). The association was maintained after additional control for cardiovascular risk factors (beta = -0.11; P = 0.031). The difference between cortisol responders and nonresponders was equivalent to approximately 2 years in aging. Conclusions: These findings suggest that cortisol responsivity may mediate, in part, the relationship between psychological stress and cellular aging. PMID- 27967320 TI - Effect of Steam Autoclaving on the Tensile Strength of Resin Cements Used for Bonding Two-Piece Zirconia Abutments. AB - The purpose of this study was to evaluate the effects of steam autoclave sterilization on the tensile strength of two types of resin cements used to bond customized CAD/CAM zirconia abutments onto titanium bases. Forty sets of zirconia abutments cemented to screwed titanium bases of implants analogs were divided into 4 groups (n = 10). Two groups were treated with a conventional chemically activated resin cement (ML, Multilink Ivoclar Vivadent) and the other two groups with a self-adhesive dual resin cement (RelyX U200, 3M ESPE). One group from each cement was submitted to steam autoclaving. The autoclave sterilization cycle was performed after 72 hours of cementation for 15 minutes at 121 degrees C and 2.1 Kgf/cm2. The samples were subjected to tensile strength testing in a universal testing machine (200 Kgf, 0.5 mm/min), from which the means and standard deviations were obtained in Newtons. Results showed (via ANOVA and Tukey's test; alpha = 0.05) that in the absence of steam autoclaving, no difference was observed in tensile strength between the cements tested: ML: 344.87 (93.79) and U200: 280 (92.42) (P = .314). Steam autoclaving, however, significantly increased tensile strength for the ML: 465.42 (87.87) compared to U200: 289.10 (49.02) (P < .001). Despite the significant increase in the ML samples (P = .013), autoclaving did not affect the tensile strength of the U200 samples (P > 0.05). The authors concluded that steam autoclaving increases the mean tensile strength of the chemically activated cement compared to the dual-cure self-adhesive cement. The performance of both cements evaluated was similar if the sterilization step was disconsidered. PMID- 27967318 TI - Effect of polymorphisms in CYP3A4, PPARA, NR1I2, NFKB1, ABCG2 and SLCO1B1 on the pharmacokinetics of lovastatin in healthy Chinese volunteers. AB - AIM: This study examined whether gene polymorphisms (CYP3A4, ABCG2, SLCO1B1, NR1I2, PPARA and NFKB1) influenced the pharmacokinetics of lovastatin in Chinese healthy subjects. PATIENTS & METHOD: Plasma concentrations of lovastatin and lovastatin acid were quantified using LC/MS/MS. RESULTS: PPARA c.208+3819 G allele carriers had approximately twofold higher AUC0-infinity and Cmax of lovastatin than wild-type (PPARA c.208+3819 AA) subjects. After adjustment for the PPARA variants, subjects with the SLCO1B1 521TT genotype had approximately 50% lower AUC0-infinity of lovastatin acid than those with 521TC/CC genotypes, while the AUC0-infinity of lovastatin lactone in NFKB1-94 DD wild-type carriers was twofold higher than in mutant homozygotes carriers. CONCLUSION: Gene polymorphisms of PPARA, SLCO1B1 and NFKB1 affected the pharmacokinetics of lovastatin. PMID- 27967319 TI - Allogeneic hematopoietic stem cell transplantation improves the prognosis of p16 deleted adult patients with acute lymphoblastic leukemia. AB - AIM: The prognostic value of CDKN2A inactivation in adult patients with acute lymphoblastic leukemia (ALL) is still under debate, and the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult ALL with p16 deletion remains to be evaluated. MATERIALS & METHODS: This study analyzed the clinical implications of p16 deletion in adult ALL and investigated the efficacy of allo-HSCT in patients with p16 deletion. RESULTS: Deletion of p16 was identified in 38.4% of the adult ALL patients, and the prevalences of hemizygous deletion, homozygous deletion and mixed hemi/homozygous of p16 were 22.1, 11.6 and 5.5%, respectively. The prevalence of p16 deletion was 39.7% in B-lineage ALL and 33.3% in T-lineage ALL. Deletion of p16 was significantly associated with higher white blood cell count (p = 0.032) and lower platelets (p = 0.023) but was not related to age, sex, percentage of bone marrow blasts, hepatosplenomegaly, CNS leukemia rate, first complete remission and relapse rate (p > 0.05). Deletion of p16 was significantly correlated with poor outcome in terms of event-free survival (EFS; p = 0.028) and overall survival (OS; p = 0.033). Twenty-two of the 33 patients with p16 deletion received allo-HSCT treatment. Patients with p16 deletion after allo-HSCT experienced higher EFS and OS than those without (52.9 vs 0%, p < 0.001; 46.8 vs 29.1%, p = 0.01, respectively). Multivariate analysis found CNS leukemia and poor response to induction chemotherapy to be the risk factors for EFS and OS, whereas no deletions of p16 and allo-HSCT were favorable factors. CONCLUSION: Deletion of p16 is a strong adverse prognostic factor in adult ALL. Testing for p16 alterations at diagnosis may help in risk stratification, and we propose to implement testing for p16 deletion in future treatment protocols. PMID- 27967323 TI - Topical Antimicrobial Agents in Wound Care. AB - Chemical control of micro-organisms relies on strategies that either inhibit growth or cause death of the organisms. Chemicals that cause death of micro organisms are known as cidal agents. Chemicals that prevent microbial growth without causing death are known as static agents. PMID- 27967321 TI - The impact of the UGT1A1*60 allele on bilirubin serum concentrations. AB - AIM: Identify the functional status of the uridine-diphosphate glucuronyl transferase 1A1 (UGT1A1) -3279T>G (*60) variant. MATERIALS & METHODS: Retrospective review of clinically obtained serum bilirubin concentrations in pediatric patients to evaluate the association of the UGT1A1 -3279T>G (*60) variant with bilirubin concentrations and assessed linkage disequilibrium of the UGT1A1 -3279T>G (*60) and A(TA)7TAA (*28) variants. RESULTS: Total bilirubin concentration did not differ between patients who had a UGT1A1*1/*1 diplotype and patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant. Total bilirubin concentration was lower in patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant than in patients homozygous for the UGT1A1 A(TA)7TAA (*28/*28) variant (p < 0.01). The -3279T>G (*60) and A(TA)7TAA (*28) variants were in strong incomplete linkage disequilibrium in both black and white patients. CONCLUSION: The presence of the UGT1A1 -3279T>G (*60) variant is not associated with increased bilirubin concentrations. PMID- 27967324 TI - Criteria for Identifying Wound Infection. AB - Criteria used to identify infection may often be restricted to the presence of pus, or pus with inflammation1. Traditional criteria have been used in many surveys and their advantage is that they are simple, reproducible and easily recognised by different observers. However, identification of infection may be difficult in some circumstances, and identifying patients who are likely to develop infection is rare. PMID- 27967325 TI - Sampling Bacterial Flora. AB - All clinicians involved in wound care are at some time or another required to send a specimen to a laboratory. However, this often involves considerable uncertainty and debate as to which specimen should be taken, where from and how. PMID- 27967327 TI - Managing Wound Infection. AB - Clinicians face many dilemmas when working with infected and non-healing wounds and there is still considerable debate as to what the aim of treating such patients should be. Should it be to eradicate specific pathogenic organisms? Or should it be to reduce the bacterial burden present in or on wounds? PMID- 27967329 TI - Association of polymorphisms in GAD1 and GAD2 genes with methamphetamine dependence. AB - AIM: Association between polymorphisms in GAD genes and methamphetamine (METH) dependence was investigated in the Thai population. MATERIALS & METHODS: Genotypes of rs769404 and rs701492 in GAD1 and rs2236418 in GAD2 polymorphisms were determined in 100 METH-dependent male subjects and 102 matched controls. RESULTS: The genotype and allele frequencies of rs2236418 (GAD2) were associated with METH dependence and METH with psychosis, in which the G allele was related to increased risk. The presence of the rs769404-rs701492 (GAD1) C-C haplotype was associated with METH psychosis. CONCLUSION: This study indicates that genetic variability in GAD1 and GAD2 contributes to risk of METH dependence and METH psychosis in the Thai population and indicates the role of the GABAergic system in these disorders. PMID- 27967328 TI - A novel acenocoumarol pharmacogenomic dosing algorithm for the Greek population of EU-PACT trial. AB - AIM: To generate and validate a pharmacogenomic-guided (PG) dosing algorithm for acenocoumarol in the Greek population. To compare its performance with other PG algorithms developed for the Greek population. PATIENTS & METHODS: A total of 140 Greek patients participants of the EU-PACT trial for acenocoumarol, a randomized clinical trial that prospectively compared the effect of a PG dosing algorithm with a clinical dosing algorithm on the percentage of time within INR therapeutic range, who reached acenocoumarol stable dose were included in the study. RESULTS: CYP2C9 and VKORC1 genotypes, age and weight affected acenocoumarol dose and predicted 53.9% of its variability. EU-PACT PG algorithm overestimated acenocoumarol dose across all different CYP2C9/VKORC1 functional phenotype bins (predicted dose vs stable dose in normal responders 2.31 vs 2.00 mg/day, p = 0.028, in sensitive responders 1.72 vs 1.50 mg/day, p = 0.003, in highly sensitive responders 1.39 vs 1.00 mg/day, p = 0.029). The PG algorithm previously developed for the Greek population overestimated the dose in normal responders (2.51 vs 2.00 mg/day, p < 0.001). CONCLUSION: Ethnic-specific dosing algorithm is suggested for better prediction of acenocoumarol dosage requirements in patients of Greek origin. PMID- 27967331 TI - The processing of Chinese compound words with ambiguous morphemes in sentence context. AB - We employed a boundary paradigm to investigate how Chinese two-character compounds (i.e., compound words) are processed during reading. The first character of the compound was an ambiguous morpheme that had a dominant and subordinate meaning. In Experiment 1, there were three previews of the second character: identical to the target character; the preview provided subordinate biasing information (the subordinate condition); the preview provided dominant biasing information (the dominant condition). An invisible boundary was inserted between the two characters. We found that gaze durations and go-past times on the compounds were longer in the subordinate condition than those in the dominant or identical conditions. In Experiment 2, the semantic similarity between target and preview words in the dominant condition was manipulated to determine whether the differences in fixation durations in Experiment 1 resulted from the semantic similarity between the preview and target words. There were significant fixation duration differences on the target word between the dominant and subordinate conditions only when the preview and target words were semantically related. This finding indicated that the whole-word meaning plays an important role in processing Chinese compounds and that the whole-word access route is the principal processing route in reading two-character compounds in Chinese. PMID- 27967330 TI - Suppression of miR-628-3p and miR-641 is involved in rifampin-mediated CYP3A4 induction in HepaRG cells. AB - AIM: This study aimed to explore the role of miRNAs in rifampin-mediated induction of CYP3A4 in HepaRG cells. MATERIALS & METHODS: Microarray was performed to determine the expression of miRNAs in rifampin-treated HepaRG cells, followed by bioinformatics and luciferase reporter gene assay to analyze miRNAs that directly target CYP3A4. Overexpression of miRNA mimics was used to study their effects on CYP3A4 induction. RESULTS: Forty-seven miRNAs were suppressed and 18 miRNAs were increased by rifampin (above twofold). MiR-628-3p and miR-641 repressed the 3'-UTR luciferase activity of CYP3A4. Overexpression of miR-628-3p and miR-641 showed significant decrease of CYP3A4 mRNA level as well as CYP3A4 induction by rifampin. CONCLUSION: miR-628-3p and miR-641 could directly target CYP3A4 and are negatively regulated in CYP3A4 induction by rifampin. PMID- 27967332 TI - The Role of Health Care Provider and Partner Decisional Support in Patients' Cancer Treatment Decision-Making Satisfaction. AB - Cancer patients rely on multiple sources of support when making treatment decisions; however, most research studies examine the influence of health care provider support while the influence of family member support is understudied. The current study fills this gap by examining the influence of health care providers and partners on decision-making satisfaction. In a cross-sectional study via an online Qualtrics panel, we surveyed cancer patients who reported that they had a spouse or romantic partner when making cancer treatment decisions (n = 479). Decisional support was measured using 5-point, single-item scales for emotional support, informational support, informational-advice support, and appraisal support. Decision-making satisfaction was measured using Holmes-Rovner and colleagues' (1996) Satisfaction With Decision Scale. We conducted a mediated regression analysis to examine treatment decision-making satisfaction for all participants and a moderated mediation analysis to examine treatment satisfaction among those patients offered a clinical trial. Results indicated that partner support significantly and partially mediated the relationship between health care provider support and patients' decision-making satisfaction but that results did not vary by enrollment in a clinical trial. This study shows how and why decisional support from partners affects communication between health care providers and cancer patients. PMID- 27967334 TI - Identification of Sensitive Measures of Recovery After External Load From Football Match Play. AB - : Objective measures of recovery from football match play could be useful for assessing athletes' readiness to train, if sensitive to preceding match load. PURPOSE: To identify the sensitivity of countermovement-jump (CMJ) performance and concentration of salivary testosterone and cortisol relative to elite football match load. METHODS: CMJ performance and salivary hormones were measured in 18 elite football players before (27, 1 h) and after (0.5, 18, 42, 66, 90 h) 3 consecutive matches. Match load was determined via accelerometer-derived PlayerLoad and divided into tertiles. Sensitivity of CMJ performance and hormone concentrations to match load was quantified with t statistics and magnitude-based inferences (change in mean as % +/- 90% confidence interval) derived with a linear mixed model. RESULTS: Jump height was reduced in medium and high load at 0.5 h (10% +/- 7% and 16% +/- 8%) and 18 h (7% +/- 4% and 9% +/- 5%) postmatch. There was a 12% +/- 7% reduction in ratio of flight time to contraction time (FT:CT) in high load at 0.5 h post, with reductions in medium and high load at 18 h. Reductions in FT:CT persisted at later postmatch time points than changes in jump height. Increased cortisol (range 55-165%) and testosterone (range 17-20%) were observed in all match loads at 0.5 h post, with individual variability thereafter. CONCLUSIONS: Measures of CMJ performance and hormonal concentrations were sensitive to levels of A League football match load. Although jump height was reduced immediately postmatch, FT:CT provided a more sensitive measure of recovery. Football match play induces an acute hormonal response with substantial individual variability thereafter. PMID- 27967333 TI - More complications with uncemented than cemented femoral stems in total hip replacement for displaced femoral neck fractures in the elderly. AB - Background and purpose - Total hip replacement (THR) is the preferred method for the active and lucid elderly patient with a displaced femoral neck fracture (FNF). Controversy still exists regarding the use of cemented or uncemented stems in these patients. We compared the effectiveness and safety between a modern cemented, and a modern uncemented hydroxyapatite-coated femoral stem in patients 65-79 years of age who were treated with THR for displaced FNF. Patients and methods - In a single-center, single-blinded randomized controlled trial, we included 69 patients, mean age 75 (65-79) and with a displaced FNF (Garden III IV). 35 patients were randomized to a cemented THR and 34 to a reverse-hybrid THR with an uncemented stem. Primary endpoints were: prevalence of all hip-related complications and health-related quality of life, evaluated with EuroQol-5D (EQ 5D) index up to 2 years after surgery. Secondary outcomes included: overall mortality, general medical complications, and hip function. The patients were followed up at 3, 12, and 24 months. Results - According to the calculation of sample size, 140 patients would be required for the primary endpoints, but the study was stopped when only half of the sample size was included (n = 69). An interim analysis at that time showed that the total number of early hip-related complications was substantially higher in the uncemented group, 9 (among them, 3 dislocations and 4 periprosthetic fractures) as compared to 1 in the cemented group. The mortality and functional outcome scores were similar in the 2 groups. Interpretation - We do not recommend uncemented femoral stems for the treatment of elderly patients with displaced FNFs. PMID- 27967335 TI - Does constraining memory maintenance reduce visual search efficiency? AB - We examine whether constraining memory retrieval processes affects performance in a cued recall visual search task. In the visual search task, participants are first presented with a memory prompt followed by a search array. The memory prompt provides diagnostic information regarding a critical aspect of the target (its colour). We assume that upon the presentation of the memory prompt, participants retrieve and maintain hypotheses (i.e., potential target characteristics) in working memory in order to improve their search efficiency. By constraining retrieval through the manipulation of time pressure (Experiments 1A and 1B) or a concurrent working memory task (Experiments 2A, 2B, and 2C), we directly test the involvement of working memory in visual search. We find some evidence that visual search is less efficient under conditions in which participants were likely to be maintaining fewer hypotheses in working memory (Experiments 1A, 2A, and 2C), suggesting that the retrieval of representations from long-term memory into working memory can improve visual search. However, these results should be interpreted with caution, as the data from two experiments (Experiments 1B and 2B) did not lend support for this conclusion. PMID- 27967336 TI - What do we need to make genetic biomarker-guided treatment for renal cell carcinoma a reality? PMID- 27967540 TI - Foot Ulcer Management. AB - It has been suggested that 45% of lower limb amputations occur in patients with diabetes1. Yet, in areas where there are specialist diabetic foot clinics, amputation rates fall. This was initially demonstrated by Edmonds et al2 and is now becoming the experience of many such clinics around the UK. The successful management of foot ulcers is dependent upon a multidisciplinary team approach, which must include both nuclear and peripheral health-care professionals, utilising a wide range of experience, skills and resources. PMID- 27967337 TI - Peak Running Intensity of International Rugby: Implications for Training Prescription. AB - PURPOSE: To quantify the duration and position-specific peak running intensities of international rugby union for the prescription and monitoring of specific training methodologies. METHODS: Global positioning systems (GPS) were used to assess the activity profile of 67 elite-level rugby union players from 2 nations across 33 international matches. A moving-average approach was used to identify the peak relative distance (m/min), average acceleration/deceleration (AveAcc; m/s2), and average metabolic power (Pmet) for a range of durations (1-10 min). Differences between positions and durations were described using a magnitude based network. RESULTS: Peak running intensity increased as the length of the moving average decreased. There were likely small to moderate increases in relative distance and AveAcc for outside backs, halfbacks, and loose forwards compared with the tight 5 group across all moving-average durations (effect size [ES] = 0.27-1.00). Pmet demands were at least likely greater for outside backs and halfbacks than for the tight 5 (ES = 0.86-0.99). Halfbacks demonstrated the greatest relative distance and Pmet outputs but were similar to outside backs and loose forwards in AveAcc demands. CONCLUSIONS: The current study has presented a framework to describe the peak running intensities achieved during international rugby competition by position, which are considerably higher than previously reported whole-period averages. These data provide further knowledge of the peak activity profiles of international rugby competition, and this information can be used to assist coaches and practitioners in adequately preparing athletes for the most demanding periods of play. PMID- 27967338 TI - Soluble lectin-like oxidized low-density lipoprotein receptor-1 as a novel biomarker for large-artery atherosclerotic stroke. AB - BACKGROUND: Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) has been shown associated with the progression of atherosclerosis in endothelial cells. We sought to assess whether the baseline serum sLOX-1 levels are correlated with the presence and short-term functional outcome of large artery atherosclerotic (LAA) stroke. METHODS: The study recruited 241 subjects, including 148 consecutive patients with acute ischemic stroke with the subtype of LAA and 93 non-stroke controls. Clinical and laboratory data, including serum concentration of sLOX-1, were collected within 24 h of admission, and the severity of LAA stroke patients was evaluated by National Institutes of Health Stroke Scale score. And functional outcome was assessed by modified Rankin Scale three months after stroke. The association between sLOX-1 level and the functional outcome at three months was analyzed by multiple logistic regression models. RESULTS: Serum levels of sLOX-1 in the LAA stroke patients were significantly higher as compared to normal controls (2.48 +/- 0.93 ng/ml vs. 2.22 +/- 0.79 ng/ml in the controls, t = 2.301, p = 0.022). The levels of serum sLOX-1 in patients with good outcome were significantly lower than those with poor outcome (2.39 +/- 0.94 ng/ml vs. 2.77 +/- 0.84 ng/ml, p = 0.032). After adjusting for potential confounders, sLOX-1 was still an independent predictor for the function outcome with an adjusted OR of 3.39 (95% CI, 1.61-7.11, p = 0.001). CONCLUSIONS: The serum sLOX-1 level was higher in patients with LAA stroke, and it was an independent predictor of functional outcome in patients with LAA ischemic stroke. PMID- 27967541 TI - Pathology of the Diabetic Foot. AB - The diabetic foot can be divided into two entities - the neuropathic foot and the neuro-ischaemic foot. It is essential to differentiate between the two, because each has characteristic complications including different types of ulcer, which require distinct therapeutic strategies. PMID- 27967542 TI - Footwear and Orthoses in Diabetes. AB - Footwear can be a valuable therapeutic aid or it can be the cause of foot problems. In patients with diabetes, unsuitable footwear may contribute significantly to foot morbidity and to incapacity1, but patients can be advised on suitable footwear to help prevent ulceration which, all too often, can lead to the worst possible outcome - amputation. PMID- 27967543 TI - Multidisciplinary Care of the Diabetic Foot. AB - Patients with diabetes account for about 1-2% of the general population, and will undergo around half of all major leg amputations. Despite this fact, there are no traditional pathways for the referral and treatment of diabetic foot disease. Physicians may view it as a surgical problem, while surgeons may see it as a diabetic complication. All too often, patients are seen as undesirable cases who take up much-needed hospital beds. Until the 1980s, morbidity and mortality associated with diabetic foot problems were unacceptably high and no effective preventive or treatment strategies were known. Health-care professionals managing foot problems in patients with diabetes tended to work in isolation and diabetic foot disease was often neglected or treated inappropriately. PMID- 27967544 TI - Diabetes: the Nature of the Disease. AB - The cause of diabetes may be primary or secondary. Primary diabetes is divided into insulin-dependent diabetes mellitus (IDDM) or type I diabetes, and non insulin-dependent diabetes mellitus (NIDDM) or type II diabetes, with the two representing different diseases from an epidemiological viewpoint. Secondary diabetes is caused by liver, pancreatic and endocrine disease, in addition to genetic syndromes and drugs. PMID- 27967599 TI - 5th European Conference on Advances in Wound Management. AB - BEIERSDORF Stand 34/40 CENTROMED LTD Stand 44 COLOPLAST LTD Stand 11/12 CONVATEC LTD Stand 23 CROOKES HEALTHCARE Stand 30 EGERTON HOSPITAL EQUIPMENT LTD Stand 39 EUROMED Stand 25 GERALD SIMONDS Stand 43 HNE HUNTLEIGH Stand 2 HYOX SYSTEM LTD Stand 14 IATROS LTD Stand 26B INNOVATIVE TECHNOLOGIES LTD Stand 41 JOHNSON & JOHNSON MEDICAL Stand 15/16 KAROMED LTD Stand 45 KCI MEDISCUS Stand 36-38 KENDALL COMPANY LTD Stand 35 MEDICAL SUPPORT SYSTEMS Stand 3 MEDI UK LTD Stand 27 MOLNLYCKE Stand 32 NIKOMED Stand 24 PARK HOUSE Stand 19 PEGASUS AIRWAVE LTD Stand I PERSTORP PHARMA LTD Stand 8 PHARMA-PLAST LTD Stand 28 POLAROID Stand 31 PRESSURE GUARD Stand 33 QUINODERM LTD Stand 34A SETON Stand 22 SMITH & NEPHEW Stand 18 SPENCO MEDICAL LTD Stand 7 TALLEY GROUP LTD Stand 4-6 3M HEALTH CARE LTD Stand 20/21 VERNON-CARUS LTD Stand 42. PMID- 27967601 TI - Carryover of aflatoxins from feed to lambari fish (Astyanax altiparanae) tissues. AB - The aim of this study was to verify the carryover of aflatoxin B1 from feed to lambari fish. Aflatoxins (AF) were incorporated into feed, checking the levels by HPLC. Treatments were: Control, feed without toxin; A, feed + 10 ug AFB1 kg-1; B, feed + 20 ug AFB1 kg-1; and C, feed + 50 ug AFB1 kg-1. Juveniles of lambari fish were placed in 12 aquariums at a density of 50 fish/m2. Fish were fed twice a day with extruded feed, at 5% of animal biomass. The unit sample was constituted by a pool of 10 fish. AFs B1, B2, G1, G2 and M1 were quantified by HPLC in fish muscle and liver after 30, 60, 90 and 120 days of experiment. There was accumulation of AFs is fish liver and muscle, mainly after 90 days. Fish from treatment C had higher levels of AFB1 in muscle when compared with the others, and AFB1 in muscle at 120 days was similar to the levels in feed. Therefore, when lambari fish is exposed on a daily and long-term basis to AFs in feed, the regulation limits for AFs in animal feed do not guarantee safety for consumers. PMID- 27967600 TI - DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer. AB - Context: Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival. Objective: The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort. Design: Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Setting: MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers. Patients: The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors). Main Outcome Measures: DFS and OS. Results: In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P < 0.0001) and OS (P < 0.0001). Methylation, Ki67, and ENSAT stage were combined in multivariate models. For DFS, methylation (P = 0.0005) and stage (P < 0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P < 0.0001), and Ki67 (P = 0.024) were independent prognostic factors. Conclusions: Tumor DNA methylation emerges as an independent prognostic factor in ACC. MS-MLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine. PMID- 27967602 TI - The Break Up: Evaluation of an Anti-Smoking Educational Campaign for Lesbians, Gays, and Bisexuals in Los Angeles County. AB - Lesbian, gay, and bisexual (LGB) adults in the United States have a higher prevalence of smoking than their heterosexual counterparts. In 2013, the Los Angeles County Department of Public Health launched a social marketing and outreach campaign called Break Up to reduce the prevalence of smoking in LGB communities. Break Up was evaluated using cross-sectional, street-intercept surveys before and near the end of campaign. Surveys measured demographics, campaign awareness, and self-reported smoking-related outcomes. Bivariate statistics and logistic regression models were used to identify whether campaign awareness was associated with smoking-related outcomes. Calls by LGB persons to a smokers' helpline were also measured. Among those interviewed at endline, 32.7% reported Break Up awareness. Awareness was associated with thinking of quitting smoking and ever taking steps to quit but not with smoking cessation (defined as not smoking in the past 30 days among those who had smoked in the past 6 months). There was a 0.7% increase in the percentage of weekly calls by LGB persons to the helpline in the year after the campaign. Break Up reached about a third of its intended audience. The campaign was associated with smoking cessation precursors and may have led to an increase in helpline utilization, but there is no evidence it affected quit attempts. This study adds to the limited literature on tobacco programs for LGB persons and, as far as we know, is one of the first to evaluate tobacco-free social marketing in this important yet understudied population. PMID- 27967603 TI - Recovery of real dye bath wastewater using integrated membrane process: considering water recovery, membrane fouling and reuse potential of membranes. AB - It has been recognized by the whole world that textile industry which produce large amounts of wastewater with strong color and toxic organic compounds is a major problematical industry requiring effective treatment solutions. In this study, reverse osmosis (RO) membranes were tested on biologically treated real dye bath wastewater with and without pretreatment by nanofiltration (NF) membrane to recovery. Also membrane fouling and reuse potential of membranes were investigated by multiple filtrations. Obtained results showed that only NF is not suitable to produce enough quality to reuse the wastewater in a textile industry as process water while RO provide successfully enough permeate quality. The results recommend that integrated NF/RO membrane process is able to reduce membrane fouling and allow long-term operation for real dye bath wastewater. PMID- 27967604 TI - Effect of photocatalytic reduction of carbon dioxide by N-Zr co-doped nano TiO2. AB - Modified sol-gel method was adopted to prepare TiO2, Zr-TiO2 and N/Zr-TiO2 composite catalyst. The as-synthesized photocatalysts were characterized by X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy, Brunner- Emmet- Teller measurement and UV-Vis diffuse reflectance spectroscopy. And the photocatalytic performance toward CO2 reduction was evaluated under ultraviolet light. The catalyst particles were demonstrated in the nanometer level size. When N and Zr are co-doped, on the one hand, Ti4+ can be replaced by Zr4 +, which leads to lattice distortion and inhibits electron-hole recombination. On the other hand, N enters into TiO2 lattice gap to form O-Ti-N bond structure, and partial Ti4+ are reduced to Ti3+. Compared with pristine TiO2, the specific surface area and the band gap of N/Zr-TiO2 were improved and reduced, respectively. The N and Zr synergistically contribute to the obviously strengthened absorption intensity in visible region, as well as significantly improved photocatalytic activity. In the gas phase reactor, when the calcination temperature was 550 degrees C, 0.125N/0.25Zr-TiO2 composite performed the highest photocatalytic activity UV irradiation for 8 h, and the corresponding CH4 yield was 11.837 umol/g, which was 87.8% higher than that of pristine TiO2. For the visible light, the CH4 yield was 9.003 umol/g after 8 h irradiation, which was 83.9% higher than that of pristine TiO2. PMID- 27967717 TI - Behind the wheel: What drives the effects of error handling? AB - Existing research comparing error management (a strategy focusing on increasing the positive and decreasing the negative consequences of errors) to error prevention (a strategy focusing on working faultlessly), has identified error management as beneficial for multiple outcomes. Yet, due to various methodological limitations, it is unclear whether the effects previously found are due to error prevention, error management, or both. We examine this in an experimental study with a 2 (error prevention: yes vs. no) * 2 (error management: yes vs. no) factorial design. Error prevention had negative effects on cognition and adaptive transfer performance. Error management alleviated worry and boosted one's perceived self-efficacy. Overall, the results show that error prevention and error management have unique outcomes on negative affect, self-efficacy, cognition, and performance. PMID- 27967605 TI - Early Developmental Disruption of Type 2 Deiodinase Pathway in Mouse Skeletal Muscle Does Not Impair Muscle Function. AB - BACKGROUND: Myogenesis is positively regulated by thyroid hormone (triiodothyronine [T3]), which is amplified by the type 2 deiodinase (D2) activation of thyroxine to T3. Global inactivation of the Dio2 gene impairs skeletal muscle (SKM) differentiation and regeneration in response to muscle injury. Given that newborn and adult mice with late developmental SKM Dio2 disruption do not develop a significant phenotype, it was hypothesized that D2 plays an early role in this process. METHODS: This was tested in mice with SKM disruption of Dio2 driven by two early developmental promoters: MYF5 and MYOD. RESULTS: MYF5 myoblasts in culture differentiate normally into myotubes, despite loss of almost all D2 activity. Dio2 mRNA levels in developing SKM obtained from MYF5-D2KO embryos (E18.5) were about 54% of control littermates, but the expression of the T3-responsive genes Myh1 and 7 and Atp2a1 and 2 were not affected. In MYF5-D2KO and MYOD-D2KO neonatal hind-limb muscle, the expression of Myh1 and 7 and Atp2a2 remained unaffected, despite 60-70% loss in D2 activity and/or mRNA. Only in MYOD-D2KO neonatal muscle was there a 40% reduction in Atp2a1 mRNA. Postnatal growth of both mouse models and SKM function as assessed by exercise capacity and measurement of muscle strength were normal. Furthermore, an analysis of the adult soleus revealed no changes in the expression of T3 responsive genes, except for an about 18% increase in MYOD-D2KO SOL Myh7 mRNA. CONCLUSION: Two mouse models of early developmental disruption of Dio2 in myocyte precursor exhibit no significant SKM phenotype. PMID- 27967827 TI - Prejudice in the pub: How alcohol and ideology loosen the tongue. AB - This study (N = 124) tested the main and interactive effects of alcohol consumption, egalitarianism, and right-wing authoritarianism (RWA) in relation to prejudice suppression in the natural environment of a British Public House (pub). Employing a quasi-experimental between-subjects design, participants who had consumed alcohol were worse at suppressing their prejudice than participants with no alcohol consumption. Further, the more participants endorsed egalitarian values, the more they were able to suppress their prejudice. This tendency was resistant to the effects of alcohol. By contrast, the stronger participants held RWA beliefs, the less they were able to suppress their prejudice. In addition, this tendency was accentuated by alcohol consumption. Results are discussed in terms of theoretical and practical implications. PMID- 27967655 TI - Encapsulation of Adenovirus BMP2-Transduced Cells with PEGDA Hydrogels Allows Bone Formation in the Presence of Immune Response. AB - Gene therapy approaches have been difficult to implement due to pre-existing immunity against the virus used for delivery. To circumvent this problem, a cell based approach was developed that avoided the use of free virus within the animal. However, even cells transduced in vitro with E1- to E3-deleted adenovirus encoding bone morphogenetic protein 2 (AdBMP2) resulted in the production of virus-neutralizing antibodies in mice. Furthermore, when mice received an intramuscular injection of nonencoding adenovirus (AdEmpty)-transduced cells, AdBMP2-transduced cells were unable to launch bone formation when an intramuscular injection of these BMP2-producing cells was delivered 1 week later. This phenomenon was not observed in NOD/SCID mice, and could be overcome in C57BL/6 mice by encapsulating the adenovirus-transduced cells in a nondegradable hydrogel poly(ethylene glycol) diacrylate (PEGDA). Data collectively suggest that PEGDA hydrogel encapsulation of AdBMP2-transduced cells prevents pre-existing immunity from suppressing BMP2-induced bone formation. PMID- 27967828 TI - Homozygous familial hypercholesterolaemia: update on management. AB - Homozygous familial hypercholesterolaemia (HoFH) is an inherited disease causing an approximately fourfold increase in blood low-density lipoprotein cholesterol (LDLC) from birth compared with the age-matched normal population owing to reduced low-density lipoprotein receptor (LDLR) activity. Such elevated cholesterol is associated with accelerated atheromatous disease, particularly of the aortic root and coronary arteries. However, HoFH is clinically heterogeneous, reflecting residual low-density lipoprotein receptor (LDLR) activity. The main objective in treating children may be stated to be the avoidance of irreversible cardiac damage requiring heart transplantation by sufficient lowering of blood cholesterol. Lipoprotein apheresis or plasmapheresis are safe means of lowering cholesterol but may be insufficient on their own. Statin drugs, PCSK9 inhibitors ezetimibe and bile acid sequestrants are relatively ineffective if LDLR activity is lacking, but should be used if effective. Two new drugs, lomitapide and mipomersen, have been licensed specifically for HoFH by some regulatory authorities. They work by reducing LDL production rate. They have been associated with fatty liver in adults. Evidence of safety in children is lacking. An alternative is liver transplantation, which replaces the missing LDLR and normalises cholesterol. Clinicians are faced with a dilemma in choosing between these options or deferring such treatment associated with potential harm. Individual case descriptions are an important means of informing clinical judgement. Management of the two cases described in this issue is discussed in the light of modern developments in transplantation and pharmacotherapy. PMID- 27968705 TI - Efficient Nonviral Transfection of Primary Intervertebral Disc Cells by Electroporation for Tissue Engineering Application. AB - Low back pain (LBP) is an increasing global health problem associated with intervertebral disc (IVD) trauma and degeneration. Current treatment options include surgical interventions with partial unsatisfactory outcomes reported such as failure to relieve LBP, nonunions, nerve injuries, or adjacent segment disease. Cell-based therapy and tissue engineered IVD constructs supplemented with transfected disc cells that incorporate factors enhancing matrix synthesis represent an appealing approach to regenerate the IVD. Gene delivery approaches using transient nonviral gene therapy by electroporation are of a high clinical translational value since the incorporated DNA is lost after few cell generations, leaving the host's genome unmodified. Human primary cells isolated from clinically relevant samples were generally found very hard to transfect compared to cell lines. In this study, we present a range of parameters (voltage pulse, number, and duration) from the Neon(r) Transfection System for efficient transfection of human and bovine IVD cells. To demonstrate efficiency, these primary cells were exemplarily transfected with the commercially available plasmid pCMV6-AC-GFP tagged with copepod turbo green fluorescent protein. Flow cytometry was subsequently applied to quantify transfection efficiency. Our results showed that two pulses of 1400 V for 20 ms revealed good and reproducible results for both human and bovine IVD cells with efficiencies >=47%. The presented parameters allow for successful human and bovine IVD cell transfection and provide an opportunity for subsequent regenerative medicine application. PMID- 27968706 TI - Radiopacity of alloplastic bone grafts measured with cone beam computed tomography: An analysis in rabbit calvaria. AB - Availability of adequate bone structure for dental implants is still a problem in dentistry. Alloplastic grafts, which promote bone regeneration, are used as bone substitutes in orthopedic and oral surgical procedures. The aim of this study was to evaluate the radiopacity of three different synthetic bone grafts in rabbit calvaria, over 3 months, using cone beam computed tomography (CBCT). Four critical-size defects were made on the calvaria of 11 rabbits. The lesions were classified into three groups according to the alloplastic grafts they received: Osteon(r) 70/30, Osteon collagen(r), and Osteon II(r) groups. The fourth group received blood clot, and served as a control. The bone samples were collected and analyzed with CBCT after the 1st, 2nd, and 3rd month. One month after surgery, the lesions that received Osteon(r) 70/30 and Osteon collagen(r) grafts showed the highest radiopacity compared to the lesions with Osteon II(r) and blood clot. After the 2nd month, the radiopacity values between the three groups that received the grafts were more similar compared to the group with blood clot. After the 3rd month, the lesions with Osteon(r) 70/30 graft showed the highest radiopacity values, followed by Osteon collagen(r) and Osteon II(r) groups. The group that received blood clot showed the lowest radiopacity values. In conclusion, the grafts used in this study had higher radiopacity values compared to blood clot. Among the grafts used, the Osteon(r) 70/30 graft showed the highest radiopacity values in the 3-month period. PMID- 27968709 TI - Five suggestions for substantial NIH reforms. AB - The National Institutes of Health needs to make radical changes to ensure that biomedical research continues to thrive in the United States. PMID- 27968708 TI - DL-2-amino-3-phosphonopropionic acid protects primary neurons from oxygen-glucose deprivation induced injury. AB - Cerebral infarction is a type of ischemic stroke and is one of the main causes of irreversible brain damage. Although multiple neuroprotective agents have been investigated recently, the potential of DL-2-amino-3-phosphonopropionic acid (DL AP3) in treating oxygen-glucose deprivation (OGD)-induced neuronal injury, has not been clarified yet. This study was aimed to explore the role of DL-AP3 in primary neuronal cell cultures. Primary neurons were divided into four groups: (1) a control group that was not treated; (2) DL-AP3 group treated with 10 MUM of DL-AP3; (3) OGD group, in which neurons were cultured under OGD conditions; and (4) OGD + DL-AP3 group, in which OGD model was first established and then the cells were treated with 10 MUM of DL-AP3. Neuronal viability and apoptosis were measured using Cell Counting Kit-8 and flow cytometry. Expressions of phospho Akt1 (p-Akt1) and cytochrome c were detected using Western blot. The results showed that DL-AP3 did not affect neuronal viability and apoptosis in DL-AP3 group, nor it changed p-Akt1 and cytochrome c expression (p > 0.05). In OGD + DL AP3 group, DL-AP3 significantly attenuated the inhibitory effects of OGD on neuronal viability (p < 0.001), and reduced OGD induced apoptosis (p < 0.01). Additionally, the down-regulation of p-Akt1 and up-regulation of cytochrome c, induced by OGD, were recovered to some extent after DL-AP3 treatment (p < 0.05 or p < 0.001). Overall, DL-AP3 could protect primary neurons from OGD-induced injury by affecting the viability and apoptosis of neurons, and by regulating the expressions of p-Akt1 and cytochrome c. PMID- 27968707 TI - Enantiomer-specific ketorolac pharmacokinetics in young women, including pregnancy and postpartum period. AB - Racemic ketorolac clearance (CL) is significantly higher at delivery, but S ketorolac disposition determines the analgesic effects. The aim of this study was to investigate the effect of pregnancy and postpartum period on enantiomer specific (S and R) intravenous (IV) ketorolac pharmacokinetics (PKs). Data in women shortly following cesarean delivery (n=39) were pooled with data in a subgroup of these women that was reevaluated in the later postpartum period (postpartum group, n=8/39) and with eight healthy female volunteers. All women received single IV bolus of 30 mg ketorolac tromethamine. Five plasma samples were collected at 1, 2, 4, 6, and 8 hours and plasma concentrations were determined using high performance liquid chromatography. Enantiomer-specific PKs were calculated using PKSolver. Unpaired analysis showed that distribution volume at steady state (Vss, L/kg) for S- and R-ketorolac was significantly higher in women shortly following cesarean delivery (n=31) compared to postpartum group (n=8) or to healthy female volunteers (n=8). CL, CL to body weight, and CL to body surface area (CL/BSA) for S- and R-ketorolac were also significantly higher in women following delivery. In addition, S/R-ketorolac CL/BSA ratio was significantly higher at delivery. Paired PK analysis in eight women shortly following delivery and in postpartum group showed the same pattern. Finally, the simultaneous increase in CL and Vss resulted in similar estimates for elimination half-life in both unpaired and paired analysis. In conclusion, pregnancy affects S-, R-, and S/R-ketorolac disposition. This is of clinical relevance since S ketorolac (analgesia) CL is even more increased compared to R-ketorolac CL, and S/R-ketorolac CL ratio is higher following delivery compared to postpartum period or to healthy female volunteers. PMID- 27968710 TI - Analysis and deconvolution of dimethylnaphthalene isomers using gas chromatography vacuum ultraviolet spectroscopy and theoretical computations. AB - An issue with most gas chromatographic detectors is their inability to deconvolve coeluting isomers. Dimethylnaphthalenes are a class of compounds that can be particularly difficult to speciate by gas chromatography - mass spectrometry analysis, because of their significant coelution and similar mass spectra. As an alternative, a vacuum ultraviolet spectroscopic detector paired with gas chromatography was used to study the systematic deconvolution of mixtures of coeluting isomers of dimethylnaphthalenes. Various ratio combinations of 75:25; 50:50; 25:75; 20:80; 10:90; 5:95; and 1:99 were prepared to test the accuracy, precision, and sensitivity of the detector for distinguishing overlapping isomers that had distinct, but very similar absorption spectra. It was found that, under reasonable injection conditions, all of the pairwise overlapping isomers tested could be deconvoluted up to nearly two orders of magnitude (up to 99:1) in relative abundance. These experimental deconvolution values were in agreement with theoretical covariance calculations performed for two of the dimethylnaphthalene isomers. Covariance calculations estimated high picogram detection limits for a minor isomer coeluting with low to mid-nanogram quantity of a more abundant isomer. Further characterization of the analytes was performed using density functional theory computations to compare theory with experimental measurements. Additionally, gas chromatography - vacuum ultraviolet spectroscopy was shown to be able to speciate dimethylnaphthalenes in jet and diesel fuel samples. PMID- 27968711 TI - Evaluation of capillary electrophoresis-mass spectrometry for the analysis of the conformational heterogeneity of intact proteins using beta2-microglobulin as model compound. AB - In this work we explored the feasibility of different CE-ESI-MS set-ups for the analysis of conformational states of an intact protein. By using the same background electrolyte at quasi physiological conditions (50 mM ammonium bicarbonate, pH 7.4) a sequential optimization was carried out, initially by evaluating a sheath-liquid interface with both a single quadrupole (SQ) and a time-of-flight (TOF) mass spectrometer; then a sheathless interface coupled with high-resolution QTOF MS was considered. Beta2-microglobulin has been taken as a model, as it is an amyloidogenic protein and its conformational changes are strictly connected to the onset of a disease. The separation of two conformers at dynamic equilibrium is achieved all the way down to the MS detection. Notably, the equilibrium ratio of the protein conformers is maintained in the electrospray source after CE separation. Strengths and weaknesses of each optimized set-up are emphasized and their feasibility in unfolding studies is evaluated. In particular, ESI-TOF MS can assign protein forms that differ by 1 Da only and sheathless interfacing is best suited to preserve protein structure integrity. This demonstrates the CE-ESI-MS performance in terms of separation, detection and characterization of conformational species that co-populate a protein solution. PMID- 27968712 TI - High-resolution laser ablation-inductively coupled plasma-mass spectrometry imaging of cisplatin-induced nephrotoxic side effects. AB - Two-dimensional elemental mapping (bioimaging) via laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was performed on 5 MUm thick formalin-fixed, paraffin-embedded kidney tissue sections from Cynomolgus monkeys administered with increasing pharmacological doses of cisplatin. Laterally resolved pixels of 1 MUm were achieved, enabling elemental analysis on a (sub )cellular level. Zones of high Pt response were observed in the renal cortex, where proximal tubules are present, the epithelium of which is responsible for partial reabsorption of cisplatin. Histopathological evaluation, of hematoxylin and eosin-stained serial sections, adjacent to the sections probed via LA-ICP-MS, revealed minimal to mild cisplatin-related lesions (<100 MUm) in the renal cortex. Necrotic proximal tubules with sloughed epithelial cells in their lumen could be linked directly to the areas with the highest accumulation of cisplatin, indicating a direct link between cellular concentration and toxicity, thereby providing more insight into the mechanisms through which renal damage occurs. PMID- 27968713 TI - A new multiresponse optimization approach in combination with a D-Optimal experimental design for the determination of biogenic amines in fish by HPLC-FLD. AB - A new strategy to approach multiresponse optimization in conjunction to a D optimal design for simultaneously optimizing a large number of experimental factors is proposed. The procedure is applied to the determination of biogenic amines (histamine, putrescine, cadaverine, tyramine, tryptamine, 2 phenylethylamine, spermine and spermidine) in swordfish by HPLC-FLD after extraction with an acid and subsequent derivatization with dansyl chloride. Firstly, the extraction from a solid matrix and the derivatization of the extract are optimized. Ten experimental factors involved in both stages are studied, seven of them at two levels and the remaining at three levels; the use of a D optimal design leads to optimize the ten experimental variables, significantly reducing by a factor of 67 the experimental effort needed but guaranteeing the quality of the estimates. A model with 19 coefficients, which includes those corresponding to the main effects and two possible interactions, is fitted to the peak area of each amine. Then, the validated models are used to predict the response (peak area) of the 3456 experiments of the complete factorial design. The variability among peak areas ranges from 13.5 for 2-phenylethylamine to 122.5 for spermine, which shows, to a certain extent, the high and different effect of the pretreatment on the responses. Then the percentiles are calculated from the peak areas of each amine. As the experimental conditions are in conflict, the optimal solution for the multiresponse optimization is chosen from among those which have all the responses greater than a certain percentile for all the amines. The developed procedure reaches decision limits down to 2.5 MUg L-1 for cadaverine or 497 MUg L-1 for histamine in solvent and 0.07 mg kg-1 and 14.81 mg kg-1 in fish (probability of false positive equal to 0.05), respectively. PMID- 27968714 TI - Dissolving capability difference based sequential extraction: A versatile tool for in-depth membrane proteome analysis. AB - Profiling membrane proteins would facilitate revealing disease mechanism and discovering new drug targets as they play essential roles in cellular signaling, substrate transport, and cell adhesion. However, the analysis of membrane proteins still remains a challenge due to their high hydrophobicity, as well as the suppression effect of high abundant soluble proteins. In this work, to achieve a membrane proteome profiling, a sample preparation strategy based on sequential extraction at the protein level assisted by a range of extraction reagents with different dissolving capabilities, followed by nano-RPLC-ESI-MS/MS analysis was developed and applied for HeLa cell line analysis. It was found that with progressively harsher extraction reagents (i.e., 2 M NaCl, 4 M urea, 0.1 M Na2CO3, and 10% 1-dodecyl-3- methyl-imidazolium chloride (C12ImCl) performed, much more high hydrophobic proteins and low abundant proteins were identified. With our developed strategy, 5553 of the identified proteins (4419 gene products) were annotated to be membrane proteins and 2573 proteins (2183 gene products) have at least one transmembrane domain, to our best knowledge, which is the most comprehensive membrane proteome dataset for HeLa cell line. Notably, 110 of the identified membrane proteins were discovered in the "missing proteins" list referred to those in the neXtProt database. All above results indicated that our strategy has great potential to tackle the difficult but relevant task of identifying and profiling membrane proteins. PMID- 27968715 TI - Diffusion characteristics of agarose hydrogel used in diffusive gradients in thin films for measurements of cations and anions. AB - The agarose hydrogel has been increasingly used as a diffusive layer in diffusive gradients in thin films (DGT) measurements. However its diffusive characteristics have not been examined in detail. In this study, the performance of agarose gel was tested in DGT measurements of eight cations (Fe(II), Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Pb(II), and Cd(II)) and eight anions (P(V), As(V), Cr(VI), Mo(VI), Sb(V), Se(VI), V(V), and W(VI)). It was found that the thickness of agarose, a key parameter in the calculation of DGT measured concentration, remained unchanged after hydration followed by storage under the following conditions: pH 2-11, ionic strength 0-1.0 M, temperature 4-40 degrees C, and with the storage time extending to 300 d. Enrichment of cations and repelling of anions were observed in the gel under the ionic strengths of < 2-3 mM and <1 mM (NaNO3), respectively, which was attributed to the electrostatic interactions of these ions with the fixed negatively charged groups (mainly pyruvate) in the gel. The diffusion coefficients of cations and anions through the agarose gel (plus a PVDF filter membrane) were on average 1.10 +/- 0.04 times of the reported diffusion coefficients through the agarose cross-linked polyacrylamide (APA) hydrogel, typically used in DGT technique. The working pH ranges for the agarose gel-assembled DGTs were 4-10 and 5-9 for anions and cations, respectively. The use of agarose gel, either individually or along with different filter membranes, affected the overall diffusion rates of cations and anions. The measured DGT concentrations of cations and anions in filtered natural freshwater and seawater were mostly in line with those measured directly. The results showed that the agarose gel can be used as one of the standard diffusive layers in DGT measurements for a wide range of inorganic and organic analytes. PMID- 27968716 TI - Investigation of the "true" extraction recovery of analytes from multiple types of tissues and its impact on tissue bioanalysis using two model compounds. AB - LC-MS/MS has been widely applied to the quantitative analysis of tissue samples. However, one key remaining issue is that the extraction recovery of analyte from spiked tissue calibration standard and quality control samples (QCs) may not accurately represent the "true" recovery of analyte from incurred tissue samples. This may affect the accuracy of LC-MS/MS tissue bioanalysis. Here, we investigated whether the recovery determined using tissue QCs by LC-MS/MS can accurately represent the "true" recovery from incurred tissue samples using two model compounds: BMS-986104, a S1P1 receptor modulator drug candidate, and its phosphate metabolite, BMS-986104-P. We first developed a novel acid and surfactant assisted protein precipitation method for the extraction of BMS-986104 and BMS-986104-P from rat tissues, and determined their recoveries using tissue QCs by LC-MS/MS. We then used radioactive incurred samples from rats dosed with 3H-labeled BMS-986104 to determine the absolute total radioactivity recovery in six different tissues. The recoveries determined using tissue QCs and incurred samples matched with each other very well. The results demonstrated that, in this assay, tissue QCs accurately represented the incurred tissue samples to determine the "true" recovery, and LC-MS/MS assay was accurate for tissue bioanalysis. Another aspect we investigated is how the tissue QCs should be prepared to better represent the incurred tissue samples. We compared two different QC preparation methods (analyte spiked in tissue homogenates or in intact tissues) and demonstrated that the two methods had no significant difference when a good sample preparation was in place. The developed assay showed excellent accuracy and precision, and was successfully applied to the quantitative determination of BMS-986104 and BMS-986104-P in tissues in a rat toxicology study. PMID- 27968717 TI - Glycated hemoglobin biosensing integration formed on Au nanoparticle-dotted tubular TiO2 nanoarray. AB - Excessive glucose present in the blood of diabetic patients binds with the hemoglobin of red blood cells resulting in the formation of glycated hemoglobin (HbA1c). Measurement of HbA1c levels may help in identifying the efficacy of the ongoing treatment and hence provide a better control over the disease. In the present study, we have synthesized a sensitive and stable scaffold, which consists of Au nanoparticles (GNPs)-dotted tubular TiO2, for the construction of an electrochemical HbA1c biosensor. 12-phosphotungstic acid has been used as a reducer after depositing well-dispersed GNPs on TiO2 nanotubes (TiO2 NTs) and an electron mediator by accelerating the electron transfer between the conductor and protein. The fabricated electrode was characterized using scanning electron microscopy (SEM), cyclic voltammetry (CV), Fourier transform infrared spectroscopy (FTIR) and electrochemical impedance spectroscopic analysis (EIS). Biosensor exhibited low detection limit (0.5 MUM), fast response time (3 s) and wide linearity (from 0.5 to 2000 MUM). The working electrode was used 100 times over 4 months, when stored at 4 degrees C. The HbA1c biosensor was then effectively used to measure the % of HbA1c in the blood of apparently healthy persons and diabetic patients. PMID- 27968718 TI - Linear Schiff-base fluorescence probe with aggregation-induced emission characteristics for Al3+ detection and its application in live cell imaging. AB - A simple Schiff-base derivative with salicylaldehyde moieties as fluorescent probe 1 was reported by aggregation-induced emission (AIE) characterization for the detection of metal ions. Spectral analysis revealed that probe 1 was highly selective and sensitive to Al3+. The probe 1 was also subject to minimal interference from other common competitive metal ions. The detection limit of Al3+ was 0.4 MUM, which is considerably lower than the World Health Organization standard (7.41 MUM), and the acceptable level of Al3+ (1.85 MUM) in drinking water. The Job's plot and the results of 1H-NMR and FT-IR analyses indicated that the binding stoichiometry ratio of probe 1 to Al3+ was 1:2. Probe 1 demonstrated a fluorescence-enhanced response upon binding with Al3+ based on AIE characterization. This response was due to the restricted molecular rotation and increased rigidity of the molecular assembly. Probe 1 exhibited good biocompatibility, and Al3+ was detected in live cells. Therefore, probe 1 is a promising fluorescence probe for Al3+ detection in the environment. PMID- 27968719 TI - Multiple signal amplified electrochemiluminescent immunoassay for brombuterol detection using gold nanoparticles and polyamidoamine dendrimers-silver nanoribbon. AB - Electrochemiluminescent (ECL) immunosensor with multiple signal amplification was designed based on gold nanoparticles (AuNPs), polyamidoamine dendrimers (PAMAM) and silver-cysteine hybrid nanoribbon (SNR). Low toxic l-cysteine capped CdSe QDs was chosen as the ECL signal probe. To verify the proposed ultrasensitive ECL immunosensor for beta-adrenergic agonists (beta-AA), we detected Brombuterol (Brom) as a proof-of-principle analyte. Therein, AuNPs as the substrate can simplify the experiment process, accelerate the electron transfer rate, and carry more coating antigen (Ag-OVA) to enlarge ECL signal. On one hand, SNR on the surface of electrode can avoid the aggregation of AuNPs, and SNR-PAMAM-AuNPs also can be acted as a good accelerator for electron transfer. On the other hand, PAMAM (16 -NH2) functionalized SNR (SNR-PAMAM) with numerous amino groups could be employed to bond abundant actived QDs to further amplify ECL signal. The new immunosensor can offer a simple, reliable, rapid, and selective detection for Brom, which have a dynamic range of 0.005-700 ng mL-1 with a low detection limit at 1.5 pg mL-1. The proposed biosensor will extend the application of nanomaterials in ECL immunoassays and open a new road for the detection of Brom and other beta-AA in the future. PMID- 27968720 TI - Fluorescence detection of pesticides using quantum dot materials - A review. AB - High pesticide use, especially in agriculture, can lead to environmental pollution and potentially adverse health effects. As result, pesticide residues end up in different media, including water and food products, which may serve as direct routes for human exposure. There is thus a continuous drive to develop analytical methods for screening and quantification of these compounds in the different environmental media in which they may occur. Development of quantum dot (QD) based sensors for monitoring pesticides has gained momentum in recent years. QD materials have excellent and unique optical properties and have high fluorescence quantum yields compared to other fluorophores. They have thus been used in numerous studies for the development of probes for organic pollutants. In this paper we specifically review their application as fluorescence probes for pesticide detection in different media including water and in fruits and vegetables. The low detection limits reported demonstrate the potential use of these methods as alternatives to expensive and time-consuming conventional techniques. We also highlight potential limitations that these probes may present when it comes to routine application. Finally we discuss possible future improvements to enhance the selectivity and robustness of these sensors. We note that there is still a need for researchers to develop standardized QD based sensors which could lead to their commercialization and routine application. PMID- 27968722 TI - A brief summary of the articles appearing in this issue of Biological Psychiatry. PMID- 27968721 TI - Analytical method for biomonitoring of endocrine-disrupting compounds (bisphenol A, parabens, perfluoroalkyl compounds and a brominated flame retardant) in human hair by liquid chromatography-tandem mass spectrometry. AB - In this paper, a method for the determination of four groups of endocrine disrupting compounds in human hair is proposed. Target compounds were a plastic monomer (bisphenol A), three parabens commonly used as preservatives (methylparaben, ethylparaben and propylparaben), six perfluoroalkyl compounds commonly used as water, oil and dirt repellents (perfluorooctane sulfonic acid and five perfluoroalkyl carboxylic acids, with alkyl chains from four to eight carbon atoms) and a brominated flame retardant (hexabromocyclododecane). All of them are of especial concern to human health because they are utilized in many everyday products. The method is based on hair incubation with methanol/acetic acid solution (85:15, v/v), extraction with acetone for 15 min in an ultrasonic bath and analysis by liquid chromatography-electrospray-tandem mass spectrometry in negative ionization mode. Limits of quantification in hair samples ranged from 0.6 ng g-1 to 6.1 ng g-1, except for hexabromocyclododecane (36 ng g-1). Recoveries were higher than 69%. Intra-day and inter-day precision, expressed as relative standard deviation, were lower than 15% and 10%, respectively. The applicability of the method was proven by analyzing the target compounds in hair samples from six volunteers. High frequencies of detection and concentrations were obtained for bisphenol A (83% of samples; concentrations up to 158 ng g-1) and parabens (100% of samples; concentrations up to 624 ng g-1). Lower concentrations were detected for the perfluoroalkyl compounds (up to 13 ng g-1). Hexabromocyclododecane was not detected. PMID- 27968723 TI - To Stay Happy, Keep Your SIRT1 Active. PMID- 27968724 TI - Sleep and Mood: Chicken or Egg? PMID- 27968725 TI - Depression and Adenylyl Cyclase: Sorting Out the Signals. PMID- 27968726 TI - Erratum to: "Online Effects of Transcranial Direct Current Stimulation in Real Time on Human Prefrontal and Striatal Metabolites" by Hone-Blanchet et al. (Biol Psychiatry 2016; 80:432-438). PMID- 27968727 TI - Effects of Maternal Prenatal Stress: Mechanisms, Implications, and Novel Therapeutic Interventions. PMID- 27968728 TI - Evidence Mounting for Gene-by-Environment Interactions at the FKBP5 Locus Predicting Psychiatric Symptoms. PMID- 27968729 TI - Fungal Light Sensing at the Bench and Beyond. AB - Visible light is a pervasive environmental signal that orients most organisms in space and time. For a fungus, the detection of light is facilitated by diverse classes of photoreceptor proteins, which in turn coordinate growth, spore dispersal, stress resistance, primary metabolism, and toxin production. We will first provide a discussion on signal input, focusing on recent insights into how fungal photoreceptors detect and transmit information at the biochemical and molecular levels. We will then pivot our discussion to how light influences fungal behaviors that are of industrial, agricultural, or even medical relevance. Because the light environment can be easily manipulated in many contexts, we will argue that understanding fungal photobiology is both an important basic and applied endeavor. PMID- 27968730 TI - The Functionality and Evolution of Eukaryotic Transcriptional Enhancers. AB - Enhancers regulate precise spatial and temporal patterns of gene expression in eukaryotes and, moreover, evolutionary changes in these modular cis-regulatory elements may represent the predominant genetic basis for phenotypic evolution. Here, we review approaches to identify and functionally analyze enhancers and their transcription factor binding sites, including assay for transposable accessible chromatin-sequencing (ATAC-Seq) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, respectively. We also explore enhancer functionality, including how transcription factor binding sites combine to regulate transcription, as well as research on shadow and super enhancers, and how enhancers can act over great distances and even in trans. Finally, we discuss recent theoretical and empirical data on how transcription factor binding sites and enhancers evolve. This includes how the function of enhancers is maintained despite the turnover of transcription factor binding sites as well as reviewing studies where mutations in enhancers have been shown to underlie morphological change. PMID- 27968732 TI - Genetics of Schizophrenia: Historical Insights and Prevailing Evidence. AB - Schizophrenia's (SZ's) heritability and familial transmission have been known for several decades; however, despite the clear evidence for a genetic component, it has been very difficult to pinpoint specific causative genes. Even so genetic studies have taught us a lot, even in the pregenomic era, about the molecular underpinnings and disease-relevant pathways. Recurring themes emerged revealing the involvement of neurodevelopmental processes, glutamate regulation, and immune system differential activation in SZ etiology. The recent emergence of epigenetic studies aimed at shedding light on the biological mechanisms underlying SZ has provided another layer of information in the investigation of gene and environment interactions. However, this epigenetic insight also brings forth another layer of complexity to the (epi)genomic landscape such as interactions between genetic variants, epigenetic marks-including cross-talk between DNA methylation and histone modification processes-, gene expression regulation, and environmental influences. In this review, we seek to synthesize perspectives, including limitations and obstacles yet to overcome, from genetic and epigenetic literature on SZ through a qualitative review of risk factors and prevailing hypotheses. Encouraged by the findings of both genetic and epigenetic studies to date, as well as the continued development of new technologies to collect and interpret large-scale studies, we are left with a positive outlook for the future of elucidating the molecular genetic mechanisms underlying SZ and other complex neuropsychiatric disorders. PMID- 27968733 TI - A missed opportunity for urban health. PMID- 27968731 TI - Advances in Dyslexia Genetics-New Insights Into the Role of Brain Asymmetries. AB - Dyslexia is a common condition affecting up to 10% school-aged children. There is strong evidence that genetics plays an important role in dyslexia and is expected to be complex in nature. Few specific susceptibility factors have been identified so far, but their functional characterization has provided novel insights into the biology of dyslexia. In particular, they point to an unexpected role of candidate genes for dyslexia in the biology of cilia, cellular organelles required in many processes including the establishment of left-right asymmetries early in development. This observation has brought back into the spotlight the old idea of a link between dyslexia and handedness. Yet much of the genetics contributing to dyslexia remains unexplained. The lack of biological markers, clear diagnostic criteria, and homogeneous assessment strategies are just some of the factors preventing the collection of the cohorts powered enough for large scale genetic studies. While the technology and methods to generate and handle large-scale data have reached unprecedented potential, the main challenge remains in establishing universal guidelines to collect suitable phenotype information across independent studies. These difficulties reflect the complex nature of dyslexia which is highly heterogeneous and often co-occurs with other neurodevelopmental disorders. PMID- 27968734 TI - Trauma: a neglected US public health emergency. PMID- 27968735 TI - Ageing in China: a ticking bomb. PMID- 27968736 TI - Research in planetary health: a call for abstracts. PMID- 27968737 TI - Offline: Migration and health-from aspiration to desperation. PMID- 27968738 TI - Wendy Graham and Oona Campbell: maternal health mavericks. PMID- 27968739 TI - Stillborn, still loved. PMID- 27968740 TI - Silver eye bath. PMID- 27968741 TI - Gerald Roy Patterson. PMID- 27968742 TI - Dear food industry: please don't pass the salt. PMID- 27968743 TI - A false aura of scientific controversy around salt? PMID- 27968744 TI - Beyond salt-where next for hypertension epidemiology? PMID- 27968745 TI - Dietary sodium: paradigm shifts from public health to clinical medicine. PMID- 27968746 TI - Sodium and cardiovascular disease. PMID- 27968747 TI - Sodium and cardiovascular disease. PMID- 27968748 TI - Sodium and cardiovascular disease. PMID- 27968749 TI - Sodium and cardiovascular disease. PMID- 27968750 TI - Sodium and cardiovascular disease - Authors' reply. PMID- 27968751 TI - Confronting inequality in newborn survival in South Sudan. PMID- 27968752 TI - Fluid Therapy: Introduction. PMID- 27968753 TI - Crystalloids: A Quick Reference for Challenges in Daily Practice. AB - There are numerous types, routes, and strategies of intravenous crystalloid therapy in veterinary medicine. Understanding basics of physiology and underlying disease pathologies can play an essential role in determining fluid therapy choices. This article provides an overview of fluid compartment physiology, a review of crystalloid types, and indications and interactions associated with intravenous crystalloid use. PMID- 27968754 TI - Natural and Synthetic Colloids in Veterinary Medicine. AB - This review article covers basic physiology underlying the clinical use of natural and artificial colloids as well as provide practice recommendations. It also touches on the recent scrutiny of these products in human medicine and how this may have an effect on their use in veterinary medicine. PMID- 27968755 TI - Alternative Access Routes for Fluid Resuscitation. AB - Fluid resuscitation in small animals is important in emergency situations and is utilized by every veterinary practice. Peripherally inserted intravenous catheters are an effective way of giving fluids to a veterinary patient. If an intravenous catheter is not obtainable, there are multiple other ways to administer fluids to a patient including dorsal pedal catheters, intraosseous catheters, central venous catheters, peripherally inserted central catheters, nasogastric tubes, nasoesophageal tubes and subcutaneous administration of fluids. This article will discuss the advantages and disadvantages of each way of administration. PMID- 27968756 TI - Palatability and Clinical Effects of an Oral Recuperation Fluid During the Recovery of Dogs With Suspected Parvoviral Enteritis. AB - Dogs infected with canine parvovirus (CPV) can develop severe enteritis that requires supportive care until voluntary food and water consumption return. An oral recuperation fluid (ORF) may assist in the overall recovery from CPV. The hypotheses of the study were that dogs with naturally infected CPV would prefer the ORF to water and that dogs consuming the ORF would have a more rapid return to voluntary appetite and improved caloric intake during the initial recovery period compared with dogs consuming water. A total of 28 dogs with CPV were enrolled. Dogs were excluded if voluntary food or water intake was present at the time of study enrollment. Dogs were randomized to either an ORF or water group. The designated fluid was offered twice daily, followed by offering the opposite fluid 1 hour later if the designated fluid was refused. Dogs also received a standardized supportive treatment protocol. Beginning on day 2, all dogs were offered a gastrointestinal diet q8h, staggered with the fluid intake trials. A total of 40% (6/15) of dogs with CPV consumed the ORF as their designated fluid, and 31% (4/13) of dogs with CPV consumed water as their designated fluid (P = .71). For those dogs who refused their designated fluid, 56% (5/9) of the dogs consuming ORF ultimately consumed water, and 22% (2/9) of the dogs consuming water also consumed the ORF (P = .33). Dogs who consumed the ORF demonstrated a more rapid return to voluntary appetite (median = 1.5 days [range: 1-3]) compared with those that consumed water (median = 4.25 days [range: 1.5-5.5], P = .01) or neither fluid (median = 2 days [range: 1.5-5.5], P = .03). Additionally, those dogs consuming the ORF demonstrated greater caloric intake [median = 100% resting energy requirement (RER), range: 61%-100%] compared with those that consumed water (median = 19% RER; range: 9%-100%; P = .004) or neither fluid (median = 37% RER; range: 3-100; P = .05). This study suggests that some dogs with CPV voluntarily consume an ORF during the recovery phase of their illness and that consumption of the ORF may foster a more rapid return of voluntary appetite as well as improved caloric intake. Additional studies are warranted to further assess additional effects of this ORF during recovery from CPV. PMID- 27968758 TI - Chronic Diarrhea in Dogs: What Do We Actually Know About It? AB - There is a paucity of research based knowledge about chronic diarrhoea in dogs. In the literature no studies can be found that confirms that round worm, whip worm, hook worm or giardia cause chronic diarrhoea in dogs. For this reason, it is questionable to study endoparasites when clarifying the reason for chronic diarrhoea in dogs. No study confirms that clostridium-, campylobacter- or salmonella species cause chronic diarrhoea signs in dogs. There is no research based information to-date that endoscopy would be helpful in the diagnosis of dogs with chronic diarrhoea or to monitor how the disease progresses. Neither no reliable laboratory test can be recommended to be used in evaluating the seriousness of the disease or to monitor the progress of the disease. There is no evidence based information on what food should be recommended for dogs suffering from diarrhoea. Only a few studies have been published that show how effective antibiotics are in the treatment of diarrhoeal dogs. Many more studies are needed before it is possible to determine how effective corticosteroids are in the treatment of diarrhoea in dogs. PMID- 27968757 TI - A Pilot Study Exploring the Plasma Potassium Variation in Dogs Undergoing Steroid Therapy and Its Clinical Importance. AB - In most situations in veterinary medicine, glucocorticoids are the drugs of choice used, that is, to reduce the inflammatory response or limit an inappropriate immune response. Their use in long-term therapy may cause side effects that may weaken the patient. The aim of the study was to evaluate possible variations in the plasma potassium concentrations and their clinical relevance in dogs undergoing steroid therapy with methylprednisolone in anti inflammatory doses. The study used a sample of 21 dogs (n = 21) presented for consultation, with a clinical condition requiring a corticosteroid therapeutic protocol with an anti-inflammatory dose of methylprednisolone. All the individuals were submitted to a corticosteroid therapeutic protocol administered orally during 18 days. During this period, 3 time points were considered: T0 (the day the prescription was first given), T1 (3 days later), and T2 (8 days later). Blood samples were collected from a peripheral vein to measure plasma potassium concentrations in T0, T1, and T2. Corticosteroid therapy on an outpatient basis statistically significantly decreased plasma potassium levels, especially between T1 and T2 (P = .03). The plasma potassium levels decreased in 12.5% of the males, compared with a decrease of 23.1% in the females. No statistically significant relationships were observe between the decreased plasma potassium levels and age, clinical condition, and patient's body weight. However, we found a statistically significant association between decreased plasma potassium levels and sex. The study results may justify the need for the systematic prescription of potassium supplements in patients undergoing steroid therapy, similar to what already occurs in human medicine. PMID- 27968759 TI - ? PMID- 27968761 TI - [Operator exposure in interventional cardiology (right vs. left radial access)]. PMID- 27968760 TI - Door in - door out assessment of patients admitted with acute ST-segment elevation myocardial infarction in hospitals without catheterization facilities. AB - BACKGROUND: Many patients with acute ST-segment elevation myocardial infarction (STEMI) are admitted to emergency departments (EDs) of centres without percutaneous coronary intervention (PCI) facilities. The 2012 European Society of Cardiology guidelines recommend transfer to a PCI centre with a "door in - door out" (DI-DO) time<=30min. PURPOSE: To report DI-DO times in a registry of patients with acute STEMI. METHODS: The RESeau des Urgences CORonarienne (RESUCOR) is a permanent registry of patients admitted with acute STEMI in 16 hospitals in the north French Alps since 2002. In patients admitted to a non-PCI centre, the DI-DO times were split into "diagnostic time" (from admission to transfer decision) and "logistical time" (from transfer decision to discharge). RESULTS: Of 2081 patients included in the registry from 2012 to 2014, 493 were admitted directly into an ED (254 PCI centre and 239 non-PCI centre). Of those admitted into an ED of a non-PCI centre, 228 were immediately transferred to a PCI centre (76 treated with thrombolysis and 132 with primary PCI). The proportions of patients with DI-DO<=30min and median (interquartile range [IQR]) DI-DO times are reported in the Table 1. Median (IQR) DIDO times were 90.5 (69 118) min for patients treated with thrombolysis and 88 (62-147) min for primary PCI. CONCLUSIONS: DI-DO times were longer than recommended. Efforts to decrease these delays are required. Transfer with a non-PCI centre ambulance is preferable. PMID- 27968762 TI - ? PMID- 27968763 TI - ? PMID- 27968764 TI - ? PMID- 27968765 TI - ? PMID- 27968766 TI - Indications for fibrinolysis in patients with ST-segment elevation myocardial infarction: From guidelines to practice. AB - BACKGROUND: European guidelines on managing ST segment elevation myocardial infarction (STEMI) during the first 12hours recommend fibrinolysis when the time elapsing between the first medical contact and balloon time (FMCBT) is more than 120minutes. AIM: To assess the real-life clinical efficacy of guidelines on fibrinolysis in managing STEMI and identify obstacles to their everyday implementation. METHODS: An observational study based on a permanent registry of reperfusion strategies and timing among patients treated in a French general hospital for STEMI with chest pain lasting for less than two hours. Patients were enrolled between January 1st 2008 and December 31st 2014. RESULTS: The study included 669 patients: 79 (11.8%) benefited from effective fibrinolysis followed by coronary arteriography (PCI) within 24hours, 445 (66.5%) underwent a primary PCI, 99 (14.8%) received a rescue PCI and 46 (6.9%) did not undergo revascularization. The FMCBT was 120minutes or longer in 209 patients: fibrinolysis was performed in 68 of these patients (32.5%), and primary PCI in 141 (114 (54.6%) without contraindications to fibrinolysis and 27 (12.9%) with contraindications). The patient's age, female gender, co-morbidities and clinical management were factors that appeared to be linked to poor compliance with the guidelines, but none were significant (P>00.5). Nor were there significant differences regarding bleeding complications between patients receiving fibrinolysis or primary PCI (P>0.05). CONCLUSION: The guidelines on fibrinolysis were not followed in 54.6% of patients when the FMCBT was more than 120minutes. Some criteria (age, gender, co-morbidities) may have been responsible for this non-compliance, although underestimating the time between first medical contact and arrival in the catheterisation laboratory could not be excluded. Further studies are necessary to improve estimates of this delay. PMID- 27968767 TI - Safety of device implantation under antipatelet therapy with ticagrelor: About 20 cases. AB - INTRODUCTION: Management of antiplatelet therapy at the time of device implantation remains controversial. This study aimed to assess the risk of bleeding complications in patients receiving ticagrelor at the time of cardiac device surgery. METHODS: We performed a multicentre (N=4), retrospective study from January 2015 to January 2016. The survey included all patients (pts) treated with ticagrelor before undergoing pacemaker, implantable-cardioverter defibrillator (ICD) implantation or generator replacement. We report haemorrhagic post-procedural complications at 1 month. A significant bleeding complication was defined as pocket hematoma requiring a surgical evacuation or prolonged hospitalization, hemothorax, pericardial effusion or tamponade. RESULTS: A total of 20 patients underwent a permanent pacemaker or ICD implantation while taking a combination of antipatelet therapy with ticagrelor and aspirin. The mean age of the patients was 65+/-9 years, 95% were male, 25% of patients were diabetics, 55% had hypertension and 50% presented a history of heart failure. All the patients had a history of acute coronary syndrome (6 [4-26] months before the procedure). The majority of implanted devices were ICDs (17, 85%) with 5 single chamber, 4 dual chambers and 9 triple chambers ICDs. Subclavian venous approach was utilized in 9 patients. The mean duration of procedure was 60minutes. One per-procedure bleeding was described due to high venous pressure, without post-procedure hematoma. A post-procedure pocket hematoma has been experienced by one patient. The subclavian approach was used for the 2 patients. No blood transfusion was needed for these 2 cases. CONCLUSION: Ticagrelor treatment at the time of heart rhythm device procedures does not seem to be associated with an increased risk of significant bleeding complications. In our study, 2 patients experienced non significant bleeding complications. PMID- 27968768 TI - ? PMID- 27968769 TI - ? PMID- 27968770 TI - ? PMID- 27968771 TI - Treatment of acute cardiac failure in the emergency department. Improve our practices? Data from the RESURCOR network. AB - BACKGROUND: In 2015, the European Society of cardiology published guidelines on the pre-hospital and early hospital management of acute cardiac failure (ACF), which included: - use of intravenous vasodilators (nitrates) when systolic blood pressure is>110mmHg; - non-invasive ventilation if oxygen saturation is<90% and/or respiratory rate is>25/min despite nasal oxygen; - using a reduced dose of intravenous furosemide (20-40mg or equivalent of the oral morning dose if already on chronic diuretic therapy) and; - early performance of echocardiography. We sought to compare the gap between these recommendations and clinical practices in French emergency departments (EDs). METHODS: We undertook a retrospective evaluation of clinical practices in 834 consecutive patients with ACF admitted in 2013 to the EDs of 16 French hospitals. Data, including patient characteristics and practices were collected from the medical records. RESULTS: Patients' mean+/ standard deviation age was 82+/-10 years and 49% were men. Clinical practices in relation to the guideline recommendations are shown in the Table 1. CONCLUSIONS: These initial data which precede publication of the current guidelines, show that use of nitrates, non-invasive ventilation, reduced diuretic dose and early echocardiography were relatively infrequent at the first point of medical care for patients presenting with ACF. These findings indicate the need for a sizable shift in practice in order to meet the new guideline recommendations. We will conduct a repeat evaluation in 2016, after implementation of a programme aimed to improve practices at these sites. PMID- 27968772 TI - ? PMID- 27968773 TI - Assessment of global longitudinal strain at low-dose anthracycline-based chemotherapy for the prediction of subsequent cardiotoxicity. AB - OBJECTIVES: The aim of this study was to assess whether global longitudinal strain (GLS) measured early during treatment with anthracycline (at a cumulative dose of 150mg/m2) can predict subsequent alterations in left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Eighty-six patients suffering from Hodgkin's disease, non-Hodgkin's lymphoma or acute leukemia and receiving anthracyclines were prospectively included. They underwent complete echocardiography on four separate occasions: baseline (V1); after reaching a cumulative dose of 150mg/m2 (V2); end of treatment (V3); one year follow-up (V4). Six patients developed cardiotoxicity defined by a decrease in LVEF by more than 10 percentage points to a value of at least less than 53% at V4. Both GLS measured at V1 and at V2 were significantly lower in the cardiotoxicity group compared with the control group (P=0.042 and P=0.01, respectively). Compared to GLS at V1, GLS obtained at V2 provided implemental predictive information and appeared to be the strongest predictor of cardiotoxicity (area under the receiver operating characteristic curve, 0.823). At a threshold of -17.45% for GLS measured at V2, the sensitivity and specificity of detecting cardiotoxicity were 67% (95%CI: [33-100%]) and 97% (95%CI: [94-100%]) respectively. CONCLUSION: GLS> 17.45%, obtained after 150mg/m2 of anthracycline therapy, is a significant predictor of future anthracycline-induced cardiotoxicity. This study should encourage physicians to perform echocardiography earlier during treatment with anthracyclines. PMID- 27968774 TI - Assessment of left anterior descending artery stenosis of intermediate severity by fractional flow reserve, instantaneous wave-free ratio and non-invasive coronary flow reserve. AB - : Assessment of the functional significance of left anterior descending coronary artery (LAD) stenosis of intermediate severity is challenging and often based on fractional flow reserve (FFR). The instantaneous wave-free ratio (IFR), a new vasodilator-free index of coronary stenosis severity, and non-invasive coronary flow reserve (CFR) by transthoracic Doppler echocardiography are also potentially useful. A direct comparison of FFR, IFR, and non-invasive CFR has never been performed. Our objective was to test the usefulness of non-invasive CFR by comparison to invasive FFR and IFR in patients with LAD stenosis of angiographic intermediate severity and stable coronary artery disease. METHODS: Ninety-four stable consecutive patients (mean age, 68+/-10years; 19 women) with angiographic proximal or mid LAD stenosis of intermediate severity (40-70% diameter stenosis on quantitative coronary angiography), were prospectively studied. They underwent IFR that was calculated as a trans-lesion pressure ratio during a specific period of baseline diastole, FFR with intracoronary bolus adenosine (180MUg), and CFR using intravenous adenosine (140MUg/kg/min over 2min) in the distal part of the LAD, the same day. CFR was defined as hyperemic peak diastolic LAD flow velocity divided by baseline flow velocity and FFR as distal pressure divided by mean aortic pressure during maximal hyperemia. RESULTS: The mean values of IFR, FFR, and CFR were 0.88+/-0.07, 0.81+/-0.09, and 2.4+/-0.6 respectively. A significant correlation was found between CFR and FFR (R=0.63, curvilinear relationship), FFR and IFR (R=0.6, linear relationship), and between CFR and IFR (R=0.5) (all, P<0.01). Using a ROC curve analysis, the best cut-off to detect a significant lesion based on FFR assessment (FFR<=0.8, N=31) was IFR<=0.88 with a sensitivity (Se) of 74%, specificity (Sp) of 73%, AUC 0.81+/-0.04; and CFR<=2 with a Se=77%, Sp=89%, AUC 0.88+/-0.04, (all, P<0.001). Based on these cut-offs, discordant results between CFR and FFR were observed in 14 cases (agreement 85%), between CFR and IFR in 26 cases (agreement 72%), and between IFR and FFR in 26 cases (agreement 72%). CONCLUSION: In stable patients with LAD stenosis of intermediate severity, non-invasive CFR is a useful tool to detect a significant lesion based on FFR. Furthermore, there was a better correlation and agreement between CFR and FFR than with IFR. PMID- 27968775 TI - Apical rotation, a simplified index of left ventricular twist is independently linked to recovery after acute anterior myocardial infarction. AB - BACKGROUND: It is unclear whether apical rotation (Ar), which in normal setting represents the dominant contributions to LV twist by comparison to basal rotation (Br), predicts viability in acute anterior myocardial infarction (AMI). Our objective was to test the usefulness of Ar as a simple index to predict LV recovery after AMI. METHODS: Fourty-five consecutive patients (mean age 60+/-14 years, mean LVEF 44+/-7%) with first AMI treated successfully by primary angioplasty underwent prospectively a comprehensive transthoracic-Doppler echocardiography including analysis of Ar, Br, and LV twist by 2-dimensional speckle tracking, using a basal and apical short axis-views, within 24h after angioplasty and 3-6months later. Recovery was defined as: - the normalization of the wall motion of more than 50% of initial abnormal segments (R1) and; - absolute improvement of LVEF>=10% (R2). RESULTS: A better correlation was found between Ar and LV twist at each stage of the disease than between Br and LV twist (acute phase, R=0.77 vs. R=0.35; follow-up, R=0.9 vs. R=0.3 [all, P<0.001 for Ar, and all, P<=0.05 for Br]). Furthermore, a better correlation was found between Ar and follow-up LVEF (R=0.57), wall motion score index (R=0.44), and global longitudinal strain (R=0.54) (all, P<0.001) than between LV twist and the same parameters (R=0.39; R=0.32; R=0.32 respectively, all P<0.05). (For Br, all, P=NS). Ar as well as LV twist were significantly associated with recovery (all, P<0.01) with an area under the curve (AUC) higher for the former than for the latter (R1, N=18: AUC-Ar=0.81 and AUC-LV twist=0.69, P=0.05; R2, N=19: AUC Ar=0.82, AUC-LV twist=0.75, P=0.1). In multivariate analysis, Ar remained an independent predictor of recovery R1 and R2 instead of LV twist (all, P<=0.01). Using a ROC curve analysis, the best cut-off of Ar to predict recovery R2 was 6.5 degrees , with Se=77% Sp=85%, P<0.001. CONCLUSION: Apical rotation is an independent predictor of segmental and global LV recovery after anterior acute anterior myocardial infarction treated successfully by primary angioplasty. PMID- 27968776 TI - The electrocardiogram of the neonate and infant. AB - The ECG in children has a number of characteristic differences compared to the ECG of the adult. The transition of the ECG in neonates after birth represents dynamic changes of the circulatory system due to the postnatal adaptation, different physiologic properties of the fetal and neonatal myocardium, the location and orientation of the heart in the chest and influence of body mass during that period and later on in childhood. The complexity of the changes implies a broad variation of ECG changes during the first days and weeks of life, whose interpretation requires expert knowledge. The ECG is an obligatory diagnostic tool in childhood arrhythmias. The long QT syndrome is an inherited rhythm disorder with risk of sudden cardiac death in early childhood. Electrocardiographic screening in neonates for the early detection of LQTS might identify individuals with an abnormal repolarization and prevent sudden death. The potential benefits of a universal screening program, even if achievable logistically and in a cost-effective manner, are however highly debatable. PMID- 27968808 TI - The ECG and the VCG: understanding cardiac electrical events in space with Grant's spatial vector approach. PMID- 27968777 TI - Noninvasive epicardial and endocardial electrocardiographic imaging of scar related ventricular tachycardia. AB - BACKGROUND: The majority of life-threatening ventricular tachycardias (VTs) are sustained by heterogeneous scar substrates with narrow strands of surviving tissue. An effective treatment for scar-related VT is to modify the underlying scar substrate by catheter ablation. If activation sequence and entrainment mapping can be performed during sustained VT, the exit and isthmus of the circuit can often be identified. However, with invasive catheter mapping, only monomorphic VT that is hemodynamically stable can be mapped in this manner. For the majority of patients with poorly tolerated VTs or multiple VTs, a close inspection of the re-entry circuit is not possible. A noninvasive approach to fast mapping of unstable VTs can potentially allow an improved identification of critical ablation sites. METHODS: For patients who underwent catheter ablation of scar-related VT, CT scan was obtained prior to the ablation procedure and 120 lead body-surface electrocardiograms (ECGs) were acquired during induced VTs. These data were used for noninvasive ECG imaging to computationally reconstruct electrical potentials on the epicardium and on the endocardium of both ventricles. Activation time and phase maps of the VT circuit were extracted from the reconstructed electrograms. They were analyzed with respect to scar substrate obtained from catheter mapping, as well as VT exits confirmed through ablation sites that successfully terminated the VT. RESULTS: The reconstructed re-entry circuits correctly revealed both epicardial and endocardial origins of activation, consistent with locations of exit sites confirmed from the ablation procedure. The temporal dynamics of the re-entry circuits, particularly the slowing of conduction as indicated by the crowding and zig-zag conducting of the activation isochrones, collocated well with scar substrate obtained by catheter voltage maps. Furthermore, the results indicated that some re-entry circuits involve both the epicardial and endocardial layers, and can only be properly interpreted by mapping both layers simultaneously. CONCLUSIONS: This study investigated the potential of ECG-imaging for beat-to-beat mapping of unstable reentrant circuits. It shows that simultaneous epicardial and endocardial mapping may improve the delineation of the 3D spatial construct of a re-entry circuit and its exit. It also shows that the use of phase mapping can reveal regions of slow conduction that collocate well with suspected heterogeneous regions within and around the scar. PMID- 27968810 TI - A Review of Available Techniques for Cardiac Output Monitoring. AB - The main objective of fluid therapy is to increase cardiac output (CO). Large, rapidly administered volumes of fluids are the cornerstone of treating patients in shock to restore circulating volume and improve tissue perfusion. However, determining exactly how much fluid a given patient requires can be challenging. If enough fluid is not given, poor tissue perfusion can lead to ischemia, anaerobic metabolism, and ultimately cell and patient death. Conversely, increased morbidity and mortality associated with excessive intravenous fluid administration has been reported in the human literature in a wide variety of conditions. This review focuses on types of available CO monitoring, their application in veterinary medicine as well as current research trends in noninvasive evaluation of CO. PMID- 27968811 TI - A Review of Central Venous Pressure and Its Reliability as a Hemodynamic Monitoring Tool in Veterinary Medicine. AB - OBJECTIVE: To review the current literature regarding central venous pressure (CVP) in veterinary patients pertaining to placement (of central line), measurement, interpretation, use in veterinary medicine, limitations, and controversies in human medicine. ETIOLOGY: CVP use in human medicine is a widely debated topic, as numerous sources have shown poor correlation of CVP measurements to the volume status of a patient. Owing to the ease of placement and monitoring in veterinary medicine, CVP remains a widely used modality for evaluating the hemodynamic status of a patient. A thorough evaluation of the veterinary and human literature should be performed to evaluate the role of CVP measurements in assessing volume status in veterinary patients. DIAGNOSIS: Veterinary patients that benefit from accurate CVP readings include those suffering from hypovolemic or septic shock, heart disease, or renal disease or all of these. Other patients that may benefit from CVP monitoring include high risk anesthetic patients undergoing major surgery, trending of fluid volume status in critically ill patients, patients with continued shock, and patients that require rapid or large amounts of fluids. THERAPY: The goal of CVP use is to better understand a patient's intravascular volume status, which would allow early goal-directed therapy. PROGNOSIS: CVP would most likely continue to play an important role in the hemodynamic monitoring of the critically ill veterinary patient; however, when available, cardiac output methods should be considered the first choice for hemodynamic monitoring. PMID- 27968813 TI - Fluid Therapy-Part II: Introduction. PMID- 27968812 TI - Owner's Perception for Detecting Feline Body Condition Based on Questionnaire and Scores. AB - To evaluate the owner's ability to identify body condition in cats, based on questionnaire and scores, as well as to obtain others' information about the cat and the owner that may be related to the body condition. Seventy-seven owned cats, aged above 11 months, were evaluated. Initially, information was obtained on age, sex, breed, and whether they had been neutered. Next, owners were asked to fill a questionnaire: the first section was about the cat's diet type, feeding regime, and activity level, and the second section was on the owners' diet, physical activity, and physical condition. The owners estimated body condition of their cats before and after seeing drawings with images. The authors also estimated body condition. Only a 5-point visual scale showed significant difference between the cat's body score assigned by the owner before and after seeing drawings, and before seeing drawings compared with the cat's body score assigned by the authors. A weak positive correlation was detected between cat's body score assigned by the 2 authors and access to any type of cat climbing systems, and weak negative correlation was detected for the variable spayed or neutered. The cat's physical activity level showed weak negative correlation with cat's body score. There was a strong positive correlation between cat's body weight and cat's body score. The owners showed ability to identify body condition in cats after seeing the drawings in both visual scales, and there was a relationship between cat's body weight and body condition score. PMID- 27968814 TI - Practical Assessment of Volume Status in Daily Practice. AB - Fluid therapy is considered the cornerstone of treatment for patients suffering from various medical ailments particularly in emergency and critical care situations where hypovolemia commonly occurs. The ability to accurately assess a patient's volume status is critical to the decision making process when synthesizing and implementing a fluid therapy plan. Both extremes, over supplementation or not supplementing enough fluid can be detrimental to the patient. Precisely assessing a patient's blood volume without access to advanced often complicated equipment and monitoring devices is challenging. The aim of this paper is to review the practical means and tools available to aide in estimating a patient's volume status. PMID- 27968815 TI - Fluid Overload in Small Animal Patients. AB - Fluid therapy is used daily by veterinary practitioners and is an essential part of treatment of many veterinary patients. However, as with all interventions, there is the potential for negative side effects resulting from fluid therapy. Fluid overload is a key side effect that has been increasingly recognized in human medicine as leading to significant negative sequelae. Evidence related to fluid overload in veterinary medicine is sparse but it is likely that the same types of negative sequelae are seen in our veterinary patients. The goal of this review is to present a definition for fluid overload in small animal veterinary patients and ways to both recognize and treat fluid overload. Additionally, ways to avoid the development of fluid overload are described. PMID- 27968816 TI - Can we not bleed? PMID- 27968817 TI - Gilbert's syndrome in haemopoietic cell transplantation. PMID- 27968818 TI - Definition of functional iron deficiency and intravenous iron supplementation - Author's reply. PMID- 27968819 TI - Definition of functional iron deficiency and intravenous iron supplementation. PMID- 27968914 TI - Massive misuse of antibiotics by university students in China: a cross-sectional survey. AB - BACKGROUND: Antimicrobial resistance is one of the greatest threats to global population health this century, and is a major contributor to rising healthcare costs worldwide. The primary cause of this resistance is antibiotic misuse, especially routine inappropriate use of antibiotics for self-limiting illnesses. In China, over prescribing of antibiotics is pervasive leading to very high and increasing rates of antimicrobial resistance in both hospital-acquired and community-acquired infections. The aim of this study was to explore the knowledge and behaviours of university students in relation to antibiotic use in six Chinese provinces. METHODS: A stratified, cluster-random sampling method was used to select students across six universities in six provinces (Zhejiang, Wuhan, NanKai, Jilin, Guizhou, and Lanzhou Universities). An anonymous online survey tool, Wen Juan Xing, was used to collect data. Students completed the survey using a smartphone application. chi2 test and logistic regression model were used to assess associations between knowledge and behaviour. Patient consent and ethical approval were obtained for this study. FINDINGS: 11 192/11 459 (98%) students completed the questionnaire. Knowledge of antibiotics and their appropriate use was poor: only 236/11 192 (2%) answered all 13 questions correctly. In terms of healthcare-seeking behaviour, of 3337/11 192 (30%) students who were ill in the preceding month, 913/3337 (27%) went to see a doctor and 600/913 (66%) of these students were prescribed antibiotics; 1711/3337 (51%) treated themselves, 507/1711 (30%) of these with antibiotics. 7057/11 192 (63%) of students keep antibiotics at home. Of 6269/11 192 (56%) students who tried to buy antibiotics from a drugstore in the preceding year, 4133/6269 (66%) tried to do so without prescription and 3964/4133 (96%) succeeded. Students who keep antibiotics at home are almost 5 times more likely to self-treat with antibiotics (OR=4.90, 95% CI 3.48-6.90). INTERPRETATION: Demand for antibiotics has an important role in the excess use of antibiotics among university students in China. An education campaign about proper use of antibiotics is an urgent priority and should involve both health professionals and the general public. Existing regulations prohibiting pharmacists to sell antibiotics over-the-counter must be enforced. FUNDING: None. PMID- 27968820 TI - Mortality outcomes after busulfan-containing conditioning treatment and haemopoietic cell transplantation in patients with Gilbert's syndrome: a retrospective cohort study. AB - BACKGROUND: Gilbert's syndrome is a common inherited disorder of bilirubin metabolism, characterised by mild, unconjugated hyperbilirubinaemia. However, the effect of Gilbert's syndrome on the disposition of some drugs can lead to unexpected toxicity. We tested the hypothesis that patients undergoing myeloablative conditioning and haemopoietic cell transplantation would have different mortality outcomes depending on whether or not they had laboratory evidence of Gilbert's syndrome. METHODS: In this retrospective cohort study, we used clinical and laboratory data of patients who had haemopoietic cell transplantation from Jan 1, 1991, to Dec 31, 2011. Patients were included if they had received high-dose conditioning regimens of cyclophosphamide plus total body irradiation (CY/TBI), busulfan plus cyclophosphamide (BU/CY), busulfan plus melphalan plus thioTEPA (BUMELTT), or melphalan before transplant. Patients were excluded if their original consent forms to report transplant outcomes were not signed, if consent was withdrawn, or if they were a prisoner. Patients with Gilbert's syndrome were defined as having laboratory values before the start of conditioning therapy for unconjugated serum bilirubin concentrations of at least 17.1 MUmol/L (>=1 mg/dL), normal conjugated serum bilirubin, and no evidence of hepatitis, cholestasis, or haemolysis. We assessed the association of Gilbert's syndrome with overall mortality and non-relapse mortality using adjusted Cox regression models at day 200 after transplantation. FINDINGS: Our study cohort was 3379 patients-1855 (55%) allograft and 1524 (45%) autograft recipients. 211 (6%) patients had Gilbert's syndrome and 3168 (94%) did not have this condition. Most patients were adults (median age 45.8 years [IQR 33.2-55.5]) with haematological malignancies. For overall mortality 664 (20%) patients had died by day 200 after transplant (47 [22%] of 211 who had Gilbert's syndrome vs 617 [19%] of 3168 who did not have Gilbert's syndrome), and for non-relapse mortality 499 (92%) patients had died before relapse was recorded (38 [18%] who had Gilbert's syndrome vs 461 [15%] who did not have Gilbert's syndrome). The effect of Gilbert's syndrome on the risk of overall mortality and non-relapse mortality by transplant day 200 varied between the conditioning regimens and donor groups. In patients conditioned with a myeloablative regimen that contained busulfan (n=1131), those with Gilbert's syndrome (n=60) were at a significantly increased risk of death and non-relapse mortality by day 200 compared with those without Gilbert's syndrome (n=1071; hazard ratio [HR] 2.30, 95% CI 1.47-3.61, p=0.00030; and 2.77, 1.71-4.49, p<0.0001). In patients who received CY/TBI or melphalan conditioning regimens, those with Gilbert's syndrome had similar outcomes to those without Gilbert's syndrome (overall mortality at day 200 HR 0.90, 95% CI 0.60-1.34, p=0.60; non-relapse mortality at day 200: 0.90, 0.56-1.45, p=0.65). Analyses of causes of death and busulfan disposition provided no mechanistic explanation for the differences in mortality. INTERPRETATION: Overall mortality and non-relapse mortality at day 200 after transplant were significantly worse in patients with Gilbert's syndrome who received busulfan-containing myeloablative conditioning regimens, compared with non-Gilbert's syndrome patients. Patients with Gilbert's syndrome should receive busulfan-containing myeloablative conditioning regimens with caution. FUNDING: US National Institutes of Health. PMID- 27968915 TI - Dynamic contrast-enhanced MRI to predict response to vinorelbine-cisplatin alone or with rh-endostatin in patients with non-small cell lung cancer and bone metastases: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Metastatic bone disease is a frequent complication of advanced non small-cell lung cancer and causes skeletal-related events which result in a poor prognosis. A standard method to assess the therapeutic response of bone metastases does not currently exist. We used dynamic contrast-enhanced MRI to obtain quantitative measures to assess the suitability of this technique to gauge therapeutic response to vinorelbine-cisplatin plus rh-endostatinfor previously untreated non-small cell lung cancer with bone metastases. METHODS: We did a phase 4, randomised, prospective, double-blind, placebo-controlled clinical trial in Shanghai Sixth People's Hospital, Shanghai, China. Inclusion criteria were non small-cell lung cancer patients with bone metastases confirmed by pathology or cytology; available imaging data of pelvic metastatic lesions; aged 18 to 75 years old; expected survival at least 3 months; not receiving taxane, bevacizumab, thalidomide, rh-endostatin, or bisphosphonate; not having radiation therapy within 3 months of enrollment into study; normal results of routine blood tests, liver and kidney function, and electrocardiogram; absence of cardiovascular disease, autoimmune disease, vasculitis, severe infection, diabetes, and other concomitant disease; and signed informed consent. Exclusion criteria were receiving granulocyte colony stimulating factor or granulocyte macrophage colony stimulating factor during chemotherapy, intolerance to adverse reaction, and allergy to contrast agents. Patients were randomly assigned to treatment group and control group at a ratio of 2:1 by random code generation by an independent biostatistician in a double-blind fashion. Participants received either vinorelbine-cisplatin plus rh-endostatin or vinorelbine-cisplatin plus placebo. Vinorelbine (25 mg/m2) and cisplatin (75 mg/m2) were administered intravenously on the first day of a 21 day cycle. Patients received rh-endostatin (7.5 mg/m2) or placebo on days 1-14 of a cycle. The primary end points were objective response rate (complete remission+partial remission)/total * 100) and disease control rate (complete remission+partial remission+stable disease)/total * 100). Measurements including Ktrans, Kep, and Ve were evaluated by dynamic contrast-enhanced MRI before treatment and after completion of 2 treatment cycles. Blood concentrations of bone metabolites, tumour markers, and tumour vascular growth related factors were measured before and after treatment. Comparisons were made using paired t-test. Kaplan-Meier survival analysis was used to indicate the correlation between some measurements and progression-free survival or overall survival. The difference in Ktrans between patients who had partial remission or stable disease group and those who had disease progression was tested using the Chi-square test. All statistical analyses were performed with SPSS version 21.0. This trial was approved by the State Food and Drug Administration (No: S20050088) and China State Food and Drug Administration. The trial is registered with China Clinical Trials Registry, number chictr-ctr 09000569. Written informed consent and ethical approval was obtained. FINDINGS: We enrolled 33 patients (aged 52-70, 15 men and 18 women) of whom 28 were evaluable (20 in treatment group and 8 in control group). Five patients were excluded: 2 patients in treatment group and 1 patient in control group used granulocyte-macrophage colony stimulating factor, and 2 patients in the control group refused treatment. Objective response rate was higher (30% vs 0%; p<0.00001), mean overall survival was longer (21.44 [SD 17.28] vs 7.71 [4.68] months, p=0.008), and reduction in capillary permeability (measured by Ktrans) was greater (60.0% vs 4.4%; p=0.026) in the group given rh-endostatin than in the control group. Disease control rate was 80% in the treatment group and 75% in the control group (p=0.07). Overall survival was longer in patients with a greater than 50% reduction in Ktrans than in patients with a decrease of up to 50% (13.2 [1.8] vs 9.8 [0.2] months, p=0.026). INTERPRETATION: Addition of rh-endostatin to treatment with vinorelbine-cisplatin increased the treatment response in patients with non-small cell lung cancer and bone metastases. Quantitative analysis using dynamic contrast-enhanced MRI can be used to evaluate therapeutic response and to predict survival of bone metastases after anti-angiogenesis therapy. Limitations of this study include the small number of patients and the single-centre design. FUNDING: National Natural Science Foundation of China [grant number 81201628]. PMID- 27968920 TI - The future of Point-Of-Care Ultrasound in internal medicine. PMID- 27968924 TI - Introduction. PMID- 27968925 TI - [Prophylactic radiotherapy for procedure-tracts metastases in pleural mesothelioma: A phase 3 trial, "SMART"... not enough]. PMID- 27968926 TI - Kids are not just little people: Pediatric versus adult dermatology approaches to skin diseases, part II. PMID- 27968927 TI - Autoimmune collagen vascular diseases: Kids are not just little people. AB - Morphea, dermatomyositis (DM), and discoid lupus erythematosus (DLE) are autoimmune collagen vascular diseases that can present at any age. In all three of these diseases, the tenants of diagnosis and treatment are largely the same in both children and adults, with a few notable differences. Children with morphea are more likely to present with the linear subtype and have a higher incidence of extracutaneous manifestations. Children often need early aggressive systemic treatment to try to prevent long-term sequelae of morphea. In DM, adult disease has a clear association with malignancy that is not seen in children. Adults have a higher rate of pulmonary involvement and increased mortality, whereas calcinosis is more common in juvenile DM. DLE in adults is generally considered to have a low rate of progression from discoid lesions alone to systemic lupus erythematosus (SLE). DLE is less common in children, but several studies have suggested a higher rate of progression from DLE to SLE in children compared with adults. PMID- 27968928 TI - Ethnic skin: Kids are not just little people. AB - There are numerous skin conditions that occur commonly in children with ethnic skin, including vitiligo, progressive macular hypomelanosis, pityriasis alba, acne keloidalis nuchae, pseudofolliculitis barbae, and keloids. Though these conditions occur in both children and adults, children may have different patterns of clinical presentation and response to therapy. In caring for such patients, important treatment considerations include side effects of systemic medications and tolerability of invasive procedures. Quality of life is an important measure and should not be compromised by either the skin disease or its treatment. PMID- 27968930 TI - Acne: Kids are not just little people. AB - Acne vulgaris is a common inflammatory disease of the pilosebaceous follicles that affects patients of all ages, from neonates to adults. We have compared and contrasted the clinical presentation of acne in neonates, infants, children, teenagers, and young adults and review the scenarios in which further systemic endocrine or hormonal tests are indicated. We also discuss age-dependent treatment considerations, including appropriate oral antimicrobial regimens and the proper dosing of isotretinoin in young children versus teenagers and adults. PMID- 27968929 TI - Nutrition and skin: Kids are not just little people. AB - There has been a surge of new data regarding the pathophysiology of skin diseases. We are appreciating the sophisticated interplay among the skin, the immune system, and the environment. More elegant and highly specific medicines have been designed to target certain immune mediators of the adaptive immune system. In parallel fashion, we are learning more about the elegance of the innate immune system and how nutrition as early as the prenatal period can affect the priming of other immune cells. Concerns about the long-term impact of new immune-modulating medicines-especially in the pediatric population-have patients asking their dermatologists for nutritional alternatives to medical therapies. Nutrients and nutritional therapies appear to play a role at different ages for different dermatoses. Probiotics are showing promise as a therapeutic option for patients older than 1 year for atopic dermatitis. Systemic contact allergens appear to be a bigger burden on the adult population with atopic dermatitis. Obesity is a growing concern for both children and adults with psoriasis. Milk and high glycemic foods have a strong impact on the teenage acne population. Vitamins A and D are addressed as piece of the alopecia areata puzzle. Zinc and homeopathy are presented finally as possible treatments to the everlasting wart. PMID- 27968931 TI - Psoriasis in adults and children: Kids are not just little people. AB - Pediatric psoriasis is a common skin disorder. Although pediatric psoriasis has many similarities to adult psoriasis, there are differences in presentation, particularly in infants. In addition, a more limited therapeutic armamentarium exists for children due to different inherent risks. Nearly all therapies are unapproved in the pediatric population, with far fewer pre- and postmarketing studies having been conducted. Despite these challenges, appropriate treatment should never be denied to a young patient, as physical and psychosocial ramifications of psoriasis in the school age child and adolescent are significant. A partnership with the patient, caregivers, and primary care providers is necessary and rewarding in meeting the challenges of this chronic, incurable disease. We address the presentation, treatment options, and counseling necessary when treating psoriasis in the pediatric population. PMID- 27968932 TI - Photodermatoses: Kids are not just little people. AB - Photodermatoses are a group of skin disorders caused by abnormal reaction to ultraviolet radiation. Photodermatoses are divided into four groups: (1) immunologically mediated photodermatoses; (2) chemical- and drug-induced photodermatoses; (3) photoaggravated dermatoses; and (4) hereditary photodermatoses. This contribution discusses differences in the approach and diagnosis of pediatric and adult patients with suspected photodermatoses, focusing on immunologically mediated photodermatoses and chemical- and drug induced photodermatoses. PMID- 27968933 TI - Nail disorders: Kids are not just little people. AB - Nail disorders comprise an important subset of dermatologic conditions and often pose both diagnostic and therapeutic challenges to the clinician. Presentation and management can differ in adults and children. Proper understanding of these differences is important in delivering optimal patient care. This contribution discusses three common nail disorders in adults and children, onychomycosis, melanonychia striata, and trachyonychia, highlighting distinct features in the adult and pediatric populations. PMID- 27968934 TI - Melanoma: Kids are not just little people. AB - Malignant melanoma can affect patients of any age. It has been well documented that the overall incidence of melanoma has increased in the past several decades, and this increase extends to the pediatric population (both preadolescent and, to a greater extent, adolescent children). Melanoma in adolescents, commonly defined as patients 11 to 19 years of age, behaves similarly to melanoma in adults; however, there are a number of distinct differences in the presentation and prognosis of melanoma in the preadolescent population. Though our treatment options for melanoma are increasing with the advent of novel drugs and clinical trials, the rarity of pediatric melanomas often excludes this population from clinical studies. The treatment options for the pediatric patient are predominantly based on adult clinical trials. Awareness of the differences in clinical presentation, as well as management of melanoma in younger patients compared with their adult counterparts, is crucial to guarantee prompt and appropriate care. PMID- 27968935 TI - Cutaneous lymphoma: Kids are not just little people. AB - Cutaneous T-cell lymphomas (CTCLs) are non-Hodgkin lymphomas that predominantly affect older patients. Onset of cutaneous lymphoma in childhood is rare, but it can present as early as the first decade of life. In both adults and children, the diagnosis of cutaneous lymphoma can be challenging because inflammatory dermatoses can mimic CTCL both clinically and histologically. The clinicopathologic manifestations can be similar in adults and younger individuals; however, differences in the prevalence of certain CTCL variants among age groups exist. Whereas the classic Alibert-Bazin-type mycosis fungoides (MF) and Sezary syndrome represent the overwhelming majority of adult cutaneous T cell lymphomas, in younger individuals, certain mycosis fungoides variants, such as hypopigmented MF, are over-represented and Sezary syndrome is extremely rare. CD30+ lymphoproliferative diseases, which include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (ALCL), represent the second most common subtype of CTCL in both adults and children; however, in the pediatric population, most of these are represented by LyP, and primary cutaneous ALCL is very rare. The prognosis is stage dependent, and the most significant prognostic factor in MF is the extent of skin involvement and the presence or absence of extracutaneous disease. The overwhelming majority of pediatric patients present with early-stage disease, and progression to more advanced stages, such as tumor stage, erythrodermic MF, and large cell transformation, which can be seen in adults, is very rare. The choice of treatment, regardless of age, is dependent on the extent of skin involvement and the presence or absence of extracutaneous disease. PMID- 27968936 TI - Mast cell disorders: Kids are not just little people. AB - Cutaneous mastocytosis is characterized by a pathologic increase in mast cells in the skin and may also involve extracutaneous organs. Symptoms, which are triggered by mast cell degranulation, vary depending on the burden of skin disease and the presence of extracutaneous disease. The clinical presentation, risk of systemic disease, pathogenesis, prognosis, and treatment options differ, largely depending on age at presentation. In the pediatric population, spontaneous remission is typical, generally by puberty, whereas in adults, progression is observed. Extracutaneous involvement and associated hematologic disorders seldom occur in children, as opposed to adults. It is therefore important to avoid overreliance on adult-based approaches to management of cutaneous mastocytosis in the pediatric population. We focus on differences in presentation, workup, and management of pediatric- and adult-onset cutaneous mast cell disorders. PMID- 27968937 TI - The fate of Hungarian Jewish dermatologists during the Holocaust: Part 2: Under Nazi rule. AB - At least 564,500 Hungarian Jews perished during the Holocaust, including many physicians. Exactly how many Jewish dermatologists were killed is not known. We have identified 62 Hungarian Jewish dermatologists from this period: 19 of these dermatologists died in concentration camps or were shot in Hungary, 3 committed suicide, and 1 died shortly after the Holocaust, exhausted by the War. Fortunately, many Hungarian Jewish dermatologists survived the Holocaust. Some had fled Europe before the Nazi takeover, as was described in Part 1 of this contribution. Two Holocaust survivors, Ferenc Foldvari and Odon Rajka, became presidents of the Hungarian Dermatologic Society and helped rebuild the profession of dermatology in Hungary after the War. This contribution provides one of the first accounts of the fate of Hungarian Jewish dermatologists during the Holocaust and serves as a remembrance of their suffering and ordeal. PMID- 27968938 TI - Bibliography of secondary sources on the history of dermatology: II. Obituaries and biographies in English supplemented through 2015. PMID- 27968939 TI - Bibliography of secondary sources on the history of dermatology: III. Books, Monographs, and Chapters in English Supplemented through 2015. PMID- 27968940 TI - Obsession with perfection: Body dysmorphia. AB - The deeply rooted fascination with beauty penetrates society worldwide. The indulgence to look and feel beautiful pervades all ages, genders, and nationalities, with research conferring a remarkable tendency to agree on measures of attractiveness among these disparate groups. Research has found that beautiful people do, in fact, receive more desirable outcomes in life and job satisfaction, family formation, and overall happiness. Humans have a tendency to respond to attractive persons more favorably, driving many patients to our clinics. Although some dissatisfaction with one's appearance is common and normal, excessive concern with certain facial or body attributes can be sign of an underlying disorder. Body dysmorphic disorder (BDD) is a disorder of self perception. It is the obsession with perfection. Defined as the impairing preoccupation with a nonexistent or minimal flaw in appearance, BDD affects 0.7 2.4% of the general population and a much larger percentage of those attempting to receive aesthetic treatments. Clinicians should be aware of this disorder and remain vigilant because such patients will not be satisfied with corrective procedures. Although not involving cosmetic intervention, the treatment of BDD does involve psychiatric referral and psychopharmacologic therapy, with patients receiving these having a much better prognosis. PMID- 27968941 TI - Addressing future demands: Development of an online gerontological nursing course. AB - Nursing students often hold negative views of and do not want to work with older people. Innovative approaches to engage nursing students in geriatric content hold the potential to improve attitudes, a crucial step in meeting the aging population's healthcare needs. This article describes the process of developing, implementing and evaluating an online, undergraduate nursing gerontology course. Development was based on Mezirow's Transformative Learning Theory. Student reflections collected from approximately 200 individuals over two semesters about knowledge gained and the effect on attitudes about aging and older adults are summarized. PMID- 27968942 TI - GAPNA Consensus Statement on Proficiencies for the APRN Gerontological Specialist Proficiency Statement 5. PMID- 27968943 TI - Save the Date! PMID- 27968944 TI - GAPNA Consensus Statement on Proficiencies for the APRN Gerontological Specialist: Proficiency Statement 6. PMID- 27968946 TI - Commemorating key research that shaped geriatrics since the new millennium. PMID- 27968945 TI - Provider partnerships improve geriatric care across the continuum. PMID- 27968947 TI - Comment on "Ultrasound of extravascular lung water: a new standard for pulmonary congestion". PMID- 27968948 TI - Mechanical Ventilation in the Critically Ill Patient: International Nursing Perspectives. PMID- 27968953 TI - Foreword: Childhood Leukemia and Primary Prevention. PMID- 27968955 TI - IMRT for head and neck cancer: Cost implications. AB - OBJECTIVES: Intensity-modulated radiotherapy (IMRT) is a dose-delivery technology allowing for a reduction in radiotherapy side effects. It has been rapidly adopted despite the lack of prospective studies showing improved outcomes. We sought to compare the cost through Medicare reimbursement patterns of surgery, IMRT, and conventional XRT in treating head and neck cancer. We then identified factors that correlate with these differences. METHODS: Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data were examined to determine treatment patterns for 47,237 patients with head and neck carcinoma from 2000 to 2007. We identified 14,748 patients that met our inclusion criteria. We then compared cost related to head and neck cancer treatments on the basis of Medicare payments. RESULTS: From 2000 to 2007, the usage of IMRT increased from 1.5% to 48.6% while the usage of conventional XRT decreased from 98.5% to 51.4% (p<0.0001). During this time, patients undergoing IMRT had a mean cost of $101,099 compared to $42,843 for XRT. For patients with early stage tumors, surgery alone cost $18,140, traditional XRT $32,296 while IMRT cost $95,047 (p<0.0001). When removing patients who underwent concomitant chemotherapy, patients treated with IMRT cost $67,576 compared to $24,955 for non-IMRT patients (p<0.0001). CONCLUSIONS: IMRT has become widely adopted as a primary treatment modality in head and neck cancer. We demonstrated that IMRT is significantly more costly than traditional treatment for head and neck cancers. Prospective studies investigating the comparative efficacy of IMRT will be needed in order to determine if this increased cost correlates with patient outcomes. LEVEL OF EVIDENCE: 2b. PMID- 27968956 TI - A genetic marker of the ACKR1 gene is present in patients with Type II congenital smell loss who have type I hyposmia and hypogeusia. AB - PURPOSE: Our previous study of Type II congenital smell loss patients revealed a statistically significant lower prevalence of an FY (ACKR1, formerly DARC) haplotype compared to controls. The present study correlates this genetic feature with subgroups of patients defined by specific smell and taste functions. METHODS: Smell and taste function measurements were performed by use of olfactometry and gustometry to define degree of abnormality of smell and taste function. Smell loss was classified as anosmia or hyposmia (types I, II or III). Taste loss was similarly classified as ageusia or hypogeusia (types I, II or III). Based upon these results patient erythrocyte antigen expression frequencies were categorized by smell and taste loss with results compared between patients within the Type II group and published controls. RESULTS: Comparison of antigen expression frequencies revealed a statistically significant decrease in incidence of an Fyb haplotype only among patients with type I hyposmia and any form of taste loss (hypogeusia). In all other patient groups erythrocyte antigens were expressed at normal frequencies. CONCLUSIONS: Data suggest that Type II congenital smell loss patients who exhibit both type I hyposmia and hypogeusia are genetically distinct from all other patients with Type II congenital smell loss. This distinction is based on decreased Fyb expression which correlated with abnormalities in two sensory modalities (hyposmia type I and hypogeusia). Only patients with these two specific sensory abnormalities expressed the Fyb antigen (encoded by the ACKR1 gene on the long arm of chromosome 1) at frequencies different from controls. PMID- 27968957 TI - Technique for improved safety in the endoscopic management of subglottic stenosis. AB - OBJECTIVE: To identify a safe approach to airway management during the endoscopic balloon dilation of subglottic stenosis BACKGROUND: Subglottic stenosis is an abnormal narrowing of the upper airway commonly managed by endoscopic technique performed on an unsecured airway. METHODS: Review of surgical treatment of subglottic stenosis cases by the senior author. TECHNIQUE: Following steroid injection and radial cuts performed either under jet anesthesia or mask ventilation with brief periods of apnea, a small endotracheal tube may be passed beyond the narrowing to permit adjacent balloon dilation with the airway secured. CONCLUSIONS: We introduce an endoscopic subglottic balloon dilation technique done with a secured airway. PMID- 27968958 TI - Correlation analysis of oral lesion sizes by various standardized criteria. AB - OBJECTIVE: Requirements of an NCI contract examining a novel treatment for leukoplakia were to compare standard bi-dimensional measurement of oral lesions to examine for correlation with Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and to examine the feasibility of digital image analysis for automated measurements. STUDY DESIGN: Retrospective review. METHODS: We examined 13 patients by bi-dimensional measurement and compared these measurements to 1) RECIST criteria, 2) scalar digital measurements using a standardized measuring device within the photograph, and 3) pixel number. RESULTS: RECIST criteria correlated (r-squared=0.8535, p<0.0001) with bi-dimensional measurements. Digitized measures in photographs correlated with bi-dimensional measurements (r squared=0.6661, p=0.0007), but were time consuming. There was minimal to no correlation between pixel number in Adobe Photoshop and the other measures. CONCLUSION: Bi-dimensional measurement of oral leukoplakia and RECIST criteria are highly correlated. Digital photography measurements, though highly correlative, are very cumbersome. We recommend bi-dimensional or longest length measurement and a simple photograph as standard of documentation for leukoplakia lesions. PMID- 27968959 TI - In situ synthesis of high swell ratio polyacrylic acid/silver nanocomposite hydrogels and their antimicrobial properties. AB - Silver nanocomposites embedded within a polymer matrix have attracted attention in recent years. Ionic polymer hydrogels comprise networks of chemically or physically cross-linked polymers that swell considerably in an appropriate solvent. In this study, we used a solution of the carboxylic monomer acrylic acid and silver nitrate to prepare nanocomposite hydrogels through ultraviolet (UV) light irradiation. Silver-impregnated biomaterial composed of acrylic acid contains only a monomer and no cross-linker. The formation of hydrogels and reduction of silver nanoparticles were affected by the preparation parameters, that is, the monomer concentration and silver nitrate concentration. The morphology, structure, and size of the silver nanocomposite hydrogels were evaluated through field emission scanning electron microscopy and UV-visible absorption. The antimicrobial activity of the samples was tested against fourstandard strains Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli; and five clinical bacterial isolates Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumonia. The silver nanocomposite hydrogels exhibited an interconnected porous structure and could absorb 400 to 550g of deionized water per gram of dried hydrogel. Moreover, these hydrogels produced a strong antibacterial effect, which can be useful in developing new superabsorbent antimicrobial pharmaceutical products. PMID- 27968960 TI - Short Takes. PMID- 27968961 TI - ? PMID- 27968954 TI - Childhood Leukemia and Primary Prevention. AB - Leukemia is the most common pediatric cancer, affecting 3800 children per year in the United States. Its annual incidence has increased over the last decades, especially among Latinos. Although most children diagnosed with leukemia are now cured, many suffer long-term complications, and primary prevention efforts are urgently needed. The early onset of leukemia-usually before 5 years of age-and the presence at birth of "pre-leukemic" genetic signatures indicate that pre- and postnatal events are critical to the development of the disease. In contrast to most pediatric cancers, there is a growing body of literature-in the United States and internationally-that has implicated several environmental, infectious, and dietary risk factors in the etiology of childhood leukemia, mainly for acute lymphoblastic leukemia, the most common subtype. For example, exposures to pesticides, tobacco smoke, solvents, and traffic emissions have consistently demonstrated positive associations with the risk of developing childhood leukemia. In contrast, intake of vitamins and folate supplementation during the preconception period or pregnancy, breastfeeding, and exposure to routine childhood infections have been shown to reduce the risk of childhood leukemia. Some children may be especially vulnerable to these risk factors, as demonstrated by a disproportionate burden of childhood leukemia in the Latino population of California. The evidence supporting the associations between childhood leukemia and its risk factors-including pooled analyses from around the world and systematic reviews-is strong; however, the dissemination of this knowledge to clinicians has been limited. To protect children's health, it is prudent to initiate programs designed to alter exposure to well-established leukemia risk factors rather than to suspend judgment until no uncertainty remains. Primary prevention programs for childhood leukemia would also result in the significant co-benefits of reductions in other adverse health outcomes that are common in children, such as detriments to neurocognitive development. PMID- 27968962 TI - ? PMID- 27968963 TI - [Emergency, the nurse and the patient]. AB - At the heart of an emergency, nurses work closely with the patient and centralise the focus of the team work. They provide technical assistance through procedures carried out in an optimal safety framework. PMID- 27968964 TI - [Evolution of the nurse's role in the management of a cardiac arrest]. AB - In France, there are 40 000 sudden deaths each year and the cardiac arrest survival rate is less than 10%. The arrival of extracorporeal cardio pulmonary resuscitation (ECPR) offers hope in the event of refractory cardiac arrest in prehospital care. Extending ECPR programmes requires more scientific evidence, training and an evolution of the role of paramedics. PMID- 27968965 TI - [Nursing practice within the French national gendarmerie intervention group]. AB - Intervening in the event of a major crisis in France and abroad, the national gendarmerie intervention group carries out complex and specific operations in varied conditions and environments. Due to the multiplicity and dangerousness of the missions, adapted and integrated medical support is essential. In this context, nurses provide operational medical assistance as close as possible to the intervention. This nursing practice in an exceptional environment requires specific knowledge and intensive training. PMID- 27968966 TI - [The nurse on a remote mineral, gas or oil extraction site]. AB - On mineral, gas or oil extraction sites, medical care is often provided in uncommon conditions by doctors or paramedical staff. Caregivers must fulfil certain requirements, but must also possess the necessary human, technical, physical and psychological qualities to be able to provide high quality care throughout their mission on a remote site. PMID- 27968967 TI - [Nurses and health officers supporting the emergency operations command]. AB - The health and medical emergency service of a departmental fire and rescue unit is a key element of emergency care in France. Health officers are present in the operations room or in the field. Often a nurse from the fire service, they may also be a doctor or pharmacist. Their mission is to optimise and to anticipate the emergency healthcare response both on a day-to-day basis as well as with extraordinary events involving numerous victims or large-scale technological, natural or terror risks. PMID- 27968968 TI - [Recruitment and training of prehospital emergency care nurses in Paris]. AB - In collaboration with the ambulance driver and the emergency doctor, the prehospital nurse provides care in a universe which is often difficult and sometimes hostile. Whether they are a nurse from the Samu (urgent medical aid service) or from the Paris fire service, how are they recruited and what training do these emergency care professionals receive? PMID- 27968969 TI - [Care seen from the other side]. AB - Treating an out-of-hospital cardiac arrest (OHCA) is a rare event. The experience of a young nurse who suffered an OHCA reminds us of the importance of activating the chain of survival at the earliest possible moment. PMID- 27968970 TI - [Working in a team around nursing values]. AB - Particularly interested in the relational aspect of care, Stephanie Lienard became a nurse at the age of 36. She began her nursing career in a prison and now works in the field of end-of-life care. PMID- 27968971 TI - [Paramedical research, a long path towards autonomy]. AB - An integral part of the care project of Versailles general hospital, paramedical research is facilitated and promoted by nursing management. It is also strongly encouraged and supported by medical professionals. Beyond the scientific interest in terms of the benefits for the quality of care, it is considered as an innovative project which unites and motivates staff, thereby favouring employee retention. PMID- 27968972 TI - [Promoting the sustainable management of hospital waste in Kinshasa]. AB - The management of hospital waste is a high-risk practice in the hospitals of Kinshasa, the largest city of the Democratic Republic of the Congo, from the point of view of public health and the environment. A multi-criteria study carried out in 4 hospitals assessed the situation and put forward solutions. PMID- 27968973 TI - ? PMID- 27968974 TI - ? PMID- 27968975 TI - ? PMID- 27968976 TI - ? PMID- 27968977 TI - ? PMID- 27968978 TI - Molecular characterization of maize bHLH transcription factor (ZmKS), a new ZmOST1 kinase substrate. AB - In order to identify potential substrates of the maize kinase in the ABA signalling network, ZmOST1 was used as bait against a library of cDNAs from dehydrated young leaves. A ZmOST1-interactive polypeptide ZmKS (gene locus tag: GRMZM2G114873), showing homology with the Arabidopsis thaliana basic helix-loop helix (bHLH) DNA-binding transcription factor was identified. Using a comparative genomic approach, the ZmKS corresponding protein was identified as conceptual translated bHLH transcription factor ABA-responsive kinase substrate. ZmKS is localized in the nucleus, shows a potential binding specificity preferentially detectable on cis-acting E-box like heptameric motifs CCACTTG and CAAGTTG, and is phosphorylated by maize protein kinase ZmOST1. ZmKS is expressed in embryo, leaf and root, expression being affected by ABA and osmotic stress. Transgenic Arabidopsis plants, with gain of ZmKS function, show a delay in germination and a transcriptional stomatal opening-facilitator activity, switchover upon ZmKS phosphorylation, suggesting that ZmKS is an ABA-repressed trans-acting activator. PMID- 27968979 TI - Death of embryos from 2300-year-old quinoa seeds found in an archaeological site. AB - In the 1970s, during excavations at Los Morrillos, San Juan, Argentina, quinoa seeds were found within ancient pumpkin crocks protected from the light and high temperatures, and preserved in the very dry conditions of the region. The radiocarbon dates confirmed the age of these seeds at around 2300 years. Sectioning of some of these seeds showed reddish-brown embryos, different from the white embryos of recently harvested quinoa seeds. The ancient seeds did not germinate. The structure of the embryo cells was examined using light and transmission electron microscopy; proteins were analyzed by electrophoresis followed by Coomassie blue and periodic acid Schiff staining and fatty acids by gas chromatography. The state of nuclear DNA was investigated by TUNEL assay, DAPI staining, ladder agarose electrophoresis and flow cytometry. Results suggest that, although the embryo tissues contained very low water content, death occurred by a cell death program in which heterochromatin density was dramatically reduced, total DNA was degraded into small fragments of less than 500bp, and some proteins were modified by non-enzymatic glycation, generating Maillard products. Polyunsaturated fatty acids decreased and became fragmented, which could be attributable to the extensive oxidation of the most sensitive species (linolenic and linoleic acids) and associated with a collapse of lipid bodies. PMID- 27968980 TI - Characterization of the calcineurin B-Like (CBL) gene family in maize and functional analysis of ZmCBL9 under abscisic acid and abiotic stress treatments. AB - In plants, calcineurin B-like proteins (CBLs) play crucial roles in regulating calcium-signaling in response to various abiotic stresses by interacting with specific CBL-interacting protein kinases (CIPKs). However, the identities and functions of CBL gene family members in maize are largely unknown. Here, we identified from the maize genome 12 CBL genes. All 12 CBLs have conserved EF-hand domains, and half harbor myristoylation motifs. We further characterized the function of one CBL gene, ZmCBL9, which can be induced by salt, dehydration, glucose and abscisic acid (ABA) treatments. Overexpression of ZmCBL9 enhanced resistance or tolerance to ABA, glucose, salt and osmotic stress in Arabidopsis and complemented the hypersensitive phenotype of the Arabidopsis cbl9 mutant in response to ABA and abiotic stress. The ZmCBL9 gene negatively regulates the expression of genes in the ABA signaling, biosynthesis and catabolism pathways. Moreover, the ZmCBL9 protein is found to interact with eight maize CIPKs and these ZmCIPK genes were up-regulated by different stress treatments, including salt, dehydration, glucose, low potassium and ABA. These results suggest that ZmCBL9 may interact with various ZmCIPKs to regulate the abiotic stress and ABA response signaling in plants. PMID- 27968981 TI - SlTIR1 is involved in crosstalk of phytohormones, regulates auxin-induced root growth and stimulates stenospermocarpic fruit formation in tomato. AB - TIR1 and its homologs act as auxin receptors and play important roles in plant growth and development in Arabidopsis thaliana. An auxin receptor homolog Solanum lycopersicum TIR1 (SlTIR1) has been isolated from tomato cultivar Micro-Tom, and SlTIR1 over-expression results in parthenocarpic fruit formation. In this study, the promoter driving the beta-glucuronidase (GUS) expression vector was constructed and stably transformed into Micro-Tom seedlings. The SlTIR1 promoter driving GUS expression accumulated predominantly in the leaf and vasculature in transgenic seedlings. Promoter analysis identified an auxin-response element (AuxRE) and two gibberellic acid (GA)-response elements in the SlTIR1 promoter. Quantitative PCR showed that SlTIR1 transcript level was down-regulated by naphthaleneacetic acid, ethephon and abscisic acid and up-regulated by GA. Furthermore, because of the lack of ability to form reproductive seeds in SlTIR1 over-expressing Micro-Tom, this limits further exploration of potential roles of SlTIR1 in auxin signaling. Here, an antisense vector and an over-expression vector of the SlTIR1 gene were stably transformed into Micro-Tom and Ailsa Craig tomato, respectively. Phenotypes and physiological analyses indicated that SlTIR1 regulated primary root growth and auxin-associated lateral root formation in Micro-Tom. Meanwhile, SlTIR1 also stimulated abnormal seed development, so-called stenospermocarpy, in Ailsa Craig. Transcript accumulations of auxin-signaling genes determined by quantitative PCR were consistent with the idea that SlTIR1 regulated plant growth and development, partially mediated by controlling the mRNA levels of auxin-signaling genes. Our work demonstrates that SlTIR1 regulated auxin-induced root growth and stimulated stenospermocarpic fruit formation. SlTIR1 may be a key mediator of the crosstalk among auxin and other hormones to co-regulate plant growth and development. PMID- 27968982 TI - Microbial homoserine lactones (AHLs) are effectors of root morphological changes in barley. AB - While colonizing the rhizosphere, bacterial intra- and inter-specific communication is accomplished by N-Acyl-homoserine-lactones (AHLs) in a density dependent manner. Moreover, plants are naturally exposed to AHLs and respond with tissue-specificity. In the present study, we investigated the influence of N hexanoyl- (C6-HSL), N-octanoyl- (C8-HSL) and N-dodecanoyl-d/l-homoserine lactone (C12-HSL) on growth and root development in barley (Hordeum vulgare L.), and identified initial reactions in root cells after AHL exposures using physiological, staining, and electrophysiological methods. Treatment with short- and long-chain AHLs modulated plant growth and branched root architecture and induced nitric oxide (NO) accumulation in the calyptra and root elongation zone of excised roots in an AHL derivative-independent way. Additionally, C6- and C8 HSL treatments stimulated K+ uptake in root cells only at certain concentrations, whereas all tested concentrations of C12-HSL induced K+ uptake. In further experiments, C8-HSL promoted membrane hyperpolarization in epidermal root cells. Thus, we conclude AHLs promote plant growth and lateral root formation, and cause NO accumulation as an early response to AHLs. Furthermore, the AHL-mediated membrane hyperpolarization is leading to increased K+ uptake of the root tissue. PMID- 27968984 TI - Gene expression and physiological responses associated to stomatal functioning in Rosa*hybrida grown at high relative air humidity. AB - High relative air humidity (RH>=85%) during growth disturbs stomatal functioning, resulting in excessive water loss in conditions of high evaporative demand. We investigated the expression of nine abscisic acid (ABA)-related genes (involved in ABA biosynthesis, oxidation and conjugation) and two non-ABA related genes (involved in the water stress response) aiming to better understand the mechanisms underlying contrasting stomatal functioning in plants grown at high RH. Four rose genotypes with contrasting sensitivity to high RH (one sensitive, one tolerant and two intermediate) were grown at moderate (62+/-3%) or high (89+/ 4%) RH. The sensitive genotype grown at high RH showed a significantly higher stomatal conductance (gs) and water loss in response to closing stimuli as compared to the other genotypes. Moreover, high RH reduced the leaf ABA concentration and its metabolites to a greater extent in the sensitive genotype as compared to the tolerant one. The large majority of the studied genes had a relevant role on stomatal functioning (NCED1, UGT75B2, BG2, OST1, ABF3 and Rh APX) while two others showed a minor contribution (CYP707A3 and BG1) and AAO3, CYP707A1 and DREB1B did not contribute to the tolerance trait. These results show that multiple genes form a highly complex regulatory network acting together towards the genotypic tolerance to high RH. PMID- 27968983 TI - APRF1 promotes flowering under long days in Arabidopsis thaliana. AB - Arabidopsis thaliana flowering time mutants revealed the function of numerous genes that regulate the transition from vegetative to reproductive growth. Analyses of their loci have shown that many of them act as chromatin modifiers. In this study, a combination of molecular and genetic approaches have been implemented, to characterize the function of APRF1 (ANTHESIS POMOTING FACTOR 1) gene in A. thaliana and to investigate its role in plant development. APRF1 encodes for a low molecular weight nuclear WDR protein which displays functional homology to the Swd2 protein, an essential subunit of the yeast histone methylation COMPASS complex. Compared to WT plants, total loss-of-function aprf1 mutants exhibited shoot apical meristem (SAM) alterations and increased growth rates. However, the vegetative phase of aprf1 plants was prolonged and bolting was delayed, indicating an impairment in flowering under long days (LD). On the contrary, overexpression of APRF1 accelerates flowering. Consistent with the late flowering phenotype, the molecular data confirmed that FLC and SOC1 expression were significantly altered in the aprf1 mutants. Our data suggest that APRF1 acts upstream of FLC and promotes flowering under LD. PMID- 27968985 TI - F-box genes: Genome-wide expansion, evolution and their contribution to pollen growth in pear (Pyrus bretschneideri). AB - F-box gene family, as one of the largest gene families in plants, plays crucial roles in regulating plant development, reproduction, cellular protein degradation and responses to biotic and abiotic stresses. However, comprehensive analysis of the F-box gene family in pear (Pyrus bretschneideri Rehd.) and other Rosaceae species has not been reported yet. Herein, we identified a total of 226 full length F-box genes in pear for the first time. And these genes were further divided into various subgroups based on specific domains and phylogenetic analysis. Intriguingly, we observed that whole-genome duplication and dispersed duplication have a major contribution to F-box family expansion. Furthermore, the dynamic evolution for different modes of gene duplication was dissected. Interestingly, we found that dispersed and tandem duplicate have been evolving at a high rate. In addition, we found that F-box genes exhibited functional specificity based on GO analysis, and most of the F-box genes were significantly enriched in the protein binding (GO: 0005515) term, supporting that F-box genes might play a critical role for gene regulation in pear. Transcriptome and digital expression profiles revealed that F-box genes are involved in the development of multiple pear tissues. Overall, these results will set stage for elaborating the biological role of F-box genes in pear and other plants. PMID- 27968986 TI - Hyperactive mutant of a wheat plasma membrane Na+/H+ antiporter improves the growth and salt tolerance of transgenic tobacco. AB - Wheat SOS1 (TaSOS1) activity could be relieved upon deletion of the C-terminal 168 residues (the auto-inhibitory domain). This truncated form of wheat SOS1 (TaSOS1-974) was shown to increase compensation (compared to wild-type TaSOS1) for the salt sensitivity of a yeast mutant strain, AXT3K, via increased Na+ transportation out of cells during salinity stress. Expression of the plasma membrane proteins TaSOS1-974 or TaSOS1 improved the growth of transgenic tobacco plants compared with wild-type plants under normal conditions. However, plants expressing TaSOS1-974 grew better than TaSOS1-transformed plants. Upon salinity stress, Na+ efflux and K+ influx rates in the roots of transgenic plants expressing TaSOS1-974 or TaSOS1 were greater than those of wild-type plants. Furthermore, compared to TaSOS1-transgenic plants, TaSOS1-974-expressing roots showed faster Na+ efflux and K+ influx, resulting in less Na+ and more K+ accumulation in TaSOS1-974-transgenic plants compared to TaSOS1-transgenic and wild-type plants. TaSOS1-974-expressing plants had the lowest MDA content and electrolyte leakage among all tested plants, indicating that TaSOS1-974 might protect the plasma membrane against oxidative damage generated by salt stress. Overall, TaSOS1-974 conferred higher salt tolerance in transgenic plants compared to TaSOS1. Consistent with this result, transgenic plants expressing TaSOS1-974 showed a better growth performance than TaSOS1-expressing and wild-type plants under saline conditions. PMID- 27968987 TI - Leaf epinasty and auxin: A biochemical and molecular overview. AB - Leaf epinasty involves the downward bending of leaves as a result of disturbances in their growth, with a greater expansion in adaxial cells as compared to abaxial surface cells. The co-ordinated anisotropy of growth in epidermal, palisade mesophyll and vascular tissues contributes to epinasty. This phenotype, which is regulated by auxin (indole-3-acetic acid, IAA), controls plant cell division and elongation by regulating the expression of a vast number of genes. Other plant hormones, such as ethylene, abscisic acid and brassinosteroids, also regulate epinasty and hyponasty. Reactive oxygen species (ROS) accumulation induced by auxins and 2,4-dichlorophenoxyacetic acid (2,4-D) triggers epinasty. The role of ROS and nitric oxide (NO) in the regulation of epinasty has recently been established. Thus, treatment with synthetic auxin 2,4-dichlorophenoxyacetic acid (2,4-D) induces disturbances in the actin cytoskeleton through ROS and NO dependent post-translational modifications in actin by carbonylation and S nitrosylation, which cause a reduction in the actin filament. Reorientation of microtubules has become a major feature of the response to auxin. The cytoskeleton is therefore a key player in epinastic development. PMID- 27968988 TI - Spatial genetic structure in wild cardoon, the ancestor of cultivated globe artichoke: Limited gene flow, fragmentation and population history. AB - Nuclear and chloroplast markers and phenotypic characters were integrated to analyse the population genetic structure of wild cardoon, Cynara cardunculus var. sylvestris, the ancestor of cultivated globe artichoke, Cynara cardunculus var. scolymus on the island of Sardinia, Italy. The spatial scale ranged from a few metres to ~200km. Wild cardoon appears to be genetically fragmented, with significant genetic divergence at various scales, indicating that gene flow is insufficient to counterbalance the effects of genetic drift or founder effects. Divergence between populations was higher for chloroplast (40%) than for nuclear markers (15%), suggesting that gene flow via seed was lower than via pollen. Two main genetic groups were detected; these correlated with differences in flowering time, capitula size, glossiness, and anthocyanin pigmentation. A complex population structure of wild cardoon emerged over small spatial scales, likely resulting from the interplay between gene dispersal, colonisation history and selective forces. Indeed, Sardinia appears to be a 'hybrid zone' of different gene pools. The island has unique diverse germplasm that has originated from hybridisation among different gene pools. The sampling of seeds from a few plants but from many sites is suggested as the best strategy to harvest the genetic diversity of wild cardoon. PMID- 27968989 TI - The cell wall DUF642 At2g41800 (TEB) protein is involved in hypocotyl cell elongation. AB - In plants, the cell wall is a complex and dynamic structure comprising high molecular weight carbohydrates and proteins. The cell wall plays an important role in several stages of the plant life cycle, including cell division, elongation and differentiation. The DUF642 family of cell wall proteins is highly conserved in spermatophytes and might be involved in pectin structural modifications. Particularly, At2g41800 is one of the most highly induced genes during the M/G1 phases of the cell cycle, and the protein encodes by this gene has been detected in cell wall proteomes of cell suspension cultures. In the present study, the expression of At2g41800 (TEB) was confirmed in primary and lateral roots, stigmatic papillae and hypocotyls. Subcellular localization studies showed that TEB is located in the cell wall. The root length and lateral root density were not affected in either of the two teb mutants studied, but the length of the hypocotyls from seedlings grown under light and dark conditions was increased. Immunogold labelling studies using JIM5 antibodies on sections of hypocotyl epidermal cells showed an important reduction of gold particles in teb mutants. The results suggested that TEB is involved in hypocotyl elongation. PMID- 27968990 TI - An ABC transporter, OsABCG26, is required for anther cuticle and pollen exine formation and pollen-pistil interactions in rice. AB - Wax, cutin and sporopollenin are essential components for the formation of the anther cuticle and the pollen exine, respectively. Their lipid precursors are synthesized by secretory tapetal cells and transported to the anther and microspore surface for deposition. However, the molecular mechanisms involved in the formation of the anther cuticle and pollen exine are poorly understood in rice. Here, we characterized a rice male sterile mutant osabcg26. Molecular cloning and sequence analysis revealed a point mutation in the gene encoding an ATP binding cassette transporter G26 (OsABCG26). OsABCG26 was specifically expressed in the anther and pistil. Cytological analysis revealed defects in tapetal cells, lipidic Ubisch bodies, pollen exine, and anther cuticle in the osabcg26 mutant. Expression of some key genes involved in lipid metabolism and transport, such as UDT1, WDA1, CYP704B2, OsABCG15, OsC4 and OsC6, was significantly altered in osabcg26 anther, possibly due to a disturbance in the homeostasis of anther lipid metabolism and transport. Additionally, wild-type pollen tubes showed a growth defect in osabcg26 pistils, leading to low seed setting in osabcg26 cross-pollinated with the wild-type pollen. These results indicated that OsABCG26 plays an important role in anther cuticle and pollen exine formation and pollen-pistil interactions in rice. PMID- 27968991 TI - WSA206, a paralog of duplicated MPF2-like MADS-box family is recruited in fertility function in Withania. AB - Best known for their implication in calyx inflation, MPF2-like genes pertinent to the STMADS11 clade of the MADS-box family exert their functions in leaf development, flowering time, inflorescence architecture and floral reversion to just name but a few. However, our knowledge about their involvement in fertility function remained obscure. Therefore the major thrust of this study was to probe the recruitment of WSA206 (MPF2-like) protein in fertility function. The WSA206 functions were revealed by knocking down and overexpressing this protein in Withania somnifera. The WSA206 promoter functions were defined by stable integration in Arabidopsis using GUS tag. The interactions of WSA206 were investigated by screening Arabidopsis Oligo-dT yeast library and YFP-split analysis. WSA206 knockdown plants revealed fewer flowers, abortion in seed set, reduction in pollen number and deformed non-viable pollen in comparison with wild type counterparts. Overexpression of WSA206 in Withania generated more berries/seeds and healthier viable pollen grains. Remarkably, along with fertility control, the impairment in calyx inflation in knockdown Withania plants and extraordinary growth of sepals in overexpression lines is observed. Thus, fertility and calyx inflation are tightly coupled traits under the control of WSA206. Coding sequence revealed SNP mutations from arginine to lysine as well as a leucine-rich motif duplication at the C-terminus, a characteristic feature of pollen specific and fertility function proteins. The protein-protein interaction spectrum of WSA206 comprises 40% of those MADS and non-MADS-box proteins implicated in floral/anther expression and embryogenesis. Predominant WSA206 promoter:GUS expression accrued in the anthers/pollen may be attributed to of the presence of GAAATTGTTA pollen specific proximal motifs along with several other anther specific homotypic cis-clusters. MPF2-like protein WSA206 through interactions with MADS-box and non-MADS-domain proteins confers male fertility in Withania regulated by anther/pollen specific promoter motif GAAATTGTTA. PMID- 27968992 TI - Evidence for a non-overlapping subcellular localization of the family I isoforms of soluble inorganic pyrophosphatase in Arabidopsis thaliana. AB - Pyrophosphate is a byproduct of macromolecular biosynthesis and its degradation gives a thermodynamic impulse to cell growth. Soluble inorganic pyrophosphatases (PPa) are present in all living cells, but in plants and other Eukaryotes membrane-bound H+-pumping pyrophosphatases may compete with these soluble counterparts for the substrate. In Arabidopsis thaliana there are six genes encoding for classic family I PPa isoforms, five cytoplasmic, and one considered to be organellar. Here, six transgenic stable A. thaliana lines, each expressing one of the PPa isoforms from this same plant species in fusion with a fluorescent protein, were obtained and analyzed under confocal and immunogold transmission electron microscopy. The results confirmed the cytoplasmic localization for isoforms 1-5, and showed an exclusive chloroplastic localization for isoform 6. In contrast to previous reports, the data presented here revealed a differential distribution pattern for the isoforms 1 and 5, in comparison to isoforms 2 and 3, and also the presence of isoform 4 in the intercellular space and cell wall, in addition to its presence in cytoplasm. To the best of our knowledge, this is the first report of a PPa family I protein localized in the intercellular space in plants. PMID- 27968993 TI - Elevated O3 increases volatile organic compounds via jasmonic acid pathway that promote the preference of parasitoid Encarsia formosa for tomato plants. AB - The elevated atmospheric O3 level may change the interactions of plants and insects, which potentially affects direct and indirect plant defences. However, the underlying mechanism of the impact of elevated O3 on indirect plant defence, namely the efficacy of natural enemies, is unclear. Here we tested a hypothesis that linked the effects of elevated O3 and whitefly herbivory on tomato volatile releases mediated by the jasmonic acid (JA) pathway with the preferences of parasitoid Encarsia formosa for two different tomato genotypes (wild-type (Wt) and JA-deficient genotype (spr2)). The O3 and whitefly herbivory significantly increased the production of volatile organic compounds (VOCs), including monoterpenes and green leaf volatiles (GLVs). The Wt plants released higher volatile levels, particularly monoterpenes, than did the spr2 plants. In Y-tube tests, limonene and Z-3-hexanol played key roles in the attraction of E. formosa. Moreover, regardless of plant genotype, the two plant genotypes were preferred by adult E. formosa under the O3 and O3+ herbivory treatments. Our results suggest that under elevated O3, the activation of the JA pathway significantly up regulates the emission rates of volatiles, through which the efficacy of natural enemy might be promoted. PMID- 27968994 TI - Knocking down expression of the auxin-amidohydrolase IAR3 alters defense responses in Solanaceae family plants. AB - In plants, indole-3-acetic acid (IAA) amido hydrolases (AHs) participate in auxin homeostasis by releasing free IAA from IAA-amino acid conjugates. We investigated the role of IAR3, a member of the IAA amido hydrolase family, in the response of Solanaceous plants challenged by biotrophic and hemi-biotrophic pathogens. By means of genome inspection and phylogenic analysis we firstly identified IAA-AH sequences and putative IAR3 orthologs in Nicotiana benthamiana, tomato and potato. We evaluated the involvement of IAR3 genes in defense responses by using virus-induced gene silencing. We observed that N. benthamiana and tomato plants with knocked-down expression of IAR3 genes contained lower levels of free IAA and presented altered responses to pathogen attack, including enhanced basal defenses and higher tolerance to infection in susceptible plants. We showed that IAR3 genes are consistently up-regulated in N. benthamiana and tomato upon inoculation with Phytophthora infestans and Cladosporium fulvum respectively. However, IAR3 expression decreased significantly when hypersensitive response was triggered in transgenic tomato plants coexpressing the Cf-4 resistance gene and the avirulence factor Avr4. Altogether, our results indicate that changes in IAR3 expression lead to alteration in auxin homeostasis that ultimately affects plant defense responses. PMID- 27968995 TI - A reduction of sucrose phosphate synthase (SPS) activity affects sucrose/starch ratio in leaves but does not inhibit normal plant growth in rice. AB - Sucrose phosphate synthase (SPS) has been shown to mediate sucrose/starch ratio in plant leaves through studies of 'starch leaf' species that mainly accumulate starch in their leaves. However, the contribution of SPS to sucrose/starch ratio in rice leaves, which mainly accumulate sucrose (i.e., 'sugar leaf'), has not been confirmed due to inconsistencies in the results of previous studies. In this study, we analyzed mutant lines with reduced SPS activity, which were generated using Tos17 insertion, RNAi, and the CRISPR/Cas9 system. The knockdown and knockout mutants of OsSPS1 showed a 29-46% reduction in SPS activity in the leaves, but the carbohydrate content in the leaves and plant growth were not significantly different from those of wild-type plants. In a double knockout mutant of OsSPS1 and OsSPS11 (sps1/sps11), an 84% reduction in leaf SPS activity resulted in higher starch accumulation in the leaves than in the wild-type leaves. However, the sps1/sps11 plants grew normally, which is in contrast to the inhibited growth of SPS mutants of Arabidopsis thaliana, a typical starch leaf plant. These results suggest that SPS has a smaller effect on the sucrose/starch ratio in leaves and growth of rice than on starch leaf species. PMID- 27968996 TI - EIN3 interferes with the sulfur deficiency signaling in Arabidopsis thaliana through direct interaction with the SLIM1 transcription factor. AB - Sulfur deficiency in plants leads to metabolic reprogramming through changes of gene expression. SLIM1 is so far the only characterized transcription factor associated strictly with sulfur deficiency stress in Arabidopsis thaliana. It belongs to the same protein family as EIN3, a major positive switch of ethylene signaling pathway. It binds to the specific cis sequence called UPE-box. Here we show that SLIM1 interacts with UPE-box as a homodimer. Interestingly, the same region of the protein is used for heterodimerization with EIN3; however, the heterodimer is not able to recognize UPE-box. Expression of several SLIM1 dependent genes is enhanced in sulfur deficiency grown Arabidopsis ein3-1 seedlings (with mutated EIN3 protein). This implies a possible regulatory mechanism of ethylene in sulfur metabolism through direct EIN3-SLIM1 interaction. PMID- 27968997 TI - Review: An integrated framework for crop adaptation to dry environments: Responses to transient and terminal drought. AB - As the incidence of water deficit and heat stress increases in many production regions there is an increasing requirement for crops adapted to these stresses. Thus it is essential to match water supply and demand, particularly during grain filling. Here we integrate Grime's ecological strategies approach with traditional drought resistance/yield component frameworks describing plant responses to water deficit. We demonstrate that water use is a function of both short and longer term trade-offs between competing demands for carbon. Agricultural crop adaptation is based on escape. Rapid growth rates and high reproductive investment maximize yield, and stress is avoided through a closely regulated, climate-appropriate annual phenology. Crops have neither the resources nor morphological capacity to withstand long periods of intense water deficit. Thus, under terminal drought, yield potential is traded off against drought escape, such that drought postponing and/or tolerance traits which extend the growing season and/or divert source from reproductive sinks are maladaptive. However, these traits do play a supporting role against transient water deficits, allowing longer season cultivars to survive by mining water through deeper roots, or restricting transpiration. Recognizing these trade-offs made within escape strategy limits will allow breeders to integrate complementary adaptive traits to transient and terminal water deficits. PMID- 27968998 TI - The arbuscular mycorrhizal fungus Rhizophagus irregularis differentially regulates the copper response of two maize cultivars differing in copper tolerance. AB - Arbuscular mycorrhiza can increase plant tolerance to heavy metals. The effects of arbuscular mycorrhiza on plant metal tolerance vary depending on the fungal and plant species involved. Here, we report the effect of the arbuscular mycorrhizal fungus Rhizophagus irregularis on the physiological and biochemical responses to Cu of two maize genotypes differing in Cu tolerance, the Cu sensitive cv. Orense and the Cu-tolerant cv. Oropesa. Development of the symbiosis confers an increased Cu tolerance to cv. Orense. Root and shoot Cu concentrations were lower in mycorrhizal than in non-mycorrhizal plants of both cultivars. Shoot lipid peroxidation increased with soil Cu content only in non mycorrhizal plants of the Cu-sensitive cultivar. Root lipid peroxidation increased with soil Cu content, except in mycorrhizal plants grown at 250mg Cu kg 1soil. In shoots of mycorrhizal plants of both cultivars, superoxide dismutase, ascorbate peroxidase, catalase and glutathione reductase activities were not affected by soil Cu content. In Cu-supplemented soils, total phytochelatin content increased in shoots of mycorrhizal cv. Orense but decreased in cv. Oropesa. Overall, these data suggest that the increased Cu tolerance of mycorrhizal plants of cv. Orense could be due to an increased induction of shoot phytochelatin biosynthesis by the symbiosis in this cultivar. PMID- 27968999 TI - Nuclear dynamics and programmed cell death in Arabidopsis root hairs. AB - In this paper we demonstrate the coupling of nuclear migration to the base of Arabidopsis root hairs with programmed cell death (PCD). Nuclear migration and positioning are fundamental processes of eukaryotic cells. To date, no evidence for a direct connection between nucleus migration and PCD has been described in the literature. Based on the findings of our previous study, we hereby further establish the regulatory role of caspase-3-like/DEVDase in root hair death and demonstrate nuclear migration to a position close to the root hair basement during PCD. In addition, continuous observation and statistical analysis have revealed that the nucleus disengages from the root hair tip and moves back to the root after the root hair grows to a certain length. Finally, pharmacological studies have shown that the meshwork of actin filaments surrounding the nucleus plays a pivotal role in nuclear movement during root hair PCD, and the basipetal movement of the nucleus is markedly inhibited by the caspase-3 inhibitor, Ac-DEVD CHO. PMID- 27969000 TI - Transcript and hormone analyses reveal the involvement of ABA-signalling, hormone crosstalk and genotype-specific biological processes in cold-shock response in wheat. AB - The effect of one-day cold-shock on the transcriptome and phytohormones (auxin, cytokinins, abscisic, jasmonic and salicylic acids) was characterised in freezing sensitive (Chinese Spring), highly freezing-tolerant (Cheyenne) and moderately freezing-tolerant (Chinese Spring substituted with Cheyenne's 5A chromosome) wheat genotypes. Altogether, 636 differentially expressed genes responding to cold-shock were identified. Defence genes encoding LEA proteins, dehydrins, chaperons and other temperature-stress responsive proteins were up-regulated in a genotype-independent manner. Abscisic acid was up-regulated by cold accompanied by adherent expression of its metabolic genes. Data revealed the involvement of particular routes within ABA-dependent signalling in response to cold-shock in the examined genotypes. Cold-shock affected gene expression along carbohydrate metabolic pathways. In photosynthesis, cold-shock changed the expression of a number of genes in the same way as it was previously reported for ABA. Overrepresentation analysis of the differentially expressed genes supported the ABA-signalling and carbohydrate metabolism results, and revealed some pronounced biological process GO categories associated with the cold-shock response of the genotypes. Protein network analysis indicated differences between the genotypes in the information flow along their signal perception and transduction, suggesting different biochemical and cellular strategies in their reaction to cold-shock. PMID- 27969001 TI - Glutathione and abscisic acid supplementation influences somatic embryo maturation and hormone endogenous levels during somatic embryogenesis in Podocarpus lambertii Klotzsch ex Endl. AB - Here we propose a protocol for embryogenic cultures induction, proliferation and maturation for the Brazilian conifer Podocarpus lambertii, and investigated the effect of abscisic acid (ABA) and glutathione (GSH) supplementation on the maturation phase. ABA, zeatin (Z) and salicylic acid (SA) endogenous levels were quantified. Number of somatic embryos obtained in ABA-supplemented treatment was significant higher than in ABA-free treatment, showing the relevance of ABA supplementation during somatic embryos maturation. Histological analysis showed the stereotyped sequence of developmental stages in conifer somatic embryos, reaching the late torpedo-staged embryo. GSH supplementation in maturation culture medium improved the somatic embryos number and morphological features. GSH 0mM and GSH 0.1mM treatments correlated with a decreased ABA endogenous level during maturation, while GSH 0.5mM treatment showed constant levels. All treatments resulted in decreased Z endogenous levels, supporting the concept that cytokinins are important during the initial cell division but not for the later stages of embryo development. The lowest SA levels found in GSH 0.5mM treatment were coincident with early embryonic development, and this treatment resulted in the highest development of somatic embryos. Thus, a correlation between lower SA levels and improved somatic embryo formation can be hypothesized. PMID- 27969003 TI - Parents in prevention: A meta-analysis of randomized controlled trials of parenting interventions to prevent internalizing problems in children from birth to age 18. AB - PURPOSE OF THE RESEARCH: Burgeoning evidence that modifiable parental factors can influence children's and adolescents' risk for depression and anxiety indicates that parents can play a crucial role in prevention of these disorders in their children. However, it remains unclear whether preventive interventions that are directed primarily at the parent (i.e. where the parent receives more than half of the intervention) are effective in reducing child internalizing (including both depression and anxiety) problems in the longer term. PRINCIPAL RESULTS: Compared to a range of comparison conditions, parenting interventions reduced child internalizing problems, at a minimum of 6months after the intervention was delivered. Mean effects were very small for measures of internalizing and depressive symptoms, and small for measures of anxiety symptoms. Pooled effects for anxiety diagnoses were significant and indicated a number needed to treat (NNT) of 10. Pooled effects for depression diagnoses approached significance but suggested a NNT of 11. These results were based on effects reported at the longest follow-up interval for each included study, which ranged from 6months up to 15years for internalizing measures, 5.5years for depressive measures, and 11years for anxiety measures. MAJOR CONCLUSIONS: Our findings underscore the likely benefits of increasing parental involvement in preventing internalizing problems, particularly anxiety problems, in young people. PMID- 27969002 TI - Smoking cessation programs for persons with schizophrenia: An urgent unmet need. PMID- 27969005 TI - Preface. PMID- 27969006 TI - Approaching 30 Incredible Years as Editor-in-Chief. PMID- 27969007 TI - Getting Your Research Published. PMID- 27969008 TI - Impact of a Pediatric and Adolescent Gynecology Curriculum on an Obstetrics and Gynecology Residency. AB - STUDY OBJECTIVE: To determine the effectiveness of a new pediatric and adolescent gynecology (PAG) curriculum for improving obstetrics/gynecology resident physician knowledge and comfort level in patient management and to describe the current deficiencies in resident physician knowledge and comfort level in PAG. DESIGN: A PAG curriculum was implemented for the obstetrics/gynecology resident physicians (n = 20) at the University of South Florida in July 2013. Before and after the curriculum was introduced, resident physicians and recent graduates of the residency program completed a survey to assess their comfort level and a knowledge assessment consisting of 20 case-based questions. SETTING: University based residency program. PARTICIPANTS: Resident physicians and recent resident physician graduates in the Department of Obstetrics and Gynecology. INTERVENTIONS: Introduction of a PAG curriculum during the 2013-2014 academic year. MAIN OUTCOME MEASURES: Improvement in resident physicians' comfort level and knowledge in PAG. RESULTS: After the curriculum was introduced, comfort increased in examining the genitals of a pediatric gynecology patient (median difference = 1.5; P = .003) and history-taking, physical examination skills, and management (median difference = 1; P = .002) compared with before the curriculum. There was no significant difference in overall quiz score (15.5 +/- 1.87 vs 15.8 +/- 1.3; P = .78). CONCLUSION: A curriculum in PAG did improve resident comfort level in managing PAG patients, but did not significantly improve knowledge of this topic. PMID- 27969009 TI - Clinical Recommendation: Vulvovaginitis. AB - Vulvovaginitis is a commonly encountered condition among prepubertal and adolescent females. The objective of this report is to provide the latest evidence regarding the diagnosis and management of vulvovaginitis in prepubertal and adolescent females. In this systematic review we used the Grading of Recommendations Assessment, Development and Evaluation evidence system. Vulvovaginal complaints are common in the pediatric and adolescent age group. The patient's age in conjunction with history and associated complaints will guide evaluation, diagnosis, and treatment. Treatment should include counseling on hygiene and voiding techniques as well as therapy for any specific pathogens identified. PMID- 27969004 TI - Sleep disturbances in adolescents with ADHD: A systematic review and framework for future research. AB - BACKGROUND: Biological mechanisms underlying symptom and prognostic heterogeneity in Attention-Deficit/Hyperactivity Disorder (ADHD) are unclear. Sleep impacts neurocognition and daytime functioning and is disrupted in ADHD, yet little is known about sleep in ADHD during adolescence, a period characterized by alterations in sleep, brain structure, and environmental demands as well as diverging ADHD trajectories. METHODS: A systematic review identified studies published prior to August 2016 assessing sleep in adolescents (aged 10-19years) with ADHD or participating in population-based studies measuring ADHD symptoms. RESULTS: Twenty-five studies were identified (19 subjective report, 6 using actigraphy/polysomnography). Findings are mixed but overall suggest associations between sleep disturbances and 1) ADHD symptoms in the population and 2) poorer clinical, neurocognitive, and functional outcomes among adolescents with ADHD. Common limitations of studies included small or non-representative samples, non standardized sleep measures, and cross-sectional methodology. CONCLUSIONS: Current data on sleep in adolescent ADHD are sparse and limited by methodological concerns. Future studies are critical for clarifying a potential role of sleep in contributing to heterogeneity of ADHD presentation and prognosis. Potential mechanisms by which sleep disturbances during adolescence may contribute to worsened symptom severity and persistence of ADHD into adulthood and an agenda to guide future research are discussed. PMID- 27969010 TI - Risk of type 2 diabetes: health care provider perceptions of prevention adherence. AB - The aim of the current study was to describe health care providers' perceptions as to why individuals may or may not follow recommendations for reducing risk of developing type 2 diabetes. A grounded theory research design guided data collection and analysis. Data were collected from 16 health care providers through semi-structured interviews. Results demonstrated that health care providers perceived prevention adherence as related to individual characteristics of the patient and activities of the provider. Specifically, providers described assessment of patient-based characteristics associated with behavior, context, and traits. In addition, providers discussed giving attention to the patient provider relationship and helping the patient incorporate small lifestyle changes. Providers might utilize social cognitive theory to understand personal and socio-structural aspects of adherence. In addition, providers should focus assessment and relationship building efforts on factors that support self efficacy. PMID- 27969011 TI - Comparing the effects of music and exercise with music for older adults with insomnia. AB - AIM: To examine the effects of a soothing music intervention before bedtime and a treadmill brisk walking exercise combined with music in the evening on sleep quality of sedentary older adults with chronic insomnia. BACKGROUND: There is evidence to support the use of complementary interventions to improve sleep. They are rarely applied in Taiwanese elderly population. METHODS: Using a crossover controlled trial, 38 participants aged 50 to 75 years were randomly assigned to a music intervention/brisk walking sequence or a brisk walking/music intervention sequence. Each participant completed two intervention sessions (separated by 1 week). Each intervention lasted 30 min. An actigraph extended with electroencephalography (EEG) and questionnaires were used to assess the sleep quality. RESULTS: Both interventions exhibited beneficial effects on subjective sleep quality in adults with insomnia. Also listening to soothing music before bedtime significantly shortened the wake time after sleep onset measured by EEG, compared with brisk walking in the evening. CONCLUSIONS: The interventions applied in this study could be applied as the evidence-based nursing interventions for insomnia older adults. PMID- 27969013 TI - Nurses' perceptions of their knowledge and barriers to ambulating hospitalized patients in acute settings. AB - PURPOSE: The purpose of this study was to understand nurses' knowledge and perceptions of the importance of patient ambulation in acute care hospital settings. The data obtained from this survey will be used to create improvement initiatives that address patient ambulation. METHOD: An exploratory, cross sectional study using a self-administered survey was conducted in two different hospital sites, and was completed by 192 nurses. A modified version of the validated and reliable tool entitled "Missed Nursing Care Survey" was used. Multivariate regressions were used to determine the relationship of demographic and workplace variables to nurses' knowledge and perceptions regarding acute adult-inpatient ambulation. RESULTS: The primary factors interfering with ambulating patients were inadequate number of staff (both clerical and nursing), urgent patient situations, and unexpected rises in patient volume and/or acuity on the unit. Small associations were found between knowledge of ambulation and years of experience, and shift worked. CONCLUSION: Study findings add to the body of knowledge by providing insight into what variables influence urban nurses' knowledge and perceptions of barriers faced when ambulating acute adult inpatients in acute hospitalized settings. The study results can be used to develop strategies and improvement initiatives that address acute adult-inpatient ambulation in acute settings and address the perceived barriers to this process. The ultimate goal is to improve the quality of care delivered, improve patient outcomes, and promote patient well-being. Implication for nursing practice, research and education will be discussed. PMID- 27969012 TI - Examining the factor structure of MUIS-C scale among baby boomers with hepatitis C. AB - BACKGROUND: Baby boomers account for two out of every three cases of hepatitis C infection in the U.S. PURPOSE: To conduct an exploratory factor analysis directed at supporting the use of the MUIS-C as a reliable instrument in measuring illness uncertainty among baby boomers with hepatitis C. METHODS: The steps of conducting a typical principal component analysis (PCA) with an oblique rotation were used on a sample of 146 participants, the sampling adequacy of items was examined via the Kaiser-Meyer-Olkin (KMO) measure, and the Bartlett's sphericity test was used for appropriateness of conducting a factor analysis. RESULTS: A two-factor structure was obtained by using Horn's parallel analysis method. The two factors explained a cumulative total of 45.8% of the variance. CONCLUSIONS: The results of the analyses indicated that the MUIS-C was a valid and reliable instrument and potentially suitable for use in baby boomer population diagnosed with hepatitis C. PMID- 27969015 TI - Medical surgical nurses describe missed nursing care tasks-Evaluating our work environment. AB - PURPOSE: The purpose of the study was to explore the nurse work environment by evaluating the self-report of missed nursing care and the reasons for the missed care. METHODS: A convenience sample of medical surgical nurses from four hospitals was invited to complete the survey for this descriptive study. The sample included 168 nurses. The MISSCARE survey assessed the frequency and reason of 24 routine nursing care elements. RESULTS: The most frequently reported missed care was ambulation as ordered, medications given within a 30 minute window, and mouth care. Moderate or significant reasons reported for the missed care were: unexpected rise in volume/acuity, heavy admissions/discharges, inadequate assistants, inadequate staff, meds not available when needed, and urgent situations. CONCLUSION: Identifying missed nursing care and reasons for missed care provides an opportunity for exploring strategies to reduce interruptions, develop unit cohesiveness, improve the nurse work environment, and ultimately leading to improved patient outcomes. PMID- 27969014 TI - Developing a tool that explores factors influencing the adoption of evidence based principles in nursing practice in Jordan. AB - AIM: To measure the psychometric properties, reliability and validity of a tool that explores factors influencing the adoption of principles of evidence-based in nursing practice in Jordan. BACKGROUND: The use of principles of evidenced-based practice in nursing practice has been widely endorsed in many countries around the world; these principles have not yet been implemented in Jordan. Factors influencing the adoption of evidence-based practice in Jordanian nursing context were not identified to date. METHODS: A descriptive, cross-sectional research design approached experienced nurses from different specialties across Jordan (3 military, 3 governmental and 5 private hospitals). RESULTS: The psychometric properties indicated a valid and reliable tool. It consisted of three factors: personal characteristics; source of professional knowledge; and organizational environment. CONCLUSIONS: Findings provided evidence on the impact of the identified factors on nurses' adoption of evidence-based practice. Although tests in this report showed the validity of this new tool, it still requires further testing to ensure its stability over time. PMID- 27969016 TI - Ineffective breathing pattern in cardiac postoperative patients: Diagnostic accuracy study. AB - PURPOSE: The aim of this study was to analyze the accuracy of the defining characteristics of ineffective breathing pattern (IBP) in postoperative cardiac patients. METHODS: A diagnostic accuracy study was performed with 98 patients. Measures of sensitivity, specificity, predictive values, likelihood ratios, diagnostic odds ratio, and area under the ROC curve were calculated. RESULTS: IBP was present in 23.5% of the patients. Alterations in depth of breathing (sensitivity 96%, negative likelihood ratio 0.11%) and pursed-lip breathing (sensitivity 99%, negative likelihood ratio 0.07%) were the most sensitive defining characteristics for IBP, while altered chest excursion (specificity 97%, positive likelihood ratio 11.41%) and prolonged expiration phase (specificity 99%, positive likelihood ratio 42.39%) were the most specific. CONCLUSION: Some clinical indicators were more related to the presence or absence of IBP than others. Knowledge of such measures can help nurses to assess patients more accurately. PMID- 27969017 TI - Transition to parenthood during the transition to modernity in Jordan: New parents' views on family and healthcare support systems. AB - AIMS AND OBJECTIVES: This study aims to explore new parents' experiences of family support during their transition to parenthood. BACKGROUND: Family support is widely considered a crucial factor in contributing toward positive outcomes for parents during transition to parenthood. However, inter-generational and socio-cultural differences among family members in understandings and practices of childcare can be a source of tension between new parents and family members. Few studies have examined the role of family support in the context of rapid social change taking place in Middle Eastern countries. This study aims to address this gap by examining the parenting experiences of young Jordanian couples within the family context they are embedded in. RESEARCH DESIGN AND METHODS: A qualitative study was conducted in Jordan involving sixty semi structured, in-depth interviews. Twenty mothers, twenty fathers, and twenty family members identified as support providers were interviewed. RESULTS: The key theme, "it's too much" emerged from interviews to describe the nature of family support experienced by new parents from marriage to pregnancy and until after the arrival of their first child. The study found varied interpretations of traditional child-care practices among older and younger generation of family members, leading to family conflict. This study also found that the lack of credible information from the health system about child-care compelled them to accept the only available information for them from their parents, often times with much resistance and reluctance. This created a situation of stress and anxiety among young parents and undermined the potential for healthy parenting experience. This study also found that not all social support during early days of parenthood led to beneficial health outcomes to mother and child."Social visiting" by family members to hospital and home, was particularly found to interfere with new parents' pursuit toward privacy and family bonding, immediately following the birth of child. CONCLUSION: This study has produced a new understanding of the experience of Jordanian new parents' transition to parenthood. This study particularly sheds light on the current dilemma in which these Jordanian new parents find themselves in, which reflect a clash between traditional and modern values. Although the findings aim to contribute to the body of literature that deals with cultural influences on new parents' experiences in Jordon, the learning could be relevant to the other contexts in the Middle Eastern societies. PMID- 27969018 TI - Nursing theory as a guide into uncharted waters: Research with parents of children undergoing cancer treatment. AB - Being a parental caregiver for a child who is undergoing cancer treatment profoundly impacts significant numbers of parental caregivers and their well being. This article focuses on the use of theory, philosophy, and empirical knowledge in guiding research designed to both describe and explain influences on well-being of parental caregivers of children undergoing cancer treatment. Other aspects of the research are discussed as well, including practice-relevant findings. Findings indicated the co-existence of both positive and negative well being and that each has unique predictors. Self-transcendence mediated the relationship between resilience and well-being in parental caregivers. Clinical implications for these findings are also presented. PMID- 27969019 TI - Facebook targeted advertisement for research recruitment: A primer for nurse researchers. AB - Recruiting participants for research studies can be challenging and costly. Innovative recruitment methods are needed. Facebook targeted advertisement offers a low-cost alternative to traditional methods that has been successfully used in research study recruitment. This primer offers nurse researchers a method utilizing social media as a recruitment tool and details Facebook targeted advertisement for research recruitment. PMID- 27969020 TI - Self-efficacy and depression predicting the health-related quality of life of outpatients with chronic heart failure in Singapore. AB - BACKGROUND: Chronic heart failure (CHF) remains as a debilitating disease that has high mortality among adults worldwide. CHF negatively impacts an individual's health-related quality of life (HRQoL), but only few studies have investigated such an impact in the Asian population. AIMS: This study aims to investigate the HRQoL of outpatients with CHF and identify its predictors among this group of patients in Singapore. METHODS: This was a cross-sectional, descriptive correlational study. A convenience sampling of 121 outpatients with CHF was recruited from a public hospital over 5 months. The Minnesota Living with Heart Failure Questionnaire (MLHFQ), Short Form-Cardiac Depression Scale, Cardiac Self Efficacy Scale, and Medical Outcomes Study Social Support Survey were used to measure the study variables. RESULTS: There were significant differences in the HRQoL as assessed using the MLHFQ between gender, educational level, and primary caregiver status (p<0.05). Self-efficacy (beta=0.637, p<0.001) and depression (beta=-0.220, p<0.001) were found to be the predictors of the HRQoL in outpatients with CHF, accounting for 67.9% of variance. CONCLUSION: The results of the study indicated that lower levels of self-efficacy and depression predicted poor HRQoL. Nursing care should focus on detecting depressive symptoms in patients with CHF. A program facilitating better self-care is important in CHF management. PMID- 27969021 TI - Features and usability assessment of a patient-centered mobile application (HeartMapp) for self-management of heart failure. AB - BACKGROUND: Mobile health technologies have emerged as a way to actively engage patients in their healthcare decision-making process. One who is well informed and motivated is thought to engage in self-management activities. Thus, the conceptual framework included "information, motivation, and behavioral change" model, with patient engagement as a mediator in the development and assessment of a mobile health application "HeartMapp" for chronic heart failure (CHF) self management. PURPOSE: To describe the development and features of the HeartMapp and preliminary assessment of the usability of HeartMapp. METHOD: A descriptive survey design was employed. A total of 37 participants (25 patients with CHF and 12 health care workers) navigated the HeartMapp and completed self-confidence and usability questionnaires. RESULTS: More than half of the patients used mobile phones to obtain health information. Patients reported moderate self-confidence (mean 26.60+/-12.18) in using HeartMapp. One in five patients reported a lack of confidence in using the chest-worn Bluetooth device. The observational data indicated that all patients completed the task of navigating the HeartMapp with little or no help. The health care members (n=12) demonstrated high confidence in recommending HeartMapp to patients (mean 4.58+/-0.67) and in utilizing data from HeartMapp for clinical decision making (mean 4.50+/-0.67). The self-confidence and usability questionnaires showed good reliability in this sample. CONCLUSION: Having access to CHF symptom monitoring and education readily available in a mobile app may motivate individuals to engage in the prescribed self-management skills to ultimately attain desired outcomes, which warrants further exploration. PMID- 27969023 TI - Comparing perceived self-management practices of adult type 2 diabetic patients after completion of a structured ADA certified diabetes self-management education program with unstructured individualized nurse practitioner led diabetes self management education. AB - PURPOSE: The purpose was to compare perceived self-management practices of adult type 2 diabetic patients after completing an American Diabetes Association (ADA) certified diabetes self-management education (DSME) program with unstructured individualized nurse practitioner led DSME. METHODS: Demographic questions and the Self-Care Inventory-Revised (SCIR) were given to two convenience sample patient groups comprising a formal DSME program group and a group within a clinical setting who received informal and unstructured individual education during patient encounters. A t-test was executed between the formal ADA certified education sample and the informal sample's SCI-R individual scores. A second t test was performed between the two samples' SCI-R mean scores. RESULTS: A t-test determined no statistically significant difference between the formal ADA structured education and informal education samples' SCI-R individual scores. There was not a statistically significant difference between the samples' SCI-R mean scores. DISCUSSION: The study results suggest that there are not superior DSME settings and instructional approaches. PMID- 27969022 TI - Guidelines for research recruitment of underserved populations (EERC). AB - PURPOSE: Despite concerted efforts to establish health equity, significant disparities persist. One roadblock to eliminating health disparities is the inadequate recruitment of underserved populations, which prevents researchers from creating culturally-tailored interventions. To further develop the science of recruitment, we argue that a systematic approach should be applied to research participant recruitment. Given the lack of practical and comprehensive recruitment conceptual frameworks or guidelines in the literature, the authors propose newly synthesized guidelines for research recruitment of underserved populations: EERC (evaluate, engage, reflect, and carefully match). METHODS: The EERC guidelines are delineated, and the application of these guidelines is illustrated through a study recently conducted by the authors. RESULTS: The guidelines consist of the following four components: 1. Evaluate the composition of the research team; 2. Engage fully with the community by working with key informants and cultural insiders; 3. Reflect the unique cultural characteristics of the community in the research conduct; and 4. Carefully use a matching technique. The application component of the article demonstrates concrete examples of how the guidelines can enhance research recruitment for an underserved population. CONCLUSION: The authors intend these guidelines to be broadly applicable for research teams regardless of research design or characteristics of the underserved population. Application of these guidelines in nursing and health science will contribute to increasing research recruitment of underserved populations, with the goal of reducing health disparities and achieving health equity for all persons. PMID- 27969024 TI - Accuracy of anxiety and depression screening tools in heart transplant recipients. AB - PURPOSE: The aim of this study was to assess the validity and reliability of psychological screening tools in outpatient heart transplant recipients. METHODS: Forty-eight heart transplant recipients completed the Patient Health Questionnaire 9-item scale (PHQ-9), Generalized Anxiety Disorder 7-item Scale (GAD-7), Kessler Psychological Distress 10-item Scale (K-10) and Medical Outcomes Short Form 36-item Health Survey. A structured psychological interview (Mini International Neuropsychiatric Interview Version 6) was conducted after completion of the questionnaires. Internal consistency, criterion validity and construct validity of the PHQ-9, GAD-7 and K-10 were evaluated. RESULTS: Internal consistency supported the reliability of the screening tools. The optimal cut-off on the PHQ-9 for depression was 10 (sensitivity=0.86; specificity=0.93). A score of 6 on the GAD-7 maximized sensitivity (0.75) and specificity (0.89) for anxiety. A score of 17 on the K-10 was the optimal cut-off for diagnosis of either anxiety or depression (sensitivity=0.83; specificity=0.84). Increasing scores on the screening tools were associated with lower health-related quality of life. CONCLUSION: Psychometric analyses support the reliability and validity of the PHQ-9, GAD-7 and K-10 as screening tools for detection of anxiety and depression in heart transplant recipients. PMID- 27969026 TI - Evaluation of a smartphone application for self-care performance of patients with chronic hepatitis B: A randomized controlled trial. AB - AIM: To verify the usefulness of a smartphone application (App) for facilitating self-care in patients with chronic hepatitis B (CHB). BACKGROUND: CHB is a global health problem, and patients with CHB need to routinely perform self-care. Health related smartphone apps could help users self-manage their disease. METHODS: Fifty-three CHB patients were assessed in this randomized controlled before-and after experimental study. The patients were randomly and equally assigned to groups that did (n=26) or did not (n=27) use the smartphone app for 12weeks. The experimental and control groups were analyzed for differences in disease knowledge, self-efficacy, and self-care before and after use of the smartphone app. RESULTS: After intervention, patients who used the app displayed significantly increased disease knowledge compared with the control group (p=.015). Self-efficacy and self-care also significantly increased in the experimental group (p=0.006 and 0.001, respectively). CONCLUSION: The smartphone app can be useful for increasing self-care in CHB patients. ABBREVIATIONS: App: application, CHB: chronic hepatitis B, CVI: content validity. PMID- 27969025 TI - Reducing nurses' stress: A randomized controlled trial of a web-based stress management program for nurses. AB - BACKGROUND: Nursing is a notoriously high-stress occupation - emotionally taxing and physically draining, with a high incidence of burnout. In addition to the damaging effects of stress on nurses' health and well being, stress is also a major contributor to attrition and widespread shortages in the nursing profession. Although there exist promising in-person interventions for addressing the problem of stress among nurses, the experience of our group across multiple projects in hospitals has indicated that the schedules and workloads of nurses can pose problems for implementing in-person interventions, and that web-based interventions might be ideally suited to addressing the high levels of stress among nurses. PURPOSE: The purpose of this study was to evaluate the effectiveness of the web-based BREATHE: Stress Management for Nurses program. METHODS: The randomized controlled trial was conducted with 104 nurses in five hospitals in Virginia and one hospital in New York. The primary outcome measure was perceived nursing-related stress. Secondary measures included symptoms of distress, coping, work limitations, job satisfaction, use of substances to relieve stress, alcohol consumption, and understanding depression and anxiety. RESULTS: Program group participants experienced significantly greater reductions than the control group on the full Nursing Stress Scale, and six of the seven subscales. No other significant results were found. Moderator analysis found that nurses with greater experience benefitted more. CONCLUSION: Using a web-based program holds tremendous promise for providing nurses with the tools they need to address nursing related stress. PMID- 27969027 TI - Workplace aggression, psychological distress, and job satisfaction among Palestinian nurses: A cross-sectional study. AB - BACKGROUND: Nurses can be exposed to aggressive behavior from patients, patient's relatives, colleagues and visitors. PURPOSE: To determine the prevalence of workplace aggression among Palestinian nurses in the Hebron district and to examine cross-sectional associations between exposure to workplace aggression and the occurrence of psychological distress and job satisfaction. METHODS: Of 372 nurses eligible for the study, 343 were included (response rate of 92.2%). The sample comprised 62% females and 38% males. The participants responded to questions about their socio-demographic status, workplace aggression (WHO questionnaires), psychological distress (General Health Questionnaire, GHQ-30), and job satisfaction (Generic Job Satisfaction Scale). RESULTS: Ninety-three (27.1%) of the respondents reported exposure to workplace aggression of any kind. Seventeen (5%) reported exposure to physical aggression, 83 (24.2%) reported exposure to verbal aggression, and 25 (7.3%) reported exposure to bullying. The patients and the patients' relatives were the main sources of physical and verbal aggression, whereas colleagues were the main source of bullying. Males reported a higher prevalence of bullying than females. Younger nurses reported a higher prevalence of exposure to physical aggression, verbal aggression and bullying. Verbal aggression was associated with more psychological distress. Bullying was associated with lower job satisfaction. CONCLUSIONS: More than a quarter of the nurses reported that they had been subject to some sort of aggression at the workplace. Verbal aggression was associated with higher psychological distress. Workplace bullying was associated with lower job satisfaction. Increased awareness and preventive measures to address this problem among health care workers are warranted. PMID- 27969028 TI - Safe and effective nursing shift handover with NURSEPASS: An interrupted time series. AB - AIM: Implementation of a locally developed evidence based nursing shift handover blueprint with a bedside-safety-check to determine the effect size on quality of handover. METHODS: A mixed methods design with: (1) an interrupted time series analysis to determine the effect on handover quality in six domains; (2) descriptive statistics to analyze the intercepted discrepancies by the bedside safety-check; (3) evaluation sessions to gather experiences with the new handover process. RESULTS: We observed a continued trend of improvement in handover quality and a significant improvement in two domains of handover: organization/efficiency and contents. The bedside-safety-check successfully identified discrepancies on drains, intravenous medications, bandages or general condition and was highly appreciated. CONCLUSION: Use of the nursing shift handover blueprint showed promising results on effectiveness as well as on feasibility and acceptability. However, to enable long term measurement on effectiveness, evaluation with large scale interrupted times series or statistical process control is needed. PMID- 27969029 TI - Evaluation of using the Chinese version of the Spirituality Index of Well-Being (SIWB) scale in Taiwanese elders. AB - PURPOSE: Spirituality and spiritual well-being have emerged as important indicators for one's quality of life and health outcomes. Nursing as a profession is concerned with a holistic approach to improve health and overall well-being. To evaluate the outcomes of holistic nursing interventions, using valid and reliable instruments to assess spiritual well-being becomes necessary. There is a lack of instruments for measuring spiritual well-being in Chinese populations. Little has been known about the feasibility of using the Spirituality Index of Well-Being (SIWB) in Taiwanese elders. The purpose of this cross-sectional study was to evaluate the uses of the translated Chinese version of the Spirituality Index of Well-Being (SIWB-C) with Taiwanese elders. METHODS: A total of 150 individual who were 65 years old or older and living in southern Taiwan were recruited from a public community center. A four-step procedure was used to translate the English version of the SIWB to the traditional Chinese language. Internal consistency, factor analysis, and correlation coefficient were conducted to evaluate the reliability and validity of the SIWB-C. RESULTS: The SIWB-C demonstrated a high internal consistency with Cronbach's alpha .95. The construct validity of SIWB-C was supported by factor analysis and by significant correlations with its subscales and the CES-D scale. CONCLUSION: The psychometric analysis indicates that the SIWB-C is a valid and reliable instrument for measuring spiritual well-being. This instrument provides a feasible and valid approach for assessing Taiwanese elders' spiritual well-being in the future. PMID- 27969030 TI - Standardizing nurse training strategies to improve knowledge and self-efficacy with tracheostomy and laryngectomy care. AB - OBJECTIVE: Appropriate tracheostomy and laryngectomy care requires that nurses maintain specific knowledge and a particular skillset, to ensure safe, competent care. Deficiencies in this nursing care remain a persistent problem. The objective of this study was to evaluate the effect of a nurse training program on knowledge and self-efficacy with tracheostomy and laryngectomy care. STUDY DESIGN: Prospective, interventional survey design. SETTING: Academic, tertiary care hospital between September 2014 and April 2015. SUBJECTS AND METHODS: 1450 nurses at an academic tertiary care hospital were surveyed on tracheostomy and laryngectomy care at two time points: before and after the implementation and completion of the nurse training program. The nurse training program included a hands-on training session and online tutorial on appropriate tracheostomy and laryngectomy care. 732 nurses completed the hands-on training and were asked to complete the online tutorial. A total of 338 surveys were collected. Survey data were collected through an online survey development platform. Analyses were performed using SAS software. Chi-square tests and t-tests were utilized with a significance level of 0.05. RESULTS: 165 pre-training surveys and 173 post training surveys were completed. Statistical analysis of the post-training data demonstrated statistically significantly higher knowledge and self-efficacy scores of nurses who completed the training than nurses who did not. CONCLUSIONS: Findings from this study reveal poor overall nursing knowledge and self-efficacy with this care and suggest that optimizing and standardizing nurse training is an effective strategy to improve nursing knowledge and self-efficacy with head and neck surgical airways. PMID- 27969031 TI - Effectiveness of nurse-delivered patient education interventions on quality of life in elders in the hospital: A systematic review. AB - BACKGROUND: Nurse-delivered education is a crucial part of nursing practice; however, evidence regarding its impact on quality of life is lacking. To our knowledge, no systematic review has addressed the effects of nurse-delivered education interventions on the quality of life in a general elderly inpatient population. OBJECTIVES: To evaluate the effectiveness of nurse-delivered education interventions compared to usual care with regard to the quality of life in elders in the hospital. METHODS: A systematic review was performed to identify randomized controlled trials examining the effects of nurse-delivered educational interventions on the quality of life in elders in the hospital. The search was performed in December 2012 in the MEDLINE (via PubMed), EMBASE (via Ovid), and CINAHL (via EBSCO) databases and was limited with regard to publication time and language. The studies were appraised according to methodological quality, and p values were extracted to determine the effectiveness of the interventions. RESULTS: Four studies were included in the review. One study testing multicomponent interventions showed positive effects on quality of life. Two studies showed no effect, and one study showed a negative effect of the intervention on quality of life. Methodological appraisal revealed single biases in most of the studies. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Because of the scarcity of positive findings, methodological issues, and heterogeneity between studies, this review could not provide evidence of the effectiveness of nurse-delivered education interventions in elders in the hospital for improving quality of life. Nurse-delivered education may be more effective as a part of multifactorial interventions. Further studies should examine interventions that focus on quality of life using validated measures. PMID- 27969032 TI - Factors that influence in vitro fertilization treatment outcomes of Chinese men: A cross-sectional study. AB - BACKGROUND: The thought of producing offspring has rooted in Chinese culture after thousands of years of feudal society. Infertility in men would bear significant psychological distress in this social environment. PURPOSE: In this study, we explored the association between the outcomes of IVF treatment and anxiety, depression, marital satisfaction, communication, sexual relationship and social support. METHODS: A cross-sectional study was conducted. A total of 202 Chinese men who received IVF treatment for the first time were investigated using socio-demographic questionnaire, Self-Rating Anxiety Scale, Self-Rating Depression Scale, ENRICH Marital Inventory and Social Support Rating Scale on the first day of IVF treatment. RESULTS: The overall prevalence of depression and anxiety was 49.1% and 27.2%, respectively. Subjects with IVF failure had higher levels of depression and anxiety, lower levels of "Marital satisfaction", "communication" and "Sexual relationship" and social support. Logistic regression analysis indicated that depression, anxiety, marital satisfaction and sexual relationship were independent predictors of IVF failure. CONCLUSION: The prevalence of depression and anxiety in Chinese men undergoing IVF was higher than that in other countries. These findings suggest that anxiety, depression, marital satisfaction, and sexual relationship are important factors leading to IVF failure. Therefore, it is important to provide psychological aid to male patients undergoing IVF treatment. PMID- 27969033 TI - The effects of antenatal education on fear of childbirth, maternal self-efficacy and post-traumatic stress disorder (PTSD) symptoms following childbirth: an experimental study. AB - BACKGROUND: Fear of birth and low childbirth self-efficacy is predictive of post traumatic stress disorder symptoms following childbirth. The efficacy of antenatal education classes on fear of birth and childbirth self-efficacy has been supported; however, the effectiveness of antenatal classes on post-traumatic stress disorder symptoms after childbirth has received relatively little research attention. PURPOSE: This study examined the effects of antenatal education on fear of childbirth, maternal self-efficacy and post-traumatic stress disorder symptoms following childbirth. DESIGN: Quasi-experimental study. METHODS: The study was conducted in a city located in the Middle Anatolia region of Turkey and data were collected between December 2013 and May 2015. Two groups of women were compared-an antenatal education intervention group (n=44), and a routine prenatal care control group (n=46). The Wijma Delivery Expectancy/Experience Questionnaire, Version A and B, Childbirth Self-efficacy Inventory and Impact of Event Scale-Revised was used to assess fear of childbirth, maternal self-efficacy and PTSD symptoms following childbirth. RESULTS: Compared to the control group, women who attended antenatal education had greater childbirth self-efficacy, greater perceived support and control in birth, and less fear of birth and post traumatic stress disorder symptoms following childbirth (all comparisons, p<0.05). CONCLUSIONS: Antenatal education appears to alleviate post-traumatic stress disorder symptoms after childbirth. PMID- 27969034 TI - The effect of the support program on the resilience of female family caregivers of stroke patients: Randomized controlled trial. AB - AIM: The purpose of the study was to determine the effect of a support program on the resilience of female family caregivers of stroke patients. METHODS: This is a randomized controlled trial. The sample consisted 70 female family caregivers (34 experimental, 36 control group). Data were collected three times (pretest posttest, follow-up test). Data were collected using the demographical data form, the Family Index of Regenerativity and Adaptation-General. RESULTS: A significant difference was determined between the experimental and control group's follow-up test scores for relative and friend support, social support and family-coping coherence. A significant difference was determined between the experimental group's mean pretest, posttest and follow-up test scores in terms of family strain, relative and friend support, social support, family coping-coherence, family hardiness and family distress. CONCLUSIONS: These results suggest that the Support Program contributes to the improvement of the components of resilience of family caregivers of stroke patients. PMID- 27969035 TI - Factors influencing sleep quality among nursing staff: Results of a cross sectional study. AB - PURPOSE: Given the intense physical and mental demands placed on nurses and other caregivers, getting sufficient sleep is essential to maintaining both individual health and professional performance. The goal of our study is to describe and analyze the self-reported sleep quality of nursing staff and identify which factors have an influence on it. METHODS: The sample was comprised of 153 female nurses over the age of 20 years who completed written surveys regarding their health status and health behavior. Their responses were subjected to ANOVA analysis with post hoc follow-up tests and logit regression was used. RESULTS: 33% of female nursing staff reported poor quality sleep. Lower quality of life, tachycardia and unequal distribution of work load were most strongly associated with poor sleep quality. CONCLUSION: Our study indicates that reducing workplace stress is a good place to start in developing a proactive strategy. A comprehensive prevention strategy should include both behavioral and situational prevention elements. Future studies should focus on identifying causal factors and developing prevention strategies. PMID- 27969036 TI - Description of good patient care at the end of life. AB - OBJECTIVES: The study's objective was to describe nurses' perceptions of and experiences with good end-of-life care in Korea. METHODS: A qualitative descriptive design was applied with 11 Korean nurses who worked in hospice and palliative care settings. Individual 90-120 minute interviews were conducted and content analysis was performed. RESULTS: The following four major themes were extracted from questions regarding nurses' experiences of good end-of-life care: 1) providing appropriate care for symptom management, 2) being present, 3) establishing good relationships, and 4) tailoring care for individualized needs. CONCLUSION: Korean nurses recognized that good end-of life care occurred within multiple ways of knowing and within multiple paradigms. Providing good care is a process of knowledge integration. To improve end-of-life care, the nursing discipline must apply various educational methods including multiple ways of knowing and paradigms. PMID- 27969038 TI - The effect of nursing care protocol on the prevention of central venous catheter related infections in neurosurgery intensive care unit. AB - PURPOSE: This clinical study was planned to determine the effect of Nursing Care Protocol on the prevention of central venous catheter-related infections in neurosurgery intensive care unit. METHOD: The study was conducted between January 2012 and December 2013. The sampling consisted of 160 patients compatible with study inclusion criteria (80 protocol and 80 control patients). Routine care was applied to the control group while the protocol group received catheter care according to the protocol formed in accordance with the suggestions of the Centers for Disease Control and Prevention. The data were collected from Patient Information Form, Follow-Up Form, and APACHE II scores. RESULTS: A significant difference existed between the two groups in terms of mean APACHE II scores on discharge (p<0.05) whereas no significant difference in terms of mean fever, number of leucocytes and lymphocytes, C-reactive protein, and days of catheter carriage (p<0.05). Hemoculture positivity was less in protocol group, and this difference was statistically significant (p<0.05). CONCLUSION: The suggested nursing care protocol is significantly efficacious in the prevention of CVC related infections. Training of healthcare workers on using this protocol is recommended. PMID- 27969039 TI - Factors associated with breastfeeding initiation time in a baby-friendly hospital in Istanbul. AB - AIM: To investigate perinatal factors that affect breastfeeding of newborns delivered at a baby-friendly public hospital in Turkey, including the time of the first physical examination by a pediatrician, the first union with their mothers, and the first breastfeeding time after delivery. METHOD: The research was conducted from May 2nd through June 30th, 2011, in a baby-friendly public hospital in Istanbul. The sample consisted of 194 mothers and their full-term newborns. The data were collected via an observation form developed by the researchers. In analyzing the data, the average, standard deviation, minimum, maximum values, Chi-square, and percentages were used. RESULTS: The results revealed that the first physical examinations of the newborns were performed approximately 53.02+/-39min (range, 1-180 min) after birth. The newborns were given to their mothers approximately 69.75+/-41min (range, 3-190 min) after birth. Consequently, the first initiated breastfeeding took place approximately 78.58+/-44min following birth, and active sucking was initiated after approximately 85.90+/-54min. A large percentage of the newborns (64.4%) were not examined by a specialist pediatrician within half an hour of birth, and 74.7% were not united with their mothers within the same period. Also, the newborns who initiated breastfeeding within the first half hour had significantly earlier success with active sucking and required significantly less assistance to achieve successful breastfeeding. CONCLUSION: The newborns in our study met with their mothers late in the birth ward because examinations of the newborns were delayed. The newborns began initial sucking later, and this chain reaction negatively impacted the breastfeeding success of the newborns. PMID- 27969037 TI - Animal models in genomic research: Techniques, applications, and roles for nurses. AB - Animal research has been conducted by scientists for over two millennia resulting in a better understanding of human anatomy, physiology, and pathology, as well as testing of novel therapies. In the molecular genomic era, pre-clinical models represent a key tool for understanding the genomic underpinnings of health and disease and are relevant to precision medicine initiatives. Nurses contribute to improved health by collecting and translating evidence from clinically relevant pre-clinical models. Using animal models, nurses can ask questions that would not be feasible or ethical to address in humans, and establish the safety and efficacy of interventions before translating them to clinical trials. Two advantages of using pre-clinical models are reduced variability between test subjects and the opportunity for precisely controlled experimental exposures. Standardized care controls the effects of diet and environment, while the availability of inbred strains significantly reduces the confounding effects of genetic differences. Outside the laboratory, nurses can contribute to the approval and oversight of animal studies, as well as translation to clinical trials and, ultimately, patient care. This review is intended as a primer on the use of animal models to advance nursing science; specifically, the paper discusses the utility of preclinical models for studying the pathophysiologic and genomic contributors to health and disease, testing interventions, and evaluating effects of environmental exposures. Considerations specifically geared to nurse researchers are also introduced, including discussion of how to choose an appropriate model and controls, potential confounders, as well as legal and ethical concerns. Finally, roles for nurse clinicians in pre-clinical research are also highlighted. PMID- 27969040 TI - Gender-based experiences on the survival of chronic renal failure patients under hemodialysis for more than 20 years. AB - BACKGROUND: Chronic kidney disease (CKD), which causes reduction in kidney function, is a common public health problem worldwide. Among patients who have received hemodialysis for 20 years, the survival rate in first 5 years is merely 39.9%. Such rate is lower than that of cancer patients. OBJECTIVES: In an effort to understand and develop helpful realistic nursing interventions, we interviewed hemodialysis patients of different genders, who have survived more than 20 years, regarding what their survival experiences meant for them. METHODS: While the phenomenological research method was used, the data were analyzed the by Colaizzi. RESULTS: We found that the essential meaning of survival experiences was as follows: the stress of hemodialysis patients is similar to that of late stage cancer patients, and the patients of each gender go through different experiences due to the country's specific cultures. However, regardless of genders, the positive supports from their families and nurses were important influences in their 20 years long survival. The results imply that an in-depth understanding of hemodialysis patients' experience is an essential element for developing effective nursing interventions. PMID- 27969042 TI - Readiness for and predictors of evidence-based practice in Greek healthcare settings. AB - BACKGROUND: Implementation of evidence-based practice (EBP) remains limited in healthcare settings and knowledge of predictors of healthcare professionals' EBP activities is lacking. AIM: To describe nurses' readiness for EBP and identify related predictors in Greek healthcare settings. RESULTS: Nurses scored high in the EBP readiness scale reflecting significant positive readiness toward EBP and consistently reported favorable attitudes toward and beliefs about EBP. However, half of them were unsure about their ability to engage in EBP despite the fact that they valued research-based practice as important. EBP specific domains including the "EBP-attitude", the "EBP-knowledge", the "informational needs" and the "workplace culture" and nurses' demographics as well, were found to be strong predictors of EBP readiness among Greek nurses. CONCLUSION: As nurses are now more aware of and open to the idea of EBP, diverse strategies and well-designed interventions to facilitate the desired change to practice are needed. PMID- 27969041 TI - Journaling as reinforcement for the resourcefulness training intervention in mothers of technology-dependent children. AB - Resourcefulness, a set of cognitive and behavioral skills used to attain, maintain, or regain health, is a factor related to depressive symptoms in mothers of children with chronic conditions and complex care needs who are dependent on medical technology such as mechanical ventilation or feeding tubes. The purpose of this secondary analysis of a randomized, controlled pilot intervention study was to determine the feasibility, acceptability and fidelity of daily journal writing as a method of reinforcement of resourcefulness training (RT) that teaches the use of social and personal resourcefulness skills. Participants returned their journals to the study office at the end of the four-week journaling exercise. Content analysis from exit interviews and journals supported the feasibility, acceptability and fidelity of daily journaling for reinforcement of RT in this population. Journal writing can be used by pediatric nurses to reinforce and promote resourcefulness skill use in parents of technology dependent children. PMID- 27969043 TI - Recruiting bereaved parents for research after infant death in the neonatal intensive care unit. AB - Understanding parental experiences following infant death in the neonatal intensive care unit (NICU) is a high research priority and a necessary first step to improving health services. However, recruiting bereaved parents to discuss their experiences on such an extremely sensitive topic can be challenging and research procedures must be planned carefully in order to get an adequate sample. There is little published in the literature detailing specific strategies for recruiting bereaved parents for grief research, especially strategies for contacting parents and identifying factors that might affect participation. The purpose of this paper is to describe the process of recruiting bereaved parents into a qualitative research study exploring parental NICU experiences and grief responses following infant death. We describe a successful recruitment plan that led to the enrollment of difficult to recruit participants such as fathers, and individuals representing minorities and those from lower socioeconomic (SES) groups. Bereaved parents of infants after an NICU hospitalization should continue to be recruited for research studies for their unique perspectives and valuable insights about the devastating experience of infant death. Participants in this study reported more benefits than harm and the results addressed a critical gap in the literature. PMID- 27969044 TI - A preliminary evaluation of trust and shared decision making among intensive care patients' family members. AB - PURPOSE: The purpose of this study was to preliminarily evaluate ICU family members' trust and shared decision making using modified versions of the Wake Forest Trust Survey and the Shared Decision Making-9 Survey. METHODS: Using a descriptive approach, the perceptions of family members of ICU patients (n=69) of trust and shared decision making were measured using the Wake Forest Trust Survey and the 9-item Shared Decision Making (SDM-9) Questionnaire. Both surveys were modified slightly to apply to family members of ICU patients and to include perceptions of nurses as well as physicians. RESULTS: Overall, family members reported high levels of trust and inclusion in decision making. Family members who lived with the patient had higher levels of trust than those who did not. Family members who reported strong agreement among other family about treatment decisions had higher levels of trust and higher SDM-9 scores than those who reported less family agreement. CONCLUSION: The modified surveys may be useful in evaluating family members' trust and shared decision making in ICU settings. Future studies should include development of a comprehensive patient-centered care framework that focuses on its central goal of maintaining provider patient/family partnerships as an avenue toward effective shared decision making. PMID- 27969045 TI - The experience of weight management in normal weight adults. AB - BACKGROUND: No prior research has been done with normal weight persons specific to their experience of weight management. PURPOSE: The purpose of this research was to discover the experience of weight management in normal weight individuals. METHOD: Glaserian grounded theory was used. Qualitative data (focus group) and quantitative data (food diary, study questionnaire, and anthropometric measures) were collected. DISCUSSION: Weight management was an ongoing process of trying to focus on living (family, work, and social), while maintaining their normal weight targets through five consciously and unconsciously used strategies. Despite maintaining normal weights, the nutritional composition of foods eaten was grossly inadequate. CONCLUSIONS: These five strategies can be used to develop new weight management strategies that could be integrated into existing weight management programs, or could be developed into novel weight management interventions. Surprisingly, normal weight individuals require dietary assessment and nutrition education to prevent future negative health consequences. PMID- 27969046 TI - Why nurse researchers should be concerned about cardiac health. PMID- 27969047 TI - What do nursing students contribute to clinical practice? The perceptions of working nurses. AB - PURPOSE: The study purpose was to elicit factors that caused satisfaction and dissatisfaction for staff registered nurses (RNs) who participated in two types of nurse student interactions: clinical rotation role-model and student preceptorship. BACKGROUND: The limited availability of practice sites for clinical experiences places essential importance on the need to understand RNs' perceptions of students' effect on their practice. METHODS: This cross sectional descriptive study surveyed RNs who worked at six acute care hospitals in two multi-hospital not-for-profit community healthcare systems in southeastern United States, using the Nursing Students' Contributions to Clinical Agencies (NSCCA) survey via SurveyMonkey(r). RESULTS: Registered nurses had positive perceptions of students' contributions in clinical rotations and student preceptorships, specifically, enhancement of the nurses' professional development was a satisfier for participants. Nurses who were student preceptors and nurses with less than ten years of experience had the most positive perceptions. Nurses in the peri natal setting had the least positive perceptions of students' contributions. CONCLUSIONS: Findings from the NSCCA survey can reveal satisfiers and dis satisfiers for RNs participating in nurse-student interactions, which academic and clinical practice nurse leaders can use to enhance the RNs' experiences. Results were used to create a series RN student preceptor training classes, which incorporated educational content that highlighted satisfiers and remediated dis satisfiers. PMID- 27969048 TI - Oral glucose efficacy on neonate's pain responses at the NICU: A quasi experimental trial of two clinical procedures. AB - AIM: This research was undertaken with the purpose of testing two research hypotheses regarding the efficacy of 10% oral glucose solution on procedural pain associated with venepuncture and nasopharyngeal suctioning within three neonatal intensive care units (NICU). The hypotheses were formulated from previous conclusions reached by other researchers highlighting the efficacy of sucrose solutions on neonates' pain responses during minor painful procedures. METHOD: A quasi-experimental trial utilising a time series design with one group was used. Data from a total of 90 neonates included 60 neonates who underwent a venepuncture and 30 neonates who underwent a nasopharyngeal suctioning procedure for clinical purposes. The neonate's pain response for each procedure was scored using the Neonatal Pain Assessment Scale (NPAS) on two separate occasions over three time periods. The pre-procedural score (T0) when the neonate received no sucrose, the inter-procedural score (T1) when the neonate was given 2ml of 10% glucose solution two minutes before the procedure (intervention group) or where oral glucose was withheld (control group) and the post-procedural score (T2) being at the end of the procedure. RESULTS: The results showed the mean NPAS scores in response to venepuncture or nasopharyngeal suctioning were significantly lower in the intervention group than the control group. CONCLUSION: This showed that oral glucose (10%) had a positive effect on the pain response during venepuncture and nasopharyngeal suctioning procedures. PMID- 27969049 TI - An interventional study to provide telephone follow-up support to open-heart surgery patients during recovery. AB - INTRODUCTION: Over 500,000 open-heart (OH) surgery procedures are performed annually to treat cardiovascular and valvular heart disease. Despite the frequency of the procedure, patients face psychosocial and physical challenges that continue long after discharge. The research question for this study was: How does a telephone supportive intervention change anxiety, depression, expectations, and physical health status (PHS) in OH surgery patients? METHODS: A quasi-experimental, repeated measures design was used. The study included a supportive telephone intervention during recovery, and measured anxiety, depression, expectations, and physical health status (PHS) preoperatively (T1) and postoperatively, three days after discharge (T2), and at 4weeks (T3) and 3months (T4) after surgery. Participants (N=28) were randomly assigned to the control (n=13) or experimental group (n=15). RESULTS: Mean scores for anxiety and depression were in the normal range across all data collection times. Scores for anxiety (p=.03) and PHS (p=.00) were statistically significant when examining how the scores changed over the four time periods. Main effect for group and interaction effects were not significant for any of the variables. CONCLUSIONS: Limitations of this pilot study suggest the need to recruit a larger, heterogeneous sample from multiple sites. Future research including patients with a known history of anxiety and depression and developing a more evidence-based practice intervention are options to consider. PMID- 27969050 TI - Effect of nocturia on next-day sedentary activity in adults with type 2 diabetes. AB - PURPOSE: Nocturia, a common cause of disturbed sleep quality and next-day fatigue, may contribute to difficulty with diabetes self-management. The purpose of this study was to examine the effect nocturia has on next-day subjectively measured mental and physical energy and objectively measured physical activity. METHODS: This secondary analysis utilized sleep diaries over one week which measured nocturia frequency and other sleep quality indicators (wake after sleep onset, sleep quality and sleep duration) along with next-day reports of mental and physical energy. Next-day physical activity was measured with the BodyMedia Sensewear armband. RESULTS: Sleep quality and sleep duration were associated with next-day physical and mental energy. Nocturia frequency (>=2 times per night) was associated with increased next-day sedentary activity. CONCLUSION: These results suggest that nocturia could negatively affect next-day physical activity in people with diabetes. PMID- 27969051 TI - Direct-breastfeeding in the neonatal intensive care unit and breastfeeding duration for premature infants. AB - AIM: To explore the relationship between direct-breastfeeding in the neonatal intensive care unit (NICU) and breastfeeding duration after discharge. BACKGROUND: Initiating and maintaining breastmilk feeding is an important goal that begins in the NICU. Little is known about direct-breastfeeding in the NICU and its relation to breastfeeding duration. METHODS: Chart review of 46 infants (<32weeks gestational age or <1500 grams) whose mothers provided breastmilk. RESULTS: One month after discharge, mothers still providing breastmilk were more likely to have provided >=1 direct-breastfeed per day in the NICU (21.16, CI: 3.13-143.25, p<0.01) and had prior breastfeeding experience (OR: 9.16, CI: 1.02 82.34, p<0.05). At 4months, mothers still providing breastmilk were more likely to have provided >=1 direct-breastfeed per day in the NICU (OR: 12.80, CI: 1.39 118.32, p<0.05). CONCLUSIONS: Direct-breastfeeding in the NICU may play an essential role in preparing mothers for breastfeeding after discharge, thus potentially impacting breastfeeding duration. PMID- 27969052 TI - A comparison study between two discharge planning tools. AB - OBJECTIVE: The objective was to compare the effectiveness between a systematic assessment tool and a traditional assessment tool for discharge planning. METHODS: This research adopted a two-group comparison study design, and convenience sampling was adopted to recruit patients requiring discharge-planning services at eight wards in a regional teaching hospital in Southern Taiwan. The postdischarge care requirements of two groups of patients were evaluated using a traditional assessment tool and a systematic assessment tool in different implementation periods, respectively. Sixty-eight patients were matched with similar age and with similar activity in daily living index scores to compare the effectiveness of the tools. RESULTS: The systematic assessment tool exhibited higher assessment integrity and placement appropriateness, as well as lower rates of rehospitalization or mortality within discharge 14 days. The two groups exhibited no significant difference in inappropriate hospital days, primary decision-makers' satisfaction, and proportion of referral professionals who meet patient care requirements. However, the differences in three items of satisfaction exhibited moderate-to-large effect sizes, which may be of clinical importance. CONCLUSIONS: To meet the needs of primary decision-makers in a family, enhance their satisfaction, and provide effective discharge-planning services, clinicians should adopt the systematic assessment tool to assess the postdischarge care requirements of a patient, and the hospital should provide relevant facilities to assist in implementing all plans. PMID- 27969054 TI - The effect of self-efficacy enhancement program on medication adherence among post-acute myocardial infarction. AB - AIM AND BACKGROUND: Studies have reported that adherence to medications after hospital discharge for myocardial infarction is poor with about 12% to 20% of patients discontinue their medications six months after discharge. This study aimed to examine the effect of self-efficacy enhancement program on medication adherence in post-acute myocardial infarction patients. METHODS: A total 44 patient with post-acute myocardial infarction were recruited from the in-patient department, Police General Hospital. The participants were random assigned into control group and experimental group. The control group received conventional care while the experimental group attended a four-week self-efficacy enhancement program, which included motivation, skill practice, and monitoring skills. The mean self-efficacy score between groups was assessed. The pill count was used to measure medication adherence. Correlations between self-efficacy and medication adherence were examined. Data were analyzed using descriptive statistic, Pearson's correlation, and t-test. RESULTS: The mean score on medication adherence of the experiment group who attended the self-efficacy enhancement program was significantly greater than the control group (t=-2.77; df=21; p=0.01). The mean scores of self-efficacy between the experimental and control group were 35.73 (SD=4.11) and 35.41 (SD=3.78). The correlations between self efficacy and medication adherence were significantly (r=1.00, p=0.00). CONCLUSION: The effectiveness of self-efficacy enhancement program was effective in improving medication adherence in Thai post-acute myocardial infarction. PMID- 27969053 TI - Self-management among patients with chronic obstructive pulmonary disease in China and its association with sociodemographic and clinical variables. AB - PURPOSE: This study aimed to examine the status of self-management in patients with COPD and its associations with sociodemographic and clinical variables. METHODS: This cross-sectional study included 154 patients with COPD (mean age, 73 years) at four hospitals in Tianjin, China. The COPD Self-Management Scale was used to describe the level of self-management, and its associations with sociodemographic and clinical variables were examined with multiple regression analysis. RESULTS: More than half of the patients with COPD had a low (30%) or moderate (27%) level of self-management. Self-management was rated highest in management of daily life and lowest in information management. Higher physical activity, higher salary, and lower age affected self-management the most positively. CONCLUSION: The overall burden of COPD in China is greater than that found in other countries. Healthcare professionals need to improve their understanding of the importance of self-management and specifically focus on increased physical activity targeting patients with poor literacy skills. PMID- 27969056 TI - Coping measurement: Creating short form of Coping and Adaptation Processing Scale using item response theory and patients dealing with chronic and acute health conditions. AB - PURPOSE: The purpose of this study was to enhance the CAPS tool by clarifying the concept of coping, using item response theory (IRT) to shorten and assess the metric equivalence of the scale, and testing the preliminary validity of the resulting shortened scale. METHODS: A descriptive design of participants from different ethnic backgrounds was employed (USA n = 347 and Panama n = 327). To select items for the shortened CAPS, a well-established multi-step process grounded in IRT was used. Further, a coping ladder was created to approximate the a priori perceived location/difficulty of each item along the coping trait scale. Items for the shortened scale were selected based on considerations central to the middle range theory of coping and adaptation processing and the results of the item calibration and model testing. RESULTS: A total of 15 items were selected. The selected items were well distributed on the coping ladder and all basic subconcepts of the middle range theory were included. Further the sum of the DIF size for the selected short form items is - 0.01, so the overall bias of the total score is minimal. Finally, concurrent and divergent validity of the new scale was demonstrated in two separate correlational studies. CONCLUSION: The 15 item Coping and Adaptation Processing Scale (CAPS)--Short-Form can be a practical tool to effectively and efficiently measure coping and adaptation in both practice and research for people dealing with both chronic and acute health conditions. PMID- 27969055 TI - A longitudinal study of working life among first-line managers in the care of older adults. AB - AIM: To study whether the number of subordinates plays a role in first-line managers' and subordinates' ratings of empowerment, stress symptoms, and leadership-management performance. The aim was also to study relationships between managers' empowerment and stress symptoms and leadership-management performance. METHODS: A longitudinal and correlational design was used. All first line managers (n=98) and their subordinates (n=2085) working in the care of older adults in five municipalities were approached. RESULTS: With fewer (<=30) subordinates per manager, there were higher ratings of structural empowerment among managers and subordinates and lower stress symptoms among subordinates, than with >=31 subordinates. Furthermore, structural empowerment was related to the managers' stress symptoms and leadership-management performance, mediated through psychological empowerment. Moreover, structural empowerment can control/adjust for large numbers of subordinates in relation to stress symptoms. CONCLUSION: The higher FLMs rated their access to empowerment, the lower stress symptoms and higher leadership-management performance they rated over time. PMID- 27969057 TI - Motor performance tests as screening instruments for frailty in the older adults. AB - OBJECTIVE: To verify the association between frailty and motor performance, and identify which test is the best predictor of frailty in the older adults. METHODS: Cross-sectional, population- and home-based study that analyzed data from 286 older adults. The association between physical performance tests and frailty was verified by binary logistic regression. The diagnostic power of the performance tests and the identification of the best cut-off points to frailty were evaluated using the ROC curve and the area under the ROC curve. RESULTS: The prevalence of frailty was 23.8%. Frailty was associated with worse performances in the 'chair stand' test (p=<0.01) and the 'pick up a pen' test (p=<0.01). Performance requiring more than 14 seconds in the 'chair stand' test proved to be a good criterion for discriminating frailty in the older adults, considering the sensitivity and specificity. CONCLUSION: The worst performances in the tests were associated with the frailty syndrome. All tests were able to predict frailty in the older adults. However, taking into account the high sensitivity of the use of the 'pick up a pen' test to confirm a diagnosis of frailty (84.6%), this is recommended for use in home environments. PMID- 27969058 TI - Quality of life and functional status of patients treated for neoplastic disease in mid-northern Poland. AB - BACKGROUND: Research into the quality of life (QoL) of people with cancer is relevant for the diagnosis of the patient's health. The collected data are used to determine somatic complaints, psychological state and the needs for nursing care. AIM: The study aimed to assess the overall QoL and functional status in relation to basic activities of daily living of patients diagnosed with cancer in our region. METHODS: Using questionnaires for assessment of QoL and functional status (Barthel Index), we surveyed 500 adult patients (250 women and 250 men) diagnosed with neoplasms of varying etiology and staying at home. RESULTS: The average QoL (+/- standard deviation) in the study population was low and amounted to 34.5 (+/-22.7) on the scale of 0-100. The most intensive symptoms were fatigue (69.9 +/- 25.5) and pain (62.7 +/- 29.1). The greatest demand for nursing care concerned grooming and bathing. CONCLUSIONS: The QoL and functioning scores of patients with neoplasmic disease were low. The caregivers (usually nurses) should strive to minimize patients' fatigue and pain. PMID- 27969059 TI - Facilitators of and barriers to HIV self-management: Perspectives of HIV-positive women in China. AB - AIMS: The aim is to explore perceived facilitators of and barriers to HIV self management for HIV-positive Chinese women. BACKGROUND: Little is known about self management among HIV-positive Chinese women in China. Understanding the experiences of this population is needed to promote self-management. METHODS: 27 in-depth interviews were conducted in Beijing and Shanghai. Facilitators included families being supportive after disclosure, patients learning how to live with HIV, antiretroviral therapy (ART) adherence, and rediscovering the meaning of life. Several barriers were also identified, including lack of support, stigma, fatigue, and financial difficulty. RESULTS: HIV disclosure is essential to obtaining necessary support. Ironically, disclosing to family members who stigmatize the disease may invite unwelcome responses. Helping HIV-positive women to decrease self-stigma and develop an effective way to disclose, if they choose to, is important. CONCLUSION: Future interventions should focus on disclosure strategies development and self-management to prevent isolation, enhance social support, and decrease self-stigma. PMID- 27969061 TI - Decreased amygdala functional connectivity in adolescents with autism: A resting state fMRI study. AB - The human brain undergoes dramatic changes in amygdala-related functional connectivity network during adolescence. Given that the amygdala is a vital component of the "social brain", the Amygdala Theory of Autism has been proposed to account for atypical patterns of socio-emotional behavior in autism. Most of the previous neuroimaging evidence has concentrated on local functional or structural abnormalities of the amygdala in relation to social deficits in autism, rather than on its integrated role as part of larger brain networks. To examine whether functional integration pattern of the amygdala is altered in autism, the current study examined sixty-five adolescent subjects (30 autism and 35 healthy controls, 12-18 years old) from two independent datasets (UCLA and Leuven) of the Autism Brain Imaging Data Exchange. Whole-brain resting-state functional connectivity maps seeded in the amygdala were calculated and compared between patient and control groups. Compared with healthy controls, adolescents with autism showed decreased functional connectivity between the amygdala and subcortical regions in both datasets, including the bilateral thalamus and right putamen. These findings support the Amygdala Theory of Autism, demonstrating altered functional connectivity pattern associated with the amygdala in autism, and provide new insights into the pathophysiology of autism. PMID- 27969060 TI - Racial discrimination predicts greater systemic inflammation in pregnant African American women. AB - PURPOSE: Chronic exposure to racial discrimination by pregnant African American women may lead to allostatic overload; thereby, predisposing women to systemic inflammation. Thus, the goal of this study was to examine if experiences of racial discrimination are related to systemic inflammation in pregnant African Americans. METHODS: A sample of 96 African American women from Chicago completed questionnaires and had blood drawn during the second trimester of pregnancy (19.7+/-2.5 weeks). RESULTS: Experiences of racial discrimination were associated with higher cytokine levels of interleukin (IL)-4 (B=2.161, 95% CI = 1.02-3.30, p<.001) and IL-6 (B=1.859, 95% CI=.61-3.11, p=.004) when controlling for covariates. CONCLUSION: These findings suggest that experiences of racial discrimination may cause physiological wear and tear on the body leading to alteration of immune functions. Nurses should inquire about women's experiences of racial discrimination and make referrals for community or church support groups for women who report racial discrimination. PMID- 27969062 TI - Editorial. PMID- 27969063 TI - Identification, synthesis and structural characterization of process related and degradation impurities of acrivastine and validation of HPLC method. AB - Four impurities (Imp-I-IV) were detected using gradient HPLC method in few laboratory batches of acrivastine in the level of 0.03-0.12% and three impurities (Imp-I-III) were found to be known and one (Imp-IV) was unknown. In forced degradation study, the drug is degraded into four degradation products under oxidation and photolytic conditions. Two impurities (Imp-III and -IV) were concurred with process related impurities whereas Imp-V and -VI were identified as new degradation impurities. Based on LC-ESI/MSn study, the chemical structures of new impurities were presumed as 1-[(2E)-3-(4-methylphenyl)-3-{6-[(1E)-3-oxobut 1-en-1-yl]pyridin-2-yl}prop-2-en-1-yl]pyrrolidin-1-ium-1-olate (Imp-IV), 1-{[3-(4 methylphenyl)-3-{6-[(1E)-3-oxobut-1-en-1-yl]pyridin-2-yl}oxiran-2 yl]methyl}pyrrolidin-1-ium-1-olate (Imp-V) and 2-[2-(4-methylphenyl)-3-[(1 oxidopyrrolidin-1-ium-1-yl)methyl]oxiran-2-yl]-6-[(1E)-3-oxobut-1-en-1-yl]pyridin 1-ium-1-olate (Imp-VI), and confirmed by their synthesis followed by spectroscopic analysis, IR, NMR (1H, 13C) and mass. An efficient and selective high-performance liquid chromatography method has been developed and resolved well the drug related substances on a Phenomenex Gemini C-18 (250*4.6mm, particle size 5MUm) column. The mobile phase was composed of sodium dihydrogen phosphate (10mM) and methanol, temperature at 25 degrees C, and a PDA detector set at 254nm used for detection. The method was validated with respect to specificity, linearity, precision, accuracy, and sensitivity and satisfactory results were achieved. Identification, synthesis, characterization of impurities and method validation were first reported in this paper. PMID- 27969064 TI - Determination of five potential genotoxic impurities in dalfampridine using liquid chromatography. AB - A sensitive and selective HPLC method was developed for identification and quantification of five Potential genotoxic impurities (PGIs) viz. Impurity-I, Impurity-II, Impurity-III, Impurity-IV and Impurity-V in Dalfampridine (Drug substance). The method utilizes Zorbax silica column (250mm*4.6mm, 5.0MUm) with UV detector in HILIC (Hydrophilic Interaction Liquid Chromatography) mode for quantitation of five PGIs. It has been validated as per International Council for Harmonisation (ICH) guidelines and is able to quantitate all PGIs at 75ppm with respect to 20mg/mL of sample concentration. It is linear in the range of 22.5 112.5ppm for all PGIs, which matches the range of LOQ-150% of estimated permitted level (75ppm). Its accuracy was established in the range from 88.14 to 107.65% for these PGIs. The correlation coefficient of each impurity was >0.999. It is a good quality control tool for quantitation of PGIs in Dalfampridine at low level. PMID- 27969065 TI - Cross cultural variations in psychiatrists' perception of mental illness: A tool for teaching culture in psychiatry. AB - A frequent debate in psychiatry is to what extent major psychiatric diagnoses are universal versus unique across cultures. We sought to identify cultural variations between psychiatrists' diagnostic practices of mental illness in Boston Massachusetts and Bangalore, India. We surveyed psychiatrists to identify differences in how frequently symptoms appear in major mental illness in two culturally and geographically different cities. Indian psychiatrists found somatic symptoms like pain, sleep and appetite to be significantly more important in depression and violent and aggressive behavior to be significantly more common in mania than did American psychiatrists. American psychiatrists found pessimism about the future to be more significant in depression and pressured speech and marked distractibility to be more significant in mania than among Indian psychiatrists. Both groups agreed the top four symptoms of psychosis were paranoia, lack of insight, delusions and auditory hallucinations and both groups agreed that visual hallucinations and motor peculiarities to be least significant. Despite a different set of resources, both groups noted similar barriers to mental health care access. However, American psychiatrists found substance abuse to be a significant barrier to care whereas Indian psychiatrists found embarrassing the family was a significant barrier to accessing care. Because psychiatrists see a large volume of individuals across different cultures, their collective perception of most common symptoms in psychiatric illness is a tool in finding cultural patterns. PMID- 27969066 TI - Depression among Indian university students and its association with perceived university academic environment, living arrangements and personal issues. AB - The aim of the study is to ascertain the level of depression among university students across gender, academic stream, semesters, perception of family environment and relationship with parents, academic performance, and family income. In addition, the study examines the association between students' perceived university academic environment, living arrangements, personal issues, and depression. Seven hypotheses were formulated for verification. A total of 717 students were recruited following the multistage cluster sampling method, and data were collected by a specially designed structured questionnaire, academic achievement record and a standardized University Students Depression Inventory. Findings disclosed that 37.7%, 13.1%, and 2.4% of the students were suffering from moderate, severe, and extremely severe depression. A significant difference was found across semester, that is, semester II students reported a higher level of depression than semester III students. So far as academic stream is concerned, students from humanities and social science were found to be suffering from more depression compared to students from science and management streams. The study further disclosed that the students who reported positive views about the university academic environment and living arrangements had lower level of depression compared to their counterparts. Personal resilience's such as being able to sharing personal problems with others and doing regular exercise were found to be associated with positive mental health. The findings of the study emphasize the need for immediate mental health support services for about 15.6% of the students who were either suffering from severe or extremely severe depression at the University. PMID- 27969067 TI - Clozapine, immunosuppressants and renal transplantation. PMID- 27969068 TI - Psychological characteristics of self-harming behavior in Korean adolescents. AB - Recently, self-injury is drawing the attention of researchers and clinicians. The purpose of this study was to investigate the prevalence and psychological characteristics of adolescents who engage in self-harm and to examine the risk factors for engaging in this harmful behavior among Korean mid-adolescents. Participants were 784 adolescents aged 13-15 years. They completed self-report questionnaires that assessed (1) Non-Suicidal Self-Injury: the Self-Harm Questionnaire, Toronto Alexithymia Scale; (2) depression: Children's Depression Inventory; (3) adolescent-parent relationship: Parental Bonding Instrument; (4) peer attachment: Inventory of Parent and Peer Attachment; and (5) academic stress. Overall, 12.4% (n=97) of participants reported engaging in self destructive behavior at least once in their lives. The primary reason for engaging in self-harm was to regulate negative emotions such as anger and sadness. As expected, the self-harm group showed statistically significant higher levels of academic stress, alexithymia, depression, and poor relationships with their parents and peers. Stepwise multiple regression analysis showed that alexithymia, depression, and peer relations were significant predictors of self harming behavior. Given that the primary reason for engaging in self-harm is to cope with negative emotions, mental health professionals in school settings should regularly evaluate self-injurious behavior and provide prevention programs for adolescents at risk. PMID- 27969069 TI - Are community treatment orders counterproductive? AB - OBJECTIVE: This article briefly reviews the literature pertaining to community treatment orders (CTOs) specifically how and why they are utilised and how effective mandated community treatment really is. This review discusses the use of CTOs in the context of the recovery model. CONCLUSIONS: This article highlights the shortfalls in the current CTO system while also demonstrating the increase in acute coercive care. The literature pertaining to the effectiveness of CTOs is inconsistent with more recent reviews denoting that there is now robust evidence the CTOs are not effective. Further treatment that aligns with the recovery model as oppose to mandated treatment is known to increase treatment compliance. PMID- 27969070 TI - Aripiprazole induced Impulse Control Disorders: Where do we stand? PMID- 27969071 TI - Smartphone-based ecological momentary assessment for Chinese patients with depression: An exploratory study in Taiwan. AB - Mobile mental health has a potential to improve the recognition and management of Chinese patients with depression. Currently, evidence regarding ecological momentary assessment (EMA) for depressive disorder mostly originates from Western studies. Herein, we examined the validity of smartphone-based EMA for depression in Chinese patients and explored the determinants of use. A smartphone application, iHOPE, was used to perform daily EMA of depression, anxiety, sleep and cognitive performance. Outpatients with depressive disorder were recruited to use iHOPE for 8 weeks. Clinical characteristics and smartphone use patterns were assessed at baseline. We enrolled 59 Chinese patients with depression. In 8 weeks, participants interacted with iHOPE for an average of 10.8 (SD=12.3) days; a trend of decreased frequency of use (p=0.03) was observed. Scores of HAM-D at baseline was associated with, of the first 2 weeks, scores of PHQ-9 (p=0.005), EMA of depression (p=0.003) and anxiety (p<0.001), and poorer sleep quality (p=0.023). Among the demographic, clinical and smartphone-use variables examined, only limited internet package for smartphone (<500M per month) predicted higher use of iHOPE (p=0.04). The present study provides initial evidence for the feasibility of smartphone-based EMA in Chinese patients with depression. Level of engagement needs to be improved before determining its clinical usefulness. PMID- 27969072 TI - A study of assessment of sexual dysfunction in male subjects with opioid dependence. AB - CONTEXT: The relationship between opioid use and sexual problems among males is complex one, as some are using opioids to increase their sexual performance while others are suffering from sexual problems due to its use. And research addressing this relationship is still limited. AIMS: The aim of the current study was to assess and evaluate sexual dysfunction in male subjects seeking treatment for opioid dependence and to compare it with healthy control group. METHODS AND MATERIAL: 60 male subjects with opioid dependence for more than one year (ICD-10 criteria) were compared to 120 healthy age & tobacco abuse matched control group (case: control=1:2) using standard questionnaires evaluating various domains of sexual dysfunction. RESULTS: Opioid dependents were found to have sexual dysfunction ranging from 53.3% to 81.7% which was significantly greater than the healthy control group (15.8% to 41.7%). CONCLUSIONS: Sexual dysfunctions are highly prevalent in opioid dependents and this should be addressed properly while assessing and treating a patient of opioid dependence. PMID- 27969073 TI - Adolescent-parent conflict in the age of social media: Case reports from India. AB - Social media activities have gained popularity amongst children and adolescents as a means of communication; giving them the opportunity for independence and social development as well as rendering them vulnerable to negative influences. In traditionally collectivistic societies like India, moving rapidly towards modernisation, not only is there a divide between parents and adolescents over the endorsement of these sites, but also regarding value systems related to autonomy and dating that are facilitated by such activities. We present cases of two adolescent girls to highlight adolescent parent conflict that arises in the age of social media in a cultural context. Further, the cases underscore that value systems and culture play an important role in resolution of such conflict. PMID- 27969074 TI - Assessing catatonia using four different instruments: Inter-rater reliability and prevalence in inpatient clinical population. AB - BACKGROUND AND AIMS: The present study aimed to assess inter-rater reliability and prevalence of catatonia according to four diagnostic methods: Bush Francis Catatonia Rating Scale (BFCRS) both screening and complete scale, Braunig's Catatonia Rating Scale (CRS), ICD 10 and DSM5. METHODS: For inter-rater reliability, different raters evaluated patients using the definitions provides by the four scales: BFCRS Screen and Total, CRS, ICD10 and DSM5. Kippendorff'alpha was used to compute the inter-rater reliability. Concordance between different systems was assessed using spearman correlation. Prevalence of catatonia was studied using the four definitions in a clinical sample of consecutive adult admissions in a psychiatry ward of a tertiary care hospital. RESULTS: The inter-rater reliability was found to be good for BFCRS Total (alpha=0.779), moderate for DSM5 and BFCRS screen (alpha=0.575 and alpha=0.514 respectively) and low for CRS and ICD10 (alpha=0.111 and alpha=0.018 respectively). BFCRS Total and DSM5 definitions of catatonia had highest concordance (rs=0.892 p<0.001). In the prevalence sample of consecutive hospital admissions, the prevalence was found to be highest with the definitions of BFCRS Screen and ICD 10 (10.3%, confidence intervals [CI] 3.9% to 16.7%), followed by BFCRS Total and DSM5 definitions 6.9%, CI 1.6% to 12.2%) and while CRS yielded the lowest prevalence rate (3.4%, CI 0% to 7.2%). CONCLUSION: Different methods used to determine catatonia in the clinical sample yield different prevalence of this condition. PMID- 27969075 TI - Prevalence, correlates, comorbidity and severity of generalized anxiety disorder in Singapore. AB - Despite its pervasiveness and associated impairment, generalized anxiety disorder (GAD) remains a poorly recognized disorder. Furthermore, given that GAD has been relatively understudied in Asia, the current study examined the prevalence, correlates and co-morbid conditions of this disorder in a multi-ethnic population of Singapore. Data was utilized from the Singapore Mental Health Study (SMHS), a cross-sectional epidemiological survey conducted among the adult population (n=6616) aged 18 years and above. The Composite International Diagnostic Interview version 3.0 (CIDI v3.0) was used to assess co-morbidity as well as the life-time and 12-month prevalence of disorders. Functional impairment and treatment-seeking behavior were also assessed. The life-time (0.9%) and 12-month (0.4%) prevalence estimates in the current study were found to be lower than those reported in Western populations but comparable to the prevalence estimates found in Asian countries. The relatively lower prevalence rate of GAD in this study suggests the possible role of culture in reporting and manifestation of anxiety symptomatology. The failure of a substantial proportion of individuals to seek treatment despite self-reported impairment was also identified as an area of concern. PMID- 27969076 TI - The impact of IL10 polymorphisms and sHLA-G levels on the risk of schizophrenia. AB - Early life immune aberrations have strongly been associated with the risk of schizophrenia. Amongst them, inflammation induced neurodevelopmental origin has emerged as one of the widely recognized underlying mechanisms. Interleukin-10 (IL 10) is an important anti-inflammatory and immunoregulatory cytokine. It modulates the expression of another immuno-inhibitory molecule, Human Leukocyte Antigen-G (HLA-G), predominantly expressed at the feto-maternal interface. Under physiological conditions, IL-10 and HLA-G molecules regulate the feto-maternal immune homeostasis by limiting the inflammatory states and influence the outcome of pregnancy. The aberrant expression of these molecules can cause pregnancy complications, which are known to confer strong risk to schizophrenia in the offspring. However, there is a considerable lack of information on the effect of the functional interactions between IL-10 and HLA-G on the risk of schizophrenia. We therefore examined the impact of possible correlation between IL-10 genetic variations and the plasma levels of soluble HLA-G (sHLA-G) on schizophrenia risk. Genotyping of IL10 (-592 C>A, -1082 A>G) single nucleotide polymorphisms (SNPs) was performed by PCR-RFLP method in 219 schizophrenia patients and 197 healthy subjects and levels of sHLA-G were estimated by ELISA in 46 patients and 44 healthy subjects. There was no significant difference in the genotype and allele frequencies between the groups for both the IL10 SNPs analyzed. However, we observed a correlation between IL10 genetic variation and plasma levels of sHLA-G in schizophrenia patients. Patients carrying CC genotype of IL10 -592C>A polymorphism had significantly lower sHLA-G levels compared to CA and AA genotypes. Our findings suggest the impact of possible correlation between IL-10 and HLA-G on schizophrenia risk. PMID- 27969077 TI - Trichobezoar (Rapunzel syndrome) in an adolescent patient with Trichotillomania and Generalized Anxiety Disorder: A case report. PMID- 27969078 TI - Sex differentials in the risk factors of post traumatic stress disorder among tsunami survivors in Tamil Nadu, India. AB - This study assessed if pre disaster, with-in disaster and post disaster factors predicted Post Traumatic Stress Disorder (PTSD) differently, among men and women survivors of the 2004 Southeast Asian tsunami in Kanyakumari district, Tamil Nadu, India. PTSD was identified using a validated tool, Impact of Events Scale Revised (IES-R) among the participants in a cross-sectional community based survey (n=485). Case control analysis of 299 subjects was done to determine the predictors of PTSD. The odds of having PTSD were 6.35 times higher in women than men. Higher odds for PTSD was seen among women who were married, aged over 40, belonged to low socioeconomic status and resided in heavily damaged areas. Protective odds for PTSD was found among women who had received more than three times of counseling services whereas men were not at risk if they were free from fear of recurrence of tsunami, when adjusted for other variables. Women were vulnerable to PTSD because of their socially constructed roles. It is important to consider gender based vulnerabilities while designing interventions to combat mental health problems among disaster affected communities. PMID- 27969079 TI - Depression and intimate partner violence among college students in Iran. AB - Intimate partner violence (IPV) is a significant public health threat and causes mental as well as physical health problems. Depression is a common mental health consequence of IPV. While Iran has a high prevalence of IPV and depression, the association between IPV and depression has not been well examined. The Iranian data from the International Dating Violence Study (IDVS) 2001-2006 (ICPSR 29583) were analyzed. Twenty-three male and 75 female college students were selected in the IDVS Iranian data. Nearly all of the participants, male and female, reported being victims and perpetrators of IPV. Female participants were more likely to report depression compared to male participants. Participants who had experienced sexual IPV reported significantly higher levels of depression compared to those who did not experience sexual IPV. However, when substance abuse and partner conflict were analyzed, the contribution of sexual IPV on depression was no longer significant. This study suggests that IPV prevention and intervention programs should take into consideration that college-aged men and women frequently experience and use violence in dating relationships. Depression interventions should be included for female students. Substance abuse and partner conflict are important risk factors for depression. PMID- 27969080 TI - Psychological health and menopause-specific quality of life of Malaysian women with type 2 diabetes. AB - Anxiety and depression are more common among females and those experiencing diabetes and menopause. Menopausal symptoms experienced by women can vary tremendously from population to population; therefore, there is a need to investigate these symptoms and associated risk factors in different communities. This study investigated the differences in psychological health and menopause specific quality of life (MENQOL) between women with and without diabetes type 2 (T2DM) in Malaysia. Women with T2DM (n=320) were matched by age range to controls without T2DM (n=320). Data were collected from March 2012 to January 2013. Delusions Symptoms States Inventory (DSSI) instrument was used to identify symptoms of depression and anxiety. Women with diabetes had higher depressive (11.8% versus 8.4%) and anxiety (8.4% versus 6.6%) symptoms compared to women without diabetes. In both groups, the most common menopausal symptom was aches (muscles and joints). Women without diabetes had significantly higher scores for the sexual domain compared to women with diabetes (4.20 versus 3.21, p=0.001). The odds that a postmenopausal woman with diabetes was depressed or anxious on the DSSI scale increased significantly when the MENQOL score on the physical, vasomotor, and psychosocial domains increased by one unit. Both diabetes and psychological problems have negative impact on MENQOL. Our findings support the view of screening postmenopausal women with diabetes for depressive and anxiety, to improve overall quality of life. PMID- 27969081 TI - Knowledge, attitude and social distance practices of young undergraduates towards mental illness in India: A comparative analysis. AB - The success of the current model of psychiatric care depends on de-stigmatization of mental illnesses, highlighting the need for research on perception of mental illnesses. This study compared the knowledge, attitude and social distancing practices of the young undergraduate sub-population towards mental illness. A cross-sectional survey was done using a pretested questionnaire, which in addition to demographic details assessed exposure, knowledge, attitude and social distancing practices for mental illnesses. The study included (N=289; 55% Females; Average age 20.5 years) responses from nearly equal number of students from medical, psychology and other courses. Medical students chiefly attributed mental illness to biological factors while students from other courses perceived mental illness as God's punishment. More medical students believed that mental illnesses can be successfully treated and appeared to have less social distancing from the mentally ill. Males mostly reported stress and brain damage as the causative factors while females attributed mental illnesses to other biological factors. Males were found to be less afraid of a communication with mentally ill and more open to the possibility of marriage with someone suffering from a mental illness. Exposure to information about mental illness led to no significant variation in the studied variables. Thus, demographic variables and the academic course contribute to variations in knowledge and attitude of young adults. Education received by medical students has a positive impact on their attitudes, highlighting the need of introduction of informative awareness measures among other courses as well. PMID- 27969082 TI - Myalgic Encephalomyelitis, chronic fatigue syndrome or systemic exercise intolerance disease: What's in a name? PMID- 27969083 TI - Health and quality of life among the caregivers of children with disabilities: A review of literature. AB - Families caring for children with disabilities face particular challenges and demands compared to those caring for children without disabilities. Evidence suggests that there is considerable variation in how caregivers of children with disabilities adapt to their caregiving demands and stressors. The different adaptations to the children with disabilities may cause different impacts on the health and well-being of caregivers. This paper provides a brief overview of the literature on the impact of caring for children with disabilities on the health and quality of life of caregivers and the factors related to the health outcomes and quality of life. A literature search was conducted by using various electronic databases, including PsychINFO, ScienceDirect, ProQuest, and MEDLINE using specific key terms. Thirty-one articles published in peer-review journals from the last six years (2009-2014) were reviewed. Most of the studies were quantitative studies. Factors discussed that impact on caregivers' health and quality of life include the caregivers' sociodemographic background and child's disability-related factors. Several mediators and moderators including coping strategies, social support, parental stress, self-esteem and self-efficacy are described in this paper. This review highlighted the importance of these factors to better understand the complex nature of stress processes and the caregivers' adaptations to their children's disabilities. PMID- 27969084 TI - Religious coping among self-harm attempters brought to emergency setting in India. AB - This study attempted to evaluate religious coping and its correlates among patients presenting with self-harm to an emergency setting and compared it with a healthy control group. Religious coping was assessed using brief RCOPE. Beck Hopelessness Scale, Beck Depression Inventory, Barratt Impulsivity Scale, Scale for Suicidal Ideations and Irritability Depression Anxiety scale were used to assess for hopelessness, depression, impulsiveness, suicidal ideations and irritability respectively. The study included 32 subjects with depression and 77 subjects without any psychiatric diagnosis who presented with self-harm and 50 healthy controls. Compared to healthy controls, those with self-harm irrespective of presence or absence of psychiatric diagnosis less often used positive religious coping and more often used negative religious coping. Further, among those without psychiatric diagnosis (with self harm), there was positive correlation of negative religious coping with impulsivity and hopelessness. Among those without psychiatric diagnosis with self-harm, both positive and negative religious coping correlated positively with depressive scores, severity of suicidal ideations, anxiety and irritability, but associations were stronger for negative religious coping than that for positive religious coping. The findings of the present study suggest that those who indulge in self harm have lower use of positive religious coping and higher use of negative religious coping. PMID- 27969086 TI - Homicide and mental disorder in a region with a high homicide rate. AB - There are few studies of the relationship between mental disorder and homicide offences from regions with high rates of homicide. We examined the characteristics and psychiatric diagnoses of homicide offenders from the Chuvash Republic of the Russian Federation, a region of Russia with a high total homicide rate. In the 30 years between 1981 and 2010, 3414 homicide offenders were the subjected to pre-trial evaluations by experienced psychiatrists, almost half of whom (1596, 46.7%) met the international classification of diseases (ICD) 10 criteria for at least one mental disorder. The six most common individual diagnoses were alcohol dependence (15.9%), acquired organic mental disorder (7.3%), personality disorder (7.1%), schizophrenia (4.4%) and intellectual disability (3.6%). More than one disorder was found in 7.4% of offenders and alcohol dependence was the most frequently diagnosed co-morbid disorder. One in ten offenders were found to be not criminally responsible for their actions. Few homicides involved the use of substances other than alcohol, and firearms were used in 1.6% of homicides. The finding that people with mental disorders other than psychosis committed a high proportion of homicides in a region with a high rate of homicide, suggests that people with mental disorders are vulnerable to similar sociological factors to those that contribute to homicide offences by people who do not have mental disorder. PMID- 27969085 TI - Auditory P300 event related potentials in acute and transient psychosis Comparison with schizophrenia. AB - BACKGROUND: Limited biological research data are available on acute and transient psychotic disorder (ATPD) vis-a-vis schizophrenia. P300 event related potentials (ERP) have been extensively studied as an important neurophysiological parameter in schizophrenia. However, no P300 ERP studies comparing the two disorders are available. We compared auditory P300 ERP in patients remitted from ATPD with schizophrenia in remission and biologically unrelated healthy controls. METHODS: In this case-control study design, 25 subjects remitted from ATPD were age /gender-matched with healthy controls and patients with schizophrenia in remission. Clinical assessment and auditory P300 ERP (amplitude and latencies at central and parietal sites, reaction time) were recorded. The ERP parameters were compared across the three groups. RESULTS: All three groups showed significant differences in P300 amplitudes and latencies at central and parietal sites. Schizophrenia group differed significantly (p<0.001) from the ATPD group in all the P300 parameters. The ATPD group was found to have lower Pz latency (p<0.05) and lower mean reaction time (p<0.001) as compared to healthy controls. CONCLUSION: The results suggest that P300 could easily distinguish between ATPD and schizophrenia in remission, thus neurophysiologically differentiating the two disorders. Lower P300 latency and reaction time, which indicate hyper arousability, distinguished ATPD from normal controls, with implications for a better understanding of ATPD. PMID- 27969087 TI - Forced normalization: An overlooked entity in epileptic patients. AB - The "forced normalization" phenomenon is characterized by acute/subacute onset of psychotic symptoms in the early post-ictal period with dramatic improvement of electrophysiological epileptiform activity. A 56 years old female with going on personality changes, maladaptive behaviours and a mild cognitive impairment since last seizure which was forty-five days ago has been admitted. An evident increase was observed in her maladaptive behaviours with the use of levetiracetam. She began describing visual hallucinations and dejavu. Control EEG performed 24h after the seizure was completely normal. Levetiracetam therapy was replaced with phenytoin. Quetiapine therapy was also administered. Psychotic symptoms disappeared. PMID- 27969088 TI - Caseness rates and risk factors for depression among Vietnamese cancer patients. AB - OBJECTIVE: Research suggests that rates of depression among general population samples in Asia may be significantly lower than in much of the rest of the world. However, whether this applies to depression among cancer patients is unclear, which is important to determine in order to identify depression treatment needs among cancer patients in this region. The purpose of the present study was to assess caseness rates of serious depression among general cancer patients in the Southeast Asian nation of Viet Nam. METHOD: A total of 695 adult cancer patients from three hospitals in Da Nang, Viet Nam served as study participants. They were assessed at one time point for (a) demographic and (b) cancer characteristics, and (c) depression symptoms. RESULTS: The overall caseness rate for serious depression was 28%. Although rates of depression in general population samples usually are significantly higher in women than men, rates of depression among men and women did not differ significantly among our cancer patients. Higher levels of depressive symptoms were found, however, as a function of lower patient income and education, occupation, cancer stage, and type of cancer, but not marital status or age. CONCLUSIONS: Caseness rates of depression are significantly elevated by a factor of 10-15 among Vietnamese cancer patients relative to general population epidemiological studies in the same region. Although a number of studies have found that rates of depression tend to be lower in Asian as compared to Western general population samples, depression rates among our Vietnamese cancer patients were similar to those reported among Western cancer patients. This suggests that whatever factors are responsible for the relatively low rates of depression observed in Asian general population samples may not be operating in regards to cancer-related depression. Overall, the value of these findings are not only that they provide information for policy makers in Viet Nam to support depression treatment among cancer patients, but also that they suggest that despite the apparent relatively low overall rates of depression it may be useful for cancer and mental health researchers in the region to conduct similar assessments for their policy makers. PMID- 27969089 TI - Effectiveness of taking in the good based-bibliotherapy intervention program among depressed Filipino female adolescents. AB - Adolescent depression is a severe mental health problem. Philippines has the highest incidence of depression in South East Asia. Depressed female adolescents habitually seek and retain negative experiences. Aim of this research was to develop and to assess effectiveness of a Taking in the Good Based-Bibliotherapy Intervention Program for female adolescents. As an innovative type of psychotherapy treatment, program aimed to build up their inner strengths by experiencing, enriching and absorbing daily events with a positive attitude and installing them in brain. Program was conducted in two phases: 1. Development of taking in the good based-bibliotherapy intervention. 2. Implementation and assessment of pioneering treatment for alleviating depression and thereby increasing positive cognitive appraisal by employing true experimental research design particularly between subjects. Beck Depression Inventory-II, Asian Adolescent Depression Scale and Kutcher Adolescent Depression Scale-11 were administered before and after implementation of the program. A total of 30 female adolescents, Filipino High School students, (mean age=13.9), were randomly assigned to experimental (n=15) and control (n=15) conditions. Data analysis was done by employing percentage and frequency distribution, mean scores, standard deviation, dependent t-test, independent t-test statistics and Cohen's d. The null hypothesis was tested at the 0.05 level of significance. Statistical analysis between the pre-test and post-test scores of the experimental group showed significant difference (p=0.000) and scores of control and experimental group showed significant difference (p=0.000) in all dependent variables in the post-test. These results revealed that "Taking in the Good based-Bibliotherapy Intervention" was effective in reducing depression in female adolescents. PMID- 27969095 TI - Editorial. PMID- 27969096 TI - Response to commentary by Alaa El-Ghoneimi. PMID- 27969097 TI - A potpourri of pediatric urology. PMID- 27969098 TI - Erratum to "Laparoscopic percutaneous inguinal hernia repair in children: Review of technique and comparison with open surgery" [J Pediatr Urol 11 (2015) 262.e1 262.e6]. PMID- 27969101 TI - Highlights from the 18th workshop on vitamin D, Delft, The Netherlands, April 21 24, 2015. PMID- 27969102 TI - Regulation, evolution and consequences of cotranslational protein complex assembly. AB - Most proteins assemble into complexes, which are involved in almost all cellular processes. Thus it is crucial for cell viability that mechanisms for correct assembly exist. The timing of assembly plays a key role in determining the fate of the protein: if the protein is allowed to diffuse into the crowded cellular milieu, it runs the risk of forming non-specific interactions, potentially leading to aggregation or other deleterious outcomes. It is therefore expected that strong regulatory mechanisms should exist to ensure efficient assembly. In this review we discuss the cotranslational assembly of protein complexes and discuss how it occurs, ways in which it is regulated, potential disadvantages of cotranslational interactions between proteins and the implications for the inheritance of dominant-negative genetic disorders. PMID- 27969440 TI - ORAL01.01: A Prospective, Multi-Institutional Assessment of Four Assays for PD-L1 Expression in NSCLC by Immunohistochemistry: Topic: Pathology. PMID- 27969441 TI - ORAL01.02: Biopsies in Initial Diagnosis of Non-Small Cell Lung Cancer in US Community Oncology Practices: Implications for First-Line Immunotherapy: Topic: Medical Oncology. PMID- 27969442 TI - ORAL01.03: CheckMate 012: Safety and Efficacy of First-Line Nivolumab and Ipilimumab in Advanced NSCLC: Topic: Medical Oncology. PMID- 27969443 TI - ORAL01.04: Phase II Trial of Atezolizumab for Patients with PD-L1-Selected Advanced NSCLC (BIRCH): Updated Efficacy and Exploratory Biomarker Results: Topic: Medical Oncology. PMID- 27969444 TI - ORAL02.01: Safety and Efficacy of Single-Agent Rovalpituzumab Tesirine, a DLL3 Targeted ADC, in Recurrent or Refractory SCLC: Topic: Medical Oncology. PMID- 27969446 TI - ORAL02.03: Robust Correlation Between Metabolic Response Measured with 18F-FDG PET Soon After Therapy and Clinical Outcome in Lung Cancer: Topic: Radiation Oncology. PMID- 27969445 TI - ORAL02.02: Efficacy and Safety of Everolimus in Advanced, Progressive, Nonfunctional Neuroendocrine Tumors (NET) of the Lung: RADIANT-4 Subgroup Analysis: Topic: Medical Oncology. PMID- 27969447 TI - ORAL02.04: Predictors of Adverse Perioperative Outcome Following Lobectomy: A Population Based Analysis: Topic: Surgery. PMID- 27969448 TI - ORAL02.05: Understanding Internal Differences in N-Category-Stratified Non-Small Cell Lung Cancer (NSCLC) Survival: Topic: Surgery. PMID- 27969449 TI - MINI01.02: Response and Plasma Genotyping from Phase I/II Trial of Ensartinib (X 396) in Patients (pts) with ALK+ NSCLC: Topic: Medical Oncology. PMID- 27969450 TI - MINI01.01: Whole Body and Intracranial Efficacy of Ceritinib in ALK-inhibitor Naive Patients with ALK+ NSCLC and Brain Metastases: Results of ASCEND 1 and 3: Topic: Medical Oncology. PMID- 27969451 TI - MINI01.03: Phase (Ph) I Study of the Safety and Efficacy of the cMET Inhibitor Capmatinib (INC280) in Patients with Advanced cMET+ NSCLC: Topic: Medical Oncology. PMID- 27969452 TI - MINI01.04: ROS1 Fusion Chinese Lung Adenocarcinoma Patients Treated with Crizotinib Detected Using Next-Generation Genotyping from ctDNA: Topic: Medical Oncology. PMID- 27969453 TI - MINI01.05: RALPB1 Mediate ALK Resistance in Non-Small Cell Lung Cancer: Topic: Medical Oncology. PMID- 27969454 TI - MINI01.06: Circulating Angiogenesis Biomarkers are Predictive for Early Stage Non Small Cell Lung Cancer Progression and Clinical Outcome: Topic: Pathology. PMID- 27969455 TI - MINI01.07: Predictors of Conversion to Thoracotomy in VATS Lobectomy Patients: Topic: Surgery. PMID- 27969456 TI - MINI01.09: Outcomes of Early Stage Large Cell Neuroendocrine Lung Carcinoma (LCNELC): A National Cancer Database (NCDB) Analysis: Topic: Medical Oncology. PMID- 27969457 TI - MINI01.08: Disparities in the Management of Patients with Stage I Small Cell Lung Cancer (SCLC): A Surveillance, Epidemiology and End Results (SEER) Analysis: Topic: Surgery. PMID- 27969458 TI - MINI01.10: Diverse Populations may be Underrepresented in Community Lung Cancer Screening Programs: Topic: Pulmonology. PMID- 27969459 TI - MINI01.11: Radiotherapy Plus EGFR TKIs for Brain Metastasis in EGFR-Mutant Non Small Cell Lung Cancer: A Retrospective Analysis of a Single Institution: Topic: Medical Oncology. PMID- 27969460 TI - MINI01.12: Angiogenesis Biomarkers are Associated with Progression Free Survival in Non-Small Cell Lung Cancer Treated with SBRT: Topic: Radiation Oncology. PMID- 27969461 TI - MINI01.13: Prediction of Lung Toxicity in the Definitive Radiotherapy of Non Small Cell Lung Cancer using Clinical, Dosimetric and Biologic Factors: Topic: Radiation Oncology. PMID- 27969462 TI - MINI01.15: Prophylactic Cranial Irradiation (PCI) for Limited Small Cell Lung Cancer (LSCLC): An IASLC Physician Survey: Topic: Radiation Oncology. PMID- 27969463 TI - MINI01.14: Self-Efficacy and Decisions in Lung Cancer: Early Stage Lung Cancer Comparative Effectiveness Research Consortium Results: Topic: Radiation Oncology. PMID- 27969464 TI - MINI01.16: Not So Easy: Readability Assessment of Patient Education Material on Non-Small Cell Lung Cancer Immunotherapy: Topic: Medical Oncology. PMID- 27969465 TI - MINI01.17: Project Reach: Piloting a Risk-Tailored Smoking Cessation Intervention for Lung Screening: Topic: Pulmonology. PMID- 27969466 TI - MINI01.18: Integration of Tobacco Cessation in a Lung Cancer Screening Program: Topic: Pulmonology. PMID- 27969467 TI - MINI01.19: Cost Analysis of Pemetrexed-Platinum with Maintenance vs. Paclitaxel Carboplatin-Bevacizumab with Maintenance in Patients with Lung Cancer: Topic: Medical Oncology. PMID- 27969468 TI - MINI01.20: Interim Quality of Life (QoL) Results from ABOUND.sqm: nab Paclitaxel/Carboplatin Induction Therapy in Squamous (SCC) NSCLC: Topic: Medical Oncology. PMID- 27969469 TI - PS01.02: Thoracic Oncology Clinical Trial Eligibility Criteria: Ongoing Increase in Recent Years: Topic: Medical Oncology. PMID- 27969470 TI - PS01.01: Simulation in the Management of EGFR-Mutated Advanced NSCLC: Seeing Beyond Age: Topic: Medical Oncology. PMID- 27969471 TI - PS01.03: Referral Practices of Medical Oncologists to Palliative Care for Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC): Topic: Medical Oncology. PMID- 27969472 TI - PS01.04: A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer: Topic: Medical Oncology. PMID- 27969473 TI - PS01.05: Early and Persistent Oligoclonal T Cell Expansion Correlates with Durable Response to Anti-PD1 Therapy in NSCLC: Topic: Medical Oncology. PMID- 27969475 TI - PS01.07: Geographical Distribution of Lung Cancer Mortality Worldwide: Topic: Pathology. PMID- 27969474 TI - PS01.06: Tumor Heterogeneity in Lesion Specific Response Creates ROS1 Fusion Mediating Resistance to Gefitinib in EGFR 19 Deletion Lung Adenocarcinoma: Topic: Medical Oncology. PMID- 27969476 TI - PS01.10: Medically Underserved and Geographically Remote Individuals may be Underrepresented in Current Lung Cancer Screening Programs: Topic: Pulmonology. PMID- 27969477 TI - PS01.08: ABOUND.PS2 Interim Safety Results: nab-Paclitaxel/Carboplatin Followed by nab-Paclitaxel in NSCLC Patients with ECOG PS of 2: Topic: Medical Oncology. PMID- 27969479 TI - PS01.13: Transbronchial Lung Biopsy on Mechanical Ventilation: Is It Safe To Do?: Topic: Pulmonology. PMID- 27969478 TI - PS01.11: Comparison of Initial (T0) Screens in UI Health's Minority-Based Lung Cancer Screening Program to that of the National Lung Screening Trial (NLST): Topic: Medical Oncology. PMID- 27969480 TI - PS01.12: C11-Choline Positron Emission Tomography and the Detection of Primary Lung Cancers: Topic: Medical Oncology. PMID- 27969481 TI - PS01.14: Diagnostic Yield in Patients Undergoing Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration: A Single Center Experience: Topic: Pulmonology. PMID- 27969482 TI - PS01.15: Outcomes after the Decision to Biopsy: Results from a Nurse Practitioner Run Multidisciplinary Lung Cancer Screening Program: Topic: Pulmonology. PMID- 27969483 TI - PS01.16: Shortening Time from Diagnosis to Treatment in NSCLC: Are Blood-Based Biopsies the Answer?: Topic: Pulmonology. PMID- 27969484 TI - PS01.18: The Characteristics of Active Pulmonary Tuberculosis in Lung Cancer Patients: Topic: Pulmonology. PMID- 27969485 TI - PS01.17: Community-Based Low-Dose Computed Tomography (LDCT) Lung Cancer Screening in the US Histoplasmosis Belt: One Year Followup: Topic: Pulmonology. PMID- 27969486 TI - PS01.19: Bilateral Endobronchial Typical Carcinoid with Bronchoscopic Therapy: A Retrospective Evaluation: Topic: Pulmonology. PMID- 27969487 TI - PS01.20: Immune Checkpoints Expression in Small Cell Lung Cancer Lines: Topic: Pathology. PMID- 27969488 TI - PS01.21: Time and Effort Required for Tissue Acquisition and Submission in Lung Cancer Clinical Trials: Topic: Pathology. PMID- 27969489 TI - PS01.22: Novel 3-Dimensional Preclinical Models: Topic: Medical Oncology. PMID- 27969490 TI - PS01.23: Epidemiology of Neuroendocrine Tumors (NET) of the Lung in the US: Analysis of 2 Large Insurance Claims Databases: Topic: Medical Oncology. PMID- 27969491 TI - PS01.24: Clinical Outcomes of Patients with Pulmonary Large Cell Neuroendocrine Carcinoma Characterized by Next-Generation Sequencing: Topic: Medical Oncology. PMID- 27969493 TI - PS01.26: Prognostic Value of the New WHO Thymoma Classification: Single Institution Cross Validation Study: Topic: Pathology. PMID- 27969492 TI - PS01.25: Large Cell Neuroendocrine Carcinoma of the Lung: Prognostic Factors of Survival and Recurrence After R0 Surgical Resection: Topic: Surgery. PMID- 27969494 TI - PS01.27: A Comparison Between Clinically Apparent Gastrointestinal Metastasis of a Primary Lung Carcinoma and the Incidence in Post-Mortem Studies: Topic: Medical Oncology. PMID- 27969496 TI - PS01.28: Epithelial Mesenchymal Transition in TKI Resistant NSCLC with T790M Mutation: Topic: Medical Oncology. PMID- 27969495 TI - PS01.29: The EGFR-mTOR Signaling Axis: a Prognostic Biomarker in Non-Small Cell Lung Carcinoma at the Time of Diagnosis: Topic: Medical Oncology. PMID- 27969497 TI - PS01.30: Domain-Specific c-Met Measurement by Quantitative Immunofluorescence and Mass Spectrometry in Non-Small Cell Lung Cancer: Topic: Pathology. PMID- 27969498 TI - PS01.31: A Reagent-Free, High Resolution Lung Cancer Diagnostic Method Based on Phenotypic Infrared Spectral Imaging: Topic: Pathology. PMID- 27969499 TI - PS01.32: High Throughput Screening of Small Molecule Inhibitors for Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) in Human Cancers: Topic: Medical Oncology. PMID- 27969500 TI - PS01.33: Change in microRNA Profile in Lung Cancer Cell Treated with Chemotherapy Cisplatin (C), Pemetrexed (P) or PC with Bevacizumab (B): Topic: Medical Oncology. PMID- 27969501 TI - PS01.34: Differential Modulation of Glutathione Metabolism in Adeno and Squamous NSCLC by 2HF: Topic: Medical Oncology. PMID- 27969502 TI - PS01.35: Assessing Combretestatin A-4-Phosphate with Multispectral Optoacoustic Tomography as a Treatment for H1299 Lung Cancer: Topic: Medical Oncology. PMID- 27969504 TI - PS01.37: Comparison Between Sanger Sequencing and ARMS qPCR Method for EGFR Gene Mutation Detection of Non-Small Cell Lung Cancer: Topic: Medical Oncology. PMID- 27969503 TI - PS01.36: Blood-Based Mutation Testing in Non-Small Cell Lung Carcinoma Patients Supports Individualized and Optimal Treatment: Topic: Medical Oncology. PMID- 27969505 TI - PS01.38: Patient with a Typical Carcinoid Initially Diagnosed as High-Grade Neuroendocrine Carcinoma: Topic: Medical Oncology. PMID- 27969506 TI - PS01.40: Artificial Intelligence, System Analysis and Simulation Modeling in Optimization of Management for Lung Cancer Patients: Topic: Surgery. PMID- 27969507 TI - PS01.39: Reach and Adoption of a Surgical Intervention to Improve Pathologic Nodal Staging Across Healthcare Systems within the US Mid-South: Topic: Surgery. PMID- 27969508 TI - PS01.41: A Novel Blood Marker of Tumor Prognosis in a Large Cohort of Esophageal Squamous Cell Carcinoma Patients: The Fibrinogen/Albumin Ratio: Topic: Surgery. PMID- 27969509 TI - PS01.42: Predictors of Incomplete Esophageal Cancer Resection: Questionable Role of Preoperative Therapy: Topic: Surgery. PMID- 27969510 TI - PS01.43: Clinically Occult N2 Non-Small Cell Lung Cancer: Timing of Chemotherapy does not affect the Oncologic Outcomes.: Topic: Surgery. PMID- 27969511 TI - PS01.44: 1,000 Video-Assisted Thoracoscopic Lobectomies: A Single institution's Experience: Topic: Surgery. PMID- 27969512 TI - PS01.46: Robotic Thymectomy: Early Stage Thymoma and Non-Tumor Benign Lesions has Comparable Perioperative Outcomes: Topic: Surgery. PMID- 27969513 TI - PS01.45: Intraoperative Blood Loss is an Independent Predictor of Poor Disease Free Survival for Patients Undergoing VATS Lobectomy for Lung Cancer: Topic: Surgery. PMID- 27969515 TI - PS01.48: Radiation Induced Changes of Indoleamine 2, 3-dioxygenase Activities Predict Overall Survival in Patients with Non-Small Cell Lung Cancer: Topic: Radiation Oncology. PMID- 27969514 TI - PS01.47: PET Volumetric Prognostic Index may be the Most Significant Survival Factor in Non-Small Cell Lung Cancer Treated with Chemoradiation: Topic: Radiation Oncology. PMID- 27969516 TI - PS01.49: Discrete and Limited Extent of N2 Nodes Associated with Better Outcome of Chemoradiotherapy: Effect of Pretreatment Pathological Diagnoses of N2: Topic: Radiation Oncology. PMID- 27969517 TI - PS01.50: Respiratory-Gated Stereotactic Body Radiation Therapy for Stage I Non Small Cell Lung Cancer: A Retrospective Review: Topic: Radiation Oncology. PMID- 27969518 TI - PS01.51: The Impact of PET Staging and Molecular Profiling on the Radiotherapy Outcomes of Primary Lung Adenocarcinoma: Topic: Radiation Oncology. PMID- 27969519 TI - PS01.52: New Chemotherapy Regimen: Does it Really Work for Esophageal Cancer Adenocarcinoma?: Topic: Medical Oncology. PMID- 27969520 TI - PS01.53: First-Line Atezolizumab Plus Chemotherapy in Chemotherapy-Naive Patients with Advanced NSCLC: A Phase III Clinical Program: Topic: Medical Oncology. PMID- 27969521 TI - PS01.54: Evaluation of Novel Blood-Based Biomarkers with Atezolizumab Monotherapy in 1L Advanced or Metastatic NSCLC (B-F1RST): Topic: Medical Oncology. PMID- 27969522 TI - PS01.55: IMpower010: Phase III Study of Atezolizumab vs BSC After Adjuvant Chemotherapy in Patients with Completely Resected NSCLC: Topic: Medical Oncology. PMID- 27969523 TI - PS01.56: IMpower110: Phase III Trial Comparing 1L Atezolizumab with Chemotherapy in PD-L1-Selected Chemotherapy-Naive NSCLC Patients: Topic: Medical Oncology. PMID- 27969524 TI - PS01.57: IMpower133: a Phase I/III Study of 1L Atezolizumab with Carboplatin and Etoposide in Patients with Extensive-Stage SCLC: Topic: Medical Oncology. PMID- 27969525 TI - PS01.58: A Phase 3 Trial of Nivolumab, Nivolumab Plus Ipilimumab, or Placebo Maintenance for Extensive-Stage SCLC After First-Line Chemotherapy: Topic: Medical Oncology. PMID- 27969526 TI - PS01.59: CheckMate 370: A Master Protocol of Phase 1/2 Studies of Nivolumab as Maintenance or First-Line +/- Standard-of-Care Therapies in Advanced NSCLC: Topic: Medical Oncology. PMID- 27969527 TI - PS01.60: Ph Ib/II, Trial of INC280 +/- Erlotinib vs Platinum + Pemetrexed in Adult pts with EGFR-Mutated, cMET amplified, EGFR TKI Resistant, Advanced NSCLC: Topic: Medical Oncology. PMID- 27969528 TI - PS01.61: Registry for the EVolution Of LUng Cancer Therapy Implementation and Outcomes Now (REVOLUTION): Registry Study in Progress: Topic: Medical Oncology. PMID- 27969529 TI - PS01.62: Long-Term Safety and Clinical Activity of Atezolizumab Monotherapy in Metastatic NSCLC: Final Results from a Phase Ia Study: Topic: Medical Oncology. PMID- 27969530 TI - PS01.63: Clinical Characteristics of Acquired Resistance with Anti-PD-1/PD-L1 in Non-Small Cell Lung Cancer (NSCLC): Topic: Medical Oncology. PMID- 27969531 TI - PS01.64: Effect of Anti-PD1 Therapy on the Incidence of Thromboembolic Events in Lung Cancer: Topic: Medical Oncology. PMID- 27969532 TI - PS01.65: EGFR Exon 19 Deletion Mutation Patients Obtain Optimal Survival in Icotinib Treated Non-Small Cell Lung Cancer Patient with Brain Metastases: Topic: Medical Oncology. PMID- 27969533 TI - PS01.66: Biomarker Stratification of Outcomes of Third-Generation EGFR TKI Therapy in Patients with Previously-Treated Advanced NSCLC: Topic: Medical Oncology. PMID- 27969534 TI - PS01.67: Case Series of MET Exon 14 Skipping Mutation-Positive Non-Small Cell Lung Cancers and Response to Crizotinib: Topic: Medical Oncology. PMID- 27969535 TI - PS01.68: Heterogeneous Clinical Syndromes Existing Within Patients with Stage IV KRAS Mutant Non-Small Cell Lung Cancer: Topic: Medical Oncology. PMID- 27969536 TI - PS01.69: Indirect Naive Comparison of ALK Inhibitors for ALK+ Non-Small Cell Lung Cancer (NSCLC) Post-Crizotinib Failure: Topic: Medical Oncology. PMID- 27969537 TI - PS01.70: Ceritinib Dosing Patterns and Outcomes of Patients with ALK+ NSCLC in a Real-World Practice in the United States: Topic: Medical Oncology. PMID- 27969538 TI - PS01.71: Patient-Driven Epidemiologic Assessment of ROS1-Fusion Driven Cancers: Topic: Medical Oncology. PMID- 27969539 TI - PS01.72: Payer and Patient Out-of-Pocket Costs: A Projection of the Financial Burden of Non-Small Cell Lung Cancer Care in the United States Through 2040: Topic: Medical Oncology. PMID- 27969540 TI - PS01.73: Have We Shifted the Therapeutic Innovation Frontier? A US Assessment of Advanced Non-Small Cell Lung Cancer (advNSCLC): Topic: Medical Oncology. PMID- 27969541 TI - PS01.74: Systemic Treatment Sequencing in US Medicare Patients with Extensive Disease (ED)-Small Cell Lung Cancer (SCLC): Topic: Medical Oncology. PMID- 27969542 TI - PS01.75: Safety Outcomes in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Platinum-Based Regimens in the US: Topic: Medical Oncology. PMID- 27969544 TI - PS01.77: Risk-Stratification for Second Primary Lung Cancer: Topic: Medical Oncology. PMID- 27969543 TI - PS01.76: Impact of Chemotherapy Intensity on Progression and Survival in Metastatic Non-Small Cell Lung Cancer: A Systematic Review: Topic: Medical Oncology. PMID- 27969545 TI - PS01.78: Evaluation of Hyponatraemia in Lung Cancer Patients: A UK Teaching Hospital Experience: Topic: Medical Oncology. PMID- 27969546 TI - PS01.79: Epidemiology and Characteristics of US Veterans with NSCLC Using US Veterans Affairs (VA) Database: Topic: Medical Oncology. PMID- 27969547 TI - PS01.80: Genome-Wide Screen of DNA Methylation Changes Reveals GABBR2 as a Novel Potential Target for EGFR 19 Deletion Adenocarcinoma with Erlotinib: Topic: Medical Oncology. PMID- 27969548 TI - Investigating copper toxicity in the tropical fish cardinal tetra (Paracheirodon axelrodi) in natural Amazonian waters: Measurements, modeling, and reality. AB - Copper at high concentrations is an ionoregulatory toxicant in fish and its toxicity is known to be strongly modulated by the water chemistry. The toxicity of Cu to the tropical fish cardinal tetra (Paracheirodon axelrodi) was investigated in waters from two major rivers of the Amazon watershed: the Rio Negro (filtered <0.45MUm, pH 5.6, DOC=8.4 mgL-1, Na=33MUM, Ca=8MUM) and the Rio Solimoes (filtered <0.45MUm, pH 6.7, DOC=2.8 mgL-1, Na=185MUM, Ca=340MUM), as well as in a natural "reference water" (groundwater) which was almost DOC-free (pH 6.0, DOC=0.34 mgL-1, Na=53MUM, Ca=5MUM). Acute 96-h mortality, Cu bioaccumulation and net flux rates of Na+, Cl-, K+ and total ammonia were determined in P. axelrodi exposed in each water. Copper speciation in each water was determined by two thermodynamic models and by potentiometry, and its toxicity was predicted based on the biotic ligand model (BLM) framework. Our results indicate that high Na+ loss is the main mode of toxic action of Cu in P. axelrodi, in accordance with general theory. Cardinal tetra showed a particularly high ability to tolerate Cu and to maintain Na+ balance, similar to the ability of this and other endemic Rio Negro species to tolerate low pH and ion-poor conditions. Cu toxicity was lower in Rio Negro than in the other two waters tested, and the free [Cu2+] at the LC50, as determined by any of the three speciation methods tested, was approximately 10-fold higher. This variation could not be captured by a realistic set of BLM parameters. At least in part, this observation may be due to gill physiological alterations induced by the abundant dissolved organic matter of the Rio Negro. The implication of this observation is that, for metals risk assessment in tropical waters, similar to the Rio Negro, care must be used in applying BLM models developed using temperate DOC and temperate species. PMID- 27969550 TI - Characterizing flow pathways in a sandstone aquifer: Tectonic vs sedimentary heterogeneities. AB - Sandstone aquifers are commonly assumed to represent porous media characterized by a permeable matrix. However, such aquifers may be heavy fractured when rock properties and timing of deformation favour brittle failure and crack opening. In many aquifer types, fractures associated with faults, bedding planes and stratabound joints represent preferential pathways for fluids and contaminants. In this paper, well test and outcrop-scale studies reveal how strongly lithified siliciclastic rocks may be entirely dominated by fracture flow at shallow depths (<=180m), similar to limestone and crystalline aquifers. However, sedimentary heterogeneities can primarily control fluid flow where fracture apertures are reduced by overburden pressures or mineral infills at greater depths. The Triassic St Bees Sandstone Formation (UK) of the East Irish Sea Basin represents an optimum example for study of the influence of both sedimentary and tectonic aquifer heterogeneities in a strongly lithified sandstone aquifer-type. This fluvial sedimentary succession accumulated in rapidly subsiding basins, which typically favours preservation of complete depositional cycles including fine grained layers (mudstone and silty sandstone) interbedded in sandstone fluvial channels. Additionally, vertical joints in the St Bees Sandstone Formation form a pervasive stratabound system whereby joints terminate at bedding discontinuities. Additionally, normal faults are present through the succession showing particular development of open-fractures. Here, the shallow aquifer (depth<=180m) was characterized using hydro-geophysics. Fluid temperature, conductivity and flow velocity logs record inflows and outflows from normal faults, as well as from pervasive bed-parallel fractures. Quantitative flow logging analyses in boreholes that cut fault planes indicate that zones of fault-related open fractures characterize ~50% of water flow. The remaining flow component is dominated by bed parallel fractures. However, such sub-horizontal fissures become the principal flow conduits in wells that penetrate the exterior parts of fault damage zones, as well as in non-faulted areas. The findings of this study have been compared with those of an earlier investigation of the deeper St Bees Sandstone aquifer (180 to 400m subsurface depth) undertaken as part of an investigation for a proposed nuclear waste repository. The deeper aquifer is characterized by significantly lower transmissivities. High overburden pressure and the presence of mineral infillings, have reduced the relative impact of tectonic heterogeneities on transmissivity here, thereby allowing matrix flow in the deeper part of the aquifer. The St Bees Sandstone aquifer contrasts the hydraulic behaviour of low-mechanically resistant sandstone rock-types. In fact, the UK Triassic Sandstone of the Cheshire Basin is low-mechanically resistant and flow is supported both by matrix and fracture. Additionally, faults in such weak-rocks are dominated by granulation seams representing flow-barriers which strongly compartmentalize the UK Triassic Sandstone in the Cheshire Basin. PMID- 27969551 TI - Marmite ecumante. PMID- 27969552 TI - Reliability of First-Trimester Ultrasonic Biopsy for the Evaluation of Placental and Myometrial Blood Perfusion and the Prediction of Preeclampsia. AB - OBJECTIVE: Low placental vascularization measured by three-dimensional (3-D) ultrasound with power Doppler can predict preeclampsia. We evaluated the reliability and reproducibility of the ultrasonic sphere biopsy (USSB) technique to evaluate placental and subplacental myometrium vascularization in the first trimester. METHODS: We performed a secondary analysis of a case-control study nested in a prospective cohort of women with a singleton pregnancy undergoing ultrasound at 11 to 14 weeks' gestation. Women who developed preeclampsia (n = 20) and randomly selected controls (n = 60) were compared. Other controls (n = 60) were also randomly selected to evaluate intra- and inter-observer reproducibility. Using 3-D power Doppler, the vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were measured from the volume of the whole placenta and the subplacental myometrium and from their respective USSB. Pearson's correlation coefficients (cc) with their P-values were calculated. RESULTS: We observed that USSB is reliable in estimating the vascularization of the whole placenta in the first trimester (cc of VI 0.83; of FI 0.62; and of VFI 0.78; P < 0.001 for all) but was not as reliable for estimating subplacental myometrium vascularization (cc of VI 0.71; of FI 0.35; and of VFI 0.73). Measurement of placental vascularization using USSB showed good to excellent intra- and inter-observer reproducibility (cc of VI 0.86 and 0.85, respectively; of FI 0.75 and 0.75, respectively; and of VFI 0.83 and 0.83, respectively; P < 0.001 for all). Finally, we observed that women who subsequently developed preeclampsia had lower placental USSB VI (2.1 vs 4.8, P = 0.02), FI (32.4 vs. 42.5, P = 0.002), and VFI (0.8 vs. 2.1, P = 0.01) than controls. CONCLUSION: First-trimester USSB of the placenta using 3-D power Doppler is a reliable and reproducible procedure for estimating placental vascularization and could be used to predict preeclampsia. PMID- 27969553 TI - Restrictions on Oral and Parenteral Intake for Low-risk Labouring Women in Hospitals Across Canada: A Cross-Sectional Study. AB - OBJECTIVE: The dietary intake allowed during the latent and active phases of labour varies between Canadian hospitals. Our objective was to document current restrictions on oral and parenteral intake for low-risk labouring women in hospitals across Canada. METHODS: We carried out a cross-sectional study of 118 Canadian hospitals that have specialized birthing centres. Information on dietary protocols for low-risk women in labour was obtained from each hospital via a brief telephone interview with the head nurse of each birthing centre. Data were presented by stage of labour, both with and without epidural anaesthesia, and also by dextrose supplementation of intravenous fluids. RESULTS: If epidural anaesthesia was not used during the active phase of labour, oral intake was restricted to clear fluids and/or ice chips in 50.9% of surveyed hospitals and oral intake could include solid food in 38.1%. However, when epidural anaesthesia was used during the active phase of labour, oral intake was restricted to clear fluids and ice chips in 82.8% of surveyed hospitals, while oral intake could include solid food in 7.2%. Furthermore, in 77.5% of hospitals, not only was oral intake during active labour with epidural anaesthesia limited to clear fluids and/or ice chips, but in addition this restrictive diet was not supplemented with parenteral dextrose. CONCLUSION: The majority of low-risk pregnant women in Canadian hospitals are subjected to caloric restriction during the active phase of labour, especially when epidural anaesthesia is administered. Further studies on this subject are warranted because such pervasive practices may have important population effects on labouring women. PMID- 27969554 TI - Obstetric and Anaesthesia Checklists for the Management of Morbidly Adherent Placenta. AB - OBJECTIVE: To develop an integrated checklist for the management of patients with suspected morbidly adherent placenta (MAP). METHODS: A checklist process was developed incrementally by clinicians in the disciplines of maternal-fetal medicine, gynaecology, medical imaging, and anaesthesia for management of women with suspected MAP. RESULTS: Over a five-year period of debriefing after individual cases, a comprehensive checklist system was developed. The checklist is activated upon referral if MAP is suspected at an initial maternal-fetal medicine consultation; the process is subsequently guided by a clinical nurse specialist, leading to a standardized program of care. CONCLUSIONS: Having a checklist process facilitates standardized care and optimal communication between specialists, providing team-based care for women with this potentially serious complication of pregnancy. PMID- 27969555 TI - Internal Iliac Artery Rupture Caused by Endovascular Balloons in a Woman with Placenta Percreta. AB - BACKGROUND: Prior to Caesarean section (CS) for morbidly adherent placenta (MAP), endovascular balloons are often placed prophylactically to minimize hemorrhage. However, there have been few reports describing complications of this intervention. CASE: A 41-year-old woman with a diagnosis of placenta percreta had endovascular balloon catheters placed before CS. Intraoperatively the right internal iliac artery ruptured, requiring vascular repair, multiple transfusions of blood and plasma, and admission to the intensive care unit. CONCLUSION: Prophylactic placement of endovascular balloons to reduce maternal hemorrhage at CS for MAP may result in complications. Until more evidence becomes available supporting their use, safety guidelines must be instated in centres using them. PMID- 27969556 TI - Severe Staphylococcus aureus Endocarditis Presenting as Peripartum Thrombotic Thrombocytopenic Purpura. AB - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening illness that occurs in both pregnant and non-pregnant women. Several other conditions can mimic the disease, which makes the diagnosis challenging. CASE: We describe a case of severe Staphylococcus aureus endocarditis that initially presented as peripartum TTP in a 39-year-old woman at 29+6 weeks' gestation. We give an overview of the diagnostic considerations and management of thrombocytopenia in pregnancy and review the literature related to TTP and peripartum infective endocarditis. CONCLUSION: Given the significant differences in definitive therapies for the spectrum of thrombocytopenic conditions that occur in pregnancy, timely and accurate diagnosis of TTP is critical for optimal management. PMID- 27969557 TI - Sigmoid Microinvasion by an Ectopic Pregnancy. AB - BACKGROUND: Approximately 2.1% to 8.6% of all pregnancies after IVF with embryo transfer have been reported to be ectopic. In this report, we present a case of presumed intestinal microperforation caused by an ectopic pregnancy following IVF. CASE: A 29-year-old woman presented with rectal bleeding. She had previously been treated for an ectopic pregnancy for which she had received two doses of methotrexate. Colonoscopy and abdominal CT angiography were performed and showed that the ectopic pregnancy was attached to the sigmoid colon. Surgery was performed to remove the ectopic pregnancy. Because intestinal microperforations were suspected, the patient received intravenous antibiotic therapy during her hospitalization. CONCLUSION: In cases of intestinal bleeding, clinicians should consider the possibility of intestinal involvement of an ectopic pregnancy, even if the response to treatment for the ectopic pregnancy has been appropriate. PMID- 27969558 TI - Characteristics of the Offspring of Women with a History of Malignancy, Excluding Congenital Malformations. AB - OBJECTIVE: To study the characteristics (except congenital malformations) of offspring born to women with a history of malignancy. METHODS: Data were obtained by linkage between four different Swedish national health registers. We compared the offspring born between 1994 and 2011 of women with a history of malignancy with all other infants. Survival of the infants was followed up through 2013. Adjusting for confounders was performed using Mantel-Haenszel methodology. We identified 7315 infants born to women with a history of a malignancy diagnosed at least 1 year before delivery. The total number of deliveries in Sweden in these years was 1 746 870, with 1 780 112 infants being born. We assessed rates of intrauterine death, preterm birth, low birth weight, and the nature of intrauterine growth. We also examined neonatal diagnoses (asphyxia, chronic respiratory condition, intracranial hemorrhage, jaundice, hypoglycemia, CNS symptoms) and infant death. RESULTS: In women with a history of malignancy, we found no significantly increased risk for stillbirth or infant death. There were elevated rates of preterm birth (OR 1.50, 95% CI 1.37 to 1.64), very preterm birth (OR 1.89, 95% CI 1.54 to 2.32), and low birth weight (OR 1.50, 95% CI 1.34 to 1.68). There was a significantly increased risk of birth asphyxia, jaundice, hypoglycemia, and low Apgar score among infants born to women with a history of malignancy (OR 1.24, 95% CI 1.15 to 1.33), and this risk was maintained after excluding infants born after IVF. CONCLUSION: We found an increased risk of preterm birth and low birth weight among infants of women with a history of malignancy, and as a result, found an increased risk of neonatal morbidity. No significant increase in risk of intrauterine or postnatal death was noted. PMID- 27969559 TI - Attitudes and Beliefs of Pregnant Women and New Mothers Regarding Influenza Vaccination in British Columbia. AB - OBJECTIVE: Although pregnant women have increased risks for influenza morbidity and mortality, influenza vaccination rates among pregnant women in Canada are consistently very low. This mixed-methods study investigated the attitudes and behaviour of pregnant women and new mothers regarding seasonal and pandemic influenza vaccination. METHODS: We conducted a baseline survey and qualitative focus groups with 34 women (26 pregnant women and 8 mothers of newborns), with a follow-up survey to assess outcomes at the end of the subsequent influenza season. Data analysis included descriptive statistics and directed content analysis based on the health belief model. RESULTS: Most women did not consider influenza vaccination to be an important preventative measure to take while pregnant, although some were more willing to consider vaccination during a pandemic. Omission bias played a substantial role as justification for not vaccinating. Participants expressed confusion about recommendations regarding vaccination during pregnancy and frustration with inconsistent messages from health care providers (HCPs), particularly with regard to pandemic vaccines. Women were vaccinated when they perceived themselves and/or their babies to be at increased risk for influenza. Vaccinated women had strong normative influences (usually an HCP or a family member) that affected their decision. Intentions accurately predicted behaviour for women who did and did not intend to be vaccinated. CONCLUSION: Pregnant women did not perceive themselves to be at increased risk for influenza and did not believe that influenza vaccination was a necessary preventative health measure. A lack of safety information about vaccination during pregnancy and inconsistent messages from HCPs were barriers to vaccine acceptance. Recommendations from maternity care providers and communication about the severity of and susceptibility to influenza for pregnant women would facilitate vaccine uptake. PMID- 27969560 TI - An Assessment of the Continuing Surgical Education Program, a Surgical Preceptor Program for Faculty Members. AB - OBJECTIVE: The Continuing Surgical Education Preceptor program (CSEP) was designed to meet population needs by facilitating development of new skills by practising surgeons. Elements include entry criteria, dedicated OR time, assigned preceptors, structured assessment of competence, a mechanism for credentialing, and a reimbursement model. This study analyzed the effectiveness of the CSEP in increasing the number of clinician educators performing laparoscopic hysterectomy (LH) without compromising rates of vaginal hysterectomy (VH) and in enhancing residents' training in performing minimally invasive hysterectomy (MIH; either LH or VH). METHODS: We performed a retrospective descriptive study to longitudinally analyze the numbers and proportions of different surgical approaches to hysterectomy at two hospital sites over five years. The CSEP was implemented differently at the two sites. Success of the program was indicated by a surgeon performing 50% or more of hysterectomies as MIH. To assess the impact on resident education, we longitudinally analyzed the number of hysterectomy teaching cases performed as MIH. RESULTS: The proportion of surgeons performing 50% of hysterectomies as MIH steadily increased in the first five years after implementation of the CSEP. At one hospital, the proportion increased from 13% to 56%, due to an increase in LH cases with no change in VH cases. The proportion of resident LH teaching cases increased from 0% to 26%, with a similar rise in the proportion of MIH cases, although it did not quite reach the target proportion of 50% or more. Contrasting the experience of the CSEP between two hospitals revealed that having OR time dedicated to MIH cases provided significantly better results. CONCLUSIONS: The CSEP is an effective and sustainable model of lifelong learning applied to teaching practising surgeons new surgical skills. PMID- 27969561 TI - Development of a Night Float Call Model for Obstetrics and Gynaecology Residency: The Process and Residents' Perceptions. AB - The 2013 pan-Canadian consensus Report on Resident Duty Hours identified that traditional 24-hour duty periods pose risks to the well-being of residents and should be avoided. In anticipation of duty-hour restrictions, the Obstetrics and Gynaecology Residency Program at the University of Toronto developed and implemented a night float (NF) call model over a three-year span. Quarterly resident surveys have consistently shown that the NF system is preferred to traditional 24-hour call and has resulted in reduced fatigue and improved continuity of patient care. Through many iterations, the NF model achieved levels of resident morale, surgical experience, and impact on family relationships that are comparable to the 24-hour call system. We review here our process for developing an NF call model and the perceptions and experiences of residents, with the goal of providing insight for other residency programs that are considering or instituting NF call systems. PMID- 27969562 TI - Real World Implications of Endometriosis and Cardiac Risk. PMID- 27969563 TI - The Roles of Multidisciplinary Team Members in the Care of Pregnant Women. PMID- 27969564 TI - Les roles des membres de l'equipe multidisciplinaire dans les soins aux femmes enceintes. PMID- 27969565 TI - Migration of an Intrauterine System. PMID- 27969566 TI - Migration d'un dispositif intra-uterin. PMID- 27969567 TI - Cauldron Bubble. PMID- 27969568 TI - Effects of resilience on quality of life in patients with bipolar disorder. AB - BACKGROUND: Few studies have examined the effects of resilience on quality of life (QOL) in patients with bipolar disorder (BD). Therefore, this study investigated the association between resilience and QOL in patients with BD and compared it to the relationship between resilience and QOL in healthy individuals. METHODS: Participants were 68 euthymic patients with BD and 68 age-, sex-, and length of education-matched controls. Sociodemographic characteristics and clinical variables of the two groups were obtained using face-to-face interviews, and all participants completed the Connor-Davidson Resilience Scale, the World Health Organization QOL-Brief Form. RESULTS: The QOL of the BD group was significantly impaired compared with that of the controls. Degree of resilience, number of depressive episodes, Clinical Global Impression scores, degree of impulsivity, and length of education were significantly correlated with QOL in the BD group. Resilience was significantly associated with overall QOL, physical subdomains of QOL, psychological subdomains of QOL, social subdomains of QOL, and environmental subdomains of QOL in the BD group, even after controlling for confounders. In the control group, resilience was significantly associated with overall QOL, the physical subdomains of QOL, psychological subdomains of QOL, and social subdomains of QOL. LIMITATIONS: The number of participants in each group was 68, which is a relatively small sample size. CONCLUSIONS: Resilience in patients with BD was independently and positively correlated with various areas of QOL. Various strategies to reinforce resilience in patients with BD are needed to improve the low QOL in this population. PMID- 27969569 TI - Biology and treatment of renal tumours in childhood. AB - In Europe, almost 1000 children are diagnosed with a malignant renal tumour each year. The vast majority of cases are nephroblastoma, also known as Wilms' tumour (WT). Most children are treated according to Societe Internationale d'Oncologie Pediatrique Renal Tumour Study Group (SIOP-RTSG) protocols with pre-operative chemotherapy, surgery, and post-operative treatment dependent on stage and histology. Overall survival approaches 90%, but a subgroup of WT, with high-risk histology and/or relapsed disease, still have a much poorer prognosis. Outcome is similarly poor for the rare non-WT, particularly for malignant rhabdoid tumour of the kidney, metastatic clear cell sarcoma of the kidney (CCSK), and metastatic renal cell carcinoma (RCC). Improving outcome and long-term quality of life requires more accurate risk stratification through biological insights. Biomarkers are also needed to signpost potential targeted therapies for high-risk subgroups. Our understanding of Wilms' tumourigenesis is evolving and several signalling pathways, microRNA processing and epigenetics are now known to play pivotal roles. Most rhabdoid tumours display somatic and/or germline mutations in the SMARCB1 gene, whereas CCSK and paediatric RCC reveal a more varied genetic basis, including characteristic translocations. Conducting early-phase trials of targeted therapies is challenging due to the scarcity of patients with refractory or relapsed disease, the rapid progression of relapse and the genetic heterogeneity of the tumours with a low prevalence of individual somatic mutations. A further consideration in improving population survival rates is the geographical variation in outcomes across Europe. This review provides a comprehensive overview of the current biological knowledge of childhood renal tumours alongside the progress achieved through international collaboration. Ongoing collaboration is needed to ensure consistency of outcomes through standardised diagnostics and treatment and incorporation of biomarker research. Together, these objectives constitute the rationale for the forthcoming SIOP-RTSG 'UMBRELLA' study. PMID- 27969570 TI - Red cell distribution width in predicting 30-day mortality in patients with pulmonary embolism. AB - PURPOSE: The aim of the study was to investigate red cell distribution width (RDW) in predicting 30-day mortality in patients with pulmonary embolism (PE). METHODS: A single-center, retrospective study design was used between January 1, 2014, and February 1, 2016. The primary end point was 30-day mortality after admission. The RDW predicting value was assessed by receiver operating characteristic curves and area under the curve. RESULTS: A total of 309 patients with PE were included. The 30-day mortality was 14.9% (46/309). The mean RDW level was 13.9%+/-0.6% (range, 10.7%-21.9%) at admission. The 30-day mortality was higher in the high-RDW-level group compared with the normal-RDW-level group (12.5% vs 23.5%, chi2=5.140, P=.023), with an odds ratio of 2.164 (95% confidence interval [CI], 1.019-4.450). Logistic regression showed that presence of shock, RDW level, and simplified pulmonary embolism severity index (sPESI) were independent risk factors for 30-day mortality in patients with PE. After adjustment by these risk factors, the adjusted odds ratio was 1.439 (95% CI, 1.024-2.116). The area under the curve for RDW predicting the 30-day mortality was 0.6646 (95% CI, 0.5585-0.7518). The cutoff was 16%. The Youden index for RDW and sPESI was 0.400 and 0.453, respectively. When adding RDW into sPESI, the modified sPESI showed highest prediction accuracy, with Youden index 0.499. CONCLUSIONS: Our results suggested that the RDW is a simple and useful indicator in predicting 30-day mortality in patients with PE. However, this conclusion showed be confirmed by prospective study with large sample. PMID- 27969571 TI - Derivation and validation of the automated search algorithms to identify cognitive impairment and dementia in electronic health records. AB - PURPOSE: Long-term cognitive impairment is a common and important problem in survivors of critical illness. We developed electronic search algorithms to identify cognitive impairment and dementia from the electronic medical records (EMRs) that provide opportunity for big data analysis. MATERIALS AND METHODS: Eligible patients met 2 criteria. First, they had a formal cognitive evaluation by The Mayo Clinic Study of Aging. Second, they were hospitalized in intensive care unit at our institution between 2006 and 2014. The "criterion standard" for diagnosis was formal cognitive evaluation supplemented by input from an expert neurologist. Using all available EMR data, we developed and improved our algorithms in the derivation cohort and validated them in the independent validation cohort. RESULTS: Of 993 participants who underwent formal cognitive testing and were hospitalized in intensive care unit, we selected 151 participants at random to form the derivation and validation cohorts. The automated electronic search algorithm for cognitive impairment was 94.3% sensitive and 93.0% specific. The search algorithms for dementia achieved respective sensitivity and specificity of 97% and 99%. EMR search algorithms significantly outperformed International Classification of Diseases codes. CONCLUSIONS: Automated EMR data extractions for cognitive impairment and dementia are reliable and accurate and can serve as acceptable and efficient alternatives to time-consuming manual data review. PMID- 27969572 TI - Failure of chemical thromboprophylaxis in critically ill medical and surgical patients with sepsis. AB - PURPOSE: Critically ill patients who develop sepsis may be at a higher risk of venous thromboembolism (VTE) prophylaxis failure; however, studies in this population are limited. The objective of this study was to identify the incidence of VTE prophylaxis failure in this population. METHODS: This retrospective review of patients admitted to the intensive care unit between February 2013 and September 2015 included patients who were diagnosed with sepsis and received heparin or enoxaparin VTE prophylaxis. RESULTS: Of the 355 patients included, 42 (12.5%) developed a VTE. Acute respiratory distress syndrome (ARDS) (31% vs 16.7%, P = .0272) and higher positive end expiratory pressure (10 vs 8, P = .0066) were associated with increased risk of VTE prophylaxis failure. Logistic regression identified ARDS an event risk factor (odds ratio, 2.58; 95% confidence interval, 1.22-5.42). The VTE was associated with an increased intensive care unit (14 vs 9 days, P = .01) and hospital length of stay (26 vs 15 days, P < .0001). The median time from sepsis diagnosis to VTE event was 9 days (interquartile range, 5-13). CONCLUSION: Critically ill patients with sepsis had a high rate of VTE prophylaxis failure with ARDS being identified as a risk factor for VTE prophylaxis failure. PMID- 27969573 TI - The clinical benefit of a follow-up thoracic computed tomography scan regarding parenchymal lung injury and acute respiratory distress syndrome in polytraumatized patients. AB - PURPOSE: To evaluate the increase of parenchymal lung injury (PLI) volume between the initial and a follow-up computed tomography (CT) scan and to ascertain which of the 2 scans was more appropriate to predict acute respiratory distress syndrome (ARDS). MATERIAL AND METHODS: From 2011 to 2015, polytraumatized patients (>=18 years; ISS >= 16) directly admitted to our level I trauma center were included in our prospective study if a follow-up CT scan was possible 24 to 48 hours after the trauma. The PLI volume was measured using volumetric analysis. Statistical calculations were performed to identify patients at risk for ARDS. RESULTS: One hundred thirty patients (mean age, 41.3 years; mean ISS, 31.9) met the inclusion criteria. Median relative PLI volume was higher in the follow-up than in the initial CTs (9.65% vs 4.84%; P = .001). The ARDS developed in 42 patients (32.3%). Their initial PLI volume was higher compared with those without ARDS (11.23% vs 2.14%; P < .0001). The ARDS incidence increased with increasing initial PLI volume. Receiver operating characteristic statistics identified initial (area under the curve = 0.753) and follow-up relative PLI volume as a predictor for ARDS (area under the curve = 0.725). CONCLUSIONS: The CT scans performed directly after admission are sufficient to define patients at risk for ARDS. Therefore, solely the incidence of PLI does not justify a routine follow-up CT scan. PMID- 27969574 TI - Disparities in hemodynamic resuscitation of the obese critically ill septic shock patient. AB - BACKGROUND: With a growing obesity epidemic, the approach to care of this patient remains controversial and in many circumstances different than the general population. Appropriate hemodynamic support, although still controversial, remains a cornerstone of septic shock therapy. Catecholamines are currently recommended by guidelines without a preferred dosing strategy. However, the use of weight-based (MUg kg-1 min-1) or nonweight-based (MUg/min) vasopressor drip rates may impact patient care in these populations. METHODS: A multicenter retrospective chart review was conducted. Patients receiving nonweight-based catecholamine infusions for septic shock were grouped into nonobese (n = 112) or obese (n = 196), and evaluated based on hemodynamic resuscitation. For the primary outcome, groups were analyzed for the requirement of a secondary hemodynamic support agent to obtain a goal mean arterial pressure of greater than or equal to 65 mm Hg. Secondary outcomes included an evaluation of time to a secondary hemodynamic support agent, time to hemodynamic stability (HDS), ability to obtain HDS at 24 hours, and death due to cardiovascular collapse. RESULTS: With the exception of weight and sex, baseline characteristics were similar among groups. Early resuscitative fluids were given at a lower weight based, but not total volume dose in the obese group (nonobese, 34.8 mL/kg vs obese, 22.4 mL/kg; P < .0001). The primary end point of addition of any secondary hemodynamic support agent was significantly greater in obese patients when adjusted for institution (nonobese, 19% vs obese, 27%; adjusted odds ratio, 0.42; 95% confidence interval, 0.23-0.77). Time to HDS was also prolonged (nonobese, 3.5 hours vs obese, 5.3 hours; P = .006). CONCLUSION: This study calls into question the adequacy of a nonweight-based approach to hemodynamic support of critically ill obese patients. This strategy seems to result in less aggressive, lower weight-based vasopressor and fluid doses, and more diverse approach than their nonobese counterparts. PMID- 27969575 TI - Women's preferences for contralateral prophylactic mastectomy following unilateral breast cancer: What risk-reduction makes it worthwhile? AB - OBJECTIVES: Contralateral prophylactic mastectomy (CPM) reduces the risk of contralateral breast cancer (BC) following unilateral BC, but may not increase survival in BRCA1/2 mutation negative women. Despite this, and the risk for adverse physical and psychological impact, uptake is increasing in BRCA1/2 mutation negative women. We aimed to quantify the degree of reduction in lifetime contralateral BC risk women required to justify CPM, and to explore demographic, disease and psychosocial predictors of preferences using Protection Motivation Theory (PMT) as a theoretical framework. Reasoning behind preferences was also examined. MATERIALS AND METHODS: 388 women previously diagnosed with unilateral BC, of negative or unknown BRCA1/2 status, were recruited from an advocacy group research database. Two hypothetical risk trade-off scenarios were used to quantify the reduction in lifetime contralateral BC risk that women judged necessary to justify CPM, using a 5% and 20% baseline. Demographic, disease and PMT measures were assessed using a questionnaire. RESULTS: Most women required their risk to be more than halved from a 5% or 20% baseline to justify CPM. Polarised preferences were also common, with some women consistently accepting or refusing CPM independent of risk/benefit trade-offs. Preferences were associated with coping self-efficacy and having a prior CPM. Explanations for judging CPM worthwhile included reducing or eliminating contralateral BC risk, attaining breast symmetry and reducing worry. CONCLUSION: Risk-reduction preferences were highly variable. Decisive factors in women's preferences for CPM related to clinical, psychological and cosmetic outcomes, but not to demographic or disease characteristics. PMID- 27969576 TI - Isolation, identification and characterization of Cystobasidium oligophagum JRC1: A cellulase and lipase producing oleaginous yeast. AB - Oleaginous yeast closely related to Cystobasidium oligophagum was isolated from soil rich in cellulosic waste. The yeast was isolated based on its ability to accumulate intracellular lipid, grow on carboxymethylcellulose (CMC) and produce lipase. It could accumulate up to 39.44% lipid in a glucose medium (12.45+/ 0.97g/l biomass production). It was able to grow and accumulate lipids (36.46%) in the medium containing CMC as the sole carbon source. The specific enzyme activities obtained for endoglucanase, exoglucanase, and beta-glucosidase were 2.27, 1.26, and 0.98IU/mg respectively. The specific enzyme activities obtained for intracellular and extracellular lipase were 2.16 and 2.88IU/mg respectively. It could grow and accumulate lipids in substrates including glycerol (42.04%), starch (41.54%), xylose (36.24%), maltose (26.31%), fructose (24.29%), lactose (21.91%) and sucrose (21.72%). The lipid profile of the organism was suitable for obtaining biodiesel with desirable fuel properties. PMID- 27969577 TI - Pilot scale biodiesel production from microbial oil of Rhodosporidium toruloides DEBB 5533 using sugarcane juice: Performance in diesel engine and preliminary economic study. AB - A successful pilot-scale process for biodiesel production from microbial oil (Biooil) produced by Rhodosporidium toruloides DEBB 5533 is presented. Using fed batch strategy (1000L working volume), a lipid productivity of 0.44g/L.h was obtained using a low-cost medium composed by sugarcane juice and urea. The microbial oil was used for biodiesel production and its performance was evaluated in diesel engine tests, showing very good performance, especially for the blend B20 SCO, when operating at 2500rpm with lower pollutant emissions (CO2 - 220% less; CO - 7-fold less; NOX 50% less and no detectable HC emissions (<0.11ppm)) when compared with the blends of standard biofuel from soybean oil. A preliminary analysis showed that microbial biodiesel is economically competitive (US$ 0.76/L) when compared to the vegetable biodiesel (US$ 0.81/L). Besides, the yield of biodiesel from microbial oil is higher (4172L/ha of cultivated sugarcane) that represents 6.3-fold the yield of standard biodiesel (661L/ha of cultivated soybean). PMID- 27969578 TI - Tailoring partially reduced graphene oxide as redox mediator for enhanced biotransformation of iopromide under methanogenic and sulfate-reducing conditions. AB - This work reports the first successful application of graphene oxide (GO) and partially reduced GO (rGO) as redox mediator (RM) to increase the biotransformation of the recalcitrant iodinated contrast medium, iopromide (IOP). Results showed that GO-based materials promoted up to 5.5 and 2.8-fold faster biotransformation of IOP by anaerobic sludge under methanogenic and sulfate reducing conditions, respectively. Correlation between the extent of reduction of GO and its redox-mediating capacity was demonstrated, which was reflected in faster removal and greater extent of biotransformation of IOP. Further analysis indicated that the biotransformation pathway of IOP involved multiple reactions including deiodination, decarboxylation, demethylation, dehydration and N dealkylation. GO-based materials could be strategically tailored and integrated in biological treatment systems to effectively enhance the redox conversion of recalcitrant pollutants commonly found in wastewater treatment systems and industrial effluents. PMID- 27973321 TI - Assessing successive bilinguals in two languages: A longitudinal look at English speaking children in France. AB - : This study examines longitudinal standardized test scores in both languages of a group of successive bilinguals with L1 English acquiring L2 French. Participants included 22 native English-speaking children living in France. French was evaluated using a standardized receptive vocabulary test, as well as tests of phonology and morphosyntax. English was evaluated using the Core Language Score subtests from the CELF-4-UK. The children varied in age (6;9-12;7) and length of exposure (0;11-3;9) to French and were tested twice at 12-month intervals. At T1, 7 children scored below norms in both languages, while only 3 did so at T2. Two out of these 3 were arguably not typically developing children. Length of exposure to French emerged as an important factor only at T1, when a number of children were in early stages of acquisition (<=18months of exposure). English scores varied by age and weekly use of English. In successive bilingual children, language performance on L2 standardized tests can be expected to be (well) below norms during the first 18 months of exposure. English scores revealed that weak L1 performance is part of typical development in this bilingual context, but that L1 retention is also a possibility. LEARNING OUTCOMES: The reader will be able to: (1) describe challenges associated with language assessment of successive bilingual children, (2) describe the impact that age and length of exposure can have on language performance in bilinguals, and (3) understand how assessing successive bilinguals using monolingual norms can lead to underestimation of language abilities. PMID- 27973323 TI - Predicting receptive vocabulary change from childhood to adulthood: A birth cohort study. AB - This study examined the parental and early childhood risk factors of different receptive vocabulary developmental profiles from childhood to adulthood. The sample (n=1914), comprised of monolingual English speaking participants, from the Mater University of Queensland Study of Pregnancy (MUSP). Receptive vocabulary was measured using the Peabody Picture Vocabulary Test-Revised (PPVT-R) at the 5 and 21-year follow ups. Four vocabulary profiles were evident: persistently typical, persistently impaired, later onset of difficulties, and resolved delays. The presence of internalising behaviours at 5 years, lower paternal educational attainment, and maternal smoking during pregnancy were associated with later onset vocabulary impairment. These findings have clinical and educational implications for identifying children 'at risk' of later deterioration in language skills. PMID- 27973322 TI - Acquisition, retention, and generalization of rhotics with and without ultrasound visual feedback. AB - PURPOSE: The purpose was to provide a preliminary within-participant comparison of speech therapy with and without exposure to ultrasound visual feedback for postvocalic rhotics (/r/- colored vowels). Effects of the two treatments on acquisition, retention, and generalization were explored. It was hypothesized that treatment with ultrasound would facilitate acquisition but hinder retention and generalization. METHODS: A single subject randomized block design was replicated across four American English-speaking participants ages 7-9 years. Each participant was trained on postvocalic /r/. Each week for seven weeks, one session with ultrasound visual feedback and one session with no ultrasound were randomly ordered. A Training Probe and Generalization Probe were used to measure acquisition within each session as well as retention and generalization between two consecutive sessions. Graphical displays of the data, effect size calculation, and statistical results from a randomization test were used to analyze the results. RESULTS: Two participants showed essentially no evidence of acquisition, retention or generalization of rhotics (<5%). Of the two who showed evidence of acquisition, one participant showed a significant advantage and large effect size for ultrasound sessions over no ultrasound sessions in acquisition of rhotics. However, no participants showed differences between treatment conditions in generalization or retention of rhotics. CONCLUSION: For some children, acquisition may be facilitated by ultrasound visual feedback. Ultrasound visual feedback neither inhibited nor facilitated retention or generalization of rhotics. As a whole, the 14 treatment sessions (7 with ultrasound and 7 without) were effective for 2 of the 4 participants when comparing pre/post generalization scores. Future studies should evaluate the effectiveness of ultrasound visual feedback given a larger dose and differing age groups. PMID- 27973324 TI - Japanese antimicrobial consumption surveillance: First report on oral and parenteral antimicrobial consumption in Japan (2009-2013). AB - No reliable national antimicrobial consumption data have been available in Japan. The Japanese antimicrobial consumption surveillance (JACS) project started to collect data nationwide on antimicrobial consumption. This paper provides the first sales data from the JACS project on oral and parenteral antimicrobial consumption in Japan as well as the trends for the years from 2009 to 2013. The population-weighted total consumption was expressed as defined daily doses (DDDs) per 1000 inhabitants per day (DID). The value of DID increased from 14.7 in 2009 to 15.8 in 2013. Notably, oral antimicrobials accounted for 92.6% (mean of 2009, 2011 and 2013) of total consumption. Oral third-generation cephalosporins, macrolides and fluoroquinolones accounted for 77.1% (mean of 2009, 2011 and 2013) of oral consumption. Consumption of antimicrobials has increased during the years 2009 and 2013 regardless of the dosage form. This is the first report regarding the population-weighted consumption of oral and parenteral antimicrobials in Japan during the years 2009 and 2013. These results provide useful information for combating the menace of antimicrobial resistance in Japan. PMID- 27973326 TI - Asthma exacerbations in a tertiary hospital: clinical features, triggers, and risk factors for hospitalization. AB - BACKGROUND: Risk factors for asthma exacerbations are not fully understood. The aim of this study was to determine the epidemiological and clinical characteristics of patients with an asthma exacerbation, potential triggers, and possible predictors of hospitalization. METHODS: A retrospective, non interventional cohort study was conducted in adult patients who attended the Emergency Department of a tertiary hospital with an asthma exacerbation during 2014. RESULTS: 831 patients (888 events) were included. The highest number of episodes occurred in January and May. Respiratory infection was considered the trigger in 523 events. 34.21% had >=260 eosinophils/mm3 (20.7%>=400 eosinophils/mm3), significantly associated with allergic asthma (p<0.0001). Risk factors for hospitalization were: older age [OR:1.58 (95% CI 1.46-1.71)]; no previous diagnosis of asthma [OR:1.40(95% CI 1.06-1.86)]; poorly controlled asthma[OR:1.78 (95% CI 1.10-2.88)]; respiratory infection [OR:2.65 (95% CI 1.95 3.62)]; and severe crisis with more treatment requirements. Of those asthmatics with >=400 eosinophils/mm3, the rate of hospitalization was lower (p<0.001). CONCLUSION: Older age, absence of a previous asthma diagnosis, uncontrolled disease or concomitant COPD are frequent among patients presenting to the ED with asthma exacerbations. There were some features associated with higher risk of admission. Blood eosinophilia should be considered as a marker of asthma, but not as a predictor of hospitalization. PMID- 27973327 TI - Baseline and residual SYNTAX score in predicting outcomes after acute infarct angioplasty. AB - AIMS: The aim of this study was to explore the utility of baseline SYNTAX score (bSS) and residual SYNTAX score (rSS) in predicting 12-month outcomes after primary percutaneous coronary intervention (PPCI). METHODS AND RESULTS: Five hundred and ninety all-comers with acute STEMI presenting for PPCI over a two year period were identified. Of these, 173 were excluded because of unsuitability for SYNTAX score calculation for this study. Two experienced observers calculated the bSS and rSS. Mortality data were sourced from the government registry. Logistic regression was used to assess the predictive power of bSS and rSS for mortality. Sensitivity analysis and a Cox proportional hazards model were used to evaluate the best cut-off for increased mortality. Of the 417 patients analysed (mean age 59 years), 81% were male and 18% were known diabetics. At 12 months, the overall mortality rate was 5.5% (23/417). An rSS of >12 was associated with a 13.95% mortality rate. The hazard ratio for mortality was 3.88 (95% CI: 1.49 10.09, p=0.005) for rSS of >12 and 3.01 (95% CI: 1.18-7.64, p=0.02) for bSS >12. The odds ratio (OR) for mortality was 1.06 (95% CI: 1.02-1.11, p=0.009) for rSS and 1.05 (95% CI: 1.02-1.1, p=0.007) for bSS. CONCLUSIONS: In STEMI patients undergoing PPCI, both bSS and rSS can predict mortality at 12 months. Every point on the rSS confers an additional 6% mortality risk. Calculation of the rSS after culprit lesion intervention may help guide management of non-culprit lesions. PMID- 27973325 TI - Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression. AB - Metastasis is the cause of more than 90% of all cancer deaths. Despite this fact, most anticancer therapeutics currently in clinical use have limited efficacy in treating established metastases. Here, we identify the endoplasmic reticulum chaperone protein, glucose-regulated protein 78 (GRP78), as a metastatic dependency in several highly metastatic cancer cell models. We find that GRP78 is consistently upregulated when highly metastatic cancer cells colonize the lung microenvironment and that mitigation of GRP78 upregulation via short hairpin RNA or treatment with the small molecule IT-139, which is currently under clinical investigation for the treatment of primary tumors, inhibits metastatic growth in the lung microenvironment. Inhibition of GRP78 upregulation and an associated reduction in metastatic potential have been shown in four highly metastatic cell line models: three human osteosarcomas and one murine mammary adenocarcinoma. Lastly, we show that downmodulation of GRP78 in highly metastatic cancer cells significantly increases median survival times in our in vivo animal model of experimental metastasis. Collectively, our data indicate that GRP78 is an attractive target for the development of antimetastatic therapies. PMID- 27973328 TI - A comparison of two-dimensional and real-time 3D transoesophageal echocardiography and angiography for assessing the left atrial appendage anatomy for sizing a left atrial appendage occlusion system: impact of volume loading. AB - AIMS: Correct sizing of a left atrial appendage (LAA) closure system is important to avoid redeployment of the device and peri-device leaks. The aims of this study were to assess the significance of two-dimensional transoesophageal echocardiography (2D-TEE), real-time 3D transoesophageal echocardiography (RT 3D TEE) and angiography for measuring the size of the LAA landing zone and to determine the impact on sizing an LAA closure device. Furthermore, we investigated the relevance of volume loading on LAA size. METHODS AND RESULTS: In a prospective study, 46 patients underwent 2D-TEE and RT 3D-TEE 24 hours prior to LAA closure, at the beginning of the procedure and just before the procedure after volume loading with an average of 1,035+/-246 ml. Angiography was performed immediately before the implantation. Maximal diameter (2.2+/-0.4 versus 2.3+/-0.4 cm; p<0.01), perimeter (6.5+/-1.0 versus 6.8+/-1.0 cm, p<0.01) and area (3.2+/ 1.0 versus 3.5+/-1.1 cm2, p<0.01) of the LAA increased significantly after volume loading. The highest correlation (R) between measurements and LAA device size was found for RT 3D-TEE-derived perimeter (R=0.97) and area (R=0.96), whereas the maximal diameter (R=0.78) measured by 2D-TEE and angiography (R=0.76) correlated less closely. Sizing based on an RT 3D-TEE-measured perimeter resulted only in 4% of undersizing the implanted device. Peri-device leaks occurred in seven cases (15%) and were associated with a lower compression of LAA devices (7+/-1.3% versus 14+/-3.2% for patients without leaks, p<0.001). CONCLUSIONS: Volume loading before LAA closure increases LAA dimensions significantly. RT 3D-TEE measurements show a closer correlation to LAA closure device size than 2D-TEE or angiographic measurements. PMID- 27973329 TI - A novel constrained, paclitaxel-coated angioplasty balloon catheter. AB - AIMS: The study aimed to assess drug adherence, transfer to the vessel wall, tolerance and efficacy of a constrained angioplasty balloon coated with an excipient-enhanced paclitaxel coating (Chocolate coated balloon [CCB]) in the porcine model. METHODS AND RESULTS: Drug adherence was investigated in vitro. Drug transfer was evaluated in porcine arteries. A stent overstretch model was chosen to provoke intimal thickening in the efficacy and tolerance study. Conventional uncoated balloons were used as controls. CCB were coated with a nominal (3 ug/mm2) and high dose (two completely overlapping inflations each at 6 ug/mm2) of paclitaxel. Efficacy was assessed by histomorphometry and quantitative coronary angiography (QCA). Tolerance, including potential downstream effects, was assessed by myocardial function and histopathology. The CCB lost 6+/-12% of dose during in vitro simulated delivery to the lesion; drug transfer to the vessel wall was 14+/-4%. QCA and histomorphometry revealed no baseline differences between treatment groups. Thirty days after treatment, both doses of the CCB resulted in a 50% reduction in neointimal thickening of arteries relative to the uncoated balloon group. Maximum neointimal thickness was 1.12+/-0.36 mm for uncoated control specimens and 0.46+/-0.06 mm and 0.44+/-0.30 mm for the two CCB doses (3 and 2*6 ug/mm2), respectively. There were no device-related animal deaths or changes in left ventricular ejection fraction or device-specific myocardial histopathologies. There were no statistically significant differences between inflammatory scores among treatment groups. CONCLUSIONS: The results demonstrate efficacy and tolerance of a mechanically unique constrained angioplasty balloon within the tested dose range of the selected paclitaxel coating in the chosen porcine preclinical model. PMID- 27973330 TI - Three-dimensional volumetric assessment of coronary artery calcification in patients with stable coronary artery disease by OCT. AB - AIMS: There is a lack of a reliable technique to quantify coronary artery calcification (CAC). Hence, we used optical coherence tomography (OCT) to quantitate three-dimensional CAC volume to examine its association with plaque characteristics. METHODS AND RESULTS: A total of 250 patients with stable angina undergoing OCT imaging before PCI were included. CAC volume was calculated from every frame of the culprit lesion and divided into tertiles (low, intermediate and high). Quantitative calcium characteristics were assessed in 107 patients who underwent both OCT and IVUS. Increase in CAC volume was associated with reduced lipid volume index, lipid length and number of lipid plaques. Diabetes and LDL cholesterol predicted less coronary calcification whereas age and prior MI predicted increased CAC after adjusting for all clinical factors. Lipid volume index (rho=-0.001 [-0.003 to -0.00003]; p=0.04) and mean calcium depth (rho=-0.02 [-0.02 to -0.01]; p=0.000) were inversely related to CAC volume after adjusting for all OCT characteristics, whereas cap thickness increased with increase in CAC volume (rho=0.01 [0.002-0.03]; p=0.02) only in unadjusted analysis. Regression analysis demonstrated a significant correlation between calcium length (rho=0.83; p<0.001) and calcium arc (rho=0.86; p<0.001) measured by IVUS and OCT. CONCLUSIONS: Target lesions with high CAC volume are characterised by reduced plaque lipid content and calcium closer to the luminal border. Fibrous cap thickness increased with increase in calcium volume. PMID- 27973331 TI - How and when to suspect spontaneous coronary artery dissection: novel insights from a single-centre series on prevalence and angiographic appearance. AB - AIMS: Spontaneous coronary artery dissection (SCAD) is an underdiagnosed entity of acute coronary syndrome (ACS). Its prevalence remains unclear due to a challenging diagnosis, particularly in instances of intramural haematoma without intimal rupture. In the present study, we aimed to: 1) estimate the prevalence of SCAD among acute coronary syndrome (ACS) patients managed in a French coronary care centre, 2) demonstrate the value of specific angiographic signs for diagnosing SCAD, and 3) confirm the incremental value of intracoronary imaging in ambiguous cases. METHODS AND RESULTS: From 1999 to 2014, 55 cases of SCAD (all women, mean age 50.1 years) were diagnosed. Ignoring age, 51 (92.7%) had <=2 cardiovascular risk factors. Thirty-six were diagnosed prospectively during the latter period (2012-2014). Among these, SCAD accounted for 35.7% of ACS (20/56) in women <60 years with <=1 cardiovascular risk factor. Upon close investigation, five angiographic features commonly observed with SCAD were identified: 1) absence of atheroma on other coronary arteries, 2) radiolucent flap(s), 3) contrast dye staining of the arterial wall, 4) starting and/or ending of the angiographic ambiguity on a side branch, 5) long narrowing of lumen calibre: smooth and linear, or stenosis of varying severity mimicking a "stick insect" or "radish" aspect. Three of the above five signs were present in 51 (92.7%) cases. Optical computed tomography (OCT) was performed in 19 cases with no complication. All explored arteries had evidence of intramural haematoma and/or intimomedial membrane separation. An intimal rupture was observed in 10 (52.6%) patients. The diseased segment initiated or ended on a side branch in 14 (73.7%) patients. CONCLUSIONS: SCAD accounts for approximately one third of ACS in young women with <=1 CRF. The combination of specific angiographic signs and OCT imaging facilitates the diagnosis of ambiguous cases without intimal rupture. PMID- 27973332 TI - Limitations of OCT in identifying and quantifying lipid components: an in vivo comparison study with IVUS-NIRS. AB - AIMS: We aimed to assess the agreement between IVUS-NIRS and OCT to assess lipid plaques in patients with acute coronary syndromes or stable angina. In addition, the impact of both macrophages and calcifications was investigated. METHODS AND RESULTS: Forty-three patients undergoing both IVUS-NIRS and OCT assessment of the culprit and/or non-culprit coronary lesions were enrolled. Cross-sections from lipid plaques, calcified plaques and normal-appearing vessel tracts were identified and matched with the two imaging techniques. Lipid arc was measured by both IVUS-NIRS and OCT. Macrophage presence and calcifications were also investigated with OCT. OCT detected a lipid plaque in 90 cross-sections (48.9%), with a sensitivity of 85.5% and a specificity of 69.7% as compared with IVUS NIRS. The percentage of OCT false positive was 20.1% and of false negative was 4.9% for lipid plaque detection. The Pearson correlation coefficient for lipid arc was 0.675, p=0.0001. Macrophages were detected in 73% of OCT false positive cross-sections. Conversely, calcifications were present in 66.7% of OCT false negative cross-sections. The variability of lipid arc was independently associated with macrophages (beta=0.295, p=0.013). CONCLUSIONS: Agreement between IVUS-NIRS and OCT for lipid plaque detection is suboptimal. The presence of macrophages and superficial calcifications on OCT negatively affects lipid detection. PMID- 27973333 TI - Reliability of physiological assessment of coronary stenosis severity using intracoronary pressure techniques: a comprehensive analysis from a large cohort of consecutive intermediate coronary lesions. AB - AIMS: We sought to assess the reliability of the most frequently used intracoronary physiologic indices (including intravenous adenosine FFR [IV-FFR], intracoronary low-dose adenosine FFR [LD-IC-FFR], intracoronary high-dose adenosine FFR [HD-IC-FFR], Pd/Pa and iFR). We also sought to analyse factors affecting their reproducibility in a real-world patient population. METHODS AND RESULTS: A total of 91 lesions in 86 consecutive patients were included. Measurements of all physiological indices were repeated within a systematic standardised prospective protocol. All measured indices showed excellent test retest reliability, with intraclass correlation coefficient (ICC) over 0.96. IV FFR showed the highest coefficient of variation (CV) values among the studied measurements (Pd/Pa: 0.05; iFR: 0.10; LD-IC-FFR: 0.10; HD-IC-FFR: 0.08; IV-FFR: 0.12). Pd/Pa was significantly less variable than the other indices. On multivariate analysis, female gender, distal lesion location, history of hypertension or kidney failure, as well as presentation as an acute coronary syndrome, were associated with more variability in all physiological intracoronary measurements. CONCLUSIONS: The reliability of most frequently used intracoronary physiologic indices is high. Clinical and anatomic factors significantly influence the reliability of these physiologic indices. PMID- 27973334 TI - Outcomes and predictors of success and complications for paravalvular leak closure: an analysis of the SpanisH real-wOrld paravalvular LEaks closure (HOLE) registry. AB - AIMS: The aim of the study was to assess the safety and efficacy of percutaneous closure of paravalvular prosthetic leak (PVL) and to identify the predictors of procedural success and early complications. METHODS AND RESULTS: A total of 514 first-attempt percutaneous PVL closure in 469 patients were included at 19 centres. Technical and procedural success was achieved in 86.6% and 73.2% of the patients, respectively. In multivariate analysis, the independent predictors for procedural success in mitral lesions were the type of device used (AMPLATZER AVP III vs. others, HR 2.68 [1.29-5.54], p=0.008) and the number of procedures performed at the centre (top quartile vs. others, HR 1.93 [1.051-3.53], p=0.03). For aortic leaks the only predictor of procedural success was the leak size (>=10 mm vs. <10 mm, HR 3.077 [1.13-8.33], p=0.027). The overall major adverse events rate (death or emergency surgery or stroke) at 30 days was 5.6%; the only predictor for combined adverse events was New York Heart Association functional Class IV (HR 4.2 [1.42-12.34], p=0.009). CONCLUSIONS: Percutaneous closure of PVL can be performed with a reasonable rate of procedural success and a low rate of major complications. The type of device used, the accumulated experience and the leak size are predictors of procedural success. PMID- 27973335 TI - Non-invasive Heart Team assessment of multivessel coronary disease with coronary computed tomography angiography based on SYNTAX score II treatment recommendations: design and rationale of the randomised SYNTAX III Revolution trial. AB - AIMS: The aim of this study was to investigate whether a Heart Team decision making process regarding the choice of revascularisation strategy based on non invasive coronary multislice computed tomography angiography (MSCT) assessment of coronary artery disease (CAD) is equivalent to the standard-of-care invasive angiography-based assessment in patients with multivessel CAD. METHODS AND RESULTS: The SYNTAX III Revolution trial is a prospective, multicentre, all comers randomised trial that will randomise two Heart Teams to select between surgical and percutaneous treatment according to either an invasive conventional angiography or a non-invasive MSCT angiography assessment in patients with multivessel CAD. The treatment selection by each Heart Team will be guided by the SYNTAX score II calculation. The primary endpoint is the level of agreement according to kappa of the initial decision by the Heart Teams on the modality of the revascularisation based on MSCT and angiography assessments. Secondary endpoints include agreement on the number of vessels requiring treatment and the coronary segments in need of revascularisation. CONCLUSIONS: The SYNTAX III Revolution trial will provide valuable information regarding the ability of a purely non-invasive coronary anatomy assessment to select accurately the most appropriate revascularisation strategy for patients with multivessel CAD. PMID- 27973336 TI - Transcatheter left atrial appendage occlusion in patients with atrial fibrillation and a high bleeding risk using aspirin alone for post-implant antithrombotic therapy. AB - AIMS: The aim of the study was to evaluate the safety and efficacy of left atrial appendage occlusion (LAAO) with the AMPLATZER Cardiac Plug (ACP) or Amulet using aspirin alone (ASA) as post-implantation antithrombotic treatment. METHODS AND RESULTS: This was a single-centre, prospective, non-randomised study on LAAO with the ACP or Amulet in a consecutive cohort (n=110) treated by ASA alone post implantation. The primary outcome was device-related thrombosis, while secondary outcomes were ischaemic stroke or major bleeding. Clinical follow-up was conducted after six weeks and 12 months with TEE and cardiac CT. One hundred and seven patients were included in the analysis. Three patients were excluded due to a mechanical valve prosthesis. CHA2DS2-VASc score was 4.4+/-1.6 and HAS-BLED 4.1+/-1.1. Successful implantation was obtained in all patients with a periprocedural complication rate of 4.6%. Median follow-up was 2.3 years, with a total of 265 patient-years. Device-related thrombosis was detected in 2/107 (1.9%) cases. Stroke occurred in 6/107 patients, with an annualised rate of 2.3%, which is a 61% risk reduction compared to the predicted rate. Annual risk of major bleeding was reduced by 57%. CONCLUSIONS: LAAO with the ACP or Amulet was safely performed with ASA monotherapy after implantation without an increased risk of device-related thrombosis or stroke. PMID- 27973338 TI - Pentastome assemblages of the Nile crocodile, Crocodylus niloticus Laurenti (Reptilia: Crocodylidae), in the Kruger National Park, South Africa. AB - Thirty-two specimens of the Nile crocodile, Crocodylus niloticus Laurenti (Reptilia: Crocodylidae), from the Kruger National Park, South Africa, and its vicinity were examined for pentastomid parasites during 1995 to 1999 and 2010 to 2011. Pentastomid parasites occurred throughout the year and were widespread in the study area with an overall prevalence of 97% and an overall mean abundance of 23.4 (0-81). Pentastome assemblages comprised six species in three sebekid genera: Alofia nilotici Riley et Huchzermeyer, 1995, A. simpsoni Riley, 1994, Leiperia cincinnalis Sambon, 1922, Sebekia cesarisi Giglioli in Sambon, 1922, S. minor (Wedl, 1861) and S. okavangoensis Riley et Huchzermeyer, 1995. The possible influence of host age, gender and geographic location (river system) on pentastome prevalence, abundance and species richness was investigated. Generally, neither host age, gender nor locality did affect infracommunities, likely because all hosts examined were adult or subadult and displayed comparable foraging behaviour, resulting in similar exposure pathways to fish intermediate hosts. Additionally, the longevity of pentastomids would contribute to accumulative infections as hosts mature. Structuring of pentastome assemblages was observed in as far as S. minor was the dominant species based on overall prevalence and abundance, followed by the equally common species S. cesarisi and L. cincinnalis. With an overall prevalence ranging from 34% to 41% and relatively low abundances, A. nilotici, A. simpsoni and S. okavangoensis form the rarer component of pentastome communities. PMID- 27973337 TI - Pressure-mediated versus pharmacologic treatment of radial artery spasm during cardiac catheterisation: a randomised pilot study. AB - AIMS: The aim of the study was to determine the effectiveness of a novel strategy to treat radial artery spasm (RAS). METHODS AND RESULTS: We conducted a prospective, randomised, single-centre, open-label trial comparing a novel strategy of pressure-mediated dilatation versus intra-arterial administration of a combination of nitroglycerine plus verapamil for the treatment of RAS. The primary endpoint was radial artery intraluminal diameter acute gain assessed by quantitative radial angiography. After screening two hundred and twenty consecutive cases, twenty patients presented with RAS and were randomised 1:1 to either strategy. Overall the mean age was 60.8+/-11.5 years and 53% were females. Pre-treatment angiographic characteristics were similar between the groups. The primary endpoint of radial artery acute gain was significantly greater in the pressure-mediated dilatation group (0.85+/-0.46 mm vs. 0.03+/-0.24 mm, p<0.001). Blood pressure drop was significantly lower in the pressure-mediated dilatation group (DeltaBP -3.8+/-24 vs. -31.6+/-19 mmHg, p<0.001). There was one case of radial artery occlusion in the pressure-mediated dilatation group at follow-up. Short-duration pain was observed during the application of pressure. CONCLUSIONS: Pressure-mediated dilatation for the treatment of RAS was feasible, with superior angiographic results compared to a pharmacologic vasodilator strategy, with no impact on blood pressure. This novel approach proved to be safe and effective and should be tested in a large randomised trial. PMID- 27973340 TI - Bio-inspired vision based robot control using featureless estimations of time-to contact. AB - Marvelous vision based dynamic behaviors of insects and birds such as perching, landing, and obstacle avoidance have inspired scientists to propose the idea of time-to-contact, which is defined as the time for a moving observer to contact an object or surface if the current velocity is maintained. Since with only a vision sensor, time-to-contact can be directly estimated from consecutive images, it is widely used for a variety of robots to fulfill various tasks such as obstacle avoidance, docking, chasing, perching and landing. However, most of existing methods to estimate the time-to-contact need to extract and track features during the control process, which is time-consuming and cannot be applied to robots with limited computation power. In this paper, we adopt a featureless estimation method, extend this method to more general settings with angular velocities, and improve the estimation results using Kalman filtering. Further, we design an error based controller with gain scheduling strategy to control the motion of mobile robots. Experiments for both estimation and control are conducted using a customized mobile robot platform with low-cost embedded systems. Onboard experimental results demonstrate the effectiveness of the proposed approach, with the robot being controlled to successfully dock in front of a vertical wall. The estimation and control methods presented in this paper can be applied to computation-constrained miniature robots for agile locomotion such as landing, docking, or navigation. PMID- 27973339 TI - A new genus of rhinebothriidean cestodes from batoid elasmobranchs, with the description of five new species and two new combinations. AB - Survey work of batoid elasmobranchs in the eastern Atlantic and Indo-Pacific revealed multiple species of a new genus of cestode. Stillabothrium Healy et Reyda gen. n. (Rhinebothriidea: Escherbothriidae) is unique in its possession of an even number of non-medial longitudinal septa in the posterior portion of the bothridia, resulting in a series of loculi that are longer than wide (i.e. vertically oriented) and are arranged in columns. Five new species of Stillabothrium are described, S. ashleyae Willsey et Reyda sp. n., S. davidcynthiaorum Daigler et Reyda sp. n., S. campbelli Delgado, Dedrick et Reyda sp. n., S. hyphantoseptum Herzog, Bergman et Reyda sp. n., S. jeanfortiae Forti, Aprill et Reyda sp. n., and two species are formally transferred to the genus, S. amuletum (Butler, 1987) comb. n., and S. cadenati (Euzet, 1954) comb. n., the latter of which is redescribed. The species differ in the configuration of the other bothridial septa and in proglottid anatomy. Species of Stillabothrium were found parasitising a total of 17 species of batoid elasmobranchs of the genera Dasyatis Rafinesque, Glaucostegus Bonaparte, Himantura Muller et Henle, Pastinachus Ruppell, Rhinobatos Linck and Zanobatus Garman, including several host species that are likely new to science. A phylogenetic hypothesis based on Bayesian analysis of 1 084 aligned positions of the D1-D3 region of 28S rDNA for 27 specimens representing 10 species of Stillabothrium and two outgroup species supported the monophyly of Stillabothrium. These results also supported morphologically determined species boundaries in all cases in which more than one specimen of a putative species was included in the analysis. Host specificity appears to vary across species of Stillabothrium, with the number of host species parasitised by each species of Stillabothrium ranging from one to four. The geographic distribution of species of Stillabothrium spans the eastern Hemisphere, including the eastern Atlantic (coastal Senegal) and several locations in the Indo-Pacific (coastal Vietnam, Borneo and Australia). In addition, Phyllobothrium biacetabulatum Yamaguti, 1960 is formally transferred into family Escherbothriidae, although its generic placement remains uncertain (species incertae sedis). PMID- 27973341 TI - Referenceless MR thermometry-a comparison of five methods. AB - Proton resonance frequency shift (PRFS) MR thermometry is commonly used to measure temperature in thermotherapy. The method requires a baseline temperature map and is therefore motion sensitive. Several referenceless MR thermometry methods were proposed to address this problem but their performances have never been compared. This study compared the performance of five referenceless methods through simulation, heating of ex vivo tissues and in vivo imaging of the brain and liver of healthy volunteers. Mean, standard deviation, root mean square, 2/98 percentiles of error were used as performance metrics. Probability density functions (PDF) of the error distribution for these methods in the different tests were also compared. The results showed that the phase gradient method (PG) exhibited largest error in all scenarios. The original method (ORG) and the complex field estimation method (CFE) had similar performance in all experiments. The phase finite difference method (PFD) and the near harmonic method (NH) were better than other methods, especially in the lower signal-to-noise ratio (SNR) and fast changing field cases. Except for PG, the PDFs of each method were very similar among the different experiments. Since phase unwrapping in ORG and NH is computationally demanding and subject to image SNR, PFD and CFE would be good choices as they do not need phase unwrapping. The results here would facilitate the choice of appropriate referenceless methods in various MR thermometry applications. PMID- 27973342 TI - The investigation of cobalt intercalation underneath epitaxial graphene on 6H SiC(0 0 0 1). AB - The intercalation behaviour of cobalt underneath both epitaxial graphene monolayer and bilayer on 6H-SiC(0001) have been investigated by scanning tunneling microscopy (STM) and density functional theory (DFT). Upon deposition, cobalt atoms prefer to agglomerate into clusters on the epitaxial graphene. After annealing the sample to 850 degrees C, the intercalation of the adsorbed cobalt atoms into both monolayer and bilayer epitaxial graphene on SiC takes place, as observed by the atomically resolved STM images. Further studies based on DFT modeling and simulated STM images show that, resulting from the interplay between the intercalated cobalt atoms and the carbon layers sandwiching it, the most energetically favourable intercalation sites of cobalt atoms underneath monolayer and bilayer graphene differ. Furthermore, the results show energy barriers of 0.60 eV and 0.41 eV for cobalt penetration through mono-vacancy defects at monolayer and bilayer graphene. PMID- 27973343 TI - An image-guided precision proton radiation platform for preclinical in vivo research. AB - There are many unknowns in the radiobiology of proton beams and other particle beams. We describe the development and testing of an image-guided low-energy proton system optimized for radiobiological research applications. A 50 MeV proton beam from an existing cyclotron was modified to produce collimated beams (as small as 2 mm in diameter). Ionization chamber and radiochromic film measurements were performed and benchmarked with Monte Carlo simulations (TOPAS). The proton beam was aligned with a commercially-available CT image-guided x-ray irradiator device (SARRP, Xstrahl Inc.). To examine the alternative possibility of adapting a clinical proton therapy system, we performed Monte Carlo simulations of a range-shifted 100 MeV clinical beam. The proton beam exhibits a pristine Bragg Peak at a depth of 21 mm in water with a dose rate of 8.4 Gy min-1 (3 mm depth). The energy of the incident beam can be modulated to lower energies while preserving the Bragg peak. The LET was: 2.0 keV um-1 (water surface), 16 keV um-1 (Bragg peak), 27 keV um-1 (10% peak dose). Alignment of the proton beam with the SARRP system isocenter was measured at 0.24 mm agreement. The width of the beam changes very little with depth. Monte Carlo-based calculations of dose using the CT image data set as input demonstrate in vivo use. Monte Carlo simulations of the modulated 100 MeV clinical proton beam show a significantly reduced Bragg peak. We demonstrate the feasibility of a proton beam integrated with a commercial x-ray image-guidance system for preclinical in vivo studies. To our knowledge this is the first description of an experimental image-guided proton beam for preclinical radiobiology research. It will enable in vivo investigations of radiobiological effects in proton beams. PMID- 27973345 TI - Quantitative vibro-acoustography of tissue-like objects by measurement of resonant modes. AB - We demonstrate a simple and computationally efficient method to recover the shear modulus pertaining to the focal volume of an ultrasound transducer from the measured vibro-acoustic spectral peaks. A model that explains the transport of local deformation information with the acoustic wave acting as a carrier is put forth. It is also shown that the peaks correspond to the natural frequencies of vibration of the focal volume, which may be readily computed by solving an eigenvalue problem associated with the vibrating region. Having measured the first natural frequency with a fibre Bragg grating sensor, and armed with an expedient means of computing the same, we demonstrate a simple procedure, based on the method of bisection, to recover the average shear modulus of the object in the ultrasound focal volume. We demonstrate this recovery for four homogeneous agarose slabs of different stiffness and verify the accuracy of the recovery using independent rheometer-based measurements. Extension of the method to anisotropic samples through the measurement of a more complete set of resonant modes and the recovery of an elasticity tensor distribution, as is done in resonant ultrasound spectroscopy, is suggested. PMID- 27973344 TI - Objective comparison of lesion detectability in low and medium-energy collimator iodine-123 mIBG images using a channelized Hotelling observer. AB - Iodine-123 mIBG imaging is widely regarded as a gold standard for diagnostic studies of neuroblastoma and adult neuroendocrine cancer although the optimal collimator for tumour imaging remains undetermined. Low-energy (LE) high resolution (HR) collimators provide superior spatial resolution. However due to septal penetration of high-energy photons these provide poorer contrast than medium-energy (ME) general-purpose (GP) collimators. LEGP collimators improve count sensitivity. The aim of this study was to objectively compare the lesion detection efficiency of each collimator to determine the optimal collimator for diagnostic imaging. The septal penetration and sensitivity of each collimator was assessed. Planar images of the patient abdomen were simulated with static scans of a Liqui-PhilTM anthropomorphic phantom with lesion-shaped inserts, acquired with LE and ME collimators on 3 different manufacturers' gamma camera systems (Skylight (Philips), Intevo (Siemens) and Discovery (GE)). Two-hundred normal and 200 single-lesion abnormal images were created for each collimator. A channelized Hotelling observer (CHO) was developed and validated to score the images for the likelihood of an abnormality. The areas under receiver-operator characteristic (ROC) curves, Az, created from the scores were used to quantify lesion detectability. The CHO ROC curves for the LEHR collimators were inferior to the GP curves for all cameras. The LEHR collimators resulted in statistically significantly smaller Azs (p < 0.05), of on average 0.891 +/- 0.004, than for the MEGP collimators, 0.933 +/- 0.004. In conclusion, the reduced background provided by MEGP collimators improved 123I mIBG image lesion detectability over LEHR collimators that provided better spatial resolution. PMID- 27973347 TI - First-principles study of the mechanism of wettability transition of defective graphene. AB - Hydrophobicity of graphene limits its application potential in polar media, therefore modifications of graphene wettability have been in an area of active research for many years. Recently, a reversible wettability transition of graphene has been reported [Sci. Rep. 4, 6450 (2014)]. The presence of undercoordinated carbon atoms in otherwise hydrophobic graphene is believed to trigger the hydrophobic to hydrophilic transition, but the underlying mechanism, especially of the reverse process, remained unclear. Using density functional theory with range-separated hybrid functional HSE06, we investigate the dissociative adsorption of up to two water molecules on the defective graphene layer containing odd number of missing lattice atoms. We show, that depending on the defect type either a full dissociation of the water molecule or a partial splitting of H2O to OH and H takes place leading to the saturation of graphene dangling bonds due to the formation of oxiranes or by hydroxyls, respectively. The dissociation barriers are significantly lower for the water dimer than for the single molecule. Our findings providing detailed insights into the remarkable differences between the reactivity of vacancy defects with water shed new light on the wettability-transition mechanism of defective graphene. PMID- 27973348 TI - Designing 3D interconnected continuous nanoporous Co/CoO core-shell nanostructure electrodes for a high-performance pseudocapacitor. AB - A high-performance supercapacitor electrode is designed and fabricated with the 3D interconnected continuous nanoporous Co/CoO core-shell hybrid nanostructure grown on nickel foam. The Co/CoO core-shell hybrid nanostructures are obtained via a hydrothermal method, followed by high-temperature annealing in hydrogen atmosphere, and finally placed in air at 50 degrees C for 1 h. The Co/CoO core shell nanostructure assembled by a conductive metal-core and a CoO shell, brings low resistance, high specific capacitance of 5.632 F cm-2 and good capability stability (81.5% capacitance retention after 6000 cycles). An asymmetric supercapacitor device built by the Co/CoO (positive electrode) and activated carbon (negative electrode) can deliver a working voltage of 1.7 V and display a high energy density of 0.002 67 Wh cm-2 at a power density of 0.001 62 W cm-2, which is far superior to that of a supercapacitor at a similar power density. PMID- 27973349 TI - Computing with volatile memristors: an application of non-pinched hysteresis. AB - The possibility of in-memory computing with volatile memristive devices, namely, memristors requiring a power source to sustain their memory, is demonstrated theoretically. We have adopted a hysteretic graphene-based field emission structure as a prototype of a volatile memristor, which is characterized by a non pinched hysteresis loop. A memristive model of the structure is developed and used to simulate a polymorphic circuit implementing stateful logic gates, such as the material implication. Specific regions of parameter space realizing useful logic functions are identified. Our results are applicable to other realizations of volatile memory devices, such as certain NEMS switches. PMID- 27973350 TI - Microstructure and ferroelectricity of BaTiO3 thin films on Si for integrated photonics. AB - Significant progress has been made in integrating novel materials into silicon photonic structures in order to extend the functionality of photonic circuits. One of these promising optical materials is BaTiO3 or barium titanate (BTO) that exhibits a very large Pockels coefficient as required for high-speed light modulators. However, all previous demonstrations show a noticable reduction of the Pockels effect in BTO thin films deposited on silicon substrates compared to BTO bulk crystals. Here, we report on the strong dependence of the Pockels effect in BTO thin films on their microstructure, and provide guidelines on how to engineer thin films with strong electro-optic response. We employ several deposition methods such as molecular beam epitaxy and chemical vapor deposition to realize BTO thin films with different morphology and crystalline structure. While a linear electro-optic response is present even in porous, polycrystalline BTO thin films with an effective Pockels coefficient r eff = 6 pm V-1, it is maximized for dense, tetragonal, epitaxial BTO films (r eff = 140 pm V-1). By identifying the key structural predictors of electro-optic response in BTO/Si, we provide a roadmap to fully exploit the linear electro-optic effect in novel hybrid oxide/semiconductor nanophotonic devices. PMID- 27973351 TI - Water equivalent path length calculations using scatter-corrected head and neck CBCT images to evaluate patients for adaptive proton therapy. AB - Proton therapy has dosimetric advantages due to the well-defined range of the proton beam over photon radiotherapy. When the proton beams, however, are delivered to the patient in fractionated radiation treatment, the treatment outcome is affected by delivery uncertainties such as anatomic change in the patient and daily patient setup error. This study aims at establishing a method to evaluate the dosimetric impact of the anatomic change and patient setup error during head and neck proton therapy. Range variations due to the delivery uncertainties were assessed by calculating water equivalent path length (WEPL) to the distal edge of tumor volume using planning CT and weekly treatment cone-beam CT (CBCT) images. Specifically, mean difference and root mean squared deviation (RMSD) of the distal WEPLs were calculated as the weekly range variations. To accurately calculate the distal WEPLs, an existing CBCT scatter correction algorithm was used. An automatic rigid registration was used to align the planning CT and treatment CBCT images, simulating a six degree-of-freedom couch correction at treatments. The authors conclude that the dosimetric impact of the anatomic change and patient setup error was reasonably captured in the differences of the distal WEPL variation with a range calculation uncertainty of 2%. The proposed method to calculate the distal WEPL using the scatter-corrected CBCT images can be an essential tool to decide the necessity of re-planning in adaptive proton therapy. PMID- 27973352 TI - Contrast enhanced ultrasound by real-time spatiotemporal filtering of ultrafast images. AB - Contrast enhanced ultrasound (CEUS) takes advantage of the nonlinear behaviour of injected microbubbles. If these contrast techniques yield good specificity between bubbles and tissues, they suffer some drawbacks, inherently linked to their dependence on nonlinear content. In recent years, plane-wave ultrasound reached frame rates of up to 20 000 fps. In this study we propose a linear technique for CEUS that takes advantage of these very high frame rates to separate bubbles from tissue without requiring nonlinearities. Data-driven spatiotemporal filtering operations are used to separate different features in the image on the basis of coherence both in space and time. Such filter recently proved to improve Doppler sensitivity (Demene et al 2015 IEEE Trans. Med. Imaging 34 2271-85). In contrast with bubbles, even slow moving ones, tissues are highly coherent both in space and time. Therefore, singular value decomposition (SVD) seems to be a powerful tool for the separation of contrast agents and tissues. In this paper, we apply SVD processing to linear ultrafast ultrasound images for CEUS Doppler. The contrast levels reached by this technique were compared to those of a nonlinear gold standard sequence (PMPI Doppler) through a flow phantom study. The SVD technique reached contrast-to-tissue ratios (CTR) up to 10 dB higher in vitro, and proved to be robust in terms of probe motion and slow flow. A trial was also conducted on a transplanted human kidney, already imaged by means of power Doppler (Claudon et al 1999 Am. J. Roentgenol. 173 41-6) and microbubbles (Kay et al 2009 Clin. Radiol. 64 1081-7). Contrast levels yielded by the SVD technique measured up to 13 dB higher than those of PMPI Doppler. PMID- 27973353 TI - Impact of physiological noise correction on detecting blood oxygenation level dependent contrast in the breast. AB - Physiological fluctuations are expected to be a dominant source of noise in blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) experiments to assess tumour oxygenation and angiogenesis. This work investigates the impact of various physiological noise regressors: retrospective image correction (RETROICOR), heart rate (HR) and respiratory volume per unit time (RVT), on signal variance and the detection of BOLD contrast in the breast in response to a modulated respiratory stimulus. BOLD MRI was performed at 3 T in ten volunteers at rest and during cycles of oxygen and carbogen gas breathing. RETROICOR was optimized using F-tests to determine which cardiac and respiratory phase terms accounted for a significant amount of signal variance. A nested regression analysis was performed to assess the effect of RETROICOR, HR and RVT on the model fit residuals, temporal signal-to-noise ratio, and BOLD activation parameters. The optimized RETROICOR model accounted for the largest amount of signal variance ([Formula: see text] = 3.3 +/- 2.1%) and improved the detection of BOLD activation (P = 0.002). Inclusion of HR and RVT regressors explained additional signal variance, but had a negative impact on activation parameter estimation (P < 0.001). Fluctuations in HR and RVT appeared to be correlated with the stimulus and may contribute to apparent BOLD signal reactivity. PMID- 27973354 TI - A diffraction correction for storage and loss moduli imaging using radiation force based elastography. AB - Noninvasive evaluation of the rheological behavior of soft tissues may provide an important diagnosis tool. Nowadays, available commercial ultrasound systems only provide shear elasticity estimation by shear wave speed assessment under the hypothesis of a purely elastic model. However, to fully characterize the rheological behavior of tissues, given by its storage (G') and loss (G") moduli, it is necessary to estimate both: shear wave speed and shear wave attenuation. Most elastography techniques use the acoustic radiation force to generate shear waves. For this type of source the shear waves are not plane and a diffraction correction is needed to properly estimate the shear wave attenuation. The use of a cylindrical wave approximation to evaluate diffraction has been proposed by other authors before. Here the validity of such approximation is numerically and experimentally revisited. Then, it is used to generate images of G' and G" in heterogeneous viscoelastic mediums. A simulation algorithm based on the anisotropic and viscoelastic Green's function was used to establish the validity of the cylindrical approximation. Moreover, two experiments were carried out: a transient elastography experiment where plane shear waves were generated using a vibrating plate and a SSI experiment that uses the acoustic radiation force to generate shear waves. For both experiments the shear wave propagation was followed with an ultrafast ultrasound scanner. Then, the shear wave velocity and shear wave attenuation were recovered from the phase and amplitude decay versus distance respectively. In the SSI experiment the cylindrical approximation was applied to correct attenuation due to diffraction effects. The numerical and experimental results validate the use of a cylindrical correction to assess shear wave attenuation. Finally, by applying the cylindrical correction G' and G" images were generated in heterogeneous phantoms and a preliminary in vivo feasibility study was carried out in the human liver. PMID- 27973355 TI - Basis material decomposition in spectral CT using a semi-empirical, polychromatic adaption of the Beer-Lambert model. AB - Following the development of energy-sensitive photon-counting detectors using high-Z sensor materials, application of spectral x-ray imaging methods to clinical practice comes into reach. However, these detectors require extensive calibration efforts in order to perform spectral imaging tasks like basis material decomposition. In this paper, we report a novel approach to basis material decomposition that utilizes a semi-empirical estimator for the number of photons registered in distinct energy bins in the presence of beam-hardening effects which can be termed as a polychromatic Beer-Lambert model. A maximum likelihood estimator is applied to the model in order to obtain estimates of the underlying sample composition. Using a Monte-Carlo simulation of a typical clinical CT acquisition, the performance of the proposed estimator was evaluated. The estimator is shown to be unbiased and efficient according to the Cramer-Rao lower bound. In particular, the estimator is capable of operating with a minimum number of calibration measurements. Good results were obtained after calibration using less than 10 samples of known composition in a two-material attenuation basis. This opens up the possibility for fast re-calibration in the clinical routine which is considered an advantage of the proposed method over other implementations reported in the literature. PMID- 27973357 TI - Flood prevention dams for arid regions at a micro-scale sub-catchment, case study: Tabuk, Saudi Arabia. AB - Unexpected flash flooding is one of the periodic hydrological problems affecting the city of Tabuk in Saudi Arabia. The region has high potential for floods as it suffers high rainfall intensity in a short time and also has high urbanization rates and topographic complexity. Constructing flood prevention dams is one option to solve this problem. A cost-effective design requires a detailed feasibility study and analysis for the selection of suitable sites. The aim of this study was to develop a method for selecting a suitable site for flood protection dams in the Abu Saba'a district, the most affected part of the city of Tabuk during the flash flood in January 2013. Spatial analysis was applied using Landsat Thematic Mapper images and Shuttle Radar Topography Mission digital elevation model to select a site in the Abu Saba'a area. A simple model using ArcGIS was built including all suggested parameters. The results showed the best site for a dam was 2 km distance backfrom the area, where all parameter values matched. The results showed that the dynamic properties of land cover can affect site selection. It is therefore suggested that more field and hydrological data should be gathered for greater accuracy. PMID- 27973358 TI - Removal of methylene blue dye from water by a spent bleaching earth biosorbent. AB - This work is about the valorization of spent bleaching earth (SBE) at low cost from the AFIA oil refinery in Algeria's western region. The biowaste has been burned to eliminate the oil traces, then it has been valorized in two ways: (i) chemically, using phosphoric acid to obtain SBEC and (ii) thermally at 750 degrees C to create SBEH. The obtained materials were used for the first time as biosorbents in the wastewater treatment field. The three biomaterials show very interesting adsorption properties, with specific surfaces of 194.2, 784.6 and 888.5 m2 g-1 for SBE, SBEC and SBEH, respectively. The analysis has revealed that the obtained materials are alumino-silicates. The three biowastes have been used to remove methylene blue dye from water. The dye was totally eliminated by a physisorption mechanism in the presence of 1 g L-1 of each biowaste after 8, 10, 20 min of contact time. The highest correlation coefficient (R2 = 0.99) was related to the Langmuir isotherm, indicating a good fit with this model, and explaining the biosorption as a monolayer process. According to this model, the adsorption capacities were 123.3, 185.2 and 188.7 mg g-1 for SBE, SBEH and SBEC, respectively. This study shows that SBE can be used as an alternative to commercial adsorbents for dye removal from water. PMID- 27973356 TI - Towards a standardization of biomethane potential tests. AB - Production of biogas from different organic materials is a most interesting source of renewable energy. The biomethane potential (BMP) of these materials has to be determined to get insight in design parameters for anaerobic digesters. Although several norms and guidelines for BMP tests exist, inter-laboratory tests regularly show high variability of BMPs for the same substrate. A workshop was held in June 2015, in Leysin, Switzerland, with over 40 attendees from 30 laboratories around the world, to agree on common solutions to the conundrum of inconsistent BMP test results. This paper presents the consensus of the intense roundtable discussions and cross-comparison of methodologies used in respective laboratories. Compulsory elements for the validation of BMP results were defined. They include the minimal number of replicates, the request to carry out blank and positive control assays, a criterion for the test duration, details on BMP calculation, and last but not least criteria for rejection of the BMP tests. Finally, recommendations on items that strongly influence the outcome of BMP tests such as inoculum characteristics, substrate preparation, test setup, and data analysis are presented to increase the probability of obtaining validated and reproducible results. PMID- 27973359 TI - Rapid start-up of one-stage deammonification MBBR without addition of external inoculum. AB - In recent years, the anammox process has emerged as a useful method for robust and efficient nitrogen removal in wastewater treatment plants (WWTPs). This paper evaluates a one-stage deammonification (nitritation and anammox) start-up using carrier material without using anammox inoculum. A continuous laboratory-scale process was followed by full-scale operation with reject water from the digesters at Bekkelaget WWTP in Oslo, Norway. A third laboratory reactor was run in operational mode to verify the suitability of reject water from thermophilic digestion for the deammonification process. The two start-ups presented were run with indigenous bacterial populations, intermittent aeration and dilution, to favour growth of the anammox bacterial branches. Evaluation was done by chemical and fluorescence in situ hybridization analyses. The results demonstrate that anammox culture can be set up in a one-stage process only using indigenous anammox bacteria and that a full-scale start-up process can be completed in less than 120 days. PMID- 27973360 TI - Iridium nanoparticles with high catalytic activity in degradation of acid red-26: an oxidative approach. AB - Nanocatalysis using metal nanoparticles constitutes one of the emerging technologies for destructive oxidation of organics such as dyes. This paper deals with the degradation of acid red-26 (AR-26), an azo dye by hexacyanoferrate (abbreviated as HCF) (III) using iridium nanoparticles. UV-vis spectroscopy has been employed to obtain the details of the oxidative degradation of the selected dye. The effect of various operational parameters such as HCF(III) concentration, pH, initial dye concentration, catalyst and temperature was investigated systematically at the lambdamax, 507 nm, of the reaction mixture. Degradation kinetics follows the first order kinetic model with respect to AR-26 and Ir nano concentrations, while with respect to the HCF(III) concentration reaction it follows first order kinetics at lower concentrations, tending towards zero order at higher concentrations. Thermodynamic parameters have been calculated by studying the reaction rate at four different temperatures. The UV-vis, high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS) analysis of degradation products showed the formation of carboxylic acid and substituted carboxylic acids as major degradation products, which are simple and less hazardous compounds. The big advantage of the present method is the recovery and reuse of iridium nanoparticles. Moreover, turnover frequencies for each catalytic cycle have been determined, indicating the long life span of Ir nanoparticles. Thus, the finding is a novel and highly economical alternative for environmental safety against pollution by dyes, and extendable for other contaminants as well. PMID- 27973361 TI - Lotus seedpod as a low-cost biomass for potential methylene blue adsorption. AB - The adsorption of methylene blue (MB) by low cost biomass lotus seedpod (LSP) was optimized by a central composite design combined with response surface methodology in aqueous solution. Solution pH, initial dye concentration and adsorbent dosage were studied as independent variables at five levels each, respectively. Analysis of variance suggested the validity of the regression model. LSP was characterized by Fourier transform infrared spectra and energy dispersive spectroscopy. The kinetics revealed that the adsorption behavior followed the pseudo-second-order model. Langmuir and Freundlich isotherm models were used to evaluate the adsorption, and the experimental data were better fitted by the Langmuir isotherm than the Freundlich isotherm. The maximum monolayer adsorption capacity of the LSP was 157.98 mg g-1 at 30 degrees C for MB adsorption. In addition, 0.2 M HCl solution could be used for reusability of LSP via desorption tests. LSP was proven to be an available and effective biosorbent for MB removal from aqueous solution. PMID- 27973362 TI - Evaluation of volcanic pumice stone as media in fixed bed sequence batch reactor for atrazine removal from aquatic environments. AB - Atrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine) is a component of S-triazine. Its characteristics make it a pollutant of ecosystems and a probable human carcinogen. The present study evaluated volcanic pumice stone as a suitable media for biological growth and biofilm development in a fixed-bed sequencing batch reactor (FBSBR) for atrazine removal from aquatic environments. The FBSBR was fed with synthetic wastewater containing sucrose and atrazine at four hydraulic retention times to assess biodegradation of atrazine by a microbial consortium for removal from aquatic environments. The maximum efficiency for atrazine and soluble chemical oxygen demand removal were 97.9% and 98.9%, respectively. The results of this research showed that the Stover Kincannon model was a very good fit (R2 > 99%) for loading atrazine onto the FBSBR. Increasing the initial concentration of atrazine increased the removal efficiency. There was no significant inhibition of the mixed aerobic microbial consortia by the atrazine. Atrazine degradation depended on its initial concentration in the wastewater and the amount of atrazine in the influent. Although this system shows good potential for atrazine removal from aqueous environments, that remaining in the effluent does not yet meet international standards. Further research is required to make this system effective for removal of atrazine from the environment. PMID- 27973363 TI - Investigation into mixing in the shallow floodplain Poyang Lake (China) using hydrological, thermal and isotopic evidence. AB - Although mixing in lakes has significant environmental and ecological implications, knowledge of mixing dynamics for shallow floodplain lakes has received little attention. In this study, hydrological, thermal and isotopic investigations were undertaken to provide evidence for the mixing in the large, shallow floodplain Poyang Lake (China). Depth profiles of water velocity, water temperature and stable hydrogen and oxygen isotope compositions were measured throughout the lake, with results showing that the water velocity differences in depth profiles are generally less than ~0.2 m/s, indicating weak stratification. Although water temperature differences of up to ~2 degrees C are observed occasionally, Poyang Lake appears to have isothermal mixed layers from the epilimnion to the hypolimnion, attributed to the presence of mostly small temperature differences (<1 degrees C). Additionally, isotope compositions reveal that the lake's water columns are almost homogeneous during various water level periods. Relative to many lakes exhibiting either no mixing or partial mixing, Poyang Lake appears to be fully mixing on a seasonal basis, depending on hydrological forcings within the lake rather than meteorological conditions. The current study will help to improve our knowledge of water flow patterns and pollutant transport in Poyang Lake and other similar floodplain lakes. PMID- 27973364 TI - Urban pluvial flood prediction: a case study evaluating radar rainfall nowcasts and numerical weather prediction models as model inputs. AB - Flooding produced by high-intensive local rainfall and drainage system capacity exceedance can have severe impacts in cities. In order to prepare cities for these types of flood events - especially in the future climate - it is valuable to be able to simulate these events numerically, both historically and in real time. There is a rather untested potential in real-time prediction of urban floods. In this paper, radar data observations with different spatial and temporal resolution, radar nowcasts of 0-2 h leadtime, and numerical weather models with leadtimes up to 24 h are used as inputs to an integrated flood and drainage systems model in order to investigate the relative difference between different inputs in predicting future floods. The system is tested on the small town of Lystrup in Denmark, which was flooded in 2012 and 2014. Results show it is possible to generate detailed flood maps in real-time with high resolution radar rainfall data, but rather limited forecast performance in predicting floods with leadtimes more than half an hour. PMID- 27973365 TI - Fabrication of sulfated nanofilter membrane based on carboxymethyl cellulose. AB - The aim of this study is to prepare sulfated carboxymethyl cellulose (SCMC) nanofilter membrane using sulfur trioxide pyridine complex (SO3/pyridine) as sulfating agent and glutaraldehyde (GA) as a crosslinking agent onto polysulfone supporting membrane. The prepared nanofilter was characterized by Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, atomic force microscopy and zeta potential. To evaluate the prepared nanofilter, various amounts of SO3/Pyridine were used and efficiency of them was investigated. The results showed that increasing the sulfate groups raised the flux from 13.87 to 29.54 L/(m2.h-1), whereas percentage rejection was increased during the separation of salt aqueous solutions and then decreased. It can be concluded that, SCMC-GA-2 (with molar ratio of SO3/pyridine to CMC of 1) shows high separation efficiency in acidic conditions and improves the hydrophilicity and charge density of the filter. PMID- 27973366 TI - Operating costs and energy demand of wastewater treatment plants in Austria: benchmarking results of the last 10 years. AB - This work presents operating costs and energy consumption of Austrian municipal wastewater treatment plants (WWTPs) (>=10,000 PE-design capacity) that have been classified into different size groups. Different processes as well as cost elements are investigated and processes with high relevance regarding operating costs and energy consumption are identified. Furthermore, the work shows the cost relevance of six investigated cost elements. The analysis demonstrates the size dependency of operating costs and energy consumption. For the examination of the energy consumption the investigated WWTPs were further classified into WWTPs with aerobic sludge stabilisation and WWTPs with mesophilic sludge digestion. The work proves that energy consumption depends mainly on the type of sludge stabilisation. The results of the investigation can help to determine reduction potential in operating costs and energy consumption of WWTPs and form a basis for more detailed analysis which helps to identify cost and energy saving potential. PMID- 27973367 TI - Removal of perfluorooctanoic acid (PFOA) in groundwater by nanofiltration membrane. AB - Perfluorooctanoic acid (PFOA) is very persistent in the environment and resistant to typical degradation processes. PFOA has been widely used in surface-active agents and as an emulsifier in several products and can contaminate groundwater. Groundwater is considered as an important source of water; hence removal of PFOA contamination in groundwater is needed. This study aimed to examine the removal of PFOA in spiked deionized water and spiked groundwater samples by nanofiltration (NF) membrane. PFOA removal efficiency was performed by using NF membrane and all samples were analysed by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). For groundwater concentration, solid phase extraction is needed before being analysed by HPLC MS/MS. The results showed that at higher pressures and higher PFOA concentrations, the PFOA removal efficiencies were slightly higher. The PFOA removal efficiency of spiked deionized water and spiked groundwater sample were 99.78-99.87% and 99.49-99.54%, respectively, which were not significantly different. PMID- 27973368 TI - Natural radionuclides in waste water discharged from coal-fired power plants in Serbia. AB - Investigation of the natural radioactivity levels in water around power plants, as well as in plants, coal, ash, slag and soil, and to assess the associated radiation hazard is becoming an emerging and interesting topic. This paper is focused on the results of the radioactivity analysis in waste water samples from five coal-fired power plants in Serbia (Nikola Tesla A, Nikola Tesla B, Kolubara, Morava and Kostolac), which were analyzed in the period 2003-2015. River water samples taken upstream and downstream from the power plants, drain water and overflow water were analyzed. In the water samples gamma spectrometry analysis was performed as well as determination of gross alpha and beta activity. Natural radionuclide 40K was detected by gamma spectrometry, while the concentrations of other radionuclides, 226Ra, 235U and 238U, usually were below the minimum detection activity (MDA). 232Th and artificial radionuclide 137Cs were not detected in these samples. Gross alpha and beta activities were determined by the alpha/beta low level proportional counter Thermo Eberline FHT 770 T. In the analyzed samples, gross alpha activity ranged from MDA to 0.47 Bq L-1, while the gross beta activity ranged from MDA to 1.55 Bq L-1. PMID- 27973369 TI - An integrated model for simulating and diagnosing the water quality based on the system dynamics and Bayesian network. AB - An integrated model for simulating and diagnosing water quality based on the system dynamics and Bayesian network (BN) is presented in the paper. The research aims to connect water monitoring downstream with outlet management upstream in order to present an efficiency outlet management strategy. The integrated model was built from two components: the system dynamics were used to simulate the water quality and the BN was applied to diagnose the reason for water quality deterioration according to the water quality simulation. The integrated model was applied in a case study of the Songhua River from the Baiqi section to the Songlin section to prove its reasonability and accuracy. The results showed that the simulation fit to the variation trend of monitoring data, and the average relative error was less than 10%. The water quality deterioration in the Songlin section was mainly found to be caused by the water quality in the upper reach and Hadashan Reservoir drain by using the diagnosis function of the integrated model based on BN. The relevant result revealed that the integrated model could provide reasonable and quantitative support for the basin manager to make a reasonable outlet control strategy to avoid more serious water quality deterioration. PMID- 27973370 TI - Biochemical characteristic along UBAF in a one-stage autotrophic nitrogen removal reactor. AB - The Up-flow biological aerated filter (UBAF) based on a one-stage autotrophic nitrogen removal process has been widely investigated nowadays. In this work, the biochemical characteristic along the volcanic-filled UBAF reactor had been studied. The results indicate that short-rod, spherical and elliptical (averaged 0.2-1.0 MUm) microorganisms with a specific irregular cauliflower profile existed in the system. Species identification showed Nitrosococcus- and Nitrosomonas related aerobic ammonium-oxidizing bacteria (AerAOB) and Candidatus Kuenenia stuttgartiensis-like anaerobic ammonium-oxidizing bacteria (AnAOB) were the predominant functional bacteria that mixed with each other and showed no distinct niche in the system. However, the bioactivity of functional microorganisms displayed differently at different filter layers, with a better pollutant-removal activity in the lower parts than in the upper parts of the UBAF. In the lower parts, compact and small zooglea formed, whereas it trended to be larger and looser along the filter. Moreover, there was better biodiversity of AerAOB in the lower part, while AnAOB showed stable and low biodiversity along the filter. PMID- 27973371 TI - A new device to select carriers for biomass immobilization and application in an aerobic/anaerobic fixed-bed sequencing batch biofilm reactor for nitrogen removal. AB - This study proposes a new approach to selecting a biofilm carrier for immobilization using dissolved oxygen (DO) microsensors to measure the thickness of aerobic and anaerobic layers in biofilm. The biofilm carriers tested were polyurethane foam, mineral coal (MC), basaltic gravel, and low-density polyethylene. Development of layers in the biofilm carrier surface was evaluated using a flow cell device, and DO profiles were conducted to determine the size of the layers (aerobic and anaerobic). MC was the biofilm carrier selected due to allowing the development of larger aerobic and anaerobic layers in the biofilm (896 and 1,058 MUm, respectively). This ability is supposed to improve simultaneous nitrogen removal by nitrification and denitrification biological processes. Thus, as a biofilm carrier, MC was used in a fixed-bed sequencing batch biofilm reactor (FB-SBBR) for treatment of wastewater with a high ammonia concentration (100-400 mgNH4+-N L-1). The FB-SBBR (15.0 L) was filled with matrices of the carrier and operated under alternating aeration and non-aeration periods of 6 h each. At a mean nitrogen loading rate of 0.55 +/- 0.10 kgNH4+-N m 3 d-1, the reactor attained a mean nitrification efficiency of 95 +/- 9% with nitrite as the main product (aerobic period). Mean denitrification efficiency during the anoxic period was 72 +/- 13%. PMID- 27973373 TI - Estimation of combined sewer overflow discharge: a software sensor approach based on local water level measurements. AB - Combined sewer overflow (CSO) structures are constructed to effectively discharge excess water during heavy rainfall, to protect the urban drainage system from hydraulic overload. Consequently, most CSO structures are not constructed according to basic hydraulic principles for ideal measurement weirs. It can, therefore, be a challenge to quantify the discharges from CSOs. Quantification of CSO discharges are important in relation to the increased environmental awareness of the receiving water bodies. Furthermore, CSO discharge quantification is essential for closing the rainfall-runoff mass-balance in combined sewer catchments. A closed mass-balance is an advantage for calibration of all urban drainage models based on mass-balance principles. This study presents three different software sensor concepts based on local water level sensors, which can be used to estimate CSO discharge volumes from hydraulic complex CSO structures. The three concepts were tested and verified under real practical conditions. All three concepts were accurate when compared to electromagnetic flow measurements. PMID- 27973372 TI - Post-treatment of palm oil mill effluent (POME) using combined persulphate with hydrogen peroxide (S2O82-/H2O2) oxidation. AB - The aim of the current study is to evaluate the effectiveness of combined persulphate with hydrogen peroxide (S2O82-/H2O2) oxidation as a post-treatment of biologically treated palm oil mill effluent (POME) for the first time in the literature. The removal efficiencies of chemical oxygen demand (COD), ammoniacal nitrogen (NH3-N), and suspended solids (SS) were 36.8%, 47.6%, and 90.6%, respectively, by S2O82- oxidation alone under certain operation conditions (i.e., S2O82- = 0.82 g, pH 11, and contact time 20 min). Nevertheless, the combined process (S2O82-/H2O2) achieved 75.8% and 87.1% removals of NH3-N and SS, respectively, under 2.45/1.63 g/g H2O2/S2O82-, pH 11, and 20 min oxidation. Moreover, 56.9% of COD was removed at pH 8.4. PMID- 27973374 TI - Inhibition kinetics and granular sludge in an ANAMMOX reactor treating mature landfill leachate. AB - The present study reports the inhibition kinetics and granular sludge in an anaerobic ammonium oxidation (ANAMMOX) - up-flow anaerobic sludge blanket reactor fed with diluted mature landfill leachate. The activity of ANAMMOX bacteria was inhibited by addition of mature landfill leachate, but gradually adapted to the leachate. The system achieved efficient nitrogen removal during 65-75 d and the average removal efficiencies for NH4+-N, NO2--N and total nitrogen (TN) were 96%, 95% and 87%, respectively. ANAMMOX was the main pathway of nitrogen removal in the system, and heterotrophic denitrification occurred simultaneously. In addition, aerobic ammonia oxidation and aerobic nitrite oxidation were active in this system. Inhibition kinetic experiments showed that the NH4+-N and NO2--N inhibition concentration threshold of ANAMMOX were 489.03 mg/L and 192.36 mg/L, respectively. ANAMMOX was significantly inhibited by mature landfill leachate, and was completely inhibited when the leachate concentration was 1,450.69 mg/L (calculated in chemical oxygen demand). Thus, the inhibition concentration of substrate and landfill leachate should be considered when applying the ANAMMOX process to landfill leachate. The color of granular sludge ANAMMOX changed from brick-red into a reddish-brown. The particle size increased from small to large, with evident granulation of the ANAMMOX sludge. PMID- 27973375 TI - 3DEEM spectroscopy analysis to assess the EPS composition in different carriers in HMBR systems. AB - A hybrid membrane bioreactor (HMBR) with biological band carriers (Reactor A) and an HMBR with suspended honeycomb carriers (Reactor B) were conducted in parallel to investigate the effects of different carriers on extracellular polymeric substances (EPS). Composition and concentration of EPS were examined by three dimensional excitation-emission matrix (3DEEM) fluorescence spectra and parallel factor analysis (PARAFAC). 3DEEM spectra demonstrated that the main organic substances of the EPS in two reactors were protein-like, humic acid-like and fulvic acid-like substances. The fluorescence intensity (FI) indicated that the protein-like composition was dominant in EPS, and its intensity in reactor B was stronger than that in A (392.94 > 250.25). Results of the FI identified from the 3DEEM by PARAFAC showed that the EPS in two reactors included two humic acid-like compositions C1 (230, 320/406 nm), C2 (250, 360/440 nm) and one protein-like C4 (230, 280/340 nm), while C3 was fulvic acid-like (220/429 nm) and protein-like (230/357 nm) in reactor A and B, respectively. The proportion and FI of protein like substances in reactor B were higher than that in A. Consequently, it was concluded that reactor A could control the membrane fouling effectively, compared with reactor B. PMID- 27973376 TI - Experimental study of hydraulics and sediment capture efficiency in catchbasins. AB - Catchbasins (also known as gully pot in the UK and Australia) are used to receive surface runoff and drain the stormwater into storm sewers. The recent interest in catchbasins is to improve their effectiveness in removing sediments in stormwater. An experimental study was conducted to examine the hydraulic features and sediment capture efficiency in catchbasins, with and without a bottom sump. A sump basin is found to increase the sediment capture efficiency significantly. The effect of inlet control devices, which are commonly used to control the amount of flow into the downstream storm sewer system, is also studied. These devices will increase the water depth in the catchbasin and increase the sediment capture efficiency. Equations are developed for predicting the sediment capture efficiency in catchbasins. PMID- 27973378 TI - Erratum: Water Science and Technology 74 (5), 1227-1234: Adaptation of microbial communities in activated sludge to 1-decyl-3-methylimidazolium bromide, Dorota Gendaszewska and Ewa Liwarska-Bizukojc, doi: 10.2166/wst.2016.317. PMID- 27973377 TI - Identification and evaluation of a dominant alga from municipal wastewater in removal of nutrients. AB - To access better removal of nutrients with algae-based techniques, a dominant alga from real municipal wastewater was identified and its capacity in removing low concentrations of nitrogen (NH+4 or NO-3) and phosphorus (PO3-4) was evaluated. Results showed that Oedogonium brevicingulatum, a filamentous green alga, was confirmed as the dominant alga in the secondary effluent of a municipal wastewater treatment plant by polymerase chain reaction-denaturing gradient gel electrophoresis. Low concentrations of NH+4 or NO-3 (<=5 mg N L-1) and PO3-4 (<=0.5 mg P L-1) were 100% removed by the algae in a 7-d test. The maximum nutrient removal rate (Vmax) and the half-saturation constant (Km) for NH+4 (10.03 +/- 0.95 mg g-1d-1 and 0.19 +/- 0.03 mg L-1) and NO-3 (8.43 +/- 0.21 mg g 1 d-1 and 0.27 +/- 0.11 mg L-1) indicated the uptake capability for NH+4 is higher than that for NO-3. Meanwhile, it showed higher affinity for PO3-4 (Vmax: 1.42 +/- 0.02 mg g-1 d-1; Km: 0.02 +/- 0.00 mg L-1) with NH+4 as nitrogen source than that (Vmax: 1.24 +/- 0.15 mg g-1 d-1; Km: 0.06 +/- 0.03 mg L-1) with NO-3 as nitrogen source. Moreover, nutrient removal efficiencies were observed steady when nitrogen/phosphorus ratio ranged from 5:1 to 20:1. These results suggest that the dominant algae from municipal wastewater have potentials to be applied in nutrient removal. PMID- 27973379 TI - A comparison of peripheral imaging technologies for bone and muscle quantification: a technical review of image acquisition. AB - The choice of an appropriate imaging technique to quantify bone, muscle, or muscle adiposity needs to be guided by a thorough understanding of its competitive advantages over other modalities balanced by its limitations. This review details the technical machinery and methods behind peripheral quantitative computed tomography (pQCT), high-resolution (HR)-pQCT, and magnetic resonance imaging (MRI) that drive successful depiction of bone and muscle morphometry, densitometry, and structure. It discusses a number of image acquisition settings, the challenges associated with using one versus another, and compares the risk benefits across the different modalities. Issues related to all modalities including partial volume artifact, beam hardening, calibration, and motion assessment are also detailed. The review further provides data and images to illustrate differences between methods to better guide the reader in selecting an imaging method strategically. Overall, investigators should be cautious of the impact of imaging parameters on image signal or contrast-to-noise-ratios, and the need to report these settings in future publications. The effect of motion should be assessed on images and a decision made to exclude prior to segmentation. A more standardized approach to imaging bone and muscle on pQCT and MRI could enhance comparability across studies and could improve the quality of meta analyses. PMID- 27973380 TI - Reference data for jumping mechanography in Canadian children, adolescents and young adults. AB - OBJECTIVES: To provide age- and sex-specific reference data for mechanography derived parameters of muscle function in Canadian children and youth using the single two-legged jump (S2LJ) with hands-on-waist. METHODS: Our sample included 2017 observations from 715 participants (9-21 years; 338 girls). Participants performed three S2LJ with hands-on-waist on a force platform (Leonardo Mechanograph, Novotec). Outcomes were maximum peak power (Pmax), Pmax/mass, peak force/body weight (Fmax/BW), force efficiency, maximum jump height (Hmax), and velocity (Vmax). We used the LMS method to construct age- and sex-specific percentile curves and mixed effects models to examine sex and ethnic differences. RESULTS: With the exception of Efficiency, mechanography outcomes were greater in girls (4-40%, p<0.05) than boys at age 9. Boys' advantage in mechanography parameters emerged in adolescence (age 11-13 years; 3-65%, p<0.05) and persisted into young adulthood, except for Fmax/BW which was not greater in boys until age 17 (4-10%, p<0.05). Mechanography outcomes were 3-9% (p<0.05) greater in Asian compared with white participants. CONCLUSIONS: We provide the first reference data for the S2LJ using the hands-on-waist protocol in children, youth and young adults. These data support previous findings using freely moving arms and can be used when evaluating muscle function in pediatric studies. PMID- 27973381 TI - Forearm muscle quality as a better indicator of physical performance than handgrip strength in older male ground golf players aged 70 to 89. AB - OBJECTIVES: To examine the associations between absolute and relative handgrip strength (HGS) and physical performance. METHODS: A total of 135 old men aged 70 89 years had muscle thickness (MT) measured by ultrasound at anterior forearm (MT ulna). Maximum voluntary HGS was measured for the dominant hand. Relative HGS was calculated as ratios of HGS to MT-ulna (HGS/MT-ulna, kg/cm), HGS to forearm girth (HGS/forearm-girth, kg/cm), and HGS to body mass (HGS/body mass, kg/kg). Physical performance was also assessed using the short physical performance battery (SPPB). RESULTS: Age was significantly correlated with absolute and relative HGS (r=-0.479 and r=-0.315 to -0.427, respectively all p<0.001) and physical performance (walking speed, r=-0.218, p=0.011; chair stand, r=0.348, p<0.001), but not with SPPB score (r=-0.083). Absolute HGS was positively correlated with usual-walking speed (r=0.354, p<0.001) and was inversely correlated with chair stand time (r=-0.386, p<0.001). The strongest correlations were seen between HGS/MT-ulna and usual-walking speed (r=0.426, p<0.001) or chair-stand (r=-0.461, p<0.001). Stepwise regression analysis revealed that HGS/MT-ulna was a significant predictor for U-walk speed (R2=0.205) and chair-stand time (R2=0.241) while absolute HGS was not a significant predictor of either one. CONCLUSION: Thus, we suggest that forearm muscle quality (HGS/MT-ulna) may be a stronger predictor of physical performance than absolute HGS in active old men. PMID- 27973382 TI - Lower insulin sensitivity is related to lower relative muscle cross-sectional area, lower muscle density and lower handgrip force in young and middle aged non diabetic men. AB - OBJECTIVES: This study investigated whether an association between insulin resistance (IR) and muscle parameters is appreciable in young healthy men, independent of obesity. Furthermore, markers of muscle metabolism and hormones/possible determinants, were explored. METHODS: 358 healthy young men were divided into a less and more insulin sensitive (LIS [age=33.2+/-5.4, BMI=23.4+/-2.3] and MIS [age=35.5+/-5.3, BMI=28.1+/-3.7]) group based on upper and lower quartile of HOMA-IR. Muscle cross-sectional area (CSA), -density, handgrip force, serum testosterone, estradiol, SHBG, Vitamin 25(OH)D, creatinine, IGF-1, IGFBP-3 and leptin levels were compared between these groups, correcting for differences in age, physical activity and fat mass. Correlations between HOMA IR and these parameters, and between muscle measures and biochemical parameters, were calculated. RESULTS: LIS is related to lower relative muscle CSA, muscle density, muscle/fat CSA ratio, relative handgrip force and level of physical activity. Furthermore, lower levels in SHBG, testosterone, Vitamin 25(OH)D and higher leptin, IGF-1 and IGFBP-3 levels were observed in LIS. Bio available T, FT, TE2, FE2, bioavailable E2, serum and urinary creatinine levels did not differ between groups. CONCLUSION: Differences in muscle performance are already present in healthy men with lower insulin sensitivity and could be possibly modifiable risk factors for the development of type 2 diabetes. PMID- 27973384 TI - Effects of fatiguing constant versus alternating intensity intermittent isometric muscle actions on maximal torque and neuromuscular responses. AB - OBJECTIVE: To determine the effects of constant versus alternating applications of torque during fatiguing, intermittent isometric muscle actions of the leg extensors on maximal voluntary isometric contraction (MVIC) torque and neuromuscular responses. METHODS: Sixteen subjects performed two protocols, each consisting of 50 intermittent isometric muscle actions of the leg extensors with equal average load at a constant 60% MVIC or alternating 40 then 80% (40/80%) MVIC with a work-to-rest ratio of 6-s on and 2-s off. MVIC torque as well as electromyographic signals from the vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF) and mechanomyographic signals from the VL were recorded pretest, immediately posttest, and 5-min posttest. RESULTS: The results indicated that there were no time-related differences between the 60% MVIC and 40/80% MVIC protocols. The MVIC torque decreased posttest (22 to 26%) and remained depressed 5-min posttest (9%). There were decreases in electromyographic frequency (14 to 19%) and mechanomyographic frequency (23 to 24%) posttest that returned to pretest levels 5-min posttest. There were no changes in electromyographic amplitude and mechanomyogrpahic amplitude. CONCLUSIONS: These findings suggested that these neuromuscular parameters did not track the fatigue-induced changes in MVIC torque after 5-min of recovery. PMID- 27973383 TI - Effect of sex on torque, recovery, EMG, and MMG responses to fatigue. AB - OBJECTIVE: The purpose of the present investigation was to examine the effect of sex on maximal voluntary isometric contraction (MVIC) torque and the EMG and MMG responses as a result of fatiguing, intermittent, submaximal (65% of MVIC), isometric elbow flexion muscle contractions. METHODS: Eighteen men and women performed MVIC trials before (pretest), after (posttest), and 5-min after (5-min recovery) performing 50 intermittent, submaximal isometric muscle contractions. Surface electromyographic (EMG) and mechanomyographic (MMG) signals were simultaneously recorded from the biceps brachii muscle. RESULTS: As a result of the fatiguing workbout torque decreased similarly from pretest to posttest for both the men (24.0%) and women (23.3%). After 5-min of recovery, torque had partially recovered for the men, while torque had returned to pretest levels for the women. For both sexes, from pretest to posttest EMG mean power frequency and MMG amplitude decreased, but returned to pretest levels after 5-min of recovery. CONCLUSIONS: In the present study, there were sex-related differences in muscle fatigue that were not associated with the EMG or MMG responses. PMID- 27973386 TI - Bone health measured using quantitative ultrasonography in adult males with muscular dystrophy. AB - OBJECTIVES: To compare muscle and bone health markers in adult males (aged 20-59 yrs) with and without muscular dystrophy (MD). METHODS: Participants included 11 Fascioscapulohumeral (FSH), 11 Becker's (Be), 9 limb girdle (LG), 11 Duchenne (DMD), and 14 non-dystrophic controls (CTRL). Physical activity was assessed using Bone (BPAQ) and disability specific (PASIPD) questionnaires. Bone QUS provided T- and Z scores from the Distal Radius (DR) and Mid-shaft tibia (MST). Tibialis anterior cross sectional area (TAACSA) was measured using B-mode ultrasound. Grip strength was measured in all but DMD. RESULTS: Physical activity was lower in DMD, FSH and BeMD than CTRL (P<0.05), and lower in DMD than other MDs (P<0.01). T and Z scores were lower in DMD and Be than CTRL (DR, P<0.05); and lower in DMD than CTRL, LG, and FSH (MST, P<0.01). TAACSA and grip strength was 35-59% and 50-58% smaller in MD than CTRL, respectively (P<0.01). Within MD, BPAQ correlated with bone QUS measures (r=0.42-0.38, P<0.01). PASIPD correlated with grip strength (r=0.65, P<0.01) and TAACSA (r=0.46, P<0.01). CONCLUSION: Muscle size, strength, and bone health was lower in adult males with MD compared to adult males without MD, the extent of this is partially determined by physical activity. PMID- 27973385 TI - Acute corticospinal and spinal modulation after whole body vibration. AB - OBJECTIVES: The objective of this study was to investigate neural effects of acute whole body vibration (WBV) on lower limb muscles regarding corticospinal and spinal excitability. METHODS: In 44 healthy subjects (16 f/ 28 m), motor evoked potentials (MEP) and H-reflexes in m. soleus (SOL) and gastrocnemius medialis (GM) were elicited before (t1), immediately after (t2), 2 (t3), 4 (t4) and 10 min after (t5) WBV. RESULTS: After WBV, MEP amplitudes were significantly increased in SOL (t2+15+/-30%, t3+22+/-32%, t4+15+/-35%, t5+20+/-30%, P<0.05), but not in GM (t2+32+/-62%, t3+9+/-35%, t4+8+/-36%, t5+22+/-47%; P=0.07). Contrarily, H-reflexes were significantly reduced in SOL (t2-19+/-28%, t3-21+/ 22%, t4-20+/-21%, t5-14+/-28%, P<0.05) and GM (t2-14+/-37%, t3-16+/-25%, t4-18+/ 29%, t5-16+/-28%, P<0.05). CONCLUSIONS: A temporary sustained enhancement of corticospinal excitability concomitant with spinal inhibition after WBV points towards persisting neural modulation in the central nervous system. This could indicate greater neural modulation over M1 and descending pathways, while the contribution of spinal pathways is reduced. PMID- 27973387 TI - Functional status of the articularis genus muscle in individuals with knee osteoarthritis. AB - OBJECTIVES: To clarify the functional status of the articularis genus muscle (AGM) in individuals with knee osteoarthritis (OA) and to analyze the muscle's relationship with knee OA. METHODS: Fifty-two individuals with knee OA (mean age, 73.4 years), 50 elderly individuals without knee OA changes (mean age, 71.2 years) and 75 young individuals (mean age, 20.2 years) were observed the AGM using ultrasonography. The thickness of the AGM, the anteroposterior distance of the suprapatellar bursa, and moving distance of the muscle insertion were measured both at rest and during isometric contraction, and values during contraction were expressed as percentages of the values at rest (%Muscle Increase, %Bursa-Increase). RESULTS: Muscle thickness at rest, %Muscle-Increase, %Bursa-Increase, and moving distance of the muscle insertion were significantly lower and anteroposterior distance of the suprapatellar bursa was significantly higher in the OA group than in the controls (p<0.001, all). In the OA group, these values for the AGM were significantly correlated with knee range of motion, knee pain, and Kellgren and Lawrence grade. CONCLUSIONS: Individuals with knee OA exhibited atrophic changes and dysfunctions of the AGM, and these were associated with symptoms. Atrophic changes and dysfunctions of the AGM may be specific changes associated with knee OA. PMID- 27973388 TI - Alterations in gene expression precede sarcopenia and osteopenia in botulinum toxin immobilized mice. AB - OBJECTIVES: To investigate alteration of bone and muscle gene expression at different time points during 3 weeks of botulinum toxin (BTX) induced immobilization and how this correlate with conventional analysis of bone and muscle. METHODS: Thirty-five 16-week-old female C57BL/6-mice were investigated; 15 were injected with BTX, 15 served as age-matched controls, and 5 as baseline. 5 BTX-injected and 5 control mice were euthanized after 1, 2, and 3 weeks. Analysis included RT-qPCR, dynamic bone histomorphometry, DEXA, uCT, mechanical testing, and muscle cell cross-sectional-area (CSA). RESULTS: Genes related to osteoblasts were expressed at a lower level after 1 week, but not after 2 and 3 weeks of disuse. Moreover, genes related to osteoclasts were expressed at a higher level after 1 and 2 weeks of disuse, whereafter they approached the level of the controls. Genes related to muscle atrophy were upregulated 1 and 2 weeks after the BTX-injection, but not after 3 weeks. In contrast, deterioration of bone microstructure and strength, and reduction in muscle cell CSA were most evident after 3 weeks of disuse. CONCLUSIONS: Gene expression should be investigated during the first two weeks of immobilization, whereas changes in bone microstructure and muscle cell CSA are most prominent after 3 weeks of immobilization. PMID- 27973389 TI - Sodium selenate treatment mitigates reduction of bone volume following traumatic brain injury in rats. AB - OBJECTIVES: Administration of sodium selenate to rats given traumatic brain injury (TBI) attenuates brain damage and improves long-term behavioural outcomes. We have previously provided evidence that TBI causes bone loss in rats, however the effect of sodium selenate treatment on bone quantity following TBI is unknown. METHODS: Rats were randomly assigned into sham injury or fluid percussion injury (FPI) groups and administered saline or sodium selenate for 12 weeks post-injury. Femora were analysed using histomorphometry, peripheral quantitative computed tomography (pQCT) and biomechanical testing. RESULTS: Distal metaphyseal trabecular bone volume fraction of FPI-selenate rats was higher than FPI-vehicle rats (41.8%; p<0.01), however, femora from selenate treated groups were shorter in length (4.3%; p<0.01) and had increased growth plate width (22.1%; p<0.01), indicating that selenate impaired long bone growth. pQCT analysis demonstrated that distal metaphyseal cortical thickness was decreased in TBI rats compared to shams (11.7%; p<0.05), however selenate treatment to TBI animals offset this reduction (p<0.05). At the midshaft we observed no differences in biomechanical measures. CONCLUSION: These are the first findings to indicate that mitigating TBI-induced neuropathology may have the added benefit of preventing osteoporosis and associated fracture risk following TBI. PMID- 27973390 TI - Effects of oncostatin M on cell proliferation and osteogenic differentiation in C3H10T1/2. AB - OBJECTIVE: To explore the effects of protein factor Oncostatin M (OSM), a member of the Interleukin-6 (IL-6) family on cell proliferation, osteogenic differentiation and mineralization. MATERIALS AND METHODS: Basal nutrient solutions of different concentrations of OSM (0, 5, 10, 20, 40, 80 ng/ml) were used. In order to divide embryonic origin between mesenchymal stem cells C3H10T1/2 of in vitro cultured mice, and the effects of in vitro proliferation efficiencies of C3H10T1/2 cells of different concentrations of OSM, the C3H10T1/2 cells were divided into four groups: (1) Basal nutrient solution group (negative control); (2) Osteogenesis induced liquid group (positive control); (3) OSM (20 ng/ml) group; (4) Experimental group (osteogenesis induced liquid + OSM (20 ng/ml)). The expressions levels of relevant osteogenesis and mineralization genes were detected. RESULTS: OSM had several effects on promoting the proliferation of embryonic origin mesenchymal stem cells C3H10T1/2 with respect to time of exposure as well as concentrations. In the present study, it has been shown that when the concentration of OSM is 20 ng/ml, the effects of promoting proliferation are most obvious. OSM can induce osteogenic differentiation of C3H10T1/2, make the process of osteogenic differentiation in advance, and promote the formation of end-stage calcium deposits and mineralized nodule, and osteogenic differentiation of C3H10T1/2 is finally achieved. CONCLUSION: OSM can promote the proliferation of C3H10T1/2, and induce its osteogenic differentiation and end stage mineralization. PMID- 27973391 TI - A 3-Center Study Reveals New Insights Into the Impact of Non-HLA Antibodies on Lung Transplantation Outcome. AB - BACKGROUND: The presence of antibodies to angiotensin type 1 receptor (AT1R) and endothelin type A receptor (ETAR) is associated with allograft rejection in kidney and heart transplantation. The aim of our study was to determine the impact of AT1R and ETAR antibodies on graft outcome in lung transplantation. METHODS: Pretransplant and posttransplant sera from 162 lung recipients transplanted at 3 centers between 2011 and 2013 were tested for antibodies to AT1R and ETAR by the enzyme-linked immunosorbent assay (ELISA) assay. Clinical parameters analyzed were: HLA antibodies at transplant, de novo donor-specific antibodies (DSA), antibody-mediated rejection (AMR), acute cellular rejection, and graft status. RESULTS: Late AMR (median posttransplant day 323) was diagnosed in 5 of 36 recipients with de novo DSA. Freedom from AMR significantly decreased for those recipients with strong/intermediate binding antibodies to AT1R (P = 0.014) and ETAR (P = 0.005). Trends for lower freedom from acute cellular rejection were observed for recipients with pretransplant antibodies to AT1R (P = 0.19) and ETAR (P = 0.32), but did not reach statistical significance. Lower freedom from the development of de novo DSA was observed for recipients with antibodies detected pretransplant to AT1R (P = 0.054), ETAR (P = 0.012), and HLA specific antibodies (P = 0.063). When the pretransplant antibody status of HLA specific antibody (hazard ratio [HR], 1.69) was considered together with either strong binding to AT1R or ETAR, an increased negative impact on the freedom from the development of de novo DSA was observed (HR, 2.26 for HLA antibodies and ETAR; HR, 2.38 for HLA antibodies and ETAR). CONCLUSIONS: These results illustrate the increased negative impact when antibodies to both HLA and non-HLA antigens are present pretransplant. PMID- 27973392 TI - Cystic Craniopharyngiomas: Microsurgical or Stereotactic Treatment? AB - BACKGROUND: Prognosis and treatment of cystic craniopharyngiomas are poorly defined. OBJECTIVE: To analyze progression-free survival (PFS) and safety profile of cystic craniopharyngiomas undergoing resection or minimally invasive drainage procedures. We compared further outcome measurements for cystic and solid tumors undergoing resection to elucidate the impact of the initial tumor composition on both PFS and the toxicity profile. METHODS: All patients with craniopharyngiomas consecutively treated between 1999 and 2014 were included. A treatment decision in favor of microsurgery or stereotactic treatment was made interdisciplinarily. For stereotactic drainage, a catheter was implanted, allowing both permanent upstream (into ventricular spaces) and downstream (into prepontine cistern) drainage. Study endpoints were tumor progression, functional outcome, and treatment toxicity. Functional endocrinological and visual outcome analyses referred to data obtained preoperatively and 6 weeks after treatment. The Kaplan Meier method was used for survival analysis. Prognostic factors were obtained from proportional hazard models. RESULTS: Seventy-nine patients were included. The distribution of clinical and tumor-related data was well balanced among patients with solid (n = 35) and cystic (n = 44) tumors and those undergoing microsurgical or stereotactic treatment. Cystic tumors had shorter PFS (5-year PFS: 53.6% vs 66.8%, P = .10) and needed significantly more therapeutic interventions, which was independent of the initial treatment mode. The endocrinological deterioration rate was high for both solid and cystic tumors after microsurgery (59.4% and 85.7%, respectively), whereas it was significantly lower for cystic tumors undergoing stereotactic treatment (23.1%, P < .001). CONCLUSION: Stereotactic bidirectional drainage of cystic craniopharyngiomas is effective and provides a better endocrinological outcome than conventional microsurgery. PMID- 27973393 TI - Sudden Cardiac Death: Autopsy Findings in 7200 Cases Between 2001 and 2015. AB - BACKGROUND: Sudden cardiac death (SCD) is a sudden unexpected event, from a cardiac cause, that occurs in less than 1 hour after the symptom onset in a person without any previous condition that would seem fatal or who was seen without any symptoms 24 hours before being found dead. OBJECTIVE: The aims of the study were to describe the features of SCD in Brasov County, Romania (400,000 inhabitants) according to local forensic department autopsy files. METHODS: We retrospectively chart reviewed a number of 7200 autopsy reports between 2001 and 2015 to identify cases of SCD. Data included cause of death, demographics, location of the event, prior known illnesses, as well as psychiatric comorbidities. RESULTS: Of 7200 autopsies effectuated during the 15-year period, we excluded 276 cases with incomplete data. The rest of the 6924 cases included 3000 autopsies (43.3%) of individuals with a violent death: accidents, suicides, and homicides. In 3924 cases (56.7%), the death was nonviolent. Of 3924 nonviolent deaths, based on the registry of Forensic department, we identified 1085 cases of SCD (749 males [69%]; mean age, 56 +/- 17.4 years). CONCLUSION: Sudden death with a cardiac etiology remained a major cause of unexpected end of life in the vast majority of cases autopsied during the study period. PMID- 27973394 TI - Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction. AB - Adrenergic receptors couple to Gs-proteins leading to transmembrane adenylyl cyclase activation and cytosolic cyclic adenosine monophosphate (cAMP) production. Cyclic AMP is also produced in the mitochondrial matrix, where it regulates respiration through protein kinase A (PKA)-dependent phosphorylation of respiratory chain complexes. We hypothesized that a blunted mitochondrial cAMP PKA pathway would participate in sepsis-induced heart dysfunction. Adult male mice were subjected to intra-abdominal sepsis. Mitochondrial respiration of cardiac fibers and myocardial contractile performance were evaluated in response to 8Br-cAMP, PKA inhibition (H89), soluble adenylyl cyclase inhibition (KH7), and phosphodiesterase inhibition (IBMX; BAY60-7550). Adenosine diphosphate (ADP) stimulated respiratory rates of cardiac fibers were reduced in septic mice. Compared with controls, stimulatory effects of 8Br-cAMP on respiration rates were enhanced in septic fibers, whereas inhibitory effects of H89 were reduced. Ser-58 phosphorylation of cytochrome c oxidase subunit IV-1 was reduced in septic hearts. In vitro, incubation of septic cardiac fibers with BAY60-7550 increased respiratory control ratio and improved cardiac MVO2 efficiency in isolated septic heart. In vivo, BAY60-7550 pre-treatment of septic mice have limited impact on myocardial function. Mitochondrial cAMP-PKA signaling is impaired in the septic myocardium. PDE2 phosphodiesterase inhibition by BAY60-7550 improves mitochondrial respiration and cardiac MVO2 efficiency in septic mice. PMID- 27973395 TI - Pioglitazone, a Peroxisome Proliferator-Activated Receptor gamma Agonist, Suppresses Rat Prostate Carcinogenesis. AB - Pioglitazone (PGZ), a peroxisome proliferator-activated receptor gamma agonist, which is known as a type 2 diabetes drug, inhibits cell proliferation in various cancer cell lines, including prostate carcinomas. This study focused on the effect of PGZ on prostate carcinogenesis using a transgenic rat for an adenocarcinoma of prostate (TRAP) model. Adenocarcinoma lesions as a percentage of overall lesions in the ventral prostate were significantly reduced by PGZ treatment in a dose-dependent manner. The number of adenocarcinomas per given area in the ventral prostate was also significantly reduced by PGZ treatment. The Ki67 labeling index in the ventral prostate was also significantly reduced by PGZ. Decreased cyclin D1 expression in addition to the inactivation of both p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)kappaB were detected in PGZ-treated TRAP rat groups. In LNCaP, a human androgen-dependent prostate cancer cell line, PGZ also inhibited cyclin D1 expression and the activation of both p38 MAPK and NFkappaB. The suppression of cultured cell growth was mainly regulated by the NFkappaB pathway as detected using specific inhibitors in both LNCaP and PC3, a human androgen-independent prostate cancer cell line. These data suggest that PGZ possesses a chemopreventive potential for prostate cancer. PMID- 27973398 TI - Microbiological Quality of Fresh Nopal Juice. AB - The consumption of fresh nopal cactus juice is widely popular among health conscious consumers in Mexico. The juice is prepared from fresh cladodes that have only been rinsed with tap water and are not subjected to a pasteurization or terminal bacterial reduction process. The aim of this study was to evaluate the microbial quality of commercially available fresh juices (n = 162) made with nopal in Texcoco, State of Mexico, during the summer and spring season. Standard microbiological methods, the PCR technique and the serological method were used for isolation and identification of bacteria. All samples contained total coliforms and 91% were positive for Escherichia coli. Although total coliforms and E. coli were detected throughout the study, their populations were significantly lower (p < 0.05) in winter and spring, respectively. Citrobacter youngae was found in 20% of the samples, an unidentified species of Citrobacter in 10%, C. freundii and Proteus mirabilis in 3%, and Salmonella Javiana in 1%. The presence of these microorganisms, especially Salmonella, in the nopal juices is unacceptable due to its health significance. The information generated in this study is relevant for human health risk assessment associated with the consumption of unpasteurized nopal juices and potential interventions to minimize pathogen contamination. PMID- 27973397 TI - p53 as a Regulator of Lipid Metabolism in Cancer. AB - Enhanced proliferation and survival are common features of cancer cells. Cancer cells are metabolically reprogrammed which aids in their survival in nutrient poor environments. Indeed, changes in metabolism of glucose and glutamine are essential for tumor progression. Thus, metabolic reprogramming is now well accepted as a hallmark of cancer. Recent findings suggest that reprogramming of lipid metabolism also occurs in cancer cells, since lipids are used for biosynthesis of membranes, post-translational modifications, second messengers for signal transduction, and as a source of energy during nutrient deprivation. The tumor suppressor p53 is a transcription factor that controls the expression of proteins involved in cell cycle arrest, DNA repair, apoptosis, and senescence. p53 also regulates cellular metabolism, which appears to play a key role in its tumor suppressive activities. In this review article, we summarize non-canonical functions of wild-type and mutant p53 on lipid metabolism and discuss their association with cancer progression. PMID- 27973396 TI - Immunoregulation in Fungal Diseases. AB - This review addresses specific regulatory mechanisms involved in the host immune response to fungal organisms. We focus on key cells and regulatory pathways involved in these responses, including a brief overview of their broader function preceding a discussion of their specific relevance to fungal disease. Important cell types discussed include dendritic cells and regulatory T cells, with a focus on specific studies relating to their effects on immune responses to fungi. We highlight the interleukin-10, programmed cell death 1, and cytotoxic T lymphocyte associated protein 4 signaling pathways and emphasize interrelationships between these pathways and the regulatory functions of dendritic cells and regulatory T cells. Throughout our discussion, we identify selected studies best illustrating the role of these cells and pathways in response to specific fungal pathogens to provide a contextual understanding of the tightly-controlled network of regulatory mechanisms critical to determining the outcome of exposure to fungal pathogens. Lastly, we discuss two unique phenomena relating to immunoregulation, protective tolerance and immune reactivation inflammatory syndrome. These two clinically-relevant conditions provide perspective as to the range of immunoregulatory mechanisms active in response to fungi. PMID- 27973399 TI - Serro 2 Virus Highlights the Fundamental Genomic and Biological Features of a Natural Vaccinia Virus Infecting Humans. AB - Vaccinia virus (VACV) has been implicated in infections of dairy cattle and humans, and outbreaks have substantially impacted local economies and public health in Brazil. During a 2005 outbreak, a VACV strain designated Serro 2 virus (S2V) was collected from a 30-year old male milker. Our aim was to phenotypically and genetically characterize this VACV Brazilian isolate. S2V produced small round plaques without associated comets when grown in BSC40 cells. Furthermore, S2V was less virulent than the prototype strain VACV-Western Reserve (WR) in a murine model of intradermal infection, producing a tiny lesion with virtually no surrounding inflammation. The genome of S2V was sequenced by primer walking. The coding region spans 184,572 bp and contains 211 predicted genes. Mutations in envelope genes specifically associated with small plaque phenotypes were not found in S2V; however, other alterations in amino acid sequences within these genes were identified. In addition, some immunomodulatory genes were truncated in S2V. Phylogenetic analysis using immune regulatory-related genes, besides the hemagglutinin gene, segregated the Brazilian viruses into two clusters, grouping the S2V into Brazilian VACV group 1. S2V is the first naturally-circulating human associated VACV, with a low passage history, to be extensively genetically and phenotypically characterized. PMID- 27973400 TI - Perfluorinated Compounds in Greenhouse and Open Agricultural Producing Areas of Three Provinces of China: Levels, Sources and Risk Assessment. AB - Field investigations on perfluoroalkyl acid (PFAA) levels in various environmental matrixes were reported, but there is still a lack of PFAA level data for agricultural environments, especially agricultural producing areas, so we collected soil, irrigation water and agricultural product samples from agricultural producing areas in the provinces of Liaoning, Shandong and Sichuan in China. The background pollution from instruments was removed and C4-C18 PFAAs were detected by LC-MS/MS. The concentrations of PFAAs in the top and deep layers of soil were compared, and the levels of PFAAs in different agricultural environments (greenhouses and open agriculture) were analyzed. We found the order of PFAA levels by province was Shandong > Liaoning > Sichuan. A descending trend of PFAA levels from top to deep soil and open to greenhouse agriculture was shown and perfluorobutanoic acid (PFBA) was considered as a marker for source analysis. Bean vegetables contribute highly to the overall PFAA load in vegetables. A significant correlation was shown between irrigation water and agricultural products. The EDI (estimated daily intake) from vegetables should be of concern in China. PMID- 27973401 TI - Heat or Cold: Which One Exerts Greater Deleterious Effects on Health in a Basin Climate City? Impact of Ambient Temperature on Mortality in Chengdu, China. AB - Background: Although studies from many countries have estimated the impact of ambient temperature on mortality, few have compared the relative impacts of heat and cold on health, especially in basin climate cities. We aimed to quantify the impact of ambient temperature on mortality, and to compare the contributions of heat and cold in a large basin climate city, i.e., Chengdu (Sichuan Province, China); Methods: We estimated the temperature-mortality association with a distributed lag non-linear model (DLNM) with a maximum lag-time of 21 days while controlling for long time trends and day of week. We calculated the mortality risk attributable to heat and cold, which were defined as temperatures above and below an "optimum temperature" that corresponded to the point of minimum mortality. In addition, we explored effects of individual characteristics; Results: The analysis provides estimates of the overall mortality burden attributable to temperature, and then computes the components attributable to heat and cold. Overall, the total fraction of deaths caused by both heat and cold was 10.93% (95%CI: 7.99%-13.65%). Taken separately, cold was responsible for most of the burden (estimate 9.96%, 95%CI: 6.90%-12.81%), while the fraction attributable to heat was relatively small (estimate 0.97%, 95%CI: 0.46%-2.35%). The attributable risk (AR) of respiratory diseases was higher (19.69%, 95%CI: 14.45%-24.24%) than that of cardiovascular diseases (11.40%, 95%CI: 6.29% 16.01%); Conclusions: In Chengdu, temperature was responsible for a substantial fraction of deaths, with cold responsible for a higher proportion of deaths than heat. Respiratory diseases exert a larger effect on death than other diseases especially on cold days. There is potential to reduce respiratory-associated mortality especially among the aged population in basin climate cities when the temperature deviates beneath the optimum. The result may help to comprehensively assess the impact of ambient temperature in basin cities, and further facilitate an appropriate estimate of the health consequences of various climate-change scenarios. PMID- 27973402 TI - The Influence of Urbanization Modes on the Spatial Circulation of Flaviviruses within Ouagadougou (Burkina Faso). AB - Dengue is an emerging infectious disease of global significance. Although this virus has been reported for a long time, its significance within the burden of diseases in West Africa is not obvious, especially in Burkina Faso. Our objective was to evaluate flavivirus presence in Ouagadougou (Burkina Faso) and the link between anti-flavivirus antibody seroprevalence and urbanization modes. A population-based cross-sectional survey was conducted and 3015 children were enrolled from Ouagadougou districts with different types and degrees of urbanization (with/without equipment and high/low building density). Flavivirus (FLAV) IgM MAC-ELISA and FLAV indirect IgG ELISA were performed. Associations between FLAV IgG presence (sign of past infection) and various independent variables were assessed using the chi-square test and a multivariate logistic regression analysis. The apparent prevalence of past flavivirus infections among the enrolled children was 22.7% (95% CI: 22.4-26.7) (n = 685). Eleven children (0.4%; 95% CI: 0.61-2.14) were positive for FLAV IgM, indicating active transmission. Factors associated with flavivirus infection were identified among the enrolled children (age, sex), householders (educational level, asset index) and in the environment (building density, water access, waste management and house appearance); however, they showed great variability according to the city districts. The water access modality did not significantly influence FLAV IgG positivity. Conversely, apparently good practices of waste management had unexpected consequences (increased risk related to municipal dumpsters). Given the scale of ongoing urbanization and the spread of arboviral diseases, close collaboration between health and city stakeholders is needed. PMID- 27973404 TI - Crop Phenology Detection Using High Spatio-Temporal Resolution Data Fused from SPOT5 and MODIS Products. AB - Timely and efficient monitoring of crop phenology at a high spatial resolution are crucial for the precise and effective management of agriculture. Recently, satellite-derived vegetation indices (VIs), such as the Normalized Difference Vegetation Index (NDVI), have been widely used for the phenology detection of terrestrial ecosystems. In this paper, a framework is proposed to detect crop phenology using high spatio-temporal resolution data fused from Systeme Probatoire d'Observation de la Tarre5 (SPOT5) and Moderate Resolution Imaging Spectroradiometer (MODIS) images. The framework consists of a data fusion method to produce a synthetic NDVI dataset at SPOT5's spatial resolution and at MODIS's temporal resolution and a phenology extraction algorithm based on NDVI time series analysis. The feasibility of our phenology detection approach was evaluated at the county scale in Shandong Province, China. The results show that (1) the Spatial and Temporal Adaptive Reflectance Fusion Model (STARFM) algorithm can accurately blend SPOT5 and MODIS NDVI, with an R2 of greater than 0.69 and an root mean square error (RMSE) of less than 0.11 between the predicted and referenced data; and that (2) the estimated phenology parameters, such as the start and end of season (SOS and EOS), were closely correlated with the field observed data with an R2 of the SOS ranging from 0.68 to 0.86 and with an R2 of the EOS ranging from 0.72 to 0.79. Our research provides a reliable approach for crop phenology mapping in areas with high fragmented farmland, which is meaningful for the implementation of precision agriculture. PMID- 27973403 TI - Development of Cell-SELEX Technology and Its Application in Cancer Diagnosis and Therapy. AB - SELEX (systematic evolution of ligands by exponential enrichment) is a process involving the progressive isolation of high selective ssDNA/RNA from a combinatorial single-stranded oligonucleotide library through repeated rounds of binding, partitioning and amplification. SELEX-derived single-stranded DNA/RNA molecules, called aptamers, are selected against a wide range of targets, including purified proteins, live cells, tissues, microorganisms, small molecules and so on. With the development of SELEX technology over the last two decades, various modified SELEX processes have been arisen. A majority of aptamers are selected against purified proteins through traditional SELEX. Unfortunately, more and more evidence showed aptamers selected against purified membrane proteins failed to recognize their targets in live cells. Cell-SELEX could develop aptamers against a particular target cell line to discriminate this cell line from others. Therefore, cell-SELEX has been widely used to select aptamers for the application of both diagnosis and therapy of various diseases, especially for cancer. In this review, the advantages and limitations of cell-SELEX and SELEX against purified protein will be compared. Various modified cell-SELEX techniques will be summarized, and application of cell-SELEX in cancer diagnosis and therapy will be discussed. PMID- 27973406 TI - An IMU-to-Body Alignment Method Applied to Human Gait Analysis. AB - This paper presents a novel calibration procedure as a simple, yet powerful, method to place and align inertial sensors with body segments. The calibration can be easily replicated without the need of any additional tools. The proposed method is validated in three different applications: a computer mathematical simulation; a simplified joint composed of two semi-spheres interconnected by a universal goniometer; and a real gait test with five able-bodied subjects. Simulation results demonstrate that, after the calibration method is applied, the joint angles are correctly measured independently of previous sensor placement on the joint, thus validating the proposed procedure. In the cases of a simplified joint and a real gait test with human volunteers, the method also performs correctly, although secondary plane errors appear when compared with the simulation results. We believe that such errors are caused by limitations of the current inertial measurement unit (IMU) technology and fusion algorithms. In conclusion, the presented calibration procedure is an interesting option to solve the alignment problem when using IMUs for gait analysis. PMID- 27973405 TI - Chronic Pain in Children and Adolescents: Diagnosis and Treatment of Primary Pain Disorders in Head, Abdomen, Muscles and Joints. AB - Primary pain disorders (formerly "functional pain syndromes") are common, under diagnosed and under-treated in children and teenagers. This manuscript reviews key aspects which support understanding the development of pediatric chronic pain, points to the current pediatric chronic pain terminology, addresses effective treatment strategies, and discusses the evidence-based use of pharmacology. Common symptoms of an underlying pain vulnerability present in the three most common chronic pain disorders in pediatrics: primary headaches, centrally mediated abdominal pain syndromes, and/or chronic/recurrent musculoskeletal and joint pain. A significant number of children with repeated acute nociceptive pain episodes develop chronic pain in addition to or as a result of their underlying medical condition "chronic-on-acute pain." We provide description of the structure and process of our interdisciplinary, rehabilitative pain clinic in Minneapolis, Minnesota, USA with accompanying data in the treatment of chronic pain symptoms that persist beyond the expected time of healing. An interdisciplinary approach combining (1) rehabilitation; (2) integrative medicine/active mind-body techniques; (3) psychology; and (4) normalizing daily school attendance, sports, social life and sleep will be presented. As a result of restored function, pain improves and commonly resolves. Opioids are not indicated for primary pain disorders, and other medications, with few exceptions, are usually not first-line therapy. PMID- 27973407 TI - Comparative miRNA Analysis of Urine Extracellular Vesicles Isolated through Five Different Methods. AB - Urine extracellular vesicles are a valuable low-invasive source of information, especially for the cells of the genitourinary tract. In the search for biomarkers, different techniques have been developed to isolate and characterize the cargo of these vesicles. In the present work, we compare five of these different isolation methods (three commercial isolation kits, ultracentrifugation, and lectin-based purification) and perform miRNA profiling using a multiplex miRNA assay. The results showed high correlation through all isolation techniques, and 48 out of 68 miRNAs were detected above the detection limit at least 10 times. The results obtained by multiplex assay were validated through Taqman qPCR. In addition, using this technique combined with a clinically friendly extracellular vesicle (uEV)-enrichment method, we performed the analysis of selected miRNAs in urine from patients affected with bladder cancer, benign prostate hyperplasia, or prostate cancer. Importantly, we found that those miRNAs could be detected in almost 100% of the samples, and no significant differences were observed between groups. Our results support the feasibility of analyzing exosomes-associated miRNAs using a methodology that requires a small volume of urine and is compatible with a clinical environment and high-throughput analysis. PMID- 27973408 TI - Structural Characterization of Oligochitosan Elicitor from Fusarium sambucinum and Its Elicitation of Defensive Responses in Zanthoxylum bungeanum. AB - Oligosaccharide elicitors from pathogens have been shown to play major roles in host plant defense responses involving plant-pathogen chemoperception and interaction. In the present study, chitosan and oligochitosan were prepared from pathogen Fusarium sambucinum, and their effects on infection of Zanthoxylum bungeanum stems were investigated. Results showed that oligochitosan inhibited the infection of the pathogen, and that the oligochitosan fraction with a degree of polymerization (DP) between 5 and 6 showed the optimal effect. Oligochitosan DP5 was purified from fraction DP5-6 and was structurally characterized using electrospray ionization mass spectrometry, Fourier transform infrared spectroscopy, and nuclear magnetic resonance spectroscopy. Oligochitosan DP5 showed significant inhibition against the infection of the pathogenic fungi on host plant stems. An investigation of the mechanism underlying this effect showed that oligochitosan DP5 increased the activities of defensive enzymes and accumulation of phenolics in host Z. bungeanum. These results suggest that oligochitosan from pathogenic fungi can mediate the infection of host plants with a pathogen by acting as an elicitor that triggers the defense system of a plant. This information will be valuable for further exploration of the interactions between the pathogen F. sambucinum and host plant Z. bungeanum. PMID- 27973409 TI - Robust Grape Cluster Detection in a Vineyard by Combining the AdaBoost Framework and Multiple Color Components. AB - The automatic fruit detection and precision picking in unstructured environments was always a difficult and frontline problem in the harvesting robots field. To realize the accurate identification of grape clusters in a vineyard, an approach for the automatic detection of ripe grape by combining the AdaBoost framework and multiple color components was developed by using a simple vision sensor. This approach mainly included three steps: (1) the dataset of classifier training samples was obtained by capturing the images from grape planting scenes using a color digital camera, extracting the effective color components for grape clusters, and then constructing the corresponding linear classification models using the threshold method; (2) based on these linear models and the dataset, a strong classifier was constructed by using the AdaBoost framework; and (3) all the pixels of the captured images were classified by the strong classifier, the noise was eliminated by the region threshold method and morphological filtering, and the grape clusters were finally marked using the enclosing rectangle method. Nine hundred testing samples were used to verify the constructed strong classifier, and the classification accuracy reached up to 96.56%, higher than other linear classification models. Moreover, 200 images captured under three different illuminations in the vineyard were selected as the testing images on which the proposed approach was applied, and the average detection rate was as high as 93.74%. The experimental results show that the approach can partly restrain the influence of the complex background such as the weather condition, leaves and changing illumination. PMID- 27973412 TI - Wi-Fi/MARG Integration for Indoor Pedestrian Localization. AB - With the wide deployment of Wi-Fi networks, Wi-Fi based indoor localization systems that are deployed without any special hardware have caught significant attention and have become a currently practical technology. At the same time, the Magnetic, Angular Rate, and Gravity (MARG) sensors installed in commercial mobile devices can achieve highly-accurate localization in short time. Based on this, we design a novel indoor localization system by using built-in MARG sensors and a Wi Fi module. The innovative contributions of this paper include the enhanced Pedestrian Dead Reckoning (PDR) and Wi-Fi localization approaches, and an Extended Kalman Particle Filter (EKPF) based fusion algorithm. A new Wi-Fi/MARG indoor localization system, including an Android based mobile client, a Web page for remote control, and a location server, is developed for real-time indoor pedestrian localization. The extensive experimental results show that the proposed system is featured with better localization performance, with the average error 0.85 m, than the one achieved by using the Wi-Fi module or MARG sensors solely. PMID- 27973410 TI - Therapeutic Resistance in Acute Myeloid Leukemia: The Role of Non-Coding RNAs. AB - Acute myeloid leukemia (AML) is caused by malignant transformation of hematopoietic stem or progenitor cells and displays the most frequent acute leukemia in adults. Although some patients can be cured with high dose chemotherapy and allogeneic hematopoietic stem cell transplantation, the majority still succumbs to chemoresistant disease. Micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNA fragments and act as key players in the regulation of both physiologic and pathologic gene expression profiles. Aberrant expression of various non-coding RNAs proved to be of seminal importance in the pathogenesis of AML, as well in the development of resistance to chemotherapy. In this review, we discuss the role of miRNAs and lncRNAs with respect to sensitivity and resistance to treatment regimens currently used in AML and provide an outlook on potential therapeutic targets emerging thereof. PMID- 27973411 TI - Effects of Low versus High Glycemic Index Sugar-Sweetened Beverages on Postprandial Vasodilatation and Inactivity-Induced Impairment of Glucose Metabolism in Healthy Men. AB - Intake of sugar-sweetened beverages (SSB) may contribute to cardiovascular risk. The aim of this study was to investigate whether functional sugars with low compared to high glycemic index (GI) have beneficial effects on arterial stiffness during a period of low-physical activity. In a controlled cross-over dietary intervention (55% CHO, 30% fat, 15% protein), 13 healthy men (age: 23.7 +/- 2.2 years, body mass index: 23.6 +/- 1.9 kg/m2) completed 2 * 1 week of low physical activity following 1 week of normal physical activity (2363 +/- 900 vs. 11,375 +/- 3124 steps/day). During inactive phases participants consumed either low-GI (isomaltulose) or high-GI SSB (maltodextrin-sucrose), providing 20% of energy requirements. Postprandial vasodilatation (augmentation index, AIx), insulin sensitivity (IS) and Glucagon-like-peptide 1 (GLP-1) responses were measured during a meal test before and after SSB-intervention. Compared to maltodextrin-sucrose-SSB, postprandial vasodilatation was prolonged (AIx after 120 min: 9.9% +/- 4.3% vs. 11.4% +/- 3.7%, p < 0.05) and GLP-1 secretion was higher with isomaltulose-SSB (total area under the GLP-1 curve (tAUCGLP)-1: 8.0 +/- 4.4 vs. 5.4 +/- 3.4 pM * 3 h; p < 0.05). One week of low-physical activity led to impaired IS that was attenuated with low-GI SSB consumption, but did not affect arterial stiffness (p > 0.05). Higher postprandial GLP-1 secretion after intake of low compared to high-GI beverages may contribute to improved postprandial vasodilatation. Although one week of low-physical activity led to marked impairment in IS, it had no effect on arterial stiffness in healthy men. PMID- 27973413 TI - Characterization of an Immunodominant Epitope in the Endodomain of the Coronavirus Membrane Protein. AB - The coronavirus membrane (M) protein acts as a dominant immunogen and is a major player in virus assembly. In this study, we prepared two monoclonal antibodies (mAbs; 1C3 and 4C7) directed against the transmissible gastroenteritis virus (TGEV) M protein. The 1C3 and 4C7 mAbs both reacted with the native TGEV M protein in western blotting and immunofluorescence (IFA) assays. Two linear epitopes, 243YSTEART249 (1C3) and 243YSTEARTDNLSEQEKLLHMV262 (4C7), were identified in the endodomain of the TGEV M protein. The 1C3 mAb can be used for the detection of the TGEV M protein in different assays. An IFA method for the detection of TGEV M protein was optimized using mAb 1C3. Furthermore, the ability of the epitope identified in this study to stimulate antibody production was also evaluated. An immunodominant epitope in the TGEV membrane protein endodomain was identified. The results of this study have implications for further research on TGEV replication. PMID- 27973414 TI - Impact of an 8-Month Trial Using Height-Adjustable Desks on Children's Classroom Sitting Patterns and Markers of Cardio-Metabolic and Musculoskeletal Health. AB - During school hours, children can sit for prolonged and unbroken periods of time. This study investigated the impact of an 8-month classroom-based intervention focusing on reducing and breaking-up sitting time on children's cardio-metabolic risk factors (i.e., body mass index, waist circumference, blood pressure) and perceptions of musculoskeletal discomfort. Two Year-6 classes (24 students per class) in one primary school were assigned to either an intervention or control classroom. The intervention classroom was equipped with height-adjustable desks and the teacher was instructed in the delivery of pedagogical strategies to reduce and break-up sitting in class. The control classroom followed standard practice using traditional furniture. At baseline, and after 8-months, time spent sitting, standing, stepping, and sitting-bouts (occasions of continuous sitting) as well as the frequency of sit-to-stand transitions were obtained from activPAL inclinometers and the time spent in light-intensity physical activity was obtained from ActiGraph accelerometers. Demographics and musculoskeletal characteristics were obtained from a self-report survey. Hierarchical linear mixed models found that during class-time, children's overall time spent sitting in long bouts (>10 min) were lower and the number of sit-to-stand transitions were higher in the intervention group compared to the control group, while no changes were observed for musculoskeletal pain/discomfort. No significant intervention effects were found for the anthropometrics measures and blood pressure. Height-adjustable desks and pedagogical strategies to reduce/break-up sitting can positively modify classroom sitting patterns in children. Longer interventions, larger and varied sample size may be needed to show health impacts; however, these desks did not increase musculoskeletal pain/discomfort. PMID- 27973416 TI - A Review on Phytochemistry and Pharmacology of Cortex Periplocae. AB - Cortex Periplocae, as a traditional Chinese herbal medicine, has been widely used for autoimmune diseases, especially rheumatoid arthritis. Due to its potential pharmaceutical values, more studies about the biological activities of Cortex Periplocae have been conducted recently. Meanwhile, the adverse reaction of Cortex Periplocae is not a negligible problem in clinic. In this article, we reviewed a series of articles and summarized the recent studies of Cortex Periplocae in the areas of phytochemistry and pharmacology. More than 100 constituents have been isolated and identified from Cortex Periplocae, including steroids, cardiac glycosides, terpenoids, and fatty acid compounds. The crude extracts of Cortex Periplocae and its active compounds exhibit various biological activities, such as cardiotonic effect, anticancer action, and anti-inflammatory effect. This paper aims to provide an overall review on the bioactive ingredients, pharmacological effect, and toxicity of this plant. Furthermore, this review suggests investigating and developing new clinical usages according to the above pharmacological effects. PMID- 27973417 TI - Applications of High-Throughput Sequencing for In Vitro Selection and Characterization of Aptamers. AB - Aptamers are identified through an iterative process of evolutionary selection starting from a random pool containing billions of sequences. Simultaneously to the amplification of high-affinity candidates, the diversity in the pool is exponentially reduced after several rounds of in vitro selection. Until now, cloning and Sanger sequencing of about 100 sequences was usually used to identify the enriched candidates. However, High-Throughput Sequencing (HTS) is now extensively used to replace such low throughput sequencing approaches. Providing a deeper analysis of the library, HTS is expected to accelerate the identification of aptamers as well as to identify aptamers with higher affinity. It is also expected that it can provide important information on the binding site of the aptamers. Nevertheless, HTS requires handling a large amount of data that is only possible through the development of new in silico methods. Here, this review presents these different strategies that have been recently developed to improve the identification and characterization of aptamers using HTS. PMID- 27973415 TI - Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies. AB - Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of morbidity and mortality in neonates. Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply and is, thus, extremely sensitive to hypoxia. Strong evidence indicates that oxidative stress plays an important role in pathogenesis and progression. Following hypoxia and ischemia, reactive oxygen species (ROS) production rapidly increases and overwhelms antioxidant defenses. A large excess of ROS will directly modify or degenerate cellular macromolecules, such as membranes, proteins, lipids, and DNA, and lead to a cascading inflammatory response, and protease secretion. These derivatives are involved in a complex interplay of multiple pathways (e.g., inflammation, apoptosis, autophagy, and necrosis) which finally lead to brain injury. In this review, we highlight the molecular mechanism for oxidative stress in HIE, summarize current research on therapeutic strategies utilized in combating oxidative stress, and try to explore novel potential clinical approaches. PMID- 27973418 TI - Varicella-Zoster Virus Infectious Cycle: ER Stress, Autophagic Flux, and Amphisome-Mediated Trafficking. AB - Varicella-zoster virus (VZV) induces abundant autophagy. Of the nine human herpesviruses, the VZV genome is the smallest (~124 kbp), lacking any known inhibitors of autophagy, such as the herpes simplex virus ICP34.5 neurovirulence gene. Therefore, this review assesses the evidence for VZV-induced cellular stress, endoplasmic-reticulum-associated degradation (ERAD), and autophagic flux during the VZV infectious cycle. Even though VZV is difficult to propagate in cell culture, the biosynthesis of the both N- and O-linked viral glycoproteins was found to be abundant. In turn, this biosynthesis provided evidence of endoplasmic reticulum (ER) stress, including a greatly enlarged ER and a greatly diminished production of cellular glycoproteins. Other signs of ER stress following VZV infection included detection of the alternatively spliced higher molecular-weight form of XBP1 as well as CHOP. VZV infection in cultured cells leads to abundant autophagosome production, as was visualized by the detection of the microtubule-associated protein 1 light chain 3-II (LC3-II). The degree of autophagy induced by VZV infection is comparable to that induced in uninfected cells by serum starvation. The inhibition of autophagic flux by chemicals such as 3-methyladenine or ATG5 siRNA, followed by diminished virus spread and titers, has been observed. Since the latter observation pointed to the virus assembly/trafficking compartments, we purified VZ virions by ultracentrifugation and examined the virion fraction for components of the autophagy pathway. We detected LC3-II protein (an autophagy marker) as well as Rab11 protein, a component of the endosomal pathway. We also observed that the virion-containing vesicles were single-walled; thus, they are not autophagosomes. These results suggested that some VZ virions after secondary envelopment were transported to the outer cell membrane in a vesicle derived from both the autophagy and endosomal pathways, such as an amphisome. Thus, these results demonstrate that herpesvirus trafficking pathways can converge with the autophagy pathway. PMID- 27973420 TI - Sugar-Annulated Oxazoline Ligands: A Novel Pd(II) Complex and Its Application in Allylic Substitution. AB - Two novel carbohydrate-derived pyridyl (PYOX)- and cyclopropyl (CYBOX) substituted oxazoline ligands were prepared from d-glucosamine hydrochloride and 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-beta-d-glucopyranose hydrochloride in two steps, respectively. The sugar-annulated PYOX ligand formed a stable metal complex with Pd(II), which was fully characterized by NMR spectroscopy and X-ray crystallography. NMR and X-ray analysis revealed a change of the conformation in the sugar moiety upon complexation with the palladium(II) species. Both glycosylated ligands resulted in high asymmetric induction (up to 98% ee) upon application as chiral ligands in the Pd-catalyzed allylic alkylation of rac-1,3 diphenylallyl acetate with dimethyl malonate (Tsuji-Trost reaction). Both ligands provided mainly the (R)-enantiomer of the alkylation product. PMID- 27973421 TI - Enhanced Stilbene Production and Excretion in Vitis vinifera cv Pinot Noir Hairy Root Cultures. AB - Stilbenes are defense molecules produced by grapevine in response to stresses including various elicitors and signal molecules. Together with their prominent role in planta, stilbenes have been the center of much attention in recent decades due to their pharmaceutical properties. With the aim of setting up a cost effective and high purity production of resveratrol derivatives, hairy root lines were established from Vitis vinifera cv Pinot Noir 40024 to study the organ specific production of various stilbenes. Biomass increase and stilbene production by roots were monitored during flask experiments. Although there was a constitutive production of stilbenes in roots, an induction of stilbene synthesis by methyl jasmonate (MeJA) after 18 days of growth led to further accumulation of epsilon-viniferin, delta-viniferin, resveratrol and piceid. The use of 100 uM MeJA after 18 days of culture in the presence of methyl-beta-cyclodextrins (MCDs) improved production levels, which reached 1034ug/g fresh weight (FW) in roots and 165 mg/L in the extracellular medium, corresponding to five-and 570-foldincrease in comparison to control. Whereas a low level of stilbene excretion was measured in controls, addition of MeJA induced excretion of up to 37% of total stilbenes. The use of MCDs increased the excretion phenomenon even more, reaching up to 98%. Our results demonstrate the ability of grapevine hairy roots to produce various stilbenes. This production was significantly improved in response to elicitation by methyl jasmonate and/or MCDs. This supports the interest of using hairy roots as a potentially valuable system for producing resveratrol derivatives. PMID- 27973422 TI - Interactions of Bovine Serum Albumin with Anti-Cancer Compounds Using a ProteOn XPR36 Array Biosensor and Molecular Docking. AB - The aim of the work was to determine the interactions of a set of anti-cancer compounds with bovine serum albumin (BSA) using a ProteOn XPR36 array biosensor and molecular docking studies. The results revealed that a total of six anti cancer compounds: gallic acid, doxorubicin, acteoside, salvianolic acid B, echinacoside, and vincristine were able to reversibly bind to the immobilized BSA. The sensorgrams of these six compounds were globally fit to a Langmuir 1:1 interaction model for binding kinetics analysis. There were significant differences in their affinity for BSA, with doxorubicin, the weakest binding compound having 1000-fold less affinity than salvianolic acid B, the strongest binding compound. However, compounds with a similar KD often exhibited markedly different kinetics due to the differences in ka and kd. Molecular docking experiments demonstrated that acteoside was partially located within sub-domain IIA of BSA, whereas gallic acid bound to BSA deep within its sub-domain IIIA. In addition, the interactions between these compounds and BSA were dominated by hydrophobic forces and hydrogen bonds. Understanding the detailed information of these anti-cancer compounds can provide important insights into optimizing the interactions and activity of potential compounds during drug development. PMID- 27973419 TI - Potential Links between Impaired One-Carbon Metabolism Due to Polymorphisms, Inadequate B-Vitamin Status, and the Development of Alzheimer's Disease. AB - Alzheimer's disease (AD) is the major cause of dementia and no preventive or effective treatment has been established to date. The etiology of AD is poorly understood, but genetic and environmental factors seem to play a role in its onset and progression. In particular, factors affecting the one-carbon metabolism (OCM) are thought to be important and elevated homocysteine (Hcy) levels, indicating impaired OCM, have been associated with AD. We aimed at evaluating the role of polymorphisms of key OCM enzymes in the etiology of AD, particularly when intakes of relevant B-vitamins are inadequate. Our review indicates that a range of compensatory mechanisms exist to maintain a metabolic balance. However, these become overwhelmed if the activity of more than one enzyme is reduced due to genetic factors or insufficient folate, riboflavin, vitamin B6 and/or vitamin B12 levels. Consequences include increased Hcy levels and reduced capacity to synthetize, methylate and repair DNA, and/or modulated neurotransmission. This seems to favor the development of hallmarks of AD particularly when combined with increased oxidative stress e.g., in apolipoprotein E (ApoE) epsilon4 carriers. However, as these effects can be compensated at least partially by adequate intakes of B-vitamins, achieving optimal B-vitamin status for the general population should be a public health priority. PMID- 27973424 TI - Non-Uniform Microstrip Antenna Array for DSRC in Single-Lane Structures. AB - Vehicular communications have been subject to a great development in recent years, with multiple applications, such as electronic payments, improving the convenience and comfort of drivers. Its communication network is supported by dedicated short range communications (DSRC), a system composed of onboard units (OBU) and roadside units (RSU). A recently conceived different set-up for the tolling infrastructures consists of placing them in highway access roads, allowing a number of benefits over common gateway infrastructures, divided into several lanes and using complex systems. This paper presents an antenna array whose characteristics are according to the DSRC standards. Additionally, the array holds an innovative radiation pattern adjusted to the new approach requirements, with an almost uniform wide beamwidth along the road width, negligible side lobes, and operating in a significant bandwidth. PMID- 27973423 TI - Regressive Effect of Myricetin on Hepatic Steatosis in Mice Fed a High-Fat Diet. AB - Myricetin is an effective antioxidant in the treatment of obesity and obesity related metabolic disorders. The objective of this study was to explore the regressive effect of myricetin on pre-existing hepatic steatosis induced by high fat diet (HFD). C57BL/6 mice were fed either a standard diet or a HFD for 12 weeks and then half of the mice were treated with myricetin (0.12% in the diet, w/w) while on their respective diets for further 12 weeks. Myricetin treatment significantly alleviated HFD-induced steatosis, decreased hepatic lipid accumulation and thiobarbituric acid reactive substance (TBARS) levels, and increased antioxidative enzyme activities, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Microarray analysis of hepatic gene expression profiles showed that myricetin significantly altered the expression profiles of 177 genes which were involved in 12 biological pathways, including the peroxisome proliferator activated receptor (PPAR) signaling pathway and peroxisome. Further research indicated that myricetin elevated hepatic nuclear Nrf2 translocation, increased the protein expression of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), reduced the protein expression of PPARgamma, and normalized the expressions of genes that were involved in peroxisome and the PPAR signaling pathway. Our data indicated that myricetin might represent an effective therapeutic agent to treat HFD induced hepatic steatosis via activating the Nrf2 pathway and the PPAR signaling pathway. PMID- 27973425 TI - Zerumbone, a Bioactive Sesquiterpene, Ameliorates Diabetes-Induced Retinal Microvascular Damage through Inhibition of Phospho-p38 Mitogen-Activated Protein Kinase and Nuclear Factor-kappaB Pathways. AB - Zerumbone ameliorates retinal damage by blocking advanced glycation end products and their receptor system in streptozotocin-diabetic rats. Because of the multiple factors involved in diabetic retinopathy (DR) etiology, the mechanisms of zerumbone that are mainly responsible for its ameliorative effect on DR need to be further clarified. In the present study, zerumbone (20 mg or 40 mg/kg) or fenofibric acid (100 mg/kg) was orally administered to diabetic rats by intragastric gavage once daily for three consecutive months. Zerumbone displayed similar characteristics to fenofibric acid in reducing retinal vascular permeability and leukostasis in diabetic rats. Fundus photographs showed that large retinal vessel diameters were decreased in zerumbone-treated diabetic rats. Zerumbone not only down-regulated the gene expression of retinal angiogenic parameters, but also reduced the expression of inflammatory cytokines and chemokines in the retina of diabetic rats. Moreover, zerumbone reduced the p38 MAPK phosphorylation and abrogated the nuclear translocation of NF-kappaB p65 in the retina of diabetic rats. In conclusion, treatment of diabetic rats with zerumbone attenuates the severity of retinal inflammation and angiogenesis, via inhibition of p38 MAPK and NF-kappaB signaling pathways. These benefits of zerumbone for DR appear to be linked to its antihyperglycemic and antihyperlipidemic effects. PMID- 27973426 TI - Impact of Cluster Zone Leaf Removal on Grapes cv. Regent Polyphenol Content by the UPLC-PDA/MS Method. AB - Leaf removal is known to enhance light exposure of clusters and therefore may affect grape composition. Owing to the risk of decreasing grape quality or sunburn as a consequence of improper sun exposure, it is crucial to determine the optimum leaf removal techniques adequate for the particular climate conditions of a vineyard area. Defoliation experiments on vine cv. Regent were conducted in two consecutive years (2014 and 2015). The effect of leaf removal treatment on the qualitative and quantitative composition of the polyphenol compounds in the grapes, with reference to the basic weather conditions of the vineyard area, located in Szczecin in the North-Western part of Poland, was assessed. Defoliation was performed manually in the cluster zone at three phenological plant stages: pre-flowering, berry-set and veraison. Leaf removal, especially early defoliation (pre-flowering), enhanced total polyphenol content, including the amount of anthocyanins, flavonols and flavan-3-ols and furthermore, it increased the amount of soluble solids, decreasing the titratable acidity in grapes. On the other hand, the treatments had a reducing impact on the phenolic acids in berries. Defoliation at earlier stages of cluster development appears to be an efficient strategy for improving berry quality in cool climate areas, however, additionally further weather data control is required to determine the effects on berry components. PMID- 27973427 TI - Expression of 3-Mercaptopyruvate Sulfurtransferase in the Mouse. AB - 3-Mercaptopyruvate sulfurtransferase (MST) is one of the principal enzymes for the production of hydrogen sulfide and polysulfides in mammalians, and emerging evidence supports the physiological significance of MST. As a fundamental study of the physiology and pathobiology of MST, it is necessary to establish the tissue distribution of MST in mice. In the present study, the expression of MST in various organs of adult and fetal mice was analyzed by Western blotting and enzyme-immunohistochemistry. Moreover, the histology of MST gene-deficient mice was examined. Western blotting revealed that all organs examined had MST. The brain, liver, kidneys testes, and endocrine organs contained large amounts of MST, but the lungs, spleen, thymus, and small intestine did not. Immunohistochemically, the MST expression pattern varies in a cell-specific manner. In the brain, neural and glial cells are positively stained; in the lung, bronchiolar cells are preferentially stained; in the liver, hepatocytes around central veins are more strongly stained; renal convoluted cells are strongly stained; and pancreatic islets are strongly stained. Fetal tissues were studied, and MST expression was found to be similar before and after birth. Histological observation revealed no remarkable findings in MST gene-deficient mice. The present study revealed fundamental information regarding the MST expression of various organs in adult and fetal mice, and the morphological phenotype of MST gene-deficient mice. PMID- 27973428 TI - Natural Terpenes as Penetration Enhancers for Transdermal Drug Delivery. AB - The greatest hindrance for transdermal drug delivery (TDD) is the barrier property of skin, especially the stratum corneum (SC). Various methodologies have been investigated and developed to enhance the penetration of drugs through the skin. Among them, the most popular approach is the application of penetration enhancers (PEs), including natural terpenes, a very safe and effective class of PEs. In the present paper, we focused on terpenes as skin PEs for TDD. The mechanism of their action, the factors affecting their penetration enhancement effect, as well as their possible skin toxicity were discussed. Terpenes abundant in nature have great potential in the development of PEs. Compared to synthetic PEs, natural terpenes have been proved to possess higher enhancement activity. Interaction with SC intercellular lipids is the main mechanism of action for terpenes. The key factor affecting the enhancement effect is the lipophilicity of both terpenes and drug molecules. In addition, a lot of terpenes have also been proved to be much less toxic compared to azone, the classic synthetic PE. In summary, terpenes may be preferred over the chemically synthesized compounds as safe and effective PEs to promote the percutaneous absorption of drugs. PMID- 27973429 TI - Velocity-Aided Attitude Estimation for Helicopter Aircraft Using Microelectromechanical System Inertial-Measurement Units. AB - This paper presents an algorithm for velocity-aided attitude estimation for helicopter aircraft using a microelectromechanical system inertial-measurement unit. In general, high- performance gyroscopes are used for estimating the attitude of a helicopter, but this type of sensor is very expensive. When designing a cost-effective attitude system, attitude can be estimated by fusing a low cost accelerometer and a gyro, but the disadvantage of this method is its relatively low accuracy. The accelerometer output includes a component that occurs primarily as the aircraft turns, as well as the gravitational acceleration. When estimating attitude, the accelerometer measurement terms other than gravitational ones can be considered as disturbances. Therefore, errors increase in accordance with the flight dynamics. The proposed algorithm is designed for using velocity as an aid for high accuracy at low cost. It effectively eliminates the disturbances of accelerometer measurements using the airspeed. The algorithm was verified using helicopter experimental data. The algorithm performance was confirmed through a comparison with an attitude estimate obtained from an attitude heading reference system based on a high accuracy optic gyro, which was employed as core attitude equipment in the helicopter. PMID- 27973430 TI - Conceptual Design of a Nano-Networking Device. AB - Nanotechnology is an emerging scientific area whose advances, among many others, have a positive direct impact on the miniaturization of electronics. This unique technology enables the possibility to design and build electronic components as well as complete devices (called nanomachines or nanodevices) at the nano scale. A nanodevice is expected to be an essential element able to operate in a nanonetwork, where a huge number of them would coordinate to acquire data, process the information gathered, and wirelessly transmit those data to end points providing innovative services in many key scenarios, such as the human body or the environment. This paper is aimed at studying the feasibility of this type of device by carefully examining their main component parts, namely the nanoprocessor, nanomemory, nanoantenna, and nanogenerator. To this end, a thorough state-of-the-art review is conveyed to discuss, substantiate, and select the most suitable current technology (commercial or pre-commercial) for each component. Then, we further contribute by developing a complete conceptual nanodevice layout taking into consideration its ultra-small size (similar to a blood cell) and its very restricted capabilities (e.g., processing, memory storage, telecommunication, and energy management). The required resources as well as the power consumption are realistically estimated. PMID- 27973431 TI - Integrated Fault Diagnosis Algorithm for Motor Sensors of In-Wheel Independent Drive Electric Vehicles. AB - An integrated fault-diagnosis algorithm for a motor sensor of in-wheel independent drive electric vehicles is presented. This paper proposes a method that integrates the high- and low-level fault diagnoses to improve the robustness and performance of the system. For the high-level fault diagnosis of vehicle dynamics, a planar two-track non-linear model is first selected, and the longitudinal and lateral forces are calculated. To ensure redundancy of the system, correlation between the sensor and residual in the vehicle dynamics is analyzed to detect and separate the fault of the drive motor system of each wheel. To diagnose the motor system for low-level faults, the state equation of an interior permanent magnet synchronous motor is developed, and a parity equation is used to diagnose the fault of the electric current and position sensors. The validity of the high-level fault-diagnosis algorithm is verified using Carsim and Matlab/Simulink co-simulation. The low-level fault diagnosis is verified through Matlab/Simulink simulation and experiments. Finally, according to the residuals of the high- and low-level fault diagnoses, fault-detection flags are defined. On the basis of this information, an integrated fault diagnosis strategy is proposed. PMID- 27973432 TI - Acoustical Direction Finding with Time-Modulated Arrays. AB - Time-Modulated Linear Arrays (TMLAs) offer useful efficiency savings over conventional phased arrays when applied in parameter estimation applications. The present paper considers the application of TMLAs to acoustic systems and proposes an algorithm for efficiently deriving the arrival angle of a signal. The proposed technique is applied in the frequency domain, where the signal and harmonic content is captured. Using a weighted average method on harmonic amplitudes and their respective main beam angles, it is possible to determine an estimate for the signal's direction of arrival. The method is demonstrated and evaluated using results from both numerical and practical implementations and performance data is provided. The use of Micro-Electromechanical Systems (MEMS) sensors allows time modulation techniques to be applied at ultrasonic frequencies. Theoretical predictions for an array of five isotropic elements with half-wavelength spacing and 1000 data samples suggest an accuracy of +/- 1 ? within an angular range of approximately +/- 50 ? . In experiments of a 40 kHz five-element microphone array, a Direction of Arrival (DoA) estimation within +/- 2 . 5 ? of the target signal is readily achieved inside a +/- 45 ? range using a single switched input stage and a simple hardware setup. PMID- 27973433 TI - Variation among Soybean Cultivars in Mesophyll Conductance and Leaf Water Use Efficiency. AB - Improving water use efficiency (WUE) may prove a useful way to adapt crop species to drought. Since the recognition of the importance of mesophyll conductance to CO2 movement from inside stomatal pores to the sites of photosynthetic carboxylation, there has been interest in how much intraspecific variation in mesophyll conductance (gm) exists, and how such variation may impact leaf WUE within C3 species. In this study, the gm and leaf WUE of fifteen cultivars of soybeans grown under controlled conditions were measured under standardized environmental conditions. Leaf WUE varied by a factor of 2.6 among the cultivars, and gm varied by a factor of 8.6. However, there was no significant correlation (r = -0.047) between gm and leaf WUE. Leaf WUE was linearly related to the sub stomatal CO2 concentration. The value of gm affected the ratio of maximum Rubisco carboxylation capacity calculated from the sub-stomatal CO2 concentration to that calculated from the CO2 concentration at the site of carboxylation. That is, variation in gm affected the efficiency of Rubisco carboxylation, but not leaf WUE. Nevertheless, there is considerable scope for genetically improving soybean leaf water use efficiency. PMID- 27973434 TI - Performance Evaluation of State of the Art Systems for Physical Activity Classification of Older Subjects Using Inertial Sensors in a Real Life Scenario: A Benchmark Study. AB - The popularity of using wearable inertial sensors for physical activity classification has dramatically increased in the last decade due to their versatility, low form factor, and low power requirements. Consequently, various systems have been developed to automatically classify daily life activities. However, the scope and implementation of such systems is limited to laboratory based investigations. Furthermore, these systems are not directly comparable, due to the large diversity in their design (e.g., number of sensors, placement of sensors, data collection environments, data processing techniques, features set, classifiers, cross-validation methods). Hence, the aim of this study is to propose a fair and unbiased benchmark for the field-based validation of three existing systems, highlighting the gap between laboratory and real-life conditions. For this purpose, three representative state-of-the-art systems are chosen and implemented to classify the physical activities of twenty older subjects (76.4 +/- 5.6 years). The performance in classifying four basic activities of daily life (sitting, standing, walking, and lying) is analyzed in controlled and free living conditions. To observe the performance of laboratory based systems in field-based conditions, we trained the activity classification systems using data recorded in a laboratory environment and tested them in real life conditions in the field. The findings show that the performance of all systems trained with data in the laboratory setting highly deteriorates when tested in real-life conditions, thus highlighting the need to train and test the classification systems in the real-life setting. Moreover, we tested the sensitivity of chosen systems to window size (from 1 s to 10 s) suggesting that overall accuracy decreases with increasing window size. Finally, to evaluate the impact of the number of sensors on the performance, chosen systems are modified considering only the sensing unit worn at the lower back. The results, similarly to the multi-sensor setup, indicate substantial degradation of the performance when laboratory-trained systems are tested in the real-life setting. This degradation is higher than in the multi-sensor setup. Still, the performance provided by the single-sensor approach, when trained and tested with real data, can be acceptable (with an accuracy above 80%). PMID- 27973435 TI - Antithymocyte Globulin Induces a Tolerogenic Phenotype in Human Dendritic Cells. AB - Antithymocyte globulin (ATG) is used in the prevention of graft-versus-host disease during allogeneic hematopoietic stem cell transplantation. It is generally accepted that ATG mediates its immunosuppressive effect primarily via depletion of T cells. Here, we analyzed the impact of ATG-Fresenius (now Grafalon(r)) on human monocyte-derived dendritic cells (DC). ATG induced a semi mature phenotype in DC with significantly reduced expression of CD14, increased expression of HLA-DR, and intermediate expression of CD54, CD80, CD83, and CD86. ATG-DC showed an increase in IL-10 secretion but no IL-12 production. In line with this tolerogenic phenotype, ATG caused a significant induction of indoleamine 2,3-dioxygenase expression and a concomitant increase in levels of tryptophan metabolites in the supernatants of DC. Further, ATG-DC did not induce the proliferation of allogeneic T cells in a mixed lymphocyte reaction but actively suppressed the T cell proliferation induced by mature DC. These data suggest that besides its well-known effect on T cells, ATG modulates the phenotype of DC in a tolerogenic way, which might constitute an essential part of its immunosuppressive action in vivo. PMID- 27973436 TI - Facilitators and Barriers of Smokers' Compliance with Smoking Bans in Public Places: A Systematic Review of Quantitative and Qualitative Literature. AB - Background: Environmental tobacco smoke (ETS) exposure is associated with an increased risk of many diseases. Many countries have ratified a national smoking ban in public places, but studies on factors related to smoking issues in public places post-ban are lacking. Aim: To identify facilitators and barriers that influenced smokers' compliance with smoking bans in public places. Methods: Using PubMed, MEDLINE, and the Web of Science database, we conducted a systematic search of English articles published before June 2015 on factors of smokers' compliance with the smoking bans in public places. Results: A total of 390 references were identified, among which seventeen articles (twelve quantitative studies, two qualitative studies, three mixed-method studies) were included in this review. These studies focused on four types of public places including recreational venues (n = 7), hospital (n = 5), school (n = 4), and workplace (n = 1). Factors at the individual-, interpersonal-, and organizational-level were identified: at the individual level, nicotine dependence, insufficiency of tobacco-related knowledge, and the negative attitudes towards smoking bans were the most commonly identified barriers; at the interpersonal level, the smoking behaviors of people around, close relatives, and friends' approval were the main barriers; and at the organizational level, the main barriers were inefficient implementation of the bans and the inconvenience of the designative smoking areas. Conclusions: This synthesis of the literature provided evidence of the identified barriers and facilitators of smokers' compliance with the smoking bans. It will be beneficial for the policy-maker to consider interventions on multiple levels of factors to overcome the barriers and enhance smokers' compliance with the smoking bans in public places. PMID- 27973437 TI - The Role of Soundscape in Nature-Based Rehabilitation: A Patient Perspective. AB - Nature-based rehabilitation (NBR) has convincing support in research, yet the underlying mechanisms are not fully understood. The present study sought to increase understanding of the role of soundscapes in NBR, an aspect paid little attention thus far. Transcribed interviews with 59 patients suffering from stress related mental disorders and undergoing a 12-week therapy programme in the rehabilitation garden in Alnarp, Sweden, were analysed using Interpretative Phenomenology Analysis (IPA). Described sounds were categorised as natural, technological or human. The results showed that patients frequently referred to natural sounds as being part of a pleasant and "quiet" experience that supported recovery and induced "soft fascination". Technological sounds were experienced as disturbing, while perception of human sounds varied depending on loudness and the social context. The study further uncovered how sound influenced patients' behaviour and experiences in the garden, through examination of three cross-theme dimensions that materialised in the study; sound in relation to overall perception, sound in relation to garden usage, and increased susceptibility to sound. The findings are discussed in relation to NBR; the need for a more nuanced understanding of susceptibility to sound among people suffering from mental fatigue was identified and design considerations for future rehabilitation gardens were formulated. PMID- 27973439 TI - Down-Regulation of Ca2+-Activated K+ Channel KCa1.1 in Human Breast Cancer MDA-MB 453 Cells Treated with Vitamin D Receptor Agonists. AB - Vitamin D (VD) reduces the risk of breast cancer and improves disease prognoses. Potential VD analogs are being developed as therapeutic agents for breast cancer treatments. The large-conductance Ca2+-activated K+ channel KCa1.1 regulates intracellular Ca2+ signaling pathways and is associated with high grade tumors and poor prognoses. In the present study, we examined the effects of treatments with VD receptor (VDR) agonists on the expression and activity of KCa1.1 in human breast cancer MDA-MB-453 cells using real-time PCR, Western blotting, flow cytometry, and voltage-sensitive dye imaging. Treatments with VDR agonists for 72 h markedly decreased the expression levels of KCa1.1 transcripts and proteins in MDA-MB-453 cells, resulting in the significant inhibition of depolarization responses induced by paxilline, a specific KCa1.1 blocker. The specific proteasome inhibitor MG132 suppressed VDR agonist-induced decreases in KCa1.1 protein expression. These results suggest that KCa1.1 is a new downstream target of VDR signaling and the down-regulation of KCa1.1 through the transcriptional repression of KCa1.1 and enhancement of KCa1.1 protein degradation contribute, at least partly, to the antiproliferative effects of VDR agonists in breast cancer cells. PMID- 27973438 TI - Pathophysiology of Non Alcoholic Fatty Liver Disease. AB - The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation. PMID- 27973440 TI - In Vitro Antitumor Active Gold(I) Triphenylphosphane Complexes Containing 7 Azaindoles. AB - A series of gold(I) complexes of the general composition [Au(naza)(PPh3)] (1-8) was prepared and thoroughly characterized (e.g., electrospray ionization (ESI) mass spectrometry and multinuclear nuclear magnetic resonance (NMR) spectroscopy). The N1-deprotonated anions of 7-azaindole or its derivatives (naza) are coordinated to the metal centre through the N1 atom of their pyrrole ring, as proved by a single crystal X-ray analysis of the complexes [Au(3I5Braza)(PPh3)] (7) and [Au(2Me4Claza)(PPh3)].1/2H2O (8'). The in vitrocytotoxicity of the complexes 1-8 was studied against both the cisplatin sensitive and -resistant variants of the A2780 human ovarian carcinoma cell line, as well as against the MRC-5 human normal fibroblast cell line. The complexes 4, 5, and 8, containing deprotonated 3-iodo-7-azaindole, 5-bromo-7-azaindole, and 2 methyl-4-chloro-7-azaindole (2Me4Claza), respectively, showed significantly higher potency (IC50 = 2.8-3.5 uM) than cisplatin (IC50 = 20.3 uM) against the A2780 cells and markedly lower effect towards the MRC-5 non-cancerous cells (IC50 = 26.0-29.2 uM), as compared with the mentioned A2780 cancer cells. The results of the flow cytometric studies of the A2780 cell cycle perturbations revealed a G2-cell cycle phase arrest of the cells treated by the representative complexes 1 and 5, which is indicative of a different mechanism of action from cisplatin (induced S-cell cycle phase arrest). The stability of the representative complex 8 in the water-containing solution as well as its ability to interact with the reduced glutathione, cysteine and bovine serum albumin was also studied using 1H and 31P-NMR spectroscopy (studied in the 50% DMF-d7/50% D2O mixture) and ESI+ mass spectrometry (studied in the 50% DMF/50% H2O mixture); DMF = dimethylformamide. The obtained results are indicative for the release of the N donor azaindole-based ligand in the presence of the used biomolecules. PMID- 27973442 TI - Disadvantaged Social Groups and the Cigarette Epidemic: Limits of the Diffusion of Innovations Vision. AB - The original four-stage model of the cigarette epidemic has been extended with diffusion of innovations theory to reflect socio-economic differences in cigarette use. Recently, two revisions of the model have been proposed: (1) separate analysis of the epidemic stages for men and women, in order to improve generalization to developing countries, and; (2) addition of a fifth stage to the smoking epidemic, in order to account for the persistence of smoking in disadvantaged social groups. By developing a cohort perspective spanning a 35 year time period in France and the USA, we uncover distinctive features which challenge the currently held vision on the evolution of smoking inequalities within the framework of the cigarette epidemic. We argue that the reason for which the model may not be fit to the lower educated is that the imitation mechanism underlying the diffusion of innovations works well with regard to adoption of the habit, but is much less relevant with regard to its rejection. Based on those observations, we support the idea that the nature and timing of the epidemic differs enough to treat the stages separately for high and low education groups, and discuss policy implications. PMID- 27973441 TI - Inflammation in Chronic Wounds. AB - Non-healing chronic wounds present a major biological, psychological, social, and financial burden on both individual patients and the broader health system. Pathologically extensive inflammation plays a major role in the disruption of the normal healing cascade. The causes of chronic wounds (venous, arterial, pressure, and diabetic ulcers) can be examined through a juxtaposition of normal healing and the rogue inflammatory response created by the common components within chronic wounds (ageing, hypoxia, ischaemia-reperfusion injury, and bacterial colonisation). Wound bed care through debridement, dressings, and antibiotics currently form the basic mode of treatment. Despite recent setbacks, pharmaceutical adjuncts form an interesting area of research. PMID- 27973443 TI - Sex-Specific Effects of Childhood Poverty on Neurocircuitry of Processing of Emotional Cues: A Neuroimaging Study. AB - BACKGROUND: There is accumulating evidence on the negative impacts of childhood poverty on physical and mental health. Previous work has suggested hyperactive neural response to social fear cues, as well as impairment in neural regulatory functions. However, despite differences found between males and females in stress related and anxiety disorders, possible sex-specific effects of poverty on emotional processing have not been explored. METHODS: We analyzed data from three previously reported experiments of childhood poverty effects on emotional processing and regulation, for sex-specific effects. Participants were 52 healthy Caucasian males and females, from a longitudinal cohort of poverty development study, who were recruited for examining the long-term effects of childhood poverty and stress. The three functional MRI studies included emotion regulation task, emotional face assessment task, and shifted attention emotion appraisal task. Brain activations that associated with childhood poverty previously were entered into a regression analysis with interaction of gender by childhood income to-need ratio as the independent variable, and age and current income-to-need ratio as variables of no interest, separately for males and females. RESULTS: Amygdala reactivity to implicitly processed fearful faces was positively correlated with childhood income-to-need in adult females but not males. On the other hand, activation in dorsolateral and ventrolateral prefrontal regions during emotion regulation by reappraisal was positively correlated with childhood income-to-need in males. CONCLUSION: Childhood poverty may exert sex-specific effects in adulthood as presented by hypersensitive emotional reactivity of the amygdala in females, and impaired emotion regulatory function of the prefrontal cortex in males. Results suggest further focus on sex-specific effects of childhood poverty. PMID- 27973444 TI - Differential Cytotoxic Potential of Silver Nanoparticles in Human Ovarian Cancer Cells and Ovarian Cancer Stem Cells. AB - The cancer stem cell (CSC) hypothesis postulates that cancer cells are composed of hierarchically-organized subpopulations of cells with distinct phenotypes and tumorigenic capacities. As a result, CSCs have been suggested as a source of disease recurrence. Recently, silver nanoparticles (AgNPs) have been used as antimicrobial, disinfectant, and antitumor agents. However, there is no study reporting the effects of AgNPs on ovarian cancer stem cells (OvCSCs). In this study, we investigated the cytotoxic effects of AgNPs and their mechanism of causing cell death in A2780 (human ovarian cancer cells) and OvCSCs derived from A2780. In order to examine these effects, OvCSCs were isolated and characterized using positive CSC markers including aldehyde dehydrogenase (ALDH) and CD133 by fluorescence-activated cell sorting (FACS). The anticancer properties of the AgNPs were evaluated by assessing cell viability, leakage of lactate dehydrogenase (LDH), reactive oxygen species (ROS), and mitochondrial membrane potential (mt-MP). The inhibitory effect of AgNPs on the growth of ovarian cancer cells and OvCSCs was evaluated using a clonogenic assay. Following 1-2 weeks of incubation with the AgNPs, the numbers of A2780 (bulk cells) and ALDH+/CD133+ colonies were significantly reduced. The expression of apoptotic and anti apoptotic genes was measured by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Our observations showed that treatment with AgNPs resulted in severe cytotoxicity in both ovarian cancer cells and OvCSCs. In particular, AgNPs showed significant cytotoxic potential in ALDH+/CD133+ subpopulations of cells compared with other subpopulation of cells and also human ovarian cancer cells (bulk cells). These findings suggest that AgNPs can be utilized in the development of novel nanotherapeutic molecules for the treatment of ovarian cancers by specific targeting of the ALDH+/CD133+ subpopulation of cells. PMID- 27973445 TI - Roles of Peroxisome Proliferator-Activated Receptor alpha in Bitter Melon Seed Oil-Corrected Lipid Disorders and Conversion of alpha-Eleostearic Acid into Rumenic Acid in C57BL/6J Mice. AB - We previously reported that bitter melon seed oil (BMSO) was an effective anti steatosis and antiobesity agent. Since the major fatty acid alpha-eleostearic acid (alpha-ESA) in BMSO is a peroxisome proliferator-activated receptor alpha (PPARalpha) activator, the objective was to investigate the role of PPARalpha in BMSO-modulated lipid disorders and alpha-ESA metabolism. C57BL/6J wild (WD) and PPARalpha knockout (KO) mice were fed a high-fat diet containing BMSO (15% soybean oil + 15% BMSO, HB) or not (30% soybean oil, HS) for 5 weeks. The HB diet significantly reduced hepatic triglyceride concentrations and increased acyl-CoA oxidase activity in WD, but not in KO mice. However, regardless of genotype, body fat percentage was lowered along with upregulated protein levels of uncoupling protein 1 (UCP1) and tyrosine hydroxylase, as well as signaling pathway of cAMP dependent protein kinase and AMP-activated protein kinase in the white adipose tissue of HB-treated groups compared to HS cohorts. In WD-HB and KO-HB groups, white adipose tissue had autophagy, apoptosis, inflammation, and browning characteristics. Without PPARalpha, in vivo reduction of alpha-ESA into rumenic acid was slightly but significantly lowered, along with remarkable reduction of hepatic retinol saturase (RetSat) expression. We concluded that BMSO-mediated anti-steatosis depended on PPARalpha, whereas the anti-adiposity effect was PPARalpha-independent. In addition, PPARalpha-dependent enzymes may participate in alpha-ESA conversion, but only have a minor role. PMID- 27973448 TI - A High-Efficiency Uneven Cluster Deployment Algorithm Based on Network Layered for Event Coverage in UWSNs. AB - Most existing deployment algorithms for event coverage in underwater wireless sensor networks (UWSNs) usually do not consider that network communication has non-uniform characteristics on three-dimensional underwater environments. Such deployment algorithms ignore that the nodes are distributed at different depths and have different probabilities for data acquisition, thereby leading to imbalances in the overall network energy consumption, decreasing the network performance, and resulting in poor and unreliable late network operation. Therefore, in this study, we proposed an uneven cluster deployment algorithm based network layered for event coverage. First, according to the energy consumption requirement of the communication load at different depths of the underwater network, we obtained the expected value of deployment nodes and the distribution density of each layer network after theoretical analysis and deduction. Afterward, the network is divided into multilayers based on uneven clusters, and the heterogeneous communication radius of nodes can improve the network connectivity rate. The recovery strategy is used to balance the energy consumption of nodes in the cluster and can efficiently reconstruct the network topology, which ensures that the network has a high network coverage and connectivity rate in a long period of data acquisition. Simulation results show that the proposed algorithm improves network reliability and prolongs network lifetime by significantly reducing the blind movement of overall network nodes while maintaining a high network coverage and connectivity rate. PMID- 27973446 TI - RNA Interference in Insect Vectors for Plant Viruses. AB - Insects and other arthropods are the most important vectors of plant pathogens. The majority of plant pathogens are disseminated by arthropod vectors such as aphids, beetles, leafhoppers, planthoppers, thrips and whiteflies. Transmission of plant pathogens and the challenges in managing insect vectors due to insecticide resistance are factors that contribute to major food losses in agriculture. RNA interference (RNAi) was recently suggested as a promising strategy for controlling insect pests, including those that serve as important vectors for plant pathogens. The last decade has witnessed a dramatic increase in the functional analysis of insect genes, especially those whose silencing results in mortality or interference with pathogen transmission. The identification of such candidates poses a major challenge for increasing the role of RNAi in pest control. Another challenge is to understand the RNAi machinery in insect cells and whether components that were identified in other organisms are also present in insect. This review will focus on summarizing success cases in which RNAi was used for silencing genes in insect vector for plant pathogens, and will be particularly helpful for vector biologists. PMID- 27973449 TI - Development and Characterization a Single-Active-Chamber Piezoelectric Membrane Pump with Multiple Passive Check Valves. AB - In order to prevent the backward flow of piezoelectric pumps, this paper presents a single-active-chamber piezoelectric membrane pump with multiple passive check valves. Under the condition of a fixed total number of passive check valves, by means of changing the inlet valves and outlet valves' configuration, the pumping characteristics in terms of flow rate and backpressure are experimentally investigated. Like the maximum flow rate and backpressure, the testing results show that the optimal frequencies are significantly affected by changes in the number inlet valves and outlet valves. The variation ratios of the maximum flow rate and the maximum backpressure are up to 66% and less than 20%, respectively. Furthermore, the piezoelectric pump generally demonstrates very similar flow rate and backpressure characteristics when the number of inlet valves in one kind of configuration is the same as that of outlet valves in another configuration. The comparison indicates that the backflow from the pumping chamber to inlet is basically the same as the backflow from the outlet to the pumping chamber. No matter whether the number of inlet valves or the number of outlet valves is increased, the backflow can be effectively reduced. In addition, the backpressure fluctuation can be significantly suppressed with an increase of either inlet valves or outlet valves. It also means that the pump can prevent the backflow more effectively at the cost of power consumption. The pump is very suitable for conditions where more accurate flow rates are needed and wear and fatigue of check valves often occur. PMID- 27973450 TI - Airborne Transducer Integrity under Operational Environment for Structural Health Monitoring. AB - This paper investigates the robustness of permanently mounted transducers used in airborne structural health monitoring systems, when exposed to the operational environment. Typical airliners operate in a range of conditions, hence, structural health monitoring (SHM) transducer robustness and integrity must be demonstrated for these environments. A set of extreme temperature, altitude and vibration environment test profiles are developed using the existing Radio Technical Commission for Aeronautics (RTCA)/DO-160 test methods. Commercially available transducers and manufactured versions bonded to carbon fibre reinforced polymer (CFRP) composite materials are tested. It was found that the DuraAct transducer is robust to environmental conditions tested, while the other transducer types degrade under the same conditions. PMID- 27973447 TI - Anti-Inflammatory Effects of Vitamin D on Human Immune Cells in the Context of Bacterial Infection. AB - Vitamin D induces a diverse range of biological effects, including important functions in bone health, calcium homeostasis and, more recently, on immune function. The role of vitamin D during infection is of particular interest given data from epidemiological studies suggesting that vitamin D deficiency is associated with an increased risk of infection. Vitamin D has diverse immunomodulatory functions, although its role during bacterial infection remains unclear. In this study, we examined the effects of 1,25(OH)2D3, the active metabolite of vitamin D, on peripheral blood mononuclear cells (PBMCs) and purified immune cell subsets isolated from healthy adults following stimulation with the bacterial ligands heat-killed pneumococcal serotype 19F (HK19F) and lipopolysaccharide (LPS). We found that 1,25(OH)2D3 significantly reduced pro inflammatory cytokines TNF-alpha, IFN-gamma, and IL-1beta as well as the chemokine IL-8 for both ligands (three- to 53-fold), while anti-inflammatory IL 10 was increased (two-fold, p = 0.016) in HK19F-stimulated monocytes. Levels of HK19F-specific IFN-gamma were significantly higher (11.7-fold, p = 0.038) in vitamin D-insufficient adults (<50 nmol/L) compared to sufficient adults (>50 nmol/L). Vitamin D also shifted the pro-inflammatory/anti-inflammatory balance towards an anti-inflammatory phenotype and increased the CD14 expression on monocytes (p = 0.008) in response to LPS but not HK19F stimulation. These results suggest that 1,25(OH)2D3 may be an important regulator of the inflammatory response and supports further in vivo and clinical studies to confirm the potential benefits of vitamin D in this context. PMID- 27973452 TI - Application of Template Matching for Improving Classification of Urban Railroad Point Clouds. AB - This study develops an integrated data-driven and model-driven approach (template matching) that clusters the urban railroad point clouds into three classes of rail track, contact cable, and catenary cable. The employed dataset covers 630 m of the Dutch urban railroad corridors in which there are four rail tracks, two contact cables, and two catenary cables. The dataset includes only geometrical information (three dimensional (3D) coordinates of the points) with no intensity data and no RGB data. The obtained results indicate that all objects of interest are successfully classified at the object level with no false positives and no false negatives. The results also show that an average 97.3% precision and an average 97.7% accuracy at the point cloud level are achieved. The high precision and high accuracy of the rail track classification (both greater than 96%) at the point cloud level stems from the great impact of the employed template matching method on excluding the false positives. The cables also achieve quite high average precision (96.8%) and accuracy (98.4%) due to their high sampling and isolated position in the railroad corridor. PMID- 27973451 TI - Evaluation of Laser-Assisted Trans-Nail Drug Delivery with Optical Coherence Tomography. AB - The nail provides a functional protection to the fingertips and surrounding tissue from external injuries. The nail plate consists of three layers including dorsal, intermediate, and ventral layers. The dorsal layer consists of compact, hard keratins, limiting topical drug delivery through the nail. In this study, we investigate the application of fractional CO2 laser that produces arrays of microthermal ablation zones (MAZs) to facilitate drug delivery in the nails. We utilized optical coherence tomography (OCT) for real-time monitoring of the laser skin tissue interaction, sparing the patient from an invasive surgical sampling procedure. The time-dependent OCT intensity variance was used to observe drug diffusion through an induced MAZ array. Subsequently, nails were treated with cream and liquid topical drugs to investigate the feasibility and diffusion efficacy of laser-assisted drug delivery. Our results show that fractional CO2 laser improves the effectiveness of topical drug delivery in the nail plate and that OCT could potentially be used for in vivo monitoring of the depth of laser penetration as well as real-time observations of drug delivery. PMID- 27973453 TI - Evaluation of Chemical Composition and Antileishmanial and Antituberculosis Activities of Essential Oils of Piper Species. AB - Essential oils from fresh Piperaceae leaves were obtained by hydrodistillation and analyzed by gas chromatography mass spectrometry (GC-MS), and a total of 68 components were identified. Principal components analysis results showed a chemical variability between species, with sesquiterpene compounds predominating in the majority of species analyzed. The composition of the essential oil of Piper mosenii was described for the first time. The cytotoxicity of the essential oils was evaluated in peritoneal macrophages and the oils of P. rivinoides, P. arboretum, and P. aduncum exhibited the highest values, with cytotoxic concentration at 50% (CC50) > 200 ug/mL. Both P. diospyrifolium and P. aduncum displayed activity against Leishmania amazonensis, and were more selective for the parasite than for the macrophages, with a selectivity index (SI) of 2.35 and >5.52, respectively. These SI values were greater than the 1 for the standard drug pentamidine. The antileishmanial activity of the essential oils of P. diospyrifolium and P. aduncum was described for the first time. P. rivinoides, P. cernuum, and P. diospyrifolium displayed moderate activity against the Mycobacterium tuberculosis H37Rv bacillus, with a minimum inhibitory concentration (MIC) of 125 ug/mL. These results are relevant and suggests their potential for therapeutic purposes. Nevertheless, further studies are required to explain the exact mechanism of action of these essential oils. PMID- 27973454 TI - Frequent Occupational Exposure to Fusarium Mycotoxins of Workers in the Swiss Grain Industry. AB - Type B trichotecens such as deoxynivalenol (DON), 3-acetyldeoxynivalenol (3 ADON), 15-acetyldeoxynivalenol (15-ADON), nivalenol (NIV) and zearalenone (ZEN) are mycotoxins contaminating wheat and wheat dust. Mycotoxins are toxic upon ingestion and considered potentially toxic when inhaled. Whereas dietary exposure to mycotoxins is controlled in food, data on occupational exposure by inhalation by grain workers are scarce. The objectives of this study were to determine the incidence of DON, 3-ADON, 15-ADON, NIV and ZEN in aerosols generated during grain harvesting and unloading and the risk of exposure of grain workers. Aerosols were collected during the threshing of 78 winter wheat fields and grain unloading of 59 grain lots in six grain terminals in the Vaud region (Switzerland). The samples represented the diversity of the winter wheat cultivar and of the farming system (88 treated with fungicides, 46 untreated). Using a HPLC MS/MS method developed to quantify mycotoxins in aerosols, we report that the mycotoxin content of aerosols was not affected by the wheat cultivars or farming system, but that the incidence of the mycotoxins differed between activities. While wheat harvesting generated on average 28, 20 and 1 ng.m-3 of DON, NIV and ZEN, respectively, grain unloading generated 53, 46 and 4 ng.m-3. Personal sampling revealed that working in a cab was an efficient protective measure. However, it was not sufficient to avoid chronic exposure to multiple mycotoxins. The most exposed activity was the cleaning, exposing workers to DON, NIV and ZEN at concentrations as high as 65, 59 and 3 ng.m-3. These data provide valuable information for future studies of mycotoxin toxicity at relevant concentrations on respiratory health. PMID- 27973456 TI - Crystallization of Galectin-8 Linker Reveals Intricate Relationship between the N terminal Tail and the Linker. AB - Galectin-8 (Gal-8) plays a significant role in normal immunological function as well as in cancer. This lectin contains two carbohydrate recognition domains (CRD) connected by a peptide linker. The N-terminal CRD determines ligand binding specificity, whereas the linker has been proposed to regulate overall Gal-8 function, including multimerization and biological activity. Here, we crystallized the Gal-8 N-terminal CRD with the peptide linker using a crystallization condition that contains Ni2+. The Ni2+ ion was found to be complexed between two CRDs via crystal packing contacts. The coordination between Ni2+ and Asp25 plays an indirect role in determining the structure of beta-strand F0 and in influencing the linker conformation which could not be defined due to its dynamic nature. The linker was also shortened in situ and crystallized under a different condition, leading to a higher resolution structure refined to 1.08 A. This crystal structure allowed definition of a short portion of the linker interacting with the Gal-8 N-terminal tail via ionic interactions and hydrogen bonds. Observation of two Gal-8 N-terminal CRD structures implies that the N terminal tail and the linker may influence each other's conformation. In addition, under specific crystallization conditions, glycerol could replace lactose and was observed at the carbohydrate binding site. However, glycerol did not show inhibition activity in hemagglutination assay. PMID- 27973458 TI - Silymarin Activates c-AMP Phosphodiesterase and Stimulates Insulin Secretion in a Glucose-Dependent Manner in HIT-T15 Cells. AB - Silymarin (SIL) is a flavonoid extracted from milk thistle seed that has been reported to decrease hyperglycemia in people with type 2 diabetes (T2D). However, it is not known whether SIL has direct secretory effects on beta-cells. Using the beta-cell line HIT-T15, SIL was shown to decrease intracellular peroxide levels and to augment glucose-stimulated insulin secretion (GSIS). However, the latter was observed using a concentration range of 25-100 uM, which was too low to affect endogenous peroxide levels. The stimulatory effect of SIL dissipated at higher concentrations (100-200 uM), and mild apoptosis was observed. The smaller concentrations of SIL also decreased cAMP phosphodiesterase activity in a Ca2+/calmodulin-dependent manner. The stimulatory effects of SIL on GSIS were inhibited by three different inhibitors of exocytosis, indicating that SIL's mechanism of stimulating GSIS operated via closing beta-cell K-ATP channels, and perhaps more distal sites of action involving calcium influx and G-proteins. We concluded that augmentation of GSIS by SIL can be observed at concentrations that also inhibit cAMP phosphodiesterase without concomitant lowering of intracellular peroxides. PMID- 27973459 TI - Percutaneous Nephrolithotomy with Amplatz and Alken Dilators: An Eight-Year Single Tertiary Care Centre Experience. AB - BACKGROUND Percutaneous nephrolithotomy (PNL) is the standard procedure for patients with renal stones over 2 cm in diameter. We analyzed complications after this procedure focusing on two different methods of tract dilation. MATERIAL AND METHODS Between August 2008 and April 2016 222 percutaneous nephrolithotomies were performed in a total of 208 patients. The Group I (n=123) comprised patients where Alken dilatators were used, while Group II (n=99) comprised patients where Amplatz dilators were used. Efficacy was examined based on ultrasound and x-ray examination one month after the procedure. Complications were recorded using Clavien Dindo classification. RESULTS Efficacy was 85.3% and 86.8% in group I and II, respectively (p=0.77). Grade I complications were present in 14.6% and 3%, grade II were present in 9.7% and 8%, grade IIIa were present in 2.4% and 2%, grade IIIb were present in 1.6% and 2%, grade IVa were present in 1.6% and 7%, grade IVb were present in 3.2% and 1% in Group I and Group II, respectively. These differences were statistically significant (p=0.03). CONCLUSIONS Efficacy was comparable between Alken dilator and Amplatz dilator groups. In group I, there were more postoperative fevers >38.5 degrees C and a higher rate of urosepsis. On the other hand, in group II we observed more pleural injuries. All differences resulted from the type of access to the kidney (inter/infracostal), punctured calyx, and utilization (or not) of access sheath rather than type of dilators itself. PMID- 27973455 TI - MicroRNAs, DNA Damage Response, and Cancer Treatment. AB - As a result of various stresses, lesions caused by DNA-damaging agents occur constantly in each cell of the human body. Generally, DNA damage is recognized and repaired by the DNA damage response (DDR) machinery, and the cells survive. When repair fails, the genomic integrity of the cell is disrupted-a hallmark of cancer. In addition, the DDR plays a dual role in cancer development and therapy. Cancer radiotherapy and chemotherapy are designed to eliminate cancer cells by inducing DNA damage, which in turn can promote tumorigenesis. Over the past two decades, an increasing number of microRNAs (miRNAs), small noncoding RNAs, have been identified as participating in the processes regulating tumorigenesis and responses to cancer treatment with radiation therapy or genotoxic chemotherapies, by modulating the DDR. The purpose of this review is to summarize the recent findings on how miRNAs regulate the DDR and discuss the therapeutic functions of miRNAs in cancer in the context of DDR regulation. PMID- 27973460 TI - Adrenal disorders and non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the developed world and its pathogenesis is complex and multifactorial. It is considered the hepatic manifestation of the metabolic syndrome and is the leading cause of hepatic cirrhosis. This review aims to present current knowledge on the involvement of the adrenal glands in the development of NAFLD. Clinical and animal studies have shown that excess glucocorticoids (GC) have been implicated in the pathogenesis of NAFLD. Patients with NAFLD seem to have a subtle chronic activation of the hypothalamic pituitary adrenal axis leading to a state of subclinical hypercortisolism. Regulators of GC such as 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), an enzyme that regenerates cortisol from inactive cortisone, and 5alpha/5beta-reductases, enzymes that increase cortisol clearance, are implicated in the development of NAFLD by amplifying local GC action. Adrenal androgen (dehydroepiandrosterone) abnormalities and increased aldosterone levels may also have a role in the development of NAFLD whereas the contribution of adrenergic signaling in NAFLD pathogenesis remains unclear. PMID- 27973457 TI - PEDF Inhibits the Activation of NLRP3 Inflammasome in Hypoxia Cardiomyocytes through PEDF Receptor/Phospholipase A2. AB - The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome has been linked to sterile inflammation, which is involved in ischemic injury in myocardial cells. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein with many biological activities, such as anti-inflammatory, antioxidant and anti-angiogenic properties. However, it is not known whether and how PEDF acts to regulate the activation of the NLRP3 inflammasome in cardiomyocytes. In the present study, we used the neonatal cardiomyocytes models of ischemia-like conditions to evaluate the mitochondrial fission and the activation of the NLRP3 inflammasome. We also determined the mechanism by which PEDF inhibits hypoxia-induced activation of the NLRP3 inflammasome. We found that PEDF decreased the activation of the NLRP3 inflammasome in neonatal cardiomyocytes through pigment epithelial-derived factor receptor/calcium-independent phospholipase A2 (PEDFR/iPLA2). Meanwhile, PEDF reduced Drp1-induced mitochondrial fission and mitochondrial fission-induced mitochondrial DNA (mtDNA), as well as mitochondrial reactive oxygen species (mtROS) release into cytosol through PEDFR/iPLA2. We also found that PEDF inhibited mitochondrial fission-induced NLRP3 inflammasome activation. Furthermore, previous research has found that endogenous cytosolic mtDNA and mtROS can serve as activators of NLRP3 inflammasome activity. Therefore, we hypothesized that PEDF can protect against hypoxia-induced activation of the NLRP3 inflammasome by inhibiting mitochondrial fission though PEDFR/iPLA2. PMID- 27973461 TI - Bone metabolism in non-alcoholic fatty liver disease: vitamin D status and bone mineral density. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and abnormal liver enzyme worldwide. NAFLD is reported to be associated with other extra-hepatic diseases including cardiovascular disease, diabetes mellites and thyroid gland abnormalities. Liver is also the source of many proteins involved in bone metabolism and is the regulator of several bone metabolism pathways. Although underlying pathogenesis is not clear, the association between NAFLD and low bone mineral density (BMD) in the forms of osteoporosis and osteopenia has been recently reported. This study aimed to review current evidences supporting the association between bone metabolism including low BMD and serum vitamin D level in patients with NAFLD. Epidemiolocal studies indicating lower BMD and vitamin D in patients with NAFLD have been reviewed. The main pathophysiological mechanisms including association of insulin resistance, serum adiponectin, ghrelin, osteopontin, osteoprotegerin, and osteocalcin with NAFLD and low BMD have been briefly reviewed and summarized. Results of current clinical trials investigating the role of vitamin D supplementation for treatment of hepatic steatosis and non-alcoholic steatohepoatitis (NASH) have been also summarized. As a conclusion, increasing evidences are now available suggesting low BMD in patients with NAFLD. Some of these studies showed association of NAFLD severity with low vitamin D and BMD. Screening and surveillance of skeletal system regarding osteoporosis/osteomalacia in patients with NAFLD may be considered in future strategies and guidelines for NAFLD management. PMID- 27973462 TI - Bismuth-based quadruple therapy modified with moxifloxacin for Helicobacter pylori eradication. AB - BACKGROUND: The aim of this study was to evaluate the efficacy, tolerability and safety of modified bismuth-based quadruple therapy for the second-line eradication treatment of Helicobacter pylori (H. pylori) infection. METHODS: Out of 758 patients treated between January 2010 and December 2015, 155 patients (20.45%) remained H. pylori positive after the first line treatment and received the second-line treatment consisting of colloidal bismuth subcitrate (240 mg twice daily), pantoprazole (40 mg twice daily), metronidazole (500 mg twice daily) and moxifloxacin (400 mg once daily) for 14 days. Six weeks after the completion of treatment patients were retested for the presence of H. pylori infection with 13C urea breath test. RESULTS: Out of 155 patients, 142 patients completed their second-line regimens. 13 patients were excluded from the study: 4 experienced adverse effects that have led to discontinuation of treatment, 5 were lost to follow-up and 4 complied poorly with medication. The eradication rates were 80.64% (125/155) and 88.02% (125/142) according to intention-to-treat and per-protocol analyses. Compliance with the therapy was 89%. CONCLUSIONS: Moxifloxacin in modified bismuth-based quadruple therapy was found to be effective and safe with good drug compliance; therefore it may be an acceptable alternative to other second-line eradication protocols. PMID- 27973463 TI - Rationale and evidences for treatment of symptomatic uncomplicated diverticular disease. AB - INTRODUCTION: Symptomatic uncomplicated diverticular disease (SUDD) is one of the possible clinical manifestations of diverticular disease. It is a common disorder characterized by chronic abdominal symptoms ranging from lower left abdominal pain to alteration of bowel habit, that significantly reduce quality of life of subject affected. The present article aims to review the current data for medical management of SUDD. EVIDENCE ACQUISITION: We analyzed the existing literature on the factors involved in the pathogenesis of SUDD and we highlighted the possible target for treatment. Treatment for SUDD should be direct to relieve chronic symptoms and prevent diverticulitis and its complications. In particular we focused on the role of probiotics, fiber-diet, mesalazine and rifaximin on these two aspects. In this setting, we conducted a PubMed search for guidelines, systematic reviews and meta-analyses and updated information to October 2016. EVIDENCE SYNTHESIS: Each topic was evaluated according to the best evidences available. Best results seemed to be obtained with combined therapies and in particular with rifaximin associated to high fiber-diet. This regimen seems to guarantee better symptoms control compared to fiber alone and it is more effective in preventing acute diverticulitis. On the contrary, no clear evidences about the efficacy of mesalazine and probiotics are available. CONCLUSIONS: The results of the studies available in literature are controversial and debatable, for this reason a clear and defined algorithm for treatment of SUDD has not yet been defined. Further randomized, double-blind, placebo controlled study are necessary. PMID- 27973464 TI - Pathogenesis of diverticulosis and diverticular disease. AB - Diverticulosis is defined by the presence of diverticula due to herniation of mucosa and muscularis mucosa through the muscularis propria at sites of vascular penetration in the colon and is asymptomatic in the vast majority affected. There are global differences of distribution, in Western industrialized societies, the most common site is in the left colon, but in Asia right sided diverticulosis predominates. Whilst present in 17.5% of a general population and 42% of all comers at endoscopy it is seen in 71% of those aged >=80 years. Diverticular disease is defined as clinically significant and symptomatic diverticulosis, which may have an absence of macroscopically overt colitis and in true diverticulitis there is macroscopic inflammation of diverticula with related acute or chronic complications. Whilst overall, diverticulitis affects only 4% of those with diverticulosis, in younger patients (aged 40-49 years) this peaks at 11%. Diverticulosis is one of the most common chronic diseases, yet research in this field on pathogenesis has lagged behind other common conditions such as diabetes mellitus. However, in the last decade there have been major advances in taxonomy that can be used to relate to patients' outcome and treatment in both medicine and surgery. It has been shown there is an association with age, diet, drugs and smoking. Genetic studies have shown a familial association and a specific gene, TNFSF 15 may predict severity of disease. The role of the microbiome has been explored and microbial and metabolomic signatures are also important in predicting disease severity. That diverticulosis is a chronic disease is shown by mucosal pathology with subtle chronic inflammation present in those with asymptomatic diverticulosis and inflammation may lead to muscular hypertrophy, enteric nerve remodeling with disordered motility. The diverticulitis quality of life instrument shows that this condition impacts markedly on patients' well-being and prevention and amelioration of complications should be the aim of treatment and further research to attain this goal is needed. PMID- 27973465 TI - Should incidental findings in diagnostic imaging be reported? AB - BACKGROUND: Recent improvements in image quality have contributed to an increasing number of incidental findings (IF). Also called as "incidentalomas", this generic term refers to an entity discovered unexpectedly on an imaging examination performed for other reason. Commonly, normal variants, minor developmental anomalies and imaging artifacts are described as potential pathology. Some IF were reported in magnetic resonance imaging (MRI) exam of temporomandibular joint (TMJ), including IF in the brain, maxillary sinus, ethmoidal cells, mastoid cells, salivary glands, muscles. The aim of this study is to evaluate the prevalence of IF on MRI of TMJ from Japanese patients. METHODS: An image archive from 872 patients referred to MRI evaluation due to TMJ symptomatology was assessed. Three experienced radiologists evaluated all images, and the final diagnosis was achieved by consensus. The data regarding IF was recorded, considering only tumor and tumor-like lesions. RESULTS: A total of 12 (1.38%) of tumor and tumor-like lesions were observed from all 872 MRI exams evaluated. The most frequent lesion was arachnoid cyst (0.45%), followed by neoplastic lesions (0.22%). CONCLUSIONS: The question "should every IF be reported?" is still difficult to answer. Relevant IF are rare, and radiologists are expected to be reasonable: think about the adverse effects of reporting an IF, and, based on their own judgment, choose for a positive or a negative answer. PMID- 27973466 TI - New options for menopausal symptoms after 15 years of WHI Study. AB - Menopausal symptoms include vasomotor symptoms (VMS), vulvar-vaginal atrophy, and loss of bone mass associated with an increased risk of fracture. Treatment of VMS consists of lifestyle changes, hormone treatment (estrogens with and without progestogens, tissue selective estrogens complex or conjugated estrogens and bazedoxifene [CE/BZA], progestogens, and tibolone), and nonhormonal treatments. Genitourinary symptoms due to vulvar-vaginal atrophy are treated with systemic and local hormones, moisturizer creams and gels, CE/BZA, and a selective estrogen receptor modulator (ospemifene). In addition to lifestyle changes, treatments for the risk of fragility fracture include calcium and vitamin D, hormone treatment, selective estrogen receptor modulators (raloxifene, BZA), bisphosphonates, strontium ranelate, denosumab, and teriparatide. This article reviews treatment options and provides treatment algorithms for women with menopausal symptoms. PMID- 27973467 TI - Correlation between high mobility group box-1 protein and chronic hepatitis B infection with severe hepatitis B and acute-on-chronic liver failure: a meta analysis. AB - INTRODUCTION: The aim of this study was to evaluate the correlation of High mobility group box 1 (HMGB1) expression in the serum with chronic hepatitis B (CHB) related liver fibrosis, severe hepatitis B and acute-on-chronic liver failure (ACLF). EVIDENCE ACQUISITION: We made a literature search in PubMed, Embase, Web of Science, Medline, Google Scholar, China National Knowledge Infrastructure, WanFang with no language restriction. Pooled data were analyzed and mean difference with corresponding 95% confidence intervals were calculated. EVIDENCE SYNTHESIS: A total of 16 relevant studies were identified. HMGB1 serum levels were higher in severe hepatitis B or ACLF patients than those in CHB patients. Pooled mean differences of HMGB1 in severe hepatitis B and ACLF patients compared with CHB patients were 4.32 (95% CI: 0.34-8.29, Z=2.13, I2=59%, P=0.03) and 15.96 (95% CI: -0.37-32.28, Z=1.92, P=0.06). Four studies showed there was a different HMGB1 expression in mild, moderate and severe CHB patients (P values were <0.05, <0.05, <0.05 and <0.01, respectively). Pooled mean difference of HMGB1 in low liver fibrosis patients compared with high liver fibrosis was -125.38 (95% CI: -539.44-288.68, Z=0.59, I2=98%, P=0.55). CONCLUSIONS: The results suggested that HMGB1 levels in the serum were statistically higher in severe hepatitis B and ACLF patients. Therefore, HMGB1 may be a useful therapeutic target for severe hepatitis B and ACLF diagnosis. PMID- 27973468 TI - Epidemiology of iodine deficiency. AB - Iodine is an essential component of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) produced by the thyroid gland. Iodine deficiency impairs thyroid hormone production and has adverse effects throughout life, particularly early in life as it impairs cognition and growth. Iodine deficiency remains a significant problem despite major national and international efforts to increase iodine intake, primarily through the voluntary or mandatory iodization of salt. Recent epidemiological data suggest that iodine deficiency is an emerging issue in industrialized countries, previously thought of as iodine-sufficient. International efforts to control iodine deficiency are slowing, and reaching the third of the worldwide population that remains deficient poses major challenges. PMID- 27973469 TI - Analysis of metabolism-related indicators and MTHFR gene polymorphism in patients with H-type hypertension. AB - BACKGROUND: This study aims to analyze the polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene in patients with hypertension, and explore the correlation between H-type hypertension and metabolic biochemical indicators such as homocysteine (Hcy). METHODS: One hundred patients with H-type hypertension and 100 patients with common hypertension were selected as the study subjects. Plasma Hcy and blood lipids, blood glucose, and other biochemical indicators were detected in the two groups. Then, the polymorphism of the MTHFR gene was compared between these two groups. RESULTS: Hcy, uric acid (UA) and creatinine (Cr) levels in the H-type hypertension group were significantly higher than those of the common hypertension group (t=4.832-14.989, P<0.05). The T allele was predominant in the MTHFR 677C/T genotype frequency distribution in the H-type hypertension group, while the C allele was predominantly in the frequency distribution in the common hypertension group (P<0.05). CONCLUSIONS: High levels of Hcy, UA and Cr are closely related to the occurrence of H-type hypertension. Homozygous mutant TT genotype of 677C/T of the MTHFR gene may be an important genetic factor of H-type hypertension. PMID- 27973470 TI - Nutritional rickets: vitamin D, calcium, and the genetic make-up. AB - BACKGROUND: The prevalence of vitamin D (vitD) deficiency presenting as rickets is increasing worldwide. Insufficient sun exposure, vitD administration, and/or calcium intake are the main causes. However, vitD system-related genes may also have a role. METHODS: Prospective study: 109 rachitic children completed a 6-mo study period or until rachitic manifestations disappeared. Thirty children were selected as controls. Clinical and biochemical data were evaluated at baseline in patients and controls and biochemistry re-evaluated at radiological healing. Therapy was stratified in three different protocols. Fifty-four single-nucleotide polymorphisms (SNPs) of five vitD system genes (VDR, CP2R1, CYP27B1, CYP24A1, and GC) were genotyped and their association with clinical and biochemcial data was analyzed. RESULTS: Therapy response was similar in terms of radiological healing although it was not so in terms of biochemical normalization. Only VDR gene (promoter, start-codon, and intronic genotypes) was rickets-associated in terms of serum 25-OH-D, calcium, radiological severity and time needed to heal. Eight patients with sufficient calcium intake and 25-OH-D levels carried a VDR genotype lacking minor allele homozygous genotypes at SNPs spread along the gene. CONCLUSION: Although patients presented epidemiologic factors strongly contributing to rickets, genetic modulation affecting predisposition, severity, and clinical course is exerted, at least in part, by VDR gene polymorphic variation. PMID- 27973471 TI - Peroxisome proliferator-activated receptor-gamma agonist pioglitazone reduces the development of necrotizing enterocolitis in a neonatal preterm rat model. AB - BACKGROUND: Factors affecting innate immunity and acting as inflammatory regulators, such as the nuclear peroxisome proliferator-activated receptors (PPAR) could be crucial in the pathogenesis of necrotizing enterocolitis (NEC). We hypothesized that the PPARgamma agonist pioglitazone (PIO) might be effective in preventing the development of NEC and/or reducing its severity. METHODS: We studied preterm rats in which NEC was induced using the hypoxia-hypothermia model. The treatment group (TG; n = 30) received enteral PIO (10 mg/kg/d) for 72 h and the control group (CG; n = 30) did not. Animals were sacrificed 96 h after birth. NEC was diagnosed evaluating histological ileum changes, and mRNA levels of IL-4, IL-12, IL-6, IL-10, INF-gamma, and TNF-alpha cytokines were measured. RESULTS: NEC occurrence was higher in the CG (18/30; 60%) than in the TG (5/30; 16.7%) and was more severe. Proinflammatory IL-12 and INF-gamma mRNA levels were significantly lower in the TG than in the CG; conversely, the anti-inflammatory IL-4 mRNA level was significantly higher in the TG than in the CG. CONCLUSION: Our results demonstrate for the first time that PIO is effective in reducing the incidence and severity of NEC and in decreasing renal injuries in a preterm rat model. PMID- 27973473 TI - High-speed and high-sensitivity parallel spectral-domain optical coherence tomography using a supercontinuum light source. AB - The three most important metrics in optical coherence tomography (OCT) are resolution, speed, and sensitivity. Because there is a complex interplay between these metrics, no previous work has obtained the best performance in all three metrics simultaneously. We demonstrate that a high-power supercontinuum source, in combination with parallel spectral-domain OCT, achieves an unparalleled combination of resolution, speed, and sensitivity. This system captures cross sectional images spanning 4 mm*0.5 mm at 1,024,000 lines/s with 2*14 MUm resolution (axial*transverse) at a sensitivity of 113 dB. Imaging using the proposed system is demonstrated on highly differentiated human bronchial epithelial cells to capture and spatially localize ciliary dynamics. PMID- 27973474 TI - Precision resonance tuning and design of SiN photonic crystal reflectors. AB - Photonic crystal reflector (PCR) membranes exhibit a resonantly enhanced normal incidence reflectivity. Many applications require this resonance to occur at a specific wavelength, however, imposing geometrical tolerances that are not reliably achieved with standard nanolithography. Here we finely tune the resonant wavelength of a freestanding Si3N4 PCR membrane with iterative hydrofluoric acid etches, achieving a 57 nm thin crystal with a resonant wavelength 0.15 nm (0.04 linewidths) away from our target (1550 nm). This thin crystal exhibits a broader, shallower transmission dip than its simulated response to plane waves, and we identify two causes related to beam collimation. Finally, we present a series of simulations and general design considerations for realizing robust, high-reflectivity resonances. PMID- 27973475 TI - Asymmetric mode scattering in strongly coupled photonic crystal nanolasers. AB - We investigate the basic mechanism of nonlinear mode competition in two semiconductor-coupled nanocavities operating in the laser regime. For this, we study energy transfer between bonding (in-phase) and anti-bonding (out-of-phase) modes of the system formed by two strongly coupled photonic crystal nanolasers. We experimentally observe mode switching from the blue-detuned to the red-detuned mode as the pump power is increased. A semi-classical description in terms of mean-field equations allows us to explain this phenomenon as stimulated scattering due to carrier population oscillations in the cavities at the mode splitting frequency. We predict such asymmetrical mode interaction to be universal in arrays of optically coupled semiconductor micro and nanocavities. PMID- 27973472 TI - In vitro and in vivo comparison between poractant alfa and the new generation synthetic surfactant CHF5633. AB - BACKGROUND: CHF5633 is a new generation synthetic surfactant containing both SP-B and SP-C analogues developed for the treatment of respiratory distress syndrome. Here, the optimal dose and its performance in comparison to the animal-derived surfactant poractant alfa were investigated. METHODS: In vitro surfactant activity was determined by means of the Wilhelmy balance and the capillary surfactometer. The dose-finding study was performed in preterm rabbits with severe surfactant deficiency. CHF5633 doses ranging from 50 to 300 mg/kg were used. Untreated animals and animals treated with 200 mg/kg of poractant alfa were included for comparison. RESULTS: In vitro, minimum surface tension (gammamin) was decreased from values above 70 to 0 mN/m by both surfactants, and they formed rapidly a film at the air-liquid interface. In vivo studies showed a clear dose dependent improvement of lung function for CHF5633. The pulmonary effect of CHF5633 200 mg/kg dose was comparable to the pulmonary response elicited by 200 mg/kg of poractant alfa in preterm rabbits. CONCLUSION: CHF5633 is as efficient as poractant alfa in our in vitro and in vivo settings. A clear dose-dependent improvement of lung function could be observed for CHF5633, with the dose of 200 mg/kg being the most efficient one. PMID- 27973476 TI - Direct wavefront manipulating for a transverse electric wave microlens. AB - Due to the polarization nature of the transverse electric electromagnetic wave, manipulating it has been a difficult task and can be even more challenging for integrated on-chip optics. In this Letter, a transverse electric wave manipulating method based on direct wavefront bending and its physical picture have been proposed. Even with only five cells, the microlens can exhibit a focusing pattern and retrieve sub-wavelength spatial features. An analytical mode has been proposed to help understand the physical picture and verify the result. This Letter facilitates the basic understanding for transverse electric wave manipulating and the design of integrated optical elements. PMID- 27973477 TI - Gap solitons in the nonlinear fractional Schrodinger equation with an optical lattice. AB - We predict the existence of gap solitons in the nonlinear fractional Schrodinger equation (NLFSE) with an imprinted optically harmonic lattice. Symmetric/antisymmetric nonlinear localized modes bifurcate from the lower/upper edge of the first/second band in defocusing/focusing Kerr media. A unique feature we revealed is that, in focusing Kerr media, stable solitons appear in the finite bandgaps with the decrease of the Levy index, which is in sharp contrast to the standard NLSE with a focusing nonlinearity. Nonlinear bound states composed by in phase and out-of-phase soliton units supported by the NLFSE are also uncovered. Our work may pave the way for the study of spatial lattice solitons in fractional dimensions. PMID- 27973478 TI - No-reference stereoscopic image-quality metric accounting for left and right similarity map and spatial structure degradation. AB - Blind quality assessment of 3D images is used to confront more real challenges than 2D images. In this Letter, we develop a no-reference stereoscopic image quality assessment (SIQA) model based on the proposed left and right (LR) similarity map and structural degradation. In the proposed method, local binary pattern features are extracted from the cyclopean image that are effective for describing the distortion of 3D images. More importantly, we first propose the LR similarity map that can indicate the stereopair quality and demonstrate that the use of LR-similarity information results in a consistent improvement in the performance. The massive experimental results on the LIVE 3D and IRCCyN IQA databases demonstrate that the designed model is strongly correlated to subjective quality evaluations and competitive to the state-of-the-art SIQA algorithms. PMID- 27973479 TI - Nonparaxial self-accelerating beams in an atomic vapor with electromagnetically induced transparency. AB - We theoretically and numerically investigate the nonparaxial self-accelerating beams in a Lambda-type three-level energy system of rubidium atomic vapor in the electromagnetically induced transparency (EIT) window. In the EIT window, the absorption of the atomic vapor is small, and robust nonparaxial self-accelerating beams can be generated. The reason is that the energy of the tail transfers to the main lobe, which then maintains its shape, owing to the self-healing effect. Media with large absorption would demand large energy to compensate, and the tail would be lifted too high to maintain the profile of an accelerating beam, so that self-accelerating beams cannot be obtained any longer. An atomic vapor with small absorption is the ideal medium to produce such self-accelerating beams and, in return, self-accelerating beams may inspire new ideas in the research associated with atomic vapors and atomic-like ensembles. PMID- 27973480 TI - On the sensitivity of distributed acoustic sensing. AB - In distributed acoustic sensing (DAS) an optical fiber is transformed into an array of thousands of "virtual microphones." Most current DAS methodologies are based on coherent interference of Rayleigh backscattered light and thus are prone to signal fading. Hence, the sensitivities of the "microphones" fluctuate randomly along the fiber. Therefore, specifying the sensitivity of DAS without considering its random nature is incomplete and of limited value. In this Letter, the statistical properties of DAS SNR and DAS sensitivity are studied in detail for the first time, to the best of our knowledge. It is shown that the mean dynamic DAS SNR is proportional to the SNR obtained in a single measurement of the fiber's "static" backscatter profile and, in turn, to the energy of the interrogation pulse. Finally, the minimum input signal, which produces a specified mean DAS SNR, is proposed as a new figure of merit for the characterization of system performances and for comparison between the sensitivities of different DAS modalities. PMID- 27973481 TI - Surface and bulk second-harmonic responses from a glass slide using tightly focused radially polarized light. AB - The radially polarized beam is tightly focused by a high numerical aperture microscope objective with adjustable cover glass correction. The intensities of a second-harmonic (SH) signal as a function of the focal position inside a glass slide for different settings of cover glass correction are measured. As compared to linear polarization illumination, the surface responses at the two surfaces of the glass slide are more easily observed in the case of radial polarization. For the first time, to the best of our knowledge, we present the experimental demonstration that surface and bulk SH responses from solid centrosymmetric materials can be separately addressed by adjusting the cover glass correction thickness and the position of the focal exciting field. PMID- 27973482 TI - Wide-band polarization controller for Si photonic integrated circuits. AB - A circuit for the management of any arbitrary polarization state of light is demonstrated on an integrated silicon (Si) photonics platform. This circuit allows us to adapt any polarization into the standard fundamental TE mode of a Si waveguide and, conversely, to control the polarization and set it to any arbitrary polarization state. In addition, the integrated thermal tuning allows kilohertz speed which can be used to perform a polarization scrambler. The circuit was used in a WDM link and successfully used to adapt four channels into a standard Si photonic integrated circuit. PMID- 27973483 TI - Precise optical surface profilometry using innovative chromatic differential confocal microscopy. AB - A broadband differential confocal method that exploits novel double-slit chromatic confocal microscopy was developed for one-shot microscopic 3D surface measurement. In situ automated optical inspection to generate microscopic surface profiles has become extremely important for ensuring strict geometric compliance in precision manufacturing. An innovative optical configuration was developed to generate a pair of orthogonally polarized incident light beams, and a pair of the conjugate light beams was detected using two slits of different widths at the corresponding conjugate imaging locations of the incident beams. A sub-micrometer depth measuring repeatability can be achieved for the one-shot reconstruction of 3D surface profiles. PMID- 27973484 TI - Pseudo-random-bit-sequence phase modulation for reduced errors in a fiber optic gyroscope. AB - Low noise and drift in a laser-driven fiber optic gyroscope (FOG) are demonstrated by interrogating the sensor with a low-coherence laser. The laser coherence was reduced by broadening its optical spectrum using an external electro-optic phase modulator driven by either a sinusoidal or a pseudo-random bit sequence (PRBS) waveform. The noise reduction measured in a FOG driven by a modulated laser agrees with the calculations based on the broadened laser spectrum. Using PRBS modulation, the linewidth of a laser was broadened from 10 MHz to more than 10 GHz, leading to a measured FOG noise of only 0.00073 deg/?h and a drift of 0.023 deg/h. To the best of our knowledge, these are the lowest noise and drift reported in a laser-driven FOG, and this noise is below the requirement for the inertial navigation of aircraft. PMID- 27973486 TI - Multi-access fiber-optic radio frequency transfer with passive phase noise compensation. AB - In this Letter, we propose and demonstrate a multi-access fiber-optic radio frequency dissemination with passive phase noise cancelation. A forward phase conjugated signal is generated at the local site by frequency mixing between the standard signal and the round-trip probe signal. A stable frequency signal is achieved by frequency mixing the tapped forward phase-conjugated signal and the backward probe signal at an arbitrary point along the fiber link. Different wavelengths for forward and backward directions are employed to efficiently suppress the effect of backscattering. At the same time, the increase of bidirectional asymmetry with the increase of user ends is avoided by employing the same wavelengths for all user ends. A multi-access frequency transfer over a 45 km fiber link based on the proposed scheme is demonstrated. The radio frequency signals with relative frequency stabilities of 10-17/20,000 s level are reproduced at two points of 5 and 40 km far from the local site along the fiber link, respectively. PMID- 27973485 TI - Electrically/optically tunable photo-aligned hybrid nematic liquid crystal Dammann grating. AB - In this Letter, we disclose a Dammann grating (DG) based on the hybrid photo aligned nematic liquid crystals (LCs). The LC cell is composed of two substrates, wherein the first substrate is treated to provide the homeotropic alignment, and the other substrate is set to provide an in-plane, patterned alignment with a mutually orthogonal easy axis in the neighboring alignment domains. Thus, the fabricated polarization independent DG generates an optical array of equally distributed energy, which is characterized by a diffraction efficiency of more than 58%, a response time <1 ms, and the driving voltage 3 V/MUm. Furthermore, the optically active alignment layer provides the optical tunability and reconfigurability for the proposed DG. With these advantageous parameters, these DGs can be applied in modern applications. PMID- 27973487 TI - Simple dispersion estimate for single-section quantum-dash and quantum-dot mode locked laser diodes. AB - The optical outputs of single-section quantum-dash and quantum-dot mode-locked lasers (MLLs) are well known to exhibit strong group velocity dispersion. Based on careful measurements of the spectral phase of the pulses from these MLLs, we confirm that the difference in group delay between the modes at either end of the MLL spectrum equals the cavity round-trip time. This observation allows us to deduce an empirical formula relating the accumulated dispersion of the output pulse to the spectral extent and free-spectral range of the MLL. We find excellent agreement with previously reported dispersion measurements of both quantum-dash and quantum-dot MLLs over a wide range of operating conditions. PMID- 27973488 TI - "Hot-wire" microfluidic flowmeter based on a microfiber coupler. AB - Using an optical microfiber coupler (MC), we present a microfluidic platform for strong direct or indirect light-liquid interaction by wrapping a MC around a functionalized capillary. The light propagating in the MC and the liquid flowing in the capillary can be combined and divorced smoothly, keeping a long-distance interaction without the conflict of input and output coupling. Using this approach, we experimentally demonstrate a "hot-wire" microfluidic flowmeter based on a gold-integrated helical MC device. The microfluid inside the glass channel takes away the heat, then cools the MC and shifts the resonant wavelength. Due to the long-distance interaction and high temperature sensitivity, the proposed microfluidic flowmeter shows an ultrahigh flow rate sensitivity of 2.183 nm/(MUl/s) at a flow rate of 1 MUl/s. The minimum detectable change of the flow rate is around 9 nl/s at 1 MUl/s. PMID- 27973489 TI - Simultaneous acquisition of absorption and fluorescence spectra of strong absorbers utilizing an evanescent supercontinuum. AB - The determination of the absorption and emission spectra of strongly absorbing molecules is challenging, and the data can be biased by self-absorption of the fluorescence signal. To overcome this problem, a total internal reflection approach is proposed. The strongly absorbing sample is placed in an evanescent field of the radiation of a supercontinuum source. The collimated reflected light encodes the absorption spectrum, and the isotropic fluorescence emission is collected in a direction perpendicular to the surface at the same time. This ensures that the emitted light has a minimum possibility of self-absorption inside the sample. PMID- 27973490 TI - Polarization insensitive silicon photonic ROADM with selectable communication direction for radio access networks. AB - We report on an experimental prototype of a low-cost silicon photonic reconfigurable optical add/drop multiplexer (ROADM). The device is able to operate with up to 12 wavelength division multiplexing channels. In order to control the polarization of the multi-wavelength signal at the input of the device, an integrated polarization controller is investigated as an alternative to the polarization diversity device architecture. The integrated ROADM is equipped with optical switches for the selection of the path direction and variable optical attenuators for optical power control. We demonstrate the polarization insensitive routing of 10 Gb/s channels between two ROADM nodes with error-free transmission. PMID- 27973491 TI - Selective transverse mode operation of an all-fiber laser with a mode-selective fiber Bragg grating pair. AB - We propose a novel approach for achieving selective transverse mode operation of few-mode all-fiber lasers. Lasing in a specific transverse mode is enabled by employing a pair of few-mode fiber Bragg gratings as an efficient transverse mode selector. As a proof-of-principle, we have implemented a ytterbium-doped all fiber laser operating in the second-order (LP11) transverse mode. The achieved output power is 81 mW, and the slope efficiency is as high as 54%. This simple and compact all-fiber laser is also capable of delivering cylindrical vector beams through appropriate polarization control. Furthermore, the approach has great scalability and can be applied to other working modes and spectral regimes. PMID- 27973492 TI - Synthesis of anisotropic optical turbulence at the laboratory. AB - At the foundation of the problem of light propagation through optical turbulence is the classical Obukhov-Kolmogorov theory. It rests in the requirement that the refractive index fluctuations should be homogeneous and isotropic. These, with other necessary assumptions, lead to the very well-known -11/3-power exponent spectrum on the inertial range; although departures have been found, they are usually associated with partially developed turbulence or its intrinsic intermittency. Recently, in optics, the interest in anisotropic fluctuations of the refractive index has gained attention. These studies are mostly theoretical, and reduce anisotropic effects to a dilatation along a coordinate direction in the three-dimensional wavenumber space. Few experimental works exists, but all of them employ simulated turbulence. In this Letter, we describe an experiment to produce anisotropic turbulence under controlled conditions; moreover, we observe anisotropy by studying the spectral power exponent of a temporal series of laser beam wandering. PMID- 27973493 TI - High-performance and linear thin-film lithium niobate Mach-Zehnder modulators on silicon up to 50 GHz. AB - Compact electro-optical modulators are demonstrated on thin films of lithium niobate on silicon operating up to 50 GHz. The half-wave voltage length product of the high-performance devices is 3.1 V.cm at DC and less than 6.5 V.cm up to 50 GHz. The 3 dB electrical bandwidth is 33 GHz, with an 18 dB extinction ratio. The third-order intermodulation distortion spurious free dynamic range is 97.3 dBHz2/3 at 1 GHz and 92.6 dBHz2/3 at 10 GHz. The performance demonstrated by the thin-film modulators is on par with conventional lithium niobate modulators but with lower drive voltages, smaller device footprints, and potential compatibility for integration with large-scale silicon photonics. PMID- 27973494 TI - Instantaneous frequency measurement of dissipative soliton resonant light pulses. AB - We measured the instantaneous frequency profile of two different dissipative soliton resonant (DSR) light pulses, the usual flat-top and less-common trapezoid shaped light pulses. The DSR light pulses were provided by an ytterbium-doped polarization-maintaining fiber ring passively mode-locked laser using the adequately selected amount of net-normal dispersion. We confirmed that the DSR light pulses have a (moderately) low linear chirp across the pulse, except at the edges, where the chirp changes exponentially. This unique instantaneous frequency behavior can be succinctly resumed by the following parameters: linear chirp slope and leading and trailing chirp lifetimes. As the pump power increases, the linear chirp slope decreases, whereas the leading and trailing chirp lifetimes do not show an appreciable change. The results are compared with previous theoretical works. PMID- 27973495 TI - Ultra-compact and low-threshold thulium microcavity laser monolithically integrated on silicon. AB - We demonstrate an ultra-compact and low-threshold thulium microcavity laser that is monolithically integrated on a silicon chip. The integrated microlaser consists of an active thulium-doped aluminum oxide microcavity beside a passive silicon nitride bus waveguide, which enables on-chip pump-input and laser-output coupling. We observe lasing in the wavelength range of 1.8-1.9 MUm under 1.6 MUm resonant pumping and at varying waveguide-microcavity gap sizes. The microlaser exhibits a threshold as low as 773 MUW (226 MUW) and a slope efficiency as high as 24% (48%) with respect to the pump power coupled into the silicon nitride bus waveguide (microcavity). Its small footprint, minimal energy consumption, high efficiency, and silicon compatibility demonstrate that on-chip thulium lasers are promising light sources for silicon microphotonic systems. PMID- 27973497 TI - Active gratings tuned by thermoplasmonics-induced phase transition in vanadium dioxide thin films. AB - We propose and investigate an active grating of gold metallic structure on vanadium dioxide (VO2) thin film illuminated by an intense light. Nonuniform phase transition in VO2 film is expected due to the thermoplasmonics effect where the plasmonic-induced light absorption features an enhanced local heat generation at nanometer-scale. The spatial profiles of the electric field, the heat generation, and the temperature distribution, as well as the temperature-dependent dielectric parameters in VO2 film, are solved numerically in a self-consistent manner. Our results show that the evolution of the metallic and semiconducting phases of VO2 changes the effective dielectric environment of the grating and modifies its optical response in a controlled way. The interplay of the thermoplasmonics effect and the phase transition processes can thus provide another degree of freedom in designing optical modulators or switches which are remotely tunable via incident light. PMID- 27973498 TI - Equalized estimation of Stokes parameters in the presence of Poisson noise for any number of polarization analysis states. AB - Estimation of the Stokes vector is based on projecting the input light on a number N of polarization analysis states. We address the optimization of the distribution of these analysis states on the Poincare sphere in the presence of signal-dependent Poisson shot noise for an arbitrary value of N. We show that if this distribution forms a spherical 3 design, the Stokes vector is estimated with minimal equally weighted variance and with estimation variances of the last three Stokes parameters equal and independent of the input Stokes vector. We also demonstrate that in the presence of Poisson shot noise, the estimation signal to noise ratio is independent of N, whereas in the presence of signal independent additive noise, it is proportional to 1/N, which means that there is a precision loss in increasing the number of measurements. PMID- 27973496 TI - First on-sky demonstration of the piezoelectric adaptive secondary mirror. AB - We propose using a piezoelectric adaptive secondary mirror (PASM) in the medium sized adaptive telescopes with a 2-4 m aperture for structure and control simplification by utilizing the piezoelectric actuators in contrast with the voice-coil adaptive secondary mirror. A closed-loop experimental setup was built for on-sky demonstration of the 73-element PASM developed by our laboratory. In this Letter, the PASM and the closed-loop adaptive optics system are introduced. High-resolution stellar images were obtained by using the PASM to correct high order wavefront errors in May 2016. To the best of our knowledge, this is the first successful on-sky demonstration of the PASM. The results show that with the PASM as the deformable mirror, the angular resolution of the 1.8 m telescope can be effectively improved. PMID- 27973499 TI - Mid-IR absorption sensing of heavy water using a silicon-on-sapphire waveguide. AB - We demonstrate a compact silicon-on-sapphire (SOS) strip waveguide sensor for mid IR absorption spectroscopy. This device can be used for gas and liquid sensing, especially to detect chemically similar molecules and precisely characterize extremely absorptive liquids that are difficult to detect by conventional infrared transmission techniques. We reliably measure concentrations up to 0.25% of heavy water (D2O) in a D2O-H2O mixture at its maximum absorption band at around 4 MUm. This complementary metal-oxide semiconductor (CMOS) compatible SOS D2O sensor is promising for applications such as measuring body fat content or detection of coolant leakage in nuclear reactors. PMID- 27973500 TI - Optical beam shifts in graphene and single-layer boron-nitride. AB - Optical beam shifts from a freestanding 2D atomic crystal are investigated. In contrast with a 3D crystal, the magnitude of the Goos-Hanchen shift depends on the surface susceptibility of the crystal and not on the wavelength of the incident light beam. The surface conductivity of the atomically thin crystal is less important in this context because it enters in the expression of the shifts only as a second-order parameter. In analogy to a 3D crystal, the magnitudes of the Imbert-Fedorov shift and of the angular shifts depend, respectively, on the wavelength and on the square of the beam angular aperture. PMID- 27973501 TI - On the generality of the Talbot condition for inducing self-imaging effects on periodic objects: erratum. AB - Corrections to Eqs. (12) and (15) in our recent publication [Opt. Lett.41, 340 (2016)OPLEDP0146-959210.1364/OL.41.000340] are presented in this erratum. PMID- 27973502 TI - Spatiotemporal characterization of supercontinuum extending from the visible to the mid-infrared in a multimode graded-index optical fiber. AB - We experimentally demonstrate that pumping a graded-index multimode fiber with sub-ns pulses from a microchip Nd:YAG laser leads to spectrally flat supercontinuum generation with a uniform bell-shaped spatial beam profile extending from the visible to the mid-infrared at 2500 nm. We study the development of the supercontinuum along the multimode fiber by the cut-back method, which permits us to analyze the competition between the Kerr-induced geometric parametric instability and stimulated Raman scattering. We also performed a spectrally resolved temporal analysis of the supercontinuum emission. PMID- 27973503 TI - Plasmonic structure: fiber grating formed by gold nanorods on a tapered fiber. AB - The authors demonstrated the fabrication of a fiber Bragg grating-like plasmonic nanostructure on the surface of a tapered optical fiber using gold nanorods (GNRs). A multimode optical fiber with core and cladding diameters of 105 and 125 MUm, respectively, was used to make a tapered fiber using a dynamic etching process. The tip diameter was ~100 nm. Light from a laser was coupled to the untapered end of the fiber, which produced a strong evanescent field around the tapered section of the fiber. The gradient force due to the evanescent field trapped the GNRs on the surface of the tapered fiber. The authors explored possible causes of the GNR distribution. The plasmonic structure will be a good candidate for sensing based on surface enhanced Raman scattering. PMID- 27973504 TI - Visible light emission from a silica microbottle resonator by second- and third harmonic generation. AB - We report the first observation of nonlinear harmonic generation and sum frequency generation (SFG) coupled with stimulated Raman scattering (SRS) via the second-order (chi(2)) and the third-order (chi(3)) nonlinearities in a silica microbottle resonator. The visible light emission due to third-harmonic generation (THG) was observed in both the output of a tapered fiber and the optical microscope images, which can be used to identify the axial mode profiles. SFG enabled by three- and four-wave mixing processes between the pump light and the light generated via SRS was also observed. Second-harmonic generation (SHG) and the SFG are enabled by chi(2) induced in silica by surface effects and multipole excitations. PMID- 27973505 TI - Tripartite nonseparability in classical optics. AB - It is possible to prepare classical optical beams which cannot be characterized by a tensor product of vectors describing each of their degrees of freedom. Here we report the experimental creation of such a nonseparable, tripartite GHZ-like state of path, polarization, and transverse modes of a classical laser beam. We use a Mach-Zehnder interferometer with an additional mirror and other optical elements to perform measurements that violate Mermin's inequality. This demonstration of a classical optical analogue of tripartite entanglement paves the path to novel optical applications inspired by multipartite quantum information protocols. PMID- 27973506 TI - Terahertz thermometry of gold nanospheres in water. AB - The photo-thermal effects of plasmonic nanoparticles are promising for cancer therapies. These treatments would greatly benefit from real-time, multi-scale temperature mapping by non-invasive means. Here we show that intense terahertz time domain spectroscopy can be used as a non-contact and high-resolution thermometer of water solutions. Using this technique, we measure the temperature change, triggered by femtosecond amplified laser pulses, of a solution of gold nanospheres in water. Extensions of this ultra-fast and non-invasive technique could open the door to real-time micro-thermometry of single cells without fluorescent labels. PMID- 27973507 TI - Spectroscopy and continuous wave laser performance of Yb3+:LuAlO3 crystal. AB - Crystal growth, polarized spectroscopic properties, lifetime measurements, and CW laser performance under diode pumping of a new Yb3+-doped LuAlO3 crystal (Yb:LuAP) are reported for the first time, to the best of our knowledge. The maximum absorption cross section of 6.6.10-20 cm2 at 978.5 nm was determined for E//c polarization. The radiative lifetime of F5/22 manifold of Yb3+ ions in LuAP was measured to be 475 MUs. CW laser action was demonstrated with output powers up to 9.6 W and slope efficiencies up to 84.5%. 82 nm tunability range was demonstrated for E//c polarization. PMID- 27973508 TI - Output features of optical parametric chirped pulse amplification in LiB3O5 near 800 nm at different phase-matching geometries. AB - We theoretically and experimentally investigated the output beam quality and wavefront distortion in four different phase-matching geometries in LBO-OPCPA at 800 nm: broadband noncollinear geometry, collinear geometry, pump-idler the Poynting vector collinear (Sp?Si) geometry, and pump-signal Poynting vector collinear (Sp?Ss) geometry. It was found that the output profile is closely related to the noncollinear angle between Poynting vectors of parametric waves. However, the wavefront evolution depends mainly on the angles between the wave vectors. Broadband noncollinear geometry has the largest spatial modulation and wavefront distortion. Good output beam quality can be achieved in collinear geometry with little wavefront distortion, but the bandwidth is only approximately 10 nm. The Sp?Ss and Sp?Si configurations result in a bandwidth of more than 20 nm with enhanced beam quality and small wavefront distortion. The two geometries have different output features wherein the former has a relatively lower modulation, and the latter shows smaller wavefront distortion. PMID- 27973509 TI - Acoustic-actuated optical coherence angiography. AB - Optical coherence tomography (OCT) angiography requires high sensitivity and image penetration for detailed microvascular monitoring. Unfortunately, no effective contrast-medium-enhanced scheme is currently available for imaging improvement. We here propose the simultaneous use of gas-filled microbubbles (MBs) and acoustic actuation to enhance the imaging contrast of OCT angiography. OCT-synchronized acoustic actuation was applied in the presence of MBs, and different moving object tracking angiographic algorithms were tested in in vitro tubing and in vivo mouse experiments. This scheme significantly enhanced the OCT angiography performance, including its sensitivity and penetration, and should advance the utilization of OCT as an effective microvascular diagnostic tool. PMID- 27973510 TI - Coherently combined master oscillator fiber power amplifiers for Advanced Virgo. AB - Stable low-noise high-power lasers are indispensable in advancing the strain sensitivity of interferometric gravitational wave detectors. Advanced LIGO and Advanced Virgo are currently under commissioning and require about 200 W of single-frequency laser power, while the future detector design may require up to the order of 500 W. In this Letter, we present the design and, to the best of our knowledge, the first experimental demonstration of the laser system for Advanced Virgo that is based on coherently combined fiber laser amplifiers. We show the long-term performance of two 40 W fiber laser amplifiers, as well as their characterization in terms of beam quality, power noise, phase noise, and beam pointing. Moreover, a simple and compact setup utilizing fibered modulators and actuators for the coherent beam combination of these two fiber laser amplifiers is reported. A combination efficiency of about 96% was achieved, and no spurious noise was observed. PMID- 27973511 TI - Noisy metamolecule: strong narrowing of fluorescence line: comment. AB - We comment on the recent Letter by Andrianov et al. [Opt. Lett.40, 3536 (2015)OPLEDP0146-959210.1364/OL.40.003536], in which they study a strongly dissipative driven bosonic mode strongly coupled to a two-level system using the quantum Monte Carlo simulations. We recalculate their quantities via sparse numerical solvers and find that their results for larger drives are incorrect, most likely due to insufficient Monte Carlo sampling in the presence of an emergent long time scale. These findings call for a corrected interpretation of the physical behavior of the studied model. PMID- 27973512 TI - Noisy metamolecule: strong narrowing of fluorescence line: reply. AB - We reply on the comment [Opt. Lett.41, 5821 (2016)10.1364/OL.41.005821OPLEDP0146 9592] regarding our Letter [Opt. Lett.40, 3536 (2015)OPLEDP0146 959210.1364/OL.40.003536], where a dissipative driven bosonic mode strongly coupled to a two-level system is studied. We show that the authors of the comment erroneously claim that the Monte Carlo simulation is insufficient. More important is the basic statement of the comment about the vanishing width of the spectral line. This means that the plasmon spectral line vanishes at a large external field. The authors of the comment do not distinguish the averages of the observables from the quasi-averages that are quite different in multistable systems where ergodicity is challenged. PMID- 27973513 TI - Cascaded third-harmonic generation with one KDP crystal. AB - For KH2PO4 (KDP) crystal, the phase-matching directions of type-II second-harmonic generation (SHG) and type-II third-harmonic generation (THG) for 1 MUm lasers are almost identical, i.e., at (theta=60 degrees , phi=0 degrees ) around. Utilizing this special property, we designed a THG converter based on one KDP crystal. A quarter-wave (lambda/4) plate was used to adjust the polarization of the SHG wave, and a round-trip optical path was used to realize the SHG and THG procedures successively. When the fundamental light source was a 1064 nm, 40 ps pulse laser, the maximum THG output at 355 nm was 1.13 mJ, and the highest THG conversion efficiency was 30.7%. To the best of our knowledge, this is the first time that the cascaded frequency upconversion processes are realized in one bulk nonlinear optical crystal. This method possesses many advantages for future applications, including high efficiency, a wide-working waveband, low cost, and applicability to many other crystals such as DKDP, ADP, DADP, and GdxY1-xCOB. PMID- 27973514 TI - Out-of-equilibrium force measurements of dual-fiber optical tweezers. AB - Optical trapping of micron-size dielectric particles in a dual-fiber tip configuration is presented. Trap oscillation and suspension flow experiments are performed to investigate the linearity of the optical forces. These measurements are completed by standard methods such as Boltzmann statistics or power spectra evaluation. Strong trapping efficiencies of 0.25 and 1.8 pN.MUm-1 have been found in the axial and transverse directions, respectively. The values obtained by the different approaches are in good agreement. The measurements show that the optical trapping potential is harmonic over the experimentally attainable distances, i.e., 2.5 and 0.6 MUm in the transverse and axial directions, respectively. PMID- 27973515 TI - Cost-effective single-lane 112 Gb/s solution for mobile fronthaul and access applications. AB - We experimentally demonstrate the possibility of transmitting 112 Gb/s PAM-4 signals over 30-km standard single-mode fibers with commercial 20-GHz components. The impact on system performance of three different equalization schemes-feed forward equalizer (FFE), Volterra filter (VF), and maximum likelihood sequence estimator (MLSE)-is investigated and compared. We prove that the |x| and x|x| components of the VF can efficiently reduce the chirp-induced signal skew distortion, and that an MLSE with only four states can be used to remove the error floor. In contrast, the performance of FFE is worse than that of VF with a 4-state MLSE, even when a 64-state MLSE is used. PMID- 27973516 TI - Amplification of a nanosecond laser pulse chain via dynamic injection locking of a laser diode. AB - We report a novel optical pulse generation method for high-speed wavelength switching of amplified nanosecond (ns) laser pulses resonant to atomic transitions. Under free-running conditions, a slave laser diode is blue-detuned with tens of GHz relative to the master laser. A nanosecond pulse chain generated by modulating the continuous-wave master laser with a fiber-pigtailed electro optical intensity modulator is injected into the slave laser diode to fast switch the slave laser's wavelength back and forth. The output beam of the slave laser is filtered by a temperature-controlled etalon to get the amplified pulse chain. Based on our dynamic injection locking scheme, we produce an ns-scale square pulse chain with an effective ON/OFF ratio ~108, considering at least the 60 dB scattering suppression by tuning the light-atom interactions with far off-resonance detuning and the 26.7 dB suppression ratio of the etalon. By studying the dynamic processes of injection locking, we determine the dependence of injection locking on both the injection power and the frequency detuning. PMID- 27973517 TI - Temporal jitter in free-running InGaAs/InP single-photon avalanche detectors. AB - Negative-feedback avalanche diodes (NFADs) provide a practical solution for different single-photon counting applications requiring free-running mode operation with low afterpulsing probability. Unfortunately, the timing jitter has never been as good as for gated InGaAs/InP single-photon avalanche diodes. Here we report on the timing jitter characterization of InGaAs/InP based NFADs with particular focus on the temperature dependence and the effect of carrier transport between the absorption and multiplication regions. Values as low as 52 ps full-width at half-maximum were obtained at an excess bias voltage of 3.5 V and an operating temperature of around -100 degrees C. PMID- 27973518 TI - Dispersion measurements in ocular media using a dual-wavelength swept source optical coherence tomography system. AB - Optical coherence tomography (OCT) has proved to be a powerful tool for the detection of microstructure in tissue. Label-free tissue differentiation on a micron scale is a promising and powerful technique for segmentation. This Letter describes a technique using a dual-wavelength OCT system to image the eye. We measure the walk-off between interfaces in A-scans, taken at two different wavelengths, to calculate the average group velocity dispersion parameter of each segment of the eye. We present measurements of the dispersion of the cornea and the aqueous humour in rat eyes. PMID- 27973519 TI - Simultaneous control of orbital angular momentum and beam profile in two-mode polarization-maintaining fiber. AB - We report simultaneous control of the orbital angular momentum (OAM) and beam profile of vortex beams generated in two-mode polarization-maintaining optical fiber. Two higher-order eigenmodes of the fiber are combined to form optical vortices. Reduced coherence between the fiber modes decreases the mode purity. Varying the coherence of the fiber modes changes the average OAM while maintaining a constant annular intensity profile. Additionally, a donut mode has been shown to be insensitive to bends and twists in the fiber. PMID- 27973520 TI - Multimode photon-exciton coupling in an organic-dye-attached photonic quasicrystal. AB - In this Letter, we present hybrid strong coupling between multiple photonic modes and excitons in an organic-dye-attached photonic quasicrystal. The excitons effectively interact with the photonic modes offered by the photonic quasicrystal, and multiple hybrid polariton bands are demonstrated in both experiments and calculations. Furthermore, by retrieving the measured dispersion map, we get the mixing fractions of photonic modes and excitons, and show that the polariton bands inherit not only the energy dispersion features, but also the damping behaviors from both the photonic modes and the excitons. Our investigation may inspire related studies on multimode light-matter interactions and achieve some potential applications for multimode sensors. PMID- 27973521 TI - Iterative creation and sensing of twisted light. AB - The iterative interaction of a photon with a sample can lead to increased sensitivity in measuring the properties of the samples, such as its refractive index or birefringence. Here we show that this principle can also be used to generate and sense states of light. In particular, we demonstrate a technique to generate states with high orbital angular momentum using a single-vortex phase plate (VPP). This is accomplished by placing the phase plate in a self-imaging cavity such that light interacts with it multiple times; for an ideal phase plate, this is equivalent to iterative applications of the angular momentum operator. Using a discrete VPP, we show that our setup realizes a high dimensional generalization of the Pauli matrix sigmax, and that the created states show sub-diffraction limited features that might find applications in structured illumination microscopy. PMID- 27973522 TI - 193 fs from an Yb:YAG oscillator mode-locked using nonlinear polarization rotation via Type I SHG with intrinsic dispersion compensation. AB - The mode-locking technique using nonlinear polarization rotation via Type I second-harmonic generation (SHG) is demonstrated on the femtosecond timescale. The narrow spectral bandwidth of the loss modulation was broadened via a double crystal approach, which allows for mode-locking broadband gain media. We prove the predicted advantages of the technique to be correct utilizing intrinsic dispersion compensation and group-velocity mismatch management to produce 193 fs pulses. This eliminates the need for dispersion compensating elements. The technique can be applied to high-power lasers at any wavelength where a suitable SHG process is possible. PMID- 27973523 TI - Phase-sensitive OTDR probe pulse shapes robust against modulation-instability fading. AB - Typical phase-sensitive optical time-domain reflectometry (phiOTDR) schemes rely on the use of coherent rectangular-shaped probe pulses. In these systems, there is a trade-off between the signal-to-noise ratio (SNR), spatial resolution, and operating range of the phiOTDR system. To increase any of these parameters, an increase in the pulse peak power is usually indispensable. However, as it is well known, there is a limit in the allowable increase in probe power due to the onset of undesired nonlinear effects such as modulation instability. In this Letter, we perform an analysis of the effect of the probe pulse shape on the visibility fading due to modulation instability. In particular, four different temporal profiles are chosen: rectangular, Gaussian, triangular, and super-Gaussian (order 2). Our numerical and experimental analyses reveal that the use of triangular or Gaussian-like pulses can significantly inhibit the visibility fading issues. As such, an increase in the range up to twofold for the same pulse energy (i.e., SNR) and nominal spatial resolution can be achieved, as compared with the results obtained when using rectangular pulses. This is due to a more robust behavior of the Gaussian and triangular pulses against the Fermi-Pasta-Ulam recurrence occurring in modulation instability. PMID- 27973524 TI - Generation of an adjustable multi-octave supercontinuum under near-IR filamentation in gaseous, supercritical, and liquid carbon dioxide. AB - A new supercontinuum (SC) source from high-pressure gas, liquid, and supercritical fluid CO2 aggregate states that covers more than two octaves (from 400 nm up to 2 MUm) is successively reported by using a 200 fs pulsed pump at 1.24 MUm under femtosecond filamentation. The key features of the proposed source are the highly adjustable nonlinear properties (comparable with condensed matter) of the medium. This allows an easy-to-achieve filamentation process, even at microjoule laser pulse energies, giving the ultrabright and broadband SC. The molecular vibrations significantly modify the SC spectrum; as a result, a bright peak in a 1.4-1.9 MUm is generated. Its position could be finely tuned by the pressure and temperature. We report that the generation of the SC in the monofilamentation regime (unlike multifilamentation) is more stable and promising for seeded optical parametric amplifiers, and the most efficient SC generation is achieved in the liquid phase of CO2. PMID- 27973525 TI - GHz bandwidth semipolar (112-2) InGaN/GaN light-emitting diodes. AB - We report on the electrical-to-optical modulation bandwidths of non-mesa-etched semipolar (112-2) InGaN/GaN light-emitting diodes (LEDs) operating at 430-450 nm grown on high-quality (112-2) GaN templates, which were prepared on patterned (101-2) r-plane sapphire substrates. The measured frequency response at -3 dB of the LEDs was up to 1 GHz. A high back-to-back data transmission rate of above 2.4 Gbps is demonstrated using a non-return-to-zero on-off keying modulation scheme. This indicates that (112-2) LEDs are suitable gigabit per second data transmission for use in visible-light communication applications. PMID- 27973526 TI - Frequency-modulated microwave generation with feedback stabilization using an optically injected semiconductor laser. AB - Generation of frequency-modulated continuous-wave (FMCW) microwave signals is investigated using the period-one (P1) dynamics of a semiconductor laser. A modulated optical injection drives the laser into P1 oscillation with a modulated microwave frequency, while adding feedback to the injection reduces the microwave phase noise. Using simply a single-mode laser, the tunability of P1 dynamics allows for wide tuning of the central frequency of the FMCW signal. A sweep range reaching 7.7 GHz is demonstrated with a sweep rate of 0.42 GHz/ns. When the external modulation frequency matches the reciprocal of the feedback delay time, feedback stabilization is manifested as an increase of the frequency comb contrast by 30 dB for the FMCW microwave signal. PMID- 27973527 TI - The Nature of Age-Related Differences in Knee Function during Walking: Implication for the Development of Knee Osteoarthritis. AB - BACKGROUND: Changes in knee kinematics have been identified in the early stages of osteoarthritis (OA). However, there is a paucity of information on the nature of kinematic change that occur with aging prior to the development of OA, This study applied a robust statistical method (Principal Component Analysis) to test the hypothesis that coupling between primary (flexion) and secondary (anterior posterior translation, internal-external rotation) joint motions in walking would differ for age groupings of healthy subjects. METHODS: Seventy-four healthy participants divided into three groups with mean ages of 24 +/- 2.3 years (younger), 48 +/- 4.7years (middle-age) and 64 +/- 2.4 years (older) were examined. Principal Component Analysis was used to characterize and statistically compare the patterns of knee joint movement and their relationships in walking. RESULTS: There were significant differences between the younger group and both the middle-age and older groups in the knee frontal plane angle and the coupling between knee flexion (PC1, p<=0.04) and the relative magnitudes of secondary plane motions in early and late stance (PC3, p<0.01). Two additional principal components (PC2, p = 0.03 and PC5, p<0.01) described differences in early stance knee flexion and relationship with secondary plane motion through-out stance for the older compared with middle-age group. CONCLUSIONS: It appears there are changes in knee kinematics that occur with aging. The kinematic differences were identified for middle-aged as well as older adults suggesting midlife changes in neuromuscular physiology or behavior may have important consequences. These kinematic measures offer the potential to identify early markers for the risk of developing knee OA with aging. PMID- 27973529 TI - Fishing Technique of Long-Fingered Bats Was Developed from a Primary Reaction to Disappearing Target Stimuli. AB - Behavioral plasticity is a key feature allowing animals to broaden their dietary niche when novel food resources become available, and long-fingered bats provide an appropriate model system to study the underpinnings of behavioral plasticity, since although generally being an insectivorous species, some individuals have been reported to catch fish. Aiming to get insight into the origin of fishing behavior in long-fingered bats, we studied in the field the differences in sensorial and mechanical reactions to insect-like (stationary) and fish-like (temporary) prey stimuli between well-known piscivorous and strictly insectivorous individuals. Both piscivorous and insectivorous individuals exhibited a qualitatively similar reaction to temporary target stimuli (longer and deeper dips and terminal echolocation phase skewed towards buzz I compared to stationary stimuli). Nevertheless, the quantitative differences observed in the sensorial and mechanical features (the intensity of the shift was significantly greater in piscivorous than in insectivorous individuals) show that piscivorous individuals have honed their capture technique likely enhancing the fishing success. Thus, our results suggest that the fishing technique was developed from a primary reaction shared by all long-fingered bats. All individuals seem to be mechanically and sensorially adapted to detect and capture fish, although under appropriate environmental conditions, they would further improve their technique by experience and/or social learning. PMID- 27973530 TI - Detecting 3D Vegetation Structure with the Galileo Space Probe: Can a Distant Probe Detect Vegetation Structure on Earth? AB - Sagan et al. (1993) used the Galileo space probe data and first principles to find evidence of life on Earth. Here we ask whether Sagan et al. (1993) could also have detected whether life on Earth had three-dimensional structure, based on the Galileo space probe data. We reanalyse the data from this probe to see if structured vegetation could have been detected in regions with abundant photosynthetic pigments through the anisotropy of reflected shortwave radiation. We compare changing brightness of the Amazon forest (a region where Sagan et al. (1993) noted a red edge in the reflectance spectrum, indicative of photosynthesis) as the planet rotates to a common model of reflectance anisotropy and found measured increase of surface reflectance of 0.019 +/- 0.003 versus a 0.007 predicted from only anisotropic effects. We hypothesize the difference was due to minor cloud contamination. However, the Galileo dataset had only a small change in phase angle (sun-satellite position) which reduced the observed anisotropy signal and we demonstrate that theoretically if the probe had a variable phase angle between 0-20 degrees , there would have been a much larger predicted change in surface reflectance of 0.1 and under such a scenario three dimensional vegetation structure on Earth could possibly have been detected. These results suggest that anisotropic effects may be useful to help determine whether exoplanets have three-dimensional vegetation structure in the future, but that further comparisons between empirical and theoretical results are first necessary. PMID- 27973528 TI - Modelling Vaccination Strategies against Rift Valley Fever in Livestock in Kenya. AB - BACKGROUND: The impacts of vaccination on the transmission of Rift Valley fever virus (RVFV) have not been evaluated. We have developed a RVFV transmission model comprising two hosts-cattle as a separate host and sheep and goats as one combined host (herein after referred to as sheep)-and two vectors-Aedes species (spp) and Culex spp-and used it to predict the impacts of: (1) reactive vaccination implemented at various levels of coverage at pre-determined time points, (2) targeted vaccination involving either of the two host species, and (3) a periodic vaccination implemented biannually or annually before an outbreak. METHODOLOGY/PRINCIPAL FINDINGS: The model comprises coupled vector and host modules where the dynamics of vectors and hosts are described using a system of difference equations. Vector populations are structured into egg, larva, pupa and adult stages and the latter stage is further categorized into three infection categories: susceptible, exposed and infectious mosquitoes. The survival rates of the immature stages (egg, larva and pupa) are dependent on rainfall densities extracted from the Tropical Rainfall Measuring Mission (TRMM) for a Rift Valley fever (RVF) endemic site in Kenya over a period of 1827 days. The host populations are structured into four age classes comprising young, weaners, yearlings and adults and four infection categories including susceptible, exposed, infectious, and immune categories. The model reproduces the 2006/2007 RVF outbreak reported in empirical surveys in the target area and other seasonal transmission events that are perceived to occur during the wet seasons. Mass reactive vaccination strategies greatly reduce the potential for a major outbreak. The results also suggest that the effectiveness of vaccination can be enhanced by increasing the vaccination coverage, targeting vaccination on cattle given that this species plays a major role in the transmission of the virus, and using both periodic and reactive vaccination strategies. CONCLUSION/SIGNIFICANCE: Reactive vaccination can be effective in mitigating the impacts of RVF outbreaks but practically, it is not always possible to have this measure implemented satisfactorily due to the rapid onset and evolution of RVF epidemics. This analysis demonstrates that both periodic and reactive vaccination ought to be used strategically to effectively control the disease. PMID- 27973531 TI - Remembered or Forgotten?-An EEG-Based Computational Prediction Approach. AB - Prediction of memory performance (remembered or forgotten) has various potential applications not only for knowledge learning but also for disease diagnosis. Recently, subsequent memory effects (SMEs)-the statistical differences in electroencephalography (EEG) signals before or during learning between subsequently remembered and forgotten events-have been found. This finding indicates that EEG signals convey the information relevant to memory performance. In this paper, based on SMEs we propose a computational approach to predict memory performance of an event from EEG signals. We devise a convolutional neural network for EEG, called ConvEEGNN, to predict subsequently remembered and forgotten events from EEG recorded during memory process. With the ConvEEGNN, prediction of memory performance can be achieved by integrating two main stages: feature extraction and classification. To verify the proposed approach, we employ an auditory memory task to collect EEG signals from scalp electrodes. For ConvEEGNN, the average prediction accuracy was 72.07% by using EEG data from pre stimulus and during-stimulus periods, outperforming other approaches. It was observed that signals from pre-stimulus period and those from during-stimulus period had comparable contributions to memory performance. Furthermore, the connection weights of ConvEEGNN network can reveal prominent channels, which are consistent with the distribution of SME studied previously. PMID- 27973532 TI - Experimental Infection of Mink Enforces the Role of Arcanobacterium phocae as Causative Agent of Fur Animal Epidemic Necrotic Pyoderma (FENP). AB - Fur Animal Epidemic Necrotic Pyoderma (FENP) is a severe, often lethal infectious disease affecting all three fur animal species: mink (Neovision vision), foxes (Vulpes lagopus) and finnraccoons (Nyctereutes procyonoides). Previous studies showed an association between Arcanobacterium phocae and FENP. An experimental infection was conducted to confirm the ability of A. phocae to infect mink either alone or concurrently with a novel Streptococcus sp. found together with A. phocae in many cases of FENP. Different inoculation methods were tested to study possible routes of transmission. Typical signs, and gross- and histopathological findings for FENP were detected when naive mink were infected with the tissue extract of mink with FENP, using a subcutaneous/ intradermal infection route. Edema, hemorrhage, necrosis and pus formation were detected in the infection site. A pure culture preparation of A. phocae alone or concurrently with the novel Streptococcus sp. caused severe acute signs of lethargy, apathy and anorexia and even mortality. The histopathological findings were similar to those found in naturally occurring cases of FENP. In contrast, the perorally infected mink presented no clinical signs nor any gross- or histopathological lesions. This study showed that A. phocae is able to cause FENP. The study also indicated that predisposing factors such as the environment, the general condition of the animals, temperature and skin trauma contribute to the development of the disease. PMID- 27973533 TI - The Reliability and Validity of Liu's Self-Report Questionnaire for Screening Putative Pre-Psychotic States (BQSPS) in Adolescents. AB - The usage of rigorous analyses based on contemporary methods to enhance psychometric properties of screening questionnaires aimed to address psychotic like experiences (PLE) is currently being encouraged. The Brief Self-Report Questionnaire for Screening Putative Pre-psychotic States (BQSPS) is a recently created tool addressing PLE beyond attenuated positive symptoms (APS). Its psychometric properties as a screening tool for first step assessment seems to be adequate, but further research is needed to evaluate certain validity aspects, particularly its dimensionality, internal structure, and psychometric properties in different populations. We assessed the reliability, construct validity, and criterion validity of BQSPS in two samples: 727 adolescents aged 13-18 years, and 245 young adults aged 18-33 years. We used exploratory structural equation modeling (ESEM), confirmatory factor analysis (CFA), and Structural Equation Modeling (SEM). The original four-factor structure was not replicated. The best fit in adolescents was obtained by a structure of three-correlated factors: social anxiety (SA), negative symptoms (NS), and positive symptoms (PS). This structure was confirmed in young adult subjects. The three-factor model reached a predictive capability with suicidality as external criterion. PLE are represented by a three-factor structure, which is highly stable between adolescent and young adult samples. Although the BQSPS seems to be a valid tool for screening PLE, its psychometric properties should be improved to obtain a more accurate measurement. PMID- 27973534 TI - climwin: An R Toolbox for Climate Window Analysis. AB - When studying the impacts of climate change, there is a tendency to select climate data from a small set of arbitrary time periods or climate windows (e.g., spring temperature). However, these arbitrary windows may not encompass the strongest periods of climatic sensitivity and may lead to erroneous biological interpretations. Therefore, there is a need to consider a wider range of climate windows to better predict the impacts of future climate change. We introduce the R package climwin that provides a number of methods to test the effect of different climate windows on a chosen response variable and compare these windows to identify potential climate signals. climwin extracts the relevant data for each possible climate window and uses this data to fit a statistical model, the structure of which is chosen by the user. Models are then compared using an information criteria approach. This allows users to determine how well each window explains variation in the response variable and compare model support between windows. climwin also contains methods to detect type I and II errors, which are often a problem with this type of exploratory analysis. This article presents the statistical framework and technical details behind the climwin package and demonstrates the applicability of the method with a number of worked examples. PMID- 27973537 TI - Correction: Sterol Biosynthesis and Azole Tolerance Is Governed by the Opposing Actions of SrbA and the CCAAT Binding Complex. AB - [This corrects the article DOI: 10.1371/journal.ppat.1005775.]. PMID- 27973535 TI - The Influence of Programmed Cell Death in Myeloid Cells on Host Resilience to Infection with Legionella pneumophila or Streptococcus pyogenes. AB - Pathogen clearance and host resilience/tolerance to infection are both important factors in surviving an infection. Cells of the myeloid lineage play important roles in both of these processes. Neutrophils, monocytes, macrophages, and dendritic cells all have important roles in initiation of the immune response and clearance of bacterial pathogens. If these cells are not properly regulated they can result in excessive inflammation and immunopathology leading to decreased host resilience. Programmed cell death (PCD) is one possible mechanism that myeloid cells may use to prevent excessive inflammation. Myeloid cell subsets play roles in tissue repair, immune response resolution, and maintenance of homeostasis, so excessive PCD may also influence host resilience in this way. In addition, myeloid cell death is one mechanism used to control pathogen replication and dissemination. Many of these functions for PCD have been well defined in vitro, but the role in vivo is less well understood. We created a mouse that constitutively expresses the pro-survival B-cell lymphoma (bcl)-2 protein in myeloid cells (CD68(bcl2tg), thus decreasing PCD specifically in myeloid cells. Using this mouse model we explored the impact that decreased cell death of these cells has on infection with two different bacterial pathogens, Legionella pneumophila and Streptococcus pyogenes. Both of these pathogens target multiple cell death pathways in myeloid cells, and the expression of bcl2 resulted in decreased PCD after infection. We examined both pathogen clearance and host resilience and found that myeloid cell death was crucial for host resilience. Surprisingly, the decreased myeloid PCD had minimal impact on pathogen clearance. These data indicate that the most important role of PCD during infection with these bacteria is to minimize inflammation and increase host resilience, not to aid in the clearance or prevent the spread of the pathogen. PMID- 27973536 TI - A Single Subcutaneous Injection of Cellulose Ethers Administered Long before Infection Confers Sustained Protection against Prion Diseases in Rodents. AB - Prion diseases are fatal, progressive, neurodegenerative diseases caused by prion accumulation in the brain and lymphoreticular system. Here we report that a single subcutaneous injection of cellulose ethers (CEs), which are commonly used as inactive ingredients in foods and pharmaceuticals, markedly prolonged the lives of mice and hamsters intracerebrally or intraperitoneally infected with the 263K hamster prion. CEs provided sustained protection even when a single injection was given as long as one year before infection. These effects were linked with persistent residues of CEs in various tissues. More effective CEs had less macrophage uptake ratios and hydrophobic modification of CEs abolished the effectiveness. CEs were significantly effective in other prion disease animal models; however, the effects were less remarkable than those observed in the 263K prion-infected animals. The genetic background of the animal model was suggested to influence the effects of CEs. CEs did not modify prion protein expression but inhibited abnormal prion protein formation in vitro and in prion-infected cells. Although the mechanism of CEs in vivo remains to be solved, these findings suggest that they aid in elucidating disease susceptibility and preventing prion diseases. PMID- 27973538 TI - Abundance and Distribution Patterns of Thunnus albacares in Isla del Coco National Park through Predictive Habitat Suitability Models. AB - Information on the distribution and habitat preferences of ecologically and commercially important species is essential for their management and protection. This is especially important as climate change, pollution, and overfishing change the structure and functioning of pelagic ecosystems. In this study, we used Bayesian hierarchical spatial-temporal models to map the Essential Fish Habitats of the Yellowfin tuna (Thunnus albacares) in the waters around Isla del Coco National Park, Pacific Costa Rica, based on independent underwater observations from 1993 to 2013. We assessed if observed changes in the distribution and abundance of this species are related with habitat characteristics, fishing intensity or more extreme climatic events, including the El Nino Southern Oscillation, and changes on the average sea surface temperature. Yellowfin tuna showed a decreasing abundance trend in the sampled period, whereas higher abundances were found in shallow and warmer waters, with high concentration of chlorophyll-a, and in surrounding seamounts. In addition, El Nino Southern Oscillation events did not seem to affect Yellowfin tuna distribution and abundance. Understanding the habitat preferences of this species, using approaches as the one developed here, may help design integrated programs for more efficient management of vulnerable species. PMID- 27973540 TI - Bicarbonate Increases Ischemia-Reperfusion Damage by Inhibiting Mitophagy. AB - During an ischemic event, bicarbonate and CO2 concentration increase as a consequence of O2 consumption and lack of blood flow. This event is important as bicarbonate/CO2 is determinant for several redox and enzymatic reactions, in addition to pH regulation. Until now, most work done on the role of bicarbonate in ischemia-reperfusion injury focused on pH changes; although reperfusion solutions have a fixed pH, cardiac resuscitation protocols commonly employ bicarbonate to correct the profound acidosis associated with respiratory arrest. However, we previously showed that bicarbonate can increase tissue damage and protein oxidative damage independent of pH. Here we show the molecular basis of bicarbonate-induced reperfusion damage: the presence of bicarbonate selectively impairs mitophagy, with no detectable effect on autophagy, proteasome activity, reactive oxygen species production or protein oxidation. We also show that inhibition of autophagy reproduces the effects of bicarbonate in reperfusion injury, providing additional evidence in support of this mechanism. This phenomenon is especially important because bicarbonate is widely used in resuscitation protocols after cardiac arrest, and while effective as a buffer, may also contribute to myocardial injury. PMID- 27973539 TI - Action Priority: Early Neurophysiological Interaction of Conceptual and Motor Representations. AB - Handling our everyday life, we often react manually to verbal requests or instruction, but the functional interrelations of motor control and language are not fully understood yet, especially their neurophysiological basis. Here, we investigated whether specific motor representations for grip types interact neurophysiologically with conceptual information, that is, when reading nouns. Participants performed lexical decisions and, for words, executed a grasp-and lift task on objects of different sizes involving precision or power grips while the electroencephalogram was recorded. Nouns could denote objects that require either a precision or a power grip and could, thus, be (in)congruent with the performed grasp. In a control block, participants pointed at the objects instead of grasping them. The main result revealed an event-related potential (ERP) interaction of grip type and conceptual information which was not present for pointing. Incongruent compared to congruent conditions elicited an increased positivity (100-200 ms after noun onset). Grip type effects were obtained in response-locked analyses of the grasping ERPs (100-300 ms at left anterior electrodes). These findings attest that grip type and conceptual information are functionally related when planning a grasping action but such an interaction could not be detected for pointing. Generally, the results suggest that control of behaviour can be modulated by task demands; conceptual noun information (i.e., associated action knowledge) may gain processing priority if the task requires a complex motor response. PMID- 27973541 TI - The In Vitro Effect of Acidic-Pepsin on Nuclear Factor KappaB Activation and Its Related Oncogenic Effect on Normal Human Hypopharyngeal Cells. AB - BACKGROUND: Extra-esophageal carcinogenesis has been widely discussed in relation to the chronic effects of laryngopharyngeal reflux and most prominently with pepsin historically central to this discussion. With refluxate known to include gastric (pepsin) and duodenal (bile) fluids, we recently demonstrated the mechanistic role of NF-kappaB in mediating the preneoplastic effects of acidic bile. However, the role of pepsin in promoting hypopharyngeal premalignant events remains historically unclear. Here, we investigate the in vitro effect of acidic pepsin on the NF-kappaB oncogenic pathway to better define its potential role in hypopharyngeal neoplasia. METHODS: Human hypopharyngeal primary cells (HHPC) and keratinocytes (HHK) were repetitively exposed to physiologic pepsin concentrations (0.1 mg/ml) at pH 4.0, 5.0 and 7.0. Cellular localization of phospho-NF-kappaB and bcl-2 was determined using immunofluorescence and western blotting. NF-kappaB transcriptional activity was tested by luc reporter and qPCR. Analysis of DNA content of pepsin treated HHK and HHPC was performed using Fluorescence-activated-cell sorting assay. To explore a possible dose related effect, pepsin concentration was reduced from 0.1 to 0.05 and 0.01 mg/ml. RESULTS: At physiologic concentration, acidic-pepsin (0.1 mg/ml at pH 4.0) is lethal to most normal hypopharyngeal cells. However, in surviving cells, no NF kappaB transcriptional activity is noted. Acidic-pepsin fails to activate the NF kappaB or bcl-2, TNF-alpha, EGFR, STAT3, and wnt5alpha but increases the Tp53 mRNAs, in both HHPC and HHK. Weakly acidic-pepsin (pH 5.0) and neutral-pepsin (pH 7.0) induce mild activation of NF-kappaB with increase in TNF-alpha mRNAs, without oncogenic transcriptional activity. Lower concentrations of pepsin at varying pH do not produce NF-kappaB activity or transcriptional activation of the analyzed genes. CONCLUSION: Our findings in vitro do not support the role of acidic-pepsin in NF-kappaB related hypopharyngeal carcinogenesis. PMID- 27973542 TI - Increased Vascularization in the Vulnerable Upstream Regions of Both Early and Advanced Human Carotid Atherosclerosis. AB - BACKGROUND: Vascularization of atherosclerotic plaques has been linked to plaque vulnerability. The aim of this study was to test if the vascularization was increased in upstream regions of early atherosclerotic carotid plaques and also to test if the same pattern of vascularization was seen in complicated, symptomatic plaques. METHODS: We enrolled 45 subjects with early atherosclerotic lesions for contrast enhanced ultrasound and evaluated the percentage of plaque area in a longitudinal ultrasound section which contained contrast agent. Contrast-agent uptake was evaluated in both the upstream and downstream regions of the plaque. We also collected carotid endarterectomy specimens from 56 subjects and upstream and downstream regions were localized using magnetic resonance angiography and analyzed using histopathology and immunohistochemistry. RESULTS: Vascularization was increased in the upstream regions of early carotid plaques compared with downstream regions (30% vs. 23%, p = 0.033). Vascularization was also increased in the upstream regions of advanced atherosclerotic lesions compared with downstream regions (4.6 vs. 1.4 vessels/mm2, p = 0.001) and was associated with intra-plaque hemorrhage and inflammation. CONCLUSIONS: Vascularization is increased in the upstream regions of both early and advanced plaques and is in advanced lesions mainly driven by inflammation. PMID- 27973543 TI - Intradermal Delivery of Antigens Enhances Specific IgG and Diminishes IgE Production: Potential Use for Vaccination and Allergy Immunotherapy. AB - Skin is protected by a tough but flexible multilayered barrier and is a front line for immune responses against invading particles. For many years now, skin has been a tissue where certain vaccines are injected for the prevention of infectious disease, however, the detailed mechanisms of the skin immune response are not yet well understood. Using thin and small injection needles, we carefully injected OVA into a restricted region of mouse skin, i.e., intradermal (ID), and examined the antibody response in comparison with subcutaneous (SC) injection or epicutaneous patch administration of OVA. Epicutaneous patches induced a high IgE response against OVA, but IgG production was low. High IgG production was induced by both ID and SC injection, moreover, ID injection induced higher IgG production without any adjutants. Furthermore, OVA-specific IgE production was diminished by ID injection. We found that ID injection could efficiently stimulate skin resident DCs, drive Th1-biased conditions and diminish IgE production. The ID injection response was regulated by Langerin+ dermal DCs, because OVA was taken up mainly by these cells and, after transiently deleting them, the IgE response was no longer diminished and IgG1 production was enhanced. We also tested whether ID injection might be an effective allergy treatment by attempting to inhibit ongoing IgE production in mice with experimentally induced high serum IgE levels. Multiple ID injections of OVA were shown to prevent elevation of serum OVA specific IgE after repeated allergen challenge. In contrast, SC OVA injection could only transiently inhibit the OVA-specific IgE production. These findings indicated that ID injection results in higher induction of antigen-specific IgG, and thus may be useful for vaccine delivery with little or no adjuvant components. Moreover, the observed diminishment of IgE and induction of Th1 biased immune responses suggest that ID may be a useful injection route for allergy immunotherapy. PMID- 27973545 TI - Myopic Loss Aversion under Ambiguity and Gender Effects. AB - Experimental evidence suggests that the frequency with which individuals get feedback information on their investments has an effect on their risk-taking behavior. In particular, when they are given information sufficiently often, they take less risks compared with a situation in which they are informed less frequently. We find that this result still holds when subjects do not know the probabilities of the lotteries they are betting upon. We also detect significant gender effects, in that the frequency with which information is disclosed mostly affects male betting behavior, and that males become more risk-seeking after experiencing a loss. PMID- 27973544 TI - Recommendations for Updating T and N Staging Systems for Nasopharyngeal Carcinoma in the Era of Intensity-Modulated Radiotherapy. AB - OBJECTIVE: The aim of this study was to compare the 2008 Chinese and the 7th edition of the American Joint Committee on Cancer (AJCC) staging systems for nasopharyngeal carcinoma and to provide proposals for updating T and N staging systems of the present staging system. METHODS: Between January 2007 and December 2012, a cohort of 752 patients with biopsy-proven, newly diagnosed, non metastatic nasopharyngeal carcinoma who were treated with intensity-modulated radiotherapy were retrospectively analysed. Prognoses were compared by T stage, N stage, and clinical stage according to the two staging systems for overall survival (OS), local relapse-free survival (LRFS), and distant metastasis-free survival (DMFS). RESULTS: In terms of both the T and N staging systems, the two current staging systems were comparable in predicting OS. The T classification of the 2008 Chinese staging system was better in predicting LRFS, while the N classification of the 7th edition AJCC staging system was superior in predicting DMFS. In the modern era of intensity-modulated radiotherapy, the staging system should be updated by down-staging the current stage T2 to T1, and it might be rational to merge subcategories N1 and N2. CONCLUSIONS: The two current staging systems each had advantages in predicting prognosis. It seems reasonable to downstage T2 to T1 and to merge N1 and N2. PMID- 27973546 TI - Effect of Regulatory Element DNA Methylation on Tissue-Type Plasminogen Activator Gene Expression. AB - Expression of the tissue-type plasminogen activator gene (t-PA; gene name PLAT) is regulated, in part, by epigenetic mechanisms. We investigated the relationship between PLAT methylation and PLAT expression in five primary human cell types and six transformed cell lines. CpG methylation was analyzed in the proximal PLAT gene promoter and near the multihormone responsive enhancer (MHRE) -7.3 kilobase pairs upstream of the PLAT transcriptional start site (TSS, -7.3 kb). In Bowes melanoma cells, the PLAT promoter and the MHRE were fully unmethylated and t-PA secretion was extremely high. In other cell types the region from -647 to -366 was fully methylated, whereas an unmethylated stretch of DNA from -121 to +94 was required but not sufficient for detectable t-PA mRNA and t-PA secretion. DNA methylation near the MHRE was not correlated with t-PA secretion. Specific methylation of the PLAT promoter region -151 to +151, inserted into a firefly luciferase reporter gene, abolished reporter gene activity. The region -121 to + 94 contains two well-described regulatory elements, a PMA-responsive element (CRE) near -106 and a GC-rich region containing an Sp1 binding site near +59. Methylation of double-stranded DNA oligonucleotides containing the CRE or the GC rich region had little or no effect on transcription factor binding. Methylated CpGs may attract co-repressor complexes that contain histone deacetylases (HDAC). However, reporter gene activity of methylated plasmids was not restored by the HDAC inhibitor trichostatin. In conclusion, efficient PLAT gene expression requires a short stretch of unmethylated CpG sites in the proximal promoter. PMID- 27973547 TI - Regulation of the Omega-3 Fatty Acid Biosynthetic Pathway in Atlantic Salmon Hepatocytes. AB - Limited availability of the n-3 fatty acids EPA and DHA have led to an interest in better understanding of the n-3 biosynthetic pathway and its regulation. The biosynthesis of alpha-linolenic acid to EPA and DHA involves several complex reaction steps including desaturation-, elongation- and peroxisomal beta oxidation enzymes. The aims of the present experiments were to gain more knowledge on how this biosynthesis is regulated over time by different doses and fatty acid combinations. Hepatocytes isolated from salmon were incubated with various levels and combinations of oleic acid, EPA and DHA. Oleic acid led to a higher expression of the Delta6 fatty acid desaturase (fad) genes Delta6fad_a, Delta6fad_b, Delta6fad_c and the elongase genes elovl2 compared with cells cultured in medium enriched with DHA. Further, the study showed rhythmic variations in expression over time. Levels were reached where a further increase in specific fatty acids given to the cells not stimulated the conversion further. The gene expression of Delta6fad_a_and Delta6fad_b responded similar to fatty acid treatment, suggesting a co-regulation of these genes, whereas Delta5fad and Delta6fad_c showed a different regulation pattern. EPA and DHA induced different gene expression patterns, especially of Delta6fad_a. Addition of radiolabelled alpha-linolenic acid to the hepatocytes confirmed a higher degree of elongation and desaturation in cells treated with oleic acid compared to cells treated with DHA. This study suggests a complex regulation of the conversion process of n-3 fatty acids. Several factors, such as that the various gene copies are differently regulated, the gene expression show rhythmic variations and gene expression only affected to a certain level, determines when you get the maximum conversion of the beneficial n-3 fatty acids. PMID- 27973549 TI - Diurnal and Reproductive Stage-Dependent Variation of Parental Behaviour in Captive Zebra Finches. AB - Parental care plays a key role in ontogeny, life-history trade-offs, sexual selection and intra-familial conflict. Studies focusing on understanding causes and consequences of variation in parental effort need to quantify parental behaviour accurately. The applied methods are, however, diverse even for a given species and type of parental effort, and rarely validated for accuracy. Here we focus on variability of parental behaviour from a methodological perspective to investigate the effect of different samplings on various estimates of parental effort. We used nest box cameras in a captive breeding population of zebra finches, Taeniopygia guttata, a widely used model system of sexual selection, intra-familial dynamics and parental care. We investigated diurnal and reproductive stage-dependent variation in parental effort (including incubation, brooding, nest attendance and number of feedings) based on 12h and 3h continuous video-recordings taken at various reproductive stages. We then investigated whether shorter (1h) sampling periods provided comparable estimates of overall parental effort and division of labour to those of longer (3h) sampling periods. Our study confirmed female-biased division of labour during incubation, and showed that the difference between female and male effort diminishes with advancing reproductive stage. We found individually consistent parental behaviours within given days of incubation and nestling provisioning. Furthermore, parental behaviour was consistent over the different stages of incubation, however, only female brooding was consistent over nestling provisioning. Parental effort during incubation did not predict parental effort during nestling provisioning. Our analyses revealed that 1h sampling may be influenced heavily by stochastic and diurnal variation. We suggest using a single longer sampling period (3h) may provide a consistent and accurate estimate for overall parental effort during incubation in zebra finches. Due to the large within-individual variation, we suggest repeated longer sampling over the reproductive stage may be necessary for accurate estimates of parental effort post-hatching. PMID- 27973548 TI - The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development. AB - Type I diabetes is caused by loss of insulin-secreting beta cells. To identify novel, pharmacologically-targetable histone-modifying proteins that enhance beta cell production from pancreatic progenitors, we performed a screen for histone modifications induced by signal transduction pathways at key pancreatic genes. The screen led us to investigate the temporal dynamics of ser-28 phosphorylated histone H3 (H3S28ph) and its upstream kinases, MSK1 and MSK2 (MSK1/2). H3S28ph and MSK1/2 were enriched at the key endocrine and acinar promoters in E12.5 multipotent pancreatic progenitors. Pharmacological inhibition of MSK1/2 in embryonic pancreatic explants promoted the specification of endocrine fates, including the beta-cell lineage, while depleting acinar fates. Germline knockout of both Msk isoforms caused enhancement of alpha cells and a reduction in acinar differentiation, while monoallelic loss of Msk1 promoted beta cell mass. Our screen of chromatin state dynamics can be applied to other developmental contexts to reveal new pathways and approaches to modulate cell fates. PMID- 27973550 TI - Might ART Adherence Estimates Be Improved by Combining Biomarker and Self-Report Data? AB - BACKGROUND: As we endeavour to examine rates of viral suppression in PLHIV, reliable data on ART adherence are needed to distinguish between the respective contributions of poor adherence and treatment failure on high viral load. Self reported data are susceptible to response bias and although biomarker data on drug presence and concentration can provide a superior, alternative method of measurement, complications due to drug-drug interactions and genetic variations can cause some inaccuracies. We investigate the feasibility of combining both biomarker and self-report data to produce a potentially more accurate measure of ART adherence. METHODS: Data were taken from a large general-population survey in the Manicaland province, Zimbabwe, conducted in 2009-2011. HIV-infected adults who had initiated ART (N = 560) provided self-report data on adherence and dried blood spot samples that were analysed for traces of ART medication. A new three category measure of ART adherence was constructed, based on biomarker data but using self-report data to adjust for cases with abnormally low and high drug concentrations due to possible drug-drug interactions and genetic factors, and was assessed for plausibility using survey data on socio-demographic correlates. RESULTS: 94.3% (528/560) and 92.7% (519/560) of the sample reported faithful adherence to their medication and had traces of ART medication, respectively. The combined measure estimated good evidence of ART adherence at 69% and excellent evidence of adherence at 53%. The regression analysis results showed plausible patterns of ART adherence by socio-demographic status with men and younger participants being more likely to adhere poorly to medication, and higher socio economic status individuals and those living in more urban locations being more likely to adhere well. CONCLUSION: Biomarker and self-reported measures of adherence can be combined in a meaningful way to produce a potentially more accurate measure of ART adherence. Results indicate that ART adherence in Manicaland is at best 69%, which not only allows for considerable room for improvement but also suggests that the area may be falling short of the UNAIDS' 90% target regarding viral suppression. Increased efforts are needed to improve ART adherence particularly amongst the young male population in rural areas of east Zimbabwe. PMID- 27973551 TI - Orchestrated Action of PP2A Antagonizes Atg13 Phosphorylation and Promotes Autophagy after the Inactivation of TORC1. AB - Target of rapamycin complex 1 (TORC1) phosphorylates autophagy-related Atg13 and represses autophagy under nutrient-rich conditions. However, when TORC1 becomes inactive upon nutrient depletion or treatment with the TORC1 inhibitor rapamycin, Atg13 dephosphorylation occurs rapidly, and autophagy is induced. At present, the phosphatases involved in Atg13 dephosphorylation remain unknown. Here, we show that two protein phosphatase 2A (PP2A) phosphatases, PP2A-Cdc55 and PP2A-Rts1, which are activated by inactivation of TORC1, are required for sufficient Atg13 dephosphorylation and autophagy induction after TORC1 inactivation in budding yeast. After rapamycin treatment, dephosphorylation of Atg13, activation of Atg1 kinase, pre-autophagosomal structure (PAS) formation and autophagy induction are all impaired in PP2A-deleted cells. Conversely, overexpression of non phosphorylatable Atg13 suppressed defects in autophagy in PP2A mutant. This study revealed that the orchestrated action of PP2A antagonizes Atg13 phosphorylation and promotes autophagy after the inactivation of TORC1. PMID- 27973552 TI - Effect of Early Expressed Human Milk on Insulin-Like Growth Factor 1 and Short Term Outcomes in Preterm Infants. AB - AIMS: Preterm breast milk contains high levels of bioactive components, including insulin-like growth factor 1 (IGF-1), that are reduced by Holder pasteurization. Animal studies have shown that milk-borne IGF-1 is likely absorbed intact in a bioactive form by the intestines. The aim of this study was to assess if early non-pasteurized expressed breast milk nutrition may affect IGF-1 plasma levels in premature infants. We also investigated the possible association between early expressed milk nutrition and short-term outcomes. METHODS: Fifty-two preterm infants with gestational age < 31 weeks were divided into two groups according to expressed breast milk intake (< or >= 50 mL/Kg/day) until 32 weeks of postmenstrual age when blood sampling for IGF-1 analysis was performed. RESULTS: In our population, early expressed breast milk does not affect IGF-1 plasma levels (p 0.48). An association was observed between early expressed milk nutrition and a lower incidence of bronchopulmonary dysplasia, sepsis, feeding intolerance, need for parenteral nutrition and length of hospitalization. CONCLUSIONS: Contrary to the results in some animal studies, our results did not seem to show that early expressed breast milk can help to maintain postnatal IGF 1 near foetal levels in preterm infants. The observed protective effect of expressed breast milk on short-term outcomes can be the starting point for further study of the effects of non-pasteurized human milk in preterm infants. PMID- 27973553 TI - Variability of the Estimated Glomerular Filtration Rate in the First Year after Kidney Transplantation Is an Independent Risk Factor for Poor Renal Allograft Outcomes: A Retrospective Cohort Study. AB - Renal function in the first year after kidney transplantation (KT) can predict long-term renal graft survival. This study investigated whether estimated glomerular filtration rate (eGFR) variability during the first year after KT is a risk factor for poor renal allograft outcomes. This retrospective cohort study included 3077 patients who underwent repeated eGFR measurements for 1 year after KT at Severance Hospital Transplantation Center between 1979 and 2012. The eGFR variability during the first year after KT was the predictor. The patients were divided into four quartile groups of eGFR variability according to the coefficient of variation for eGFR (eGFR-CV). We selected a cutoff of eGFR-CV for graft failure and performed the sensitivity analyses. The graft outcome was worse in the highest quartile group of eGFR variability than in the other groups among all patients (Q4: HR 1.631, 95% CI 1.278-2.081; p < 0.0001) and among patients without AR (Q4: HR 1.425, 95% CI 1.024-1.982; p = 0.0358) after adjusting for eGFR at 1 year after KT and other covariates. Additionally, all-cause mortality was higher in this highest quartile group than in the other groups among all patients but not among patients without AR. Higher eGFR-CVs than the cutoff were significantly associated with a high risk of graft failure among all patients (HR 1.670, 95% CI 1.395-2.000; p < 0.0001) and among patients without AR (HR 1.899, 95% CI 1.457-2.477; p < 0.0001) after fully adjusting for covariates. For all cause mortality, a higher eGFR-CV was an independent risk factor among all patients but not among patients without AR after adjusting for covariates. eGFR variability in the first year after KT is an independent risk factor for poor renal allograft outcomes. PMID- 27973555 TI - Correction: Variant Exported Blood-Stage Proteins Encoded by Plasmodium Multigene Families Are Expressed in Liver Stages Where They Are Exported into the Parasitophorous Vacuole. AB - [This corrects the article DOI: 10.1371/journal.ppat.1005917.]. PMID- 27973554 TI - Strategies for Enriching Variant Coverage in Candidate Disease Loci on a Multiethnic Genotyping Array. AB - Investigating genetic architecture of complex traits in ancestrally diverse populations is imperative to understand the etiology of disease. However, the current paucity of genetic research in people of African and Latin American ancestry, Hispanic and indigenous peoples in the United States is likely to exacerbate existing health disparities for many common diseases. The Population Architecture using Genomics and Epidemiology, Phase II (PAGE II), Study was initiated in 2013 by the National Human Genome Research Institute to expand our understanding of complex trait loci in ethnically diverse and well characterized study populations. To meet this goal, the Multi-Ethnic Genotyping Array (MEGA) was designed to substantially improve fine-mapping and functional discovery by increasing variant coverage across multiple ethnicities at known loci for metabolic, cardiovascular, renal, inflammatory, anthropometric, and a variety of lifestyle traits. Studying the frequency distribution of clinically relevant mutations, putative risk alleles, and known functional variants across multiple populations will provide important insight into the genetic architecture of complex diseases and facilitate the discovery of novel, sometimes population specific, disease associations. DNA samples from 51,650 self-identified African ancestry (17,328), Hispanic/Latino (22,379), Asian/Pacific Islander (8,640), and American Indian (653) and an additional 2,650 participants of either South Asian or European ancestry, and other reference panels have been genotyped on MEGA by PAGE II. MEGA was designed as a new resource for studying ancestrally diverse populations. Here, we describe the methodology for selecting trait-specific content for use in multi-ethnic populations and how enriching MEGA for this content may contribute to deeper biological understanding of the genetic etiology of complex disease. PMID- 27973556 TI - Application of Mixed Effects Limits of Agreement in the Presence of Multiple Sources of Variability: Exemplar from the Comparison of Several Devices to Measure Respiratory Rate in COPD Patients. AB - INTRODUCTION: The Bland-Altman limits of agreement method is widely used to assess how well the measurements produced by two raters, devices or systems agree with each other. However, mixed effects versions of the method which take into account multiple sources of variability are less well described in the literature. We address the practical challenges of applying mixed effects limits of agreement to the comparison of several devices to measure respiratory rate in patients with chronic obstructive pulmonary disease (COPD). METHODS: Respiratory rate was measured in 21 people with a range of severity of COPD. Participants were asked to perform eleven different activities representative of daily life during a laboratory-based standardised protocol of 57 minutes. A mixed effects limits of agreement method was used to assess the agreement of five commercially available monitors (Camera, Photoplethysmography (PPG), Impedance, Accelerometer, and Chest-band) with the current gold standard device for measuring respiratory rate. RESULTS: Results produced using mixed effects limits of agreement were compared to results from a fixed effects method based on analysis of variance (ANOVA) and were found to be similar. The Accelerometer and Chest-band devices produced the narrowest limits of agreement (-8.63 to 4.27 and -9.99 to 6.80 respectively) with mean bias -2.18 and -1.60 breaths per minute. These devices also had the lowest within-participant and overall standard deviations (3.23 and 3.29 for Accelerometer and 4.17 and 4.28 for Chest-band respectively). CONCLUSIONS: The mixed effects limits of agreement analysis enabled us to answer the question of which devices showed the strongest agreement with the gold standard device with respect to measuring respiratory rates. In particular, the estimated within-participant and overall standard deviations of the differences, which are easily obtainable from the mixed effects model results, gave a clear indication that the Accelerometer and Chest-band devices performed best. PMID- 27973557 TI - Encoding in Balanced Networks: Revisiting Spike Patterns and Chaos in Stimulus Driven Systems. AB - Highly connected recurrent neural networks often produce chaotic dynamics, meaning their precise activity is sensitive to small perturbations. What are the consequences of chaos for how such networks encode streams of temporal stimuli? On the one hand, chaos is a strong source of randomness, suggesting that small changes in stimuli will be obscured by intrinsically generated variability. On the other hand, recent work shows that the type of chaos that occurs in spiking networks can have a surprisingly low-dimensional structure, suggesting that there may be room for fine stimulus features to be precisely resolved. Here we show that strongly chaotic networks produce patterned spikes that reliably encode time dependent stimuli: using a decoder sensitive to spike times on timescales of 10's of ms, one can easily distinguish responses to very similar inputs. Moreover, recurrence serves to distribute signals throughout chaotic networks so that small groups of cells can encode substantial information about signals arriving elsewhere. A conclusion is that the presence of strong chaos in recurrent networks need not exclude precise encoding of temporal stimuli via spike patterns. PMID- 27973558 TI - Carbamylated Low-Density Lipoprotein (cLDL)-Mediated Induction of Autophagy and Its Role in Endothelial Cell Injury. AB - Patients with chronic kidney disease (CKD) have high risk of cardiovascular complications. Plasma levels of carbamylated proteins produced by urea-derived isocyanate or thiocyanate are elevated in CKD patients and that they are significant predictors of cardiovascular events and all-cause mortality. Carbamylated LDL (cLDL) has pro-atherogenic properties and is known to affect major biological processes relevant to atherosclerosis including endothelial cell injury. The underlying mechanisms of cLDL-induced endothelial cell injury are not well understood. Although autophagy has been implicated in atherosclerosis, cLDL mediated induction of autophagy and its role in endothelial cell injury is unknown. Our studies demonstrate that human coronary artery endothelial cells (HCAECs) respond to cLDL by specific induction of key autophagy proteins including LC3-I, beclin-1, Atg5, formation of lipid-conjugated LC3-II protein, and formation of punctate dots of autophagosome-associated LC3-II. We demonstrated that autophagy induction is an immediate response to cLDL and occurred in a dose and time-dependent manner. Inhibition of cLDL-induced autophagy by a specific siRNA to LC3 as well as by an autophagy inhibitor provided protection from cLDL-induced cell death and DNA fragmentation. Our studies demonstrate that autophagy plays an important role in cLDL-mediated endothelial cell injury and may provide one of the underlying mechanisms for the pathogenesis of cLDL-induced atherosclerosis in CKD patients. PMID- 27973559 TI - Food-Induced Emotional Resonance Improves Emotion Recognition. AB - The effect of food substances on emotional states has been widely investigated, showing, for example, that eating chocolate is able to reduce negative mood. Here, for the first time, we have shown that the consumption of specific food substances is not only able to induce particular emotional states, but more importantly, to facilitate recognition of corresponding emotional facial expressions in others. Participants were asked to perform an emotion recognition task before and after eating either a piece of chocolate or a small amount of fish sauce-which we expected to induce happiness or disgust, respectively. Our results showed that being in a specific emotional state improves recognition of the corresponding emotional facial expression. Indeed, eating chocolate improved recognition of happy faces, while disgusted expressions were more readily recognized after eating fish sauce. In line with the embodied account of emotion understanding, we suggest that people are better at inferring the emotional state of others when their own emotional state resonates with the observed one. PMID- 27973560 TI - Identification of the Functional Variant(s) that Explain the Low-Density Lipoprotein Receptor (LDLR) GWAS SNP rs6511720 Association with Lower LDL-C and Risk of CHD. AB - BACKGROUND: The Low-Density Lipoprotein Receptor (LDLR) SNP rs6511720 (G>T), located in intron-1 of the gene, has been identified in genome-wide association studies (GWAS) as being associated with lower plasma levels of LDL-C and a lower risk of coronary heart disease (CHD). Whether or not rs6511720 is itself functional or a marker for a functional variant elsewhere in the gene is not known. METHODS: The association of LDLR SNP rs6511720 with incidence of CHD and levels of LDL-C was determined by reference to CARDIoGRAM, C4D and Global lipids genetics consortium (GLGC) data. SNP annotation databases were used to identify possible SNP function and prioritization. Luciferase reporter assays in the liver cell line Huh7 were used to measure the effect of variant genotype on gene expression. Electrophoretic Mobility Shift Assays (EMSAs) were used to identify the Transcription Factors (TFs) involved in gene expression regulation. RESULTS: The phenotype-genotype analysis showed that the rs6511720 minor allele is associated with lower level of LDL-C [beta = -0.2209, p = 3.85 x10-262], and lower risk of CHD [log (OR) = 0.1155, p = 1.04 x10-7]. Rs6511720 is in complete linkage. Rs6511720 is in complete linkage disequilibrium (LD) with three intron-1 SNPs (rs141787760, rs60173709, rs57217136). Luciferase reporter assays in Huh7 cells showed that the rare alleles of both rs6511720 and rs57217136 caused a significant increase in LDLR expression compared to the common alleles (+29% and +24%, respectively). Multiplex Competitor-EMSAs (MC-EMSA) identified that the transcription factor serum response element (SRE) binds to rs6511720, while retinoic acid receptor (RAR) and signal transducer and activator of transcription 1 (STAT1) bind to rs57217136. CONCLUSION: Both LDLR rs6511720 and rs57217136 are functional variants. Both these minor alleles create enhancer-binding protein sites for TFs and may contribute to increased LDLR expression, which is consequently associated with reduced LDL-C levels and 12% lower CHD risk. PMID- 27973561 TI - Cross-Classification of Human Urinary Lipidome by Sex, Age, and Body Mass Index. AB - Technological advancements in past decades have led to the development of integrative analytical approaches to lipidomics, such as liquid chromatography mass spectrometry (LC/MS), and information about biogenic lipids is rapidly accumulating. Although several cohort-based studies have been conducted on the composition of urinary lipidome, the data on urinary lipids cross-classified by sex, age, and body mass index (BMI) are insufficient to screen for various abnormalities. To promote the development of urinary lipid metabolome-based diagnostic assay, we analyzed 60 urine samples from healthy white adults (young (c.a., 30 years) and old (c.a., 60 years) men/women) using LC/MS. Women had a higher urinary concentration of omega-3 12-lipoxygenase (LOX)-generated oxylipins with anti-inflammatory activity compared to men. In addition, young women showed increased abundance of poly-unsaturated fatty acids (PUFAs) and cytochrome P450 (P450)-produced oxylipins with anti-hypertensive activity compared with young men, whereas elderly women exhibited higher concentration of 5-LOX-generated anti inflammatory oxylipins than elderly men. There were no significant differences in urinary oxylipin levels between young and old subjects or between subjects with low and high BMI. Our findings suggest that sex, but neither ages nor BMI could be a confounding factor for measuring the composition of urinary lipid metabolites in the healthy population. The information showed contribute to the development of reliable biomarker findings from urine. PMID- 27973562 TI - The PNPLA3 Genetic Variant rs738409 Influences the Progression to Cirrhosis in HIV/Hepatitis C Virus Coinfected Patients. AB - Contradictory data about the impact of the rs738409 steatosis-related polymorphism within PNPLA3 gene on liver fibrosis progression in HIV/hepatitis C virus (HIV/HCV)-coinfected patients have been reported. Our objective was to test whether this, and other polymorphisms previously related to fatty liver disease in HIV infection linked to SAMM50 or LPPR4 genes, influence liver fibrosis progression in HIV/HCV-coinfected individuals. Three hundred and thirty two HIV/HCV-coinfected patients who consecutively attended four Spanish university hospitals from November 2011 to July 2013 were included. A liver stiffness cut off of 14.6 kPa, as determined by transient elastography, was used to diagnose cirrhosis. Liver stiffness progression was studied in 171 individuals who had two available LS determinations without anti-HCV treatment between them. Moreover, 28 HIV/HCV-coinfected patients who underwent liver transplant, as well as 19 non cirrhotic coinfected individuals used as controls, were included in an additional study. Only rs738409 was associated with cirrhosis: 45 (29.6%) of 152 G allele carriers versus 36 (20.0%) of 180 CC carriers showed cirrhosis (multivariate p = 0.018; adjusted odds ratio = 1.98; 95% confidence interval = 1.12-3.50). Also, 21 (30.4%) of 69 G allele carriers versus 16 (15.7%) of 102 CC patients showed significant liver stiffness progression (adjusted p-value = 0.015; adjusted odds ratio = 2.89; 95% confidence interval = 1.23-6.83). Finally, the proportion of rs738409 G allele carriers was significantly higher in transplanted individuals than in controls (p = 0.044, odds ratio = 3.43; 95% confidence interval = 1.01 11.70). Our results strongly suggest that the rs738409 polymorphism is associated with liver fibrosis progression in HIV/HCV-coinfected patients. PMID- 27973563 TI - Frequent Use of Emergency Departments by the Elderly Population When Continuing Care Is Not Well Established. AB - INTRODUCTION: The elderly, who suffer from multiple chronic diseases, represent a substantial proportion of Emergency Department (ED) frequent users, thus contributing to ED overcrowding, although they could benefit from other health care facilities, if those were available. The aim of this study was to evaluate and characterize hospital visits of older patients (age 65 or greater) to the ED of a university teaching hospital in Rome from the 1st of January to the 31st of December 2014, in order to identify clinical and social characteristics potentially associated with "elderly frequent users". MATERIAL AND METHODS: A retrospective study was performed during the calendar year 2014 (1st January 2014 - 31st December 2014) analyzing all ED admissions to the University Hospital of Rome Tor Vergata. Variables collected included age, triage code, arrival data, discharge diagnosis, and visit outcome. We performed a risk analysis using univariate binary logistic regression models. RESULTS: A total number of 38,016 patients accessed the ED, generating 46,820 accesses during the study period, with an average of 1.23 accesses for patient. The elderly population represented a quarter of the total ED population and had an increased risk of frequent use (OR 1.5: CI 1.4-1.7) and hospitalization (OR 3.8: CI 3.7-4). Moreover, they showed a greater diagnostic complexity, as demonstrated by the higher incidence of yellow and red priority codes compared to other ED populations (OR 3.1: CI 2.9 3.2). DISCUSSION: Older patients presented clinical and social characteristics related to the definition of "elderly frail frequent users". The fact that a larger number of hospitalizations occurred in such patients is indirect evidence of frailty in this specific population, suggesting that hospital admissions may be an inappropriate response to frailty, especially when continued care is not established. CONCLUSION: Enhancement of continuity of care, establishment of a tracking system for those who are at greater risk of visiting the ED and evaluating fragile individuals should be the highest priority in addressing ED frequent usage by the elderly. PMID- 27973564 TI - Chondroitinase C Selectively Degrades Chondroitin Sulfate Glycosaminoglycans that Inhibit Axonal Growth within the Endoneurium of Peripheral Nerve. AB - The success of peripheral nerve regeneration is highly dependent on the regrowth of axons within the endoneurial basal lamina tubes that promote target-oriented pathfinding and appropriate reinnervation. Restoration of nerve continuity at this structural level after nerve transection injury by direct repair and nerve grafting remains a major surgical challenge. Recently, biological approaches that alter the balance of growth inhibitors and promoters in nerve have shown promise to improve appropriate axonal regeneration and recovery of peripheral nerve function. Chondroitin sulfate proteoglycans (CSPGs) are known inhibitors of axonal growth. This growth inhibition is mainly associated with a CSPG's glycosaminoglycan chains. Enzymatic degradation of these chains with chondroitinase eliminates this inhibitory activity and, when applied in vivo, can improve the outcome of nerve repair. To date, these encouraging findings were obtained with chondroitinase ABC (a pan-specific chondroitinase). The aim of this study was to examine the distribution of CSPG subtypes in rodent, rabbit, and human peripheral nerve and to test more selective biological enzymatic approaches to improve appropriate axonal growth within the endoneurium and minimize aberrant growth. Here we provide evidence that the endoneurium, but not the surrounding epineurium, is rich in CSPGs that have glycosaminoglycan chains readily degraded by chondroitinase C. Biochemical studies indicate that chondroitinase C has degradation specificity for 6-sulfated glycosaminoglycans found in peripheral nerve. We found that chondroitinase C degrades and inactivates inhibitory CSPGs within the endoneurium but not so much in the surrounding nerve compartments. Cryoculture bioassays (neurons grown on tissue sections) show that chondroitinase C selectively and significantly enhanced neuritic growth associated with the endoneurial basal laminae without changing growth-inhibiting properties of the surrounding epineurium. Interestingly, chondroitinase ABC treatment increased greatly the growth-promoting properties of the epineurial tissue whereas chondroitinase C had little effect. Our evidence indicates that chondroitinase C effectively degrades and inactivates inhibitory CSPGs present in the endoneurial Schwann cell basal lamina and does so more specifically than chondroitinase ABC. These findings are discussed in the context of improving nerve repair and regeneration and the growth-promoting properties of processed nerve allografts. PMID- 27973566 TI - When Optimal Feedback Control Is Not Enough: Feedforward Strategies Are Required for Optimal Control with Active Sensing. AB - Movement planning is thought to be primarily determined by motor costs such as inaccuracy and effort. Solving for the optimal plan that minimizes these costs typically leads to specifying a time-varying feedback controller which both generates the movement and can optimally correct for errors that arise within a movement. However, the quality of the sensory feedback during a movement can depend substantially on the generated movement. We show that by incorporating such state-dependent sensory feedback, the optimal solution incorporates active sensing and is no longer a pure feedback process but includes a significant feedforward component. To examine whether people take into account such state dependency in sensory feedback we asked people to make movements in which we controlled the reliability of sensory feedback. We made the visibility of the hand state-dependent, such that the visibility was proportional to the component of hand velocity in a particular direction. Subjects gradually adapted to such a sensory perturbation by making curved hand movements. In particular, they appeared to control the late visibility of the movement matching predictions of the optimal controller with state-dependent sensory noise. Our results show that trajectory planning is not only sensitive to motor costs but takes sensory costs into account and argues for optimal control of movement in which feedforward commands can play a significant role. PMID- 27973565 TI - Nutritional Profile and Chemical Stability of Pasta Fortified with Tilapia (Oreochromis niloticus) Flour. AB - Physicochemical parameters of pasta enriched with tilapia (Oreochromis niloticus) flour were investigated. Five formulations were prepared with different concentrations of tilapia flour as partial substitute of wheat flour: pasta without tilapia flour (PTF0%), pasta with 6% (PTF6%), 12% (PTF12%), 17% (PTF17%), and 23% (PTF23%) of tilapia flour. The formulations were assessed for proximate composition, fatty acid and amino acid profile on day 1 whereas, instrumental color parameters (L*, a* and b* values), pH, water activity (aw), and lipid and protein oxidation were evaluated on days 1, 7, 14, and 21 of storage at 25 degrees C. Fortification with tilapia flour increased (p < 0.05) protein, lipid, ash, total essential amino acids, and total polyunsaturated fatty acids contents. In addition, supplementation of pasta with tilapia flour decreased (p < 0.05) lightness and water activity while redness, yellowness, pH values, and lipid oxidation were increased (p < 0.05) in a level-dependent manner. Nevertheless, all formulations were exhibited storage stability at 25 degrees C. In general, protein oxidation was greater (p < 0.05) in the pasta containing 12%, 17%, and 23% of tilapia flour than their counterparts, and the storage promoted an increase (p < 0.05) on the carbonyl content in all formulations. Thus, pasta with 6% of tilapia flour has the potential to be a technological alternative to food industry for the nutritional enrichment of traditional pasta with negligible negative effects on the chemical stability of the final product during 21 days at 25 degrees C. PMID- 27973568 TI - Yessotoxin, a Marine Toxin, Exhibits Anti-Allergic and Anti-Tumoural Activities Inhibiting Melanoma Tumour Growth in a Preclinical Model. AB - Yessotoxins (YTXs) are a group of marine toxins produced by the dinoflagellates Protoceratium reticulatum, Lingulodinium polyedrum and Gonyaulax spinifera. They may have medical interest due to their potential role as anti-allergic but also anti-cancer compounds. However, their biological activities remain poorly characterized. Here, we show that the small molecular compound YTX causes a slight but significant reduction of the ability of mast cells to degranulate. Strikingly, further examination revealed that YTX had a marked and selective cytotoxicity for the RBL-2H3 mast cell line inducing apoptosis, while primary bone marrow derived mast cells were highly resistant. In addition, YTX exhibited strong cytotoxicity against the human B-chronic lymphocytic leukaemia cell line MEC1 and the murine melanoma cell line B16F10. To analyse the potential role of YTX as an anti-cancer drug in vivo we used the well-established B16F10 melanoma preclinical mouse model. Our results demonstrate that a few local application of YTX around established tumours dramatically diminished tumour growth in the absence of any significant toxicity as determined by the absence of weight loss and haematological alterations. Our data support that YTX may have a minor role as an anti-allergic drug, but reveals an important potential for its use as an anti-cancer drug. PMID- 27973567 TI - Utility of a Lateral Flow Immunoassay (LFI) to Detect Burkholderia pseudomallei in Soil Samples. AB - BACKGROUND: Culture is the gold standard for the detection of environmental B. pseudomallei. In general, soil specimens are cultured in enrichment broth for 2 days, and then the culture broth is streaked on an agar plate and incubated further for 7 days. However, identifying B. pseudomallei on the agar plates among other soil microbes requires expertise and experience. Here, we evaluate a lateral flow immunoassay (LFI) developed to detect B. pseudomallei capsular polysaccharide (CPS) in clinical samples as a tool to detect B. pseudomallei in environmental samples. METHODOLOGY/PRINCIPAL FINDINGS: First, we determined the limit of detection (LOD) of LFI for enrichment broth of the soil specimens. Soil specimens (10 grams/specimen) culture negative for B. pseudomallei were spiked with B. pseudomallei ranging from 10 to 105 CFU, and incubated in 10 ml of enrichment broth in air at 40 degrees C. Then, on day 2, 4 and 7 of incubation, 50 MUL of the upper layer of the broth were tested on the LFI, and colony counts to determine quantity of B. pseudomallei in the broth were performed. We found that all five soil specimens inoculated at 10 CFU were negative by LFI on day 2, but four of those five specimens were LFI positive on day 7. The LOD of the LFI was estimated to be roughly 3.8x106 CFU/ml, and culture broth on day 7 was selected as the optimal sample for LFI testing. Second, we evaluated the utility of the LFI by testing 105 soil samples from Northeast Thailand. All samples were also tested by standard culture and quantitative PCR (qPCR) targeting orf2. Of 105 soil samples, 35 (33%) were LFI positive, 25 (24%) were culture positive for B. pseudomallei, and 79 (75%) were qPCR positive. Of 11 LFI positive but standard culture negative specimens, six were confirmed by having the enrichment broth on day 7 culture positive for B. pseudomallei, and an additional three by qPCR. The LFI had 97% (30/31) sensitivity to detect soil specimens culture positive for B. pseudomallei. CONCLUSIONS/SIGNIFICANCE: The LFI can be used to detect B. pseudomallei in soil samples, and to select which samples should be sent to reference laboratories or proceed further for bacterial isolation and confirmation. This could considerably decrease laboratory workload and assist the development of a risk map for melioidosis in resource-limited settings. PMID- 27973570 TI - Use of Fluorescence Lifetime Imaging Microscopy (FLIM) as a Timer of Cell Cycle S Phase. AB - Incorporation of thymidine analogues in replicating DNA, coupled with antibody and fluorophore staining, allows analysis of cell proliferation, but is currently limited to monolayer cultures, fixed cells and end-point assays. We describe a simple microscopy imaging method for live real-time analysis of cell proliferation, S phase progression over several division cycles, effects of anti proliferative drugs and other applications. It is based on the prominent (~ 1.7 fold) quenching of fluorescence lifetime of a common cell-permeable nuclear stain, Hoechst 33342 upon the incorporation of 5-bromo-2'-deoxyuridine (BrdU) in genomic DNA and detection by fluorescence lifetime imaging microscopy (FLIM). We show that quantitative and accurate FLIM technique allows high-content, multi parametric dynamic analyses, far superior to the intensity-based imaging. We demonstrate its uses with monolayer cell cultures, complex 3D tissue models of tumor cell spheroids and intestinal organoids, and in physiological study with metformin treatment. PMID- 27973569 TI - Variations on a Theme: Antennal Lobe Architecture across Coleoptera. AB - Beetles comprise about 400,000 described species, nearly one third of all known animal species. The enormous success of the order Coleoptera is reflected by a rich diversity of lifestyles, behaviors, morphological, and physiological adaptions. All these evolutionary adaptions that have been driven by a variety of parameters over the last about 300 million years, make the Coleoptera an ideal field to study the evolution of the brain on the interface between the basic bauplan of the insect brain and the adaptions that occurred. In the current study we concentrated on the paired antennal lobes (AL), the part of the brain that is typically responsible for the first processing of olfactory information collected from olfactory sensilla on antenna and mouthparts. We analyzed 63 beetle species from 22 different families and thus provide an extensive comparison of principal neuroarchitecture of the AL. On the examined anatomical level, we found a broad diversity including AL containing a wide range of glomeruli numbers reaching from 50 to 150 glomeruli and several species with numerous small glomeruli, resembling the microglomerular design described in acridid grasshoppers and diving beetles, and substructures within the glomeruli that have to date only been described for the small hive beetle, Aethina tumida. A first comparison of the various anatomical features of the AL with available descriptions of lifestyle and behaviors did so far not reveal useful correlations. In summary, the current study provides a solid basis for further studies to unravel mechanisms that are basic to evolutionary adaptions of the insect olfactory system. PMID- 27973571 TI - Non-Publication Is Common among Phase 1, Single-Center, Not Prospectively Registered, or Early Terminated Clinical Drug Trials. AB - The objective of this study was to investigate the occurrence and determinants of non-publication of clinical drug trials in the Netherlands.All clinical drug trials reviewed by the 28 Institutional Review Boards (IRBs) in the Netherlands in 2007 were followed-up from approval to publication. Candidate determinants were the sponsor, phase, applicant, centers, therapeutic effect expected, type of trial, approval status of the drug(s), drug type, participant category, oncology or other disease area, prospective registration, and early termination. The main outcome was publication as peer reviewed article. The percentage of trials that were published, crude and adjusted odds ratio (OR), and 95% confidence interval (CI) were used to quantify the associations between determinants and publication. In 2007, 622 clinical drug trials were reviewed by IRBs in the Netherlands. By the end of follow-up, 19 of these were rejected by the IRB, another 19 never started inclusion, and 10 were still running. Of the 574 trials remaining in the analysis, 334 (58%) were published as peer-reviewed article. The multivariable logistic regression model identified the following determinants with a robust, statistically significant association with publication: phase 2 (60% published; adjusted OR 2.6, 95% CI 1.1-5.9), phase 3 (73% published; adjusted OR 4.1, 95% CI 1.7-10.0), and trials not belonging to phase 1-4 (60% published; adjusted OR 3.2, 95% CI 1.5 to 6.5) compared to phase 1 trials (35% published); trials with a company or investigator as applicant (63% published) compared to trials with a Contract Research Organization (CRO) as applicant (50% published; adjusted OR 1.7; 95% CI 1.1-2.8); and multicenter trials also conducted in other EU countries (68% published; adjusted OR 2.2, 95% CI 1.1-4.4) or also outside the European Union (72% published; adjusted OR 2.0, 95% CI 1.0-4.0) compared to single-center trials (45% published). Trials that were not prospectively registered (48% published) had a lower likelihood of publication compared to prospectively registered trials (75% published; adjusted OR 0.5, 95% CI 0.3-0.8), as well as trials that were terminated early (33% published) compared to trials that were completed as planned (64% published; adjusted OR 0.2, 95% CI 0.1-0.3). The non publication rate of clinical trials seems to have improved compared to previous inception cohorts, but is still far from optimal, in particular among phase 1, single-center, not prospectively registered, and early terminated trials. PMID- 27973573 TI - Characterizing the Mechanical Properties of Running-Specific Prostheses. AB - The mechanical stiffness of running-specific prostheses likely affects the functional abilities of athletes with leg amputations. However, each prosthetic manufacturer recommends prostheses based on subjective stiffness categories rather than performance based metrics. The actual mechanical stiffness values of running-specific prostheses (i.e. kN/m) are unknown. Consequently, we sought to characterize and disseminate the stiffness values of running-specific prostheses so that researchers, clinicians, and athletes can objectively evaluate prosthetic function. We characterized the stiffness values of 55 running-specific prostheses across various models, stiffness categories, and heights using forces and angles representative of those measured from athletes with transtibial amputations during running. Characterizing prosthetic force-displacement profiles with a 2nd degree polynomial explained 4.4% more of the variance than a linear function (p<0.001). The prosthetic stiffness values of manufacturer recommended stiffness categories varied between prosthetic models (p<0.001). Also, prosthetic stiffness was 10% to 39% less at angles typical of running 3 m/s and 6 m/s (10 degrees -25 degrees ) compared to neutral (0 degrees ) (p<0.001). Furthermore, prosthetic stiffness was inversely related to height in J-shaped (p<0.001), but not C shaped, prostheses. Running-specific prostheses should be tested under the demands of the respective activity in order to derive relevant characterizations of stiffness and function. In all, our results indicate that when athletes with leg amputations alter prosthetic model, height, and/or sagittal plane alignment, their prosthetic stiffness profiles also change; therefore variations in comfort, performance, etc. may be indirectly due to altered stiffness. PMID- 27973572 TI - Zoonotic Cryptosporidium Species in Animals Inhabiting Sydney Water Catchments. AB - Cryptosporidium is one of the most common zoonotic waterborne parasitic diseases worldwide and represents a major public health concern of water utilities in developed nations. As animals in catchments can shed human-infectious Cryptosporidium oocysts, determining the potential role of animals in dissemination of zoonotic Cryptosporidium to drinking water sources is crucial. In the present study, a total of 952 animal faecal samples from four dominant species (kangaroos, rabbits, cattle and sheep) inhabiting Sydney's drinking water catchments were screened for the presence of Cryptosporidium using a quantitative PCR (qPCR) and positives sequenced at multiple loci. Cryptosporidium species were detected in 3.6% (21/576) of kangaroos, 7.0% (10/142) of cattle, 2.3% (3/128) of sheep and 13.2% (14/106) of rabbit samples screened. Sequence analysis of a region of the 18S rRNA locus identified C. macropodum and C. hominis in 4 and 17 isolates from kangaroos respectively, C. hominis and C. parvum in 6 and 4 isolates respectively each from cattle, C. ubiquitum in 3 isolates from sheep and C. cuniculus in 14 isolates from rabbits. All the Cryptosporidium species identified were zoonotic species with the exception of C. macropodum. Subtyping using the 5' half of gp60 identified C. hominis IbA10G2 (n = 12) and IdA15G1 (n = 2) in kangaroo faecal samples; C. hominis IbA10G2 (n = 4) and C. parvum IIaA18G3R1 (n = 4) in cattle faecal samples, C. ubiquitum subtype XIIa (n = 1) in sheep and C. cuniculus VbA23 (n = 9) in rabbits. Additional analysis of a subset of samples using primers targeting conserved regions of the MIC1 gene and the 3' end of gp60 suggests that the C. hominis detected in these animals represent substantial variants that failed to amplify as expected. The significance of this finding requires further investigation but might be reflective of the ability of this C. hominis variant to infect animals. The finding of zoonotic Cryptosporidium species in these animals may have important implications for the management of drinking water catchments to minimize risk to public health. PMID- 27973574 TI - Ginkgolide B Exerts Cardioprotective Properties against Doxorubicin-Induced Cardiotoxicity by Regulating Reactive Oxygen Species, Akt and Calcium Signaling Pathways In Vitro and In Vivo. AB - The aim of this study was to evaluate the effect of Ginkgolide B (GB) on doxorubicin (DOX) induced cardiotoxicity in vitro and in vivo. Rat cardiomyocyte cell line H9c2 was pretreated with GB and subsequently subjected to doxorubicin treatment. Cell viability and cell apoptosis were assessed by MTT assay and Hoechst staining, respectively. Reactive oxygen species (ROS), Akt phosphorylation and intracellular calcium were equally determined in order to explore the underlying molecular mechanism. To verify the in vivo therapeutic effect of GB, we established a mouse model of cardiotoxicity and determined left ventricle ejection fraction (LVEF) and left ventricular mass (LVM). The in vitro experimental results indicated that pretreatment with GB significantly decreases the viability and apoptosis of H9c2 cells by decreasing ROS and intracellular calcium levels and activating Akt phosphorylation. In the in vivo study, we recorded an improved LVEF and a decreased LVM in the group of cardiotoxic rats treated with GB. Altogether, our findings anticipate that GB exerts a cardioprotective effect through possible regulation of the ROS, Akt and calcium pathways. The findings suggest that combination of GB with DOX in chemotherapy could help avoid the cardiotoxic side effects of GB. PMID- 27973575 TI - ANCA-Associated Glomerulonephritis: Risk Factors for Renal Relapse. AB - Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild-moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray's regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8 14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray's model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different. PMID- 27973576 TI - The Rim and the Ancient Mariner: The Nautical Horizon Affects Postural Sway in Older Adults. AB - On land, the spatial magnitude of postural sway (i.e., the amount of sway) tends to be greater when participants look at the horizon than when they look at nearby targets. By contrast, on ships at sea, the spatial magnitude of postural sway in young adults has been greater when looking at nearby targets and less when looking at the horizon. Healthy aging is associated with changes in the movement patterns of the standing body sway, and these changes typically are interpreted in terms of age-related declines in the ability to control posture. To further elucidate the mechanisms associated with these changes we investigated control of posture in a setting that poses substantial postural challenges; standing on a ship at sea. In particular, we explored postural sway on a ship at sea when older adults looked at the horizon or at nearby targets. We evaluated the kinematics of the center of pressure in terms of spatial magnitude (i.e., the amount of sway) and multifractality (a measure of temporal dynamics). We found that looking at the horizon significantly affected the multifractality of standing body, but did not systematically influence the spatial magnitude of sway. We discuss the results in terms of age-related changes in the perception and control of dynamic body orientation. PMID- 27973578 TI - Strain-Dependent Transcriptome Signatures for Robustness in Lactococcus lactis. AB - Recently, we demonstrated that fermentation conditions have a strong impact on subsequent survival of Lactococcus lactis strain MG1363 during heat and oxidative stress, two important parameters during spray drying. Moreover, employment of a transcriptome-phenotype matching approach revealed groups of genes associated with robustness towards heat and/or oxidative stress. To investigate if other strains have similar or distinct transcriptome signatures for robustness, we applied an identical transcriptome-robustness phenotype matching approach on the L. lactis strains IL1403, KF147 and SK11, which have previously been demonstrated to display highly diverse robustness phenotypes. These strains were subjected to an identical fermentation regime as was performed earlier for strain MG1363 and consisted of twelve conditions, varying in the level of salt and/or oxygen, as well as fermentation temperature and pH. In the exponential phase of growth, cells were harvested for transcriptome analysis and assessment of heat and oxidative stress survival phenotypes. The variation in fermentation conditions resulted in differences in heat and oxidative stress survival of up to five 10 log units. Effects of the fermentation conditions on stress survival of the L. lactis strains were typically strain-dependent, although the fermentation conditions had mainly similar effects on the growth characteristics of the different strains. By association of the transcriptomes and robustness phenotypes highly strain-specific transcriptome signatures for robustness towards heat and oxidative stress were identified, indicating that multiple mechanisms exist to increase robustness and, as a consequence, robustness of each strain requires individual optimization. However, a relatively small overlap in the transcriptome responses of the strains was also identified and this generic transcriptome signature included genes previously associated with stress (ctsR and lplL) and novel genes, including nanE and genes encoding transport proteins. The transcript levels of these genes can function as indicators of robustness and could aid in selection of fermentation parameters, potentially resulting in more optimal robustness during spray drying. PMID- 27973577 TI - Poly(Lactic Acid) Nanoparticles Targeting alpha5beta1 Integrin as Vaccine Delivery Vehicle, a Prospective Study. AB - Biodegradable polymeric nanoparticles are vehicles of choice for drug delivery and have the ability to encapsulate and present at their surface different molecules of interest. Among these bio-nanocarriers, poly(lactic acid) (PLA) nanoparticles have been used as adjuvant and vehicle for enhanced vaccine efficacy. In order to develop an approach to efficient vaccine delivery, we developed nanoparticles to target alpha5beta1 positive cells. We first overproduced, in bacteria, human fibronectin FNIII9/10 recombinant proteins possessing an integrin alpha5beta1 binding site, the RGDS sequence, or a mutated form of this site. After having confirmed the integrin binding properties of these recombinant proteins in cell culture assays, we were able to formulate PLA nanoparticles with these FNIII9/10 proteins at their surface. We then confirmed, by fluorescence and confocal microscopy, an enhanced cellular uptake by alpha5beta1+ cells of RGDS-FNIII9/10 coated PLA nanoparticles, in comparison to KGES-FNIII9/10 coated or non-coated controls. As a first vaccination approach, we prepared PLA nanoparticles co-coated with p24 (an HIV antigen), and RGDS- or KGES FNIII9/10 proteins, followed by subcutaneous vaccine administration, in mice. Although we did not detect improvements in the apparent humoral response to p24 antigen in the serum of RGDS/p24 nanoparticle-treated mice, the presence of the FNIII proteins increased significantly the avidity index of anti-p24 antibodies compared to p24-nanoparticle-injected control mice. Future developments of this innovative targeted vaccine are discussed. PMID- 27973579 TI - Knockdown of CREB3/Luman by shRNA in Mouse Granulosa Cells Results in Decreased Estradiol and Progesterone Synthesis and Promotes Cell Proliferation. AB - Luman (also known as LZIP or CREB3) is a transcription factor and a member of the cAMP responsive element-binding (CREB) family proteins. Although Luman has been detected in apoptotic granulosa cells and disorganized atretic bodies, the physiological function of Luman in follicular development has not been reported. Our objective is to determine the role of Luman in folliculogenesis by knocking down Luman expression in mouse GCs (granulosa cells) using shRNA. Luman expression was successfully knocked down in mouse GCs at the mRNA and protein level, as confirmed by real-time quantitative PCR, western blot and immunofluorescence staining, respectively. Knockdown of Luman significantly decreased the concentrations of estradiol (E2) and progesterone (P4) in cell culture medium. Furthermore, Luman knockdown promoted cell proliferation but had no effect on cell apoptosis. To elucidate the regulatory mechanism underlying the effects of Luman knockdown on steroid synthesis and cell cycle, we measured the mRNA and protein expression levels of several related genes. The expression of Star, Cyp19a1, and Cyp1b1, which encode steroidogenic enzymes, was down regulated, while that of Cyp11a1 and Runx2, which also encode steroidogenic enzymes, was up-regulated. The expression of the cell cycle factors Cyclin A1, Cyclin B1, Cyclin D2, and Cyclin E was significantly up-regulated. Among apoptosis-related genes, only Bcl-2 was down-regulated, while Caspase 3, Bax and p53 were not significantly affected, suggesting that Luman knockdown may regulate cell cycle activity and hormone secretion at the transcriptional and translational level in mouse GCs. The expression of two important genes associated with folliculogenesis in mouse GCs, Has2 and Ptgs2, were also significantly altered by Luman knockdown. In conclusion, the findings of this study indicate that Luman regulates mouse GCs modulation of steroid synthesis, cell cycle activity and other regulators of folliculogenesis. PMID- 27973580 TI - A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is an inherited disease of the heart muscle characterized by otherwise unexplained thickening of the left ventricle. Left ventricular outflow tract (LVOT) obstruction is present in approximately two thirds of patients and substantially increases the risk of disease complications. Invasive treatment with septal myectomy or alcohol septal ablation can improve symptoms and functional status, but currently available drugs for reducing obstruction have pleiotropic effects and variable therapeutic responses. New medical treatments with more targeted pharmacology are needed, but the lack of preclinical animal models for HCM with LVOT obstruction has limited their development. HCM is a common cause of heart failure in cats, and a subset exhibit systolic anterior motion of the mitral valve leading to LVOT obstruction. MYK-461 is a recently-described, mechanistically novel small molecule that acts at the sarcomere to specifically inhibit contractility that has been proposed as a treatment for HCM. Here, we use MYK-461 to test whether direct reduction in contractility is sufficient to relieve LVOT obstruction in feline HCM. We evaluated mixed-breed cats in a research colony derived from a Maine Coon/mixed breed founder with naturally-occurring HCM. By echocardiography, we identified five cats that developed systolic anterior motion of the mitral valve and LVOT obstruction both at rest and under anesthesia when provoked with an adrenergic agonist. An IV MYK-461 infusion and echocardiography protocol was developed to serially assess contractility and LVOT gradient at multiple MYK-461 concentrations. Treatment with MYK-461 reduced contractility, eliminated systolic anterior motion of the mitral valve and relieved LVOT pressure gradients in an exposure-dependent manner. Our findings provide proof of principle that acute reduction in contractility with MYK-461 is sufficient to relieve LVOT obstruction. Further, these studies suggest that feline HCM will be a valuable translational model for the study of disease pathology, particularly LVOT obstruction. PMID- 27973582 TI - Relationship of Iron Deficiency and Serum Ferritin Levels with Pulmonary Hypertension: The Jackson Heart Study. AB - PURPOSE: Iron deficiency is prevalent in idiopathic pulmonary arterial hypertension (IPAH), but whether iron deficiency or ferritin levels are associated with pulmonary hypertension (PH) in the general population is unknown. METHODS: We performed a cross-sectional analysis of data on iron deficiency (exposure), and PH (pulmonary artery systolic pressure>40mmHg on echocardiogram) (outcome) on subjects with complete data on exposures and outcomes as well as covariates (n = 2,800) enrolled in the Jackson Heart Study, a longitudinal prospective observational cohort study of heart disease in African-Americans from Jackson, Mississippi. Iron deficiency was defined as a serum ferritin level < 15ng/mL (females); < 30ng/mL (males). We determined crude prevalence ratios (PRs) for PH in iron deficient versus non-iron deficient groups using modified Poisson regression modeling. We also analyzed the prevalence of PH by sex-specific quartiles of ferritin (Females <= 47ng/mL; > 47ng/mL- 95ng/mL; > 95ng/mL- 171ng/mL; > 171ng/mL; Males <= 110ng/mL; > 110ng/mL- 182ng/mL; > 182ng/mL- 294ng/mL; > 294ng/mL), using the same modeling technique with the lowest quartile as the referent. RESULTS: Median pulmonary artery systolic pressure was 27mmHg (interquartile range 23-31mmHg) in the study cohort. 147 subjects (5.2%) had PH and 140 (5.0%) had iron deficiency. However, of the 147 subjects with PH, only 4 were also iron deficient. The crude PH PR was 0.5 (95% CI 0.2-1.4) in iron deficiency compared to non-deficient. In analysis by quartiles of ferritin, adjusting for age and sex, there was no evidence of association with PH in quartiles 2 (PR 1.1, 95% CI 0.7-1.6), 3 (PR 0.8, 95% CI 0.5-1.3), or 4 (PR 0.8, 95% CI 0.5-1.2) compared with quartile 1 (referent group, PR 1). Further analyses of the relationship between PH and ferritin as a log-transformed continuous variable or by quartiles of serum iron showed similar results. CONCLUSIONS: In the Jackson Heart Study, the prevalence of PH was similar in iron-deficient and non-iron deficient subjects. There was no evidence of association between ferritin (or serum iron) levels and PH. CLINICAL IMPLICATIONS: Iron deficiency has been associated with IPAH, a rare disorder. However, in a large community based sample of African-Americans, there was no evidence that iron deficiency or low iron levels were associated with PH. PMID- 27973581 TI - The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review. AB - IMPORTANCE: Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in neurodegenerative diseases (ND) such as Alzheimer's disease (AD) and Parkinson's disease (PD). OBJECTIVE: To systematically review studies investigating epigenetic marks in AD or PD. METHODS: Eleven bibliographic databases (Embase.com, Medline (Ovid), Web of-Science, Scopus, PubMed, Cinahl (EBSCOhost), Cochrane Central, ProQuest, Lilacs, Scielo and Google Scholar) were searched until July 11th 2016 to identify relevant articles. We included all randomized controlled trials, cohort, case control and cross-sectional studies in humans that examined associations between epigenetic marks and ND. Two independent reviewers, with a third reviewer available for disagreements, performed the abstract and full text selection. Data was extracted using a pre-designed data collection form. RESULTS: Of 6,927 searched references, 73 unique case-control studies met our inclusion criteria. Overall, 11,453 individuals were included in this systematic review (2,640 AD and 2,368 PD outcomes). There was no consistent association between global DNA methylation pattern and any ND. Studies reported epigenetic regulation of 31 genes (including cell communication, apoptosis, and neurogenesis genes in blood and brain tissue) in relation to AD and PD. Methylation at the BDNF, SORBS3 and APP genes in AD were the most consistently reported associations. Methylation of alpha-synuclein gene (SNCA) was also found to be associated with PD. Seven studies reported histone protein alterations in AD and PD. CONCLUSION: Many studies have investigated epigenetics and ND. Further research should include larger cohort or longitudinal studies, in order to identify clinically significant epigenetic changes. Identifying relevant epigenetic changes could lead to interventional strategies in ND. PMID- 27973584 TI - Implications of Fine-Grained Habitat Fragmentation and Road Mortality for Jaguar Conservation in the Atlantic Forest, Brazil. AB - Jaguar (Panthera onca) populations in the Upper Parana River, in the Brazilian Atlantic Forest region, live in a landscape that includes highly fragmented areas as well as relatively intact ones. We developed a model of jaguar habitat suitability in this region, and based on this habitat model, we developed a spatially structured metapopulation model of the jaguar populations in this area to analyze their viability, the potential impact of road mortality on the populations' persistence, and the interaction between road mortality and habitat fragmentation. In more highly fragmented populations, density of jaguars per unit area is lower and density of roads per jaguar is higher. The populations with the most fragmented habitat were predicted to have much lower persistence in the next 100 years when the model included no dispersal, indicating that the persistence of these populations are dependent to a large extent on dispersal from other populations. This, in turn, indicates that the interaction between road mortality and habitat fragmentation may lead to source-sink dynamics, whereby populations with highly fragmented habitat are maintained only by dispersal from populations with less fragmented habitat. This study demonstrates the utility of linking habitat and demographic models in assessing impacts on species living in fragmented landscapes. PMID- 27973585 TI - Impacts of Steel-Slag-Based Silicate Fertilizer on Soil Acidity and Silicon Availability and Metals-Immobilization in a Paddy Soil. AB - Slag-based silicate fertilizer has been widely used to improve soil silicon- availability and crop productivity. A consecutive early rice-late rice rotation experiment was conducted to test the impacts of steel slag on soil pH, silicon availability, rice growth and metals-immobilization in paddy soil. Our results show that application of slag at a rate above higher or equal to 1 600 mg plant available SiO2 per kg soil increased soil pH, dry weight of rice straw and grain, plant-available Si concentration and Si concentration in rice shoots compared with the control treatment. No significant accumulation of total cadmium (Cd) and lead (Pb) was noted in soil; rather, the exchangeable fraction of Cd significantly decreased. The cadmium concentrations in rice grains decreased significantly compared with the control treatment. In conclusion, application of steel slag reduced soil acidity, increased plant-availability of silicon, promoted rice growth and inhibited Cd transport to rice grain in the soil-plant system. PMID- 27973583 TI - Structure and Mechanism of Staphylococcus aureus TarS, the Wall Teichoic Acid beta-glycosyltransferase Involved in Methicillin Resistance. AB - In recent years, there has been a growing interest in teichoic acids as targets for antibiotic drug design against major clinical pathogens such as Staphylococcus aureus, reflecting the disquieting increase in antibiotic resistance and the historical success of bacterial cell wall components as drug targets. It is now becoming clear that beta-O-GlcNAcylation of S. aureus wall teichoic acids plays a major role in both pathogenicity and antibiotic resistance. Here we present the first structure of S. aureus TarS, the enzyme responsible for polyribitol phosphate beta-O-GlcNAcylation. Using a divide and conquer strategy, we obtained crystal structures of various TarS constructs, mapping high resolution overlapping N-terminal and C-terminal structures onto a lower resolution full-length structure that resulted in a high resolution view of the entire enzyme. Using the N-terminal structure that encapsulates the catalytic domain, we furthermore captured several snapshots of TarS, including the native structure, the UDP-GlcNAc donor complex, and the UDP product complex. These structures along with structure-guided mutants allowed us to elucidate various catalytic features and identify key active site residues and catalytic loop rearrangements that provide a valuable platform for anti-MRSA drug design. We furthermore observed for the first time the presence of a trimerization domain composed of stacked carbohydrate binding modules, commonly observed in starch active enzymes, but adapted here for a poly sugar-phosphate glycosyltransferase. PMID- 27973587 TI - How Elephant Seals (Mirounga leonina) Adjust Their Fine Scale Horizontal Movement and Diving Behaviour in Relation to Prey Encounter Rate. AB - Understanding the diving behaviour of diving predators in relation to concomitant prey distribution could have major practical applications in conservation biology by allowing the assessment of how changes in fine scale prey distribution impact foraging efficiency and ultimately population dynamics. The southern elephant seal (Mirounga leonina, hereafter SES), the largest phocid, is a major predator of the southern ocean feeding on myctophids and cephalopods. Because of its large size it can carry bio-loggers with minimal disturbance. Moreover, it has great diving abilities and a wide foraging habitat. Thus, the SES is a well suited model species to study predator diving behaviour and the distribution of ecologically important prey species in the Southern Ocean. In this study, we examined how SESs adjust their diving behaviour and horizontal movements in response to fine scale prey encounter densities using high resolution accelerometers, magnetometers, pressure sensors and GPS loggers. When high prey encounter rates were encountered, animals responded by (1) diving and returning to the surface with steeper angles, reducing the duration of transit dive phases (thus improving dive efficiency), and (2) exhibiting more horizontally and vertically sinuous bottom phases. In these cases, the distance travelled horizontally at the surface was reduced. This behaviour is likely to counteract horizontal displacement from water currents, as they try to remain within favourable prey patches. The prey encounter rate at the bottom of dives decreased with increasing diving depth, suggesting a combined effect of decreased accessibility and prey density with increasing depth. Prey encounter rate also decreased when the bottom phases of dives were spread across larger vertical extents of the water column. This result suggests that the vertical aggregation of prey can regulate prey density, and as a consequence impact the foraging success of SESs. To our knowledge, this is one of only a handful of studies showing how the vertical distributions and structure of prey fields influence the prey encounter rates of a diving predator. PMID- 27973586 TI - Characterization of the Fishing Lines in Titiwai (=Arachnocampa luminosa Skuse, 1890) from New Zealand and Australia. AB - Animals use adhesive secretions in a plethora of ways, either for attachment, egg anchorage, mating or as either active or passive defence. The most interesting function, however, is the use of adhesive threads to capture prey, as the bonding must be performed within milliseconds and under unsuitable conditions (movement of prey, variable environmental conditions, unfavourable attack angle, etc.) to be nonetheless successful. In the following study a detailed characterization of the prey capture system of the world-renowned glowworm group Arachnocampa from the macroscopic to the ultrastructural level is performed. The data reveal that the adhesive droplets consist mostly of water and display hygroscopic properties at varying humidity levels. The droplet core of Arachnocampa luminosa includes a certain amount of the elements sodium, sulphur and potassium (beside carbon, oxygen and nitrogen), while a different element composition is found in the two related species A. richardsae and A. tasmaniensis. Evidence for lipids, carbohydrates and proteins was negative on the histochemical level, however X-ray photoelectron spectroscopy confirm the presence of peptides within the droplet content. Different to earlier assumptions, the present study indicates that rather than oxalic acid, urea or uric acid are present in the adhesive droplets, presumably originating from the gut. Comparing the capture system in Arachnocampa with those of orb-spiders, large differences appear not only regarding the silky threads, but also, in the composition, hygroscopic properties and size of the mucous droplets. PMID- 27973589 TI - Cryptic Species Due to Hybridization: A Combined Approach to Describe a New Species (Carex: Cyperaceae). AB - Disappearance of diagnostic morphological characters due to hybridization is considered to be one of the causes of the complex taxonomy of the species-rich (ca. 2000 described species) genus Carex (Cyperaceae). Carex furva s.l. belongs to section Glareosae. It is an endemic species from the high mountains of the Iberian Peninsula (Spain and Portugal). Previous studies suggested the existence of two different, cryptic taxa within C. furva s.l. Intermediate morphologies found in the southern Iberian Peninsula precluded the description of a new taxa. We aimed to determine whether C. furva s.l. should be split into two different species based on the combination of morphological and molecular data. We sampled ten populations across its full range and performed a morphological study based on measurements on herbarium specimens and silica-dried inflorescences. Both morphological and phylogenetic data support the existence of two different species within C. furva s.l. Nevertheless, intermediate morphologies and sterile specimens were found in one of the southern populations (Sierra Nevada) of C. furva s.l., suggesting the presence of hybrid populations in areas where both supposed species coexist. Hybridization between these two putative species has blurred morphological and genetic limits among them in this hybrid zone. We have proved the utility of combining molecular and morphological data to discover a new cryptic species in a scenario of hybridization. We now recognize a new species, C. lucennoiberica, endemic to the Iberian Peninsula (Sierra Nevada, Central system and Cantabrian Mountains). On the other hand, C. furva s.s. is distributed only in Sierra Nevada, where it may be threatened by hybridization with C. lucennoiberica. The restricted distribution of both species and their specific habitat requirements are the main limiting factors for their conservation. PMID- 27973588 TI - Within Host Evolution Selects for a Dominant Genotype of Mycobacterium tuberculosis while T Cells Increase Pathogen Genetic Diversity. AB - Molecular epidemiological assessments, drug treatment optimization, and development of immunological interventions all depend on understanding pathogen adaptation and genetic variation, which differ for specific pathogens. Mycobacterium tuberculosis is an exceptionally successful human pathogen, yet beyond knowledge that this bacterium has low overall genomic variation but acquires drug resistance mutations, little is known of the factors that drive its population genomic characteristics. Here, we compared the genetic diversity of the bacteria that established infection to the bacterial populations obtained from infected tissues during murine M. tuberculosis pulmonary infection and human disseminated M. bovis BCG infection. We found that new mutations accumulate during in vitro culture, but that in vivo, purifying selection against new mutations dominates, indicating that M. tuberculosis follows a dominant lineage model of evolution. Comparing bacterial populations passaged in T cell-deficient and immunocompetent mice, we found that the presence of T cells is associated with an increase in the diversity of the M. tuberculosis genome. Together, our findings put M. tuberculosis genetic evolution in a new perspective and clarify the impact of T cells on sequence diversity of M. tuberculosis. PMID- 27973590 TI - Investigating Power Density and the Degree of Nonlinearity in Intrinsic Components of Anesthesia EEG by the Hilbert-Huang Transform: An Example Using Ketamine and Alfentanil. AB - Empirical mode decomposition (EMD) is an adaptive filter bank for processing nonlinear and non-stationary signals, such as electroencephalographic (EEG) signals. EMD works well to decompose a time series into a set of intrinsic mode functions with specific frequency bands. An IMF therefore represents an intrinsic component on its correspondingly intrinsic frequency band. The word of 'intrinsic' means the frequency is totally adaptive to the nature of a signal. In this study, power density and nonlinearity are two critical parameters for characterizing the amplitude and frequency modulations in IMFs. In this study, a nonlinearity level is quantified using degree of waveform distortion (DWD), which represents the characteristic of waveform distortion as an assessment of the intra-wave modulation of an IMF. In the application of anesthesia EEG analysis, the assessments of power density and DWD for a set of IMFs represent dynamic responses in EEG caused by two different anesthesia agents, Ketamine and Alfentanil, on different frequency bands. Ketamine causes the increase of power density and the decrease of nonlinearity on gamma-band neuronal oscillation, which cannot be found EEG responses of group B using Alfentanil. Both agents cause an increase of power density and a decrease of nonlinearity on beta-band neuronal oscillation accompany with a loss of consciousness. Moreover, anesthesia agents cause the decreases of power density and nonlinearity (i.e. DWD) for the low-frequency IMFs. PMID- 27973591 TI - Attentional Selection Accompanied by Eye Vergence as Revealed by Event-Related Brain Potentials. AB - Neural mechanisms of attention allow selective sensory information processing. Top-down deployment of visual-spatial attention is conveyed by cortical feedback connections from frontal regions to lower sensory areas modulating late stimulus responses. A recent study reported the occurrence of small eye vergence during orienting top-down attention. Here we assessed a possible link between vergence and attention by comparing visual event related potentials (vERPs) to a cue stimulus that induced attention to shift towards the target location to the vERPs to a no-cue stimulus that did not trigger orienting attention. The results replicate the findings of eye vergence responses during orienting attention and show that the strength and time of eye vergence coincide with the onset and strength of the vERPs when subjects oriented attention. Our findings therefore support the idea that eye vergence relates to and possibly has a role in attentional selection. PMID- 27973592 TI - Using Optimal Control to Disambiguate the Effect of Depression on Sensorimotor, Motivational and Goal-Setting Functions. AB - Differentiating the ability from the motivation to act is of central importance to psychiatric disorders in general and depression in particular. However, it has been difficult to develop quantitative approaches to relate depression to poor motor performance in goal-directed tasks. Here, we use an inverse optimal control approach to provide a computational framework that can be used to infer and factorize performance deficits into three components: sensorimotor speed, goal setting and motivation. Using a novel computer-simulated driving experiment, we found that (1) severity of depression is associated with both altered sensorimotor speed and motivational function; (2) moderately to severely depressed individuals show an increased distance from the stop sign indicating aversive learning affecting goal setting functions. Taken together, the inverse optimal control framework can disambiguate on an individual basis the sensorimotor from the motivational dysfunctions in depression, which may help to develop more precisely targeted interventions. PMID- 27973594 TI - Enjoyment for High-Intensity Interval Exercise Increases during the First Six Weeks of Training: Implications for Promoting Exercise Adherence in Sedentary Adults. AB - This is the first study to show that enjoyment for high-intensity interval exercise increases with chronic training. Prior acute studies typically report high-intensity interval training (HIT) as being more enjoyable than moderate continuous training (MCT) unless the high-intensity intervals are too strenuous or difficult to complete. It follows that exercise competency may be a critical factor contributing to the enjoyment of HIT, and therefore building competency through chronic training may be one way to increase its enjoyment. To test this, we randomly assigned sedentary young adults to six weeks of HIT or MCT, and tracked changes in their enjoyment for the exercise. Enjoyment for HIT increased with training whereas enjoyment for MCT remained constant and lower. Changes in exercise enjoyment were predicted by increases in workload, suggesting that strength adaptions may be important for promoting exercise enjoyment. The results point to HIT as a promising protocol for promoting exercise enjoyment and adherence in sedentary young adults. PMID- 27973593 TI - Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility. AB - Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer's patches is essential for the efficient spread of disease to the brain. To replicate within Peyer's patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer's patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer's patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases. PMID- 27973596 TI - Leadership as an Emergent Feature in Social Organizations: Insights from A Laboratory Simulation Experiment. AB - Recent theoretical contributions have suggested a theory of leadership that is grounded in complexity theory, hence regarding leadership as a complex process (i.e., nonlinear; emergent). This article tests if complexity leadership theory promotes efficiency in work groups. 40 groups of five participants each had to complete four decision making tasks using the city simulation game SimCity4. Before engaging in the four decision making tasks, participants received information regarding what sort of leadership behaviors were more adequate to help them perform better. Results suggest that if complexity leadership theory is applied, groups can achieve higher efficiency over time, when compared with other groups where complexity leadership is not applied. This study goes beyond traditional views of leadership as a centralized form of control, and presents new evidence suggesting that leadership is a collective and emergent phenomenon, anchored in simple rules of behavior. PMID- 27973595 TI - Ecologically Different Fungi Affect Arabidopsis Development: Contribution of Soluble and Volatile Compounds. AB - Plant growth and development can be influenced by mutualistic and non-mutualistic microorganisms. We investigated the ability of the ericoid endomycorrhizal fungus Oidiodendron maius to influence growth and development of the non-host plant Arabidopsis thaliana. Different experimental setups (non-compartmented and compartmented co-culture plates) were used to investigate the influence of both soluble and volatile fungal molecules on the plant phenotype. O. maius promoted growth of A. thaliana in all experimental setups. In addition, a peculiar clumped root phenotype, characterized by shortening of the primary root and by an increase of lateral root length and number, was observed in A. thaliana only in the non-compartmented plates, suggesting that soluble diffusible molecules are responsible for this root morphology. Fungal auxin does not seem to be involved in plant growth promotion and in the clumped root phenotype because co cultivation with O. maius did not change auxin accumulation in plant tissues, as assessed in plants carrying the DR5::GUS reporter construct. In addition, no correlation between the amount of fungal auxin produced and the plant root phenotype was observed in an O. maius mutant unable to induce the clumped root phenotype in A. thaliana. Addition of active charcoal, a VOC absorbant, in the compartmented plates did not modify plant growth promotion, suggesting that VOCs are not involved in this phenomenon. The low VOCs emission measured for O. maius further corroborated this hypothesis. By contrast, the addition of CO2 traps in the compartmented plates drastically reduced plant growth, suggesting involvement of fungal CO2 in plant growth promotion. Other mycorrhizal fungi, as well as a saprotrophic and a pathogenic fungus, were also tested with the same experimental setups. In the non-compartmented plates, most fungi promoted A. thaliana growth and some could induce the clumped root phenotype. In the compartmented plate experiments, a general induction of plant growth was observed for most other fungi, especially those producing higher biomass, further strengthening the role of a nonspecific mechanism, such as CO2 emission. PMID- 27973597 TI - Fast Dissemination of New HIV-1 CRF02/A1 Recombinants in Pakistan. AB - A number of HIV-1 subtypes are identified in Pakistan by characterization of partial viral gene sequences. Little is known whether new recombinants are generated and how they disseminate since whole genome sequences for these viruses have not been characterized. Near full-length genome (NFLG) sequences were obtained by amplifying two overlapping half genomes or next generation sequencing from 34 HIV-1-infected individuals in Pakistan. Phylogenetic tree analysis showed that the newly characterized sequences were 16 subtype As, one subtype C, and 17 A/G recombinants. Further analysis showed that all 16 subtype A1 sequences (47%), together with the vast majority of sequences from Pakistan from other studies, formed a tight subcluster (A1a) within the subtype A1 clade, suggesting that they were derived from a single introduction. More in-depth analysis of 17 A/G NFLG sequences showed that five shared similar recombination breakpoints as in CRF02 (15%) but were phylogenetically distinct from the prototype CRF02 by forming a tight subcluster (CRF02a) while 12 (38%) were new recombinants between CRF02a and A1a or a divergent A1b viruses. Unique recombination patterns among the majority of the newly characterized recombinants indicated ongoing recombination. Interestingly, recombination breakpoints in these CRF02/A1 recombinants were similar to those in prototype CRF02 viruses, indicating that recombination at these sites more likely generate variable recombinant viruses. The dominance and fast dissemination of new CRF02a/A1 recombinants over prototype CRF02 suggest that these recombinant have more adapted and may become major epidemic strains in Pakistan. PMID- 27973598 TI - Effects of Exercise on the Structure and Circulation of Choroid in Normal Eyes. AB - AIMS: To determine the effects of dynamic exercise on the circulation and the luminal and stromal areas of the choroid in normal eyes. METHODS: This was a prospective interventional study of 38 eyes of 38 normal subjects enrolled by invitation. The systolic and diastolic blood pressures, heart rate, intraocularpressure, mean ocular perfusion pressure (MOPP), choroidal blood velocity, and enhanced depth imaging optical coherence tomographic (EDI-OCT) images were recorded before, and immediately after mild dynamic exercise. The same measurements were recorded after 10 min of rest. The choroidal blood velocity was measured bylaser speckle flowgraphy, and the mean blur rate was used for the evaluations. The horizontal EDI-OCT images of the subfoveal choroid were converted to binary images. The central choroidal thickness (CCT), total cross sectional choroidal area, luminal areas, stromal areas, and the ratio of luminal area to total choroidal area (L/C ratio) were determined from these images. RESULTS: The systolic and diastolic blood pressures, heart rate, MOPP, and the mean blur rate were significantly increased immediately after the exercise and significantly decreased 10 minutes after the exercise. There wereno significant changes in the mean CCT, the mean total choroidal area, the mean luminal and stromal areas, and the mean L/C ratio after the exercise. CONCLUSIONS: Our results suggest that a rest period is needed before measurements of blood flow velocity but not necessary for the EDI-OCT imaging to determine the choroidal thickness and area. PMID- 27973600 TI - Efficient 2-Nitrophenol Chemical Sensor Development Based on Ce2O3 Nanoparticles Decorated CNT Nanocomposites for Environmental Safety. AB - Ce2O3 nanoparticle decorated CNT nanocomposites (Ce2O3.CNT NCs) were prepared by a wet-chemical method in basic medium. The Ce2O3.CNT NCs were examined using FTIR, UV/Vis, Field-Emission Scanning Electron Microscopy (FESEM), X-ray electron dispersive spectroscopy (XEDS), X-ray photoelectron spectroscopy (XPS), and powder X-ray diffraction (XRD). A selective 2-nitrophenol (2-NP) sensor was developed by fabricating a thin-layer of NCs onto a flat glassy carbon electrode (GCE, surface area = 0.0316 cm2). Higher sensitivity including linear dynamic range (LDR), long-term stability, and enhanced electrochemical performances towards 2-NP were achieved by a reliable current-voltage (I-V) method. The calibration curve was found linear (R2 = 0.9030) over a wide range of 2-NP concentration (100 pM ~ 100.0 mM). Limit of detection (LOD) and sensor sensitivity were calculated based on noise to signal ratio (~3N/S) as 60 +/- 0.02 pM and 1.6*10-3 MUAMUM-1cm-2 respectively. The Ce2O3.CNT NCs synthesized by a wet chemical process is an excellent way of establishing nanomaterial decorated carbon materials for chemical sensor development in favor of detecting hazardous compounds in health-care and environmental fields at broad-scales. Finally, the efficiency of the proposed chemical sensors can be applied and utilized in effectively for the selective detection of toxic 2-NP component in environmental real samples with acceptable and reasonable results. PMID- 27973599 TI - Transcriptional Orchestration of the Global Cellular Response of a Model Pennate Diatom to Diel Light Cycling under Iron Limitation. AB - Environmental fluctuations affect distribution, growth and abundance of diatoms in nature, with iron (Fe) availability playing a central role. Studies on the response of diatoms to low Fe have either utilized continuous (24 hr) illumination or sampled a single time of day, missing any temporal dynamics. We profiled the physiology, metabolite composition, and global transcripts of the pennate diatom Phaeodactylum tricornutum during steady-state growth at low, intermediate, and high levels of dissolved Fe over light:dark cycles, to better understand fundamental aspects of genetic control of physiological acclimation to growth under Fe-limitation. We greatly expand the catalog of genes involved in the low Fe response, highlighting the importance of intracellular trafficking in Fe-limited diatoms. P. tricornutum exhibited transcriptomic hallmarks of slowed growth leading to prolonged periods of cell division/silica deposition, which could impact biogeochemical carbon sequestration in Fe-limited regions. Light harvesting and ribosome biogenesis transcripts were generally reduced under low Fe while transcript levels for genes putatively involved in the acquisition and recycling of Fe were increased. We also noted shifts in expression towards increased synthesis and catabolism of branched chain amino acids in P. tricornutum grown at low Fe whereas expression of genes involved in central core metabolism were relatively unaffected, indicating that essential cellular function is protected. Beyond the response of P. tricornutum to low Fe, we observed major coordinated shifts in transcript control of primary and intermediate metabolism over light:dark cycles which contribute to a new view of the significance of distinctive diatom pathways, such as mitochondrial glycolysis and the ornithine-urea cycle. This study provides new insight into transcriptional modulation of diatom physiology and metabolism across light:dark cycles in response to Fe availability, providing mechanistic understanding for the ability of diatoms to remain metabolically poised to respond quickly to Fe input and revealing strategies underlying their ecological success. PMID- 27973602 TI - A New Chytridiomycete Fungus Intermixed with Crustacean Resting Eggs in a 407 Million-Year-Old Continental Freshwater Environment. AB - The 407-million-year-old Rhynie Chert (Scotland) contains the most intact fossilised remains of an early land-based ecosystem including plants, arthropods, fungi and other microorganisms. Although most studies have focused on the terrestrial component, fossilised freshwater environments provide critical insights into fungal-algal interactions and the earliest continental branchiopod crustaceans. Here we report interactions between an enigmatic organism and an exquisitely preserved fungus. The fungal reproductive structures are intermixed with exceptionally well-preserved globular spiny structures interpreted as branchiopod resting eggs. Confocal laser scanning microscopy enabled us to reconstruct the fungus and its possible mode of nutrition, the affinity of the resting eggs, and their spatial associations. The new fungus (Cultoraquaticus trewini gen. et sp. nov) is attributed to Chytridiomycota based on its size, consistent formation of papillae, and the presence of an internal rhizoidal system. It is the most pristine fossil Chytridiomycota known, especially in terms of rhizoidal development and closely resembles living species in the Rhizophydiales. The spiny resting eggs are attributed to the crustacean Lepidocaris rhyniensis, dating branchiopod adaptation to life in ephemeral pools to the Early Devonian. The new fungal interaction suggests that, as in modern freshwater environments, chytrids were important to the mobilisation of nutrients in early aquatic foodwebs. PMID- 27973601 TI - High-Dose Opioid Prescribing and Opioid-Related Hospitalization: A Population Based Study. AB - AIMS: To examine the impact of national clinical practice guidelines and provincial drug policy interventions on prevalence of high-dose opioid prescribing and rates of hospitalization for opioid toxicity. DESIGN: Interventional time-series analysis. SETTING: Ontario, Canada, from 2003 to 2014. PARTICIPANTS: Ontario Drug Benefit (ODB) beneficiaries aged 15 to 64 years from 2003 to 2014. INTERVENTIONS: Publication of Canadian clinical practice guidelines for use of opioids in chronic non-cancer pain (May 2010) and implementation of Ontario's Narcotics Safety and Awareness Act (NSAA; November 2011). MEASUREMENTS: Three outcomes were explored: the rate of opioid use among ODB beneficiaries, the prevalence of opioid prescriptions exceeding 200 mg and 400 mg morphine equivalents per day, and rates of opioid-related emergency department visits and hospital admissions. FINDINGS: Over the 12 year study period, the rate of opioid use declined 15.2%, from 2764 to 2342 users per 10,000 ODB eligible persons. The rate of opioid use was significantly impacted by the Canadian clinical practice guidelines (p-value = .03) which led to a decline in use, but no impact was observed by the enactment of the NSAA (p-value = .43). Among opioid users, the prevalence of high-dose prescribing doubled (from 4.2% to 8.7%) over the study period. By 2014, 40.9% of recipients of long-acting opioids exceeded daily doses of 200 mg morphine or equivalent, including 55.8% of long-acting oxycodone users and 76.3% of transdermal fentanyl users. Moreover, in the last period, 18.7% of long-acting opioid users exceeded daily doses of 400 mg morphine or equivalent. Rates of opioid-related emergency department visits and hospital admissions increased 55.0% over the study period from 9.0 to 14.0 per 10,000 ODB beneficiaries from 2003 to 2013. This rate was not significantly impacted by the Canadian clinical practice guidelines (p-value = .68) or enactment of the NSAA (p value = .59). CONCLUSIONS: Although the Canadian clinical practice guidelines for use of opioids in chronic non-cancer pain led to a decline in opioid prescribing rates among ODB beneficiaries these guidelines and subsequent Ontario legislation did not result in a significant change in rates of opioid-related hospitalizations. Given the prevalence of high dose opioid prescribing in this population, this suggests that improved strategies and programs for the safe prescribing of long-acting opioids are needed. PMID- 27973603 TI - Mucosal Expression of T Cell Gene Variants Is Associated with Differential Resistance to Teladorsagia circumcincta. AB - Resistance of sheep to the gastrointestinal nematode Teladorsagia circumcincta is a heritable characteristic. Control of parasite colonization and egg production is strongly linked to IgA antibody levels regulated by Th2 T cell activation within lymphoid tissue; and persistently-infected susceptible animals develop an inflammatory Th1/Th17 response within the abomasum that fails to control infection. Differential T cell polarization therefore is associated with parasite resistance and/or susceptibility and is controlled by a specific set of transcription factors and cytokine receptors. Transcript variants of these genes have been characterized in sheep, while in humans and mice different variants of the genes are associated with inflammatory diseases. RT-qPCR was used to quantify mucosal expression of the transcript variants of the sheep genes in trickle infected animals with defined phenotypic traits. Genes that encode full-length GATA3 and IL17RB were shown to be significantly increased in resistant sheep that had controlled parasite infection. Expression levels of both were significantly negatively correlated with abomasal worm count (a parameter of susceptibility) and positively correlated with body weight (a parameter of resistance). These data show that polarized Th2 T cells within the abomasal mucosa play an important role in the maintenance of resistance. PMID- 27973604 TI - Bacterial Communities Differ among Drosophila melanogaster Populations and Affect Host Resistance against Parasitoids. AB - In Drosophila, diet is considered a prominent factor shaping the associated bacterial community. However, the host population background (e.g. genotype, geographical origin and founder effects) is a factor that may also exert a significant influence and is often overlooked. To test for population background effects, we characterized the bacterial communities in larvae of six genetically differentiated and geographically distant D. melanogaster lines collected from natural populations across Europe. The diet for these six lines had been identical for ca. 50 generations, thus any differences in the composition of the microbiome originates from the host populations. We also investigated whether induced shifts in the microbiome-in this case by controlled antibiotic administration-alters the hosts' resistance to parasitism. Our data revealed a clear signature of population background on the diversity and composition of D. melanogaster microbiome that differed across lines, even after hosts had been maintained at the same diet and laboratory conditions for over 4 years. In particular, the number of bacterial OTUs per line ranged from 8 to 39 OTUs. Each line harboured 2 to 28 unique OTUs, and OTUs that were highly abundant in some lines were entirely missing in others. Moreover, we found that the response to antibiotic treatment differed among the lines and significantly altered the host resistance to the parasitoid Asobara tabida in one of the six lines. Wolbachia, a widespread intracellular endosymbiont associated with parasitoid resistance, was lacking in this line, suggesting that other components of the Drosophila microbiome caused a change in host resistance. Collectively, our results revealed that lines that originate from different population backgrounds show significant differences in the established Drosophila microbiome, outpacing the long-term effect of diet. Perturbations on these naturally assembled microbiomes to some degree influenced the hosts' resistance against natural parasites. PMID- 27973605 TI - Parameter Scaling for Epidemic Size in a Spatial Epidemic Model with Mobile Individuals. AB - In recent years, serious infectious diseases tend to transcend national borders and widely spread in a global scale. The incidence and prevalence of epidemics are highly influenced not only by pathogen-dependent disease characteristics such as the force of infection, the latent period, and the infectious period, but also by human mobility and contact patterns. However, the effect of heterogeneous mobility of individuals on epidemic outcomes is not fully understood. Here, we aim to elucidate how spatial mobility of individuals contributes to the final epidemic size in a spatial susceptible-exposed-infectious-recovered (SEIR) model with mobile individuals in a square lattice. After illustrating the interplay between the mobility parameters and the other parameters on the spatial epidemic spreading, we propose an index as a function of system parameters, which largely governs the final epidemic size. The main contribution of this study is to show that the proposed index is useful for estimating how parameter scaling affects the final epidemic size. To demonstrate the effectiveness of the proposed index, we show that there is a positive correlation between the proposed index computed with the real data of human airline travels and the actual number of positive incident cases of influenza B in the entire world, implying that the growing incidence of influenza B is attributed to increased human mobility. PMID- 27973606 TI - Evolution at 'Sutures' and 'Centers': Recombination Can Aid Adaptation of Spatially Structured Populations on Rugged Fitness Landscapes. AB - Epistatic interactions among genes can give rise to rugged fitness landscapes, in which multiple "peaks" of high-fitness allele combinations are separated by "valleys" of low-fitness genotypes. How populations traverse rugged fitness landscapes is a long-standing question in evolutionary biology. Sexual reproduction may affect how a population moves within a rugged fitness landscape. Sex may generate new high-fitness genotypes by recombination, but it may also destroy high-fitness genotypes by shuffling the genes of a fit parent with a genetically distinct mate, creating low-fitness offspring. Either of these opposing aspects of sex require genotypic diversity in the population. Spatially structured populations may harbor more diversity than well-mixed populations, potentially amplifying both positive and negative effects of sex. On the other hand, spatial structure leads to clumping in which mating is more likely to occur between like types, diminishing the effects of recombination. In this study, we use computer simulations to investigate the combined effects of recombination and spatial structure on adaptation in rugged fitness landscapes. We find that spatially restricted mating and offspring dispersal may allow multiple genotypes inhabiting suboptimal peaks to coexist, and recombination at the "sutures" between the clusters of these genotypes can create genetically novel offspring. Sometimes such an offspring genotype inhabits a new peak on the fitness landscape. In such a case, spatially restricted mating allows this fledgling subpopulation to avoid recombination with distinct genotypes, as mates are more likely to be the same genotype. Such population "centers" can allow nascent peaks to establish despite recombination. Spatial structure may therefore allow an evolving population to enjoy the creative side of sexual recombination while avoiding its destructive side. PMID- 27973607 TI - Serum-Sphingosine-1-Phosphate Concentrations Are Inversely Associated with Atherosclerotic Diseases in Humans. AB - BACKGROUND AND OBJECTIVES: Atherosclerotic changes of arteries are the leading cause for deaths in cardiovascular disease and greatly impair patient's quality of life. Sphingosine-1-phosphate (S1P) is a signaling sphingolipid that regulates potentially pro-as well as anti-atherogenic processes. Here, we investigate whether serum-S1P concentrations are associated with peripheral artery disease (PAD) and carotid stenosis (CS). METHODS AND RESULTS: Serum was sampled from blood donors (controls, N = 174) and from atherosclerotic patients (N = 132) who presented to the hospital with either clinically relevant PAD (N = 102) or CS (N = 30). From all subjects, serum-S1P was measured by mass spectrometry and blood parameters were determined by routine laboratory assays. When compared to controls, atherosclerotic patients before invasive treatment to restore blood flow showed significantly lower serum-S1P levels. This difference cannot be explained by risk factors for atherosclerosis (old age, male gender, hypertension, hypercholesteremia, obesity, diabetes or smoking) or comorbidities (Chronic obstructive pulmonary disease, kidney insufficiency or arrhythmia). Receiver operating characteristic curves suggest that S1P has more power to indicate atherosclerosis (PAD and CS) than high density lipoprotein-cholesterol (HDL-C). In 35 patients, serum-S1P was measured again between one and six months after treatment. In this group, serum-S1P concentrations rose after treatment independent of whether patients had PAD or CS, or whether they underwent open or endovascular surgery. Post-treatment S1P levels were highly associated to platelet numbers measured pre-treatment. CONCLUSIONS: Our study shows that PAD and CS in humans is associated with decreased serum-S1P concentrations and that S1P may possess higher accuracy to indicate these diseases than HDL-C. PMID- 27973609 TI - Laser Fluorescence Illuminates the Soft Tissue and Life Habits of the Early Cretaceous Bird Confuciusornis. AB - In this paper we report the discovery of non-plumage soft tissues in Confuciusornis, a basal beaked bird from the Early Cretaceous Jehol Biota in northeastern China. Various soft tissues are visualized and interpreted through the use of laser-stimulated fluorescence, providing much novel anatomical information about this early bird, specifically reticulate scales covering the feet, and the well-developed and robust pro- and postpatagium. We also include a direct comparison between the forelimb soft tissues of Confuciusornis and modern avian patagia. Furthermore, apparently large, fleshy phalangeal pads are preserved on the feet. The reticulate scales, robust phalangeal pads as well as the highly recurved pedal claws strongly support Confuciusornis as an arboreal bird. Reticulate scales are more rounded than scutate scales and do not overlap, thus allowing for more flexibility in the toe. The extent of the pro- and postpatagium and the robust primary feather rachises are evidence that Confuciusornis was capable of powered flight, contrary to previous reports suggesting otherwise. A unique avian wing shape is also reconstructed based on plumage preserved. These soft tissues combined indicate an arboreal bird with the capacity for short-term (non-migratory) flight, and suggest that, although primitive, Confuciusornis already possessed many relatively advanced avian anatomical characteristics. PMID- 27973608 TI - Microbial Community Composition Impacts Pathogen Iron Availability during Polymicrobial Infection. AB - Iron is an essential nutrient for bacterial pathogenesis, but in the host, iron is tightly sequestered, limiting its availability for bacterial growth. Although this is an important arm of host immunity, most studies examine how bacteria respond to iron restriction in laboratory rather than host settings, where the microbiome can potentially alter pathogen strategies for acquiring iron. One of the most important transcriptional regulators controlling bacterial iron homeostasis is Fur. Here we used a combination of RNA-seq and chromatin immunoprecipitation (ChIP)-seq to characterize the iron-restricted and Fur regulons of the biofilm-forming opportunistic pathogen Aggregatibacter actinomycetemcomitans. We discovered that iron restriction and Fur regulate 4% and 3.5% of the genome, respectively. While most genes in these regulons were related to iron uptake and metabolism, we found that Fur also directly regulates the biofilm-dispersing enzyme Dispersin B, allowing A. actinomycetemcomitans to escape from iron-scarce environments. We then leveraged these datasets to assess the availability of iron to A. actinomycetemcomitans in its primary infection sites, abscesses and the oral cavity. We found that A. actinomycetemcomitans is not restricted for iron in a murine abscess mono-infection, but becomes restricted for iron upon co-infection with the oral commensal Streptococcus gordonii. Furthermore, in the transition from health to disease in human gum infection, A. actinomycetemcomitans also becomes restricted for iron. These results suggest that host iron availability is heterogeneous and dependent on the infecting bacterial community. PMID- 27973610 TI - How Insightful Is 'Insight'? New Caledonian Crows Do Not Attend to Object Weight during Spontaneous Stone Dropping. AB - It is highly difficult to pinpoint what is going through an animal's mind when it appears to solve a problem by 'insight'. Here, we searched for an information processing error during the emergence of seemingly insightful stone dropping in New Caledonian crows. We presented these birds with the platform apparatus, where a heavy object needs to be dropped down a tube and onto a platform in order to trigger the release of food. Our results show New Caledonian crows exhibit a weight inattention error: they do not attend to the weight of an object when innovating stone dropping. This suggests that these crows do not use an understanding of force when solving the platform task in a seemingly insightful manner. Our findings showcase the power of the signature-testing approach, where experiments search for information processing biases, errors and limits, in order to make strong inferences about the functioning of animal minds. PMID- 27973611 TI - Publication Trends in Acupuncture Research: A 20-Year Bibliometric Analysis Based on PubMed. AB - OBJECTIVE: Acupuncture has become popular and widely practiced in many countries around the world. Despite the large amount of acupuncture-related literature that has been published, broader trends in the prevalence and scope of acupuncture research remain underexplored. The current study quantitatively analyzes trends in acupuncture research publications in the past 20 years. METHODS: A bibliometric approach was used to search PubMed for all acupuncture-related research articles including clinical and animal studies. Inclusion criteria were articles published between 1995 and 2014 with sufficient information for bibliometric analyses. Rates and patterns of acupuncture publication within the 20 year observational period were estimated, and compared with broader publication rates in biomedicine. Identified eligible publications were further analyzed with respect to study type/design, clinical condition addressed, country of origin, and journal impact factor. RESULTS: A total of 13,320 acupuncture related publications were identified using our search strategy and eligibility criteria. Regression analyses indicated an exponential growth in publications over the past two decades, with a mean annual growth rate of 10.7%. This compares to a mean annual growth rate of 4.5% in biomedicine. A striking trend was an observed increase in the proportion of randomized clinical trials (RCTs), from 7.4% in 1995 to 20.3% in 2014, exceeding the 4.5% proportional growth of RCTs in biomedicine. Over the 20 year period, pain was consistently the most common focus of acupuncture research (37.9% of publications). Other top rankings with respect to medical focus were arthritis, neoplasms/cancer, pregnancy or labor, mood disorders, stroke, nausea/vomiting, sleep, and paralysis/palsy. Acupuncture research was conducted in 60 countries, with the top 3 contributors being China (47.4%), United States (17.5%), and United Kingdom (8.2%). Retrieved articles were published mostly in complementary and alternative medicine (CAM) journals with impact factors ranging between 0.7 and 2.8 in the top 20 journals, followed by journals specializing in neuroscience, pain, anesthesia/analgesia, internal medicine and comprehensive fields. CONCLUSION: Acupuncture research has grown markedly in the past two decades, with a 2-fold higher growth rate than for biomedical research overall. Both the increases in the proportion of RCTs and the impact factor of journals support that the quality of published research has improved. While pain was a consistently dominant research focus, other topics gained more attention during this time period. These findings provide a context for analyzing strengths and gaps in the current state of acupuncture research, and for informing a comprehensive strategy for further advancing the field. PMID- 27973612 TI - Long-Lasting WNT-TCF Response Blocking and Epigenetic Modifying Activities of Withanolide F in Human Cancer Cells. AB - The WNT-TCF signaling pathway participates in adult tissue homeostasis and repair, and is hyperactive in a number of human diseases including cancers of the colon. Whereas to date there are no antagonists approved for patient use, a potential problem for their sustained use is the blockade of WNT signaling in healthy tissues, thus provoking potentially serious co-lateral damage. Here we have screened a library of plant and microorganism small molecules for novel WNT signaling antagonists and describe withanolide F as a potent WNT-TCF response blocker. This steroidal lactone inhibits TCF-dependent colon cancer xenograft growth and mimics the effects of genetic blockade of TCF and of ivermectin, a previously reported WNT-TCF blocker. However, withanolide F is unique in that it imposes a long-lasting repression of tumor growth, WNT-TCF targets and cancer stem cell clonogenicity after drug treatment. These findings are paralleled by its modulation of chromatin regulators and its alteration of overall H3K4me1 levels. Our results open up the possibility to permanently repress essential signaling responses in cancer cells through limited treatments with small molecules. PMID- 27973614 TI - Migratory Connectivity at High Latitudes: Sabine's Gulls (Xema sabini) from a Colony in the Canadian High Arctic Migrate to Different Oceans. AB - The world's Arctic latitudes are some of the most recently colonized by birds, and an understanding of the migratory connectivity of circumpolar species offers insights into the mechanisms of range expansion and speciation. Migratory divides exist for many birds, however for many taxa it is unclear where such boundaries lie, and to what extent these affect the connectivity of species breeding across their ranges. Sabine's gulls (Xema sabini) have a patchy, circumpolar breeding distribution and overwinter in two ecologically similar areas in different ocean basins: the Humboldt Current off the coast of Peru in the Pacific, and the Benguela Current off the coasts of South Africa and Namibia in the Atlantic. We used geolocators to track Sabine's gulls breeding at a colony in the Canadian High Arctic to determine their migratory pathways and wintering sites. Our study provides evidence that birds from this breeding site disperse to both the Pacific and Atlantic oceans during the non-breeding season, which suggests that a migratory divide for this species exists in the Nearctic. Remarkably, members of one mated pair wintered in opposite oceans. Our results ultimately suggest that colonization of favorable breeding habitat may be one of the strongest drivers of range expansion in the High Arctic. PMID- 27973613 TI - Vaccinia Virus Immunomodulator A46: A Lipid and Protein-Binding Scaffold for Sequestering Host TIR-Domain Proteins. AB - Vaccinia virus interferes with early events of the activation pathway of the transcriptional factor NF-kB by binding to numerous host TIR-domain containing adaptor proteins. We have previously determined the X-ray structure of the A46 C terminal domain; however, the structure and function of the A46 N-terminal domain and its relationship to the C-terminal domain have remained unclear. Here, we biophysically characterize residues 1-83 of the N-terminal domain of A46 and present the X-ray structure at 1.55 A. Crystallographic phases were obtained by a recently developed ab initio method entitled ARCIMBOLDO_BORGES that employs tertiary structure libraries extracted from the Protein Data Bank; data analysis revealed an all beta-sheet structure. This is the first such structure solved by this method which should be applicable to any protein composed entirely of beta sheets. The A46(1-83) structure itself is a beta-sandwich containing a co purified molecule of myristic acid inside a hydrophobic pocket and represents a previously unknown lipid-binding fold. Mass spectrometry analysis confirmed the presence of long-chain fatty acids in both N-terminal and full-length A46; mutation of the hydrophobic pocket reduced the lipid content. Using a combination of high resolution X-ray structures of the N- and C-terminal domains and SAXS analysis of full-length protein A46(1-240), we present here a structural model of A46 in a tetrameric assembly. Integrating affinity measurements and structural data, we propose how A46 simultaneously interferes with several TIR-domain containing proteins to inhibit NF-kappaB activation and postulate that A46 employs a bipartite binding arrangement to sequester the host immune adaptors TRAM and MyD88. PMID- 27973615 TI - Soluble Milk Protein Supplementation with Moderate Physical Activity Improves Locomotion Function in Aging Rats. AB - Aging is associated with a loss of muscle mass and functional capacity. Present study was designed to compare the impact of specific dairy proteins on muscular function with or without a low-intensity physical activity program on a treadmill in an aged rat model. We investigated the effects of nutritional supplementation, five days a week over a 2-month period with a slow digestible protein, casein or fast digestible proteins, whey or soluble milk protein, on strength and locomotor parameters in sedentary or active aged Wistar RjHan rats (17-19 months of age). An extensive gait analysis was performed before and after protein supplementation. After two months of protein administration and activity program, muscle force was evaluated using a grip test, spontaneous activity using an open field and muscular mass by specific muscle sampling. When aged rats were supplemented with proteins without exercise, only minor effects of different diets on muscle mass and locomotion were observed: higher muscle mass in the casein group and improvement of stride frequencies with soluble milk protein. By contrast, supplementation with soluble milk protein just after physical activity was more effective at improving overall skeletal muscle function in old rats compared to casein. For active old rats supplemented with soluble milk protein, an increase in locomotor activity in the open field and an enhancement of static and dynamic gait parameters compared to active groups supplemented with casein or whey were observed without any differences in muscle mass and forelimb strength. These results suggest that consumption of soluble milk protein as a bolus immediately after a low intensity physical activity may be a suitable nutritional intervention to prevent decline in locomotion in aged rats and strengthen the interest to analyze the longitudinal aspect of locomotion in aged rodents. PMID- 27973616 TI - Transcriptome Analysis Provides a Preliminary Regulation Route of the Ethylene Signal Transduction Component, SlEIN2, during Tomato Ripening. AB - Ethylene is crucial in climacteric fruit ripening. The ethylene signal pathway regulates several physiological alterations such as softening, carotenoid accumulation and sugar level reduction, and production of volatile compounds. All these physiological processes are controlled by numerous genes and their expression simultaneously changes at the onset of ripening. Ethylene insensitive 2 (EIN2) is a key component for ethylene signal transduction, and its mutation causes ethylene insensitivity. In tomato, silencing SlEIN2 resulted in a non ripening phenotype and low ethylene production. RNA sequencing of SlEIN2-silenced and wild type tomato, and differential gene expression analyses, indicated that silencing SlEIN2 caused changes in more than 4,000 genes, including those related to photosynthesis, defense, and secondary metabolism. The relative expression level of 28 genes covering ripening-associated transcription factors, ethylene biosynthesis, ethylene signal pathway, chlorophyll binding proteins, lycopene and aroma biosynthesis, and defense pathway, showed that SlEIN2 influences ripening inhibitor (RIN) in a feedback loop, thus controlling the expression of several other genes. SlEIN2 regulates many aspects of fruit ripening, and is a key factor in the ethylene signal transduction pathway. Silencing SlEIN2 ultimately results in lycopene biosynthesis inhibition, which is the reason why tomato does not turn red, and this gene also affects the expression of several defense-associated genes. Although SlEIN2-silenced and green wild type fruits are similar in appearance, their metabolism is significantly different at the molecular level. PMID- 27973618 TI - GDTN: Genome-Based Delay Tolerant Network Formation in Heterogeneous 5G Using Inter-UA Collaboration. AB - With a more Internet-savvy and sophisticated user base, there are more demands for interactive applications and services. However, it is a challenge for existing radio access networks (e.g. 3G and 4G) to cope with the increasingly demanding requirements such as higher data rates and wider coverage area. One potential solution is the inter-collaborative deployment of multiple radio devices in a 5G setting designed to meet exacting user demands, and facilitate the high data rate requirements in the underlying networks. These heterogeneous 5G networks can readily resolve the data rate and coverage challenges. Networks established using the hybridization of existing networks have diverse military and civilian applications. However, there are inherent limitations in such networks such as irregular breakdown, node failures, and halts during speed transmissions. In recent years, there have been attempts to integrate heterogeneous 5G networks with existing ad hoc networks to provide a robust solution for delay-tolerant transmissions in the form of packet switched networks. However, continuous connectivity is still required in these networks, in order to efficiently regulate the flow to allow the formation of a robust network. Therefore, in this paper, we present a novel network formation consisting of nodes from different network maneuvered by Unmanned Aircraft (UA). The proposed model utilizes the features of a biological aspect of genomes and forms a delay tolerant network with existing network models. This allows us to provide continuous and robust connectivity. We then demonstrate that the proposed network model has an efficient data delivery, lower overheads and lesser delays with high convergence rate in comparison to existing approaches, based on evaluations in both real-time testbed and simulation environment. PMID- 27973617 TI - Quantifying Geographic Variation in Health Care Outcomes in the United States before and after Risk-Adjustment. AB - BACKGROUND: Despite numerous studies of geographic variation in healthcare cost and utilization at the local, regional, and state levels across the U.S., a comprehensive characterization of geographic variation in outcomes has not been published. Our objective was to quantify variation in US health outcomes in an all-payer population before and after risk-adjustment. METHODS AND FINDINGS: We used information from 16 independent data sources, including 22 million all-payer inpatient admissions from the Healthcare Cost and Utilization Project (which covers regions where 50% of the U.S. population lives) to analyze 24 inpatient mortality, inpatient safety, and prevention outcomes. We compared outcome variation at state, hospital referral region, hospital service area, county, and hospital levels. Risk-adjusted outcomes were calculated after adjusting for population factors, co-morbidities, and health system factors. Even after risk adjustment, there exists large geographical variation in outcomes. The variation in healthcare outcomes exceeds the well publicized variation in US healthcare costs. On average, we observed a 2.1-fold difference in risk-adjusted mortality outcomes between top- and bottom-decile hospitals. For example, we observed a 2.3 fold difference for risk-adjusted acute myocardial infarction inpatient mortality. On average a 10.2-fold difference in risk-adjusted patient safety outcomes exists between top and bottom-decile hospitals, including an 18.3-fold difference for risk-adjusted Central Venous Catheter Bloodstream Infection rates. A 3.0-fold difference in prevention outcomes exists between top- and bottom decile counties on average; including a 2.2-fold difference for risk-adjusted congestive heart failure admission rates. The population, co-morbidity, and health system factors accounted for a range of R2 between 18-64% of variability in mortality outcomes, 3-39% of variability in patient safety outcomes, and 22 70% of variability in prevention outcomes. CONCLUSION: The amount of variability in health outcomes in the U.S. is large even after accounting for differences in population, co-morbidities, and health system factors. These findings suggest that: 1) additional examination of regional and local variation in risk-adjusted outcomes should be a priority; 2) assumptions of uniform hospital quality that underpin rationale for policy choices (such as narrow insurance networks or antitrust enforcement) should be challenged; and 3) there exists substantial opportunity for outcomes improvement in the US healthcare system. PMID- 27973619 TI - Effects of Low Dose Metformin on Metabolic Traits in Clozapine-Treated Schizophrenia Patients: An Exploratory Twelve-Week Randomized, Double-Blind, Placebo-Controlled Study. AB - BACKGROUND: Metformin has been used for alleviating metabolic abnormalities in patients with schizophrenia. The lowest dose of metformin to treat metabolic abnormalities in clozapine-treated patients is 1000 mg/d. This study was designed to determine whether metformin at 500 mg/d and 1000 mg/d is effective in improving the metabolic profiles of clozapine-treated patients with pre-existing metabolic abnormalities, and whether its effectiveness depends on metformin dosage. METHODS: In this 12-week, randomized, double-blind, placebo-controlled trial, metformin at 500 mg/d or 1000 mg/d was prescribed to clozapine-treated patients with schizophrenia who had pre-existing metabolic abnormalities. The recruited patients underwent physical and laboratory evaluations at weeks 4, 8, and 12. The outcomes were any changes in metabolic traits. RESULTS: Among the 96 clozapine-treated patients with schizophrenia screened for the trial, 55 patients with pre-existing metabolic abnormalities were randomly assigned to placebo (n = 18), metformin dosage at 500 mg/d (n = 18), and metformin dosage at 1000 mg/d (n = 19) groups. The body weight (BW) of patients in the metformin 1000 mg/d group significantly decreased, by a mean of 0.97 kg over the 12 week trial period. Moreover, patients in the metformin at 500 mg/d and 1000 mg/d groups had a significant decrease in body mass index (BMI) after 12 weeks, with the mean decrease being 0.70 and 0.50 kg/m2, respectively. No significant changes were observed in the other metabolic parameters of patients in the three groups. CONCLUSIONS: Our results demonstrated that a low metformin dosage of either 500 mg/d or 1000 mg/d for 12 weeks slightly reduced the BW and BMI of clozapine treated patients with pre-existing metabolic abnormalities. A longer period of treatment with a larger sample is warranted to determine the factors that influence the metformin treatment response. TRIAL REGISTRATION: ClinicalTrials.gov NCT02751307. PMID- 27973620 TI - A Genome-Wide SNP Linkage Analysis Suggests a Susceptibility Locus on 6p21 for Ankylosing Spondylitis and Inflammatory Back Pain Trait. AB - OBJECTIVES: To screen susceptibility loci for ankylosing spondylitis (AS) using an affected-only linkage analysis based on high-density single nucleotide polymorphisms (SNPs) in a genome-wide manner. PATIENTS AND METHODS: AS patients from ten families with Cantonese origin of China were enrolled in the study. Blood samples were genotyped using genomic DNA derived from peripheral blood leukocytes by Illumina HumanHap 610-Quad SNP Chip. Genotype data were generated using the Illumina BeadStudio 3.2 software. PLINK package was used to remove non autosomal SNPs and to further eliminate markers of typing errors. An affected only linkage analysis was carried out using both non-parametric and parametric linkage analyses, as implemented in MERLIN. RESULT: Seventy-eight AS patients (48 males and 30 females, mean age: 39+/-16 years) were enrolled in the study. The mean age of onset was 23+/-10 years and mean duration of disease was 16.7+/-12.2 years. Iritis (2/76, 2.86%), dactylitis (5/78, 6.41%), hip joint involvement (9/78, 11.54%), peripheral arthritis (22/78, 28.21%), inflammatory back pain (IBP) (69/78, 88.46%) and HLA-B27 positivity (70/78, 89.74%) were observed in these patients. Using non-parameter linkage analysis, we found one susceptibility locus for AS, IBP and HLA-B27 in 6p21 respectively, spanning about 13.5Mb, 20.9Mb and 21.2Mb, respectively No significant results were found in the other clinical trait groups including dactylitis, hip involved and arthritis. The identical susceptibility locus region spanning above 9.44Mb was detected in AS IBP and HLA B27 by the parametric linkage analysis. CONCLUSION: Our genome-wide SNP linkage analysis in ten families with ankylosing spondylitis suggests a susceptibility locus on 6p21 in AS, which is a risk locus for IBP in AS patients. PMID- 27973622 TI - Choosing Important Health Outcomes for Comparative Effectiveness Research: An Updated Review and Identification of Gaps. AB - BACKGROUND: The COMET (Core Outcome Measures in Effectiveness Trials) Initiative promotes the development and application of core outcome sets (COS), including relevant studies in an online database. In order to keep the database current, an annual search of the literature is undertaken. This study aimed to update a previous systematic review, in order to identify any further studies where a COS has been developed. Furthermore, no prioritization for COS development has previously been undertaken, therefore this study also aimed to identify COS relevant to the world's most prevalent health conditions. METHODS: The methods used in this updated review followed the same approach used in the original review and the previous update. A survey was also sent to the corresponding authors of COS identified for inclusion in this review, to ascertain what lessons they had learnt from developing their COS. Additionally, the COMET database was searched to identify COS that might be relevant to the conditions with the highest global prevalence. RESULTS: Twenty-five reports relating to 22 new studies were eligible for inclusion in the review. Further improvements were identified in relation to the description of the scope of the COS, use of the Delphi technique, and the inclusion of patient participants within the development process. Additionally, 33 published and ongoing COS were identified for 13 of the world's most prevalent conditions. CONCLUSION: The development of a reporting guideline and minimum standards should contribute towards future improvements in development and reporting of COS. This study has also described a first approach to identifying gaps in existing COS, and to priority setting in this area. Important gaps have been identified, on the basis of global burden of disease, and the development and application of COS in these areas should be considered a priority. PMID- 27973623 TI - Self-assembling Venturi-like peptide nanotubes. AB - We describe the design and synthesis of self-assembling peptide nanotubes that have an internal filter area and whose length and internal diameters, at the entrance and in the constricted area, are precisely controlled. PMID- 27973624 TI - Correction: Molecular and ionic diffusion in aqueous - deep eutectic solvent mixtures: probing inter-molecular interactions using PFG NMR. AB - Correction for 'Molecular and ionic diffusion in aqueous - deep eutectic solvent mixtures: probing inter-molecular interactions using PFG NMR' by Carmine D'Agostino et al., Phys. Chem. Chem. Phys., 2015, 17, 15297-15304. PMID- 27973625 TI - Ordering block copolymers with structured electrodes. AB - We study the kinetics of alignment and registration of block copolymers in an inhomogeneous electric field by computer simulations of a soft, coarse-grained model. The two blocks of the symmetric diblock copolymers are characterized by different dielectric constants. First, we demonstrate that a combination of graphoepitaxy and a homogeneous electric field extends the maximal distance between the topographical guiding patterns that result in defect-free ordering compared to graphoepitaxy alone. In a second study, the electric field in the thin block copolymer film is fabricated by spatially structured electrodes on an isolating substrate arranged in a one-dimensional periodic array; no additional topographical guiding patterns are applied. The dielectrophoretic effect induces long-range orientational order of the lamellae and, additionally, registers the lamellar structure with the electrodes due to the field inhomogeneities at the edges of the structured electrodes. Thus, orientational and translational order is established by the inhomogeneous electric field. The simulations identify a process protocol of time-dependent electric potentials that suppresses defect formation by initially forming a sandwich-like structure and subsequently reorienting these lying into standing lamellae that are registered with the structure of the electrodes. This process-directed self-assembly results in large defect-free arrays of aligned and registered lamellae using electrodes with a saw tooth period of 4 lamellar periodicities, L0, and a spacing of 10L0. PMID- 27973621 TI - Chronic Olanzapine Treatment Induces Disorders of Plasma Fatty Acid Profile in Balb/c Mice: A Potential Mechanism for Olanzapine-Induced Insulin Resistance. AB - BACKGROUND: Atypical antipsychotics such as olanzapine cause metabolic side effects leading to obesity and insulin resistance. The underlying mechanisms remain elusive. In this study we investigated the effects of chronic treatment of olanzapine on the fatty acid composition of plasma in mice. METHODS: Twenty 8 week female Balb/c mice were randomly assigned to two groups: the OLA group and the control group. After treatment with olanzapine (10 mg/kg/day) or vehicle intraperitoneally for 8 weeks, fasting glucose, insulin levels and oral glucose tolerance test were determined. Effects on plasma fatty acid profile and plasma indices of D5 desaturase, D6 desaturase and SCD1 activity were also investigated. RESULTS: Chronic administration of olanzapine significantly elevated fasting glucose and insulin levels, impaired glucose tolerance, but did not increase body weight. Total saturated fatty acids and n-6 polyunsaturated fatty acids were significantly increased and total monounsaturated fatty acids were significantly decreased, while total n-3 polyunsaturated fatty acids showed no prominent changes. Chronic olanzapine treatment significantly up-regulated D6 desaturase activity while down-regulating D5 desaturase activity. Palmitic acid (C16:0), dihomo-gamma-linolenic acid (C20:3n-6) and D6 desaturase were associated with an increase probability of insulin resistance, whereas nervonic acid (C24:1) and SCD1 were significantly associated with a lower insulin resistance probability. CONCLUSIONS: All results indicated that such drug-induced effects on fatty acid profile in plasma were relevant for the metabolic adverse effects associated with olanzapine and possibly other antipsychotics. Further studies are needed to investigate geneticand other mechanisms to explain how plasma fatty acids regulate glucose metabolism and affect the risk of insulin resistance. PMID- 27973626 TI - Electrokinetic flows in liquid crystal thin films with fixed anchoring. AB - We study ionic and mass transport in a liquid crystalline fluid film in its nematic phase under an applied electrostatic field. Both analytic and numerical solutions are given for some prototypical configurations of interest in electrokinetics: thin films with spatially nonuniform nematic director that are either periodic or comprise a set of isolated disclinations. We present a quantitative description of the mechanisms inducing spatial charge separation in the nematic, and of the structure and magnitude of the resulting flows. The fundamental solutions for the charge distribution and flow velocities induced by disclinations of topological charge m = -1/2, 1/2 and 1 are given. These solutions allow the analysis of several designer flows, such as "pusher" flows created by three colinear disclinations, the flow induced by an immersed spherical particle (equivalent to an m = 1 defect) and its accompanying m = -1 hyperbolic hedgehog defect, and the mechanism behind nonlinear ionic mobilities when the imposed field is perpendicular to the line joining the defects. PMID- 27973627 TI - Supramolecular bidentate phosphine ligand scaffolds from deconstructed Hamilton receptors. AB - There is constant demand for new ligand archictectures on which inorganic and organometallic structures can be leveraged. An important, but often synthetically challenging, class of ligands is bidentate phosphines. Here we report self assembling, supramolecular bidentate ligand scaffolds based on deconstructed Hamilton receptors with binding affinities up to 800 +/- 100 M-1. PMID- 27973628 TI - Toward highly sensitive surface-enhanced Raman scattering: the design of a 3D hybrid system with monolayer graphene sandwiched between silver nanohole arrays and gold nanoparticles. AB - We report a novel graphene-metal hybrid system by introducing monolayer graphene between gold nanoparticles (Au NPs) and silver nanohole (Ag NH) arrays. The design incorporates three key advantages to promote the surface-enhanced Raman scattering (SERS) sensing capacity: (i) making full use of the single-atomic feature of graphene for generating uniform sub-nanometer spaces; (ii) maintaining the bottom layer of Ag nanoarrays with an ordered manner for facilitating the transfer of graphene films and assembly of the top layer of Au NPs; (iii) integrating the advantages of the strong plasmonic effect of Ag, the chemical stability of Au, as well as the mechanical flexibility and biological compatibility of graphene. In this configuration, the plasmonic properties can be fine-tuned by separately optimizing the horizontal or vertical gaps between the metal NPs. Exactly, sub-20 nm spaces between the horizontally patterned Ag tips constructed by adjacent Ag NHs, and sub-nanometer scale graphene gaps between the vertically distributed Au NP-Ag NH have been achieved. Finite element numerical simulations demonstrate that the multi-dimensional plasmonic couplings (including the Au NP-Au NP, Au NP-Ag NH and Ag NH-Ag NH couplings) promote for the hybrid platform an electric field enhancement up to 137 times. Impressively, the as prepared 3D Au NP-graphene-Ag NH array hybrid structure manifests ultrahigh SERS sensitivity with a detection limit of 10-13 M for R6G molecules, as well as good reproducibility and stability. This work represents a step towards high performance SERS substrate fabrication, and opens up a new route for graphene plasmonic hybrids in SERS applications. PMID- 27973629 TI - Design of nanocarriers for nanoscale drug delivery to enhance cancer treatment using hybrid polymer and lipid building blocks. AB - Polymer-lipid hybrid nanoparticles (PLN) are an emerging nanocarrier platform made from building blocks of polymers and lipids. PLN integrate the advantages of biomimetic lipid-based nanoparticles (i.e. solid lipid nanoparticles and liposomes) and biocompatible polymeric nanoparticles. PLN are constructed from diverse polymers and lipids and their numerous combinations, which imparts PLN with great versatility for delivering drugs of various properties to their nanoscale targets. PLN can be classified into two types based on their hybrid nanoscopic structure and assembly methods: Type-I monolithic matrix and Type-II core-shell systems. This article reviews the history of PLN development, types of PLN, lipid and polymer candidates, fabrication methods, and unique properties of PLN. The applications of PLN in delivery of therapeutic or imaging agents alone or in combination for cancer treatment are summarized and illustrated with examples. Important considerations for the rational design of PLN for advanced nanoscale drug delivery are discussed, including selection of excipients, synthesis processes governing formulation parameters, optimization of nanoparticle properties, improvement of particle surface functionality to overcome macroscopic, microscopic and cellular biological barriers. Future directions and potential clinical translation of PLN are also suggested. PMID- 27973630 TI - Synthesis of end-functionalized glycopolymers containing alpha(2,8) disialic acids via pi-allyl nickel catalyzed coordinating polymerization and their interaction with Siglec-7. AB - An allene monomer containing an alpha(2,8) disialic acid was polymerized by a pi allyl nickel complex with an azido group to produce end-functional glycopolymers with an excellent polydispersity index. The polymers allowed terminal modification with a fluorescent dye by click chemistry. The glycopolymers can dissociate Siglec-7-GD3 interactions at low concentrations. PMID- 27973631 TI - An efficient approach to trans-4-hydroxy-5-substituted 2-pyrrolidinones through a stereoselective tandem Barbier process: divergent syntheses of (3R,4S)-statines, (+)-preussin and (-)-hapalosin. AB - A diastereoselective approach to trans-4-hydroxy-5-substituted 2-pyrrolidinones 1 (P1 = TBS, P2 = H) has been developed through a stereoselective tandem Barbier process of (R,SRS)-8 with alkyl and aryl bromide. The stereochemistry at the C-5 stereogenic center of the trans-4-hydroxy-5-substituted 2-pyrrolidinones was solely controlled by alpha-alkoxy substitution. This effective approach was successfully used to prepare a variety of substituted (3R,4S)-statines 2. In addition, two bioactive natural products of (+)-preussin 4 and hapalosin 5 were effectively synthesized through this stereoselective tandem Barbier process. PMID- 27973632 TI - Novel multiferroic state and ME enhancement by breaking the AFM frustration in LuMn1-xO3. AB - This study provides a comprehensive insight into the effects of controlled off stoichiometry on the structural and multiferroic properties of the hexagonal manganite LuMn1-xO3+delta (x = 0.02; delta ~ 0), supported by neutron powder diffraction measurements confirming single phase P63cm symmetry and evidencing a relevant ferromagnetic component, below TN ~ 90 K, which breaks the archetypal geometrically frustrated antiferromagnetic state typically ascribed to LuMnO3. The perturbations in the triangular disposition of spins prompt an additional electric polarization contribution and a clear enhancement of the magnetoelectric coupling which are in good agreement with the results of first principles calculations. In addition, Raman spectroscopy, dielectric permittivity, pyroelectric current and magnetic measurements as a function of temperature point out the precursor effects of the magnetic phase transitions involving a strong coupling between spins, lattice and electric order, even above the Neel temperature. PMID- 27973633 TI - Potentiometric sensing of nucleic acids using chemically modified nanopores. AB - Unlike the overwhelming majority of nanopore sensors that are based on the measurement of a transpore ionic current, here we introduce a potentiometric sensing scheme and demonstrate its application for the selective detection of nucleic acids. The sensing concept uses the charge inversion that occurs in the sensing zone of a nanopore upon binding of negatively charged microRNA strands to positively charged peptide-nucleic acid (PNA) modified nanopores. The initial anionic permselectivity of PNA-modified nanopores is thus gradually changed to cationic permselectivity, which can be detected simply by measuring the nanoporous membrane potential. A quantitative theoretical treatment of the potentiometric microRNA response is provided based on the Nernst-Planck/Poisson model for the nanopore system assuming first order kinetics for the nucleic acid hybridization. An excellent correlation between the theoretical and experimental results was observed, which revealed that the binding process is focused at the nanopore entrance with contributions from both in pore and out of pore sections of the nanoporous membrane. The theoretical treatment is able to give clear guidelines for further optimization of potentiometric nanopore-based nucleic acid sensors by predicting the effect of the most important experimental parameters on the potential response. PMID- 27973634 TI - Influence of humidity on tribo-electric charging and segregation in shaken granular media. AB - We study the effect of humidity on the charge accumulation of polymer granulates shaken vertically in a stainless steel container. This setup allows us to control the humidity level from 5% to 100%RH while performing automated charge measurements in a Faraday cup directly connected to the shaking container. We find that samples of approximately 2000 polymer spheres become highly charged at low humidity levels (<30%RH), but acquire almost no charge for humidity levels above 80%RH. The transition between these two regimes does depend on the material, as does the sign of the charge. For the latter we find a correlation with the contact angle of the polymer with only very hydrophilic particles attaining positive charges. We show that this humidity dependence of tribo charging can be used to control segregation in shaken binary mixtures. PMID- 27973635 TI - alphavbeta3-Isoform specific erbium complexes highly specific for bladder cancer imaging and photodynamic therapy. AB - We have synthesized a bifunctional erbium-porphyrin tumor imaging and PDT agent (Er-R3) that is capable of killing bladder cancer cells via its selective binding to the integrin alphavbeta3 isoform overexpressed on the cell membrane. PMID- 27973636 TI - Electronic halocyclization and radical haloazidation of benzene-linked 1,7-dienes for the synthesis of functionalized 3,1-benzoxazines. AB - A novel electronic halocyclization and radical haloazidation of benzene-linked 1,7-dienes for the formation of functionalized 3,1-benzoxazines has been achieved by using TMSN3 as an azido source and NBS as a halogen source. This methodology is highlighted by its mild conditions and wide substrate scope, which concomitantly introduces one C-N and two C-halogen bonds into one molecule. PMID- 27973637 TI - Nitric oxide release via oxygen atom transfer from nitrite at copper(ii). AB - Nitric oxide is a vital signaling molecule that controls blood flow and oxygenation and nitrite serves as an important reservoir for nitric oxide in biology. While copper containing enzymes are known to reduce nitrite to nitric oxide, herein we report a new pathway to release nitric oxide via oxygen atom transfer from nitrite at a copper(ii) site. PMID- 27973638 TI - Synthesis of sialic acid derivatives based on chiral substrate-controlled stereoselective aldol reactions using pyruvic acid oxabicyclo[2.2.2]octyl orthoester. AB - The synthesis of sialic acids and their analogs was accomplished based on substrate-controlled asymmetric aldol reactions between sterically complicated aldehydes easily prepared from commercially available carbohydrates and a novel pyruvic acid oxabicyclo[2.2.2]octyl orthoester. Systematic aldol reaction studies using chiral aldehydes revealed that alpha,beta,gamma-benzyloxy-substituted aldehydes with an alpha,beta-anti relative configuration preferentially provided the Felkin products with the 4,5-anti configuration with high diastereoselectivity. The relative beta,gamma-configuration in alpha,beta,gamma benzyloxy-substituted aldehydes with an alpha,beta-syn arrangement exerted a secondary effect on the diastereoselectivity of the stereogenic center formed in aldol reactions, and alpha,beta-syn-beta,gamma-anti benzyloxyaldehyde exhibited superior diastereoselectivity to alpha,beta-syn-beta,gamma-syn benzyloxyaldehyde to yield the Felkin products. PMID- 27973639 TI - Preventing General Surgery Residency Attrition-It Is All About the Mentoring. PMID- 27973640 TI - A 51-Year-Old Man With Exercise-Induced Syncope. PMID- 27973641 TI - Women's Mental Health and Well-being 5 Years After Receiving or Being Denied an Abortion: A Prospective, Longitudinal Cohort Study. AB - Importance: The idea that abortion leads to adverse psychological outcomes has been the basis for legislation mandating counseling before obtaining an abortion and other policies to restrict access to abortion. Objective: To assess women's psychological well-being 5 years after receiving or being denied an abortion. Design, Setting, and Participants: This study presents data from the Turnaway Study, a prospective longitudinal study with a quasi-experimental design. Women were recruited from January 1, 2008, to December 31, 2010, from 30 abortion facilities in 21 states throughout the United States, interviewed via telephone 1 week after seeking an abortion, and then interviewed semiannually for 5 years, totaling 11 interview waves. Interviews were completed January 31, 2016. We examined the psychological trajectories of women who received abortions just under the facility's gestational limit (near-limit group) and compared them with women who sought but were denied an abortion because they were just beyond the facility gestational limit (turnaway group, which includes the turnaway-birth and turnaway-no-birth groups). We used mixed effects linear and logistic regression analyses to assess whether psychological trajectories differed by study group. Main Outcomes and Measures: We included 6 measures of mental health and well being: 2 measures of depression and 2 measures of anxiety assessed using the Brief Symptom Inventory, as well as self-esteem, and life satisfaction. Results: Of the 956 women (mean [SD] age, 24.9 [5.8] years) in the study, at 1 week after seeking an abortion, compared with the near-limit group, women denied an abortion reported more anxiety symptoms (turnaway-births, 0.57; 95% CI, 0.01 to 1.13; turnaway-no-births, 2.29; 95% CI, 1.39 to 3.18), lower self-esteem (turnaway births, -0.33; 95% CI, -0.56 to -0.09; turnaway-no-births, -0.40; 95% CI, -0.78 to -0.02), lower life satisfaction (turnaway-births, -0.16; 95% CI, -0.38 to 0.06; turnaway-no-births, -0.41; 95% CI, -0.77 to -0.06), and similar levels of depression (turnaway-births, 0.13; 95% CI, -0.46 to 0.72; turnaway-no-births, 0.44; 95% CI, -0.50 to 1.39). Conclusions and Relevance: In this study, compared with having an abortion, being denied an abortion may be associated with greater risk of initially experiencing adverse psychological outcomes. Psychological well being improved over time so that both groups of women eventually converged. These findings do not support policies that restrict women's access to abortion on the basis that abortion harms women's mental health. PMID- 27973642 TI - Laser Treatments for Postinflammatory Hyperpigmentation: A Systematic Review. AB - Importance: Lasers are gaining interest as a treatment option for postinflammatory hyperpigmentation (PIH) but can pose a clinical dilemma given the risk for laser-induced or exacerbated PIH. Objective: To assess the clinical evidence for the use of lasers in the treatment of PIH. Evidence Review: A systematic review was performed by searching PubMed databases from January 1, 1990, through May 31, 2016. Included studies involved laser treatment for PIH with the degree of pigmentation as a measure of outcome. The search was filtered to include only clinical studies written in the English language. Study methods were analyzed and the reproducibility of the studies was graded. Outcome measures varied from study to study and included concentration of melanin and hemoglobin, patient satisfaction questionnaires, clinical photography, subjective clinical improvement, light microscopy, melanin index, reflectance spectroscopy, and/or skin biopsy evaluated by a blinded dermatopathologist. Findings: Of 1295 results, 20 unique studies with 224 patients met the inclusion criteria. These studies included 1 randomized clinical observer-blinded study (6 patients), 4 nonrandomized clinical trials (133 patients), 1 cohort study (34 patients), 7 case series (44 patients), and 7 case reports (7 patients). Multiple lasers were studied; however, most of the studies were not methodologically rigorous. Some studies showed no improvement or worsening of PIH after laser treatment. The most extensively studied device was the Q-switched Nd:YAG laser, which has shown promising results based on multiple outcome measures as listed above. Conclusions and Relevance: Some lasers may be beneficial in the treatment of PIH. The evidence suggests that additional studies would be required to determine the benefit of laser treatment of PIH. PMID- 27973644 TI - Influence of optical material properties on the perception of liquids. AB - In everyday life we encounter a wide range of liquids (e.g., water, custard, toothpaste) with distinctive optical appearances and viscosities. Optical properties (e.g., color, translucency) are physically independent of viscosity, but, based on experience with real liquids, we may associate specific appearances (e.g., water, caramel) with certain viscosities. Conversely, the visual system may discount optical properties, enabling "viscosity constancy" based primarily on the liquid's shape and motion. We investigated whether optical characteristics affect the perception of viscosity and other properties of liquids. We simulated pouring liquids with viscosities ranging from water to molten glass and rendered them with nine different optical characteristics. In Experiment 1, observers (a) adjusted a match stimulus until it had the same perceived viscosity as a test stimulus with different optical properties, and (b) rated six physical properties of the test stimuli (runniness, shininess, sliminess, stickiness, warmth, wetness). We tested moving and static stimuli. In Experiment 2, observers had to associate names with every liquid in the stimulus set. We find that observers' viscosity matches correlated strongly with the true viscosities and that optical properties had almost no effect. However, some ratings of liquid properties did show substantial interactions between viscosity and optical properties. Observers associate liquid names primarily with optical cues, although some materials are associated with a specific viscosity or combination of viscosity and optics. These results suggest viscosity is inferred primarily from shape and motion cues but that optical characteristics influence recognition of specific liquids and inference of other physical properties. PMID- 27973646 TI - NIH Charts a Path for Nutrition Science. PMID- 27973645 TI - Clarifying the role of target similarity, task relevance and feature-based suppression during sustained inattentional blindness. AB - How is feature-based attention distributed when engaged in a challenging attentional task? Thanks to formative electrophysiological and psychophysical work, we know a great deal about the spatial distribution of attention, but much less is known about how feature-based attention is allocated. In a large-scale online study, we investigated the distribution of attention to color space using a sustained inattentional blindness task. In order to query what parts of color space were being attended or inhibited, we varied the color of an unexpected stimulus on the final trial. Noticing rates for this stimulus indicate that when engaged in a difficult task that involves tracking items of one color and ignoring items of two different colors, observers attend the target color and inhibit the to-be ignored colors. Further, similarity to the target drives detection such that colors more similar to the target are more likely to be detected. Finally, our data suggest that when possible, observers inhibit regions of color space rather than individuating specific colors and adjusting the level of inhibition for a particular color accordingly. Together, our data support the notion of feature-based suppression for task relevant (to-be ignored) information, but we found no evidence of an inhibitory surround based on target color similarity. PMID- 27973643 TI - Syntactic Versus Memory Accounts of the Sentence Comprehension Deficits of Specific Language Impairment: Looking Back, Looking Ahead. AB - Purpose: Compared with same-age typically developing peers, school-age children with specific language impairment (SLI) exhibit significant deficits in spoken sentence comprehension. They also demonstrate a range of memory limitations. Whether these 2 deficit areas are related is unclear. The present review article aims to (a) review 2 main theoretical accounts of SLI sentence comprehension and various studies supporting each and (b) offer a new, broader, more integrated memory-based framework to guide future SLI research, as we believe the available evidence favors a memory-based perspective of SLI comprehension limitations. Method: We reviewed the literature on the sentence comprehension abilities of English-speaking children with SLI from 2 theoretical perspectives. Results: The sentence comprehension limitations of children with SLI appear to be more fully captured by a memory-based perspective than by a syntax-specific deficit perspective. Conclusions: Although a memory-based view appears to be the better account of SLI sentence comprehension deficits, this view requires refinement and expansion. Current memory-based perspectives of adult sentence comprehension, with proper modification, offer SLI investigators new, more integrated memory frameworks within which to study and better understand the sentence comprehension abilities of children with SLI. PMID- 27973647 TI - When and How to Teach Residents to Operate. PMID- 27973649 TI - A Faculty-Student Mentoring Program to Enhance Collaboration in Public Health Research in Surgery. PMID- 27973648 TI - Complementing Operating Room Teaching With Video-Based Coaching. AB - Importance: Surgical expertise demands technical and nontechnical skills. Traditionally, surgical trainees acquired these skills in the operating room; however, operative time for residents has decreased with duty hour restrictions. As in other professions, video analysis may help maximize the learning experience. Objective: To develop and evaluate a postoperative video-based coaching intervention for residents. Design, Setting, and Participants: In this mixed methods analysis, 10 senior (postgraduate year 4 and 5) residents were videorecorded operating with an attending surgeon at an academic tertiary care hospital. Each video formed the basis of a 1-hour one-on-one coaching session conducted by the operative attending; although a coaching framework was provided, participants determined the specific content collaboratively. Teaching points were identified in the operating room and the video-based coaching sessions; iterative inductive coding, followed by thematic analysis, was performed. Main Outcomes and Measures: Teaching points made in the operating room were compared with those in the video-based coaching sessions with respect to initiator, content, and teaching technique, adjusting for time. Results: Among 10 cases, surgeons made more teaching points per unit time (63.0 vs 102.7 per hour) while coaching. Teaching in the video-based coaching sessions was more resident centered; attendings were more inquisitive about residents' learning needs (3.30 vs 0.28, P = .04), and residents took more initiative to direct their education (27% [198 of 729 teaching points] vs 17% [331 of 1977 teaching points], P < .001). Surgeons also more frequently validated residents' experiences (8.40 vs 1.81, P < .01), and they tended to ask more questions to promote critical thinking (9.30 vs 3.32, P = .07) and set more learning goals (2.90 vs 0.28, P = .11). More complex topics, including intraoperative decision making (mean, 9.70 vs 2.77 instances per hour, P = .03) and failure to progress (mean, 1.20 vs 0.13 instances per hour, P = .04) were addressed, and they were more thoroughly developed and explored. Excerpts of dialogue are presented to illustrate these findings. Conclusions and Relevance: Video-based coaching is a novel and feasible modality for supplementing intraoperative learning. Objective evaluation demonstrates that video-based coaching may be particularly useful for teaching higher-level concepts, such as decision making, and for individualizing instruction and feedback to each resident. PMID- 27973651 TI - Prognostic Factors of Survival in Dermatofibrosarcoma Protuberans. PMID- 27973652 TI - Prognostic Factors of Survival in Dermatofibrosarcoma Protuberans-Reply. PMID- 27973653 TI - The Mystery of the Christmas Tree. PMID- 27973654 TI - Preventing Syphilis in the 20th Century-The Metchnikoff Pomade. PMID- 27973655 TI - The Folklore of Herpes Zoster. PMID- 27973656 TI - Aloe Vera in Dermatology-The Plant of Immortality. PMID- 27973657 TI - African Scarification. PMID- 27973658 TI - The Ancient Remedies of Alopecia. PMID- 27973659 TI - Atypical Moles. PMID- 27973661 TI - Hearing Loss and Cognitive-Communication Test Performance of Long-Term Care Residents With Dementia: Effects of Amplification. AB - Purpose: The study aims were (a) to explore the relationship between hearing loss and cognitive-communication performance of individuals with dementia, and (b) to determine if hearing loss is accurately identified by long-term care (LTC) staff. The research questions were (a) What is the effect of amplification on cognitive communication test performance of LTC residents with early- to middle-stage dementia and mild-to-moderate hearing loss? and (b) What is the relationship between measured hearing ability and hearing ability recorded by staff using the Resident Assessment Instrument-Minimum Data Set 2.0 (RAI-MDS; Hirdes et al., 1999)? Method: Thirty-one residents from 5 long-term care facilities participated in this quasiexperimental crossover study. Residents participated in cognitive communication testing with and without amplification. RAI-MDS ratings of participants' hearing were compared to audiological assessment results. Results: Participants' speech intelligibility index scores significantly improved with amplification; however, participants did not demonstrate significant improvement in cognitive-communication test scores with amplification. A significant correlation was found between participants' average pure-tone thresholds and RAI MDS ratings of hearing, yet misclassification of hearing loss occurred for 44% of participants. Conclusions: Measuring short-term improvement of performance-based cognitive communication may not be the most effective means of assessing amplification for individuals with dementia. Hearing screenings and staff education remain necessary to promote hearing health for LTC residents. PMID- 27973662 TI - Severe Oral Ulcers Associated With Nivolumab Treatment. PMID- 27973663 TI - Phenomenological model of visual acuity. AB - We propose in this work a model for describing visual acuity (V) as a function of defocus and pupil diameter. Although the model is mainly based on geometrical optics, it also incorporates nongeometrical effects phenomenologically. Compared to similar visual acuity models, the proposed one considers the effect of astigmatism and the variability of best corrected V among individuals; it also takes into account the accommodation and the "tolerance to defocus," the latter through a phenomenological parameter. We have fitted the model to the V data provided in the works of Holladay et al. and Peters, showing the ability of this model to accurately describe the variation of V against blur and pupil diameter. We have also performed a comparison between the proposed model and others previously published in the literature. The model is mainly intended for use in the design of ophthalmic compensations, but it can also be useful in other fields such as visual ergonomics, design of visual tests, and optical instrumentation. PMID- 27973665 TI - The Democratization of Medical Research and Education Through Social Media: The Potential and the Peril. PMID- 27973664 TI - Adaptive optics assisted and optical coherence tomography guided fs-laser system for ophthalmic surgery in the posterior eye. AB - While fs-lasers are clinically established for surgery in the anterior eye, their use in the posterior eye is impeded by aberrations and focus position errors. We implemented a laboratory system to investigate whether fs-laser surgery in the posterior eye is made more feasible by aberration correction and tomographic image guidance. Aberration correction is obtained by adaptive optics (AO) and the image guidance is accomplished by optical coherence tomography (OCT). System characteristic measurements and cutting experiments were performed inside an eye model. By aberration correction, wavefront errors were reduced from 270 nm root mean-square (rms) to 64 nm rms, ignoring Zernike terms for tilts and focus. The Strehl ratio of the assigned point spread function is improved from 0.11 to 0.78. The threshold pulse energy of laser-induced optical breakdown in water is lowered from about 3.0 to about 1.3???J measured at the eye model entrance. After laser cutting of a synthetic foil placed 300???m in front of porcine retinal tissue with the corrected system, postoperative three-dimensional OCT imaging showed no lesions in the tissue. Our results corroborate that AO and OCT will be two essential assistive components for possible clinical systems for fs-laser-based surgery in the posterior eye. PMID- 27973666 TI - What Lengths Should We Go to for Fluoroscopy-Free Resuscitative Endovascular Balloon Occlusion of the Aorta? PMID- 27973668 TI - Making Every Mobile Heart Count! PMID- 27973667 TI - Networks and Nosology in Posttraumatic Stress Disorder. PMID- 27973669 TI - Pure-Tone-Spondee Threshold Relationships in Functional Hearing Loss: A Test of Loudness Contribution. AB - Purpose: The purpose of this article is to examine explanations for pure-tone average-spondee threshold differences in functional hearing loss. Method: Loudness magnitude estimation functions were obtained from 24 participants for pure tones (0.5 and 1.0 kHz), vowels, spondees, and speech-shaped noise as a function of level (20-90 dB SPL). Participants listened monaurally through earphones. Loudness predictions were obtained for the same stimuli by using a computational, dynamic loudness model. Results: When evaluated at the same SPL, speech-shaped noise was judged louder than vowels/spondees, which were judged louder than tones. Equal-loudness levels were inferred from fitted loudness functions for the group. For the clinical application, the 2.1-dB difference between spondees and tones at equal loudness became a 12.1-dB difference when the stimuli were converted from SPL to HL. Conclusions: Nearly all of the pure-tone average-spondee threshold differences in functional hearing loss are attributable to references for calibration for 0 dB HL for tones and speech, which are based on detection and recognition, respectively. The recognition threshold for spondees is roughly 9 dB higher than the speech detection threshold; persons feigning a loss, who base loss magnitude on loudness, do not consider this difference. Furthermore, the dynamic loudness model was more accurate than the static model. PMID- 27973671 TI - Feasibility of Obtaining Measures of Lifestyle From a Smartphone App: The MyHeart Counts Cardiovascular Health Study. AB - Importance: Studies have established the importance of physical activity and fitness, yet limited data exist on the associations between objective, real-world physical activity patterns, fitness, sleep, and cardiovascular health. Objectives: To assess the feasibility of obtaining measures of physical activity, fitness, and sleep from smartphones and to gain insights into activity patterns associated with life satisfaction and self-reported disease. Design, Setting, and Participants: The MyHeart Counts smartphone app was made available in March 2015, and prospective participants downloaded the free app between March and October 2015. In this smartphone-based study of cardiovascular health, participants recorded physical activity, filled out health questionnaires, and completed a 6 minute walk test. The app was available to download within the United States. Main Outcomes and Measures: The feasibility of consent and data collection entirely on a smartphone, the use of machine learning to cluster participants, and the associations between activity patterns, life satisfaction, and self reported disease. Results: From the launch to the time of the data freeze for this study (March to October 2015), the number of individuals (self-selected) who consented to participate was 48 968, representing all 50 states and the District of Columbia. Their median age was 36 years (interquartile range, 27-50 years), and 82.2% (30 338 male, 6556 female, 10 other, and 3115 unknown) were male. In total, 40 017 (81.7% of those who consented) uploaded data. Among those who consented, 20 345 individuals (41.5%) completed 4 of the 7 days of motion data collection, and 4552 individuals (9.3%) completed all 7 days. Among those who consented, 40 017 (81.7%) filled out some portion of the questionnaires, and 4990 (10.2%) completed the 6-minute walk test, made available only at the end of 7 days. The Heart Age Questionnaire, also available after 7 days, required entering lipid values and age 40 to 79 years (among 17 245 individuals, 43.1% of participants). Consequently, 1334 (2.7%) of those who consented completed all fields needed to compute heart age and a 10-year risk score. Physical activity was detected for a mean (SD) of 14.5% (8.0%) of individuals' total recorded time. Physical activity patterns were identified by cluster analysis. A pattern of lower overall activity but more frequent transitions between active and inactive states was associated with equivalent self-reported cardiovascular disease as a pattern of higher overall activity with fewer transitions. Individuals' perception of their activity and risk bore little relation to sensor-estimated activity or calculated cardiovascular risk. Conclusions and Relevance: A smartphone-based study of cardiovascular health is feasible, and improvements in participant diversity and engagement will maximize yield from consented participants. Large-scale, real-world assessment of physical activity, fitness, and sleep using mobile devices may be a useful addition to future population health studies. PMID- 27973670 TI - Fixed-Distance Model for Balloon Placement During Fluoroscopy-Free Resuscitative Endovascular Balloon Occlusion of the Aorta in a Civilian Population. AB - Importance: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an innovative procedure in the treatment of noncompressible truncal hemorrhage. However, readily available fluoroscopy remains a limiting factor in its widespread implementation. Several methods have been proposed to perform REBOA without fluoroscopic guidance, and these methods were adapted predominantly from the military theater. Objective: To develop a method for performing REBOA in a civilian population using a standardized distance from a set point of entry. Design, Setting, and Participants: A retrospective study of whole-body computed tomographic (CT) scans from a cohort of 280 consecutive civilian trauma patients from University Hospitals of Lyon, France, was used to calculate the endovascular distances from both femoral arteries at the level of the upper border of the symphysis pubis to aortic zone I (descending thoracic aorta) and zone III (infrarenal aorta). These whole-body CT scans were performed between 2013 and 2015. Data were analyzed from July 16 to December 7, 2015. Main Outcomes and Measures: Two segments (1 per zone) common to all CT scans were isolated, and their location, length, prevalence in the cohort, and predicted prevalence in the general population were calculated by inverting 99% certainty tolerance limits. Results: Among the 280 trauma patients (140 men and 140 women) in this study, the mean (SD) height was 170.7 (8.7) cm, and the mean (SD) age was 38.8 (16.5) years. The common segment in zone I (414-474 mm) existed in all CT scans. The common segment in zone III (236-256 mm) existed in 99.6% and 97.9% of CT scans from the right and left femoral arteries, respectively. These segments are expected to exist in 98.7% (zone I) and 94.9% (zone III) of the general population. Conclusions and Relevance: Target distances for blind placement of REBOA exist with more than 94% prevalence in a civilian population. These findings support the expanded use of REBOA in emergency department and prehospital settings. Validation for safety and efficacy on cadaveric and clinical models is necessary. PMID- 27973672 TI - First Steps Into the Brave New Transdiscipline of Mobile Health. PMID- 27973673 TI - Prevalence and Causes of Attrition Among Surgical Residents: A Systematic Review and Meta-analysis. AB - Importance: Attrition of residents from general surgery training programs is relatively high; however, there are wide discrepancies in the prevalence and causes of attrition reported among surgical residents in previous studies. Objective: To summarize the estimate of attrition prevalence among general surgery residents. Data Sources: We searched the Medline, EMBASE, Cochrane, PsycINFO, and ERIC databases (January 1, 1946, to October 22, 2015) for studies reporting on the prevalence and causes of attrition in surgical residents, as well as the characteristics and destinations of residents who left general surgery training programs. Database searches were conducted on October 22, 2015. Study Selection: Eligibility criteria included all studies reporting on the primary (attrition prevalence) or secondary (causes of attrition and characteristics and destination of residents who leave residency programs) outcomes in peer-reviewed journals. Commentaries, reviews, and studies reporting on preliminary surgery programs were excluded. Of the 41 full-text articles collected from the title/abstract screening, 22 studies (53.7%) met the selection criteria. Data Extraction and Synthesis: Two reviewers independently collected and summarized the data. We calculated pooled estimates using random effects meta analyses where appropriate. Main Outcome and Measure: Attrition prevalence of general surgery residents. Results: Overall, we included 22 studies that reported on residents (n = 19 821) from general surgery programs. The pooled estimate for the overall attrition prevalence among general surgery residents was 18% (95% CI, 14%-21%), with significant between-study variation (I2 = 96.8%; P < .001). Attrition was significantly higher among female compared with male (25% vs 15%, respectively; P = .008) general surgery residents, and most residents left after their first postgraduate year (48%; 95% CI, 39%-57%). Departing residents often relocated to another general surgery program (20%; 95% CI, 15%-24%) or switched to anesthesia (13%; 95% CI, 11%-16%) and other specialties. The most common reported causes of attrition were uncontrollable lifestyle (range, 12%-87.5%) and transferring to another specialty (range, 19%-38.9%). Conclusions and Relevance: General surgery programs have relatively high attrition, with female residents more likely to leave their training programs than male residents. Residents most often relocate or switch to another specialty after the first postgraduate year owing to lifestyle-related issues. PMID- 27973674 TI - White Scale Sign for Xeroderma. PMID- 27973675 TI - Self-confidence and Embarrassment About Partner-Assisted Skin Self-examination for Melanoma. PMID- 27973676 TI - Shift workers have similar leisure-time physical activity levels as day workers but are more sedentary at work. AB - Objective Physical inactivity has been hypothesized as an underlying factor for the association between shift work and adverse health outcomes. We compared leisure-time and occupational physical activity and sedentary behavior between day, night, and non-night shift workers. Methods We identified 612 day workers, 139 night shift workers and 61 non-night shift workers aged 18-65 years (54% men) in two Danish studies: the New method for Objective Measurements of physical Activity in Daily living (NOMAD) and the Danish Physical ACTivity cohort with Objective measurements (DPhacto) between 2011-2013. Sedentary behavior, light, and moderate-to-vigorous physical activity were measured using an accelerometer. Physical activity was expressed as percentage of leisure and work time spent in each activity. Linear regression analyses were used to test differences in physical activity and sedentary behavior between day, night, and non-night shift workers. Results No differences in leisure-time sedentary behavior and physical activity were observed between day and shift workers (P>0.05). Non-night shift workers spent 7.2% [95% confidence interval (95% CI) 2.3-12.1) more time in occupational sedentary behavior than day workers and 5.9% (95% CI -10.1- -1.7) and 1.9% (95% CI -3.7- -0.2) less time in occupational light and moderate-to vigorous physical activity, respectively. Compared to day workers, night shift workers spent 4.3% (95% CI 2.4-6.1) more time at work in uninterrupted sedentary periods of >=30 minutes. Conclusions Shift workers had similar leisure-time physical activity patterns as day workers, but were more sedentary at work. Future research should elucidate whether occupational physical inactivity and sedentary behavior contributes to shift work-related adverse health effects. PMID- 27973677 TI - Occupational self-coding and automatic recording (OSCAR): a novel web-based tool to collect and code lifetime job histories in large population-based studies. AB - Objectives The standard approach to the assessment of occupational exposures is through the manual collection and coding of job histories. This method is time consuming and costly and makes it potentially unfeasible to perform high quality analyses on occupational exposures in large population-based studies. Our aim was to develop a novel, efficient web-based tool to collect and code lifetime job histories in the UK Biobank, a population-based cohort of over 500 000 participants. Methods We developed OSCAR (occupations self-coding automatic recording) based on the hierarchical structure of the UK Standard Occupational Classification (SOC) 2000, which allows individuals to collect and automatically code their lifetime job histories via a simple decision-tree model. Participants were asked to find each of their jobs by selecting appropriate job categories until they identified their job title, which was linked to a hidden 4-digit SOC code. For each occupation a job title in free text was also collected to estimate Cohen's kappa (kappa) inter-rater agreement between SOC codes assigned by OSCAR and an expert manual coder. Results OSCAR was administered to 324 653 UK Biobank participants with an existing email address between June and September 2015. Complete 4-digit SOC-coded lifetime job histories were collected for 108 784 participants (response rate: 34%). Agreement between the 4-digit SOC codes assigned by OSCAR and the manual coder for a random sample of 400 job titles was moderately good [kappa=0.45, 95% confidence interval (95% CI) 0.42-0.49], and improved when broader job categories were considered (kappa=0.64, 95% CI 0.61 0.69 at a 1-digit SOC-code level). Conclusions OSCAR is a novel, efficient, and reasonably reliable web-based tool for collecting and automatically coding lifetime job histories in large population-based studies. Further application in other research projects for external validation purposes is warranted. PMID- 27973678 TI - Clinical feasibility of Xbox KinectTM training for stroke rehabilitation: A single-blind randomized controlled pilot study. AB - OBJECTIVE: To evaluate the feasibility and safety of Xbox KinectTM training of the upper extremity in subacute stroke rehabilitation. DESIGN: A single-blind, randomized controlled, pilot study. PATIENTS: Twenty consecutive patients with stroke. METHODS: Participants were allocated randomly to 2 groups: the control group received conventional therapy and the experimental group received additional Xbox KinectTM training for 20 sessions. Feasibility and safety were evaluated by treatment attendance rate, patient feedback, proportion of adverse events, and Borg Scale (Borg CR10). RESULTS: Twenty of 131 screened individuals were recruited. Data for 19 patients (73.7% male; mean age 62 years (range 38 79)) were analysed. Treatment attendance ratio for total training time and training time/session was 87% and 90%, respectively. All participants reported that training with the Xbox KinectTM was enjoyable and beneficial. No serious adverse events occurred. Fatigue was the most common adverse event. The mean Borg CR10 score was 7.80, reflecting a very high level of fatigue. The experimental group showed significantly greater improvement than the control group in the Box and Blocks Test, Wolf Motor Function Test and Brunnstrom motor recovery stages. CONCLUSION: Xbox KinectTM training appears feasible and safe in upper extremity ehabilitation after stroke. It could enhance motor and functional recovery of the affected upper extremity as an adjunctive method. PMID- 27973679 TI - Effect on body composition and bone mineral density of walking with a robotic exoskeleton in adults with chronic spinal cord injury. AB - OBJECTIVE: To examine the effect on body composition and bone mineral density of locomotor training using a robotic exoskeleton in individuals with spinal cord injury. STUDY DESIGN: Interventional study. SUBJECTS/METHODS: Five adults with a non-progressive traumatic complete sensorimotor spinal cord injury who were using a wheelchair as a primary mode of mobility. Participants performed a personalized 6-week progressive locomotor training programme using a robotic exoskeleton 3 times/week for up to 60 min. Body composition measures were determined using dual energy X-ray absorptiometry and peripheral quantitative computed tomography. RESULTS: A significant increase in leg and appendicular lean body mass and a decrease in total, leg and appendicular fat mass was observed after the intervention. Furthermore, the calf muscle cross-sectional area increased significantly after the intervention. Finally, although not statistically significant, there was an increase of 14.5% in bone mineral density of the tibia, which may be clinically significant. A decrease of > 5 % was also noted for subcutaneous adipose tissue and intramuscular adipose tissue. CONCLUSION: Locomotor training using a robotic exoskeleton appears to be associated with improvements in body composition and, potentially, bone health. PMID- 27973680 TI - Prostaglandin E2 potentiates interferon-gamma-induced nitric oxide production in cultured rat microglia. AB - Prostaglandin E2 (PGE2 ) plays crucial roles in managing microglial activation through the prostanoid EP2 receptor, a PGE2 receptor subtype. In this study, we report that PGE2 enhances interferon-gamma (IFN-gamma)-induced nitric oxide production in microglia. IFN-gamma increased the release of nitrite, a metabolite of nitric oxide, which was augmented by PGE2 , although PGE2 by itself slightly affects nitrite release. The potentiating effect of PGE2 was positively associated with increased expression of inducible nitric oxide synthase. In contrast to nitrite release induced by IFN-gamma, lipopolysaccharide-induced nitrite release was not affected by PGE2 . An EP2 agonist, ONO-AE1-259-01 also augmented IFN-gamma-induced nitrite release, while an EP1 agonist, ONO-DI-004, an EP3 agonist, ONO-AE-248, or an EP4 agonist, ONO-AE1-329, did not. In addition, the potentiating effect of PGE2 was inhibited by an EP2 antagonist, PF-04418948, but not by an EP1 antagonist, ONO-8713, an EP3 antagonist, ONO-AE3-240, or an EP4 antagonist, ONO-AE3-208, at 10-6 M. Among the EP agonists, ONO-AE1-259-01 alone was able to accumulate cyclic adenosine monophosphate (AMP), and among the EP antagonists, PF-04418948 was the only one able to inhibit PGE2 -increased intracellular cyclic AMP accumulation. On the other hand, IFN-gamma promoted phosphorylation of signal transducer and activator of transcription 1, which was not affected by PGE2 . Furthermore, other prostanoid receptor agonists, PGD2 , PGF2alpha , iloprost, and U-46119, slightly affected IFN-gamma-induced nitrite release. These results indicate that PGE2 potentiates IFN-gamma-induced nitric oxide production in microglia through the EP2 receptor, which may shed light on one of the pro-inflammatory aspects of PGE2 . PMID- 27973681 TI - Dynamic vs. static social networks in models of parasite transmission: predicting Cryptosporidium spread in wild lemurs. AB - Social networks provide an established tool to implement heterogeneous contact structures in epidemiological models. Dynamic temporal changes in contact structure and ranging behaviour of wildlife may impact disease dynamics. A consensus has yet to emerge, however, concerning the conditions in which network dynamics impact model outcomes, as compared to static approximations that average contact rates over longer time periods. Furthermore, as many pathogens can be transmitted both environmentally and via close contact, it is important to investigate the relative influence of both transmission routes in real-world populations. Here, we use empirically derived networks from a population of wild primates, Verreaux's sifakas (Propithecus verreauxi), and simulated networks to investigate pathogen spread in dynamic vs. static social networks. First, we constructed a susceptible-exposed-infected-recovered model of Cryptosporidium spread in wild Verreaux's sifakas. We incorporated social and environmental transmission routes and parameterized the model for two different climatic seasons. Second, we used simulated networks and greater variation in epidemiological parameters to investigate the conditions in which dynamic networks produce larger outbreak sizes than static networks. We found that average outbreak size of Cryptosporidium infections in sifakas was larger when the disease was introduced in the dry season than in the wet season, driven by an increase in home range overlap towards the end of the dry season. Regardless of season, dynamic networks always produced larger average outbreak sizes than static networks. Larger outbreaks in dynamic models based on simulated networks occurred especially when the probability of transmission and recovery were low. Variation in tie strength in the dynamic networks also had a major impact on outbreak size, while network modularity had a weaker influence than epidemiological parameters that determine transmission and recovery. Our study adds to emerging evidence that dynamic networks can change predictions of disease dynamics, especially if the disease shows low transmissibility and a long infectious period, and when environmental conditions lead to enhanced between group contact after an infectious agent has been introduced. PMID- 27973682 TI - Repeatability, heritability, and age-dependence of seasonal plasticity in aggressiveness in a wild passerine bird. AB - Labile characters allow individuals to flexibly adjust their phenotype to changes in environmental conditions. There is growing evidence that individuals can differ both in average expression and level of plasticity in this type of character. Both of these aspects are studied in conjunction within a reaction norm framework. Theoreticians have investigated the factors promoting variation in reaction norm intercepts (average phenotype) and slopes (level of plasticity) of a key labile character: behaviour. A general prediction from their work is that selection will favour the evolution of repeatable individual variation in level of plasticity only under certain ecological conditions. While factors promoting individual repeatability of plasticity have thus been identified, empirical estimates of this phenomenon are largely lacking for wild populations. We assayed aggressiveness of individual male great tits (Parus major) twice during their egg-laying stage and twice during their egg-incubation stage to quantify each male's level of seasonal plasticity. This procedure was applied during six consecutive years; all males breeding in our plots during those years were assayed, resulting in repeated measures of individual reaction norms for any individual breeding in multiple years. We quantified among- and within-individual variation in reaction norm components, allowing us to estimate repeatability of seasonal plasticity. Using social pedigree information, we further partitioned reaction norm components into their additive genetic and permanent environmental counterparts. Cross-year individual repeatability for the intercepts (average aggressiveness) and slopes (level of seasonal plasticity) of the aggressiveness reaction norms were 0.574 and 0.516 respectively. The mean of the posterior distributions suggested modest heritabilities (h2 = 0.260 for intercepts; h2 = 0.266 for slopes), but these estimates were relatively uncertain. Males behaved more aggressively in areas with higher breeding densities, and became less aggressive and less plastic with increasing age; plasticity thus varied within individuals and was multidimensional in nature. This empirical study quantified cross-year individual repeatability, heritability and age-related reversible plasticity in behaviour. Acknowledging such patterns of multi-level variation is important not only for testing behavioural ecology theory concerning the evolution of repeatable differences in behavioural plasticity but also for predicting how reversible plasticity may evolve in natural populations. PMID- 27973683 TI - Climatic conditions produce contrasting influences on demographic traits in a long-distance Arctic migrant. AB - The manner in which patterns of variation and interactions among demographic rates contribute to population growth rate (lambda) is key to understanding how animal populations will respond to changing climatic conditions. Migratory species are likely to be particularly sensitive to climatic conditions as they experience a range of different environments throughout their annual cycle. However, few studies have provided fully integrated demographic analyses of migratory populations in response to changing climatic conditions. Here, we employed integrated population models to demonstrate that the environmental conditions experienced during a short but critical period play a central role in the demography of a long-distance migrant, the light-bellied Brent goose (Branta bernicla hrota). Female survival was positively associated with June North Atlantic Oscillation (NAO) values, whereas male survival was not. In contrast, breeding productivity was negatively associated with June NAO, suggesting a trade off between female survival and reproductive success. Both adult female and adult male survival showed low temporal variation, whereas there was high temporal variation in recruitment and breeding productivity. In addition, while annual population growth was positively correlated with annual breeding productivity, a sensitivity analysis revealed that population growth was most sensitive to changes in adult survival. Our results demonstrate that the environmental conditions experienced during a relatively short-time window at the start of the breeding season play a critical role in shaping the demography of a long-distant Arctic migrant. Crucially, different demographic rates responded in opposing directions to climatic variation, emphasising the need for integrated analysis of multiple demographic traits when understanding population dynamics. PMID- 27973684 TI - The impact of arthrocentesis with and without hyaluronic acid injection in the prognosis and synovial fluid myeloperoxidase levels of patients with painful symptomatic internal derangement of temporomandibular joint: a randomised controlled clinical trial. AB - We aimed to assess the relationship between myeloperoxidase (MPO) and internal derangement (ID) of temporomandibular joint (TMJ) and effects of arthrocentesis procedure, either alone or in combination with hyaluronic acid (HA) injection on the prognosis of ID of TMJ. A prospective randomised controlled trial has been conducted through patients, who underwent arthrocentesis for the treatment of ID of TMJ, were randomly divided into two groups. Group SS (n = 10) and Group HA (n = 14) patients were assigned 0.9% NaCl solution and sodium hyaluronate intra articularly, respectively. Synovial fluid samples were assayed for MPO at the time of arthrocentesis and pain visual analogue scale (VAS) and maximum mouth opening (MMO) scores were recorded at pre- and post-operative periods as well as first-week, first-month and third-month intervals. There was a statistically significant decrease in MPO levels between the first to second arthrocenteses only in Group 2 (P = 0.001). Both VAS scores and MMO measurements decreased in the course of time following arthrocentesis and do not differ between the patients administered HA or SS. Similarly MPO levels do not change significantly between the two groups at either first or second arthrocenteses. In HA group, MPO levels significantly decreased from first to second sessions. In HA group, MPO levels decreased significantly only in patients with clinical success. Arthrocentesis procedure improves both pain VAS and MMO scores in the course of time, but these parameters do not differ between patients receiving either HA or SS. HA significantly reduces levels of MPO in synovial fluid, but SS does not. HA appears to alleviate inflammation inside the TMJ in patients with TMJ-ID. PMID- 27973685 TI - Posterior teeth occlusion and dysphagia risk in older nursing home residents: a cross-sectional observational study. AB - The total number of natural teeth was related to swallowing function among older adults; however, limited information is available regarding the impact of occluding pairs of teeth on swallowing function. This study aimed to examine the association between posterior teeth occlusion and dysphagia risk in older nursing home residents. This cross-sectional study included 238 residents aged >=60 years from eight nursing homes in Aso City, Japan. Swallowing function was evaluated using the modified water swallowing test (MWST); the primary outcome was dysphagia risk (MWST score <=3). Posterior teeth occlusion was assessed using number of functional tooth units (FTUs), determined based on number and location of the remaining natural and artificial teeth on implant-supported, fixed or removable prostheses. Univariate and multivariate logistic regression analyses were performed to examine the association between posterior teeth occlusion and dysphagia risk, adjusted for the covariates of number of natural teeth, demographic characteristics, comorbidities, physical function, body mass index and cognitive function. Of the 238 subjects, 44 (18.5%) were determined to be at risk of dysphagia based on the MWST scores. The odds ratio (OR) of dysphagia risk decreased in subjects with higher total FTUs [OR = 0.92, 95% confidence interval (CI) 0.87-0.98]. After adjusting for covariates, this association remained significant (OR = 0.90, 95% CI 0.84-0.97). Loss of posterior teeth occlusion was independently associated with dysphagia risk in older nursing home residents. Maintaining and restoring posterior teeth occlusion may be an effective measure to prevent dysphagia. PMID- 27973686 TI - Effects of electromagnetic fields on bone loss in hyperthyroidism rat model. AB - Optimal therapeutics for hyperthyroidism-induced osteoporosis are still lacking. As a noninvasive treatment, electromagnetic fields (EMF) have been proven to be effective for treating osteoporosis in non-hyperthyroidism conditions. We herein systematically evaluated the reduced effects of EMF on osteoporosis in a hyperthyroidism rat model. With the use of Helmholtz coils and an EMF stimulator, 15 Hz/1 mT EMF was generated. Forty-eight 5-month-old male Sprague-Dawley rats were randomly divided into four different groups: control, levothyroxine treated (L-T4), EMF exposure + levothyroxine (EMF + L-T4), and EMF exposure without levothyroxine administration (EMF). All rats were treated with L-T4 (100 mg/day) except those in control and EMF groups. After 12 weeks, the results obtained from bone mineral density analyses and bone mechanical measurements showed significant differences between L-T4 and EMF + L-T4 groups. Micro CT and bone histomorphometric analyses indicated that trabecular bone mass and architecture in distal femur and proximal tibia were augmented and restored partially in EMF + L-T4 group. In addition, bone thyroid hormone receptors (THR) expression of hyperthyroidism rats was attenuated in EMF + L-T4 group, compared to control group, which was not observed in L-T4 group. According to these results, we concluded that 15 Hz/1 mT EMF significantly inhibited bone loss and micro architecture deterioration in hyperthyroidism rats, which might occur due to reduced THR expression caused by EMF exposure. Bioelectromagnetics. 38:137-150, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27973688 TI - Paediatric parenting stress in fathers and mothers of young children with Type 1 diabetes: a longitudinal study. AB - AIM: To compare levels of paediatric parenting stress in the fathers and mothers of young children with Type 1 diabetes and study the variation in this stress over time. METHODS: One hundred and twelve parents (56 mothers and 56 fathers) of young children (0-7 years) with Type 1 diabetes participated in this study. They completed the Pediatric Inventory for Parents to assess paediatric parenting stress (frequency and difficulty scores on the Communication, Emotional Distress, Medical Care and Role Functioning subscales and Total Score); 44 mothers (79%) and 31 fathers (55%) completed the questionnaire again, 1 year later. Independent and paired sample t-tests were used to examine the differences between fathers and mothers and the changes over time. Cohen's d effect sizes were also calculated. RESULTS: Mothers scored significantly higher than fathers on the stress subscales for Communication frequency and difficulty, Emotional Distress frequency and difficulty, Medical Care frequency and Total Score frequency and difficulty (d ranged from -0.44 to -0.56). Furthermore, fathers reported a decrease in Medical Care frequency (d = 0.10) and an increase in Emotional Distress difficulty (d = -0.32) and Total Score difficulty (d = -0.29), whereas mothers reported a decrease in Emotional Distress frequency, Medical Care frequency and Total Score frequency (d ranged from 0.31 to 0.66) over a 1-year period. CONCLUSIONS: These results show that within families with a young child with Type 1 diabetes, the burden of care increases in fathers and decreases in mothers, suggesting that fathers assume more responsibility for care of their child with Type 1 diabetes as the child grows. PMID- 27973687 TI - The therapeutic potential of targeting chemokine signalling in the treatment of chronic pain. AB - Chronic pain is a distressing condition, which is experienced even when the painful stimulus, whether surgery or disease related, has subsided. Current treatments for chronic pain show limited efficacy and come with a host of undesirable side-effects, and thus there is a need for new, more effective therapies to be developed. The mechanisms underlying chronic pain are not fully understood at present, although pre-clinical models have facilitated the progress of this understanding considerably in the last decade. The mechanisms underlying chronic pain were initially thought to be neurocentric. However, we now appreciate that non-neuronal cells play a significant role in nociceptive signalling through their communication with neurons. One of the major signalling pathways, which mediates neuron/non-neuronal communication, is chemokine signalling. In this review, we discuss selected chemokines that have been reported to play a pivotal role in the mechanisms underlying chronic pain in a variety of pre-clinical models. Approaches that target each of the chemokines discussed in this review come with their advantages and disadvantages; however, the inhibition of chemokine actions is emerging as an innovative therapeutic strategy, which is now reaching the clinic, with the chemokine Fractalkine and its CX3 CR1 receptor leading the way. This article is part of the special article series "Pain". PMID- 27973689 TI - Inequalities in access to biological treatments for psoriasis: results from the Italian Psocare registry. AB - BACKGROUND: Limited evidence is available on the impact of socioeconomic factors on drug prescriptions for psoriasis. OBJECTIVES: To investigate factors influencing prescription of conventional vs. biological treatment for patients with psoriasis, based on the Italian Psocare registry, with a special focus on socioeconomic factors. METHODS: This was a cross-sectional study evaluating the baseline data of patients included in the Psocare registry. All of the consecutive adult patients with a diagnosis of chronic plaque psoriasis or psoriatic arthritis who were prescribed a systemic treatment for psoriasis at participating centres were included in this study. Univariate and multivariate analyses of the baseline factors associated with a biologics prescription were performed. RESULTS: From September 2005 to September 2009, 12 838 patients were identified. A multivariate analysis revealed that, among other factors, completing a level of education higher than lower secondary school and being employed as a manager or a professional were independent factors associated with a biologics prescription at entry in the registry. Additional analyses on the association between these two variables and a severe psoriasis condition [Psoriasis Area Severity Index (PASI) score > 20] revealed a significantly increasing trend of severe disease towards lower educational attainment, while unemployed patients were more likely to have a more severe condition compared with the other categories of workers. CONCLUSIONS: We documented inequalities of drug prescriptions for psoriasis in Italy, with a trend towards a higher frequency of prescription for more expensive biologics in higher socioeconomic sectors of the population. PMID- 27973690 TI - Single mandibular implant study - denture satisfaction in the elderly. AB - To investigate whether there are differences in patients' denture satisfaction when an implant placed in the midline of the edentulous mandible is loaded either immediately or three months later, after second-stage surgery. One hundred and fifty-eight edentulous patients received a single implant in the midline of the mandible. After randomisation, it was loaded either immediately after implant placement (N = 81, group A) or three months later, after a submerged healing phase and a second-stage surgery (N = 77, group B). Patients' denture satisfaction aspects were assessed, using visual analogue scales (VAS), before treatment, one month after implant placement during the submerged healing phase (only group B) and one and four months after implant loading. The statistical analysis was performed using the Wilcoxon signed-rank and rank-sum tests. One month after loading, a significant improvement in comfort, function and stability of the mandibular denture could be observed in both groups (P <= 0.05). A slight but not significant improvement was found between one and four months after loading. Patients with second-stage surgery and delayed loading rated the stability and fit of the mandibular denture as significantly better than patients who had immediate loading. A single implant in the edentulous mandible significantly increased patients' denture satisfaction. After four months, stability and fit of the mandibular denture were considered better when a delayed loading protocol had been followed. A single mandibular implant in the edentulous mandible significantly increases patients' denture satisfaction, regardless of the loading protocol. PMID- 27973693 TI - Reliability and validity of a tool to measure the severity of tongue thrust in children: the Tongue Thrust Rating Scale. AB - This study aimed to develop a scale called Tongue Thrust Rating Scale (TTRS), which categorised tongue thrust in children in terms of its severity during swallowing, and to investigate its validity and reliability. The study describes the developmental phase of the TTRS and presented its content and criterion-based validity and interobserver and intra-observer reliability. For content validation, seven experts assessed the steps in the scale over two Delphi rounds. Two physical therapists evaluated videos of 50 children with cerebral palsy (mean age, 57.9 +/- 16.8 months), using the TTRS to test criterion-based validity, interobserver and intra-observer reliability. The Karaduman Chewing Performance Scale (KCPS) and Drooling Severity and Frequency Scale (DSFS) were used for criterion-based validity. All the TTRS steps were deemed necessary. The content validity index was 0.857. A very strong positive correlation was found between two examinations by one physical therapist, which indicated intra-observer reliability (r = 0.938, P < 0.001). A very strong positive correlation was also found between the TTRS scores of two physical therapists, indicating interobserver reliability (r = 0.892, P < 0.001). There was also a strong positive correlation between the TTRS and KCPS (r = 0.724, P < 0.001) and a very strong positive correlation between the TTRS scores and DSFS (r = 0.822 and r = 0.755; P < 0.001). These results demonstrated the criterion-based validity of the TTRS. The TTRS is a valid, reliable and clinically easy-to-use functional instrument to document the severity of tongue thrust in children. PMID- 27973692 TI - Type 2 diabetes mellitus in people with severe mental illness: inequalities by ethnicity and age. Cross-sectional analysis of 588 408 records from the UK. AB - AIMS: To investigate whether the association of severe mental illness with Type 2 diabetes varies by ethnicity and age. METHODS: We conducted a cross-sectional analysis of data from an ethnically diverse sample of 588 408 individuals aged >=18 years, registered to 98% of general practices (primary care) in London, UK. The outcome of interest was prevalent Type 2 diabetes. RESULTS: Relative to people without severe mental illness, the relative risk of Type 2 diabetes in people with severe mental illness was greatest in the youngest age groups. In the white British group the relative risks were 9.99 (95% CI 5.34, 18.69) in those aged 18-34 years, 2.89 (95% CI 2.43, 3.45) in those aged 35-54 years and 1.16 (95% CI 1.04, 1.30) in those aged >=55 years, with similar trends across all ethnic minority groups. Additional adjustment for anti-psychotic prescriptions only marginally attenuated the associations. Assessment of estimated prevalence of Type 2 diabetes in severe mental illness by ethnicity (absolute measures of effect) indicated that the association between severe mental illness and Type 2 diabetes was more marked in ethnic minorities than in the white British group with severe mental illness, especially for Indian, Pakistani and Bangladeshi individuals with severe mental illness. CONCLUSIONS: The relative risk of Type 2 diabetes is elevated in younger populations. Most associations persisted despite adjustment for anti-psychotic prescriptions. Ethnic minority groups had a higher prevalence of Type 2 diabetes in the presence of severe mental illness. Future research and policy, particularly with respect to screening and clinical care for Type 2 diabetes in populations with severe mental illness, should take these findings into account. PMID- 27973691 TI - Effects of diet and insulin on dopamine transporter activity and expression in rat caudate-putamen, nucleus accumbens, and midbrain. AB - Food restriction (FR) and obesogenic (OB) diets are known to alter brain dopamine transmission and exert opposite modulatory effects on behavioral responsiveness to psychostimulant drugs of abuse. Mechanisms underlying these diet effects are not fully understood. In this study, we examined diet effects on expression and function of the dopamine transporter (DAT) in caudate-putamen (CPu), nucleus accumbens (NAc), and midbrain regions. Dopamine (DA) uptake by CPu, NAc or midbrain synapto(neuro)somes was measured in vitro with rotating disk electrode voltammetry or with [3 H]DA uptake and was found to correlate with DAT surface expression, assessed by maximal [3 H](-)-2-beta-carbomethoxy-3-beta-(4 fluorophenyl)tropane binding and surface biotinylation assays. FR and OB diets were both found to decrease DAT activity in CPu with a corresponding decrease in surface expression but had no effects in the NAc and midbrain. Diet treatments also affected sensitivity to insulin-induced enhancement of DA uptake, with FR producing an increase in CPu and NAc, likely mediated by an observed increase in insulin receptor expression, and OB producing a decrease in NAc. The increased expression of insulin receptor in NAc of FR rats was accompanied by increased DA D2 receptor expression, and the decreased DAT expression and function in CPu of OB rats was accompanied by decreased DA D2 receptor expression. These results are discussed as partial mechanistic underpinnings of diet-induced adaptations that contribute to altered behavioral sensitivity to psychostimulants that target the DAT. PMID- 27973694 TI - Corticotropin releasing factor dose-dependently modulates excitatory synaptic transmission in the noradrenergic nucleus locus coeruleus. AB - The noradrenergic nucleus locus coeruleus (LC) is critically involved in the stress response and receives afferent input from a number of corticotropin releasing factor (CRF) containing structures. Several in vivo and in vitro studies in rat have shown that CRF robustly increases the firing rate of LC neurons in a dose-dependent manner. While it is known that these increases are dependent on CRF receptor subtype 1 and mediated by effects of cAMP intracellular signaling cascades on potassium conductance, the impact of CRF on synaptic transmission within LC has not been clarified. In the present study, we used whole-cell patch clamp electrophysiology to assess how varying concentrations of bath-applied CRF affect AMPA-receptor dependent spontaneous excitatory post synaptic currents (sEPSCs). Compared to vehicle, 10, 25, and 100 nm CRF had no significant effects on any sEPSC parameters. Fifty nanomolar CRF, however, significantly increased sEPSC amplitude, half-width, and charge transfer, while these measures were significantly decreased by 200 nm CRF. These observations suggest that stress may differentially affect ongoing excitatory synaptic transmission in LC depending on how much CRF is released from presynaptic terminals. Combined with the well-documented effects of CRF on membrane properties and spontaneous LC discharge, these observations may help explain how stress and CRF release are able to modulate the signal to noise ratio of LC neurons. These findings have implications for how stress affects the fidelity of signal transmission and information flow through LC and how it might impact norepinephrine release in the CNS. PMID- 27973695 TI - Organic Multilayer Films Studied by Scanning Tunneling Microscopy. AB - This Minireview focuses exclusively on work with scanning tunneling microscopy to study the self-assembled multilayer films (SAMTs) of organic molecules. The pi conjugated organic molecules form different structures within different monolayers on various substrates. The interplay between molecule-substrate and intermolecular interactions plays a key role in determining the stacking mode of organic multilayer films. Different substrates strongly influence the organic film growth and electronic properties of the organic molecules. Geometric and electronic structures of SAMTs are important factors that may determine device performance. In addition to the inorganic interface, this Minireview addresses the organic-organic interface. Homo- and hetero-SAMTs of organic molecules are also considered. The subtle interplay between structural and electronic characteristics, on one hand, and functionality and reactivity, on the other hand, are highlighted. PMID- 27973696 TI - Agreement between DSM-IV and DSM-5 criteria for alcohol use disorder among outpatients suffering from depressive and anxiety disorders. AB - BACKGROUND AND OBJECTIVES: Since significant differences have been reported, we estimated agreement between DSM-5 and DSM-IV criteria for alcohol use disorder (AUD). METHODS: We assessed 327 outpatients (mean age: 45.2 +/- 13.4) with depressive or anxiety disorders. RESULTS: Absolute differences in prevalence rates between DSM-5 and DSM-IV AUD ranged from -1.1% (subjects with anxiety disorders) to +1.8% (tobacco smokers). The agreement was excellent (k = 0.88), also accounting for specific subgroups (relevant k coefficients >0.80). DISCUSSION AND CONCLUSIONS: DSM-5 criteria did not inflate AUD rates. SCIENTIFIC SIGNIFICANCE: Our results have epidemiological significance since, unlike previous reports, we found diagnostic stability between new and old AUD criteria in this clinical population. (Am J Addict 2017;26:53-56). PMID- 27973697 TI - Enhanced regeneration potential of mobilized dental pulp stem cells from immature teeth. AB - OBJECTIVES: We have previously demonstrated that dental pulp stem cells (DPSCs) isolated from mature teeth by granulocyte colony-stimulating factor (G-CSF) induced mobilization method can enhance angiogenesis/vasculogenesis and improve pulp regeneration when compared with colony-derived DPSCs. However, the efficacy of this method in immature teeth with root-formative stage has never been investigated. Therefore, the aim of this study was to examine the stemness, biological characteristics, and regeneration potential in mobilized DPSCs compared with colony-derived DPSCs from immature teeth. MATERIALS AND METHODS: Mobilized DPSCs isolated from immature teeth were compared to colony-derived DPSCs using methods including flow cytometry, migration assays, mRNA expression of angiogenic/neurotrophic factor, and induced differentiation assays. They were also compared in trophic effects of the secretome. Regeneration potential was further compared in an ectopic tooth transplantation model. RESULTS: Mobilized DPSCs had higher migration ability and expressed more angiogenic/neurotrophic factors than DPSCs. The mobilized DPSC secretome produced a higher stimulatory effect on migration, immunomodulation, anti-apoptosis, endothelial differentiation, and neurite extension. In addition, vascularization and pulp regeneration potential were higher in mobilized DPSCs than in DPSCs. CONCLUSIONS: G-CSF-induced mobilization method enhances regeneration potential of colony derived DPSCs from immature teeth. PMID- 27973698 TI - Acute intoxication due to Wisteria floribunda seed in seven young children. AB - BACKGROUND: Wisteria floribunda is a vine commonly found in Korea, Japan, and the USA. The objective of this observational study was to assess the toxicity of W. floribunda seeds in young children. METHODS: Of 28 children in a kindergarten who participated in a field trip, seven ingested W. floribunda seeds: six half of the seed and one a whole seed. These seven children were admitted to the Gachon University Gil Medical Center in Incheon, Korea. RESULTS: All of the children had vomiting within 4 h of ingesting the W. floribunda seed; the child who ingested a whole seed began to vomit 2 h after ingestion. By 5 h after ingestion, they all complained of abdominal pain and one child was lethargic. Leukocytosis was observed in all of the children. Abdominal pain and vomiting subsided in all of the children within 2 days after admission. The average duration of hospitalization was 3.1 days. CONCLUSIONS: W. floribunda seed ingestion induced gastrointestinal and neurologic symptoms in these young children. Given that the onset of vomiting was earlier in the child who ingested a whole seed than in the children who had ingested only a half, the amount of ingested seeds may be associated with the severity of the symptoms. Ingestion of half a raw W. floribunda seed can cause gastrointestinal symptoms in young children and even result in hospitalization. PMID- 27973700 TI - Strange bedfellows? Nurses as Responsible Clinicians under the Mental Health Act (England & Wales). PMID- 27973699 TI - Synthesis of Novel MU-Star Copolymers with Poly(N-Octyl Benzamide) and Poly(epsilon-Caprolactone) Miktoarms through Chain-Growth Condensation Polymerization, Styrenics-Assisted Atom Transfer Radical Coupling, and Ring Opening Polymerization. AB - Star copolymers are known to phase separate on the nanoscale, providing useful self-assembled morphologies. In this study, the authors investigate synthesis and assembly behavior of miktoarm star (MU-star) copolymers. The authors employ a new strategy for the synthesis of unprecedented MU-star copolymers presenting poly(N octyl benzamide) (PBA) and poly(epsilon-caprolactone) (PCL) arms: a combination of chain-growth condensation polymerization, styrenics-assisted atom transfer radical coupling, and ring-opening polymerization. Gel permeation chromatography, mass-analyzed laser desorption/ionization mass spectrometry, and 1 H NMR spectroscopy reveal the successful synthesis of a well-defined (PBA11 )2 -(PCL15 )4 MU-star copolymer (Mn,NMR ~ 12 620; D = 1.22). Preliminary examination of the PBA2 PCL4 MU-star copolymer reveals assembled nanofibers having a uniform diameter of ~20 nm. PMID- 27973701 TI - Phenotype and genotype analyses in seven families with dentinogenesis imperfecta or dentin dysplasia. AB - OBJECTIVE: Hereditary dentin defects can be categorised into two classes according to their clinical manifestations: dentinogenesis imperfecta (DGI), which includes three types (DGI-I, DGI-II and DGI-III), and dentin dysplasia (DD), which includes two types (DD-I and DD-II). This study investigated the phenotypic characteristics and genetic causes of hereditary dentin defects in seven Chinese families. MATERIALS AND METHODS: Seven families affected with DGI II, DGI-III or DD-II were enrolled. Clinical examinations were performed to determine the phenotypic characteristics, and DNA samples were collected for Sanger sequencing. RESULTS: Clinical diagnoses revealed DGI-II in five families, DGI-III in one family and DD-II in one family. Variants of the dentin sialophosphoprotein (DSPP) gene were found in six of the seven families. Of these, c.52G>T was identified in two families. Each of the remaining four families had a different variant: c.2684delG, c.52-2A>G, c.1874-1877delACAG and c.3509-3521del13bp; the last three variants were novel. CONCLUSIONS: This is the first study to analyse all three important types of hereditary dentin defect and include comprehensive genetic analyses of both dentin sialoprotein and dentin phosphoprotein in Chinese families. This study expands the spectrum of DSPP variants, highlighting their associated phenotypic continuum. PMID- 27973702 TI - Singlet Fission: Progress and Prospects in Solar Cells. AB - The third generation of photovoltaic technology aims to reduce the fabrication cost and improve the power conversion efficiency (PCE) of solar cells. Singlet fission (SF), an efficient multiple exciton generation (MEG) process in organic semiconductors, is one promising way to surpass the Shockley-Queisser limit of conventional single-junction solar cells. Traditionally, this MEG process has been observed as an intermolecular process in organic materials. The implementation of intermolecular SF in photovoltaic devices has achieved an external quantum efficiency of over 100% and demonstrated significant promise for boosting the PCE of third generation solar cells. More recently, efficient intramolecular SF has been reported. Intramolecular SF materials are modular and have the potential to overcome certain design constraints that intermolecular SF materials possess, which may allow for more facile integration into devices. PMID- 27973703 TI - A nomogram based on preoperative inflammatory markers predicting the overall survival of pancreatic ductal adenocarcinoma. AB - BACKGROUND AND AIMS: Developing a preoperative prediction model for estimating the risk of pancreatic ductal adenocarcinoma (PDAC) patients before pancreaticoduodenectomy is a difficult task. The purpose of current study was to develop a prognostic nomogram based on inflammatory markers for PDAC patients. METHODS: Cox regression analysis was performed to calculate the overall survival (OS) and assess the prognostic factors based on 265 PDAC patients undergone surgery. The nomogram was built to estimate the probability of 1-year, 3-year, and 5-year OS. The predictive accuracy of nomogram was determined by concordance index, calibration curve, and time dependent receiver operating characteristics. RESULTS: In multivariable Cox analysis, vascular invasion, Tumor Grade, TNM stage, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and albumin/globulin ratio were significantly associated with OS, which were all assembled into nomogram. The calibration curves for probability of survival showed optimal agreement between nomogram prediction and actual observation. The concordance index for 1-year, 3-year and 5-year OS prediction were 0.860 (95% confidence intervals (CI): 0.837-0.885), 0.837 (95%CI: 0.819-0.856), and 0.809 (95%CI: 0.787-0.829), respectively. The area under time dependent receiver operating characteristics curve of 1-year, 3-year, and 5-year OS prediction were 0.938 (95%CI: 0.886-0.989), 0.844 (95%CI: 0.782-0.906), and 0.884 (95%CI: 0.792 0.976), suggesting high discriminative ability of nomogram. It allowed significant distinction survival outcomes by grouping the patients evenly into three subgroups after sorting by total points. CONCLUSIONS: Based on clinicopathology characteristics and inflammatory markers, we developed a nomogram providing an individualized risk estimate for PDAC patients. PMID- 27973704 TI - Crosstalk between Hippo signalling and miRNAs in tumour progression. AB - The Hippo signalling pathway co-ordinately modulates cell regeneration and organ size, and its deregulation contributes to tumorigenesis through many cellular processes, including overproliferation, apoptosis resistance and cell migration. Recent discoveries have shed new light on how microRNAs (miRNAs) are closely linked to the Hippo pathway in tumour progression. Hippo signalling has been reported to affect widespread miRNA biogenesis. In turn, several miRNAs regulate Hippo signalling, which contributes to carcinogenesis. This article will provide an overview of the crosstalk between Hippo signalling and miRNAs in the development of cancer and further appraise potential targets for therapeutic intervention. PMID- 27973705 TI - Metabolic engineering of Mannheimia succiniciproducens for succinic acid production based on elementary mode analysis with clustering. AB - Mannheimia succiniciproducens, a capnophilic gram-negative rumen bacterium, has been employed for the efficient production of succinic acid. Although M. succiniciproducens metabolism was previously studied using a genome-scale metabolic model, more metabolic characteristics are to be understood. To this end, elementary mode analysis accompanied with clustering ('EMC' analysis) is used to gain further insights on metabolic characteristics of M. succiniciproducens allowing efficient succinic acid production. Elementary modes (EMs) generated from the central carbon metabolic network of M. succiniciproducens are clustered to systematically analyze succinic acid production routes. Based on the results of EMC analysis, zwf gene is identified as a novel overexpression target for the improved succinic acid production. This gene is overexpressed in a previously constructed succinic acid-overproducing M. succiniciproducens LPK7 strain. Heterologous NADPH-dependent mdh is later intuitively selected for overexpression to synergistically improve succinic acid production by utilizing abundant NADPH pool mediated by the overexpressed zwf. The LPK7 strains co-expressing mdh alone and both zwf and mdh genes are subjected to fed-batch fermentation to better examine their succinic acid production performances. Strategies of EMC analysis will be useful for further metabolic engineering of M. succiniciproducens and other microorganisms to improve production of succinic acid and other chemicals of interest. PMID- 27973706 TI - The Direct Observation of Nurse Practitioner Care study: An overview of the NP/patient visit. AB - BACKGROUND AND PURPOSE: While there is a preponderance of studies that demonstrate the quality of nurse practitioner (NP) practice, little is known on the practice style of NPs. The Direct Observation of Nurse Practitioner Care study provided the first national direct observation and characterization of patient care delivered by primary care NPs. METHODS: The setting for this study was ambulatory care practices of NPs located throughout the United States. A nested sample was utilized, consisting of 22 NPs during visits with 245 patients. Observational data were collected during each visit using the Davis observation code (DOC). Patient information was collected from chart reviews and postvisit surveys. Each NP filled out a demographic and practice survey. CONCLUSIONS: Visits to NPs were 18 min on average, and were most frequently for new/acute problems (45.1%) or routine chronic problems (30.2%). Overall, NPs spent the most time planning treatment, history taking, and providing health education. Topics that NPs frequently provided health education about included medication action and side effects, disease process education, diet, and nutrition. IMPLICATIONS FOR PRACTICE: Data from this study will allow for detailed characterizations of a patient-NP visit and average length of the visit and the time use based on the DOC. PMID- 27973707 TI - Moonlighting chaperone-like activity of the universal regulatory 14-3-3 proteins. AB - The ubiquitous eukaryotic 14-3-3 proteins coordinate multiple cellular processes due to their well-known regulatory function, which is based on specific recognition of phosphorylated motifs in their partners. In this context, 14-3-3 proteins have been called 'chaperones'. Although in the classical meaning this is not fully correct, recent studies have revealed that they can indeed be an integral part of the protein quality control system, as they (a) display ATP independent anti-aggregation ('holdase') activity, similar to that of the unrelated small heat shock proteins, (b) assist in clearing misfolded proteins by directing them to proteasomes or aggresomes, (c) cooperate with classical chaperones for substrate refolding, and also (d) are associated with neurodegenerative disorders by affecting aggregation of tau, prion protein, alpha synuclein, huntingtin, etc. Importantly, these activities are usually independent of substrate phosphorylation and therefore should be considered as distinct, 'moonlighting' functions of 14-3-3 proteins that mimic and complement the functions of dedicated molecular chaperones. Although the precise mechanism of this activity is still unknown, it has been shown that it is not dependent on the unstructured C-terminal region or the amphipathic phosphopeptide-binding groove. However, since disassembly of 14-3-3 dimers significantly increases their chaperone-like activity, the dimer interface, located in the N terminus, possessing a high disorder propensity and pronounced hydrophobicity, is likely to be involved. Various factors affecting the oligomeric status of 14-3-3 proteins can thus regulate the balance between regulatory phosphomotif binding and genuine chaperone-like activity. Understanding the latter mode of 14-3-3 functioning is fundamental to defining the underlying molecular mechanisms for a range of human disorders. PMID- 27973708 TI - PEOT/PBT Guides Enhance Nerve Regeneration in Long Gap Defects. AB - Development of new nerve guides is required for replacing autologous nerve grafts for the repair of long gap defects after nerve injury. A nerve guide comprised only of electrospun fibers able to bridge a critical (15 mm) nerve gap in a rat animal model is reported for the first time. The nerve conduits are made of poly(ethylene oxide terephthalate) and poly(butylene terephthalate) (PEOT/PBT), a biocompatible copolymer composed of alternating amorphous, hydrophilic poly(ethylene oxide terephthalate), and crystalline, hydrophobic poly(butylene terephthalate) segments. These guides show suitable mechanical properties, high porosity, and fibers aligned in the longitudinal axis of the guide. In vitro studies show that both neurites and Schwann cells exhibit growth alignment with PA fibers. In vivo studies reveal that, after rat sciatic nerve transection and repair with PEOT/PBT guides, axons grow occupying a larger area compared to silicone tubes. Moreover, after repair of limiting (10 mm) and critical (15 mm) nerve gaps, PEOT/PBT guides significantly increase the percentage of regenerated nerves, the number of regenerated myelinated axons, and improve motor, sensory, and autonomic reinnervation in both gaps. This nerve conduit design combines the properties of PEOT/PBT with electrospun structure, demonstrating that nerve regeneration through long gaps can be achieved through the design of instructive biomaterial constructs. PMID- 27973709 TI - Cationic and Neutral Rotaxanes Having Different Functional Groups in the Axle Molecule and Their Coordination to PtII. AB - Dibenzo[24]crown-8 (DB24C8) forms rotaxanes with a linear molecule having a dialkylammonium group and a triazole group as well as with the acetylation product of a cationic axle molecule. The former cationic rotaxane is stabilized by multiple intermolecular hydrogen bonds between the NH2+ and oxyethylene groups. The neutral rotaxane contains the macrocycle in the vicinity of the terminal aryl group. The co-conformation of both the cationic and neutral rotaxanes can be fixed by coordination of the triazole group of the axle molecule to PtCl2 (dmso)2 . A 1 H NMR spectroscopic study on the thermodynamics of the Pt coordination revealed a larger association constant for the rotaxanes than for the corresponding axle molecules and a larger value for the neutral rotaxane than for the cationic rotaxane. PMID- 27973710 TI - Single Cell Microgel Based Modular Bioinks for Uncoupled Cellular Micro- and Macroenvironments. AB - Modular bioinks based on single cell microgels within distinct injectable prepolymers enable uncoupling of biomaterials' micro- and macroenvironments. These inks allow biofabrication of 3D constructs that recapitulate the multiscale modular design of native tissues with a single cell resolution. This approach represents a major step forward in endowing engineered constructs with the multifunctionality that underlies the behavior of native tissues. PMID- 27973713 TI - Subjects with temporomandibular joint disc displacement do not feature any peculiar changes in body posture. AB - The presence of body posture changes among patients with temporomandibular disorders (TMD) has been a controversial topic in dentistry. Based on that, the aim of this study was to assess postural features of pain-free subjects with internal derangement of the temporomandibular joint (TMJ), viz. disc displacement, when compared to subjects with normal disc position. A total of 21 subjects with unilateral, pain-free TMJ disc displacement (DD) and 21 subjects without any TMD signs of symptoms were assessed for body posture changes by means of posturographic evaluation of several body segments and postural balance reactions through the centre of mass during jaw movements using a balance platform. Posturographic measurements showed the absence of any significant differences between the two groups in any of the outcome parameters. Similarly, all balance platform responses to mandibular movements were not different between groups. There are no significant differences in body posture between subjects with and without unilateral disc displacement in the temporomandibular joint. Such observations, indicating a well-preserved postural balance in the presence of TMJ internal derangement, put into serious question the potential influence of TMJ disorders on whole body posture and viceversa. PMID- 27973712 TI - Experimental evidence for sexual selection against inbred males. AB - The detrimental effects of matings between relatives are well known. However, few studies determine the extent to which inbreeding depression in males is due to natural or sexual selection. Importantly, measuring fitness or key fitness components, rather than phenotypic traits allows more accurate estimation of inbreeding depression. We investigate how differences in inbreeding and juvenile diet (i.e. early stressful environment) influence a key component of male fitness, namely their reproductive success. We experimentally created inbred and outbred male mosquitofish (Gambusia holbrooki) by mating full-sibs (f = 0.25). We show that this led to a 23% reduction in genome-wide heterozygosity based on SNPs. Males were raised on different diets early in life to create high-stress and low-stress rearing environments. We then allowed adult males to compete freely for females to test if inbreeding, early diet and their interaction affect a male's share of paternity. Early diet had no effect on paternity, but outbred males sired almost twice as many offspring as inbred males (n = 628 offspring from 122 potential sires). Using artificial insemination methods we determined that this was unlikely to be due to early embryo mortality of eggs fertilised by inbred males: there was no evidence that male inbreeding status affects the realised fecundity of females (n = 288). Given there was no difference in male mortality in our competitive mating experiment, the lower reproductive success of inbred males can most parsimoniously be attributed to inbreeding negatively affecting sexually selected traits that affect male mating success and/or sperm competitiveness. We discuss which sexually selected traits might be involved. PMID- 27973711 TI - Wisteria floribunda agglutinin-positive human Mac-2 binding protein predicts the risk of HBV-related liver cancer development. AB - BACKGROUND & AIMS: Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+ -M2BP) can be used to assess the degree of liver fibrosis, but few studies have investigated its prognostic utility. We evaluated whether serum WFA+ -M2BP can predict the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. METHODS: A total of 1323 CHB patients with WFA+ -M2BP test results between 2009 and 2011 were included in this retrospective analysis. RESULTS: The mean age of patients (793 men) was 51.0 years. During the follow-up period (median 60.3 months), 52 (3.9%) patients developed HCC. Age, the proportion of male gender, the presence of diabetes and cirrhosis, and levels of aspartate aminotransferase, alpha-foetoprotein, and WFA+ -M2BP were significantly greater in patients with HCC than in those without HCC, whereas serum albumin levels and platelet counts were significantly lower in patients with HCC than in those without HCC (all P<.05). In multivariate analysis, WFA+ -M2BP level was an independent predictor of HCC development (adjusted hazard ratio 1.143, 95% CI: 1.139-1.829), along with male gender and diabetes (all P<.05). In patients without cirrhosis (n=1087), WFA+ -M2BP levels >=1.8 were associated with a higher risk of HCC development (P<.001 by log-rank test), whereas WFA+ -M2BP levels >=1.8 tended to be associated with a higher risk of HCC development in patients with cirrhosis (n=236) (P=.073 by log-rank test). CONCLUSIONS: WFA+ -M2BP level can independently predict HCC development. Further studies should investigate whether WFA+ -M2BP level could be incorporated into surveillance strategies for CHB patients. PMID- 27973714 TI - Ethics of Mitochondrial Replacement Techniques: A Habermasian Perspective. AB - Jurgen Habermas is regarded as a central bioconservative commentator in the debate on the ethics of human prenatal genetic manipulations. While his main work on this topic, The Future of Human Nature, has been widely examined in regard to his position on prenatal genetic enhancement, his arguments regarding prenatal genetic therapeutic interventions have for the most part been overlooked. In this work I do two things. First, I present the three necessary conditions that Habermas establishes for a prenatal genetic manipulation to be regarded as morally permissible. Second, I examine if mitochondrial replacement techniques meet these necessary conditions. I investigate, specifically, the moral permissibility of employing pronuclear transfer and maternal spindle transfer. I conclude that, according to a Habermasian perspective on prenatal genetic manipulation, maternal spindle transfer (without using a preselected sperm and egg) and pronuclear transfer are morally impermissible. Maternal spindle transfer is, in principle, morally permissible, but only when we have beforehand preselected a sperm and an egg for our reproductive purpose. These findings are relevant for bioconservatives, both for those who hold a Habermasian stance and for those who hold something akin to a Habermasian stance, because they answer the question: what should bioconservatives do regarding mitochondrial replacement techniques? In fact, the answer to this question does not only normatively prescribe what bioconservatives should do in terms of their personal morality, but it also points towards what kind of legislation regulating mitochondrial replacement techniques they should aim at. PMID- 27973715 TI - The Ethics of Mitochondrial Replacement. PMID- 27973717 TI - Corrigendum. PMID- 27973716 TI - Is Mitochondrial Donation Germ-Line Gene Therapy? Classifications and Ethical Implications. AB - The classification of techniques used in mitochondrial donation, including their role as purported germ-line gene therapies, is far from clear. These techniques exhibit characteristics typical of a variety of classifications that have been used in both scientific and bioethics scholarship. This raises two connected questions, which we address in this paper: (i) how should we classify mitochondrial donation techniques?; and (ii) what ethical implications surround such a classification? First, we outline how methods of genetic intervention, such as germ-line gene therapy, are typically defined or classified. We then consider whether techniques of mitochondrial donation fit into these, whether they might do so with some refinement of these categories, or whether they require some other approach to classification. To answer the second question, we discuss the relationship between classification and several key ethical issues arising from mitochondrial donation. We conclude that the properties characteristic of mitochondrial inheritance mean that most mitochondrial donation techniques belong to a new sub-class of genetic modification, which we call 'conditionally inheritable genomic modification' (CIGM). PMID- 27973718 TI - Human Nuclear Genome Transfer (So-Called Mitochondrial Replacement): Clearing the Underbrush. AB - In this article, I argue that there is no compelling therapeutic 'need' for human nuclear genome transfer (so-called mitochondrial replacement) to prevent mitochondrial diseases caused by mtDNA mutations. At most there is a strong interest in (i.e. 'want' for) this technology on the part of some women and couples at risk of having children with mitochondrial disease, and perhaps also a 'want' on the part of some researchers who see the technology as a useful precedent - one that provides them with 'a quiet way station' in which to refine the micromanipulations techniques essential for other human germline interventions and human cloning. In advance of this argument, I review basic information about mitochondrial disease and novel genetic strategies to prevent the transmission of mutated mitochondria. Next, I address common features of contemporary debates and discussions about so-called mitochondrial replacement. First, I contest the cliche that science-and-(bio)technology is fast outpacing ethics. Second, I dispute the accuracy of the term 'mitochondrial replacement'. Third, I provide a sustained critique of the purported 'need' for genetically related children. In closing, I call into question the mainly liberal defense of human nuclear genome transfer. I suggest an alternative frame of reference that pays particular attention to issues of social justice. I conclude that our limited resources (time, talent, human eggs, and money) should be carefully expended in pursuit of the common good, which does not include pandering to acquired desires (i.e., wants). PMID- 27973719 TI - Mitochondrial Replacement Techniques: Who are the Potential Users and will they Benefit? AB - In February 2015 the UK became the first country to legalise high-profile mitochondrial replacement techniques (MRTs), which involve the creation of offspring using genetic material from three individuals. The aim of these new cell reconstruction techniques is to prevent the transmission of maternally inherited mitochondrial disorders to biological offspring. During the UK debates, MRTs were often positioned as a straightforward and unique solution for the 'eradication' of mitochondrial disorders, enabling hundreds of women to have a healthy, biologically-related child. However, many questions regarding future applications and potential users remain. Drawing on a current qualitative study on reproductive choices in the context of mitochondrial disorders, this article illustrates how the potential limitations of MRTs have been obscured in public debates by contrasting the claims made about the future beneficiaries with insights from families affected by mitochondrial disorders and medical experts. The analysis illuminates the complex choices with which families and individuals affected by mitochondrial disorders are faced, which have thus far remained invisible. An argument is presented for improved information for the public as well as an intensification of critical empirical research around the complex and specific needs of future beneficiaries of new reproductive biotechnologies. PMID- 27973720 TI - Corrigendum. PMID- 27973721 TI - Do Mitochondrial Replacement Techniques Affect Qualitative or Numerical Identity? AB - Mitochondrial replacement techniques (MRTs), known in the popular media as 'three parent' or 'three-person' IVFs, have the potential to enable women with mitochondrial diseases to have children who are genetically related to them but without such diseases. In the debate regarding whether MRTs should be made available, an issue that has garnered considerable attention is whether MRTs affect the characteristics of an existing individual or whether they result in the creation of a new individual, given that MRTs involve the genetic manipulation of the germline. In other words, do MRTs affect the qualitative identity or the numerical identity of the resulting child? For instance, a group of panelists on behalf of the UK Human Fertilisation and Embryology Authority (HFEA) has claimed that MRTs affect only the qualitative identity of the resulting child, while the Working Group of the Nuffield Council on Bioethics (NCOB) has argued that MRTs would create a numerically distinct individual. In this article, I shall argue that MRTs do create a new and numerically distinct individual. Since my explanation is different from the NCOB's explanation, I shall also offer reasons why my explanation is preferable to the NCOB's explanation. PMID- 27973722 TI - A Mitochondrial Story: Mitochondrial Replacement, Identity and Narrative. AB - Mitochondrial replacement techniques (MRT) are intended to avoid the transmission of mitochondrial diseases from mother to child. MRT represent a potentially powerful new biomedical technology with ethical, policy, economic and social implications. Among other ethical questions raised are concerns about the possible effects on the identity of children born from MRT, their families, and the providers or donors of mitochondria. It has been suggested that MRT can influence identity (i) directly, through altering the genetic makeup and physical characteristics of the child, or (ii) indirectly through changing the child's experience of disease, and by generating novel intrafamilial relationships that shape the sense of self. In this article I consider the plausibility and ethical implications of these proposed identity effects, but I focus instead on a third way in which identity may be affected, through the mediating influence of the wider social world on MRT effects on identity. By taking a narrative approach, and examining the nature and availability of identity narratives, I conclude that while neither direct genetic nor indirect experiential effects can be excluded, social responses to MRT are more likely to have a significant and potentially damaging influence on the generation of MRT children's narratives of identity. This conclusion carries some implications for the collective moral responsibility we hold to ensure that MRT, if implemented, are practised in ethically justifiable ways. PMID- 27973723 TI - Influence of cognitive function on quality of life in anorexia nervosa patients. AB - AIM: The purpose of this study was to elucidate determinants of quality of life (QOL) in anorexia nervosa (AN) patients. METHODS: Twenty-one female patients with AN participated in the study. QOL was assessed with the 36-Item Short Form Health Survey (SF-36), and cognitive function was evaluated using the Wisconsin Card Sorting Test Keio version, the Rey Complex Figure Test, and the Social Cognition Screening Questionnaire. Clinical symptoms were evaluated with the Beck Depression Inventory-II, the State-Trait Anxiety Inventory-Form JYZ (STAI-JYZ), and the Maudsley Obsessive Compulsive Inventory. RESULTS: The Difficulty Maintaining Set score of the Wisconsin Card Sorting Test Keio version was negatively correlated to the SF-36 Physical Component Summary. Scores of the Beck Depression Inventory-II and the STAI-JYZ State and Trait were negatively correlated to the SF-36 Mental Component Summary (MCS), and the Central Coherence Index 30-min Delayed Recall score of the Rey Complex Figure Test was positively correlated with the MCS. Stepwise regression analysis showed that the Difficulty Maintaining Set score was an independent predictor of the Physical Component Summary and scores for Central Coherence Index 30-min Delayed Recall and the STAI JYZ Trait-predicted MCS. CONCLUSION: These results suggest that not only trait anxiety but also poor central coherence and impaired ability to maintain new rule worsen AN patients' QOL. PMID- 27973724 TI - Investigations on Antioxidant, Antiproliferative and COX-2 Inhibitory Potential of Alkaloids from Anthocephalus cadamba (Roxb.) Miq. Leaves. AB - In the present study, an ayurvedic medicinal plant, Anthocephalus cadamba (Roxb.) Miq. commonly known as 'Kadamb' was explored for its potential against oxidative stress and cancer. The fractions namely AC-4 and ACALK (alkaloid rich fraction) were isolated from A. cadamba leaves by employing two different isolation methods and evaluated for their in vitro antioxidant and antiproliferative activity. The structure of the isolated AC-4 was characterized tentatively as dihydrocadambine by using various spectroscopic techniques such as ESI-QTOF-MS, 1 H- and 13 C-NMR, DEPT, COSY, HMQC, and HMBC. Results of various antioxidant assays viz. 2,2 diphenyl-1-picrylhydrazyl (DPPH), ABTS cation radical, superoxide anion radical scavenging, and plasmid nicking assay demonstrated that both the fractions viz. AC-4 and ACALK possess ability to scavenge DPPH, ABTS radicals and effectively protected plasmid pBR322 DNA from damage caused by hydroxyl radicals. Further, when both fractions were evaluated for their potential to suppress growth of HeLa and COLO 205 cells, only ACALK fraction showed antiproliferative effects. ACALK exhibited GI50 of 205.98 and 99.54 MUg/ml in HeLa and COLO 205 cell lines, respectively. Results of Hoechst staining in cervical carcinoma (HeLa) cells confirmed that ACALK induced cell death in HeLa cells via apoptotic mode. Both the fractions also inhibited COX-2 enzyme activity. PMID- 27973725 TI - Synthesis of Novel Hybrids of Thymoquinone and Artemisinin with High Activity and Selectivity Against Colon Cancer. AB - Colorectal cancer causes 0.5 million deaths each year. To combat this type of cancer the development of new specific drug candidates is urgently needed. In the present work seven novel thymoquinone-artemisinin hybrids with different linkers were synthesized and tested for their in vitro anticancer activity against a panel of various tumor cell lines. The thymoquinone-artesunic acid hybrid 7 a, in which both subunits are connected via an ester bond, was found to be the most active compound and selectively decreased the viability of colorectal cancer cells with an IC50 value of 2.4 MUm (HCT116) and 2.8 MUm (HT29). Remarkably, hybrid 7 a was up to 20-fold more active than its parent compounds (thymoquinone and artesunic acid), while not affecting nonmalignant colon epithelial HCEC cells (IC50 >100 MUm). Moreover, the activity of hybrid 7 a was superior to that of various 1:1 mixtures of thymoquinone and artesunic acid. Furthermore, hybrid 7 a was even more potent against both colon cancer cell lines than the clinically used drug 5-fluorouracil. These results are another excellent proof of the hybridization concept and confirm that the type and length of the linker play a crucial role for the biological activity of a hybrid drug. Besides an increase in reactive oxygen species (ROS), elevated levels of the DNA-damage marker gamma H2AX were observed. Both effects seem to be involved in the molecular mechanism of action for hybrid 7 a in colorectal cancer cells. PMID- 27973727 TI - Effect of carrageenan addition on the rennet-induced gelation of skim milk. PMID- 27973726 TI - Nuclear transplantation, the conservation of the genome, and prospects for cell replacement. AB - Initial nuclear transplantation experiments in Xenopus eggs provided the first evidence for the conservation of the genome after cellular differentiation. This Discovery-in-Context Review recounts the early experiments that led to successful nuclear transfer in amphibians and the establishment of totipotency of a differentiated cell and shows how these discoveries paved the way for similar cloning experiments in other organisms. PMID- 27973729 TI - Accurate estimates of age at maturity from the growth trajectories of fishes and other ectotherms. AB - Age at maturity (AAM) is a key life history trait that provides insight into ecology, evolution, and population dynamics. However, maturity data can be costly to collect or may not be available. Life history theory suggests that growth is biphasic for many organisms, with a change-point in growth occurring at maturity. If so, then it should be possible to use a biphasic growth model to estimate AAM from growth data. To test this prediction, we used the Lester biphasic growth model in a likelihood profiling framework to estimate AAM from length at age data. We fit our model to simulated growth trajectories to determine minimum data requirements (in terms of sample size, precision in length at age, and the cost to somatic growth of maturity) for accurate AAM estimates. We then applied our method to a large walleye Sander vitreus data set and show that our AAM estimates are in close agreement with conventional estimates when our model fits well. Finally, we highlight the potential of our method by applying it to length at age data for a variety of ectotherms. Our method shows promise as a tool for estimating AAM and other life history traits from contemporary and historical samples. PMID- 27973728 TI - Nitrogen removal in Myriophyllum aquaticum wetland microcosms for swine wastewater treatment: 15 N-labelled nitrogen mass balance analysis. AB - BACKGROUND: Ecological treatments are effective for treating agricultural wastewater. In this study, wetland microcosms vegetated with Myriophyllum aquaticum were designed for nitrogen (N) removal from two strengths of swine wastewater, and 15 N-labelled ammonium (NH4+ -N) was added to evaluate the dominant NH4+ -N removal pathway. RESULTS: The results showed that 98.8% of NH4+ N and 88.3% of TN (TN: 248.6 mg L-1 ) were removed from low-strength swine wastewater (SW1) after an incubation of 21 days, with corresponding values for high-strength swine wastewater (SW2) being 99.2% of NH4+ -N and 87.8% of TN (TN: 494.9 mg L-1 ). Plant uptake and soil adsorption respectively accounted for 24.0% and 15.6% of the added 15 N. Meanwhile, above-ground tissues of M. aquaticum had significantly higher biomass and TN content than below-ground (P < 0.05). 15 N mass balance analysis indicated that gas losses contributed 52.0% to the added 15 N, but the N2 O flux constituted only 7.5% of total gas losses. The dynamics of NO3- -N and N2 O flux revealed that strong nitrification and denitrification occurred in M. aquaticum microcosms, which was a dominant N removal pathway. CONCLUSION: These findings demonstrated that M. aquaticum could feasibly be used to construct wetlands for high N-loaded animal wastewater treatment. (c) 2016 Society of Chemical Industry. PMID- 27973730 TI - Photobiomodulation or low-level laser therapy. PMID- 27973731 TI - Photodynamic Therapy (PDT). PMID- 27973732 TI - Projected changes in prevailing winds for transatlantic migratory birds under global warming. AB - A number of terrestrial bird species that breed in North America cross the Atlantic Ocean during autumn migration when travelling to their non-breeding grounds in the Caribbean or South America. When conducting oceanic crossings, migratory birds tend to associate with mild or supportive winds, whose speed and direction may change under global warming. The implications of these changes for transoceanic migratory bird populations have not been addressed. We used occurrence information from eBird (1950-2015) to estimate the geographical location of population centres at a daily temporal resolution across the annual cycle for 10 transatlantic migratory bird species. We used this information to estimate the location and timing of autumn migration within the transatlantic flyway. We estimated how prevailing winds are projected to change within the transatlantic flyway during this time using daily wind speed anomalies (1996-2005 and 2091-2100) from 29 Atmosphere-Ocean General Circulation Models implemented under CMIP5. Autumn transatlantic migrants have the potential to encounter strong westerly crosswinds early in their transatlantic journey at intermediate and especially high migration altitudes, strong headwinds at low and intermediate migration altitudes within the Caribbean that increase in strength as the season progresses, and weak tailwinds at intermediate and high migration altitudes east of the Caribbean. The CMIP5 simulations suggest that, during this century, the likelihood of autumn transatlantic migrants encountering strong westerly crosswinds will diminish. As global warming progresses, the need for species to compensate or drift under the influence of strong westerly crosswinds during the initial phase of their autumn transatlantic journey may be diminished. Existing strategies that promote headwind avoidance and tailwind assistance will likely remain valid. Thus, climate change may reduce time and energy requirements and the chance of mortality or vagrancy during a specific but likely critical portion of these species' autumn migration journey. PMID- 27973734 TI - Two-Color Three-State Luminescent Lanthanide Core-Shell Crystals. AB - Luminescent core-shell crystals based on lanthanide tris-dipicolinate complexes were obtained from the successive growing of two different lanthanide complex layers. Selective or simultaneous emission of each part of the crystal can be achieved by a careful choice of the excitation wavelength. PMID- 27973735 TI - The role of p38alpha in Schwann cells in regulating peripheral nerve myelination and repair. AB - Myelination in the peripheral nervous system (PNS) is controlled by both positive and negative regulators within Schwann cells to ensure timely onset and correct myelin thickness for saltatory conduction by neurons. Transcription factors such as Sox10, octamer-binding transcription factor 6 (Oct6) and Krox20 form a positive regulatory network, whereas negative regulators such as cJun and Sox2 oppose myelination in Schwann cells. The role of the p38 MAPK pathway has been studied in PNS myelination, but its precise function remains unclear, with both positive and negative effects of p38 activity reported upon both myelination and processes of nerve repair. To clarify the role of p38 MAPK in the PNS, we have analysed mice with a Schwann cell-specific ablation of the major p38 isoform, p38alpha. In line with previous findings of an inhibitory role for p38 MAPK, we observe acceleration of post-natal myelination in p38alpha null nerves, a delay in myelin down-regulation following injury, together with a small increase in levels of re-myelination following injury. Finally we explored roles for p38alpha in controlling axonal regeneration and functional repair following PNS injury and observe that loss of p38alpha function in Schwann cells does not appear to affect these processes as previously reported. These studies therefore provide further proof for a role of p38 MAPK signalling in the control of myelination by Schwann cells in the PNS, but do not show an apparent role for signalling by this MAP kinase in Schwann cells controlling other elements of Wallerian degeneration and functional repair following injury. Cover Image for this issue: doi: 10.1111/jnc.13793. PMID- 27973733 TI - New insights into the evolutionary origins of the recombination-activating gene proteins and V(D)J recombination. AB - The adaptive immune system of jawed vertebrates relies on V(D)J recombination as one of the main processes to generate the diverse array of receptors necessary for the recognition of a wide range of pathogens. The DNA cleavage reaction necessary for the assembly of the antigen receptor genes from an array of potential gene segments is mediated by the recombination-activating gene proteins RAG1 and RAG2. The RAG proteins have been proposed to originate from a transposable element (TE) as they share mechanistic and structural similarities with several families of transposases and are themselves capable of mediating transposition. A number of RAG-like proteins and TEs with sequence similarity to RAG1 and RAG2 have been identified, but only recently has their function begun to be characterized, revealing mechanistic links to the vertebrate RAGs. Of particular significance is the discovery of ProtoRAG, a transposon superfamily found in the genome of the basal chordate amphioxus. ProtoRAG has many of the sequence and mechanistic features predicted for the ancestral RAG transposon and is likely to be an evolutionary relative of RAG1 and RAG2. In addition, early observations suggesting that RAG1 is able to mediate V(D)J recombination in the absence of RAG2 have been confirmed, implying independent evolutionary origins for the two RAG genes. Here, recent progress in identifying and characterizing RAG-like proteins and the TEs that encode them is summarized and a refined model for the evolution of V(D)J recombination and the RAG proteins is presented. PMID- 27973737 TI - A quantitative framework to estimate the relative importance of environment, spatial variation and patch connectivity in driving community composition. AB - Perhaps the most widely used quantitative approach in metacommunity ecology is the estimation of the importance of local environment vs. spatial structuring using the variation partitioning framework. Contrary to metapopulation models, however, current empirical studies of metacommunity structure using variation partitioning assume a space-for-dispersal substitution due to the lack of analytical frameworks that incorporate patch connectivity predictors of dispersal dynamics. Here, a method is presented that allows estimating the relative importance of environment, spatial variation and patch connectivity in driving community composition variation within metacommunities. The proposed approach is illustrated by a study designed to understand the factors driving the structure of a soft-bottom marine polychaete metacommunity. Using a standard variation partitioning scheme (i.e. where only environmental and spatial predictors are used), only about 13% of the variation in metacommunity structure was explained. With the connectivity set of predictors, the total amount of explained variation increased up to 51% of the variation. These results highlight the importance of considering predictors of patch connectivity rather than just spatial predictors. Given that information on connectivity can be estimated by commonly available data on species distributions for a number of taxa, the framework presented here can be readily applied to past studies as well, facilitating a more robust evaluation of the factors contributing to metacommunity structure. PMID- 27973736 TI - Anaemia in school-aged children in an Australian Indigenous community. AB - OBJECTIVE: Indigenous Australians have poorer health outcomes compared to the non Indigenous population. Malnutrition, and subsequently iron-deficiency anaemia, impairs childhood development. The aim of this study was to identify the prevalence of anaemia in school-aged children of an Australian Indigenous community and evaluate the effectiveness of treatment. DESIGN: A retrospective cohort study. SETTING: A Northern Territory Indigenous community. PARTICIPANTS: Two hundred and one school-age students (5-15 years old) undergoing annual school screening. MAIN OUTCOME MEASURES: Presence of anaemia. Anaemic and non-anaemic students were compared to determine any differences in age, gender, BMI and past history of anaemia. The response to treatment was analysed using initial and repeat haemoglobin results. RESULTS: Altogether, 201 students were screened with 105 (52%) classified as anaemic. No significant association was found between anaemic students and age, gender, BMI or prior history of anaemia. After treatment, the mean rise in haemoglobin was 13% (95% CI 11-15) at the 4-week interval. Age (P = 0.17), gender (P = 0.53) and weight (P = 0.14) were not significantly associated with treatment efficacy. Only 11 students (17%) were still anaemic after treatment. DISCUSSION: Anaemia in Indigenous Australian school-aged children is a major public health issue. The prevalence of anaemia in this population is 52% and many times higher than that of the general Australian population. As per current guidelines, the recommended treatment is effective in over 80% at the 4-week interval. Community wide interventions are required to combat this alarming issue. PMID- 27973738 TI - Effects of Grilling on Total Polyphenol Content and Antioxidant Capacity of Eggplant (Solanum melongena L.). AB - Cooking can change the polyphenol contents of eggplant. This study elucidated the effects of grilling on total polyphenol content (TPC), antioxidant capacity, and the inner structures of eggplant. After identical hollowing, cylindrical eggplant samples were prepared and were then grilled until their center temperatures (CT) respectively reached 50, 65, 75, 85, and 95 degrees C. Chemical assays and observations of the inner structures clarified that TPC and 1, 1-diphenyl-2 picrylhydrazyl (DPPH) radical scavenging activity decreased as CT increased when CT was below 65 degrees C. Results also showed that TPC and DPPH radical scavenging activity increased as CT increased when CT was between 65 degrees C and 95 degrees C. For CT 65 degrees C, the samples retained polyphenol oxidase (PPO) activity up to 40% of the raw state activity. The 3 grilled eggplant models, chlorogenic acid, chlorogenic acid-sugar and chlorogenic acid-amino acid model, yielded results showing that phenol functional groups on chlorogenic acid were thermally stable and that phenol functional groups on chlorogenic acid reacted neither with sugar nor with amino acids. Results show that PPO activity is a primary reason for the decrease of the 2 indices. Optical microscopic and scanning electron microscopic observations revealed collapsed cells and inter tissue cracks around the surface area for CT 85 and 95 degrees C. Scanning electron microscopic observations clarified that intercellular bonds for CT 85 and 95 degrees C became thinner than those for CT 75 degrees C around the middle area. The phenomena explained above are reasons for the increase of TPC and DPPH radical scavenging activity. PMID- 27973739 TI - Phosphatidylinositol-3-phosphate in the regulation of autophagy membrane dynamics. AB - Phosphatidylinositol-3-phosphate (PI3P) is a key player in membrane dynamics and trafficking regulation. Most PI3P is associated with endosomal membranes and with the autophagosome preassembly machinery, presumably at the endoplasmic reticulum. The enzyme responsible for most PI3P synthesis, VPS34 and proteins such as Beclin1 and ATG14L that regulate PI3P levels are positive modulators of autophagy initiation. It had been assumed that a local PI3P pool was present at autophagosomes and preautophagosomal structures, such as the omegasome and the phagophore. This was recently confirmed by the demonstration that PI3P-binding proteins participate in the complex sequence of signalling that results in autophagosome assembly and activity. Here we summarize the historical discoveries of PI3P lipid kinase involvement in autophagy, and we discuss the proposed role of PI3P during autophagy, notably during the autophagosome biogenesis sequence. PMID- 27973740 TI - Clinical features and factors associated with non-carious cervical lesions and dentin hypersensitivity. AB - Determining the factors associated with NCCLs and DH in populations could guide the implementation of specific preventive measures. This study evaluated the clinical features and factors associated with non-carious cervical lesions (NCCLs) and dentin hypersensitivity (DH) in a Brazilian population. The participants were 118 patients at the Dentistry Clinic of our dental school. They completed an interview to obtain personal information and determine the possible factors associated with NCCLs and DH. Clinical examination was undertaken to record the NCCLs, shape of the lesion and certain occlusal factors. DH was diagnosed by air and probe tests. Data were analysed with the multilevel Poisson regression and prevalence ratios, and the respective 95% confidence intervals were calculated. The prevalence of NCCLs and DH among patients was 67.8% and 51.7%, respectively. Of a total number of 2902 teeth examined, 9.65% had NCCLs and 5.82% were sensitive to air. The most affected teeth for both conditions were the premolars. Most of the NCCLs were wedge-shaped and located in the maxilla. The factors associated with NCCLs and DH were age and presence of premature occlusal contacts. NCCLs were also significantly associated with consumption of wine and alcoholic beverages, and DH with consumption of acidic fruits and juices. NCCLs were a common finding, with higher frequency in more advanced age groups, the maxilla and premolars. A significant association occurred between NCCLs, premature contacts and consumption of wine and alcoholic beverages. DH was associated with NCCLs, premature contacts and with the consumption of acidic fruits and juices. PMID- 27973741 TI - Clicking the brain into deep sleep. Commentary on Weigenand et al. (). PMID- 27973742 TI - Haptophyte Diversity and Vertical Distribution Explored by 18S and 28S Ribosomal RNA Gene Metabarcoding and Scanning Electron Microscopy. AB - Haptophyta encompasses more than 300 species of mostly marine pico- and nanoplanktonic flagellates. Our aims were to investigate the Oslofjorden haptophyte diversity and vertical distribution by metabarcoding, and to improve the approach to study haptophyte community composition, richness and proportional abundance by comparing two rRNA markers and scanning electron microscopy (SEM). Samples were collected in August 2013 at the Outer Oslofjorden, Norway. Total RNA/cDNA was amplified by haptophyte-specific primers targeting the V4 region of the 18S, and the D1-D2 region of the 28S rRNA. Taxonomy was assigned using curated haptophyte reference databases and phylogenetic analyses. Both marker genes showed Chrysochromulinaceae and Prymnesiaceae to be the families with highest number of Operational Taxonomic Units (OTUs), as well as proportional abundance. The 18S rRNA data set also contained OTUs assigned to eight supported and defined clades consisting of environmental sequences only, possibly representing novel lineages from family to class. We also recorded new species for the area. Comparing coccolithophores by SEM with metabarcoding shows a good correspondence with the 18S rRNA gene proportional abundances. Our results contribute to link morphological and molecular data and 28S to 18S rRNA gene sequences of haptophytes without cultured representatives, and to improve metabarcoding methodology. PMID- 27973743 TI - Tyr72 and Tyr80 are Involved in the Formation of an Active Site of a Luciferase of Copepod Metridia longa. AB - Luciferase of copepod Metridia longa (MLuc) is a naturally secreted enzyme catalyzing the oxidative decarboxylation of coelenterazine with the emission of light. To date, three nonallelic isoforms of different lengths (17-24 kDa) for M. longa luciferase have been cloned. All the isoforms are single-chain proteins consisting of a 17-residue signal peptide for secretion, variable N-terminal part and conservative C-terminus responsible for luciferase activity. In contrast to other bioluminescent proteins containing a lot of aromatic residues which are frequently involved in light emission reaction, the C-terminal part of MLuc contains only four Phe, two Tyr, one Trp and two His residues. To figure out whether Tyr residues influence bioluminescence, we constructed the mutants with substitution of Tyr to Phe (Y72F and Y80F). Tyrosine substitutions do not eliminate the ability of luciferase to bioluminescence albeit significantly reduce relative specific activity and change bioluminescence kinetics. In addition, the Tyr replacements have no effect on bioluminescence spectrum, thereby indicating that tyrosines are not involved in the emitter formation. However, as it was found that the intrinsic fluorescence caused by Tyr residues is quenched by a reaction substrate, coelenterazine, in concentration-dependent manner, we infer that both tyrosine residues are located in the luciferase substrate-binding cavity. PMID- 27973744 TI - Aptamer-Based SERS Detection of Lysozyme on a Food-Handling Surface. AB - Undeclared food allergens due to cross contamination of processing equipment is a leading cause for food product recalls. Therefore, there is a great need for developing rapid and sensitive methods to detect food allergens. In this paper, an aptamer highly specific to egg white lysozyme was coupled to dendritic silver nanoparticles in order to perform surface enhanced Raman spectroscopy (SERS). The procedure was successfully tested in water and on a stainless steel food-handling surface. The lowest detectable concentration for lysozyme was 0.5 MUg/mL in water and 5 MUg/mL on a stainless steel food-handling surface. Principal component analysis shows a significant change in SERS spectra when lysozyme was present, suggesting the successful capture of lysozyme by the aptamer. Quantification of lysozyme target was also shown from 0 to 6 MUg/mL, that is, 0, 0.5, 2, 6 MUg/mL. Overall method took less than 40 min. The developed method can be extended to detect other food allergens using specific aptamers. PMID- 27973745 TI - Association between changes in oestradiol and follicle-stimulating hormone levels during the menopausal transition and risk of diabetes. AB - AIM: To investigate the association between changes in oestradiol and follicle stimulating hormone levels during the menopausal transition and incident diabetes. METHODS: We followed 1407 pre-menopausal women, aged 42-52 years at baseline, who experienced natural menopause, from baseline to the 12th annual follow-up visit in the Study of Women's Health Across the Nation (SWAN). Diabetes was defined based on fasting glucose level, medication use and self-report of physician diagnosis. Cox proportional hazards regression was used to evaluate the associations of incident diabetes with three components of the rate of change in hormones: the intercept (pre-menopausal levels) and two piece-wise slopes representing change during the early and late transition, respectively. RESULTS: During 15 years of follow-up, 132 women developed diabetes. After adjusting for potential confounders, a higher oestradiol intercept, but not its rate of change, was borderline significantly associated with lower risk of diabetes [hazard ratio for an interquartile range increase (75.2 pmol/L) 0.53, 95% CI 0.27-1.06]. For follicle-stimulating hormone, a greater rate of increase in the early transition, but not the intercept or late transition, was significantly associated with lower risk of diabetes [hazard ratio for an interquartile range increase (5.9 IU/L/year) 0.31, 95% CI 0.10-0.94]. CONCLUSIONS: Lower pre-menopausal oestradiol levels and a slower rate of follicle-stimulating hormone change during the early transition were associated with higher risk of developing diabetes. Given that obesity plays an important role in diabetes risk and in the levels and changes in oestradiol and follicle-stimulating hormone over the menopausal transition, weight control in earlier mid-life is important to prevent future diabetes development. PMID- 27973748 TI - Identifying and Understanding Strong Vibronic Interaction Effects Observed in the Asymmetry of Chiral Molecule Photoelectron Angular Distributions. AB - Electron-ion coincidence imaging is used to study chiral asymmetry in the angular distribution of electrons emitted from randomly-oriented enantiomers of two molecules, methyloxirane and trifluoromethyloxirane, upon ionization by circularly polarized VUV synchrotron radiation. Vibrationally-resolved photoelectron circular dichroism (PECD) measurements of the outermost orbital ionization reveal unanticipated large fluctuations in the magnitude of the forward-backward electron scattering asymmetry, including even a complete reversal of direction. Identification and assignment of the vibrational excitations is supported by Franck-Condon simulations of the photoelectron spectra. A previously proposed quasi-diatomic model for PECD is developed and extended to treat polyatomic systems. The parametric dependence of the electronic dipole matrix elements on nuclear geometry is evaluated in the adiabatic approximation. It provokes vibrational level dependent shifts in amplitude and phase, to which the chiral photoelectron angular distributions are especially sensitive. It is shown that single quantum excitation of those vibrational modes, which experience only a relatively small displacement of the ion equilibrium geometry along the normal coordinate and which are then only weakly excited in the Franck-Condon limit, can be accompanied by big shifts in scattering phase; hence the observed big fluctuations in PECD asymmetry for such modes. PMID- 27973747 TI - Quinolinic acid induces neuritogenesis in SH-SY5Y neuroblastoma cells independently of NMDA receptor activation. AB - Glutamate and nicotinamide adenine dinucleotide (NAD+ ) have been implicated in neuronal development and several types of cancer. The kynurenine pathway of tryptophan metabolism includes quinolinic acid (QA) which is both a selective agonist at N-methyl-D-aspartate (NMDA) receptors and also a precursor for the formation of NAD+ . The effect of QA on cell survival and differentiation has therefore been examined on SH-SY5Y human neuroblastoma cells. Retinoic acid (RA, 10 MUm) induced differentiation of SH-SY5Y cells into a neuronal phenotype showing neurite growth. QA (50-150 nm) also caused a concentration-dependent increase in the neurite/soma ratio, indicating differentiation. Both RA and QA increased expression of the neuronal marker beta3-tubulin in whole-cell homogenates and in the neuritic fraction assessed using a neurite outgrowth assay. Expression of the neuronal proliferation marker doublecortin revealed that, unlike RA, QA did not decrease the number of mitotic cells. QA-induced neuritogenesis coincided with an increase in the generation of reactive oxygen species. Neuritogenesis was prevented by diphenylene-iodonium (an inhibitor of NADPH oxidase) and superoxide dismutase, supporting the involvement of reactive oxygen species. NMDA itself did not promote neuritogenesis and the NMDA antagonist dizocilpine (MK-801) did not prevent quinolinate-induced neuritogenesis, indicating that the effects of QA were independent of NMDA receptors. Nicotinamide caused a significant increase in the neurite/soma ratio and the expression of beta3-tubulin in the neuritic fraction. Taken together, these results suggest that QA induces neuritogenesis by promoting oxidizing conditions and affecting the availability of NAD+ , independently of NMDA receptors. PMID- 27973749 TI - Banting Memorial Lecture 2016 Reducing lifetime risk of complications in adolescents with Type 1 diabetes. AB - Adolescence is a challenging period of life for any young person, and for those with Type 1 diabetes, physiological and psychological factors can result in a deterioration in glycaemic control. In young people with Type 1 diabetes, puberty may be an additional risk factor impacting on the lifetime risk for renal and cardiovascular complications. Our longitudinal studies have identified that increases in urinary albumin excretion through childhood are associated with the development of microalbuminuria and a generalized endotheliopathy linked to cardiovascular risk. Screening of participants recruited to the Adolescent type 1 Diabetes cardio-renal Intervention Trial (AdDIT) confirms that these early changes in albumin excretion are related to both diabetic nephropathy and cardiovascular risk; in part, independent of glycaemic control. Thus, as well as current attempts to improve glycaemic control through enhanced targeted insulin delivery, pumps, sensors and closed loop, we have explored the role of angiotensin-converting enzyme inhibitors and statins in providing cardio-renal protection during adolescence. PMID- 27973746 TI - Maintenance of certification: How performance in practice changes improve tobacco cessation in addiction psychiatrists' practice. AB - BACKGROUND AND OBJECTIVES: In 2000, the American Board of Medical Specialties implemented the Maintenance of Certification (MOC), a structured process to help physicians identify and implement a quality improvement project to improve patient care. This study reports on findings from an MOC Performance in Practice (PIP) module designed and evaluated by addiction psychiatrists who are members of the American Academy of Addiction Psychiatry (AAAP). METHOD: A 3-phase process was utilized to recruit AAAP members to participate in the study. The current study utilized data from 154 self-selected AAAP members who evaluated the effectiveness of the MOC Tobacco Cessation PIP. RESULTS: Of the physicians participating, 76% (n = 120) completed the Tobacco PIP. A paired t-test analysis revealed that reported changes in clinical measure documentation were significant across all six measures. Targeted improvement efforts focused on a single clinical measure. Results found that simple change projects designed to improve clinical practice led to substantial changes in self-reported chart documentation for the selected measure. CONCLUSIONS: The current findings suggest that addiction psychiatrists can leverage the MOC process to improve clinical care. SCIENTIFIC SIGNIFICANCE: The study demonstrates that a quality improvement collaborative can support an MOC process to help addiction psychiatrists eliminate barriers to access to tobacco cessation treatment. (Am J Addict 2017;26:34-41). PMID- 27973750 TI - Controlled release and intracellular protein delivery from mesoporous silica nanoparticles. AB - Protein therapeutics are promising candidates for disease treatment due to their high specificity and minimal adverse side effects; however, targeted protein delivery to specific sites has proven challenging. Mesoporous silica nanoparticles (MSN) have demonstrated to be ideal candidates for this application, given their high loading capacity, biocompatibility, and ability to protect host molecules from degradation. These materials exhibit tunable pore sizes, shapes and volumes, and surfaces which can be easily functionalized. This serves to control the movement of molecules in and out of the pores, thus entrapping guest molecules until a specific stimulus triggers release. In this review, we will cover the benefits of using MSN as protein therapeutic carriers, demonstrating that there is great diversity in the ways MSN can be used to service proteins. Methods for controlling the physical dimensions of pores via synthetic conditions, applications of therapeutic protein loaded MSN materials in cancer therapies, delivering protein loaded MSN materials to plant cells using biolistic methods, and common stimuli-responsive functionalities will be discussed. New and exciting strategies for controlled release and manipulation of proteins are also covered in this review. While research in this area has advanced substantially, we conclude this review with future challenges to be tackled by the scientific community. PMID- 27973751 TI - Creating Honeycomb Structures in Porous Polymers by Osmotic Transport. AB - Understanding why honeycombs are shaped the way they are has moved biologists, physicists, chemists, and mathematicians alike. It was only recently that the honeycombs' shape "at birth" was included in the ongoing discussions: at birth, the cells are spherical but then transform into the well-known hexagons. It was proposed that a flow of wax-driven by surface tension effects-is the reason for this transformation. Our recent work on synthetic polymer foams with honeycomb like structures points towards a very different mechanism. Just like in honeycomb cells, we observe that a spherical "initial state" transforms into a hexagon shaped "final state" during polymerization. We have experimental evidence that a concentration gradient arises during polymerization, which transports monomers such that the spherical template becomes a honeycomb structure with walls of homogeneous thickness. The knowledge about this mechanism suggests promising strategies for the development of lightweight materials with optimized mechanical properties. PMID- 27973752 TI - The Effects of Egg and Diacetyl Tartaric Acid Esters of Monoglycerides Addition on Storage Stability, Texture, and Sensory Properties of Gluten-Free Sorghum Bread. AB - The impact of whole egg addition (as is) at 20%, 25%, or 30% (flour basis) on sorghum bread quality was evaluated. The use of the antistaling agent diacetyl tartaric acid esters of monoglycerides (DATEM) at 0.5% (flour basis) at each of the egg addition levels was also studied. Evaluated quality factors included color, specific volume, and crumb structure. Texture analysis was performed to evaluate the rate of quality loss based on changes in crumb hardness values over time. A trained sensory panel evaluated bread quality attributes by descriptive analysis. Sorghum breads with egg had larger specific volumes than the control, while DATEM had a negative effect on the volume of sorghum gluten-free bread. Inclusion of egg in the bread formula improved cell structure and produced darker crust (P < 0.05). The addition of egg reduced bread hardness and slowed the rate of quality loss over a 12-d storage period. Descriptive analysis confirmed the findings of texture analysis. Control breads were significantly harder (P < 0.05) than egg-containing bread at days 0 and 4. This research demonstrates that addition of eggs to a gluten-free sorghum bread formulation results in improved storage stability and better overall quality and acceptability of the product. PMID- 27973753 TI - Vagal nerve stimulation modifies neuronal activity and the proteome of excitatory synapses of amygdala/piriform cortex. AB - Vagal Nerve Stimulation (VNS) Therapy(r) is a United States Food and Drug Administration approved neurotherapeutic for medically refractory partial epilepsy and treatment-resistant depression. The molecular mechanisms underlying its beneficial effects are unclear. We hypothesized that one mechanism involves neuronal activity-dependent modifications of central nervous system excitatory synapses. To begin to test this hypothesis, we asked whether VNS modifies the activity of neurons in amygdala and hippocampus. Neuronal recordings from adult, freely moving rats revealed that activity in both amygdala and hippocampus was modified by VNS immediately after its application, and changes were detected following 1 week of stimulation. To investigate whether VNS modifies the proteome of excitatory synapses, we established a label-free, quantitative liquid chromatography-tandem mass spectrometry workflow that enables global analysis of the constituents of the postsynaptic density (PSD) proteome. PSD proteins were biochemically purified from amygdala/piriform cortex of VNS- or dummy-treated rats following 1-week stimulation, and individual PSD protein levels were quantified by liquid chromatography-tandem mass spectrometry analysis. We identified 1899 unique peptides corresponding to 425 proteins in PSD fractions, of which expression levels of 22 proteins were differentially regulated by VNS with changes greater than 150%. Changes in a subset of these proteins, including significantly increased expression of neurexin-1alpha, cadherin 13 and voltage dependent calcium channel alpha2delta1, the primary target of the antiepileptic drug gabapentin, and decreased expression of voltage-dependent calcium channel gamma3, were confirmed by western blot analysis of PSD samples. These results demonstrate that VNS modulates excitatory synapses through regulating a subset of the PSD proteome. Our study reveals molecular targets of VNS and point to possible mechanisms underlying its beneficial effects, including activity dependent formation of excitatory synapses. PMID- 27973754 TI - Transplantation of embryonic spinal cord neurons to the injured distal nerve promotes axonal regeneration after delayed nerve repair. AB - Peripheral nerve injury (PNI) usually results in poor functional recovery. Nerve repair is the common clinical treatment for PNI but is always obstructed by the chronic degeneration of the distal stump and muscle. Cell transplantation can alleviate the muscle atrophy after PNI, but the subsequent recovery of the locomotive function is seldom described. In this study, we combined cell transplantation and nerve repair to investigate whether the transplantation of embryonic spinal cord cells could benefit the delayed nerve repair. The experiment consisted of 3 stages: transection of the tibial nerve to induce 'pre degeneration', a second surgery performed 2 weeks later for transplantation of E14 embryonic spinal cord cells or vehicle (culture medium) at the distal end of the injured nerve, and, 3 months later, the removal of the grafted cells and the cross-suturing of the residual distal end to the proximal end of a freshly cut ipsilateral common peroneal (CP) nerve. Cell survival and fate after the transplantation were investigated, and the functional recovery after the cross suturing was compared between the groups. The grafted cells could survive and generate motor neurons, extending axons that were subsequently myelinated and forming synapses with the muscle. After the cross-suturing, the axonal regeneration from the proximal stump of the injured CP nerve and the functional recovery of the denervated gastrocnemius muscle were significantly promoted in the group receiving the cells. Our study presents a new perspective indicating that the transplantation of embryonic spinal cord neurons may be a valuable therapeutic strategy for PNI. PMID- 27973755 TI - Electrical Cardioversion of an Irregular Narrow QRS Tachycardia to a Regular Narrow QRS Tachycardia. PMID- 27973756 TI - Fluorescent Labeling and Biodistribution of Latex Nanoparticles Formed by Surfactant-Free RAFT Emulsion Polymerization. AB - The authors report the preparation of a novel range of functional polyacrylamide stabilized polystyrene nanoparticles, obtained by surfactant-free reversible addition-fragmentation chain transfer (RAFT) emulsion polymerization, their fluorescent tagging, cellular uptake, and biodistribution. The authors show the versatility of the RAFT emulsion process for the design of functional nanoparticles of well-defined size that can be used as drug delivery vectors. Functionalization with a fluorescent tag offers a useful visualization tool for tracing, localization, and clearance studies of these carriers in biological models. The studies are carried out by labeling the sterically stabilized latex particles chemically with rhodamine B. The fluorescent particles are incubated in a healthy human renal proximal tubular cell line model, and intravenously injected into a mouse model. Cellular localization and biodistribution of these particles on the biological models are explored. PMID- 27973757 TI - Alleviative effect of ciliary neurotrophic factor analogue on high fat-induced hepatic steatosis is partially independent of the central regulation. AB - Ciliary neurotrophic factor (CNTF) analogues were reported to ameliorate fatty liver in db/db or high-fat diet-fed mice. It is generally thought that CNTF exerts its actions centrally. The aim of this study was to investigate whether peripheral effects of CNTF analogues are involved in the therapeutic effect on high fat-induced hepatic steatosis. The rat model of fatty liver was induced by a high-fat diet (HFD) for 12 weeks. In the next 2 weeks, rats were fed the HFD along with subcutaneous injection of vehicle or mutant recombinant human CNTF (rhmCNTF 0.05-0.2 mg/kg per day). Steatotic HepG2 cells were induced by 50% fetal bovine serum (FBS) for 48 hours, and then treated with rhmCNTF for 24 hours. The results showed that after rhmCNTF treatment, hepatic triglyceride (TG) accumulation was attenuated both in vivo and in vitro. RhmCNTF increased protein expression of CPT-1 and PPARalpha, and decreased SREBP-1c, FAS and SCD-1 in steatotic HepG2 cells. But the production of nitric oxide and 8-isoPGF2alpha in steatotic HepG2 cells was not affected by rhmCNTF. These results suggest that rhmCNTF has a peripheral effect that alleviates fat-induced hepatic steatosis. PMID- 27973758 TI - Structural analysis and unique molecular recognition properties of a Bauhinia forficata lectin that inhibits cancer cell growth. AB - : Lectins have been used at length for basic research and clinical applications. New insights into the molecular recognition properties enhance our basic understanding of carbohydrate-protein interactions and aid in the design/development of new lectins. In this study, we used a combination of cell based assays, glycan microarrays, and X-ray crystallography to evaluate the structure and function of the recombinant Bauhinia forficata lectin (BfL). The lectin was shown to be cytostatic for several cancer cell lines included in the NCI-60 panel; in particular, it inhibited growth of melanoma cancer cells (LOX IMVI) by over 95%. BfL is dimeric in solution and highly specific for binding of oligosaccharides and glycopeptides with terminal N-acetylgalactosamine (GalNAc). BfL was found to have especially strong binding (apparent Kd = 0.5-1.0 nm) to the tumor-associated Tn antigen. High-resolution crystal structures were determined for the ligand-free lectin, as well as for its complexes with three Tn glycopeptides, globotetraose, and the blood group A antigen. Extensive analysis of the eight crystal structures and comparison to structures of related lectins revealed several unique features of GalNAc recognition. Of special note, the carboxylate group of Glu126, lining the glycan-binding pocket, forms H-bonds with both the N-acetyl of GalNAc and the peptide amido group of Tn antigens. Stabilization provided by Glu126 is described here for the first time for any GalNAc-specific lectin. Taken together, the results provide new insights into the molecular recognition of carbohydrates and provide a structural understanding that will enable rational engineering of BfL for a variety of applications. DATABASE: Structural data are available in the PDB under the accession numbers 5T50, 5T52, 5T55, 5T54, 5T5L, 5T5J, 5T5P, and 5T5O. PMID- 27973760 TI - Evaluation of the Lactate Plus monitor for plasma lactate concentration measurement in dogs. AB - OBJECTIVE: To compare the Lactate Plus handheld monitor to a reference blood gas analyzer for determining plasma lactate concentrations in canine whole blood. DESIGN: Prospective observational study. SETTING: University teaching hospital. ANIMALS: Ninety-four dogs hospitalized or admitted through the emergency service provided 125 blood samples. Only dogs that required a venous or arterial blood gas evaluation as a part of their diagnostic assessment or ongoing management were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Canine whole blood samples were assayed for plasma lactate concentration with a reference blood gas analyzer and the Lactate Plus monitor. Correlation and Bland-Altman analyses were used to compare results between the 2 methods. A subset of blood samples was repeatedly analyzed with the Lactate Plus to assess monitor precision. Plasma lactate measurements from the Lactate Plus monitor showed excellent correlation with those from the reference analyzer (rho = 0.98, P < 0.0001). Bland-Altman analysis revealed a small bias (0.1296). Agreement between the 2 methods was less consistent for lactate concentrations >5 mmol/L. The coefficient of variation ranged from 0-26.2% (median, 3.7%) and was <15% for 50/53 samples. CONCLUSIONS: The Lactate Plus provides a fast and affordable method to measure plasma lactate concentration in dogs. Results showed excellent agreement with the reference analyzer and precision of the instrument was acceptable. PMID- 27973759 TI - An update on the implications of cyclin D1 in oral carcinogenesis. AB - Cyclin D1 promotes cell cycle progression during G1 phase, a key event in G1-S transition. The protein is encoded by gene CCND1, located in chromosomal band 11q13. Cyclin D1 plays key roles in cell biology, including cell proliferation and growth regulation, mitochondrial activity modulation, DNA repair, and cell migration control. CCND1 gene and its protein cyclin D1 are frequently altered by different molecular mechanisms, including amplification, chromosomal translocations, mutations, and activation of the pathways involved in cyclin D1 expression, alterations which appear to be essential in the development of human cancers, including oral carcinoma. This is the first published review of the specific features of cyclin D1 overexpression in oral oncogenesis. Starting with the physiological regulation of cyclin D1, there is an evaluation of its functions, overexpression mechanisms, and the implications of the oncogenic activation of CCND1/cyclin D1 in oral squamous cell carcinoma. The potential diagnostic and prognostic value of cyclin D1 is reviewed. The influence of CCND1/cyclin D1 on tumor size and clinical stage is reported, and an update is provided on the utilization of cyclin D1 as therapeutic target and on the combination of cyclin D1 inhibitors with cytotoxic agents. Future research lines in this field are also proposed. PMID- 27973761 TI - Effects of oral 3% hydrogen peroxide used as an emetic on the gastroduodenal mucosa of healthy dogs. AB - OBJECTIVE: To characterize the extent of mucosal injury on the upper gastrointestinal tract following oral administration of 3% hydrogen peroxide (H2 O2 ) to induce emesis in normal dogs. DESIGN: Prospective clinical study. SETTING: Specialty referral hospital. ANIMALS: Seven staff-owned, healthy, adult dogs. INTERVENTIONS: Six dogs were assigned to the H2 O2 group and 1 dog was assigned as the apomorphine control. Dogs were anesthetized for gastroduodenoscopy with gross inspection and gastroduodenal biopsies at time 0 and 4 hours, 24 hours, 1 week, and 2 weeks following administration of oral 3% H2 O2 or subconjunctival apomorphine. Gross esophageal, gastric, and duodenal mucosal lesion scoring was performed by 2 blinded, experienced scorers. Biopsy samples were evaluated histologically by a veterinary pathologist. MEASUREMENTS AND MAIN RESULTS: Grade I esophagitis was noted in 2 dogs at 4 hours and in 1 dog at 2 weeks, while grade III esophagitis was observed in 1 dog 1 week following H2 O2 administration. At 4 hours, gastric mucosal lesions were visualized in all dogs, and lesions worsened by 24 hours. Mild to moderate duodenal mucosal lesions were visualized up to 24 hours after administration. Histopathology identified the most severe gastric lesions at 4 hours as hemorrhage; at 24 hours as degeneration, necrosis, and mucosal edema; and at 1 week as inflammation. By 2 weeks, most visual and histopathologic lesions were resolved. No histopathologic lesions were identified at any time point in the dog administered apomorphine. CONCLUSIONS: Significant visual and histopathologic gastric lesions occurred following administration of 3% H2 O2 in all dogs. Less severe visual duodenal lesions were identified. As compared to H2 O2 dogs, minimal gross gastroduodenal lesions and normal histopathology were identified in the apomorphine control. PMID- 27973762 TI - Intra-articular injections of HYADD4-G in male professional soccer players with traumatic or degenerative knee chondropathy. A pilot, prospective study. AB - BACKGROUND: Knee injuries are very common in some sports and particularly in soccer due to the highly repetitive loading of the mechanical stress involved in this practice. Knee-joint injuries account for 40% of all different kinds of lesions. Traumatic or degenerative patellofemoral or tibialfemoral chondropaties of knee cause disabling symptoms, joint pain and/or dysfunctions. The aim of the study was to evaluate the effects of HYADD4-G, a hydrogel based on a hyaluronic acid derivative, in professional soccer players affected by traumatic or degenerative knee chondropathy. METHODS: Thirty male professional soccer players participants in the Italian League 2014-2015, affected by traumatic or degenerative knee patellofemoral (N.=12) or tibiofemoral (N.=18) chondropathy assessed through MRI and/or arthroscopy of knee joints and the ICRS staging (International Cartilage Repair Society <=3a), were enrolled in this pilot prospective study. Patients underwent 2 intra-articular (IA) injections of HYADD4 G (3 mL of 8 mg/mL) at one week interval. Patients were prospectively evaluated at baseline and then at 1, 3 and 6 months after the treatment by the Osteoarthritis Outcome Score (KOOS) Score (main outcome) and by the Visual Analog Scale (VAS) to evaluate pain. RESULTS: A significant improvement in all clinical endpoints from pretreatment to different times of evaluation was found in all patients. ANOVA with repeated measure using the SPSS has showed significantly better results in term of KOOS and VAS scores at 1, 3 and 6 months compared to the pre-injection value (P<0.05). CONCLUSIONS: IA HYADD4-G is highly effective to improve resting and walking pain in professional male soccer players with traumatic or degenerative knee chondropathy. PMID- 27973763 TI - Synthesis of Continuous Conductive PEDOT:PSS Nanofibers by Electrospinning: A Conformal Coating for Optoelectronics. AB - A process to synthesize continuous conducting nanofibers were developed using PEDOT:PSS as a conducting polymer and an electrospinning method. Experimental parameters were carefully explored to achieve reproducible conductive nanofibers synthesis in large quantities. In particular, relative humidity during the electrospinning process was proven to be of critical importance, as well as doping post-treatment involving glycols and alcohols. The synthesized fibers were assembled as a mat on glass substrates, forming a conductive and transparent electrode and their optoelectronic have been fully characterized. This method produces a conformable conductive and transparent coating that is well-adapted to nonplanar surfaces, having very large aspect ratio features. A demonstration of this property was made using surfaces having deep trenches and high steps, where conventional transparent conductive materials fail because of a lack of conformability. PMID- 27973764 TI - Aerosol Delivery of Functionalized Gold Nanoparticles Target and Activate Dendritic Cells in a 3D Lung Cellular Model. AB - Nanocarrier design combined with pulmonary drug delivery holds great promise for the treatment of respiratory tract disorders. In particular, targeting of dendritic cells that are key immune cells to enhance or suppress an immune response in the lung is a promising approach for the treatment of allergic diseases. Fluorescently encoded poly(vinyl alcohol) (PVA)-coated gold nanoparticles, functionalized with either negative (-COO-) or positive (-NH3+) surface charges, were functionalized with a DC-SIGN antibody on the particle surface, enabling binding to a dendritic cell surface receptor. A 3D coculture model consisting of epithelial and immune cells (macrophages and dendritic cells) mimicking the human lung epithelial tissue barrier was employed to assess the effects of aerosolized AuNPs. PVA-NH2 AuNPs showed higher uptake compared to that of their -COOH counterparts, with the highest uptake recorded in macrophages, as shown by flow cytometry. None of the AuNPs induced cytotoxicity or necrosis or increased cytokine secretion, whereas only PVA-NH2 AuNPs induced higher apoptosis levels. DC-SIGN AuNPs showed significantly increased uptake by monocyte-derived dendritic cells (MDDCs) with subsequent activation compared to non-antibody conjugated control AuNPs, independent of surface charge. Our results show that DC SIGN conjugation to the AuNPs enhanced MDDC targeting and activation in a complex 3D lung cell model. These findings highlight the potential of immunoengineering approaches to the targeting and activation of immune cells in the lung by nanocarriers. PMID- 27973765 TI - Long-Cycling Aqueous Organic Redox Flow Battery (AORFB) toward Sustainable and Safe Energy Storage. AB - Redox flow batteries (RFBs) are a viable technology to store renewable energy in the form of electricity that can be supplied to electricity grids. However, widespread implementation of traditional RFBs, such as vanadium and Zn-Br2 RFBs, is limited due to a number of challenges related to materials, including low abundance and high costs of redox-active metals, expensive separators, active material crossover, and corrosive and hazardous electrolytes. To address these challenges, we demonstrate a neutral aqueous organic redox flow battery (AORFB) technology utilizing a newly designed cathode electrolyte containing a highly water-soluble ferrocene molecule. Specifically, water-soluble (ferrocenylmethyl)trimethylammonium chloride (FcNCl, 4.0 M in H2O, 107.2 Ah/L, and 3.0 M in 2.0 NaCl, 80.4 Ah/L) and N1-ferrocenylmethyl-N1,N1,N2,N2,N2 pentamethylpropane-1,2-diaminium dibromide, (FcN2Br2, 3.1 M in H2O, 83.1 Ah/L, and 2.0 M in 2.0 M NaCl, 53.5 Ah/L) were synthesized through structural decoration of hydrophobic ferrocene with synergetic hydrophilic functionalities including an ammonium cation group and a halide anion. When paired with methyl viologen (MV) as an anolyte, resulting FcNCl/MV and FcN2Br2/MV AORFBs were operated in noncorrosive neutral NaCl supporting electrolytes using a low-cost anion-exchange membrane. These ferrocene/MV AORFBs are characterized as having high theoretical energy density (45.5 Wh/L) and excellent cycling performance from 40 to 100 mA/cm2. Notably, the FcNCl/MV AORFBs (demonstrated at 7.0 and 9.9 Wh/L) exhibited unprecedented long cycling performance, 700 cycles at 60 mA/cm2 with 99.99% capacity retention per cycle, and delivered power density up to 125 mW/cm2. These AORFBs are built from earth-abundant elements and are environmentally benign, thus representing a promising choice for sustainable and safe energy storage. PMID- 27973766 TI - Multifunctional Dendrimer Ligands for High-Efficiency, Solution-Processed Quantum Dot Light-Emitting Diodes. AB - We present multifunctional dendrimer ligands that serve as the charge injection controlling layer as well as the adhesive layer at the interfaces between quantum dots (QDs) and the electron transport layer (ETL) in quantum dot light-emitting diodes (QLEDs). Specifically, we use primary amine-functionalized dendrimer ligands (e.g., a series of poly(amidoamine) dendrimers (PADs, also referred to PAMAM)) that bind to the surface of QDs by replacing the native ligands (oleic acids) and also to the surface of ZnO ETL. PAD ligands control the electron injection rate from ZnO ETL into QDs by altering the electronic energy levels of the surface of ZnO ETL and thereby improve the charge balance within QDs in devices, leading to the enhancement of the device efficiency. As an ultimate achievement, the device efficiency (peak external quantum efficiency) improves by a factor of 3 by replacing the native ligands (3.86%) with PAD ligands (11.36%). In addition, multibranched dendrimer ligands keep the QD emissive layer intact during subsequent solution processing, enabling us to accomplish solution processed QLEDs. The approach and results in the present study emphasize the importance of controlling the ligands of QDs to enhance QLED performance and also offer simple yet effective chemical mean toward all-solution-processed QLEDs. PMID- 27973767 TI - New Advances in Nanotechnology-Based Diagnosis and Therapeutics for Breast Cancer: An Assessment of Active-Targeting Inorganic Nanoplatforms. AB - Breast cancer is a major cause of suffering and mortality among women. Limitations in the current diagnostic methods and treatment approaches have led to new strategies to positively impact the survival rates and quality of life of breast cancer patients. Nanotechnology offers a real possibility of mitigating breast cancer mortality by early-stage cancer detection and more precise diagnosis as well as more effective treatments with minimal side effects. The current nanoplatforms approved for breast cancer therapeutics are based on passive tumor targeting using organic nanoparticles and have not provided the expected significant improvements in the clinic. In this review, we present the emerging approaches in breast cancer nanomedicine based on active targeting using versatile inorganic nanoplatforms with biomedical relevance, such as gold, silica, and iron oxide nanoparticles, as well as their efficacy in breast cancer imaging, drug and gene delivery, thermal therapy, combinational therapy, and theranostics in preclinical studies. The main challenges for clinical translation and perspectives are discussed. PMID- 27973769 TI - Plasmonic Schirmer Strip for Human Tear-Based Gouty Arthritis Diagnosis Using Surface-Enhanced Raman Scattering. AB - Biomarkers in tear fluid have attracted much interest in daily healthcare sensing and monitoring. Recently, surface-enhanced Raman scattering (SERS) has enabled highly sensitive label-free detection of small molecules. However, a highly stable straightforward tear assay with superior sensitivity is still under development in tear collection and analysis. Here we report a plasmonic Schirmer strip for on-demand, rapid, and simple identification of biomarkers in human tears. The diagnostic strip features gold nanoislands directly and evenly formed on the top surface of cellulose fibers, which maintain a hygroscopic nature for an efficient collection of tear production as well as provide plasmonic enhancement in SERS signals for identification of tear molecules. The uric acid in human tears was quantitatively detected at physiological levels (25-150 MUM) by using SERS. The experimental results also clearly reveal a strong linear correlation between uric acid level in both human tears and blood for gouty arthritis diagnosis. This functional paper strip enables noninvasive diagnosis of disease-related biomarkers and healthcare monitoring using human tears. PMID- 27973768 TI - Identification of a Catalytic Iron-Hydride at the H-Cluster of [FeFe] Hydrogenase. AB - Hydrogenases couple electrochemical potential to the reversible chemical transformation of H2 and protons, yet the reaction mechanism and composition of intermediates are not fully understood. In this Communication we describe the biophysical properties of a hydride-bound state (Hhyd) of the [FeFe]-hydrogenase from Chlamydomonas reinhardtii. The catalytic H-cluster of [FeFe]-hydrogenase consists of a [4Fe-4S] subcluster ([4Fe-4S]H) linked by a cysteine thiol to an azadithiolate-bridged 2Fe subcluster ([2Fe]H) with CO and CN- ligands. Mossbauer analysis and density functional theory (DFT) calculations show that Hhyd consists of a reduced [4Fe-4S]H+ coupled to a diferrous [2Fe]H with a terminally bound Fe hydride. The existence of the Fe-hydride in Hhyd was demonstrated by an unusually low Mossbauer isomer shift of the distal Fe of the [2Fe]H subcluster. A DFT model of Hhyd shows that the Fe-hydride is part of a H-bonding network with the nearby bridging azadithiolate to facilitate fast proton exchange and catalytic turnover. PMID- 27973770 TI - Effects on Biotransformation, Oxidative Stress, and Endocrine Disruption in Rainbow Trout (Oncorhynchus mykiss) Exposed to Hydraulic Fracturing Flowback and Produced Water. AB - The effects of hydraulic fracturing (HF) flowback and produced water (HF-FPW), a complex saline mixture of injected HF fluids and deep formation water that return to the surface, was examined in rainbow trout (Oncorhynchus mykiss). Exposure to HF-FPWs resulted in significant induction of ethoxyresorufin-O-deethylase (EROD) activity in both liver and gill tissues. Increased lipid peroxidation via oxidative stress was also detected by thiobarbituric acid reactive substances (TBARS) assay. The mRNA expressions of a battery of genes related to biotransformation, oxidative stress, and endocrine disruption were also measured using quantitative real-time polymerase chain reaction (Q-RT-PCR). The increased expression of cyp1a (2.49 +/- 0.28-fold), udpgt (2.01 +/- 0.31-fold), sod (1.67 +/- 0.09-fold), and gpx (1.58 +/- 0.10-fold) in raw sample exposure group (7.5%) indicated elevated metabolic enzyme activity, likely through the aryl hydrocarbon receptor pathway, and generation of reactive oxygen species. In addition, the elevated vtg and era2 expression demonstrated endocrine disrupting potential exerted by HF-FPW in rainbow trout. The overall results suggested HF-FPW could cause significant adverse effects on fish, and the organic contents might play the major role in its toxicity. Future studies are needed to help fully determine the toxic mechanism(s) of HF-FPW on freshwater fish, and aid in establishing monitoring, treatment, and remediation protocols for HF-FPW. PMID- 27973771 TI - Lipidic Carbo-benzenes: Molecular Probes of Magnetic Anisotropy and Stacking Properties of alpha-Graphyne. AB - Solubilization of the C18 fundamental circuit of alpha-graphyne has been envisaged by decoration with aliphatic chains R = n-CnH2n+1. The synthesis and characterization of p-dialkyl-tetraphenyl-carbo-benzenes (n = 2, 8, 14, 20) are thus presented and compared to the monoalkyl series produced concomitantly. In both series, a dramatic enhancement of solubility in organic solvents (CH2Cl2, CHCl3) is observed for n >= 8, and in the dialkyl series, the melting decomposition temperature of the solid products is shown to decrease linearly from 208 degrees C for n = 2 to 149 degrees C for n = 20. Fluoroalkyl analogues with R = n-C8H4F13 are also described. The products display classical UV-vis electronic spectra of carbo-benzenes in solution (lambdamax = 445.5 +/- 1 nm, epsilon ~ 200 000 L.mol-1.cm-1). They are also characterized by UV-vis absorption in the solid state, which is found to be correlated with the color and crystal packing. The methylene groups of R provide an experimental probe of the magnetic anisotropy and aromaticity of the C18 ring through the progressive NMR shielding of the 1H nuclei from ca. 4.70 to 1.25 ppm going away from the border of the ring (as far as 8 A away). All alkyl-carbo-benzenes were also found to be highly crystalline. Seven of them have been characterized by X-ray diffraction analysis and the C18 columnar packing compared in a systematic manner. Crystals of the diethyl and bistetradecyl derivatives, containing no solvent molecule, provided the first examples of direct pi-stacking of carbo-benzene rings, with inter-ring distances very close to calculated interlayer distances in AB and ABC alpha graphityne (3.255 and 3.206 A vs 3.266 and 3.201 A, respectively). PMID- 27973772 TI - Relativistic Effects on Electron-Nucleus Hyperfine Coupling Studied with an Exact 2-Component (X2C) Hamiltonian. AB - An exact 2-component (X2C) transformation of the one-electron Hamiltonian is used to transform nuclear hyperfine magnetic field operators from the 4-component Dirac picture to 2-component form. Numerical applications are concerned with hyperfine coupling constants of one-electron and many-electron atoms, as well as the HgH radical, using spin-unrestricted scalar X2C Hartree-Fock and Kohn-Sham theory. Reference data for 2-component generalized-collinear X2C calculations, including spin-orbit coupling, are also provided for selected cases. Calculations for one-electron atomic n s states with n = 1-3 show that the X2C transformed hyperfine operators give accurate hyperfine coupling constants. Kohn-Sham one electron self-interaction errors for these states are small. The performance of the X2C transformed hyperfine operator for many-electron systems is also promising. The method is straightforward to implement in codes using spin unrestricted (1-component) or 2-component spinor orbitals. PMID- 27973773 TI - 1D-2D-3D Transformation Synthesis of Hierarchical Metal-Organic Framework Adsorbent for Multicomponent Alkane Separation. AB - A new hierarchical MOF consisting of Cu(II) centers connected by benzene tricarboxylates (BTC) is prepared by thermoinduced solid transformation of a dense CuBTC precursor phase. The mechanism of the material formation has been thoroughly elucidated and revealed a transformation of a ribbon-like 1D building unit into 2D layers and finally a 3D network. The new phase contains excess copper, charge compensated by systematic hydroxyl groups, which leads to an open microporous framework with tunable permanent mesoporosity. The new phase is particularly attractive for molecular separation. Energy consumption of adsorptive separation processes can be lowered by using adsorbents that discriminate molecules based on adsorption entropy rather than enthalpy differences. In separation of a 11-component mixture of C1-C6 alkanes, the hierarchical phase outperforms the structurally related microporous HKUST-1 as well as silicate-based hierarchical materials. Grand canonical Monte Carlo (GCMC) simulation provides microscopic insight into the structural host-guest interaction, confirming low adsorption enthalpies and significant entropic contributions to the molecular separation. The unique three-dimensional hierarchical structure as well as the systematic presence of Cu(II) unsaturated coordination sites cause this exceptional behavior. PMID- 27973774 TI - Chemoselective Coupling of 1,1-Bis[(pinacolato)boryl]alkanes for the Transition Metal-Free Borylation of Aryl and Vinyl Halides: A Combined Experimental and Theoretical Investigation. AB - A new transition-metal-free borylation of aryl and vinyl halides using 1,1 bis[(pinacolato)boryl]alkanes as boron sources is described. In this transformation one of the boron groups from 1,1-bis[(pinacolato)boryl]alkanes is selectively transferred to aryl and vinyl halides in the presence of sodium tert butoxide as the only activator to form organoboronate esters. Under the developed borylation conditions, a broad range of organohalides are borylated with excellent chemoselectivity and functional group compatibility, thus offering a rare example of a transition-metal-free borylation protocol. Experimental and theoretical studies have been performed to elucidate the reaction mechanism, revealing the unusual formation of Lewis acid/base adduct between organohalides and alpha-borylcarbanion, generated in situ from the reaction of 1,1 bis[(pinacolato)boryl]alkanes with an alkoxide base, to facilitate the borylation reactions. PMID- 27973775 TI - An EOM-CCSD-PCM Benchmark for Electronic Excitation Energies of Solvated Molecules. AB - In this work, we benchmark the equation of motion coupled cluster with single and double excitations (EOM-CCSD) method combined with the polarizable continuum model (PCM) for the calculation of electronic excitation energies of solvated molecules. EOM-CCSD is one of the most accurate methods for computing one electron excitation energies, and accounting for the solvent effect on this property is a key challenge. PCM is one of the most widely employed solvation models due to its adaptability to virtually any solute and its efficient implementation with density functional theory methods (DFT). Our goal in this work is to evaluate the reliability of EOM-CCSD-PCM, especially compared to time dependent DFT-PCM (TDDFT-PCM). Comparisons between calculated and experimental excitation energies show that EOM-CCSD-PCM consistently overestimates experimental results by 0.4-0.5 eV, which is larger than the expected EOM-CCSD error in vacuo. We attribute this decrease in accuracy to the approximated solvation model. Thus, we investigate a particularly important source of error: the lack of H-bonding interactions in PCM. We show that this issue can be addressed by computing an energy shift, DeltaHB, from bare-PCM to microsolvation + PCM at DFT level. Our results show that such a shift is independent of the functional used, contrary to the absolute value of the excitation energy. Hence, we suggest an efficient protocol where the EOM-CCSD-PCM transition energy is corrected by DeltaHB(DFT), which consistently improves the agreement with the experimental measurements. PMID- 27973776 TI - Imaging Single-Chain Nanoparticle Folding via High-Resolution Mass Spectrometry. AB - Herein, we introduce the first approach to map single-chain nanoparticle (SCNP) folding via high-resolution electrospray ionization mass spectrometry (ESI MS) coupled with size exclusion chromatography. For the first time, the successful collapse of polymeric chains into SCNPs is imaged by characteristic mass changes, providing detailed mechanistic information regarding the folding mechanism. As SCNP system we employed methyl methacrylate (MMA) statistically copolymerized with glycidyl methacrylate (GMA), resulting in p(MMA-stat-GMA), subsequently collapsed by using B(C6F5)3 as catalyst. Both the precursor polymer and the SCNPs can be well ionized via ESI MS, and the strong covalent cross-links are stable during ionization. Our high-resolution mass spectrometric approach can unambiguously differentiate between two mechanistic modes of chain collapse for every chain constituting the SCNP sample. PMID- 27973777 TI - Synthetic Core Promoters as Universal Parts for Fine-Tuning Expression in Different Yeast Species. AB - Synthetic biology and metabolic engineering experiments frequently require the fine-tuning of gene expression to balance and optimize protein levels of regulators or metabolic enzymes. A key concept of synthetic biology is the development of modular parts that can be used in different contexts. Here, we have applied a computational multifactor design approach to generate de novo synthetic core promoters and 5' untranslated regions (UTRs) for yeast cells. In contrast to upstream cis-regulatory modules (CRMs), core promoters are typically not subject to specific regulation, making them ideal engineering targets for gene expression fine-tuning. 112 synthetic core promoter sequences were designed on the basis of the sequence/function relationship of natural core promoters, nucleosome occupancy and the presence of short motifs. The synthetic core promoters were fused to the Pichia pastoris AOX1 CRM, and the resulting activity spanned more than a 200-fold range (0.3% to 70.6% of the wild type AOX1 level). The top-ten synthetic core promoters with highest activity were fused to six additional CRMs (three in P. pastoris and three in Saccharomyces cerevisiae). Inducible CRM constructs showed significantly higher activity than constitutive CRMs, reaching up to 176% of natural core promoters. Comparing the activity of the same synthetic core promoters fused to different CRMs revealed high correlations only for CRMs within the same organism. These data suggest that modularity is maintained to some extent but only within the same organism. Due to the conserved role of eukaryotic core promoters, this rational design concept may be transferred to other organisms as a generic engineering tool. PMID- 27973779 TI - Concatemers of Outer Membrane Protein A Take Detours in the Folding Landscape. AB - Outer membrane protein A (OmpA) is the most abundant protein in the outer membrane of Escherichia coli. The N-terminal domain forms an eight-stranded membrane-embedded beta-barrel that is widely used as a model protein for in vitro folding into the membrane and into surfactant micelles. Under conditions that include a low surfactant concentration, OmpA can form stable higher-order structures by intermolecular association. Other beta-barrel membrane proteins also associate to form noncovalently linked trimers in vivo. This inspired us to test how topological constraints imposed by intramolecular links between individual OmpA molecules affect this process. Here we report on the properties of concatemers consisting of two and three copies of the transmembrane part of OmpA. Both concatemers could be folded to a native state in surfactant micelles according to spectroscopy and electrophoretic band shifts. This native state had the same thermodynamic stability against chemical denaturation as the original OmpA. Above 1.5 M GdmCl, concatemerization increased both refolding and unfolding rates, which we attribute to entropic effects. However, below 1.5 M GdmCl, folding kinetics were 2-3 orders of magnitude slower and more complex, involving a greater degree of parallel folding steps and species that could be classified as off-pathway. Only OmpA2 could quantitatively be folded into vesicles (though to an extent lower than that of OmpA), while OmpA3 formed three species with different levels of folding. Thus, close spatial and sequential proximity of OmpA domains on the same polypeptide chain have a strong tendency to trap the protein in different misfolded states. PMID- 27973781 TI - Vibrational Optical Activity of BODIPY Dimers: The Role of Magnetic-Electric Coupling in Vibrational Excitons. AB - The vibrational exciton (VE) interpretation of intense bisignated couplets in vibrational circular dichroism (VCD) spectra of a pair of atropisomeric BODIPY (boron dipyrrin) dimers is discussed. The role of intrinsic magnetic moments is crucial to reproduce the different behaviors of quasi-isomeric BODIPY dimers with different aryl junction. PMID- 27973778 TI - Direct Observation of Nanosecond Water Exchange Dynamics at a Protein Metal Site. AB - Nanosecond ligand exchange dynamics at metal sites within proteins is essential in catalysis, metal ion transport, and regulatory metallobiochemistry. Herein we present direct observation of the exchange dynamics of water at a Cd2+ binding site within two de novo designed metalloprotein constructs using 111mCd perturbed angular correlation (PAC) of gamma-rays and 113Cd NMR spectroscopy. The residence time of the Cd2+-bound water molecule is tens of nanoseconds at 20 degrees C in both proteins. This constitutes the first direct experimental observation of the residence time of Cd2+ coordinated water in any system, including the simple aqua ion. A Leu to Ala amino acid substitution ~10 A from the Cd2+ site affects both the equilibrium constant and the residence time of water, while, surprisingly, the metal site structure, as probed by PAC spectroscopy, remains essentially unaltered. This implies that remote mutations may affect metal site dynamics, even when structure is conserved. PMID- 27973782 TI - Constant-Distance Mode Nanospray Desorption Electrospray Ionization Mass Spectrometry Imaging of Biological Samples with Complex Topography. AB - A new approach for constant-distance mode mass spectrometry imaging (MSI) of biological samples using nanospray desorption electrospray ionization (nano-DESI) was developed by integrating a shear-force probe with the nano-DESI probe. The technical concept and basic instrumental setup, as well as the general operation of the system are described. Mechanical dampening of resonant oscillations due to the presence of shear forces between the probe and the sample surface enabled the constant-distance imaging mode via a computer-controlled closed-feedback loop. The capability of simultaneous chemical and topographic imaging of complex biological samples is demonstrated using living Bacillus subtilis ATCC 49760 colonies on agar plates. The constant-distance mode nano-DESI MSI enabled imaging of many metabolites, including nonribosomal peptides (surfactin, plipastatin, and iturin) on the surface of living bacterial colonies, ranging in diameter from 10 to 13 mm, with height variations up to 0.8 mm above the agar plate. Co registration of ion images to topographic images provided higher-contrast images. Based on this effort, constant-mode nano-DESI MSI proved to be ideally suited for imaging biological samples of complex topography in their native states. PMID- 27973783 TI - Optimized Long-Range Corrected Density Functionals for Electronic and Optical Properties of Bare and Ligated CdSe Quantum Dots. AB - The reliable prediction of optical and fundamental gaps of finite size systems using density functional theory requires to account for the potential self interaction error, which is notorious for degrading the description of charge transfer transitions. One solution is provided by parametrized long-range corrected functionals such as LC-BLYP, which can be tuned such as to describe certain properties of the particular system at hand. Here, bare and 3 mercaptoprotionic acid covered Cd33Se33 quantum dots are investigated using the optimally tuned LC-BLYP functional. The range separation parameter, which determines the switching on of the exact exchange contribution, is found to be 0.12 bohr-1 and 0.09 bohr-1 for the bare and covered quantum dot, respectively. It is shown that density functional optimization indeed yields optical and fundamental gaps and thus exciton binding energies, considerably different compared with standard functionals such as the popular PBE and B3LYP ones. This holds true, despite the well established fact that the leading transitions are localized on the quantum dot and do not show pronounced long-range charge transfer character. PMID- 27973784 TI - Sequence Control of Macromers via Iterative Sequential and Exponential Growth. AB - A general strategy through the use of direct azidation of alcohols allowed the sequence control of macromers via both the iterative sequential growth and iterative exponential growth methods. The chemistry was highly efficient in building polymers from a sequence of compositionally different macromers tethered together in close proximity. Using the DPPA/DBU method for near quantitative azidation of the benzyl alcohol moiety, sequence controlled polymers were made via a direct and one-step procedure for CuAAC activation. With four different macromers, spherical miktoarm star-like polymers of 50 000 molecular weight were prepared with a low dispersity, and the polymer coil size depended on the type of added macromer. Polymers made via the iterative methods opens the way for the design of advanced materials with predictable properties. PMID- 27973785 TI - Critical Role of Different Immobilized Biocatalysts of a Given Lipase in the Selective Ethanolysis of Sardine Oil. AB - Different immobilized derivatives of two lipases were tested as catalysts of the synthesis of ethyl esters of omega-3 fatty acids during the ethanolysis of sardine oil in solvent-free systems at 25 degrees C. Lipases from Thermomyces lanuginosus (TLL) and Lecitase Ultra (a phospholipase with lipolytic activity) were studied. Lipases were adsorbed on hydrophobic Sepabeads C18 through the open active center and on an anion-exchanger Duolite with the active center exposed to the reaction medium. TLL-Sepabeads derivatives exhibit a high activity of 9 UI/mg of immobilized enzyme, and they are 20-fold more active than TLL-Duolite derivatives and almost 1000-fold more active than Lipozyme TL IM (the commercial derivative from Novozymes). Lecitase-Sepabeads exhibit a high selectivity for the synthesis of the ethyl ester of EPA that is 43-fold faster than the synthesis of the ethyl ester of DHA. PMID- 27973786 TI - Dynamics of a Room Temperature Ionic Liquid in Supported Ionic Liquid Membranes vs the Bulk Liquid: 2D IR and Polarized IR Pump-Probe Experiments. AB - Supported ionic liquid membranes (SILMs) are membranes that have ionic liquids impregnated in their pores. SILMs have been proposed for advanced carbon capture materials. Two-dimensional infrared (2D IR) and polarization selective IR pump probe (PSPP) techniques were used to investigate the dynamics of reorientation and spectral diffusion of the linear triatomic anion, SeCN-, in poly(ether sulfone) (PES) membranes and room-temperature ionic liquid (RTIL), 1-ethyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide (EmimNTf2). The dynamics in the bulk EmimNTf2 were compared to its dynamics in the SILM samples. Two PES membranes, PES200 and PES30, have pores with average sizes, ~300 nm and ~100 nm, respectively. Despite the relatively large pore sizes, the measurements reveal that the reorientation of SeCN- and the RTIL structural fluctuations are substantially slower in the SILMs than in the bulk liquid. The complete orientational randomization, slows from 136 ps in the bulk to 513 ps in the PES30. 2D IR measurements yield three time scales for structural spectral diffusion (SSD), that is, the time evolution of the liquid structure. The slowest decay constant increases from 140 ps in the bulk to 504 ps in the PES200 and increases further to 1660 ps in the PES30. The results suggest that changes at the interface propagate out and influence the RTIL structural dynamics even more than a hundred nanometers from the polymer surface. The differences between the IL dynamics in the bulk and in the membranes suggest that studies of bulk RTIL properties may be poor guides to their use in SILMs in carbon capture applications. PMID- 27973787 TI - Allylation and Alkylation of Biologically Relevant Nucleophiles by Diallyl Sulfides. AB - Allyl sulfides are bioactive phytochemicals found in garlic, onion, and other members of the genus Allium. Here we showed that diallyl disulfide and diallyl trisulfide can transfer allyl side chains to low molecular weight thiols. Diallyl monosulfide is inert with respect to this allyl transfer reaction. On the other hand, diallyl sulfone, a known metabolite of diallyl monosulfide, alkylates both amines and thiols under physiologically relevant conditions via isomerization to an electrophilic vinyl sulfone. PMID- 27973788 TI - Intramolecular Charge Transfer and Ion Pairing in N,N-Diaryl Dihydrophenazine Photoredox Catalysts for Efficient Organocatalyzed Atom Transfer Radical Polymerization. AB - Photoexcited intramolecular charge transfer (CT) states in N,N-diaryl dihydrophenazine photoredox catalysts are accessed through catalyst design and investigated through combined experimental studies and density functional theory (DFT) calculations. These CT states are reminiscent of the metal to ligand charge transfer (MLCT) states of ruthenium and iridium polypyridyl complexes. For cases where the polar CT state is the lowest energy excited state, we observe its population through significant solvatochromic shifts in emission wavelength across the visible spectrum by varying solvent polarity. We propose the importance of accessing CT states for photoredox catalysis of atom transfer radical polymerization lies in their ability to minimize fluorescence while enhancing electron transfer rates between the photoexcited photoredox catalyst and the substrate. Additionally, solvent polarity influences the deactivation pathway, greatly affecting the strength of ion pairing between the oxidized photocatalyst and the bromide anion and thus the ability to realize a controlled radical polymerization. Greater understanding of these photoredox catalysts with respect to CT and ion pairing enables their application toward the polymerization of methyl methacrylate for the synthesis of polymers with precisely tunable molecular weights and dispersities typically lower than 1.10. PMID- 27973789 TI - Effects of Polar Compounds Generated from the Deep-Frying Process of Palm Oil on Lipid Metabolism and Glucose Tolerance in Kunming Mice. AB - In the present study, effects of deep-fried palm oil, specifically polar compounds generated during the frying process, on animal health including lipid and glucose metabolism and liver functions were investigated. Kunming mice were fed a high-fat diet containing deep-fried palm oil or purified polar compounds for 12 weeks. Their effects on animal health including hepatic lipid profile, antioxidant enzyme activity, serum biochemistry, and glucose tolerance were analyzed. Our results revealed that the consumption of polar compounds was related to the change of lipid deposition in liver and adipose tissue, as well as glucose tolerance alteration in Kunming mice. Correspondingly, the transcription study of genes involved in lipid metabolism including PPARalpha, Acox1, and Cpt1alpha indicated that polar compounds probably facilitated the fatty acid oxidation on peroxisomes, whereas lipid oxidation in mitochondria was suppressed. Furthermore, glucose tolerance test (GTT) revealed that a high amount of polar compound intake impaired glucose tolerance, indicating its effect on glucose metabolism in vivo. Our results provide critical information on the effects of polar compounds generated from the deep-frying process of palm oil on animal health, particularly liver functions and lipid and glucose metabolism, which is important for the evaluation of the biosafety of frying oil. PMID- 27973790 TI - Interpreting Interactions between Ozone and Residual Petroleum Hydrocarbons in Soil. AB - We evaluated how gas-phase O3 interacts with residual petroleum hydrocarbons in soil. Total petroleum hydrocarbons (TPH) were 18 +/- 0.6 g/kg soil, and TPH carbon constituted ~40% of the dichloromethane-extractable carbon (DeOC) in the soil. At the benchmark dose of 3.4 kg O3/kg initial TPH, TPH carbon was reduced by nearly 6 gC/kg soil (40%), which was accompanied by an increase of about 4 gC/kg soil in dissolved organic carbon (DOC) and a 4-fold increase in 5-day biochemical oxygen demand (BOD5). Disrupting gas channeling in the soil improved mass transport of O3 to TPH bound to soil and increased TPH removal. Ozonation resulted in two measurable alterations of the composition of the organic carbon. First, part of DeOC was converted to DOC (~4.1 gC/kg soil), 75% of which was not extractable by dichloromethane. Second, the DeOC containing saturates, aromatics, resins, and asphaltenes (SARA), was partially oxidized, resulting in a decline in saturates and aromatics, but increases in resins and asphaltenes. Ozone attack on resins, asphaltenes, and soil organic matter led to the production of NO3-, SO42 , and PO43-. The results illuminate the mechanisms by which ozone gas interacted with the weathered petroleum residuals in soil to generate soluble and biodegradable products. PMID- 27973791 TI - Switchable Synthesis of Pyrroles and Pyrazines via Rh(II)-Catalyzed Reaction of 1,2,3-Triazoles with Isoxazoles: Experimental and DFT Evidence for the 1,4 Diazahexatriene Intermediate. AB - 4-Aminopyrrole-3-carboxylates and pyrazine-2-carboxylates were synthesized from 5 alkoxyisoxazoles and 1-sulfonyl-1,2,3-triazoles by tuning the Rh(II) catalyst and the reaction conditions. The reaction in chloroform at 100 degrees C under Rh2(OAc)4 catalysis provides 4-aminopyrrole-3-carboxylates in good yields. The use of Rh2(Piv)4 in refluxing toluene results in the formation of 1,2 dihydropyrazine-2-carboxylates as the main products, which can be converted by a one-pot procedure to pyrazine-2-carboxylates by heating with catalytic amounts of TsOH. According to the NMR and DFT investigations of the reaction mechanism, pyrroles and dihydropyrazines are formed, respectively, via 1,5- and 1,6 cyclization of common (5Z)-1,4-diazahexa-1,3,5-triene intermediates. The influence of the nature of the catalyst on the product distribution is rationalized in terms of the Rh-catalyzed isomerization of a pyrrolin-2-ylium-3 aminide zwitterion, the primary product of 1,4-diazahexatriene 1,5-cyclization. PMID- 27973792 TI - Resolved (v1, v2 = 1) Combination Vibrational States of CF3 Fragments in the Photofragment Translational Spectra of CF3I. AB - The photodissociation of CF3I -> CF3(v1,v2) + I*/I has been investigated at 248, 266, and 277 nm with our high resolution mini-TOF photofragment translational spectrometer. Based on the theoretical calculations of Clary and of Bowman et al., now in this manuscript, we assign 701 cm-1 to the CF symmetric stretch (breathing) nu1 mode, and 1086 cm-1 to the umbrella nu2 mode of the CF3 fragment. In the obtained TOF spectra of I+ from the I* channel, situated in the 701 cm-1 gaps between the original series of (v1, 0) vibrational peaks, a new series of weaker (v1, 1) vibrational peaks are partially resolved. These observed new peaks with 1086 cm-1 nu2 mode excitation have never been reported in previous literature. In the TOF spectra of I+ from the I channel, the new series of (v1, 1) peaks are also partially resolved. However, these spectra of I channel are less satisfactory, because for higher Eavl and higher ET, the higher resolution of PTS is required. The potential energy at the curve crossing point and the excitation of CF3 (v1, 2) and (v1, 3) vibrational states have been also analyzed. PMID- 27973793 TI - Envisaging Structural Insight of a Terminally Protected Proline Dipeptide by Raman Spectroscopy and Density Functional Theory Analyses. AB - The proline residue in a protein sequence generates constraints to its secondary structure as the associated torsion angles become a part of the heterocyclic ring. It becomes more significant when two consecutive proline residues link via amide linkage and produce additional configurational constraint to a protein's folding and stability. In the current manuscript we have illustrated conformation preference of a novel dipeptide, (R)-tert-butyl 2-((S)-2 (methoxycarbonyl)pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate. The dipeptide crystallized in the orthorhombic crystalline state and produced rod-shaped macroscopic material. The analysis of the crystal coordinates showed dihedral angles (phi, psi) of the interlinked amide groups as (+72 degrees , -147 degrees ) and the dihedral angles (phi, psi) produced with the next carbonyl were (-68 degrees , +151 degrees ), indicating polyglycine II (PGII) and polyproline II (PPII)-like helix states at the N- and C-terminals, respectively. These two states, PGII and PPII, are mirror image configurations and are expected to produce similar vibration bands from the associated carbonyl groups. However, the unique atomic arrangement in the molecule produces three carbonyl groups and one of them was very specific, being part of the main peptide linkage that connects both the pyrrolidine rings. The carbonyl group in the peptide bond exhibited a Raman vibration frequency at ~1642 cm-1 and is considered a signatory Raman marker band for the peptide bond linking two heterochiral proline residues. The carbonyl group (t-Boc) at the N-terminal of the peptide showed a characteristic vibration at ~1685 cm-1 and the C-terminal carbonyl group as a part of the ester showed a vibration signature at a significantly high frequency (1746 cm-1). Conformation analyses performed with density functional theory (DFT) calculations depicted that the dipeptide was stabilized in vacuum with dihedral angles (+72 degrees , -154 degrees ) and (-72 degrees , +151 degrees ) at the N- and C terminals, respectively. Molecular dynamics (MD) simulation also showed that the peptide conformation having dihedral angles around (+75 degrees , -150 degrees ) and (-75 degrees , +150 degrees ) at the N- and C-terminals, respectively, was reasonably stable in water. Due to unique absence of the amide N-H, the peptide was ineffective in forming any intramolecular hydrogen bonding. MD investigation, however, revealed an intermolecular hydrogen bonding interaction with the water molecules, leading to its stability in aqueous solution. Metadynamics simulation analysis of the dipeptide in water also supported the PGII-PPII-like conformation at the N- and C-terminals, respectively, as the energetically stable conformation among the other possible combinations of conformations. The possible electronic transitions along with the HOMO-LUMO analysis further depicted the stability of the dipeptide in water and their possible absorption pattern. Time-dependent density functional theory (TDDFT) analysis showed strong negative rotatory strength of the dipeptide around 210 nm in water and acetonitrile, and it could be the source of experimentally observed high-amplitude negative absorption in the circular dichroism (CD) spectra around 200-203 nm. The very weak positive band (signature) in the region at ~228 nm in CD spectra could also be correlated to the positive rotatory strength at 228 nm observed in ECD. To test the effect of such a dipeptide on a living cell, an MTT assay was performed and the result indicated no cytotoxic effect toward human hepatocellular carcinoma Hep G2 cancer cell lines. PMID- 27973794 TI - Chemical Composition and Properties of the Liquid-Vapor Interface of Aqueous C1 to C4 Monofunctional Acid and Alcohol Solutions. AB - The liquid-vapor interface is playing an important role in aerosol and cloud chemistry in cloud droplet activation by aerosol particles and potentially also in ice nucleation. We have employed the surface sensitive and chemically selective X-ray photoelectron spectroscopy (XPS) technique to examine the liquid vapor interface for mixtures of water and small alcohols or small carboxylic acids (C1 to C4), abundant chemicals in the atmosphere in concentration ranges relevant for cloud chemistry or aerosol particles at the point of activation into a cloud droplet. A linear correlation was found between the headgroup carbon 1s core-level signal intensity and the surface excess derived from literature surface tension data with the offset being explained by the bulk contribution to the photoemission signal. The relative interfacial enhancement of the carboxylic acids over the carboxylates at the same bulk concentration was found to be highest (nearly 20) for propionic acid/propionate and still about 5 for formic acid/formate, also in fair agreement with surface tension measurements. This provides direct spectroscopic evidence for high carboxylic acid concentrations at aqueous solution-air interfaces that may be responsible for acid catalyzed chemistry under moderately acidic conditions with respect to their bulk aqueous phase acidity constant. By assessing the ratio of aliphatic to headgroup C 1s signal intensities XPS also provides information about the orientation of the molecules. The results indicate an increasing orientation of alcohols and neutral acids toward the surface normal as a function of chain length, along with increasing importance of lateral hydrophobic interactions at higher surface coverage. In turn, the carboxylate ions exhibit stronger orientation toward the surface normal than the corresponding neutral acids, likely caused by the stronger hydration of the charged headgroup. PMID- 27973795 TI - Correction to "Modeling the Radical Chemistry in an Oxidation Flow Reactor: Radical Formation and Recycling, Sensitivities, and the OH Exposure Estimation Equation". PMID- 27973796 TI - Celebrating Our 120th Anniversary. PMID- 27973798 TI - Quasi-Restricted Orbital Treatment for the Density Functional Theory Calculations of the Spin-Orbit Term of Zero-Field Splitting Tensors. AB - A quasi-restricted orbital (QRO) approach for the calculation of the spin-orbit term of zero-field splitting tensors (DSO tensors) by means of density functional theory (DFT) importantly features in the fact that it is free from spin contamination problems because it uses spin eigenfunctions for the zeroth order wave functions. In 2011, however, Schmitt and co-workers pointed out that in the originally proposed QRO working equation some possible excitations were not included in their sum-over-states procedure, which causes spurious DSO contributions from closed-shell subsystems located far from the magnetic molecule under study. We have revisited the derivation of the QRO working equation and modified it, making it include all possible types of excitations in the sum-over states procedure. We have found that the spurious DSO contribution can be eliminated by taking into account contributions from all possible types of singly excited configuration state functions. We have also found that only the SOMO(alpha) -> SOMO(beta) excited configurations have nonzero contributions to the DSO tensors as long as alpha and beta spin orbitals have the same spatial distributions and orbital energies. For the DSO tensor calculations, by using a ground state wave function free from spin contamination, we propose a natural orbital-based Pederson-Khanna (NOB-PK) method, which utilizes the single determinant wave function consisting of natural orbitals in conjunction with the Pederson-Khanna (PK) type perturbation treatment. Some relevant calculations revealed that the NOB-PK method can afford more accurate DSO tensors than the conventional PK method as well as the QRO approach in MnII complexes and ReIV based single molecule magnets. PMID- 27973797 TI - Photophysical Properties and Electronic Structure of Porphyrins Bearing Zero to Four meso-Phenyl Substituents: New Insights into Seemingly Well Understood Tetrapyrroles. AB - Six free base porphyrins bearing 0-4 meso substituents have been examined by steady-state and time-resolved absorption and fluorescence spectroscopy in both toluene and N,N-dimethylformamide (DMF). The lifetime of the lowest singlet excited state (S1) decreases with an increase in the number of meso-phenyl groups; the values in toluene are H2P-0 (15.5 ns) > H2P-1 (14.9 ns) > H2P-2c (14.4 ns) > H2P-2t (13.8 ns) ~ H2P-3 (13.8 ns) > H2P-4 (12.8 ns), where "H2P" refers to the core free base porphyrin, the numerical suffix indicates the number of meso-phenyl groups, and "c" and "t" refer to cis and trans, respectively. The opposite trend is found for the fluorescence quantum yield; the values in toluene are H2P-0 (0.049) < H2P-1 (0.063) ~ H2P-2c (0.063) < H2P-2t (0.071) < H2P-3 (0.073) < H2P-4 (0.090). Similar trends occur in DMF. All radiative and nonradiative (internal conversion and intersystem crossing) rate constants for S1 decay increase with the increasing number of meso-phenyl groups. The increase in the rate constant for fluorescence parallels an increase in oscillator strength of the S0 -> S1 absorption manifold. The trend is reproduced by time-dependent density functional theory calculations. The calculations within the context of the four-orbital model reveal that the enhanced S0 <-> S1 radiative probabilities derive from a preferential effect of the meso-phenyl groups to raise the energy of the highest occupied molecular orbital, which underpins a parallel bathochromic shift in the S0 -> S1 absorption wavelength. Polarizations of the S1 and S2 excited states with respect to molecular structural features (e.g., the central proton axis) are analyzed in the context of historical conventions for porphyrins versus chlorins and bacteriochlorins, where some ambiguity exists, including for porphine, one of the simplest tetrapyrroles. Collectively, the study affords fundamental insights into the photophysical properties and electronic structure of meso-phenylporphyrins that should aid their continued widespread use as benchmarks for tetrapyrrole-based architectures in chemical, solar-energy, and life-sciences research. PMID- 27973800 TI - Probing Electronic Wave Functions of Sodium-Doped Clusters: Dyson Orbitals, Anisotropy Parameters, and Ionization Cross-Sections. AB - We apply high-level ab initio methods to describe the electronic structure of small clusters of ammonia and dimethyl ether (DME) doped with sodium, which provide a model for solvated electrons. We investigate the effect of the solvent and cluster size on the electronic states. We consider both energies and properties, with a focus on the shape of the electronic wave function and the related experimental observables such as photoelectron angular distributions. The central quantity in modeling photoionization experiments is the Dyson orbital, which describes the difference between the initial N-electron and final (N-1) electron states of a system. Dyson orbitals enter the expression of the photoelectron matrix element, which determines total and partial photoionization cross-sections. We compute Dyson orbitals for the Na(NH3)n and Na(DME)m clusters using correlated wave functions (obtained with equation-of-motion coupled-cluster model for electron attachment with single and double substitutions) and compare them with more approximate Hartree-Fock and Kohn-Sham orbitals. We also analyze the effect of correlation and basis sets on the shapes of Dyson orbitals and the experimental observables. PMID- 27973799 TI - Anharmonicity in the Vibrational Spectra of Naphthalene and Naphthalene-d8: Experiment and Theory. AB - In this paper, we report the gas phase infrared (IR) spectra of naphthalene and naphthalene-d8 recorded in the mid-infrared region (3200-500 cm-1) using a heated multipass long path gas cell. Several combination bands appear as shoulders and satellite peaks in the 3200-2600 cm-1region along with the C-H stretch fundamental bands. Experimental IR spectra of these molecules were systematically analyzed with vibrational self-consistent field (VSCF) theory, vibrational second order perturbation theory (VPT2) and vibrational couple cluster method (VCCM) with two different potential energy surfaces obtained using B3LYP and MP2 methods. A comparative study between these two PESs was made to match the observed spectra. Final assignment of the IR spectra of naphthalene and naphthalene-d8 was done using the VCCM with MP2 potential, which provided the best match. PMID- 27973801 TI - Models of Isotopic Water Diffusion in Spherical Aerosol Particles. AB - Isotopic exchange experiments that utilize D2O and H2O have received attention as a method for studying water diffusion in high viscosity aerosol particles. However, the mathematical models used to retrieve diffusion coefficients from these measurements have yet to be critically examined. Here, two models for the isotopic exchange of D2O and H2O in spherical particles are analyzed and compared. The primary difference between the two models is the choice of boundary condition at the surface of the spherical particle. In one model, it is assumed that the concentration of D2O at the surface is fixed, while in the other model, it is assumed that, at the particle surface, the concentration of D2O in the condensed phase is in equilibrium with D2O vapor. Closed-form expressions for the two boundary value problems that describe these physical models are found and discussed. Then, specific examples of aqueous droplets containing either sucrose, citric acid, and shikimic acid are examined with both models. It is found that at low relative humidities the choice of boundary condition has a negligible effect on the predicted lifetime of isotopic exchange, while at high relative humidities predicted lifetimes can differ by orders of magnitude. The implication of this result is that the choice of model can greatly affect diffusion coefficients retrieved from experimental measurements under certain conditions. Finally, discrepancies between diffusion coefficients measured using isotopic exchange and water sorption and desorption experiments are discussed. PMID- 27973802 TI - An ab Initio Study on the Structure, Energetics, and Spectra of Cl-...(CO2)n Clusters. AB - Structures, energetics, and photoelectron spectral properties of Cl-...(CO2)n (n = 1-8) clusters are studied by ab initio electronic structure methods, namely, Moller-Plesset second-order perturbation theory (MP2) correlated consistent, aug cc-pvtz basis functions. The most stable structure for each size is evaluated by using both bottom-up and top-down approaches. It is observed that CO2 molecules approach to the chloride anion in an asymmetric way except for Cl-...(CO2)8 cluster. We do observe the applicability of the simple classical electrostatic model for charge-quadrupole interactions to the solvation of the chloride anion by the solvent CO2. Both vertical electron detachment energies and solvation energies are calculated for all the clusters at the MP2 level. We do observe an excellent agreement between theory and experiment for the vertical detachment energy, solvation energy, and gas phase detachment energy of chloride anion. It is also observed that the detachment energy of the chloride anion is increased by 4.09 eV due to the solvation effect of bulk CO2 and it is quite small in contrast to the increase of 5.29 eV due to the solvation effect of polar solvent, water. PMID- 27973803 TI - Ab Initio Vibrational Spectroscopy of cis- and trans-Formic Acid from a Global Potential Energy Surface. AB - A global analytic potential energy surface for the ro-vibrational dynamics of cis and trans-formic acid is presented, constructed using LASSO-based regression to reproduce CCSD(T)(F12*)/cc-pVTZ-F12 energies. The fit is accurate to 0.25% has an RMS deviation from the ab initio data of 9 cm-1 for the energy range 0-15000 cm 1. Converged J = 0 vibrational eigenstates are reported, computed using vibrational configuration interaction with an internal coordinate path Hamiltonian for the torsional motion connecting the cis and trans rotamers. Methodological choices concerning the appropriate definitions of the curvilinear and diabatic bath coordinates are discussed. The zero point of the cis rotamer is 1412 cm-1 above that of the trans, which lies at 7354 cm-1. The computed fundamentals match the bands recorded from gas-phase IR spectroscopy with an RMSD of only 3 cm-1. A fresh assignment of the overtone spectra of both the cis and trans rotamers is presented for the energy range 0-4720 cm-1, where 14 out of the 51 bands are reassigned on the basis of the VCI calculations. PMID- 27973804 TI - Efficient Geometry Optimization of Large Molecular Systems in Solution Using the Fragment Molecular Orbital Method. AB - The analytic gradient is derived for the frozen domain formulation of the fragment molecular orbital (FMO) method combined with the polarizable continuum model. The accuracy is tested in comparison to full FMO calculations for a representative set of systems in terms of the gradient accuracy, protein-ligand binding energies, and optimized structures. The frozen domain method reproduced geometries optimized with full FMO within 0.03-0.09 A in terms of reduced mean square deviations, whereas a single-point gradient calculation is accelerated by the factor of 38 (Trp-cage protein in explicit solvent, PDB: 1L2Y ) and 12 (crambin, PDB: 1CRN ). The method is applied to a geometry optimization of the K Ras protein-ligand complex (4Q03) using two domain definitions, and the optimized structures are consistent with experiment. Pair interaction analysis is used to identify residues important in binding the ligand. PMID- 27973805 TI - Substrate Sulfoxidation by an Iron(IV)-Oxo Complex: Benchmarking Computationally Calculated Barrier Heights to Experiment. AB - High-valent metal-oxo oxidants are common reactive species in synthetic catalysts as well as heme and nonheme iron enzymes. In general, they efficiently react with substrates through oxygen atom transfer, and for a number of cases, experimental rate constants have been determined. However, because these rate constants are generally measured in a polar solution, it has been found difficult to find computational methodologies to reproduce experimental trends and reactivities. In this work, we present a detailed computational study into para-substituted thioanisole sulfoxidation by a nonheme iron(IV)-oxo complex. A range of density functional theory methods and basis sets has been tested for their suitability to describe the reaction mechanism and compared with experimentally obtained free energies of activation. It is found that the enthalpy of activation is reproduced well, but all methods overestimate the entropy of activation by about 50%, for which we recommend a correction factor. The effect of solvent and dispersion on the barrier heights is explored both at the single-point level and also through inclusion in geometry optimizations, and particularly, solvent is seen as highly beneficial to reproduce experimental free energies of activation. Interestingly, in general, experimental trends and Hammett plots are reproduced well with almost all methods and procedures, and only a systematic error seems to apply for these chemical systems. Very good agreement between experiment and theory is found for a number of different methods, including B3LYP and PBE0, and procedures that are highlighted in the paper. PMID- 27973806 TI - Nearest-Neighbor and Non-Nearest-Neighbor Interactions between Substituents in the Benzene Ring. Experimental and Theoretical Study of Functionally Substituted Benzamides. AB - Standard molar enthalpies of formation of 2- and 4-hydroxybenzamides were measured by combustion calorimetry. Vapor pressures of benzamide and 2 hydroxybenzamide were derived by the transpiration method. Standard molar enthalpies of sublimation or vaporization of these compounds at 298 K were obtained from vapor pressure temperature dependence. Thermochemical data on benzamides with hydroxyl, methyl, methoxy, amino, and amide substituents were collected, evaluated, and tested for internal consistency. The high-level G4 quantum-chemical method was used for mutual validation of the experimental and theoretical gas-phase enthalpies of formation. Sets of nearest-neighbor and non nearest-neighbor interactions between substituents in the benzene ring have been evaluated. A simple incremental procedure has been suggested for a quick appraisal of the vaporization and gas-phase formation enthalpies of the substituted benzamides. PMID- 27973807 TI - Calculated Resonance Vibrational Raman Optical Activity Spectra of Naproxen and Ibuprofen. AB - Determining the absolute configuration of a molecule is possible by means of various chiroptical spectroscopic methods, one of them being vibrational Raman optical activity (VROA). By adopting a laser excitation wavelength in resonance with an electronic transition, the weak spectral signals can be selectively enhanced. We implement a Kohn-Sham methodology for the calculation of resonance and off-resonance VROA spectra to (S)-naproxen and (S)-ibuprofen and discuss their band patterns. The resonance enhancement of the VROA spectrum of (S) naproxen at an incident wavelength of 514.5 nm caused by an absorption tail as well as the typical off-resonance behavior of the VROA spectrum of (S)-ibuprofen at the same incident wavelength can be well reproduced. VROA spectra are also predicted under full resonance conditions. PMID- 27973808 TI - Implementation of INDO/SCI with COSMO Implicit Solvation and Benchmarking for Solvatochromic Shifts. AB - Accurate and rapid quantum mechanical prediction of solvatochromic shifts, particularly in systems where charge transfer plays a significant role, is important for many aspects of molecular and material design. Although the semiempirical INDO/SCI approach is computationally efficient and performs well for charge-transfer states, the availability of implicit solvent approaches has been limited. Here, we implement the COSMO solvent model with a perturbative state-specific correction to the excited-state energies with the INDO/SCI method. We show that for a series of prototypical pi-conjugated molecules, our newly implemented INDO/SCI/COSMO model yields more accurate absorption energies and comparably accurate solvatochromic shifts to those computed using TD-omegaB97XD and CIS with COSMO solvation at a substantially lower computational cost. PMID- 27973809 TI - Theoretical Investigation of Substituent Effects on the Dihydroazulene/Vinylheptafulvene Photoswitch: Increasing the Energy Storage Capacity. AB - We have investigated the effects of substituents on the properties of the dihydroazulene/vinylheptafulvene photoswitch. The focus is on the changes of the thermochemical properties by placing electron withdrawing and donating groups on the monocyano and dicyano structures of the parent dihydroazulene and vinylheptafulvene compounds. We wish to increase the energy storage capacity, that is, the energy difference between the dihydroazulene and vinylheptafulvene isomers, of the photoswitch by computational molecular design and have performed over 9000 electronic structure calculations using density functional theory. Based on these calculations, we obtain design rules for how to increase the energy storage capacity of the photoswitch. Furthermore, we have investigated how the activation energy for the thermally induced vinylheptafulvene to dihydroazulene conversion depends on the substitution pattern, and based on these results, we have outlined molecular design considerations for obtaining new desired target structures exhibiting long energy storage times. Selected candidate systems have also been investigated in terms of optical properties to elucidate how sensitive the absorption maxima are to the functionalizations. PMID- 27973810 TI - Threshold Collision-Induced Dissociation of Proton-Bound Hydrazine and Dimethylhydrazine Clusters. AB - Threshold collision-induced dissociation (TCID) using a guided ion beam tandem mass spectrometer is performed on (N2H4)nH+ where n = 2-4 and on the proton-bound unsymmetrical 1,1-dimethylhydrazine (UDMH) dimer complex. The primary dissociation pathway for all reactants consists of loss of a single hydrazine (or UDMH) molecule followed by the sequential loss of additional hydrazine molecules at higher collision energies for n = 3 and 4. The data were analyzed using a statistical model after accounting for internal and kinetic energy distributions, multiple collisions, and kinetic shifts to obtain 0 K bond dissociation energies (BDEs). These are also converted to values at room temperature by using a rigid rotor/harmonic oscillator approximation and theoretical molecular constants. Experimental BDEs are compared to theoretical BDEs determined at the B3LYP, M06, mPW1PW91, PBE0, MP2(full), and CCSD(T) levels of theory with and without empirical dispersion with a 6-311+G(2d,2p) basis set. The structures of all clusters are explored and exhibit extensive hydrogen bonding. PMID- 27973811 TI - Conjugation Length Distribution in Poly(p-phenylenevinylene) (PPV) Films. AB - We studied the absorption line-shape of poly(p-phenylenevinylene) (PPV) films deposited via spin coating and Langmuir-Blodgett techniques with the intent of identifying the conjugation length distribution in these two types of films, a key morphological aspect of conjugated polymer films. We treated the excitons in the polymer as independent oligomer excitons and modeled the absorption spectra of the individual oligomers using simple expressions for the oligomer size dependence of the gap energy, the line-broadening factor, the transition dipole moment and the Huang-Rhys parameter. We validated these expressions by independent measurements on phenyl-based oligomers and Density Functional Theory calculations. Our results show clear evidence that, for both types of PPV films, the conjugation length distribution depends exponentially on the segment size. Our results also set a lower limit, of about ten repeat units, for the maximum exciton length of three different phenyl-based oligomers. PMID- 27973812 TI - CH3NH3PbI3, A Potential Solar Cell Candidate: Structural and Spectroscopic Investigations. AB - Hybrid organic-inorganic metal halides of the type CH3NH3PbX3 have emerged as potential materials for photovoltaic applications. In this paper we discuss structural, electronic, and optical spectroscopy investigations performed on high quality single crystals of CH3NH3PbI3. Our results conclusively suggest that CH3NH3PbI3 crystallizes in centrosymmetric space group and the methylammonium moiety exhibits disordered packing at room temperature. Extracted values of the exciton binding energy, the electron-phonon coupling constant, and the schematic energy level diagram constructed from the emission broadening, Raman, and photoemission spectroscopy measurements clearly show the potential of this system in photovoltaic applications. PMID- 27973813 TI - Theoretical Investigation of Molecular and Electronic Structures of Buckminsterfullerene-Silicon Quantum Dot Systems. AB - Density functional theory (DFT) and density functional tight binding (DFTB) molecular dynamics (DFTB/MD) simulations of embedding and relaxation of buckminsterfullerene C60 molecules chemisorbed on (001) and (111) surfaces and inside bulk silicon lattice were performed. DFT calculations of chemisorbed fullerenes on both surfaces show that the C60 molecule deformation was very small and the C60 binding energies were roughly ~4 eV. The charge analysis shows that the C60 molecule charges on (001) and (111) surfaces were between -2 and -3.5 electrons, respectively, that correlates well with the number of C-Si bonds linking the fullerene molecule and the silicon surface. DFT calculations of the C60 molecule inside bulk silicon confirm that the C60 molecule remains stable with the deformation energy values of between 11 and 15 eV for geometries with different C60 configurations. The formation of some C-Si bonds causes local silicon amorphization and corresponding electronic charge uptake on the embedded fullerene cages. Charge analysis confirms that a single C60 molecule can accept up to 20 excessive electrons that can be used in practice, wherein the main charge contribution is located on the fullerene's carbon atoms bonded to silicon atoms. These DFT calculations correlate well with DFTB/MD simulations of the embedding process. In this process, the C60 molecule was placed on the top of the Si(111) surface, and it was further exposed by a stream of silicon dimers, resulting in subsequent overgrowth by silicon. PMID- 27973814 TI - Role of Molecular Flexibility and Colloidal Descriptions of Proteins in Crowded Environments from Small-Angle Scattering. AB - Small-angle scattering is a powerful technique to study molecular conformation and interactions of proteins in solution and in amorphous solids. We have investigated the role of multiple protein configurations in the interaction parameters derived from small-angle scattering for proteins in concentrated solutions. In order to account for the wide configurational space sampled by proteins, we generate ensembles of atomistic structures for lysozyme and monoclonal antibodies, representing globular and flexible proteins, respectively. While recent work has argued that a colloidal approach is inadequate to model proteins, because of the large configurational space that they sample in solution, we find a range of length scales where colloidal models can be used to describe solution scattering data while simultaneously accounting for structural flexibility. We provide insights to determine the length scales where isotropic colloidal models can be used, and find smoothly varying sets of interaction parameters that encompass ensembles of structures. This approach may play an important role in the definition of long-range interactions in coarse-grained models of flexible proteins with experimental scattering constraints. Additionally, we apply the decoupling approximation to ensembles of lysozyme structures with atomistic detail and observe remarkably different results when using geometric solids, such as ellipsoids. The insights from this study provide guidelines for the analysis of small-angle scattering profiles of proteins in crowded environments. PMID- 27973815 TI - Interplay of Noncovalent Interactions in Ionic Liquid/Sodium Bis(2-ethylhexyl) Sulfosuccinate Mixtures: From Lamellar to Bicontinuous Cubic Liquid Crystalline Phase. AB - Phase transitions in mixtures of imidazolium based ionic liquid ([C12mim]Br) and anionic double tail surfactant, sodium bis(2-ethylhexyl) sulfosuccinate (AOT), were studied using a multitechnique approach. The system was primarily chosen for its expected ability to form a variety of lamellar and nonlamellar liquid crystalline phases which can transform into each other via different mechanisms. Depending on the bulk composition and total surfactant concentration, mixed micelles, coacervates, and lamellar and inverse bicontinuous cubic liquid crystalline phase were observed. Along with electrostatic attractions and geometric packing constraints, additional noncovalent interactions (hydrogen bonding, pi-pi stacking) enhanced attractive interactions and stabilized low curvature aggregates. At stoichiometric conditions, coexistence of coacervates and vesicles was found at lower, while bicontinuous cubic phase and vesicles were present at higher total surfactant concentrations. The phase transitions from a dispersed lamellar to inverse cubic bicontinuous phase occur as a consequence of charge shielding and closer packing of oppositely charged headgroups followed by a change in bilayer curvature. Transition is continuous with both phases coexisting over a relatively broad range of concentrations and very likely involves a sponge-like phase as a structural intermediate. To the best of our knowledge, this type of phase transition has not been observed before in surface active ionic liquid/surfactant mixtures. PMID- 27973816 TI - Structure of Aqueous Trehalose Solution by Neutron Diffraction and Structural Modeling. AB - The molecular structure of an aqueous solution of the disaccharide trehalose (C12H22O11) has been studied by neutron diffraction and empirical potential structure refinement modeling. Six different isotope compositions with 33 wt % trehalose (corresponding to 38 water molecules per trehalose molecule) were measured to ensure that water-water, trehalose-water, and trehalose-trehalose correlations were accurately determined. In fact, this is the first neutron diffraction study of an aqueous trehalose solution in which also the nonexchangeable hydrogen atoms in trehalose are deuterated. With this approach, it was possible to determine that (1) there is a substantial hydrogen bonding between trehalose and water (~11 hydrogen bonds per trehalose molecule), which is in contrast to previous neutron diffraction studies, and (2) there is no tendency of clustering of trehalose, in contrast to what is generally observed by molecular dynamics simulations and experimentally found for other disaccharides. Thus, the results give the structural picture that trehalose prefers to interact with water and participate in a hydrogen-bonded network. This strong network character of the solution might be one of the key reasons for its extraordinary stabilization effect on biological materials. PMID- 27973817 TI - Ion-Specific Effects in Carboxylate Binding Sites. AB - Specific ion binding by carboxylates (-COO-) is a broadly important topic because -COO- is one of the most common functional groups coordinated to metal ions in metalloproteins and synthetic polymers. We apply quantum chemical methods and the quasi-chemical free-energy theory to investigate how variations in the number of COO- ligands in a binding site determine ion-binding preferences. We study a series of monovalent (Li+, Na+, K+, Cs+) and divalent (Zn2+, Ca2+) ions relevant to experimental work on ion channels and ionomers. Of two competing hypotheses, our results support the ligand field strength hypothesis and follow the reverse Hofmeister series for ion solvation and ion transfer from aqueous solution to binding sites with the preferred number of ligands. New insight arises from the finding that ion-binding sequences can be manipulated and even reversed just by constraining the number of carboxylate ligands in the binding sites. Our results help clarify the discrepancy in ion association between molecular ligands in aqueous solutions and ionomers, and their chemical analogues in ion-channel binding sites. PMID- 27973818 TI - Location of Varying Hydrophobicity Zinc(II) Phthalocyanine-Type Photosensitizers in Methoxy Poly(ethylene oxide) and Poly(l-lactide) Block Copolymer Micelles Using 1H NMR and XPS Techniques. AB - Hydrophobic zinc(II) phthalocyanine-type derivatives, solubilized in polymeric micelles (PMs), provide a befitting group of so-called nanophotosensitizers, suitable for a variety of photodynamic therapy (PDT) protocols. The factors that influence the success of such products in PDT are the location of the active cargo in the PMs and the nanocarrier-enhanced ability to safely interact with biological systems and fulfill their therapeutic functions. Therefore, the aim of this work was to determine the solubilization loci of three phthalocyanines of varying hydrophobicity, i.e., zinc(II) phthalocyanine (ZnPc), along with its tetrasulfonic acid (ZnPc-sulfo4) and perfluorinated (ZnPcF16) derivatives, loaded in polymeric micelles of methoxy poly(ethylene oxide)-b-poly(l-lactide) (mPEG-b PLLA), by means of 1H nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) combined with ion sputtering. Furthermore, the microenvironment influence upon the chemical and physical status of the solubilized cargo in PMs, expressed by photobleaching and reactive oxygen species (ROS) generation comparing to the same properties of native cargoes in solution, was also evaluated and discussed in regards to the probing location data. The studied phthalocyanine-loaded PMs exhibited good physical stability, high drug loading efficiency, and a size of less than ca. 150 nm with low polydispersity indices. The formation of polymeric micelles and the solubilization locus were investigated by 1H NMR and XPS. ZnPc localized within the PM core, whereas both ZnPcF16 and ZnPc-sulfo4 - in the corona of PMs. We proved that the cargo locus is crucial for the photochemical properties of the studied phthalocyanines; the increase in photostability and ability to generate ROS in micellar solution compared to free photosensitizer was most significant for the photosensitizer in the PM core. Our results indicate the role of the cargo location in the PM microenvironment and demonstrate that such attempts are fundamental for improving the properties of photosensitizers and their assumed efficiency as nanophotosensitizers in PDT. PMID- 27973821 TI - Selective Crystallization of Phosphoester Coordination Polymer for the Separation of Neodymium and Dysprosium: A Thermodynamic Approach. AB - Thermodynamics of the formation of coordination polymers (CPs) or metal-organic frameworks (MOFs) has not been focused on, whereas many CPs or MOFs have been synthesized in a solution. With a view of separating Nd3+ and Dy3+ in an aqueous solution, we demonstrate that crystallization of the CPs of Nd3+ and Dy3+ based on dibutyl phosphoric acid (Hdbp) can be thermodynamically described; crystallization yields of [Ln(dbp)3] (Ln = Nd or Dy) complex are predicted well using a simple calculation, which takes the apparent solubility products (Kspa) for [Ln(dbp)3] and the acid dissociation constant of Hdbp into account. The Kspa values of [Nd(dbp)3] and [Dy(dbp)3] are experimentally determined to be (1.3 +/- 0.1) * 10-14 and (2.9 +/- 0.4) * 10-18 M4, respectively, at 20 degrees C. The ratio of these Kspa values, that is, ca. 4500, is significantly larger than the ratio of the solubility products for inorganic salts of Nd3+ and Dy3+. Therefore, Nd3+ and Dy3+ are selectively crystallized in an aqueous solution via the formation of CPs. Under optimized conditions, Dy3+ crystallization is preferable, whereas Nd3+ remains in the solution phase, where the ratio of the Dy molar content to the total metal content (i.e., Nd + Dy) in the crystal is higher than 0.9. The use of acids, such as HCl or HNO3, has no practical impact on the separation in an aqueous solution. PMID- 27973819 TI - Entire-Dataset Analysis of NMR Fast-Exchange Titration Spectra: A Mg2+ Titration Analysis for HIV-1 Ribonuclease H Domain. AB - This article communicates our study to elucidate the molecular determinants of weak Mg2+ interaction with the ribonuclease H (RNH) domain of HIV-1 reverse transcriptase in solution. As the interaction is weak (a ligand-dissociation constant >1 mM), nonspecific Mg2+ interaction with the protein or interaction of the protein with other solutes that are present in the buffer solution can confound the observed Mg2+-titration data. To investigate these indirect effects, we monitored changes in the chemical shifts of backbone amides of RNH by recording NMR 1H-15N heteronuclear single-quantum coherence spectra upon titration of Mg2+ into an RNH solution. We performed the titration under three different conditions: (1) in the absence of NaCl, (2) in the presence of 50 mM NaCl, and (3) at a constant 160 mM Cl- concentration. Careful analysis of these three sets of titration data, along with molecular dynamics simulation data of RNH with Na+ and Cl- ions, demonstrates two characteristic phenomena distinct from the specific Mg2+ interaction with the active site: (1) weak interaction of Mg2+, as a salt, with the substrate-handle region of the protein and (2) overall apparent lower Mg2+ affinity in the absence of NaCl compared to that in the presence of 50 mM NaCl. A possible explanation may be that the titrated MgCl2 is consumed as a salt and interacts with RNH in the absence of NaCl. In addition, our data suggest that Na+ increases the kinetic rate of the specific Mg2+ interaction at the active site of RNH. Taken together, our study provides biophysical insight into the mechanism of weak metal interaction on a protein. PMID- 27973822 TI - Temperature Dependence of Static and Dynamic Heterogeneities in a Water-Ethanol Binary Mixture and a Study of Enhanced, Short-Lived Fluctuations at Low Concentrations. AB - Many aqueous binary mixtures, such as water-ethanol, are known to exhibit multiple structural transformations that are apparently driven by intermolecular hydrophobic interaction as well as hydrogen bonding. These interactions often cooperate to form special types of self-assembled structures. We study the effect of temperature on the formation of transient ethanol clusters as well as on the transient dynamic heterogeneity induced in the system due to such clustering. A major finding of the work is the existence of a strong temperature dependence of the extent of structural heterogeneity. Distinct signatures of dynamic heterogeneity of ethanol molecules are also found to appear with lowering of temperature. This is attributed to the formation of transient ethanol clusters that are known to have a small lifetime (of the order of a few picoseconds only). The transient dynamical features of dynamic heterogeneity are expected to affect those relaxation processes occurring at subpicosecond time scales. The present analyses reveal a number of interesting features, which were not explored earlier in this widely studied binary mixture. PMID- 27973820 TI - Spectroscopic and Thermodynamic Characterization of the Metal-Binding Sites in the LH1-RC Complex from Thermophilic Photosynthetic Bacterium Thermochromatium tepidum. AB - The light-harvesting 1 reaction center (LH1-RC) complex from thermophilic photosynthetic bacterium Thermochromatium (Tch.) tepidum exhibits enhanced thermostability and an unusual LH1 Qy transition, both induced by Ca2+ binding. In this study, metal-binding sites and metal-protein interactions in the LH1-RC complexes from wild-type (B915) and biosynthetically Sr2+-substituted (B888) Tch. tepidum were investigated by isothermal titration calorimetry (ITC), atomic absorption (AA), and attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopies. The ITC measurements revealed stoichiometric ratios of approximately 1:1 for binding of Ca2+, Sr2+, or Ba2+ to the LH1 alphabeta subunit, indicating the presence of 16 binding sites in both B915 and B888. The AA analysis provided direct evidence for Ca2+ and Sr2+ binding to B915 and B888, respectively, in their purified states. Metal-binding experiments supported that Ca2+ and Sr2+ (or Ba2+) competitively associate with the binding sites in both species. The ATR-FTIR difference spectra upon Ca2+ depletion and Sr2+ substitution demonstrated that dissociation and binding of Ca2+ are predominantly responsible for metal-dependent conformational changes of B915 and B888. The present results are largely compatible with the recent structural evidence that another binding site for Sr2+ (or Ba2+) exists in the vicinity of the Ca2+ binding site, a part of which is shared in both metal-binding sites. PMID- 27973823 TI - Reversible Excited-State Proton Geminate Recombination: Revisited. AB - About three decades ago, Pines and Huppert found that the excited-state proton transfer to water from a photoacid (8-hydroxy-1,3,6-pyrene trisulfonate (HPTS)) is followed by an efficient diffusion-assisted reversible geminate-recombination of the proton. To model the reaction, Pines, Huppert, and Agmon used the Debye Smoluchowski equation with boundary conditions appropriate for reversible contact reaction kinetics. This reaction model has been used successfully to quantitatively fit the experimental data of the time-resolved fluorescence of HPTS and several commonly used photoacids. A consequence of the reversibility of this reaction is an apparent long-time tail of the photoacid fluorescence signal, obeying (after lifetime correction) a t-3/2 power law asymptotics. Recently, Lawler and Fayer reported that in bulk water the observed power-law decay of the long-time fluorescence tail of HPTS is -1.1 rather than -1.5, as expected from the spherically symmetric diffusion model. In the current study, we reaffirm our previous reports of the power-law behavior of HPTS fluorescence. We also demonstrate that molecular-level complications such as the deviation from spherical symmetry, rotational dynamics, competitive proton binding to the sulfonate moieties of HPTS, distance-dependent diffusion coefficient, and the initial starting point of the proton can affect the observed kinetics only at intermediate times, but not at asymptotically long times. Theoretically, we analyze the rebinding kinetics in terms of the number of extrema of the logarithmic derivative, showing subtle effects on the direction of approach to the asymptotic line (whether from above or below), which also appears to be corroborated experimentally. PMID- 27973824 TI - Unusual Chiroptical Properties of the Cryptophane-222 Skeleton. AB - Enantiopure cryptophane-222 derivative (1) devoid of substituents was obtained via high-performance liquid chromatography (HPLC) using chiral stationary phases. The chiroptical properties of 1 were determined from polarimetry, electronic circular dichroism (ECD), synchrotron radiation circular dichroism (SRCD), vibrational circular dichroism (VCD), and Raman optical activity (ROA) experiments and were compared to those of the cryptophane-A (2) derivative. Unusual polarimetric results were obtained for 1 in CHCl3 solvent as the sign of the optical rotation (OR) values changes in the nonresonance region above 365 nm, whereas no change was observed in the CH2Cl2 solvent. ECD spectra in the 1La and 1Lb regions were very similar for the two solutions and could not explain these unusual polarimetric properties. In contrast, SRCD spectra in the 1Bb region revealed spectral differences for the two solutions, which have been associated with conformational changes of the three linkers by time-dependent density functional theory (TDDFT) calculations. DFT calculations of the OR support that conformational changes may explain the polarimetric results obtained for the two solvents. Finally, TDDFT calculations of the ECD as well as DFT calculations of the VCD and ROA allowed the attribution of the (-)589-PP absolute configuration for 1 in solution, as determined from the X-ray structures of 1. PMID- 27973825 TI - Effect of the Charge Regulation Behavior of Polyelectrolytes on Their Nonequilibrium Complexation with Oppositely Charged Surfactants. AB - The nonequilibrium features of oppositely charged macromolecule/surfactant mixtures have been the subject of intensive research recently. Although the nature and extent of polyion charge crucially affect the development of trapped states in these systems, their role in the nonequilibrium association is still poorly understood. In the present study, the impact of mixing on the complexation of hexadecyltrimethylammonium bromide (CTAB) with sodium poly[(vinyl alcohol)-co (vinyl sulfate)] (PVAS) and poly(acrylic acid) (PAA) samples of similar charge densities has been compared using a variety of experimental methods. The results indicate largely different nonequilibrium behavior depending on the polyions. In the case of the weak polyacid PAA, the binding of CTAB increases its ionization degree, which leads to enhanced equilibrium two-phase concentration range, where kinetically arrested states can be observed upon rapid mixing of the solution components. In contrast, the charge density of the double-hydrophilic PVAS copolymer is fixed, and in addition to the binding of CTAB onto its vinyl sulfate groups, the surfactant molecules also bind onto the vinyl alcohol segments of the copolymer. These factors result in reduced precipitation concentration range and diminishing nonequilibrium effects with decreasing polyion charge density. Our study clearly demonstrates that the charge regulation behavior of various polyelectrolytes can be successfully used to tune the nonequilibrium characteristics of macromolecule/surfactant association. PMID- 27973826 TI - QM/MM-Based Calculations of Absorption and Emission Spectra of LSSmOrange Variants. AB - The goal of this computational work is to gain new insight into the photochemistry of the fluorescent protein (FP) LSSmOrange. This FP is of interest because besides exhibiting the eponymous large spectral shift (LSS) between the absorption and emission energies, it has been experimentally observed that it can also undergo a photoconversion process, which leads to a change in the absorption wavelength of the chromophore (from 437 to 553 nm). There is strong experimental evidence that this photoconversion is caused by decarboxylation of a glutamate located in the close vicinity of the chromophore. Still, the exact chemical mechanism of the decarboxylation process as well as the precise understanding of structure-property relations in the measured absorption and emission spectra is not yet fully understood. Therefore, hybrid quantum mechanics/molecular mechanics (QM/MM) calculations are performed to model the absorption and emission spectra of the original and photoconverted forms of LSSmOrange. The necessary force-field parameters of the chromophore are optimized with CGenFF and the FFToolkit. A thorough analysis of QM methods to study the excitation energies of this specific FP chromophore has been carried out. Furthermore, the influence of the size of the QM region has been investigated. We found that QM/MM calculations performed with time-dependent density functional theory (CAM-B3LYP/D3/6-31G*) and QM calculations performed with the semiempirical ZIndo/S method including a polarizable continuum model can describe the excitation energies reasonably well. Moreover, already a small QM region size seems to be sufficient for the study of the photochemistry in LSSmOrange. Especially, the calculated ZIndo spectra are in very good agreement with the experimental ones. On the basis of the spectra obtained, we could verify the experimentally assigned structures. PMID- 27973827 TI - Impact of Salt Co- and Counterions on Rheological Properties and Structure of Wormlike Micellar Solutions. AB - Rheological properties of aqueous solutions of long-tailed cationic surfactant erucyl bis-(hydroxyethyl)methylammonium chloride (EHAC) were examined as a function of concentration Cs of different inorganic salts (KCl, CaCl2, and LaCl3) at a fixed surfactant concentration of 0.6 wt %. The structural evolution of micelles was followed by small-angle neutron scattering and cryogenic transmission electron microscopy. It was observed that, upon addition of salt, the zero-shear viscosity eta0 of semidilute surfactant solutions goes through a maximum by passing the following three regimes: eta0 ~ Cs10 (regime I), eta0 ~ Cs3.5 (regime II), and eta0 ~ Cs-2 (regime III). In regime I, the micelles grow in length; in regime II, the linear growth of micelles proceeds simultaneously with their branching; and in regime III, the branching becomes dominating. With increase in the salt valence, the viscosity curves shift to a lower salt content, indicating that these salts are more effective in inducing micellar elongation and branching, as they contain a larger amount of anionic species Cl- screening the repulsion between cationic surfactant heads. Diverse roles of salt co- and counterions (i.e., salt ions that are similar and oppositely charged with respect to surfactant head groups) at different salt concentrations were demonstrated. It was shown that at low salt concentrations corresponding to the rising branch of the viscosity curve (regimes I and II), salt counterions (Cl-) fully determine the rheological behavior of the system. At high salt concentrations, when the electrostatic repulsions between micelles and salt co-ions are essentially screened, the co-ions start affecting the rheological properties. Under these conditions, monovalent co-ions (K+) provide much lower viscosity of surfactant solutions than the multivalent ones (Ca2+, La3+), which is consistent with theoretical predictions that suggest the penetration of K+ inside the micellar corona increasing the charge of the micelles and therefore hindering their growth. PMID- 27973828 TI - Time-Resolved Photoelectron Spectroscopy of the Hydrated Electron: Comparing Cavity and Noncavity Models to Experiment. AB - We use nonadiabatic mixed quantum/classical molecular dynamics to simulate recent time-resolved photoelectron spectroscopy (TRPES) experiments on the hydrated electron, and compare the results for both a cavity and a noncavity simulation model to experiment. We find that cavity-model hydrated electrons show an "adiabatic" relaxation mechanism, with ground-state cooling that is fast on the time scale of the internal conversion, a feature that is in contrast to the TRPES experiments. A noncavity hydrated electron model, however, displays a "nonadiabatic" relaxation mechanism, with rapid internal conversion followed by slower ground-state cooling, in good qualitative agreement with experiment. We also show that the experimentally observed early time red shift and loss of anisotropy of the excited-state TRPES peak are consistent with hydrated electron models with homogeneously broadened absorption spectra, but not with those with inhomogeneously broadened absorption spectra. Finally, we find that a decreasing photoionization cross section upon cooling causes the excited-state TRPES peak to decay faster than the underlying radiationless relaxation process, so that the experimentally observed 60-75 fs peak decay corresponds to an actual excited state lifetime of the hydrated electron that is more likely ~100 fs. PMID- 27973829 TI - Understanding the Effect of Solvent Structure on Organic Reaction Outcomes When Using Ionic Liquid/Acetonitrile Mixtures. AB - The rate constant for the reaction between hexan-1-amine and 4 methoxybenzaldehyde was determined in ionic liquids containing an imidazolium cation. The effect on the rate constant of increasing the length of the alkyl substituent on the cation was examined in a number of ionic liquid/acetonitrile mixtures. In general it was found that there was no significant effect of changing the alkyl substituent on the rate constant of this process, suggesting that any nanodomains in these mixtures do not have a significant effect on the outcome of this process. A series of small-angle X-ray scattering and wide-angle X-ray scattering experiments were performed on mixtures of the ionic liquid 1 butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([Bmim][N(CF3SO2)2]) and acetonitrile; this work indicated that the main structural changes in the mixtures occur by about a 0.2 mole fraction of ionic liquid in the mixture (chiIL). This region at which the main changes in the solvent structuring occurs corresponds to the region at which the main changes in the rate constant and activation parameters occur for SN2 and condensation reactions examined previously; this is the first time that such a correlation has been observed. To examine the ordering of the solvent about the nucleophile hexan-1-amine, WAXS experiments were performed on a number of [Bmim][N(CF3SO2)2]/acetonitrile/hexan-1 amine mixtures, where it was found that some of the patterns featured asymmetric peaks as well as additional peaks not observed in the [Bmim][N(CF3SO2)2]/acetonitrile mixtures; this suggests that the addition of hexan-1-amine to the mixture affects the bulk structure of the liquid. The SAXS/WAXS patterns of mixtures of 1-butyl-2,3-dimethylimidazolium bis(trifluoromethanesulfonyl)imide ([Bm2im][N(CF3SO2)2]) and acetonitrile were also determined, with the results suggesting that [Bm2im][N(CF3SO2)2] is more ordered than [Bmim][N(CF3SO2)2] due to an enhancement in the short-range interactions. PMID- 27973830 TI - Probing Molecular Interactions between Ammonium-Based Ionic Liquids and N,N Dimethylacetamide: A Combined FTIR, DLS, and DFT Study. AB - The present study investigates the effects of the alkyl chain length of the cationic head-group of some ammonium-based ionic liquids (ILs) (having the same anion) on the interaction between the ILs and N,N-dimethylacetamide (DMA). The molecular interactions between the studied ILs, tetraethylammonium hydroxide (TEAH), tetrapropylammonium hydroxide (TPAH), tetrabutylammonium hydroxide (TBAH), and their binary mixtures with DMA were studied using the Fourier transform infrared spectroscopy (FTIR) technique, dynamic light scattering (DLS) experiments, and quantum chemical calculations. It was observed from both experimental FTIR analysis and theoretical studies that the strength of intermolecular interactions, such as hydrogen bonding, ion-ion interactions, and induced dipole interactions, between the ILs and DMA depends on the alkyl chain length of the IL cation head-group. The interaction of DMA with IL is energetically favorable and occurs via direct interactions between the IL anion and the carbonyl oxygen of DMA. The results further revealed that the shorter the alkyl chain length of the cationic head-group of the ILs, the stronger the interaction with the DMA molecule, such that the strength of interactions between the ILs and DMA follows the order TEAH > TPAH > TBAH. This trend can be attributed to the increased self-organized aggregation with increasing alkyl chain length of the IL cation. PMID- 27973831 TI - Partial and Complete Wetting in Ultralow Interfacial Tension Multiphase Blends with Polylactide. AB - The control of phase structuring in multiphase blends of polylactide (PLA) with other polymers is a viable approach to promote its broader implementation. In this article, ternary and quaternary blends of PLA with poly(butylene succinate) (PBS), poly(butylene adipate-co-terephthalate) (PBAT), and poly(3-hydroxybutyrate co-hydroxyvalerate) (PHBV) are prepared by melt blending. The interfacial tensions between components are measured using three different techniques, and a Fourier transform infrared imaging technique is developed for the purpose of unambiguous phase identification. A tricontinuous complete wetting behavior is observed for the ternary 33PLA/33PBS/33PBAT blend before and after quiescent annealing, which correlates closely with spreading theory analysis. In the quaternary PLA/PBS/PBAT/PHBV blend, a concentration-dependent wetting behavior is found. At 10 vol % PBAT, self-assembled partially wet droplets of PBAT are observed at the interface of PBS and PHBV, and they remain stable after quiescent annealing as predicted by spreading theory. In contrast, at 25 vol % PBAT, a quadruple continuous system is observed after mixing, which only transforms to partially wet PBAT droplets after subsequent annealing. These results clearly indicate the potential of composition control during the mixing of multiphase systems to result in a complete change of spreading behavior. PMID- 27973832 TI - Celebrating Our 120th Anniversary. PMID- 27973833 TI - CMIRS Solvation Model for Methanol: Parametrization, Testing, and Comparison with SMD, SM8, and COSMO-RS. AB - The new continuum solvation model, composite method for implicit representation of solvent (CMIRS), proposed by Pomogaeva and Chipman and implemented in GAMESS was parametrized for methanol solvent, with the aim of using it for ionic reactions in solution. The model was tested for predicting single-ion solvation free energy, pKa of acids and protonated bases, and the activation free-energy barriers of SN2 and SNAr reactions in methanol. A comparison was performed with other continuum models, such as SMD, SM8, and COSMO-RS. For a prediction of pKa and free-energy barriers, the order of performance was CMIRS > COSMO-RS > SMD > SM8. In particular, the CMIRS model is much superior to the other continuum models for predicting pKa of acids (without empirical corrections) and is able to evenly describe hard ions like methoxide and charge-dispersed ions like 2,4,6 trinitrophenol. On the basis of our results, we suggest that the field-extremum contribution, present in CMIRS, should be included in continuum solvation models, which can result in substantial improvement in the modeling of ionic reactions in solution. PMID- 27973835 TI - Anion Dependent Dynamics and Water Solubility Explained by Hydrogen Bonding Interactions in Mixtures of Water and Aprotic Heterocyclic Anion Ionic Liquids. AB - Molecular dynamics simulations were used to compare water solubilities and the effects of water on the structure and dynamics of ionic liquids (ILs) composed of phosphonium cations paired with azolide and phenolate anions. The addition of water decreases ordering of the ions compared to the dry ILs with the exception of anion-anion ordering in the phenolate IL. The result is that the dynamics of the azolide ionic liquids increase significantly upon addition of water, whereas the phenolate IL dynamics show little change. The relative water solubilities were compared through calculation of Henry's law constants. Water is much more soluble in the phenolate IL due to strong hydrogen bonding interactions between water and the phenolate oxygen atom. Anions can therefore be selected to control IL-water hydrogen bonding for optimal performance in applications such as CO2 separation. PMID- 27973834 TI - Experimental and Theoretical Investigations of Infrared Multiple Photon Dissociation Spectra of Asparagine Complexes with Zn2+ and Cd2+ and Their Deamidation Processes. AB - Complexes of asparagine (Asn) cationized with Zn2+ and Cd2+ were examined by infrared multiple photon dissociation (IRMPD) action spectroscopy using light generated from a free electron laser. Electrospray ionization yielded complexes of deprotonated Asn with Zn2+, [Zn(Asn-H)]+, and intact Asn with CdCl+, CdCl+(Asn). Series of low energy conformers for each complex were found using quantum chemical calculations in order to identify the structures formed experimentally. The experimentally obtained spectra were compared to those calculated from optimized structures at the B3LYP/6-311+G(d,p) level for [Zn(Asn H)]+ and the B3LYP/def2-TZVP level with an SDD effective core potential on cadmium for the CdCl+(Asn) system. The main binding motif observed for the CdCl+ complex is a charge solvated, tridentate [N, CO, COs] structure where the metal binds to the backbone amino group and carbonyl oxygens of the carboxylic acid and side-chain amide groups. The Zn2+ system deprotonates at the backbone carboxylic acid and prefers a [N, CO-, COs] binding motif, where binding was observed at the carboxylate site along with the backbone amino group and side-chain carbonyl groups. In both cases, the theoretically determined lowest-energy conformers explain the experimental [Zn(Asn-H)]+ and CdCl+(Asn) spectra well. Additionally, complete mechanistic pathways were found for each of the major dissociation reactions of [Zn(Asn-H)]+ (primary loss of CO2, followed by the sequential loss of NH3) and CdCl+(Asn) (concomitant loss of NH3 + CO). PMID- 27973836 TI - Hofmeister Anion Effects on Thermodynamics of Caffeine Partitioning between Aqueous and Cyclohexane Phases. AB - Specific anion effects on the thermodynamics of caffeine partitioning between aqueous and cyclohexane phases were studied in the presence of 11 sodium salts by utilizing UV-vis spectroscopy. It is observed that weakly hydrated anions such as ClO4-, SCN-, and I- salt caffeine into the aqueous phase and increase the standard Gibbs free energy for caffeine transfer. On the other hand, well hydrated anions such as CO32- and SO42- salt caffeine molecules out of the aqueous solution and promote the transfer process. Results suggest that weakly hydrated anions associate with the hydrophobic patches of caffeine including three methyl groups and a flat heteroatomic ring to solvate caffeine molecules. Well-hydrated anions are excluded from the caffeine surface to salt caffeine molecules out of aqueous solution. Moreover, the enthalpy and entropy of caffeine transfer were obtained by measuring the standard Gibbs free energy for caffeine transfer at varied temperatures. The transfer of caffeine from the aqueous to cyclohexane phase was an endothermic process driven by the entropy of caffeine transfer. However, the trend in standard Gibbs free energy across the Hofmeister series was determined by the enthalpy of caffeine transfer. These results provide an enthalpic origin to explain the Hofmeister trends in aqueous solution. PMID- 27973837 TI - Molecular Dynamics Simulation of Skin Lipids: Effect of Ceramide Chain Lengths on Bilayer Properties. AB - Stratum corneum (SC), the outer layer of skin, serves as a barrier for pathogens and maintains the trans-epidermal water loss. The lipid matrix of SC is the major diffusion-rate-limiting pathway as molecules will have to pass through it. Ceramides play a key role in structuring and maintaining the barrier function of the skin. In this study, atomistic molecular dynamics (MD) simulations were used to systematically investigate the effects of the chain length of ceramide (CER) tails on the properties of the bilayer at a skin temperature of 310 K. The barrier properties were examined by means of permeation studies of water through the model membrane using steered MD simulations. Our studies revealed that shorter chains of one leaflet of the bilayer do not interdigitate with the chains of the other leaflet and lead to more free space in the middle of the bilayer, thereby leading to higher permeability. In CERs with dissimilar chain lengths, the lipids on one chain interdigitate with the other leaflet lipids, increasing the electron density in the middle of the bilayer. The bilayer thickness increases with increase in the CER chain length. The permeability of smaller chain CERs was found to be an order of magnitude higher than that of the longer chain CERs. PMID- 27973838 TI - Molecular Dynamics of a Hydrated Collagen Peptide: Insights into Rotational Motion and Residence Times of Single-Water Bridges in Collagen. AB - Magnetic resonance transverse spin relaxation time constants (T2) of water protons in ordered collagenous tissues are dependent on the orientation of the tissue relative to the static magnetic field. This dependence is commonly referred to as the magic angle (MA) effect and has been attributed to the restricted rotational motion of icelike water bridges in the hydrated triple helix collagen molecule. Understanding of the molecular mechanism of the MA effect is important for clinical and research applications of magnetic resonance spectroscopy and imaging to tissues, such as articular cartilage, tendons, and ligaments. In this work, we have used molecular dynamics simulations to investigate the subnanosecond time scale dynamics of single-water bridges in a model collagen peptide. We ascertain the residence times and the patterns of restricted rotational motion of water molecules. The key findings are strongly anisotropic rotation patterns of water molecules at bridge sites and a dynamic, rather than icelike, nature of the single-water bridges within the individual triple-helix collagen molecule. PMID- 27973839 TI - On the Molecular Form of Amyloid Marker, Auramine O, in Human Insulin Fibrils. AB - Designing extrinsic fluorescence sensors for amyloid fibrils is a very active and important area of research. Recently, an ultrafast molecule rotor dye, Auramine O (AuO), has been projected as a fluorescent amyloid marker. It has been claimed that AuO scores better than the most extensively utilized gold-standard amyloid probe, Thioflavin-T (ThT). This advantage arises from the fact that AuO, in addition to its usual emission band (~500 nm), also displays a large red-shifted emission band (~560 nm), exclusively in the presence of human insulin fibril medium and not in the native protein or buffer media. On the contrary, for ThT, the emission maximum (~490 nm) largely remains unchanged while going from protein to fibril. This otherwise unknown large red-shifted emission band of AuO, observed in the presence of human insulin fibrils, was tentatively attributed to a species formed upon fast proton dissociation from excited AuO. It was proposed that because of the long excited-state lifetime (~1.8 ns) of AuO upon association with human insulin fibrils, this fast proton dissociation from excited AuO could be observed, which is otherwise not observed in buffer or native protein media, owing to its very short excited-state lifetime (~1 ps). Herein, we show that despite the long excited-state lifetime of AuO in other fibrillar media (human serum albumin and lysozyme), the new red-shifted emission band at 560 nm is not observed, thus possibly suggesting a different origin of the red-shifted emission band of AuO in human insulin fibril medium. We convincingly show that this red shifted band of AuO (~560 nm) could be observed under conditions that promote dye aggregation, such as a premicellar concentration of surfactants and polyelectrolytes. These AuO aggregates display strong emission wavelength dependence of transient decay traces, similar to that for AuO in human insulin fibril medium. Detailed time-resolved emission spectral (TRES) measurements suggest that the AuO/premicellar surfactant and AuO/human insulin fibril system share similar features, such as a dynamic red-shift in TRES and an isoemissive point in the time-resolved area-normalized emission spectra, suggesting that the characteristic red-shifted emission band of AuO in human insulin fibril medium may arise from AuO aggregates. PMID- 27973840 TI - Engineering a pH-Regulated Switch in the Major Light-Harvesting Complex of Plants (LHCII): Proof of Principle. AB - Under excess light, photosynthetic organisms employ feedback mechanisms to avoid photodamage. Photoprotection is triggered by acidification of the lumen of the photosynthetic membrane following saturation of the metabolic activity. A low pH triggers thermal dissipation of excess absorbed energy by the light-harvesting complexes (LHCs). LHCs are not able to sense pH variations, and their switch to a dissipative mode depends on stress-related proteins and allosteric cofactors. In green algae the trigger is the pigment-protein complex LHCSR3. Its C-terminus is responsible for a pH-driven conformational change from a light-harvesting to a quenched state. Here, we show that by replacing the C-terminus of the main LHC of plants with that of LHCSR3, it is possible to regulate its excited-state lifetime solely via protonation, demonstrating that the protein template of LHCs can be modified to activate reversible quenching mechanisms independent of external cofactors and triggers. PMID- 27973842 TI - Phototropic Guest-Host Liquid Crystal Systems: Environmental Effects on Naphthopyran Kinetics. AB - Photoinduced isothermal and order-increasing phase transitions can be observed in guest-host liquid crystal mixtures containing naphthopyran derivatives. The changes are attributed to the different geometry and a less energetically favorable interaction with the liquid crystal molecules for the ground state naphthopyran species with respect to the photoproduct. In this study, we have investigated the thermal relaxation of the naphthopyran photoproduct back to the initial species as a function of temperature and excitation conditions. It was found that the thermal relaxation is typically first-order and its characteristic rate has a temperature dependence that is different in the anisotropic and isotropic states of the mesogenic solvents. In particular, the activation energy for thermal relaxation is larger in the ordered phases of mesogenic solvents relative to their isotropic phase. The findings suggests that the naphthopyran relaxation is hindered by the organization of the host environment. These results will be useful to build a more complete understanding of the mutual guest-host interactions in naphthopyran-containing guest-host LC systems. PMID- 27973841 TI - Conformational Substrate Selection Contributes to the Enzymatic Catalytic Reaction Mechanism of Pin1. AB - Conformational changes in enzymes and their role in their catalytic activity have been thoroughly addressed experimentally and theoretically. There is a vivid discussion in the field of enzyme catalysis on whether conformational changes of the enzyme are coupled to catalysis, or whether transition state stabilization through the preorganized protein and its electrostatic properties govern the catalysis. In this study, an additional contribution to the catalysis of one specific enzyme, Pin1, is proposed, which arises from its conformational selection of the peptide substrate from aqueous solution with the lowest activation barrier. The most stable conformers of the reactant (cis) and product (trans) peptide were identified through molecular dynamics simulations in combination with metadynamics. The cis-trans isomerization reaction was studied with quantum mechanical/molecular mechanical molecular dynamics simulations and density functional theory together with the mean reaction force, which allows us to separate structural and electronic contributions to the activation barrier. Our results show that enzyme Pin1 binds the trans isomer in the conformation of the peptide with the smallest activation barrier and reduces the barrier further through specific substrate-enzyme interactions, as we have shown previously. The activation barrier of the cis peptide is independent of the conformer and remains unchanged in the enzyme. PMID- 27973843 TI - Reevaluation of Neptunium-Nitric Acid Radiation Chemistry by Multiscale Modeling. AB - Multiscale modeling has been used to quantitatively reevaluate the radiation chemistry of neptunium in a range of aerated nitric acid solutions (0.1-6.0 mol dm-3). Exact calculation of initial radiolytic yields accounting for changes in radiation track chemistry was found to be crucial for reproducing experimental data. The gamma irradiation induces changes in the Np(VI)/Np(V) oxidation-state distribution, predominantly driven by reactions involving HNO2, H2O2, NO2*, and NO3* from the radiolysis of aqueous nitric acid. Oxidation of Np(V) by NO3* (k = 8.1 * 108 dm3 mol-1 s-1) provides the initial increase in Np(VI) concentration, while also delaying net reduction of Np(VI) by consuming HNO2. Reduction of Np(VI) is dominated by thermal reactions with HNO2 (k = 0.7-73 dm3 mol-1 s-1) and H2O2 (k = 1.9 dm3 mol-1 s-1). A steady state is eventually established once the concentration of Np(V) is sufficiently high to be oxidized by NO2* (k = 2.4 * 102 3.1 * 104 dm3 mol-1 s-1). An additional thermal oxidation reaction between Np(V) and HNO3 (k = 2.0 * 103 dm3 mol-1 s-1) is required for nitric acid concentrations >4.0 mol dm-3. For 0.1 mol dm-3 HNO3, the rate of Np(VI) reduction is in excess of that which can be accounted for by radiolytic product mass balance, suggesting the existence of a catalytic-acid-dependent reduction process. PMID- 27973844 TI - Modeling Carbon Dioxide Vibrational Frequencies in Ionic Liquids: II. Spectroscopic Map. AB - The primary challenge for connecting molecular dynamics (MD) simulations to linear and two-dimensional infrared measurements is the calculation of the vibrational frequency for the chromophore of interest. Computing the vibrational frequency at each time step of the simulation with a quantum mechanical method like density functional theory (DFT) is generally prohibitively expensive. One approach to circumnavigate this problem is the use of spectroscopic maps. Spectroscopic maps are empirical relationships that correlate the frequency of interest to properties of the surrounding solvent that are readily accessible in the MD simulation. Here, we develop a spectroscopic map for the asymmetric stretch of CO2 in the 1-butyl-3-methylimidazolium hexafluorophosphate ([C4C1im][PF6]) ionic liquid (IL). DFT is used to compute the vibrational frequency of 500 statistically independent CO2-[C4C1im][PF6] clusters extracted from an MD simulation. When the map was tested on 500 different CO2-[C4C1im][PF6] clusters, the correlation coefficient between the benchmark frequencies and the predicted frequencies was R = 0.94, and the root-mean-square error was 2.7 cm-1. The calculated distribution of frequencies also agrees well with experiment. The spectroscopic map required information about the CO2 angle, the electrostatics of the surrounding solvent, and the Lennard-Jones interaction between the CO2 and the IL. The contribution of each term in the map was investigated using symmetry adapted perturbation theory calculations. PMID- 27973845 TI - Molecular Model for HNBR with Tunable Cross-Link Density. AB - We introduce a chemically inspired, all-atom model of hydrogenated nitrile butadiene rubber (HNBR) and assess its performance by computing the mass density and glass-transition temperature as a function of cross-link density in the structure. Our HNBR structures are created by a procedure that mimics the real process used to produce HNBR, that is, saturation of the carbon-carbon double bonds in NBR, either by hydrogenation or by cross-linking. The atomic interactions are described by the all-atom "Optimized Potentials for Liquid Simulations" (OPLS-AA). In this paper, first, we assess the use of OPLS-AA in our models, especially using NBR bulk properties, and second, we evaluate the validity of the proposed model for HNBR by investigating mass density and glass transition as a function of the tunable cross-link density. Experimental densities are reproduced within 3% for both elastomers, and qualitatively correct trends in the glass-transition temperature as a function of monomer composition and cross-link density are obtained. PMID- 27973846 TI - Effect of the Functional Groups of Racemic Rodlike Schiff Base Mesogens on the Stabilization of Blue Phase in Binary Mixture Systems. AB - Four series of rodlike racemic Schiff base mesogens possessing different alkyl chains and two types of linkages, ester and alkynyl linkages, were synthesized and applied to induce cubic blue phases (BPs) in simple binary mixture systems. The mesophases of these Schiff base mesogens were confirmed by variable temperature X-ray diffraction and the characteristic texture from polarized optical microscopy (POM). In general, when chiral additive S-(+)-2-octyl 4-(4 hexyloxybenzoyloxy)benzoate (S811; 20-40 wt %) is added into the rodlike racemic salicylaldimine-based mesogens, the cubic BPs could be observed and its temperature range is larger than 20 K. The widest temperature range of the cubic BP (35 K) can be observed in the blending mixture composed of rodlike racemic salicylaldimine-based mesogen OH-TIn possessing alkynyl linkage and 35-40 wt % S811. However, Schiff base mesogens possessing alkynyl linkage show a direct isotropic to chiral nematic transition when equal amount of chiral dopant is added. Notably, the termination temperature of BPs is very close to room temperature (ca. 35 degrees C) after 40.0 wt % S811 is added into the salicylaldimine-based mesogens possessing terminal alkyl chains and ester linkage. Interestingly, wide BPs (>30 K) can also be induced by adding chiral additive 1,4:3,6-dianhydro-2,5-bis[4-(n-hexyl-1-oxy)benzoic acid]sorbitol (ISO(6OBA)2) with a high helical twisting power into the racemic Schiff base mesogen possessing ester linkage. Cubic BPI and BPII can be confirmed by reflectance spectra and POM. The results of reflectance spectra indicate that the binary mixture composed of salicylaldimine-based mesogens and S811 easily exhibits a supercooling effect and induces BPI. However, only BPII can be observed in all binary mixtures containing Schiff base mesogens. On the basis of our experimental results and molecular modeling, we suppose that the values of biaxiality, polarizability, and the dipole moment of molecular geometry are the main factors that affect BP stabilization. PMID- 27973847 TI - Photoabsorption Tolerance of Intrinsic Point Defects and Oxidation in Black Phosphorus Quantum Dots. AB - Black phosphorus quantum dots (BPQDs) exhibit excellent optical and photothermal properties and promising applications in optoelectronics and biomedicine. However, various intrinsic structural defects and oxidation are nearly unavoidable in preparation of BPQDs and how they affect the electronic and optical properties remains unclear. Here, by employing time-dependent density functional theory, we reveal that there are two types of photoabsorption in BPQDs for both point defects and oxidation. A close structure-absorption relation is unraveled: BPQDs are defect-tolerant and show excellent photoabsorption as long as the coordination number (CN) of defective P atoms is 3. By contrast, the unsaturated or oversaturated P atoms with CN ? 3 create in-gap-states (IGSs) and completely quench the optical absorption. An effective way to eliminate the IGSs and repair the photoabsorption of defective BPQDs via sufficient hydrogen passivation is further proposed. PMID- 27973848 TI - Prediction of a Mobile Solid State in Dense Hydrogen under High Pressures. AB - Solid rigidity and liquid-scale mobility are thought to be incompatible in elemental substances. One cannot have an elemental solid that is long-range positionally ordered wherein the atoms flow like in a liquid simultaneously. The only exception might be the hypothetical supersolid state of 4He. In this work, we demonstrate that such exotic state could exist even in the classical regime. Using ab initio molecular dynamics (AIMD) and ab initio path integral molecular dynamics (AI-PIMD), a novel state of dense hydrogen that simultaneously has both long-range spatial ordering and liquid-scale atomic mobility is discovered at 1 to 1.5 TPa (1 TPa ~ 10 000 000 atmospheric pressures). The features distinct from a normal solid and liquid are carefully characterized, and the stability and melting behavior are investigated. Extensive AI-PIMD simulations further revealed that this state might be (meta-)stable even at ultralow temperatures, suggesting an emerging candidate for an alternative type of supersolid state in dense metallic hydrogen. PMID- 27973849 TI - Molecular Origin of Electric Double-Layer Capacitance at Multilayer Graphene Edges. AB - Multilayer graphenes have been widely used as active materials for electric double-layer capacitors (EDLCs), where their numerous edges are demonstrated to play a crucial role in charge storage. In this work, the interfacial structure and capacitive behaviors of multilayer graphene edges with representative interlayer spacing are studied via molecular dynamics (MD) simulations. Compared with planar graphite surfaces, edges can achieve a 2-fold increase in the specific capacitance at a wider interlayer spacing of ~5.0 A. Unusually, the molecular origins for achieved charge storage are predominantly attributed to the structural evolutions of solvents occurring in the double layer, going beyond the traditional views of regulating the capacitance by ion adsorption/separation. Specifically, diverse ionic distributions exhibit similar screening ability and EDLC thickness, while water molecules can counterbalance the interfacial electric fields more effectively at edge site. The as-obtained findings will be instructive in designing graphene-based EDLCs for advanced capacitive performances. PMID- 27973850 TI - Detection of Liquid Penetration of a Micropillar Surface Using the Quartz Crystal Microbalance. AB - A quantitative characterization of the wetting states of droplets on hydrophobic textured surfaces requires direct measurement of the liquid penetration into surface cavities, which is challenging. Here, the use of quartz crystal microbalance (QCM) technology is reported for the characterization of the liquid penetration depth on a micropillar-patterned surface. The actual liquid-air interface of the droplet was established by freezing the droplet and characterizing it using a cryogenically focused ion beam/scanning electron microscope (cryo FIB-SEM) technique. It was found that a direct correlation exists between the liquid penetration depth and the responses of the QCM. A very small frequency shift of the QCM (1.5%) was recorded when the droplet was in the Cassie state, whereas a significant frequency shift was observed when the wetting state changed to the Wenzel state (where full liquid penetration occurs). Furthermore, a transition from the Cassie to the Wenzel state can be captured by the QCM technique. An acoustic-structure-interaction based numerical model was developed to further understand the effect of penetration. The numerical model was validated by experimentally measured responses of micropillar-patterned QCMs. The results also show a nonlinear response of the QCM to the increasing liquid penetration depth. This research provides a solid foundation for utilizing QCM sensors for liquid penetration and surface wettability characterization. PMID- 27973851 TI - Tunable Aggregation-Induced Emission of Polyoxometalates via Amino Acid-Directed Self-Assembly and Their Application in Detecting Dopamine. AB - In this work, through the aqueous phase self-assembly of an Eu-containing polyoxometalate (POM), Na9[EuW10O36].32H2O (EuW10) and different amino acids, we obtained spontaneously formed vesicles that showed luminescence enhancement for EuW10 and arginine (Arg), lysine (Lys), or histidine (His) complexes, but luminescence quenching for EuW10 and glutamic acid (Glu) or aspartic acid (Asp) complexes. The binding mechanisms between them have been explored at the molecular level by using different characterization techniques. It was found that EuW10 acted as polar head groups interact with the positively charged residues for alkaline amino acids, protonated amide groups for acidic amino and nonpolar acid aminos through electrostatic interactions, and the remaining segments of amino acids served as relatively hydrophobic parts aggregated together forming bilayer membrane structures. Moreover, the different influences of amino acids on the fluorescence property of EuW10 revealed that the electrostatic interaction between the positive charged group of amino acid and the polyanionic cluster dominates the fluorescence properties of assemblies. Furthermore, a turn-off sensing application of the EuW10/Arg platform to probe dopamine (DA) against various other biological molecules such as neurotransmitters or amino acids was also established. The concept of combining POMs with amino acids extends the research category of POM-based functional materials and devices. PMID- 27973852 TI - Calcium Silicate Phases Explained by High-Temperature-Resistant Phosphate Probe Molecules. AB - In this work, high-temperature-resistant phosphate molecules are applied to characterize ultrathin (100 nm) calcium silicate (C-S) phases. These C-S phases are synthesized on silicon wafers, and the interaction of phosphates with the C-S phases is studied by means of in situ transmission Fourier transform infrared (FTIR) spectroscopy. At room temperature, the chemistry of the system is dominated by the formation of calcium phosphates (C-P). In the case of temperature rising to 1000 degrees C, the C-S phases are regenerated. FTIR results are analyzed on the basis of first-principles calculations and further supported by complementary time-of-flight secondary ion mass spectrometry (ToF SIMS) experiments. This study provides a detailed and self-consistent picture of the chemical and structural properties of interfaces such as the one between the atmosphere and ultrathin C-S phases (gas/C-S) and the one between them and silicon wafers (C-S/Si bulk). The material combination of ultrathin C-S phases grown on silicon wafers might in the future have great potential in selective chemistry, catalysis, and sensing technology as well as in semiconductor manufacturing. PMID- 27973854 TI - Effect of Particle Size on Drug Loading and Release Kinetics of Gefitinib-Loaded PLGA Microspheres. AB - Polymeric microspheres have gained widespread application as drug eluting depots. Typically, drug-loaded polymeric microspheres are prepared by oil-in-water emulsification which yields a product with a broad size distribution. The aim of the present study was to investigate the properties of different size-fractions of drug-loaded microspheres, in order to delineate whether particle size governs drug loading efficiency and release profile. Gefitinib-loaded PLGA-based microspheres were prepared using an oil-in-water solvent evaporation method and wet-sieved to obtain well-defined size fractions of 5 +/- 1, 32 +/- 4, 70 +/- 3, and 130 +/- 7 MUm, respectively. The average drug loading of unfractionated microspheres was 6.3 +/- 0.4% w/w, while drug loading of sieved fractions ranged from 2.4 +/- 0.3 to 7.6 +/- 0.9% w/w for smallest to largest microparticles. X ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis demonstrated that gefitinib was amorphously dispersed in the PLGA matrix, with no apparent shift in the Tg of PLGA indicating the absence of direct molecular interactions of the drug and polymer due to the formation of small drug particles embedded in PLGA. In vitro drug release was studied with microspheres embedded in dextran hydrogels to avoid their aggregation during the incubation conditions. Microspheres smaller than 50 MUm showed rapid diffusion-based release reaching completion within 2 days when particles have not degraded yet. Larger microspheres, however, showed a sigmoidal release pattern that continued for three months in which diffusion (early stage) as well as particle erosion (later stage) governed drug release. Scanning electron microscopy (SEM) and polymer degradation data showed that larger microspheres degraded faster than smaller ones, which is in line with autocatalytic PLGA degradation upon acidification within the core of microparticles. In conclusion, we showed that different size fractions of drug-loaded microspheres showed quite distinct drug loading and release kinetics. Control of microparticle size by fractionation is therefore an important determinant for obtaining well-defined and reproducible sustained release depots. PMID- 27973853 TI - Cytotoxic and Proinflammatory Effects of Metal-Based Nanoparticles on THP-1 Monocytes Characterized by Combined Proteomics Approaches. AB - Thorough characterization of toxic effects of nanoparticles (NP) is desirable due to the increasing risk of potential environmental contamination by NP. In the current study, we combined three recently developed proteomics approaches to assess the effects of Au, CuO, and CdTe NP on the innate immune system. The human monocyte cell line THP-1 was employed as a model. The anticancer drugs camptothecin and doxorubicin were used as positive controls for cell death, and lipopolysaccharide was chosen as a positive control for proinflammatory activation. Despite equivalent overall toxicity effect (50 +/- 10% dead cells), the three NP induced distinctly different proteomics signatures, with the strongest effect being induced by CdTe NP, followed by CuO and gold NP. The CdTe toxicity mechanism involves down-regulation of topoisomerases. The effect of CuO NP is most reminiscent of oxidative stress and involves up-regulation of proteins involved in heat response. The gold NP induced up-regulation of the inflammatory mediator, NF-kappaB, and its inhibitor TIPE2 was identified as a direct target of gold NP. Furthermore, gold NP triggered activation of NF-kappaB as evidenced by phosphorylation of the p65 subunit. Overall, the combined proteomics approach described here can be used to characterize the effects of NP on immune cells. PMID- 27973855 TI - Alkyldisulfanium Salts: Isolable, Electrophilic Sulfur Reagents Competent for Polyene Cyclizations. AB - Tools that can effect electrophilic sulfur-promoted cation-pi cyclizations are generally lacking, especially using alkylsulfide-based reagents. Herein we report that combining three different 1,2-dithioethers with Cl2 and SbCl5 generates isolable alkyldisulfanium salts that can effect such reactions. These new reagents can install -SMe, -SEt, and -SCH2CH2CF3 in modest, moderate, or good yield on diverse frameworks, including polyenes that terminate with electron deficient groups. We also show that reagents such as dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) can accomplish similar chemistry. PMID- 27973856 TI - Nucleation of Graphene Layers on Magnetic Oxides: Co3O4(111) and Cr2O3(0001) from Theory and Experiment. AB - We report directly grown strongly adherent graphene on Co3O4(111) by carbon molecular beam epitaxy (C MBE) at 850 K and density functional theory (DFT) findings that the first graphene layer is reconstructed to fit the Co3O4 surface, while subsequent layers retain normal graphene structure. This adherence to the Co3O4 structure results from partial bonding of half the carbons to top oxygens of the substrate. This structure is validated by X-ray photoelectron spectroscopy and low-energy electron diffraction studies, showing layer-by-layer graphene growth with ~0.08 electrons/carbon atom transferred to the oxide from the first graphene layer, in agreement with DFT. In contrast, for Cr2O3 DFT finds no strong bonding to the surface and C MBE on Cr2O3(0001) yields only graphite formation at 700 K, with C desorption above 800 K. Thus strong graphene-to-oxide charge transfer aids nucleation of graphene on incommensurate oxide substrates and may have implications for spintronics. PMID- 27973857 TI - Cyclizing Pentapeptides: Mechanism and Application of Dehydrophenylalanine as a Traceless Turn-Inducer. AB - Dehydrophenylalanine is used as a traceless turn-inducer in the total synthesis of dichotomin E. Macrocyclization of the monomer is achieved in high yields and selectivity over cyclodimerization under conditions 100 times more concentrated than previously achieved. The enamide facilitates ring closing, and Rh-catalyzed hydrogenation of the unsaturated cyclic peptide results in selective formation of the natural product or its epimer, depending on our choice of phosphine ligand. NMR analysis and molecular modeling revealed that the linear peptide adopts a left-handed alpha-turn that preorganizes the N- and C-termini toward macrocyclization. PMID- 27973859 TI - Nanoscale Charge-Balancing Mechanism in Alkali-Substituted Calcium-Silicate Hydrate Gels. AB - Alkali-activated materials and related alternative cementitious systems are sustainable technologies that have the potential to substantially lower the CO2 emissions associated with the construction industry. However, these systems have augmented chemical compositions as compared to ordinary Portland cement (OPC), which may impact the evolution of the hydrate phases. In particular, calcium silicate-hydrate (C-S-H) gel, the main hydrate phase in OPC, is likely to be altered at the atomic scale due to changes in the bulk chemical composition, specifically via the addition of alkalis (i.e., Na or K) and aluminum. Here, via density functional theory calculations, we reveal the presence of a charge balancing mechanism at the molecular level in C-S-H gel (as modeled using crystalline 14 A tobermorite) when alkalis and aluminum atoms are introduced into the structure. Different structural representations are obtained depending on the level of substitution and the degree of charge balancing incorporated in the structures. The impact of these substitutional and charge balancing effects on the structures is assessed by analyzing the formation energies, local bonding environments, diffusion barriers and mechanical properties. The results of this computational study provide information on the phase stability of alkali/aluminum containing C-S-H gels, shedding light on the fundamental atomic level mechanisms that play a crucial role in these complex disordered materials. PMID- 27973858 TI - Surface Recombination and Collection Efficiency in Perovskite Solar Cells from Impedance Analysis. AB - The large diffusion lengths recurrently measured in perovskite single crystals and films signal small bulk nonradiative recombination flux and locate the dominant carrier recombination processes at the outer interfaces. Surface recombination largely determines the photovoltaic performance, governing reductions under short-circuit current and open-circuit voltage. Quantification of recombination losses is necessary to reach full understanding of the solar cell operating principles. Complete impedance model is given, which connects capacitive and resistive processes to the electronic kinetics at the interfaces. Carrier collection losses affecting the photocurrent have been determined to equal 1%. Photovoltage loss is linked to the decrease in surface hole density, producing 0.3 V reduction with respect to the ideal radiative limit. Our approach enables a comparison among different structures, morphologies, and processing strategies of passivation and buffer layers. PMID- 27973860 TI - Establishing and Understanding Adsorption-Energy Scaling Relations with Negative Slopes. AB - Adsorption-energy scaling relations are widely used for the design of catalytic materials. To date, only linear scaling relations are known in which the slopes are positive. Considering the adsorption energies of F, O, N, C, and B on transition metals, we show here that scaling relations with negative slopes also exist between certain adsorbates. The origin of such unconventional scaling relations is analyzed in terms of common descriptors such as d-band center, work function, number of outer electrons, electronic charge on the adsorbates, integrated crystal orbital overlap populations, and crystal orbital Hamilton populations. Conventional scaling relations are formed between adsorbates such as F, O, N, and C, which create ionic-like bonds with surfaces. Conversely, anomalous scaling relations are established between those and covalently bound adsorbates such as B. This widens the theory of adsorption-energy scaling relations and opens new avenues in physical chemistry and catalysis, for instance, in direct borohydride fuel cells. PMID- 27973861 TI - Kinetic Pathways and Mechanisms of Two-Step Nucleation in Crystallization. AB - Crystallizations often pass through multiple intermediate structures before reaching the final state, such as amorphous precursors, polymorphs, or denser liquid droplets. However, the atomistic pathways from these metastable phases to final crystals still remain unclear. Here, we investigated the structure evolution process from liquid to final crystals of homogeneous nucleation by atomic-scale simulations and analyzed the intrinsic mechanisms that influence the nucleation pathways. Three different pathways of two-step nucleation were found by visualizing the precursors' evolutions, and some new micromechanisms of two step nucleation are revealed. We suggest that the solid bond fluctuations can trigger the formation of intermediate precursors, while the precursors' packing density dominates the structural transformation pathways from intermediate phases to crystals. These findings not only shed light on the mechanisms of nucleation but also provide guidance for future refinements of two-step nucleation theory. PMID- 27973863 TI - CdCl2 Treatment-Induced Enhanced Conductivity in CdTe Solar Cells Observed Using Conductive Atomic Force Microscopy. AB - The rear surfaces of CdTe photovoltaic devices without back contacts, grown by close-spaced sublimation (CSS), were analyzed using conductive atomic force microscopy (C-AFM). As-deposited and CdCl2-treated CdTe samples were compared to clarify the effect of the treatment on charge flow through grains and grain boundaries. The CdCl2-treated samples exhibit a more homogeneous and enhanced current flow across the grains as compared to the as-deposited samples. The grain boundaries show variable current. Under high bias, grain boundaries dominate current flow when the main junction is reverse biased and with the conducting current in reverse breakdown. Under the opposite bias conditions, where the contact of the conductive tip to the surface is reverse biased and under breakdown conditions, the current flow is uniform with little contrast between grains and grain boundaries. The results are interpreted as resulting from the improved crystallinity of the CdTe with reduced p-type doping along the grain boundaries. PMID- 27973862 TI - Correlated Fluctuations and Intraband Dynamics of J-Aggregates Revealed by Combination of 2DES Schemes. AB - The intraband exciton dynamics of molecular aggregates is a crucial initial step to determine the possibly coherent nature of energy transfer and its implications for the ensuing interband relaxation pathways in strongly coupled excitonic systems. In this work, we fully characterize the intraband dynamics in linear J aggregates of porphyrins, good model systems for multichromophoric assemblies in biological antenna complexes. Using different 2D electronic spectroscopy schemes together with Raman spectroscopy and theoretical modeling, we provide a full characterization of the inner structure of the main one-exciton band of the porphyrin aggregates. We find that the redistribution of population within the band occurs with a characteristic time of 280 fs and dominates the modulation of an electronic coherence. While we do not find that the coupling to vibrations significantly affects the dynamics of excitonic coherence, our results suggest that exciton fluctuations are nevertheless highly correlated. PMID- 27973864 TI - Tracking Co(I) Intermediate in Operando in Photocatalytic Hydrogen Evolution by X ray Transient Absorption Spectroscopy and DFT Calculation. AB - X-ray transient absorption spectroscopy (XTA) and optical transient spectroscopy (OTA) were used to probe the Co(I) intermediate generated in situ from an aqueous photocatalytic hydrogen evolution system, with [RuII(bpy)3]Cl2.6H2O as the photosensitizer, ascorbic acid/ascorbate as the electron donor, and the Co polypyridyl complex ([CoII(DPA-Bpy)Cl]Cl) as the precatalyst. Upon exposure to light, the XTA measured at Co K-edge visualizes the grow and decay of the Co(I) intermediate, and reveals its Co-N bond contraction of 0.09 +/- 0.03 A. Density functional theory (DFT) calculations support the bond contraction and illustrate that the metal-to-ligand pi back-bonding greatly stabilizes the penta-coordinated Co(I) intermediate, which provides easy photon access. To the best of our knowledge, this is the first example of capturing the penta-coordinated Co(I) intermediate in operando with bond contraction by XTA, thereby providing new insights for fundamental understanding of structure-function relationship of cobalt-based molecular catalysts. PMID- 27973865 TI - Ti2CO2 Nanotubes with Negative Strain Energies and Tunable Band Gaps Predicted from First-Principles Calculations. AB - MXenes, a series of two-dimensional (2D) layered early transition metal carbide, nitride, and carbonitride, have been prepared by exfoliating MAX phases recently. In addition to 2D planar MXene, one-dimensional tubular forms-MXene nanotubes-are also expected to form. Herein, we design atomic models for Ti2C as well as Ti2CO2 nanotubes in the 1-4 nm diameter range and investigate their basic properties through density functional theory (DFT). It is shown that though the strain energy of Ti2C nanotubes are always positive, Ti2CO2 nanotubes have negative strain energies when diameter beyond 2.5 nm, indicating that they could possibly folded from 2D Ti2CO2 nanosheets. Moreover, the band gap of Ti2CO2 nanotubes decrease with the growing diameter and the maximum band gap can reach up to 1.1 eV, over 3 times that of their planar form. Thus, tunable band gaps provide strong evidence for the effectiveness of nanostructuring on the electronic properties of Ti2CO2 nanotubes. PMID- 27973866 TI - Oxidation of the para-Tolyl Radical by Molecular Oxygen under Single-Collison Conditions: Formation of the para-Toloxy Radical. AB - Crossed molecular beam experiments were performed to elucidate the chemical dynamics of the para-tolyl (CH3C6H4) radical reaction with molecular oxygen (O2) at an average collision energy of 35.3 +/- 1.4 kJ mol-1. Combined with theoretical calculations, the results show that para-tolyl is efficiently oxidized by molecular oxygen to para-toloxy (CH3C6H4O) plus ground-state atomic oxygen via a complex forming, overall exoergic reaction (experimental, -33 +/- 16 kJ mol-1; computational, -42 +/- 8 kJ mol-1). The reaction dynamics are analogous to those observed for the phenyl (C6H5) plus molecular oxygen system which suggests the methyl group is a spectator during para-tolyl oxidation and that application of phenyl thermochemistry and reaction rates to para-substituted aryls is likely a suitable approximation. PMID- 27973867 TI - Orbital Control of Photochemical Rearrangement of 4-Aryl-1,1-dicyano-1-butenes through the Hyperconjugative Substitution on the Linker Chain. AB - Hyperconjugative interaction was demonstrated to play a vital role in the photochemistry of 4-aryl-1,1-dicyano-1-butenes. Thus a simple substituent on the benzylic position effectively induced a new photoreactivity to afford an allylic rearrangement product that is not obtained for the parent substrate. The natural bond orbital analysis was employed to reveal the enhanced relative contributions of hyperconjugation in the excited state, which dramatically alter the photochemical outcomes not only by reducing the strength of the allylic/benzylic bond but more crucially by affecting the conformer distribution. PMID- 27973868 TI - Lower Electric Field-Driven Magnetic Phase Transition and Perfect Spin Filtering in Graphene Nanoribbons by Edge Functionalization. AB - Perfect spin filtering is an important issue in spintronics. Although such spin filtering showing giant magnetoresistance was suggested using graphene nanoribbons (GNRs) on both ends of which strong magnetic fields were applied, electric field controlled spin filtering is more interesting due to much easier precise control with much less energy consumption. Here we study the magnetic/nonmagnetic behaviors of zigzag GNRs (zGNRs) under a transverse electric field and by edge functionalization. Employing density functional theory (DFT), we show that the threshold electric field to attain either a half-metallic or nonmagnetic feature is drastically reduced by introducing proper functional groups to the edges of the zGNR. From the current-voltage characteristics of the edge-modified zGNR under an in-plane transverse electric field, we find a remarkable perfect spin filtering feature, which can be utilized for a molecular spintronic device. Alteration of magnetic properties by tuning the transverse electric field would be a promising way to construct magnetic/nonmagnetic switches. PMID- 27973869 TI - Pressure-Induced Structural Evolution and Band Gap Shifts of Organometal Halide Perovskite-Based Methylammonium Lead Chloride. AB - Organometal halide perovskites are promising materials for optoelectronic devices. Further development of these devices requires a deep understanding of their fundamental structure-property relationships. The effect of pressure on the structural evolution and band gap shifts of methylammonium lead chloride (MAPbCl3) was investigated systematically. Synchrotron X-ray diffraction and Raman experiments provided structural information on the shrinkage, tilting distortion, and amorphization of the primitive cubic unit cell. In situ high pressure optical absorption and photoluminescence spectra manifested that the band gap of MAPbCl3 could be fine-tuned to the ultraviolet region by pressure. The optical changes are correlated with pressure-induced structural evolution of MAPbCl3, as evidenced by band gap shifts. Comparisons between Pb-hybrid perovskites and inorganic octahedra provided insights on the effects of halogens on pressure-induced transition sequences of these compounds. Our results improve the understanding of the structural and optical properties of organometal halide perovskites. PMID- 27973870 TI - Implications of Charge Penetration for Heteroatom-Containing Organic Semiconductors. AB - The noncovalent interactions of neutral pi-conjugated cores, pertinent to organic semiconductor materials, are intimately related to their charge transport properties and involve a subtle interplay of dispersion, Pauli repulsion, and electrostatic contributions. Realizing structural arrangements that are both energetically preferred and sufficiently conductive is a challenge. We tackle this problem by means of charge penetration contribution to the interaction energy, boosted in systems containing large heteroatoms (e.g., sulfur, selenium, phosphorus, silicon, and arsenic). We find that in both the model and "realistic" dimers of such heteroatom-containing cores dispersion is balanced out by the exchange and interaction energy is instead governed by substantial charge penetration. These systems also feature stronger electronic couplings compared to the dispersion-driven dimers of oligoacenes and/or the herringbone assemblies. Thus, charge penetration, enhanced in the pi-conjugated cores comprising larger heteroatoms, arises as an attractive strategy toward potentially more stable and efficient organic electronic materials. PMID- 27973871 TI - Unveiling the Reactivity of a Synthetic Mimic of the Oxygen Evolving Complex. AB - We simulated for the first time the oxygen-oxygen bond formation in a synthetic calcium-tetra manganese complex recently developed by Zhang and co-workers. In spite of promising structural similarities to the native oxygen evolving complex (OEC) in Photosystem II, several uncertainties on the mimic stability in water and on its potential catalytic activity still persist. Here, we characterized at density functional theory level the electronic and structural features of the Sn states of the complex, along with the oxygen-oxygen bond formation reaction, proposing a reasonable model for the hydrate complex. As a main finding, both the synthetic compound and the natural OEC show very close energetic barriers for the oxo-oxyl coupling process, suggesting that key electronic features of the natural OEC reactivity are well reproduced. This result strongly encourages the use of this synthetic complex in combination with other molecular assemblies for the design of successful artificial leaves. PMID- 27973873 TI - Ultralow-Threshold Single-Mode Lasing from Phase-Pure CdSe/CdS Core/Shell Quantum Dots. AB - The development of colloidal quantum dot (QD) lasers is blocked by Auger recombination (AR). Here, phase-pure wurtzite CdSe/CdS core/shell QDs with controlled shell thickness are reported, which possess nearly defect-free core/shell interfaces. Benefiting from increased volume, electron-hole partial spatial separation, and nearly defect-free alloyed interface, this series of QDs exhibit a greater than 3 orders of magnitude decrease in AR rates with increasing shell thickness. Consequently, the amplified spontaneous emission threshold of the QDs with an 11 monolayer CdS shell is found to reach a minimum of 16 MUJ cm 2. A record long lifetime (>1000 ps) and extraordinarily large bandwidth (>170 nm) of optical gain are observed by employing ultrafast transient absorption spectroscopy. We leverage the low-threshold gain of the QDs to fabricate microlasers that display single-mode operation and an ultralow threshold of ~2 MUJ cm-2. Our results represent a valuable step toward practical QD lasers. PMID- 27973872 TI - Reaction Mechanism of the Multiple-Electron Oxygen Reduction Reaction on the Surfaces of Gold and Platinum Nanoparticles Loaded on Titanium(IV) Oxide. AB - Au and Pt nanoparticles with varying mean particle size and comparable loading amounts were loaded on the surface of TiO2 (Au/TiO2 and Pt/TiO2, respectively). The photocatalytic activities of Au/TiO2 and Pt/TiO2 for the oxygen reduction reaction (ORR) in an aerated aqueous solution containing 4% ethanol were compared under ultraviolet-light irradiation at 298 K. The initial rate of H2O2 generation (or H2O2 formation rate) in the Au/TiO2 system is much greater than that in the Pt/TiO2 system regardless of the metal particle size. To clarify the origin for the striking difference in the activity, the photocatalytic ORR on the model slabs (M28/(TiO2)32 and M50/(TiO2)96, M = Au and Pt) was simulated by density functional theory (DFT) calculations taking the solvation effect into consideration. The DFT calculations clearly show that regardless of the cluster size, H2O2 formation more easily occurs structurally and energetically for the Au/TiO2 system, whereas H2O is generated with the O-O bond cleavage in the Pt/TiO2 system. PMID- 27973874 TI - Synthesis and Optical Properties of Lead-Free Cesium Tin Halide Perovskite Quantum Rods with High-Performance Solar Cell Application. AB - Herein, the fabrication of a lead-free cesium tin halide perovskite produced via a simple solvothermal process is reported for the first time. The resulting CsSnX3 (X = Cl, Br, and I) quantum rods show composition-tunable photoluminescence (PL) emissions over the entire visible spectral window (from 625 to 709 nm), as well as significant tunability of the optical properties. In this study, we demonstrate that through hybrid materials (CsSnX3) with different halides, the system can be tunable in terms of PL. By replacing the halide of the CsSnX3 quantum rods, a power conversion efficiency of 12.96% under AM 1.5 G has been achieved. This lead-free quantum rod replacement has demonstrated to be an effective method to create an absorber layer that increases light harvesting and charge collection for photovoltaic applications in its perovskite phase. PMID- 27973875 TI - Ultrafast Recombination Dynamics in Dye-Sensitized SnO2/TiO2 Core/Shell Films. AB - Interfacial dynamics are investigated in SnO2/TiO2 core/shell films derivatized with a Ru(II)-polypyridyl chromophore ([RuII(bpy)2(4,4'-(PO3H2)2bpy)]2+, RuP) using transient absorption methods. Electron injection from the chromophore into the TiO2 shell occurs within a few picoseconds after photoexcitation. Loss of the oxidized dye through recombination occurs across time scales spanning 10 orders of magnitude. The majority (60%) of charge recombination events occur shortly after injection (tau = 220 ps), while a small fraction (<=20%) of the oxidized chromophores persists for milliseconds. The lifetime of long-lived charge separated states (CSS) depends exponentially on shell thickness, suggesting that the injected electrons reside in the SnO2 core and must tunnel through the TiO2 shell to recombine with oxidized dyes. While the core/shell architecture extends the lifetime in a small fraction of the CSS, making water oxidation possible, the subnanosecond recombination process has profound implications for the overall efficiencies of dye-sensitized photoelectrosynthesis cells (DSPECs). PMID- 27973876 TI - Narrow Linewidth Excitonic Emission in Organic-Inorganic Lead Iodide Perovskite Single Crystals. AB - Hybrid perovskite thin films have demonstrated impressive performance for solar energy conversion and optoelectronic applications. However, further progress will benefit from a better knowledge of the intrinsic photophysics of materials. Here, the temperature-dependent emission properties of CH3NH3PbI3 single crystals are investigated and compared to those of thin polycrystalline films by means of steady-state and time-resolved photoluminescence spectroscopy. Single crystals photoluminescence present a sharp excitonic emission at high energy, with full width at half maximum of only 5 meV, assigned to free excitonic recombination. We highlight a strong thermal broadening of the free excitonic emission, due to exciton-LO-phonon coupling. The emission turned to be very short-lived with a subnanosecond dynamics, mainly induced by the fast trapping of the excitons. The free excitonic emission is completely absent of the thin film spectra, which are dominated by trap state bands. PMID- 27973877 TI - Possible Room-Temperature Ferromagnetism in Self-Assembled Ensembles of Paramagnetic and Diamagnetic Molecular Semiconductors. AB - Owing to long spin-relaxation time and chemically customizable physical properties, molecule-based semiconductor materials like metal-phthalocyanines offer promising alternatives to conventional dilute magnetic semiconductors/oxides (DMSs/DMOs) to achieve room-temperature (RT) ferromagnetism. However, air-stable molecule-based materials exhibiting both semiconductivity and magnetic-order at RT have so far remained elusive. We present here the concept of supramolecular arrangement to accomplish possibly RT ferromagnetism. Specifically, we observe a clear hysteresis-loop (Hc ~ 120 Oe) at 300 K in the magnetization versus field (M-H) plot of the self-assembled ensembles of diamagnetic Zn-phthalocyanine having peripheral F atoms (ZnFPc; S = 0) and paramagnetic Fe-phthalocyanine having peripehral H atoms (FePc; S = 1). Tauc plot of the self-assembled FePc...ZnFPc ensembles showed an optical band gap of ~1.05 eV and temperature-dependent current-voltage (I-V) studies suggest semiconducting characteristics in the material. Using DFT+U quantum-chemical calculations, we reveal the origin of such unusual ferromagnetic exchange interaction in the supramolecular FePc...ZnFPc system. PMID- 27973878 TI - Electrostatic Origin of Stabilization in MoS2-Organic Nanocrystals. AB - Negatively charged molybdenum disulfide layers form stable organic-inorganic layered nanocrystals when reacted with organic cations in solution. The reasons why this self-assembly process leads to a single-phase compound with a well defined interlayer distance in given conditions are, however, poorly understood to date. Here, for the first time, we quantify the interactions determining the cation packing and stability of the MoS2-organic nanocrystals and find that the main contribution arises from Coulomb forces. The study was performed on the series of new layered compounds of MoS2 with naphthalene derivatives, forming several distinct phases depending on reaction conditions. Starting with structural models derived from powder X-ray diffraction data and TEM, we evaluate their cohesion energy by modeling layer separation with periodic PW-DFT-D calculations. The results provide a reliable approach for estimation of the stability of MoS2-based heterolayered compounds. PMID- 27973879 TI - The Photochemical Branching Ratio in 1,6-Dinitropyrene Depends on the Excitation Energy. AB - Nitropolycyclic aromatic hydrocarbons constitute one of the most disconcerting classes of pollutants. Photochemical degradation is thought to be a primary mode of their natural removal from the environment, but the microscopic mechanism leading to product formation as a function of excitation wavelength is poorly understood. In this Letter, it is revealed that excitation of 1,6-dinitropyrene with 425, 415, or 340 nm radiation leads to an increasing amount of radical production through photodissociation at the expense of triplet-state population the two primary reaction pathways in this class of pollutants. Radical formation requires overcoming an energy barrier in the excited singlet manifold. This activation energy explains the large fraction of the initial singlet-state population that intersystem crosses to a doorway triplet state, instead of leading overwhelmingly to photodissociation. The unforeseen excitation wavelength dependence of this branching process is expected to regulate the photochemistry of 1,6-dinitropyrene and possibly of other nitroaromatic pollutants in the environment. PMID- 27973880 TI - Theoretical Insights into Sub-Terahertz Acoustic Vibrations of Proteins Measured in Single-Molecule Experiments. AB - Proteins are an important class of nanobioparticles with acoustical modes in the sub-THz frequency range. There is considerable interest to measure and establish the role of these acoustical vibrations for biological function. So far, the technique providing the most detailed information about the acoustical modes of proteins is the very recent Extraordinary Acoustic Raman (EAR) spectroscopy. In this technique, proteins are trapped in nanoholes and excited by two optical lasers of slightly different wavelengths producing an electric field at low frequency (<100 GHz). We demonstrate that the acoustical modes of proteins studied by EAR spectroscopy are both infrared- and Raman-active modes, and we provided interpretation of the spectroscopic fingerprints measured at the single molecule level. A combination of the present calculations with techniques based on the excitation of a single nanobioparticle by an electric field, such as EAR spectroscopy, should provide a wealth of information on the role of molecular dynamics for biological function. PMID- 27973881 TI - Anion Bridging-Induced Structural Transformation of Cellulose Dissolved in Ionic Liquid. AB - We performed structural investigations of cellulose mixed with 1-ethyl-3 methylimidazolium acetate ([Emim][OAc]) in the entire concentration range (0-100 mol %) by wide-angle X-ray scattering with the aid of quantum chemical calculations and 13C solid-state NMR spectroscopy. We particularly focused on a highly concentrated region (>=30 mol %), which has previously been overlooked. At concentrations of 15-30 mol %, a periodic peak corresponding to cellulose chain alignment emerged; this is associated with a lyotropic cholesteric liquid crystalline phase. At concentrations of >=30 mol %, the structure is transformed into ordered layers where OAc anions and Emim cations intercalate. This transformation is found to be driven by a change in the interaction between the IL anions and the OH groups of cellulose. At low concentrations, the anion mainly interacts with the OH group of cellulose in a 1:1 ratio, as previously reported; at high concentrations, the anions bridge the OH groups of two cellulose chains. PMID- 27973882 TI - Imaging van der Waals Interactions. AB - The van der Waals interactions are responsible for a large diversity of structures and functions in chemistry, biology, and materials. Discussion of van der Waals interactions has focused on the attractive potential energy that varies as the inverse power of the distance between the two interacting partners. The origin of the attractive force is widely discussed as being due to the correlated fluctuations of electron charges that lead to instantaneous dipole-induced dipole attractions. Here, we use the inelastic tunneling probe to image the potential energy surface associated with the van der Waals interactions of xenon atoms. PMID- 27973883 TI - Decoupling Interfacial Charge Transfer from Bulk Diffusion Unravels Its Intrinsic Role for Efficient Charge Extraction in Perovskite Solar Cells. AB - In a perovskite solar cell, the overall photoinduced charge-transfer (CT) process comprises both charge diffusion through the bulk to perovskite/electrode interfaces and interfacial electron and hole transfer to electrodes. In this study, we decoupled these two entangled processes by investigating the film thickness-dependent CT dynamics from CH3NH3PbI3 perovskites to [6,6]-phenyl-C61 butyric acid methyl ester (PCBM) (electron acceptor) and spiro-OMeTAD (hole acceptor). By fitting ultrafast transient absorption kinetics to an explicit "diffusion-coupled charge-transfer" model, we found that the charge diffusion from the film interior to perovskite/electrode interfaces took ~200 ps to a few nanoseconds, depending on the thickness of perovskite film; the subsequent interfacial charge transfer was ultrafast, ~6 ps for electron transfer to PCBM and ~8 ps for hole transfer to spiro-OMeTAD, and led to efficient charge extraction (>90%) to electrodes in a 400 nm thick film. Our results indicate that the picosecond interfacial charge transfer is a key to high-performance perovskite solar cells. PMID- 27973884 TI - Can Quantized Vibrational Effects Be Obtained from Ehrenfest Mixed Quantum Classical Dynamics? AB - We explore the question of whether mean-field or "Ehrenfest" mixed quantum classical dynamics is capable of capturing the quantized vibrational features in photoabsorption spectra that result from infrared and Raman-active vibrational transitions. We show that vibrational and electronic absorption spectra can indeed be obtained together within a single Ehrenfest simulation. Furthermore, the electronic transitions show new sidebands that are absent in electronic dynamics simulations with fixed nuclei. Inspection of the electronic sidebands reveals that the spacing corresponds to vibrational frequencies of totally symmetric vibrational modes of the ground electronic state. A simple derivation of the time-evolving dipole in the presence of external fields and vibrational motion shows the origin of these features, demonstrating that mixed quantum classical Ehrenfest dynamics is capable of producing infrared, Raman, and electronic absorption spectra from a single simulation. PMID- 27973885 TI - Estimating the Derivative Coupling Vector Using Gradients. AB - The difference gradient and derivative coupling vectors span the branching planes of conical intersections between electronic states. While gradients are commonly available in many electronic structure methods, the derivative coupling vectors are not always implemented and ready for use in characterizing conical intersections. This Letter shows how the derivative coupling vectors can be computed to high accuracy (direction and magnitude) using energy and gradient information. The new method is based on the combination of a linear-coupling two state Hamiltonian and a finite-difference Davidson approach for computing the branching plane. Benchmark cases are provided showing these vectors can be efficiently computed near conical intersections. PMID- 27973886 TI - Ionization of Cellobiose in Aqueous Alkali and the Mechanism of Cellulose Dissolution. AB - Cellulose, one of the most abundant renewable resources, is insoluble in most common solvents but dissolves in aqueous alkali under a narrow range of conditions. To elucidate the solubilization mechanism, we performed electrophoretic NMR on cellobiose, a subunit of cellulose, showing that cellobiose acts as an acid with two dissociation steps at pH 12 and 13.5. Chemical shift differences between cellobiose in NaOH and NaCl were estimated using 2D NMR and compared to DFT shift differences upon deprotonation. The dissociation steps are the deprotonation of the hemiacetal OH group and the deprotonation of one of four OH groups on the nonreducing anhydroglucose unit. MD simulations reveal that aggregation is suppressed upon charging cellulose chains in solution. Our findings strongly suggest that cellulose is to a large extent charged in concentrated aqueous alkali, a seemingly crucial factor for solubilization. This insight, overlooked in the current literature, is important for understanding cellulose dissolution and for synthesis of new sustainable materials. PMID- 27973887 TI - Ballistic Diffusion in Polyaromatic Hydrocarbons on Graphite. AB - This work presents an experimental picture of molecular ballistic diffusion on a surface, a process that is difficult to pinpoint because it generally occurs on very short length scales. By combining neutron time-of-flight data with molecular dynamics simulations and density functional theory calculations, we provide a complete description of the ballistic translations and rotations of a polyaromatic hydrocarbon (PAH) adsorbed on the basal plane of graphite. Pyrene, C16H10, adsorbed on graphite is a unique system, where at relative surface coverages of about 10-20% its mean free path matches the experimentally accessible time/space scale of neutron time-of-flight spectroscopy (IN6 at the Institut Laue-Langevin). The comparison between the diffusive behavior of large and small PAHs such as pyrene and benzene adsorbed on graphite brings a strong experimental indication that the interaction between molecules is the dominating mechanism in the surface diffusion of polyaromatic hydrocarbons adsorbed on graphite. PMID- 27973888 TI - Subpicosecond Photon-Energy-Dependent Hole Transfer from PbS Quantum Dots to Conjugated Polymers. AB - We use transient absorption (TA) spectroscopy to study the origin of photon energy dependent hole transfer yields in blends of PbS quantum dots with the conjugated polymer poly(3-hexylthiophene-2,5-diyl) (P3HT). We selectively excite only the quantum dots at two different wavelengths and measure the polymer ground state bleach resulting from the transfer of photoexcited holes. The higher photon energy pump shows a greater prompt yield of hole transfer compared to the lower photon-energy excitation, on time scales sufficient to out-compete hot carrier cooling in lead chalcogenide quantum dots. We interpret the results as evidence that the excess energy of nonthermalized, or "hot," excitons resulting from higher photon-energy excitation allows more efficient charge transfer to the polymer in these systems. The data also demonstrate slow charge transfer rates, up to ~1 ns, of the relaxed excitations on the PbS dots. These findings help to clarify the role of excess photon energy and carrier relaxation dynamics on free carrier generation in donor/acceptor solar cells. PMID- 27973889 TI - Fano Scattering: Manifestation of Acoustic Phonons at the Nanoscale. AB - Size-dependent asymmetric low-frequency Raman line shapes have been observed from silicon (Si) nanostructures (NSs) due to a quantum confinement effect. The acoustic phonons in Si NSs interact with an intraband quasi-continuum to give rise to Fano interaction in the low-frequency range. The experimental asymmetric Raman line shape has been explained by developing a theoretical model that incorporates the quantum-confined phonons interacting with an intraband quasi continuum available in Si NSs as a result of discretization of energy levels with unequal separation. We discover that a phenomenon similar to Brillouin scattering is possible at the nanoscale in the low-frequency regime and thus may be called "Fano scattering" in general. A method has been proposed to extract information about nonradiative transitions from the Fano scattering data where these nonradiative transitions are involved as an intraband quasi-continuum in modulation with discrete acoustic phonons. PMID- 27973890 TI - Sum Frequency Generation of Acetonitrile on a Rutile (110) Surface from Density Functional Theory-Based Molecular Dynamics. AB - We present the calculation of vibrational sum frequency generation for molecules adsorbed on a semiconductor surface via density functional theory-based molecular dynamics. Using an efficient approach relying on the Gaussian and plane waves method and density functional perturbation theory, acetonitrile adsorbed on a rutile (110) surface has been studied, the vapor-solid interface of which has recently been investigated experimentally. Further analysis of the orientation of the acetonitrile molecules directly adsorbed on the rutile (110) surface agrees well with parameters derived from experiment. This opens a promising way for detailed study of semiconductor interfaces, which is of particular importance with respect to numerous applications such as, for instance, in materials design. PMID- 27973891 TI - Iodine Migration and Degradation of Perovskite Solar Cells Enhanced by Metallic Electrodes. AB - We monitored the evolution in time of pinhole-free structures based on FTO/TiO2/CH3NH3PbI2.6Cl0.4 layers, with and without spiro-OMeTAD and counter electrodes (Ag, Mo/Ag, and Au), aged at 24 degrees C in a dark nitrogen atmosphere. In the absence of electrodes, no degradation occurs. While devices with Au show only a 10% drop in power conversion efficiency, remaining stable after a further overheating at 70 degrees C, >90% is lost when using Ag, with the process being slower for Mo/Ag. We demonstrate that iodine is dislocated by the electric field between the electrodes, and this is an intrinsic cause for electromigration of I- from the perovskite until it reaches the anode. The iodine exhaustion in the perovskite layer is produced when using Ag electrodes, and AgI is formed. We hypothesize that in the presence of Au the iodine migration is limited due to the buildup of I- negative space charge accumulated at the perovskite-OMeTAD interface. PMID- 27973892 TI - Beyond Kohn-Sham Approximation: Hybrid Multistate Wave Function and Density Functional Theory. AB - A multistate density functional theory (MSDFT) is presented in which the energies and densities for the ground and excited states are treated on the same footing using multiconfigurational approaches. The method can be applied to systems with strong correlation and to correctly describe the dimensionality of the conical intersections between strongly coupled dissociative potential energy surfaces. A dynamic-then-static framework for treating electron correlation is developed to first incorporate dynamic correlation into contracted state functions through block-localized Kohn-Sham density functional theory (KSDFT), followed by diagonalization of the effective Hamiltonian to include static correlation. MSDFT can be regarded as a hybrid of wave function and density functional theory. The method is built on and makes use of the current approximate density functional developed in KSDFT, yet it retains its computational efficiency to treat strongly correlated systems that are problematic for KSDFT but too large for accurate WFT. The results presented in this work show that MSDFT can be applied to photochemical processes involving conical intersections. PMID- 27973893 TI - Direct Observation of Reversible Transformation of CH3NH3PbI3 and NH4PbI3 Induced by Polar Gaseous Molecules. AB - Despite its competitive photovoltaic efficiency, the structural transformations of the prototypical hybrid perovskite, methylammonium lead iodide, are facilitated by interactions with polar molecules. Changes in optical and electronic properties upon exposure to ammonia potentially can enable the use of hybrid perovskites in gas-sensing applications. We investigated the effects of ammonia on CH3NH3PbI3 by exposing perovskite films to a wide range of vapor pressures. Spectroscopic analyses indicated that ammonium cations replaced the methylammonium cations in the perovskite crystal, thereby resulting in the formation of NH4PbI3. The transformation of CH3NH3PbI3 to NH4PbI3 caused distinct changes in the morphology of the film and its crystalline structure; however, the introduction of CH3NH2 gas reversed these changes. An in-depth understanding of the reversible chemical and structural alterations resulting from exposure to polar molecules can advance the development of hybrid perovskite sensors and provide insight into mechanisms by which perovskites convert due to interactions with polar molecules. PMID- 27973894 TI - The Role of DNA Looping in the Search for Specific Targets on DNA by Multisite Proteins. AB - Many cellular processes involve simultaneous interactions between DNA and protein molecules at several locations. They are regulated and controlled by special protein-DNA complexes, which are known as synaptic complexes or synaptosomes. Because of the multisite nature of involved proteins, it was suggested that during the formation of synaptic complexes DNA loops might appear, but their role is unclear. We developed a theoretical model that allowed us to evaluate the effect of transient DNA loop formation. It is based on a discrete-state stochastic method that explicitly takes into account the free-energy contributions due to the appearance of DNA loops. The formation of the synaptic complexes is viewed as a search for a specific binding site on DNA by the protein molecule already bound to DNA at another location. It was found that the search might be optimized by varying the position of the target and the total length of DNA. Furthermore, the formation of transient DNA loops leads to faster dynamics if it is associated with favorable enthalpic contributions to nonspecific protein DNA interactions. It is also shown that DNA looping might reduce stochastic noise in the system. PMID- 27973896 TI - Spotlights: Volume 7, Issue 24. PMID- 27973897 TI - Celebrating Our 120th Anniversary. PMID- 27973895 TI - Noncanonical Photocycle Initiation Dynamics of the Photoactive Yellow Protein (PYP) Domain of the PYP-Phytochrome-Related (Ppr) Photoreceptor. AB - The photoactive yellow protein (PYP) from Halorhodospira halophila (Hhal) is a bacterial photoreceptor and model system for exploring functional protein dynamics. We report ultrafast spectroscopy experiments that probe photocycle initiation dynamics in the PYP domain from the multidomain PYP-phytochrome related photoreceptor from Rhodospirillum centenum (Rcen). As with Hhal PYP, Rcen PYP exhibits similar excited-state dynamics; in contrast, Rcen PYP exhibits altered photoproduct ground-state dynamics in which the primary I0 intermediate as observed in Hhal PYP is absent. This property is attributed to a tighter, more sterically constrained binding pocket around the p-coumaric acid chromophore due to a change in the Rcen PYP protein structure that places Phe98 instead of Met100 in contact with the chromophore. Hence, the I0 state is not a necessary step for the initiation of productive PYP photocycles and the ubiquitously studied Hhal PYP may not be representative of the broader PYP family of photodynamics. PMID- 27973898 TI - Thermalization and Thermal Transport in Molecules. AB - The nature and rate of thermal transport through molecular junctions depend on the length over which thermalization occurs. For junctions formed by alkane chains, in which thermalization occurs only slowly, measurements reveal that thermal resistance is controlled by bonding with the substrates, whereas fluorination can introduce thermal resistance within the molecules themselves, although the mechanism remains unclear. Here we present results of quantum mechanical calculations of elastic and inelastic scattering rates, the length over which thermalization occurs, and thermal conductance in alkane and perfluoroalkane junctions. The contribution to thermalization of quantum effects that give rise to many-body localization (MBL) in isolated molecules is examined. While MBL does not occur due to dephasing, thermalization is typically too slow to establish local temperature if the same molecule in isolation exhibits MBL. The results indicate limitations on the applicability of classical molecular simulations in modeling thermal transport in molecular junctions. PMID- 27973899 TI - Auger Recombination in Chemical Vapor Deposition-Grown Monolayer WS2. AB - Reduced dimensionality and strong Coulombic interactions in monolayer semiconductors lead to enhanced many-body interactions. Here, we report Auger recombination, i.e., exciton-exciton annihilation, in large-area chemical vapor deposition-grown monolayer WS2. Using ultrafast spectroscopy, we experimentally determine the Auger rate to be 0.089 +/- 0.001 cm2/s at room temperature, which is an order of magnitude greater than the bulk value. This nonradiative recombination pathway dominates, regardless of excitation energy, for exciton densities greater than 8.0 +/- 0.6 * 1010 cm-2 and below the Mott density. Higher energy excitation above the A exciton resonance may initially produce a hot electron-hole gas that precedes exciton formation. Therefore, we use resonant excitation of the A exciton to ensure accuracy and avoid artifacts associated with other photogenerated species. PMID- 27973900 TI - Three-Dimensional Optical Tomography and Correlated Elemental Analysis of Hybrid Perovskite Microstructures: An Insight into Defect-Related Lattice Distortion and Photoinduced Ion Migration. AB - Organic lead halide perovskites have recently been proposed for applications in light-emitting devices of different sorts. More specifically, regular crystalline microstructures constitute an efficient light source and fulfill the geometrical requirements to act as resonators, giving rise to waveguiding and optical amplification. Herein we show three-dimensional laser scanning confocal tomography studies of different types of methylammonium lead bromide microstructures which have allowed us to dissect their photoemission properties with a precision of 0.036 MUm3. This analysis shows that their spectral emission presents strong spatial variations which can be attributed to defect-related lattice distortions. It is also largely enhanced under light exposure, which triggers the migration of halide ions away from illuminated regions, eventually leading to a strongly anisotropic degradation. Our work points to the need for performing an optical quality test of individual crystallites prior to their use in optoelectronics devices and provides a means to do so. PMID- 27973902 TI - Transport-Induced Inversion of Screening Ionic Charges in Nanochannels. AB - This work reveals a counterintuitive but basic process of ionic screening in nanofluidic channels. Steady-state numerical simulations and mathematical analysis show that, under significant longitudinal ionic transport, the screening ionic charges can be locally inverted in the channels: their charge sign becomes the same as that of the channel surface charges. The process is identified to originate from the coupling of ionic electro-diffusion transport and junction two dimensional electrostatics. This finding may expand our understanding of ionic screening and electrical double layers in nanochannels. Furthermore, the charge inversion process results in a body-force torque on channel fluids, which is a possible mechanism for vortex generation in the channels and their nonlinear current-voltage characteristics. PMID- 27973901 TI - Probing Photocurrent Nonuniformities in the Subcells of Monolithic Perovskite/Silicon Tandem Solar Cells. AB - Perovskite/silicon tandem solar cells with high power conversion efficiencies have the potential to become a commercially viable photovoltaic option in the near future. However, device design and optimization is challenging because conventional characterization methods do not give clear feedback on the localized chemical and physical factors that limit performance within individual subcells, especially when stability and degradation is a concern. In this study, we use light beam induced current (LBIC) to probe photocurrent collection nonuniformities in the individual subcells of perovskite/silicon tandems. The choices of lasers and light biasing conditions allow efficiency-limiting effects relating to processing defects, optical interference within the individual cells, and the evolution of water-induced device degradation to be spatially resolved. The results reveal several types of microscopic defects and demonstrate that eliminating these and managing the optical properties within the multilayer structures will be important for future optimization of perovskite/silicon tandem solar cells. PMID- 27973903 TI - Capturing the Ultrafast Vibrational Decoherence of Hydrogen Bonding in Interfacial Water. AB - Vibrational sum-frequency generation (vSFG) measurements in the frequency and time domains reveal that the interfacial hydrogen bonded OH stretch at the water/calcium fluoride interface is composed of two populations oriented oppositely. The time-resolved vSFG free-induction decay suggested that, whereas the strongly hydrogen bonded OH vibrational stretches, centered near 3140 +/- 11 cm-1, are oriented toward bulk water and lose their collective coherence within ~70 +/- 7 fs, the weakly hydrogen bonded OH species, centered near 3410 +/- 12 cm 1, are pointed toward the interface and dephase within ~50 +/- 6 fs. PMID- 27973904 TI - Determination of Peukert's Constant Using Impedance Spectroscopy: Application to Supercapacitors. AB - Peukert's equation is widely used to model the rate dependence of battery capacity, and has recently attracted attention for application to supercapacitors. Here we present a newly developed method to readily determine Peukert's constant using impedance spectroscopy. Impedance spectroscopy is ideal for this purpose as it has the capability of probing electrical performance of a device over a wide range of time-scales within a single measurement. We demonstrate that the new method yields consistent results with conventional galvanostatic measurements through applying it to commercially available supercapacitors. Additionally, the novel method is much simpler and more precise, making it an attractive alternative for the determination of Peukert's constant. PMID- 27973905 TI - Mobility-Lifetime Products in MAPbI3 Films. AB - Photovoltaic solar cells operate under steady-state conditions that are established during the charge carrier excitation and recombination. However, to date no model of the steady-state recombination scenario in halide perovskites has been proposed. In this Letter we present such a model that is based on a single type of recombination center, which is deduced from our measurements of the illumination intensity dependence of the photoconductivity and the ambipolar diffusion length in those materials. The relation between the present results and those from time-resolved measurements, such as photoluminescence that are commonly reported in the literature, is discussed. PMID- 27973906 TI - Role of Spin-Dependent Terms in the Relationship among Nuclear Spin-Rotation and NMR Magnetic Shielding Tensors. AB - The broadly accepted procedure to obtain the experimental absolute scale of NMR magnetic shieldings, sigma, is well-known for nonheavy atom-containing molecules. It was uncovered more than 40 years ago by the works of Ramsey and Flygare. They found a quite accurate relationship among sigma and the nuclear spin-rotation constants. Its relativistic extension was very recently proposed, although it has an intrinsic weakness because a new SO-S two-component term needs to be considered. We show how to overcome this problem. We found that (nuYS - nuYatom,S) generalizes the SO-S term, where nuYS = ??[((r - rY) * alpha)/(|r - rY|3)]; S(4)??, r - rY is the electron position with respect to the position of nucleus Y, and S(4) is the four-component total electron spin. When including this new term, one finds that the best of our relativistic Flygare-like models fits quite well with the results of the most accurate method available at the moment. We also show that the difference among the parallel component of sigma(Xe) in XeF2 and sigma(Xe) of the free atom is almost completely described by that new term. PMID- 27973907 TI - How the Zundel (H5O2+) Potential Can Be Used to Predict the Proton Stretch and Bend Frequencies of Larger Protonated Water Clusters. AB - From a series of seminal experiments on the IR spectra of protonated water clusters and associated theoretical analyses, it is clear that the energies and spectral features of the proton stretch and bend modes are very sensitive functions of the cluster size. Here we show that this dynamic range can be understood by examining the sensitivity of these modes in the potential of the Zundel cation, H5O2+, as the separation of the two water monomers is varied. As this distance increases, the proton increasingly localizes on a monomer, and this is encoded in the IR spectrum of the proton vibrational modes. The quantitative predictions from this simple correlation are verified for the H7O3+ and H9O4+ clusters, for which new benchmark harmonic frequencies are reported. The predictions are also in good accord with trends seen experimentally and previous calculations for these and five other clusters, including H+(H2O)21. PMID- 27973908 TI - Temperature Dependence of the Energy Levels of Methylammonium Lead Iodide Perovskite from First-Principles. AB - Environmental effects and intrinsic energy-loss processes lead to fluctuations in the operational temperature of solar cells, which can profoundly influence their power conversion efficiency. Here we determine from first-principles the effects of temperature on the band gap and band edges of the hybrid pervoskite CH3NH3PbI3 by accounting for electron-phonon coupling and thermal expansion. From 290 to 380 K, the computed band gap change of 40 meV coincides with the experimental change of 30-40 meV. The calculation of electron-phonon coupling in CH3NH3PbI3 is particularly intricate as the commonly used Allen-Heine-Cardona theory overestimates the band gap change with temperature, and excellent agreement with experiment is only obtained when including high-order terms in the electron phonon interaction. We also find that spin-orbit coupling enhances the electron phonon coupling strength but that the inclusion of nonlocal correlations using hybrid functionals has little effect. We reach similar conclusions in the metal halide perovskite CsPbI3. Our results unambiguously confirm for the first time the importance of high-order terms in the electron-phonon coupling by direct comparison with experiment. PMID- 27973909 TI - Effective Riemannian Diffusion Model for Conformational Dynamics of Biomolecular Systems. AB - We present a Riemannian formalism for effective diffusion of biomolecules in collective variable spaces that provides a robust framework for conformational free energy calculation methods. Unlike their Euclidean counterparts, the Riemannian potential of mean force (PMF) and minimum free energy path (MFEP) are invariant under coordinate transformations. The presented formalism can be readily employed to modify the collective variable based enhanced sampling techniques, such as umbrella sampling (US) commonly used in biomolecular simulations, to take into account the role of intrinsic geometry of collective variable space. Although our model is mathematically equivalent to a Euclidean diffusion with a position-dependent diffusion tensor, the Riemannian formulation provides a more convenient framework for free energy calculation methods and path finding algorithms aimed at characterizing the effective conformational dynamics of biomolecules. A simple three-dimensional toy model and a pentapeptide (met enkephalin) simulated in an explicit solvent environment are used to illustrate the workings of the formalism and its implementation. PMID- 27973910 TI - Water-Induced Zwitterionization of Glycine: Stabilization Mechanism and Spectral Signatures. AB - Not only the question of how many water molecules are required to stabilize the physiologically relevant charge-separated zwitterionic form of amino acids upon solvation but also the stabilization mechanism is still under debate. It is well known that a water bridge connecting the carboxyl with the amino group must be established. Here, we show that this is not yet a sufficient condition to stabilize the zwitterion. Instead, the formation of a bifurcated H-bonded water wire that connects the two charged groups turns out to be the key, which explains why an unexpectedly large number of water molecules of about nine is required to enable zwitterionization of microsolvated glycine. Moreover, this bifurcated wire allows one to pinpoint a frequency window that enables the detection of zwitterionization by spectroscopy. These findings will be relevant to probe and rationalize microsolvation-induced zwitterionization of not only amino acids but of other acid/base reactions that involve somewhat distant such functional groups within the same molecule. PMID- 27973911 TI - Charging and Discharging Channels in Photoluminescence Intermittency of Single Colloidal CdSe/CdS Core/Shell Quantum Dot. AB - Understanding photoluminescence (PL) intermittency of single quantum dots (QDs) (intensity blinking by randomly switching between distinguishable brightness states under continuous excitation) has been a long-standing fundamental challenge and potential roadblock for their applications. Here we introduce a new analysis method for single-molecule spectroscopy that treats the blinking as photochemical/chemical processes (switching between neutral/bright and charged/dim states). It uncovers the channels for charging (bright to dim) and discharging (dim to bright) involved in PL blinking of single CdSe/CdS core/shell QDs. Both charging and discharging of the single CdSe/CdS core/shell QD possess a photochemical channel (~10-5 to 10-6 events/photon) that linearly depends on excitation in both single- and multi-exciton regime. These two linear channels coupled to a spontaneous discharging channel (~2 events/s) to dictate the QDs from nonblinking to gradually blinking under increasing excitation. For high quality CdSe/CdS core/shell QDs, Auger ionization of multiexciton for both charging and discharging is negligible. PMID- 27973912 TI - Carrier Decay Properties of Mixed Cation Formamidinium-Methylammonium Lead Iodide Perovskite [HC(NH2)2]1-x[CH3NH3]xPbI3 Nanorods. AB - Organic-inorganic lead iodide perovskites are efficient materials for photovoltaics and light-emitting diodes. We report carrier decay dynamics of nanorods of mixed cation formamidinium and methylammonium lead iodide perovskites [HC(NH2)2]1-x[CH3NH3]xPbI3 (FA1-xMAxPbI3) synthesized through a simple solution method. The structure and FA/MA composition ratio of the single-crystal FA1 xMAxPbI3 nanorods are fully characterized, which shows that the mixed cation FA1 xMAxPbI3 nanorods are stabilized in the perovskite structure. The photoluminescence (PL) emission from FA1-xMAxPbI3 nanorods continuously shifts from 821 to 782 nm as the MA ratio (x) increases from 0 to 1 and is shown to be inhomogeneously broadened. Time-resolved PL from individual FA1-xMAxPbI3 nanorods demonstrates that lifetimes of mixed cation FA1-xMAxPbI3 nanorods are longer than those of the pure FAPbI3 or MAPbI3 nanorods, and the FA0.4MA0.6PbI3 displays the longest average PL lifetime of about 2 MUs. These results suggest that mixed cation FA1-xMAxPbI3 perovskites are promising for high-efficiency photovoltaics and other optoelectronic applications. PMID- 27973913 TI - Graphic support resources for workers with intellectual disability engaged in office tasks: a comparison with verbal instructions from a work mate. AB - BACKGROUND: Research into workplace adjustments for people with disabilities is a fundamental challenge of supported employment. The aim of the present work is to investigate the effect of several graphic resources as natural support for workers with intellectual disability. METHODS: Two case studies were conducted to assess the performance of five workers engaged in office tasks, with three different support conditions. RESULTS: Results reveal a 20% increase in quality of performance of the tasks undertaken with graphic support as compared to support in which the participants received verbal instructions (VIs) from a work mate; and between 25 and 30% as compared to a control condition which included no help of any kind. CONCLUSIONS: These findings are consistent with previous studies which support the possibility of generating, at low cost, iconic materials (with maps or simple graphics), which progressively facilitate workers' autonomy, without dependence or help from the job trainer. We observed that the worst performance is in the support condition with VIs, this shows the limitations of this type of natural support, which is provided on demand by work mates without specialist knowledge of work support. Implications for Rehabilitation We studied the use of various types of natural support for people with intellectual disability in their workplace. The findings suggest that, with some brief training, the simple use in the workplace of graphic help on a card can increase between 20 and 30% the quality of performance of certain work tasks carried out by workers with intellectual disability. This advantage contrasts with the high cost or lower "manageability" of other material resources of natural support based on the use of technology. PMID- 27973915 TI - Towards a framework for preventing community violence among youth. AB - This article, in an effort to assist the selection and deployment of evidence informed strategies, proposes a new conceptual framework for responding to community violence among youth. First, the phenomenon of community violence is understood in context using a new violence typology organized along a continuum. Second, the need for a new anti-community violence framework is established. Third, a framework is developed, blending concepts from the fields of public safety and public health. Fourth, evidence from systematic reviews and meta analyses concerning community violence is summarized and categorized. Finally, an anti-violence framework populated with evidence-informed strategies is presented and discussed. PMID- 27973914 TI - The discordance between subjectively and objectively measured physical function in women with fibromyalgia: association with catastrophizing and self-efficacy cognitions. The al-Andalus project. AB - PURPOSE: People with fibromyalgia experience a disagreement between patient reported (i.e., subjective) and performance-based (i.e., objective) status. This study aimed to (i) corroborate the discordance between subjectively and objectively measured physical function and (ii) examine whether catastrophizing (worrying, pain magnifying, and helpless cognitions) and self-efficacy (believing capable to manage pain) are independently associated with this discordance. METHODS: This population-based cross-sectional study included 405 women with fibromyalgia and 193 age-matched female controls. Participants completed the Pain Catastrophizing Scale, Chronic Pain Self-efficacy Scale, and physical functioning subscales of the Revised Fibromyalgia Impact Questionnaire and Short Form-36 (SF 36) health survey. Objective physical function was measured with the Senior Fitness Test battery. Subjective and objective physical functions were expressed as deviation from the general population in standard deviation (SD) units using means and SD of the control group. RESULTS: In fibromyalgia, subjective physical function was worse than objective physical function (p < 0.001). Higher catastrophizing was consistently associated with greater discordance between subjective and objective physical function, while self-efficacy was only significantly associated with this discordance when subjective physical function was assessed by means of the SF-36. CONCLUSIONS: Subjective physical function is more impaired than objective physical function in fibromyalgia, yet both are markedly impaired. Catastrophizing cognitions are associated with this discordance. In particular, high catastrophizing may promote a feeling of reduced ability to do meaningful activities of daily living (i.e., restrictions) that people with fibromyalgia are actually able to. Therefore, catastrophizing should be assessed and potentially targeted when focusing on improving physical function in fibromyalgia. Implications for rehabilitation Rehabilitation should focus on physical exercise programs to help women with fibromyalgia to improve their reduced physical function. In rehabilitation settings, physical function of people with fibromyalgia should be evaluated by both subjective and objective assessments to fully understand physical functioning and to test the existence of discordance between both assessments. In case of a large discordance between subjective and objective physical function, a physical exercise program might be better complemented with cognitive management techniques to reduce catastrophizing and subjective physical dysfunction. When people with fibromyalgia experience high levels of catastrophizing, subjective assessments seem to be poor indicators of physical function. PMID- 27973916 TI - Health consequences of intimate partner violence against married women: a population-based study in northern Iran. AB - The effects of different types of intimate partner violence (IPV) on mental health are understudied. The aim of this study was to analyse the association between women's mental health and physical, psychological and sexual IPV. We invited subjects of a population-based survey conducted in 2015 in Rasht, Iran, on IPV against women to complete the General Health Questionnaire (GHQ-28). The present research study is a secondary study based on these data and archival data from the 2015 study. For analysis, multivariate analysis of covariance was used. Additionally, predictors of IPV were evaluated using linear regression. A total of 2091 married women were surveyed. The participants were divided into abused women (n = 512, 24.5%) and non-abused women (n = 1579, 75.5%). The pattern of IPV among our patients showed more instances of psychological aggression than physical assault, sexual coercion or injury. Our results show that the non psychotic psychiatric disorders of the victims were significantly impaired in all aspects, including somatic symptoms, anxiety/insomnia, social dysfunction, and depression. Except social dysfunction, the psychological and sexual abuse were significant predictors of other aspects of mental health. Our findings suggest that risk of IPV is high in this population. They also indicate that various forms of abuse are different from each other in terms of predicting a victim's mental health. Different strategies may be required to reduce and prevent this violence. Additional research is needed to confirm and expand upon our findings. PMID- 27973917 TI - Mitochondrial variations in the MT-ND4 and MT-TL1 genes are associated with male infertility. AB - : Mitochondrial gene mutations have been reported to be associated with sperm motility and the quality of semen. The aim of this study was to investigate whether the two mitochondrial genes (MT-ND4 and MT-TL1) are involved in Chinese male infertility. A total of 97 asthenospermia patients and 80 fertile controls were recruited in this case-control study. Genomic DNA were extracted from the sperm of all participants. Two mitochondrial DNA genes (MT-ND4 and MT-TL1) were amplified by using polymerase chain reaction (PCR) with the gene-specific primers and sequenced on an ABI 3730XL DNA sequencer. For the MT-ND4 gene, we found a total of 64 and 54 nucleotide substitutions in patients and controls, respectively, with no discrepancy in the mutation rates (66.0% vs. 67.5%, p>0.05). However, one mutation (g.11084A>G, p.T109A) leading to an amino acid substitution in a highly conserved residue and predicted to be deleterious was detected only in the cases. For another gene MT-TL1, a novel mutation (g.3263C>T) near the anticodon TAA was identified in an asthenospermia patient and was absent from normal controls. However, the mutation positions in the cases varied from the controls and one highly conserved mutation (g.11084A>G, p.T109A) which was not found in the controls and probably caused damage to the protein structure might contribute to asthenospermia. For another gene MT-TL1, a highly conservative novel mutation which is located closely next to the anticodon also might contribute to asthenospermia. Our result suggests that the MT-ND4 and MT TL1 genes might be associated with Chinese male infertility. ABBREVIATIONS: MT ND4: mitochondrially encoded NADH dehydrogenase 4; MT-TL1: mitochondrially encoded tRNA leucine 1 (UUA/G); PCR: polymerase chain reaction; OXPHOS: mitochondrial oxidative phosphorylation; ATP: adenosine triphosphate; mtDNA: mitochondrial DNA; SNPs: single nucleotide substitutions; AD: alzheimer's disease; PD: parkinson's disease; MELAS: mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; ROS: reactive oxygen species. PMID- 27973918 TI - Living at a residency away from home during radiotherapy as narrated by 52 patients with breast cancer: a cage of safety and discomfort. AB - PURPOSE: In the Nordic countries many patients with cancer conclude their treatment with 5-6 weeks of radiotherapy while staying at a residency far away from home. The experience of this stay, from a rehabilitation perspective, has not previously been studied. METHOD: Fifty-two women with breast cancer were followed with repeated thematic interviews from diagnosis up to 2 years. RESULTS: The majority of women saw both pros and cons with their stay, and overall the stay could be described as "A cage of safety and discomfort". Pros included "Safety", "Closeness and learning", and "Feeling like being on holiday", while cons included "An intruding self-image", "Isolation and increased vulnerability", and "A loss of function". Some patients supported their own rehabilitation by socializing with their "fellow sisters", while others isolated themselves and mainly found it burdensome to be there. CONCLUSIONS: The residence becomes an interactional field with the potential to facilitate patients in resuming a new everyday life. The women who do not interact with others and/or who are stuck with feelings of anxiety should be offered the opportunity to take part in a group exclusively for "fellow sisters" in a similar situation. Implications for Rehabilitation Staying in accommodations together with other patients receiving daily radiotherapy for cancer for 5-6 weeks lends itself to personal interactions with a rehabilitative impact. Some patients take advantage of this possibility, which might facilitate the integration of the cancer experience into a new self image. To some more vulnerable patients the stay at the patient hotel is burdensome, and these patients represent a target group for staff interventions aiming to facilitate their stay and their resumption of a new everyday life. A suggestion is that the specialist nurses meet with every patient after about a week in order to identify women who would benefit from psychosocial interventions. PMID- 27973919 TI - Effectiveness of technology-based distance physical rehabilitation interventions on physical activity and walking in multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: To determine the effectiveness of technology-based distance physical rehabilitation interventions in multiple sclerosis (MS) on physical activity and walking. DATA SOURCES: A systematic literature search was conducted in seven databases from January 2000 to September 2016. Randomized controlled trials of technology-based distance physical rehabilitation interventions on physical activity and walking outcome measures were included. METHODS: Methodological quality of the studies was determined and a meta-analysis was performed. In addition, a subanalysis of technologies and an additional analysis comparing to no treatment were conducted. RESULTS: The meta-analysis consisted of 11 studies. The methodological quality was good (8/13). The Internet, telephone, exergaming, and pedometers were the technologies enabling distance physical rehabilitation. Technology-based distance physical rehabilitation had a large effect on physical activity (standard mean difference (SMD) 0.59; 95% confidence interval (95% CI) 0.38 to 0.79; p < 0.00001) compared to control group with usual care, minimal treatment, and no treatment. A large effect was also observed on physical activity (SMD 0.59; 95% CI 0.34 to 0.83; p < 0.00001) when compared to no treatment alone. There were no differences in walking and the subanalysis of technologies. CONCLUSIONS: Technology-based distance physical rehabilitation increased physical activity among persons with MS, but further research on walking in MS is needed. Implications for Rehabilitation Technology-based distance physical rehabilitation interventions increase physical activity among persons with MS. This study was unable to identify if the technologies (Internet, telephone, or combinations) lead to differing effects on physical activity or walking in the distance physical rehabilitation interventions in MS. Further research on the effectiveness of technology-based distance physical rehabilitation interventions on walking in MS is needed. PMID- 27973921 TI - How adults with cardiac conditions in Singapore understand the Patient Activation Measure (PAM-13) items: a cognitive interviewing study. AB - PURPOSE: Validation studies of the PAM-13 have found differences in scale performance, suggesting that health beliefs embedded in different cultures and/or self-management needs of different client groups influence how people respond to the items. The purpose of this study was to examine how adults with cardiac conditions in Singapore interpreted and responded to the PAM-13, to investigate possible reasons for differences in responses and to propose solutions to overcome them. METHODS: We conducted retrospective cognitive interviews with 13 participants in an out-patient heart center. Interviews were transcribed and analyzed based on the framework approach to qualitative analysis. The four stages from Tourangeau's cognitive model were used as a framework to index the data from each item. RESULTS: There was variation in comprehension of questions leading to variation in responses. Comprehension issues were due to terms perceived by participants to be vague and the use of English terms uncommon in Singapore. Cultural influences impacted decision processes and problems with response processes of the self-rating Likert scale surfaced. CONCLUSIONS: This study reinforces the need to culturally adapt the tool, even when language translation is not necessary. Providing Likert scales with a larger number of may widen the relevance of PAM-13 in Singapore. Implications for rehabilitation Need to culturally adapt assessment tool, even when language translation is not necessary. Consider using Likert scales with a larger number of categories when using in Asian countries such as Singapore. Caution must be taken when using PAM 13 levels to decide interventions for each individual. PMID- 27973920 TI - Transition to adult services - a positive step. AB - Following the success of antiretroviral therapy, an expanding cohort of adolescents with perinatally acquired HIV (PaHIV) is transitioning into adult care. Dedicated multidisciplinary transitional care HIV services have been established in the UK. However, published data on patient satisfaction with such services are sparse. A single centre survey of patient satisfaction was conducted in January 2014, and results compared to a previous similar survey in 2009. Patients were asked to complete a questionnaire regarding views of their care using a 7-point Likert scale. 51/96 attended within the time period and all completed the survey, compared with 21 in 2009. Ninety-two percent were satisfied with the care provided by the clinic, compared to 100% in 2009. The proportion who felt moving to their current service had a positive effect on their health increased from 68% in 2009 to 81% in 2014. Ninety-two percent were satisfied with the overall care provided by the clinic, compared to 100% in 2009. Ninety-four percent agreed that staff knew how to talk and listen to young people, 96% agreed staff were able to explain their treatments and problems clearly in a way that they could understand. Ninety-six percent felt that a clinic specifically for young people was useful. Despite a marked increase in clinic attendees and unchanged levels of service provision, patient satisfaction remained high. Patients strongly value the provision of dedicated services for young people. PMID- 27973922 TI - Minimal differences in prevalence and spectrum of organic disease at upper gastrointestinal endoscopy between selected secondary care patients with symptoms of gastro-oesophageal reflux or dyspepsia. AB - OBJECTIVES: Gastro-oesophageal reflux and dyspepsia are felt to be separate upper gastrointestinal (GI) conditions. We aimed to measure the degree of overlap between them, and assess whether endoscopic findings differed. MATERIAL AND METHODS: Demographic, symptom, upper GI endoscopy and histology data were collected from consecutive adults in secondary care. Patients were categorised according to whether they reported gastro-oesophageal reflux alone, dyspepsia alone or both, and patient demographics and endoscopic findings were compared. RESULTS: Of 1167 patients, 97 (8.3%) had gastro-oesophageal reflux alone, 571 (48.9%) dyspepsia alone, and 499 (42.8%) overlap. Patients with overlap symptoms were more likely to smoke, compared with those with gastro-oesophageal reflux alone, or dyspepsia alone (p = .009), but there were no other differences. Patients with gastro-oesophageal reflux alone or overlap had a higher prevalence of erosive oesophagitis (18.6% and 15.4% respectively, p < .001), but this was still the commonest diagnosis among those with dyspepsia alone (7.2%). No significant differences were seen in prevalence of other endoscopic findings. CONCLUSIONS: Gastro-oesophageal reflux and dyspepsia symptoms commonly overlap. There were minimal differences in demographics or spectrum of underlying organic disease between various symptom groups, suggesting that restrictive classifications according to predominant symptom may not be clinically useful. PMID- 27973924 TI - Sexual dysfunction in female patients with type 2 diabetes mellitus: a cross sectional single-centre study among Turkish patients. AB - The aim of the study was to assess the prevalence of female sexual function and related factors in Turkish women with type 2 diabetes mellitus (T2DM). A total of 93 female patients diagnosed with T2DM (age 48.0 +/- 7.2 years (Mean +/- SD) were included. Data on age, diabetes age, HbA1c level, educational level, diabetes treatment, diabetes-related complications, co-morbid disorders and concomitant medications were recorded, as were the scores obtained using a Female Sexual Function Index (FSFI) questionnaire. Sexual dysfunction was noted in 55.9% of patients including problems related to desire (60.2%), arousal (52.7%), lubrication (55.9%), orgasm (51.6%) and satisfaction (58.1%) as well as pain during sexual intercourse (54.8%). Total scores were correlated negatively to age (r= -0.329, p = 0.001) and duration of diabetes (r= -0.246, p = 0.018), while significantly higher in patients with than without hypertension (19.6 vs. 22.4, p = 0.012) and with than without insulin therapy (20.0 vs. 23.7, p = 0.050). Our findings indicate the adverse effects of T2DM on sexual function in 55.9% of women in all domains of sexual response cycle, although this seems to be associated with older age, longer duration of diabetes, insulin and antidepressant therapy, presence of hypertension as well as end-organ complications of neuropathy and coronary artery disease (CAD). PMID- 27973923 TI - Prevention and control of malaria in pregnancy - new threats, new opportunities? AB - INTRODUCTION: Over 100 million women and their babies are at risk of malaria in pregnancy each year. Malaria prevention in pregnancy relies on long-lasting insecticidal nets (LLINs), and, in Africa, intermittent preventive treatment in pregnancy (IPTp). Increasing resistance of malaria parasites to sulfadoxine pyrimethamine, the only drug endorsed for IPTp, and increasing mosquito resistance to pyrethroids used in LLINs, threaten the efficacy of these proven strategies, while operational challenges restrict their implementation in areas of great need. Areas Covered: This review summarizes strategies for malaria prevention in pregnancy (both currently used and those undergoing preclinical and clinical evaluation), primarily drawing on publications and study protocols from the last decade. Challenges associated with each strategy are discussed, including the particular problem of HIV and malaria in pregnancy, and areas of further research are highlighted. Expert Commentary: Alternative drugs for IPTp are needed. Dihydroartemisinin-piperaquine is particularly promising, but requires further evaluation, and might contribute to artemisinin resistance. Intermittent screening and treatment in pregnancy (ISTp) is an alternative to IPTp that could reduce unnecessary antenatal drug exposure and resistance risk, but it is not recommended with current, insensitive screening tests. Optimal strategies for areas of low or declining malaria transmission remain to be determined. PMID- 27973925 TI - A reduced gastric corpus microvascular blood flow during Ivor-Lewis esophagectomy detected by laser speckle contrast imaging technique. AB - BACKGROUND: Reduced microvascular blood flow is related to anastomotic insufficiency following esophagectomy, emphasizing a need for intraoperative monitoring of the microcirculation. This study evaluated if laser speckle contrast imaging (LSCI) was able to detect intraoperative changes in gastric microcirculation. METHODS: Gastric microcirculation was assessed prior to and after reconstruction of gastric continuity in 25 consecutive patients operated for adenocarcinoma with open Ivor-Lewis esophagectomy while hemodynamic variables were recorded. RESULTS: During upper laparotomy, microcirculation at the corpus decreased by 25% from baseline to mobilization of the stomach (p = .008) and decreased further (to a total decrease of 40%) following gastric pull to the thorax (p = .013). On the other hand, microcirculation at the antrum did not change significantly after gastric mobilization (p = .091). The decrease in corpus microcirculation took place unrelated to central cardiovascular variables. CONCLUSION: Using LSCI technique, we identified a reduced microcirculation at the corpus area during open Ivor-Lewis esophagectomy. LSCI provides an option for real-time assessment of gastric microcirculation and could form basis for intraoperative stabilization of the microcirculation. PMID- 27973926 TI - Drug-induced liver injury: a cohort study on patients referred to the Danish transplant center over a five year period. AB - OBJECTIVE: The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors of poor outcome. MATERIALS AND METHODS: We identified all patients diagnosed with DILI at the Department of Hepatology, Rigshospitalet, from March 2007 to November 2012. The following parameters were registered from patient files: drug causing DILI, symptoms, comorbidity, biochemistry, treatment and outcome. RESULTS: Of 43 patients, 25 (58%) were female with a mean age of 54 years. The two most frequent causes of DILI were Disulfiram (30%) and antibiotics (19%). The most common symptoms were jaundice, nausea, fatigue and gastrointestinal discomfort. At the time of admission, the most frequent biochemical findings included bilirubin elevated to above 3.2 * ULN, ALT elevated to above 9 * ULN in 86%, INR above 1.4 in 70%. Twenty two patients needed treatment in the liver intensive care unit. Fifteen patients developed acute liver failure with a severe outcome. Six patients were liver transplanted and nine patients died. Jaundice, a moderately elevated bilirubin level or INR at presentation was predictive of severe outcome. CONCLUSION: In this retrospective study, 35% of patients with DILI developed severe acute liver failure and were either liver transplanted or died. Our results underline that DILI may be severe and run a fatal course, and that bilirubin and INR levels may predict poor outcome. PMID- 27973927 TI - Qualitative research in rehabilitation science: opportunities, challenges, and future directions. AB - PURPOSE: Qualitative research has had a significant impact within rehabilitation science over time. During the past 20 years the number of qualitative studies published per year in Disability and Rehabilitation has markedly increased (from 1 to 54). In addition, during this period there have been significant changes in how qualitative research is conceptualized, conducted, and utilized to advance the field of rehabilitation. The purpose of this article is to reflect upon the progress of qualitative research within rehabilitation to date, to explicate current opportunities and challenges, and to suggest future directions to continue to strengthen the contribution of qualitative research in this field. METHODS: Relevant literature searches were conducted in electronic data bases and reference lists. Pertinent literature was examined to identify current opportunities and challenges for qualitative research use in rehabilitation and to identify future directions. RESULTS: Six key areas of opportunity and challenge were identified: (a) paradigm shifts, (b) advancements in methodology, (c) emerging technology, (d) advances in quality evaluation, (e) increasing popularity of mixed methods approaches, and (f) evolving approaches to knowledge translation. Two important future directions for rehabilitation are posited: (1) advanced training in qualitative methods and (2) engaging qualitative communities of research. CONCLUSION: Qualitative research is well established in rehabilitation and has an important place in the continued growth of this field. Ongoing development of qualitative researchers and methods are essential. Implications for Rehabilitation Qualitative research has the potential to improve rehabilitation practice by addressing some of the most pervasive concerns in the field such as practitioner-client interaction, the subjective and lived experience of disability, and clinical reasoning and decision making. This will serve to better inform those providing rehabilitation services thereby benefiting patients that are utilizing these services. Changes over time in how qualitative research is conceptualized, conducted, and utilized to advance rehabilitation science have resulted in a number of unique opportunities and challenges in using qualitative research that must be considered within this field. Advances in methodology and increased expectations for evaluation must be considered to ensure quality and credibility of qualitative rehabilitation research within rehabilitation. Improved quality and credibility may increase likelihood of research dissemination and use by clinicians intervening within the rehabilitation process in order to improve clinical practice. In order to maximize opportunities and mitigate challenges there are two principal future directions for rehabilitation scientists to consider: (1) advancing training in qualitative methods to adequately prepare future rehabilitation scientists and (2) engaging qualitative communities of research. PMID- 27973928 TI - Tyrosine and tryptophan hydroxylases as therapeutic targets in human disease. AB - INTRODUCTION: The ancient and ubiquitous monoamine signalling molecules serotonin, dopamine, norepinephrine, and epinephrine are involved in multiple physiological functions. The aromatic amino acid hydroxylases tyrosine hydroxylase (TH), tryptophan hydroxylase 1 (TPH1), and tryptophan hydroxylase 2 (TPH2) catalyse the rate-limiting steps in the biosynthesis of these monoamines. Genetic variants of TH, TPH1, and TPH2 genes are associated with neuropsychiatric disorders. The interest in these enzymes as therapeutic targets is increasing as new roles of these monoamines have been discovered, not only in brain function and disease, but also in development, cardiovascular function, energy and bone homeostasis, gastrointestinal motility, hemostasis, and liver function. Areas covered: Physiological roles of TH, TPH1, and TPH2. Enzyme structures, catalytic and regulatory mechanisms, animal models, and associated diseases. Interactions with inhibitors, pharmacological chaperones, and regulatory proteins relevant for drug development. Expert opinion: Established inhibitors of these enzymes mainly target their amino acid substrate binding site, while tetrahydrobiopterin analogues, iron chelators, and allosteric ligands are less studied. New insights into monoamine biology and 3D-structural information and new computational/experimental tools have triggered the development of a new generation of more selective inhibitors and pharmacological chaperones. The enzyme complexes with their regulatory 14-3-3 proteins are also emerging as therapeutic targets. PMID- 27973929 TI - Supports and barriers to implementation of routine clinical assessment for children with cerebral palsy: A mixed-methods study. AB - PURPOSE: The purpose of this study is to investigate supports and barriers to evidence-based routine clinical assessment of children with cerebral palsy. METHOD: This mixed methods study included physiotherapists, occupational therapists and speech pathologists providing services to children with cerebral palsy (3-18 years) within five organizations across Australia. Four organizations initiated standardized routine clinical data collection (Commencing organizations), and one had previously mandated routine assessment (Comparison organization). Participants completed the Supports and Barriers Questionnaire (n = 227) and participated in focus groups (n = 8 groups, 37 participants). Quantitative data were summarized descriptively, qualitative data were analyzed thematically and comparisons between organizations assessed. RESULTS: Organizational structures, resources, therapists within organizations, assessment tools, and children and families were, on average, viewed as supportive of routine clinical assessment. There were no differences between the Comparison and Commencing organizations except 'therapists within the organization' were viewed as more supportive by the Commencing organizations (p = 0.037). Five themes were derived from qualitative analyzes: motivation to adopt routine clinical assessment; acquiring and utilizing expertise; ensuring effective ongoing communication; availability and distribution of resources; and therapist perceptions of child and family wishes. CONCLUSIONS: Organizations experience challenges to effective and sustained implementation of routine clinical assessment. Adequate resourcing and positive, clear communication were perceived as critical for success. Implications for Rehabilitation The value of routine clinical assessment of children with cerebral palsy is undisputed. Tailored solutions to organization-specific challenges are required when implementing routine clinical assessment for children with cerebral palsy. Positive, clear communication of organizational priorities by management may assist AHPs to prioritize workload activities when changing practice. PMID- 27973930 TI - Comorbidities and Subgroups of Patients Surviving Severe Acute Hypercapnic Respiratory Failure in the Intensive Care Unit. AB - RATIONALE: No methodical assessment of the lung, cardiac, and sleep function of patients surviving an acute hypercapnic respiratory failure episode requiring admission to the intensive care unit (ICU) has been reported in the literature. OBJECTIVES: To prospectively investigate the prevalence and impact of comorbidities in patients treated by mechanical ventilator support (invasive or noninvasive) for acute hypercapnic respiratory failure in the ICU. METHODS: Seventy-eight consecutive patients admitted for an episode of acute hypercapnic respiratory failure underwent an assessment of lung, cardiac, and sleep function by pulmonary function tests, transthoracic echocardiography, and polysomnography 3 months after ICU discharge. MEASUREMENTS AND MAIN RESULTS: Sixty-seven percent (52 of 78) of patients exhibited chronic obstructive pulmonary disease (COPD), although only 19 had been previously diagnosed. Patients without COPD were primarily obese. Prevalence of severe obstructive sleep apnea was 51% (95% confidence interval, 34-69) in patients with COPD and 81% (95% confidence interval, 54-96) in patients without COPD. Previously undiagnosed cardiac dysfunction with preserved ejection fraction was highly prevalent (44%), as was hypertension (67%). More than half of the population demonstrated at least three major comorbidities known to precipitate acute hypercapnic respiratory failure. Multimorbidity was associated with longer time to hospital discharge. Hospital readmission or death occurred in 46% of patients over an average of 3.5 months after discharge. CONCLUSIONS: Severe hypercapnic respiratory failure requiring ICU admission resulted primarily from COPD or obesity. Major comorbidities are highly prevalent in both cases and most often ignored. Surviving acute hypercapnic respiratory failure should be an opportunity to systematically evaluate lung, heart, and sleep functions to improve poor outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 02111876). PMID- 27973933 TI - Erratum. PMID- 27973931 TI - Anesthetic Management of a Patient With Emanuel Syndrome. AB - Emanuel syndrome is associated with supernumerary chromosome, which consists of the extra genetic material from chromosome 11 and 22. The frequency of this syndrome has been reported as 1 in 110,000. It is a rare anomaly associated with multiple systemic malformations such as micrognathia and congenital heart disease. In addition, patients with Emanuel syndrome may have seizure disorders. We experienced anesthetic management of a patient with Emanuel syndrome who underwent palatoplasty. This patient had received tracheotomy due to micrognathia. In addition, he had atrial septal defect, mild pulmonary artery stenosis, and cleft palate. Palatoplasty was performed without any complication during anesthesia. Close attention was directed to cardiac function, seizure, and airway management. PMID- 27973934 TI - Patients With Type 2 Diabetes: Anesthetic Management in the Ambulatory Setting. Part 1: Pathophysiology and Associated Disease States. AB - The increasing prevalence of diabetes mellitus in the general population has many implications for the ambulatory anesthesia provider. Complications, particularly associated with poor glycemic control, can affect multiple organ systems and jeopardize the safety of any planned anesthetic. It is essential that anesthesiologists and sedation providers have in-depth knowledge of the pathophysiology of diabetes mellitus and the comorbid conditions that commonly accompany it. Anesthesiologists and sedation providers must also understand certain surgical and anesthetic considerations when planning an effective and safe anesthetic for diabetic patients. This is a 2-part series concerning perioperative glycemic control for patients with diabetes mellitus. Part 1 will focus on the physiology of diabetes and its associated disease states. Part 2 will address the pharmacology associated with the wide variety of medications used to treat the disorder and the most recent guidelines for blood glucose management in ambulatory surgical patients. PMID- 27973936 TI - Recovery Profile and Patient Satisfaction After Ambulatory Anesthesia for Dental Treatment-A Crossover Comparison Between Propofol and Sevoflurane. AB - The purpose of this study was to determine which anesthetic was preferable for ambulatory anesthesia: propofol alone or sevoflurane alone. A crossover study was performed to compare the recovery profile and patient satisfaction after 2 anesthesia methods. Twenty healthy patients with severe anxiety toward dental treatment undergoing 2 sessions of day-case dental treatment received either propofol or sevoflurane anesthesia. The order of these methods was randomized. The depths of anesthesia were kept constant using bispectral index (BIS) monitoring. Observations on recovery profiles were performed in the emergence phase, in the recovery phase, and 24 hours after discharge. Patient satisfaction and preference were obtained by a questionnaire. Most of the recovery profiles in the emergence phase such as time to eye opening to respond to verbal command, time to BIS >= 75, and time to extubation were shorter in the sevoflurane group than in the propofol group. All recovery profiles in the recovery phase showed no differences between the 2 groups. Based on the subject's satisfaction and preference, propofol was evaluated as a better anesthetic for ambulatory anesthesia than sevoflurane. Higher patient satisfaction and a greater preference for future dental treatment were revealed for propofol anesthesia. Propofol may be more suitable for ambulatory anesthesia for dental treatment. PMID- 27973937 TI - New and Emerging Medications. PMID- 27973938 TI - Anesthetic Management of a Patient With Ehlers-Danlos Syndrome. AB - We describe the case of a 37-year-old woman who had been diagnosed with Ehlers Danlos syndrome (EDS) 4 years earlier and was scheduled to undergo removal of synovial chondromatosis in the temporomandibular joint. EDS is a heritable connective tissue disorder and has 6 types. In this case, the patient was classified into EDS hypermobility type. The major clinical feature of this type is joint hypermobility. The patient had sprain or subluxation of the elbows and ankles and dislocation of the knees. Anticipated problems during general anesthesia would be affected by the disease type. For this patient, extra attention was directed to positional injury-induced neuropathy and articular luxation, cutaneous injuries, injuries related to intubation and ventilation, and postoperative pain. Anesthesia was induced with propofol, remifentanil, and rocuronium and maintained with oxygen-air-desflurane, propofol, remifentanil, fentanyl, and rocuronium. In this case, the patient was safely managed without adverse events. PMID- 27973939 TI - Asystole From Direct Laryngoscopy: A Case Report and Literature Review. AB - The rare and potentially fatal complication of asystole during direct laryngoscopy is linked to direct vagal stimulation. This case describes asystole in an 85-year-old female who underwent suspension microlaryngoscopy with tracheal dilation for subglottic stenosis. Quick recognition of this rare event with immediate cessation of laryngoscopy resulted in the return of normal sinus rhythm. This incident emphasizes the implications of continued vigilance during laryngoscopy and the importance of communication between the anesthesia and surgical staff to identify and treat this rare complication. The case was successfully concluded by premedication with an anticholinergic and by increasing the depth of anesthesia. PMID- 27973940 TI - Preliminary Evidence Supports Modification of Retraction Technique to Prevent Needlestick Injuries. AB - A modified retraction technique was introduced into the DDS degree preclinical anesthesia course in 2011 with the goal of reducing needlestick exposure incidents. In numerous studies of dental exposures, injuries from dental anesthetic needles account for the highest proportion of all exposures. The purpose of this study was to assess the preliminary impact of a modified retraction technique on the incidence of blood and body fluids (BBF) exposure incidents associated with needles during injection. Data from evaluations of students from 2014 and 2015 were obtained and tracked to determine whether the modified retraction technique was "excellent," "clinically acceptable," or "clinically unacceptable." Data were collected to determine if the patient perceived the modified retraction technique as "comfortable" or "correctable when addressed" to help improve student technique for future injections. Likewise, data from the blood-borne exposure database where all information related to BBF exposures is recorded were reviewed and the information separated by year and class. This study presents preliminary data only and because of the small sample size does not lend itself to validation by statistical analysis. However, the technique effectively removes the operator's hand from the field during injection, reducing the risk of accidental intraoral needlestick to the nondominant hand of the operator. PMID- 27973942 TI - In Memoriam: Dr James K. Grainger. PMID- 27973941 TI - The Effect of Various Concentrations of Nitrous Oxide and Oxygen on the Hypersensitive Gag Reflex. AB - The purpose of this study was to compare the effectiveness of various concentrations of N2O/O2 on obtunding a hypersensitive gag reflex. We hypothesized that the administration of nitrous oxide and oxygen would obtund a hypersensitive gag reflex enough to allow a patient to tolerate the placement and holding of a digital x-ray sensor long enough to obtain a dental radiograph. Volunteers claiming to have a hypersensitive gag reflex were first screened to validate their claim and then tested by placing a size 2 digital x-ray sensor in the position for a periapical radiograph of the right mandibular molar area and holding it in place for 10 seconds. Subjects were first tested using room air only, then 30%, 50%, or 70% nitrous oxide until they were able to tolerate the sensor without gagging or discomfort. A visual analog scale was used for subjective responses, and other statistical tests were used to analyze the results. We found that for some subjects, 30% nitrous oxide was sufficient; for others, 50% was needed; and for the remainder of the subjects, 70% was sufficient to tolerate the test. Using a combination of 70% nitrous oxide and 30% oxygen allowed all patients claiming to have a hypersensitive gag reflex to tolerate the placement and holding of a digital x-ray sensor long enough to take a periapical radiograph. PMID- 27973943 TI - Correlation Between Body Movements and Salivary Secretion During Sedation. AB - During dental sedation, control of the cough reflex is crucial for a safe and smooth procedure. Accumulated saliva is one of the predisposing factors for coughing. Body movements during dental sedation appear to enhance salivation. Therefore, the aim of this study was to investigate the difference in salivary secretion between the with-movements state and the without-movements state during sedation. Salivary weight for 1 min was measured 3 times in 27 patients with intellectual disability during dental treatment under deep sedation with midazolam and propofol. The observed variables were body movements, bispectral index (BIS), and predicted propofol effect-site concentration. A total of 81 measurements were classified into the with-movements state (n = 39; ie, measurements during which body movements were observed) or the without-movements state (n = 42; ie, measurements during which no body movements were observed). The median salivary weight was significantly smaller in the without-movements state compared with the with-movements state (0.03 vs 0.11 g, P < .0001). The BIS was significantly lower in the without-movements state. There was no significant difference in the predicted propofol effect-site concentration between the 2 states. Significant correlation was observed between salivary weight and BIS in the with-movements state (r = 0.44, P = .004). The findings indicate that salivary secretion decreased according to deep sedation. Furthermore, immobility also reduced salivary secretion. We concluded that one reason that immobility is beneficial is because of the resulting decreased salivary secretion during dental treatment under deep sedation. PMID- 27973944 TI - A population-based study of smoking, serum cotinine and exhaled nitric oxide among asthmatics and a healthy population in the USA. AB - BACKGROUND: Fractional concentration of exhaled nitric oxide (FeNO) is recommended by the American Thoracic Society (ATS) as a noninvasive biomarker of airway inflammation. In addition to inflammation, many factors may be associated with FeNO, particularly tobacco exposure; however, only age has been included as an influential factor for children below 12 years. Numerous studies have demonstrated negative associations between tobacco exposure and FeNO levels with self-reported data, but few with an objective assessment of smoking. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 2007-2012 were analyzed to examine the association between FeNO and active/passive tobacco. Exposure was assessed by both self-report and serum cotinine levels among 11,160 subjects aged 6-79 years old with asthma, or without any respiratory disease. RESULTS: Study results indicated 28.8% lower FeNO, 95% CI [25.2%, 32.3%] and 38.1% lower FeNO, 95% CI: [28.1, 46.2] was observed among healthy and asthmatic participants with serum cotinine in the highest quartile compared to those in the lowest quartile, respectively. Self-reported smoking status and recent tobacco use were also associated with decreased FeNO. Self-reported passive smoking was significantly associated with a 1.0% decrease in FeNO 95% CI [0.0, 2.0] among asthmatic subjects but not among healthy subjects. CONCLUSIONS: Active smoking, whether measured by self-report or serum cotinine, was associated with decreased FeNO levels. In addition to age, increased attention should be given to tobacco exposure when using FeNO as a biomarker in clinical practice. Additional research is needed to establish reference value of FeNO considering the impact of tobacco exposure. PMID- 27973945 TI - Sevoflurane induces cognitive impairments via the MiR-27b/LIMK1-signaling pathway in developing rats. AB - Exposure to sevoflurane in neonatal rats could induce learning deficits and abnormal social behaviors, but the specific molecular mechanism is unknown. Postnatal day-7 SD rats were treated with 3% sevoflurane plus 30% oxygen/air or 30% oxygen/air. As the rats grew, the Morris water maze (MWM) and fear conditioning tests were performed to evaluate cognitive function, while the expression of LIMK1 was analyzed by western blot. Luciferase reporter assay was performed to investigate the interaction between LIMK1 and miR-27b. The expression of miR-27b was measured by real-time polymerase chain reaction (PCR) after exposure to sevoflurane. Once the miR-27b inhibitor was transfected into the neurons, the expression of LIMK1 was analyzed by real-time PCR and western blot. Exposure to sevoflurane in neonatal rats induced memory and learning impairments according to the MWM and fear conditioning tests. Sevoflurane increased the expression of miR-27b and reduced the expression of LIMK1 in the brain tissues of rats compared to the control group. The results of the luciferase reporter assay showed that LIMK1 was a direct target of miR-27b. In the primary neurons, the inhibition of miR-27b could reverse the down-regulating effects of sevoflurane on LIMK1 expression. We suggest that sevoflurane-induced learning and memory impairments in rats might be mediated via the miR-27b-LIMK1 signaling pathway. PMID- 27973946 TI - Effect of soft-tissue impingement on range of motion during posterior approach Total Hip Arthroplasty: an in vivo measurement study. AB - PURPOSE: While implant impingement and bony impingement have been recognized as causes of poor outcomes in total hip arthroplasty (THA), reports of soft-tissue impingement are rare. To clarify the issue, the effect of anterior capsule resection on hip range of motion (ROM) was quantitatively measured in vivo during posterior approach THA using a CT-based hip navigation system. MATERIALS AND METHODS: For 47 patients (51 hips), hip ROM was measured intraoperatively before and after resection of the anterior hip capsule, and the difference was compared. RESULTS: Resection of the anterior hip capsule brought about an average 6 degrees increase of ROM in the direction of flexion with internal rotation and did not markedly change ROM in other directions. CONCLUSIONS: During THA through a posterior approach, soft-tissue impingement by the anterior hip capsule can occur. Clinically, we expect that resection of the anterior hip capsule can reduce the risk of posterior instability without increasing the risk of anterior instability. PMID- 27973947 TI - Biomechanical comparison of fixation systems in posterior wall fracture of acetabular by finite element analysis. AB - BACKGROUND: The use of reconstruction plates and lag screws has been recommended for fractures to the posterior wall of the acetabulum. However, little information about the rigidity of recommended forms of fracture fixation is available. This study aimed to evaluate the biomechanical difference among the fixation systems. METHODS: A posterior wall fracture, which is represented by softer elements with lower elastic modulus, was created along an arc of 40-90 degrees about the acetabular rim. Three different fixation systems: screws alone, reconstruction plate with screws, reconstruction plate with T-shaped plates were used to fix the posterior wall fractures to the acetabulum. RESULTS: All three fixation system can be used to obtain good functional outcomes. The reconstruction plate with T-shaped plates was beneficial to increasing the effective stiffness, decreasing the stress concentration and enhancing the rigidity of fracture fixation. So this fixation system served an ideal result in the analysis. CONCLUSION: Theoretically, the reconstruction plate with T-shaped plates system may reduce many of the risks and limitations compared to the other fixation systems. This fixation system may result in a clinical benefit. PMID- 27973948 TI - High-fidelity haptic and visual rendering for patient-specific simulation of temporal bone surgery. AB - Medical imaging techniques provide a wealth of information for surgical preparation, but it is still often the case that surgeons are examining three dimensional pre-operative image data as a series of two-dimensional images. With recent advances in visual computing and interactive technologies, there is much opportunity to provide surgeons an ability to actively manipulate and interpret digital image data in a surgically meaningful way. This article describes the design and initial evaluation of a virtual surgical environment that supports patient-specific simulation of temporal bone surgery using pre-operative medical image data. Computational methods are presented that enable six degree-of-freedom haptic feedback during manipulation, and that simulate virtual dissection according to the mechanical principles of orthogonal cutting and abrasive wear. A highly efficient direct volume renderer simultaneously provides high-fidelity visual feedback during surgical manipulation of the virtual anatomy. The resulting virtual surgical environment was assessed by evaluating its ability to replicate findings in the operating room, using pre-operative imaging of the same patient. Correspondences between surgical exposure, anatomical features, and the locations of pathology were readily observed when comparing intra-operative video with the simulation, indicating the predictive ability of the virtual surgical environment. PMID- 27973950 TI - A computer-assisted navigation technique to perform bone tumor resection without dedicated software. AB - PURPOSE: In oncological orthopedics, navigation systems are limited to use in specialized centers, because specific, expensive, software is necessary. To resolve this problem, we present a technique using general spine navigation software to resect tumors located in different segments. MATERIALS AND METHODS: This technique requires a primary surgery during which screws are inserted in the segment where the bone tumor is; next, a CT scan of the entire segment is used as a guide in a second surgery where a resection is performed under navigation control. We applied this technique in four selected cases. To evaluate the procedure, we considered resolution obtained, quality of the margin and its control. RESULTS: In all cases, 1 mm resolution was obtained; navigation allowed perfect control of the osteotomies, reaching the minimum wide margin when desired. No complications were reported and all patients were free of disease at follow-up (average 25.5 months). CONCLUSIONS: This technique allows any bone segment to be recognized by the navigation system thanks to the introduction of screws as landmarks. The minimum number of screws required is four, but the higher the number of screws, the greater the accuracy and resolution. In our experience, five landmarks, placed distant from one another, is a good compromise. Possible disadvantages include the necessity to perform two surgeries and the need of a major surgical exposure; nevertheless, in our opinion, the advantages of better margin control justify the application of this technique in centers where an intraoperative CT scanner, synchronized with a navigation system or a dedicated software for bone tumor removal were not available. PMID- 27973949 TI - Robot-assisted Heller's myotomy for achalasia in children. AB - BACKGROUND: Achalasia is rare in children. Surgical options include open, laparoscopic and robotic approaches. However, Heller's myotomy remains the treatment of choice. This report describes our experience with robot-assisted Heller's myotomy in children and presents a review of the literature. METHODS: Included in this study are children who underwent robot-assisted Heller's myotomy for esophageal achalasia via the Da Vinci surgical system between 2004 and 2015 at King Saud University Medical City, Riyadh, Saudi Arabia. The medical records of these patients were reviewed for demographic data, presenting symptoms, diagnostic modalities, operative procedures, complications, outcomes and follow ups. RESULTS: Six patients were identified. The age of the patients at surgery ranged between 2 and 12 years (mean 7.1 years). The most common presenting symptoms were dysphagia, vomiting and nocturnal cough. Contrast swallow and upper gastrointestinal endoscopy established a diagnosis of esophageal achalasia in all of the patients. Four patients underwent esophageal dilatation 2-5 times before the definitive procedure. All patients underwent successful robot-assisted Heller's myotomy with concomitant partial posterior fundoplication. The postoperative course was uneventful. Five patients had a complete resolution of the symptoms and one patient improved. The follow-up assessments have been consistent and have ranged from 0.5 to 11 years (mean 4.4 years). CONCLUSION: Robotic-assisted Heller's myotomy for esophageal achalasia in children is safe and effective and is a suitable alternative to open and laparoscopic approaches. PMID- 27973951 TI - Patient-specific modeling of the trochlear morphologic anomalies by means of hyperbolic paraboloids. AB - Diagnostic and therapeutic purposes are issuing pressing demands to improve the evaluation of the dysplasia condition of the femoral trochlea. The traditional clinical assessment of the dysplasia, based on Dejour classification, recognized 4 increasing (A, B, C, D) levels of severity. It has been extensively questioned in the literature that this classification methodology can be defective suggesting that quantitative measures can ensure more reliable criteria for the dysplasia severity assessment. This study reports on a novel technique to model the trochlear surface (TS), digitally reconstructed by 3D volumetric imaging, using three hyperbolic paraboloids (HP), one to describe the global trochlear aspect, two to represent the local aspects of the medial and lateral compartments, respectively. Results on a cohort of 43 patients, affected by aspecific anterior knee pain, demonstrate the consistency of the estimated model parameters with the morphologic aspect of the TS. The obtained small fitting error (on average lower than 0.80 mm) demonstrated that the ventral aspect of the trochlear morphology can be modeled with high accuracy by HPs. We also showed that HP modeling provides a continuous representation of morphologic variations in shape parameter space while we found that similar morphologic anomalies of the trochlear aspect are actually attributed to different severity grades in the Dejour classification. This finding is in agreement with recent works in the literature reporting that morphometric parameters can only optimistically be used to discriminate between the Grade A and the remaining three grades. In conclusion, we can assert that the proposed methodology is a further step toward modeling of anatomical surfaces that can be used to quantify deviations to normality on a patient-specific basis. PMID- 27973952 TI - Accuracy of estimating Unicondylar Knee Replacement implant varus/valgus angles from antero-posterior radiographs. AB - Unicondylar Knee Replacement (UKR) is an orthopedic surgical procedure to reduce pain and improve function in the knee. Load-bearing long-standing antero posterior (AP) radiographs are typically used postoperatively to measure the leg alignment and assess the varus/valgus implant orientation. However, implant out of-plane rotations, user variability, and X-ray acquisition parameters introduce errors in the estimation of the implant varus/valgus estimation. Previous work has explored the accuracy of various imaging modalities in this estimation. In this work, we explored the impact of out-of-plane rotations and X-ray acquisition parameters on the estimation of implant component varus/valgus angles. For our study, we used a single CT scan and positioned femoral and tibial implants under varying orientations within the CT volume. Then, a custom software application was used to obtain digitally reconstructed radiographs from the CT scan with implants under varying orientations. Two users were then asked to manually estimate the varus/valgus angles for the implants. We found that there was significant inter-user variability (p < 0.05) in the varus/valgus estimates for the two users. However, the 'ideal' measurements, obtained using actual implant orientations, showed small errors due to variations in implant orientation. We also found that variation in the projection center does not have a statistically significant impact (p < 0.01) on the estimation of implant varus/valgus angles. We conclude that manual estimates of UKR implant varus/valgus orientations are unreliable. PMID- 27973953 TI - Simulation of multi-probe radiofrequency ablation guided by optical surgery navigation system under different active modes. AB - Radiofrequency ablation (RFA) is a crucial alternative treatment for liver cancer with the advantages of minimal invasion and a fast prognosis. However, two problems limit its further application: the orientation of the puncture point and the ablation of large tumors. The optical surgery navigation system in the RFA presents a promising approach for solving the localization problem in the puncturing process, which greatly increases puncture accuracy and has overcome the disadvantages of traditional RFA surgery. In addition, the use of multiple electrodes in the RFA (multi-probe RFA) is proposed and is applied clinically to deal with large tumors. In this study, we present a multi-probe RFA model using the finite element method (FEM) combined with a self-developed optical surgical navigation system. A real 3D liver model was adopted as an effective reference. Based on this model, two-probe RFA simulations were performed under different active modes. An analysis was conducted from the perspective of the temperature and electric potential fields and cell necrosis. The simulation results showed that different active modes had separate advantages and were suitable for different situations. Understanding their advantages can not only help doctors make surgical plans that fit the patients' conditions, but also the understanding can offer a virtual surgery platform for further development in the preoperative planning of RFA incorporated with the surgery navigation system. PMID- 27973954 TI - A biomechanical study of relationship between sternum defect patterns and thoracic respiration. AB - BACKGROUND: Various types of sternum defects are produced after the removal of thoracic tumors involving the sternum. The present study aims to elucidate the relationship between the defect patterns and their effects on thoracic respiration. METHODS: Ten sets of finite element models were produced simulating thoraces of 10 persons and termed normal models. With each of the 10 normal models, the sternum was removed in six different ways to produce new models termed defect models. Defect models were categorized into hemi-superior (H-S), hemi-inferior (H-I), hemi-whole length (H-W), bilateral-superior (B-S), bilateral inferior (B-I), and bilateral-whole length (B-W) defect types, depending on the locations of the defects. Respiratory movement was dynamically simulated with these models. The volume change the thoraces present during respiration was measured to evaluate the effectiveness of thoracic respiration. This value - defined as DeltaV - was calculated and was compared between normal and defect models. RESULTS: With H-W and B-W type models, DeltaV dropped to around 20% of normal values. With H-S and B-S type models, DeltaV dropped to around 50% of normal values. With H-I and B-I type models, DeltaV presented values almost equivalent to those of normal models. CONCLUSION: Effectiveness of thoracic respiration is seriously impaired when the whole length of the sternum is absent. Reconstruction of the defect is essential for these cases. However, since the upper part of the sternum is most important for effective thoracic respiration, priority should be placed on the upper part in performing reconstruction. PMID- 27973955 TI - How does adding anatomical landmarks as fiducial points in the point-matching registration of neuronavigation influence registration accuracy? AB - Skin markers (SMs) are usually used as fiducial points in registration of neuronavigation, but the areas in which they can be adhered to are restricted, which usually results in poor distribution of the SMs and a large registration error. In this research, we studied whether the registration accuracy can be improved by adding anatomical landmarks (ALs), which are thought to have a larger localization error than SMs. A series of random SM configurations were generated, and for each SM configuration, we generated a corresponding SM-AL configuration by adding several ALs. We then compared the accuracy of the point-matching registration of the SM configurations with that of the corresponding SM-AL configurations. Experiment results indicated that adding ALs always made the mean target registration error of the whole head fall into a lower and narrower range, which meant that the registration became more accurate and more stable. In addition, adding more ALs resulted in a better performance. PMID- 27973956 TI - Inferior gluteal artery detection at the greater sciatic notch with a computer assisted navigation system during pelvic and sacral tumor resection. AB - BACKGROUND: During pelvic and sacral tumor resection, important vessels, such as the inferior gluteal artery underneath the sciatic notch, are easily injured because of their invisibility. We employed a computer-assisted navigation system to preserve the inferior gluteal artery at the sciatic notch with visualization of the inferior gluteal artery at the sciatic notch, thus maintaining blood flow to the gluteus maximus. METHODS: We present the results of seven patients (five men and two women) with a mean age of 64.8 years (58.4-78.8) in whom computer assisted navigation surgery had been carried out for pelvic and sacral tumor resections. RESULTS: Postoperative enhanced computed tomography (CT) confirmed the preservation of the inferior gluteal artery in all cases. At a mean follow-up of 21.3 months (3-39), the total postoperative complication rate was 25% (n = 2), including hematoma (n = 1) and wound necrosis (n = 1). There were no cases of deep infection. CONCLUSION: This new application of computer-assisted navigation to pelvic and sacral tumor resection can contribute to reducing postoperative complications related to insufficient flap perfusion. PMID- 27973957 TI - Endoscopic transnasal removal of an intraconal foreign body using an image-guided surgical system. AB - Foreign bodies lodged in the intraconal space of the orbit pose a surgical challenge due to its deep location behind the globe. Image-guided endoscopic transnasal surgery facilitates the localization of the metallic foreign bodies and enables its safe removal with minimal surrounding tissue damage and optic nerve injury. PMID- 27973958 TI - Validation of a fibula graft cutting guide for mandibular reconstruction: experiment with rapid prototyping mandible model. AB - OBJECTIVE: We examined whether cutting a fibula graft with a surgical guide template, prepared with computer-aided design/computer-aided manufacturing (CAD/CAM), would improve the precision and accuracy of mandibular reconstruction. METHODS: Thirty mandibular rapid prototype (RP) models were allocated to experimental (N = 15) and control (N = 15) groups. Thirty identical fibular RP models were assigned randomly, 15 to each group. For reference, we prepared a reconstructed mandibular RP model with a three-dimensional printer, based on surgical simulation. In the experimental group, a stereolithography (STL) surgical guide template, based on simulation, was used for cutting the fibula graft. In the control group, the fibula graft was cut manually, with reference to the reconstructed RP mandible model. The mandibular reconstructions were compared to the surgical simulation, and errors were calculated for both the STL surgical guide and the manual methods. RESULTS: The average differences in three dimensional, minimum distances between the reconstruction and simulation were 9.87 +/- 6.32 mm (mean +/- SD) for the STL surgical guide method and 14.76 +/- 10.34 mm (mean +/- SD) for the manual method. DISCUSSION: The STL surgical guide method incurred less error than the manual method in mandibular reconstruction. A fibula cutting guide improved the precision of reconstructing the mandible with a fibula graft. PMID- 27973959 TI - Three-dimensional digitalized virtual planning for saphenous artery flap: a pilot study. AB - OBJECTIVE: Since the 1970s, research and applications on flap and muscle flap had solved many problems in microsurgical reconstruction. However, the traditional flap design is completely dependent on two-dimensional (2D) images. The purpose of this study was to discuss the methods in the visualization of saphenous artery flap by digitalized technique and its applications by digitalized technique. METHODS: Two adult fresh cadaver specimens, one male and one female, were subject to radiographic computerized tomography (CT) scanning before and after perfused with lead oxide-gelatine mixture, whose collimation are 0.625 mm (120 kV, 110 mA, 512 * 512 matrix). Through Amira 5.4.1 software, the 2D images in DICOM format were transformed into the 3D models of the entire region. The structures of saphenous artery were observed and the digitized visible models of saphenous artery flap were established through three-dimensional (3D) computerized reconstructions methods from these data using Amira 5.4.1 software. Next six cases of soft-tissue defects of the tibia region, involving the exposure bones underwent contrast-enhanced CT angiography of lower limbs utilizing a 64-row multi-slice spiral CT after median cubital vein injection with Ultravist (3.5 ml/s). 2D images from these data in DICOM format were transformed into computer. The structures of saphenous artery flap were observed and measured using Amira 5.4.1 software. Then, all cases were treated by saphenous artery flap. RESULTS: The 3D reconstructed visible models established from these datasets perfectly displayed the saphenous artery flap anatomy. In six cases, the main trunk and branched of the blood vessels in the designed flap were consistent with the surgical findings. The starting point of the saphenous artery to the average distance of the knee clearance were 119.2 +/- 9.6 mm, the average diameter of the saphenous artery from the starting point were 1.5 +/- 0.3 mm. The range of flap was 8.0 * 5.0 cm to 20.0 * 8.0 cm. All flaps survived well. After 8-24 months' follow-up the knee flexion was 120-140 degrees , the straight 0-10 degrees . There was no case appeared incision infection. CONCLUSIONS: The preoperative use of 3D digitalized virtual planning for the saphenous artery flap improves the surgical accuracy, decreases the operation time and increases the survival rate of the flap. PMID- 27973960 TI - The accuracy and the safety of individualized 3D printing screws insertion templates for cervical screw insertion. AB - STUDY DESIGN: Clinical trial for cervical screw insertion by using individualized 3-dimensional (3D) printing screw insertion templates device. OBJECTIVE: The objective of this study is to evaluate the safety and accuracy of the individualized 3D printing screw insertion template in the cervical spine. MATERIALS AND METHODS: Ten patients who underwent posterior cervical fusion surgery with cervical pedicle screws, laminar screws or lateral mass screws between December 2014 and December 2015 were involved in this study. The patients were examined by CT scan before operation. The individualized 3D printing templates were made with photosensitive resin by a 3D printing system to ensure the screw shafts entered the vertebral body without breaking the pedicle or lamina cortex. The templates were sterilized by a plasma sterilizer and used during the operation. The accuracy and the safety of the templates were evaluated by CT scans at the screw insertion levels after operation. RESULTS: The accuracy of this patient-specific template technique was demonstrated. Only one screw axis greatly deviated from the planned track and breached the cortex of the pedicle because the template was split by rough handling and then we inserted the screws under the fluoroscopy. The remaining screws were inserted in the track as preoperative design and the screw axis deviated by less than 2 mm. Vascular or neurologic complications or injuries did not happen. And no infection, broken nails, fracture of bone structure, or screw pullout occurred. CONCLUSION: This study verified the safety and the accuracy of the individualized 3D printing screw insertion templates in the cervical spine as a kind of intraoperative screw navigation. This individualized 3D printing screw insertion template was user friendly, moderate cost, and enabled a radiation-free cervical screw insertion. PMID- 27973961 TI - Application of preoperative registration and automatic tracking technique for image-guided maxillofacial surgery. AB - OBJECTIVE: To investigate the practicality of preoperative registration technique in navigational surgery of facial skeleton. METHODS: Five cases were underwent navigational surgery with the preoperative registration technique. The accuracy of registration process was determined, and the deviation between planning model and postoperative computed tomography (CT) model was detected. RESULTS: In each case, the preoperative registration was successful for navigational surgery. Preoperative registration and automatic tracking enabled registration free in the operation procedure. The registration precision measured by the system was less than 0.8 mm. The deviation between the intraoperative anatomy and the CT image was less than 1.5 mm. CONCLUSIONS: Preoperative registration technique demonstrates the potential for improved workflow and accuracy in navigational surgery procedures. This technique was found to be particularly advantageous in cases of mandible navigational surgery in which the dynamic reference frame's hard to be fixed. PMID- 27973962 TI - Computer-assisted virtual preoperative planning in orthopedic surgery for acetabular fractures based on actual computed tomography data. AB - Acetabular fractures have always been very challenging for orthopedic surgeons; therefore, appropriate preoperative evaluation and planning are particularly important. This study aimed to explore the application methods and clinical value of preoperative computer simulation (PCS) in treating pelvic and acetabular fractures. Spiral computed tomography (CT) was performed on 13 patients with pelvic and acetabular fractures, and Digital Imaging and Communications in Medicine (DICOM) data were then input into Mimics software to reconstruct three dimensional (3D) models of actual pelvic and acetabular fractures for preoperative simulative reduction and fixation, and to simulate each surgical procedure. The times needed for virtual surgical modeling and reduction and fixation were also recorded. The average fracture-modeling time was 45 min (30-70 min), and the average time for bone reduction and fixation was 28 min (16-45 min). Among the surgical approaches planned for these 13 patients, 12 were finally adopted; 12 cases used the simulated surgical fixation, and only 1 case used a partial planned fixation method. PCS can provide accurate surgical plans and data support for actual surgeries. PMID- 27973963 TI - Flexible robotic endoscopy: current and original devices. AB - Two current major research topics concern the incorporation of flexible robotic endoscopy systems developed for natural-orifice translumenal endoscopic surgery (NOTES), primarily for the purpose of remote forceps operation, into endoscopic submucosal dissection (ESD) and other flexible endoscopic treatments and the use of robots for the manipulation of flexible endoscopes themselves with the aim of enabling the remote insertion of colonoscopes, etc. However, there are still many challenges that remain to be addressed; the ideal robotic endoscope has not yet been realized. This article reviews the ongoing developments and our own efforts in the area of flexible robotic endoscopy. PMID- 27973964 TI - How deep can straight instruments be inserted into the femoral canal: a simulation study based on cadaveric femora. AB - Determining how deep instruments can be inserted into the femoral canal without touching adjacent structures is a fundamental necessity for navigating instruments in primary and revision total hip arthroplasty. The aim of the study was to determine the reachable depth of a straight instrument inserted into the femur canal during primary and revision total hip arthroplasty. Based on the three-dimensional data of twenty-six femurs, obtained from a CT scan, the insertion depth of a virtual, straight instrument was accessed by a simulation. The effect of the diameter of the virtual instrument and the extension of the osteotomy were evaluated. Without extending the osteotomy, 100% of the femoral canal was reachable to a depth of 5.1-6.3 cm for instruments with a diameter of 10 mm. The depth was measured from the lower edge of the osteotomy. A maximum lateral extension of the osteotomy by 1 cm enlarges the access to a depth of 8.8 cm. The results provide a theoretical basis for the limitations of guiding instruments used for the preparation of the femoral canal. Bone preserving methods need the development of angulated instruments to reach deep areas in the femoral canal. PMID- 27973965 TI - Tracking multiple surgical instruments in a near-infrared optical system. AB - Surgical navigation systems can assist doctors in performing more precise and more efficient surgical procedures to avoid various accidents. The near-infrared optical system (NOS) is an important component of surgical navigation systems. However, several surgical instruments are used during surgery, and effectively tracking all of them is challenging. A stereo matching algorithm using two intersecting lines and surgical instrument codes is proposed in this paper. In our NOS, the markers on the surgical instruments can be captured by two near infrared cameras. After automatically searching and extracting their subpixel coordinates in the left and right images, the coordinates of the real and pseudo markers are determined by the two intersecting lines. Finally, the pseudo markers are removed to achieve accurate stereo matching by summing the codes for the distances between a specific marker with the other two markers on the surgical instrument. Experimental results show that the markers on the different surgical instruments can be automatically and accurately recognized. The NOS can accurately track multiple surgical instruments. PMID- 27973966 TI - A computer-assisted robotic platform for vascular procedures exploiting 3D US based tracking. AB - BACKGROUND: Cardiovascular diseases are the first cause of death globally: an estimated 17.5 million people died in 2012. By combining the benefits of magnetic navigation and ultrasound (US) imaging, the authors proposed a robotic platform (i.e. the MicroVAST platform) for intravascular medical procedures. METHODS: A 3D imaging US-based tracking algorithm is implemented for the navigation of a magnetic-dragged soft-tethered device. Tests were performed to evaluate the algorithm in terms of tracking error and precision of locomotion. RESULTS: The 3D imaging US-based algorithm tracked the endovascular device with an error of 6.4 +/- 2.8 pixels and a mean displacement between the endovascular device and the preoperative path of 13.6 +/- 4.5 mm (computational time of 12.2 +/- 1.5 ms and 30.7 +/- 6.1 matched features). CONCLUSIONS: The MicroVAST platform includes innovative solutions for navigation allowing for an assisted magnetic locomotion of medical devices in the cardiovascular district by combining a 3D imaging US based tracking algorithm with pre-operative data. PMID- 27973967 TI - 10-Year patient satisfaction compared between computer-assisted navigation and conventional techniques in minimally invasive surgery total knee arthroplasty. AB - BACKGROUND: Both minimally invasive surgery (MIS) and computer-assisted surgery (CAS) in total knee arthroplasty have been scientifically linked with surgical benefits. However, the long-term results of these techniques are still controversial. Most surgeons assessed the surgical outcomes with regard to knee alignment and range of motion, but these factors may not reflect subjective variables, namely patient satisfaction. PURPOSE: To compare satisfaction and functional outcomes between two technical procedures in MIS total knee arthroplasty, namely computer-assisted MIS and conventional MIS procedure, operated on a sample group of patients after 10 years. METHODS: Seventy cases of posterior-stabilized total knee prostheses were implanted using a computer assisted system and were compared to 74 cases of matched total knee prostheses of the same implant using conventional technique. Both groups underwent arthrotomy by 2 cm limited quadriceps exposure minimally invasive surgery (2 cm Quad MIS). At an average of 10 years after surgery, self-administered patient satisfaction and WOMAC scales were administered and analyzed. RESULTS: Demographic data of both groups including sex, age, preoperative WOMAC and post-operative duration were not statistically different. Post-operative WOMAC for the computer-assisted group was 38.94 +/- 5.68, while the conventional one stood at 37.89 +/- 6.22. The median of self-administered patient satisfaction scales of the computer-assisted group was 100 (min37.5-max100), while the conventional one was 100 (min25 max100). p Value was 0.889. There was one re-operative case in the conventional MIS group due to peri-prosthetic infection which was treated with debridement, polyethylene exchanged and intravenous antibiotics. CONCLUSIONS: The 10-year outcomes of computer-assisted MIS total knee arthroplasty are not superior to that of the conventional MIS technique in function and patient satisfaction. 10 years may not be enough to show the difference between these two techniques. PMID- 27973968 TI - Serum soluble tumour necrosis factor receptor-2 (sTNFR2) as a biomarker of kidney tissue damage and long-term renal outcome in lupus nephritis. AB - OBJECTIVES: We investigated the performance of soluble tumour necrosis factor receptor-2 (sTNFR2) as a biomarker of renal activity, damage, treatment response, and long-term outcome in lupus nephritis (LN). METHOD: Serum sTNFR2 levels were assessed in 64 LN patients (52 proliferative, 12 membranous) before and after induction treatment, and in 314 non-lupus controls. In LN patients, renal biopsies were performed at baseline and post-treatment. Patients with >= 50% reduced proteinuria, normal or improved estimated glomerular filtration rate (eGFR) by >= 25%, and inactive urinary sediment were considered clinical responders (CRs). Patients with >= 50% improved renal activity index were considered histopathological responders (HRs). Long-term renal outcome was determined using the chronic kidney disease (CKD) stage after a median follow-up of 11.3 years. RESULTS: sTNFR2 levels were elevated in LN patients versus controls both at baseline (p < 0.001) and post-treatment (p < 0.001), and decreased following treatment (p < 0.001). Baseline sTNFR2 correlated with Chronicity Index scores in both baseline (r = 0.34, p = 0.006) and post-treatment (r = 0.43, p < 0.001) biopsies. In membranous LN, baseline sTNFR2 levels were higher in CRs (p = 0.048) and HRs (p = 0.03) than in non-responders, and decreased only in CRs (p = 0.03). Both baseline (p = 0.02) and post-treatment (p = 0.03) sTNFR2 levels were associated with decreasing eGFR throughout long-term follow-up, and post-treatment levels were higher in patients with long-term follow-up CKD stage >= 3 versus 1-2 (p = 0.008). CONCLUSIONS: Our data suggest serum sTNFR2 as a marker of kidney tissue damage and a predictor of long-term prognosis in LN, and merit further evaluation of sTNFR2 as a predictor of clinical and histopathological treatment outcomes in membranous LN. PMID- 27973969 TI - Hyperactivity and impulsivity in adult attention-deficit/hyperactivity disorder is related to glutamatergic dysfunction in the anterior cingulate cortex. AB - OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is closely linked to the dysregulation of dopaminergic and noradrenergic neurotransmission in the fronto-striatal neural network, including the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC). Additionally, increasing evidence supports the involvement of the glutamatergic system in the pathophysiology of ADHD. Impulsivity, a core symptom in patients with ADHD, has been repeatedly associated with glutamatergic neurotransmission, and pharmacological treatment of ADHD has been shown to reduce glutamate levels in the prefrontal cortex. METHODS: We investigated glutamate levels in the ACC and the DLPFC in 30 adults with ADHD and 30 healthy controls using single-voxel proton magnetic resonance spectroscopy on a 3T scanner. RESULTS: The ADHD group showed a significant increase in glutamate in the ACC compared to controls, no significant differences in metabolites were observed in the DLPFC. Overall, glutamate levels in the ACC were positively correlated with ADHD symptomatology, especially hyperactivity and impulsivity symptoms. CONCLUSIONS: Increased levels of glutamate in the ACC, which were positively correlated with hyperactivity and impulsivity, support the hypothesis that dysfunctional glutamatergic neurotransmission is at least partially responsible for ADHD symptomatology. Modulation of glutamatergic neurotransmission might therefore be a promising avenue for future pharmacological interventions. PMID- 27973970 TI - Potential Renoprotective Effects of Rosemary and Thyme Against Gentamicin Toxicity in Rats. AB - Gentamicin (GM) is a drug used commonly against gram-negative bacteria. Its therapeutic use is mainly limited by its nephrotoxicity. This investigation was aimed at evaluating the nephroprotective effects of rosemary (RM; Rosmarinus officinalis) and thyme (TV; Thymus vulgaris) against GM toxicity. Rats were divided into four groups. Normal control group was treated intraperitoneally (i.p.) with saline; positive control group was administered GM 60 mg/kg/day i.p.; RM group was co-administered 8% RM aqueous extract, 10 mL/kg/day, orally with GM; and TV group was co-administered 8% TV aqueous extract orally, 10 mL/kg/day with GM. Both RM and TV groups extracted significantly ameliorated plasma kidney function biomarkers, and reduced malondialdhyde and glucose levels. Meanwhile, RM extract significantly modulated the electrolyte concentration and increased plasma insulin levels as compared with the GM group. However, the aqueous extract of RM showed more pronounced effects than TV extract. Our data were confirmed by histopathological examination and deoxyribonucleic acid (DNA) fragmentation analysis. Deleterious histopathological changes and increased DNA fragmentation induced by GM treatment were markedly controlled by the co-administration of RM and TV. Such renoprotective influence of RM and TV suggests their concurrent supplementation with GM therapy to limit GM toxicity. PMID- 27973971 TI - Bilateral Ischemic Retinal Vasculitis in Metastatic Cutaneous Melanoma Patient Treated with Dabrafenib and Trametinib: A Case Report. PMID- 27973972 TI - Erratum. PMID- 27973973 TI - Pentraxin 3 in serum and synovial fluid of patients with rheumatoid arthritis with and without autoantibodies. AB - OBJECTIVES: Pentraxin 3 (PTX3) is a locally produced multifunctional protein involved in inflammation, matrix deposition, and immunity. As patients with seropositive rheumatoid arthritis (RA) have a more severe disease course and higher risk of joint destruction than seronegative patients, the aim of the present study was to examine differences in PTX3 in synovial fluid (SF) (and serum) in seropositive compared to seronegative RA, and other local markers of inflammation and destruction. METHOD: Ninety-seven RA patients with knee effusion were included. Serum and SF levels of PTX3, as well as serum levels of anti citrullinated protein antibody and rheumatoid factor of immunoglobulin A and M subclasses, and markers of inflammation and potential destruction in SF: white blood cell counts, tumour necrosis factor, interleukin-6, vascular endothelial growth factor, metalloproteinase 3, and cartilage oligomeric matrix protein, were analysed. In addition, a radiographic knee examination was performed. RESULTS: Seropositive patients had significantly higher PTX3 levels in SF than seronegative patients, whereas there was no difference for serum levels. SF-PTX3 levels correlated with disease activity and with local inflammatory markers, especially polymorphonuclear cells, and with autoantibody levels. There was no correlation between PTX3 levels in serum and SF. CONCLUSION: The correlation of disease activity and autoantibody levels with SF-PTX3 levels in antibody-positive patients suggests a role for PTX3 in the inflammatory process specifically in seropositive RA joints, and supports the hypothesis that seropositive and seronegative RA are different disease entities. Polymorphonuclear granulocytes may be an important source of PTX3 in RA SF. PMID- 27973974 TI - Short-term effect of dark chocolate consumption on routine haemostasis testing. AB - This experimental study was designed to investigate the sort-term impact of dark chocolate ingestion on routine haemostasis tests in healthy volunteers. The study population consisted in 15 healthy male volunteers who ingested 50 g of 90% cocoa chocolate within 3-5 min. Blood was drawn early in the morning, immediately before chocolate ingestion and 4 h afterwards, for assessment of activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen. A significant increase of triglycerides (1.4 +/- 0.6 versus 1.0 +/- 0.5 mmol/L; p < .001), APTT (32.1 +/- 2.2 versus 31.1 +/- 2.0 s; p < .001) and PT (9.8 +/- 0.5 versus 9.7 +/- 0.4 s; p = .008) was observed 4 h after ingestion of dark chocolate, whereas fibrinogen values remained unchanged (2.6 +/- 0.5 versus 2.5 +/- 0.5 g/L; p = .063). Overall, we observed a mean percentage increase of 3.1% for APTT and 1.2% for PT. These results suggest that dark chocolate intake may have an impact on secondary haemostasis. PMID- 27973975 TI - Solution stability of Captisol-stabilized melphalan (Evomela) versus Propylene glycol-based melphalan hydrochloride injection. AB - PURPOSE: The objective of this study was to compare the stability of recently approved Captisol-stabilized propylene glycol-free melphalan injection (EvomelaTM) against currently marketed propylene glycol-based melphalan injection. The products were compared as reconstituted solutions in vials as well as admixture solutions prepared from normal saline in infusion bags. METHODS: Evomela and propylene glycol-based melphalan injection were reconstituted in normal saline and organic custom diluent, respectively, according to their package insert instructions. The reconstituted solutions were diluted in normal saline to obtain drug admixture solutions at specific drug concentrations. Stability of the solutions was studied at room temperature by assay of melphalan and determination of melphalan-related impurities. RESULTS: Results show that based on the increase in total impurities in propylene glycol-based melphalan injection at 0.45 mg/mL, Evomela admixture solutions are about 5, 9, 15 and 29 times more stable at concentrations of 0.45, 1.0, 2.0 and 5.0 mg/mL, respectively. Results confirmed that reconstituted Evomela solution can be stored in the vial for up to 1 h at RT or for up to 24 h at refrigerated temperature (2 8 degrees C) with no significant degradation. After storage in the vial, it remains stable for an additional 3-29 h after preparation of admixture solution in infusion bags at concentrations of 0.25-5.0 mg/mL, respectively. In addition, Evomela solution in saline, at concentration of 5.0 mg/mL melphalan was bacteriostatic through 72 h storage at 2-8 degrees C. CONCLUSION: Formulation of melphalan with Captisol technology significantly improved stability compared to melphalan hydrochloride reconstituted with propylene-glycol based diluents. PMID- 27973976 TI - Where to look for the scabies mite. PMID- 27973977 TI - Risk of varicocele in patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic disease: a population-based case-control study. PMID- 27973978 TI - Reduction of anterior glenohumeral dislocations: a new closed reduction technique. AB - OBJECTIVE: A new closed reduction technique for anterior glenohumeral dislocations and tuberosity fracture dislocations is introduced. METHODS: Forty one consecutive patients with an acute anterior glenohumeral dislocation or tuberosity fracture dislocation underwent closed reduction by an orthopaedic surgeon employing this new method. RESULTS: Closed reduction was successful in 88% of patients using the reduction maneuver. Associated fracture with glenohumeral dislocation did not influence the success rate of the reduction maneuver. An assistant was needed in 15% of cases. No complications related to the reduction maneuver were noted amongst the cohort. CONCLUSION: This novel reduction technique is safe demonstrating excellent success rates both for anterior shoulder dislocations and tuberosity fracture-dislocations. PMID- 27973979 TI - Effects of step-feeding and intermittent aeration on organics and nitrogen removal in a horizontal subsurface flow constructed wetland. AB - The effect of step feed strategy and intermittent aeration on removal of chemical oxygen demand (COD) and nitrogen was investigated in a laboratory scale horizontal subsurface flow constructed wetland (HSSFCW). Wetland was divided into four zones along the length (zone I to IV), and influent was introduced into first and third zones by step feeding. Continuous study was carried out in four phases. In phases I to III, 30% of influent was bypassed to zone III for denitrification along with organics removal. Intermittent aeration was provided only in zone II at 2.5 L/min for 4 h/day, during phases II, III and IV. In phase I, 87% COD and 43% NH4+-N (ammonia-nitrogen) removal were obtained from influents of 331 and 30 mg/L, respectively. In phase II study, external aeration resulted in 97% COD and 71% NH4+-N removal in the wetland. In phase IV, 40% of feed was delivered to zone III. Higher supply of organic in zone III resulted in higher denitrification, and total nitrogen removal rate increased to 70% from 56%. In the final effluent, concentration of NO3--N was 9-11 mg/L in phase I to III and decreased to 4 mg/L in phase IV. Batch study showed that COD and NH4+-N removal followed first order kinetics in different zones of wetland. PMID- 27973980 TI - Sulfamethazine removal by means of a combined process coupling an oxidation pretreatment and activated sludge culture - preliminary results. AB - A coupled electrochemical process and biological treatment was used to remove a biorecalcitrant antibiotic: sulfamethazine (SMT). The pretreatment was performed in a home-made flow cell involving graphite felt as a working electrode at potentials of 1 and 1.6 V/saturated calomel electrode (SCE); it was followed by a biological process involving activated sludge purchased from a local wastewater treatment plant. Activated sludge cultures of pretreated and non-pretreated SMT solution were carried out for 3 weeks, and different parameters were monitored, especially total organic carbon (TOC) and SMT concentrations. high-performance liquid chromatography results revealed that the target molecule was not assimilated by activated sludge. However, and confirming the improvement previously observed for the biological oxygen demand/chemical oxygen demand (BOD5/COD) ratio, from 0.08 before electrolysis to 0.58 after electrolysis, a pretreatment step in oxidation at 1.6 V/SCE led to a fast decrease of TOC during the subsequent biological treatment, since the mineralization yields increased from 10% for a non-pretreated SMT solution to 76.6% after electrolysis in oxidation (1.6 V/SCE), confirming the efficiency of coupling the electro oxidation process with a biological treatment for the mineralization of SMT. Moreover, when the electrolysis was performed at 1 V/SCE, no biodegradation was observed, underlining the importance of the electrochemical pretreatment. PMID- 27973981 TI - MYB-QKI drives childhood brain tumors via tripartite mechanism. PMID- 27973982 TI - Pupil-size asymmetry is a physiologic trait related to gender, attentional function, and personality. AB - A small difference in the size of the two pupils is common in healthy individuals, a condition termed benign or physiologic anisocoria (BA). Past research indicates that BA is probably caused by asymmetry in sympathetic nervous system (SNS) function [e.g., Rosenberg (2008). Physiologic anisocoria: A manifestation of a physiologic sympathetic asymmetry. Neuro-Ophthalmology, 32, 147-149]. This study is the first to show that BA varies with psychological factors linked to brain asymmetry and autonomic arousal, including gender, attention, and personality. Males exhibited a more directional BA than females, consistent with greater hemispheric lateralization in males. BA also varied with a self-report measure of attentional function, consistent with evidence of hemispheric asymmetry in visuospatial attention networks. Finally, BA varied with personality traits linked to autonomic arousal. Individuals exhibiting higher Meanness and Boldness, and lower Empathy scores tended to show more directional BA. This link between personality traits and BA may be related to brain asymmetries in autonomic arousal and emotion-related processing. If future studies employing direct measures of lateralized brain activity confirm the link between BA and SNS asymmetries, this new metric may prove useful in discovering new relationships between brain organization and psychological function, and how these relationships vary across individuals. PMID- 27973983 TI - Application of a nanofibrous composite membrane to the fertilizer-driven forward osmosis process for irrigation water use. AB - In this study, we fabricated a nanofibrous composite (NFC) membrane as a substrate to produce forward osmosis (FO) membranes, and we also assessed the use of liquid fertilizer as a draw solution for the FO process in order to produce agricultural irrigation water. Commercial cellulose triacetate (CTA) and thin film composite (TFC) FO membranes were included in this study. Under FO tests, the NFC, CTA, and TFC membranes achieved initial osmotic water flux values of 35.31, 6.85, and 3.31 L/m2.h and final osmotic water flux values of 12.62, 6.31, and 3.85 L/m2 h, respectively. The reason for the high osmotic water flux of the NFC membrane is because its nanofiber layer has low tortuosity, high porosity, and a low thickness, resulting in a reduction in the internal concentration polarization phenomenon. When liquid fertilizer was used as the draw solution, the water flux values in the FO experiments for the NFC, CTA, and TFC membranes were 15.54, 5.46, and 2.54 L/m2 h. Finally, our results revealed that the FO process using liquid fertilizer as a draw solution can be applied to produce agricultural irrigation water from brackish water and the newly fabricated NFC membrane can be applied to the FO process. PMID- 27973984 TI - Medicare Payment for Behavioral Health Integration. PMID- 27973985 TI - Relationship between sustained unilateral hand clench, emotional state, line bisection performance, and prefrontal cortical activity: A functional near infrared spectroscopy study. AB - Sustained unilateral hand clenching alters perceptual processing and affective/motivational state, with these alterations presumed to reflect increased hemispheric activity contralateral to the side of motor movement. However, data from electroencephalographic and imaging studies are contradictory regarding the relationship between sustained hand clenching and brain activity. In order to investigate the relationship between brain activity, sustained unilateral hand clenching, and changes in affect and perceptual processing, frontal hemispheric activity was measured via functional near-infrared spectroscopy (fNIRS), using derived O2Hb prior to, during, and post-sustained unilateral hand clench. Participants' mood and spatial perception were recorded pre- and post-clenching. Sustained unilateral hand clenching altered brain activity and mood, but not spatial perception. Results revealed increased O2Hb bilaterally following sustained unilateral hand clenching, relative to baseline, regardless of hand. In agreement with previous fNIRS studies, sustained unilateral hand clenching resulted in greater ipsilateral, compared with contralateral, O2Hb. An interaction between side of hand clench and change in mood was in the direction predicted by theories of hemispheric lateralization of emotion: Following left-hand clenching, individuals became more affectively negative, and following right-hand clenching, they became more affectively positive. PMID- 27973986 TI - Population Health - A Bipartisan Agenda for the Incoming Administration from State Leaders. PMID- 27973987 TI - Determination of the priority substances regulated by 2000/60/EC and 2008/105/EC Directives in the surface waters supplying water treatment plants of Athens, Greece. AB - An investigation into the occurrence of priority substances regulated by 2000/60/EC Water Framework Directive and 2008/105/EC Directive was conducted for a period of one year in the surface water sources supplying the water treatment plants (WTPs) of Athens and in the raw water of WTPs. Samples from four reservoirs and four water treatment plants of Athens were taken seasonally. The substances are divided into seven specific groups, including eight volatile organic compounds (VOCs), diethylhexylphthalate, four organochlorine pesticides (OCPs), three organophosphorus/organonitrogen pesticides (OPPs/ONPs), four triazines and phenylurea herbicides, pentachlorophenol, and four metals. The aforementioned substances belong to different chemical categories, and different analytical methods were performed for their determination. The results showed that the surface waters that feed the WTPs of Athens are not burdened with significant levels of toxic substances identified as European Union (EU) priority substances. Atrazine, hexachlorocyclohexane, endosulfan, trifluralin, anthracene and 4-nonylphenol were occasionally observed at very low concentrations. Their presence in a limited number of cases could be attributed to waste disposal, agricultural activities, and to a limited industrial activity in the area nearby the water bodies. PMID- 27973988 TI - Characterisation of extended-spectrum beta-lactamase and AmpC beta-lactamase producing Enterobacteriaceae isolated from companion animals in New Zealand. AB - AIMS: To assess the occurrence of, and characterise, extended-spectrum beta lactamase (ESBL) and AmpC beta-lactamase (AmpC)-producing Enterobacteriaceae isolated by veterinary diagnostic laboratories from infection sites in companion animals in New Zealand. METHODS: Selected Enterobacteriaceae isolates were submitted by seven New Zealand veterinary diagnostic laboratories. They were isolated from infection sites in companion animals between June 2012 and June 2013, and were resistant to amoxicillin-clavulanic acid, fluoroquinolones, or any combination of two or more antimicrobials. Based on disk diffusion test results, the isolates were phenotypically categorised according to production of ESBL and AmpC. Genes for ESBL and AmpC production were amplified by PCR and sequenced. Escherichia coli isolates were also typed by multilocus sequence typing. RESULTS: A total of 115 isolates matching the inclusion criteria were obtained from the participating laboratories, of which 74 (64%) originated from dogs and 29 (25%) from cats. Seven bacterial species were identified, of which E. coli was the most common (87/115, 76%). Of the 115 isolates, 10 (9%) expressed the ESBL phenotype, 43 (37%) the AmpC phenotype, and seven (6%) both ESBL and AmpC phenotypes. Of the 60 ESBL and AmpC-producing isolates, 36 (60%) were E. coli. Amongst these isolates, 27/60 (45%) were classified as multidrug resistant, compared with 15/55 (27%) non-ESBL or AmpC-producing isolates (p<0.01). Ninety five isolates were resistant to amoxicillin-clavulanic acid and 58 (61%) of these were ESBL or AmpC producing. The predominant ESBL genes were blaCTX-M-14 and blaCTX-M-15, and the dominant plasmid-encoded AmpC gene was blaCMY-2. Thirty-eight E. coli multilocus sequence types (ST) were identified, and the most prevalent were ST12 (12/89, 13%), ST131 (6/89, 7%) and ST648 (6/89, 7%). ESBL and AmpC-producing isolates accounted for 35/1,082 (3.2%) of the Enterobacteriaceae isolated by one laboratory network over the study period. CONCLUSIONS AND CLINICAL RELEVANCE: ESBL and AmpC-producing Enterobacteriaceae were associated with clinical infections in companion animals in New Zealand, and were often multidrug resistant. In this study, these organisms accounted for <5% of all Enterobacteriaceae isolated from infection sites by one laboratory network, but their prevalence among isolates resistant to amoxicillin-clavulanic acid was 61%. Therefore routine secondary testing for ESBL and AmpC production by Enterobacteriaceae that are resistant to amoxicillin-clavulanic acid in primary testing could improve the accuracy of definitive antimicrobial therapy in companion animals in New Zealand. PMID- 27973990 TI - A One Health future to meet the AMR challenge? PMID- 27973989 TI - Prospective randomized controlled study on the effects of Saccharomyces boulardii CNCM I-745 and amoxicillin-clavulanate or the combination on the gut microbiota of healthy volunteers. AB - Probiotics are believed to be beneficial in maintaining a healthy gut microbiota whereas antibiotics are known to induce dysbiosis. This study aimed to examine the effects of the probiotic Saccharomyces boulardii CNCM I-745 (SB), the antibiotic Amoxicillin-Clavulanate (AC) and the combination on the microbiota and symptoms of healthy humans. Healthy subjects were randomized to one of 4 study groups: SB for 14 days, AC for 7 days, SB plus AC, Control (no treatment). Participants gave stool samples and completed gastro-intestinal symptom questionnaires. Microbiota changes in stool specimens were analyzed using 16s rRNA gene pyrosequencing (bTEFAP). Only one subject withdrew prematurely due to adverse events. Subjects treated by S boulardii + AC had fewer adverse events and tolerated the study regimen better than those receiving the AC alone. Control subjects had a stable microbiota throughout the study period. Significant microbiota changes were noted in the AC alone group during antibiotic treatment. AC associated changes included reduced prevalence of the genus Roseburia and increases in Escherichia, Parabacteroides, and Enterobacter. Microbiota alterations reverted toward baseline, but were not yet completely restored 2 weeks after antibiotherapy. No significant shifts in bacterial genera were noted in the SB alone group. Adding SB to AC led to less pronounced microbiota shifts including less overgrowth of Escherichia and to a reduction in antibiotic associated diarrhea scores. Antibiotic treatment is associated with marked microbiota changes with both reductions and increases in different genera. S. boulardii treatment can mitigate some antibiotic-induced microbiota changes (dysbiosis) and can also reduce antibiotic-associated diarrhea. PMID- 27973991 TI - Neonatal protection and preterm birth reduction following maternal group B streptococcus vaccination in a mouse model. AB - PURPOSE: Evaluate effects of maternal immunization in a mouse model of Group B Streptococcus (GBS) vaginal colonization using clinical isolates. MATERIALS AND METHODS: Female pregnant mice were immunized with heat-killed GBS 21 days before pregnancy and were inoculated intravaginally with GBS cultures (5 * 107 CFU twice a day for three days) from the 16th day of pregnancy. Gestation period and mice survival were monitored. Maternal anti-GBS IgG levels have been determined by ELISA analysis in vaccinated, unvaccinated mothers and newborns. RESULTS: Maternal immunization before pregnancy provided protection to newborns for three of the four GBS strains used. Evaluation of the immunogenicity showed that this vaccination induced higher levels of IgG in vaccinated compared to unvaccinated dams and the presence of antibodies in the offspring at embryonic and postnatal age, and a Th1 response and high levels of IgG2a subclass antibody and IFN-gamma were detected. A significant reduction of preterm births was observed in vaccinated mothers (p< 0.05). CONCLUSIONS: Our finding suggest that vaccinated mothers could protect their progeny from GBS infection and preterm birth through passive immunization. The proposed mouse model may represent a noninvasive and effective tool to investigate pathogenetic mechanisms of GBS ascending infection and for vaccine protection studies. PMID- 27973992 TI - Character-complexity effects in Chinese reading and visual search: A comparison and theoretical implications. AB - Three eye-movement experiments were conducted to examine how the complexity of characters in Chinese words (i.e., number of strokes per character) influences their processing and eye-movement behaviour. In Experiment 1, English speakers with no significant knowledge of Chinese searched for specific low-, medium-, and high-complexity target characters in a multi-page narrative containing characters of varying complexity (3-16 strokes). Fixation durations and skipping rates were influenced by the visual complexity of both the target characters and the characters being searched even though participants had no knowledge of Chinese. In Experiment 2, native Chinese speakers performed the same character-search task, and a similar pattern of results was observed. Finally, in Experiment 3, a second sample of native Chinese speakers read the same text used in Experiments 1 and 2, with text characters again exhibiting complexity effects. These results collectively suggest that character-complexity effects on eye movements may not be due to lexical processing per se but may instead reflect whatever visual processing is required to know whether or not a character corresponds to an episodically represented target. The theoretical implications of this for our understanding of normal reading are discussed. PMID- 27973993 TI - "Zombie" Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York. AB - BACKGROUND: New psychoactive substances constitute a growing and dynamic class of abused drugs in the United States. On July 12, 2016, a synthetic cannabinoid caused mass intoxication of 33 persons in one New York City neighborhood, in an event described in the popular press as a "zombie" outbreak because of the appearance of the intoxicated persons. METHODS: We obtained and tested serum, whole blood, and urine samples from 8 patients among the 18 who were transported to local hospitals; we also tested a sample of the herbal "incense" product "AK 47 24 Karat Gold," which was implicated in the outbreak. Samples were analyzed by means of liquid chromatography-quadrupole time-of-flight mass spectrometry. RESULTS: The synthetic cannabinoid methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3 carboxamido)-3-methylbutanoate (AMB-FUBINACA, also known as MMB-FUBINACA or FUB AMB) was identified in AK-47 24 Karat Gold at a mean (+/-SD) concentration of 16.0+/-3.9 mg per gram. The de-esterified acid metabolite was found in the serum or whole blood of all eight patients, with concentrations ranging from 77 to 636 ng per milliliter. CONCLUSIONS: The potency of the synthetic cannabinoid identified in these analyses is consistent with strong depressant effects that account for the "zombielike" behavior reported in this mass intoxication. AMB FUBINACA is an example of the emerging class of "ultrapotent" synthetic cannabinoids and poses a public health concern. Collaboration among clinical laboratory staff, health professionals, and law enforcement agencies facilitated the timely identification of the compound and allowed health authorities to take appropriate action. PMID- 27973996 TI - From the Journals. AB - THE DOCTOR-PATIENT RELATIONSHIP PREVENTING LEG ULCER RECURRENCE EVIDENCE-BASED PRACTICE IN BURN MANAGEMENT. PMID- 27973995 TI - Comparison between HPSEC-OCD and F-EEMs for assessing DBPs formation in water. AB - In this study, natural organic matter (NOM) in source water, as well as the treated water after coagulation with or without potassium permanganate (KMnO4) preoxidation, was characterized by using high performance size exclusion chromatography with organic carbon detector (HPSEC-OCD) and fluorescence excitation emission matrices (F-EEMs) with parallel factor (PARAFAC) analysis. Bulk parameters, such as dissolved organic carbon (DOC) and ultraviolet light absorbance at 254 nm (UV254), were also analyzed. The results show that KMnO4 preoxidation caused the breakdown of high molecular weight (MW) organics into low MW organics. All organics, whether those that existed in the source water or those generated by KMnO4 preoxidation, could be partly removed by coagulation. Combining the derived organic fractions obtained from HPSEC-OCD with peak-fitting and from F-EEMs with PARAFAC on the same sample, humic substances have been specified as the main organic composition. Further, the predictive models for trihalomethanes formation potential (THMFP) and haloacetic acids formation potential (HAAFP) based on organic fractions from HPSEC-OCD have higher accuracy than those based on the components from PARAFAC modeling. These models provide useful tools to specify the organic fractions from HPSEC-OCD and F-EEMs that constitute active precursors towards trihalomethanes (THMs) or haloacetic acids (HAAs) formation in water. Further, by knowing the major organic precursors, it would facilitate choosing the appropriate water treatment process for disinfection by-products (DBPs) control. PMID- 27973994 TI - Influence of static magnetic fields up to 700 mT and dihydrochalcones on the antioxidant response in fibroblasts. AB - The effects of a static magnetic field (SMF) and the dihydrochalcones phloretin and phloridzin on the redox homeostasis of fibroblasts were investigated. The aim of the present study was to determine the redox homeostasis of fibroblasts that were simultaneously exposed to a static magnetic field and the dihydrochalcones phloretin and phloridzin. The fibroblasts were cultured for 72 h in special magnetic test chambers at different moderate intensities (0.4, 0.55 and 0.7 T). In this report, the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione transferase (GST); the concentrations of malondialdehyde (MDA), adenosine triphosphate (ATP) and total antioxidant status were measured using commercially available kits. We did not observe any impairment in the redox balance in cells in fibroblasts that were only exposed to static magnetic fields of different intensities or In fibroblast cultured with dihydrochalcones and exposed to static magnetic field increase the SOD, GPx, GST activities and MDA concentration. Our investigations revealed that the activities of SOD, GPx, GST and the concentration of MDA that were determined for the fibroblasts that were cultured with dihydrochalcones were higher in the presence of a static magnetic field. Our results indicated that exposure to SMF (0.7 T) with dihydrochalcones induces oxidative stress in fibroblasts. PMID- 27973997 TI - Letters. AB - COMMUNITY GUIDELINES ON PRESSURE AREA CARE NECROTISING FASCIITIS INTERNET SOURCES MEPITEL: A 'STICKY' SUBJECT. PMID- 27973998 TI - Aetiologies and outcomes of wounds in an outpatient programme. AB - This study reviewed the records of all new patients seen in an outpatient wound care programme during a six-month period. Most of the 115 patients were referred by physicians in internal medicine or family practice (48%) or surgeons (39%); 101 had a wound (88%). Of the 92 who had their wound measured at the time of their first clinic visit, 72 (78%) had their largest wound located on a lower extremity and 40% of all lower extremity wounds were on the feet. Wounds were most frequently due to pressure (36%), venous insufficiency (16%), diabetic neuropathy (16%), or arterial insufficiency (1 3%). Within 12 months of their initial presentation, wound closure was documented in 35 of the 92 patients (38%). Of the four most common aetiologies, the healing rate was highest in wounds attributable to venous insufficiency (67%) (p < 0.02). PMID- 27974000 TI - Characteristics of Hospital Emergency Room Visits for Mental and Substance Use Disorders. AB - OBJECTIVE: This study compared characteristics of visits to emergency rooms (ERs) for mental and substance use disorders and for physical health conditions to establish a baseline against which to measure changes after full implementation of the Affordable Care Act (ACA) and parity legislation. METHODS: The retrospective, cross-sectional analysis fit a logistic regression model to pooled data comprising 193,526 observations from National Hospital Ambulatory Medical Care Survey (NHAMCS) data from 2005 to 2011. RESULTS: ER visits for mental or substance use disorders increased from 27.9 per 1,000 ER visits in 2005 to 35.1 in 2011. Homeless persons and nursing home residents had the highest rates of such visits-173.7 and 95.2 per 1,000 ER visits, respectively, in 2011. CONCLUSIONS: Understanding differences in profiles of ER visits on the basis of the reason for the visit can inform the design of more cost-effective policies to guide ER intake, after further implementation of the ACA and parity legislation. PMID- 27973999 TI - OnTrackNY: The Development of a Coordinated Specialty Care Program for Individuals Experiencing Early Psychosis. AB - OnTrackNY is a coordinated specialty care program that delivers early intervention services to youths experiencing a first episode of nonaffective psychosis. Treatment aims to help individuals improve their mental health and achieve personal goals related to work, school, and social relationships. This column describes OnTrackNY's progression from a research project to real-world implementation. The authors describe the treatment model, approach to training and dissemination, and procedures for collecting and sharing data with OnTrackNY teams and provide data on client characteristics and selected outcomes. PMID- 27974001 TI - Technology in Mental Health: Creating New Knowledge and Inventing the Future of Services. AB - The mental health services now in place are intrinsically linked with the technology that has been at our disposal for decades of research and practice. Advancements in Web, mobile, sensor, and informatics technology can do more than serve as tools to enhance existing models of care. Novel technologies can help us better understand the very nature of mental illness and revise our fundamental assumptions about the structure, boundaries, and modalities of mental health treatment. Recognizing the unprecedented opportunities new technology offers to improve the outcomes of people with mental illness, Psychiatric Services announces a new column on technology and mental health. PMID- 27974002 TI - Psychological Distress and Rates of Health Insurance Coverage and Use and Affordability of Mental Health Services, 2013-2014. AB - OBJECTIVE: The study compared changes in rates of health insurance coverage, utilization and affordability of mental health services, and reported satisfaction with health coverage between 2013 and 2014 for people in moderate and severe psychological distress with people in no or low psychological distress. METHODS: A nationally representative data set restricted to participants ages 26 to 65 (N=35,602) was used. Changes in outcome measures were calculated by using linear regression adjusted for the complex survey design. RESULTS: Relative to individuals with no or low levels of psychological distress, individuals with moderate distress showed gains on selected outcome measures, and they experienced net improvements on several measures. Individuals with severe psychological distress showed fewer net improvements and no relative improvements compared with individuals with no or low levels of psychological distress, although they reported net increases in subjective satisfaction with health care. CONCLUSIONS: Between 2013 and 2014, selected health care outcomes improved for individuals in moderate psychological distress but not for individuals in severe distress. PMID- 27974003 TI - The Mental Health Parity and Addiction Equity Act (MHPAEA) Evaluation Study: Impact on Quantitative Treatment Limits. AB - OBJECTIVE: The Mental Health Parity and Addiction Equity Act (MHPAEA) significantly changed regulations governing behavioral health benefits for large, commercially insured employers. Pre-MHPAEA, many plans covered only a specific number of behavioral health treatment days or visits; post-MHPAEA, such quantitative treatment limits (QTLs) were allowed only if they were "at parity" with medical-surgical limits. This study assessed MHPAEA's effect on the prevalence of behavioral health QTLs. METHODS: Analyses used 2008-2013 specialty behavioral health benefit design data for Optum large-group plans, both carve outs (N=2,257 plan-years, corresponding to 1,527 plans and 40 employers) and carve-ins (N=11,644 plan-years, 3,569 plans, and 340 employers). Descriptive statistics were calculated for limits existing at parity implementation, distinguished by accumulation period (annual or lifetime), level of care (inpatient, intermediate, or outpatient), unit (days, visits, or courses), condition, and network level. Proportions of plans using specific limits during the preparity (2008-2009), transition (2010), and postparity (2011-2013) periods were compared with Fisher's exact tests. RESULTS: Preparity, the most common QTLs were annual visit or day limits. Accounting for overlap in limit types, 89% of regular carve-out plans, 90% of in-network-only carve-outs, and 77% of carve-in plans limited outpatient visits; 66% of regular carve-out plans, 74% of in network-only carve-outs, and 73% of carve-ins limited inpatient or intermediate days. Postparity, QTLs almost entirely disappeared (p<.001). CONCLUSIONS: Before MHPAEA, QTLs were common. Postimplementation, virtually all plans dropped such limits, suggesting that MHPAEA was effective at eliminating QTLs. However, increasing access to behavioral health care will mean going beyond such QTL changes and looking at other areas of benefit management. PMID- 27974004 TI - Barriers to Integrating Mental Health Services in Community-Based Primary Care Settings in Mexico City: A Qualitative Analysis. AB - OBJECTIVE: Despite the high prevalence of mental disorders in Mexico, minimal mental health services are available and there are large gaps in mental health treatment. Community-based primary care settings are often the first contact between patients and the health system and thus could serve as important settings for assessing and treating mental disorders. However, no formal assessment has been undertaken regarding the feasibility of implementing these services in Mexico. Before tools are developed to undertake such an assessment, a more nuanced understanding of the microprocesses affecting mental health service delivery must be acquired. METHODS: A qualitative study used semistructured interviews to gather information from 25 staff in 19 community-based primary care clinics in Mexico City. Semistructured interviews were analyzed by using the meaning categorization method. In a second phase of coding, emerging themes were compared with an established typology of barriers to health care access. RESULTS: Primary care staff reported a number of significant barriers to implementing mental health services in primary care clinics, an already fragile and underfunded system. Barriers included the following broad thematic categories: service issues, language and cultural issues, care recipient characteristics, and issues with lack of knowledge. CONCLUSIONS: Results indicate that the implementation of mental health services in primary care clinics in Mexico will be difficult. However, the information in this study can help inform the integration of mental health into community-based primary care in Mexico through the development of adequate evaluative tools to assess the feasibility and progress of integrating these services. PMID- 27974005 TI - Carrots and Sticks on Opposite Sides of the Atlantic: Integration Incentives for People With Serious Mental Illness in England. AB - Integrating care pathways between primary and specialist mental health care is seen as integral to improving the health of people with mental illness. Multiple integration initiatives have been implemented, but few have tried to integrate care for people with serious mental illness. This column describes two such initiatives in the United States and in England. The two schemes are compared according to the population they target, payment mechanisms, accountability structures, service delivery, outcomes, and lessons learned. PMID- 27974006 TI - Safety and effectiveness of therapeutic magnetic resonance in diabetic foot ulcers: a prospective randomised controlled trial. AB - OBJECTIVE: To test the efficacy and safety of therapeutic magnetic resonance (TMR) in the management of diabetic foot ulcers (DFU), the authors designed a prospective randomised controlled trial in three highly specialised diabetic foot clinics. METHOD: All the patients consecutively visited in a period of 18 months were screened according to the inclusion (presence of an ulcer >1 cm2 in the foot lasting at least 6 weeks; ABPI>0.6; consent to participate in the study) and exclusion (Charcot's foot; local or systemic infections; chronic renal failure; any wearable electrically-driven life-supporting device) criteria. Patients, who were treated according to international guideline protocols, were randomised into two groups: group A received for four weeks the sham application of TMR, while group B received the active TMR for the same period. People were followed-up to 10 weeks and healing rate (HR), healing time (HT), rate of granulation tissue on wound bed (% GT), reduction of the area of the lesion (?AL) and a score (0-3) evaluating erythema, oedema, pain and tenderness, respectively, were measured. Adverse events (AE) were registered and monitored throughout the study. RESULTS: No differences were observed in HR, HT and ?AL between the two groups during follow-up, while % GT and the scores for erythema, oedema and pain at 10 weeks showed significant (p<0.05) improvements in group B compared with group A and versus baseline. When restricted to non-ischaemic patients (ABPI>0.8), ?AL was significantly (p<0.05) more pronounced in group B than in group A. No difference in AE occurrence was observed between the two groups. CONCLUSION: Our study, despite not being able to demonstrate the effectiveness of TMR on healing rate at 10 weeks, with 4 weeks of active treatment in neuro-ischaemic DFUs, shows positive effects on clinical aspects of the DFU and is associated with a significant increase of GT in the wound bed. DECLARATION OF INTEREST: The study has been fully sponsored by Thereson S.p.A., manufacturer of TMR devices. PMID- 27974007 TI - Impact of optimal anticoagulation therapy on chronic venous ulcer healing in thrombophilic patients with post-thrombotic syndrome. AB - OBJECTIVE: Post-thrombotic syndrome (PTS) is the long-term sequelae of deep venous thrombosis (DVT). PTS clinical manifestations include chronic leg pain, oedema, lipodermatosclerosis and ulcers. The objective of this study is to determine in patients with documented history of thrombophilias and DVT whether the number of previous thrombotic events and optimal anticoagulation therapy are associated with the time to venous ulcer healing following the start of compression therapy. METHOD: Retrospective analysis performed in thrombophilic patients under the age of 50 years old with chronic venous ulcers secondary to DVT at the wound clinic in the National Institute of Medical Sciences and Nutrition 'Salvador Zubiran ' in Mexico City. Variables such as the number or episodes of thrombotic events, type of hypercoagulable disorder, optimal anticoagulation therapy with Warfarin monitored by therapeutic International Normalised Ratio (INR) (2-3) and compliance to compression therapy were examined. Patients that underwent superficial or perforator vein interruption or endovascular recanalisation of deep veins were excluded from the study. RESULTS: From a database of 29 patients with chronic venous ulcers followed in our clinic from January 1992 to September 2012, only 13 patients (61% female) met the inclusion criteria. Mean age+/-standard deviation (SD) was 32+/-12 years old. Of these, seven (54%) patients with suboptimal INR presented with an average of two previous thrombotic events and the remaining six (46%) patients with optimal INR only one event (p=0.28), the mean time to the clinical manifestation of a venous ulcer after the first episode of DVT was 39 months (range: 12-72) for patients with suboptimal INR and 82 months (range: 12-216) for those with optimal anticoagulation therapy (p=0.11). During the mean follow-up period of 52 months, all patients in optimal anticoagulation healed their ulcer; their mean time for wound healing was 44 months (range: 4-102). In the suboptimal INR group, only four healed the ulcers with an mean of 72 months (range: 2-204) (p=0.94). CONCLUSION: There seems to be an association between an optimal anticoagulation therapy with Warfarin monitored by INR and wound healing rates in thrombophilic patients with chronic venous ulcers. Further research is warranted. DECLARATION OF INTEREST: The authors have no conflict of interest. PMID- 27974009 TI - Therapeutic effectiveness of a Calendula officinalis extract in venous leg ulcer healing. AB - OBJECTIVE: Non-healing venous leg ulcers (VLUs) have a significant effect on patients' quality of life and substantially increase expenditures in health-care systems. The aim of this study was to evaluate the clinical efficacy of the Calendula officinalis extract, Plenusdermax, in the treatment of VLUs. METHOD: Patients treated with Calendula officinalis extract (n=38) and control patients (n=19) were evaluated every two weeks for 30 weeks or until their ulcers healed. Assessments included determination of the wound area by planimetry, infection control, and evaluation of the clinical aspects of the wounds. The percentage of healing velocity per week (%HVw), taking the initial area at baseline into account, was also determined. RESULTS: The proportion of the treatment patients achieving complete epithelialisation was 72 % and 32 % in the treatment and control groups, respectively. The average healing time was approximately 12 weeks in the treatment group and 25 % in control patients. Patients with ulcers treated with Calendula officinalis extract had a significant 4-fold increase in percentage healing velocity per week, 7.4 %, compared with 1.7 % in the control group. No adverse events were observed during the Calendula officinalis extract treatment. CONCLUSION: Our findings indicate that Calendula officinalis extract is an effective treatment for VLUs. DECLARATION OF INTEREST: The authors have no conflict of interest. PMID- 27974008 TI - A novel native collagen dressing with advantageous properties to promote physiological wound healing. AB - OBJECTIVE: Chronic hard-to-heal wounds generate high costs and resource use in western health systems and are the focus of intense efforts to improve healing outcomes. Here, we introduce a novel native collagen (90 %):alginate (10 %) wound dressing and compare it with the established oxidised dressings Method: Matrices were analysed by atomic force microscopy (AMF), scanning electron microscopy (SEM), and immunoelectron microscopy for collagen types I, III and V. Viability assays were performed with NIH-3T3 fibroblasts. Matrix metalloproteinase (MMP) binding was analysed, and the effect of the wound dressings on platelet-derived growth factor B homodimer (PDGF-BB) was investigated. RESULTS: Unlike oxidised regenerated cellulose (ORC)/collagen matrix and ovine forestomach matrix (OFM), the three-dimensional structure of the native collagen matrix (NCM) was found to be analogous to intact, native, dermal collagen. Fibroblasts seeded on the NCM showed exponential growth whereas in ORC/collagen matrix or OFM, very low rates of proliferation were observed after 7 days. MMP sequestration was effective and significant in the NCM. In addition, the NCM was able to significantly stabilise PDGF-BB in vitro. CONCLUSION: We hypothesise that the observed microstructure of the NCM allows for an effective binding of MMPs and a stabilisation and protection of growth factors and also promotes the ingrowth of dermal fibroblasts, potentially supporting the re commencement of healing in previously recalcitrant wounds. DECLARATION OF INTEREST: This work was supported by BSN Medical, Hamburg, Germany. PMID- 27974010 TI - Outcomes of acute dermal irritation and sensitisation tests on active dressings for chronic wounds: a comparative study. AB - OBJECTIVE: Chronic, non-healing ulcers are a significant problem in clinical practice. The numerous complications, associated with toxicological and allergic reactions, caused by certain compounds in active dressings have been reported. The aim of this study was to evaluate the local skin tolerance of active dressings and determine which of them carries a risk of causing local skin reactions. METHOD: We tested six active dressings from different categories (hydrogel dressing, chitosan sponge dressing, silver nanoparticles dressing, dry flax fibres dressing alone and coated with linfix or oilfix) for acute irritation in rabbits and for sensitisation in guinea pigs. RESULTS: Only the dry flax fibre dressing showed no irritant and sensitisation effects. The remaining dressings obtained Cumulative Irritation Index from 0.00-0.35 and evoked sensitisation reaction in up to 20 % animals, which according to skin reaction category puts them in the non-to mildly-irritating and sensitising products group. CONCLUSION: Based on the findings, it should be considered that although analysed dressings do not present a serious risk of allergic reactions in humans, only the dry flax fibre dressing can be perceived as having negligible risk. Declaration of interest The authors have no conflict of interests. PMID- 27974011 TI - Use of anteromedial thigh perforator flap and immunological implications of Gorlin-Goltz syndrome: a case study. AB - Gorlin-Goltz syndrome is mainly characterised by the development of numerous multicentric and relapsing cutaneous basal cell carcinomas (BCCs). A major problem for patients with Gorlin-Goltz syndrome is the large amount of BCCs that can invade the deep underlying structures, especially the face. Here, we describe the case of a 23-year-old male affected by Gorlin-Goltz syndrome. He had recurrent BCCs on a hairless scalp and dorsum since he was 17 years old and underwent four surgical procedures to excise BCCs, including a reconstruction with anteromedial thigh perforator flap. For each of the surgical procedures, a phenotypic study on peripheral blood mononuclear cells using flow cytometry was performed on the same day of surgery, and on days 7, 14 and 21 after surgery. The role of the tumour-specific cytolytic immune response as a potential future treatment of syndromic BCCs and its trend in relation to surgical ablation of large portions of tumour tissue was examined, and the cosmetic and therapeutic results are shown. PMID- 27974012 TI - Reduction of pressure ulcer size with high-voltage pulsed current and high frequency ultrasound: a randomised trial. AB - OBJECTIVE: International guidelines recommend the use of ultrasound (US) and electrical stimulation (ES) for treating chronic and recurrent pressure ulcers (PUs). The methodology of these procedures, however, still needs elaboration and confirmation by clinical studies. This parallel-group, randomised, single-blind, prospective, controlled clinical trial was conducted to determine whether by using high-frequency ultrasound (HFUS) and high-voltage monophasic pulsed current (HVMPC), the rate of change in the area of older patients' PUs can be accelerated. METHOD: Patients were randomly assigned to receive either: standard wound care (SWC) involving supportive care and topical treatments; SWC+US (1MHz; 0.5 W/cm2; 20%; 1-3 minutes/cm2); or SWC+ES (HVMPC, 154 us, 100 pps, 100 V, 250 uC/sec, 50 minutes/day). US and ES were administered once a day, 5 days a week. The primary outcome was change in PU surface area measured against baseline after 6 weeks of treatment with SWC, SWC+US, and SWC+ES. RESULTS: We recruited 77 patients, aged 60-95 years (80% aged over 70 years of age), with 88 Category II, III and IV PUs were enrolled in the study. The percentage reduction in the surface area of PUs at the end of treatment was significantly greater in the SWC+US group (mean +/- standard deviation, 77.48+/-11.59 %; p=0.024) and the SWC+ES group (76.19+/-32.83%; p=0.030) versus the control group (48.97+/-53.42%). The SWC+ES group also had a significantly greater proportion of PUs that decreased in area by at least 50% or closed than the control group (p=0.05 and 0.031, respectively). The SWC+US and SWC+ES groups were not statistically significant different regarding treatment results. Clinical side effects were not recorded. CONCLUSION: The results show that HFUS and HVMPC are comparable regarding their effectiveness in reducing the size of PUs in older people. DECLARATION OF INTEREST: The authors have nothing to disclose. All research activities were funded by the Academy of Physical Education, Katowice, Poland. PMID- 27974013 TI - A narrative review of microbial biofilm in postoperative surgical site infections: clinical presentation and treatment. AB - OBJECTIVE: The global impact of surgical site infections (SSIs) on health-care systems is considerable: many are related to the formation of a microbial biofilm. Biofilm plays a significant role in the pathogenesis of implantable device-related infections and are also important in persistent postoperative skin and soft tissue wound infections. METHOD: PubMed and OVID databases were searched for relevant articles regarding biofilm-associated infection in surgery, including epidemiology, diagnosis, treatment and management. RESULTS: Biofilm associated infections increase the use of health-care resources, prolong length of stay, increase cost of antibiotic therapy, result in additional surgical revisions and extend rehabilitation after discharge from health care. Staphylococcus aureus and Staphylococcus epidermidis are the most common isolates recovered from device-related infections. Early infection occurs within two weeks of implantation and is associated with intraoperative wound contamination; late onset infections are often occult prolonging recognition by weeks, months and in some cases, years. Biofilm is a physical barrier against antibodies and granulocytic cell populations which may also impede the penetration of antibiotics. The ideal strategy for preventing biofilm-associated SSI is to prevent intraoperative contamination through compliance with effective surgical care bundles. Management of postoperative biofilm-associated infections involves surgical debridement followed by irrigation with antimicrobial agents and removal of infected devices, followed by insertion of antimicrobial adjuncts such as antimicrobial spacers, beads or sutures together with selective therapeutic agents that penetrate the mature biofilm. CONCLUSION: Biofilm-associated infections are a significant source of postoperative morbidity and mortality. Appropriate interventional strategies are warranted to reduce the risk of intraoperative contamination. DECLARATION OF INTEREST: The authors have no conflicts. PMID- 27974015 TI - Improving skin care through data: a pitch for patient safety incident reporting. PMID- 27974014 TI - Treatment of multiple wounds of aplasia cutis congenita on the lower limb: a case report. AB - INTRODUCTION: Aplasia cutis congenita (ACC) is a rare congenital disease, characterised by absence of skin, that can affect different parts of the body. ACC is more frequent on the scalp, but can involve limbs, with partial-or total thickness loss of skin, with a functional impairment of the joint affected. There is no clear indication for surgical or conservative treatment, therefore, it would be helpful to find scientific support for the optimal treatment strategies. CLINICAL PRESENTATION: We present a case of a newborn female, with six wounds on the inferior limbs, treated with conservative therapy. To prevent infection and promote healing, the defects were kept moist and covered with non adherent/antimicrobical dressings. Complete wound healing occurred in eight weeks. The duration of follow-up was three years. RESULTS: In this kind of ACC with superficial partial-thickness wounds of the lower limbs, conservative treatment was successful. The same conservative treatment can be proposed for larger or deeper wounds of lower limbs with no involvement of underlying structures, with delayed scar excision after the complete growth of the patient. ACC scar excision could require complex tissue rearrangement, tissue expansion, or skin grafting. CONCLUSION: In the evaluation for treatment of ACC of inferior limbs, even in cases of total-thickness skin loss, even on joints, the conservative approach could be considered as the first choice. DECLARATION OF INTEREST: None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript. PMID- 27974016 TI - Dealing with disclosure: Perspectives from HIV-positive children and their older carers living in rural south-western Uganda. AB - There are limited data on the challenges faced by carers, in particular older carers, in managing the difficult task of status disclosure for HIV-positive children. We report findings from qualitative interviews with 18 care dyads of older people and HIV-positive children living in rural south-western Uganda. Our data provide insights into perceptions and norms influencing communication during and following disclosure among both carers and children, including those shaped by gendered expectations of girls' and boys' sexual behaviour. Young participants reported several advantages of knowing their status and showed considerable resilience in the face of HIV disclosure. Better and more support is needed to help health workers and carers (particularly older carers) manage cross generational communication around HIV disclosure and other related aspects of sexual and reproductive health as critical aspects of children's psychosocial development and well-being. PMID- 27974018 TI - Risky sexual behaviour among women: Does economic empowerment matter? Case of Gabon, Mozambique, Sierra-Leone and Zambia. AB - The link between economic empowerment and high risky sexual behaviour has been debated by different scholars in various settings. However, no consistently clear connection between poverty and lack of education has been found regarding engagement in risky sexual behaviour. Also, not much research has been done to examine the strength of these relationships for adolescents and women. The objectives of this study were to assess the relationship between female economic empowerment and risky sexual behaviour in Africa. Using the latest Demographic and Health Surveys Data (DHS 2011-2014) from Gabon, Mozambique, Sierra Leone and Zambia, univariate, bivariate and multivariate analysis was done on women aged 15 to 49 to examine the patterns of and differences in the association between women's economic empowerment and risky sexual behaviour. The findings both at community and individual level indicate that empowered women (higher education and wealth household) and adolescents aged 15 to 19 are highly significantly associated with engagement in high risky behaviour. The result of this study stresses the need to look further than individual factors in the quest to resolve risky sexual behaviour in Africa. The interrelations between female economic empowerment and engagement in risky sexual behaviour are more complicated and less straightforward than usually presumed. PMID- 27974019 TI - Advancing gender equality to improve HIV prevention: A study of practice. AB - Addressing gender inequality as a social driver of HIV risk and vulnerability has become a key activity of non-governmental organisations (NGOs) in South Africa. This paper sheds light on the environmental factors that influence gender and HIV activities in this context. A multisite ethnographic study including 150 hours of participant observation and 32 in-depth interviews was conducted with 26 NGOs carrying out gender and HIV prevention interventions. Using thematic network analysis, 108 different intervention activities were identified, categorised and further analysed to explore environmental factors that influence the design and delivery of these activities. The findings highlight how practitioners draw on different theories of change about how to address the gender inequalities that contribute to HIV risk and vulnerability, which in turn influence the way interventions are delivered. Despite these theoretical differences, commonalities arise in practitioners' use of popular narratives about the right to health and lived experiences of AIDS to ensure interventions are contextually relevant and to gain buy-in from participants. Other environmental factors influencing intervention activities include the role that insecure funding for gender plays in undermining the capacity of practitioners to design interventions based on their local knowledge and experience by forcing NGOs to adapt to the priorities of international donors. PMID- 27974017 TI - HIV care and treatment experiences among female sex workers living with HIV in sub-Saharan Africa: A systematic review. AB - Female sex workers (FSW) living with HIV in sub-Saharan Africa have poor engagement to HIV care and treatment. Understanding the HIV care and treatment engagement experiences of FSW has important implications for interventions to enhance care and treatment outcomes. We conducted a systematic review to examine the HIV care experiences and determinants of linkage and retention in care, antiretroviral therapy (ART) initiation, and ART adherence and viral suppression among FSW living with HIV in sub-Saharan Africa. The databases PubMed, Embase, Web of Science, SCOPUS, CINAHL, Global Health, Psycinfo, Sociological Abstracts, and Popline were searched for variations of search terms related to sex work and HIV care and treatment among sub-Saharan African populations. Ten peer-reviewed articles published between January 2000 and August 2015 met inclusion criteria and were included in this review. Despite expanded ART access, FSW in sub-Saharan Africa have sub-optimal HIV care and treatment engagement outcomes. Stigma, discrimination, poor nutrition, food insecurity, and substance use were commonly reported and associated with poor linkage to care, retention in care, and ART initiation. Included studies suggest that interventions with FSW should focus on multilevel barriers to engagement in HIV care and treatment and explore the involvement of social support from intimate male partners. Our results emphasise several critical points of intervention for FSW living with HIV, which are urgently needed to enhance linkage to HIV care, retention in care, and treatment initiation, particularly where the HIV prevalence among FSW is greatest. PMID- 27974020 TI - AIDS at 35: A midlife crisis. PMID- 27974021 TI - Experiences of alcohol consumption and taking antiretroviral medication among men living with HIV in Tshwane, South Africa. AB - Hazardous alcohol consumption may compromise optimal antiretroviral therapy (ART) adherence among patients. Adoption of hegemonic notions of masculinity may encourage health-risk behaviours, such as alcohol consumption, and discourage health-enhancing behaviours, such as ART adherence among men. This study aimed to explore linkages between masculinity, alcohol consumption, and taking ART medication among male ART recipients in South Africa. Male facilitators conducted five focus group discussions with 27 black male ART recipients aged between 28 and 65 years at five ART clinics. Eligibility criteria were: 18 years or older, at least three months on ART, and alcohol consumption in the past three months. Data were analysed inductively using thematic content analysis. The men demonstrated a masculinity that fostered commitment to taking ART. However, normative notions of masculinity in the men's social circles often compromised their timeous taking of medication. Fears of alcohol-ART interactions often led to intentional non-adherence to ART when drinking. Finally, healthcare provider patient power dynamics seemed to prevent the men from discussing their challenges regarding alcohol use and ART adherence with their healthcare providers. Interventions that focus on addressing harmful hegemonic notions of masculinity among men are needed in community settings such as drinking establishments where men tend to socialise. Patient-centred approaches which enhance men's sense of involvement in their treatment are needed in healthcare settings. PMID- 27974022 TI - Integrated intervention for mental health co-morbidity in HIV-positive individuals: A public health assessment. AB - In South Africa, where it is estimated that more people have HIV than anywhere else in the world, HIV/AIDS and psychological disorder co-morbidity have been shown both to exacerbate the late diagnosis and treatment of psychological disorders and to affect adherence to ARVs. Targeted, affordable and evidence based strategies to reach these populations are essential. Against this backdrop, a pilot project and situational assessment aimed at determining the context of psychological care and HIV treatment services in South Africa was undertaken. The situational analysis consisted of individual interviews, a patient survey, and a retrospective medical record data review. Training and mentorship were conducted from 2011 to 2013 by the Foundation for Professional Development (FPD) in five anti-retroviral therapy (ART) clinics in the Tshwane-Metsweding area. Data were both descriptively and inferentially analysed. Outcomes indicate that the general structure of HIV services is well organised and well run in the sampled clinics. However, mental healthcare and HIV services need to be integrated further. There is also a need to develop and pilot-test appropriate materials and models for the delivery of mental healthcare within the parameters of affordability, acceptability and availability further, and to advocate the advancement of mental health and HIV treatment and policy integration. PMID- 27974023 TI - Ensuring an optimal environment for peer education in South African schools: Goals, systems, standards and policy options for effective learning. AB - Peer education has long been seen as a key health promotion strategy and an important tool in preventing HIV infection. In South African schools, it is currently one of the strategies employed to do so. Based on both a recent research study of peer education across 35 schools and drawing on multiple previous studies in South Africa, this paper examines the key elements of peer education that contribute to its effectiveness and asks how this aligns with current educational and health policies. From this research, it summarises and proposes shared goals and aims, minimum standards of implementation and reflects on the necessary infrastructure required for peer education to be effective. In light of these findings, it offers policy recommendations regarding who should be doing peer education and the status peer education should have in a school's formal programme. PMID- 27974024 TI - The intersection of antiretroviral therapy, peer support programmes, and economic empowerment with HIV stigma among HIV-positive women in West Nile Uganda. AB - HIV stigma remains a major problem of the AIDS epidemic in sub-Saharan Africa. Women fear impending social stigma including blame, isolation and abuse. HIV infection and HIV stigma interact cyclically, creating and reinforcing economic and social exclusion for individuals living with HIV. Evidence suggests that interventions for people living with HIV infection that include, in combination, antiretroviral therapy (ART), peer support and economic empowerment are likely to be more effective than if used alone. We report a qualitative study in West Nile Uganda that explored perceptions of HIV stigma among fifty-four HIV-positive women who had similar access to ART and HIV peer support programmes, but varying levels of participation (full-time, intermittent, none) in economic empowerment programmes. Our study found that access to ART, peer support groups, and economic empowerment programmes helped to curb perceptions of deep-seated HIV stigma for participants. More expressions of usefulness, hope and psychological well-being prevailed with participants who had increased participation in economic empowerment programmes. Our findings underscore the value of HIV outreach programmes which combine ART, peer support and economic empowerment to alleviate HIV stigma. Further research to quantify the interaction of these factors is warranted. PMID- 27974025 TI - The relationship between HIV and AIDS and water scarcity in Nyamakate resettlements land, north-central Zimbabwe. AB - HIV and AIDS and water variability have been studied separately, yet, they impact on rural households simultaneously in an interactive manner. The study provide narratives on various realities from a study in the Nyamakate community that illustrates the dialectical relationship between HIV and AIDS and water scarcity. A qualitative research methodology was employed, and the following data collection tools were used: semi-structured interviews, focus group discussions (FGDs) and participant observations. The study showed that in the Nyamakate area, HIV- and AIDS-affected households utilise more water if there is a bedridden patient. Such households utilise an average of 145 litres per day and reported a water shortage of 103 litres per day. Although community rules and customs stipulate that water should be accessible to everyone, exclusion of HIV- and AIDS affected households is underlined by cultural issues, scorn at poor levels of hygiene, infectious opportunistic infections and labour shortage, which limited access to water points by households directly affected by HIV and AIDS. In cases where women were overwhelmed with caregiving roles, men fetch water. We conclude that HIV and AIDS and water scarcity are dialectically related and hence should be considered in an interactive manner in order to understand the challenges faced by affected households. PMID- 27974026 TI - NIH Policy on Single-IRB Review - A New Era in Multicenter Studies. PMID- 27974027 TI - Dietary Sodium and Cardiovascular Disease Risk. PMID- 27974028 TI - Dietary Sodium and Cardiovascular Disease Risk. PMID- 27974029 TI - Betrixaban in Acutely Ill Medical Patients. PMID- 27974030 TI - Betrixaban in Acutely Ill Medical Patients. PMID- 27974031 TI - Craniectomy for Traumatic Intracranial Hypertension. PMID- 27974032 TI - Craniectomy for Traumatic Intracranial Hypertension. PMID- 27974033 TI - Patellar Fracture with Sleeve Avulsion. PMID- 27974034 TI - Smoking and Mortality - Beyond Established Causes. PMID- 27974035 TI - Breakthroughs for Whom? Global Diabetes Care and Equitable Design. PMID- 27974036 TI - Nitrates in Heart Failure with Preserved Ejection Fraction. PMID- 27974037 TI - Case 38-2016. A 52-Year-Old Woman with Recurrent Oligodendroglioma. PMID- 27974038 TI - African Trypanosomiasis. PMID- 27974040 TI - The Human Intestinal Microbiome in Health and Disease. PMID- 27974039 TI - Transforming Evidence Generation to Support Health and Health Care Decisions. PMID- 27974041 TI - Multiple Variants of Klebsiella pneumoniae Producing Carbapenemase in One Patient. PMID- 27974042 TI - Designing and construction of simulated constructed wetland for treatment of sewage containing metals. AB - A simulated horizontal flow constructed wetland (CW) has been designed with gravel medium and aquatic plants Typha latifolia and Polygonum hydropiper to assess its performance efficiency for sewage treatment. Monitoring of fully developed CW revealed a high removal of nutrients and metals from sewage after treatment at varying retention times. The percent (%) removal of biological oxygen demand, total dissolved solids, total suspended solids, PO4-P and total nitrogen in CW planted with T. latifolia were 88.20, 61.9, 72.12, 74.23 and 66.78%; however, with P. hydropiper, reductions were 79.47, 53.47, 55.46, 60.40 and 52.87%, respectively, at 8 d retention time. In addition, T. latifolia and P. hydropiper accumulated substantial amount of metals in their tissues particularly in roots. T. latifolia root accumulated maximum amount of Zn (40.44 ug/g dw) followed by Cu (39.24 ug/g dw), Pb (37.78 ug/g dw) and Cr (19.95 ug/g dw) as compared to P. hydropiper, which was 17.85, 33.43, 36.19 and 9.67 ug/g dw, respectively. Further, plant-specific high translocation factor (>1) of metals were observed at different retention times. Results suggest that simulated CW may be applied as an ecofriendly and low-cost tool to treat sewage before discharge into a fresh water body. PMID- 27974043 TI - Airplane pilot mental health and suicidal thoughts: a cross-sectional descriptive study via anonymous web-based survey. AB - BACKGROUND: The Germanwings Flight 9525 crash has brought the sensitive subject of airline pilot mental health to the forefront in aviation. Globally, 350 million people suffer from depression-a common mental disorder. This study provides further information on this important topic regarding mental health especially among female airline pilots. This is the first study to describe airline pilot mental health-with a focus on depression and suicidal thoughts outside of the information derived from aircraft accident investigations, regulated health examinations, or identifiable self-reports, which are records protected by civil aviation authorities and airline companies. METHODS: This is a descriptive cross-sectional study via an anonymous web-based survey administered between April and December 2015. Pilots were recruited from unions, airline companies, and airports via convenience sampling. Data analysis included calculating absolute number and prevalence of health characteristics and depression scores. RESULTS: One thousand eight hundred thirty seven (52.7%) of the 3485 surveyed pilots completed the survey, with 1866 (53.5%) completing at least half of the survey. 233 (12.6%) of 1848 airline pilots responding to the Patient Health Questionnaire 9 (PHQ-9), and 193 (13.5%) of 1430 pilots who reported working as an airline pilot in the last seven days at time of survey, met depression threshold-PHQ-9 total score >= 10. Seventy-five participants (4.1%) reported having suicidal thoughts within the past two weeks. We found a significant trend in proportions of depression at higher levels of use of sleep aid medication (trend test z = 6.74, p < 0.001) and among those experiencing sexual harassment (z = 3.18, p = 0.001) or verbal harassment (z = 6.13, p < 0.001). CONCLUSION: Hundreds of pilots currently flying are managing depressive symptoms perhaps without the possibility of treatment due to the fear of negative career impacts. This study found 233 (12.6%) airline pilots meeting depression threshold and 75 (4.1%) pilots reporting having suicidal thoughts. Although results have limited generalizability, there are a significant number of active pilots suffering from depressive symptoms. We recommend airline organizations increase support for preventative mental health treatment. Future research will evaluate additional risk factors of depression such as sleep and circadian rhythm disturbances. PMID- 27974044 TI - Effects of protonation on the hydrolysis of triphosphate in vacuum and the implications for catalysis by nucleotide hydrolyzing enzymes. AB - BACKGROUND: Nucleoside triphosphate (NTP) hydrolysis is a key reaction in biology. It involves breaking two very stable bonds (one P-O bond and one O-H bond of water), in either a concurrent or a sequential way. Here, we systematically examine how protonation of the triphosphate affects the mechanism of hydrolysis. RESULTS: The hydrolysis reaction of methyl triphosphate in vacuum is computed with protons in various numbers and position on the three phosphate groups. Protonation is seen to have a strong catalytic effect, with the reaction mechanism depending highly on the protonation pattern. CONCLUSION: This dependence is apparently complicated, but is shown to obey a well-defined set of rules: Protonation of the alpha- and beta-phosphate groups favors a sequential hydrolysis mechanism, whereas gamma-protonation favors a concurrent mechanism, the two effects competing with each other in cases of simultaneous protonation. The rate-limiting step is always the breakup of the water molecule while it attacks the gamma-phosphorus, and its barrier is lowered by gamma-protonation. This step has significantly lower barriers in the sequential reactions, because the dissociated gamma-metaphosphate intermediate (PgammaO3-) is a much better target for water attack than the un-dissociated gamma-phosphate (-PgammaO42-). The simple chemical logic behind these rules helps to better understand the catalytic strategy used by NTPase enzymes, as illustrated here for the catalytic pocket of myosin. A set of rules was determined that describes how protonating the phosphate groups affects the hydrolysis mechanism of methyl triphosphate: Protonation of the alpha- and/or beta- phosphate groups promotes a sequential mechanism in which P-O bond breaking precedes the breakup of the attacking water, whereas protonation of the gamma-phosphate promotes a concurrent mechanism and lowers the rate-limiting barrier of water breakup. The role played by individual protein residues in the catalytic pocket of triphosphate hydrolysing enzymes can be assigned accordingly. PMID- 27974045 TI - Cumulative subgroup analysis to reduce waste in clinical research for individualised medicine. AB - BACKGROUND: Although subgroup analyses in clinical trials may provide evidence for individualised medicine, their conduct and interpretation remain controversial. METHODS: Subgroup effect can be defined as the difference in treatment effect across patient subgroups. Cumulative subgroup analysis refers to a series of repeated pooling of subgroup effects after adding data from each of related trials chronologically, to investigate the accumulating evidence for subgroup effects. We illustrated the clinical relevance of cumulative subgroup analysis in two case studies using data from published individual patient data (IPD) meta-analyses. Computer simulations were also conducted to examine the statistical properties of cumulative subgroup analysis. RESULTS: In case study 1, an IPD meta-analysis of 10 randomised trials (RCTs) on beta blockers for heart failure reported significant interaction of treatment effects with baseline rhythm. Cumulative subgroup analysis could have detected the subgroup effect 15 years earlier, with five fewer trials and 71% less patients, than the IPD meta analysis which first reported it. Case study 2 involved an IPD meta-analysis of 11 RCTs on treatments for pulmonary arterial hypertension that reported significant subgroup effect by aetiology. Cumulative subgroup analysis could have detected the subgroup effect 6 years earlier, with three fewer trials and 40% less patients than the IPD meta-analysis. Computer simulations have indicated that cumulative subgroup analysis increases the statistical power and is not associated with inflated false positives. CONCLUSIONS: To reduce waste of research data, subgroup analyses in clinical trials should be more widely conducted and adequately reported so that cumulative subgroup analyses could be timely performed to inform clinical practice and further research. PMID- 27974046 TI - Can CCTV identify people in public transit stations who are at risk of attempting suicide? An analysis of CCTV video recordings of attempters and a comparative investigation. AB - BACKGROUND: Suicides incur in all public transit systems which do not completely impede access to tracks. We conducted two studies to determine if we can reliably identify in stations people at risk of suicide in order to intervene in a timely manner. The first study analysed all CCTV recordings of suicide attempters in Montreal underground stations over 2 years to identify behaviours indicating suicide risk. The second study verified the potential of using those behaviours to discriminate attempters from other passengers in real time. METHODS: First study: Trained observers watched CCTV video recordings of 60 attempters, with 2-3 independent observers coding seven easily observable behaviours and five behaviours requiring interpretation (e.g. "strange behaviours," "anxious behaviour"). Second study: We randomly mixed 63 five-minute CCTV recordings before an attempt with 56 recordings from the same cameras at the same time of day, and day of week, but when no suicide attempt was to occur. Thirty-three undergraduate students after only 10 min of instructions watched the recordings and indicated if they observed each of 13 behaviours identified in the First Study. RESULTS: First study: Fifty (83%) of attempters had easily observable behaviours potentially indicative of an impending attempt, and 37 (61%) had two or more of these behaviours. Forty-five (75%) had at least one behaviours requiring interpretation. Twenty-two witnesses attempted to intervene to stop the attempt, and 75% of attempters had behaviours indicating possible ambivalence (e.g. waiting for several trains to pass; trying to get out of the path of the train). Second study: Two behaviours, leaving an object on the platform and pacing back and forth from the yellow line (just before the edge of the platform), could identify 24% of attempters with no false positives. The other target behaviours were also present in non-attempters. However, having two or more of these behaviours indicated a likelihood of being at risk of attempting suicide. CONCLUSIONS: We conclude that real time observations of CCTV monitors, automated computer monitoring of CCTV signals, and/or training of drivers and transit personnel on behavioural indications of suicide risk, may identify attempters with few false positives, and potentially save lives. PMID- 27974048 TI - Selective suppression of the alpha isoform of p38 MAPK rescues late-stage tau pathology. AB - BACKGROUND: Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer's disease and related tauopathies. We previously demonstrated that the microglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 mitogen activated protein kinase (p38 MAPK) in the hTau mouse model of tauopathy that was deficient for microglial fractalkine receptor CX3CR1. METHOD: We report an isoform-selective, brain-permeable, and orally bioavailable small molecule inhibitor of p38alpha MAPK (MW181) and its effects on tau phosphorylation in vitro and in hTau mice. RESULTS: First, pretreatment of mouse primary cortical neurons with MW181 completely blocked inflammation-induced p38alpha MAPK activation and AT8 (pS199/pS202) site tau phosphorylation, with the maximum effect peaking at 60-90 min after stimulation. Second, treatment of old (~20 months of age) hTau mice with MW181 (1 mg/kg body weight; 14 days via oral gavage) significantly reduced p38alpha MAPK activation compared with vehicle administered hTau mice. This also resulted in a significant reduction in AT180 (pT231) site tau phosphorylation and Sarkosyl-insoluble tau aggregates. Third, MW181 treatment significantly increased synaptophysin protein expression and resulted in improved working memory. Fourth, MW181 administration reduced phosphorylated MAPK-activated protein kinase 2 (pMK2) and phosphorylated activating transcription factor 2 (pATF2), which are known substrates of p38alpha MAPK. Finally, MW181 reduced the expression of interferon-gamma and interleukin 1beta. CONCLUSIONS: Taken together, these studies support p38alpha MAPK as a valid therapeutic target for the treatment of tauopathies. PMID- 27974050 TI - Neonatal milk supplementation in lambs has persistent effects on growth and metabolic function that differ by sex and gestational age. AB - The perinatal environment has a major influence on long-term health and disease risk. Preterm birth alters early-life environment and is associated with altered metabolic function in adulthood. Whether preterm birth per se or the early nutritional interventions used to support growth in preterm infants underpins this association is unknown. Lambs born preterm, following dexamethasone induction of labour, or spontaneously at term were randomised to receive nutrient supplementation, analogous to the milk fortifier used clinically or water as a control for the first 2 weeks after birth. Thereafter, nutrition was not different between groups. Growth was monitored, and the glucose-insulin axis function was assessed in juvenile (4 months) and adult life (14 months). Early nutrition influenced adult metabolic function and body composition to a greater extent than preterm birth. In supplemented females, arginine-stimulated insulin secretion was increased in preterm but reduced in term-born juveniles compared with controls (repeated-measures ANOVA P<0.01). In supplemented preterm males, adult weight, ponderal index (PI) and fasting insulin concentrations were elevated compared with preterm controls (weight, 75 (sem 3) v. 69 (sem 2) kg; PI, 48.0 (sem 2.1) v. 43.7 (sem 1.7) kg/m3; fasting insulin, 0.19 (sem 0.02) v. 0.10 (sem 0.02) ng/ml). Conversely, supplemented term-born males had reduced adult weight, PI and fasting insulin concentrations compared with term-born controls (weight, 64 (sem 2) v. 70 (sem 2) kg; PI, 44.4 (sem 1.8) v. 48.2 (sem 1.7) kg/m3; fasting insulin, 0.09 (sem 0.02) v. 0.14 (sem 0.02) ng/ml; all group*supplement interactions P<0.05). Adult metabolic health may reflect both gestational age at birth and early nutrition. Human studies are urgently needed to investigate the adult sex-specific health implications of neonatal nutritional strategies. PMID- 27974047 TI - FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors. AB - BACKGROUND: About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies. METHODS: We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer related genes of 186 GISTs to assess for their somatic alterations. RESULTS: We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1-HOOK3, FGFR1-TACC1) and one harbored an ETV6-NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1-TACC1 and ETV6-NTRK3 fusions. CONCLUSIONS: Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST. Trial registration NCT 02576431. Registered October 12, 2015. PMID- 27974051 TI - Goggle-like Appearance of Injured Cerebellothalamic Axons Surrounding Red Nuclei in Holmes Tremor. PMID- 27974052 TI - Hospital-Onset Bloodstream Infection Rates After Discontinuing Active Surveillance Cultures for Methicillin-Resistant Staphylococcus aureus in a Regional Burn Center. PMID- 27974049 TI - The draft genome of whitefly Bemisia tabaci MEAM1, a global crop pest, provides novel insights into virus transmission, host adaptation, and insecticide resistance. AB - BACKGROUND: The whitefly Bemisia tabaci (Hemiptera: Aleyrodidae) is among the 100 worst invasive species in the world. As one of the most important crop pests and virus vectors, B. tabaci causes substantial crop losses and poses a serious threat to global food security. RESULTS: We report the 615-Mb high-quality genome sequence of B. tabaci Middle East-Asia Minor 1 (MEAM1), the first genome sequence in the Aleyrodidae family, which contains 15,664 protein-coding genes. The B. tabaci genome is highly divergent from other sequenced hemipteran genomes, sharing no detectable synteny. A number of known detoxification gene families, including cytochrome P450s and UDP-glucuronosyltransferases, are significantly expanded in B. tabaci. Other expanded gene families, including cathepsins, large clusters of tandemly duplicated B. tabaci-specific genes, and phosphatidylethanolamine-binding proteins (PEBPs), were found to be associated with virus acquisition and transmission and/or insecticide resistance, likely contributing to the global invasiveness and efficient virus transmission capacity of B. tabaci. The presence of 142 horizontally transferred genes from bacteria or fungi in the B. tabaci genome, including genes encoding hopanoid/sterol synthesis and xenobiotic detoxification enzymes that are not present in other insects, offers novel insights into the unique biological adaptations of this insect such as polyphagy and insecticide resistance. Interestingly, two adjacent bacterial pantothenate biosynthesis genes, panB and panC, have been co-transferred into B. tabaci and fused into a single gene that has acquired introns during its evolution. CONCLUSIONS: The B. tabaci genome contains numerous genetic novelties, including expansions in gene families associated with insecticide resistance, detoxification and virus transmission, as well as numerous horizontally transferred genes from bacteria and fungi. We believe these novelties likely have shaped B. tabaci as a highly invasive polyphagous crop pest and efficient vector of plant viruses. The genome serves as a reference for resolving the B. tabaci cryptic species complex, understanding fundamental biological novelties, and providing valuable genetic information to assist the development of novel strategies for controlling whiteflies and the viruses they transmit. PMID- 27974053 TI - Courtship and mating behaviour in the parasitoid wasp Cotesia urabae (Hymenoptera: Braconidae): mate location and the influence of competition and body size on male mating success. AB - Cotesia urabae is a solitary larval endoparasitoid that was introduced into New Zealand in 2011 as a classical biological control agent against Uraba lugens. A detailed knowledge of its reproductive biology is required to optimize mass rearing efficiency. In this study, the courtship and mating behaviour of C. urabae is described and investigated from a series of experiments, conducted to understand the factors that influence male mating success. Cotesia urabae males exhibited a high attraction to virgin females but not mated females, whereas females showed no attraction to either virgin or mated males. Male mating success was highest in the presence of a male competitor. Also, the time to mate was shorter and copulation duration was longer when a male competitor was present. Larger male C. urabae had greater mating success than smaller males when paired together with a single female. This knowledge can now be utilized to improve mass rearing methods of C. urabae for the future. PMID- 27974054 TI - Heritability of tic disorders: a twin-family study. AB - BACKGROUND: Genetic-epidemiological studies that estimate the contributions of genetic factors to variation in tic symptoms are scarce. We estimated the extent to which genetic and environmental influences contribute to tics, employing various phenotypic definitions ranging between mild and severe symptomatology, in a large population-based adult twin-family sample. METHOD: In an extended twin family design, we analysed lifetime tic data reported by adult mono- and dizygotic twins (n = 8323) and their family members (n = 7164; parents and siblings) from 7311 families in the Netherlands Twin Register. We measured tics by the abbreviated version of the Schedule for Tourette and Other Behavioral Syndromes. Heritability was estimated by genetic structural equation modeling for four tic disorder definitions: three dichotomous and one trichotomous phenotype, characterized by increasingly strictly defined criteria. RESULTS: Prevalence rates of the different tic disorders in our sample varied between 0.3 and 4.5% depending on tic disorder definition. Tic frequencies decreased with increasing age. Heritability estimates varied between 0.25 and 0.37, depending on phenotypic definitions. None of the phenotypes showed evidence of assortative mating, effects of shared environment or non-additive genetic effects. CONCLUSIONS: Heritabilities of mild and severe tic phenotypes were estimated to be moderate. Overlapping confidence intervals of the heritability estimates suggest overlapping genetic liabilities between the various tic phenotypes. The most lenient phenotype (defined only by tic characteristics, excluding criteria B, C and D of DSM-IV) rendered sufficiently reliable heritability estimates. These findings have implications in phenotypic definitions for future genetic studies. PMID- 27974055 TI - Host-microbiome interactions in human type 2 diabetes following prebiotic fibre (galacto-oligosaccharide) intake. AB - Aberrant microbiota composition and function have been linked to several pathologies, including type 2 diabetes. In animal models, prebiotics induce favourable changes in the intestinal microbiota, intestinal permeability (IP) and endotoxaemia, which are linked to concurrent improvement in glucose tolerance. This is the first study to investigate the link between IP, glucose tolerance and intestinal bacteria in human type 2 diabetes. In all, twenty-nine men with well controlled type 2 diabetes were randomised to a prebiotic (galacto oligosaccharide mixture) or placebo (maltodextrin) supplement (5.5 g/d for 12 weeks). Intestinal microbial community structure, IP, endotoxaemia, inflammatory markers and glucose tolerance were assessed at baseline and post intervention. IP was estimated by the urinary recovery of oral 51Cr-EDTA and glucose tolerance by insulin-modified intravenous glucose tolerance test. Intestinal microbial community analysis was performed by high-throughput next-generation sequencing of 16S rRNA amplicons and quantitative PCR. Prebiotic fibre supplementation had no significant effects on clinical outcomes or bacterial abundances compared with placebo; however, changes in the bacterial family Veillonellaceae correlated inversely with changes in glucose response and IL-6 levels (r -0.90, P=0.042 for both) following prebiotic intake. The absence of significant changes to the microbial community structure at a prebiotic dosage/length of supplementation shown to be effective in healthy individuals is an important finding. We propose that concurrent metformin treatment and the high heterogeneity of human type 2 diabetes may have played a significant role. The current study does not provide evidence for the role of prebiotics in the treatment of type 2 diabetes. PMID- 27974056 TI - A pilot study using "apps" as a novel strategy for the management of challenging behaviors seen in people living in residential care. AB - BACKGROUND: Many adults living in residential care will demonstrate challenging behaviors. Non-pharmacological strategies are recommended as first-line treatment. Using applications (apps) is a novel approach to managing these behaviors, and has yet to be assessed in this group. This paper describes a pilot study to test apps as a novel non-pharmacological strategy to manage challenging behaviors in adults living in residential care. METHODS: A non-blinded, non randomized crossover trial design was implemented which compared apps to a control situation and usual care to determine whether apps were able to decrease challenging behaviors. The primary outcome measure was the Neuropsychiatric Inventory (NPI) that measures the frequency and severity of these behaviors. RESULTS: Fifteen residents participated whose mean age was 78.5 years. There were a range of diagnoses and comorbidities, including dementia and schizophrenia. IPads were used as the medium for delivering the apps and residential care staff implemented the interventions. There was a significant decrease in the total NPI score using the apps intervention (10.6 points) compared to the control (17.7 points) and to usual care (21.1 points). There was positive qualitative feedback from the staff who were involved in the study, but they also cited barriers such as lack of confidence using the apps and lack of time. CONCLUSIONS: Although this was a small and limited study, results suggest that using apps may be a feasible and personalized approach to managing challenging behaviors. A more rigorous study design that includes larger sample sizes and staff training may enable further research and benefits in this area. PMID- 27974057 TI - Validation of ICD-9-CM Diagnosis Codes for Surgical Site Infection and Noninfectious Wound Complications After Mastectomy. AB - BACKGROUND Few studies have validated ICD-9-CM diagnosis codes for surgical site infection (SSI), and none have validated coding for noninfectious wound complications after mastectomy. OBJECTIVES To determine the accuracy of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes in health insurer claims data to identify SSI and noninfectious wound complications, including hematoma, seroma, fat and tissue necrosis, and dehiscence, after mastectomy. METHODS We reviewed medical records for 275 randomly selected women who were coded in the claims data for mastectomy with or without immediate breast reconstruction and had an ICD-9-CM diagnosis code for a wound complication within 180 days after surgery. We calculated the positive predictive value (PPV) to evaluate the accuracy of diagnosis codes in identifying specific wound complications and the PPV to determine the accuracy of coding for the breast surgical procedure. RESULTS The PPV for SSI was 57.5%, or 68.9% if cellulitis-alone was considered an SSI, while the PPV for cellulitis was 82.2%. The PPVs of individual noninfectious wound complications ranged from 47.8% for fat necrosis to 94.9% for seroma and 96.6% for hematoma. The PPVs for mastectomy, implant, and autologous flap reconstruction were uniformly high (97.5%-99.2%). CONCLUSIONS Our results suggest that claims data can be used to compare rates of infectious and noninfectious wound complications after mastectomy across facilities, even though PPVs vary by specific type of postoperative complication. The accuracy of coding was highest for cellulitis, hematoma, and seroma, and a composite group of noninfectious complications (fat necrosis, tissue necrosis, or dehiscence). Infect Control Hosp Epidemiol 2017;38:334-339. PMID- 27974058 TI - Effect of heavy-equipment aided environmental nebulization on Aedes aegypti vectors of Dengue, Zika and Chikungunya in Sao Paulo, Brazil. AB - The control of dengue constitutes a great challenge for public health; however, the methods normally used have shown themselves to be insufficient to keep the indices of infestation of Aedes aegypti under control. Recently, beyond the large number of cases and deaths associated with dengue, new risks have arisen such as those represented by chikungunya fever and Zika. In the light of the great significance of these problems within the public health context, two areas in a municipality in the interior of the State of Sao Paulo, Brazil were selected in 2014. One of them, Bairro Cidade Nova, was submitted to the conventional method of nebulization with portable equipment, and the other, Bairro Jardim Europa, received the application of the insecticide by means of heavy-equipment coupled to the vehicle. During the project, 1355 mosquito eggs were collected, 1105 of them in Bairro Cidade Nova and 205 in Bairro Jardim Europa. After the applications with heavy-equipment in the months of March and April, the number of cases of the disease reported in the month of April for Bairro Jardim Europa was less than half that of Bairro Cidade Nova, which had received the conventional treatment. The nebulization with the heavy-equipment may constitute a viable and effective strategy for achieving better results in the control of Ae. aegypti. PMID- 27974059 TI - The diversity and evolution of nematodes (Pharyngodonidae) infecting New Zealand lizards. AB - Host-parasite co-evolutionary studies can shed light on diversity and the processes that shape it. Molecular methods have proven to be an indispensable tool in this task, often uncovering unseen diversity. This study used two nuclear markers (18S rRNA and 28S rRNA) and one mitochondrial (cytochrome oxidase subunit I) marker to investigate the diversity of nematodes of the family Pharyngodonidae parasitizing New Zealand (NZ) lizards (lygosomine skinks and diplodactylid geckos) and to explore their co-evolutionary history. A Bayesian approach was used to infer phylogenetic relationships of the parasitic nematodes. Analyses revealed that nematodes parasitizing skinks, currently classified as Skrjabinodon, are more closely related to Spauligodon than to Skrjabinodon infecting NZ geckos. Genetic analyses also uncovered previously undetected diversity within NZ gecko nematodes and provided evidence for several provisionally cryptic species. We also examined the level of host-parasite phylogenetic congruence using a global-fit approach. Significant congruence was detected between gecko-Skrjabinodon phylogenies, but our results indicated that strict co-speciation is not the main co-evolutionary process shaping the associations between NZ skinks and geckos and their parasitic nematodes. However, further sampling is required to fully resolve co-phylogenetic patterns of diversification in this host-parasite system. PMID- 27974060 TI - Contribution of binge eating behaviour to cardiometabolic risk factors in subjects starting a weight loss or maintenance programme. AB - The contribution of binge eating (BE) behaviour to cardiometabolic risk factors has been scarcely investigated so far. Previous studies have not considered the nutritional status and lifestyle of subjects suffering from BE. The aim of this study was to evaluate the contribution of BE to the metabolic syndrome (MS), its components, high total cholesterol and high LDL in a large sample of subjects, taking into account nutritional status, dietary habits, smoking status and physical activity. For this purpose, 5175 adults seeking a weight loss or maintenance programme were recruited. Anthropometrical measurements and blood parameters were measured. BE was evaluated using the Binge Eating Scale (BES). A fourteen-item questionnaire was used to evaluate the adherence to the Mediterranean diet. Smoking status and physical activity were investigated by interview. BE prevalence was 0.16 (95 % CI 0.15, 0.17). A sex- and age-adjusted Poisson regression model showed a higher prevalence of MS in binge eaters (0.33; 95 % CI 0.28, 0.37) compared with non-binge eaters (0.27; 95 % CI 0.25, 0.28, P=0.011). However, the statistical difference was lost after inclusion of BMI and lifestyle parameters in the multiple-adjusted model. We also evaluated the association between the continuous outcomes of interest and the BES score using a multivariable median regression model. We observed a positive, but clinically irrelevant, association between BES score and HDL levels (P<0.001). In conclusion, BE does not seem to be independently related to cardiometabolic risk factors. However, the screening and treatment of BE are of clinical relevance in order to reduce the risk of developing obesity. PMID- 27974061 TI - Diet in Saudi Arabia: findings from a nationally representative survey. AB - OBJECTIVE: No recent original studies on the pattern of diet are available for Saudi Arabia at the national level. The present study was performed to describe the consumption of foods and beverages by Saudi adults. DESIGN: The Saudi Health Interview Survey (SHIS) was conducted in 2013. Data were collected through interviews and anthropometric measurements were done. A diet history questionnaire was used to determine the amount of consumption for eighteen food or beverage items in a typical week. SETTING: The study was a household survey in all thirteen administrative regions of Saudi Arabia. SUBJECTS: Participants were 10 735 individuals aged 15 years or older. RESULTS: Mean daily consumption was 70.9 (se 1.3) g for fruits, 111.1 (se 2.0) g for vegetables, 11.6 (se 0.3) g for dark fish, 13.8 (se 0.3) g for other fish, 44.2 (se 0.7) g for red meat, 4.8 (se 0.2) g for processed meat, 10.9 (se 0.3) g for nuts, 219.4 (se 5.1) ml for milk and 115.5 (se 2.6) ml for sugar-sweetened beverages. Dietary guideline recommendations were met by only 5.2 % of individuals for fruits, 7.5 % for vegetables, 31.4 % for nuts and 44.7 % for fish. The consumption of processed foods and sugar-sweetened beverages was high in young adults. CONCLUSIONS: Only a small percentage of the Saudi population met the dietary recommendations. Programmes to improve dietary behaviours are urgently needed to reduce the current and future burden of disease. The promotion of healthy diets should target both the general population and specific high-risk groups. Regular assessments of dietary status are needed to monitor trends and inform interventions. PMID- 27974063 TI - Leishmaniasis and various immunotherapeutic approaches. AB - Leishmaniasis is a vector-borne infectious disease caused by multiple Leishmania (L.) species with diverse clinical manifestations. There is currently no vaccine against any form of the disease approved in humans, and chemotherapy is the sole approach for treatment. Unfortunately, treatment options are limited to a small number of drugs, partly due to high cost and significant adverse effects. The other obstacle in leishmaniasis treatment is the potential for drug resistance, which has been observed in multiple endemic countries. Immunotherapy maybe another important avenue for controlling leishmaniasis and could help patients control the disease. There are different approaches for immunotherapy in different infectious diseases, generally with low-cost, limited side-effects and no possibility to developing resistance. In this paper, different immunotherapy approaches as alternatives to routine drug treatment will be reviewed against leishmaniasis. PMID- 27974062 TI - Interventions to reduce the impact of unemployment and economic hardship on mental health in the general population: a systematic review. AB - BACKGROUND: Job loss, debt and financial difficulties are associated with increased risk of mental illness and suicide in the general population. Interventions targeting people in debt or unemployed might help reduce these effects. METHOD: We searched MEDLINE, Embase, The Cochrane Library, Web of Science, and PsycINFO (January 2016) for randomized controlled trials (RCTs) of interventions to reduce the effects of unemployment and debt on mental health in general population samples. We assessed papers for inclusion, extracted data and assessed risk of bias. RESULTS: Eleven RCTs (n = 5303 participants) met the inclusion criteria. All recruited participants were unemployed. Five RCTs assessed 'job-club' interventions, two cognitive behaviour therapy (CBT) and a single RCT assessed each of emotional competency training, expressive writing, guided imagery and debt advice. All studies were at high risk of bias. 'Job club' interventions led to improvements in levels of depression up to 2 years post intervention; effects were strongest among those at increased risk of depression (improvements of up to 0.2-0.3 s.d. in depression scores). There was mixed evidence for effectiveness of group CBT on symptoms of depression. An RCT of debt advice found no effect but had poor uptake. Single trials of three other interventions showed no evidence of benefit. CONCLUSIONS: 'Job-club' interventions may be effective in reducing depressive symptoms in unemployed people, particularly those at high risk of depression. Evidence for CBT-type interventions is mixed; further trials are needed. However the studies are old and at high risk of bias. Future intervention studies should follow CONSORT guidelines and address issues of poor uptake. PMID- 27974064 TI - Diet quality and its relationship with central obesity among Mexican Americans: findings from National Health and Nutrition Examination Survey (NHANES) 1999 2012. AB - OBJECTIVE: Using the Healthy Eating Index-2010 (HEI-2010), the present study aimed to examine diet quality and the impact of overall diet quality and its components on central obesity among Mexican-American men and women. DESIGN: Cross sectional data from NHANES 1999-2012 were used. The HEI-2010 data, including twelve components for a total score of 100, were collected with a 24 h recall interview. Central obesity was defined as a waist circumference of >=88 cm for women and >=102 cm for men. Weighted logistic regressions were performed to assess associations between HEI-2010 scores and central obesity. SETTING: National Health and Nutrition Examination Survey (NHANES) 1999-2012. SUBJECTS: A total of 6847 Mexican Americans aged >=20 years with reliable dietary recall status and non-pregnancy status. RESULTS: Higher HEI-2010 total score was associated with lower odds of central obesity in Mexican-American men (OR; 95 % CI=0.98; 0.98, 1.00). Among all Mexican Americans, one-unit higher score of total fruit and sodium (i.e. lower level of intake) was associated with 4 % (0.96; 0.93, 0.99) and 2 % (0.98; 0.96, 0.99) lower odds of central obesity, respectively. However, a higher total proteins score was associated with higher odds of central obesity (1.08; 1.00, 1.16). In gender-specific analyses, a higher whole fruit or sodium score was inversely associated with central obesity in men but not in women. CONCLUSIONS: HEI-2010 scores of total fruit and sodium were inversely associated with central obesity among all Mexican Americans. However, total proteins score and central obesity was positively associated. In Mexican American men, HEI-2010 total and whole fruit scores were inversely associated with central obesity. PMID- 27974065 TI - Evaluation of the impacts of climate change on disease vectors through ecological niche modelling. AB - Vector-borne diseases are exceptionally sensitive to climate change. Predicting vector occurrence in specific regions is a challenge that disease control programs must meet in order to plan and execute control interventions and climate change adaptation measures. Recently, an increasing number of scientific articles have applied ecological niche modelling (ENM) to study medically important insects and ticks. With a myriad of available methods, it is challenging to interpret their results. Here we review the future projections of disease vectors produced by ENM, and assess their trends and limitations. Tropical regions are currently occupied by many vector species; but future projections indicate poleward expansions of suitable climates for their occurrence and, therefore, entomological surveillance must be continuously done in areas projected to become suitable. The most commonly applied methods were the maximum entropy algorithm, generalized linear models, the genetic algorithm for rule set prediction, and discriminant analysis. Lack of consideration of the full-known current distribution of the target species on models with future projections has led to questionable predictions. We conclude that there is no ideal 'gold standard' method to model vector distributions; researchers are encouraged to test different methods for the same data. Such practice is becoming common in the field of ENM, but still lags behind in studies of disease vectors. PMID- 27974066 TI - Does saliva composition affect the formation of sialolithiasis? AB - OBJECTIVE: Saliva composition may affect sialolithiasis formation; thus, this study compared the salivary inorganic composition of sialolithiasis patients with that of healthy controls, and determined whether salivary inorganic composition changes after sialolithiasis surgery. METHODS: The study included 40 patients with sialolithiasis and 40 matched healthy controls. Patients were examined before and after sialolithiasis surgery; controls were examined once. Flow rate and the inorganic saliva composition in unstimulated whole saliva were assessed. RESULTS: Patients' salivary flow prior to surgery was significantly lower compared to that of healthy controls, but equalised after surgery. Prior to surgery, patients' saliva exhibited higher concentrations of calcium, magnesium, phosphorous compared to that of healthy controls. The concentration of most ions remained high after sialolithiasis surgery. CONCLUSION: Sialolithiasis patients had increased salivary concentrations of the ions that constitute the main inorganic phase of most sialoliths, and this may confer a risk for developing sialolithiasis. PMID- 27974067 TI - 5-Hydroxyvitamin D concentration in paediatric cancer patients from Scotland: a prospective cohort study. AB - Children with cancer are potentially at a high risk of plasma 25-hydroxyvitamin D (25(OH)D) inadequacy, and despite UK vitamin D supplementation guidelines their implementation remains inconsistent. Thus, we aimed to investigate 25(OH)D concentration and factors contributing to 25(OH)D inadequacy in paediatric cancer patients. A prospective cohort study of Scottish children aged 75 nmol/l). In all, eighty-two patients (median age 3.9, interquartile ranges (IQR) 1.9-8.8; 56 % males) and thirty-five controls (median age 6.2, IQR 4.8-9.1; 49 % males) were recruited. 25(OH)D inadequacy was highly prevalent in the controls (63 %; 22/35) and in the patients (64 %; 42/65) at both baseline and during treatment (33-50 %). Non-supplemented children had the highest prevalence of 25(OH)D inadequacy at every stage with 25(OH)D median ranging from 32.0 (IQR 21.0-46.5) to 45.0 (28.0 64.5) nmol/l. Older age at baseline (R -0.46; P<0.001), overnutrition (BMI>=85th centile) at 3 months (P=0.005; relative risk=3.1) and not being supplemented at 6 months (P=0.04; relative risk=4.3) may have contributed to lower plasma 25(OH)D. Paediatric cancer patients are not at a higher risk of 25(OH)D inadequacy than healthy children at diagnosis; however, prevalence of 25(OH)D inadequacy is still high and non-supplemented children have a higher risk. Appropriate monitoring and therapeutic supplementation should be implemented. PMID- 27974068 TI - Endolymphatic sac drainage for the treatment of Meniere's disease. AB - OBJECTIVE: To describe the results obtained with endolymphatic sac drainage in patients with Meniere's disease. METHOD: A retrospective case review study was conducted of 95 Meniere's disease patients who underwent endolymphatic sac drainage in a tertiary care referral centre, after failing a long course of medical management. The main outcome measures were vertigo control and hearing preservation. RESULTS: In patients with unilateral disease, vertigo control was obtained in 94.3 per cent of patients. A significant improvement in cochlear function was seen in 14 per cent of patients, and hearing was preserved or improved in 88 per cent. For the bilateral group, vertigo control was obtained in 85.7 per cent of patients and cochlear function improved in 28 per cent. Hearing preservation was attained in 71 per cent of these patients. CONCLUSION: Endolymphatic sac drainage is a good surgical option for patients with incapacitating endolymphatic hydrops, providing a high percentage of vertigo control and hearing preservation. PMID- 27974069 TI - Connecting the dots in child undernutrition. PMID- 27974070 TI - Reduced mobility but high survival: thermal tolerance and locomotor response of the specialist herbivore, Pareuchaetes insulata (Walker) (Lepidoptera: Erebidae), to low temperatures. AB - Disentangling the responses of insects to variations in their thermal environment is central to our understanding of the evolution of temperature-dependent performance in these species. Here, we report results of experiments examining the effects of high (upper lethal temperature = ULT) and low (lower lethal temperature = LLT) temperature and exposure time on the survival of larvae and adults of a multivoltine, nocturnal moth species, Pareuchaetes insulata, a biological control agent whose impact on an invasive weed, Chromolaena odorata has been variable in South Africa. The influence of temperature and acclimation on locomotion performance of the moth was also investigated. Temperature and duration of exposure significantly affected survival of both adults and larvae of P. insulata with more extreme temperatures and/or longer durations proving to be more lethal. Third instar larvae and adults are both freeze intolerant and had LT50 of -5.9 and -4.7 degrees C, respectively, after a 2 h exposure. Although cold acclimation was beneficial to the nocturnal larvae, temperatures below 10 degrees C significantly reduce their locomotion activities. The average daily minimum temperatures in the coldest months at three locations in South Africa are over 5 degrees C lower than those of Fort Lauderdale, Florida, USA, where P. insulata was originally collected. Our results suggest that lethal high or low temperatures at short timescales are trivial in explaining the variable performance of P. insulata, but reduced locomotion at sub-lethal temperatures may be an important driver of the population dynamics of the biocontrol agent (especially in winter months) and may consequently explain the low population levels of the moth because of possible reduced feeding by larvae during night time low temperatures. PMID- 27974071 TI - Cervical lymph node metastasis in adenoid cystic carcinoma of the major salivary glands. AB - OBJECTIVE: To verify the prevalence of cervical lymph node metastasis in adenoid cystic carcinoma of major salivary glands, and to establish recommendations for elective neck treatment. METHODS: A search was conducted of the US National Library of Medicine database. Appropriate articles were selected from the abstracts, and the original publications were obtained to extract data. RESULTS: Among 483 cases of major salivary gland adenoid cystic carcinoma, a total of 90 (18.6 per cent) had cervical metastasis. The prevalence of positive nodes from adenoid cystic carcinoma was 14.5 per cent for parotid gland, 22.5 per cent for submandibular gland and 24.7 per cent for sublingual gland. Cervical lymph node metastasis occurred more frequently in patients with primary tumour stage T3-4 adenoid cystic carcinoma, and was usually located in levels II and III in the neck. CONCLUSION: Adenoid cystic carcinoma of the major salivary glands is associated with a significant prevalence of cervical node metastasis, and elective neck treatment is indicated for T3 and T4 primary tumours, as well as tumours with other histological risk factors. PMID- 27974072 TI - Changes occurred in the testes and DNA pattern of males wax moth (Galleria mellonella) first generation as a result of irradiation of their parents. AB - Nowadays, the sterile insect technique is broadly used as a pest control measure. Therefore, the present study was conducted to investigate the alteration occurred in testes and DNA pattern as an effect of inherited sterility. Full grown pupae of the wax moth, Galleria mellonella were irradiated with 80 and 160 Gy of gamma irradiation. The size of the testes was decreased by increasing of gamma irradiation dose. Also, the size of the testes was decreased in F 1 males comparing with the size of the testes of both the parents and the untreated control. The effects of gamma rays on the DNA patterns of adult male parents and F 1 males showed alterations among the controls, the treated parents and F 1 individuals. Exposure to radiation caused very frequently the appearance of some extra bands and the deficiency of others in the arbitrary random amplified polymorphic DNA-polymerase chain reaction amplification patterns of the irradiated insects. PMID- 27974073 TI - Memory for emotional images differs according to the presence of depressive symptoms in individuals at risk for dementia. AB - BACKGROUND: Studies of amnestic mild cognitive impairment (aMCI) and late-life depression (LLD) have examined the similarities and differences between these syndromes, but few have investigated how the cognitive profile of comorbid aMCI and subclinical depressive symptoms (aMCI/D+) may compare to that of aMCI or LLD. Memory biases for certain types of emotional information may distinguish these groups. METHODS: A total of 35 aMCI, 23 aMCI/D+, 13 LLD, and 17 elderly controls (CONT) rated the valence (positive, negative, or neutral) of 30 pictures from the International Affective Picture System. Mean percent positive, negative, and neutral images recalled was compared within groups immediately and 30 minutes later. RESULTS: Overall memory performance was comparable in aMCI and aMCI/D+, and both recalled fewer items than CONT and LLD. Group differences emerged when valence ratings were considered: at immediate and delayed recall, positive and negative pictures were generally better-remembered than neutral pictures by CONT, aMCI, and LLD, but valence was not associated with recall in aMCI/D+. Follow-up analyses suggested that the perceived intensity of stimuli may explain the emotional enhancement effect in CONT, aMCI, and LLD. CONCLUSIONS: Results support previous research suggesting that the neuropsychological profile of aMCI/D+ is different from that of aMCI and LLD. Although depressed and non-depressed individuals with aMCI recall comparable quantities of information, the quality of the recalled information differs significantly. On theoretical grounds, this suggests the existence of distinct neurobiological or neurofunctional manifestations in both groups. Practically, these differences may guide the development of personalized emotion-focused encoding strategies in cognitive training programs. PMID- 27974074 TI - Sex-Related Differences in Emotion Recognition in Multi-concussed Athletes. AB - OBJECTIVES: Concussion is defined as a complex pathophysiological process affecting the brain. Although the cumulative and long-term effects of multiple concussions are now well documented on cognitive and motor function, little is known about their effects on emotion recognition. Recent studies have suggested that concussion can result in emotional sequelae, particularly in females and multi-concussed athletes. The objective of this study was to investigate sex related differences in emotion recognition in asymptomatic male and female multi concussed athletes. METHODS: We tested 28 control athletes (15 males) and 22 multi-concussed athletes (10 males) more than a year since the last concussion. Participants completed the Post-Concussion Symptom Scale, the Beck Depression Inventory-II, the Beck Anxiety Inventory, a neuropsychological test battery and a morphed emotion recognition task. Pictures of a male face expressing basic emotions (anger, disgust, fear, happiness, sadness, surprise) morphed with another emotion were randomly presented. After each face presentation, participants were asked to indicate the emotion expressed by the face. RESULTS: Results revealed significant sex by group interactions in accuracy and intensity threshold for negative emotions, together with significant main effects of emotion and group. CONCLUSIONS: Male concussed athletes were significantly impaired in recognizing negative emotions and needed more emotional intensity to correctly identify these emotions, compared to same-sex controls. In contrast, female concussed athletes performed similarly to same-sex controls. These findings suggest that sex significantly modulates concussion effects on emotional facial expression recognition. (JINS, 2017, 23, 65-77). PMID- 27974075 TI - Health-Related Quality of Life in Older Coastal Residents After Multiple Disasters. AB - OBJECTIVE: Exposure to multiple disasters, both natural and technological, is associated with extreme stress and long-term consequences for older adults that are not well understood. In this article, we address age differences in health related quality of life in older disaster survivors exposed to the 2005 Hurricanes Katrina and Rita and the 2010 BP Deepwater Horizon oil spill and the role played by social engagement in influencing these differences. METHODS: Participants were noncoastal residents, current coastal residents, and current coastal fishers who were economically affected by the BP oil spill. Social engagement was estimated on the basis of disruptions in charitable work and social support after the 2005 hurricanes relative to a typical year before the storms. Criterion measures were participants' responses to the SF-36 Health Survey which includes composite indexes of physical (PCS) and mental (MCS) health. RESULTS: The results of logistic regressions indicated that age was inversely associated with SF-36 PCS scores. A reduction in perceived social support after Hurricane Katrina was also inversely associated with SF-36 MCS scores. CONCLUSIONS: These results illuminate risk factors that impact well-being among older adults after multiple disasters. Implications of these data for psychological adjustment after multiple disasters are considered. (Disaster Med Public Health Preparedness. 2017;11:90-96). PMID- 27974076 TI - The New Methodology and Chemical Contrast Observation by Use of the Energy Selective Back-Scattered Electron Detector. AB - We report on a robust method for chemical element-sensitive imaging by scanning electron microscopy (SEM). The commercial Auriga FE-SEM microscope (Carl Zeiss, Oberkochen, Germany), equipped with an energy-selective grid detector (EsB) as a part of the experimental setup, was applied for generation of chemical contrast at low accelerating voltages, which is gentle for sensitive samples. The EsB-grid detector, conceptually adapted by us as an energy retarding field analyzer (RFA), was used to detect the two-dimensional (2D) energy spectrum for the first time. The electron energy spectrum measured by sweeping the retarding grid potential revealed thresholds corresponding to electronic transitions in the specimen, followed by 2D-derivation treatment applied just at the observed thresholds. This allowed chemical mapping by SEM. In this report the 273 eV Auger transition in carbon deposited onto the Si(100) sample was chosen as a source for chemical contrast in the SEM image. In addition to Auger electrons, we expect analogous energy-selective contrast enhancement for inelastically scattered electrons, for example, in plasmonic contrast and elastically scattered electrons, for example in phase contrast, our method, proved for carbon, is expected to apply to a broader list of elements as a general capability of chemical mapping, at several fold better lateral resolution when compared with energy dispersive spectroscopy (EDS). PMID- 27974077 TI - Urinary iodine concentration identifies pregnant women as iodine deficient yet school-aged children as iodine sufficient in rural Niger. AB - OBJECTIVE: To assess iodine status among pregnant women in rural Zinder, Niger and to compare their status with the iodine status of school-aged children from the same households. DESIGN: Seventy-three villages in the catchment area of sixteen health centres were randomly selected to participate in the cross sectional survey. SETTING: Salt iodization is mandatory in Niger, requiring 20-60 ppm iodine at the retail level. SUBJECTS: A spot urine sample was collected from randomly selected pregnant women (n 662) and one school-aged child from the same household (n 373). Urinary iodine concentration (UIC) was assessed as an indicator of iodine status in both groups. Dried blood spots (DBS) were collected from venous blood samples of pregnant women and thyroglobulin (Tg), thyroid stimulating hormone and total thyroxine were measured. Iodine content of household salt samples (n 108) was assessed by titration. RESULTS: Median iodine content of salt samples was 5.5 ppm (range 0-41 ppm), 98 % had an iodine content 40 ug/l. CONCLUSIONS: In this region of Niger, most salt is inadequately iodized. UIC in pregnant women indicated iodine deficiency, whereas UIC of school-aged children indicated marginally adequate iodine status. Thus, estimating population iodine status based solely on monitoring of UIC among school-aged children may underestimate the risk of iodine deficiency in pregnant women. PMID- 27974078 TI - Operation Canine Lifeline: Recommendations for Enhancing Prehospital Care for Government Working Dogs. AB - Operation Canine Lifeline was a tabletop exercise developed by students and faculty of Boston University School of Medicine's Healthcare Emergency Management master's program. The tabletop exercise led to discussion on current protocols for canines working in the field, what occurs if a canine encounters a toxin in the field, and what to do in situations of national security that require working with civilian agencies. This discussion led to the creation of a set of recommendations around providing prehospital veterinary care to government working dogs. The recommendations include a government-run veterinary toxicology hotline for the sole use of the government, issuing handlers deployment kits and preprogrammed smartphones that contain information on the care practices for dogs, and an increased effort for civilian integration, through local emergency medical services, in the emergency care of government canines. (Disaster Med Public Health Preparedness. 2017;11:15-20). PMID- 27974079 TI - Positive correlation between regional emergency medical resources and mortality in severely injured patients: results from the Korean National Hospital Discharge In-depth Survey. AB - OBJECTIVES: In South Korea, injury is a public health problem due to its high incidence and high mortality. To improve emergency medical systems, the government announced plans to increase the emergency medical resources for each region. This study investigated the association between regional emergency medical resources and mortality during hospitalization in severely injured inpatients. METHODS: To analyse mortality for severely injured inpatients, we used the Korean National Hospital Discharge In-depth Survey data, consisting of 18,621 hospitalizations from 2005-2012. Generalized estimating equations were analysed to examine the association between mortality during hospitalization and both individual and regional variables. RESULTS: Mortality during hospitalization occurred in 913 (4.9%) cases. Patients in regions with a higher number of emergency departments (odds ratio [OR]=0.94, 95% confidence interval [CI]: 0.91 0.98), a higher number of ambulances (OR=0.99, 95% CI: 0.98-0.99), and a higher number of registered nurses per emergency department (OR=0.88, 95% CI: 0.83-0.94) had a lower risk of mortality during hospitalization. CONCLUSIONS: Our findings suggest that regional emergency medical resources are associated with a lower risk of mortality during hospitalization in severely injured patients. Thus, health care policymakers need to determine the proper distribution of emergency medical resources for each region and the function of emergency departments to provide a superior quality of emergency medical services to patients. PMID- 27974080 TI - Predictions of methane emission levels and categories based on milk fatty acid profiles from dairy cows. AB - Milk fatty acid (MFA) have already been used to model methane (CH4) emissions from dairy cows. However, the data sets used to develop these models covered limited variation in dietary conditions, reducing the robustness of the predictions. In this study, a data set containing 140 observations from nine experiments (41 Holstein cows) was used to develop models predicting CH4 expressed as g/day, g/kg dry matter intake (DMI) and g/kg milk. The data set was divided into a training (n=112) and a test data set (n=28) for model development and validation, respectively. A generalized linear mixed model was fitted to the data using the marginal R 2 (m) and the Akaike information criterion to evaluate the models. The coefficient of determination of validation (R 2 (v)) for different models developed ranged between 0.18 and 0.41. Form the intake-related parameters, only inclusion of total DMI improved the prediction (R 2 (v)=0.58). In addition, in an attempt to further explore the relationships between MFA and CH4 emissions, the data set was split into three categories according to CH4 emissions: LOW (lowest 25% CH4 emissions); HIGH (highest 25% CH4 emissions); and MEDIUM (50% remaining observations). An ANOVA revealed that concentrations of several MFA differed for observations in HIGH compared with observations in LOW. Furthermore, the Gini coefficient was used to describe the MFA distribution for groups of MFA in each CH4 emission category. The relative distribution of the MFA, particularly of the odd- and branched-chain fatty acids and mono-unsaturated fatty acids of observations in category HIGH differed from those in the other categories. Finally, in an attempt to validate the potential of MFA to identify cases of high or low emissions, the observations were re-classified into HIGH, MEDIUM and LOW according to the proportion of each individual MFA. The proportion of observations correctly classified were recorded. This was done for each individual MFA and for the calculated Gini coefficients, finding that a maximum of 67% of observations were correctly classified as HIGH CH4 (trans-12 C18:1) and a maximum of 58% of observations correctly classified as LOW CH4 (cis-9 C17:1). Gini coefficients did not improve this classification. These results suggest that MFA are not yet reliable predictors of specific amounts of CH4 emitted by a cow, while holding a modest potential to differentiate cases of high or low emissions. PMID- 27974081 TI - Electron Probe Microanalysis of Ni Silicides Using Ni-L X-Ray Lines - ERRATUM. PMID- 27974082 TI - The future of psychiatric rehabilitation. PMID- 27974083 TI - The ADAPT model: bridging the gap between psychosocial and individual responses to mass violence and refugee trauma. PMID- 27974084 TI - Insight, self-stigma and psychosocial outcomes in Schizophrenia: a structural equation modelling approach. AB - AIMS: Poor insight is prevalent in patients with schizophrenia and has been associated with acute illness severity, medication non-adherence and poor treatment outcomes. Paradoxically, high insight has been associated with various undesirable outcomes, including low self-esteem, depression and low subjective quality of life (QoL) in patients with schizophrenia. Despite the growing body of studies conducted in Western countries supporting the pernicious effects of improved insight in psychosis, which bases on the level of self-stigma, the effects are unclear in non-Western societies. The current study examined the role of self-stigma in the relationship between insight and psychosocial outcomes in a Chinese population. METHODS: A total of 170 outpatients with schizophrenia spectrum disorders were recruited from two general university hospitals. Sociodemographic data and clinical variables were recorded and self-report scales were employed to measure self-stigma, depression, insight, self-esteem and subjective QoL. Structural equation modelling (SEM) was used to analyse the cross sectional data. RESULTS: High levels of self-stigma were reported by 39% of the participants (n = 67). The influences of insight, self-stigma, self-esteem and depression on subjective QoL were confirmed by the SEM results. Our model with the closest fit to the data (chi 2 = 33.28; df = 20; p = 0.03; chi 2/df = 1.66; CFI = 0.98; TLI = 0.97; RMSEA = 0.06) demonstrated that self-stigma might fully mediate the association of insight with low self-esteem, depression and poor subjective QoL. High insight into illness contributed to self-stigma, which caused low self-esteem and depression and, consequently, low QoL. Notably, insight did not directly affect self-esteem, depression or QoL. Furthermore, the association of insight with poor psychosocial outcomes was not moderated by self stigma. CONCLUSIONS: Our findings support the mediating model of insight relevant to the poor psychosocial outcomes of individuals diagnosed with schizophrenia in non-Western societies, in which self-stigma plays a pivotal role. These findings elucidate the direct and indirect effects of insight on psychosocial outcomes and imply that identifying and correcting self-stigma in people with schizophrenia could be beneficial. Additional studies are required to identify whether several other neurocognitive or psychosocial variables mediate or moderate the association of insight with self-esteem, depression and QoL in patients with schizophrenia. Studies with detailed longitudinal assessments are necessary to confirm our findings. PMID- 27974086 TI - Pichia chibodasensis sp. nov., isolated in Indonesia. AB - Three strains (14Y260T, 14Y268 and 14Y276) of xylose-assimilating yeasts were isolated from decayed wood and soil collected in West Java in Indonesia. A phylogenetic analysis was performed based on the sequences of the D1/D2 domains of LSU, SSU and EF-1alpha, and the three strains were found to belong to the genus Pichia. The morphological, biochemical, physiological and chemotaxonomic characteristics indicated that these strains were distinct from other closely related species. Strains 14Y260T, 14Y268 and 14Y276 belonged to the Pichia clade and represent a novel species, named Pichia chibodasensis sp. nov. ; The type strain is 14Y260T (=NBRC 111569T=InaCC Y1042T). PMID- 27974085 TI - Reclassification of Aeromonas sharmana to a new genus as Pseudaeromonas sharmana gen. nov., comb. nov., and description of Pseudaeromonas pectinilytica sp. nov. isolated from a freshwater stream. AB - A Gram-reaction-negative, rod-shaped, facultatively anaerobic, motile bacterium, designated strain AR1T, was isolated from a freshwater stream in Jeonju, South Korea. Strain AR1T showed highest 16S rRNA gene sequence similarity (96.83 %) and also formed a separate clade with Aeromonas sharmana GPTSA-6T in the phylogenetic tree reconstructed among the members of the family Aeromonadaceae. Major cellular fatty acids are summed feature 3 (C16 : 1omega7c/C16 : 1omega6c) and C16: 0. Diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol are the predominant polar lipids. The genomic DNA G+C content was found to be 54.7 mol%. However, earlier studies on 16S rRNA gene, gyrB, rpoD and universal target region of cpn60 sequences of the members of the genus Aeromonas recommended the transfer of Aeromonas sharmana to a new genus. Hence, based on the comparative polyphasic data obtained during the present study and also on the previous recommendations, it is proposed that Aeromonas sharmana be transferred to a novel genus as Pseudaeromonas sharmana gen. nov., comb. nov. with strain GPTSA-6T (=DSM 17445T=MTCC 7090T=CIP 109378T=CCUG 54939T) as the type strain of the type species of the genus. Also, it is proposed that strain AR1T be designated as a representative of a novel species of this new genus, namely Pseudaeromonas pectinilytica sp. nov. The type strain is AR1T (=KCTC 42754T=JCM 31503T). PMID- 27974087 TI - Anaeromicrobium sediminis gen. nov., sp. nov., a fermentative bacterium isolated from deep-sea sediment. AB - A novel anaerobic, mesophilic, heterotrophic bacterium, designated strain DY2726DT, was isolated from West Pacific Ocean sediments. Cells were long rods (0.5-0.8 um wide, 4-15 um long), Gram-positive and motile by means of flagella. The temperature and pH ranges for growth were 25-40 degrees C and pH 6.5-9.0, while optimal growth occurred at 37 degrees C and pH 7.5, with a generation time of 76 min. The strain required sea salts for growth at concentrations from 10 to 30 g l-1 (optimum at 20 g l-1). Substrates used as carbon sources were yeast extract, tryptone, glucose, cellobiose, starch, gelatin, dextrin, fructose, fucose, galactose, galacturonic acid, gentiobiose, glucosaminic acid, mannose, melibiose, palatinose and rhamnose. Products of fermentation were carbon dioxide, acetic acid and butyric acid. Strain DY2726DT was able to reduce amorphous iron hydroxide, goethite, amorphous iron oxides, anthraquinone-2,6-disulfonate and crotonate, but did not reduce sulfur, sulfate, thiosulfate, sulfite or nitrate. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain DY2726DT was affiliated to the family Clostridiaceae and was most closely related to the type strains of Alkaliphilus transvaalensis (90.0 % similarity) and Alkaliphilus oremlandii (89.6 %). The genomic DNA G+C content was 33.4 mol%. The major cellular fatty acids of strain DY2726DT were C16 : 1, C14 : 0 and C16 : 0. On the basis of its phenotypic and genotypic properties, strain DY2726DT is suggested to represent a novel species of a new genus in the family Clostridiaceae, for which the name Anaeromicrobium sediminis gen. nov., sp. nov. is proposed. The type strain of Anaeromicrobium sediminis is DY2726DT (=JCM 30224T=MCCC 1A00776T). PMID- 27974088 TI - Nocardia xestospongiae sp. nov., isolated from a marine sponge in the Andaman Sea. AB - A marine sponge-derived actinomycete, strain ST01-07T, was isolated from Xestospongia sp. collected from the Andaman Sea. The strain was characterised taxonomically using a polyphasic approach. The strain contained meso diaminopimelic acid in the peptidoglycan, whole-cell sugars were arabinose, galactose, glucose, mannose and ribose. Mycolic acids that co-migrated with those from Nocardia araoensis NBRC 100135T were observed in whole-cell extracts. MK 8(H4omega-cycl) was the predominant menaquinone. Major cellular fatty acids were C17 : 1omega8c, C16 : 0 and C17 : 0. The diagnostic phospholipids in the cell consisted of diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol. Phylogenetic analysis based on the 16S rRNA gene sequence showed that strain ST01-07T belonged to the genus Nocardia and was most closely related to N. araoensis IFM 0575T (98.71 % 16S rRNA gene sequence similarity), Nocardia niwae W9241T (98.56 %), Nocardia beijingensis AS4.1521T (98.41 %) and Nocardia arthritidis IFM 10035T (98.36 %). In addition, low DNA-DNA relatedness values (13.6+/-0.1% to 40.1+/-0.6%) confirmed that strain ST01-07T represents a novel species of the genus Nocardia, for which the name Nocardia xestospongiae sp. nov., is proposed. The type strain is ST01-07T (=BCC 45622T=NBRC 109069T). PMID- 27974089 TI - Rhodosporidiobolus geoffroeae sp. nov., a basidiomycetous yeast isolated from the waste deposit of the attine ant Acromyrmex lundii. AB - A novel basidiomycetous yeast was isolated from the waste deposit of the attine ant Acromyrmex lundii (Hymenoptera: Formicidae). The field colony was located in Santurce town, Santa Fe province, Argentina. The description of the novel species was based on strain LLU043T. Analysis of the D1/D2 domains of the LSU rRNA gene sequences in GenBank demonstrated that strain LLU043T, belongs to the Rhodosporidiobolus clade and is closely related to Rhodosporidiobolus lusitaniae and Rhodosporidioboluscolostri with 97 % similarity to the two species. The novel species differs from R. lusitaniae and R. colostri in some physiological characteristics such as the lack of assimilation of cellobiose, salicin, succinate, citrate and ethylamine. The name Rhodosporidiobolus geoffroeae sp. nov. is proposed, with LLU043T (=CBS 12828T=CBMAI 1618T) as the type strain. PMID- 27974090 TI - Desulfuribacillus stibiiarsenatis sp. nov., an obligately anaerobic, dissimilatory antimonate- and arsenate-reducing bacterium isolated from anoxic sediments, and emended description of the genus Desulfuribacillus. AB - A novel anaerobic, Gram-stain-negative, endospore-forming bacterium, designated strain MLFW-2T, was isolated from anoxic sediments collected from the drainage area of a geothermal spring near Mono Lake, CA, USA. Optimal growth was achieved at 34 degrees C and pH 8.25-8.50 in medium containing 0.75 % (w/v) NaCl. Catalase, but not oxidase, was produced. Strain MLFW-2T was an obligate anaerobe capable of respiring with nitrate, nitrite, DMSO, arsenate, antimonate, selenate and selenite as terminal electron acceptors. Lactate, pyruvate, formate and H2 could serve as electron donors to support growth. The isolate was incapable of fermentation. The predominant fatty acids were C16 : 0, C16 : 1omega9c, C16 : 1omega7c, C18 : 1omega9c and C18 : 1omega7c. The major polar lipids were phosphatidylglycerol and phosphatidylethanolamine. The only isoprenoid quinone detected was menaquinone 7 (MK-7). The DNA G+C content was 38.2 mol%. Phylogenetic analysis based on the 16S rRNA gene sequence demonstrated that strain MLFW-2T was a member of the order Bacillales and was most closely related to Desulfuribacillus alkaliarsenatis AHT28T (93.9 % similarity). On the basis of phenotypic and phylogenomic evidence, strain MLFW-2T represents a novel species of the genus Desulfuribacillus, for which the name Desulfuribacillus stibiiarsenatis sp. nov. is proposed. The type strain is MLFW-2T (=DSM 28709T=JCM 30866T). An emended description of the genus Desulfuribacillus is also provided. PMID- 27974091 TI - Arachidicoccus ginsenosidivorans sp. nov., with ginsenoside-converting activity isolated from ginseng cultivating soil. AB - A Gram-reaction-negative, catalase- and oxidase-positive, aerobic, non-motile, light yellow and rod-shaped bacterium (designated Gsoil 809T) isolated from soil of ginseng field, was characterized by a polyphasic approach to clarify its taxonomic position. Strain Gsoil 809T was observed to grow optimally at 30 degrees C and at pH 7.0 on nutrient agar medium. Strain Gsoil 809T possessed beta glucosidase activity, which was responsible for its ability to transform protopanaxatriol-type ginsenoside Rg1 to ginsenoside Rh1. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain Gsoil 809T belongs to the genus Arachidicoccus of the family Chitinophagaceae and was most closely related to Arachidicoccusrhizosphaerae Vu-144T (98.1 % 16S rRNA gene sequence similarity). The DNA G+C content was 39.4 mol%. The DNA-DNA hybridization value between strain Gsoil 809T and A.rhizosphaerae Vu-144T was 41.27+/-1.03 %. The major polar lipids were phosphatidylethanolamine and an unknown polar lipid. The predominant quinone was MK-7. The major fatty acids were iso-C15 : 0, iso-C15 : 1 G, iso-C17 : 0 3-OH and summed feature 3, which supported the affiliation of Gsoil 809T to the genus Arachidicoccus. Strain Gsoil 809T contained homospermidineas the major polyamine. Moreover, the physiological and biochemical test results and low DNA-DNA relatedness value allowed the phenotypic and genotypic differentiation of strain Gsoil 809T from recognized species of the genus Arachidicoccus. Therefore, strain Gsoil 809T represents a novel species of the genus Arachidicoccus, for which the name Arachidicoccus ginsenosidivorans sp. nov. is proposed. The type strain is Gsoil 809T (=KCTC 22820T=JCM 30984T). PMID- 27974092 TI - Sporosalibacterium tautonense sp. nov., a thermotolerant, halophilic, hydrolytic bacterium isolated from a gold mine, and emended description of the genus Sporosalibacterium. AB - A novel strictly anaerobic, thermotolerant, moderately halophilic, organotrophic bacterium, strain MRo-4T, was isolated from a sample of a microbial mat, developed under the flow of subsurface water in TauTona gold mine, South Africa. Cells of the novel isolate stained Gram-positive and were motile, spore-forming rods, 0.2-0.3 um in width and 5-20 um in length. Strain MRo-4T grew at 25-50 degrees C, at pH 7.0-8.8 and at an NaCl concentration of 5-100 g l-1. The isolate was able to ferment yeast extract, peptone and mono-, oligo- and polysaccharides, including cellulose and chitin. Elemental sulfur, thiosulfate, sulfate, sulfite, nitrate, nitrite, fumarate and arsenate were not reduced. The major fatty acids were iso-C15 : 0, iso-C15 : 0 dimethyl acetyl and anteiso-C15 : 0. The G+C content of the DNA was 32.9 mol%. Phylogenetic analysis of 16S rRNA gene sequences of strain MRo-4T and its nearest relatives showed its affiliation to the genus Sporosalibacterium. Sporosalibacteriumfaouarense SOL3f37T, the only valid published representative of the genus, appeared to be its closest relative (96.8 % 16S rRNA gene sequence similarity). However, strains MRo-4T and S. faouarense SOL3f37T differed in temperature, pH and salinity ranges for growth, requirement for yeast extract and substrate profiles. Based on the phylogenetic analysis and physiological properties of the novel isolate, we propose a novel species, Sporosalibacterium tautonense sp. nov. The type strain is MRo-4T (=DSM 28179T=VKM B-2948T). PMID- 27974093 TI - Serum immunoglobulin G4 in giant cell arteritis and polymyalgia rheumatica. AB - OBJECTIVES: To date, no specific serum marker for giant cell arteritis and polymyalgia rheumatica has been established in routine practice. Therefore, the aim of this study was to examine whether immunoglobulin G4 serum concentrations could be a potential biomarker for the differentiation of both diseases. METHODS: Serum immunoglobulin G4 (IgG4) concentrations were measured in patients with giant cell arteritis (n=41) and polymyalgia rheumatica (n=27) by an in-house enzyme-linked immunosorbent assay. In the subgroup of untreated patients with disease activity (polymyalgia rheumatica n=27, giant cell arteritis n=19) additional parameters of T-helper 2 cell inflammatory responses were analysed. RESULTS: IgG4-values above the prior determined cut-off value of 1400 MUg/ml in giant cell arteritis were rare and also significantly less frequent in giant cell arteritis than in polymyalgia rheumatica patients (7.3% vs. 44.4%; p<0.001). The relative risk that patients with clinical features of PMR, presenting without elevated IgG4 levels, have simultaneously GCA was 5.8 compared to those patients with elevated IgG4 levels. In untreated patients absolute counts of eosinophilic leukocytes were lower in giant cell arteritis than in polymyalgia rheumatica (p=0.002) and the cytokines interleukin-4 (p=0.013) and interleukin-10 (p=0.033) were less frequently detectable in giant cell arteritis than in polymyalgia rheumatica. CONCLUSIONS: In giant cell arteritis serum levels of IgG4 usually are within the normal range. In polymyalgia rheumatica however, increased IgG4 serum levels are frequently found. Normal IgG4 serum levels in polymyalgia rheumatica may have predictive value in identifying patients with additional, clinically non apparent giant cell arteritis. PMID- 27974094 TI - Long-term safety of anti-TNF agents on the liver of patients with spondyloarthritis and potential occult hepatitis B viral infection: an observational multicentre study. AB - OBJECTIVES: The aim of the study was to retrospectively evaluate the long-term safety profile of anti-tumour necrosis factor (TNF)-alpha agents on the liver of patients with spondyloarthritis (SpA) and a previously resolved hepatitis B virus (HBV) infection. METHODS: Medical records from 992 consecutive outpatients receiving anti-TNF-alpha therapy between 2007 and 2015 were retrospectively reviewed. HBV infection was assessed evaluating HBV surface antigen (HBsAg), antibodies to HBsAg (anti-HBs), antibodies to hepatitis B core (anti-HBc), and HBV-DNA levels. In patients with a previously resolved HBV infection, serum levels of aminotransferase (AST/ALT) were also assessed every three months, while HBsAg and HBV-DNA every six months. RESULTS: We identified 131 consecutive patients (70 males, 61 females) with SpA and resolved HBV infection. At baseline none of the patients were positive for HBV-DNA, and AST/ALT levels were within the normal range with no subsequent increase during the observational treatment period. None received antiviral therapy prior to or during anti-TNF drug administration. At the end of the follow-up period (75.50+/-33.37 months) no viral reactivation was observed in anti-HBc positive patients, regardless of anti HBs positivity. During the whole follow-up, HBV-DNA was undetectable in all patients, HBsAg remained negative, and it was not necessary to discontinue biologic therapy because of liver damage. CONCLUSIONS: Our results confirm that pre-emptive antiviral prophylaxis may not be necessary routine, but strict monitoring for AST/ALT levels, as well as for changes in HBV serology and HBV-DNA remain necessary and seem a realistic and cost-effective approach to identify early viral reactivation. PMID- 27974095 TI - Occlusive vasculopathy in human immunodeficiency virus (HIV)-associated vasculitis: unusual clinical and imaging course. AB - Human immunodeficiency virus (HIV)-associated vasculitis is a rare secondary systemic vasculitis involving small and medium arteries. We report a 42-year-old man with uncontrolled HIV infection presenting with long-lasting abdominal pain. An abdominal CT angiography revealed multiple microaneurysms and stenoses in intrarenal arteries, with involvement of mesenteric and hepatic arteries. HIV associated vasculitis was diagnosed and glucocorticoids and raltegravir-based antiretroviral therapy were administered with good initial clinical and virological response. Several episodes of acute intestinal ischaemia were later developed requiring bowel resections of which histological examination showed vascular occlusive fibrotic changes without active vasculitic lesions. Vasculitis persisted in remission and intrarenal microaneurysms disappeared. PMID- 27974096 TI - Positive correlation between inflammation on sacroiliac joint MRI and serum C terminal telopeptide of type-I collagen in ankylosing spondylitis but not in non radiographic axial spondyloarthritis. AB - OBJECTIVES: To identify the clinical disease activity scores and laboratory markers that best reflect magnetic resonance imaging (MRI)-determined sacroiliac joint (SIJ) inflammation in ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). METHODS: This cross-sectional study included all consecutive patients who presented with axial spondyloarthritis in 2013-2015. All underwent SIJ MRI. The bone marrow oedema in the inflammatory lesions on MRI was scored using the SPondyloArthritis Research Consortium of Canada (SPARCC) method. Bone-specific alkaline phosphatase (BALP), serum C-terminal telopeptide of type-I collagen (sCTX-I), and inflammatory markers were measured. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS) were assessed. The correlations between the MRI determined SIJ inflammation scores and disease activity scores and laboratory variables were evaluated. RESULTS: Of the 81 patients with axSpA, 45 had AS and 36 had nr-axSpA. The AS and nr-axSpA groups did not differ in terms of disease activity scores, physical functional index, or MRI-determined SIJ inflammation. Erythrocyte sedimentation rate, C-reactive protein, and ASDAS correlated with MRI inflammatory scores in nr-axSpA but not in AS. sCTX-I correlated with MRI determined SIJ inflammatory scores in AS only. BASDAI and BALP levels did not associate with MRI inflammatory scores in either group. Multivariate analysis showed that sCTX-I associated independently with MRI inflammatory score in AS (beta=17.047, p=0.038). CONCLUSIONS: Inflammatory markers and ASDAS correlated with active sacroiliitis on MRI in nr-axSpA only. In AS, only sCTX-I correlated with active inflammation on SIJ MRI. sCTX-I may be useful as a marker of objective inflammation in AS. PMID- 27974097 TI - In early inflammatory polyarthritis more intensive management according to the 2010 ACR/EULAR criteria leads to higher rates of clinical remission: comparison of two cohorts treated according to different treat-to-target protocols. AB - OBJECTIVES: The aim of this study was to compare the 12-month probability of remission in early inflammatory arthritis with a milder treatment based on the 1987 criteria or a more intensive protocol based on the 2010 criteria. METHODS: Patients with rheumatoid arthritis (RA) or undifferentiated arthritis (UA) (2005 2012) were included. Before October 2010, patients fulfilling the 1987 criteria received methotrexate (MTX) and possibly low-dose prednisone, while UA hydroxychloroquine (HCQ) (1987-driven cohort). From October 2010, patients fulfilling the 2010 criteria received higher dose MTX and low-dose prednisone, while UA HCQ (2010-driven cohort). Treatment was increased to achieve DAS28 low disease activity. Clinical remission, defined by DAS28, was evaluated at subsequent visits in the whole population. Hazard ratios (HR) adjusted for age, sex, baseline DAS28, symptoms duration, MTX dose and prednisone were calculated by Cox regression. RESULTS: 677 patients were included (468 in 1987-driven cohort, 209 in 2010-driven cohort), with no significant differences in age, gender, autoantibodies and pain. The 2010-driven cohort had significantly fewer tender and swollen joints, lower acute phase reactants, DAS28 and HAQ and achieved more frequently remission even when the analysis was adjusted for all confounders (adjusted HR (95% CI) 1.73 (1.34, 2.22)) and limited to per protocol patients (adjusted HR (95%CI) 1.49 (1.11, 2.02). CONCLUSIONS: Treating patients with early arthritis according to a more intensive protocol leads to higher remission rate. The results of this study support the use of a strategy led by the 2010 criteria with more intensive treatment strategies in the management of early arthritis. PMID- 27974098 TI - Use of biologic agents in idiopathic inflammatory myopathies in Sweden: a descriptive study of real life treatment. AB - OBJECTIVES: Biologic treatment has revolutionised treatment in rheumatology in the last decades. Patients with idiopathic inflammatory myopathies (IIM) have so far only been treated with biologics off-label, with little published follow-up on those who are treated and how they are treated. We therefore set out to characterise the Swedish IIM patients who have been treated with biologics. METHODS: By linking Swedish registers we identified 95 patients with IIM who were treated with biologics between 2000 and 2011. Via chart review the diagnoses were validated and clinical characteristics extracted. RESULTS: In total, 95 individuals with IIM and biologic treatment were identified. Median disease duration was 5.5 years at start of biologics. All patients had been treated with prednisolone and failed at least one previous DMARD before the start of first biologic. Rituximab was the most common biologic drug, followed by anakinra and TNFinhibitors. Median overall treatment length was 10 months and varied between 5 and 12.5 months or the different therapies. CONCLUSIONS: Off-label treatment of IIMs is often tried and seldom successful. This study shows a large unmet need for novel treatments and therapies in IIM. It is therefore important to follow these patients in a structured way to learn about effects and potential risks for different subgroups of IIM associated with different therapies. PMID- 27974099 TI - TNF inhibitors increase fat mass in inflammatory rheumatic disease: a systematic review with meta-analysis. AB - OBJECTIVES: To assess body composition of patients with inflammatory rheumatic disease and the effect of TNF inhibitors on it. METHODS: This was systematic review with meta-analysis of studies consulted on PubMed, Cochrane Library and EMBASE and assessing body composition in patients with rheumatoid arthritis or spondyloarthritis. We compared i) patients with healthy controls and ii) body components before and after TNF inhibitors. RESULTS: Among the 703 articles reviewed, 19 met the inclusion criteria. In patients with rheumatoid arthritis, a significant increase in fat mass (+1.85 kg, p=0.02), adiposity (+3.53%, p<0.00001) and android mass (+1.7 kg, p<0.00001) and a significant decrease in lean mass (-3.03 kg, p=0.01), were observed. In patients with spondyloarthritis, a significant but modest increase in fat mass (+0.69 kg, p=0.03) and a significant decrease in lean mass (-3.74 kg, p=0.03) were observed. Nine studies assessed impact of TNF inhibitors on body composition, with an increase of fat mass in the short and long term in all studies. Data on lean mass were controversial. Two studies found an increase in visceral or android mass under TNF inhibitors. CONCLUSIONS: Patients with inflammatory rheumatic disease have a significant decrease in lean mass and increase in fat mass. The use of TNF inhibitors is associated with a further increase in fat mass including android fat, which could potentially have cardiovascular consequences. PMID- 27974100 TI - Clinical and genetic associations of radiographic sacroiliitis and its different patterns in psoriatic arthritis. AB - OBJECTIVES: We aimed to 1) identify clinical and genetic associations of sacroiliitis (SI) in patients with psoriatic arthritis (PsA), and 2) describe the different radiographic patterns of SI in PsA and their clinical and genetic associations. METHODS: 283 PsA patients, fulfilling CASPAR criteria, underwent detailed skin and rheumatologic assessments. In addition, HLA-B*27 and B*080101 status was recorded, which have been shown as the key genetic markers of radiographic SI in PsA. Grade 2 Unilateral or bilateral radiographic changes of SI were required for inclusion and involvement was further defined as asymmetrical or symmetrical. RESULTS: 70 patients (25%) had radiographic SI; all either with a present or past history of backache. Regression analysis demonstrated a significant association of SI with peripheral joint erosions (p=0.043), PASI maximum (p=0.041), younger age of PsA onset (p=<0.001), presence of HLA-B*0801 (p=0.002) and only marginal significance with HLA-B*2705 (p=0.059). Asymmetrical SI was noted in 51 patients (73%). In striking contrast to those patients with symmetrical SI, patients with asymmetrical SI were more likely to be female (p=0.04), have a trend towards more severe nail disease (p=0.08) and peripheral joint erosions (p=0.08), more osteolysis (p=0.01), more HLA-B*0801 positivity (p=0.001) and much less HLA-B*270502 positivity (p=<0.001). CONCLUSIONS: PsA developing at a younger age, severe skin disease, peripheral joint erosions, and HLA-B*0801 are significantly associated with SI, and there was only a marginal trend towards significance for HLA-B*2705. HLA-B*27 positive Axial-PsA patients resemble AS, while HLA-B*0801 positive Axial-PsA patients have asymmetrical and/or unilateral SI, which are typical of PsA. PMID- 27974101 TI - Response to methotrexate predicts long-term mortality of patients with rheumatoid arthritis independent of the degree of response: results of a re-evaluation 30 years after baseline. AB - OBJECTIVES: To assess if there is a correlation between the degree of response to treatment with methotrexate (MTX) and long-term mortality in a cohort of patients with rheumatoid arthritis (RA) established in Germany in the early eighties. METHODS: RA patients who had started MTX treatment between 1980 and 1987 were included. One year after baseline, the treatment response was evaluated. Responders were defined as patients with at least 20% decline in the swollen joint count (out of 32 joints) and the ESR with a prednisone dosage <5 mg/day. Thereafter, assessments were performed at 10, 18, and 30 years after baseline. Standardised mortality ratios (SMR) were calculated, Cox regression and logistic regression were performed. RESULTS: The cohort comprised 271 patients. In 2015, about 30 years after the initiation of MTX therapy, 185 patients (68%) were deceased, 52 (19%) lost to follow-up and 34 alive. The response after the first year of MTX treatment was the strongest predictor of survival with a hazard ratio of 0.44 (95% confidence interval [CI]: 0.30-0.65). However, even responders still had an SMR of 1.37 (95% CI 1.31-1.65), but this was much worse for non-responders who had an SMR of 4.22 (95% CI 3.13-5.56). Using Cox regression analysis no difference was detected between responders with more than 50% improvement (38% of all patients) and those with 20-50% improvement (28%). CONCLUSIONS: The predictive value of a response to one year of MTX therapy for long-term mortality of RA patients is independent of the degree of response. PMID- 27974102 TI - Role for a water-soluble form of CoQ10 in female subjects affected by fibromyalgia. A preliminary study. AB - Decreased antioxidant capacity and increased oxidative stress have been observed in fibromyalgia patients. Some trials have also shown that CoQ10 levels are reduced in these patients but that supplementation can restore levels and reduce fibromyalgia symptoms, including pain and fatigue. We evaluated the effect of administration of a finished form of CoQ10 (DDM Chinone(r)) at a dose of 200 mg*2/day in 22 female subjects with a diagnosis of fibromyalgia in a randomized, open-label, cross-over study. Our results show that, compared to a control group, administration of CoQ10 significantly improved most pain-related outcomes by 24 37%, including fatigue (by ~22%) and sleep disturbance (by ~33%). These results confirm the considerable role played by CoQ10 in reducing pain, fatigue, and sleep disturbance in subjects affected by fibromyalgia. PMID- 27974103 TI - Disease activity and vascular involvement in retroperitoneal fibrosis: first experience with fully integrated 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging compared to clinical and laboratory parameters. AB - OBJECTIVES: The aim of this study was to evaluate the value of fully integrated [18F]-FDG PET/MRI in the assessment of retroperitoneal fibrosis with regard to disease activity, extent and vascular involvement compared to clinical and laboratory parameters. METHODS: Seventeen [18F]-FDG PET/MRI examinations were performed in fourteen patients. Qualitative (visual 4-point scale) and quantitative PET parameters (maximum standardised uptake value, SUVmax; target background ratio, TBR) as well as RF thickness and volume were correlated to clinical and inflammatory parameters and compared between therapy-naive patients and patients under immunosuppression. Evidence for associated large-vessel vasculitis was examined. Magnetic resonance angiography (MRA) was performed to detect aneurysms or stenoses. RESULTS: Clinical parameters, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) only incompletely displayed inflammatory activity and did not correlate with PET/MRI parameters. In 29% (4/17) resp. 50% (8/16) of PET/MRI examinations active disease was detected although CRP resp. ESR were in the normal range. SUVmax, TBR and volume of the retroperitoneal mass differed significantly between therapy-naive patients and patients under therapy (SUVmax p=0.004, TBR p=0.015, volume p=0.015), whereas thickness of the retroperitoneal mass did not (p=0.406). Large-vessel vasculitis was detected in 21% (3/14) and aortic aneurysms in 14% (2/14) of patients. Vasculitis occurred apart from the site of RF in two patients. CONCLUSIONS: Whole body hybrid [18F]-FDG-PET/MRI is superior to clinical and inflammatory parameters in disease activity assessment of RF. There may be substantial disease activity despite inflammatory parameters in the normal range. Associated large-vessel vasculitis and aneurysms may occur apart from the site of RF. PMID- 27974104 TI - Long-term safety and efficacy of canakinumab in cryopyrin-associated periodic syndrome: results from an open-label, phase III pivotal study in Japanese patients. AB - OBJECTIVES: To assess the long-term safety and efficacy of canakinumab in Japanese patients with cryopyrin-associated periodic syndrome (CAPS). METHODS: In this open-label phase 3 study, Japanese patients aged >=2 years with CAPS received canakinumab 2-8 mg/kg subcutaneously every 8 weeks. The duration of the core treatment phase was 24 weeks followed by 22 months extension phase. The primary objective was the proportion of patients free of clinical and serologic relapse at week 24. RESULTS: The study enrolled 19 Japanese patients (median age, 14 years; range, 2-48 years) with CAPS [MWS, 7 (36.8%); NOMID, 12 (63.2%)] for a median of 109 weeks. Fifteen patients (79%) achieved a complete response by day 15, 18 (94.7%) by week 24 and all by week 48. At the end of the study, 18 (95%) were free from relapse and 11 (57.9%) were assessed as having no disease activity by the PGA. Thirteen (68%) patients (MWS, 4; NOMID, 9) had their canakinumab dose increased during the trial. All patients experienced at least one adverse event (AE), the most common being infections (100%) and 5 (26.3%) reported serious AEs. No deaths were reported and the only patient who discontinued the study early withdrew consent. CONCLUSIONS: Regular canakinumab treatment every 8 weeks at dose levels from 2-8 mg/kg, based on the clinical need, represents a successful strategy to induce rapid and complete response while maintain long-term disease control in Japanese patients with CAPS. The safety profile of canakinumab was consistent with that observed from previous studies. PMID- 27974105 TI - Anti-TNF treatment response in rheumatoid arthritis patients with moderate disease activity: a prospective observational multicentre study (MODERATE). AB - OBJECTIVES: Rheumatoid arthritis (RA) patients with moderate disease activity show progression of joint damage and have impaired quality of life, physical function, work and daily activities. Little is known about management of patients with moderate RA. The aim of the study was to assess the 1-year response to anti TNF in biologic-naive RA patients with moderate (3.2 =18 years, had disease onset after 16 years old, moderate disease at baseline (DAS28 score >3.2 and <=5.1), and were naive to anti TNF treatment. RESULTS: Among 157 RA patients, 93 (59%) underwent etanercept, 43 (22%) adalimumab, 26 (17%) certolizumab, 10 golimumab and 2 infliximab; 80% of patients were still in treatment after 12-month observation. One-year clinical remission was achieved by 27 RA patients (21%), reduction of DAS28 score greater than 1.2 was observed in 75 (58%) patients. Moderate and good response according to EULAR criteria was observed in 59 (46%) and 45 (35%) patients, respectively. CONCLUSIONS: Results confirm the efficacy of anti-TNF alpha also in moderate RA patients, who may achieve a substantial decrease of disease activity, and improve their quality of life. The low rate of patients achieving remission may suggest that therapeutic strategies should be more timely and aggressive. PMID- 27974107 TI - [An interpretation of consensus statements on diagnostic criteria for multiple sclerosis and demyelinating diseases of the central nervous system in children (2012 version)]. AB - The International Pediatric Multiple Sclerosis Study Group (IPMSSG) put forward the 2007 version of the diagnostic criteria for multiple sclerosis and other immune-mediated demyelinating diseases of the central nervous system in children in 2007 ("2007 version" for short). In 2012, IPMSSG proposed the new diagnostic criteria with reference to the latest research achievements of 150 members ("2012 version" for short). The 2012 version of the consensus statements covers the diagnostic criteria for acute disseminated encephalomyelitis, clinically isolated syndrome, neuromyelitis optica, and multiple sclerosis in children. As the two IPMSSG members in China, the authors give an interpretation of the 2012 version of the consensus statements with reference to related literature and clinical and scientific experience. The authors focus on how the 2012 version comprehensively and thoroughly elaborates on the clinical features, diagnostic criteria, influencing factors, and new ideas of acute demyelinating diseases of the central nervous system in children. These become more operable in clinical diagnosis and treatment of multiple sclerosis and other immune-mediated demyelinating diseases of the central nervous system in children. PMID- 27974106 TI - Fulminant bilateral papilloedema during low-dose steroid taper in a child with systemic idiopathic arthritis treated with tocilizumab. AB - Systemic juvenile idiopathic arthritis (SJIA) is one of the most severe forms of arthritis that affects children younger than 16 years of age at onset. SJIA often requires corticosteroids to control the inflammation. However, long-term corticosteroid use may have adverse effects, including intracranial hypertension (IH). Biologic therapies have been used as corticosteroid sparing agents. We report the first case of a child with steroid-dependent SJIA treated with tocilizumab, an IL-6 receptor monoclonal antibody, who developed fulminant IH, bilateral papilloedema and vision loss when oral prednisone was weaned from 2 to 1 mg per day. Despite repeated lumbar punctures and high dose acetazolamide, he required urgent unilateral optic nerve sheath fenestration (ONSF). This endoscopic surgical intervention released the pressure exerted by the cerebrospinal fluid on the optic nerve and stopped the progression of vision loss. Nine weeks after the diagnosis of bilateral papilloedema, his vision was completely restored in one eye and partially recovered in the contralateral one. Long-term treatment with corticosteroids even at very low dose and tocilizumab may predispose to severe IH, papilloedema and vision loss. The role that tocilizumab might have played in this case in unclear. Early recognition and prompt treatment of papilloedema is crucial in avoiding permanent vision loss. Fulminant papilloedema in an immunocompromised child carries additional significant challenges. Early ONSF is a safe and effective intervention in refractory papilloedema. Children with severe papilledema secondary to IH should be managed by a multidisciplinary team in tertiary centres. PMID- 27974108 TI - [Screening and identification of apolipoprotein A-I as a potential marker for hepatoblastoma in children]. AB - OBJECTIVE: To screen and identify serum biomarkers for childhood hepatoblastoma (HB). METHODS: The serum samples from 30 children with hepatoblastoma (HB), 20 children with systemic inflammatory response syndrome, and 20 normal children were treated with magnetic bead-based weak cation exchange chromatography. The platform of surface-enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS) was used to eliminate the interference of inflammatory factors and to screen out the differentially expressed proteins in serum between tumor group and normal group. After the purification and separation of target proteins were performed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, matrix-assisted laser desorption/ionization-time of flight-mass spectrometry was used to determine their amino acid sequences. The SwissProt database was searched for matched proteins. Finally, real-time PCR and ELISA were used to verify and measure the expression of target proteins. RESULTS: After SELDI-TOF-MS was used for screening and elimination of the interference of inflammatory factors, a differentially expression protein with a mass-to-charge ratio of 9 348 Da was found in serum between HB group and normal group, and the HB group had significantly lower expression of this protein than the normal group (p<0.05). This protein was identified as apolipoprotein A-1 (Apo A-I). Real-time PCR and ELISA verified the low mRNA and protein expression of Apo A-I in serum in the HB group and high expression in serum in the normal group. CONCLUSIONS: Apo A I can be used as a non-inflammatory protein marker for HB and has a certain value in the early diagnosis of HB. PMID- 27974109 TI - [Expression of WT1 gene in children with acute myeloid leukemia]. AB - OBJECTIVE: To study WT1 gene expression in children with acute myeloid leukemia (AML) and its possible correlations to clinical outcomes. METHODS: Bone marrow samples were collected from 45 children with AML (excluding acute promyelocytic leukemia, AML-M3) at different time points of AML treatment and follow-up. WT1 gene expression levels in bone marrow mononuclear cells were assayed by real-time fluorescence quantitative PCR. The correlation between WT1 expression and prognosis was retrospectively analyzed. RESULTS: The WT1 expression level in AML children with bone marrow blast cell percentage of >60% was significantly higher than in those with bone marrow blast cell percentage of <= 60% (p<0.05). The lower WT1 expression level was documented in children with AML-M2 compared with in children with other non-M2 subtypes (p<0.05). WT1 expression level in patients in complete remission was significantly lower than that in patients at diagnosis or relapse (p<0.01). The 2-year disease-free survival (DFS) in patients with higher WT1 expression was significantly lower than in those with lower WT1 expression at the end of induction chemotherapy (p<0.05). The 2-year overall survival (OS) and DFS in patients with >=1 log WT1 reduction range were significantly higher than those with <1 log reduction of WT1 expression level at the end of induction chemotherapy (p<0.05). WT1 expression levels tended to rise 2-3 months prior to bone marrow relapse. CONCLUSIONS: WT1 expression level is closely correlated prognosis in children with AML. Dynamic monitoring of WT1 expression level is of great clinical importance in terms of individualized management, prognosis evaluation and relapse prediction. PMID- 27974110 TI - [Clinical features and outcomes of neuroblastoma patients aged above 5 years]. AB - OBJECTIVE: To investigate the clinical features and outcomes of neuroblastoma (NB) children aged above 5 years, and to provide a theoretical basis for improving prognosis. METHODS: A retrospective analysis was performed for the clinical data of 54 previously untreated NB children, and their clinical features and outcome were analyzed. The Kaplan-Meier method was used for survival analysis. RESULTS: Among the 54 children, there were 36 boys and 18 girls, and all of them had stage 3 or 4 NB. Of all the children, 41 (41/54, 76%) had retroperitoneal space-occupying lesions, 10 (10/54, 18%) had mediastinal space occupying lesions, 2 (2/54, 4%) had intraspinal space-occupying lesions, and 1 (1/54, 2%) had pelvic space-occupying lesions. At the end of the follow-up, 30 children (30/54, 56%) survived, among whom 23 (77%) achieved disease-free survival (9 achieved complete remission after chemotherapy for recurrence), 6 (20%) achieved partial remission of tumor (all of them received chemotherapy again due to recurrence), and 1 (3%) experienced progression (with progression after chemotherapy again due to recurrence); 24 children (44%) died, among whom 22 died after chemotherapy again due to recurrence and 2 died of multiple organ failure during the first treatment. According to the Kaplan-Meier survival analysis, the mean survival time was 53.8 months, and the children with stage 3 NB had a significantly higher overall survival rate than those with stage 4 NB (80% vs 53%; p<0.01). The children with recurrence had a significantly lower mean survival time than those without recurrence (51.68 months vs 62.57 months; p<0.01). CONCLUSIONS: Older children often have late-stage NB, but standard treatment can improve their outcomes. PMID- 27974111 TI - [Expression of regulatory T cells and natural killer T cells in peripheral blood of children with Wilms tumor]. AB - OBJECTIVE: To study the changes and clinical significance of CD4+CD25+CD127low regulatory T cells (Treg) and CD3+CD16+CD56+ natural killer T cells (NKT) in peripheral blood of children with Wilms tumor. METHODS: Twenty-one children with Wilms tumor were enrolled as the case group, and twenty-one healthy children for physical examinations were enrolled as the control group. Flow cytometry was used to detect the levels of CD4+CD25+CD127low T cells and CD3+CD16+CD56+ T cells in peripheral blood of two groups. RESULTS: The level of Treg cells in peripheral blood of the case group was significantly lower than in the control group (p<0.05). The level of NKT cells in peripheral blood of the case group was significantly higher than in the control group (p<0.05). CONCLUSIONS: Treg cells and NKT cells play important roles in the occurrence and development of Wilms tumor. Treg cells and NKT cells may be useful indexes for evaluating immunological function in children with Wilms tumor. PMID- 27974112 TI - [Effect of early caffeine treatment on the need for respirator therapy in preterm infants with respiratory distress syndrome]. AB - OBJECTIVE: To study the efficacy of early caffeine treatment in preterm infants with respiratory distress syndrome (RDS). METHODS: A prospective controlled clinical trial was performed. A total of 59 preterm infants with RDS were enrolled and divided into a caffeine group (30 infants) and a control group (29 infants). Caffeine was administered in the caffeine group and control group at the same dosage at 12-24 hours after birth and before extubation respectively. The respirator parameters and the incidence rates of ventilator-associated pneumonia (VAP) and apnea were compared between the two groups. RESULTS: Compared with the control group, the caffeine group had significantly lower peak inspiratory pressure, peak fraction of inspired oxygen, and incidence rate of VAP (p<0.05), as well as significantly shorter intubation time, NCPAP time, and total duration of oxygen supply (p<0.05). In addition, the caffeine group had a significantly longer time to first onset of apnea after extubation (p<0.05) and significantly fewer times of onset of apnea 1-2 days after extubation (p<0.01), as compared with the control group. CONCLUSIONS: Early caffeine treatment can reduce the need for assisted ventilation in preterm infants with RDS, help with early extubation and ventilator weaning, reduce the oxygen time in the late stage, reduce the incidence of VAP, and prevent the development of apnea after extubation. PMID- 27974113 TI - [Association between maternal pre-pregnancy body mass index and adverse outcomes of late preterm infants]. AB - OBJECTIVE: To study the association between maternal pre-pregnancy body mass index (BMI) and adverse outcomes of late preterm infants (LPI). METHODS: A total of 367 LPI who were born from January 2011 to December 2015 and admitted to the neonatal ward were enrolled. The BMI criteria for Chinese population were used to analyze the factors for maternal pre-pregnancy BMI and its association with adverse outcomes of LPI (1 minute Apgar score <=7, delivery room resuscitation, hospitalization days after birth >7 days, and ventilation duration >=6 hours). RESULTS: Of all LPIs, there were 64 LPI (17.4%) in the low maternal pre-pregnancy BMI group, 243 LPI (66.2%) in the normal maternal pre-pregnancy BMI group, and 60 LPI (16.4%) in the high maternal pre-pregnancy BMI group. Low pre-pregnancy BMI was the risk factor for 1 minute Apgar score <=7 (OR=3.243, 95% CI: 1.102-9.546) and need for delivery room resuscitation (OR=3.492, 95%CI: 1.090-11.190), and high pre-pregnancy BMI was the risk factor for hospitalization days after birth >7 days (OR=1.992, 95%CI: 1.024-3.874). CONCLUSIONS: Abnormal maternal pre pregnancy BMI has adverse effects on the outcomes of LPI. In order to reduce these adverse outcomes BMI should be controlled within the normal range in pregnant women. PMID- 27974114 TI - [Clinical efficacy of porcine pulmonary surfactant combined with budesonide suspension intratracheal instillation in the treatment of neonatal meconium aspiration syndrome]. AB - OBJECTIVE: To study the clinical efficacy of porcine pulmonary surfactant (PS) combined with budesonide suspension intratracheal instillation in the treatment of neonatal meconium aspiration syndrome (MAS). METHODS: Seventy neonates with MAS were enrolled for a prospective study. The neonates were randomly assigned to PS alone treatment group and PS+budesonide treatment group (n=35 each). The PS alone treatment group was given PS (100 mg/kg) by intratracheal instillation. The treatment group was given budesonide suspension (0.25 mg/kg) combined with PS (100 mg/kg). RESULTS: The rate of repeated use of PS in the PS+ budesonide group was significantly lower than that in the PS alone group 12 hours after treatment (p<0.05). The improvement of PaO2/FiO2, TcSaO2, PaO2, and PaCO2 in the PS+ budesonide group was significantly greater than that in the PS alone group 6, 12, and 24 hours after treatment (p<0.05). The chest X-ray examination showed that the pulmonary inflammation absorption in the PS+ budesonide group was significantly better than that in the PS alone group 48 hours after treatment (p<0.05). The incidence of complications in the PS+budesonide group was significantly lower than that in the PS alone group (p<0.05), and the average hospitalization duration was significantly shorter than that in the PS alone group (p<0.01). CONCLUSIONS: PS combined with budesonide suspension intratracheal instillation for the treatment of neonatal MAS is effective and superior to PS alone treatment. PMID- 27974115 TI - [Maple syrup urine disease and gene mutations in twin neonates]. AB - OBJECTIVE: To investigate the clinical features of one pair of twin neonates with maple syrup urine disease (MSUD) in the Chinese Han population and pathogenic mutations in related genes, and to provide guidance for the early diagnosis and treatment of MSUD. METHODS: The clinical and imaging data of the twin neonates were collected. The peripheral blood samples were collected from the twin neonates and their parents to detect the genes related to MSUD (BCKDHA, BCKDHB, DBT, and DLD). The loci with gene mutations were identified, and a bioinformatic analysis was performed. RESULTS: Two mutations were detected in the BCKDHB gene, missense mutation c.304G>A (p.Gly102Arg) and nonsense mutation c.331C>T (p.Arg111*), and both of them were heterozygotes. The mutation c.304G>A (p.Gly102Arg) had not been reported in the world. Their father carried the missense mutation c.304G>A (p.Gly102Arg), and their mother carried the nonsense mutation c.331C>T (p.Arg111*). CONCLUSIONS: The c.331C>T (p.Arg111*) heterozygous mutation in BCKDHB gene is the pathogenic mutation in these twin neonates and provides a genetic and molecular basis for the clinical features of children with MSUD. PMID- 27974116 TI - [Association between tumor necrosis factor-alpha G-308A polymorphisms and genetic susceptibility to spontaneous preterm birth]. AB - OBJECTIVE: To study the association between tumor necrosis factor-alpha (TNF alpha) G-308A polymorphisms and genetic susceptibility to spontaneous preterm birth (SPTB). METHODS: The case group enrolled 753 SPTB infants and the control group included 681 term infants. TNF-alpha G-308A polymorphisms were genotyped using Sequenom MassARRAY(r)SNP. RESULTS: The frequencies of the allele (G and A) in the case and control groups were not significantly different (P=0.35). The frequencies of the genotypes (GG, GA and AA) in the case and control groups were not significantly different (P=0.64). The logistic regression analysis found that TNF-alpha G-308A was not associated with genetic susceptibility to SPTB (OR=0.85; 95%CI: 0.61-1.19; P=0.35). CONCLUSIONS: There is no association between the polymorphisms of TNF-alpha G-308A and the genetic susceptibility to SPTB. PMID- 27974117 TI - [Association of T lymphocyte subsets and allergens with Mycoplasma pneumoniae infection complicated by wheezing in infants and young children]. AB - OBJECTIVE: To investigate the percentage of T lymphocyte subsets and allergen screening results in infants and young children with Mycoplasma pneumoniae (MP) infection complicated by wheezing. METHODS: Flow cytometry was used to measure the percentage of peripheral blood T cell subsets in 354 infants and young children with MP infection complicated by wheezing (MP wheezing group), 336 infants and young children with MP infection but without wheezing (MP non wheezing group), and 277 children with recurrent wheezing (recurrent wheezing group). Allergen screening was also performed for these children. RESULTS: Both the MP wheezing group and recurrent wheezing group had significantly lower percentages of CD3+ and CD3+CD8+ lymphocytes than the MP non-wheezing group (p<0.05). The MP groups with or without wheezing had a significantly higher percentage of CD3+CD4+ lymphocytes than the recurrent wheezing group (p<0.05). Both the MP wheezing group and recurrent wheezing group had significantly higher percentages of CD3-CD19+ and CD19+CD23+ lymphocytes than the MP non-wheezing group (p<0.05), and the recurrent wheezing group had the highest percentages (p<0.05). The overall positive rate of food allergens was significantly higher than that of inhaled allergens (30.3% vs 14.7%; p<0.05). The positive rates of food and inhaled allergens in the recurrent wheezing group and MP wheezing group were significantly higher than in the MP non-wheezing group (p<0.05), and the recurrent wheezing group had the highest rates. CONCLUSIONS: Imbalance of T lymphocyte subsets and allergic constitution play important roles in the pathogenesis of MP infection complicated by wheezing in infants and young children. PMID- 27974118 TI - [Risk factors for recurrent wheezing in infants and young children suffering from dust mite allergy after their first wheezing]. AB - OBJECTIVE: To investigate the risk factors for recurrent wheezing in infants and young children suffering from dust mite allergy after their first wheezing. METHODS: A total of 1 236 infants and young children who experienced a first wheezing episode and were hospitalized between August 2014 and February 2015 were enrolled, among whom 387 were allergic to dust mites. These infants and young children were followed up to 1 year after discharge. A total of 67 infants and young children who experienced 3 or more recurrent wheezing episodes within 1 year were enrolled as the recurrent wheezing group, while 84 infants and young children who did not experience recurrent wheezing during follow-up were enrolled as the control group. Univariate analysis and multivariate logistic stepwise regression analysis were performed to investigate the risk factors for recurrent wheezing in these patients. RESULTS: The univariate analysis showed that the age on admission, wheezing time before admission, Mycoplasma pneumoniae infection rate, and influenza virus infection rate were associated with recurrent wheezing. The multivariate logistic stepwise regression analysis showed that the older age on admission (OR=2.21, P=0.04) and Mycoplasma pneumoniae infection (OR=3.54, P=0.001) were independent risk factors for recurrent wheezing. CONCLUSIONS: Infants and young children who are allergic to dust mites, especially young children, have a significantly increased risk of recurrent wheezing if they are complicated by Mycoplasma pneumoniae infection during the first wheezing episode. PMID- 27974119 TI - [Relationship between interleukin-17A gene polymorphisms and the susceptibility to childhood asthma]. AB - OBJECTIVE: To explore the relationship between polymorphisms of interleukin-17A (IL-17A) gene promoter (-197G/A and -692C/T) and the susceptibility to childhood asthma, to further identify the candidate genes for asthma, and to provide a basis for early prevention of asthma in high-risk children. METHODS: Sixty-five outpatients or inpatients with childhood asthma between August 2013 and August 2015 were assigned to asthma group. Seventy healthy children within the same period were assigned to control group. Using peripheral venous blood from the two groups, PCR with sequence-specific primers was carried out to determine single nucleotide polymorphisms at positions -197G/A and -692C/T in IL-17A gene promoter. A statistical analysis was used to evaluate differences in genotype and allele frequencies between the two groups. RESULTS: Compared with the control group, the asthma group had significantly higher frequencies of TT genotype (29% vs 16%; P=0.012) and T allele (52% vs 42%; P=0.039) at position -692C/T of IL-17A gene. Children with T allele had 1.413-fold higher risk of childhood asthma than those with C allele (OR=1.413, 95%CI: 1.015-1.917). There were no significant differences in genotype and allele frequencies at position -197G/A in IL-17A gene between the two groups (p>0.05). CONCLUSIONS: Polymorphisms at position -692C/T in IL-17A gene promoter is associated with the susceptibility to childhood asthma. Children with -692T allele are more susceptible to childhood asthma. There is no significant relationship between polymorphisms at position -197G/A in IL-17A gene promoter and the susceptibility to childhood asthma. PMID- 27974120 TI - [Influencing factors for duration of viral nucleic acid shedding in children with influenza A]. AB - OBJECTIVE: To investigate the features and duration of viral nucleic acid shedding in children with influenza A. METHODS: The clinical data of 90 children with influenza A with positive influenza A virus nucleic acid in nasopharyngeal swab detected by PCR were collected, and these children were divided into simple influenza A group (n=10), influenza A-pneumonia group (n=61), influenza A-nervous system damage group (n=10), and influenza A-underlying disease group (n=9). A retrospective analysis was performed for clinical features, treatment process, duration of viral nucleic acid shedding, and prognosis. RESULTS: The most common symptoms in these children were fever (89/90, 99%), cough (89/90, 99%), running nose (69/90, 77%), shortness of breath (26/90, 29%), and myalgia (23/90, 26%). The mean duration of viral nucleic acid shedding in 90 children was 9.4+/-2.9 days. The simple influenza A group had a significantly shorter duration of viral nucleic acid shedding than the influenza A-pneumonia, influenza A-nervous system damage, and influenza A-underlying disease groups (p<0.05), while there were no significant differences between the influenza A-pneumonia, influenza A-nervous system damage, and influenza A-underlying disease groups (p>0.05). The children who received antiviral therapy within 48 hours after disease onset had significantly shorter duration of viral nucleic acid shedding and time to body temperature recovery than those who received antiviral therapy more than 48 hours after disease onset (p<0.05). Of all the children with body temperature recovery, 83% still tested positive for viral nucleic acid. CONCLUSIONS: Complications, underlying diseases, and timing of antiviral therapy are influencing factors for the duration of influenza A virus nucleic acid shedding, and whether body temperature returns to normal cannot be used to decide whether to continue antiviral therapy. PMID- 27974121 TI - [Clinical value of fluorescence lateral flow immunoassay in diagnosis of influenza A in children]. AB - OBJECTIVE: To evaluate the clinical value of a new type of fluorescence lateral flow immunoassay in rapid detection of influenza A virus. METHODS: A total of 378 samples of nasopharyngeal secretions were collected from 378 children with influenza-like symptoms to detect the influenza A virus by fluorescence lateral flow immunoassay, colloidal gold immunoassay, and RT-PCR between July 2015 and August 2015. RESULTS: Of the 378 samples, 81 (21.4%) were positive for influenza A virus by RT-PCR. Compared with RT-PCR, the sensitivities of fluorescence lateral flow immunoassay and colloidal gold immunoassay were 90.1% (73/81) and 75.3% (61/81), respectively, and the specificities were 99.3% (295/297) and 98.3% (292/297), respectively. The average threshold cycle (Ct) value for the positive samples detected by the fluorescence lateral flow immunoassay (30.6) was higher than that for the positive samples detected by the colloidal gold immunoassay (28.7). CONCLUSIONS: Compared with colloidal gold immunoassay, fluorescence lateral flow immunoassay has higher sensitivity, specificity, and concordance rate with RT-PCR, suggesting that it can be used for early screening and diagnosis of influenza A. PMID- 27974122 TI - [Association between IL-19 gene polymorphisms and hepatitis B virus susceptibility in children]. AB - OBJECTIVE: To study the association between the single nucleotide polymorphisms (SNP) of interleukin (IL)-19 and susceptibility to hepatitis B virus (HBV) infection in children. METHODS: A case-control study was performed, and 136 children with positive HBsAg(case group) and 297 healthy children with negative HBsAg(control group) were enrolled. PCR and DNA sequencing were used for genotyping. RESULTS: There were significant differences in the frequencies of genotypes of IL-19 rs1798 between the case and control groups. The case group also had a significantly higher proportion of children with CG genotype than the control group (p<0.05). There were significant differences in the frequencies of genotypes and alleles of IL-19 rs2243191 between the HBV infection and non infection groups among children who born to HBV-positive mothers. The infection group had significantly higher proportions of children with TC and CC genotypes and C allele than the non-infection group (p<0.05). CONCLUSIONS: The SNP of IL-19 rs1798 may be associated with susceptibility to hepatitis B in children, and the SNP of IL-19 rs2243191 may be associated with susceptibility to breakthrough HBV infection in children at a high risk of HBV infection. PMID- 27974123 TI - [CPT2 gene mutation analysis and prenatal diagnosis in a family with carnitine palmitoyltransferase II deficiency]. AB - This study aimed to identify the type of carnitine palmitoyltransferase 2 (CPT2) gene mutation in the child with carnitine palmitoyltransferase II (CPT II) deficiency and her parents and to provide the genetic counseling and prenatal diagnosis for the family members. As the proband, a 3-month-old female baby was admitted to the hospital due to fever which had lasted for 8 hours. Tandem mass spectrometric analysis for blood showed an elevated plasma level of acylcarnitine, which suggested CPT II deficiency. The genomic DNA was extracted from peripheral blood of the patient and her parents. Five exon coding regions and some intron regions at the exon/intron boundaries of the CPT2 gene were analyzed by PCR and Sanger sequencing. Amniotic fluid was taken from the mother during the second trimester, and DNA was extracted to analyze the type of CPT2 gene mutation. Sanger sequencing results showed that two mutations were identified in the CPT2 gene of the proband: c.886C>T (p.R296X) and c.1148T>A (p.F383Y), which were inherited from the parents; the second child of the mother inherited the mutation of c.886C>T (p.R296X) and showed normal acylcarnitine spectrum and normal development after birth. It is concluded that the analysis of CPT2 gene mutations in the family suggested that the proband died of CPT II deficiency and that the identification of the mutations was helpful in prenatal diagnosis in the second pregnancy. PMID- 27974125 TI - [Clinical features of mild encephalitis/encephalopathy with a reversible splenial lesion in children]. AB - OBJECTIVE: To investigate the clinical features of mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) in children. METHODS: The clinical data of 8 children with MERS were retrospectively analyzed. RESULTS: The mean age of onset was 5 years and 2 months (range 10 months to 12 years). The major clinical features included a history of prodromal infection, and among these children, 5 had pyrexia and 4 had vomiting. Of all the children, 6 were manifested as convulsion and 3 each were manifested as disturbance of consciousness and paroxysmal paropsia. Cranial diffusion-weighted magnetic resonance imaging (MRI) showed high signals in the splenium of the corpus callosum. Among these children, one child had symmetric and multiple long T1 and long T2 signals in the bilateral centrum semiovale and part of the temporal white matter. MRI reexamination performed after 5-30 days showed the disappearance of abnormal signals in all the children. The children were followed up for 3 months to 2 years, and no child experienced abnormal neurodevelopment. CONCLUSIONS: The development of MERS in children is closely associated with infection. MERS is characterized by high signals in the splenium of the corpus callosum on cranial diffusion-weighted MRI. Most children have good prognosis. PMID- 27974124 TI - [Clinical efficacy of different doses of gamma globulin combined with glucocorticoid in treatment of moderate/severe acute Guillain-Barre syndrome in children: a comparative analysis]. AB - OBJECTIVE: To investigate the clinical efficacy and safety of intravenous injection of low-dose versus high-dose gamma globulin combined with glucocorticoid pulse therapy in the treatment of children with moderate/severe acute Guillain-Barre syndrome (GBS). METHODS: A total of 100 children with moderate/severe acute GBS were randomly assigned to low-dose group (n=48) and high-dose group (n=52). The children in the low-dose and high-dose groups were treated with 0.2 g/(kg . d) and 0.4 g/(kg . d) gamma globulin respectively combined with methylprednisolone. The two groups were compared in terms of the time to improvements of symptoms after treatment, serum levels of inflammatory factors, proportion of children undergoing invasive ventilation, treatment response rate, and adverse events. RESULTS: After 5 days of treatment, the low- and high-dose groups had significant reductions in serum levels of tumor necrosis factor-alpha, interleukin-6, and C-reactive protein, and there were no significant differences in the reductions of these markers between the two groups. There were no significant differences between the two groups in the time to recovery of respiratory muscle paralysis, time to an improvement in muscle strength of one grade, time to recovery of sensory disturbance, and length of hospital stay. There was no significant difference in the treatment response rate between the low- and high-dose groups (90% vs 92%). There were also no significant differences in the incidence rates of pyrexia, headache, nausea, and palpitation between the two groups. CONCLUSIONS: Low-dose versus high-dose gamma globulin combined with methylprednisolone pulse therapy have comparable clinical efficacy and safety in the treatment of children with moderate/severe acute GBS. PMID- 27974126 TI - [The neuroprotective role of exogenous TERT gene in neonatal rats with hypoxic ischemic brain damage]. AB - OBJECTIVE: To study the effect of telomerase reverse transcriptase (TERT) on cell apoptosis in neonatal rat brains after hypoxic-ischemic brain injury (HIBD). METHODS: A total of 72 neonatal rats were divided into sham, vehicle, HIBD and TERT groups. HIBD was induced by Rice method in the later three groups. The neonatal rats in the vehicle and TERT groups were injected with plasmids containing mock or full length TERT by an intracerebroventricular injection 30 minutes after hypoxic-ischemic (HI) injury. Pathological changes of brain tissue were observed by hematoxylin and eosin (HE) staining. Western blot was used to detect the protein expression of TERT, apoptosis-inducing factor (AIF) and cleaved caspase 3 (CC3). Apoptotic cells were detected by TUNEL staining. RESULTS: Western blot showed that TERT protein was dramatically increased in the vehicle, HIBD and TERT groups compared with the sham group. Compared with the vehicle and HIBD groups, TERT protein in the TERT group was significantly upregulated. Compared with the sham group, there was a significant increase in apoptotic index and expression of AIF and CC3 proteins in the vehicle and HIBD groups (p<0.01). The TERT group showed decreased expression of AIF and CC3 proteins and apoptotic index compared with the vehicle and HIBD groups (p<0.01). CONCLUSIONS: TERT can inhibit cell apoptosis induced by HI and might have a neuroprotective role in developing brain with HIBD. PMID- 27974127 TI - [Prediction of microRNA-296-5p target genes and its application in lung development]. AB - OBJECTIVE: To predict the target genes of rno-microRNA-296-5p (miR-296) using bioinformatics software and databases, and to provide a theoretical basis for further studies of biological effects of miR-296 in fetal lung development. METHODS: PubMed and Google were used to search for all reported literature on miR 296. The miRBase database was used to determine the sequence and evolutionary conservatism of miR-296. The TargetScans database was used to predict the target genes of miR-296. The DAVID Bioinformatics Resources 6.8 database was used for the functional enrichment analysis of the target genes. The KEGG database was used to analyze the signaling pathways of target genes. RESULTS: miR-296 was reported to play important roles in many biological processes and have a high degree of sequence conservation among species. The target genes of miR-296 were involved in biological processes, cell components, and molecular function. Those target genes were significantly enriched in the mitogen-activated protein kinase signaling pathway, Wnt signaling pathway, and transforming growth factor-beta signaling pathway (p<0.05). CONCLUSIONS: The bioinformatics analysis of the target genes of miR-296 provides a basis for studying biological effects and mechanism of action of miR-296 in lung development. PMID- 27974128 TI - [Research advances in susceptible genes for developmental dyslexia in children]. AB - Developmental dyslexia in children is one of the neurodevelopmental disorders and is affected by various susceptible genes. In recent years, researchers have found some susceptible genes for dyslexia via chromosome analysis, genome-wide association studies, association analysis, gene function research, neuroimaging, and neurophysiological techniques. This article reviews the research advances in susceptible genes for developmental dyslexia, and with the study on susceptible genes for dyslexia, it lays a foundation for in-depth studies on the "gene-brain behavior" level and provides scientific clues for exploring etiology and pathogenesis of dyslexia. PMID- 27974129 TI - [Clinical evaluation and management of neonates with disorder of sexual development]. AB - Disorder of sexual development or disorder of sex differentiation (DSD) refers to the inconsistency between karyotype and gonad phenotype and/or gonad anatomy in neonates and is manifested as the difficulty in identifying neonates' sex. According to the karyotype, DSD is classified as 46,XY DSD, 46,XX DSD, and sex chromosome DSD. A combination of detailed medical history, physical examination, and laboratory and imaging examinations is required for the diagnosis and comprehensive assessment of neonatal DSD and the determination of potential causes in clinical practice. Sex identification can only be made after all diagnostic evaluations have been completed. Sex identification of DSD neonates is influenced by various medical and social factors, including genotype (karyotype), sex hormones (levels of testosterone, dihydrotestosterone, and adrenal steroids), sex phenotype (appearance of internal and external genitals), reproduction (fertility potential), feelings of their parents, and even social acceptance and religious customs. A team with multidisciplinary cooperation is required, and patients must be involved in the whole process of sex identification. The major task of neonatal physicians for DSD is to assess the condition of neonates and provide management. PMID- 27974130 TI - [Research advances in association between vitamin D and Kawasaki disease and related mechanisms of action]. AB - Vitamin D is an important steroid hormone, which has a wide biological effect and is the protective factor against cardiovascular disease and other diseases. At present, the etiology and pathogenesis of Kawasaki disease (KD) remain unknown, but recent studies have shown that vitamin D insufficiency or deficiency is associated with KD. Vitamin D insufficiency or deficiency may affect KD via its influence on inflammatory response, adipokine, endothelial function, platelet function, and DNA methylation and increase the risk of coronary artery lesions. This article reviews the research advances in the association between vitamin D and KD and possible mechanisms of action. PMID- 27974131 TI - Lyssavirus-reactive antibodies in Swedish bats. AB - INTRODUCTION: To study the presence of European bat lyssavirus (EBLV) infections in bat reservoirs in Sweden, active surveillance was performed during the summers from 2008 to 2013. MATERIAL AND METHODS: Bat specimens were collected at >20 bat colonies in the central, southeastern, and southern parts of Sweden. In total, blood and saliva of 452 bats were examined by a virus neutralization test and by reverse transcription polymerase chain reactions (RT-PCRs). RESULTS AND DISCUSSION: EBLV neutralizing antibodies were detected in 14 Daubenton's bats (Myotis daubentonii), all trapped in Skane or Smaland (south and southeast of Sweden). The result was not unexpected since EBLV has been shown to be present in many neighboring countries, for example, Denmark, Finland, Germany, and Norway. However, Sweden has been regarded free of rabies in terrestrial mammals since 1896. Although very rare, spillover of EBLV into other animals and humans have occurred, and the risk of EBLV infection to other species including humans should not be ignored. This is the first report of lyssavirus infection in Swedish bats. PMID- 27974132 TI - Faculty development in point of care ultrasound for internists. AB - Lack of general medicine faculty expertise is a likely contributor to the slow adoption of point of care ultrasound (POCUS) by internal medicine (IM) residency training programs. We developed a 10-week faculty development program, during which 15 faculty members participated in 2 hours and 10 hours of online didactic and hands-on training, respectively. Pre-post comparisons showed that there were statistically significant improvements in faculty participants' ability to interpret images (p<0.001), perceived understanding of the capabilities and limitations of POCUS (p=0.003), comfort using POCUS to make clinical decisions (p=0.003), and perceptions regarding the extent to which POCUS can improve patient care (p=0.026). The next challenge for IM programs is to improve access to ultrasound machines and provide follow-up workshops to facilitate further development of skills and integration of POCUS into daily practice by general medicine faculty. PMID- 27974133 TI - Dimensional structure of DSM-5 posttraumatic stress symptoms in Spanish trauma victims. AB - BACKGROUND: Confirmatory factor analytic studies have shown that posttraumatic stress disorder (PTSD) symptoms included in the fifth edition of the Diagnostic and Statistical Manual Disorders (DSM-5) may be better explained by two 6-factor models (the Externalizing Behaviours model and the Anhedonia model) and a 7 factor Hybrid model. The latter model comprises the symptom clusters of intrusion, avoidance, negative affect, anhedonia, externalizing behaviours, and anxious and dysphoric arousal. This model has received empirical support mainly in American samples. Of note, there have been a limited number of studies conducted on samples from other countries. OBJECTIVE: This study aimed to examine the underlying dimensionality of DSM-5 PTSD symptoms in a Spanish clinical sample exposed to a range of traumatic events. METHOD: Participants included 165 adults (78.8% females) seeking treatment in trauma services in the Madrid area (Spain). PTSD was assessed using the Global Assessment of Posttraumatic Stress Scale 5, a Spanish self-report instrument assessing posttraumatic symptoms according to the DSM-5 criteria. Confirmatory factor analyses were conducted in Mplus. RESULTS: Both the 7-factor Hybrid model and the 6-factor Anhedonia model demonstrated good and equivalent fit to the data. CONCLUSIONS: The findings of this study replicate and extend previous research by providing support for both the 7-factor Hybrid model and the 6-factor Anhedonia model in a clinical sample of Spanish trauma survivors. Given equivalent fit for these two models and the fewer number of latent factors in the Anhedonia model, it was selected as optimal in a traumatized Spanish sample. Implications and future research directions are discussed. PMID- 27974136 TI - Levels and trends of contaminants in humans of the Arctic. AB - The Arctic Monitoring and Assessment Programme (AMAP) is one of the six working groups established under the Arctic Council. AMAP is tasked with monitoring the levels of contaminants present in the Arctic environment and people as well as assessing their effects on a continuous basis, and reporting these results regularly. Most of the presented data have been collected over the last 20 years and are from all eight Arctic countries. Levels of contaminants appear to be declining in some of the monitored Arctic populations, but it is not consistent across the Arctic. Most Arctic populations continue to experience elevated levels of these contaminants compared to other populations monitored globally. There are certain contaminants, such as perfluorinated compounds and polybrominated diphenyl ethers, which are still increasing in Arctic populations. These contaminants require more investigation to find out the predominant and important sources of exposure, and whether they are being transported to the Arctic through long-range transport in the environment. PMID- 27974135 TI - Overview of ongoing cohort and dietary studies in the Arctic. AB - This article gives an overview of the ongoing cohort and dietary studies underlying the assessment of population health in the Arctic. The emphasis here is on a description of the material, methods and results or preliminary results for each study. Detailed exposure information is available in an article in this journal, whereas another paper describes the effects associated with contaminant exposure in the Arctic. The cohort descriptions have been arranged geographically, beginning in Norway and moving east to Finland, Sweden, Russia and the other Arctic countries and ultimately to the Faroe Islands. No cohort studies have been reported for Alaska or Iceland. PMID- 27974138 TI - Overview of human health in the Arctic: conclusions and recommendations. AB - This article is intended to provide an overview of the key conclusions, knowledge gaps and key recommendations based on the recent 2015 Arctic human health assessment under the Arctic Monitoring and Assessment Program. This assessment was based primarily on data from human health monitoring and research studies and peer-reviewed literature published since the last assessment in 2009. PMID- 27974139 TI - Adaptation in Arctic circumpolar communities: food and water security in a changing climate. AB - The AMAP Human Health Assessment Group has developed different adaptation strategies through a long-term collaboration with all Arctic countries. Different adaptation strategies are discussed, with examples mainly from native population groups in Alaska. PMID- 27974140 TI - An update on risk communication in the Arctic. AB - BACKGROUND: Arctic residents can be exposed to a wide range of contaminants through consumption of traditional (country) foods (i.e. food from wild animals and plants that are hunted, caught or collected locally in the Arctic). Yet these foods provide excellent nutrition, promote social cohesion, meet some spiritual needs for connectedness to the land and water, reinforce cultural ties, are economically important and promote overall good health for many. The risk and benefit balance associated with the consumption of traditional Arctic foods is complicated to communicate and has been referred to as the "Arctic Dilemma". This article gives an update on health risk communication in the Arctic region. It briefly summarizes some research on risk communication methodologies as well as approaches to an evaluation of the outcomes of risk communication initiatives. It provides information on specific initiatives in several Arctic countries, and particularly those that were directed at Indigenous populations. This article also summarizes some international versus local risk communication activities and the complexity of developing and delivering messages designed for different audiences. Finally, the potential application of social media for risk communication and a summary of "best practices" based on published literature and a survey of Inuit in a few Arctic countries are described. CONCLUSION: Several of the risk communication initiatives portrayed in this article indicate that there is only limited awareness of the outcome of risk communication messages. In some cases, risk communication efforts appear to have been successful, at least when effectiveness is measured in an indirect way, for example, by lower contaminant levels. However, due to missing effectiveness evaluation studies, uncertainty remains as to whether a specific risk communication method was successful and could be clearly linked to behavioural changes that resulted in decreased contaminant exposure. PMID- 27974141 TI - New approaches in human health risk assessment. AB - Studies on the precise impact of environmental pollutants on human health are difficult to undertake and interpret, because many genetic and environmental factors influence health at the same time and to varying degrees. Our chapter in the AMAP report was based on new approaches to describe risks and future needs. In this paper, we will introduce the issues associated with risk assessment of single chemicals, and present suggestions for future studies as well as a summary of lessons learned during the health-related parts of the European Union-funded FP7 project ArcRisk (Arctic Health Risks: Impacts on health in the Arctic and Europe owing to climate-induced changes in contaminant cycling, 2009-2014; www.arcrisk.eu). PMID- 27974137 TI - Health effects associated with measured levels of contaminants in the Arctic. AB - The Human Health Assessment Group has over the past decade recommended that effect studies be conducted in the circumpolar area. Such studies examine the association between contaminant exposure in the Arctic populations and health effects. Because foetuses and young children are the most vulnerable, effect studies are often prospective child cohort studies. The emphasis in this article is on a description of the effects associated with contaminant exposure in the Arctic. The main topics addressed are neurobehavioural, immunological, reproductive, cardiovascular, endocrine and carcinogenic effect. For each topic, the association between exposure and effects is described, and some results are reported for similar studies outside the Arctic. PMID- 27974142 TI - AMAP assessment 2015: human health in the Arctic. PMID- 27974143 TI - Key indicators of obstetric and neonatal care in the Republic of Sakha (Yakutia). AB - In the absence of a medical birth registry, the official statistics are the only sources of information about pregnancy outcomes in the Republic of Sakha (Yakutia) (RS). We analysed the official statistical data about birth rate, fertility, infant and maternal mortality in the RS in the period 2003-2014. Compared with all-Russian data, the RS had a higher birth rate, especially in rural districts. Maternal and infant mortality were also higher compared with all Russian data, but had a decreasing trend. The majority of deaths occurred in the small level 1 units. We suggest that establishment of good predelivery transportation of pregnant women with high risk of complications from remote areas and centralization of risk deliveries with improved prenatal and neonatal care could improve the pregnancy outcome in Yakutia. PMID- 27974144 TI - The Treatment of Scabies. AB - BACKGROUND: Scabies is a contagious infestation transmitted by skin-to-skin contact and sometimes by contact with contaminated material. The scabies mite burrows into the skin, producing a papular rash and severe itch at typical sites of predilection. METHODS: We systematically reviewed the literature to compare the efficacy of various anti-scabies agents, including a calculation of relative risks and confidence intervals. RESULTS: A literature search yielded 596 initial hits; after screening in accor-dance with the defined inclusion and exclusion criteria, 16 studies were selected for this review. Among topical treatments for scabies, permethrin was equally effective or more effective than crotamiton or benzyl benzoate. In a comparison of topical versus systemic treatment, topical permethrin and systemic ivermectin did not differ substantially in efficacy (7 comparative studies revealed no difference; one revealed a difference in favor of permethrin). Comparative trials of topical benzyl benzoate versus systemic ivermectin yielded inconsistent findings. Single and double administrations of ivermectin were similarly effective. In trials involving entire populations with a high prevalence of scabies, systemic ivermectin was found to be superior to topical permethrin. CONCLUSION: There are hardly any differences in efficacy between the available treatments for scabies. Single administrations of permethrin 5%, crotamiton 10%, and systemic ivermectin are all comparably effective. There are differences in the frequeny and ease of application as well as when eradicating scabies in populations with a high prevalence. PMID- 27974146 TI - High accuracy navigation information estimation for inertial system using the multi-model EKF fusing adams explicit formula applied to underwater gliders. AB - The underwater navigation system, mainly consisting of MEMS inertial sensors, is a key technology for the wide application of underwater gliders and plays an important role in achieving high accuracy navigation and positioning for a long time of period. However, the navigation errors will accumulate over time because of the inherent errors of inertial sensors, especially for MEMS grade IMU (Inertial Measurement Unit) generally used in gliders. The dead reckoning module is added to compensate the errors. In the complicated underwater environment, the performance of MEMS sensors is degraded sharply and the errors will become much larger. It is difficult to establish the accurate and fixed error model for the inertial sensor. Therefore, it is very hard to improve the accuracy of navigation information calculated by sensors. In order to solve the problem mentioned, the more suitable filter which integrates the multi-model method with an EKF approach can be designed according to different error models to give the optimal estimation for the state. The key parameters of error models can be used to determine the corresponding filter. The Adams explicit formula which has an advantage of high precision prediction is simultaneously fused into the above filter to achieve the much more improvement in attitudes estimation accuracy. The proposed algorithm has been proved through theory analyses and has been tested by both vehicle experiments and lake trials. Results show that the proposed method has better accuracy and effectiveness in terms of attitudes estimation compared with other methods mentioned in the paper for inertial navigation applied to underwater gliders. PMID- 27974145 TI - Head Lice. AB - BACKGROUND: Conflicting information about the proper treatment of head lice has given rise to uncertainty among patients and treating personnel. For example, the reported efficacy of permethrin fell from 97% in the 1990s to 30% in 2010. METHODS: Review of the literature based on a selective search of PubMed. RESULTS: In Germany, outbreaks of head lice mainly occur among 5- to 13-year-olds returning to school after the summer vacation. Nymphs hatch from eggs after an average of 8 days and become sexually mature lice over the ensuing 9 days. The main route of transmission is direct head-to-head contact; transmission via inanimate objects is of no relevance. Symptoms arise 4-6 weeks after an initial infestation; many affected persons have no symptoms at all. Wet combing is the most sensitive method of establishing the diagnosis and monitoring treatment. Resistance to neurotoxic pediculocidal drugs is increasing around the world. Dimethicones are the treatment of choice, with 97% efficacy. Outbreaks must be managed with the synchronous treatment of all infested persons to break the chain of infestation. If the agent used is not ovicidal, the treatment must be repeated in 8-10 days and sometimes in a further 7 days as well. CONCLUSION: Outbreaks of head lice can be successfully terminated by synchronous treatment with ovicidal dimethicones. PMID- 27974148 TI - Salmonella-induced inflammasome activation in humans. AB - Inflammasomes are macromolecular complexes that assemble upon recognition of pathogen- or danger-associated molecular patterns. Inflammasome assembly is nucleated by the oligomerisation of specific, activated pattern recognition receptors within the cytosol. Inflammasomes function as platforms for the activation of the caspase-1 protease, which in turn triggers the maturation and secretion of the pro-inflammatory cytokines IL-1beta and IL-18, and initiates pyroptosis, a highly inflammatory form of lytic cell death. Recently, additional inflammatory caspases (murine caspase-11, and human caspase-4/5) were also reported to be activated upon a pyroptosis-inducing 'non-canonical inflammasome' by direct recognition of lipopolysaccharide (LPS), a pathogen-associated molecular pattern. Here we review and discuss recent advances in our understanding of inflammasome-mediated host defence against Salmonella particularly in human cells, and their implications for cellular survival and cytokine secretion. PMID- 27974147 TI - Dual activities of ritanserin and R59022 as DGKalpha inhibitors and serotonin receptor antagonists. AB - Diacylglycerol kinase alpha (DGKalpha) catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). Recently, DGKalpha was identified as a therapeutic target in various cancers, as well as in immunotherapy. Application of small-molecule DGK inhibitors, R59022 and R59949, induces cancer cell death in vitro and in vivo. The pharmacokinetics of these compounds in mice, however, are poor. Thus, there is a need to discover additional DGK inhibitors not only to validate these enzymes as targets in oncology, but also to achieve a better understanding of their biology. In the present study, we investigate the activity of ritanserin, a compound structurally similar to R59022, against DGKalpha. Ritanserin, originally characterized as a serotonin (5-HT) receptor (5-HTR) antagonist, underwent clinical trials as a potential medicine for the treatment of schizophrenia and substance dependence. We document herein that ritanserin attenuates DGKalpha kinase activity while increasing the enzyme's affinity for ATP in vitro. In addition, R59022 and ritanserin function as DGKalpha inhibitors in cultured cells and activate protein kinase C (PKC). While recognizing that ritanserin attenuates DGK activity, we also find that R59022 and R59949 are 5-HTR antagonists. In conclusion, ritanserin, R59022 and R59949 are combined pharmacological inhibitors of DGKalpha and 5-HTRs in vitro. PMID- 27974149 TI - The threshold vs LNT showdown: Dose rate findings exposed flaws in the LNT model part 2. How a mistake led BEIR I to adopt LNT. AB - This paper reveals that nearly 25 years after the National Academy of Sciences (NAS), Biological Effects of Ionizing Radiation (BEIR) I Committee (1972) used Russell's dose-rate data to support the adoption of the linear-no-threshold (LNT) dose response model for genetic and cancer risk assessment, Russell acknowledged a significant under-reporting of the mutation rate of the historical control group. This error, which was unknown to BEIR I, had profound implications, leading it to incorrectly adopt the LNT model, which was a decision that profoundly changed the course of risk assessment for radiation and chemicals to the present. PMID- 27974150 TI - (Climate) Change in young people's minds - From categories towards interconnections between the anthroposphere and natural sphere. AB - The grand challenges of the 21st century will increasingly require societies to reconsider the pathways taken thus far. Engagement with climate change is of ever growing importance to young people. They will be confronted with the effects of climate change throughout their entire lives and, as future decision-makers, they will vitally shape societal developments. Education will thus play a crucial role in the transformation to a sustainable society. In terms of awareness-raising, an important first step in preparing young people for the challenges of the 21st century is to understand what content is connected with climate change. As complex challenges, such as climate change, demand ways of thinking that go beyond categories, interconnections between the anthroposphere and the natural sphere have to be taken into consideration. This study provides an insight into the questions and topics young people develop whilst becoming involved in climate change in an in-school learning setting and in an out-of-school learning setting (a high mountain environment). The analysis focuses on the question of in which spheres students predominantly make their thematic choices and how far the interconnections between different spheres are formed. Our results show that the choice of the learning setting influences the topics students connect with climate change. Interconnections between sub-spheres of the anthroposphere and natural sphere are made only occasionally. These findings serve as a basis for reconsidering the content and foundation of climate change communication with young people. We recommend that climate change educational programmes should include phases that allow the following: a) involvement with climate change issues related to single spheres in the first phase, and b) consideration of the interconnections between spheres when becoming involved with climate change issues in the second phase. As the educational setting can considerably influence the focus of the learning process, it should be chosen thoughtfully. PMID- 27974151 TI - Using a passive air sampler to monitor air-soil exchange of organochlorine pesticides in the pasture of the central Tibetan Plateau. AB - Air-soil exchange is a key process controlling the fate of persistent organic pollutants (POPs). However, the "sink effect" of soil for POPs in Tibetan pasture has not been clear. In NamCo, in the central Tibetan Plateau (TP) where the land is covered by grass, a modified passive air sampler (PAS) (thickness: 2cm) was tested. Using the PAS, the atmospheric gaseous phase organochlorine pesticides (OCPs) at 11 heights from close-to-surface (2cm) to 200cm above ground, in summer and in winter, were measured. Concentrations of OCPs in summer were higher than those in winter. Both in summer and winter, atmospheric concentrations of OCPs decreased with decreasing height from 200 to 2cm, indicating that OCPs were being deposited from air to soil. Air deposition of OCPs was possibly driven by wind speed. Furthermore, based on air OCPs at 0-3cm near the surface, the interface exchange of OCPs between air and soil was studied by the fugacity method. The results showed that pastural soil in the TP was a "sink" of OCPs even in summer. The mean deposition fluxes of alpha-HCH, gamma-HCH and o,p'-DDT were 0.72, 0.24 and 0.54pg/h/m2, respectively, and it was estimated that the level of these pollutants in the soil will double every 24, 66 and 206years, respectively. This study will contribute to the further understanding of global cycling of POPs in different land covers. PMID- 27974152 TI - Standards for providing safe acute ischaemic stroke thrombectomy services (September 2015). PMID- 27974153 TI - Tenascin-C deficiency protects mice from experimental autoimmune encephalomyelitis. AB - The extracellular matrix glycoprotein tenascin-C (TnC) has been increasingly appreciated as a molecule susceptibly reacting to abnormalities in the mammalian immune system. TnC expression is elevated in inflamed tissues outside the immune system, but also in lymphoid organs. It participates in the promotion of inflammatory responses. Here, the role of TnC in a paradigm of CNS autoimmunity was investigated. Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, was induced in mice deficient in TnC (TnC-/- mice). Amelioration of EAE was observed in these mice in comparison to their wild-type (TnC+/+) littermates. Since T helper (Th)1 and Th17 cells play a dominant role in the pathogenesis of EAE, these cells were investigated in addition to analyzing locomotor functions and pro-inflammatory cytokine levels. Smaller numbers of interferon-gamma-producing Th1 cells and reduced ability of Th17 cells to produce interleukin-17 were observed in spleens of TnC-/- mice challenged by immunization with the myelin associated glycoprotein (MOG) when compared to TnC+/+ mice. There was no difference in Th1 and Th17 responses in non-immunized TnC-/- and TnC+/+ mice, thus excluding generalized immunosuppression in TnC-/- mice. These results show that TnC is important for the pathogenesis of CNS autoimmunity and that its deficiency interferes with Th1 and Th17 encephalitogenic potentials. PMID- 27974154 TI - In-air versus underwater comparison of 3D reconstruction accuracy using action sport cameras. AB - Action sport cameras (ASC) have achieved a large consensus for recreational purposes due to ongoing cost decrease, image resolution and frame rate increase, along with plug-and-play usability. Consequently, they have been recently considered for sport gesture studies and quantitative athletic performance evaluation. In this paper, we evaluated the potential of two ASCs (GoPro Hero3+) for in-air (laboratory) and underwater (swimming pool) three-dimensional (3D) motion analysis as a function of different camera setups involving the acquisition frequency, image resolution and field of view. This is motivated by the fact that in swimming, movement cycles are characterized by underwater and in air phases what imposes the technical challenge of having a split volume configuration: an underwater measurement volume observed by underwater cameras and an in-air measurement volume observed by in-air cameras. The reconstruction of whole swimming cycles requires thus merging of simultaneous measurements acquired in both volumes. Characterizing and optimizing the instrumental errors of such a configuration makes mandatory the assessment of the instrumental errors of both volumes. In order to calibrate the camera stereo pair, black spherical markers placed on two calibration tools, used both in-air and underwater, and a two-step nonlinear optimization were exploited. The 3D reconstruction accuracy of testing markers and the repeatability of the estimated camera parameters accounted for system performance. For both environments, statistical tests were focused on the comparison of the different camera configurations. Then, each camera configuration was compared across the two environments. In all assessed resolutions, and in both environments, the reconstruction error (true distance between the two testing markers) was less than 3mm and the error related to the working volume diagonal was in the range of 1:2000 (3*1.3*1.5m3) to 1:7000 (4.5*2.2*1.5m3) in agreement with the literature. Statistically, the 3D accuracy obtained in the in-air environment was poorer (p<10-5) than the one in the underwater environment, across all the tested camera configurations. Related to the repeatability of the camera parameters, we found a very low variability in both environments (1.7% and 2.9%, in-air and underwater). This result encourage the use of ASC technology to perform quantitative reconstruction both in-air and underwater environments. PMID- 27974155 TI - Tools for evaluating environmental performance at Brazilian public ports: Analysis and proposal. AB - The port sector critically needs improved management techniques to evaluate its environmental performance. In the present study, we conducted an exploratory research to understand the metrics used in the Brazilian public ports to assess their environmental performance. We considered two state agencies and two port authorities of southern Brazil. As preliminary results, we found that economic factors are excluded in the tools for measuring environmental performance. A system of indicators to address this shortcoming was then proposed, but it could not be applied because of data deficiencies. Thus, the system was divided into two parts: a simplified system with 7 indicators (measuring costs related to criteria were measured only technically) and an advanced system with 5 indicators (approaching costs were currently difficult to measure). Thus, the proposed indicators can be applied by port authorities to facilitate decision-making related to environmental management. As suggestions for further work, we propose research that includes more ports, both public and private, to provide an overview at the national level. PMID- 27974156 TI - Floating Marine Debris in waters of the Mexican Central Pacific. AB - The presence of marine debris has been reported recently in several oceans basins; there is very little information available for Mexican Pacific coasts, however. This research examined the composition, possible sources, distribution, and density of Floating Marine Debris (FMD) during nine research surveys conducted during 2010-2012 in the Mexican Central Pacific (MCP). Of 1820 floating objects recorded, 80% were plastic items. Sources of FMD were determined using key objects, which indicated that the most were related to the presence of the industrial harbor and of a growing fishing industry in the study area. Densities were relatively high, ranging from 40 to 2440objects/km2; the highest densities were recorded in autumn. FMD were distributed near coastal regions, mainly in Jalisco, influenced by river outflow and surface currents. Our results seem to follow worldwide trends and highlight the need for further studies on potential ecological impacts within coastal waters of the MCP. PMID- 27974157 TI - Development of double chain phosphatidylcholine functionalized polymeric monoliths for immobilized artificial membrane chromatography. AB - This study described a simple synthetic methodology for preparing biomembrane mimicking monolithic column. The suggested approach not only simplifies the preparation procedure but also improves the stability of double chain phosphatidylcholine (PC) functionalized monolithic column. The physicochemical properties of the optimized monolithic column were characterized by scanning electron microscopy, energy-dispersive X-ray spectrometry, and nano-LC. Satisfactory column permeability, efficiency, stability and reproducibility were obtained on this double chain PC functionalized monolithic column. It is worth noting that the resulting polymeric monolith exhibits great potential as a useful alternative of commercial immobilized artificial membrane (IAM) columns for in vitro predication of drug-membrane interactions. Furthermore, the comparative study of both double chain and single chain PC functionalized monoliths indicates that the presence or absence of glycerol backbone and the number of acyl chains are not decisive for the predictive ability of IAM monoliths on drug-membrane interactions. This novel PC functionalized monolithic column also exhibited good selectivity for a protein mixture and a set of pharmaceutical compounds. PMID- 27974158 TI - Clinicopathological Features of Cardiac Glycolipid Storage Disease in an Adult Pug. AB - A 12-year-old neutered male pug suffered cardiac arrest and died under general anaesthesia during diagnostic imaging for evaluation of exercise intolerance and respiratory crisis. Histopathological evaluation revealed two types of storage material, glycolipid and lipopigment, having differential distributions in multiple organs. The heart was most strikingly affected and other less affected tissues included the liver, brain, kidneys and skin. Cardiomyocytes were swollen with extensive sarcoplasmic vacuolation together with coalescing areas of myocardial fibrosis. Transmission electron microscopy revealed irregular myelin like structures and complex concentric lamellar bodies dominating the sarcoplasm and displacing myofibrils. These findings were consistent with a lysosomal storage disease (LSD) as the cause of cardiac disease and death. The unique clinical presentation, histomorphology and ultrastructural features of the material suggested a glycolipid storage disease most closely resembling Anderson Fabry (Fabry) disease in man. Fabry disease is a LSD that can present in later life and is characterized by loss of alpha-galactosidase A function and, often, accumulation of glycosphingolipids in tissues including the heart, kidneys, vascular endothelium and smooth muscle. PMID- 27974159 TI - Phenolic constituents from the root bark of Morus alba L. and their cardioprotective activity in vitro. AB - A flavanone C-glycoside, steppogenin-5'-C-beta-D-glucopyranoside, six prenylated 2-arylbenzofuran derivatives, moracin O-3"-O-beta-D-glucopyranoside, moracin O-3' O-beta-D-xylopyranoside, moracin P-2"-O-beta-D-glucopyranoside, moracin P-3'-O beta-D-glucopyranoside, moracin P-3'-O-alpha-L-arabinopyranoside and moracin P-3' O-[beta-D-glucopyranosyl-(1 -> 2)]-alpha-L-arabinopyranoside, two phenolic acids, 2,4-dihydroxy-5-(4-hydroxybenzyl) benzoic acid and 2,4-dihydroxy-5-(3,4 dihydroxybenzyl) benzoic acid, as well as three known compounds, moracinoside C, moracin O, and moracin P were isolated from the root bark of Morus alba L. Their structures were ascertained on the basis of spectroscopic evidence. The protective effects of the compounds against doxorubicin-induced cardiomyopathy in H9c2 cells was investigated in vitro. Of all of the isolated compounds, moracin P 3'-O-beta-D-glucopyranoside, moracin O and moracin P had a strong protective influence against doxorubicin-induced cell death with EC50 values of 9.5 +/- 2.6, 4.5 +/- 1.3, and 8.8 +/- 2.4 MUM, respectively. PMID- 27974161 TI - Mismatch Receptive Fields in Mouse Visual Cortex. AB - In primary visual cortex, a subset of neurons responds when a particular stimulus is encountered in a certain location in visual space. This activity can be modeled using a visual receptive field. In addition to visually driven activity, there are neurons in visual cortex that integrate visual and motor-related input to signal a mismatch between actual and predicted visual flow. Here we show that these mismatch neurons have receptive fields and signal a local mismatch between actual and predicted visual flow in restricted regions of visual space. These mismatch receptive fields are aligned to the retinotopic map of visual cortex and are similar in size to visual receptive fields. Thus, neurons with mismatch receptive fields signal local deviations of actual visual flow from visual flow predicted based on self-motion and could therefore underlie the detection of objects moving relative to the visual flow caused by self-motion. VIDEO ABSTRACT. PMID- 27974160 TI - Capturing and Manipulating Activated Neuronal Ensembles with CANE Delineates a Hypothalamic Social-Fear Circuit. AB - We developed a technology (capturing activated neuronal ensembles [CANE]) to label, manipulate, and transsynaptically trace neural circuits that are transiently activated in behavioral contexts with high efficiency and temporal precision. CANE consists of a knockin mouse and engineered viruses designed to specifically infect activated neurons. Using CANE, we selectively labeled neurons that were activated by either fearful or aggressive social encounters in a hypothalamic subnucleus previously known as a locus for aggression, and discovered that social-fear and aggression neurons are intermixed but largely distinct. Optogenetic stimulation of CANE-captured social-fear neurons (SFNs) is sufficient to evoke fear-like behaviors in normal social contexts, whereas silencing SFNs resulted in reduced social avoidance. CANE-based mapping of axonal projections and presynaptic inputs to SFNs further revealed a highly distributed and recurrent neural network. CANE is a broadly applicable technology for dissecting causality and connectivity of spatially intermingled but functionally distinct ensembles. PMID- 27974162 TI - Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo. AB - Tauopathies are neurodegenerative disorders that affect distinct brain regions, progress at different rates, and exhibit specific patterns of tau accumulation. The source of this diversity is unknown. We previously characterized two tau strains that stably maintain unique conformations in vitro and in vivo, but did not determine the relationship of each strain to parameters that discriminate between tauopathies such as regional vulnerability or rate of spread. We have now isolated and characterized 18 tau strains in cells based on detailed biochemical and biological criteria. Inoculation of PS19 transgenic tau (P301S) mice with these strains causes strain-specific intracellular pathology in distinct cell types and brain regions, and induces different rates of network propagation. In this system, strains alone are sufficient to account for diverse neuropathological presentations, similar to those that define human tauopathies. Further study of these strains can thus establish a structural logic that governs these biological effects. PMID- 27974164 TI - A Mechanosensory Circuit that Mixes Opponent Channels to Produce Selectivity for Complex Stimulus Features. AB - Johnston's organ is the largest mechanosensory organ in Drosophila; it analyzes movements of the antenna due to sound, wind, gravity, and touch. Different Johnston's organ neurons (JONs) encode distinct stimulus features. Certain JONs respond in a sustained manner to steady displacements, and these JONs subdivide into opponent populations that prefer push or pull displacements. Here, we describe neurons in the brain (aPN3 neurons) that combine excitation and inhibition from push/pull JONs in different ratios. Consequently, different aPN3 neurons are sensitive to movement in different parts of the antenna's range, at different frequencies, or at different amplitude modulation rates. We use a model to show how the tuning of aPN3 neurons can arise from rectification and temporal filtering in JONs, followed by mixing of JON signals in different proportions. These results illustrate how several canonical neural circuit components rectification, opponency, and filtering-can combine to produce selectivity for complex stimulus features. PMID- 27974163 TI - Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate. AB - Mutations in several genes encoding centrosomal proteins dramatically decrease the size of the human brain. We show that Aspm (abnormal spindle-like, microcephaly-associated) and Wdr62 (WD repeat-containing protein 62) interact genetically to control brain size, with mice lacking Wdr62, Aspm, or both showing gene dose-related centriole duplication defects that parallel the severity of the microcephaly and increased ectopic basal progenitors, suggesting premature delamination from the ventricular zone. Wdr62 and Aspm localize to the proximal end of the mother centriole and interact physically, with Wdr62 required for Aspm localization, and both proteins, as well as microcephaly protein Cep63, required to localize CENPJ/CPAP/Sas-4, a final common target. Unexpectedly, Aspm and Wdr62 are required for normal apical complex localization and apical epithelial structure, providing a plausible unifying mechanism for the premature delamination and precocious differentiation of progenitors. Together, our results reveal links among centrioles, apical proteins, and cell fate, and illuminate how alterations in these interactions can dynamically regulate brain size. PMID- 27974165 TI - Retrospective Multicenter Analysis of the Accuracy of Clinical Examination by Community Physicians in Diagnosing Developmental Dysplasia of the Hip. AB - OBJECTIVES: To determine among general practitioners (GPs) the most common clinical findings that raised concern for developmental dysplasia of the hip (DDH) and necessitated an orthopedic outpatient referral. In addition, we assessed the sensitivity and specificity of the most common of these clinical findings. STUDY DESIGN: We performed a multicenter retrospective review of all referrals by GPs to local orthopedic outpatient departments for DDH over a 12 month period. All patients had undergone pelvic radiographs, and the acetabular index (AI) was measured. The AI was used as a reference test to assess the accuracy of the clinical examination in diagnosing DDH. Sensitivity and specificity of each clinical sign was calculated. RESULTS: Twenty-six of 174 (14.9%) referred patients were diagnosed with DDH, defined as an AI score > 30. The most common indication for referral, per the GP letter was asymmetrical skin folds (97 patients, 45.8%), followed by hip click (42 patients, 19.8%), and limb shortening (34 patients, 16%). Sensitivities and specificities, respectively, among findings were asymmetric skin folds 46.2% (95% CI 26.6%-66.6%) and 42.6% (95% CI 34.5%-51.0%), hip click 23.1% (95% CI 9.0%-43.6%) and 75.7% (95% CI 67.9% 82.3%), limb shortening 30.8% (95% CI 14.3%-51.8%) and 82.4% (75.3%-88.2%), and reduced abduction 19.2% (95% CI 6.6%-39.4%) and 91.9% (95% CI 86.3%-95.7%). Using logistic regression analysis, no clinical sign was found to be a statistically significant indicator of an abnormal AI. CONCLUSIONS: Clinical examination by GPs does not reliably detect radiographically-defined DDH. None of the clinical findings by the GP showed an acceptable level of sensitivity. Absence of reduced abduction and limb shortening are relevant negatives given the high level of specificity of these signs. PMID- 27974166 TI - Predicting Undernutrition at Age 2 Years with Early Attained Weight and Length Compared with Weight and Length Velocity. AB - OBJECTIVE: To estimate the abilities of weight and length velocities vs attained growth measures to predict stunting, wasting, and underweight at age 2 years. STUDY DESIGN: We analyzed data from a community-based cohort study (The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development study [MAL-ED] study) in Bhaktapur, Nepal. A total of 240 randomly selected children were enrolled at birth and followed up monthly up to age 24 months. Linear and logistic regression models were used to predict malnutrition at 2 years of age with growth velocity z scores at 0-3, 0-6, 3-6, 6-9, 6-12, and 9-12 months (using the World Health Organization Growth Standards) or attained growth at 0, 3, 6, and 12 months as predictors. RESULTS: At age 2 years, 4% of the children were wasted, 13% underweight, and 21% stunted. Children who were malnourished at age 2 years had lower mean growth z scores already at birth and throughout the study period. Anthropometric indicators in infancy were significant predictors for growth at the age of 2 years during most periods and at most ages in infancy. Weight-for-age z score, length-for-age z score, and weight-for-length z score at age 12 months had excellent areas under the curve (91-95) to predict the value of the same indicator at age 24 months. Maximum area under the curve values for weight and length velocity were somewhat lower (70-84). CONCLUSIONS: Growth measured at one time point in infancy was better correlated with undernutrition at age 2 years than growth velocity. PMID- 27974167 TI - Lower Basal Insulin Dose is Associated with Better Control in Type 1 Diabetes. AB - OBJECTIVE: To test the hypothesis that lower basal insulin doses may be paradoxically associated with better diabetic control, we assessed the association between the basal insulin dose and hemoglobin A1c (HbA1c) level in a group of children and young adults with type 1 diabetes. STUDY DESIGN: This was a retrospective study of 89 patients with type 1 diabetes (mean age, 14.67 +/- 4.8 years; range, 3-29 years) treated in a single outpatient clinic. Forty-six of the 89 patients were treated with continuous subcutaneous insulin infusion, and the other 43 were treated with multiple daily injections (glargine as basal insulin). The daily basal insulin dose was taken either as downloaded from the insulin pump or as registered in the chart at the most recent clinic visit. Glucose data were taken from computerized registration of downloaded patient glucometers. The mean time between data download and HbA1c determination was 0.9 +/- 0.78 months. HbA1c level and basal insulin dose were entered with other variables in a multivariable linear regression model. RESULTS: There was a significant correlation between injection of less total daily basal insulin and lower HbA1c level (Pearson correlation, 0.441; P < .001). Optimal HbA1c level was associated with use of 0.28 +/- 0.08 U/kg/day of basal insulin (35 +/- 10% basal/total). CONCLUSION: With lower basal insulin levels, lower HbA1C was achieved despite the same total bolus dose. The optimal basal dose as determined by this study is similar to that found in fasting individuals of similar age. PMID- 27974168 TI - Droperidol or Olanzapine, Intramuscularly or Intravenously, Monotherapy or Combination Therapy for Sedating Acute Behavioral Disturbance. PMID- 27974170 TI - Getting It Right the First Time: Defining Regionally Relevant Training Curricula and Provider Core Competencies for Point-of-Care Ultrasound Education on the African Continent. AB - Significant evidence identifies point-of-care ultrasound (PoCUS) as an important diagnostic and therapeutic tool in resource-limited settings. Despite this evidence, local health care providers on the African continent continue to have limited access to and use of ultrasound, even in potentially high-impact fields such as obstetrics and trauma. Dedicated postgraduate emergency medicine residency training programs now exist in 8 countries, yet no current consensus exists in regard to core PoCUS competencies. The current practice of transferring resource-rich PoCUS curricula and delivery methods to resource-limited health systems fails to acknowledge the unique challenges, needs, and disease burdens of recipient systems. As emergency medicine leaders from 8 African countries, we introduce a practical algorithmic approach, based on the local epidemiology and resource constraints, to curriculum development and implementation. We describe an organizational structure composed of nexus learning centers for PoCUS learners and champions on the continent to keep credentialing rigorous and standardized. Finally, we put forth 5 key strategic considerations: to link training programs to hospital systems, to prioritize longitudinal learning models, to share resources to promote health equity, to maximize access, and to develop a regional consensus on training standards and credentialing. PMID- 27974171 TI - Design: A Neglected Modality for Improvement. PMID- 27974172 TI - Advances in structural studies of recombination mediator proteins. AB - Recombination mediator proteins (RMPs) are critical for genome integrity in all organisms. They include phage UvsY, prokaryotic RecF, -O, -R (RecFOR) and eukaryotic Rad52, Breast Cancer susceptibility 2 (BRCA2) and Partner and localizer of BRCA2 (PALB2) proteins. BRCA2 and PALB2 are tumor suppressors implicated in cancer. RMPs regulate binding of RecA-like recombinases to sites of DNA damage to initiate the most efficient non-mutagenic repair of broken chromosome and other deleterious DNA lesions. Mechanistically, RMPs stimulate a single-stranded DNA (ssDNA) hand-off from ssDNA binding proteins (ssbs) such as gp32, SSB and RPA, to recombinases, activating DNA repair only at the time and site of the damage event. This review summarizes structural studies of RMPs and their implications for understanding mechanism and function. Comparative analysis of RMPs is complicated due to their convergent evolution. In contrast to the evolutionary conserved ssbs and recombinases, RMPs are extremely diverse in sequence and structure. Structural studies are particularly important in such cases to reveal common features of the entire family and specific features of regulatory mechanisms for each member. All RMPs are characterized by specific DNA binding domains and include variable protein interaction motifs. The complexity of such RMPs corresponds to the ever-growing number of DNA metabolism events they participate in under normal and pathological conditions and requires additional comprehensive structure-functional studies. PMID- 27974169 TI - Antibiotics-First Versus Surgery for Appendicitis: A US Pilot Randomized Controlled Trial Allowing Outpatient Antibiotic Management. AB - STUDY OBJECTIVE: Randomized trials suggest that nonoperative treatment of uncomplicated appendicitis with antibiotics-first is safe. No trial has evaluated outpatient treatment and no US randomized trial has been conducted, to our knowledge. This pilot study assessed feasibility of a multicenter US study comparing antibiotics-first, including outpatient management, with appendectomy. METHODS: Patients aged 5 years or older with uncomplicated appendicitis at 1 US hospital were randomized to appendectomy or intravenous ertapenem greater than or equal to 48 hours and oral cefdinir and metronidazole. Stable antibiotics-first treated participants older than 13 years could be discharged after greater than or equal to 6-hour emergency department (ED) observation with next-day follow-up. Outcomes included 1-month major complication rate (primary) and hospital duration, pain, disability, quality of life, and hospital charges, and antibiotics-first appendectomy rate. RESULTS: Of 48 eligible patients, 30 (62.5%) consented, of whom 16 (53.3%) were randomized to antibiotics-first and 14 (46.7%) to appendectomy. Median age was 33 years (range 9 to 73 years), median WBC count was 15,000/MUL (range 6,200 to 23,100/MUL), and median computed tomography appendiceal diameter was 10 mm (range 7 to 18 mm). Of 15 antibiotic-treated adults, 14 (93.3%) were discharged from the ED and all had symptom resolution. At 1 month, major complications occurred in 2 appendectomy participants (14.3%; 95% confidence interval [CI] 1.8% to 42.8%) and 1 antibiotics-first participant (6.3%; 95% CI 0.2% to 30.2%). Antibiotics-first participants had less total hospital time than appendectomy participants, 16.2 versus 42.1 hours, respectively. Antibiotics-first-treated participants had less pain and disability. During median 12-month follow-up, 2 of 15 antibiotics-first-treated participants (13.3%; 95% CI 3.7% to 37.9%) developed appendicitis and 1 was treated successfully with antibiotics; 1 had appendectomy. No more major complications occurred in either group. CONCLUSION: A multicenter US trial comparing antibiotics-first to appendectomy, including outpatient management, is feasible to evaluate efficacy and safety. PMID- 27974173 TI - Multivariate analysis as an advantageous approach for prediction of the adverse outcome in head and neck microvascular reconstructive surgery. AB - BACKGROUND: The use of a free flap has become a mainstay of reconstruction following the ablative surgery in head and neck. The success rates are about 90%, however, several factors have been described to have an adverse effect on free flap survival. METHODS: We have performed a retrospective analysis of the treatment outcome of 93 microvascular flaps and evaluated the factors influencing the risk of flap loss including patients' age, body mass index, smoking, general medical history and previous oncological treatment. RESULTS: Out of 93 flaps the total necrosis have been observed in 15 flaps with gradual improvement in the consecutive years. In individual analysis the patients age, BMI, and comorbidities did not reveal any significant relation. The history of any previous oncological treatment represented a significant adverse factor of success rate (p=0.035), and was even more significant when patients experienced all treatment modalities prior to the reconstructive procedure (p=0.009). Multivariate logistic regression model indicated that only surgery (p=0.0008), chemotherapy (p=0.02), cardiovascular diseases (p=0.05) and patient's age (p=0.02) represented significant factors impairing the success rate. CONCLUSION: Incorporating multivariate analysis represents important statistical approach for better prediction of free flaps survival in head and neck reconstructive surgery. Incorporation of additional collective information could provide more precise approach in the risk of the flap loss assessment. PMID- 27974174 TI - Women in Metabolism: Part IV. AB - The "Rosies" of Cell Metabolism are wrapping up 2016 with a fourth installment of the "Women in Metabolism" series. We are delighted to present ten women scientists who are leaders in the metabolism field, with their words on the value of perseverance, passion, ingenuity, and a bit of serendipity. PMID- 27974175 TI - Of TICE in Men. AB - Cholesterol homeostasis is achieved by balancing rates of endogenous synthesis, absorption, and elimination. Although biliary secretion into the intestinal lumen is classically considered as the only significant route for cholesterol elimination, Jakulj et al. (2016) reveal in this issue how transintestinal cholesterol excretion (TICE) accounts for substantial cholesterol losses. PMID- 27974176 TI - Ticking in Place for the Microbiome to Message Out. AB - In a recent issue of Cell, Thaiss et al. (2016) report that gut microbiota exhibit diurnal rhythmicity in biogeographical localization and metabolomics during the 24 hr light-dark cycle. This oscillation, together with the host circadian clock, co-regulates the colonic and hepatic epigenome and transcriptome. PMID- 27974177 TI - Serine Metabolism Links Tumor Suppression to the Epigenetic Landscape. AB - Intermediary metabolism provides substrates that shape epigenetic status, but whether this interaction can be responsible for oncogenesis is largely unknown. In a recent issue of Nature, Kottakis et al. (2016) now show that the common tumor suppressor gene LKB1 can function by mediating this connection through an LKB1/AMPK/mTOR signaling axis. PMID- 27974178 TI - Assisted Living in the Atheroma: Elderly Macrophages Promote Plaques. AB - Age dominates as a risk factor for human atherosclerosis, yet the underlying mechanisms remain elusive. A recent report described accumulation of senescent cells in atheromata of hypercholesterolemic mice and provides novel insights into how genes expressed by aging cells associate with the characteristics of human plaques implicated in cardiovascular events. PMID- 27974179 TI - Browning of White Adipose Tissue with Roscovitine Induces a Distinct Population of UCP1+ Adipocytes. AB - Brown-like adipocytes exist in several adipose depots including white (WAT) as well as brown (BAT). Activation of these UCP1+ cells is a potential therapeutic strategy to combat obesity. Studies have shown that posttranslational modifications of PPARgamma regulate select adipocyte programs. Deacetylation of K268 and K293 in the ligand-binding domain of PPARgamma by Sirt1 induces browning of WAT. Phosphorylation of S273 of PPARgamma by CDK5 or ERK stimulates a diabetogenic program of gene expression in WAT. Here, we report that roscovitine, a CDK inhibitor, prevents S273 phosphorylation and promotes formation of UCP1+ (brite) adipocytes in WAT. It also enhances energy expenditure as well as prevents diet-induced obesity and insulin resistance. Analysis of fluorescence activated cell-sorted UCP1+ adipocytes shows that the mRNA signature of brite adipocytes is distinct from beige adipocytes, which arise through catecholamine signaling. These results suggest that brown-like adipocytes in WAT may arise from multiple origins. PMID- 27974181 TI - Macrophage Metabolism Shapes Angiogenesis in Tumors. PMID- 27974180 TI - Indoleamine 2,3-Dioxygenase-Expressing Aortic Plasmacytoid Dendritic Cells Protect against Atherosclerosis by Induction of Regulatory T Cells. PMID- 27974182 TI - Retraction Notice to: Activation of the PPAR/PGC-1alpha Pathway Prevents a Bioenergetic Deficit and Effectively Improves a Mitochondrial Myopathy Phenotype. PMID- 27974183 TI - Growth hormone deficiency in children. PMID- 27974184 TI - Genetic causes of isolated and combined pituitary hormone deficiency. AB - Research over the last 20 years has led to the elucidation of the genetic aetiologies of Isolated Growth Hormone Deficiency (IGHD) and Combined Pituitary Hormone Deficiency (CPHD). The pituitary plays a central role in growth regulation, coordinating the multitude of central and peripheral signals to maintain the body's internal balance. Naturally occurring mutation in humans and in mice have demonstrated a role for several factors in the aetiology of IGHD/CPHD. Mutations in the GH1 and GHRHR genes shed light on the phenotype and pathogenesis of IGHD whereas mutations in transcription factors such as HESX1, PROP1, POU1F1, LHX3, LHX4, GLI2 and SOX3 contributed to the understanding of CPHD. Depending upon the expression patterns of these molecules, the phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo optic dysplasia (SOD) and holoprosencephaly. Although numerous monogenic causes of growth disorders have been identified, most of the patients with IGHD/CPHD remain with an explained aetiology as shown by the relatively low mutation detection rate. The introduction of novel diagnostic approaches is now leading to the disclosure of novel genetic causes in disorders characterized by pituitary hormone defects. PMID- 27974185 TI - Models of GH deficiency in animal studies. AB - Growth hormone (GH) is a peptide hormone released from pituitary somatotrope cells that promotes growth, cell division and regeneration by acting directly through the GH receptor (GHR), or indirectly via hepatic insulin-like growth factor 1 (IGF1) production. GH deficiency (GHD) can cause severe consequences, such as growth failure, changes in body composition and altered insulin sensitivity, depending of the origin, time of onset (childhood or adulthood) or duration of GHD. The highly variable clinical phenotypes of GHD can now be better understood through research on transgenic and naturally-occurring animal models, which are widely employed to investigate the origin, phenotype, and consequences of GHD, and particularly the underlying mechanisms of metabolic disorders associated to GHD. Here, we reviewed the most salient aspects of GH biology, from somatotrope development to GH actions, linked to certain GHD types, as well as the animal models employed to reproduce these GHD-associated alterations. PMID- 27974186 TI - Classical and non-classical causes of GH deficiency in the paediatric age. AB - Growth hormone deficiency (GHD) may result from a failure of hypothalamic GHRH production or release, from congenital disorders of pituitary development, or from central nervous system insults including tumors, surgery, trauma, radiation or infiltration from inflammatory diseases. Idiopathic, isolated GHD is the most common sporadic form of hypopituitarism. GHD may also occur in combination with other pituitary hormone deficiencies, and is often referred to as hypopituitarism, combined pituitary hormone deficiency (CPHD), multiple pituitary hormone deficiency (MPHD) or panhypopituitarism. Children without any identifiable cause of their GHD are commonly labeled as having idiopathic hypopituitarism. MRI imaging is the technique of choice in the diagnosis of children with hypopituitarism. Marked differences in MRI pituitary gland morphology suggest different etiologies of GHD and different prognoses. Pituitary stalk agenesis and ectopic posterior pituitary (EPP) are specific markers of permanent GHD, and patients with these MRI findings show a different clinical and endocrine outcome compared to those with normal pituitary anatomy or hypoplastic pituitary alone. Furthermore, the classic triad of ectopic posterior pituitary gland, pituitary stalk hypoplasia/agenesis, and anterior pituitary gland hypoplasia is generally associated with permanent GHD. T2 DRIVE images aid in the identification of pituitary stalk without the use of contrast medium administration. Future developments in imaging techniques will undoubtedly reveal additional insights. Mutations in a number of genes encoding transcription factors - such as HESX1, SOX2, SOX3, LHX3, LHX4, PROP1, POU1F1, PITX, GLI3, GLI2, OTX2, ARNT2, IGSF1, FGF8, FGFR1, PROKR2, PROK2, CHD7, WDR11, NFKB2, PAX6, TCF7L1, IFT72, GPR161 and CDON - have been associated with pituitary dysfunction and abnormal pituitary gland development; the correlation of genetic mutations to endocrine and MRI phenotypes has improved our knowledge of pituitary development and management of patients with hypopituitarism, both in terms of possible genetic counseling, and of early diagnosis of evolving anterior pituitary hormone deficiencies. PMID- 27974187 TI - Diagnosis of growth hormone deficiency in the paediatric and transitional age. AB - Growth hormone deficiency is a rare cause of childhood short stature, but one for which treatment exists in the form of recombinant human growth hormone. A diagnosis of growth hormone deficiency is made based on auxology, biochemistry and imaging. Although no diagnostic gold standard exists, growth hormone provocation tests are considered the mainstay of diagnostic investigations. However, these must be interpreted with caution in view of issues with variability and reproducibility, as well as the limited evidence-base for cut-off values used to distinguish growth hormone deficient and non-growth hormone deficient subjects. In addition, nutritional and pubertal status can affect results, with no consensus on the role of priming with sex steroid hormones. Difficulties with assays exist both for growth hormone as well as insulin-like growth factor-1. Pituitary magnetic resonance imaging is a useful diagnostic, and possibly prognostic, aid. Although genetic testing is not routine, the discovery of more relevant mutations makes it an increasingly important investigation. Children with growth hormone deficiency are retested biochemically on completion of growth, to assess whether they remain so into adulthood. PMID- 27974188 TI - Treatment of growth hormone deficiency in children, adolescents and at the transitional age. AB - Recombinant human growth hormone (rhGH) has been available since 1985. Before 1985 growth hormone (GH) was extracted from cadaveric pituitary glands, but this was stopped in most countries that year, following the recognition that it could transmit Creutzfeldt-Jacob disease. The primary goal of rhGH treatment in GHD patients is to normalize height during childhood and adolescence and attain an adult height within the normal range and within the target height range (genetic potential). Genome-wide association studies have been used increasingly to study the genetic influence on height. There is a wide response to rhGH therapy, likely due to compliance issues, severity of GH deficiency and patient's sensitivity to rhGH. While some pediatric endocrinologists will use a fixed dose of rhGH, most will use an auxology-based dosing approach. This will involve starting at the lower end of the dose range and then titrating upwards based on the patient's response to therapy with measurement of IGF-1 concentrations to ensure that the patient is not over treated or undertreated. Although treatment of children with GHD with rhGH has generally been safe, careful follow-up by a pediatric endocrinologist in partnership with the pediatrician or primary care physician is recommended. The aim of this paper is to review the strategies and recommendations for treatment of GHD in children and patients in the transition to adult care. PMID- 27974189 TI - Metabolic alterations in paediatric GH deficiency. AB - Growth hormone (GH) has a large number of metabolic effects, involving lipid and glucose homoeostasis, lean and fat mass. Growth hormone deficiency (GHD) is associated with a metabolic profile similar to the Metabolic Syndrome which is characterized by dyslipidemia, insulin resistance, haemostatic alterations, oxidative stress, and chronic inflammation. GH replacement treatment in GHD children improves these cardiovascular risk factors, while cessation of GH is associated with a deterioration of most of these risk factors. However, it is unclear whether the changes of these risk factors are associated with an increased risk of cardiovascular diseases especially after discontinuing GH treatment. GH treatment itself can lead to insulin resistance, which probably also influences the cardiovascular health status. Therefore, longitudinal studies with the primary outcome cardiovascular diseases are needed in GHD children. Furthermore, new approaches such as metabolomic studies might be helpful to understand the relationship between GHD, GH treatment, and cardiovascular diseases. PMID- 27974191 TI - Diagnosis and treatment of GH deficiency in Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) results from under-expression of the paternally derived chromosomal region 15q11-13. Growth failure is a recognized feature of PWS, and both quantitative and qualitative defects of the GH/IGF-I axis revealing GH deficiency (GHD) have been demonstrated in most children with PWS. In PWS adults, criteria for GHD are biochemically fulfilled in 8-38% of the studied cohorts. Published data support benefits of early institution of GH therapy (GHT) in PWS children, with positive effects on statural growth, body composition, metabolic homeostasis, and neurocognitive function. Like in pediatric PWS, GHT also yields beneficial effects on lean and body fat, exercise capacity, and quality of life of PWS adults. Although GHT has been generally administered safely in PWS children and adults, careful surveillance of risks is mandatory during prolonged GH replacement for all PWS individuals. PMID- 27974190 TI - Muscle and skeletal health in children and adolescents with GH deficiency. AB - In addition to promoting linear growth, GH plays a key role in the regulation of bone and muscle development and metabolism. Although GH deficiency is frequently listed among the causes of secondary osteoporosis in children, its impact on bone and muscle health and on fracture risk is still not completely established. Current data suggest that childhood-onset GH deficiency can affect bone and muscle mass and strength, with GH replacement therapy exerting beneficial effects. Moreover, GH withdrawal at final height can result in reduced peak bone and muscle mass, potentially leading to increased fracture risk in adulthood. Thus, the muscle-bone unit in GH deficient subjects should be monitored during childhood and adolescence in order to prevent osteoporosis and increased fracture risk and GH replacement should be tailored to ensure an optimal bone and muscle health. PMID- 27974192 TI - GH deficiency in adult survivors of childhood cancer. AB - Childhood cancer survivors (CCS) are a fast growing population, but late adverse effects of cancer therapies are not rare. In CCS treated with cranial radiotherapy, growth hormone deficiency (GHD) is a well-known occurrence and the potential impact of GH replacement therapy on the global outcome of CCS is under continuous evaluation. In the present review, we discuss advantages and disadvantages of GH replacement therapy in survivors of pediatric malignancies, taking into consideration the different reasons for treating GHD during childhood or adult life. It is doubtless that GH treatment is advisable to obtain a normal growth in pediatric patients. As far as the beginning/continuation of the replacement therapy in adult age is concerned, contrasting results have been reported in literature. The suggestion is that the decision to treat adult CCS should be taken after careful evaluation of each patient's clinical history and of the potential side effects, in agreement with the patients. PMID- 27974193 TI - Perinatal exposure to lead (Pb) induces ultrastructural and molecular alterations in synapses of rat offspring. AB - Lead (Pb), environmentally abundant heavy-metal pollutant, is a strong toxicant for the developing central nervous system. Pb intoxication in children, even at low doses, is found to affect learning and memorizing, with devastating effects on cognitive function and intellectual development. However, the precise mechanism by which Pb impairs synaptic plasticity is not fully elucidated. The purpose of this study was to investigate the effect of pre- and neonatal exposure to low dose of Pb (with Pb concentrations in whole blood below 10MUg/dL) on the synaptic structure and the pre- and postsynaptic proteins expression in the developing rat brain. Furthermore, the level of brain-derived neurotrophic factor (BDNF) was analyzed. Pregnant female Wistar rats received 0.1% lead acetate (PbAc) in drinking water from the first day of gestation until weaning of the offspring, while the control animals received drinking water. During the feeding of pups, mothers from the Pb-group were continuously receiving PbAc. Pups of both groups were weaned at postnatal day 21 and then until postnatal day 28 received only drinking water. 28-day old pups were sacrificed and the ultrastructural changes as well as expression of presynaptic (VAMP1/2, synaptophysin, synaptotagmin-1, SNAP25, syntaxin-1) and postsynaptic (PSD-95) proteins were analyzed in: forebrain cortex, cerebellum and hippocampus. Our data revealed that pre- and neonatal exposure to low dose of Pb promotes pathological changes in synapses, including nerve endings swelling, blurred and thickened synaptic cleft structure as well as enhanced density of synaptic vesicles in the presynaptic area. Moreover, synaptic mitochondria were elongated, swollen or shrunken in Pb treated animals. These structural abnormalities were accompanied by decrease in the level of key synaptic proteins: synaptotagmin-1 in cerebellum, SNAP25 in hippocampus and syntaxin-1 in cerebellum and hippocampus. In turn, increased level of synaptophysin was noticed in the cerebellum, while the expression of postsynaptic PSD-95 was significantly decreased in forebrain cortex and cerebellum, and raised in hippocampus. Additionally, we observed the lower level of BDNF in all brain structures in comparison to control animals. In conclusion, perinatal exposure to low doses of Pb caused pathological changes in nerve endings associated with the alterations in the level of key synaptic proteins. All these changes can lead to synaptic dysfunction, expressed by the impairment of the secretory mechanism and thereby to the abnormalities in neurotransmission as well as to the neuronal dysfunction. PMID- 27974194 TI - The Left Hand Doesn't Know What the Right Hand Is Doing-or Does It? AB - In this issue of Cell Reports, Ossmy and Mukamel (2016) show that virtual reality enhances learning of new motor sequences through practice with one hand and synchronous feedback of the other hand moving. The approach holds promise for motor rehabilitation. PMID- 27974196 TI - A Combinatorial CRISPR-Cas9 Attack on HIV-1 DNA Extinguishes All Infectious Provirus in Infected T Cell Cultures. AB - Current drug therapies effectively suppress HIV-1 replication but do not inactivate the provirus that persists in latent reservoirs. Recent studies have found that the guide RNA (gRNA)-directed CRISPR/Cas9 system can be used for sequence-specific attack on this proviral DNA. Although potent inhibition of virus replication was reported, HIV-1 can escape from a single antiviral gRNA by mutation of the target sequence. Here, we demonstrate that combinations of two antiviral gRNAs delay viral escape, and identify two gRNA combinations that durably block virus replication. When viral escape is prevented, repeated Cas9 cleavage leads to saturation of major mutations in the conserved target sequences that encode critical proteins. This hypermutation coincides with the loss of replication-competent virus as scored in sensitive co-cultures with unprotected cells, demonstrating complete virus inactivation. These results provide a proof of-principle that HIV-1-infected cells can be functionally cured by dual-gRNA CRISPR/Cas9 treatment. PMID- 27974195 TI - Human Stem Cell-like Memory T Cells Are Maintained in a State of Dynamic Flux. AB - Adaptive immunity requires the generation of memory T cells from naive precursors selected in the thymus. The key intermediaries in this process are stem cell-like memory T (TSCM) cells, multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. In theory, antigen specificity within the TSCM pool may be imprinted statically as a function of largely dormant cells and/or retained dynamically by more transitory subpopulations. To explore the origins of immunological memory, we measured the turnover of TSCM cells in vivo using stable isotope labeling with heavy water. The data indicate that TSCM cells in both young and elderly subjects are maintained by ongoing proliferation. In line with this finding, TSCM cells displayed limited telomere length erosion coupled with high expression levels of active telomerase and Ki67. Collectively, these observations show that TSCM cells exist in a state of perpetual flux throughout the human lifespan. PMID- 27974197 TI - Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a Transcriptional Network of E47, Spi-B, and SOCS3. AB - The transcription factor Foxp3 dominantly controls regulatory T (Treg) cell function, and only its continuous expression guarantees the maintenance of full Treg cell-suppressive capacity. However, transcriptional regulators maintaining Foxp3 transcription are incompletely described. Here, we report that high E47 transcription factor activity in Treg cells resulted in unstable Foxp3 expression. Under homeostatic conditions, Treg cells expressed high levels of the E47 antagonist Id3, thus restricting E47 activity and maintaining Foxp3 expression. In contrast, stimulation of Id3-deficient or E47-overexpressing Treg cells resulted in the loss of Foxp3 expression in a subset of Treg cells in vivo and in vitro. Mechanistic analysis indicated that E47 activated expression of the transcription factor Spi-B and the suppressor of cytokine signaling 3 (SOCS3), which both downregulated Foxp3 expression. These findings demonstrate that the balance of Id3 and E47 controls the maintenance of Foxp3 expression in Treg cells and, thus, contributes to Treg cell plasticity. PMID- 27974198 TI - Proline Catabolism Modulates Innate Immunity in Caenorhabditis elegans. AB - Metabolic pathways are regulated to fuel or instruct the immune responses to pathogen threats. However, the regulatory roles for amino acid metabolism in innate immune responses remains poorly understood. Here, we report that mitochondrial proline catabolism modulates innate immunity in Caenorhabditis elegans. Modulation of proline catabolic enzymes affects host susceptibility to bacterial pathogen Pseudomonas aeruginosa. Mechanistically, proline catabolism governs reactive oxygen species (ROS) homeostasis and subsequent activation of SKN-1, a critical transcription factor regulating xenobiotic stress response and pathogen defense. Intriguingly, proline catabolism-mediated activation of SKN-1 requires cell-membrane dual-oxidase Ce-Duox1/BLI-3, highlighting the importance of interaction between mitochondrial and cell-membrane components in host defense. Our findings reveal how animals utilize metabolism of a single amino acid to defend against a pathogen and identify proline catabolism as a component of innate immune signaling. PMID- 27974199 TI - Glucagon-like Peptide 1 Receptor Signaling in Acinar Cells Causes Growth Dependent Release of Pancreatic Enzymes. AB - Incretin-based therapies are widely used for type 2 diabetes and now also for obesity, but they are associated with elevated plasma levels of pancreatic enzymes and perhaps a modestly increased risk of acute pancreatitis. However, little is known about the effects of the incretin hormone glucagon-like peptide 1 (GLP-1) on the exocrine pancreas. Here, we identify GLP-1 receptors on pancreatic acini and analyze the impact of receptor activation in humans, rodents, isolated acini, and cell lines from the exocrine pancreas. GLP-1 did not directly stimulate amylase or lipase release. However, we saw that GLP-1 induces phosphorylation of the epidermal growth factor receptor and activation of Foxo1, resulting in cell growth with concomitant enzyme release. Our work uncovers GLP-1 induced signaling pathways in the exocrine pancreas and suggests that increases in amylase and lipase levels in subjects treated with GLP-1 receptor agonists reflect adaptive growth rather than early-stage pancreatitis. PMID- 27974200 TI - Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human beta-Cardiac Myosin. AB - Hypertrophic cardiomyopathy (HCM) is a heritable cardiovascular disorder that affects 1 in 500 people. A significant percentage of HCM is attributed to mutations in beta-cardiac myosin, the motor protein that powers ventricular contraction. This study reports how two early-onset HCM mutations, D239N and H251N, affect the molecular biomechanics of human beta-cardiac myosin. We observed significant increases (20%-90%) in actin gliding velocity, intrinsic force, and ATPase activity in comparison to wild-type myosin. Moreover, for H251N, we found significantly lower binding affinity between the S1 and S2 domains of myosin, suggesting that this mutation may further increase hyper contractility by releasing active motors. Unlike previous HCM mutations studied at the molecular level using human beta-cardiac myosin, early-onset HCM mutations lead to significantly larger changes in the fundamental biomechanical parameters and show clear hyper-contractility. PMID- 27974201 TI - Functional Mutations Form at CTCF-Cohesin Binding Sites in Melanoma Due to Uneven Nucleotide Excision Repair across the Motif. AB - CTCF binding sites are frequently mutated in cancer, but how these mutations accumulate and whether they broadly perturb CTCF binding are not well understood. Here, we report that skin cancers exhibit a highly specific asymmetric mutation pattern within CTCF motifs attributable to ultraviolet irradiation and differential nucleotide excision repair (NER). CTCF binding site mutations form independently of replication timing and are enriched at sites of CTCF/cohesin complex binding, suggesting a role for cohesin in stabilizing CTCF-DNA binding and impairing NER. Performing CTCF ChIP-seq in a melanoma cell line, we show CTCF binding site mutations to be functional by demonstrating allele-specific reduction of CTCF binding to mutant alleles. While topologically associating domains with mutated CTCF anchors in melanoma contain differentially expressed cancer-associated genes, CTCF motif mutations appear generally under neutral selection. However, the frequency and potential functional impact of such mutations in melanoma highlights the need to consider their impact on cellular phenotype in individual genomes. PMID- 27974202 TI - The Drosophila Clock Neuron Network Features Diverse Coupling Modes and Requires Network-wide Coherence for Robust Circadian Rhythms. AB - In animals, networks of clock neurons containing molecular clocks orchestrate daily rhythms in physiology and behavior. However, how various types of clock neurons communicate and coordinate with one another to produce coherent circadian rhythms is not well understood. Here, we investigate clock neuron coupling in the brain of Drosophila and demonstrate that the fly's various groups of clock neurons display unique and complex coupling relationships to core pacemaker neurons. Furthermore, we find that coordinated free-running rhythms require molecular clock synchrony not only within the well-characterized lateral clock neuron classes but also between lateral clock neurons and dorsal clock neurons. These results uncover unexpected patterns of coupling in the clock neuron network and reveal that robust free-running behavioral rhythms require a coherence of molecular oscillations across most of the fly's clock neuron network. PMID- 27974204 TI - Neural Network Underlying Intermanual Skill Transfer in Humans. AB - Physical practice with one hand results in performance gains of the other (un practiced) hand, yet the role of sensory feedback and underlying neurophysiology is unclear. Healthy subjects learned sequences of finger movements by physical training with their right hand while receiving real-time movement-based visual feedback via 3D virtual reality devices as if their immobile left hand was training. This manipulation resulted in significantly enhanced performance gain with the immobile hand, which was further increased when left-hand fingers were yoked to passively follow right-hand voluntary movements. Neuroimaging data show that, during training with manipulated visual feedback, activity in the left and right superior parietal lobule and their degree of coupling with motor and visual cortex, respectively, correlate with subsequent left-hand performance gain. These results point to a neural network subserving short-term motor skill learning and may have implications for developing new approaches for learning and rehabilitation in patients with unilateral motor deficits. PMID- 27974203 TI - Serotonin 1B Receptors Regulate Prefrontal Function by Gating Callosal and Hippocampal Inputs. AB - Both medial prefrontal cortex (mPFC) and serotonin play key roles in anxiety; however, specific mechanisms through which serotonin might act on the mPFC to modulate anxiety-related behavior remain unknown. Here, we use a combination of optogenetics and synaptic physiology to show that serotonin acts presynaptically via 5-HT1B receptors to selectively suppress inputs from the contralateral mPFC and ventral hippocampus (vHPC), while sparing those from mediodorsal thalamus. To elucidate how these actions could potentially regulate prefrontal circuit function, we infused a 5-HT1B agonist into the mPFC of freely behaving mice. Consistent with previous studies that have optogenetically inhibited vHPC-mPFC projections, activating prefrontal 5-HT1B receptors suppressed theta-frequency mPFC activity (4-12 Hz), and reduced avoidance of anxiogenic regions in the elevated plus maze. These findings suggest a potential mechanism, linking specific receptors, synapses, patterns of circuit activity, and behavior, through which serotonin may regulate prefrontal circuit function, including anxiety related behaviors. PMID- 27974205 TI - TRPV1 Nociceptor Activity Initiates USP5/T-type Channel-Mediated Plasticity. AB - Peripheral nerve injury and tissue inflammation result in upregulation of the deubiquitinase USP5, thus causing a dysregulation of T-type calcium channel activity and increased pain sensitivity. Here, we have explored the role of afferent fiber activity in this process. Conditioning stimulation of optogenetically targeted cutaneous TRPV1 expressing nociceptors, but not that of non-nociceptive fibers, resulted in enhanced expression of USP5 in mouse dorsal root ganglia and spinal dorsal horn, along with decreased withdrawal thresholds for thermal and mechanical stimuli that abated after 24 hr. This sensitization was drastically reduced by an interfering peptide that prevented USP5-Cav3.2 association. Sensitization was relieved by pharmacological block of TRPV1 afferents, but not of myelinated neurons. In spinal cord slice recordings, we could optogenetically trigger an activity-dependent potentiation of presynaptic neurotransmission in the spinal dorsal horn that relied on Cav3.2 channel activity. This neuronal-activity-induced USP5 upregulation may underlie a protective, transient sensitization of the pain pathway. PMID- 27974207 TI - DNA Replication Origins in Immunoglobulin Switch Regions Regulate Class Switch Recombination in an R-Loop-Dependent Manner. AB - Class switch recombination (CSR) at the immunoglobulin heavy chain (IgH) locus generates antibody isotypes. CSR depends on double-strand breaks (DSBs) induced by activation-induced cytidine deaminase (AID). Although DSB formation and repair machineries are active in G1 phase, efficient CSR is dependent on cell proliferation and S phase entry; however, the underlying mechanisms are obscure. Here, we show that efficient CSR requires the replicative helicase, the Mcm complex. Mcm proteins are enriched at IgH switch regions during CSR, leading to assembly of facultative replication origins that require Mcm helicase function for productive CSR. Assembly of CSR-associated origins is facilitated by R loops and promotes the physical proximity (synapsis) of recombining switch regions, which is reduced by R loop inhibition or Mcm complex depletion. Thus, R loops contribute to replication origin specification that promotes DSB resolution in CSR. This suggests a mechanism for the dependence of CSR on S phase and cell division. PMID- 27974206 TI - Distal Limb Patterning Requires Modulation of cis-Regulatory Activities by HOX13. AB - The combinatorial expression of Hox genes along the body axes is a major determinant of cell fate and plays a pivotal role in generating the animal body plan. Loss of HOXA13 and HOXD13 transcription factors (HOX13) leads to digit agenesis in mice, but how HOX13 proteins regulate transcriptional outcomes and confer identity to the distal-most limb cells has remained elusive. Here, we report on the genome-wide profiling of HOXA13 and HOXD13 in vivo binding and changes of the transcriptome and chromatin state in the transition from the early to the late-distal limb developmental program, as well as in Hoxa13-/-; Hoxd13-/- limbs. Our results show that proper termination of the early limb transcriptional program and activation of the late-distal limb program are coordinated by the dual action of HOX13 on cis-regulatory modules. PMID- 27974208 TI - Structural Dynamics of the YidC:Ribosome Complex during Membrane Protein Biogenesis. AB - Members of the YidC/Oxa1/Alb3 family universally facilitate membrane protein biogenesis, via mechanisms that have thus far remained unclear. Here, we investigated two crucial functional aspects: the interaction of YidC with ribosome:nascent chain complexes (RNCs) and the structural dynamics of RNC-bound YidC in nanodiscs. We observed that a fully exposed nascent transmembrane domain (TMD) is required for high-affinity YidC:RNC interactions, while weaker binding may already occur at earlier stages of translation. YidC efficiently catalyzed the membrane insertion of nascent TMDs in both fluid and gel phase membranes. Cryo-electron microscopy and fluorescence analysis revealed a conformational change in YidC upon nascent chain insertion: the essential TMDs 2 and 3 of YidC were tilted, while the amphipathic helix EH1 relocated into the hydrophobic core of the membrane. We suggest that EH1 serves as a mechanical lever, facilitating a coordinated movement of YidC TMDs to trigger the release of nascent chains into the membrane. PMID- 27974209 TI - TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation. AB - Significant insights into disease pathogenesis have been gleaned from population level genetic studies; however, many loci associated with complex genetic disease contain numerous genes, and phenotypic associations cannot be assigned unequivocally. In particular, a gene-dense locus on chromosome 11 (61.5-61.65 Mb) has been associated with inflammatory bowel disease, rheumatoid arthritis, and coronary artery disease. Here, we identify TMEM258 within this locus as a central regulator of intestinal inflammation. Strikingly, Tmem258 haploinsufficient mice exhibit severe intestinal inflammation in a model of colitis. At the mechanistic level, we demonstrate that TMEM258 is a required component of the oligosaccharyltransferase complex and is essential for N-linked protein glycosylation. Consequently, homozygous deficiency of Tmem258 in colonic organoids results in unresolved endoplasmic reticulum (ER) stress culminating in apoptosis. Collectively, our results demonstrate that TMEM258 is a central mediator of ER quality control and intestinal homeostasis. PMID- 27974210 TI - Downregulation of a GPCR by beta-Arrestin2-Mediated Switch from an Endosomal to a TGN Recycling Pathway. AB - Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in nutrient homeostasis. GIP receptor (GIPR) is constitutively internalized and returned to the plasma membrane, atypical behavior for a G protein-coupled receptor (GPCR). GIP promotes GIPR downregulation from the plasma membrane by inhibiting recycling without affecting internalization. This transient desensitization is achieved by altered intracellular trafficking of activated GIPR. GIP stimulation induces a switch in GIPR recycling from a rapid endosomal to a slow trans-Golgi network (TGN) pathway. GPCR kinases and beta arrestin2 are required for this switch in recycling. A coding sequence variant of GIPR, which has been associated with metabolic alterations, has altered post activation trafficking characterized by enhanced downregulation and prolonged desensitization. Downregulation of the variant requires beta-arrestin2 targeting to the TGN but is independent of GPCR kinases. The single amino acid substitution in the variant biases the receptor to promote GIP-stimulated beta-arrestin2 recruitment without receptor phosphorylation, thereby enhancing downregulation. PMID- 27974211 TI - Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells. AB - The complexity of liver tumorigenesis is underscored by the recently observed anti-oncogenic effects of oncoproteins, although the mechanisms are unclear. Shp2/Ptpn11 is a proto-oncogene in hematopoietic cells and antagonizes the effect of tumor suppressor Pten in leukemogenesis. In contrast, we show here cooperative functions of Shp2 and Pten in suppressing hepatocarcinogenesis. Ablating both Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH) and promoted genesis of liver tumor-initiating cells likely due to augmented cJun expression/activation and elevated ROS and inflammation in the hepatic microenvironment. Inhibiting cJun partially suppressed NASH-driven liver tumorigenesis without improving NASH. SHP2 and PTEN deficiencies were detected in liver cancer patients with poor prognosis. These data depict a mechanism of hepato-oncogenesis and suggest a potential therapeutic strategy. PMID- 27974213 TI - Reversal of Defective Mitochondrial Biogenesis in Limb-Girdle Muscular Dystrophy 2D by Independent Modulation of Histone and PGC-1alpha Acetylation. AB - Mitochondrial dysfunction occurs in many muscle degenerative disorders. Here, we demonstrate that mitochondrial biogenesis was impaired in limb-girdle muscular dystrophy (LGMD) 2D patients and mice and was associated with impaired OxPhos capacity. Two distinct approaches that modulated histones or peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1alpha) acetylation exerted equivalent functional effects by targeting different mitochondrial pathways (mitochondrial biogenesis or fatty acid oxidation[FAO]). The histone deacetylase inhibitor Trichostatin A (TSA) changed chromatin assembly at the PGC-1alpha promoter, restored mitochondrial biogenesis, and enhanced muscle oxidative capacity. Conversely, nitric oxide (NO) triggered post translation modifications of PGC-1alpha and induced FAO, recovering the bioenergetics impairment of muscles but shunting the defective mitochondrial biogenesis. In conclusion, a transcriptional blockade of mitochondrial biogenesis occurred in LGMD-2D and could be recovered by TSA changing chromatin conformation, or it could be overcome by NO activating a mitochondrial salvage pathway. PMID- 27974212 TI - Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition. AB - Intratumoral heterogeneity is a hallmark of glioblastoma multiforme and thought to negatively affect treatment efficacy. Here, we establish libraries of glioma initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability among clones, including a range of responses to radiation and drugs. This widespread variability was observed as a continuum of multitherapy resistance phenotypes linked to a proneural-mesenchymal shift in the transcriptome. Multitherapy resistance was associated with a semi-stable cell state that was characterized by an altered DNA methylation pattern at promoter regions of mesenchymal master regulators and enhancers. The gradient of cell states within the GIC compartment constitutes a distinct form of heterogeneity. Our findings may open an avenue toward the development of new therapeutic rationales designed to reverse resistant cell states. PMID- 27974214 TI - Optic Atrophy 1 Is Epistatic to the Core MICOS Component MIC60 in Mitochondrial Cristae Shape Control. AB - The mitochondrial contact site and cristae organizing system (MICOS) and Optic atrophy 1 (OPA1) control cristae shape, thus affecting mitochondrial function and apoptosis. Whether and how they physically and functionally interact is unclear. Here, we provide evidence that OPA1 is epistatic to MICOS in the regulation of cristae shape. Proteomic analysis identifies multiple MICOS components in native OPA1-containing high molecular weight complexes disrupted during cristae remodeling. MIC60, a core MICOS protein, physically interacts with OPA1, and together, they control cristae junction number and stability, OPA1 being epistatic to MIC60. OPA1 defines cristae width and junction diameter independently of MIC60. Our combination of proteomics, biochemistry, genetics, and electron tomography provides a unifying model for mammalian cristae biogenesis by OPA1 and MICOS. PMID- 27974216 TI - Reversible Induction of Pain Hypersensitivity following Optogenetic Stimulation of Spinal Astrocytes. AB - While glial activation is an integral part of pain pathogenesis, the existence of a causal relationship between glia and pain processing has yet to be demonstrated in vivo. Here, we have investigated whether the activation of spinal astrocytes could directly evoke pain hypersensitivity in vivo via the use of optogenetic techniques. Optogenetic stimulation of channelrhopdopsin-2 (ChR)-expressing spinal astrocytes induced pain hypersensitivity in a reversible and time dependent manner, which was accompanied by glial activation, NR1 phosphorylation, ATP release, and the production of proalgesic mediators. Photostimulation of ChR2 expressing astrocytes in culture and spinal slices recapitulated in vivo findings, demonstrating the release of proalgesic mediators and electrophysiological disinhibition of spinal projection neurons. These findings deepen our understanding of the role of astrocytes in pain pathogenesis and provide the scientific basis for an astrocyte-oriented pain treatment. PMID- 27974217 TI - Epigenomics-Based Identification of Major Cell Identity Regulators within Heterogeneous Cell Populations. AB - Cellular heterogeneity within embryonic and adult tissues is involved in multiple biological and pathological processes. Here, we present a simple epigenomic strategy that allows the functional dissection of cellular heterogeneity. By integrating H3K27me3 chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) data, we demonstrate that the presence of broad H3K27me3 domains at transcriptionally active genes reflects the heterogeneous expression of major cell identity regulators. Using dorsoventral patterning of the spinal neural tube as a model, the proposed approach successfully identifies the majority of previously known dorsoventral patterning transcription factors with high sensitivity and precision. Moreover, poorly characterized patterning regulators can be similarly predicted, as shown for ZNF488, which confers p1/p2 neural progenitor identity. Finally, we show that, as our strategy is based on universal chromatin features, it can be used to functionally dissect cellular heterogeneity within various organisms and tissues, thus illustrating its potential applicability to a broad range of biological and pathological contexts. PMID- 27974215 TI - Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes. AB - Rare variants enriched for functions in chromatin regulation and neuronal synapses have been linked to autism. How chromatin and DNA methylation interact with environmental exposures at synaptic genes in autism etiologies is currently unclear. Using whole-genome bisulfite sequencing in brain tissue and a neuronal cell culture model carrying a 15q11.2-q13.3 maternal duplication, we find that significant global DNA hypomethylation is enriched over autism candidate genes and affects gene expression. The cumulative effect of multiple chromosomal duplications and exposure to the pervasive persistent organic pollutant PCB 95 altered methylation of more than 1,000 genes. Hypomethylated genes were enriched for H2A.Z, increased maternal UBE3A in Dup15q corresponded to reduced levels of RING1B, and bivalently modified H2A.Z was altered by PCB 95 and duplication. These results demonstrate the compounding effects of genetic and environmental insults on the neuronal methylome that converge upon dysregulation of chromatin and synaptic genes. PMID- 27974219 TI - Sustained Rhythmic Brain Activity Underlies Visual Motion Perception in Zebrafish. PMID- 27974218 TI - An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice. AB - The NLRP3 inflammasome plays a critical role in host defense by facilitating caspase I activation and maturation of IL-1beta and IL-18, whereas dysregulation of inflammasome activity results in autoinflammatory disease. Factors regulating human NLRP3 activity that contribute to the phenotypic heterogeneity of NLRP3 related diseases have largely been inferred from the study of Nlrp3 mutant mice. By generating a mouse line in which the NLRP3 locus is humanized by syntenic replacement, we show the functioning of the human NLRP3 proteins in vivo, demonstrating the ability of the human inflammasome to orchestrate immune reactions in response to innate stimuli. Humanized mice expressing disease associated mutations develop normally but display acute sensitivity to endotoxin and develop progressive and debilitating arthritis characterized by granulocytic infiltrates, elevated cytokines, erosion of bones, and osteoporosis. This NLRP3 dependent arthritis model provides a platform for testing therapeutic reagents targeting the human inflammasome. PMID- 27974220 TI - Histone H3 Lysine 9 Acetylation Obstructs ATM Activation and Promotes Ionizing Radiation Sensitivity in Normal Stem Cells. AB - Dynamic spatiotemporal modification of chromatin around DNA damage is vital for efficient DNA repair. Normal stem cells exhibit an attenuated DNA damage response (DDR), inefficient DNA repair, and high radiosensitivity. The impact of unique chromatin characteristics of stem cells in DDR regulation is not yet recognized. We demonstrate that murine embryonic stem cells (ES) display constitutively elevated acetylation of histone H3 lysine 9 (H3K9ac) and low H3K9 tri-methylation (H3K9me3). DNA damage-induced local deacetylation of H3K9 was abrogated in ES along with the subsequent H3K9me3. Depletion of H3K9ac in ES by suppression of monocytic leukemia zinc finger protein (MOZ) acetyltransferase improved ATM activation, DNA repair, diminished irradiation-induced apoptosis, and enhanced clonogenic survival. Simultaneous suppression of the H3K9 methyltransferase Suv39h1 abrogated the radioprotective effect of MOZ inhibition, suggesting that high H3K9ac promoted by MOZ in ES cells obstructs local upregulation of H3K9me3 and contributes to muted DDR and increased radiosensitivity. PMID- 27974222 TI - USP10 Is an Essential Deubiquitinase for Hematopoiesis and Inhibits Apoptosis of Long-Term Hematopoietic Stem Cells. AB - Self-renewal, replication, and differentiation of hematopoietic stem cells (HSCs) are regulated by cytokines produced by niche cells in fetal liver and bone marrow. HSCs must overcome stresses induced by cytokine deprivation during normal development. In this study, we found that ubiquitin-specific peptidase 10 (USP10) is a crucial deubiquitinase for mouse hematopoiesis. All USP10 knockout (KO) mice died within 1 year because of bone marrow failure with pancytopenia. Bone marrow failure in these USP10-KO mice was associated with remarkable reductions of long term HSCs (LT-HSCs) in bone marrow and fetal liver. Such USP10-KO fetal liver exhibited enhanced apoptosis of hematopoietic stem/progenitor cells (HSPCs) including LT-HSCs but not of lineage-committed progenitor cells. Transplantation of USP10-competent bone marrow cells into USP10-KO mice reconstituted multilineage hematopoiesis. These results suggest that USP10 is an essential deubiquitinase in hematopoiesis and functions by inhibiting apoptosis of HSPCs including LT-HSCs. PMID- 27974221 TI - Cell-Based Delivery of Interleukin-13 Directs Alternative Activation of Macrophages Resulting in Improved Functional Outcome after Spinal Cord Injury. AB - The therapeutic effects of mesenchymal stem cell (MSC) transplantation following spinal cord injury (SCI) to date have been limited. Therefore, we aimed to enhance the immunomodulatory properties of MSCs via continuous secretion of the anti-inflammatory cytokine interleukin-13 (IL-13). By using MSCs as carriers of IL-13 (MSC/IL-13), we investigated their therapeutic potential, compared with non engineered MSCs, in a mouse model of SCI. We show that transplanted MSC/IL-13 significantly improve functional recovery following SCI, and also decrease lesion size and demyelinated area by more than 40%. Further histological analyses in CX3CR1EGFP/+ CCR2RFP/+ transgenic mice indicated that MSC/IL-13 significantly decrease the number of resident microglia and increase the number of alternatively activated macrophages. In addition, the number of macrophage-axon contacts in MSC/IL-13-treated mice was decreased by 50%, suggesting a reduction in axonal dieback. Our data provide evidence that transplantation of MSC/IL-13 leads to improved functional and histopathological recovery in a mouse model of SCI. PMID- 27974225 TI - Challenges Facing Pediatric Nursing. PMID- 27974224 TI - Social-Emotional Development of Toddlers: Randomized Controlled Trial of an Office-Based Intervention. AB - PURPOSE: During the toddler years, temper tantrums and impulsive behaviors are the norm. These behaviors can frustrate even the most experienced mothers. DESIGN AND METHODS: A prospective, double blind, randomized controlled trial using pre test/post-test experimental design was used to examine the effectiveness of an office-based educational program to improve maternal confidence and the social emotional development of toddlers. The Toddler Care Questionnaire (TCQ) was administered to all mothers as a pre and post intervention test. The treatment intervention was a videotaped (DVD) parenting skills intervention on the social emotional development of toddlers and on maternal confidence in caring for toddlers. RESULTS: Sixty mothers and 60 toddlers entered the study with 29 mothertoddler dyads randomized to the treatment group and 31 to the control group. Twenty-six (26) mother-toddler dyads in the treatment and 25 mother toddler dyads in the control group completed the study. Pairwise comparisons of adjusted means showed significant improvements for both toddler groups on the Brigance toddler screen, and no statistically significant difference in gains between the groups. The mixed model results for the TCQ showed an overall significant improvement from preto post-test, and a non-significant interaction between group and time indicting no significant difference in gains seen by treatment groups. CONCLUSIONS: Brief educational programs on DVD's are an efficient way to offer information to mothers while in the office waiting area. PRACTICE IMPLICATIONS: Pediatric nurses who encounter mothers who struggle with caring for their toddlers may find brief-office based interventions a valuable tool for educating parents. PMID- 27974223 TI - Rbf Regulates Drosophila Spermatogenesis via Control of Somatic Stem and Progenitor Cell Fate in the Larval Testis. AB - The Drosophila testis has been fundamental to understanding how stem cells interact with their endogenous microenvironment, or niche, to control organ growth in vivo. Here, we report the identification of two independent alleles for the highly conserved tumor suppressor gene, Retinoblastoma-family protein (Rbf), in a screen for testis phenotypes in X chromosome third-instar lethal alleles. Rbf mutant alleles exhibit overproliferation of spermatogonial cells, which is phenocopied by the molecularly characterized Rbf11 null allele. We demonstrate that Rbf promotes cell-cycle exit and differentiation of the somatic and germline stem cells of the testes. Intriguingly, depletion of Rbf specifically in the germline does not disrupt stem cell differentiation, rather Rbf loss of function in the somatic lineage drives overproliferation and differentiation defects in both lineages. Together our observations suggest that Rbf in the somatic lineage controls germline stem cell renewal and differentiation non-autonomously via essential roles in the microenvironment of the germline lineage. PMID- 27974226 TI - Adverse event and error of unexpected life-threatening events within 24hours of ED admission. AB - OBJECTIVES: Errors and adverse events associated with unexpected life-threatening events including unplanned transfer to the intensive care unit (ICU) and unexpected death after emergency department (ED) hospitalization are not well characterized. We performed this study to investigate the role of unexpected life threatening events as a trigger to capture errors and adverse events for ED patient safety. METHODS: This prospective observational study enrolled adult non trauma patients with unexpected life-threatening events within 24h of general ward admission from the ED of a medical center in Taiwan. The period of study was one year (in 2013); the medical records of enrolled patients were reviewed to identify adverse events and errors. We measured the incidence rate of adverse events or errors. Preventability, type, and physical injury severity of adverse events were investigated. RESULTS: Of 33,224 adult non-trauma ward admissions from the ED, 100 admissions (0.3%) met the study criteria. Incidence rate was 2% and 15% for errors and adverse events, respectively. In admissions involving error, all were preventable and the error type was overlooked of severity. In admissions that involved adverse events, 93.3% were preventable. There were 20% of admissions that resulted in death and 60% developed with severe physical injury. The adverse event types were diagnosis issues (53.3%), management issues (40%), and medication adverse events (6.7%). CONCLUSIONS: Unexpected life threatening events within 24h of admission from the ED could be a useful trigger tool to identify preventable adverse events with serious physical injury in ED. PMID- 27974227 TI - Evaluation of a commercial loop-mediated isothermal amplification assay for diagnosis of Bordetella pertussis infection. AB - We evaluated a commercial loop-mediated isothermal amplification (LAMP) assay kit for Bordetella pertussis detection. The LAMP primers were designed to target the ptxP1 allele of the pertussis toxin promoter, but the assay could detect B. pertussis ptxP3 and ptxP8 strains in addition to ptxP1 strains, with high analytical sensitivity. PMID- 27974228 TI - Evaluating metabolic response to light exposure in Lactobacillus species via targeted metabolic profiling. AB - This study reported metabolic profiles of three representative strains from Lactobacillus species, and explored their metabolic response to visible light exposure. We utilized strains from three Lactobacillus species, Lactobacillus acidophilus, Lactobacillus fermentum and Lactobacillus delbrueckii as our model bacteria and applied mass spectrometry base targeted metabolomics to specifically investigate 221 metabolites within multiple metabolic pathways. Similar and diverse metabolome from three tested strains were discovered. Furthermore, all three Lactobacillus strains demonstrated different metabolic profiles in comparison between light expose verse control. In all three strains, 12 metabolites were detected to have significant differences (p-value<0.01) in light exposure culture compared to the control samples (culture grown without light exposure). Principal components analysis using these significantly changed metabolites clearly separated the exposure and control groups in all three studied Lactobacillus strains. Additionally, metabolic pathway impact analysis indicated that several commonly impacted pathways can be observed. PMID- 27974230 TI - Sex differences on drugs affecting behavior. PMID- 27974229 TI - Selective estrogen receptor modulators and the vitamin D analogue eldecalcitol block bone loss in male osteoporosis. AB - Rapid increases in the number of elderly people have dramatically increased the number of female and male osteoporosis patients. Osteoporosis often causes bone fragility fractures, and males exhibit particularly poor prognosis after these fractures, indicating that control of osteoporosis is crucial to maintain quality of men's lives. However, osteoporosis therapies available for men have lagged behind advances available for women. Here, we show that three selective estrogen receptor modulators (SERMs), namely, raloxifene, bazedoxifene, and tamoxifen, plus the vitamin D analogue ED71, also called eldecalcitol, completely block orchiectomy-induced, testosterone-depleted bone loss in male mice in vivo. Patients treated with hormone deprivation therapy for prostate cancer also exhibit male osteoporosis, and bone management is critical for these patients. Given that androgen replacement therapy is not an option for these patients, our results represent a novel approach potentially useful to control male osteoporosis. PMID- 27974231 TI - Fatal self-envenomation in a brown tree snake, Boiga irregularis, from south-east Queensland. AB - The case history and clinical signs of a fatal self-envenomation event by a brown tree snake, Boiga irregularis, in South-east Queensland, Australia, are presented. Clinical signs began 20 minutes post-envenomation with muscle twitching, ataxia, and heat seeking behavior which progressed to partial paralysis by 6 hours, generalised paralysis and respiratory arrest at 10 hours and cardiac arrest by 12 hours post-envenomation. Clinical signs are suggestive of potent neurotoxicity for B. irregularis to its own venom. PMID- 27974232 TI - High intraspecific variability of Echinococcus granulosus sensu stricto in Chile. AB - Echinococcus granulosus sensu stricto is the major cause of cystic echinococcosis in most human and animal cases in the world and the most widespread species within the E. granulosus sensu lato complex. E. granulosus s.s. remains endemic in South America together with other species of the Echinococcus genus, especially in some areas in Argentina, Brazil, Chile and Peru. Except for a single human case caused by E. canadensis (G6) described in the literature, only E. granulosus s.s. has been found in the Chilean territory. In the current study 1609bp of the cox1 gene from 69 Chilean isolates of E. granulosus s.s. from humans and animals were analysed. In total, 26 cox1 haplotypes were found, including the widespread haplotype EG01 (22 isolates) and also EGp1 (5), EgRUS7 (1), EgAus02 (1) and EgAus03 (2). Twenty-one different haplotype not previously described were identified from 38 Chilean isolates designated EgCL1-EgCL21. Previous work had described low variability of E. granulosus s.s. in South America, based on isolates from Peru. Results obtained in this work challenge the previously described idea of the low diversity of the parasite in South America, and warrant future investigation on the origin and spread of the parasite in the continent after the Spanish arrival. PMID- 27974234 TI - Physical activity, screen time and the risk of subjective health complaints in school-aged children. AB - Internationally, subjective health complaints have become increasingly prevalent in children. Thus, a comprehensive understanding of the determinants of health complaints is needed to inform effective policies and strategies. This study explores if meeting physical activity and total screen time (TST) recommendations are associated with the risk of reporting health complaints weekly or more. The 2014 Irish Health Behaviour in School-aged Children study collected questionnaire data from 10,474 10-17year olds. Children reported how often they experienced eight health complaints as less than weekly or weekly or more. Children who met moderate-to-vigorous physical activity recommendations were active for 60min/day in the past seven days. Three types of screen based activity were categorised to reflect if children met TST recommendations of <=2h/day. Poisson regression examined the association between meeting recommendations and the risk of health complaints. The prevalence of individual health complaints ranged from 20.4-44.3% in girls and from 10.1-35.4% in boys. Overall, 5.1% (4.5-5.6%) of girls and 8.7% (7.8-9.5%) of boys met both (physical activity and TST) recommendations, while two thirds of girls (67.3%, 66.1-68.5%) and over half of boys (55.0%, 53.5-56.6%) met neither recommendation. Not meeting TST recommendations was significantly associated with the risk of reporting health complaints while associations with physical activity were less apparent. Children who did not meet either recommendation had a significantly increased risk for six of the health complaints when compared to those who met both recommendations. As health complaints and poor lifestyle behaviours were common in children, population level measures are warranted. PMID- 27974233 TI - Increased deposition of glycosaminoglycans and altered structure of heparan sulfate in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant deposition of extracellular matrix (ECM) constituents, including glycosaminoglycans (GAGs), that may play a role in remodelling processes by influencing critical mediators such as growth factors. We hypothesize that GAGs may be altered in IPF and that this contribute to create a pro-fibrotic environment. The aim of this study was therefore to examine the fine structure of heparan sulfate (HS), chondroitin/dermatan sulfate (CS/DS) and hyaluronan (HA) in lung samples from IPF patients and from control subjects. GAGs in lung samples from severe IPF patients and donor lungs were analyzed with HPLC. HS was assessed by immunohistochemistry and collagen was quantified as hydroxyproline content. The total amount of HS, CS/DS and HA was increased in IPF lungs but there was no significant difference in the total collagen content. We found a relative increase in total sulfation of HS due to increment of 2-O, 6-O and N-sulfation and a higher proportion of sulfation in CS/DS. Highly sulfated HS was located in the border zone between denser areas and more normal looking alveolar parenchyma in basement membranes of blood vessels and airways, that were immuno-positive for perlecan, as well as on the cell surface of spindle-shaped cells in the alveolar interstitium. These findings show for the first time that both the amount and structure of glycosaminoglycans are altered in IPF. These changes may contribute to the tissue remodelling in IPF by altering growth factor retention and activity, creating a pro-fibrotic ECM landscape. PMID- 27974235 TI - NIPTL-Novo: Non-isobaric peptide termini labeling assisted peptide de novo sequencing. AB - : A simple and effective de novo sequencing strategy assisted by non-isobaric peptide termini labeling, NIPTL-Novo, was established. The y-series ions and b series ions of peptides can be clearly distinguished according to the different mass tags incorporated in N-terminus and C-terminus. This is helpful for improving the accuracy of peptide sequencing and increasing the sequencing speed. For the spectra commonly identified by both de novo sequencing and database searching software (Mascot or Maxquant), NIPTL-Novo gave identical result to more than 85% of these spectra. Furthermore, the quantitative profiling of the sample can be performed simultaneously along with de novo sequencing. Finally, this strategy can be applied to discover the peptides with potential mutation sites by combining with mass-defect based isotopic labeling. SIGNIFICANCE: The aim of the research presented in this paper is to establish a simple but effective de novo sequencing strategy based on non-isobaric peptide termini labeling, named NIPTL Novo. First, different mass tags incorporated in N-terminus and C-terminus generated by non-isobaric peptide termini labeling will help to distinguish both b and y ion series, which significantly simplify the MS/MS spectra and reduce the time consumption for de novo sequencing. Second, the isolation window of this strategy is just 4Da, much smaller than most existed labeling assisted de novo sequencing methods, which reduces the interferences caused by co-fragmentation ions. Third, the quantitative profiling of the sample can be performed simultaneously along with the de novo sequencing, and the quantitative accuracy is comparable to other chemical labeling methods. Finally, this strategy was expanded to the analysis of peptide mutation with combination of mass-defect based labeling, and two reliable mutated peptides were discovered. PMID- 27974236 TI - Integrative therapy decreases the risk of lupus nephritis in patients with systemic lupus erythematosus: A population-based retrospective cohort study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Evidence on alleviating the risk of lupus nephritis by integrative therapy with conventional medicine (CM) and herbal medicine (HM) had not been addressed. AIM OF THE STUDY: We investigated the integrative effect associated the risk by a retrospective Systemic Lupus Erythematosus (SLE) cohort from Taiwan National Health Insurance Research Database (NHIRD). MATERIALS AND METHODS: SLE patients with a catastrophic illness certificate (CIC) were retrospectively enrolled from the SLE cohort of the Taiwan NHIRD between 1997 and 2011. The patients were divided into an integrative medicine (IM: integrated CM plus HM) and a non-IM (CM only) group with 1:1 propensity score matching. Cox proportional regression model and the Kaplan-Meier method were conducted to estimate the hazard ratio (HR) for lupus nephritis in the cohort. RESULTS: Among 16,645 newly diagnosed SLE patients holding a CIC (SLE/CIC), 1933 had received HM and 1571 had received no HM treatment. After propensity score matching, there were 273 patients with lupus nephritis-120 in the IM group and 153 in the non-IM group. The adjusted HR (0.68, 95% confidence interval [CI]: 0.54-0.87, p<0.01) for lupus nephritis was lower in the IM group than in the non-IM group. The adjusted HR (0.69, 95% CI: 0.54-0.88, p<0.001) for lupus nephritis was also lower in the group of patients who had received CM plus HM than in the group that received CM only. The core pattern of HM prescriptions, which were integrated with CM for preventing lupus nephritis, was "Sheng-Di Huang" (raw Rehmannia glutinosa Libosch.), "Mu-Dan-Pi" (Paeonia suffruticosa Andr.), "Dan-Shan" (Salvia miltiorrhiza Bge.), "Zhi-Bo-Di-Huang-Wan.", and "Chi Shao" (Paeoniae lactiflorae Rubra). CONCLUSION: Integrative therapy decreased the risk of lupus nephritis among SLE patients in Taiwan. Further investigation of the pharmacological mechanism and clinical efficacy are warranted. PMID- 27974237 TI - Copy number variation analysis and methylome profiling of a GNAQ-mutant primary meningeal melanocytic tumor and its liver metastasis. AB - Primary meningeal melanocytic tumors have genetic similarities with uveal melanomas, including GNAQ or GNA11 mutations. While BAP1 mutations and loss of chromosome 3 have adverse prognostic meaning in uveal melanoma, genetic alterations associated with metastasis have not been investigated in primary meningeal melanocytic tumors. We describe a 43-year-old female with a GNAQ mutated, BAP1-wt melanocytic tumor originating in the parietal brain region and liver metastases 4years after initial diagnosis. After repeated surgery and chemotherapy she was treated with the immunomodulatory agent ipilimumab. Tissue from the primary and recurrent intracranial tumor (histologically originally diagnosed as intermediate-grade melanocytoma resp. melanoma) and from the liver metastasis was investigated for genome-wide copy number variations and DNA methylation profile. Complete loss of 10p and 19p, partial loss of 16p and a small deletion on 10q were only present in the liver metastasis and not in the intracranial tumors. The DNA methylation profiles of the intracranial tumors and the liver metastasis resembled those of meningeal melanocytomas. In conclusion, in this report we show that a distant metastasis of a meningeal melanocytic tumor has a similar methylation profile as the primary tumor and suggest that particular copy number variations may be associated with metastatic behavior. PMID- 27974238 TI - Maternal administration of magnesium sulfate promotes cell proliferation in hippocampus dentate gyrus in offspring mice after exposing to prenatal stress. AB - Prenatal stress (PS) inhibits cell proliferation in the hippocampal dentate gyrus (DG), which is related to hippocampal anatomy and function abnormality. The aim of the study was to investigate the effects of magnesium sulfate (MgSO4) on PS induced cell proliferation suppression in offspring during embryonic stage and postnatal spatial learning. MgSO4 administration was performed after PS treatment on pregnant mice. Mice were randomly divided into four groups: non-PS or PS maternal mice injected with MgSO4 or saline (P+NS, P+MG, C+MG and C+NS group). Corticosterone was collected from amniotic fluid of mother mice on day 17 of embryonic stage (E17). The ability for spatial learning and memory of pups postnatal 3 week was evaluated using water maze assay. Additionally, cell proliferation was detected by assessing the expression of Ki67 using immunohistochemistry in mice fetuses or pups. PS significantly increased corticosterone level in amniotic fluid (P<0.05) and impaired the spatial learning and memory (P+NS vs C+NS of latency time and track path length: P<0.05) of offspring on postnatal day 21. However, MgSO4 administration could reverse PS induced spatial learning and memory disability (P+MG vs P+NS, P<0.05). Additionally, PS reduced the number of Ki67-positive cell in hippocampal DG on E17, E19 and postnatal day 21 (P+NS vs C+NS, P<0.05), which were also abrogated by maternal administration of MgSO4 (P+MG vs P+NS, P<0.05). Collectively, prenatal administration of MgSO4 can reverse PS-induced reduction of cell proliferation in hippocampal DG during embryonic stage and postnatal spatial learning. PMID- 27974239 TI - A codon-optimized Mecp2 transgene corrects breathing deficits and improves survival in a mouse model of Rett syndrome. AB - Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that is primarily caused by mutations in the methyl CpG binding protein 2 gene (MECP2). RTT is the second most prevalent cause of intellectual disability in girls and there is currently no cure for the disease. The finding that the deficits caused by the loss of Mecp2 are reversible in the mouse has bolstered interest in gene therapy as a cure for RTT. In order to assess the feasibility of gene therapy in a RTT mouse model, and in keeping with translational goals, we investigated the efficacy of a self-complementary AAV9 vector expressing a codon-optimized version of Mecp2 (AAV9-MCO) delivered via a systemic approach in early symptomatic Mecp2 deficient (KO) mice. Our results show that AAV9-MCO administered at a dose of 2*1011 viral genome (vg)/mouse was able to significantly increase survival and weight gain, and delay the occurrence of behavioral deficits. Apneas, which are one of the core RTT breathing deficits, were significantly decreased to WT levels in Mecp2 KO mice after AAV9-MCO administration. Semi-quantitative analysis showed that AAV9-MCO administration in Mecp2 KO mice resulted in 10 to 20% Mecp2 immunopositive cells compared to WT animals, with the highest Mecp2 expression found in midbrain regions known to regulate cardio-respiratory functions. In addition, we also found a cell autonomous increase in tyrosine hydroxylase levels in the A1C1 and A2C2 catecholaminergic Mecp2+ neurons in treated Mecp2 KO mice, which may partly explain the beneficial effect of AAV9-MCO administration on apneas occurrence. PMID- 27974240 TI - ASCEPT-Celebrating 50 years. PMID- 27974242 TI - Introduction to the Special issue Country in focus: Pharmacology in Australia. PMID- 27974241 TI - A2B adenosine receptors stimulate IL-6 production in primary murine microglia through p38 MAPK kinase pathway. AB - The hallmark of neuroinflammation is the activation of microglia, the immunocompetent cells of the CNS, releasing a number of proinflammatory mediators implicated in the pathogenesis of neuronal diseases. Adenosine is an ubiquitous autacoid regulating several microglia functions through four receptor subtypes named A1, A2A, A2B and A3 (ARs), that represent good targets to suppress inflammation occurring in CNS. Here we investigated the potential role of ARs in the modulation of IL-6 secretion and cell proliferation in primary microglial cells. The A2BAR agonist 2-[[6-Amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl] 2-pyridinyl]thio]-acetamide (BAY60-6583) stimulated IL-6 increase under normoxia and hypoxia, in a dose- and time-dependent way. In cells incubated with the blockers of phospholipase C (PLC), protein kinase C epsilon (PKC-epsilon) and PKC delta (PKC-delta) the IL-6 increase due to A2BAR activation was strongly reduced, whilst it was not affected by the inhibitor of adenylyl cyclase (AC). Investigation of cellular signalling involved in the A2BAR effect revealed that only the inhibitor of p38 mitogen activated protein kinase (MAPK) was able to block the agonist's effect on IL-6 secretion, whilst inhibitors of pERK1/2, JNK1/2 MAPKs and Akt were not. Stimulation of p38 by BAY60-6583 was A2BAR dependent, through a pathway affecting PLC, PKC-epsilon and PKC-delta but not AC, in both normoxia and hypoxia. Finally, BAY60-6583 increased microglial cell proliferation involving A2BAR, PLC, PKC-epsilon, PKC-delta and p38 signalling. In conclusion, A2BARs activation increased IL-6 secretion and cell proliferation in murine primary microglial cells, through PLC, PKC-epsilon, PKC-delta and p38 pathways, thus suggesting their involvement in microglial activation and neuroinflammation. PMID- 27974243 TI - Editor's perspectives - December 2016. PMID- 27974244 TI - A new method to analyze protein sequence similarity using Dynamic Time Warping. AB - Sequences similarity analysis is one of the major topics in bioinformatics. It helps researchers to reveal evolution relationships of different species. In this paper, we outline a new method to analyze the similarity of proteins by Discrete Fourier Transform (DFT) and Dynamic Time Warping (DTW). The original symbol sequences are converted to numerical sequences according to their physico chemical properties. We obtain the power spectra of sequences from DFT and extend the spectra to the same length to calculate the distance between different sequences by DTW. Our method is tested in different datasets and the results are compared with that of other software algorithms. In the comparison we find our scheme could amend some wrong classifications appear in other software. The comparison shows our approach is reasonable and effective. PMID- 27974245 TI - RhoA GTPase oxidation stimulates cell proliferation via nuclear factor-kappaB activation. AB - Reactive oxygen species (ROS) produced by many kinds of stimuli are essential for cellular signaling including cell proliferation. The dysregulation of ROS, therefore, is related to a variety of diseases including cancer. However, it was not clearly elucidated how ROS regulate cell proliferation and tumorigenesis. In this study, we investigated a mechanism by which the oxidation of RhoA GTPase regulates nuclear factor-kappaB (NF-kappaB) and cell proliferation. Hydrogen peroxide activated NF-kappaB and RhoA GTPase, but did not activate RhoA C16/20A mutant, an oxidation-resistant form. Remarkably, the oxidation of RhoA reduced its affinity towards RhoGDI, leading to the dissociation of RhoA-RhoGDI complex. Si-Vav2, a guanine nucleotide exchange factor (GEF), inhibited RhoA activation upon hydrogen peroxide. The oxidized RhoA (oxRhoA)-GTP was readily bound to IkappaB kinase gamma (IKKgamma), whereas oxidized RhoGDI did not bind to IKKgamma. The oxRhoA-GTP bound to IKKgamma activated IKKbeta, leading to IkappaB phosphorylation and degradation, consequently NF-kappaB activation. Hydrogen peroxide induced cell proliferation, but RhoA C16/20A mutant suppressed cell proliferation and tumorigenesis. Conclusively, RhoA oxidation at Cys16/20 is critically involved in cell proliferation and tumorigenesis through NF-kappaB activation in response to ROS. PMID- 27974246 TI - MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin Deficient Diabetes via Pancreatic beta-Cell Proliferation. AB - Major symptoms of diabetes mellitus manifest, once pancreatic beta-cell numbers have become inadequate. Although natural regeneration of beta-cells after injury is very limited, bone marrow (BM) transplantation (BMT) promotes their regeneration through undetermined mechanism(s) involving inter-cellular (BM cell to-beta-cell) crosstalk. We found that two microRNAs (miRNAs) contribute to BMT induced beta-cell regeneration. Screening murine miRNAs in serum exosomes after BMT revealed 42 miRNAs to be increased. Two of these miRNAs (miR-106b-5p and miR 222-3p) were shown to be secreted by BM cells and increased in pancreatic islet cells after BMT. Treatment with the corresponding anti-miRNAs inhibited BMT induced beta-cell regeneration. Furthermore, intravenous administration of the corresponding miRNA mimics promoted post-injury beta-cell proliferation through Cip/Kip family down-regulation, thereby ameliorating hyperglycemia in mice with insulin-deficient diabetes. Thus, these identified miRNAs may lead to the development of therapeutic strategies for diabetes. PMID- 27974248 TI - Effects of spacer orientations on the cake formation during membrane fouling: Quantitative analysis based on 3D OCT imaging. AB - Spacer design plays an important role in improving the performance of membrane processes for water/wastewater treatment. This work focused on a fundamental issue of spacer design, i.e., investigating the effects of spacer orientations on the fouling behavior during a membrane process. A series of fouling experiments with different spacer orientation were carried out to in situ characterize the formation of a cake layer in a spacer unit cell via 3D optical coherence tomography (OCT) imaging. The cake layers formed at different times were digitalized for quantitatively analyzing the variation in the cake morphology as a function of time. In particular, the local deposition rates were evaluated to determine the active regions where the instantaneous changes in deposit thickness were significant. The characterization results indicate that varying the spacer orientation could substantially change the evolution of membrane fouling by particulate foulants and thereby result in a cake layer with various morphologies; the competition between growth and erosion at different locations would instantaneously respond to the micro-hydrodynamic environment that might change with time. This work confirms that the OCT-based characterization method is a powerful tool for exploring novel spacer design. PMID- 27974247 TI - Annexin A2 is critical for blood-testis barrier integrity and spermatid disengagement in the mammalian testis. AB - Throughout spermatogenesis, two important processes occur at late stage VIII of the seminiferous epithelial cycle in the rat testis: preleptotene spermatocytes commence entry into the adluminal compartment and step 19 spermatids release from the seminiferous epithelium. Presently, it is not clear how these processes, which involve extensive restructuring of unique Sertoli-Sertoli and Sertoli-germ cell junctions, are mediated. We aimed to determine whether annexin A2 (ANXA2), a Ca2+-dependent and phospholipid-binding protein, participates in cell junction dynamics. To address this, in vitro and in vivo RNA interference studies were performed on prepubertal Sertoli cells and adult rat testes. The endpoints of Anxa2 knockdown were determined by immunoblotting, morphological analyses, fluorescent immunostaining, and barrier integrity assays. In the testis, ANXA2 localized to the Sertoli cell stalk, with specific staining at the blood-testis barrier and the concave (ventral) surface of elongated spermatids. ANXA2 also bound actin when testis lysates were used for immunoprecipitation. Anxa2 knockdown was found to disrupt the Sertoli cell/blood-testis barrier in vitro and in vivo. The disruption in barrier function was substantiated by changes in the localization of claudin-11, zona occludens-1, N-cadherin, and beta-catenin. Furthermore, Anxa2 knockdown resulted in spermiation defects caused by a dysfunction of tubulobulbar complexes, testis-specific actin-rich ultrastructures that internalize remnant cell junction components prior to spermiation. Additionally, there were changes in the localization of several tubulobulbar complex component proteins, including actin-related protein 3, cortactin, and dynamin I/II. Our results indicate that ANXA2 is critical for the integrity of the blood-testis barrier and the timely release of spermatids. PMID- 27974249 TI - Elimination of Naegleria fowleri from bulk water and biofilm in an operational drinking water distribution system. AB - Global incidence of primary amoebic meningoencephalitis cases associated with domestic drinking water is increasing. The need for understanding disinfectant regimes capable of eliminating the causative microorganism, Naegleria fowleri, from bulk water and pipe wall biofilms is critical. This field study demonstrated the successful elimination of N. fowleri from the bulk water and pipe wall biofilm of a persistently colonised operational drinking water distribution system (DWDS), and the prevention of further re-colonisation. A new chlorination unit was installed along the pipe line to boost the free chlorine residual to combat the persistence of N. fowleri. Biofilm and bulk water were monitored prior to and after re-chlorination (RCl), pre-rechlorination (pre-RCl) and post rechlorination (post-RCl), respectively, for one year. A constant free chlorine concentration of > 1 mg/L resulted in the elimination of N. fowleri from both the bulk water and biofilm at the post-RCl site. Other amoeba species were detected during the first two months of chlorination, but all amoebae were eliminated from both the bulk water and biofilm at post-RCl after 60 days of chlorination with free chlorine concentrations > 1 mg/L. In addition, a dynamic change in the biofilm community composition and a four log reduction in biofilm cell density occurred post-RCl. The pre-RCl site continued to be seasonally colonised by N. fowleri, but the constant free chlorine residual of > 1 mg/L prevented N. fowleri from recolonising the bulk and pipe wall biofilm at the post-RCl site. To our knowledge, this is the first study to demonstrate successful removal of N. fowleri from both the bulk and pipe wall biofilm and prevention of re colonisation of N. fowleri in an operational DWDS. The findings of this study are of importance to water utilities in addressing the presence of N. fowleri and other amoeba in susceptible DWDSs. PMID- 27974250 TI - The influence of genetic predisposition and autoimmune hepatitis inducing antigens in disease development. AB - : Autoimmune hepatitis (AIH) is defined as a chronic liver inflammation with loss of tolerance against hepatocytes. The etiology and pathophysiology of AIH are still poorly understood because reliable animal models are limited. Therefore, we recently introduced a model of experimental murine AIH by a self-limited adenoviral infection with the AIH type 2 antigen formiminotransferase cyclodeaminase (FTCD). We could demonstrate that break of humoral tolerance towards liver specific autoantigens like FTCD and cytochrome P450 2D6 (CYP2D6) is not dependent on the genetic background. However, the development of AIH in autoantibody positive animals is determined by genetic background genes. We could also show that the break of humoral tolerance is necessary but not sufficient for the development of AIH. In contrast the break of tolerance against the ubiquitously expressed nuclear antigens (ANAs) is strictly dependent on genetic predisposition. Priming with the UGA suppressor tRNA-associated protein (soluble liver antigen; SLA) is a strong inducer of ANA reactivity, but not sufficient to cause AIH development thereby questioning the importance of anti-SLA immune response as an important driver in AIH. Monogenetic mutations such as Aire deficiency can cause AIH in otherwise genetically resistant strains. CONCLUSION: The results have important implications for our understanding of the pathophysiology of AIH development and for the interpretation of humoral antibody responses in AIH. PMID- 27974251 TI - Commentary to "Prospective assessment of cosmesis before and after genital surgery". PMID- 27974254 TI - Reply by Authors. PMID- 27974252 TI - Radiation Dosage for Percutaneous PAD Treatment is Different in Cardiovascular Disciplines: Results From an Eleven Year Population Based Registry in the Metropolitan Area of Hamburg. AB - OBJECTIVE: The worldwide prevalence of peripheral artery disease (PAD) has evolved to an intervention as the primary treatment option and therefore radiation is used with escalating incidence. Dose area product (DAP) correlates well with the total energy imparted to the patient during fluoroscopic interventions. This study aims to determine whether there are any associations among stage of disease, gender, age, and expertise on the radiation dose in single endovascular treatments of PAD. METHODS: This study was a prospective, mandatory, population based cross-sectional registry design. In total, 24,000 invasive percutaneous endovascular treatments of PAD conducted in the metropolitan area of Hamburg (Germany) were consecutively collected between January 2004 and December 2015. DAP was analysed by discipline conducting the procedure, Fontaine classification, patient gender, and age. RESULTS: Statistically significant differences in median DAP values were found. The lowest median DAP values were observed in surgical centres (7.1 vs. 18.0 Gy*cm2, p<.001) and in endovascular revascularisations (ER) following multidisciplinary consultation (11.6 vs. 23.4 Gy*cm2, p<.001). Considering the treatment of intermittent claudication, men had statistically significantly higher DAP values compared with women. Furthermore, lower median DAP values were observed in higher age groups, with lowest dosages in octogenarians. CONCLUSION: This is the first large population based study on DAP during ER for PAD. Several significant differences in median DAP values were observed, although patient stratification was comparable. Pre-operative therapy strategy planning can lead to lower DAP values, emphasising the importance of further vascular research and quality improvement projects targeting this topic. To date, available evidence is limited and therefore there is no accepted range of DAP levels. However, the ever increasing use of fluoroscopic interventions means that further investigation into radiation exposure to patients and healthcare professionals is required in order to keep DAP levels low. PMID- 27974253 TI - V-shaped pits in HVPE-grown GaN associated with columnar inversion domains originating from foreign particles of alpha-Si3N4 and graphitic carbon. AB - The v-shaped pits (so-called V-pits) observed in hydride-vapor-phase-epitaxy grown GaN and associated with the columnar inversion domains originating from foreign particles were investigated. The inversion domains on the front and back surfaces of the test sample were recognized after chemical mechanical polishing. It was found that the V-pits originate from the columnar inversion domains. The inversion domains, in turn, arise from the particles that exist on a low temperature GaN buffer layer on sapphire substrate. Using transmission electron microscopy, these particles were found to be of alpha-Si3N4 and graphitic carbon. Such particles are attributable to the components of the reactor and adhere to the low-temperature GaN buffer layer, which has a surface roughness of the order of several nanometers. Thus, an effective way of obtaining HVPE-grown thick GaN layers without the V-pits associated with columnar IDs is to maintain the parts of the HVPE chamber properly to prevent foreign particles from being generated. PMID- 27974255 TI - Reply by Authors. PMID- 27974256 TI - Editorial Comment. PMID- 27974257 TI - Editorial Comment. PMID- 27974259 TI - Editorial Comment. PMID- 27974258 TI - Parental Preference Assessment for Vesicoureteral Reflux Management in Children. AB - PURPOSE: Parents of children with vesicoureteral reflux are presented with a variety of management options, which in many cases offer a similar risk-benefit ratio. To facilitate shared decision making, parental preferences regarding vesicoureteral reflux treatment options need to be acknowledged. We aimed to characterize the clinical experience of parents and elicit core themes affecting decision making in regard to managing vesicoureteral reflux in their child. MATERIALS AND METHODS: A semistructured, qualitative interview script was developed and vetted by 25 pediatric urologists to discuss treatment options for vesicoureteral reflux. Additional patient interviews were conducted until new themes failed to arise. Content analysis was performed to extract all statements that described treatment options. Similar statements were combined until a final list of unique themes emerged. RESULTS: A total of 26 interviews were performed, yielding 689 statements about overall parent experiences with managing vesicoureteral reflux in the child and 450 statements (65%) pertaining to treatment options. Of the 13 themes that emerged, those most commonly considered were the prevention of future urinary tract infections by 85% of parents, the efficacy rate of treatment options by 85%, the burden of daily maintenance or compliance by 77%, antibiotic resistance by 69%, chronic kidney damage by 62% and invasiveness by 58%. CONCLUSIONS: Our study emphasizes that when choosing a treatment option for vesicoureteral reflux in their child, parent preferences regarding risks and benefits are variable. However, their chief concerns include whether a method decreases the risk of urinary tract infections, has an acceptable efficacy rate and aligns itself with the capabilities of the family. These themes help frame discussions between families and clinicians regarding vesicoureteral reflux management, and they can facilitate shared decision making. PMID- 27974260 TI - Editorial Comment. PMID- 27974261 TI - Editorial Comment. PMID- 27974262 TI - CD14 is not involved in the uptake of synthetic CpG oligonucleotides. AB - We have previously shown that DEC205, a surface receptor expressed at high levels on CD8+DC, is able to capture synthetic CpG oligonucleotides (ODN) and is required for optimal responsiveness. However, even in the absence of DEC205, CD8+DC are able to respond to CpG ODN, albeit suboptimally. This suggested that additional receptors might contribute to the uptake of CpG ODN. CD14 represented an ideal candidate as it is expressed by DC and has been shown to bind and facilitate the uptake of CpG ODN. However, when CD14-deficient (CD14-/-) mice and normal B6 mice were injected with CpG ODN, CD8+DC were equivalently activated as assessed by the upregulation of the co-stimulatory molecules CD40 and CD80. Furthermore, the level of serum IL-6 and IL-12 produced in response to CpG ODN was comparable in CD14-/- and B6 mice. Importantly, mice deficient in both DEC205 and CD14 had comparable responses to mice lacking DEC205 alone, both in terms of cytokine production and DC activation, arguing that CD14 did not contribute to responses to CpG ODN. For CD14 to act as an uptake receptor for CpG ODN, it must first capture CpG ODN. To this end we assessed the capacity of cell surface CD14 to bind CpG ODN. Although we unequivocally confirmed that CD14 is required for the binding of its known ligand LPS, CD14 was not required for binding or responses to A-, B-, and C- Class CpG ODN. Our studies dispute the claim that CD14 is involved in CpG ODN capture. PMID- 27974263 TI - Inhibition kinetics of nitritation and half-nitritation of old landfill leachate in a membrane bioreactor. AB - Nitritation can be used as a pretreatment for anaerobic ammonia oxidation (anammox). Various control strategies for nitritation and half-nitritation of old landfill leachate in a membrane bioreactor were investigated in this study and the inhibition kinetics of substrate, product and old landfill leachate on nitritation were analyzed via batch tests. The results demonstrated that old landfill leachate nitritation in the membrane bioreactor can be achieved by adjusting the influent loading and dissolved oxygen (DO). From days 105-126 of the observation period, the average effluent concentration was 871.3 mg/L and the accumulation rate of [Formula: see text] was 97.2%. Half-nitritation was realized quickly by adjusting hydraulic retention time and DO. A low-DO control strategy appeared to best facilitate long-term and stable operation. Nitritation inhibition kinetic experiments showed that the inhibition of old landfill leachate was stronger than that of the substrate [Formula: see text] or product [Formula: see text] . The ammonia oxidation rate dropped by 22.2% when the concentration of old landfill leachate (calculated in chemical oxygen demand) was 1600.2 mg/L; further, when only free ammonia or free nitrous acid were used as a single inhibition factor, the ammonia oxidation rate dropped by 4.7-6.5% or 14.5 15.9%, respectively. Haldane, Aiba, and a revised inhibition kinetic model were adopted to separately fit the experimental data. The R2 correlation coefficient values for these three models were 0.982, 0.996, and 0.992, respectively. PMID- 27974264 TI - Effect of carbon source on nitrogen removal in anaerobic ammonium oxidation (anammox) process. AB - Anaerobic ammonium oxidation (anammox) has been regarded as an efficient process to treat high-strength wastewater without organic carbon source. To investigate nitrogen removal performance of anammox in presence of organic carbon source can broaden its application on organic wastewater treatment. In this work, effect of carbon source on anammox process was explored. Operating temperature was set at 35 +/- 1 degrees C. Influent pH and hydraulic retention time were 7.5 and 6 h, respectively. Effluent [Formula: see text] was affected little with COD no more than 480 mg/L. Independent of carbon source content, nitrite removal rate was around 99%. The variation of [Formula: see text] lagged behind [Formula: see text] at high COD content, and pH could be used as an indicator for [Formula: see text] removal. Specific anammox activity dropped from 0.39 to 0.19 [Formula: see text] at COD=720 mg/L. The remodified logistic model was quite appropriate for describing the nitrogen removal kinetics and predicting the performance of anammox process in presence of carbon source. PMID- 27974265 TI - Management of elderly patients suffering from cancer: Assessment of perceived burden and of quality of life of primary caregivers. AB - OBJECTIVE: To evaluate the perceived burden and the quality of life (QoL) at 3 and 6months of the primary caregiver (PC) of patients aged 70 and over suffering from cancer and the predictors of QoL in this population. METHODS: In this prospective observational study, 98 patients aged 70 and older with cancer and 96 PCs were included between 01/06/2014 and 18/03/2015. The Medical Outcomes Study 12-item Short Form Health Survey (SF-12) was used to assess the QoL of PCs and the Zarit Burden Interview (ZBI) was used to measure the perceived burden at 3 and 6months. The major determinants of QoL were identified using mixed linear models for the dimensions of the SF-12 that showed an average difference of at least 5 points between baseline and follow-up at 6months. RESULTS: The QoL scores of PCs showed a decrease in the dimensions "role emotional" and "bodily pain" over 6months. In multivariate analysis, the main determinants of QoL for "role emotional" were the PC's age (p=0.005), a low perceived burden (p<0.0001) and a functionally independent patient (p=0.01), and for "bodily pain" was a low perceived burden (p<0.0001) and the non-use of hormone therapy during the treatment (p<0.0001). CONCLUSION: The main determinants of the QoL of PCs concerned factors inherent to the PC (age and perceived burden) and patient (functional independence). PMID- 27974266 TI - Aerosol delivery of stabilized polyester-siRNA nanoparticles to silence gene expression in orthotopic lung tumors. AB - Tremendous progress has been made in the development of delivery carriers for small RNA therapeutics. However, most achievements have focused on the treatment of liver-associated diseases because conventional lipid and lipidoid nanoparticles (LNPs) readily accumulate in the liver after intravenous (i.v.) administration. Delivering RNAs to other organs and tumor tissues remains an ongoing challenge. Here, we utilized a 540-member combinatorial functional polyester library to discover nanoparticles (NPs) that enable efficacious siRNA delivery to A549 lung cancer cells in vitro and in vivo. PE4K-A13-0.33C6 and PE4K A13-0.33C10 NPs were efficiently internalized into A549-Luc cells within 4 h. The addition of PEG 2000 DMG lipid or Pluronic F-127 onto the surface of the polyplexes reduced the surface charge of NPs, resulting in an increase of serum stability. We then explored aerosol delivery of stabilized PE4K-A13-0.33C6 and PE4K-A13-0.33C10 NPs to implanted orthotopic lung tumors. We found that by altering the administration route from i.v. to aerosol, the NPs could avoid liver accumulation and instead be specifically localized only in the lungs. This resulted in significant gene silencing in the A549 orthotopic lung tumors. Due to the ability to deliver siRNA to non-liver targets, this approach provides a privileged route for gene silencing in the lungs. PMID- 27974267 TI - Phytoestrogens and sterols in waters with cyanobacterial blooms - Analytical methods and estrogenic potencies. AB - Compounds with estrogenic potencies and their adverse effects in surface waters have received much attention. Both anthropogenic and natural compounds contribute to overall estrogenic activity in freshwaters. Recently, estrogenic potencies were also found to be associated with cyanobacteria and their blooms in surface waters. The present study developed and compared the solid phase extraction and LC-MS/MS analytical approaches for determination of phytoestrogens (8 flavonoids biochanin A, coumestrol, daidzein, equol, formononetin, genistein, naringenin, apigenin - and 5 sterols - ergosterol, beta-sitosterol, stigmasterol, campesterol, brassicasterol) and cholesterol in water. The method was used for analyses of samples collected in stagnant water bodies dominated by different cyanobacterial species. Concentrations of individual flavonoids ranged from below the limit of detection to 3.58 ng/L. Sterols were present in higher amounts up to 2.25 MUg/L. Biological potencies of these phytoestrogens in vitro were characterized using the hERalpha-HeLa-9903 cell line. The relative estrogenic potencies (compared to model estrogen - 17beta-estradiol) of flavonoids ranged from 2.25E-05 to 1.26E-03 with coumestrol being the most potent. None of the sterols elicited estrogenic response in the used bioassay. Estrogenic activity was detected in collected field water samples (maximum effect corresponding to 2.07 ng/L of 17beta-estradiol equivalents, transcriptional assay). At maximum phytoestrogens accounted for only 1.56 pg/L of 17beta-estradiol equivalents, contributing maximally 8.5% of the total estrogenicity of the water samples. Other compounds therefore, most likely of anthropogenic origin such as steroid estrogens, are probably the major drivers of total estrogenic effects in these surface waters. PMID- 27974268 TI - Biotransformation of acyclovir by an enriched nitrifying culture. AB - This work evaluates the biodegradation of the antiviral drug acyclovir by an enriched nitrifying culture during ammonia oxidation and without the addition of ammonium. The study on kinetics was accompanied with the structural elucidation of biotransformation products through batch biodegradation experiments at two different initial levels of acyclovir (15 mg L-1 and 15 MUg L-1). The pseudo first order kinetic studies of acyclovir in the presence of ammonium indicated the higher degradation rates under higher ammonia oxidation rates than those constant degradation rates in the absence of ammonium. The positive correlation was found between acyclovir degradation rate and ammonia oxidation rate, confirming the cometabolism of acyclovir by the enriched nitrifying culture in the presence of ammonium. Formation of the product carboxy-acyclovir (P239) indicated the main biotransformation pathway was aerobic oxidation of the terminal hydroxyl group, which was independent on the metabolic type (i.e. cometabolism or metabolism). This enzyme-linked reaction might be catalyzed by monooxygenase from ammonia oxidizing bacteria or heterotrophs. The formation of carboxy-acyclovir was demonstrated to be irrelevant to the acyclovir concentrations applied, indicating the revealed biotransformation pathway might be the dominant removal pathway of acyclovir in wastewater treatment. PMID- 27974269 TI - Effects of ozonation pretreatment on natural organic matter and wastewater derived organic matter - Possible implications on the formation of ozonation by products. AB - The aim of this study was to investigate possible implications of natural and wastewater derived organic matter in river water that is subsequently used following treatment for drinking purposes. River water was subjected to lab-scale ozonation experiments under different ozone doses (0.1, 0.4, 0.8, 1.0 and 2.0 mgO3/mgC) and contact times (1, 3, 5, 8 and 10 min). Mixtures of river water with humic acids or wastewaters (sewage wastewater and secondary effluents) at different proportions were also ozonated. Dissolved organic carbon and biodegradable dissolved organic carbon concentrations as well as spectroscopic characteristics (UV absorbance and fluorescence intensities) of different types of dissolved organic matter and possible changes due to the ozonation treatment are presented. River water, humic substances and wastewater exhibited distinct spectroscopic characteristics that could serve for pollution source tracing. Wastewater impacted surface water results in higher formation of carbonyl compounds. However, the formation yield (MUg/mgC) of wastewaters was lower than that of surface water possibly due to different composition of wastewater derived organic matter and the presence of scavengers, which may limit the oxidative efficiency of ozone. PMID- 27974270 TI - Assessing trace elements in striped dolphins from the Strait of Gibraltar: Clues to link the bioaccumulation in the westernmost Mediterranean Sea area and nearest Atlantic Ocean. AB - Dolphins are considered sentinel species in the marine environment. The Strait of Gibraltar is the only passage between the Mediterranean Sea and the Atlantic Ocean, being the transitional region which connects these two basins and one of the most important routes of cetacean migration worldwide. In this work, eight trace elements (TE) were studied in 45 samples of liver, kidney and muscle, from 15 specimens stranded in this study area. The preliminary results show, among others, the patterns of distribution of the TE in the target organs studied, the influence of sex, length and developmental stage in these TE concentrations and the Se/Hg ratio. Subsequently, the results of TE concentrations in liver have being compared to previous data on S. coeruleoalba from the westernmost Mediterranean Sea and the nearest Atlantic Ocean. For some elements (e.g. for As), concentrations are similar to those obtained from Atlantic samples, despite in other cases (e.g. for Cd) results are lined up with those observed in Mediterranean studies. In addition, in the case of some TE (e.g. Se and Zn) the results are in the middle of those reported for both basins, reinforcing the idea of the Strait of Gibraltar being a transitional zone. Present study is the first research regarding this issue in this outstanding region, aiming to give insights of how this matchless area can help to link TE concentrations observed in these Atlantic and Mediterranean threatened species. PMID- 27974271 TI - Silver nanoparticles induce oocyte maturation in zebrafish (Danio rerio). AB - Public concern regarding silver nanoparticles (AgNPs) in the environment has been increasing since they can cause adverse effects in some aquatic species. However, few data are actually available on the effects of AgNPs on the germ cells. In the present study, we used the zebrafish ovarian follicle as a model to assess the potentially adverse effects of AgNPs on oocyte maturation (germinal vesicle breakdown, GVBD) in vitro. Similar to the maturation inducing hormone (17alpha, 20beta-dihydroxy-4-pregnen-3-one), AgNPs induced GVBD, and reduced the total cyclic adenosine monophosphate (cAMP) concentration in zebrafish ovarian follicles. The results from transmission electron microscope observation and Hoechst 33342 staining clearly indicated that AgNPs induced apoptosis in ovarian follicle cells surrounding the oocyte. Similar to AgNPs, AgNO3 also induced GVBD, decreased cAMP concentration and induced apoptosis of ovarian follicle cells. However, the results from gene expression analysis showed that transcript levels of oxidative stress related genes were more sensitive to AgNPs than AgNO3. Further more, H2O2 has an ability to induce zebrafish oocytes maturation by induction of apoptosis in ovarian follicle cells. Taken together, the results from our study indicated that oxidative stress appeared to be one of important mechanisms in AgNP induced apoptosis in ovarian follicle cells, which further triggered the GVBD. PMID- 27974272 TI - Single and joint toxic effects of five selected pesticides on the early life stages of zebrafish (Denio rerio). AB - Instead of individual ones, pesticides are usually detected in water environment as mixtures of contaminants. Laboratory tests were conducted in order to investigate the effects of individual and joint pesticides (phoxim, atrazine, chlorpyrifos, butachlor and lambda-cyhalothrin) on zebrafish (Denio rerio). Results from 96-h semi-static toxicity test indicated that lambda-cyhalothrin had the greatest toxicity to the three life stages (embryonic, larval and juvenile stages) of D. rerio with LC50 values ranging from 0.0031 (0.0017-0.0042) to 0.38 (0.21-0.53) mg a.i. L-1, followed by butachlor and chlorpyrifos with LC50 values ranging from 0.45 (0.31-0.59) to 1.93 (1.37-3.55) and from 0.28 (0.13-0.38) to 13.03 (7.54-19.71) mg a.i. L-1, respectively. In contrast, atrazine showed the least toxicity with LC50 values ranging from 6.09 (3.34-8.35) to 34.19 (24.42 51.9) mg a.i. L-1. The larval stage of D. rerio was a vulnerable period to most of the selected pesticides in the multiple life stages tested. Pesticide mixtures containing phoxim and lambda-cyhalothrin exerted synergistic effects on the larvae of D. rerio. Moreover, the binary mixture of phoxim-atrazine also displayed synergistic response to zebrafish. It has been assumed that most chemicals are additive in toxicity. Therefore, it is crucial to clarify the synergistic interaction for pesticide regulators and environment managers. In the present study, our data provided a clear picture on ecological risk of these pesticide mixtures to aquatic organisms. Moreover, joint effects play a more important role than individual ones, which require more attention when defining standard for water environment quality and risk assessment protocols. PMID- 27974273 TI - Anthropogenic organochlorine compounds as potential tracers for regional water masses: A case study of estuarine plume, coastal eddy, wind-driven upwelling and long-range warm current. AB - Water masses are the crucial factor driving the terrigenous anthropogenic organochlorine compounds (OCs) migration from the coast to open sea. Therefore, organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were investigated in the Northern South China Sea (NSCS), where different types of water masses are generated by the East Asian summer monsoon: Pearl River estuary plume (PREP), Guangdong offshore eddy (GDEC), South China Sea warm current (SCSWC) and wind-driven upwelling current (WDUC). No discrepant distributions of OC concentrations were found in these water masses (p > 0.05). However, compositions and diagnostic ratios of HCHs, DDTs, trans- or cis-chlordane and PCBs could reflect the discrepancies in the input, transport and transformation of OCs caused by the hydrological characteristics of water masses, therefore, this allowing them to serve as potential tracers of regional water masses. In detail, alpha/gamma-HCH and beta-HCH percentages could indicate the weathered residue in the GDEC, long-range transport in the SCSWC, rapid photodegradation in the surface WDUC and biodegradation in the deep WDUC, respectively. The predominance of o, p'-DDT and p, p'-DDT could indicate fresh input in the PREP, GDEC and WDUC. DDT/DDTs of ratios <0.5 also reflected long-range transport in the SCSWC. Different DDD/DDE ratios indicated different oxygen environments of microbial degradation in the surface and deep water of the WDUC. Trans/cis chlordane ratios could indicate the selective degradation of trans-chlordane in different water masses. Finally, a higher proportion of penta-PCB could reflect the strong paint additive sources carried by river erosion in the PREP. PMID- 27974274 TI - Metal inhibition on the reactivity of manganese dioxide toward organic contaminant oxidation in relation to metal adsorption and ionic potential. AB - Coexisting metal ions may significantly inhibit the oxidative reactivity of manganese oxides toward organic contaminants in metal-organic multi-pollutant waters. While the metal inhibition on the oxidation of organic contaminants by manganese oxides has previously been reported, the extent of the inhibition in relation to metal properties has not been established. Six alkali, alkaline, and transition metals, as well as two testing metals were evaluated for their abilities to inhibit the reactivity of birnessite. Regardless of the pathways of phenol and diuron oxidation (polymerization vs. breakdown), the extent of metal inhibition depended mainly on the metal itself and its concentration. The observed metal inhibition efficiency followed the order of Mn2+ > Co2+ > Cu2+ > Al3+ > Mg2+ > K+, consistent with metal adsorption on birnessite. The first-order organic oxidation rate constant (kobs) was linearly negatively correlated with metal adsorption (qe) on birnessite. These observations demonstrated that the metal inhibition efficiency was determined by metal adsorption on birnessite. The slopes of the kobs-qe varied among metals and followed the order of K+ > Ca2+ > Mg2+ > Mn2+ > Cd2+ > Co2+ > Cu2+ > Al3+. These slopes defined intrinsic inhibitory abilities of metals. As metals were adsorbed hydrated on birnessite, the intrinsic inhibitory ability was significantly linearly correlated with ionic potentials of metals, leading to a single straight line. Metals with multiple d electrons in the outermost orbit with polarizing energy that promotes hydrolysis sat slightly below the line, and vice versa. PMID- 27974275 TI - Quality-of-life metrics with vagus nerve stimulation for epilepsy from provider survey data. AB - OBJECTIVE: Drug-resistant epilepsy is a devastating disorder associated with diminished quality of life (QOL). Surgical resection leads to seizure freedom and improved QOL in many epilepsy patients, but not all individuals are candidates for resection. In these cases, neuromodulation-based therapies such as vagus nerve stimulation (VNS) are often used, but most VNS studies focus exclusively on reduction of seizure frequency. QOL changes and predictors with VNS remain poorly understood. METHOD: Using the VNS Therapy Patient Outcome Registry, we examined 7 metrics related to QOL after VNS for epilepsy in over 5000 patients (including over 3000 with >=12months follow-up), as subjectively assessed by treating physicians. Trends and predictors of QOL changes were examined and related to post-operative seizure outcome and likelihood of VNS generator replacement. RESULTS: After VNS therapy, physicians reported patient improvement in alertness (58-63%, range over follow-up period), post-ictal state (55-62%), cluster seizures (48-56%), mood change (43-49%), verbal communication (38-45%), school/professional achievements (29-39%), and memory (29-38%). Predictors of net QOL improvement included shorter time to implant (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.1-1.6), generalized seizure type (OR, 1.2; 95% CI, 1.0-1.4), female gender (OR, 1.2; 95% CI, 1.0-1.4), and Caucasian ethnicity (OR, 1.3; 95% CI, 1.0-1.5). No significant trends were observed over time. Patients with net QOL improvement were more likely to have favorable seizure outcomes (chi square [chi2]=148.1, p<0.001) and more likely to undergo VNS generator replacement (chi2=68.9, p<0.001) than those with worsened/unchanged QOL. SIGNIFICANCE: VNS for drug-resistant epilepsy is associated with improvement on various QOL metrics subjectively rated by physicians. QOL improvement is associated with favorable seizure outcome and a higher likelihood of generator replacement, suggesting satisfaction with therapy. It is important to consider QOL metrics in neuromodulation for epilepsy, given the deleterious effects of seizures on patient QOL. PMID- 27974276 TI - T4 bacteriophage conjugated magnetic particles for E. coli capturing: Influence of bacteriophage loading, temperature and tryptone. AB - This work demonstrates the use of bacteriophage conjugated magnetic particles (Fe3O4) for the rapid capturing and isolation of Escherichia coli. The investigation of T4 bacteriophage adsorption to silane functionalised Fe3O4 with amine (NH2), carboxylic (COOH) and methyl (CH3) surface functional groups reveals the domination of net electrostatic and hydrophobic interactions in governing bacteriophage adsorption. The bare Fe3O4 and Fe3O4-NH2 with high T4 loading captured 3-fold more E. coli (~70% capturing efficiency) compared to the low loading T4 on Fe3O4-COOH, suggesting the significance of T4 loading in E. coli capturing efficiency. Importantly, it is further revealed that E. coli capture is highly dependent on the incubation temperature and the presence of tryptone in the media. Effective E. coli capturing only occurs at 37 degrees C in tryptone containing media with the absence of either conditions resulted in poor bacteria capture. The incubation temperature dictates the capturing ability of Fe3O4/T4, whereby T4 and E. coli need to establish an irreversible binding that occurred at 37 degrees C. The presence of tryptophan-rich tryptone in the suspending media was also critical, as shown by a 3-fold increase in E. coli capture efficiency of Fe3O4/T4 in tryptone-containing media compared to that in tryptone-free media. This highlights for the first time that successful bacteria capturing requires not only an optimum tailoring of the particle's surface physicochemical properties for favourable bacteriophage loading, but also an in-depth understanding of how factors, such as temperature and solution chemistry influence the subsequent bacteriophage-bacteria interactions. PMID- 27974277 TI - Finite mixture modeling approach for developing crash modification factors in highway safety analysis. AB - This study aimed to investigate the relative performance of two models (negative binomial (NB) model and two-component finite mixture of negative binomial models (FMNB-2)) in terms of developing crash modification factors (CMFs). Crash data on rural multilane divided highways in California and Texas were modeled with the two models, and crash modification functions (CMFunctions) were derived. The resultant CMFunction estimated from the FMNB-2 model showed several good properties over that from the NB model. First, the safety effect of a covariate was better reflected by the CMFunction developed using the FMNB-2 model, since the model takes into account the differential responsiveness of crash frequency to the covariate. Second, the CMFunction derived from the FMNB-2 model is able to capture nonlinear relationships between covariate and safety. Finally, following the same concept as those for NB models, the combined CMFs of multiple treatments were estimated using the FMNB-2 model. The results indicated that they are not the simple multiplicative of single ones (i.e., their safety effects are not independent under FMNB-2 models). Adjustment Factors (AFs) were then developed. It is revealed that current Highway Safety Manual's method could over- or under estimate the combined CMFs under particular combination of covariates. Safety analysts are encouraged to consider using the FMNB-2 models for developing CMFs and AFs. PMID- 27974278 TI - A group theoretical model of symmetry cognition. AB - We report on two experiments, published originally in Japanese, on judged goodness and simplicity of dot patterns with reflectional and rotational symmetries (with 1-4 reflection axes and repeats, respectively) under free viewing tasks. We found that (a) both goodness and simplicity increase monotonously with the number of transformations under which a pattern is invariant; (b) stimulus outlines, such as squares and hexagons, affect both goodness and simplicity; and (c) factors such as contrast polarity and collinearity affect simplicity rather than goodness. The employed free-viewing tasks contrast with detection tasks involving short presentation times, and based on behavioural and neurophysiological evidence, we conclude that this transformational approach captures late rather than early aspects of visio cognitive processing of visual regularities. PMID- 27974279 TI - Sequestering ability to Cu2+ of a new bodipy-based dye and its behavior as in vitro fluorescent sensor. AB - A Bodipy (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) derivative has been conceived and synthesized starting from l-aspartic acid, as a selective turn-off sensor of Cu2+ ions. Its acid-base properties were determined to study the formation of metal/sensor complex species by titration of solutions each containing a different metal ion, such as Cu2+, Ca2+, Zn2+, Pb2+ and Hg2+ and different metal/sensor ratios. The speciation models allowed us to simulate the distribution of the metal/sensor complex species at the normal concentrations of the corresponding metals present in biological fluids. The distribution diagrams, obtained by varying the concentration of sensor 1, clearly indicate that sensor 1 responds selectively to Cu2+ at micromolar concentrations, even in the presence of other more abundant metal cations Ca2+. Finally, we analyzed the cellular uptake of sensor 1 on human erythrocytes and its ability to chelate Cu2+ in the cellular environment. Results indicate that it crosses the plasmatic membrane and colors the cells of a bright fluorescent red. Exposing the fluorescent cells to Cu2+ results in a complete cellular photobleaching of the red fluorescence, indicating that sensor 1 is able to detect metal changes in the cytosolic environment. PMID- 27974281 TI - Spirituality and spiritual care perspectives among baccalaureate nursing students in Saudi Arabia: A cross-sectional study. AB - BACKGROUND: No study has been undertaken to understand how spirituality and spiritual care is perceived and implemented by Saudi nursing students undergoing training for their future professional roles as nurses. OBJECTIVES: This study was conducted to investigate the perception of Baccalaureate nursing students toward spirituality and spiritual care. DESIGN: A descriptive, cross-sectional design was employed. SETTINGS AND PARTICIPANTS: A convenience sample of 338 baccalaureate nursing students in two government-run universities in Saudi Arabia was included in this study. METHODS: A self-administered questionnaire, consisting of a demographic and spiritual care background information sheet and the Spiritual Care-Giving Scale Arabic version (SCGS-A), was used for data collection. A multivariate multiple regression analysis and multiple linear regression analyses were performed accordingly. RESULTS: The mean value on the SCGS-A was 3.84+/-1.26. Spiritual perspective received the highest mean (4.14+/ 1.45), followed by attribute for spiritual care (3.96+/-1.48), spiritual care attitude (3.81+/-1.47), defining spiritual care (3.71+/-1.51) and spiritual care values (3.57+/-1.47). Gender, academic level and learning spiritual care from classroom or clinical discussions showed a statistically significant multivariate effect on the five factors of SCGS-A. CONCLUSIONS: Efforts should be done to formally integrate holistic concept including all the facets of spirituality and spiritual care in the nursing curriculum. The current findings can be used to inform the development and testing of holistic nursing conceptual framework in nursing education in Saudi Arabia and other Arab Muslim countries. PMID- 27974280 TI - Characterization of the second conserved domain in the heme uptake protein HtaA from Corynebacterium diphtheriae. AB - HtaA is a heme-binding protein that is part of the heme uptake system in Corynebacterium diphtheriae. HtaA contains two conserved regions (CR1 and CR2). It has been previously reported that both domains can bind heme; the CR2 domain binds hemoglobin more strongly than the CR1 domain. In this study, we report the biophysical characteristics of HtaA-CR2. UV-visible spectroscopy and resonance Raman experiments are consistent with this domain containing a single heme that is bound to the protein through an axial tyrosine ligand. Mutants of conserved tyrosine and histidine residues (Y361, H412, and Y490) have been studied. These mutants are isolated with very little heme (<=5%) in comparison to the wild-type protein (~20%). Reconstitution after removal of the heme with butanone gave an alternative form of the protein. The HtaA-CR2 fold is very stable; it was necessary to perform thermal denaturation experiments in the presence of guanidinium hydrochloride. HtaA-CR2 unfolds extremely slowly; even in 6.8M GdnHCl at 37 degrees C, the half-life was 5h. In contrast, the apo forms of WT HtaA-CR2 and the aforementioned mutants unfolded at much lower concentrations of GdnHCl, indicating the role of heme in stabilizing the structure and implying that heme transfer is effected only to a partner protein in vivo. PMID- 27974282 TI - Aqueous fraction of Alstonia boonei de Wild leaves suppressed inflammatory responses in carrageenan and formaldehyde induced arthritic rats. AB - Alstonia boonie de Wild is an ethnomedical plant used as therapy against inflammatory disorders. This study evaluated the most active anti-inflammatory and anti-oxidant fraction of A. boonei leaves using in vitro and in vivo models. Quantitative phytochemical analysis, anti-protein denaturation and hypotonicity induced hemolysis of human red blood cell membrane (HRBC), radical scavenging activity assays, carrageenan and formaldehyde-induced inflammation models were carried out. Results showed that aqueous and ethyl acetate fractions of 70% methanol extract of A. boonie leaves contained high quantities of total phenolic and flavonoid compounds compared with hexane and butanol fractions. Aqueous fraction of A. boonie leaves significantly (P<0.05) inhibited heat-induced protein denaturation, stabilized hypotonicity-induced hemolysis of HRBC, scavenged DPPH, NO and H2O2 radicals in a concentration-dependent manner compared with other fractions in vitro. In addition, orally administered 50-250-mg/kg body weight (b.w.) aqueous fraction of A. boonei leaves suppressed carrageenan-induced rat paw edema thickness by 74.32%, 79.22% and 89.86% respectively at 6th h in a dose-dependent manner comparable with animals treated with standard diclofenac sodium (88.69%) in vivo. Furthermore, investigation of formaldehyde-induced inflammation in rats showed that 50-250 mg/kg b.w. aqueous fraction of A. boonei reduced plasma alanine aminotransferase and aspartate aminotransferase activities. Aqueous fraction of A. boonei also suppressed eosinophils, monocytes and basophils, total white blood cell, total platelet, neutrophil and lymphocyte counts and modulated plasma lipid profile compared with control group. Aqueous fraction of A. boonei leaves exhibited substantial active anti-inflammatory and antioxidant activities. Hence, an aqueous fraction of A. boonei leaves could be channeled towards pharmaceutical drug development. In addition, this study provided scientific insight to account for the traditional use of A. boonei leaves in ethnomedical practice. PMID- 27974283 TI - The potential role of oxytocin and perinatal factors in the pathogenesis of autism spectrum disorders - review of the literature. AB - Autism Spectrum Disorders (ASD) are characterized by: social and communication impairments, and by restricted repetitive behaviors. The aim of the present paper is to review abnormalities of oxytocin (OXT) and related congenital malformations in ASD. A literature search was conducted in the PubMed database up to 2016 for articles related to the pathomechanism of ASD, abnormalities of OXT and the OXT polymorphism in ASD. The pathomechanism of ASD has yet to be. The development of ASD is suggested to be related to abnormalities of the oxytocin-arginin vasopressin system. Previous results suggest that OXT and arginine vasopressin (AVP) may play a role in the etiopathogenesis of ASD. PMID- 27974284 TI - Decreased responsiveness following lithium discontinuation in bipolar disorder: A naturalistic observation study. AB - Lithium is a cornerstone in treatment of bipolar disorder. Findings are conflicting as to whether acquired unresponsiveness occurs following the discontinuation. Retrospective life chart data were evaluated to investigate the incidence of loss of response. Sixty-five patients chosen from a larger cohort, followed with prospective life charts, who discontinued lithium and had a second lithium treatment. Patients who had at least 2 mood episodes when they were drug naive to describe the natural frequency of illness and 3 mood episodes before the discontinuation were included. The type of response was defined as excellent, partial, or poor according to mirror design method. Eighteen of 65 patients (27.6%) had a decreased response to lithium following its discontinuation. Nine of these patients (13.8%) were unresponsive and nine patients (13.8%) had attenuated response to second lithium treatment. The mean time of discontinuation was longer in the patients who show decreased response (245.8+268.2 vs. 117.9+149.8 days, p=.01). Those who had episode recurrences during the discontinuation were more likely to show reduced responsiveness upon re treatment. After discontinuation of lithium treatment, more than a quarter of the patients showed an attenuated response or unresponsiveness, and initial partial responders more likely to show unresponsiveness than excellent responders. PMID- 27974286 TI - Points of View: Heat maps PMID- 27974285 TI - Increased incidence of clinical hypotension with etomidate compared to ketamine for intubation in septic patients: A propensity matched analysis. AB - PURPOSE: This study compared the incidence of clinical hypotension between ketamine and etomidate within a 24 hour period following endotracheal intubation. MATERIALS AND METHODS: This single-center, retrospective propensity-matched cohort study included septic patients admitted to our medical intensive care unit who received either etomidate or ketamine for intubation. Clinical hypotension was defined as any one of the following: mean arterial pressure (MAP) decrease >40% compared to baseline and MAP <70 mmHg, MAP <60 mmHg, initiation of a vasopressor, or increase to >30% of the initial vasopressor dose. RESULTS: Patients were matched based on propensity scores determined by demographics and baseline characteristics. A total of 384 (200 etomidate and 184 ketamine) patients were included for analysis with 230 patients (115 in each group) matched. Clinical hypotension was less prevalent in patients who received ketamine as compared to etomidate [51.3% vs. 73% (odds ratio=0.39, 95% confidence interval=0.22-0.67, P=.001]. The etomidate group experienced significantly lower MAPs at time periods 6.1-12 hours (65.1 mmHg vs. 69.3 mmHg, P=.01) and 12.1-24 hours (63.9 mmHg vs. 68.4 mmHg, P=.003). CONCLUSIONS: Ketamine was associated with a lower incidence of clinical hypotension within the 24 hour period following endotracheal intubation in septic patients. PMID- 27974287 TI - A Test of Concept Study of At-Home, Self-Administered HIV Testing With Web-Based Peer Counseling Via Video Chat for Men Who Have Sex With Men. AB - BACKGROUND: Men who have sex with men (MSM), particularly MSM who identify as African-American or Black (BMSM), are the sociodemographic group that is most heavily burdened by the human immunodeficiency virus (HIV) epidemic in the United States. To meet national HIV testing goals, there must be a greater emphasis on novel ways to promote and deliver HIV testing to MSM. Obstacles to standard, clinic-based HIV testing include concerns about stigmatization or recognition at in-person testing sites, as well as the inability to access a testing site due to logistical barriers. OBJECTIVE: This study examined the feasibility of self administered, at-home HIV testing with Web-based peer counseling to MSM by using an interactive video chatting method. The aims of this study were to (1) determine whether individuals would participate in at-home HIV testing with video chat-based test counseling with a peer counselor, (2) address logistical barriers to HIV testing that individuals who report risk for HIV transmission may experience, and (3) reduce anticipated HIV stigma, a primary psychosocial barrier to HIV testing. METHODS: In response to the gap in HIV testing, a pilot study was developed and implemented via mailed, at-home HIV test kits, accompanied by HIV counseling with a peer counselor via video chat. A total of 20 MSM were enrolled in this test of concept study, 80% of whom identified as BMSM. RESULTS: All participants reported that at-home HIV testing with a peer counseling via video chat was a satisfying experience. The majority of participants (13/18, 72%) said they would prefer for their next HIV testing and counseling experience to be at home with Web-based video chat peer counseling, as opposed to testing in an office or clinic setting. Participants were less likely to report logistical and emotional barriers to HIV testing at the 6-week and 3-month follow-ups. CONCLUSIONS: The results of this study suggest that self-administered HIV testing with Web-based peer counseling is feasible and that MSM find it to be a satisfactory means by which they can access their test results. This study can serve as a general guideline for future, larger-scale studies of Web-based HIV test counseling for MSM. PMID- 27974288 TI - Virus-like particle vaccine by intranasal vaccination elicits protective immunity against respiratory syncytial viral infection in mice. AB - Respiratory syncytial virus (RSV) is a leading cause of lower respiratory infection in infants and children, but there is still no licensed vaccine available. In this report, we developed virus-like particle (VLP) vaccines based on the Bac-to-Bac baculovirus expression system, consisting of an influenza virus matrix (M1) protein and the RSV fusion protein (F) or glycoprotein (G). These RSV VLPs were identified by western blot analysis and electron microscopy. Female BALB/c mice immunized intranasally (i.n.) with RSV-F VLPs, RSV-G VLPs, or both showed viral-specific antibody responses against RSV. Total IgG, IgG1, IgG2a, and mucosal IgA were detected in mice with RSV-F plus RSV-G VLPs, revealing potent cellular and mucosal immune responses. Moreover, we found that these mixed RSV VLPs conferred enhanced protection against live RSV challenges, showing significant decreases in lung viral replication and obvious attenuation of histopathological changes associated with viral infections. These results demonstrate that RSV-F plus RSV-G VLPs by intranasal vaccination is a promising vaccine candidate that warrants further evaluation using cotton rat and primate models. PMID- 27974289 TI - Systematic review is the highest level of evidence for knee osteoarthritis injection options, not expert society guidelines. PMID- 27974290 TI - Aquatic exercise for osteoarthritis of the knee or hip (PEDro synthesis). PMID- 27974291 TI - Organ-cultured, prestripped donor tissue for DMEK surgery: clinical outcomes. AB - AIM: To determine whether clinical performance is negatively affected by prestripping Descemet membrane endothelial keratoplasty (DMEK) grafts from organ cultured corneas. METHODS: We reviewed clinical records of all patients who underwent DMEK surgery for Fuchs endothelial dystrophy between 28 October 2014 and 11 August 2015. Grafts had been prepared from organ-cultured corneoscleral buttons 24 hours prior to surgery or during surgery. We included only patients for which at least one follow-up examination was available at a minimum of 2 months postoperatively. MAIN OUTCOME MEASURES: best-corrected visual acuity (BCVA), central corneal thickness, endothelial cell count and rebubbling rates. RESULTS: Data given are mean+/-SD. No statistically significant differences were recorded at baseline between the partially stripped group (n=65) and the control group (n=72) with regard to donor age (70+/-9 vs 69+/-8 years; p=0.49), donor cornea endothelial cell density (2586+/-604 vs 2522+/-186 cells/mm2; p=0.6), BCVA (before DMEK: 0.77+/-0.5 vs 0.63+/-0.3 logMAR; p=0.27; before triple-DMEK: 0.56+/ 0.2 vs 0.52+/-0.2 logMAR; p=0.33) or central corneal thickness (621+/-72 vs 607+/ 53 MUm; p=0.49). Mean follow-up was 149+/-83 versus 148+/-77 days; p=0.79. No statistically significant differences were observed between the two groups postoperatively with regard to BCVA (after DMEK: 0.25+/-0.2 vs 0.21+/-0.2 logMAR; p=0.59; after triple-DMEK: 0.22+/-0.2 vs 0.2+/-0.1 logMAR; p=0.98), central corneal thickness (502+/-42 vs 508+/-41 MUm; p=0.47), endothelial cell count (1537+/-245 vs 1551+/-287 cells/mm2; p=0.65) and number of graft detachments requiring rebubbling (4.6% vs 9.7%; p=0.33). CONCLUSIONS: We found no evidence that the use of prestripped DMEK grafts is inferior to same-day preparation in organ-cultured corneas within the given follow-up. PMID- 27974292 TI - Marital History and Survival After Stroke. AB - BACKGROUND: Stroke is among the leading causes of disability and death in the United States, and nearly 7 million adults are currently alive after experiencing a stroke. Although the risks associated with having a stroke are well established, we know surprisingly little about how marital status influences survival in adults with this condition. This study is the first prospective investigation of how marital history is related to survival after stroke in the United States. METHODS AND RESULTS: Data from a nationally representative sample of older adults who experienced a stroke (n=2351) were used to examine whether and to what extent current marital status and past marital losses were associated with risks of dying after the onset of disease. Results showed that the risks of dying following a stroke were significantly higher among the never married (hazard ratio [HR], 1.71; 95% CI, 1.31-2.24), remarried (HR, 1.23; 95% CI, 1.06 1.44), divorced (HR, 1.23; 95% CI, 1.01-1.49), and widowed (HR, 1.25; 95% CI, 1.10-1.43) relative to those who remained continuously married. We also found that having multiple marital losses was especially detrimental to survival regardless of current marital status and accounting for multiple socioeconomic, psychosocial, behavioral, and physiological risk factors. CONCLUSIONS: Marital history is significantly associated with survival after stroke. Additional studies are needed to further examine the mechanisms contributing to the associations and to better understand how this information can be used to personalize care and aggressively treat vulnerable segments of the population. PMID- 27974294 TI - Spontaneous 8-ball hyphaema in a toddler. PMID- 27974293 TI - Duration of Analgesic Use and Risk of Hearing Loss in Women. AB - Aspirin, nonsteroidal antiinflammatory drugs (NSAID), and acetaminophen are commonly used. Frequent use of analgesics has been associated with a higher risk of hearing loss. However, the association between duration of analgesic use and the risk of hearing loss is unclear. We investigated the relationship between duration of analgesic use and self-reported hearing loss among 55,850 women in the Nurses' Health Study. Cox proportional hazards regression was used to adjust for potential confounders. During 873,376 person-years of follow-up (1990-2012), longer durations of NSAID use (for >6 years of use compared with <1 year, multivariable-adjusted relative risk = 1.10, 95% confidence interval: 1.06, 1.15; P for trend < 0.001) and acetaminophen use (for >6 years of use compared with <1 year, multivariable-adjusted relative risk = 1.09, 95% confidence interval: 1.04, 1.14; P for trend < 0.001) were associated with higher risks of hearing loss. Duration of aspirin use was not associated with hearing loss (for >6 years of use compared with <1 year, multivariable-adjusted relative risk = 1.01, 95% confidence interval: 0.97, 1.05; P for trend = 0.35). In this cohort of women, longer durations of NSAID and acetaminophen use were associated with slightly higher risks of hearing loss, but duration of aspirin use was not. Considering the high prevalence of analgesic use, this may be an important modifiable contributor to hearing loss. PMID- 27974295 TI - Cardiovascular health, growth and gonadal function in children and adolescents with congenital adrenal hyperplasia. AB - After the introduction of replacement therapy with glucocorticoids and mineralocorticoids in the 1950s, congenital adrenal hyperplasia (CAH) is no longer a life-limiting condition. However, due to the successful introduction of medical steroid hormone replacement, CAH has become a chronic condition, with associated comorbidities and long-term health implications. The aim of treatment is the replacement of mineralocorticoids and glucocorticoids and the normalisation of elevated androgen concentrations. Long-term consequences of the condition and current treatment regimens include unfavourable changes in the cardiovascular risk profile, impaired growth, testicular adrenal rest tumours (TART) in male and subfertility in both male and female patients with CAH. Optimising replacement therapy in patients with CAH remains challenging. On one hand, treatment with supraphysiological doses of glucocorticoids might be required to normalise androgen concentrations and decrease size or presence of TARTs. On the other hand, treatment with supraphysiological doses of glucocorticoids is associated with an increased prevalence of unfavourable cardiovascular and metabolic risk profiles as well as impaired longitudinal growth and gonadal function. Therefore, treatment of children and adults with CAH requires an individualised approach. Careful monitoring for early signs of complications is already warranted during paediatric healthcare provision to prevent and reduce the impact of comorbidities in later life. PMID- 27974296 TI - Colombia sees fourfold increase in microcephaly cases in a year. PMID- 27974297 TI - Hunt says health spending must rise as part of GDP over coming decades. PMID- 27974298 TI - miR-958 inhibits Toll signaling and Drosomycin expression via direct targeting of Toll and Dif in Drosophila melanogaster. AB - Drosophila melanogaster is widely used as a model system to study innate immunity and signaling pathways related to innate immunity, including the Toll signaling pathway. Although this pathway is well studied, the precise mechanisms of posttranscriptional regulation of key components of the Toll signaling pathway by microRNAs (miRNAs) remain obscure. In this study, we used an in silico strategy in combination with the Gal80ts-Gal4 driver system to identify microRNA-958 (miR 958) as a candidate Toll pathway regulating miRNA in Drosophila We report that overexpression of miR-958 significantly reduces the expression of Drosomycin, a key antimicrobial peptide involved in Toll signaling and the innate immune response. We further demonstrate in vitro and in vivo that miR-958 targets the Toll and Dif genes, key components of the Toll signaling pathway, to negatively regulate Drosomycin expression. In addition, a miR-958 sponge rescued the expression of Toll and Dif, resulting in increased expression of Drosomycin. These results, not only revealed a novel function and modulation pattern of miR 958, but also provided a new insight into the underlying molecular mechanisms of Toll signaling in regulation of innate immunity. PMID- 27974300 TI - S-nitrosylation and S-glutathionylation of Cys134 on troponin I have opposing competitive actions on Ca2+ sensitivity in rat fast-twitch muscle fibers. AB - Nitric oxide is generated in skeletal muscle with activity and decreases Ca2+ sensitivity of the contractile apparatus, putatively by S-nitrosylation of an unidentified protein. We investigated the mechanistic basis of this effect and its relationship to the oxidation-induced increase in Ca2+ sensitivity in mammalian fast-twitch (FT) fibers mediated by S-glutathionylation of Cys134 on fast troponin I (TnIf). Force-[Ca2+] characteristics of the contractile apparatus in mechanically skinned fibers were assessed by direct activation with heavily Ca2+-buffered solutions. Treatment with S-nitrosylating agents, S nitrosoglutathione (GSNO) or S-nitroso-N-acetyl-penicillamine (SNAP), decreased pCa50 ( = -log10 [Ca2+] at half-maximal activation) by ~-0.07 pCa units in rat and human FT fibers without affecting maximum force, but had no effect on rat and human slow-twitch fibers or toad or chicken FT fibers, which all lack Cys134. The Ca2+ sensitivity decrease was 1) fully reversed with dithiothreitol or reduced glutathione, 2) at least partially reversed with ascorbate, indicative of involvement of S-nitrosylation, and 3) irreversibly blocked by low concentration of the alkylating agent, N-ethylmaleimide (NEM). The biotin-switch assay showed that both GSNO and SNAP treatments caused S-nitrosylation of TnIfS glutathionylation pretreatment blocked the effects of S-nitrosylation on Ca2+ sensitivity, and vice-versa. S-nitrosylation pretreatment prevented NEM from irreversibly blocking S-glutathionylation of TnIf and its effects on Ca2+ sensitivity, and likewise S-glutathionylation pretreatment prevented NEM block of S-nitrosylation. Following substitution of TnIf into rat slow-twitch fibers, S nitrosylation treatment caused decreased Ca2+ sensitivity. These findings demonstrate that S-nitrosylation and S-glutathionylation exert opposing effects on Ca2+ sensitivity in mammalian FT muscle fibers, mediated by competitive actions on Cys134 of TnIf. PMID- 27974299 TI - Nitric oxide: what's new to NO? AB - Nitric oxide (NO) is one of the critical components of the vasculature, regulating key signaling pathways in health. In macrovessels, NO functions to suppress cell inflammation as well as adhesion. In this way, it inhibits thrombosis and promotes blood flow. It also functions to limit vessel constriction and vessel wall remodeling. In microvessels and particularly capillaries, NO, along with growth factors, is important in promoting new vessel formation, a process termed angiogenesis. With age and cardiovascular disease, animal and human studies confirm that NO is dysregulated at multiple levels including decreased production, decreased tissue half-life, and decreased potency. NO has also been implicated in diseases that are related to neurotransmission and cancer although it is likely that these processes involve NO at higher concentrations and from nonvascular cell sources. Conversely, NO and drugs that directly or indirectly increase NO signaling have found clinical applications in both age-related diseases and in younger individuals. This focused review considers recently reported advances being made in the field of NO signaling regulation at several levels including enzymatic production, receptor function, interacting partners, localization of signaling, matrix-cellular and cell-to-cell cross talk, as well as the possible impact these newly described mechanisms have on health and disease. PMID- 27974302 TI - Short-term changes on MRI predict long-term changes on radiography in rheumatoid arthritis: an analysis by an OMERACT Task Force of pooled data from four randomised controlled trials. AB - OBJECTIVE: In rheumatoid arthritis (RA), MRI provides earlier detection of structural damage than radiography (X-ray) and more sensitive detection of intra articular inflammation than clinical examination. This analysis was designed to evaluate the ability of early MRI findings to predict subsequent structural damage by X-ray. METHODS: Pooled data from four randomised controlled trials (RCTs) involving 1022 RA hands and wrists in early and established RA were analysed. X-rays were scored using van der Heijde-modified or Genant-modified Sharp methods. MRIs were scored using Outcome Measures in Rheumatology (OMERACT) RA MRI Score (RAMRIS). Data were analysed at the patient level using multivariable logistic regression and receiver operating characteristic curve analyses. RESULTS: Progression of MRI erosion scores at Weeks 12 and 24 predicted progression of X-ray erosions at Weeks 24 and 52, with areas under the curve (AUCs) of 0.64 and 0.74, respectively. 12-week and 24-week changes in MRI osteitis scores were similarly predictive of 24-week and 52-week X-ray erosion progressions; pooled AUCs were 0.78 and 0.77, respectively. MRI changes in synovitis at Weeks 12 and 24 also predicted progression of X-ray joint damage (erosion and joint-space narrowing) at Weeks 24 and 52 (AUCs=0.72 and 0.65, respectively). CONCLUSIONS: Early changes in joint damage and inflammation detected with MRI predict changes in joint damage evident on subsequent X-rays. These findings support the use of MRI as a valid method for monitoring structural damage in short-duration RCTs. PMID- 27974304 TI - Improving hip fracture outcomes with integrated orthogeriatric care: a comparison between two accepted orthogeriatric models. AB - Background: our orthopaedic trauma unit serves a large elderly population, admitting 400-500 hip fractures annually. A higher than expected mortality was detected amongst these patients, prompting a change in the hip fracture pathway. The aim of this study was to assess the impact of a change in orthogeriatric provision on hip fracture outcomes and care quality indicators. Patients and Methods: the hip fracture pathway was changed from a geriatric consultation service to a completely integrated service on a dedicated orthogeriatric ward. A total of 1,894 consecutive patients with hip fractures treated in the 2 years before and after this intervention were analysed. Results: despite an increase in case complexity, the intervention resulted in a significant reduction in mean length of stay from 27.5 to 21 days (P < 0.001), a significant reduction in mean time to surgery from 41.8 to 27.2 h (P < 0.001) and a significant 22% reduction in 30-day mortality (13.2-10.3%, P = 0.04). After controlling for the effects of age, gender, American Society of Anesthesiology (ASA) Grade and abbreviated mental test score (AMTS), the effect of integrating orthogeriatric services into the hip fracture pathway significantly reduced the risk of mortality (odds ratio 0.68, P = 0.03). Conclusions: changing our hip fracture service from a geriatric consultation model of care to an integrated orthogeriatric model significantly improved mortality and performance indicators. This is the first study to directly compare two accepted models of orthogeriatric care in the same hospital. PMID- 27974301 TI - Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis. AB - OBJECTIVE: Osteoarthritis (OA) has a strong genetic component but the success of previous genome-wide association studies (GWAS) has been restricted due to insufficient sample sizes and phenotype heterogeneity. Our aim was to examine the effect of clinically relevant endophenotyping according to site of maximal joint space narrowing (maxJSN) and bone remodelling response on GWAS signal detection in hip OA. METHODS: A stratified GWAS meta-analysis was conducted in 2118 radiographically defined hip OA cases and 6500 population-based controls. Signals were followed up by analysing differential expression of proximal genes for bone remodelling endophenotypes in 33 pairs of macroscopically intact and OA-affected cartilage. RESULTS: We report suggestive evidence (p<5*10-6) of association at 6 variants with OA endophenotypes that would have been missed by using presence of hip OA as the disease end point. For example, in the analysis of hip OA cases with superior maxJSN versus cases with non-superior maxJSN we detected association with a variant in the LRCH1 gene (rs754106, p=1.49*10-7, OR (95% CIs) 0.70 (0.61 to 0.80)). In the comparison of hypertrophic with non-hypertrophic OA the most significant variant was located between STT3B and GADL1 (rs6766414, p=3.13*10-6, OR (95% CIs) 1.45 (1.24 to 1.69)). Both of these associations were fully attenuated in non-stratified analyses of all hip OA cases versus population controls (p>0.05). STT3B was significantly upregulated in OA-affected versus intact cartilage, particularly in the analysis of hypertrophic and normotrophic compared with atrophic bone remodelling pattern (p=4.2*10-4). CONCLUSIONS: Our findings demonstrate that stratification of OA cases into more homogeneous endophenotypes can identify genes of potential functional importance otherwise obscured by disease heterogeneity. PMID- 27974305 TI - Cross-national comparison of medication use in Australian and Dutch nursing homes. AB - Background: cross-national comparisons can be used to explore therapeutic areas and identify potential medication issues. Methods: we used cross-sectional pharmacy supply data to explore medication use for nursing home residents in Australia (AU n = 26 homes, 1,560 residents) and the Netherlands (NL n = 6 homes, 2,037 residents). Binary logistic regression analysis was used to calculate the sex and aged adjusted odds ratios (OR) and associated 95% confidence intervals with a flexible Bonferroni-Holm procedure used to adjust for multiple hypothesis testing. Results: total use of antipsychotics (AU: 37.7%, NL: 40.3%; OR 0.91 (0.79-1.04, P = 0.16) and antibacterials (66.8% AU, 62.4% NL, OR 1.08 (0.93-1.24, P = 0.31) was similar, but choice of individual agents differed between the two countries. Differences were observed in the use of antithrombotics (46.7% AU, 64.7% NL, OR 0.48 (0.42-0.56, P > 0.01), ophthalmologicals (44.3% AU, 22.1% NL, OR 2.80 (2.42-3.24, P < 0.001), laxatives (77.1% AU, 65.8% NL, OR 1.65 (1.41 1.92, P < 0.001). Conclusion: while the general prevalence of medication use in nursing home residents was similar across the two countries, distinct differences existed in the choice of agent among therapeutic groups. Comparing use between countries identified a number of potential medication related problem areas that need further exploration. PMID- 27974306 TI - Common eye diseases in older adults of southern Germany: results from the KORA Age study. AB - Purpose: a population-based study in the region of Augsburg (Germany, KORA) was used to identify the prevalence of eye diseases and their risk factors in a sample of aged individuals. Methods: data originated from the KORA-Age study collected in 2012 and 822 participants (49.6% women, 50.4% men, aged 68-96 years) were asked standardised questions about eye diseases. Positive answers were validated and specified by treating ophthalmologists. Additional information came from laboratory data. Polymorphic markers were tested for candidate genes. Results: we received validations and specifications for 339 participants. The most frequent eye diseases were cataracts (299 cases, 36%), dry eyes (120 cases, 15%), glaucoma (72 cases, 9%) and age-related macular degeneration (AMD) (68 cases, 8%). Almost all participants suffering from glaucoma or from AMD also had cataracts. Cataract surgery was associated with diabetes (in men; OR = 2.24; 95% confidence interval [CI] 1.11-4.53; P = 0.025) and smoking (in women; OR = 6.77; CI 1.62-28.35; P = 0.009). In men, treatments in airway diseases was associated with cataracts (glucocorticoids: OR = 5.29, CI 1.20-23.37; P = 0.028; sympathomimetics: OR = 4.57, CI 1.39-15.00; P = 0.012). Polymorphisms in two genes were associated with AMD (ARMS2: OR = 2.28, CI 1.48-3.51; P = 0.005; CFH: OR = 2.03, CI 1.35-3.06; P = 0.010). Conclusion: combinations of eye diseases were frequent at old age. The importance of classical risk factors like diabetes, hypertension and airway diseases decreased either due to a survivor bias leaving healthier survivors in the older age group, or due to an increased influence of other up to now unknown risk factors. PMID- 27974307 TI - A foodservice approach to enhance energy intake of elderly subacute patients: a pilot study to assess impact on patient outcomes and cost. AB - Background: effective strategies are required to support the nutritional status of patients. Objectives: to evaluate a foodservice nutrition intervention on a range of participant outcomes and estimate its cost. Design: parallel controlled pilot study. Setting: subacute hospital ward. Subjects: all consecutively admitted adult patients were eligible for recruitment under waiver of consent. Methods: the intervention was a modified hospital menu developed by substituting standard items with higher energy options. The control was the standard menu. All participants received usual multidisciplinary care. Outcomes were change in weight and hand grip strength (HGS) between admission and day 14 and; energy and protein intake and patient satisfaction with the foodservice at day 14. The additional cost of the intervention was also estimated. Results: the median (interquartile range) age of participants (n = 122) was 83 (75-87) years and length of stay was 19 (11-32) days. One-third (38.5%) were malnourished at admission. There was no difference in mean (SD) HGS change (1.7 (5.1) versus 1.4 (5.8) kg, P = 0.798) or weight change (-0.55 (3.43) versus 0.26 (3.33) %, P = 0.338) between the intervention and control groups, respectively. The intervention group had significantly higher mean (SD) intake of energy (132 (38) versus 105 (34) kJ/kg/day, P = 0.003) and protein (1.4 (0.6) versus 1.1 (0.4) g protein/kg/day, P = 0.035). Both groups were satisfied with the foodservice. The additional cost was L4.15/participant/day. Conclusions: in this pilot, the intervention improved intake and may be a useful strategy to address malnutrition. Further consideration of clinical and cost implications is required in a fully powered study. PMID- 27974308 TI - Prospective associations between problematic eating attitudes in midchildhood and the future onset of adolescent obesity and high blood pressure. AB - BACKGROUND: Clinically diagnosed eating disorders may have adverse cardiometabolic consequences, including overweight or obesity and high blood pressure. However, the link between problematic eating attitudes in early adolescence, which can lead to disordered eating behaviors, and future cardiometabolic health is, to our knowledge, unknown. OBJECTIVE: We assessed whether variations in midchildhood eating attitudes influence the future development of overweight or obesity and high blood pressure. DESIGN: Of 17,046 children who participated in the Promotion of Breastfeeding Intervention Trial (PROBIT), we included 13,557 participants (79.5% response rate) who completed the Children's Eating Attitudes Test (ChEAT) at age 11.5 y and in whom we measured adiposity and blood pressure at ages 6.5, 11.5, and 16 y. We assessed whether ChEAT scores >=85th percentile (indicative of problematic eating attitudes) compared with scores <85th percentile at age 11.5 y were associated with new onset overweight, obesity, high systolic blood pressure, or high diastolic blood pressure between midchildhood and early adolescence. RESULTS: After controlling for baseline sociodemographic confounders, we observed positive associations of problematic eating attitudes at age 11.5 y with new-onset obesity (OR: 2.18; 95% CI: 1.58, 3.02), new-onset high systolic blood pressure (OR: 1.34; 95% CI: 1.05, 1.70), and new-onset high diastolic blood pressure (OR: 1.25; 95% CI: 0.99, 1.58) at age 16 y. After further controlling for body mass index at age 6.5 y, problematic eating attitudes remained positively associated with new-onset obesity (OR: 1.80; 95% CI: 1.28, 2.53); however, associations with new-onset high blood pressure were attenuated (OR: 1.14; 95% CI: 0.89, 1.45 and OR: 1.09; 95% CI: 0.86, 1.39 for new-onset systolic and diastolic blood pressure, respectively). CONCLUSIONS: Problematic eating attitudes in midchildhood seem to be related to the development of obesity in adolescence, a relatively novel observation with potentially important public health implications for obesity control. PROBIT was registered at clinicaltrials.gov as NCT01561612 and isrctn.com as ISRCTN37687716. PMID- 27974309 TI - Analytical ingredient content and variability of adult multivitamin/mineral products: national estimates for the Dietary Supplement Ingredient Database. AB - BACKGROUND: Multivitamin/mineral products (MVMs) are the dietary supplements most commonly used by US adults. During manufacturing, some ingredients are added in amounts exceeding the label claims to compensate for expected losses during the shelf life. Establishing the health benefits and harms of MVMs requires accurate estimates of nutrient intake from MVMs based on measures of actual rather than labeled ingredient amounts. OBJECTIVES: Our goals were to determine relations between analytically measured and labeled ingredient content and to compare adult MVM composition with Recommended Dietary Allowances (RDAs) and Tolerable Upper Intake Levels. DESIGN: Adult MVMs were purchased while following a national sampling plan and chemically analyzed for vitamin and mineral content with certified reference materials in qualified laboratories. For each ingredient, predicted mean percentage differences between analytically obtained and labeled amounts were calculated with the use of regression equations. RESULTS: For 12 of 18 nutrients, most products had labeled amounts at or above RDAs. The mean measured content of all ingredients (except thiamin) exceeded labeled amounts (overages). Predicted mean percentage differences exceeded labeled amounts by 1.5 13% for copper, manganese, magnesium, niacin, phosphorus, potassium, folic acid, riboflavin, and vitamins B-12, C, and E, and by ~25% for selenium and iodine, regardless of labeled amount. In contrast, thiamin, vitamin B-6, calcium, iron, and zinc had linear or quadratic relations between the labeled and percentage differences, with ranges from -6.5% to 8.6%, -3.5% to 21%, 7.1% to 29.3%, -0.5% to 16.4%, and -1.9% to 8.1%, respectively. Analytically adjusted ingredient amounts are linked to adult MVMs reported in the NHANES 2003-2008 via the Dietary Supplement Ingredient Database (http://dsid.usda.nih.gov) to facilitate more accurate intake quantification. CONCLUSIONS: Vitamin and mineral overages were measured in adult MVMs, most of which already meet RDAs. Therefore, nutrient overexposures from supplements combined with typical food intake may have unintended health consequences, although this would require further examination. PMID- 27974310 TI - Serum potassium is a predictor of incident diabetes in African Americans with normal aldosterone: the Jackson Heart Study. AB - BACKGROUND: Low-normal potassium is a risk factor for diabetes and may account for some of the racial disparity in diabetes risk. Aldosterone affects serum potassium and is associated with insulin resistance. OBJECTIVES: We sought to confirm the association between potassium and incident diabetes in an African American cohort, and to determine the effect of aldosterone on this association. DESIGN: We studied participants from the Jackson Heart Study, an African-American adult cohort, who were without diabetes at baseline. With the use of logistic regression, we characterized the associations of serum, dietary, and urinary potassium with incident diabetes. In addition, we evaluated aldosterone as a potential effect modifier of these associations. RESULTS: Of 2157 participants, 398 developed diabetes over 8 y. In a minimally adjusted model, serum potassium was a significant predictor of incident diabetes (OR: 0.83; 95% CI: 0.74, 0.92 per SD increment in serum potassium). In multivariable models, we found a significant interaction between serum potassium and aldosterone (P = 0.046). In stratified multivariable models, in those with normal aldosterone (<9 ng/dL, n = 1163), participants in the highest 2 potassium quartiles had significantly lower odds of incident diabetes than did those in the lowest potassium quartile [OR (95% CI): 0.61 (0.39, 0.97) and 0.54 (0.33, 0.90), respectively]. Among those with high-normal aldosterone (>=9 ng/dL, n = 202), we found no significant association between serum potassium and incident diabetes. In these stratified models, serum aldosterone was not a significant predictor of incident diabetes. We found no statistically significant associations between dietary or urinary potassium and incident diabetes. CONCLUSIONS: In this African-American cohort, we found that aldosterone may modify the association between serum potassium and incident diabetes. In participants with normal aldosterone, high-normal serum potassium was associated with a lower risk of diabetes than was low-normal serum potassium. Additional studies are warranted to determine whether serum potassium is a modifiable risk factor that could be a target for diabetes prevention. This trial was registered at clinicaltrials.gov as NCT00415415. PMID- 27974311 TI - Role of timing and dose of energy received in patients with acute lung injury on mortality in the Intensive Nutrition in Acute Lung Injury Trial (INTACT): a post hoc analysis. AB - BACKGROUND: Our trial INTACT (Intensive Nutrition in Acute Lung Injury Trial) was designed to compare the impact of feeding from acute lung injury (ALI) diagnosis to hospital discharge, an interval that, to our knowledge, has not yet been explored. It was stopped early because participants who were randomly assigned to energy intakes at nationally recommended amounts via intensive medical nutrition therapy experienced significantly higher mortality hazards than did those assigned to standard nutrition support care that provided energy at 55% of recommended concentrations. OBJECTIVE: We assessed the influence of dose and timing of feeding on hospital mortality. DESIGN: Participants (n = 78) were dichotomized as died or discharged alive. Associations between the energy and protein received overall, early (days 1-7), and late (days >=8) and the hazards of hospital mortality were evaluated between groups with multivariable analysis methods. RESULTS: Higher overall energy intake predicted significantly higher mortality (OR: 1.14, 95% CI: 1.02, 1.27). Among participants enrolled for >=8 d (n = 66), higher early energy intake significantly increased the HR for mortality (HR: 1.17, 95% CI: 1.07, 1.28), whereas higher late energy intake was significantly protective (HR: 0.91, 95% CI: 0.83, 1.0). Results were similar for early but not late protein (grams per kilogram) exposure (early-exposure HR: 8.9, 95% CI: 2.3, 34.3; late-exposure HR: 0.15, 95% CI: 0.02, 1.1). Threshold analyses indicated early mean intakes >=18 kcal/kg significantly increased subsequent mortality. CONCLUSIONS: Providing kilocalories per kilogram or grams of protein per kilogram early post-ALI diagnosis at recommended levels was associated with significantly higher hazards for mortality, whereas higher late energy intakes reduced mortality hazards. This time-varying effect violated the Cox proportionality assumption, indicating that feeding trials in similar populations should extend beyond 7 d and use time-varying statistical methods. Future trials are required for corroboration. INTACT was registered at clinicaltrials.gov as NCT01921101. PMID- 27974313 TI - Dear John Hunter. PMID- 27974312 TI - Dietary patterns and cardiometabolic and endocrine plasma biomarkers in US women. AB - BACKGROUND: Healthful dietary patterns have been associated with lower risks of type 2 diabetes and coronary artery disease, but their relations with intermediate markers of cardiometabolic and endocrine health are less established. OBJECTIVE: We evaluated the Dietary Approaches to Stop Hypertension (DASH), the alternate Mediterranean diet (aMED), and the Alternate Healthy Eating Index (aHEI) diet-quality scores with cardiometabolic and endocrine plasma biomarkers in US women. DESIGN: The trial was a cross-sectional analysis of 775 healthy women in the Women's Lifestyle Validation Study that was conducted within the NHS (Nurses' Health Study) and NHS II longitudinal cohorts. Multiple linear regression models adjusted for potential confounders were used to estimate associations between quartiles of dietary pattern-adherence scores that were derived from a food-frequency questionnaire and plasma biomarker concentrations that were collected simultaneously. RESULTS: In multivariable models in which highest and lowest quartiles of dietary pattern scores were compared, 1) DASH was significantly associated with higher concentrations of high-density lipoprotein (9%) and sex-hormone binding globulin (SHBG) (21%), and lower concentrations of leptin (28%), triglycerides (19%), and C-peptide (4%) (all P-trend <= 0.04); 2) the aMED was associated with 19% higher SHBG and 16% lower triglycerides (P-trend = 0.02 and 0.003, respectively); and 3) the aHEI was associated with significantly higher concentrations of insulin (16%) and SHBG (19%) and lower concentrations of leptin (18%) (all P-trend <= 0.02). Further adjustment for body mass index (BMI) attenuated these associations but remained significant for 1) DASH with leptin and triglycerides and 2) the aMED with triglycerides (all P trend <= 0.03). CONCLUSIONS: Adherence to healthful dietary patterns is associated with favorable concentrations of many cardiometabolic and endocrine biomarkers. These relations are mediated in part by BMI. PMID- 27974316 TI - Characterizing the dynamic interaction among gastric emptying, glucose absorption, and glycemic control in nondiabetic obese adults. AB - The effects of altered gastric emptying on glucose absorption and kinetics are not well understood in nondiabetic obese adults. The aim of this work was to develop a physiology-based model that can characterize and compare interactions among gastric emptying, glucose absorption, and glycemic control in nondiabetic obese and lean healthy adults. Dynamic glucose, insulin, and gastric emptying (measured with breath test) data from 12 nondiabetic obese and 12 lean healthy adults were available until 180 min after an oral glucose tolerance test (OGTT) with 10, 25, and 75 g of glucose. A physiology-based model was developed to characterize glucose kinetics applying nonlinear mixed-effects modeling with NONMEM7.3. Glucose kinetics after OGTT was described by a one-compartment model with an effect compartment to describe delayed insulin effects on glucose clearance. After the interactions between individual gastric emptying and glucose absorption profiles were accounted for, the glucose absorption rate was found to be similar in nondiabetic obese and lean controls. Baseline glucose concentration was estimated to be only marginally higher in nondiabetic obese subjects (4.9 vs. 5.2 mmol/l), whereas insulin-dependent glucose clearance in nondiabetic obese subjects was found to be cut in half compared with lean controls (0.052 vs. 0.029 l/min) and the insulin concentration associated with 50% of insulin-dependent glucose elimination rate was approximately twofold higher in nondiabetic obese subjects compared with lean controls (7.1 vs. 15.3 MUU/ml). Physiology-based models can characterize and compare the dynamic interaction among gastric emptying, glucose absorption and glycemic control in populations of interest such as lean healthy and nondiabetic obese adults. PMID- 27974314 TI - Kolliker-Fuse nuclei regulate respiratory rhythm variability via a gain-control mechanism. AB - Respiration varies from breath to breath. On the millisecond timescale of spiking, neuronal circuits exhibit variability due to the stochastic properties of ion channels and synapses. Does this fast, microscopic source of variability contribute to the slower, macroscopic variability of the respiratory period? To address this question, we modeled a stochastic oscillator with forcing; then, we tested its predictions experimentally for the respiratory rhythm generated by the in situ perfused preparation during vagal nerve stimulation (VNS). Our simulations identified a relationship among the gain of the input, entrainment strength, and rhythm variability. Specifically, at high gain, the periodic input entrained the oscillator and reduced variability, whereas at low gain, the noise interacted with the input, causing events known as "phase slips", which increased variability on a slow timescale. Experimentally, the in situ preparation behaved like the low-gain model: VNS entrained respiration but exhibited phase slips that increased rhythm variability. Next, we used bilateral muscimol microinjections in discrete respiratory compartments to identify areas involved in VNS gain control. Suppression of activity in the nucleus tractus solitarii occluded both entrainment and amplification of rhythm variability by VNS, confirming that these effects were due to the activation of the Hering-Breuer reflex. Suppressing activity of the Kolliker-Fuse nuclei (KFn) enhanced entrainment and reduced rhythm variability during VNS, consistent with the predictions of the high-gain model. Together, the model and experiments suggest that the KFn regulates respiratory rhythm variability via a gain control mechanism. PMID- 27974315 TI - Mechanisms of blood pressure salt sensitivity: new insights from mathematical modeling. AB - Mathematical modeling is an important tool for understanding quantitative relationships among components of complex physiological systems and for testing competing hypotheses. We used HumMod, a large physiological model, to test hypotheses of blood pressure (BP) salt sensitivity. Systemic hemodynamics, renal, and neurohormonal responses to chronic changes in salt intake were examined during normal renal function, fixed low or high plasma angiotensin II (ANG II) levels, bilateral renal artery stenosis, increased renal sympathetic nerve activity (RSNA), and decreased nephron numbers. Simulations were run for 4 wk at salt intakes ranging from 30 to 1,000 mmol/day. Reducing functional kidney mass or fixing ANG II increased salt sensitivity. Salt sensitivity, associated with inability of ANG II to respond to changes in salt intake, occurred with smaller changes in renal blood flow but greater changes in glomerular filtration rate, renal sodium reabsorption, and total peripheral resistance (TPR). However, clamping TPR at normal or high levels had no major effect on salt sensitivity. There were no clear relationships between BP salt sensitivity and renal vascular resistance or extracellular fluid volume. Our robust mathematical model of cardiovascular, renal, endocrine, and sympathetic nervous system physiology supports the hypothesis that specific types of kidney dysfunction, associated with impaired regulation of ANG II or increased tubular sodium reabsorption, contribute to BP salt sensitivity. However, increased preglomerular resistance, increased RSNA, or inability to decrease TPR does not appear to influence salt sensitivity. This model provides a platform for testing competing concepts of long-term BP control during changes in salt intake. PMID- 27974317 TI - Sex difference in the contribution of GABAB receptors to tibial neuromodulation of bladder overactivity in cats. AB - This study investigated the role of gamma-aminobutyric acid subtype B (GABAB) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical administration of dilute (0.5%) acetic acid (AA) in alpha chloralose-anesthetized cats. To inhibit bladder overactivity, tibial or pudendal nerve stimulation (TNS or PNS) was applied at 5 Hz and two or four times threshold (T) intensity for inducing toe or anal sphincter twitch. TNS at 2T or 4T intensity significantly (P < 0.05) increased the bladder capacity to 173.8 +/- 16.2 or 198.5 +/- 24.1%, respectively, of control capacity. Meanwhile, PNS at 2T or 4T intensity significantly (P < 0.05) increased the bladder capacity to 217 +/ 18.8 and 221.3 +/- 22.3% of control capacity, respectively. CGP52432 (a GABAB receptor antagonist) at intravenous dosages of 0.1-1 mg/kg completely removed the TNS inhibition in female cats but had no effect in male cats. CGP52432 administered intravenously also had no effect on control bladder capacity or the pudendal inhibition of bladder overactivity. These results reveal a sex difference in the role of GABAB receptors in tibial neuromodulation of bladder overactivity in cats and that GABAB receptors are not involved in either pudendal neuromodulation or irritation-induced bladder overactivity. PMID- 27974319 TI - MicroRNA-30e targets BNIP3L to protect against aldosterone-induced podocyte apoptosis and mitochondrial dysfunction. AB - MicroRNAs are essential for the maintenance of podocyte homeostasis. Emerging evidence has demonstrated a protective role of microRNA-30a (miR-30a), a member of the miR-30 family, in podocyte injury. However, the roles of other miR-30 family members in podocyte injury are unclear. The present study was undertaken to investigate the contribution of miR-30e to the pathogenesis of podocyte injury induced by aldosterone (Aldo), as well as the underlying mechanism. After Aldo treatment, miR-30e was reduced in a dose-and time-dependent manner. Notably, overexpression of miR-30e markedly attenuated Aldo-induced apoptosis in podocytes. In agreement with this finding, miR-30e silencing led to significant podocyte apoptosis. Mitochondrial dysfunction (MtD) has been shown to be an early event in Aldo-induced podocyte injury. Here we found that overexpression of miR 30e improved Aldo-induced MtD while miR-30e silencing resulted in MtD. Next, we found that miR-30e could directly target the BCL2/adenovirus E1B-interacting protein 3-like (BNIP3L) gene. Aldo markedly enhanced BNIP3L expression in podocytes, and silencing of BNIP3L largely abolished Aldo-induced MtD and cell apoptosis. On the contrary, overexpression of BNIP3L induced MtD and apoptosis in podocytes. Together, these findings demonstrate that miR-30e protects mitochondria and podocytes from Aldo challenge by targeting BNIP3L. PMID- 27974318 TI - A perspective on chronic kidney disease progression. AB - Chronic kidney disease (CKD) will progress to end stage without treatment, but the decline of renal function may not be linear. Compared with glomerular filtration rate and proteinuria, new surrogate markers, such as kidney injury molecule-1, neutrophil gelatinase-associated protein, apolipoprotein A-IV, and soluble urokinase receptor, may allow potential intervention and treatment in the earlier stages of CKD, which could be useful for clinical trials. New omic-based technologies reveal potential new genomic and epigenomic mechanisms that appear different from those causing the initial disease. Various clinical studies also suggest that acute kidney injury is a major risk for progressive CKD. To ameliorate the progression of CKD, the first step is optimizing renin-angiotensin aldosterone system blockade. New drugs targeting endothelin, transforming growth factor-beta, oxidative stress, and inflammatory- and cell-based regenerative therapy may have add-on benefit. PMID- 27974320 TI - From 20th century metabolic wall charts to 21st century systems biology: database of mammalian metabolic enzymes. AB - The organization of the mammalian genome into gene subsets corresponding to specific functional classes has provided key tools for systems biology research. Here, we have created a web-accessible resource called the Mammalian Metabolic Enzyme Database (https://hpcwebapps.cit.nih.gov/ESBL/Database/MetabolicEnzymes/MetabolicEnzymeDat base.html) keyed to the biochemical reactions represented on iconic metabolic pathway wall charts created in the previous century. Overall, we have mapped 1,647 genes to these pathways, representing ~7 percent of the protein-coding genome. To illustrate the use of the database, we apply it to the area of kidney physiology. In so doing, we have created an additional database (Database of Metabolic Enzymes in Kidney Tubule Segments: https://hpcwebapps.cit.nih.gov/ESBL/Database/MetabolicEnzymes/), mapping mRNA abundance measurements (mined from RNA-Seq studies) for all metabolic enzymes to each of 14 renal tubule segments. We carry out bioinformatics analysis of the enzyme expression pattern among renal tubule segments and mine various data sources to identify vasopressin-regulated metabolic enzymes in the renal collecting duct. PMID- 27974321 TI - Changes of choroidal structure after intravitreal aflibercept therapy for polypoidal choroidal vasculopathy. AB - AIMS: To quantify the changes of the choroidal structure in the enhanced depth imaging optical coherence tomographic (EDI-OCT) images after intravitreal aflibercept (IVA) injections for polypoidal choroidal vasculopathy (PCV). METHODS: Retrospective, observational case series. Forty eyes of 40 treatment naive patients who underwent IVA for PCV were examined by EDI-OCT before, and 3 months and 12 months after IVA. The EDI-OCT images were binarised by ImageJ software. The cross-sectional luminal and stromal areas of the inner and outer subfoveal choroid of 1500 um width were quantified. RESULTS: The stromal but not the luminal area of the inner choroid was significantly decreased at 3 months and 12 months after the IVA (stromal area, both p<0.001; luminal area, both p>0.050). On the other hand, the luminal but not the stromal area of the outer choroid was significantly decreased at 3 months and 12 months (luminal area, both p<0.001; stromal area, both p>0.050). The Pachychoroid Index, ratio of luminal/stromal area (L/S ratio) of the outer choroid divided by the L/S ratio of the inner choroid, was significantly decreased at 3 months and 12 months (both p<0.050). The Pachychoroid Index was increased and returned almost to the baseline level after recurrences and decreased again after successful re-treatment. The baseline Pachychoroid Index was significantly correlated with the presence of a dry macula, thinner fovea and better visual acuity at 12 months (all p<0.050). CONCLUSION: The binarisation of the EDI-OCT images can be used to quantify the activity of PCV and to predict the prognosis after IVA. PMID- 27974323 TI - Do celebrity endorsements matter? Observational study of BRCA gene testing and mastectomy rates after Angelina Jolie's New York Times editorial. AB - OBJECTIVE: To examine the effect on BRCA testing and mastectomy rates of a widely viewed 2013 New York Times editorial by public figure Angelina Jolie that endorsed BRCA testing and announced Jolie's decision to undergo preventive mastectomy. DESIGN: Observational study with difference-in-difference analysis. SETTING: Commercially insured US population. PARTICIPANTS: Women aged 18-64 years with claims in the Truven MarketScan commercial claims database (n=9 532 836). MAIN OUTCOME MEASURES: Changes in BRCA testing rates in the 15 business days before versus after 14 May 2013 (editorial date) compared with the change in the same period in 2012; mastectomy rates in the months before and after publication, both overall and within 60 days of BRCA testing among women who were tested; national estimates of incremental tests and expenditures associated with Jolie's article in the 15 days after publication. RESULTS: Daily BRCA test rates increased immediately after the 2013 editorial, from 0.71 tests/100 000 women in the 15 business days before to 1.13 tests/100 000 women in the 15 business days after publication. In comparison, daily test rates were similar in the same period in 2012 (0.58/100 000 women in the 15 business days before 14 May versus 0.55/100 000 women in the 15 business days after), implying a difference-in difference absolute daily increase of 0.45 tests/100 000 women or a 64% relative increase (P<0.001). The editorial was associated with an estimated increase of 4500 BRCA tests and $13.5m (L10.8m; ?12.8) expenditure nationally among commercially insured adult women in those 15 days. Increased BRCA testing rates were sustained throughout 2013. Overall mastectomy rates remained unchanged in the months after publication, but 60 day mastectomy rates among women who had a BRCA test fell from 10% in the months before publication to 7% in the months after publication, suggesting that women who underwent tests as a result of to the editorial had a lower pre-test probability of having the BRCA mutation than women tested before the editorial. CONCLUSIONS: Celebrity endorsements can have a large and immediate effect on use of health services. Such announcements can be a low cost means of reaching a broad audience quickly, but they may not effectively target the subpopulations that are most at risk for the relevant underlying condition. PMID- 27974324 TI - The evolutionary history of Eugenia sect. Phyllocalyx (Myrtaceae) corroborates historically stable areas in the southern Atlantic forests. AB - BACKGROUND AND AIMS: Eugenia sect. Phyllocalyx Nied. includes 14 species endemic to the Neotropics, mostly distributed in the Atlantic coastal forests of Brazil. Here the first comprehensive phylogenetic study of this group is presented, and this phylogeny is used as the basis to evaluate the recent infrageneric classification in Eugenia sensu lato (s.l.) to test the history of the evolution of traits in the group and test hypotheses associated with the history of this clade. METHODS: A total of 42 taxa were sampled, of which 14 were Eugenia sect. Phyllocalyx for one nuclear (ribosomal internal transcribed spacer) and four plastid markers (psbA-trnH, rpl16, trnL-rpl32 and trnQ-rps16). The relationships were reconstructed based on Bayesian analysis and maximum likelihood. Additionally, ancestral area analysis and modelling methods were used to estimate species dispersal, comparing historically climatic stable (refuges) and unstable areas. KEY RESULTS: Maximum likelihood and Bayesian inferences indicate that Eugenia sect. Phyllocalyx is paraphyletic and the two clades recovered are characterized by combinations of morphological characters. Phylogenetic relationships support a link between Cerrado and south-eastern species and a difference in the composition of species from north-eastern and south-eastern Atlantic forest. Refugia and stable areas identified within unstable areas suggest that these areas were important to maintain diversity in the Atlantic forest biodiversity hotspot. CONCLUSION: This study provides a robust phylogenetic framework to address important historical questions for Eugenia s.l. within an evolutionary context, supporting the need for better taxonomic study of one of the largest genera in the Neotropics. Furthermore, valuable insight is offered into diversification and biome shifts of plant species in the highly environmentally impacted Atlantic forest of South America. Evidence is presented that climate stability in the south-eastern Atlantic forest during the Quaternary contributed to the highest levels of plant diversity in this region that acted as a refugium. PMID- 27974325 TI - One hundred and twenty-five years of the Annals of Botany. Part 2: the years 1937 to 2012. AB - BACKGROUND: Annals of Botany is a peer-reviewed plant biology journal. It was started in 1887, making it the oldest continuously published plant science title. A previous article [Jackson MB. 2015. One hundred and twenty-five years of the Annals of Botany Part 1: the first 50 years (1887-1936). Annals of Botany 115: : 1-18] summarized events leading to its founding, highlighted the individuals involved and examined the Journal's achievements and management practices over the first 50 years to 1937. This second article covers the next 75 years. SOURCES OF INFORMATION: The account draws principally on the Journal's own records, minute books, financial accounts, original letters and notes held by the Annals of Botany Company, the Journal's owners and managers. CONTENT: In 1937, its 51st year, the Journal was re-launched as Annals of Botany New Series and its volume numbers were reset to No. I. The present article evaluates the evolution of the New Series up to 2012, Annals of Botany's 125th anniversary year. The period includes a 2-year run-up to World War II, six war years and their immediate aftermath, and then on through increasingly competitive times. The ebb and flow of the Journal's fortunes are set against a roll-call of the often highly distinguished scientists who managed and edited the Journal. The article also examines an internal crisis in the 1980s that radically altered the Journal's organization in ways that were, ultimately, to its benefit. The narrative is set against changes to economic conditions in Great Britain over the period, to the evolving nature and geographical distribution of much experimental plant science and to the digital revolution that, from the late 20th century, transformed the workings of Annals of Botany and of scientific publishing more generally. PMID- 27974331 TI - QUESTION 1: What is the best therapy for children with Kawasaki disease who fail to respond to initial intravenous immunoglobulin? PMID- 27974326 TI - Genetic diversity and structure of wild populations of Carica papaya in Northern Mesoamerica inferred by nuclear microsatellites and chloroplast markers. AB - BACKGROUND AND AIMS: Few studies have evaluated the genetic structure and evolutionary history of wild varieties of important crop species. The wild papaya (Carica papaya) is a key element of early successional tropical and sub-tropical forests in Mexico, and constitutes the genetic reservoir for evolutionary potential of the species. In this study we aimed to determine how diverse and structured is the genetic variability of wild populations of C. papaya in Northern Mesoamerica. Moreover, we assessed if genetic structure and evolutionary history coincide with hypothetized (1) pre-Pleistocene events (Isthmus of Tehuantepec sinking), (2) Pleistocene refugia or (3) recent patterns. METHODS: We used six nuclear and two chloroplast (cp) DNA markers to assess the genetic diversity and phylogeographical structure of 19 wild populations of C. papaya in its natural distribution in Northern Mesoamerica. KEY RESULTS: We found high genetic diversity (Ho = 0.681 for nuclear markers, and h = 0.701 for cpDNA markers) and gene flow between populations of C. papaya (migration r up to 420 km). A lack of phylogeographical structure was found with the cpDNA markers (NST < GST), whereas a recent population structure was inferred with the nuclear markers. Evidence indicates that pre-Pleistocene events or refugia did not play an important role in the genetic structuring of wild papaya. CONCLUSIONS: Because of its life history characteristics and lack of an ancient phylogeographical structure found with the cpDNA markers, we suggest that C. papaya was dispersed throughout the lowland rain forests of Mexico (along the coastal plains and foothills of Sierras). This scenario supports the hypothesis that tropical forests in Northern Mesoamerica did not experience important climate fluctuations during the Pleistocene, and that the life history of C. papaya could have promoted long-distance dispersal and rapid colonization of lowland rainforests. Moreover, the results obtained with the nuclear markers suggest recent human disturbances. The fragmentation of tropical habitats in Northern Mesoamerica appears to be the main driver of genetic structuring, and the major threat to the dispersion and survival of the species in the wild. PMID- 27974330 TI - Post-exposure prophylaxis guidelines for children and adolescents potentially exposed to HIV. AB - UK guidelines for HIV post-exposure prophylaxis (PEP) in adults have recently been updated. Indications for PEP have been modified and there has been a change in the recommended antiretroviral therapy for adults to a combination of raltegravir with tenofovir and emtricitabine (Truvada). Raltegravir and tenofovir are now available in paediatric formulations and offer improved safety and tolerability over previously recommended ritonavir-boosted lopinavir with zidovudine. This guideline provides recommendations for those caring for children potentially exposed to HIV and other bloodborne viruses in primary care, emergency departments, secondary care and specialist paediatric HIV centres. PMID- 27974332 TI - Towards evidence based medicine for paediatricians. PMID- 27974335 TI - Advances in the medical management of skin and soft tissue infections. AB - Skin and soft tissue infections are some of the most common infectious disease diagnoses in both inpatient and outpatient settings. With bacterial resistance to antimicrobials growing, decision making on empiric antibiotics is becoming increasingly difficult. Additionally, the most recent guidance from a professional society on the treatment of skin and soft tissue infections was published in 2014 by the Infectious Diseases Society of America and is now two years old. New antimicrobial agents have been developed and approved for the treatment of skin and soft tissue infections since then, and more are in the pipeline. This review summarizes the evidence on treatments that are new or in development and the potential repurposing of old antimicrobials. The clinical utility of these treatments is also discussed. PMID- 27974336 TI - Medicine under fire. PMID- 27974337 TI - Competition watchdog finds new target: overpriced generics. PMID- 27974338 TI - Dispelling the nice or naughty myth: retrospective observational study of Santa Claus. AB - OBJECTIVE: To determine which factors influence whether Santa Claus will visit children in hospital on Christmas Day. DESIGN: Retrospective observational study. SETTING: Paediatric wards in England, Northern Ireland, Scotland, and Wales. PARTICIPANTS: 186 members of staff who worked on the paediatric wards (n=186) during Christmas 2015. MAIN OUTCOME MEASURES: Presence or absence of Santa Claus on the paediatric ward during Christmas 2015. This was correlated with rates of absenteeism from primary school, conviction rates in young people (aged 10-17 years), distance from hospital to North Pole (closest city or town to the hospital in kilometres, as the reindeer flies), and contextual socioeconomic deprivation (index of multiple deprivation). RESULTS: Santa Claus visited most of the paediatric wards in all four countries: 89% in England, 100% in Northern Ireland, 93% in Scotland, and 92% in Wales. The odds of him not visiting, however, were significantly higher for paediatric wards in areas of higher socioeconomic deprivation in England (odds ratio 1.31 (95% confidence interval 1.04 to 1.71) in England, 1.23 (1.00 to 1.54) in the UK). In contrast, there was no correlation with school absenteeism, conviction rates, or distance to the North Pole. CONCLUSION: The results of this study dispel the traditional belief that Santa Claus rewards children based on how nice or naughty they have been in the previous year. Santa Claus is less likely to visit children in hospitals in the most deprived areas. Potential solutions include a review of Santa's contract or employment of local Santas in poorly represented regions. PMID- 27974339 TI - After "the end of local government as we know it," what next for social care? PMID- 27974340 TI - End-of-life decisions for fragile neonates: navigating between opinion and evidence-based medicine. PMID- 27974341 TI - Vertical muscle transposition with silicone band belting in VI nerve palsy. AB - A woman aged 60 years developed a Millard-Gubler syndrome after a diagnosis of a cavernous angioma in the median and paramedian areas of the pons. In this context, she presented a right VI nerve palsy, right conjugate gaze palsy, facial palsy and left hemiparesis. To improve the complete VI nerve palsy, we planned a modified transposition approach, in which procedure we made a partial transposition of vertical rectus with a silicone band that was fixated posteriorly. After the procedure, the patient gained the ability to slightly abduct the right eye. We found no compensatory torticollis in the primary position of gaze. There was also an improvement of elevation and depression movements of the right eye. We obtained satisfactory results with a theoretically reversible technique, which is adjustable intraoperatively with no need of muscle detachment, preventing anterior segment ischaemia and allowing simultaneous recession of the medial rectus muscles, if necessary. PMID- 27974342 TI - Use of thromboelastography in the management of liver cirrhosis and accelerated intravascular coagulation and fibrinolysis (AICF). AB - In the presented case, the authors describe an obese middle-aged man that presented to the emergency department for persistent oedema, scleral icterus and fatigue. He was admitted to the hospital and diagnosed with liver cirrhosis via transjugular liver biopsy. He continued to bleed from the biopsy site for 5 days from accelerated intravascular coagulation and fibrinolysis (AICF) requiring multiple transfusions of packed red blood cells, fresh-frozen plasma and cryoprecipitate. The authors then used thromboelastography (TEG) to further characterise the patient's coagulopathy, which revealed platelet inhibition. The results of the TEG significantly changed future transfusion management. Finally, the authors conducted a literature review to summarise the current literature available for the use of TEG in the management of liver cirrhosis with AICF. PMID- 27974343 TI - Combined central retinal vein and branch retinal artery occlusion in hyperhomocysteinaemia. PMID- 27974344 TI - Iliopsoas abscess caused by chronic urolithiasis and pyelonephritis. PMID- 27974345 TI - Growth Differentiation Factor 15 as a Novel Biomarker for Metformin. AB - OBJECTIVE: Metformin is a commonly used glucose-lowering drug. However, apart from glycemic measures, no biomarker for its presence or dose has been identified. RESEARCH DESIGN AND METHODS: A total of 237 biomarkers were assayed in baseline serum from 8,401 participants (2,317 receiving metformin) in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. Regression models were used to identify biomarkers for metformin use. RESULTS: Growth differentiation factor 15 (GDF15) was strongly linked to metformin, such that the odds of metformin use per SD increase in level varied from 3.73 (95% CI 3.40, 4.09) to 3.94 (95% CI 3.59, 4.33) depending on the other included variables. For the remaining 25 linked biomarkers, the odds ranged from 0.71 to 1.24. A 1.64 ng/mL higher GDF15 level predicted a 188-mg higher metformin dose (P < 0.0001). CONCLUSIONS: GDF15 levels are a biomarker for the use of metformin in people with dysglycemia, and its concentration reflects the dose of metformin. PMID- 27974346 TI - Nominal ISOMERs (Incorrect Spellings Of Medicines Eluding Researchers)-variants in the spellings of drug names in PubMed: a database review. AB - OBJECTIVE: To examine how misspellings of drug names could impede searches for published literature. DESIGN: Database review. DATA SOURCE: PubMed. REVIEW METHODS: The study included 30 drug names that are commonly misspelt on prescription charts in hospitals in Birmingham, UK (test set), and 30 control names randomly chosen from a hospital formulary (control set). The following definitions were used: standard names-the international non-proprietary names, variant names-deviations in spelling from standard names that are not themselves standard names in English language nomenclature, and hidden reference variants variant spellings that identified publications in textword (tw) searches of PubMed or other databases, and which were not identified by textword searches for the standard names. Variant names were generated from standard names by applying letter substitutions, omissions, additions, transpositions, duplications, deduplications, and combinations of these. Searches were carried out in PubMed (30 June 2016) for "standard name[tw]" and "variant name[tw] NOT standard name[tw]." RESULTS: The 30 standard names of drugs in the test set gave 325 979 hits in total, and 160 hidden reference variants gave 3872 hits (1.17%). The standard names of the control set gave 470 064 hits, and 79 hidden reference variants gave 766 hits (0.16%). Letter substitutions (particularly i to y and vice versa) and omissions together accounted for 2924 (74%) of the variants. Amitriptyline (8530 hits) yielded 18 hidden reference variants (179 (2.1%) hits). Names ending in "in," "ine," or "micin" were commonly misspelt. Failing to search for hidden reference variants of "gentamicin," "amitriptyline," "mirtazapine," and "trazodone" would miss at least 19 systematic reviews. A hidden reference variant related to Christmas, "No-el", was rare; variants of "X-miss" were rarer. CONCLUSION: When performing searches, researchers should include misspellings of drug names among their search terms. PMID- 27974347 TI - Coronary revascularization in diabetic patients with chronic kidney disease. PMID- 27974348 TI - Thomas Dover: doctor, privateer, and rescuer of Robinson Crusoe. PMID- 27974349 TI - Prevention of depression and anxiety: is the whole better than the sum of the parts? PMID- 27974351 TI - Re: 'Two minds with but a single thought ...'. PMID- 27974352 TI - Reply to Stamm et al. PMID- 27974350 TI - Genetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates from Mendelian Randomization. AB - BACKGROUND: Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI. METHODS: We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: FTO genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance-weighted meta-analysis. RESULTS: In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (FTO: 0.43 [95% confidence interval, 0.32-0.54] kg/m2 per A-allele, P<0.001; BMI gene score: 1.05 [95% confidence interval, 0.90 1.20] kg/m2 per 1-U increase, P<0.001) and incident AF (FTO, hazard ratio, 1.07 [1.02-1.11] per A-allele, P=0.004; BMI gene score, hazard ratio, 1.11 [1.05-1.18] per 1-U increase, P<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04-1.26) per kg/m2, P=0.005 (FTO) and 1.11 (1.05-1.17) per kg/m2, P<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04-1.06] per kg/m2, P<0.001). Multivariable adjustment did not significantly change findings. CONCLUSIONS: Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF. PMID- 27974354 TI - We read spam a lot: prospective cohort study of unsolicited and unwanted academic invitations. AB - OBJECTIVES: To assess the amount, relevance, content, and suppressibility of academic electronic spam invitations to attend conferences or submit manuscripts. DESIGN: Prospective cohort study. SETTING: Email accounts of participating academics. PARTICIPANTS: Five intrepid academics and a great many publishers, editors, and conference organisers. INTERVENTION: Unsubscribing from sender's distribution lists. MAIN OUTCOME MEASURES: Number of spam invitations received before, immediately after, and one year after unsubscribing from senders' distribution lists. The proportion of duplicate invitations was also assessed and the relevance of each invitation graded to the recipient's research interests. A qualitative assessment of the content of spam invitations was conducted. RESULTS: At baseline, recipients received an average of 312 spam invitations each month. Unsubscribing reduced the frequency of the invitations by 39% after one month but by only 19% after one year. Overall, 16% of spam invitations were duplicates and 83% had little or no relevance to the recipients' research interests. Spam invitations were characterised by inventive language, flattery, and exuberance, and they were sometimes baffling and amusing. CONCLUSIONS: Academic spam is common, repetitive, often irrelevant, and difficult to avoid or prevent. PMID- 27974353 TI - VEGF blockade enhances the antitumor effect of BRAFV600E inhibition. AB - The development of resistance remains a major obstacle to long-term disease control in cancer patients treated with targeted therapies. In BRAF-mutant mouse models, we demonstrate that although targeted inhibition of either BRAF or VEGF initially suppresses the growth of BRAF-mutant tumors, combined inhibition of both pathways results in apoptosis, long-lasting tumor responses, reduction in lung colonization, and delayed onset of acquired resistance to the BRAF inhibitor PLX4720. As well as inducing tumor vascular normalization and ameliorating hypoxia, this approach induces remodeling of the extracellular matrix, infiltration of macrophages with an M1-like phenotype, and reduction in cancer associated fibroblasts. At the molecular level, this therapeutic regimen results in a de novo transcriptional signature, which sustains and explains the observed efficacy with regard to cancer progression. Collectively, our findings offer new biological rationales for the management of clinical resistance to BRAF inhibitors based on the combination between BRAFV600E inhibitors with anti angiogenic regimens. PMID- 27974355 TI - Determination of Morin in Maclura cochinchinensis Heartwood by HPLC. AB - The HPLC-DAD method was developed to determine morin content in Maclura cochinchinensis Corner heartwood extract. The chromatographic separation was performed using a Hypersil BDS C18 column, isocratic solvent system of 0.5% acetic acid in water:acetonitrile (80:20) with 1.0 mL/min flow rate and detected at 355 nm. The standard curve of morin was linear in the range of 7-905 MUg/mL. The method was precise with intra-day relative standard deviation (RSD) of lower than 1% and 2.06% for inter-day RSD. The method accuracy represented by percent recover was 99.58%. The highly efficient HPLC system developed from this study could detect morin contents in M. cochinchinensis heartwood samples collected from various locations in Thailand in the range of 0.74-1.57% w/w. This developed method provided a useful standardization procedure of M. cochincihinesis materials for further application in pharmacy and other commercial developments. PMID- 27974356 TI - Making three-dimensional echocardiography more tangible: a workflow for three dimensional printing with echocardiographic data. AB - Three-dimensional (3D) printing is a rapidly evolving technology with several potential applications in the diagnosis and management of cardiac disease. Recently, 3D printing (i.e. rapid prototyping) derived from 3D transesophageal echocardiography (TEE) has become possible. Due to the multiple steps involved and the specific equipment required for each step, it might be difficult to start implementing echocardiography-derived 3D printing in a clinical setting. In this review, we provide an overview of this process, including its logistics and organization of tools and materials, 3D TEE image acquisition strategies, data export, format conversion, segmentation, and printing. Generation of patient specific models of cardiac anatomy from echocardiographic data is a feasible, practical application of 3D printing technology. PMID- 27974357 TI - Tuberculosis (NICE clinical guideline 33). PMID- 27974358 TI - Metformin with insulin does not improve the glycaemic control of overweight/obese adolescents with type 1 diabetes. PMID- 27974359 TI - Safety and mid-term outcome of catheter ablation of ventricular tachycardia in octogenarians. AB - Aims: Radiofrequency (RF) catheter ablation (CA) is superior to standard medical therapy in controlling recurrent ventricular tachycardia (VT). The majority of procedures have been performed in a middle-aged population. The outcome of VT ablation in the elderly has not been described. Methods and results: We retrospectively studied the outcome and safety of CA of VT in octogenarians performed in four European centres. The population consisted of patients presenting with recurrent VT refractory to medical therapy. Patients aged over 80 years were compared with younger patients undergoing CA. Clinical characteristics, procedural data, complications, and outcomes were examined. Implantable cardioverter-defibrillator (ICD) therapy data were collected. A total of 54 consecutive octogenarian patients underwent RF CA of VT and represented the study group (42 males, age 82.8 +/- 2.7 years) compared with a control group of 104 younger patients (85 males, age 66.7 +/- 8.9 years). Mean follow-up was 33 +/ 48 months. Implantable cardioverter-defibrillators were present in 81 and 86% of patients, respectively (P = 0.93). Left ventricular ejection fraction was 29% +/- 8.2 in octogenarians vs. 34% +/- 10.2 in the younger group (P < 0.01). More major complications occurred in octogenarians (18 vs. 2%, P < 0.01). During follow-up, there were more ICD shocks in the octogenarians (28 vs. 15%, P < 0.01). The Kaplan-Meier curve of survival after VT ablation confirms comparable survival rates at 1 year, but the elderly have poor survival in the mid-term. Survival in the elderly post VT ablation is comparable with that in an age-matched cohort with ICDs but no VT storm. Conclusion: Octogenarians undergoing CA of VT have more risk factors, higher risk of complications and ICD shocks, but demonstrate comparable short-term survival rates. PMID- 27974360 TI - Two New Species of Simulium (Gomphostilbia) (Diptera: Simuliidae) From Flores, Indonesia. AB - Two new species, Simulium (Gomphostilbia) sunapii and S. (G.) rangatense, are described based on adults, pupae, and mature larvae from Flores, in the eastern part of the Sunda Archipelago, Indonesia. Simulium (G.) sunapii sp. nov. is placed in the S. asakoae species-group, representing the easternmost geographical record for the group in this archipelago. It is characterized by a small number of male upper-eye large facets in eight or nine vertical columns and 12 horizontal rows. Simulium (G.) rangatense sp. nov. is placed in the S. ceylonicum species-group and is characterized by the pupal gill with six filaments. This new species, together with two related species of the S. ceylonicum species-group in Flores, suggests the species radiation of this species-group might have been accompanied by a reduction of the number of pupal gill filaments from eight to four through six. Taxonomic notes are provided to distinguish these two new species from related species. PMID- 27974361 TI - One In Five Inpatient Emergency Department Cases May Lead To Surprise Bills. AB - A surprise medical bill is a bill from an out-of-network provider that was not expected by the patient or that came from an out-of-network provider not chosen by the patient. In 2014, 20 percent of hospital inpatient admissions that originated in the emergency department (ED), 14 percent of outpatient visits to the ED, and 9 percent of elective inpatient admissions likely led to a surprise medical bill. PMID- 27974363 TI - Stefan Jentsch (1955-2016)-Maestro of the ubiquitin family. PMID- 27974364 TI - A Christmas renaissance. PMID- 27974365 TI - NK cells require antigen-specific memory CD4+ T cells to mediate superior effector functions during HSV-2 recall responses in vitro. AB - Natural killer (NK) cells have an important role in mounting protective innate responses against genital herpes simplex virus type 2 (HSV-2) infections. However their role as effectors in adaptive immune responses against HSV-2 is unclear. Here, we demonstrate that NK cells from C57BL/6 mice in an ex vivo splenocyte culture produce significantly more interferon gamma (IFN-gamma) upon re-exposure to HSV-2 antigens in a mouse model of genital HSV-2 immunization. We find that naive NK cells do not require any prior stimulation or priming to be activated to produce IFN-gamma. Our results demonstrate that HSV-2-experienced CD4+ T cells have a crucial role in coordinating NK cell activation and that their presence during HSV-2 antigen presentation is required to activate NK cells in this model of secondary immune response. We also examined the requirement of cell-to-cell contacts for both CD4+ T cells and NK cells. NK cells are dependent on direct interactions with other HSV-2-experienced splenocytes, and CD4+ T cells need to be in close proximity to NK cells to activate them. This study revealed that NK cells do not exhibit any memory toward HSV-2 antigens and, in fact, require specific interactions with HSV-2-experienced CD4+ T cells to produce IFN-gamma. PMID- 27974362 TI - SHARPIN regulates collagen architecture and ductal outgrowth in the developing mouse mammary gland. AB - SHARPIN is a widely expressed multifunctional protein implicated in cancer, inflammation, linear ubiquitination and integrin activity inhibition; however, its contribution to epithelial homeostasis remains poorly understood. Here, we examined the role of SHARPIN in mammary gland development, a process strongly regulated by epithelial-stromal interactions. Mice lacking SHARPIN expression in all cells (Sharpincpdm), and mice with a stromal (S100a4-Cre) deletion of Sharpin, have reduced mammary ductal outgrowth during puberty. In contrast, Sharpincpdm mammary epithelial cells transplanted in vivo into wild-type stroma, fully repopulate the mammary gland fat pad, undergo unperturbed ductal outgrowth and terminal differentiation. Thus, SHARPIN is required in mammary gland stroma during development. Accordingly, stroma adjacent to invading mammary ducts of Sharpincpdm mice displayed reduced collagen arrangement and extracellular matrix (ECM) stiffness. Moreover, Sharpincpdm mammary gland stromal fibroblasts demonstrated defects in collagen fibre assembly, collagen contraction and degradation in vitro Together, these data imply that SHARPIN regulates the normal invasive mammary gland branching morphogenesis in an epithelial cell extrinsic manner by controlling the organisation of the stromal ECM. PMID- 27974366 TI - An optimized method for measuring fatty acids and cholesterol in stable isotope labeled cells. AB - Stable isotope labeling has become an important methodology for determining lipid metabolic parameters of normal and neoplastic cells. Conventional methods for fatty acid and cholesterol analysis have one or more issues that limit their utility for in vitro stable isotope-labeling studies. To address this, we developed a method optimized for measuring both fatty acids and cholesterol from small numbers of stable isotope-labeled cultured cells. We demonstrate quantitative derivatization and extraction of fatty acids from a wide range of lipid classes using this approach. Importantly, cholesterol is also recovered, albeit at a modestly lower yield, affording the opportunity to quantitate both cholesterol and fatty acids from the same sample. Although we find that background contamination can interfere with quantitation of certain fatty acids in low amounts of starting material, our data indicate that this optimized method can be used to accurately measure mass isotopomer distributions for cholesterol and many fatty acids isolated from small numbers of cultured cells. Application of this method will facilitate acquisition of lipid parameters required for quantifying flux and provide a better understanding of how lipid metabolism influences cellular function. PMID- 27974368 TI - Reinventing the community hospital: a retrospective population-based cohort study of a natural experiment using register data. AB - OBJECTIVES: To investigate whether implementation of municipal acute bed units (MAUs) resulting from the Norwegian Coordination Reform (2012) was associated with reductions in hospital admissions, particularly for the elderly. DESIGN: A municipality-based retrospective comparative cohort study using monthly population-based registry data analysed with fixed-effects log-log regressions. SETTING: Norwegian municipalities and hospitals. POPULATION: All patients admitted to secondary hospital care in Norway between 2010 and 2014, excluding psychiatric admissions, with additional focus on admission type and elderly age subgroups. MAIN OUTCOME MEASURES: Monthly admission rates in total and by age group for all patients, patients admitted with acute conditions and with acute conditions at internal medicine departments. RESULTS: The introduction of MAUs was associated with a small yet significant overall negative effect on hospital admissions. The reduction in all admissions was significant for the entire population (-1.2%, 95% CI -2.0% to -0.0%) and slightly stronger for those aged 80 years and above (-1.9%, 95% CI -3.0% to -1.0%). The more detailed analysis of the elderly population aged 80 years and above revealed that effects were affected by the institutional characteristics of the MAUs. The significant effects ranged between -1.6% and -8.6%, depending on the availability of physicians on duty at the MAUs, the MAUs location or combinations thereof. CONCLUSIONS: Introduction of MAUs following implementation of the Norwegian Coordination Reform in 2012 was associated with a significant reduction in hospital admissions primarily for the elderly. Our findings suggest that this type of intermediate care is a viable option in an effort to alleviate the burden on hospitals by reducing the acute secondary care admission volume. Further examinations focused on cost effectiveness, health status of patients, number of patients treated at the MAUs and comparing other intermediate care alternatives would all add important perspectives to the issue. PMID- 27974367 TI - Hand-related physical function in rheumatic hand conditions: a protocol for developing a patient-reported outcome measurement instrument. AB - INTRODUCTION: There is no consensus about what constitutes the most appropriate patient-reported outcome measurement (PROM) instrument for measuring physical function in patients with rheumatic hand conditions. Existing instruments lack psychometric testing and vary in feasibility and their psychometric qualities. We aim to develop a PROM instrument to assess hand-related physical function in rheumatic hand conditions. METHODS AND ANALYSIS: We will perform a systematic search to identify existing PROMs to rheumatic hand conditions, and select items relevant for hand-related physical function as well as those items from the Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) item bank that are relevant to patients with rheumatic hand conditions. Selection will be based on consensus among reviewers. Content validity of selected items will be established through the use of focus groups. If patients deem necessary, we will develop new items based on the patients' input. We will examine whether it is valid to score all selected and developed items on the same scale as the original items from the PROMIS PF item bank. Our analyses will follow the methods used for calibrating the original PROMIS PF item bank in US samples, which were largely based on the general PROMIS approach. ETHICS AND DISSEMINATION: This study will be carried out in accordance with the Helsinki Declaration. Ethics approvals will be obtained where necessary, and signed informed consent will be obtained from all participants. We aim to disseminate the results of the study through publication in international peer reviewed journals and at international conferences. PMID- 27974369 TI - Setting priorities for research in medical nutrition education: an international approach. AB - OBJECTIVES: To identify the research priorities for medical nutrition education worldwide. DESIGN: A 5-step stakeholder engagement process based on methodological guidelines for identifying research priorities in health. PARTICIPANTS: 277 individuals were identified as representatives for 30 different stakeholder organisations across 86 countries. The stakeholder organisations represented the views of medical educators, medical students, doctors, patients and researchers in medical education. INTERVENTIONS: Each stakeholder representative was asked to provide up to three research questions that should be deemed as a priority for medical nutrition education. MAIN OUTCOME MEASURES: Research questions were critically appraised for answerability, sustainability, effectiveness, potential for translation and potential to impact on disease burden. A blinded scoring system was used to rank the appraised questions, with higher scores indicating higher priority (range of scores possible 36-108). RESULTS: 37 submissions were received, of which 25 were unique research questions. Submitted questions received a range of scores from 62 to 106 points. The highest scoring questions focused on (1) increasing the confidence of medical students and doctors in providing nutrition care to patients, (2) clarifying the essential nutrition skills doctors should acquire, (3) understanding the effectiveness of doctors at influencing dietary behaviours and (4) improving medical students' attitudes towards the importance of nutrition. CONCLUSIONS: These research questions can be used to ensure future projects in medical nutrition education directly align with the needs and preferences of research stakeholders. Funders should consider these priorities in their commissioning of research. PMID- 27974370 TI - Should all anticoagulated patients with head injury receive a CT scan? Decision analysis modelling of an observational cohort. AB - OBJECTIVES: It is not currently clear whether all anticoagulated patients with a head injury should receive CT scanning or only those with evidence of traumatic brain injury (eg, loss of consciousness or amnesia). We aimed to determine the cost-effectiveness of CT for all compared with selective CT use for anticoagulated patients with a head injury. DESIGN: Decision-analysis modelling of data from a multicentre observational study. SETTING: 33 emergency departments in England and Scotland. PARTICIPANTS: 3566 adults (aged >=16 years) who had suffered blunt head injury, were taking warfarin and underwent selective CT scanning. MAIN OUTCOME MEASURES: Estimated expected benefits in terms of quality adjusted life years (QALYs) were the entire cohort to receive a CT scan; estimated increased costs of CT and also the potential cost implications associated with patient survival and improved health. These values were used to estimate the cost per QALY of implementing a strategy of CT for all patients compared with observed practice based on guidelines recommending selective CT use. RESULTS: Of the 1420 of 3534 patients (40%) who did not receive a CT scan, 7 (0.5%) suffered a potentially avoidable head injury-related adverse outcome. If CT scanning had been performed in all patients, appropriate treatment could have gained 3.41 additional QALYs but would have incurred L193 149 additional treatment costs and L130 683 additional CT costs. The incremental cost effectiveness ratio of L94 895/QALY gained for unselective compared with selective CT use is markedly above the threshold of L20-30 000/QALY used by the UK National Institute for Care Excellence to determine cost-effectiveness. CONCLUSIONS: CT scanning for all anticoagulated patients with head injury is not cost-effective compared with selective use of CT scanning based on guidelines recommending scanning only for those with evidence of traumatic brain injury. TRIAL REGISTRATION NUMBER: NCT 02461498. PMID- 27974371 TI - Patients' perceptions and experiences of the prevention of hospital-acquired thrombosis: a qualitative study. AB - OBJECTIVE: To examine patients' understanding of hospital-associated thrombosis, and their experiences of thromboprophylaxis. DESIGN: Qualitative study using semi structured interviews with 31 patients requiring venous thromboembolism (VTE) prophylaxis following a recent hospital admission. Interviews were audio recorded, transcribed verbatim and analysed thematically using framework analysis. SETTING: 4 hospitals in Birmingham and Oxford. RESULTS: All the participants received thromboprophylaxis following surgical procedures. Participants were aware of a risk of blood clots; however, they lacked a good understanding of VTE and its components. Experiences of VTE prophylaxis were characterised with good adherence to heparin injections and poor adherence to elastic compression stockings, largely due to perceived lack of clarity in guidance from health professionals. Participants had limited knowledge of the signs and symptoms of VTE and would value improved education on VTE. CONCLUSIONS: Findings suggest that patient education is often inadequate and impacts negatively on patients' involvement in VTE prevention. An enhanced patient education programme incorporating a consistent message on the appropriate use of elastic compression stockings and description of VTE symptoms is likely to optimise the effectiveness of the prevention of hospital-associated thrombosis. Physicians may use the results of this study to improve individual patient education. PMID- 27974374 TI - Correction. PMID- 27974372 TI - Non-communicable diseases in decontamination workers in areas affected by the Fukushima nuclear disaster: a retrospective observational study. AB - OBJECTIVES: To assess the prevalence of non-communicable diseases (NCDs), and whether NCDs were treated or not, among hospitalised decontamination workers who moved to radio-contaminated areas after Japan's 2011 Fukushima Daiichi Nuclear Power Plant disaster. METHODS: We retrospectively extracted records of decontamination workers admitted to Minamisoma Municipal General Hospital between 1 June 2012 and 31 August 2015, from hospital records. We investigated the incidence of underlying NCDs such as hypertension, dyslipidaemia and diabetes among the decontamination workers, and their treatment status, in addition to the reasons for their hospital admission. RESULTS: A total of 113 decontamination workers were admitted to the hospital (112 male patients, median age of 54 years (age range: 18-69 years)). In terms of the demographics of underlying NCDs in this population, 57 of 72 hypertensive patients (79.2%), 37 of 45 dyslipidaemic patients (82.2%) and 18 of 27 hyperglycaemic patients (66.7%) had not been treated for their NCDs before admission to the hospital. CONCLUSIONS: A high burden of underlying NCDs was found in hospitalised decontamination workers in Fukushima. Managing underlying diseases such as hypertension, hyperlipidaemia and diabetes mellitus is essential among this population. PMID- 27974376 TI - Navigating the Island of Reil: how to understand the insular cortex. AB - Insular-onset seizures are rare and easily misdiagnosed. In this article, we aim to highlight the often distinctive semiology of seizures involving the insula with reference to three cases. We suggest three points to aid the recognition of seizures involving the insula: (1) Seizures originating in the insula frequently present with a sensation of laryngeal constriction, dyspnoea or unpleasant somatosensory symptoms; (2) Seizures involving the anterior insula may have a silent onset, but tend to propagate rapidly to motor areas causing motor or hypermotor symptoms; (3) Seizures involving the posterior insula cause somatosensory symptoms, which are normally contralateral to the seizure onset. PMID- 27974375 TI - Catch Plus thrombectomy device in acute stroke: initial evaluation. AB - OBJECTIVE: To report our initial experience with the Catch Plus thrombectomy device (CPD) in patients with acute ischemic stroke (AIS). MATERIALS AND METHODS: We retrospectively evaluated the procedural variables as well as the clinical and angiographic outcomes of patients with acute occlusion of a major intracranial artery in the anterior circulation who were treated with CPD at our center. Baseline characteristics (gender, age, comorbidities, cardiovascular risk factors, National Institutes of Health Stroke Scale (NIHSS) score, and vessel occlusion sites) of these patients were recorded. Thrombolysis in Cerebral Infarction (TICI) score, incidence of symptomatic and asymptomatic bleeding, and 90 day modified Rankin Scale (mRS) scores were evaluated as indicators of outcome. RESULTS: 38 patients with a mean age of 67.5 years were treated with CPD. Mean time from symptom onset to procedure initiation was 226.7 min. Recanalization (TICI 2b-3) was achieved in 27 patients (71.1%). The median NIHSS score on admission was 20. Rates of symptomatic and asymptomatic intracerebral hemorrhage were 7.9% and 13.2%, respectively. The 90 day clinical follow-up data were available for 37 patients. The 90 day mortality rate was 18.9%, and the 90 day clinically acceptable functional outcome (mRS score <=2) rate was 43.2% (mRS score 0-3, 54.1%). Very distal thrombectomy involving the cortical arteries was performed on four patients without complications. CONCLUSIONS: Our initial experience suggests that mechanical thrombectomy with the CPD improves 90 day outcomes of patients with AIS by facilitating effective recanalization. PMID- 27974373 TI - Incidence and risk factors for type 2 diabetes mellitus in transitional Thailand: results from the Thai cohort study. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is increasingly prevalent in countries undergoing rapid development, including Thailand. We assessed T2DM incidence over an 8-year period in a nationwide cohort of Thai adults. METHODS: Thai Cohort Study participants were surveyed in 2005, 2009 and 2013. The analysed cohort members were aged (15-88), did not have diabetes in 2005 and were followed up by questionnaire in 2013 (n=39 507). T2DM was ascertained using self-report, which has been validated using physician interviews. We calculated the 8-year cumulative incidence of T2DM. Multivariable logistic regression assessed associations between potential risk factors and T2DM incidence. RESULTS: 8-year cumulative incidence of T2DM (2005 to 2013) was 177 per 10 000 (95% CI 164 to 190). Crude and age-standardised cumulative incidences of T2DM by sex were 249 per 10 000 (95% CI 226 to 272) and 222 per 10 000 (95% CI 219 to 225) for men; and 119 per 10 000 (95% CI 105 to 133) and 96 per 10 000 (95% CI 94 to 98) for women, respectively. T2DM increased significantly for both sexes with increasing age and body mass index (BMI) (p trend <0.001 for both). Residence in an urban area as a child associated with T2DM among men and women (OR=1.4, 95% CI 1.1 to 1.7 and OR=1.4, 95% CI 1.01 to 1.79); this was no longer statistically significant after adjusting for BMI. Among men, smoking (OR=1.7, 95% CI 1.3 to 2.2) and alcohol intake (OR=1.8, 95% CI 1.1 to 3.0) were associated with T2DM. CONCLUSIONS: This study found that the sociodemographic and lifestyle changes that have accompanied Thailand's economic development are associated with T2DM risk in a large cohort of Thai adults. Our findings highlight the need to address these transitions to prevent a further increase in the national incidence of T2DM, particularly among Thai men. PMID- 27974377 TI - Sleep apnoea and the neurologist. AB - There is increasing awareness and interest in the complex and extensive inter relationships between sleep disorders and neurological disorders. This review focuses on the clinical interactions between obstructive sleep apnoea and stroke, headaches, epilepsy, cognition and idiopathic Parkinson's disease. We highlight to the neurologist the importance of taking a sleep history and considering the diagnosis and treatment of obstructive sleep apnoea. PMID- 27974380 TI - Incorporation of Zolpidem into Hair and Its Distribution after a Single Administration. AB - To obtain fundamental information on the drug incorporation into hair, time course changes in drug distribution along single-strand hair were observed after a single oral administration of zolpidem (ZP), one of the most frequently used hypnotic agents. Quantitative sectional hair analyses of 1-mm segments were performed for each single-strand hair using a validated LC-MS/MS procedure. ZP was detected in all specimens plucked at 10 and 24 hours after a single dose, and the distribution ranged over the whole hair root (4-5 mm in length). A significantly high concentration of ZP was detected in the hair bulb region, whereas much lower concentrations were widely observed in the upper part of the hair root of those samples; this suggested that the incorporation of ZP occurred in two regions, mainly in the hair bulb and to a lesser extent in the upper dermis zone. The ZP-positive area formed lengths of up to 10-12 mm after a single administration, indicating that its incorporation from the hair bulb would continue for about 2 weeks. Time-course changes in the ZP concentration in the hair root additionally revealed that only a small portion of ZP that initially concentrated in the bulb was successively incorporated into the hair matrix and moved toward the keratinized region as hair grew. These findings should be taken into account upon discussing individual drug-use history based on hair analysis. The matrix-assisted laser desorption/ionization mass spectrometry imaging of ZP in the same kinds of hair specimens was also successfully achieved. PMID- 27974379 TI - A pseudouridine synthase module is essential for mitochondrial protein synthesis and cell viability. AB - Pseudouridylation is a common post-transcriptional modification in RNA, but its functional consequences at the cellular level remain largely unknown. Using a proximity-biotinylation assay, we identified a protein module in mitochondrial RNA granules, platforms for post-transcriptional RNA modification and ribosome assembly, containing several proteins of unknown function including three uncharacterized pseudouridine synthases, TRUB2, RPUSD3, and RPUSD4. TRUB2 and RPUSD4 were previously identified as core essential genes in CRISPR/Cas9 screens. Depletion of the individual enzymes produced specific mitochondrial protein synthesis and oxidative phosphorylation assembly defects without affecting mitochondrial mRNA levels. Investigation of the molecular targets in mitochondrial RNA by pseudouridine-Seq showed that RPUSD4 plays a role in the pseudouridylation of a single residue in the 16S rRNA, a modification that is essential for its stability and assembly into the mitochondrial ribosome, while TRUB2/RPUSD3 were similarly involved in pseudouridylating specific residues in mitochondrial mRNAs. These results establish essential roles for epitranscriptomic modification of mitochondrial RNA in mitochondrial protein synthesis, oxidative phosphorylation, and cell survival. PMID- 27974381 TI - Difference in Mechanism-Based Inhibition of Cytochrome P450 3A4 and 3A5 by a Series of Fluoroquinolone Antibacterial Agents. AB - A series of fluoroquinolone antibacterial compounds were found to be irreversible (compounds 1-5) and quasi-irreversible (compounds 6-9) inhibitors of CYP3A4. The purpose of this study was to evaluate their mechanism-based inhibition (MBI) potency against CYP3A5. Compounds 1-5 were also irreversible inhibitors of CYP3A5, whereas compounds 6-9 showed neither irreversible nor quasi-irreversible inhibition of CYP3A5. Compounds 6 and 8 did not form a metabolite-intermediate complex with the heme of CYP3A5 during incubation. The structural analysis of the metabolites after incubation of compounds 1 and 6 with CYP3A5 revealed that their metabolites were identical to those produced by CYP3A4, including the precursors of which are speculated to account for the MBI of CYP3A4. The homology modeling of CYP3A5 suggests that four residues around the nitroso intermediate of compound 6 in the substrate-binding pocket of CYP3A4 correspond with the bulkier residues in CYP3A5-especially Phe210 in CYP3A5-which might contribute to the steric hindrance with the nitroso intermediate of compound 6. The substrate-binding pocket structure of CYP3A5 might prevent the nitroso intermediate from coordinate binding with the heme, thereby preventing quasi-irreversible inhibition. Our study may provide new insights into the observable differences between the inhibition of CYP3A4 and CYP3A5. PMID- 27974378 TI - Architecture of the yeast Elongator complex. AB - The highly conserved eukaryotic Elongator complex performs specific chemical modifications on wobble base uridines of tRNAs, which are essential for proteome stability and homeostasis. The complex is formed by six individual subunits (Elp1 6) that are all equally important for its tRNA modification activity. However, its overall architecture and the detailed reaction mechanism remain elusive. Here, we report the structures of the fully assembled yeast Elongator and the Elp123 sub-complex solved by an integrative structure determination approach showing that two copies of the Elp1, Elp2, and Elp3 subunits form a two-lobed scaffold, which binds Elp456 asymmetrically. Our topological models are consistent with previous studies on individual subunits and further validated by complementary biochemical analyses. Our study provides a structural framework on how the tRNA modification activity is carried out by Elongator. PMID- 27974382 TI - Functional Characterization of 34 CYP2A6 Allelic Variants by Assessment of Nicotine C-Oxidation and Coumarin 7-Hydroxylation Activities. AB - CYP2A6, a member of the cytochrome P450 (P450) family, is one of the enzymes responsible for the metabolism of therapeutic drugs and such tobacco components as nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and N nitrosodiethylamine. Genetic polymorphisms in CYP2A6 are associated with individual variation in smoking behavior, drug toxicities, and the risk of developing several cancers. In this study, we conducted an in vitro analysis of 34 allelic variants of CYP2A6 using nicotine and coumarin as representative CYP2A6 substrates. These variant CYP2A6 proteins were heterologously expressed in 293FT cells, and their enzymatic activities were assessed on the basis of nicotine C-oxidation and coumarin 7-hydroxylation activities. Among the 34 CYP2A6 variants, CYP2A6.2, CYP2A6.5, CYP2A6.6, CYP2A6.10, CYP2A6.26, CYP2A6.36, and CYP2A6.37 exhibited no enzymatic activity, whereas 14 other variants exhibited markedly reduced activity toward both nicotine and coumarin. These comprehensive in vitro findings may provide useful insight into individual differences in smoking behavior, drug efficacy, and cancer susceptibility. PMID- 27974383 TI - High-Sensitivity Troponin T vs I in Acute Coronary Syndrome: Prediction of Significant Coronary Lesions and Long-term Prognosis. AB - BACKGROUND: High-sensitivity cardiac troponin (hs-cTn) T and I assays are established as crucial tools for the diagnosis of acute myocardial infarction (AMI), as they have been found superior to old troponin assays. However, eventual differences between the assays in prediction of significant coronary lesions and long-term prognosis in patients with acute coronary syndrome (ACS) have not been fully unraveled. METHODS: Serum concentrations of hs-cTnT (Roche), hs-cTnI (Abbott), and amino-terminal pro-B-type natriuretic peptide (NT-proBNP; Roche) in 390 non-ST-elevation (NSTE) ACS patients were evaluated in relation to significant coronary lesions on coronary angiography (defined as a stenosis >50% of the luminal diameter, with need for revascularization) and prognostic accuracy for cardiovascular mortality, all-cause mortality, as well as the composite end point of cardiovascular mortality and hospitalizations for AMI or heart failure. RESULTS: The mean (SD) follow-up was 2921 (168) days. Absolute hs-cTnI concentrations were significantly higher than the hs-cTnT concentrations. The relationship between analyzed biomarkers and significant coronary lesions on coronary angiography, as quantified by the area under the ROC curve (AUC), revealed no difference between hs-cTnT [AUC, 0.81; 95% CI, 0.77-0.86] and hs-cTnI (AUC, 0.81; 95% CI, 0.76-0.86; P = NS). NT-proBNP was superior to both hs-cTn assays regarding prognostic accuracy for both cardiovascular and all-cause mortality and for the composite end point during follow-up, also in multivariate analyses. CONCLUSIONS: The hs-cTnT and hs-cTnI assays displayed a similar ability to predict significant coronary lesions in NSTE-ACS patients. NT-proBNP was superior to both hs-cTn assays as a marker of long-term prognosis in this patient group. PMID- 27974384 TI - BRCA Testing by Single-Molecule Molecular Inversion Probes. AB - BACKGROUND: Despite advances in next generation DNA sequencing (NGS), NGS-based single gene tests for diagnostic purposes require improvements in terms of completeness, quality, speed, and cost. Single-molecule molecular inversion probes (smMIPs) are a technology with unrealized potential in the area of clinical genetic testing. In this proof-of-concept study, we selected 2 frequently requested gene tests, those for the breast cancer genes BRCA1 and BRCA2, and developed an automated work flow based on smMIPs. METHODS: The BRCA1 and BRCA2 smMIPs were validated using 166 human genomic DNA samples with known variant status. A generic automated work flow was built to perform smMIP-based enrichment and sequencing for BRCA1, BRCA2, and the checkpoint kinase 2 (CHEK2) c.1100del variant. RESULTS: Pathogenic and benign variants were analyzed in a subset of 152 previously BRCA-genotyped samples, yielding an analytical sensitivity and specificity of 100%. Following automation, blind analysis of 65 in-house samples and 267 Norwegian samples correctly identified all true-positive variants (>3000), with no false positives. Consequent to process optimization, turnaround times were reduced by 60% to currently 10-15 days. Copy number variants were detected with an analytical sensitivity of 100% and an analytical specificity of 88%. CONCLUSIONS: smMIP-based genetic testing enables automated and reliable analysis of the coding sequences of BRCA1 and BRCA2. The use of single-molecule tags, double-tiled targeted enrichment, and capturing and sequencing in duplo, in combination with automated library preparation and data analysis, results in a robust process and reduces routine turnaround times. Furthermore, smMIP-based copy number variation analysis could make independent copy number variation tools like multiplex ligation-dependent probes amplification dispensable. PMID- 27974385 TI - Simulation Models of Misclassification Error for Single Thresholds of High Sensitivity Cardiac Troponin I Due to Assay Bias and Imprecision. AB - BACKGROUND: Clinical outcome studies for cardiac troponins (cTn) are expensive and difficult to design owing to variation in patients, in the assays, and in the incidence of different types of myocardial infarction (MI). To overcome these difficulties, simulation models were used to estimate the rate of misclassification error for MI and risk prediction resulting from assay bias and imprecision. METHODS: Finite mixture analysis of Abbott high-sensitivity cTnI (hs cTnI) results at time 0 h in patients presenting early with acute coronary syndrome (ACS) symptoms to the emergency department (ED) [n = 145, Reducing the Time Interval for Identifying New Guideline (RING) study] allowed derivation of a simulation data set (n = 10000). hs-cTnI concentrations were modified by addition of bias or imprecision error. The percentage of all 10000 modified hs-cTnI results that were misclassified for MI at thresholds of 2, 5, 26.2, and 52 ng/L was determined by Monte Carlo simulation. Analyses were replicated with an all comer emergency department (ED) population (n = 1137) ROMI (Optimum Troponin Cutoffs for ACS in the ED) study. RESULTS: In the RING study, simulation at 26.2 ng/L (99th percentile) and 52-ng/L thresholds were affected by both bias +/-2 ng/L and imprecision (10%-20%) and had misclassification rates of 0.4% to 0.6%. Simulations at the 2-ng/L and 5-ng/L thresholds were only affected by bias. Misclassification rates at bias of +/-1 ng/L were 10% for the 2-ng/L threshold, and 5% for the 5-ng/L threshold. CONCLUSIONS: Simulation models predicted that hs cTnI results are seldom misclassified (<1% of patients) when interpretative thresholds are near or exceed the overall 99th percentile. However, simulation models also predicted that low hs-cTnI results, as recommended in guidelines, are prone to misclassification of 5%-10% of patients. PMID- 27974386 TI - Combined Count- and Size-Based Analysis of Maternal Plasma DNA for Noninvasive Prenatal Detection of Fetal Subchromosomal Aberrations Facilitates Elucidation of the Fetal and/or Maternal Origin of the Aberrations. AB - BACKGROUND: Noninvasive prenatal detection of fetal subchromosomal copy number aberrations (CNAs) can be achieved through massively parallel sequencing of maternal plasma DNA. However, when a mother herself is a carrier of a CNA, one cannot discern if her fetus has inherited the CNA. In addition, false-positive results would become more prevalent when more subchromosomal regions are analyzed. METHODS: We used a strategy that combined count- and size-based analyses of maternal plasma DNA for the detection of fetal subchromosomal CNAs in 7 target regions for 10 test cases. RESULTS: For the 5 cases in which CNAs were present only in the fetus, the size-based approach confirmed the aberrations detected by the count-based approach. For the 5 cases in which the mother herself carried an aberration, we successfully deduced that 3 of the fetuses had inherited the aberrations and that the other 2 fetuses had not inherited the aberrations. No false positives were observed in this cohort. CONCLUSIONS: Combined count- and size-based analysis of maternal plasma DNA permits the noninvasive elucidation of whether a fetus has inherited a CNA from its mother who herself is a carrier of the CNA. This strategy has the potential to improve the diagnostic specificity of noninvasive prenatal testing. PMID- 27974387 TI - Decrease of Serum IGF-I following Transsphenoidal Pituitary Surgery for Acromegaly. AB - BACKGROUND: In the immediate postoperative period following resection of growth hormone (GH)-secreting pituitary tumors, serum concentrations of GH have limited ability to predict remission of acromegaly. Since many actions of GH actions are mediated by insulin-like growth factor-1 (IGF-I), we aimed to determine the rates of fall of IGF-I during 72 h after surgical resection of pituitary tumors. METHODS: We studied patients who were undergoing pituitary surgery for acromegaly. IGF-I was measured by LC-MS and GH by immunoassay. Remission was defined by the combination of serum GH <0.4 ng/mL during oral glucose tolerance testing performed 8 weeks after the surgical procedure and normal IGF-I at >=8 weeks. RESULTS: During the first 72 h after surgery, the mean (SD) rate of decline of IGF-I was 185 (61) ng/mL per 24 h in those who achieved remission (n = 23), with a mean (SD) apparent half-life of 55 (19) h. IGF-I had decreased to <65% of the preoperative IGF-I on postoperative day 2 in 20 of 23 remission patients (87%) vs none of 5 patients who did not achieve remission. GH was <2.7 ng/mL on day 2 in 21 of 23 remission patients (91%), but in none of the nonremission patients. The combination of IGF-I and GH on day 2 separated the remission and nonremission groups of patients. CONCLUSIONS: Rapid decline of serum IGF-I during the immediate postoperative period warrants further study as an analytically independent adjunct to GH measurement for early prediction of biochemical remission of acromegaly. PMID- 27974388 TI - Monitoring Glycemic Control in End-Stage Renal Disease: What Should Be Measured? PMID- 27974390 TI - Subinhibitory concentrations of punicalagin reduces expression of virulence related exoproteins by Staphylococcus aureus. AB - Staphylococcus aureus produces a number of virulence factors. The major virulence factors exhibited by S aureus include various antigens, enzymes, cytotoxins and exotoxins (e.g. hemolysins, enterotoxins and toxic shock syndrome toxin). In this report, we show the influence of punicalagin on the secretion of exoprotein from S aureus by western blotting, tumor necrosis factor (TNF) release assay and quantitative RT-PCR. When added to S aureus cultures at an OD600 of 0.9, graded subinhibitory concentrations of punicalagin reduced the production of alpha toxin, SEA and SEB in methicillin-resistant Staphylococcus aureus in a dose dependent manner. Consistently, punicalagin reduced TNF-inducing activity by S aureus culture supernatants. Here, the transcriptional level of agr (accessory gene regulator) in S aureus was inhibited by punicalagin, suggesting that the reduced transcription may affect the secretion of exotoxins. These findings suggest that the expression of alpha-toxin and enterotoxins in S aureus is sensitive to the action of punicalagin, which may be an advantageous candidate in the treatment of toxigenic staphylococcal disease. PMID- 27974391 TI - Quantifying in situ growth rate of a filamentous bacterial species in activated sludge using rRNA:rDNA ratio. AB - If the in situ growth rate of filamentous bacteria in activated sludge can be quantified, researchers can more accurately assess the effect of operating conditions on the growth of filaments and improve the mathematical modeling of filamentous bulking. We developed a method to quantify the in situ specific growth rate of Sphaerotilus natans (a model filament) in activated sludge using the species-specific 16S rRNA:rDNA ratio. Primers targeting the 16S rRNA of S. natans were designed, and real-time PCR and RT-PCR were used to quantify DNA and RNA levels of S. natans, respectively. A positive linear relationship was found between the rRNA:rDNA ratio (from 440 to 4500) and the specific growth rate of S. natans (from 0.036 to 0.172 h-1) using chemostat experiments. The in situ growth rates of S. natans in activated sludge samples from three water reclamation facilities were quantified, illustrating how the approach can be applied in a complex environment such as activated sludge. PMID- 27974389 TI - Structure and lipid-binding properties of the kindlin-3 pleckstrin homology domain. AB - Kindlins co-activate integrins alongside talin. They possess, like talin, a FERM domain (4.1-erythrin-radixin-moiesin domain) comprising F0-F3 subdomains, but with a pleckstrin homology (PH) domain inserted in the F2 subdomain that enables membrane association. We present the crystal structure of murine kindlin-3 PH domain determined at a resolution of 2.23 A and characterise its lipid binding using biophysical and computational approaches. Molecular dynamics simulations suggest flexibility in the PH domain loops connecting beta-strands forming the putative phosphatidylinositol phosphate (PtdInsP)-binding site. Simulations with PtdInsP-containing bilayers reveal that the PH domain associates with PtdInsP molecules mainly via the positively charged surface presented by the beta1-beta2 loop and that it binds with somewhat higher affinity to PtdIns(3,4,5)P3 compared with PtdIns(4,5)P2 Surface plasmon resonance (SPR) with lipid headgroups immobilised and the PH domain as an analyte indicate affinities of 300 uM for PtdIns(3,4,5)P3 and 1 mM for PtdIns(4,5)P2 In contrast, SPR studies with an immobilised PH domain and lipid nanodiscs as the analyte show affinities of 0.40 uM for PtdIns(3,4,5)P3 and no affinity for PtdIns(4,5)P2 when the inositol phosphate constitutes 5% of the total lipids (~5 molecules per nanodisc). Reducing the PtdIns(3,4,5)P3 composition to 1% abolishes nanodisc binding to the PH domain, as does site-directed mutagenesis of two lysines within the beta1 beta2 loop. Binding of PtdIns(3,4,5)P3 by a canonical PH domain, Grp1, is not similarly influenced by SPR experimental design. These data suggest a role for PtdIns(3,4,5)P3 clustering in the binding of some PH domains and not others, highlighting the importance of lipid mobility and clustering for the biophysical assessment of protein-membrane interactions. PMID- 27974392 TI - Phage therapy targeting Escherichia coli-a story with no end? AB - Bacteriophages (phages) or bacterial viruses have long been proposed as an alternative therapy against antibiotic-resistant bacteria such as Escherichia coli Even though poorly documented in the scientific literature, a long clinical history of phage therapy in countries such as Russia and Georgia suggests potential value in the use of phages as antibacterial agents. Escherichia coli is responsible for a wide range of diseases, intestinal (diarrhoea) and extraintestinal (UTI, septicaemia, pneumoniae, meningitis), making it an ideal target for phage therapy. This review discusses the latest research focusing on the potential of phage therapy to tackle E. coli-related illnesses. No intact phages are approved in EU or USA for human therapeutic use, but many successful in vitro and in vivo studies have been reported. However, additional research focused on in vivo multispecies models and human trials are required if phage therapy targeting E. coli pathotypes can be a story with happy end. PMID- 27974393 TI - Temperature-regulated expression of type VI secretion systems in fish pathogen Pseudomonas plecoglossicida revealed by comparative secretome analysis. AB - Pseudomonas plecoglossicida is a facultative fish pathogen. Recent studies showed that P. plecoglossicida infection in fish was associated with temperature. The aim of this study was to compare the secretomes of P. plecoglossicida cultured in vitro at representative temperatures for pathogenic (20 degrees C) and less pathogenic (30 degrees C) phenotypes. Thirteen proteins in the culture supernatants of P. plecoglossicida showed significant difference in abundance at 20 vs. 30 degrees C. Four proteins were strongly increased at 20 degrees C, including two hemolysin co-regulated proteins (Hcp) that are part of the bacterial type VI secretion system (T6SS), flagellin and an unknown protein. Immunoblot analysis verified the induced secretion of Hcps at 20 degrees C. Furthermore, the upregulation of Hcps at 20 degrees C was confirmed at transcriptional level by RT-qPCR analysis, which also demonstrated the induction of expression of other T6SS-related genes at 20 degrees C. Taken together, we demonstrate the presence of two functionally active T6SS proteins in fish pathogenic P. plecoglossicida strains, as evidenced by the secretion of the T6SS substrate Hcp, the production of which were found to be controlled by temperature. Our findings also support efforts to develop vaccines targeting secreted virulence factors as prophylactic strategies for diseases in fish caused by P. plecoglossicida. PMID- 27974394 TI - rTMS affects working memory performance, brain activation and functional connectivity in patients with multiple sclerosis. AB - OBJECTIVE: To investigate the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) on working memory performance, while measuring task-related brain activation and task-related brain connectivity in patients with multiple sclerosis (MS). METHODS: 17 patients with MS and 11 healthy controls (HCs) underwent 3 experimental sessions (baseline, real-rTMS, sham-rTMS), all including an N-back task (3 task loads: N1, N2, N3; control condition: N0) inside the MR scanner. Prior to imaging, real-rTMS (10 Hz) was applied to the right DLPFC. The stimulation site was defined based on individually assessed N-back task activation at baseline and located using neuronavigation. Changes in whole brain functional activation and functional connectivity with the right DLPFC were calculated. RESULTS: N-back task accuracy (N2 and N3) improved after real-rTMS (and not after sham-rTMS) compared with baseline (p=0.029 and p=0.015, respectively), only in patients. At baseline, patients with MS, compared with HCs, showed higher task-related frontal activation (left DLPFC, N2>N0), which disappeared after real-rTMS. Task-related (N1>N0) functional connectivity between the right DLPFC and the right caudate nucleus and bilateral (para)cingulate gyrus increased in patients after real-rTMS when compared with sham stimulation. CONCLUSIONS: In patients with MS, N-back accuracy improved while frontal hyperactivation (seen at baseline relative to HCs) disappeared after real-rTMS. Together with the changes in functional connectivity after real-rTMS in patients, these findings may represent an rTMS-induced change in network efficiency in patients with MS, shifting patients' brain function towards the healthy situation. This implicates a potentially relevant role for rTMS in cognitive rehabilitation in MS. PMID- 27974395 TI - Lamins and metabolism. AB - Lamins are nuclear intermediate filaments (IFs) with important roles in most nuclear activities, including nuclear organization and cell-cycle progression. Mutations in human lamins cause over 17 different diseases, termed laminopathies. Most of these diseases are autosomal dominant and can be roughly divided into four major groups: muscle diseases, peripheral neuronal diseases, accelerated aging disorders and metabolic diseases including Dunnigan type familial partial lipodystrophy (FLPD), acquired partial lipodystrophy (APL) and autosomal dominant leucodystrophy. Mutations in lamins are also associated with the metabolic syndrome (MS). Cells derived from patients suffering from metabolic laminopathies, as well as cells derived from the corresponding animal models, show a disruption of the mechanistic target of rapamycin (mTOR) pathway, abnormal autophagy, altered proliferative rate and down-regulation of genes that regulate adipogenesis. In addition, treating Hutchinson-Gilford progeria syndrome (HGPS) cells with the mTOR inhibitor rapamycin improves their fate. In this review, we will discuss the ways by which lamin genes are involved in the regulation of cell metabolism. PMID- 27974396 TI - An emerging epidemic: cancer and heart failure. AB - Heart disease and cancer are the two leading causes of mortality globally. Cardiovascular complications of cancer therapy significantly contribute to the global burden of cardiovascular disease. Heart failure (HF) in particular is a relatively common and life-threatening complication. The increased risk is driven by the shared risk factors for cancer and HF, the direct impact of cancer therapy on the heart, an existing care gap in the cardiac care of patients with cancer and the increasing population of adult cancer survivors. The clear relationship between cancer treatment initiation and the potential for myocardial injury makes this population attractive for prevention strategies, targeted cardiovascular monitoring and treatment. However, there is currently no consensus on the optimal strategy for managing this at-risk population. Uniform treatment using cardioprotective medications may reduce the incidence of HF, but would impose frequently unnecessary and burdensome side effects. Ideally we could use validated risk-prediction models to target HF-preventive strategies, but currently no such models exist. In the present review, we focus on evidence and rationales for contemporary clinical decision-making in this novel field and discuss issues, including the burden of HF in patients with cancer, the reasons for the elevated risk and potential prevention strategies. PMID- 27974397 TI - Assignment of Opsonic Values to Pneumococcal Reference Serum 007sp for Use in Opsonophagocytic Assays for 13 Serotypes. AB - Opsonophagocytic assays (OPAs) are routinely used for assessing the immunogenicity of pneumococcal vaccines, with OPA data often being utilized for licensure of new vaccine formulations. However, no reference serum for pneumococcal OPAs is available, making evaluation of data among different laboratories difficult. This international collaboration was initiated to (i) assign consensus opsonic indexes (OIs) to FDA pneumococcal reference serum lot 007sp (here referred to as 007sp) and a panel of serum samples used for calibration of the OPA and (ii) determine if the normalization of the OPA results obtained with test samples to those obtained with 007sp decreases the variability in OPA results among laboratories. To meet these goals, six participating laboratories tested a panel of serum samples in five runs for 13 serotypes. For each serum sample, consensus OIs were obtained using a mixed-effects analysis of variance model. For the calibration serum samples, normalized consensus values were also determined on the basis of the results obtained with 007sp. For each serotype, the overall reduction in interlaboratory variability was calculated by comparing the coefficients of variation of the unadjusted and the normalized values. Normalization of the results substantially reduced the interlaboratory variability, ranging from a 15% reduction in variability for serotype 9V to a 64% reduction for serotype 7F. Normalization also increased the proportion of data within 2-fold of the consensus value from approximately 70% (average for all serotypes) to >90%. On the basis of the data obtained in this study, pneumococcal reference standard lot 007sp will likely be a useful reagent for the normalization of pneumococcal OPA results from different laboratories. The data also support the use of the 16 FDA serum samples used for calibration of the OPA as part of the initial evaluation of new assays or periodic assessment of established assays. PMID- 27974400 TI - Persistent long-term urinary incontinence post parturition. PMID- 27974399 TI - Serological Analysis of Tuberculosis in Goats by Use of the Enferplex Caprine TB Multiplex Test. AB - Tuberculosis in goats is usually diagnosed clinically, at postmortem, or by a positive skin test. However, none of these approaches detects all infected animals. Serology offers an additional tool to identify infected animals missed by current tests. We describe the use of the Enferplex Caprine TB serology test to aid the management of a large dairy goat herd undergoing a tuberculosis breakdown. Initial skin and serology testing showed that IgG antibodies were present in both serum and milk from 100% of skin test-positive animals and in serum and milk from 77.8 and 95.4% of skin test-negative animals, respectively. A good correlation was observed between serum and milk antibody levels. The herd had been vaccinated against Mycobacterium avium subsp. paratuberculosis, but no direct serological cross-reactions were found. Subsequent skin testing revealed 13.7% positive animals, 64.9% of which were antibody positive, while 42.1% of skin test-negative animals were seropositive. Antibody responses remained high 1 month later (57.1% positive), and the herd was slaughtered. Postmortem analysis of 20 skin test-negative goats revealed visible lesions in 6 animals, all of which had antibodies to six Mycobacterium bovis antigens. The results provide indirect evidence that serology testing with serum or milk could be a useful tool in the diagnosis and management of tuberculosis in goats. PMID- 27974398 TI - Safety and Immunogenicity of the Recombinant Mycobacterium bovis BCG Vaccine VPM1002 in HIV-Unexposed Newborn Infants in South Africa. AB - Tuberculosis is a global threat to which infants are especially vulnerable. Effective vaccines are required to protect infants from this devastating disease. VPM1002, a novel recombinant Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccine previously shown to be safe and immunogenic in adults, was evaluated for safety in its intended target population, namely, newborn infants in a region with high prevalence of tuberculosis. A total of 48 newborns were vaccinated intradermally with VPM1002 (n = 36) or BCG Danish strain (n = 12) in a phase II open-labeled, randomized trial with a 6-month follow-up period. Clinical and laboratory measures of safety were evaluated during this time. In addition, vaccine-induced immune responses to mycobacteria were analyzed in whole-blood stimulation and proliferation assays. The safety parameters and immunogenicity were comparable in the two groups. Both vaccines induced interleukin-17 (IL-17) responses; however, VPM1002 vaccination led to an increase of CD8+ IL-17+ T cells at the week 16 and month 6 time points. The incidence of abscess formation was lower for VPM1002 than for BCG. We conclude that VPM1002 is a safe, well tolerated, and immunogenic vaccine in newborn infants, confirming results from previous trials in adults. These results strongly support further evaluation of the safety and efficacy of this vaccination in larger studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01479972.). PMID- 27974401 TI - Newer drugs to treat prostate symptoms are associated with increased risk of falls. PMID- 27974402 TI - Link between length of hospital stay and mortality among hip fracture patients varies across healthcare systems. PMID- 27974403 TI - Physical activity can successfully be promoted to older adults within a primary care setting by trained nurses. PMID- 27974404 TI - High proportion of elderly patients who are admitted to hospital are entering the last year of their lives. PMID- 27974405 TI - Have you seen the Evidence-Based Nursing blog? Evidence-Based Nursing blogs: highlighting contemporary issues in nursing. PMID- 27974406 TI - Thrombotic Microangiopathy in Inverted Formin 2-Mediated Renal Disease. AB - The demonstration of impaired C regulation in the thrombotic microangiopathy (TMA) atypical hemolytic uremic syndrome (aHUS) resulted in the successful introduction of the C inhibitor eculizumab into clinical practice. C abnormalities account for approximately 50% of aHUS cases; however, mutations in the non-C gene diacylglycerol kinase-epsilon have been described recently in individuals not responsive to eculizumab. We report here a family in which the proposita presented with aHUS but did not respond to eculizumab. Her mother had previously presented with a post-renal transplant TMA. Both the proposita and her mother also had Charcot-Marie-Tooth disease. Using whole-exome sequencing, we identified a mutation in the inverted formin 2 gene (INF2) in the mutational hotspot for FSGS. Subsequent analysis of the Newcastle aHUS cohort identified another family with a functionally-significant mutation in INF2 In this family, renal transplantation was associated with post-transplant TMA. All individuals with INF2 mutations presenting with a TMA also had aHUS risk haplotypes, potentially accounting for the genetic pleiotropy. Identifying individuals with TMAs who may not respond to eculizumab will avoid prolonged exposure of such individuals to the infectious complications of terminal pathway C blockade. PMID- 27974407 TI - State-of-the-Art Review of Echocardiographic Imaging in the Evaluation and Treatment of Functional Tricuspid Regurgitation. AB - Functional or secondary tricuspid regurgitation (TR) is the most common cause of severe TR in the Western world. The presence of functional TR, either isolated or in combination with left heart disease, is associated with unfavorable natural history. Surgical mortality for isolated tricuspid valve interventions remains higher than for any other single valve surgery, and surgical options for repair do not have consistent long-term durability. In addition, as more patients undergo transcatheter left valve interventions, developing transcatheter solutions for functional TR has gained greater momentum. Numerous transcatheter devices are currently in early clinical trials. All patients require an assessment of valve morphology and function, and transcatheter devices typically require intraprocedural guidance by echocardiography. The following review will describe tricuspid anatomy, define echocardiographic views for evaluating tricuspid valve morphology and function, and discuss imaging requirements for the current transcatheter devices under development for the treatment of functional TR. PMID- 27974408 TI - Interstitial Fibrosis, Functional Status, and Outcomes in Heart Failure With Preserved Ejection Fraction: Insights From a Prospective Cardiac Magnetic Resonance Imaging Study. AB - BACKGROUND: Myocardial extracellular volume (ECV) accumulation is one of the key pathophysiologic features of heart failure with preserved ejection fraction (HFpEF). Our aims were to (1) measure ECV by cardiac magnetic resonance T1 mapping using the modified Look-Locker inversion recovery (MOLLI) sequence, (2) validate MOLLI-ECV against histology, and (3) investigate the relationship between MOLLI-ECV and prognosis in HFpEF. METHODS AND RESULTS: One-hundred seventeen consecutive HFpEF patients underwent cardiac magnetic resonance imaging, coronary angiography, and invasive hemodynamic assessments at baseline. Eighteen patients also underwent left ventricular biopsy for histological analysis (Histo-ECV). To assess the prognostic impact of MOLLI-ECV, its association with hospitalization for heart failure/cardiac death was tested by multivariable Cox regression analysis. Histo-ECV was 30.1+/-4.6% and was significantly correlated with MOLLI-ECV (R=0.494, P=0.037). Patients were followed for 24.0 months (6.0-32.0 months), during which 34 had a cardiac event. By Kaplan-Meier analysis, patients with MOLLI-ECV >= the median (28.9%) had shorter event-free survival (log-rank, P=0.028). MOLLI-ECV significantly correlated with N-terminal prohormone of brain natriuretic peptide (P<0.001), 6 minute walk distance (P=0.004), New York Heart Association functional class (P=0.009), right atrial pressure (P=0.037), and stroke volume (P=0.043). By multivariable Cox regression analysis, MOLLI-ECV was associated with outcome among imaging variables (P=0.038) but not after adjustment for clinical and invasive hemodynamic parameters. CONCLUSIONS: We demonstrate that MOLLI-ECV in HFpEF accurately reflects histological ECV, correlates with markers of disease severity, and is associated with outcome among cardiac magnetic resonance parameters but not after adjustment for important clinical and invasive hemodynamic parameters. Nevertheless, MOLLI-ECV has the potential of becoming an important biomarker in HFpEF. PMID- 27974409 TI - Heart Failure With Preserved Ejection Fraction: Have We Finally Found the Perfect Noninvasive Biomarker? PMID- 27974411 TI - Antimicrobial Stewardship: How the Microbiology Laboratory Can Right the Ship. AB - Antimicrobial stewardship is a bundle of integrated interventions employed to optimize the use of antimicrobials in health care settings. While infectious disease-trained physicians, with clinical pharmacists, are considered the main leaders of antimicrobial stewardship programs, clinical microbiologists can play a key role in these programs. This review is intended to provide a comprehensive discussion of the different components of antimicrobial stewardship in which microbiology laboratories and clinical microbiologists can make significant contributions, including cumulative antimicrobial susceptibility reports, enhanced culture and susceptibility reports, guidance in the preanalytic phase, rapid diagnostic test availability, provider education, and alert and surveillance systems. In reviewing this material, we emphasize how the rapid, and especially the recent, evolution of clinical microbiology has reinforced the importance of clinical microbiologists' collaboration with antimicrobial stewardship programs. PMID- 27974416 TI - Metastatic ER+ Breast Cancer's Genomic Landscape. AB - Whole-exome and transcriptome sequencing have yielded a clearer picture of the molecular differences between ER-positive primary and metastatic breast cancer. Comparing metastatic breast tumor samples with matched primary tumor tissue, researchers found clinically relevant mutations in various genes, including ESR1 and RB1, that were acquired during metastasis. Their findings may better guide the selection of therapies for patients no longer benefiting from ER-targeted agents. PMID- 27974414 TI - The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis. AB - : Patients with postpartum breast cancer are at increased risk for metastasis compared with age-matched nulliparous or pregnant patients. Here, we address whether circulating tumor cells have a metastatic advantage in the postpartum host and find the postlactation rodent liver preferentially supports metastasis. Upon weaning, we observed liver weight loss, hepatocyte apoptosis, extracellular matrix remodeling including deposition of collagen and tenascin-C, and myeloid cell influx, data consistent with weaning-induced liver involution and establishment of a prometastatic microenvironment. Using intracardiac and intraportal metastasis models, we observed increased liver metastasis in post weaning BALB/c mice compared with nulliparous controls. Human relevance is suggested by a ~3-fold increase in liver metastasis in patients with postpartum breast cancer (n = 564) and by liver-specific tropism (n = 117). In sum, our data reveal a previously unknown biology of the rodent liver, weaning-induced liver involution, which may provide insight into the increased liver metastasis and poor prognosis of women diagnosed with postpartum breast cancer. SIGNIFICANCE: We find that patients with postpartum breast cancer are at elevated risk for liver metastasis. We identify a previously unrecognized biology, namely weaning-induced liver involution, that establishes a prometastatic microenvironment, and which may account in part for the poor prognosis of patients with postpartum breast cancer. Cancer Discov; 7(2); 177-87. (c)2016 AACR.This article is highlighted in the In This Issue feature, p. 115. PMID- 27974418 TI - Schrodinger's fetus. PMID- 27974415 TI - Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers. AB - : Luminal breast cancers are typically estrogen receptor-positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown, and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-kappaB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo Finally, although the cooperative effects on RAS drive invasion, NF-kappaB activation triggers epithelial-to-mesenchymal transition and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions. SIGNIFICANCE: The lack of insight into mechanisms that underlie the aggressive behavior of luminal B breast cancers impairs treatment decisions and therapeutic advances. Here, we show that two RasGAP tumor suppressors are concomitantly suppressed in aggressive luminal B tumors and demonstrate that they drive metastasis by activating RAS and NF-kappaB. Cancer Discov; 7(2); 202-17. (c)2016 AACR.See related commentary by Sears and Gray, p. 131This article is highlighted in the In This Issue feature, p. 115. PMID- 27974417 TI - Notch Inhibitor Shows Modest Efficacy. AB - Data from a phase I study indicate that LY3039478 is modestly effective against a range of advanced or metastatic cancers. The investigational Notch-signaling inhibitor induced partial responses and stable disease in patients with breast cancer and rare malignancies such as adenoid cystic carcinoma and leiomyosarcoma. PMID- 27974410 TI - The Human Ureaplasma Species as Causative Agents of Chorioamnionitis. AB - The human Ureaplasma species are the most frequently isolated microorganisms from the amniotic fluid and placentae of women who deliver preterm and are also associated with spontaneous abortions or miscarriages, neonatal respiratory diseases, and chorioamnionitis. Despite the fact that these microorganisms have been habitually found within placentae of pregnancies with chorioamnionitis, the role of Ureaplasma species as a causative agent has not been satisfactorily explained. There is also controversy surrounding their role in disease, particularly as not all women infected with Ureaplasma spp. develop chorioamnionitis. In this review, we provide evidence that Ureaplasma spp. are associated with diseases of pregnancy and discuss recent findings which demonstrate that Ureaplasma spp. are associated with chorioamnionitis, regardless of gestational age at the time of delivery. Here, we also discuss the proposed major virulence factors of Ureaplasma spp., with a focus on the multiple-banded antigen (MBA), which may facilitate modulation/alteration of the host immune response and potentially explain why only subpopulations of infected women experience adverse pregnancy outcomes. The information presented within this review confirms that Ureaplasma spp. are not simply "innocent bystanders" in disease and highlights that these microorganisms are an often underestimated pathogen of pregnancy. PMID- 27974419 TI - Force-feeding, hunger strikes, Guantanamo and autonomy: replies to George Annas, Charles Foster and Michael Gross. PMID- 27974420 TI - Towards a European code of medical ethics. Ethical and legal issues. AB - The feasibility of a common European code of medical ethics is discussed, with consideration and evaluation of the difficulties such a project is going to face, from both the legal and ethical points of view. On the one hand, the analysis will underline the limits of a common European code of medical ethics as an instrument for harmonising national professional rules in the European context; on the other hand, we will highlight some of the potentials of this project, which could be increased and strengthened through a proper rulemaking process and through adequate and careful choice of content. We will also stress specific elements and devices that should be taken into consideration during the establishment of the code, from both procedural and content perspectives. Regarding methodological issues, the limits and potentialities of a common European code of medical ethics will be analysed from an ethical point of view and then from a legal perspective. The aim of this paper is to clarify the framework for the potential but controversial role of the code in the European context, showing the difficulties in enforcing and harmonising national ethical rules into a European code of medical ethics. PMID- 27974421 TI - Amoral enhancement. AB - Moral enhancement can be an attractive proposal, but contrary to cognitive enhancement, it is hard to define what kind of intervention would constitute moral enhancement. In an ongoing debate about the subject, Douglas argued that biomedically decreasing countermoral emotions would do so and would be morally permissible in particular cases. Harris disagreed, and one of his arguments is that failing to address the intellectual aspects of moral decisions-and simply targeting countermoral emotions-would effectively undermine our freedom by reducing our options to act immorally. In a consequent paper, Douglas defended his position. In this paper, I examine Douglas' response to Harris concern about the loss of freedom with biomedical moral enhancement. I argue that Douglas' framework for moral reasoning on which he bases his argument that biomedical intervention is in some cases permissible lacks soundness, and that it apparently undermines morality. Harris insists that morality requires freedom of choice, yet Douglas and Harris have different conceptions of freedom of choice. Douglas' focus on quantity in his defence does not engage with Harris focus on quality of choice. Thus, the kind of biomedical enhancement that Douglas defends is not moral-nor immoral-but amoral enhancement. PMID- 27974422 TI - Freedom of Information Act: scalpel or just a sharp knife? AB - The concluding statement of the Burns Commission, established to evaluate whether changes are needed to the Freedom of Information Act (FOIA), ruled no major legislative changes were required. As such Freedom of Information (FOI) legislation still enables anyone to obtain information from public authorities. In this brief report article we explore arguments regarding FOI as an instrument for healthcare research using an international research programme as a case study. PMID- 27974412 TI - Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges. AB - Acinetobacter is a complex genus, and historically, there has been confusion about the existence of multiple species. The species commonly cause nosocomial infections, predominantly aspiration pneumonia and catheter-associated bacteremia, but can also cause soft tissue and urinary tract infections. Community-acquired infections by Acinetobacter spp. are increasingly reported. Transmission of Acinetobacter and subsequent disease is facilitated by the organism's environmental tenacity, resistance to desiccation, and evasion of host immunity. The virulence properties demonstrated by Acinetobacter spp. primarily stem from evasion of rapid clearance by the innate immune system, effectively enabling high bacterial density that triggers lipopolysaccharide (LPS)-Toll-like receptor 4 (TLR4)-mediated sepsis. Capsular polysaccharide is a critical virulence factor that enables immune evasion, while LPS triggers septic shock. However, the primary driver of clinical outcome is antibiotic resistance. Administration of initially effective therapy is key to improving survival, reducing 30-day mortality threefold. Regrettably, due to the high frequency of this organism having an extreme drug resistance (XDR) phenotype, early initiation of effective therapy is a major clinical challenge. Given its high rate of antibiotic resistance and abysmal outcomes (up to 70% mortality rate from infections caused by XDR strains in some case series), new preventative and therapeutic options for Acinetobacter spp. are desperately needed. PMID- 27974424 TI - Arclight: a pocket ophthalmoscope for the 21st century. PMID- 27974427 TI - Fever after a safari in Africa. PMID- 27974423 TI - VEGF165b Modulates Endothelial VEGFR1-STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease. AB - RATIONALE: Atherosclerotic-arterial occlusions decrease tissue perfusion causing ischemia to lower limbs in patients with peripheral arterial disease (PAD). Ischemia in muscle induces an angiogenic response, but the magnitude of this response is frequently inadequate to meet tissue perfusion requirements. Alternate splicing in the exon-8 of vascular endothelial growth factor (VEGF)-A results in production of proangiogenic VEGFxxxa isoforms (VEGF165a, 165 for the 165 amino acid product) and antiangiogenic VEGFxxxb (VEGF165b) isoforms. OBJECTIVE: The antiangiogenic VEGFxxxb isoforms are thought to antagonize VEGFxxxa isoforms and decrease activation of VEGF receptor-2 (VEGFR2), hereunto considered the dominant receptor in postnatal angiogenesis in PAD. Our data will show that VEGF165b inhibits VEGFR1 signal transducer and activator of transcription (STAT)-3 signaling to decrease angiogenesis in human and experimental PAD. METHODS AND RESULTS: In human PAD versus control muscle biopsies, VEGF165b: (1) is elevated, (2) is bound higher (versus VEGF165a) to VEGFR1 not VEGFR2, and (3) levels correlated with decreased VEGFR1, not VEGFR2, activation. In experimental PAD, delivery of an isoform-specific monoclonal antibody to VEGF165b versus control antibody enhanced perfusion in animal model of severe PAD (Balb/c strain) without activating VEGFR2 signaling but with increased VEGFR1 activation. Receptor pull-down experiments demonstrate that VEGF165b inhibition versus control increased VEGFR1-STAT3 binding and STAT3 activation, independent of Janus-activated kinase-1)/Janus-activated kinase-2. Using VEGFR1+/- mice that could not increase VEGFR1 after ischemia, we confirm that VEGF165b decreases VEGFR1-STAT3 signaling to decrease perfusion. CONCLUSIONS: Our results indicate that VEGF165b prevents activation of VEGFR1 STAT3 signaling by VEGF165a and hence inhibits angiogenesis and perfusion recovery in PAD muscle. PMID- 27974428 TI - A shocking twist. PMID- 27974429 TI - BET 1: Lateral chest radiography and the diagnosis of pneumonia in children. AB - A short cut review was carried out to establish whether a standard frontal view CXR as good as standard frontal and lateral views at diagnosing pneumonia in children with a clinical suspicion of that diagnosis. Three papers presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. It is concluded that the addition of a lateral view does not appear to significantly improve the accuracy of pneumonia diagnosis in children by emergency physicians, when compared with frontal view alone. PMID- 27974431 TI - BET 2: Ice water immersion, other vagal manoeuvres or adenosine for SVT in children. AB - A short cut review was carried out to establish whether a vagal manoeuvre was better than or as good as adenosine at safely terminating supraventricular tachycardia in children. Forty unique papers were found in Medline and Embase using the reported searches, of which five were relevant. A hand search of the forty unique citations identified a further nine relevant papers. Thus, 14 papers presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that the evidence on the management of SVT in children is made up of poor-quality retrospective cohort studies or case series. This best evidence shows that ice water to the face appears to be a safe, quick, effective and non-invasive treatment for paediatric SVT. Adenosine also appears safe and effective, but is more invasive. Valsalva and carotid sinus massage are less effective. PMID- 27974432 TI - Incidence and Determinants of Complications in Rotational Atherectomy: Insights From the National Clinical Data (J-PCI Registry). AB - BACKGROUND: The usage of rotational atherectomy (RA) is growing in the current percutaneous coronary intervention (PCI) because of the expansion of PCI indication to more complex lesions. However, the complications after RA have been linked to procedure-related morbidity and mortality. The purpose of this study was to investigate the incidence and determinants of complications in RA using a large nationwide registration system in Japan (J-PCI). METHODS AND RESULTS: The primary composite outcome of this study was defined as the occurrence of in hospital death, cardiac tamponade, and emergent surgery after RA. A total of 13 335 RA cases (3.2% of registered PCI cases) were analyzed. The composite outcome was observed in 175 cases (1.31%) and included 80 in-hospital deaths (0.60%), 86 tamponades (0.64%), and 24 emergent surgeries (0.18%). The clinical variables associated with occurrence of the composite outcome were age (odds ratio [OR] 1.03 per unit increment, 95% confidence interval [CI] 1.02-1.05), impaired kidney function (OR 1.59, 95% CI 1.15-2.19), previous myocardial infarction (OR 1.69, 95% CI 1.21-2.35), emergent PCI (OR 4.02, 95% CI 1.66-8.27), and triple-vessel disease (versus single-vessel disease: OR 2.17, 95% CI 1.43-3.28). Notably, institutional volume of RA cases was inversely associated with the composite outcomes (high- versus low-volume institution: OR 0.56, 95% CI 0.36-0.89). CONCLUSIONS: The reported incidence of important procedure-related complication rate was 1.3%, with each component ranging between 0.2% and 0.6% in J-PCI. Its determinants were both patient related (age, impaired kidney function, and previous myocardial infarction) and procedure related (emergent procedures, number of diseased vessels, and institutional volume of RA). PMID- 27974433 TI - Rotational Atherectomy in Clinical Practice: The Art of Tightrope Walking. PMID- 27974434 TI - Staphylococcusepidermidis Small-Colony Variants Are Induced by Low pH and Their Frequency Reduced by Lysosomal Alkalinization. PMID- 27974435 TI - Reply to Perez and Patel. PMID- 27974436 TI - Genetic and Targeted eQTL Mapping Reveals Strong Candidate Genes Modulating the Stress Response During Chicken Domestication. AB - The stress response has been largely modified in all domesticated animals, offering a strong tool for genetic mapping. In chickens, ancestral Red Junglefowl react stronger both in terms of physiology and behavior to a brief restraint stress than domesticated White Leghorn, demonstrating modified functions of the hypothalamic-pituitary-adrenal (HPA) axis. We mapped quantitative trait loci (QTL) underlying variations in stress-induced hormone levels using 232 birds from the 12th generation of an advanced intercross between White Leghorn and Red Junglefowl, genotyped for 739 genetic markers. Plasma levels of corticosterone, dehydroepiandrosterone (DHEA), and pregnenolone (PREG) were measured using LC MS/MS in all genotyped birds. Transcription levels of the candidate genes were measured in the adrenal glands or hypothalamus of 88 out of the 232 birds used for hormone assessment. Genes were targeted for expression analysis when they were located in a hormone QTL region and were differentially expressed in the pure breed birds. One genome-wide significant QTL on chromosome 5 and two suggestive QTL together explained 20% of the variance in corticosterone response. Two significant QTL for aldosterone on chromosome 2 and 5 (explaining 19% of the variance), and one QTL for DHEA on chromosome 4 (explaining 5% of the variance), were detected. Orthologous DNA regions to the significant corticosterone QTL have been previously associated with the physiological stress response in other species but, to our knowledge, the underlying gene(s) have not been identified. SERPINA10 had an expression QTL (eQTL) colocalized with the corticosterone QTL on chromosome 5 and PDE1C had an eQTL colocalized with the aldosterone QTL on chromosome 2. Furthermore, in both cases, the expression levels of the genes were correlated with the plasma levels of the hormones. Hence, both these genes are strong putative candidates for the domestication-induced modifications of the stress response in chickens. Improved understanding of the genes associated with HPA-axis reactivity can provide insights into the pathways and mechanisms causing stress-related pathologies. PMID- 27974437 TI - A High Copy Suppressor Screen for Autophagy Defects in Saccharomyces arl1Delta and ypt6Delta Strains. AB - In Saccharomyces cerevisiae, Arl1 and Ypt6, two small GTP-binding proteins that regulate membrane traffic in the secretory and endocytic pathways, are also necessary for autophagy. To gain information about potential partners of Arl1 and Ypt6 specifically in autophagy, we carried out a high copy number suppressor screen to identify genes that when overexpressed suppress the rapamycin sensitivity phenotype of arl1Delta and ypt6Delta strains at 37 degrees . From the screen results, we selected COG4, SNX4, TAX4, IVY1, PEP3, SLT2, and ATG5, either membrane traffic or autophagy regulators, to further test whether they can suppress the specific autophagy defects of arl1Delta and ypt6Delta strains. As a result, we identified COG4, SNX4, and TAX4 to be specific suppressors for the arl1Delta strain, and IVY1 and ATG5 for the ypt6Delta strain. Through this screen, we were able to confirm several membrane traffic and autophagy regulators that have novel relationships with Arl1 and Ypt6 during autophagy. PMID- 27974439 TI - The Complex Transcriptional Response of Acaryochloris marina to Different Oxygen Levels. AB - Ancient oxygenic photosynthetic prokaryotes produced oxygen as a waste product, but existed for a long time under an oxygen-free (anoxic) atmosphere, before an oxic atmosphere emerged. The change in oxygen levels in the atmosphere influenced the chemistry and structure of many enzymes that contained prosthetic groups that were inactivated by oxygen. In the genome of Acaryochloris marina, multiple gene copies exist for proteins that are normally encoded by a single gene copy in other cyanobacteria. Using high throughput RNA sequencing to profile transcriptome responses from cells grown under microoxic and hyperoxic conditions, we detected 8446 transcripts out of the 8462 annotated genes in the Cyanobase database. Two-thirds of the 50 most abundant transcripts are key proteins in photosynthesis. Microoxic conditions negatively affected the levels of expression of genes encoding photosynthetic complexes, with the exception of some subunits. In addition to the known regulation of the multiple copies of psbA, we detected a similar transcriptional pattern for psbJ and psbU, which might play a key role in the altered components of photosystem II. Furthermore, regulation of genes encoding proteins important for reactive oxygen species scavenging is discussed at genome level, including, for the first time, specific small RNAs having possible regulatory roles under varying oxygen levels. PMID- 27974440 TI - Expression Patterns of Atlantic Sturgeon (Acipenser oxyrinchus) During Embryonic Development. AB - During teleost ontogeny the larval and embryonic stages are key stages, since failure during this period of tissue differentiation may cause malformations, developmental delays, poor growth, and massive mortalities. Despite the rapid advances in sequencing technologies, the molecular backgrounds of the development of economically important but endangered fish species like the Atlantic sturgeon (Acipenser oxyrinchus) have not yet been thoroughly investigated. The current study examines the differential expression of transcripts involved in embryonic development of the Atlantic sturgeon. Addressing this goal, a reference transcriptome comprising eight stages was generated using an Illumina HiSequation 2500 platform. The constructed de novo assembly counted to 441,092 unfiltered and 179,564 filtered transcripts. Subsequently, the expression profile of four developmental stages ranging from early (gastrula) to late stages of prelarval development [2 d posthatching (dph)] were investigated applying an Illumina MiSeq platform. Differential expression analysis revealed distinct expression patterns among stages, especially between the two early and the two later stages. Transcripts upregulated at the two early stages were mainly enriched in transcripts linked to developmental processes, while transcripts expressed at the last two stages were mainly enriched in transcripts important to muscle contraction. Furthermore, important stage-specific expression has been detected for the hatching stage with transcripts enriched in molecule transport, and for the 2 dph stage with transcripts enriched in visual perception and lipid digestion. Our investigation represents a significant contribution to the understanding of Atlantic sturgeon embryonic development, and transcript characterization along with the differential expression results will significantly contribute to sturgeon research and aquaculture. PMID- 27974438 TI - Transcriptome Analysis of Drosophila melanogaster Third Instar Larval Ring Glands Points to Novel Functions and Uncovers a Cytochrome p450 Required for Development. AB - In Drosophila melanogaster larvae, the ring gland (RG) is a control center that orchestrates major developmental transitions. It is a composite organ, consisting of the prothoracic gland, the corpus allatum, and the corpora cardiaca, each of which synthesizes and secretes a different hormone. Until now, the RG's broader developmental roles beyond endocrine secretion have not been explored. RNA sequencing and analysis of a new transcriptome resource from D. melanogaster wandering third instar larval RGs has provided a fascinating insight into the diversity of developmental signaling in this organ. We have found strong enrichment of expression of two gene pathways not previously associated with the RG: immune response and fatty acid metabolism. We have also uncovered strong expression for many uncharacterized genes. Additionally, RNA interference against RG-enriched cytochrome p450s Cyp6u1 and Cyp6g2 produced a lethal ecdysone deficiency and a juvenile hormone deficiency, respectively, flagging a critical role for these genes in hormone synthesis. This transcriptome provides a valuable new resource for investigation of roles played by the RG in governing insect development. PMID- 27974441 TI - Reply: PGS for recurrent pregnancy loss-still an open question. PMID- 27974442 TI - The value of cytogenetic analysis of the product of conception before preimplantation genetic screening. PMID- 27974443 TI - PGS for recurrent pregnancy loss: still an open question. PMID- 27974444 TI - Reply: The value of cytogenetic analysis of the product of conception before preimplantation genetic screening. PMID- 27974445 TI - Sex differences in the relationship between socioeconomic status and cardiovascular disease: a systematic review and meta-analysis. AB - BACKGROUND: Low socioeconomic status (SES) is a known risk factor for cardiovascular disease (CVD) but whether its effects are comparable in women and men is unknown. METHODS: PubMed MEDLINE was systematically searched. Studies that reported sex-specific estimates, and associated variability, of the relative risk (RR) for coronary heart disease (CHD), stroke or CVD according to a marker of SES (education, occupation, income or area of residence), for women and men were included. RRs were combined with those derived from cohort studies using individual participant data. Data were pooled using random effects meta-analyses with inverse variance weighting. Estimates of the ratio of the RRs (RRR), comparing women with men, were computed. RESULTS: Data from 116 cohorts, over 22 million individuals, and over 1 million CVD events, suggest that lower SES is associated with increased risk of CHD, stroke and CVD in women and men. For CHD, there was a significantly greater excess risk associated with lower educational attainment in women compared with men; comparing lowest with highest levels, the age-adjusted RRR was 1.24 (95% CI 1.09 to 1.41) and the multiple-adjusted RRR was 1.34 (1.09 to 1.63). For stroke, the age-adjusted RRR was 0.93 (0.72 to 1.18), and the multiple-adjusted was RRR 0.79 (0.53 to 1.19). Corresponding results for CVD were 1.18 (1.03 to 1.36), 1.23 (1.03 to 1.48), respectively. Similar results were observed for other markers of SES for all three outcomes. CONCLUSIONS: Reduction of socioeconomic inequalities in CHD and CVD outcomes might require different approaches for men and women. PMID- 27974446 TI - Desynchronization does not contribute to intracortical inhibition and facilitation: a paired-pulse paradigm study combined with TST. AB - The paired-pulse (PP) transcranial magnetic stimulation (TMS) paradigms allow the exploration of the motor cortex physiology. The triple stimulation technique (TST) improves conventional TMS by reducing effects of desynchronization of motor neuron discharges allowing a precise evaluation of the corticospinal conduction. The objective of our study was to explore PP TMS paradigms combined with the TST to study whether the desynchronization contributes to these phenomena and whether the combined TMS-TST protocol could improve the consistency of responses. We investigated the PP paradigms of short intracortical inhibition (SICI) with 2 ms interstimulus interval (ISI) and of intracortical facilitation (ICF) with 10 ms ISI in 22 healthy subjects applying either conventional TMS alone or combined with the TST protocol. The results of the PP paradigms combined with the TST of SICI and ICF do not differ from those with conventional TMS. However, combining the PP paradigm with the TST reduces their variability. These results speak against a contribution of the desynchronization of motor neuron discharges to the PP paradigms of SICI and ICF. Combining the PP TMS paradigm with the TST may improve their consistency, but the interindividual variability remains such that it precludes their utility for clinical practice.NEW & NOTEWORTHY Combining the triple stimulation technique with the paired-pulse stimulation paradigm improves the consistency of short intracortical inhibition and facilitation and could be useful in research, but the interindividual variability precludes their utility for clinical practice. Our findings do not suggest that desynchronization of descending discharges following transcranial magnetic stimulation contributes to short intracortical inhibition or intracortical facilitation. PMID- 27974447 TI - Restricted transfer of learning between unimanual and bimanual finger sequences. AB - When training bimanual skills, such as playing piano, people sometimes practice each hand separately and at a later stage combine the movements of the two hands. This poses the critical question of whether motor skills can be acquired by separately practicing each subcomponent or should be trained as a whole. In the present study, we addressed this question by training human subjects for 4 days in a unimanual or bimanual version of the discrete sequence production task. Both groups were then tested on trained and untrained sequences on both unimanual and bimanual versions of the task. Surprisingly, we found no evidence of transfer from trained unimanual to bimanual or from trained bimanual to unimanual sequences. In half the participants, we also investigated whether cuing the sequences on the left and right hand with unique letters would change transfer. With these cues, untrained sequences that shared some components with the trained sequences were performed more quickly than sequences that did not. However, the amount of this transfer was limited to ~10% of the overall sequence-specific learning gains. These results suggest that unimanual and bimanual sequences are learned in separate representations. Making participants aware of the interrelationship between sequences can induce some transferrable component, although the main component of the skill remains unique to unimanual or bimanual execution.NEW & NOTEWORTHY Studies in reaching movement demonstrated that approximately half of motor learning can transfer across unimanual and bimanual contexts, suggesting that neural representations for unimanual and bimanual movements are fairly overlapping at the level of elementary movement. In this study, we show that little or no transfer occurred across unimanual and bimanual sequential finger movements. This result suggests that bimanual sequences are represented at a level of the motor hierarchy that integrates movements of both hands. PMID- 27974448 TI - The inion response revisited: evidence for a possible cerebellar contribution to vestibular-evoked potentials produced by air-conducted sound stimulation. AB - This study investigated the effect of eye gaze and head position on vestibular evoked potentials (VsEPs). Head position would be expected to affect myogenic sources, and eye position is known to affect ocular myogenic responses (ocular vestibular-evoked myogenic potentials), whereas a neurogenic source should behave otherwise. Eleven healthy subjects were recruited, and VsEPs, using 72-channel EEG, were recorded at a fixed intensity above the vestibular threshold. Three eye gaze and three head positions were tested (-20 degrees , 0 degrees , and +20 degrees to the horizontal). Short-latency potentials showed that in addition to the expected effect of gaze on infraocular (IO') leads, where up-gaze gives a maximum response, significant changes in amplitude were also observed in electrodes remote from the eyes and in particular, from contralateral parietal occipital (PO) and neck (CB') leads. Short-latency potentials of similar latency were observed (p10/n17 and n10/p17, respectively). The pattern of change with gaze in the PO leads was distinct from that observed for the IO' leads. For the PO leads, the maximum response was obtained with neutral gaze, and this was also distinct from that observed for CB' electrodes, where a maximal response was observed with head flexion in the second wave but not the first. Evidence of modulation of N42 and N1 potentials with both eye and head position was also observed. Head- and eye-position manipulation thus suggests that the inion response consists of an early neurogenic component, as well as myogenic responses. The p10/n17 at PO, in particular, may be an indicator of vestibulocerebellar projections.NEW & NOTEWORTHY Loud sounds were used to activate vestibular receptors in human volunteers and the effects of head and eye position studied for short-latency responses. A potential (p10/n17) recorded in the parieto-occipital leads showed behavior not expected for a response with a myogenic origin. Source modeling suggested a possible origin from the cerebellum. It may represent a new indicator of human vestibulocerebellar function. PMID- 27974449 TI - Characteristics of breathing rate control mediated by a subregion within the pontine parabrachial complex. AB - The role of the dorsolateral pons in the control of expiratory duration (Te) and breathing frequency is incompletely understood. A subregion of the pontine parabrachial-Kolliker-Fuse (PB-KF) complex of dogs was identified via microinjections, in which localized pharmacologically induced increases in neuronal activity produced increases in breathing rate while decreases in neuronal activity produced decreases in breathing rate. This subregion is also very sensitive to local and systemic opioids. The purpose of this study was to precisely characterize the relationship between the PB-KF subregion pattern of altered neuronal activity and the control of respiratory phase timing as well as the time course of the phrenic nerve activity/neurogram (PNG). Pulse train electrical stimulation patterns synchronized with the onset of the expiratory (E) and/or phrenic inspiratory (I) phase were delivered via a small concentric bipolar electrode while the PNG was recorded in decerebrate, vagotomized dogs. Step frequency patterns during the E phase produced a marked frequency-dependent decrease in Te, while similar step inputs during the I phase increased inspiratory duration (Ti) by 14 +/- 3%. Delayed pulse trains were capable of pacing the breathing rate by terminating the E phase and also of triggering a consistent stereotypical inspiratory PNG pattern, even when evoked during apnea. This property suggests that the I-phase pattern generator functions in a monostable circuit mode with a stable E phase and a transient I phase. Thus the I pattern generator must contain neurons with nonlinear pacemaker-like properties, which allow the network to rapidly obtain a full on-state followed by relatively slow inactivation. The activated network can be further modulated and supplies excitatory drive to the neurons involved with pattern generation.NEW & NOTEWORTHY A circumscribed subregion of the pontine medial parabrachial nucleus plays a key role in the control of breathing frequency primarily via changes in expiratory duration. Excitation of this subregion triggers the onset of the inspiratory phase, resulting in a stereotypical ramplike phrenic activity pattern independent of time within the expiratory phase. The ability to pace the I-burst rate suggests that the in vivo I-pattern generating network must contain functioning pacemaker neurons. PMID- 27974452 TI - Bursting deep dorsal horn neurons: the pharmacological target for the antispastic effects of zolmitriptan? AB - In a recent publication, Thaweerattanasinp et al. (J Neurophysiol 116: 1644-1653, 2016) investigated spinal cord injury and firing properties of deep dorsal horn neurons during NMDA or zolmitriptan application by employing electrophysiology in an in vitro spinal cord preparation. Deep dorsal horn neurons were classified into bursting, simple, or tonic firing groups,with bursting neurons showing NMDA and zolmitriptan sensitivity. We discuss the findings in a methodological framework and propose future experiments of importance for translating the results into physiological settings. PMID- 27974451 TI - Muscle afferent excitability testing in spinal root-intact rats: dissociating peripheral afferent and efferent volleys generated by intraspinal microstimulation. AB - Presynaptic inhibition of the sensory input from the periphery to the spinal cord can be evaluated directly by intra-axonal recording of primary afferent depolarization (PAD) or indirectly by intraspinal microstimulation (excitability testing). Excitability testing is superior for use in normal behaving animals, because this methodology bypasses the technically challenging intra-axonal recording. However, use of excitability testing on the muscle or joint afferent in intact animals presents its own technical challenges. Because these afferents, in many cases, are mixed with motor axons in the peripheral nervous system, it is crucial to dissociate antidromic volleys in the primary afferents from orthodromic volleys in the motor axon, both of which are evoked by intraspinal microstimulation. We have demonstrated in rats that application of a paired stimulation protocol with a short interstimulus interval (ISI) successfully dissociated the antidromic volley in the nerve innervating the medial gastrocnemius muscle. By using a 2-ms ISI, the amplitude of the volleys evoked by the second stimulation was decreased in dorsal root-sectioned rats, but the amplitude did not change or was slightly increased in ventral root-sectioned rats. Excitability testing in rats with intact spinal roots indicated that the putative antidromic volleys exhibited dominant primary afferent depolarization, which was reasonably induced from the more dorsal side of the spinal cord. We concluded that excitability testing with a paired-pulse protocol can be used for studying presynaptic inhibition of somatosensory afferents in animals with intact spinal roots.NEW & NOTEWORTHY Excitability testing of primary afferents has been used to evaluate presynaptic modulation of synaptic transmission in experiments conducted in vivo. However, to apply this method to muscle afferents of animals with intact spinal roots, it is crucial to dissociate antidromic and orthodromic volleys induced by spinal microstimulation. We propose a new method to make this dissociation possible without cutting spinal roots and demonstrate that it facilitates excitability testing of muscle afferents. PMID- 27974453 TI - Epigenetic Networks Regulate the Transcriptional Program in Memory and Terminally Differentiated CD8+ T Cells. AB - Epigenetic mechanisms play a critical role during differentiation of T cells by contributing to the formation of stable and heritable transcriptional patterns. To better understand the mechanisms of memory maintenance in CD8+ T cells, we performed genome-wide analysis of DNA methylation, histone marking (acetylated lysine 9 in histone H3 and trimethylated lysine 9 in histone), and gene expression profiles in naive, effector memory (EM), and terminally differentiated EM (TEMRA) cells. Our results indicate that DNA demethylation and histone acetylation are coordinated to generate the transcriptional program associated with memory cells. Conversely, EM and TEMRA cells share a very similar epigenetic landscape. Nonetheless, the TEMRA transcriptional program predicts an innate immunity phenotype associated with genes never reported in these cells, including several mediators of NK cell activation (VAV3 and LYN) and a large array of NK receptors (e.g., KIR2DL3, KIR2DL4, KIR2DL1, KIR3DL1, KIR2DS5). In addition, we identified up to 161 genes that encode transcriptional regulators, some of unknown function in CD8+ T cells, and that were differentially expressed in the course of differentiation. Overall, these results provide new insights into the regulatory networks involved in memory CD8+ T cell maintenance and T cell terminal differentiation. PMID- 27974450 TI - Coupling multielectrode array recordings with silver labeling of recording sites to study cervical spinal network connectivity. AB - Midcervical spinal interneurons form a complex and diffuse network and may be involved in modulating phrenic motor output. The intent of the current work was to enable a better understanding of midcervical "network-level" connectivity by pairing the neurophysiological multielectrode array (MEA) data with histological verification of the recording locations. We first developed a method to deliver 100-nA currents to electroplate silver onto and subsequently deposit silver from electrode tips after obtaining midcervical (C3-C5) recordings using an MEA in anesthetized and ventilated adult rats. Spinal tissue was then fixed, harvested, and histologically processed to "develop" the deposited silver. Histological studies verified that the silver deposition method discretely labeled (50-MUm resolution) spinal recording locations between laminae IV and X in cervical segments C3-C5. Using correlative techniques, we next tested the hypothesis that midcervical neuronal discharge patterns are temporally linked. Cross-correlation histograms produced few positive peaks (5.3%) in the range of 0-0.4 ms, but 21.4% of neuronal pairs had correlogram peaks with a lag of >=0.6 ms. These results are consistent with synchronous discharge involving mono- and polysynaptic connections among midcervical neurons. We conclude that there is a high degree of synaptic connectivity in the midcervical spinal cord and that the silver-labeling method can reliably mark metal electrode recording sites and "map" interneuron populations, thereby providing a low-cost and effective tool for use in MEA experiments. We suggest that this method will be useful for further exploration of midcervical network connectivity.NEW & NOTEWORTHY We describe a method that reliably identifies the locations of multielectrode array (MEA) recording sites while preserving the surrounding tissue for immunohistochemistry. To our knowledge, this is the first cost-effective method to identify the anatomic locations of neuronal ensembles recorded with a MEA during acute preparations without the requirement of specialized array electrodes. In addition, evaluation of activity recorded from silver-labeled sites revealed a previously unappreciated degree of connectivity between midcervical interneurons. PMID- 27974454 TI - The Systemic Lupus Erythematosus-Associated Single Nucleotide Polymorphism rs1143678 in Integrin alphaM Cytoplasmic Tail Generates a 14-3-3zeta Binding Site That Is Proinflammatory. AB - The leukocyte integrin alphaMbeta2 (CR3 or Mac-1) has both proinflammatory and immune regulatory functions. Genome-wide association studies have identified several ITGAM (alphaM subunit) single nucleotide polymorphisms that are associated with systemic lupus erythematosus. The single nucleotide polymorphism rs1143678 substitutes Pro1146 for Ser in the integrin alphaM cytoplasmic tail. A detailed functional characterization of this substitution is lacking. Using transfected human cell lines, reconstituted mouse bone marrow neutrophils, and bone marrow-derived macrophages (BMDMs), we showed that P1146S (PS) substitution promoted integrin alphaMbeta2-mediated adhesion, spreading, and migration of cells on iC3b and fibrinogen. In the presence of LPS together with iC3b or fibrinogen, the expression levels of IL-6 and TNF-alpha in integrin alphaM(PS)beta2 BMDMs were significantly higher than those of integrin alphaM(wild-type)beta2 BMDMs, and they showed faster kinetics of Erk1/2 activation through the src family kinase(s)-Syk signaling pathway. Integrin alphaM(PS)beta2 BMDMs also exhibited higher levels of active RhoA and phagocytic activity. Mechanistically, P1146S substitution in the alphaM cytoplasmic tail generates a noncanonical 14-3-3zeta binding site that modulates integrin alphaM(PS)beta2 outside-in signaling. PMID- 27974455 TI - Cutting Edge: Murine Mast Cells Rapidly Modulate Metabolic Pathways Essential for Distinct Effector Functions. AB - There is growing appreciation that cellular metabolic and bioenergetic pathways do not play merely passive roles in activated leukocytes. Rather, metabolism has important roles in controlling cellular activation, differentiation, survival, and effector function. Much of this work has been performed in T cells; however, there is still very little information regarding mast cell metabolic reprogramming and its effect on cellular function. Mast cells perform important barrier functions and help control type 2 immune responses. In this study we show that murine bone marrow-derived mast cells rapidly alter their metabolism in response to stimulation through the FcepsilonRI. We also demonstrate that specific metabolic pathways appear to be differentially required for the control of mast cell function. Manipulation of metabolic pathways may represent a novel point for the manipulation of mast cell activation. PMID- 27974457 TI - Dimethyl Fumarate Treatment Mediates an Anti-Inflammatory Shift in B Cell Subsets of Patients with Multiple Sclerosis. AB - The therapeutic mode of action of dimethyl fumarate (DMF), approved for treating patients with relapsing-remitting multiple sclerosis, is not fully understood. Recently, we and others demonstrated that Ab-independent functions of distinct B cell subsets are important in mediating multiple sclerosis (MS) relapsing disease activity. Our objective was to test whether and how DMF influences both the phenotype and functional responses of disease-implicated B cell subsets in patients with MS. High-quality PBMC were obtained from relapsing-remitting MS patients prior to and serially after initiation of DMF treatment. Multiparametric flow cytometry was used to monitor the phenotype and functional response-profiles of distinct B cell subsets. Total B cell counts decreased following DMF treatment, largely reflecting losses of circulating mature/differentiated (but not of immature transitional) B cells. Within the mature B cell pool, DMF had a greater impact on memory than naive B cells. In keeping with these in vivo effects, DMF treatment in vitro remarkably diminished mature (but not transitional B cell) survival, mediated by inducing apoptotic cell death. Although DMF treatment (both in vivo and in vitro) minimally impacted B cell IL 10 expression, it strongly reduced B cell expression of GM-CSF, IL-6, and TNF alpha, resulting in a significant anti-inflammatory shift of B cell response profiles. The DMF-mediated decrease in B cell proinflammatory cytokine responses was further associated with reduced phosphorylation of STAT5/6 and NF-kappaB in surviving B cells. Together, these data implicate novel mechanisms by which DMF may modulate MS disease activity through shifting the balance between pro- and anti-inflammatory B cell responses. PMID- 27974456 TI - Kinetics of Myeloid-Derived Suppressor Cell Frequency and Function during Simian Immunodeficiency Virus Infection, Combination Antiretroviral Therapy, and Treatment Interruption. AB - During chronic lentiviral infection, poor clinical outcomes correlate both with systemic inflammation and poor proliferative ability of HIV-specific T cells; however, the connection between the two is not clear. Myeloid-derived suppressor cells (MDSC), which expand during states of elevated circulating inflammatory cytokines, may link the systemic inflammation and poor T cell function characteristic of lentiviral infections. Although MDSC are partially characterized in HIV and SIV infection, questions remain regarding their persistence, activity, and clinical significance. We monitored MDSC frequency and function in SIV-infected rhesus macaques. Low MDSC frequency was observed prior to SIV infection. Post-SIV infection, MDSC were elevated in acute infection and persisted during 7 mo of combination antiretroviral drug therapy (cART). After cART interruption, we observed MDSC expansion of surprising magnitude, the majority being granulocytic MDSC. At all stages of infection, granulocytic MDSC suppressed CD4+ and CD8+ T cell proliferation in response to polyclonal or SIV specific stimulation. In addition, MDSC frequency correlated significantly with circulating inflammatory cytokines. Acute and post-cART levels of viremia were similar, however, the levels of inflammatory cytokines and MDSC were more pronounced post-cART. Expanded MDSC during SIV infection, especially during the post-cART inflammatory cytokine surge, likely limit cellular responses to infection. As many HIV curative strategies require cART interruption to determine efficacy, our work suggests treatment interruption-induced MDSC may especially undermine the effectiveness of such strategies. MDSC depletion may enhance T cell responses to lentiviral infection and the effectiveness of curative approaches. PMID- 27974458 TI - Cutting Edge: LL-37-Mediated Formyl Peptide Receptor-2 Signaling in Follicular Dendritic Cells Contributes to B Cell Activation in Peyer's Patch Germinal Centers. AB - Peyer's patches (PPs) are the major mucosal immune-inductive site, and germinal centers (GCs) in PPs determine the quality of the Abs produced. PP GCs are continuously induced by the gut microbiota, and their maintenance contributes to the induction of strong IgA responses to Ags. In this study, we investigated the role of formyl peptide receptor (FPR)-mediated signaling in the maintenance of PP GCs, because FPRs recognize the microbiota and initiate an innate immune response by chemotaxis. We found that follicular dendritic cells (FDCs), a key organizer of B cell follicles and GCs in mucosal immunity, express Fpr2. Additionally, Fpr2 mediated signaling in PP FDCs promoted Cxcl13 and B cell activating factor expression, as well as B cell proliferation and activation. Therefore, we suggest that Fpr2-mediated signaling in FDCs plays a key role in GC maintenance in PPs and results in an Ag-specific IgA response in the gut mucosal immune compartment. PMID- 27974459 TI - Identification of the RNA Pyrophosphohydrolase RppH of Helicobacter pylori and Global Analysis of Its RNA Targets. AB - RNA degradation is crucial for regulating gene expression in all organisms. Like the decapping of eukaryotic mRNAs, the conversion of the 5'-terminal triphosphate of bacterial transcripts to a monophosphate can trigger RNA decay by exposing the transcript to attack by 5'-monophosphate-dependent ribonucleases. In both biological realms, this deprotection step is catalyzed by members of the Nudix hydrolase family. The genome of the gastric pathogen Helicobacter pylori, a Gram negative epsilonproteobacterium, encodes two proteins resembling Nudix enzymes. Here we present evidence that one of them, HP1228 (renamed HpRppH), is an RNA pyrophosphohydrolase that triggers RNA degradation in H. pylori, whereas the other, HP0507, lacks such activity. In vitro, HpRppH converts RNA 5' triphosphates and diphosphates to monophosphates. It requires at least two unpaired nucleotides at the 5' end of its substrates and prefers three or more but has only modest sequence preferences. The influence of HpRppH on RNA degradation in vivo was examined by using RNA-seq to search the H. pylori transcriptome for RNAs whose 5'-phosphorylation state and cellular concentration are governed by this enzyme. Analysis of cDNA libraries specific for transcripts bearing a 5'-triphosphate and/or monophosphate revealed at least 63 potential HpRppH targets. These included mRNAs and sRNAs, several of which were validated individually by half-life measurements and quantification of their 5'-terminal phosphorylation state in wild-type and mutant cells. These findings demonstrate an important role for RppH in post-transcriptional gene regulation in pathogenic Epsilonproteobacteria and suggest a possible basis for the phenotypes of H. pylori mutants lacking this enzyme. PMID- 27974461 TI - The GS Protein-coupled A2a Adenosine Receptor Controls T Cell Help in the Germinal Center. AB - T follicular helper (TFH) cells have been shown to be critically required for the germinal center (GC) reaction where B cells undergo class switch recombination and clonal selection to generate high affinity neutralizing antibodies. However, detailed knowledge of the physiological cues within the GC microenvironment that regulate T cell help is limited. The cAMP-elevating, Gs protein-coupled A2a adenosine receptor (A2aR) is an evolutionarily conserved receptor that limits and redirects cellular immunity. However, the role of A2aR in humoral immunity and B cell differentiation is unknown. We hypothesized that the hypoxic microenvironment within the GC facilitates an extracellular adenosine-rich milieu, which serves to limit TFH frequency and function, and also promotes immunosuppressive T follicular regulatory cells (TFR). In support of this hypothesis, we found that following immunization, mice lacking A2aR (A2aRKO) exhibited a significant expansion of T follicular cells, as well as increases in TFH to TFR ratio, GC T cell frequency, GC B cell frequency, and class switching of GC B cells to IgG1. Transfer of CD4 T cells from A2aRKO or wild type donors into T cell-deficient hosts revealed that these increases were largely T cell intrinsic. Finally, injection of A2aR agonist, CGS21680, following immunization suppressed T follicular differentiation, GC B cell frequency, and class switching of GC B cells to IgG1. Taken together, these observations point to a previously unappreciated role of GS protein-coupled A2aR in regulating humoral immunity, which may be pharmacologically targeted during vaccination or pathological states in which GC-derived autoantibodies contribute to the pathology. PMID- 27974460 TI - Metnase Mediates Loading of Exonuclease 1 onto Single Strand Overhang DNA for End Resection at Stalled Replication Forks. AB - Stalling at DNA replication forks generates stretches of single-stranded (ss) DNA on both strands that are exposed to nucleolytic degradation, potentially compromising genome stability. One enzyme crucial for DNA replication fork repair and restart of stalled forks in human is Metnase (also known as SETMAR), a chimeric fusion protein consisting of a su(var)3-9, enhancer-of-zeste and trithorax (SET) histone methylase and transposase nuclease domain. We previously showed that Metnase possesses a unique fork cleavage activity necessary for its function in replication restart and that its SET domain is essential for recovery from hydroxyurea-induced DNA damage. However, its exact role in replication restart is unclear. In this study, we show that Metnase associates with exonuclease 1 (Exo1), a 5'-exonuclease crucial for 5'-end resection to mediate DNA processing at stalled forks. Metnase DNA cleavage activity was not required for Exo1 5'-exonuclease activity on the lagging strand daughter DNA, but its DNA binding activity mediated loading of Exo1 onto ssDNA overhangs. Metnase-induced enhancement of Exo1-mediated DNA strand resection required the presence of these overhangs but did not require Metnase's DNA cleavage activity. These results suggest that Metnase enhances Exo1-mediated exonuclease activity on the lagging strand DNA by facilitating Exo1 loading onto a single strand gap at the stalled replication fork. PMID- 27974462 TI - Down-regulation of microRNA-451a facilitates the activation and proliferation of CD4+ T cells by targeting Myc in patients with dilated cardiomyopathy. AB - CD4+ T cells are abnormally activated in patients with dilated cardiomyopathy (DCM) and might be associated with the immunopathogenesis of the disease. However, the underlying mechanisms of CD4+ T cell activation remain largely undefined. Our aim was to investigate whether the dysregulation of microRNAs (miRNAs) was associated with CD4+ T cell activation in DCM. CD4+ T cells from DCM patients showed increased expression levels of CD25 and CD69 and enhanced proliferation in response to anti-CD3/28, indicating an activated state. miRNA profiling analysis of magnetically sorted CD4+ T cells revealed a distinct pattern of miRNA expression in CD4+ T cells from DCM patients compared with controls. The level of miRNA-451a (miR-451a) was significantly decreased in the CD4+ T cells of DCM patients compared with that of the controls. The transfection of T cells with an miR-451a mimic inhibited their activation and proliferation, whereas an miR-451a inhibitor produced the opposite effects. Myc was directly inhibited by miR-451a via interaction with its 3'-UTR, thus identifying it as an miR-451a target in T cells. The knockdown of Myc suppressed the activation and proliferation of T cells, and the expression of Myc was significantly up regulated at the mRNA level in CD4+ T cells from patients with DCM. A strong inverse correlation was observed between the Myc mRNA expression and miR-451a transcription level. Our data suggest that the down-regulation of miR-451a contributes to the activation and proliferation of CD4+ T cells by targeting the transcription factor Myc in DCM patients and may contribute to the immunopathogenesis of DCM. PMID- 27974463 TI - A Disease-associated Mutant of NLRC4 Shows Enhanced Interaction with SUG1 Leading to Constitutive FADD-dependent Caspase-8 Activation and Cell Death. AB - Nod-like receptor family card containing 4 (NLRC4)/Ipaf is involved in recognition of pathogen-associated molecular patterns leading to caspase-1 activation and cytokine release, which mediate protective innate immune response. Point mutations in NLRC4 cause autoinflammatory syndromes. Although all the mutations result in constitutive caspase-1 activation, their phenotypic presentations are different, implying that these mutations cause different alterations in properties of NLRC4. NLRC4 interacts with SUG1 and induces caspase 8-mediated cell death. Here, we show that one of the autoinflammatory syndrome causing mutants of NLRC4, H443P, but not T337A and V341A, constitutively activates caspase-8 and induces apoptotic cell death in human lung epithelial cells. Compared with wild type NLRC4, the H443P mutant shows stronger interaction with SUG1 and with ubiquitinated cellular proteins. Phosphorylation of NLRC4 at Ser533 plays a crucial role in caspase-8 activation and cell death. However, H443P mutant does not require Ser533 phosphorylation for caspase-8 activation and cell death. Caspase-8 activation by NLRC4 and its H443P mutant are dependent on the adaptor protein FADD. A phosphomimicking mutant of NLRC4, S533D does not require SUG1 activity for inducing cell death. Ubiquitin-tagged NLRC4 could induce cell death and activate caspase-8 independent of Ser533 phosphorylation. Our work suggests that SUG1-mediated signaling results in enhanced ubiquitination and regulates FADD-dependent caspase-8 activation by NLRC4. We show that the autoinflammation-associated H443P mutant is altered in interaction with SUG1 and ubiquitinated proteins, triggering constitutive caspase-8-mediated cell death dependent on FADD but independent of Ser533 phosphorylation. PMID- 27974464 TI - Affinity Maturation of a Cyclic Peptide Handle for Therapeutic Antibodies Using Deep Mutational Scanning. AB - Meditopes are cyclic peptides that bind in a specific pocket in the antigen binding fragment of a therapeutic antibody such as cetuximab. Provided their moderate affinity can be enhanced, meditope peptides could be used as specific non-covalent and paratope-independent handles in targeted drug delivery, molecular imaging, and therapeutic drug monitoring. Here we show that the affinity of a recently reported meditope for cetuximab can be substantially enhanced using a combination of yeast display and deep mutational scanning. Deep sequencing was used to construct a fitness landscape of this protein-peptide interaction, and four mutations were identified that together improved the affinity for cetuximab 10-fold to 15 nm Importantly, the increased affinity translated into enhanced cetuximab-mediated recruitment to EGF receptor overexpressing cancer cells. Although in silico Rosetta simulations correctly identified positions that were tolerant to mutation, modeling did not accurately predict the affinity-enhancing mutations. The experimental approach reported here should be generally applicable and could be used to develop meditope peptides with low nanomolar affinity for other therapeutic antibodies. PMID- 27974465 TI - Dynamic Lipid-dependent Modulation of Protein Topology by Post-translational Phosphorylation. AB - Membrane protein topology and folding are governed by structural principles and topogenic signals that are recognized and decoded by the protein insertion and translocation machineries at the time of initial membrane insertion and folding. We previously demonstrated that the lipid environment is also a determinant of initial protein topology, which is dynamically responsive to post-assembly changes in membrane lipid composition. However, the effect on protein topology of post-assembly phosphorylation of amino acids localized within initially cytoplasmically oriented extramembrane domains has never been investigated. Here, we show in a controlled in vitro system that phosphorylation of a membrane protein can trigger a change in topological arrangement. The rate of change occurred on a scale of seconds, comparable with the rates observed upon changes in the protein lipid environment. The rate and extent of topological rearrangement were dependent on the charges of extramembrane domains and the lipid bilayer surface. Using model membranes mimicking the lipid compositions of eukaryotic organelles, we determined that anionic lipids, cholesterol, sphingomyelin, and membrane fluidity play critical roles in these processes. Our results demonstrate how post-translational modifications may influence membrane protein topology in a lipid-dependent manner, both along the organelle trafficking pathway and at their final destination. The results provide further evidence that membrane protein topology is dynamic, integrating for the first time the effect of changes in lipid composition and regulators of cellular processes. The discovery of a new topology regulatory mechanism opens additional avenues for understanding unexplored structure-function relationships and the development of optimized topology prediction tools. PMID- 27974466 TI - Steps for Shigella Gatekeeper Protein MxiC Function in Hierarchical Type III Secretion Regulation. AB - Type III secretion systems are complex nanomachines used for injection of proteins from Gram-negative bacteria into eukaryotic cells. Although they are assembled when the environmental conditions are appropriate, they only start secreting upon contact with a host cell. Secretion is hierarchical. First, the pore-forming translocators are released. Second, effector proteins are injected. Hierarchy between these protein classes is mediated by a conserved gatekeeper protein, MxiC, in Shigella As its molecular mechanism of action is still poorly understood, we used its structure to guide site-directed mutagenesis and to dissect its function. We identified mutants predominantly affecting all known features of MxiC regulation as follows: secretion of translocators, MxiC and/or effectors. Using molecular genetics, we then mapped at which point in the regulatory cascade the mutants were affected. Analysis of some of these mutants led us to a set of electron paramagnetic resonance experiments that provide evidence that MxiC interacts directly with IpaD. We suggest how this interaction regulates a switch in its conformation that is key to its functions. PMID- 27974469 TI - On complicity and compromise: a reply. PMID- 27974467 TI - Cyclic AMP Inhibits the Activity and Promotes the Acetylation of Acetyl-CoA Synthetase through Competitive Binding to the ATP/AMP Pocket. AB - The high-affinity biosynthetic pathway for converting acetate to acetyl-coenzyme A (acetyl-CoA) is catalyzed by the central metabolic enzyme acetyl-coenzyme A synthetase (Acs), which is finely regulated both at the transcriptional level via cyclic AMP (cAMP)-driven trans-activation and at the post-translational level via acetylation inhibition. In this study, we discovered that cAMP directly binds to Salmonella enterica Acs (SeAcs) and inhibits its activity in a substrate competitive manner. In addition, cAMP binding increases SeAcs acetylation by simultaneously promoting Pat-dependent acetylation and inhibiting CobB-dependent deacetylation, resulting in enhanced SeAcs inhibition. A crystal structure study and site-directed mutagenesis analyses confirmed that cAMP binds to the ATP/AMP pocket of SeAcs, and restrains SeAcs in an open conformation. The cAMP contact residues are well conserved from prokaryotes to eukaryotes, suggesting a general regulatory mechanism of cAMP on Acs. PMID- 27974470 TI - Teaching, learning and assessment of medical ethics at the UK medical schools. AB - OBJECTIVES: To evaluate the UK undergraduate medical ethics curricula against the Institute of Medical Ethics (IME) recommendations; to identify barriers to teaching and assessment of medical ethics and to evaluate perceptions of ethics faculties on the preparation of tomorrow's doctors for clinical practice. DESIGN: Questionnaire survey of the UK medical schools enquiring about content, structure and location of ethics teaching and learning; teaching and learning processes; assessment; influences over institutional approach to ethics education; barriers to teaching and assessment; perception of student engagement and perception of student preparation for clinical practice. PARTICIPANTS: The lead for medical ethics at each medical school was invited to participate (n=33). RESULTS: Completed responses were received from 11/33 schools (33%). 73% (n=8) teach all IME recommended topics within their programme. 64% (n=7) do not include ethics in clinical placement learning objectives. The most frequently cited barrier to teaching was lack of time (64%, n=7), and to assessment was lack of time and suitability of assessments (27%, n=3). All faculty felt students were prepared for clinical practice. CONCLUSIONS: IME recommendations are not followed in all cases, and ethics teaching is not universally well integrated into clinical placement. Barriers to assessment lead to inadequacies in this area, and there are few consequences for failing ethics assessments. As such, tomorrow's patients will be treated by doctors who are inadequately prepared for ethical decision making in clinical practice; this needs to be addressed by ethics leads with support from medical school authorities. PMID- 27974468 TI - Dysregulation of CUL4A and CUL4B Ubiquitin Ligases in Lung Cancer. AB - The Cullin-RING ubiquitin ligase 4 (CRL4) is implicated in controlling cell cycle, DNA damage repair, and checkpoint response based on studies employing cell lines and mouse models. CRL4 proteins, including CUL4A and CUL4B, are often highly accumulated in human malignancies. Elevated CRL4 attenuates DNA damage repair and increases genome instability that is believed to facilitate tumorigenesis. However, this has yet to be evaluated in human patients with cancer. In our study, 352 lung cancer and 62 normal lung specimens of Asian origin were constructed into tissue microarrays of four distinct lung cancer subtypes. Expression of CUL4A, CUL4B, and their substrates was detected by immunohistochemistry and analyzed statistically for their prognostic value and association with DNA damage response and genomic instability. Our results show that both CUL4A and CUL4B are overexpressed in the majority of lung carcinomas (PCUL4A <0.001 and PCUL4B <0.001) and significantly associated with tumor size (PCUL4A <0.001 and PCUL4B = 0.002), lymphatic invasion (PCUL4A = 0.004 and PCUL4B <0.001), metastasis (PCUL4A = 0.019 and PCUL4B = 0.006), and advanced TNM stage (PCUL4A <0.001 and PCUL4B <0.001), which parallels gene amplification and abnormal activation of the canonical WNT signaling. Moreover, overexpression of CUL4A, but not CUL4B, is significantly associated with tobacco smoking (p = 0.01) and is inversely correlated with XPC and P21, both of which are substrates of CUL4A (PCUL4A = 0.019 and PCUL4B = 0.006). Higher levels of CUL4A or CUL4B are significantly associated with the overall survival of patients (PCUL4A <0.001 and PCUL4B <0.001) and progression-free survival (PCUL4A <0.001 and PCUL4B = 0.001). Our findings revealed that CUL4A and CUL4B are differentially associated with etiologic factors for pulmonary malignancies and are independent prognostic markers for the survival of distinct lung cancer subtypes. PMID- 27974471 TI - 50 Years of Cognitive Aging Theory. AB - OBJECTIVES: The objectives of this Introduction to the Journal of Gerontology: Psychological Sciences special issue on "50 Years of Cognitive Aging Theory" are to provide a brief overview of cognitive aging research prior to 1965 and to highlight significant developments in cognitive aging theory over the last 50 years. METHOD: Historical and recent theories of cognitive aging were reviewed, with a particular focus on those not directly covered by the articles included in this special issue. RESULTS: Prior to 1965, cognitive aging research was predominantly descriptive, identifying what aspects of intellectual functioning are affected in older compared with younger adults. Since the mid-1960s, there has been an increasing interest in how and why specific components of cognitive domains are differentially affected in aging and a growing focus on cognitive aging neuroscience. DISCUSSION: Significant advances have taken place in our theoretical understanding of how and why certain components of cognitive functioning are or are not affected by aging. We also know much more now than we did 50 years ago about the underlying neural mechanisms of these changes. The next 50 years undoubtedly will bring new theories, as well as new tools (e.g., neuroimaging advances, neuromodulation, and technology), that will further our understanding of cognitive aging. PMID- 27974472 TI - Better Cognition in New Birth Cohorts of 70 Year Olds, But Greater Decline Thereafter. AB - OBJECTIVES: To evaluate birth cohort differences in level of cognition and rate of change in old age. METHODS: Data were drawn from three population-based Swedish samples including age-homogenous cohorts born 1901/02, 1906/07, and 1930, and measured on the same cognitive tests at ages 70, 75, and 79 as part of the Gerontological and Geriatric Populations Studies in Gothenburg (H70). We fitted growth curve models to the data using a Bayesian framework and derived estimates and inferences from the marginal posterior distributions. RESULTS: We found moderate to large birth cohort effects in level of performance on all cognitive outcomes. Later born cohorts, however, showed steeper linear rate of decline on reasoning, spatial ability, and perceptual- and motor-speed, but not on picture recognition memory and verbal ability. DISCUSSION: These findings provide strong evidence for substantial birth cohort effects in cognition in older ages and emphasize the importance of life long environmental factors in shaping cognitive aging trajectories. Inferences from cognitive testing, and standardization of test scores, in elderly populations must take into account the substantial birth cohort differences. PMID- 27974473 TI - Lifecourse Activity Participation From Early, Mid, and Later Adulthood as Determinants of Cognitive Aging: The Lothian Birth Cohort 1921. AB - OBJECTIVES: To examine potential sensitive periods for activity participation across adulthood to reduce cognitive decline and to determine whether associations persist after accounting for the lifetime stability of cognitive ability. METHOD: The Lothian Birth Cohort 1921 is a longitudinal study of cognitive aging. Participants were born in 1921 and most completed a mental ability test at the age of 11 years. Cognitive assessments were completed at mean ages 79 (N = 550), 83 (N = 321), 87 (N = 235), and 90 years (N = 129). Participants provided retrospective details of their activity participation for young (20-35 years), mid (40-55 years), and later adulthood (60-75 years), and contemporaneously at age 79. RESULTS: Associations between activity and the level of, and change in, cognitive ability in old age were examined with latent growth curve models. Accounting for demographics and childhood cognitive ability, engagement in leisure activities in midlife was positively associated with cognitive ability level (path coefficient = .32), whereas higher physical activity in later adulthood was associated with less cognitive decline (.27). DISCUSSION: The findings support a lifecourse approach in identifying determinants of cognitive aging; leisure and physical activity during different periods of adulthood may enhance cognitive abilities or reduce decline. PMID- 27974481 TI - UNC-84: "LINC-ing" chromosome movement and double strand break repair. AB - Assaults to our DNA take place at a high frequency and are incompatible with life. In this issue, Lawrence et al. (2016. J. Cell Biol https://doi.org/10.1083/jcb.201604112) demonstrate that a novel complex links the nucleus with cytoplasmic microtubules for the promotion of DNA repair by homologous recombination. PMID- 27974474 TI - Cognitive Function in Low-Income and Low-Literacy Settings: Validation of the Tablet-Based Oxford Cognitive Screen in the Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa (HAALSI). AB - OBJECTIVES: 1. Assess validity of the Oxford Cognitive Screen (OCS-Plus), a domain-specific cognitive assessment designed for low-literacy settings, especially in low- and middle-income countries (LMIC); 2. Advance theoretical contributions in cognitive neuroscience in domain-specific cognitive function and cognitive reserve, especially related to dementia. METHOD: In a cross-sectional study of a sample of 1,402 men and women aged 40-79 in the Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa (HAALSI), we administered OCS-Plus along with health and sociodemographic assessments. HAALSI is a representative sample of older adults in Agincourt, South Africa contributing to normative understanding of cognition in LMIC. We report measure distributions, construct and external validity of the OCS-Plus. RESULTS: OCS-Plus has excellent construct and external validity. Intra-class correlations between similar basic measures of orientation in OCS-Plus and in HAALSI assessments was 0.79, and groups of people performing well on the OCS-Plus verbal memory also showed superior performance on HAALSI verbal memory. The OCS-Plus scores showed consistent associations with age and education and domain-specific associations with alcohol and depression. Younger respondents and the more educated did better on all assessments. DISCUSSION: The OCS-Plus represents a major methodological advance in dementia studies in LMICs, and enhances understanding of cognitive aging. PMID- 27974483 TI - Cytokinetic rings mind the gap. PMID- 27974482 TI - Robust gap repair in the contractile ring ensures timely completion of cytokinesis. AB - Cytokinesis in animal cells requires the constriction of an actomyosin contractile ring, whose architecture and mechanism remain poorly understood. We use laser microsurgery to explore the biophysical properties of constricting rings in Caenorhabditis elegans embryos. Laser cutting causes rings to snap open. However, instead of disintegrating, ring topology recovers and constriction proceeds. In response to severing, a finite gap forms and is repaired by recruitment of new material in an actin polymerization-dependent manner. An open ring is able to constrict, and rings repair from successive cuts. After gap repair, an increase in constriction velocity allows cytokinesis to complete at the same time as controls. Our analysis demonstrates that tension in the ring increases while net cortical tension at the site of ingression decreases throughout constriction and suggests that cytokinesis is accomplished by contractile modules that assemble and contract autonomously, enabling local repair of the actomyosin network. Consequently, cytokinesis is a highly robust process impervious to discontinuities in contractile ring structure. PMID- 27974485 TI - Chromosome Evolution: Molecular Mechanisms and Evolutionary Consequences. PMID- 27974486 TI - Estimating Diversity of Black Flies in the Simulium ignescens and Simulium tunja Complexes in Colombia: Chromosomal Rearrangements as the Core of Integrative Taxonomy. AB - Black flies (Diptera: Simuliidae) are distributed throughout the world, with more than 2200 formally described species. The family is renowned for its high frequency of cryptic species, offering an opportunity for integrative taxonomy, based on morphological, chromosomal, and molecular approaches. The biodiversity within Simulium (Psilopelmia) ignescens and S. (Psilopelmia) tunja in Colombia was estimated from the larval stage; 10 morphoforms were recognized based on 7 structural characters. This remarkable morphological variation was evaluated through 23 markers on the polytene chromosomes. We established 1 new cytoform in each nominal species. The congruence of the morphological and chromosomal assignments was evaluated using the mitochondrial marker Cytochrome Oxidase subunit I (COI) for each morphoform. The molecular data supported the chromosomal recognition of cytoforms (i.e., cryptic species). We also established the suitability of the COI marker for linking the pupal stage with each cytoform. Our results reveal the presence of hidden biodiversity in S. ignescens and S. tunja and demonstrate the power of polytene chromosomes as a tool for evaluating simuliid diversity, while illustrating the importance of integrated analyses in modern taxonomy. PMID- 27974484 TI - Buprenorphine, Norbuprenorphine, R-Methadone, and S-Methadone Upregulate BCRP/ABCG2 Expression by Activating Aryl Hydrocarbon Receptor in Human Placental Trophoblasts. AB - Opioid dependence during pregnancy is a rising concern. Maintaining addicted pregnant women on long-acting opioid receptor agonist is the most common strategy to manage drug abuse in pregnant women. Methadone (MET) and buprenorphine (BUP) are widely prescribed for opiate maintenance therapy. Norbuprenorphine (NBUP) is the primary active metabolite of BUP. These medications can cross the placenta to the fetus, leading to postpartum neonatal abstinence syndrome. Despite their use during pregnancy, little is known about the cellular changes in the placenta brought about by these drugs. In this study, we showed that BUP, NBUP, and MET at clinically relevant plasma concentrations significantly induced BCRP mRNA up to 10-fold in human model placental JEG3 and BeWo cells and in primary human villous trophoblasts, and this induction was abrogated by CH223191, an aryl hydrocarbon receptor (AhR)-specific antagonist. These drugs increased AhR recruitment onto the AhR-response elements and significantly induced breast cancer resistance protein (BCRP) gene transcription. AhR overexpression further increased BCRP mRNA and protein expression. Knockdown of AhR by shRNA decreased BCRP expression, and this decrease was reversed by rescuing AhR expression. Finally, induction of BCRP expression in JEG3 and BeWo cells was accompanied by an increase in its efflux activity. Collectively, we have demonstrated, for the first time, that BUP, NBUP, and MET are potent AhR agonists and can induce BCRP in human placental trophoblasts by activating AhR. Given the critical role of BCRP in limiting fetal exposure to drugs and xenobiotics, long-term use of these medications may affect fetal drug exposure by altering BCRP expression in human placenta. PMID- 27974487 TI - A Century of Sex Determination in Flowering Plants. AB - Plants have evolved a diverse array of strategies for sexual reproduction, particularly through the modification of male and female organs at distinct points in development. The immense variation in sexual systems across the land plants provides a unique opportunity to study the genetic, epigenetic, phylogenetic, and ecological underpinnings of sex determination. Here, we reflect on more than a century of research into flowering plant sex determination, placing a particular focus on the foundational genetic and cytogenetic observations, experiments, and hypotheses. Building on the seminal work on the genetics of plant sex, modern comparative genomic analyses now allow us to address longstanding questions about sex determination and the origins of sex chromosomes. PMID- 27974492 TI - Highly individualistic rates of plant phenological advance associated with arctic sea ice dynamics. AB - We analysed 12 years of species-specific emergence dates of plants at a Low Arctic site near Kangerlussuaq, Greenland to investigate associations with sea ice dynamics, a potential contributor to local temperature variation in near coastal tundra. Species displayed highly variable rates of phenological advance, from a maximum of -2.55 +/- 0.17 and -2.93 +/- 0.51 d yr-1 among a graminoid and forb, respectively, to a minimum of -0.55 +/- 0.19 d yr-1 or no advance at all in the two deciduous shrub species. Monthly Arctic-wide sea ice extent was a significant predictor of emergence timing in 10 of 14 species. Despite variation in rates of advance among species, these rates were generally greatest in the earliest emerging species, for which monthly sea ice extent was also the primary predictor of emergence. Variation among species in rates of phenological advance reshuffled the phenological community, with deciduous shrubs leafing out progressively later relative to forbs and graminoids. Because early species advanced more rapidly than late species, and because rates of advance were greatest in species for which emergence phenology was associated with sea ice dynamics, accelerating sea ice decline may contribute to further divergence between early- and late-emerging species in this community. PMID- 27974494 TI - Correction to 'Bacteria facilitate prey retention by the pitcher plant Darlingtonia californica'. PMID- 27974493 TI - Variation in growth of Damaraland mole-rats is explained by competition rather than by functional specialization for different tasks. AB - In some eusocial insect societies, adaptation to the division of labour results in multimodal size variation among workers. It has been suggested that variation in size and growth among non-breeders in naked and Damaraland mole-rats may similarly reflect functional divergence associated with different cooperative tasks. However, it is unclear whether individual growth rates are multimodally distributed (as would be expected if variation in growth is associated with specialization for different tasks) or whether variation in growth is unimodally distributed, and is related to differences in the social and physical environment (as would be predicted if there are individual differences in growth but no discrete differences in developmental pathways). Here, we show that growth trajectories of non-breeding Damaraland mole-rats vary widely, and that their distribution is unimodal, contrary to the suggestion that variation in growth is the result of differentiation into discrete castes. Though there is no evidence of discrete variation in growth, social factors appear to exert important effects on growth rates and age-specific size, which are both reduced in large social groups. PMID- 27974495 TI - A Systematic Review of Proximal Neck Dilatation After Endovascular Repair for Abdominal Aortic Aneurysm. AB - PURPOSE: To provide an updated systematic literature review and summarize current evidence on proximal aortic neck dilatation (AND) after endovascular aneurysm repair (EVAR). METHODS: A review of the English-language medical literature from 1991 to 2015 was conducted using MEDLINE and EMBASE to identify studies reporting AND after EVAR. Studies considered for inclusion and full-text review fulfilled the following criteria: (1) reported AND after EVAR, (2) included at least 5 patients, and (3) provided data on AND quantification. The search identified 26 articles published between 1998 and 2015 that encompassed 9721 patients (median age 71.8 years; 9439 men). RESULTS: AND occurred in 24.6% of patients (95% CI 18.6% to 31.8%) over a period ranging from 15 months to 9 years after EVAR. No significant dilatation of the suprarenal part of the aorta was reported by most studies. The incidence of combined clinical events (endoleak type I, migration, reintervention during follow-up) was higher in the AND group (26%) when compared with 2% in the group without AND (OR 28.7, 95% CI 5.43 to 151.67, p<0.001). CONCLUSION: AND affects a considerable proportion of EVAR patients and was related to worse clinical outcome, as indicated by increased rates of type I endoleak, migration, and reinterventions. Future studies should focus on a better understanding of the pathophysiology, predictors, and risk factors of AND, which could identify patients who may warrant a different EVAR strategy and/or a closer post-EVAR surveillance strategy. PMID- 27974496 TI - End-stage renal disease after occupational lead exposure: 20 years of follow-up. AB - OBJECTIVES: Whether low-level exposure to lead may give rise to chronic kidney disease or end-stage renal disease (ESRD) is debated. In this study, we aimed to specifically investigate if low-level occupational exposure to lead was associated with increased incidence of ESRD. METHODS: The incidence of starting renal replacement therapy as a result of ESRD was examined in a cohort of10 303 lead-workers who had controlled blood lead concentrations due to a compulsory occupational health surveillance programme in Sweden during the time period 1977 1990. The ESRD incidence (obtained through register-linkage) among the lead exposed workers was compared with the age, sex and calendar period-adjusted expected incidence based on data from the Swedish renal registry. Dose-response association was evaluated in external (general population) and internal (within the occupational cohort) comparisons by highest achieved blood lead level. RESULTS: There were 30 (0.29%) individuals in the cohort who developed ESRD during the median follow-up period of 26.3 years. The standardised incidence ratio (SIR) for ESRD incidence was 0.79 (95% CI 0.54 to 1.13). Among those who achieved the highest blood lead (>41.4 ug/dL), the SIR was 1.01 (0.44 to 1.99). There was no evidence of a dose-response relationship between the maximum achieved blood lead or the cumulative blood lead exposure and ESRD in external or internal comparisons. CONCLUSIONS: This study of workers with documented occupational lead exposures followed for 20 years shows no statistically significant association between lead exposure (following the current occupational recommendations for Sweden) and ESRD. PMID- 27974497 TI - The Promiscuous sumA Missense Suppressor from Salmonella enterica Has an Intriguing Mechanism of Action. AB - While most missense suppressors have very narrow specificities and only suppress the allele against which they were isolated, the sumA missense suppressor from Salmonella enterica serovar Typhimurium is a promiscuous or broad-acting missense suppressor that suppresses numerous missense mutants. The sumA missense suppressor was identified as a glyV tRNA Gly3(GAU/C) missense suppressor that can recognize GAU or GAC aspartic acid codons and insert a glycine amino acid instead of aspartic acid. In addition to rescuing missense mutants caused by glycine to aspartic acid changes as expected, sumA could also rescue a number of other missense mutants as well by changing a neighboring (contacting) aspartic acid to glycine, which compensated for the other amino acid change. Thus the ability of sumA to rescue numerous missense mutants was due in part to the large number of glycine codons in genes that can be mutated to an aspartic acid codon and in part to the general tolerability and/or preference for glycine amino acids in proteins. Because the glyV tRNA Gly3(GAU/C) missense suppressor has also been extensively characterized in Escherichia coli as the mutA mutator, we demonstrated that all gain-of-function mutants isolated in a glyV tRNA Gly3(GAU/C) missense suppressor are transferable to a wild-type background and thus the increased mutation rates, which occur in glyV tRNA Gly3(GAU/C) missense suppressors, are not due to the suppression of these mutants. PMID- 27974498 TI - Statistical Methods for Identifying Sequence Motifs Affecting Point Mutations. AB - Mutation processes differ between types of point mutation, genomic locations, cells, and biological species. For some point mutations, specific neighboring bases are known to be mechanistically influential. Beyond these cases, numerous questions remain unresolved, including: what are the sequence motifs that affect point mutations? How large are the motifs? Are they strand symmetric? And, do they vary between samples? We present new log-linear models that allow explicit examination of these questions, along with sequence logo style visualization to enable identifying specific motifs. We demonstrate the performance of these methods by analyzing mutation processes in human germline and malignant melanoma. We recapitulate the known CpG effect, and identify novel motifs, including a highly significant motif associated with A[Formula: see text]G mutations. We show that major effects of neighbors on germline mutation lie within [Formula: see text] of the mutating base. Models are also presented for contrasting the entire mutation spectra (the distribution of the different point mutations). We show the spectra vary significantly between autosomes and X-chromosome, with a difference in T[Formula: see text]C transition dominating. Analyses of malignant melanoma confirmed reported characteristic features of this cancer, including statistically significant strand asymmetry, and markedly different neighboring influences. The methods we present are made freely available as a Python library https://bitbucket.org/pycogent3/mutationmotif. PMID- 27974500 TI - Starvation-Induced Stress Response Is Critically Impacted by Ceramide Levels in Caenorhabditis elegans. AB - Our understanding of the cellular mechanisms by which animals regulate their response to starvation is limited, despite the strong relevance of the problem to major human health issues. The L1 diapause of Caenorhabditis elegans, where first stage larvae arrest in response to a food-less environment, is an excellent system to study this mechanism. We found, through genetic manipulation and lipid analysis, that biosynthesis of ceramide, particularly those with longer fatty acid side chains, critically impacts animal survival during L1 diapause. Genetic interaction analysis suggests that ceramide may act in both insulin-IGF-1 signaling (IIS)-dependent and IIS-independent pathways to affect starvation survival. Genetic and expression analyses indicate that ceramide is required for maintaining the proper expression of previously characterized starvation responsive genes, genes that are regulated by the IIS pathway and tumor suppressor Rb, and genes responsive to pathogen. These findings provide an important insight into the roles of sphingolipid metabolism, not only in starvation response, but also in aging and food-response-related human health problems. PMID- 27974499 TI - Human SOD1 ALS Mutations in a Drosophila Knock-In Model Cause Severe Phenotypes and Reveal Dosage-Sensitive Gain- and Loss-of-Function Components. AB - Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease and familial forms can be caused by numerous dominant mutations of the copper-zinc superoxide dismutase 1 (SOD1) gene. Substantial efforts have been invested in studying SOD1-ALS transgenic animal models; yet, the molecular mechanisms by which ALS-mutant SOD1 protein acquires toxicity are not well understood. ALS-like phenotypes in animal models are highly dependent on transgene dosage. Thus, issues of whether the ALS-like phenotypes of these models stem from overexpression of mutant alleles or from aspects of the SOD1 mutation itself are not easily deconvolved. To address concerns about levels of mutant SOD1 in disease pathogenesis, we have genetically engineered four human ALS causing SOD1 point mutations (G37R, H48R, H71Y, and G85R) into the endogenous locus of Drosophila SOD1 (dsod) via ends-out homologous recombination and analyzed the resulting molecular, biochemical, and behavioral phenotypes. Contrary to previous transgenic models, we have recapitulated ALS-like phenotypes without overexpression of the mutant protein. Drosophila carrying homozygous mutations rendering SOD1 protein enzymatically inactive (G85R, H48R, and H71Y) exhibited neurodegeneration, locomotor deficits, and shortened life span. The mutation retaining enzymatic activity (G37R) was phenotypically indistinguishable from controls. While the observed mutant dsod phenotypes were recessive, a gain of-function component was uncovered through dosage studies and comparisons with age-matched dsod null animals, which failed to show severe locomotor defects or nerve degeneration. We conclude that the Drosophila knock-in model captures important aspects of human SOD1-based ALS and provides a powerful and useful tool for further genetic studies. PMID- 27974501 TI - Human Facial Shape and Size Heritability and Genetic Correlations. AB - The human face is an array of variable physical features that together make each of us unique and distinguishable. Striking familial facial similarities underscore a genetic component, but little is known of the genes that underlie facial shape differences. Numerous studies have estimated facial shape heritability using various methods. Here, we used advanced three-dimensional imaging technology and quantitative human genetics analysis to estimate narrow sense heritability, heritability explained by common genetic variation, and pairwise genetic correlations of 38 measures of facial shape and size in normal African Bantu children from Tanzania. Specifically, we fit a linear mixed model of genetic relatedness between close and distant relatives to jointly estimate variance components that correspond to heritability explained by genome-wide common genetic variation and variance explained by uncaptured genetic variation, the sum representing total narrow-sense heritability. Our significant estimates for narrow-sense heritability of specific facial traits range from 28 to 67%, with horizontal measures being slightly more heritable than vertical or depth measures. Furthermore, for over half of facial traits, >90% of narrow-sense heritability can be explained by common genetic variation. We also find high absolute genetic correlation between most traits, indicating large overlap in underlying genetic loci. Not surprisingly, traits measured in the same physical orientation (i.e., both horizontal or both vertical) have high positive genetic correlations, whereas traits in opposite orientations have high negative correlations. The complex genetic architecture of facial shape informs our understanding of the intricate relationships among different facial features as well as overall facial development. PMID- 27974502 TI - Genetic Mechanisms Leading to Sex Differences Across Common Diseases and Anthropometric Traits. AB - Common diseases often show sex differences in prevalence, onset, symptomology, treatment, or prognosis. Although studies have been performed to evaluate sex differences at specific SNP associations, this work aims to comprehensively survey a number of complex heritable diseases and anthropometric traits. Potential genetically encoded sex differences we investigated include differential genetic liability thresholds or distributions, gene-sex interaction at autosomal loci, major contribution of the X-chromosome, or gene-environment interactions reflected in genes responsive to androgens or estrogens. Finally, we tested the overlap between sex-differential association with anthropometric traits and disease risk. We utilized complementary approaches of assessing GWAS association enrichment and SNP-based heritability estimation to explore explicit sex differences, as well as enrichment in sex-implicated functional categories. We do not find consistent increased genetic load in the lower-prevalence sex, or a disproportionate role for the X-chromosome in disease risk, despite sex heterogeneity on the X for several traits. We find that all anthropometric traits show less than complete correlation between the genetic contribution to males and females, and find a convincing example of autosome-wide genome-sex interaction in multiple sclerosis (P = 1 * 10-9). We also find some evidence for hormone responsive gene enrichment, and striking evidence of the contribution of sex differential anthropometric associations to common disease risk, implying that general mechanisms of sexual dimorphism determining secondary sex characteristics have shared effects on disease risk. PMID- 27974504 TI - Analysis of the mechanism of radiation-induced upregulation of mitochondrial abundance in mouse fibroblasts. AB - Mitochondria strongly contribute to the maintenance of cellular integrity through various mechanisms, including oxidative adenosine triphosphate production and calcium homeostasis regulation. Therefore, proper regulation of the abundance, distribution and activity of mitochondria is crucial for the maintenance of cellular homeostasis. Previous studies have shown that ionizing radiation (IR) alters mitochondrial functions, suggesting that mitochondria are likely to be an important target of IR. Though IR reportedly influences cellular mitochondrial abundance, the mechanism remains largely unknown. In this study, we examined how IR influences mitochondrial abundance in mouse fibroblasts. When mouse NIH/3T3 cells were exposed to X-rays, a time-dependent increase was observed in mitochondrial DNA (mtDNA) and mitochondrial mass, indicating radiation-induced upregulation of mitochondrial abundance. Meanwhile, not only did we not observe a significant change in autophagic activity after irradiation, but in addition, IR hardly influenced the expression of two mitochondrial proteins, cytochrome c oxidase subunit IV and cytochrome c, or the mRNA expression of Polg, a component of DNA polymerase gamma. We also observed that the expression of transcription factors involved in mitochondrial biogenesis was only marginally affected by IR. These data imply that radiation-induced upregulation of mitochondrial abundance is an event independent of macroautophagy and mitochondrial biogenesis. Furthermore, we found evidence that IR induced long-term cell cycle arrest and cellular senescence, indicating that these events are involved in regulating mitochondrial abundance. Considering the growing significance of mitochondria in cellular radioresponses, we believe the present study provides novel insights into understanding the effects of IR on mitochondria. PMID- 27974505 TI - Metabolomic screening using ESI-FT MS identifies potential radiation-responsive molecules in mouse urine. AB - The demand for establishment of high-throughput biodosimetric methods is increasing. Our aim in this study was to identify low-molecular-weight urinary radiation-responsive molecules using electrospray ionization Fourier transform mass spectrometry (ESI-FT MS), and our final goal was to develop a sensitive biodosimetry technique that can be applied in the early triage of a radiation emergency medical system. We identified nine metabolites by statistical comparison of mouse urine before and 8 h after irradiation. Time-course analysis showed that, of these metabolites, thymidine and either thymine or imidazoleacetic acid were significantly increased dose-dependently 8 h after radiation exposure; these molecules have already been reported as potential radiation biomarkers. Phenyl glucuronide was significantly decreased 8 h after radiation exposure, irrespective of the dose. Histamine and 1-methylhistamine were newly identified by MS/MS and showed significant, dose-dependent increases 72 h after irradiation. Quantification of 1-methylhistamine by enzyme-linked immunosorbent assay (ELISA) analysis also showed a significant increase 72 h after 4 Gy irradiation. These results suggest that urinary metabolomics screening using ESI-FT MS can be a powerful tool for identifying promising radiation responsive molecules, and that urinary 1-methylhistamine is a potential radiation responsive molecule for acute, high-dose exposure. PMID- 27974503 TI - Traffic Through the Trans-Golgi Network and the Endosomal System Requires Collaboration Between Exomer and Clathrin Adaptors in Fission Yeast. AB - Despite its biological and medical relevance, traffic from the Golgi to the plasma membrane (PM) is one of the least understood steps of secretion. Exomer is a protein complex that mediates the trafficking of certain cargoes from the trans Golgi network/early endosomes to the PM in budding yeast. Here, we show that in Schizosaccharomyces pombe the Cfr1 and Bch1 proteins constitute the simplest form of an exomer. Cfr1 co-immunoprecipitates with Assembly Polypeptide adaptor 1 (AP 1), AP-2, and Golgi-localized, gamma-adaptin ear domain homology, ARF-binding (GGA) subunits, and cfr1+ interacts genetically with AP-1 and GGA genes. Exomer defective cells exhibit multiple mild defects, including alterations in the morphology of Golgi stacks and the distribution of the synaptobrevin-like Syb1 protein, carboxypeptidase missorting, and stress sensitivity. S. pombe apm1Delta cells exhibit a defect in trafficking through the early endosomes that is severely aggravated in the absence of exomer. apm1Delta cfr1Delta cells exhibit a dramatic disorganization of intracellular compartments, including massive accumulation of electron-dense tubulovesicular structures. While the trans-Golgi network/early endosomes are severely disorganized in the apm1Delta cfr1Delta strain, gga21Delta gga22Delta cfr1Delta cells exhibit a significant disturbance of the prevacuolar/vacuolar compartments. Our findings show that exomer collaborates with clathrin adaptors in trafficking through diverse cellular compartments, and that this collaboration is important to maintain their integrity. These results indicate that the effect of eliminating exomer is more pervasive than that described to date, and suggest that exomer complexes might participate in diverse steps of vesicle transport in other organisms. PMID- 27974507 TI - Validation of the relative insensitivity of volumetric-modulated arc therapy (VMAT) plan quality to gantry space resolution. AB - Volumetric-modulated arc therapy (VMAT) is an efficient form of radiotherapy used to deliver intensity-modulated radiotherapy beams. The aim of this study was to investigate the relative insensitivity of VMAT plan quality to gantry angle spacing (GS). Most previous VMAT planning and dosimetric work for GS resolution has been conducted for single arc VMAT. In this work, a quantitative comparison of dose-volume indices (DIs) was made for partial-, single- and double-arc VMAT plans optimized at 2 degrees , 3 degrees and 4 degrees GS, representing a large variation in deliverable multileaf collimator segments. VMAT plans of six prostate cancer and six head-and-neck cancer patients were simulated for an Elekta SynergyS(r) Linac (Elekta Ltd, Crawley, UK), using the SmartArcTM module of Pinnacle3 TPS, (version 9.2, Philips Healthcare). All optimization techniques generated clinically acceptable VMAT plans, except for the single-arc for the head-and-neck cancer patients. Plan quality was assessed by comparing the DIs for the planning target volume, organs at risk and normal tissue. A GS of 2 degrees , with finest resolution and consequently highest intensity modulation, was considered to be the reference, and this was compared with GS 3 degrees and 4 degrees . The differences between the majority of reference DIs and compared DIs were <2%. The metrics, such as treatment plan optimization time and pretreatment (phantom) dosimetric calculation time, supported the use of a GS of 4 degrees . The ArcCHECKTM phantom-measured dosimetric agreement verifications resulted in a >95.0% passing rate, using the criteria for gamma (3%, 3 mm). In conclusion, a GS of 4 degrees is an optimal choice for minimal usage of planning resources without compromise of plan quality. PMID- 27974506 TI - Ionizing radiation regulates long non-coding RNAs in human peripheral blood mononuclear cells. AB - Long non-coding RNAs (lncRNAs) are non-protein coding transcripts that modulate mRNA and microRNA (miRNA) expression, thereby controlling multiple cellular processes, including transcriptional regulation of gene expression, cell differentiation and apoptosis. Ionizing radiation (IR), a strong cellular stressor, is known to influence gene expression of irradiated cells, mainly by activation of oxidative processes. Whether and how IR also affects lncRNA expression in human peripheral blood mononuclear cells (PBMCs) is still poorly understood. Exposure of PBMCs to IR dose-dependently activated p53 and its downstream target p21, ultimately leading to cell-cycle arrest and/or apoptosis. Cleavage of caspase-3, a specific process during apoptotic cell death, was detectable at doses as low as 30 Gy. Transcriptome analysis of 60 Gy-irradiated PBMCs revealed a strong time-dependent regulation of a variety of lncRNAs. Among many unknown lncRNAs we also identified a significant upregulation of Trp53cor1, MEG3 and TUG1, which have been shown to be involved in the regulation of cell cycle and apoptotic processes mediated by p53. In addition, we found 177 miRNAs regulated in the same samples, including several miRNAs that are known targets of upregulated lncRNAs. Our data show that IR dose-dependently regulates the expression of a wide spectrum of lncRNAs in PBMCs, suggesting a crucial role for lncRNAs in the complex regulatory machinery activated in response to IR. PMID- 27974508 TI - Adequate target volume in total-body irradiation by intensity-modulated radiation therapy using helical tomotherapy: a simulation study. AB - Recently, intensity-modulated radiation therapy (IMRT) has been used for total body irradiation (TBI). Since the planning target volume (PTV) for TBI includes the surrounding air, a dose prescription to the PTV provides high fluence to the body surface. Thus with just a small set-up error, the body might be exposed to a high-fluence beam. This study aims to assess which target volume should be prescribed the dose, such as a clinical target volume (CTV) with a margin, or a CTV that excludes the surface area of the skin. Three treatment plans were created for each patient: the 5-mm clipped plan (Plan A), the 0-mm margin plan (Plan B) and the 5-mm margin plan (Plan C). The CTV was the whole body. PTVs were the CTV with the exception of 5 mm from the skin surface in Plan A, equal to the CTV in Plan B, and the CTV with a 5 mm margin in Plan C. The prescribed dose was 12 Gy in six fractions. To assess the influence of the set-up error, dose distributions were simulated on computed tomography (CT) images shifted 2 pixels (= 4.296 mm), 5 pixels (= 10.74 mm) and 10 pixels (= 21.48 mm) in the lateral direction from the original CT. With a set-up error of 10.74 mm, V110% was 8.8%, 11.1% and 23.3% in Plans A, B and C, respectively. The prescription to the PTV containing the surrounding air can be paradoxically vulnerable to a high-dose as a consequence of a small set-up error. PMID- 27974509 TI - Proton beam therapy for liver metastases from gastric cancer. AB - Liver metastases from gastric cancer (LMGC) is a non-curable, fatal disease with a 5-year survival rate of <10%. Although various local treatments have been applied, their clinical utility has not been established. The purpose of this study was to investigate the safety and effectiveness of proton beam therapy (PBT) for the treatment of patients with LMGC. A total of nine patients (seven men, two women; aged 56-78 years) with LMGC who received PBT between 2002 and 2012 were retrospectively reviewed. Patients who had tumors confined to the liver were investigated, and patients who had extrahepatic tumors were excluded. Six of the patients had solitary tumors, and three patients had multiple tumors. The total irradiation dose was 64-77 Gy relative biological effectiveness (RBE), and three patients received concurrent chemotherapy. The overall and progression-free survival (OS and PFS) rates, local control (LC) rate, and adverse effects were investigated. All patients completed treatment without interruption, and late adverse effects of higher than Grade 3 were not observed. The OS rates at 1, 3 and 5 years were 100%, 78% and 56%, respectively (median, 5.5 years); the PFS rates were 67%, 40% and 40% (median, 2.6 years); and the LC rates were 89%, 71% and 71%. PBT was demonstrated to be a safe treatment, and the OS and PFS rates were not inferior to those for other types of local treatment. Therefore, PBT should be considered as an effective local treatment option for patients with LMGC. PMID- 27974510 TI - Modeling cell survival and change in amount of DNA during protracted irradiation. AB - Hyper-radiosensitivity (HRS) is a well-known bioresponse under low-dose or low dose-rate exposures. Although disorder of the DNA repair function, non-targeted effects and accumulation of cells in G2 have been experimentally observed, the mechanism for inducing HRS by long-term irradiation is still unclear. On the basis of biological experiments and a theoretical study, we have shown that change in the amount of DNA associated with accumulation of cells in G2 enhances radiosensitivity. To demonstrate continuous irradiation with 250 kVp X-rays, we adopted a fractionated regimen of 0.186 or 1.00 Gy per fraction at intervals of 1 h (i.e. 0.186 Gy/h, 1.00 Gy/h on average) to Chinese Hamster Ovary (CHO)-K1 cells. The change in the amount of DNA during irradiation was quantified by flow cytometric analysis with propidium iodide (PI). Concurrently, we attempted a theoretical evaluation of the DNA damage by using a microdosimetric-kinetic (MK) model that was modified to incorporate the change in the amount of DNA. Our experimental results showed that the fraction of the cells in G2/M phase increased by 6.7% with 0.186 Gy/h and by 22.1% with 1.00 Gy/h after the 12th irradiation. The MK model considering the change in amount of DNA during the irradiation exhibited a higher radiosensitivity at a high dose range, which could account for the experimental clonogenic survival. The theoretical results suggest that HRS in the high dose range is associated with an increase in the total amount of DNA during irradiation. PMID- 27974511 TI - Correction. PMID- 27974514 TI - Neural correlates of side-specific odour memory in mushroom body output neurons. AB - Humans and other mammals as well as honeybees learn a unilateral association between an olfactory stimulus presented to one side and a reward. In all of them, the learned association can be behaviourally retrieved via contralateral stimulation, suggesting inter-hemispheric communication. However, the underlying neuronal circuits are largely unknown and neural correlates of across-brain-side plasticity have yet not been demonstrated. We report neural plasticity that reflects lateral integration after side-specific odour reward conditioning. Mushroom body output neurons that did not respond initially to contralateral olfactory stimulation developed a unique and stable representation of the rewarded compound stimulus (side and odour) predicting its value during memory retention. The encoding of the reward-associated compound stimulus is delayed by about 40 ms compared with unrewarded neural activity, indicating an increased computation time for the read-out after lateral integration. PMID- 27974515 TI - Behavioural hypervolumes of spider communities predict community performance and disbandment. AB - Trait-based ecology argues that an understanding of the traits of interactors can enhance the predictability of ecological outcomes. We examine here whether the multidimensional behavioural-trait diversity of communities influences community performance and stability in situ We created experimental communities of web building spiders, each with an identical species composition. Communities contained one individual of each of five different species. Prior to establishing these communities in the field, we examined three behavioural traits for each individual spider. These behavioural measures allowed us to estimate community wide behavioural diversity, as inferred by the multidimensional behavioural volume occupied by the entire community. Communities that occupied a larger region of behavioural-trait space (i.e. where spiders differed more from each other behaviourally) gained more mass and were less likely to disband. Thus, there is a community-wide benefit to multidimensional behavioural diversity in this system that might translate to other multispecies assemblages. PMID- 27974516 TI - Atmospheric rivers and the mass mortality of wild oysters: insight into an extreme future? AB - Climate change is predicted to increase the frequency and severity of extreme events. However, the biological consequences of extremes remain poorly resolved owing to their unpredictable nature and difficulty in quantifying their mechanisms and impacts. One key feature delivering precipitation extremes is an atmospheric river (AR), a long and narrow filament of enhanced water vapour transport. Despite recent attention, the biological impacts of ARs remain undocumented. Here, we use biological data coupled with remotely sensed and in situ environmental data to describe the role of ARs in the near 100% mass mortality of wild oysters in northern San Francisco Bay. In March 2011, a series of ARs made landfall within California, contributing an estimated 69.3% of the precipitation within the watershed and driving an extreme freshwater discharge into San Francisco Bay. This discharge caused sustained low salinities (less than 6.3) that almost perfectly matched the known oyster critical salinity tolerance and was coincident with a mass mortality of one of the most abundant populations throughout this species' range. This is a concern, because wild oysters remain a fraction of their historical abundance and have yet to recover. This study highlights a novel mechanism by which precipitation extremes may affect natural systems and the persistence of sensitive species in the face of environmental change. PMID- 27974513 TI - Bacterial Proteasomes: Mechanistic and Functional Insights. AB - Regulated proteolysis is essential for the normal physiology of all organisms. While all eukaryotes and archaea use proteasomes for protein degradation, only certain orders of bacteria have proteasomes, whose functions are likely as diverse as the species that use them. In this review, we discuss the most recent developments in the understanding of how proteins are targeted to proteasomes for degradation, including ATP-dependent and -independent mechanisms, and the roles of proteasome-dependent degradation in protein quality control and the regulation of cellular physiology. Furthermore, we explore newly established functions of proteasome system accessory factors that function independently of proteolysis. PMID- 27974518 TI - Passive drift or active swimming in marine organisms? AB - Predictions of organismal movements in a fluid require knowing the fluid's velocity and potential contributions of the organism's behaviour (e.g. swimming or flying). While theoretical aspects of this work are reasonably well-developed, field-based validation is challenging. A much-needed study recently published by Briscoe and colleagues in Proceedings of the Royal Society B compared movements and distribution of satellite-tracked juvenile sea turtles to virtual particles released in a data-assimilating hindcast ocean circulation model. Substantial differences observed between turtles and particles were considered evidence for an important role of active swimming by turtles. However, the experimental design implicitly assumed that transport predictions were insensitive to (i) start location, (ii) tracking duration, (iii) depth, and (iv) physical processes not depicted in the model. Here, we show that the magnitude of variation in physical parameters between turtles and virtual particles can profoundly alter transport predictions, potentially sufficient to explain the reported differences without evoking swimming behaviour. We present a more robust method to derive the environmental contributions to individual movements, but caution that resolving the ocean velocities experienced by individual organisms remains a problem for assessing the role of behaviour in organismal movements and population distributions. PMID- 27974519 TI - Postcopulatory sexual selection influences baculum evolution in primates and carnivores. AB - The extreme morphological variability of the baculum across mammals is thought to be the result of sexual selection (particularly, high levels of postcopulatory selection). However, the evolutionary trajectory of the mammalian baculum is little studied and evidence for the adaptive function of the baculum has so far been elusive. Here, we use Markov chain Monte Carlo methods implemented in a Bayesian phylogenetic framework to reconstruct baculum evolution across the mammalian class and investigate the rate of baculum length evolution within the primate order. We then test the effects of testes mass (postcopulatory sexual selection), polygamy, seasonal breeding and intromission duration on the baculum in primates and carnivores. The ancestral mammal did not have a baculum, but both ancestral primates and carnivores did. No relationship was found between testes mass and baculum length in either primates or carnivores. Intromission duration correlated with baculum presence over the course of primate evolution, and prolonged intromission predicts significantly longer bacula in extant primates and carnivores. Both polygamous and seasonal breeding systems predict significantly longer bacula in primates. These results suggest the baculum plays an important role in facilitating reproductive strategies in populations with high levels of postcopulatory sexual selection. PMID- 27974520 TI - Recombination in the eggs and sperm in a simultaneously hermaphroditic vertebrate. AB - When there is no recombination (achiasmy) in one sex, it is in the heterogametic one. This observation is so consistent that it constitutes one of the few patterns in biology that may be regarded as a 'rule' and Haldane (Haldane 1922 J. Genet. 12, 101-109. (doi:10.1007/BF02983075)) proposed that it might be driven by selection against recombination in the sex chromosomes. Yet differences in recombination rates between the sexes (heterochiasmy) have also been reported in hermaphroditic species that lack sex chromosomes. In plants-the vast majority of which are hermaphroditic-selection at the haploid stage has been proposed to drive heterochiasmy. Yet few data are available for hermaphroditic animals, and barely any for hermaphroditic vertebrates. Here, we leverage reciprocal crosses between two black hamlets (Hypoplectrus nigricans, Serranidae), simultaneously hermaphroditic reef fishes from the wider Caribbean, to generate high-density egg and sperm-specific linkage maps for each parent. We find globally higher recombination rates in the eggs, with dramatically pronounced heterochiasmy at the chromosome peripheries. We suggest that this pattern may be due to female meiotic drive, and that this process may be an important source of heterochiasmy in animals. We also identify a large non-recombining region that may play a role in speciation and local adaptation in Hypoplectrus. PMID- 27974517 TI - Evolutionary heritage influences Amazon tree ecology. AB - Lineages tend to retain ecological characteristics of their ancestors through time. However, for some traits, selection during evolutionary history may have also played a role in determining trait values. To address the relative importance of these processes requires large-scale quantification of traits and evolutionary relationships among species. The Amazonian tree flora comprises a high diversity of angiosperm lineages and species with widely differing life history characteristics, providing an excellent system to investigate the combined influences of evolutionary heritage and selection in determining trait variation. We used trait data related to the major axes of life-history variation among tropical trees (e.g. growth and mortality rates) from 577 inventory plots in closed-canopy forest, mapped onto a phylogenetic hypothesis spanning more than 300 genera including all major angiosperm clades to test for evolutionary constraints on traits. We found significant phylogenetic signal (PS) for all traits, consistent with evolutionarily related genera having more similar characteristics than expected by chance. Although there is also evidence for repeated evolution of pioneer and shade tolerant life-history strategies within independent lineages, the existence of significant PS allows clearer predictions of the links between evolutionary diversity, ecosystem function and the response of tropical forests to global change. PMID- 27974521 TI - The influence of wing morphology upon the dispersal, geographical distributions and diversification of the Corvides (Aves; Passeriformes). AB - New species are sometimes known to arise as a consequence of the dispersal and establishment of populations in new areas. It has nevertheless been difficult to demonstrate an empirical link between rates of dispersal and diversification, partly because dispersal abilities are challenging to quantify. Here, using wing morphology as a proxy for dispersal ability, we assess this relationship among the global radiation of corvoid birds. We found that species distributions are associated with wing shape. Widespread species (occurring on both islands and continents), and those that are migratory, exhibit wing morphologies better adapted to long-distance flight compared with sedentary continental or insular forms. Habitat preferences also strongly predict wing form, with species that occur in canopies and/or areas of sparse vegetation possessing dispersive morphologies. By contrast, we found no significant differences in diversification rates among either the migratory or habitat classifications, but species distributed in island settings diversify at higher rates than those found on continents. This latter finding may reflect the elevated dispersal capabilities of widespread taxa, facilitating the radiation of these lineages across insular areas. However, as the correlations between wing morphology and diversification rates were consistently weak throughout our dataset, this suggests that historical patterns of diversification are not particularly well reflected by present-day wing morphology. PMID- 27974522 TI - Automatic facial mimicry in response to dynamic emotional stimuli in five-month old infants. AB - Human adults automatically mimic others' emotional expressions, which is believed to contribute to sharing emotions with others. Although this behaviour appears fundamental to social reciprocity, little is known about its developmental process. Therefore, we examined whether infants show automatic facial mimicry in response to others' emotional expressions. Facial electromyographic activity over the corrugator supercilii (brow) and zygomaticus major (cheek) of four- to five month-old infants was measured while they viewed dynamic clips presenting audiovisual, visual and auditory emotions. The audiovisual bimodal emotion stimuli were a display of a laughing/crying facial expression with an emotionally congruent vocalization, whereas the visual/auditory unimodal emotion stimuli displayed those emotional faces/vocalizations paired with a neutral vocalization/face, respectively. Increased activation of the corrugator supercilii muscle in response to audiovisual cries and the zygomaticus major in response to audiovisual laughter were observed between 500 and 1000 ms after stimulus onset, which clearly suggests rapid facial mimicry. By contrast, both visual and auditory unimodal emotion stimuli did not activate the infants' corresponding muscles. These results revealed that automatic facial mimicry is present as early as five months of age, when multimodal emotional information is present. PMID- 27974523 TI - Epidemiological models to control the spread of information in marine mammals. AB - Socially transmitted wildlife behaviours that create human-wildlife conflict are an emerging problem for conservation efforts, but also provide a unique opportunity to apply principles of infectious disease control to wildlife management. As an example, California sea lions (Zalophus californianus) have learned to exploit concentrations of migratory adult salmonids below the fish ladders at Bonneville Dam, impeding endangered salmonid recovery. Proliferation of this foraging behaviour in the sea lion population has resulted in a controversial culling programme of individual sea lions at the dam, but the impact of such culling remains unclear. To evaluate the effectiveness of current and alternative culling strategies, we used network-based diffusion analysis on a long-term dataset to demonstrate that social transmission is implicated in the increase in dam-foraging behaviour and then studied different culling strategies within an epidemiological model of the behavioural transmission data. We show that current levels of lethal control have substantially reduced the rate of social transmission, but failed to effectively reduce overall sea lion recruitment. Earlier implementation of culling could have substantially reduced the extent of behavioural transmission and, ultimately, resulted in fewer animals being culled. Epidemiological analyses offer a promising tool to understand and control socially transmissible behaviours. PMID- 27974524 TI - A biogeographic network reveals evolutionary links between deep-sea hydrothermal vent and methane seep faunas. AB - Deep-sea hydrothermal vents and methane seeps are inhabited by members of the same higher taxa but share few species, thus scientists have long sought habitats or regions of intermediate character that would facilitate connectivity among these habitats. Here, a network analysis of 79 vent, seep, and whale-fall communities with 121 genus-level taxa identified sedimented vents as a main intermediate link between the two types of ecosystems. Sedimented vents share hot, metal-rich fluids with mid-ocean ridge-type vents and soft sediment with seeps. Such sites are common along the active continental margins of the Pacific Ocean, facilitating connectivity among vent/seep faunas in this region. By contrast, sedimented vents are rare in the Atlantic Ocean, offering an explanation for the greater distinction between its vent and seep faunas compared with those of the Pacific Ocean. The distribution of subduction zones and associated back-arc basins, where sedimented vents are common, likely plays a major role in the evolutionary and biogeographic connectivity of vent and seep faunas. The hypothesis that decaying whale carcasses are dispersal stepping stones linking these environments is not supported. PMID- 27974531 TI - Cracking an improbable sensory map. PMID- 27974525 TI - 16S pan-bacterial PCR can accurately identify patients with ventilator-associated pneumonia. AB - : Ventilator-associated pneumonia (VAP) remains a challenge to intensive care units, with secure diagnosis relying on microbiological cultures that take up to 72 hours to provide a result. We sought to derive and validate a novel, real-time 16S rRNA gene PCR for rapid exclusion of VAP. Bronchoalveolar lavage (BAL) was obtained from two independent cohorts of patients with suspected VAP. Patients were recruited in a 2-centre derivation cohort and a 12-centre confirmation cohort. Confirmed VAP was defined as growth of >104 colony forming units/ml on semiquantitative culture and compared with a 16S PCR assay. Samples were tested from 67 patients in the derivation cohort, 10 (15%) of whom had confirmed VAP. Using cycles to cross threshold (Ct) values as the result of the 16S PCR test, the area under the receiver operating characteristic (ROC) curve (AUROC) was 0.94 (95% CI 0.86 to 1.0, p<0.0001). Samples from 92 patients were available from the confirmation cohort, 26 (28%) of whom had confirmed VAP. The AUROC for Ct in this cohort was 0.89 (95% CI 0.83 to 0.95, p<0.0001). This study has derived and assessed the diagnostic accuracy of a novel application for 16S PCR. This suggests that 16S PCR in BAL could be used as a rapid test in suspected VAP and may allow better stewardship of antibiotics. TRIAL REGISTRATION NUMBER: VAPRAPID trial ref NCT01972425. PMID- 27974526 TI - Chronotherapy for hypertension in obstructive sleep apnoea (CHOSA): a randomised, double-blind, placebo-controlled crossover trial. AB - BACKGROUND: Obstructive sleep apnoea (OSA) is an important cause of secondary hypertension. Nocturnal hypertension is particularly prevalent in OSA and is a strong predictor of cardiovascular mortality. Studies in patients with essential hypertension have suggested that nocturnal administration of antihypertensives improves nocturnal blood pressure (BP) without elevating daytime BP. We evaluated the efficacy of this technique in patients with OSA with stage I/II hypertension, both before and after the addition of CPAP. METHODS: In this double-blind randomised placebo-controlled crossover trial, patients with moderate-to-severe OSA and hypertension received 6 weeks each of evening or morning perindopril with opposing time-matched placebo. CPAP therapy was subsequently added for 8 weeks in addition to either morning or evening perindopril. The primary outcome was sleep systolic BP (SBP) using 24-hour BP monitoring, analysed using linear mixed models. RESULTS: Between March 2011 and January 2015, 85 patients were randomised, 79 completed both dosing times, 78 completed the CPAP phase. Sleep SBP reduced significantly from baseline with both evening (-6.9 mm Hg) and morning (-8.0 mm Hg) dosing, but there was no difference between dosing times (difference: 1.1 mm Hg, 95% CI -0.3 to 2.5). However, wake SBP reduced more with morning (-9.8 mm Hg) than evening (-8.0 mm Hg) dosing (difference: 1.8 mm Hg, 95% CI 1.1 to 2.5). Addition of CPAP to either evening or morning dosing further reduced sleep SBP, but by a similar amount (evening: -3.2 mm Hg, 95% CI -5.1 to 1.3; morning: -3.3 mm Hg, 95% CI -5.2 to 1.5). CONCLUSIONS: Our findings support combining OSA treatment with morning administration of antihypertensives. Unlike in essential hypertension, our results do not support evening administration of antihypertensives, at least with perindopril. Further research is required before this strategy can be widely adopted into hypertension guidelines and clinical practice. TRIAL REGISTRATION NUMBER: ACTRN12611000216910, Results. PMID- 27974533 TI - The unusual eyes of Xenos peckii (Strepsiptera: Xenidae) have green- and UV- sensitive photoreceptors. AB - The highly specialized evolution of Strepsiptera has produced one of the most unusual eyes among mature insects, perhaps in line with their extremely complex and challenging life cycle. This relatively rare insect order is one of the few for which it has been unclear what spectral classes of photoreceptors any of its members may possess, an even more apt question given the nocturnal evolution of the group. To address this question, we performed electroretinograms on adult male Xenos peckii: we measured spectral responses to equi-quantal monochromatic light flashes of different wavelengths, and established VlogI relationships to calculate spectral sensitivities. Based on opsin template fits, we found maximal spectral sensitivity (lambdamax) in the green domain at 539 nm. Application of a green light to 'bleach' green receptors revealed that a UV peak was contributed to by an independent UV opsin with a lambdamax of 346 nm. Transcriptomics and a phylogenetic analysis including 50 other opsin sequences further confirmed the presence of these two opsin classes. While these findings do not necessarily indicate that these unorthodox insects have color vision, they raise the possibility that UV vision plays an important role in the ability of X. peckii males to find the very cryptic strepsipteran females that are situated within their wasp hosts. PMID- 27974532 TI - Can invertebrates see the e-vector of polarization as a separate modality of light? AB - The visual world is rich in linearly polarized light stimuli, which are hidden from the human eye. But many invertebrate species make use of polarized light as a source of valuable visual information. However, exploiting light polarization does not necessarily imply that the electric (e)-vector orientation of polarized light can be perceived as a separate modality of light. In this Review, I address the question of whether invertebrates can detect specific e-vector orientations in a manner similar to that of humans perceiving spectral stimuli as specific hues. To analyze e-vector orientation, the signals of at least three polarization sensitive sensors (analyzer channels) with different e-vector tuning axes must be compared. The object-based, imaging polarization vision systems of cephalopods and crustaceans, as well as the water-surface detectors of flying backswimmers, use just two analyzer channels. Although this excludes the perception of specific e-vector orientations, a two-channel system does provide a coarse, categoric analysis of polarized light stimuli, comparable to the limited color sense of dichromatic, 'color-blind' humans. The celestial compass of insects employs three or more analyzer channels. However, that compass is multimodal, i.e. e-vector information merges with directional information from other celestial cues, such as the solar azimuth and the spectral gradient in the sky, masking e-vector information. It seems that invertebrate organisms take no interest in the polarization details of visual stimuli, but polarization vision grants more practical benefits, such as improved object detection and visual communication for cephalopods and crustaceans, compass readings to traveling insects, or the alert 'water below!' to water-seeking bugs. PMID- 27974534 TI - How the bending kinematics of swimming lampreys build negative pressure fields for suction thrust. AB - Swimming animals commonly bend their bodies to generate thrust. For undulating animals such as eels and lampreys, their bodies bend in the form of waves that travel from head to tail. These kinematics accelerate the flow of adjacent fluids, which alters the pressure field in a manner that generates thrust. We used a comparative approach to evaluate the cause-and-effect relationships in this process by quantifying the hydrodynamic effects of body kinematics at the body-fluid interface of the lamprey, Petromyzon marinus, during steady-state swimming. We compared the kinematics and hydrodynamics of healthy control lampreys to lampreys whose spinal cord had been transected mid-body, resulting in passive kinematics along the posterior half of their body. Using high-speed particle image velocimetry (PIV) and a method for quantifying pressure fields, we detail how the active bending kinematics of the control lampreys were crucial for setting up strong negative pressure fields (relative to ambient fields) that generated high-thrust regions at the bends as they traveled all along the body. The passive kinematics of the transected lamprey were only able to generate significant thrust at the tail, relying on positive pressure fields. These different pressure and thrust scenarios are due to differences in how active versus passive body waves generated and controlled vorticity. This demonstrates why it is more effective for undulating lampreys to pull, rather than push, themselves through the fluid. PMID- 27974535 TI - Coloration mechanisms and phylogeny of Morpho butterflies. AB - Morpho butterflies are universally admired for their iridescent blue coloration, which is due to nanostructured wing scales. We performed a comparative study on the coloration of 16 Morpho species, investigating the morphological, spectral and spatial scattering properties of the differently organized wing scales. In numerous previous studies, the bright blue Morpho coloration has been fully attributed to the multi-layered ridges of the cover scales' upper laminae, but we found that the lower laminae of the cover and ground scales play an important additional role, by acting as optical thin film reflectors. We conclude that Morpho coloration is a subtle combination of overlapping pigmented and/or unpigmented scales, multilayer systems, optical thin films and sometimes undulated scale surfaces. Based on the scales' architecture and their organization, five main groups can be distinguished within the genus Morpho, largely agreeing with the accepted phylogeny. PMID- 27974536 TI - The groEL Gene Is a Promising Target for Species-Level Identification of Tsukamurella. PMID- 27974537 TI - Ebola Preparedness: Diagnosis Improvement Using Rapid Approaches for Proficiency Testing. AB - The unprecedented 2015 Ebolavirus (EBOV) outbreak in West Africa was declared a public health emergency, making diagnosis and quality of testing a global issue. The accuracy of laboratory diagnostic capacity for EBOV was assessed in 2014 to 2016 using a proficiency testing (PT) strategy developed by the Royal College of Pathologists of Australasia Quality Assurance Programs (RCPAQAP) in Biosecurity. Following a literature search, EBOV-specific gene targets were ranked according to the frequency of their use in published methods. The most commonly used gene regions (nucleoprotein [NP], glycoprotein [GP], and RNA-dependent RNA polymerase [L]) were selected for the design of in vitro RNA transcripts to be included in the simulated EBOV specimens used for EBOV detection with PCR-based assays. Specimens were tested for stability and found to be stable on long-term storage (1 year) at -80 degrees C and on shorter-term storage in lyophilized form (1 week at ambient temperature and a subsequent week at -80 degrees C). These specimens were used in three EBOV PTs offered from April 2014 to March 2016. In the first and third PTs, all laboratories (3/3 and 9/9, respectively) correctly identified specimens containing EBOV RNA transcripts, while in the second PT, all but one laboratory (5/6) correctly confirmed the presence of EBOV. The EBOV PT panel was useful for ensuring the competency of laboratories in detecting EBOV in the absence of readily available clinical samples. The simulated EBOV specimen was safe, stable, and reliable and can be used in lyophilized form for future EBOV PT programs, allowing simplicity of transport. PMID- 27974538 TI - Identification of Escherichia coli and Shigella Species from Whole-Genome Sequences. AB - Escherichia coli and Shigella species are closely related and genetically constitute the same species. Differentiating between these two pathogens and accurately identifying the four species of Shigella are therefore challenging. The organism-specific bioinformatics whole-genome sequencing (WGS) typing pipelines at Public Health England are dependent on the initial identification of the bacterial species by use of a kmer-based approach. Of the 1,982 Escherichia coli and Shigella sp. isolates analyzed in this study, 1,957 (98.4%) had concordant results by both traditional biochemistry and serology (TB&S) and the kmer identification (ID) derived from the WGS data. Of the 25 mismatches identified, 10 were enteroinvasive E. coli isolates that were misidentified as Shigella flexneri or S. boydii by the kmer ID, and 8 were S. flexneri isolates misidentified by TB&S as S. boydii due to nonfunctional S. flexneri O antigen biosynthesis genes. Analysis of the population structure based on multilocus sequence typing (MLST) data derived from the WGS data showed that the remaining discrepant results belonged to clonal complex 288 (CC288), comprising both S. boydii and S. dysenteriae strains. Mismatches between the TB&S and kmer ID results were explained by the close phylogenetic relationship between the two species and were resolved with reference to the MLST data. Shigella can be differentiated from E. coli and accurately identified to the species level by use of kmer comparisons and MLST. Analysis of the WGS data provided explanations for the discordant results between TB&S and WGS data, revealed the true phylogenetic relationships between different species of Shigella, and identified emerging pathoadapted lineages. PMID- 27974539 TI - Nosocomial Outbreak of Drug-Resistant Streptococcus pneumoniae Serotype 9V in an Adult Respiratory Medicine Ward. AB - Streptococcus pneumoniae infections arising in hospitalized patients are often assumed to be sporadic and linked to community acquisition. Here, whole-genome sequencing was used to demonstrate nosocomial acquisition of antimicrobial resistant sequence type 156 (ST156) serotype 9V S. pneumoniae in 3 respiratory patients that resulted in two bacteremias and one lower respiratory tract infection. Two of the cases arose in patients who had recently been discharged from the hospital and were readmitted from the community. Nosocomial spread was suspected solely because of the highly unusual resistance pattern and case presentations within 24 h of one another. The outbreak highlights the potential for rapid transmission and the short incubation period in the respiratory ward setting. PMID- 27974540 TI - Sequence Type 631 Vibrio parahaemolyticus, an Emerging Foodborne Pathogen in North America. PMID- 27974542 TI - Evaluation of the Parasight Platform for Malaria Diagnosis. AB - The World Health Organization estimates that nearly 500 million malaria tests are performed annually. While microscopy and rapid diagnostic tests (RDTs) are the main diagnostic approaches, no single method is inexpensive, rapid, and highly accurate. Two recent studies from our group have demonstrated a prototype computer vision platform that meets those needs. Here we present the results from two clinical studies on the commercially available version of this technology, the Sight Diagnostics Parasight platform, which provides malaria diagnosis, species identification, and parasite quantification. We conducted a multisite trial in Chennai, India (Apollo Hospital [n = 205]), and Nairobi, Kenya (Aga Khan University Hospital [n = 263]), in which we compared the device to microscopy, RDTs, and PCR. For identification of malaria, the device performed similarly well in both contexts (sensitivity of 99% and specificity of 100% at the Indian site and sensitivity of 99.3% and specificity of 98.9% at the Kenyan site, compared to PCR). For species identification, the device correctly identified 100% of samples with Plasmodium vivax and 100% of samples with Plasmodium falciparum in India and 100% of samples with P. vivax and 96.1% of samples with P. falciparum in Kenya, compared to PCR. Lastly, comparisons of the device parasite counts with those of trained microscopists produced average Pearson correlation coefficients of 0.84 at the Indian site and 0.85 at the Kenyan site. PMID- 27974541 TI - Characterization and Diagnostic Application of Trypanosoma cruzi Trypomastigote Excreted-Secreted Antigens Shed in Extracellular Vesicles Released from Infected Mammalian Cells. AB - Chagas disease, caused by Trypanosoma cruzi, although endemic in many parts of Central and South America, is emerging as a global health threat through the potential contamination of blood supplies. Consequently, in the absence of a gold standard assay for the diagnosis of Chagas disease, additional antigens or strategies are needed. A proteomic analysis of the trypomastigote excreted secreted antigens (TESA) associated with exosomal vesicles shed by T. cruzi identified ~80 parasite proteins, with the majority being trans-sialidases. Mass spectrometry analysis of immunoprecipitation products performed using Chagas immune sera showed a marked enrichment in a subset of TESA proteins. Of particular relevance for diagnostic applications were the retrotransposon hot spot (RHS) proteins, which are absent in Leishmania spp., parasites that often confound diagnosis of Chagas disease. Interestingly, serological screens using recombinant RHS showed a robust immunoreactivity with sera from patients with clinical stages of Chagas ranging from asymptomatic to advance cardiomyopathy and this immunoreactivity was comparable to that of crude TESA. More importantly, no cross-reactivity with RHS was detected with sera from patients with malaria, leishmaniasis, toxoplasmosis, or African sleeping sickness, making this protein an attractive reagent for diagnosis of Chagas disease. PMID- 27974543 TI - Evaluation of the GenoType MTBDRsl Version 2.0 Assay for Second-Line Drug Resistance Detection of Mycobacterium tuberculosis Isolates in South Africa. AB - Early detection of resistance to second-line antituberculosis drugs is important for the management of multidrug-resistant tuberculosis (MDR-TB). The GenoType MTBDRsl version 2.0 (VER 2.0) line probe assay has been redesigned for molecular detection of resistance-conferring mutations of fluoroquinolones (FLQ) (gyrA and gyrB genes) and second-line injectable drugs (SLID) (rrs and eis genes). The study evaluated the diagnostic performance of the GenoType MTBDRsl VER 2.0 assay for the detection of second-line drug resistance compared with phenotypic drug susceptibility testing (DST), using the Bactec MGIT 960 system on Mycobacterium tuberculosis complex isolates from South Africa. A total of 268 repository isolates collected between 2012 and 2014, which were rifampin monoresistant or MDR based on DST, were selected. MTBDRsl VER 2.0 testing was performed on these isolates and the results analyzed. The MTBDRsl VER 2.0 sensitivity and specificity indices for culture isolates were the following: FLQ, 100% (95% confidence interval [CI] 95.8 to 100%) and 98.9% (95% CI, 96.1 to 99.9%); SLID, 89.2% (95% CI, 79.1 to 95.6%) and 98.5% (95% CI, 95.7 to 99.7%). The sensitivity and specificity observed for individual SLID were the following: amikacin, 93.8% (95% CI, 79.2 to 99.2%) and 98.5% (95% CI, 95.5 to 99.7%); kanamycin, 89.2% (95% CI, 79.1 to 95.6%) and 98.5% (95% CI, 95.5 to 99.7%); and capreomycin, 86.2% (95% CI, 68.3 to 96.1%) and 95.9% (95% CI, 92.2 to 98.2%). An interoperator reproducibility of 100% and an overall interlaboratory performance of 93% to 96% were found. The overall improvement in sensitivity and specificity with excellent reproducibility makes the GenoType MTBDRsl VER 2.0 a highly suitable tool for rapid screening of clinical isolates for second-line drug resistance for use in high-burden TB/HIV settings. PMID- 27974544 TI - Detection of Tilapia Lake Virus in Clinical Samples by Culturing and Nested Reverse Transcription-PCR. AB - Tilapia are an important group of farmed fish that serve as a significant protein source worldwide. In recent years, substantial mortality of wild tilapia has been observed in the Sea of Galilee and in commercial ponds in Israel and Ecuador. We have identified the etiological agent of these mass die-offs as a novel orthomyxo like virus and named it tilapia lake virus (TiLV). Here, we provide the conditions for efficient isolation, culturing, and quantification of the virus, including the use of susceptible fish cell lines. Moreover, we describe a sensitive nested reverse transcription-PCR (RT-PCR) assay allowing the rapid detection of TiLV in fish organs. This assay revealed, for the first time to our knowledge, the presence of TiLV in diseased Colombian tilapia, indicating a wider distribution of this emerging pathogen and stressing the risk that TiLV poses for the global tilapia industry. Overall, the described procedures should provide the tilapia aquaculture industry with important tools for the detection and containment of this pathogen. PMID- 27974545 TI - The Ongoing Genetic Adaptation of Streptococcus pneumoniae. AB - Streptococcus pneumoniae has demonstrated a remarkable ability to adapt during the conjugate vaccine era. The increasing incidence of serotype 35B disease and emergence of a multidrug-resistant clone reported in this issue of the Journal of Clinical Microbiology (L. Olarte et al., J Clin Microbiol 55:724-734, 2017, https://doi.org/10.1128/JCM.01778-16) underscore the limitations of pneumococcal vaccines that target the polysaccharide capsule. PMID- 27974546 TI - Copy Number Heterogeneity of JC Virus Standards. AB - Quantitative PCR is a diagnostic mainstay of clinical virology, and accurate quantitation of viral load among labs requires the use of international standards. However, the use of multiple passages of viral isolates to obtain sufficient material for international standards may result in genomic changes that complicate their use as quantitative standards. We performed next-generation sequencing to obtain single-nucleotide resolution and relative copy number of JC virus (JCV) clinical standards. Strikingly, the WHO international standard and the Exact v1/v2 prototype standards for JCV showed 8-fold and 4-fold variation in genomic coverage between different loci in the viral genome, respectively, due to large deletions in the large T antigen region. Intriguingly, several of the JCV standards sequenced in this study with large T antigen deletions were cultured in cell lines immortalized using simian virus 40 (SV40) T antigen, suggesting the possibility of transcomplementation in cell culture. Using a cutoff 5% allele fraction for junctional reads, 7 different rearrangements were present in the JC virus sequences present in the WHO standard across multiple library preparations and sequencing runs. Neither the copy number differences nor the rearrangements were observed in a clinical sample with a high copy number of JCV or a plasmid control. These results were also confirmed by the quantitative real-time PCR (qPCR), droplet digital PCR (ddPCR), and Sanger sequencing of multiple rearrangements. In summary, targeting different regions of the same international standard can result in up to an 8-fold difference in quantitation. We recommend the use of next-generation sequencing to validate standards in clinical virology. PMID- 27974547 TI - Molecular Epidemiology of Clostridium difficile Infection in Hospitalized Patients in Eastern China. AB - Few studies on risk factors for and transmission of Clostridium difficile infection (CDI) in China have been reported. A cross-sectional study was conducted for 3 years in eastern China. Consecutive stool specimens from hospitalized patients with diarrhea were cultured for C. difficile. C. difficile isolates from these patients then were analyzed for toxin genes, genotypes, and antimicrobial resistance. A severity score for the CDI in each patient was determined by a blinded review of the medical record, and these scores ranged from 1 to 6. A total of 397 out of 3,953 patients (10.0%) with diarrhea were found to have CDI. Severity of CDI was mild to moderate, and the average (+/- standard deviation) severity score was 2.61 +/- 1.01. C. difficile was isolated from stool specimens in 432 (10.9%) of all the patients who had diarrhea. C. difficile genotypes were determined by multilocus sequence analysis and PCR ribotyping; sequence type 37 (ST37)/ribotype 017 (RT017) (n = 68, 16.5%) was the dominant genotype. Eleven patients (16.2%) with this genotype had a CDI severity score of 5. Overall, three RTs and four STs were predominant; these genotypes were associated with significantly different antimicrobial resistance patterns in comparison to all genotypes (chi2 = 79.56 to 97.76; P < 0.001). Independent risk factors associated with CDI included age greater than 55 years (odds ratio [95% confidence interval], 26.80 [18.76 to 38.29]), previous hospitalization (12.42 [8.85 to 17.43]), previous antimicrobial treatment within 8 weeks (150.56 [73.11 to 310.06]), hospital stay more than 3 days before sampling (2.34 [1.71 to 3.22]), undergoing chemotherapy (3.31 [2.22 to 4.92]), and undergoing abdominal surgery (4.82 [3.54 to 6.55]). CDI is clearly a problem in eastern China and has a prevalence of 10.0% in hospitalized patients. Among risk factors for CDI, the advanced age threshold was younger for Chinese patients than that reported for patients in developed countries. PMID- 27974548 TI - Universal Human Papillomavirus Typing Assay: Whole-Genome Sequencing following Target Enrichment. AB - We designed a universal human papillomavirus (HPV) typing assay based on target enrichment and whole-genome sequencing (eWGS). The RNA bait included 23,941 probes targeting 191 HPV types and 12 probes targeting beta-globin as a control. We used the Agilent SureSelect XT2 protocol for library preparation, Illumina HiSeq 2500 for sequencing, and CLC Genomics Workbench for sequence analysis. Mapping stringency for type assignment was determined based on 8 (6 HPV-positive and 2 HPV-negative) control samples. Using the optimal mapping conditions, types were assigned to 24 blinded samples. eWGS results were 100% concordant with Linear Array (LA) genotyping results for 9 plasmid samples and fully or partially concordant for 9 of the 15 cervical-vaginal samples, with 95.83% overall type specific concordance for LA genotyping. eWGS identified 7 HPV types not included in the LA genotyping. Since this method does not involve degenerate primers targeting HPV genomic regions, PCR bias in genotype detection is minimized. With further refinements aimed at reducing cost and increasing throughput, this first application of eWGS for universal HPV typing could be a useful method to elucidate HPV epidemiology. PMID- 27974549 TI - TSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication. AB - OBJECTIVE: We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. DESIGN: We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models. RESULTS: We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n=18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumour behaviour. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant TSC2-mutant PDTXs, we demonstrated the therapeutic benefits of the hypersensitivity towards rapamycin treatment. CONCLUSIONS: Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyperactivation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signalling, with potential significance of effective specific drug therapy. PMID- 27974551 TI - Apicobasal polarity and Ras/Raf/MEK/ERK signalling in cancer. PMID- 27974550 TI - A comparative effectiveness trial of two faecal immunochemical tests for haemoglobin (FIT). Assessment of test performance and adherence in a single round of a population-based screening programme for colorectal cancer. AB - AIM: To compare acceptability and diagnostic accuracy of a recently available faecal immunochemical test (FIT) system (HM-JACKarc) with the FIT routinely used in an established screening programme (OC-Sensor). DESIGN: Randomised controlled trial (ISRCTN20086618) within a population-based colorectal cancer (CRC) screening programme. Subjects eligible for invitation in the Umbria Region (Italy) programme were randomised (ratio 1:1) to be screened using one of the FIT systems. RESULTS: Screening uptake among the 48 888 invitees was the same for both systems among subjects invited in the first round and higher with OC-Sensor than with HM-JACKarc (relative risk (RR): 1.03; 95% CI 1.02 to 1.04) among those invited in subsequent rounds. Positivity rate (PR) was similar with OC-Sensor (6.5%) as with HM-JACKarc (6.2%) among subjects performing their first FIT screening and higher with OC-Sensor (5.6%, RR: 1.25, 95% CI 1.12 to 1.40) than with HM-JACKarc (4.4%) among those screened in previous rounds. Positive predictive value (PPV) (OC-Sensor: 25.9%, HM-JACKarc: 25.6%) and detection rate (DR) (OC-Sensor: 1.40%; HM-JACKarc: 1.42%) for advanced neoplasia (AN: CRC + advanced adenoma) were similar among subjects performing their first FIT screening. The differences in the AN PPV (OC-Sensor: 20.3%, HM-JACKarc: 22.6%) and DR (OC-Sensor: 0.96%, HM-JACKarc: 0.83%) among those screened in previous rounds were not statistically significant. The number needed to scope to detect one AN was 3.9 (95% CI 5.8 to 2.9) and 3.9 (95% CI 5.5 to 2.9) at first and 4.9 (95% CI 5.8 to 4.2) and 4.4 (95% CI 5.3 to 3.7) at subsequent screening, with OC Sensor and HM-JACKarc, respectively. CONCLUSIONS: Our results suggest that acceptability and diagnostic performance of HM-JACKarc and of OC-Sensor systems are similar in a screening setting. TRIAL REGISTRATION NUMBER: ISRCTN20086618; Results. PMID- 27974552 TI - Do diverticula provide a unique niche for microbiota which can lead to activation of the innate immune system? PMID- 27974553 TI - TRPM8 polymorphisms associated with increased risk of IBS-C and IBS-M. PMID- 27974554 TI - Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice. AB - : Herpes simplex virus 1 (HSV-1) establishes latency in neural tissues of immunocompetent mice but persists in both peripheral and neural tissues of lymphocyte-deficient mice. Thymidine kinase (TK) is believed to be essential for HSV-1 to persist in neural tissues of immunocompromised mice, because infectious virus of a mutant with defects in both TK and UL24 is detected only in peripheral tissues, but not in neural tissues, of severe combined immunodeficiency mice (T. Valyi-Nagy, R. M. Gesser, B. Raengsakulrach, S. L. Deshmane, B. P. Randazzo, A. J. Dillner, and N. W. Fraser, Virology 199:484-490, 1994, https://doi.org/10.1006/viro.1994.1150). Here we find infiltration of CD4 and CD8 T cells in peripheral and neural tissues of mice infected with a TK-negative mutant. We therefore investigated the significance of viral TK and host T cells for HSV-1 to persist in neural tissues using three genetically engineered mutants with defects in only TK or in both TK and UL24 and two strains of nude mice. Surprisingly, all three mutants establish persistent infection in up to 100% of brain stems and 93% of trigeminal ganglia of adult nude mice at 28 days postinfection, as measured by the recovery of infectious virus. Thus, in mouse neural tissues, host T cells block persistent HSV-1 infection, and viral TK is dispensable for the virus to establish persistent infection. Furthermore, we found 30- to 200-fold more virus in neural tissues than in the eye and detected glycoprotein C, a true late viral antigen, in brainstem neurons of nude mice persistently infected with the TK-negative mutant, suggesting that adult mouse neurons can support the replication of TK-negative HSV-1. IMPORTANCE: Acyclovir is used to treat herpes simplex virus 1 (HSV-1)-infected immunocompromised patients, but treatment is hindered by the emergence of drug-resistant viruses, mostly those with mutations in viral thymidine kinase (TK), which activates acyclovir. TK mutants are detected in brains of immunocompromised patients with persistent infection. However, answers to the questions as to whether TK-negative (TK-) HSV-1 can establish persistent infection in brains of immunocompromised hosts and whether neurons in vivo are permissive for TK- HSV-1 remain elusive. Using three genetically engineered HSV-1 TK- mutants and two strains of nude mice deficient in T cells, we found that all three HSV-1 TK- mutants can efficiently establish persistent infection in the brain stem and trigeminal ganglion and detected glycoprotein C, a true late viral antigen, in brainstem neurons. Our study provides evidence that TK- HSV-1 can persist in neural tissues and replicate in brain neurons of immunocompromised hosts. PMID- 27974555 TI - VP24-Karyopherin Alpha Binding Affinities Differ between Ebolavirus Species, Influencing Interferon Inhibition and VP24 Stability. AB - : Zaire ebolavirus (EBOV), Bundibugyo ebolavirus (BDBV), and Reston ebolavirus (RESTV) belong to the same genus but exhibit different virulence properties. VP24 protein, a structural protein present in all family members, blocks interferon (IFN) signaling and likely contributes to virulence. Inhibition of IFN signaling by EBOV VP24 (eVP24) involves its interaction with the NPI-1 subfamily of karyopherin alpha (KPNA) nuclear transporters. Here, we evaluated eVP24, BDBV VP24 (bVP24), and RESTV VP24 (rVP24) interactions with three NPI-1 subfamily KPNAs (KPNA1, KPNA5, and KPNA6). Using purified proteins, we demonstrated that each VP24 binds to each of the three NPI-1 KPNAs. bVP24, however, exhibited approximately 10-fold-lower KPNA binding affinity than either eVP24 or rVP24. Cell-based assays also indicate that bVP24 exhibits decreased KPNA interaction, decreased suppression of IFN induced gene expression, and a decreased half-life in transfected cells compared to eVP24 or rVP24. Amino acid sequence alignments between bVP24 and eVP24 also identified residues within and surrounding the previously defined eVP24-KPNA5 binding interface that decrease eVP24-KPNA affinity or bVP24-KPNA affinity. VP24 mutations that lead to reduced KPNA binding affinity also decrease IFN inhibition and shorten VP24 half-lives. These data identify novel functional differences in VP24-KPNA interaction and reveal a novel impact of the VP24-KPNA interaction on VP24 stability. IMPORTANCE: The interaction of Ebola virus (EBOV) VP24 protein with host karyopherin alpha (KPNA) proteins blocks type I interferon (IFN) signaling, which is a central component of the host innate immune response to viral infection. Here, we quantitatively compared the interactions of VP24 proteins from EBOV and two members of the Ebolavirus genus, Bundibugyo virus (BDBV) and Reston virus (RESTV). The data reveal lower binding affinity of the BDBV VP24 (bVP24) for KPNAs and demonstrate that the interaction with KPNA modulates inhibition of IFN signaling and VP24 stability. The effect of KPNA interaction on VP24 stability is a novel functional consequence of this virus-host interaction, and the differences identified between viral species may contribute to differences in pathogenesis. PMID- 27974557 TI - African Swine Fever Virus Gets Undressed: New Insights on the Entry Pathway. AB - African swine fever virus (ASFV) is a large, multienveloped DNA virus composed of a genome-containing core successively wrapped by an inner lipid envelope, an icosahedral protein capsid, and an outer lipid envelope. In keeping with this structural complexity, recent studies have revealed an intricate entry program. This Gem highlights how ASFV uses two alternative pathways, macropinocytosis and clathrin-mediated endocytosis, to enter into the host macrophage and how the endocytosed particles undergo a stepwise, low pH-driven disassembly leading to inner envelope fusion and core delivery in the cytoplasm. PMID- 27974556 TI - RPLP1 and RPLP2 Are Essential Flavivirus Host Factors That Promote Early Viral Protein Accumulation. AB - : The Flavivirus genus contains several arthropod-borne viruses that pose global health threats, including dengue viruses (DENV), yellow fever virus (YFV), and Zika virus (ZIKV). In order to understand how these viruses replicate in human cells, we previously conducted genome-scale RNA interference screens to identify candidate host factors. In these screens, we identified ribosomal proteins RPLP1 and RPLP2 (RPLP1/2) to be among the most crucial putative host factors required for DENV and YFV infection. RPLP1/2 are phosphoproteins that bind the ribosome through interaction with another ribosomal protein, RPLP0, to form a structure termed the ribosomal stalk. RPLP1/2 were validated as essential host factors for DENV, YFV, and ZIKV infection in two human cell lines: A549 lung adenocarcinoma and HuH-7 hepatoma cells, and for productive DENV infection of Aedes aegypti mosquitoes. Depletion of RPLP1/2 caused moderate cell-line-specific effects on global protein synthesis, as determined by metabolic labeling. In A549 cells, global translation was increased, while in HuH-7 cells it was reduced, albeit both of these effects were modest. In contrast, RPLP1/2 knockdown strongly reduced early DENV protein accumulation, suggesting a requirement for RPLP1/2 in viral translation. Furthermore, knockdown of RPLP1/2 reduced levels of DENV structural proteins expressed from an exogenous transgene. We postulate that these ribosomal proteins are required for efficient translation elongation through the viral open reading frame. In summary, this work identifies RPLP1/2 as critical flaviviral host factors required for translation. IMPORTANCE: Flaviviruses cause important diseases in humans. Examples of mosquito-transmitted flaviviruses include dengue, yellow fever and Zika viruses. Viruses require a plethora of cellular factors to infect cells, and the ribosome plays an essential role in all viral infections. The ribosome is a complex macromolecular machine composed of RNA and proteins and it is responsible for protein synthesis. We identified two specific ribosomal proteins that are strictly required for flavivirus infection of human cells and mosquitoes: RPLP1 and RPLP2 (RPLP1/2). These proteins are part of a structure known as the ribosomal stalk and help orchestrate the elongation phase of translation. We show that flaviviruses are particularly dependent on the function of RPLP1/2. Our findings suggest that ribosome composition is an important factor for virus translation and may represent a regulatory layer for translation of specific cellular mRNAs. PMID- 27974558 TI - Mechanism of Protein Kinase R Inhibition by Human Cytomegalovirus pTRS1. AB - Double-stranded RNAs (dsRNA) produced during human cytomegalovirus (HCMV) infection activate the antiviral kinase protein kinase R (PKR), which potently inhibits virus replication. The HCMV pTRS1 and pIRS1 proteins antagonize PKR to promote HCMV protein synthesis and replication; however, the mechanism by which pTRS1 inhibits PKR is unclear. PKR activation occurs in a three-step cascade. First, binding to dsRNA triggers PKR homodimerizaton. PKR dimers then autophosphorylate, leading to a conformational shift that exposes the binding site for the PKR substrate eIF2alpha. Consistent with previous in vitro studies, we found that pTRS1 bound and inhibited PKR. pTRS1 binding to PKR was not mediated by an RNA intermediate, and mutations in the pTRS1 RNA binding domain did not affect PKR binding or inhibition. Rather, mutations that disrupted the pTRS1 interaction with PKR ablated the ability of pTRS1 to antagonize PKR activation by dsRNA. pTRS1 did not block PKR dimerization and could bind and inhibit a constitutively dimerized PKR kinase domain. In addition, pTRS1 binding to PKR inhibited PKR kinase activity. Single amino acid point mutations in the conserved eIF2alpha binding domain of PKR disrupted pTRS1 binding and rendered PKR resistant to inhibition by pTRS1. Consistent with a critical role for the conserved eIF2alpha contact site in PKR binding, pTRS1 bound an additional eIF2alpha kinase, heme-regulated inhibitor (HRI), and inhibited eIF2alpha phosphorylation in response to an HRI agonist. Together our data suggest that pTRS1 inhibits PKR by binding to conserved amino acids in the PKR eIF2alpha binding site and blocking PKR kinase activity.IMPORTANCE The antiviral kinase PKR plays a critical role in controlling HCMV replication. This study furthered our understanding of how HCMV evades inhibition by PKR and identified new strategies for how PKR activity might be restored during infection to limit HCMV disease. PMID- 27974559 TI - mTOR Promotes Antiviral Humoral Immunity by Differentially Regulating CD4 Helper T Cell and B Cell Responses. AB - : mTOR has important roles in regulation of both innate and adaptive immunity, but whether and how mTOR modulates humoral immune responses have yet to be fully understood. To address this issue, we examined the effects of rapamycin, a specific inhibitor of mTOR, on B cell and CD4 T cell responses during acute infection with lymphocytic choriomeningitis virus. Rapamycin treatment resulted in suppression of virus-specific B cell responses by inhibiting proliferation of germinal center (GC) B cells. In contrast, the number of memory CD4 T cells was increased in rapamycin-treated mice. However, the drug treatment caused a striking bias of CD4 T cell differentiation into Th1 cells and substantially impaired formation of follicular helper T (Tfh) cells, which are essential for humoral immunity. Further experiments in which mTOR signaling was modulated by RNA interference (RNAi) revealed that B cells were the primary target cells of rapamycin for the impaired humoral immunity and that reduced Tfh formation in rapamycin-treated mice was due to lower GC B cell responses that are essential for Tfh generation. Additionally, we found that rapamycin had minimal effects on B cell responses activated by lipopolysaccharide (LPS), which stimulates B cells in an antigen-independent manner, suggesting that rapamycin specifically inhibits B cell responses induced by B cell receptor stimulation with antigen. Together, these findings demonstrate that mTOR signals play an essential role in antigen specific humoral immune responses by differentially regulating B cell and CD4 T cell responses during acute viral infection and that rapamycin treatment alters the interplay of immune cell subsets involved in antiviral humoral immunity. IMPORTANCE: mTOR is a serine/threonine kinase involved in a variety of cellular activities. Although its specific inhibitor, rapamycin, is currently used as an immunosuppressive drug in transplant patients, it has been reported that rapamycin can also stimulate pathogen-specific cellular immunity in certain circumstances. However, whether and how mTOR regulates humoral immunity are not well understood. Here we found that rapamycin treatment predominantly inhibited GC B cell responses during viral infection and that this led to biased helper CD4 T cell differentiation as well as impaired antibody responses. These findings suggest that inhibition of B cell responses by rapamycin may play an important role in regulation of allograft-specific antibody responses to prevent organ rejection in transplant recipients. Our results also show that consideration of antibody responses is required in cases where rapamycin is used to stimulate vaccine-induced immunity. PMID- 27974561 TI - On the Analysis of Intrahost and Interhost Viral Populations: Human Cytomegalovirus as a Case Study of Pitfalls and Expectations. AB - Intrahost and interhost assessments of viral diversity are often treated as measures of separate and distinct evolutionary processes, with numerous investigations reporting seemingly incompatible results between the two. For example, in human cytomegalovirus, the nucleotide diversity estimates are 10-fold higher for interhost data, while the number of segregating (i.e., polymorphic) sites is 6-fold lower. These results have been interpreted as demonstrating that sampled intrahost variants are strongly deleterious. In reality, however, these observations are fully consistent with standard population genetic expectations. Here, we analyze published intra- and interhost data sets within this framework, utilizing statistical inference tools to quantify the fitness effects of segregating mutations. Further, we utilize population level simulations to clarify expectations under common evolutionary models. Contrary to common claims in the literature, these results suggest that most observed polymorphisms are likely nearly neutral with regard to fitness and that standard population genetic models in fact well predict observed levels of both intra- and interhost variability. IMPORTANCE With the increasing number of evolutionary virology studies examining both intrahost and interhost patterns of genomic variation, a number of seemingly incompatible results have emerged, revolving around the far greater level of observed intrahost than interhost variation. This has led many authors to suggest that the great majority of sampled within-host polymorphisms are strongly deleterious. Here, we demonstrate that there is in fact no incompatibility of these results and, indeed, that the vast majority of sampled within-host variation is likely neutral. These results thus represent a major shift in the current view of observed viral variation. PMID- 27974560 TI - Zika Virus Infects Early- and Midgestation Human Maternal Decidual Tissues, Inducing Distinct Innate Tissue Responses in the Maternal-Fetal Interface. AB - : Zika virus (ZIKV) has emerged as a cause of congenital brain anomalies and a range of placenta-related abnormalities, highlighting the need to unveil the modes of maternal-fetal transmission. The most likely route of vertical ZIKV transmission is via the placenta. The earliest events of ZIKV transmission in the maternal decidua, representing the maternal uterine aspect of the chimeric placenta, have remained unexplored. Here, we show that ZIKV replicates in first trimester human maternal-decidual tissues grown ex vivo as three-dimensional (3D) organ cultures. An efficient viral spread in the decidual tissues was demonstrated by the rapid upsurge and continued increase of tissue-associated ZIKV load and titers of infectious cell-free virus progeny, released from the infected tissues. Notably, maternal decidual tissues obtained at midgestation remained similarly susceptible to ZIKV, whereas fetus-derived chorionic villi demonstrated reduced ZIKV replication with increasing gestational age. A genome wide transcriptome analysis revealed that ZIKV substantially upregulated the decidual tissue innate immune responses. Further comparison of the innate tissue response patterns following parallel infections with ZIKV and human cytomegalovirus (HCMV) revealed that unlike HCMV, ZIKV did not induce immune cell activation or trafficking responses in the maternal-fetal interface but rather upregulated placental apoptosis and cell death molecular functions. The data identify the maternal uterine aspect of the human placenta as a likely site of ZIKV transmission to the fetus and further reveal distinct patterns of innate tissue responses to ZIKV. Our unique experimental model and findings could further serve to study the initial stages of congenital ZIKV transmission and pathogenesis and evaluate the effect of new therapeutic interventions. IMPORTANCE: In view of the rapid spread of the current ZIKV epidemic and the severe manifestations of congenital ZIKV infection, it is crucial to learn the fundamental mechanisms of viral transmission from the mother to the fetus. Our studies of ZIKV infection in the authentic tissues of the human maternal-fetal interface unveil a route of transmission whereby virus originating from the mother could reach the fetal compartment via efficient replication within the maternal decidual aspect of the placenta, coinhabited by maternal and fetal cells. The identified distinct placental tissue innate immune responses and damage pathways could provide a mechanistic basis for some of the placental developmental abnormalities associated with ZIKV infection. The findings in the unique model of the human decidua should pave the way to future studies examining the interaction of ZIKV with decidual immune cells and to evaluation of therapeutic interventions aimed at the earliest stages of transmission. PMID- 27974562 TI - In Vivo Imaging with Bioluminescent Enterovirus 71 Allows for Real-Time Visualization of Tissue Tropism and Viral Spread. AB - Hand, foot, and mouth disease (HFMD) is a reemerging illness caused by a variety of enteroviruses. The main causative agents are enterovirus 71 (EV71), coxsackievirus A16 (CVA16), and, most recently, coxsackievirus A6 (CVA6). Enterovirus infections can vary from asymptomatic infections to those with a mild fever and blisters on infected individuals' hands, feet, and throats to infections with severe neurological complications. Viral persistence for weeks postinfection (wpi) has also been documented by the demonstration of virus in children's stools. However, little is known about disease progression, viral spread, and tissue tropism of these viruses. These types of studies are limited because many recently developed mouse models mimic the severe neurological complications that occur in a small percentage of enterovirus infections. In the present study, we documented real-time EV71 infection in two different mouse strains by the use of in vivo imaging. Infection of BALB/c mice with a bioluminescent mouse-adapted EV71 construct (mEV71-NLuc) resulted in a lack of clinical signs of disease but in relatively high viral replication, as visualized by luminescence, for 2 wpi. In contrast, mEV71-NLuc infection of AG129 mice (alpha/beta and gamma interferon receptor deficient) showed rapid spread and long term persistence of the virus in the brain. Interestingly, AG129 mice that survived infection maintained luminescence in the brain for up to 8 wpi. The results we present here will allow future studies on EV71 antiviral drug susceptibility, vaccine efficacy, transmissibility, and pathogenesis. IMPORTANCE We report here that a stable full-length enterovirus 71 (EV71) reporter construct was used to visualize real-time viral spread in AG129 and BALB/c mice. To our knowledge, this is the first report of in vivo imaging of infection with any member of the Picornaviridae family. The nanoluciferase (NLuc) gene, one of the smallest luciferase genes currently available, was shown to be stable in the EV71 genome for eight passages on rhabdomyosarcoma cells. Real-time visualization of EV71 infection in mice identified areas of tropism that would have been missed by traditional methods, including full characterization of EV71 replication in BALB/c mice. Additionally, the bioluminescent construct allowed for increased speed and sensitivity of cell culture assays and will allow future studies involving various degrees of enterovirus infection in mice, not just severe infections. Our data suggest that interferon plays an important role in controlling EV71 infection in the central nervous system of mice. PMID- 27974563 TI - Human CD4+ T Cell Responses to an Attenuated Tetravalent Dengue Vaccine Parallel Those Induced by Natural Infection in Magnitude, HLA Restriction, and Antigen Specificity. AB - Dengue virus (DENV) is responsible for growing numbers of infections worldwide and has proven to be a significant challenge for vaccine development. We previously demonstrated that CD8+ T cell responses elicited by a dengue live attenuated virus (DLAV) vaccine resemble those observed after natural infection. In this study, we screened peripheral blood mononuclear cells (PBMCs) from donors vaccinated with a tetravalent DLAV vaccine (TV005) with pools of dengue virus derived predicted major histocompatibility complex (MHC) class II binding peptides. The definition of CD4+ T cell responses after live vaccination is important because CD4+ T cells are known contributors to host immunity, including cytokine production, help for CD8+ T and B cells, and direct cytotoxicity against infected cells. While responses to all antigens were observed, DENV-specific CD4+ T cells were focused predominantly on the capsid and nonstructural NS3 and NS5 antigens. Importantly, CD4+ T cell responses in vaccinees were similar in magnitude and breadth to those after natural infection, recognized the same antigen hierarchy, and had similar profiles of HLA restriction. We conclude that TV005 vaccination has the capacity to elicit CD4+ cell responses closely mirroring those observed in a population associated with natural immunity.IMPORTANCE The development of effective vaccination strategies against dengue virus infection is of high global public health interest. Here we study the CD4 T cell responses elicited by a tetravalent live attenuated dengue vaccine and show that they resemble responses seen in humans naturally exposed to dengue virus. This is an important issue, since it is likely that optimal immunity induced by a vaccine requires induction of CD4+ responses against the same antigens as those recognized as dominant in natural infection. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection against dengue virus. PMID- 27974564 TI - Within-Host Evolution of Simian Arteriviruses in Crab-Eating Macaques. AB - : Simian arteriviruses are a diverse clade of viruses infecting captive and wild nonhuman primates. We recently reported that Kibale red colobus virus 1 (KRCV-1) causes a mild and self-limiting disease in experimentally infected crab-eating macaques, while simian hemorrhagic fever virus (SHFV) causes lethal viral hemorrhagic fever. Here we characterize how these viruses evolved during replication in cell culture and in experimentally infected macaques. During passage in cell culture, 68 substitutions that were localized in open reading frames (ORFs) likely associated with host cell entry and exit became fixed in the KRCV-1 genome. However, we did not detect any strong signatures of selection during replication in macaques. We uncovered patterns of evolution that were distinct from those observed in surveys of wild red colobus monkeys, suggesting that these species may exert different adaptive challenges for KRCV-1. During SHFV infection, we detected signatures of selection on ORF 5a and on a small subset of sites in the genome. Overall, our data suggest that patterns of evolution differ markedly among simian arteriviruses and among host species. IMPORTANCE: Certain RNA viruses can cross species barriers and cause disease in new hosts. Simian arteriviruses are a diverse group of related viruses that infect captive and wild nonhuman primates, with associated disease severity ranging from apparently asymptomatic infections to severe, viral hemorrhagic fevers. We infected nonhuman primate cell cultures and then crab-eating macaques with either simian hemorrhagic fever virus (SHFV) or Kibale red colobus virus 1 (KRCV-1) and assessed within-host viral evolution. We found that KRCV-1 quickly acquired a large number of substitutions in its genome during replication in cell culture but that evolution in macaques was limited. In contrast, we detected selection focused on SHFV ORFs 5a and 5, which encode putative membrane proteins. These patterns suggest that in addition to diverse pathogenic phenotypes, these viruses may also exhibit distinct patterns of within-host evolution both in vitro and in vivo. PMID- 27974512 TI - Murine Electrophysiological Models of Cardiac Arrhythmogenesis. AB - Cardiac arrhythmias can follow disruption of the normal cellular electrophysiological processes underlying excitable activity and their tissue propagation as coherent wavefronts from the primary sinoatrial node pacemaker, through the atria, conducting structures and ventricular myocardium. These physiological events are driven by interacting, voltage-dependent, processes of activation, inactivation, and recovery in the ion channels present in cardiomyocyte membranes. Generation and conduction of these events are further modulated by intracellular Ca2+ homeostasis, and metabolic and structural change. This review describes experimental studies on murine models for known clinical arrhythmic conditions in which these mechanisms were modified by genetic, physiological, or pharmacological manipulation. These exemplars yielded molecular, physiological, and structural phenotypes often directly translatable to their corresponding clinical conditions, which could be investigated at the molecular, cellular, tissue, organ, and whole animal levels. Arrhythmogenesis could be explored during normal pacing activity, regular stimulation, following imposed extra-stimuli, or during progressively incremented steady pacing frequencies. Arrhythmic substrate was identified with temporal and spatial functional heterogeneities predisposing to reentrant excitation phenomena. These could arise from abnormalities in cardiac pacing function, tissue electrical connectivity, and cellular excitation and recovery. Triggering events during or following recovery from action potential excitation could thereby lead to sustained arrhythmia. These surface membrane processes were modified by alterations in cellular Ca2+ homeostasis and energetics, as well as cellular and tissue structural change. Study of murine systems thus offers major insights into both our understanding of normal cardiac activity and its propagation, and their relationship to mechanisms generating clinical arrhythmias. PMID- 27974565 TI - Infectious Bursal Disease Virus Subverts Autophagic Vacuoles To Promote Viral Maturation and Release. AB - Autophagy functions as an intrinsic antiviral defense. However, some viruses can subvert or even enhance host autophagic machinery to increase viral replication and pathogenesis. The role of autophagy during avibirnavirus infection, especially late stage infection, remains unclear. In this study, infectious bursal disease virus (IBDV) was used to investigate the role of autophagy in avibirnavirus replication. We demonstrated IBDV induction of autophagy as a significant increase in puncta of LC3+ autophagosomes, endogenous levels of LC3 II, and ultrastructural characteristics typical of autophagosomes during the late stage of infection. Induction of autophagy enhances IBDV replication, whereas inhibition of autophagy impairs viral replication. We also demonstrated that IBDV infection induced autophagosome-lysosome fusion, but without active degradation of their contents. Moreover, inhibition of fusion or of lysosomal hydrolysis activity significantly reduced viral replication, indicating that virions utilized the low-pH environment of acidic organelles to facilitate viral maturation. Using immuno-transmission electron microscopy (TEM), we observed that a large number of intact IBDV virions were arranged in a lattice surrounded by p62 proteins, some of which lay between virions. Additionally, many virions were encapsulated within the vesicular membranes, with an obvious release stage observed by TEM. The autophagic endosomal pathway facilitates low-pH-mediated maturation of viral proteins and membrane-mediated release of progeny virions.IMPORTANCE IBDV is the most extensively studied virus in terms of molecular characteristics and pathogenesis; however, mechanisms underlying the IBDV life cycle require further exploration. The present study demonstrated that autophagy enhances viral replication at the late stage of infection, and the autophagy pathway facilitates IBDV replication complex function and virus assembly, which is critical to completion of the virus life cycle. Moreover, the virus hijacks the autophagic vacuoles to mature in an acidic environment and release progeny virions in a membrane-mediated cell-to-cell manner. This autophagic endosomal pathway is proposed as a new mechanism that facilitates IBDV maturation, release, and reinternalization. This report presents a concordance in exit strategies among some RNA and DNA viruses, which exploit autophagy pathway for their release from cells. PMID- 27974566 TI - CD63 Regulates Epstein-Barr Virus LMP1 Exosomal Packaging, Enhancement of Vesicle Production, and Noncanonical NF-kappaB Signaling. AB - Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV)-encoded oncoprotein that is packaged into small extracellular vesicles (EVs) called exosomes. Trafficking of LMP1 into multivesicular bodies (MVBs) alters the content and function of exosomes. LMP1-modified exosomes enhance the growth, migration, and invasion of malignant cells, demonstrating the capacity to manipulate the tumor microenvironment and enhance the progression of EBV associated cancers. Despite the growing evidence surrounding the significance of LMP1-modified exosomes in cancer, very little is understood about the mechanisms that orchestrate LMP1 incorporation into these vesicles. Recently, LMP1 was shown to be copurified with CD63, a conserved tetraspanin protein enriched in late endosomal and lysosomal compartments. Here, we demonstrate the importance of CD63 presence for exosomal packaging of LMP1. Nanoparticle tracking analysis and gradient purification revealed an increase in extracellular vesicle secretion and exosomal proteins following LMP1 expression. Immunoisolation of CD63-positive exosomes exhibited accumulation of LMP1 in this vesicle population. Functionally, CRISPR/Cas9 knockout of CD63 resulted in a reduction of LMP1-induced particle secretion. Furthermore, LMP1 packaging was severely impaired in CD63 knockout cells, concomitant with a disruption in the perinuclear localization of LMP1. Importantly, LMP1 trafficking to lipid rafts and activation of NF-kappaB and PI3K/Akt pathways remained intact following CD63 knockout, while mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and noncanonical NF-kappaB activation were observed to be increased. These results suggest that CD63 is a critical player in LMP1 exosomal trafficking and LMP1 mediated enhancement of exosome production and may play further roles in limiting downstream LMP1 signaling.IMPORTANCE EBV is a ubiquitous gamma herpesvirus linked to malignancies such as nasopharyngeal carcinoma, Burkitt's lymphoma, and Hodgkin's lymphoma. In the context of cancer, EBV hijacks the exosomal pathway to modulate cell-to-cell signaling by secreting viral components such as an oncoprotein, LMP1, into host cell membrane-bound EVs. Trafficking of LMP1 into exosomes is associated with increased oncogenicity of these secreted vesicles. However, we have only a limited understanding of the mechanisms surrounding exosomal cargo packaging, including viral proteins. Here, we describe a role of LMP1 in EV production that requires CD63 and provide an extensive demonstration of CD63-mediated exosomal LMP1 release that is distinct from lipid raft trafficking. Finally, we present further evidence of the role of CD63 in limiting LMP1-induced noncanonical NF-kappaB and ERK activation. Our findings have implications for future investigations of physiological and pathological mechanisms of exosome biogenesis, protein trafficking, and signal transduction, especially in viral-associated tumorigenesis. PMID- 27974567 TI - Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34+ Human Progenitor Cells. AB - The establishment of human cytomegalovirus (HCMV) latency and persistence relies on the successful infection of hematopoietic cells, which serve as sites of viral persistence and contribute to viral spread. Here, using blocking antibodies and pharmacological inhibitors, we document that HCMV activation of the epidermal growth factor receptor (EGFR) and downstream phosphatidylinositol 3-kinase (PI3K) mediates viral entry into CD34+ human progenitor cells (HPCs), resulting in distinct cellular trafficking and nuclear translocation of the virus compared to that in other immune cells, such as we have documented in monocytes. We argue that the EGFR allows HCMV to regulate the cellular functions of these replication restricted cells via its signaling activity following viral binding. In addition to regulating HCMV entry/trafficking, EGFR signaling may also shape the early steps required for the successful establishment of viral latency in CD34+ cells, as pharmacological inhibition of EGFR increases the transcription of lytic IE1/IE2 mRNA while curbing the expression of latency-associated UL138 mRNA. EGFR signaling following infection of CD34+ HPCs may also contribute to changes in hematopoietic potential, as treatment with the EGFR kinase (EGFRK) inhibitor AG1478 alters the expression of the cellular hematopoietic cytokine interleukin 12 (IL-12) in HCMV-infected cells but not in mock-infected cells. These findings, along with our previous work with monocytes, suggest that EGFR likely serves as an important determinant of HCMV tropism for select subsets of hematopoietic cells. Moreover, our new data suggest that EGFR is a key receptor for efficient viral entry and that the ensuing signaling regulates important early events required for successful infection of CD34+ HPCs by HCMV.IMPORTANCE HCMV establishes lifelong persistence within the majority of the human population without causing overt pathogenesis in healthy individuals. Despite this, reactivation of HCMV from its latent reservoir in the bone marrow causes significant morbidity and mortality in immunologically compromised individuals, such as bone marrow and solid organ transplant patients. Lifelong persistent infection has also been linked with the development of various cardiovascular diseases in otherwise healthy individuals. Current HCMV therapeutics target lytic replication, but not the latent viral reservoir; thus, an understanding of the molecular basis for viral latency and persistence is paramount to controlling or eliminating HCMV infection. Here, we show that the viral signalosome activated by HCMV binding to its entry receptor, EGFR, in CD34+ HPCs initiates early events necessary for successful latent infection of this cell type. EGFR and associated signaling players may therefore represent promising targets for mitigating HCMV persistence. PMID- 27974569 TI - Human Adenovirus Type 37 Uses alphaVbeta1 and alpha3beta1 Integrins for Infection of Human Corneal Cells. AB - Epidemic keratoconjunctivitis (EKC) is a severe, contagious ocular disease that affects 20 to 40 million individuals worldwide every year. EKC is mainly caused by six types of human adenovirus (HAdV): HAdV-8, -19, -37, -53, -54, and -56. Of these, HAdV-8, -19, and -37 use sialic acid-containing glycans as cellular receptors. alphaVbeta3, alphaVbeta5, and a few additional integrins facilitate entry and endosomal release of other HAdVs. With the exception of a few biochemical analyses indicating that HAdV-37 can interact physically with alphaVbeta5, little is known about the integrins used by EKC-causing HAdVs. Here, we investigated the overall integrin expression on human corneal cells and found expression of alpha2, alpha3, alpha6, alphaV, beta1, and beta4 subunits in human corneal in situ epithelium and/or in a human corneal epithelial (HCE) cell line but no or less accessible expression of alpha4, alpha5, beta3, or beta5. We also identified the integrins used by HAdV-37 through a series of binding and infection competition experiments and different biochemical approaches. Together, our data suggest that HAdV-37 uses alphaVbeta1 and alpha3beta1 integrins for infection of human corneal epithelial cells. Furthermore, to confirm the relevance of these integrins in the HAdV-37 life cycle, we developed a corneal multilayer tissue system and found that HAdV-37 infection correlated well with the patterns of alphaV, alpha3, and beta1 integrin expression. These results provide further insight into the tropism and pathogenesis of EKC-causing HAdVs and may be of importance for future development of new antiviral drugs.IMPORTANCE Keratitis is a hallmark of EKC, which is caused by six HAdV types (HAdV-8, -19, 37, -53, -54, and -56). HAdV-37 and some other HAdV types interact with integrin alphaVbeta5 in order to enter nonocular human cells. In this study, we found that alphaVbeta5 is not expressed on human corneal epithelial cells, thus proposing other host factors mediate corneal infection. Here, we first characterized integrin expression patterns on corneal tissue and corneal cells. Among the integrins identified, competition binding and infection experiments and biochemical assays pointed out alphaVbeta1 and alpha3beta1 to be of importance for HAdV-37 infection of corneal tissue. In the absence of a good animal model for EKC-causing HAdVs, we also developed an in vitro system with multilayer HCE cells and confirmed the relevance of the suggested integrins during HAdV-37 infection. PMID- 27974571 TI - Socioeconomic correlations and stratification in social-communication networks. AB - The uneven distribution of wealth and individual economic capacities are among the main forces, which shape modern societies and arguably bias the emerging social structures. However, the study of correlations between the social network and economic status of individuals is difficult due to the lack of large-scale multimodal data disclosing both the social ties and economic indicators of the same population. Here, we close this gap through the analysis of coupled datasets recording the mobile phone communications and bank transaction history of one million anonymized individuals living in a Latin American country. We show that wealth and debt are unevenly distributed among people in agreement with the Pareto principle; the observed social structure is strongly stratified, with people being better connected to others of their own socioeconomic class rather than to others of different classes; the social network appears to have assortative socioeconomic correlations and tightly connected 'rich clubs'; and that individuals from the same class live closer to each other but commute further if they are wealthier. These results are based on a representative, society-large population, and empirically demonstrate some long-lasting hypotheses on socioeconomic correlations, which potentially lay behind social segregation, and induce differences in human mobility. PMID- 27974568 TI - IRAV (FLJ11286), an Interferon-Stimulated Gene with Antiviral Activity against Dengue Virus, Interacts with MOV10. AB - Dengue virus (DENV) is a member of the genus Flavivirus and can cause severe febrile illness. Here, we show that FLJ11286, which we refer to as IRAV, is induced by DENV in an interferon-dependent manner, displays antiviral activity against DENV, and localizes to the DENV replication complex. IRAV is an RNA binding protein and localizes to cytoplasmic processing bodies (P bodies) in uninfected cells, where it interacts with the MOV10 RISC complex RNA helicase, suggesting a role for IRAV in the processing of viral RNA. After DENV infection, IRAV, along with MOV10 and Xrn1, localizes to the DENV replication complex and associates with DENV proteins. Depletion of IRAV or MOV10 results in an increase in viral RNA. These data serve to characterize an interferon-stimulated gene with antiviral activity against DENV, as well as to propose a mechanism of activity involving the processing of viral RNA. IMPORTANCE Dengue virus, a member of the family Flaviviridae, can result in a life-threatening illness and has a significant impact on global health. Dengue virus has been shown to be particularly sensitive to the effects of type I interferon; however, little is known about the mechanisms by which interferon-stimulated genes function to inhibit viral replication. A better understanding of the interferon-mediated antiviral response to dengue virus may aid in the development of novel therapeutics. Here, we examine the influence of the interferon-stimulated gene IRAV (FLJ11286) on dengue virus replication. We show that IRAV associates with P bodies in uninfected cells and with the dengue virus replication complex after infection. IRAV also interacts with MOV10, depletion of which is associated with increased viral replication. Our results provide insight into a newly identified antiviral gene, as well as broadening our understanding of the innate immune response to dengue virus infection. PMID- 27974570 TI - Channel-Inactivating Mutations and Their Revertant Mutants in the Envelope Protein of Infectious Bronchitis Virus. AB - It has been shown previously in the severe acute respiratory syndrome coronavirus (SARS-CoV) that two point mutations, N15A and V25F, in the transmembrane domain (TMD) of the envelope (E) protein abolished channel activity and led to in vivo attenuation. Pathogenicity was recovered in mutants that also regained E protein channel activity. In particular, V25F was rapidly compensated by changes at multiple V25F-facing TMD residues located on a neighboring monomer, consistent with a recovery of oligomerization. Here, we show using infected cells that the same mutations, T16A and A26F, in the gamma-CoV infectious bronchitis virus (IBV) lead to, in principle, similar results. However, IBV E A26F did not abolish oligomer formation and was compensated by mutations at N- and C-terminal extramembrane domains (EMDs). The C-terminal EMD mutations clustered along an insertion sequence specific to gamma-CoVs. Nuclear magnetic resonance data are consistent with the presence of only one TMD in IBV E, suggesting that recovery of channel activity and fitness in these IBV E revertant mutants is through an allosteric interaction between EMDs and TMD. The present results are important for the development of IBV live attenuated vaccines when channel-inactivating mutations are introduced in the E protein.IMPORTANCE The ion channel activity of SARS-CoV E protein is a determinant of virulence, and abolishment of channel activity leads to viral attenuation. E deletion may be a strategy for generating live attenuated vaccines but can trigger undesirable compensatory mechanisms through modifications of other viral proteins to regain virulence. Therefore, a more suitable approach may be to introduce small but critical attenuating mutations. For this, the stability of attenuating mutations should be examined to understand the mechanisms of reversion. Here, we show that channel-inactivating mutations of the avian infectious bronchitis virus E protein introduced in a recombinant virus system are deficient in viral release and fitness and that revertant mutations also restored channel activity. Unexpectedly, most of the revertant mutations appeared at extramembrane domains, particularly along an insertion specific for gammacoronaviruses. Our structural data propose a single transmembrane domain in IBV E, suggesting an allosteric interaction between extramembrane and transmembrane domains. PMID- 27974572 TI - Shock-like haemodynamic responses induced in the primary visual cortex by moving visual stimuli. AB - It is shown that recently discovered haemodynamic waves can form shock-like fronts when driven by stimuli that excite the cortex in a patch that moves faster than the haemodynamic wave velocity. If stimuli are chosen in order to induce shock-like behaviour, the resulting blood oxygen level-dependent (BOLD) response is enhanced, thereby improving the signal to noise ratio of measurements made with functional magnetic resonance imaging. A spatio-temporal haemodynamic model is extended to calculate the BOLD response and determine the main properties of waves induced by moving stimuli. From this, the optimal conditions for stimulating shock-like responses are determined, and ways of inducing these responses in experiments are demonstrated in a pilot study. PMID- 27974573 TI - Dietary adaptions in the ultrastructure of dinosaur dentine. AB - Teeth are key to understanding the feeding ecology of both extant and extinct vertebrates. Recent studies have highlighted the previously unrecognized complexity of dinosaur dentitions and how specific tooth tissues and tooth shapes differ between taxa with different diets. However, it is unknown how the ultrastructure of these tooth tissues contributes to the differences in feeding style between taxa. In this study, we use third harmonic generation microscopy and scanning electron microscopy to examine the ultrastructure of the dentine in herbivorous and carnivorous dinosaurs to understand how the structure of this tissue contributes to the overall utility of the tooth. Morphometric analyses of dentinal tubule diameter, density and branching rates reveal a strong signal for dietary preferences, with herbivorous saurischian and ornithischian dinosaurs consistently having higher dentinal tubule density than their carnivorous relatives. We hypothesize that this relates to the hardness of the dentine, where herbivorous taxa have dentine that is more resistant to breakage and wear at the dentine-enamel junction than carnivorous taxa. This study advocates the detailed study of dentine and the use of advanced microscopy techniques to understand the evolution of dentition and feeding ecology in extinct vertebrates. PMID- 27974575 TI - Microstructural and geometric influences in the protective scales of Atractosteus spatula. AB - Atractosteus spatula has been described as a living fossil (having existed for 100 Myr), retaining morphological characteristics of early ancestors such as the ability to breathe air and survive above water for hours. Its highly effective armour consists of ganoid scales. We analyse the protective function of the scales and identify key features which lead to their resistance to failure. Microstructural features include: a twisted cross-plied mineral arrangement that inhibits crack propagation in the external ganoine layer, mineral crystals that deflect cracks in the bony region in order to activate the strength of mineralized collagen fibrils, and saw-tooth ridges along the interface between the two scale layers which direct cracks away from the intrinsically weak interface. The macroscale geometry is additionally evaluated and it is shown that the scales retain full coverage in spite of minimal overlap between adjacent scales while conforming to physiologically required strain and maintaining flexibility via a process in which adjacent rows of scales slide and concurrently reorient. PMID- 27974574 TI - Sphingosine 1-phosphate receptor 1 regulates the directional migration of lymphatic endothelial cells in response to fluid shear stress. AB - The endothelial cells that line blood and lymphatic vessels undergo complex, collective migration and rearrangement processes during embryonic development, and are known to be exquisitely responsive to fluid flow. At present, the molecular mechanisms by which endothelial cells sense fluid flow remain incompletely understood. Here, we report that both the G-protein-coupled receptor sphingosine 1-phosphate receptor 1 (S1PR1) and its ligand sphingosine 1-phosphate (S1P) are required for collective upstream migration of human lymphatic microvascular endothelial cells in an in vitro setting. These findings are consistent with a model in which signalling via S1P and S1PR1 are integral components in the response of lymphatic endothelial cells to the stimulus provided by fluid flow. PMID- 27974576 TI - A tale of two antennules: the performance of crab odour-capture organs in air and water. AB - Odour capture is an important part of olfaction, where dissolved chemical cues (odours) are brought into contact with chemosensory structures. Antennule flicking by marine crabs is an example of discrete odour capture (sniffing) where an array of chemosensory hairs is waved through the water to create a flow-no flow pattern based on a narrow range of speeds, diameters of and spacings between hairs. Changing the speed of movement and spacing of hairs at this scale to manipulate flow represents a complicated fluid dynamics problem. In this study, we use numerical simulation of the advection and diffusion of a chemical gradient to reveal how morphological differences of the hair arrays affect odour capture. Specifically, we simulate odour capture by a marine crab (Callinectes sapidus) and a terrestrial crab (Coenobita rugosus) in both air and water to compare performance. We find that the antennule morphologies of each species are adaptions to capturing odours in their native habitats. Sniffing is an important part of odour capture for marine crabs in water where the diffusivity of odorant molecules is low and flow through the array is necessary. On the other hand, flow within the hair array diminishes odour-capture performance in air where diffusivities are high. This study highlights some of the adaptations necessary to transition from water to air. PMID- 27974577 TI - Uncovering emergent interactions in three-way combinations of stressors. AB - Understanding how multiple stressors interact is needed to predict the dynamical outcomes of diverse biological systems, ranging from drug-resistant pathogens that are combated and treated with combination drug therapies to ecosystems impacted by environmental toxicants or disturbances. Nevertheless, extensive studies of higher-order (more than two component) interactions have been lacking. Here, we conduct experiments using 20 three-drug combinations and their effects on the bacterial growth of Escherichia coli We report our measurements of growth rates in single, pairwise and triple-drug combinations. To uncover emergent interactions, we derive a simple framework to calculate expectations for three way interactions based on the measured impact of each individual stressor and of each pairwise interaction. Using our framework, we find that (i) emergent antagonisms are more common than emergent synergies and (ii) emergent antagonisms are more common and emergent synergies are more rare than would be inferred from measures of net effects that do not disentangle pairwise interactions from three way interactions. PMID- 27974578 TI - Variability in individual activity bursts improves ant foraging success. AB - Using experimental and computational methods, we study the role of behavioural variability in activity bursts (or temporal activity patterns) for individual and collective regulation of foraging in A. senilis ants. First, foraging experiments were carried out under special conditions (low densities of ants and food and absence of external cues or stimuli) where individual-based strategies are most prevalent. By using marked individuals and recording all foraging trajectories, we were then able to precisely quantify behavioural variability among individuals. Our main conclusions are that (i) variability of ant trajectories (turning angles, speed, etc.) is low compared with variability of temporal activity profiles, and (ii) this variability seems to be driven by plasticity of individual behaviour through time, rather than the presence of fixed behavioural stereotypes or specialists within the group. The statistical measures obtained from these experimental foraging patterns are then used to build a general agent based model (ABM) which includes the most relevant properties of ant foraging under natural conditions, including recruitment through pheromone communication. Using the ABM, we are able to provide computational evidence that the characteristics of individual variability observed in our experiments can provide a functional advantage (in terms of foraging success) to the group; thus, we propose the biological basis underpinning our observations. Altogether, our study reveals the potential utility of experiments under simplified (laboratory) conditions for understanding information-gathering in biological systems. PMID- 27974584 TI - eComment. Could the definitive chemoradiated stage III non-small-cell-lung cancer N3 patient be "saved" by salvation lung resection? PMID- 27974585 TI - eComment. Can we really infer anything from this cohort? PMID- 27974586 TI - eComment: More with less: the role of minimally invasive surgery as a bridging procedure in the treatment of aorto-oesophageal fistula. PMID- 27974588 TI - Trends in the Screening and Treatment of Retinopathy of Prematurity. AB - OBJECTIVES: To determine the current practice patterns of retinopathy of prematurity (ROP) screening and treatment and the attitudes toward new screening and treatment modalities in level III and level IV NICUs, as reported by medical directors. METHODS: Surveys were mailed to the medical directors of 847 level III NICUs identified in the 2011 American Academy of Pediatrics directory in April 2015. In September 2015, responses were compared with American Academy of Pediatrics guidelines and previous reports. Within-sample comparisons were made by level, setting, size, and academic status. RESULTS: Respondents indicated that ROP screening is most often performed in their NICUs by pediatric and/or retina specialists (90%); retinal imaging devices are infrequently used (21%). Treatment is performed by pediatric (39%) and/or retina (57%) specialists in the NICU, usually under conscious sedation (60%). The most common treatment modality was laser photocoagulation (85%), followed by anti-vascular endothelial growth factor injection (20%). Some NICUs do not provide treatment services (28%), often due to a lack of ophthalmologists (78%). Respondents showed slightly more agreement (35%) than disagreement (25%) that a retinal imaging device could replace indirect ophthalmoscopy (40% were neutral). More respondents agreed than disagreed (30% vs 15%) that telemedicine for ROP screening is safe, but most were neutral (55%). CONCLUSIONS: Screening and treatment of ROP are not implemented uniformly in NICUs across the United States. Concerns regarding an insufficient ROP workforce are validated. PMID- 27974590 TI - Winds of Change. PMID- 27974589 TI - Tigecycline Therapy in an Infant for Ventriculoperitoneal Shunt Meningitis. AB - Shunt infections are seen in 3% to 20% of patients who have cerebrospinal fluid (CSF) shunts. Although the staphylococcal species are the most common cause of shunt-related infections, Gram-negative bacteria are increasingly reported with higher mortality rates. Tigecycline, a glycylcycline, is not approved for children. But in the era of nosocomial infections due to multidrug-resistant pathogens, it can be the life-saving option. We report an infant with ventriculoperitoneal shunt-related meningitis treated with a tigecycline combination regimen. A 5-month-old boy who had a ventriculoperitoneal shunt was admitted with meningitis. Extended spectrum beta-lactamase-producing Klebsiella pneumoniae grew in the CSF. At the end of the fourth week of intravenous meropenem plus gentamicin therapy, carbapenem-resistant K pneumoniae grew in the CSF (mean inhibitory concentration value for meropenem >4 MUg/mL, by E-test). The infected shunt was removed, and an external ventricular drainage catheter was inserted. With permission, intravenous tigecycline (1.2 mg/kg per dose twice a day) and intrathecal amikacin were added to the meropenem. Intrathecal amikacin could be given for only 7 days. On the sixth day of tigecycline treatment, the CSF was sterilized. Antibiotic therapy was given and consisted of a total of 60 days of meropenem and 20 days of tigecycline therapy. Because no available efficacy and safety data from randomized-controlled studies exist, tigecycline must be used only as salvage therapy, in combination with other drugs, for critically ill children who have no alternative treatment options. PMID- 27974591 TI - The Effect of Formulation, Process, and Method Variables on the Reconstitution Time in Dual Chamber Syringes. AB - : Reconstitution time of dried products is influenced by various factors including formulation, process, and reconstitution method itself. This manuscript describes factors affecting reconstitution in a dual chamber syringe using highly concentrated human monoclonal antibody and bovine serum albumin model formulations. Freezing and drying conditions had only minor impact on the reconstitution time, whereas the primary container and thus the geometry of the lyophilization cake played a major role. Prewarmed diluent and agitation decreased reconstitution time. For effective agitation, short displacements and high agitation frequencies were found to be desirable conditions to minimize reconstitution time for a given lyophilization cake while foam formation was minimized. The article also provides general strategies (e.g., reduction of lyophilized cake density, use of an optimized fill finish process, and suitable method parameters) to reduce reconstitution time, especially for drug product presented in a dual chamber syringe configuration. LAY ABSTRACT: Dried drug products need to be reconstituted to a liquid form before being applied parenteral. Reconstitution time is an important attribute and needs to be as fast as possible in order to serve patients' compliance. Reconstitution time is influenced by various factors including formulation, process, and the reconstitution method itself. The article provides general strategies (e.g., reduction of dried drug product cake density, use of an optimized fill finish process, and suitable method parameters) to reduce reconstitution time, especially for drug product presented in a dual chamber syringe. Fast reconstitution of lyophilisates in dual chamber syringe can be achieved by a combination of optimized manufacturing procedures and clear instructions for the end-user (e.g., roll syringe between palms to warm and agitate it to accelerate reconstitution). PMID- 27974592 TI - Dose Uniformity of Scored and Unscored Tablets: Application of the FDA Tablet Scoring Guidance for Industry. AB - PURPOSE: This U.S. Food and Drug Administration (FDA) laboratory study examines the impact of tablet splitting, the effect of tablet splitters, and the presence of a tablet score on the dose uniformity of two model drugs. METHODS: Whole tablets were purchased from five manufacturers for amlodipine and six for gabapentin. Two splitters were used for each drug product, and the gabapentin tablets were also split by hand. Whole and split amlodipine tablets were tested for content uniformity following the general chapter of the United States Pharmacopeia (USP) Uniformity of Dosage Units <905>, which is a requirement of the new FDA Guidance for Industry on tablet scoring. The USP weight variation method was used for gabapentin split tablets based on the recommendation of the guidance. RESULTS: All whole tablets met the USP acceptance criteria for the Uniformity of Dosage Units. Variation in whole tablet content ranged from 0.5 to 2.1 standard deviation (SD) of the percent label claim. Splitting the unscored amlodipine tablets resulted in a significant increase in dose variability of 6.5 25.4 SD when compared to whole tablets. Split tablets from all amlodipine drug products did not meet the USP acceptance criteria for content uniformity. Variation in the weight for gabapentin split tablets was greater than the whole tablets, ranging from 1.3 to 9.3 SD. All fully scored gabapentin products met the USP acceptance criteria for weight variation. CONCLUSION: Size, shape, and the presence or absence of a tablet score can affect the content uniformity and weight variation of amlodipine and gabapentin tablets. Tablet splitting produced higher variability. Differences in dose variability and fragmentation were observed between tablet splitters and hand splitting. These results are consistent with the FDA's concerns that tablet splitting can have an effect on the amount of drug present in a split tablet and available for absorption. LAY ABSTRACT: Tablet splitting has become a very common practice in the United States and throughout the world. Tablets are often split to modify dose strength, make swallowing easier, and reduce cost to the consumer. To better address product quality for this widely used practice, the U.S. Food and Drug Administration (FDA) published a Guidance for Industry that addresses tablet splitting. The guidance provides testing criteria for scored tablets, which is a part of the FDA review process for drugs. The model drugs selected for this study were amlodipine and gabapentin, which have different sizes, shapes, and tablet scores. Whole and split amlodipine tablets were tested for drug content because of a concern that the low-dose strength may cause greater variability. Whole and split gabapentin tablets were tested for weight variation because of their higher dosage strength of 600 mg. All whole tablets met the acceptance criteria for the Uniformity of Dosage Units based on the guidance recommendations. When unscored amlodipine tablets were split by a splitter, all formulations did not meet the acceptance criteria. When fully scored gabapentin tablets were split by hand and by splitter, they met the acceptance criteria. The findings of this FDA study indicated physical characteristics such as size, shape, and tablet score can affect the uniformity of split tablets. PMID- 27974593 TI - Lebecetin, a C-type lectin, inhibits choroidal and retinal neovascularization. AB - Angiogenesis is a cause of visual impairment and blindness in the wet form of age related macular degeneration and in ischemic retinopathies. Current therapies include use of anti-VEGF agents to reduce choroidal neovascularization (CNV) and edema. These treatments are effective in most cases, but spontaneous or acquired resistance to anti-VEGF and possible adverse effects of long-term VEGF inhibition in the retina and choroid highlight a need for additional alternative therapies. Integrins alphavbeta3 and alphavbeta5, which regulate endothelial cell proliferation and stabilization, have been implicated in ocular angiogenesis. Lebecetin (LCT) is a 30-kDa heterodimeric C-type lectin that is isolated from Macrovipera lebetina venom and interacts with alpha5beta1- and alphav-containing integrins. We previously showed that LCT inhibits human brain microvascular endothelial cell adhesion, migration, proliferation, and tubulogenesis. To evaluate the inhibitory effect of LCT on ocular angiogenesis, we cultured aortic and choroidal explants in the presence of LCT and analyzed the effect of LCT on CNV in the mouse CNV model and on retinal neovascularization in the oxygen induced retinopathy model. Our data demonstrate that a single injection of LCT efficiently reduced CNV and retinal neovascularization in these models. Montassar, F., Darche, M., Blaizot, A., Augustin, S., Conart, J.-B., Millet, A., Elayeb, M., Sahel, J.-A., Reaux-Le Goazigo, A., Sennlaub, F., Marrakchi, N., Messadi, E., Guillonneau, X. Lebecetin, a C-type lectin, inhibits choroidal and retinal neovascularization. PMID- 27974595 TI - Celebrating 75 years of Nutrition Reviews. PMID- 27974594 TI - Complement-mediated inhibition of adiponectin regulates perivascular inflammation and vascular injury in hypertension. AB - Perivascular adipose tissue (PVAT)-derived adiponectin (APN) is a secreted adipokine that protects against hypertension-related cardiovascular injury. However, the regulation of APN expression in hypertension remains to be explored. In this study, we demonstrated that down-regulation of APN was associated with complement activation in the PVAT of desoxycorticosterone acetate (DOCA)-salt hypertensive mice. Complement 3-deficient hypertensive mice were protected from ANP decrease in the PVAT. APN deficiency blockaded the protective effects of complement inhibition against hypertensive vascular injury. Mechanistically, complement 5a (C5a)-induced TNF-alpha secretion from macrophages is required for inhibiting APN expression in adipocytes. Macrophage depletion reversed C5a agonist peptide-induced TNF-alpha up-regulation and APN down-regulation in the PVAT of DOCA mice. Moreover, we detected increased macrophage infiltration and C5a expression associated with decreased APN expression in adipose tissue from patients with aldosterone-producing adenoma. These results identify a novel interaction between macrophages and adipocytes in the PVAT, where complement mediated inhibition of APN acts as a potential risk factor for hypertensive vascular inflammation.-Ruan, C.-C., Ma, Y., Ge, Q., Li, Y., Zhu, L.-M., Zhang, Y., Kong, L.-R., Wu, Q-H., Li, F., Cheng, L., Zhao, A. Z., Zhu, D.-L., Gao, P.-J. Complement-mediated inhibition of adiponectin regulates perivascular inflammation and vascular injury in hypertension. PMID- 27974596 TI - Improving diet sustainability through evolution of food choices: review of epidemiological studies on the environmental impact of diets. AB - The Food and Agriculture Organization defines sustainable diets as nutritionally adequate, safe, healthy, culturally acceptable, economically affordable diets that have little environmental impact. This review summarizes the studies assessing, at the individual level, both the environmental impact and the nutritional quality or healthiness of self-selected diets. Reductions in meat consumption and energy intake were identified as primary factors for reducing diet-related greenhouse gas emissions. The choice of foods to replace meat, however, was crucial, with some isocaloric substitutions possibly increasing total diet greenhouse gas emissions. Moreover, nutritional adequacy was rarely or only partially assessed, thereby compromising the assessment of diet sustainability. Furthermore, high nutritional quality was not necessarily associated with affordability or lower environmental impact. Hence, when identifying sustainable diets, each dimension needs to be assessed by relevant indicators. Finally, some nonvegetarian self-selected diets consumed by a substantial fraction of the population showed good compatibility with the nutritional, environmental, affordability, and acceptability dimensions. Altogether, the reviewed studies revealed the scarcity of standardized nationally representative data for food prices and environmental indicators and suggest that diet sustainability might be increased without drastic dietary changes. PMID- 27974598 TI - Calculating the metabolizable energy of macronutrients: a critical review of Atwater's results. AB - The current values for metabolizable energy of macronutrients were proposed in 1910. Since then, however, efforts to revise these values have been practically absent, creating a crucial need to carry out a critical analysis of the experimental methodology and results that form the basis of these values. Presented here is an exhaustive analysis of Atwater's work on this topic, showing evidence of considerable weaknesses that compromise the validity of his results. These weaknesses include the following: (1) the doubtful representativeness of Atwater's subjects, their activity patterns, and their diets; (2) the extremely short duration of the experiments; (3) the uncertainty about which fecal and urinary excretions contain the residues of each ingested food; (4) the uncertainty about whether or not the required nitrogen balance in individuals was reached during experiments; (5) the numerous experiments carried out without valid preliminary experiments; (6) the imprecision affecting Atwater's experimental measurements; and (7) the numerous assumptions and approximations, along with the lack of information, characterizing Atwater's studies. This review presents specific guidelines for establishing new experimental procedures to estimate more precise and/or more accurate values for the metabolizable energy of macronutrients. The importance of estimating these values in light of their possible dependence on certain nutritional parameters and/or physical activity patterns of individuals is emphasized. The use of more precise values would allow better management of the current overweight and obesity epidemic. PMID- 27974597 TI - What is the appropriate upper limit for added sugars consumption? AB - Dramatic increases in obesity and diabetes have occurred worldwide over the past 30 years. Some investigators have suggested that these increases may be due, in part, to increased added sugars consumption. Several scientific organizations, including the World Health Organization, the Scientific Advisory Council on Nutrition, the Dietary Guidelines Advisory Committee 2015, and the American Heart Association, have recommended significant restrictions on upper limits of sugars consumption. In this review, the scientific evidence related to sugars consumption and its putative link to various chronic conditions such as obesity, diabetes, heart disease, nonalcoholic fatty liver disease, and the metabolic syndrome is examined. While it appears prudent to avoid excessive calories from sugars, the scientific basis for restrictive guidelines is far from settled. PMID- 27974602 TI - Commentary: Combining Ascending Aorta and Aortic Arch TEVAR. PMID- 27974604 TI - Turning the page. PMID- 27974600 TI - Role of folic acid in nitric oxide bioavailability and vascular endothelial function. AB - Folic acid is a member of the B-vitamin family and is essential for amino acid metabolism. Adequate intake of folic acid is vital for metabolism, cellular homeostasis, and DNA synthesis. Since the initial discovery of folic acid in the 1940s, folate deficiency has been implicated in numerous disease states, primarily those associated with neural tube defects in utero and neurological degeneration later in life. However, in the past decade, epidemiological studies have identified an inverse relation between both folic acid intake and blood folate concentration and cardiovascular health. This association inspired a number of clinical studies that suggested that folic acid supplementation could reverse endothelial dysfunction in patients with cardiovascular disease (CVD). Recently, in vitro and in vivo studies have begun to elucidate the mechanism(s) through which folic acid improves vascular endothelial function. These studies, which are the focus of this review, suggest that folic acid and its active metabolite 5-methyl tetrahydrofolate improve nitric oxide (NO) bioavailability by increasing endothelial NO synthase coupling and NO production as well as by directly scavenging superoxide radicals. By improving NO bioavailability, folic acid may protect or improve endothelial function, thereby preventing or reversing the progression of CVD in those with overt disease or elevated CVD risk. PMID- 27974603 TI - Endovascular Repair of Type IIIb Endoleak With the Amplatzer Septal Occluder. AB - PURPOSE: To report the successful treatment of a type IIIb endoleak with an Amplatzer Septal Occluder. CASE REPORT: A 76-year-old man was found to have a type IIIb endoleak in the proximal body component of a fenestrated graft at 4 year surveillance imaging; the leak was associated with rapid aneurysm growth. The anatomy of the graft and position of the fabric defect precluded treatment by relining with a secondary endograft. The defect was demonstrated with catheter angiography, sized with an angioplasty balloon, and repaired using an Amplatzer Septal Occluder. Follow-up imaging at 6 months showed no endoleak and marked reduction in the aneurysm size. CONCLUSION: The Amplatzer Septal Occluder may be considered as an option for managing type IIIb endoleaks. PMID- 27974599 TI - Dietary strategies for improving iron status: balancing safety and efficacy. AB - In light of evidence that high-dose iron supplements lead to a range of adverse events in low-income settings, the safety and efficacy of lower doses of iron provided through biological or industrial fortification of foodstuffs is reviewed. First, strategies for point-of-manufacture chemical fortification are compared with biofortification achieved through plant breeding. Recent insights into the mechanisms of human iron absorption and regulation, the mechanisms by which iron can promote malaria and bacterial infections, and the role of iron in modifying the gut microbiota are summarized. There is strong evidence that supplemental iron given in nonphysiological amounts can increase the risk of bacterial and protozoal infections (especially malaria), but the use of lower quantities of iron provided within a food matrix, ie, fortified food, should be safer in most cases and represents a more logical strategy for a sustained reduction of the risk of deficiency by providing the best balance of risk and benefits. Further research into iron compounds that would minimize the availability of unabsorbed iron to the gut microbiota is warranted. PMID- 27974605 TI - Is there a crisis in clinical consultations? PMID- 27974606 TI - Dairy Food Intake Is Inversely Associated with Risk of Hypertension: The Singapore Chinese Health Study. AB - BACKGROUND: Epidemiological evidence from Western populations suggests that dairy food intake may reduce the risk of hypertension, probably through its calcium content. However, there are no epidemiological studies among Asian populations with generally lower dairy and calcium consumption. OBJECTIVE: The relation between dairy or calcium intake and risk of hypertension was evaluated in a Chinese population in Singapore. METHODS: The analysis included 37,124 Chinese men and women aged 45-74 y who participated in the Singapore Chinese Health Study in 1993-1998. The subjects included in the present study had no history of cancer, hypertension, or cardiovascular disease at baseline and completed >=1 follow-up interview. Diet at baseline was assessed by using a validated 165-item semiquantitative food-frequency questionnaire. The occurrence of new, physician diagnosed hypertension was ascertained through follow-up interviews during 1999 2004 and 2006-2010. The Cox proportional hazard regression method was used to compute HRs and 95% CIs with adjustment for potential confounders. RESULTS: Dairy food intake was inversely associated with the risk of hypertension in a dose dependent manner: HRs across quartiles were 1.00 (lowest quartile, reference), 0.97 (95% CI: 0.92, 1.02), 0.98 (95% CI: 0.92, 1.03), and 0.93 (95% CI: 0.88, 0.98) (P-trend = 0.01). Milk accounted for ~80% of all dairy products consumed in this population. Daily milk drinkers had a lower risk of hypertension (HR: 0.94; 95% CI: 0.89, 0.99) than did nondrinkers. Nondairy calcium intake contributed 80% of total calcium intake. Although dairy calcium intake was associated with a lower risk of hypertension (HR comparing extreme quartiles: 0.88; 95% CI: 0.83, 0.94; P-trend < 0.001), there was no association for nondairy calcium intake (HR: 1.02; 95% CI: 0.94, 1.10; P-trend = 0.58). CONCLUSIONS: Baseline dairy food intake, and specifically that of milk, may reduce the risk of developing hypertension in Chinese adults, and this may not be associated with the calcium component. PMID- 27974607 TI - Mechanism of membrane fusion induced by vesicular stomatitis virus G protein. AB - The glycoproteins (G proteins) of vesicular stomatitis virus (VSV) and related rhabdoviruses (e.g., rabies virus) mediate both cell attachment and membrane fusion. The reversibility of their fusogenic conformational transitions differentiates them from many other low-pH-induced viral fusion proteins. We report single-virion fusion experiments, using methods developed in previous publications to probe fusion of influenza and West Nile viruses. We show that a three-stage model fits VSV single-particle fusion kinetics: (i) reversible, pH dependent, G-protein conformational change from the known prefusion conformation to an extended, monomeric intermediate; (ii) reversible trimerization and clustering of the G-protein fusion loops, leading to an extended intermediate that inserts the fusion loops into the target-cell membrane; and (iii) folding back of a cluster of extended trimers into their postfusion conformations, bringing together the viral and cellular membranes. From simulations of the kinetic data, we conclude that the critical number of G-protein trimers required to overcome membrane resistance is 3 to 5, within a contact zone between the virus and the target membrane of 30 to 50 trimers. This sequence of conformational events is similar to those shown to describe fusion by influenza virus hemagglutinin (a "class I" fusogen) and West Nile virus envelope protein ("class II"). Our study of VSV now extends this description to "class III" viral fusion proteins, showing that reversibility of the low-pH-induced transition and architectural differences in the fusion proteins themselves do not change the basic mechanism by which they catalyze membrane fusion. PMID- 27974608 TI - Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control. AB - Macrocyclic small molecules are attractive tools in the development of sensors, new materials, and therapeutics. Within early-stage drug discovery, they are increasingly sought for their potential to interact with broad surfaces of peptidic receptors rather than within their narrow folds and pockets. Cyclization of linear small molecule precursors is a straightforward strategy to constrain conformationally mobile motifs, but forging a macrocycle bond typically becomes more difficult at larger ring sizes. We report the development of a general approach to discrete collections of oligomeric macrocyclic depsipeptides using an oligomerization/macrocyclization process governed by a series of Mitsunobu reactions of hydroxy acid monomers. Ring sizes of 18, 24, 30, and 36 are formed in a single reaction from a didepsipeptide, whereas sizes of 24, 36, and 60 result from a tetradepsipeptide. The ring-size selectivity inherent to the approach can be modulated by salt additives that enhance the formation of specific ring sizes. Use of chemical synthesis to prepare the monomers suggests broad access to functionally and stereochemically diverse collections of natural product-like oligodepsipeptide macrocycles. Two cyclodepsipeptide natural products were prepared along with numerous unnatural oligomeric congeners to provide rapid access to discrete collections of complex macrocyclic small molecules from medium (18) to large (60) ring sizes. PMID- 27974610 TI - Recommending teams promotes prosocial lending in online microfinance. AB - This paper reports the results of a large-scale field experiment designed to test the hypothesis that group membership can increase participation and prosocial lending for an online crowdlending community, Kiva. The experiment uses variations on a simple email manipulation to encourage Kiva members to join a lending team, testing which types of team recommendation emails are most likely to get members to join teams as well as the subsequent impact on lending. We find that emails do increase the likelihood that a lender joins a team, and that joining a team increases lending in a short window (1 wk) following our intervention. The impact on lending is large relative to median lender lifetime loans. We also find that lenders are more likely to join teams recommended based on location similarity rather than team status. Our results suggest team recommendation can be an effective behavioral mechanism to increase prosocial lending. PMID- 27974609 TI - Resting-state hemodynamics are spatiotemporally coupled to synchronized and symmetric neural activity in excitatory neurons. AB - Brain hemodynamics serve as a proxy for neural activity in a range of noninvasive neuroimaging techniques including functional magnetic resonance imaging (fMRI). In resting-state fMRI, hemodynamic fluctuations have been found to exhibit patterns of bilateral synchrony, with correlated regions inferred to have functional connectivity. However, the relationship between resting-state hemodynamics and underlying neural activity has not been well established, making the neural underpinnings of functional connectivity networks unclear. In this study, neural activity and hemodynamics were recorded simultaneously over the bilateral cortex of awake and anesthetized Thy1-GCaMP mice using wide-field optical mapping. Neural activity was visualized via selective expression of the calcium-sensitive fluorophore GCaMP in layer 2/3 and 5 excitatory neurons. Characteristic patterns of resting-state hemodynamics were accompanied by more rapidly changing bilateral patterns of resting-state neural activity. Spatiotemporal hemodynamics could be modeled by convolving this neural activity with hemodynamic response functions derived through both deconvolution and gamma variate fitting. Simultaneous imaging and electrophysiology confirmed that Thy1 GCaMP signals are well-predicted by multiunit activity. Neurovascular coupling between resting-state neural activity and hemodynamics was robust and fast in awake animals, whereas coupling in urethane-anesthetized animals was slower, and in some cases included lower-frequency (<0.04 Hz) hemodynamic fluctuations that were not well-predicted by local Thy1-GCaMP recordings. These results support that resting-state hemodynamics in the awake and anesthetized brain are coupled to underlying patterns of excitatory neural activity. The patterns of bilaterally symmetric spontaneous neural activity revealed by wide-field Thy1-GCaMP imaging may depict the neural foundation of functional connectivity networks detected in resting-state fMRI. PMID- 27974611 TI - Activation of Glutamatergic Fibers in the Anterior NAc Shell Modulates Reward Activity in the aNAcSh, the Lateral Hypothalamus, and Medial Prefrontal Cortex and Transiently Stops Feeding. AB - : Although the release of mesoaccumbal dopamine is certainly involved in rewarding responses, recent studies point to the importance of the interaction between it and glutamate. One important component of this network is the anterior nucleus accumbens shell (aNAcSh), which sends GABAergic projections into the lateral hypothalamus (LH) and receives extensive glutamatergic inputs from, among others, the medial prefrontal cortex (mPFC). The effects of glutamatergic activation of aNAcSh on the ingestion of rewarding stimuli as well as its effect in the LH and mPFC are not well understood. Therefore, we studied behaving mice that express a light-gated channel (ChR2) in glutamatergic fibers in their aNAcSh while recording from neurons in the aNAcSh, or mPFC or LH. In Thy1-ChR2, but not wild-type, mice activation of aNAcSh fibers transiently stopped the mice licking for sucrose or an empty sipper. Stimulation of aNAcSh fibers both activated and inhibited single-unit responses aNAcSh, mPFC, and LH, in a manner that maintains firing rate homeostasis. One population of licking-inhibited pMSNs in the aNAcSh was also activated by optical stimulation, suggesting their relevance in the cessation of feeding. A rewarding aspect of stimulation of glutamatergic inputs was found when the Thy1-ChR2 mice learned to nose-poke to self-stimulate these inputs, indicating that bulky stimulation of these fibers are rewarding in the sense of wanting. Stimulation of excitatory afferents evoked both monosynaptic and polysynaptic responses distributed in the three recorded areas. In summary, we found that activation of glutamatergic aNAcSh fibers is both rewarding and transiently inhibits feeding. SIGNIFICANCE STATEMENT: We have established that the activation of glutamatergic fibers in the anterior nucleus accumbens shell (aNAcSh) transiently stops feeding and yet, because mice self-stimulate, is rewarding in the sense of wanting. Moreover, we have characterized single-unit responses of distributed components of a hedonic network (comprising the aNAcSh, medial prefrontal cortex, and lateral hypothalamus) recruited by activation of glutamatergic aNAcSh afferents that are involved in encoding a positive valence signal important for the wanting of a reward and that transiently stops ongoing consummatory actions, such as licking. PMID- 27974612 TI - Stimulation of Dorsolateral Prefrontal Cortex Enhances Adaptive Cognitive Control: A High-Definition Transcranial Direct Current Stimulation Study. AB - : Conflict adaptation is a hallmark effect of adaptive cognitive control and refers to the adjustment of control to the level of previously experienced conflict. Conflict monitoring theory assumes that the dorsolateral prefrontal cortex (DLPFC) is causally involved in this adjustment. However, to date, evidence in humans is predominantly correlational, and heterogeneous with respect to the lateralization of control in the DLPFC. We used high-definition transcranial direct current stimulation (HD-tDCS), which allows for more focal current delivery than conventional tDCS, to clarify the causal involvement of the DLPFC in conflict adaptation. Specifically, we investigated the regional specificity and lateralization of potential beneficial stimulation effects on conflict adaptation during a visual flanker task. One hundred twenty healthy participants were assigned to four HD-tDCS conditions: left or right DLPFC or left or right primary motor cortex (M1). Each group underwent both active and sham HD-tDCS in crossover, double-blind designs. We obtained a sizeable conflict adaptation effect (measured as the modulation of the flanker effect as a function of previous response conflict) in all groups and conditions. However, this effect was larger under active HD-tDCS than under sham stimulation in both DLPFC groups. In contrast, active stimulation had no effect on conflict adaptation in the M1 groups. In sum, the present results indicate that the DLPFC plays a causal role in adaptive cognitive control, but that the involvement of DLPFC in control is not restricted to the left or right hemisphere. Moreover, our study confirms the potential of HD-tDCS to modulate cognition in a regionally specific manner. SIGNIFICANCE STATEMENT: Conflict adaptation is a hallmark effect of adaptive cognitive control. While animal studies have suggested causal involvement of the DLPFC in this phenomenon, such evidence is currently lacking in humans. The present study used high-definition transcranial direct current stimulation (HD tDCS) to demonstrate that the DLPFC is causally involved in conflict adaptation in humans. Our study confirms a central claim of conflict monitoring theory, which up to now has predominantly relied on correlational studies. Our results further indicate an equal involvement of the left and right DLPFC in adaptive control, whereas stimulation of a control region-the primary motor cortex-had no effect on adaptive control. The study thus confirms the potential of HD-tDCS to modulate cognition in a regionally specific manner. PMID- 27974613 TI - A Novel Multisensory Integration Task Reveals Robust Deficits in Rodent Models of Schizophrenia: Converging Evidence for Remediation via Nicotinic Receptor Stimulation of Inhibitory Transmission in the Prefrontal Cortex. AB - : Atypical multisensory integration is an understudied cognitive symptom in schizophrenia. Procedures to evaluate multisensory integration in rodent models are lacking. We developed a novel multisensory object oddity (MSO) task to assess multisensory integration in ketamine-treated rats, a well established model of schizophrenia. Ketamine-treated rats displayed a selective MSO task impairment with tactile-visual and olfactory-visual sensory combinations, whereas basic unisensory perception was unaffected. Orbitofrontal cortex (OFC) administration of nicotine or ABT-418, an alpha4beta2 nicotinic acetylcholine receptor (nAChR) agonist, normalized MSO task performance in ketamine-treated rats and this effect was blocked by GABAA receptor antagonism. GABAergic currents were also decreased in OFC of ketamine-treated rats and were normalized by activation of alpha4beta2 nAChRs. Furthermore, parvalbumin (PV) immunoreactivity was decreased in the OFC of ketamine-treated rats. Accordingly, silencing of PV interneurons in OFC of PV Cre mice using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) selectively impaired MSO task performance and this was reversed by ABT 418. Likewise, clozapine-N-oxide-induced inhibition of PV interneurons in brain slices was reversed by activation of alpha4beta2 nAChRs. These findings strongly imply a role for prefrontal GABAergic transmission in the integration of multisensory object features, a cognitive process with relevance to schizophrenia. Accordingly, nAChR agonism, which improves various facets of cognition in schizophrenia, reversed the severe MSO task impairment in this study and appears to do so via a GABAergic mechanism. Interactions between GABAergic and nAChR receptor systems warrant further investigation for potential therapeutic applications. The novel behavioral procedure introduced in the current study is acutely sensitive to schizophrenia-relevant cognitive impairment and should prove highly valuable for such research. SIGNIFICANCE STATEMENT: Adaptive behaviors are driven by integration of information from different sensory modalities. Multisensory integration is disrupted in patients with schizophrenia, but little is known about the neural basis of this cognitive symptom. Development and validation of multisensory integration tasks for animal models is essential given the strong link between functional outcome and cognitive impairment in schizophrenia. We present a novel multisensory object oddity procedure that detects selective multisensory integration deficits in a rat model of schizophrenia using various combinations of sensory modalities. Moreover, converging data are consistent with a nicotinic-GABAergic mechanism of multisensory integration in the prefrontal cortex, results with strong clinical relevance to the study of cognitive impairment and treatment in schizophrenia. PMID- 27974615 TI - Interaction of Instrumental and Goal-Directed Learning Modulates Prediction Error Representations in the Ventral Striatum. AB - : Goal-directed and instrumental learning are both important controllers of human behavior. Learning about which stimulus event occurs in the environment and the reward associated with them allows humans to seek out the most valuable stimulus and move through the environment in a goal-directed manner. Stimulus-response associations are characteristic of instrumental learning, whereas response outcome associations are the hallmark of goal-directed learning. Here we provide behavioral, computational, and neuroimaging results from a novel task in which stimulus-response and response-outcome associations are learned simultaneously but dominate behavior at different stages of the experiment. We found that prediction error representations in the ventral striatum depend on which type of learning dominates. Furthermore, the amygdala tracks the time-dependent weighting of stimulus-response versus response-outcome learning. Our findings suggest that the goal-directed and instrumental controllers dynamically engage the ventral striatum in representing prediction errors whenever one of them is dominating choice behavior. SIGNIFICANCE STATEMENT: Converging evidence in human neuroimaging studies has shown that the reward prediction errors are correlated with activity in the ventral striatum. Our results demonstrate that this region is simultaneously correlated with a stimulus prediction error. Furthermore, the learning system that is currently dominating behavioral choice dynamically engages the ventral striatum for computing its prediction errors. This demonstrates that the prediction error representations are highly dynamic and influenced by various experimental context. This finding points to a general role of the ventral striatum in detecting expectancy violations and encoding error signals regardless of the specific nature of the reinforcer itself. PMID- 27974614 TI - SNX27 Deletion Causes Hydrocephalus by Impairing Ependymal Cell Differentiation and Ciliogenesis. AB - : Hydrocephalus is a brain disorder derived from CSF accumulation due to defects in CSF clearance. Although dysfunctional apical cilia in the ependymal cell layer are causal to the onset of hydrocephalus, mechanisms underlying proper ependymal cell differentiation are largely unclear. SNX27 is a trafficking component required for normal brain function and was shown previously to suppress gamma secretase-dependent amyloid precursor protein and Notch cleavage. However, it was unclear how SNX27-dependent gamma-secretase inhibition could contribute to brain development and pathophysiology. Here, we describe and characterize an Snx27 deleted mouse model for the ependymal layer defects of deciliation and hydrocephalus. SNX27 deficiency results in reductions in ependymal cells and cilia density, as well as severe postnatal hydrocephalus. Inhibition of Notch intracellular domain signaling with gamma-secretase inhibitors reversed ependymal cells/cilia loss and dilation of lateral ventricles in Snx27-deficient mice, giving strong indication that Snx27 deletion triggers defects in ependymal layer formation and ciliogenesis through Notch hyperactivation. Together, these results suggest that SNX27 is essential for ependymal cell differentiation and ciliogenesis, and its deletion can promote hydrocephalus pathogenesis. SIGNIFICANCE STATEMENT: Down's syndrome (DS) in humans and mouse models has been shown previously to confer a high risk for the development of pathological hydrocephalus. Because we have previously described SNX27 as a component that is consistently downregulated in DS, we present here a robust Snx27-deleted mouse model that produces hydrocephalus and associated ciliary defects with complete penetrance. In addition, we find that gamma-secretase/Notch modulation may be a candidate drug target in SNX27-associated hydrocephalus such as that observed in DS. Based on these findings, we anticipate that future study will determine whether modulation of a SNX27/Notch/gamma-secretase pathway can also be of therapeutic interest to congenital hydrocephalus. PMID- 27974617 TI - Hermes Regulates Axon Sorting in the Optic Tract by Post-Trancriptional Regulation of Neuropilin 1. AB - : The establishment of precise topographic maps during neural development is facilitated by the presorting of axons in the pathway before they reach their targets. In the vertebrate visual system, such topography is seen clearly in the optic tract (OT) and in the optic radiations. However, the molecular mechanisms involved in pretarget axon sorting are poorly understood. Here, we show in zebrafish that the RNA-binding protein Hermes, which is expressed exclusively in retinal ganglion cells (RGCs), is involved in this process. Using a RiboTag approach, we show that Hermes acts as a negative translational regulator of specific mRNAs in RGCs. One of these targets is the guidance cue receptor Neuropilin 1 (Nrp1), which is sensitive to the repellent cue Semaphorin 3A (Sema3A). Hermes knock-down leads to topographic missorting in the OT through the upregulation of Nrp1. Restoring Nrp1 to appropriate levels in Hermes-depleted embryos rescues this effect and corrects the axon-sorting defect in the OT. Our data indicate that axon sorting relies on Hermes-regulated translation of Nrp1. SIGNIFICANCE STATEMENT: An important mechanism governing the formation of the mature neural map is pretarget axon sorting within the sensory tract; however, the molecular mechanisms involved in this process remain largely unknown. The work presented here reveals a novel function for the RNA-binding protein Hermes in regulating the topographic sorting of retinal ganglion cell (RGC) axons in the optic tract and tectum. We find that Hermes negatively controls the translation of the guidance cue receptor Neuropilin-1 in RGCs, with Hermes knock-down resulting in aberrant growth cone cue sensitivity and axonal topographic misprojections. We characterize a novel RNA-based mechanism by which axons restrict their translatome developmentally to achieve proper targeting. PMID- 27974616 TI - The Right Superior Frontal Gyrus and Individual Variation in Proactive Control of Impulsive Response. AB - : A hallmark of cognitive control is the ability to rein in impulsive responses. Previously, we used a Bayesian model to describe trial-by-trial likelihood of the stop signal or p(Stop) and related regional activations to p(Stop) to response slowing in a stop signal task. Here, we characterized the regional processes of conflict anticipation in association with intersubject variation in impulse control in 114 young adults. We computed the stop signal reaction time (SSRT) and a measure of motor urgency, indexed by the reaction time (RT) difference between go and stop error trials or "GoRT - SERT," where GoRT is the go trial RT and SERT is the stop error RT. Motor urgency and SSRT were positively correlated across subjects. A linear regression identified regional activations to p(Stop), each in correlation with SSRT and motor urgency. We hypothesized that shared neural activities mediate the correlation between motor urgency and SSRT in proactive control of impulsivity. Activation of the ventromedial prefrontal cortex, posterior cingulate cortex and right superior frontal gyrus (SFG) during conflict anticipation correlated negatively with the SSRT. Activation of the right SFG also correlated negatively with GoRT - SERT. Therefore, activation of the right SFG was associated with more efficient response inhibition and less motor urgency. A mediation analysis showed that right SFG activation to conflict anticipation mediates the correlation between SSRT and motor urgency bidirectionally. The current results highlight a specific role of the right SFG in translating conflict anticipation to the control of impulsive response, which is consistent with earlier studies suggesting its function in action restraint. SIGNIFICANCE STATEMENT: Individuals vary in impulse control. However, the neural bases underlying individual variation in proactive control of impulsive responses remain unknown. Here, in a large sample of young adults, we showed that activation of the right superior frontal gyrus (SFG) during conflict anticipation is positively correlated with the capacity of inhibitory control and negatively with motor urgency in the stop signal task. Importantly, activity of the right SFG mediates the counteracting processes of inhibitory control and motor urgency across subjects. The results support a unique role of the right SFG in individual variation in cognitive control. PMID- 27974618 TI - Neural Correlates of Fear in the Periaqueductal Gray. AB - : The dorsal and ventral periaqueductal gray (dPAG and vPAG, respectively) are embedded in distinct survival networks that coordinate, respectively, innate and conditioned fear-evoked freezing. However, the information encoded by the PAG during these survival behaviors is poorly understood. Recordings in the dPAG and vPAG in rats revealed differences in neuronal activity associated with the two behaviors. During innate fear, neuronal responses were significantly greater in the dPAG compared with the vPAG. After associative fear conditioning and during early extinction (EE), when freezing was maximal, a field potential was evoked in the PAG by the auditory fear conditioned stimulus (CS). With repeated presentations of the unreinforced CS, animals displayed progressively less freezing accompanied by a reduction in event-related field potential amplitude. During EE, the majority of dPAG and vPAG units increased their firing frequency, but spike-triggered averaging showed that only ventral activity during the presentation of the CS was significantly coupled to EMG-related freezing behavior. This PAG-EMG coupling was only present for the onset of freezing activity during the CS in EE. During late extinction, a subpopulation of units in the dPAG and vPAG continued to show CS-evoked responses; that is, they were extinction resistant. Overall, these findings support roles for the dPAG in innate and conditioned fear and for the vPAG in initiating but not maintaining the drive to muscles to generate conditioned freezing. The existence of extinction-susceptible and extinction-resistant cells also suggests that the PAG plays a role in encoding fear memories. SIGNIFICANCE STATEMENT: The periaqueductal gray (PAG) orchestrates survival behaviors, with the dorsal (dPAG) and ventral (vPAG) PAG concerned respectively with innate and learnt fear responses. We recorded neural activity from dPAG and vPAG in rats during the expression of innate fear and extinction of learned freezing. Cells in dPAG responded more robustly during innate fear, but dPAG and vPAG both encoded the time of the conditioned stimulus during early extinction and displayed extinction sensitive and resistant characteristics. Only vPAG discharge was correlated with muscle activity, but this was limited to the onset of conditioned freezing. The data suggest that the roles of dPAG and vPAG in fear behavior are more complex than previously thought, including a potential role in fear memory. PMID- 27974620 TI - Will the circle be unbroken: specific mutations in the yeast Sm protein ring expose a requirement for assembly factor Brr1, a homolog of Gemin2. AB - A seven-subunit Sm protein ring assembles around specific U-rich RNA segments of the U1, U2, U4, and U5 snRNPs that direct pre-mRNA splicing. Using human snRNP crystal structures to guide mutagenesis in Saccharomyces cerevisiae, we gained new insights into structure-function relationships of the SmD1 and SmD2 subunits. Of 18 conserved amino acids comprising their RNA-binding sites or intersubunit interfaces, only Arg88 in SmD1 and Arg97 in SmD2 were essential for growth. Tests for genetic interactions with non-Sm splicing factors identified benign mutations of SmD1 (N37A, R88K, R93A) and SmD2 (R49A, N66A, R97K, D99A) that were synthetically lethal with null alleles of U2 snRNP subunits Lea1 and/or Msl1. Tests of 264 pairwise combinations of SmD1 and SmD2 alleles with each other and with a collection of SmG, SmE, SmF, SmB, and SmD3 alleles revealed 92 instances of inter-Sm synthetic lethality. We leveraged the Sm mutant collection to illuminate the function of the yeast Sm assembly factor Brr1 and its relationship to the metazoan Sm assembly factor Gemin2. Mutations in the adjacent SmE (K83A), SmF (K32A, F33A, R74K), SmD2 (R49A, N66A, E74A, R97K, D99A), and SmD1 (E18A, N37A) subunits-but none in the SmG, SmD3, and SmB subunits-were synthetically lethal with brr1Delta. Using complementation of brr1Delta lethality in two Sm mutant backgrounds as an in vivo assay of Brr1 activity, we identified as essential an N-terminal segment of Brr1 (amino acids 24-47) corresponding to the Gemin2 alpha1 helix that interacts with SmF and a Brr1 C-terminal peptide (336QKDLIE341) that, in Gemin2, interacts with SmD2. PMID- 27974621 TI - Characterization of a TUTase/RNase complex required for Drosophila gametogenesis. AB - Post-transcriptional regulatory strategies that involve coupling between terminal uridyltransferase (TUTase) and exoribonuclease enzymes have recently been characterized in diverse species. Of note, the 3' exoribonuclease Dis3L2 has received substantial attention as a factor that metabolizes uridylated substrates in contexts such as general mRNA degradation, turnover of specific miRNAs, and quality control of noncoding RNAs. To date, most studies of Dis3L2 have focused on fungi and mammalian cells. Here, we introduce Drosophila as a system that permits analysis of molecular mechanisms as well as the ability to interrogate organismal phenotypes. We started with a structure-function analysis of the Drosophila TUTase Tailor, which we recently identified to inhibit biogenesis of splicing-derived miRNA hairpins. Next, we show that Tailor/Dis3L2 form a complex via N-terminal domains in the respective proteins that are distinct from their catalytic domains. In vitro, Dis3L2 has nuclease activity, but substrate oligouridylation by Tailor stimulates their degradation by Dis3L2, especially for structured substrates. We analyzed mutants of Tailor and Dis3L2, which are viable and lack overt morphological defects. Instead, these mutants exhibit defects in female and male fertility, implying specific requirements in the germline. Dis3L2 defects are more severe than Tailor, and their requirements appear stronger in males than in females. In particular, loss of Dis3L2 completely blocks productive spermatogenesis, causing male sterility. RNA-seq analysis from single- and double mutant testes reveals aberrant gene expression programs and suggests that noncoding RNAs may be preferentially affected by Dis3L2. Overall, our studies of a new tailing/trimming complex reveal unexpectedly specific requirements during gametogenesis. PMID- 27974622 TI - The conserved SNARE SEC-22 localizes to late endosomes and negatively regulates RNA interference in Caenorhabditis elegans. AB - Small RNA pathways, including RNA interference (RNAi), play crucial roles in regulation of gene expression. Initially considered to be cytoplasmic, these processes have later been demonstrated to associate with membranes. For example, maturation of late endosomes/multivesicular bodies (MVBs) is required for efficient RNAi, whereas fusion of MVBs to lysosomes appears to reduce silencing efficiency. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) mediate membrane fusion and are thus at the core of membrane trafficking. In spite of this, no SNARE has previously been reported to affect RNAi. Here, we demonstrate that in Caenorhabditis elegans, loss of the conserved SNARE SEC-22 results in enhanced RNAi upon ingestion of double-stranded RNA. Furthermore, SEC-22 overexpression inhibits RNAi in wild-type animals. We find that overexpression of SEC-22 in the target tissue (body wall muscle) strongly suppresses the sec-22(-) enhanced RNAi phenotype, supporting a primary role for SEC-22 in import of RNAi silencing signals or cell autonomous RNAi. A functional mCherry::SEC-22 protein localizes primarily to late endosomes/MVBs and these compartments are enlarged in animals lacking sec-22 SEC-22 interacts with late endosome-associated RNA transport protein SID-5 in a yeast two-hybrid assay and functions in a sid-5-dependent manner. Taken together, our data indicate that SEC 22 reduces RNAi efficiency by affecting late endosome/MVB function, for example, by promoting fusion between late endosomes/MVBs and lysosomes. To our knowledge, this is the first report of a SNARE with a function in small RNA-mediated gene silencing. PMID- 27974626 TI - Biocompute Objects-A Step towards Evaluation and Validation of Biomedical Scientific Computations. AB - The unpredictability of actual physical, chemical, and biological experiments due to the multitude of environmental and procedural factors is well documented. What is systematically overlooked, however, is that computational biology algorithms are also affected by multiplicity of parameters and have no lesser volatility. The complexities of computation protocols and interpretation of outcomes is only a part of the challenge: There are also virtually no standardized and industry accepted metadata schemas for reporting the computational objects that record the parameters used for computations together with the results of computations. Thus, it is often impossible to reproduce the results of a previously performed computation due to missing information on parameters, versions, arguments, conditions, and procedures of application launch. In this article we describe the concept of biocompute objects developed specifically to satisfy regulatory research needs for evaluation, validation, and verification of bioinformatics pipelines. We envision generalized versions of biocompute objects called biocompute templates that support a single class of analyses but can be adapted to meet unique needs. To make these templates widely usable, we outline a simple but powerful cross-platform implementation. We also discuss the reasoning and potential usability for such concept within the larger scientific community through the creation of a biocompute object database initially consisting of records relevant to the U.S. Food and Drug Administration. A biocompute object database record will be similar to a GenBank record in form; the difference being that instead of describing a sequence, the biocompute record will include information related to parameters, dependencies, usage, and other information related to specific computational instance. This mechanism will extend similar efforts and also serve as a collaborative ground to ensure interoperability between different platforms, industries, scientists, regulators, and other stakeholders interested in biocomputing. PMID- 27974623 TI - Genetic regulation and function of epidermal growth factor receptor signalling in patterning of the embryonic Drosophila brain. AB - The specification of distinct neural cell types in central nervous system development crucially depends on positional cues conferred to neural stem cells in the neuroectoderm. Here, we investigate the regulation and function of the epidermal growth factor receptor (EGFR) signalling pathway in early development of the Drosophila brain. We find that localized EGFR signalling in the brain neuroectoderm relies on a neuromere-specific deployment of activating (Spitz, Vein) and inhibiting (Argos) ligands. Activated EGFR controls the spatially restricted expression of all dorsoventral (DV) patterning genes in a gene- and neuromere-specific manner. Further, we reveal a novel role of DV genes-ventral nervous system defective (vnd), intermediate neuroblast defective (ind), Nkx6-in regulating the expression of vein and argos, which feed back on EGFR, indicating that EGFR signalling stands not strictly atop the DV patterning genes. Within this network of genetic interactions, Vnd acts as a positive EGFR feedback regulator. Further, we show that EGFR signalling becomes dependent on single minded-expressing midline cells in the posterior brain (tritocerebrum), but remains midline-independent in the anterior brain (deuto- and protocerebrum). Finally, we demonstrate that activated EGFR controls the proper formation of brain neuroblasts by regulating the number, survival and proneural gene expression of neuroectodermal progenitor cells. These data demonstrate that EGFR signalling is crucially important for patterning and early neurogenesis of the brain. PMID- 27974624 TI - Genome recoding by tRNA modifications. AB - RNA modifications are emerging as an additional regulatory layer on top of the primary RNA sequence. These modifications are particularly enriched in tRNAs where they can regulate not only global protein translation, but also protein translation at the codon level. Modifications located in or in the vicinity of tRNA anticodons are highly conserved in eukaryotes and have been identified as potential regulators of mRNA decoding. Recent studies have provided novel insights into how these modifications orchestrate the speed and fidelity of translation to ensure proper protein homeostasis. This review highlights the prominent modifications in the tRNA anticodon loop: queuosine, inosine, 5 methoxycarbonylmethyl-2-thiouridine, wybutosine, threonyl-carbamoyl-adenosine and 5-methylcytosine. We discuss the functional relevance of these modifications in protein translation and their emerging role in eukaryotic genome recoding during cellular adaptation and disease. PMID- 27974628 TI - Quantitative Microbial Risk Assessment of Pharmaceutical Products. AB - Monitoring of microbiological quality in the pharmaceutical industry is an important criterion that is required to justify safe product release to the drug market. Good manufacturing practice and efficient control on bioburden level of product components are critical parameters that influence the microbiological cleanliness of medicinal products. However, because microbial dispersion through the samples follows Poisson distribution, the rate of detection of microbiologically defective samples lambda (lambda) decreases when the number of defective units per batch decreases. When integrating a dose-response model of infection (Pinf) of a specific objectionable microbe with a contamination module, the overall probability of infection from a single batch of pharmaceutical product can be estimated. The combination of Pinf with detectability chance of the test (Pdet) will yield a value that could be used as a quantitative measure of the possibility of passing contaminated batch units of product with a certain load of a specific pathogen and infecting the final consumer without being detected in the firm. The simulation study can be used to assess the risk of contamination and infection from objectionable microorganisms for sterile and non sterile products.LAY ABSTRACT: Microbial contamination of pharmaceutical products is a global problem that may lead to infection and possibly death. While reputable pharmaceutical companies strive to deliver microbiologically safe products, it would be helpful to apply an assessment system for the current risk associated with pharmaceutical batches delivered to the drug market. The current methodology may be helpful also in determining the degree of improvement or deterioration on the batch processing flow until reaching the final consumer. Moreover, the present system is flexible and can be applied to other industries such as food, cosmetics, or medical devices manufacturing and processing fields to assess the microbiological risk of the processed and manufactured batch. PMID- 27974629 TI - Throughput Optimization of Continuous Biopharmaceutical Manufacturing Facilities. AB - In order to operate profitably under different product demand scenarios, biopharmaceutical companies must design their facilities with mass output flexibility in mind. Traditional biologics manufacturing technologies pose operational challenges in this regard due to their high costs and slow equipment turnaround times, restricting the types of products and mass quantities that can be processed. Modern plant design, however, has facilitated the development of lean and efficient bioprocessing facilities through footprint reduction and adoption of disposable and continuous manufacturing technologies. These development efforts have proven to be crucial in seeking to drastically reduce the high costs typically associated with the manufacturing of recombinant proteins. In this work, mathematical modeling is used to optimize annual production schedules for a single-product commercial facility operating with a continuous upstream and discrete batch downstream platform. Utilizing cell culture duration and volumetric productivity as process variables in the model, and annual plant throughput as the optimization objective, 3-D surface plots are created to understand the effect of process and facility design on expected mass output. The model shows that once a plant has been fully debottlenecked it is capable of processing well over a metric ton of product per year. Moreover, the analysis helped to uncover a major limiting constraint on plant performance, the stability of the neutralized viral inactivated pool, which may indicate that this should be a focus of attention during future process development efforts.LAY ABSTRACT: Biopharmaceutical process modeling can be used to design and optimize manufacturing facilities and help companies achieve a predetermined set of goals. One way to perform optimization is by making the most efficient use of process equipment in order to minimize the expenditure of capital, labor and plant resources. To that end, this paper introduces a novel mathematical algorithm used to determine the most optimal equipment scheduling configuration that maximizes the mass output for a facility producing a single product. The paper also illustrates how different scheduling arrangements can have a profound impact on the availability of plant resources, and identifies limiting constraints on the plant design. In addition, simulation data is presented using visualization techniques that aid in the interpretation of the scientific concepts discussed. PMID- 27974627 TI - Simulated Leaching (Migration) Study for a Model Container-Closure System Applicable to Parenteral and Ophthalmic Drug Products. AB - A simulating leaching (migration) study was performed on a model container closure system relevant to parenteral and ophthalmic drug products. This container-closure system consisted of a linear low-density polyethylene bottle (primary container), a polypropylene cap and an elastomeric cap liner (closure), an adhesive label (labeling), and a foil overpouch (secondary container). The bottles were filled with simulating solvents (aqueous salt/acid mixture at pH 2.5, aqueous buffer at pH 9.5, and 1/1 v/v isopropanol/water), a label was affixed to the filled and capped bottles, the filled bottles were placed into the foil overpouch, and the filled and pouched units were stored either upright or inverted for up to 6 months at 40 degrees C. After storage, the leaching solutions were tested for leached substances using multiple complementary analytical techniques to address volatile, semi-volatile, and non-volatile organic and inorganic extractables as potential leachables.The leaching data generated supported several conclusions, including that (1) the extractables (leachables) profile revealed by a simulating leaching study can qualitatively be correlated with compositional information for materials of construction, (2) the chemical nature of both the extracting medium and the individual extractables (leachables) can markedly affect the resulting profile, and (3) while direct contact between a drug product and a system's material of construction may exacerbate the leaching of substances from that material by the drug product, direct contact is not a prerequisite for migration and leaching to occur.LAY ABSTRACT: The migration of container-related extractables from a model pharmaceutical container-closure system and into simulated drug product solutions was studied, focusing on circumstances relevant to parenteral and ophthalmic drug products. The model system was constructed specifically to address the migration of extractables from labels applied to the outside of the primary container. The study demonstrated that (1) the extractables that do migrate can be correlated to the composition of the materials used to construct the container-closure systems, (2) the extent of migration is affected by the chemical nature of the simulating solutions and the extractables themselves, and (3) even though labels may not be in direct contact with a contained solution, label-related extractables can accumulate as leachables in those solutions. PMID- 27974630 TI - Reflections on OEM in 2016. PMID- 27974631 TI - What drives neutrophils to the alveoli in ARDS? PMID- 27974633 TI - Outcomes from hospitalised acute exacerbations of COPD: a bundle of optimism? PMID- 27974632 TI - Optimum low dose CT screening interval for lung cancer: the answer from NELSON? PMID- 27974636 TI - Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy. AB - Myeloperoxidase is expressed exclusively in granulocytes and immature myeloid cells and transforms the topoisomerase II (TOP2) poisons etoposide and mitoxantrone to chemical forms that have altered DNA damaging properties. TOP2 poisons are valuable and widely used anticancer drugs, but they are associated with the occurrence of secondary acute myeloid leukemias. These factors have led to the hypothesis that myeloperoxidase inhibition could protect hematopoietic cells from TOP2 poison-mediated genotoxic damage and, therefore, reduce the rate of therapy-related leukemia. We show here that myeloperoxidase activity leads to elevated accumulation of etoposide- and mitoxantrone-induced TOP2A and TOP2B-DNA covalent complexes in cells, which are converted to DNA double-strand breaks. For both drugs, the effect of myeloperoxidase activity was greater for TOP2B than for TOP2A. This is a significant finding because TOP2B has been linked to genetic damage associated with leukemic transformation, including etoposide-induced chromosomal breaks at the MLL and RUNX1 loci. Glutathione depletion, mimicking in vivo conditions experienced during chemotherapy treatment, elicited further MPO dependent increase in TOP2A and especially TOP2B-DNA complexes and DNA double strand break formation. Together these results support targeting myeloperoxidase activity to reduce genetic damage leading to therapy-related leukemia, a possibility that is enhanced by the recent development of novel specific myeloperoxidase inhibitors for use in inflammatory diseases involving neutrophil infiltration. PMID- 27974637 TI - Non-cell-autonomous Effects of Autophagy Inhibition in Tumor Cells Promote Growth of Drug-resistant Cells. AB - Autophagy, the mechanism by which cells deliver material to the lysosome, has been associated with resistance to anticancer drugs, leading autophagy inhibition to be widely studied as a potential chemosensitization strategy for cancer cells. This strategy is based on the idea that inhibition of autophagy will increase drug sensitivity and kill more cancer cells. Here we report an unintended negative effect of this strategy. When modeling the effect of drug resistance in a heterogeneous cancer cell population, we found that autophagy inhibition in drug-sensitive tumor cells causes increased growth of drug-resistant cells in the population through a mechanism involving caspase activation and prostaglandin E2 signaling. These results emphasize the importance of understanding how autophagy manipulation in a tumor cell can have both cell-autonomous and nonautonomous effects and suggest that attempts to chemosensitize by inhibiting autophagy could be enhanced by adopting methods aimed at reducing tumor repopulation. PMID- 27974638 TI - Untangling ciliary access and enrichment of two rhodopsin-like receptors using quantitative fluorescence microscopy reveals cell-specific sorting pathways. AB - Resolution limitations of optical systems are major obstacles for determining whether proteins are enriched within cell compartments. Here we use an approach to determine the degree of membrane protein ciliary enrichment that quantitatively accounts for the differences in sampling of the ciliary and apical membranes inherent to confocal microscopes. Theory shows that cilia will appear more than threefold brighter than the surrounding apical membrane when the densities of fluorescently labeled proteins are the same, thus providing a benchmark for ciliary enrichment. Using this benchmark, we examined the ciliary enrichment signals of two G protein-coupled receptors (GPCRs)-the somatostatin receptor 3 and rhodopsin. Remarkably, we found that the C-terminal VxPx motif, required for efficient enrichment of rhodopsin within rod photoreceptor sensory cilia, inhibited enrichment of the somatostatin receptor in primary cilia. Similarly, VxPx inhibited primary cilium enrichment of a chimera of rhodopsin and somatostatin receptor 3, where the dual Ax(S/A)xQ ciliary targeting motifs within the third intracellular loop of the somatostatin receptor replaced the third intracellular loop of rhodopsin. Rhodopsin was depleted from primary cilia but gained access, without being enriched, with the dual Ax(S/A)xQ motifs. Ciliary enrichment of these GPCRs thus operates via distinct mechanisms in different cells. PMID- 27974639 TI - Visualizing the dynamic coupling of claudin strands to the actin cytoskeleton through ZO-1. AB - The organization and integrity of epithelial tight junctions depend on interactions between claudins, ZO scaffolding proteins, and the cytoskeleton. However, although binding between claudins and ZO-1/2/3 and between ZO-1/2/3 and numerous cytoskeletal proteins has been demonstrated in vitro, fluorescence recovery after photobleaching analysis suggests interactions in vivo are likely highly dynamic. Here we use superresolution live-cell imaging in a model fibroblast system to examine relationships between claudins, ZO-1, occludin, and actin. We find that GFP claudins make easily visualized dynamic strand patches between two fibroblasts; strand dynamics is constrained by ZO-1 binding. Claudin association with actin is also dependent on ZO-1, but colocalization demonstrates intermittent rather than continuous association between claudin, ZO-1, and actin. Independent of interaction with ZO-1 or actin, claudin strands break and reanneal; pulse-chase-pulse analysis using SNAP-tagged claudins showed preferential incorporation of newly synthesized claudins into break sites. Although claudin strand behavior in fibroblasts may not fully recapitulate that of epithelial tight junction strands, this is the first direct demonstration of the ability of ZO-1 to stabilize claudin strands. We speculate that intermittent tethering of claudins to actin may allow for accommodation of the paracellular seal to physiological or pathological alterations in cell shape or movement. PMID- 27974641 TI - Proper cytoskeletal architecture beneath the plasma membrane of red blood cells requires Ttll4. AB - Mammalian red blood cells (RBCs) circulate through blood vessels, including capillaries, for tens of days under high mechanical stress. RBCs tolerate this mechanical stress while maintaining their shape because of their elastic membrane skeleton. This membrane skeleton consists of spectrin-actin lattices arranged as quasi-hexagonal units beneath the plasma membrane. In this study, we found that the organization of the RBC cytoskeleton requires tubulin tyrosine ligase-like 4 (Ttll4). RBCs from Ttll4-knockout mice showed larger average diameters in smear test. Based on the rate of hemolysis, Ttll4-knockout RBCs showed greater vulnerability to phenylhydrazine-induced oxidative stress than did wild-type RBCs. Ultrastructural analyses revealed the macromolecular aggregation of cytoskeletal components in RBCs of Ttll4-knockout mice. Immunoprecipitation using the anti-glutamylation antibody GT335 revealed nucleosome assembly protein 1 (NAP1) to be the sole target of TTLL4 in the RBCs, and NAP1 glutamylation was completely lost in Ttll4-knockout RBCs. In wild-type RBCs, the amount of glutamylated NAP1 in the membrane was nearly double that in the cytosol. Furthermore, the absence of TTLL4-dependent glutamylation of NAP1 weakened the binding of NAP1 to the RBC membrane. Taken together, these data demonstrate that Ttll4 is required for proper cytoskeletal organization in RBCs. PMID- 27974642 TI - The nanoscale spatial organization of B-cell receptors on immunoglobulin M- and G expressing human B-cells. AB - B-cell activation is initiated by the binding of antigen to the B-cell receptor (BCR). Here we used dSTORM superresolution imaging to characterize the nanoscale spatial organization of immunoglobulin M (IgM) and IgG BCRs on the surfaces of resting and antigen--activated human peripheral blood B-cells. We provide insights into both the fundamental process of antigen-driven BCR clustering and differences in the spatial organization of IgM and IgG BCRs that may contribute to the characteristic differences in the responses of naive and memory B-cells to antigen. We provide evidence that although both IgM and IgG BCRs reside in highly heterogeneous protein islands that vary in size and number of BCR single-molecule localizations, both resting and activated B-cells intrinsically maintain a high frequency of single isolated BCR localizations, which likely represent BCR monomers. IgG BCRs are more clustered than IgM BCRs on resting cells and form larger protein islands after antigen activation. Small, dense BCR clusters likely formed via protein-protein interactions are present on the surface of resting cells, and antigen activation induces these to come together to form less dense, larger islands, a process likely governed, at least in part, by protein-lipid interactions. PMID- 27974640 TI - Fidgetin regulates cultured astrocyte migration by severing tyrosinated microtubules at the leading edge. AB - Microtubule (MT) organization is essential for many cellular events, including mitosis, migration, and cell polarity. Fidgetin (Fign), an ATP-dependent, MT severing protein, contributes to the regulation of MT configuration by cutting and trimming MT polymers. Functions of Fign have been indicated in neurite outgrowth, mitosis, meiosis, and cellular migration. Here we focus on migration of astrocytes. We find that Fign plays an essential role in cultured astrocyte migration by preferentially targeting MTs (or regions of MTs) that are rich in tyrosinated tubulin, a marker for especially dynamic MTs or especially dynamic regions of MTs. Inhibition of cellular migration induced by Fign knockdown can be rescued with concomitant knockdown of kinesin-12, a motor protein best known for its role in mitosis. We propose a novel working model for MT reconfiguration underlying cellular migration elicited by the functional cooperation of two distinct MT-related proteins. PMID- 27974643 TI - Increased total sodium concentration in gray matter better explains cognition than atrophy in MS. AB - OBJECTIVE: To investigate whether brain total sodium accumulation assessed by 23Na MRI is associated with cognitive deficit in relapsing-remitting multiple sclerosis (RRMS). METHODS: Eighty-nine participants were enrolled in the study (58 patients with RRMS with a disease duration <=10 years and 31 matched healthy controls). Patients were classified as cognitively impaired if they failed at least 2 tasks on the Brief Repeatable Battery. MRI was performed at 3T using 23Na MRI to obtain total sodium concentration (TSC) in the different brain compartments (lesions, normal-appearing white matter [NAWM], gray matter [GM]) and 1H- magnetization-prepared rapid gradient echo to assess GM atrophy (GM fraction). RESULTS: The mean disease duration was 3.1 years and the median Expanded Disability Status Scale score was 1 (range 0-4.5). Thirty-seven patients were classified as cognitively preserved and 21 as cognitively impaired. TSC was increased in GM and NAWM in cognitively impaired patients compared to cognitively preserved patients and healthy controls. Voxel-wise analysis demonstrated that sodium accumulation was mainly located in the neocortex in cognitively impaired patients. Regression analysis evidenced than the 2 best independent predictors of cognitive impairment were GM TSC and age. Receiver operating characteristic analyses demonstrated that sensitivity and specificity of the GM TSC to classify patients according to their cognitive status were 76% and 71%, respectively. CONCLUSIONS: This study provides 2 main findings. (1) In RRMS, total sodium accumulation in the GM is better associated with cognitive impairment than GM atrophy; and (2) total sodium accumulation in patients with cognitive impairment is mainly located in the neocortex. PMID- 27974644 TI - Sulfonylurea receptor-associated channels: Involvement in disease and therapeutic implications. PMID- 27974646 TI - Distracting attention in phobic postural vertigo normalizes leg muscle activity and balance. AB - OBJECTIVE: To examine the triggering causes of inadequate neuromuscular regulation of posture and subjective imbalance in patients with phobic postural vertigo (PPV), a subtype of functional dizziness. METHODS: Postural performance was assessed by center-of-pressure displacements and surface EMG of lower-limb muscles (the tibialis anterior and soleus) in 10 patients with PPV and 10 healthy controls under 4 stance conditions: standing with eyes open or closed and with or without an additional cognitive dual task. The level of muscle cocontraction and the characteristics of open- and closed-loop postural control were analyzed. RESULTS: At baseline (i.e., standing with eyes open without dual task), patients exhibited increased muscle cocontractions (p = 0.003), which were further associated with increased open-loop diffusion activity (p = 0.022) and a lowering of the primary feedback threshold for closed-loop control (p = 0.003). However, postural performance of patients improved considerably and normalized to that of healthy controls when performing an additional dual task. CONCLUSIONS: PPV is characterized by a dissociation of subjective postural instability and objectively maintained balance capabilities. The dual-task effects on balance in patients with PPV indicate that this dissociation might result from an increased attention to postural adjustments at baseline, which is normally required only during demanding balance situations. This internal focus on balance control promotes an inappropriate neuromuscular regulation of posture, with increased muscle cocontractions, higher short-term body sway, and an oversensitivity to external stimuli. However, if patients are distracted, muscle cocontractions and balance control normalize. Such distraction may therefore be an effective coping strategy for preventing PPV attacks in susceptible patients. PMID- 27974645 TI - Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations. AB - OBJECTIVE: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. METHODS: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of vision. We quantified mitophagy in dermal fibroblasts, using 2 high throughput imaging systems, by visualizing colocalization of mitochondrial fragments with engulfing autophagosomes. RESULTS: Fibroblasts from 3 biallelic OPA1(-/-) patients with severe DOA had increased mitochondrial fragmentation and mitochondrial DNA (mtDNA)-depleted cells due to decreased levels of OPA1 protein. Similarly, in siRNA-treated control fibroblasts, profound OPA1 knockdown caused mitochondrial fragmentation, loss of mtDNA, impaired mitochondrial function, and mitochondrial mislocalization. Compared to controls, basal mitophagy (abundance of autophagosomes colocalizing with mitochondria) was increased in (1) biallelic patients, (2) monoallelic patients with DOA plus, and (3) OPA1 siRNA-treated control cultures. Mitophagic flux was also increased. Genetic knockdown of the mitophagy protein ATG7 confirmed this by eliminating differences between patient and control fibroblasts. CONCLUSIONS: We demonstrated increased mitophagy and excessive mitochondrial fragmentation in primary human cultures associated with DOA plus due to biallelic OPA1 mutations. We previously found that increased mitophagy (mitochondrial recycling) was associated with visual loss in another mitochondrial optic neuropathy, Leber hereditary optic neuropathy (LHON). Combined with our LHON findings, this implicates excessive mitochondrial fragmentation, dysregulated mitophagy, and impaired response to energetic stress in the pathogenesis of mitochondrial optic neuropathies, potentially linked with mitochondrial mislocalization and mtDNA depletion. PMID- 27974648 TI - Alternative RNA Processing of Topoisomerase IIalpha in Etoposide-Resistant Human Leukemia K562 Cells: Intron Retention Results in a Novel C-Terminal Truncated 90 kDa Isoform. AB - DNA topoisomerase IIalpha (TOP2alpha) is a prominent target for anticancer drugs whose clinical efficacy is often limited by chemoresistance. Using antibody specific for the N-terminal of TOP2alpha, immunoassays indicated the existence of two TOP2alpha isoforms, 170 and 90 kDa, present in K562 leukemia cells and in an acquired etoposide (VP-16)-resistant clone (K/VP.5). TOP2alpha/90 expression was dramatically increased in etoposide-resistant K/VP.5 compared with parental K562 cells. We hypothesized that TOP2alpha/90 was the translation product of novel alternatively processed pre-mRNA, confirmed by 3'-rapid amplification of cDNA ends, polymerase chain reaction, and sequencing. TOP2alpha/90 mRNA includes retained intron 19, which harbors an in-frame stop codon, and two consensus poly(A) sites. The processed transcript is polyadenylated. TOP2alpha/90 mRNA encodes a 90,076-Da translation product missing the C-terminal 770 amino acids of TOP2alpha/170, replaced by 25 unique amino acids through translation of the exon 19/intron 19 read-through. Immunoassays, utilizing antisera raised against these unique amino acids, confirmed that TOP2alpha/90 is expressed in both cell types, with overexpression in K/VP.5 cells. Immunodetection of complex of enzyme-to-DNA and single-cell gel electrophoresis (Comet) assays demonstrated that K562 cells transfected with a TOP2alpha/90 expression plasmid exhibited reduced etoposide mediated TOP2alpha-DNA covalent complexes and decreased etoposide-induced DNA damage, respectively, compared with similarly treated K562 cells transfected with empty vector. Because TOP2alpha/90 lacks the active site tyrosine (Tyr805) of full-length TOP2alpha, these results strongly suggest that TOP2alpha/90 exhibits dominant-negative properties. Further studies are underway to characterize the mechanism(s) by which TOP2alpha/90 plays a role in acquired resistance to etoposide and other TOP2alpha targeting agents. PMID- 27974649 TI - The influence of season on carbon allocation to suberin and other stem components of cork oak saplings. AB - The growth pattern of cork oak (Quercus suber L.), an important component of South Mediterranean woodlands, is seasonal. Seasonality has been found for shoot, radial and cork ring growth as well as for carbon (C) photoassimilation, nutrients remobilization and water relations, among other physiological aspects. However, little is known about the seasonality of C allocation to cork oak chemical compounds, including suberin, a major component of cork. In order to achieve this goal, an isotopic tracer experiment was conducted using 18-month-old cork oaks so that the fate of C photoassimilated in different seasons could be traced into biochemical (main organic) stem components. Two distinct patterns of C allocation, associated with the stages of active plant growth and dormancy, were identified and described. Evidence was provided that translocation of photoassimilated C to stems does not cease during the dormancy period and that suberin is the major C sink for the C assimilated throughout the whole active growth period, as compared with other stem components. PMID- 27974647 TI - Dementia risk in renal dysfunction: A systematic review and meta-analysis of prospective studies. AB - OBJECTIVE: Renal dysfunction has been linked with increased risk for cognitive impairment and dementia, but studies are conflicting. For that reason, the aim of the present systematic review and meta-analysis is to summarize the best available evidence on the prospective association between potential markers of renal dysfunction and development of cognitive impairment or dementia. METHODS: Medline, Embase, and Cochrane Database of Systematic Reviews were searched for potential publications until August 1, 2016. Studies were eligible if they fulfilled the following criteria: population-based study, prospective design, >=100 participants, aged >=45 years, >=1 year follow-up, and cognition/dementia outcomes. Where appropriate, random effects meta-analyses were conducted yielding pooled odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Twenty-two out of 8,494 abstracts fulfilled the eligibility criteria. Sufficient evidence was found for albuminuria, mixed results for estimated glomerular filtration rate (eGFR), insufficient support for cystatin C, and tentative evidence for serum creatinine and creatinine clearance. Meta-analyses of 5 studies representing 27,805 persons showed a 35% increased risk of cognitive impairment or dementia in those with albuminuria (OR 1.35, 95% CI 1.06-1.73, p = 0.015), whereas eGFR <60 mL/min/1.73 m2 showed no significant association (OR 1.28, 95% CI 0.99-1.65, p = 0.063). No meta-analyses could be done for serum creatinine, creatinine clearance, or cystatin C. CONCLUSIONS: The overall evidence for an association between renal dysfunction and cognitive impairment or dementia is modest. Evidence suggests that albuminuria is associated with higher odds of developing cognitive impairment or dementia. PMID- 27974650 TI - Short-term dynamics of evaporative enrichment of xylem water in woody stems: implications for ecohydrology. AB - In ecohydrology, it is generally assumed that xylem water reflects the water source used by plants. Several studies have reported isotopic enrichment within woody tissues, particularly during dormancy periods or after long periods of inactivity. However, little is known about the short-term dynamics of this process. Here we assessed the magnitude and dynamics of xylem isotopic enrichment in suberized twigs of pines and oaks. We performed a series of laboratory experiments, in which we monitored hourly changes in water content and isotopic composition under two contrasting scenarios of sap flow restriction. First, we simulated the effect of extreme hydraulic failure by excising twigs to restrict sap flow, while sealing the wounds to ensure that water loss took place only through the leaves or bark, as would be the case for evaporation in attached stems. Second, we studied the effect of reduced leaf transpiration by darkening with aluminium foil all the leaves of healthy, well-watered saplings growing in pot conditions. We found evidence of fast evaporative enrichment in metabolically active stems, as a consequence of a temporal decline in sap flow rates, and not necessarily linked to a traceable decline in stem water content. The excision experiments showed significant isotopic changes (~+10/00 in oxygen) appearing in <1 h. Similarly, the pot experiment showed a progressive increase in isotope composition (up to +80/00 in oxygen in a 3-day cycle) when the leaves were covered, and a rapid recovery to initial values when sap flow rates were re established. We conclude that evaporative enrichment of xylem water in stems is a highly dynamic process that may have significant effects even during short periods of restricted water flow. This has important implications for the study of plant water uptake, as well as for ecosystem- and global-scale hydrological models. PMID- 27974651 TI - Consistent leaf respiratory response to experimental warming of three North American deciduous trees: a comparison across seasons, years, habitats and sites. AB - Most vascular plants acclimate respiration to changes in ambient temperature, but explicit tests of these responses in field settings are rare, and how acclimation responses vary in space and time is relatively unstudied, hindering our ability to predict respiratory release of carbon under future climatic conditions. We measured temperature response curves of leaf respiration for three deciduous tree species from 2009 to 2012 in a field warming experiment (+3.4 degrees C above ambient) in both open and understory conditions at two sites in the southern boreal forest in Minnesota, USA. We analyzed the effects of warming on leaf respiration, and how the effects varied among species, times of season (early, middle and late parts of the growing season), sites, habitats (understory, open) and years. We hypothesized that the respiration exponent (Q10) of the short-term temperature response curve and the degree of acclimation would be smaller under conditions where plants were more likely to be substrate limited, such as in the understory or the margins of the growing season. However, in contrast to these predictions, stable Q10 and strong respiratory acclimation were consistently observed. For each species, the Q10 did not vary with experimental warming, nor was its response to warming influenced by time of season, year, site or habitat. Strong leaf respiratory acclimation to warming occurred in each species and was consistent across most sources of variation. Most of the leaf traits studied were not affected by warming, while the Q10-leaf nitrogen and R25-soluble carbohydrate relationships were observed, and shifted with warming, implying that acclimation may be associated with the adjustment in respiratory capacity and its relation to leaf nitrogen and soluble carbohydrate content. Consistent Q10 and acclimation across habitats, sites, times of season and years suggest that modeling of temperature acclimation may be possible with relatively simple functions. PMID- 27974652 TI - Nighttime stomatal conductance differs with nutrient availability in two temperate floodplain tree species. AB - Nighttime water flow varies between plant species and is a phenomenon for which the magnitude, purpose and consequences are widely discussed. A potential benefit of nighttime stomata opening may be increased nutrient availability during the night since transpiration affects the mass flow of soil water towards plant roots. We investigated how nitrogen (N) and phosphorus (P) fertilization, and short-term drought affected stomatal conductance of Fraxinus excelsior L. and Ulmus laevis Pallas during the day (gs) and night (gn), and how these factors affected growth for a period of 18 weeks. Both species were found to open their stomata during the night, and gn responded to nutrients and water in a different manner than gs. Under N-deficiency, F. excelsior had higher gn, especially when P was sufficient, and lower pre-dawn leaf water potential (Psipd), supporting our assumption that nutrient limitation leads to increases in nighttime water uptake. Under P-deficiency, F. excelsior had higher relative root production and, thus, adjusted its biomass allocation under P shortage, while sufficient N but not P contributed to overall higher biomasses. In contrast, U. laevis had higher gn and lower root:shoot ratio under high nutrient (especially N) availability, whereas both sufficient N and P produced higher biomasses. Compared with well-watered trees, the drought treatment did not affect any growth parameter but it resulted in lower gn, minimum stomatal conductance and Psipd of F. excelsior. For U. laevis, only gs during July was lower when drought-treated. In summary, the responses of gs and gn to nutrients and drought depended on the species and its nutrient uptake strategy, and also the timing of measurement during the growing season. Eutrophication of floodplain forests dominated by F. excelsior and U. laevis may, therefore, considerably change nighttime transpiration rates, leading to ecosystem-level changes in plant-water dynamics. Such changes may have more severe consequences in the future as a higher frequency of drought events is predicted under climate change. PMID- 27974657 TI - Worldwide news and comment. PMID- 27974653 TI - Effects of prolonged drought stress on Scots pine seedling carbon allocation. AB - As the number of drought occurrences has been predicted to increase with increasing temperatures, it is believed that boreal forests will become particularly vulnerable to decreased growth and increased tree mortality caused by the hydraulic failure, carbon starvation and vulnerability to pests following these. Although drought-affected trees are known to have stunted growth, as well as increased allocation of carbon to roots, still not enough is known about the ways in which trees can acclimate to drought. We studied how drought stress affects belowground and aboveground carbon dynamics, as well as nitrogen uptake, in Scots pine (Pinus sylvestris L.) seedlings exposed to prolonged drought. Overall 40 Scots pine seedlings were divided into control and drought treatments over two growing seasons. Seedlings were pulse-labelled with 13CO2 and litter bags containing 15N-labelled root biomass, and these were used to follow nutrient uptake of trees. We determined photosynthesis, biomass distribution, root and rhizosphere respiration, water potential, leaf osmolalities and carbon and nitrogen assimilation patterns in both treatments. The photosynthetic rate of the drought-induced seedlings did not decrease compared to the control group, the maximum leaf specific photosynthetic rate being 0.058 and 0.045 umol g-1 s-1 for the drought and control treatments, respectively. The effects of drought were, however, observed as lower water potentials, increased osmolalities as well as decreased growth and greater fine root-to-shoot ratio in the drought-treated seedlings. We also observed improved uptake of labelled nitrogen from soil to needles in the drought-treated seedlings. The results indicate acclimation of seedlings to long-term drought by aiming to retain sufficient water uptake with adequate allocation to roots and root-associated mycorrhizal fungi. The plants seem to control water potential with osmolysis, for which sufficient photosynthetic capability is needed. PMID- 27974659 TI - Screen and you shall find. PMID- 27974658 TI - Eating to boost gut microbial diversity. PMID- 27974660 TI - Alzheimer's medicine: beta-Amyloid takes a siP. PMID- 27974662 TI - Erratum for the Perspective: "Imaging approaches to optimize molecular therapies" by R. Weissleder, M. C. Schwaiger, S. S. Gambhir, H. Hricak. PMID- 27974661 TI - A new lease on half-life. PMID- 27974663 TI - PIK3CA mutations enable targeting of a breast tumor dependency through mTOR mediated MCL-1 translation. AB - Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that combined inhibition of B cell lymphoma extra large (BCL-XL) and the mammalian target of rapamycin (mTOR)/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple-negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses myeloid cell leukemia-1 (MCL 1) protein translation only in PIK3CA mutant tumors, creating a synthetic dependence on BCL-XL This dual dependence on BCL-XL and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of the molecular subtype or PIK3CA mutational status. Furthermore, this dependence distinguishes breast cancers from normal breast epithelial cells, which are neither primed for apoptosis nor dependent on BCL-XL/MCL-1, suggesting a potential therapeutic window. By tilting the balance of pro- to antiapoptotic signals in the mitochondria, dual inhibition of MCL-1 and BCL-XL also sensitizes breast cancer cells to standard-of-care cytotoxic and targeted chemotherapies. Together, these results suggest that patients with PIK3CA mutant breast cancers may benefit from combined treatment with inhibitors of BCL-XL and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-XL may be effective in tumors lacking PIK3CA mutations. PMID- 27974664 TI - Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. AB - A bacterial etiology of rheumatoid arthritis (RA) has been suspected since the beginnings of modern germ theory. Recent studies implicate mucosal surfaces as sites of disease initiation. The common occurrence of periodontal dysbiosis in RA suggests that oral pathogens may trigger the production of disease-specific autoantibodies and arthritis in susceptible individuals. We used mass spectrometry to define the microbial composition and antigenic repertoire of gingival crevicular fluid in patients with periodontal disease and healthy controls. Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA. The citrullinome in periodontitis mirrored patterns of hypercitrullination observed in the rheumatoid joint, implicating this mucosal site in RA pathogenesis. Proteomic signatures of several microbial species were detected in hypercitrullinated periodontitis samples. Among these, Aggregatibacter actinomycetemcomitans (Aa), but not other candidate pathogens, induced hypercitrullination in host neutrophils. We identified the pore-forming toxin leukotoxin A (LtxA) as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking membranolytic pathways that sustain autoantigen citrullination in the RA joint. Moreover, LtxA induced changes in neutrophil morphology mimicking extracellular trap formation, thereby releasing the hypercitrullinated cargo. Exposure to leukotoxic Aa strains was confirmed in patients with RA and was associated with both anticitrullinated protein antibodies and rheumatoid factor. The effect of human lymphocyte antigen-DRB1 shared epitope alleles on autoantibody positivity was limited to RA patients who were exposed to Aa These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA. PMID- 27974665 TI - The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene. AB - Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesized that gene expression from gonosomes (sex chromosomes) might play an important role. We demonstrate that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit from two X chromosomes. The gonosomal protein phosphatase 2 regulatory subunit B, beta (PPP2R3B) gene is located on the pseudoautosomal region (PAR) of the X chromosome in females and the Y chromosome in males. We observed that, despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression was lower in males than in females and was independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate-recognizing subunit of protein phosphatase 2A. PR70 decreased melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing the cell division cycle 6 (CDC6)-chromatin licensing and DNA replication factor 1 (CDT1) interaction, which delays the firing of origins of DNA replication. Hence, PR70 functionally behaves as an X-linked tumor suppressor gene. PMID- 27974668 TI - Importance of Adjunct Delivery Techniques to Optimize Deployment Success of Distal Protection Filters During Vein Graft Intervention. AB - OBJECTIVES: This study assessed the impact of adjunct delivery techniques on the deployment success of distal protection filters in saphenous vein grafts (SVGs). BACKGROUND: Despite their proven clinical benefit, distal protection devices are underutilized in SVG interventions. Deployment of distal protection filters can be technically challenging in the presence of complex anatomy. Techniques that facilitate the delivery success of these devices could potentially improve clinical outcomes and promote greater use of distal protection. METHODS: Outcomes of 105 consecutive SVG interventions with attempted use of a FilterWire distal protection device (Boston Scientific) were reviewed. In patients in whom filter delivery initially failed, the success of attempted redeployment using adjunct delivery techniques was assessed. Two strategies were utilized sequentially: (1) a 0.014" moderate-stiffness hydrophilic guidewire was placed first to function as a parallel buddy wire to support subsequent FilterWire crossing; and (2) if the buddy-wire approach failed, predilation with a 2.0 mm balloon at low pressure was performed followed by reattempted filter delivery. RESULTS: The study population consisted of 80 men and 25 women aged 73 +/- 10 years. Mean SVG age was 14 +/- 6 years. Complex disease (American College of Cardiology/American Heart Association class B2 or C) was present in 92%. Initial delivery of the FilterWire was successful in 82/105 patients (78.1%). Of the 23 patients with initial failed delivery, 8 (35%) had successful deployment with a buddy wire alone, 7 (30%) had successful deployment with balloon predilation plus buddy wire, 4 (17%) had failed reattempt at deployment despite adjunct maneuvers, and in 4 (17%) no additional attempts at deployment were made at the operator's discretion. Deployment failure was reduced from 21.9% initially to 7.6% after use of adjunct delivery techniques (P<.01). No adverse events were observed with these measures. CONCLUSIONS: Deployment of distal protection devices can be technically difficult with complex SVG disease. Adjunct delivery techniques are important to optimize deployment success of distal protection filters during SVG intervention. PMID- 27974667 TI - Molecular determinants of human neutralizing antibodies isolated from a patient infected with Zika virus. AB - The 2015-2016 outbreak of Zika virus (ZIKV) disease has affected many countries and is a major public health concern. ZIKV is associated with fetal microcephaly and neurological complications, and countermeasures are needed to treat and prevent ZIKV infection. We report the isolation of 13 specific human monoclonal antibodies from a single patient infected with ZIKV. Two of the isolated antibodies (Z23 and Z3L1) demonstrated potent ZIKV-specific neutralization in vitro without binding or neutralizing activity against strains 1 to 4 of dengue virus, the closest relative to ZIKV. These two antibodies provided postexposure protection to mice in vivo. Structural studies revealed that Z23 and Z3L1 bound to tertiary epitopes in envelope protein domain I, II, or III, indicating potential targets for ZIKV-specific therapy. Our results suggest the potential of antibody-based therapeutics and provide a structure-based rationale for the design of future ZIKV-specific vaccines. PMID- 27974666 TI - Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury. AB - Emerging evidence supports a role for innate immunity and microglia in Alzheimer's disease (AD) pathophysiology. However, no marker related to microglia has been included in the temporal evolution models of AD. TREM2 is a transmembrane protein involved in innate immunity and is selectively expressed by microglia and genetically linked to AD and other neurodegenerative disorders. Its ectodomain is released by proteolysis as a soluble variant (sTREM2) and can be detected in the cerebrospinal fluid (CSF). In patients with autosomal dominant AD, we tested how many years before the expected symptom onset did CSF sTREM2 increase in mutation carriers (MCs) compared to noncarriers (NCs). We also determined the temporal sequence of changes in CSF sTREM2 and markers for amyloid deposition and neurodegeneration as well as cognitive performance. We included 218 participants consisting of 127 MC and 91 NC siblings from the Dominantly Inherited Alzheimer Network. We observed that CSF sTREM2 increased in MCs compared to NCs 5 years before the expected symptom onset and this difference remained significant until 5 years after the expected symptom onset. Changes in CSF sTREM2 occurred after alterations were observed in markers for brain amyloidosis and neuronal injury. We propose that microglial activation occurs several years before the expected symptom onset, but after amyloidosis and neuronal injury have already occurred. PMID- 27974669 TI - Initial Experience of Bioabsorbable Polymer Everolimus-Eluting Synergy Stents in High-Risk Patients Undergoing Complex Percutaneous Coronary Intervention With Early Discontinuation of Dual-Antiplatelet Therapy. AB - AIMS: As more elderly and co-morbid patients require percutaneous revascularization, 1 year of dual-antiplatelet therapy (DAPT) becomes concerning. Synergy stents (Boston Scientific) allow for early cessation of DAPT. This study assessed those in our unit who underwent percutaneous coronary intervention (PCI) with a Synergy stent to examine a minimum of 6 months of clinical outcomes after early discontinuation of DAPT. METHODS AND RESULTS: All non-trial patients in our unit who had PCI with a Synergy stent from August 2013 to February 2016 were retrospectively analyzed. Follow-up was by medical record review or direct contact for postprocedural complications or adverse events. In total, 185 patients underwent PCI with a Synergy stent over 1 year prior. The mean patient age was 72.0 +/- 11.0 years (range, 41-97 years). Stenting involved left main stem (14.1%), multivessel disease (33.0%), and chronic total occlusion (33.0%). DAPT discontinuation occurred in 78.4% by 3 months with no stent thrombosis. Three patients required target-vessel revascularization (TVR) by 1 year. There were no cardiac deaths or myocardial infarctions. Twenty-five patients were able to have non-cardiac procedures within the study period. CONCLUSION: The use of the Synergy everolimus-eluting stent allows for early discontinuation of DAPT, reducing risk of bleeding complications and facilitating non-cardiac procedures, without an increase in stent thrombosis and with excellent results for TVR. PMID- 27974671 TI - p62 at the crossroad of the ubiquitin-proteasome system and autophagy. PMID- 27974670 TI - The SYNTAX Score Does Not Predict Risk of Adverse Events in Patients With Non-ST Elevation Acute Coronary Syndrome Who Undergo Coronary Artery Bypass Graft Surgery. AB - OBJECTIVES: We tested the ability of the SYNTAX score (SS) to predict 1-year adverse outcomes for patients with non-ST segment elevation acute coronary syndromes (NSTE-ACS) who undergo coronary artery bypass graft (CABG) surgery. BACKGROUND: The SS effectively risk stratifies patients who undergo percutaneous coronary intervention, but not patients with stable coronary disease who undergo CABG. METHODS: We calculated the SS for 457 patients with NSTE-ACS in the angiographic substudy of the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) trial who underwent CABG. We stratified and compared patients according to SS tertiles. We tested the ability of the SS, as a linear covariate, to predict adverse events by univariate analyses and by univariate and multivariable Cox proportional hazards model. We also tested the predictive abilities of the Age, Creatinine Clearance, and Ejection Fraction (ACEF) score, the clinical SS, and the logistic clinical SS. RESULTS: The median SS was 23 (interquartile range, 15-30). Baseline clinical characteristics were similar among the groups. One-year mortality and major adverse cardiovascular events (all-cause death, myocardial infarction, any stroke, or urgent revascularization) were similar between the groups (P=.13 and P=.62, respectively). Receiver operating characteristic curves, net reclassification indices, and integrated discrimination indices did not improve with SS, clinical SS, or logistic clinical SS compared with the ACEF score. CONCLUSIONS: The anatomical SS does not appear to be useful in risk stratifying patients with NSTE ACS who undergo CABG. Clinical variables may better risk stratify patients with complex coronary artery disease considered for CABG. PMID- 27974672 TI - Long-term outcomes and propensity score matching analysis: rectal cancer resection for patients with elevated preoperative risk. AB - BACKGROUND: It is still controversial about the treatment strategy for rectal cancer patients with elevated operative risk and elder rectal cancer patients. METHODS: This study presented a retrospective single center experience in rectal cancer proctectomy for high operative risk patients. High operative risk patient was defined as Cr-POSSUM > 5% combined with associated risk factors. 220 in 1477 consecutive patients met the inclusion criteria. RESULTS: 132 patients were selected (66:66) after propensity score matching. The total complication rate between conventional open rectal resection (71 %) and laparoscopic surgery (41%) was significantly different (p = 0.0005). There is a significantly positive correlation between open surgery and advanced Dindo Classification (p = 0.02). Cr POSSUM is positively correlated with Dindo Classification (p = 0.01). There was no significant difference in survival rate among stage I~II, different age groups or different Cr-POSSUM score sub-groups. However, stage III-IV tumor patients in laparoscopic group experienced improved overall survival rate. (p < 0.0001). For patients with preoperative pulmonary or renal disease, patients in laparoscopic group also had better long term prognosis (p = 0.03, p = 0.049). CONCLUSIONS: The results demonstrate the potential advantages of laparoscopic rectal cancer resection for high operative risk patients, especially for the patients with preoperative respiratory or renal disease and stage III cancer. PMID- 27974673 TI - mir-218-2 promotes glioblastomas growth, invasion and drug resistance by targeting CDC27. AB - Glioma has become a significant global health problem with substantial morbidity and mortality, underscoring the importance of elucidating its underlying molecular mechanisms. Recent studies have identified mir-218 as an anti-oncogene; however, the specific functions of mir-218-1 and mir-218-2 remain unknown, especially the latter. The objective of this study was to further investigate the role of mir-218-2 in glioma. Our results indicated that mir-218-2 is highly overexpressed in glioma. Furthermore, we showed that mir-218-2 is positively correlated with the growth, invasion, migration, and drug susceptibility (to beta lapachone) of glioma cells. In vitro, the overexpression of mir-218-2 promoted glioma cell proliferation, invasion, and migration. In addition, the overexpression of mir-218-2 in vivo was found to increase glioma tumor growth. Accordingly, the inhibition of mir-218-2 resulted in the opposite effects. Cell division cycle 27 (CDC27), the downstream target of mir-218-2, is involved in the regulation of glioma cells. Our results indicate that the overexpression of CDC27 counteracted the function of mir-218-2 in glioma cells. These novel findings provide new insight in the application of mir-218-2 as a potential glioma treatment. PMID- 27974674 TI - Sweyjawbu expression is a predictor of ALK rearrangement status in lymphoma. AB - In recent years molecular subtyping has become an important tool for accurate diagnosis of many cancers; for example, the detection of ALK rearrangements in lymphoma and lung cancer helps clinicians provide more precise diagnosis and treatment. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are two routine approaches used to detect ALK rearrangements. However, difficulties with acquisition of biopsy samples, high costs, and long waiting time for results negatively impact the application of these methods. A rapid and inexpensive alternative would be a useful complement to current ALK rearrangement detection. We identified a novel gene, sweyjawbu, from Affymetrix microarray studies. Its expression correlated strongly with ALK in an analysis of 1037 cancer cell lines (correlation coefficient = 0.92). By comparing sweyjawbu transcript levels, it was possible to discriminate 12 ALK rearrangement-positive lymphoma samples from 64 ALK rearrangement-negative lymphomas. Moreover, combining measurements of sweyjawbu expression and the ratio of the 5' and 3' portions of the ALK transcript provided even more accurate identification of ALK rearrangement-positive lymphomas. This novel approach is an excellent complement or alternative to existing FISH and IHC methodologies. PMID- 27974675 TI - NEDD9 may regulate hepatocellular carcinoma cell metastasis by promoting epithelial-mesenchymal-transition and stemness via repressing Smad7. AB - Overexpression of neural precursor cell expressed, developmentally downregulated 9 (NEDD9) is a prognostic marker of many cancers, including hepatocellular carcinoma (HCC). However, the functions and mechanisms of NEDD9 are unclear. We found that upregulation of NEDD9 promoted migration, invasion and cell-to extracellular matrix adhesion of HCC cells. NEDD9 also induced the epithelial mesenchymal transition (EMT) and expression of matrix metalloprotein 2 (MMP2). Increased aldehyde dehydrogenase (ALDH) activity and CD133-positive cells were observed in HCC cells with high expression of NEDD9, corresponding to greater sphere formation in cancer stem cells (CSCs). NEDD9 deregulated Smad7 expression to inhibit Smad signaling and binding to the FAK-Src-Crk complex. We propose that this is the mechanism by which NEDD9 induced CSC properties. PMID- 27974676 TI - In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia. AB - The novel aminopeptidase potentiated alkylating agent melflufen, was evaluated for activity in acute myeloid leukemia in a range of in vitro models, as well as in a patient derived xenograft study. All tested AML cell lines were highly sensitive to melflufen while melphalan was considerably less potent. In the HL-60 cell line model, synergy was observed for the combination of melflufen and cytarabine, an interaction that appeared sequence dependent with increased synergy when melflufen was added before cytarabine. Also, in primary cultures of AML cells from patients melflufen was highly active, while normal PBMC cultures appeared less sensitive, indicating a 7-fold in vitro therapeutic index. Melphalan, on the other hand, was only 2-fold more potent in the AML patient samples compared with PBMCs. Melflufen was equally active against non-malignant, immature CD34+ progenitor cells and a more differentiated CD34+ derived cell population (GM14), whereas the stem cell like cells were less sensitive to melphalan. Finally, melflufen treatment showed significant anti-leukemia activity and increased survival in a patient derived xenograft of AML in mice. In conclusion, melflufen demonstrates high and significant preclinical activity in AML and further clinical evaluation seem warranted in this disease. PMID- 27974678 TI - Prognostic value of increased KPNA2 expression in some solid tumors: A systematic review and meta-analysis. AB - BACKGROUND: Karyopherin alpha2 (KPNA2), a member of the Karyopherin alpha family, has recently been reported to play an important role in tumor progression. However, the association between KPNA2 expression and prognosis in cancer remains controversial. So we performed this meta-analysis to evaluate whether expression of KPNA2 was associated with prognosis in patients with solid tumor. METHODS/FINDINGS: 24 published eligible studies, including 6164 cases, were identified and included in this meta-analysis through searching of PubMed, EMBASE and Web of Science. We found that KPNA2 expression was an independent predictor for the prognosis of solid tumor with primary outcome (overall survival [OS]: pooled HR=1.767, 95% CI=1.503-2.077, P<0.001) and secondary outcomes (time to recurrence [TTR], recurrence free survival [RFS] and progression free survival [PFS]). However, the association between KPNA2 overexpression and disease free survival [DFS] in solid tumors was not significant (pooled HR=1.653, 95% CI=0.903 3.029, P=0.104). Furthermore, the subgroup analysis revealed that KPNA2 overexpression was associated with poor OS in East-Asian patients and European patients, as well as patients with gastric and colorectal cancer. CONCLUSION: KPNA2 expression may be a useful prognostic biomarker to monitor cancer prognosis. Further prospective studies with larger sample sizes are required to confirm our findings. PMID- 27974677 TI - Histone demethylase lysine demethylase 5B in development and cancer. AB - Histone methylation is one of the most important chromatin posttranslational modifications. It has a range of influences on nuclear functions including epigenetic inheritance, transcriptional regulation and the maintenance of genome integrity. Changes in histone methylation status take part in various physiological and pathological processes. KDM5B (lysine demethylase 5B, also called JARID1B or PLU-1) encodes the histone H3 lysine4 (H3K4) demethylase and exhibits a strong transcriptional repression activity. KDM5B plays a role in cell differentiation, stem cell self-renewal and other developmental progresses. Recent studies showed that KDM5B expression was increased in breast, bladder, lung, prostate and many other tumors and promotes tumor initiation, invasion and metastasis. Given its association with tumor progression and prognosis of cancer patients, KDM5B was proposed to be a novel target for the prevention and treatment of human cancers. In this review, we will summarize recent advances in our understanding of the regulation and function of KDM5B in development and cancer. PMID- 27974679 TI - KRAS mutation analysis of washing fluid from endoscopic ultrasound-guided fine needle aspiration improves cytologic diagnosis of pancreatic ductal adenocarcinoma. AB - EUS-FNA becomes one of the most important diagnostic modalities for PDACs. However, acquired tissue specimens were sometimes insufficient to make a definite cytological diagnosis. On the other hand, KRAS mutation is the most frequently acquired genetic alteration found more than 90% of PDACs. To investigate the way to improve diagnostic accuracy for PDACs using both cytological examination and KRAS mutation analysis would be a great help. Therefore, the aims of this study were to evaluate usefulness of conventional cytological examination combined with KRAS mutation analysis with modified PCR technology to improve the sensitivity and the accuracy. We enrolled 43 patients with solid pancreatic masses and 86 EUS FNA specimens were obtained. During the EUS-FNA, the needle catheter was flushed with 2 cc of saline and the washed fluid was collected for KRAS mutation analysis for the first 2 passes; PNAClampTM KRAS Mutation Detection Kit. There were 46 specimens from the 23 PDACs and 40 specimens from the 20 other pancreatic diseases. The sensitivity, specificity and accuracy were as follows; conventional cytopathologic examination: 63%, 100% and 80%; combination of cytopathologic examination and K-ras mutation analysis: 87%, 100% and 93%. Furthermore, KRAS mutation was detected 11 out of 17 PDAC samples whose cytopathology results were inconclusive. KRAS mutation analysis with PNAClampTM technique using washing fluid from EUS-FNA along with cytological examination may not only improve the diagnostic accuracy of PDACs, but also establish the platform using genetic analysis which would be helpful as diagnostic modality for PDACs. PMID- 27974680 TI - Midkine is a serum and urinary biomarker for the detection and prognosis of non small cell lung cancer. AB - Midkine, a heparin-binding growth factor, has been identified as a promising cancer biomarker. In non-small cell lung cancer (NSCLC), the serum and urine midkine levels have not been intensively investigated. The aim of the present study was to investigate the diagnostic and prognostic potential of serum and urine midkine levels in patients with NSCLC. The serum midkine levels were measured in 153 patients with NSCLC, 23 patients with benign pulmonary disease and 95 healthy controls using ELISA. Urine midkine levels were examined in 20 controls and 45 patients with NSCLC. Midkine expression in tumor tissues from 72 patients with NSCLC who underwent definitive surgical resection without any pre operative treatments was examined by immunohistochemistry. Serum levels were significantly higher in patients with NSCLC than in healthy controls (657.36+/ 496.58 pg/ml vs. 194.49+/-122.57 pg/ml, P<0.001). As shown in the ROC curve analysis, the sensitivity and specificity of the cut-off serum midkine concentration of 400 pg/ml for predicting the presence of NSCLC were 71.2% and 88.1%, respectively. Positive correlations between the serum midkine levels and immunohistochemistry staining scores (r=0.315, P=0.007) and between the serum midkine levels and urine midkine levels (r=0.636, P<0.001) were observed using Spearman's bivariate correlations. The serum midkine concentration was identified as an independent prognostic factor by multivariate analysis, and its overexpression yielded a relative risk of death of 2.072 (0.01. PMID- 27974681 TI - Loss of expression of the recycling receptor, FcRn, promotes tumor cell growth by increasing albumin consumption. AB - Tumor cells rely on high concentrations of amino acids to support their growth and proliferation. Although increased macropinocytic uptake and lysosomal degradation of the most abundant serum protein, albumin, in Ras-transformed cells can meet these demands, it is not understood how the majority of tumor cells that express wild type Ras achieve this. In the current study we reveal that the neonatal Fc receptor, FcRn, regulates tumor cell proliferation through the ability to recycle its ligand, albumin. By contrast with normal epithelial cells, we show that human FcRn is present at very low or undetectable levels in the majority of tumor cell lines analyzed. Remarkably, shRNA-mediated ablation of FcRn expression in an FcRn-positive tumor cell line results in a substantial growth increase of tumor xenografts, whereas enforced expression of this receptor by lentiviral transduction has the reverse effect. Moreover, intracellular albumin and glutamate levels are increased by the loss of FcRn-mediated recycling of albumin, combined with hypoalbuminemia in tumor-bearing mice. These studies identify a novel role for FcRn as a suppressor of tumor growth and have implications for the use of this receptor as a prognostic indicator and therapeutic target. PMID- 27974682 TI - Association of polymorphisms in the telomere-related gene ACYP2 with lung cancer risk in the Chinese Han population. AB - Single nucleotide polymorphisms (SNPs) in the telomere-associated gene ACYP2 are associated with increased lung cancer risk. We explored the correlation between ACYP2 SNPs and lung cancer susceptibility in the Chinese Han population. A total of 554 lung cancer patients and 603 healthy controls were included in this study. Thirteen SNPs in ACYP2 were selected. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis. Multivariate logistic regression analysis was used assess the correlation between SNPs and lung cancer. We found that rs1682111 was associated with increased lung cancer risk in the recessive model (crude, OR=1.50, 95%CI: 1.04-2.16, p=0.029; adjusted for age, OR=1.55, 95%CI: 1.04-2.30, p=0.029), as was rs11896604 in the codominant model (crude, OR=0.65, 95%CI: 0.33-1.28, p=0.045; adjusted for age, OR=0.74, 95%CI: 0.36-1.53, p=0.049) and over-dominant model (crude, OR=1.30, 95%CI: 1.02-1.66, p=0.032; adjusted for age, OR=1.37, 95%CI: 1.05-1.78, p=0.020). Finally, rs843720 was associated with increased lung cancer risk in the recessive model (crude, OR=1.43, 95%CI: 1.02-2.02, p=0.040; adjusted for age, OR=1.48, 95%CI: 1.02-2.15, p=0.040). Thus three SNPs in ACYP2 (rs1682111, rs11896604 and rs843720) associate with lung cancer in the Chinese Han population. PMID- 27974683 TI - CLDN1 expression in cervical cancer cells is related to tumor invasion and metastasis. AB - Even though infection with human papillomaviruses (HPV) is very important, it is not the sole cause of cervical cancer. Because it is known that genetic variations that result from HPV infection are probably the most important causes of cervical cancer, we used human whole genome array comparative genomic hybridization to detect the copy number variations of genes in cervical squamous cell carcinoma. The results of the array were validated by PCR, FISH and immunohistochemistry. We find that the copy number and protein expression of claudin-1 (CLDN1) increase with the progression of cervical cancer. The strong positive staining of CLDN1 in the cervical lymph node metastasis group received a significantly higher score than the staining in the group with no lymph node metastasis of cervical cancer tissues. The overexpression of CLDN1 in SiHa cells can increase anti-apoptosis ability and promote invasive ability of these cells accompanied by a decrease in expression of the epithelial marker E-cadherin as well as an increase in the expression of the mesenchymal marker vimentin. CLDN1 induces the epithelial-mesenchymal transition (EMT) through its interaction with SNAI1. Furthermore, we demonstrate that CLDN1 overexpression has significant effects on the growth and metastasis of xenografted tumors in athymic mice. These data suggest that CLDN1 promotes invasion and metastasis in cervical cancer cells via the expression of EMT/invasion-related genes. Therefore, CLDN1 could be a potential therapeutic target for the treatment of cervical cancer. PMID- 27974685 TI - Prognostic value of whole-body SUVmax of nodal and extra-nodal lesions detected by 18F-FDG PET/CT in extra-nodal NK/T-cell lymphoma. AB - We analyzed data from 54 newly-diagnosed persons with extra-nodal natural killer/T-cell (NK/T) lymphoma, who had a pretreatment 18F-FDG PET/CT study, to determine whether the sum of SUVmax of all the nodal and extra-nodal lesions predicted progression-free survival (PFS) and/or overall survival (OS). Three models (WB1SUVmax, WB2SUVmax, WB3SUVmax) based on the basis of the sum of SUVmax of the whole-body SUVmax of 11 nodal and 10 extra-nodal lesions were tested. The discrimination value of these models was evaluated using time-dependent receiver operator characteristic (ROC) curves and corresponding areas under the curve (AUC) in training and validation cohorts. Findings were validated in an independent cohort of 15 subjects. ROC curve analysis showed the optimal cut-off values for WB1SUVmax, WB2SUVmax and WB3SUVmax were 15.8 (sensitivity 92%, specificity 67%, AUC 0.811; P<0.001), 12.7 (sensitivity 96%; specificity 57%; AUC 0.785; P<0.001) and 15.8 (sensitivity 88%; specificity 70%; AUC 0.793; P<0.001). Multivariate analyses indicated WB3SUVmax was independently associated with PFS (hazard ratio [HR]=3.67, 95% confidence interval [95% CI]=1.19, 11.29; P=0.023) and OS (HR= 4.51 [1.02, 19.91]; P=0.047). WB3SUVmax calculated based of the sum of the SUVmax of 3 nodal and 10 extra-nodal lesions was significantly associated with PFS and OS. PMID- 27974684 TI - Macrophage production and activation are dependent on TRIM33. AB - The tripartite motif (TRIM) family of proteins plays important roles in innate immunity and antimicrobial infection. None of these proteins has been shown to directly regulate transcription of genes in monocyte/macrophage except TRIM33 that we have recently shown to be a macrophage specific transcriptional inhibitor of Ifnb1. Using ChIP-seq analyses, we now report that TRIM33 is bound to two fold more genes in immature than in mature myeloid cell lines. When located near the same genes, TRIM33 is bound to different sequences in the two cell lines suggesting a role of TRIM33 in both immature and mature myeloid cells. Accordingly, expression of TRIM33 in immature myeloid cells is necessary for efficient production of small peritoneal macrophages, monocytes and bone marrow derived macrophage (BMDM) and TRIM33 targets a subset of genes involved in the inflammatory response only in mature myeloid cells. Functionally, this targeting is associated with impaired repression of pathways regulating the late phases of lipopolysaccharide (LPS) activation of BMDM and a high sensitivity to LPS in vivo when the trim33 gene is inactivated in mature myeloid cells. These findings pinpoint TRIM33 as an important transcriptional actor of monocyte/macrophage mediated inflammation. PMID- 27974687 TI - The effects of pprI gene of Deinococcus radiodurans R1 on acute radiation injury of mice exposed to 60Co gamma-ray radiation. AB - The role of the pprI gene from Deinococcus radiodurans R1 in therapy of acute radiation injury of a mammalian host was investigated. We injected a plasmid containing the pprI gene into the muscle of mice exposed to total 6Gy of 60Co gamma-ray radiation. After injection, we used in vivo gene electroporation technology to transfer the pprI gene into the cell. We found the PprI protein was expressed significantly at 1 d after irradiation, but there was no expression of pprI gene 7 d post-irradiation. The expression of pprI gene evidently decreased the death rate of mice exposed to lethal dose radiation, significantly relieved effects on blood cells in the acute stage, shortened the persistence time of the decrease of lymphocytes, and decreased the apoptotic rates of spleen cells, thymocytes and bone marrow cells. The expression of Rad51 protein in the lungs, livers, and kidneys was significantly higher in the mice treated with the pprI plasmid after irradiation. However, there were no obvious differences for Rad52 protein expression. We conclude that the prokaryotic pprI gene of D. radiodurans R1 first was expressed in mammalian cells. The expressed prokaryotic PprI protein has distinct effects of the prevention and treatment on acute radiation injury of mammal. The effects of radio-resistance may relate to expression of Rad51 protein which is homologous with RecA from D. radiodurans. PMID- 27974686 TI - Autophagy-dependent danger signaling and adaptive immunity to poorly immunogenic tumors. AB - Recent data suggest that autophagy does not influence spontaneous and therapy elicited tumor infiltration by immune cells in murine models of melanoma and breast carcinoma. These findings, which have been obtained in the absence of a therapeutically relevant anticancer immune response, indicate that the intrinsically low immunogenicity of some tumors cannot be compensated for by increased danger signaling. PMID- 27974688 TI - Looking for the best anti-colitis medicine: A comparative analysis of current and prospective compounds. AB - Ulcerative colitis (UC) is a chronic lifelong inflammatory disorder of the colon, which, while untreated, has a relapsing and remitting course with increasing risk of progression toward colorectal cancer. Current medical treatment strategies of UC mostly focus on inhibition of the signs and symptoms of UC to induce remission and prevent relapse of disease activity, minimizing the impact on quality of life, but not affecting the cause of disease. To date, however, there is no single reliable treatment agent and/or strategy capable of effectively controlling colitis progression throughout the patient's life without side effects, remission, or resistance. Taking into consideration an urgent need for the new colitis treatment strategies, targets and/or modulators of inflammation, we have tested current and prospective compounds for colitis treatment and directly compared their anti-colitis potency using a dextran sulfate sodium (DSS) mouse model of colitis. We have introduced a composite score - a multi-parameters comparison tool - to assess biological potency of different compounds. PMID- 27974690 TI - Benefit of Sunitinib in the treatment of pulmonary primitive neuroectodermal tumors: a case report and literature review. AB - Primitive neuroectodermal tumor (PNET) is a highly aggressive small round celltumor but is extremely rare in the lung. Next-generation sequencing (NGS) has led to breakthroughs for genetic analyses and personalizedmedicine approaches for cancer treatment.We report the case of a 30-year-old woman with an advanced pulmonary PNET treated with multiple chemotherapeutic regimens, and achieved a partial response (PR) as a best response. However, there was a disease progression after these treatment regimens.The NGS revealed the presence of a copy number loss (CNL) of Von Hippel-Lindau (VHL), CDKN2A/B and TP53 genes. The specific VHL CNL has not previously been associated with PNET, but has been reported in other tumors and has been associated with response to Sunitinib. Sunitinibwas then instituted for this patient and resulted in PR after the failure of multiple chemotherapeutic regimens. To our knowledge, this is the first report of pulmonary PNET with CNL of VHL gene that benefits from Sunitinib treatment. This case illustrates the potential of clinicalNGS to open unexpected avenues for treatment and thereby improve patient outcomes. PMID- 27974691 TI - Percutaneous laser ablation: a new contribution to unresectable high-risk metastatic retroperitoneal lesions? AB - BACKGROUND & AIMS: Metastasis in retroperitoneal lymph nodes is one of the signs of advanced stage or terminal stage of malignancy. We performed a trial to assess the safety and efficacy of ultrasonography (US)-guided local neodymium-doped yttrium aluminum garnet (Nd:YAG) laser ablation for metastatic lymph nodes in the retroperitoneal region. METHODS: We evaluated 4 cases of retroperitoneal metastatic lymph nodes treated using US-guided Nd:YAG laser ablation. Additionally, we reviewed the PubMed database for articles on thermal ablation of retroperitoneal lesions until March 2016, without language limitations. RESULTS: In our study, all lesions were nearly completely ablated with mild discomfort, including pain and fever at the 3-month follow-up. In the literature review, a total of 398 patients with 491 retroperitoneal tumors were identified, and complications after the procedure included enterovesical fistula, fecal incontinence, and hematoma. CONCLUSIONS: Percutaneous laser ablation could be a theoretically promising approach for retroperitoneal metastatic lesions. ClinicalTrials.gov number: NCT02822053. PMID- 27974693 TI - Induction chemotherapy followed by concurrent chemoradiation and nimotuzumab for locoregionally advanced nasopharyngeal carcinoma: preliminary results from a phase II clinical trial. AB - Overexpression of epidermal growth factor receptor can be found in more than 80% of patients with locoregionally advanced nasopharyngeal carcinoma and is associated with shorter survival. In this work, we evaluated the feasibility of adding nimotuzumab to chemoradiation in locoregionally advanced nasopharyngeal carcinoma. Twenty-three patients with clinically staged T3-4 or any node-positive disease were enrolled. They were scheduled to receive one cycle of induction chemotherapy followed by intensity-modulated radiotherapy, weekly administration of nimotuzumab and concurrent chemotherapy. Results showed that all patients received a full course of radiotherapy, 19(82.6%)patients completed the scheduled neoadjuvant and concurrent chemotherapy, and 22(95.7%) patients received >=6 weeks of nimotuzumab. During the period of concurrent chemoradiation and nimotuzumab, grade 3-4 toxicities occurred in 14(60.9%) patients: 8 (34.8%) had grade 3-4 oral mucositis, 6(26.1%) had grade 3 neutropenia, and 1(4.3%) had grade 3 dermatitis. No acne-like rash was observed. With a median follow-up of 24.1 months, the 2-year progression-free survival and overall survival were 83.5% and 95.0%, respectively. In conclusion, concurrent administration of chemoradiation and nimotuzumab was well-tolerated with good compliance. Preliminary clinical outcome data appear encouraging with favorable normal tissue toxicity results comparing with historical data of concurrent chemoradiation plus cetuximab. PMID- 27974689 TI - PD-1 and its ligands are important immune checkpoints in cancer. AB - Checkpoint programmed death-1 (PD-1)/programmed cell death ligands (PD-Ls) have been identified as negative immunoregulatory molecules that promote immune evasion of tumor cells. The interaction of PD-1 and PD-Ls inhibits the function of T cells and tumor-infiltrating lymphocytes (TIL) while increasing the function of immunosuppressive regulatory T cells (Tregs). This condition causes the tumor cells to evade immune response. Thus, the blockade of PD-1/PD-L1 enhances anti tumor immunity by reducing the number and/or the suppressive activity of Tregs and by restoring the activity of effector T cells. Furthermore, some monoclonal antibodies blockading PD-1/PD-Ls axis have achieved good effect and received Food and Drug Administration approval. The role of PD-1/PD-Ls in tumors has been well studied, but little is known on the mechanism by which PD-1 blocks T-cell activation. In this study, we provide a brief overview on the discovery and regulatory mechanism of PD-1 and PD-L1 dysregulation in tumors, as well as the function and signaling pathway of PD-1 and its ligands; their roles in tumor evasion and clinical treatment were also studied. PMID- 27974692 TI - Multi-delay ASL can identify leptomeningeal collateral perfusion in endovascular therapy of ischemic stroke. AB - BACKGROUND AND PURPOSE: Multi-delay arterial spin-labeling (ASL) perfusion imaging has been used as a promising modality to evaluate cerebral perfusion. Our aim was to assess the association of leptomeningeal collateral perfusion scores based on ASL parameters with outcome of endovascular treatment in patients with acute ischemic stroke (AIS) in the middle cerebral artery (MCA) territory. MATERIALS AND METHODS: ASL data at 4 post-labeling delay (PLD) times (PLD = 1.5, 2, 2.5, 3 s) were acquired during routine clinical magnetic resonance examination on AIS patients prior to endovascular treatment. A 3-point scale of leptomeningeal collateral perfusion grade on 10 anatomic regions was determined based on arterial transit times (ATT), cerebral blood flow (CBF), and arterial cerebral blood volume (CBV), estimated by the multi-delay ASL protocol. Based on a 90-day modified Rankin Scale (mRS), the patients were dichotomized to moderate/good (mRS 0-3) and poor outcome (mRS 4-6) and the regional collateral flow scores were compared. RESULTS: Fifty-five AIS patients with unilateral MCA stroke (mean 73.95+/-14.82 years) including 23 males were enrolled. Compared with poor outcome patients, patients with moderate to good outcomes had a significantly higher leptomeningeal collateral perfusion scores on CBV (3.01+/ 2.11 vs. 1.82+/-1.51, p=0.024) but no differences on scores on CBF (2.31+/-1.61 vs. 1.66+/-1.32, p=0.231) and ATT (2.67+/-2.33 vs. 3.42+/-3.37, p=0.593). CONCLUSIONS: Higher leptomeningeal collateral perfusion scores on CBV images by ASL may be a specific marker of clinical outcome after endovascular treatment in patients with acute MCA ischemic stroke. Further study with larger sample size is warranted. PMID- 27974695 TI - CT-guided percutaneous laser ablation of metastatic lung cancer: three cases report and literature review. AB - OBJECTIVE: To report the efficacy and safety of CT-guided percutaneous laser ablation (PLA) for metastatic lung tumors. METHODS: Three cases of metastatic lung cancer underwent CT-guided PLA, and we searched for previously published articles on the minimally invasive CT-guided RFA or MWA for lung tumors in recent five years. RESULTS: With the guidance of CT, all lesions had good prognosis under laser ablation. Case 1 suffering from severe pulmonary dysfunction and diffuse pulmonary bullae, had small pneumothorax. CT scan obtained four months following the ablation showed two lesions had complete responses and one partial response. Case 2 had successful complete response with absent lung mass, and also had a good postoperative condition without any discomfort in the two-month follow up. Case 3 showed partial response and improved greatly after five months. 962 cases (mean age of 45.7 years, 62.2% male) of 1297 lung tumors with detailed information were identified from 27 articles. Of these cases, the minority manifested complications such as pneumothorax, hemoptysis, hemothorax, pneumonia, pain and fever. CONCLUSIONS: Percutaneous CT-guided PLA could be a safe and promising minimally invasive treatment for patients with primary lung cancer or unresectable pulmonary metastases, especially multineedle PLA in large tumors, which still needs more large-scale prospective studies to convince this method in the future. PMID- 27974694 TI - Hormophysa triquerta polyphenol, an elixir that deters CXCR4- and COX2-dependent dissemination destiny of treatment-resistant pancreatic cancer cells. AB - Therapy-resistant pancreatic cancer (PC) cells play a crucial role in tumor relapse, recurrence, and metastasis. Recently, we showed the anti-PC potential of an array of seaweed polyphenols and identified efficient drug deliverables. Herein, we investigated the benefit of one such deliverable, Hormophysa triquerta polyphenol (HT-EA), in regulating the dissemination physiognomy of therapy resistant PC cells in vitro,and residual PC in vivo. Human PC cells exposed to ionizing radiation (IR), with/without HT-EA pre-treatment were examined for the alterations in the tumor invasion/metastasis (TIM) transcriptome (93 genes, QPCR profiling). Utilizing a mouse model of residual PC, we investigated the benefit of HT-EA in the translation regulation of crucial TIM targets (TMA-IHC). Radiation activated 30, 50, 15, and 38 TIM molecules in surviving Panc-1, Panc 3.27, BxPC3, and MiaPaCa-2 cells. Of these, 15, 44, 12, and 26 molecules were suppressed with HT-EA pre-treatment. CXCR4 and COX2 exhibited cell-line independent increases after IR, and was completely suppressed with HT-EA, across all PC cells. HT-EA treatment resulted in translational repression of IR-induced CXCR4, COX2, beta-catenin, MMP9, Ki-67, BAPX, PhPT-1, MEGF10, and GRB10 in residual PC. Muting CXCR4 or COX2 regulated the migration/invasion potential of IR-surviving cells, while forced expression of CXCR4 or COX2 significantly increased migration/invasion capabilities of PC cells. Further, treatment with HT EA significantly inhibited IR-induced and CXCR4/COX2 forced expression-induced PC cell migration/invasion. This study (i) documents the TIM blueprint in therapy resistant PC cells, (ii) defines the role of CXCR4 and COX2 in induced metastatic potential, and (iii) recognizes the potential of HT-EA in deterring the CXCR4/COX2-dependent dissemination destiny of therapy-resistant residual PC cells. PMID- 27974696 TI - Sp1-mediated transcriptional activation of miR-205 promotes radioresistance in esophageal squamous cell carcinoma. AB - Radiotherapy for esophageal squamous cell carcinoma (ESCC) patients is limited by resistance to ionizing radiation (IR). However, the roles and mechanisms of microRNAs in radioresistance are obscure. Here, we investigated that microRNA-205 (miR-205) was upregulated in radioresistant (RR) ESCC cells compared with the parental cells. Overexpression of miR-205 promoted colony survival post-IR, whereas depletion of miR-205 sensitized ESCC cells to IR in vitro and in vivo. Further, we demonstrated that miR-205 promoted radioresistance by enhancing DNA repair, inhibiting apoptosis and activating epithelial-mesenchymal transition (EMT). Mechanistically, miR-205, upregulated post-IR, was demonstrated to be activated by Sp1 in parallel with its host gene, miR-205HG, both of which showed a perfect correlation. We also identified and validated phosphatase and tensin homolog (PTEN), as a target of miR-205 that promoted radioresistance via PI3K/AKT pathway. Lastly, increased miR-205 expression was closely associated with decreased PTEN expression in ESCC tissues and miR-205 expression predicted poor prognosis in patients with ESCC. Taken together, these findings identify miR-205 as a critical determinant of radioresistance and a biomarker of prognosis. The Sp1-mediated transcriptional activation of miR-205 promotes radioresistance through PTEN via PI3K/AKT pathway in ESCC. Inhibition of miR-205 expression may be a new strategy for radiotherapy in ESCC. PMID- 27974697 TI - Surrogate in vitro activation of innate immunity synergizes with interleukin-7 to unleash rapid antigen-driven outgrowth of CD4+ and CD8+ human peripheral blood T cells naturally recognizing MUC1, HER2/neu and other tumor-associated antigens. AB - Effective adoptive immunotherapy has proved elusive for many types of human cancer, often due to difficulties achieving robust expansion of natural tumor specific T-cells from peripheral blood. We hypothesized that antigen-driven T cell expansion might best be triggered in vitro by acute activation of innate immunity to mimic a life-threatening infection. Unfractionated peripheral blood mononuclear cells (PBMC) were subjected to a two-step culture, first synchronizing their exposure to exogenous antigens with aggressive surrogate activation of innate immunity, followed by gamma-chain cytokine-modulated T-cell hyperexpansion. Step 1 exposure to GM-CSF plus paired Toll-like receptor agonists (resiquimod and LPS), stimulated abundant IL-12 and IL-23 secretion, as well as upregulated co-stimulatory molecules and CD11c expression within the myeloid (CD33+) subpopulation. Added synthetic long peptides (>20aa) derived from widely expressed oncoproteins (MUC1, HER2/neu and CMVpp65), were reliably presented to CD4+ T-cells and cross-presented to CD8+ T-cells. Both presentation and cross presentation demonstrated proteasomal and Sec61 dependence that could bypass the endoplasmic reticulum. Step 2 exposure to exogenous IL-7 or IL-7+IL-2 produced selective and sustained expansion of both CD4+ and CD8+ peptide-specific T-cells with a predominant interferon-gamma-producing T1-type, as well as the antigen specific ability to lyse tumor targets. Other gamma-chain cytokines and/or combinations were initially proliferogenic, but followed by a contractile phase not observed with IL-7 or IL-7+IL-2. Regulatory T-cells were minimally propagated under these culture conditions. This mechanistically rational culture sequence, effective even for unvaccinated donors, enables rapid preparation of T-cells recognizing tumor-associated antigens expressed by the majority of human cancers, including pancreatic cancers, breast cancers and glioblastomas. PMID- 27974698 TI - Genome wide copy number analyses of superficial esophageal squamous cell carcinoma with and without metastasis. AB - Superficial esophageal squamous cell carcinoma (ESCC) is generally considered a subtype of less invasive ESCC. Yet a subset of these superficial ESCC would have metastasis after esophagostomy or endoscopic resection and lead to poor prognosis. The objective of this study is to determine biomarkers that can identify such subset of superficial ESCC that would have metastasis after surgery using genome wide copy number alteration (CNA) analyses. The CNAs of 38 cases of superficial ESCCs originated from radical surgery, including 19 without metastasis and 19 with metastasis within 5 years' post-surgery, were analyzed using Affymetrix OncoScanTM FFPE Assay. A 39-gene signature was identified which characterized the subset of superficial ESCC with high risk of metastasis after surgery. In addition, recurrent CNAs of superficial ESCC were also investigated in the study. Amplification of 11q13.3 (FGF4) and deletion of 9p21.3 (CDKN2A) were found to be recurrent in all 38 superficial ESCCs analyzed. Notably amplifications of 3p26.33 (SOX2OT), 8q24.21 (MYC), 14q21.1 (FOXA1) and deletion of 3p12.1 (GBE1) were only found to be recurrent in metastaic superficial ESCCs. In conclusion, using CNAs analyses, we identify a 39-gene signature which characterizes the high risk metastatic superficial ESCCs and discover several recurrent CNAs that might be the driver alterations in metastasis among superficial ESCCs. PMID- 27974699 TI - Polymorphisms in nucleotide excision repair genes and risk of primary prostate cancer in Chinese Han populations. AB - Genetic variants of nucleotide excision repair (NER) genes have been extensively investigated for their roles in the development of prostate cancer (PCa); however, the published results have been inconsistent. In a hospital-based case control study of 1,004 PCa cases and 1,055 cancer-free controls, we genotyped eight potentially functional single nucleotide polymorphisms (SNPs) of NER genes (i.e., XPC, rs2228001 T>G and rs1870134 G>C; XPD, rs13181 T>G and rs238406 G>T; XPG, rs1047768 T>C, rs751402 C>T, and rs17655 G>C; and XPF, rs2276464 G>C) and assessed their associations with risk of PCa by using logistic regression analysis. Among these eight SNPs investigated, only XPC rs1870134 CG/CC variant genotypes were associated with a decreased risk of prostate cancer under a dominant genetic model (adjusted odds ratio [OR] = 0.77, 95% confidence interval [CI] = 0.64-1.91, P = 0.003). Phenotype-genotype analysis also suggested that the XPC rs1870134 CG/CC variant genotypes were associated with significantly decreased expression levels of XPC mRNA in a mix population of different ethnicities. These findings suggested that XPC SNPs may contribute to risk of PCa in Eastern Chinese men. PMID- 27974700 TI - Tunneling nanotube (TNT) formation is downregulated by cytarabine and NF-kappaB inhibition in acute myeloid leukemia (AML). AB - Acute myeloid leukemia (AML) is a bone marrow derived blood cancer where intercellular communication in the leukemic bone marrow participates in disease development, progression and chemoresistance. Tunneling nanotubes (TNTs) are intercellular communication structures involved in transport of cellular contents and pathogens, also demonstrated to play a role in both cell death modulation and chemoresistance. Here we investigated the presence of TNTs by live fluorescent microscopy and identified TNT formation between primary AML cells and in AML cell lines. We found that NF-kappaB activity was involved in TNT regulation and formation. Cytarabine downregulated TNTs and inhibited NF-kappaB alone and in combination with daunorubicin, providing additional support for involvement of the NF-kappaB pathway in TNT formation. Interestingly, daunorubicin was found to localize to lysosomes in TNTs connecting AML cells indicating a novel function of TNTs as drug transporting devices. We conclude that TNT communication could reflect important biological features of AML that may be explored in future therapy development. PMID- 27974702 TI - Tumor compactness improves the preoperative volumetry-based prediction of the pathological complete response of rectal cancer after preoperative concurrent chemoradiotherapy. AB - In addition to clinical factors (tumor and node stage) and treatment factors (equivalent radiotherapy dose and chemotherapy regimen), we assessed whether different performances of various tumor volume measurements help predict the pathological complete response (pCR) of locally advanced rectal cancer (LARC) after preoperative concurrent chemoradiotherapy (CCRT). A total of 122 patients with LARC treated with a long course of CCRT, between December 2009 and March 2015, were enrolled in this bi-institutional study. Tumor delineation was based on standard T2-weighted magnetic resonance imaging or contrast-enhanced computed tomography before CCRT. Tumor compactness was defined as the ratio of the volume and the surface area. The tumor compactness-corrected TV (TCTV) was defined as the ratio of the real TV (RTV) and tumor compactness. Twenty-three (18.9%) patients had a pCR. Areas under the curve of the receiver operating characteristic for pCR prediction calculated using the RTV, cylindrical approximated TV (CATV), and TCTV were 0.724, 0.747, and 0.780, respectively. The prediction performance of TCTV was significantly more efficient than that of both RTV (P = 0.0057) and CATV (P = 0.0329). Multivariate logistic regression analysis revealed tumor compactness (P = 0.001), RTV (P = 0.042), and preoperative clinical nodal status (P = 0.044) as significant predictors of a pCR. In addition, poor tumor compactness was closely associated with lymphovascular space invasion (P = 0.008) and pathological nodal status (P = 0.003). For patients with LARC receiving preoperative CCRT, tumor compactness is a useful radiomic parameter for improving the volumetric based prediction model. PMID- 27974701 TI - Prognostic role of NF-YA splicing isoforms and Lamin A status in low grade endometrial cancer. AB - Although most cases of low grade (G1) endometrial cancer (EC) do not behave aggressively, in rare instances, can progress in a highly aggressive manner. In this study we analyzed formalin-fixed, paraffin-embedded (FFPE) EC tissues to find novel clinical and biological features to help diagnosis and treatment of G1 ECs s in order to better stratify patient risk of recurrence. A retrospective cohort of FFPE specimens from patients with EC (n=87) and benign tissue specimens (NE) from patients who underwent a hysterectomy to treat other benign disease (n = 13) were collected. Total RNA and proteins were extracted and analyzed, respectively, by quantitative PCR and western blotting. NF-YAs is expressed and lamin A is down-modulated in all high grade (G2 and G3) ECs. In G1 ECs, NF-YAs expression is heterogeneous being expressed only in a subset of these tumours. Interestingly, the G1 ECs that express NF-YAs display low levels of lamin A similar to those present in G2 and G3 ECs. Of note, this pattern of NF-YAs and lamin A expression correlates with tumor aggressiveness assessed by comparative analysis with estrogen receptor (ER) status and epithelial-mesenchymal transition (EMT) markers thus suggesting its potential role as biomarker of tumour aggressiveness in G1 EC. In all grade ECs, lamin A is strongly downmodulated, being its expression inversely correlated with tumor aggressiveness and its loss of expression. We identified NF-YAs and lamin A expression levels as novel potential biomarkers useful to identify G1 ECs patients with risk of recurrence. PMID- 27974703 TI - Fe3O4 nanoparticles and cryoablation enhance ice crystal formation to improve the efficiency of killing breast cancer cells. AB - The key problem of cryoablation is that only freezing is often unable to kill the capillaries at tumor edges, leading to a high rate of recurrence. Here, we found that Fe3O4 nanoparticles were highly useful to improve the freezing capability of cryosurgery due to their ability to alter intracellular ice formation (IIF) and growth in tumor cells. The killing efficiency of cryoablation for MCF-7 breast cancer cells can be expected to be enhanced as the Fe3O4 nanoparticles concentration increased, it was mainly because that more IIF was induced by the participation of Fe3O4 nanoparticles during freezing, recrystallization and thawing. Furthermore, our results also showed that recrystallization contributed to the formation of extracellular embryonic crystals, which was capable of enhancing the efficiency of killing MCF-7 cells. This research is to develop an understanding of the mechanism of the cryoablation enhancing the killing efficiency in the presence of the Fe3O4 nanoparticles, and to promote their further application in tumor therapy. PMID- 27974705 TI - Are neurological complications of monoclonal gammopathy of undetermined significance underestimated? AB - OBJECTIVES: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignancy preceding multiple myeloma (MM) or related disorders. Neurological symptoms caused by the monoclonal immunoglobulins or free light-chains are often associated with a high morbidity. We analyzed the prevalence of neuropathy, clinical features and the long-term outcome in 223 patients (pts.) with MGUS. PATIENTS AND METHODS: Between 1/2005 and 3/2015, 223 adult pts. with MGUS were identified in our database. RESULTS: In36/223 pts. (16%) a neuropathy was diagnosed (MGUS associated neuropathy, MGUS-N). 20 pts. (55%) had a distal symmetric axonal neuropathy, 10 pts. (28%) had a chronic inflammatory demyelinating polyneuropathy and 6 pts (17%) a distal acquired demyelinating symmetric polyneuropathy. In MGUS-NN (without neuropathy) and in MGUS-N, progression to smoldering MM, MM or Waldenstrom's macroglobulinemia (WM) occurred in 17% of the pts. The Immunoglobulin subtype was predominantly IgG in MGUS-NN and IgM in MGUS-N and >=5.5% plasma cells in the bone-marrow predicted progression to MM and AL-amyloidosis in MGUS-NN and to WM in MGUS-N (p<0.05). CONCLUSION: Due to the substantial prevalence of neuropathies, MGUS pts. should be monitored carefully and referred to a specialized center if neurological symptoms occur. PMID- 27974704 TI - MED15 overexpression in prostate cancer arises during androgen deprivation therapy via PI3K/mTOR signaling. AB - Androgen deprivation therapy (ADT) is the main therapeutic option for advanced prostate cancer (PCa). After initial regression, most tumors develop into castration-resistant PCa (CRPC). Previously, we found the Mediator complex subunit MED15 to be overexpressed in CRPC and to correlate with clinical outcome. Therefore, we investigated whether MED15 is implicated in the signaling changes taking place during progression to CRPC. Immunohistochemistry (IHC) for MED15 on matched samples from the same patients before and after ADT reveals significantly increased MED15 expression after ADT in 72%. A validation cohort comprising samples before and after therapy confirmed our observations. Protein analysis for pAKT and pSMAD3 shows that MED15 correlates with PI3K and TGFbeta activities, respectively, and that hyper-activation of both pathways simultaneously correlates with highest levels of MED15. We further show that MED15 protein expression increases in LNCaP cells under androgen deprivation, and via EGF mediated PI3K activation. PI3K/mTOR and TGFbeta-receptor inhibition results in decreased MED15 expression. MED15 knockdown reduces LNCaP cell viability and induces apoptosis during androgen deprivation, while cell cycle is not affected. Collectively, MED15 overexpression arises during ADT via hyper-activation of PI3K/mTOR signaling, thus MED15 may serve as a predictive marker for response to PI3K/mTOR inhibitors. Furthermore, MED15 is potentially a therapeutic target for the treatment of CRPC. PMID- 27974706 TI - TM4SF1 promotes the self-renewal of esophageal cancer stem-like cells and is regulated by miR-141. AB - Cancer stem-like cells have been identified in primary human tumors and cancer cell lines. Previously we found TM4SF1 gene was highly expressed in side population (SP) cells from esophageal squamous cell carcinoma (ESCC) cell lines, but the role and underlying mechanism of TM4SF1 in ESCC remain unclear. In this study, we observed TM4SF1 was up-regulated but miR-141 was down-regulated in SP cells isolated from ESCC cell lines. TM4SF1 could stimulate the self-renewal ability and carcinogenicity of esophageal cancer stem-like cells, and promote cell invasion and migration. In miR-141 overexpression cells, the expression of TM4SF1 was significantly reduced. We also found that overexpression of miR-141 could abolish the self-renewal ability and carcinogenicity of esophageal cancer stem-like cells and decrease cell invasion and migration by suppressing TM4SF1. Consequently, TM4SF1 is a direct target gene of miR-141. The regulation of TM4SF1 by miR-141 may play an important role in controlling self-renewals of esophageal cancer stem-like cells. It may also promote the development of new therapeutic strategies and efficient drugs to target ESCC stem-like cells. PMID- 27974707 TI - Cancer upregulated gene 2 induces epithelial-mesenchymal transition of human lung cancer cells via TGF-beta signaling. AB - Cancer upregulated gene 2 (CUG2) enhances cell migration and invasion, but the underlying mechanism has not been revealed. Herein, CUG2 decreased the expression of E-cadherin and increased the expression of N-cadherin and vimentin, characteristics of the epithelial-mesenchymal transition (EMT). A CUG2 deletion mutant, lacking interaction with nucleophosmin 1 (NPM1), or suppression of NPM1 reduced wound healing and cell invasion, indicating that CUG2-mediated EMT requires NPM1. CUG2 enhanced activation of Smad2/3 and expression of Snail and Twist, while the CUG2 silence decreased these TGF-beta signaling pathways, leading to suppression of EMT. NPM silence also inhibited the CUG2-induced TGF beta signaling. These results suggest that TGF-beta signaling is involved in CUG2 induced EMT. Treatment with EW-7197, a novel inhibitor of TGF-beta signaling, diminished CUG2-mediated EMT and inhibition of Akt, ERK, JNK, and p38 MAPK, non canonical TGF-beta signaling molecules, also decreased expression of Smad2/3, Snail and Twist, leading to inhibition of EMT. The results confirm that TGF-beta signaling is essential for CUG2-mediated EMT. Interestingly, TGF-beta enhanced CUG2 expression. We further found that both CUG2-induced TGF-beta production and TGF-beta-induced CUG2 up-regulation required a physical interaction between Sp1 and Smad2/3 in the CUG2 and TGF-beta promoter, as demonstrated by a promoter reporter assay, immunoprecipitation, and ChIP assay. These results indicated close crosstalk between CUG2 and TGF-beta. Conversely, suppression of CUG2 or NPM1 did not completely inhibit TGF-beta-induced EMT, indicating that the effect of TGF-beta on EMT is dominant over the effect of CUG2 on EMT. Collectively, our findings suggest that CUG2 induces the EMT via TGF-beta signaling. PMID- 27974708 TI - Alveolar Hypoxia-Induced Pulmonary Inflammation: From Local Initiation to Secondary Promotion by Activated Systemic Inflammation. AB - Pulmonary hypertension (PH) is a pathological condition with high mortality and morbidity. Hypoxic PH (HPH) is a common form of PH occurring mainly due to lung disease and/or hypoxia. Most causes of HPH are associated with persistent or intermittent alveolar hypoxia, including exposure to high altitude and chronic obstructive respiratory disease. Recent evidence suggests that inflammation is a critical step for HPH initiation and development. A detailed understanding of the initiation and progression of pulmonary inflammation would help in exploring potential clinical treatments for HPH. In this review, the mechanism for alveolar hypoxia-induced local lung inflammation and its progression are discussed as follows: (1) low alveolar PO2 levels activate resident lung cells, mainly the alveolar macrophages, which initiate pulmonary inflammation; (2) systemic inflammation is induced by alveolar hypoxia through alveolar macrophage activation; (3) monocytes are recruited into the pulmonary circulation by alveolar hypoxia-induced macrophage activation, which then contributes to the progression of pulmonary inflammation during the chronic phase of alveolar hypoxia, and (4) alveolar hypoxia-induced systemic inflammation contributes to the development of HPH. We hypothesize that a combination of alveolar hypoxia induced local lung inflammation and the initiation of systemic inflammation ("second hit") is essential for HPH progression. PMID- 27974709 TI - Adenovirus-Mediated Overexpression of Septin 2 Attenuates alpha-Smooth Muscle Actin Expression and Adventitial Myofibroblast Migration Induced by Angiotensin II. AB - Phenotypic transformation from adventitial fibroblasts (AFs) to myofibroblasts (MFs) is critical for vascular remodeling. Septin 2 was found to be downregulated during the differentiation of AFs to MFs induced by angiotensin II (Ang II); however, the role of septin 2 in this process is still unknown. In this study, we investigate whether septin 2 contributes to the adventitial MF phenotypic modulation caused by Ang II. The decreased level of septin 2 and the increased expression of alpha-smooth muscle actin (alpha-SMA), a marker of MFs, were readily observed in Ang II-stimulated MF differentiation. After gene transfer of septin 2, the expression of alpha-SMA was markedly decreased and the MF migration response to Ang II was inhibited. Furthermore, the inhibition of RhoA, another molecule involved in MF phenotypic modulation, decreased the motility of MFs and the expression of septin 2 triggered in Ang II. Finally, transfection of septin 2 rescued the level of acetyl-alpha-tubulin in MFs. These findings demonstrate that, as a downstream molecule of RhoA, septin 2 blunted the responses of AFs to Ang II by protecting alpha-tubulin acetylation, which suggests that septin 2 may serve as a potential therapeutic target for vascular injury. PMID- 27974710 TI - Clinical Predictors of Response to Prednisone Plus Cyclophosphamide in Patients with Idiopathic Membranous Nephropathy. AB - BACKGROUND: Complete remission (CR) and partial remission (PR) are beneficial to the long-term outcome of patients with idiopathic membranous nephropathy (iMN). However, we are lacking in studies that evaluate the clinical predictors of response to treatment with prednisone plus cyclophosphamide (CP). The objectives of the study are to identify clinical factors that could predict clinical remission or relapse in patients with iMN who were treated with prednisone plus i.v. CP therapy. METHODS: This retrospective study recruited a total of 102 eligible patients diagnosed with biopsy-proven iMN between January 2010 and December 2013 in our center. All subjects were treated with prednisone plus i.v. CP for at least 6 months. Primary outcome was remission, including both CR and PR. Demographic data and clinical data at baseline and month 3 of treatment with CP were assessed. RESULTS: The proportion of patients with remission (both CR and PR) was 82.4%, over an average follow-up duration of 15 (10-27.5) months. Fifty two of them experienced a CR. Baseline proteinuria and the reduction of proteinuria at month 3 of CP treatment were independent predictors of remission (p < 0.05) and CR (p < 0.05). In addition, the presence of a PR versus a CR was associated with the risk of relapse (hazards ratio 21.521, 95% CI 4.534-102.150, p < 0.001). CONCLUSIONS: Patients with low proteinuria at baseline and high reduction of proteinuria at month 3 of treatment with CP were more likely to achieve remission and CR. The presence of only a PR may act as a useful predictor of relapse after completion of CP therapy. PMID- 27974711 TI - Skin Wound Healing: An Update on the Current Knowledge and Concepts. AB - BACKGROUND: The integrity of healthy skin plays a crucial role in maintaining physiological homeostasis of the human body. The skin is the largest organ system of the body. As such, it plays pivotal roles in the protection against mechanical forces and infections, fluid imbalance, and thermal dysregulation. At the same time, it allows for flexibility to enable joint function in some areas of the body and more rigid fixation to hinder shifting of the palm or foot sole. Many instances lead to inadequate wound healing which necessitates medical intervention. Chronic conditions such as diabetes mellitus or peripheral vascular disease can lead to impaired wound healing. Acute trauma such as degloving or large-scale thermal injuries are followed by a loss of skin organ function rendering the organism vulnerable to infections, thermal dysregulation, and fluid loss. METHODS: For this update article, we have reviewed the actual literature on skin wound healing purposes focusing on the main phases of wound healing, i.e., inflammation, proliferation, epithelialization, angiogenesis, remodeling, and scarring. RESULTS: The reader will get briefed on new insights and up-to-date concepts in skin wound healing. The macrophage as a key player in the inflammatory phase will be highlighted. During the epithelialization process, we will present the different concepts of how the wound will get closed, e.g., leapfrogging, lamellipodial crawling, shuffling, and the stem cell niche. The neovascularization represents an essential component in wound healing due to its fundamental impact from the very beginning after skin injury until the end of the wound remodeling. Here, the distinct pattern of the neovascularization process and the special new functions of the pericyte will be underscored. At the end, this update will present 3 topics of high interest in skin wound healing issues, dealing with scarring, tissue engineering, and plasma application. CONCLUSION: Although wound healing mechanisms and specific cell functions in wound repair have been delineated in part, many underlying pathophysiological processes are still unknown. The purpose of the following update on skin wound healing is to focus on the different phases and to brief the reader on the current knowledge and new insights. Skin wound healing is a complex process, which is dependent on many cell types and mediators interacting in a highly sophisticated temporal sequence. Although some interactions during the healing process are crucial, redundancy is high and other cells or mediators can adopt functions or signaling without major complications. PMID- 27974712 TI - Outcome of Combination Therapy with Sofosbuvir and Ledipasvir for Chronic Type C Liver Disease. AB - INTRODUCTION: Recently, the treatment of chronic hepatitis C has markedly advanced. A phase III clinical study of combination therapy with sofosbuvir (SOF) and ledipasvir (LDV) was conducted in Japan, and the additive therapeutic effects were reported. In this study, we report the results of treatment in our hospital. METHODS: Of 147 patients with chronic type C liver disease who had consulted our hospital since September 2015 and received SOF/LDV therapy, in 91 subjects a sustained virological response of 12 weeks (SVR12) could be evaluated. RESULTS: In all 91 patients, end treatment response was achieved. Subsequently, recrudescence was noted in 1 before the completion of treatment (week 12); an SVR12 was achieved in 90 patients (99%). The following adverse reactions were observed in 3 patients (3.3%): bradycardia, paroxysmal atrial fibrillation, and heart failure with QT prolongation, which were associated with heart disease. CONCLUSION: A favorable SVR was achieved by SOF/LDV therapy even in elderly patients, those with liver cirrhosis, or those having undergone radical treatment of liver cancer. Furthermore, a high tolerance was demonstrated, but adverse reactions associated with the heart may appear in patients with heart disease as an underlying disease; strict management during treatment is necessary. PMID- 27974713 TI - One-Year Follow-Up after Endobronchial Valve Treatment in Patients with Emphysema without Collateral Ventilation Treated in the STELVIO Trial. AB - BACKGROUND: One-way endobronchial valve (EBV) treatment has shown safety and efficacy at 6 months after treatment in patients with severe emphysema and confirmed absence of interlobar collateral ventilation. Longer follow-up in this subgroup is not available. OBJECTIVES: To investigate the efficacy and safety of EBV treatment of the STELVIO cohort at a 1-year follow-up. METHODS: Emphysema patients who have been treated with EBV in the STELVIO trial were invited for a voluntary 1-year follow-up visit. Both the original treatment group and the control group who crossed over to treatment have been included. Analyses are performed on the patients who attended the 1-year follow-up visit. RESULTS: Sixty four patients received EBV treatment. At 1 year, 40 patients (26 female; mean age 59 +/- 8 years; FEV1 0.86 +/- 0.29 L; RV 4.56 +/- 1.00 L; 6MWD 367 +/- 78 m; and SGRQ 56 +/- 13 points) visited the hospital. Significant improvements (p < 0.001) were found for FEV1 (+17%, 95% CI, 11 to 24), RV (-687 mL, 95% CI, -918 to -456), 6MWD (+61 m, 95% CI, 42 to 80), and SGRQ (-11 points, 95% CI, -17 to -6). Two patients died: 1 after 58 days due to progressive respiratory failure and 1 after 338 days of follow-up due to a myocardial infarction. Seventeen percent of the patients underwent valve replacement and 22% of the initially treated patients had permanent valve removal. In 22% of the patients, pneumothoraces occurred before 6 months, and none occurred between 6 and 12 months. CONCLUSIONS: EBV treatment results in clinically relevant benefits at 1 year of follow-up. Maintenance bronchoscopies to achieve this are needed. This study supports the use of EBV treatment in carefully selected patients with severe emphysema without collateral ventilation. PMID- 27974714 TI - Contrast-Enhanced Tissue Harmonic Imaging versus Phase Inversion Harmonic Sonographic Imaging for the Delineation of Hepatocellular Carcinomas. AB - OBJECTIVE: To compare contrast tissue harmonic imaging (THI) with low mechanical index (MI) and conventional contrast harmonic imaging (CHI) with respect to lesion visibility of hepatocellular carcinoma (HCC). METHODS: One hundred and twenty-five patients (84 men and 41 women, age range 39-94 years, mean age 74 years) with 100 naive HCCs and 30 lesions after radiofrequency ablation (RFA) for HCC were evaluated. One hundred and four patients had liver cirrhosis of Child Pugh class A, and the remaining 21 had Child-Pugh class B cirrhosis. The lesion conspicuity and intratumoral echogenicity during the postvascular phase were compared using conventional CHI and contrast THI with low MI. RESULTS: The MI values ranged from 0.20 to 0.30 on conventional CHI and from 0.30 to 0.35 on contrast THI. Regarding HCC lesion conspicuity, contrast THI with low MI was clearer in 79 lesions (60.8%), equal in 34 lesions (26.2%), and less clear in 17 lesions (13.1%) when compared with conventional CHI. The lesion conspicuity with contrast THI was significantly better than that with conventional CHI (p < 0.01). All of the postablative lesions were well delineated in patients who received RFA. CONCLUSION: Low-MI contrast THI was superior to conventional CHI with respect to lesion visibility of HCCs and might offer good imaging for the guiding of RFA. PMID- 27974715 TI - HIV Drug Resistance and Phylogeny Profile in Naive and Antiretroviral-Experienced Patients in Tehran, Iran. AB - BACKGROUND: Increasing the accessibility of antiretroviral therapy (ART) has caused the emergence of drug resistance in patients receiving ART and in naive patients. The aim of this study was to evaluate HIV subtype and drug resistance between naive patients and ART-experienced patients. METHODS: Blood samples were collected from 78 antiretroviral and naive HIV-1 patients; antiretroviral resistant mutations and subtyping were then determined by sequencing pol regions. RESULTS: Phylogenetic analysis revealed that 96.1% of sequences belong to the CRF35-AD subtype. Transmitted drug resistance was determined in 14% of drug-naive patients and 40% of ART-experienced patients. CONCLUSION: The findings of this study illustrated the importance of resistance testing before and during ART treatment. This study can be used to set up a best medicine strategy in Iranian guidelines. PMID- 27974716 TI - Early BMI Gain and Later Height Growth Predicts Higher DHEAS Concentrations in 7 Year-Old Chilean Children. AB - BACKGROUND: Accelerated weight and height gain in infancy have been associated with premature adrenarche. However, the exact tempo of these events remains undefined. Thus, our goal was to assess the relationship between early BMI and height growth in different periods before 7 years of age and plasma DHEAS levels at 7 years of age. METHODS: This is a longitudinal follow-up of participants of the Growth and Obesity Chilean Cohort Study (GOCS) that represents Chilean children from low- to middle-income families. The subjects were 972 children (48% girls) with birth weights of 2,500-4,500 g for whom serial weight and height measurements from birth until 7 years were available. At 7 years of age, we also measured DHEAS, IGF-I, leptin, insulin, and other metabolic markers in serum. The main outcome of interest was plasma DHEAS concentrations at 7 years of age. RESULTS: At 7 years of age, children with DHEAS >75th percentile of the sample were taller and fatter and presented higher HOMA-IR and IGF-I than their counterparts (p < 0.05). Children with higher DHEAS were heavier at 4 years of age and beyond compared to their counterparts (higher BMI [BMI SDS at 4 years: 1.16, 95% CI 1.02-1.29 vs. 0.83, 95% CI 0.76-0.91, p < 0.001]) and taller at 7 years of age (height SDS at 7 years: 0.19, 95% CI -0.08 to 0.31 vs. -0.001, 95% CI -0.06 to 0.06, p < 0.005). CONCLUSIONS: We observed weight and BMI from 2 to 4 years, and height gains from 4 to 7 years were associated with higher DHEAS levels at 7 years. PMID- 27974717 TI - Classification of Tattoo Complications in a Hospital Material of 493 Adverse Events. AB - BACKGROUND/AIMS: Tattooing is a global trend. Clinical knowledge of complications is based on case reports collected over a century. Larger cohorts reflecting complications associated with contemporary trends are lacking. METHODS: The study was a retrospective review of a consecutive cohort of patients with tattoo complications diagnosed in the "Tattoo Clinic" of Bispebjerg University Hospital in Copenhagen, Denmark, from 2008 to 2015, based on patient history and systematic clinical examination. RESULTS: A total of 493 tattoo complications in 405 patients were studied. Overall, 184 (37%) presented allergic reactions with plaque elevation in 32.2%, excessive hyperkeratosis in 3.7%, and ulceration in 1.4%, predominantly observed in red tattoos and nuances of red; 66 (13%) presented papulo-nodular reactions, mainly observed in black tattoos (considered non-allergic) and due to pigment agglomeration; 53 (11%) had bacterial infections; 46 (9%) were psycho-social complications; 144 (30%) belonged to several specific diagnostic entities, including photosensitivity, pain syndrome, and lymphopathy. We found no cases of cutaneous or other malignancies. Sarcoidosis was primarily seen in black tattoos and was a common associated disease, found in 23 reactions (5%), compared to the background population. CONCLUSION: The study introduces a new concept of classification of tattoo complications based on simple tools such as patient history and objective findings supplemented with histology. The study reflects complications originating from presently used tattoo inks, often with organic pigments. The introduced classification has been submitted to the World Health Organisation (WHO) as a proposal to the 11th revision of the International Classification of Diseases. PMID- 27974718 TI - c-Myb Overexpression in Cytology Smears of Tracheobronchial and Pulmonary Adenoid Cystic Carcinomas. AB - AIMS: Adenoid cystic carcinoma (AdCC) is a malignant epithelial neoplasm that occurs rarely in the lower respiratory tract (LRT). AdCC at various sites is associated with the novel fusion transcript MYB-NFIB, along with the overexpression of the Myb protein. The expression of the Myb protein in AdCC of the LRT has not been evaluated much. STUDY DESIGN: Cases of AdCC of the LRT diagnosed on cytology or histology were retrieved from our institutional archives. c-Myb expression was analyzed on immunocytochemistry/immunohistochemistry (ICC/IHC) and was correlated with clinicopathological parameters. RESULTS: Twenty-three samples of AdCC originating from the LRT were included in the study. Four cases were diagnosed on cytology, 3 of which had corresponding histology specimens. The remaining 19 cases had either biopsy or resection. Most of the patients presented with endobronchial mass. The mean age was 49.4 years and a male predominance was seen. ICC and IHC for c-Myb showed positivity in 75 and 59% of the cases, respectively. Western blot was used to validate IHC results. CONCLUSION: AdCC of the LRT is rare and hence poses diagnostic difficulty. Cytology smears can be utilized for c-Myb ICC. The presence of c-Myb immunopositivity in most cases may possibly make Myb a diagnostic biomarker and a therapeutic target for personalized treatment. PMID- 27974719 TI - Acetylcholinesterase Activity Measurement and Clinical Features of Delirium. AB - AIMS: Cholinergic deficiency is commonly implicated in the pathophysiology of delirium. We aimed to investigate the relationship between directly measured serum acetylcholinesterase (AChE) activity and (1) clinical features of delirium and (2) outcomes among older hospital patients with delirium. METHODS: Hospitalised patients with delirium were recruited, and delirium motor subtype, severity and duration of delirium were measured. Serum AChE activity was measured using a colorimetric assay. RESULTS: The mean AChE activity for the whole sample was 2.46 MUmol/MUL/min (standard deviation 1.75). Higher AChE activity was associated with increased likelihood of hypoactive delirium rather than the hyperactive or mixed subtype (odds ratio 1.98, 95% confidence interval 1.10 3.59). CONCLUSION: Higher AChE activity was associated with hypoactive delirium but did not predict outcomes. Simple enhancement of cholinergic neurotransmission may not be sufficient to treat delirium. PMID- 27974720 TI - Anemia and Long-Term Renal Prognosis in Patients with Post-Renal Acute Kidney Injury of Nonmalignant Cause. AB - BACKGROUND/AIMS: The renal prognosis of post-renal acute kidney injury (PoR-AKI) has not been verified so far. The objective of this study was to assess the association of baseline anemia with long-term renal prognosis in patients with PoR-AKI. METHODS: We performed a multicenter retrospective cohort study. Consecutive adult patients from December 2006 to February 2010, who met the requirements as mentioned in the definition of PoR-AKI, were included. Patients without data on baseline renal function and at 6 months after PoR-AKI were excluded. We set baseline hemoglobin (Hb) level (g/dl) as the main exposure to be tested. The main outcome measure was long-term renal prognosis as determined by the difference between proximate estimated glomerular filtration rate (eGFR) at 6 months after diagnosis of PoR-AKI and baseline eGFR prior to the occurrence of the present PoR-AKI (DeltaeGFR after 6 months) using the general linear model. RESULTS: We included 136 patients with PoR-AKI. The most frequent cause of PoR AKI was malignancy, accounting for 39.0% (n = 53) of cases. Multivariate analysis adjusted for possible confounders showed that DeltaeGFR after 6 months significantly changed by -4.28 ml/min/1.73 m2 for every 1 g/dl lower Hb at diagnosis (95% CI 1.86-6.69, p < 0.01). An additional multivariate analysis that was stratified by the presence or absence of malignancy as the cause of PoR-AKI yielded the same significant result only in the stratum of the nonmalignant cause of PoR-AKI. CONCLUSION: Patients with a nonmalignant cause of PoR-AKI who have baseline anemia may have poor long-term renal prognosis. In these cases, close observation of renal function after renal recovery may be required. PMID- 27974721 TI - Liquid Biopsy: A Future Tool for Posttreatment Surveillance in Head and Neck Cancer? AB - The prognosis of head and neck squamous cell carcinoma (HNSCC) is largely based on disease stage. Despite improvements in treatment, recurrence rates are still considered high. Currently, disease progression or regression after curative treatment is monitored by clinical evaluation combined with flexible endoscopy and/or imaging. However, specificity of imaging is low due to the posttreatment effects. Detection of circulating tumor DNA (ctDNA) from blood samples of HNSCC patients is a minimally invasive technique that could lead to an earlier detection of recurrence. In addition, digital droplet PCR (ddPCR) could be used to sensitively detect these mutational targets. Future study on ctDNA using ddPCR in blood samples of HNSCC patients is recommended during the follow-up stage to detect recurrences in a timely manner. PMID- 27974722 TI - Fragile and Enduring Positive Affect: Implications for Adaptive Aging. AB - There is robust evidence linking interindividual differences in positive affect (PA) with adaptive psychological and physical health outcomes. However, recent research has suggested that intraindividual variability or fluctuations in PA states over time may also be an important predictor of individual health outcomes. Here, we report on research that focuses on PA level and various forms of PA dynamics (variability, instability, inertia, and reactivity) in relation to health. PA level refers to the average level of positive feelings. In contrast, PA dynamics refer to short-term changes in PA that unfold over time. We discuss how consideration of both PA level and PA dynamics can provide a framework for reconciling when high PA is conducive or detrimental to health. We conclude that more work on PA dynamics is needed, especially in combination with PA level, and suggest productive questions for future inquiry in this area. PMID- 27974723 TI - Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging Related Disease. AB - The recent advent of genome and epigenome editing technologies has provided a new paradigm in which the landscape of the human genome and epigenome can be precisely manipulated in their native context. Genome and epigenome editing technologies can be applied to many aspects of aging research and offer the potential to develop novel therapeutics against age-related diseases. Here, we discuss the latest technological advances in the CRISPR-based genome and epigenome editing toolbox, and provide insight into how these synthetic biology tools could facilitate aging research by establishing in vitro cell and in vivo animal models to dissect genetic and epigenetic mechanisms underlying aging and age-related diseases. We discuss recent developments in the field with the aims to precisely modulate gene expression and dynamic epigenetic landscapes in a spatial and temporal manner in cellular and animal models, by complementing the CRISPR-based editing capability with conditional genetic manipulation tools including chemically inducible expression systems, optogenetics, logic gate genetic circuits, tissue-specific promoters, and the serotype-specific adeno associated virus. We also discuss how the combined use of genome and epigenome editing tools permits investigators to uncover novel molecular pathways involved in the pathophysiology and etiology conferred by risk variants associated with aging and aging-related disease. A better understanding of the genetic and epigenetic regulatory mechanisms underlying human aging and age-related disease will significantly contribute to the developments of new therapeutic interventions for extending health span and life span, ultimately improving the quality of life in the elderly populations. PMID- 27974724 TI - Myocardial Infarction after Ozone Therapy: Is Ozone Therapy Dr. Jekyll or Mr. Hyde? PMID- 27974725 TI - Azoospermia and Testicular Hypoplasia in a Boar Carrier of a Novel Y-Autosome Translocation. AB - Few sex-autosome chromosome abnormalities have been documented in domestic animal species. In humans, Y-autosome chromosome abnormalities may occur at a rate of 1/2,000 live births, whereas in the domestic pig only 2 Y-autosome reciprocal translocations have been previously described. During a routine cytogenetic screening of young boars, we identified a new Y-autosome translocation carrier, which after puberty showed semen devoid of sperm and testicular hypoplasia with spermatogenesis arrest. Whole chromosome painting by FISH analysis corroborated the reciprocal nature of the chromosomal exchanges between the Y chromosome and SSC13. The possible causes for the observed meiotic arrest of the carrier are reviewed. PMID- 27974726 TI - Genome Information of Maribacter dokdonensis DSW-8 and Comparative Analysis with Other Maribacter Genomes. AB - Maribacter dokdonensis DSW-8 was isolated from the seawater off Dokdo in Korea. To investigate the genomic features of this marine bacterium, we sequenced its genome and analyzed the genomic features. After de novo assembly and gene prediction, 16 contigs totaling 4,434,543 bp (35.95% G+C content) in size were generated and 3,835 protein-coding sequences, 36 transfer RNAs, and 6 ribosomal RNAs were detected. In the genome of DSW-8, genes encoding the proteins associated with gliding motility, molybdenum cofactor biosynthesis, and utilization of several kinds of carbohydrates were identified. To analyze the genomic relationships among Maribacter species, we compared publically available Maribacter genomes, including that of M. dokdonensis DSW-8. A phylogenomic tree based on 1,772 genes conserved among the eight Maribacter strains showed that Maribacter speices isolated from seawater are distinguishable from species originating from algal blooms. Comparison of the gene contents using COG and subsystem databases demonstrated that the relative abundance of genes involved in carbohydrate metabolism are higher in seawater-originating strains than those of algal blooms. These results indicate that the genomic information of Maribacter species reflects the characteristics of their habitats and provides useful information for carbon utilization of marine flavobacteria. PMID- 27974727 TI - Impact of a Glyphosate-Tolerant Soybean Line on the Rhizobacteria, Revealed by Illumina MiSeq. AB - The global commercial cultivation of transgenic crops, including glyphosate tolerant soybean, has increased widely in recent decades with potential impact on the environment. The bulk of previous studies showed different results on the effects of the release of transgenic plants on the soil microbial community, especially rhizosphere bacteria. In this study, comparative analyses of the bacterial communities in the rhizosphere soils and surrounding soils were performed between the glyphosate-tolerant soybean line NZL06-698 (or simply N698), containing a glyphosate-insensitive EPSPS gene, and its control cultivar Mengdou12 (or simply MD12), by a 16S ribosomal RNA gene (16S rDNA) amplicon sequencing-based Illumina MiSeq platform. No statistically significant difference was found in the overall alpha diversity of the rhizosphere bacterial communities, although the species richness and evenness of the bacteria increased in the rhizosphere of N698 compared with that of MD12. Some influence on phylogenetic diversity of the rhizosphere bacterial communities was found between N698 and MD12 by beta diversity analysis based on weighted UniFrac distance. Furthermore, the relative abundances of part rhizosphere bacterial phyla and genera, which included some nitrogen-fixing bacteria, were significantly different between N698 and MD12. Our present results indicate some impact of the glyphosate-tolerant soybean line N698 on the phylogenetic diversity of rhizosphere bacterial communities together with a significant difference in the relative abundances of part rhizosphere bacteria at different classification levels as compared with its control cultivar MD12, when a comparative analysis of surrounding soils between N698 and MD12 was used as a systematic contrast study. PMID- 27974728 TI - Enhancing the Physical Properties and Lifespan of Bacterial Quorum Quenching Media through Combination of Ionic Cross-Linking and Dehydration. AB - Quorum quenching (QQ) bacteria entrapped in a polymeric composite hydrogel (QQ medium) have been successfully applied in membrane bioreactors (MBRs) for effective biofouling control. However, in order to bring QQ technology closer to practice, the physical strength and lifetime of QQ media should be improved. In this study, enforcement of physical strength, as well as an extension of the lifetime of a previously reported QQ bacteria entrapping hollow cylinder (QQ-HC), was sought by adding a dehydration procedure following the cross-linking of the polymeric hydrogel by inorganic compounds like Ca2+ and boric acid. Such prepared medium demonstrated enhanced physical strength possibly through an increased degree of physical cross-linking. As a result, a longer lifetime of QQ-HCs was confirmed, which led to improved biofouling mitigation performance of QQ-HC in an MBR. Furthermore, QQ-HCs stored under dehydrated condition showed higher QQ activity when the storage time lasted more than 90 days owing to enhanced cell viability. In addition, the dormant QQ activity after the dehydration step could be easily restored through reactivation with real wastewater, and the reduced weight of the dehydrated media is expected to make handling and transportation of QQ media highly convenient and economical in practice. PMID- 27974729 TI - Secondary Metabolites Production and Plant Growth Promotion by Pseudomonas chlororaphis and P. aurantiaca Strains Isolated from Cactus, Cotton, and Para Grass. AB - Fluorescent pseudomonads have been isolated from halophytes, mesophytes, and xerophytes of Pakistan. Among these, eight isolates, GS-1, GS-3, GS-4, GS-6, GS 7, FS-2 (cactus), ARS-38 (cotton), and RP-4 (para grass), showed antifungal activity and were selected for detailed study. Based on biochemical tests and 16S rRNA gene sequences, these were identified as strains of P. chlororaphis subsp. chlororaphis and aurantiaca. Secondary metabolites of these strains were analyzed by LC-MS. Phenazine-1-carboxylic acid (PCA), 2-hydroxy-phenazine, Cyclic Lipopeptide (white line-inducing principle (WLIP)), and lahorenoic acid A were detected in variable amounts in these strains. P. aurantiaca PB-St2 was used as a reference as it is known for the production of these compounds. The phzO and PCA genes were amplified to assure that production of these compounds is not an artifact. Indole acetic acid production was confirmed and quantified by HPLC. HCN and siderophore production by all strains was observed by plate assays. These strains did not solubilize phosphate, but five strains were positive for zinc solubilization. Wheat seedlings were inoculated with these strains to observe their effect on plant growth. P. aurantiaca strains PB-St2 and GS-6 and P. chlororaphis RP-4 significantly increased both root and shoot dry weights, as compared with uninoculated plants. However, P. aurantiaca strains FS-2 and ARS-38 significantly increased root and shoot dry weights, respectively. All strains except PB-St2 and ARS-38 significantly increased the root length. This is the first report of the isolation of P. aurantiaca from cotton and cactus, P. chlororaphis from para grass, WLIP and lahorenoic acid A production by P. chlororaphis, and zinc solubilization by P. chlororaphis and P. aurantiaca. PMID- 27974730 TI - Highly Sensitive Detection of Low-Abundance White Spot Syndrome Virus by a Pre Amplification PCR Method. AB - White spot syndrome virus (WSSV) is a major threat to the shrimp farming industry and so far there is no effective therapy for it, and thus early diagnostic of WSSV is of great importance. However, at the early stage of infection, the extremely low-abundance of WSSV DNA challenges the detection sensitivity and accuracy of PCR. To effectively detect low-abundance WSSV, here we developed a pre-amplification PCR (pre-amp PCR) method to amplify trace amounts of WSSV DNA from massive background genomic DNA. Combining with normal specific PCR, 10 copies of target WSSV genes were detected from ~1010 magnitude of backgrounds. In particular, multiple target genes were able to be balanced amplified with similar efficiency due to the usage of the universal primer. The efficiency of the pre amp PCR was validated by nested-PCR and quantitative PCR, and pre-amp PCR showed higher efficiency than nested-PCR when multiple targets were detected. The developed method is particularly suitable for the super early diagnosis of WSSV, and has potential to be applied in other low-abundance sample detection cases. PMID- 27974731 TI - EGb 761 Protects Cardiac Microvascular Endothelial Cells against Hypoxia/Reoxygenation Injury and Exerts Inhibitory Effect on the ATM Pathway. AB - Ginkgo biloba extract (EGb 761) has been widely used clinically to reduce myocardial ischemia reperfusion injury (MIRI). Microvascular endothelial cells (MVECs) may be a proper cellular model in vitro for the effect and mechanism study against MIRI. However, the protective effect of EGb 761 on MVECs resisting hypoxia/reoxygenation (H/R) injury is little reported. In this study, H/R-injured MVECs were treated with EGb 761, and then the cell viability, apoptosis, ROS production, SOD activity, caspase-3 activity, and protein level of ATM, gamma H2AX, p53, and Bax were measured. ATM siRNA was transfected to study the changes of protein in the ATM pathway. EGb 761 presented protective effect on H/R-injured MVECs, with decreasing cell death, apoptosis, and ROS, and elevated SOD activity. Next, EGb 761 could inhibit H/R-induced ATM, gamma-H2AX, p53, and Bax in a dose dependent manner. Moreover, ATM siRNA also could inhibit H/R-induced ATM, gamma H2AX, p53, and Bax. Overall, these findings verify that EGb 761 protects cardiac MVECs from H/R injury, and for the first time, illustrate the influence on the ATM pathway and apoptosis by EGb 761 via dampening ROS. PMID- 27974732 TI - Prebiotic Effects of Poly-Gamma-Glutamate on Bacterial Flora in Murine Gut. AB - Prebiotics improve the growth or activities of specific microbial genera and species in the gut microbiota in order to confer health benefits to the host. In this study, we investigated the effect of poly-gamma-glutamate (gamma-PGA) as a prebiotic on the gut microbiota of mice and the organ distributions of gamma-PGA in mice. Pyrosequencing analysis for 16S rRNA genes of bacteria indicated that oral administration of gamma-PGA increased the abundance of Lactobacillales while reducing the abundance of Clostridiales in murine guts. It is suggested that oral administration of gamma-PGA can be helpful for modulating the gut microbiota as a prebiotic. PMID- 27974733 TI - Enhanced Production of Itaconic Acid through Development of Transformed Fungal Strains of Aspergillus terreus. AB - Metabolic engineering with a high-yielding mutant, A. terreus AN37, was performed to enhance the production of itaconic acid (IA). Reportedly, the gene cluster for IA biosynthesis is composed of four genes: reg (regulator), mtt (mitochondrial transporter), cad (cis-aconitate decarboxylase), and mfs (membrane transporter). By overexpressing each gene of the IA gene cluster in A. terreus AN37 transformed by the restriction enzyme-mediated integration method, several transformants showing high productivity of IA were successfully obtained. One of the AN37/cad transformants could produce a very high amount of IA (75 g/l) in shake-flask cultivations, showing an average of 5% higher IA titer compared with the high yielding control strain. Notably, in the case of the mfs transformants, a maximal increase of 18.3% in IA production was observed relative to the control strain under the identical fermentation conditions. Meanwhile, the overexpression of reg and mtt genes showed no significant improvements in IA production. In summary, the overexpressed cis-aconitate decarboxylase (CAD) and putative membrane transporter (MFS) appeared to have positive influences on the enhanced IA productivity of the respective transformant. The maximal increases of 13.6~18.3% in IA productivity of the transformed strains should be noted, since the parallel mother strain used in this study is indeed a very high-performance mutant that has been obtained through intensive rational screening programs in our laboratory. PMID- 27974734 TI - Antibiofilm and Anti-beta-Lactamase Activities of Burdock Root Extract and Chlorogenic Acid against Klebsiella pneumoniae. AB - Small phytochemicals have been successfully adopted as antibacterial chemotherapies and are being increasingly viewed as potential antibiofilm agents. Some of these molecules are known to repress biofilm and toxin production by certain bacterial and yeast pathogens, but information is lacking with regard to the genes allied with biofilm formation. The present study was performed to investigate the inhibitory effect of burdock root extract (BRE) and of chlorogenic acid (CGA; a component of BRE) on clinical isolates of Klebsiella pneumoniae. BRE and CGA exhibited significant antibiofilm activity against K. pneumoniae without inflicting any harm to its planktonic counterparts. In vitro assays supported the beta-lactamase inhibitory effect of CGA and BRE while in silico docking showed that CGA bound strongly with the active sites of sulfhydryl variable-1 beta-lactamase. Furthermore, the mRNA transcript levels of two biofilm associated genes (type 3 fimbriae mrkD and trehalose-6-phosphate hydrolase treC) were significantly downregulated in CGA- and BRE-treated samples. In addition, CGA inhibited biofilm formation by Escherichia coli and Candida albicans without affecting their planktonic cell growth. These findings show that BRE and its component CGA have potential use in antibiofilm strategies against persistent K. pneumoniae infections. PMID- 27974735 TI - Deinococcus rubrus sp. nov., a Bacterium Isolated from Antarctic Coastal Sea Water. AB - Two Gram-staining-negative, red-pinkish, coccus-shaped, non-motile, and aerobic bacterial strains, designated Ant21T and Ant22, were isolated from the Antarctic coastal sea water. Strains Ant21T and Ant22 showed UVC and gamma radiation resistance. Phylogenetic analyses based on 16S rRNA gene sequences determined that these strains belong to the genus Deinococcus. Through the analyses of the 16S rRNA gene sequences, strains Ant21T and Ant22 were found to have 97.7% and 97.8% similarity to Deinococcus marmoris DSM 12784T and 97.0% and 97.2% similarity to Deinococcus saxicola AA-1444T, respectively. The sequence similarity with the type strains of other Deinococcus species was less than 96.9% for both strains. Strains Ant21T and Ant22 shared relatively high 16S rRNA gene sequence similarity (99.3%) and had a closely related DNA reassociation value of 84 +/- 0.5%. Meanwhile, they showed a low level of DNA-DNA hybridization (<30%) with other closely related species of the genus Deinococcus. The two strains also showed typical chemotaxonomic features for the genus Deinococcus, in terms of the major polar lipid (phosphoglycolipid) and the major fatty acids (C16:0, C16:1omega6c/omega7c, iso-C17:0 , and iso-C15:0). They grew at temperatures between 4 degrees C and 30 degrees C and at pH values of 6.0-8.0. Based on the physiological characteristics, the 16S rRNA gene sequence analysis results, and the low DNA-DNA reassociation level with Deionococcus marmoris, strains Ant21T (= KEMB 9004-167T =JCM 31436T) and Ant22 (KEMB 9004-168 =JCM 31437) represent novel species belonging to the genus Deinococcus, for which the name Deinococcus rubrus is proposed. PMID- 27974736 TI - Hed1 Promotes Meiotic Crossover Formation in Saccharomyces cerevisiae. AB - Homologous recombination occurs between homologous chromosomes and is significantly involved in programmed double-strand break (DSB) repair. Activation of two recombinases, Rad51 and Dmc1, is essential for an interhomolog bias during meiosis. Rad51 participates in both mitotic and meiotic recombination, and its strand exchange activity is regulated by an inhibitory factor during meiosis. Thus, activities of Rad51 and Dmc1 are coordinated to promote homolog bias. It has been reported that Hed1, a meiosis-specific protein in budding yeast, regulates Rad51-dependent recombination activity. Here, we investigated the role of Hed1 in meiotic recombination by ectopic expression of the protein after pre meiotic replication in Saccharomyces cerevisiae. DNA physical analysis revealed that the overexpression of Hed1 delays the DSB-to-joint molecule (JM) transition and promotes interhomolog JM formation. The study indicates a possible role of Hed1 in controlling the strand exchange activity of Rad51 and, eventually, meiotic crossover formation. PMID- 27974737 TI - Genomic Insights and Its Comparative Analysis with Yersinia enterocolitica Reveals the Potential Virulence Determinants and Further Pathogenicity for Foodborne Outbreaks. AB - Yersinia enterocolitica is a well-known foodborne pathogen causing gastrointestinal infections worldwide. The strain Y. enterocolitica FORC_002 was isolated from the gill of flatfish (plaice) and its genome was sequenced. The genomic DNA consists of 4,837,317 bp with a GC content of 47.1%, and is predicted to contain 4,221 open reading frames, 81 tRNA genes, and 26 rRNA genes. Interestingly, genomic analysis revealed pathogenesis and host immune evasion associated genes encoding guanylate cyclase (Yst), invasin (Ail and Inv), outer membrane protein (Yops), autotransporter adhesin A (YadA), RTX-like toxins, and a type III secretion system. In particular, guanylate cyclase is a heat-stable enterotoxin causing Yersinia-associated diarrhea, and RTX-like toxins are responsible for attachment to integrin on the target cell for cytotoxic action. This genome can be used to identify virulence factors that can be applied for the development of novel biomarkers for the rapid detection of this pathogen in foods. PMID- 27974738 TI - Significance of Viable but Nonculturable Escherichia coli: Induction, Detection, and Control. AB - Diseases caused by foodborne or waterborne pathogens are emerging. Many pathogens can enter into the viable but nonculturable (VBNC) state, which is a survival strategy when exposed to harsh environmental stresses. Pathogens in the VBNC state have the ability to evade conventional microbiological detection methods, posing a significant and potential health risk. Therefore, controlling VBNC bacteria in food processing and the environment is of great importance. As the typical one of the gram-negatives, Escherichia coli (E. coli) is a widespread foodborne and waterborne pathogenic bacterium and is able to enter into a VBNC state in extreme conditions (similar to the other gram-negative bacteria), including inducing factors and resuscitation stimulus. VBNC E. coli has the ability to recover both culturability and pathogenicity, which may bring potential health risk. This review describes the concrete factors (nonthermal treatment, chemical agents, and environmental factors) that induce E. coli into the VBNC state, the condition or stimulus required for resuscitation of VBNC E. coli, and the methods for detecting VBNC E. coli. Furthermore, the mechanism of genes and proteins involved in the VBNC E. coli is also discussed in this review. PMID- 27974739 TI - Full-Body Analysis of Age-Adjusted Alignment in Adult Spinal Deformity Patients and Lower-Limb Compensation. AB - STUDY DESIGN: Single-center retrospective review. OBJECTIVE: The present study evaluates the effect of increasing spinal deformity deviation from age-adjusted alignment ideals on lower extremity compensation. SUMMARY OF BACKGROUND DATA: Although current understanding of compensatory mechanisms in adult spinal deformity (ASD) is progressing due to full-body stereographic assessment, the effect of age-adjusted deformity targets on lower-limb compensation remains unexamined. METHODS: ASD patients 18 years or older with biplanar full-body stereographic x-rays were included. Patients were stratified into age cohorts: younger than 40 years, 40-65 years, 65 years or older. Age-specific alignment goals (IDEAL) for pelvic tilt (PT), spinopelvic mismatch (PI-LL), sagittal vertical axis (SVA), and T1 pelvic angle (TPA) were calculated for each patient using published formulas and compared to patients' real (ACTUAL) radiographic parameters. The difference between ACTUAL and IDEAL alignment (OFFSET) was calculated. Analysis of variance compared ACTUAL, IDEAL, and OFFSET between age groups, and OFFSET was correlated with lower-limb compensation (sacrofemoral angle, pelvic shift, knee angle, ankle angle). RESULTS: Seven hundred seventy eight patients with (74.1% female) were included. ACTUAL and IDEAL alignments matched for PT (P = 0.37) in patients younger than 40 years, SVA (P = 0.12) in patients 40 to 65 years and PT, SVA, and TPA (P > 0.05) in patients 65 years or older. SVA and TPA OFFSETs decreased significantly with increasing age (P < 0.001). Hip extension correlated with all OFFSETs in patients younger than 40 years (positively with PT, PI-LL, TPA; negatively with SVA). Knee flexion correlated with PI-LL, SVA, and TPA, across all age groups with strongest correlations (0.525 < r < 0.605) in patients 40 to 65 years. Ankle dorsiflexion only correlated positively with PT and PI-LL offsets in older (older than 40 years) age groups. Posterior pelvic displacement correlated positively with all OFFSET groups, and was highest (0.526 < r <0.712) in patients ages 40 to 65 years. CONCLUSION: Age-adjusted ideals for sagittal alignment provide targets for patients with ASD. Offsets from actual alignment (more severe sagittal deformity) revealed differential recruitment of lower-limb extension, which varied significantly with age. LEVEL OF EVIDENCE: 3. PMID- 27974740 TI - A Case Report and Literature Review of Eculizumab Withdrawal in Atypical Hemolytic-Uremic Syndrome. AB - BACKGROUND Recent advances in the treatment of atypical hemolytic-uremic syndrome (aHUS) have resulted to better long-term survival rates for patients with this life-threatening disease. However, many questions remain such as whether or not long-term treatment is necessary in some patients and what are the risks of prolonged therapy. CASE REPORT Here, we discuss the case of a 37-year-old woman with CFH and CD46 genetic abnormalities who developed aHUS with severe renal failure. She was successfully treated with three doses of rituximab and a three month treatment with eculizumab. After eculizumab withdrawal, symptoms of thrombotic micro-angiopathy (TMA) recurred, therefore eculizumab treatment was restarted. The patient exhibited normal renal function and no symptoms of aHUS at one-year follow-up with further eculizumab treatment. CONCLUSIONS This case highlights the clinical challenges of the diagnosis and management of patient with aHUS with complement-mediated TMA involvement. Attention was paid to the consequences of the treatment withdrawal. Exact information regarding genetic abnormalities and renal function associated with aHUS, as well as estimations of the relapse risk and monitoring of complement tests may provide insights into the efficacy of aHUS treatment, which will enable the prediction of therapeutic responses and testing of new treatment options. Improvements in our understanding of aHUS and its causes may facilitate the identification of patients in whom anti complement therapies can be withdrawn without risk. PMID- 27974741 TI - Iodine-131: An Effective Method for Treating Lymph Node Metastases of Differentiated Thyroid Cancer. AB - BACKGROUND The aim of this study was to assess the efficacy of radioactive iodine 131 (131I) therapy for lymph node metastasis of differentiated thyroid cancer (DTC) and to identify influential factors using univariate and multivariate analyses to determine if identified factors influence the efficacy of treatment. MATERIAL AND METHODS This study included a retrospective review of 218 patients with histologically proven DTC in the post-operation stage. After thyroid tissue remnants were eliminated with 131I therapy, patients' lymph node status was confirmed by ultrasound and by 131I whole body scan regarding lymph node metastasis, and then patients were treated with 131I as appropriate. The treatment efficacy was assessed and possible influencing factors were identified using univariate and multivariate analyses. RESULTS The total effective rate of 131I therapy was 88.07% (including a cure rate of 20.64% and an improvement rate of 67.43%). The non-effective rate was 11.93%. Of the total 406 lymph nodes of 218 patients, 319 lymph nodes (78.57%) were judged to be effectively cured, including 133 (32.75%) lymph nodes that were totally eliminated and 186 (45.82%) lymph nodes that shrank. Eighty-seven (21.43%) of the 406 lymph nodes had no obvious change. No lymph nodes were found to be in a continuously enlarging state. Distant metastasis, size of lymph node, human serum thyroglobulin (HTG) level, and condition of thyroid remnants ablation were identified as the independent factors influencing the efficacy of treatment using univariate and multivariate analyses. CONCLUSIONS The use of 131I is a promising treatment for lymph node metastasis of DCT. Distant metastasis, size of lymph nodes, HTG level, and condition of thyroid remnant ablation were independent factors influencing the treatment efficacy. PMID- 27974742 TI - Lyme borreliosis. PMID- 27974743 TI - High-order synchronization of hair cell bundles. AB - Auditory and vestibular hair cell bundles exhibit active mechanical oscillations at natural frequencies that are typically lower than the detection range of the corresponding end organs. We explore how these noisy nonlinear oscillators mode lock to frequencies higher than their internal clocks. A nanomagnetic technique is used to stimulate the bundles without an imposed mechanical load. The evoked response shows regimes of high-order mode-locking. Exploring a broad range of stimulus frequencies and intensities, we observe regions of high-order synchronization, analogous to Arnold Tongues in dynamical systems literature. Significant areas of overlap occur between synchronization regimes, with the bundle intermittently flickering between different winding numbers. We demonstrate how an ensemble of these noisy spontaneous oscillators could be entrained to efficiently detect signals significantly above the characteristic frequencies of the individual cells. PMID- 27974744 TI - Notch regulates Th17 differentiation and controls trafficking of IL-17 and metabolic regulators within Th17 cells in a context-dependent manner. AB - Th17 cells play critical roles in host defense and autoimmunity. Emerging data support a role for Notch signaling in Th17 cell differentiation but whether it is a positive or negative regulator remains unclear. We report here that T cell specific deletion of Notch receptors enhances Th17 cell differentiation in the gut, with a corresponding increase in IL-17 secretion. An increase in Th17 cell frequency was similarly observed following immunization of T cell specific Notch mutant mice with OVA/CFA. However, in this setting, Th17 cytokine secretion was impaired, and increased intracellular retention of IL-17 was observed. Intracellular IL-17 co-localized with the CD71 iron transporter in the draining lymph node of both control and Notch-deficient Th17 cells. Immunization induced CD71 surface expression in control, but not in Notch-deficient Th17 cells, revealing defective CD71 intracellular transport in absence of Notch signaling. Moreover, Notch receptor deficient Th17 cells had impaired mTORC2 activity. These data reveal a context-dependent impact of Notch on vesicular transport during high metabolic demand suggesting a role for Notch signaling in the bridging of T cell metabolic demands and effector functions. Collectively, our findings indicate a prominent regulatory role for Notch signaling in the fine-tuning of Th17 cell differentiation and effector function. PMID- 27974745 TI - Mechanisms of RIPK3-induced inflammation. AB - Receptor-interacting protein kinase 3 (RIP3/RIPK3) is a multifunctional regulator of cell death and inflammation. It controls signalling downstream of the tumor necrosis factor (TNF) receptor family, DNA-dependent activator of IFN-regulatory factors (DAI) and toll-like receptors (TLRs). Today, it is also widely recognized as a component of caspase-independent cell death known as necroptosis, and cytokine production via activation of the inflammasome. Its role in inflammasome activation, in particular, make the interpretation of its role in vivo more complex. In this review, we focus on divergent roles for RIPK3 in cell death and inflammation. PMID- 27974746 TI - Role of Fc-FcgammaR interactions in the antitumor activity of therapeutic antibodies. AB - The use of antibody therapy for cancer has steadily increased in recent years and has become standard treatment for numerous tumor types. It is now appreciated that the clinical activity of these antibodies relies upon their specific interactions with Fc receptors in addition to the well-studied target-binding region. The interactions mediated by antibody Fc domains can strongly affect the functional outcome of antibody therapy. The Fc portion of an antibody defines its interaction with numerous immune cells and has become an intense area of research as selecting the optimal Fc can greatly enhance the activity as well as mechanism of action of therapeutic antibodies. Recent advances in antibody engineering have enabled the development of antibodies that have altered Fc receptor interactions to take advantage of these findings. Engineering the Fc can fulfill diverse functions such as enhancing effector function for killing of tumor cells or depletion of unwanted immune subsets, enhancing agonist receptor signaling on particular immune cells or eliminating interaction with Fc receptors to avoid cellular depletion or toxicity in normal tissues. This review highlights important data and studies examining the role of Fc-Fc receptor interactions in therapeutic antibodies with a considerations for the future of engineered antibody therapy. PMID- 27974747 TI - Adsorption of phosphate in water using one-step synthesized zirconium-loaded reduced graphene oxide. AB - In this account, a one-step green hydrothermal method for zirconium-loaded reduced graphene oxide (RGO-Zr) adsorbent was developed in pure water. It is based on the formation of initially strong-coupling RGO-Zr nanocomposites followed by in situ reduction of GO to RGO during the hydrothermal treatment. The phosphate adsorption performance of the as-prepared nanocomposites was investigated in aqueous environment under various conditions. The characterization results of RGO-Zr nanocomposites showed that ZrO2 was successfully integrated onto the RGO sheets in amorphous. The data from equilibrium phosphate adsorption on RGO-Zr revealed that the adsorption kinetics followed a pseudo-second-order kinetic model, where the adsorption isotherm fitted the Langmuir isotherm model with a maximum adsorption capacity of 27.71 mg P/g at pH 5 and 298 K. The improved phosphate adsorption on RGO-Zr was caused by the dispersion of ZrO2 on the RGO surface. Furthermore, the phosphate adsorption was found insensitive to the increase in pH while it was sensitive to the increase in temperature. The coexisting anions of SO42-, F-, Cl-, NO3- and CO32- affected the phosphate adsorption in a different way. Results suggest that the present RGO-Zr adsorbent has the potential for controlling phosphorus pollution in water. PMID- 27974749 TI - Astrophysics: Dark matter may not be so clumpy. PMID- 27974750 TI - Trump: time to seize environmental gains. PMID- 27974748 TI - Printing soft matter in three dimensions. AB - Light- and ink-based three-dimensional (3D) printing methods allow the rapid design and fabrication of materials without the need for expensive tooling, dies or lithographic masks. They have led to an era of manufacturing in which computers can control the fabrication of soft matter that has tunable mechanical, electrical and other functional properties. The expanding range of printable materials, coupled with the ability to programmably control their composition and architecture across various length scales, is driving innovation in myriad applications. This is illustrated by examples of biologically inspired composites, shape-morphing systems, soft sensors and robotics that only additive manufacturing can produce. PMID- 27974752 TI - Biomaterials: How additives preserve vaccines. PMID- 27974753 TI - Synthetic biology: Designer cells treat diabetic mice. PMID- 27974755 TI - Polymers. PMID- 27974756 TI - Resolved images of a protostellar outflow driven by an extended disk wind. AB - Young stars are associated with prominent outflows of molecular gas. The ejection of gas is believed to remove angular momentum from the protostellar system, permitting young stars to grow by the accretion of material from the protostellar disk. The underlying mechanism for outflow ejection is not yet understood, but is believed to be closely linked to the protostellar disk. Various models have been proposed to explain the outflows, differing mainly in the region where acceleration of material takes place: close to the protostar itself ('X-wind', or stellar wind), in a larger region throughout the protostellar disk (disk wind), or at the interface between the two. Outflow launching regions have so far been probed only by indirect extrapolation because of observational limits. Here we report resolved images of carbon monoxide towards the outflow associated with the TMC1A protostellar system. These data show that gas is ejected from a region extending up to a radial distance of 25 astronomical units from the central protostar, and that angular momentum is removed from an extended region of the disk. This demonstrates that the outflowing gas is launched by an extended disk wind from a Keplerian disk. PMID- 27974759 TI - Materials: Graphene putty feels the beat. PMID- 27974760 TI - Neuroscience: Transplanted brain cells calm fear. PMID- 27974762 TI - Astronomy: Gaia charts one billion stars. PMID- 27974761 TI - Animal behaviour: Ants 'talk' by swapping spit. PMID- 27974754 TI - The seahorse genome and the evolution of its specialized morphology. AB - Seahorses have a specialized morphology that includes a toothless tubular mouth, a body covered with bony plates, a male brood pouch, and the absence of caudal and pelvic fins. Here we report the sequencing and de novo assembly of the genome of the tiger tail seahorse, Hippocampus comes. Comparative genomic analysis identifies higher protein and nucleotide evolutionary rates in H. comes compared with other teleost fish genomes. We identified an astacin metalloprotease gene family that has undergone expansion and is highly expressed in the male brood pouch. We also find that the H. comes genome lacks enamel matrix protein-coding proline/glutamine-rich secretory calcium-binding phosphoprotein genes, which might have led to the loss of mineralized teeth. tbx4, a regulator of hindlimb development, is also not found in H. comes genome. Knockout of tbx4 in zebrafish showed a 'pelvic fin-loss' phenotype similar to that of seahorses. PMID- 27974764 TI - Energy: Solar power pays off. PMID- 27974763 TI - Sustainable polymers from renewable resources. AB - Renewable resources are used increasingly in the production of polymers. In particular, monomers such as carbon dioxide, terpenes, vegetable oils and carbohydrates can be used as feedstocks for the manufacture of a variety of sustainable materials and products, including elastomers, plastics, hydrogels, flexible electronics, resins, engineering polymers and composites. Efficient catalysis is required to produce monomers, to facilitate selective polymerizations and to enable recycling or upcycling of waste materials. There are opportunities to use such sustainable polymers in both high-value areas and in basic applications such as packaging. Life-cycle assessment can be used to quantify the environmental benefits of sustainable polymers. PMID- 27974766 TI - Marine reserves: Sustainable fisheries need reserves. PMID- 27974768 TI - Ecology: Extinctions on the warm front. PMID- 27974767 TI - Accessing non-natural reactivity by irradiating nicotinamide-dependent enzymes with light. AB - Enzymes are ideal for use in asymmetric catalysis by the chemical industry, because their chemical compositions can be tailored to a specific substrate and selectivity pattern while providing efficiencies and selectivities that surpass those of classical synthetic methods. However, enzymes are limited to reactions that are found in nature and, as such, facilitate fewer types of transformation than do other forms of catalysis. Thus, a longstanding challenge in the field of biologically mediated catalysis has been to develop enzymes with new catalytic functions. Here we describe a method for achieving catalytic promiscuity that uses the photoexcited state of nicotinamide co-factors (molecules that assist enzyme-mediated catalysis). Under irradiation with visible light, the nicotinamide-dependent enzyme known as ketoreductase can be transformed from a carbonyl reductase into an initiator of radical species and a chiral source of hydrogen atoms. We demonstrate this new reactivity through a highly enantioselective radical dehalogenation of lactones-a challenging transformation for small-molecule catalysts. Mechanistic experiments support the theory that a radical species acts as an intermediate in this reaction, with NADH and NADPH (the reduced forms of nicotinamide adenine nucleotide and nicotinamide adenine dinucleotide phosphate, respectively) serving as both a photoreductant and the source of hydrogen atoms. To our knowledge, this method represents the first example of photo-induced enzyme promiscuity, and highlights the potential for accessing new reactivity from existing enzymes simply by using the excited states of common biological co-factors. This represents a departure from existing light driven biocatalytic techniques, which are typically explored in the context of co factor regeneration. PMID- 27974770 TI - Ethnicity: Diversity is future for genetic analysis. PMID- 27974771 TI - Trump: renewables for self-sufficiency. PMID- 27974769 TI - The rise of plastic bioelectronics. AB - Plastic bioelectronics is a research field that takes advantage of the inherent properties of polymers and soft organic electronics for applications at the interface of biology and electronics. The resulting electronic materials and devices are soft, stretchable and mechanically conformable, which are important qualities for interacting with biological systems in both wearable and implantable devices. Work is currently aimed at improving these devices with a view to making the electronic-biological interface as seamless as possible. PMID- 27974773 TI - Italy: Stop government picking professors. PMID- 27974774 TI - Ralph J. Cicerone (1943-2016). PMID- 27974772 TI - Mimicking biological functionality with polymers for biomedical applications. AB - The vast opportunities for biomaterials design and functionality enabled by mimicking nature continue to stretch the limits of imagination. As both biological understanding and engineering capabilities develop, more sophisticated biomedical materials can be synthesized that have multifaceted chemical, biological and physical characteristics designed to achieve specific therapeutic goals. Mimicry is being used in the design of polymers for biomedical applications that are required locally in tissues, systemically throughout the body, and at the interface with tissues. PMID- 27974775 TI - Lifespan effects of mitochondrial mutations. PMID- 27974777 TI - Primatology: Macaques vocally equipped to speak. PMID- 27974776 TI - Chemical biology: A radical change in enzyme catalysis. PMID- 27974779 TI - Italian scientists won't miss departing Prime Minister Matteo Renzi. PMID- 27974780 TI - Three minutes with Hans Rosling will change your mind about the world. PMID- 27974778 TI - Polymers with autonomous life-cycle control. AB - The lifetime of man-made materials is controlled largely by the wear and tear of everyday use, environmental stress and unexpected damage, which ultimately lead to failure and disposal. Smart materials that mimic the ability of living systems to autonomously protect, report, heal and even regenerate in response to damage could increase the lifetime, safety and sustainability of many manufactured items. There are several approaches to achieving these functions using polymer based materials, but making them work in highly variable, real-world situations is proving challenging. PMID- 27974781 TI - CRISPR heavyweights battle in US patent court. PMID- 27974782 TI - Simply studying populism is no longer enough. PMID- 27974783 TI - Sequence reveals genes behind bizarre sea-horse traits. PMID- 27974784 TI - Controversial impact factor gets a heavyweight rival. PMID- 27974785 TI - Donald Trump's choice for head of the US environment agency is dismaying. PMID- 27974786 TI - Does it matter if Donald Trump has a science adviser? PMID- 27974787 TI - Corporate culture spreads to Scandinavian institutes. PMID- 27974789 TI - Trump nominations, Brexit impact and space icon dies. PMID- 27974788 TI - Tech giants open virtual worlds to bevy of AI programs. PMID- 27974790 TI - Make better, safer biomaterials. PMID- 27974791 TI - Algorithms compete to predict recipe for cancer vaccine. PMID- 27974792 TI - Detection and control of charge states in a quintuple quantum dot. AB - A semiconductor quintuple quantum dot with two charge sensors and an additional contact to the center dot from an electron reservoir is fabricated to demonstrate the concept of scalable architecture. This design enables formation of the five dots as confirmed by measurements of the charge states of the three nearest dots to the respective charge sensor. The gate performance of the measured stability diagram is well reproduced by a capacitance model. These results provide an important step towards realizing controllable large scale multiple quantum dot systems. PMID- 27974794 TI - Corrigendum: PI3Kgamma is a molecular switch that controls immune suppression. PMID- 27974793 TI - Targeting metastasis-initiating cells through the fatty acid receptor CD36. AB - The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44bright cells in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36+ metastasis-initiating cells in a CD36-dependent manner. The use of neutralizing antibodies to block CD36 causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects. Clinically, the presence of CD36+ metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumours. Together, our results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis. PMID- 27974796 TI - Systems biology: Molecular memoirs of a cellular family. PMID- 27974797 TI - Biomaterials: Sharks shift their spine into high gear. PMID- 27974795 TI - Cryo-EM structure of the open high-conductance Ca2+-activated K+ channel. AB - The Ca2+-activated K+ channel, Slo1, has an unusually large conductance and contains a voltage sensor and multiple chemical sensors. Dual activation by membrane voltage and Ca2+ renders Slo1 central to processes that couple electrical signalling to Ca2+-mediated events such as muscle contraction and neuronal excitability. Here we present the cryo-electron microscopy structure of a full-length Slo1 channel from Aplysia californica in the presence of Ca2+ and Mg2+ at a resolution of 3.5 A. The channel adopts an open conformation. Its voltage-sensor domain adopts a non-domain-swapped attachment to the pore and contacts the cytoplasmic Ca2+-binding domain from a neighbouring subunit. Unique structural features of the Slo1 voltage sensor suggest that it undergoes different conformational changes than other known voltage sensors. The structure reveals the molecular details of three distinct divalent cation-binding sites identified through electrophysiological studies of mutant Slo1 channels. PMID- 27974798 TI - Mechanism of early dissemination and metastasis in Her2+ mammary cancer. AB - Metastasis is the leading cause of cancer-related deaths; metastatic lesions develop from disseminated cancer cells (DCCs) that can remain dormant. Metastasis initiating cells are thought to originate from a subpopulation present in progressed, invasive tumours. However, DCCs detected in patients before the manifestation of breast-cancer metastasis contain fewer genetic abnormalities than primary tumours or than DCCs from patients with metastases. These findings, and those in pancreatic cancer and melanoma models, indicate that dissemination might occur during the early stages of tumour evolution. However, the mechanisms that might allow early disseminated cancer cells (eDCCs) to complete all steps of metastasis are unknown. Here we show that, in early lesions in mice and before any apparent primary tumour masses are detected, there is a sub-population of Her2+p-p38lop-Atf2loTwist1hiE-cadlo early cancer cells that is invasive and can spread to target organs. Intra-vital imaging and organoid studies of early lesions showed that Her2+ eDCC precursors invaded locally, intravasated and lodged in target organs. Her2+ eDCCs activated a Wnt-dependent epithelial mesenchymal transition (EMT)-like dissemination program but without complete loss of the epithelial phenotype, which was reversed by Her2 or Wnt inhibition. Notably, although the majority of eDCCs were Twist1hiE-cadlo and dormant, they eventually initiated metastasis. Our work identifies a mechanism for early dissemination in which Her2 aberrantly activates a program similar to mammary ductal branching that generates eDCCs that are capable of forming metastasis after a dormancy phase. PMID- 27974799 TI - Early dissemination seeds metastasis in breast cancer. AB - Accumulating data suggest that metastatic dissemination often occurs early during tumour formation, but the mechanisms of early metastatic spread have not yet been addressed. Here, by studying metastasis in a HER2-driven mouse breast cancer model, we show that progesterone-induced signalling triggers migration of cancer cells from early lesions shortly after HER2 activation, but promotes proliferation in advanced primary tumour cells. The switch from migration to proliferation was regulated by increased HER2 expression and tumour-cell density involving microRNA-mediated progesterone receptor downregulation, and was reversible. Cells from early, low-density lesions displayed more stemness features, migrated more and founded more metastases than cells from dense, advanced tumours. Notably, we found that at least 80% of metastases were derived from early disseminated cancer cells. Karyotypic and phenotypic analysis of human disseminated cancer cells and primary tumours corroborated the relevance of these findings for human metastatic dissemination. PMID- 27974800 TI - Near-atomic-resolution cryo-EM analysis of the Salmonella T3S injectisome basal body. AB - The type III secretion (T3S) injectisome is a specialized protein nanomachine that is critical for the pathogenicity of many Gram-negative bacteria, including purveyors of plague, typhoid fever, whooping cough, sexually transmitted infections and major nosocomial infections. This syringe-shaped 3.5-MDa macromolecular assembly spans both bacterial membranes and that of the infected host cell. The internal channel formed by the injectisome allows for the direct delivery of partially unfolded virulence effectors into the host cytoplasm. The structural foundation of the injectisome is the basal body, a molecular lock-nut structure composed predominantly of three proteins that form highly oligomerized concentric rings spanning the inner and outer membranes. Here we present the structure of the prototypical Salmonella enterica serovar Typhimurium pathogenicity island 1 basal body, determined using single-particle cryo-electron microscopy, with the inner-membrane-ring and outer-membrane-ring oligomers defined at 4.3 A and 3.6 A resolution, respectively. This work presents the first, to our knowledge, high-resolution structural characterization of the major components of the basal body in the assembled state, including that of the widespread class of outer-membrane portals known as secretins. PMID- 27974802 TI - Metastasis: Pathways of parallel progression. PMID- 27974801 TI - Structural basis for gating the high-conductance Ca2+-activated K+ channel. AB - The precise control of an ion channel gate by environmental stimuli is crucial for the fulfilment of its biological role. The gate in Slo1 K+ channels is regulated by two separate stimuli, intracellular Ca2+ concentration and membrane voltage. Slo1 is thus central to understanding the relationship between intracellular Ca2+ and membrane excitability. Here we present the Slo1 structure from Aplysia californica in the absence of Ca2+ and compare it with the Ca2+ bound channel. We show that Ca2+ binding at two unique binding sites per subunit stabilizes an expanded conformation of the Ca2+ sensor gating ring. These conformational changes are propagated from the gating ring to the pore through covalent linkers and through protein interfaces formed between the gating ring and the voltage sensors. The gating ring and the voltage sensors are directly connected through these interfaces, which allow membrane voltage to regulate gating of the pore by influencing the Ca2+ sensors. PMID- 27974804 TI - Structural biology: Ion-channel mechanisms revealed. PMID- 27974803 TI - Correlated fluorescence blinking in two-dimensional semiconductor heterostructures. AB - 'Blinking', or 'fluorescence intermittency', refers to a random switching between 'ON' (bright) and 'OFF' (dark) states of an emitter; it has been studied widely in zero-dimensional quantum dots and molecules, and scarcely in one-dimensional systems. A generally accepted mechanism for blinking in quantum dots involves random switching between neutral and charged states (or is accompanied by fluctuations in charge-carrier traps), which substantially alters the dynamics of radiative and non-radiative decay. Here, we uncover a new type of blinking effect in vertically stacked, two-dimensional semiconductor heterostructures, which consist of two distinct monolayers of transition metal dichalcogenides (TMDs) that are weakly coupled by van der Waals forces. Unlike zero-dimensional or one dimensional systems, two-dimensional TMD heterostructures show a correlated blinking effect, comprising randomly switching bright, neutral and dark states. Fluorescence cross-correlation spectroscopy analyses show that a bright state occurring in one monolayer will simultaneously lead to a dark state in the other monolayer, owing to an intermittent interlayer carrier-transfer process. Our findings suggest that bilayer van der Waals heterostructures provide unique platforms for the study of charge-transfer dynamics and non-equilibrium-state physics, and could see application as correlated light emitters in quantum technology. PMID- 27974805 TI - Stem cells: Valine starvation leads to a hungry niche. PMID- 27974806 TI - Chemical intervention in plant sugar signalling increases yield and resilience. AB - The pressing global issue of food insecurity due to population growth, diminishing land and variable climate can only be addressed in agriculture by improving both maximum crop yield potential and resilience. Genetic modification is one potential solution, but has yet to achieve worldwide acceptance, particularly for crops such as wheat. Trehalose-6-phosphate (T6P), a central sugar signal in plants, regulates sucrose use and allocation, underpinning crop growth and development. Here we show that application of a chemical intervention strategy directly modulates T6P levels in planta. Plant-permeable analogues of T6P were designed and constructed based on a 'signalling-precursor' concept for permeability, ready uptake and sunlight-triggered release of T6P in planta. We show that chemical intervention in a potent sugar signal increases grain yield, whereas application to vegetative tissue improves recovery and resurrection from drought. This technology offers a means to combine increases in yield with crop stress resilience. Given the generality of the T6P pathway in plants and other small-molecule signals in biology, these studies suggest that suitable synthetic exogenous small-molecule signal precursors can be used to directly enhance plant performance and perhaps other organism function. PMID- 27974808 TI - Heart failure: Phase II trial results of omecamtiv mecarbil. PMID- 27974809 TI - Arrhythmias: Weight loss and reduced risk of atrial fibrillation. PMID- 27974810 TI - Genetics: HMGCR and PCSK9 variants and cardiovascular risk. PMID- 27974811 TI - Recessive PIEZO2 stop mutation causes distal arthrogryposis with distal muscle weakness, scoliosis and proprioception defects. AB - The genetic work-up of arthrogryposis is challenging due to the diverse clinical and molecular etiologies. We report a-183/12-year-old boy, from a 2nd degree consanguineous family, who presented at 36/12 years with hypotonia, distal laxity, contractures, feeding difficulties at birth. He required surgery for progressive scoliosis at 16 years of age, and walked independently since then with an unstable gait and coordination defects. His latest examination at 18 years of age revealed a proprioceptive defect and loss-of-joint position sense in the upper limbs. Somatosensory evoked potentials supported bilateral involvement of dorsal column-medial lemniscal sensory pathways and nerve conduction studies revealed a mild axonal neuropathy. Muscle biopsy showed myopathic changes with neonatal myosin expression. Mendeliome sequencing led to the discovery of a recessive stop mutation in piezo-type mechanosensitive ion channel component 2 (PIEZO2, NM_022068, c.1384C>T, p.R462*). PIEZO2 is a nonselective cation channel, expressed in sensory endings of proprioceptors innervating muscle spindles and Golgi tendon organs. Dominant PIEZO2 mutations were described in patients with distal arthrogryposis type 5 and Marden-Walker syndrome. Sensory ataxia and proprioception defect with dorsal column involvement together with arthrogryposis, myopathy, scoliosis and progressive respiratory failure may represent a distinct clinical phenotype, and indicate recessive mutations in PIEZO2. PMID- 27974807 TI - Long-term neprilysin inhibition - implications for ARNIs. AB - Neprilysin has a major role in both the generation and degradation of bioactive peptides. LCZ696 (valsartan/sacubitril, Entresto), the first of the new ARNI (dual-acting angiotensin-receptor-neprilysin inhibitor) drug class, contains equimolar amounts of valsartan, an angiotensin-receptor blocker, and sacubitril, a prodrug for the neprilysin inhibitor LBQ657. LCZ696 reduced blood pressure more than valsartan alone in patients with hypertension. In the PARADIGM-HF study, LCZ696 was superior to the angiotensin-converting enzyme inhibitor enalapril for the treatment of heart failure with reduced ejection fraction, and LCZ696 was approved by the FDA for this purpose in 2015. This approval was the first for chronic neprilysin inhibition. The many peptides metabolized by neprilysin suggest many potential consequences of chronic neprilysin inhibitor therapy, both beneficial and adverse. Moreover, LBQ657 might inhibit enzymes other than neprilysin. Chronic neprilysin inhibition might have an effect on angio-oedema, bronchial reactivity, inflammation, and cancer, and might predispose to polyneuropathy. Additionally, inhibition of neprilysin metabolism of amyloid-beta peptides might have an effect on Alzheimer disease, age-related macular degeneration, and cerebral amyloid angiopathy. Much of the evidence for possible adverse consequences of chronic neprilysin inhibition comes from studies in animal models, and the relevance of this evidence to humans is unknown. This Review summarizes current knowledge of neprilysin function and possible consequences of chronic neprilysin inhibition that indicate a need for vigilance in the use of neprilysin inhibitor therapy. PMID- 27974812 TI - Association of a single nucleotide polymorphism upstream of ICOS with Japanese autoimmune hepatitis type 1. AB - Autoimmune hepatitis (AIH) is an uncommon chronic autoimmune liver disease. Several studies reported the association of polymorphisms between CD28, CTLA4 and ICOS gene cluster in 2q33.2 with autoimmune or inflammatory diseases. The previous genome-wide association study on type 1 AIH in a European population has reported a risk G allele of a single nucleotide polymorphism (SNP), rs4325730, in this region. Here, we conducted an association study of this SNP with type 1 AIH in a Japanese population, as a replication study.An association study of rs4325730 was conducted in 343 Japanese AIH patients and 315 controls.We found that rs4325730 is associated with AIH (P=0.0173, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.05-1.62, under the allele model for G allele, P=0.0070, OR 1.62, 95% CI 1.14-2.31, under the dominant model for G allele). This SNP was strongly associated with definite AIH (P=0.0134, OR 1.36, 95% CI 1.07 1.74; under allele model for G, P=0.0035, OR 1.85, 95% CI 1.22-2.81, under dominant model for G).This is the first replication association study of rs4325730 upstream of ICOS with AIH in the Japanese population and rs4325730G is a risk allele. PMID- 27974813 TI - Comparison of the phenotypes of patients harboring in-frame deletions starting at exon 45 in the Duchenne muscular dystrophy gene indicates potential for the development of exon skipping therapy. AB - Exon skipping therapy has recently received attention for its ability to convert the phenotype of lethal Duchenne muscular dystrophy (DMD) to a more benign form, Becker muscular dystrophy (BMD), by correcting the open reading frame. This therapy has mainly focused on a hot-spot (exons 45-55) mutation in the DMD gene. Exon skipping of an entire stretch of exons 45-55 is an approach applicable to 46.9% of DMD patients. However, the resulting phenotype is not yet fully understood. Here we examined the clinical profiles of 24 patients with BMD resulting from deletions starting at exon 45. The Delta45-55 group ranged in age from 2 to 87 years; no mortality was observed, and one patient was ambulatory at 79 years of age. The age at which patients became wheelchair-bound in the Delta45 48 group (18-88 years old) was approximately 50 years. Cardiomyopathy was well controlled by pharmaceuticals in both deletion groups. In contrast, the Delta45 47 and Delta45-49 groups exhibited more severe phenotypes than those with other mutations: the age at which patients in the Delta45-49 group became wheelchair bound was around 30-40 years. Our study shows that clinical severity differs between each hot-spot deletion. PMID- 27974814 TI - Revealing patterns of cultural transmission from frequency data: equilibrium and non-equilibrium assumptions. AB - A long tradition of cultural evolutionary studies has developed a rich repertoire of mathematical models of social learning. Early studies have laid the foundation of more recent endeavours to infer patterns of cultural transmission from observed frequencies of a variety of cultural data, from decorative motifs on potsherds to baby names and musical preferences. While this wide range of applications provides an opportunity for the development of generalisable analytical workflows, archaeological data present new questions and challenges that require further methodological and theoretical discussion. Here we examine the decorative motifs of Neolithic pottery from an archaeological assemblage in Western Germany, and argue that the widely used (and relatively undiscussed) assumption that observed frequencies are the result of a system in equilibrium conditions is unwarranted, and can lead to incorrect conclusions. We analyse our data with a simulation-based inferential framework that can overcome some of the intrinsic limitations in archaeological data, as well as handle both equilibrium conditions and instances where the mode of cultural transmission is time-variant. Results suggest that none of the models examined can produce the observed pattern under equilibrium conditions, and suggest. instead temporal shifts in the patterns of cultural transmission. PMID- 27974815 TI - Simultaneous observation of free and defect-bound excitons in CH3NH3PbI3 using four-wave mixing spectroscopy. AB - Solar cells incorporating organic-inorganic perovskite, which may be fabricated using low-cost solution-based processing, have witnessed a dramatic rise in efficiencies yet their fundamental photophysical properties are not well understood. The exciton binding energy, central to the charge collection process, has been the subject of considerable controversy due to subtleties in extracting it from conventional linear spectroscopy techniques due to strong broadening tied to disorder. Here we report the simultaneous observation of free and defect-bound excitons in CH3NH3PbI3 films using four-wave mixing (FWM) spectroscopy. Due to the high sensitivity of FWM to excitons, tied to their longer coherence decay times than unbound electron- hole pairs, we show that the exciton resonance energies can be directly observed from the nonlinear optical spectra. Our results indicate low-temperature binding energies of 13 meV (29 meV) for the free (defect bound) exciton, with the 16 meV localization energy for excitons attributed to binding to point defects. Our findings shed light on the wide range of binding energies (2-55 meV) reported in recent years. PMID- 27974816 TI - Mid-infrared, super-flat, supercontinuum generation covering the 2-5 MUm spectral band using a fluoroindate fibre pumped with picosecond pulses. AB - Broadband, mid-infrared supercontinuum generation in a step-index fluoroindate fibre is reported. By using ~70-picosecond laser pulses at 2.02 MUm, provided by an optical parametric generator, a wide spectrum with a cut-off wavelength at 5.25 MUm and a 5-dB bandwidth covering the entire 2-5 MUm spectral interval has been demonstrated for the first time. The behaviour of the supercontinuum was investigated by changing the peak power and the wavelength of the pump pulses. This allowed the optimal pumping conditions to be determined for the nonlinear medium that was used. The optical damage threshold for the fluoroindate fibre was experimentally found to be ~200 GW/cm2. PMID- 27974817 TI - Rats overexpressing the dopamine transporter display behavioral and neurobiological abnormalities with relevance to repetitive disorders. AB - The dopamine transporter (DAT) plays a pivotal role in maintaining optimal dopamine signaling. DAT-overactivity has been linked to various neuropsychiatric disorders yet so far the direct pathological consequences of it has not been fully assessed. We here generated a transgenic rat model that via pronuclear microinjection overexpresses the DAT gene. Our results demonstrate that DAT overexpression induces multiple neurobiological effects that exceeded the expected alterations in the corticostriatal dopamine system. Furthermore, transgenic rats specifically exhibited behavioral and pharmaco-therapeutic profiles phenotypic of repetitive disorders. Together our findings suggest that the DAT rat model will constitute a valuable tool for further investigations into the pathological influence of DAT overexpression on neural systems relevant to neuropsychiatric disorders. PMID- 27974819 TI - Adjacent tooth trauma in complicated mandibular third molar surgery: Risk degree classification and digital surgical simulation. AB - Analysis of adjacent tooth resistance is essential in wisdom teeth extraction to prevent adjacent tooth trauma, however it lacks adequate attention nowadays. This study aims at suggesting special extraction methods based on adjacent tooth resistance analysis for prevention of adjacent tooth damage. In this study, 136 complicated mandibular third molars extracted using piezosurgery were reviewed and classified based on the adjacent teeth resistances shown in orthopantomogram (OPG) during their mesio-distal rotations: degree I refers to teeth with no adjacent teeth resistance; degree II refers to teeth with resistance released after mesial-half crown sectioning; degree III refers to teeth which still had resistance after mesial-half crown sectioning. With the use of surgical simulations using cone beam computerized tomography (CBCT) reconstruction, all teeth in degree I were designed to rotate mesio-distally; 86.36%(38/44) teeth in degree II were designed to rotate mesio-distally after mesio-half crown sectioning; 69.09%(36/55) teeth in degree III were designed to rotate bucco lingually. All teeth were extracted successfully, and only one adjacent tooth was subluxated due to the incomplete bone removal. Our study suggested that in order to prevent adjacent teeth trauma, complete bone removal is of importance, and impacted teeth with higher adjacent teeth trauma risks should consider bucco lingual rotations. PMID- 27974818 TI - Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation. AB - Toxic metals are known to inhibit DNA repair but the underlying mechanisms of inhibition are still not fully understood. DNA repair enzymes such as human uracil-DNA glycosylase (hUNG) perform the initial step in the base excision repair (BER) pathway. In this work, we showed that cadmium [Cd(II)], a known human carcinogen, inhibited all activity of hUNG at 100 MUM. Computational analyses based on 2 MUs equilibrium, 1.6 MUs steered molecular dynamics (SMD), and QM/MM MD determined that Cd(II) ions entered the enzyme active site and formed close contacts with both D145 and H148, effectively replacing the catalytic water normally found in this position. Geometry refinement by density functional theory (DFT) calculations showed that Cd(II) formed a tetrahedral structure with D145, P146, H148, and one water molecule. This work for the first time reports Cd(II) inhibition of hUNG which was due to replacement of the catalytic water by binding the active site D145 and H148 residues. Comparison of the proposed metal binding site to existing structural data showed that D145:H148 followed a general metal binding motif favored by Cd(II). The identified motif offered structural insights into metal inhibition of other DNA repair enzymes and glycosylases. PMID- 27974820 TI - A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics During Influenza. AB - Secondary bacterial infections increase morbidity and mortality of influenza A virus (IAV) infections. Bacteria are able to invade due to virus-induced depletion of alveolar macrophages (AMs), but this is not the only contributing factor. By analyzing a kinetic model, we uncovered a nonlinear initial dose threshold that is dependent on the amount of virus-induced AM depletion. The threshold separates the growth and clearance phenotypes such that bacteria decline for dose-AM depletion combinations below the threshold, stay constant near the threshold, and increase above the threshold. In addition, the distance from the threshold correlates to the growth rate. Because AM depletion changes throughout an IAV infection, the dose requirement for bacterial invasion also changes accordingly. Using the threshold, we found that the dose requirement drops dramatically during the first 7d of IAV infection. We then validated these analytical predictions by infecting mice with doses below or above the predicted threshold over the course of IAV infection. These results identify the nonlinear way in which two independent factors work together to support successful post influenza bacterial invasion. They provide insight into coinfection timing, the heterogeneity in outcome, the probability of acquiring a coinfection, and the use of new therapeutic strategies to combat viral-bacterial coinfections. PMID- 27974821 TI - Tracking the Impact of Excisional Cervical Treatment on the Cervix using Biospectroscopy. AB - Local excisional treatment for cervical intra-epithelial neoplasia (CIN) is linked to significant adverse sequelae including preterm birth, with cone depth and radicality of treatment correlating to the frequency and severity of adverse events. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy can detect underlying cervical disease more accurately than conventional cytology. The chemical profile of cells pre- and post-treatment may differ as a result of altered biochemical processes due to excision, or treatment of the disease. Since pre-treatment cervical length varies amongst women, the percentage of cervix excised may correlate more accurately to risk than absolute dimensions. We show that treatment for CIN significantly alters the biochemistry of the cervix, compared with women who have not had treatment; this is due to the removal of cervical tissue rather than the removal of the disease. However, the spectra do not seem to correlate to the cone depth or proportion of cervical length excised. Future research should aim to explore the impact of treatment in a larger cohort. PMID- 27974822 TI - The double-domain cytidine deaminase APOBEC3G is a cellular site-specific RNA editing enzyme. AB - APOBEC3G is a cytidine deaminase with two homologous domains and restricts retroelements and HIV-1. APOBEC3G deaminates single-stranded DNAs via its C terminal domain, whereas the N-terminal domain is considered non-catalytic. Although APOBEC3G is known to bind RNAs, APOBEC3G-mediated RNA editing has not been observed. We recently discovered RNA editing by the single-domain enzyme APOBEC3A in innate immune cells. To determine if APOBEC3G is capable of RNA editing, we transiently expressed APOBEC3G in the HEK293T cell line and performed transcriptome-wide RNA sequencing. We show that APOBEC3G causes site-specific C to-U editing of mRNAs from over 600 genes. The edited cytidines are often flanked by inverted repeats, but are largely distinct from those deaminated by APOBEC3A. We verified protein-recoding RNA editing of selected genes including several that are known to be involved in HIV-1 infectivity. APOBEC3G co-purifies with highly edited mRNA substrates. We find that conserved catalytic residues in both cytidine deaminase domains are required for RNA editing. Our findings demonstrate the novel RNA editing function of APOBEC3G and suggest a role for the N-terminal domain in RNA editing. PMID- 27974823 TI - Roles of human POLD1 and POLD3 in genome stability. AB - DNA replication is essential for cellular proliferation. If improperly controlled it can constitute a major source of genome instability, frequently associated with cancer and aging. POLD1 is the catalytic subunit and POLD3 is an accessory subunit of the replicative Pol delta polymerase, which also functions in DNA repair, as well as the translesion synthesis polymerase Pol zeta, whose catalytic subunit is REV3L. In cells depleted of POLD1 or POLD3 we found a differential but general increase in genome instability as manifested by DNA breaks, S-phase progression impairment and chromosome abnormalities. Importantly, we showed that both proteins are needed to maintain the proper amount of active replication origins and that POLD3-depletion causes anaphase bridges accumulation. In addition, POLD3-associated DNA damage showed to be dependent on RNA-DNA hybrids pointing toward an additional and specific role of this subunit in genome stability. Interestingly, a similar increase in RNA-DNA hybrids-dependent genome instability was observed in REV3L-depleted cells. Our findings demonstrate a key role of POLD1 and POLD3 in genome stability and S-phase progression revealing RNA DNA hybrids-dependent effects for POLD3 that might be partly due to its Pol zeta interaction. PMID- 27974824 TI - Induction of a robust immunity response against novel duck reovirus in ducklings using a subunit vaccine of sigma C protein. AB - Novel duck reovirus (NDRV) disease emerged in China in 2011 and continues to cause high morbidity and about 5.0 to 50% mortality in ducklings. Currently there are no approved vaccines for the virus. This study aimed to assess the efficacy of a new vaccine created from the baculovirus and sigma C gene against NDRV. In this study, a recombinant baculovirus containing the sigma C gene was constructed, and the purified protein was used as a vaccine candidate in ducklings. The efficacy of sigma C vaccine was estimated according to humoral immune responses, cellular immune response and protection against NDRV challenge. The results showed that sigma C was highly expressed in Sf9 cells. Robust humoral and cellular immune responses were induced in all ducklings immunized with the recombinant sigma C protein. Moreover, 100% protection against lethal challenge with NDRV TH11 strain was observed. Summary, the recombinant sigma C protein could be utilized as a good candidate against NDRV infection. PMID- 27974825 TI - Low expression of CXCR1/2 on neutrophils predicts poor survival in patients with hepatitis B virus-related acute-on-chronic liver failure. AB - Polymorphonuclear neutrophils (PMNs) and proinflammatory cytokines have been implicated in the pathogenesis of acute-on-chronic liver failure (ACLF). But the utility of CXC chemokine receptor expression on PMNs as a biomarker for prediction of disease severity is still uncertain. In this study, we investigated the dynamic expression of CXCR1 and CXCR2 on neutrophils, and found that patients with hepatitis B virus-related ACLF displayed low expression of CXCR1 and CXCR2 on peripheral neutrophils compared with healthy subjects and patients with chronic hepatitis B. This expression pattern was correlated with disease severity. Additionally, increased production of IL-8 in peripheral blood was significantly associated with reduced CXCR1 and CXCR2 expression, as shown by the decreased CXCR1 and CXCR2 expression on neutrophils after treating neutrophils with plasma from ACLF patients. This effect could be overcomed through IL-8 blockage with an anti-IL-8 antibody. We also found that IL-8 production and neutrophil infiltration were coordinately increased in the liver tissue of HBV ACLF patients, and this increase was associated with liver inflammation. Overall, increased production of IL-8 associated with neutrophils infiltration into the liver and decreased CXCR1/2 expression on peripheral neutrophils. CXCR1 and CXCR2 expression levels could be served as early markers to predict the severity of ACLF. PMID- 27974826 TI - AECHL-1 targets breast cancer progression via inhibition of metastasis, prevention of EMT and suppression of Cancer Stem Cell characteristics. AB - Triple negative breast cancer (TNBC) features among the most aggressive manifestations of cancer due to its enhanced metastatic potential and immunity to therapeutics which target hormone receptors. Under such scenarios, anti-cancer compounds with an ability to influence multiple targets, or an entire process, will have an advantage over specific signal transduction inhibitors. To counter the metastatic threat it is essential to target cellular components central to the processes of cancer cell migration and adaptation. Our previous work on a novel triterpenoid, AECHL-1, explored its anti-cancer potential, and linked it to elevated ER stress in cancer cells, while its anti-angiogenic potential was credited for its ability to manipulate the cytoskeleton. Here, we broaden its range of action by showing that it curbs the metastatic ability of TNBC cells, both in vitro in MDA-MB-231 cell line and in vivo, in mouse models of metastasis. AECHL-1 does so by disrupting the cytoskeletal network, and also suppressing NF kappaB and beta-Catenin mediated key molecular pathways. These activities also contributed to AECHL-1 mediated suppression of TGF-beta/TNF-alpha induced Epithelial to Mesenchymal Transition (EMT) and cancer stem cell characteristic. Thus, we present AECHL-1 as a promising therapeutic inhibitor of metastatic disease. PMID- 27974827 TI - Investigating the human Calcineurin Interaction Network using the piphiLxVP SLiM. AB - Ser/thr phosphorylation is the primary reversible covalent modification of proteins in eukaryotes. As a consequence, it is the reciprocal actions of kinases and phosphatases that act as key molecular switches to fine tune cellular events. It has been well documented that ~400 human ser/thr kinases engage substrates via consensus phosphosite sequences. Strikingly, we know comparatively little about the mechanism by which ~40 human protein ser/thr phosphatases (PSPs) dephosphorylate ~15000 different substrates with high specificity. The identification of substrates of the essential PSP calcineurin (CN) has been exceptionally challenging and only a small fraction has been biochemically confirmed. It is now emerging that CN binds regulators and substrates via two short linear motifs (SLiMs), the well-studied PxIxIT SLiM and the LxVP SLiM, which remains controversial at the molecular level. Here we describe the crystal structure of CN in complex with its substrate NFATc1 and show that the LxVP SLiM is correctly defined as piphiLxVP. Bioinformatics studies using the piphiLxVP SLiM resulted in the identification of 567 potential CN substrates; a small subset was experimentally confirmed. This combined structural-bioinformatics approach provides a powerful method for dissecting the CN interaction network and for elucidating the role of CN in human health and disease. PMID- 27974828 TI - Structural implications of Ca2+-dependent actin-bundling function of human EFhd2/Swiprosin-1. AB - EFhd2/Swiprosin-1 is a cytoskeletal Ca2+-binding protein implicated in Ca2+ dependent cell spreading and migration in epithelial cells. EFhd2 domain architecture includes an N-terminal disordered region, a PxxP motif, two EF hands, a ligand mimic helix and a C-terminal coiled-coil domain. We reported previously that EFhd2 displays F-actin bundling activity in the presence of Ca2+ and this activity depends on the coiled-coil domain and direct interaction of the EFhd2 core region. However, the molecular mechanism for the regulation of F-actin binding and bundling by EFhd2 is unknown. Here, the Ca2+-bound crystal structure of the EFhd2 core region is presented and structures of mutants defective for Ca2+-binding are also described. These structures and biochemical analyses reveal that the F-actin bundling activity of EFhd2 depends on the structural rigidity of F-actin binding sites conferred by binding of the EF-hands to Ca2+. In the absence of Ca2+, the EFhd2 core region exhibits local conformational flexibility around the EF-hand domain and C-terminal linker, which retains F-actin binding activity but loses the ability to bundle F-actin. In addition, we establish that dimerisation of EFhd2 via the C-terminal coiled-coil domain, which is necessary for F-actin bundling, occurs through the parallel coiled-coil interaction. PMID- 27974830 TI - Stress physiology and weapon integrity of intertidal mantis shrimp under future ocean conditions. AB - Calcified marine organisms typically experience increased oxidative stress and changes in mineralization in response to ocean acidification and warming conditions. These effects could hinder the potency of animal weapons, such as the mantis shrimp's raptorial appendage. The mechanical properties of this calcified weapon enable extremely powerful punches to be delivered to prey and aggressors. We examined oxidative stress and exoskeleton structure, mineral content, and mechanical properties of the raptorial appendage and the carapace under long-term ocean acidification and warming conditions. The predatory appendage had significantly higher % Mg under ocean acidification conditions, while oxidative stress levels as well as the % Ca and mechanical properties of the appendage remained unchanged. Thus, mantis shrimp tolerate expanded ranges of pH and temperature without experiencing oxidative stress or functional changes to their weapons. Our findings suggest that these powerful predators will not be hindered under future ocean conditions. PMID- 27974832 TI - Forest type effects on the retention of radiocesium in organic layers of forest ecosystems affected by the Fukushima nuclear accident. AB - The Fukushima Daiichi nuclear power plant disaster caused serious radiocesium (137Cs) contamination of forest ecosystems over a wide area. Forest-floor organic layers play a key role in controlling the overall bioavailability of 137Cs in forest ecosystems; however, there is still an insufficient understanding of how forest types influence the retention capability of 137Cs in organic layers in Japanese forest ecosystems. Here we conducted plot-scale investigations on the retention of 137Cs in organic layers at two contrasting forest sites in Fukushima. In a deciduous broad-leaved forest, approximately 80% of the deposited 137Cs migrated to mineral soil located below the organic layers within two years after the accident, with an ecological half-life of approximately one year. Conversely, in an evergreen coniferous forest, more than half of the deposited 137Cs remained in the organic layers, with an ecological half-life of 2.1 years. The observed retention behavior can be well explained by the tree phenology and accumulation of 137Cs associated with litter materials with different degrees of degradation in the organic layers. Spatial and temporal patterns of gamma-ray dose rates depended on the retention capability. Our results demonstrate that enhanced radiation risks last longer in evergreen coniferous forests than in deciduous broad-leaved forests. PMID- 27974831 TI - Human dental stem cells suppress PMN activity after infection with the periodontopathogens Prevotella intermedia and Tannerella forsythia. AB - Periodontitis is characterized by inflammation associated with the colonization of different oral pathogens. We here aimed to investigate how bacteria and host cells shape their environment in order to limit inflammation and tissue damage in the presence of the pathogen. Human dental follicle stem cells (hDFSCs) were co cultured with gram-negative P. intermedia and T. forsythia and were quantified for adherence and internalization as well as migration and interleukin secretion. To delineate hDFSC-specific effects, gingival epithelial cells (Ca9-22) were used as controls. Direct effects of hDFSCs on neutrophils (PMN) after interaction with bacteria were analyzed via chemotactic attraction, phagocytic activity and NET formation. We show that P. intermedia and T. forsythia adhere to and internalize into hDFSCs. This infection decreased the migratory capacity of the hDFSCs by 50%, did not disturb hDFSC differentiation potential and provoked an increase in IL-6 and IL-8 secretion while leaving IL-10 levels unaltered. These environmental modulations correlated with reduced PMN chemotaxis, phagocytic activity and NET formation. Our results suggest that P. intermedia and T. forsythia infected hDFSCs maintain their stem cell functionality, reduce PMN-induced tissue and bone degradation via suppression of PMN-activity, and at the same time allow for the survival of the oral pathogens. PMID- 27974829 TI - Evidence for a LOS and a capsular polysaccharide in Capnocytophaga canimorsus. AB - Capnocytophaga canimorsus is a dog's and cat's oral commensal which can cause fatal human infections upon bites or scratches. Infections mainly start with flu like symptoms but can rapidly evolve in fatal septicaemia with a mortality as high as 40%. Here we present the discovery of a polysaccharide capsule (CPS) at the surface of C. canimorsus 5 (Cc5), a strain isolated from a fulminant septicaemia. We provide genetic and chemical data showing that this capsule is related to the lipooligosaccharide (LOS) and probably composed of the same polysaccharide units. A CPS was also found in nine out of nine other strains of C. canimorsus. In addition, the genomes of three of these strains, sequenced previously, contain genes similar to those encoding CPS biosynthesis in Cc5. Thus, the presence of a CPS is likely to be a common property of C. canimorsus. The CPS and not the LOS confers protection against the bactericidal effect of human serum and phagocytosis by macrophages. An antiserum raised against the capsule increased the killing of C. canimorsus by human serum thus showing that anti-capsule antibodies have a protective role. These findings provide a new major element in the understanding of the pathogenesis of C. canimorsus. PMID- 27974835 TI - Rethinking the process of detrainment: jets in obstructed natural flows. AB - A thorough understanding of the mixing and diffusion of turbulent jets released in porous obstructions is still lacking in literature. This issue is undoubtedly of interest because it is not strictly limited to vegetated flows, but also includes outflows which come from different sources and which spread among oyster or wind farms, as well as aerial pesticide treatments sprayed onto orchards. The aim of the present research is to analyze this process from a theoretical point of view. Specifically, by examining the entrainment coefficient, it is deduced that the presence of a canopy prevents a momentum jet from having an entrainment process, but rather promotes its detrainment. In nature, detrainment is usually associated with buoyancy-driven flows, such as plumes or density currents flowing in a stratified environment. The present study proves that detrainment occurs also when a momentum-driven jet is issued in a not-stratified obstructed current, such as a vegetated flow. PMID- 27974833 TI - Tissue Extract Fractions from Starfish Undergoing Regeneration Promote Wound Healing and Lower Jaw Blastema Regeneration of Zebrafish. AB - Natural bioactive materials provide an excellent pool of molecules for regenerative therapy. In the present study, we amputate portions of the arms of Archaster typicus starfish, extract and separate the active biomaterials, and compare the effects of each fraction on in vitro wound healing and in vivo lower jaw regeneration of zebrafish. Compared with crude extract, normal hexane fractions (NHFs) have a remarkable effect on cellular proliferation and collective migration, and exhibit fibroblast-like morphology, while methanol water fractions (MWFs) increase cell size, cell-cell adhesion, and cell death. Relative to moderate mitochondrialand lysosomal aggregation in NHFs-cultured cells, MWFs-cultured cells contain more and bigger lysosomal accumulations and clump detachment. The in vivo zebrafish lower jaw regeneration model reveals that NHFs enhance blastema formation and vasculogenesis, while MWFs inhibit fibrogenesis and induce cellular transformation. Gene expression analyses indicate that NHFs and MWFs separately activate blastema-characteristic genes as well as those genes-related to autophagy, proteasome, and apoptosis either during cell scratch healing or ganciclovir-induced apoptosis. Our results suggest that bioactive compounds from NHFs and MWFs could induce blastema formation and remodeling, respectively, and prevent tissue overgrowth. PMID- 27974834 TI - Electron beam-formed ferromagnetic defects on MoS2 surface along 1 T phase transition. AB - 1 T phase incorporation into 2H-MoS2 via an optimal electron irradiation leads to induce a weak ferromagnetic state at room temperature, together with the improved transport property. In addition to the 1T-like defects, the electron irradiation on the cleaved MoS2 surface forms the concentric circle-type defects that are caused by the 2 H/1 T phase transition and the vacancies of the nearby S atoms of the Mo atoms. The electron irradiation-reduced bandgap is promising in vanishing the Schottky barrier to attaining spintronics device. The simple method to control and improve the magnetic and electrical properties on the MoS2 surface provides suitable ways for the low-dimensional device applications. PMID- 27974838 TI - Neurodegenerative disease: Probing prions. PMID- 27974836 TI - Simulating and Optimising Quantum Thermometry Using Single Photons. AB - A classical thermometer typically works by exchanging energy with the system being measured until it comes to equilibrium, at which point the readout is related to the final energy state of the thermometer. A recent paper noted that with a quantum thermometer consisting of a single spin/qubit, temperature discrimination is better achieved at finite times rather than once equilibration is essentially complete. Furthermore, preparing a qubit thermometer in a state with quantum coherence instead of an incoherent one improves its sensitivity to temperature differences. Implementing a recent proposal for efficiently emulating an arbitrary quantum channel, we use the quantum polarisation state of individual photons as models of "single-qubit thermometers" which evolve for a certain time in contact with a thermal bath. We investigate the optimal thermometer states for temperature discrimination, and the optimal interaction times, confirming that there is a broad regime where quantum coherence provides a significant improvement. We also discuss the more practical question of thermometers composed of a finite number of spins/qubits (greater than one), and characterize the performance of an adaptive protocol for making optimal use of all the qubits. PMID- 27974839 TI - Neural development: Balancing the pruning programmes. PMID- 27974840 TI - Psychiatric disorders: Age-dependent auditory abnormalities. PMID- 27974837 TI - Room-temperature magnetic topological Weyl fermion and nodal line semimetal states in half-metallic Heusler Co2TiX (X=Si, Ge, or Sn). AB - Topological semimetals (TSMs) including Weyl semimetals and nodal-line semimetals are expected to open the next frontier of condensed matter and materials science. Although the first inversion breaking Weyl semimetal was recently discovered in TaAs, its magnetic counterparts, i.e., the time-reversal breaking Weyl and nodal line semimetals, remain elusive. They are predicted to exhibit exotic properties distinct from the inversion breaking TSMs including TaAs. In this paper, we identify the magnetic topological semimetal states in the ferromagnetic half metal compounds Co2TiX (X = Si, Ge, or Sn) with Curie temperatures higher than 350 K. Our first-principles band structure calculations show that, in the absence of spin-orbit coupling, Co2TiX features three topological nodal lines. The inclusion of spin-orbit coupling gives rise to Weyl nodes, whose momentum space locations can be controlled as a function of the magnetization direction. Our results not only open the door for the experimental realization of topological semimetal states in magnetic materials at room temperature, but also suggest potential applications such as unusual anomalous Hall effect in engineered monolayers of the Co2TiX compounds at high temperature. PMID- 27974842 TI - Perception: Coding for choice. PMID- 27974841 TI - Towards a mechanistic understanding of the human subcortex. AB - The human subcortex is a densely populated part of the brain, of which only 7% of the individual structures are depicted in standard MRI atlases. In vivo MRI of the subcortex is challenging owing to its anatomical complexity and its deep location in the brain. The technical advances that are needed to reliably uncover this 'terra incognita' call for an interdisciplinary human neuroanatomical approach. We discuss the emerging methods that could be used in such an approach and the incorporation of the data that are generated from these methods into model-based cognitive neuroscience frameworks. PMID- 27974844 TI - Learning and memory: The cannabinoid connection. PMID- 27974845 TI - Metabolism: A rapid satiety circuit. PMID- 27974846 TI - Synaptic transmission: Separating transmission modes. PMID- 27974843 TI - Structural plasticity and reorganisation in chronic pain. AB - Chronic pain is not simply a temporal continuum of acute pain. Studies on functional plasticity in neural circuits of pain have provided mechanistic insights and linked various modulatory factors to a change in perception and behaviour. However, plasticity also occurs in the context of structural remodelling and reorganisation of synapses, cells and circuits, potentially contributing to the long-term nature of chronic pain. This Review discusses maladaptive structural plasticity in neural circuits of pain, spanning multiple anatomical and spatial scales in animal models and human patients, and addresses key questions on structure-function relationships. PMID- 27974847 TI - Cell biology of the neuron: Endocytic mediators. PMID- 27974848 TI - Glia: Glial messenging. PMID- 27974849 TI - Glia: An astrocytic influence. PMID- 27974850 TI - Hepatitis C Virus Infection of Cultured Human Hepatoma Cells Causes Apoptosis and Pyroptosis in Both Infected and Bystander Cells. AB - Individuals infected with hepatitis C virus (HCV) are at high risk of developing progressive liver disease, including cirrhosis and hepatocellular carcinoma (HCC). How HCV infection causes liver destruction has been of significant interest for many years, and apoptosis has been proposed as one operative mechanism. In this study, we employed a tissue culture-adapted strain of HCV (JFH1T) to test effects of HCV infection on induction of programmed cell death (PCD) in Huh-7.5 cells. We found that HCV infection reduced the proliferation rate and induced caspase-3-mediated apoptosis in the infected cell population. However, in addition to apoptosis, we also observed infected cells undergoing caspase-1-mediated pyroptosis, which was induced by NLRP3 inflammasome activation. By co-culturing HCV-infected Huh-7.5 cells with an HCV-non-permissive cell line, we also demonstrated induction of both apoptosis and pyroptosis in uninfected cells. Bystander apoptosis, but not bystander pyroptosis, required cell-cell contact between infected and bystander cells. In summary, these findings provide new information on mechanisms of cell death in response to HCV infection. The observation that both apoptosis and pyroptosis can be induced in bystander cells extends our understanding of HCV-induced pathogenesis in the liver. PMID- 27974852 TI - Four microRNAs Signature for Survival Prognosis in Colon Cancer using TCGA Data. AB - This study aims to develop microRNA expression signature for colon cancer survival prognosis based on the Cancer Genomic Common database. miRNAs levels between colon cancer and non-cancer tissues were screened by t-test (p < 0.05). Kaplan-Meier survival method was used to discriminate survival significant miRNAs, followed by miRNAs index accumulation to power the miRNAs-survival reliability. In the end, we test the selected miRNAs in HT126 colon cancer cells to validate its anti-cancer effect. The study identified a 84-miRNAs signature. Of the above 84 miRNAs, we got four miRNAs which were survival associated by using ROC curve method and Kaplan-Meier survival method (p < 0.001). The result showed that low risk group had quite a low death rate, the survival rate was over 80%. The high risk group had survival rate lower than 20%, which was also extremely lower than the overall survival rate. In the HT126 cells study, cell growth assay showed miR-130a sponge inhibited colon cancer cells growth and sensitized the anti-cancer drug effect of 5-FU to blocked cancer cell growth. We developed a prognostic 4-microRNA expression signature for colon cancer patient survival, and validated miR-130a sponge could sensitized 5-FU anti-cancer effect. PMID- 27974851 TI - Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis. AB - A key unanswered question in the pathophysiology of rheumatoid arthritis (RA) is how systemic autoimmunity progresses to joint-specific inflammation. In patients with seropositive RA (that is, characterized by the presence of autoantibodies) evidence is accumulating that immunity against post-translationally modified (such as citrullinated) autoantigens might be triggered in mucosal organs, such as the lung, long before the first signs of inflammation are seen in the joints. However, the mechanism by which systemic autoimmunity specifically homes to the joint and bone compartment, thereby triggering inflammation, remains elusive. This Review summarizes potential pathways involved in this joint-homing mechanism, focusing particularly on osteoclasts as the primary targets of anti citrullinated protein antibodies (ACPAs) in the bone and joint compartment. Osteoclasts are dependent on citrullinating enzymes for their normal differentiation and are unique in displaying citrullinated antigens on their cell surface in a non-inflamed state. The binding of ACPAs to osteoclasts releases the chemokine IL-8, leading to bone erosion and pain. This process initiates a chain of events that could lead to attraction and activation of neutrophils, resulting in a complex series of proinflammatory processes in the synovium, eventually leading to RA. PMID- 27974853 TI - Human cellular CYBA UTR sequences increase mRNA translation without affecting the half-life of recombinant RNA transcripts. AB - Modified nucleotide chemistries that increase the half-life (T1/2) of transfected recombinant mRNA and the use of non-native 5'- and 3'-untranslated region (UTR) sequences that enhance protein translation are advancing the prospects of transcript therapy. To this end, a set of UTR sequences that are present in mRNAs with long cellular T1/2 were synthesized and cloned as five different recombinant sequence set combinations as upstream 5'-UTR and/or downstream 3'-UTR regions flanking a reporter gene. Initial screening in two different cell systems in vitro revealed that cytochrome b-245 alpha chain (CYBA) combinations performed the best among all other UTR combinations and were characterized in detail. The presence or absence of CYBA UTRs had no impact on the mRNA stability of transfected mRNAs, but appeared to enhance the productivity of transfected transcripts based on the measurement of mRNA and protein levels in cells. When CYBA UTRs were fused to human bone morphogenetic protein 2 (hBMP2) coding sequence, the recombinant mRNA transcripts upon transfection produced higher levels of protein as compared to control transcripts. Moreover, transfection of human adipose mesenchymal stem cells with recombinant hBMP2-CYBA UTR transcripts induced bone differentiation demonstrating the osteogenic and therapeutic potential for transcript therapy based on hybrid UTR designs. PMID- 27974854 TI - Characterization of the Complete Mitochondrial Genome of Leucoma salicis (Lepidoptera: Lymantriidae) and Comparison with Other Lepidopteran Insects. AB - The complete mitochondrial genome (mitogenome) of Leucoma salicis (Lepidoptera: Lymantriidae) was sequenced and annotated. It is a circular molecule of 15,334 bp, containing the 37 genes usually present in insect mitogenomes. All protein coding genes (PCGs) are initiated by ATN codons, other than cox1, which is initiated by CGA. Three of the 13 PCGs had an incomplete termination codon, T or TA, while the others terminated with TAA. The relative synonymous codon usage of the 13 protein-coding genes (PCGs) was consistent with those of published lepidopteran sequences. All tRNA genes had typical clover-leaf secondary structures, except for the tRNASer (AGN), in which the dihydrouridine (DHU) arm could not form a stable stem-loop structure. The A + T-rich region of 325 bp had several distinctive features, including the motif 'ATAGA' followed by an 18 bp poly-T stretch, a microsatellite-like (AT)7 element, and an 11-bp poly-A present immediately upstream of tRNAMet. Relationships among 32 insect species were determined using Maximum Likelihood (ML), Neighbor Joining (NJ) and Bayesian Inference (BI) phylogenetic methods. These analyses confirm that L. salicis belongs to the Lymantriidae; and that Lymantriidae is a member of Noctuoidea, and is a sister taxon to Erebidae, Nolidae and Noctuidae, most closely related to Erebidae. PMID- 27974855 TI - Exercising alone versus with others and associations with subjective health status in older Japanese: The JAGES Cohort Study. AB - Although exercising with others may have extra health benefits compared to exercising alone, few studies have examined the differences. We sought to examine whether the association of regular exercise to subjective health status differs according to whether people exercise alone and/or with others, adjusting for frequency of exercise. The study was based on the Japan Gerontological Evaluation Study (JAGES) Cohort Study data. Participants were 21,684 subjects aged 65 or older. Multivariable logistic regression models were used to examine the association. The adjusted odds ratios (ORs) for poor self-rated health were significantly lower for people who exercised compared to non-exercisers. In analyses restricted to regular exercisers the ORs for poor health were 0.69 (95% confidence intervals: 0.60-0.79) for individuals exercising alone more often than with others, 0.74 (0.64-0.84) for people who were equally likely to exercise alone as with others, 0.57 (0.43-0.75) for individuals exercising with others more frequently than alone, and 0.79 (0.64-0.97) for individuals only exercising with others compared to individuals only exercising alone. Although exercising alone and exercising with others both seem to have health benefits, increased frequency of exercise with others has important health benefits regardless of the total frequency of exercise. PMID- 27974856 TI - Functional Morphology of the Arm Spine Joint and Adjacent Structures of the Brittlestar Ophiocomina nigra (Echinodermata: Ophiuroidea). AB - The skeletal morphology of the arm spine joint of the brittlestar Ophiocomina nigra was examined by scanning electron microscopy and the associated epidermis, connective tissue structures, juxtaligamental system and muscle by optical and transmission electron microscopy. The behaviour of spines in living animals was observed and two experiments were conducted to establish if the spine ligament is mutable collagenous tissue: these determined (1) if animals could detach spines to which plastic tags had been attached and (2) if the extension under constant load of isolated joint preparations was affected by high potassium stimulation. The articulation normally operates as a flexible joint in which the articular surfaces are separated by compliant connective tissue. The articular surfaces comprise a reniform apposition and peg-in-socket mechanical stop, and function primarily to stabilise spines in the erect position. Erect spines can be completely immobilised, which depends on the ligament having mutable tensile properties, as was inferred from the ability of animals to detach tagged spines and the responsiveness of isolated joint preparations to high potassium. The epidermis surrounding the joint has circumferential constrictions that facilitate compression folding and unfolding when the spine is inclined. The interarticular connective tissue is an acellular meshwork of collagen fibril bundles and may serve to reduce frictional forces between the articular surfaces. The ligament consists of parallel bundles of collagen fibrils and 7-14 nm microfibrils. Its passive elastic recoil contributes to the re-erection of inclined spines. The ligament is permeated by cell processes containing large dense-core vesicles, which belong to two types of juxtaligamental cells, one of which is probably peptidergic. The spine muscle consists of obliquely striated myocytes that are linked to the skeleton by extensions of their basement membranes. Muscle contraction may serve mainly to complete the process of spine erection by ensuring close contact between the articular surfaces. PMID- 27974857 TI - The Incredible Years Parents and Babies Program: A Pilot Randomized Controlled Trial. AB - INTRODUCTION: Infancy is an important period of life; adverse experiences during this stage can have both immediate and lifelong impacts on the child's mental health and well-being. This study evaluates the effects of offering the Incredible Years Parents and Babies (IYPB) program as a universal intervention. METHOD: We conducted a pragmatic, two-arm, parallel pilot randomized controlled trial; 112 families with newborns were randomized to the IYPB program (76) or usual care (36) with a 2:1 allocation ratio. The primary outcome was parenting confidence at 20 weeks(Karitane Parenting Confidence Scale and Parental Stress Scale). Secondary outcomes include measures of parent health, parent-child relationship, infant development, parent-child activities, and network. Interviewers and data analysts were blind to allocation status. Multiple linear regression analyses were used for evaluating the effects of the intervention. RESULTS: There were no intervention effects on the primary outcomes. Only one effect was detected for secondary outcomes, intervention mothers reported a significantly smaller network than control mothers (beta = -0.15 [-1.85,-0.28]). When examining the lowest-functioning mothers in moderator analyses, we found that intervention mothers reported significantly higher parent stress (beta = 5.33 [0.27,10.38]), lower parenting confidence (beta = -2.37 [-4.45,-0.29]), and worse mental health than control mothers (beta = -18.62 [-32.40,-4.84]). In contrast, the highest functioning intervention mothers reported significantly lower parent stress post-intervention (beta = -6.11 [-11.07,-1.14]). CONCLUSION: Overall, we found no effects of the IYPB as a universal intervention for parents with infants. The intervention was developed to be used with groups of low functioning families and may need to be adapted to be effective with universal parent groups. The differential outcomes for the lowest and highest functioning families suggest that future research should evaluate the effects of delivering the IYPB intervention to groups of parents who have similar experiences with parenting and mental health. TRIAL REGISTRATION: ClinicalTrials.gov NCT01931917. PMID- 27974858 TI - Longitudinal Study of Transmission in Households with Visceral Leishmaniasis, Asymptomatic Infections and PKDL in Highly Endemic Villages in Bihar, India. AB - BACKGROUND: Visceral Leishmaniasis (VL) is a neglected tropical disease that afflicts some of the poorest populations in the world including people living in the Bihar state of India. Due to efforts from local governments, NGOs and international organizations, the number of VL cases has declined in recent years. Despite this progress, the reservoir for transmission remains to be clearly defined since it is unknown what role post kala-azar dermal leishmaniasis (PKDL) and asymptomatic infections play in transmission. This information is vital to establish effective surveillance and monitoring to sustainably eliminate VL. METHODOLOGY/PRINCIPAL FINDINGS: We performed a longitudinal study over a 24-month period to examine VL transmission and seroconversion in households with VL, PKDL and asymptomatic infections in the Saran and Muzaffarpur districts of Bihar. During the initial screening of 5,144 people in 16 highly endemic villages, 195 cases of recently treated VL, 116 healthy rK39 positive cases and 31 PKDL cases were identified. Approximately half of the rK39-positive healthy cases identified during the initial 6-month screening period were from households (HHs) where a VL case had been identified. During the 18-month follow-up period, seroconversion of family members in the HHs with VL cases, PKDL cases, and rK39-positive individuals was similar to control HHs. Therefore, seroconversion was highest in HHs closest to the time of VL disease of a household member and there was no evidence of higher transmission in households with PKDL or healthy rK39-positive HHs. Moreover, within the PKDL HHs, (the initial 31 PKDL cases plus an additional 66 PKDL cases), there were no cases of VL identified during the initial screen or the 18-month follow-up. Notably, 23% of the PKDL cases had no prior history of VL suggesting that infection resulting directly in PKDL is more common than previously estimated. CONCLUSIONS/SIGNIFICANCE: These observations argue that acute VL cases represent the major reservoir for transmission in these villages and early identification and treatment of VL cases should remain a priority for VL elimination. We were unable to obtain evidence that transmission occurs in HHs with a PKDL case. PMID- 27974859 TI - Voriconazole Composited Polyvinyl Alcohol/Hydroxypropyl-beta-Cyclodextrin Nanofibers for Ophthalmic Delivery. AB - Voriconazole (VRC) incorporated in composited polyvinyl alcohol (PVA)/hydroxypropyl-beta-cyclodextrin (HPbetaCD) blended nanofibers were produced via electrospinning for efficient ophthalmic delivery. The VRC loading capacity increased with increasing HPbetaCD content. The optimal solution for electrospinning consisted of 8% (w/v) PVA, 4% (w/v) HPbetaCD and 0.5% (w/v) VRC. The nanofibers exhibited bead-free average fiber diameters of 307+/-31 nm and VRC was released in vitro in a sustained manner. The VRC nanofibers were characterized by infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The proton nuclear magnetic resonance (1H-NMR) was used to analyze the molar ratio of HPbetaCD/VRC in the nanofibers. Compared with a VRC solution, the nanofibers significantly prolonged the half life, and increased the bioavailability of VRC in rabbit tears. No obvious signs of irritation were observed after application in the conjunctival sac. VRC nanofibers are promising for ophthalmic drug delivery and further pharmacodynamics studies are needed. PMID- 27974860 TI - A Novel Microfluidic Assay for Rapid Phenotypic Antibiotic Susceptibility Testing of Bacteria Detected in Clinical Blood Cultures. AB - BACKGROUND: Appropriate antibiotic therapy is critical in the management of severe sepsis and septic shock to reduce mortality, morbidity and health costs. New methods for rapid antibiotic susceptibility testing are needed because of increasing resistance rates to standard treatment. AIMS: The purpose of this study was to evaluate the performance of a novel microfluidic method and the potential to directly apply this method on positive blood cultures. METHODS: Minimum inhibitory concentrations (MICs) of ciprofloxacin, ceftazidime, tigecycline and/or vancomycin for Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus were determined using a linear antibiotic concentration gradient in a microfluidic assay. Bacterial growth along the antibiotic gradient was monitored using automated time-lapse photomicrography and growth inhibition was quantified by measuring greyscale intensity changes in the images. In addition to pure culture MICs, vancomycin MICs were determined for S. aureus from spiked and clinical blood cultures following a short centrifugation step. The MICs were compared with those obtained with the Etest and for S. aureus and vancomycin also with macrodilution. RESULTS: The MICs obtained with the microfluidic assay showed good agreement internally as well as with the Etest and macrodilution assays, although some minor differences were noted between the methods. The time to possible readout was within the range of 2 to 5 h. CONCLUSIONS: The examined microfluidic assay has the potential to provide rapid and accurate MICs using samples from positive clinical blood cultures and will now be tested using other bacterial species and antibiotics. PMID- 27974861 TI - A comparison between wolves, Canis lupus, and dogs, Canis familiaris, in showing behaviour towards humans. AB - Both human and nonhuman primates use imperative pointing to request a desired object from another individual. Gaze alternation often accompanies such pointing gestures, and in species that have no hands this can in itself function as imperative pointing. Dogs have exceptional skills in communicating with humans. The early development of these skills is suggested to have been facilitated by domestication. Adult wolves socialized with humans can use human-provided information to find food in various situations, but it is unclear whether they would use gaze alternation to show their human partner a target location they cannot reach on their own. In our experiment, we tested wolves and dogs in a task where they could indicate an out-of-reach food location to one of two human partners. One partner reacted in a cooperative way and gave the food hidden in the indicated location to the subject whereas the other responded in a competitive way and ate the food herself. Our results suggest that wolves, as well as dogs, use 'showing' behaviours to indicate a food location to a human partner, and that both can adjust their communication to the cooperativeness of their human partners, showing more indicating signals in the presence of the cooperative partner than in the presence of the competitive one. We conclude that wolves and dogs, both kept in packs under the same conditions, can use humans as cooperative partners, and point imperatively in order to receive a desired out-of reach object. It seems that intensive socialization with humans enables both wolves and dogs to communicate cooperatively about a food location with humans, most probably relying on skills that evolved to promote social coordination within their packs. PMID- 27974862 TI - Effect of the application of cattle urine with or without the nitrification inhibitor DCD, and dung on greenhouse gas emissions from a UK grassland soil. AB - Emissions of nitrous oxide (N2O) from soils from grazed grasslands have large uncertainty due to the great spatial variability of excreta deposition, resulting in heterogeneous distribution of nutrients. The contribution of urine to the labile N pool, much larger than that from dung, is likely to be a major source of emissions so efforts to determine N2O emission factors (EFs) from urine and dung deposition are required to improve the inventory of greenhouse gases from agriculture. We investigated the effect of the application of cattle urine and dung at different times of the grazing season on N2O emissions from a grassland clay loam soil. Methane emissions were also quantified. We assessed the effect of a nitrification inhibitor, dicyandiamide (DCD), on N2O emissions from urine application and also included an artificial urine treatment. There were significant differences in N2O EFs between treatments in the spring (largest from urine and lowest from dung) but not in the summer and autumn applications. We also found that there was a significant effect of season (largest in spring) but not of treatment on the N2O EFs. The resulting EF values were 2.96, 0.56 and 0.11% of applied N for urine for spring, summer and autumn applications, respectively. The N2O EF values for dung were 0.14, 0.39 and 0.10% for spring, summer and autumn applications, respectively. The inhibitor was effective in reducing N2O emissions for the spring application only. Methane emissions were larger from the dung application but there were no significant differences between treatments across season of application. PMID- 27974863 TI - Climate, migration, and the local food security context: Introducing Terra Populus. AB - Studies investigating the connection between environmental factors and migration are difficult to execute because they require the integration of microdata and spatial information. In this article, we introduce the novel, publically available data extraction system Terra Populus (TerraPop), which was designed to facilitate population-environment studies. We showcase the use of TerraPop by exploring variations in the climate-migration association in Burkina Faso and Senegal based on differences in the local food security context. Food security was approximated using anthropometric indicators of child stunting and wasting derived from Demographic and Health Surveys (DHS) and linked to the TerraPop extract of climate and migration information. We find that an increase in heat waves was associated with a decrease in international migration from Burkina Faso, while excessive precipitation increased international moves from Senegal. Significant interactions reveal that the adverse effects of heat waves and droughts are strongly amplified in highly food insecure Senegalese departments. PMID- 27974864 TI - Comparative Lateralizing Ability of Multimodality MRI in Temporal Lobe Epilepsy. AB - Purpose. The objective is to compare lateralizing ability of three quantitative MR (qMRI) modalities to depict changes of hippocampal architecture with clinical entities in temporal lobe epilepsy. Methods. We evaluated 14 patients with clinical and EEG proven diagnosis of unilateral TLE and 15 healthy volunteers. T1 weighted 3D dataset for volumetry, single-voxel 1H MR spectroscopy (MRS), and diffusion tensor imaging (DTI) were performed for bilateral hippocampi of all subjects. Results. Individual volumetric measurements provided accurate lateralization in 85% of the patients, spectroscopy in 57%, and DTI in 57%. Higher lateralization ratios were acquired combining volumetry-spectroscopy (85%), spectroscopy-DTI (85%), and volumetry-DTI (100%). Significantly decreased NAA/(Cho+Cr) ratios (p = 0.002) and increased FA (p = 0.001) values were obtained in ipsilateral to epileptogenic hippocampus. Duration of epilepsy and FA values showed a significant negative correlation (p = 0.016, r = -0.847). The history of febrile convulsion associated with ipsilateral increased ADC values (p = 0.015, r = 0.851) and reduced NAA/(Cho+Cr) ratios (p = 0.047, r = -761). Conclusion. Volumetry, MRS, and DTI studies provide complementary information of hippocampal pathology. For lateralization of epileptogenic focus and preoperative examination, volumetry-DTI combination may be indicative of diagnostic accuracy. PMID- 27974865 TI - Association of Heme Oxygenase 1 with Lung Protection in Malaria-Associated ALI/ARDS. AB - Malaria is a serious disease, caused by the parasite of the genus Plasmodium, which was responsible for 440,000 deaths in 2015. Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the main clinical complications in severe malaria. The murine model DBA/2 reproduces the clinical signs of ALI/ARDS in humans, when infected with Plasmodium berghei ANKA. High levels of HO-1 were reported in cases of severe malaria. Our data indicated that the HO-1 mRNA and protein expression are increased in mice that develop malaria associated ALI/ARDS (MA-ALI/ARDS). Additionally, the hemin, a HO-1 inducing drug, prevented mice from developing MA-ALI/ARDS when administered prior to the development of MA-ALI/ARDS in this model. Also, hemin treatment showed an amelioration of respiratory parameters in mice, high VEGF levels in the sera, and a decrease in vascular permeability in the lung, which are signs of ALI/ARDS. Therefore, the induction of HO-1 before the development of MA-ALI/ARDS could be protective. However, the increased expression of HO-1 on the onset of MA-ALI/ARDS development may represent an effort to revert the phenotype of this syndrome by the host. We therefore confirm that HO-1 inducing drugs could be used for prevention of MA-ALI/ARDS in humans. PMID- 27974866 TI - CD4+ T Cell Fate in Glomerulonephritis: A Tale of Th1, Th17, and Novel Treg Subtypes. AB - Multiple studies have identified CD4+ T cells as central players of glomerulonephritis (GN). Cells of the Th1 and Th17 responses cause renal tissue damage, while Tregs mediate protection. Recently, a high degree of plasticity among these T cell lineages was proposed. During inflammation, Th17 cells were shown to have the potential of transdifferentiation into Th1, Th2, or alternatively anti-inflammatory Tr1 cells. Currently available data from studies in GN, however, do not indicate relevant Th17 to Th1 or Th2 conversion, leaving the Th17 cell fate enigmatic. Tregs, on the other hand, were speculated to transdifferentiate into Th17 cells. Again, data from GN do not support this concept. Rather, it seems that previously unrecognized subspecialized effector Treg lineages exist. These include Th1 specific Treg1 as well as Th17 directed Treg17 cells. Furthermore, a bifunctional Treg subpopulation was recently identified in GN, which secrets IL-17 and coexpresses Foxp3 together with the Th17 characteristic transcription factor RORgammat. Similarities between these different and highly specialized effector Treg subpopulations with the corresponding T helper effector cell lineages might have resulted in previous misinterpretation as Treg transdifferentiation. In summary, Th17 cells have a relatively stable phenotype during GN, while, in the case of Tregs, currently available data suggest lineage heterogeneity rather than plasticity. PMID- 27974868 TI - SR-HARDI: Spatially Regularizing High Angular Resolution Diffusion Imaging. AB - High angular resolution diffusion imaging (HARDI) has recently been of great interest in mapping the orientation of intra-voxel crossing fibers, and such orientation information allows one to infer the connectivity patterns prevalent among different brain regions and possible changes in such connectivity over time for various neurodegenerative and neuropsychiatric diseases. The aim of this paper is to propose a penalized multi-scale adaptive regression model (PMARM) framework to spatially and adaptively infer the orientation distribution function (ODF) of water diffusion in regions with complex fiber configurations. In PMARM, we reformulate the HARDI imaging reconstruction as a weighted regularized least squares regression (WRLSR) problem. Similarity and distance weights are introduced to account for spatial smoothness of HARDI, while preserving the unknown discontinuities (e.g., edges between white matter and grey matter) of HARDI. The L1 penalty function is introduced to ensure the sparse solutions of ODFs, while a scaled L1 weighted estimator is calculated to correct the bias introduced by the L1 penalty at each voxel. In PMARM, we integrate the multiscale adaptive regression models (Li et al., 2011), the propagation-separation method (Polzehl and Spokoiny, 2000), and Lasso (least absolute shrinkage and selection operator) (Tibshirani, 1996) to adaptively estimate ODFs across voxels. Experimental results indicate that PMARM can reduce the angle detection errors on fiber crossing area and provide more accurate reconstruction than standard voxel wise methods. PMID- 27974867 TI - Elevated Admission Base Deficit Is Associated with a Complex Dynamic Network of Systemic Inflammation Which Drives Clinical Trajectories in Blunt Trauma Patients. AB - We hypothesized that elevated base deficit (BD) >= 4 mEq/L upon admission could be associated with an altered inflammatory response, which in turn may impact differential clinical trajectories. Using clinical and biobank data from 472 blunt trauma survivors, 154 patients were identified after excluding patients who received prehospital IV fluids or had alcohol intoxication. From this subcohort, 84 patients had a BD >= 4 mEq/L and 70 patients with BD < 4 mEq/L. Three samples within the first 24 h were obtained from all patients and then daily up to day 7 after injury. Twenty-two cytokines and chemokines were assayed using LuminexTM and were analyzed using two-way ANOVA and dynamic network analysis (DyNA). Multiple mediators of the innate and lymphoid immune responses in the BD >= 4 group were elevated differentially upon admission and up to 16 h after injury. DyNA revealed a higher, sustained degree of interconnectivity of the inflammatory response in the BD >= 4 patients during the initial 16 h after injury. These results suggest that elevated admission BD is associated with differential immune/inflammatory pathways, which subsequently could predispose patients to follow a complicated clinical course. PMID- 27974870 TI - Hemodynamic Response to Upper Airway Obstruction in Hypertensive and Normotensive Pregnant Women. AB - Background. Mild obstructive sleep apnea is common in pregnancy and may have an exacerbating role in gestational hypertension, although currently the interaction between these two diseases is uncertain. Methods. We analyzed 43 pregnant subjects, 28 with gestational hypertension (GH) and 15 with normal healthy pregnancy, by level I polysomnography. Additionally, diastolic and systolic blood pressure changes in response to obstructive respiratory events were measured by noninvasive beat-by-beat monitoring. We also assessed a subgroup (n = 27) of women with respiratory disturbance indexes <5, for blood pressure responses to very subtle obstructive respiratory disturbances ("airflow reductions"). Results. The mean +/- standard deviation respiratory disturbance index of our 28 GH women and 15 healthy pregnant women was 10.1 +/- 9.9 mmHg and 3.0 +/- 3.8 mmHg, respectively. Systolic and diastolic pressure responses to these events were 30.1 +/- 12.8 mmHg and 16.0 +/- 6.1 mmHg for GH women and 29.1 +/- 14.2 mmHg and 14.3 +/- 7.7 mmHg for healthy women. For the 27 women in whom we assessed for airflow reduction events, the hemodynamic responses were 27.1 +/- 12.3 mmHg systolic and 14.4 +/- 6.7 mmHg diastolic. Interpretation. Upper airway obstructive events of any severity are associated with a substantial transient blood pressure response in both healthy pregnant and GH women. Whether or not these events have a clinically significant impact on women with GH remains uncertain. PMID- 27974871 TI - Determination of Growth-Phase Dependent Influences Exerted by Prions on Yeast Lipid Content Using HPTLC-Densitometry. AB - Prions of the baker's yeast Saccharomyces cerevisiae allow for the inheritance of complex traits based solely on the acquisition of cytoplasmic protein aggregates and confer distinctive phenotypes to the cells which harbor them, creating heterogeneity within an otherwise clonal cell population. These phenotypes typically arise from a loss-of-function of the prion-forming protein that is unable to perform its normal cellular function(s) while sequestered in prion amyloid aggregates, but the specific biochemical consequences of prion infection are poorly understood. To begin to address this issue, we initiated a direct investigation into the potential control that yeast prions exert over fungal lipid content by utilizing the prions [URE3] and [PSI+], the first two prions discovered in yeast. We utilized silica gel high-performance thin-layer chromatography (HPTLC)-densitometry to conduct pair-wise quantifications of the relative levels of free sterols, free fatty acids, and triacylglycerols [petroleum ether-diethyl ether-acetic acid (80:20:1) mobile phase, phosphomolybdic acid (PMA) detection reagent]; steryl esters and squalene (hexane petroleum ether-diethyl ether-acetic acid (50:20;5:1), PMA]; and phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol (chloroform-diethyl ether-acetic acid (65:25:4.5), cupric sulfate-phosphoric acid) in otherwise clonal prion-infected ([PSI+] or [URE3]) and prion-free ([psi ] or [ure-o]) cells in two growth phases: log-phase and stationary phase. Our analysis revealed multiple statistically significant differences (p < 0.00625) between prion-infected and prion-free cells. Interestingly, prion-induced changes varied dramatically by growth phase, indicating that prions exert differential influences on cell physiology between log and stationary growth. Further experimental replication and extension of the analysis to other prions is expected to resolve additional physiological effects of prion infection. This investigation demonstrates that HPTLC-densitometry is an effective method for studying prion-induced alterations in lipid content in yeast. PMID- 27974869 TI - Community Level Association between Home Health and Nursing Home Performance on Quality and Hospital 30-day Readmissions for Medicare Patients. AB - We evaluated whether community-level home health agencies and nursing home performance is associated with community-level hospital 30-day all-cause risk standardized readmission rates for Medicare patients used data from the Centers for Medicare & Medicaid Service from 2010 to 2012. Our final sample included 2,855 communities that covered 4,140 hospitals with 6,751,713 patients, 13,060 nursing homes with 1,250,648 residents, and 7,613 home health agencies providing services to 35,660 zipcodes. Based on a mixed effect model, we found that increasing nursing home performance by one star for all of its 4 measures and home health performance by 10 points for all of its 6 measures is associated with decreases of 0.25% (95% CI 0.17-0.34) and 0.60% (95% CI 0.33-0.83), respectively, in community-level risk-standardized readmission rates. PMID- 27974872 TI - Studies on exercise physiology and performance testing of racehorses performed in Japan during the 1930s using recovery rate as an index. AB - The history of research on the exercise physiology of racehorses in Japan dates back to the 1930s. A research report entitled "Studies on exercise physiology and performance testing of the racehorse", published in 1933 by Shigeo Matsuba and Torao Shimamura of The University of Tokyo, was epoch-making and the most important study in the history of equine exercise physiology in Japan. Research results were reported from 92 Thoroughbred racehorses in a large-scale project during the period of 1928 to 1932 at the Shimofusa Imperial Farm and the Koiwai Farm, which were the two greatest racehorse farms at that time. A total of 20 physiological variables were measured to evaluate the fitness of Thoroughbred racehorses before exercise (Pre), just after exercise (Post), 1 hr after exercise (1 hr), 2 hr after exercise (2 hr), and 3 hr after exercise (3 hr) in order to calculate their recovery rates as an index of fitness and performance. The percentage of the Pre value at 1 hr, 2 hr, and 3 hr was calculated. When the percentage of a variable reached 95-105% of the Pre value, the variable was considered to be recovered. The percentage of the total number of variables that were recovered for each time period was calculated, and an overall average was calculated from them; Matsuba and Shimamura proposed calling this overall average the "recovery rate", which could then be applied to evaluate each horse. The effects of training on racehorses were subsequently evaluated by measuring the various physiological variables and the recovery rate. PMID- 27974873 TI - Quantitative evaluation of cervical cord compression by computed tomographic myelography in Thoroughbred foals. AB - Five Thoroughbred foals (age, 8-33 weeks; median age, 31 weeks; weight, 122-270 kg; median weight, 249 kg) exhibiting ataxia with suspected cervical myelopathy (n=4) and limb malformation (n=1) were subjected to computed tomographic (CT) myelography. The areas of the subarachnoid space and cervical cord were measured on transverse CT images. The area of the cervical cord was divided by the area of subarachnoid space, and stenosis ratios were quantitatively evaluated and compared on the basis of histopathological examination. The sites with a ratio above 52.8% could have been primary lesion sites in the histopathological examination, although one site with a ratio of 54.1% was not a primary lesion site. Therefore, in this study, a ratio between 52.8-54.1% was suggested to be borderline for physical compression that damages the cervical cord. All the cervical vertebrae could not be scanned in three of the five cases. Therefore, CT myelography is not a suitable method for locating the site of compression, but it should be used for quantitative evaluation of cervical stenosis diagnosed by conventional myelography. In conclusion, the stenosis ratios determined using CT myelography could be applicable for detecting primary lesion sites in the cervical cord. PMID- 27974874 TI - Effects of a single use of the GnRH analog buserelin on the induction of ovulation and endocrine profiles in heavy draft mares. AB - We observed structural changes in the follicles and uterus of heavy draft mares during estrus and examined the effect of a single injection of the gonadotropin releasing hormone analog buserelin on ovulation and endocrine profiles. Twenty two heavy draft mares were divided into a buserelin-treated group (n=8) and a control group (n=14). Mares were given an intramuscular injection of 40 ug buserelin when they presented signs of estrus to a teaser stallion, had >=45 mm diameter follicles, and presented decreased uterine edema compared with the previous examination. The follicles and uterus were monitored using transrectal ultrasound imaging and measurement of blood levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, and estradiol-17beta. The ovulation rates within 48 hr was significantly higher in the treated group (100%, 8/8) than in the control group (57.1%, 8/14; P=0.051). The mean +/- SEM time before confirmation of ovulation was 29 +/- 9 hr for the treated group and 59 +/- 7 hr for the control group. There were no significant differences in mating frequency, double ovulation rate, or fertility rate between the two groups. One to two days after administering buserelin, LH and FSH temporarily increased, and in the control group, LH was high during ovulation, whereas FSH temporarily increased with the growth of the follicle. These results indicate that a single injection of 40 ug buserelin when follicles are at least 45 mm in diameter and uterine edema is decreased is effective for inducing ovulation. PMID- 27974875 TI - Profiling of exercise-induced transcripts in the peripheral blood cells of Thoroughbred horses. AB - Transcriptome analyses based on DNA microarray technology have been used to investigate gene expression profiles in horses. In this study, we aimed to identify exercise-induced changes in the expression profiles of genes in the peripheral blood of Thoroughbred horses using DNA microarray technology (15,429 genes on 43,603 probes). Blood samples from the jugular vein were collected from six horses before and 1 min, 4 hr, and 24 hr after all-out running on a treadmill. After the normalization of microarray data, a total of 26,830 probes were clustered into four groups and 11 subgroups showing similar expression changes based on k-mean clustering. The expression level of inflammation-related genes, including interleukin-1 receptor type II (IL-1R2), matrix metallopeptidase 8 (MMP8), protein S100-A8 (S100-A8), and serum amyloid A (SAA), increased at 4 hr after exercise, whereas that of c-Fos (FOS) increased at 1 min after exercise. These results indicated that the inflammatory response increased in the peripheral blood cells after exercise. Our study also revealed the presence of genes that may not be affected by all-out exercise. In conclusion, transcriptome analysis of peripheral blood cells could be used to monitor physiological changes induced by various external stress factors, including exercise, in Thoroughbred racehorses. PMID- 27974876 TI - Evaluation of housekeeping genes for quantitative gene expression analysis in the equine kidney. AB - Housekeeping genes (HKGs) are used as internal controls for normalising and calculating the relative expression of target genes in RT-qPCR experiments. There is no unique universal HKG and HKGs vary among organisms and tissues, so this study aimed to determine the most stably expressed HKGs in the equine kidney. The evaluated HKGs included 18S ribosomal RNA (18S), 28S ribosomal RNA (28S), ribosomal protein L32 (RPL32), beta-2-microglobulin (B2M), glyceraldehyde-3 phosphate dehydrogenase (GAPDH), succinate dehydrogenase complex (SDHA), zeta polypeptide (YWHAZ), and hypoxanthine phosphoribosyltransferase 1 (HPRT1). The HKGs expression stability data were analysed with two software packages, geNorm and NormFinder. The lowest stability values for geNorm suggests that YWHAZ and HPRT1 would be most optimal (M=0.31 and 0.32, respectively). Further, these two genes had the best pairwise stability value using NormFinder (geNorm V=0.085). Therefore, these two genes were considered the most useful for RT-qPCR studies in equine kidney. PMID- 27974877 TI - Validation of the bispectral index as an indicator of anesthetic depth in Thoroughbred horses anesthetized with sevoflurane. AB - To evaluate the bispectral index (BIS) as an indicator of anesthetic depth in Thoroughbred horses, BIS values were measured at multiple stages of sevoflurane anesthesia in five horses anesthetized with guaifenesin and thiopental following premedication with xylazine. There was no significant difference between the BIS values recorded at end-tidal sevoflurane concentrations of 2.8% (median 60 ranging from 47 to 68) and 3.5% (median 71 ranging from 49 to 82) in anesthetized horses. These BIS values during anesthesia were significantly lower (P<0.01) than those in awake horses (median 98 ranging from 98 to 98) or sedated horses (median 92 ranging from 80 to 93). During the recovery phase, the BIS values gradually increased over time but did not significantly increase until the horses showed movement. In conclusion, the BIS value could be useful as an indicator of awakening during the recovery period in horses, as previous reported. PMID- 27974878 TI - Learning to drive in young adults with language impairment. AB - Language impairment (LI) is a common developmental disorder which affects many aspects of young people's functional skills and engagement with society. Little is known of early driving behaviour in those with this disability. This longitudinal study examines early driving experience in a sample of young adults with LI, compared with a sample of typically developing age-matched peers (AMPs). At age 24 years, significantly fewer participants with LI had acquired a driving licence. A crucial hurdle for those with LI appeared to be the Theory part of the (UK) test. Logistic regression analysis indicated that language ability and a measure of independence at age 17 contributed to the prediction of licence possession at age 24. There was no evidence of differences in traffic violations or accident rates between those with and without LI. There is little evidence that young people with LI are at greater risk on the roads than peers without LI, but some individuals with LI might benefit from support in the course of preparation for driving and in the driving test. PMID- 27974880 TI - Differences in Practices Between Rural and Urban First Responders: Examining how First Responders Handle Irritant Gas Syndrome Agent (IGSA) Disasters in Rural Versus Urban Settings. PMID- 27974881 TI - Assessment of Innovative Emergency Department Information Displays in a Clinical Simulation Center. AB - The objective of this work was to assess the functional utility of new display concepts for an emergency department information system created using cognitive systems engineering methods, by comparing them to similar displays currently in use. The display concepts were compared to standard displays in a clinical simulation study during which nurse-physician teams performed simulated emergency department tasks. Questionnaires were used to assess the cognitive support provided by the displays, participants' level of situation awareness, and participants' workload during the simulated tasks. Participants rated the new displays significantly higher than the control displays in terms of cognitive support. There was no significant difference in workload scores between the display conditions. There was no main effect of display type on situation awareness, but there was a significant interaction; participants using the new displays showed improved situation awareness from the middle to the end of the session. This study demonstrates that cognitive systems engineering methods can be used to create innovative displays that better support emergency medicine tasks, without increasing workload, compared to more standard displays. These methods provide a means to develop emergency department information systems-and more broadly, health information technology-that better support the cognitive needs of healthcare providers. PMID- 27974879 TI - Unusually High Archaeal Diversity in a Crystallizer Pond, Pomorie Salterns, Bulgaria, Revealed by Phylogenetic Analysis. AB - Recent studies on archaeal diversity in few salterns have revealed heterogeneity between sites and unique structures of separate places that hinder drawing of generalized conclusions. Investigations on the archaeal community composition in P18, the biggest crystallizer pond in Pomorie salterns (PS) (34% salinity), demonstrated unusually high number of presented taxa in hypersaline environment. Archaeal clones were grouped in 26 different operational taxonomic units (OTUs) assigned to 15 different genera from two orders, Halobacteriales and Haloferacales. All retrieved sequences were related to culturable halophiles or unculturable clones from saline (mostly hypersaline) niches. New sequences represented 53.9% of archaeal OTUs. Some of them formed separate branches with 90% similarity to the closest neighbor. Present results significantly differed from the previous investigations in regard to the number of presented genera, the domination of some genera not reported before in such extreme niche, and the identification of previously undiscovered 16S rRNA sequences. PMID- 27974882 TI - PLAT: An Automated Fault and Behavioural Anomaly Detection Tool for PLC Controlled Manufacturing Systems. AB - Operational faults and behavioural anomalies associated with PLC control processes take place often in a manufacturing system. Real time identification of these operational faults and behavioural anomalies is necessary in the manufacturing industry. In this paper, we present an automated tool, called PLC Log-Data Analysis Tool (PLAT) that can detect them by using log-data records of the PLC signals. PLAT automatically creates a nominal model of the PLC control process and employs a novel hash table based indexing and searching scheme to satisfy those purposes. Our experiments show that PLAT is significantly fast, provides real time identification of operational faults and behavioural anomalies, and can execute within a small memory footprint. In addition, PLAT can easily handle a large manufacturing system with a reasonable computing configuration and can be installed in parallel to the data logging system to identify operational faults and behavioural anomalies effectively. PMID- 27974883 TI - Artificial Neural Network and Genetic Algorithm Hybrid Intelligence for Predicting Thai Stock Price Index Trend. AB - This study investigated the use of Artificial Neural Network (ANN) and Genetic Algorithm (GA) for prediction of Thailand's SET50 index trend. ANN is a widely accepted machine learning method that uses past data to predict future trend, while GA is an algorithm that can find better subsets of input variables for importing into ANN, hence enabling more accurate prediction by its efficient feature selection. The imported data were chosen technical indicators highly regarded by stock analysts, each represented by 4 input variables that were based on past time spans of 4 different lengths: 3-, 5-, 10-, and 15-day spans before the day of prediction. This import undertaking generated a big set of diverse input variables with an exponentially higher number of possible subsets that GA culled down to a manageable number of more effective ones. SET50 index data of the past 6 years, from 2009 to 2014, were used to evaluate this hybrid intelligence prediction accuracy, and the hybrid's prediction results were found to be more accurate than those made by a method using only one input variable for one fixed length of past time span. PMID- 27974884 TI - Utilization of the Discrete Differential Evolution for Optimization in Multidimensional Point Clouds. AB - The Differential Evolution (DE) is a widely used bioinspired optimization algorithm developed by Storn and Price. It is popular for its simplicity and robustness. This algorithm was primarily designed for real-valued problems and continuous functions, but several modified versions optimizing both integer and discrete-valued problems have been developed. The discrete-coded DE has been mostly used for combinatorial problems in a set of enumerative variants. However, the DE has a great potential in the spatial data analysis and pattern recognition. This paper formulates the problem as a search of a combination of distinct vertices which meet the specified conditions. It proposes a novel approach called the Multidimensional Discrete Differential Evolution (MDDE) applying the principle of the discrete-coded DE in discrete point clouds (PCs). The paper examines the local searching abilities of the MDDE and its convergence to the global optimum in the PCs. The multidimensional discrete vertices cannot be simply ordered to get a convenient course of the discrete data, which is crucial for good convergence of a population. A novel mutation operator utilizing linear ordering of spatial data based on the space filling curves is introduced. The algorithm is tested on several spatial datasets and optimization problems. The experiments show that the MDDE is an efficient and fast method for discrete optimizations in the multidimensional point clouds. PMID- 27974885 TI - Association of Endoscopic Features of Gastric Mucosa with Helicobacter pylori Infection in Chinese Patients. AB - The aim of this study is to identify and consolidate reliable endoscopic features associated with H. pylori infection in gastric mucosa, which is one of the major causes of gastric cancer. A total of 256 Chinese patients with symptomatic stomach disturbances were enrolled. Pathological examination was conducted using a light microscope and biopsy specimens stained with hematoxylin-eosin. Endoscopic examination was performed using a high resolution video endoscope. The association between endoscopic features and pathological H. pylori diagnosis was compared, and endoscopic features significantly associated with H. pylori infection were identified. A total of 14 endoscopic features were observed. Six of the 14 endoscopic features, including mucus on the gastric mucosa, diffuse redness, spotty redness of fundic mucosa, enlarged fold, mucosal edema, and RAC (type D and type I), were highly associated with H. pylori infection and were significantly sensitive and specific predictors for H. pylori diagnosis. The type R RAC was not significantly associated with H. pylori diagnosis. Our results indicate that conventional endoscopy features can be used to diagnose H. pylori in Chinese patients and can help determine the risk factor for gastric cancer. PMID- 27974886 TI - Diagnostic Value of Fecal Calprotectin (S100 A8/A9) Test in Children with Chronic Abdominal Pain. AB - Objectives. The aim of the study was to establish whether fecal calprotectin concentration (FCC) may be useful in children with chronic abdominal pain to differentiate between inflammatory bowel disease (IBD), other inflammatory gastrointestinal disorders, and functional gastrointestinal disorders. Methods. The study included 163 patients (median age 13 years), who were assigned to four study groups: group 0 (control), 22 healthy children; group 1, 33 children with functional gastrointestinal disorders; group 2, 71 children with inflammatory gastrointestinal disorders other than IBD; group 3, 37 children with IBD. FCC was measured using ELISA assay. Results. In group 0 and group 1 FCCs were below 100 MUg/g. Low FCCs were found in 91% of patients in group 2. In patients with IBD FCCs were markedly elevated with median value of 1191.5 MUg/g. However, in children with inflammatory gastrointestinal disorders other than IBD and in children with IBD mean FCCs were significantly higher compared with the control group. Significant differences in FCCs were also found between group 1 and group 2, between group 1 and group 3, and between group 2 and group 3. Conclusion. FCC is the best parameter allowing for differentiation between IBD, other inflammatory gastrointestinal disorders, and functional gastrointestinal disorders. High FCC is associated with a high probability of IBD and/or other inflammatory gastrointestinal disorders, and it allows excluding functional gastrointestinal disorders. PMID- 27974887 TI - The Single Wire Ureteral Access Sheath, Both Safe and Economical. AB - Introduction. Novel disposable products for ureteroscopy are often inherently more expensive than conventional ones. For example, the Cook Flexor(c) ParallelTM (Flexor) access sheath is designed for ease and efficiency of gaining upper tract access with a solitary wire. We analyze the cost combinations, efficiency, and safety of disposable products utilized for upper tract access, including the Flexor and standard ureteral access sheath. Methods. We performed a retrospective review from January 2014 to October 2014 of patients undergoing URS for nephrolithiasis, who were prestented for various reasons (e.g., infection). Common combinations most utilized at our institution include "Classic," "Flexor," and "Standard." Total costs per technique were calculated. Patient characteristics, operative parameters, and outcomes were compared among the groups. Results. The most commonly used technique involved a standard ureteral sheath and was the most expensive ($294). The second most utilized and least expensive combination involved the Flexor, saving up to $80 per case (27%). All access sheaths were placed successfully and without complications. There were no significant differences in operative time, blood loss, or complications. Conclusions. In prestented patients within this study, the Flexor combination was the most economical. Although the savings appear modest, long-term impact on costs can be substantial. PMID- 27974888 TI - An Iterative, Mixed Usability Approach Applied to the Telekit System from the Danish TeleCare North Trial. AB - Objective. The aim of the present study is to evaluate the usability of the telehealth system, coined Telekit, by using an iterative, mixed usability approach. Materials and Methods. Ten double experts participated in two heuristic evaluations (HE1, HE2), and 11 COPD patients attended two think-aloud tests. The double experts identified usability violations and classified them into Jakob Nielsen's heuristics. These violations were then translated into measurable values on a scale of 0 to 4 indicating degree of severity. In the think-aloud tests, COPD participants were invited to verbalise their thoughts. Results. The double experts identified 86 usability violations in HE1 and 101 usability violations in HE2. The majority of the violations were rated in the 0-2 range. The findings from the think-aloud tests resulted in 12 themes and associated examples regarding the usability of the Telekit system. The use of the iterative, mixed usability approach produced both quantitative and qualitative results. Conclusion. The iterative, mixed usability approach yields a strong result owing to the high number of problems identified in the tests because the double experts and the COPD participants focus on different aspects of Telekit's usability. This trial is registered with Clinicaltrials.gov, NCT01984840, November 14, 2013. PMID- 27974889 TI - Regional Anaesthesia Is Associated with Shorter Postanaesthetic Care and Less Pain Than General Anaesthesia after Upper Extremity Surgery. AB - Introduction. For surgery on the upper extremity, the anaesthetist often has a choice between regional anaesthesia (RA) and general anaesthesia (GA). We sought to investigate the possible differences between RA and GA after upper extremity surgery with regard to postoperative patient comfort. Methods. This is a retrospective observational study that was performed at an acute care secondary referral centre. One hundred and eighty-seven procedures involving orthopaedic surgery on the upper extremity were included. The different groups (RA and GA) were compared regarding the primary outcome variable, length of stay in Postanaesthesia Unit, and secondary outcome variables, opioid consumption and nausea treatment. Results. RA was associated with significantly shorter median length of stay (99 versus 171 minutes). In the GA group, 32% of the patients received opioid analgesics and 21% received antiemetics. In the RA group, none received opioid analgesics and 3% received antiemetics. Conclusion. In this observational study, RA was superior to GA for surgery of the upper extremity regarding Postanaesthesia Care Unit length of stay, number of doses of analgesic, and number of doses of antiemetic administered. PMID- 27974890 TI - Clinical Significance of Molecular Diagnostic Tools for Bacterial Bloodstream Infections: A Systematic Review. AB - Bacterial bloodstream infection (bBSI) represents any form of invasiveness of the blood circulatory system caused by bacteria and can lead to death among critically ill patients. Thus, there is a need for rapid and accurate diagnosis and treatment of patients with septicemia. So far, different molecular diagnostic tools have been developed. The majority of these tools focus on amplification based techniques such as polymerase chain reaction (PCR) which allows the detection of nucleic acids (both DNA and small RNAs) that are specific to bacterial species and sequencing or nucleic acid hybridization that allows the detection of bacteria in order to reduce delay of appropriate antibiotic therapy. However, there is still a need to improve sensitivity of most molecular techniques to enhance their accuracy and allow exact and on time antibiotic therapy treatment. In this regard, we conducted a systematic review of the existing studies conducted in molecular diagnosis of bBSIs, with the main aim of reporting on clinical significance and benefits of molecular diagnosis to patients. We searched both Google Scholar and PubMed. In total, eighteen reviewed papers indicate that shift from conventional diagnostic methods to molecular tools is needed and would lead to accurate diagnosis and treatment of bBSI. PMID- 27974892 TI - Cauliflower Leave, an Agricultural Waste Biomass Adsorbent, and Its Application for the Removal of MB Dye from Aqueous Solution: Equilibrium, Kinetics, and Thermodynamic Studies. AB - Cauliflower leaf powder (CLP), a biosorbent prepared from seasonal agricultural crop waste material, has been employed as a prospective adsorbent for the removal of a basic dye, methylene blue (MB) from aqueous solution by the batch adsorption method under varying conditions, namely, initial dye concentration, adsorbent dose, solution pH, and temperature. Characterization of the material by FTIR and SEM indicates the presence of functional groups and rough coarse surface suitable for the adsorption of methylene blue over it. Efforts were made to fit the isotherm data using Langmuir, Freundlich, and Temkin equation. The experimental data were best described by Freundlich isotherm model, with an adsorption capacity of 149.22 mg/g at room temperature. To evaluate the rate of methylene blue adsorption onto CLP, pseudo-first-order, pseudo-second-order, and intraparticle diffusion models were employed. The experimental data were best described by the pseudo-second-order kinetic model. Evaluation of thermodynamic parameters such as changes in enthalpy, entropy, and Gibbs' free energy showed the feasible, spontaneous, and exothermic nature of the adsorption process. On the basis of experimental results obtained, it may be concluded that the CLP prepared from agricultural waste has considerable potential as low-cost adsorbent in wastewater treatment for the removal of basic dye, MB. PMID- 27974891 TI - Impact of Exposure to Fenitrothion on Vital Organs in Rats. AB - This study was designed to investigate the impact of oral administration of fenitrothion (10 mg/kg) on liver, kidney, brain, and lung function in rats. The effect was studied on days 7, 14, 21, 28, and 42. Our results have shown deterioration in liver function as evidenced by the elevation in serum ALT, AST, ALP, and bilirubin and reduction in albumin and hepatic glycogen. This was associated with a state of hyperglycemia and hyperlipidemia and increased prothrombin time, while hemoglobin content was reduced. In addition, the kidney function was reduced as indicated by the elevation in serum creatinine, uric acid, and BUN, while the serum levels of magnesium, potassium, and sodium were reduced. This study also showed an impairment in brain neurotransmitter (elevated 5-HT, glutamate, GABA, and reduced dopamine and norepinephrine level). This was associated with a reduction in the barrier capacity in brain and lung. Fenitrothion also caused a decrease in cholinesterase activity in serum, lung, and brain activity associated with a state of oxidative stress in all tested organs and hyperammonemia. These results support the hazards of pesticide use and shows the importance of minimizing pesticide use or discovering new safe pesticides. PMID- 27974893 TI - Recoverable, Record-High Lactic Acidosis in a Patient with Glycogen Storage Disease Type 1: A Mixed Type A and Type B Lactate Disorder. AB - A 17-year-old patient with GSD type 1a (von Gierke disease) was hospitalized with an extremely elevated serum lactate following an intercurrent infection and interruption of his frequent intake of carbohydrates. The patient developed shock, oliguric renal failure, and cardiorespiratory failure requiring mechanical ventilation and inotropes. At the peak of metabolic decompensation and clinical instability, serum lactate reached a level of 47.6 mmol/L which was accompanied by a severe anion gap metabolic acidosis with a pH of 6.8 and bicarbonate of 4 meq/L. The patient was stabilized with massive infusions of sodium bicarbonate (45 meq/h) and glucose and recovered without the need for dialysis. This patient illustrates pathophysiologic mechanisms involved in the development of extreme mixed type A and type B lactic acidemia, reflecting altered metabolic pathways in GSD type 1, combined with tissue hypoperfusion. The rationale for the specific interventions in this case is outlined. PMID- 27974894 TI - Pulmonary Artery Dissection: A Fatal Complication of Pulmonary Hypertension. AB - Pulmonary artery dissection is extremely rare but it is a really life-threatening condition when it happens. Most patients die suddenly from major bleeding or tamponade caused by direct rupture into mediastinum or retrograde into the pericardial sac. What we are reporting is a rare case of a 46-year-old female patient whose pulmonary artery dissection involves both the pulmonary valve and right pulmonary artery. The patient had acute chest pain and severe dyspnea, and the diagnosis of pulmonary artery dissection was confirmed by ultrasonography and CT angiography. Moreover, its etiology, clinical manifestations, and management are also discussed in this article. PMID- 27974895 TI - Survivin Improves Reprogramming Efficiency of Human Neural Progenitors by Single Molecule OCT4. AB - Induced pluripotent stem (iPS) cells have been generated from human somatic cells by ectopic expression of four Yamanaka factors. Here, we report that Survivin, an apoptosis inhibitor, can enhance iPS cells generation from human neural progenitor cells (NPCs) together with one factor OCT4 (1F-OCT4-Survivin). Compared with 1F-OCT4, Survivin accelerates the process of reprogramming from human NPCs. The neurocyte-originated induced pluripotent stem (NiPS) cells generated from 1F-OCT4-Survivin resemble human embryonic stem (hES) cells in morphology, surface markers, global gene expression profiling, and epigenetic status. Survivin keeps high expression in both iPS and ES cells. During the process of NiPS cell to neural cell differentiation, the expression of Survivin is rapidly decreased in protein level. The mechanism of Survivin promotion of reprogramming efficiency from NPCs may be associated with stabilization of beta catenin in WNT signaling pathway. This hypothesis is supported by experiments of RT-PCR, chromatin immune-precipitation, and Western blot in human ES cells. Our results showed overexpression of Survivin could improve the efficiency of reprogramming from NPCs to iPS cells by one factor OCT4 through stabilization of the key molecule, beta-catenin. PMID- 27974896 TI - Echocardiography as a Screening Test for Myocardial Scarring in Children with Hypertrophic Cardiomyopathy. AB - Introduction. Hypertrophic cardiomyopathy (HCM) is burdened with morbidity and mortality including tachyarrhythmias and sudden cardiac death. These complications are attributed in part to the formation of proarrhythmic scars in the myocardium. The presence of extensive LGE is a risk factor for adverse outcomes in HCM. Late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (cMRI) is the standard for the noninvasive evaluation of myocardial scars. However, echocardiography represents an attractive screening tool for myocardial scarring. The aim of this study was to compare the suitability of echocardiography to detect myocardial scars to the standard of cMRI-LGE. Methods. The cMRI studies and echocardiograms from 56 consecutive children with HCM were independently evaluated for the presence of cMRI-LGE and echocardiographic evidence of scarring by expert readers. Results. Echocardiography had a high sensitivity (93%) and negative predictive value (94%) in comparison to LGE. The false positive rate was high, leading to a low specificity (37%) and a low positive predictive value (35%). Conclusions. Given the poor specificity and positive predictive value, echocardiography is not a suitable screening test for the presence of myocardial scarring in children with HCM. However, children without echocardiographic evidence of myocardial scarring may not need to undergo cardiac magnetic resonance imaging to "rule in" LGE. PMID- 27974897 TI - Process Mapping in a Pediatric Emergency Department to Minimize Missed Urinary Tract Infections. AB - Urinary tract infections (UTIs) are common in young children and are seen in emergency departments (EDs) frequently. Left untreated, UTIs can lead to more severe conditions. Our goal was to undertake a quality improvement (QI) initiative to help minimize the number of children with missed UTIs in a newly established tertiary care pediatric emergency department (PED). A retrospective chart review was undertaken to identify missed UTIs in children < 3 years old who presented to a children's hospital's ED with positive urine cultures. It was found that there was no treatment or follow-up in 12% of positive urine cultures, indicating a missed or possible missed UTI in a significant number of children. Key stakeholders were then gathered and process mapping (PM) was completed, where gaps and barriers were identified and interventions were subsequently implemented. A follow-up chart review was completed to assess the impact of PM in reducing the number of missed UTIs. Following PM and its implementation within the ED, there was no treatment or follow-up in only 1% of cases. Based on our results, the number of potentially missed UTIs in the ED decreased dramatically, indicating that PM can be a successful QI tool in an acute care pediatric setting. PMID- 27974898 TI - Serum Vitamin D Levels and Vitamin D Supplement in Adult Patients with Asthma Exacerbation. AB - Introduction. Vitamin D deficiency has been linked to an increased risk of asthma exacerbations. Objective. This study aimed to compare vitamin D status during the period of severe asthma exacerbations and investigate if vitamin D supplementation improves asthma control. Methods. A total of 47 asthmatic patients and 40 healthy subjects participated in this study. Serum 25 hydroxyvitamin D (25(OH)D), asthma control test (ACT) score, and % predicted peak expiratory flow rate were evaluated in the period with and without severe asthma exacerbations. After that, we provided vitamin D2 supplements to the patients with low vitamin D levels for 3 months. Results. At the period of asthma exacerbation, the prevalence of vitamin D deficiency and insufficiency was 38.29% and 34.04%. There was no significant difference in the levels of serum 25(OH)D with and without asthma exacerbations but the levels were significantly higher in the healthy group. Serum 25(OH)D levels significantly correlated with ACT score. Moreover, vitamin D2 supplementation improved asthma control in uncontrolled asthma group. Conclusions. Hypovitaminosis D was common in asthmatic patients but was not the leading cause of asthma exacerbations. Serum 25(OH)D levels correlated with the ability to control asthma. Improving vitamin D status might be a benefit in uncontrolled asthmatic patients. PMID- 27974899 TI - Yoga Helps Put the Pieces Back Together: A Qualitative Exploration of a Community Based Yoga Program for Cancer Survivors. AB - Objective. A qualitative research methods approach was used to explore the experiences of participants in an ongoing community-based yoga program developed for cancer survivors and their support persons. Methods. 25 participants took part in a series of semistructured focus groups following a seven-week yoga program and at three- and six-month follow-ups. Focus groups were transcribed verbatim and analyzed using a process of inductive thematic analysis. Results. The group was comprised of 20 cancer survivors, who were diagnosed on average 25.40 (20.85) months earlier, and five support persons. Participants had completed the yoga program an average of 3.35 (3.66) times previously and attended approximately 1.64 (0.70) of three possible focus groups. Four key themes were identified: (1) safety and shared understanding; (2) cancer-specific yoga instruction; (3) benefits of yoga participation; (4) mechanisms of yoga practice. Conclusions. Qualitative research provides unique and in-depth insight into the yoga experience. Specifically, cancer survivors and support persons participating in a community-based yoga program discussed their experiences of change over time and were acutely aware of the beneficial effects of yoga on their physical, psychological, and social well-being. Further, participants were able to articulate the mechanisms they perceived as underpinning the relationship between yoga and improved well-being as they developed their yoga practice. PMID- 27974900 TI - The Hair Growth-Promoting Effect of Rumex japonicus Houtt. Extract. AB - Rumex japonicus Houtt. is traditionally used as a medicinal plant to treat patients suffering from skin disease in Korea. However, the beneficial effect of Rumex japonicus Houtt. on hair growth has not been thoroughly examined. Therefore, the present study aims to investigate the hair growth-promoting effect of Rumex japonicus (RJ) Houtt. root extract using human dermal papilla cells (DPCs), HaCaT cells, and C57BL/6 mice model. RJ induced antiapoptotic and proliferative effects on DPCs and HaCaT cells by increasing Bcl-2/Bax ratio and activating cellular proliferation-related proteins, ERK and Akt. RJ also increased beta-catenin via the inhibition of GSK-3beta. In C57BL/6 mice model, RJ promoted the anagen induction and maintained its period. Immunohistochemistry analysis demonstrated that RJ upregulated Ki-67 and beta-catenin expressions, suggesting that the hair growth effect of RJ may be mediated through the reinforcement of hair cell proliferation. These results provided important insights for the possible mechanism of action of RJ and its potential as therapeutic agent to promote hair growth. PMID- 27974901 TI - Role of the ER/NO/cGMP Signaling Pathway in the Promotion of Osteogenic Differentiation of Rat Bone Marrow Mesenchymal Stem Cells by Actaea racemosa Extract. AB - Purpose/Objective. To investigate the effect of Actaea racemosa (AR) extract on in vitro osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs) via the ER/NO/cGMP signaling pathway. Methods/Materials. Rat BMSCs were treated with osteogenic differentiation-inducing medium containing AR; estrogen receptor antagonist, ICI 182,780 (10-6 mol/L); and nitric oxide synthase inhibitor, L-nitro arginine methyl ester (L-NAME, 6 * 10-3 mol/L). Markers of osteogenic differentiation (alkaline phosphatase [ALP] activity, osteocalcin secretion, and calcium ion deposit levels) and the levels of key signaling molecules (nitric oxide synthase [NOS], nitric oxide [NO], and cyclic guanosine monophosphate [cGMP]) were assessed. Results. AR (10-1-10-6 g/L) increased ALP activity in a dose-dependent manner, and the highest ALP, osteocalcin, and osteoprotegerin activities were achieved at an AR concentration of 10-4 g/L. Therefore, the concentration of 10-4 g/L was used for promoting osteogenic differentiation of BMSCs in subsequent analyses. At this concentration, AR increased the levels of NO and cGMP, and such effects could be blocked by the estrogen receptor antagonist (ICI 182,780) and nitric oxide synthase inhibitor (L NAME). Conclusion. AR induced osteogenic differentiation of rat BMSCs through the ER/NO/cGMP signaling pathway. This finding provides the theoretical foundation for the mechanism of AR in the treatment of postmenopausal osteoporosis. PMID- 27974902 TI - The Effects of Four-Week Multivitamin Supplementation on Mood in Healthy Older Women: A Randomized Controlled Trial. AB - Objective. Nutritional deficiencies have been associated with cognitive decline and mood disturbances. Vitamin intake can influence mood and randomized controlled trials have demonstrated that multivitamin supplements are capable of reducing mild symptoms of mood dysfunction. However, few studies have focussed on healthy older women. Methods. This study investigated the effects of four weeks' multivitamin supplementation on mood in 76 healthy women aged 50-75 years. Mood was assessed before and after intervention in the laboratory using measures of current mood and retrospective experiences of mood over the past week or longer. Mobile phones were used to assess changes in real-time mood ratings, twice weekly in the home. Results. There were no multivitamin-related benefits identified for measures of current mood or reflections of recent mood when measured in the laboratory. In-home assessments, where mood was rated several hours after dose, revealed multivitamin supplementation improved ratings of stress, with a trend to reduce mental fatigue. Conclusions. Over four weeks, subtle changes to stress produced by multivitamin supplementation in healthy older women may not be detected when only pre- and posttreatment mood is captured. In-home mobile phone based assessments may be more sensitive to the effects of nutritional interventions compared to traditional in-laboratory assessments. PMID- 27974905 TI - Autophagy Protects from Raddeanin A-Induced Apoptosis in SGC-7901 Human Gastric Cancer Cells. AB - Raddeanin A (RA) is an extractive from Anemone raddeana Regel, a traditional Chinese medicine. The aim of this study is to assess the efficacy of RA against human gastric cancer (GC) cells (SGC-7901) and explore its mechanism. MTT assay showed that RA inhibition of proliferation of SGC-7901 cells increased in a dose dependent manner. Flow cytometry analysis and Hoechst 33258 staining showed that RA induced apoptosis on SGC-7901 cells. Meanwhile, it induced autophagy. Western blotting analysis showed that the RA induces apoptosis and autophagy by activating p38 MAPK pathway and inhibiting mTOR pathway. Further studies showed that autophagy inhibition could protect from RA-induced apoptosis in SGC-7901 cells. In conclusion, RA can induce SGC-7901 cell apoptosis and autophagy by activating p38 MAPK pathway. And autophagy can protect SGC-7901 cells from apoptosis induced by RA. PMID- 27974906 TI - Gene Transfer for Pain: A tool to cope with the intractable, or an unethical endurance-enhancing technology? PMID- 27974904 TI - Evaluation of a Standardized Extract from Morus alba against alpha-Glucosidase Inhibitory Effect and Postprandial Antihyperglycemic in Patients with Impaired Glucose Tolerance: A Randomized Double-Blind Clinical Trial. AB - To evaluate the antihyperglycemic effect of a standardized extract of the leaves of Morus alba (SEMA), the present study was designed to investigate the alpha glucosidase inhibitory effect and acute single oral toxicity as well as evaluate blood glucose reduction in animals and in patients with impaired glucose tolerance in a randomized double-blind clinical trial. SEMA was found to inhibit alpha-glucosidase at a fourfold higher level than the positive control (acarbose), in a concentration-dependent manner. Moreover, blood glucose concentration was suppressed by SEMA in vivo. Clinical signs and weight changes were observed when conducting an evaluation of the acute toxicity of SEMA through a single-time administration, with clinical observation conducted more than once each day. After administration of the SEMA, observation was for 14 days; all of the animals did not die and did not show any abnormal symptoms. In addition, the inhibitory effects of rice coated with SEMA were evaluated in a group of impaired glucose tolerance patients on postprandial glucose and a group of normal persons, and results showed that SEMA had a clear inhibitory effect on postprandial hyperglycemia in both groups. Overall, SEMA showed excellent potential in the present study as a material for improving postprandial hyperglycemia. PMID- 27974903 TI - Morphine Antidependence of Erythroxylum cuneatum (Miq.) Kurz in Neurotransmission Processes In Vitro. AB - Opiate abuse has been studied to cause adaptive changes observed in the presynaptic release and the mediated-synaptic plasticity proteins. The involvement of neuronal SNARE proteins reveals the role of the neurotransmitter release in expressing the opioid actions. The present study was designed to determine the effect of the alkaloid extract of Erythroxylum cuneatum (E. cuneatum) against chronic morphine and the influences of E. cuneatum on neurotransmission processes observed in vitro. The human neuroblastoma cell line, SK-N-SH, was treated with the morphine, methadone, or E. cuneatum. The cell lysates were collected and tested for alpha-synuclein, calmodulin, vesicle associated membrane protein 2 (VAMP 2), and synaptotagmin 1. The extract of E. cuneatum was observed to upregulate the decreased expression of dependence proteins, namely, alpha-synuclein and calmodulin. The effects were comparable to methadone and control. The expressions of VAMP 2 and synaptotagmin 1 were normalised by the plant and methadone. The extract of E. cuneatum was postulated to treat dependence symptoms after chronic morphine and improve the soluble N ethylmaleimide-sensitive factor activating protein receptor (SNARE) protein involved in synaptic vesicle after. PMID- 27974907 TI - Automatic Approach for Lung Segmentation with Juxta-Pleural Nodules from Thoracic CT Based on Contour Tracing and Correction. AB - This paper presents a fully automatic framework for lung segmentation, in which juxta-pleural nodule problem is brought into strong focus. The proposed scheme consists of three phases: skin boundary detection, rough segmentation of lung contour, and pulmonary parenchyma refinement. Firstly, chest skin boundary is extracted through image aligning, morphology operation, and connective region analysis. Secondly, diagonal-based border tracing is implemented for lung contour segmentation, with maximum cost path algorithm used for separating the left and right lungs. Finally, by arc-based border smoothing and concave-based border correction, the refined pulmonary parenchyma is obtained. The proposed scheme is evaluated on 45 volumes of chest scans, with volume difference (VD) 11.15 +/- 69.63 cm3, volume overlap error (VOE) 3.5057 +/- 1.3719%, average surface distance (ASD) 0.7917 +/- 0.2741 mm, root mean square distance (RMSD) 1.6957 +/- 0.6568 mm, maximum symmetric absolute surface distance (MSD) 21.3430 +/- 8.1743 mm, and average time-cost 2 seconds per image. The preliminary results on accuracy and complexity prove that our scheme is a promising tool for lung segmentation with juxta-pleural nodules. PMID- 27974908 TI - Cushing's disease: a multidisciplinary overview of the clinical features, diagnosis, and treatment. AB - Cushing's disease is considered a rare condition characterized by the hypersecretion of the adrenocorticotropic hormone (ACTH) due to a pituitary adenoma that ultimately causes endogenous hypercortisolism by stimulating the adrenal glands. The clinical signs suggesting Cushing's disease, such as obesity, moon face, hirsutism, and facial plethora are already present on presentation. Endogenous hypercortisolism is associated with an increased risk of cardiovascular and metabolic manifestations, as well as respiratory disorders, psychiatric complications, osteoporosis and infections, leading to high rates of morbidity and mortality. It is vital to diagnose Cushing's disease as early as possible and to implement a treatment plan to lead to a successful prognosis and a low number of complications. The goal of this article was to review the clinical, diagnostic and treatment aspects of Cushing's disease using the most recent available guidelines. PMID- 27974910 TI - Glucose-6-phosphate dehydrogenase deficiency (G6PD) as a risk factor of male neonatal sepsis. AB - Introduction.Neonatal sepsis is a disease process, which represents the systemic response of bacteria entering the bloodstream during the first 28 days of life. The prevalence of sepsis is higher in male infants than in females, but the exact cause is unknown. Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose phosphate pathway, which leads to the production of NADPH. NADPH is required for the respiratory burst reaction in white blood cells (WBCs) to destroy microorganisms. The purpose of this study was to evaluate the prevalence of G6PD deficiency in neonates with sepsis. Materials and methods.This study was performed on 76 neonates with sepsis and 1214 normal neonates from February 2012 to November 2014 in the west of Iran. The G6PD deficiency status was determined by fluorescent spot test. WBCs number and neutrophils percentages were measured and compared in patients with and without G6PD deficiency. Results.The prevalence of the G6PD deficiency in neonates with sepsis was significantly higher compared to the control group (p=0.03). WBCs number and neutrophils percentages in G6PD deficient patients compared with patients without G6PD deficiency were decreased, but were not statistically significant (p=0.77 and p=0.86 respectively). Conclusions.G6PD deficiency is a risk factor of neonatal sepsis and also a justification for more male involvement in this disease. Therefore, newborn screening for this disorder is recommended. PMID- 27974911 TI - The etiopathogenesis of uterine fibromatosis. AB - Uterine fibroids or uterine leiomyomas are the most common benign tumors of the uterus among women of fertile age, while the etiology is still incompletely elucidated. The occurrence and development of the fibromatosis may be related to certain risk factors and genic mechanisms, although the exact causes are not yet fully known. The development of uterine fibroids is correlated not only with the metabolism and with the level of female sexual hormones, estrogen, and progesterone, but also with the number of these hormone receptors expressed on the surface of the myometrium. Proliferative effects of estrogen and progesterone may be exercised through proinflammatory factors (TNF alpha), growth factors (IGF1, IGF2, TGFbeta3 and betaFGF) or inhibitors of apoptosis (p53 suppression). A number of predisposing factors such as ethnicity - black skin, early menarche, nulliparity, caffeine and alcohol, chronic inflammation, obesity, were also identified. Approximately 40% of the uterine fibroids are caused by the same cytogenetic alterations found in the other tumor types such as kidney, lung, or leiomyosarcoma. As part of a system dysfunction, uterine fibromatosis was connected to other disorders such as AHT (arterial hypertension), endometrium adenocarcinoma, adenomyosis, endometriosis, diabetes mellitus, breast tumors, seemingly with a common causality. The action and effect of some hormonal imbalances over the various organs depend on the histological and local expression particularities of the various receptors, being the cause for many disorders, among which the uterine fibromatosis, coexisting or accompanying the later. This article examines and summarizes the latest data refreshed literature etiopathogenesis offering indicators of uterine fibroids. PMID- 27974909 TI - Cutaneous complications of molecular targeted therapy used in oncology. AB - : The new molecular targeted therapy has been developed over the past decades by using the molecular targeted molecular changes discovered in specific types of cancer. Unfortunately, most of these agents (epidermal growth factor receptors, multi-targeted small molecule tyrosine kinase inhibitors, monoclonal antibodies) have severe cutaneous adverse reactions, that not only interfere with the patient's quality of life, but also are dose-limiting and may require treatment interruptions. These cutaneous complications and their management must be very well known by any oncologist and dermatologist who treat oncologic patients. ABBREVIATIONS: EGFR = epidermal growth factor receptors, EGFRI = epidermal growth factor receptors inhibitors. PMID- 27974912 TI - Importance of cystic pedicle dissection in laparoscopic cholecystectomy in order to avoid the common bile duct injuries. AB - The dissection of the cystic pedicle represents the "main" issue in performing the cholecystectomy, as well as the surgical moment when many accidents may happen. The paper analyzes the most frequent causes, which can generate iatrogenic injuries of the common bile duct (CBD) during the dissection of the cystic pedicle, such as the ductal and vascular anatomical variants, the local pathological transformation, human errors, etc. PMID- 27974913 TI - Product policy - the main component of the marketing mix in the Romanian health services. AB - The objectives of the reforms in the EU healthcare systems are based on the implementation of the marketing concept in the health systems, which are, among other things: * efficient management of the financial resources and control costs of the rendered health services; * increased satisfaction of the clients of health care services; * broad accessibility to health services; * effective implementation of modern technologies; * rational stimulation of medical services consumption; * achievement of a fair and neutral competition between the public/ private providers and health insurance companies; * introduction of performance criteria in order to increase the incomes of the medical staff and hierarchy in hospitals; * implementation of modern management methods in health services management; * decentralization of the public healthcare system. Product policy in the medical system of healthcare - the most important component of the marketing mix - is the attitude that addresses a medical organization to the volume, structure, and diversity of services subject to their own activities in relation to the requirements of the services market and the competitive actions of other medical institutions. PMID- 27974914 TI - Modulating the extension of axillary lymphadenectomy for early stage breast cancer. AB - Axillary lymph node evaluation remains essential in breast cancer surgery, first as a prognostic factor, because it indicates the degree of dissemination of the disease to the main lymphatic drainage basin of the breast, and, on the other hand, as an element of preventing the local relapse. In the era of the sentinel lymph node, complete axillary lymphadenectomy, considered valuable until recently, but as therapeutic and diagnostic, has become an intervention performed increasingly rare in selected cases. Axillary lymphatic tissue resections are accompanied by morbidity (lymphedema, paresthesia, limitations of arm movement) and symptom magnitude is proportional to the extension of the intervention. For this reason, a solution to avoid these kinds of complications was looked for. Since Gould, in 1960, who mentioned cancer parotid and continuing with Cabanas, Morton, or Veronesi, many surgeons have contributed to the development of safe techniques with which the multidisciplinary team involved in the surgical treatment for breast cancer could perform a safe oncological intervention and at the same time could conserve the healthy tissue, thus limiting morbidity. To achieve this standard, axillary lymphadenectomy has passed through several stages, from over radical interventions that followed the Halsted era, in which, besides axillary lymph nodes, the internal mammary and jugulo-carotidian lymph nodes were excised, to the absence of axillary surgery and replacing it with radiation therapy. PMID- 27974915 TI - Spatial distribution and the prevalence of speech disorders in the provinces of Iran. AB - The paper reveals the presence of certain factors that generate inefficiency - in the area of government programmes for labor market inclusion of persons with disabilities (PWD) -, as outlined by the specific instruments of the (external) public performance audit. The identified causes are mostly related to the fact that the drawing up of the necessary budgets for projects related to the social and professional integration of persons with disabilities was not based on the local needs and, thus, the available material, financial and human resources have been overlooked. Referring to a period of five years (2006-2010), it was pointed out that the methodologies related to the targeted projects did not mention any clear regulations regarding the criteria that have to be met by the applicants participating in the selection for projects funded from non-refundable resources. Subsequently, certain non-refundable contracts have been assigned to certain executors (NGO types), even though they did not meet the criteria either in terms of eligibility or in terms of the completion of the objectives mentioned in the project proposals, therefore resulting in illegal payments made towards such parties. PMID- 27974916 TI - Dental color assessment through TTB exercises. AB - : Aim.To verify the impact of taking the Toothguide Training Box (TTB) exercise in improving the individual ability to correctly determine dental color. Material and method.A prospective study was conducted on the 5th year dental students. The participants were required to carry out 3 distinct steps: visual color determination for sample tabs out of the 3DMaster shade guide, the TTB exercise and another color determination after training completion. Results.The sample included 60 students (19M/ 41F) with a mean age of 24, which made 360 color determinations of 6 shade tabs before and after TTB exercise. 32,5% (n=117) of the color determinations were incorrect in both moments, and the value was incorrectly determined just in 11% of them. Students found 3L1.5 and 3M2 colors as the hardest to determine. The results suggested that a single TTB training exercise did not have a high positive influence on the individual capacity to correctly determine the color for tabs out of the shade guide. Conclusions.While there is no evidence of an immediate positive impact of the TTB exercise in evaluating and determining different color variations for sample key elements, through repeat exercises, the individual perception can be improved and thus the correct determination of dental color and its correct codification can be increased. ABBREVIATIONS: TTB = Tooth Training Box, CIE = Commission internationale de l'eclairage, L = lightness, C = chroma, H = hue. PMID- 27974917 TI - Paraesophageal hernia repair with bifacial mesh. AB - Background.The paraesophageal hiatus hernias (PHH) are relatively uncommon, but an increased incidence has been reported and they now account for 5-10% of all hiatus hernias. The surgical treatment is recommended for all the patients with this pathology because of high risk of complications: obstruction, incarceration, strangulation or perforation. The use of prostheses is recommended in the process of repairing the giant PHH because the main problem of this operation is the high rate of recurrence. Case presentation.The patient is a 44-year-old male with a large and symptomatic paraesophageal hernia. Diagnosis was confirmed by instrumental examination. An elective laparoscopic repair was carried out by using polypropylene bifacial anti adhesive synthetic mesh (Surgimesh XB Aspide Medical). The postoperative period passed without severe complications. Conclusions.The laparoscopic approach as a therapeutic option can be successfully used in the repair of paraesophageal hernia. A selective use based on clinical experience was recommended, as the technique appeared to be safe, and in case of large hiatus hernia with hiatal defect, greater than 5 cm, the application of synthetic material to minimize the recurrence rate was recommended. PMID- 27974918 TI - Cervical cerclage in advanced prolapsed fetal membranes - Case presentation. AB - The case presentation of a transvaginal cervical cerclage performed at a 7 cm dilation in a patient in the 22nd week of pregnancy, followed by a prolongation of the pregnancy until the gestational age of 38 weeks, was reported in the context of many similar cases managed by the authors of the article during a program of screening and prevention of preterm birth. The particularity of the case was the lack of a preterm birth in the medical history of the patient and the installation of the isthmus-cervix incompetence in the second pregnancy, after an on term pregnancy. What should be evidenced is the importance transvaginal cervical ultrasound evaluation has in the early diagnosis of this pathology during pregnancy, this being the only method of determining the efficacy of the content of the internal cervical os. Transvaginal cervical exploration has to be implemented as a screening method both in the high-risk patients and in the absence of a suggestive medical history. PMID- 27974919 TI - Brief report: Serial capillary lactate measurement predict the evolution of early sepsis. AB - OBJECTIVE: In intensive care settings, blood lactate level measurement proved to be an excellent predictor of outcomes. In patients requiring less urgent treatment, the arterial blood lactate is less sensitive and its usefulness remains to be proven. Capillary blood lactate dosing, an emergent point-of-care technique readily available should be more sensitive to changes in these settings. METHOD: prospective, observational, monocentric study conducted in a polyvalent internal medicine ward in a French University Hospital. The inclusion criteria were the existence of new symptoms of abrupt onset in an otherwise stable patient. All the patients had a point of care measurement of baseline capillary and venous lactate levels (EDGE, ApexBio) and standardized control before any therapeutic means were initiated. A follow-up test was performed once again within 12 to 36 hours. All the patients received standard medical care adapted to their condition. The primary outcomes were considered dying within 30 days or requiring intensive care or invasive therapeutic procedures. RESULTS: 13 patients were analyzed. Seven patients reached the composite outcome with 3 deaths. The superimposed complication proved to be infectious in every case. The median lactate levels were at baseline (mmol/ l): capillary Mc0=5.2(2.16), venous Mv0=2.3(2.0) and arterial Ma0=1.8(1.7) and at follow-up (mmol/ l) capillary: Mc1=3.3(1.1), venous Mv1=1.8(1.8) and arterial Ma1=1.3(0.7). In nonparametric analysis, the absence of normalization of capillary lactate at follow-up was correlated well with poor outcomes (p=.05). This was not the case of arterial or venous lactate measurements. The positive lactate clearance was present in the majority of patients (83.3%) but it did not predict the outcomes (p=.435) and there was no correlation between the baseline lactate and the clinical outcome (p>.05). CONCLUSION: In non intensive care settings, capillary lactate level could be a more sensitive method than the classical lactate measurement for predicting the outcomes of acute conditions, especially infectious. A persistently high lactate level rather than its initial value or clearance seems to correlate better with poorer outcomes. ABBREVIATIONS: SSC = Surviving sepsis campaign, ED = Emergency department, ICU = intensive care unit, , POC = Point of care, ICC = inter class coefficient. PMID- 27974920 TI - Oxidative stress in androgenetic alopecia. AB - : Rationale:Androgenetic alopecia is not considered a life threatening disease but can have serious impacts on the patient's psychosocial life. Genetic, hormonal, and environmental factors are considered responsible for the presence of androgenetic alopecia. Recent literature reports have proved the presence of inflammation and also of oxidative stress at the level of dermal papilla cells of patients with androgenetic alopecia Objective:We have considered of interest to measure the oxidative stress parameters in the blood of patients with androgenetic alopecia Methods and results:27 patients with androgenetic alopecia and 25 age-matched controls were enrolled in the study. Trolox Equivalent Antioxidant Capacity (TEAC), malondialdehyde (MDA) and total thiols levels were measured on plasma samples. Superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) activities, and also non protein thiols levels together with TEAC activity were determined on erythrocytes samples No statistically significant changes were observed for TEAC erythrocytes, non-protein thiols, GPx and CAT activities. Significantly decreased (p<0.01) SOD activity was found in patients with androgenetic alopecia. For plasma samples decreased TEAC activity (p<0.001), increased MDA levels (p<0.001) and no change in total thiols concentration were found in patients when compared with the controls. Discussions:Decreased total antioxidant activity and increased MDA levels found in plasma samples of patients with androgenetic alopecia are indicators of oxidative stress presence in these patients. Significantly decreased SOD activity but no change in catalase, glutathione peroxidase, non protein thiols level and total antioxidant activity in erythrocytes are elements which suggest the presence of a compensatory mechanism for SOD dysfunction in red blood cells of patients with androgenetic alopecia. ABBREVIATIONS: AAG = androgenetic alopecia, MDA = malondialdehyde, SOD = superoxide dismutase, CAT = catalase, GPx = glutathione peroxidase, GSH = glutathione, GST = glutathione transferase, SH = thiols, TEAC = trolox equivalent antioxidant capacity, ABTS = 2,2'-azino-bis (3 ethylbenzothiazoline-6-sulfonic acid), CDNB = 1-chloro-2,4-dinitrobenzene. PMID- 27974921 TI - Post-treatment periapical periodontitis X-ray versus CBCT - a case report. AB - Post treatment periapical periodontitis is usually caused by residual microbes, due to poorly treated root canals and microleakage. Our clinical case proved that orthograde, single-visit endodontic re-treatment is the first choice for the clinician. Cone Beam Computed Tomography (CBCT) images detect the presence and the real extension of the periapical periodontitis and the outcome of the endodontic treatment, in terms of healing the bone defect. Compared with the limited 2-D data obtained by using the radiograph, the CBCT shows a 3-D image of the tooth, the root canal, and the surrounding tissue. PMID- 27974922 TI - Outcome of urinary bladder cancer after combined therapies. AB - Rationale:Urinary bladder cancer is the fourth most common cancer in men and the eighth in women, being an important public health issue. Methods:: Medical files of 155 patients (132M/ 23F) with urinary bladder cancer treated between 2006 and 2012 were retrospectively analyzed. The median age at diagnosis was 65 years (range: 19-85 years). Disease free survival (DFS) for patients with complete tumor resection receiving adjuvant treatment and progression free survival (PFS) for patients with post-operative residual disease was estimated. Results:The distribution of the stage disease was: 50 patients (32.2%) stage II, 47 (30.3%) stage III, 58 (37.4%) stage IV. Radical cystectomy was performed in 56 patients (36.1%), while 99 patients (63.9%) underwent repeated transurethral resection of the urinary bladder tumor (TURBT). Postoperative treatment included multimodal therapy in 47 patients (30.3%) (chemotherapy and external beam radiation), external beam radiation alone in 57 patients (36.8%) and chemotherapy alone (methotrexate, vinblastine, doxorubicin, and cisplatin-MVAC or gemcitabine+platinum) in 51 patients (32.9%). After a median follow-up of 31 months (range: 3-79 months), 51 patients (32.9%) presented local recurrence, 32 patients (21%) distant recurrence (metastases), 10 patients (6.4%) both local and distant recurrence, and 62 patients (40%) were free of disease. The median duration until progression was 27 months. Discussion:Despite the combined therapy approaches, urinary bladder carcinoma remains an aggressive disease, with a high relapse rate. Earlier diagnosis, aggressive radical surgery in intention to cure (cystectomy), and adjuvant multimodal treatment (radiotherapy and chemotherapy) are needed for survival improvement. PMID- 27974924 TI - Academic collaboration for health. PMID- 27974923 TI - Uhthoff's phenomenon 125 years later - what do we know today? AB - 125 years have passed since Wilhelm Uhthoff reported the symptoms he observed after an increased body temperature from physical exertion. Those symptoms, which might have led to the transient impairment of vision in patients with Multiple Sclerosis and also observed in optic neuritis, were later named after him "Uhthoff's phenomenon". This has defined the strategy of rehabilitation procedures in Multiple Sclerosis for more than 100 years, restricting the use of thermal treatments and the possibility of aerobic exercises. The current state of knowledge concerning the Uhthoff's phenomenon and its influence on comprehensive rehabilitation in Multiple Sclerosis were presented in the current review report. PMID- 27974926 TI - Type 2 diabetes mellitus in children and adolescents: a relatively new clinical problem within pediatric practice. AB - Type 2 diabetes mellitus is a complex, chronic metabolic disease, presents a heterogeneous etiology, with risk factors at the social level and behavioral, environmental, and genetic susceptibility. It is associated with serious complications, but the early diagnosis and initiation of therapy may prevent or delay the onset of long-term complications. In children and adolescents, it was observed in particular increasing the prevalence of T2DM along with obesity, which is associated with insulin resistance. Patient and family education for a young person with T2DM is very important and will focus on behavioral changes (diet and activity). PMID- 27974925 TI - New pharmacological strategies in rheumatic diseases. AB - Targeting the pathogenic pathway of chronic inflammation represents an unmet challenge for controlling disease activity, preventing functional disability, and maintaining an adequate quality of life in patients with rheumatic diseases. Abatacept, a novel molecule that inhibits co-stimulation signal, induces an inhibitory effect on the T-cells. This will further interfere with the activity of several cell lines, leading to the normalization of the immune response. In the latest years, abatacept has been extensively investigated in studies of rheumatoid arthritis for which it was recently approved as a second line biologic treatment in Romania. This review presents the clinical efficacy of abatacept in several rheumatic diseases and highlights the safety profile of this biological agent. Abbreviations: ACR = American College of Rheumatology, ADR = Adverse drug reaction, APC = antigen presenting cell, ApS = psoriatic arthritis, CRP = C reactive protein, CTLA-4 = Cytotoxic T-Cell Lymphocyte Antigen-4, DAS = Disease activity score, DMARDs = Disease modifying antirheumatic drugs, EMA = European Medicine Agency, EULAR = European League Against Rheumatism, FDA = Food and Drugs Administration, HBV = Hepatitis B virus, JIA = Juvenile Idiopathic Arthritis, LDA = low disease activity (LDA), MRI = magnetic resonance imaging (MRI), MTX = methotrexate, RA = rheumatoid arthritis, RCT = randomized controlled trial, SS = Sjogren's syndrome, TCR = T cell receptor. PMID- 27974927 TI - Development of new immunotherapy treatments in different cancer types. AB - Cancer immunotherapy involves the use of therapeutic modalities that determine a manipulation of the immune system by using immune agents such as cytokines, vaccines, cell therapies and humoral, transfection agents. Immunotherapy of cancer has to stimulate the host's anti-tumor response by increasing the effector cell number and the production of soluble mediators and decrease the host's suppressor mechanisms by inducing tumor killing environment and by modulating immune checkpoints. Immunotherapy seems to work better in more immunogenic tumors. Making a review of literature, the article presents the new immunologic treatments in cancers less presented in the latest conferences, cancers in which, immunotherapy is still under investigation. Bladder cancer was the first indication for which immunotherapy was used in 1970. A promising clinical research in bladder cancer is the use of immune checkpoint inhibitors. Although breast cancer is considered immunologically silent, several preclinical and clinical studies suggested that immunotherapy has the potential to improve the clinical outcomes for patients with breast cancer. Cervical cancer, brain cancer, head and neck cancer and colorectal and esophageal cancers are cancer types for which new immune-based cancer treatments are currently under development. Recent agents used in clinical trials will be described in before mentioned cancers. PMID- 27974928 TI - Minimally invasive surgery of diabetic foot - review of current techniques. AB - The term diabetic foot is usually used to indicate advanced foot pathology (complex clinical situations correlating diabetic foot ulcers, diabetic foot infections, Charcot foot, and critical limb ischemia). The early recognition of the etiology of these foot lesions is essential for the therapeutic decision in order to achieve a good functional result. Several surgical procedures involving the foot have been developed in order to promote healing and avoid complications. Traditionally, surgery has been performed in an open way. The literature regarding the performance and efficacy of classical osteotomies and arthrodesis is inconsistent. This can be attributed to several variables, such as differences in patient clinical aspects and the panel of surgical techniques utilized. As with other surgical specialties, fluoroscopic imaging and minimally invasive tools are now being incorporated in these procedures. The use of high speed burrs associated with specialized osteosynthesis implants, offers several advantages over classical techniques. The ability to associate these gestures to complex protocols is beginning to be currently developed. The respect for the soft tissues is considered one of the first advantages. Despite the limited time since they were introduced in clinical practice, functional results seemed to be consistent, supporting the use of this technology. PMID- 27974930 TI - Oxidative stress and antioxidant status in patients with complicated urolithiasis. AB - In recent years, intense efforts have been made to clarify the pathogenesis of urolithiasis, which affects more than 10% of the population of developed countries. Currently, a number of studies have assumed a key role in the pathogenesis of oxalate urolithiasis, which is the most common one that belongs to the active forms of oxygen generated in the kidney, as a result of the activation of free radical oxidation that occurs in the interaction of calcium oxalate crystals with renal tubular epithelial cells. In the current work, oxidant and antioxidant status were assessed in the blood of patients with complicated urolithiasis pre - and post surgery. The surgical treatment of complicated urolithiasis leads a decrease of the oxidative stress and an increase in the potential of antiradical and antiperoxidative protection. PMID- 27974929 TI - Crushing injuries of the foot and ankle, with complex open fractures: result of a prospective study with a 3 year follow-up. AB - The objective of this study was to determine the compared results of both the reconstruction surgery and the amputation in severe crushing of the foot, which led to open fractures. The type of study. Prospective. Background. Two major trauma hospitals (Floreasca Clinical Emergency Hospital and "Bagdasar Arseni" Clinical Emergency Hospital) from the university center in Bucharest. Patients. 21 patients, who sustained crushing of the foot with resulting Gustilo type III open fractures, were involved. The exclusion criteria were represented by open fractures that had very gross destructions of the neurovascular bundle, for which the amputation was the only solution, with no modality to reconstruct whatsoever. Treatment. An immediate amputation (at 24, 48 hours after a thorough debridement, proper patient resuscitation, and detailed imaging investigation - the technique of delayed emergency) and reconstruction surgery were performed. Methods of evaluation. Three variables were used: the Sickness Impact Profile (SIP) score, the Visual Analogue Scale (VAS) for the residual pain and the number of rehospitalizations for secondary surgical procedures. Results. When comparing the two lots of patients, first in which the amputation patients were included and second in which the reconstruction patients were included, it was noticed that there was a less favorable prognostic in the second lot for a three-year follow up period. Conclusions. The patients with a mangled foot, in which reconstruction surgery of the bone and soft tissue envelope was performed, had a worse prognostic than those who had an amputation as a first intention. Abbreviations: SIP = Sickness Impact Profile, VAS = Visual Analogue Scale, MVA = Motor Vehicle Accident, STSG = Split Thickness Skin Graft. PMID- 27974931 TI - The benefits of a comprehensive rehabilitation program in patients diagnosed with spastic quadriplegia. AB - Spastic quadriplegia has as an etiopathogenic substrate, a non-progressive brain lesion; however, the clinical manifestations of the disease evolve over time. Children diagnosed with spastic quadriplegia show a variety of symptoms in different areas: sensorimotor, emotional, cognitive, and social. The purpose of this study was to assess the functional status in patients diagnosed with spastic quadriplegia, who followed a complex medical rehabilitation program, during a year, and highlight the importance of using physical and kinetic techniques in improving their status. A total of 10 children diagnosed with spastic quadriplegia were included in the study and the Gross Motor Function Classification System (GMFCS) and manual ability classification system (MACS) were used to evaluate the functionality status of each patient. Every patient was evaluated initially (T1), after six months of program (T2), and after they completed the study. All the children were originally monitored daily, for 5 days per week for a period of one month, then two times a week for a year. A statistically significant difference regarding the modification of the GMFCS and MACS stage was found, which occurred between the first and the third evaluation. The inverse correlation of the statistical significance between the ages of patients and the decrease in GMFCS or MACS stage was highlighted; the younger the patient, the more the scale decreased. A direct link between the gross motor function and the manual ability was noticed. Applying a complex rehabilitation program has proven efficient by improving both the gross motor functionality and the manual ability. PMID- 27974932 TI - Correlations between the semiologic changes and the imaging aspects in the lateral bulbar infarction. AB - The study aimed to evaluate the correlations between the clinical and paraclinical data in the lateral bulbar infarction, benefiting from the access to the semiologic characteristics of a group studied and the MRI angiography, without a contrast agent, through the 3D TOF technique combined with MIP, as an imaging technique for the evaluation of the arterial lesion. The study group included 20 patients with lateral bulbar infarction, 14 men, and 6 women aged between 21 and 80 years, the mean age being 56, 9 years, who were enrolled in the study in the period 2012 and 2014, following the admission in the National Institute of Neurology and Neurovascular Diseases. All the patients enrolled in this stage study, performed brain MRI - in the Medinst laboratory, which included the following sequences T1, T2, Flair, DWI, MRI angiography without contrast agent (3D TOF combined with MIP). The study was retrospective. Following the analysis of the 3D TOF sequences combined with MIP, it was found that in the group studied, 8 patients had damage at the level of the vertebral artery, 2 at the level of the posterior inferior cerebellar artery and 10 patients presented mixed lesions of both the vertebral artery and of the PICA artery. In terms of the mechanism involved, most of the lateral bulbar infarctions were generated by arterial dissection (9 cases) and 6 cases had atheroma as etiology. Regarding the risk factors, dyslipidemia and smoking predominated in the studied group and the most common signs and symptoms were gait abnormalities, the ataxia of the limbs, dysphonia, and Horner syndrome. Abbreviations: 3D TOF = 3D time of flight angiography, MIP = maximum intensity projection, MRI = magnetic resonance imaging, CT = computed tomography, FLAIR = fluid attenuated inversion recovery, DWI = diffusion weighted imaging, HTA = hypertension, DZ II = diabetes mellitus, VA = vertebral artery, PICA = posterior inferior cerebellar artery, VG = vertigo, NT = nystagmus, N/ E = nausea/ emesis, DP = dysphagia, PVP = pharyngeal/ vocal cord paresis, HS = Horner syndrome, PTH = pain/ temperature hypesthesia, LA = ipsilateral limb ataxia, GA = Gait ataxia, C-R-F = Cardiovascular risk factors, L = left, R = right. PMID- 27974933 TI - Effects of caffeine on locomotor activity in streptozotocin-induced diabetic rats. AB - Diabetes mellitus modifies the expression of adenosine receptors in the brain. Caffeine acts as an antagonist of A1 and A2A adenosine receptors and was shown to have a dose-dependent biphasic effect on locomotion in mice. The present study investigated the link between diabetes and locomotor activity in an animal model of streptozotocin-induced diabetes, and the effects of a low-medium dose of caffeine in this relation. The locomotor activity was investigated by using Open Field Test at 6 weeks after diabetes induction and after 2 more weeks of chronic caffeine administration. Diabetes decreased locomotor activity (total distance moved and mobility time). Chronic caffeine exposure impaired the locomotor activity in control rats, but not in diabetic rats. Our data suggested that the medium doses of caffeine might block the A2A receptors, shown to have an increased density in the brain of diabetic rats, and improve or at least maintain the locomotor activity, offering a neuroprotective support in diabetic rats. Abbreviations: STZ = streptozotocin, OFT = Open Field Test. PMID- 27974934 TI - Ultrasound diagnostic of mesonephric paraovarian cyst - case report. AB - Paraovarian cysts are a rare pathology, constituting 10-20% of the adnexal masses. The origin can be represented by paramesonephric ducts (Hydatid cysts of Morgagni), vestiges of mesonephric ducts also represented by mesothelium, or neoplastic (cystadenomas or cystadenofibromas) that are mostly benign. Borderline or malignant paraovarian tumors are encountered less often. This article presents a case of paraovarian cyst in a 37-year-old patient, with a history of 2 pregnancies, completed by cesarean. The patient sought medical attention for an asymptomatic voluminous ovarian cyst, detected in a routine ultrasound scan. Laboratory tests and tumor markers were within normal limits. Transvaginal ultrasound and color Doppler revealed a cystic adnexal mass with 10 cm transonic, smooth, homogeneous content, avascular walls with no internal papillary projections, with a "hyperechoic line" sign of delimitation from the ovarian capsule, mostly visible when the adnexa was mobilized. The diagnostic and curative laparoscopic surgery was successful, followed by a quick recovery. The histopathological exam confirmed the benignity and the origin of the paraovarian cyst. The case was discussed in the context of the literature review concerning this pathology, drawing attention to the real possibility of differentiating ovarian from paraovarian cysts by ultrasound. PMID- 27974935 TI - The time for surgery of peritonitis associated with peritoneal dialysis. AB - Peritonitis is the main complication of peritoneal dialysis (PD) and also an important factor for raising the cost of the method to the level of hemodialysis. Associated with PD, peritonitis is responsible for the increase of morbidity and mortality of the procedure and, at the same time, the main cause of the technique failure. Severe and prolonged peritonitis or repeated episodes of peritonitis lead to ultrafiltration failure. Peritonitis treatment should aim for a rapid remission of inflammation in order to preserve the peritoneal membrane functional integrity. The treatment of PD peritonitis consists mainly of antibiotic therapy, surgical intervention not being usually required. However, it is of outmost importance to differentiate the so-called "catheter related" peritonitis from secondary peritonitis due to visceral lesions, in which the surgical treatment comes first. The confusion between secondary and "catheter related" peritonitis may lead to serious errors in choosing the correct treatment, endangering the patient's life. The differential diagnosis between a refractory or secondary peritonitis in a peritoneal dialyzed patient may be very difficult. In front of a refractory PD peritonitis, surgical exploration must not be delayed. Also we have to keep in mind that the aim of peritonitis treatment is the saving of the peritoneal membrane and not the catheter. PMID- 27974936 TI - Vallecular cysts in clinical practice: report of two cases. AB - The objective of the two case reports was to discuss the pathogenesis, origin, and therapeutic options for vallecular cysts. Method of Study. 2 children diagnosed in our department were treated by transoral endoscopic surgery, using cold instruments, suspension laryngoscopy and the operating microscope. Results. Both cases presented breathing and deglutition problems at diagnosis. The surgery aimed the complete excision, with cold instruments, via transoral access. No complications occurred and the postoperative healing was uneventful. No recurrences were observed on the long-term follow-up. Conclusion. Clinical, imagistic, and surgical data support the thyroglossal duct origin of vallecular cysts (base of tongue variant) and the complete excision is required to obtain long lasting cure. PMID- 27974937 TI - 5 -year complex clinical and histopathological follow-up of a case of early gastric carcinoma (signet ring cells type). AB - The paper presents the case of a male patient, hospitalized for acute abdomen due to perforated callous ulcer. Though the clinical appearance suggested a benign pathology, the histopathological exam of the resection piece showed multicentric early gastric carcinoma, signet ring cell type. At the patient's request, total gastrectomy was not performed, a conservative solution being chosen instead. Superior digestive endoscopy with biopsy and oncological dispensarization was performed one month after surgery, then at every 6 months. After 2 years of benign results, the histopathological exam revealed the presence of malign singlet ring cells in the bioptic specimen. Respecting the patient's option of preserving a good quality of life, subtotal gastrectomy with Pean type gastroenteroanastomosis was performed followed by postoperatory chemotherapy. Endoscopic and oncological follow-up were performed at every six months for another 3 years (up to present), and the evolution was favorable with no local or metastatic recurrence. Histopathological examination was of great help in the surgical management of this case, allowing a fortunate early diagnosis, a conservative surgical approach, and the preserving of a good quality of life. PMID- 27974939 TI - Prenatal ultrasound diagnosis and pregnancy outcome of umbilical cord knot - debate regarding ethical aspects of a series of cases. AB - True umbilical cord knot appears to be a relatively common complication that occurs in 0.3%-1.3% of all pregnancies and it is correlated with an increased incidence of SGA infants, premature birth, need for neonatal intensive care and fetal death. The aim of the article was to evaluate the incidence of the true umbilical cord knot in the University Emergency Hospital, Bucharest, for a period of 5 years and its association with premature birth, low birth weight, low Apgar score at 1 minute and the need for neonatal intensive care. By reviewing the total number of women who delivered in this unit between January 1st 2011 and December 31st 2015, the percentage of the diagnosis antepartum and intrapartum, the outcome of these pregnancies, and the reflection of this condition on the fetal status, were evaluated. During 5 years, 133 (0.71%) of 18.500 deliveries were diagnosed with true umbilical cord knot, only 16 (0.08%) cases were diagnosed by ultrasound antepartum. The mean maternal age was 34.3 years. About 30% of the studied cases (39) presented this condition at the third delivery or more. A personal history for diabetes corresponded to 27 cases (20.3%). From our database, it resulted that only 12 fetuses (10.5%) required neonatal intensive care and presented an Apgar score lower than 7 at 1 minute. Prenatal diagnosis of a true umbilical cord knot is rarely encountered and sonography skills are needed. Complementary methods such as color Doppler and 3D HD Flow are reliable for the diagnostic when true umbilical cord knots are suspected after a 2D scan. Several risk factors can guide the expectancy, such as advanced maternal age, polyhydramnios, multiparty or diabetes. PMID- 27974938 TI - Spontaneous vertebral artery dissection with multiple supratentorial and infratentorial acute infarcts in the posterior circulation Case report. AB - The article represents a case of a young patient with atypical clinical and paraclinical presentation of vertebral artery dissection by multiple cerebral infarcts, localized at the supratentorial and infratentorial levels in the posterior circulation. A case of a 21-year-old man, without a history of trauma in the cervical area or at the cranial level, without recent chiropractic maneuvers or practicing a sport, which required rapid, extreme, rotational movements of the neck, was examined. He presented to the emergency room with nausea, numbness of the left limbs, dysarthria, and incoordination of walking, with multiple objective signs at the neurological examination, which revealed right vertebral artery subacute dissection after the paraclinical investigations. The case was particular due to the atypical debut symptomatology, through the installation of the clinical picture in stages, during 4 hours and by multiple infarcts through the artery-to-artery embolic mechanism in the posterior cerebral territory. Abbreviations: PICA = posterior inferior cerebellar artery, CT = computed tomography, MRI = magnetic resonance imaging, angio MRI = mangnetic resonance angiography, FLAIR = fluid attenuated inversion recovery, FS = fat suppression, ADC = apparent diffusion coefficient, DWI = diffusion weighted imaging, T1/ T2 = T1/ T2 weighted image-basic pulse sequences in MRI, VA = vertebral artery, 3D-TOF = 3D Time of Flight. PMID- 27974940 TI - Orientation to the patient as a marketing strategy in the Romanian healthcare system. AB - In the context of the European political and socio-economic changes of the early 90s, health care reform in Romania has become inevitable, both for patients and for health professionals in the system. The first stage of the health care reform in Romania is focused on decentralization and improving primary health care. The Romanian medical system is currently in the process of changing the mentality, which requires time, patience, and perseverance, despite the unforeseeable or resistance inevitably faced. It is a commonly known and recognized fact that in this painful period of transition, Romanian medicine, like other fields too, has traveled a winding road, with obstacles (medical malpractices, scandals in the press related to the misappropriation of funds or underfunding of the public health system, etc.) often hard to overcome. PMID- 27974941 TI - A modern method of treatment: The role of silver dressings in promoting healing and preventing pathological scarring in patients with burn wounds. AB - Burn wounds are a global public health problem, which affects all countries, no matter the development stage and occurs in all age groups, from toddlers to elderly. In spite of burns being the cause of numerous household and work accidents, there are still no clear stated unanimous rules for their treatment. Every day new products appear on the market, each of them trying to prove more effective. Since ancient times, silver has been known for its antimicrobial properties, so it has been used for a long time in the treatment of burns and other types of wounds. One of the relatively modern methods of treatment is applying silver sheets on the scald lesions. In this paper, which was part of a larger study (research for a PhD thesis), concerning prevention and treatment of the post-burn pathological scars, the cases of some patients with burns, who were treated by using the above mentioned method were presented and analyzed. The results obtained by applying silver sheets were then commented and interpreted, pointing out the advantages and disadvantages compared to silver sulfadiazine creams and ointments, which have already been used at a large scale. The prevention and treatment of post-burn pathological (hypertrophic and keloid) scars is a field in which still little is known and in which there are also no clearly set therapy plans. We hope that through this research and the following ones we will manage to establish some major guidelines concerning the prevention of pathological scars, which are not only disabling, but also a major aesthetic issue for any patient, in order to obtain better outcomes. PMID- 27974942 TI - Osteosynthesis using plates and screws after removing a limited area of the periosteum in order to reduce misclassified during radiological assessment metacarpal shaft fractures. AB - Hand fractures are one of the most common causes for presenting to the emergency room. Metacarpal fractures count about 18 to 44% of all hand fractures, and are most often standalone closed injuries, without misplacement, not needing operative treatment. We present a case in which osteosynthesis with plates and screws was used to reduce two metacarpal fractures in order to allow an early motion recovery, despite the fact that a small portion of the periosteum needed to be removed. The type of fractures were misclassified according to the radiological findings, therefore the correct diagnosis was established during surgery. The results according to the radiological aspects and to the DASH score were excellent with 95% function recovery at twelve months. In this case, the use of osteosynthesis with plates and screws led to a good fracture healing without any major complications. However, there are a series of complications related to this method that should be taken into consideration. Being misled by the radiological aspects of the fractures, the most certain way to classify a metacarpal shaft fracture is through exploratory surgery, even if in most of the cases the three radiological views are enough to establish the diagnosis. Abbreviations: DASH score = Disability of Arm, Shoulder and Hand score, TAM = Total Active Motion, MCP = metacarpal phalangeal joint, PIP = proximal inter phalangeal joint. PMID- 27974945 TI - Upcoming IJTMB Initiatives from the Interim Executive Editor. AB - It is an honor and a privilege to be appointed the Interim Executive Editor for the IJTMB; I am lucky to have some initiatives that were already in development by the previous editorial team that I hope to bring to fruition over the next few months. First, I hope to increase the Journal's Internet presence through social media to expand readership and encourage new submitters. The second initiative is a mentoring program to assist writers with their submissions to the Journal. Finally, I, and the rest of the editorial staff, will continue to evaluate the process, procedures, and forms used in peer review. I hope to move these initiatives forward and by doing so, bring in new readers, submitters, and reviewers to the Journal. PMID- 27974943 TI - Preeclampsia screening from the patient's perspective. AB - Preeclampsia represents an important cause of maternal and fetal morbidity and mortality. The early identification of pregnant women at risk represents a priority in reducing preeclampsia complications. For a better evaluation of the importance of preeclampsia screening, a questionnaire was developed. Methods. The questionnaire based on 14 items was distributed online. The form was anonymously completed. All forms consisted of simple questions. Results. Data from 151 completed forms were collected and analyzed. The analysis revealed the importance of arterial pressure control. 15% of the responders needed hypertensive treatment in pregnancy. They were interested in completing the preeclampsia risk test (88%). Conclusions. The results suggested that preeclampsia screening and measurement of the atrial pressure may become a valuable tool for evaluating and for determining the diagnosis in question, but the possibility of emotional distress for the subjects at risk of developing the condition should be taken in consideration. PMID- 27974946 TI - Meet the New Education and Practice Section Editor. AB - This article serves as an introduction to Grant J. Rich, PhD LMT BCTMB, the new IJTMB Education and Practice Section Editor, and describes his education and experience. PMID- 27974944 TI - Regional Influence of Cannabinoid CB1 Receptors in the Regulation of Ethanol Self Administration by Wistar Rats. AB - Substantial evidence suggests a facilitatory influence of cannabinoid CB1 receptors in the modulation of ethanol consumption by rodents. Studies performed in rats selectively bred for high alcohol preference point to an involvement of CB1 receptors in the nucleus accumbens (NAC), ventral tegmental area (VTA) and medial prefrontal cortex (mPFC) in the modulation ethanol self-administration. However, the neural mechanisms through which CB1 receptors regulate ethanol intake in out-bred Wistar rats have not been investigated. The present study evaluated alterations in ethanol self-administration induced by localized infusions of the CB1 receptor antagonist SR141716A (0, 1 and 3 MUg/side) into the NAC, anterior and posterior VTA and mPFC. Separate groups of Wistar rats were trained to operantly respond for an oral ethanol solution and prepared with bilateral injection cannulae aimed at each brain region. Results revealed significant decreases in ethanol intake following intra-NAC SR141716A administration, consistent with our prior observation of ethanol-induced increases extracellular 2-arachidonoyl glycerol (2-AG) in this brain region. We also observed a significant dose-dependent reduction in ethanol intake following SR141716A administration into the posterior, but not anterior VTA, consistent with evidence of a specific involvement of the posterior VTA in the regulation of ethanol intake. Ethanol consumption was unaltered following intra-mPFC SR141716A administration and ethanol self-administration did not induce robust changes in anandamide or 2-AG levels in mPFC microdialysates. These findings implicate an involvement of CB1 receptors in the NAC and posterior VTA, but not anterior VTA and mPFC in the regulation of ethanol self-administration behavior by outbred Wistar rats. PMID- 27974947 TI - Impact of Massage Therapy on Fatigue, Pain, and Spasticity in People with Multiple Sclerosis: a Pilot Study. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic, immune-mediated, inflammatory disease that leads to fatigue, pain, and spasticity, as well as other sensorimotor and cognitive changes. Often traditional medical approaches are ineffective in alleviating these disruptive symptoms. Although about one-third of surveyed individuals report they use massage therapy (MT) as an adjunct to medical treatment, there is little empirical evidence that MT is effective for symptom management in people with MS. PURPOSE: To measure the effects of MT on fatigue, pain, spasticity, perception of health, and quality of life in people with MS. SETTING: Not-for-profit long-term care facility. PARTICIPANTS: Twenty four of 28 enrolled individuals with MS (average age = 47.38, SD = 13.05; 22 female) completed all MT sessions and outcome assessments. RESEARCH DESIGN: Nonrandomized, pre-post pilot study. INTERVENTION: Standardized MT routine one time a week for six weeks. MAIN OUTCOME MEASURES: Modified Fatigue Index Scale (MFIS), MOS Pain Effects Scale (MOS Pain), and Modified Ashworth Scale (MAS). Secondary outcome measures: Mental Health Inventory (MHI) and Health Status Questionnaire (HSQ). RESULTS: There was a significant improvement in MFIS (p < .01), MOS Pain (p < .01), MHI (p < .01), and HSQ (p < .01), all with a large effect size (ES) (Cohen's d = -0.76, 1.25, 0.93, -1.01, respectively). There was a significant correlation between change scores on the MFIS and the MOS Pain (r = 0.532, p < .01), MHI (r = -0.647, p < .01), and subscales of the HSQ (ranging from r = -0.519, to -0.619, p < .01). CONCLUSIONS: MT as delivered in this study is a safe and beneficial intervention for management of fatigue and pain in people with MS. Decreasing fatigue and pain appears to correlate with improvement in quality of life, which is meaningful for people with MS who have a chronic disease resulting in long-term health care needs. PMID- 27974948 TI - Utilizing Chair Massage to Address One Woman's Health in Rural Ghana West Africa: a Case Report. AB - BACKGROUND AND OBJECTIVES: There is limited access to health care in rural Ghana and virtually no rehabilitative services available. This situation presents a unique opportunity to utilize chair massage in addressing women's health in rural Ghana, particularly when it comes to muscle pain and fatigue from heavy labor. The objective of this case report is to determine the results of chair massage as a strategy to reduce neck, shoulder, and back pain, while increasing range of motion. CASE PRESENTATION: The patient is a 63-year-old Ghanaian female, who was struck by a public transport van while carrying a 30-50 pound load on her head, two years prior. The accident resulted in a broken right humerus and soft tissue pain. A traditional medicine practitioner set the bone, however there was no post accident rehabilitation available. At the time of referral, she presented complaints of shoulder, elbow, and wrist pain. In addition, she was unable to raise her right hand to her mouth for food intake. RESULTS: The results of this case report include an increase in range of motion, as well as elimination of pain in the right shoulder, elbow, and hand. Visual assessments showed an approximate increase of ROM within the ranges of 45-65 degrees in the right arm, as well as 10-15 degrees in 4th and 5th fingers. There was also a decrease in muscle hypertonicity in the thoracic and cervical areas, and a profound increase in quality of life for the patient. DISCUSSION: This case report illustrates how therapeutic chair massage was utilized to address a common health concern for one woman in rural Ghana. It also demonstrates that pre-existing musculoskeletal disorders and pain may be eliminated with massage intervention. Massage therapy may be important to ameliorating certain types of health problems in remote rural villages in low income countries. PMID- 27974949 TI - Partial Oxygen Pressure Affects the Expression of Prognostic Biomarkers HIF-1 Alpha, Ki67, and CK20 in the Microenvironment of Colorectal Cancer Tissue. AB - Hypoxia is prognostically important in colorectal cancer (CRC) therapy. Partial oxygen pressure (pO2) is an important parameter of hypoxia. The correlation between pO2 levels and expression levels of prognostic biomarkers was measured in CRC tissues. Human CRC tissues were collected and pO2 levels were measured by OxyLite. Three methods for tissue fixation were compared, including formalin, Finefix, and Finefix-plus-microwave. Immunohistochemistry (IHC) staining was conducted by using the avidin-biotin complex technique for detecting the antibodies to hypoxia inducible factor-1 (HIF-1) alpha, cytokeratin 20 (CK20), and cell proliferation factor Ki67. The levels of pO2 were negatively associated with the size of CRC tissues. Finefix-plus-microwave fixation has the potential to replace formalin. Additionally, microwave treatment improved Finefix performance in tissue fixation and protein preservation. The percentage of positive cells and gray values of HIF-1 alpha, CK20, and Ki67 were associated with CRC development (P < 0.05). The levels of pO2 were positively related with the gray values of Ki67 and negatively related with the values of HIF-1 alpha and CK20 (P < 0.05). Thus, the levels of microenvironmental pO2 affect the expression of predictive biomarkers HIF-1 alpha, CK20, and Ki67 in the development of CRC tissues. PMID- 27974951 TI - AUTOMATED AGATSTON SCORE COMPUTATION IN A LARGE DATASET OF NON ECG-GATED CHEST COMPUTED TOMOGRAPHY. AB - The Agatston score, computed from ECG-gated computed tomography (CT), is a well established metric of coronary artery disease. It has been recently shown that the Agatston score computed from chest CT (non ECG-gated) studies is highly correlated with the Agatston score computed from cardiac CT scans. In this work we present an automated method to compute the Agatston score from chest CT images. Coronary arteries calcifications (CACs) are defined as voxels contained within the coronary arteries with a value greater or equal to 130 Hounsfield Units (HU). CACs are automatically detected in chest CT studies by locating the heart, generating a region of interest around it, thresholding the image in such region and applying a set of rules to discriminate CACs from calcifications in the main vessels or from metallic implants. We evaluate the methodology in a large cohort of 1500 patients for whom manual reference standard is available. Our results show that the Pearson correlation coefficient between manual and automated Agatston score is rho = 0.86 (p < 0.0001). PMID- 27974952 TI - DERIVATION OF A TEST STATISTIC FOR EMPHYSEMA QUANTIFICATION. AB - Density masking is the de-facto quantitative imaging phenotype for emphysema that is widely used by the clinical community. Density masking defines the burden of emphysema by a fixed threshold, usually between -910 HU and -950 HU, that has been experimentally validated with histology. In this work, we formalized emphysema quantification by means of statistical inference. We show that a non central Gamma is a good approximation for the local distribution of image intensities for normal and emphysema tissue. We then propose a test statistic in terms of the sample mean of a truncated non-central Gamma random variable. Our results show that this approach is well-suited for the detection of emphysema and superior to standard density masking. The statistical method was tested in a dataset of 1337 samples obtained from 9 different scanner models in subjects with COPD. Results showed an increase of 17% when compared to the density masking approach, and an overall accuracy of 94.09%. PMID- 27974950 TI - Evidence of a Redox-Dependent Regulation of Immune Responses to Exercise-Induced Inflammation. AB - We used thiol-based antioxidant supplementation (n-acetylcysteine, NAC) to determine whether immune mobilisation following skeletal muscle microtrauma induced by exercise is redox-sensitive in healthy humans. According to a two trial, double-blind, crossover, repeated measures design, 10 young men received either placebo or NAC (20 mg/kg/day) immediately after a muscle-damaging exercise protocol (300 eccentric contractions) and for eight consecutive days. Blood sampling and performance assessments were performed before exercise, after exercise, and daily throughout recovery. NAC reduced the decline of reduced glutathione in erythrocytes and the increase of plasma protein carbonyls, serum TAC and erythrocyte oxidized glutathione, and TBARS and catalase activity during recovery thereby altering postexercise redox status. The rise of muscle damage and inflammatory markers (muscle strength, creatine kinase activity, CRP, proinflammatory cytokines, and adhesion molecules) was less pronounced in NAC during the first phase of recovery. The rise of leukocyte and neutrophil count was decreased by NAC after exercise. Results on immune cell subpopulations obtained by flow cytometry indicated that NAC ingestion reduced the exercise induced rise of total macrophages, HLA+ macrophages, and 11B+ macrophages and abolished the exercise-induced upregulation of B lymphocytes. Natural killer cells declined only in PLA immediately after exercise. These results indicate that thiol-based antioxidant supplementation blunts immune cell mobilisation in response to exercise-induced inflammation suggesting that leukocyte mobilization may be under redox-dependent regulation. PMID- 27974953 TI - Habitual Sleep Deprivation is Associated with ?Type 2 Diabetes: A Case-Control Study. AB - OBJECTIVES: It is suggested that a minimum of eight hours of sleep per night is needed for metabolism to work normally. The aim of the study was to determine the association of habitual sleep deprivation and type 2 diabetes mellitus (T2DM). METHODS: We conducted a case-control study comparing patients with T2DM with age and sex matched healthy controls. Standard sleep questionnaires (the Berlin and Epworth Sleepiness Scale) and a weekly diary were used by patients to self-report habitual sleep. RESULTS: A total of 172 diabetics and 188 healthy controls were enrolled in the study. There was a significant difference between T2DM and healthy controls in nocturnal sleep duration (p = 0.033). There was a significant association between nocturnal sleep duration of fewer than six hours and T2DM (chi2 = 14.0; p = 0.0001). There was no significant difference in daytime sleepiness and daytime naps between the T2DM and control groups (p = 0.452; p = 0.581, respectively). CONCLUSIONS: A nocturnal sleep duration < 6 hours is associated with T2DM. PMID- 27974954 TI - Is Coasting Valuable in All Patients with Any Cause of Infertility? AB - OBJECTIVES: This study aimed to assess the influence of coasting duration on the number and quality of oocytes and fertilization rate in male factor infertile women and those with polycystic ovary syndrome (PCOS). METHODS: In this prospective observational follow-up study, 114 patients undergoing coasting (53 women with male factor infertility and 61 women with PCOS) were evaluated at the Royan Institute Research Center, Iran, between 2010 and 2012. RESULTS: The results were analyzed according to the coasting periods of 1-4 days. In normal females, the number of oocytes retrieved was significantly reduced after the second day (p = 0.004). In addition, a statistically significant drop was observed in the number of metaphase II oocytes and fertilization rate after the third day (p = 0.006 and p = 0.006, respectively). No significant differences were observed in the number and quality of oocytes retrieved and fertilization rate with regard to coasting days in PCOS patients. CONCLUSION: Coasting with duration of more than three days should be performed with caution in normal females who are at risk of developing ovarian hyperstimulation syndrome. PMID- 27974955 TI - Reproducibility of Manual Platelet Estimation Following Automated Low Platelet Counts. AB - OBJECTIVES: Manual platelet estimation is one of the methods used when automated platelet estimates are very low. However, the reproducibility of manual platelet estimation has not been adequately studied. We sought to assess the reproducibility of manual platelet estimation following automated low platelet counts and to evaluate the impact of the level of experience of the person counting on the reproducibility of manual platelet estimates. METHODS: In this cross-sectional study, peripheral blood films of patients with platelet counts less than 100 * 109/L were retrieved and given to four raters to perform manual platelet estimation independently using a predefined method (average of platelet counts in 10 fields using 100* objective multiplied by 20). Data were analyzed using intraclass correlation coefficient (ICC) as a method of reproducibility assessment. RESULTS: The ICC across the four raters was 0.840, indicating excellent agreement. The median difference of the two most experienced raters was 0 (range: -64 to 78). The level of platelet estimate by the least-experienced rater predicted the disagreement (p = 0.037). When assessing the difference between pairs of raters, there was no significant difference in the ICC (p = 0.420). CONCLUSIONS: The agreement between different raters using manual platelet estimation was excellent. Further confirmation is necessary, with a prospective study using a gold standard method of platelet counts. PMID- 27974956 TI - Correlation of Intraoperative Frozen Section Report and Histopathological Diagnosis of ?Central Nervous System Tumors - A Six-Year Retrospective Study. AB - OBJECTIVES: To evaluate the degree of agreement between the intraoperative frozen section (FS) reporting of central nervous system (CNS) tumors and final histopathological diagnosis based on permanent paraffin section. METHODS: All CNS tumor cases with a diagnosis at FS and subsequent permanent section (n = 261) taken from 2007 to 2012 were retrospectively reviewed. Twenty percent of FS were double-checked by a senior pathologist as part of the study and the intraobserver agreement between the pathologist and the agreement between final report, and initial FS report was estimated by the intraclass correlation coefficient (ICC). RESULTS: A total of 261 cases were reviewed. The most common diagnosis was glioblastoma (grade IV) and meningioma (grade I-II) forming 45.6% of cases. Fifty three cases were subjected to intraobserver agreement of histological diagnosis. There was nearly perfect intraobserver agreement on histopathology (ICC = 0.9). Out of 261 cases, 224 cases showed a strong agreement between the FS diagnosis and final histological diagnosis (ICC = 0.747). A discrepancy between the FS and final diagnosis were found in eight cases. The disagreement did not relate to any specific tumor type. However, in three cases, the discrepancy was in the grading of the glioma. In 29 cases, a definite opinion could not be given on FS as the samples examined were nonrepresentative. CONCLUSIONS: Histopathological slides classified by World Health Organization criteria of CNS tumors had excellent intraobserver agreement. Our results show a moderate to high degree of agreement in the intraoperative diagnosis of CNS lesions using FS. However, there are limitations, and some lesions are a diagnostic challenge. There is a need to improve our diagnostic skills and knowledge of possible errors and establish better communication with neurosurgeons. PMID- 27974957 TI - Prevalence and Covariates of Polypharmacy in Elderly Patients on Discharge from a Tertiary ?Care Hospital in Oman. AB - OBJECTIVES: To evaluate the prevalence of polypharmacy in relation to gender, comorbidity, and age among elderly patients upon discharge from an academic tertiary care hospital in Muscat, Oman. METHODS: This cross-sectional study was conducted at Sultan Qaboos University Hospital between February and July 2014. We reviewed the electronic medical records of elderly patients aged >= 60 years who were admitted to any of the hospital's medical wards during the study period and collected data on age, gender, and diagnoses. We also collected information on the medications prescribed on discharge. Polypharmacy was defined as the concurrent use of >= 5 medications. RESULTS: A total of 431 elderly inpatients were enrolled, of which approximately 50% were female. Polypharmacy was identified in 76.3% of discharge prescriptions. Gender (adjusted odds ratio (aOR), 1.17; 95% CI 0.73, 1.88, p = 0.502) and age (aOR, 0.98; 95% CI 0.95, 1.00, p = 0.075) had no impact on polypharmacy. On the other hand, a significant association between polypharmacy and comorbidity was observed (aOR, 1.31; 95% CI 1.12, 1.54, p = 0.001). Cardiovascular diagnosis on admission was also identified as being associated with polypharmacy (aOR, 2.66; 95% CI 1.49, 4.75, p = 0.001). More patients had cardiovascular diseases on admission (31.0%), followed by infections (23.0%), and gastrointestinal diseases (13.0%). The most commonly prescribed drugs on discharge were cardiovascular drugs (48.0%), followed by drugs acting on the gastrointestinal system (11.0%), endocrine system (9.2%), and nutrition and blood (7.5%). CONCLUSIONS: The prevalence of polypharmacy among elderly medical patients discharged from our hospital was high (76.3%) and was associated with a number of comorbidities and cardiovascular disease as a cause of admission, but not with age or gender. The prevalence of polypharmacy in our institution raises significant concerns over its potential impact on patients' health outcomes and requires further investigation. Raising physicians' awareness of health implications of polypharmacy may help reduce the incidence of medication-related adverse events and improve treatment outcomes. PMID- 27974958 TI - Frequency of Antiseptic Resistance Among Staphylococcus aureus and Coagulase Negative Staphylococci Isolated From a University Hospital in Central Iran. AB - OBJECTIVES: Reduced biocide susceptibility in Staphylococci is associated with various antiseptic resistance genes encoding efflux systems. Our aim was to determine the susceptibility to three disinfectant agents, including benzalkonium chloride (BAC), benzethonium chloride (BZT), and chlorhexidine digluconate (CHDG) among clinical isolates of Staphylococcus aureus and coagulase-negative Staphylococci (CoNS). METHODS: The minimum inhibitory concentration (MIC) of 60 methicillin-resistant S. aureus (MRSA), 54 methicillin-sensitive S. aureus (MSSA) and 51 CoNS isolates from a single hospital to three biocidal agents (BAC, BZT, and CHDG) was determined. Biocide resistance genes (qacA/B, smr, qacG, qacH, qacJ, and norA) were analyzed by the polymerase chain reaction assay. RESULTS: All isolates had MICs for BAC and BZT from 0.25 to 8 ug/mL, and for CHDG from 0.5 to 64 ug/mL. qacA/B was the most common biocide resistance gene among all 165 Staphylococcus isolates (76; 46%), which comprised 38 (63.3%) MRSA, 14 (25.9%) MSSA, and 24 (47%) CoNS. Eleven (6.7%) and 24 (14.5%) isolates among the 165 Staphylococci carried smr and norA genes, respectively. In contrast, other resistance genes such as qacG, qacH, and qacJ were absent in all Staphylococci studied. The qacA/B and smr genes were detected concomitantly in 3% of isolates, and 23.6% strains of the total 165 Staphylococcus isolates were negative for each studied gene. CONCLUSIONS: The carriage of several biocide resistance genes, including qacA/B, smr, and norA, alone or concurrently, is associated with reduced susceptibility. Use of antiseptics may select for antibiotic-resistant strains and assist their survival in the healthcare environment. PMID- 27974959 TI - A 10-Year Retrospective Analysis of 64 Cases of Cystic Lesions of the Oral and Maxillofacial Region in a Nigerian Tertiary Hospital. AB - OBJECTIVES: Orofacial cysts are broadly divided into odontogenic and nonodontogenic types, epithelial or non-epithelial, and developmental or inflammatory in origin. The odontogenic cyst is an osseous-destructive lesion that most commonly affects the jaw. It is formed by activation of odontogenic cell rests entrapped within the bone or gingival tissue of the jaws, such as the epithelial remains of Malassez, the dental lamina (cell rests of Serres), or the enamel organ. METHODS: We performed a retrospective study of all histologically diagnosed cysts of the orofacial region seen at the Maxillofacial clinic of the Ahmadu Bello University Teaching Hospital, Nigeria, between January 2003 and December 2012. RESULTS: Over the 10-year study period, 64 cases of cystic lesions of the orofacial region were seen in 1162 pathological specimens, representing 5.5%. Of these, there were 35 (54.7%) lesions in males and 29 (45.3%) in females giving a M:F ratio of 1.2:1. The age of the patients ranged from 4-64 years old (mean = 26.3 years). Dentigerous cyst (n = 21; 32.8%) was the most predominant lesion followed by periodontal (n = 12; 18.8%) and radicular cysts (n = 10; 15.6%). CONCLUSIONS: Cysts of the orofacial region are common in this environment and like previous studies from Nigeria odontogenic cysts are not uncommon, the most predominant being dentigerous cysts. PMID- 27974961 TI - Pancreatic Tuberculosis with Markedly Elevated CA 19-9 Levels: A Diagnostic Pitfall. AB - Despite the high prevalence of tuberculosis (TB) in developing countries, isolated pancreatic TB is rare and is usually seen in immunocompromised patients. It presents with non-specific signs and symptoms and may mimic malignancy both clinically and radiologically. Cytologic and histologic confirmation is required to establish the definitive diagnosis. We present a case of a 25-year-old male with a pancreatic mass and markedly elevated serum cancer antigen (CA) 19-9 levels raising the suspicion of malignancy but with a histopathologic picture of TB. This case suggests that clinicians should have a heightened suspicion of pancreatic TB when faced with discrete pancreatic lesions even though elevated tumor markers may indicate malignancy. It is important to perform appropriate diagnostic testing and initiate antitubercular therapy early. PMID- 27974962 TI - Hamartoma of Palatine Tonsil: A Rare Case. AB - Hamartomas are disorganized but benign masses composed of cells indigenous to the involved site. They have been reported in almost all organs but are rare in the head and neck region, especially the pharynx. We describe the case of a six-month old male infant who presented with acute respiratory symptoms due to a pedunculated polypoid mass arising from his left palatine tonsil. He underwent a tonsillectomy and removal of the polyp after initial stabilization. Histopathological examination showed features consistent with hamartoma. The child had an uneventful recovery and follow-up after one year showed no evidence of recurrence. Our case highlights that rare benign lesions like hamartoma originating in the oral cavity, even in infants, can have such an acute presentation and should be considered in differential diagnosis. PMID- 27974960 TI - Prevalence and Associated Factors of Genital and Sexually Transmitted Infections in Married Women of Iran. AB - OBJECTIVES: This study aimed to determine the prevalence of genital and sexually transmitted infections and its related factors in married women in Iran. METHODS: We conducted a cross-sectional study of 4 274 married women living in urban and rural areas of the Zanjan province from 2012 to 2013. We used stratified cluster sampling to select the participants. Data collection included demographic characteristics, reproductive status, and cervical cytology results. RESULTS: The prevalence of lower genital infections and sexually transmitted infections were 20.1% and 7.4%, respectively. The most common vaginal infection was bacterial vaginosis with a prevalence of 8.5%, and the most common sexually transmitted infection was Trichomonas vaginalis (1.4%). The use of the intrauterine device (IUD) as a contraceptive, living in an urban area, and experiencing vaginal discharge were significantly related to genital tract and sexually transmitted infections. CONCLUSIONS: There was a high prevalence of genital infection among women living in Zanjab. Screening and treatment of genital infection are necessary to prevent adverse consequences in women who use an IUD or live in urban areas. PMID- 27974963 TI - Bullous Systemic Lupus Erythematosus and Lupus Nephritis in a Young Girl. AB - Bullous systemic lupus erythematosus (BSLE) is an autoimmune blistering disease occurring in patients with systemic lupus erythematosus (SLE). It is a rare disease, especially in children. A 14-year-old girl initially presented with fatigue, generalized vesiculobullous skin lesions, and ulcers over the hard palate and oral mucosa. Clinical investigations revealed hematuria and proteinuria, a high erythrocyte sedimentation rate and titer of antinuclear antibody, and anti-double-stranded DNA. Skin biopsy findings were suggestive of BSLE. A renal biopsy confirmed the features of class V lupus nephritis. Based on the clinical features and investigations, a diagnosis of BSLE with nephritis was made. She received methylprednisolone pulse therapy and hydroxychloroquine; however, it did not alleviate the vesiculobullous eruption, so treatment with dapsone started and resulted in the dramatic disappearance of the lesions. Interruption of dapsone due to hemolysis did not aggravate the bullous disease. During follow-up, she had multiple flare-ups of disease and nephritis without rebound of bullous lesions. BSLE is a rare presentation of SLE in children. Differentiating it from other skin bullous diseases and SLE with blister is important for the correct management. The unusual presentation of this disease may delay the diagnosis and therefore requires a high index of clinical suspicion. PMID- 27974965 TI - A Young Man with Bilateral Testicular Pain and Swelling. PMID- 27974964 TI - Aggressive Angiomyxoma of the Pelvis and Perineum: A Case Report and Literature Review. AB - Aggressive angiomyxoma (AA) is a rare mesenchymal tumor that usually occurs in the pelvis and perineum of young females. AA can simulate Bartholin's gland cyst, abscess, lipoma, simple labial cyst, or other pelvic soft tissue tumors. Cross sectional imaging, particularly magnetic resonance imaging (MRI), plays an essential role in the diagnosis and management of AA. We report a case of AA in a 38-year-old woman with typical MRI features. We also present the findings of a literature review on the radiological features of this disease. PMID- 27974967 TI - Erratum: The reversal phase of the bone-remodeling cycle: cellular prerequisites for coupling resorption and formation. AB - [This corrects the article DOI: 10.1038/bonekey.2014.56.]. PMID- 27974966 TI - Human dignity of patients with cardiovascular disease admitted to hospitals of Kerman, Iran, in 2015. AB - The human dignity of patients with cardiovascular disease (CVD) is an important issue, because of patients' dependence upon caregivers, and because it impacts all aspects of their quality of life (QOL). Therefore, understanding and improving the status of dignity among these patients is of great importance. This study aimed to determine the status of dignity in patients with CVD admitted to cardiac intensive care units (CICUs) in Iran. This cross-sectional descriptive study was performed in 2015 on 200 patients admitted to the CICUs of hospitals affiliated to Kerman University of Medical Sciences, Iran. The participants were selected using random sampling method. Patients' understanding of dignity was assessed through the reliable and valid Persian version of the Patient Dignity Inventory (PDI). Patients who were able to read and write or speak Persian and were conscious were included in the study. Data were analyzed using descriptive statistics tests, independent t-test, and one-way ANOVA in SPSS software. The mean age of the study participants was 59.0 +/- 17.0. The mean score of human dignity was 3.60 +/- 1.39. The mean scores of the factors of loss of independence, emotional distress and uncertainty, changes in ability and mental image, and the loss of human dignity were 3.94 +/- 1.06, 3.63 +/- 1.37, 3.57 +/- 1.20, and 3.30 +/- 2.08, respectively. A significant statistical correlation was observed between human dignity and the demographic characteristics of gender and frequency of hospitalizations in a CICU and a significant difference between those who lived alone and those who lived with family was observed (P < 0.05). Patients hospitalized in CICUs experience numerous problems associated with human dignity in each of its four dimensions. It is recommended that a study be conducted to investigate the relationship between the human dignity of patients with CVD and their QOL, anxiety, and depression. PMID- 27974968 TI - Periosteum mechanobiology and mechanistic insights for regenerative medicine. AB - Periosteum is a smart mechanobiological material that serves as a habitat and delivery vehicle for stem cells as well as biological factors that modulate tissue genesis and healing. Periosteum's remarkable regenerative capacity has been harnessed clinically for over two hundred years. Scientific studies over the past decade have begun to decipher the mechanobiology of periosteum, which has a significant role in its regenerative capacity. This integrative review outlines recent mechanobiological insights that are key to modulating and translating periosteum and its resident stem cells in a regenerative medicine context. PMID- 27974969 TI - A novel technique of needle setting for curvilinear endobronchial ultrasound: Improved efficiency with no cost. AB - BACKGROUND: Standard instructions for biopsy using the convex curvilinear endobronchial ultrasound scope include visualization and adjustment of the sheath housing the biopsy needle before every puncture. In our practice, we pre-set this relationship before inserting the endobronchial ultrasound scope and leave it fixed for every puncture. OBJECTIVE: We postulated that this approach is more efficient than repeated re-adjustment and aimed to show that it would not increase the frequency of endobronchial ultrasound scope damage. METHODS: Retrospective review of every biopsy using the endobronchial ultrasound scope over a 6-year period with documentation of damages and costs. RESULTS: There were 15 scope damages out of 1792 procedures (0.8%). Eight damages were determined to be due to needle damage, one due to patient bite, three due to Williams airway abrasions, and three were camera failures. All damages occurred during the first 5 years of the study. Costs totaled US$138,725, for an average of US$23,120 per year. This rate of damages appears to be similar to or lower than that reported when standard instructions are followed. CONCLUSION: Pre-setting of the biopsy needle when the endobronchial ultrasound scope is used leads to greater efficiency and no increase in scope damages. PMID- 27974970 TI - Dental considerations in anaesthesia. AB - Dental trauma as a result of anaesthesia practice is a relevant issue concerning morbidity and litigation. The investigator aimed to consolidate pertinent information on this issue to aid in the redressal of such an occurrence. A review of this relevant literature alongwith the author's suggestions towards the management of the various kinds of dental trauma sustained as a result of anaesthesia practice is presented. PMID- 27974971 TI - The psychological wellbeing of Iranian journalists: a descriptive study. AB - OBJECTIVE: Iran ranks 173 out of 180 countries on an index of press freedom. The purpose of the study was to assess the psychological wellbeing of Iranian journalists and document the stressors encountered in their work. DESIGN: A secure website was established and participants were given their unique identifying number and password to access the site. SETTING: Newsrooms in Iran and the diaspora. PARTICIPANTS: Responses were received from 114 journalists (76%) of whom 65.8% were living in the diaspora. The mean age was 37.8 years (SD = 7.30) and 57% male. MAIN OUTCOMES MEASURES: Type of stressor and behavioural data: Impact of Event Scale-revised for posttraumatic stress disorder, Beck Depression Inventory-II for depression. RESULTS: Stressors include arrest (41.2%), torture (19.3%), assault (10.5%), intimidation (51.4%) and family threatened (43.1%). Eighty nine (78.1%) journalists had stopped working on a story because of intimidation. Arrest, torture, intimidation and family threatened were associated with more intrusive and arousal PTSD symptoms (p < .01 to .001) and assault and intimidation with more depressive symptoms (p < .05). Almost a third of Iranian journalists regularly used barbiturates, with use correlating with symptoms of intrusion (p < .0001), avoidance (p < .01), arousal (p < .0001) and depression (p < .0001). 46.5% of Iranian journalists were not receiving therapy for their distress. CONCLUSIONS: The findings, the first of their kind, provide data highlighting the extraordinary degree of danger confronted by Iranian journalists, their emotional distress in response to this and their proclivity to self-medicate with barbiturates. PMID- 27974972 TI - Acute Kidney Injury in Diabetes Mellitus. AB - Diabetes mellitus (DM) significantly increases the overall morbidity and mortality, particularly by elevating the cardiovascular risk. The kidneys are severely affected as well, partly as a result of intrarenal athero- and arteriosclerosis but also due to noninflammatory glomerular damage (diabetic nephropathy). DM is the most frequent cause of end-stage renal disease in our society. Acute kidney injury (AKI) remains a clinical and prognostic problem of fundamental importance since incidences have been increased in recent years while mortality has not substantially been improved. As a matter of fact, not many studies particularly addressed the topic "AKI in diabetes mellitus." Aim of this article is to summarize AKI epidemiology and outcomes in DM and current recommendations on blood glucose control in the intensive care unit with regard to the risk for acquiring AKI, and finally several aspects related to postischemic microvasculopathy in AKI of diabetic patients shall be discussed. We intend to deal with this relevant topic, last but not least with regard to increasing incidences and prevalences of both disorders, AKI and DM. PMID- 27974973 TI - Day of Surgery Admission in Total Joint Arthroplasty: Why Are Surgeries Cancelled? An Analysis of 3195 Planned Procedures and 114 Cancellations. AB - Background. Day of surgery admission (DOSA) is becoming standard practice as a means of reducing cost in total joint arthroplasty. Aims. The aim of our study was to audit the use of DOSA in a specialty hospital and identify reasons for cancellation. Methods. A retrospective study of patients presenting for hip or knee arthroplasty between 2008 and 2013 was performed. All patients were assessed at the preoperative assessment clinic (PAC). Results. Of 3195 patients deemed fit for surgery, 114 patients (3.5%) had their surgery cancelled. Ninety-two cancellations (80%) were due to the patient being deemed medically unsuitable for surgery by the anaesthetist. Cardiac disease was the most common reason for cancellation (n = 27), followed by pulmonary disease (n = 22). 77 patients (67.5%) had their operation rescheduled and successfully performed in our institution at a later date. Conclusion. DOSA is associated with a low rate of cancellations on the day of surgery. Patients with cardiorespiratory comorbidities are at greatest risk of cancellation. PMID- 27974974 TI - Musical Electroacupuncture May Be a Better Choice than Electroacupuncture in a Mouse Model of Alzheimer's Disease. AB - Objectives. To compare musical electroacupuncture and electroacupuncture in a mouse model of Alzheimer's disease. Methods. In this study, 7.5-month-old male senescence-accelerated mouse prone 8 (SAMP8) mice were used as an Alzheimer's disease animal model. In the normal control paradigm, 7.5-month-old male SAMR1 mice were used as the blank control group (N group). After 15 days of treatment, using Morris water maze test, micro-PET, and immunohistochemistry, the differences among the musical electroacupuncture (MEA), electroacupuncture (EA), Alzheimer's disease (AD), and normal (N) groups were assessed. Results. The Morris water maze test, micro-PET, and immunohistochemistry revealed that MEA and EA therapies could improve spatial learning and memory ability, glucose metabolism level in the brain, and Abeta amyloid content in the frontal lobe, compared with the AD group (P < 0.05). Moreover, MEA therapy performed better than EA treatment in decreasing amyloid-beta levels in the frontal lobe of mice with AD. Conclusion. MEA therapy may be superior to EA in treating Alzheimer's disease as demonstrated in SAMP8 mice. PMID- 27974975 TI - Novel Use of an Orbital Atherectomy Device for In-Stent Restenosis: Lessons Learned. AB - We present a case of a 67-year-old man with stage III chronic kidney disease, uncontrolled diabetes mellitus, coronary artery disease, and high surgical risk who presented with two episodes of acute coronary syndrome attributed to in-stent restenosis (ISR) associated with heavily calcified lesions. In this case, we were able to improve luminal patency with orbital atherectomy system (OAS); however, withdrawal of the device resulted in a device/stent interaction, causing failure of the device. Given limitations in current evidence and therapies, managing ISR can be a technical and cognitive challenge. Balloon expansion of the affected region often provides unsatisfactory results, possibly related to significant calcium burden. OAS could be an efficacious way of reestablishing luminal patency in ISR lesions, as these lesions are often heavily calcified. PMID- 27974976 TI - Sinus Venosus Atrial Septal Defect Complicated by Eisenmenger Syndrome and the Role of Vasodilator Therapy. AB - Sinus venosus atrial septal defect is a rare congenital, interatrial communication defect at the junction of the right atrium and the vena cava. It accounts for 5-10% of cases of all atrial septal defects. Due to the rare prevalence and anatomical complexity, diagnosing sinus venous atrial septal defects poses clinical challenges which may delay diagnosis and treatment. Advanced cardiac imaging studies are useful tools to diagnose this clinical entity and to delineate the anatomy and any associated communications. Surgical correction of the anomaly is the primary treatment. We discuss a 43-year-old Hispanic female patient who presented with dyspnea and hypoxia following a laparoscopic myomectomy. She had been diagnosed with peripartum cardiomyopathy nine years ago at another hospital. Transesophageal echocardiography and computed tomographic angiography of the chest confirmed a diagnosis of sinus venosus atrial septal defect. She was also found to have pulmonary arterial hypertension and Eisenmenger syndrome. During a hemodynamic study, she responded to vasodilator and she was treated with Ambrisentan and Tadalafil. After six months, her symptoms improved and her pulmonary arterial hypertension decreased. We also observed progressive reversal of the right-to-left shunt. This case illustrates the potential benefit of vasodilator therapy in reversing Eisenmenger physiology, which may lead to surgical repair of the atrial septal defect as the primary treatment. PMID- 27974977 TI - Total CAD/CAM Supported Method for Manufacturing Removable Complete Dentures. AB - The incorporation of computer-aided design/computer-aided manufacturing (CAD/CAM) technology into complete denture fabrication brings about several advantages to the fabrication process, providing better predictability of the desired outcomes and high accuracy of denture fit, mainly because the milling of prepolymerized acrylic resin eliminates the shrinkage of the acrylic base. Also, there is a decrease in the porosity when compared to a conventionally processed denture, and consequently there is a decrease in the retention of Candida albicans on the denture base. The presented workflow for complete denture fabrication presents a totally wax-free manufacturing process, combining rapid prototyping (RP) and rapid milling. With the presented technique, the maxillomandibular relation (MMR) and the ideal setup of the tooth arrangement are developed by using occlusion rims and trial setup made with RP. For the definitive final denture, the denture base and the basal surfaces of the conventional denture teeth were milled according to the individual clinical situation. Posteriorly, the teeth were adapted and bonded into the milled sockets of the milled base. PMID- 27974979 TI - An Endocrine Jaw Lesion: Dentist Perspective in Diagnosis. AB - Brown tumor is a rare nonneoplastic focal giant cell lesion that occurs in hyperparathyroidism patients with a prevalence rate of 0.1% in jaws. We report an extremely rare case of brown tumor in mandible of a 40-year-old female patient that presented as the first clinical manifestation of hyperparathyroidism. Dentist played a pivotal role in the present case by the early diagnosis of lesion and its intervention. PMID- 27974978 TI - Palatal Swelling: A Diagnostic Enigma. AB - Giant cell tumor (GCT) of bone is a giant-cell-rich bony lesion associated with abundant multinucleated osteoclast-type giant cells. It is a primary neoplasm of bone with characteristic clinical, radiological, and pathological features. It is an expansive and lytic lesion without periosteal reaction and prominent peripheral sclerosis. Giant cells are also seen in other diseases like giant cell granuloma of the jaws, traumatic bone cyst, aneurysmal bone cyst, and jaw tumor of hyperparathyroidism. We present a unique case of GCT of palate in a 30-year old female. PMID- 27974980 TI - Differential Impairment of Interferon-gamma Responses in Two Cases of Pulmonary Nontuberculous Mycobacterial Disease. AB - Nontuberculous mycobacteria (NTMs) are weakly virulent intracellular pathogens that are common in food and water supplies. The persistent culture of these organisms in the setting of clinical infection warrants investigation of immune function. In cases of isolated pulmonary NTM (PNTM) disease, underlying immune defects have not been clearly identified. We present two patients with isolated PNTM infection who demonstrated differentially impaired IFN-gamma production across a range of stimuli. These cases show that cellular IFN-gamma responses may be defective in a proportion of patient suffering PNTM disease and that when assessing responses, the stimulant used in the testing is important to delineate defective cell populations. Impaired IFN-gamma responses to IL-12 + BCG seem to be a poor prognostic indicator in PNTM disease and in these cases were not improved by adjuvant IFN-gamma. PMID- 27974981 TI - An Overlapping Case of Miller Fisher Syndrome, Bickerstaff's Encephalitis, and the ASMAN Variant of Guillain-Barre Syndrome. AB - A 56-year-old man presented with a 3-day history of progressive tingling of the hands, unsteadiness, and diplopia. He was initially diagnosed clinically with Miller Fisher Syndrome (MFS) but later developed limb weakness consistent with Guillain-Barre Syndrome (GBS) and subsequently reduced consciousness consistent with Bickerstaff's brainstem encephalitis (BBE). Neurophysiology revealed an axonal motor and sensory neuropathy, in keeping with the Acute Motor and Sensory Axonal Neuropathy (AMSAN) variant of GBS. We believe that our patient had an MFS AMSAN-BBE overlap syndrome. This is supported by his glycolipid antibody profile with high titres of anti-GQ1b IgG antibody and anti-GD1a IgG antibody. Anti-GQ1b antibodies are frequently found in both MFS and BBE and the anti-GD1a antibody is associated with axonal forms of GBS. Overlapping cases of MFS and BBE are well described, and because the same antibody is often found in both conditions, it is thought that they share a common autoimmune mechanism. BBE has also been previously reported in association with GBS lending support that it also lies on the same spectrum. This overlapping case of ASMAN variant of GBS, MFS, and BBE provides further support that these conditions are part of the same spectrum. PMID- 27974982 TI - A Case Report of Aggressive Angiomyxoma in Pregnancy: Do Hormones Play a Role? AB - Aggressive angiomyxoma is a rare, locally invasive tumor that generally affects the perineum and pelvis of reproductive age females. Aggressive angiomyxoma is often misdiagnosed, resulting in the delay of the treatment. Case reports show increased growth of the tumor during pregnancy, thus suggesting a hormonal dependency. We report this rare condition in a 29-year-old primigravid female with a growing mass on the right labium majus at 20 weeks' gestation. The patient also developed a smaller mass on the left labium majus at 37 weeks' gestation. The patient underwent a primary cesarean section with resection of the right labial mass, with a final diagnosis of aggressive angiomyxoma. The lesion on her left labium majus resolved spontaneously postpartum. This case report supports a hormonal involvement in this tumor. PMID- 27974983 TI - Ectropion and Conjunctival Mass in a Patient with Primary Bilateral Conjunctival Amyloidosis. AB - Background. Amyloidosis is a group of disorders characterized by deposition of an extracellular protein, known as amyloid, in an abnormal fibrillar form with highly characteristic histopathologic staining properties. The clinical presentation can vary from a focal, localized lesion where amyloidosis has minor clinical consequences to extensive systemic disease that can involve any organ system of the body. Ocular amyloidosis can occur as a localized lesion or as a part of a systemic disorder. Conjunctival amyloidosis is an uncommon condition that is rarely associated with systemic disease. It may be a manifestation of an immunologic disorder. Case Report. We report the case of a patient with bilateral conjunctival amyloidosis who was referred to us with the suspicion of a malignant conjunctival lesion. Examination of both eyes showed a yellow-pink mass with prominent intrinsic vessels, subconjunctival hemorrhage, and ectropion of the left lower eyelid. Diagnosis of primary localized conjunctival amyloidosis was made based on histopathologic evaluation of incisional biopsy and negative systemic work-up. Conclusion. Ocular amyloidosis is a rare disease that is slowly progressive and has a wide variety of clinical presentations. Consequently, the clinical diagnosis is often overlooked or delayed. Definitive diagnosis is achieved through histopathologic evaluation of biopsy specimen. PMID- 27974984 TI - Technical Innovation Case Report: Ultrasound-Guided Prolotherapy Injection for Insertional Achilles Calcific Tendinosis. AB - We describe the use of ultrasound guidance for hyperosmolar dextrose (prolotherapy) injection of the distal calcaneal tendon specifically just anterior to identified enthesophytes in patients with insertional Achilles calcific tendinosis refractory to conservative treatment. This specific technique has not to our knowledge been described or used in literature previously. PMID- 27974985 TI - Anomalous Origin of the Left Common Carotid Artery from the Main Pulmonary Artery: A Rare Association in an Infant with CHARGE Syndrome. AB - Case Report. Isolated carotid artery originating from the pulmonary trunk is an exceedingly rare anomalous origin of head and neck vessels. We present this finding, along with a persistent embryonic trigeminal artery, in a male infant with multiple cardiac defects and other congenital anomalies associated with CHARGE syndrome. After extensive investigations, cardiac catheterization revealed the anomalous left common carotid artery arising from the cranial aspect of the main pulmonary artery. There was retrograde flow in this vessel, resulting from the lower pulmonary pressure, essentially stealing arterial supply from the left anterior cerebral circulation. The persistent left-sided trigeminal artery provided collateral flow from the posterior circulation to the left internal carotid artery territory, allowing for safe ligation of the anomalous origin of the left common carotid artery, thereby reversing the steal of arterial blood flow into the pulmonary circulation and resulting in a net improvement of cerebral perfusion. Conclusion. The possibility of this vascular anomaly should be considered in all infants with CHARGE syndrome. Surgical repair or ligation should be tailored to the specific patient circumstances, following a careful delineation of all sources of cerebral perfusion. PMID- 27974986 TI - Primary Pulmonary Meningioma Simulating a Pulmonary Metastasis. AB - Primary pulmonary meningiomas represent a rare tumor entity. Few cases have been reported in the English medical literature, and they have almost all been solitary and benign in nature, with the exception of several extremely rare cases. We report herein a case of PPM that raised suspicion of a pulmonary metastatic tumor initially, as it was depicted as a single, round, small, ground glass opacity pulmonary nodule on a chest computed tomography scan, in a 55-year old man with a history of buccal cancer. Increased awareness of the clinical and radiologic characteristics of this rare category can assist a multidisciplinary team to perform adequate management. PMID- 27974987 TI - A Case Report of Acute Diverticulitis in "Pseudodiverticulosis" after Hemorpex System(r) Procedure. AB - Introduction. In the last years many mini-invasive approaches were developed in order to reduce postoperative pain and complication after haemorrhoid surgery: one of these alternatives is represented by Hemorpex System, a relatively young technique that combines transanal dearterialization with mucopexy through a dedicated proctoscope. Case Presentation. A 78-year-old male patient was admitted to the Emergency Department for acute urinary retention and elevated temperature. Hemorpex procedure was performed 4 years before. Clinical, endoscopic, and radiological findings demonstrated the presence of multiple diverticula-like structures fulfilled by purulent fluid and a deep alteration of the normal anatomy of the rectum. He was treated following the standard protocol of acute diverticulitis and full recovery from symptoms was achieved. Discussion. Hemorpex System is a young technique, and nowadays-available studies lack long-term follow up data. Anatomical changes induced by the procedure are consistent and definitive. Our patient luckily demonstrated a prompt response to conservative treatment, but it must be taken into account that, in case of medical treatment failure, surgical approach would be necessary and the actual patient anatomical changes could lead the surgeon to unavoidable threatening maneuvers. PMID- 27974989 TI - Inflammatory Myofibroblastic Tumor of the Bladder: 2 Rare Cases Managed with Laparoscopic Partial Cystectomy. AB - Two cases of inflammatory myofibroblastic tumor (IMT) of the bladder are reported here. Both patients were male and presented with macroscopic hematuria; in the first case terminal hematuria was associated with irritative voiding symptoms. The second case was a smoker with hematuria unresponsive to medical treatment and anemia. Clinical presentation, pathological features, treatment, and prognosis are discussed. Due to rarity of this pathological condition, there are no guidelines concerning treatment and follow-up. We present our follow-up scheme and highlight the use of laparoscopic partial cystectomy as a successful treatment approach. PMID- 27974988 TI - Surgical Management of Giant Genital Condyloma Acuminata by Using Double Keystone Flaps. AB - Condyloma acuminata in the external genitalia (genital warts) is a sexually transmitted disease that is often caused by human papillomavirus (HPV). We report a case of giant genital condyloma acuminata in a 35-year-old male patient with HIV comorbidity treated by wide surgical excision. Excision defect was covered with split thickness skin graft (STSG) and double keystone flaps. There was no complication after surgery. Ten months following surgery, there was no new condyloma lesion and the patient had normal voiding and erectile functions. PMID- 27974990 TI - Pediatric Heart Failure, Lagging, and Sagging of Care in Low Income Settings: A Hospital Based Review of Cases in Ethiopia. AB - Introduction. Causes of acute heart failure in children range from simple myocarditis complicating chest infection to complex structural heart diseases. Objective. To describe patterns, predictors of mortality, and management outcomes of acute heart failure in children. Methods. In retrospective review, between February 2012 and October 2015 at a tertiary center, 106 admitted cases were selected consecutively from discharge records. Data were extracted from patients chart and analyzed using SPSS software package. t-test and statistical significance at P value < 0.05 with 95% CI were used. Result. Acute heart failure accounted for 2.9% of the total pediatric admissions. The age ranged from 2 months up to 14 years with mean age of 8 years. Male to female ratio is 1 : 2.1. Rheumatic heart disease accounted for 53.7%; pneumonia, anemia, infective endocarditis, and recurrence of acute rheumatic fever were the main precipitating causes. Death occurred in 19% of cases. Younger age at presentation, low hemoglobin concentration, and undernutrition were associated with death with P value of 0.00, 0.01, and 0.02, respectively. Conclusions and Recommendation. Pediatric heart failure in our settings is diagnosed mainly in older age groups and mostly precipitated due to preventable causes. Significant mortality is observed in relation to factors that can be preventable in children with underlying structural heart disease. Early suspicion and diagnosis of cases may reduce the observed high mortality. PMID- 27974992 TI - Determination of Metal Impurities in Carbon Nanotubes Sampled Using Surface Wipes. AB - Residual metal impurities in carbon nanotubes (CNTs) provide a means to distinguish CNT from non-CNT sources of elemental carbon in environmental samples. A practical and cost-effective analytical approach is needed to support routine surface monitoring of CNT metal tracers using wipe sampling. Wipe sampling for CNT metal tracers is considered a qualitative indicator of the presence of CNTs, not a quantitative exposure metric. In this study, two digestion approaches (microwave-assisted nitric acid/H2O2 digestion and ultrasonic nitric/HF acid digestion) in conjunction with Inductively Coupled Plasma Mass Spectrometry (ICP-MS) determination were evaluated for their ability to extract metal impurities from CNT particles captured on wipe substrates. Aliquots of different carbon nanotubes (including NIST 2483 single-wall CNT) with and without GhostWipesTM (ASTM E-1792 compliant) were used to compare the performance of the digestion methods. The microwave digestion method accommodated the bulky wipe sample and also eliminated potential ICP-MS signal interferences related to incomplete digestion. Although quantitative recoveries requiring lengthy multistep digestion protocols may be necessary in other applications, the near-total recoveries achieved in the present study for CNT catalyst elements were adequate for identifying surface contamination of CNTs in the workplace using wipe sampling. PMID- 27974991 TI - Increased Blood Pressure Variability Is Associated with Worse Neurologic Outcome in Acute Anterior Circulation Ischemic Stroke. AB - Background. Although research suggests that blood pressure variability (BPV) is detrimental in the weeks to months after acute ischemic stroke, it has not been adequately studied in the acute setting. Methods. We reviewed acute ischemic stroke patients from 2007 to 2014 with anterior circulation stroke. Mean blood pressure and three BPV indices (standard deviation, coefficient of variation, and successive variation) for the intervals 0-24, 0-72, and 0-120 hours after admission were correlated with follow-up modified Rankin Scale (mRS) in ordinal logistic regression models. The correlation between BPV and mRS was further analyzed by terciles of clinically informative stratifications. Results. Two hundred and fifteen patients met inclusion criteria. At all time intervals, increased systolic BPV was associated with higher mRS, but the relationship was not significant for diastolic BPV or mean blood pressure. This association was strongest in patients with proximal stroke parent artery vessel occlusion and lower mean blood pressure. Conclusion. Increased early systolic BPV is associated with worse neurologic outcome after ischemic stroke. This association is strongest in patients with lower mean blood pressure and proximal vessel occlusion, often despite endovascular or thrombolytic therapy. This hypothesis generating dataset suggests potential benefit for interventions aimed at reducing BPV in this patient population. PMID- 27974993 TI - Study on the Effect of the Three-Dimensional Electrode in Degradation of Methylene Blue by Lithium Modified Rectorite. AB - This study presents the electrochemical degradation of methylene blue (MB) wastewater in a synthetic solution using three-dimensional particle electrodes. The novel particle electrodes were fabricated in this work using the lithium modified rectorite (Li-REC). The adsorption property of the fabricated particle electrodes was studied in a series of experiments. The optimum electrochemical operating conditions of plate distance, cell voltage, and concentration of electrolyte were 2 cm, 9 V, and 0.06 mol L-1, respectively. It was also found that microwave irradiation can effectively improve the adsorption property and electrical property of the fabricated electrodes. In addition, the scanning electron microscope (SEM) of the fabricated electrodes was investigated. The experimental results revealed the order of adsorption property and electrical property of the fabricated electrodes. So, fabricated electrodes are not only of low cost and mass produced, but also efficient to achieve decolorization of MB solution. PMID- 27974995 TI - The Ebola Crisis and the Corresponding Public Behavior: A System Dynamics Approach. AB - BACKGROUND: The interaction of several sociocultural and environmental factors during an epidemic crisis leads to behavioral responses that consequently make the crisis control a complex problem. METHODS: The system dynamics approach has been adopted to study the relationships between spread of disease, public attention, situational awareness, and community's response to the Ebola epidemic. RESULTS: In developing different simulation models to capture the trend of death and incidence data from the World Health Organization for the Ebola outbreak, the final model has the best fit to the historical trends. Results demonstrate that the increase of quarantining rate over time due to increase in situational awareness and performing safe burials had a significant impact on the control of epidemic. However, public attention did not play a significant role. CONCLUSION: The best fit to historical data are achieved when behavioral factors specific to West Africa like studying the Situational Awareness and Public Attention are included in the model. However, by ignoring the sociocultural factors, the model is not able to represent the reality; therefore, in the case of any epidemics, it is necessary that all the parties and community members find the most significant behavioral factors that can curb the epidemic. PMID- 27974994 TI - Nitric oxide leads to cytoskeletal reorganization in the retinal pigment epithelium under oxidative stress. AB - Light is a risk factor for various eye diseases, including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). We aim to understand how cytoskeletal proteins in the retinal pigment epithetlium (RPE) respond to oxidative stress, including light and how these responses affect apoptotic signaling. Previously, proteomic analysis revealed that the expression levels of vimentin and serine/threonine protein phosphatase 2A (PP2A) are significantly increased when mice are exposed under continuous light for 7 days compared to a condition of 12 hrs light/dark cycling exposure using retina degeneration 1 (rd1) model. When melatonin is administered to animals while they are exposed to continuous light, the levels of vimentin and PP2A return to a normal level. Vimentin is a substrate of PP2A that directly binds to vimentin and dephosphorylates it. The current study shows that upregulation of PP2Ac (catalytic subunit) phosphorylation negatively correlates with vimentin phosphorylation under stress condition. Stabilization of vimentin appears to be achieved by decreased PP2Ac phosphorylation by nitric oxide induction. We tested our hypothesis that site-specific modifications of PP2Ac may drive cytoskeletal reorganization by vimentin dephosphorylation through nitric oxide signaling. We speculate that nitric oxide determines protein nitration under stress conditions. Our results demonstrate that PP2A and vimentin are modulated by nitric oxide as a key element involved in cytoskeletal signaling. The current study suggests that external stress enhances nitric oxide to regulate PP2Ac and vimentin phosphorylation, thereby stabilizing or destabilizing vimentin. Phosphorylation may result in depolymerization of vimentin, leading to nonfilamentous particle formation. We propose that a stabilized vimentin might act as an anti-apoptotic molecule when cells are under oxidative stress. PMID- 27974996 TI - Performance, Reliability, Usability, and Safety of the ID-Cap System for Ingestion Event Monitoring in Healthy Volunteers: A Pilot Study. AB - Background: Nonadherence to prescribed medications is an important consideration in the clinical management of patients and in clinical research and drug development. The ID-Cap System is a novel technology that provides an objective measure of medication ingestion and enables real-time reporting of verified medication adherence data at the dose level. The ID-Cap System consists of an ingestible microsensor that is embedded in an oral dosage form and, once activated by stomach fluid, communicates digital messages to an external wearable reader to confirm ingestion. Objective: The objective of this exploratory study was to evaluate the performance, reliability, usability, and safety of the ID-Cap System for remote monitoring of 20 ingestion events over four weeks in 20 healthy volunteers. Design: This study was an open-label, single-arm, exploratory study of the ID-Cap System. The study design included the following three phases: 1) screening phase, 2) treatment phase consisting of 20 daily capsule ingestion events over a four-week period, and 3) follow-up phase consisting of a follow-up study visit that included an abdominal X-ray and a follow-up phone call. The initial use of the ID-Cap Reader and ingestion of the first study capsule were directly observed by the investigator during the first study visit. Subsequent study capsule ingestions were completed outside the research facility at the study participant's home or other location of his or her choice with ingestion assessed using the ID-Cap System. Setting: The study was conducted at a single clinical research site in Gainesville, Florida. Participants: Twenty healthy volunteers were enrolled in this four-week pilot study that was conducted between September and November 2014. Measurements: Study measurements included ID-Tag detection indicating capsule ingestion, utilization of the ID-Cap System consistent with instructions for use, adverse event reports, discontinuations of the System during the study, and safety assessments related to excretion of the ID-Tags through abdominal X-ray evaluations. Results: Positive detection accuracy was 100 percent for the 20 directly observed ingestions of study capsules that occurred during the initial study visits. Of the 384 ingestion events that were self-administered by the study participants without direct observation, 371 were accurately detected using the ID-Cap System. Overall adherence to the prescribed study capsules as measured by the ID-Cap System was 97.75 percent (391 detections/400 expected ingestion events). Significant intra-individual and inter individual variability in the timing of self-administered doses was observed in this study. No adverse events were reported, and no study participants discontinued use of the ID-Cap System for any reason during the study. There was no evidence indicating retention of ID-Tags based on abdominal X-ray evaluations. Conclusion: The ID-Cap System enables accurate measurement of medication adherence for oral drug therapy at the dose level. This study supports the clinical validation of the technology and feasibility in using the system for the collection and real-time reporting of medication adherence in the clinical management of patients and in clinical research and drug development. PMID- 27974997 TI - The Depression Inventory Development Workgroup: A Collaborative, Empirically Driven Initiative to Develop a New Assessment Tool for Major Depressive Disorder. AB - The Depression Inventory Development project is an initiative of the International Society for CNS Drug Development whose goal is to develop a comprehensive and psychometrically sound measurement tool to be utilized as a primary endpoint in clinical trials for major depressive disorder. Using an iterative process between field testing and psychometric analysis and drawing upon expertise of international researchers in depression, the Depression Inventory Development team has established an empirically driven and collaborative protocol for the creation of items to assess symptoms in major depressive disorder. Depression-relevant symptom clusters were identified based on expert clinical and patient input. In addition, as an aid for symptom identification and item construction, the psychometric properties of existing clinical scales (assessing depression and related indications) were evaluated using blinded datasets from pharmaceutical antidepressant drug trials. A series of field tests in patients with major depressive disorder provided the team with data to inform the iterative process of scale development. We report here an overview of the Depression Inventory Development initiative, including results of the third iteration of items assessing symptoms related to anhedonia, cognition, fatigue, general malaise, motivation, anxiety, negative thinking, pain and appetite. The strategies adopted from the Depression Inventory Development program, as an empirically driven and collaborative process for scale development, have provided the foundation to develop and validate measurement tools in other therapeutic areas as well. PMID- 27974998 TI - Assessment of Cognitive and Neurologic Recovery in Ischemic Stroke Drug Trials: Results from a Randomized, Double-blind, Placebo-controlled Study. AB - Objective. Ischemic stroke is a serious medical condition with limited therapeutic options. The evaluation of the therapeutic potential of novel pharmacological interventions is carried-out in Phase II trials. The study design, primarily intended to evaluate efficacy and safety, is a balance between utilizing as few patients as possible to minimize safety risk and enrolling sufficient patients to detect unambiguous efficacy signals. We sought to determine whether post-stroke recovery outcomes based on behavioral measures of cognitive and motor impairment yielded additional information beyond that of clinician-based methods. Design. This was a multicenter, multinational, randomized, parallel group, controlled versus placebo, efficacy, and safety study of PF-03049423 for treatment of acute ischemic stroke. Settings and participants. Our study subjects were acute ischemic stroke inpatients. Measurements. Outcome measures were derived from rating scales (Modified Rankin Scale, Barthel Index, and National Institutes of Health Stroke Scale) and behavioral tests (Box and Blocks Test, Hand Grip Strength Test, 10-Meter Walk Test, Repeatable Battery Assessment of Neuropsychological Status Naming and Coding Subtests, Line Cancellation Test, and Recognition Memory Test). Assessments were performed at Days 7, 14, 30, 60, and 90. Post-hoc analyses of correlations among the outcome measures at each measurement time point on a cohort of 137 subjects were conducted. Results. Results support the validity of measures from Box and Blocks Test, Hand Grip Strength Test, 10-Meter Walk Test, and Repeatable Battery Assessment of Neuropsychological Status Coding Subtests to monitor post-stroke recovery in clinical trial settings. Notably, the Recognition Memory Test did not show a correlation with the Modified Rankin Scale, and, in fact, did not show improvement over time. Conclusion. The behavioral measures of cognitive and motor functions included in this study may extend the evaluation of the therapeutic potential of new treatments for stroke recovery. The lack of correlation between Recognition Memory Test and the traditional efficacy endpoints, at least in part due to absence of any improvement in recognition memory, suggests that there may be cognitive elements not detected by the Modified Rankin Scale. This is clinically relevant and memory improvement has potential as an endpoint in future trials aiming to improve certain aspects of cognition. PMID- 27975000 TI - Cariprazine for Schizophrenia and Bipolar Disorder. AB - Schizophrenia and bipolar disorder are associated with significant morbidity and mortality. Although atypical antipsychotics reduce positive and negative symptoms of schizophrenia as well as manic or mixed episodes of bipolar disorder, they are associated with varying degrees of metabolic adverse effects. This necessitates continued development of efficacious yet metabolically favorable treatments. Cariprazine was recently approved to treat adult patients with schizophrenia and manic or mixed episodes. It was well-tolerated and adverse reactions included akathisia, extrapyramidal symptoms, nausea, or constipation. Cariprazine is taken once daily without regard to food. The dose should be adjusted in patients who receive CYP450 inhibitors, and it should not be given to patients with severe hepatic or renal disease. This article reviews mechanisms of action, efficacy, tolerability (including adverse effects), dosing, and contraindications of cariprazine. PMID- 27974999 TI - Eszopiclone-induced Parasomnia with Suicide Attempt: A Case Report. AB - Eszopiclone is a benzodiazepine-like hypnotic that is commonly prescribed to treat insomnia. However, eszopiclone's efficacy has been questionable in several clinical trials, and its pharmacologic profile makes its effects on sleep and behavior difficult to predict. We report a case demonstrating an instance of eszopiclone-induced parasomnia involving paranoia and a suicide attempt in a patient taking eszopiclone. We explore possible biochemical explanations examining the pharmacologic profile of eszopiclone and its potential for drug drug interactions, especially with concomitant administration of monoaminergic medications such as antidepressants. Caution should be exercised when prescribing these medications, and evidence-based treatments for insomnia (e.g., cognitive behavioral therapy, biofeedback, sedating antidepressants) should be considered prior to sedative-hypnotic administration. PMID- 27975001 TI - Consent to Treatment of Minors, Revisited. PMID- 27975002 TI - Delirium or Dementia? PMID- 27975003 TI - Efficacy of Autologous Platelet-rich Plasma Glue in Weight Loss Sequelae Surgery and Breast Reduction: A Prospective Study. AB - BACKGROUND: Seroma and hematoma formations are the most common complications after plastic surgery. The aim of this study was to assess the efficacy of autologous platelet-rich plasma (A-PRP) glue to reduce postoperative wound complications and improve surgical outcomes. METHODS: Fifty-four patients were included in this study. They underwent breast reduction surgery, abdominoplasty, or limb lifting with A-PRP glue application on the entire surface of the subcutaneous tissue at the time of suture. Retrospective data were used for the control group. The primary endpoint was the incidence of postoperative seroma or hematoma. The secondary endpoint was the Patient and Observer Scar Assessment Scale score. RESULTS: Demographics and clinical characteristics were not statistically different between the A-PRP glue group and the control group regarding age, sex ratio, and body mass index. After abdominoplasty, 37.5% of patients (3/8) in the control group experienced seroma and hematoma complications versus 12.5% of patients (2/16) in the A-PRP glue group (P = 0.55 and P = 0.25, respectively). After limb lifting, 50% of patients experienced postoperative complications in the control group versus no patient in the A-PRP glue group (P = 0.03*; * indicates that the P value is significant). After breast reduction, no patient experienced complication in the A-PRP glue group versus 25% of patients in the control group who experienced hematoma (P = 0.04*). The scar quality assessed 12 months after surgery showed no statistical differences between the groups. CONCLUSIONS: A-PRP glue seems effective to prevent seroma formation after limb lifting and hematoma formation after breast reduction. Wound-healing quality did not seem to be improved. PMID- 27975004 TI - Donor-site Morbidity of Medial and Lateral Thigh-based Flaps: A Comparative Study. AB - BACKGROUND: Free and pedicled medial and lateral thigh-based flaps are common reconstructive procedures. However, there have been no comparative studies of morbidity between medial and lateral donor sites. METHODS: We conducted an Enterprise Data Warehouse-based review of all the senior authors' (R.D.G., G.A.D., and M.S.A.) thigh-based free and pedicled flaps. Patient demographic data, donor-site complications, drain duration, and number of postoperative visits were collected and compared. Complications were also compared between fasciocutaneous flaps and muscle or myocutaneous flaps, and skin grafted donor sites. RESULTS: We analyzed 352 flap donor sites, with 155 medial and 197 lateral. Two hundred seventeen (217) flaps were pedicled. Flap types included 127 gracilis, 27 rectus femoris, 134 anterolateral thigh, and 36 vastus lateralis only flaps. There were no significant differences in complications between medial (17.4%) and lateral thigh (21.3%) donor sites, although lateral thigh flaps had a mean of 1 additional postoperative visit. Rates of wound dehiscence/healing issues were significantly higher in both gracilis myocutaneous flaps (25.9%) and flaps requiring a skin grafted donor site (31.2%). Postoperative therapeutic anticoagulation was the only significant risk factor for a donor-site complication. Flap complications resulted in increased drain duration and postoperative office visits. CONCLUSIONS: Donor-site morbidity is similar in both lateral and medial thigh-based flaps. The inclusion of muscle in the flap from either donor site does not seem to increase complications, but the inclusion of a skin paddle with gracilis muscle, or a skin grafted lateral thigh donor site, results in increased wound healing complications. PMID- 27975005 TI - Eight-strand Cross-locked Cruciate Flexor Tendon Repair Using Double-stranded Suture: A Description of the Surgical Technique. AB - This article describes a technique for improved repair of digital flexor tendon laceration. Eight-strand cross-locked cruciate repair using 4-0 caliber double stranded suture is not bulky and has a smooth configuration for tendon gliding. Additionally, it has sufficient strength for early postoperative active motion exercise. PMID- 27975006 TI - Primary Fat Grafting to the Pectoralis Muscle during Latissimus Dorsi Breast Reconstruction. AB - BACKGROUND: Latissimus dorsi flap is one of the best options for immediate and delayed breast reconstruction. However, this technique is limited by the tissue volume provided by the flap. To improve breast volume while reducing complications, fat grafting is now very often used in addition to latissimus dorsi flap. To the best of our knowledge, fat grafting was always performed as a second-line surgery, at least a few months after the flap procedure. We aimed to report our experience with an associated breast reconstruction technique combining musculocutaneous latissimus dorsi flap with intrapectoral lipofilling for totally autologous breast reconstruction. METHODS: Between September 2014 and January 2015, 20 patients underwent this technique for unilateral autologous breast reconstruction (14 delayed and 6 immediate breast reconstructions). A mean harvested fat volume of 278 ml (range: 190-350 ml) and a mean injected fat volume of 228 ml (range: 170-280 ml) were used. RESULTS: None of the patients experienced complications, such as flap necrosis, breast skin necrosis, hematomas, or infection. One of the patients developed a seroma, which was treated with 3 drainage punctions. Only 2 patients underwent delayed fat grafting procedure. CONCLUSION: Totally autologous breast reconstruction combining latissimus dorsi flap and intrapectoral fat grafting in the same procedure is a new technique allowing increased breast volume in a single surgery. PMID- 27975008 TI - Successful Treatment of Pyoderma Gangrenosum after Augmentation Mastopexy Using Vacuum Therapy. AB - BACKGROUND: Pyoderma gangrenosum (PG) is a rare, severe, destructive neutrophilic dermatosis characterized by a progressive, necrotizing process after skin injury. Its cause is still unknown, and diagnosis represents a challenge when ulcers are seen after surgery. Bacterial infection is not found in the wounds. Patients exhibit "pathergy" with the appearance of new lesions after local trauma such as surgical procedures, debridements, and wound care, suggesting altered inflammatory response. The objective of this study was to review the literature and report a case of PG that was satisfactorily treated with vacuum therapy (vacuum-assisted closure [VAC]). CASE REPORT: A 19-year-old healthy patient presented with skin ulceration 4 days after augmentation mastopexy, progressing to extensive necrosis. On the eighth day, she underwent debridement and implant removal. Two days later, the necrotic process was again evident and progressed, resulting in a significant increase in wound size, with each wound reaching 20 * 25 cm. Intense and diffuse neutrophilic exudate and areas of necrosis were present. Systemic corticosteroids and VAC under general anesthesia were initiated 5 days after the second surgery. From the fourth VAC session, some adherence between the mammary gland and pectoral muscles was visible, so deep sutures avoiding the dermis were placed to direct wound closure. CONCLUSIONS: PG is a life-threatening complication with devastating outcomes. Early diagnosis is critical. Although some reported cases needed up to 2 years for wound closure, in this case, VAC therapy allowed the patient to be discharged after only 42 days and permitted wound closure without the need for skin grafts. PMID- 27975007 TI - Embryonic Stem Cell-like Population in Dupuytren's Disease. AB - BACKGROUND: Recent research has identified mesenchymal stem cells (MSCs) within Dupuytren's disease (DD) tissue and they have been proposed to give rise to the myofibroblasts, implicated in the progression of this condition. The aim of this study was to identify and characterize the primitive population that might be upstream of the MSC population, within DD. METHODS: Formalin-fixed paraffin embedded 4-um-thick sections of DD cords and nodules obtained from 6 patients underwent 3,3-diaminobenzidine and immunofluorescent immunohistochemical staining for embryonic stem cell (ESC) markers OCT4, NANOG, SOX2, pSTAT3, and SALL4 and endothelial markers CD34 and ERG. NanoString gene expression analysis was performed to determine the transcriptional activation of these markers. RESULTS: Immunohistochemical staining demonstrated the expression of ESC markers OCT4, NANOG, SOX2, pSTAT3, and SALL4 on the endothelium of the microvessels expressing CD34 and ERG, particularly those surrounding the DD nodules. NanoString analysis confirmed the transcriptional activation of OCT4, NANOG, STAT3, and SALL4, but not SOX2. CONCLUSION: This article demonstrates the novel finding of an ESC-like population expressing ESC markers OCT4, NANOG, SOX2, pSTAT3, and SALL4, localized to the endothelium of the microvessels within DD tissue, suggesting a potential therapeutic target for this condition. PMID- 27975010 TI - Reconstruction of the Ptotic Breast Using Wise Pattern Skin Deepithelialization. AB - Reconstruction of ptotic or large breasts is challenging due to skin redundancy after skin-sparing mastectomy. Skin reduction can be performed with a long horizontal ellipse, but this often flattens the breast and leaves conspicuous scars medially on the chest. Wise pattern skin reduction is an effective technique for shaping, but excision of skin within the Wise pattern can lead to high rates of skin necrosis and implant exposure or infection. This study describes a technique where the Wise pattern skin is preserved, but deepithelialized, allowing apparent reduction of the skin with preservation of the subdermal plexus. This study reviews data for case series of 26 breasts in 15 patients who have undergone this technique with simultaneous prosthetic reconstruction using an expander. PMID- 27975009 TI - Effect of Previous Irradiation on Vascular Thrombosis of Microsurgical Anastomosis: A Preclinical Study in Rats. AB - BACKGROUND: The objective of the present investigation was to compare the effect of neoadjuvant irradiation on the microvascular anastomosis in cervical bundle using an experimental model in rats. METHODS: One hundred forty male Sprague Dawley rats were allocated into 4 groups: group I, control, arterial microanastomosis; group II, control, venous microanastomosis; group III, arterial microanastomosis with previous irradiation (20 Gy); and group IV, venous microanastomosis with previous irradiation (20 Gy). Clinical parameters, technical values of anastomosis, patency, and histopathological parameters were evaluated. RESULTS: Irradiated groups (III and IV) and vein anastomosis groups (II and IV) showed significantly increased technical difficulties. Group IV showed significantly reduced patency rates (7/35) when compared with the control group (0/35). Radiotherapy significantly decreased the patency rates of the vein (7/35) when compared with the artery (1/35). Groups III and IV showed significantly reduced number of endothelial cells and also showed the presence of intimal thickening and adventitial fibrosis as compared with the control group. CONCLUSION: Neoadjuvant radiotherapy reduces the viability of the venous anastomosis in a preclinical rat model with a significant increase in the incidence of vein thrombosis. PMID- 27975011 TI - "Well Digging" Subcraniotomy Strategy with Navigation for Optic Nerve Decompression in Frontoorbital Fibrous Dysplasia: Preliminary Experience. AB - BACKGROUND: During the past decades, surgical intervention has been the primary treatment modality for frontoorbital fibrous dysplasia involving optic nerve. However, controversy has surrounded the role of optic nerve decompression in a number of ways. Herein, we describe 3 patients with frontoorbital fibrous dysplasia involving optic nerve, who underwent a "well digging" subcraniotomy strategy with navigation for intraorbital unit optic nerve decompression. METHODS: From 2013 to 2015, 3 patients with frontoorbital fibrous dysplasia were investigated in a retrospective manner. They underwent unilateral intraorbital optic nerve decompression with the help of "well digging" strategy and navigation. The key procedures comprise preoperative software simulation, frontoorbital subcraniotomy (like digging a well), expanding cone-shaped surgical field, intraorbital unit optic nerve decompression with navigation, correcting frontal-orbital dystopias, and deformities. RESULTS: Both at the immediate postoperative period and during the 3-12 months follow-up, 2 cases showed improvement of visual acuity in the affected eye and 1 case showed no deterioration. Other ocular examinations including eye movement were stable. Subsequent reconstruction yielded a satisfactory cosmetic result. No postoperative complications happened. CONCLUSIONS: In our philosophy, surgical management should be tailored to each patient, which is based on the most possible potential etiology. We consider that the intraorbital optic nerve decompression may be more feasible and safer with the help of "well digging" strategy and navigation, especially for those with exophthalmos, orbital volume decreasing, and nonacute visual loss. PMID- 27975012 TI - The Mirror Effect on Social Media Self-perceived Beauty and Its Implications for Cosmetic Surgery. PMID- 27975013 TI - Free Medial Plantar Flap Connection with a Posterior Tibial Artery Flap in Reconstruction of Fore-Mid Foot Skin Defect. AB - BACKGROUND: Although there are many surgical treatments for covering the skin defect of the fore-mid foot, how to reconstruct the weight-bearing region remains a challenge. The weight-bearing region of the sole needs to withstand the pressure and shearing stresses of walking, so the plantar skin is anatomically different from other skins in the areas of texture, thickness, subcutaneous tissue, etc. Medial plantar flaps that are harvested from the instep region are regarded as the first choice for weight-bearing region reconstruction because of their excellent functional and aesthetic long-term result. However, when facing an extensive skin defect on a weight-bearing area such as a fore-mid foot avulsion, the application of this flap is limited because if we put the flap in a weight-bearing area of the forefoot, the set of vessels will be exposed to outside. METHODS: We suggest 2 connected free flaps (posterior tibial artery flap and medial plantar flap) pedicled with 1 set of vessels. The medial plantar flap was used to cover the skin defect of the weight-bearing area in the forefoot. The dorsal skin defect of the injured foot was covered with a posterior tibial artery flap and supplied the medial plantar flap with the posterior tibial vessel. The midfoot skin defect was repaired by a full-skin grafting. RESULTS: Long-term follow-up results showed that the shape and function of the injured limbs recovered almost entirely. CONCLUSION: This method of connected flaps is suitable for repairing large skin defects of the fore-mid foot. PMID- 27975014 TI - The Nipple-Areola Preserving Mastectomy: The Value of Adding a Delay Procedure. AB - BACKGROUND: Conservative mastectomy procedures, such as the nipple-sparing mastectomy (NSM), present appealing options for patients with small invasive or noninvasive malignancies and those needing prophylactic mastectomies. Despite outstanding postoperative cosmetic results, nipple-areola complex (NAC) and mastectomy skin flap (MSF) survival remains a concern. We present our two-stage nipple-areola preserving (NAP) mastectomy, which aims to decrease the rate of NAC loss and MSF necrosis after conservative mastectomies. MATERIAL AND METHODS: Seventy patients who underwent NSM because of malignant and benign conditions were divided into 2 groups: those who underwent our two-stage NAP mastectomy were matched to the group of mastectomy patients without preservation techniques. Demographic data and postoperative results were retrospectively assessed. RESULTS: The NAP group comprised 45 flaps (24 patients), and the NSM group comprised 75 flaps (46 patients). None were actively smoking. The mean time between the delay of the flap and breast reconstruction was 17.6 days (range, of 10-35 days) in the NAP group. No signs of NAC vascular compromise were observed in the NAP group. Nipple necrosis rates were significantly greater (P = 0.0136) in the NSM group: 9 cases in the NSM group versus none within the NAP group. Two patients within the NAP group required nipple excision at the time of their mastectomies after biopsies performed at the time of the NAC delay were positive for malignancy or atypia. CONCLUSIONS: Vascular delay techniques favor the blood supply of a tissue after a surgical wound, effectively improving the survival of the NAC and MSF after nipple-sparing mastectomies. PMID- 27975015 TI - Implantable Doppler Probes for Postoperatively Monitoring Free Flaps: Efficacy. A Systematic Review and Meta-analysis. AB - BACKGROUND: Although clinical assessment remains the gold standard for monitoring the circulation of free flaps, several adjunct techniques promote timely salvage by detecting circulation compromise early. The objective of this systematic review was to evaluate the efficacy of an implantable Doppler probe for postoperatively monitoring free flaps. MATERIALS AND METHODS: English-language articles evaluating the efficacy of implantable Doppler probes compared with clinical assessment for postoperatively monitoring free flaps were analyzed. The outcome measures were total flap failure rates, salvage rates, sensitivity, false positive rates, and positive likelihood ratios. RESULTS: Of the 504 citations identified, 6 comparative studies were included for meta-analysis. An implantable Doppler probe significantly lowered the flap failure rate (risk ratio: 0.40; 95% confidence interval: 0.21-0.75) and raised the successful salvage rate (risk ratio: 1.73; 95% confidence interval: 1.16-2.59). Pooled sensitivity was higher (1.00 vs 0.98), the positive likelihood ratio was lower (72.16 vs 220.48), and the false-positive rate was higher (0.01 vs 0) in the implantable Doppler probe group than in the clinical assessment group. CONCLUSION: An implantable Doppler probe is significantly more efficacious than clinical assessment for postoperatively monitoring free flaps. PMID- 27975016 TI - Upper Lip Reconstruction after Oncologic Resection by a Sliding Advancement Cheek Flap with Buccal Mucosal Eversion. PMID- 27975017 TI - Endoscopic Adipofascial Radial Forearm Flap Reconstruction of a Clival Defect. AB - Skull base surgical defects present unique challenges to anatomic and functional reconstruction. Fortunately, many endonasal skull base defects are successfully managed with a variety of local and regional reconstructive techniques. However, when prior surgery or radiotherapy eliminates the use of these local and regional reconstructive options, more elaborate free tissue transfer techniques are required. Managing endoscopic skull base defects of the anterior cranial fossa and clivus is further complicated by the limited access afforded for flap inset. The following case report describes durable reconstruction of a clival defect with an endoscopically-tunneled adipofascial radial forearm tissue transfer. The case highlights importance of a multidisciplinary surgical team approach with strong foundations in endonasal skull base and reconstructive surgery to achieve successful reconstruction of complex endonasal defects. PMID- 27975018 TI - Systemic Allergic Reaction to Red Tattoo Ink Requiring Excision. PMID- 27975019 TI - Usefulness of the Clavien-Dindo Classification in Understanding the Limitations and Indications of Larynx-preserving Esophageal Reconstruction. AB - BACKGROUND: The Clavien-Dindo (CD) classification is used to evaluate the severity of surgical complications. However, its usefulness in esophageal reconstruction has not been reported. To address this, this case series study used the CD classification to evaluate the complications after cervical esophageal reconstruction with free jejunum transfer or supercharged pedicled intestinal transfer. METHODS: All consecutive patients who underwent esophageal cancer surgery with larynx-preserving free jejunum or pedicled ileocolic transfer in June 2012-December 2015 were identified. The postoperative complications were classified using the CD classification. RESULTS: In total, 22 patients (20 men and 2 women; mean age, 63.3 years) underwent esophageal cancer reconstruction with larynx-preserving free jejunum transfer (n = 9) and supercharged pedicled intestinal transfer (n = 13). Seven patients underwent prophylactic tracheotomy. Four patients underwent emergent tracheotomy 1 or 5 days after surgery. The most frequent complication was recurrent nerve paralysis (RNP) (n = 8). Of these 8 RNP cases, 6 and 2 were classified as CD I and III complications, respectively. Pneumonia was the next most common complication (n = 7). Of these 7 pneumonia cases, 5 and 2 were classified as CD II and III, respectively. There were 2 cases of intestinal anastomosis leakage (CD II and III). On average, patients were able to start oral alimentation 15.1 (9-35) days after surgery. CONCLUSIONS: Our analysis with the CD classification suggested that vascularized free jejunum transfer or supercharge-drainage pedicled ileocolic transfer prevents postoperative intestinal anastomosis leakage and that prophylactic tracheotomy is especially indicated in cases with significant surgical damage in the cervical region. PMID- 27975020 TI - Divided and Sliding Superficial Temporal Artery Flap for Primary Donor-site Closure. AB - Superficial temporal artery (STA) flaps are often used for reconstruction of hair bearing areas. However, primary closure of the donor site is not easy when the size of the necessary skin island is relatively large. In such cases, skin grafts are needed at the donor site, resulting in baldness. We have solved this issue by applying the divided and sliding flap technique, which was first reported for primary donor-site closure of a latissimus dorsi musculocutaneous flap. We applied this technique to the hair-bearing STA flap, where primary donor-site closure is extremely beneficial for preventing baldness consequent to skin grafting. The STA flap was divided into 3, and creation of large flap was possible. Therefore, we concluded that the divided and sliding STA flap could at least partially solve the donor-site problem. Although further investigation is necessary to validate the maximum possible flap size, this technique may be applicable to at least small defects that are common after skin cancer ablation or trauma. PMID- 27975021 TI - A Novel Technique That Protects the Lips during Orthognathic Surgery. AB - Serious lip injuries can occur during orthognathic surgery. Although an Angle Wider device, which is commonly used during orthognathic surgery, provides some lip protection, it leaves more than half of the lip exposed to surgical instruments. Here, we describe a novel technique to protect the entire upper and lower lips during orthognathic surgery using a minilaparotomy wound edge protector (Lap-Protector). We used this method in 60 patients who have undergone orthognathic surgeries such as sagittal split ramus osteotomy and Le Fort I osteotomy since 2009, and no lip injuries have occurred. Although this technique can be somewhat challenging at first and creates some difficulty in exposing the surgical field on the lateral side, we believe that using a wound edge protector minimizes the risk of lip injury during orthognathic surgery. PMID- 27975022 TI - Topical Negative Pressure on Burns: An Innovative Method for Wound Exudate Collection. AB - Burn wound exudate is an important source of information on the wound-healing process and systemic improvement of burn patients. Identification of biomarkers for the prediagnosis of local or systemic complications in patients will have a great impact on adapting personalized procedures in burn treatment. No efficient exudate collection method exists that offers a direct and continuous collection over time. We developed an innovative system based on the negative pressure wound therapy technique to directly collect exudate from burn wounds over several days after burn. This method did not cause any complication or pain for patients, and positive influence on wound healing was seen. Exudate samples were further used in different projects for studying biochemical profile, trace element content, kinetics of bacterial growth, and cell cytotoxicity. PMID- 27975023 TI - Complication Rates With Human Acellular Dermal Matrices: Retrospective Review of 211 Consecutive Breast Reconstructions. AB - BACKGROUND: Human acellular dermal matrix (HADM) is commonly used to provide coverage and support for breast reconstruction. The primary purpose of this study was to evaluate the complication rates associated with breast reconstruction procedures when performed in conjunction with multiple types of HADM in a consecutive series. METHODS: After receiving institutional review board approval, medical records from a single surgeon were retrospectively reviewed for 126 consecutive patients (170 breasts and 211 procedures) who received a breast reconstruction or revision with implantation of HADM between 2012 and 2014. Patient demographics, surgical technique, and the complication profile of 4 major types of HADM were evaluated by procedure. Complication data were primarily evaluated for infection, seroma formation, necrosis, and other complications requiring additional surgery. RESULTS: The total complication rate was 19.4%. The complication rates were not statistically different between all 4 types of HADM: Alloderm (n = 143); Alloderm RTU (n = 19); FlexHD (n = 18); hMatrix (n = 32) (P > 0.05). Smokers and large-breasted women (>=500 g) had a significantly higher complication rate than the rest of the population (P < 0.01 and P < 0.03, respectively). The complication rates associated with all other patient cohorts analyzed (age, body mass index, comorbid conditions, cancer diagnosis, prepectoral technique) showed no influence on complication rates (P > 0.05). CONCLUSIONS: In characteristically similar cohorts, there was no statistically significant difference in complication rates based on type of HADM; however, certain risk factors and anatomy should be considered before HADM-assisted breast reconstruction. PMID- 27975024 TI - Epidermal Graft Accelerates the Healing of Acute Wound: A Self-controlled Case Report. AB - Wound care represents a significant socioeconomic burden, with over half of chronic wounds taking up to a year to heal. Measures to accelerate wound healing are beneficial to patients and also reduce the cost and burden of wound management. Epidermal grafting (EG) is an emerging option for autologous skin grafting in the outpatient setting to improve wound healing. Although several case series have previously reported good clinical outcome with EG, the healing rate in comparison to conservative wound management is not known. In this report, we compare the weekly healing rate of 2 separate wounds in the same patient, one treated with EG and the other with dressings. The treated wound showed accelerated healing, with the healing rate being the highest at the first 2 weeks after EG. The average healing time of the treated wound was 40% faster compared with the control wound. EG accelerates healing of acute wounds, potentially reducing the healthcare cost and surgical burden. PMID- 27975025 TI - Nasal Reshaping with Hyaluronic Acid: An Alternative or Complement to Surgery. AB - BACKGROUND: Rhinoplasty has traditionally been preferred for correction of nasal defects. Long-term clinical experience with hyaluronic acid (HA) injection as an alternative or complement to rhinoplasty is presented. METHODS: A retrospective review of the author's clinical experience with HA gel for nasal reshaping from 1997 to 2012 was conducted, with treatments performed during 1998, 2005, and 2012 selected for detailed review. RESULTS: More than 250 patients were treated for nasal reshaping with HA since 1997. In addition to being a complement to surgery, HA injection successfully addressed nasal defects that would have been difficult to correct surgically. The effect persisted for >1 year in most patients (>5 y in some patients), with individual variations. No serious complications occurred. When comparing the 3 years reviewed in detail, new indications for nasal reshaping with HA gel became evident over time, which was also reflected by the increase in number of patients treated (1998: n = 2; 2005: n = 22; 2012: n = 51). Of these patients, 55 (73%) received HA injection instead of rhinoplasty, 20 (27%) received HA injection after rhinoplasty, and 5 (7%) underwent rhinoplasty after HA injection. The mean injection volume was 0.4 mL HA gel/treatment. All patients were satisfied with the primary outcome of treatment. Retreatment was performed in 32 patients (43%). CONCLUSIONS: Injection of HA gel is a valuable tool for nasal reshaping. It can also be used for correction of minor postrhinoplasty defects in appropriate patients. PMID- 27975026 TI - Combined Use of an Anterolateral Thigh Flap and Superficial Inferior Epigastric Artery Flap for Reconstruction of an Extensive Abdominal Wall Defect. AB - Reconstruction of large abdominal wall defects is challenging. We herein report the successful reconstruction of an extensive abdominal wall defect using a novel combination of flaps after sarcoma resection. A 74-year-old man presented with a dedifferentiated liposarcoma on his abdominal wall. He underwent excision of the tumor, which resulted in an extensive abdominal wall defect. The defect was reconstructed with a pedicled anterolateral thigh flap with an iliotibial tract and a pedicled superficial inferior epigastric artery flap. No skin graft was necessary. The wounds healed successfully, and no herniation occurred. The combination of an anterolateral thigh flap and a superficial inferior epigastric artery flap is a versatile option for reconstruction of extensive abdominal wall defects. PMID- 27975028 TI - The Unilateral Cleft Lip Repair and Primary Cleft Rhinoplasty. AB - Supplemental Digital Content is available in the text. PMID- 27975027 TI - Use of Platelet-rich Plasma for Vulvovaginal Autoimmune Conditions Like Lichen Sclerosus. AB - BACKGROUND: Lichen sclerosus (LS) is an inflammatory dermatosis with autoimmune pathogenesis. Although relatively common, its true incidence is unknown and likely underestimated. LS is usually anogenital, but in around 10% of patients, it can present as extragenital lesions. Continuous administration of topical corticosteroids is the mainstay of medical treatment. Other treatments are available but are only occasionally prescribed along with or instead of topical steroids. Injection of platelet-rich plasma (PRP) into affected areas has been reported to result in the regeneration of normal skin. In this study, we aimed to evaluate the safety, symptom resolution, and objective improvement in patients with autoimmune condition like genital LS after treatment with PRP. METHODS: Over a 2-year period at FBW Gynaecology Plus, we had a total of 28 patients with confirmed LS on biopsy, unresponsive to topical steroid treatment. After acquiring informed consent, patients' own blood was centrifuged on site and injected under local anesthesia to the external genitalia. RESULTS: Almost all of our patients showed clinical improvement in the size of their lesions, and in 8 cases, lesions totally disappeared after treatment with PRP. Symptoms disappeared in 15 of the 28 patients after treatment, with no need for further steroid therapy in 23 patients. Thirteen women experienced partial symptom relief. CONCLUSIONS: Based on our limited findings, we hypothesize that PRP presents a potential alternative to topical steroids for treatment of vulvovaginal autoimmune conditions such as LS. A larger pilot and/or randomized controlled trial study is required to evaluate this finding further. PMID- 27975030 TI - Reconstruction after Excision of Hidradenitis Suppurativa: Are Skin Grafts Better than Flaps? AB - After surgical excision of hidradenitis suppurativa, reconstruction with a skin graft or a flap is performed when primary closure is not possible. However, the recurrence rate is reportedly high even after wide surgical excision. It is still unclear which reconstruction method provides the lowest recurrence rate. In this report, we present a case of intractable hidradenitis suppurativa in the bilateral perineal region. After wide excision and repair with bilateral groin flaps, a unilateral groin flap was replaced with a split-thickness skin graft because of flap necrosis. Although the skin graft repair region has been recurrence free for 4 years postoperatively, other regions with flap repair showed recurrence 1 year postoperatively, leading to reexcision and repair with a split-thickness skin graft. The current case provides an opportunity to reconsider the optimal surgical strategy for hidradenitis suppurativa. Taking into consideration the fact that hair follicles and sweat glands are involved in the etiology of hidradenitis suppurativa, split-thickness skin grafting, which lack cutaneous appendages, may be superior to flap repair or primary closure in terms of recurrence. PMID- 27975029 TI - Barriers to Reconstructive Hand Surgery for Rheumatoid Arthritis in China: A Multicenter Survey of Patients and Physicians. AB - BACKGROUND: China has a similar rheumatoid arthritis (RA) disease burden compared with other countries, yet RA patients rarely receive surgical treatment for hand deformities that limit function and impact appearance. We investigated potential barriers to rheumatoid hand surgery in China. METHODS: Patients with RA, rheumatologists, and hand surgeons at 3 large tertiary hospitals in Beijing completed questionnaires that assess knowledge and attitudes surrounding RA hand surgery. We calculated descriptive statistics and compared responses among groups using chi-square and Fisher exact tests as appropriate. RESULTS: One hundred RA patients with hand deformities and 94 physicians completed the surveys. No patients had received hand surgery, and just 13% were aware of this treatment option. Patients and physicians most frequently cited uncertain effectiveness of surgery, high cost, and risk of surgical complications as potential barriers to hand reconstruction. Rheumatologists reported low rates of referral to hand surgeons (39% referred <5% of the time and 31% never referred). Most hand surgeons (69%) had not performed metacarpophalangeal arthroplasty, a common procedure for RA hand deformities, within the past year. Some had never performed this operation. CONCLUSIONS: This survey revealed multiple barriers that support previous observations of infrequent reconstruction of RA hand deformities in China. These obstacles can be addressed through patient education, coordination between specialists, and more robust hand surgeon training in common RA procedures through the application of international plastic surgery collaborations. PMID- 27975031 TI - Median Nerve Trifurcation. AB - Median nerve trifurcation in the carpal tunnel has only rarely been described and never reported to be found at surgery. We present the first such case, highlighting a median nerve trifurcation found at carpal tunnel release. Consideration of amendment of the Lanz classification should be made to account for such cases, and surgeons should be aware of possible anatomical variations to avoid iatrogenic injury. PMID- 27975032 TI - Flexor Tendon Repair Postoperative Rehabilitation: The Saint John Protocol. AB - The Saint John Protocol describes a rehabilitation program of up to half a fist of protected true active finger flexion beginning 3 to 5 days after flexor tendon repair. We no longer use full fist place and hold. We illustrate with film and text the reasons for these changes. PMID- 27975035 TI - Patient in the Sitting Position to Improve Comfort in Follicular Unit Extraction. PMID- 27975034 TI - Subcutaneous Implant-based Breast Reconstruction with Acellular Dermal Matrix/Mesh: A Systematic Review. AB - BACKGROUND: The availability of acellular dermal matrix (ADM) and synthetic mesh products has prompted plastic surgeons to revisit subcutaneous implant-based breast reconstruction. The literature is limited, however, with regards to evidence on patient selection, techniques, and outcomes. METHODS: A systematic review of the Medline and Cochrane databases was performed for original studies reporting breast reconstruction with ADM or mesh, and subcutaneous implant placement. Studies were analyzed for level of evidence, inclusion/exclusion criteria for subcutaneous reconstruction, reconstruction characteristics, and outcomes. RESULTS: Six studies (186 reconstructions) were identified for review. The majority of studies (66.7%) were level IV evidence case series. Eighty percent of studies had contraindications for subcutaneous reconstruction, most commonly preoperative radiation, high body mass index, and active smoking. Forty percent of studies commenting on patient selection assessed mastectomy flap perfusion for subcutaneous reconstruction. Forty-five percent of reconstructions were direct-to-implant, 33.3% 2-stage, and 21.5% single-stage adjustable implant, with ADM utilized in 60.2% of reconstructions versus mesh. Pooled complication rates included: major infection 1.2%, seroma 2.9%, hematoma 2.3%, full nipple areola complex necrosis 1.1%, partial nipple-areola complex necrosis 4.5%, major flap necrosis 1.8%, wound healing complication 2.3%, explantation 4.1%, and grade III/IV capsular contracture 1.2%. CONCLUSIONS: Pooled short-term complication rates in subcutaneous alloplastic breast reconstruction with ADM or mesh are low in preliminary studies with selective patient populations, though techniques and outcomes are variable across studies. Larger comparative studies and better defined selection criteria and outcomes reporting are needed to develop appropriate indications for performing subcutaneous implant-based reconstruction. PMID- 27975033 TI - Examination of Epithelial Mesenchymal Transition in Keloid Tissues and Possibility of Keloid Therapy Target. AB - BACKGROUND: Keloid is a fibroproliferative skin disorder that is characterized by collagen accumulation and blood vessel proliferation in the reticular layer of the dermis. It is caused by prolonged inflammation after cutaneous injury. Several studies suggested recently that epithelial mesenchymal transition (EMT) is involved in the development of fibrosis. This study assessed whether EMT also participates in keloid development and/or aggravation. METHODS: Resected keloid (n = 19) and normal skin (n = 13) samples were subjected to immunohistochemical, immunofluorescent, and Western blot analyses of their expression of epidermal (E cadherin) and mesenchymal (vimentin) proteins. RESULTS: Immunohistochemical analysis showed that the keloid tissues had more vimentin-positive cells in the epidermis than the normal tissues. When normal primary keratinocytes were cultured with proinflammatory cytokines, the cobblestone-shaped cells changed to a spindle shape and many vimentin-positive cells were detected. When immortalized HaCaT keratinocytes were cocultured in split-well plates with normal or keloid derived fibroblasts, they also underwent EMT, as indicated by their greater vimentin expression on Western blot analysis compared with HaCaT cells that were cultured alone. CONCLUSIONS: EMT was observed in keloid specimens. EMT was induced by inflammatory cytokines and fibroblasts. EMT may be involved in keloid generation and/or aggravation and may have potential as a keloid treatment target. PMID- 27975036 TI - Breast Desmoid Tumor after Ductal Carcinoma Treatment: Salvaging a DIEP Flap Reconstruction. AB - Supplemental Digital Content is available in the text. PMID- 27975037 TI - Abdominal Wall Reconstruction Using Retrorectus Self-adhering Mesh: A Novel Approach. AB - BACKGROUND: In abdominal wall reconstruction, the retrorectus plane offers an ideal location for mesh placement. Mesh fixation in this plane is often achieved using transfascial sutures, which risks entrapping intercostal nerves and causing significant pain, and takes time to place. A novel alternative is the use of sutureless self-adhering mesh. Although the use of this mesh in inguinal hernias has been well described, studies on its use in abdominal wall reconstruction are lacking. METHODS: Consecutive patients who underwent ventral hernia repair with retrorectus mesh were reviewed. This included patients who received transfascially sutured mesh and those who received sutureless self-adhering mesh. All patients were followed up for at least 12 months. The amount of narcotics required by each patient postoperatively was calculated. Surgical-site occurrences (SSOs) and hernia recurrence and bulge were measured. RESULTS: Twenty six patients underwent abdominal wall reconstruction with retrorectus mesh. This included 12 patients with transfascially sutured mesh and 14 patients with self adhering mesh. Mean follow-up was 600 days. Baseline characteristics were similar between the 2 groups. Patients receiving self-adhering mesh required significantly less narcotics than patients with transfascially sutured mesh. There were no significant differences in the rate of SSOs between the 2 groups. No hernia recurrences, bulges, or chronic pain occurred in either group. CONCLUSIONS: This is the first study to compare the outcomes of retrorectus self adhering mesh and transfascially sutured mesh in abdominal wall reconstruction. Our results show low rates of SSO, recurrence, and bulge with both options, with significantly less acute pain with self-adhering mesh. PMID- 27975038 TI - New B-cell Lymphomas in the Setting of a Previous Rare Breast Implant-Associated B-cell Lymphoma. AB - We present a follow-up of a patient who underwent right-sided subtotal mastectomy and placement of right-sided saline implant in 1968 for a phyllodes tumor and then in 2012 was diagnosed with a rare B-cell type lymphoma of the right breast. In 2015, she was diagnosed with diffuse large B-cell lymphoma involvement of the left breast and left leg and experienced subsequent self-regression of leg lesions without therapy. PMID- 27975039 TI - Tumescent Technique in Vascularized Composite Allotransplantation Secondary Surgery. PMID- 27975040 TI - Determining Length and Position of Pedicle Vessels Using a Flap Model with Vascular Tape. AB - In free-flap surgery, if the appropriate length of the pedicle and the distance necessary for separation of the artery and vein are determined earlier during flap elevation, the operative time and the stress placed on the flap pedicle can be reduced. However, the pedicle of a flap passes through 3-dimensional structures, particularly in head and neck reconstructions, and because of the difference in body shapes between individuals, even experienced microsurgeons may misjudge the required distance. To date, no easy method to counteract this problem has been reported. Accordingly, we have developed a technique for estimating the required pedicle length necessary for safe vascular anastomosis, as well as the distance necessary for separation of the artery and vein, by using a flap model with vascular tapes. Between June 2014 and April 2016, we applied our technique to 12 patients undergoing head and neck reconstruction and 1 patient undergoing breast reconstruction. In the 13 cases in which the present technique was used, we could estimate the length of each pedicle smoothly and efficiently. Furthermore, considerable excess or deficiency did not occur in the vascular anastomosis. The present technique is recommended as it allows the effective tailoring of the flap pedicle in free-flap surgery. PMID- 27975041 TI - Insufficient fibrinogen response following free flap surgery is associated with bleeding complications. AB - Background: Microvascular tissue transfer has become a safe and reliable tool in the reconstructive armamentarium, yielding high success rates. However, little is known about the changes in coagulation after free tissue transfer and their potential impact on morbidity. Methods: Fibrinogen concentration and platelet count among other values were available and assessed in 139 undergoing free tissue transfer before, immediately after, and 1-3 as well as 8-11 days after surgery. In patients undergoing urgent revision for either bleeding or microvascular thrombosis, blood samples were drawn directly before re exploration. Results: In the patients without any surgical revision and in those with thrombosis of the microvascular pedicle, both fibrinogen concentration and platelet count increased significantly during the early and late post-operative window. Patients that developed bleeding necessitating re-exploration showed an inadequate increase in fibrinogen levels, resulting in significantly lower concentrations compared to the other two groups. There were no significant differences in platelet count or PTT between these groups. Conclusion: Free flap surgery induces acute and subacute changes in coagulation, comparable to other major surgeries and severe injuries. This leads to an increase in platelet count and fibrinogen over the post-operative course. Patients that developed bleeding requiring surgical re-exploration showed an insufficient increase in fibrinogen, resulting in significantly lower fibrinogen levels. Therefore, monitoring and correction of fibrinogen levels might aid in preventing or treating bleeding complications following free flap surgery. PMID- 27975042 TI - Predictive values derived from lower wisdom teeth developmental stages on orthopantomograms to calculate the chronological age in adolescence and young adults as a prerequisite to obtain age-adjusted informed patient consent prior to elective surgical procedures in young patients with incomplete or mismatched personal data. AB - Introduction: Surgical procedures require informed patient consent, which is mandatory prior to any procedure. These requirements apply in particular to elective surgical procedures. The communication with the patient about the procedure has to be comprehensive and based on mutual understanding. Furthermore, the informed consent has to take into account whether a patient is of legal age. As a result of large-scale migration, there are eventually patients planned for medical procedures, whose chronological age can't be assessed reliably by physical inspection alone. Age determination based on assessing wisdom tooth development stages can be used to help determining whether individuals involved in medical procedures are of legal age, i.e., responsible and accountable. At present, the assessment of wisdom tooth developmental stages barely allows a crude estimate of an individual's age. This study explores possibilities for more precise predictions of the age of individuals with emphasis on the legal age threshold of 18 years. Material and Methods: 1,900 dental orthopantomograms (female 938, male 962, age: 15-24 years), taken between the years 2000 and 2013 for diagnosis and treatment of diseases of the jaws, were evaluated. 1,895 orthopantomograms (female 935, male 960) of 1,804 patients (female 872, male 932) met the inclusion criteria. The archives of the Department of Diagnostic Radiology in Dentistry, University Medical Center Hamburg-Eppendorf, and of an oral and maxillofacial office in Rostock, Germany, were used to collect a sufficient number of radiographs. An effort was made to achieve almost equal distribution of age categories in this study group; 'age' was given on a particular day. The radiological criteria of lower third molar investigation were: presence and extension of periodontal space, alveolar bone loss, emergence of tooth, and stage of tooth mineralization (according to Demirjian). Univariate and multivariate general linear models were calculated. Using hierarchical multivariate analyses a formula was derived quantifying the development of the four parameters of wisdom tooth over time. This model took repeated measurements of the same persons into account and is only applicable when a person is assessed a second time. The second approach investigates a linear regression model in order to predict the age. In a third approach, a classification and regression tree (CART) was developed to derive cut-off values for the four parameters, resulting in a classification with estimates for sensitivity and specificity. Results: No statistically significant differences were found between parameters related to wisdom tooth localization (right or left side). In univariate analyses being of legal age was associated with consecutive stages of wisdom tooth development, the obliteration of the periodontal space, and tooth emergence, as well with alveolar bone loss; no association was found with tooth mineralization. Multivariate models without repeated measurements revealed imprecise estimates because of the unknown individual-related variability. The precision of these models is thus not very good, although it improves with advancing age. When calculating a CART-analysis and a receiver operating characteristics - area under the curve of 78% was achieved; when maximizing both specificity and sensitivity, a Youden's index of 47% was achieved (with 73% specificity and 74% sensitivity). Discussion: This study provides a basis to help determine whether a person is 18 years or older in individuals who are assumed to be between 15 and 24 years old. From repeated measurements, we found a linear effect of age on the four parameters in the individuals. However, this information can't be used for prognosis, because of the large intra-individual variability. Thus, although the development of the four parameters can be estimated over time, a direct conclusion with regard to age can't be drawn from the parameters without previous biographic information about a person. While a single parameter is of limited value for calculating the target age of 18 years, combining several findings, that can be determined on a standard radiography, may potentially be a more reliable diagnostic tool for estimating the target age in both sexes. However, a high degree of precision can't be achieved. The reason for persistent uncertainty lies in the wide chronological range of wisdom tooth development, which stretches from well below to above the 18th life year. The regression approach thus seems not optimal. Although sensitivity and specificity of the CART-model are moderately high, this model is still not reliable as a diagnostic tool. Our findings could have impact, e.g. on elective surgeries for young individuals with unknown biography. However, these results cannot replace social engagement, in particular thorough physical examination of patients and careful registration of their histories. Further studies on the use of this calculation method in different ethnic groups would be desirable. PMID- 27975044 TI - Facilitators of and barriers to accessing clinical prevention services for the South Asian population in Surrey, British Columbia: a qualitative study. AB - BACKGROUND: British Columbia falls short in uptake of recommended clinical prevention services, with even lower rates among immigrant populations. This study explored facilitators of and barriers to uptake of clinical prevention services among people from South Asia, who represent 31% of the population in Surrey, British Columbia. METHODS: We used a qualitative descriptive approach and employed vignettes in a focus group setting to elicit perspectives of South Asian people on accessing clinical prevention services. Participants aged 40 years or more were recruited between October 2014 and February 2015 from health care and community settings such as older-adult housing, day programs and health education events. Letters of introduction to the study were provided in English or Punjabi or both to all potential participants. We conducted qualitative content analysis of the results. RESULTS: Sixty-two South Asian adults (36 women and 26 men) aged 40-87 years participated in 1 of 8 focus groups in health care or community settings. Facilitators of and barriers to accessing clinical prevention services were noted at the patient, primary care provider and health care system levels. Facilitators at the patient level included taking ownership over one's health, health literacy and respecting the provider's advice; barriers included fear of the diagnosis, death and/or procedures, perceived low risk of disease or utility of the intervention, and side effects of procedures. Provider factors centred on a trust-based patient-provider relationship, strong communication and adequate time during visits. Health care system factors included such facilitators as processes to routinely offer prevention services as part of other health care or social services, systems that encourage prevention-oriented family practice and services at low or no cost to the patient. INTERPRETATION: Our findings validate previously identified facilitators of and barriers to accessing preventive care for immigrant populations. However, the results suggest that system-level factors influencing the duration of primary care visits may have a more salient impact on uptake of clinical prevention services in this population. PMID- 27975043 TI - Predictive value of neuron-specific enolase for prognosis in patients with moderate or severe traumatic brain injury: a systematic review and meta-analysis. AB - BACKGROUND: Prognosis is difficult to establish early after moderate or severe traumatic brain injury despite representing an important concern for patients, families and medical teams. Biomarkers, such as neuron-specific enolase, have been proposed as potential early prognostic indicators. Our objective was to determine the association between neuron-specific enolase and clinical outcomes, and the prognostic value of neuron-specific enolase after a moderate or severe traumatic brain injury. METHODS: We searched MEDLINE, Embase, The Cochrane Library and Biosis Previews, and reviewed reference lists of eligible articles to identify studies. We included cohort studies and randomized controlled trials that evaluated the prognostic value of neuron-specific enolase to predict mortality or Glasgow Outcome Scale score in patients with moderate or severe traumatic brain injury. Two reviewers independently collected data. The pooled mean differences were analyzed using random-effects models. We assessed risk of bias using a customized Quality Assessment of Diagnostic Accuracy Studies (QUADAS 2) tool. Subgroup and sensitivity analyses were performed based on a priori hypotheses. RESULTS: We screened 5026 citations from which 30 studies (involving 1321 participants) met our eligibility criteria. We found a significant positive association between neuron-specific enolase serum levels and mortality (10 studies, n = 474; mean difference [MD] 18.46 ug/L, 95% confidence interval [CI] 10.81 to 26.11 ug/L; I2 = 83%) and a Glasgow Outcome Scale <= 3 (14 studies, n = 603; MD 17.25 ug/L, 95% CI 11.42 to 23.07 ug/L; I2 = 82%). We were unable to determine a clinical threshold value using the available patient data. INTERPRETATION: In patients with moderate or severe traumatic brain injury, increased neuron-specific enolase serum levels are associated with unfavourable outcomes. The optimal neuron-specific enolase threshold value to predict unfavourable prognosis remains unknown and clinical decision-making is currently not recommended until additional studies are made available. PMID- 27975045 TI - Comparing surgical trays with redundant instruments with trays with reduced instruments: a cost analysis. AB - BACKGROUND: When prearranged standard surgical trays contain instruments that are repeatedly unused, the redundancy can result in unnecessary health care costs. Our objective was to estimate potential savings by performing an economic evaluation comparing the cost of surgical trays with redundant instruments with surgical trays with reduced instruments ("reduced trays"). METHODS: We performed a cost-analysis from the hospital perspective over a 1-year period. Using a mathematical model, we compared the direct costs of trays containing redundant instruments to reduced trays for 5 otolaryngology procedures. We incorporated data from several sources including local hospital data on surgical volume, the number of instruments on redundant and reduced trays, wages of personnel and time required to pack instruments. From the literature, we incorporated instrument depreciation costs and the time required to decontaminate an instrument. We performed 1-way sensitivity analyses on all variables, including surgical volume. Costs were estimated in 2013 Canadian dollars. RESULTS: The cost of redundant trays was $21 806 and the cost of reduced trays was $8803, for a 1-year cost saving of $13 003. In sensitivity analyses, cost savings ranged from $3262 to $21 395, based on the surgical volume at the institution. Variation in surgical volume resulted in a wider range of estimates, with a minimum of $3253 for low volume to a maximum of $52 012 for high-volume institutions. INTERPRETATION: Our study suggests moderate savings may be achieved by reducing surgical tray redundancy and, if applied to other surgical specialties, may result in savings to Canadian health care systems. PMID- 27975046 TI - Comparing stage of diagnosis of cervical cancer at presentation in immigrant women and long-term residents of Ontario: a retrospective cohort study. AB - BACKGROUND: Globally, cervical cancer is the fourth most common cancer in women and 7th most common cancer overall. Cervical cancer is highly preventable with screening. Previous work has shown that immigrants are less likely to undergo screening than nonimmigrants in Ontario, Canada. We examined whether immigrant women are more likely to present with later stage cervical cancer than long-term residents of the province. METHODS: We conducted a retrospective matched cohort study of women with cervical cancer diagnosed between 2010 and 2014 using provincial administrative health data. We compared the odds of late-stage diagnosis between immigrants and long-term residents, adjusting for socioeconomic measures, comorbidities and health care use. The outcome of interest was stage of cervical cancer diagnosis, defined as early (stage I) or late (stages II-IV). We confirmed results with a cohort of women with cancer diagnosed between 2007 and 2012. RESULTS: Complete staging data were available for 218 immigrants and 1348 matched long-term residents. We found no association between immigrant status and stage at diagnosis (adjusted odds ratio [OR] 0.94, 95% confidence interval [CI] 0.63-1.39). Factors that did show significant association with late-stage diagnosis were physician characteristics, whether a woman had previously undergone screening and had visited a gynecologist in the past 3 years. These results were echoed in the 2007-2012 cohort (immigrants v. long-term residents, OR 0.94, 95% CI 0.71-1.20). INTERPRETATION: Our results show that being an immigrant is not associated with late-stage diagnosis of cervical cancer in Ontario. Programs broadly aimed at immigrants may require a targeted approach to address higher-risk subgroups. PMID- 27975048 TI - How Can Genomic Tools Contribute to the Conservation of Endangered Organisms. PMID- 27975047 TI - Trends in influenza vaccine coverage and vaccine hesitancy in Canada, 2006/07 to 2013/14: results from cross-sectional survey data. AB - BACKGROUND: Past studies have reported influenza vaccination coverage below national targets, but up-to-date estimates are needed to understand trends and to identify areas for intervention. The objective of this study was to describe recent trends in influenza vaccination in Canada, timing of uptake and reasons for not receiving the vaccine. METHODS: We pooled data from the 2007 to 2014 cycles of the Canadian Community Health Survey. Using bootstrapped survey weights, we examined influenza vaccine coverage by various groups, including by age and by presence of chronic medical conditions. RESULTS: The overall sample included 481 526 respondents. Across all survey cycles combined, 29% of respondents reported receiving seasonal influenza vaccination in the past 12 months. Coverage levels were fairly consistent during the study period, but varied by province or territory. Vaccination coverage decreased over time among those aged 65 years and older. Among those who received a vaccination, it was most common to do so in October or November. Among those not vaccinated, the most frequently cited reason was believing it was unnecessary. INTERPRETATION: Influenza vaccination coverage continues to fall below national targets, with substantial declines seen among those aged 65 years and older, a group for which vaccination is particularly important. More intensive efforts are needed to improve coverage in Canada, particularly for high-risk groups. PMID- 27975049 TI - Risk Factors and Treatment for Hemorrhage after Pancreaticoduodenectomy: A Case Series of 423 Patients. AB - The study aimed to investigate the risk factors of postpancreatectomy hemorrhage (PPH) after pancreaticoduodenectomy (PD). A retrospective analysis of 423 patients who underwent PD between January 2008 and January 2014 was conducted. The overall incidence and all-cause mortality of PPH were 9.9% (42/423) and 2.1% (9/423), respectively. Independent risk factors of early PPH were revascularization (odds ratio (OR) = 6.786; 95% confidence interval (95% CI): 1.785-25.792; P = 0.005), history of abdominal surgery (OR = 5.009; 95% CI: 1.968 12.749; P = 0.001), and preoperative albumin levels (OR = 4.863; 95% CI: 1.962 12.005; P = 0.001). Independent risk factors of late PPH included postoperative pancreatic leakage (OR = 4.696; 95% CI: 1.605-13.740; P = 0.005), postoperative biliary fistula (OR = 6.096; 95% CI: 1.575-23.598; P = 0.009), postoperative abdominal infection (OR = 4.605; 95% CI: 1.108-19.144; P = 0.036), revascularization (OR = 9.943; 95% CI: 1.900-52.042; P = 0.007), history of abdominal surgery (OR = 8.790; 95% CI: 2.779-27.806; P < 0.001), and preoperative albumin levels (OR = 5.563; 95% CI: 1.845-16.776; P = 0.002). PMID- 27975050 TI - Clinical Performance of an Ultrahigh Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders. AB - Copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) significantly contribute to the etiology of neurodevelopmental disorders, such as developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD). This study summarizes the results of 3.5 years of CMA testing by a CLIA-certified clinical testing laboratory 5487 patients with neurodevelopmental conditions were clinically evaluated for rare copy number variants using a 2.8-million probe custom CMA optimized for the detection of CNVs associated with neurodevelopmental disorders. We report an overall detection rate of 29.4% in our neurodevelopmental cohort, which rises to nearly 33% when cases with DD/ID and/or MCA only are considered. The detection rate for the ASD cohort is also significant, at 25%. Additionally, we find that detection rate and pathogenic yield of CMA vary significantly depending on the primary indications for testing, the age of the individuals tested, and the specialty of the ordering doctor. We also report a significant difference between the detection rate on the ultrahigh resolution optimized array in comparison to the array from which it originated. This increase in detection can significantly contribute to the efficient and effective medical management of neurodevelopmental conditions in the clinic. PMID- 27975051 TI - Pathological Predictors of Shunt Stenosis and Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt. AB - Background. Transjugular intrahepatic portosystemic shunt (TIPS) is an artificial channel from the portal vein to the hepatic vein or vena cava for controlling portal vein hypertension. The major drawbacks of TIPS are shunt stenosis and hepatic encephalopathy (HE); previous studies showed that post-TIPS shunt stenosis and HE might be correlated with the pathological features of the liver tissues. Therefore, we analyzed the pathological predictors for clinical outcome, to determine the risk factors for shunt stenosis and HE after TIPS. Methods. We recruited 361 patients who suffered from portal hypertension symptoms and were treated with TIPS from January 2009 to December 2012. Results. Multivariate logistic regression analysis showed that the risk of shunt stenosis was increased with more severe inflammation in the liver tissue (OR, 2.864; 95% CI: 1.466 5.592; P = 0.002), HE comorbidity (OR, 6.266; 95% CI, 3.141-12.501; P < 0.001), or higher MELD score (95% CI, 1.298-1.731; P < 0.001). Higher risk of HE was associated with shunt stenosis comorbidity (OR, 6.266; 95% CI, 3.141-12.501; P < 0.001), higher stage of the liver fibrosis (OR, 2.431; 95% CI, 1.355-4.359; P = 0.003), and higher MELD score (95% CI, 1.711-2.406; P < 0.001). Conclusion. The pathological features can predict individual susceptibility to shunt stenosis and HE. PMID- 27975053 TI - Erratum to "Inhibitory Effect of Long-Chain Fatty Acids on Biogas Production and the Protective Effect of Membrane Bioreactor". AB - [This corrects the article DOI: 10.1155/2016/7263974.]. PMID- 27975052 TI - Histopathological Evaluation of Contrast-Induced Acute Kidney Injury Rodent Models. AB - Contrast-induced acute kidney injury (CI-AKI) can occur in 3-25% of patients receiving radiocontrast material (RCM) despite appropriate preventive measures. Often patients with an atherosclerotic vasculature have to receive large doses of RCM. Thus, animal studies to uncover the exact pathomechanism of CI-AKI are needed. Sensitive and specific histologic end-points are lacking; thus in the present review we summarize the histologic appearance of different rodent models of CI-AKI. Single injection of RCM causes overt renal damage only in rabbits. Rats and mice need an additional insult to the kidney to establish a clinically manifest CI-AKI. In this review we demonstrate that the concentrating ability of the kidney may be responsible for species differences in sensitivity to CI-AKI. The most commonly held theory about the pathomechanism of CI-AKI is tubular cell injury due to medullary hypoxia. Thus, the most common additional insult in rats and mice is some kind of ischemia. The histologic appearance is tubular epithelial cell (TEC) damage; however severe TEC damage is only seen if RCM is combined by additional ischemia. TEC vacuolization is the first sign of CI-AKI, as it is a consequence of RCM pinocytosis and lysosomal fusion; however it is not sensitive as it does not correlate with renal function and is not specific as other forms of TEC damage also cause vacuolization. In conclusion, histopathology alone is insufficient and functional parameters and molecular biomarkers are needed to closely monitor CI-AKI in rodent experiments. PMID- 27975055 TI - Clinical Effects of the Probing Method with Depth Gauge for Determining the Screw Depth of Locking Proximal Humeral Plate. AB - Background. The use of locking plates has gained popularity to treat proximal humeral fractures. However, the complication rates remain high. Biomechanical study suggested that subchondral screw-tip abutment significantly increased the stability of plant. We present a simple method to obtain the proper screw length through the depth gauge in elderly patients and compared the clinical effects with traditional measuring method. Methods. 40 patients were separated into two groups according to the two surgical methods: the probing method with depth gauge and the traditional measuring method. The intraoperative indexes and postoperative complications were recorded. The Constant and Murley score was used for the functional assessment in the 12th month. Results. Operative time and intraoperative blood loss indicated no statistical differences. X-ray exposure time and the patients with screw path penetrating the articular cartilage significantly differed. Postoperative complications and Constant and Murley score showed no statistical differences. Conclusions. Probing method with depth gauge is an appropriate alternative to determine the screw length, which can make the screw-tip adjoin the subchondral bone and keep the articular surface of humeral head intact and at the same time effectively avoid frequent X-ray fluoroscopy and adjusting the screws. PMID- 27975054 TI - Diet, Lifestyles, Family History, and Prostate Cancer Incidence in an East Algerian Patient Group. AB - Prostate cancer (PC) is the fourth most common cancer in men and the sixth leading cause of death in Algeria. To examine the relationship between lifestyle factors, including diet, and family history and PC risk, a case-control study was performed in an eastern Algerian population, comprising 90 patients with histologically confirmed PC and 190 controls. Data collection was carried out through a structured questionnaire and statistical analysis was performed to evaluate the different variables. The data showed that consumption of lamb and beef meat and high intake of animal fat and dairy products increased PC risk. Seven to thirteen vegetables servings per week and fourteen or more servings decreased PC risk by 62% and 96%, respectively. Seven to fourteen fruit servings per week decrease PC risk by 98%. Green tea consumption reduced the risk of PC but the results were statistically borderline. Increased risk was observed for individuals with family history of PC in first and in second degree. A positive strong association was also found for alcohol and smoking intake and a dose response relationship existed for quantity and history of smoking. This study suggests that dietary habits, lifestyle factors, and family history have influence on the development of PC in Algerian population. PMID- 27975056 TI - Is Laparoendoscopic Single-Site Adrenalectomy a Feasible Alternative in Treating Aldosterone-Producing Adenoma? AB - Objective. To compare laparoendoscopic single-site (LESS) and conventional multiport adrenalectomy in patients with aldosterone-producing adenoma (APA). Material and Methods. We retrospectively reviewed patients who had been clinically confirmed with unilateral APA and who underwent LESS or multiport adrenalectomy between 2009 and 2014. Perioperative data were obtained for all patients. Blood pressure and the levels of serum aldosterone, renin, and potassium were checked periodically. Results. We identified 45 APA patients in the LESS group and 71 in the multiport group. The baseline characteristics were matched between two groups. All adrenalectomies were completed successfully, except one with laparoscopic conversion in the single-port group and one open conversion in the multiport group. After a mean follow-up around one year, there were no significant group differences in the improvement of hypertension, number of types of medication taken, and cure of hypokalemia after operation. Conclusions. Our study confirm that LESS adrenalectomy achieved similar clinical and functional outcomes as conventional multiport adrenalectomy for management of unilateral APA. PMID- 27975057 TI - ZFP91: A Noncanonical NF-kappaB Signaling Pathway Regulator with Oncogenic Properties Is Overexpressed in Prostate Cancer. AB - Novel molecular targets are being searched to aid in prostate cancer diagnosis and therapy. Recently, ZFP91 zinc finger protein has been found to be upregulated in prostate cancer cell lines. It is a potentially important oncogenic protein; however only limited data regarding its biological function and expression patterns are available. To date, ZFP91 has been shown to be a key factor in activation of noncanonical NF-kappaB signaling pathway as well as to be involved in HIF-1alpha signaling in cancer cells. The present study aimed to characterize ZFP91 expression in prostate cancer specimens. Furthermore, since our earlier reports showed discrepancies between ZFP91 mRNA and protein levels, we studied this interrelationship in LNCaP and PC-3 prostate cancer cell lines using siRNA mediated knockdown. QPCR analysis revealed marked upregulation of ZFP91 mRNA in the majority of prostate cancer specimens. Transfection of prostate cancer cells with ZFP91 siRNA resulted in a 10-fold decrease in mRNA levels. On a protein level, however, no inhibitory effect was observed over the time of the cell culture. We conclude that ZFP91 is overexpressed in prostate cancer and that potential accumulation of the ZFP91 protein in studied cells may be of importance in prostate cancer biology. PMID- 27975058 TI - Low-Intensity Ultrasound Combined with Hematoporphyrin Monomethyl Ether in the Treatment of Experimental Periodontitis in Rats. AB - Objectives. This study aims to evaluate the efficacy of hematoporphyrin monomethyl ether- (HMME-) mediated sonodynamic therapy (SDT) on experimental periodontal disease in rats. Methods. Periodontal disease was induced by submerging ligatures at the first maxillary molar subgingival region in forty eight male SD rats. After 30 days, the ligatures were removed. The rats were randomly allocated into four groups; the experimental SDT group was treated through hypodermic injection of 40 MUg/mL HMME and 3 W/cm2 low-intensity ultrasound irradiation (1 MHz, 600 s). Those in control groups received 40 MUg/mL HMME alone (control 1 group) or 3 W/cm2 ultrasound irradiation alone (control 2 group) or were subjected to neither HMME nor ultrasound (control 3 group). After 10 days of treatment, all rats were euthanized, the maxilla was obtained for histological examination, and the alveolar bone level was evaluated by histometric analysis. Results. The control groups showed more bone loss (P < 0.05) after 10 days of treatment than the SDT group. There is no significant difference among the control groups (P > 0.05). Conclusions. HMME mediated SDT was an effective therapy of experimental periodontal tissue in rats. PMID- 27975059 TI - Upregulation of Oxidative Stress Related Genes in a Chronic Kidney Disease Attributed to Specific Geographical Locations of Sri Lanka. AB - Objective. To infer the influence of internal and external oxidative stress in chronic kidney disease patients of unknown etiology (CKDu) in Sri Lanka, by analyzing expression of genes related directly or indirectly to oxidative stress: glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferase mu 1 (GSTM1), glucose-6-phosphate dehydrogenase (G6PD), fibroblast growth factor-23 (FGF23), and NLR family pyrin domain containing 3 (NLRP3). Methods. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was carried out for the selected populations: CKDu patients (n = 43), chronic kidney disease patients (CKD; n = 14), healthy individuals from a CKDu endemic area (GHI; n = 9), and nonendemic area (KHI; n = 16). Fold changes were quantified relative to KHI. Results. GCLC had greater than threefold upregulation in all three study groups, with a maximum of 7.27-fold upregulation in GHI (p = 0.000). GSTM1 was not expressed in 25.6% of CKDu and 42.9% of CKD patients, but CKDu patients expressing GSTM1 showed upregulation of 2.60-fold (p < 0.05). Upregulation of FGF23 and NLRP3 genes in CKD and CKDu was observed (p < 0.01), with greater fold changes in CKD. Conclusion. Results suggest higher influence of external sources of oxidative stress in CKDu, possibly owing to environmental conditions. PMID- 27975060 TI - The Epidemiological, Morphological, and Clinical Aspects of the Cervical Ribs in Humans. AB - A familiarity with the anatomy of some types of bone anomalies is necessary for clinicians involved in many medical areas. The aim of this paper is to review the newest literature concerning the morphology, embryology, clinical image, and therapeutic methods of the cervical ribs in the humans. The incidence of cervical ribs has been found to vary from 0.58% in Malaysian population to 6.2% in Turkish population. Cervical ribs have clinical implications that are generally divided into neurological or vascular. This study is of particular importance for clinicians, as early identification of cervical ribs may prevent life-threatening complications. PMID- 27975061 TI - Influence of Surface Properties on Adhesion Forces and Attachment of Streptococcus mutans to Zirconia In Vitro. AB - Zirconia is becoming a prevalent material in dentistry. However, any foreign bodies inserted may provide new niches for the bacteria in oral cavity. The object of this study was to explore the effect of surface properties including surface roughness and hydrophobicity on the adhesion and biofilm formation of Streptococcus mutans (S. mutans) to zirconia. Atomic force microscopy was employed to determine the zirconia surface morphology and the adhesion forces between the S. mutans and zirconia. The results showed that the surface roughness was nanoscale and significantly different among tested groups (P < 0.05): Coarse (23.94 +/- 2.52 nm) > Medium (17.00 +/- 3.81 nm) > Fine (11.89 +/- 1.68 nm). The contact angles of the Coarse group were the highest, followed by the Medium and the Fine groups. Increasing the surface roughness and hydrophobicity resulted in an increase of adhesion forces and early attachment (2 h and 4 h) of S. mutans on the zirconia but no influence on the further development of biofilm (6 h~24 h). Our findings suggest that the surface roughness in nanoscale and hydrophobicity of zirconia had influence on the S. mutans initial adhesion force and early attachment instead of whole stages of biofilm formation. PMID- 27975062 TI - Identification of Five Novel Salmonella Typhi-Specific Genes as Markers for Diagnosis of Typhoid Fever Using Single-Gene Target PCR Assays. AB - Salmonella Typhi (S. Typhi) causes typhoid fever which is a disease characterised by high mortality and morbidity worldwide. In order to curtail the transmission of this highly infectious disease, identification of new markers that can detect the pathogen is needed for development of sensitive and specific diagnostic tests. In this study, genomic comparison of S. Typhi with other enteric pathogens was performed, and 6 S. Typhi genes, that is, STY0201, STY0307, STY0322, STY0326, STY2020, and STY2021, were found to be specific in silico. Six PCR assays each targeting a unique gene were developed to test the specificity of these genes in vitro. The diagnostic sensitivities and specificities of each assay were determined using 39 S. Typhi, 62 non-Typhi Salmonella, and 10 non-Salmonella clinical isolates. The results showed that 5 of these genes, that is, STY0307, STY0322, STY0326, STY2020, and STY2021, demonstrated 100% sensitivity (39/39) and 100% specificity (0/72). The detection limit of the 5 PCR assays was 32 pg for STY0322, 6.4 pg for STY0326, STY2020, and STY2021, and 1.28 pg for STY0307. In conclusion, 5 PCR assays using STY0307, STY0322, STY0326, STY2020, and STY2021 were developed and found to be highly specific at single-gene target resolution for diagnosis of typhoid fever. PMID- 27975063 TI - A Multiagent System for Dynamic Data Aggregation in Medical Research. AB - The collection of medical data for research purposes is a challenging and long lasting process. In an effort to accelerate and facilitate this process we propose a new framework for dynamic aggregation of medical data from distributed sources. We use agent-based coordination between medical and research institutions. Our system employs principles of peer-to-peer network organization and coordination models to search over already constructed distributed databases and to identify the potential contributors when a new database has to be built. Our framework takes into account both the requirements of a research study and current data availability. This leads to better definition of database characteristics such as schema, content, and privacy parameters. We show that this approach enables a more efficient way to collect data for medical research. PMID- 27975064 TI - Statin as a Combined Therapy for Advanced-Stage Ovarian Cancer: A Propensity Score Matched Analysis. AB - Background. Despite the great achievements in the treatment of advanced-stage ovarian cancer, it is still a severe condition with an unfavorable 5-year survival rate. Statins have been suggested to reduce the risk of several cancers beyond their cholesterol-lowing effects. However, the prognostic significance of statins in patients with advanced-stage ovarian cancer remains controversial. Methods. A retrospective study was performed to evaluate the association between statin intake and overall survival (OS) among patients with advanced-stage ovarian cancer. Patients who underwent cytoreductive surgery followed by courses of intravenous chemotherapy were matched through a propensity score analysis. Results. A total of 60 propensity-matched patients were included. Women in statin group showed a similar OS than the nonstatin counterparts (P = 0.966), whereas residual tumor was significantly associated with better OS (P = 0.013) and was an independent factor that associated with OS (P = 0.002, hazard ratio = 5.460, and 95% confidence interval: 1.894 to 15.742) in multivariable analysis. Conclusions. Our results suggested that statin usage was not associated with improved OS in patients with advanced-stage ovarian cancer undergoing surgery and chemotherapy. Considering the retrospective nature and the relative small sample size of the study, further prospective studies and random control trials are needed. PMID- 27975065 TI - Biomechanical Comparison of Modified Suture Bridge Using Rip-Stop versus Traditional Suture Bridge for Rotator Cuff Repair. AB - Purpose. To compare the biomechanical properties of 3 suture-bridge techniques for rotator cuff repair. Methods. Twelve pair-matched fresh-frozen shoulder specimens were randomized to 3 groups of different repair types: the medially Knotted Suture Bridge (KSB), the medially Untied Suture Bridge (USB), and the Modified Suture Bridge (MSB). Cyclic loading and load-to-failure test were performed. Parameters of elongation, stiffness, load at failure, and mode of failure were recorded. Results. The MSB technique had the significantly greatest load to failure (515.6 +/- 78.0 N, P = 0.04 for KSB group; P < 0.001 for USB group), stiffness (58.0 +/- 10.7 N/mm, P = 0.005 for KSB group; P < 0.001 for USB group), and lowest elongation (1.49 +/- 0.39 mm, P = 0.009 for KSB group; P = 0.001 for USB group) among 3 groups. The KSB repair had significantly higher ultimate load (443.5 +/- 65.0 N) than USB repair (363.5 +/- 52.3 N, P = 0.024). However, there was no statistical difference in stiffness and elongation between KSB and USB technique (P = 0.396 for stiffness and P = 0.242 for elongation, resp.). The failure mode for all specimens was suture pulling through the cuff tendon. Conclusions. Our modified suture bridge technique (MSB) may provide enhanced biomechanical properties when compared with medially knotted or knotless repair. Clinical Relevance. Our modified technique may represent a promising alternative in arthroscopic rotator cuff repair. PMID- 27975066 TI - Association of Postbreakfast Triglyceride and Visit-to-Visit Annual Variation of Fasting Plasma Glucose with Progression of Diabetic Nephropathy in Patients with Type 2 Diabetes. AB - Urinary albumin/creatinine ratio (ACR) was measured at baseline and after a median follow-up of 6.0 years in 161 patients with type 2 diabetes. Intrapersonal means and SD of HbA1c, systolic BP, fasting, and postmeal plasma glucose (FPG and PMPG, resp.) and serum triglycerides (FTG and PMTG, resp.) were calculated in each patient during the first 12 months after enrollment. Associations of these variables with nephropathy progression (15 patients with progression of albuminuric stages and 5 with ACR doubling within the microalbuminuric range) were determined by multivariate logistic regression analysis providing odds ratio with 95% confidential interval. Patients with nephropathy progression, compared with those without nephropathy progression, had higher HbA1c (p < 0.01). They also had higher means and SD of FPG (both p < 0.05), FTG (both p < 0.05), and PMTG (p = 0.001). Multivariate logistic regression analysis demonstrated that SD FPG (1.036, 1.001-1.073, p = 0.04) and PMTG (1.013, 1.008-1.040, p = 0.001) were significant predictors of progression of nephropathy even after adjustment for mean FPG and SD-FTG, age, sex, BMI, waist circumference, diabetes duration and therapy, means and SDs of HbA1c, PPG, FTG and systolic BP, baseline ACR, smoking status, and uses of antihypertensive and lipid-lowering medications. Consistency of glycemic control and management of postmeal TG may be important to prevent nephropathy progression in type 2 diabetic patients. PMID- 27975067 TI - Hyperlactatemia and the Outcome of Type 2 Diabetic Patients Suffering Acute Myocardial Infarction. AB - Background. Increased lactate production is frequent in unregulated/complicated diabetes mellitus. Methods. Three groups, each consisting of 40 patients (type 2 diabetics with myocardial infarction, DM+AMI, nondiabetics suffering myocardial infarction, MI, and diabetics with no apparent cardiovascular pathology, DM group), were tested for pH, serum bicarbonate and electrolytes, blood lactate, and CK-MB. Results. Blood lactate levels were markedly higher in AMI+DM compared to MI group (4.54 +/- 1.44 versus 3.19 +/- 1.005 mmol/L, p < 0.05); they correlated with the incidence of heart failure (rho = 0.66), cardiac rhythm disorders (rho = 0.54), oxygen saturation (rho = 0.72), CK-MB levels (rho = 0.62), and poor short-term outcome. Lactic acidosis in DM+AMI group was not always related to lethal outcome. Discussion. The lactate cutoff value associated with grave prognosis depends on the specific disease. While some authors proposed cutoff values ranging from 0.76 to 4 mmol/L, others argued that only occurrence of lactic acidosis may be truly predictive of lethal outcome. Conclusion. Both defective glucose metabolism and low tissue oxygenation may contribute to the lactate production in diabetic patients with acute myocardial infarction; high lactate levels indicate increased risk for poor outcome in this population comparing to nondiabetic patients. The rise in blood lactate concentration in diabetics with AMI was associated with increased incidence of heart failure, severe arrhythmias, cardiogenic shock, and high mortality rate. PMID- 27975068 TI - Quercetin Isolated from Toona sinensis Leaves Attenuates Hyperglycemia and Protects Hepatocytes in High-Carbohydrate/High-Fat Diet and Alloxan Induced Experimental Diabetic Mice. AB - The development of diabetes mellitus is related to oxidant stress induced by a high carbohydrate/high-fat diet (HFD). Quercetin, as a major bioactive component in Toona sinensis leaves (QTL), is a natural antioxidant. However, the exact mechanism by which QTL ameliorate diabetes mellitus is still unknown. In this study, we investigated the hypoglycemic effects and hepatocytes protection of QTL on HFD and alloxan induced diabetic mice. Intragastric administration of QTL significantly reduced body weight gain, serum glucose, insulin, total cholesterol, triglyceride, low density lipoprotein-cholesterol, alanine aminotransferase, and aspartate aminotransferase serum levels compared to those of diabetic mice. Furthermore, it significantly attenuated oxidative stress, as determined by lipid peroxidation, nitric oxide content, and inducible nitric oxide synthase activity and as a result attenuated liver injury. QTL also significantly suppressed the diabetes-induced activation of the p65/NF-kappaB and ERK1/2/MAPK pathways, as well as caspase-9 and caspase-3 levels in liver tissues of diabetic mice. Finally, micrograph analysis of liver samples showed decreased cellular organelle injury in hepatocytes of QTL treated mice. Taken together, QTL can be viewed as a promising dietary agent that can be used to reduce the risk of diabetes mellitus and its secondary complications by ameliorating oxidative stress in the liver. PMID- 27975069 TI - The Suppressed Induction of Human Mature Cytotoxic T Lymphocytes Caused by Asbestos Is Not due to Interleukin-2 Insufficiency. AB - We previously reported that exposure to chrysotile B (CB) asbestos suppressed the induction of mature cytotoxic T lymphocytes (CTLs) during mixed lymphocyte reaction assays (MLRs) with a decrease in the proliferation of immature CTLs. However, the mechanism responsible for the effect of asbestos fibers on the differentiation of CTLs remains unclear. Since interleukin-2 (IL-2) is a regulator of T lymphocyte proliferation, we examined the effect of IL-2 addition on suppressed CTL differentiation in CB-exposed cultures using flow cytometry (FCM). When IL-2 was added at 1 ng/mL on the second day of MLRs, the asbestos caused decreases in the proliferation and percentages of CD25+ and CD45RO+ cells in CD8+ lymphocytes were not recovered by IL-2 addition, although the decrease in percentage of granzyme B+ cells was partially recovered. CD8+ lymphocytes from the IL-2-treated culture with asbestos showed the same degree of cytotoxicity as those in cultures without IL-2 or asbestos. These findings indicate that IL-2 insufficiency is not the main cause for the suppressed induction of CTLs by asbestos exposure, although they suggest a potential for the improvement of such suppressed CTL functions. Secretory factors other than IL-2 in addition to membrane-bound stimulatory molecules may play a role in asbestos-caused suppressed CTL differentiation. PMID- 27975070 TI - Overexpression of MMP-3 and uPA with Diminished PAI-1 Related to Metastasis in Ductal Breast Cancer Patients Attending a Public Hospital in Mexico City. AB - Extracellular matrix metalloproteases and the fibrinolytic system are important protease systems interacting with each other in charge of remodeling and recycling of tissues. Their role in tumor invasion and metastasis is often discussed. In this study several metalloproteases such as MMP-1, MMP-3, MMP-9, and TIMP-1 together with molecules from the fibrinolytic system like uPA, its receptor uPAR, and its inhibitor, PAI-1, were studied by immune-histochemistry to establish a comparison with and without metastasis. From the (118) primary tumors of Mexican patients with ductal breast cancer studied, 56% were grade II and 69% were size T2; the group with metastatic ganglia included 64 samples (54.3%). In patients with metastasis the estimated expression of MMP-3 and uPA (resp., 28% and 45%) was higher than that from no metastatic tumors; it means there is higher expression of both markers in metastatic tumors (p < 0.05). At the same time, metastatic tumors showed statistically significant lower signal of PAI-1 (24%) than tumors without metastasis (p < 0.05). We concluded that overexpression of MMP-3 and uPA, altogether with diminished expression of PAI-1 from metastatic tumors, might be a crucial step towards metastasis in ductal breast cancer. Nevertheless, additional studies in different populations are necessary to establish a pattern. PMID- 27975073 TI - Postsplenectomy Prophylaxis: A Persistent Failure to Meet Standard? AB - A retrospective case review of patients that underwent emergency splenectomy or splenic preservation from May 2003 to April 2014 was undertaken at a single center. The results highlight failures in administration of postsplenectomy vaccination for emergency splenectomy patients. In this study, we highlight methods to improve postsplenectomy care. PMID- 27975072 TI - Evaluation of Shoulder-Stabilizing Braces: Can We Prevent Shoulder Labrum Injury in Collegiate Offensive Linemen? AB - BACKGROUND: Shoulder injuries remain one of the most common injuries among collegiate football athletes. Offensive linemen in particular are prone to posterior labral pathology. PURPOSE: To evaluate the efficacy of shoulder bracing in collegiate offensive linemen with respect to injury prevention, severity, and lost playing time. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Offensive linemen at a single collegiate institution wore bilateral shoulder stabilizing braces for every contact practice and game beginning in the spring of 2013. Between spring of 2007 and fall of 2012, offensive linemen did not wear any shoulder braces. Player injury data were collected for all contact practices and games throughout these time periods to highlight differences with brace use. RESULTS: Forty-five offensive linemen (90 shoulders) participated in spring and fall college football seasons between 2007 and 2015. There were 145 complete offensive linemen seasons over the course of the study. Offensive linemen not wearing shoulder braces completed 87 seasons; offensive linemen wearing shoulder braces completed 58 seasons. Posterior labral tear injury rates were calculated for players who wore the shoulder braces (0.71 per 1000 athlete-exposures) compared with shoulders of players who did not wear the braces (1.90 per 1000 athlete-exposures). The risk ratio was 0.46 (95% CI, 0.16-1.30; P = .14). Mean time (contact practices and games) missed due to injury was significant, favoring less time missed by players who used braces (8.7 vs 36.60 contact practices and games missed due to injury; P = .0019). No significant difference in shoulder labral tears requiring surgery was found for brace use compared with no brace use. CONCLUSION: Shoulder-stabilizing braces were shown not to prevent posterior labral tears among collegiate offensive lineman, although they were associated with less time lost to injury. The results of this study have clinical significance, indicating that wearing a shoulder brace provides a protective factor for offensive linemen. PMID- 27975074 TI - Imported Case of Lassa Fever in Sweden With Encephalopathy and Sensorineural Hearing Deficit. AB - We describe an imported case of Lassa fever with both encephalopathy and bilateral sensorineural hearing deficit. Absence of fever during hospitalization, initially nonspecific symptoms, and onset of hearing deficit in a late stage of disease probably contributed to delayed diagnosis (14 days after admittance to hospital). The pathogenesis of neurological manifestations of Lassa fever is poorly understood and no specific treatment was given. A total of 118 personnel had close contact with the patient, but no secondary cases occurred. This case highlights the importance of considering Lassa fever as a differential diagnosis in patients with recent travel to endemic areas. PMID- 27975075 TI - Retrospective Study Investigating the Seroprevalence of Anaplasma phagocytophilum in Manitoba, Canada: 2011-2014. AB - Human granulocytic anaplasmosis is currently not nationally notifiable in Canada. This for the most part accounts for gross under-estimation of true incidence and prevalence of HGA and would potentially culminate in clinical missed opportunities. To the best of our knowledge, this is the first report on the seroprevalence of Anaplasma phagocytophilum in a Canadian jurisdiction with known established black-legged tick populations. PMID- 27975071 TI - New Mechanisms of Tumor-Associated Macrophages on Promoting Tumor Progression: Recent Research Advances and Potential Targets for Tumor Immunotherapy. AB - The majority of basic and clinical studies have shown a protumor function of tumor-associated macrophages (TAMs), which represent a large proportion of matrix cells. TAMs promote tumorigenesis, and their number is related to the malignancy degree and poor prognosis of many kinds of tumors. Macrophage plasticity makes it possible to change the tumor microenvironment and remodel antitumor immunity during cancer immunotherapy. Increasing numbers of studies have revealed the effects of TAMs on the tumor microenvironment, for example, via promotion of tumor growth and tumorigenesis and through an increase in the number of cancer stem cells or via facilitation of angiogenesis, lymphangiogenesis, and metastasis. Investigators also proposed tumor-immunological treatments targeting TAMs by inhibiting TAM recruitment and differentiation, by regulating TAM polarization, and by blocking factors and pathways associated with the protumor function of TAMs. This comprehensive review presents recent research on TAMs in relation to prediction of poor outcomes, remodeling of the tumor immune microenvironment, and immunological targeted therapies. PMID- 27975076 TI - The Role of Antimicrobial Stewardship in the Clinical Microbiology Laboratory: Stepping Up to the Plate. AB - We report the development of a collaborative relationship between antimicrobial stewardship and clinical microbiology that incorporates stewardship practices into daily laboratory rounds. Antimicrobial stewardship involvement on rounds was a welcomed and effective initiative with substantial rates of intervention. New opportunities to positively impact use of antimicrobials and laboratory resources were realized. PMID- 27975079 TI - Strong-willed but not successful: The importance of strategies in recovery from addiction. AB - INTRODUCTION: Philosophers, cognitive and social psychologists and laypeople often subscribe to the view that willpower is central to recovery from addiction. But there are reasons to suspect that willpower is much less important to explaining recovery than this view suggests. METHODS: Here we report findings from a qualitative longitudinal study on how substance dependent people see their agency and self-control, and how their self-control develops over time. 69 opioid, alcohol and methamphetamine dependent people were interviewed over a 3 year period. RESULTS: Most of the participants described themselves as strong willed; in fact, as very strong willed. However, there seemed no correlation between having a (self-assessed) strong will and recovery status. Rather, the number of strategies cited by participants distinguished those in stable recovery from those who were not. Participants in recovery were also more enthusiastic about strategies than those who have not succeeded in controlling substance use. Willpower remained important, but was itself used strategically. CONCLUSIONS: People with addiction seem not to be short on willpower; rather, recovery is dependent on developing strategies to preserve willpower by controlling the environment. PMID- 27975077 TI - Microbial Ecology: Where are we now? AB - Conventional microbiological methods have been readily taken over by newer molecular techniques due to the ease of use, reproducibility, sensitivity and speed of working with nucleic acids. These tools allow high throughput analysis of complex and diverse microbial communities, such as those in soil, freshwater, saltwater, or the microbiota living in collaboration with a host organism (plant, mouse, human, etc). For instance, these methods have been robustly used for characterizing the plant (rhizosphere), animal and human microbiome specifically the complex intestinal microbiota. The human body has been referred to as the Superorganism since microbial genes are more numerous than the number of human genes and are essential to the health of the host. In this review we provide an overview of the Next Generation tools currently available to study microbial ecology, along with their limitations and advantages. PMID- 27975078 TI - Technical note: Recommendations for a standard procedure to assess cortical bone at the tissue-level in vivo using impact microindentation. AB - Impact microindentation is a novel method for measuring the resistance of cortical bone to indentation in patients. Clinical use of a handheld impact microindentation technique is expanding, highlighting the need to standardize the measurement technique. Here, we describe a detailed standard operation procedure to improve the consistency and comparability of the measurements across centers. PMID- 27975080 TI - Excretory Function of Intestinal Tract Enhanced in Kidney Impaired Rats Caused by Adenine. AB - The main aim of the study was to prove the compensative effect of intestine for renal function. Rat kidney was impaired by intragastrically administrating adenine (400 mg per day for 5 days). Intestinal tract was harvested and equally divided into 20 segments except cecum. Kidneys were harvested and histologically examined with hematoxylin-eosin staining kits. Uric acid, urea (BUN), and creatinine in serum were determined with assay kits, and BUN and creatinine in every intestinal segment were also determined. The results showed that adenine was able to increase uric acid level in serum from 20.98 +/- 6.98 MUg/mL to 40.77 +/- 7.52 MUg/mL and cause renal function damage with BUN (from 3.87 +/- 0.62 mM to 12.33 +/- 3.27 mM) and creatinine (from 51.48 +/- 6.98 MUM to 118.25 +/- 28.63 MUM) increasing in serum and with abnormally micromorphological changes in kidney. The amount of BUN and creatinine distributed in intestinal tract was positively correlated with those in blood. In impaired renal function rats, the amount of BUN (from 4.26 +/- 0.21 MUMole to 10.72 +/- 0.55 MUMole) and creatinine (from 681.4 +/- 23.3 nMole to 928.7 +/- 21.3 nMole) distributed in intestinal tract significantly increased. All the results proved that intestinal tract had excretory function compensative for renal function. PMID- 27975081 TI - Laparoscopic Treatment of Adrenal Tumors: A Single-Center Experience with 58 Patients. AB - Background. The aim of this study is to discuss the laparoscopic approach and assess the immunohistochemical expression profiles of synaptophysin, Ki-67, and inhibin and patient outcomes in adrenal masses through a series of cases treated at our institution. Method. The study was conducted on 58 patients who were diagnosed with adrenal masses. All cases were operated on laparoscopically for adrenal masses. Results. Both inhibin and synaptophysin were found positive in 45 patients (77,6%). Ki-67 was negative in 11 patients, whereas it was found positive in 42 with a rate of 1%. The size of the masses ranged from 1 up to 9 cm (mean 4,3 +/- 1,5). Urine hormone excretion was measured within normal ranges in 47 out of 58 patients (81%). Most of the diagnosed patients were harboring Cortical Adenoma (n: 38; 65,5%). All of the masses were successfully resected without complication except 3 patients. Because of complications of bleeding, the operation was converted to open surgery for 2 patients. Conclusion. Morbidity, mortality, and healing were comparable, regardless of tumor size, yet involvement in both laparoscopic and adrenal surgery was required. Our results suggested that laparoscopic adrenalectomy should replace open surgery as the standard treatment for most adrenal masses. PMID- 27975082 TI - The Association of Hepatitis C Serological Status with Several Risk Factors in Indonesia. AB - Hepatitis is an inflammation of the liver commonly caused by viral infection such as hepatitis A, B, C, D, and E but it is also possible by other causes. Infection with hepatitis C virus is also referred to as a disguise because the early infection is often asymptomatic that often goes undetected. This study aims at determining the several associated risk factors with hepatitis C serological status. The study design is cross-sectional. The biomedical data collection was carried out in 33 provinces in Indonesia with a population in urban blocks, census in Indonesia, where the sample is all household members over the age of one year from selected households by signing the informed consent. Total block census in selected urban area is about 971-block census with a total sample of 15.536 households. The results showed that there is a correlation between hepatitis C serological status and demographic group and that the age and occupation groups showed significant P value obtained at 0.001 (OR = 3.27, CI = 1.84-5.81) and 0.209 (OR = 0.23, CI = 0.59-0.94). In conclusion, there are risk factors such as age and occupation that have a correlation of being infected with hepatitis C serological status. PMID- 27975084 TI - Slanted, asymmetric microfluidic lattices as size-selective sieves for continuous particle/cell sorting. AB - Hydrodynamic microfluidic platforms have been proven to be useful and versatile for precisely sorting particles/cells based on their physicochemical properties. In this study, we demonstrate that a simple lattice-shaped microfluidic pattern can work as a virtual sieve for size-dependent continuous particle sorting. The lattice is composed of two types of microchannels ("main channels" and "separation channels"). These channels cross each other in a perpendicular fashion, and are slanted against the macroscopic flow direction. The difference in the densities of these channels generates an asymmetric flow distribution at each intersection. Smaller particles flow along the streamline, whereas larger particles are filtered and gradually separated from the stream, resulting in continuous particle sorting. We successfully sorted microparticles based on size with high accuracy, and clearly showed that geometric parameters, including the channel density and the slant angle, critically affect the sorting behaviors of particles. Leukocyte sorting and monocyte purification directly from diluted blood samples have been demonstrated as biomedical applications. The presented system for particle/cell sorting would become a simple but versatile unit operation in microfluidic apparatus for chemical/biological experiments and manipulations. PMID- 27975085 TI - Synergistic effect of the composite films formed by zeolitic imidazolate framework 8 (ZIF-8) and porous nickel films for enhanced amperometric sensing of hydrazine. AB - A novel ZIF-Ni composite film has been successfully prepared by a facile method involving the in situ deposition of ZIF-8 on a nickel porous film which is fabricated by selectively etching copper from a dense Ni/Cu alloy film. The nanostructures of the resulting ZIF-Ni composite films are carefully examined by a combination of scanning electron microscopy (SEM), X-ray diffraction (XRD) analysis, Fourier transform infrared (FT-IR) spectroscopy, energy dispersive X ray (EDX), and nitrogen adsorption-desorption. Cyclic voltammetric and amperometric studies show the enhanced electrocatalytic properties of the ZIF-Ni composite film electrodes toward hydrazine oxidation relative to the synergistic effect of ZIF-8 and porous Ni films. The application potential of the composite films as amperometric detectors is explored for the determination of hydrazine. A high sensitivity of 805.5 MUA mM-1 for hydrazine detection with a low detection limit of 0.021 MUM (S/N = 3) and a wide linear range from 2.5 MUM to 28 mM are revealed for this new type of composite film as the detecting electrode. Moreover, the composite films exhibit excellent selectivity and remarkable stability for the oxidation of hydrazine. This can offer new opportunities for the fast and selective detection of hydrazine and provide a promising platform for sensor designs for hydrazine detection. PMID- 27975086 TI - Ligand-responsive upregulation of 3' CITE-mediated translation in a wheat germ cell-free expression system. AB - We have rationally constructed a novel regulation-type of artificial riboswitch that ligand-dose dependently upregulates translation initiation mediated by a 3' cap-independent translation element (3' CITE) with no major hybridization switches in a plant expression system (wheat germ extract). PMID- 27975083 TI - MicroRNA-based screens for synthetic lethal interactions with c-Myc. AB - microRNAs (miRs) are small, non-coding RNAs, which play crucial roles in the development and progression of human cancer. Given that miRs are stable, easy to synthetize and readily introduced into cells, they have been viewed as having potential therapeutic benefit in cancer. c-Myc (Myc) is one of the most commonly deregulated oncogenic transcription factors and has important roles in the pathogenesis of cancer, thus making it an important, albeit elusive therapeutic target. Here we review the miRs that have been identified as being both positive and negative targets for Myc and how these participate in the complex phenotypes that arise as a result of Myc-driven transformation. We also discussseveral recent reports of Myc-synthetic lethal interactions with miRs.These highlight the importance and complexity of miRs in Myc-mediated biological functions and the opportunities for Myc-driven human cancer therapies. PMID- 27975088 TI - Spatial quenching of a molecular charge-transfer process in a quantum fluid: the Csx-C60 reaction in superfluid helium nanodroplets. AB - A recent experimental study [Renzler et al., J. Chem. Phys., 2016, 145, 181101] on superfluid helium nanodroplets reported different reactivities for Cs atoms and Cs2 dimers with C60 fullerenes inside helium droplets. Alkali metal atoms and clusters are heliophobic, therefore typically residing on the droplet surface, while fullerenes are fully immersed into the droplet. In this theoretical study, which combines standard methods of computational chemistry with orbital-free helium density functional theory, we show that the experimental findings can be interpreted in the light of a quenched electron-transfer reaction between the fullerene and the alkali dopant, which is additionally hindered by a reaction barrier stemming from the necessary extrusion of helium upon approach of the two reactants. PMID- 27975087 TI - DNA-affibody nanoparticles for inhibiting breast cancer cells overexpressing HER2. AB - In this study, we have prepared a DNA-affibody nanoparticle which mimics a antibody in its ability to specifically target the HER2 receptor. This nanoparticle has a smaller size (95 kDa) than the monoclonal antibody, trastuzumab (150 kDa) and at least two-fold greater activity toward BT474 cells than trastuzumab. The DNA in this nanoparticle structure has two functions, namely as a support to anchor two affibody molecules and as a vehicle to non covalently bind multiple copies of a small molecule drug for drug delivery. Each DNA-affibody nanoparticle can bind ~53 molecules of doxorubicin (DOX) to form a complex, which exhibits greater selectivity toward and inhibition of breast cancer cells overexpressing HER2 than doxorubicin does. As expected, the nanoparticle exhibits lesser inhibition of cells expressing HER2 at a low level. Thus, the nanoparticle represents a highly efficacious agent for inhibiting cancer cells which overexpress HER2, but with low toxicity toward normal cells. PMID- 27975089 TI - A highly conductive electrolyte for molten oxide fuel cells. AB - A gas-tight and ductile solid/liquid delta-Bi2O3-0.2 wt% B2O3 electrolyte for molten oxide fuel cells (MOFCs) is developed. The MOFCs are a new class of intermediate temperature fuel cells. The composite, consisting of solid (delta Bi2O3) and liquid (molten Bi2O3 + B2O3) oxygen ion-conducting phases, demonstrates the promising application as an MOFC electrolyte with the highest oxygen ionic conductivity. PMID- 27975091 TI - Structure and infrared spectra of hydrocarbon interstellar dust analogs. AB - A theoretical study of the structure and mid infrared (IR) spectra of interstellar hydrocarbon dust analogs is presented, based on DFT calculations of amorphous solids. The basic molecular structures for these solids are taken from two competing literature models. The first model considers small aromatic units linked by aliphatic chains. The second one assumes a polyaromatic core with hydrogen and methyl substituents at the edges. The calculated spectra are in reasonably good agreement with those of aliphatic-rich and graphitic-rich samples of hydrogenated amorphous carbon (HAC) generated in our laboratory. The theoretical analysis allows the assignment of the main vibrations in the HAC spectra and shows that there is a large degree of mode mixing. The calculated spectra show a marked dependence on the density of the model solids, which evinces the strong influence of the environment on the strengths of the vibrational modes. The present results indicate that the current procedure of estimating the hydrogen and graphitic content of HAC samples through the decomposition of IR features into vibrational modes of individual functional groups is problematic owing to the mentioned mode mixing and to the difficulty of assigning reliable and unique band strengths to the various molecular vibrations. Current band strengths from the literature might overestimate polyaromatic structures. Comparison with astronomical observations suggests that the average structure of carbonaceous dust in the diffuse interstellar medium lies probably in between those of the two models considered, though closer to the more aliphatic structure. PMID- 27975092 TI - Guest-tuned spin crossover in flexible supramolecular assemblies templated by a halide (Cl-, Br- or I-). AB - Ligand 1,3-bis(3-(pyridin-2-yl)-1H-pyrazol-5-yl)benzene, L, forms mononuclear spin crossover complexes [FeL3]2+ with pendant arms that cause them to dimerize through numerous intermolecular interactions forming supramolecular (X@[FeL3]2)3+ cations. They have the flexibility to encapsulate Cl-, Br- or I-, which allow tuning the magnetic properties, in the solid state and in solution. PMID- 27975090 TI - Near infrared spectroscopic assessment of developing engineered tissues: correlations with compositional and mechanical properties. AB - Articular cartilage degeneration causes pain and reduces the mobility of millions of people annually. Regeneration of cartilage is challenging, due in part to its avascular nature, and thus tissue engineering approaches for cartilage repair have been studied extensively. Current techniques to assess the composition and integrity of engineered tissues, including histology, biochemical evaluation, and mechanical testing, are destructive, which limits real-time monitoring of engineered cartilage tissue development in vitro and in vivo. Near infrared spectroscopy (NIRS) has been proposed as a non-destructive technique to characterize cartilage. In the current study, we describe a non-destructive NIRS approach for assessment of engineered cartilage during development, and demonstrate correlation of these data to gold standard mid infrared spectroscopic measurements, and to mechanical properties of constructs. Cartilage constructs were generated using bovine chondrocyte culture on polyglycolic acid (PGA) scaffolds for six weeks. BMP-4 growth factor and ultrasound mechanical stimulation were used to provide a greater dynamic range of tissue properties and outcome variables. NIR spectra were collected daily using an infrared fiber optic probe in diffuse reflectance mode. Constructs were harvested after three and six weeks of culture and evaluated by the correlative modalities of mid infrared (MIR) spectroscopy, histology, and mechanical testing (equilibrium and dynamic stiffness). We found that specific NIR spectral absorbances correlated with MIR measurements of chemical composition, including relative amount of PGA (R = 0.86, p = 0.02), collagen (R = 0.88, p = 0.03), and proteoglycan (R = 0.83, p = 0.01). In addition, NIR-derived water content correlated with MIR-derived proteoglycan content (R = 0.76, p = 0.04). Both equilibrium and dynamic mechanical properties generally improved with cartilage growth from three to six weeks. In addition, significant correlations between NIRS-derived parameters and mechanical properties were found for constructs that were not treated with ultrasound (PGA (R = 0.71, p = 0.01), water (R = 0.74, p = 0.02), collagen (R = 0.69, p = 0.04), and proteoglycan (R = 0.62, p = 0.05)). These results lay the groundwork for extension to arthroscopic engineered cartilage assessment in clinical studies. PMID- 27975093 TI - Biomimetic synthesis of cerium oxide nanosquares on RGO and their enhanced photocatalytic activities. AB - Water splitting based on heterogeneous photocatalytic nanomaterials is an attractive approach for generating hydrogen as a clean chemical fuel from solar energy. However, the high defect-induced recombination rate of photoexcited electron-hole pairs and poor photostability have greatly limited the heterophotocatalysts' practical application. Herein, we used a biotemplate method to give reduced graphene oxide (RGO) a remarkable unique bio-porous morphology with significant anti-aggregation of CeO2 square quantum dots (SQDs) when growing them in situ during a simple hydrothermal process. Biomorphic CeO2 SQDs-RGO has higher electrical conductivity and a narrowed band gap due to there being abundant oxygen vacancies, which results in more effective photo-induced charge generation, transfer and separation. The composite is able to act as an active visible light photocatalyst for highly efficient hydrogen generation applications. Such biomimetic designs could inspire immense research in synthesizing materials with a controlled structure and morphology toward achieving novel graphene-based nanocomposite photocatalysts for solar energy conversion. PMID- 27975094 TI - Critical evaluation of spectral information of benchtop vs. portable near infrared spectrometers: quantum chemistry and two-dimensional correlation spectroscopy for a better understanding of PLS regression models of the rosmarinic acid content in Rosmarini folium. AB - In the present work the performances of one benchtop and two different types of miniaturized near-infrared (NIR)-spectrometers were tested and compared for the first time by the determination of the rosmarinic acid (RA) content of dried and powdered Rosmarini folium. The recorded NIR spectra were utilized in hyphenation with multivariate data analysis (MVA) to calculate Partial Least Squares (PLS) regression models. Quality parameters obtained from Cross Validation (CV) revealed that the benchtop NIR-device "NIRFlex N-500 FT-NIR spectrometer" achieved the best result with a R2 of 0.91 and a RPD of 3.27. The miniaturized NIR-device "MicroNIR 2200 spectrometer" showed a satisfying calibration quality with a R2 of 0.84 and a RPD of 2.46. The miniaturized NIR-device "ThermoScientific microPHAZIR" with a R2 of 0.73 and a RPD of 1.88 was less precise and needs to be improved. The measured spectra of the different devices were additionally investigated by two-dimensional correlation spectroscopy (2D COS) analysis, which supported the performed PLS regression models as well as identified the discrepancies for microPHAZIR and MicroNIR 2200 compared to NIRFlex N-500. With the aim to obtain a better understanding of the factors which determine the analyzed PLS regression models, the NIR spectrum of RA was reproduced through application of fully anharmonic quantum chemical calculation. A good agreement between the experimental and theoretical NIR spectra and detailed band assignments of RA were obtained in the 8000-4000 cm-1 wavenumber region. Subsequently, this enabled us to attribute the main influences in the regression coefficients plots. This study demonstrated that the performance of NIR spectroscopy with benchtop and miniaturized devices as a fast and non invasive technique is able to replace time- and resource-consuming analytical tools. Referring to the developed application of the RA content quantification this work is especially interesting for the continuous growing phytopharmaceutical industry and its quality control. The results reveal the importance of monitoring the performances of available NIR-spectrometers in every analytical area. PMID- 27975095 TI - Bu4NI/tBuOOH catalyzed, alpha-regioselective cross-dehydrogenative coupling of BODIPY with allylic alkenes and ethers. AB - A Bu4NI/tBuOOH-catalyzed, highly regioselective cross-dehydrogenative coupling (CDC) of the alpha-C-H bond(s) of the BODIPY core has been developed. The alpha regioselective alkylation reaction utilizes easily accessible coupling partners, namely commercial allylic alkenes and ethers - even common, inert organic solvents, such as tetrahydrofuran, diethyl ether and 1,4-dioxane. The high alpha regioselectivity of this CDC reaction is attributable to the radical process involved and provides a facile access to a variety of alpha-functionalized BODIPYs, which are hard to access through current synthetic methods. PMID- 27975096 TI - Fluorescence detection of endogenous bisulfite in liver cancer cells using an effective ESIPT enhanced FRET platform. AB - Probe L-HF1, which featured large (pseudo) Stokes shifts and high FRET efficiency, was designed on a new ESIPT enhanced FRET platform for the detection of HSO3-/SO32-. L-HF1 could detect endogenous bisulfite in HepG2 cells but not in L-02 cells, implying the different bisulfite levels in normal and cancer cells of liver. PMID- 27975097 TI - An injectable collagen/poly(gamma-glutamic acid) hydrogel as a scaffold of stem cells and alpha-lipoic acid for enhanced protection against renal dysfunction. AB - Mesenchymal stem cells (MSCs) can ameliorate renal injury and accelerate repair of acute kidney injury. Herein, we developed a collagen/poly(gamma-glutamic acid) (gamma-PGA) hydrogel as an injectable scaffold for the delivery of mouse MSCs (mMSCs) and anti-oxidant drugs into injured sites. By the introduction of gamma PGA into conventional collagen, the viscosity of collagen was reduced at ambient temperature for easy handling, while the elastic and viscous moduli of collagen were increased and a new porous structure was generated near body temperature. When in situ gel-forming collagen/gamma-PGA hydrogels loaded with mMSCs and alpha lipoic acid (LA) were administered to a mouse model of renal dysfunction, they significantly attenuated the level of blood urea nitrogen and creatinine, which resulted from the increased retention of therapeutic mMSCs and the controlled release of anti-oxidant drugs at the injured site. These findings suggested that this novel type of hydrogel could be applied as an injectable scaffold for use in regenerative medicine. PMID- 27975100 TI - Hyperglycaemia suppresses microRNA expression in platelets to increase P2RY12 and SELP levels in type 2 diabetes mellitus. AB - Megakaryocyte (MK)-derived miRNAs have been detected in platelets. Here, we analysed the expression of platelet and circulating miR-223, miR-26b, miR-126 and miR-140 that might be altered with their target mRNAs in type 2 diabetes mellitus (DM2). MiRNAs were isolated from leukocyte-depleted platelets and plasma samples obtained from 28 obese DM2, 19 non-DM obese and 23 healthy individuals. The effect of hyperglycaemia on miRNAs was also evaluated in MKs using MEG-01 and K562 cells under hyperglycaemic conditions after 8 hours up to four weeks. Quantitation of mature miRNA, pre-miRNAs and target mRNA levels (P2RY12 and SELP) were measured by RT-qPCR. To prove the association of miR-26b and miR-140 with SELP (P-selectin) mRNA level, overexpression or inhibition of these miRNAs in MEG 01 MKs was performed using mimics or anti-miRNAs, respectively. The contribution of calpain substrate Dicer to modulation of miRNAs was studied by calpain inhibition. Platelet activation was evaluated via surface P-selectin by flow cytometry. Mature and pre-forms of investigated miRNAs were significantly reduced in DM2, and platelet P2RY12 and SELP mRNA levels were elevated by two-fold at increased platelet activation compared to controls. Significantly blunted miRNA expressions were observed by hyperglycaemia in MEG-01 and K562-MK cells versus baseline values, while the manipulation of miR-26b and miR-140 expression affected SELP mRNA level. Calpeptin pretreatment restored miRNA levels in hyperglycaemic MKs. Overall, miR-223, miR-26b, miR-126 and miR-140 are expressed at a lower level in platelets and MKs in DM2 causing upregulation of P2RY12 and SELP mRNAs that may contribute to adverse platelet function. PMID- 27975098 TI - Endotoxaemia-augmented murine venous thrombosis is dependent on TLR-4 and ICAM-1, and potentiated by neutropenia. AB - Venous thromboembolism is a major cause of death during and immediately post sepsis. Venous thrombosis (VT) is mediated by cell adhesion molecules and leukocytes, including neutrophil extracellular traps (NETs). Sepsis, or experimentally, endotoxaemia, shares similar characteristics and is modulated via toll like receptor 4 (TLR4). This study was undertaken to determine if endotoxaemia potentiates early stasis thrombogenesis, and secondarily to determine the role of VT TLR4, ICAM-1 and neutrophils (PMNs). Wild-type (WT), ICAM-1-/- and TLR4-/- mice underwent treatment with saline or LPS (10 mg/kg i. p.) alone, or followed by inferior vena cava (IVC) ligation to generate stasis VT. In vivo microscopy of leukocyte trafficking was performed in non-thrombosed mice, and tissue and plasma were harvested during early VT formation. Pre thrombosis, circulating ICAM-1 was elevated and increased leukocyte adhesion and rolling occurred on the IVC of LPS-treated mice. Post-thrombosis, endotoxaemic mice formed larger, platelet-poor thrombi. Endotoxaemic TLR4-/- mice did not have an augmented thrombotic response and exhibited significantly decreased circulating ICAM-1 compared to endotoxaemic WT controls. Endotoxaemic ICAM-1-/- mice had significantly smaller thrombi compared to controls. Hypothesising that PMNs localised to the inflamed endothelium were promoting thrombosis, PMN depletion using anti-Ly6G antibody was performed. Paradoxically, VT formed without PMNs was amplified, potentially related to endotoxaemia induced elevation of PAI-1 and circulating FXIII, and decreased uPA. Endotoxaemia enhanced early VT occurs in a TLR-4 and ICAM-1 dependent fashion, and is potentiated by neutropenia. ICAM-1 and/or TLR-4 inhibition may be a unique strategy to prevent sepsis-associated VT. PMID- 27975101 TI - More than an anticoagulant: Do heparins have direct anti-inflammatory effects? AB - The heparins, well-known for their anticoagulant properties, may also have anti inflammatory effects that could contribute to their effectiveness in the treatment of venous thromboembolism and other vascular diseases. This review focuses on the inflammatory pathophysiology that underlies the development of thrombosis and the putative effects of heparin on these pathways. We present evidence supporting the use of heparin for other indications, including autoimmune disease, malignancy, and disseminated intravascular coagulation. These considerations highlight the need for further research to elucidate the mechanisms of the possible pleiotropic effects of the heparins, with a view to advancing treatments based upon heparin derivatives. PMID- 27975099 TI - Paradoxical bleeding and thrombotic episodes of dysprothrombinaemia due to a homozygous Arg382His mutation. AB - We have characterised the pathogenic basis of dysprothrombinaemia in a patient exhibiting paradoxical bleeding and thrombotic defects during pregnancy and postpartum. Genetic analysis revealed that the proband is homozygous for the prothrombin Arg382His mutation, possessing only ~1 % clotting activity. The proband experienced severe bleeding episodes during her pregnancy, which required treatment with prothrombin complex concentrates, and then pulmonary embolism and deep-vein thrombosis at 28 days postpartum, which required treatment with LMWH and fresh frozen plasma. Analysis of haemostatic parameters revealed that the subject had elevated FDP and DD and decreased fibrinogen levels, indicating the presence of hyperfibrinolysis. Thrombin generation and clotting assays with the proband's plasma in the presence of soluble thrombomodulin and tissue-type plasminogen activator indicated a defect in activation of both protein C and thrombin activatable fibrinolysis inhibitor (TAFI). Unlike normal plasma, no TAFI activation could be detected in the patient's plasma. The expression and characterisation of recombinant prothrombin Arg382His indicated that zymogen activation by prothrombinase was markedly impaired and the activation of protein C and TAFI by thrombin-Arg382His was impaired 600-fold and 2500-fold, respectively. The recombinant thrombin mutant exhibited impaired catalytic activity toward both fibrinogen and PAR1 as determined by clotting and signalling assays. However, the mutant activated factor XI normally in both the absence and presence of polyphosphates. Arg382 is a key residue on (pro)exosite-1 of prothrombin and kinetic analysis of substrate activation suggested that the poor zymogenic activity of the mutant is due to its inability to bind factor Va in the prothrombinase complex. PMID- 27975102 TI - Atherosclerosis revisited from a clinical perspective: still an inflammatory disease? AB - Compelling experimental results have substantiated the immune-driven inflammatory nature of atherosclerosis. Most of the scientific advances over the past decades have been achieved by relying on transgenic animal models that have been employed with increasing levels of sophistication. However, recent failures in translating various anti-inflammatory therapeutic strategies for use in humans might raise some skepticism with regards to an inflammatory causality underlying human atherosclerosis. By applying a dialectical approach, this Perspective aims to challenge and deduce the nature of atherosclerosis by reviewing results exclusively derived from human studies and recent clinical trials, as "things may not always be, what they appear". PMID- 27975103 TI - Reasons for the persistent incidence of venous thromboembolism. AB - Reasons for trends in venous thromboembolism (VTE) incidence are uncertain. It was our objective to determine VTE incidence trends and risk factor prevalence, and estimate population-attributable risk (PAR) trends for each risk factor. In a population-based cohort study of all residents of Olmsted County, Minnesota from 1981-2010, annual incidence rates were calculated using incident VTE cases as the numerator and age- and sex-specific Olmsted County population estimates as the denominator. Poisson regression models were used to assess the relationship of crude incidence rates to year of diagnosis, age at diagnosis, and sex. Trends in annual prevalence of major VTE risk factors were estimated using linear regression. Poisson regression with time-dependent risk factors (person-years approach) was used to model the entire population of Olmsted County and derive the PAR. The age- and sex-adjusted annual VTE incidence, 1981-2010, did not change significantly. Over the time period, 1988-2010, the prevalence of obesity, surgery, active cancer and leg paresis increased. Patient age, hospitalisation, surgery, cancer, trauma, leg paresis and nursing home confinement jointly accounted for 79 % of incident VTE; obesity accounted for 33 % of incident idiopathic VTE. The increasing prevalence of obesity, cancer and surgery accounted in part for the persistent VTE incidence. The PAR of active cancer and surgery, 1981-2010, significantly increased. In conclusion, almost 80 % of incident VTE events are attributable to known major VTE risk factors and one third of incident idiopathic VTE events are attributable to obesity. Increasing surgery PAR suggests that concurrent efforts to prevent VTE may have been insufficient. PMID- 27975105 TI - Transient inherited antithrombin deficiency: a real phenomenon? PMID- 27975106 TI - Aspects of Pediatric Hepatology and Access to Pediatric Health Care. PMID- 27975107 TI - Pediatricians as Psychiatrists. AB - The overall health of children and teenagers is dependent on their physical and psychological health. As pediatricians, it is important to enquire about the mental health of children and adolescents at the well-child visit. Screening for depression and attention-deficit/hyperactivity disorder is an important component of that visit. Understanding these disorders and the long-term effects on both the child and family as well as managing psychotherapeutic and pharmacological treatments are now becoming a critical part of pediatric care for children and adolescents. [Pediatr Ann. 2016;45(12):e408-e411.]. PMID- 27975104 TI - Prognostic significance of tPA/PAI-1 complex in patients with heart failure and preserved ejection fraction. AB - Heart failure with preserved ejection fraction (HFpEF) represents a major epidemic, clinical and public health problem with rising patient numbers every year. Traditional markers for heart failure have been shown to be of limited sensitivity in patients with HFpEF, as those do not reflect pathophysiology of the disease properly. Dysregulation of haemostasis is thought to be central for the initiation and progression of HFpEF. For this reason, we aimed to assess markers of fibrinolytic activity as potential biomarkers for risk assessment in patients with HFpEF. We evaluated blood coagulation parameters in 370 patients with HFpEF included in the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. Within an observation period of 9.7 years, 40 percent of these patients died from any cause. tPA/PAI-1 complex significantly predicted all-cause mortality with a hazard ratio (HR) of 1.24 (95 % confidence interval [CI] 1.04 1.47) per increase of 1 SD and cardiovascular mortality with a HR 1.26 (95 % CI 1.02-1.56) per increase of 1 SD. Both associations remained significant after adjustment for cardiovascular risk factors, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and frequent HFpEF- related comorbidities. Importantly, tPA/PAI-1 complex had additional prognostic value above and beyond NT-proBNP as indicated by integrated discrimination improvement (0.0157, p=0.017). In conclusion, the concentration of tPA/PAI-1 complex is an independent predictor of mortality from all causes and from cardiovascular causes in patients with HFpEF. The concomitant measurement of tPA/PAI-1 complex might be useful in clinical practice to add prognostic value to traditional markers of heart failure. PMID- 27975108 TI - Pediatric Hepatology. PMID- 27975109 TI - Cholestasis in Infancy. AB - Jaundice is a key manifestation of hepatobiliary disease in all age groups. Jaundice is a common finding in the first 2 weeks after birth, occurring in 2.4% to 15% of newborns. The neonatal liver is at increased susceptibility to cholestasis, with an incidence ranging from 1 in 2,500 to 1 in 5,000 live births. Etiologies vary, but the most common is biliary atresia. In 2004, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition published guidelines for the evaluation of cholestasis that clearly stated any infant with jaundice persisting beyond age 2 weeks (3 weeks in breast-fed infants with an otherwise normal history and physical examination) should be evaluated with a fractionated serum bilirubin level. Prompt evaluation, diagnosis, and intervention are vital to optimize timely intervention and improve clinical outcomes. This article discusses the etiology, diagnosis and evaluation of cholestatis in infants. [Pediatr Ann. 2016;45(12):e414-e419.]. PMID- 27975110 TI - Viral Hepatitis in Children: A Through E. AB - Hepatitis is defined as inflammation of the liver. This inflammation can be acute and self-limited, chronic (leading to cirrhosis and an increased risk for hepatocellular carcinoma), or fulminant (requiring lifesaving liver transplantation). Although there are many causes of hepatitis, this article focuses on the main childhood viral hepatidities: types A, B, C, D, and E. This review discusses the main characteristics of each virus, including salient epidemiology, clinical characteristics, diagnosis, treatment, and prevention strategies. [Pediatr Ann. 2016;45(12):e420-e426.]. PMID- 27975111 TI - An Overview of Cirrhosis in Children. AB - Cirrhosis is the end result of nearly all forms of progressive liver disease. The diffuse hepatic process can be characterized as a state of inflammation progressing to fibrosis and resulting in nodular regeneration, ultimately leading to disorganized liver architecture and function. The underlying etiology of cirrhosis in children may often differ from adults owing to specific disease processes that manifest in childhood, including biliary atresia, galactosemia, and neonatal hepatitis. Although basic management strategies in children are similar to those in adults, the care given to children with cirrhosis must keep the child's growth and development of paramount importance. [Pediatr Ann. 2016;45(12):e427-e432.]. PMID- 27975112 TI - Acute Liver Failure. AB - Pediatric acute liver failure (ALF) is a complex and rapidly progressive syndrome that results from a variety of age-dependent etiologies. It is defined by the acute onset of liver disease with no evidence of chronic liver disease. There must be biochemical or clinical evidence of severe liver dysfunction as defined by an international normalized ratio (INR) >=2. If hepatic encephalopathy is present, INR should be >=1.5. Unfortunately, due to the rarity of ALF in pediatric patients, there is a paucity of diagnostic and management algorithms and each patient must have an individualized approach. [Pediatr Ann. 2016;45(12):e433-e438.]. PMID- 27975113 TI - Pediatric Liver Transplantation: An Update for the Pediatrician. AB - Pediatric liver transplantation is a state-of-the-art treatment for children with end-stage liver disease. Over the past few decades, the advent of new surgical techniques using split liver grafts and living donors has drastically increased the organ availability for pediatric patients, while advances in immunosuppression have improved overall outcomes. The pediatrician is a key player in the multidisciplinary team that cares for these children starting with the timely referral of children who require liver transplantation to the active participation in optimizing the child's overall health before and after transplantation. [Pediatr Ann. 2016;45(12):e439-e445.]. PMID- 27975114 TI - The Ketogenic Diet: A Practical Guide for Pediatricians. AB - The ketogenic diet is an effective treatment for drug-resistant epilepsies in children. In addition, it is the first-line treatment for some metabolic disorders, such as glucose transporter 1 deficiency syndrome. This article discusses the proposed mechanisms of a ketogenic diet's antiseizure action, its clinical indications, and its contraindications. The steps involved in ketogenic diet initiation, monitoring, and management of its side effects are also discussed. This review provides general pediatricians with the necessary skills to provide comprehensive care of children using the ketogenic diet and counsel their families and caregivers. [Pediatr Ann. 2016;45(12):e446-e450.]. PMID- 27975115 TI - Neuroimaging of neuropathic pain: review of current status and future directions. AB - The goal of this review is to discuss the various imaging modalities to study neuropathic pain and its future implication in understanding pain network, for the diagnosis and management of patients with chronic neuropathic pain. Neuropathic pain is characterized by pain secondary to lesions or dysfunction of the central nervous system (CNS) or the peripheral nervous system. Neuropathic pain is generally chronic and disabling, and responds poorly to conventional treatment. Although our understanding of the imaging changes in chronic pain state is evolving, we still face practical challenges in implementing these finding to objectively diagnose and follow treatment response in patients with chronic pain and to guide targeted and individualized treatment to each chronic pain condition. PMID- 27975116 TI - Long-term safety assessment in children who received hydrolyzed protein formulas with Lactobacillus rhamnosus GG: a 5-year follow-up. AB - : Extensively hydrolyzed (EH) formula with Lactobacillus rhamnosus GG (LGG) was demonstrated to alleviate cow's milk allergy (CMA) symptoms and promote faster acquisition of tolerance to cow's milk protein. We previously demonstrated that partially hydrolyzed (PH) and EH formulas with LGG supported normal growth in healthy-term infants through 120 days of age. The objective of the current study was to evaluate growth, development, and specific adverse events through 5 years of age in participants from that cohort who continued receiving study formula. Infants who completed a double-blind, randomized growth and tolerance study were eligible to continue receiving the assigned study formula through 1 year of age (control: EH casein formula, EHF, or one of two investigational formulas: EH casein formula with LGG (EHF-LGG) or a PH formula with LGG (PHF-LGG)) and participate in follow-up through 5 years of age. Anthropometric measures, behavior development, and specific adverse events were recorded. No significant differences in achieved weight and height or behavioral development outcomes at 3 or 5 years of age were observed among study groups. Few statistically significant differences in the incidence of specific infection-related events through years 3 or 5 were observed among study groups, none of which were considered clinically relevant. CONCLUSION: Extensively and partially hydrolyzed formulas with LGG were associated with normal growth and development and long-term safety through 5 years of age. What is Known: * Infants with cow's milk allergy often experience allergic manifestations that can lead to poor nutrition status and poor growth. * Providing partially hydrolyzed (PH) and EH formulas with or without LGG in infants can support normal growth in healthy-term infants. What is New: * This study provides long-term safety data for the first 5 years of life on the use of extensively and partially hydrolyzed formulas with LGG when fed through 1 year of age. * Extensively and partially hydrolyzed formulas with LGG are associated with normal growth, development, and long-term safety through 5 years of age. PMID- 27975117 TI - Influence of temperature, precipitation, and cultivar characteristics on changes in the spectrum of pathogenic fungi in winter wheat. AB - In view of the threat posed by climate change, we studied the influence of temperature, precipitation, cultivar characteristics, and technical management measures on the occurrence of phytopathogenic fungi in wheat during 2009-2013. This work involved experiments at two sites differing in average temperatures and precipitation. Temperature and precipitation appear to influence differences in the spectrum of phytopathogenic fungi at the individual sites. In 2009 (the warmest year), Alternaria triticina was dominant. In 2010 (having the smallest deviations from the average for individual years), Septoria tritici dominated. In 2011, Puccinia triticina was most prominent, while in 2012, the genus Drechslera (Pyrenophora) and in 2013, S. tritici and Drechslera tritici-repentis (DTR) dominated. Temperature and precipitation levels in the individual spring months (warmer March to May) played a large role, especially for the leaf rust P. triticina in 2011. A change of only 1 degrees C with different precipitation during a year played a significant role in changing wheat's fungal spectrum. Cluster analysis showed the differences between single pathogenic fungi on wheat in a single year due to temperature and precipitation. Alternaria abundance was strongly influenced by year (p < 0.001) while locality was significant only in certain years (2012, 2013; p = 0.004 and 0.015, respectively). The same factors were revealed to be significant in the case of Puccinia, but locality played a role (p < 0.001) in different years (2011, 2013). The abundance of S. tritici and Pyrenophora tritici-repentis (Drechslera tritici-repentis) was influenced only by year (p < 0.001). PMID- 27975118 TI - [PKT - Palliative competence test for physicians : Design and validation of a questionnaire to assess knowledge and specific self-efficacy expectations of physicians in palliative care]. AB - BACKGROUND: Providing end of life care for dying patients and those with life threatening diseases is one of the core competences of physician. During the course of training all physicians should develop a sharpened perception of symptoms and acquire competence in the relief and therapy of pain. OBJECTIVES: The Hospital of Saint John of God in Vienna, Austria, provides an educational program for residents concerning end of life care. Treatment of pain is one of the major topics. A questionnaire (PKT) was designed in order to evaluate the efficiency of this program. MATERIAL AND METHODS: The Japanese PEACE questionnaire for assessing palliative knowledge of physicians was translated into German and the items checking specific self-efficacy expectations in palliative care in the Bonn palliative knowledge test (Bonner Palliativwissenstests) were transformed into physician duties. The new combination of 52 items was validated by testing groups of physicians with different levels of palliative education and experience. RESULTS: The 37 physicians who had received palliative education scored better in the knowledge section than the 46 without palliative education: 21 vs. 16 correct answers out of 28 (p < 0.001). In these two groups we also found a differences in self efficacy expectations in palliative care: 46 vs. 35 points out of 54 (p < 0.001). Having worked in a specialized palliative setting (n = 33) was associated with higher scores in palliative knowledge 23 vs. 16 points (p < 0.001) as well as in self-efficacy expectations 47 vs. 35 (p < 0.001). CONCLUSION: The PKT is a German questionnaire that was validated to assess the efficiency of palliative education for physicians. PMID- 27975119 TI - [The arduous route of a 33-year-old woman with headache]. AB - This article presents the case of a 33-year-old female patient with exacerbation of a pre-existing tension type headache. The exacerbation occurred within the scope of an infection and persisted after the infection had receded. The excessive diagnostic approaches went on for weeks and only finally came to an end with the diagnosis of a pregnancy. The impacts of hormonal changes on headaches caused by pregnancy are discussed as well as postinfection events. PMID- 27975122 TI - [A nomogram for the prediction of malignancy in branch-duct IPMN]. PMID- 27975120 TI - Nested PCR targeting intergenic spacer (IGS) in genotyping of Giardia duodenalis isolated from symptomatic and asymptomatic infected Egyptian school children. AB - Distinct sequences of Giardia duodenalis assemblages raised the hypothesis that certain assemblages may contribute to its clinical outcome. However, sequences analysis is time consuming, expensive, and needs many manual operations. Nested PCR targeting intergenic spacer (IGS) region was applied successfully to genotype G. duodenalis. This study aimed to identify the prevalence of G. duodenalis assemblages among giardiasis school children and its relation to the presence of symptoms using nested IGS/PCR. Of 65 microscopically confirmed Giardia-positive samples, 65 samples were genotyped proving high sensitivity (92.3%) of IGS/PCR. Negative IGS/PCR samples were also negative for beta-giardin gene. Subassemblage AI was the commonest with 66.6% (20/30) among asymptomatic children compared to 53.3% (16/30) of symptomatic, while assemblage B was found in 40% (12/30) of symptomatic compared to 20% (6/30) of asymptomatic. The difference was significant. AII was only found in asymptomatic with 13.4% (4/30), while mixed infections (AI&B) were recorded only in 6.6% (2/30) of symptomatic group. A significant relation was found between younger children susceptibility for AI and B infections as presented in 77.7 (12/16) and 83.3% (10/12) of symptomatic, respectively, and 80 (16/80) and 33.4% (2/4) of asymptomatic, respectively. Significant relations were found between AI with intermittent diarrhea and B with chronic. A significant relation was found between assemblage distributions and heavy infection intensity. In conclusion, higher incidence of assemblage B among symptomatic children compared to asymptomatic could denote its possible pathogenic potential. PMID- 27975123 TI - [Different techniques for pancreatic anastomosis]. PMID- 27975121 TI - [Mechanobiology of fracture healing part 2 : Relevance for internal fixation of fractures]. AB - Clinical studies do not allow a quantitative correlation between stability of fracture fixation and outcome of bone healing. This limits the biomechanical improvement of fracture fixation techniques. The most practical quantitative parameter to describe the stability of a fracture fixation is the stiffness. This can be determined for several types of fixation through biomechanical methods and in some clinical studies in vivo. By using numerical fracture healing models, it is now possible to use the tissue differentiation rules found in basic research to calculate optimal stiffness parameters for various fixation techniques. For a tibial fracture as an example the possibilities of a numerical fracture healing simulation have been demonstrated. The effects of the diameter of an intramedullary nail, type of fracture, fracture gap size and nail material on healing could be demonstrated. To circumvent complex and time consuming calculations for several fixations a map was calculated which shows the expected bone healing quality as a function of the axial stiffness and the shear stiffness of the fixation device. By comparing the stiffness of various fixation techniques with the stiffness map it becomes evident that the methods most often used (e.g. unreamed nail, plate and external fixator) have a low shear and/or rotational stiffness that is too low to achieve the optimal healing outcome. The high axial stiffness of plates next to the plate surface can lead to very low tissue strain directly adjacent to the plate and can delay the bone healing process at this location. PMID- 27975124 TI - [Updated definition of sepsis : Implications for diagnostics and therapy principles]. AB - Until a short time ago the criteria for sepsis were based on the assumption that sepsis is primarily caused by the inflammatory reaction of the body to an infection, which does not correspond to the current knowledge on the pathophysiology of sepsis. Accordingly, sepsis is now defined as a life threatening organ dysfunction due to a falsely regulated response of the body to an infection. Septic shock occurs when a condition of persisting hypotension with the continuous need for vasopressor agents and serum lactate levels of >2 mmol/l despite administration of sufficient volume and fluid is present. These new definitions are discussed in this article with respect to the consequences for the diagnosis of sepsis. This review article also presents the current controversies on the most important aspects of the therapy of sepsis. PMID- 27975126 TI - Value of postmortem studies in deceased neonatal and pediatric intensive care unit patients. AB - Worldwide, various autopsy studies have shown a decrease in the diagnostic error rate over the last years. The cause of this positive development is mainly due to the improvement of modern medicine. However, intensive care unit patients are thought to have a higher risk for diagnostic errors, which is documented in several studies in the adult population. In contrast, there is only limited information about diagnostic errors in pediatrics, particularly in pediatric and neonatal intensive care units. The aims of this study were to analyze the spectrum of childhood death, determine the prevalence and distribution of autopsy confirmed diagnostic errors, and describe patient characteristics that might have influenced the discordance between antemortem and postmortem findings. We analyzed 143 autopsy reports from 2004 to 2013 and correlated these with clinical reports. The overall autopsy rate during this interval was 20.3%. The leading causes of death were congenital malformations (28%), diseases closely associated with perinatal disorders (25%), disorders of the cardiovascular system (18%), and infections (15%). Additional findings were obtained in 23% of the autopsies. Major diagnostic errors were found in 6%, the lowest reported value in a developed country as yet. Most cases (75%) showed complete concordance between clinical diagnoses and postmortem findings, in line with improvements in diagnostic and therapeutic processes over the last decades. In conclusion, autopsy of neonates, infants, and children represents an important tool for monitoring the quality of pediatric and neonatal medical care. PMID- 27975127 TI - Sequential treatment with thrombopoietin-receptor agonists (TPO-RAs) in immune thrombocytopenia (ITP): experience in our center. PMID- 27975128 TI - [Bilateral eye injuries by external transversal force]. AB - A 49-year-old female victim of violent crime with an acute bilateral loss of vision was referred to our hospital. The ophthalmological evaluation showed complete subconjunctival hemorrhage of both eyes, bilateral hemophthalmos and hypotonia of the left eye. These raised the suspicion of an occult scleral rupture. We immediately performed exploratory surgery and found a perforating scleral lesion of the left eye and a penetrating scleral lesion of the right eye. Furthermore, a small, cruciform wound was detected on the left temple. In cooperation with the department of radiology, the extraordinary injury pattern was reconstructed: a horizontal stab wound with perforation of the left eye and penetration of the right eye caused by a screwdriver. Visual rehabilitation necessitated further surgical interventions. Besides the intraoperative approach, immediate primary wound management within 100 h of trauma plays a pivotal role for long-term outcome. PMID- 27975125 TI - Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence. AB - RATIONALE: It has recently been found that chronic treatment with the highly selective, brain-penetrating Y5 receptor antagonist, Lu AA33810 [N-[[trans-4 [(4,5-dihydro [1] benzothiepino[5,4-d] thiazol-2-yl) amino] cyclohexyl]methyl] methanesulfonamide], produces antidepressant-like effects in the rat chronic mild stress model. OBJECTIVE: In the present study, we investigated the possible antidepressant-like activity of Lu AA33810 in rats subjected to glial ablation in the prefrontal cortex (PFC) by the gliotoxin L-AAA, which is an astroglial degeneration model of depression. RESULTS: We observed that Lu AA33810 administered intraperitoneally at a single dose of 10 mg/kg both reversed depressive-like behavioral changes in the forced swim test (FST) and prevented degeneration of astrocytes in the mPFC. The mechanism of antidepressant and glioprotective effects of Lu AA33810 has not been studied, so far. We demonstrated the contribution of the noradrenergic rather than the serotonergic pathway to the antidepressant-like action of Lu AA33810 in the FST. Moreover, we found that antidepressant-like effect of Lu AA33810 was connected with the influence on brain-derived neurotrophic factor (BDNF) protein expression. We also demonstrated the antidepressant-like effect of Lu AA33810 in the FST in rats which did not receive the gliotoxin. We found that intracerebroventricular injection of the selective MAPK/ERK inhibitor U0126 (5 MUg/2 MUl) and the selective PI3K inhibitor LY294002 (10 nmol/2 MUl) significantly inhibited the anti-immobility effect of Lu AA33810 in the FST in rats, suggesting that MAPK/ERK and PI3K signaling pathways could be involved in the antidepressant-like effect of Lu AA33810. CONCLUSION: O ur results indicate that Lu AA33810 exerts an antidepressant-like effect and suggest the Y5 receptors as a promising target for antidepressant therapy. PMID- 27975130 TI - Does alcohol consumption modify the risk of endometrial cancer? A dose-response meta-analysis of prospective studies. AB - BACKGROUND: Epidemiological studies have provided controversial evidence of an association between alcohol intake and endometrial cancer (EC) risk. The World Cancer Research Fund/American Institute for Cancer Research classifies alcohol as having a "limited-no conclusion" grade of evidence in the Endometrial Cancer 2013 Report (the latest version). OBJECTIVE: The purpose of this meta-analysis is to systematically analyze the effect of alcohol intake on EC risk. METHODS: We conducted a dose-response meta-analysis of prospective cohort studies identified from the PubMed, Embase, Cochrane Library and China Biological Medicine databases. Categorical and dose-response meta-analyses were conducted to estimate the effects of alcohol on EC risk. RESULTS: A total of 10 studies involving 9766 cases and 1,612,798 participants were included in this meta-analysis. Overall, the relative risk(RR) for alcohol intake on EC was 1.04 (95% CI 0.88-1.22). The RRs for alcohol intake from wine, beer, and liquor were 1.10 (95% CI 0.80-1.51), 0.94 (95% CI 0.72-1.22), and 1.04 (95% CI 0.86-1.27), respectively). When alcohol consumption was stratified by drinking level, the RRs for moderate and heavy alcohol intake were 0.95 (95% CI 0.89-1.01) and 1.00 (95% CI 0.88-1.13), respectively. In the subgroup analyses, this association was not modified by other lifestyle factors or the characteristics of the study design and population. No significant associations were detected in the dose-response meta analyses. CONCLUSIONS: Alcohol intake is not associated with EC regardless of the beverage choice and alcohol consumption level. More studies are warranted in other populations, such as Asians and Africans. PMID- 27975129 TI - Elevated serum interleukin-37 level is a predictive biomarker of poor prognosis in epithelial ovarian cancer patients. AB - PURPOSE: Interleukin-37 (IL-37) has been identified as a novel anti-inflammatory cytokine which is involved in tumor development. This study aimed to evaluate the expression of IL-37 in serum and determine its clinical significance in human epithelial ovarian cancer (EOC). METHODS: Enzyme-linked immunosorbent assay (ELISA) was performed to examine the serum IL-37 levels in 76 patients with EOC and 76 healthy controls. The association of IL-37 levels with clinical factors and prognosis of EOC patients was analyzed. The diagnostic accuracy of serum IL 37 was performed by receiver operator characteristic (ROC) curve analysis. RESULTS: Serum IL-37 levels in patients with EOC (187.3 +/- 75.57 pg/ml) were significantly higher than those in healthy controls (84.89 +/- 28.92 pg/ml, P < 0.001). High serum IL-37 levels were significantly associated with FIGO stage (P < 0.001), tumor size (P = 0.002), lymph node metastasis (P = 0.021), positive recurrence (P = 0.047) and residual tumor size (P < 0.001). The Kaplan-Meier survival analysis demonstrated that high serum IL-37 levels were significantly associated with poor overall survival and the progression-free survival (log rank, P = 0.026, and P = 0.039, respectively). Univariate and multivariate analysis indicated that serum IL-37 levels (HR = 3.007, 95% CI 2.125-4.842, P = 0.008) were an independent prognostic factor for EOC patients. ROC curve analyses revealed an AUC (the areas under the ROC curve) of 0.881 (95% CI 0.829-0.945; P < 0.001). CONCLUSIONS: High serum IL-37 levels are associated with an unfavorable prognosis of EOC patients. IL-37 may serve as a promising and useful prognostic biomarker for EOC. PMID- 27975133 TI - "A safe-repositioning maneuver for the management of benign paroxysmal positional vertigo: Gans vs. Epley maneuver; a randomized comparative clinical trial": something else about Gans maneuver. PMID- 27975132 TI - Acute methotrexate toxicity presenting with bullous lesions: an unusual presentation. PMID- 27975131 TI - Impact of genetic and nongenetic factors on interindividual variability in 4beta hydroxycholesterol concentration. AB - PURPOSE: Individual variability in the endogenous CYP3A metabolite 4beta hydroxycholesterol (4betaOHC) is substantial, but to which extent this is determined by genetic and nongenetic factors remains unclear. The aim of the study was to evaluate the explanatory power of candidate genetic variants and key nongenetic factors on individual variability in 4betaOHC levels in a large naturalistic patient population. METHODS: We measured 4betaOHC concentration in serum samples from 655 patients and used multiple linear regression analysis to estimate the quantitative effects of CYP3A4*22, CYP3A5*3, and POR*28 variant alleles, comedication with CYP3A inducers, inhibitors and substrates, sex, and age on individual 4betaOHC levels. RESULTS: 4betaOHC concentration ranged >100 fold in the population, and the multiple linear regression model explained about one fourth of the variability (R 2 = 0.23). Only comedication with inducers or inhibitors, sex, and POR genotype were significantly associated with individual variability in 4betaOHC level. The estimated quantitative effects on 4betaOHC levels were greatest for inducer comedication (+>313%, P < 0.001), inhibitor comedication (-34%, P = 0.021), and female sex (+30%, P < 0.001), while only a modestly elevated 4betaOHC level was observed in carriers vs. noncarriers of POR*28 (+11%, P = 0.023). CONCLUSIONS: These findings suggest that the CYP3A4*22, CYP3A5*3, and POR*28 variant alleles are of limited importance for overall individual variability in 4betaOHC levels compared to nongenetic factors. PMID- 27975134 TI - Microbial Life and Death in a Foxing Stain: a Suggested Mechanism of Photographic Prints Defacement. AB - The gelatin-silver halide black and white prints represent an enormous photography heritage with a great value. Unaesthetic phenomena, the foxing stains that are caused by microbial growth on surface, have been described in stamps, drawings, books, and tissues but, until now, scarcely for photographic materials. In this study, a combination of various techniques, including culture-dependent and culture-independent approaches (RNA and DNA analysis), scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) and MU-Raman spectroscopy supported by X-ray fluorescence analysis (XRF), permitted to describe the microbial contamination dynamics of foxing stains present on the surface of two gelatin-silver halide photographs. The investigation provided also information on the effects of microbial activity on the materials' chemistry of the two prints. The action of microbial community resulted locally in either (a) formation of mixed aluminum-iron-potassium phosphate compounds that could be attributed to the hydrolytic activity of bacteria, (b) leaching of barite, PMID- 27975136 TI - Effects of initial moisture content of Korean traditional wheat-based fermentation starter nuruk on microbial abundance and diversity. AB - The brewing of makgeolli, one of Korea's most popular alcoholic beverages that is gaining popularity globally, is facilitated by nuruk, a traditional Korean cereal starter. The nuruk microbiome greatly influences the fermentation process as well as the nutritional, hygienic, and aromatic qualities of the product. This study is a continuation of our efforts to examine nuruk biodiversity at a depth previously unattainable. In this study, microfloral dynamics in wheat-based nuruk C, composed of traditional ingredients such as barley, green gram, and wheat and fermented under various internal moisture contents of 20% (C20), 26% (C26), and 30% (C30), was evaluated using 454 pyrosequencing during the 30-day fermentation process. Rarefaction analysis and alpha diversity parameters indicated adequate sampling. C20 showed the greatest fungal richness and diversity, C20 and C26 exhibited similar bacterial richness and diversity, while C30 had low fungal and bacterial richness. Fungal taxonomic assignments revealed that the initial moisture content caused selective enrichment of Aspergillus candidus with a decreasing trend during fermentation, whereas Saccharomycetales sp. exhibited increasing relative abundance with increasing moisture content from day 6 of the fermentation process. Depending on initial moisture level, changes in bacterial communities were also observed in the genera Streptomyces, Bacillus, and Staphylococcus, with decreasing trends whereas Saccharopolyspora exhibited a sigmoidal trend with the highest abundance in C26. These findings demonstrate the possible impact of initial moisture content of nuruk on microfloral richness, diversity, and dynamics; this study is thus a step toward our ultimate goal of enhancing the quality of nuruk. PMID- 27975135 TI - Accuracy of non-arthrographic 3T MR imaging in evaluation of intra-articular pathology of the hip in femoroacetabular impingement. AB - OBJECTIVE: To investigate the accuracy of non-arthrographic 3-T MRI compared to hip arthroscopy in the assessment of labral and cartilaginous pathology in patients with suspected FAI. MATERIALS AND METHODS: Following IRB approval and waived consent, 42 consecutive cases of suspected FAI with non-arthrographic 3-T MRI and arthroscopy of the hip were reviewed. High-resolution TSE MR imaging was evaluated in consensus by two musculoskeletal radiologists, blinded to arthroscopic findings, for the presence of labral tears and articular cartilage lesions. Acetabular cartilage was categorized as normal, degeneration/fissuring, delamination, or denudation. MRI findings were compared to arthroscopy. Sensitivity, specificity, accuracy, and predictive values for MRI were calculated using arthroscopy as the standard of reference. RESULTS: Forty-two hips in 38 patients with a mean age of 29 (range 13-45 years) were assessed. Mean interval between MRI and arthroscopy was 154 days (range 27-472 days). MRI depicted 41 cases with labral tears (sensitivity 100%, specificity 50%, accuracy 98%, PPV 98%, NPV 100%), 11 cases with femoral cartilage abnormalities (sensitivity 85%, specificity 100%, accuracy 95%, PPV 100%, NPV 94%), and 36 cases with acetabular cartilage lesions (sensitivity 94% specificity 67%, accuracy 90%, PPV 94%, NPV 67%). Of the 36 cases with acetabular cartilage lesions on MRI, 7 were characterized as degeneration/fissuring, 26 as delamination, and 3 as denudation, with discordant results between MRI and arthroscopy for grading of articular cartilage in ten cases. CONCLUSION: Non-arthrographic 3-T MR imaging is a highly accurate technique for evaluation of the labrum and cartilage in patients with clinically suspected FAI. PMID- 27975137 TI - Expression and secretion of glycosylated heparin biosynthetic enzymes using Komagataella pastoris. AB - Heparin, an anticoagulant drug, is biosynthesized in selected animal cells. The heparin biosynthetic enzymes mainly consist of sulfotransferases and all are integral transmembrane glycoproteins. These enzymes are generally produced in engineered Escherichia coli as without their transmembrane domains as non glycosylated fusion proteins. In this study, we used the yeast, Komagataella pastoris, to prepare four sulfotransferases involved in heparin biosynthesis as glycoproteins. While the yields of these yeast-expressed enzymes were considerably lower than E. coli-expressed enzymes, these enzymes were secreted into the fermentation media simplifying their purification and were endotoxin free. The activities of these sulfotransferases, expressed as glycoproteins in yeast, were compared to the bacterially expressed proteins. The yeast-expressed sulfotransferase glycoproteins showed improved kinetic properties than the bacterially expressed proteins. PMID- 27975139 TI - Foramina parietalia permagna: familial and radiological evaluation of two cases and review of literature. AB - PURPOSE: Foramina parietalia permagna is a variable intramembranous ossification defect of the parietal bones. Foramina parietalia permagna have an autosomal dominant inheritance, and it is showed that mutations in chromosome 5 and 11 are causing this anomaly. Enlarged parietal foramina occurs extremely rare. They are usually asymptomatic, but occasional headache, vomiting, pain over unprotected cerebral cortex, and seizures may be experienced by the patients. In the literature, some associated congenital bony defects, soft tissue pathologies, underlying neuronal deficits, and vascular variations have been described. METHODS: We report two cases of foramina parietal permagna with their pedigrees and genetic analysis. RESULTS: In case 1, cytogenetic analysis revealed a mutation of the ALX4 gene and all of the members of the family diagnosed with FPP. MRI revealed inferior vermian cerebellar hypoplasia. Surgery was not considered. In case 2, cytogenetic analysis could not be obtained because of financial reasons. Cranial MRI revealed hypoplastic right transverse sinus and sigmoid sinus, with a persistent parafalcine sinus. Surgery was not considered. CONCLUSION: Despite of its rarity, genetic background and some important associated anomalies make foramina parietalia permagna more than an uncommon insignificant genetic disorder. PMID- 27975138 TI - Selection of epitopes from self-antigens for eliciting Th2 or Th1 activity in the treatment of autoimmune disease or cancer. AB - Vaccines have been valuable tools in the prevention of infectious diseases, and the rapid development of new vectors against constantly mutating foreign antigens in viruses such as influenza has become a regular, seasonal exercise. Harnessing the immune response against self-antigens is not necessarily analogous or as achievable by iterative processes, and since the desired outcome includes leaving the targeted organism intact, requires some precision engineering. In vaccine based treatment of autoimmunity and cancer, the proper selection of antigens and generation of the desired antigen-specific therapeutic immunity has been challenging. Both cases involve a threshold of existing, undesired immunity that must be overcome, and despite considerable academic and industry efforts, this challenge has proven to be largely refractory to vaccine approaches leveraging enhanced vectors, adjuvants, and administration strategies. There are in silico approaches in development for predicting the immunogenicity of self-antigen epitopes, which are being validated slowly. One simple approach showing promise is the functional screening of self-antigen epitopes for selective Th1 antitumor immunogenicity, or inversely, selective Th2 immunogenicity for treatment of autoimmune inflammation. The approach reveals the importance of confirming both Th1 and Th2 components of a vaccine immunogen; the two can confound one another if not parsed but may be used individually to modulate antigen-specific inflammation in autoimmune disease or cancer. PMID- 27975140 TI - Profound hypothermia after adenosine kinase inhibition in A1AR-deficient mice suggests a receptor-independent effect of intracellular adenosine. AB - Administration of the nucleoside adenosine has been shown to induce hypothermia in a number of species, an effect mediated predominantly by the adenosine 1 receptor (A1AR) subtype. The present experiments were performed to explore the possibility that the rise of intracellular adenosine levels expected to accompany adenosine administration may contribute to the hypothermic effect of adenosine independent of A1AR activation. Since phosphorylation of adenosine by adenosine kinase (ADK) is causal in the maintenance of low intracellular adenosine, we have examined the effect of ADK inhibition on core body temperature (CBT). Our data show that inhibition of ADK by A-134974 causes a long-lasting deep hypothermia in wild-type mice. Since there was an about 4-fold increase of adenosine plasma levels, experiments were repeated in A1AR-/- mice. ADK inhibition caused deep hypothermia despite the absence of A1AR, although the effect was significantly reduced compared to WT. Furthermore, the dose-dependent hypothermia caused by adenosine administration in WT mice was found to be reduced, but not abolished in A1AR-/- mice. To assess the possible role of A2AR and A3AR activation in our experimental setting, we compared the effects of the agonists CPA (A1AR), CGS21680 (A2AR), and IB-MECA (A3AR) on CBT. Hypothermia induced by CPA was much greater than that caused by CGS21680 or IB-MECA indicating that A1AR activation is the major receptor-dependent pathway for adenosine-induced hypothermia under our experimental conditions. Induction of deep hypothermia by inhibition of ADK, maintenance of this effect in A1AR-/- mice, and maintenance of adenosine-induced hypothermia in A1AR-deficient mice suggest that a receptor-independent action of adenosine requiring intact function of adenosine kinase contributes importantly to the hypothermia induced by adenosine. PMID- 27975141 TI - Glucose and angiotensin II-derived endothelial extracellular vesicles regulate endothelial dysfunction via ERK1/2 activation. AB - In various diseases, including diabetes, extracellular vesicles (EVs) have been detected in circulation and tissues. EVs are small membrane vesicles released from various cell types under varying conditions. Recently, endothelial cell derived EVs (EEVs) were identified as a marker of endothelial dysfunction in diabetes, but the ensuing mechanisms remain poorly understood. In this study, we dissected the ensuing pathways with respect to nitric oxide (NO) production under the condition of type 2 diabetes. Human umbilical vein endothelial cells (HUVECs) were stimulated with glucose alone and with glucose in combination with angiotensin II (Ang II) for 48 h. In supernatants from glucose + Ang II stimulated HUVECs, release of EEVs was assessed using Western blotting with an anti-CD144 antibody. EEV release was significantly increased after stimulation of HUVECs, and high glucose + Ang II-derived EEVs impaired ACh-induced vascular relaxation responses and NO production in mice aortic rings. Furthermore, high glucose + Ang II-derived EEVs induced ERK1/2 signalling and decreased endothelial NO synthase (eNOS) protein expression in mice aortas. Furthermore, in the presence of the MEK/ERK1/2 inhibitor PD98059, high glucose plus Ang II treatment stimulated EEVs in HUVECs and those EEVs prevented the impairments of ACh-induced relaxation and NO production in mice aortas. These data strongly indicate that high glucose and Ang II directly affect endothelial cells and the production of EEVs; the resultant EEVs aggravate endothelial dysfunction by regulating eNOS protein levels and ERK1/2 signalling in mice aortas. PMID- 27975142 TI - An introduction to the sugar code. AB - Carbohydrates have physiological importance far beyond their roles as source of energy (glycolysis) and activated hydrogen for synthesis (pentosephosphate pathway) or as constituent of the backbone of nucleic acids and of cell wall polysaccharides. The extent of compositional and structural variability of their oligomers (glycans) is unsurpassed in Nature due to the unique property of independently combining the following parameters with sequence: anomeric status, linkage positions, ring size, addition of branches and site-specific introduction of substitutions. The monosaccharides (letters of the third alphabet of life) thus generate 'words' (signals) of high-density coding capacity. These 'words' are part of the glycans on proteins and lipids, and the glycome represented by these 'words' in their entirety has cell type-dependent features. The often limited intramolecular flexibility of oligosaccharides along with an abundance of contact points for intermolecular interactions is ideal for binding processes. Glycan-based 'words' can thus be 'read,' and their message translated into cellular effects by receptors called lectins. This journal's special issue covers central aspects of the concept of the sugar code. PMID- 27975144 TI - Golgi apparatus dis- and reorganizations studied with the aid of 2-deoxy-D glucose and visualized by 3D-electron tomography. AB - We studied Golgi apparatus disorganizations and reorganizations in human HepG2 hepatoblastoma cells by using the nonmetabolizable glucose analogue 2-deoxy-D glucose (2DG) and analyzing the changes in Golgi stack architectures by 3D electron tomography. Golgi stacks remodel in response to 2DG-treatment and are replaced by tubulo-glomerular Golgi bodies, from which mini-Golgi stacks emerge again after removal of 2DG. The Golgi stack changes correlate with the measured ATP-values. Our findings indicate that the classic Golgi stack architecture is impeded, while cells are under the influence of 2DG at constantly low ATP-levels, but the Golgi apparatus is maintained in forms of the Golgi bodies and Golgi stacks can be rebuilt as soon as 2DG is removed. The 3D-electron microscopic results highlight connecting regions that interlink membrane compartments in all phases of Golgi stack reorganizations and show that the compact Golgi bodies mainly consist of continuous intertwined tubules. Connections and continuities point to possible new transport pathways that could substitute for other modes of traffic. The changing architectures visualized in this work reflect Golgi stack dynamics that may be essential for basic cell physiologic and pathologic processes and help to learn, how cells respond to conditions of stress. PMID- 27975145 TI - Dynamic contrast-enhanced MR imaging in predicting progression of enhancing lesions persisting after standard treatment in glioblastoma patients: a prospective study. AB - OBJECTIVES: To prospectively explore the value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting the progression of enhancing lesions persisting after standard treatment in patients with surgically resected glioblastoma (GBM). METHODS: Forty-seven GBM patients, who underwent near-total tumorectomy followed by concurrent chemoradiation therapy (CCRT) with temozolomide (TMZ) between May 2014 and February 2016, were enrolled. Twenty-four patients were finally analyzed for measurable enhancing lesions persisting after standard treatment. DCE-MRI parameters were calculated at enhancing lesions. Mann Whitney U tests and multivariable stepwise logistic regression were used to compare parameters between progression (n = 16) and non-progression (n = 8) groups. RESULTS: Mean Ktrans and ve were significantly lower in progression than in non-progression (P = 0.037 and P = 0.037, respectively). The 5th percentile of the cumulative Ktrans histogram was also significantly lower in the progression than in non-progression group (P = 0.017). Mean ve was the only independent predictor of progression (P = 0.007), with a sensitivity of 100%, specificity of 63%, and an overall accuracy of 88% at a cut-off value of 0.873. CONCLUSIONS: DCE MRI may help predict the progression of enhancing lesions persisting after the completion of standard treatment in patients with surgically resected GBM, with mean ve serving as an independent predictor of progression. KEY POINTS: * Enhancing lesions may persist after standard treatment in GBM patients. * DCE-MRI may help predict the progression of the enhancing lesions. * Mean K trans and v e were lower in progression than in non-progression group. * DCE-MRI may help identify patients requiring close follow-up after standard treatment. * DCE-MRI may help plan treatment strategies for GBM patients. PMID- 27975146 TI - T2-weighted MRI-derived textural features reflect prostate cancer aggressiveness: preliminary results. AB - PURPOSE: To evaluate the diagnostic relevance of T2-weighted (T2W) MRI-derived textural features relative to quantitative physiological parameters derived from diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI in Gleason score (GS) 3+4 and 4+3 prostate cancers. MATERIALS AND METHODS: 3T multiparametric-MRI was performed on 23 prostate cancer patients prior to prostatectomy. Textural features [angular second moment (ASM), contrast, correlation, entropy], apparent diffusion coefficient (ADC), and DCE pharmacokinetic parameters (Ktrans and Ve) were calculated from index tumours delineated on the T2W, DW, and DCE images, respectively. The association between the textural features and prostatectomy GS and the MRI-derived parameters, and the utility of the parameters in differentiating between GS 3+4 and 4+3 prostate cancers were assessed statistically. RESULTS: ASM and entropy correlated significantly (p < 0.05) with both GS and median ADC. Contrast correlated moderately with median ADC. The textural features correlated insignificantly with Ktrans and Ve. GS 4+3 cancers had significantly lower ASM and higher entropy than 3+4 cancers, but insignificant differences in median ADC, Ktrans, and Ve. The combined texture-MRI parameters yielded higher classification accuracy (91%) than the individual parameter sets. CONCLUSION: T2W MRI-derived textural features could serve as potential diagnostic markers, sensitive to the pathological differences in prostate cancers. KEY POINTS: * T2W MRI-derived textural features correlate significantly with Gleason score and ADC. * T2W MRI-derived textural features differentiate Gleason score 3+4 from 4+3 cancers. * T2W image textural features could augment tumour characterization. PMID- 27975147 TI - Safety and efficacy of multilevel vertebroplasty for painful osteolytic spinal metastases: a single-centre experience. AB - OBJECTIVE: To retrospectively assess the safety and efficacy of percutaneous vertebroplasty (PVP) for painful osteolytic spinal metastases when treating more than three vertebrae per session. METHODS: A total of 153 patients with painful osteolytic spinal metastases underwent PVP. Group A patients (n = 93) underwent PVP at up to three vertebral levels per session. Group B patients (n = 60) underwent PVP at more than three levels in one session. Pain, quality of life (QoL), and mobility were assessed before and after PVP. Minor and major complications were systematically assessed. RESULTS: Both groups experienced significant pain relief and QoL improvement after the intervention (p < 0.001). Mobility improvement was observed in both groups, despite worse mobility status before PVP in group B compared with group A. There was no significant difference between the two groups throughout the follow-up period in overall pain relief and improvement in QoL and mobility. There was also no significant difference between groups in minor and major complications. CONCLUSIONS: Multilevel vertebroplasty is safe and effective for the treatment of multiple osteolytic spinal metastases. Multilevel PVP relieves pain and improves QoL and mobility. KEY POINTS: * Percutaneous vertebroplasty is safe and effective for painful osteolytic spinal metastases. * Multilevel vertebroplasty does not cause more complications than single-level vertebroplasty. * Multiple spinal metastases patients may regain functional independence after multilevel vertebroplasty. PMID- 27975143 TI - Sialylation of N-glycans: mechanism, cellular compartmentalization and function. AB - Sialylated N-glycans play essential roles in the immune system, pathogen recognition and cancer. This review approaches the sialylation of N-glycans from three perspectives. The first section focuses on the sialyltransferases that add sialic acid to N-glycans. Included in the discussion is a description of these enzymes' glycan acceptors, conserved domain organization and sequences, molecular structure and catalytic mechanism. In addition, we discuss the protein interactions underlying the polysialylation of a select group of adhesion and signaling molecules. In the second section, the biosynthesis of sialic acid, CMP sialic acid and sialylated N-glycans is discussed, with a special emphasis on the compartmentalization of these processes in the mammalian cell. The sequences and mechanisms maintaining the sialyltransferases and other glycosylation enzymes in the Golgi are also reviewed. In the final section, we have chosen to discuss processes in which sialylated glycans, both N- and O-linked, play a role. The first part of this section focuses on sialic acid-binding proteins including viral hemagglutinins, Siglecs and selectins. In the second half of this section, we comment on the role of sialylated N-glycans in cancer, including the roles of beta1-integrin and Fas receptor N-glycan sialylation in cancer cell survival and drug resistance, and the role of these sialylated proteins and polysialic acid in cancer metastasis. PMID- 27975148 TI - Complications encountered in ultrasonography-guided radiofrequency ablation of benign thyroid nodules and recurrent thyroid cancers. AB - OBJECTIVES: To evaluate the complication rates and describe the possible complications of ultrasonography-guided radiofrequency ablation (RFA) of benign thyroid nodules (BTN) and recurrent thyroid cancers (RTC), and to compare the complication rates between BTN and RTC. METHODS: This retrospective study reviewed 875 patients who underwent RFA for BTN (746 patients; 83.5%) or RTC (129 patients; 14.7%). Medical records were reviewed for all types of complications occurring during and after the RFA procedure. The baseline characteristics and the complication rates of BTN and RTC were compared. RESULTS: The overall complication rate was 3.5% (31/875), and the major complication rate was 1.6% (14/875). The major complication rate of RTC was significantly higher than that of BTN (5.4% vs. 0.9%, P = 0.002), while there were no significant differences in the minor complications rate. New complications, such as Horner syndrome, spinal accessory nerve injury, and complications due to lidocaine toxicity, were also revealed. CONCLUSIONS: Various complications of RFA may occur in both BTN and RTC, although the complication rate is low. To understand the broad spectrum of complications and minimise the complications and sequela, the suggested technical tips and cervical anatomy are essential. KEY POINTS: * The overall complication rate was 3.5% (31/875). * The major complication rate was 1.6% (14/875). * The major complication rate of RTC was significantly higher than BTN. * There were only four patients showing persistent symptoms (0.5%). * Unreported new complications were also demonstrated. PMID- 27975149 TI - CT-guided transgluteal biopsy for systematic sampling of the prostate in patients without rectal access: a 13-year single-center experience. AB - OBJECTIVES: The purpose of our study was to examine the safety and diagnostic utility of transgluteal CT-guided prostate biopsy for prostate sampling in patients without rectal access. METHODS: Seventy-three biopsies were performed in 65 patients over a 13-year period (2002-2015). Mean prostate-specific antigen (PSA) at biopsy was 7.8 ng/mL (range 0.37-31.5). Electronic medical records were reviewed for procedural details and complications. Mean PSA and number of cores in malignant and benign cohorts were compared with Student's t test. RESULTS: Technical success rate was 97.3% (71/73; mean cores 8, range 3-28). Of these, 43.6% (31/71) yielded malignancy (mean Gleason score 7, range 6-10) and 56.3% (40/71) yielded benign tissue. The only complication was an asymptomatic periprostatic hematoma (1/73; 1.4%). In 14 patients who underwent surgery, Gleason scores were concordant in 71.4% (10/14) and discordant in 28.6% (4/14; Gleason 6 on biopsy but Gleason 7 on surgical specimen). Mean effective radiation dose was 18.5 mSv (median 15.0, range 4.4-86.2). There was no significant difference in either mean PSA (p = 0.06) or number of core specimens (p = 0.33) between malignant and benign cohorts. CONCLUSION: CT-guided transgluteal prostate biopsy is highly safe and reliable for the detection of prostate cancer in men without rectal access. KEY POINTS: * Prostate cancer detection in men without rectal access is challenging. * CT-guided transgluteal prostate biopsy is safe and effective in these patients. * CT-guided biopsy may be particularly effective in diagnosing high-grade prostate cancer. * Unilateral CT-guided biopsy may be effective in patients with focal lesions. * The radiation exposure with this technique is acceptable. PMID- 27975151 TI - Retraction Note to: A Report on the Internal Retreat Meeting of the Stem Cell Network North Rhine Westphalia. PMID- 27975150 TI - Re-exposure to low osmolar iodinated contrast media in patients with prior moderate-to-severe hypersensitivity reactions: A multicentre retrospective cohort study. AB - OBJECTIVES: To evaluate the outcomes of re-exposure to low-osmolar iodinated contrast medium (LOCM) in patients with a history of moderate-to-severe hypersensitivity reaction (HSR). METHODS: We retrospectively evaluated a cohort comprising all subjects satisfying the following conditions at 11 centres: (1) experienced a moderate-to-severe HSR to LOCM by December 2014, and (2) underwent contrast-enhanced computed tomography after the initial HSR between January 2014 and December 2014. RESULTS: A total of 150 patients with 328 instances of re exposure were included; the recurrence rate of HSR was 19.5%. Patients with severe initial HSR exhibited a higher recurrence rate of severe HSR compared to patients with moderate initial HSR, despite more intensive premedication. In the multivariate analysis, the independent risk factors for recurrence of HSR were diabetes, chronic urticaria, drug allergy other than to iodinated contrast media (ICM) and severe initial HSR. The risk of recurrent HSR was 67.1% lower in cases where the implicated ICM was changed to another one (odds ratio: 0.329; P = 0.001). However, steroid premedication did not show protective effects against recurrent HSR. CONCLUSION: In high-risk patients who have previously experienced a moderate-to-severe initial HSR to LOCM, we should consider changing the implicated ICM to reduce recurrence risk. KEY POINTS: * In patients with moderate to-severe HSR, steroid premedication only shows limited effectiveness. * Changing the implicated ICM can reduce the recurrence of HSR to ICM. * Diabetes, chronic urticaria and drug allergies increase the risk of ICM HSR. PMID- 27975152 TI - Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer. AB - BACKGROUND: Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. METHODS: Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. RESULTS: Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m2 weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). CONCLUSION: Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation. PMID- 27975153 TI - Failure of the Obesity Surgery Mortality Risk Score (OS-MRS) to Predict Postoperative Complications After Bariatric Surgery. A Single-Center Series and Systematic Review. AB - BACKGROUND: The obesity surgery mortality risk score (OS-MRS) was developed to determine the risk of postoperative mortality in patients undergoing bariatric surgery. The aim of the present study is to assess the utility of this score for preventing the risk of postoperative complications from bariatric surgery. METHODS: Prospective study of 321 patients undergoing bariatric surgery to whom the OS-MRS was applied. Postoperative complications were classified according to the Clavien-Dindo system. The relation between the OS-MRS and the appearance of complications and mortality was analyzed. A Medline/Embase search was conducted using bariatric surgery, mortality, and complications as key words. Studies using the OS-MRS to predict morbidity and mortality were included. RESULTS: Of the 321 patients, 303 (94.3%) underwent gastric bypass and the remaining 18 (5.6%) a sleeve gastrectomy. The OS-MRS classified 178 patients as class A (55.5%), 129 as class B (40.2%), and 14 as class C (4.4%). According to the Clavien-Dindo system, 10.4% of the complications were >=III. There was one death (class B). No significant association was found between the OS-MRS and the rate of complications. CONCLUSIONS: In our study, the OS-MRS is not correlated with the appearance of early complications or mortality. Future studies must focus on systems for predicting the appearance and severity of postoperative complications classified according to the Clavien-Dindo system, and not only on mortality. PMID- 27975154 TI - Prognostic impact of metastatic pattern in stage IV breast cancer at initial diagnosis. AB - PURPOSE: To analyze the prognostic influence of metastatic pattern (MP) compared with other biologic and clinical factors in stage IV breast cancer at initial diagnosis (BCID) and evaluate factors associated with specific sites of metastases (SSM). METHODS: We evaluated women with stage IV BCID with known metastatic sites, reported to the Surveillance, Epidemiology and End Results program from 2010 to 2013. MP was categorized as bone-only, visceral, bone and visceral (BV), and other. Univariate and multivariate analyses determined the effects of each variable on overall survival (OS). Logistic regression examined factors associated with SSM. RESULTS: We included 9143 patients. Bone represented 37.5% of patients, visceral 21.9%, BV 28.8%, and other 11.9%. Median OS by MP was as follows: bone 38 months, visceral 21 months, BV 19 months, and other 33 months (P < 0.0001). Univariate analysis showed that higher number of metastatic sites had worse prognosis. In multivariate analysis, older age (hazard ratio 1.9), black race (hazard ratio 1.17), grade 3/4 tumors (hazard ratio 1.6), triple negative (hazard ratio 2.24), BV MP (hazard ratio 2.07), and unmarried patients (hazard ratio 1.25) had significantly shorter OS. As compared with HR+/HER2- tumors, triple-negative and HR-/HER2+ had higher odds of brain, liver, lung, and other metastases. HR+/HER2+ had higher odds of liver metastases. All three subtypes had lower odds of bone metastases. CONCLUSIONS: There were substantial differences in OS according to MP. Tumor subtypes have a clear influence among other factors on SSM. We identified several prognostic factors that could guide therapy selection in treatment naive patients. PMID- 27975155 TI - "Harvesting" and Use of Human (Embryonic) Stem Cells: An Islamic Evaluation. AB - This paper gives insight into the Islamic bioethical discussion on harvesting and using human embryonic (hESC) and adult stem cells. It describes some of the Islamic legal mechanisms involved in the bioethical discourse among Muslims. As the contemporary Islamic bioethical discourse is very diverse, the paper focuses on the critical discussion of related resolutions of the Saudi-based Islamic Fiqh Academy due to the esteem in which the IFA is held in the Islamic world and the pertinence of their rulings on this issue. This study discusses the different sources of human adult and embryonic stem cells and their use from an Islamic perspective, while questioning some directions the Islamic bioethical discourse has taken. The paper invites interested parties to deliberate the use of some of the legal means resorted to in the ongoing Islamic bioethical discourse. PMID- 27975156 TI - How Should We Respond to Non-Dominant Healing Practices, the Example of Homeopathy. AB - The debate around the ethics of homeopathy in recent issues of the journal has been approached as a binary question; is homeopathy ethical or not? This paper suggests that this is an unhelpful question and instead discusses a framework to establish the extent to which the dominant (medical) culture should tolerate non dominant health practices such as homeopathy. This requires a sophisticated understanding of the placebo effect, a critical evaluation of what evidence is available, a consideration of the harm that the non-dominant practice might cause, and a consideration of how this might be affected by the culture of the patient. This is presented as a matter of cultural competence. At a clinical level clinicians need to respect the values and beliefs of their patients and communicate with all the practitioners involved in a patient's care. At a societal level there are a number of factors to be considered when a community decides which practices to tolerate and to what extent. PMID- 27975157 TI - How Can Respectfulness in Medical Professionals Be Increased? A Complex But Important Question. AB - Respectfulness is demanded of doctors and predicts more positive patient health related outcomes, but research is scarce on ways to promote it. This study explores two ways to conceptualize unconditional respect from medical students, defined as respect paid to people on the basis of their humanity, in order to inform strategies to increase it. Unconditional respect conceptualized as an attitude suggests that unconditional respect and conditional respect are additive, whereas unconditional respect conceptualized as a personality trait suggests that people who are high on unconditional respect afford equal respect to all humans regardless of their merits. One hundred and eighty-one medical students completed an unconditional respect measure then read a description of a respect-worthy or a non-respect-worthy man and indicated their respect towards him. The study found a main effect for unconditional respect and a main effect for target respect-worthiness but no interaction between the two when respect paid to the target was assessed, supporting the attitude-based conceptualization. This suggests that unconditional respect can be increased through relevant interventions aimed at increasing the relative salience to doctors of the human worth of individuals. Interventions to increase unconditional respect are discussed. PMID- 27975158 TI - Compensatory increase of functional connectivity density in adolescents with internet gaming disorder. AB - Behavioral studies have demonstrated visual attention bias and working memory deficits in individuals with internet gaming disorder (IGD). Neuroimaging studies demonstrated that individuals with IGD presented abnormalities in brain structures and functions including resting-state functional connectivity (rsFC) disturbance. However, most previous studies investigated IGD-related rsFC alterations by using hypothesis-driven methods with priori selection of a region of interest, which cannot provide a full picture of the rsFC changes in IGD individuals. In this study, we recruited 27 male IGD adolescents and 35 demographically matched healthy controls (HCs) to investigate abnormal connective property of each voxel within whole brain of IGD adolescents using resting-state functional connectivity density (rsFCD) method, and further to evaluate the relationship between altered rsFCD and behavioral performances of visual attention and working memory. The results exhibited no significant intergroup difference in behavioral performance (visual working memory and attention). The IGD adolescents exhibited higher global/long-range rsFCD in the bilateral dorsal lateral prefrontal cortex (DLPFC) and the right inferior temporal cortex (ITC)/fusiform compared with the HCs. Although no significant correlation survived after Bonferroni correction, higher global/long-range rsFCD of the bilateral DLPFC was correlated with the Young's internet addiction test (IAT) score and/or behavioral performance in IGD adolescents using an uncorrected threshold of P < 0.05. In conclusion, IGD adolescents demonstrated increased rsFCD in the brain regions involved in working memory, spatial orientation and attention processing, which indicated that increased rsFCD may reflect a compensatory mechanism for maintaining the normal behavioral performance in IGD adolescents compared with the HCs. PMID- 27975159 TI - Neural correlates of increased risk-taking propensity in sleep-deprived people along with a changing risk level. AB - Risky decision-making under a changing risk level is a complex process involving contextual information. The neural mechanism underlying how sleep deprivation (SD) influences risky decision-making behaviors with a changing risk level has yet to be elucidated. In this study, we used the Balloon Analogue Risk Task (BART) during functional magnetic resonance imaging to investigate the neural correlates of SD-induced changes on decision-making behaviors at different risk levels. Thirty-seven healthy male adults were recruited in this within-subjects, repeat-measure, counterbalanced study. These individuals were examined during a state of rested wakefulness state and after nearly 36 h of total SD. The results showed that SD increased the activation of risk modulation in the left inferior frontal gyrus and were positively correlated with risk-taking propensity after SD. Activation in the ventral striatum and thalamus during cash out was increased, and activation in the middle temporal gyrus after explosion (loss of money) was decreased in sleep-deprived subjects, providing additional evidence for greater risk-taking propensity after SD. These results extend our understanding of the neural mechanism underlying alteration of the risk-taking propensity in sleep-deprived individuals. PMID- 27975161 TI - Extraction, selenylation modification and antitumor activity of the glucan from Castanea mollissima Blume. AB - The present study aimed to characterize the glucan from C. mollissima Blume fruits and its selenium derivative, then investigate their antitumor activity in vitro. A glucan, designated as CPA, was firstly isolated from the fruits of C. mollissima Blume. Structure analysis indicated that CPA was a linear 1,6-alpha-D glucan with the average molecular weight about 2.0 * 103 kDa. The selenylation modification derivative of CPA (sCPA), exhibited a stronger antiproliferative effect on tumor cells than CPA in vitro. CPA and sCPA could induce HeLa cells apoptosis and decrease mitochondrial membrane potential. sCPA could also arrest HeLa cells in S phase, promote reactive oxygen species generation and activate caspase-3 activity in HeLa cells. These results manifest that CPA and sCPA inhibit the proliferation of HeLa cells via different mechanisms, which is meaningful for their potential use as antitumor drugs. PMID- 27975162 TI - The regulatory role of heparin on c-Met signaling in hepatocellular carcinoma cells. AB - The role of heparin as an anticoagulant is well defined; however, its role in tumorigenesis and tumor progression is not clear yet. Some studies have shown that anticoagulant treatment in cancer patients improve overall survival, however, recent clinical trials have not shown a survival benefit in cancer patients receiving heparin treatment. In our previous studies we have shown the inhibitory effects of heparin on Hepatocyte Growth Factor (HGF)-induced invasion and migration in hepatocellular carcinoma (HCC) cells. In this study, we showed the differential effects of heparin on the behaviors of HCC cells based on the presence or absence of HGF. In the absence of HGF, heparin activated HGF/c-Met signaling and promoted motility and invasion in HCC cells. Heparin treatment led to c-Met receptor dimerization and activated c-Met signaling in an HGF independent manner. Heparin-induced c-Met activation increased migration and invasion through ERK1/2, early growth response factor 1 (EGR1) and Matrix Metalloproteinases (MMP) axis. Interestingly, heparin modestly decreased the proliferation of HCC cells by inhibiting activatory phosphorylation of Akt. The inhibition of c-Met signaling reversed heparin-induced increase in motility and invasion and, proliferation inhibition. Our study provides a new perspective into the role of heparin on c-Met signaling in HCC. PMID- 27975160 TI - Glycosylation: a hallmark of cancer? AB - The hallmarks of cancer are characterized by functional capabilities that allow cancer cells to survive, proliferate and disseminate during the multistep tumorigenesis. Cancer being a cellular disease, changes in cellular glycoproteins play an important role in malignant transformation and cancer progression. The present review summarizes various studies that depicted correlation of glycosylation with tumor initiation, progression and metastasis, which are helpful in early diagnosis, disease monitoring and prognosis. The results are further strengthened by our reports, which depicted alterations in sialylation and fucosylation in different cancers. Alterations in glycosyltransferases are also involved in formation of various tumor antigens (e.g. Sialyl Lewis x) which serves as ligand for the cell adhesion molecule, selectin which is involved in adhesion of cancer cells to vascular endothelium and thus contributes to hematogenous metastasis. Increased glycosylation accompanied by alterations in glycosyltranferases, glycosidases, glycans and mucins (MUC)s are also involved in loss of E-cadherin, a key molecule implicated in metastatic dissemination of cells. The present review also summarizes the correlation of glycosylation with all the hallmarks of cancer. The enormous progress in the design of novel inhibitors of pathway intermediates of sialylation and fucosylation can prove wonders in combating the dreadful disease. The results provide the evidence that altered glycosylation is linked to tumor initiation, progression and metastasis. Hence, it can be considered as a new hallmark of cancer development and strategies to develop novel glycosylation targeted molecules should be strengthened. PMID- 27975163 TI - Profile of Peng Li. PMID- 27975164 TI - Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection. AB - Aortic dissection (AD) is a devastating, heterogeneous condition of aorta. The homeostasis between collagens and matrix metalloproteases (MMPs)/tissue inhibitors of MMPs (TIMPs) system in the extracellular matrix plays an important role for structure and functions of aorta. However, our knowledge on association between variants of genes in this system and pathogenesis of AD is very limited. We analyzed all yet known coding human genes of collagens (45 genes), MMPs/TIMPs (27 genes) in 702 sporadic AD patients and in 163 matched healthy controls, by using massively targeted next-generation and Sanger sequencing. To define the pathogenesis of potential disease-causing candidate genes, we performed transcriptome sequencing and pedigree co-segregation analysis in some genes and generated Col5a2 knockout rats. We identified 257 pathogenic or likely pathogenic variants which involved 88.89% (64/72) genes in collagens-MMPs/TIMPs system and accounted for 31.05% (218/702) sporadic AD patients. In them, 84.86% patients (185/218) carried one variant, 12.84% two variants and 2.30% more than two variants. Importantly, we identified 52 novel probably pathogenic loss-of function (LOF) variants (20 nonsense, 16 frameshift, 14 splice sites, one stop loss, one initiation codon) in 11.06% (50/452) AD patients, which were absent in 163 controls (P=2.5*10-5). Transcriptome sequencing revealed that identified variants induced dyshomeostasis in expression of collagens-TIMPs/MMPs systems. The Col5a2 -/- rats manifested growth retardation and aortic dysplasia. Our study provides a first comprehensive map of genetic alterations in collagens-MMPs/TIMPs system in sporadic AD patients and suggests that variants of these genes contribute largely to AD pathogenesis. PMID- 27975165 TI - Screening somatic cell nuclear transfer parameters for generation of transgenic cloned cattle with intragenomic integration of additional gene copies that encode bovine adipocyte-type fatty acid-binding protein (A-FABP). AB - Somatic cell nuclear transfer (SCNT) is frequently used to produce transgenic cloned livestock, but it is still associated with low success rates. To our knowledge, we are the first to report successful production of transgenic cattle that overexpress bovine adipocyte-type fatty acid binding proteins (A-FABPs) with the aid of SCNT. Intragenomic integration of additional A-FABP gene copies has been found to be positively correlated with the intramuscular fat content in different farm livestock species. First, we optimized the cloning parameters to produce bovine embryos integrated with A-FABP by SCNT, such as applied voltage field strength and pulse duration for electrofusion, morphology and size of donor cells, and number of donor cells passages. Then, bovine fibroblast cells from Qinchuan cattle were transfected with A-FABP and used as donor cells for SCNT. Hybrids of Simmental and Luxi local cattle were selected as the recipient females for A-FABP transgenic SCNT-derived embryos. The results showed that a field strength of 2.5 kV/cm with two 10-MUs duration electrical pulses was ideal for electrofusion, and 4-6th generation circular smooth type donor cells with diameters of 15-25 MUm were optimal for producing transgenic bovine embryos by SCNT, and resulted in higher fusion (80%), cleavage (73%), and blastocyst (27%) rates. In addition, we obtained two transgenic cloned calves that expressed additional bovine A-FABP gene copies, as detected by PCR-amplified cDNA sequencing. We proposed a set of optimal protocols to produce transgenic SCNT derived cattle with intragenomic integration of ectopic A-FABP-inherited exon sequences. PMID- 27975166 TI - Green and Selective Fluorescent Sensor for Detection of Sn (IV) and Mo (VI) Based on Boron and Nitrogen-Co-Doped Carbon Dots. AB - A green and simple microwave-assisted method was used to synthesis water-soluble boron and nitrogen-co-doped carbon dots (B-N-CDs). These B-N-CDs were successfully used for the fluorescent determination of Sn4+ and Mo6+ ions. This probe had a fast response time at pH = 4 with high sensitivity and selectivity. Linear correlation between F0/F and the concentration was seen in the range of 0.2-18 MUM and 0.2-25 MUM for Sn4+ and Mo6+, respectively. Under optimum condition, the limit of detection (LOD) for Sn4+ and Mo6+ were 150 nM and 132 nM, respectively. The performance of the sensor was evaluated by different real samples such as tap, river and mineral water, canned fish sample and tomato samples. PMID- 27975167 TI - LRRK2 Expression Is Deregulated in Fibroblasts and Neurons from Parkinson Patients with Mutations in PINK1. AB - Mutations in PINK1 (PARK6), a serine/threonine kinase involved in mitochondrial homeostasis, are associated with early onset Parkinson's disease. Fibroblasts from Parkinson's disease patients with compound heterozygous mutations in exon 7 (c.1488 + 1G > A; c.1252_1488del) showed no apparent signs of mitochondrial impairment. To elucidate changes primarily caused by lack of functional PINK1, we over-expressed wild-type PINK1, which induced a significant downregulation of LRRK2 (PARK8). Indeed, we found that LRRK2 protein basal levels were significantly higher in the mutant PINK1 fibroblasts. To examine the interaction between the two PARK genes in a disease-relevant cell context, we generated induced pluripotent stem cell (iPSC) lines from mutant, carrier and control fibroblasts by lentiviral-mediated re-programming. Efficiency of neural induction and dopamine differentiation using a floor-plate induction protocol was similar in all genotypes. As observed in fibroblasts, PINK1 mutant neurons showed increased LRRK2 expression both at the RNA and protein level and transient over expression of wild-type PINK1 efficiently downregulated LRRK2 levels. Additionally, we confirmed a dysregulation of LRRK2 expression in fibroblasts from patients with a different homozygous mutation in PINK1 exon 4, c.926G > A (G309D). Thus, our results identify a novel role of PINK1 modulating the levels of LRRK2 in Parkinson's disease fibroblasts and neurons, suggest a convergent pathway for these PARK genes, and broaden the role of LRRK2 in the pathogenesis of Parkinson's disease. PMID- 27975170 TI - Neuroprotective Effects of Antidepressants via Upregulation of Neurotrophic Factors in the MPTP Model of Parkinson's Disease. AB - Neurotrophic factors are essential for neuronal survival, plasticity, and development and have been implicated in the action mechanism of antidepressants. In this study, we assessed the neurotrophic factor-inducing and neuroprotective properties of antidepressants. In the first part of the study, we found that fluoxetine, imipramine, and milnacipran (i.p., 20 mg/kg/day for 1 week or 3 weeks) upregulated brain-derived neurotrophic factor in the striatum and substantia nigra both at 1 week and 3 weeks. In contrast, an increase in the glial-derived neurotrophic factor was more obvious at 3 weeks after the antidepressants treatment. Specifically, it was found that fluoxetine and imipramine are more potent in raising the levels of neurotrophic factors than milnacipran. Furthermore, antidepressants elevated the phosphorylation of extracellular signal-regulated-protein kinase (ERK1/2) and the serine/threonine kinase Akt. In the second part of the study, we compared the neuroprotective effects of fluoxetine, imipramine, and milnacipran in the 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Pretreament with fluoxetine, imipramine or milnacipran for 3 weeks reduced MPTP-induced dopaminergic neurodegeneration and microglial activation in the nigrostriatal pathway. Neurochemical analysis by HPLC exhibited that antidepressants attenuated the depletion of striatal dopamine. In consistent, beam test showed that behavioral impairment was ameliorated by antidepressants. Neuroprotective effects were more prominent in the fluoxetine or imipramine treatment group than in milnacipran treatment group. Finally, we found that neuroprotection of the antidepressants against 1-methyl-4-phenylpyridinium neurotoxicity in SH-SY5Y cells was attenuated by ERK or Akt inhibitor. These results indicate that neuroprotection by antidepressants might be associated with the induction of neurotrophic factors, and antidepressant could be a potential therapeutic intervention for treatment of Parkinson's disease. PMID- 27975169 TI - Proapoptotic Requirement of Ribosomal Protein L11 in Ribosomal Stress-Challenged Cortical Neurons. AB - While impaired ribosomal biogenesis is observed in neurodegenerative diseases, its pathogenic contributions are not clear. For instance, it is well established that in rodent neurons, genetic inhibition of RNA-polymerase 1 that transcribes rRNA results in structural disruption of the nucleolus, neuronal apoptosis, and neurodegeneration. However, in most neurodegenerative diseases, nucleolar morphology is unaffected. It is reported here that in primary cortical neurons from newborn rats, inhibition of ribosomal biogenesis by shRNA-mediated knockdowns of several ribosomal proteins including S6, S14, or L4 resulted in p53 mediated apoptosis despite absence of structural disruption of the nucleolus. Conversely, knockdown of the RP L11, which in nonneuronal systems mediates p53 activation downstream of ribosomal stress, protected neurons against inhibition of ribosomal biogenesis but not staurosporine. Moreover, overexpression of L11 enhanced p53-driven transcription and increased neuronal apoptosis. In addition, inhibition of p53, or L11 knockdown, blocked apoptosis in response to the RNA analog 5-fluorouridine which perturbed nucleolar structure, inhibited ribosomal synthesis, and activated p53. Although the DNA double-strand break (DSB) inducer etoposide activated p53, nucleolar structure appeared intact. However, by activating the DNA damage response kinase ATM, etoposide increased 47S pre-rRNA levels, and enhanced nucleolar accumulation of nascent RNA, suggesting slower rRNA processing and/or increased Pol1 activity. In addition, shL11 reduced etoposide-induced apoptosis. Therefore, seemingly normal morphology of the neuronal nucleolus does not exclude presence of ribosomal stress. Conversely, targeting the ribosomal stress-specific signaling mediators including L11 offers a novel approach to uncover neurodegenerative contributions of deregulated ribosomal synthesis as exemplified in DSB-challenged neurons. PMID- 27975172 TI - Region-Specific Dok2 Overexpression Associates with Poor Prognosis in Human Astrocytoma. AB - Astrocytoma is the most frequent malignancies of the brain. Despite present clinical advancements, median survival time in malignant forms remains poor. Downstream of kinase protein 2 (Dok2) is adaptor protein known to modulate the effect of tyrosine kinase. Previously, Dok2 is shown to be marker of poor prognosis in colorectal and gastric cancer, and reduced levels of Dok2 were reported in lung adenocarcinoma and gastric cancer. The aim of the present study was to evaluate prognostic significance of pDok2 expression in surgically resected astrocytoma tissue samples. In the present study, 47 numbers of tissue samples were collected from patients who underwent surgery for astrocytoma. Temporal lobe epilepsy tissues were used as control. Real-time PCR was used to study transcript expression while protein expression was studied by western blotting and immunohistochemistry. The pDok2 expression was categorized as pDok2 positive and pDok2 negative on the basis of intensity of protein expression. This observation was confirmed by two independent pathologists. Control and few GII tissues were used as reference on account for low expression of pDok2 protein. Basic information of patients as anatomic origin of tumor and follow-up details were retrieved from hospital registry. Kaplan-Meier test was used to analyze the association of pDok2 expression and survival outcome in clinical cases. Real-time PCR signifies pDok2 is overexpressed in high-grade (GIII + GIV) tissue samples compared with low-grade (GII) and control brain tissue samples (p < 0.005). Western blotting and immunohistochemistry analysis signifies overexpression of pDok2 protein expression in tumor tissue samples as compared with control brain tissues. Clinico-pathological analysis reveals 83% of high-grade astrocytoma (GIII + GIV) and 30% of low-grade (GII) tissue samples which were detected with pDok2 expression. Tumor location was found to be predominant at the frontal and temporal lobes. Survival studies underline prognostic importance of pDok2 protein. Median survival of 20 months was reported with patients with positive pDok2 expression (95% CI 0.083 to 0.49). Taken together, pDok2 protein overexpression is associated with poor prognosis in astrocytoma clinical cases and appears to be an attractive target for therapeutic intervention. Noticeable anatomic origin at the frontal and temporal lobe suggests site-specific role of developmental factors in tumor occurrence. PMID- 27975168 TI - Molecular Alterations in the Cerebellum of Sporadic Creutzfeldt-Jakob Disease Subtypes with DJ-1 as a Key Regulator of Oxidative Stress. AB - Cerebellar damage and granular and Purkinje cell loss in sporadic Creutzfeldt Jakob disease (sCJD) highlight a critical involvement of the cerebellum during symptomatic progression of the disease. In this project, global proteomic alterations in the cerebellum of brain from the two most prevalent subtypes (MM1 and VV2) of sCJD were studied. Two-dimensional gel electrophoresis (2DE) coupled mass spectrometric identification revealed 40 proteins in MM1 and 43 proteins in VV2 subtype to be differentially expressed. Of those, 12 proteins showed common differential expression in their expression between two subtypes. Differentially expressed proteins mainly belonged to (i) cell cycle, gene expression and cell death; (ii) cellular stress response/oxidative stress (OS) and (iii) signal transduction and synaptic functions, related molecular functions. We verified 10 differentially expressed proteins at transcriptional and translational level as well. Interestingly, protein deglycase DJ-1 (an antioxidative protein) showed an increase in its messenger RNA (mRNA) expression in both MM1 and VV2 subtypes but protein expression only in VV2 subtype in cerebellum of sCJD patients. Nuclear translocalization of DJ-1 confirmed its expressional alteration due to OS in sCJD. Downstream experiments showed the activation of nuclear factor erythroid-2 related factor 2 (Nrf2)/antioxidative response element (ARE) pathway. DJ-1 protein concentration was significantly increased during the clinical phase in cerebrospinal fluid of sCJD patients and also at presymptomatic and symptomatic stages in cerebellum of humanized PrP transgenic mice inoculated with sCJD (MM1 and VV2) brain. These results suggest the implication of oxidative stress during the pathophysiology of sCJD. PMID- 27975171 TI - Voluntary Physical Exercise Induces Expression and Epigenetic Remodeling of VegfA in the Rat Hippocampus. AB - A healthy lifestyle, including regular physical exercise, is generally believed to improve cognitive function and enhance neurogenesis. Such physical exercise induced effects are associated with increased brain expression of neurotrophic and growth factors. In the present study, we investigated Bdnf, Igf-1, Fgf-2, Egf, and VegfA messenger RNA (mRNA) expression levels in the male rat hippocampus and frontal cortex after 2 weeks of voluntary physical exercise. Whereas the expression of Fgf-2 was upregulated in the hippocampus and prefrontal cortex by physical exercise, the expression levels of Bdnf transcript 1, Bdnf transcript 4, Igf-1, and VegfA were upregulated only in the hippocampus. We focused our subsequent analyses on the VegfA gene, which encodes vascular endothelial growth factor, a signaling molecule important for angiogenesis, vasculogenesis, and neurogenesis. To study the epigenetic mechanisms involved in the physical exercise-mediated induction of VegfA expression, we used oxidative and non oxidative bisulfite pyrosequencing to analyze VegfA promoter DNA methylation and DNA hydroxymethylation. We observed discrete DNA hypomethylation at specific CpG sites in rats that engaged in physical exercise relative to sedentary rats. This is exemplified by a CpG site located within a VegfA promoter Sp1/Sp3 transcription factor recognition element. DNA hydroxymethylation was present at the VegfA promoter, but no differences in DNA hydroxymethylation were observed in rats that engaged in physical exercise relative to sedentary rats. Moreover, we observed increased Tet1 and decreased Dnmt3b mRNA expression in the hippocampi of rats that engaged in physical exercise. The presented results substantiate the involvement of epigenetics as a mediator of the beneficial effects of physical exercise and point to the importance of analyzing factors beyond Bdnf to delineate the mechanisms behind the functional impacts of physical exercise in mediating benefits to the brain. PMID- 27975173 TI - Acetyl-L-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats. AB - Parkinson's disease is accompanied by nonmotor symptoms including cognitive impairment, which precede the onset of motor symptoms in patients and are regulated by dopamine (DA) receptors and the mesocorticolimbic pathway. The relative contribution of DA receptors and astrocytic glutamate transporter (GLT 1) in cognitive functions is largely unexplored. Similarly, whether microglia derived increased immune response affects cognitive functions and neuronal survival is not yet understood. We have investigated the effect of acetyl-L carnitine (ALCAR) on cognitive functions and its possible underlying mechanism of action in 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rats. ALCAR treatment in 6-OHDA-lesioned rats improved memory functions as confirmed by decreased latency time and path length in the Morris water maze test. ALCAR further enhanced D1 receptor levels without altering D2 receptor levels in the hippocampus and prefrontal cortex (PFC) regions, suggesting that the D1 receptor is preferentially involved in the regulation of cognitive functions. ALCAR attenuated microglial activation and release of inflammatory mediators through balancing proinflammatory and anti-inflammatory cytokines, which subsequently enhanced the survival of mature neurons in the CA1, CA3, and PFC regions and improved cognitive functions in hemiparkinsonian rats. ALCAR treatment also improved glutathione (GSH) content, while decreasing oxidative stress indices, inducible nitrogen oxide synthase (iNOS) levels, and astrogliosis resulting in the upregulation of GLT-1 levels. Additionally, ALCAR prevented the loss of dopaminergic (DAergic) neurons in ventral tagmental area (VTA)/substantia nigra pars compacta (SNpc) regions of 6-OHDA-lesioned rats, thus maintaining the integrity of the nigrostriatal pathway. Together, these results demonstrate that ALCAR treatment in hemiparkinsonian rats ameliorates neurodegeneration and cognitive deficits, hence suggesting its therapeutic potential in neurodegenerative diseases. PMID- 27975176 TI - The Patient-Psychiatrist Relationship on the Axis of the Other and the Same. AB - The patient-psychiatrist relationship is a cornerstone of psychiatric professionalism and ethics. We discuss this topic along the axis of the Other and the Same, concepts defined by continental philosophy. The self of Anglo-American philosophy is typically described in individualistic terms. Individualism, autonomy and ideal self are valorized within the current model of care. These characteristics belong to the Lacanian Imaginary Order, which is the core of narcissism. Patients may yearn for another model of interaction. For Levinas, ethics should not involve a search for perfectionism and accomplishment but responsibility toward others. Ethics is, according to him, rooted in the calling into question of one's Sameness by the other's Otherness. The question of hospitality and of the welcoming of Otherness is central to his thought. Derrida further asks whether hospitality is not an interruption of the self. Hospitality may thus become a fundamental way of re-thinking clinical practices. A relationship to the Other as an-other is characterized as of Euclidian-type, establishing borders between the self and the Other, whereas a relationship to the Other as same is characterized as of fractal-type, emphasizing similarities between self and other as same and obliterating boundaries. Winnicott's object relating versus use of object and Buber's I-you and I-it relations are also examined along the axis of Sameness and Otherness. Since psychiatric clinical practice requires to our view adequate and adaptive to and fro movements along this axis, the two forms of relating to the Other are discussed both theoretically and through a clinical case presentation. PMID- 27975174 TI - Dysregulation of Intracellular Ca2+ in Dystrophic Cortical and Hippocampal Neurons. AB - Duchenne muscular dystrophy (DMD) is an inherited X-linked disorder characterized by skeletal muscle wasting, cardiomyopathy, as well as cognitive impairment. Lack of dystrophin in striated muscle produces dyshomeostasis of resting intracellular Ca2+ ([Ca2+]i), Na+ ([Na+]i), and oxidative stress. Here, we test the hypothesis that similar to striated muscle cells, an absence of dystrophin in neurons from mdx mice (a mouse model for DMD) is also associated with dysfunction of [Ca2+]i homeostasis and oxidative stress. [Ca2+]i and [Na+]i in pyramidal cortical and hippocampal neurons from 3 and 6 months mdx mice were elevated compared to WT in an age-dependent manner. Removal of extracellular Ca2+ reduced [Ca2+]i in both WT and mdx neurons, but the decrease was greater and age-dependent in the latter. GsMTx-4 (a blocker of stretch-activated cation channels) significantly decreased [Ca2+]i and [Na+]i in an age-dependent manner in all mdx neurons. Blockade of ryanodine receptors (RyR) or inositol triphosphate receptors (IP3R) reduced [Ca2+]i in mdx. Mdx neurons showed elevated and age-dependent reactive oxygen species (ROS) production and an increase in neuronal damage. In addition, mdx mice showed a spatial learning deficit compared to WT. GsMTx-4 intraperitoneal injection reduced neural [Ca2+]i and improved learning deficit in mdx mice. In summary, mdx neurons show an age-dependent dysregulation in [Ca2+]i and [Na+]i which is mediated by plasmalemmal cation influx and by intracellular Ca2+ release through the RyR and IP3R. Also, mdx neurons have elevated ROS production and more extensive cell damage. Finally, a reduction of [Ca2+]i improved cognitive function in mdx mice. PMID- 27975175 TI - Minimally Toxic Dose of Lipopolysaccharide and alpha-Synuclein Oligomer Elicit Synergistic Dopaminergic Neurodegeneration: Role and Mechanism of Microglial NOX2 Activation. AB - The aim of this study is to investigate the role and mechanism of microglial NOX2 activation in minimally toxic dose of LPS and Syn-elicited synergistic dopaminergic neurodegeneration. NOX2+/+ and NOX2-/- mice and multiple primary cultures were treated with LPS and/or Syn in vivo and in vitro. Neuronal function and morphology were evaluated by uptake of related neurotransmitter and immunostaining with specific antibody. Levels of superoxide, intracellular reactive oxygen species, mRNA and protein of relevant molecules, and dopamine were detected. LPS and Syn synergistically induce selective and progressive dopaminergic neurodegeneration. Microglia are functionally and morphologically activated, contributing to synergistic dopaminergic neurotoxicity elicited by LPS and Syn. NOX2-/- mice are more resistant to synergistic neurotoxicity than NOX2+/+mice in vivo and in vitro, and NOX2 inhibitor protects against synergistic neurotoxicity through decreasing microglial superoxide production, illustrating a critical role of microglial NOX2. Microglial NOX2 is activated by LPS and Syn as mRNA and protein levels of NOX2 subunits P47and gp91 are enhanced. Molecules relevant to microglial NOX2 activation include PKC-sigma, P38, ERK1/2, JNK, and NF-KBP50 as their mRNA and protein levels are elevated after treatment with LPS and Syn. Combination of exogenous and endogenous environmental factors with minimally toxic dose synergistically propagates dopaminergic neurodegeneration through activating microglial NOX2 and relevant signaling molecules, casting a new light for PD pathogenesis. PMID- 27975177 TI - Involvement of histaminergic and noradrenergic receptors in the oxytocin-induced food intake in neonatal meat-type chicks. AB - Oxytocin neurons have a physiological role in food intake and energy balance. Several studies have shown that central histaminergic and adrenergic systems synapse on oxytocin neurons but there is no information for their interaction on food intake regulation in birds. The purpose of this study was to examine the effects of intracerebroventricular (ICV) injection of alpha-fluoromethylhistidine (alpha-FMH, histidine decarboxylase inhibitor), chlorpheniramine (histamine H1 receptors antagonist), famotidine (histamine H2 receptors antagonist), thioperamide (histamine H3 receptors antagonist), prazosin (alpha1 receptor antagonist), yohimbine (alpha2 receptor antagonist), metoprolol (beta1 adrenergic receptor antagonist), ICI 118,551 (beta2 adrenergic receptor antagonist) and SR59230R (beta3 adrenergic receptor antagonist) on oxytocin-induced hypophagia in 3-h food-deprived (FD3) neonatal broiler chicken. In Experiment 1, 3 h-fasted chicks were given an ICV injection of saline, alpha-FMH (250 nmol), oxytocin (10 MUg) and co-injection of alpha-FMH + oxytocin. Experiments 2-9 were similar to experiment 1 except birds were injected with chlorpheniramine (300 nmol), famotidine (82 nmol), thioperamide (300 nmol), prazosin (10 nmol), yohimbine (13 nmol), metoprolol (24 nmol), ICI 118,551(5 nmol) and SR59230R (20 nmol) instead of alpha-FMH, respectively. After injection cumulative food intake was measured until 120 min post injection. According to the results, ICV injection of oxytocin significantly decreased food intake in broiler chickens (P < 0.001). ICV injection of alpha-FMH significantly attenuated hypophagic effect of oxytocin (P < 0.001). Also, co-injection of chlorpheniramine plus oxytocin significantly decreased the effect of oxytocin on food intake (P < 0.001). Co-administration of thioperamide and oxytocin significantly amplified hypophagic effect of oxytocin in chickens (P < 0.001). In addition, ICI 118,551 attenuated hypophagic effect of oxytocin (P < 0.001); while famotidine, prazosin, yohimbine, metoprolol and SR59230R had no effect on oxytocin- induced food intake in FD3 broiler chickens. These results suggest that the effect of oxytocin on food intake is probably mediated by histaminergic (via H1 and H3 receptors) and noradrenergic (via beta2 receptors) systems in broiler chickens. PMID- 27975179 TI - A Rare Case of Metastatic Colorectal Carcinoma in the Testicle. PMID- 27975178 TI - Central sleep apnea in multiple sclerosis: a pilot study. AB - PURPOSE: The purpose of the present study is to investigate sleep-disordered breathing and symptoms of sleepiness in a consecutive clinical cohort of multiple sclerosis (MS) patients. METHODS: Twenty-one (16 females) community-dwelling adults aged 18-75 years with MS and an Expanded Disability Status Scale score between 2 and 6 were recruited consecutively from an academic teaching hospital MS clinic. Participants performed a home sleep study (ResMed ApneaLink Plus) to objectively quantify sleep-disordered breathing. Subjective sleepiness and its impact were assessed using the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and Functional Outcomes of Sleep Questionnaire. RESULTS: Three (one female) of the 19 participants who completed home overnight testing had central sleep apnea (median apnea-hypopnea index = 15 [range = 8-36] events/h sleep, median nadir SaO2 = 88 % [range = 81-88]). There were no cases of obstructive sleep apnea. Thirty-three percent of participants reported excessive daytime sleepiness, and 71% reported poor sleep quality. CONCLUSIONS: Home sleep testing was well tolerated, and a high proportion of central rather than obstructive sleep apnea was observed in a clinical MS sample. Possible reasons include brainstem or spinal cord lesions from MS affecting the control of breathing. Poor sleep quality and daytime sleepiness were common in this group. PMID- 27975180 TI - Characteristics of Gastric Cancer in Lebanon: a Descriptive Study from a Single Institutional Experience. AB - BACKGROUND: The epidemiology of gastric cancer in the Middle East has never been described. Therefore, the characteristics of gastric cancer in the Lebanese population will be reported in this study. PATIENTS AND METHODS: A retrospective study that included all patients diagnosed with gastric cancer at Hotel Dieu de France University Hospital in Beirut, Lebanon between 2010 and 2016 was conducted. All eligible patients were reviewed for demographic and epidemiologic analysis. RESULTS: The study included 123 patients diagnosed with gastric cancer. The median age at diagnosis was 59 years (range 15-72 years), and the median ECOG performance status was 2 (range 1-4). Most patients were metastatic at diagnosis (52.8%), and diffuse pathology type was predominant (39%). HER2 was positive in 16.2% and correlated with the occurrence of hepatic metastasis (p = 0.048). The HER2 status did not differ significantly between the histological subtypes, the site of the tumor, the stage of the gastric cancer at diagnosis, and the recurrence of cancer (p > 0.05). CONCLUSION: Gastric cancer in the Lebanese population is characterized by aggressive features such as advanced stage at diagnosis, high prevalence of diffuse type histology, and HER2 positivity. PMID- 27975181 TI - Patient Experience After Receiving a Diagnosis of Gastric Cancer in the USA. AB - PURPOSE: This study investigated the patient perspective during cancer treatment and throughout the survivorship period and to understand how the patient experience may be related to choices for the treatment of gastric cancer. METHODS: Eligible patients in the Vector Oncology electronic medical records database were >=18 years of age, diagnosed with gastric cancer, and received active treatment. Quality of life (QOL) was collected using the Patient Care Monitor (PCM). Time to deterioration in QOL and overall survival were measured, adjusting for demographic and baseline clinical characteristics. Logistic regression model and classification and regression trees (CART) were used to identify factors associated with treatment choice. RESULTS: There were 776 patients in this study, of whom 301 (38.8%) reported QOL data. Most patients reported problems on all PCM subscales; problems were more common during the treatment period. Median time to deterioration of PCM subscales ranged from 42 days for treatment side effects to 331 days for impaired performance. Median survival was low: 6.9 and 5.5 months from the start of first- and second-line therapy, respectively. The choices made between therapeutic options were primarily associated with the site at which the oncologist practiced. CONCLUSIONS: Patients with gastric cancer report a considerable number of concerns on all subscales of the PCM, particularly during active treatment periods. The treatment heterogeneity and relative lack of clinical and symptom- or QOL-related factors associated with treatment choice suggest a gap in evidence that must be filled. PMID- 27975182 TI - Evaluating the Correlation Between the Survival Rate of Patients with Esophageal Squamous Cell Carcinoma and Expression of p53 and Cyclin D1 Biomarkers Along with Other Prognostic Factors. AB - OBJECTIVE: In the present study, we aimed to evaluate the relationship between the survival rate of patients with esophageal squamous cell carcinoma (SCC) and expression of two biomarkers along with age, gender, tumor margin, depth of invasion, site of tumor, tumor diameter, tumor grade, number of involved nodes, and vascular invasion. MATERIALS AND METHODS: In this retrospective survey, medical records of patients referred to the Shohada-e Tajrish hospital during 2001 to 2005 were reviewed and subjects with definite diagnosis of SCC were included. Required data were extracted from the patients' records, and their prepared paraffin-embedded tissue blocks were collected under supervision of two pathologists. Immunohistochemistry (IHC) analysis was performed at the Firoozgar hospital in Tehran, Iran. RESULTS: The studied population included 20 men (74%) and 7 women (26%). The mean age at diagnosis was 58 +/- 22. Results showed significantly higher survival rates in women compared to men (85.7 vs. 40%) (p = 0.001) and in patients with well-differentiated tumors compared to poor differentiated cases (20 vs. 5%) (p = 0.004). No significant relationship was found between p53 expression and prognostic factors like age, gender, the site, grade, and size of the tumor, depth of invasion, involvement of lymph nodes, and vascular invasion. CONCLUSION: Positivity of p53 and cyclin D1 was not found to be predictive of survival in patients with esophageal SCC which might be due to the small sample size of the present survey. Further investigations with larger sample populations and longer follow-ups are required to evaluate this correlation. PMID- 27975183 TI - Who Chooses STEM Careers? Using A Relative Cognitive Strength and Interest Model to Predict Careers in Science, Technology, Engineering, and Mathematics. AB - Career aspirations in science, technology, engineering, and mathematics (STEM) are formulated in adolescence, making the high school years a critical time period for identifying the cognitive and motivational factors that increase the likelihood of future STEM employment. While past research has mainly focused on absolute cognitive ability levels in math and verbal domains, the current study tested whether relative cognitive strengths and interests in math, science, and verbal domains in high school were more accurate predictors of STEM career decisions. Data were drawn from a national longitudinal study in the United States (N = 1762; 48 % female; the first wave during ninth grade and the last wave at age 33). Results revealed that in the high-verbal/high-math/high-science ability group, individuals with higher science task values and lower orientation toward altruism were more likely to select STEM occupations. In the low verbal/moderate-math/moderate-science ability group, individuals with higher math ability and higher math task values were more likely to select STEM occupations. The findings suggest that youth with asymmetrical cognitive ability profiles are more likely to select careers that utilize their cognitive strengths rather than their weaknesses, while symmetrical cognitive ability profiles may grant youth more flexibility in their options, allowing their interests and values to guide their career decisions. PMID- 27975186 TI - An integrated microfluidic PCR system with immunomagnetic nanoparticles for the detection of bacterial pathogens. AB - There is growing interest in rapid microbial pre-concentration methods to lower the detection limit of bacterial pathogens of low abundance in samples. Here, we report an integrated microfluidic PCR system that enables bacterial cells of interest in samples to be concentrated prior to PCR. It consists of two major compartments: a preconcentration chamber for the immunomagnetic separation of bacterial cells, and a PCR chamber for the DNA amplification of the concentrated cells. We demonstrate the feasibility of the system for the detection of microbial pathogens by preconcentrating the human pathogen Escherichia coli O157:H7, and also amplifying its DNA. The detection limit of E. coli O157:H7 in the PCR system is 1 * 103 CFU (colony forming unit)/mL. On-chip processing steps, including preconcentration and PCR steps, take less than two hours. Our system can serve as a rapid, specific, and quantitative platform for the detection of microbial pathogens in samples of large volume. PMID- 27975185 TI - L71F mutation in rat cardiac troponin T augments crossbridge recruitment and detachment dynamics against alpha-myosin heavy chain, but not against beta-myosin heavy chain. AB - The N-terminal extension of human cardiac troponin T (TnT), which modulates myofilament Ca2+ sensitivity, contains several hypertrophic cardiomyopathy (HCM) causing mutations including S69F. However, the functional consequence of S69F mutation is unknown. The human analog of S69F in rat TnT is L71F (TnTL71F). Because the functional consequences due to structural changes in the N-terminal extension are influenced by the type of myosin heavy chain (MHC) isoform, we hypothesized that the TnTL71F-mediated effect would be differently modulated by alpha- and beta-MHC isoforms. TnTL71F and wild-type rat TnT were reconstituted into de-membranated muscle fibers from normal (alpha-MHC) and propylthiouracil treated rat hearts (beta-MHC) to measure steady-state and dynamic contractile parameters. The magnitude of the TnTL71F-mediated attenuation of Ca2+-activated maximal tension was greater in alpha- than in beta-MHC fibers. For example, TnTL71F attenuated maximal tension by 31% in alpha-MHC fibers but only by 10% in beta-MHC fibers. Furthermore, TnTL71F reduced myofilament Ca2+ sensitivity by 0.11 pCa units in alpha-MHC fibers but only by 0.05 pCa units in beta-MHC fibers. TnTL71F augmented rate constants of crossbridge recruitment and crossbridge detachment dynamics in alpha-MHC fibers but not in beta-MHC fibers. Collectively, our data demonstrate that TnTL71F induces greater contractile deficits against alpha-MHC than against beta-MHC background. PMID- 27975187 TI - Pharmacokinetic-Pharmacodynamic Modeling of the Anti-Tumor Effect of Sunitinib Combined with Dopamine in the Human Non-Small Cell Lung Cancer Xenograft. AB - PURPOSE: To investigate the anti-tumor effect of sunitinib in combination with dopamine in the treatment of nu/nu nude mice bearing non-small cell lung cancer (NSCLC) A549 cells and to develop the combination PK/PD model. Further, simulations were conducted to optimize the administration regimens. METHODS: A PK/PD model was developed based on our preclinical experiment to explore the relationship between plasma concentration and drug effect quantitatively. Further, the model was evaluated and validated. By fixing the parameters obtained from the PK/PD model, simulations were built to predict the tumor suppression under various regimens. RESULTS: The synergistic effect was observed between sunitinib and dopamine in the study, which was confirmed by the effect constant (GAMA, estimated as 2.49). The enhanced potency of dopamine on sunitinib was exerted by on/off effect in the PK/PD model. The optimal dose regimen was selected as sunitinib (120 mg/kg, q3d) in combination with dopamine (2 mg/kg, q3d) based on the simulation study. CONCLUSIONS: The synergistic effect of sunitinib and dopamine was demonstrated by the preclinical experiment and confirmed by the developed PK/PD model. In addition, the regimens were optimized by means of modeling as well as simulation, which may be conducive to clinical study. PMID- 27975188 TI - Vitamin D deficiency is associated with acute ischemic stroke, C-reactive protein, and short-term outcome. AB - The aim of this study was to investigate whether vitamin D deficiency (VDD) is associated with acute ischemic stroke, inflammatory markers, and short-term outcome. 168 acute ischemic stroke patients and 118 controls were included. The modified Rankin Scale (mRS) was applied up to 8 h of admission (baseline) and after three-months follow-up, and blood samples were obtained up to 24 h of admission to evaluate serum levels of 25-hydroxivitamin D [25(OH)D] and inflammatory markers. Vitamin D levels classified the individuals in sufficient (VDS >= 30.0 ng/mL), insufficient (VDI 20.0-29.9 ng/mL), and deficient (VDD < 20.0 ng/mL) status. Patients had lower levels of 25(OH)D, higher frequency of VDD (43.45% vs. 5.08%, OR: 16.64, 95% CI: 5.66-42.92, p < 0.001), and higher inflammatory markers than controls (p < 0.05). Patients with VDD showed increased high sensitivity C-reactive protein (hsCRP) levels than those with VDS status (p = 0.043); those with poor outcome presented with lower 25(OH)D levels than those with good outcome (p = 0.008); moreover, 25(OH)D levels were negatively correlated with mRS after three-months follow-up (r = -0.239, p = 0.005). The associations between VDD and higher hsCRP levels and between 25(OH)D levels and poor outcome at short-term in acute ischemic stroke patients suggest the important role of vitamin D in the inflammatory response and pathophysiology of this ischemic event. PMID- 27975190 TI - Investigation of Marek's disease virus from chickens in central Ethiopia. AB - Marek's disease (MD) is a lymphoproliferative and neuropathic disease of domestic chickens and less commonly, turkeys and quails, caused by a highly contagious, cell-associated, oncogenic herpesvirus. In Ethiopia, MD is believed to be introduced with importation of exotic and crossbred to improve the poultry production and has been reported to be a potential threat to the poultry sector both in backyard and commercial farming systems. This study was aimed at isolation and molecular analysis of MD virus isolates circulating in chicken population in the central part of Ethiopia where commercial farms are populated. From September 2013 to January 2014, clinical and post-mortem examination were conducted on diseased chickens suspected of MD virus infection. Representative spleen and feather follicle samples were collected following sterile procedure, and infectious virus isolation was performed using primary chicken fibroblast cell culture. Cell culture inoculated with suspension of pathological samples developed characteristic MD virus cytopathic effect of rounding of the cells and small plaques. Further analysis of the virus was conducted by conventional PCR amplifying the ICP4 gene fragment from eleven tissue samples using MD virus specific primers. PCR products were further sequenced and analyzed. Nucleotide sequence similarity search of the local isolates resulted a high degree of sequence similarity with Gallid Herpes virus type 2 strain (Marek's disease virus type 1, JN034558). To our knowledge, the present study is the first report conducted on virus isolation and molecular characterization of MD virus isolates circulated in Ethiopia. Eleven ICP4-like gene fragment (318 bp) sequences generated in the present study were uploaded in the public database (KU842366 76). Further research on virus isolation, genetic characterization, and infection dynamics is recommended targeting chickens of all age groups reared in different agro-ecological zones under different production system. PMID- 27975189 TI - Arabidopsis ANAC069 binds to C[A/G]CG[T/G] sequences to negatively regulate salt and osmotic stress tolerance. AB - KEY MESSAGE: ANAC069 binds to the DNA sequence of C[A/G]CG[T/G] to regulate the expression of genes, resulting in decreased ROS scavenging capability and proline biosynthesis, which contribute to increased sensitivity to salt and osmotic stress. NAM-ATAF1/2 and CUC2 (NAC) proteins are plant-specific transcription factors that play important roles in abiotic stress responses. In the present study, we characterized the physiological and regulatory roles of Arabidopsis thaliana ANAC069 in response to abiotic stresses. Arabidopsis plants overexpressing ANAC069 displayed increased sensitivity to abscisic acid, salt, and osmotic stress. Conversely, ANAC069 knockdown plants showed enhanced tolerance to salt and osmotic stress, but no change in ABA sensitivity. Further studies showed that ANAC069 inhibits the expression of SOD, POD, GST, and P5CS genes. Consequently, the transcript level of ANAC069 correlated negatively with the reactive oxygen species (ROS) scavenging ability and the proline level. The genes regulated by ANAC069 were further studied using a gene chip on a genome wide scale, and 339 and 226 genes up- and downregulated by ANAC069 were identified. Analysis of the promoters of the genes affected by ANAC069 suggested that ANAC069 regulates the expression of genes mainly through interacting with the DNA sequence C[A/G]CG[T/G] in response to abiotic stresses. Collectively, our data suggest that ANAC069 could recognize C[A/G]CG[T/G] sequences to regulate the expression of genes that negatively regulates salt and osmotic stress tolerance by decreasing ROS scavenging capability and proline biosynthesis. PMID- 27975192 TI - Tuning the Hydrophilic/Hydrophobic Balance to Control the Structure of Chitosan Films and Their Protein Release Behavior. AB - The control over the crystallinity of chitosan and chitosan/ovalbumin films can be achieved via an appropriate balance of the hydrophilic/hydrophobic interactions during the film formation process, which then controls the release kinetics of ovalbumin. Chitosan films were prepared by solvent casting. The presence of the anhydrous allomorph can be viewed as a probe of the hydrophobic conditions at the neutralization step. The semicrystalline structure, the swelling behavior of the films, the protein/chitosan interactions, and the release behavior of the films were impacted by the DA and the film processing parameters. At low DAs, the chitosan films neutralized in the solid state corresponded to the most hydrophobic environment, inducing the crystallization of the anhydrous allomorph with and without protein. The most hydrophilic conditions, leading to the hydrated allomorph, corresponded to non-neutralized films for the highest DAs. For the non-neutralized chitosan acetate (amorphous) films, the swelling increased when the DA decreased, whereas for the neutralized chitosan films, the swelling decreased. The in vitro release of ovalbumin (model protein) from chitosan films was controlled by their swelling behavior. For fast swelling films (DA = 45%), a burst effect was observed. On the contrary, a lag time was evidenced for DA = 2.5% with a limited release of the protein. Furthermore, by blending chitosans (DA = 2.5% and 45%), the release behavior was improved by reducing the burst effect and the lag time. The secondary structure of ovalbumin was partially maintained in the solid state, and the ovalbumin was released under its native form. PMID- 27975191 TI - Significance of insulin resistance and oxidative stress in dairy cattle with subclinical ketosis during the transition period. AB - Health problems occurring during the transition period in dairy cattle are of utmost importance as they can decrease the animal's reproductive performance and favor the development of various metabolic diseases with resultant significant reproductive disorders. Among the commonly reported metabolic diseases occurring during that time, hyperketonemia is the most prevalent and could provoke a significant economic impact. The failing of a dairy cow to transit optimally between pregnancy and lactation is economically very relevant and should be considered. Until now, the role of insulin resistance (IR) in the etiology of subclinical ketosis (SCK) in dairy cattle is not clearly understood. This review aims to shed some light on the role of IR and oxidative stress in dairy cows with SCK during the transition period. The data presented in this review demonstrates that dairy cows could be vulnerable to the development of negative energy balance during transition. Moreover, the transitional cows could succumb to both IR and oxidative stress; however, the exact role of IR in cows with SCK needs further investigations. It is imperative to elaborate a suitable nutritional strategy to facilitate an easy transit of cows through this critical period and to minimize health problems and improve productivity during lactation. PMID- 27975193 TI - Inhibition of Glomerular Mesangial Cell Proliferation by siPDGF-B- and siPDGFR beta-Containing Chitosan Nanoplexes. AB - Mesangioproliferative glomerulonephritis is a disease that has a high incidence in humans. In this disease, the proliferation of glomerular mesangial cells and the production of extracellular matrix are important. In recent years, the RNAi technology has been widely used in the treatment of various diseases due to its capability to inhibit the gene expression with high specificity and targeting. The objective of this study was to decrease mesangial cell proliferation by knocking down PDGF-B and its receptor, PDGFR-beta. To be able to use small interfering RNAs (siRNAs) in the treatment of this disease successfully, it is necessary to develop appropriate delivery systems. Chitosan, which is a biopolymer, is used as a siRNA delivery system in kidney drug targeting. In order to deliver siRNA molecules targeted at PDGF-B and PDGFR-beta, chitosan/siRNA nanoplexes were prepared. The in vitro characterization, transfection studies, and knockdown efficiencies were studied in immortalized and primary rat mesangial cells. In addition, the effects of chitosan nanoplexes on mesangial cell proliferation and migration were investigated. After in vitro transfection, the PDGF-B and PDGFR-beta gene silencing efficiencies of PDGF-B and PDGFR-beta targeting siRNA-containing chitosan nanoplexes were 74 and 71% in immortalized rat mesangial cells and 66 and 62% in primary rat mesangial cells, respectively. siPDGF-B- and siPDGFR-beta-containing nanoplexes indicated a significant decrease in mesangial cell migration and proliferation. These results suggested that mesangial cell proliferation may be inhibited by silencing of the PDGF-B signaling pathway. Gene silencing approaches with chitosan-based gene delivery systems have promise for the efficient treatment of renal disease. PMID- 27975194 TI - On the Biology of the Colombian Fluted Scale, Crypticerya multicicatrices Kondo & Unruh (Hemiptera: Monophlebidae). AB - The Colombian fluted scale Crypticerya multicicatrices Kondo & Unruh (Hemiptera: Monophlebidae) is a polyphagous insect pest native to continental Colombia and reported on 148 species, mainly palms (Arecaceae); mango, Mangifera indica (Anacardiaceae); and leguminous trees and shrubs (Fabaceae). The biology and ecological parameters of C. multicicatrices were investigated using as a host plant Caesalpinia pluviosa var. peltophoroides (Fabaceae) under two environmental conditions: semifield (max temp., 31.5 +/- 3.0 degrees C; max. RH, 78.9 +/- 6.0%) and a glass house (max. temp., 37.1 +/- 5.1 degrees C, max. RH, 67.0 +/- 6.2%) in the premises of Corpoica, Palmira Research Station. The duration of the different developmental stages was highly different under both temperature conditions. First- and third-instar nymphs, the period of ovisac growth of the adult, and the duration of the life cycle were significantly higher in the semifield conditions compared to the glass house conditions. In contrast, the second-instar nymph stage was shorter in the semifield conditions. The duration of the fourth-instar stage (adult) and the reproductive period were the same in both environments. As for the evaluated ecological parameters, a great difference was found between the two environmental conditions, where the net reproductive rate (R o) and mean generation time (T) were significantly higher in the semifield conditions than in the glass house conditions. The obtained biological and ecological information is an essential tool for finding strategies to control this insect pest. This is the first detailed study on the biology of a species in the genus Crypticerya Cockerell. PMID- 27975195 TI - Serious games and blended learning; effects on performance and motivation in medical education. AB - INTRODUCTION: More efficient, flexible training models are needed in medical education. Information technology offers the tools to design and develop effective and more efficient training. The aims of this thesis were: 1) Compare the effectiveness of blended versus classroom training for the acquisition of knowledge; 2) Investigate the effectiveness and critical design features of serious games for performance improvement and motivation. METHODS: Five empirical studies were conducted to answer the research questions and a descriptive study on an evaluation framework to assess serious games was performed. RESULTS: The results of the research studies indicated that: 1) For knowledge acquisition, blended learning is equally effective and attractive for learners as classroom learning; 2) A serious game with realistic, interactive cases improved complex cognitive skills for residents, with limited self-study time. Although the same game was motivating for inexperienced medical students and stimulated them to study longer, it did not improve their cognitive skills, compared with what they learned from an instructional e-module. This indicates an 'expertise reversal effect', where a rich learning environment is effective for experts, but may be contra-productive for novices (interaction of prior knowledge and complexity of format). DISCUSSION: A blended design is equally effective and attractive as classroom training. Blended learning facilitates adaptation to the learners' knowledge level, flexibility in time and scalability of learning. Games may support skills learning, provided task complexity matches the learner's competency level. More design-based research is needed on the effects of task complexity and other design features on performance improvement, for both novices and experts. PMID- 27975196 TI - Economic Studies in Motor Neurone Disease: A Systematic Methodological Review. AB - BACKGROUND: Motor neurone disease (MND) is a devastating condition which greatly diminishes patients' quality of life and limits life expectancy. Health technology appraisals of future interventions in MND need robust data on costs and utilities. Existing economic evaluations have been noted to be limited and fraught with challenges. OBJECTIVE: The aim of this study was to identify and critique methodological aspects of all published economic evaluations, cost studies, and utility studies in MND. METHODS: We systematically reviewed all relevant published studies in English from 1946 until January 2016, searching the databases of Medline, EMBASE, Econlit, NHS Economic Evaluation Database (NHS EED) and the Health Economics Evaluation Database (HEED). Key data were extracted and synthesised narratively. RESULTS: A total of 1830 articles were identified, of which 15 economic evaluations, 23 cost and 3 utility studies were included. Most economic studies focused on riluzole (n = 9). Six studies modelled the progressive decline in motor function using a Markov design but did not include mutually exclusive health states. Cost estimates for a number of evaluations were based on expert opinion and were hampered by high variability and location specific characteristics. Few cost studies reported disease-stage-specific costs (n = 3) or fully captured indirect costs. Utilities in three studies of MND patients used the EuroQol EQ-5D questionnaire or standard gamble, but included potentially unrepresentative cohorts and did not consider any health impacts on caregivers. CONCLUSION: Economic evaluations in MND suffer from significant methodological issues such as a lack of data, uncertainty with the disease course and use of inappropriate modelling framework. Limitations may be addressed through the collection of detailed and representative data from large cohorts of patients. PMID- 27975197 TI - Characterization of indoor diesel exhaust emissions from the parking garage of a school. AB - Diesel exhaust (DE) emissions from a parking garage located in the basement of a school were characterized during spring and winter using direct reading devices and integrated sampling methods. Concentrations of CO and NO2 were evaluated using electrochemical sensors and passive colorimetric tubes, respectively. Elemental and total carbon concentrations were measured using the NIOSH 5040 method. Particle number concentrations (PNCs), respirable particulate matter (PMresp) mass concentrations, and size distributions were evaluated using direct reading devices. Indoor concentrations of elemental carbon, PNC, CO, and NO2 showed significant seasonal variation; concentrations were much higher during winter (p < 0.01). Concentrations of the PMresp and total carbon did not show significant seasonal variation. Pearson correlation coefficients were 0.9 (p < 0.01) and 0.94 (p < 0.01) between the parking garage and ground floor average daily PNCs, and between the parking garage and first floor average daily PNCs, respectively. Since DE is the main identified source of fine and ultrafine particles in the school, these results suggest that DE emissions migrate from the parking garage into the school. Our results highlight the relevance of direct reading instruments in identifying migration of contaminants and suggest that monitoring PNC is a more specific way of assessing exposure to DE than monitoring the common PMresp fraction. PMID- 27975198 TI - Maximization of cell growth and lipid production of freshwater microalga Chlorella vulgaris by enrichment technique for biodiesel production. AB - Chlorella vulgaris was cultivated under limitation and starvation and under controlled conditions using different concentrations of nitrate (NaNO3) and phosphate (K2HPO4 and KH2PO4) chemicals in modified Bold basal medium (BBM). The biomass and lipid production responses to different media were examined in terms of optical density, cell density, dry biomass, and lipid productivity. In the 12 day batch culture period, the highest biomass productivity obtained was 72.083 mg L-1 day-1 under BBM - NcontrolPlimited condition. The highest lipid content, lipid concentration, and lipid productivity obtained were 53.202 %, 287.291 mg/L, and 23.449 mg L-1 day-1 under BBM - NControlPDeprivation condition, respectively. Nitrogen had a major effect in the biomass concentration of C. vulgaris, while no significant effect was found for phosphorus. Nitrogen and phosphorus starvation was found to be the strategy affecting the lipid accumulation and affected the lipid composition of C. vulgaris cultures. PMID- 27975199 TI - Allelopathic effect boosts Chrysosporum ovalisporum dominance in summer at the expense of Microcystis panniformis in a shallow coastal water body. AB - The increased occurrence of harmful cyanobacterial species and, with this, higher frequency of cyanobacteria blooms, closely associated with eutrophication and climate change, have attracted increasing attention worldwide. However, competition mechanisms between the different bloom-forming cyanobacteria species remain to be elucidated. In this paper, for the first time, the allelopathic effect of the cyanobacterium Chrysosporum ovalisporum on the cyanobacterium Microcystis panniformis is reported. The results of our study conducted in a Chinese shallow coastal water body demonstrated that the biomass of M. panniformis was relatively low during the C. ovalisporum blooming period. Co cultivation of a C. ovalisporum strain with a M. panniformis strain showed strong inhibition of the growth of M. panniformis but stimulation of C. ovalisporum. Thus, filtrate of C. ovalisporum culture had a strong inhibitory effect on the performance of M. panniformis by decreasing the maximum optical quantum yield (F v/F m), the electron transport rate (ETR) of PS II and the onset of light saturation (I k) and by increasing the alkaline phosphatase (ALP) activity and superoxide dismutase (SOD) activity of M. panniformis. Our results suggest that the inter-specific allelopathic effect plays an important role in the competition between different cyanobacteria species. We foresee the importance of C. ovalisporum to intensify in a future warmer world, not least in small- to medium sized, warm and high conductivity coastal water bodies. PMID- 27975200 TI - Effectiveness and intermediates of microcystin-LR degradation by UV/H2O2 via 265 nm ultraviolet light-emitting diodes. AB - Although the degradation of cyanotoxins by 254 nm UV/H2O2 has been well elucidated, the efficiency and mechanism involved are not necessarily true for other UV wavelengths. The degradation of microcystin-LR (MC-LR), a representative cyanotoxin, was explored by UV/H2O2 using 265 nm ultraviolet light-emitting diode (UV-LED). The results indicated that 265 nm UV/H2O2 treatment had a high removal efficiency of MC-LR ([MC-LR] = 0.1 MUM, apparent rate constants reached 0.2077 min-1, half-time at 3.3 min). The qualitative analyses demonstrated that three novel intermediates, C48H74N10O15 (molecular weight = 1030.5335), C36H58N10O14 (854.4134), and C33H54N10O14 (814.3821), were generated in 265 nm UV/H2O2. Five published intermediates were also confirmed. The generative pathway of these products mainly involved free hydroxyl radical oxidation, resulting in consecutive hydroxyl substitutions and hydroxyl additions of unsaturated bonds in MC-LR. The toxicity of MC-LR was weaken with a relative low mineralization. The electrical energy per order values were calculated to be in the range of 0.00447 to 0.00612 kWh m-3 order-1 for 100-5000 MUg L-1 MC-LR. Overall, 265 nm UV LED/H2O2 can be used as an alternative effective technology to improve the removal efficiency of MC-LR in water. PMID- 27975201 TI - Health assessment using aqua-quality indicators of alpine streams (Khunjerab National Park), Gilgit, Pakistan. AB - This preliminary research was conducted to evaluate the alpine stream health by using water quality as an indicator in Khunjerab National park of the Karakoram ranges located in Pak-China boarder Pakistan having altitude of 3660 m. This study investigated the stream health in the context of the presence or absence of sensitive species, their diversity, and their taxa richness. The water and macroinvertebrate samples were collected from 17 different locations from upstream and downstream of the river by using random sampling method. Macroinvertebrate samples were obtained using kick net (500-MUm mesh size) and hand-picking method (NYSDEC). A total of 710 counts including 41 families of macroinvertebrates were recorded comprising of 7 orders including: Ephemeroptera (46%) being the most dominant group, Plecoptera (33%), Trichoptera (5%), Chironomidae (Diptera) (14%), Heteroptera (1%), and Coleoptera (1%). Ephemeroptera, Trichoptera, and Plecoptera (EPT) were found in abundance at the main source, Qarchanai, Dhee, and Tourqeen Nullah, as compared to the other locations of the stream. The most dominant macroinvertebrate was Ephemeroptera whose relative abundance is Pi = 0.49 by using the Shannon index. However, different statistical tools, including principal component analysis (PCA), cluster analysis (CA), ANOVA, and linear regression model, show a strong correlation between water quality and macroinvertebrates. The overall results of the biological indicators showed better ecological health at downstream compared to upstream. This study will provide basic information and understanding about the macroinvertebrates for future researchers, and the data will be helpful for upcoming research programs on alpine streams for the discovery and occurrences of macroinvertebrates and associated fauna. PMID- 27975202 TI - Contamination level, distribution and health risk assessment of heavy and toxic metallic and metalloid elements in a cultivated mushroom Pleurotus florida (Mont.) singer. AB - There are great concentrations of toxic metallic and metalloid elements such as lead, arsenic, mercury, cadmium or silver in many species of mushrooms comparative to other fruits and vegetables. In this study, contamination with heavy and toxic metallic and metalloid elements in the cultivated mushroom of (Pleurotus florida (Mont.) Singer) is investigated. P. florida was cultivated on different substrates; wheat straw (as blank), wheat straw + pine cone, wheat straw + soybean straw and wheat straw + urea and the effects of these substrates on contamination levels of Mn, Fe, Cu, Zn, As, Cd, and Pb were analyzed. The results showed that the concentrations of essential elements (Mn, Fe, Cu, and Zn) in the target mushroom are at the typical levels. The estimated daily intakes of studied metallic and metalloid elements were below their oral reference dosage mentioned by the international regulatory bodies. Health risk index (HRI) was calculated to evaluate the consumer's health risk assessment from the metal intake that contaminated in the cultivated mushroom of P. florida on the different nutrient sources. In this study, the individual HRIs were less than 1, which indicates insignificant potential health risk associated with the consumption of target mushroom from the studied substrates. Based on the HRIs values among the toxic metallic and metalloid elements, As in the target mushroom in the substrate of the wheat straw + pine cone is the main sources of risk, and it may cause severe health problems. Thus, this study suggests that the concentrations of heavy and toxic elements should be periodically monitored in cultivated mushrooms. PMID- 27975203 TI - Loss of malin, but not laforin, results in compromised autophagic flux and proteasomal dysfunction in cells exposed to heat shock. AB - Heat stress to a cell leads to the activation of heat shock response, which is required for the management of misfolded and unfolded proteins. Macroautophagy and proteasome-mediated degradation are the two cellular processes that degrade polyubiquitinated, misfolded proteins. Contrasting pieces of evidence exist on the effect of heat stress on the activation of the above-mentioned degradative pathways. Laforin phosphatase and malin E3 ubiquitin ligase, the two proteins defective in Lafora neurodegenerative disorder, are involved in cellular stress response pathways and are required for the activation of heat shock transcription factor - the heat shock factor 1 (HSF1) - and, consequently, for cellular protection under heat shock. While the role of laforin and malin in the proteolytic pathways is well established, their role in cellular recovery from heat shock was not explored. To address this, we investigated autophagic flux, proteasomal activity, and the level of polyubiquitinated proteins in Neuro2a cells partially silenced for laforin or malin protein and exposed to heat shock. We found that heat shock was able to induce autophagic flux, proteasomal activity and reduce the polyubiquitinated proteins load in the laforin-silenced cells but not in the malin-deficient cells. Loss of malin leads to reduced proteasomal activity in the heat-shocked cells. Taken together, our results suggest a distinct mode of action for laforin and malin in the heat shock-induced proteolytic processes. PMID- 27975205 TI - A System for Multi-Domain Contextualization of Personal Health Data. AB - Current telehealth systems are used to improve the treatment of chronic diseases by collecting medical data at the patient and transferring them to a remote medical institution. Research shows that such medical practice can be substantially improved if the measured parameters are greater in number and of more diverse nature. Emerging consumer solutions for monitoring personal health and wellness, as well as various resources from domains like internet, telecommunications and smart living, can be used as possible sources for exploration of an individual's wider health context. It was our aim to design an internet of things solutions, which would combine these sources of information into context information, complementary to health data. An internet of things platform was designed and implemented and integration with an established e health system was provided to enrich telehealth data with context information by aggregating and processing cross-domain inputs from various sources. The approach was validated on a use case scenario. The concept was tried in a scenario related to prevention and management of heart disease. The system's advanced graphic correlation features are expected to help physicians and patients identify true roots of health problems. Medical researchers are also expected to benefit from a deeper insight into complex cross-domain parameter dependencies that determine an individual's health. PMID- 27975206 TI - Mobile Telemedicine Implementation with WiMAX Technology: A Case Study of Ghana. AB - Telemedicine has become an effective means of delivering quality healthcare in the world. Across the African continent, Telemedicine is increasingly being recognized as a way of improving access to quality healthcare. The use of technology to deliver quality healthcare has been demonstrated as an effective way of overcoming geographic barriers to healthcare in pilot Telemedicine projects in certain parts of Kumasi, Ghana. However because of poor network connectivity experienced in the pilot projects, the success of the pilot networks could not be extended to cover the whole city of Kumasi and other surrounding villages. Fortunately, recent deployment of WiMAX in Ghana has delivered higher data rates at longer distances with improved network connectivity. This paper examines the feasibility of using WiMAX in deploying a city wide Mobile Telemedicine solution. The network architecture and network parameter simulations of the proposed Mobile Telemedicine network using WiMAX are presented. Five WiMAX Base Stations have been suggested to give ubiquitous coverage to the proposed Mobile Telemedicine sites in the network using adaptive 4 * 4 MIMO antenna configurations. PMID- 27975204 TI - A disulfide-bonded DnaK dimer is maintained in an ATP-bound state. AB - DnaK, a major Hsp70 molecular chaperones in Escherichia coli, is a widely used model for studying Hsp70s. We recently solved a crystal structure of DnaK in complex with ATP and showed that DnaK was packed as a dimer in the crystal structure. Our previous biochemical studies supported the formation of a specific DnaK dimer as observed in the crystal structure in solution in the presence of ATP and suggested an important role of this dimer in efficient interaction with Hsp40 co-chaperones. In this study, we dissected the biochemical properties of this DnaK dimer. To restrict DnaK in this dimer form, we mutated two residues on the dimer interface to cysteine, A303C, and H541C. Upon oxidation, this DnaK A303C-H541C protein formed a specific dimer linked by disulfide bonds formed between A303C and H541C only in the presence of ATP, consistent with the crystal structure. Intriguingly, this disulfide-bond-linked dimer of DnaK-A303C-H541C has reduced ATPase activity and decreased affinity for peptide substrate. More interestingly, unlike wild-type DnaK, the peptide substrate-binding kinetics of this dimer is drastically accelerated even in the absence of ATP, suggesting this dimer is restricted in an ATP-bound conformation regardless of nucleotide bound, which was further supported by our analysis using tryptophan fluorescence and ATP induced peptide release. Thus, formation of the dimer restricted DnaK in an ATP bound state and blocked the progression through the chaperone cycle. Productive progression through the chaperone cycle requires the dissociation of this transient dimer. Surprisingly, a significantly compromised interaction with Hsp40 co-chaperone was observed for this disulfide-bond-linked dimer. Thus, dissociation of this DnaK dimer is equally crucial for efficient Hsp40 interaction. An initial interaction between Hsp70 and Hsp40 requires the formation of DnaK dimer; but a stable Hsp70-Hsp40 interaction may follow the dissociation of the dimer. PMID- 27975207 TI - [Joint replacement in the elderly]. AB - Special characteristics must be taken into consideration for replacement arthroplasty in the elderly. The indications, preoperative preparation, postoperative care, implant selection, intraoperative technique, as well as clinical results reveal sometimes substantial differences compared to younger patients. Based on these findings it is important to individualize the approach to patient therapy, especially due to distinct differences between chronological and biological age in the elderly, in association with the level of activity and expectations on the new joint. All types of implants, each with implant-specific characteristics that must be taken into consideration, are available independent of the age of the patient. In summary, attributes such as stability and pain-free mobility have to be given priority in the elderly. PMID- 27975208 TI - [Renal decapsulation for the treatment of anuria : A "forgotten" treatment from the early 20th century]. AB - In the early 20th century, Harrison first performed renal decapsulation in anuric children with scarlet fever and observed improvement in renal function postoperatively. The pathophysiological explanation was seen in intraparenchymal renal pressure due to edema which was improved by surgical decapsulation. The technique of decapsulation was simple excision after incision and blunt dissection of the renal parenchyma. Renal decapsulation then became a procedure commonly used for many indications in inflammatory renal conditions; indications were renal angioneurosis, hydronephrosis, toxic, bacterial and chronic nephritis, renal abscess and even eclampsia. With the beginning of the antibiotic era, renal decapsulation became obsolete and has disappeared from the urological spectrum completely. PMID- 27975210 TI - Proteomes, Their Compositions and Their Sources. AB - Biological samples of human and animal origin are utilized in research for many purposes and in a variety of scientific fields, including mass spectrometry-based proteomics. Various types of samples, including organs, tissues, cells, body fluids such as blood, plasma, cerebrospinal fluid, saliva and semen, can be collected from humans or animals and processed for proteomics analysis. Depending on the physiological state and sample origin, collected samples are used in research and diagnostics for different purposes. In mass spectrometry-based proteomics, body fluids and tissues are commonly used in discovery experiments to search for specific protein markers that can distinguish physiological from pathophysiological states, which in turn offer new diagnosis strategies and help developing new drugs to prevent disease more efficiently. Cell lines in combination with technologies such as Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) have broader application and are used frequently to investigate the mechanism of a disease or to investigate for the mechanism of a drug function. All of these are important components for defining the mechanisms of disease, discovering new pharmaceutical treatments and finally testing side effects of newly discovered drugs. PMID- 27975211 TI - Protein Fractionation and Enrichment Prior to Proteomics Sample Preparation. AB - Proteins may be considered as polypeptides large enough to have a well-defined tertiary, or three-dimensional structure. In aqueous media, this structure is typically one in which polar and charged amino acid residues are on the surface while hydrophobic residues tend to be sequestered in the core and reasonably inaccessible to the aqueous environment. Proteins that are not normally found free in aqueous media, such as membrane proteins and apolipoproteins, can have tertiary structures that deviate from this model. In general, the biological activity of proteins requires the preservation of their tertiary structure, and this sets more limits upon the chromatography than is true of peptides. In proteomics, the concern is with which proteins are present and in what quantity rather than maintaining biological activity. Such applications are freer to use mobile and stationary phases that denature protein structure. However, considerations of solubility and recovery may still set more limits on the chromatography than is the case with peptides. PMID- 27975212 TI - Sample Preparation for Mass Spectrometry-Based Proteomics; from Proteomes to Peptides. AB - Mass spectrometry (MS) has become the predominant technology to analyze proteins due to it ability to identify and characterize proteins and their modifications with high sensitivity and selectivity (Aebersold and Mann, Nature 422(6928):198 207, 2003; Han et al., Curr Opin Chem Biol 12(5):483-490, 2008). While mass spectrometry instruments have improved rapidly over the past couple of decades, mass spectrometry results have remained largely dependent on sample preparation and quality. Sample ionization and mass measurements are susceptible to a wide variety of interferences, including buffers, salts, polymers, and detergents. These contaminants also impair MS system performance, often requiring time consuming maintenance or costly repairs to restore function. The goal of this chapter is to describe the rationale, considerations, and general techniques used to prepare samples for proteomic mass spectrometry analysis. PMID- 27975209 TI - Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia. AB - AIMS/HYPOTHESIS: Post-bariatric hypoglycaemia (PBH) is a rare, but severe, metabolic disorder arising months to years after bariatric surgery. It is characterised by symptomatic postprandial hypoglycaemia, with inappropriately elevated insulin concentrations. The relative contribution of exaggerated incretin hormone signalling to dysregulated insulin secretion and symptomatic hypoglycaemia is a subject of ongoing inquiry. This study was designed to test the hypothesis that PBH and associated symptoms are primarily mediated by glucagon-like peptide-1 (GLP-1). METHODS: We conducted a double-blinded crossover study wherein eight participants with confirmed PBH were assigned in random order to intravenous infusion of the GLP-1 receptor (GLP-1r) antagonist. Exendin (9-39) (Ex-9), or placebo during an OGTT on two separate days at the Stanford University Clinical and Translational Research Unit. Metabolic, symptomatic and pharmacokinetic variables were evaluated. Results were compared with a cohort of BMI- and glucose-matched non-surgical controls (NSCs). RESULTS: Infusion of Ex-9 decreased the time to peak glucose and rate of glucose decline during OGTT, and raised the postprandial nadir by over 70%, normalising it relative to NSCs and preventing hypoglycaemia in all PBH participants. Insulin AUC and secretion rate decreased by 57% and 71% respectively, and peak postprandial insulin was normalised relative to NSCs. Autonomic and neuroglycopenic symptoms were significantly reduced during Ex-9 infusion. CONCLUSIONS/INTERPRETATION: GLP-1r blockade prevented hypoglycaemia in 100% of individuals, normalised beta cell function and reversed neuroglycopenic symptoms, supporting the conclusion that GLP-1 plays a primary role in mediating hyperinsulinaemic hypoglycaemia in PBH. Competitive antagonism at the GLP-1r merits consideration as a therapeutic strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02550145. PMID- 27975213 TI - Plant Structure and Specificity - Challenges and Sample Preparation Considerations for Proteomics. AB - Plants are considered as a simple structured organism when compared to humans and other vertebrates. The number of organs and tissue types is very limited. Instead the origin of the complexity comes from the high number and variety of plant species that exist, with >300,000 compared to 5000 in mammals. Proteomics, defined as the large-scale study of the proteins present in a tissue, cell or cellular compartment at a defined time point, was introduced in 1994. However, the first publications reported in the plant proteomics field only appeared at the beginning of the twenty-first century. Since these early years, the increase of proteomic studies in plants has only followed a linear trend. The main reason for this stems from the challenges specific to studying plants, those of protein extraction from cells with variously strengthened cellulosic cell walls, and a high abundance of interfering compounds, such as phenolic compounds and pigments located in plastids throughout the plant. Indeed, the heterogeneity between different organs and tissue types, between species and different developmental stages, requires the use of optimized plant protein extraction methods as described in this section. The second bottleneck of plant proteomics, which will not be discussed or reviewed here, is the lack of genomic information. Without sequence databases of the >300,000 species, proteomic studies of plants, especially of those that are not considered economically relevant, are impossible to accomplish. PMID- 27975214 TI - Improving Proteome Coverage by Reducing Sample Complexity via Chromatography. AB - High performance liquid chromatography (HPLC) is currently one of the most powerful analytical tools that has revolutionized the field of proteomics. Formerly known as high pressure liquid chromatography, this technique was introduced in the early 1960s to improve the efficiency of liquid chromatography separations using small stationary phase particles packed in columns. Since its introduction, continued advancements in column technology, development of different stationary phase materials and improved instrumentation has allowed the full potential of this technique to be realized. The various modes of HPLC in combination with mass spectrometry has evolved into the principal analytical technique in proteomics. It is now common practice to combine different types of HPLC in a multidimensional workflow to identify and quantify peptides and proteins with high sensitivity and resolution from limited amounts of samples. More recently, the introduction of Ultra High Performance Liquid Chromatography (UHPLC) has further raised the level of performance of this technique with significant increases in resolution, speed and sensitivity. The number of applications of HPLC and UHPLC in proteomics has been rapidly expanding and will continue to be a pivotal analytical technique. The aim of the following sections is to familiarize the beginner with the various HPLC methods routinely used in proteomics and provide sufficient practical knowledge regarding each of them to develop a separation and analytical protocol. PMID- 27975215 TI - Database Search Engines: Paradigms, Challenges and Solutions. AB - The first step in identifying proteins from mass spectrometry based shotgun proteomics data is to infer peptides from tandem mass spectra, a task generally achieved using database search engines. In this chapter, the basic principles of database search engines are introduced with a focus on open source software, and the use of database search engines is demonstrated using the freely available SearchGUI interface. This chapter also discusses how to tackle general issues related to sequence database searching and shows how to minimize their impact. PMID- 27975216 TI - Mass Analyzers and Mass Spectrometers. AB - Mass spectrometers are comprised of three main components: an ion source, a mass analyzer, and a detector. Ionization of the analyte occurs in the ion source and the resulting ions are counted at the detector. However, it is the mass analyzer that is responsible for determing the mass-to-charge ratio (m/z) of the ions (Jennings KR, Dolnikowski GG, Method Enzymol 193:37-61, 1990). Therefore, it is primarily the analyzer that allows the mass spectrometer to serve its primary goal - determining the mass of the analytes being measured. This becomes important in the field of molecular biology, where biomolecules may be of low molecular weight or often take on multiple charges (z) after ionization (Fenn JB, Mann M, Meng CK, Wong SF, Whitehouse CM, Science 246:64-71, 1989). For this reason, the choice of analyzer is dependant on the properties of the analyte after ionization and the requirements of the experiment being performed. PMID- 27975217 TI - Top-Down Mass Spectrometry: Proteomics to Proteoforms. AB - This chapter highlights many of the fundamental concepts and technologies in the field of top-down mass spectrometry (TDMS), and provides numerous examples of contributions that TD is making in biology, biophysics, and clinical investigations. TD workflows include variegated steps that may include non specific or targeted preparative strategies, orthogonal liquid chromatography techniques, analyte ionization, mass analysis, tandem mass spectrometry (MS/MS) and informatics procedures. This diversity of experimental designs has evolved to manage the large dynamic range of protein expression and diverse physiochemical properties of proteins in proteome investigations, tackle proteoform microheterogeneity, as well as determine structure and composition of gas-phase proteins and protein assemblies. PMID- 27975218 TI - Platforms and Pipelines for Proteomics Data Analysis and Management. AB - Since mass spectrometry was introduced as the core technology for large-scale analysis of the proteome, the speed of data acquisition, dynamic ranges of measurements, and data quality are continuously improving. These improvements are triggered by regular launches of new methodologies and instruments. PMID- 27975219 TI - Tandem Mass Spectrum Sequencing: An Alternative to Database Search Engines in Shotgun Proteomics. AB - Protein identification via database searches has become the gold standard in mass spectrometry based shotgun proteomics. However, as the quality of tandem mass spectra improves, direct mass spectrum sequencing gains interest as a database independent alternative. In this chapter, the general principle of this so-called de novo sequencing is introduced along with pitfalls and challenges of the technique. The main tools available are presented with a focus on user friendly open source software which can be directly applied in everyday proteomic workflows. PMID- 27975220 TI - Visualization, Inspection and Interpretation of Shotgun Proteomics Identification Results. AB - Shotgun proteomics is a high throughput technique for protein identification able to identify up to several thousand proteins from a single sample. In order to make sense of this large amount of data, proteomics analysis software is needed, aimed at making the data intuitively accessible to beginners as well as experienced scientists. This chapter provides insight on where to start when analyzing shotgun proteomics data, with a focus on explaining the most common pitfalls in protein identification analysis and how to avoid them. Finally, the move to seeing beyond the list of identified proteins and to putting the results into a bigger biological context is discussed. PMID- 27975221 TI - Protein Inference. AB - Protein inference is one of the most important steps in protein identification, which transforms peptides identified from tandem mass spectra into a list of proteins. In this chapter, we provide a brief introduction on this problem and present a short summary on the existing protein inference methods in the literature. PMID- 27975222 TI - Modification Site Localization in Peptides. AB - There are a large number of search engines designed to take mass spectrometry fragmentation spectra and match them to peptides from proteins in a database. These peptides could be unmodified, but they could also bear modifications that were added biologically or during sample preparation. As a measure of reliability for the peptide identification, software normally calculates how likely a given quality of match could have been achieved at random, most commonly through the use of target-decoy database searching (Elias and Gygi, Nat Methods 4(3): 207 214, 2007). Matching the correct peptide but with the wrong modification localization is not a random match, so results with this error will normally still be assessed as reliable identifications by the search engine. Hence, an extra step is required to determine site localization reliability, and the software approaches to measure this are the subject of this part of the chapter. PMID- 27975223 TI - Useful Web Resources. AB - An increasing number of web resources are available for aiding in proteomics research. Databases contain repositories of proteins and associated information. A recent article by Chen et al. (Genomics Proteomics Bioinformatics 13(1):36-39, 2015) evaluates a number of MS-based proteomics repositories containing MS and expression data, including repositories devoted to cataloguing high confidence post-translational modifications. Many sites have tools developed by research labs that are shared with the community and online tutorials and videos for learning how to use the tools. This chapter contains a selection of web sites useful for proteomics analyses but is by no means comprehensive. Using a search engine such as Google is the easiest way to find the sites using the name given below. PMID- 27975224 TI - Mass Spectrometry-Based Protein Quantification. AB - Quantification of individual proteins and even entire proteomes is an important theme in proteomics research. Quantitative proteomics is an approach to obtain quantitative information about proteins in a sample. Compared to qualitative or semi-quantitative proteomics, this approach can provide more insight into the effects of a specific stimulus, such as a change in the expression level of a protein and its posttranslational modifications, or to a panel of proposed biomarkers in a given disease state. Proteomics methodologies, along with a variety of bioinformatics approaches, are a major tool in quantitative proteomics. As the theory and technological aspects underlying the proteomics methodologies will be extensively described in Chap. 20 , and protein identification as a prerequisite of quantification has been discussed in Chap. 17 , we will focus on the quantitative proteomics bioinformatics algorithms and software tools in this chapter. Our goal is to provide researchers and newcomers a rational framework to select suitable bioinformatics tools for data analysis, interpretation, and integration in protein quantification. Before doing so, a brief overview of quantitative proteomics is provided. PMID- 27975225 TI - Bioinformatics Tools for Proteomics Data Interpretation. AB - Biological systems function via intricate cellular processes and networks in which RNAs, metabolites, proteins and other cellular compounds have a precise role and are exquisitely regulated (Kumar and Mann, FEBS Lett 583(11):1703-1712, 2009). The development of high-throughput technologies, such as the Next Generation DNA Sequencing (NGS) and DNA microarrays for sequencing genomes or metagenomes, have triggered a dramatic increase in the last few years in the amount of information stored in the GenBank and UniProt Knowledgebase (UniProtKB). GenBank release 210, reported in October 2015, contains 202,237,081,559 nucleotides corresponding to 188,372,017 sequences, whilst there are only 1,222,635,267,498 nucleotides corresponding to 309,198,943 sequences from Whole Genome Shotgun (WGS) projects. In the case of UniProKB/Swiss-Prot, release 2015_12 (December 9, 2015) contains 196,219,159 amino acids that correspond to 550,116 entries. Meanwhile, UniProtKB/TrEMBL (release 2015_12 of December 9 2015) contains 1,838,851,8871 amino acids corresponding to 555,270,679 entries. Proteomics has also improved our knowledge of proteins that are being expressed in cells at a certain time of the cell cycle. It has also allowed the identification of molecules forming part of multiprotein complexes and an increasing number of posttranslational modifications (PTMs) that are present in proteins, as well as the variants of proteins expressed. PMID- 27975226 TI - Identification, Quantification, and Site Localization of Protein Posttranslational Modifications via Mass Spectrometry-Based Proteomics. AB - Posttranslational modifications (PTMs) are important biochemical processes for regulating various signaling pathways and determining specific cell fate. Mass spectrometry (MS)-based proteomics has been developed extensively in the past decade and is becoming the standard approach for systematic characterization of different PTMs on a global scale. In this chapter, we will explain the biological importance of various PTMs, summarize key innovations in PTMs enrichment strategies, high-performance liquid chromatography (HPLC)-based fractionation approaches, mass spectrometry detection methods, and lastly bioinformatic tools for PTMs related data analysis. With great effort in recent years by the proteomics community, highly efficient enriching methods and comprehensive resources have been developed. This chapter will specifically focus on five major types of PTMs; phosphorylation, glycosylation, ubiquitination/sumosylation, acetylation, and methylation. PMID- 27975227 TI - Protein-Protein Interaction Detection Via Mass Spectrometry-Based Proteomics. AB - Analysis of protein-protein interactions is one of the mainstays of mass spectrometry-based proteomics and recent developments, which have simplified the methodology, have permitted non-specialised laboratories to adopt the approach. We introduce and review three complimentary methods which allow for the targeted, global and site-specific analysis of protein complexes. Co-precipitation of endogenous or ectopically expressed proteins and their complexes followed by proteomic analysis allows for the discovery and accurate quantification of specific protein interactions. Whereas complimentary methods, such as co purification of entire complexes based on physico-chemical attributes, can give a snap-shot of the composition and dynamics of protein complexes on a global scale. Cross-linking on the other hand can pinpoint the amino acids involved in protein protein interactions to such a resolution that the likely complex can be reconstructed computationally. PMID- 27975229 TI - Introduction to Clinical Proteomics. AB - Within the context of this section, biomarkers are defined as a panel of proteins and peptides that are predictive of the risk for developing a pathological condition. It is important to note here that the use of the descriptor 'panel' is purposeful in that single "biomarkers" are rarely sufficient to permit accurate prediction of a pathological condition. More specifically, the primary application of a biomarker panel is that it serves as a molecular indicator of the severity of a disease or its early response to treatment. In this way, biomarkers enable the application of precision medicine, an approach that tailors specific interventions to those individuals that would most benefit. For a recent comprehensive review of the proteomic-based biomarker development process with a focus on bladder cancer, the reader is directed to Frantzi et al. [Clin Transl Med 3:7, 2014], or a special issue with multiple reviews [Stuhler and Poschmann, Biochim Biophys Acta Proteins Proteomics 1844:859-1058, Elsevier, B V, 2014]. PMID- 27975230 TI - Discovery of Candidate Biomarkers. AB - Properly performed, biomarker discovery can lead to effective candidates that can ultimately serve as predictors of disease, medical condition, define therapeutic parameters, and many other applications in medicine. Preferably, biomarkers comprise a panel of indicators, e.g. proteins and/or peptides that can be predictive or diagnostic of the medical condition of interest. Emphasis here is placed on "panel," as single candidates are rarely sufficient to provide the necessary sensitivity and specificity. To develop an effective panel that survives the development process described in Chap. 19 , proper experimental design and attention to important statistical parameters are critical to ensure success. Errors in discovery can lead to an inefficient use of expensive resources, as these may not be uncovered until the latter stages in biomarker development. Hence, accuracy, precision, and an estimate of the power of the proposed analyses are critical in the discovery of the panel of candidate biomarkers by proteomic methods, as is the selection of statistical approaches to refine and appropriately reduce the dataset for subsequent confirmatory assays. PMID- 27975231 TI - Statistical Approaches to Candidate Biomarker Panel Selection. AB - The statistical analysis of robust biomarker candidates is a complex process, and is involved in several key steps in the overall biomarker development pipeline (see Fig. 22.1, Chap. 19 ). Initially, data visualization (Sect. 22.1, below) is important to determine outliers and to get a feel for the nature of the data and whether there appear to be any differences among the groups being examined. From there, the data must be pre-processed (Sect. 22.2) so that outliers are handled, missing values are dealt with, and normality is assessed. Once the processed data has been cleaned and is ready for downstream analysis, hypothesis tests (Sect. 22.3) are performed, and proteins that are differentially expressed are identified. Since the number of differentially expressed proteins is usually larger than warrants further investigation (50+ proteins versus just a handful that will be considered for a biomarker panel), some sort of feature reduction (Sect. 22.4) should be performed to narrow the list of candidate biomarkers down to a more reasonable number. Once the list of proteins has been reduced to those that are likely most useful for downstream classification purposes, unsupervised or supervised learning is performed (Sects. 22.5 and 22.6, respectively). PMID- 27975232 TI - Qualification and Verification of Protein Biomarker Candidates. AB - The importance of biomarkers has long been recognized by the public, scientific community, and industry. Yet despite extensive efforts and funding investments in biomarker discovery, only 109 protein biomarkers in plasma or serum were approved by the US Food and Drug Administration throughout 2008 (Anderson NL. Clin Chem 56:177-185, 2010), and even fewer protein biomarkers are currently used routinely in the clinic. In recent years, the introduction of new protein biomarkers approved by the US Food and Drug Administration has fallen to an average of 1.5 per year (a median of only 1 per year) (Anderson NL. Clin Chem 56:177-185, 2010). The low efficiency of biomarker development is due to several reasons, including the poor quality of clinical samples, the gap between subjective clinical definition of a disease and objective protein measurements, and high false discovery rate of differentially expressed proteins identified in the initial discovery phase (Rifai N, Gillette MA, Carr SA. Nat Biotechnol 24:971-983, 2006). It has become clear that the vast majority of differentially expressed proteins identified in the discovery phase will ultimately fail as useful clinical biomarkers, and only few true positive candidates can move through the biomarker development pipeline. Isolation of true biomarkers from the large pool of differentially expressed proteins identified in the discovery phase becomes the greatest challenge and the bottleneck in most biomarker pipelines. To succeed, after the initial discovery study (see Chap. 20 ), the authenticity of biomarker candidates need to be tested in a pilot study with high throughput, high accuracy and reasonable cost. This essential process is addressed by qualification and verification phase of the biomarker development pipeline. PMID- 27975233 TI - Protocol for Standardizing High-to-Moderate Abundance Protein Biomarker Assessments Through an MRM-with-Standard-Peptides Quantitative Approach. AB - Quantitative mass spectrometry (MS)-based approaches are emerging as a core technology for addressing health-related queries in systems biology and in the biomedical and clinical fields. In several 'omics disciplines (proteomics included), an approach centered on selected or multiple reaction monitoring (SRM or MRM)-MS with stable isotope-labeled standards (SIS), at the protein or peptide level, has emerged as the most precise technique for quantifying and screening putative analytes in biological samples. To enable the widespread use of MRM based protein quantitation for disease biomarker assessment studies and its ultimate acceptance for clinical analysis, the technique must be standardized to facilitate precise and accurate protein quantitation. To that end, we have developed a number of kits for assessing method/platform performance, as well as for screening proposed candidate protein biomarkers in various human biofluids. Collectively, these kits utilize a bottom-up LC-MS methodology with SIS peptides as internal standards and quantify proteins using regression analysis of standard curves. This chapter details the methodology used to quantify 192 plasma proteins of high-to-moderate abundance (covers a 6 order of magnitude range from 31 mg/mL for albumin to 18 ng/mL for peroxidredoxin-2), and a 21-protein subset thereof. We also describe the application of this method to patient samples for biomarker discovery and verification studies. Additionally, we introduce our recently developed Qualis-SIS software, which is used to expedite the analysis and assessment of protein quantitation data in control and patient samples. PMID- 27975228 TI - Protein Structural Analysis via Mass Spectrometry-Based Proteomics. AB - Modern mass spectrometry (MS) technologies have provided a versatile platform that can be combined with a large number of techniques to analyze protein structure and dynamics. These techniques include the three detailed in this chapter: (1) hydrogen/deuterium exchange (HDX), (2) limited proteolysis, and (3) chemical crosslinking (CX). HDX relies on the change in mass of a protein upon its dilution into deuterated buffer, which results in varied deuterium content within its backbone amides. Structural information on surface exposed, flexible or disordered linker regions of proteins can be achieved through limited proteolysis, using a variety of proteases and only small extents of digestion. CX refers to the covalent coupling of distinct chemical species and has been used to analyze the structure, function and interactions of proteins by identifying crosslinking sites that are formed by small multi-functional reagents, termed crosslinkers. Each of these MS applications is capable of revealing structural information for proteins when used either with or without other typical high resolution techniques, including NMR and X-ray crystallography. PMID- 27975235 TI - Inflammatory Bowel Disease-Related Abstracts Presented at National Conferences in the USA Are Frequently Unpublished as Full Manuscripts. AB - BACKGROUND: Numerous abstracts related to inflammatory bowel disease (IBD) are presented at national conferences in the USA. The overall rate of publication of these abstracts as complete manuscripts is unknown . METHODS: Abstracts submitted to the 2010 American College of Gastroenterology (ACG), Advances in Inflammatory Bowel Diseases (AIBD), and the American Gastroenterological Association abstracts at Digestive Disease Week (DDW) were reviewed. Each abstract was reviewed manually by two authors for type of research, study design, patient population, and outcome. Both PubMed and Google were then searched to determine whether the abstract was published as a full manuscript within five years of the conference. Univariate and multivariate logistic regression analysis was carried out using Stata 14.1. RESULTS: In total, 872 abstracts were reviewed. 49% (426/872) were published as complete manuscripts within five years of the conference. The average length of time to publication was 1.87 years (range 0-5). 42% of abstracts from ACG, 58% from AIBD, and 23% from DDW were eventually published (p < 0.0001). However, abstracts presented at DDW had the shortest time to publication compared to the other conferences (p = 0.002). Factors predictive of eventual publication include: number of authors (mean 7.5 for published vs 6.4 for unpublished p = 0.0001), clinical research compared to basic and translational (p = 0.026), and studies assessing drug safety with no adverse effects reported (p = 0.006). CONCLUSION: Nearly 50% of the abstracts presented at major gastroenterology conferences in the USA are published as full manuscripts 5 years after the conference. Further studies are needed to assess why so many abstracts are not published. PMID- 27975234 TI - Pharmacokinetics and derivation of an anticancer dosing regimen for the novel anti-cancer agent isobutyl-deoxynyboquinone (IB-DNQ), a NQO1 bioactivatable molecule, in the domestic felid species. AB - Isobutyl-deoxynyboquinone (IB-DNQ) is a selective substrate for NAD(P)H:quinone oxidoreductase (NQO1), an enzyme overexpressed in many solid tumors. Following activation by NQO1, IB-DNQ participates in a catalytic futile reduction/reoxidation cycle with consequent toxic reactive oxygen species generation within the tumor microenvironment. To elucidate the potential of IB DNQ to serve as a novel anticancer agent, in vitro studies coupled with in vivo pharmacokinetic and toxicologic investigations in the domestic felid species were conducted to investigate the tractability of IB-DNQ as a translationally applicable anticancer agent. First, using feline oral squamous cell carcinoma (OSCC) as a comparative cancer model, expressions of NQO1 were characterized in not only human, but also feline OSCC tissue microarrays. Second, IB-DNQ mediated cytotoxicity in three immortalized feline OSCC cell lines were studied under dose dependent and sequential exposure conditions. Third, the feasibility of administering IB-DNQ at doses predicted to achieve cytotoxic plasma concentrations and biologically relevant durations of exposure were investigated through pharmacokinetic and tolerability studies in healthy research felines. Intravenous administration of IB-DNQ at 1.0-2.0 mg/kg achieved peak plasma concentrations and durations of exposure reaching or exceeding predicted in vitro cytotoxic concentrations. Clinical adverse side effects including ptyalism and tachypnea exhibited during and post-IV infusion of IB-DNQ were transient and tolerable. Additionally, IB-DNQ administration did not produce acute or delayed onset unacceptable hematologic, non-hematologic, or off-target oxidative toxicities. Collectively, the findings reported here within provide important safety and pharmacokinetic data to support the continued development of IB-DNQ as a novel anticancer strategy for NQO1 expressing cancers. PMID- 27975237 TI - Pharmacokinetics of Deferiprone in Patients with beta-Thalassaemia : Impact of Splenectomy and Iron Status. AB - BACKGROUND AND OBJECTIVE: Iron-rich transfusions and/or a compensatory increase in iron absorption ultimately result in iron loading in patients with beta thalassaemia. Hence, without iron chelation, iron accumulates relentlessly. Deferiprone has been shown to be capable of reducing the iron burden in patients with b-thalassaemia. However, there is wide interpatient variation in deferiprone induced urinary iron excretion (UIE). We hypothesized that splenectomy and iron status might influence the pharmacokinetic profiles of deferiprone in patients with beta-thalassaemia/haemoglobin E, and the present study was aimed at examining this hypothesis. STUDY PARTICIPANTS AND METHODS: Thirty-one patients with beta-thalassaemia/haemoglobin E (20 splenecto-mized and 11 non splenectomized patients) were enrolled in the study. After an overnight fast, the subjects received a single oral dose of deferiprone 25 mg/kg of body weight. Blood samples were collected pre-dosing and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 and 480 minutes after dosing. Urine output was pooled and collected at 0 2, 2-4, 4-8, 8-12 and 12-24 hour intervals. Serum and urine concentrations of deferiprone and its metabolite deferiprone glucuronide were determined using a validated high-performance liquid chromatography method. Serum deferiprone chelated iron and UIE were determined using a validated colourimetric method. RESULTS: No significant difference in the pharmacokinetic parameters of non conjugated deferiprone was observed between splenectomized and non-splenectomized patients. However, the maximum serum concentration (Cmax) and the area under the serum concentration-time curve (AUC) from time zero to infinity (AUCinfinity) values of deferiprone glucuronide were significantly lower (both p < 0.05) in splenectomized patients (median 53.2umol/L and 12 634 umol . min/L, respectively) than in non-splenectomized patients (median 70.5 umol/L and 20 601 mmol . min/L, respectively). The Cmax and the AUC from time zero to the time of the last measurable concentration (AUClast) values of serum deferiprone-chelated iron, as well as UIE, were significantly higher (p < 0.001) in splenectomized patients (median values 7.1 umol/L, 1645 mmol . min/L and 77.1 mmol, respectively) than in non-splenectomized patients (median values 3.1 umol/L, 545 mmol . min/L and 12.5 umol, respectively). Urinary excretion of non-conjugated deferiprone and deferiprone glucuronide did not differ between the two groups. Further analyses using multiple linear regressions indicated that the iron profiles (non transferrin-bound iron and ferritin) were significant predictors of the pharmacokinetic parameters of non-conjugated deferiprone, deferiprone-chelated iron and UIE. In addition, splenectomy status was identified as the strongest predictor of the AUClast of deferiprone-chelated iron and UIE. CONCLUSION: Both iron and splenectomy status have significant effects on the pharmacokinetics and iron chelation efficacy of deferiprone. A greater degree of iron overload in splenectomized patients results in alterations in pharmacokinetic parameters (the Cmax and AUC) of deferiprone glucuronide and deferiprone-chelated iron, as well as a significant increase in UIE. PMID- 27975236 TI - Impact of High-Dose Vitamin D3 Supplementation in Patients with Crohn's Disease in Remission: A Pilot Randomized Double-Blind Controlled Study. AB - AIM: To assess the tolerability and efficacy of high-dose vitamin D3 in patients with Crohn's disease (CD). METHODS: This was a randomized, double-blind placebo controlled trial of high-dose vitamin D3 at 10,000 IU daily (n = 18) compared to 1000 IU daily (n = 16) for 12 months in patients with CD in remission. The primary outcome was change in serum 25-hydroxy-vitamin D levels. Secondary outcomes included clinical relapse rates and changes in mood scores. RESULTS: High-dose vitamin D3 at 10,000 IU daily significantly improved 25-hydroxy-vitamin D levels from a mean of 73.5 nmol/L [standard deviation (SD) 11.7 nmol/L] to 160.8 nmol/L (SD 43.2 nmol/L) (p = 0.02). On an intention-to-treat basis, the rate of relapse was not significantly different between patients receiving low- and high-dose vitamin D3 (68.8 vs 33.3%, p = 0.0844). In per-protocol analysis, clinical relapse of Crohn's disease was less frequently observed in patients receiving a high dose (0/12 or 0%) compared to those receiving a low dose of 1000 IU daily (3/8 or 37.5%) (p = 0.049). Improvement in anxiety and depression scores and a good safety profile were observed in both groups treated with vitamin D3. CONCLUSIONS: Oral supplementation with high-dose vitamin D3 at 10,000 IU daily significantly improved serum 25-hydroxy-vitamin D levels. Rates of clinical relapse were similar between both groups. Larger studies using high-dose vitamin D3 for treatment of inflammatory bowel diseases are warranted. CLINICALTRIALS. GOV REGISTRATION NO: NCT02615288. PMID- 27975240 TI - Erratum. PMID- 27975238 TI - Predictive Performance of a Recently Developed Population Pharmacokinetic Model for Morphine and its Metabolites in New Datasets of (Preterm) Neonates, Infants and Children. AB - BACKGROUND AND OBJECTIVE: Model validation procedures are crucial when models are to be used to develop new dosing algorithms. In this study, the predictive performance of a previously published paediatric population pharmacokinetic model for morphine and its metabolites in children younger than 3 years (original model) is studied in new datasets that were not used to develop the original model. METHODS: Six external datasets including neonates and infants up to 1 year were obtained from four different research centres. These datasets contained postoperative patients, ventilated patients and patients on extracorporeal membrane oxygenation (ECMO) treatment. Basic observed versus predicted plots, normalized prediction distribution error analysis, model refitting, bootstrap analysis, subpopulation analysis and a literature comparison of clearance predictions were performed with the new datasets to evaluate the predictive performance of the original morphine pharmacokinetic model. RESULTS: The original model was found to be stable and the parameter estimates were found to be precise. The concentrations predicted by the original model were in good agreement with the observed concentrations in the four datasets from postoperative and ventilated patients, and the model-predicted clearances in these datasets were in agreement with literature values. In the datasets from patients on ECMO treatment with continuous venovenous haemofiltration (CVVH) the predictive performance of the model was good as well, whereas underprediction occurred, particularly for the metabolites, in patients on ECMO treatment without CVVH. CONCLUSION: The predictive value of the original morphine pharmacokinetic model is demonstrated in new datasets by the use of six different validation and evaluation tools. It is herewith justified to undertake a proof-of-principle approach in the development of rational dosing recommendations - namely, performing a prospective clinical trial in which the model-based dosing algorithm is clinically evaluated. PMID- 27975241 TI - Conformational Dynamics of Intracellular Tau Protein Revealed by CD and SAXS. AB - A native conformation of a protein is essential for its biological role. In certain conditions, some proteins show non-native conformations, leading to aggregation, which in turn may produce severe pathologies. Such physiological conditions are classified as protein misfolding diseases. Alzheimer's disease (AD) is the most common form of dementia. Extracellular senile plaques formed by Amyloid beta and intracellular aggregates formed by microtubule-associated protein Tau (MAPT) are the hallmarks of AD. Physiological role of MAPT is to maintain the integrity and stability of microtubules, however it tends to self aggregate forming intracellular paired helical filaments (PHFs) during AD. MAPT is also subjected to various post-translational modifications such as phosphorylation, glycosylation, truncation, and acetylation. Being natively unfolded, MAPT is prone to full characterization at atomic level. Small-angle X ray scattering (SAXS) is often applied in combination with other biophysical methods, like nuclear magnetic resonance (NMR), circular dichroism (CD), fluorescence spectroscopy, analytical ultracentrifugation (AUC), or dynamic light scattering (DLS) to characterize natively unfolded systems. Here we describe the practical aspects of MAPT characterization by SAXS and CD in detail as well as outline the inferred structural and functional implications. PMID- 27975242 TI - Global Conformation of Tau Protein Mapped by Raman Spectroscopy. AB - Alzheimer's disease (AD) is one of the neurodegenerative disease characterized by progressive neuronal loss in the brain. Its two major hallmarks are extracellular senile plaques and intracellular neurofibrillary tangles (NFTs), formed by aggregation of amyloid beta-42 (Abeta-42) and Tau protein respectively. Abeta-42 is a transmembrane protein, which is produced after the sequential action of beta and gamma-secretases, thus obtained peptide is released extracellularly and gets deposited on the neuron forming senile plaques. NFTs are composed of microtubule associated protein-Tau (MAPT). Tau protein's major function is to stabilize the microtubule that provides a track on which the cargo proteins are shuttled and the stabilized microtubule also maintains shape and integrity of the neuronal cell. Tau protein is subjected to various modifications such as phosphorylation, ubiquitination, glycation, acetylation, truncation, glycosylation, deamination, and oxidation; these modifications ultimately lead to its aggregation. Phosphorylation is the major modification and is extensively studied with respect to Tau protein. Tau protein, however, undergoes certain level of phosphorylation and dephosphorylation, which regulates its affinity for microtubule and ultimately leading to microtubule assembly and disassembly. Our main aim was to study the native state of longest isoform of Tau (hTau40WT-4R2N) and its shortest isoform, (hTau23WT-3R0N), at various temperatures such as 10, 25, and 37 degrees C. Raman spectroscopic results suggested that the proportion of random coils or unordered structure depends on the temperature of the protein environment. Upon increase in the temperature from 10 to 37 degrees C, the proportion of random coils or unordered structures increased in the case of hTau40WT. However, we did not find a significant effect of temperature on the structure of hTau23WT. This current approach enables one to analyze the global conformation of soluble Tau in solution. PMID- 27975243 TI - Molecular Dynamics Simulation of Tau Peptides for the Investigation of Conformational Changes Induced by Specific Phosphorylation Patterns. AB - The Tau protein plays an important role due to its biomolecular interactions in neurodegenerative diseases. The lack of stable structure and various posttranslational modifications such as phosphorylation at various sites in the Tau protein pose a challenge for many experimental methods that are traditionally used to study protein folding and aggregation. Atomistic molecular dynamics (MD) simulations can help around deciphering relationship between phosphorylation and various intermediate and stable conformations of the Tau protein which occur on longer timescales. This chapter outlines protocols for the preparation, execution, and analysis of all-atom MD simulations of a 21-amino acid-long phosphorylated Tau peptide with the aim of generating biologically relevant structural and dynamic information. The simulations are done in explicit solvent and starting from nearly extended configurations of the peptide. The scaled MD method implemented in AMBER14 was chosen to achieve enhanced conformational sampling in addition to a conventional MD approach, thereby allowing the characterization of folding for such an intrinsically disordered peptide at 293 K. Emphasis is placed on the analysis of the simulation trajectories to establish correlations with NMR data (i.e., chemical shifts and NOEs). Finally, in-depth discussions are provided for commonly encountered problems. PMID- 27975244 TI - Tau Interaction with Tubulin and Microtubules: From Purified Proteins to Cells. AB - Microtubules (MTs) play an important role in many cellular processes and are dynamic structures regulated by an important network of microtubules-associated proteins, MAPs, such as Tau. Tau has been discovered as an essential factor for MTs formation in vitro, and its region implicated in binding to MTs has been identified. By contrast, the affinity, the stoichiometry, and the topology of Tau MTs interaction remain controversial. Indeed, depending on the experiment conditions a wide range of values have been obtained. In this chapter, we focus on three biophysical methods, turbidimetry, cosedimentation assay, and Forster Resonance Energy Transfer to study Tau-tubulin interaction both in vitro and in cell. We highlight precautions that must be taken in order to avoid pitfalls and we detail the nature of the conclusions that can be drawn from these methods about Tau-tubulin interaction. PMID- 27975245 TI - X-Ray Structural Study of Amyloid-Like Fibrils of Tau Peptides Bound to Small Molecule Ligands. AB - Atomic structures of Tau involved in Alzheimer's disease complexed with small molecule binders are the first step to define the Tau pharmacophore, leading the way to a structure-based design of improved diagnostics and therapeutics. Yet the partially disordered and polymorphic nature of Tau hinders structural analyses. Fortunately, short segments from amyloid proteins, which exhibit similar biophysical properties to the full-length proteins, also form fibrils and oligomers, and their atomic structures can be determined using X-ray microcrystallography. Such structures were successfully used to design amyloid inhibitors. This chapter describes experimental procedures used to determine crystal structures of Tau peptide segments in complex with small-molecule binders. PMID- 27975246 TI - Detection and Quantification Methods for Fibrillar Products of In Vitro Tau Aggregation Assays. AB - Alzheimer's disease is characterized in part by the intracellular misfolding and aggregation of tau protein. The aggregates, which range in size from small oligomers to large filaments, are markers for disease diagnosis and staging, potential vectors for disease propagation, and candidate sources of neurotoxicity. Here we present protocols for synthesizing large tau aggregates characterized by filamentous morphology and cross-beta-sheet structure from monomeric full-length tau precursors in vitro. We also describe their detection and quantification through thioflavin dye binding, filter trap, and transmission electron microscopy methods. These methods cover applications requiring high throughput capability as well as those requiring high-resolution analysis of aggregation mechanism. PMID- 27975247 TI - Fourier Transform Infrared (FTIR) Spectroscopy, Ultraviolet Resonance Raman (UVRR) Spectroscopy, and Atomic Force Microscopy (AFM) for Study of the Kinetics of Formation and Structural Characterization of Tau Fibrils. AB - Kinetic studies of tau fibril formation in vitro most commonly employ spectroscopic probes such as thioflavinT fluorescence and laser light scattering or negative stain transmission electron microscopy. Here, I describe the use of Fourier transform infrared (FTIR) spectroscopy, ultraviolet resonance Raman (UVRR) spectroscopy, and atomic force microscopy (AFM) as complementary probes for studies of tau aggregation. The sensitivity of vibrational spectroscopic techniques (FTIR and UVRR) to secondary structure content allows for measurement of conformational changes that occur when the intrinsically disordered protein tau transforms into cross-beta-core containing fibrils. AFM imaging serves as a gentle probe of structures populated over the time course of tau fibrillization. Together, these assays help further elucidate the structural and mechanistic complexity inherent in tau fibril formation. PMID- 27975248 TI - Assays for the Screening and Characterization of Tau Aggregation Inhibitors. AB - Aggregation of tau protein is a pathological hallmark of Alzheimer's disease and other neurodegenerative tauopathies. Inhibition of tau aggregation could provide a method for the treatment of these disorders. Methods to identify tau aggregation inhibitors (TAIs) in vitro are useful and here we describe assays for TAIs using purified recombinant tau protein fragments in a cell-free immunoassay format and a stably transfected cell model to create a more physiological environment. PMID- 27975249 TI - Tau Oligomers as Pathogenic Seeds: Preparation and Propagation In Vitro and In Vivo. AB - Tau oligomers have been shown to be the main toxic tau species in a number of neurodegenerative disorders. In order to study tau oligomers both in vitro and in vivo, we have established methods for the reliable preparation, isolation, and detection of tau oligomers. Methods for the seeding of tau oligomers, isolation of tau oligomers from tissue, and detection of tau oligomers using tau oligomer specific antibodies by biochemical and immunohistochemical methods are detailed below. PMID- 27975251 TI - The Study of Posttranslational Modifications of Tau Protein by Nuclear Magnetic Resonance Spectroscopy: Phosphorylation of Tau Protein by ERK2 Recombinant Kinase and Rat Brain Extract, and Acetylation by Recombinant Creb-Binding Protein. AB - Nuclear magnetic resonance (NMR) spectroscopy can be used as an analytical tool to investigate posttranslational modifications of protein. NMR is a valuable tool to map the interaction regions of protein partners. Here, we present protocols that have been developed in the course of our studies of the neuronal Tau protein. Tau is found aggregated in the neurons of Alzheimer's disease patients. Development of the disease is accompanied by increased, abnormal phosphorylation and acetylation of Tau. We have used NMR to investigate how these posttranslational modifications of Tau affect the interactions with its partners. We present here detailed protocols of in vitro phosphorylation of Tau by recombinant kinase, ERK2, or kinase activity of rat brain extracts, and acetylation by recombinant Creb-binding protein (CBP) acetyltransferase. The analytical characterization of the modified Tau by NMR spectroscopy is additionally described. PMID- 27975252 TI - Tag-Free Semi-Synthesis of the Tau Protein. AB - Expressed protein ligation (EPL) is a valuable tool to study site-specific functionalities on proteins such as posttranslational modifications. The purification of such ligation products from EPL mixtures can be cumbersome due to a small size difference between the expressed protein portion and the desired ligated protein. Therefore, affinity tags are often required, which remain on the protein after purification. Herein, we present an efficient protocol to install a photocleavable biotin building block on synthetic C-terminal tau[390-441] and describe its use for purification of full-length semi-synthetic tau[1-441]. PMID- 27975250 TI - Mass Spectrometry Analysis of Lysine Posttranslational Modifications of Tau Protein from Alzheimer's Disease Brain. AB - Recent advances in mass spectrometry (MS)-based proteomics have greatly facilitated the robust identification and quantification of posttranslational modifications (PTMs), including those that are present at substoichiometric site occupancies. The abnormal posttranslational modification and accumulation of the microtubule-associated protein tau has been implicated in the pathogenesis of Alzheimer's disease (AD), and it is thought that the primary mode of regulation of tau occurs through PTMs. Several studies have been published regarding tau phosphorylation; however, other tau PTMs such as ubiquitylation, acetylation, methylation, oxidation, sumoylation, nitration, and glycosylation have not been analyzed as extensively. The comprehensive detection and delineation of these PTMs is critical for drug target discovery and validation. Lysine-directed PTMs including ubiquitylation, acetylation, and methylation play key regulatory roles with respect to the rates of tau turnover and aggregation. MS-based analytical approaches have been used to gain insight into the tau lysine-directed PTM signature that is most closely associated with neurofibrillary lesion formation. This chapter provides details pertaining to the liquid chromatography tandem mass spectrometry (LC-MS/MS)-based analysis of the lysine-directed posttranslational modification of tau. PMID- 27975253 TI - Production of O-GlcNAc Modified Recombinant Tau in E. coli and Detection of Ser400 O-GlcNAc Tau In Vivo. AB - Assembly of the microtubule-associated protein tau (tau) into paired helical filaments that ultimately give rise to neurofibrillary tangles (NFTs) makes up one half of the two hallmark pathologies of Alzheimer's disease (AD). Tau has been shown to be modified with O-linked N-acetylglucosamine residues (O-GlcNAc), which is the modification of serine and threonine residues of nucleocytoplasmic proteins with N-acetyl-D-glucosamine (GlcNAc) moieties. Increasing O-GlcNAc in mouse models of tauopathy has been shown to hinder the progression of symptoms in these mice and impair the aggregation of tau into NFTs. In order to study how O GlcNAc on tau may contribute to the protective effects observed in tauopathy mouse models, it is beneficial to study O-GlcNAc modified tau in vitro. Here we describe a method for producing, purifying and enriching recombinant tau that is O-GlcNAc modified. These methods have enabled the identification of O-GlcNAc modification sites on tau including Ser400. We further describe the detection of Ser400 O-GlcNAc on tau from brain lysates. PMID- 27975254 TI - Two-Dimensional Electrophoresis Protocols to Analyze the Microtubule-Associated Tau Proteins from Several Biological Sources. AB - Technology breakthrough in proteomics enables to gather qualitative and quantitative information about a protein or a complex mixture of proteins. Two dimensional gel electrophoresis remains an interesting technique, which provides an overview of the complexity of isovariants from a single protein when coupled to western blotting. Here, we describe a detailed protocol for the two dimensional analysis of microtubule-associated Tau isovariants from cell to human or mouse brain tissue. We provide protocol enabling to separate native and Tau proteins that are aggregated in neurodegenerative disorders such as Alzheimer's disease. PMID- 27975255 TI - A Simple Method to Avoid Nonspecific Signal When Using Monoclonal Anti-Tau Antibodies in Western Blotting of Mouse Brain Proteins. AB - In Alzheimer's disease and other tauopathies, tau displays several abnormal post translation modifications such as hyperphosphorylation, truncation, conformation, and oligomerization. Mouse monoclonal antibodies have been raised against such tau modifications for research, diagnostic, and therapeutic purposes. However, many of these primary antibodies are at risk of giving nonspecific signals in common Western blotting procedures. Not because they are unspecific, but because the secondary antibodies used to detect them will also detect the heavy chain of endogenous mouse immunoglobulins (Igs), and give a nonspecific signal at the same molecular weight than tau protein (around 50 kDa). Here, we propose the use of anti-light chain secondary antibodies as a simple and efficient technique to prevent nonspecific Igs signals at around 50 kDa. We demonstrate the efficacy of this method by removing artifactual signals when using monoclonal antibodies directed at tau phosphorylation (AT100, 12E8, AT270), tau truncation (TauC3), tau oligomerization (TOMA), or tau abnormal conformation (Alz50), in wild-type, 3*Tg AD, and tau knockout mice. PMID- 27975256 TI - Flow Cytometry Analysis and Quantitative Characterization of Tau in Synaptosomes from Alzheimer's Disease Brains. AB - Synaptosomes, resealed nerve terminals that form when tissue is homogenized in isotonic medium, are a model system that has been a key source of knowledge about neurotransmission. Synaptosomes contain mitochondria, cytoskeletal proteins, and release neurotransmitters; many have postsynaptic elements. Cryopreservation at the time of autopsy makes it possible to prepare synaptosomes from human samples. Flow cytometry is a powerful analytic technique that precisely measures fluorescence on a cell-by-cell basis, and also indicates particle size and complexity with a routine parameter that measures light scattering. We describe here a procedure for flow cytometry analysis of tau in synaptosomes, a procedure that enables (1) "purification" of synaptosomes from the P-2 fraction (crude synaptosomes) by gating on particle size, and (2) quantitative measure of tau immunofluorescence in individual terminals. Application of flow cytometry to study of synaptosomes has yielded important information, not possible with routine biochemistry, about synaptic pathology in Alzheimer's disease. PMID- 27975257 TI - In Vivo Microdialysis of Brain Interstitial Fluid for the Determination of Extracellular Tau Levels. AB - Tau is a microtubule binding protein highly abundant in cytoplasm of neurons. However now there is compelling evidence that it is also physiologically released in the extracellular space. Tau is detectable in culture media of various cells, cerebrospinal fluid (CSF), and brain interstitial fluid (ISF). Being able to measure extracellular tau levels in vivo would deep our understanding on the underlying mechanisms of physiological/pathological tau release from neurons. To meet this need, this chapter describes an in vivo microdialysis protocol and materials for the measurement of extracellular tau in ISF from freely moving mice. PMID- 27975258 TI - Proximity Ligation Assay: A Tool to Study Endogenous Interactions Between Tau and Its Neuronal Partners. AB - Tau is a microtubule associated protein (MAP) that is expressed in neurons of the central nervous system. Tau proteins are deregulated in a group of pathologies, including Alzheimer's disease, commonly called tauopathies. Therefore intensive research has been conducted to understand both the regulation of Tau and its involvement in neuronal cellular pathways. Since its originally described interactor tubulin, Tau has been described to interact with several other proteins, including tyrosine kinases (Src, Fyn, Lck) and Phospholipase C-gamma. In this chapter, we describe the use of proximity ligation assay as a versatile method to study the endogenous interaction of Tau with these different neuronal partners and use the recently identified Tau interactor Bin1 as case study. PMID- 27975259 TI - Finding MAPT Mutations in Frontotemporal Dementia and Other Tauopathies. AB - Sanger sequencing is a classic technique in molecular genetics to detect single nucleotide DNA variants in genomic DNA. Here we describe the detection of MAPT mutations by polymerase chain reaction amplification of patient genomic DNA followed by bidirectional Sanger sequencing. Exon trapping is a technique whereby genomic DNA covering the exon of interest and flanking intronic sequence is cloned into the intron of an expression vector and transfected into human cell lines. RNA is extracted and splicing products are examined by reverse transcriptase PCR and agarose gel electrophoresis. We outline the application of this technique to assess the effect of novel DNA variants on the splicing efficiency of MAPT exon 10, a common mechanism of disease for pathogenic MAPT mutations. PMID- 27975260 TI - Tracking Tau in Neurons: How to Grow, Fix, and Stain Primary Neurons for the Investigation of Tau in All Developmental Stages. AB - Primary neurons have proved to be an invaluable tool for the investigation of Tau in the context of neuronal development and neurodegeneration. Culturing neurons usually is time consuming and requires multiple feeding steps and media exchanges, and either the use of proprietary media supplements or tedious preparation of complex media. Here we describe a relatively cheap and easy cell culture procedure based on a commercially available neuronal culture supplement (NS21) of known composition, as well as basic fixation techniques. Further, we demonstrate a staining technique that can be carried out in pre-coated hydrophobic multi-well plates, which minimizes antibody consumption and allows fast and convenient processing of samples for immunofluorescence microscopy of endogenous Tau in primary neurons. We also provide a protocol that allows cryopreservation of fixed cells for years without loss of Tau stainability. PMID- 27975261 TI - Tracking Tau in Neurons: How to Transfect and Track Exogenous Tau into Primary Neurons. AB - Primary neurons have proved to be an essential tool for investigating neuronal polarity in general and polarized Tau distribution in particular. However, mature primary neurons are notoriously difficult to transfect with nonviral vectors and are very sensitive both to cytoskeletal manipulation and to imaging. Common nonviral transfections require the use of a monolayer of supportive glia or high density cultures, both of which complicate imaging. Here, we provide a simple nonviral transfection method enabling transfection of Tau to achieve expression levels comparable to endogenous Tau. This allows to investigate specific effects on, e.g., distribution and transport of Tau, without grossly affecting other cytoskeleton-based parameters such as microtubule density or microtubule-based transport. PMID- 27975262 TI - Image-Based Analysis of Intracellular Tau Aggregation by Using Tau-BiFC Cell Model. AB - Abnormal tau aggregation is a pathological hallmark of neurodegenerative disease classified as tauopathy. Preventing tau aggregation becomes an important therapeutic strategy to cure tau-mediated neurodegeneration. Here, we describe a method to investigate intracellular tau aggregation by using a recently developed tau aggregation cell-based model named tau-BiFC. High-throughput and high contents screening method for quantifying intracellular tau aggregation would expedite the discovery of drugs that inhibit tau aggregation. PMID- 27975263 TI - FRET and Flow Cytometry Assays to Measure Proteopathic Seeding Activity in Biological Samples. AB - Transcellular propagation of protein aggregates-or seeds-is increasingly implicated as a mechanism for disease progression in many neurodegenerative disorders, including Alzheimer's disease and the related tauopathies. While neuropathology generally originates in one discrete brain region, pathology progresses as disease severity advances, often along discrete neural networks. The stereotypical spread of tau pathology suggests that cell-to-cell transfer of toxic protein aggregates could underlie disease progression, and recent studies implicate seeding as a proximal marker of disease, as compared to standard histological and biochemical analyses. Commonly used metrics for protein aggregation detection, however, lack sensitivity, are not quantitative, and/or undergo subjective classification. Here, we describe a FRET and flow cytometry cell-based assay that allows for rapid and quantitative detection of protein aggregates from human and rodent biological specimens. PMID- 27975264 TI - In Vivo Imaging of Tau Aggregates in the Mouse Retina. AB - Aggregates of hyperphosphorylated tau can be observed in the human brain affected by various neurodegenerative disorders. The development of a noninvasive technique for the visualization of these protein accumulations is a promising task. In the following protocol, we describe a method to image fibrillar tau in the retina of a transgenic mouse model of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). This technique can be highly valuable for the preclinical in vivo testing of approaches that target tau aggregation. PMID- 27975265 TI - In Vivo Hyperthermic Stress Model: An Easy Tool to Study the Effects of Oxidative Stress on Neuronal Tau Functionality in Mouse Brain. AB - Oxidative damage is an early event in neurodegenerative disorders such as Alzheimer disease. To increase oxidative stress in AD-related mouse models is essential to study early mechanisms involved in the physiopathology of these diseases. In this chapter, we describe an experimental mouse model of transient and acute hyperthermic stress to induce in vivo an increase of oxidative stress in the brain of any kind of wild-type or transgenic mouse. PMID- 27975266 TI - Identification of Tau Toxicity Modifiers in the Drosophila Eye. AB - Drosophila is a powerful model to study human diseases thanks to its genetic tools and ease of screening. Human genes can be expressed in targeted organs and their toxicity assessed on easily scorable external phenotypes that can be used as readout to perform genetic screen of toxicity modifiers. In this chapter, I describe how to express human Tau protein in the Drosophila eye, assess protein expression by western blot, assess Tau toxicity by quantifying the size of the Tau-induced rough eye, and perform a genetic screen of modifiers of Tau toxicity in the Drosophila eye. PMID- 27975267 TI - Regulation of Neurotrophic Factors During Pathogenic Tau-Aggregation: A Detailed Protocol for Double-Labeling mRNA by In Situ Hybridization and Protein Epitopes by Immunohistochemistry. AB - Alzheimer's disease (AD), most tauopathies, and other neurodegenerative diseases are highly associated with impaired neurotrophin regulation and imbalanced neutrophin distribution. Tau phosphorylation occurs at different sites of the tau protein and some phospho-epitopes are associated with normal ageing (like tau phosphorylated at Ser202/Thr205 detected by the antibody clone AT8) and others are highly associated with AD (abnormally phosphorylated tau at Thr212/Ser214 detected by the antibody clone AT100). Neurotrophins are crucial for the survival and maintenance of distinct neuronal population; therefore, their supply is essential for a healthy brain. Though their importance is well known, their analysis in tissue is not trivial and needs careful consideration. Here, a detailed a protocol is presented, how to combine in situ hybridization (ISH) with immunohistochemistry (IHC) to analyze neurotrophins during tau neuropathology and the results were confirmed by immunological methods. In addition, the preparation of the riboprobes is presented step-by-step. Since there are growing evidences for the relevance of neurotrophic factor distribution in the pathogenesis of AD, this technique is one useful tool to investigate the underlying mechanisms and therapeutic intervention. PMID- 27975268 TI - Pin1 Knockout Mice: A Model for the Study of Tau Pathology in Alzheimer's Disease. AB - Pin1 knockout in mice causes age-dependent neuropathy characterized by motor and behavioral deficits, tau hyper phosphorylation, tau filament formation, and neuronal degradation. Here, we describe the methods with mouse behavior test, immunostaining, and immunoblotting to detect many aspects of neurodegeneration in Pin1 knockout mice. PMID- 27975269 TI - Egg Activation at Fertilization. AB - Fertilization is the union of gametes to initiate development of a new individual. The female gamete is formed during oogenesis. The process begins when, in the early embryo, primordial germ cells arise and subsequently colonize the genital ridges. They differentiate into oogonia, start meiosis, and become primary oocytes. The cell cycle of the primary oocytes then becomes arrested in mid-meiosis for an extended period of time. Prior to ovulation the oocytes undergo a growth phase and their sizes increase significantly. A hormonal cue then triggers oocyte maturation that involves the resumption of meiosis, the completion of the first meiotic division, and, as a result, the reduction in the diploid chromosome number. The cell cycle then stops again; in vertebrates this arrest occurs at the metaphase stage of the second meiotic division. Meiosis resumes at fertilization, when the sperm activates the egg, i.e., it causes a series of changes that are required for the initiation of embryo development. This is achieved by triggering an elevation in the egg's intracellular free calcium concentration. In response, the fertilized egg completes meiosis and enters the first embryonic cell cycle. PMID- 27975271 TI - Regulation of Cell Division. AB - The challenging task of mitotic cell divisions is to generate two genetically identical daughter cells from a single precursor cell. To accomplish this task, a complex regulatory network evolved, which ensures that all events critical for the duplication of cellular contents and their subsequent segregation occur in the correct order, at specific intervals and with the highest possible fidelity. Transitions between cell cycle stages are triggered by changes in the phosphorylation state and levels of components of the cell cycle machinery. Entry into S-phase and M-phase are mediated by cyclin-dependent kinases (Cdks), serine threonine kinases that require a regulatory cyclin subunit for their activity. Resetting the system to the interphase state is mediated by protein phosphatases (PPs) that counteract Cdks by dephosphorylating their substrates. To avoid futile cycles of phosphorylation and dephosphorylation, Cdks and PPs must be regulated in a manner such that their activities are mutually exclusive. PMID- 27975272 TI - Vertebrate Embryonic Cleavage Pattern Determination. AB - The pattern of the earliest cell divisions in a vertebrate embryo lays the groundwork for later developmental events such as gastrulation, organogenesis, and overall body plan establishment. Understanding these early cleavage patterns and the mechanisms that create them is thus crucial for the study of vertebrate development. This chapter describes the early cleavage stages for species representing ray-finned fish, amphibians, birds, reptiles, mammals, and proto vertebrate ascidians and summarizes current understanding of the mechanisms that govern these patterns. The nearly universal influence of cell shape on orientation and positioning of spindles and cleavage furrows and the mechanisms that mediate this influence are discussed. We discuss in particular models of aster and spindle centering and orientation in large embryonic blastomeres that rely on asymmetric internal pulling forces generated by the cleavage furrow for the previous cell cycle. Also explored are mechanisms that integrate cell division given the limited supply of cellular building blocks in the egg and several-fold changes of cell size during early development, as well as cytoskeletal specializations specific to early blastomeres including processes leading to blastomere cohesion. Finally, we discuss evolutionary conclusions beginning to emerge from the contemporary analysis of the phylogenetic distributions of cleavage patterns. In sum, this chapter seeks to summarize our current understanding of vertebrate early embryonic cleavage patterns and their control and evolution. PMID- 27975273 TI - Localization in Oogenesis of Maternal Regulators of Embryonic Development. AB - Cell polarity generates intracellular asymmetries and functional regionalization in tissues and morphogenetic processes. Cell polarity in development often relies on mechanisms of RNA localization to specific subcellular domains to define the identity of future developing tissues. The totipotent egg of most animals illustrates in a grand way the importance of cell polarity and RNA localization in regulating multiple crucial developmental events. The polarization of the egg arises during its development in oogenesis. RNAs localize asymmetrically in the early oocyte defining its animal-vegetal (AV) axis, which upon further elaboration in mid- and late-oogenesis stages produces a mature egg with specific localized factors along its AV axis. These localized factors will define the future anterior-posterior (AP) and dorsal-ventral (DV) axes of the embryo. Furthermore, AV polarity confines germ cell determinants to the vegetal pole, from where they redistribute to the cleavage furrows of the 2- and 4-cell stage embryo, ultimately specifying the primordial germ cells (PGCs). The sperm entry region during fertilization is also defined by the AV axis. In frogs and fish, sperm enters through the animal pole, similar to the mouse where it enters predominantly in the animal half. Thus, AV polarity establishment and RNA localization are involved in all the major events of early embryonic development. In this chapter, we will review the RNA localization mechanisms in vertebrate oocytes that are key to embryonic patterning, referring to some of the groundbreaking studies in frog oocytes and incorporating the current genetic evidence from the zebrafish. PMID- 27975274 TI - Vertebrate Axial Patterning: From Egg to Asymmetry. AB - The emergence of the bilateral embryonic body axis from a symmetrical egg has been a long-standing question in developmental biology. Historical and modern experiments point to an initial symmetry-breaking event leading to localized Wnt and Nodal growth factor signaling and subsequent induction and formation of a self-regulating dorsal "organizer." This organizer forms at the site of notochord cell internalization and expresses primarily Bone Morphogenetic Protein (BMP) growth factor antagonists that establish a spatiotemporal gradient of BMP signaling across the embryo, directing initial cell differentiation and morphogenesis. Although the basics of this model have been known for some time, many of the molecular and cellular details have only recently been elucidated and the extent that these events remain conserved throughout vertebrate evolution remains unclear. This chapter summarizes historical perspectives as well as recent molecular and genetic advances regarding: (1) the mechanisms that regulate symmetry-breaking in the vertebrate egg and early embryo, (2) the pathways that are activated by these events, in particular the Wnt pathway, and the role of these pathways in the formation and function of the organizer, and (3) how these pathways also mediate anteroposterior patterning and axial morphogenesis. Emphasis is placed on comparative aspects of the egg-to-embryo transition across vertebrates and their evolution. The future prospects for work regarding self organization and gene regulatory networks in the context of early axis formation are also discussed. PMID- 27975275 TI - Establishment of the Vertebrate Germ Layers. AB - The process of germ layer formation is a universal feature of animal development. The germ layers separate the cells that produce the internal organs and tissues from those that produce the nervous system and outer tissues. Their discovery in the early nineteenth century transformed embryology from a purely descriptive field into a rigorous scientific discipline, in which hypotheses could be tested by observation and experimentation. By systematically addressing the questions of how the germ layers are formed and how they generate overall body plan, scientists have made fundamental contributions to the fields of evolution, cell signaling, morphogenesis, and stem cell biology. At each step, this work was advanced by the development of innovative methods of observing cell behavior in vivo and in culture. Here, we take an historical approach to describe our current understanding of vertebrate germ layer formation as it relates to the long standing questions of developmental biology. By comparing how germ layers form in distantly related vertebrate species, we find that highly conserved molecular pathways can be adapted to perform the same function in dramatically different embryonic environments. PMID- 27975270 TI - Controlling the Messenger: Regulated Translation of Maternal mRNAs in Xenopus laevis Development. AB - The selective translation of maternal mRNAs encoding cell-fate determinants drives the earliest decisions of embryogenesis that establish the vertebrate body plan. This chapter will discuss studies in Xenopus laevis that provide insights into mechanisms underlying this translational control. Xenopus has been a powerful model organism for many discoveries relevant to the translational control of maternal mRNAs because of the large size of its oocytes and eggs that allow for microinjection of molecules and the relative ease of manipulating the oocyte to egg transition (maturation) and fertilization in culture. Consequently, many key studies have focused on the expression of maternal mRNAs during the oocyte to egg transition (the meiotic cell cycle) and the rapid cell divisions immediately following fertilization. This research has made seminal contributions to our understanding of translational regulatory mechanisms, but while some of the mRNAs under consideration at these stages encode cell-fate determinants, many encode cell cycle regulatory proteins that drive these early cell cycles. In contrast, while maternal mRNAs encoding key developmental (i.e., cell-fate) regulators that function after the first cleavage stages may exploit aspects of these foundational mechanisms, studies reveal that these mRNAs must also rely on distinct and, as of yet, incompletely understood mechanisms. These findings are logical because the functions of such developmental regulatory proteins have requirements distinct from cell cycle regulators, including becoming relevant only after fertilization and then only in specific cells of the embryo. Indeed, key maternal cell-fate determinants must be made available in exquisitely precise amounts (usually low), only at specific times and in specific cells during embryogenesis. To provide an appreciation for the regulation of maternal cell fate determinant expression, an overview of the maternal phase of Xenopus embryogenesis will be presented. This section will be followed by a review of translational mechanisms operating in oocytes, eggs, and early cleavage-stage embryos and conclude with a discussion of how the regulation of key maternal cell fate determinants at the level of translation functions in Xenopus embryogenesis. A key theme is that the molecular asymmetries critical for forming the body axes are established and further elaborated upon by the selective temporal and spatial regulation of maternal mRNA translation. PMID- 27975276 TI - Mechanisms of Vertebrate Germ Cell Determination. AB - Two unique characteristics of the germ line are the ability to persist from generation to generation and to retain full developmental potential while differentiating into gametes. How the germ line is specified that allows it to retain these characteristics within the context of a developing embryo remains unknown and is one focus of current research. Germ cell specification proceeds through one of two basic mechanisms: cell autonomous or inductive. Here, we discuss how germ plasm driven germ cell specification (cell autonomous) occurs in both zebrafish and the frog Xenopus. We describe the segregation of germ cells during embryonic development of solitary and colonial ascidians to provide an evolutionary context to both mechanisms. We conclude with a discussion of the inductive mechanism as exemplified by both the mouse and axolotl model systems. Regardless of mechanism, several general themes can be recognized including the essential role of repression and posttranscriptional regulation of gene expression. PMID- 27975278 TI - Clearance of Parental Products. AB - The beginning of development is controlled parentally. For example, early zygotic proteosynthesis produces proteins encoded by the maternal transcriptome. As parental factors become replaced by factors synthesized in the embryo, parental developmental control is gradually passed to the embryo. This chapter focuses on the clearance of parental factors during oocyte-to-embryo transition in vertebrates. Coordinated removal of parental factors erases ancestral oocyte identity of the zygote and facilitates reprogramming of gene expression into a state that will support development of a new organism. Here, we will review functional and mechanistic aspects of clearance of selected parental factors from early embryos, including different types of maternal RNAs, proteins, erasure of chromatin features of maternal and paternal genomes, as well as consumption of yolk and elimination of paternal mitochondria. PMID- 27975277 TI - Cell Cycle Remodeling and Zygotic Gene Activation at the Midblastula Transition. AB - Following fertilization, vertebrate embryos delay large-scale activation of the zygotic genome from several hours in fish and amphibians to several days in mammals. Externally developing embryos also undergo synchronous and extraordinarily rapid cell divisions that are accelerated by promiscuous licensing of DNA replication origins, absence of gap phases and cell cycle checkpoints, and preloading of the egg with maternal RNAs and proteins needed to drive early development. After a species-specific number of cell divisions, the cell cycle slows and becomes asynchronous, gap phases appear, checkpoint functions are acquired, and large-scale zygotic gene activation begins. These events, along with clearance of maternal RNAs and proteins, define the maternal to zygotic transition and are coordinated at a developmental milestone termed the midblastula transition (MBT). Despite the relative quiescence of the zygotic genome in vertebrate embryos, genes required for clearance of maternal RNAs and for the initial steps in mesoderm induction are robustly transcribed before MBT. The coordination and timing of the MBT depends on a mechanism that senses the ratio of nuclear to cytoplasmic content as well as mechanisms that are independent of the nuclear-cytoplasm ratio. Changes in chromatin architecture anticipate zygotic gene activation, and maternal transcription factors identified as regulators of pluripotency play critical roles in kick-starting the transition from the proliferative, pluripotent state of the early embryo to the more lineage committed phase of development after the MBT. This chapter describes the regulation of the cell cycle and the activation of zygotic gene expression before and after the MBT in vertebrate embryos. PMID- 27975279 TI - An Introduction to Proteome Bioinformatics. AB - High-throughput techniques are indispensable for aiding basic and translational research. Among them, recent advances in proteomics techniques have allowed biomedical researchers to characterize the proteome of multiple organisms. This remarkable advancement have been well complemented by proteome bioinformatics methods and tools. Proteome bioinformatics refers to the study and application of informatics in the field of proteomics. This chapter provides an overview of computational strategies, methods, and techniques reported in this book for bioinformatics analysis of protein data. An outline of many bioinformatics tools, databases, and proteomic techniques described in each of the chapters is given here. PMID- 27975280 TI - Proteomic Data Storage and Sharing. AB - With the advent of high-throughput genomic and proteomic techniques, there is a massive amount of multidimensional data being generated and has increased several orders of magnitude. But the amount of data that is cataloged in the central repositories and shared publicly with the scientific community does not correlate the same rate at which the data is generated. Here, in this chapter, we discuss various proteomics data repositories that are freely accessible to the researchers for further downstream meta-analysis. PMID- 27975281 TI - Choosing an Optimal Database for Protein Identification from Tandem Mass Spectrometry Data. AB - Database searching is the preferred method for protein identification from digital spectra of mass to charge ratios (m/z) detected for protein samples through mass spectrometers. The search database is one of the major influencing factors in discovering proteins present in the sample and thus in deriving biological conclusions. In most cases the choice of search database is arbitrary. Here we describe common search databases used in proteomic studies and their impact on final list of identified proteins. We also elaborate upon factors like composition and size of the search database that can influence the protein identification process. In conclusion, we suggest that choice of the database depends on the type of inferences to be derived from proteomics data. However, making additional efforts to build a compact and concise database for a targeted question should generally be rewarding in achieving confident protein identifications. PMID- 27975282 TI - Label-Based and Label-Free Strategies for Protein Quantitation. AB - The precise quantification of changes between various physiological states in a biological system is highly complex in nature. Over the past few years, in combination with classical methods, mass spectrometry based approaches have become an indispensable tool in deciphering exact abundance of proteins in composite mixtures. The technique is now well established and employs both label based and label-free quantitation strategies. Label-based quantitation methods utilize stable isotope labels which are incorporated within the peptides, introducing an expectable mass difference within the two or more experimental conditions. In contrast, label-free proteomics quantitates both relative and absolute protein quantity by utilizing signal intensity and spectral counting of peptides. This chapter focuses on the commonly used quantitative mass spectrometry methods for high-throughput proteomic analysis. PMID- 27975283 TI - TMT One-Stop Shop: From Reliable Sample Preparation to Computational Analysis Platform. AB - In this chapter we describe the workflow we use for labeled quantitative proteomics analysis using tandem mass tags (TMT) starting with the sample preparation and ending with the multivariate analysis of the resulting data. We detail the step-by-step process from sample processing, labeling, fractionation, and data processing using Proteome Discoverer through to data analysis and interpretation in the context of a multi-run experiment. The final analysis and data interpretation rely on an R package we call TMTPrepPro, which are deployed on a local GenePattern server, and used for generating various outputs which are also outlined herein. PMID- 27975284 TI - Unassigned MS/MS Spectra: Who Am I? AB - Recent advances in high resolution tandem mass spectrometry (MS) has resulted in the accumulation of high quality data. Paralleled with these advances in instrumentation, bioinformatics software have been developed to analyze such quality datasets. In spite of these advances, data analysis in mass spectrometry still remains critical for protein identification. In addition, the complexity of the generated MS/MS spectra, unpredictable nature of peptide fragmentation, sequence annotation errors, and posttranslational modifications has impeded the protein identification process. In a typical MS data analysis, about 60 % of the MS/MS spectra remains unassigned. While some of these could attribute to the low quality of the MS/MS spectra, a proportion can be classified as high quality. Further analysis may reveal how much of the unassigned MS spectra attribute to search space, sequence annotation errors, mutations, and/or posttranslational modifications. In this chapter, the tools used to identify proteins and ways to assign unassigned tandem MS spectra are discussed. PMID- 27975285 TI - Methods to Calculate Spectrum Similarity. AB - Scoring functions that assess spectrum similarity play a crucial role in many computational mass spectrometry algorithms. These functions are used to compare an experimentally acquired fragmentation (MS/MS) spectrum against two different types of target MS/MS spectra: either against a theoretical MS/MS spectrum derived from a peptide from a sequence database, or against another, previously acquired MS/MS spectrum. The former is typically encountered in database searching, while the latter is used in spectrum clustering and spectral library searching. The comparison between acquired versus theoretical MS/MS spectra is most commonly performed using cross-correlations or probability derived scoring functions, while the comparison of two acquired MS/MS spectra typically makes use of a normalized dot product, especially in spectrum library search algorithms. In addition to these scoring functions, Pearson's or Spearman's correlation coefficients, mean squared error, or median absolute deviation scores can also be used for the same purpose. Here, we describe and evaluate these scoring functions with regards to their ability to assess spectrum similarity for theoretical versus acquired, and acquired versus acquired spectra. PMID- 27975286 TI - Proteotypic Peptides and Their Applications. AB - Recent advances in mass spectrometry based proteomic techniques and publicly available large proteomic repositories are being exploited to characterize the proteome of multiple organisms. While humongous amount of proteomic data is being acquired and analyzed, many biological questions still remain unanswered. Proteotypic peptides which uniquely represent target proteins or a protein isoform are used as an alternative strategy for protein identification in the field of immunological methods and targeted proteomic techniques. Using different computational approaches, resources and techniques used in the identification of proteotypic peptides of target proteins is discussed here. PMID- 27975287 TI - Statistical Evaluation of Labeled Comparative Profiling Proteomics Experiments Using Permutation Test. AB - Comparative profiling proteomics experiments are important tools in biological research. In such experiments, tens to hundreds of thousands of peptides are measured simultaneously, with the goal of inferring protein abundance levels. Statistical evaluation of these datasets are required to determine proteins that are differentially abundant between the test samples. Previously we have reported the non-normal distribution of SILAC datasets, and demonstrated the permutation test to be a superior method for the statistical evaluation of non-normal peptide ratios. This chapter outlines the steps and the R scripts that can be used for performing permutation analysis with false discovery rate control via the Benjamini-Yekutieli method. PMID- 27975288 TI - De Novo Peptide Sequencing: Deep Mining of High-Resolution Mass Spectrometry Data. AB - High resolution mass spectrometry has revolutionized proteomics over the past decade, resulting in tremendous amounts of data in the form of mass spectra, being generated in a relatively short span of time. The mining of this spectral data for analysis and interpretation though has lagged behind such that potentially valuable data is being overlooked because it does not fit into the mold of traditional database searching methodologies. Although the analysis of spectra by de novo sequences removes such biases and has been available for a long period of time, its uptake has been slow or almost nonexistent within the scientific community. In this chapter, we propose a methodology to integrate de novo peptide sequencing using three commonly available software solutions in tandem, complemented by homology searching, and manual validation of spectra. This simplified method would allow greater use of de novo sequencing approaches and potentially greatly increase proteome coverage leading to the unearthing of valuable insights into protein biology, especially of organisms whose genomes have been recently sequenced or are poorly annotated. PMID- 27975289 TI - Phylogenetic Analysis Using Protein Mass Spectrometry. AB - Through advances in molecular biology, comparative analysis of DNA sequences is currently the cornerstone in the study of molecular evolution and phylogenetics. Nevertheless, protein mass spectrometry offers some unique opportunities to enable phylogenetic analyses in organisms where DNA may be difficult or costly to obtain. To date, the methods of phylogenetic analysis using protein mass spectrometry can be classified into three categories: (1) de novo protein sequencing followed by classical phylogenetic reconstruction, (2) direct phylogenetic reconstruction using proteolytic peptide mass maps, and (3) mapping of mass spectral data onto classical phylogenetic trees. In this chapter, we provide a brief description of the three methods and the protocol for each method along with relevant tools and algorithms. PMID- 27975290 TI - Bioinformatics Methods to Deduce Biological Interpretation from Proteomics Data. AB - High-throughput proteomics studies generate large amounts of data. Biological interpretation of these large scale datasets is often challenging. Over the years, several computational tools have been developed to facilitate meaningful interpretation of large-scale proteomics data. In this chapter, we describe various analyses that can be performed and bioinformatics tools and resources that enable users to do the analyses. Many Web-based and stand-alone tools are relatively user-friendly and can be used by most biologists without significant assistance. PMID- 27975291 TI - A Systematic Bioinformatics Approach to Identify High Quality Mass Spectrometry Data and Functionally Annotate Proteins and Proteomes. AB - In the past decade, proteomics and mass spectrometry have taken tremendous strides forward, particularly in the life sciences, spurred on by rapid advances in technology resulting in generation and conglomeration of vast amounts of data. Though this has led to tremendous advancements in biology, the interpretation of the data poses serious challenges for many practitioners due to the immense size and complexity of the data. Furthermore, the lack of annotation means that a potential gold mine of relevant biological information may be hiding within this data. We present here a simple and intuitive workflow for the research community to investigate and mine this data, not only to extract relevant data but also to segregate usable, quality data to develop hypotheses for investigation and validation. We apply an MS evidence workflow for verifying peptides of proteins from one's own data as well as publicly available databases. We then integrate a suite of freely available bioinformatics analysis and annotation software tools to identify homologues and map putative functional signatures, gene ontology and biochemical pathways. We also provide an example of the functional annotation of missing proteins in human chromosome 7 data from the NeXtProt database, where no evidence is available at the proteomic, antibody, or structural levels. We give examples of protocols, tools and detailed flowcharts that can be extended or tailored to interpret and annotate the proteome of any novel organism. PMID- 27975292 TI - Network Tools for the Analysis of Proteomic Data. AB - Recent advancements in high-throughput technologies such as mass spectrometry have led to an increase in the rate at which data is generated and accumulated. As a result, standard statistical methods no longer suffice as a way of analyzing such gigantic amounts of data. Network analysis, the evaluation of how nodes relate to one another, has over the years become an integral tool for analyzing high throughput proteomic data as they provide a structure that helps reduce the complexity of the underlying data.Computational tools, including pathway databases and network building tools, have therefore been developed to store, analyze, interpret, and learn from proteomics data. These tools enable the visualization of proteins as networks of signaling, regulatory, and biochemical interactions. In this chapter, we provide an overview of networks and network theory fundamentals for the analysis of proteomics data. We further provide an overview of interaction databases and network tools which are frequently used for analyzing proteomics data. PMID- 27975293 TI - Determining the Significance of Protein Network Features and Attributes Using Permutation Testing. AB - Network analysis methods are increasing in popularity. An approach commonly applied to analyze proteomics data involves the use of protein-protein interaction (PPI) networks to explore the systems-level cooperation between proteins identified in a study. In this context, protein interaction networks can be used alongside the statistical analysis of proteomics data and traditional functional enrichment or pathway enrichment analyses. In network analysis it is possible to adjust for some of the complexities that arise due to the known, explicit interdependence between the measured quantities, in particular, differences in the number of interactions between proteins. Here we describe a method for calculating robust empirical p-values for protein interaction networks. We also provide a worked example with python code demonstrating the implementation of this methodology. PMID- 27975294 TI - Bioinformatics Tools and Resources for Analyzing Protein Structures. AB - The dramatic increase in the number of protein sequences and structures deposited in biological databases has led to the development of many bioinformatics tools and programs to manage, validate, compare, and interpret this large volume of data. In addition, powerful tools are being developed to use this sequence and structural data to facilitate protein classification and infer biological function of newly identified proteins. This chapter covers freely available bioinformatics resources on the World Wide Web that are commonly used for protein structure analysis. PMID- 27975295 TI - In Silico Approach to Identify Potential Inhibitors for Axl-Gas6 Signaling. AB - Axl-Gas6 signaling plays an important role in numerous cancers. Axl kinase, a member of receptor tyrosine kinase family is activated by different mechanisms with Gas6 as its major activator. Targeting the Axl with inhibitors may block the binding of Gas6 and further hinders the activation of Axl. This in turn inhibits the Axl-Gas6 signaling. Thus, inhibitors of the Axl kinase may serve as ideal drug candidates for treating many human cancers. In this study we carried out virtual screening of drug-like molecules from ZINC database to identify potential inhibitors for Axl kinase. Our virtual screening study showed that ZINC83758120, ZINC34079369, and ZINC83758121 are potential drug-like lead molecules to inhibit Axl kinase. PMID- 27975296 TI - Erratum to: The Type I Restriction Enzymes as Barriers to Horizontal Gene Transfer: Determination of the DNA Target Sequences Recognised by Livestock Associated Methicillin-Resistant Staphylococcus aureus Clonal Complexes 133/ST771 and 398. PMID- 27975297 TI - cUMP hydrolysis by PDE3A. AB - As previously reported, the cardiac phosphodiesterase PDE3A hydrolyzes cUMP. Moreover, cUMP-degrading activity was detected in cow and dog hearts several decades ago. Our aim was to characterize the enzyme kinetic parameters of PDE3A mediated cUMP hydrolysis and to investigate whether cUMP and cUMP-hydrolyzing PDEs are present in cardiomyocytes. PDE3A-mediated cUMP hydrolysis was characterized in time course, inhibitor, and Michaelis-Menten kinetics experiments. Intracellular cyclic nucleotide (cNMP) concentrations and the mRNAs of cUMP-degrading PDEs were quantitated in neonatal rat cardiomyocytes (NRCMs) and murine HL-1 cardiomyogenic cells. Moreover, we investigated cUMP degradation in HL-1 cell homogenates and intact cells. Educts (cNMPs) and products (NMPs) of the PDE reactions were detected by HPLC-coupled tandem mass spectrometry. PDE3A degraded cUMP (measurement of UMP formation) with a K M value of ~143 MUM and a V max value of ~42 MUmol/min/mg. PDE3A hydrolyzed cAMP with a K M value of ~0.7 MUM and a V max of ~1.2 MUmol/min/mg (determination of AMP formation). The PDE3 inhibitor milrinone inhibited cUMP hydrolysis (determination of UMP formation) by PDE3A (K i = 57 nM). Significant amounts of cUMP as well as of PDE3A mRNA (in addition to PDE3B and PDE9A transcripts) were detected in HL-1 cells and NRCMs. Although HL-1 cell homogenates contain a milrinone-sensitive cUMP-hydrolyzing activity, intact HL-1 cells may use additional PDE3-independent mechanisms for cUMP disposal. PDE3A is a low-affinity and high-velocity PDE for cUMP. Future studies should investigate biological effects of cUMP in cardiomyocytes and the role of PDE3A in detoxifying high intracellular cUMP concentrations under pathophysiological conditions. PMID- 27975298 TI - Capsaicin partially mimics heat in mouse fibroblast cells in vitro. AB - Capsaicin activates transient receptor potential vanilloid 1 (TRPV1), a cation channel in the transient receptor potential family, resulting in the transient entry of Ca2+ and Mg2+ and a warm sensation. However, the effects of capsaicin on cells have not fully elucidated in fibroblasts. In this study, we investigated whether capsaicin could induce signal transduction in mouse fibroblast cells and compared the effect with that of heat-induced signal transduction. The activation of the mitogen-activated protein kinases (MAPKs) ERK and p38 MAPK, expression levels of heat shock protein 70 (HSP70) and HSP90, actin assembly, and cell proliferation were analyzed in NIH3T3 mouse fibroblast cells. A 15-min stimulation with capsaicin (~100 MUM) phosphorylated ERK and p38 MAPK and induced actin assembly. A 2-day stimulation with capsaicin increased the level of HSP70, but not HSP90, and the 2-day stimulation with capsaicin (~100 MUM) did not affect cell proliferation. A 15-min exposure to moderate heat (39.5 degrees C) phosphorylated both ERK and p38 MAPK and induced actin assembly to similar degrees as stimulation with capsaicin. A 2-day exposure to moderate heat increased the levels of both HSP70 and HSP90 and prevented cell proliferation. However, the 2-day stimulation with capsaicin (100 MUM) failed to prevent heat shock-induced cell death. Thus, our results suggest that the effects of capsaicin on fibroblast cells partially differ from those of heat. Notably, the 2-day stimulation with capsaicin was not sufficient to develop heat tolerance in fibroblast cells. PMID- 27975299 TI - Nilotinib, a tyrosine kinase inhibitor exhibits protection against acute pancreatitis-induced lung and liver damage in rats. AB - This investigation explored the nilotinib action in the management of acute pancreatitis (AP) and AP-induced lung and liver injury. AP was induced in Sprague Dawley (SD) rats with L-arginine. Treatment with nilotinib with or without L arginine was applied for 7 days. Marked deterioration in serum amylase, lipase, aspartate amino transferase (AST), alanine amino transferase (ALT), lactate dehydrogenase (LDH), nitric oxide (NO), total protein content, and transforming growth factor beta1 (TGF-beta1) along with pancreatic, hepatic, and pulmonary tissue lipid peroxidation (MDA) after induction of AP while significant reduction in tissues superoxide dismutase (SOD), glutathione (GSH) with marked edema, hemorrhage, and perivascular inflammation with acinar cell necrosis, along with elevated pancreatic percentage expression of TGF-beta1 and nuclear factor kappa B (NF-kappaB), were observed in the AP group. Nilotinib markedly ameliorated biochemical and histopathologic changes during AP, thus preserving the pancreas, liver, and lung histologically through mechanism involving antioxidant and anti inflammatory actions. PMID- 27975300 TI - Nephroprotective efficacy of ceftriaxone against cisplatin-induced subchronic renal fibrosis in rats. AB - Cisplatin, or cis-diamminedichloridoplatinum(II), (CDDP) is a broad-spectrum antineoplastic chemotherapeutic agent with a potent efficacy against several malignancies. Its main clinical antineoplastic therapy-limiting adverse effect is nephrotoxicity, where the developments of effective nephroprotectors are needed. Therefore, the present study aimed to investigate the nephroprotective and antifibrotic potential of ceftriaxone (CTX) against CDDP-induced toxicity. Male Wister rats were treated with saline or CTX (100 or 200 mg kg-1 bw) an hour before CDDP administration (1 mg kg-1 bw). All the treatments were intraperitoneally administered twice weekly for consecutive 10 weeks. Twenty-four hours after last CDDP dose, blood samples were collected, then the animals were euthanized and their kidneys were isolated for measurements. CDDP significantly increased serum uric acid, urea, and creatinine contents. Toxicopathic changes showed that CDDP induced marked tubulointerstitial damage, overexpressed fibrogenic factors alpha-smooth muscle actin (alpha-SMA) and transforming growth factor-beta1 (TGF-beta1), and down expressed cellular proliferating biomarker bromodeoxyuridine (BrdU). CTX pretreatment, particularly 200 mg/kg bw, improved the renal function biomarkers; histoarchitecture; and alpha-SMA, TGF-beta1, and BrdU expressions. It could be concluded that CTX is endowed with antifibrotic properties and could be, therefore, used as adjuvant therapy to improve CDDP induced nephrotoxicity. Further clinical researches are necessary to evaluate whether CTX may exhibit a new therapeutic choice for treating renal fibrotic diseases. PMID- 27975303 TI - NTCP-Reconstituted In Vitro HBV Infection System. AB - Sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a functional receptor for hepatitis B virus (HBV). Expressing human NTCP in human hepatoma HepG2 cells (HepG2-NTCP) renders these cells susceptible for HBV infection. The HepG2-NTCP stably transfected cell line provides a much-needed and easily accessible platform for studying the virus. HepG2-NTCP cells could also be used to identify chemicals targeting key steps of the virus life cycle including HBV covalent closed circular (ccc) DNA, and enable the development of novel antivirals against the infection.Many factors may contribute to the efficiency of HBV infection on HepG2-NTCP cells, with clonal differences among cell line isolates, the source of viral inoculum, and infection medium among the most critical ones. Here, we provide detailed protocols for efficient HBV infection of HepG2-NTCP cells in culture; generation and selection of single cell clones of HepG2-NTCP; production of infectious HBV virion stock through DNA transfection of recombinant plasmid that enables studying primary clinical HBV isolates; and assessing the infection with immunostaining of HBV antigens and Southern blot analysis of HBV cccDNA. PMID- 27975302 TI - Vitamin D deficiency is associated with functional decline and falls in frail elderly women despite supplementation. AB - : We examined the impact of daily supplementation on vitamin D deficiency, function, and falls in female long-term care residents. Initial vitamin D deficiency was associated with greater functional decline and increased fall risk despite guideline-recommended supplementation, highlighting the importance of preventing vitamin D deficiency in frail elderly. INTRODUCTION: Institute of Medicine (IOM) guidelines recommend 800 IU vitamin D daily for older adults and maintaining serum 25-hydroxyvitamin D [25(OH) D] above 20 ng/ml for optimal skeletal health. The adequacy of IOM guidelines for sustaining function and reducing falls in frail elderly is unknown. METHODS: Female long-term care residents aged >=65 enrolled in an osteoporosis clinical trial were included in this analysis (n = 137). Participants were classified based on baseline 25(OH) D levels as deficient (<20 ng/ml, n = 26), insufficient (20-30 ng/ml, n = 40), or sufficient (>30 ng/ml, n = 71). Deficient women were provided initial vitamin D repletion (50,000 IU D3 weekly for 8 weeks). All were supplemented with 800 IU vitamin D3 daily for 24 months. Annual functional assessments included Activities of Daily Living (ADLs), Instrumental ADL (IADL), physical performance test (PPT), gait speed, cognition (SPMSQ), and mental health (PHQ-9). We used linear mixed models for analysis of functional measures and logistic regression for falls. RESULTS: Daily supplementation maintained 25(OH) D levels above 20 ng/ml in 95% of participants. All groups demonstrated functional decline. Women initially deficient had a greater decline in physical function at 12 (IADL -2.0 +/- 0.4, PPT -3.1 +/- 0.7, both p < 0.01) and 24 months (IADL -2.5 +/- 0.6, ADL -2.5 +/- 0.6, both p < 0.01), a larger increase in cognitive deficits at 12 months (1.7 +/ 0.4: p = 0.01) and more fallers (88.5%, p = 0.04) compared to those sufficient at baseline, despite supplementation to sufficient levels. CONCLUSIONS: IOM guidelines may not be adequate for frail elderly. Further study of optimal 25(OH) D levels for maintaining function and preventing falls is needed. PMID- 27975301 TI - Vertebral cross-sectional area: an orphan phenotype with potential implications for female spinal health. AB - A high priority in imaging-based research is the identification of the structural basis that confers greater risk for spinal disorders. New evidence indicates that factors related to sex influence the fetal development of the axial skeleton. Girls are born with smaller vertebral cross-sectional area compared to boys-a sexual dimorphism that is present throughout life and independent of body size. The smaller female vertebra is associated with greater flexibility of the spine that could represent the human adaptation to fetal load. It also likely contributes to the higher prevalence of spinal deformities, such as exaggerated lordosis and progressive scoliosis in adolescent girls when compared to boys, and to the greater susceptibility for spinal osteoporosis and vertebral fractures in elderly women than men. PMID- 27975304 TI - Hepatitis B Virus Infection of HepaRG Cells, HepaRG-hNTCP Cells, and Primary Human Hepatocytes. AB - Investigations of virus-host interactions rely on suitable in vitro cell culture systems that efficiently support virus infection. Such systems should ideally provide conditions that resemble those of natural host cells, e.g., the cell-type specific signaling and metabolic pathways. For HBV infection, primary human hepatocytes (PHHs) are the most faithful system fulfilling these requirements but access to these cells is limited. Moreover, the reproducibility of experimental results depends on many factors including the preparation method or variability of the donors. The human liver cell line HepaRG, after differentiation, resembles PHHs with respect to many hepatocyte-specific markers including the expression of cytochrome P450 enzymes, liver-specific transcription factors, and transporter proteins like the HBV-specific receptor, sodium taurocholate co-transporting polypeptide (NTCP). HepaRG cells have also been shown to express key molecules of the innate immune system. So far, the HepaRG cell line is the only one allowing both studies on HBV/HDV infection and liver-specific drug toxicity and metabolism. The relative low susceptibility of HepaRG cells when compared with PHHs depends on various factors and can partially be overcome by constitutive expression of the receptor NTCP, allowing infection without full differentiation. Ectopic NTCP expression does not interfere with the ability of cell differentiation induced by DMSO. Here, we describe in detail how to technically perform HBV infection in vitro with these cells. The methods can be used to explore the mechanism of HBV infection and to build an antiviral screening platform suitable for evaluation of drug efficacy in cells that are metabolically close to primary human hepatocytes. PMID- 27975305 TI - Live Cell Imaging Confocal Microscopy Analysis of HBV Myr-PreS1 Peptide Binding and Uptake in NTCP-GFP Expressing HepG2 Cells. AB - To obtain basic knowledge about specific molecular mechanisms involved in the entry of pathogens into cells is the basis for establishing pharmacologic substances blocking initial viral binding, infection, and subsequent viral spread. Lack of information about key cellular factors involved in the initial steps of HBV infection has hampered the characterization of HBV binding and entry for decades. However, recently, the liver-specific sodium-dependent taurocholate cotransporting polypeptide (NTCP) has been discovered as a functional receptor for HBV and HDV, thus opening the field for new concepts of basic binding and entry of HBV and HDV. Here, we describe practical issues of a basic in vitro assay system to examine kinetics and mechanisms of receptor-dependent HBV binding, uptake, and intracellular trafficking by live-cell imaging confocal microscopy. The assay system is comprised of HepG2 cells expressing a NTCP-GFP fusion-protein and chemically synthesized, fluorophore-labeled part of HBV surface protein, spanning the first N-terminal 48 amino acids of preS1 of the large hepatitis B virus surface protein. PMID- 27975306 TI - Intracytoplasmic Transport of Hepatitis B Virus Capsids. AB - The early steps of HBV entry remain largely unknown despite the recent discovery of an HBV-specific entry receptor. Following entry HBV capsids have to be transported through the cytoplasm to the nuclear periphery, followed by nuclear entry. These steps have to take place in a coordinated manner to allow delivery of the genome into the nucleus. Due to the viscosity of the cytoplasm, the intracytoplasmic translocation has to be active and directed.Here, we describe protocols that can be applied to investigations of the HBV capsid with the cytoplasmic transport systems. We have chosen to present two independent experimental approaches, which allow avoiding artifacts. Aside of the specific capsid detection system, the protocols can be applied to any other viral structure. PMID- 27975307 TI - A Homokaryon Assay for Nucleocytoplasmic Shuttling Activity of HBV Core Protein. AB - Hepatitis B virus (HBV) core protein (HBc) can be present in both nucleus and cytoplasm. The arginine-rich domain (ARD) at the cytoplasmic tail of HBc contains both a nuclear localization signal (NLS) and nuclear export signal (NES). We established a homokaryon assay to detect the dynamic trafficking of HBc between nucleus and cytoplasm in hepatocytes. Using immunofluorescence assay (IFA) and PEG-induced cell-cell fusion, we demonstrated that a chimeric reporter protein of SV40 large T antigen, when fused in-frame with HBc ARD, can shuttle from a donor nuclei (green) to the recipient nuclei (red) in the context of binucleated or polynucleated hybrid cells. The shuttling activity driven by HBc ARD can be measured quantitatively by this IFA method. PMID- 27975308 TI - Analyses of HBV cccDNA Quantification and Modification. AB - Covalently closed circular DNA (cccDNA) serves as the transcriptional template of hepatitis B virus (HBV) replication in the nucleus of infected cells. It ensures the persistence of HBV even if replication is blocked. Immune-mediated killing of infected hepatocytes, cell division, or cytokine induced non-cytolytic degradation of cccDNA can induce the loss of cccDNA. For studies on HBV control, the analysis of cccDNA integrity and its exact quantification is very important. Here, we describe different methods for HBV cccDNA quantification and modification. PMID- 27975309 TI - Detection of HBV cccDNA Methylation from Clinical Samples by Bisulfite Sequencing and Methylation-Specific PCR. AB - Mapping of DNA methylation is essential in understanding the process of HBV covalently closed circular DNA (cccDNA) transcription. Here, bisulfite sequencing PCR and methylation-specific PCR, two PCR-based approaches used in determining and quantifying the DNA methylation pattern, are described. PMID- 27975310 TI - A T7 Endonuclease I Assay to Detect Talen-Mediated Targeted Mutation of HBV cccDNA. AB - Gene editing using designer nucleases is now widely used in many fields of molecular biology. The technology is being developed for the treatment of viral infections such as persistant hepatitis B virus (HBV). The replication intermediate of HBV comprising covalently closed circular DNA (cccDNA) is stable and resistant to available licensed antiviral agents. Advancing gene editing as a means of introducing targeted mutations into cccDNA thus potentially offers the means to cure infection by the virus. Essentially, targeted mutations are initiated by intracellular DNA cleavage, then error-prone nonhomologous end joining results in insertions and deletions (indels) at intended sites. Characterization of these mutations is crucial to confirm activity of potentially therapeutic nucleases. A convenient tool for evaluation of the efficiency of target cleavage is the single strand-specific endonuclease, T7EI. Assays employing this enzyme entail initial amplification of DNA encompassing the targeted region. Thereafter the amplicons are denatured and reannealed to allow hybridization between indel-containing and wild-type sequences. Heteroduplexes that contain mismatched regions are susceptible to action by T7EI and cleavage of the hybrid amplicons may be used as an indicator of efficiency of designer nucleases. The protocol described here provides a method of isolating cccDNA from transfected HepG2.2.15 cells and evaluation of the efficiency of mutation by a transcription activator-like effector nuclease that targets the surface open reading frame of HBV. PMID- 27975311 TI - Detection of Hepatocyte Clones Containing Integrated Hepatitis B Virus DNA Using Inverse Nested PCR. AB - Chronic hepatitis B virus (HBV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC), leading to ~600,000 deaths per year worldwide. Many of the steps that occur during progression from the normal liver to cirrhosis and/or HCC are unknown. Integration of HBV DNA into random sites in the host cell genome occurs as a by-product of the HBV replication cycle and forms a unique junction between virus and cellular DNA. Analyses of integrated HBV DNA have revealed that HCCs are clonal and imply that they develop from the transformation of hepatocytes, the only liver cell known to be infected by HBV. Integrated HBV DNA has also been shown, at least in some tumors, to cause insertional mutagenesis in cancer driver genes, which may facilitate the development of HCC. Studies of HBV DNA integration in the histologically normal liver have provided additional insight into HBV-associated liver disease, suggesting that hepatocytes with a survival or growth advantage undergo high levels of clonal expansion even in the absence of oncogenic transformation. Here we describe inverse nested PCR (invPCR), a highly sensitive method that allows detection, sequencing, and enumeration of virus-cell DNA junctions formed by the integration of HBV DNA. The invPCR protocol is composed of two major steps: inversion of the virus-cell DNA junction and single-molecule nested PCR. The invPCR method is highly specific and inexpensive and can be tailored to DNA extracted from large or small amounts of liver. This procedure also allows detection of genome-wide random integration of any known DNA sequence and is therefore a useful technique for molecular biology, virology, and genetic research. PMID- 27975312 TI - Highly Sensitive Detection of HBV RNA in Liver Tissue by In Situ Hybridization. AB - As soon as HBV was identified, HBV localization at the cellular level became instrumental in studying HBV infection. Multiple methodologies for detection of viral antigens and nucleic acids at the cellular level, not only in patient derived liver biopsy samples, but also in many other experimental systems, have been developed over the years. Recently, the development of highly sensitive and specific in situ hybridization systems enabled detection of cellular mRNAs at the single copy level. Adaptation of such a system (ViewRNA ISH Tissue Assay; Affymetrix, Santa Clara, CA, USA) for the detection of viral RNAs allowed us to reliably identify hepatitis C virus RNA positive cells in the liver of HCV infected patients. Similarly, this protocol enabled detection of very rare HBV positive cells in liver biopsy tissue. Here, we now describe the specifics of the protocol for detection of HBV RNA using the ViewRNA ISH system. The protocol focuses on probe set design, sample preparation and data interpretation for accurate HBV RNA detection in liver tissue samples. The methodology is straightforward and will be very useful in the study of basic HBV virology as well as in clinical applications. PMID- 27975313 TI - Immunofluorescent Staining for the Detection of the Hepatitis B Core Antigen in Frozen Liver Sections of Human Liver Chimeric Mice. AB - The hepatitis B virus (HBV) is the causative agent for chronic hepatitis B infection, which affects an estimate of 240 million people worldwide and puts them at risk of developing terminal liver disease. The life cycle of the virus and its interactions with the host immune system are still incompletely understood, and currently available treatment options rarely achieve a cure. Therefore, basic research and new drug development are needed. One parameter for measuring the intrahepatic activity of the virus is monitoring the production of the HBV core antigen (HBcAg), which not only serves as the main structural protein of its nucleocapsid but is also recruited to the covalently closed circular DNA (cccDNA), the nuclear HBV genome responsible for infection persistence. Here, we report a sensitive immunofluorescence staining method to detect HBcAg in cryopreserved liver sections. The method combines conventional immunofluorescence staining procedures with the Tyramide Signal Amplification (TSA) system. PMID- 27975314 TI - Measuring Changes in Cytosolic Calcium Levels in HBV- and HBx-Expressing Cultured Primary Hepatocytes. AB - Chronic infection with hepatitis B virus (HBV) remains a major worldwide health concern and is the leading cause of hepatocellular carcinoma (HCC). The HBV X protein (HBx) is the only regulatory protein encoded in the HBV genome; HBx stimulates HBV replication in vivo and in vitro. HBx also regulates cytosolic Ca2+ signaling, and altered Ca2+ signaling is associated with the development of many diseases, including HCC. Importantly, many HBx functions, including HBx modulation of cell proliferation, apoptosis, and transcription pathways, have been linked to changes in cytosolic Ca2+ signaling. Additionally, several stages of HBV replication, including capsid formation and activation of the HBV polymerase, are dependent on intracellular Ca2+. Consequently, defining the molecular mechanism that underlies HBV and HBx modulation of cytosolic Ca2+ levels is important for understanding HBV pathogenesis and the role of HBx in HBV replication. Here, we describe a single-cell Ca2+-imaging protocol that we use to investigate HBV and HBx effects on the level of cytosolic Ca2+. We specifically outline two methods that we use to evaluate HBV and HBx regulation of cytosolic Ca2+ levels in cultured primary hepatocytes. This protocol can also be adapted for use in liver cell lines. PMID- 27975315 TI - In Vitro Assays for RNA Binding and Protein Priming of Hepatitis B Virus Polymerase. AB - The hepatitis B virus (HBV) polymerase synthesizes the viral DNA genome from the pre-genomic RNA (pgRNA) template through reverse transcription. Initiation of viral DNA synthesis is accomplished via a novel protein priming mechanism, so named because the polymerase itself acts as a primer, whereby the initiating nucleotide becomes covalently linked to a tyrosine residue on the viral polymerase. Protein priming, in turn, depends on specific recognition of the packaging signal on pgRNA called epsilon. These early events in viral DNA synthesis can now be dissected in vitro as described here.The polymerase is expressed in mammalian cells and purified by immunoprecipitation. The purified protein is associated with host cell factors, is enzymatically active, and its priming activity is epsilon dependent. A minimal epsilon RNA construct from pgRNA is co-expressed with the polymerase in cells. This RNA binds to and co immunoprecipitates with the polymerase. Modifications can be made to either the epsilon RNA or the polymerase protein by manipulating the expression plasmids. Also, the priming reaction itself can be modified to assay for the initiation or subsequent DNA synthesis during protein priming, the susceptibility of the polymerase to chemical inhibitors, and the precise identification of the DNA products upon their release from the polymerase. The identity of associated host factors can also be evaluated. This protocol closely mirrors our current understanding of the RNA binding and protein priming steps of the HBV replication cycle, and it is amenable to modification. It should therefore facilitate both basic research and drug discovery. PMID- 27975316 TI - In Vitro Enzymatic and Cell Culture-Based Assays for Measuring Activity of HBV RNaseH Inhibitors. AB - HBV is a small, enveloped DNA virus that replicates by reverse transcription via an RNA intermediate. Current anti-HBV treatment regiments that include interferon alpha and nucleos(t)ide analogs have insufficient efficiency, are of long duration and can be accompanied by systemic side effects. Though HBV RNaseH is essential for viral replication, it is unexploited as a drug target against HBV. RNaseH inhibitors that actively block viral replication would represent an important addition to the potential new drugs for treating HBV infection. Here we describe two methods to measure the activity of RNaseH inhibitors. DNA oligonucleotide-directed RNA cleavage assay allows low-throughput screening of compounds for potential anti-HBV RNaseH activity in vitro. Analysis of preferential inhibition of plus-polarity DNA strand synthesis by HBV RNaseH inhibitors in a cell culture model of HBV replication can be used to validate the efficiency of these compounds to block viral replication. PMID- 27975318 TI - Microtiter-Format Assays for HBV Antigen Quantitation in Nonclinical Applications. AB - Measurement of secreted HBV antigens in cell culture is an important endpoint in many experimental settings. Here we describe convenient and inexpensive protocols for 96-well format sandwich ELISA assays for this purpose, in which there are many options for customization of antibodies used and other parameters. These protocols can be adapted to use for animal serum samples, compound library screening, and other purposes. PMID- 27975317 TI - Detection of Hepatitis B Virus Particles Released from Cultured Cells by Particle Gel Assay. AB - The culture fluid of HBV replicating cells contains a mixture of viral particles with different structural and genetic components, including enveloped infectious virions, genome-free virion, envelope-only subviral particles, and nonenveloped naked capsids. Based on their different physical and chemical properties, the enveloped and nonenveloped particles can be separated by the native agarose gel electrophoresis and transferred onto a positively charged microporous membrane, then the virus particle-associated protein components and nucleic acid content can be detected by antibody-based enzyme immunoassay (EIA) and hybridization, respectively. Such convenient experimental procedure is called HBV particle assay and described in detail in this chapter. The particle gel assay can be used to study viral and host regulations of HBV virus morphogenesis and egress, and for antiviral assessment of HBV inhibitors as well. PMID- 27975319 TI - Deep Sequencing of the Hepatitis B Virus Genome: Analysis of Multiple Samples by Implementation of the Illumina Platform. AB - The quasispecies variation of hepatitis B virus (HBV) was believed to be a viral response to antiviral treatment and host immune pressure. Sanger sequencing was previously the classic approach for quasispecies analysis, but this method was also time-consuming and laborious. Ultra-deep sequencing has been widely used in viral quasispecies research, especially for low-frequency mutation detection. Here we present a multiple samples deep sequencing method employing the Illumina platform to detect HBV quasispecies variation in patient-derived samples. PMID- 27975320 TI - Generation of Replication-Competent Hepatitis B Virus Genome from Blood Samples for Functional Characterization. AB - Hepatitis B virus (HBV) infection can be associated with a spectrum of clinical outcomes. Transient transfection of the clinical HBV isolates in human hepatoma cell lines can establish their biological properties to shed light on their different pathogenic potentials, yet very few clinical HBV isolates have been functionally characterized so far. The technical challenges include faithful amplification of the full-length HBV genome from clinical samples and conversion into a replication-competent form. We have improved a published method to amplify the full-length HBV genome from blood samples. Two alternative approaches are used to render the cloned HBV genome replication competent: release and circularization of the 3.2-kb HBV genome prior to each transfection experiment or conversion of the monomeric clone into a tandem dimer version. PMID- 27975321 TI - Hydrodynamic HBV Transfection Mouse Model. AB - Hydrodynamic HBV transfection mouse model is an established method of the last decade where macromolecules, non-normally permeable to cell membrane, are delivered intracellular. The basic principle is that a large volume of solution, containing HBV plasmid construct, is infused rapidly in circulation to permit the preferential entrance of these macromolecules to liver parenchymal cells. The aim of this chapter is to describe the basic principles of the hydrodynamic HBV transfection in mouse models. PMID- 27975322 TI - An ELISPOT-Based Assay to Measure HBV-Specific CD8+ T Cell Responses in Immunocompetent Mice. AB - Despite some important limitations, immunocompetent mouse models of HBV replication remain an essential tool for studying cellular and humoral immunity to the virus. CD8+ T cells are a critical component of the immune response to HBV due to their ability to both kill virus-infected hepatocytes and produce cytokines such as IFN-gamma that non-cytopathically inhibit virus replication. A number of techniques can be used to measure the magnitude, specificity, and functionality of HBV-specific CD8+ T cells, each having its own unique advantages. We describe here the enzyme-linked immunospot (ELISPOT)-based assay, which, compared to other methods, is sensitive, cost-effective, and rapid and requires relatively little optimization, specialized training, or equipment. PMID- 27975324 TI - Partial Hepatectomy and Castration of HBV Transgenic Mice. AB - Hepatitis B virus (HBV) is a hepatotropic virus. Its infection can cause liver injury and regeneration, and its replication is affected by the gender. Transgenic mice that carry a 1.3-mer overlength HBV DNA genome productively replicate HBV in hepatocytes and have been very useful for studying the replication and pathogenesis of HBV in vivo. By using this mouse model, the relationship between HBV and liver injury and regeneration as well as the effect of the gender on HBV gene expression and replication has been studied. In this chapter, we describe the surgical procedures of partial hepatectomy and castration and provide examples to demonstrate how these surgical procedures may be used to study the effect of HBV on liver regeneration and the effect of androgen on HBV replication. PMID- 27975323 TI - Advanced Method for Isolation of Mouse Hepatocytes, Liver Sinusoidal Endothelial Cells, and Kupffer Cells. AB - Separation of pure cell populations from the liver is a prerequisite to study the role of hepatic parenchymal and non-parenchymal cells in liver physiology, pathophysiology, and immunology. Traditional methods for hepatic cell separation usually purify only single cell types from liver specimens. Here, we describe an efficient method that can simultaneously purify populations of hepatocytes (HCs), liver sinusoidal endothelial cells (LSECs), and Kupffer cells (KCs) from a single mouse liver specimen. A liberase-based perfusion technique in combination with a low-speed centrifugation and magnetic-activated cell sorting (MACS) led to the isolation and purification of HCs, KCs, and LSECs with high yields and purity. PMID- 27975325 TI - Studying HBV Infection and Therapy in Immune-Deficient NOD-Rag1-/-IL2RgammaC-null (NRG) Fumarylacetoacetate Hydrolase (Fah) Knockout Mice Transplanted with Human Hepatocytes. AB - Chimeric mouse models with a humanized liver provide a unique tool to study hepatic virus diseases, including viral infection, viral pathogenesis, and antiviral therapy. Here we describe a detailed protocol for studying hepatitis B infection in NRG-derived fumarylacetoacetate hydrolase (Fah) knockout mice repopulated with human hepatocytes. The procedures include (1) maintenance and genotyping of the homozygous NRG-fah/fah mutant mice (NRG/F), (2) intrasplenic injection of human hepatocytes, (3) NTBC drug reduction cycling to improve human hepatocyte repopulation, (4) human albumin detection, and (5) HBV infection and detection. The method is simple and allows for highly reproducible generation of NRG/F-hu Hep mice for studying HBV infection and therapy. PMID- 27975326 TI - Measurement of Antiviral Effect and Innate Immune Response During Treatment of Primary Woodchuck Hepatocytes. AB - An estimated 350 million people are chronically infected with hepatitis B virus (HBV), and over one million people die each year due to HBV-associated liver diseases, such as cirrhosis and liver cancer. Current therapeutics for chronic HBV infection are limited to nucleos(t)ide analogs and interferon. These anti-HBV drugs in general reduce viral load and improve the long-term outcome of infection but very rarely lead to a cure. Thus, new therapies for chronic HBV infection need to be developed by utilizing liver cell lines and primary cultures and small laboratory animals capable of replicating HBV or surrogate hepadnaviruses for antiviral testing. Natural infection with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to HBV, occurs in woodchucks. Chronic WHV infection has been established over decades as a suitable model for evaluating direct acting antivirals as well as vaccines, vaccine adjuvants, and immunotherapeutics because animals are fully immunocompetent. Before HBV-specific compounds are applied to woodchucks, they are usually tested in primary woodchuck hepatocytes (PWHs) replicating WHV at high levels for confirming drug specificity against viral or host targets. Here we describe a protocol for the isolation of PWHs from liver of WHV-infected woodchucks, maintenance in culture, and use in assays for determining antiviral efficacy, safety, and associated host innate immune response of new experimental drugs. Exemplary assays were performed with the nucleoside analog, lamivudine, and the immunomodulator, interferon-alpha. PMID- 27975327 TI - Levels and distributions of organochlorine pesticides in the soil-groundwater system of vegetable planting area in Tianjin City, Northern China. AB - To study the influence of long-term pesticide application on the distribution of organochlorine pesticides (OCPs) in the soil-groundwater system, 19 soil samples and 19 groundwater samples were collected from agricultural area with long-term pesticide application history in Northern China. Results showed that the composition of OCPs changed significantly from soil to groundwater. For example, ?DDT, ?HCH, and ?heptachlor had high levels in the soil and low levels in the groundwater; in contrast, endrin had low level in the soil and high level in the groundwater. Further study showed that OCP distribution in the soil was significantly influenced by its residue time, soil organic carbon level, and small soil particle contents (i.d. <0.0002 mm). Correlation analysis also indicates that the distribution of OCPs in the groundwater was closely related to the levels of OCPs in the soil layer, which may act as a pollution source. PMID- 27975328 TI - A Priori Intrinsic PTM Size Parameters for Predicting the Ion Mobilities of Modified Peptides. AB - The rising profile of ion mobility spectrometry (IMS) in proteomics has driven the efforts to predict peptide cross-sections. In the simplest approach, these are derived by adding the contributions of all amino acid residues and post translational modifications (PTMs) defined by their intrinsic size parameters (ISPs). We show that the ISPs for PTMs can be calculated from properties of constituent atoms, and introduce the "impact scores" that govern the shift of cross-sections from the central mass-dependent trend for unmodified peptides. The ISPs and scores tabulated for 100 more common PTMs enable predicting the domains for modified peptides in the IMS/MS space that would guide subproteome investigations. Graphical Abstract ?. PMID- 27975329 TI - Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9. AB - The phenotypic axis of invasion and proliferation in malignant glioma cells is a well-documented phenomenon. Invasive glioma cells exhibit a decreased proliferation rate and a resistance to apoptosis, and invasive tumor cells dispersed in brain subsequently revert to proliferation and contribute to secondary tumor formation. One miRNA can affect dozens of mRNAs, and some miRNAs are potent oncogenes. Multiple miRNAs are implicated in glioma malignancy, and several of which have been identified to regulate tumor cell motility and division. Using rat 9 L gliosarcoma and human U87 glioblastoma cell lines, we investigated miRNAs associated with the switch between glioma cell invasion and proliferation. Using micro-dissection of 9 L glioma tumor xenografts in rat brain, we identified disparate expression of miR-9 between cells within the periphery of the primary tumor, and those comprising tumor islets within the invasive zone. Modifying miR-9 expression in in vitro assays, we report that miR 9 controls the axis of glioma cell invasion/proliferation, and that its contribution to invasion or proliferation is biphasic and dependent upon local tumor cell density. In addition, immunohistochemistry revealed elevated hypoxia inducible factor 1 alpha (HIF-1alpha) in the invasive zone as compared to the primary tumor periphery. We also found that hypoxia promotes miR-9 expression in glioma cells. Based upon these findings, we propose a hypothesis for the contribution of miR-9 to the dynamics glioma invasion and satellite tumor formation in brain adjacent to tumor. PMID- 27975330 TI - An integrated approach to monitoring ecosystem services and agriculture: implications for sustainable agricultural intensification in Rwanda. AB - Maintaining the long-term sustainability of human and natural systems across agricultural landscapes requires an integrated, systematic monitoring system that can track crop productivity and the impacts of agricultural intensification on natural resources. This study presents the design and practical implementation of a monitoring framework that combines satellite observations with ground-based biophysical measurements and household surveys to provide metrics on ecosystem services and agricultural production at multiple spatial scales, reaching from individual households and plots owned by smallholder farmers to 100-km2 landscapes. We developed a set of protocols for monitoring and analyzing ecological and agricultural household parameters within two 10 * 10-km landscapes in Rwanda, including soil fertility, crop yield, water availability, and fuelwood sustainability. Initial results suggest providing households that rely on rainfall for crop irrigation with timely climate information and improved technical inputs pre-harvest could help increase crop productivity in the short term. The value of the monitoring system is discussed as an effective tool for establishing a baseline of ecosystem services and agriculture before further change in land use and climate, identifying limitations in crop production and soil fertility, and evaluating food security, economic development, and environmental sustainability goals set forth by the Rwandan government. PMID- 27975331 TI - Historical and seasonal dynamics of phosphorus mobility in Sancha Lake of Southwest China's Sichuan Province. AB - Phosphorus (P) fractionations in the surface sediment of Sancha Lake in China's southwestern Sichuan Province were examined to assess the potential P release at the water-sediment interface and to understand its seasonal (2009-2010) and historical dynamics (1989-2010) in the surface water. Elevated P concentrations were detected in the sediment at main reservoir inflow, south canal of the Dujiangyan irrigation network, and intensive cage fish farming area, accounting for 32 and 40% of current total P discharges. The highest total P concentration (11,200 MUg P g-1) was observed in the upper sediment below intensive fish farming area with a specific enrichment of HCl-P (51% of total P) mainly from fish feeds and feces. These sediments had larger MgCl2-P pools with higher diffusive P fluxes (0.43-0.47 mg m-2 d-1) from surface sediment than those from other areas (0.25-0.42 mg m-2 d-1). The general small proportion of MgCl2-P (5.7 10%) and low diffusive P fluxes from surface sediment (<0.02% of sediment P storage (0-1 cm)) indicate low mobility and slow release of P from sediments. The sediment as an internal P source led to a 3-4-year lag for P concentration decrease in the surface water after restriction of anthropogenic P discharges since 2005. Thus, the peak P concentration in April and September could be explained as a combined effect of supplementing internal loading via reductive processes in sediments and seasonal water vertical circulation in the early spring and fall. Policy played a crucial role in reducing P inputs to the lake. PMID- 27975333 TI - Re: "Two Minds with but a Single Thought ...". PMID- 27975334 TI - Reply by the Authors of the Original Article. PMID- 27975332 TI - Traffic noise mapping of Indian roads through smartphone user community participation. AB - Road traffic noise pollution is a global hazard, and rapid urbanization has aggravated the problem. This paper explores a novel approach which involves a smartphone user community to monitor the prevalent noise. The system involves a client application on smartphones that records noise, processes the information and communicates to a server and shares the information as visual noise levels on Google(r) Maps. A fuzzy logic-based classification of noise is proposed. Results from residential, commercial, and industrial areas of the northern region of India are demonstrated. The noise levels are generally found to be higher than the prescribed standards. The experiment demonstrates the huge potential of user community participation in monitoring noise pollution. PMID- 27975335 TI - Tommaso Falcone, MD, FRCS(C), FACOG. PMID- 27975336 TI - Growth rate of small pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: results from an endoscopic ultrasound based cohort study. AB - Background and aims In multiple endocrine neoplasia type 1 (MEN1), endoscopic ultrasound (EUS) is used for identification and follow-up of pancreatic neuroendocrine tumors (PNETs). The role of EUS in surveillance of small ( < 20 mm) PNETs is unclear, mostly because the natural course of these lesions is largely unknown. We aimed to determine annual growth and incidence rate of small PNETs in patients with MEN1 using EUS-based surveillance. Patients and methods Linear array EUS procedures in patients with MEN1 between 2002 and 2015 were identified. Number, size, and location of PNETs were recorded. Annual growth of PNETs < 20 mm identified at the initial EUS ("prevalent" PNETs) and during follow up ("incident" PNETs) was calculated using mixed model linear regression analysis. Results A total of 54 patients were identified and 38 patients were included. In all, 226 PNETs were identified (median size 5.0 mm, interquartile range 3.7 - 7.5) of which 124 (55 %) were prevalent and 102 (45 %) were incident PNETs. Annual incidence rate was 0.79 PNETs/year (95 % confidence interval [CI] 0.73 to 0.87). Overall growth rate was 0.10 mm/year (95 %CI 0.02 to 0.19; P = 0.01); PNETs < 10 mm (n = 198) did not grow (P = 0.23), whereas PNETs >= 10 mm (n = 28) grew 0.44 mm/year (95 %CI 0.10 to 0.78; P = 0.01). Prevalent PNETs grew 0.21 mm/year (95 %CI 0.10 - 0.32; P < 0.001), whereas incident PNETs did not grow (P = 0.26). Conclusions The annual growth rate of small, solid PNETs in patients with MEN1 is lower than previously thought. Surveillance intervals could probably be prolonged without compromising safety. PMID- 27975337 TI - Hospital volume and adverse events following esophageal endoscopic submucosal dissection in Japan. AB - Background and study aims Esophageal endoscopic submucosal dissection (ESD) has gradually acquired popularity as a minimally invasive surgery for early cancers not only in Japan, but also in other countries. However, most reported outcomes have been based on relatively small samples of patients from specialized centers. Therefore, the association between hospital volume and the rate of adverse events following esophageal ESD has been poorly understood. Patients and methods Using a nationwide administrative database in Japan, we identified patients who underwent esophageal ESD between 1 July 2007 and 31 March 2013. Hospital volume was defined as the number of esophageal ESD procedures performed per year at each hospital and was categorized into quartiles. Results In total, 12 899 esophageal ESD procedures at 699 institutions were identified during the study period. Perforation and perforation-related disorders were observed in 422 patients (3.3 %), and one patient died after perforation. There was a significant association between a lower hospital volume and a higher proportion of adverse events following esophageal ESD. Although not statistically significant, a similar tendency was observed in the occurrence of blood transfusion within 1 week after ESD and all-cause in-hospital death. Multivariable logistic regression analysis showed that hospitals with very high case volumes were less likely to experience adverse events following esophageal ESD than hospitals with very low volumes. Conclusions The proportion of perforation and perforation-related disorders following esophageal ESD was permissibly low, and there was a linear association between higher hospital volume and lower rates of adverse events following esophageal ESD. PMID- 27975338 TI - [Use of Mental Health Service Among Young Adults on Unemployment Benefit Before and after Receiving Counseling at a Psychiatric Liaison Department]. AB - OBJECTIVE: To determine mental health service utilization before and after consultation of a psychiatric liaison service ("Support 25") among youths aged 16 24 years suffering from mental disorders and receiving unemployment benefits. METHODS: Longitudinal registration of mental health service use over a 9-month period (N=148); measurement of possible moderators with questionnaires and rating scales. RESULTS: Mental health service utilization increased from initially 22% to 40% and 47.5% 3 and 6 months after receiving individual treatment recommendation. Low-threshold psychosocial counseling was frequented more often than specific psychiatric or psychotherapeutic treatment. Subjects who contacted mental health services showed a trend towards a lower level of psychosocial functioning than subjects who did not seek treatment. Stigma-related factors did not hinder mental health service use. CONCLUSIONS: Despite a high degree of psychiatric morbidity, the surveyed sample of unemployed youths had problems to successfully enter mental health services. Although a substantial increase in service use was observed after receiving psychoeducational information at a psychiatric liaison service, the use of low-threshold counseling predominated. This finding suggests that the mental health system should adapt better to the specific needs of young unemployed, for example, by expanding low-threshold psychiatric pre-treatment offers at vocational centers. PMID- 27975339 TI - [Cross-Sectional Analysis of the Health and Social Structure in Germany]. AB - This research was conducted to find out if there are differences in health and social structure and, thus, living conditions within Germany on a federal state level. So far, research projects have mainly focused on either more aggregate or more small-scale, regional planning areas. However, due to the political, governmental, and institutional structures prevalent in Germany, it seems necessary to conduct health and social structure analyses not only on the macro and micro but also on the meso level. This would enable meeting the specific information requirements of all existing German political spheres and public health planning levels comprehensively. A set of 53 indicators taken from official German statistics was used to conduct a factor analysis. The latter revealed that the health and social structures could be thoroughly depicted by a total of 3 factors (indices) that, in total, explain roughly 80% of the total variance. In this case, the first index accounts for about 38%, the second for about 31%, and the third index explain roughly 11%. Testing the results through hierarchical as well k-Means cluster analyses provided additional confirmation. Overall, the results show great differences in health and social structures in Germany on a federal state level. In addition, a more in-depth look at the nature of the results shows that one needs to distinguish between 4, or rather even a total of 8 subregions. Most importantly, these findings reveal that the frequently and widely discussed East-West discrepancies do not enable an adequately differentiated approach to this issue. Rather, aside from aspects such as federal city state and state area differences, structures in Germany show several different and highly significant types of North-South divides. PMID- 27975340 TI - [History of Aniridia]. PMID- 27975341 TI - Refractive Lenticule Implantation for Correction of Ametropia: Case Reports and Literature Review. AB - The ReLEx(r) technique allows correction of refractive errors through the creation and extraction of refractive stromal lenticules. Contrary to excimer laser corneal refractive procedures, where the stromal tissue is photoablated, the extracted lenticules obtained with ReLEx(r) can be preserved. Recent studies and case reports have described autologous re-implantation and allogeneic implantation of refractive lenticules into femtosecond-laser created stromal pockets in order to reverse the refractive outcome of a myopic corneal refractive procedure, correct hyperopia, aphakia, presbyopia and treat keratoconus. The use of stromal lenticules has also been described for therapeutic purposes, with an allogenic lenticule being transplanted under a LASIK flap in order to restore corneal volume and reduce the refractive error in a case of excessive stromal tissue removal after LASIK. This review summarises the results of the latest case reports and studies that describe the implantation of cryopreserved or fresh refractive stromal lenticules and discusses the feasibility, safety and refractive outcomes of the procedure, on the basis of published literature as well as our own experience. PMID- 27975343 TI - Need for Better Diabetes Treatment: The Therapeutic Potential of NMDA Receptor Antagonists. AB - Diabetes mellitus is the most common metabolic disorder in children and adolescents. Optimal control of blood glucose concentration is essential to prevent acute and diabetic long-term complications. The options to treat diabetes have clearly improved over the last decades, however, to date neither type 1 diabetes nor type 2 diabetes mellitus can be cured. Therefore, diabetes research aims at developing beta-cell protective agents that prevent or even reverse diabetes onset. N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are widely expressed in the central nervous system (CNS) where they hold central roles in CNS function. NMDAR dysfunction is associated with several neurological and psychiatric disorders and therefore NMDAR modulators have several potential therapeutic indications. Only little is known about the role of pancreatic NMDA receptors. Our data provide evidence that inhibition of pancreatic NMDARs, either genetically or pharmacologically with the over-the counter drug dextromethorphan, increases glucose-stimulated insulin secretion from mouse and human pancreatic islets, improves glucose tolerance in mice and individuals with diabetes and promotes islet cell survival under diabetogenic conditions. Thus, our data indicate for the first time that NMDAR antagonists could serve as adjunct treatment for diabetes mellitus. The development of a safe, blood glucose lowering and particularly beta-cell protective medication would significantly enhance current diabetes treatment. PMID- 27975342 TI - Health-Related Behaviour Among Children of Childhood Cancer Survivors in Germany. AB - Purpose: Childhood cancer survivors fear that previous therapy could not only impair their own but also their children's health. We examined whether health related behaviour in children of childhood cancer survivors differs from the general population. Methods: Our first nationwide survey wave (2013-2014) surveyed offspring health in 396 German childhood cancer survivors known to have a child of their own. Answers about health behaviour were analysed using descriptive statistics. Data were collected for 418 offspring and 394 could be integrated for matched-pair analyses with data from the German general population (KIGGS, n=17 641). Results: Teeth-cleaning routine, body-mass-index or subjective body image evaluation by parents were no different from children in the general population. Parents who included a cancer survivor smoked less in the presence of their children (p=0.01). During pregnancy, mothers in cancer survivor parent pairs abstained from drinking alcohol more often (p=0.01) and smoked less (p=0.05). While the calculated effect sizes (Phi) were generally low (0.135 0.247), children from cancer survivors played less outdoors than peers did (p=0.01). Boys participated in sports outside a club more often (p=0.05) and watched less TV on weekdays (p=0.01) and girls spent more time on the computer during weekdays than peers did (p=0.01). Conclusions: This study provides the first data for health-related behaviour in cancer survivors' offspring and sheds light on differences to parenting in the general population. Multivariate analyses in a larger study population are needed to relate these differences to fear issues in cancer survivors. PMID- 27975345 TI - ? PMID- 27975344 TI - [Current Practice of Pre- and Postnatal Screening and Future Developments for Evidence Based Guidelines]. AB - Objectives: In this selective review we provide an overview of the current pre- and postnatal screenings up to 18 years established in Germany to inform physicians of different medical fields (gynecologists, pediatricians, general practitioners, other medical specialists who treat children, adolescents or pregnant females). Current State: Research on screening for different types of cancer has frequently failed to show any benefit. Thus, there is a need to broaden the evidence basis related to medical screenings especially for children and adolescents. Outlook: Potential future developments of pre- and postnatal screenings are illustrated including their social impact. The lack of an early detection of mental health problems is pointed out. An interdisciplinary collaboration and research is required to accumulate evidence with regard to medical screenings and to consider health economic and ethical aspects. PMID- 27975346 TI - ? PMID- 27975347 TI - ? PMID- 27975348 TI - ? PMID- 27975349 TI - ? PMID- 27975350 TI - Diagnosis of Neuropathic Components in Patients with Back Pain Before and After Surgery. AB - Background: The perception of back pain subjective is hard for physicians to measure. For this reason, questionnaires are an important instrument to evaluate the pain 1. The main point of this study was to verify differentiation of pain symptoms in patients with different pain mechanisms. The most important parameter was the PainDetect questionnaire, which can differentiate between nociceptive and neuropathic pain. Additional parameters were measured before and after surgery to characterise pain symptoms in detail. Material and Methods: We selected patients with diagnosed vertebral compression fracture, herniated disc or with spinal cord compression. To characterise the preoperative condition on admittance, we collected the data from the physical examination, as well as clinical data, including X-ray, CT and MRI. To characterise the pain, we used the painDetect questionnaire, the Oswestry Index questionnaire (ODI) and the visual analogue scale (VAS). Depending on the diagnosis, patients were treated by surgery (radiofrequency kyphoplasty, nucleotomy, spondylodesis). At 2 to 3 days and 6 months after surgery, we repeated the questionnaire and compared the results with those before the operation. Data on patient satisfaction and adverse events were also collected. Results: This study included 62 patients with vertebral compression fracture (group 1: VBF, 89 % female, mean age 71 years) and 77 patients with herniated disc or spinal cord compression (group 2: non-VBF, 55 % female, mean age 53 years). There was no difference between both groups in preoperative pain intensity (acute, maximum, average): median ordinal scale 0 to 10; group 1: 6, 8, 7; group 2: 6, 9, 7. The total score in the painDetect questionnaire differed significantly between the two groups (median group 1 = 9, group 2 = 17; effect size r = 0.5; p = 0.000). The existence of neuropathic pain was presumed (> 90 %) in 3 % of the patients in group 1 and in 13 % of patients it was not excluded. In contrast, in group 2 it was presumed (> 90 %) in 43 % of patients and in 30 % of patients it could not be excluded. Patients with vertebral compression fracture had greater pain intensity (VAS 71) than patients from group 2 (VAS 53). There was no difference in the total score of the Oswestry questionnaire between the two groups (56 % vs. 58 %). Pain intensity was significantly reduced in both groups after the operations. Six months postoperatively, pain intensity (median ordinal scale 0 to 10; acute, maximum, average) was 2, 5, 3 in group 1 and 2, 4, 2 in group 2. Moreover, the final scores of the painDetect questionnaires were significantly lower in both groups after the operations (4 in both groups). The median score of the ODI was reduced in both groups, with an effect size of 0.6. 98 % of the patients in group 1 and 94 % in group 2 were satisfied with the outcome of the operation. Conclusion: The preoperative pain characteristics of patients with vertebral compression fracture is different from those of patients with herniated disc or with spinal cord compression. 43 % of patients in group 2 exhibited a neuropathic pain component and in 30 % this could not be excluded. In contrast, in group 1 only 3 % of the patients exhibited a neuropathic pain component. Postoperatively, pain symptoms were significant reduced in both groups, so that the risk of chronic pain was considerably less. PMID- 27975351 TI - [3D Fluoroscopy-Navigated Magerl Fusion of the 1st and 2nd Cervical Vertebra]. AB - Background: Treatment of type II fractures of the odontoid process is still controversial. Besides conservative treatment, there are surgical options, including anterior screw fixation, as first described by Bohler and Magerl, or procedures using a dorsal approach. Many authors prefer dorsal fusion of C1 and 2, due to the reliable, biomechanical stability. In this context, pedicle screw fixation, as described by Harms, and transarticular screw fixation of the atlantoaxial joints, as described by Magerl, have to be mentioned. With the use of intraoperative fluoroscopic navigation, the risk of neurovascular lesions caused by abortive drilling or malposition of screws has been significantly decreased. In 1993, Eysel and Roosen established a subclassification of type II fractures of the odontoid process and gave treatment recommendations for each of the three subtypes. While there was an outcome for type A and B fractures treated by anterior screw fixation, the authors recommended performing dorsal stabilisation at type C fractures. Indication: In accordance with the recommendations of Eysel and Roosen, an 82 year old man, suffering from a type II C fracture of the odontoid process, underwent navigated, transarticular screw fixation of C1 and C2. Method: Once the 3D-fluoroscopy scan had been performed, the correct drilling direction in the axial, coronary and sagittal views of C1 and 2 was found using the navigated drillguide. After K-wires had been inserted in this direction on both sides, a second 3D-scan was performed to recontrol placement of the K-wires. Cannulated screws were introduced and the rods were installed, bearing the atlas hook to fixate the posterior atlas. Conclusion: In summary, dorsal, transarticular fusion of C1 and C2 is a successful treatment option, rarely leading to complications and is accompanied by reduced radiation exposure to the operating team. PMID- 27975352 TI - [Periprosthetic Femoral Fractures: Classification and Therapy]. AB - Periprosthetic femoral fractures can be categorized into proximal fractures around a hip stem or distally around a knee arthroplasty. This paper focuses on the proximal periprosthetic fractures. It is important to classify the fracture at diagnosis and to perform accurate planning of the surgery. Basically it is necessary to decide if the implant is fixed or loose, in the latter case a revision surgery including the change of the endoprosthesis is neccessary. If the implant is fixed an open reduction and internal fixation can be done. All implants have to be available on site because in the course of the intervention the plan could change. Due to rising numbers of primary arthroplasties and more elderly patients an increase of periprosthetic fractures can be expected. The treatment of periprosthetic fractures is an economic and surgical challenge. It is important to provide competence for these cases concerning both operative techniques and interdisciplinary treatment. PMID- 27975353 TI - [Lifespan of Doctorate and Non-doctorate Physicians in Northrine]. AB - AIM: The purpose of this study was to evaluate the lifespan of physicians in North Rhine depending on the criterion if they had graduated with a Dr. med. thesis under German law or not. North Rhine is part of the German federal state North Rhine-Westphalia. METHODS: The date of birth and date of death of 1133 deceased physicians from the journal of the medical association of North Rhine were recorded according to their doctoral degree from January 2013 until June 2016 inclusive. For the calculation of their length of life, the descriptive statistics and for further statistical analysis, the R program 1 was applied. RESULTS: Physicians with a doctoral degree under German law (Dr. med.) reached an average age of 80.9 +/- 12.1 years whereas physicians without a dissertation reached an age of 67.6 +/- 13.8 years, on average. After correction for year of birth no significant difference between the average lifespan of the two groups could be found. CONCLUSION: The analysis of the survival data of deceased physicians showed a much longer length of life if they had graduated with a doctoral thesis under German law, which was not significant after a year of birth correction. For every statistical analysis possible confounders need to be considered. PMID- 27975354 TI - [Microbiome and winter flab]. AB - The tendency to increased body fat storage depends on microbiota. Their composition follows a natural annual rhythm, as apparent by hibernating animals and humans living close to nature. Life shaped by "western industrialization", including microbiome shocks such as antibiotics, low-fiber and low-bacteria diets combined with the consumption of industrialized food leads to the loss of bacterial species in the body. This induces deficiency symptoms, diseases and results in lower energy yields from food. It might also result in the loss of intestinal mucous and "leaky gut". Inflammation then contributes to dyslipidemia and obesity. The diversity of microbial species is transmitted to the offspring. Humans living in close touch with nature have a significantly higher bacterial diversity than people in the "developed world". Microbiome therapy including thorough chewing, established meal rhythms, healthy high-fiber diet and strategic intake of bacteria can regenerate this effects. PMID- 27975355 TI - [Christmas from an allergist's perspective]. AB - The customs and traditions associated with Christmas may result in allergic reactions to allergens that are typical for this period. On the one hand the rise in prevalence of allergic diseases has continued in the industrialized world for the last decades and allergies are regarded as widespread diseases. On the other hand the 21th century is a time of "allergy delusion". This review summarizes the facts about allergic reactions to Christmas typical decoration, food and behavior. Taken together, allergic reactions to Christmas tree, poinsettia, Christmas cactus, perfumed candles, Christmas typical food, common gifts like mobile phones and laptops, frankincense, myrrh and pollens have been described but in very rare instances. The chance to survive Christmas without allergic symptoms is high, particularly for non-atopics. PMID- 27975356 TI - [Is nutritional obesity a substance use disorder?] AB - Today, food addiction has become an increasing area of research. Multiple studies aim to characterize individuals in terms of food addiction based on the assumption, that hyperpalatable foods rich of salt, sugar and fat may induce a cluster of behavioral changes that may resemble a substance use disorder, despite the fact that to date there is no evidence, that nutritional factors lead to an addictive eating-like behavior in humans. In this review article, we aim to introduce the basic experiments, that build the framework upon which food addiction is being investigated and to critically discuss the concept of food addiction. PMID- 27975357 TI - [Light and Medicine]. AB - There would be no life without light. The rotation of the earth around its axis has introduced the development of biological clocks in all living subjects regulating all functions of the body. The rhythms best described are the 24 hour/circadian and the seasonal rhythms. The rhythmic composition around the body clock has great impact on health and disease, both in diagnostics and treatment. Nowadays, bright light, e.g. in seasonal affective disorder, can be regarded as a drug, being even more effective than selective serotonin reuptake inhibitors. PMID- 27975358 TI - [Music in health promotion and therapeutic practice. Cultural, theoretical and clinical perspectives.] AB - Music can serve as a shelter and music therapy can provide spaces for symbolic experience and the modification of behavioural and cognitive patterns. Explaining the power of music, ancient theories speak of an analogy between music and man. Similar views are also found in modern music therapy such as Sound Work, a voice body-based model. Complementary to the aspect of analogy, the principle of transformation is of vital importance, such as the transitions between the five elements, the solid organs and the pentatonic scale in Chinese music therapy, for instance. Distinct modes of matter-mind-transitions define the theoretical framework of neuro-psychologically based music therapy. A triadic model encompassing neuro-endocrine, psychological and aesthetic facets explains the preventive and therapeutic effect of music in stress-associated disorders and burnout. Finally, a new voice-based model (Arion Psychovocal Therapy) is presented. Integrating anthropological theories, anatomical perspectives of movement, and artistic features it focuses on psychiatry, psycho-prevention, and public health and highlights the interdisciplinary nature of music in medicine. PMID- 27975359 TI - [The Makropulos affair or the nightmare of eternal life]. PMID- 27975361 TI - [Monastery Medicine - What's the story behind it? What's reasonable, what's no good?] AB - "Monastery medicine" refers to the traditional medieval European medicine, which was above all in the hands of monks and nuns. We warn against the uncritical application of the historical treatment recommendations, such as by Hildegard von Bingen, as herbal humoralpathological drugs are not always harmless. Modern phytotherapy, however, is well-founded in science. Combined with adapted monastic elements such as dietetics and regulative therapy, as the basis of a "new monastery medicine", it can be used as a supplement to academic medicine. PMID- 27975360 TI - [Denial of pregnancy]. AB - With an incidence of 1:500, denial of pregnancy is a rather frequent incident in obstetrics. Strikingly, in our society, this issue is placed under a taboo. Reasons might be our moral values and socialization. Since pregnancy and motherhood have to be associated with joy, other sensations are often perceived as socially not accepted and thus denied. A similar phenomenon exists e. g. with postnatal depression.In all existing studies on denial of pregnancy, it was proven that there are no significant at-risk groups. Instead, it occurs in all social and educated classes and no association with parity was shown.Psychologically, the denial can be understood as an adaptive or anxiety disorder. Unconsciously, it serves as a defense mechanism against intrapsychic conflicts. Reinterpretation of physical changes allow sustained unconscious and thus conflict even in the presence of fetal movements and while body weight and abdominal girth are increasing.Lacking and insufficient preventive examinations increase risks for mother and child. Especially, when delivery takes place without professional help.The earlier the pregnant woman realizes her condition, if necessary with help from a reference person or medical personnel, the lower the risks. This implies to train detection and overcome fear of addressing the woman. After the pregnancy is revealed, the woman needs to be integrated into a social network, which conveys that denial of pregnancy is not a psychotic symptom and occurs more often than assumed. If this succeeds, the perspective for mother and child is favorable. PMID- 27975362 TI - [Religiosity and Mental Health]. AB - Since 1978, two systematic evidence-based reviews of the available data on religiosity and mental health in the field of psychiatry have been done. More than 70 % found a relationship between level of religious/spiritual involvement and less mental disorder (positive), some found mixed results (positive and negative), and only about 5 % reported more mental disorder (negative), as was originally suggested by Sigmund Freud. There is good evidence that religious involvement is correlated with better mental health in the areas of depression, substance abuse, and suicide; some evidence in stress-related disorders and dementia; insufficient evidence in bipolar disorder and schizophrenia, and no data in many other mental disorders. PMID- 27975363 TI - [Reducing viral load in life-threatening viral diseases using snowdrops]. AB - In the case of life-threatening viral diseases, viral load is associated with mortality. A new and innovative therapeutic approach is the reduction of viral load by extracorporeal elimination without simultaneously weakening the immune system by removing specific antibodies. Basis of this therapy is a modified plasma filter coated with a lectin derived from the snowdrop. PMID- 27975364 TI - [Natural science vs. natural philosophy: Friedrich Theodor von Frerichs and the emergence of modern western medicine in the 19th century]. AB - The beginnings of modern western medicine reach to about 1800 when under the liberating influence of French Revolution observation of diseases was started to follow more scientifically justified criteria. At that time speculative doctrines prevailed, e. g. those set up natural philosopher Schelling. In this context Internist Friedrich Theodor von Frerichs at Berlin Charite University Hospital gained great merits because of his struggle for a scientifically-based experimental clinical medicine. This is demonstrated nicely in a recently found autograph document. PMID- 27976360 TI - Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injection. AB - BACKGROUND: Embryo transfer (ET) was traditionally performed two days after oocyte retrieval; however, developments in culture media have allowed embryos to be maintained in culture for longer periods. Delaying transfer from Day two to Day three would allow for further development of the embryo and might have a positive effect on pregnancy outcomes. OBJECTIVES: To determine if there are any differences in live birth and pregnancy rates when embryo transfer is performed on day three after oocyte retrieval, compared with day two, in infertile couples undergoing treatment with in vitro fertilisation (IVF), including intracytoplasmic sperm injection (ICSI). SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid) from the inception of the databases to 26th April 2016. We also searched ClinicalTrials.gov and the WHO portal for ongoing trials plus citation lists of relevant publications, review articles and included studies, as well as abstracts of appropriate scientific meetings. SELECTION CRITERIA: Randomised controlled trials that compared Day 3 versus Day 2 embryo transfer after oocyte retrieval during an IVF or ICSI treatment cycle in infertile couples. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information. The primary outcome measures were live birth rate and ongoing pregnancy rate. MAIN RESULTS: We included 15 studies. Fourteen studies reported data per woman (2894 women) and one study reported data per cycle (969 cycles). The quality of the evidence using the GRADE approach ranged from moderate quality to very low quality. The main reasons for downgrading evidence were poor methodological reporting, selective reporting, inconsistency and imprecision. Live birth per woman - Overall, there was no evidence of a difference in live birth rate between Day three and Day two embryo transfer (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.89 to 1.23; three studies, n = 1200 women; I2 = 63%; very low quality evidence). The data suggest that if 32% of women who underwent a Day two embryo transfer had a live birth, then between 28% to 39% of women undergoing a Day three embryo transfer would have a live birth. Ongoing pregnancy per woman - There was no evidence of a difference between Day three and Day two embryo transfer for ongoing pregnancy (RR 0.98, 95% CI 0.85 to 1.12; six studies, n = 1740 women; I2 = 52%; very low quality of evidence). The data suggest that if 33% of women undergoing a Day two embryo transfer had an ongoing pregnancy then between 28% to 37% of women undergoing a Day three embryo transfer would have an ongoing pregnancy. Clinical pregnancy per woman - There was no evidence of a difference between Day three and Day two embryo transfer for the chance of a clinical pregnancy (RR 1.08, 95% CI 0.98 to 1.19; 12 studies, n = 2461, I2 = 51%; very low quality evidence). The data suggest that if 39% of women undergoing Day two embryo transfer had a clinical pregnancy, then between 38% to 46% of women undergoing a Day three embryo transfer would have a clinical pregnancy. Multiple pregnancy per woman - There was no evidence of a difference between Day three and Day two embryo transfer for the risk of a multiple pregnancy (RR 1.12, 95% CI 0.86 to 1.44; eight studies, n = 1837; I2 = 0%; moderate quality evidence). The data suggest that if 11% of women undergoing Day two embryo transfer had a multiple pregnancy, then between 9% to 15% of women undergoing a Day three embryo transfer would have a multiple pregnancy. Miscarriage rate per woman - There was no evidence of a difference between Day three and Day two embryo transfer for the risk of miscarriage (RR 1.16, 95% CI 0.84 to 1.60; nine studies, n = 2153 women, I2 = 26%; moderate quality evidence). The data suggest that if 6% of women undergoing Day two embryo transfer had a miscarriage, then between 5% to 10% of women undergoing a Day three embryo transfer would have a miscarriage. Ectopic pregnancy rate per woman - There was no evidence of a difference between Day three and Day two embryo transfer for the risk of ectopic pregnancy (RR 0.99, 95% CI 0.29 to 3.40; six studies, n = 1531 women, I2 = 0%; low quality evidence). The data suggest that if 0.7% of women undergoing Day two embryo transfer have an ectopic pregnancy, then between 0.2% to 2% of women undergoing Day three embryo transfer would have an ectopic pregnancy.Subgroup analysis for pregnancy outcomes did not identify any differential effect between IVF and ICSI.None of the included studies prespecified complication rate (e.g. OHSS), fetal abnormality or women's evaluation of the procedure as outcomes in their studies. AUTHORS' CONCLUSIONS: Twelve of 15 studies contributed data that could be included in meta-analyses. The quality of the evidence ranged from moderate to very low. Only three of the 15 studies reported data for live birth, although the data for ongoing pregnancy and clinical pregnancy are consistent with the live birth data, suggesting no difference between Day three and Day two embryo transfer for these outcomes. There was no evidence of a difference identified between Day three and Day two embryo transfer for multiple pregnancy, miscarriage or ectopic pregnancy per woman randomised. No data were reported for complication rate, fetal abnormality or woman's evaluation of the procedure. The current evidence has not identified any evidence of differences in pregnancy outcomes between Day two and Day three embryo transfers. Any further studies comparing these timings of embryo transfer are unlikely to alter the findings and we suggest that this review no longer be updated. PMID- 27976361 TI - Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. AB - BACKGROUND: Nasal continuous positive airway pressure (NCPAP) is a strategy for maintaining positive airway pressure throughout the respiratory cycle through the application of bias flow of respiratory gas to an apparatus attached to the nose. Treatment with NCPAP is associated with decreased risk of mechanical ventilation and might be effective in reducing chronic lung disease. Nasal intermittent positive pressure ventilation (NIPPV) is a form of noninvasive ventilation during which patients are exposed intermittently to higher levels of airway pressure, along with NCPAP through the same nasal device. OBJECTIVES: To examine the risks and benefits of early NIPPV versus early NCPAP alone for preterm infants at risk of or in respiratory distress within the first hours after birth.Primary endpoints are respiratory failure and the need for intubated ventilatory support during the first week of life. Secondary endpoints include chronic lung disease (CLD) (oxygen therapy at 36 weeks' postmenstrual age), air leaks, duration of respiratory support, duration of oxygen therapy, intraventricular hemorrhage, and incidence of mortality. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 9), MEDLINE via PubMed (1966 to September 28, 2015), Embase (1980 to September 28, 2015), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to September 28, 2015). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi randomized trials. A member of the Cochrane Neonatal Review Group handsearched abstracts from the European Society of Pediatric Research (ESPR). We contacted the authors of ongoing clinical trials to ask for information. SELECTION CRITERIA: We considered all randomized and quasi-randomized controlled trials. Studies selected compared NIPPV versus NCPAP treatment, starting at birth or shortly thereafter in preterm infants (< 37 weeks' gestational age). DATA COLLECTION AND ANALYSIS: We performed data collection and analysis using the recommendations of the Cochrane Neonatal Review Group. MAIN RESULTS: Ten trials, enrolling a total of 1061 infants, met criteria for inclusion in this review. Meta-analyses of these studies showed significantly reduced risk of meeting respiratory failure criteria (typical risk ratio (RR) 0.65, 95% confidence interval (CI) 0.51 to 0.82; typical risk difference (RD) -0.09, 95% CI -0.13 to 0.04) and needing intubation (typical RR 0.78, 95% CI 0.64 to 0.94; typical RD 0.07, 95% CI -0.12 to -0.02) among infants treated with early NIPPV compared with early NCPAP. The meta-analysis did not demonstrate a reduction in the risk of CLD among infants randomized to NIPPV (typical RR 0.78, 95% CI 0.58 to 1.06). Investigators observed no evidence of harm. Review authors graded the quality of the evidence as moderate (unblinded studies). AUTHORS' CONCLUSIONS: Early NIPPV does appear to be superior to NCPAP alone for decreasing respiratory failure and the need for intubation and endotracheal tube ventilation among preterm infants with respiratory distress syndrome. Additional studies are needed to confirm these results and to assess the safety of NIPPV compared with NCPAP alone in a larger patient population. PMID- 27976362 TI - Differential effects of school experiences on active citizenship among German and Turkish-origin students. AB - While research suggests that schools can foster active citizenship among youth, studies have not tested whether ethnic minority youth may benefit differently from school experiences than ethnic majority youth. In this study of 219 students (138 German majority and 81 Turkish-origin minority; Mage = 18.26; 55% females), we examined the association between different experiences at school and 4 indicators of youth active citizenship, controlling for various socio-demographic characteristics. Although value of social studies was associated with three out of four active citizenship indicators among both ethnic groups, the effects of the other school-related variables on active citizenship were moderated by ethnicity. Specifically, indicators of classroom climate, such as open classroom climate and classroom community, were only associated with greater active citizenship among Turkish-minority youth, while participatory factors, such as engagement in school decisions, were only associated with active citizenship among native German youth. PMID- 27976363 TI - Acute skin and hair symptoms followed by severe, delayed eye complications in subjects using the synthetic opioid MT-45. AB - BACKGROUND: The introduction of unclassified new psychoactive substances (NPS) on the recreational drugs market through open online sale ('legal highs' or 'Internet drugs') continues unabated and represents a growing health hazard. The use of NPS has resulted in numerous, severe, adverse events and fatalities, due to unintended overdose or unknown toxic side-effects. OBJECTIVES: To try to find a possible common underlying cause for the skin-hair-eye symptoms complex observed in three men. METHODS: From late 2013 to mid-2014, three Swedish men aged 23-34 years with a history of recreational drug use independently presented with similar and very remarkable clinical signs, requiring extensive examination and prolonged treatment. RESULTS: Common clinical signs included hair depigmentation, hair loss, widespread folliculitis and dermatitis, painful intertriginous dermatitis, dry eyes, and elevated liver enzymes. Two of them also showed transverse white Mees' lines (leukonychia striata) on the fingernails and toenails, suggesting a temporary, drug-induced, disorganized keratinization. The clinical signs gradually disappeared over time. However, later on, two developed severe bilateral secondary cataracts requiring surgery. Because drug tests within the Swedish STRIDA project had demonstrated intake of the NPS opioid MT-45 in all patients, this was suspected to be the common causative agent. CONCLUSIONS: These cases highlight the importance for physicians and health professionals to consider the increasing number of novel, untested recreational drugs, as a potential cause of unusual and otherwise unrecognized clinical signs and symptoms. PMID- 27976364 TI - Transgenic modification of potato pectic polysaccharides also affects type and level of cell wall xyloglucan. AB - BACKGROUND: Genes encoding pectic enzymes were introduced into wild-type potato Karnico. Cell wall materials were extracted from Karnico and transgenic lines expressing beta-galactosidase (beta-Gal-14) or rhamnogalacturonan lyase (RGL-18). Pectic polysaccharides from the beta-Gal-14 transgenic line exhibited rhamnogalacturonan-I structural elements with shorter galactan side chains, whereas the RGL-18 transgenic line had less rhamnogalacturonan-I structures than Karnico. Xyloglucan in primary cell walls interacts with pectin and other cell wall polysaccharides and controls cell growth. RESULTS: Xyloglucan extracts from transgenic lines had different levels of monosaccharides compared to wild-type. Most XXGG-type xyloglucans from Karnico and RGL-18 alkali-extractable extracts predominantly consisted of XXGG and XSGG building blocks. Karnico and RGL-18 4 mol L-1 extracts had small proportions of the XXXG-type xyloglucan, whereas beta Gal-14 extracts also contained the XXXG-type xyloglucan. The peak ratios of XSGG/XXGG were 1.9, 2.4 and 1.1 for 4 mol L-1 extracts of Karnico, RGL-18 and beta-Gal-14 lines, respectively. CONCLUSION: After transgenic modification on pectin, the xyloglucan building blocks may have been changed. The beta-Gal-14 lines mostly present XXXG-type repeating units instead of the XXGG-type in 4 mol L-1 extracts. The ratio of XSGG/XXGG repeating units also changed, indicating that the transgenic modification of pectin altered xyloglucan structure during plant development. (c) 2016 Society of Chemical Industry. PMID- 27976365 TI - Heterotopic vascularized lymph node transfer to the medial calf without a skin paddle for restoration of lymphatic function: Proof of concept. AB - BACKGROUND: The use of heterotopic vascularized lymph node transfer (HVLNT) for the treatment of lower extremity lymphedema is still evolving. Current techniques, either place the lymph nodes in the thigh without a skin paddle or at the ankle requiring an unsightly and often bulky skin paddle for closure. We explored the feasibility of doing a below-knee transfer without a skin paddle using the medial sural vessels as recipient vessels and report our experience in 21 patients. METHODS: A retrospective review of all patients who underwent HVLNT to the medial calf was performed. Postoperative magnetic resonance angiography (MRA) and lymphoscintigraphy (LS) were analyzed to assess lymph node viability and function after transfer. RESULTS: Twenty-one patients underwent HVLNT to the medial calf. Postoperative imaging was performed at an average of 11 months after surgery. Thirteen patients had postoperative MRA, of whom 12 demonstrated viable lymph nodes. Seven patients underwent postoperative LS, of whom three demonstrated uptake in the transferred nodes. In the other four patients, the injectate failed to reach the level of the proximal calf. CONCLUSION: We provide proof of concept that HVLNT to the lower leg using the medial sural vessels without a skin paddle can result in viable and functional lymph nodes in the setting of lower extremity lymphedema. J. Surg. Oncol. 2017;115:90-95. (c) 2016 Wiley Periodicals, Inc. PMID- 27976366 TI - Proteomic signatures reveal a dualistic and clinically relevant classification of anal canal carcinoma. AB - Aetiologically linked to HPV infection, malignancies of the anal canal have substantially increased in incidence over the last 20 years. Although most anal squamous cell carcinomas (SCCs) respond well to chemoradiotherapy, about 30% of patients experience a poor outcome, for undetermined reasons. Despite cumulative efforts for discovering independent predictors of overall survival, both nodal status and tumour size are still the only reliable factors predicting patient outcome. Recent efforts have revealed that the biology of HPV-related lesions in the cervix is strongly linked to the originally infected cell population. To address the hypothesis that topography also influences both gene expression profile and behaviour of anal (pre)neoplastic lesions, we correlated both proteomic signatures and clinicopathological features of tumours arising from two distinct portions of the anal canal: the lower part (squamous zone) and the more proximal anal transitional zone. Although microdissected cancer cells appeared indistinguishable by morphology (squamous phenotype), unsupervised clustering analysis of the whole proteome significantly highlighted the heterogeneity that exists within anal canal tumours. More importantly, two region-specific subtypes of SCC were revealed. The expression profile (sensitivity/specificity) of several selected biomarkers (keratin filaments) further confirmed the subclassification of anal (pre)cancers based on their cellular origin. Less commonly detected compared to their counterparts located in the squamous mucosa, SCCs originating in the transitional zone more frequently displayed a poor or basaloid differentiation, and were significantly correlated with reduced disease-free and overall survivals. Taken together, we present direct evidence that anal canal SCC comprises two distinct entities with different cells of origin, proteomic signatures, and survival rates. This study forms the basis for a dualistic classification of anal carcinoma, with implications for management, outcome expectations, and possibly therapy. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27976367 TI - A genetic screen for zebrafish mutants with hepatic steatosis identifies a locus required for larval growth. AB - In a screen for zebrafish larval mutants with excessive liver lipid accumulation (hepatic steatosis), we identified harvest moon (hmn). Cytoplasmic lipid droplets, surrounded by multivesicular structures and mitochondria whose cristae appeared swollen, are seen in hmn mutant hepatocytes. Whole body triacylglycerol is increased in hmn mutant larvae. When we attempted to raise mutants, which were morphologically normal at the developmental stage that the screen was conducted, to adulthood, we observed that most hmn mutants do not survive to the juvenile period when raised. An arrest in growth occurs in the late larval period without obvious organ defects. Maternal zygotic mutants have no additional defects, suggesting that the mutation affects a late developmental process. The developmental window between embryogenesis and the metamorphosis remains under studied, and hmn mutants might be useful for exploring the molecular and anatomic processes occurring during this transition period. PMID- 27976368 TI - Clinical vs. DSM diagnosis of bipolar disorder, borderline personality disorder and their co-occurrence. AB - OBJECTIVE: To investigate the extent and reasons contributing to discrepancies between those receiving a DSM as against a clinical diagnosis of a bipolar disorder (BP) and/or a borderline personality disorder (BPD). METHOD: We interviewed participants previously receiving a BP or BPD diagnosis, studying those who met DSM or clinical criteria for one or both conditions. We compared the numbers of participants allocated to the three diagnostic categories according to rater strategy to calculate concordance rates and determine reasons for discordance. RESULTS: Rates of assignment to BP, BPD and comorbid BP/BPD varied according to the diagnostic strategy. Concordance rates were reduced as BP disorder duration criteria were relaxed, with discordance mainly arising from clinical allocation of a BP disorder for those DSM assigned as unipolar depression. Rates of BPD allocation varied marginally, with discordance mostly arising from so clinically diagnosed receiving a comorbid BP/BPD DSM diagnosis. Finally, DSM overestimated comorbidity compared with clinician diagnoses. Of central importance, not imposing the DSM duration criteria for BP did not increase the prevalence of misdiagnosing BPD, a finding at variance with the literature. CONCLUSION: Rates and reasons for discordance between clinical and DSM diagnosis are detailed, which should assist clinical decision-making. PMID- 27976369 TI - Clomiphene and other antioestrogens for ovulation induction in polycystic ovarian syndrome. AB - BACKGROUND: Subfertility due to anovulation is a common problem in women. First line oral treatment is with antioestrogens such as clomiphene citrate, but resistance may be apparent with clomiphene. Alternative and adjunctive treatments have been used including tamoxifen, dexamethasone, and bromocriptine. The effectiveness of these is to be determined. OBJECTIVES: To determine the relative effectiveness of antioestrogen agents including clomiphene alone or in combination with other medical therapies in women with subfertility associated with anovulation, possibly caused by polycystic ovarian syndrome. SEARCH METHODS: We conducted a search of the Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, and CINAHL (all from inception to August 2016) to identify relevant randomised controlled trials (RCTs). We searched the United Kingdom National Institute for Clinical Excellence (NICE) guidelines and the references of relevant reviews and RCTs. We also searched the clinical trial registries for ongoing trials (inception until August 2016). SELECTION CRITERIA: We considered RCTs comparing oral antioestrogen agents for ovulation induction (alone or in conjunction with medical therapies) in anovulatory subfertility. We excluded insulin-sensitising agents, aromatase inhibitors, and hyperprolactinaemic infertility. DATA COLLECTION AND ANALYSIS: Two review authors independently performed data extraction and quality assessment. The primary outcome was live birth; secondary outcomes were pregnancy, ovulation, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome, and adverse effects. MAIN RESULTS: This is a substantive update of a previous review. We identified an additional 13 studies in the 2016 update. The review now includes 28 RCTs (3377 women) and five RCTs awaiting classification. Five of the 28 included trials reported live birth/ongoing pregnancy. Secondary outcomes were poorly reported.The quality of the evidence ranged from low to very low. The primary reasons for downgrading the evidence were imprecision and risk of bias associated with poor reporting. Antioestrogen versus placebo Live birth rate, miscarriage rate, multiple pregnancy rate, and ovarian hyperstimulation syndrome (OHSS)No data were reported for these outcomes. Clinical pregnancy rateClomiphene citrate was associated with an increased chance of a clinical pregnancy compared with placebo, though the size of the benefit was very uncertain (odds ratio (OR) 5.91, 95% confidence interval (CI) 1.77 to 19.68; 3 studies; 133 women; low-quality evidence). If the chance of a clinical pregnancy was 5% in the placebo group, then between 8% and 50% of women would have a clinical pregnancy in the clomiphene group. Clomiphene citrate versus tamoxifen Live birth rateThere was no clear evidence of a difference in the chance of a live birth between the clomiphene citrate and tamoxifen groups (OR 1.24, 95% CI 0.59 to 2.62; 2 studies; 195 women; low-quality evidence). If 20% of women in the tamoxifen group had a live birth, then between 13% and 40% of women in the clomiphene citrate group would have a live birth. Miscarriage rateThere was no clear evidence of a difference in the chance of a miscarriage between the clomiphene citrate and tamoxifen groups (OR 1.81, 95% CI 0.80 to 4.12; 4 studies; 653 women; low-quality evidence). If 3% of women in the tamoxifen group had a miscarriage, then between 2% and 10% in the clomiphene citrate group would have a miscarriage. Clinical pregnancy rateThere was no clear evidence of a difference in the chance of a clinical pregnancy between the clomiphene citrate and tamoxifen groups (OR 1.30, 95% CI 0.92 to 1.85; 5 studies; 757 women; I2 = 69%; low-quality evidence). If 22% of women in the tamoxifen group had a clinical pregnancy, then between 21% and 35% in the clomiphene citrate group would have a clinical pregnancy. Multiple pregnancy rate There was insufficient evidence of a difference in the chance of a multiple pregnancy between the clomiphene citrate group (OR 2.34, 95% CI 0.34 to 16.04; 3 studies; 567 women; very low-quality evidence). If 0% of women in the tamoxifen group had a multiple pregnancy, then between 0% and 0.5% of women in the clomiphene group would have a multiple pregnancy. OHSSThere were no instances of OHSS in either the clomiphene citrate or the tamoxifen group reported from three studies. Clomiphene citrate with tamoxifen versus tamoxifen alone Clinical pregnancy rateThere was insufficient evidence to determine whether there was a difference between groups (OR 3.32, 95% CI 0.12 to 91.60; 1 study; 20 women; very low quality evidence). No data were reported for the other outcomes. Other comparisons of interestLimited evidence suggested that compared with a gonadotropin, clomiphene citrate was associated with a reduced chance of a pregnancy, ongoing pregnancy, or live birth, with no clear evidence of a difference in multiple pregnancy rates.The comparison of clomiphene citrate plus medical adjunct versus clomiphene alone was limited by the number of trials reporting the comparison and poor reporting of clinical outcomes relevant to this systematic review and by the number of adjuncts reported (ketoconazole, bromocriptine, dexamethasone, combined oral contraceptive, human chorionic gonadotropin, hormone supplementation). The addition of dexamethasone or combined oral contraceptive suggested a possible benefit in pregnancy outcomes, but findings were very uncertain and further research is required to confirm this.There was limited evidence suggesting that a 10-day regimen of clomiphene citrate improves pregnancy outcomes compared with a 5-day regimen. Data for early versus late regimens of clomiphene citrate were insufficient to be able to make a judgement on differences for pregnancy outcomes. AUTHORS' CONCLUSIONS: We found evidence suggesting that clomiphene citrate improves the chance of a clinical pregnancy compared with placebo, but may reduce the chance of live birth or ongoing pregnancy when compared with a gonadotropin. Due to low event rates, we advise caution interpreting these data.The comparison of clomiphene citrate plus medical adjunctive versus clomiphene alone was limited by the number of trials reporting the comparison. The evidence was very low quality and no firm conclusions could be drawn, but very limited evidence suggested a benefit from adjunctive dexamethasone or combined oral contraceptives. Low-quality evidence suggested that a 10-day regimen of clomiphene citrate improves pregnancy rates compared with a 5-day regimen, but further research is required. PMID- 27976370 TI - Droperidol for psychosis-induced aggression or agitation. AB - BACKGROUND: People experiencing acute psychotic illnesses, especially those associated with agitated or violent behaviour, may require urgent pharmacological tranquillisation or sedation. Droperidol, a butyrophenone antipsychotic, has been used for this purpose in several countries. OBJECTIVES: To estimate the effects of droperidol, including its cost-effectiveness, when compared to placebo, other 'standard' or 'non-standard' treatments, or other forms of management of psychotic illness, in controlling acutely disturbed behaviour and reducing psychotic symptoms in people with schizophrenia-like illnesses. SEARCH METHODS: We updated previous searches by searching the Cochrane Schizophrenia Group Register (18 December 2015). We searched references of all identified studies for further trial citations and contacted authors of trials. We supplemented these electronic searches by handsearching reference lists and contacting both the pharmaceutical industry and relevant authors. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) with useable data that compared droperidol to any other treatment for people acutely ill with suspected acute psychotic illnesses, including schizophrenia, schizoaffective disorder, mixed affective disorders, the manic phase of bipolar disorder or a brief psychotic episode. DATA COLLECTION AND ANALYSIS: For included studies, we assessed quality, risk of bias and extracted data. We excluded data when more than 50% of participants were lost to follow-up. For binary outcomes, we calculated standard estimates of risk ratio (RR) and the corresponding 95% confidence intervals (CI). We created a 'Summary of findings' table using GRADE. MAIN RESULTS: We identified four relevant trials from the update search (previous version of this review included only two trials). When droperidol was compared with placebo, for the outcome of tranquillisation or asleep by 30 minutes we found evidence of a clear difference (1 RCT, N = 227, RR 1.18, 95% CI 1.05 to 1.31, high-quality evidence). There was a clear demonstration of reduced risk of needing additional medication after 60 minutes for the droperidol group (1 RCT, N = 227, RR 0.55, 95% CI 0.36 to 0.85, high-quality evidence). There was no evidence that droperidol caused more cardiovascular arrhythmia (1 RCT, N = 227, RR 0.34, 95% CI 0.01 to 8.31, moderate quality evidence) and respiratory airway obstruction (1 RCT, N = 227, RR 0.62, 95% CI 0.15 to 2.52, low-quality evidence) than placebo. For 'being ready for discharge', there was no clear difference between groups (1 RCT, N = 227, RR 1.16, 95% CI 0.90 to 1.48, high-quality evidence). There were no data for mental state and costs.Similarly, when droperidol was compared to haloperidol, for the outcome of tranquillisation or asleep by 30 minutes we found evidence of a clear difference (1 RCT, N = 228, RR 1.01, 95% CI 0.93 to 1.09, high-quality evidence). There was a clear demonstration of reduced risk of needing additional medication after 60 minutes for participants in the droperidol group (2 RCTs, N = 255, RR 0.37, 95% CI 0.16 to 0.90, high-quality evidence). There was no evidence that droperidol caused more cardiovascular hypotension (1 RCT, N = 228, RR 2.80, 95% CI 0.30 to 26.49,moderate-quality evidence) and cardiovascular hypotension/desaturation (1 RCT, N = 228, RR 2.80, 95% CI 0.12 to 67.98, low quality evidence) than haloperidol. There was no suggestion that use of droperidol was unsafe. For mental state, there was no evidence of clear difference between the efficacy of droperidol compared to haloperidol (Scale for Quantification of Psychotic Symptom Severity, 1 RCT, N = 40, mean difference (MD) 0.11, 95% CI -0.07 to 0.29, low-quality evidence). There were no data for service use and costs.Whereas, when droperidol was compared with midazolam, for the outcome of tranquillisation or asleep by 30 minutes we found droperidol to be less acutely tranquillising than midazolam (1 RCT, N = 153, RR 0.96, 95% CI 0.72 to 1.28, high-quality evidence). As regards the 'need for additional medication by 60 minutes after initial adequate sedation, we found an effect (1 RCT, N = 153, RR 0.54, 95% CI 0.24 to 1.20, moderate-quality evidence). In terms of adverse effects, we found no statistically significant differences between the two drugs for either airway obstruction (1 RCT, N = 153, RR 0.13, 95% CI 0.01 to 2.55, low-quality evidence) or respiratory hypoxia (1 RCT, N = 153, RR 0.70, 95% CI 0.16 to 3.03, moderate-quality evidence) - but use of midazolam did result in three people (out of around 70) needing some sort of 'airway management' with no such events in the droperidol group. There were no data for mental state, service use and costs.Furthermore, when droperidol was compared to olanzapine, for the outcome of tranquillisation or asleep by any time point, we found no clear differences between the older drug (droperidol) and olanzapine (e.g. at 30 minutes: 1 RCT, N = 221, RR 1.02, 95% CI 0.94 to 1.11, high-quality evidence). There was a suggestion that participants allocated droperidol needed less additional medication after 60 minutes than people given the olanzapine (1 RCT, N = 221, RR 0.56, 95% CI 0.36 to 0.87, high-quality evidence). There was no evidence that droperidol caused more cardiovascular arrhythmia (1 RCT, N = 221, RR 0.32, 95% CI 0.01 to 7.88, moderate-quality evidence) and respiratory airway obstruction (1 RCT, N = 221, RR 0.97, 95% CI 0.20 to 4.72, low-quality evidence) than olanzapine. For 'being ready for discharge', there was no difference between groups (1 RCT, N = 221, RR 1.06, 95% CI 0.83 to 1.34, high-quality evidence). There were no data for mental state and costs. AUTHORS' CONCLUSIONS: Previously, the use of droperidol was justified based on experience rather than evidence from well-conducted and reported randomised trials. However, this update found high quality evidence with minimal risk of bias to support the use of droperidol for acute psychosis. Also, we found no evidence to suggest that droperidol should not be a treatment option for people acutely ill and disturbed because of serious mental illnesses. PMID- 27976371 TI - Apolipoprotein C-I plays a role in the pathogenesis of glomerulosclerosis. AB - Diabetic nephropathy is the leading cause of end-stage renal disease. Diabetic patients have increased plasma concentrations of apolipoprotein C-I (apoCI), and meta-analyses found that a polymorphism in APOC1 is associated with an increased risk of developing nephropathy. To investigate whether overexpressing apoCI contributes to the development of kidney damage, we studied renal tissue and peritoneal macrophages from APOC1 transgenic (APOC1-tg) mice and wild-type littermates. In addition, we examined renal material from autopsied diabetic patients with and without diabetic nephropathy and from autopsied control subjects. We found that APOC1-tg mice, but not wild-type mice, develop albuminuria, renal dysfunction, and glomerulosclerosis with increased numbers of glomerular M1 macrophages. Moreover, compared to wild-type macrophages, stimulated macrophages isolated from APOC1-tg mice have increased cytokine expression, including TNF-alpha and TGF-beta, both of which are known to increase the production of extracellular matrix proteins in mesangial cells. These results suggest that APOC1 expression induces glomerulosclerosis, potentially by increasing the cytokine response in macrophages. Furthermore, we detected apoCI in the kidneys of diabetic patients, but not in control kidneys. Moreover, patients with diabetic nephropathy have significantly more apoCI present in glomeruli compared to diabetic patients without nephropathy, suggesting that apoCI could be involved in the development of diabetic nephropathy. ApoCI co localized with macrophages. Therefore, apoCI is a promising new therapeutic target for patients at risk of developing nephropathy. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27976372 TI - Purification and characterization of peroxidase from sprouted green gram (Vigna radiata) roots and removal of phenol and p-chlorophenol by immobilized peroxidase. AB - BACKGROUND: Peroxidase activity was increased during germination of green gram and such an increase may have benefits in many physiological processes. The present study aimed to investigate the optimum conditions for the extraction, purification and characterization of peroxidase from the germinated green gram roots and also its application for the removal of phenols in water. RESULTS: Peroxidase activity was increased by 300-fold in 5-day germinated green gram. Because the root was rich in peroxidase activity, peroxidase from roots was isolated and purified to homogeneity. The purified peroxidase showed a single band on sodium dodecyl sulphate-polyacrylamide gel electrophoresis with a molecular weight of 50 kDa, an optimum pH of 5.5 and a pH stability ranging from 5 to 9. The enzyme had 50% residual activity at 70 degrees C. It catalyzed the oxidation of a variety of substrates. The Km value of the enzyme was 1.28 mmol L 1 for o-dianisidine and 0.045 mmol L-1 for H2 O2 . The enzyme lost 100% activity in the presence of dithiothreitol and cysteine. The addition of copper ion increased the enzyme activity by three-fold. Both soluble and immobilized peroxidases removed more phenol than p-chlorphenol, whereas horseradish peroxidase removed more p-chlorphenol. Thus, the green gram root peroxidase showed good pH and temperature stability, as well as the ability to remove phenolic compounds from effluent. CONCLUSION: Peroxidase with good thermal and pH stability was purified from germinated green gram roots and has the ability to oxidize phenolic compounds from waste water. (c) 2016 Society of Chemical Industry. PMID- 27976375 TI - Quantification of anatomical variation at the atlanto-occipital articulation: morphometric resolution of commingled human remains within the repatriation documentation process. AB - Within many institutional collections are skeletal and mummified human remains representing a part of our species' adaptation and evolution to various biocultural environments. Archaeologically recovered individuals come from deep into our past, and possess information that provides insight into population history, genetics, diet, health and other questions relevant to all living peoples. Academic concerns have been raised regarding the reinterment of these collections due to the rise of the international repatriation movement, the passage of various laws and implementation of institutional policies. While all potential research questions cannot be anticipated, the proactive documentation of collections is one way to ensure primary data are maintained for future study. This paper explores developments in digitization technology that allow the archive of virtual copies of human remains, and an example of how anatomical and archaeological collections can be digitized towards pragmatic research goals. The anatomical variability of the human atlanto-occipital (AO) articular surfaces was studied using non-metric categorical shape, 2D measurement and 3D morphometric analyses to provide reference standards for the reassociation of individuals from commingled skeletal remains, such as found in some archaeological sites or forensic investigations including mass grave or mass disaster recovery scenes. Results suggest that qualitative shape observations and caliper-derived measurements of the articulating AO condyles tend to display significant sexual dimorphism and biological ancestry-related size and shape differences. Variables derived from a scanned 3D mesh, such as condylar angle and articular surface curvature, quantify biomechanical variation and display a stronger congruency within individuals. It is recommended that a two-stage approach involving initial screening and identification of possible reassociation candidates is accomplished with a linear osteometric approach, followed by 3D laser scanning of the candidate joint surfaces for morphometric analyses to confirm reassociations when destructive DNA typing is not allowed or otherwise impractical due to cost or other resource restrictions. PMID- 27976373 TI - Tumour-associated macrophage-mediated survival of myeloma cells through STAT3 activation. AB - Overcoming drug resistance is one of the greatest challenges in the treatment of multiple myeloma (MM). The interaction of myeloma cells with the bone marrow (BM) microenvironment is a major factor contributing to drug resistance. Tumour associated macrophages (TAMs) with different polarization states constitute an important component of this microenvironment. Previous studies have revealed a role of TAMs in MM cell survival and drug resistance; however, the impact of macrophage polarization (anti-tumoural 'M1' versus pro-tumoural 'M2'-like phenotype) in this process has not yet been described. Here, the presence of TAMs was confirmed in BM sections from MM patients, both at diagnosis and relapse, with two M2 markers, CD163 and CD206. By following different TAM subpopulations during disease progression in the syngeneic murine 5T33MM model, we demonstrated a decrease in the number of inflammatory monocytes and an increase in the number of M2-oriented TAMs in BM. Co-culture experiments demonstrated that macrophages provide a survival benefit to myeloma cells that is maintained after treatment with several classes of anti-myeloma agent (melphalan and bortezomib); the greatest effect was observed with M2-polarized macrophages. The pro-survival effect was associated with activation of the STAT3 pathway in 5T33MM cells, less cleavage of caspase-3, and thus less apoptosis. AZD1480, an ATP-competitive JAK2 inhibitor, abrogated the observed TAM-mediated MM cell survival, and partially inhibited resistance to bortezomib. Despite having only a small quantitative impact on myeloid cells in vivo, AZD1480 treatment alone and in combination with bortezomib significantly reduced tumour load. In conclusion, M2 TAMs are present in the MM microenvironment, and contribute to MM cell survival and protection from drug-induced apoptosis. As a result of TAM-induced activation of the STAT3 pathway, 5T33MM cells are sensitized to AZD1480 treatment. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27976374 TI - Cognitive therapy as an early treatment for post-traumatic stress disorder in children and adolescents: a randomized controlled trial addressing preliminary efficacy and mechanisms of action. AB - BACKGROUND: Few efficacious early treatments for post-traumatic stress disorder (PTSD) in children and adolescents exist. Previous trials have intervened within the first month post-trauma and focused on secondary prevention of later post traumatic stress; however, considerable natural recovery may still occur up to 6 months post-trauma. No trials have addressed the early treatment of established PTSD (i.e. 2- to 6-months post-trauma). METHODS: Twenty-nine youth (8-17 years) with PTSD (according to age-appropriate DSM-IV or ICD-10 diagnostic criteria) after a single-event trauma in the previous 2-6 months were randomly allocated to Cognitive Therapy for PTSD (CT-PTSD; n = 14) or waiting list (WL; n = 15) for 10 weeks. RESULTS: Significantly more participants were free of PTSD after CT-PTSD (71%) than WL (27%) at posttreatment (intent-to-treat, 95% CI for difference .04 .71). CT-PTSD yielded greater improvement on child-report questionnaire measures of PTSD, depression and anxiety; clinician-rated functioning; and parent-reported outcomes. Recovery after CT-PTSD was maintained at 6- and 12-month posttreatment. Beneficial effects of CT-PTSD were mediated through changes in appraisals and safety-seeking behaviours, as predicted by cognitive models of PTSD. CT-PTSD was considered acceptable on the basis of low dropout and high treatment credibility and therapist alliance ratings. CONCLUSIONS: This trial provides preliminary support for the efficacy and acceptability of CT-PTSD as an early treatment for PTSD in youth. Moreover, the trial did not support the extension of 'watchful waiting' into the 2- to 6-month post-trauma window, as significant improvements in the WL arm (particularly in terms of functioning and depression) were not observed. Replication in larger samples is needed, but attention to recruitment issues will be required. PMID- 27976376 TI - Italian and Spanish commercial tomato sauces for pasta dressing: study of sensory and head-space profiles by Flash Profiling and solid-phase microextraction-gas chomatography-mass spectrometry. AB - BACKGROUND: The sensory and head-space profiles of Italian and Spanish commercial tomato sauces were investigated. The Flash Profiling method was used to evaluate sensory characteristics. Samples within each set were ranked according to selected descriptors. One hundred volatile compounds were identified by solid phase microextraction-gas chomatography-mass spectrometry. RESULTS: For Italian samples, the sensory notes of basil/aromatic herbs, acid and cooked tomato were among those perceived most by the assessors, whereas, in Spanish samples, the sensory attributes of garlic/onion and onion/sweet pepper and, in Italian samples, cooked tomato were among those found most frequently. Data were elaborated using multivariate statistical approaches and interesting correlations were observed among the different sensory attributes and related volatile compounds. CONCLUSION: Spanish samples were characterized by the highest content of volatiles linked to the thermal treatment of tomatoes and to raw and sauteed garlic and onion, whereas the Italian samples were characterized by terpenic compounds typical of basil and volatile molecules derived from fresh tomato. These results confirm the influence of both formulation and production processes on the aromatic profile (sensory attributes and volatile compounds) of tomato products, which is probably related to the different eating habits and culinary traditions in Italy and Spain. (c) 2016 Society of Chemical Industry. PMID- 27976377 TI - Association between corpus callosum development on magnetic resonance imaging and diffusion tensor imaging, and neurodevelopmental outcome in neonates born very preterm. AB - AIM: To characterize corpus callosum development in neonates born very preterm from early in life to term-equivalent age and its relationship with neurodevelopmental outcome at 18 months corrected age. METHOD: In a prospective cohort of 193 neonates born preterm, 24 to 32 weeks' gestation, we used magnetic resonance imaging and diffusion tensor imaging acquired early in life (n=193) and at term-equivalent age (n=159) to measure corpus callosum development: mid sagittal area (including corpus callosum subdivisions) and length, and fractional anisotropy from the genu and splenium. We examined the association of (1) intraventricular haemorrhage (IVH) and white matter injury (WMI) severity, and (2) neurodevelopmental outcome at 18 months corrected age with corpus callosum development. RESULTS: Severe WMI and severe IVH were strongly associated with reduced corpus callosum area (both p<0.001) and WMI with lower fractional anisotropy (p=0.002). Mild WMI predicted smaller corpus callosum area only posteriorly; mild IVH predicted smaller area throughout. Adverse motor outcome was associated with smaller corpus callosum size in the posterior subdivision (p=0.003). Abnormal cognitive outcomes were associated with lower corpus callosum fractional anisotropy (p=0.008). INTERPRETATION: In newborn infants born very preterm, brain injury is associated with changes in simple metrics of corpus callosum development. In this population, the development of the corpus callosum, as reflected by size and microstructure, is associated with neurodevelopmental outcomes at 18 months corrected age. PMID- 27976378 TI - The human brain endothelial barrier: transcytosis of AAV9, transduction by AAV2: An Editorial Highlight for 'Trafficking of adeno-associated virus vectors across a model of the blood-brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells'. AB - Read the highlighted article 'Trafficking of adeno-associated virus vectors across a model of the blood-brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells' on page 216. PMID- 27976379 TI - Feeding ecology of silky sharks Carcharhinus falciformis associated with floating objects in the western Indian Ocean. AB - The silky shark Carcharhinus falciformis is commonly associated with floating objects, including fish aggregating devices (FADs), in the Indian Ocean. While the motives for this associative behaviour are unclear, it does make them vulnerable to capture in the tuna purse seine fishery that makes extensive use of FADs. Here, the diet of 323 C. falciformis, caught at FADs in the Indian Ocean, was investigated to test the hypothesis that trophic benefits explain the associative behaviour. A high proportion of stomachs with fresh contents (57%) suggested that extensive feeding activity occurred while associated with FADs. Multiple dietary indices showed that typical non-associative prey types dominated, but were supplemented with fishes typically found at FADs. While the trophic benefits of FAD association may be substantial, our results suggest that associative behaviour is not driven solely by feeding. PMID- 27976380 TI - Musculoskeletal anatomy of the pelvic fin of Polypterus: implications for phylogenetic distribution and homology of pre- and postaxial pelvic appendicular muscles. AB - As a member of the most basal clade of extant ray-finned fishes (actinopterygians) and of one of the most basal clades of osteichthyans (bony fishes + tetrapods), Polypterus can provide insights into the ancestral anatomy of both ray-finned and lobe-finned fishes, including those that gave rise to tetrapods. The pectoral fin of Polypterus has been well described but, surprisingly, neither the bones nor the muscles of the pelvic fin are well known. We stained and dissected the pelvic fin of Polypterus senegalus and Polypterus delhezi to offer a detailed description of its musculoskeletal anatomy. In addition to the previously described adductor and abductor muscles, we found preaxial and postaxial muscles similar to those in the pectoral fin of members of this genus. The presence of pre- and postaxial muscles in both the pectoral and pelvic fins of Polypterus, combined with recent descriptions of similar muscles in the lobe-finned fishes Latimeria and Neoceratodus, suggests that they were present in the most recent common ancestor of bony fishes. These results have crucial implications for the evolution of appendicular muscles in both fish and tetrapods. PMID- 27976381 TI - American undergraduate students' value development during the Great Recession. AB - The Great Recession's influence on American undergraduate students' values was examined, testing Greenfield's and Kasser's theories concerning value development during economic downturns. Study 1 utilised aggregate-level data to investigate (a) population-level value changes between the pre-recession (2004-2006: n = 824,603) and recession freshman cohort (2008-2010: n = 662,262) and (b) overall associations of population-level values with national economic climates over long term periods by correlating unemployment rates and concurrent aggregate-level values across 1966-2015 (n = 10 million). Study 2 examined individual-level longitudinal value development from freshman to senior year, and whether the developmental trajectories differed between those who completed undergraduate education before the Great Recession (freshmen in 2002, n = 12,792) versus those who encountered the Great Recession during undergraduate years (freshmen in 2006, n = 13,358). Results suggest American undergraduate students' increased communitarianism (supporting Greenfield) and materialism (supporting Kasser) during the Great Recession. The recession also appears to have slowed university students' development of positive self-views. Results contribute to the limited literature on the Great Recession's influence on young people's values. They also offer theoretical and practical implications, as values of this privileged group of young adults are important shapers of societal values, decisions, and policies. PMID- 27976382 TI - Early glycolipid (POA) in pro-oligodendroblasts revealed to be sulfatide: An Editorial Highlight for 'Sulfatide species with various fatty acid chains in oligodendrocytes at different developmental stages determined by imaging mass spectrometry'. AB - Read the highlighted article 'Sulfatide species with various fatty acid chains in oligodendrocytes at different developmental stages determined by imaging mass spectrometry' on page 435. PMID- 27976383 TI - Luigi Provasoli award recipients. PMID- 27976384 TI - Taxonomic Reshuffling of the Cladophoraceae. PMID- 27976385 TI - A Spatially Periodic Solute Boundary for MT3DMS and PHT3D. AB - The assumption of spatial repetition is commonly made when producing bedform scale models of the hyporheic zone. Two popular solute transport codes, MT3DMS and PHT3D, do not currently provide the necessary boundary condition required to simulate spatial periodicity in hyporheic zone transport problems. In this study, we develop a spatially periodic boundary (SPB) for solutes that is compatible with a SPB that was previously developed for MODFLOW to simulate the flow component of spatially periodic problems. The approach is ideal for simulating groundwater flow and transport patterns under repeating surface features, such as ripples or dunes on the bottom of a lake or stream. The appropriate block centered finite-difference approach to implement the boundary is presented and the necessary source code modifications are discussed. The performance of the solute SPB, operating in conjunction with the groundwater flow SPB, is explored through comparison of a multi-bedform hyporheic-zone model with a single bedform variant. The new boundary conditions perform well in situations where both dispersive effects and lateral seepage flux in the underflow regime beneath the hyporheic zone are minimal. PMID- 27976386 TI - Growth and annual survival estimates to examine the ecology of larval lamprey and the implications of ageing error in fitting models. AB - This study used existing western brook lamprey Lampetra richardsoni age information to fit three different growth models (i.e. von Bertalanffy, Gompertz and logistic) with and without error in age estimates. Among these growth models, there was greater support for the logistic and Gompertz models than the von Bertalanffy model, regardless of ageing error assumptions. The von Bertalanffy model, however, appeared to fit the data well enough to permit survival estimates; using length-based estimators, annual survival varied between 0.64 (95% credibility interval: 0.44-0.79) and 0.81 (0.79-0.83) depending on ageing and growth process error structure. These estimates are applicable to conservation and management of L. richardsoni and other western lampreys (e.g. Pacific lamprey Entosphenus tridentatus) and can potentially be used in the development of life-cycle models for these species. These results also suggest that estimators derived from von Bertalanffy growth models should be interpreted with caution if there is high uncertainty in age estimates. PMID- 27976388 TI - Covariate Balancing through Naturally Occurring Strata. AB - OBJECTIVE: To provide an alternative to propensity scoring (PS) for the common situation where there are interacting covariates. SETTING: We used 1.3 million assessments of residents of the United States Veterans Affairs nursing homes, collected from January 1, 2000, through October 9, 2012. DESIGN: In stratified covariate balancing (SCB), data are divided into naturally occurring strata, where each stratum is an observed combination of the covariates. Within each stratum, cases with, and controls without, the target event are counted; controls are weighted to be as frequent as cases. This weighting procedure guarantees that covariates, or combination of covariates, are balanced, meaning they occur at the same rate among cases and controls. Finally, impact of the target event is calculated in the weighted data. We compare the performance of SCB, logistic regression (LR), and propensity scoring (PS) in simulated and real data. We examined the calibration of SCB and PS in predicting 6-month mortality from inability to eat, controlling for age, gender, and nine other disabilities for 296,051 residents in Veterans Affairs nursing homes. We also performed a simulation study, where outcomes were randomly generated from treatment, 10 covariates, and increasing number of covariate interactions. The accuracy of SCB, PS, and LR in recovering the simulated treatment effect was reported. FINDINGS: In simulated environment, as the number of interactions among the covariates increased, SCB and properly specified LR remained accurate but pairwise LR and pairwise PS, the most common applications of these tools, performed poorly. In real data, application of SCB was practical. SCB was better calibrated than linear PS, the most common method of PS. CONCLUSIONS: In environments where covariates interact, SCB is practical and more accurate than common methods of applying LR and PS. PMID- 27976389 TI - Passive heat therapy: the next hot thing for cardiovascular health! PMID- 27976390 TI - Enhanced functional sympatholysis through endothelial signalling in healthy young men and women. PMID- 27976387 TI - Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets. AB - : Adipose tissue (AT) is an active endocrine organ with the ability to dynamically secrete a wide range of adipocytokines. Importantly, its secretory profile is altered in various cardiovascular disease states. AT surrounding vessels, or perivascular AT (PVAT), is recognized in particular as an important local regulator of vascular function and dysfunction. Specifically, PVAT has the ability to sense vascular paracrine signals and respond by secreting a variety of vasoactive adipocytokines. Due to the crucial role of PVAT in regulating many aspects of vascular biology, it may constitute a novel therapeutic target for the prevention and treatment of vascular disease pathogenesis. Signalling pathways in PVAT, such as those using adiponectin, H2 S, glucagon-like peptide 1 or pro inflammatory cytokines, are among the potential novel pharmacological therapeutic targets of PVAT. LINKED ARTICLES: This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc. PMID- 27976391 TI - Can a bout of exercise harm the human heart? PMID- 27976392 TI - Adrenaline and the carotid body during hypoglycaemia: an amplifying mechanism? PMID- 27976393 TI - Reply from Geoffrey L. Hartley and Stephen S. Cheung. PMID- 27976394 TI - Drugs and bugs: turning on the heat through UCP1 and UCP3. PMID- 27976395 TI - The mechanistic basis of the power-time relationship: potential role of the group III/IV muscle afferents. PMID- 27976396 TI - An intricate balance of muscle damage and protein synthesis: the key players in skeletal muscle hypertrophy following resistance training. PMID- 27976397 TI - The physiology of interval training: a new target to HIIT. PMID- 27976398 TI - Pushing it to the limit: enhanced diffusing membrane capacity facilitates greater pulmonary diffusing capacity in athletes during exercise. PMID- 27976399 TI - Harder, better, faster, longer? Investigating the physiological threshold of endurance exercise. PMID- 27976400 TI - Tracking diaphragm movement by using ultrasound to assess its strength. PMID- 27976401 TI - Mechanisms of resistance exercise-induced muscle hypertrophy: 'You can't make an omelette without breaking eggs'. PMID- 27976402 TI - Skeletal muscle stem cell defects in burn-induced cachexia. PMID- 27976403 TI - Rac1 is a novel regulator of exercise-induced glucose uptake. PMID- 27976404 TI - Voluntary activation and cerebral blood flow: better measurement leads to less argument. PMID- 27976405 TI - Abnormal muscle metaboreflex control of ventilation in patients with chronic obstructive pulmonary disease: what mechanisms should be blamed? PMID- 27976407 TI - Potassium uptake and redistribution in Cabernet Sauvignon and Syrah grape tissues and its relationship with grape quality parameters. AB - BACKGROUND: The present study investigated the potassium (K) levels in petiole and other grape tissues during ripening in Vitis vinifera Shiraz and Cabernet Sauvignon, grown in areas with differences in vigour, as well as with and without leaf thinning. Potassium levels in petiole, seeds, skin and flesh were related to grape pH, acidity, berry weight and total soluble solids. RESULTS: Differences in K levels in petiole were in accordance with the differences in soil K. Leaf thinning gave rise to higher K levels in petiole but, in grape tissues, the differences were not significant in all samplings, with greater differences at the end of the growing cycle. Potassium levels per berry in grape tissues increased from veraison to harvest, with K mainly accumulated in skins and, to a lesser extent, in flesh. Potassium levels in flesh positively correlated with pH and total soluble solids, whereas the correlation with titratable acidity was negative. CONCLUSIONS: Grape juice pH and total soluble solids positively correlated with K, whereas titratable acidity correlated negatively. Leaf thinning increased K levels in petiole, although differences in K levels in grape tissues were not significant. This suggests the need to consider the K berry concentration when aiming to optimise K fertilisation programmes. (c) 2016 Society of Chemical Industry. PMID- 27976406 TI - Evaluation of phenolic antioxidant content in organically and conventionally grown buckwheat herb crop and its regrowth. AB - BACKGROUND: Buckwheat herb is known in the pharmaceutical industry as a material rich in phenolics. Buckwheat is also capable of regrowing and producing an additional harvest in the same year. Although buckwheat herb is a popular material, it is not known whether the regrowth has features of the same quality as the first harvest. Therefore, using the herb of 15 varieties of buckwheat cultivated in Lithuania, the present study aimed to examine biometric properties, phenolic content and antioxidant activity as material quality indicators for buckwheat herb and its regrowth under organic and conventional farming conditions. RESULTS: The highest amount of rutin was indicated in the organically cultivated regrowth of 2015. Buckwheat material accumulated significantly (P < 0.05) lower amounts of other phenolics. A significant correlation between phenolic content and antioxidant activity was observed in the herb and its regrowth in both farming systems. CONCLUSION: Regrowth was of similar quality to the first harvest in terms of phenolic content and antioxidant activity, although a downward trend in several biometric features was observed: the height of the regrowth plants was up to two-fold smaller and biomass was five- to nine-fold lower compared to that of the first harvest plants. Organic and industrial farming systems were determined to produce plants of similar quality. (c) 2016 Society of Chemical Industry. PMID- 27976408 TI - Combined effect of carnosol, rosmarinic acid and thymol on the oxidative stability of soybean oil using a simplex centroid mixture design. AB - BACKGROUND: Oxidation taking place during the use of oil leads to the deterioration of both nutritional and sensorial qualities. Natural antioxidants from herbs and plants are rich in phenolic compounds and could therefore be more efficient than synthetic ones in preventing lipid oxidation reactions. This study was aimed at the valorization of Tunisian aromatic plants and their active compounds as new sources of natural antioxidant preventing oil oxidation. RESULTS: Carnosol, rosmarinic acid and thymol were isolated from Rosmarinus officinalis and Thymus capitatus by column chromatography and were analyzed by nuclear magnetic resonance. Their antioxidant activities were measured by DPPH, ABTS and FRAP assays. These active compounds were added to soybean oil in different proportions using a simplex-centroid mixture design. Antioxidant activity and oxidative stability of oils were determined before and after 20 days of accelerated oxidation at 60 degrees C. CONCLUSION: Results showed that bioactive compounds are effective in maintaining oxidative stability of soybean oil. However, the binary interaction of rosmarinic acid and thymol caused a reduction in antioxidant activity and oxidative stability of soybean oil. Optimum conditions for maximum antioxidant activity and oxidative stability were found to be an equal ternary mixture of carnosol, rosmarinic acid and thymol. (c) 2016 Society of Chemical Industry. PMID- 27976410 TI - Determination of oxathiapiprolin concentration and dissipation in grapes and soil by ultrahigh-performance liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: The residue concentrations and dissipation rate of a new oxathiapiprolin fungicide in grapes and soil were investigated to provide an evaluation for the safe use of oxathiapiprolin in grapes. Pesticide residue was extracted by acetonitrile, then purified by solid-phase extraction with an Envi Carb cartridge and determined by ultrahigh-performance liquid chromatography tandem mass spectrometry. RESULTS: The fortified recoveries ranged from 85.2% to 99.0%, with relative standard deviations of 1.7-4.5%. The limit of quantitation for oxathiapiprolin in grapes and soil was 0.002 mg kg-1 . The mean initial deposits of oxathiapiprolin in grapes were 0.345-0.565 mg kg-1 , with half-lives of 8.6-9.2 days. The mean initial deposits of oxathiapiprolin in soil were 0.078 0.273 mg kg-1 , with half-lives of 7.6-12.0 days. The oxathiapiprolin residue in grapes and soil was 0.002-0.022 mg kg-1 and 0.002-0.123 mg kg-1 when sampling 14 days after application, respectively. CONCLUSION: The residue in the grapes was less than 0.01 mg kg-1 when sampling 28 days after application, which suggested that the application rate of 20 mg a.i. kg-1 for this fungicide should be used to ensure that treated grapes can be considered safe for humans to consume when sampling 28 days after the final application. (c) 2016 Society of Chemical Industry. PMID- 27976411 TI - Comparative community structure of archaea in rumen of buffaloes and cattle. AB - BACKGROUND: Detailed knowledge of the community structure of methanogens is essential for amelioration of methane emission from livestock species. Several studies have indicated that predominant methanogens of buffalo rumen are different from those in cattle. However, predominant genera of methanogens reported by individual studies varied primarily because of limited scope of sampling, sequencing of limited number of sequences and potential PCR bias in individual studies. In this study, the collective comparative diversity of methanogenic archaea in the rumen of cattle and buffaloes was examined by performing a meta-analysis of all the 16S rRNA (rrn) sequences deposited in GenBank. RESULTS: Ruminal methanogen sequences of buffalo were clustered into 900 species-level operational taxonomic units (OTUs), and ruminal methanogen sequences of cattle were clustered into 1522 species level OTUs. The number of species-level OTUs shared between cattle and buffaloes was 229 (10.4% of all OTUs), comprising 1746 sequences (27% of the total 6447 sequences). According to taxonomic classification by three different classifiers, Methanobrevibacter was found to be the most predominant genus both in cattle (69-71% of sequences) as well as buffaloes (65.1-68.9% of sequences). Percentage of Methanomicrobium was much higher (P < 0.05) in the case of buffalo (18%) than that of cattle (4.5%). On the other hand, percentages of Methanosphaera- and Methanomassiliicoccus-like methanogens were much higher (P < 0.05) in cattle than in buffaloes. CONCLUSION: This study indicated that there is a substantial difference in community structure of ruminal methanogens of cattle and buffaloes. The study has also indicated that the percent of species-level operational taxonomic units shared between cattle and buffalo is very low, and thus host species-specific methane mitigation strategies need to be developed for cattle and buffaloes. (c) 2016 Society of Chemical Industry. PMID- 27976412 TI - A pair of new elemanolide sesquiterpene lactones from Elephantopus scaber L. PMID- 27976413 TI - Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists. AB - Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium-dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure-activity relationships (SARs) focusing on new strategies to target this channel. PMID- 27976414 TI - Low Testosterone Alters the Activity of Mouse Prostate Stem Cells. AB - BACKGROUND: Low serum testosterone (low T) has been repeatedly linked to worse outcomes in men with newly diagnosed prostate cancer (PC). How low T contributes to these outcomes is unknown. Here we demonstrate that exposure to low T causes significant changes in the mouse prostate and prostate stem cells. METHODS: Mice were castrated and implanted with capsules to achieve castrate, normal, or sub physiological levels of T. After 6 weeks of treatment, LC-MS/MS was used to quantify the levels of T and dihydrotestosterone (DHT) in serum and prostate tissue. FACS was used to quantify the percentages of purported prostate stem and transit amplifying (TA) cells in mouse prostates. Prostate tissues were also stained for the presence of CD68+ cells and RNA was extracted from prostate tissue or specific cell populations to measure changes in transcript levels with low T treatment. RESULTS: Despite having significantly different levels of T and DHT in the serum, T and DHT concentrations in prostate tissue from different T treatment groups were similar. Low T treatment resulted in significant alterations in the expression of androgen biosynthesis genes, which may be related to maintaining prostate androgen levels. Furthermore, the expression of androgen-regulated genes in the prostate was similar among all T treatment groups, demonstrating that the mouse prostate can maintain functional levels of androgens despite low serum T levels. Low T increased the frequency of prostate stem and TA cells in adult prostate tissue and caused major transcriptional changes in those cells. Gene ontology analysis suggested that low T caused inflammatory responses and immunofluorescent staining indicated that low T treatment led to the increased presence of CD68+ macrophages in prostate tissue. CONCLUSIONS: Low T alters the AR signaling axis which likely leads to maintenance of functional levels of prostate androgens. Low T also induces quantitative and qualitative changes in prostate stem cells which appear to lead to inflammatory macrophage infiltration. These changes are proposed to lead to an aggressive phenotype once cancers develop and may contribute to the poor outcomes in men with low T. Prostate 77:530-541, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27976409 TI - Oral drug absorption in pediatrics: the intestinal wall, its developmental changes and current tools for predictions. AB - The dissolution, intestinal absorption and presystemic metabolism of a drug depend on its physicochemical characteristics but also on numerous physiological (e.g. gastrointestinal pH, volume, transit time, morphology) and biochemical factors (e.g. luminal enzymes and flora, intestinal wall enzymes and transporters). Over the past decade, evidence has accumulated indicating that these factors may differ in children and adults resulting in age-related changes in drug exposure and drug response. Thus, drug dosage may require adjustment for the pediatric population to ensure the desired therapeutic outcome and to avoid side-effects. Although tremendous progress has been made in understanding the effects of age on intestinal physiology and function, significant knowledge gaps remain. Studying and predicting pharmacokinetics in pediatric patients remains challenging due to ethical concerns associated with clinical trials in this vulnerable population, and because of the paucity of predictive in vitro and in vivo animal assays. This review details the current knowledge related to developmental changes determining intestinal drug absorption and pre-systemic metabolism. Supporting experimental approaches as well as physiologically based pharmacokinetic modeling are also discussed together with their limitations and challenges. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976415 TI - Up-Regulation of Follistatin-Like 1 By the Androgen Receptor and Melanoma Antigen A11 in Prostate Cancer. AB - BACKGROUND: High affinity androgen binding to the androgen receptor (AR) activates genes required for male sex differentiation and promotes the development and progression of prostate cancer. Human AR transcriptional activity involves interactions with coregulatory proteins that include primate-specific melanoma antigen-A11 (MAGE-A11), a coactivator that increases AR transcriptional activity during prostate cancer progression to castration-resistant/recurrent prostate cancer (CRPC). METHODS: Microarray analysis and quantitative RT-PCR were performed to identify androgen-regulated MAGE-A11-dependent genes in LAPC-4 prostate cancer cells after lentivirus shRNA knockdown of MAGE-A11. Chromatin immunoprecipitation was used to assess androgen-dependent AR recruitment, and immunocytochemistry to localize an androgen-dependent protein in prostate cancer cells and tissue and in the CWR22 human prostate cancer xenograft. RESULTS: Microarray analysis of androgen-treated LAPC-4 prostate cancer cells indicated follistatin-like 1 (FSTL1) is up-regulated by MAGE-A11. Androgen-dependent up regulation of FSTL1 was inhibited in LAPC-4 cells by lentivirus shRNA knockdown of AR or MAGE-A11. Chromatin immunoprecipitation demonstrated AR recruitment to intron 10 of the FSTL1 gene that contains a classical consensus androgen response element. Increased levels of FSTL1 protein in LAPC-4 cells correlated with higher levels of MAGE-A11 relative to other prostate cancer cells. FSTL1 mRNA levels increased in CRPC and castration-recurrent CWR22 xenografts in association with predominantly nuclear FSTL1. Increased nuclear localization of FSTL1 in prostate cancer was suggested by predominantly cytoplasmic FSTL1 in benign prostate epithelial cells and predominantly nuclear FSTL1 in epithelial cells in CRPC tissue and the castration-recurrent CWR22 xenograft. AR expression studies showed nuclear colocalization of AR and endogenous FSTL1 in response to androgen. CONCLUSION: AR and MAGE-A11 cooperate in the up-regulation of FSTL1 to promote growth and progression of CRPC. Prostate 77:505-516, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27976416 TI - Effects of nucleoside analogue prescription for hepatitis B on the incidence of liver cancer in Hong Kong: a territory-wide ecological study. AB - BACKGROUND: The temporal relationship between nucleoside analogue therapy for chronic hepatitis B (CHB) and liver cancer development has not been evaluated at a population level. AIM: To investigate the impact of nucleoside analogue prescription on liver cancer incidence in a CHB-prevalent region. METHODS: We obtained territory-wide nucleoside analogue prescription data from 1999, when nucleoside analogue was first available in Hong Kong, to 2012 and the population based liver cancer incidence data from 1990 to 2012. We compared the liver cancer incidences from 1990 to 1998 and 1999 to 2012 with adjustment for local hepatitis B surface antigen seroprevalence. RESULTS: Nucleoside analogue prescription patient headcount increased from 2006 per year in 1999 to 26 411 in 2012. Prescription volume in 2012 was highest among 55-64 years (30.3%), higher than 65 74 years (13.0%) and >=75 years (5.8%). Age-standardised liver cancer incidence 1999-2012 decreased by 1.88%/year (95% CI 3.34% to 0.42%/year). NA therapy was associated with decline in age-adjusted liver cancer incidence (2.7 per 100 000 persons, P < 0.001, 95% CI 1.4-4.0 per 100 000 persons). Fifty-five to sixty-four years age group had the most significant decline (men: 24.0 per 100 000 persons, P = 0.001, 95% CI 11.4-36.6 per 100 000 persons; women: 8.5 per 100 000 persons, P = 0.009, 95% CI 2.3-14.6 per 100 000 persons). No significant association was noted in age groups 65-74 years and >=75 years (both P > 0.05). CONCLUSIONS: Nucleoside analogue prescription was associated with a reduction of overall liver cancer incidence in a CHB-prevalent region. The lack of association among individuals of >=65 years was consistent with the low nucleoside analogue prescription volume in elderly patients, mitigating the impact of CHB treatment on liver cancer. PMID- 27976417 TI - A UPLC/MS/MS method for determination of protosappanin B in rat plasma and its application of a pharmacokinetic and bioavailability study. AB - Caesalpinia sappan L. is a traditional medicinal plant which is used for promoting blood circulation and cerebral apoplexy therapy in China. Previous reports showed that the extracts of Caesalpinia sappan L. could exert vasorelaxant activity and anti-inflammation activity. Protosappanin B is a major constituent of C. sappan L., and showed several important bioactivities. The separation was achieved by an Acquity UPLC BEH Symmetry Shield RP18 column (1.7 MUm, 2.1 * 100 mm) column with the gradient mobile phase consisting of 5 mm ammonium acetate aqueous solution and acetonitrile. Detection was carried out by using negative-ion electrospray tandem mass spectrometry via multiple reaction monitoring. Plasma samples were preprocessed by an extraction with ethyl acetate, and apigenin was used as internal standard. The current UPLC-MS/MS assay was validated for linearity, accuracy, intraday and interday precisions, stability, matrix effects and extraction recovery. After oral and intravenous administration, the main pharmacokinetic parameters were as follows: peak concentrations, 83.5 +/- 46.2 and 1329.6 +/- 343.6 ng/mL; areas under the concentration-time curve, 161.9 +/- 69.7 and 264.9 +/- 56.3 MUg h/L; and half lives, 3.4 +/- 0.9 and 0.3 +/- 0.1 h, respectively. The absolute bioavailability in rats of protosappanin B was 12.2%. The method has been successfully applied to a pharmacokinetic and bioavailability study of protosappanin B in rats. PMID- 27976418 TI - Semiparametric time varying coefficient model for matched case-crossover studies. AB - In matched case-crossover studies, it is generally accepted that the covariates on which a case and associated controls are matched cannot exert a confounding effect on independent predictors included in the conditional logistic regression model. This is because any stratum effect is removed by the conditioning on the fixed number of sets of the case and controls in the stratum. Hence, the conditional logistic regression model is not able to detect any effects associated with the matching covariates by stratum. However, some matching covariates such as time often play an important role as an effect modification leading to incorrect statistical estimation and prediction. Therefore, we propose three approaches to evaluate effect modification by time. The first is a parametric approach, the second is a semiparametric penalized approach, and the third is a semiparametric Bayesian approach. Our parametric approach is a two stage method, which uses conditional logistic regression in the first stage and then estimates polynomial regression in the second stage. Our semiparametric penalized and Bayesian approaches are one-stage approaches developed by using regression splines. Our semiparametric one stage approach allows us to not only detect the parametric relationship between the predictor and binary outcomes, but also evaluate nonparametric relationships between the predictor and time. We demonstrate the advantage of our semiparametric one-stage approaches using both a simulation study and an epidemiological example of a 1-4 bi-directional case crossover study of childhood aseptic meningitis with drinking water turbidity. We also provide statistical inference for the semiparametric Bayesian approach using Bayes Factors. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976419 TI - Authentic sheep meat in the European Union: Factors influencing and validating its unique meat quality. AB - Authentic meat products are gaining attention through their unique quality characteristics linked to their origin. Various factors are known to influence the quality of fresh meat. This review describes the different Protected Designation of Origin (PDO) and Protected Geographical Indication (PGI) lamb types and discusses the factors which influences its unique sensory and chemical characteristics. Flavour, aroma, texture and colour play an integral part in the sensory quality of denomination of origin fresh meat products. For authentic fresh sheep meat the sensory (as well as chemical) quality is largely influenced by diet followed by breed, age and gender. However, diet forms the link with the geographical area of origin, which together with the traditional production system and sheep breeds used, lends the product its authentic nature. This review shows how diet linked to origin can affect the quality of the meat and furthermore how other factors such as breed can also have an effect. Research relating to the authentic lamb types were evaluated and the shortcomings highlighted in order to assist with the development of PDO and PGI specifications in the future. (c) 2016 Society of Chemical Industry. PMID- 27976420 TI - Myopathology in congenital myopathies. AB - Congenital myopathies are clinically and genetically a heterogeneous group of early onset neuromuscular disorders, characterized by hypotonia and muscle weakness. Clinical severity and age of onset are variable. Many patients are severely affected at birth while others have a milder, moderately progressive or nonprogressive phenotype. Respiratory weakness is a major clinical aspect that requires regular monitoring. Causative mutations in several genes have been identified that are inherited in a dominant, recessive or X-linked manner, or arise de novo. Muscle biopsies show characteristic pathological features such as nemaline rods/bodies, cores, central nuclei or caps. Small type 1 fibres expressing slow myosin are a common feature and may sometimes be the only abnormality. Small cores (minicores) devoid of mitochondria and areas showing variable myofibrillar disruption occur in several neuromuscular disorders including several forms of congenital myopathy. Muscle biopsies can also show more than one structural defect. There is considerable clinical, pathological and genetic overlap with mutations in one gene resulting in more than one pathological feature, and the same pathological feature being associated with defects in more than one gene. Increasing application of whole exome sequencing is broadening the clinical and pathological spectra in congenital myopathies, but pathology still has a role in clarifying the pathogenicity of gene variants as well as directing molecular analysis. PMID- 27976421 TI - Trait-based prediction of extinction risk of small-bodied freshwater fishes. AB - Small body size is generally correlated with r-selected life-history traits, including early maturation, short-generation times, and rapid growth rates, that result in high population turnover and a reduced risk of extinction. Unlike other classes of vertebrates, however, small freshwater fishes appear to have an equal or greater risk of extinction than large fishes. We explored whether particular traits explain the International Union for Conservation of Nature (IUCN) Red List conservation status of small-bodied freshwater fishes from 4 temperate river basins: Murray-Darling, Australia; Danube, Europe; Mississippi-Missouri, North America; and the Rio Grande, North America. Twenty-three ecological and life history traits were collated for all 171 freshwater fishes of <=120 mm total length. We used generalized linear mixed-effects models to assess which combination of the 23 traits best explained whether a species was threatened or not threatened. We used the best models to predict the probability of 29 unclassified species being listed as threatened. With and without controlling for phylogeny at the family level, small body size-among small-bodied species-was the most influential trait correlated with threatened species listings. The k-folds cross-validation demonstrated that body size and a random effect structure that included family predicted the threat status with an accuracy of 78% (SE 0.5). We identified 10 species likely to be threatened that are not listed as such on the IUCN Red List. Small body size is not a trait that provides universal resistance to extinction, particularly for vertebrates inhabiting environments affected by extreme habitat loss and fragmentation. We hypothesize that this is because small bodied species have smaller home ranges, lower dispersal capabilities, and heightened ecological specialization relative to larger vertebrates. Trait data and further model development are needed to predict the IUCN conservation status of the over 11,000 unclassified freshwater fishes, especially those under threat from proposed dam construction in the world's most biodiverse river basins. PMID- 27976422 TI - Desert pastoralists' negative and positive effects on rare wildlife in the Gobi. AB - In arid regions of the developing world, pastoralists and livestock commonly inhabit protected areas, resulting in human-wildlife conflict. Conflict is inextricably linked to the ecological processes shaping relationships between pastoralists and native herbivores and carnivores. To elucidate relationships underpinning human-wildlife conflict, we synthesized 15 years of ecological and ethnographic data from Ikh Nart Nature Reserve in Mongolia's Gobi steppe. The density of argali (Ovis ammon), the world's largest wild sheep, at Ikh Nart was among the highest in Mongolia, yet livestock were >90% of ungulate biomass and dogs >90% of large-carnivore biomass. For argali, pastoral activities decreased food availability, increased mortality from dog predation, and potentially increased disease risk. Isotope analyses indicated that livestock accounted for >50% of the diet of the majority of gray wolves (Canis lupus) and up to 90% of diet in 25% of sampled wolves (n = 8). Livestock composed at least 96% of ungulate prey in the single wolf pack for which we collected species-specific prey data. Interviews with pastoralists indicated that wolves annually killed 1 4% of Ikh Nart's livestock, and pastoralists killed wolves in retribution. Pastoralists reduced wolf survival by killing them, but their livestock were an abundant food source for wolves. Consequently, wolf density appeared to be largely decoupled from argali density, and pastoralists had indirect effects on argali that could be negative if pastoralists increased wolf density (apparent competition) or positive if pastoralists decreased wolf predation (apparent facilitation). Ikh Nart's argali population was stable despite these threats, but livestock are increasingly dominant numerically and functionally relative to argali. To support both native wildlife and pastoral livelihoods, we suggest training dogs to not kill argali, community insurance against livestock losses to wolves, reintroducing key native prey species to hotspots of human-wolf conflict, and developing incentives for pastoralists to reduce livestock density. PMID- 27976423 TI - Mohs micrographic surgery of rare cutaneous tumours. AB - BACKGROUND: Recurrence rates after Mohs micrographic surgery (MMS) for rare cutaneous tumours are poorly defined. OBJECTIVE: To investigate the recurrence rate after MMS for rare cutaneous tumours at a university centre. METHODS & MATERIALS: Retrospective review of all rare cutaneous tumours treated with MMS at a large university centre between January 2008 and December 2012. To detect all recurrences, patients were linked to The Nationwide Network and registry of histo and cytopathology (PALGA). RESULTS: In total, 80 patients with 80 tumours were included. Tumour types included dermatofibrosarcoma protuberans (27), atypical fibroxanthoma (22), Merkel cell carcinoma (8), microcystic adnexal carcinoma (9), sebaceous carcinoma (6), extramammary Paget's disease (2) and other (6). Mean follow-up time was 3.7 years (standard deviation 1.4) during which two atypical fibroxanthomas recurred (2.5%). CONCLUSION: This large case series shows that MMS is an appropriate treatment for rare cutaneous tumours with a recurrence rate less than 3%. Preferably, MMS for rare cutaneous tumours is performed in experienced multidisciplinary centres to further improve the quality of treatment. PMID- 27976424 TI - High-Operating-Temperature Direct Ink Writing of Mesoscale Eutectic Architectures. AB - High-operating-temperature direct ink writing (HOT-DIW) of mesoscale architectures that are composed of eutectic silver chloride-potassium chloride. The molten ink undergoes directional solidification upon printing on a cold substrate. The lamellar spacing of the printed features can be varied between approximately 100 nm and 2 um, enabling the manipulation of light in the visible and infrared range. PMID- 27976425 TI - Enhancement of the Performance of Perovskite Solar Cells, LEDs, and Optical Amplifiers by Anti-Solvent Additive Deposition. AB - The efficiency of perovskite optoelectronic devices is increased by a novel method; its suitability for perovskite solar cells, light-emitting diodes, and optical amplifiers is demonstrated. The method is based on the introduction of organic additives during the anti-solvent step in the perovskite thin-film deposition process. Additives passivate grain boundaries reducing non-radiative recombination. The method can be easily extended to other additives. PMID- 27976426 TI - Men's perspectives on fall risk and fall prevention following participation in a group-based programme conducted at Men's Sheds, Australia. AB - Research on older men's views regarding fall prevention is limited. The purpose of this qualitative study was to explore the experiences and perspectives of older men regarding fall risk and prevention so that fall prevention programmes can better engage older men. Eleven men who had taken part in a group-based fall prevention programme called Stepping On conducted at Men's Sheds in Sydney, Australia, participated in semi-structured interviews during June and July 2015 which were audio-recorded and transcribed. Data were coded and analysed using constant comparative methods. Over-arching theoretical categories were developed into a conceptual framework linking programme context and content with effects of programme participation on men. Men's Sheds facilitated participation in the programme by being inclusive, male-friendly places, where Stepping On was programmed into regular activities and was conducted in an enjoyable, supportive atmosphere. Programme content challenged participants to think differently about themselves and their personal fall risk, and provided practical options to address fall risk. Two major themes were identified: adjusting the mindset where men adopted a more cautious mindset paying greater attention to potential fall risks, being careful, concentrating and slowing down; and changing the ways where men acted purposefully on environmental hazards at home and incorporated fall prevention exercises into their routine schedules. Practitioners can engage and support older men to address falls by better understanding men's perspectives on personal fall risk and motivations for action. PMID- 27976427 TI - Effects of TSLP on obstetrical and gynecological diseases. AB - Thymic stromal lymphopoietin (TSLP) is produced mainly by epithelial cells and was originally found to stimulate the growth and activation of B cells, but it is now shown to function on both hematopoietic and non-hematopoietic cell lineages. Despite a number of studies focusing on the role of TSLP in Th2 response for allergic disorders, it is becoming increasingly evident that TSLP may also be involved in multiple other disease states. This review will focus on recent advances on the effects of TSLP on obstetrical and gynecological diseases, including pregnancy failure, endometriosis, and cervical cancer. PMID- 27976429 TI - Gestational diabetes: the controversy continues. PMID- 27976428 TI - Long intragenic non-coding RNA lincRNA-p21 suppresses development of human prostate cancer. AB - OBJECTIVES: Prostate cancer is one of the most frequent malignancies in men, worldwide, although its underlying mechanisms are not fully understood. Long non coding RNAs participate in development of human cancers. In this invetsigation, we aimed to study the roles of lincRNA-p21 in development of human prostate cancer. MATERIALS AND METHODS: Expression of lincRNA-p21 was assessed by real time PCR in cell lines and in human tissues. Lentivirus carrying sh-lincRNA-p21, lincRNA-p21 or control constructs were used to determine their effects on cell proliferation and apoptosis. A mouse xenograft model was employed to explore the functions of lincRNA-p21 on cancer cell population growth in vivo. Relationships between p53 downstream genes and lincRNA-p21 levels were explored by real-time PCR, western blotting and chromatin immunoprecipitation. RESULTS: LincRNA-p21 was found to be down-regulated in human prostate cancer, and low levels of lincRNA p21 correlated with high disease stage and prediction of poor survival. We further showed that lincRNA-p21 inhibited prostate cancer cell proliferation and colony formation in vitro and reduced rate of prostate cancer cell population growth in vivo. Study of mechanisms involved revealed that lincRNA-p21 promoted apoptosis and induced expression of p53 downstream genes by regulating p53 binding to their promoters. Finally, we showed that expression of p53 downstream genes was reduced in the malignant prostate tissues, which correlated with lincRNA-p21 level. CONCLUSIONS: Our findings indicated that lincRNA-p21 inhibited development of human prostate cancer partly by regulating p53 downstream gene expression and partly by apoptotic activation. PMID- 27976430 TI - Pure, White and Deadly... Expensive: A Bitter Sweetness in Health Care Expenditure. AB - This paper analyses the impact of sugar availability/intake on diabetes expenditure and on total health care expenditure. Building this macroeconomic analysis upon the literature on the determinants of health care expenditure, we estimate a dynamic panel data model over a sample of 156 countries for the period 1995-2014. After controlling for the traditional determinants of health care spending, we find that an increase in sugar availability/intake leads to a significant rise in diabetes expenditure (per capita and per diabetic) and in the growth rate of total health care expenditure per capita. Moreover, we show that this causal relation is present in both developed and developing countries. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976432 TI - Trichobacteriosis axillaris caused by Dermabacter hominis. PMID- 27976431 TI - Inhibition of adipose tissue PPARgamma prevents increased adipocyte expansion after lipectomy and exacerbates a glucose-intolerant phenotype. AB - OBJECTIVES: Adipose tissue plays a fundamental role in glucose homeostasis. For example, fat removal (lipectomy, LipX) in lean mice, resulting in a compensatory 50% increase in total fat mass, is associated with significant improvement in glucose tolerance. This study was designed to further examine the link between fat removal, adipose tissue compensation and glucose homeostasis using a peroxisome proliferator-activated receptor gamma (PPAR gamma; activator of adipogenesis) knockout mouse. MATERIAL AND METHODS: The study involved PPARgamma knockout (FKOgamma) or control mice (CON), subdivided into groups that received LipX or Sham surgery. We reasoned that as the ability of adipose tissue to expand in response to LipX would be compromised in FKOgamma mice, so would improvements in glucose homeostasis. RESULTS: In CON mice, LipX increased total adipose depot mass (~60%), adipocyte number (~45%) and changed adipocyte distribution to smaller cells. Glucose tolerance was improved (~30%) in LipX CON mice compared to Shams. In FKOgamma mice, LipX did not result in any significant changes in adipose depot mass, adipocyte number or distribution. LipX FKOgamma mice were also characterized by reduction of glucose tolerance (~30%) compared to shams. CONCLUSIONS: Inhibition of adipose tissue PPARgamma prevented LipX-induced increases in adipocyte expansion and produced a glucose-intolerant phenotype. These data support the notion that adipose tissue expansion is critical to maintain and/or improvement in glucose homeostasis. PMID- 27976433 TI - Tuning the Intrinsic Photophysical Properties of Chlorophyll a. AB - In nature, the finely tuned photophysical properties of chlorophyll a (Chla) are vital to the capture and transfer of sunlight during photosynthesis. In order to better understand how these properties are influenced by the molecular environment, we have examined the intrinsic spectroscopy of Chla in vacuo. Visible photodissociation action spectra (an indirect measure of absorption) of gaseous protonated Chla and Chla complexed with metal cations are reported. These show that spectral features within the Soret band (~350-445 nm) have markedly different intensities depending on the identity of the cation. In contrast, fluorescence emission spectra of metalated Chla complexes show only small dependences on the identity of the metal ion, with emission maxima shifting from 661 to 654 nm. Remarkably, replacing the metal ion with a proton turns off the fluorescence of this key pigment. Density functional theory geometry-optimized structures indicate that the most favorable site of protonation differs from that of metal cationization, and may help explain the surprising on/off behavior of Chla's intrinsic fluorescence. PMID- 27976434 TI - Cultural Competence in the Treatment of Addictions: Theory, Practice and Evidence. AB - Culturally and linguistically diverse (CALD) populations often have high rates of addictive disorders, but lower rates of treatment seeking and completion than the mainstream population. A significant barrier to treatment is the lack of culturally relevant and appropriate treatment. A literature review was conducted to identify relevant literature related to cultural competence in mental health services delivery and specifically treatment for addictive disorders. Several theoretical models of cultural competence in therapy have been developed, but the lack of rigorous research limits the empirical evidence available. Research indicates that culturally competent treatment practices including providing therapy and materials in the client's language, knowledge, understanding and appreciation for cultural perspectives and nuances, involving the wider family and community and training therapists can enhance client engagement, retention and treatment outcomes for substance use and gambling. Further methodologically rigorous research is needed to isolate the impact of cultural competence for the treatment of addictions and guide research to determine treatment efficacy within specific CALD populations. Training therapists and recruiting therapists and researchers from CALD communities is important to ensure an ongoing focus and improved outcomes for CALD populations due to the importance of engaging these populations with addiction treatment. Copyright (c) 2016 John Wiley & Sons, Ltd. Key Practitioner Message: The treatment needs of culturally diverse individuals with addictions are often not met. Theoretical models can guide therapists in incorporating cultural competence. Culturally targeted treatments increase recruitment, retention and treatment outcomes. Cultural competence includes matching clinicians and clients on linguistic and cultural backgrounds as well as being mindful of the impact of culture on client's experience of addiction problems. Few methodologically rigorous trials have been conducted to guide treatment practices and research needs to be incorporated into existing culturally relevant treatment services. PMID- 27976435 TI - Manganese-enhanced MRI (ME MRI) in evaluation of the auditory pathway in an experimental rat model. AB - This study aimed to explore the optimal dose and manner of administration for visualization of the auditory pathway on manganese-enhanced MRI (ME MRI). Twenty four healthy male Sprague-Dawley rats were randomly divided into three experimental groups (n = 8 for Groups A, B and C). The rats in Groups A, B and C were subjected to MnCl2 injection through the tympanum, inner ear endolymph and perilymph, respectively (0.2 M for four rats and 0.4 M for the others in each group) and observed at 1, 2, 3, 4, 7 and 10 days after the operation with 3.0 T MRI. The signal intensity (SI) and dynamic changes of the auditory pathways at various times, and at two doses through three injection routes, were compared by statistical analysis. Administration of MnCl2 through the perilymph best showed the complete auditory pathway (P < 0.01), whereas administration though the tympanum only demonstrated part of the pathway. The SI was highest at 24 h after administration of the tracer and began to decline at 48 h. The SI of the auditory cortex was higher after the injection of 0.4 M MnCl2 than that of 0.2 M MnCl2 . ME MRI best demonstrated the whole auditory pathway at 24 h after the injection of 0.4 M MnCl2 through the perilymph in the rat, which provided an optimal method for the study of ME MRI of the auditory pathway in the animal model. PMID- 27976436 TI - Quality of life in childhood, adolescence and adult food allergy: Patient and parent perspectives. AB - BACKGROUND: Studies of children with food allergy typically only include the mother and have not investigated the relationship between the amount of allergen needed to elicit a clinical reaction (threshold) and health-related quality of life (HRQL). Our aims were (i) to compare self-reported and parent-reported HRQL in different age groups, (ii) to evaluate the impact of severity of allergic reaction and threshold on HRQL, and (iii) to investigate factors associated with patient-reported and parent-reported HRQL. METHODS: Age-appropriate Food Allergy Quality of Life Questionnaires (FAQLQ) were completed by 73 children, 49 adolescents and 29 adults with peanut, hazelnut or egg allergy. Parents (197 mothers, 120 fathers) assessed their child's HRQL using the FAQLQ-Parent form. Clinical data and threshold values were obtained from a hospital database. Significant factors for HRQL were investigated using univariate and multivariate regression. RESULTS: Female patients reported greater impact of food allergy on HRQL than males did. Egg and hazelnut thresholds did not affect HRQL, but lower peanut threshold was associated with worse HRQL. Both parents scored their child's HRQL better than the child's own assessment, but whereas mother-reported HRQL was significantly affected by limitations in the child's social life, father reported HRQL was affected by limitations in the family's social life. Severity of allergic reaction did not contribute significantly to HRQL. CONCLUSION: The risk of accidental allergen ingestion and limitations in social life are associated with worse HRQL. Fathers provide a unique perspective and should have a greater opportunity to contribute to food allergy research. PMID- 27976437 TI - Monitoring structural changes in Demodex mites under topical Ivermectin in rosacea by means of reflectance confocal microscopy: a case series. PMID- 27976440 TI - More Speed, More Color, More Visibility, More Chemistry, More Fun! AB - More competitive than ever: Chemistry-A European Journal now offers Accepted Article options for more speed, free color for more distinction, and more engagement with the scientific community through social media for more visibility. In addition, to cater for the growing number of excellent submissions, the journal will publish 72 issues over the coming year. PMID- 27976442 TI - Erratum. PMID- 27976438 TI - Insomnia complaints in lean patients with obstructive sleep apnea negatively affect positive airway pressure treatment adherence. AB - The objective of this study was to evaluate the determinants of long-term adherence to positive airway pressure treatment among patients with obstructive sleep apnea, with special emphasis on patients who stop positive airway pressure treatment within 1 year. This is a prospective long-term follow-up of subjects in the Icelandic Sleep Apnea Cohort who were diagnosed with obstructive sleep apnea between 2005 and 2009, and started on positive airway pressure treatment. In October 2014, positive airway pressure adherence was obtained by systematically evaluating available clinical files (n = 796; 644 males, 152 females) with moderate to severe obstructive sleep apnea (apnea-hypopnea index >=15 events per h). The mean follow-up time was 6.7 +/- 1.2 years. In total, 123 subjects (15.5%) returned their positive airway pressure device within the first year, 170 (21.4%) returned it later and 503 (63.2%) were still using positive airway pressure. The quitters within the first year had lower body mass index, milder obstructive sleep apnea, less sleepiness, and more often had symptoms of initial and late insomnia compared with long-term positive airway pressure users at baseline. Both initial and late insomnia were after adjustment still significantly associated with being an early quitter among subjects with body mass index <30 kg m-2 , but not among those with body mass index >=30 kg m-2 . The prevalence of early quitters decreased significantly during the study period (2005-2009). Almost two thirds of patients with moderate to severe obstructive sleep apnea are positive airway pressure users after 7 years. Obesity level, obstructive sleep apnea severity and daytime sleepiness are important determinants of long-term adherence. Symptoms of initial and late insomnia are associated with early quitting on positive airway pressure among non-obese subjects. PMID- 27976443 TI - Scientific Research and Publication. PMID- 27976439 TI - Prospective multicentre cohort study on 9154 surgical procedures to assess the risk of postoperative bleeding - a DESSI study. AB - BACKGROUND: To date, there is still a debate how to deal with patients receiving antithrombotic agents prior to surgical procedures on the skin. OBJECTIVE: To prospectively assess complications after dermatosurgical interventions, especially bleeding, depending on anticoagulation therapy. METHODS: Patients underwent surgery consecutively as scheduled, without randomization, whether or not they were currently taking anticoagulants. Nine institutions of the DESSI (DErmatoSurgical Study Initiative) working group documented patient data prospectively on a standardized study sheet prior to and after 9154 dermatosurgical interventions. RESULTS: Bleeding complications were observed in 7.14% of cases (654/9154 surgeries). A severe bleed requiring intervention by a physician occurred in 83 surgeries (0.91%). In multivariate analysis, INR, length of the defect, perioperative antibiotic treatment, current treatment with anticoagulation therapy, age and surgery on hidradenitis suppurativa/acne inversa (HS/AI) were significant parameters independently influencing the risk of bleeding. Discontinuation of phenprocoumon therapy and subsequent switching to low molecular weight heparin was associated with the highest risk of bleeding (9.26%). CONCLUSION: Bleeding complications in skin surgery are generally rare. Even if slightly increased complication rates are found in patients taking anticoagulants during skin surgery, platelet inhibitors should not be stopped prior to surgery. If a surgical procedure in patients on a combination therapy of 2 or more antiplatelet cannot be postponed, it should be conducted with the patient remaining on combination therapy. Discontinuation of DOACs is recommended 24 h prior to surgery. Bridging of phenprocoumon should be terminated. In patients with a bleeding history, the INR value should be within the therapeutic range. PMID- 27976447 TI - Impact of sleep restriction versus idealized sleep on emotional experience, reactivity and regulation in healthy adolescents. AB - Sleep loss is associated with affective disturbances and disorders; however, there is limited understanding of specific mechanisms underlying these links, especially in adolescence. The current study tested the effects of sleep restriction versus idealized sleep on adolescents' emotional experience, reactivity and regulation (specifically cognitive reappraisal). Following 1 week of sleep monitoring, healthy adolescents (n = 42; ages 13-17 years) were randomized to 1 night of sleep restriction (4 h) or idealized sleep (9.5 h). The following day, adolescents provided self-reports of affect and anxiety and completed a laboratory-based task to assess: (1) emotional reactivity in response to positive, negative, and neutral images from the International Affective Picture System (IAPS); and (2) ability to use cognitive reappraisal to decrease negative emotional responses. Large effects were observed for the adverse impact of sleep restriction on positive affect and anxiety as well as a medium-sized effect for negative affect, compared to the idealized sleep condition. Subjective reactivity to positive and neutral images did not differ between the groups, but a moderate effect was detected for reactivity to negative images whereby sleep restricted teens reported greater reactivity. Across both sleep conditions, use of cognitive reappraisal down-regulated negative emotion effectively; however, sleep restriction did not impact upon adolescents' ability to use this strategy. These findings add to a growing body of literature demonstrating the deleterious effects of sleep restriction on aspects of emotion and highlight directions for future research in adolescents. PMID- 27976449 TI - Climate change-induced vegetation shifts lead to more ecological droughts despite projected rainfall increases in many global temperate drylands. AB - Drylands occur worldwide and are particularly vulnerable to climate change because dryland ecosystems depend directly on soil water availability that may become increasingly limited as temperatures rise. Climate change will both directly impact soil water availability and change plant biomass, with resulting indirect feedbacks on soil moisture. Thus, the net impact of direct and indirect climate change effects on soil moisture requires better understanding. We used the ecohydrological simulation model SOILWAT at sites from temperate dryland ecosystems around the globe to disentangle the contributions of direct climate change effects and of additional indirect, climate change-induced changes in vegetation on soil water availability. We simulated current and future climate conditions projected by 16 GCMs under RCP 4.5 and RCP 8.5 for the end of the century. We determined shifts in water availability due to climate change alone and due to combined changes of climate and the growth form and biomass of vegetation. Vegetation change will mostly exacerbate low soil water availability in regions already expected to suffer from negative direct impacts of climate change (with the two RCP scenarios giving us qualitatively similar effects). By contrast, in regions that will likely experience increased water availability due to climate change alone, vegetation changes will counteract these increases due to increased water losses by interception. In only a small minority of locations, climate change-induced vegetation changes may lead to a net increase in water availability. These results suggest that changes in vegetation in response to climate change may exacerbate drought conditions and may dampen the effects of increased precipitation, that is, leading to more ecological droughts despite higher precipitation in some regions. Our results underscore the value of considering indirect effects of climate change on vegetation when assessing future soil moisture conditions in water-limited ecosystems. PMID- 27976448 TI - Point-of-care Ultrasound for Nonangulated Distal Forearm Fractures in Children: Test Performance Characteristics and Patient-centered Outcomes. AB - OBJECTIVES: Distal forearm fractures are the most common fracture type in children. Point-of-care-ultrasound (POCUS) is increasingly being used, and preliminary studies suggest that it offers an accurate approach to diagnosis. However, outcomes such as pain, satisfaction, and procedure duration have not been explored but may be salient to the widespread acceptance of this technology by caregivers and children. Our objectives were to examine the test performance characteristics of POCUS for nonangulated distal forearm injuries in children and compare POCUS to x-ray with respect to pain, caregiver satisfaction, and procedure duration. METHODS: We conducted a cross-sectional study involving children aged 4-17 years with a suspected nonangulated distal forearm fracture. Participants underwent both x-ray and POCUS assessment. The primary outcome was sensitivity between POCUS and x-ray, the reference standard. Secondary outcomes included self-reported pain using the Faces Pain Scale-Revised, caregiver satisfaction using a five-item Likert scale, and procedure duration. RESULTS: POCUS was performed in 169 children of whom 76 were diagnosed with a fracture including 61 buckle fractures. Sensitivity of POCUS for distal forearm fractures was 94.7% (95% confidence interval [CI] = 89.7-99.8) and specificity was 93.5% (95% CI = 88.6-98.5). POCUS was associated with a significantly lower median (interquartile range [IQR]) pain score compared to x-ray: 1 (0-2) versus 2 (1-3), respectively (median difference = 0.5; 95% CI = 0.5-1; p < 0.001) and no significant difference in median (IQR) caregiver satisfaction score: 5 (0) versus 5 (4-5), respectively (median difference = 0, 95% CI = 0, p = 1.0). POCUS was associated with a significantly lower median (IQR) procedure duration versus x ray: 1.5 (0.8-2.2) minutes versus 27 (15-58) minutes, respectively (median difference = 34.1, 95% CI = 26.8-41.5, p < 0.001). CONCLUSIONS: Our findings suggest that POCUS assessment of distal forearm injuries in children is accurate, timely, and associated with low levels of pain and high caregiver satisfaction. PMID- 27976450 TI - Studying the Safety and Performance of Rapid Sequence Intubation: Data Collection Method Matters. AB - OBJECTIVE: We sought to describe and compare chart and video review as data collection sources for the study of emergency department (ED) rapid sequence intubation (RSI). METHODS: This retrospective cohort study compares the availability and content of key RSI outcome and process data from two sources: chart and video data from 12 months of pediatric ED RSI. Key outcomes included adverse effects (oxyhemoglobin desaturation, physiologic changes, inadequate paralysis, vomiting), process components (number of laryngoscopy attempts, end tidal CO2 detection), and timing data (duration of preoxygenation and laryngoscopy attempts). RESULTS: We reviewed 566 documents from 114 cases with video data. Video review detected higher rates of adverse effects (67%) than did chart review (46%, p < 0.0001), identifying almost twice the rate of desaturation noted in the chart (34% vs. 18%, p = 0.0002). The performance and timing of key RSI processes were significantly more reliably available via video review (timing and duration of preoxygenation, as well as timing, duration, and number of laryngoscopy attempts, all p < 0.05). Video review identified 221 laryngoscopy attempts, whereas chart review only identified 187. CONCLUSIONS: When compared with video review for retrospective study of RSI in a pediatric ED, chart review significantly underestimated adverse effects, inconsistently contained data on important RSI process elements, rarely provided time data, and often conflicted with observations made on video review. Interpretation of and design of future studies of RSI should take into consideration the quality of the data source. PMID- 27976452 TI - Leaf chlorophyll content as a proxy for leaf photosynthetic capacity. AB - Improving the accuracy of estimates of forest carbon exchange is a central priority for understanding ecosystem response to increased atmospheric CO2 levels and improving carbon cycle modelling. However, the spatially continuous parameterization of photosynthetic capacity (Vcmax) at global scales and appropriate temporal intervals within terrestrial biosphere models (TBMs) remains unresolved. This research investigates the use of biochemical parameters for modelling leaf photosynthetic capacity within a deciduous forest. Particular attention is given to the impacts of seasonality on both leaf biophysical variables and physiological processes, and their interdependent relationships. Four deciduous tree species were sampled across three growing seasons (2013 2015), approximately every 10 days for leaf chlorophyll content (ChlLeaf ) and canopy structure. Leaf nitrogen (NArea ) was also measured during 2014. Leaf photosynthesis was measured during 2014-2015 using a Li-6400 gas-exchange system, with A-Ci curves to model Vcmax. Results showed that seasonality and variations between species resulted in weak relationships between Vcmax normalized to 25 degrees C (Vcmax25) and NArea (R2 = 0.62, P < 0.001), whereas ChlLeaf demonstrated a much stronger correlation with Vcmax25 (R2 = 0.78, P < 0.001). The relationship between ChlLeaf and NArea was also weak (R2 = 0.47, P < 0.001), possibly due to the dynamic partitioning of nitrogen, between and within photosynthetic and nonphotosynthetic fractions. The spatial and temporal variability of Vcmax25 was mapped using Landsat TM/ETM satellite data across the forest site, using physical models to derive ChlLeaf . TBMs largely treat photosynthetic parameters as either fixed constants or varying according to leaf nitrogen content. This research challenges assumptions that simple NArea -Vcmax25 relationships can reliably be used to constrain photosynthetic capacity in TBMs, even within the same plant functional type. It is suggested that ChlLeaf provides a more accurate, direct proxy for Vcmax25 and is also more easily retrievable from satellite data. These results have important implications for carbon modelling within deciduous ecosystems. PMID- 27976451 TI - Arteriogenesis in murine adipose tissue is contingent on CD68+ /CD206+ macrophages. AB - OBJECTIVE: The surgical transfer of skin, fat, and/or muscle from a donor site to a recipient site within the same patient is a widely performed procedure in reconstructive surgeries. A surgical pretreatment strategy that is intended to increase perfusion in the flap, termed "flap delay," is a commonly employed technique by plastic surgeons prior to flap transplantation. Here, we explored whether CD68+ /CD206+ macrophages are required for arteriogenesis within the flap by performing gain-of-function and loss-of-function studies in a previously published flap delay murine model. METHODS AND RESULTS: Local injection of M2 polarized macrophages into the flap resulted in an increase in collateral vessel diameter. Application of a thin biomaterial film loaded with a pharmacological agent (FTY720), which has been previously shown to recruit CD68+ /CD206+ macrophages to remodeling tissue, increased CD68+ /CD206+ cell recruitment and collateral vessel enlargement. Conversely, when local macrophage populations were depleted within the inguinal fat pad via clodronate liposome delivery, we observed fewer CD68+ cells accompanied by diminished collateral vessel enlargement. CONCLUSIONS: Our study underscores the importance of macrophages during microvascular adaptations that are induced by flap delay. These studies suggest a mechanism for a translatable therapeutic target that may be used to enhance the clinical flap delay procedure. PMID- 27976453 TI - Seasonality constraints to livestock grazing intensity. AB - Increasing food production is essential to meet the future food demand of a growing world population. In light of pressing sustainability challenges such as climate change and the importance of the global livestock system for food security as well as GHG emissions, finding ways to increasing food production sustainably and without increasing competition for food crops is essential. Yet, many unknowns relate to livestock grazing, in particular grazing intensity, an essential variable to assess the sustainability of livestock systems. Here, we explore ecological limits to grazing intensity (GI; i.e. the fraction of net primary production consumed by grazing animals) by analysing the role of seasonality in natural grasslands. We estimate seasonal limitations to GI by combining monthly net primary production data and a map of global livestock distribution with assumptions on the length of nonfavourable periods that can be bridged by livestock (e.g. by browsing dead standing biomass, storage systems or biomass conservation). This allows us to derive a seasonality-limited potential GI, which we compare with the GI prevailing in 2000. We find that GI in 2000 lies below its potential on 39% of the total global natural grasslands, which has a potential for increasing biomass extraction of up to 181 MtC/yr. In contrast, on 61% of the area GI exceeds the potential, made possible by management. Mobilizing this potential could increase milk production by 5%, meat production by 4% or contribute to free up to 2.8 Mio km2 of grassland area at the global scale if the numerous socio-ecological constraints can be overcome. We discuss socio ecological trade-offs, which may reduce the estimated potential considerably and require the establishment of sound monitoring systems and an improved understanding of livestock system's role in the Earth system. PMID- 27976454 TI - Zika virus: Future reproductive concerns. AB - The pandemic spread of Zika virus (ZIKV), a member of the flavivirus genus of the Flaviviridae family, has become a major public health concern. Reproductive specialists are particularly concerned over the spread of ZIKV as it is now known to have both sexual and transplacental routes of transmission resulting in fetal congenital abnormalities. Other members of the Flaviviridae family, hepatitis C virus (HCV) and bovine viral diarrhea virus (BVDV) (which primarily affects cattle), are well known to reproductive specialists as both sexually transmitted illnesses that are capable of vertical transmission. Congenital infection with BVDV also has a predilection for neuro-teratogenicity as has been seen with ZIKV. HCV and BVDV are also known to be capable of persistent infection in offspring. Could this be the case with ZIKV? Examining what we know about HCV and BVDV, in addition to what we have already learned about ZIKV, may answer some of the questions that remain about ZIKV. Herein, we review the current literature as it pertains to ZIKV vertical transmission and neuro-teratogenicity and compare it to what is known about HCV and BVDV. PMID- 27976455 TI - Evaluation of the p-AKT, p-JNK and FoxO3a function in oral epithelial dysplasia. AB - OBJECTIVES: To evaluate the expression of p-AKT, p-JNK, FoxO3a, and Ki-67 in samples of oral squamous cell carcinoma (OSCC) and oral epithelial dysplasias (OEDs) to understand their possible involvement in the malignant transformation process of oral lesions. MATERIALS AND METHODS: Tissue samples of 20 cases of OSCCs, 20 OEDs, and normal oral mucosa were subjected to immunohistochemistry reactions for anti-p-AKT, anti-p-JNK, anti-FoxO3a, and anti-Ki-67 antibodies. It was analyzed using quantitative (number of immunostained cells) and qualitative (immunostaining intensity) parameters in different cell immunostaining sublocations. RESULTS: Nuclear p-AKT was observed significantly greater immunostaining in OSCC (21.2 +/- 19.0) than in dysplasias (7.9 +/- 8.1) and controls (1.8 +/- 4.7) (P = 0.002). Immunostaining of strong nuclear p-JNK was greater in controls (48.3 +/- 13.7) than in OEDs (11.0 +/- 10.3) and OSCCs (1.1 +/- 1.3) (P < 0.001). Strong nuclear immunostaining of FoxO3a proved to be absent in OSCCs (0.0 +/- 0.1) with little staining on dysplasias (3.2 +/- 5.4) and increased expression in controls (13.5 +/- 4.8) (P < 0.001). Immunostaining of strong nuclear Ki-67 was grater in OSCCs (48.1 +/- 49.6) than in OED (11.8 +/- 10.6) and controls (1.9 +/- 2.0) (P < 0.001). CONCLUSIONS: Malignant process of OEDs in this research may involve the same mechanisms of established malignant lesions. PMID- 27976456 TI - Neoatherosclerosis after paclitaxel-eluting stent implantation: Ex vivo intravascular image and histopathology. PMID- 27976457 TI - Global Health and Emergency Care: Overcoming Clinical Research Barriers. AB - OBJECTIVES: There are many barriers impeding the conduct of high-quality emergency care research, particularly in low- and middle-income countries. Several of these barriers were originally outlined in 2013 as part of the Academic Emergency Medicine Global Health and Emergency Care Consensus Conference. This paper seeks to establish a broader consensus on the barriers to emergency care research globally and proposes a comprehensive array of new recommendations to overcome these barriers. METHODS: An electronic survey was conducted of a purposive sample of global emergency medicine research experts from around the world to describe the major challenges and solutions to conducting emergency care research in low-resource settings and rank them by importance. The Global Emergency Medicine Think Tank Clinical Research Working Group at the Society for Academic Emergency Medicine 2016 Annual Meeting utilized a modified Delphi technique for consensus-based decision making to categorize and expand upon these barriers and develop a comprehensive array of proposed solutions. RESULTS: The working group identified four broad categories of barriers to conducting emergency care research globally, including 1) the limited availability of research personnel, particularly those with prior research training; 2) logistic barriers and lack of standardization of data collection; 3) ethical barriers to conducting research in resource-limited settings, particularly when no local institutional review board is available; and 4) the relative dearth of funding for global emergency care research. Proposed solutions included building a diverse and interdisciplinary research team structured to promote mentorship of junior researchers, utilizing local research assistants or technologic tools such as telemedicine for language translation, making use of new tools such as mobile health (mHealth) to standardize and streamline data collection, identifying alternatives to local institutional review board approval and the use of community consent when appropriate, and increased advocacy for global emergency care research funding. CONCLUSIONS: Significant barriers to the conduct of high-quality global emergency care research persist, and innovative strategies need to be adopted to promote and grow the field of global emergency care research. This paper provides a global consensus on the most important barriers identified, as well as recommendations for cost-effective strategies for overcoming these barriers with the overall goal of promoting high-quality research and improving emergency care worldwide. PMID- 27976458 TI - Grassland gross carbon dioxide uptake based on an improved model tree ensemble approach considering human interventions: global estimation and covariation with climate. AB - Grassland ecosystems act as a crucial role in the global carbon cycle and provide vital ecosystem services for many species. However, these low-productivity and water-limited ecosystems are sensitive and vulnerable to climate perturbations and human intervention, the latter of which is often not considered due to lack of spatial information regarding the grassland management. Here by the application of a model tree ensemble (MTE-GRASS) trained on local eddy covariance data and using as predictors gridded climate and management intensity field (grazing and cutting), we first provide an estimate of global grassland gross primary production (GPP). GPP from our study compares well (modeling efficiency NSE = 0.85 spatial; NSE between 0.69 and 0.94 interannual) with that from flux measurement. Global grassland GPP was on average 11 +/- 0.31 Pg C yr-1 and exhibited significantly increasing trend at both annual and seasonal scales, with an annual increase of 0.023 Pg C (0.2%) from 1982 to 2011. Meanwhile, we found that at both annual and seasonal scale, the trend (except for northern summer) and interannual variability of the GPP are primarily driven by arid/semiarid ecosystems, the latter of which is due to the larger variation in precipitation. Grasslands in arid/semiarid regions have a stronger (33 g C m-2 yr-1 /100 mm) and faster (0- to 1-month time lag) response to precipitation than those in other regions. Although globally spatial gradients (71%) and interannual changes (51%) in GPP were mainly driven by precipitation, where most regions with arid/semiarid climate zone, temperature and radiation together shared half of GPP variability, which is mainly distributed in the high-latitude or cold regions. Our findings and the results of other studies suggest the overwhelming importance of arid/semiarid regions as a control on grassland ecosystems carbon cycle. Similarly, under the projected future climate change, grassland ecosystems in these regions will be potentially greatly influenced. PMID- 27976459 TI - Current perspectives in coronary microvascular dysfunction. AB - The coronary arterial system consists of large epicardial coronary arteries, pre arterioles, and arterioles, which together closely regulate CBF. Structural, functional, and extravascular abnormalities of the microcirculation lead to CMD. CMD can present with symptoms suggestive of CAD, often in the absence of significant obstructive epicardial CAD. Conventional invasive angiography does not allow direct visualization of the microcirculation. Invasive indices, such as CBF and CFR, and non-invasive imaging modalities, such as CMR and PET, can be used to quantify absolute MBF and enable a direct and accurate assessment of coronary microvascular function. CMD appears to be more prevalent in women, typically presenting with symptoms of ischemia with unobstructed coronary arteries, and has a relatively unfavorable prognosis. CMD is classified clinically depending on the presence or absence of epicardial CAD, myocardial disease, or iatrogenic causes. Although invasive intracoronary techniques can be used to detect CMD, these cannot provide insight into the mechanisms involved in its pathogenesis. Imaging modalities such as CMR and cardiac PET are becoming indispensable tools in the evaluation of suspected CMD. PMID- 27976460 TI - Interventional therapies and in-hospital outcomes in acute coronary syndromes complicated by von Willebrand disease. AB - INTRODUCTION: von Willebrand disease (VWD) is one of the most common inherited bleeding disorders. AIM: Investigate the impact of the VWD bleeding tendency on in-hospital management of acute coronary syndromes (ACS). METHODS: Using discharge data from the National Inpatient Sample (NIS), the features of presentation and in-hospital treatment among ACS hospital discharges with and without a VWD diagnosis were investigated. A total of 264 case discharges and 705 860 control discharges were identified. RESULTS AND CONCLUSIONS: There was a significantly higher percentage of women among the case discharges compared to the control discharges (59.5% and 39.4%, respectively; P < 0.001). The rate of medical therapy alone [i.e. avoidance of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)] was significantly higher among unstable angina cases than controls (55.0% vs. 46.4%; P = 0.01), and among cases undergoing PCI, bare-metal stents (BMS) were utilized in preference to drug eluting stents (DES) (adjusted OR = 3.5); P < 0.001). No difference in in hospital death was identified, but reported bleeding among discharges that underwent CABG was higher in cases compared to controls (12.9% vs. 5.2%; P = 0.047). Although medical and interventional management of ACS appears to be well tolerated in the majority of hospitalized patients with VWD, the gender ratio is reversed, interventions and DES are utilized less frequently and procedure related bleeding may be increased, calling for further study. PMID- 27976462 TI - Global thermal niche models of two European grasses show high invasion risks in Antarctica. AB - The two non-native grasses that have established long-term populations in Antarctica (Poa pratensis and Poa annua) were studied from a global multidimensional thermal niche perspective to address the biological invasion risk to Antarctica. These two species exhibit contrasting introduction histories and reproductive strategies and represent two referential case studies of biological invasion processes. We used a multistep process with a range of species distribution modelling techniques (ecological niche factor analysis, multidimensional envelopes, distance/entropy algorithms) together with a suite of thermoclimatic variables, to characterize the potential ranges of these species. Their native bioclimatic thermal envelopes in Eurasia, together with the different naturalized populations across continents, were compared next. The potential niche of P. pratensis was wider at the cold extremes; however, P. annua life history attributes enable it to be a more successful colonizer. We observe that particularly cold summers are a key aspect of the unique Antarctic environment. In consequence, ruderals such as P. annua can quickly expand under such harsh conditions, whereas the more stress-tolerant P. pratensis endures and persist through steady growth. Compiled data on human pressure at the Antarctic Peninsula allowed us to provide site-specific biosecurity risk indicators. We conclude that several areas across the region are vulnerable to invasions from these and other similar species. This can only be visualized in species distribution models (SDMs) when accounting for founder populations that reveal nonanalogous conditions. Results reinforce the need for strict management practices to minimize introductions. Furthermore, our novel set of temperature based bioclimatic GIS layers for ice-free terrestrial Antarctica provide a mechanism for regional and global species distribution models to be built for other potentially invasive species. PMID- 27976461 TI - Safety and efficacy of direct-acting antivirals for the treatment of chronic hepatitis C in a real-world population aged 65 years and older. AB - The availability of direct-acting antiviral agents (DAA) regimens has expanded the pool of patients eligible for treatment. However, data on the virologic response and tolerability of DAAs in elderly patients are lacking. We evaluated the efficacy and safety of DAAs in patients with advanced fibrosis/cirrhosis in real-life practice with the focus on those aged >=65 years. Between January and December 2015, all consecutive patients with HCV-related advanced fibrosis/cirrhosis treated with DAA at eleven tertiary referral centres in Emilia Romagna (Italy) were enrolled. Regimen choice was based on viral genotype and stage of disease, according to guidelines. The primary end point was sustained virologic response 12 weeks after the end of treatment (SVR12). Overall, 282 of 556 (50.7%) patients evaluated were elderly, most of them with cirrhosis. Antiviral therapy was stopped prematurely in four (1.4%) patients. Two patients, both with cirrhosis, died during treatment due to worsening of liver/renal function. SVR12 was achieved by 94.7% and was comparable to that obtained in patients aged <65 (P=.074). Similar data were also reported in subgroup of patients aged >=75 years. All patients with advanced fibrosis achieved virologic response. SVR12 was 80.8% in Child-Pugh-Turcotte (CTP)-B cirrhosis and 95.4% in CTP-A (P=.013). According to genotype, the SVR12 was achieved in 172 of 181 (95%) with genotype 1b cirrhosis and in 44 of 48 (91.7%) with genotype 2 cirrhosis. In conclusions, in a real-world setting, DAAs are safe and effective in elderly patients with HCV-related advanced fibrosis/cirrhosis, but SVR12 is lower with worsening CTP class. PMID- 27976463 TI - High expression of programmed cell death 1 ligand 1 in lung adenocarcinoma is a poor prognostic factor particularly in smokers and wild-type epidermal growth factor receptor cases. AB - A clinical implication of programmed cell death 1 ligand 1 (PD-L1) expression in lung adenocarcinoma has not been well established. We evaluated PD-L1 expression immunohistochemically on 296 surgically resected lung adenocarcinomas to investigate a clinical implication of PD-L1 expression especially in terms of smoking history and epidermal growth-factor receptor (EGFR) mutation status. Patients were classified into high- and low-PD-L1 expression groups. The high expression group (n = 107) showed a significantly higher proportion of smokers and poor differentiation compared with the low-expression group (n = 189). Survival analysis showed that the prognosis of the high-expression group was worse in overall survival than that of the low-expression group (3-year overall survival 85 vs. 94%, P = 0.005). Stratified survival analyses showed that the prognoses of the high-expression group were worse than those of the low expression group in both strata of smokers and wild-type EGFR (P = 0.009 and P = 0.007, respectively). We found that high PD-L1 expression was a poor prognostic factor in the smokers or the patients with wild-type EGFR, whereas it was not the case in those who never smoked or those with EGFR mutation, implying the importance of adenocarcinoma driver mutations and etiology. PMID- 27976465 TI - Determination of the Nail Psoriasis Severity Index improvement rate standards for nail psoriasis treatment in a phase IV clinical trial of ustekinumab: the MARCOPOLO study. PMID- 27976464 TI - Methods for Collecting Paired Observations From Emergency Medical Services and Emergency Department Providers for Pediatric Cervical Spine Injury Risk Factors. AB - OBJECTIVES: Cervical spine injuries (CSIs) after blunt trauma in children are rare, but cause substantial morbidity and mortality. Emergency medical services (EMS) and emergency department (ED) providers routinely use spinal precautions and cervical spine imaging, respectively, during the management of children experiencing blunt trauma. These practices lack evidence, and there is concern that they may be harmful. A pediatric CSI risk assessment tool is needed to inform EMS and ED provider decision making. Creating this tool requires prospective data collection from EMS and ED providers at the time of patient evaluation. The purpose of this article is to describe the methods used to prospectively capture paired EMS and ED provider observations of children cared for after blunt trauma. Given the rarity of prospective observational research with EMS, the novel use of Research Electronic Data Capture (REDCap) in this study, and the potential to inform future studies, we are publishing our methodology in advance of outcome data related to the risk assessment tool. METHODS: The study was conducted at four tertiary children's hospitals as a prerequisite for a planned larger study to derive a CSI risk assessment tool. We created a web-based, branch-logic questionnaire using the REDCap data collection system. The survey was administered via tablet computer to ED providers evaluating children with blunt trauma and, if applicable, to EMS providers who provided patient care at the scene. We collected information regarding factors determined a priori to be plausibly associated with CSI in children. Eligible children presenting to the ED after blunt trauma with at least one of the following one of the following were included: prehospital EMS spinal precautions, ED trauma team evaluation, or cervical spine imaging in the ED. Exclusions included penetrating trauma, language barrier, or state's custody. Enrollment occurred when research coordinators (RCs) were available, generally 12-16 hours/day. RCs approached EMS providers prior to departing the ED and ED providers after they completed their patient assessments. An ED provider survey was required for enrollment. Enrolled children were followed for 28 days to determine the presence of CSI (primary outcome) by subsequent imaging or by patient/family telephone follow-up for those without imaging. RESULTS: Over 18 months, we prospectively enrolled 4,144 of 5,764 (71.9%) eligible children, including 74 of 110 (67.3%) children diagnosed with CSI. Enrollment during RC hours was 85.9%. Fifty-three enrolled children were withdrawn from the study. Of those in the final study cohort, 36.5% arrived by EMS scene response in spinal precautions. The remaining 63.5% arrived by EMS scene response without spinal precautions or by private vehicle or interfacility transfer. EMS scene response providers completed surveys for 60.2% of enrolled children arriving in spinal precautions. RCs missed the EMS providers for 37.1% of children; however, EMS declined participation for only 2.6%. CONCLUSIONS: Our method of data collection demonstrates the ability to prospectively capture paired observations from EMS and ED personnel for children undergoing evaluation after blunt trauma. While this methodology will be used to implement and evaluate a CSI tool in future studies, it may also be adapted to studies requiring prospective data collection from EMS and ED personnel. PMID- 27976466 TI - Fast Sampling, Analyses and Chemometrics for Plant Breeding: Bitter Acids, Xanthohumol and Terpenes in Lupulin Glands of Hops (Humulus lupulus). AB - INTRODUCTION: The valuable secondary metabolites in hops (bitter acids, xanthohumol, volatile monoterpenes and sesquiterpenes) are sequestered in lupulin glands (extracellular trichomes) which can be collected and analysed with little or no sample preparation. OBJECTIVES: To determine whether high throughput screening of lupulin glands composition, by fast analyses and chemometrics, could be used for breeder selection of hops with key flavour attributes. METHODS: Lupulin glands from 139 plants (39 cultivars/advanced selections) were analysed by Raman and 1 H NMR spectroscopy, and head-space solid-phase microextraction (HS SPME) GC-FID. The digital X,Y-data were subjected to principal component analysis (PCA) and the results compared with conventional analyses of extracts of whole hops from the same plants. Quantitative 1 H NMR analyses were also done for the bitter acids. RESULTS: Raman spectroscopy rapidly identified hops cultivars with high xanthohumol concentrations and high alpha:beta bitter acid ratios. 1 H NMR spectroscopy was slower, requiring a solvent extraction, but distinguished cultivars by cohumulone content as well as alpha:beta acid ratios. HS-SPME-GC rapidly distinguished aroma hops with high myrcene and farnesene contents, and pinpointed a novel selection with unusual sesquiterpenes. The quantitative NMR analyses showed correlations between bitter acid concentrations related to biosynthetic pathways. CONCLUSIONS: Analysis of lupulin glands gave reliable results for the main quality indicators used by hops breeders, potentially avoiding harvesting, drying and solvent extracting whole hops. PCA of digital X,Y data rapidly discriminated different hops chemotypes, and highlighted plants with potential for new flavourcultivars. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976467 TI - Rapid Species-level Identification of Salvias by Chemometric Processing of Ambient Ionisation Mass Spectrometry-derived Chemical Profiles. AB - INTRODUCTION: The Salvia genus contains numerous economically important plants that have horticultural, culinary and nutraceutical uses. They are often similar in appearance, making species determination difficult. Species identification of dried Salvia products is also challenging since distinguishing plant morphological features are no longer present. OBJECTIVE: The development of a simple high-throughput method of analysis of fresh and dried Salvia leaves that would permit rapid species-level identification and detection of diagnostic biomarkers. METHODOLOGY: Plant leaves were analysed in their native form by DART MS without the need for any sample preparation steps. This furnished chemical fingerprints characteristic of each species. In the same experiment, in-source collision-induced dissociation was used to identify biomarkers. Biomarker presence was also independently confirmed by GC-MS. Chemometric processing of DART-MS profiles was performed by kernel discriminant analysis (KDA) and soft independent modelling of class analogy (SIMCA) to classify the fingerprints according to species. RESULTS: The approach was successful despite the occurrence of diurnal cycle and plant-age related chemical profile variations within species. In a single rapid experiment, the presence of essential oil biomarkers such as 3-carene, alpha-pinene, beta-pinene, beta-thujone, beta-caryophyllene, camphor and borneol could be confirmed. The method was applied to rapid identification and differentiation of Salvia apiana, S. dominica, S. elegans, S. officinalis, S. farinacea and S. patens. CONCLUSION: Species-level identification of Salvia plant material could be accomplished by chemometric processing of DART HRMS-derived chemical profiles of both fresh and dried Salvia material. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976468 TI - Molecular Fingerprint Comparison of Closely Related Rose Varieties based on UHPLC HRMS Analysis and Chemometrics. AB - INTRODUCTION: The "Jardin de Granville" modern rose variety not only combines the morphological properties of its two parental cultivars, but also possesses better agronomic characteristics (abundant blooms, strong growth and vitality, high resistance to common rose diseases). In addition, it shows remarkable biological properties such as a high ability to decrease inflammatory and oxidative stress on skin cells. That is why Parfums Christian Dior selected this rose variety to be an active ingredient in luxury cosmetics. OBJECTIVES: To identify the characteristic molecular signature of "Jardin de Granville" compared with its parents "Annapurna" and "John Clare", by the mean of a non-targeted metabolomic comparison. MATERIAL AND METHODS: Wood, flower and leaf hydro-alcoholic extracts were analysed by UHPLC-ESI-HRMS. The fingerprints were then submitted to unsupervised multivariate analyses involving principal component analysis (PCA) and hierarchical ascendant classification (HAC). Analysis of variance (ANOVA) was finally performed to highlight the significant differences in each group of organs. RESULTS: The extracts were composed of phenolic compounds such as hydrolysable and condensed tannins and flavonol derivatives. Three groups of extracts were clustered as a function of the variety. The compounds overexpressed in "Jardin de Granville" variety were highlighted thanks to ANOVA test. Flower was the most discriminative organ with 15 overexpressed molecules. Auto MS/MS analyses led to their tentative identifications. CONCLUSION: The non-targeted metabolomic approach revealed the importance of tannins to discriminate close rose varieties. The overexpressed hydrolysable tannins characteristic of "Jardin de Granville" can be responsible for the antioxidant and anti-inflammatory properties of the rose cosmetic ingredients. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976469 TI - NMR-based Metabolomics to Study the Cold-acclimation Strategy of Two Miscanthus Genotypes. AB - INTRODUCTION: Abiotic stress is a major cause of yield loss in plant culture. Miscanthus, a perennial C4 grass, is now considered a major source of renewable energy, especially for biofuel production. During the first year of planting in Northern Europe, Miscanthus was exposed to frost temperature, which generated high mortality in young plants and large loss of yield. One strategy to avoid such loss is to apply cold-acclimation, which confers on plants a better resistance to low temperature. OBJECTIVES: The aim of this study is to describe the effect of a cold-acclimation period on the metabolome of two Miscanthus genotypes that vary in their frost sensitivity at the juvenile stage. Miscanthus * giganteus (GIG) is particularly sensitive to frost, whereas Miscanthus sinensis August Feder (AUG) is tolerant. MATERIALS AND METHODS: Polar metabolite extraction was performed on Miscanthus, grown in non-acclimated or cold acclimated conditions. Extracts were analysed by 1 H-NMR followed by multivariate statistical analysis. Discriminant metabolites were identified. RESULTS: More than 40 metabolites were identified in the two Miscanthus genotypes. GIG and AUG showed a different metabolic background before cold treatment, probably related to their genetic background. After cold-acclimation, GIG and AUG metabolomes remained different. The tolerant genotype showed notably higher levels of accumulation in proline, sucrose and maltose when subjected to cold. CONCLUSION: These two genotypes seem to have a different adaptation strategy in cold conditions. The studied change in the metabolome concerns different types of molecules related to the cold-tolerant behaviour of Miscanthus. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976471 TI - Coxiella burnetii: Serological reactions and bacterial shedding in primiparous dairy cows in an endemically infected herd-impact on milk yield and fertility. AB - Coxiella burnetii (C. burnetii) is the causative agent of Q fever both in humans and animals. The objectives of this study were to investigate seropositivity and bacterial shedding in heifers and primiparous cows in an endemically infected herd and to assess the effects on post-partum diseases, fertility and milk production. At the age of 9 months, 96 Holstein heifers were included. Sampling was performed reproduction-orientated: at the beginning of the study, at detection of first pregnancy, 3 weeks before expected calving date (blood serum), at parturition and after 21, 42, 100 and 150 days in milk (DIM) (blood serum, vaginal swabs and milk). Serum samples were investigated by a commercial ELISA for the presence of specific antibodies and vaginal swabs and milk samples by PCR to detect C. burnetii DNA. Individual animal data (calving ease, stillbirth, retained foetal membranes, puerperal metritis, endometritis after 42 DIM, presence of corpus luteum after 42 DIM, interval calving-first service, interval calving-conception, number of inseminations until 150 DIM, proportion of pregnant cows until 100 and 150 DIM, proportion of pregnant cows after first service and data of the dairy herd improvement test) were documented. All heifers were seronegative at the age of 9 months and 3 weeks before the expected calving date. Subsequently, the proportion of seropositive animals and the antibody score increased significantly towards 42 and 100 DIM, respectively. Vaginal C. burnetii shedding was highest at parturition (30.9%), while the most positive milk samples were detected after 100 DIM (15.3%). Coxiella burnetii seropositivity and shedding had no impact on parameters of reproduction. However, milk fat yield was declined in puerperal vaginal shedders and cows which seroconverted during their first 42 DIM, respectively. PMID- 27976470 TI - ESI-MS2 and Anti-inflammatory Studies of Cyclopropanic Triterpenes. UPLC-ESI-MS and MS2 Search of Related Metabolites from Donella ubanguiensis. AB - INTRODUCTION: Triterpenes are one of the largest secondary metabolites groups spread in the plant kingdom with various skeletons. These metabolites have showed various bioactivities including anti-inflammatory activity. OBJECTIVE: The study aims to explore the mass spectrometry fragmentation of donellanic acids A-C (DA A C), three compounds identified from Donella ubanguiensis; in addition, the fragmentation behaviour of these metabolites will serve as a fingerprint to search and characterise triterpenes congeners in fruits, bark and wood crude extracts of D. ubanguiensis. This work was prompted by the anti-inflammatory activity on leukocyte migration, exudate concentrations and myeloperoxidase activity obtained for DA A-B. METHODOLOGY: The bioactivity was performed on mouse model of pleurisy induced by carrageenan and the parameters were analysed by veterinarian automated cell counter and colorimetric assays. While the tandem mass analyses of DA A-C were carried out by a direct infusion ESI-QTOF-MS/MS, the extracts were studied by UPLC-ESI-QTOF-MS and UPLC-ESI-QTOF-MS/MS. RESULTS: DA A displayed interesting anti-inflammatory activity by inhibiting leukocyte migration, exudate concentrations and myeloperoxidase activity (p < 0.05) while DA B was weakly active (p > 0.05). Moreover, the diagnostic of the MS2 behaviour of DA A-C in conjunction with the chromatograms and the obtained MS2 data of the crude extract led to the characterisation of three cyclopropane triterpenes (T1 T3) and six saponins (T4-T9) from the fruits, the bark, and the wood extracts. CONCLUSIONS: Donella species deserve more investigation since metabolites related to the anti-inflammatory compound (DA A) could be identified. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976472 TI - Why patients self-refer to the Emergency Department: A qualitative interview study. AB - RATIONALE, AIMS, AND OBJECTIVES: There have been multiple studies investigating reasons for patients to self-refer to the Emergency Department (ED). The majority made use of questionnaires and excluded patients with urgent conditions. The goal of this qualitative study is to explore what motives patients have to self-refer to an ED, also including patients in urgent triage categories. METHODS: In a large teaching hospital in the Netherlands, a qualitative interview study focusing on reasons for self-referring to the ED was performed. Self-referred patients were included until no new reasons for attending the ED were found. Exclusion criteria were as follows: not mentally able to be interviewed or not speaking Dutch. Patients who were in need of urgent care were treated first, before being asked to participate. Interviews followed a predefined topic guide. Practicing cyclic analysis, the interview topic guide was modified during the inclusion period. Interviews were recorded on an audio recorder, transcribed verbatim, and anonymized. Two investigators independently coded the information and combined the codes into meaningful clusters. Subsequently, these were categorized into themes to build a framework of reasons for self-referral to the ED. Characteristic quotes were used to illustrate the acquired theoretical framework. RESULTS: Thirty self-referred patients were interviewed. Most of the participants were male (63%), with a mean age of 46 years. Two main themes emerged from the interviews that are pertinent to the patients' decisions to attend the ED: (1) health concerns and (2) practical issues. CONCLUSIONS: This study found that there are 2 clearly distinctive reasons for self-referral to the ED: health concerns or practical motives. Self-referral because of practical motives is probably most suitable for strategies that aim to reduce inappropriate ED visits. PMID- 27976473 TI - Risky future for Mediterranean forests unless they undergo extreme carbon fertilization. AB - Forest performance is challenged by climate change but higher atmospheric [CO2 ] (ca ) could help trees mitigate the negative effect of enhanced water stress. Forest projections using data assimilation with mechanistic models are a valuable tool to assess forest performance. Firstly, we used dendrochronological data from 12 Mediterranean tree species (six conifers and six broadleaves) to calibrate a process-based vegetation model at 77 sites. Secondly, we conducted simulations of gross primary production (GPP) and radial growth using an ensemble of climate projections for the period 2010-2100 for the high-emission RCP8.5 and low emission RCP2.6 scenarios. GPP and growth projections were simulated using climatic data from the two RCPs combined with (i) expected ca ; (ii) constant ca = 390 ppm, to test a purely climate-driven performance excluding compensation from carbon fertilization. The model accurately mimicked the growth trends since the 1950s when, despite increasing ca , enhanced evaporative demands precluded a global net positive effect on growth. Modeled annual growth and GPP showed similar long-term trends. Under RCP2.6 (i.e., temperatures below +2 degrees C with respect to preindustrial values), the forests showed resistance to future climate (as expressed by non-negative trends in growth and GPP) except for some coniferous sites. Using exponentially growing ca and climate as from RCP8.5, carbon fertilization overrode the negative effect of the highly constraining climatic conditions under that scenario. This effect was particularly evident above 500 ppm (which is already over +2 degrees C), which seems unrealistic and likely reflects model miss-performance at high ca above the calibration range. Thus, forest projections under RCP8.5 preventing carbon fertilization displayed very negative forest performance at the regional scale. This suggests that most of western Mediterranean forests would successfully acclimate to the coldest climate change scenario but be vulnerable to a climate warmer than +2 degrees C unless the trees developed an exaggerated fertilization response to [CO2 ]. PMID- 27976474 TI - Chlorophyll fluorescence tracks seasonal variations of photosynthesis from leaf to canopy in a temperate forest. AB - Accurate estimation of terrestrial gross primary productivity (GPP) remains a challenge despite its importance in the global carbon cycle. Chlorophyll fluorescence (ChlF) has been recently adopted to understand photosynthesis and its response to the environment, particularly with remote sensing data. However, it remains unclear how ChlF and photosynthesis are linked at different spatial scales across the growing season. We examined seasonal relationships between ChlF and photosynthesis at the leaf, canopy, and ecosystem scales and explored how leaf-level ChlF was linked with canopy-scale solar-induced chlorophyll fluorescence (SIF) in a temperate deciduous forest at Harvard Forest, Massachusetts, USA. Our results show that ChlF captured the seasonal variations of photosynthesis with significant linear relationships between ChlF and photosynthesis across the growing season over different spatial scales (R2 = 0.73, 0.77, and 0.86 at leaf, canopy, and satellite scales, respectively; P < 0.0001). We developed a model to estimate GPP from the tower-based measurement of SIF and leaf-level ChlF parameters. The estimation of GPP from this model agreed well with flux tower observations of GPP (R2 = 0.68; P < 0.0001), demonstrating the potential of SIF for modeling GPP. At the leaf scale, we found that leaf Fq '/Fm ', the fraction of absorbed photons that are used for photochemistry for a light-adapted measurement from a pulse amplitude modulation fluorometer, was the best leaf fluorescence parameter to correlate with canopy SIF yield (SIF/APAR, R2 = 0.79; P < 0.0001). We also found that canopy SIF and SIF-derived GPP (GPPSIF ) were strongly correlated to leaf-level biochemistry and canopy structure, including chlorophyll content (R2 = 0.65 for canopy GPPSIF and chlorophyll content; P < 0.0001), leaf area index (LAI) (R2 = 0.35 for canopy GPPSIF and LAI; P < 0.0001), and normalized difference vegetation index (NDVI) (R2 = 0.36 for canopy GPPSIF and NDVI; P < 0.0001). Our results suggest that ChlF can be a powerful tool to track photosynthetic rates at leaf, canopy, and ecosystem scales. PMID- 27976475 TI - Regulation of bone remodeling by vitamin K2. AB - All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, minerals, vitamins, and water. The skeleton requires nutrients for development, maintaining bone mass and density. If the skeletal nutritional requirements are not met, the consequences can be quite severe. In recent years, there has been growing interest in promotion of bone health and inhibition of vascular calcification by vitamin K2. This vitamin regulates bone remodeling, an important process necessary to maintain adult bone. Bone remodeling involves removal of old or damaged bone by osteoclasts and its replacement by new bone formed by osteoblasts. The remodeling process is tightly regulated, when the balance between bone resorption and bone formation shifts to a net bone loss results in the development of osteoporosis in both men and women. In this review, we focus on our current understanding of the effects of vitamin K2 on bone cells and its role in prevention and treatment of osteoporosis. PMID- 27976476 TI - Treatment of primary hyperhidrosis with oral anticholinergic medications: a systematic review. AB - Primary hyperhidrosis is a condition characterized by excessive sweating. Patients are treated off-license with oral anticholinergic medications and report adverse events associated with systemic anticholinergic interactions. This review assesses clinical evidence of efficacy, impact on quality of life and adverse events associated with oral anticholinergic therapy for primary hyperhidrosis. PRISMA guidelines were implemented to complete a systematic review (PROSPERO:CRD42016036326). MEDLINE, EMBASE and PubMed were searched from 1946 to 2015. Inclusion criteria included observational and experimental studies, anticholinergic medication use in primary hyperhidrosis, oral therapy and clear diagnostic and outcome measures. Twenty-three articles relevant to the inclusion criteria were analysed. Oxybutynin therapy improved symptoms in an average of 76.2% (range 60-97%) patients and improved QOL in 75.6% (range 57.6-100%) of patients. Methantheline bromide therapy was associated with a 41% reduction in axillary sweating, 16.4% reduction in palmar sweating, 25% decrease in HDSS score and 40.9% increase in DLQI score. Outcome measures of glycopyrrolate therapy were too variable to collate. Dry mouth was reported in 73.4% (range 43.3-100%) of participants taking oxybutynin 10 mg/day, 38.6% (range 27.8-63.2%) of patients taking glycopyrrolate and 68.8% of patients taking methantheline bromide. Nine studies reported that patients stopped therapy due to adverse events. In eight of these studies, a mean of 10.9% of total participants ceased treatment due to dry mouth. Evidence of oral anticholinergic therapy for hyperhidrosis is limited. However, its use is associated with improvement in quality of life and clinical symptoms but at the cost of considerable adverse events. PMID- 27976477 TI - Chemical Synthesis of K34-Ubiquitylated H2B for Nucleosome Reconstitution and Single-Particle Cryo-Electron Microscopy Structural Analysis. AB - Post-translational modifications (e.g., ubiquitylation) of histones play important roles in dynamic regulation of chromatin. Histone ubiquitylation has been speculated to directly influence the structure and dynamics of nucleosomes. However, structural information for ubiquitylated nucleosomes is still lacking. Here we report an alternative strategy for total chemical synthesis of homogenous histone H2B-K34-ubiquitylation (H2B-K34Ub) by using acid-cleavable auxiliary mediated ligation of peptide hydrazides for site-specific ubiquitylation. Synthetic H2B-K34Ub was efficiently incorporated into nucleosomes and further used for single-particle cryo-electron microscopy (cryo-EM) imaging. The cryo-EM structure of the nucleosome containing H2B-K34Ub suggests that two flexible ubiquitin domains protrude between the DNA chains of the nucleosomes. The DNA chains around the H2B-K34 sites shift and provide more space for ubiquitin to protrude. These analyses indicated local and slight structural influences on the nucleosome with ubiquitylation at the H2B-K34 site. PMID- 27976479 TI - Are two crutches better than one? The ongoing dilemma on the effects and need for left ventricular unloading during veno-arterial extracorporeal membrane oxygenation. PMID- 27976478 TI - Ferritin levels and risk of heart failure-the Atherosclerosis Risk in Communities Study. AB - AIMS: Severe iron overload is associated with cardiac damage, while iron deficiency has been related to worse outcomes in subjects with heart failure (HF). This study investigated the relationship between ferritin, a marker of iron status, and the incidence of HF in a community-based cohort. METHODS AND RESULTS: We examined 1063 participants who were free of heart failure from the Atherosclerosis Risk in Communities (ARIC) Study in whom ferritin serum levels were measured at baseline (1987-1989). The participants (mean age 52.7 +/- 5.5 years, 62% women), were categorized in low (<30 ng/mL; n = 153), normal (30-200 ng/mL in women and 30-300 ng/mL in men; n = 663), and high (>200 ng/mL in women and >300 ng/mL in men; n = 247) ferritin levels. Multivariable Cox proportional hazards models were used to evaluate the relationship between ferritin and incident HF. After 21 +/- 4.6 years of follow-up, HF occurred in 144 (13.5%) participants. When compared with participants with normal ferritin levels, participants with low ferritin levels had a higher risk of HF [hazard ratio (HR) = 2.24, 95% confidence interval (CI) 1.15-4.35; P = 0.02] as did those with high ferritin levels (HR = 1.81, 95% CI 1.01-3.25; P = 0.04), after adjusting for potential confounders. Notably, low ferritin levels remained associated with incident HF even after excluding subjects with anaemia (HR = 2.28, 95% CI 1.11 4.68; P = 0.03). CONCLUSION: Derangements in iron metabolism, either low or high ferritin serum levels, were associated with higher risk of incident HF in a general population, even without concurrent anaemia. These findings suggest that iron imbalance might play a role in the development of HF. PMID- 27976480 TI - Social framework of pediatric heart recipients who have survived more than 15 post-transplant years: A single-center experience. AB - To evaluate social development of pediatric heart transplant (tx) recipients who have lived 15 or more years after transplantation. Among 498 pediatric patients, age less than 18 years, who underwent heart transplantation, at a single institution, 337 were performed between 1985 and 1998. We identified all who survived more than 15 years and engaged them in a survey regarding employment, education, marital, and social status. One hundred and eighty-three recipients (54.3%; 183/337) have survived greater than 15 years; of these, 150 (81.9%) subjects are alive with age ranging from 15.04 from 28 years (median, 23.6 years). Forty-two patients (23%) are independent, 127 (69%) were living at home, and 14 (8%) have been lost to follow-up. Ninety-nine survivors (66%) responded to the survey study. Currently, five recipients are married. Seventy-four completed high school, 21 are enrolled in high school, and four did not complete high school. Of the 47 recipients who started college, 27 are currently enrolled, 11 graduated, and nine did not finish college. Ninety-four patients have health insurance, 40 are employed, and 31 receive financial assistance for a disability. The majority of recipients of pediatric heart transplantation are able to reach reasonable academic milestones, achieve social well-being, and professional independence. PMID- 27976481 TI - Irradiation with UV-C inhibits TNF-alpha-dependent activation of the NF-kappaB pathway in a mechanism potentially mediated by reactive oxygen species. AB - Pathways depending on the NF-kappaB transcription factor are essential components of cellular response to stress. Plethora of stimuli modulating NF-kappaB includes inflammatory signals, ultraviolet radiation (UV) and reactive oxygen species (ROS), yet interference between different factors affecting NF-kappaB remains relatively understudied. Here, we aim to characterize the influence of UV radiation on TNF-alpha-induced activity of the NF-kappaB pathway. We document inhibition of TNF-alpha-induced activation of NF-kappaB and subsequent suppression of NF-kappaB-regulated genes in cells exposed to UV-C several hours before TNF-alpha stimulation. Accumulation of ROS and subsequent activation of NRF2, p53, AP-1 and NF-kappaB-dependent pathways, with downstream activation of antioxidant mechanisms (e.g., SOD2 and HMOX1 expression), is observed in the UV treated cells. Moreover, NF-kappaB inhibition is not observed if generation of UV induced ROS is suppressed by chemical antioxidants. It is noteworthy that stimulation with TNF-alpha also generates a wave of ROS, which is suppressed in cells pre-treated by UV. We postulate that irradiation with UV-C activates antioxidant mechanisms, which in turn affect ROS-mediated activation of NF-kappaB by TNF-alpha. Considering a potential cross talk between p53 and NF-kappaB, we additionally compare observed effects in p53-proficient and p53-deficient cells and find the UV-mediated suppression of TNF-alpha-activated NF-kappaB in both types of cells. PMID- 27976483 TI - Hyposalivation and xerostomia among Parkinson's disease patients and its impact on quality of life. AB - OBJECTIVE: Parkinson's disease (PD) adversely affects oral health (OH). However, the informative value of xerostomia compared to objective parameters and its impact on quality of life (QoL) are still unclear. This study aimed to explore whether xerostomia correlates with hyposalivation and to define its impact on OH related QoL. MATERIALS AND METHODS: Whole stimulated saliva (WSS) was collected from 30 patients with PD and 30 matched healthy controls. Objective parameters (community periodontal index of treatment needs, plaque/gingivitis index, mucosa situation and cheilitis angularis) and questionnaires (German Oral Health Impact Profile [OHIPG]-14, visual analogue scale [VAS], xerostomia [yes/no] and the Unified Parkinson's Disease Rating Scale-II) were assessed. RESULTS: Eighty-seven per cent of patients with PD showed hyposalivation vs 50% of controls (P = 0.001); 50% of patients with PD reported xerostomia, and none of controls (P < 0.001). The OHIPG-14 was impaired in patients with PD compared to controls (P < 0.001), PD patients with xerostomia reported mean VAS values of 4.1 (s.d.: 2.2). WSS did not correlate with VAS values. CONCLUSIONS: Half of the patients with PD reported xerostomia and underestimated their xerostomic status, with higher probability than healthy controls. WSS did not reflect the grade of xerostomia. Patients with PD suffered from impaired OH-related QoL. Dental teams should not overlook these oral health risks. PMID- 27976484 TI - High-Throughput Screening of Catalytic H2 Production. AB - Hydrogenases, ferredoxins, and ferredoxin-NADP+ reductases (FNR) are redox proteins that mediate electron metabolism in vivo, and are also potential components for biological H2 production technologies. A high-throughput H2 production assay device (H2 PAD) is presented that enables simultaneous evaluation of 96 individual H2 production reactions to identify components that improve performance. Using a CCD camera and image analysis software, H2 PAD senses the chemo-optical response of Pd/WO3 thin films to the H2 produced. H2 PAD enabled discovery of hydrogenase and FNR mutants that enhance biological H2 production is reported. From a library of 10 080 randomly mutated Clostridium pasteurianum [FeFe] hydrogenases, we found a mutant with nearly 3-fold higher H2 production specific activity. From a library of 400 semi-randomly mutated Oryza sativa FNR, the top hit enabled a 60 % increase in NADPH-driven H2 production rates. H2 PAD can also facilitate elucidation of fundamental biochemical mechanisms within these systems. PMID- 27976485 TI - Sequential strategy for umbilical cord blood transplantation in a Korean Fanconi anemia girl with refractory acute myelomonocytic leukemia and complex karyotype. PMID- 27976482 TI - A Chiral Nitrogen Ligand for Enantioselective, Iridium-Catalyzed Silylation of Aromatic C-H Bonds. AB - Iridium catalysts containing dative nitrogen ligands are highly active for the borylation and silylation of C-H bonds, but chiral analogs of these catalysts for enantioselective silylation reactions have not been developed. We report a new chiral pyridinyloxazoline ligand for enantioselective, intramolecular silylation of symmetrical diarylmethoxy diethylsilanes. Regioselective and enantioselective silylation of unsymmetrical substrates was also achieved in the presence of this newly developed system. Preliminary mechanistic studies imply that C-H bond cleavage is irreversible, but not the rate-determining step. PMID- 27976486 TI - Is it permissible for a child with neurodevelopmental disabilities to be a living donor transplant candidate, but not a deceased donor candidate? Should donor source influence transplant center deliberations? AB - Limited data from surveys and highly publicized cases suggest that pediatric transplant providers and the public may use different standards when evaluating a potential transplant candidate with severe neurodevelopmental disabilities depending on whether a parent or other living donor has been identified. The purpose of this article is to explore the arguments in favor and against differing standards of candidacy for living and deceased donor transplants in pediatric solid organ transplantation using the example of children with severe neurodevelopmental disabilities. I conclude that donor source should not be a relevant consideration of pediatric transplant teams when considering the candidacy of a potential recipient. PMID- 27976487 TI - A Stable Neutral Radical in the Coordination Sphere of Aluminum. AB - The neutral radical (Me2 -cAAC)2 AlCl2 (2) is stabilized by cyclic (alkyl)(amino)carbenes (cAACs). Complex 2 was synthesized by reduction of the Me2 -cAAC:->AlCl3 (1) adduct with KC8 in the presence of another equivalent of Me2 cAAC. The crystal structure of 2 shows that the Al-C bond lengths of the two carbenes bound to the Al center are considerably different, which is likely the result of intermolecular interactions. Quantum-chemical calculations from the gas phase give an equilibrium structure with identical Al-C bond lengths. Compound 2 exhibits monoradical character, which was confirmed by EPR measurements. A bonding analysis indicates that the unpaired electron resides mainly at the carbene carbon atoms. Compound 2 is an example for an unusual neutral Al radical. PMID- 27976488 TI - Azacitidine as a bridge to allogeneic hematopoietic cell transplantation in a pediatric patient with Fanconi anemia and acute myeloid leukemia. AB - HCT is the definitive therapy for patients with FA and AML. Conventional cytotoxic agents cause potential DNA damage, and currently, there is no established regimen for these patients prior to HCT. A 13-year-old male with FA and refractory AML was given azacitidine, achieved morphologic remission and underwent HCT. At 95 days after HCT, he relapsed. Azacitidine along with DLI was used as first salvage therapy. Azacitidine was overall well tolerated with minimal side effects. In patients with AML and FA, azacitidine can be considered an alternative to conventional chemotherapy. PMID- 27976489 TI - Improving the quality of nurse-influenced patient care in the intensive care unit. AB - BACKGROUND: Quality of care is a major focus in the intensive care unit (ICU). AIM: To describe a nurse-initiated quality improvement (QI) project that improved the care of critically ill patients in a New Zealand tertiary ICU. DESIGN: A framework for QI was developed and implemented as part of a practice change initiative. METHODS: Audit data were collected, analysed and reported across seven nurse-influenced patient care standards. The seven standards were enteral nutrition delivered within 24 h of admission, timely administration of antibiotics, sedation holds for eligible patients, early mobilization and three pressure ulcer prevention strategies. RESULTS: Comparison of audit data collected in 2014 and 2015 demonstrated improvements in five of the seven standards. Those standards with the largest practice improvements were related to the following standards: all eligible patients have enteral nutrition commenced within the first 24 h of ICU admission (3% increase); all eligible patients receive antibiotics within 30 min of prescription time (6% increase); all eligible patients have a daily sedation interruption (DSI; 24% increase); and all eligible patients are mobilized daily in their ICU stay (11% increase in percentage of patients mobilized daily). CONCLUSIONS: The nursing-initiated QI project demonstrated improved ICU patient care in relation to early enteral nutrition commencement, DSIs and early and daily mobilizing. RELEVANCE TO CLINICAL PRACTICE: The use of a nursing QI framework incorporating audit and feedback is one method of evaluating and enhancing the quality of care and improving patient outcomes. This initiative demonstrated the improved quality of nursing care for ICU patients, particularly in relation to early enteral nutrition commencement, timely antibiotics, DSIs and daily mobilizing. It is thus highly relevant to critical care nursing teams, particularly those working to create a culture where change is safe, achievable and valued. PMID- 27976490 TI - Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotypes 1 and 4 hepatitis C virus (HCV) infection in patients with severe renal impairment: A multicentre experience. AB - Limited data are available on direct-acting antivirals for treating hepatitis C virus (HCV) infection in patients with severe renal impairment. The aim of this study was to evaluate the effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) +/- dasabuvir (DSV) +/- ribavirin (RBV) in patients with stage 4 or 5 chronic kidney disease (CKD) and HCV genotype 1 or 4 infection in real clinical practice, and to investigate pharmacological interactions. This retrospective study included patients treated with OBV/PTV/r+DSV+/-RBV or OBV/PTV/r+RBV with CKD stage 4 (eGFR: 15-29 mL/min/1.73m2 ) or 5 (eGFR<15 mL/min/1.73m2 or requiring dialysis) and HCV infection by genotypes 1 and 4 between April 2015 and October 2015 in nine Spanish centres. Sustained virological response at 12 weeks (SVR12) was assessed, and clinical and laboratory data, fibrosis stage, adverse events and pharmacological interactions were reported. Forty-six patients were included: 10 (21.7%) had CKD stage 4 and 36 (78.2%) CKD stage 5. Seventeen (36.9%) had cirrhosis. SVR12 rate in the intention-to-treat population was 95.7%. Twenty-one (45.6%) received RBV, which was discontinued in two (9.5%) patients. Anaemia (haemoglobin <10 g/dl) occurred in 12 patients (57.1%) with RBV vs 10 (40.0%) without RBV (P=.246). Renal function remained stable during antiviral therapy. Nine patients (19.5%) experienced serious adverse events unrelated to antiviral therapy. Concomitant medication was discontinued or modified in 41.3% of patients. In conclusion, the effectiveness of OBV/PTV/r+/-DSV+/-RBV in patients with CKD 4-5 was similar to that observed in those with normal renal function and was not associated with severe adverse events. PMID- 27976493 TI - Graphene Oxide Restricts Growth and Recrystallization of Ice Crystals. AB - We show graphene oxide (GO) greatly suppresses the growth and recrystallization of ice crystals, and ice crystals display a hexagonal shape in the GO dispersion. Preferred adsorption of GO on the ice crystal surface in liquid water leads to curved ice crystal surface. Therefore, the growth of ice crystal is suppressed owing to the Gibbs-Thompson effect, that is, the curved surface lowers the freezing temperature. Molecular dynamics simulation analysis reveals that oxidized groups on the basal plane of GO form more hydrogen bonds with ice in comparison with liquid water because of the honeycomb hexagonal scaffold of graphene, giving a molecular-level mechanism for controlling ice formation. Application of GO for cryopreservation shows that addition of only 0.01 wt % of GO to a culture medium greatly increases the motility (from 24.3 % to 71.3 %) of horse sperms. This work reports the control of growth of ice with GO, and opens a new avenue for the application of 2D materials. PMID- 27976492 TI - H1-antihistamines Reduce Progression to Anaphylaxis Among Emergency Department Patients With Allergic Reactions. AB - OBJECTIVES: H1-antihistamines (H1a) can be used to treat emergency department (ED) patients with allergic reactions; however, this is inconsistently done, likely because there is no evidence that this therapy has an impact on serious outcomes. Among ED patients initially presenting with allergic reactions, we investigated whether H1a were associated with lower rates of progression to anaphylaxis. METHODS: This was a retrospective cohort study conducted at two urban Canadian EDs from April 1, 2007, to March 31, 2012. We included consecutive adult patients with allergic reactions while excluding those presenting with anaphylaxis, according to prespecified criteria. The primary outcome was the proportion of patients who subsequently developed anaphylaxis during medical care, either by emergency medical services (EMS) or in the ED. A prespecified subgroup analysis excluded patients who received H1a prior to EMS or ED contact. We compared those who received H1a and those who did not and used multivariable regression and propensity score adjustment techniques to compare outcomes. RESULTS: Of 2,376 overall patients included, 1,880 (79.1%) were managed with H1a. Of the latter group, 36 of 1,880 (1.9%) developed anaphylaxis, compared to 17 of 496 (3.4%) in the non-H1a-treated group (adjusted odds ratio [AOR] = 0.34, 95% confidence interval [CI] = 0.17-0.70; number needed to treat [NNT] to benefit = 44.74, 95% CI = 35.36-99.67). In the subgroup analysis of 1,717 patients who did not receive H1a prior to EMS or ED contact, a similar association was observed (AOR = 0.26, 95% CI = 0.10-0.50; NNT to benefit 38.20, 95% CI = 32.58-55.24). CONCLUSIONS: Among ED patient with allergic reactions, H1a administration was associated with a lower likelihood of progression to anaphylaxis. These data indicate that early H1a treatment in the ED or prehospital setting may decrease progression to anaphylaxis. PMID- 27976491 TI - Effectiveness and safety of ombitasvir, paritaprevir, ritonavir +/- dasabuvir +/- ribavirin: An early access programme for Spanish patients with genotype 1/4 chronic hepatitis C virus infection. AB - Over the last 5 years, therapies for hepatitis C virus (HCV) infection have improved significantly, achieving sustained virologic response (SVR) rates of up to 100% in clinical trials in patients with HCV genotype 1. We investigated the effectiveness and safety of ombitasvir/paritaprevir/ritonavir+/-dasabuvir in an early access programme. This was a retrospective, multicentre, national study that included 291 treatment-naive and treatment-experienced patients with genotype 1 or 4 HCV infection. Most patients (65.3%) were male, and the mean age was 57.5 years. The mean baseline viral load was 6.1 log, 69.8% had HCV 1b genotype, 72.9% had cirrhosis and 34.7% were treatment-naive. SVR at 12 weeks posttreatment was 96.2%. Four patients had virological failure (1.4%), one leading to discontinuation. There were no statistical differences in virological response according to genotype or liver fibrosis. Thirty patients experienced serious adverse events (SAEs) (10.3%), leading to discontinuation in six cases. Hepatic decompensation was observed in five patients. Four patients died during treatment or follow-up, three of them directly related to liver failure. Multivariate analyses showed a decreased probability of achieving SVR associated with baseline albumin, bilirubin and Child-Pugh score B, and a greater probability of developing SAEs related to age and albumin. This combined therapy was highly effective in clinical practice with an acceptable safety profile and low rates of treatment discontinuation. PMID- 27976494 TI - Clinical Factors and Expenditures Associated With ICD-9-CM Coded Trauma for the U.S. Population: A Nationally Representative Study. AB - BACKGROUND: There is a lack of information on annual healthcare expenditures both per person and for the U.S. population associated with trauma, as identified by International Classification of Disease Ninth Revision, Clinical Modification (ICD-9-CM) codes. METHODS: This paper employed a two-part model to estimate the unadjusted and adjusted annual per individual expenditures and population burden of trauma exposure for the U.S. population, using a nationally representative survey of medical care expenditures. In addition, we estimated a logit model to examine the demographic and comorbidity factors associated with the likelihood of experiencing trauma. RESULTS: Approximately 18.2% of U.S. adults were found to have trauma exposure during the survey year of 2011. The most frequent trauma ICD 9-CM code was injury not elsewhere classified/not otherwise specified. Adjusted likelihood of trauma was higher among individuals under the age of 65; males; non Hispanic whites; nonmarried or never married; and individuals living with comorbidities of stroke, joint pain, arthritis, and asthma. The most expensive of the top 10 ICD-9-CM trauma codes was dislocation of the knee. Significant differences in expenditure categories were found for office-based, outpatient, emergency department (ED), dental, and other medical care. After adjustment for comorbidities and demographics, the adjusted per-person burden of trauma was estimated to be $1,689 (95% confidence interval [CI] = $1,006 to $2,372), with an incremental burden on the U.S. population of $60.8 billion per year. CONCLUSIONS: Trauma results in a significant healthcare expenditure burden, both per person and on the U.S. POPULATION: Clinicians should be aware that individuals in the U.S. population with certain comorbidities such as stroke, joint pain, arthritis, and asthma are more likely to have trauma and that differences exist in expenditures for office-based, outpatient, dental, and the ED. PMID- 27976495 TI - Detection of DNA double-strand breaks by pulsed-field gel electrophoresis. AB - A DNA double-strand break (DSB) is one of the most cytotoxic DNA lesions because unrepaired DSBs cause chromosomal aberrations and cell death. Although many physiological DSBs occur at DNA replication sites, the molecular mechanisms underlying this remain poorly understood. There was therefore a need to develop a highly specific method to detect DSB fragments containing DNA replication sites. Here we investigated whether pulsed-field gel electrophoresis (PFGE) combined with visualization of DNA replication sites by immunoblotting using halogenized deoxyuridines, such as BrdU and IdU, was sufficient for this detection. Our methodology enabled us to reproduce previously reported data. In addition, this methodology was also applied to the detection of bacterial infection-induced DSBs on human chromosomal DNA. Based on our findings, we propose that this strategy combining PFGE with immunoblot analysis will be applicable to studies analyzing the mechanistic details of DNA repair, the DNA damage response and the activity of DNA-damaging agents. PMID- 27976496 TI - Synthesis and Properties of Tin Sulfide Thin Films from Nanocolloids Prepared by Pulsed Laser Ablation in Liquid. AB - Tin sulfide (SnS) nanoparticles were synthesized by pulsed laser ablation in liquid (PLAL) technique using an Nd:YAG laser operated at 532 nm. SnS thin films were deposited by spraying the colloidal suspension onto the heated substrates. The influence of different liquid media (dimethyl formamide and isopropyl alcohol) on the thin film properties were studied. Morphology, crystalline structure, and chemical composition of the nanoparticles were identified using transmission electron microscopy with energy dispersive X-ray analysis. The crystalline structure of the thin films was analyzed by using grazing incidence X ray diffraction, and the chemical states by X-ray photoelectron spectroscopy. Scanning electron microscopy was employed for the morphological analysis of the thin films. Annealing the films at 380 degrees C improved the crystallinity of the films exhibiting a layered morphology, which may be useful in optoelectronic and sensing applications. Cyclic voltammetry studies showed that the films have good electrochemical properties. PMID- 27976497 TI - Prospective and Explicit Clinical Validation of the Ottawa Heart Failure Risk Scale, With and Without Use of Quantitative NT-proBNP. AB - OBJECTIVES: We previously developed the Ottawa Heart Failure Risk Scale (OHFRS) to assist with disposition decisions for acute heart failure patients in the emergency department (ED). We sought to prospectively evaluate the accuracy, acceptability, and potential impact of OHFRS. METHODS: This prospective observational cohort study was conducted at six tertiary hospital EDs. Patients with acute heart failure were evaluated by ED physicians for the 10 OHFRS criteria and then followed for 30 days. Quantitative NT-proBNP was measured where feasible. Serious adverse event (SAE) was defined as death within 30 days, admission to monitored unit, intubation, noninvasive ventilation, myocardial infarction, or relapse resulting in hospital admission within 14 days. RESULTS: We enrolled 1,100 patients with mean (+/-SD) age 77.7 (+/-10.7) years. SAEs occurred in 170 (15.5%) cases (19.4% if admitted and 10.2% if discharged). Compared to actual practice, using an admission threshold of OHFRS score > 1 would have increased sensitivity (71.8% vs. 91.8%) but increased admissions (57.2% vs. 77.6%). For 684 cases with NT-proBNP values, using a threshold score > 1 would have significantly increased sensitivity (69.8% vs. 95.8%) while increasing admissions (60.8% vs. 88.0%). In only 11.9% of cases did physicians indicate discomfort with use of OHFRS. CONCLUSION: Prospective clinical validation found the OHFRS tool to be highly sensitive for SAEs in acute heart failure patients, albeit with an increase in admission rates. When available, NT proBNP values further improve sensitivity. With adequate physician training, OHFRS should help improve and standardize admission practices, diminishing both unnecessary admissions for low-risk patients and unsafe discharge decisions for high-risk patients. PMID- 27976499 TI - Imidacloprid seed treatments affect individual ant behavior and community structure but not egg predation, pest abundance or soybean yield. AB - BACKGROUND: Neonicotinoid seed treatments are under scrutiny because of their variable efficacy against crop pests and for their potential negative impacts on non-target organisms. Ants provide important biocontrol services in agroecosystems and can be indicators of ecosystem health. This study tested for effects of exposure to imidacloprid plus fungicide or fungicide-treated seeds on individual ant survival, locomotion and foraging capabilities and on field ant community structure, pest abundance, ant predation and yield. RESULTS: Cohorts of ants exposed to either type of treated seed had impaired locomotion and a higher incidence of morbidity and mortality but no loss of foraging capacity. In the field, we saw no difference in ant species richness, regardless of seed treatment. Blocks with imidacloprid did have higher species evenness and diversity, probably owing to variable effects of the insecticide on different ant species, particularly Tetramorium caespitum. Ant predation on sentinel eggs, pest abundance and soybean growth and yield were similar in the two treatments. CONCLUSION: Both seed treatments had lethal and sublethal effects on ant individuals, and the influence of imidacloprid seed coating in the field was manifested in altered ant community composition. Those effects, however, were not strong enough to affect egg predation, pest abundance or soybean yield in field blocks. (c) 2016 Society of Chemical Industry. PMID- 27976500 TI - Hemoglobinopathy testing: the significance of accuracy and pitfalls in HbA2 determination. PMID- 27976501 TI - Pore Topology Effects in Positron Annihilation Spectroscopy of Zeolites. AB - Positron annihilation spectroscopy (PAS) is a powerful method to study the size and connectivity of pores in zeolites. The lifetime of positronium within the host material is commonly described by the Tao-Eldrup model. However, one of its largest limitations arises from the simple geometries considered for the shape of the pores, which cannot describe accurately the complex topologies in zeolites. Here, an atomic model that combines the Tao potential with the crystallographic structure is introduced to calculate the distribution and lifetime of Ps intrinsic to a given framework. A parametrization of the model is undertaken for a set of widely applied zeolite framework types (*BEA, FAU, FER, MFI, MOR, UTL), before extending the model to all known structures. The results are compared to structural and topological descriptors, and to the Tao-Eldrup model adapted for zeolites, demonstrating the intricate dependence of the lifetime on the pore architecture. PMID- 27976498 TI - Insulin treatment restores islet microvascular vasomotion function in diabetic mice. AB - BACKGROUND: The microcirculation plays an important role in the pathogenesis of diabetes and its complications. We hypothesized that pancreatic islet microvascular (PIM) vasomotion, as a parameter of pancreatic islet microcirculation function, is abnormal in diabetic mice and that insulin treatment may reverse this dysfunction. METHODS: Mice were randomly assigned to non-diabetic control, untreated diabetic, and insulin-treated diabetic groups (n = 6 in each group). Separate groups of streptozotocin (STZ)-induced diabetic and high-fat diet-fed mice were used as a model of hyperglycemia. Insulin-treated diabetic mice were treated with 1-1.5 IU/day insulin for 1 week. Laser Doppler monitors were used to evaluate PIM vasomotion. Morphological and ultrastructural changes in islet endothelial cells were determined by immunohistochemistry and transmission electron microscopy. Glucagon, insulin, vascular endothelial growth factor (VEGF)-A, and platelet endothelial cell adhesion molecule (PECAM-1) expression was determined by immunohistochemistry and Western blotting. RESULTS: In both untreated diabetic groups, the pancreatic islet microcirculation was unable to regulate PIM vasomotion. The rhythm of vasomotion was irregular, and the average blood perfusion, amplitude, frequency, and relative velocity of vasomotion were significantly lower than in non-diabetic controls. Insulin treatment restored the functional status of PIM vasomotion. In islet endothelial cells from both untreated diabetic groups, the mitochondria were swollen with disarrangement of the cristae, and the distribution of PECAM-1 was discontinuous. Insulin treatment significantly increased the reduced expression of PECAM-1 in both untreated diabetic groups and VEGF-A expression in untreated STZ-diabetic mice. CONCLUSION: The results suggest that the functional status of PIM vasomotion is impaired in diabetic mice but can be restored by insulin. PMID- 27976502 TI - Chance and design in proinsecticide discovery. AB - Many insecticides are inactive on their target sites in the form that is sold and applied, needing first to be bioactivated. This proinsecticide strategy has often been achieved by design, through systematic derivatization of intrinsically active molecules with protecting groups that mask their toxic effects until their selective removal in target insects by metabolic enzymes generates the toxiphore. Proinsecticides can be designed to gain selectivity between target and non-target organisms, or to improve bioavailability by enhancing plant or insect uptake. In most cases, however, chance trumps design in proinsecticide discovery: most first in-class products that we now know to be proinsecticides were only discovered a posteriori to be such, often after having been on the market for years. Knowing the active form of an insecticide is essential to mode of action identification, and early mode of action studies on novel chemotypes should take into account the possibility that the compounds might be proinsecticides. This paper reviews examples of proinsecticides in the marketplace, strategies for making proinsecticides and techniques for unmasking proinsecticides in mode of action studies. Our analysis of global agrochemical sales data shows that 34% of the dollar value of crop insecticides used in 2015 were proinsecticides. (c) 2016 Society of Chemical Industry. PMID- 27976503 TI - Effect of temperature and seven storage media on human periodontal ligament fibroblast viability. AB - BACKGROUND/AIM: Natural resources, such as coconut water, propolis, and egg whites, have been examined as possible storage media for avulsed teeth. However, there is a lack of research focused on the efficacy of these three products together compared with Hank's balanced salt solution and milk. The aim of this study was to evaluate the capacity of seven storage media to maintain the viability of human periodontal ligament fibroblasts (PDLFs). MATERIAL AND METHODS: PDLFs were kept at 5 degrees C and 20 degrees C, in skimmed milk (SMilk), whole milk (WMilk), recently prepared Hank's balanced salt solution (HBSS), Save-A-Tooth(r) system's HBSS (Save), natural coconut water (Coconut), Propolis, and egg white (Egg) for 3, 6, 24, 48, 72, 96, and 120 h, through the analysis of tetrazolium salt-based colorimetric (MTT) assay. RESULTS: At 5 degrees C, SMilk and WMilk were better than HBSS in maintaining cell viability, from 24 h onward. At 20 degrees C, HBSS was the best storage medium at 96 and 120 h. At both temperatures, from 6 h onward, Coconut, Propolis and Egg were less effective than SMilk, WMilk, and HBSS. In general, the performance of Coconut, Propolis and Egg were not influenced by storage temperature. However, the lowest temperature undermined the effectiveness of HBSS from 24 h and favored SMilk and WMilk, from 96 and 48 h onward, respectively. Save and water were the worst storage media. CONCLUSION: SMilk was the best storage medium, followed by WMilk and HBSS. Coconut, Propolis, and Egg can be indicated for the conservation of PDLF up to 3 h. The lower temperature (5 degrees C) undermined the effectiveness of HBSS and favored SMilk and WMilk. PMID- 27976504 TI - A novel flow cytometry-based method of analyzing Heinz bodies. AB - INTRODUCTION: Heinz bodies are important to diagnosing and managing patients. However, microscopic examination of Heinz bodies has several disadvantages, demonstrating the need for a better method. We explored the potential use of flow cytometry to examine Heinz bodies. METHODS: Whole-blood samples were collected from patients deficient in G6PD and healthy volunteers. Acetylphenylhydrazine was used to induce formation of Heinz bodies in red blood cells (RBCs). Then, RBCs positive for Heinz bodies were examined using a FACSCanto II cytometer. RESULTS: RBCs treated with acetylphenylhydrazine formed Heinz bodies and emitted a broad spectrum of fluorescence that could be detected by flow cytometry. The maximum emission of fluorescence was observed at 45 min after the incubation with acetylphenylhydrazine. In addition, the fluorescence emitted was stable for at least 72 h. The flow cytometer could detect the RBCs positive for Heinz bodies even if they made up as little as 0.1% of the total RBC population. Furthermore, the percentage and number, respectively, of RBCs positive for Heinz bodies in G6PD-deficient patients and normal donors exhibited a mean +/- standard deviation (SD) of 68.9 +/- 27.5 vs. 50.9 +/- 28.6 and 96 014 +/-35 732 cells/MUL vs. 74 688 +/- 36 514 cells/MUL. CONCLUSION: Heinz bodies induced by acetylphenylhydrazine emit fluorescence, and this fluorescence could be examined using flow cytometry. Our study suggests the potential use of the developed method to investigate the formation of Heinz bodies in clinical samples. PMID- 27976505 TI - Lentiviral transduction and subsequent loading with nanoparticles do not affect cell viability and proliferation in hair-follicle-bulge-derived stem cells in vitro. AB - The application of stem cells in the treatment of various degenerative diseases is highly promising. However, cell-based therapy could be limited by the problem of low viability of grafted cells and uncertainty about their fate. The combination of molecular imaging and contrast-enhanced MRI may give more insight into the survival and behavior of grafted stem cells. We explore hair-follicle bulge-derived stem cells (HFBSCs) as a potential candidate for autologous cell based therapy. HFBSCs are transduced with a lentiviral construct with genes coding for bioluminescent (Luc2) and fluorescent (copGFP) reporter proteins, and subsequently loaded with magnetic nanoparticles to enable MRI visualization. Thus, we investigate for the first time if lentiviral transduction and cellular loading with nanoparticles have a cytotoxic effect upon these stem cells. Transduction efficiency, proliferation rate, cell viability and reporter protein co-expression during long-term culture of transduced HFBSCs were studied using fluorescence and bioluminescence microscopy. In addition, the effect of TMSR50 nanoparticles on proliferation and viability was investigated using the MTS assay and bioluminescence microscopy. The amount of TMSR50-loaded HFBSCs needed to reach signal threshold for MRI was assessed using an agarose phantom. Transduction with the Luc2-copGFP construct did not influence senescence, proliferation, doubling time, and differentiation of the HFBSCs. CopGFP expression was visible immediately after transduction and persisted for at least 15 passages, concomitantly with Luc2 expression. Cellular loading with TMSR50 nanoparticles did not affect cell viability and proliferation. The results imply that combined MRI and bioluminescence imaging may enable in vivo localization and long-term monitoring of grafted viable HFBSCs. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976506 TI - USPIO enhanced lymph node MRI using 3D multi-echo GRE in a rabbit model. AB - Ultrasmallsuperparamagnetic iron oxide (USPIO) has been suggested to be a negative MR contrast agent to detect metastatic lymph nodes. Previously reported studies have evaluated the diagnostic performance of USPIO-enhanced MR lymph node imaging based on signal intensity. In this study, we investigate the specific performance of three different parametric approaches (normalized signal intensity, R2 * and susceptibility) using 3D multi-echo gradient echo to quantify the USPIO particles in lymph nodes. Nine rabbits with VX2 tumor implants were scanned before and after USPIO injection. From 3D multi-echo GRE magnitude and phase data, we generated multi-echo combined T2 *-weighted images, an R2 * map, and a quantitative susceptibility map. Eighteen lymph nodes (nine reactive and nine metastatic) were evaluated and showed remarkable signal drops in the area of USPIO accumulation. On parametric analysis, the R2 * difference before and after USPIO injection was significantly different (p < 0.05) between reactive and metastatic lymph nodes; in contrast, the normalized signal intensity and susceptibility were not significantly different between the nodes. Our study showed the potential utility of USPIO-enhanced MRI using R2* mapping from 3D multi-echo GRE for the detection of lymph node metastasis and parametric analysis of lymph node status in a rabbit model. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976507 TI - Basis of ACCase and ALS inhibitor resistance in Hordeum glaucum Steud. AB - BACKGROUND: Acetyl coenzyme-A carboxylase (ACCase) and/or acetolactate synthase (ALS) inhibitor resistance has been identified by herbicide resistance screening in eight populations obtained from cropping regions of South Australia. This study aimed to quantify the level of resistance and characterise the molecular basis of resistance to ACCase and ALS inhibitors in these H. glaucum populations. RESULTS: H. glaucum populations from the Upper-North region were highly resistant (resistance index RI > 12) to the aryloxyphenoxypropionate (APP) herbicides quizalofop and haloxyfop and less resistant (RI = 2-12) to cyclohexanedione (CHD) herbicide clethodim, and some Mid-North populations had a low level of resistance (RI = 2-6) to the sulfonylurea (SU) herbicide mesosulfuron. Gene sequencing confirmed the presence of Ile-1781-Leu, Ile-2041-Asn and Gly-2096-Ala mutations in the ACCase gene, with no mutation found in the ALS gene. The use of the known metabolic inhibitor malathion in combination with mesosulfuron enhanced the activity of this herbicide. These populations were also susceptible to SU herbicide sulfometuron. CONCLUSION: This study has documented APP-to-CHD herbicide cross-resistance, the first case of ACCase inhibitor resistance due to Ile-2041-Asn mutation, and characterised the resistance to ALS inhibitors in H. glaucum. Resistance to ACCase inhibitors is due to a target-site mutation. The reversal of SU resistance by malathion and susceptibility to sulfometuron suggests that non-target-site mechanisms confer resistance to ALS inhibitors. (c) 2016 Society of Chemical Industry. PMID- 27976508 TI - Obesity, weight change, and chronic kidney disease in patients with type 2 diabetes mellitus: A longitudinal study in Taiwan. AB - BACKGROUND: The aim of the present study was to investigate relationships between the risk of chronic kidney disease (CKD) and obesity and weight changes in Asian patients with type 2 diabetes. METHODS: At baseline (2003-05), 1187 diabetic patients aged 30-70 years were recruited to the study, with follow-up surveys completed in 2008, 2009, and 2010. Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2 ; body mass index (BMI) was categorised as normal (18.5-22.9 kg/m2 ), overweight (23-27.4 kg/m2 ), or obese (>=27.5 kg/m2 ); waist circumference (WC) >=80 cm for women and >=90 cm for men was taken to indicate abdominal obesity. Changes in weight and WC were calculated from baseline to each follow-up survey. Relative risk (RR) and 95% confidence intervals (CIs) of CKD were estimated. To estimate the risk for incident CKD, associations were examined in patients without CKD at baseline (n = 881). RESULTS: Over 7 years of follow-up, obesity (RR 1.48; 95% CI 1.08-2.04; P = 0.015) and high WC (RR 1.23; 95% CI 1.00-1.52; P = 0.049) were associated with CKD after adjusting for covariates. Among participants without CKD at baseline, those who gained >10% weight (RR 1.43; 95% CI 1.07-1.90; P = 0.015) and in whom WC increased >15% (RR 1.37; 95% CI 1.01-1.85; P = 0.045) had a higher risk of incident CKD than those who remained stable (+/-5% changes in weight or WC). CONCLUSIONS: Diabetic patients who are obese and those with excessive central fat were more likely to have CKD. Large weight gain (>10%) and increases in WC (>15%) independently predicted incident CKD. PMID- 27976509 TI - Energy-Saving Electrolytic Hydrogen Generation: Ni2 P Nanoarray as a High Performance Non-Noble-Metal Electrocatalyst. AB - It is highly attractive but challenging to develop earth-abundant electrocatalysts for energy-saving electrolytic hydrogen generation. Herein, we report that Ni2 P nanoarrays grown in situ on nickel foam (Ni2 P/NF) behave as a durable high-performance non-noble-metal electrocatalyst for hydrazine oxidation reaction (HzOR) in alkaline media. The replacement of the sluggish anodic oxygen evolution reaction with such the more thermodynamically favorable HzOR enables energy-saving electrochemical hydrogen production with the use of Ni2 P/NF as a bifunctional catalyst for anodic HzOR and cathodic hydrogen evolution reaction. When operated at room temperature, this two-electrode electrolytic system drives 500 mA cm-2 at a cell voltage as low as 1.0 V with strong long-term electrochemical durability and 100 % Faradaic efficiency for hydrogen evolution in 1.0 m KOH aqueous solution with 0.5 m hydrazine. PMID- 27976511 TI - alpha-Arylation and Ring Expansion of Annulated Cyclobutanones: Stereoselective Synthesis of Functionalized Tetralones. AB - alpha-Arylcyclobutanones display unique reactivity that makes them valuable synthetic intermediates and target molecules. We describe the preparation of alpha-aryl- and alpha-heteroarylcyclobutanones through a direct alpha-arylation reaction. Problematic fragmentations are avoided by the use of LiOt Bu, which promotes a rapid but reversible self-aldol reaction that slowly releases the enolate required for alpha-arylation. We also demonstrate the ring expansion of alpha-arylcyclobutanones, a process that is highlighted in the stereoselective synthesis of 1-methoxy coniothyrinone D. PMID- 27976510 TI - Evaluation of salicylic acid peeling in comparison with topical tretinoin in the treatment of postinflammatory hyperpigmentation. AB - BACKGROUND: Postinflammatory hyperpigmentation (PIH) is an acquired hyperpigmentation that involves areas of prior cutaneous inflammation. In addition to prevention, there are a variety of medications and procedures used to treat PIH. AIM OF THE WORK: The aim of this work was to evaluate the efficacy, tolerability, and safety of salicylic acid peeling in comparison with topical tretinoin in the treatment of PIH. PATIENTS AND METHODS: This study included forty-five patients with PIH lesions. The patients were divided into three groups, group I was treated with salicylic acid peeling 20-30%, group II was treated with topical tretinoin 0.1%, and group III was treated with combination of salicylic acid peel and topical tretinoin. The patients were assessed clinically to evaluate the efficacy, tolerability, and safety of the treatment. Dermoscopy was carried out to the recurrent or nonimproved cases only. RESULTS: Combination of salicylic acid peel and topical tretinoin treatment showed significant clinical improvement of PIH than each treatment alone with no complications. There was no significant difference in the recurrence rate between the three groups. There was nonsignificant difference between the efficacy of the treatment and the PIH type in the studied groups. There was nonsignificant difference between the efficacy of the treatment and the duration of the PIH except for group III. CONCLUSION: Combination treatment modality is believed to be preferred in the treatment of PIH due to its higher efficacy than single treatment alone, with well tolerability, less side effects, and low recurrence rate. PMID- 27976513 TI - What next after basal insulin? Treatment intensification with lixisenatide in Asian patients with type 2 diabetes mellitus. AB - There is increasing evidence that the pathophysiology of type 2 diabetes mellitus (T2DM) in Asian patients differs from that in Western patients, with early phase insulin deficiencies, increased postprandial glucose excursions, and increased sensitivity to insulin. Asian patients may also experience higher rates of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as nausea and vomiting, compared with their Western counterparts. These factors should be taken into consideration when selecting therapy for basal insulin treatment intensification in Asian patients. However, the majority of studies to establish various agents for treatment intensification in T2DM have been conducted in predominantly Western populations, and the levels of evidence available in Chinese or Asian patients are limited. This review discusses the different mechanisms of action of short-acting, prandial, and long acting GLP-1RAs in addressing hyperglycemia, and describes the rationale and available clinical data for basal insulin in combination with the short-acting prandial GLP-1RA lixisenatide, with a focus on treatment of Asian patients with T2DM. PMID- 27976512 TI - FGF2 antagonizes aberrant TGFbeta regulation of tropomyosin: role for posterior capsule opacity. AB - Transforming growth factor (TGF) beta2 and fibroblast growth factor (FGF) 2 are involved in regulation of posterior capsule opacification (PCO) and other processes of epithelial-mesenchymal transition (EMT) such as cancer progression, wound healing and tissue fibrosis as well as normal embryonic development. We previously used an in vivo rodent PCO model to show the expression of tropomyosin (Tpm) 1/2 was aberrantly up-regulated in remodelling the actin cytoskeleton during EMT. In this in vitro study, we show the Tpms family of cytoskeleton proteins are involved in regulating and stabilizing actin microfilaments (F actin) and are induced by TGFbeta2 during EMT in lens epithelial cells (LECs). Importantly, we found TGFbeta2 and FGF2 played contrasting roles. Stress fibre formation and up-regulation of alpha-smooth muscle actin (alphaSMA) induced by TGFbeta2 could be reversed by Tpm1/2 knock-down by siRNA. Expression of Tpm1/2 and stress fibre formation induced by TGFbeta2 could be reversed by FGF2. Furthermore, FGF2 delivery to TGFbeta-treated LECs perturbed EMT by reactivating the mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) pathway and subsequently enhanced EMT. Conversely, MEK inhibitor (PD98059) abated the FGF2-mediated Tpm1/2 and alphaSMA suppression. However, we found that normal LECs which underwent EMT showed enhanced migration in response to combined TGFbeta and FGF2 stimulation. These findings may help clarify the mechanism reprogramming the actin cytoskeleton during morphogenetic EMT cell proliferation and fibre regeneration in PCO. We propose that understanding the physiological link between levels of FGF2, Tpm1/2 expression and TGFbetas-driven EMT orchestration may provide clue(s) to develop therapeutic strategies to treat PCO based on Tpm1/2. PMID- 27976515 TI - A single dose of Low-molecular-weight Heparin (LMWH) invalidates the use of D dimer as part of a Deep Vein Thrombosis (DVT) diagnostic algorithm. PMID- 27976514 TI - Silent disease progression in clinically stable heart failure. AB - Heart failure with reduced ejection fraction (HFrEF) is a progressive disorder whereby cardiac structure and function continue to deteriorate, often despite the absence of clinically apparent signs and symptoms of a worsening disease state. This silent yet progressive nature of HFrEF can contribute to the increased risk of death-even in patients who are 'clinically stable', or who are asymptomatic or only mildly symptomatic-because it often goes undetected and/or undertreated. Current therapies are aimed at improving clinical symptoms, and several agents more directly target the underlying causes of disease; however, new therapies are needed that can more fully address factors responsible for underlying progressive cardiac dysfunction. In this review, mechanisms that drive HFrEF, including ongoing cardiomyocyte loss, mitochondrial abnormalities, impaired calcium cycling, elevated LV wall stress, reactive interstitial fibrosis, and cardiomyocyte hypertrophy, are discussed. Additionally, limitations of current HF therapies are reviewed, with a focus on how these therapies are designed to counteract the deleterious effects of compensatory neurohumoral activation but do not fully prevent disease progression. Finally, new investigational therapies that may improve the underlying molecular, cellular, and structural abnormalities associated with HF progression are reviewed. PMID- 27976516 TI - Prospective registry for laparoscopic liver resection. AB - INTRODUCTION: Laparoscopic liver resection (LLR) has been widely performed throughout the world. Although prospective registry studies to clarify the safety of LLR have been feasible, no prior multicenter prospective study has addressed this issue. We have conducted a multicenter prospective cohort study to reveal the current status of LLR in Japan. METHODS: From April 2015 to March 2016, candidates for LLR were preoperatively enrolled at 12 institutions. The primary end-point was surgical safety, which was evaluated based on surgical factors and on short-term and midterm outcomes. RESULTS: A total of 102 patients were enrolled. Planned laparoscopic procedures included 96 pure laparoscopies, 1 hand assisted laparoscopy, and 5 hybrid techniques. Non-anatomical partial resection or left lateral sectionectomy were performed in almost all cases. The median duration of surgery was 221 min. The median blood loss was 80.5 mL. Conversion was required for four patients (3.9%). The 90-day postoperative morbidities with grades more severe than II in the Clavien-Dindo classification were observed in six patients (5.9%). The median postoperative hospital stay was 9.5 days. No cases involved reoperation or mortality. CONCLUSION: Minor resection of LLR has been performed safely. To ensure the safe dissemination of LLR, including for major resection, a larger multicenter prospective study is required. PMID- 27976518 TI - Classification of needling for trabeculectomy blebs. PMID- 27976519 TI - Tetraphenylmethane-Arylamine Hole-Transporting Materials for Perovskite Solar Cells. AB - A new class of hole-transporting materials (HTM) containing tetraphenylmethane (TPM) core have been developed. After thermal, charge carrier mobility, and contact angle tests, it was found that TPA-TPM (TPA: arylamine derivates side group) showed higher glass-transition temperature and larger water-contact angle than spiro-OMeTAD with comparable hole mobility. Photoluminescence and impedance spectroscopy studies indicate that TPA-TPM's hole-extraction ability is comparable to that of spiro-OMeTAD. SEM and AFM results suggest that TPA-TPM has a smooth surface. When TPA-TPM is used in mesoscopic perovskite solar cells, power conversion efficiency comparable to that of spiro-OMeTAD is achieved. Notably, the perovskite solar cells employing TPA-TPM show better long-term stability than that of spiro-OMeTAD. Moreover, TPA-TPM can be prepared from relatively inexpensive raw materials with a facile synthetic route. The results demonstrate that TPM-arylamines are a new class of HTMs for efficient and stable perovskite solar cells. PMID- 27976517 TI - Warmed, humidified CO2 insufflation benefits intraoperative core temperature during laparoscopic surgery: A meta-analysis. AB - BACKGROUND: Intraoperative hypothermia is linked to postoperative adverse events. The use of warmed, humidified CO2 to establish pneumoperitoneum during laparoscopy has been associated with reduced incidence of intraoperative hypothermia. However, the small number and variable quality of published studies have caused uncertainty about the potential benefit of this therapy. This meta analysis was conducted to specifically evaluate the effects of warmed, humidified CO2 during laparoscopy. METHODS: An electronic database search identified randomized controlled trials performed on adults who underwent laparoscopic abdominal surgery under general anesthesia with either warmed, humidified CO2 or cold, dry CO2 . The main outcome measure of interest was change in intraoperative core body temperature. RESULTS: The database search identified 320 studies as potentially relevant, and of these, 13 met the inclusion criteria and were included in the analysis. During laparoscopic surgery, use of warmed, humidified CO2 is associated with a significant increase in intraoperative core temperature (mean temperature change, 0.3 degrees C), when compared with cold, dry CO2 insufflation. CONCLUSION: Warmed, humidified CO2 insufflation during laparoscopic abdominal surgery has been demonstrated to improve intraoperative maintenance of normothermia when compared with cold, dry CO2. PMID- 27976521 TI - Racing chemistry: A century of challenges and progress. AB - Horseracing has been called 'one of the first quintessentially modern sports'. Its urge towards standardization, its mathematically set odds, its concern with weights, and its pioneering embrace of drug-testing reflect an empirical temperament crucial to its transformation from a gentleman's pastime to a global industry funded by wagering. Ironically, in the late nineteenth century, it was modern science itself, and in particular the purification and synthesis of the drugs of nature, that turned the doping of racing animals - a practice recorded in antiquity - into an organized criminal enterprise. This paper presents original research into the history of racing chemistry in Australia in the context of developments in the field worldwide. Using a case-study approach based on extensive archival materials, it reveals unpublished diaries kept by an analyst working at Sydney Racing Laboratory in the 1950s that document conflicts between scientists over identification of performance drugs in racing animals. The author presents evidence that augments and revises earlier narratives concerning the history of the establishment of laboratory control at Australian racetracks and the removal of the country's first official analyst for racing, Miss Jean Kimble. The Kimble case illustrates the inevitable political, professional, and personal pressures that bear upon drug-testing in sports, and also conflicts between scientists over standards and priorities. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976520 TI - Synthesis of Concentrated Methylcyclohexane as Hydrogen Carrier through Photoelectrochemical Conversion of Toluene and Water. AB - A photoelectrochemical (PEC) cell consisting of a Pt-loaded carbon black (Pt/C) based membrane electrode assembly (MEA) and a particulate SrTiO3 photoanode effected selective PEC conversion of toluene and water into methylcyclohexane (MCH) at concentrations up to >99 vol %. This cell exhibited 100 % faradaic efficiency (FE) and 18 % incident-photon-to-current conversion efficiency (IPCE) at 320 nm without an external bias voltage in the PEC hydrogenation of pure toluene. It was also found that strong alkaline conditions are beneficial with the present MEA to suppress the competitive side reaction of hydrogen evolution, resulting in a high FE of 94 % even during MCH production from 1 vol % toluene in MCH. This study successfully demonstrated that the present PEC system is capable of producing concentrated MCH as a promising hydrogen carrier and that MCH production from toluene and water represents a means of artificial photosynthesis. PMID- 27976522 TI - The support needs of patients waiting for publicly funded bariatric surgery - implications for health service planners. AB - The objective of this study was to investigate the experience of waiting for publicly funded bariatric surgery in an Australian tertiary healthcare setting. Focus groups and individual interviews involving people waiting for or who had undergone publicly funded bariatric surgery were audio-recorded, transcribed and analysed thematically. A total of 11 women and 6 men engaged in one of six focus groups in 2014, and an additional 10 women and 9 men were interviewed in 2015. Mean age was 53 years (range 23-66); mean waiting time was 6 years (range 0-12), and mean time since surgery was 4 years (range 0-11). Waiting was commonly reported as emotionally challenging (e.g. frustrating, depressing, stressful) and often associated with weight gain (despite weight-loss attempts) and deteriorating physical health (e.g. development of new or worsening obesity related comorbidity or decline in mobility) or psychological health (e.g. development of or worsening depression). Peer support, health and mental health counselling, integrated care and better communication about waitlist position and management (e.g. patient prioritization) were identified support needs. Even if wait times cannot be reduced, better peer and health professional supports, together with better communication from health departments, may improve the experience or outcomes of waiting and confer quality-of-life gains irrespective of weight loss. PMID- 27976523 TI - Neonatal Maternal Deprivation Enhances Presynaptic P2X7 Receptor Transmission in Insular Cortex in an Adult Rat Model of Visceral Hypersensitivity. AB - AIMS: Insular cortex (IC) is involved in processing the information of pain. The aim of this study was to investigate roles and mechanisms of P2X7 receptors (P2X7Rs) in IC in development of visceral hypersensitivity of adult rats with neonatal maternal deprivation (NMD). METHODS: Visceral hypersensitivity was quantified by abdominal withdrawal reflex threshold to colorectal distension (CRD). Expression of P2X7Rs was determined by qPCR and Western blot. Synaptic transmission in IC was recorded by patch-clamp recording. RESULTS: The expression of P2X7Rs and glutamatergic neurotransmission in IC was significantly increased in NMD rats when compared with age-matched controls. Application of BzATP (P2X7R agonist) enhanced the frequency of spontaneous excitatory postsynaptic currents (sEPSC) and miniature excitatory postsynaptic currents (mEPSC) in IC slices of control rats. Application of BBG (P2X7R antagonist) suppressed the frequencies of sEPSC and mEPSC in IC slices of NMD rats. Microinjection of BzATP into right IC significantly decreased CRD threshold in control rats while microinjection of BBG or A438079 into right IC greatly increased CRD threshold in NMD rats. CONCLUSION: Data suggested that the enhanced activities of P2X7Rs in IC, likely through a presynaptic mechanism, contributed to visceral hypersensitivity of adult rats with NMD. PMID- 27976525 TI - Electrochemical Water Oxidation by a Catalyst-Modified Metal-Organic Framework Thin Film. AB - Water oxidation, a key component in artificial photosynthesis, requires high overpotentials and exhibits slow reaction kinetics that necessitates the use of stable and efficient heterogeneous water-oxidation catalysts (WOCs). Here, we report the synthesis of UiO-67 metal-organic framework (MOF) thin films doped with [Ru(tpy)(dcbpy)OH2 ]2+ (tpy=2,2':6',2''-terpyridine, dcbpy=5,5'-dicarboxy 2,2'-bipyridine) on conducting surfaces and their propensity for electrochemical water oxidation. The electrocatalyst oxidized water with a turnover frequency (TOF) of (0.2+/-0.1) s-1 at 1.71 V versus the normal hydrogen electrode (NHE) in buffered solution (pH~7) and exhibited structural and electrochemical stability. The electroactive sites were distributed throughout the MOF thin film on the basis of scan-ratedependent voltammetry studies. This work demonstrates a promising way to immobilize large concentrations of electroactive WOCs into a highly robust MOF scaffold and paves the way for future photoelectrochemical water-splitting systems. PMID- 27976526 TI - Child Development: New Diagnoses for the NANDA International. AB - OBJECTIVE: The paper proposes new diagnoses on child development (CD) for NANDA International. METHODS: The study followed the recommended steps of Developmental Processes for NANDA International Nursing Diagnoses. It was a secondary analysis study on the findings of a concept analysis study on CD. RESULTS: A proposal of labels and components of three diagnoses: "Delayed child development," "Risk for delayed child development," and "Readiness for enhanced child development." CONCLUSIONS: The proposed diagnoses represent all the complexity of CD. IMPLICATIONS FOR NURSING PRACTICE: The proposed diagnoses can support nurses in the development of a comprehensive care plan on the health of children. OBJETIVO: propor novos diagnosticos de enfermagem para a NANDA-International que abordem o desenvolvimento infantil. METODO: Este estudo seguiu as etapas recomendadas para o desenvolvimento de diagnosticos de enfermagem da NANDA-International. Foi realizado a partir dos resultados da analise de conceito do termo desenvolvimento infantil. RESULTADOS: Propostos os titulos e os componentes de tres diagnosticos: "Atraso no desenvolvimento infantil," "Risco de atraso no desenvolvimento infantil," e "Disposicao para desenvolvimento infantil melhorado." CONCLUSOES: Os diagnosticos propostos contemplam toda a complexidade do desenvolvimento infantil. IMPLICACOES PARA A PRATICA DE ENFERMAGEM: Os novos diagnosticos podem subsidiar o enfermeiro na elaboracao de um plano de cuidados integrais a saude da crianca. PMID- 27976524 TI - Engineered Hydrogels for Local and Sustained Delivery of RNA-Interference Therapies. AB - It has been nearly two decades since RNA-interference (RNAi) was first reported. While there are no approved clinical uses, several phase II and III clinical trials suggest the great promise of RNAi therapeutics. One challenge for RNAi therapies is the controlled localization and sustained presentation to target tissues, to both overcome systemic toxicity concerns and to enhance in vivo efficacy. One approach that is emerging to address these limitations is the entrapment of RNAi molecules within hydrogels for local and sustained release. In these systems, nucleic acids are either delivered as siRNA conjugates or within nanoparticles. A plethora of hydrogels has been implemented using these approaches, including both traditional hydrogels that have already been developed for other applications and new hydrogels developed specifically for RNAi delivery. These hydrogels have been applied to various applications in vivo, including cancer, bone regeneration, inflammation and cardiac repair. This review will examine the design and implementation of such hydrogel RNAi systems and will cover the most recent applications of these systems. PMID- 27976527 TI - Skin regeneration with all accessory organs following ablation with irreversible electroporation. AB - Skin scar formation is a complex process that results in the formation of dense extracellular matrix (ECM) without normal skin appendages such as hair and glands. The absence of a scarless healing model in adult mammals prevents the development of successful therapies. We show that irreversible electroporation of skin drives its regeneration with all accessory organs in normal adult rats. Pulsed electric fields at 500 V, with 70 MUs pulse duration and 1000 pulses delivered at 3 Hz, applied through two electrodes separated by 2 mm lead to massive cell death. However, the ECM architecture of the skin was preserved. Six months after the ablation, the epidermis, sebaceous glands, panniculus carnosus, hair follicles, microvasculature and arrector pili muscle were altogether re formed in the entire ablated area. These results suggest a key role of the ECM architecture in the differentiation, migration and signalling of cells during scarless wound healing. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976529 TI - Protein-Modified CuS Nanotriangles: A Potential Multimodal Nanoplatform for In Vivo Tumor Photoacoustic/Magnetic Resonance Dual-Modal Imaging. AB - Controllable preparation of water-soluble multifunctional nanoprobes is of great significance for cancer early diagnosis. In this study, protein-modified hydrophilic copper sufide (CuS) nanotriangles with tunable absorption in the second near-infrared region are developed in the presence of halide ions. Further, gadolinium ions chelated diethylenetriaminepentaacetic acid is conjugated on it by using the unique characteristics of the protein-protected nanotriangles. Specifically, the as-obtained nanostructures are investigated as contrast agents for enhanced in vivo photoacoustic/magnetic resonance dual-modal tumor imaging. More importantly, in vitro and in vivo toxicity analysis are also performed, which show that the dual-modal nanoprobes are biocompatible for most of the cases. It is demonstrated that the novel as-prepared protein-modified nanotriangles are able to work as a nanoplatform to construct dual-modal nanoprobes, which paves a new avenue for improving the photoacoustic/magnetic resonance imaging contrast in cancer detection. It should be pointed out that other functional blocks may also be linked on it, which makes it a general method to design multifunctional nanoprobes. PMID- 27976530 TI - Description of the novel KIR3DL3*04802 allele identified in a southern Chinese Han individual. AB - The novel KIR3DL3*04802 allele differs from the closest allele KIR3DL3*04801 by a single synonymous mutation. PMID- 27976528 TI - Streptococcus mutans SpaP binds to RadD of Fusobacterium nucleatum ssp. polymorphum. AB - Adhesin-mediated bacterial interspecies interactions are important elements in oral biofilm formation. They often occur on a species-specific level, which could determine health or disease association of a biofilm community. Among the key players involved in these processes are the ubiquitous fusobacteria that have been recognized for their ability to interact with numerous different binding partners. Fusobacterial interactions with Streptococcus mutans, an important oral cariogenic pathogen, have previously been described but most studies focused on binding to non-mutans streptococci and specific cognate adhesin pairs remain to be identified. Here, we demonstrated differential binding of oral fusobacteria to S. mutans. Screening of existing mutant derivatives indicated SpaP as the major S. mutans adhesin specific for binding to Fusobacterium nucleatum ssp. polymorphum but none of the other oral fusobacteria tested. We inactivated RadD, a known adhesin of F. nucleatum ssp. nucleatum for interaction with a number of gram-positive species, in F. nucleatum ssp. polymorphum and used a Lactococcus lactis heterologous SpaP expression system to demonstrate SpaP interaction with RadD of F. nucleatum ssp. polymorphum. This is a novel function for SpaP, which has mainly been characterized as an adhesin for binding to host proteins including salivary glycoproteins. In conclusion, we describe an additional role for SpaP as adhesin in interspecies adherence with RadD-SpaP as the interacting adhesin pair for binding between S. mutans and F. nucleatum ssp. polymorphum. Furthermore, S. mutans attachment to oral fusobacteria appears to involve species and subspecies-dependent adhesin interactions. PMID- 27976532 TI - Redox-Neutral Rhodium-Catalyzed [4+1] Annulation through Formal Dehydrogenative Vinylidene Insertion. AB - A synthetic protocol for the expedient construction of 5-methylene-1H-pyrrol 2(5H)-one derivatives through rhodium-catalyzed [4+1] annulation with gem difluoroacrylate as the C1 component was reported. By taking advantage of the twofold C-F bond cleavage occurring during the annulation, this reaction not only allows the synthesis of these heterocyclic compounds under overall oxidant-free conditions but also renders the transformation stereospecific. The very mild reaction conditions employed ensure compatibility with a wide variety of synthetically useful functional groups. PMID- 27976531 TI - Chemistry Future: Priorities and Opportunities from the Sustainability Perspective. AB - To celebrate the 10 year anniversary of ChemSusChem, we as the chairmen of the editorial board are writing this Essay to summarize important scientific contributions to our journal during the past decade in terms of sustainable science and technology. Bibliometric analysis of published papers show that biorefinery, solar energy conversion, energy-storage materials, and carbon dioxide utilizations attracted most attention in this area. According to our own knowledge and understanding and from the sustainability point of view, we are also pointing out those research directions that we believe can play key roles in the future chemistry to meet the grand challenges in energy and environment. Hopefully, these perspective aspects will provide the readers with new angles to look at the chemistry in the coming decades and inspire the development of new technologies to make our society sustainable. PMID- 27976534 TI - Modeling of complex antibody elution behavior under high protein load densities in ion exchange chromatography using an asymmetric activity coefficient. AB - A main requirement for the implementation of model-based process development in industry is the capability of the model to predict high protein load densities. The frequently used steric mass action isotherm assumes a thermodynamically ideal system and, hence constant activity coefficients. In this manuscript, an industrial antibody purification problem under high load conditions is considered where this assumption does not hold. The high protein load densities, as commonly applied in industrial downstream processing, may lead to complex elution peak shapes. Using Mollerup's generalized ion-exchange isotherm (GIEX), the observed elution peak shapes could be modeled. To this end, the GIEX isotherm introduced two additional parameters to approximate the asymmetric activity coefficient. The effects of these two parameters on the curvature of the adsorption isotherm and the resulting chromatogram are investigated. It could be shown that they can be determined by inverse peak fitting and conform with the mechanistic demands of model-based process development. PMID- 27976533 TI - Phytoecdysteroids as antifeedants towards several beetles that include polyphagous and monophagous feeding guilds. AB - BACKGROUND: Plants are thought to produce ecdysteroids as a means of protection from insect herbivores. Some insects will not feed on plants containing high amounts of phytoecdysteroids, and this response could be limited to monophagous and oligophagous insects. The aim of this study was to determine whether phytoecdysteroids could inhibit feeding in several species of beetles that range from monophagous to polyphagous. RESULTS: Here we demonstrate that phytoecdysteroids, including 20-hydroxyecdysone, prevent several beetle species from feeding on preferred host plants, including the polyphagous Japanese beetle Popillia japonica (Scarabaeidae). Phytoecdysteroids prevented feeding damage when sprayed onto soybean plants in no-choice and choice assays in a dose-dependent manner. Laboratory assays indicate that other plants could be protected from Japanese beetle herbivory, including linden, wild grape, elm, Virginia creeper and rose leaves. Additional beetle species tested in the family Chrysomelidae included the oligophagous Cerotoma trifurcata and Diabrotica virgifera virgifera and the monophagous Trirhabda canadensis. All species were prevented from feeding when their preferred host plants were treated with phytoecdysteroids. CONCLUSION: This study demonstrates that beetles, representing polyphagous and monophagous feeding guilds, can be prevented from feeding when phytoecdysteroids are applied to the leaf surface. The phytoecdysteroids could be utilized in pest management towards a variety of beetles, including the more pestiferous polyphagous species, if the compounds are placed on the leaf surface. (c) 2016 Society of Chemical Industry. PMID- 27976535 TI - Patient goals in rheumatoid arthritis care: A systematic review and qualitative synthesis. AB - OBJECTIVE: During the clinical encounter, rheumatoid arthritis (RA) patient goals for care often go unexplored. The aim of the present systematic review was to identify needs, goals and expectations of RA patients in order better to guide systematic elicitation of patient goals in clinical encounters. METHODS: An academic librarian searched MEDLINE, PsychINFO and the Cochrane Library using a specialized algorithm developed to identify articles about patient goals for RA care. Investigators screened search results according to prespecified inclusion criteria and then reviewed included articles and synthesized the evidence qualitatively, utilizing an inductive approach. RESULTS: A total of 909 titles were retrieved in the literature search, of which 871 were excluded after a title/abstract screen. Of the remaining 38, 22 papers were included in the final review. Investigators identified four major themes in the literature: (a) the bodily experience of RA; (b) achieving normalcy and maintaining wellness; (c) social connectedness and support; and (d) interpersonal and healthcare system interactions. CONCLUSION: Patients' goals when receiving care for RA are multidimensional and span several facets of everyday life. Goals for RA care should be collaboratively developed between patients and providers, with particular attention to the patient's life context and priorities. PMID- 27976537 TI - Human Skin 3D Bioprinting Using Scaffold-Free Approach. AB - Organ in vitro synthesis is one of the last bottlenecks between tissue engineering and transplantation of synthetic organs. Bioprinting has proven its capacity to produce 3D objects composed of living cells but highly organized tissues such as full thickness skin (dermis + epidermis) are rarely attained. The focus of the present study is to demonstrate the capability of a newly developed ink formulation and the use of an open source printer, for the production of a really complete skin model. Proofs are given through immunostaining and electronic microscopy that the bioprinted skin presents all characteristics of human skin, both at the molecular and macromolecular level. Finally, the printability of large skin objects is demonstrated with the printing of an adult size ear. PMID- 27976536 TI - A Facile and Versatile Method to Endow Biomaterial Devices with Zwitterionic Surface Coatings. AB - The surface modification of implantable biomaterials with zwitterionic phosphorylcholine polymer is demonstrated through mussel-mimetic catecholamine polymer thin films. Using this method, the surfaces of alginate hydrogel microspheres and polystyrene microbeads, a model material known to produce robust foreign body responses and fibrosis, are successfully modified to reduce the tissue reaction by reducing the fibrosis in immunocompetent C57BL/6J mice. PMID- 27976538 TI - Cryopreservation and hypothermic storage of lacrimal gland: towards enabling delivery of regenerative medicine therapies for treatment of dry eye syndrome. AB - Severe dry eye syndrome (DES) can cause painful loss of vision and may result from lacrimal gland dysfunction. Current treatments are palliative, so a causative therapy is desirable. The ability to (cryo)preserve lacrimal gland tissue or epithelial cells would simplify this. Here, lacrimal gland tissue was cryopreserved in 10% dimethylsulphoxide in liquid nitrogen, or stored at 4 degrees C in culture medium for up to 7 days, and compared with fresh tissue using immunohistochemistry. Cultures were initiated from fresh and stored tissue, and cells characterised in P1 for proliferation (WST-1), colony-forming efficiency (CFE) and secretory capacity (immunocytochemistry and beta hexosaminidase activity assay). Tissue stored for > 3 days at 4 degrees C displayed grossly altered tissue architecture when compared with fresh tissue, decreased acinus density and increased caspase-3 activity. Cryopreserved tissue showed less obvious signs of damage without caspase-3 activation. Storage at 4 degrees C and cryopreservation delayed epithelial outgrowth compared with that from fresh tissue initially (p < 0.05) but, by day 9, all explants showed comparable outgrowth (~90%), except tissue stored at 4 degrees C for 3 or 7 days (p < 0.05 compared with fresh tissue). Epithelial cell yields per explant were similar from fresh and stored tissue, apart from tissue stored at 4 degrees C for 7 days (p < 0.01). In P1, epithelial cells from fresh and stored tissue were largely equivalent in terms of: proliferation; CFE (~21%); Rab3D, HexA and lysozyme expression; mucin production; and beta-hexosaminidase activity. These data demonstrate that cryo(preservation) of lacrimal gland tissue and cells is possible, which may enable use of autologous cells in regenerative medicine approaches to treating DES. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976539 TI - Porous Ionic Polymers as a Robust and Efficient Platform for Capture and Chemical Fixation of Atmospheric CO2. AB - Direct use of atmospheric CO2 as a C1 source to synthesize high-value chemicals through environmentally benign processes is of great interest, yet challenging. Porous heterogeneous catalysts that are capable of simultaneously capturing and converting CO2 are promising candidates for such applications. Herein, a family of organic ionic polymers with nanoporous structure, large surface area, strong affinity for CO2 , and very high density of catalytic active sites (halide ions) was synthesized through the free-radical polymerization of vinylfunctionalized quaternary phosphonium salts. The resultant porous ionic polymers (PIPs) exhibit excellent activities in the cycloaddition of epoxides with atmospheric CO2 , outperforming the corresponding soluble phosphonium salt analogues and ranking among the highest of known metal-free catalytic systems. The high CO2 uptake capacity of the PIPs facilitates the enrichment of CO2 molecules around the catalytic centers, thereby benefiting its conversion. We have demonstrated for the first time that atmospheric CO2 can be directly converted to cyclic carbonates at room temperature using a heterogeneous catalytic system under metal solvent free conditions. Moreover, the catalysts proved to be robust and fully recyclable, demonstrating promising potential for practical utilization for the chemical fixation of CO2 . Our work thereby paves a way to the advance of PIPs as a new type of platform for capture and conversion of CO2 . PMID- 27976540 TI - A helping hand: GuideLiner use to facilitate stent delivery. AB - The GuideLiner catheter system is a tool that can be used to increase procedural success in complex percutaneous coronary intervention. The safety profile of the device has improved with successive generations and with increased operator experience. Methods to utilize the GuideLiner safely and effectively are described in this article. PMID- 27976542 TI - Acute kidney injury after percutaneous coronary intervention: Rationale of the AKI-MATRIX (acute kidney injury-minimizing adverse hemorrhagic events by transradialaccess site and systemic implementation of AngioX) sub-study. PMID- 27976541 TI - Radial Artery Catheterization: Which is Right...I Mean Correct? AB - The radial artery has gained favor as the access of choice for many operators due to a lower risk of vascular complications. The vascular anatomy of the left upper extremity may be more conducive to cardiac catheterization given reduced subclavian tortuosity. The left radial artery continues to be an arrow in the quiver of modern interventional cardiologist and may provide less radiation exposure when compared to the right radial artery. PMID- 27976543 TI - Aorto-Ostial Lesions: Battling an Old Foe. AB - Aorto-ostial lesions (AOLs) entail several diagnostic and treatment challenges. The Flash Ostial System enables flaring of the overhanging stent, optimizing stent deployment in AOLs. Careful planning is essential to achieve optimal stent implantation and avoid early and late complications during the treatment of AOLs. PMID- 27976544 TI - Post PCI Angina: Painful in Many Ways! AB - Based on a multi-payer claims database, post-PCI angina (or chest pain) was frequent, occurring in 28% of patients at 1-year and 40% at 3 years. Patients with post-PCI angina had more physician and emergency department visits, diagnostic testing, (including repeat cardiac catheterization 29 vs. 4%) and hospitalizations at 1-year leading to markedly higher total direct medical costs. These results should stimulate further research into the etiology of post-PCI angina and strategies to decrease both the frequency and the significant economic burden associated with the challenging problem. PMID- 27976545 TI - Influences of audible radiation-monitors or radiopaque-pads on operator and patient dose. AB - Real-time awareness of their own radiation exposure reduced operator irradiation. The use of radiopaque pads did not significantly reduce operator irradiation. Real or perceived measures that reduce operator risk may bias clinical decisions toward "more complete" procedures and increase patient dose. PMID- 27976546 TI - Radial Access Optimization in the Nascent Post-Adoption Era. AB - Post-procedural upper extremity dysfunction (UED) remains one of the few potential questions about the overall benefits of the transradial approach (TRA) to endovascular procedures compared to femoral (TFA). Data on UED is limited, but the most comprehensive study curiously shows similar incidence of post-procedural UED with TFA as TRA. The effects of trAnsRadial perCUtaneouS coronary intervention on upper extremity function (ARCUS) study will investigate whether patient characteristics influence radial access outcomes such as UED. ARCUS may herald a post-radial-adoption era of more detailed strategies for radial access optimization, typical of a maturing technology. PMID- 27976547 TI - Invasive Hemodynamic Assessment During Mitra-Clip Implantation: Should It Be the New Standard? AB - Transesophageal echocardiography (TEE) assessment after MitraClip implantation is limited by unequal orifices and jets, eccentric regurgitation, and the acute change of the annulus geometry. Periprocedural real-time invasive hemodynamic assessment of the mitral valve function requires experience in hemodynamic monitoring interpretation. However, it provides excellent accuracy as it does not take into account the changes of the mitral apparatus geometry and jet direction after MitraClip placement. While we seek to expand indications of Mitraclip to other patient subgroups, we should consider routine ancillary invasive hemodynamic assessment, in order to optimize our understanding, procedural results. PMID- 27976548 TI - Percutaneous balloon valvuloplasty in carcinoid pulmonary valve stenosis. AB - More than half of patients with carcinoid syndrome develop carcinoid valve disease. Both the tricuspid and pulmonary valve are often involved. Symptoms of carcinoid syndrome with flushing, diarrhea, and bronchospasm often precedes cardiac symptoms. We report a case of carcinoid initially presenting with rapid development of right heart failure due to severe pulmonary valve stenosis. In untreated carcinoid, there is a risk of carcinoid crisis with anesthesia and surgery. In local anesthesia, we performed a sub-acute balloon pulmonary valvuloplasty. The procedure was successful without any residual pulmonary valve stenosis and with immediately relief of dyspnea. The final diagnostic workup for the underlying malignancy continued the day after valvuloplasty. (c) 2015 Wiley Periodicals, Inc. PMID- 27976549 TI - Dynamic Sheaths, in the Nick of Time or Past Their Prime? AB - Risk factors for vascular complications include a sheath to femoral artery ratio (SFAR) > 1.05, use of sheaths >19 Fr, peripheral artery disease, female gender, and a learning curve. High rates of technical and procedural success were achieved with low rates of major vascular and bleeding complications. However, SFAR > 1.05, gender, diabetes, renal insufficiency, calcification, tortuosity, or aneurysm were not independent risk factors in this study. Despite an SFAR > 1.05 in 23 patients, increased rates of vascular complications were not seen using the SoloPath sheath. These findings may increase the pool of transfemoral TAVI patients. PMID- 27976550 TI - Direct Conversion of Wheat Straw into Electricity with a Biomass Flow Fuel Cell Mediated by Two Redox Ion Pairs. AB - In this paper, a biomass flow fuel cell to directly convert wheat straw to electricity at low temperature (80-90 degrees C) and atmospheric pressure is presented. Two redox ion pairs, Fe3+ /Fe2+ and VO2+ /VO2+ , acting as redox catalysts and charge carriers, were used in the anode and cathode flow tanks, respectively. The wheat straw was first oxidized by Fe3+ in the anode tank at approximately 100 degrees C. The reduced Fe2+ in the anode was used to construct a fuel cell with VO2+ in the cathode. The VO2+ ions were reduced to VO2+ and regenerated to VO2+ by oxygen oxidation. The wheat straw flow fuel cell showed a power output of 100 mW cm-2 . Mediated with liquid Fe3+ carriers, the solid powder of wheat straw could be gradually degraded into low-molecular-weight organic molecules and even oxidized to CO2 at the anode without using noble-metal catalysts. The overpotential for the electrodes of the flow fuel cell was examined and the energy cost was estimated. PMID- 27976551 TI - Serum vitamin D levels during activation and remission periods of patients with juvenile idiopathic arthritis and familial Mediterranean fever. AB - The aim of this study was to determine the frequency of vitamin D deficiency and/or insufficiency in children with juvenile idiopathic arthritis (JIA) and familial Mediterranean fever (FMF) and to assess the relationship between vitamin D and disease activity. Sixty four patients with JIA, thirty six patients with FMF and one hundred healthy children were enrolled in this study. Vitamin D levels were measured during activation and remission periods in the patients with JIA and during attack and attack free periods in the patients with FMF. The mean vitamin D levels were found to be 18. 9+/-11 ng/ml and 18.6+/-9.2 ng/ml during activation and remission periods of disease, respectively, in the patients with JIA, 16+/-8.5 ng/ml and 13.1+/-6.4 ng/ml during attack and attack-free periods, respectively, in the patients with FMF and 26.7+/-10.5 ng/ml in the healthy children. There was no significant difference between vitamin D levels during activation and remission periods in the patients with JIA, whereas vitamin D levels during attack free periods were lower compared to attack periods in the patients with FMF. No significant relationship was found between disease activity and serum vitamin D levels. The vitamin D levels of the children with JIA and FMF were significantly lower compared to the healthy children. The frequency of vitamin D deficiency and insufficiency was considerably high among the patients with JIA and FMF. PMID- 27976552 TI - Parotidectomy outcomes, diagnosis and complications on pediatric patients; Twelve years of experiences in a tertiary care center. AB - The aim of this study is to evaluate parotid masses management in pediatric population. From June 2002 to December 2014, 13 patients under the age of 18 with parotid tumors were treated via surgery at Hacettepe University Department of Otorhinolaryngology. Information on patients' demographics, clinical and histopathologic tumor characteristics and treatment modalities with results was obtained from medical records, retrospectively. The age was ranging between 8-17 years. Ten (76.9%) patients had benign tumors and 8 (61.5%) of them were pleomorphic adenoma. One case had chronic sialadenitis with sialolithiasis and one patient had fluoride follicular hyperplasia. Three patients had malignant tumors; two of them were adenoid cystic carcinoma and one case of malignant melanoma metastasis. Twelve cases had undergone partial parotidectomy. Only one total parotidectomy was performed which was the patient with malignant melanoma. None of the patients had major complications or facial nerve palsy. During the 3 years follow up period, recurrence or Frey syndrome had not been detected but the case with malignant melanoma had distant metastasis during the follow up time. Although pediatric parotid masses are unusual, they can represent a variety of pathological diagnoses, including malignancy. Parotidectomy remains the mainstay of treatment and surgical experience is needed for low complication rates especially in children. PMID- 27976553 TI - Screening 5 and 6 year-old children starting primary school for development and language. AB - Beginning school is an important milestone for children. Children's readiness for school involves cognitive, physical, and emotional development. Certain school programs allow children to start first grade after 66 months of age, together with 72 month-old children. In order to estimate school readiness, we screened children before starting first grade and compared their school performance according to their age and socio-demographic characteristics. Marmara School Readiness, Denver II developmental screening, and language assessment tests were applied. Language delays were more frequent and school readiness test scores were lower in the younger group compared to older children. However, school achievement did not differ between the two age groups. Preschool education, parental income and education affected performance in most tests. Preschool screening seems effective in detecting children with lower than average developmental skills, and the school system may provide a practical opportunity for providing support to those children. PMID- 27976554 TI - Stepwise diet management in pediatric gastrointestinal graft versus host disease. AB - Gastrointestinal tract is one of the major systems affected by graft-versus-host disease (GVHD). Injury to the gut during conditioning therapy before stem-cell transplantation (SCT) plays a pivotal role in the initiation of inflammatory stimuli. We reviewed medical records of the patients who underwent SCT between April 2010 and June 2013 in our center. A stepwise upgrade diet was given to the children with acute GI-GVHD (Gastrointestinal GVHD) including parenteral and enteral nutrition. A total of 105 patients underwent SCT and seven patients developed grade III-IV acute GI-GVHD. Total parenteral nutrition (TPN) was initiated to all patients after the diagnosis of GI-GVHD and minimal enteral nutrition (1-2 ml/kg/day standard pediatric enteral formula/special meat soup) was given to the patients. GI-GVHD improved in all patients with no change in body weight, and recovery to a normal diet took 10-30 days. Stepwise diet management of oral nutrition contributed to rapid improvement of grades III-IV acute GI-GVHD. PMID- 27976555 TI - Are the methylenetetrahydrofolate reductase 1298 and 677 gene polymorphisms related to optic glioma and hamartoma risk in neurofibromatosis type 1 patients? AB - The methylenetetrahydrofolate reductase (MTHFR) gene plays a key role in carcinogenesis through its effects on DNA synthesis and methylation and also has a significant role in the etiology of many disorders, such as diabetes, migraine, and cardiovascular disease. Neurofibromatoses (NF) are autosomal dominant inherited diseases that can affect tissues such as bone and skin and predispose individuals to tumor development in various parts of the nervous system or body. Optic nerve glioma and brain tumors are common in children with NF, and leukemia and lymphoma incidence is also higher than normal. We therefore aimed to investigate the possible relationship between the MTHFR gene polymorphism and accompanying tumors such as neurofibroma, hamartoma, and optic glioma in children with NF1 found to have the MTHFR 677 and MTHFR 1298 gene polymorphism in this study. We included 55 pediatric patients diagnosed with NF1 between 2005 and 2014 in the study group. The control group included 44 healthy subjects without acute or chronic disease findings. A significant relationship was found between the MTHFR A1298C polymorphism and the incidence of optic glioma (p=0.014) (AA vs. AC: OR 11, 95% CI 1.27-95.17; AA vs. CC: OR 7.33, 95% CI 0.35-150.70). We also found a significant relationship between the MTHFR C1298C polymorphism and the incidence of hamartoma (p=0.019) (AA vs. AC: OR 2.12, 95% CI 0.662-6.809; p=0.203). Epilepsy incidence was high in subjects with MTHFR C677C. The MTHFR A1298C, C1298C, and C677C gene polymorphisms can be associated with a higher optic glioma, hamartoma, and epilepsy incidence, respectively, in patients diagnosed with neurofibromatosis type 1. PMID- 27976556 TI - Functional outcomes of mandibular distraction for the relief of severe airway obstruction and feeding difficulties in neonates with Pierre Robin sequence. AB - The purpose of this study was to review the application of mandibular distraction to relieve severe airway obstruction or feeding problems of neonates. Thirteen neonates with Pierre Robin sequence who underwent bilateral mandibular distraction between 2010 and 2013 for relief of their severe airway obstruction or feeding problems were retrospectively reviewed. The mean preoperative and postoperative airway diameters were 3.89+/-1.64 and 9.03+/-1.98 mm. respectively and significant difference was observed with distraction (p < 0.001). The rate of severe airway infection also significantly decreased from 69.2% to 23.1% (p=0.016). 84.6% of the patients were able to be fed orally at discharge whereas 6 patients (46.2%) required support via orogastric tube before distraction (p=0.125). No growth disturbance, dental complications or malocclusion was observed in the long-term follow up. Mandibular distraction appears to be a promising and effective surgical option for relieving airway obstruction and feeding problems in severe Pierre Robin Sequence patients. PMID- 27976557 TI - Prepubertal vaginal discharge: Vaginoscopy to rule out foreign body. AB - Medical records of all prepubertal patients who underwent vaginoscopy to rule out vaginal foreign body between 2004 and 2013 were reviewed retrospectively. All patients were evaluated by pediatricians prior to surgical consultation. Vaginoscopy is performed in the operating room under general anesthesia. During the study period, 20 girls with persistent vaginal discharge with a mean age of 6.8 years (1-13 years) underwent vaginoscopy to rule out vaginal foreign body. Six patients had bloody vaginal discharge and 4 had recurrent vaginal bleeding lasting for more than one month. Ten patients had purulent vaginal discharge lasting for 1-7 months. None of vaginal cultures revealed pathological bacteria or candida species. Preoperative imaging techniques revealed vaginal foreign body in one patient only. Vaginoscopy demonstrated vaginal foreign bodies in four patients. Foreign bodies were grass inflorescence, safety pin and undefined brownish particles (n=2), which may be pieces of toilet paper or feces. There was no complication related to vaginoscopy and removal of foreign body. Hymen integrity was preserved in all patients. Persistent or recurrent vaginal discharge in prepubertal girls should raise the suspect of vaginal foreign body. Continuous flow vaginoscopy is mandatory to detect and remove any vaginal foreign body. Early diagnosis would prevent complications secondary to long-standing foreign bodies. PMID- 27976558 TI - Carotid intima-media thickness and arterial stiffness as early markers of atherosclerosis in pediatric celiac disease. AB - The association between pediatric celiac disease (CD) and atherosclerosis is unknown. Our aim was to investigate whether pediatric CD patients have an increased risk of atherosclerosis. We evaluated the premature atherosclerosis by pulse wave velocity (PWV) and carotid intima-media thickness (cIMT). A total of 37 CD patients (20 girls, mean age 13+/-3.3 years) and 36 healthy age and sex matched controls were enrolled. Mean duration of CD was 47.1+/-32.3 months and 40.5% of patients had positive tissue transglutaminase antibody (tTg) IgA. Total cholesterol level was lower in CD (p=0.026) and cIMT was lower in tTg IgA antibody negative CD (p=0.030). cIMT was significantly correlated with tTg IgA antibody positivity (r=0.336; p=0.042). Adherence to strict gluten-free diet is associated with decreased cIMT, suggesting that gluten withdrawal seems to have a beneficial effect on premature atherosclerosis. PMID- 27976559 TI - Clinical accuracy of non-contact infrared thermometer from umbilical region in children: A new side. AB - Measurement from axillary site with digital thermometer has been accepted as the most accurate method. But this method is time consuming. Tympanic and forehead measurements are often used but don't always seem to be more appropriate. Another site, umbilical region, could be an alternative site. This study aims to compare the measurements with axillary digital thermometer and non-contact infrared thermometers at sites from umbilicus and forehead to determine whether umbilical site could be used accurately in children. For each method, 2,048 measurements in total were performed. Using axillary method as gold standard, with a cut-off temperature of 38oC, the sensitivities and specificities, positive and negative predictive values of umbilical and forehead temperatures and area under the ROC curve were determined in non obese children. There was a significant positive correlation between axillary and umbilical temperatures with a correlation coefficient of 0.78. The average difference between the mean of both axillary and umbilical temperatures was -0.47 +/- 0.65 degrees C. The Bland-Altman plot showed good accuracy with only 2.5 % of the readings falling outside the 95% level of confidence. Umbilical measurements showed sensitivity of 71.7% and specificity of 95.8%. The area under the ROC curve was 0.93. The easy application may lead noncontact measurements from umbilicus site to be the preferable method for health care providers, but agreement limits mentioned in this study should be considered. PMID- 27976560 TI - Evaluation of the removal reasons of totally implantable venous devices in children: a retrospective study. AB - Totally implantable venous access devices (TIVADs) increase the quality of life in children with hematologic and oncologic diseases or organ failures. The aim of this study is to determine the reasons for port removal. The port catheters, implanted and removed in patients between January 2000 and June 2013 were evaluated retrospectively. The patients were divided into two groups, whose port catheters were removed due to completed therapy (completed therapy group, CTG) and whose port catheters were removed because of a port catheter-related complications (complication group, CG). In the CG, the patients whose port catheters are removed for infectious reasons are investigated for whether there is a relationship with age, gender, body mass index (BMI), height and weight at the time of port implantation and removal. In total, 242 patients who underwent port implantation and removal were included in the study. The male to female ratio was 1.32/1 and the mean age of the patients was 9.4+/-4.9 years (0-24 year). Patients were enrolled in CTG (n=170, 70.2%), and CG (n=72, 29%). There is a positive correlation between BMI and infections (p < 0.05). In the CG, patients under steroid treatment had higher incidence of non-infectious causes than infectious causes (p < 0.05). Oppositely, non infectious complications were higher in steroid free patients (p < 0.05). There was no catheter related mortality in the entire study group. The hematological malignancies and solid tumors are the most common underlying primary disease in patients with port removal because of complications. Infectious complications are most common cause of port removal in children and despite other microorganism, fungi should be considered as a cause of catheter related infections. PMID- 27976561 TI - Congenital malaria: Importance of diagnosis and treatment in pregnancy. AB - Congenital malaria, in which infants are directly infected with malaria parasites from their mother prior to or during birth, is a potentially life-threatening condition that occurs at relatively low rates in malaria endemic regions. We report an unusual case of a 23-day-old girl with neonatal Plasmodium vivax malaria, suspected primarily on the basis of positive maternal history that her mother had malaria during her pregnancy and was cured with chloroquine therapy. Infant presented with fever, thrombocytopenia and a significant parasitemia. She responded to chloroquine antimalarial therapy and was discharged successfully 10 days after admission. We emphasize the importance of diagnosis and treatment in pregnancy and follow-up with these newborns after birth by neonatologists and pediatric specialists. PMID- 27976562 TI - Venlafaxine intoxication in an adolescent presenting with severe lactic acidosis. AB - Venlafaxine is a selective serotonin noradrenaline reuptake inhibitor and commonly prescribed antidepressant in adults. Most patients overdosing with venlafaxine develop only mild symptoms. Severe toxicity is reported with the most common symptoms being CNS depression, serotonin toxicity, seizure, or cardiac conduction abnormalities. However, lactic acidosis is an uncommon adverse effect. Here, we present the first case in the literature reporting lactic acidosis due to venlafaxine overuse in an adolescent. PMID- 27976563 TI - Effects of physiotherapy combined with sirolimus in a patient with vascular malformation: A case report. AB - The aim of the present case report was to investigate the effects of a physiotherapy program combined with sirolimus in a child patient with upper extremity edema and joint limitation due to low-flow vascular malformation. This case report included an 11-year-old male patient (26 kg, 130 cm) diagnosed with congenital lymphovascular malformation on the left and right chest. The patient, who had edema on the upper left extremity and experienced joint limitations, was administered complete decongestive therapy (CDT) and manual therapy in combination with sirolimus. Physiotherapy included a total of 24 sessions, 3 sessions a week for 8 weeks. Following the physiotherapy, the patient was assigned to a home therapy program, and then the maintenance phase of the CDT was initiated. Evaluations were carried out at baseline, at the end of week 8, and after 12 months. Following the physiotherapy program combined with sirolimus, a decrease in extremity volume, an increase in joint movement range, and an improvement in disease-related complaints were observed. Physiotherapy methods combined with sirolimus may be an effective treatment method in patients with vascular malformations. However, further studies with larger sample size are warranted. PMID- 27976564 TI - Nasal chondromesenchymal hamartoma, a rare pediatric tumor: Case report. AB - Nasal chondromesenchymal hamartoma has characteristic clinicopathological features and it is accepted as the upper airway analogue of mesenchymal hamartoma of the chest wall. It is a rare lesion and only 31 cases have been reported in the English literature until 2014. In this article, a 13-year-old nasal chondromesenchymal hamartoma case is presented, which is the first nasal chondromesenchymal hamartoma case from Turkey. Although, nasal chondromesenchymal hamartoma has been accepted as a benign lesion, the possibility of malignant transformation should be kept in mind, and detailed histologic examination should be performed particularly in adult nasal chondromesenchymal hamartoma cases. PMID- 27976565 TI - Different clinical spectrum of leptospirosis. AB - Leptospirosis is a prevalent zoonotic disease. Human infection usually occurs through exposure to environmental sources. Clinical course of leptospirosis is variable. We presented five patients, aged between 4-14 years, having a history of contact with rodents and symptoms 7-10 days after contact. The first three cases were relatives and had contact with dead rats after applying insecticides to bakery across from their house. The first case diagnosed as isolated meningitis, others as flu-like illness. The fourth case had a contact history with a rat inundate in the canalization and diagnosed as acute hepatitis. The last case, living in a village with poor sanitation, developed secondary hemophagocytic syndrome. ELISA was performed for diagnosis. High dose penicillin and additional immunosuppressive drugs for the last case were used. All cases showed recovery within 10 days. Leptospirosis should be considered in any patient presenting with an abrupt onset or prolonged fever, myalgia, headache and jaundice. PMID- 27976566 TI - Ceftriaxone-induced hemolytic anemia in a child successfully managed with intravenous immunoglobulin. AB - Drug-induced hemolytic anemia is an immune-mediated phenomenon that leads to the destruction of red blood cells. Here, we present a case of life-threatening ceftriaxone-induced hemolytic anemia (CIHA) in a previously healthy 3-year-old girl. We also reviewed the literature to summarize the clinical features and treatment of hemolytic anemia. Acute hemolysis is a rare side effect of ceftriaxone therapy associated with high mortality. Our patient had a sudden loss of consciousness with macroscopic hematuria and her hemoglobin dropped from 10.2 to 2.2 g/dl over 4 hours, indicating that the patient had life-threatening hemolysis after an intravascular dose of ceftriaxone who had previously been treated with ceftriaxone in intramuscular form for six days. CIHA is associated with a positive direct antiglobulin test, revealing the presence of IgG in all cases and C3d in most cases. Our patient's direct antiglobulin test was positive for IgG (3+) and for C3d (4+). The case was managed successfully with supportive measures and intravenous immunoglobulin therapy. Ceftriaxone is used very frequently in children; an early diagnosis and proper treatment of hemolytic anemia are essential to improve the patient outcome. The pathophysiological mechanism is the same as for non-drug autoimmune hemolytic anemia. However, there is still no consensus treatment for CIHA. Intravenous immunoglobulin can be used in clinical emergencies, such as our case, or in refractory cases. PMID- 27976567 TI - Successful treatment of refractory listeria meningitis and bacteremia with trimethoprim-sulfamethoxazole in an immunocompetent child. AB - Listeria monocytogenes is an important cause of life-threatening bacteremia and meningoencephalitis in neonates, pregnant women, the elderly, and immunocompromised individuals. However, it is an uncommon cause of illness in immunocompetent children beyond the neonatal period. Ampicillin with or without an aminoglycoside remains the best treatment for listeriosis. Here, we report a rare case of Listeria meningitis and bacteremia in a 7-month-old immunocompetent girl, which was refractory to ampicillin plus gentamicin treatment and successfully treated by the addition of TMP/SMX. PMID- 27976568 TI - An unexpected diagnostic course of systemic lupus erythematosus. AB - Thrombotic microangiopathy (TM), especially thrombotic thrombocytopenic purpura (TTP) is described in systemic lupus erythematosus (SLE) as a severe hematological involvement. However hemolytic uremic syndrome (HUS) is seen less frequently in SLE, particularly as an initial presentation. Here we present a 15 year old boy presenting with gross hematuria, decreased urinary output and petechial lesions. He was diagnosed as atypical HUS according to the classical triad of TM, along with observation of hypocomplementemia and negative stool cultures. In addition, his symptoms fulfilled the 2012 revised criteria for the classification of SLE. He was treated with plasma infusions and methylprednisolone/prednisone. At follow up his laboratory findings and general condition improved and no relapse was seen. PMID- 27976569 TI - Horseshoe kidney with growth retardation: Don't forget Turner syndrome. AB - Horseshoe kidney is the most frequent renal fusion anomaly that is usually asymptomatic and isolated malformation. However it can be seen with various syndromes and chromosomal anomalies. It was reported that 15-35% of Turner syndrome cases (TS) also display horseshoe kidney condition. TS is a chromosomal anomaly that had been characterized by delayed puberty, short body height and gonadal dysgenesis. In this report a five-year-old girl with horseshoe kidney, which has growth retardation during follow-up as only symptom of Turner syndrome. PMID- 27976570 TI - Aberrant cervical thymus and the role of ultrasonography: A case report. AB - Ectopic/aberrant cervical thymic tissue is a rare cause of neck mass and usually detected incidentally. Aberrant thymic tissue can occur anywhere in the course of thymic descent from the angle of the mandible to the superior mediastinum. We report a case of aberrant cervical thymus demonstrated by ultrasound. PMID- 27976571 TI - [Fluoroquinolones: Non-antibacterial properties]. AB - Fluoroquinolones are a class of well-established chemotherapeutic agents with a potent biological activity being the structure of 4-quinolone-3-carboxilic acids privileged because it contains different sites for functionalization allowing expand its use in clinical practice for their antifungal, antiviral and anticancer activities. Quinolones structural changes have resulted in a first, second, third and fourth generation of drugs so it is advisable to continue modifying existing structures in new ways to generate compounds with desirable biological and pharmacological properties. PMID- 27976572 TI - Separation and Identification of Anthocyanins Extracted from Blueberry Wine Lees and Pigment Binding Properties toward beta-Glucosidase. AB - Anthocyanins were isolated from blueberry wine lees using Sephadex LH-20 column chromatography and semipreparative high-performance liquid chromatography (semipreparative HPLC) and then identified by HPLC-DAD-ESI-MS/MS. Our results show that malvidin-3-hexose (Mv-3-hex) and malvidin-3-(6'acetyl)-hexose (Mv-3-ace hex) are the major components in the anthocyanin extracts of blueberry wine lees (>90%). The binding characteristics of Mv-3-hex and Mv-3-ace-hex with beta glucosidase were investigated by fluorescence spectroscopy, circular dichroism (CD) spectroscopy, and molecular docking. Spectroscopic analysis revealed that beta-glucosidase fluorescence quenched by Mv-3-hex and Mv-3-ace-hex follows a static mode. Binding of Mv-3-hex and Mv-3-ace-hex to beta-glucosidase mainly depends on electrostatic force. The result from CD spectra shows that adaptive structure rearrangement and increase of beta-sheet structure occur only in the presence of Mv-3-ace-hex. A molecular docking study suggests that Mv-3-ace-hex has stronger binding with beta-glucosidase than Mv-3-hex. PMID- 27976573 TI - Monitoring Photochemical Reaction Pathways of Tungsten Hexacarbonyl in Solution from Femtoseconds to Minutes. AB - Metal-organic complexes are widely used across disciplines for energy and biological applications, however, their photophysical and photochemical reaction coordinates remain unclear in solution due to pertaining molecular motions on ultrafast time scales. In this study, we apply transient absorption and tunable femtosecond stimulated Raman spectroscopy (FSRS) to investigate the UV photolysis of tungsten hexacarbonyl and subsequent solvent binding events. On the macroscopic time scale with UV lamp irradiation, no equilibrated intermediate is observed from W(CO)6 to W(CO)5(solvent), corroborated by vibrational normal mode calculations. Upon 267 nm femtosecond laser irradiation, the excited-state absorption band within ~400-500 nm exhibits distinct dynamics in methanol, tetrahydrofuran, and acetonitrile on molecular time scales. In methanol, solvation of the nascent pentacarbonyl-solvent complex occurs in ~8 ps and in tetrahydrofuran, 13 ps which potentially involves the associative oxygen-donating ligand rearrangement reaction. In contrast, a stimulated emission feature above 480 nm emerges after ~1 ps in acetonitrile with a nitrogen-donating ligand. These structural dynamics insights demonstrate the combined resolving power of ultrafast electronic and stimulated Raman spectroscopy to elucidate photochemistry of functional organometallic complexes in solution. The delineated reaction pathways in relation to ligand nucleophilicity and solvent reorientation time provide the rational design principles for solution precursors in nanowrite applications. PMID- 27976574 TI - Method Dependence of Proline Ring Flexibility in the Poly-l-Proline Type II Polymer. AB - We studied the sensitivity of the energetic and geometrical features of the proline ring (pyrrolidine) to the quantum mechanical computational approach by adopting the proline monomer, trimer, and polymer, as simplified collagen protein models. Within the Density Functional Theory (DFT) approach, we tested the ability of different functionals (GGA PBE and the hybrid B3LYP), added with a posteriori empirical dispersion corrections (D), to predict the conformational potential energy surface of the five-membered heterocycle pyrrolidine ring for the above models, dictating the collagen main features. We also compared the DFT D results with those from the recently proposed cost-effective HF-3c method and our variant HF-3c-027, both based on Hartree-Fock Hamiltonian and Gaussian minimal basis set properly corrected for basis set superposition error, structure deficiencies, and dispersion interactions. We found that dispersion interactions are essential to destabilize specific conformers. While the HF-3c and its HF-3c 027 variant are unreliable to predict accurately the energy of the ring conformers, structures are accurate. Indeed, the cost-effective DFT-D//HF-3c-027 approach in which the energetic is from the accurate DFT-D method on HF-3c-027 structures provides energetic in line with that derived by the costly DFT-D//DFT D approach, paving the way to simulate more realistic collagen models of much larger size. The adoption of either PBE or B3LYP functional for the electronic part of the DFT-D method gives very similar results, recommending the first as the most cost-effective method for simulating large collagen models. The predicted most stable conformation computed for the periodic poly proline (type II) model allows for a higher flexibility, in agreement with experimental studies on collagen protein. The present results open the way to large-scale calculations of the collagen/hydroxyapatite system, crucial for understanding the atomistic details in bones and teeth. PMID- 27976575 TI - Experimental and Theoretical Evaluations of the Galvanomagnetic Effect in an Individual Bismuth Nanowire. AB - The galvanomagnetic effect is evaluated experimentally and theoretically in an individual bismuth nanowire encapsulated within a quartz template. A small section of the side surface of the encapsulated bismuth nanowire is exposed using focused ion beam processing, and a total of six carbon film electrodes are fabricated on the exposed nanowire surface by in situ deposition in order to be able to perform electrical measurements on the nanowire. The results show that the galvanomagnetic effect in the nanowire is affected by carrier collisions at the nanowire boundary; this is particularly the case at low temperatures. The Hall mobilities of electrons and holes are determined based on the measured Hall coefficient and magnetoresistivity values. It is found that the carrier mobility in the bismuth nanowire is lower than that in bulk bismuth and that it plateaus at low temperatures, as predicted by the calculation model used in the study, which takes into account the carrier mean free path limitation imposed by the small diameter of the nanowire. PMID- 27976576 TI - Probing Conformers of Benzene Dimer with Intermolecular Coulombic Decay Spectroscopy. AB - Benzene dimer is a prototype to study intermolecular interactions between aromatic systems. Owing to the weak interactions between the molecules within the dimer, several conformational geometries are nearly isoenergetic and thus coexist even at low temperatures. Furthermore, standard spectroscopies are unable to distinguish between them. In this work, we study the electronic relaxation processes following inner-valence ionization of benzene and the lowest conformers of benzene dimer. We show that the kinetic energy distributions of the secondary electrons emitted via two autoionization mechanisms, namely, the Auger and the intermolecular coulombic decay (ICD) effects, provide a means to probe the conformers of benzene dimer. The proposed spectroscopy opens the way to a better characterization of weakly bound molecular clusters. PMID- 27976578 TI - Unimolecular rearrangements connecting hydroxyethylidene (CH3-C-OH), acetaldehyde (CH3-CH:O), and vinyl alcohol (CH2:CH-OH). PMID- 27976579 TI - Dependence of Solvent Diffusion on Hydrophobic Block Length within Amphiphilic Hydrophobic Block Copolymer Membranes. AB - Pore networks and water diffusion within model (amphiphilic-hydrophobic) diblock copolymer membranes in the presence of 16 vol % water is studied by dissipative particle dynamics in combination with Monte Carlo tracer diffusion calculations. The amphiphilic block (parent architecture (A[A3C])10) is composed of a backbone that contains 10 consecutively connected hydrophobic A beads; to each A bead, a side chain is grafted composed of three connected A beads and a pendant hydrophilic C bead. Hydrophobic blocks are constructed from x covalently bonded A beads, with x = 20, 30, or 50. Water diffusion through the pores is modeled by Monte Carlo tracer diffusion within more than 500 mapped morphologies. Long range water diffusion within the amphiphilic-hydrophobic ((A[A3C])10-Ax) diblock architectures increases with hydrophobic block length. Diffusion increases with Q = ?Nbond?|C||1 - C|-1, where C is the hydrophilic C bead fraction and ?Nbond? the average number of bonds that A beads are separated from the nearest C bead. These trends are also anticipated for amphiphilic parent architectures (ACA3)10, (A2[C]A2)10, and (A2[AC]A)10. This is explained by the squeezing of water from the hydrophobic phase into the amphiphilic phase. Two characteristic distances are observed: The shorter distance corresponds to the interpore (or intercluster) separation within the "parent architecture-water" phase and obeys the earlier obtained linear relation between intercluster distance and ?Nbond?amphi of the amphiphilic parent architecture. The longer distance is governed by the phase separation between the amphiphilic-water phase and hydrophobic blocks. PMID- 27976580 TI - Through-Space Charge Interaction Substituent Effects in Molecular Catalysis Leading to the Design of the Most Efficient Catalyst of CO2-to-CO Electrochemical Conversion. AB - The starting point of this study of through-space substituent effects on the catalysis of the electrochemical CO2-to-CO conversion by iron(0) tetraphenylporphyrins is the linear free energy correlation between through structure electronic effects and the iron(I/0) standard potential that we established separately. The introduction of four positively charged trimethylanilinium groups at the para positions of the tetraphenylporphyrin (TPP) phenyls results in an important positive deviation from the correlation and a parallel improvement of the catalytic Tafel plot. The assignment of this catalysis boosting effect to the Coulombic interaction of these positive charges with the negative charge borne by the initial Fe0-CO2 adduct is confirmed by the negative deviation observed when the four positive charges are replaced by four negative charges borne by sulfonate groups also installed in the para positions of the TPP phenyls. The climax of this strategy of catalysis boosting by means of Coulombic stabilization of the initial Fe0-CO2 adduct is reached when four positively charged trimethylanilinium groups are introduced at the ortho positions of the TPP phenyls. The addition of a large concentration of a weak acid-phenol-helps by cleaving one of the C-O bonds of CO2. The efficiency of the resulting catalyst is unprecedented, as can be judged by the catalytic Tafel plot benchmarking with all presently available catalysts of the electrochemical CO2-to CO conversion. The maximal turnover frequency (TOF) is as high as 106 s-1 and is reached at an overpotential of only 220 mV; the extrapolated TOF at zero overpotential is larger than 300 s-1. This catalyst leads to a highly selective formation of CO (practically 100%) in spite of the presence of a high concentration of phenol, which could have favored H2 evolution. It is also very stable, showing no significant alteration after more than 80 h of electrolysis. PMID- 27976577 TI - Understanding the Phosphorylation Mechanism by Using Quantum Chemical Calculations and Molecular Dynamics Simulations. AB - Phosphorylation is one of the most frequent post-translational modifications on proteins. It regulates many cellular processes by modulation of phosphorylation on protein structure and dynamics. However, the mechanism of phosphorylation induced conformational changes of proteins is still poorly understood. Here, we report a computational study of three representative groups of tyrosine in ADP ribosylhydrolase 1, serine in BTG2, and serine in Sp100C by using six molecular dynamics (MD) simulations and quantum chemical calculations. Added phosphorylation was found to disrupt hydrogen bond, and increase new weak interactions (hydrogen bond and hydrophobic interaction) during MD simulations, leading to conformational changes. Quantum chemical calculations further indicate that the phosphorylation on tyrosine, threonine, and serine could decrease the optical band gap energy (Egap), which can trigger electronic transitions to form or disrupt interactions easily. Our results provide an atomic and electronic description of how phosphorylation facilitates conformational and dynamic changes in proteins, which may be useful for studying protein function and protein design. PMID- 27976581 TI - Phosphatase POPX2 Exhibits Dual Regulatory Functions in Cancer Metastasis. AB - Cancer metastasis is a complex mechanism involving multiple processes. Previously, our integrative proteome, transcriptome, and phosphoproteome study reported that the levels of serine/threonine phosphatase POPX2 were positively correlated with cancer cell motility through modulating MAPK signaling. Surprisingly, here we found that POPX2 knockdown cells induced more numerous and larger tumor nodules in lungs in longer term animal studies. Interestingly, our analysis of DNA microarray data from cancer patient samples that are available in public databases shows that low POPX2 expression is linked to distant metastasis and poor survival rate. These observations suggest that lower levels of POPX2 may favor tumor progression in later stages of metastasis. We hypothesize that POPX2 may do so by modulation of angiogenesis. Secretome analysis of POPX2-knockdown MDA-MB-231 cells using LC-MS/MS-based SILAC quantitative proteomics and cytokine array show that silencing of POPX2 leads to increased secretion of exosomes, which may, in turn, induce multiple pro-angiogenic cytokines. This study, combined with our previous findings, suggests that a single ubiquitously expressed phosphatase POPX2 influences cancer metastasis via modulating multiple biological processes including MAPK signaling and exosome cytokine secretion. PMID- 27976582 TI - Hysteresis and the Cholesterol Dependent Phase Transition in Binary Lipid Mixtures with the Martini Model. AB - Extensive Martini simulation data, totaling 5 ms, is presented for binary mixtures of dipalmitoylphosphatidylcholine (DPPC) and cholesterol. Using simulation initiated from both gel (so) and liquid-disordered (Ld) phases, significant and strongly cholesterol-dependent hysteresis in the enthalpy as a function of temperature is observed for cholesterol mole fractions from 0 to 20 mol %. Although the precise phase transition temperature cannot be determined due to the hysteresis, the data are consistent with a first order gel to fluid transition, which increases in temperature with cholesterol. At 30 mol % cholesterol, no hysteresis is observed, and there is no evidence for a continuous transition, in either structural parameters like the area per lipid or in the heat capacity as a function of temperature. The results are consistent with a single uniform phase above a critical cholesterol composition between 20 and 30 mol % in Martini, while highlighting the importance and difficulty of obtaining the equilibrium averages to locate phase boundaries precisely in computational models of lipid bilayers. PMID- 27976584 TI - Direct Laser Writing-Based Programmable Transfer Printing via Bioinspired Shape Memory Reversible Adhesive. AB - Flexible and stretchable electronics offer a wide range of unprecedented opportunities beyond conventional rigid electronics. Despite their vast promise, a significant bottleneck lies in the availability of a transfer printing technique to manufacture such devices in a highly controllable and scalable manner. Current technologies usually rely on manual stick-and-place and do not offer feasible mechanisms for precise and quantitative process control, especially when scalability is taken into account. Here, we demonstrate a spatioselective and programmable transfer strategy to print electronic microelements onto a soft substrate. The method takes advantage of automated direct laser writing to trigger localized heating of a micropatterned shape memory polymer adhesive stamp, allowing highly controlled and spatioselective switching of the interfacial adhesion. This, coupled to the proper tuning of the stamp properties, enables printing with perfect yield. The wide range adhesion switchability further allows printing of hybrid electronic elements, which is otherwise challenging given the complex interfacial manipulation involved. Our temperature-controlled transfer printing technique shows its critical importance and obvious advantages in the potential scale-up of device manufacturing. Our strategy opens a route to manufacturing flexible electronics with exceptional versatility and potential scalability. PMID- 27976583 TI - Enhanced Antiglioma Efficacy of Ultrahigh Loading Capacity Paclitaxel Prodrug Conjugate Self-Assembled Targeted Nanoparticles. AB - Glioblastoma multiforme (GBM) presents one of the most lethal brain tumor with a dismal prognosis. And nanodrug delivery system (nano-DDS) have raised a lot of concern, while the conventional nanoformulations addressed many limitations, especially the low drug loading capacity and poor stability in vivo. Herein, we proposed PTX prodrug (PTX-SS-C18) conjugate self-assembled nanoparticles (PSNPs) functionalized with Pep-1, glioma homing peptide, to overcome the blood brain tumor barrier (BBTB) via interleukin 13 receptor alpha2 (IL-13Ralpha2)-mediated endocytosis for targeting GMB. This nanocarrier was with ultrahigh drug loading capacity (56.03%) and redox-sensitivity to the up-expression of glutathione in glioma tumors. And compared with PEG-PSNPs, Pep-PSNPs could significantly enhance cellular uptake in U87MG cells via IL-13Ralpha2-mediated endocytosis. Enhanced cytotoxicity of Pep-PSNPs against U87MG cells and BCEC cells pretreated with glutathione monoester (GSH-OEt) confirmed that this nanosystem was sensitive to reduction environment, and there was significant difference between targeting and nontargeting groups in MTT assay. Real-time fluorescence image of intracranialU87MG glioma-bearing mice revealed that Pep-PSNPs could more efficiently accumulate at tumor site and improve the penetration. Furthermore, the ex vivo fluorescence imaging and corresponding semiquantitative results displayed that the glioma fluorescence intensity of Pep-PSNPs group was 1.74-fold higher than that of nontargeting group. Pep-PSNPs exhibited remarkable antiglioblastoma efficacy with an extended median survival time. In conclusion, Pep-PSNPs had a promising perspective as a targeting drug delivery system of PTX for glioma treatment. PMID- 27976585 TI - Redox Active Ion-Paired Excited States Undergo Dynamic Electron Transfer. AB - Ion-pair interactions between a cationic ruthenium complex, [Ru(dtb)2(dea)][PF6]2, C12+ where dea is 4,4'-diethanolamide-2,2'-bipyridine and dtb is 4,4'-di-tert-butyl-2,2'-bipyridine, and chloride, bromide, and iodide are reported. A remarkable result is that a 1:1 iodide:excited-state ion-pair, [C12+, I-]+*, underwent diffusional electron-transfer oxidation of iodide that did not occur when ion-pairing was absent. The ion-pair equilibrium constants ranged 104 106 M-1 in CH3CN and decreased in the order Cl- > Br- > I-. The ion-pairs had longer-lived excited states, were brighter emitters, and stored more free energy than did the non-ion-paired states. The 1H NMR spectra revealed that the halides formed tight ion-pairs with the amide and alcohol groups of the dea ligand. Electron-transfer reactivity of the ion-paired excited state was not simply due to it being a stronger photooxidant than the non-ion-paired excited state. Instead, work term, DeltaGw was the predominant contributor to the driving force for the reaction. Natural bond order calculations provided natural atomic charges that enabled quantification of DeltaGw for all the atoms in C12+ and [C12+, I-]+* presented herein as contour diagrams that show the most favorable electrostatic positions for halide interactions. The results were most consistent with a model wherein the non-ion-paired C12+* excited state traps the halide and prevents its oxidation, but allows for dynamic oxidation of a second iodide ion. PMID- 27976586 TI - Photoactive/Passive Molecular Glass Blends: An Efficient Strategy to Optimize Azomaterials for Surface Relief Grating Inscription. AB - Irradiation of azomaterials causes various photophysical and photomechanical effects that can be exploited for the preparation of functional materials such as surface relief gratings (SRGs). Herein, we develop and apply an efficient strategy to optimize the SRG inscription process by decoupling, for the first time, the important effects of the azo content and glass transition temperature (Tg). We prepare blends of a photoactive molecular glass functionalized with the azo Disperse Red 1 (gDR1) with a series of analogous photopassive molecular glasses. Blends with 10 and 40 mol % of gDR1 are completely miscible, present very similar optical properties, and cover a wide range of Tg from below to well above ambient temperature. SRG inscription experiments show that the diffraction efficiency (DE), residual DE, and initial inscription rate reach a maximum when Tg is 25-40 degrees C above ambient temperature for low to high azo content, respectively. Indeed, for a fixed 40 mol % azo content, choosing the optimal Tg enables doubling the SRG inscription rate and increasing DE 6-fold. Moreover, a higher azo content enables higher DE for a similar Tg. Spectroscopy measurements indicate that the photo-orientation of DR1 and its thermal stability are maximal with Tg around 70 degrees C, independent of the azo content. We conclude that the SRG potential of azomaterials depends on their capability to photo-orient but that the matrix rigidity eventually limits the inscription kinetics, leading to an optimal Tg that depends on the azo content. This study exposes clear material design guidelines to optimize the SRG inscription process and the photoactivity of azomaterials. PMID- 27976587 TI - Electroreductive Remediation of Halogenated Environmental Pollutants. AB - Electrochemical reduction of halogenated organic compounds is gaining increasing attention as a strategy for the remediation of environmental pollutants. We begin this review by discussing key components (cells, electrodes, solvents, and electrolytes) in the design of a procedure for degrading a targeted pollutant, and we describe and contrast some experimental techniques used to explore and characterize the electrochemical behavior of that pollutant. Then, we describe how to probe various mechanistic features of the pertinent electrochemistry (including stepwise versus concerted carbon-halogen bond cleavage, identification of reaction intermediates, and elucidation of mechanisms). Knowing this information is vital to the successful development of a remediation procedure. Next, we outline techniques, instrumentation, and cell designs involved in scaling up a benchtop experiment to an industrial-scale system. Finally, the last and major part of this review is directed toward surveying electrochemical studies of various categories of halogenated pollutants (chlorofluorocarbons; disinfection byproducts; pesticides, fungicides, and bactericides; and flame retardants) and looking forward to future developments. PMID- 27976588 TI - Collapse-Swelling Transitions of a Thermoresponsive, Single Poly(N isopropylacrylamide) Chain in Water. AB - We present molecular dynamics (MD) simulations of a single poly(N isopropylacrylamide) (PNIPAM) chain in explicit water at temperatures between 270 and 320 K near the lower critical solution temperature (LCST). The force-fields of OPLS-AA and TIP4P/2005 are used for a PNIPAM chain and water molecules, respectively. Three independent simulations with durations of 1 MUs are performed at each temperature for a 30-mer PNIPAM chain starting with three distinct conformations: extended, loosely collapsed, and tightly collapsed states. The simulation trajectories exhibit reversible conformational transitions between swollen- and collapsed-chain conformations, which has rarely been reported in previous simulation studies, with the overall transition occurring at different temperatures depending on the initial conformation. The inconsistency of the transition temperatures depending on the initial conformation implies that, in spite of the simulation duration of 1 MUs distinctly longer than that in previous simulation studies, the conformational sampling from the MD simulations is not enough to draw conclusions on equilibrium properties. Instead of evaluating average properties, therefore, the focus is on dynamic changes in the chain conformation during reversible collapse-swelling transitions at each temperature. The simulation trajectories are analyzed in terms of the radius of gyration, intrachain distances, hydrophobic contacts, and chain-water and intrachain hydrogen bonding. In particular, the formation of stable intrachain hydrogen bonds is a signature of the tightly collapsed-chain conformations that persist, once formed, for the entire simulation duration. PMID- 27976589 TI - A Key Role of Xanthophylls That Are Not Embedded in Proteins in Regulation of the Photosynthetic Antenna Function in Plants, Revealed by Monomolecular Layer Studies. AB - The main physiological function of LHCII (light-harvesting pigment-protein complex of photosystem II), the largest photosynthetic antenna complex of plants, is absorption of light quanta and transfer of excitation energy toward the reaction centers, to drive photosynthesis. However, under strong illumination, the photosynthetic apparatus faces the danger of photodegradation and therefore excitations in LHCII have to be down-regulated, e.g., via thermal energy dissipation. One of the elements of the regulatory system, operating in the photosynthetic apparatus under light stress conditions, is a conversion of violaxanthin, the xanthophyll present under low light, to zeaxanthin, accumulated under strong light. In the present study, an effect of violaxanthin and zeaxanthin on the molecular organization and the photophysical properties of LHCII was studied in a monomolecular layer system with application of molecular imaging (atomic force microscopy, fluorescence lifetime imaging microscopy) and spectroscopy (UV-Vis absorption, FTIR, fluorescence spectroscopy) techniques. The results of the experiments show that violaxanthin promotes the formation of supramolecular LHCII structures preventing dissipative excitation quenching while zeaxanthin is involved in the formation of excitonic energy states able to quench chlorophyll excitations in both the higher (B states) and lower (Q states) energy levels. The results point to a strategic role of xanthophylls that are not embedded in a protein environment, in regulation of the photosynthetic light harvesting activity in plants. PMID- 27976590 TI - Highly Oxidized Second-Generation Products from the Gas-Phase Reaction of OH Radicals with Isoprene. AB - The gas-phase reaction of OH radicals with isoprene has been investigated in an atmospheric pressure flow tube at 293 +/- 0.5 K with special attention to the second-generation products. Reaction conditions were optimized to achieve a predominant reaction of RO2 radicals with HO2 radicals. Chemical ionization atmospheric pressure interface-time-of-flight mass spectrometry served as the analytical technique in order to follow the formation of RO2 radicals and closed shell products containing at least four O atoms in the molecule. The reaction products were detected as adducts with the reagent ions using acetate, lactate, or nitrate in the ionization process. Observed signals were attributed to a series of C5-products with multiple hydroxy, hydroperoxy, and probably carbonyl groups. H/D exchange experiments supported the product identification. The generation of the detected second-generation products can be mechanistically explained starting from the OH radical reaction of hydroxy hydroperoxide isomers, HO-C5H8-OOH. These isomers represent the dominant products of the initial OH radical attack on isoprene. Dihydroxy dihydroperoxides, (HO)2-C5H8-(OOH)2, were analyzed as the main second-generation products beside the dihydroxy epoxides. A simple kinetic analysis revealed that the observed second-generation products in total (other than dihydroxy epoxides) were formed with an estimated molar yield of 10.0-1.5+2.1 % with respect to converted hydroxy hydroperoxides. A formation yield of 5.8-0.9+1.3 % has been deduced for the main product (HO)2-C5H8-(OOH)2. The detected, highly oxidized isoprene products represent potential secondary organic aerosol precursors. An annual, global (HO)2-C5H8-(OOH)2 formation strength of (16-35) * 106 metric tons is estimated based on product measurements of this study and literature data regarding the formation of the dihydroxy epoxide isomers for an annual isoprene emission of 454 * 106 metric tons of carbon. PMID- 27976591 TI - Efficacy of pulsed high-intensity laser therapy on pain, functional capacity, and gait in children with haemophilic arthropathy. AB - AIM: The aim of this study was to evaluate the effects of pulsed high-intensity laser therapy (HILT) on pain, functional capacity, and gait in children with haemophilia. METHODS: Thirty children with haemophilia type A with ages ranging from 9 to 13 years were selected for this study. They were assigned randomly, into two equal treatment groups. The laser group received the traditional physical therapy programme plus active laser (total energy of 1500 J through three phases/3 sessions/week), whereas the placebo group received the same physical therapy programme plus placebo laser over three consecutive months. Baseline and post-treatment assessments used the visual analogue scale (VAS) to evaluate pain, a 6-min walk test (6MWT) to evaluate functional capacity, and the GAITRite(r) system to evaluate gait parameters. RESULTS: Children in the laser group showed significant improvement in pain, functional capacity, and gait parameters compared to those in the placebo group (p < 0.05). Post-treatment functional capacity for the laser and placebo groups were 316.6 +/- 35.27 and 288 +/- 43.3 m, respectively. CONCLUSIONS: HILT is an effective modality in reducing pain, increasing functional capacity, and improving gait performance in children with haemophilic arthropathy. Implications for Rehabilitation Haemophilic arthropathy due to recurrent joint bleeding leads to physical, psychological, and socioeconomic problems in children with haemophilia and reduces their quality of life. Early physiotherapeutic interventions help to prevent and treat the sequelae of recurrent haemarthrosis. High-intensity laser therapy has been introduced as non-invasive and an effective physiotherapy modality for rapid pain control, with consequent improvement in children's quality of life. High intensity laser therapy should be used as an adjunct to exercise programme in the rehabilitation of children with haemophilic arthropathy. PMID- 27976592 TI - Chemical profiling of the tuber of Stephania cambodica Gagnep. (Menispermaceae) and analytical control by UHPLC-DAD. AB - A new aporphine glycoside (1), named 'angkorwatine', and eight known alkaloids: oblongine (2), stepharine (3), asimilobine-beta-d-glucopyranoside (4), isocorydine (5), tetrahydropalmatine (THP) (6), jatrorrhizine (7), palmatine (PAL) (8), and roemerine (ROE) (9) were simultaneously isolated from the tuber of Stephania cambodica. The development and validation of UHPLC-DAD method was carried out for the quantification of marker compounds (PAL, ROE, THP) of S. cambodica. In addition to good selectivity and linearity (r2 > 0.997), trueness, precision, and accuracy of the method did not exceed the acceptance limit of +/ 10% for ROE, THP and +/-20% for PAL. Consequently, this method is able to provide accurate results between 1.39-4.18 MUg/mL, 2.01-30.72 MUg/mL, and 4.29-64.42 MUg/mL for PAL, ROE, and THP, respectively. This study shows that the validated UHPLC method is a rapid, innovative and effective analytical approach to control quality of tubers of S. cambodica and to regulate the usage of this plant in traditional medicine. PMID- 27976593 TI - Antimicrobial resistance in Enterococcus strains isolated from healthy domestic dogs. AB - Enterococci are opportunistic bacteria that cause severe infections in animals and humans, capable to acquire, express, and transfer antimicrobial resistance. Susceptibility to 21 antimicrobial agents was tested by the disk diffusion method in 222 Enterococcus spp. strains isolated from the fecal samples of 287 healthy domestic dogs. Vancomycin and ampicillin minimum inhibitory concentrations (MICs) and high-level aminoglycoside resistance (HLAR) tests were also performed. Isolates showed resistance mainly to streptomycin (88.7%), neomycin (80.6%), and tetracycline (69.4%). Forty-two (18.9%) isolates showed an HLAR to streptomycin and 15 (6.7%) to gentamicin. Vancomycin and ampicillin MIC values showed 1 and 18 resistant strains, respectively. One hundred and thirty-six (61.2%) strains were classified as multidrug resistant and six (2.7%) strains as possibly extensively drug-resistant bacteria. Enterococcus faecium and Enterococcus faecalis were the most prevalent antimicrobial resistant species. Companion animals, which often live in close contact with their owners and share the same environment, represent a serious source of enterococci resistant to several antibiotics; for this reason, they may be a hazard for public health by providing a conduit for the entrance of resistance genes into the community. PMID- 27976594 TI - A qualitative study exploring factors that influence enrollment in outpatient cardiac rehabilitation. AB - PURPOSE: This study explored patients' decision-making about whether or not to enroll in cardiac rehabilitation (CR), an underutilized program that is associated with significantly improved health outcomes. METHOD: Face-to-face interviews were conducted with acute coronary syndrome patients (n = 14) after referral to a local CR center, but prior to program enrollment. Thematic analysis was used to derive themes from interview transcripts. RESULTS: Three themes emerged including anticipated benefit, perceived ability, and contextual influences. Participants believed key benefits of CR would be access to specialist health care providers, improved longevity, reduced cardiovascular risk, as well as improved motivation, accountability, learning opportunities, and general fitness. Participants were concerned about their ability to engage in and travel to exercise sessions, pay the program fee, and manage scheduling conflicts. Contextual influences on decision-making included health care provider recommendation, first impressions of the CR center, knowledge gaps about what CR entails, input from family and peers, and psychological distress. CONCLUSION: The period following CR referral but prior to enrollment represents an optimal opportunity to promote in-the-moment decisions in favor of CR. Patients report both positive and negative aspects of CR, suggesting individualized efforts to resolve ambivalence may increase program participation. Implications for Rehabilitation Cardiovascular disease is a leading cause of mortality worldwide. Cardiac rehabilitation (CR) is an effective secondary prevention strategy to improve cardiovascular morbidity and mortality, but only a subset of eligible patients enroll. After referral but prior to enrollment, patients anticipate both positive and negative aspects of CR participation. Individualized efforts to resolve ambivalence, address knowledge gaps, and problem-solve barriers may increase uptake into CR programs. PMID- 27976595 TI - Effect of Non-Surgical Periodontal Treatment on Gingival Crevicular Fluid and Serum Endocan, Vascular Endothelial Growth Factor-A, and Tumor Necrosis Factor Alpha Levels. AB - BACKGROUND: Periodontitis is a chronic inflammatory disease that occurs due to the interaction between pathogenic microorganisms and host defenses. Endocan is a proteoglycan secreted by endothelial cells under the control of inflammatory cytokines. Aims of the study are to determine serum and gingival crevicular fluid (GCF) endocan levels in the pathogenesis of periodontal diseases, supported with vascular endothelial growth factor (VEGF-A) and tumor necrosis factor (TNF)-alpha levels. This study additionally aims to evaluate correlation between GCF endocan levels, VEGF-A, and TNF-alpha levels with periodontal probing depth (PD). METHODS: The study consists of two groups: group 1 (n = 20), healthy individuals; group 2 (n = 20), individuals with generalized chronic periodontitis (CP). Clinical measurements were recorded; GCF and serum samples were obtained from each participant before and 6 weeks after therapy. Levels of biomarkers were measured by enzyme-linked immunosorbent assay. Intergroup comparisons of biochemical and clinical parameters were analyzed by Kruskal-Wallis/Bonferroni adjusted Mann-Whitney U test using statistical software. RESULTS: Serum and GCF endocan, VEGF-A, and TNF-alpha levels were significantly higher in patients with CP than in healthy individuals (P <0.001) and decreased after treatment (P <0.03). A significant correlation was observed between GCF TNF-alpha and PD (4 mm <= PD <=5 mm and PD >=6 mm). A significant relationship was found among GCF endocan and TNF-alpha, VEGF-A, CAL, and GI for all groups (P <0.05). CONCLUSIONS: Endocan and TNF-alpha levels, both in GCF and serum, increased from health to periodontitis and decreased with non-surgical periodontal treatment. Within the limits of the study, endocan may be considered as a potential inflammatory marker for periodontal disease. PMID- 27976596 TI - Influence of Non-Impacted Third Molars on Pathologies of Adjacent Second Molars: A Retrospective Study. AB - BACKGROUND: Although removal of impacted third molars (I-M3s) is common in dental clinics, the decision to retain or remove asymptomatic non-impacted third molars (N-M3s) presents a significant challenge. This study investigates influence of N M3s on pathologies of adjacent second molars (A-M2s). METHODS: Clinical status of M3s was evaluated, and presence of distal caries, external root resorption (ERR), and alveolar bone loss (ABL) of A-M2s was assessed by orthopantomograms (OPGs). Prevalence of A-M2 pathologies was evaluated and association between N-M3s and pathologies of A-M2s was analyzed by multivariate logistic regression. Significance level was set at 0.05. RESULTS: OPGs from 1,958 patients were included in the present study. Among these patients, 45.1% presented with at least one N-M3, and 44.2% of retained M3s were non-impacted. Where N-M3s were present, prevalence of distal caries, ERR, and ABL of A-M2s was 10.0%, 0.8%, and 40.4%, respectively. Although N-M3s did not increase the odds of caries or ERR of A-M2s, presence of N-M3s was associated with 1.77 times higher likelihood of ABL from A-M2s when data were adjusted for age and sex. CONCLUSIONS: Presence of N M3s, even if they are asymptomatic, represents an important risk factor for periodontal health of A-M2s. This finding should be considered during clinical decision making regarding retention or extraction of N-M3s, especially when these teeth are non-functional or when their removal will not affect overall occlusal function. PMID- 27976599 TI - Helminth parasites of finfish commercial aquaculture in Latin America. AB - Latin America has tripled production by aquaculture up to 78 million tonnes in the past 20 years. However, one of the problems that aquaculture is facing is the presence of helminth parasites and the diseases caused by them in the region. In this review we have collected all the available information on helminths affecting commercial aquaculture in Latin America and the Caribbean (LAC), emphasizing those causing serious economic losses. Monogeneans are by far the most common and aggressive parasites affecting farmed fish in LAC. They have been recognized as serious pathogens in intensive fish culture because they reach high levels of infection rapidly, and can infect other phylogenetically related fish species. The next most important group comprises the larval stages of digeneans (metacercariae) such as Diplostomum sp. and Centrocestus formosanus, which cause serious damage to farmed fish. Since LAC aquaculture has been based mainly on exotic species (tilapia, salmon, trout and carp), most of their parasites have been brought into the region together with the fish for aquaculture. Recently, one of us (A.I.P.-T.) has suggested that monogeneans, which have generally been considered to be harmless, can produce serious effects on the growth of cultured Nile tilapia. Therefore, the introduction of fish together with their 'harmless' parasites into new sites, regions or countries in LAC should be considered a breakdown of biosecurity in those countries involved. Therefore, the application of quarantine procedures and preventive therapeutic treatments should be considered before allowing these introductions into a country. PMID- 27976598 TI - Callous-unemotional behaviors in early childhood: Genetic and environmental contributions to stability and change. AB - Callous-unemotional (CU) behaviors demonstrate meaningful individual differences in early childhood, even in nonclinical samples with low mean levels of CU, but the factors underlying this variation have not been examined. This study investigated genetic and environmental contributions to individual differences and to sources of continuity and change in CU in toddler twins (145 monozygotic, 169 dizygotic) assessed at ages 2 and 3 years. CU, as assessed by the Child Behavior Checklist 1.5-5 (Achenbach & Rescorla, 2000), was moderately stable across age (r = .45, p < .0001). Longitudinal biometric analyses revealed genetic and nonshared environmental influences on CU at both ages, with no significant contribution from shared environmental factors. Stability from age 2 to 3 was due to genetic factors, whereas change was due to both genetic and nonshared environmental influences. This genetic and nonshared environmental change was substantial, suggesting malleability of CU in early childhood. Over 50% of the genetic influences and 100% of the nonshared environmental influences on CU at age 3 were independent of those that operated at age 2. Implications of novel sources of variance across age are discussed. PMID- 27976600 TI - Clinical improvements following bilateral anterior capsulotomy in treatment resistant depression. AB - BACKGROUND: The purpose of this study was to evaluate a programme of lesion surgery carried out on patients with treatment-resistant depression (TRD). METHOD: This was a retrospective study looking at clinical and psychometric data from 45 patients with TRD who had undergone bilateral stereotactic anterior capsulotomy surgery over a period of 15 years, with the approval of the Mental Health Act Commission (37 with unipolar depression and eight with bipolar disorder). The Beck Depression Inventory (BDI) before and after surgery was used as the primary outcome measure. The Montgomery-Asberg Depression Rating Scale was administered and cognitive aspects of executive and memory functions were also examined. We carried out a paired-samples t test on the outcome measures to determine any statistically significant change in the group as a consequence of surgery. RESULTS: Patients improved on the clinical measure of depression after surgery by -21.20 points on the BDI with a 52% change. There were no significant cognitive changes post-surgery. Six patients were followed up in 2013 by phone interview and reported a generally positive experience. No major surgical complications occurred. CONCLUSIONS: With the limitations of an uncontrolled, observational study, our data suggest that capsulotomy can be an effective treatment for otherwise TRD. Performance on neuropsychological tests did not deteriorate. PMID- 27976597 TI - Mycobacterial cell wall biosynthesis: a multifaceted antibiotic target. AB - Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), is recognized as a global health emergency as promoted by the World Health Organization. Over 1 million deaths per year, along with the emergence of multi- and extensively-drug resistant strains of Mtb, have triggered intensive research into the pathogenicity and biochemistry of this microorganism, guiding the development of anti-TB chemotherapeutic agents. The essential mycobacterial cell wall, sharing some common features with all bacteria, represents an apparent 'Achilles heel' that has been targeted by TB chemotherapy since the advent of TB treatment. This complex structure composed of three distinct layers, peptidoglycan, arabinogalactan and mycolic acids, is vital in supporting cell growth, virulence and providing a barrier to antibiotics. The fundamental nature of cell wall synthesis and assembly has rendered the mycobacterial cell wall as the most widely exploited target of anti-TB drugs. This review provides an overview of the biosynthesis of the prominent cell wall components, highlighting the inhibitory mechanisms of existing clinical drugs and illustrating the potential of other unexploited enzymes as future drug targets. PMID- 27976601 TI - An appraisal of the taxonomy and nomenclature of trypanosomatids presently classified as Leishmania and Endotrypanum. AB - We propose a taxonomic revision of the dixenous trypanosomatids currently classified as Endotrypanum and Leishmania, including parasites that do not fall within the subgenera L. (Leishmania) and L. (Viannia) related to human leishmaniasis or L. (Sauroleishmania) formed by leishmanias of lizards: L. colombiensis, L. equatorensis, L. herreri, L. hertigi, L. deanei, L. enriettii and L. martiniquensis. The comparison of these species with newly characterized isolates from sloths, porcupines and phlebotomines from central and South America unveiled new genera and subgenera supported by past (RNA PolII gene) and present (V7V8 SSU rRNA, Hsp70 and gGAPDH) phylogenetic analyses of the organisms. The genus Endotrypanum is restricted to Central and South America, comprising isolates from sloths and transmitted by phlebotomines that sporadically infect humans. This genus is the closest to the new genus Porcisia proposed to accommodate the Neotropical porcupine parasites originally described as L. hertigi and L. deanei. A new subgenus Leishmania (Mundinia) is created for the L. enriettii complex that includes L. martiniquensis. The new genus Zelonia harbours trypanosomatids from Neotropical hemipterans placed at the edge of the Leishmania Endotrypanum-Porcisia clade. Finally, attention is drawn to the status of L. siamensis and L. australiensis as nomem nudums. PMID- 27976602 TI - "Providing a Roof" and More to Communities Affected by Typhoon Haiyan in the Philippines: the Medecins Sans Frontieres Experience. AB - OBJECTIVES: Typhoon Haiyan hit the Philippines in November 2013 and left a trail of destruction. As part of its emergency response, Medecins Sans Frontieres distributed materials for reconstructing houses and boats as standardized kits to be shared between households. Community engagement was sought and communities were empowered in deciding how to make the distributions. We aimed to answer, Was this effective and what lessons were learned? METHODS: A cross-sectional survey using a semi-structured questionnaire was conducted in May 2014 and included all community leaders and 269 households in 22 barangays (community administrative areas). RESULTS: All houses were affected by the typhoon, of which 182 (68%) were totally damaged. All households reported having received and used the housing material. However, in 238 (88%) house repair was incomplete because the materials provided were insufficient or inappropriate for the required repairs. CONCLUSION: This experience of emergency mass distribution of reconstruction or repair materials of houses and boats led by the local community was encouraging. The use of "standardized kits" resulted in equity issues, because households were subjected to variable degrees of damage. A possible way out is to follow up the emergency distribution with a needs assessment and a tailored distribution. (Disaster Med Public Health Preparedness. 2017;11:285-289). PMID- 27976603 TI - Dietary patterns associated with overweight and obesity among Brazilian schoolchildren: an approach based on the time-of-day of eating events. AB - Several studies reported that the timing of eating events has critical implications in the prevention of obesity, but dietary patterns regarding the time-of-day have not been explored in children. The aim of this study was to derive latent food patterns of daily eating events and to examine their associations with overweight/obesity among schoolchildren. A population-based cross-sectional study was conducted with 7-10-year-old Brazilian schoolchildren (n 1232) who completed the Previous Day Food Questionnaire, illustrated with twenty-one foods/beverages in six daily eating events. Latent class analysis was used to derive dietary patterns whose association with child weight status was evaluated by multivariate multinomial regression. Four mutually exclusive latent classes of dietary patterns were identified and labelled according to the time-of day of eating events and food intake probability (FIP): (A) higher FIP only at lunch; (B) lower FIP at all eating events; (C) higher FIP at lunch, afternoon and evening snacks; (D) lower FIP at breakfast and at evening snack, higher FIP at other meals/snacks. The percentages of children within these classes were 32.3, 48.6, 15.1 and 4.0 %, respectively. After controlling for potential confounders, the mean probabilities of obesity for these classes were 6 % (95 % CI 3.0, 9.0), 13 % (95 % CI 9.0, 17.0), 12 % (95 % CI 6.0, 19) and 11 % (95 % CI 5.0, 17.0), in the same order. In conclusion, the children eating traditional lunch with rice and beans as the main meal of the day (class A) had the lowest obesity risk, thus reinforcing the importance of both the food type and the time-of-day of its intake for weight status. PMID- 27976604 TI - Acceptability and potential effectiveness of commercial portion control tools amongst people with obesity. AB - Exposure to large portion sizes is a risk factor for obesity. Specifically designed tableware may modulate how much is eaten and help with portion control. We examined the experience of using a guided crockery set (CS) and a calibrated serving spoon set (SS) by individuals trying to manage their weight. Twenty-nine obese adults who had completed 7-12 weeks of a community weight-loss programme were invited to use both tools for 2 weeks each, in a crossover design, with minimal health professional contact. A paper-based questionnaire was used to collect data on acceptance, perceived changes in portion size, frequency, and type of meal when the tool was used. Scores describing acceptance, ease of use and perceived effectiveness were derived from five-point Likert scales from which binary indicators (high/low) were analysed using logistic regression. Mean acceptance, ease of use and perceived effectiveness were moderate to high (3.7 4.4 points). Tool type did not have an impact on indicators of acceptance, ease of use and perceived effectiveness (P>0.32 for all comparisons); 55 % of participants used the CS on most days v. 21 % for the SS. The CS was used for all meals, whereas the SS was mostly used for evening meals. Self-selected portion sizes increased for vegetables and decreased for chips and potatoes with both tools. Participants rated both tools as equally acceptable, easy to use and with similar perceived effectiveness. Formal trials to evaluate the impact of such tools on weight control are warranted. PMID- 27976605 TI - Measuring diet in the 21st century: use of new technologies. AB - The advent of the internet and smartphone technology has allowed dietary assessment to reach the 21st century! The variety of foods available on the supermarket shelf is now greater than ever before. New approaches to measuring diet may help to reduce measurement error and advance our understanding of nutritional determinants of disease. This advance provides the potential to capture detailed dietary data on large numbers of individuals without the need for costly and time-consuming manual nutrition coding. This aim of the present paper is to review the need for new technologies to measure diet with an overview of tools available. The three main areas will be addressed: (1) development of web-based tools to measure diet; (2) use of smartphone apps to self-monitor diet; (3) improving the quality of dietary assessment through development of an online library of tools. A practical example of the development of a web-based tool to assess diet myfood24 (www.myfood24.org) will be given exploring its potential, limitations and challenges. The development of a new food composition database using back-of-pack information will be described. Smartphone apps used to measure diet with a focus on obesity will be reviewed. Many apps are unreliable in terms of tracking, and most are not evaluated. Accurate and consistent measurement of diet is needed for public health and epidemiology. The choice of the most appropriate dietary assessment method tends to rely on experience. The DIET@NET partnership has developed best practice guidelines for selection of dietary assessment tools, which aim to improve the quality, consistency and comparability of dietary data. These developments provide us with a step-change in our ability to reliably characterise food and nutrient intake in population studies. The need for high-quality, validated systems will be important to fully realise the benefits of new technologies. PMID- 27976609 TI - Atlas of neuropathological lesions in epilepsy surgery: Hippocampal sclerosis, ILAE Type 2 (CA1 - predominant neuronal loss) PMID- 27976606 TI - The progression of coeliac disease: its neurological and psychiatric implications. AB - The aim of the paper is to show the various neurological and psychiatric symptoms in coeliac disease (CD). CD is a T cell-mediated, tissue-specific autoimmune disease which affects genetically susceptible individuals after dietary exposure to proline- and glutamine-rich proteins contained in certain cereal grains. Genetics, environmental factors and different immune systems, together with the presence of auto-antigens, are taken into account when identifying the pathogenesis of CD. CD pathogenesis is related to immune dysregulation, which involves the gastrointestinal system, and the extra-intestinal systems such as the nervous system, whose neurological symptoms are evidenced in CD patients. A gluten-free diet (GFD) could avoid cerebellar ataxia, epilepsy, neuropathies, migraine and mild cognitive impairment. Furthermore, untreated CD patients have more symptoms and psychiatric co-morbidities than those treated with a GFD. Common psychiatric symptoms in untreated CD adult patients include depression, apathy, anxiety, and irritability and schizophrenia is also common in untreated CD. Several studies show improvement in psychiatric symptoms after the start of a GFD. The present review discusses the state of the art regarding neurological and psychiatric complications in CD and highlights the evidence supporting a role for GFD in reducing neurological and psychiatric complications. PMID- 27976610 TI - Unexpected migration of free light chains in urinary protein electrophoresis. AB - Urinary protein electrophoresis analysis (UPE) is an essential investigation for the study of abnormal proteins in urines. The interpretation of this analysis must be comprehensive and relevant. Indeed, UPE is often requested by clinicians and may have an important impact in patient's management. This paper presents two cases with free light chains showing unexpected electrophoretic migration which can lead to the misinterpretation of results. This article helps biologists to keep in mind the interest of UPE among the several analyses useful in the laboratory. PMID- 27976612 TI - Atlas of neuropathological lesions in epilepsy surgery: Hippocampal sclerosis, ILAE Type 1 PMID- 27976611 TI - Atlas of neuropathological lesions in epilepsy surgery: No hippocampal sclerosis (ILAE classification 2013) PMID- 27976614 TI - Atlas of neuropathological lesions in epilepsy surgery: Hippocampal sclerosis, ILAE Type 3 (CA4 predominant neuronal loss) PMID- 27976613 TI - Discoid lupus erythematosus occurring in an area previously affected by herpes zoster virus: Wolf's isotopic reaction? PMID- 27976616 TI - "Silver economy", a lever to another development? PMID- 27976617 TI - Dysphagia: a geriatric syndrome? AB - Dysphagia is a common condition in the elderly but often not systematically explored. The "geriatric syndromes" refer to the multifactorial health conditions that occur when the cumulative effects of functional disorders of multiple systems make an individual vulnerable to face the challenges of situations. This article assumes that dysphagia is a geriatric syndrome and provides arguments in favor of it. In this context its' approach requires screening followed by an interdisciplinary management involving various professional geriatric teams. PMID- 27976618 TI - Relationship between body composition and bone mineral density, related to physical activity, in elderly women. AB - Changes in body composition, including a decrease in muscle and bone mass, accompany aging. Analyse the influence of lean mass on bone mineral density, related to physical activity, in elderly women. 37 women were included in this study via an osteoporosis consultation. Body composition and bone mineral density (BMD) measurements were performed using Dual-energy X-ray absorptiometry methodology (DXA). The BMD was measured at the femoral neck. Each participant had a physical activity test to respond and had to perform handgrip, a four meter walk and one leg balance. Simple regression analyze showed a positive association between lean masse et BMD; after multiple linear regression analysis, we found a positive association between BMD, lean mass, and one leg balance; lean masse and one leg balance were two independent variable. Bone Mineral density was signicantly associated to lean mass and one leg balance. PMID- 27976619 TI - Editorial. PMID- 27976620 TI - Amnesia, memory disturbances and epilepsy. AB - The epileptic syndromes, notably the temporal lobe epilepsy, frequently include memory disturbances. These memory disturbances may occur during seizures, i.e. ictal memory disturbances, or between seizures, i.e. interictal memory disturbances. Two atypical clinical epileptic syndromes should be pointed out in the elderly: the transient epileptic amnesia and the epileptic pseudodementia. Both represent potentially reversible memory disturbances and have a treatment based on antiepileptic drugs. Transient epileptic amnesia (TEA) is a subtype of medial temporal lobe epilepsy with late onset. TEA is characterized by recurrent episodes of acute transient amnesia lasting less than one hour. The main differential diagnosis is transient global amnesia (TGA). Conversely to TGA, TEA have a shorter duration, is recurrent but have a clear-cut response to antiepileptic drugs. Interictal memory disturbances consist of autobiographic memory disorders and long term forgetting. Epileptic pseudodementia is a pure disturbance of verbal episodic memory, stable over time. It is due to very frequent and recurrent subtle temporal lobe seizures. Response to antiepileptic drugs is less evident. PMID- 27976621 TI - Benefits of game-based leisure activities in normal aging and dementia. AB - Given the increasing prevalence of dementia and the limited efficacy of pharmacological treatments, it is crucial to improve the knowledge of the factors that might delay the onset of dementia for developing non-pharmacological interventions. Recent studies have provided evidence that game-based interventions, especially the practice of video games, could improve the cognitive functioning (e.g. executive functions) in older adults and in demented patients. The positive effects of these games have also been demonstrated on physical health (e.g. improvement of balance and gait). Video gamed-based interventions may also alleviate mood or behavioral disorders, and increase interactions with friends, family, caregivers or other patients. The positive impact of games on these domains (cognitive and physical decline, social isolation) suggests that game-based interventions might contribute to delay the onset of dementia. Thus, playing games might be considered as a protective factor in dementia and even more as a potential non-pharmacological strategy in dementia rather than leisure activity. PMID- 27976622 TI - Exploration of sleep disorders in the elderly: which particularities? AB - There are many reasons to take into consideration the sleep disorders in the elderly. The sleep quality degrades with age and is strongly affected by medical conditions, intrinsic sleep disorders, or by a combination of these factors. Other age-related conditions such as severe dementia, dependence or living in institution worsen sleep disturbances in older people. When living alone elderly people, being cognitively impaired and medically disabled, may not be able to complain about sleep problems. Sleep disorders are thus underdiagnosed, unmarked, and insufficiently investigated in the elderly. In this heterogeneous population, sleep assessment should include a global geriatric approach and be individually adapted for each subject. The sleep interview must specially include medical comorbidities, medication uses, and aged-related changes of lifestyle such as retirement, loss of spouse, hospitalization or institutionalization. In the elderly with loss of autonomy, standard sleep assessment is not always adequate and must be replaced by shorter, simpler or observation-based tests such as the Sleep disorders inventory, Observation-based nocturnal sleep inventory, Observation and interview based diurnal sleepiness inventory. When sleep log is impossible, actimetry is an excellent alternative for studying sleep-wake rhythm. Ventilatory polygraphy is a simpler test for detecting sleep apnea than polysomnography. Utilization of sophisticated investigations should be discussed when the feasibility and usefulness is limited. PMID- 27976623 TI - Social cognition in normal and pathological aging. AB - The concept of social cognition refers to a set of skills and to emotional and social experiences regulating relationships between individuals. This concept is appropriate in order to help us to explain individual human behaviours and behaviours in groups. Social cognition involves social knowledge, perception and processing of social cues, and the representation of mental states. The concept of social cognition thus refers to a multitude of skills. This paper stops on several of them, namely theory of mind, empathy, moral reasoning, emotional processing and emotional regulation. We propose a conceptual approach to each of these skills also stopping on their cerebral underpinnings. We also make an inventory of knowledge about the effects of age and neurodegenerative diseases on social cognition. PMID- 27976624 TI - Palliative care for dementia patients. AB - Dementia is a life-limiting disease without curative treatments but the data suggest that advanced dementia is not viewed as a terminal diagnosis by physicians. Although symptoms of dementia and cancer patients are similar, palliative care is less frequently proposed for dementia patients. However, professionals and family members of demented patients strongly favor comfort care for end-stage dementia. To improve the patients' relief near the end of life, advance care planning with patients and their proxies should be encouraged. It should start as soon as possible so that the patient can still be actively involved and his preferences, values, needs and beliefs elicited. Written advance directives or enrollment in hospice care are associated with quality of dying. Yet caregivers are sometimes concerned about applying palliative care too early or that advance plans would be invalidated if relatives or patients changed their mind. Therefore, general practitioners and palliative care specialists need to better collaborate to provide greater information and improve comfort and quality of life of dementia patients. PMID- 27976625 TI - Caregivers' representations of elders who drink too much alcohol: crossroads between professional home caregivers and hospitals nurses. AB - Being old or having alcohol use disorders are two unfavorable conditions for receiving help or optimal care. When these two conditions are associated, professionals are even less attracted to work with old alcoholics. To address this issue, from the professionnals perspective, two studies based on research interviews were crossed, one was conducted with 17 professional home caregivers and the other with 29 hospital nurses. A double analysis of the collected speech was manually performed, then computerized by the Alceste(r) software. This qualitative research, may have indirectly selected the most favorable agents concerned by the issue: those who agreed to answer. Professional home caregivers have negative and demeaning representations of older drinkers (manipulative, nasty, violent...), which generate feelings of powerlessness when faced with them and deleterious identifications. Despite an expressed lack of training and a lack of support for their activities, these agents are able to develop skills in their caregiving interventions, and find professional satisfaction by accompanying them. Nurses also have an initial negative impression of elders misusing alcohol, but these professionals rapidly consider them as less violent and more approachable than younger adults with alcohol use disorder. The exchanges with these old alcoholic patients, often resort to humor, in a possible attempt for proximity, while the same agents report only very few skills to care for elderly alcoholics. Despite all these negative precedents, care is possible and develops itself in daily practice. Beyond initial and spontaneous adverse reactions, while they feel very isolated and little supported in their actions, professional home caregivers as well as nurses, develop daily assistance and care with elders misusing alcohol. The professional home caregivers' expectancy for training and the nurses' expectancy for support could help improve the first approach of these elders and the quality of care offered to them. PMID- 27976627 TI - A new R package and web application for detecting bilateral asymmetry in parasitic infections. AB - When parasites invade paired structures of their host non-randomly, the resulting asymmetry may have both pathological and ecological significance. To facilitate the detection and visualisation of asymmetric infections we have developed a free software tool, Analysis of Symmetry of Parasitic Infections (ASPI). This tool has been implemented as an R package (https://cran.r-project.org/package=aspi) and a web application (https://wayland.shinyapps.io/aspi). ASPI can detect both consistent bias towards one side, and inconsistent bias in which the left side is favoured in some hosts and the right in others. Application of ASPI is demonstrated using previously unpublished data on the distribution of metacercariae of species of Diplostomum von Nordmann, 1832 in the eyes of ruffe Gymnocephalus cernua (Linnaeus). Invasion of the lenses appeared to be random, with the proportion of metacercariae in the left and right lenses showing the pattern expected by chance. However, analysis of counts of metacercariae from the humors, choroid and retina revealed asymmetry between eyes in 38% of host fish. PMID- 27976628 TI - Hybrid opto-chemical doping in Ag nanoparticle-decorated monolayer graphene grown by chemical vapor deposition probed by Raman spectroscopy. AB - The novel opto-chemical doping effect in Ag nanoparticle-decorated monolayer graphene grown by chemical vapor deposition has been investigated using Raman spectroscopy for the first time. We used both noble metal nanoparticles and optical excitation, in a hybrid opto-chemical route, to tune the doping level in graphene. Metal nanoparticle-induced chemical effects and laser power-induced substrate effects alter the doping nature of graphene from p- to n-type. Compared with earlier studies, the proposed method significantly lowers the laser intensity required for optical power-dependent doping, resulting in prevention of damage to the sample due to local heating. Some other interesting observations are the enhanced peak intensity in the Raman spectrum of graphene, enhancement of the D-band intensity and the introduction of G-band splitting. This novel, cheap and easily implemented hybrid optical-chemical doping strategy could be very useful for tuning graphene plasmons on the widely used Si/SiO2 substrates for various photonic device applications. PMID- 27976629 TI - Subsurface contrast due to friction in heterodyne force microscopy. AB - The nondestructive imaging of subsurface structures on the nanometer scale has been a long-standing desire in both science and industry. A few impressive images were published so far that demonstrate the general feasibility by combining ultrasound with an atomic force microscope. From different excitation schemes, heterodyne force microscopy seems to be the most promising candidate delivering the highest contrast and resolution. However, the physical contrast mechanism is unknown, thereby preventing any quantitative analysis of samples. Here we show that friction at material boundaries within the sample is responsible for the contrast formation. This result is obtained by performing a full quantitative analysis, in which we compare our experimentally observed contrasts with simulations and calculations. Surprisingly, we can rule out all other generally believed responsible mechanisms, like Rayleigh scattering, sample (visco)elasticity, damping of the ultrasonic tip motion, and ultrasound attenuation. Our analytical description paves the way for quantitative subsurface AFM imaging. PMID- 27976630 TI - Nickel oxide nanotube synthesis using multiwalled carbon nanotubes as sacrificial templates for supercapacitor application. AB - A novel approach for the fabrication of nickel oxide nanotubes based on multiwalled carbon nanotubes as a sacrificial template is described. Electroless deposition is employed to deposit nickel onto carbon nanotubes. The subsequent annealing of the product in the presence of air oxidizes nickel to nickel oxide, and carbon is released as gaseous carbon dioxide, leaving behind nickel oxide nanotubes. Electron microscopy and elemental mapping confirm the formation of nickel oxide nanotubes. New chelating polyelectrolytes are used as dispersing agents to achieve high colloidal stability for both the nickel-coated carbon nanotubes and the nickel oxide nanotubes. A gravimetric specific capacitance of 245.3 F g-1 and an areal capacitance of 3.28 F cm-2 at a scan rate of 2 mV s-1 is achieved, with an electrode fabricated using nickel oxide nanotubes as the active element with a mass loading of 24.1 mg cm-2. PMID- 27976632 TI - Evaluation of 99mTc-labeled PSMA-SPECT/CT imaging in prostate cancer patients who have undergone biochemical relapse. AB - Using conventional imaging modalities, it is difficult to detect recurrent lesions in prostate cancer patients who have undergone biochemical relapse, especially in patients with low prostate-specific antigen (PSA) levels. We retrospectively reviewed the files of fifty patients with histopathologically confirmed prostate cancer who underwent 99mTc-labeled prostate-specific membrane antigen (PSMA) single-photon emission computed tomography (SPECT)/computed tomography (CT), magnetic resonance imaging (MRI), and bone scan within a 30-day period. PSMA-SPECT/CT indicated metastatic lesions in 39 patients and had a higher detection rate (78.0%) than bone scan (34.0%) or MRI (40.0%). The diagnostic efficiency of PSMA-SPECT/CT imaging for bone and lymph node metastases (50.0% and 42.0%) was better than bone scan (34.0% and 0.0%) or MRI (24.0% and 20.0%). PSMA-SPECT/CT provided a higher detection rate at serum PSA levels of <=1 ng ml-1, 1-4 ng ml-1, 4-10 ng ml-1, and >10 ng ml-1. No correlation was found between Gleason score, PSA level, and the tracer tumor/background ratio of metastatic lesions. With the aid of PSMA-SPECT/CT imaging, the therapeutic strategy was changed for 31 patients, and this may have enhanced their clinical outcome. In conclusion, PSMA-SPECT/CT imaging could detect more metastatic lesions and achieve a higher detection rate than conventional imaging modalities at different serum PSA levels in prostate cancer patients who had undergone biochemical relapse. PMID- 27976631 TI - Sertraline-induced reproductive toxicity in male rats: evaluation of possible underlying mechanisms. AB - This study was conducted to clarify the toxic effects of sertraline (SRT) on the reproductive system of male rats and to elucidate the underlying mechanisms. Rats were treated orally with SRT at doses of 5, 10, and 20 mg kg-1 for 28 consecutive days. At the end of the treatment period, sperm concentration, sperm motility, and sperm morphology were investigated by computer-assisted sperm analysis system whereas sperm DNA damage was detected by comet assay. The oxidative status of the testes was investigated, and a histopathological examination was conducted. Serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured to determine the effects of SRT on the spermatogenesis process. One-way ANOVA, post-hoc Dunnett's T3 test for the sperm comet assay, and post-hoc Tukey's test for the others were performed for statistical analysis. The results showed that SRT caused an increase in sperm DNA damage and induced histopathological lesions in all groups treated with SRT. There was abnormal sperm morphology and increased malondialdehyde (MDA) in the 10 mg kg-1 treatment group. More dramatic changes were observed in the 20 mg kg-1 treatment group. Decreased sperm count was accompanied by a significant increase in abnormal sperm morphology, DNA damage, and degeneration in cellular-tubular structures. Serum LH and testosterone levels were elevated in the 20 mg kg-1 treatment group. Decreased glutathione (GSH) and increased MDA were signs of enhanced oxidative stress (OS). In conclusion, SRT induced testicular toxicity in a dose-dependent manner and OS is suggested as a crucial mechanism. PMID- 27976633 TI - Partial splenic embolization for gastroesophageal variceal bleeding: A potential long waiting to be tapped. PMID- 27976634 TI - Partial splenic embolization has beneficial effects for the management of gastroesophageal variceal hemorrhage. AB - BACKGROUND/AIMS: Partial splenic embolization (PSE) is used in the management of gastroesophageal variceal hemorrhage (GEVH). However, it is uncertain whether it has beneficial effects for GEVH patients in preventing variceal recurrence and variceal hemorrhage, as well as promoting overall survival (OS), when it is combined with conventional therapies. MATERIALS AND METHODS: The databases including PubMed, EMBASE, Web of Science, Google scholar, and Cochrane Central Register of Controlled Trials were searched up to 11th of November, 2015. Meta analyses were performed by using Review Manager 5.3 software for analyzing the risk of bias, Newcastle-Ottawa Scale for assessing the bias of cohort studies, and GRADEprofiler software for assessing outcomes obtained from the meta analyses. RESULTS: A total of 1505 articles were reviewed, and 1 randomized controlled trial and 5 cohort studies with 244 participants were eligible for inclusion. The pooled hazard ratio (HR) of variceal recurrence is 0.50 (95% confidence interval (CI) 0.37, 0.68; P< 0.00001; I2 = 0%). The pooled HR of variceal hemorrhage is 0.24 (95% CI 0.15, 0.39; P< 0.00001; I2 = 0%). The pooled HR of OS is 0.50 (95% CI 0.33, 0.67; P< 0.00001; I2 = 0%). Meta-analyses demonstrated statistically significant superiority of combinational therapies over conventional therapies in preventing variceal recurrence and variceal hemorrhage and prolonging OS. The complications related to PSE were mild or moderate and nonfatal. CONCLUSIONS: The results indicate that PSE has beneficial effects for GEVH patients, however, future investigation with a larger number of subjects in clinical trials is warranted. PMID- 27976636 TI - Intraperitoneal administration of apigenin in liver ischemia/reperfusion injury protective effects. AB - BACKGROUND/AIMS: Hepatic injury caused by ischemia/reperfusion (I/R) is a clinical problem associated with major liver surgery. Among other flavonoids, apigenin has shown a promising effect on I/R cases. In this study, we have investigated the effects of apigenin after liver I/R injury in rats. MATERIALS AND METHODS: Forty eight rats were randomized into the following eight groups: (1) Control-sham group: rats subjected to the surgical procedure, except for liver I/R; (2) DMSO group: rats subjected to surgery, except for liver I/R given the apigenin solvent dimethyl-sulfoxide intraperitoneally; (3) C60 group; (4) C120 group; (5) C240 group: rats underwent liver ischemia for 45 min followed by reperfusion for 60 min, 120 min, and 240 min; (6) AP60 group; (7) AP120 group; (8) AP240 group: rats underwent liver ischemia for 45 min, and then given apigenin (5 mg) intraperitoneally followed by reperfusion for 60 min, 120 min, and 240 min. Reverse transcription polymerase chain reaction was performed on liver tissues to measure BCL-2/BAX expression, enzyme-linked immunosorbent assay to measure M30/M65 and ICAM-1. Immunohistochemistry was used to identify M30 biomarker in liver tissues. STATISTICAL ANALYSIS: Quantitative variables were tested by Kolmogorov-Smirnov test, repeated measures analysis of variance/Friedman test. Gene levels were assessed by Student's t-test/Mann Whitney U-test. RESULTS: BCL-2 levels were significantly higher in I/R apigenin groups than in I/R control groups. BAX levels were lower in the AP240 group than in C240 group. Prolongation of reperfusion resulted in increased activation of M30. ICAM-1 levels were lower in the AP240 group than in C240 group. CONCLUSIONS: Apigenin seems to inhibit the process of apoptosis and ameliorate the hepatic I/R injury. PMID- 27976635 TI - Outcome of phlebotomy for treating nonalcoholic fatty liver disease: A systematic review and meta-analysis. AB - BACKGROUND/AIMS: No medications have been approved for managing nonalcoholic fatty liver disease (NAFLD). Lifestyle intervention is the mainstay for its treatment. Hyperferritinemia, which appears to be associated with the severity of liver injury and insulin resistance, is frequently observed in patients with NAFLD. PATIENTS AND METHODS: We conducted a systematic review and meta-analysis of the outcomes of four interventional trials regarding the effect of phlebotomy in patients with NAFLD versus the outcomes of NAFLD patients who did not undergo phlebotomy. Primary outcome was the pooled mean difference (MD) of the homeostasis model assessment of insulin resistance (HOMA-IR). The secondary outcomes were the changes in liver enzymes and the lipid profile. RESULTS: Four interventional studies involving 438 participants were included in the meta analysis. HOMA-IR was lower in patients who underwent phlebotomy, with an MD of 0.84 [95% confidence interval (CI) 0.01 to 1.67, I2 = 72%]. Phlebotomy also significantly reduced the alanine aminotransferase (MD = 10.05, 95% CI 7.19 12.92, I2 = 34%) and triglyceride (MD = 9.89, 95% CI 4.96-14.83, I2 = 22%) levels and increased the high-density cholesterol level (MD = 3.48, 95% CI 2.03-4.92, I2 = 18%). CONCLUSION: Phlebotomy decreased insulin resistance and liver transaminase levels in patients with NAFLD. In addition, it improved their lipid profile. PMID- 27976637 TI - Thromboembolic events in patients with inflammatory bowel disease. AB - BACKGROUND/AIMS: Inflammatory bowel disease (ulcerative colitis and Crohn's disease) is characterized by a chronic inflammatory condition, and is accompanied by abnormalities in coagulation and a hyper-coagulable state. This study was conducted to examine the risk factors for developing Thromboembolic Events in Inflammatory Bowel Disease (IBD) in a population with prevalent consanguinity. PATIENTS AND METHODS: Patients with a definitive diagnosis of IBD who were seen in the gastroenterology clinic of King Khalid University Hospital (Riyadh, Saudi Arabia) from 2010- to 2012, were asked to participate in this prospective cohort study, and were followed for one 1 year. Data was collected using specifically designed case report forms (CRF) by trained research personnel. RESULTS: A total of 100 Saudi patients with IBD were studied. There were 51 (51%) women and the mean +/- standard deviation (SD) age of the group was 31.24 +/- 10.78 years. Those with Crohn's disease constituted 72% of the patients, and 28% had ulcerative colitis. Eight patients (8%) had at least one Thrombotic Event ([six deep venous thrombosis (DVT), and two pulmonary embolism (PE)]. Family history of deep venous thrombosis was present in 5%, and family history of pulmonary embolism (PE) in 4% of the patients. After adjusting for age and gender, a family history of Thrombotic event was identified as to be the only statistically significant predictor of thrombosis in IBD patients (RR = 9.22, 95% CI: 2.10- 40.43). CONCLUSION: In a population with high consanguinity, Thromboembolic events (DVT and PE) had a prevalence of 8% among IBD patients, positive family history of pulmonary embolism was a predictor of thrombosis. Further studies are needed to explore the role of genetic factors in this population. PMID- 27976638 TI - Effect of angiotensin-converting enzyme inhibitor, lisinopril on morphological and biochemical aspects of fibrotic liver regeneration. AB - BACKGROUND/AIMS: Hepatic fibrosis results in defective liver regeneration following partial hepatectomy. Angiotensin converting enzyme (ACE) inhibitors can enhance liver regeneration and are also involved in the reduction of hepatic fibrosis. The present study has been conducted to evaluate the potential effect of an ACE inhibitor, lisinopril, on the morphological and biochemical aspects of fibrotic liver regeneration. MATERIALS AND METHODS: Eight-week old female Sprague Dawley rats were made fibrotic by intragastric carbon tetrachloride treatment. Rats were given saline or lisinopril (1 mg/kg) orally for 1 week and were subjected to sham surgery or two-third partial hepatectomy. Liver regenerative and functional capacities were determined 48 hours post surgery. RESULTS: Lisinopril administration did not affect the regeneration rate, proliferation cell nuclear antigen count, and hepatocellular area of fibrotic livers following partial hepatectomy. No statistically significant difference between treated and control rats regarding mitotic count, hepatocyte nuclear area, and binuclear hepatocyte frequency was observed. Serum biochemical analysis showed that lisinopril non-significantly decreased the partial hepatectomy induced elevated levels of alanine aminotransferase, aspartate transaminase, and alkaline phosphatase whereas lactate dehydrogenase and total bilirubin levels were significantly reduced. No marked reduction in hepatic collagen content and alpha smooth actin positive cells was observed by lisinopril treatment. CONCLUSION: ACE inhibitor lisinopril did not produce major histomorphological alterations in regenerating fibrotic liver following partial hepatectomy, however, it may improve its functional capability. PMID- 27976639 TI - p16 protein is upregulated in a stepwise fashion in colorectal adenoma and colorectal carcinoma. AB - BACKGROUND/AIMS: p16 is tumor suppressor gene acting as a cell cycle regulator. The present study was conducted to compare p16 expression in normal, dysplastic, and malignant colonic mucosae, and to explore its relation to clinicopathological variables and follow-up data in colorectal carcinoma (CRC). PATIENTS AND METHODS: Tissue microarrays were performed from 25 normal colonic mucosae, 41 colonic adenomas, and 191 CRC, with corresponding 50 nodal metastases. Immunohistochemistry was performed using anti-p16 antibody, sections were scored, and statistical analysis was performed. K-ras mutation detection was also performed. RESULTS: Immunoexpression of p16 was significantly higher in CRC than in adenomas (P = 0.033) and normal colonic mucosa (P = 0.005). There was no statistically significant difference between p16 expression in CRC and nodal metastasis. There was no significant association between p16 immunoexpression in CRC and all clinicopathological data and survival probability. K-ras mutations were detected in 34% of CRC. However, there was no correlation between K-ras status and p16 expression (P = 0.325). CONCLUSION: Absence of p16 expression is correlated to a benign course of CRC adenomas. p16 has a key role in CRC progression and can be used as a marker for colorectal adenoma. On the other hand, it has no role as a predictive and/or prognostic factor in CRC. Further extended studies are required to explore the role of p16 as indicator of premalignant lesions in the colon and to test its relation with CRC histological grade, as well as to test its value as a new therapeutic target. PMID- 27976640 TI - Cardiac functions assessment in children with celiac disease and its correlation with the degree of mucosal injury: Doppler tissue imaging study. AB - BACKGROUND/AIMS: Celiac disease (CD)-associated cardiologic disorders is a growing concern. However, data regarding cardiac affection in children with CD are few. This study aimed at assessing the subclinical impact of CD on the global myocardial performance in Saudi children with CD using Doppler tissue imaging (DTI). PATIENTS AND METHODS: Conventional two-dimensional echocardiography was performed among 20 Saudi children with CDas well as 20 age and sex-matched healthy controls. DTI were used to determine right ventricular (RV) and left ventricular (LV) Tei indexes. These findings were correlated with the Modified Marsh Classification of the histologic findings in CD. RESULTS: LV and RV Tei indexes were significantly higher in children with CD than the control group (mean +/- standard deviation: 0.47 +/- 0.05 vs. 0.31 +/- 0.18; P< 0.0005 and 0.51 +/- 0.04 vs. 0.32 +/- 0.05; P< 0.0001, respectively). RV Tei index was found to be positively correlated with the Modified Marsh Classification of CD (r = 0.7753, P< 0.0001). LV Tei index tended to be more affected in patients with more severe histologic findings, however, such relation did not reach statistical significance (r = 0.2479, P = 0.292). Fractional shortening did not correlate with the Modified Marsh Classification of histologic findings in CD patients (r= 0.11, P = 0.641). CONCLUSIONS: Subclinical myocardial dysfunction of both ventricles occurs in children with CD. The DTI method appears to be more sensitive than conventional two-dimensional echocardiography in the early detection of myocardial dysfunction in children with CD. PMID- 27976641 TI - Deoxyschizandrin suppresses dss-induced ulcerative colitis in mice. AB - BACKGROUND/AIMS: Deoxyschizandrin as one of the most important component of Schisandra chinensis (Turcz.) Baill plays an immunomodulatory role in a variety of diseases, yet its role in ulcerative colitis remains to be elucidated. We aimed to investigate the role of deoxyschizandrin in DSS-induced ulcerative colitis in mice. PATIENTS AND METHODS: In the present study, an inflammation model of cells was constructed to confirm the anti-inflammatory effect of deoxyschizandrin. Then a mouse model with Dextran sulfate sodium sulfate (DSS) induced ulcerative colitis was constructed, and the effects of deoxyschizandrin on mouse colon inflammation, apoptosis, and CD4 T lymphocyte infiltration in ulcerative colitis were examined. RESULT: Deoxyschizandrin could improve the symptoms of ulcerative colitis, determined by hematoxylin-eosin (HE) staining and histopathological scores. Moreover, deoxyschizandrin reduced the levels of inflammatory cytokines, suppressed CD4 T cell infiltration, and effectively inhibited apoptosis in the colon of DSS-induced ulcerative colitis mice. CONCLUSION: In summary, deoxyschizandrin can effectively rescue the symptoms of DSS-induced ulcerative colitis in mice by inhibiting inflammation. T cell infiltration and apoptosis in the colon, suggesting that deoxyschizandrin could be a potential drug in treating ulcerative colitis. PMID- 27976642 TI - Solitary rectal ulcer syndrome: A single-center case series. AB - BACKGROUND/AIM: Solitary rectal ulcer syndrome (SRUS) is a benign, chronic defecation disorder with varied presentations. The aim of this study is to summarize the clinical features, endoscopic findings, histological appearance, and treatment strategies associated with SRUS. PATIENTS AND METHODS: This is a retrospective study of all patients diagnosed with SRUS at the King Faisal Specialist Hospital and Research Centre in Riyadh from January 2003 to December 2013. Cases were identified using the Department of Pathology database. Data were obtained from medical records that included clinical manifestation, endoscopic findings, and histopathological features. RESULTS: Twenty patients were identified. The mean age was 42.5 years (+/-18.5) and 55% were females. Most of the patients presented with bleeding per rectum (85%), constipation (75%), and straining (50%), with a mean symptom duration of 26.7 months. The most common associated factors identified were constipation (75%), history of rectal surgery (25%), digital rectal manipulation (20%), and rectal prolapse (20%). Endoscopic findings included a single ulcer (50%) and multiple ulcers (30%); 55% had a polypoidal appearance. On histopathology, there was surface ulceration (95%), fibrosis of the lamina propria (60%), distorted architecture (55%), and muscle hypertrophy with increased mucin production (50%). Patients were treated conservatively and none required surgery. CONCLUSION: SRUS is a rare disorder with variable clinical presentations. Stool softeners, a high fiber diet in addition to topical mesalamine, and biofeedback proved to be effective in this patient population. PMID- 27976644 TI - Sustainable development goals: Challenges and opportunities. PMID- 27976643 TI - Gluten-Free hepatomiracle in "celiac hepatitis": A case highlighting the rare occurrence of nutrition-induced near total reversal of advanced steatohepatitis and cirrhosis. AB - Regression of hepatic fibrosis is increasingly becoming a reality, both in clinical as well as experimental models. Reversal or near-total regression of marked liver steatohepatitis and fibrosis, however, remains a rare event. We report the case of a 20-year-old female presenting with diarrhea due to celiac disease and biopsy proven cirrhosis with portal hypertension who had a remarkable clinical improvement in response to a gluten free diet (GFD). A follow-up liver biopsy 9 months after the initiation of GFD revealed a remarkable regression of both fibrosis as well as steatosis. Villous atrophy, as seen in patients with celiac disease, could lead to a deprivation of trophic factors leading to liver injury and subsequent cirrhosis. A gluten-free dietary regimen can produce a reversal of fibrosis leading to the amelioration of symptoms associated even with advanced liver disease. PMID- 27976645 TI - Changes in sexual behavior and contraceptive use after HIV acquisition and factors associated with risky sexual practices among people living with HIV in selected Indian cities. AB - BACKGROUND: Sexual behavior and contraceptive use among HIV-infected persons are a neglected issue in public health programs. OBJECTIVES: To understand sexual practices and contraceptive use of people living with HIV (PLHIV) before and after being diagnosed with the infection and assess the providers' perspectives on provision of contraceptives to PLHIV, the quality of services provided and linkages between reproductive health and HIV services. METHODS: A mix method design study using a purposive sampling was undertaken enrolling PLHIV from ART centers and PLHIV networks across three cities in India. Doctors and counselors providing HIV services at public hospitals were also interviewed. RESULTS: Use of condoms increased from 35% to 81% after being diagnosed with HIV. Consistent condom use was 69% compared to only 8.7% before being diagnosed with HIV. Nearly 41% (297) of participants indulged in one or more forms of risky sexual behaviors. Significant correlates of risky sexual practices were: participants who were middle-aged (25-33 years), formerly married, currently not on antiretroviral therapy, and received negligible information on contraception from service providers leading to poor knowledge on safe sex and dual protection. Information from service providers reveals a lack of specific program guidelines to comprehensively address family planning (FP) issues through HIV programs. CONCLUSION: The study throws light on missed opportunities to address contraceptive needs of PLHIV and recommends training service providers and operationalizing a strategy to link HIV and FP services. PMID- 27976646 TI - Risk factors of suicide among patients admitted with suicide attempt in Tata main hospital, Jamshedpur. AB - BACKGROUND: More than one lakh lives are lost every year due to suicide in India. In the last three decades (from 1975 to 2005), the suicide rate has increased by 43%. Jamshedpur is an Industrial town, which is rapidly growing and having population with mixed cultural background. Recently, there has been increasing trend in a number of suicide attempt across various age groups; there are around 300 cases of suicide attempt admitted to Tata Main Hospital each year. OBJECTIVE: To study the risk factors associated with suicide attempts. METHODS: The study was carried out in the Tata Main Hospital, Jamshedpur. Over a period of 6 months, we gathered data of 101 suicide attempters referred from medical, surgical departments and casualties and taken up for the study. Data were collected on specific pro forma was prepared to collect various others risk factors. RESULTS: More number of female patients compared to male, younger age, lower-middle income group, urban background, school educated, and unemployed were more represented in this study. In 70% of patients, psychiatric disorder was found, but few among them had prior treatment. Increased family conflicts, marital problems, financial difficulties, and perceived humiliations are some of the risk factors. CONCLUSION: The early identification and treatment of vulnerable populations with risk factors for suicide across the lifespan will help in planning and implementing strategies for prevention. PMID- 27976647 TI - Case profile, volume analysis, and dropout rate of antirabies vaccination regimens among animal bite victims in Gujarat. AB - BACKGROUND: Rabies is a preventable neglected public health problem and associated with multiple cultural, religious, and social practices, myths in our country. There is a lack of organized surveillance system to measure the incidence of animal bite and human rabies as well as to evaluate cost-saving of different routes, regimen, and types of antirabies vaccines (ARV)/immunoglobulin available in India. OBJECTIVES: The objective of this study is to know dropout rate in intradermal (i.d.) ARV regimen among animal bite and to analyze the utilized volume of ARV by a different route of vaccine administration. METHODS: A total of 250 animal bite victims were followed up at ARV Clinic (ARVC). Volume utilization of i.d. route over intramuscular (i.m.) route was analyzed among the patients who attended ARVC during the past 2 years. Total dropout and delayed compliance rates of ARV regimen among different group were compared by Chi-square test. RESULTS: The i.d. route was about five times more volume and cost-saving than i.m. route. The majority of victims belonged to 15-30 years (27.60%) and children <15 years (26.40%) and had wound at their lower limbs (85%) mainly bitten by dogs (98%). Thirty-four percent total dropout and 31.5% delayed compliance observed particularly during the last dose of i.d. regimen. There was no significant difference in dropout rates among different demographic groups. Half of the victims practiced wound toilet on the same day of bite. Only 68% received the first dose of ARV within 24 h of the exposure. CONCLUSION: Children and young adults are at higher risk of having dog bite. I.d. ARV regimen is more volume and cost-saving than i.m. one and proper counseling and follow-up should be arranged to complete the vaccination schedule. PMID- 27976648 TI - Descriptive evaluation of cigarettes and other tobacco products act in a North Indian city. AB - BACKGROUND: India is a signatory to Framework Convention on Tobacco Control and also enacted cigarettes and other tobacco products Act (COTPA) in 2003. OBJECTIVES: To undertake a comprehensive assessment (Section 4, 5, 6, 7, 8, and 9 under COTPA) of legislation against tobacco products in a North Indian city. METHODS: An observational, cross-sectional study was conducted at 108 public places which included educational institutions, offices, health institutes, transit sites, and hotels/restaurants. Structured checklists with compliance indicators for various sections under COTPA were used. Different brands of tobacco products were observed for pictorial warnings. RESULTS: No active smoking was observed at 80.5% public places, while 54.6% places had displayed "No smoking" signage. About 68.5% public places were found free of evidence of smell/ashes of recent smoking, and 86.1% places had no smoking aids. Merely, one third public places (36.1%) were complying with all Section 4 indicators. Around 42.3% point of sale had advertisements of tobacco products, and 73.1% had a display of tobacco products visible to minors. Around 60% educational institutions displayed signages as per Section 6b of COTPA, and 32.5% had tobacco shops being run within 100 yards of institution's radius. There was minimal smoking activity within the campus. Health warnings were present in 80.8% of tobacco products, more with Indian brands as compared to foreign brands. CONCLUSION: The city of Chandigarh, which was declared the first smoke-free city of India, showed poor compliance with COTPA. PMID- 27976649 TI - Potential of probiotics in hypercholesterolemia: A meta-analysis. AB - Human studies on the effects of probiotics on lowering blood cholesterol levels have not yielded conclusive results. A meta-analysis of randomized controlled trials evaluating the effect of probiotics on lipid profile was conducted. Articles were reviewed systematically from web search bases; PubMed, Cochrane Clinical Trial Registry. Those studies which were meeting the inclusion criteria providing matching placebo, at least single blind for probiotics and placebo, providing mean and standard deviations and not involving the use of probiotics were selected. 14 studies from 12 randomized controlled trials were analyzed providing information of 606 normo/hypercholesterolemic patients using Review Manager 5.3 (The Cochrane Collaboration, Oxford, UK). The pooled mean net change for total cholesterol (TC) is -8.40 mg/dl (-13.63, -3.61), for low-density lipoprotein (LDL) is -6.63 mg/dl (-10.63, -2.63), for high-density-lipoprotein cholesterol is 0.59 mg/dl (-0.92, 2.09), and for triglycerides is -1.32 mg/dl ( 6.49, 3.85). The findings of the analysis conclude that probiotics supplementation does lower serum TC and LDL-cholesterol levels significantly and hence a reduction in the risk factor of developing coronary heart disease. PMID- 27976650 TI - Premarital health counseling: A must. AB - Premarital Health Counseling (PMHC) is emerging as a growing trend worldwide. The couples are provided with accurate and unbiased information and assistance, who are planning to get marry with the aim of screening, educating, and counseling about nutritional disorders, communicable diseases, medical conditions, hereditary/genetic disorders, and guiding for a healthy pregnancy. Premarital screening and adequate counseling are essential for changing attitudes toward consanguineous marriage particularly in places where consanguineous and "tribal" marriages are common, resulting in a high incidence of genetic disorders. Although making PMHC obligatory in India may appear to be a very exciting and promising proposal, its implementation still has various ethical issues and other barriers that need to be addressed. PMID- 27976651 TI - Plight of street children: An explorative study from Varanasi, India. AB - Rapid pace of unplanned urbanization in the developing countries has resulted in a large proportion of children becoming homeless, leading to multiple children living on the streets. These children are highly vulnerable to exploitation and abuse. Against this background, studies on the situational analysis of street children across India are needed; therefore, a study to assess the condition of street children in the city of Varanasi was planned. Street children registered with a nongovernmental organization were contacted. Four hundred and fifteen children were selected by random sampling, and this group was administered a semi structured interview containing 35 items. It was found that all forms of abuse were common, but physical abuse (74%) was highest and the police (25.5%) was an important perpetrator. Younger children were much more vulnerable. The sample commonly had boys and between the ages of 10 and 15 years. It was concluded that these children need policies to be incorporated into the mainstream. PMID- 27976652 TI - Decline and disparity in maternal mortality in pre- and post-national health mission period in India. AB - Country- and state-wise maternal mortality shows the highest disparity among health statistics. The erstwhile National Rural Health Mission. (NRHM) in India aimed reduction in maternal mortality ratio. (MMR) to <100 per lakh live births. Accordingly, many new initiatives were planned and started. This analysis was carried out using data from the Sample Registration System. The data from 1997 to 1998 are available which dates 8 years prior to the launching of NRHM. Hence, comparison period was considered as 8 years of implementation of NRHM. The overall decline in MMR prior to NRHM was 36% and after NRHM implementation 30%. The difference is not significant. The best states and lowest states had changed, but the disparity also has remained almost at the ratio of 1:5. The pace of decline has not increased after NRHM. As well disparity ratio has not reduced indicating the differentially better treatment to the vulnerable states was not adequate. PMID- 27976653 TI - Hypertension treatment and control in a rural cohort in Thiruvallur, Tamil Nadu, India. AB - Hypertension is a public health problem with low detection and treatment rates in India. We resurveyed 1284 patients with hypertension already identified in baseline survey of the cohort in Thiruvallur district, Tamil Nadu, India. The objective was to estimate the proportion of patients with drug treatment, hypertension control and lifestyle modification at follow-up (median follow-up 27 months). Overall, only 19.9% of the patients took drugs and 45.3% had blood pressure under control. Among 256 patients on drugs, 179 (69.9%) were on a single drug, 71 (27.7%) on two drugs, and six (2.3%) on three drugs. Commonly prescribed drugs based on the prescription review were beta blockers (50.4%), calcium channel blockers (36.7%), angiotensin-converting-enzyme inhibitor (18.4%), and diuretics (11.7%). Salt reduction was reported by 49.7% of the patients. There is a need for strengthening the health systems for effective management of hypertension and patient education to ensure active involvement in the long-term care. PMID- 27976654 TI - Rolling out of kangaroo mother care in secondary level facilities in Bihar-Some experiences. AB - BACKGROUND: Preterm birth is one of the leading causes of under-five child deaths worldwide and in India. Kangaroo mother care (KMC) is a powerful and easy-to-use method to promote health and well-being and reduce morbidity and mortality in preterm/low birth weight (LBW) babies. OBJECTIVE: As the part of the roll-out of India Newborn Action Plan interventions, we implemented KMC in select facilities with an objective to assess the responsiveness of public health system to roll out KMC. METHODS: KMC intervention was implemented in two select high priority districts, Gaya and Purnea in Bihar over the duration of 8 months from August 2015 to March 2016. The implementation of intervention was phased out into; situation analysis, implementation of intervention, and interim assessment. KMC model, as envisaged keeping in mind the building blocks of health system, was established in 6 identified health-care facilities. A pretested simple checklist was used to assess the awareness, knowledge, skills, and practice of KMC during baseline situational analysis and interim assessment phases for comparison. RESULTS: The intervention clearly seemed to improve the awareness among auxiliary nurse midwives/nurses about KMC. Improvements were also observed in the availability of infrastructure required for KMC and support logistics like facility for manual expression of breast milk, cups/suitable devices such as paladi cups for feeding small babies and digital weighing scale. Although the recording of information regarding LBW babies and KMC practice improved, still there is scope for much improvement. CONCLUSION: There is a commitment at the national level to promote KMC in every facility. The present experience shows the possibility of rolling out KMC in secondary level facilities with support from government functionaries. PMID- 27976655 TI - An assessment of bicycle intervention to improve service delivery by accredited social health activists in selected blocks of West Champaran district of Bihar. AB - BACKGROUND: Several programmatic and logistic issues affect the overall performance of Accredited Social Health Activists (ASHAs). Bihar Government provided bicycles to ASHAs in West Champaran district for increasing coverage of services by improving their mobility. OBJECTIVE: To assess the use of bicycles by ASHAs and it's effect on service delivery. It also captures the perspectives of ASHAs in terms of its utilization for performing tasks. METHODS: A community based quasi-experimental study was undertaken during March-May 2016. Proportion of newborn babies visited within 24 h of birth was the primary outcome. Data were collected from two intervention blocks (West Champaran district) and a control block from the neighboring East Champaran district. A total of 323 (177 from intervention blocks and 146 from control block) mothers having children <3 years of age and who had delivered at home were interviewed. Besides, 88 ASHAs working in intervention blocks were also interviewed. RESULTS: Significantly higher proportion of mothers and newborn babies (44%) received postnatal care within 24 h of delivery in intervention blocks as compared to the control block (16%, P < 0.001). Nearly 73.1% of ASHAs were using the bicycle themselves. ASHAs were twice more likely to visit a newborn on the day of delivery if she was provided with mobility support. However, the likelihood of continuing visits after the 1st day was not statistically significant. CONCLUSION: The intervention demonstrated the potential of ASHAs to improve their functioning at the grass-root level. The scale-up of bicycle intervention should be supplemented with reforms in financial incentives disbursement and better system support. PMID- 27976656 TI - Using nonpneumatic anti-shock garment for postpartum hemorrhage management and referral at the public health facilities: A pilot study in two districts of Bihar. AB - BACKGROUND: Nonpneumatic anti-shock garment (NASG) is a first-aid device that can save lives of women experiencing postpartum hemorrhage (PPH). OBJECTIVE: The aim was to explore the feasibility of implementation of NASG intervention at select public health primary care facilities in two high priority districts of Bihar. METHODS: Qualitative design was used to document the NASG implementation process. In-depth interviews were conducted with health-care providers in November December 2015. These healthcare providers were chosen purposively based on their involvement in the use of NASG. The implementation process of NASG, process of training for its use, challenges faced during the rollout of implementation and the recommendations for improving the implementation were explored. RESULTS: Initially, a baseline study was conducted to assess the knowledge and skills of health-care providers regarding diagnosis and management of PPH. Implementation consisted of orientation and training of service providers on the identification of PPH cases and usage of the NASG garment during referrals. The interviews with stakeholders reflected that even after training and appropriate introduction of the practice of using the NASG bag, the initiative did not make a difference in ameliorating the situation of PPH management in the health facilities over 6 months. CONCLUSION: This study provides lessons for implementation and scaling up of NASG in public health systems, not only in Bihar but also other similar settings. It also calls for robust implementation research studies to generate evidence on the use of NASG at the primary health-care facilities as an intervention in program settings. PMID- 27976657 TI - Rollout of quality assurance interventions in labor room in two districts of Bihar, India. AB - BACKGROUND: Quality of care at the facilities during childbirth remains a major concern. Improved quality could have the greatest dividend in saving maternal and newborn lives. OBJECTIVE: The objective of this study was to implement quality assurance measures in the labor rooms of select public health facilities in two districts of Bihar. METHODS: The labor room quality assurance intervention was implemented in two districts, Gaya and Purnea in Bihar. Health facilities having >200 deliveries/month were assessed using labor room quality assurance checklist developed by the Ministry of Health and Family Welfare. The critical gaps affecting service delivery were identified, and a list of priority actions for quality improvement was developed. An intervention model was rolled out in consultation with the district authorities focusing on the building blocks of the health system. The interventions were implemented from August 2014 to March 2016 in selected facilities after which an assessment was conducted. RESULTS: Initial assessment of labor room was conducted in 24 facilities. After 2 years of intervention, there was a definite improvement in quality assurance scores in most facilities. The infection control scores increased by 20 points in Gaya (from 40 to 59.9) and 10 points in Purnea (from 57.6 to 67.1). The highest gain in scores was observed in quality management component in Gaya (from 6.2 to 58.2). The model attempted to incorporate all the elements of the health system to ensure scalability and sustainability. CONCLUSION: It is possible to have an implementable quality assurance mechanism within public health system with sustained efforts and commitment. PMID- 27976658 TI - Computer tablet-based health technology for strengthening maternal and child tracking in Bihar. AB - BACKGROUND: UNICEF along with the State Government of Bihar launched a computer tablet-based Mother and Child Tracking System (MCTS) in 2014, to capture real time data online and to minimize the challenges faced with the conventional MCTS. OBJECTIVE: The article reports the process of implementation of tablet-based MCTS in Bihar. METHODS: In-depth interviews with medical officers, program managers, data managers, auxiliary nurse midwives (ANMs), and a monitoring and evaluation specialist were conducted in October 2015 to understand the process of implementation, challenges and possibility for sustainability, and scale-up of the innovation. RESULTS: MCTS innovation was introduced initially in one Primary Health Centre each in Gaya and Purnia districts. The device, supported with Android MCTS software and connected to a dummy server, was given to ANMs. ANMs were trained in its application. The innovation allows real-time data entry, instant uploading, and generation of day-to-day work plans for easy tracking of beneficiaries for providing in-time health-care services. The nonlinking of the dummy server to the national MCTS portal has not lessened the burden of data entry operators, who continue to enter data into the national portal as before. CONCLUSION: The innovation has been successfully implemented to meet its objective of tracking the beneficiaries. The national database should be linked to the dummy server or visible impact. The model is sustainable if the challenges can be met. Mobile technology offers a tremendous opportunity to strengthen the capacity of frontline workers and clinicians and increase the quality, completeness, and timeliness of delivery of critical health services. PMID- 27976659 TI - Mobile-based effective vaccine management tool: An m-health initiative implemented by UNICEF in Bihar. AB - BACKGROUND: UNICEF launched the mobile-based Effective Vaccine Management (EVM) system in Bihar in 2014 along with the state government to electronically capture information and identify gaps in the existing vaccine management system for appropriate action. OBJECTIVE: This study accessed the implementation process of this initiative. METHODS: Quantitative data related to vaccine supply chain management indicators were collected in November-December 2015 using factsheets and dashboards, representing the situation of the vaccine supply and cold chain management system at regular intervals since the launch. In-depth interviews were conducted with the program specialists to understand the initiative's genesis, its challenges and strengths. RESULTS: This initiative resulted in an increased cold chain space from 49% (July 2014) to 87% (September 2015), deployment of sufficient human resource; 38 cold chain technicians for regular maintenance of the machines and equipment, installation of necessary equipment, and upgradation of state and regional vaccine stores. In health facilities, district vaccine stores, and regional vaccine stores, marked improvements were observed in the overall EVM criteria indicators (82%, 84%, and 80% in September 2015, respectively, as against 51%, 46%, and 43% in July 2014, respectively) as well as EVM category indicators (83%, 84%, and 76% in September 2015, respectively, as compared to 54%, 53%, and 54% in July 2014, respectively). CONCLUSION: The EVM mobile initiative was successfully implemented and it complies with its objective of providing experienced guidance to the human resource responsible for vaccine cold chain management. The initiative is scalable and its sustainability depends on its thoughtful merger with the existing immunization ecosystem. PMID- 27976660 TI - Assessment of newborn care corners in selected public health facilities in Bihar. AB - BACKGROUND: A functional newborn care corner (NBCC) is critical to provide immediate care to newborns including resuscitation, warmth, and initial care to sick newborns. NBCC provides an acceptable environment for all infants at birth, and it is mandatory for all delivery points at all levels in the health system including operation theaters. OBJECTIVE: The objective of this study was to find the status of availability of NBCCs and service provision in selected public health facilities of Bihar. METHODS: A total of 57 NBCCs, having high delivery load (>100 deliveries/month), across 25 high-priority districts in Bihar, were selected purposively in consultation with the State Health Society, Bihar, for the assessment. These facilities were assessed for the availability and/or functioning of infrastructure, equipment maintenance, human resource, supply of drugs and consumables, adherence to protocols, and record keeping. RESULTS: Only 22.8% of the NBCCs were found to be fully functional, majority (68.4%) were partially functional, and 9% were nonfunctional. Thirty-seven (64.9%) NBCCs were located inside the labor room premises. Approximately, one-third of the neonates delivered were kept in NBCCs. Equipment though available lacked the provision of annual maintenance contract. Essential drugs such as adrenaline (24.6%) and Vitamin K injection (42.1%) were not available in many facilities. Only 6.2% of the newborns had low birth weight, indicating underreporting. Majority of the health-care staff available were trained but possessed poor skills. Data recording and reporting was also suboptimal. CONCLUSION: The network of NBCCs needs to be strengthened across the state and linked with higher facilities to achieve the desired reduction in neonatal morbidity and mortality. PMID- 27976661 TI - An approach to interpreting restrictive spirometric pattern results in occupational settings. AB - OBJECTIVES: The aim of this review is to provide an updated overview of definition, epidemiology, diagnostic algorithm and occupational exposures related to abnormal restrictive spirometrical pattern (RSP) in order to improve the correct interpretation of spirometry test results by occupational healthcare providers. METHODS: A review of the scientific English literature of the last 25 years was carried out with MEDLINE and related keywords [(restricti* AND spirometr*) AND occupational]. The first step analysis covered 40 studies and the second step the reference list. Results are presented in four major aims and subquestions. RESULTS: A spirometrical pattern of reduced VC (Vital Capacity), together with a normal FEV1 (Forced Expiratory Volume in 1 Second)/VC ratio, is suggestive, though not diagnostic of restrictive ventilatory defect (RVD). The prevalence of RSP is high in some studies, comparable to obstructive pattern, and could be associated to chronic medical conditions (diabetes, congestive heart failure, obesity, hypertension) as well as to increased risk of mortality and lung cancer. In order to predict true restrictive defect [TLC-(Total Lung Capacity) 50 Hz). Such steady-state LFPs could reflect underlying synaptic activity that does not necessarily lead to cortical spiking in response to natural fast time-varying vocal sequences. PMID- 27976692 TI - Anticancer activity of a monobenzyltin complex C1 against MDA-MB-231 cells through induction of Apoptosis and inhibition of breast cancer stem cells. AB - In the present study, we examined the cytotoxic effects of Schiff base complex, [N-(3,5-dichloro-2-oxidobenzylidene)-4-chlorobenzyhydrazidato](o methylbenzyl)aquatin(IV) chloride, and C1 on MDA-MB-231 cells and derived breast cancer stem cells from MDA-MB-231 cells. The acute toxicity experiment with compound C1 revealed no cytotoxic effects on rats. Fluorescent microscopic studies using Acridine Orange/Propidium Iodide (AO/PI) staining and flow cytometric analysis using an Annexin V probe confirmed the occurrence of apoptosis in C1-treated MDA-MB-231 cells. Compound C1 triggered intracellular reactive oxygen species (ROS) production and lactate dehydrogenase (LDH) releases in treated MDA-MB-231 cells. The Cellomics High Content Screening (HCS) analysis showed the induction of intrinsic pathways in treated MDA-MB-231 cells, and a luminescence assay revealed significant increases in caspase 9 and 3/7 activity. Furthermore, flow cytometric analysis showed that compound C1 induced G0/G1 arrest in treated MDA-MB-231 cells. Real time PCR and western blot analysis revealed the upregulation of the Bax protein and the downregulation of the Bcl-2 and HSP70 proteins. Additionally, this study revealed the suppressive effect of compound C1 against breast CSCs and its ability to inhibit the Wnt/beta-catenin signaling pathways. Our results demonstrate the chemotherapeutic properties of compound C1 against breast cancer cells and derived breast cancer stem cells, suggesting that the anticancer capabilities of this compound should be clinically assessed. PMID- 27976693 TI - Patient-specific structural effects on hemodynamics in the ischemic lower limb artery. AB - Lower limb peripheral artery disease is a prevalent chronic non-communicable disease without obvious symptoms. However, the effect of ischemic lower limb peripheral arteries on hemodynamics remains unclear. In this study, we investigated the variation of the hemodynamics caused by patient-specific structural artery characteristics. Computational fluid dynamic simulations were performed on seven lower limb (including superficial femoral, deep femoral and popliteal) artery models that were reconstructed from magnetic resonance imaging. We found that increased wall shear stress (WSS) was mainly caused by the increasing severity of stenosis, bending, and branching. Our results showed that the increase in the WSS value at a stenosis at the bifurcation was 2.7 Pa. In contrast, the isolated stenosis and branch caused a WSS increase of 0.7 Pa and 0.5 Pa, respectively. The WSS in the narrow popliteal artery was more sensitive to a reduction in radius. Our results also demonstrate that the distribution of the velocity and pressure gradient are highly structurally related. At last, Ultrasound Doppler velocimeter measured result was presented as a validation. In conclusion, the distribution of hemodynamics may serve as a supplement for clinical decision-making to prevent the occurrence of a morbid or mortal ischemic event. PMID- 27976694 TI - Chemical formation of hybrid di-nitrogen calls fungal codenitrification into question. AB - Removal of excess nitrogen (N) can best be achieved through denitrification processes that transform N in water and terrestrial ecosystems to di-nitrogen (N2) gas. The greenhouse gas nitrous oxide (N2O) is considered an intermediate or end-product in denitrification pathways. Both abiotic and biotic denitrification processes use a single N source to form N2O. However, N2 can be formed from two distinct N sources (known as hybrid N2) through biologically mediated processes of anammox and codenitrification. We questioned if hybrid N2 produced during fungal incubation at neutral pH could be attributed to abiotic nitrosation and if N2O was consumed during N2 formation. Experiments with gas chromatography indicated N2 was formed in the presence of live and dead fungi and in the absence of fungi, while N2O steadily increased. We used isotope pairing techniques and confirmed abiotic production of hybrid N2 under both anoxic and 20% O2 atmosphere conditions. Our findings question the assumptions that (1) N2O is an intermediate required for N2 formation, (2) production of N2 and N2O requires anaerobiosis, and (3) hybrid N2 is evidence of codenitrification and/or anammox. The N cycle framework should include abiotic production of N2. PMID- 27976695 TI - Relationship between handedness and joint involvement in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is characterized by autoimmune chronic joint inflammation, which is worsened by mechanical stress. It is still inconclusive whether joints on the right side or the dominant side get more damaged in RA since the limited number of patients analyzed in the previous study had made it difficult to separately analyze right-handed and left-handed patients. Here, we enrolled 334 RA patients, the biggest number of patients in studies to address this issue and separately analyzed right-handed and left-handed patients. As a result, we observed that joints on the dominant side got clinically and radiologically more involved in the right-handed patients (p <= 0.0030). Importantly, this tendency was also seen in the left-handed patients, while it was not statistically significant due to the small sample size. This tendency was observed in each component of clinical or radiological involvement. Thus, handedness influences the laterality of clinical and radiological joint involvement in RA. PMID- 27976697 TI - Detecting sulphate aerosol geoengineering with different methods. AB - Sulphate aerosol injection has been widely discussed as a possible way to engineer future climate. Monitoring it would require detecting its effects amidst internal variability and in the presence of other external forcings. We investigate how the use of different detection methods and filtering techniques affects the detectability of sulphate aerosol geoengineering in annual-mean global-mean near-surface air temperature. This is done by assuming a future scenario that injects 5 Tg yr-1 of sulphur dioxide into the stratosphere and cross-comparing simulations from 5 climate models. 64% of the studied comparisons would require 25 years or more for detection when no filter and the multi-variate method that has been extensively used for attributing climate change are used, while 66% of the same comparisons would require fewer than 10 years for detection using a trend-based filter. This highlights the high sensitivity of sulphate aerosol geoengineering detectability to the choice of filter. With the same trend based filter but a non-stationary method, 80% of the comparisons would require fewer than 10 years for detection. This does not imply sulphate aerosol geoengineering should be deployed, but suggests that both detection methods could be used for monitoring geoengineering in global, annual mean temperature should it be needed. PMID- 27976696 TI - Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect. AB - Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides (TG) as lipid droplets in the liver. Although lipid-metabolizing enzymes are considered important in NAFLD, the involvement of phospholipase D1 (PLD1) has not yet been studied. Here, we show that the genetic ablation of PLD1 in mice induces NAFLD due to an autophagy defect. PLD1 expression was decreased in high-fat diet-induced NAFLD. Subsequently, PLD1 deficiency led to an increase in hepatic TGs and liver weight. Autophagic flux was blocked in Pld1-/- hepatocytes, with decreased beta-oxidation rate, reduced oxidation-related gene expression, and swollen mitochondria. The dynamics of autophagy was restored by treatment with the PLD product, phosphatidic acid (PA) or adenoviral PLD1 expression in Pld1-/- hepatocytes, confirming that lysosomal PA produced by PLD1 regulates autophagy. Notably, PLD1 expression in Pld1-/- liver significantly reduced hepatic lipid accumulation, compared with Pld1-/- liver. Thus, PLD1 plays an important role in hepatic steatosis via the regulation of autophagy. PMID- 27976698 TI - Epithelial ovarian carcinoma diagnosis by desorption electrospray ionization mass spectrometry imaging. AB - Ovarian cancer is highly prevalent among European women, and is the leading cause of gynaecological cancer death. Current histopathological diagnoses of tumour severity are based on interpretation of, for example, immunohistochemical staining. Desorption electrospray mass spectrometry imaging (DESI-MSI) generates spatially resolved metabolic profiles of tissues and supports an objective investigation of tumour biology. In this study, various ovarian tissue types were analysed by DESI-MSI and co-registered with their corresponding haematoxylin and eosin (H&E) stained images. The mass spectral data reveal tissue type-dependent lipid profiles which are consistent across the n = 110 samples (n = 107 patients) used in this study. Multivariate statistical methods were used to classify samples and identify molecular features discriminating between tissue types. Three main groups of samples (epithelial ovarian carcinoma, borderline ovarian tumours, normal ovarian stroma) were compared as were the carcinoma histotypes (serous, endometrioid, clear cell). Classification rates >84% were achieved for all analyses, and variables differing statistically between groups were determined and putatively identified. The changes noted in various lipid types help to provide a context in terms of tumour biochemistry. The classification of unseen samples demonstrates the capability of DESI-MSI to characterise ovarian samples and to overcome existing limitations in classical histopathology. PMID- 27976699 TI - Leisure-Time Physical Activity and Academic Performance: Cross-Lagged Associations from Adolescence to Young Adulthood. AB - Physical activity and academic performance are positively associated, but the direction of the association is poorly understood. This longitudinal study examined the direction and magnitude of the associations between leisure-time physical activity and academic performance throughout adolescence and young adulthood. The participants were Finnish twins (from 2,859 to 4,190 individuals/study wave) and their families. In a cross-lagged path model, higher academic performance at ages 12, 14 and 17 predicted higher leisure-time physical activity at subsequent time-points (standardized path coefficient at age 14: 0.07 (p < 0.001), age 17: 0.12 (p < 0.001) and age 24: 0.06 (p < 0.05)), whereas physical activity did not predict future academic performance. A cross-lagged model of co-twin differences suggested that academic performance and subsequent physical activity were not associated due to the environmental factors shared by co-twins. Our findings suggest that better academic performance in adolescence modestly predicts more frequent leisure-time physical activity in late adolescence and young adulthood. PMID- 27976701 TI - Porphyrins produce uniquely ephemeral animal colouration: a possible signal of virginity. AB - Colours that underlie animal pigmentation can either be permanent or renewable in the short term. Here we describe the discovery of a conspicuous salmon-pink colouration in the base of bustard feathers and down that has never been reported because of its extraordinarily brief expression. HPLC analyses indicated that its constituent pigments are coproporphyrin III and protoporphyrin IX, which are prone to photodegradation. Accordingly, an experimental exposure of feathers of three bustard species to sunlight produced a rapid disappearance of the salmon pink colouration, together with a marked decrease in reflectance around 670 nm coinciding with the absorption of porphyrin photoproducts. The disappearance of the salmon-pink colouration can occur in a period as short as 12 min, likely making it the most ephemeral colour phenotype in any extant bird. The presence of this colour trait in males performing sexual displays may thus indicate to females a high probability that the males were performing their first displays and would engage in their first copulations in the breeding season. In dominant males, sperm quality decreases over successive copulations, thus porphyrin-based colouration may evolve as a signal of virginity that allows females to maximize their fitness in lek mating systems. PMID- 27976700 TI - High-throughput and automated diagnosis of antimicrobial resistance using a cost effective cellphone-based micro-plate reader. AB - Routine antimicrobial susceptibility testing (AST) can prevent deaths due to bacteria and reduce the spread of multi-drug-resistance, but cannot be regularly performed in resource-limited-settings due to technological challenges, high costs, and lack of trained professionals. We demonstrate an automated and cost effective cellphone-based 96-well microtiter-plate (MTP) reader, capable of performing AST without the need for trained diagnosticians. Our system includes a 3D-printed smartphone attachment that holds and illuminates the MTP using a light emitting-diode array. An inexpensive optical fiber-array enables the capture of the transmitted light of each well through the smartphone camera. A custom designed application sends the captured image to a server to automatically determine well-turbidity, with results returned to the smartphone in ~1 minute. We tested this mobile-reader using MTPs prepared with 17 antibiotics targeting Gram-negative bacteria on clinical isolates of Klebsiella pneumoniae, containing highly-resistant antimicrobial profiles. Using 78 patient isolate test-plates, we demonstrated that our mobile-reader meets the FDA-defined AST criteria, with a well-turbidity detection accuracy of 98.21%, minimum-inhibitory-concentration accuracy of 95.12%, and a drug-susceptibility interpretation accuracy of 99.23%, with no very major errors. This mobile-reader could eliminate the need for trained diagnosticians to perform AST, reduce the cost-barrier for routine testing, and assist in spatio-temporal tracking of bacterial resistance. PMID- 27976702 TI - MiR-150 promotes cellular metastasis in non-small cell lung cancer by targeting FOXO4. AB - Previous studies have shown that dysregulation of microRNA-150 (miR-150) is associated with aberrant proliferation of human non-small cell lung cancer (NSCLC) cells. However, whether miR-150 has a critical role in NSCLC cell metastasis is unknown. Here, we reveal that the critical pro-metastatic role of miR-150 in the regulation of epithelial-mesenchymal-transition (EMT) through down regulation of FOXO4 in NSCLC. In vitro, miR-150 targets 3'UTR region of FOXO4 mRNA, thereby negatively regulating its expression. Clinically, the expression of miR-150 was frequently up-regulated in metastatic NSCLC cell lines and clinical specimens. Contrarily, FOXO4 was frequently down-regulated in NSCLC cell lines and clinical specimens. Functional studies show that ectopic expression of miR 150 enhanced tumor cell metastasis in vitro and in a mouse xenograft model, and triggered EMT-like changes in NSCLC cells (including E-cadherin repression, N cadherin and Vimentin induction, and mesenchymal morphology). Correspondingly, FOXO4 knockdown exhibited pro-metastatic and molecular effects resembling the effect of miR-150 over-expression. Moreover, NF-kappaB/snail/YY1/RKIP circuitry regulated by FOXO4 were likely involved in miR-150-induced EMT event. Simultaneous knockdown of miR-150 and FOXO4 abolished the phenotypic and molecular effects caused by individual knockdown of miR-150. Therefore, our study provides previously unidentified pro-metastatic roles and mechanisms of miR-150 in NSCLC. PMID- 27976703 TI - The genome of Rhizobiales bacteria in predatory ants reveals urease gene functions but no genes for nitrogen fixation. AB - Gut-associated microbiota of ants include Rhizobiales bacteria with affiliation to the genus Bartonella. These bacteria may enable the ants to fix atmospheric nitrogen, but no genomes have been sequenced yet to test the hypothesis. Sequence reads from a member of the Rhizobiales were identified in the data collected in a genome project of the ant Harpegnathos saltator. We present an analysis of the closed 1.86 Mb genome of the ant-associated bacterium, for which we suggest the species name Candidatus Tokpelaia hoelldoblerii. A phylogenetic analysis reveals a relationship to Bartonella and Brucella, which infect mammals. Novel gene acquisitions include a gene for a putative extracellular protein of more than 6,000 amino acids secreted by the type I secretion system, which may be involved in attachment to the gut epithelium. No genes for nitrogen fixation could be identified, but genes for a multi-subunit urease protein complex are present in the genome. The urease genes are also present in Brucella, which has a fecal-oral transmission pathway, but not in Bartonella, which use blood-borne transmission pathways. We hypothesize that the gain and loss of the urease function is related to transmission strategies and lifestyle changes in the host-associated members of the Rhizobiales. PMID- 27976704 TI - Epidemiological analysis of hemorrhagic fever with renal syndrome in China with the seasonal-trend decomposition method and the exponential smoothing model. AB - Hemorrhagic fever with renal syndrome (HFRS) is one of the most common infectious diseases globally. With the most reported cases in the world, the epidemic characteristics are still remained unclear in China. This paper utilized the seasonal-trend decomposition (STL) method to analyze the periodicity and seasonality of the HFRS data, and used the exponential smoothing model (ETS) model to predict incidence cases from July to December 2016 by using the data from January 2006 to June 2016. Analytic results demonstrated a favorable trend of HFRS in China, and with obvious periodicity and seasonality, the peak of the annual reported cases in winter concentrated on November to January of the following year, and reported in May and June also constituted another peak in summer. Eventually, the ETS (M, N and A) model was adopted for fitting and forecasting, and the fitting results indicated high accuracy (Mean absolute percentage error (MAPE) = 13.12%). The forecasting results also demonstrated a gradual decreasing trend from July to December 2016, suggesting that control measures for hemorrhagic fever were effective in China. The STL model could be well performed in the seasonal analysis of HFRS in China, and ETS could be effectively used in the time series analysis of HFRS in China. PMID- 27976705 TI - Comparison of impulsivity in non-problem, at-risk and problem gamblers. AB - As a non-substance addiction, gambling disorder represents the model for studying the neurobiology of addiction without toxic consequences of chronic drug use. From a neuropsychological perspective, impulsivity is deemed as a potential construct responsible in the onset and development of drug addiction. The objective of this study was to investigate the associations between impulsivity and gambling status in young adults with varying severity of gambling. A sample of 1120 college students, equally divided into non-problem, at-risk and problem gamblers, were administered multiple measures of impulsivity including the UPPSP Impulsive Behaviors Scale (UPPSP), the Barratt Impulsiveness Scale-11 (BIS-11), and the Delay-discounting Test (DDT). Compared with non-problem gamblers, both at risk gamblers and problem gamblers displayed elevated scores on Negative Urgency, Positive Urgency, Motor Impulsiveness, and Attentional Impulsiveness. Problem gamblers showed higher scores than at-risk gamblers on Positive Urgency. Logistic regression models revealed that only Negative Urgency positively predicted both at-risk gambling and problem gambling compared to non-problem gambling. These results suggest that dimensions of impulsivity may be differentially linked to gambling behavior in young adults, with Negative Urgency putatively identified as an important impulsivity-related marker for the development of gambling disorder, which may provide a better understanding of the pathogenesis. PMID- 27976707 TI - A pathway-centric view of spatial proximity in the 3D nucleome across cell lines. AB - In various contexts, spatially proximal genes have been shown to be functionally related. However, the extent to which spatial proximity of genes in a pathway contributes to the pathway's context-specific activity is not known. Leveraging Hi-C data in six human cell-lines, we show that spatial proximity of genes in a pathway is highly correlated with the pathway's context-specific expression and function. Furthermore, spatial proximity of pathway genes correlates with interactions of their protein products, and the specific pathway genes that are proximal to one another tend to occupy higher levels in the regulatory hierarchy. In addition to intra-pathway proximity, related pathways are spatially proximal to one another and housekeeping-genes tend to be proximal to several other pathways suggesting their coordinating role. Substantially extending previous works, our study reveals a pathway-centric organization of 3D-nucleome, whereby, functionally related interacting driver genes tend to be in spatial-proximity in a context-specific manner. PMID- 27976706 TI - Novel platform technology for modular mucosal vaccine that protects against streptococcus. AB - The upper respiratory tract (URT) is the major entry site for human pathogens and strategies to activate this network could lead to new vaccines capable of preventing infection with many pathogens. Group A streptococcus (GAS) infections, causing rheumatic fever, rheumatic heart disease, and invasive disease, are responsible for substantial morbidity and mortality. We describe an innovative vaccine strategy to induce mucosal antibodies of significant magnitude against peptide antigens of GAS using a novel biocompatible liposomal platform technology. The approach is to encapsulate free diphtheria toxoid (DT), a standard vaccine antigen, within liposomes as a source of helper T-cell stimulation while lipidated peptide targets for B-cells are separately displayed on the liposome surface. As DT is not physically conjugated to the peptide, it is possible to develop modular epitopic constructs that simultaneously activate IgA producing B-cells of different and complementary specificity and function that together neutralize distinct virulence factors. An inflammatory cellular immune response is also induced. The immune response provides profound protection against streptococcal infection in the URT. The study describes a new vaccine platform for humoral and cellular immunity applicable to the development of vaccines against multiple mucosal pathogens. PMID- 27976709 TI - Evaluation of efficacy and safety for recombinant human adenovirus-p53 in the control of the malignant pleural effusions via thoracic perfusion. AB - A certain number of studies have showed that p53 gene transfer has an anti-tumor activity in vitro and in vivo. This study was to evaluate the efficacy and safety of thoracic perfusion of recombinant human adenovirus p53 (rAd-p53, Gendicine) for controlling malignant pleural effusion (MPE). We searched for the relevant studies from the database of MEDLINE, Web of Science, EMBASE, Cochrance Library and CNKI to collect the trials concerning the efficacy and safety of rAd-p53 to treat MPE. Fourteen randomised controlled trials (RCTs) with 879 patients were involved in this analysis. The rAd-p53 combined with chemotherapeutic agents significantly improved the overall response rate (ORR) (P < 0.001; odds ratio = 3.73) and disease control rate (DCR) (P < 0.001; odds ratio = 2.32) of patients with MPE as well as the quality of life (QOL) of patients (P < 0.001; odds ratio = 4.27), compared with that of chemotherapeutic agents alone. In addition, the participation of rAd-p53 did not have an obvious impact on the most of incidence of adverse reactions (AEs) (P < 0.05) except the fever (P < 0.001). However, the fever was self-limited and could be tolerated well. The application of rAd-p53 through thoracic perfusion for treating MPE had a better efficacy and safety, which could be a potential choice for controlling MPE. PMID- 27976708 TI - A window into the brain mechanisms associated with noise sensitivity. AB - Noise sensitive individuals are more likely to experience negative emotions from unwanted sounds and they show greater susceptibility to adverse effects of noise on health. Noise sensitivity does not originate from dysfunctions of the peripheral auditory system, and it is thus far unknown whether and how it relates to abnormalities of auditory processing in the central nervous system. We conducted a combined electroencephalography and magnetoencephalography (M/EEG) study to measure neural sound feature processing in the central auditory system in relation to the individual noise sensitivity. Our results show that high noise sensitivity is associated with altered sound feature encoding and attenuated discrimination of sound noisiness in the auditory cortex. This finding makes a step towards objective measures of noise sensitivity instead of self-evaluation questionnaires and the development of strategies to prevent negative effects of noise on the susceptible population. PMID- 27976710 TI - Spring maize yield, soil water use and water use efficiency under plastic film and straw mulches in the Loess Plateau. AB - To compare the soil water balance, yield and water use efficiency (WUE) of spring maize under different mulching types in the Loess Plateau, a 7-year field experiment was conducted in the Changwu region of the Loess Plateau. Three treatments were used in this experiment: straw mulch (SM), plastic film mulch (PM) and conventional covering without mulch (CK). Results show that the soil water change of dryland spring maize was as deep as 300 cm depth and hence 300 cm is recommended as the minimum depth when measure the soil water in this region. Water use (ET) did not differ significantly among the treatments. However, grain yield was significantly higher in PM compared with CK. WUE was significantly higher in PM than in CK for most years of the experiment. Although ET tended to be higher in PM than in the other treatments (without significance), the evaporation of water in the fallow period also decreased. Thus, PM is sustainable with respect to soil water balance. The 7-year experiment and the supplemental experiment thus confirmed that straw mulching at the seedling stage may lead to yield reduction and this effect can be mitigated by delaying the straw application to three-leaf stage. PMID- 27976712 TI - Condensed-matter equation of states covering a wide region of pressure studied experimentally. AB - The relationships among the pressure P, volume V, and temperature T of solid state materials are described by their equations of state (EOSs), which are often derived from the consideration of the finite-strain energy or the interatomic potential. These EOSs consist of typically three parameters to determine from experimental P-V-T data by fitting analyses. In the empirical approach to EOSs, one either refines such fitting parameters or improves the mathematical functions to better simulate the experimental data. Despite over seven decades of studies on EOSs, none has been found to be accurate for all types of solids over the whole temperature and pressure ranges studied experimentally. Here we show that the simple empirical EOS, P = alpha1(PV) + alpha2(PV)2 + alpha3(PV)3, in which the pressure P is indirectly related to the volume V through a cubic polynomial of the energy term PV with three fitting parameters alpha1 - alpha3, provides accurate descriptions for the P-vs-V data of condensed matter in a wide region of pressure studied experimentally even in the presence of phase transitions. PMID- 27976711 TI - Interstitial Cystitis-Associated Urinary Metabolites Identified by Mass Spectrometry Based Metabolomics Analysis. AB - This study on interstitial cystitis (IC) aims to identify a unique urine metabolomic profile associated with IC, which can be defined as an unpleasant sensation including pain and discomfort related to the urinary bladder, without infection or other identifiable causes. Although the burden of IC on the American public is immense in both human and financial terms, there is no clear diagnostic test for IC, but rather it is a disease of exclusion. Very little is known about the clinically useful urinary biomarkers of IC, which are desperately needed. Untargeted comprehensive metabolomic profiling was performed using gas chromatography/mass-spectrometry to compare urine specimens of IC patients or health donors. The study profiled 200 known and 290 unknown metabolites. The majority of the thirty significantly changed metabolites before false discovery rate correction were unknown compounds. Partial least square discriminant analysis clearly separated IC patients from controls. The high number of unknown compounds hinders useful biological interpretation of such predictive models. Given that urine analyses have great potential to be adapted in clinical practice, research has to be focused on the identification of unknown compounds to uncover important clues about underlying disease mechanisms. PMID- 27976714 TI - Photonic Weyl point in a two-dimensional resonator lattice with a synthetic frequency dimension. AB - Weyl points, as a signature of 3D topological states, have been extensively studied in condensed matter systems. Recently, the physics of Weyl points has also been explored in electromagnetic structures such as photonic crystals and metamaterials. These structures typically have complex three-dimensional geometries, which limits the potential for exploring Weyl point physics in on chip integrated systems. Here we show that Weyl point physics emerges in a system of two-dimensional arrays of resonators undergoing dynamic modulation of refractive index. In addition, the phase of modulation can be controlled to explore Weyl points under different symmetries. Furthermore, unlike static structures, in this system the non-trivial topology of the Weyl point manifests in terms of surface state arcs in the synthetic space that exhibit one-way frequency conversion. Our system therefore provides a versatile platform to explore and exploit Weyl point physics on chip. PMID- 27976713 TI - Genetically manipulated phages with improved pH resistance for oral administration in veterinary medicine. AB - Orally administered phages to control zoonotic pathogens face important challenges, mainly related to the hostile conditions found in the gastrointestinal tract (GIT). These include temperature, salinity and primarily pH, which is exceptionally low in certain compartments. Phage survival under these conditions can be jeopardized and undermine treatment. Strategies like encapsulation have been attempted with relative success, but are typically complex and require several optimization steps. Here we report a simple and efficient alternative, consisting in the genetic engineering of phages to display lipids on their surfaces. Escherichia coli phage T7 was used as a model and the E. coli PhoE signal peptide was genetically fused to its major capsid protein (10 A), enabling phospholipid attachment to the phage capsid. The presence of phospholipids on the mutant phages was confirmed by High Performance Thin Layer Chromatography, Dynamic Light Scattering and phospholipase assays. The stability of phages was analysed in simulated GIT conditions, demonstrating improved stability of the mutant phages with survival rates 102-107 pfu.mL-1 higher than wild-type phages. Our work demonstrates that phage engineering can be a good strategy to improve phage tolerance to GIT conditions, having promising application for oral administration in veterinary medicine. PMID- 27976715 TI - Heritability of the shape of subcortical brain structures in the general population. AB - The volumes of subcortical brain structures are highly heritable, but genetic underpinnings of their shape remain relatively obscure. Here we determine the relative contribution of genetic factors to individual variation in the shape of seven bilateral subcortical structures: the nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus. In 3,686 unrelated individuals aged between 45 and 98 years, brain magnetic resonance imaging and genotyping was performed. The maximal heritability of shape varies from 32.7 to 53.3% across the subcortical structures. Genetic contributions to shape extend beyond influences on intracranial volume and the gross volume of the respective structure. The regional variance in heritability was related to the reliability of the measurements, but could not be accounted for by technical factors only. These findings could be replicated in an independent sample of 1,040 twins. Differences in genetic contributions within a single region reveal the value of refined brain maps to appreciate the genetic complexity of brain structures. PMID- 27976717 TI - Temporal pairwise spike correlations fully capture single-neuron information. AB - To crack the neural code and read out the information neural spikes convey, it is essential to understand how the information is coded and how much of it is available for decoding. To this end, it is indispensable to derive from first principles a minimal set of spike features containing the complete information content of a neuron. Here we present such a complete set of coding features. We show that temporal pairwise spike correlations fully determine the information conveyed by a single spiking neuron with finite temporal memory and stationary spike statistics. We reveal that interspike interval temporal correlations, which are often neglected, can significantly change the total information. Our findings provide a conceptual link between numerous disparate observations and recommend shifting the focus of future studies from addressing firing rates to addressing pairwise spike correlation functions as the primary determinants of neural information. PMID- 27976716 TI - Dendritic excitation-inhibition balance shapes cerebellar output during motor behaviour. AB - Feedforward excitatory and inhibitory circuits regulate cerebellar output, but how these circuits interact to shape the somatodendritic excitability of Purkinje cells during motor behaviour remains unresolved. Here we perform dendritic and somatic patch-clamp recordings in vivo combined with optogenetic silencing of interneurons to investigate how dendritic excitation and inhibition generates bidirectional (that is, increased or decreased) Purkinje cell output during self paced locomotion. We find that granule cells generate a sustained depolarization of Purkinje cell dendrites during movement, which is counterbalanced by variable levels of feedforward inhibition from local interneurons. Subtle differences in the dendritic excitation-inhibition balance generate robust, bidirectional changes in simple spike (SSp) output. Disrupting this balance by selectively silencing molecular layer interneurons results in unidirectional firing rate changes, increased SSp regularity and disrupted locomotor behaviour. Our findings provide a mechanistic understanding of how feedforward excitatory and inhibitory circuits shape Purkinje cell output during motor behaviour. PMID- 27976719 TI - The in vivo hydrocarbon formation by vanadium nitrogenase follows a secondary metabolic pathway. AB - The vanadium (V)-nitrogenase of Azotobacter vinelandii catalyses the in vitro conversion of carbon monoxide (CO) to hydrocarbons. Here we show that an A. vinelandii strain expressing the V-nitrogenase is capable of in vivo reduction of CO to ethylene (C2H4), ethane (C2H6) and propane (C3H8). Moreover, we demonstrate that CO is not used as a carbon source for cell growth, being instead reduced to hydrocarbons in a secondary metabolic pathway. These findings suggest a possible role of the ancient nitrogenase as an evolutionary link between the carbon and nitrogen cycles on Earth and establish a solid foundation for biotechnological adaptation of a whole-cell approach to recycling carbon wastes into hydrocarbon products. Thus, this study has several repercussions for evolution-, environment- and energy-related areas. PMID- 27976720 TI - Oscillatory integration windows in neurons. AB - Oscillatory synchrony among neurons occurs in many species and brain areas, and has been proposed to help neural circuits process information. One hypothesis states that oscillatory input creates cyclic integration windows: specific times in each oscillatory cycle when postsynaptic neurons become especially responsive to inputs. With paired local field potential (LFP) and intracellular recordings and controlled stimulus manipulations we directly test this idea in the locust olfactory system. We find that inputs arriving in Kenyon cells (KCs) sum most effectively in a preferred window of the oscillation cycle. With a computational model, we show that the non-uniform structure of noise in the membrane potential helps mediate this process. Further experiments performed in vivo demonstrate that integration windows can form in the absence of inhibition and at a broad range of oscillation frequencies. Our results reveal how a fundamental coincidence-detection mechanism in a neural circuit functions to decode temporally organized spiking. PMID- 27976718 TI - Amphibian gut microbiota shifts differentially in community structure but converges on habitat-specific predicted functions. AB - Complex microbial communities inhabit vertebrate digestive systems but thorough understanding of the ecological dynamics and functions of host-associated microbiota within natural habitats is limited. We investigate the role of environmental conditions in shaping gut and skin microbiota under natural conditions by performing a field survey and reciprocal transfer experiments with salamander larvae inhabiting two distinct habitats (ponds and streams). We show that gut and skin microbiota are habitat-specific, demonstrating environmental factors mediate community structure. Reciprocal transfer reveals that gut microbiota, but not skin microbiota, responds differentially to environmental change. Stream-to-pond larvae shift their gut microbiota to that of pond-to-pond larvae, whereas pond-to-stream larvae change to a community structure distinct from both habitat controls. Predicted functions, however, match that of larvae from the destination habitats in both cases. Thus, microbial function can be matched without taxonomic coherence and gut microbiota appears to exhibit metagenomic plasticity. PMID- 27976722 TI - Ventral tegmental area glutamate neurons co-release GABA and promote positive reinforcement. AB - In addition to dopamine neurons, the ventral tegmental area (VTA) contains GABA-, glutamate- and co-releasing neurons, and recent reports suggest a complex role for the glutamate neurons in behavioural reinforcement. We report that optogenetic stimulation of VTA glutamate neurons or terminals serves as a positive reinforcer on operant behavioural assays. Mice display marked preference for brief over sustained VTA glutamate neuron stimulation resulting in behavioural responses that are notably distinct from dopamine neuron stimulation and resistant to dopamine receptor antagonists. Whole-cell recordings reveal EPSCs following stimulation of VTA glutamate terminals in the nucleus accumbens or local VTA collaterals; but reveal both excitatory and monosynaptic inhibitory currents in the ventral pallidum and lateral habenula, though the net effects on postsynaptic firing in each region are consistent with the observed rewarding behavioural effects. These data indicate that VTA glutamate neurons co-release GABA in a projection-target-dependent manner and that their transient activation drives positive reinforcement. PMID- 27976723 TI - Study of Repetitive Movements Induced Oscillatory Activities in Healthy Subjects and Chronic Stroke Patients. AB - Repetitive movements at a constant rate require the integration of internal time counting and motor neural networks. Previous studies have proved that humans can follow short durations automatically (automatic timing) but require more cognitive efforts to track or estimate long durations. In this study, we studied sensorimotor oscillatory activities in healthy subjects and chronic stroke patients when subjects were performing repetitive finger movements. We found the movement-modulated changes in alpha and beta oscillatory activities were decreased with the increase of movement rates in finger lifting of healthy subjects and the non-paretic hands in stroke patients, whereas no difference was found in the paretic-hand movements at different movement rates in stroke patients. The significant difference in oscillatory activities between movements of non-paretic hands and paretic hands could imply the requirement of higher cognitive efforts to perform fast repetitive movements in paretic hands. The sensorimotor oscillatory response in fast repetitive movements could be a possible indicator to probe the recovery of motor function in stroke patients. PMID- 27976721 TI - A large-scale genome-wide association and meta-analysis identified four novel susceptibility loci for leprosy. AB - Leprosy, a chronic infectious disease, results from the uncultivable pathogen Mycobacterium leprae (M. leprae), and usually progresses to peripheral neuropathy and permanent progressive deformity if not treated. Previously published genetic studies have identified 18 gene/loci significantly associated with leprosy at the genome-wide significant level. However as a complex disease, only a small proportion of leprosy risk could be explained by those gene/loci. To further identify more susceptibility gene/loci, we hereby performed a three-stage GWAS comprising 8,156 leprosy patients and 15,610 controls of Chinese ancestry. Four novel loci were identified including rs6807915 on 3p25.2 (P=1.94 * 10-8, OR=0.89), rs4720118 on 7p14.3 (P=3.85 * 10-10, OR=1.16), rs55894533 on 8p23.1 (P=5.07 * 10-11, OR=1.15) and rs10100465 on 8q24.11 (P=2.85 * 10-11, OR=0.85). Altogether, these findings have provided new insight and significantly expanded our understanding of the genetic basis of leprosy. PMID- 27976724 TI - Differential IL-1beta secretion by monocyte subsets is regulated by Hsp27 through modulating mRNA stability. AB - Monocytes play a central role in regulating inflammation in response to infection or injury, and during auto-inflammatory diseases. Human blood contains classical, intermediate and non-classical monocyte subsets that each express characteristic patterns of cell surface CD16 and CD14; each subset also has specific functional properties, but the mechanisms underlying many of their distinctive features are undefined. Of particular interest is how monocyte subsets regulate secretion of the apical pro-inflammatory cytokine IL-1beta, which is central to the initiation of immune responses but is also implicated in the pathology of various auto immune/auto-inflammatory conditions. Here we show that primary human non classical monocytes, exposed to LPS or LPS + BzATP (3'-O-(4-benzoyl)benzyl-ATP, a P2X7R agonist), produce approx. 80% less IL-1beta than intermediate or classical monocytes. Despite their low CD14 expression, LPS-sensing, caspase-1 activation and P2X7R activity were comparable in non-classical monocytes to other subsets: their diminished ability to produce IL-1beta instead arose from 50% increased IL 1beta mRNA decay rates, mediated by Hsp27. These findings identify the Hsp27 pathway as a novel therapeutic target for the management of conditions featuring dysregulated IL-1beta production, and represent an advancement in understanding of both physiological inflammatory responses and the pathogenesis of inflammatory diseases involving monocyte-derived IL-1beta. PMID- 27976726 TI - Increased levels of the oxidative stress biomarker 8-iso-prostaglandin F2alpha in wastewater associated with tobacco use. AB - Wastewater analysis has been demonstrated to be a complementary approach for assessing the overall patterns of drug use by a population while the full potential of wastewater-based epidemiology has yet to be explored. F2 isoprostanes are a prototype wastewater biomarker to study the cumulative oxidative stress at a community level. In this work, 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) was analysed in raw 24 h-composite wastewater samples collected from 4 Norwegian and 7 other European cities in 2014 and 2015. Using the same samples, biomarkers of alcohol (ethyl sulfate) and tobacco (trans-3' hydroxycotinine) use were also analysed to investigate any possible correlation between 8-iso-PGF2alpha and the consumption of the two drugs. The estimated per capita daily loads of 8-iso-PGF2alpha in the 11 cities ranged between 2.5 and 9.9 mg/day/1000 inhabitants with a population-weighted mean of 4.8 mg/day/1000 inhabitants. There were no temporal trends observed in the levels of 8-iso PGF2alpha, however, spatial differences were found at the inter-city level correlating to the degree of urbanisation. The 8-iso-PGF2alpha mass load was found to be strongly associated with that of trans-3'-hydroxycotinine while it showed no correlation with ethyl sulfate. The present study shows the potential for 8-iso-PGF2alpha as a wastewater biomarker for the assessment of community public health. PMID- 27976728 TI - Thumb Imprint Based Detection of Hyperbilirubinemia Using Luminescent Gold Nanoclusters. AB - Early and easy detection of diseases, using point-of-care and inexpensive devices, not only provides option for early treatment but also reduces the risk of propagation. Herein we report the fabrication of a robust film based luminescence indicator of bilirubin, which can indicate hyperbilirubinemia through the thumb imprint of the patient. The UV-light induced luminescence intensity of the film, made out of chitosan stabilised gold (Au) nanoclusters, which was effectively quenched in the presence of Cu2+ ions, recovered in the presence of bilirubin from skin or blood serum. Moreover, the sensitivity of detection of bilirubin was tuneable with the amount of Cu2+ added, thereby facilitating the detection of the desired concentration range of bilirubin. PMID- 27976725 TI - Modulation of gut microbiota and delayed immunosenescence as a result of syringaresinol consumption in middle-aged mice. AB - Age-associated immunological dysfunction (immunosenescence) is closely linked to perturbation of the gut microbiota. Here, we investigated whether syringaresinol (SYR), a polyphenolic lignan, modulates immune aging and the gut microbiota associated with this effect in middle-aged mice. Compared with age-matched control mice, SYR treatment delayed immunosenescence by enhancing the numbers of total CD3+ T cells and naive T cells. SYR treatment induced the expression of Bim as well as activation of FOXO3 in Foxp3+ regulatory T cells (Tregs). Furthermore, SYR treatment significantly enhanced the Firmicutes/Bacteroidetes ratio compared with that in age-matched controls by increasing beneficial bacteria, Lactobacillus and Bifidobacterium, while reducing the opportunistic pathogenic genus, Akkermansia. In addition, SYR treatment reduced the serum level of lipopolysaccharide-binding protein, an inflammatory marker, and enhanced humoral immunity against influenza vaccination to the level of young control mice. Taken together, these findings suggest that SYR may rejuvenate the immune system through modulation of gut integrity and microbiota diversity as well as composition in middle-aged mice, which may delay the immunosenescence associated with aging. PMID- 27976727 TI - The protective role of MLCP-mediated ERM dephosphorylation in endotoxin-induced lung injury in vitro and in vivo. AB - The goal of this study was to investigate the role of MLC phosphatase (MLCP) in a LPS model of acute lung injury (ALI). We demonstrate that ectopic expression of a constitutively-active (C/A) MLCP regulatory subunit (MYPT1) attenuates the ability of LPS to increase endothelial (EC) permeability. Down-regulation of MYPT1 exacerbates LPS-induced expression of ICAM1 suggesting an anti-inflammatory role of MLCP. To determine whether MLCP contributes to LPS-induced ALI in vivo, we utilized a nanoparticle DNA delivery method to specifically target lung EC. Expression of a C/A MYPT1 reduced LPS-induced lung inflammation and vascular permeability. Further, increased expression of the CS1beta (MLCP catalytic subunit) also reduced LPS-induced lung inflammation, whereas the inactive CS1beta mutant increased vascular leak. We next examined the role of the cytoskeletal targets of MLCP, the ERM proteins (Ezrin/Radixin/Moesin), in mediating barrier dysfunction. LPS-induced increase in EC permeability was accompanied by PKC mediated increase in ERM phosphorylation, which was more prominent in CS1beta depleted cells. Depletion of Moesin and Ezrin, but not Radixin attenuated LPS induced increases in permeability. Further, delivery of a Moesin phospho-null mutant into murine lung endothelium attenuated LPS-induced lung inflammation and vascular leak suggesting that MLCP opposes LPS-induced ALI by mediating the dephosphorylation of Moesin and Ezrin. PMID- 27976729 TI - Interactomic analysis of REST/NRSF and implications of its functional links with the transcription suppressor TRIM28 during neuronal differentiation. AB - RE-1 silencing transcription factor (REST) is a transcriptional repressor that regulates gene expression by binding to repressor element 1. However, despite its critical function in physiology, little is known about its interaction proteins. Here we identified 204 REST-interacting proteins using affinity purification and mass spectrometry. The interactome included proteins associated with mRNA processing/splicing, chromatin organization, and transcription. The interactions of these REST-interacting proteins, which included TRIM28, were confirmed by co immunoprecipitation and immunocytochemistry, respectively. Gene Ontology (GO) analysis revealed that neuronal differentiation-related GO terms were enriched among target genes that were co-regulated by REST and TRIM28, while the level of CTNND2 was increased by the knockdown of REST and TRIM28. Consistently, the level of CTNND2 increased while those of REST and TRIM28 decreased during neuronal differentiation in the primary neurons, suggesting that CTNND2 expression may be co-regulated by both. Furthermore, neurite outgrowth was increased by depletion of REST or TRIM28, implying that reduction of both REST and TRIM28 could promote neuronal differentiation via induction of CTNND2 expression. In conclusion, our study of REST reveals novel interacting proteins which could be a valuable resource for investigating unidentified functions of REST and also suggested functional links between REST and TRIM28 during neuronal development. PMID- 27976730 TI - Associative nitrogen fixation in nodules of the conifer Lepidothamnus fonkii (Podocarpaceae) inhabiting ombrotrophic bogs in southern Patagonia. AB - Biological N2 fixation (BNF) in the rhizosphere of Podocarpaceae is currently attributed to unspecific diazotrophs with negligible impact on N acquisition. Here, we report specific and high associative BNF in dead cells of root nodules of Lepidothamnus fonkii distributed in ombrotrophic peatlands of Patagonia. BNF of nodulated roots, intact plants of L. fonkii and rhizospheric peat was assessed by 15N2 and acetylene reduction. Diazotrophs were identified by electron microscopy, analysis of nitrogenase encoding genes (nifH) and transcripts, and 16S rRNA. Nitrogenase encoding nifH transcripts from root nodules point to Beijerinckiaceae (Rhizobiales), known as free-living diazotrophs. Electron microscopy and 16S rRNA analysis likewise identified active Beijerinckiaceae in outer dead cells of root nodules. NifH transcripts from the rhizopshere peat revealed diverse active diazotrophs including Beijerinckiaceae. Both methods revealed high activity of nitrogenase rates in cut roots of L. fonkii (2.5 MUmol N g-1 d.w. d-1 based on 15N2 assay; 2.4 MUmol C2H4 g-1 d.w. d-1 based on acetylene reduction assay). The data suggest that (i) nodules recruit diazotrophic Beijerinckiaceae from peat, (ii) dead nodule cells provide an exclusive habitat for Beijerinckiaceae, and (iii) BNF in L. fonkii is one potent pathway to overcome N deficiency in ombrotrophic peatlands of Patagonia. PMID- 27976731 TI - Genetic variation in IGF1 predicts renal cell carcinoma susceptibility and prognosis in Chinese population. AB - Insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3) play an important role in the development and progression of renal cell carcinoma (RCC). We evaluated the association of functional polymorphisms in IGF1 and IGFBP3 with susceptibility and prognosis of RCC. We genotyped nine potentially functional polymorphisms in IGF1 and IGFBP3 and assessed their association with risk of RCC in a two-stage case-control study compromising 1027 cases and 1094 controls, and with prognosis in a cohort of 311 patients. We found rs5742714 in the 3'-UTR of IGF1 was significantly associated with risk and prognosis of RCC. In the combined set, the rs5742714 GC/CC genotypes were significantly associated with decreased risk of RCC compared with the GG genotype (OR = 0.82; 95% CI = 0.68-0.98, P = 0.002). Furthermore, patients with the rs5742714 GC/CC genotypes showed improved survival than those with the GG genotype (Log-rank P = 0.025, HR = 0.36, 95% CI = 0.14-0.93). Besides, the rs5742714 GC/CC genotypes were associated with significantly decreased expression of IGF1 mRNA and lower IGF1 serum levels. Moreover, the luciferase reporter assays revealed the potential effect of rs5742714 genotype on the binding of microRNAs to IGF1. Our findings suggest that the IGF1 polymorphism rs5742714 may be a genetic predictor of susceptibility and prognosis of RCC. PMID- 27976732 TI - Biological characteristics comparison of HBV rtA181T mutants with truncated or substituted HBsAg expression in vitro and in vivo model systems. AB - The hepatitis B virus(HBV) polymerase rtA181T mutation is selected during long term antiviral therapy. As the polymerase gene completely overlaps with the envelope (S) gene, HBV rtA181T mutation also carries sW172 mutations. In this study, we investigated whether there were biological differences between rtA181T/sW172* (coding truncated HBsAg) and rtA181T/sW172L (coding substituted HBsAg) mutants. In cell experiments, a slight decline of viral replication was observed in both two mutants as compared to wild-type strains, but the levels of supernatant HBsAg and HBV DNA in rtA181T/sW172* were significantly lower than those in rtA181T/sW172L transfected cells. In animal experiments, we were amazed to find that viral replication in rtA181T/sW172* mutant increased and maintained significantly longer than that in rtA181T/sW172L mutant, while no significant difference was observed between rtA181T/sW172L and wild-type strains. Compared with wild-type strains, there were intracellular accumulations of HBsAg and HBcAg in rtA181/sW172* but none in rtA181/sW172L mutant strains. Importantly, we also found that truncated HBsAg could increase the activity of HBV core promoter, but substituted HBsAg could not. In summary, the characteristics of above two rtA181T mutants mentioned above were significantly different, and it is necessary and important for us to distinguish sW172* truncated mutation from sW172L substituted mutation. PMID- 27976733 TI - Prognostic value of circulating regulatory T cell subsets in untreated non-small cell lung cancer patients. AB - The role of the different circulating regulatory T-cells (Treg) subsets, as well as their correlation with clinical outcome of non-small cell lung cancer (NSCLC) patients is poorly understood. Peripheral blood from 156 stage III/IV chemotherapy-naive NSCLC patients and 31 healthy donors (HD) was analyzed with flow cytometry for the presence and functionality of CD4+ Treg subsets (naive, effector and terminal effector). Their frequencies were correlated with the clinical outcome. All CD4+ Treg subsets exhibited highly suppressive activity by TGF-beta and IL-10 production. The percentages of naive Treg were found elevated in NSCLC patients compared to HD and were associated with poor clinical outcome, whereas the percentage of terminal effector Treg was lower compared to HD and higher levels were correlated with improved clinical response. At baseline, normal levels of naive and effector Treg were associated with longer overall survival (OS) compared to high levels, while the high frequency of the terminal effector Treg was correlated with longer Progression-Free Survival and OS. It is demonstrated, for first time, that particular CD4+ Treg subtypes are elevated in NSCLC patients and their levels are associated to the clinical outcome. The blocking of their migration to the tumor site may be an effective therapeutic strategy. PMID- 27976734 TI - The Unravelling of the Genetic Architecture of Plasminogen Deficiency and its Relation to Thrombotic Disease. AB - Although plasminogen is a key protein in fibrinolysis and several mutations in the plasminogen gene (PLG) have been identified that result in plasminogen deficiency, there are conflicting reports to associate it with the risk of thrombosis. Our aim was to unravel the genetic architecture of PLG in families with plasminogen deficiency and its relationship with spontaneous thrombotic events in these families. A total of 13 individuals from 4 families were recruited. Their genetic risk profile of thromboembolism was characterized using the Thrombo inCode kit. Only one family presented genetic risk of thromboembolism (homozygous carrier of F12 rs1801020 and F13A1 rs5985). The whole PLG was tested using Next Generation Sequencing (NGS) and 5 putative pathogenic mutations were found (after in silico predictions) and associated with plasminogen deficiency. Although we can not find genetic risk factors of thrombosis in 3 of 4 families, even the mutations associated with plasminogen deficiency do not cosegregated with thrombosis, we can not exclude plasminogen deficiency as a susceptibility risk factor for thrombosis, since thrombosis is a multifactorial and complex disease where unknown genetic risk factors, in addition to plasminogen deficiency, within these families may explain the thrombotic tendency. PMID- 27976735 TI - Pollen and spores as biological recorders of past ultraviolet irradiance. AB - Solar ultraviolet (UV) irradiance is a key driver of climatic and biotic change. Ultraviolet irradiance modulates stratospheric warming and ozone production, and influences the biosphere from ecosystem-level processes through to the largest scale patterns of diversification and extinction. Yet our understanding of ultraviolet irradiance is limited because no method has been validated to reconstruct its flux over timescales relevant to climatic or biotic processes. Here, we show that a recently developed proxy for ultraviolet irradiance based on spore and pollen chemistry can be used over long (105 years) timescales. Firstly we demonstrate that spatial variations in spore and pollen chemistry correlate with known latitudinal solar irradiance gradients. Using this relationship we provide a reconstruction of past changes in solar irradiance based on the pollen record from Lake Bosumtwi in Ghana. As anticipated, variations in the chemistry of grass pollen from the Lake Bosumtwi record show a link to multiple orbital precessional cycles (19-21 thousand years). By providing a unique, local proxy for broad spectrum solar irradiance, the chemical analysis of spores and pollen offers unprecedented opportunities to decouple solar variability, climate and vegetation change through geologic time and a new proxy with which to probe the Earth system. PMID- 27976736 TI - Aptamer-PEG-modified Fe3O4@Mn as a novel T1- and T2- dual-model MRI contrast agent targeting hypoxia-induced cancer stem cells. AB - Hypoxia-induced cancer stem cells have been known to be involved in tumour metastasis, resistance to chemo/radio therapy and tumour recurrence. Magnetic Resonance Imaging is a widely used imaging tool for cancers in clinics and research. To develop T1-positive and T2-negative dual mode MRI agents for more comprehensive and accurate diagnostic information under hypoxic conditions, a hypoxia-inducible factor-1alpha based aptamer and Mn(II)-modified nanoparticles D Fe3O4@PMn were synthesized and characterized. In vitro and in vivo studies show that D-Fe3O4@PMn NPs are biocompatible and less cytotoxic and can produce significant contrast enhancement in T1- and T2-weighted MR imaging. Furthermore, the D-Fe3O4@PMn NPs enable targeted dual-contrast T1- and T2-weighted MR imaging of cancer cells expressing high levels of HIF-1alpha and cancer stem cell-related proteins under hypoxic condition. In conclusion, NPs with HIF-1alpha and Mn(II) are promising diagnostic agents for dual-mode T1 and T2 imaging by targeting cancer stem cells as they are non-toxic and biocompatible. PMID- 27976737 TI - Altered systemic bile acid homeostasis contributes to liver disease in pediatric patients with intestinal failure. AB - Intestinal failure (IF)-associated liver disease (IFALD), as a major complication, contributes to significant morbidity in pediatric IF patients. However, the pathogenesis of IFALD is still uncertain. We here investigate the roles of bile acid (BA) dysmetabolism in the unclear pathogenesis of IFALD. It found that the histological evidence of pediatric IF patients exhibited liver injury, which was characterized by liver bile duct proliferation, inflammatory infiltration, hepatocyte apoptosis and different stages of fibrosis. The BA compositions were altered in serum and liver of pediatric IF patients, as reflected by a primary BA dominant composition. In IF patients, the serum FGF19 levels decreased significantly, and were conversely correlated with ileal inflammation grades (r = -0.50, p < 0.05). In ileum, the inflammation grades were inversely associated with farnesoid X receptor (FXR) expression (r = -0.55, p < 0.05). In liver, the expression of induction of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1) increased evidently. In conclusion, ileum inflammation decreases FXR expression corresponding to reduce serum FGF19 concentration, along with increased hepatic bile acid synthesis, leading to liver damages in IF patients. PMID- 27976738 TI - Integrating Information in Biological Ontologies and Molecular Networks to Infer Novel Terms. AB - : Currently most terms and term-term relationships in Gene Ontology (GO) are defined manually, which creates cost, consistency and completeness issues. Recent studies have demonstrated the feasibility of inferring GO automatically from biological networks, which represents an important complementary approach to GO construction. These methods (NeXO and CliXO) are unsupervised, which means 1) they cannot use the information contained in existing GO, 2) the way they integrate biological networks may not optimize the accuracy, and 3) they are not customized to infer the three different sub-ontologies of GO. Here we present a semi-supervised method called Unicorn that extends these previous methods to tackle the three problems. Unicorn uses a sub-tree of an existing GO sub-ontology as training part to learn parameters in integrating multiple networks. Cross validation results show that Unicorn reliably inferred the left-out parts of each specific GO sub-ontology. In addition, by training Unicorn with an old version of GO together with biological networks, it successfully re-discovered some terms and term-term relationships present only in a new version of GO. Unicorn also successfully inferred some novel terms that were not contained in GO but have biological meanings well-supported by the literature. AVAILABILITY: Source code of Unicorn is available at http://yiplab.cse.cuhk.edu.hk/unicorn/. PMID- 27976740 TI - Origin of sample size effect: Stochastic dislocation formation in crystalline metals at small scales. AB - In crystalline metals at small scales, the dislocation density will be increased by stochastic events of dislocation network, leading to a universal power law for various material structures. In this work, we develop a model obeyed by a probability distribution of dislocation density to describe the dislocation formation in terms of a chain reaction. The leading order terms of steady-state of probability distribution gives physical and quantitative insight to the scaling exponent n values in the power law of sample size effect. This approach is found to be consistent with experimental n values in a wide range. PMID- 27976739 TI - Multivoxel neurofeedback selectively modulates confidence without changing perceptual performance. AB - A central controversy in metacognition studies concerns whether subjective confidence directly reflects the reliability of perceptual or cognitive processes, as suggested by normative models based on the assumption that neural computations are generally optimal. This view enjoys popularity in the computational and animal literatures, but it has also been suggested that confidence may depend on a late-stage estimation dissociable from perceptual processes. Yet, at least in humans, experimental tools have lacked the power to resolve these issues convincingly. Here, we overcome this difficulty by using the recently developed method of decoded neurofeedback (DecNef) to systematically manipulate multivoxel correlates of confidence in a frontoparietal network. Here we report that bi-directional changes in confidence do not affect perceptual accuracy. Further psychophysical analyses rule out accounts based on simple shifts in reporting strategy. Our results provide clear neuroscientific evidence for the systematic dissociation between confidence and perceptual performance, and thereby challenge current theoretical thinking. PMID- 27976741 TI - Weighing Scale-Based Pulse Transit Time is a Superior Marker of Blood Pressure than Conventional Pulse Arrival Time. AB - Pulse transit time (PTT) is being widely pursued for cuff-less blood pressure (BP) monitoring. Most efforts have employed the time delay between ECG and finger photoplethysmography (PPG) waveforms as a convenient surrogate of PTT. However, these conventional pulse arrival time (PAT) measurements include the pre-ejection period (PEP) and the time delay through small, muscular arteries and may thus be an unreliable marker of BP. We assessed a bathroom weighing scale-like system for convenient measurement of ballistocardiography and foot PPG waveforms - and thus PTT through larger, more elastic arteries - in terms of its ability to improve tracking of BP in individual subjects. We measured "scale PTT", conventional PAT, and cuff BP in humans during interventions that increased BP but changed PEP and smooth muscle contraction differently. Scale PTT tracked the diastolic BP changes well, with correlation coefficient of -0.80 +/- 0.02 (mean +/- SE) and root-mean squared-error of 7.6 +/- 0.5 mmHg after a best-case calibration. Conventional PAT was significantly inferior in tracking these changes, with correlation coefficient of -0.60 +/- 0.04 and root-mean-squared-error of 14.6 +/- 1.5 mmHg (p < 0.05). Scale PTT also tracked the systolic BP changes better than conventional PAT but not to an acceptable level. With further development, scale PTT may permit reliable, convenient measurement of BP. PMID- 27976745 TI - The December 2015 North Pole Warming Event and the Increasing Occurrence of Such Events. AB - In late December 2015, widespread media interest revolved around forecasts that the surface air temperature at the North Pole would rise above freezing. Although there has been significant interest in the enhanced warming that is occurring at high northern latitudes, a process known as arctic amplification, remarkably little is known about these midwinter warming events at the pole including their frequency, duration and magnitude as well as the environmental conditions responsible for their occurrence. Here we use buoy and radiosonde data along with operational weather forecasts and atmospheric reanalyses to show that such events are associated with surface cyclones near the pole as well as a highly perturbed polar vortex. They occur once or twice each decade with the earliest identified event taking place in 1959. In addition, the warmest midwinter temperatures at the North Pole have been increasing at a rate that is twice as large as that for mean midwinter temperatures at the pole. It is argued that this enhanced trend is consistent with the loss of winter sea ice from the Nordic Seas that moves the reservoir of warm air over this region northwards making it easier for weather systems to transport this heat polewards. PMID- 27976742 TI - Increased Fetal Thymocytes Apoptosis Contributes to Prenatal Nicotine Exposure induced Th1/Th2 Imbalance in Male Offspring Mice. AB - Nicotine, a definite risk factor during pregnancy, is an immunomodulator. This study was designed to investigate the effects of prenatal nicotine exposure (PNE) on the balance of Th1/Th2 in offspring, and further explore the developmental origin mechanisms from the perspective of fetal thymocytes apoptosis. Pregnant Balb/c mice were administered 1.5 mg/kg nicotine subcutaneously twice per day from gestational day (GD) 9 to GD18. Results showed that PNE could cause a Th2 shift in male offspring, manifested as increased ratio of IgG1/IgG2a, IL-4 production in serum, and IL-4/IFN-gamma expression ratio in spleen. Increased apoptosis of total thymocytes and CD4SP and reduced cell proportion of CD4SP were found in PNE male offspring on postnatal day (PND) 14 and PND 49. In the fetuses, decreased body weight and organ index of fetal thymus, histological changes in fetal thymus, reduced CD4SP proportion and increased fetal thymocyte apoptosis were observed in nicotine group. The increased mRNA expression of genes involved in Fas-mediated apoptotic pathway and protein expression of Fas were also detected. In conclusion, PNE could cause a Th2 shift in male offspring mediated by reduced CD4+ T cells output, which may result from the increasing apoptosis of total thymocytes and CD4SP. PMID- 27976743 TI - Microcystin-Leucine Arginine Causes Cytotoxic Effects in Sertoli Cells Resulting in Reproductive Dysfunction in Male Mice. AB - Microcystin-leucine arginine (MC-LR) is a potent toxin for Sertoli cells. However, the specific molecular mechanisms of MC-induced cytotoxicity still remain unclear. In this study, we performed a comprehensive analyses of changes of miRNAs and mRNAs in Sertoli cells treated with MC-LR. Through computational approaches, we showed the pivotal roles of differentially expressed miRNAs that were associated with cell metabolism, cellular growth and proliferation, cell-to cell signaling and interaction and cellular movement. Ingenuity Pathway Analyses (IPA) revealed some differentially expressed miRNAs and mRNAs that may cause reproductive system diseases. Target gene analyses suggested that destruction in tight junctions (TJ) and adherens junctions (AJ) in testes may be mediated by miRNAs. Consistent with a significant enrichment of chemokine signaling pathways, we observed numerous macrophages in the testes of mice following treatment with MC-LR, which may cause testicular inflammation. Moreover, miR-98-5p and miR-758 were predicted to bind the 3'-UTR region of the mitogen-activated protein kinase 11 (MAPK11, p38 beta isoform) gene which stimulates tumor necrosis factor-alpha (TNF-alpha) expression in Sertoli cells. TNF-alpha could interact with the tumor necrosis factor receptor 1 (TNFR1) on germ cells leading to induction of germ cell apoptosis. Collectively, our integrated miRNA/mRNA analyses provided a molecular paradigm, which was experimentally validated, for understanding MC-LR induced cytotoxicity. PMID- 27976744 TI - Low-affinity CD4+ T cells are major responders in the primary immune response. AB - A robust primary immune response has been correlated with the precursor number of antigen-specific T cells, as identified using peptide MHCII tetramers. However, these tetramers identify only the highest-affinity T cells. Here we show the entire CD4+ T-cell repertoire, inclusive of low-affinity T cells missed by tetramers, using a T-cell receptor (TCR) signalling reporter and micropipette assay to quantify naive precursors and expanded populations. In vivo limiting dilution assays reveal hundreds more precursor T cells than previously thought, with higher-affinity tetramer-positive T cells, comprising only 5-30% of the total antigen-specific naive repertoire. Lower-affinity T cells maintain their predominance as the primary immune response progresses, with no enhancement of survival of T cells with high-affinity TCRs. These findings demonstrate that affinity for antigen does not control CD4+ T-cell entry into the primary immune response, as a diverse range in affinity is maintained from precursor through peak of T-cell expansion. PMID- 27976746 TI - Real-time detection of dielectric anisotropy or isotropy in unconventional oil gas reservoir rocks supported by the oblique-incidence reflectivity difference technique. AB - Current geological extraction theory and techniques are very limited to adequately characterize the unconventional oil-gas reservoirs because of the considerable complexity of the geological structures. Optical measurement has the advantages of non-interference with the earth magnetic fields, and is often useful in detecting various physical properties. One key parameter that can be detected using optical methods is the dielectric permittivity, which reflects the mineral and organic properties. Here we reported an oblique-incidence reflectivity difference (OIRD) technique that is sensitive to the dielectric and surface properties and can be applied to characterization of reservoir rocks, such as shale and sandstone core samples extracted from subsurface. The layered distribution of the dielectric properties in shales and the uniform distribution in sandstones are clearly identified using the OIRD signals. In shales, the micro cracks and particle orientation result in directional changes of the dielectric and surface properties, and thus, the isotropy and anisotropy of the rock can be characterized by OIRD. As the dielectric and surface properties are closely related to the hydrocarbon-bearing features in oil-gas reservoirs, we believe that the precise measurement carried with OIRD can help in improving the recovery efficiency in well-drilling process. PMID- 27976747 TI - Evidence for spin-to-charge conversion by Rashba coupling in metallic states at the Fe/Ge(111) interface. AB - The spin-orbit coupling relating the electron spin and momentum allows for spin generation, detection and manipulation. It thus fulfils the three basic functions of the spin field-effect transistor. However, the spin Hall effect in bulk germanium is too weak to produce spin currents, whereas large Rashba effect at Ge(111) surfaces covered with heavy metals could generate spin-polarized currents. The Rashba spin splitting can actually be as large as hundreds of meV. Here we show a giant spin-to-charge conversion in metallic states at the Fe/Ge(111) interface due to the Rashba coupling. We generate very large charge currents by direct spin pumping into the interface states from 20 K to room temperature. The presence of these metallic states at the Fe/Ge(111) interface is demonstrated by first-principles electronic structure calculations. By this, we demonstrate how to take advantage of the spin-orbit coupling for the development of the spin field-effect transistor. PMID- 27976748 TI - A simple and low-cost combustion method to prepare monoclinic VO2 with superior thermochromic properties. AB - In this approach, the VO2 nanoparticles have been successfully fabricated via combusting the low-cost precursor solution consisted of NH4VO3, C2H6O2 and C2H5OH. By the XRD, TEM and XPS analysis, it can be found that the synthetic monoclinic VO2 is single crystal and no impurity is defined. After dispersing the VO2 nanoparticles into the polymer, the solar modulation of VO2-based composite film is up to 12.5% with luminous transmission and haze around 62.2% and 0.5%, respectively. In other words, the composite films show high performance of thermochromic properties. This could open an efficient way to fabricate low-cost and large-scale VO2 (M) nanoparticles and thermochromic films. PMID- 27976749 TI - Nonlinear plasmonic dispersion and coupling analysis in the symmetric graphene sheets waveguide. AB - We study the nonlinear dispersion and coupling properties of the graphene-bounded dielectric slab waveguide at near-THz/THz frequency range, and then reveal the mechanism of symmetry breaking in nonlinear graphene waveguide. We analyze the influence of field intensity and chemical potential on dispersion relation, and find that the nonlinearity of graphene affects strongly the dispersion relation. As the chemical potential decreases, the dispersion properties change significantly. Antisymmetric and asymmetric branches disappear and only symmetric one remains. A nonlinear coupled mode theory is established to describe the dispersion relations and its variation, which agrees with the numerical results well. Using the nonlinear couple model we reveal the reason of occurrence of asymmetric mode in the nonlinear waveguide. PMID- 27976750 TI - COMPASS: Continuous Open Mouse Phenotyping of Activity and Sleep Status. AB - Background Disruption of rhythms in activity and rest occur in many diseases, and provide an important indicator of healthy physiology and behaviour. However, outside the field of sleep and circadian rhythm research, these rhythmic processes are rarely measured due to the requirement for specialised resources and expertise. Until recently, the primary approach to measuring activity in laboratory rodents has been based on voluntary running wheel activity. By contrast, measuring sleep requires the use of electroencephalography (EEG), which involves invasive surgical procedures and time-consuming data analysis. Methods Here we describe a simple, non-invasive system to measure home cage activity in mice based upon passive infrared (PIR) motion sensors. Careful calibration of this system will allow users to simultaneously assess sleep status in mice. The use of open-source tools and simple sensors keeps the cost and the size of data files down, in order to increase ease of use and uptake. Results In addition to providing accurate data on circadian activity parameters, here we show that extended immobility of >40 seconds provides a reliable indicator of sleep, correlating well with EEG-defined sleep (Pearson's r >0.95, 4 mice). Conclusions Whilst any detailed analysis of sleep patterns in mice will require EEG, behaviourally-defined sleep provides a valuable non-invasive means of simultaneously phenotyping both circadian rhythms and sleep. Whilst previous approaches have relied upon analysis of video data, here we show that simple motion sensors provide a cheap and effective alternative, enabling real-time analysis and longitudinal studies extending over weeks or even months. The data files produced are small, enabling easy deposition and sharing. We have named this system COMPASS - Continuous Open Mouse Phenotyping of Activity and Sleep Status. This simple approach is of particular value in phenotyping screens as well as providing an ideal tool to assess activity and rest cycles for non specialists. PMID- 27976752 TI - Erratum to: The SABRTooth feasibility trial protocol: a study to determine the feasibility and acceptability of conducting a phase III randomised controlled trial comparing stereotactic ablative radiotherapy (SABR) with surgery in patients with peripheral stage I non-small cell lung cancer (NSCLC) considered to be at higher risk of complications from surgical resection. AB - [This corrects the article DOI: 10.1186/s40814-016-0046-2.]. PMID- 27976751 TI - Hepitopes: A live interactive database of HLA class I epitopes in hepatitis B virus. AB - Increased clinical and scientific scrutiny is being applied to hepatitis B virus (HBV), with focus on the development of new therapeutic approaches, ultimately aiming for cure. Defining the optimum natural CD8+ T cell immune responses that arise in HBV, mediated by HLA class I epitope presentation, may help to inform novel immunotherapeutic strategies. Therefore, we have set out to develop a comprehensive database of these epitopes in HBV, coined 'Hepitopes'. This undertaking has its foundations in a systematic literature review to identify the sites and sequences of all published class I epitopes in HBV. We also collected information regarding the methods used to define each epitope, and any reported associations between an immune response to this epitope and disease outcome. The results of this search have been collated into a new open-access interactive database that is available at http://www.expmedndm.ox.ac.uk/hepitopes. Over time, we will continue to refine and update this resource, as well as inviting contributions from others in the field to support its development. This unique new database is an important foundation for ongoing investigations into the nature and impact of the CD8+ T cell response to HBV. PMID- 27976753 TI - Sparsity and Biomechanics Inspired Integration of Shape and Speckle Tracking for Cardiac Deformation Analysis. AB - Cardiac motion analysis, particularly of the left ventricle (LV), can provide valuable information regarding the functional state of the heart. We propose a strategy of combining shape tracking and speckle tracking based displacements to calculate the dense deformation field of the myocardium. We introduce the use and effects of l1 regularization, which induces sparsity, in our integration method. We also introduce regularization to make the dense fields more adhering to cardiac biomechanics. Finally, we motivate the necessity of temporal coherence in the dense fields and demonstrate a way of doing so. We test our method on ultrasound (US) images acquired from six open-chested canine hearts. Baseline and post-occlusion strain results are presented for an animal, where we were able to detect significant change in the ischemic region. Six sets of strain results were also compared to strains obtained from tagged magnetic resonance (MR) data. Median correlation (with MR-tagging) coefficients of 0.73 and 0.82 were obtained for radial and circumferential strains respectively. PMID- 27976754 TI - Engaging Students in Science Courses: Lessons of Change from the Arctic. AB - Where you live should have something to do with what you teach. In the Arctic, this idea of place-based education-teaching and sharing knowledge that is needed to live well- is central to the UARCTIC consortium and the 4th International Polar Year educational reform effort. A place-based issue oriented context can engage students in chemistry concepts when it intersects with their experience and lives. This article examines the rationale and means of integrating local concerns such as world view, culture, traditional knowledge and policy into both general and specialized chemistry courses. More broadly, capacious place-based issues should be widely adapted by all curriculum reform efforts to demonstrate the connectivity between science and societal understanding of technological options. A case in point is the inclusion of indigenous perspectives in a non majors general chemistry course when the concepts of scientific method, ice and water resources, genetic engineering, etc. are discussed. In a specialized course on radioactivity in the north, topics connected nuclear chemistry and radioactivity to people and energy. The local landscape should be central to science courses and involve issues relevant to stewardship, a component of the indigenous world view. The historical issues can be connected to current nuclear energy and uranium mining as they relate to the risks and benefits for the local community. This article will make the case that curriculum reform that focuses on real-world topics will not only engage students so that they perform well in class but also spark their interest so that they continue learning after the course is over. PMID- 27976755 TI - Erratum to: Methods and processes for development of a CONSORT extension for reporting pilot randomized controlled trials. AB - [This corrects the article DOI: 10.1186/s40814-016-0065-z.]. PMID- 27976756 TI - Quantitative cross-linking/mass spectrometry reveals subtle protein conformational changes. AB - Quantitative cross-linking/mass spectrometry (QCLMS) probes protein structural dynamics in solution by quantitatively comparing the yields of cross-links between different conformational statuses. We have used QCLMS to understand the final maturation step of the proteasome lid and also to elucidate the structure of complement C3(H2O). Here we benchmark our workflow using a structurally well described reference system, the human complement protein C3 and its activated cleavage product C3b. We found that small local conformational changes affect the yields of cross-linking residues that are near in space while larger conformational changes affect the detectability of cross-links. Distinguishing between minor and major changes required robust analysis based on replica analysis and a label-swapping procedure. By providing workflow, code of practice and a framework for semi-automated data processing, we lay the foundation for QCLMS as a tool to monitor the domain choreography that drives binary switching in many protein-protein interaction networks. PMID- 27976758 TI - Double electron-electron resonance with multiple non-selective chirp refocusing. AB - A new approach to double electron-electron resonance (DEER) for distance determination involving nitroxide spin labels at dilute concentrations is presented. In general, DEER pulse sequences rely on double resonance between pump and observer spins excited by selective pulses at two distinct microwave frequencies. In the new approach abbreviated as nDEER, non-selective chirp pulses that refocus all relevant spin pairs are combined with DEER. This non-selective refocusing results in suppression of unmodulated contributions, such as the constant contribution as well as the background curvature due to inter-molecular spin partners in ordinary DEER data. Due to this dipolar attenuation effect, primary nDEER data are closer to the dipolar modulation of primary interest than ordinary DEER data. Restrictions of nDEER are that secondary information related to these unmodulated contributions becomes difficult to retrieve. Accordingly, incomplete deconvolution of the inter-molecular background prevents the application of nDEER to rigid spin pairs at high concentrations. A key advantage of nDEER is the high fidelity of the chirp refocusing pulses, which is important for nDEER schemes that incorporate dynamical decoupling to access longer distances. In this context, nDEER with Carr-Purcell (CP) pulse trains having N = 2 and N = 4 refocusing pulses are demonstrated. These CP nDEER sequences require a total of N + 2 pulses, which is less than the 2N + 1 pulses required for CP DEER schemes. The pump pulse position is incremented throughout the refocusing pulses, which restricts the minimum time increment to 96 ns on our spectrometer and therefore complicates application to distances below 3 nm. At Q-band frequencies, unwanted modulations related to pulse imperfections contribute only 3.5% relative to the principal nDEER modulation. Accordingly, there is no need for dedicated data reconstruction methods as in CP DEER methods. PMID- 27976757 TI - Efficient and versatile CRISPR engineering of human neurons in culture to model neurological disorders. AB - The recent identification of multiple new genetic causes of neurological disorders highlights the need for model systems that give experimental access to the underlying biology. In particular, the ability to couple disease-causing mutations with human neuronal differentiation systems would be beneficial. Gene targeting is a well-known approach for dissecting gene function, but low rates of homologous recombination in somatic cells (including neuronal cells) have traditionally impeded the development of robust cellular models of neurological disorders. Recently, however, CRISPR/Cas9 gene editing technologies have expanded the number of systems within which gene targeting is possible. Here we adopt as a model system LUHMES cells, a commercially available diploid human female mesencephalic cell line that differentiates into homogeneous mature neurons in 1 2 weeks. We describe optimised methods for transfection and selection of neuronal progenitor cells carrying targeted genomic alterations using CRISPR/Cas9 technology. By targeting the endogenous X-linked MECP2 locus, we introduced four independent missense mutations that cause the autism spectrum disorder Rett syndrome and observed the desired genetic structure in 3-26% of selected clones, including gene targeting of the inactive X chromosome. Similar efficiencies were achieved by introducing neurodevelopmental disorder-causing mutations at the autosomal EEF1A2 locus on chromosome 20. Our results indicate that efficiency of genetic "knock-in" is determined by the location of the mutation within the donor DNA molecule. Furthermore, we successfully introduced an mCherry tag at the MECP2 locus to yield a fusion protein, demonstrating that larger insertions are also straightforward in this system. We suggest that our optimised methods for altering the genome of LUHMES cells make them an attractive model for the study of neurogenetic disorders. PMID- 27976759 TI - The nanoscience behind the art of in-meso crystallization of membrane proteins. AB - The structural changes occurring at the nanoscale level within the lipid bilayer and driving the in-meso formation of large well-diffracting membrane protein crystals have been uniquely characterized for a model membrane protein, intimin. Importantly, the order to order transitions taking place within the bilayer and the lipidic nanostructures required for crystal growth have been shown to be general, occurring for both the cubic and the sponge mesophase crystallization pathways. For the first time, a transient fluid lamellar phase has been observed and unambiguously assigned for both crystallization pathways, present at the earliest stages of protein crystallogenesis but no longer observed once the crystals surpass the size of the average lyotropic liquid crystalline domain. The reported time-resolved structural investigation provides a significantly improved and general understanding of the nanostructural changes taking place within the mesophase during in-meso crystallization which is a fundamental advance in the enabling area of membrane protein structural biology. PMID- 27976761 TI - A full dimensional potential for H2O2 (X1A) covering all dissociation channels. AB - This work presents a new full dimensional potential energy surface for the ground singlet state of hydrogen peroxide, H2O2. This potential is based on a 3 * 3 matrix to accurately reproduce all the different dissociation channels in accordance with the Wigner-Witmer rules, namely, O(1D) + H2O(X1A1), OH(X2Pi) + OH(X2Pi), O2(a1Deltag) + H2(X1Sigmag+) e H(2S) + HO2(X2A''). It has been obtained by fitting more than 38 thousand ab initio energies computed using the aug-cc pVTZ and aug-cc-pVQZ basis sets and extrapolated to the basis set limit. The functional form used to represent the four-body short-range interactions is based on a sum of polynomial functions of the fourth degree multiplied by a range factor, both built with intrinsic permutation symmetry and centred at specific reference geometries, to which the ab initio points computed are assigned based on a k-means algorithm. It also accounts for the electrostatic dipole-dipole interaction between two OH(2Pi) fragments. PMID- 27976762 TI - The total and the differential mean pore anisotropy in porous solids and the ranking of pores according to Zipf's law. AB - In this work the property of total pore anisotropy in porous solids is introduced. Its calculation is based on a combination of the specific surface area Sp and the specific pore volume Vp estimated via typical nitrogen porosimetry data and tested in two kinds of porous materials: a group of spinels CoAl2O4 with differentiated random porosities and a second group of silicas SiO2 with ordered porosity modulated by the addition of LaFeO3 nanoparticles. Two basic complementary expressions of total pore anisotropy were estimated: (i) the specific total mean pore anisotropy bmean,total = (N.b) ~ [Sp3]/[Vp2] corresponding to the total anisotropy value of all N hypothetical similar pores in one gram of a solid with mean size Dmean = 4Vp/Sp and anisotropy b = Ltotal/Dmean. The bmean,total takes a unique value for each particular porous material. (ii) The specific differential mean pore anisotropies bmean,diff = (Ni.bi) ~ [Spi3]/[Vpi2] corresponding to the spectrum of partial anisotropy values bmean,diff = Li/Di of Ni pores with similar size Di = 4Vi/Si possessing differential pore volume Vpi and differential specific surface area Spi. The bmean diff takes different values at each particular partial pressure and exhibits a distribution as a function of pore radius bmean,diff = f(ri). It is shown that plots of log(bmean,diff) = f(log(ri)) lead to the ranking of pores according to the Zipf's law log(Ni) = A - B log(Vpi). This ranking is not obeyed by the pores exhibiting appreciable local pore anisotropy. PMID- 27976760 TI - Benzimidazopurine nucleosides from N6-aryl adenosine derivatives by PhI(OAc)2 mediated C-N bond formation, no metal needed. AB - The reaction of a variety of N6-aryl 2'-deoxyadenosine and adenosine derivatives with PhI(OAc)2 in 1,1,1,3,3,3-hexafluoro-2-propanol provides a facile access to benzimidazopurine nucleoside analogues by metal-free C-N bond formation with a purinyl nitrogen atom. These reactions likely proceed via radical-cation/radical processes as indicated by radical inhibition experiments. PMID- 27976763 TI - What will freestanding borophene nanoribbons look like? An analysis of their possible structures, magnetism and transport properties. AB - We report a density-functional theory study of the stability and electronic structure of two recently proposed borophene sheets with Pmmn symmetry and nonzero thickness. We then investigate nanoribbons (BNRs) derived from these nanostructures, with particular attention to technologically relevant properties like magnetism and electronic transport. We consider two perpendicular directions for the edges of the stripes as well as different lateral widths. We show that the Pmmn8 sheet, with 8 atoms in its unit cell and generated by two interpenetrating lattices, has a larger binding energy than the Pmmn2 sheet, with only 2 atoms per unit cell. We also use their phonon spectra to show that the mechanical stability of the Pmmn8 sheet is superior to that of the Pmmn2 sheet. Nanoribbons derived from Pmmn8 are not only more stable than those derived from Pmmn2, but also more interesting from the technological point of view. We find a rich variety of magnetic solutions, depending on the borophene "mother structure", edge orientation, width and, in the case of Pmmn8-derived BNRs, the sublattice of edge atoms. We show that one can build BNRs with magnetic moment in both, one or none of the edges, as well as with parallel or antiparallel magnetic coupling between the edges when magnetic; moreover, their electronic character can be semiconducting, metallic or half-metallic, creating a perfect spin valve at low bias. These different behaviors are reflected in their densities of states, spin density and electronic transport coefficients, which are analyzed in detail. Our work provides a complete overview of what one may expect if nanoribbons are cut out from Pmmn sheets with a view to potential technological applications. PMID- 27976765 TI - Controlling disorder in the ZnGa2O4:Cr3+ persistent phosphor by Mg2+ substitution. AB - We have studied in this work the effect of increasing structural disorder on the persistent luminescence of a Cr3+ doped zinc gallate spinel. This disorder was introduced by progressive substitution of Zn2+ by Mg2+ ions, and was studied by photoluminescence, X-ray diffraction, extended X-ray absorption fine structure (EXAFS), X-ray absorption near edge structure (XANES) and electron paramagnetic resonance (EPR) spectroscopy. It was found that increasing the Mg/Zn substitution decreases the number of Cr3+ in undistorted sites and increases the number of Cr3+ with neighbouring antisite defects and with neighbouring Cr3+ ions (referred to as Cr clusters), which in turn decreases the intensity of persistent luminescence. Both XANES and EPR spectra could be simulated by a linear combination of Cr3+ spectra with three types of Cr3+ environments. The increasing disorder was found to be correlated with a decrease of the average Cr-O bond length and a decrease of crystal field strength experienced by Cr3+ ions. PMID- 27976766 TI - CO2 capture in ionic liquid 1-alkyl-3-methylimidazolium acetate: a concerted mechanism without carbene. AB - Ionic liquids (ILs) provide a promising medium for CO2 capture. Recently, the family of ILs comprising imidazolium-based cations and acetate anions, such as 1 ethyl-3-methylimidazolium acetate (EMI+OAc-), has been found to react with CO2 and form carboxylate compounds. N-Heterocyclic carbene (NHC) is widely assumed to be responsible by directly reacting with CO2 though NHC has not been detected in these ILs. Herein, a computational analysis of CO2 capture in EMI+OAc- is presented. Quantum chemistry calculations predict that NHC is unstable in a polar environment, suggesting that NHC is not formed in EMI+OAc-. Ab initio molecular dynamics simulations indicate that an EMI+ ion "activated" by the approach of a CO2 molecule can donate its acidic proton to a neighboring OAc- anion and form a carboxylate compound with the CO2 molecule. Analysis of this termolecular process indicates that the EMI+-to-OAc- proton transfer and the formation of 1-ethyl-3 methylimidazolium-2-carboxylate occur essentially concurrently. Based on these findings, a novel concerted mechanism that does not involve NHC is proposed for CO2 capture. PMID- 27976764 TI - Development of magneto-plasmonic nanoparticles for multimodal image-guided therapy to the brain. AB - Magneto-plasmonic nanoparticles are one of the emerging multi-functional materials in the field of nanomedicine. Their potential for targeting and multi modal imaging is highly attractive. In this study, magnetic core/gold shell (MNP@Au) magneto-plasmonic nanoparticles were synthesized by citrate reduction of Au ions on magnetic nanoparticle seeds. Hydrodynamic size and optical properties of magneto-plasmonic nanoparticles synthesized with the variation of Au ions and reducing agent concentrations were evaluated. The synthesized magneto-plasmonic nanoparticles exhibited superparamagnetic properties, and their magnetic properties contributed to the concentration-dependent contrast in magnetic resonance imaging (MRI). The imaging contrast from the gold shell part of the magneto-plasmonic nanoparticles was also confirmed by X-ray computed tomography (CT). The transmigration study of the magneto-plasmonic nanoparticles using an in vitro blood-brain barrier (BBB) model proved enhanced transmigration efficiency without disrupting the integrity of the BBB, and showed potential to be used for brain diseases and neurological disorders. PMID- 27976767 TI - Gold-silver@TiO2 nanocomposite-modified plasmonic photoanodes for higher efficiency dye-sensitized solar cells. AB - In the present investigation, gold-silver@titania (Au-Ag@TiO2) plasmonic nanocomposite materials with different Au and Ag compositions were prepared using a simple one-step chemical reduction method and used as photoanodes in high efficiency dye-sensitized solar cells (DSSCs). The Au-Ag incorporated TiO2 photoanode demonstrated an enhanced solar-to-electrical energy conversion efficiency of 7.33%, which is ~230% higher than the unmodified TiO2 photoanode (2.22%) under full sunlight illumination (100 mW cm-2, AM 1.5G). This superior solar energy conversion efficiency was mainly due to the synergistic effect between the Au and Ag, and their surface plasmon resonance effect, which improved the optical absorption and interfacial charge transfer by minimizing the charge recombination process. The influence of the Au-Ag composition on the overall energy conversion efficiency was also explored, and the optimized composition with TiO2 was found to be Au75-Ag25. This was reflected in the femtosecond transient absorption dynamics in which the electron-phonon interaction in the Au nanoparticles was measured to be 6.14 ps in TiO2/Au75:Ag25, compared to 2.38 ps for free Au and 4.02 ps for TiO2/Au100:Ag0. The slower dynamics indicates a more efficient electron-hole separation in TiO2/Au75:Ag25 that is attributed to the formation of a Schottky barrier at the interface between TiO2 and the noble metal(s) that acts as an electron sink. The significant boost in the solar energy conversion efficiency with the Au-Ag@TiO2 plasmonic nanocomposite showed its potential as a photoanode for high-efficiency DSSCs. PMID- 27976768 TI - Dynamics of a bioinert polymer in hydrated states by dielectric relaxation spectroscopy. AB - The chain dynamics of well-defined poly(2-methoxyethyl acrylate) (PMEA), which has been used in practice as a bioinert coating for heart-lung machines, was examined as a function of water content by dielectric relaxation spectroscopy (DRS). Two relaxation processes observed in both dried and hydrated films were assigned to the segmental motion (alpha-process) and the relatively smaller scale motion such as the hindered rotation of side chains (beta-process). Water molecules adsorbed on PMEA made the alpha-process faster, meaning that water molecules in PMEA played the role of a plasticizer. Combining the above knowledge with the depth dependence of water content in the PMEA film previously obtained by neutron reflectivity, the segmental dynamics of PMEA at the water interface, which should be crucial to bio-inertness, is discussed. We found that the segmental motion was markedly faster than that in the bulk and almost comparable to the side chain motion. PMID- 27976769 TI - Soft nanoparticles: nano ionic networks of associated ionic polymers. AB - Directing the formation of nanostructures that serve as building blocks of membranes presents an immense step towards engineering controlled polymeric ion transport systems. Using the exquisite atomic detail captured by molecular dynamics simulations, we follow the assembly of a co-polymer that consists of polystyrene sulfonate tethered symmetrically to hydrophobic blocks, realizing a new type of long lived solvent-responsive soft nanoparticle. PMID- 27976770 TI - Synthesis and physical chemical properties of 2-amino-4 (trifluoromethoxy)butanoic acid - a CF3O-containing analogue of natural lipophilic amino acids. AB - 2-Amino-2-(trifluoromethoxy)butanoic acid (O-trifluoromethyl homoserine) was synthesized as a racemate and in both enantiomeric forms. The measured pKa and log D values establish the compound as a promising analogue of natural aliphatic amino acids. PMID- 27976771 TI - NiMn layered double hydroxides as efficient electrocatalysts for the oxygen evolution reaction and their application in rechargeable Zn-air batteries. AB - High performance catalysts for the oxygen evolution reaction (OER) are in demand to improve the re-chargeability of Zn-air batteries. In this work, atomically dispersed NiMn layered double hydroxides are prepared via simple hydrothermal synthesis and tested as the OER catalyst in rechargeable Zn-air batteries. NiMn layered double hydroxides with the optimized Ni : Mn molar feeding ratio have good crystallinity, big interlayer spacing, and large surface area, which are beneficial to enhance their catalytic activity. They are highly active and stable during the OER, showing an overpotential of 0.35 V, a Tafel slope of 40 mV dec-1, and remarkable stability during 16 h of a chronopotentiometry test. Rechargeable Zn-air batteries with NiMn layered double hydroxides as the OER catalyst exhibit a low charge voltage of ~2 V which is stable for up to 200 cycles. This study illustrates a platform to enhance the catalytic activity of the OER catalyst via fine-tuning the composition and physical properties of the materials and their application for rechargeable metal-air batteries. PMID- 27976772 TI - Scalable exfoliation and dispersion of two-dimensional materials - an update. AB - The preparation of dispersions of single- and few-sheet 2D materials in various solvents, as well as the characterization methods applied to such dispersions, is critically reviewed. Motivating factors for producing single- and few-sheet dispersions of 2D materials in liquids are briefly discussed. Many practical applications are expected for such materials that do not require high purity formulations and tight control of donor and acceptor concentrations, as required in conventional Fab processing of semiconductor chips. Approaches and challenges encountered in exfoliating 2D materials in liquids are reviewed. Ultrasonication, mechanical shearing, and electrochemical processing approaches are discussed, and their respective limitations and promising features are critiqued. Supercritical and more conventional liquid and solvent processing are then discussed in detail. The effects of various types of stabilizers, including surfactants and other amphiphiles, as well as polymers, including homopolymeric electrolytes, nonionic polymers, and nanolatexes, are discussed. Consideration of apparent successes of stabilizer-free dispersions indicates that extensive exfoliation in the absence of dispersing aids results from processing-induced surface modifications that promote stabilization of 2D material/solvent interactions. Also apparent paradoxes in "pristineness" and optical extinctions in dispersions suggest that there is much we do not yet quantitatively understand about the surface chemistry of these materials. Another paradox, emanating from modeling dilute solvent-only exfoliation by sonication using polar components of solubility parameters and surface tension for pristine graphene with no polar structural component, is addressed. This apparent paradox appears to be resolved by realizing that the reactivity of graphene to addition reactions of solvent radicals produced by sonolysis is accompanied by unintended polar surface modifications that promote attractive interactions with solvent. This hypothesis serves to define important theoretical and experimental studies that are needed. We conclude that the greatest promise for high volume and high concentration processing lies in applying methods that have not yet been extensively reported, particularly wet comminution processing using small grinding media of various types. PMID- 27976773 TI - Direct synthesis of gamma-pyrones by electrophilic condensation of beta ketoesters. AB - Triflic anhydride is a versatile electrophile that is able to activate poor nucleophiles. Herein, we show that readily available beta-keto esters are activated by Tf2O furnishing gamma-pyrones. Mechanistic studies suggest that this transformation proceeds via a double triflation, formation of an oxocarbenium intermediate and dealkylation promoted by a crucial nitrile additive. PMID- 27976774 TI - Multiple-wavelength surface patterns in models of biological chiral liquid crystal membranes. AB - We present a model to investigate the formation of surface patterns in biological materials through the interaction of anisotropic interfacial tension, bending elasticity, and capillarity at their free surfaces. Focusing on the cholesteric liquid crystal (CLC) material model, the generalized shape equation for anisotropic interfaces using the Rapini-Papoular anchoring and Helfrich free energies is applied to understand the formation of multi-length scale patterns, such as those found in floral petals. The chiral liquid crystal-membrane model is shown to be analogous to a driven pendulum, a connection that enables generic pattern classification as a function of bending elasticity, liquid crystal chirality and anchoring strength. The unique pattern-formation mechanism emerging from the model here presented is based on the nonlinear interaction between bending-driven folding and anchoring-driven creasing. The predictions are shown to capture accurately the two-scale wrinkling of certain tulips. These new findings enable not only to establish a new paradigm for characterizing surface wrinkling in biological liquid crystals, but also to inspire the design of functional surface structures. PMID- 27976776 TI - Probing the adhesion properties of alginate hydrogels: a new approach towards the preparation of soft colloidal probes for direct force measurements. AB - The adhesion of alginate hydrogels to solid surfaces was probed by atomic force microscopy (AFM) in the sphere/plane geometry. For this purpose a novel approach has been developed for the immobilization of soft colloidal probes onto AFM cantilevers, which is inspired by techniques originating from cell biology. The aspiration and consecutive manipulation of hydrogel beads by micropipettes allows the entire manipulation sequence to be carried-out in situ. Hence, any alteration of the hydrogel beads upon drying can be excluded. The adhesive behaviour of alginate hydrogels was first evaluated by determining the distribution of pull off forces on self-assembled monolayers (SAMs) terminating in different functional groups (-CH3, -OH, -NH2, -COOH). It was demonstrated that solvent exclusion plays practically no role in the adhesion process, in clear difference to solid colloidal probes. The adhesion of alginate beads is dominated by chemical interactions rather than solvent exclusion, in particular in the case of amino-terminated SAMs. The data set acquired on the SAMs provided the framework to relate the adhesion of alginate beads on recombinant spider silk protein films to specific functional groups. The preparation of soft colloidal probes and the presented approach in analysing the adhesive behaviour is not limited to alginate hydrogel beads but can be generally applied for probing and understanding the adhesion behaviour of hydrogels on a wide range of substrates, which would be relevant for various applications such as biomedical surface modification or tissue engineering. PMID- 27976775 TI - Complexation and synergistic boundary lubrication of porcine gastric mucin and branched poly(ethyleneimine) in neutral aqueous solution. AB - Lubrication of soft polydimethylsiloxane (PDMS) elastomer interfaces was studied in aqueous mixtures of porcine gastric mucin (PGM) and branched polyethyleneimine (b-PEI) at neutral pH and various ionic strengths (0.1-1.0 M). While neither PGM nor b-PEI improved lubrication compared to polymer-free buffer solution, their mixtures produced a synergistic lubricating effect by reducing friction coefficients by nearly two orders of magnitude, especially at slow sliding speed in the boundary lubrication regime. An array of spectroscopic studies revealed that small cationic b-PEI molecules were able to strongly bind and penetrate into large anionic PGM molecules, producing an overall contraction of the randomly coiled PGM conformation. The interaction also affected the structure of the folded PGM protein terminals, decreased the surface potential and increased light absorbance in PGM:b-PEI mixtures. Adding an electrolyte (NaCl) weakened the aggregation between PGM and b-PEI, and degraded the lubrication synergy, indicating that electrostatic interactions drive PGM:b-PEI complexation. PMID- 27976777 TI - Arginine-induced porphyrin-based self-assembled nanostructures for photocatalytic applications under simulated sunlight irradiation. AB - In this communication, we have investigated the arginine-induced fabrication of porphyrin (TCPP)-based supramolecular nanostructures. These self-assembled porphyrin nanostructures such as nanobelts show enhanced photocatalytic activity for the photodegradation of pollutant Rhodamine B under simulated visible-light irradiation. PMID- 27976778 TI - Reaction of phosphinylated nitrosoalkenes with electron-rich heterocycles. Electrophilic aromatic substitution vs. cycloaddition. AB - The behavior of phosphinyl nitrosoalkenes with indole, pyrrole and 2,5 dimethylpyrrole is described. The reaction of nitrosoalkenes with indole leads to the formation of 3-substituted indoles. While a concerted asynchronous [4 + 2] cycloaddition process may explain the formation of 3-substituted indole when a methyl group is present at the 3-position of nitrosoalkene, the presence of a 3 methoxycarbonyl group at the same position of nitrosoalkene increases its electrophilic character, and both mechanisms, an electrophilic aromatic substitution and a [4 + 2] cycloaddition process, are predicted to be competitive, although thermodynamically the cycloaddition is favoured. Phosphinyl nitrosoalkenes react with pyrrole leading to the corresponding 2-substituted pyrroles, while the treatment of 2,5-dimethylpyrrole with these nitrosoalkenes gives rise to the formation of bicyclic 1,2-oxazines. The mechanism of the reaction of phosphinyl nitrosoalkenes with pyrrole and 2,5-dimethylppyrrole may be explained by an initial hetero-Diels-Alder cycloaddition in both cases, but only subsequent rearomatization in the case of pyrrole. Theoretical studies show very good agreement with the experimental findings and the proposed mechanisms. PMID- 27976779 TI - Parietin: an efficient photo-screening pigment in vivo with good photosensitizing and photodynamic antibacterial effects in vitro. AB - The photophysical, photoinduced pro-oxidant and antibacterial properties in vitro of the natural occurring parietin (PTN; 1,8-dihydroxy-3-methoxy-6-methyl-9,10 anthraquinone) were evaluated. PTN was extracted from the lichen identified as Teloschistes flavicans (Sw.) Norm. (Telochistaceae). Results indicate that in chloroform solution, PTN presents spectroscopic features corresponding to an excited-state intramolecular proton-transfer (ESIPT) state with partial keto-enol tautomerization. In argon-saturated solutions, the singlet excited state is poorly fluorescent (PhiF = 0.03), decaying by efficient intersystem crossing to an excited triplet state 3PTN*, as detected by laser-flash photolysis experiments. In the presence of triplet molecular oxygen, the 3PTN* was fully quenched producing singlet molecular oxygen (1O2) with a quantum yield of 0.69. In addition, in buffer solutions, PTN has the ability to also generate a superoxide radical anion (O2-) in a human leukocyte model and its production was enhanced under UVA-Vis irradiation. Finally, the in vitro antibacterial capability of PTN in the dark and under UVA-Vis illumination was compared in microbial cultures of both Gram positive and negative bacteria. As a result, PTN showed promising photo-induced antibacterial activity through the efficient photosensitized generation of both 1O2 and O2- species. Thus, we have demonstrated that PTN, an efficient photo-screening pigment in lichens, is also a good photosensitizer in solution with promising applications in antibacterial photodynamic therapy. PMID- 27976780 TI - A method for the quantification of 8-methoxypsoralen by mass spectrometry for offline extracorporeal photopheresis. AB - BACKGROUND: Extracorporeal photopheresis (ECP) is an efficient method to treat various autoimmune diseases, cutaneous T-cell lymphoma, and graft-versus-host disease. It is based on the ex vivo inactivation of lymphocytes by 8 methoxypsoralen (8-MOP)/UV light treatment. Despite the adhesive, lipophilic nature of 8-MOP, no quality control is established for the ECP procedure. METHODS: We developed a sensitive high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) assay to monitor residual 8-MOP concentration after UVA irradiation in the whole blood supernatant after acetonitrile precipitation. RESULTS: The preanalytical stability of 8-MOP exceeded 7 days, allowing batch mode analysis. Linearity was determined with R2 above 0.99. The 8 MOP concentrations decreased exponentially after UV exposure, with decay constants of 0.0259 in plasma and 0.0528 in saline. The recovery of 8-MOP in photopheresates was about 68%, indicating binding to DNA as well as to plastic structures. UVA induced no 8-MOP fragmentation, but caused self-adducts under extreme conditions (10-fold UV dosage). CONCLUSIONS: Detection of 8-MOP proved to be feasible and demonstrated that the doses were in the pharmaceutically active range. PMID- 27976781 TI - [Towards a positive psychiatry?] PMID- 27976782 TI - [Ethnic differences in forensic psychiatry: an exploratory study at a Dutch forensic psychiatric centre]. AB - BACKGROUND: Compared to the percentage of ethnic minorities in the general population, ethnic minorities are overrepresented in forensic psychiatry. If these minorities are to be treated successfully, we need to know more about this group. So far, however, little is known about the differences between mental disorders and types of offences associated with patients of non-Dutch descent and those associated with patients of Dutch descent.
AIM: To take the first steps to obtain the information we need in order to provide customised care for patients of non-Dutch descent.
METHOD: It proved possible to identify differences between patients of Dutch and non-Dutch descent with regard to treatment, diagnosis and offences committed within a group of patients who were admitted to the forensic psychiatric centre Oostvaarderskliniek during the period 2001 - 2014.
RESULTS: The treatment of patients of non-Dutch descent lasted longer than the treatment of patients of Dutch descent (8.5 year versus 6.6 year). Furthermore, patients from ethnic minority groups were diagnosed more often with schizophrenia (49.1% versus 21.4%), but less often with pervasive developmental disorders or sexual disorders. Patients of non-Dutch descent were more often convicted for sexual crimes where the victim was aged 16 years or older, whereas patients of Dutch descent were convicted of sexual crimes where the victim was under 16.
CONCLUSION: There are differences between patients of Dutch and non-Dutch descent with regard to treatment duration, diagnosis and offences they commit. Future research needs to investigate whether these results are representative for the entire field of forensic psychiatry and to discover the reasons for these differences. PMID- 27976783 TI - [Diagnostics and treatment of autism spectrum disorders in older adults: a study by experts]. AB - BACKGROUND: Empirical research into the diagnostics and treatment of older adults with autism spectrum disorders (ASD) is very limited; so far, only 17 studies have been published. ASD, however, is not confined to child and adult psychiatry. Increasingly, ASD is being identified and treated within the domain of geriatric psychiatry.
AIM: To investigate diagnostic and therapeutic aspects of ASD in older adults, and to obtain insight into how these aspects are related to ageing.
METHOD: Delphi techniques were employed via rounds of questionnaires put to experts; consensus was considered to have been achieved when a minimum of two-thirds of the experts 'agreed' or 'fully agreed' to a statement on a five point scale.
RESULTS: Consensus was achieved for 10 of the 17 statements. According to the experts, older patients with ASD, form a specific group in psychiatry. With regard to diagnosis, there was a consensus that increased attention needs to be given to age-related aspects by linking symptoms more specifically to the patient's phase of life and to the ageing process. In the treatment of older adults with ASD, adjustments need to be made in relation to ageing.
CONCLUSION: This study by experts provides additional starting points for more research into specific topics relating to diagnostic and therapeutic aspects of ASD in geriatric psychiatry; these topics include validation of screening and diagnostic instruments, the adjustment of protocols for treatment, psycho-education and the effects of ageing in patients with ASD. PMID- 27976785 TI - [The importance of neuropsychological assessment for forensic psychiatric evaluations of defendants]. AB - BACKGROUND: In criminal law, increased interest is being shown in brain disorders, cognitive impairment and neuroimaging, particularly in connection with pre-trial reports. In a number of cases the contribution made by neuropsychology to the forensic diagnosis is considerable, and there is a need for further clarification.
AIM: To clarify the relevance of the neuropsychological assessment of suspects and to explore the implications for forensic psychiatry.
METHOD: We discuss recent literature and present a characteristic case selected from the Dutch jurisdiction.
RESULTS: On the basis of neuropsychological assessment it is possible to obtain insight into the relation between brain disorders and criminal behaviour. The case that we present shows that the court may consider the influence of cognitive impairment on behavior to be very important.
CONCLUSION: Neurocognitive disorders can make an important contribution to psychiatric assessments of defendants. In the forensic practice a combined diagnostic approach consisting of psychiatric evaluation, neurological assessment of behaviour, imaging techniques and neuropsychological assessment, is clearly preferable. PMID- 27976784 TI - [The quality of life of patients in long-term forensic psychiatric care]. AB - BACKGROUND: Quality of life (QoL) is an important issue in long term forensic psychiatric care (LFPC).
AIM: To provide an overview of the knowledge that has been obtained over the last few years about patients' QoL in LFPC.
METHOD: The quality of life in LFPC has been researched every year since 2007. The research has involved the use of the Forensic Inpatient Quality of Life Questionnaire (FQL) which was developed specifically for patients in LFPC. During the longitudinal research project several studies were conducted in order to identify some of the factors that possibly define patients' QoL.
RESULTS: The QoL of patients in LFPC seems to depend less on patient characteristics and more on the environmental circumstances and on the degree to which the patients have accepted these circumstances. Research has also shown that professional carers do not seem to be sufficiently aware of the QoL of their patients.
CONCLUSION: The fact that it is mainly environmental circumstances that are being associated with QoL offers a positive perspective on improving/optimizing QoL of patients in LFPC. Professional carers could, for instance, be trained to discuss QoL with their patients in a structured manner. This would enable carers to identify potential aspects that require further improvement and to optimise these aspects in discussion with their patients. PMID- 27976786 TI - [Tailored pharmacotherapy. Consultations about medication in a care programme for depression]. AB - BACKGROUND: Despite the increasing rationalisation of mental health care, there are no specific recommendations regarding the number of contacts between a patient and a psychiatrist for the pharmacotherapy that forms part of the combined outpatient treatment (antidepressants and psychotherapy) of depression. AIM: To consider the possibility of drawing up an advisory document regarding frequency, number and duration of consultations about medication in combined treatment for depression. METHOD: We reviewed the literature and had qualitative interviews with psychiatrists and trainees in psychiatric residency. RESULTS: The literature focuses predominantly on diagnostics and patient characteristics that determine the amount of care required. Advice on medication and pharmacotherapy is provided only by experts. According to the interviews, in psychiatric practice many factors influence the number and duration of consultations. Nevertheless, a distinctive pattern emerged. CONCLUSION: Regarding medication in the acute treatment phase, five or six visits to a psychiatrist are sufficient for most patients. Extra consultations have to be arranged for smaller groups of less stable patients and for crisis-prone patients. PMID- 27976787 TI - [Combining a classic monoamine oxidase inhibitor with a tricyclic antidepressant in therapy-resistant depression: a case report and literature review]. AB - BACKGROUND: Combining a monoamine oxidase inhibitor (MAOI) with a tricyclic antidepressant (TCA) is considered to be contra-indicated because there is a risk that the recipient develops a serotonin syndrome. An accidental clinical observation motivated us to search and study publications relating to the risk and effectivity of combining these two types of antidepressants.
AIM: To search and study articles on the risks and effectivity of combining the use of MAOIs and TCAs in the treatment of therapy-resistant depression.
METHOD: We searched in PubMed and also studied relevant articles that papers referred to in the database.
RESULTS: Because many case-reports have been misinterpreted, the patients' risk of developing a serotonin syndrome and other complications as a result of the combined use of MAOIs and TCAs is overestimated. The literature provides some evidence that the combination therapy may be effective for some patients who have not responded to TCA or MAO-I monotherapy. Combination therapy seems to be safe if monitored carefully and if TCAs with marked serotonergic affinity are avoided. To enhance safety, the MAOI should be added to a TCA or both the TCA and MAOI should be started simultaneously and titrated slowly.
CONCLUSION: The combination of a MAOI and a TCA can be a possible treatment for patients with treatment resistant depression when monotherapy with either a TCA or a MAOI has failed. PMID- 27976789 TI - [From first assessment to classification: pragmatic and according to principle, or problematic?] PMID- 27976788 TI - [Delayed diagnosis in a patient with Creutzfeldt-Jakob disease in a psychiatric hospital]. AB - A 51-year-old female teacher of dance was referred to the diagnostic unit of our psychiatric hospital with symptoms of anxiety and depression. The clinical image was suggestive of organic pathology, but this could not be determined with certainty until a late stage. We discuss the course of the patient's illness. Her symptoms appeared to be psychiatric and closely resembled those of Creutzfeldt Jakob disease. We comment on some of the signs that could have led to an earlier diagnosis and we discuss the tools that are needed. PMID- 27976790 TI - Levosimendan: New hope therapy for takotsubo syndrome. PMID- 27976791 TI - Fractional flow reserve measurement modification with monorail pressure catheter. PMID- 27976792 TI - Angiographic detection of fatal acute aortic dissection Stanford type A under resuscitation. PMID- 27976793 TI - TRIAD system catalase, insulin, and low dose aspirin neutralize the effect of dermcidin isoform-2 and prevent cell death in acute myocardial infarction and recurrence of the disease. PMID- 27976794 TI - Mother-and-child catheter-facilitated optical coherence tomography: A novel approach to improve intracoronary imaging. AB - BACKGROUND: Our aim was to prospectively analyze the usefulness of mother-and child catheter approach with the GuideLiner(r) (GL) catheter extension system to overcome some potential limitations associated with the use of optical coherence tomography (OCT). METHODS: We included consecutive patients referred to our institution for coronary angiogram in whom OCT image acquisition was obtained using GL. From February 2015 to May 2016, a total of 19 procedures (18 patients) were prospectively included. RESULTS: In more than two thirds of the procedures, the OCT catheter was unable to cross the coronary stenosis prior to the use of GL. The right coronary artery was the most frequently involved coronary vessel (63%). The main reason for using GL (47% of cases) was poor engagement of the coronary ostium and lack of support of the guiding catheter (47%). Eventually, in 18 out of 19 procedures, a good quality OCT image was obtained and, when indicated, successful percutaneous coronary intervention with stent implantation was performed. Of note, there were no serious complications related to the use of GL during OCT imaging. CONCLUSIONS: Optical coherence tomography through a catheter extension system is a useful technique able to overcome some of the limitations associated with this imaging technique ensuring adequate blood clearance and thus optimal image quality. PMID- 27976795 TI - First-in-human experience with the Cardia Ultraseal left atrial appendage closure device: The feasibility study. PMID- 27976796 TI - Endovascular management of heavily calcified abdominal aorta dissection during transcatheter aortic valve implantation. PMID- 27976797 TI - Comparable vascular response of a new generation sirolimus eluting stents when compared to fluoropolymer everolimus eluting stents in the porcine coronary restenosis model. AB - BACKGROUND: Novel sirolimus eluting stents (SES) have shown non-inferior clinical outcomes when compared to everolimus eluting stents (EES), however only limited preclinical data have been published. Therefore, we evaluate vascular response of a new generation biodegradable polymer SES (BP-SES: Alex Plus, Balton) and fluoropolymer EES (EES: Xience Pro, Abbott) in the porcine coronary restenosis model. METHODS: A total of 40 stents were implanted with 120% overstretch in coronaries of 17 domestic swine: 16 BP-SES, 16 EES and 8 bare metal controls (BMS). Following 28 and 90 days, coronary angiography and optical coherence tomography (OCT) was performed, animals sacrificed and stented segments harvested for pathological evaluation. RESULTS: At 28 days neointimal thickness in OCT was lowest in the BP-SES when compared to EES and BMS (0.18 +/- 0.1 vs. 0.39 +/- 0.1 vs. 0.34 +/- 0.2 mm, respectively; p = 0.04). There was no difference in the proportion of malapposed or uncovered struts, although protruding covered struts were more common in BP-SES (14.8 +/- 10% vs. 4.1 +/- 4% vs. 3.7 +/- 6%; p = 0.03). In pathology, the lowest neointimal thickness was confirmed in BP-SES (p < 0.05). The inflammation score was significantly lower in BP-SES and EES when compared to BMS (0.24 +/- 0.1 vs. 0.4 +/- 0.1 vs. 0.77 +/- 0.4; p < 0.01) whilst EES and BP-SES had higher fibrin scores than BMS (1.2 +/- 0.4 vs. 1.3 +/- 0.3 vs. 0.17 +/- 0.2; p < 0.01). At 90 days neointimal coverage and thickness in OCT was comparable between groups and healing in histopathology was complete. CONCLUSIONS: New generation, BP-SES show similar vascular healing and biocompatibility profile with marginally higher degree of restenosis inhibition, when compared to fluoropolymer EES in the porcine coronary restenosis model. PMID- 27976798 TI - Identification and validation of microRNAs as endogenous controls for quantitative polymerase chain reaction in plasma for stable coronary artery disease. AB - BACKGROUND: Circulating microRNAs (miRNAs) have been proved to serve as biomarkers for diagnosis and assessment of prognosis of coronary artery disease (CAD). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is a widely-used technique to estimate expression levels of circulating miRNAs. Selection of optimal endogenous control (EC) remains critical to obtain reliable qPCR data of miRNAs expression. However, reference controls for normalization of circulating miRNA in CAD are still lacking. The purpose of this study was to identify stably expressed miRNAs to normalize RT-qPCR data derived from plasma in stable CAD. METHODS: We identified 10 stably expressed candidate ECs by combining miRNA microarray screening and literature screening. These 10 candidate ECs were estimated by RT-qPCR and the data were analyzed by NormFinder and BestKeeper algorithm. RESULTS: Two most stable ECs were identified as EC candidates and they were subsequently validated in another larger cohort. The 2 candidates were also validated by normalizing the expression levels of miR-21. In general, they were superior to the commonly used reference gene RNU6 in quantification cycle (Cq) value, stability value and normalization effect. CONCLUSIONS: Our results demonstrated that miR-6090 and miR-4516 can be used as reference genes for plasma miRNA analysis in stable CAD. PMID- 27976799 TI - Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review. AB - BACKGROUND: This is an updated version of the original Cochrane Review, first published in Issue 1, 2003 and updated in 2015. This review is one in a series of Cochrane Reviews investigating pair-wise monotherapy comparisons.Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenobarbitone are commonly used broad-spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for partial onset seizures, and is used in the USA and Europe. Phenobarbitone is no longer considered a first-line treatment because of concerns over associated adverse events, particularly documented behavioural adverse events in children treated with the drug. However, phenobarbitone is still commonly used in low- and middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenobarbitone in individual trials; however, the confidence intervals generated by these studies are wide, and therefore, synthesising the data of the individual trials may show differences in efficacy. OBJECTIVES: To review the time to withdrawal, remission, and first seizure of carbamazepine compared with phenobarbitone when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types). SEARCH METHODS: For the latest update, we searched the following databases on 18 August 2016: the Cochrane Epilepsy Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid, from 1946), the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov), and the World Health Organization International Clinical Trials Registry Platform (ICTRP). Previously we also searched SCOPUS (from 1823) as an alternative to Embase, but this is no longer necessary, because randomised controlled trials (RCTs) and quasi-RCTs in Embase are now included in CENTRAL. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. SELECTION CRITERIA: RCTs in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of carbamazepine monotherapy versus phenobarbitone monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'adverse events'. We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), with the generic inverse variance method used to obtain the overall pooled HR and 95% CI. MAIN RESULTS: IPD were available for 836 participants out of 1455 eligible individuals from six out of 13 trials; 57% of the potential data. For remission outcomes, HR > 1 indicated an advantage for phenobarbitone, and for first seizure and withdrawal outcomes, HR > 1 indicated an advantage for carbamazepine.The main overall results (pooled HR adjusted for seizure type, 95% CI) were HR 1.50 for time to withdrawal of allocated treatment (95% CI 1.15 to 1.95; P = 0.003); HR 0.93 for time to achieve 12-month remission (95% CI 0.72 to 1.20; P = 0.57); HR 0.99 for time to achieve six-month remission (95% CI 0.80 to 1.23; P = 0.95); and HR 0.87 for time to first seizure (95% CI 0.72 to 1.06; P = 0.18). Results suggest an advantage for carbamazepine over phenobarbitone in terms of time to treatment withdrawal and no statistically significant evidence between the drugs for the other outcomes. We found evidence of a statistically significant interaction between treatment effect and seizure type for time to first seizure recurrence (Chi2 test for subgroup differences P = 0.03), where phenobarbitone was favoured for partial onset seizures (HR 0.76, 95% CI 0.60 to 0.96; P = 0.02) and carbamazepine was favoured for generalised onset seizures (HR 1.23, 95% CI 0.88 to 1.77; P = 0.27). We found no evidence of an interaction between treatment effect and seizure type for the other outcomes. However, methodological quality of the included studies was variable, with 10 out of the 13 included studies (4 out of 6 studies contributing IPD) judged at high risk of bias for at least one methodological aspect, leading to variable individual study results, and therefore, heterogeneity in the analyses of this review. We conducted sensitivity analyses to examine the impact of poor methodological aspects, where possible. AUTHORS' CONCLUSIONS: Overall, we found evidence suggestive of an advantage for carbamazepine in terms of drug effectiveness compared with phenobarbitone (retention of the drug in terms of seizure control and adverse events) and evidence suggestive of an association between treatment effect and seizure type for time to first seizure recurrence (phenobarbitone favoured for partial seizures and carbamazepine favoured for generalised seizures). However, this evidence was judged to be of low quality due to poor methodological quality and the potential impact on individual study results (and therefore variability (heterogeneity) present in the analysis within this review), we encourage caution when interpreting the results of this review and do not advocate that the results of this review alone should be used in choosing between carbamazepine and phenobarbitone. We recommend that future trials should be designed to the highest quality possible with considerations for allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results. PMID- 27976800 TI - Clinical value of jointly detection serum lactate dehydrogenase/pleural fluid adenosine deaminase and pleural fluid carcinoembryonic antigen in the identification of malignant pleural effusion. AB - BACKGROUND: Limited data are available for the diagnostic value, and for the diagnostic sensitivity and specificity of joint detection of serum lactate dehydrogenase (sLDH)/pleural fluid adenosine deaminase (pADA) and pleural fluid carcinoembryonic antigen (pCEA) in malignant pleural effusion (MPE). METHODS: We collected 987 pleural effusion specimens (of which 318 were malignant pleural effusion, 374 were tubercular pleural effusion, and 295 were parapneumonic effusion specimens) from the First Affiliated Hospital of Wenzhou Medical University from July 2012 to March 2016. The pADA, sLDH, pleural fluid LDH (pLDH), serum C-reactive protein (sCRP), pleural fluid protein, pCEA, white blood cell (WBC), and red blood cell (RBC) were analyzed, and the clinical data of each group were collected for statistical analysis. RESULTS: The level of sLDH/pADA, pCEA, and RBC from the MPE group was markedly higher than the tuberculosis pleural effusion (TB) group (Mann-Whitney U=28422.000, 9278.000, 30518, P=.000, .000, .000) and the parapneumonic pleural fluid group (Mann-Whitney U=5972.500, 7113.000, 36750.500, P=.000, .000, .000). The receiver operating characteristic curve ROC showed that the area under the ROC curve (AUC) (=0.924, 0.841) of pCEA and sLDH/pADA (cutoff=4.9, 10.6) were significantly higher than other markers for the diagnosis of MPE. Thus, joint detection of pCEA and sLDH/pADA suggested that the sensitivity, specificity, and AUC was 0.94, 81.70, and 94.32 at the cutoff 0.16 and diagnostic performance was higher than pCEA or sLDH/pADA. CONCLUSION: Joint detection of sLDH/pADA and pCEA can be used as a good indicator for the identification of benign and MPE with higher sensitivity and specificity than pCEA or sLDH/pADA. PMID- 27976802 TI - Progress in Publishing: Benefits for JBMR Authors, Reviewers, and Readers. PMID- 27976801 TI - Serologic antibodies in relation to outcome in postoperative Crohn's disease. AB - BACKGROUND AND AIM: Disease recurs frequently after Crohn's disease resection. The role of serological antimicrobial antibodies in predicting recurrence or as a marker of recurrence has not been well defined. METHODS: A total of 169 patients (523 samples) were prospectively studied, with testing peri-operatively, and 6, 12 and 18 months postoperatively. Colonoscopy was performed at 18 months postoperatively. Serologic antibody presence (perinuclear anti-neutrophil cytoplasmic antibody [pANCA], anti-Saccharomyces cerevisiae antibodies [ASCA] IgA/IgG, anti-OmpC, anti-CBir1, anti-A4-Fla2, anti-Fla-X) and titer were tested. Quartile sum score (range 6-24), logistic regression analysis, and correlation with phenotype, smoking status, and endoscopic outcome were assessed. RESULTS: Patients with >= 2 previous resections were more likely to be anti-OmpC positive (94% vs 55%, >= 2 vs < 2, P = 0.001). Recurrence at 18 months was associated with anti-Fla-X positivity at baseline (49% vs 29%; positive vs negative, P = 0.033) and 12 months (52% vs 31%, P = 0.04). Patients positive (n = 28) for all four antibacterial antibodies (anti-CBir1, anti-OmpC, anti-A4-Fla2, and anti-Fla-X) at baseline were more likely to experience recurrence at 18 months than patients negative (n = 32) for all four antibodies (82% vs 18%, P = 0.034; odds ratio 6.4, 95% confidence interval 1.16-34.9). The baseline quartile sum score for all six antimicrobial antibodies was higher in patients with severe recurrence (Rutgeert's i3-i4) at 18 months, adjusted for clinical risk factors (odds ratio 1.16, 95% confidence interval 1.01-1.34, P = 0.039). Smoking affected antibody status. CONCLUSIONS: Anti-Fla-X and presence of all anti-bacterial antibodies identifies patients at higher risk of early postoperative Crohn's disease recurrence. Serologic screening pre-operatively may help identify patients at increased risk of recurrence. PMID- 27976803 TI - CD31+ Cells From Peripheral Blood Facilitate Bone Regeneration in Biologically Impaired Conditions Through Combined Effects on Immunomodulation and Angiogenesis. AB - Controlled revascularization and inflammation are key elements regulating endogenous regeneration after (bone) tissue trauma. Peripheral blood-derived cell subsets, such as regulatory T-helper cells and circulating (endothelial) progenitor cells, respectively, can support endogenous tissue healing, whereas effector T cells that are associated with an aged immune system can hinder bone regeneration. CD31 is expressed by diverse leukocytes and is well recognized as a marker of circulating endothelial (precursor) cells; however, CD31 is absent from the surface of differentiated effector T cells. Thus, we hypothesized that by separating the inhibitory fractions from the supportive fractions of circulating cells within the peripheral blood (PB) using the CD31 marker, bone regeneration in biologically compromised conditions, such as those observed in aged patients, could be improved. In support of our hypothesis, we detected an inverse correlation between CD31+ cells and effector T cells in the hematomas of human fracture patients, dependent on the age of the patient. Furthermore, we demonstrated the regenerative capacity of human PB-CD31+ cells in vitro. These findings were translated to a clinically relevant rat model of impaired bone healing. The transplantation of rat PB-CD31+ cells advanced bone tissue restoration in vivo and was associated with an early anti-inflammatory response, the stimulation of (re)vascularization, and reduced fibrosis. Interestingly, the depletion or enrichment of the highly abundant CD31+/14+ monocytes from the mixed CD31+ cell population diminished tissue regeneration at different levels, suggesting combined effects within the PB-CD31+ subsets. In summary, an intraoperative enrichment of PB-CD31+ cells might be a novel option to facilitate endogenous regeneration under biologically impaired situations by supporting immunomodulation and vascularization. (c) 2016 American Society for Bone and Mineral Research. PMID- 27976804 TI - A longitudinal real-life comparison study of natalizumab and fingolimod. AB - BACKGROUND: Different retrospective studies compared natalizumab and fingolimod in relapsing-remitting multiple sclerosis (RRMS), with conflicting results. We aimed to explore the prescriptive attitude and the clinical outcome of the two therapies. METHODS: We retrospectively included all RRMS patients treated with natalizumab (n=101) or fingolimod (n=78) as their first second-line therapy with at least 24-month follow-up. Demographic and clinical features were recorded to calculate the propensity score (PS). Outcomes of interest were annualized relapse rate (ARR), risk of relapse, and change in the EDSS RESULTS: At baseline, natalizumab patients were younger and had a shorter disease duration, a higher number of relapse in 1 year (1yR) and 2 years (2yR) and overall (ARR-PT) pretherapy, compared to fingolimod patients. On therapy, the proportion of relapsing patients and the mean RR were similar in the two groups. However, the change in the ARR was higher in natalizumab than in fingolimod group (P<.002), but, using PS as a covariate, it was comparable (P=.960). Similarly, the change in EDSS was significantly different for the two groups (P<.004), but not after adjusting for the PS (P=.321). CONCLUSION: We observed a comparable efficacy on ARR reduction and on EDSS progression with natalizumab and fingolimod correcting through PS, suggesting that the efficacy difference observed before correction might derive from the clinical attitude in prescribing natalizumab in more active MS patients in real life. PMID- 27976805 TI - Mutations in CRLF1 cause familial achalasia. AB - We here report a family from Libya with three siblings suffering from early onset achalasia born to healthy parents. We analyzed roughly 5000 disease-associated genes by a next-generation sequencing (NGS) approach. In the analyzed sibling we identified two heterozygous variants in CRLF1 (cytokine receptor-like factor 1). Mutations in CRLF1 have been associated with autosomal recessive Crisponi or cold induced sweating syndrome type 1 (CS/CISS1), which among other symptoms also manifests with early onset feeding difficulties. Segregation analysis revealed compound heterozygosity for all affected siblings, while the unaffected mother carried the c.713dupC (p.Pro239Alafs*91) and the unaffected father carried the c.178T>A (p.Cys60Ser) variant. The c.713dupC variant has already been reported in affected CS/CISS1 patients, the pathogenicity of the c.178T>A variant was unclear. As reported previously for pathogenic CRLF1 variants, cytokine receptor like factor 1 protein secretion from cells transfected with the c.178T>A variant was severely impaired. From these results we conclude that one should consider a CRLF1-related disorder in early onset achalasia even if other CS/CISS1 related symptoms are missing. PMID- 27976806 TI - Effect of temperature on chronic toxicity of copper, zinc, and nickel to Daphnia magna. AB - Few studies have considered the effect of temperature on the chronic sensitivity of Daphnia magna to other stressors. The present study investigated the effect of temperature on chronic metal toxicity and whether this effect differed among 4 different D. magna clones. Life table experiments were performed with copper, zinc, and nickel at 15 degrees C, 20 degrees C, and 25 degrees C. General linear modeling indicated that chronic Cu, Zn, and Ni toxicity to D. magna were all significantly affected by temperature. When averaged across clones, our results suggest that chronic metal toxicity to D. magna was higher at 15 degrees C than at 20 degrees C, which is the temperature used in standard toxicity tests. At 15 degrees C, the 21-d median effect concentrations (EC50s) of Cu, Zn, and Ni were 1.4 times, 1.1 times, and 1.3 times lower than at 20 degrees C, respectively. At 25 degrees C, chronic Cu and Zn toxicity did not change in comparison with 20 degrees C, but chronic Ni toxicity was lower (21-d EC50 of nickel at 25 degrees C was 1.6 times higher than at 20 degrees C). The same trends were observed for Cu and Ni when the 21-d 10% and 20% effect concentrations were considered as the effect estimator, but not for Zn, which warns against extrapolating temperature effects on chemical toxicity across effect sizes. Overall, however, chronic metal toxicity was generally highest at the lowest temperature investigated (15 degrees C), which is in contrast with the usually observed higher acute metal toxicity at higher temperatures. Furthermore, the effect of temperature on chronic Ni toxicity depended significantly on the clone. This warns against extrapolating results about effect of temperature on chemical toxicity from single clone studies to the population level. Environ Toxicol Chem 2017;36:1909-1916. (c) 2016 SETAC. PMID- 27976807 TI - Under Reporting of Suicide Ideation in US Army Population Screening: An Ongoing Challenge. AB - Previous research in US Army Soldiers shows rates of mental health concerns as two to four times higher on anonymous surveys than on postdeployment health assessments. In this study, Soldiers presenting for health reassessment completed two questionnaires on suicide risk factors: one linked to the health assessment and one anonymous. About 5.1% of respondents reported suicide ideation on the anonymous questionnaire, 3.0% on the linked questionnaire, and 0.9% on the health reassessment. About 56.4% who reported suicide ideation anonymously told nobody of their thoughts. Current screening procedures identify only one in seven Soldiers experiencing suicide ideation and highlight the need for alternative risk-detection strategies. PMID- 27976808 TI - BRAFi-associated panniculitis - an emerging side effect with a variable histological picture: report of two cases and review of the literature. PMID- 27976809 TI - Enantiospecific tritium labeling of 28-homocastasterone. AB - A regiospecific and enantiospecific synthesis of tritium-labeled 28 homocastasterone is reported. Appropriate chlorocarbonate, efficiently synthesized from the starting 28-homocastasterone in an overall yield of 46%, undergoes catalytic tritium dechlorination by the T2 /Pd[0]/Et3 N system, providing 28-[3beta-3 H]homocastasterone, in a good yield, radiochemical purity (>97%), and with a high specific activity (5.8 Ci/mmol). PMID- 27976810 TI - Jasmonic acid-mediated defense suppresses brassinosteroid-mediated susceptibility to Rice black streaked dwarf virus infection in rice. AB - Plant hormones play a vital role in plant immune responses. However, in contrast to the relative wealth of information on hormone-mediated immunity in dicot plants, little information is available on monocot-virus defense systems. We used a high-throughput-sequencing approach to compare the global gene expression of Rice black-streaked dwarf virus (RBSDV)-infected rice plants with that of healthy plants. Exogenous hormone applications and transgenic rice were used to test RBSDV infectivity and pathogenicity. Our results revealed that the jasmonic acid (JA) pathway was induced while the brassinosteroid (BR) pathway was suppressed in infected plants. Foliar application of methyl jasmonate (MeJA) or brassinazole (BRZ) resulted in a significant reduction in RBSDV incidence, while epibrassinolide (BL) treatment increased RBSDV infection. Infection studies using coi1-13 and Go mutants demonstrated JA-mediated resistance and BR-mediated susceptibility to RBSDV infection. A mixture of MeJA and BL treatment resulted in a significant reduction in RBSDV infection compared with a single BL treatment. MeJA application efficiently suppressed the expression of BR pathway genes, and this inhibition depended on the JA coreceptor OsCOI1. Collectively, our results reveal that JA-mediated defense can suppress the BR-mediated susceptibility to RBSDV infection. PMID- 27976811 TI - Uremic Serum Impairs Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stromal Cells. AB - Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is characterized by an increased fracture risk. Bone marrow mesenchymal stromal cells (BMSCs) may be involved in the pathogenesis of bone disease and, in view of their promising potential applications in bone tissue engineering, the effect of uremia on BMSCs regenerative potential represents a central issue. The present study evaluated in vitro the effect of a serum pool from hemodialysis patients on BMSCs to observe its influence on osteogenic differentiation. Besides alterations in spatial organization and cytotoxicity along with hyperproliferation, gene expression analysis suggested an impairment in the osteogenic differentiation. More importantly, Receptor activator of nuclear factor kappa-B ligand (RANKL) was upregulated with a mild reduction in osteoprotegerin levels. In summary, uremic environment seems to impair BMSCs osteogenic differentiation. Moreover BMSCs themselves may enhance osteoclastogenesis, feasibly contributing to the altered bone remodeling in CKD-MBD patients. J. Cell. Physiol. 232: 2201-2209, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27976812 TI - Hurricane Sandy Exposure Alters the Development of Neural Reactivity to Negative Stimuli in Children. AB - This study examined whether exposure to Hurricane Sandy-related stressors altered children's brain response to emotional information. An average of 8 months (Mage = 9.19) before and 9 months after (Mage = 10.95) Hurricane Sandy, 77 children experiencing high (n = 37) and low (n = 40) levels of hurricane-related stress exposure completed a task in which the late positive potential, a neural index of emotional reactivity, was measured in response to pleasant and unpleasant, compared to neutral, images. From pre- to post-Hurricane Sandy, children with high stress exposure failed to show the same decrease in emotional reactivity to unpleasant versus neutral stimuli as those with low stress exposure. Results provide compelling evidence that exposure to natural disaster-related stressors alters neural emotional reactivity to negatively valenced information. PMID- 27976814 TI - Neural mechanisms of attention become more specialised during infancy: Insights from combined eye tracking and EEG. AB - : The Fixation Shift Paradigm (FSP) measures infants' ability to shift gaze from a central fixation stimulus to a peripheral target (e.g. Hood & Atkinson, 1993: Infant Behavior and Development, 16(4), 405-422). Cortical maturation has been suggested as crucial for the developing ability to shift attention. This study investigated the development of neural mechanisms by combining EEG with simultaneous eye tracking during FSP testing, in typically developing infants aged between 1 and 8 months. The most prominent neural response was a frontal positivity which occurred only in the hemisphere contralateral to the target in the youngest infants but became more ipsilateral with age. This changing lateralisation was associated with improving ability to shift attention (decreasing saccade latencies and fewer 'sticky fixations'-failures to disengage attention from the central target). These findings suggest that the lateralisation of neural responses develops during infancy, possibly due to developing intracortical connections, allowing infants to shift attention more efficiently. RESEARCH HIGHLIGHTS: Successful use of combined simultaneous remote eye tracking and EEG to measure infant attention shifts. Neural responses involved in attention shifts change in the first year of life. The lateralisation of EEG responses changes with age in the first year of life. Frontal cortex is involved in attention shifts from around 2 months of age. PMID- 27976813 TI - Evaluation of drug efficacy of DPP-4 inhibitors based on theoretical analysis with pharmacokinetics and pharmacodynamics. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors are used clinically as therapeutic agents for the treatment of diabetes. To determine the rate of DPP-4 inhibition induced by these inhibitors, pharmacokinetic and pharmacodynamic parameters were used to theoretically examine the relationship between the rate of DPP-4 inhibition and clinical efficacy following the administration of four different DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, linagliptin) by focusing on the increase in the level of glucagon-like peptide-1 (GLP-1) induced by their administration. On the basis of the relationship shown, changes in clinical efficacy in association with dose change were examined in order to discuss clinical dosage from the standpoint of proper usage. The results indicate that a high rate of DPP-4 inhibition is necessary for the onset of the effect of an administered the DPP-4 inhibitor and that the average value for the DPP-4 inhibition rate can be utilized as a common parameter of clinical efficacy. Furthermore, the efficacy profiles of the present DPP-4 inhibitors could be demonstrated on the basis of an increase in the GLP-1 level. It is considered that the present findings provide useful information for promoting the proper clinical use of DPP-4 inhibitors. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976815 TI - High relative abundance of the stable fly Stomoxys calcitrans is associated with lumpy skin disease outbreaks in Israeli dairy farms. AB - The vector of lumpy skin disease (LSD), a viral disease affecting Bovidae, is currently unknown. To evaluate the possible vector of LSD virus (LSDV) under field conditions, a yearlong trapping of dipterans was conducted in dairy farms that had been affected by LSD, 1-2 years previously. This was done in order to calculate monthly relative abundances of each dipteran in each farm throughout the year. The relative abundances of Stomoxys calcitrans (Diptera: Muscidae) in the months parallel to the outbreaks (December and April) were significantly higher than those of other dipterans. A stable fly population model based on weather parameters for the affected area was used to validate these findings. Its results were significantly correlated with S. calcitrans abundance. This model, based on weather parameters during the epidemic years showed that S. calcitrans populations peaked in the months of LSD onset in the studied farms. These observations and model predictions revealed a lower abundance of stable flies during October and November, when LSD affected adjacent grazing beef herds. These findings therefore suggest that S. calcitrans is a potential vector of LSD in dairy farms and that another vector is probably involved in LSDV transmission in grazing herds. These findings should be followed up with vector competence studies. PMID- 27976817 TI - RDC-enhanced structure calculation of a beta-heptapeptide in methanol. AB - Residual dipolar couplings (RDCs) are a rich source of structural information that goes beyond the range covered by the nuclear Overhauser effect or scalar coupling constants. They can only be measured in partially oriented samples. RDC studies of peptides in organic solvents have so far been focused on samples in chloroform or DMSO. Here, we show that stretched poly(vinyl acetate) can be used for the partial alignment of a linear beta-peptide with proteinogenic side chains in methanol. 1 DCH , 1 DNH , and 2 DHH RDCs were collected with this sample and included as restraints in a simulated annealing calculation. Incorporation of RDCs in the structure calculation process improves the long-range definition in the backbone of the resulting 314 -helix and uncovers side-chain mobility. Experimental side-chain RDCs of the central leucine and valine residues are in good agreement with predicted values from a local three-state model. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27976816 TI - BOYS, EARLY RISK FACTORS FOR ALCOHOL PROBLEMS, AND THE DEVELOPMENT OF THE SELF: AN INTERCONNECTED MATRIX. AB - Alcohol-use disorders are a major public health issue worldwide. Although drinking and problematic alcohol use usually begins during adolescence, developmental origins of the disorder can be traced back to infancy and early childhood. Identification of early risk factors is essential to understanding developmental origins. Using data from the Michigan Longitudinal Study, an ongoing, prospective, high-risk family study, this article summarizes findings of family context and functioning of both children and parents. We draw attention to the development of the self, an understudied aspect of very young children being reared in alcoholic families that exacerbates exposure to high childhood adverse experiences. We also provide evidence demonstrating that young boys are embedded in a dynamic system of genes, epigenetic processes, brain organization, family dynamics, peers, community, and culture that strengthens risky developmental pathways if nothing is done to intervene during infancy and early childhood. PMID- 27976821 TI - Heavy Grignard Reagents: Synthesis, Physical and Structural Properties, Chemical Behavior, and Reactivity. AB - The Grignard reaction offers a straight forward atom-economic synthesis of organomagnesium halides, which undergo redistribution reactions (Schlenk equilibrium) yielding diorganylmagnesium and magnesium dihalides. The homologous organocalcium complexes (heavy Grignard reagents) gained interest only quite recently owing to several reasons. The discrepancy between the inertness of this heavy alkaline earth metal and the enormous reactivity of its organometallics hampered a vast and timely development after the first investigation more than 100 years ago. In this overview the synthesis of organocalcium reagents is described as is the durability in ethereal solvents. Aryl-, alkenyl-, and alkylcalcium halides are prepared by direct synthesis. Characteristic structural features and NMR parameters are discussed. Ligand redistribution reactions can be performed by addition of potassium tert-butanolate to ethereal solutions of arylcalcium iodides yielding soluble diarylcalcium, whereas sparingly soluble potassium iodide and calcium bis(tert-butanolate) precipitate. Furthermore, reactivity studies with respect to metalation and addition to unsaturated organic compounds and metal-based Lewis acids, leading to the formation of heterobimetallic complexes, are presented. PMID- 27976819 TI - Warming and provenance limit tree recruitment across and beyond the elevation range of subalpine forest. AB - Climate niche models project that subalpine forest ranges will extend upslope with climate warming. These projections assume that the climate suitable for adult trees will be adequate for forest regeneration, ignoring climate requirements for seedling recruitment, a potential demographic bottleneck. Moreover, local genetic adaptation is expected to facilitate range expansion, with tree populations at the upper forest edge providing the seed best adapted to the alpine. Here, we test these expectations using a novel combination of common gardens, seeded with two widely distributed subalpine conifers, and climate manipulations replicated at three elevations. Infrared heaters raised temperatures in heated plots, but raised temperatures more in the forest than at or above treeline because strong winds at high elevation reduced heating efficiency. Watering increased season-average soil moisture similarly across sites. Contrary to expectations, warming reduced Engelmann spruce recruitment at and above treeline, as well as in the forest. Warming reduced limber pine first year recruitment in the forest, but had no net effect on fourth-year recruitment at any site. Watering during the snow-free season alleviated some negative effects of warming, indicating that warming exacerbated water limitations. Contrary to expectations of local adaptation, low-elevation seeds of both species initially recruited more strongly than high-elevation seeds across the elevation gradient, although the low-provenance advantage diminished by the fourth year for Engelmann spruce, likely due to small sample sizes. High- and low-elevation provenances responded similarly to warming across sites for Engelmann spruce, but differently for limber pine. In the context of increasing tree mortality, lower recruitment at all elevations with warming, combined with lower quality, high provenance seed being most available for colonizing the alpine, portends range contraction for Engelmann spruce. The lower sensitivity of limber pine to warming indicates a potential for this species to become more important in subalpine forest communities in the coming centuries. PMID- 27976820 TI - Integration of expression quantitative trait loci and pleiotropy identifies a novel psoriasis susceptibility gene, PTPN1. AB - BACKGROUND: Psoriasis is a common inflammatory skin disease, whereas schizophrenia is a psychiatric disorder with substantial comorbidity. Although these two disorders manifest with apparently unrelated phenotypes, there is some evidence suggesting that they share common genetic factors. METHODS: We implemented a genetic analysis incorporating pleiotropy and annotation to genome wide association summary statistics data for approximately 120 000 psoriasis and schizophrenia samples, as well as whole blood expression quantitative trait loci in 5311 samples. RESULTS: We observed a significant pleiotropic effect between psoriasis and schizophrenia (p = 5.92 * 10-43 ). We characterized an enrichment of whole blood expression quantitative trait loci in genome-wide association data for psoriasis and schizophrenia (q1 /q0 > 1.5, p < 10-77 ) and we revealed that common variants for both diseases were more likely to confer expression quantitative trait loci effects (q1 /q0 = 4.197, SE = 0.183). Through joint analysis of the associations in the combined psoriasis and schizophrenia data set, we identified a potential susceptibility PTPN1 gene for psoriasis, which may affect the risk of psoriasis through modulation of the function of TYK2 kinase. CONCLUSIONS: The results of the present study highlight the expression quantitative trait loci enrichment and pleiotropy in psoriasis and schizophrenia, and also suggest a possible key role of the PTPN1 gene in the etiology of psoriasis. PMID- 27976818 TI - Selenophenes: Introducing a New Element into the Core of Non-Steroidal Estrogen Receptor Ligands. AB - The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for the estrogen receptor (ER) has been well recognized. In this study we expanded the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERalpha and ERbeta. Careful structure-activity relationship (SAR) analysis of their ER binding affinities showed that most selenophenes are ERbeta-selective, with the position of the phenol substituents on the selenophene core and the nature of these substituents having a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2 f) has the highest relative binding affinity (RBA) of 24.3 for ERbeta. In transcription assays, most selenophenes were found to exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2 b), bis(4 fluoro-3-hydroxyphenyl)3-bromoselenophene (6 f), and 2,3,5 tris(hydroxyphenyl)thiophenes (8 b and 8 d) profiling as superagonists for ERalpha; however, several compounds display a range of ERalpha or ERbeta antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8 c showing antiproliferative effects similar to that of 4 hydroxytamoxifen in breast cancer MCF-7 cells while being nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the estrogen receptor. PMID- 27976822 TI - Multi-criteria decision analysis applied to harmful algal bloom management: A case study. AB - Harmful algal blooms (HABs) have received greater attention in recent years due to an increase in the frequency of outbreaks and a growing potential for blooms to exact considerable economic losses and negatively impact ecosystem health. Human activity has been shown to intensify HAB outbreaks through increased eutrophication, elevated local air and water temperatures, disturbance of the thermal stratification of lakes, and modification of local hydrology. With the advent of new remediation technologies and a better understanding of the ecological factors affecting HABs, mitigating the adverse effects of HABs has become more feasible than ever before but still requires balancing mitigation efficiency, environmental impacts, costs, and stakeholder needs. In the present paper, we discuss potential HAB management solutions and propose using a Multi Criteria Decision Analysis (MCDA) framework to analyze the perspectives and priorities of various stakeholders as they pertain to 4 major considerations for HAB mitigation: human health, environmental impact, social impact, and technical feasibility. A hypothetical case study of an HAB-affected lake is used to demonstrate how stakeholders may prioritize HAB management alternatives within the MCDA framework. Integr Environ Assess Manag 2017;13:631-639. (c) 2016 SETAC. PMID- 27976823 TI - 150 Years of the German Chemical Society (GDCh), New Board Members, and More. AB - Should manuscripts by young authors with low H indices be directly rejected? Such crazy ideas can be extrapolated from the notion that lots of citations are a guarantee for high quality. Such flawed developments in scientific publishing are one theme of the Editorial by the Editor in Chief of Angewandte Chemie, as are far more positive aspects, such as the activities of the German Chemical Society (GDCh; Gesellschaft Deutscher Chemiker) in it anniversary year, 2017. PMID- 27976824 TI - Overexpression of cannabinoid receptor 1 in esophageal squamous cell carcinoma is correlated with metastasis to lymph nodes and distant organs, and poor prognosis. AB - In patients with esophageal squamous cell carcinoma (ESCC), the status of metastasis to lymph nodes is strongly associated with prognosis. Consequently, development of a biomarker to detect the presence of metastasis would be clinically valuable. In this study, we found that overexpression of cannabinoid receptor 1 (CB1R) was applicable as a marker for prediction of metastasis in ESCC. CB1R overexpression was detected immunohistochemically in 54 of 88 cases (61.4%). The intensity of CB1R expression was uniform in both intraepithelial and invasive regions in each case, and was significantly correlated with the status of metastasis to lymph nodes (P = 0.046) and distant organs (P = 0.047). Furthermore, multivariate analysis revealed that CB1R overexpression was independently associated with poor prognosis (P = 0.019). Biological analysis of CB1R overexpression using ESCC cell lines revealed that CB1R activation appeared to promote cell proliferation and invasion. On the basis of these findings, we propose that evaluation of CB1R expression status in biopsy specimens of ESCC using immunohistochemistry might be clinically useful for prediction of metastasis to lymph nodes and distant organs. PMID- 27976825 TI - Auer rod-like inclusions in monoclonal B-cell lymphoproliferative disorder: A potential diagnostic pitfall. PMID- 27976826 TI - Challenges in assigning endocrine-specific modes of action: Recommendations for researchers and regulators. AB - As regulatory programs evaluate substances for their endocrine-disrupting properties, careful study design and data interpretation are needed to distinguish between responses that are truly endocrine specific and those that are not. This is particularly important in regulatory environments where criteria are under development to identify endocrine-disrupting properties to enable hazard-based regulation. Irrespective of these processes, most jurisdictions use the World Health Organization/International Programme on Chemical Safety definition of an endocrine disruptor, requiring that a substance is demonstrated to cause a change in endocrine function that consequently leads to an adverse effect in an intact organism. Such a definition is broad, and at its most cautious might capture many general mechanisms that would not specifically denote an endocrine disruptor. In addition, endocrine responses may be adaptive in nature, designed to maintain homeostasis rather than induce an irreversible adverse effect. The likelihood of indirect effects is increased in (eco)toxicological studies that require the use of maximum tolerated concentrations or doses, which must produce some adverse effect. The misidentification of indirect effects as truly endocrine mediated has serious consequences for prompting animal- and resource-intensive testing and regulatory consequences. To minimize the risk for misidentification, an objective and transparent weight-of-evidence procedure based on biological plausibility, essentiality, and empirical evidence of key events in an adverse outcome pathway is recommended to describe the modes of action that may be involved in toxic responses in nontarget organisms. Confounding factors such as systemic toxicity, general stress, and infection can add complexity to such an evaluation and should be considered in the weight of evidence. A recommended set of questions is proffered to help guide researchers and regulators in discerning endocrine and nonendocrine responses. Although many examples provided in this study are based on ecotoxicology, the majority of the concepts and processes are applicable to both environmental and human health assessments. Integr Environ Assess Manag 2017;13:280-292. (c) 2016 SETAC. PMID- 27976827 TI - New Conjugated meso-Tetrafluorenylporphyrin-Cored Derivatives as Fluorescent Two Photon Photosensitizers for Singlet Oxygen Generation. AB - A series of three conjugated meso-porphyrin dendrimers containing conjugated dendrons featuring 2,7-fluorenyl groups, incorporating overall 8, 12, or 28 fluorenyl units have been synthesized and characterized. The photophysical properties of these new compounds were studied in the context of photodynamic therapy. The relevant linear and nonlinear optical properties were measured in organic media and useful structure-properties relationships were derived. PMID- 27976828 TI - Clinically mild encephalopathy with a reversible splenial lesion and nonconvulsive status epilepticus in a schizophrenic patient with neuroleptic malignant syndrome. PMID- 27976829 TI - Bicyclo[3.2.0]heptane as a Core Structure for Conformational Locking of 1,3-Bis Pharmacophores, Exemplified by GABA. AB - The synthesis and X-ray crystal structures of syn and anti 4-N-Boc aminobicyclo[3.2.0]heptane-1-carboxylic acids are described. The placement of the N-Boc-amino groups in the two stereoisomers in either pseudo-equatorial or pseudo axial positions renders the molecules conformationally locked, with N-Boc protected gamma-aminobutyric acid (GABA) embedded within the bicyclic core. Despite the different conformations of the urethane and distinct crystal packing, the bicyclic core units of the two stereoisomers adopt virtually identical structures. They correspond to in silico models of the parent bicyclic core and a systematic array of disubstituted derivatives. The study documents an intrinsic property of the bicyclo[3.2.0]heptane core to favor adoption of a boat-like conformation, which is largely unaffected by various substitution patterns. The structural concepts are useful in the design of molecules with spatial and directional fixation of pharmacophoric groups. PMID- 27976830 TI - Mitochondrial protein import in trypanosomes: Expect the unexpected. AB - Mitochondria have many different functions, the most important one of which is oxidative phosphorylation. They originated from an endosymbiotic event between a bacterium and an archaeal host cell. It was the evolution of a protein import system that marked the boundary between the endosymbiotic ancestor of the mitochondrion and a true organelle that is under the control of the nucleus. In present day mitochondria more than 95% of all proteins are imported from the cytosol in a proces mediated by hetero-oligomeric protein complexes in the outer and inner mitochondrial membranes. In this review we compare mitochondrial protein import in the best studied model system yeast and the parasitic protozoan Trypanosoma brucei. The 2 organisms are phylogenetically only remotely related. Despite the fact that mitochondrial protein import has the same function in both species, only very few subunits of their import machineries are conserved. Moreover, while yeast has 2 inner membrane protein translocases, one specialized for presequence-containing and one for mitochondrial carrier proteins, T. brucei has a single inner membrane translocase only, that mediates import of both types of substrates. The evolutionary implications of these findings are discussed. PMID- 27976831 TI - The C-terminal tails of heterotrimeric kinesin-2 motor subunits directly bind to alpha-tubulin1: Possible implications for cilia-specific tubulin entry. AB - The assembly of microtubule-based cytoskeleton propels the cilia and flagella growth. Previous studies have indicated that the kinesin-2 family motors transport tubulin into the cilia through intraflagellar transport. Here, we report a direct interaction between the C-terminal tail fragments of heterotrimeric kinesin-2 and alpha-tubulin1 isoforms in vitro. Blot overlay screen, affinity purification from tissue extracts, cosedimentation with subtilisin-treated microtubule and LC-ESI-MS/MS characterization of the tail fragment-associated tubulin identified an association between the tail domains and alpha-tubulin1A/D isotype. The interaction was confirmed by Forster's resonance energy transfer assay in tissue-cultured cells. The overexpression of the recombinant tails in NIH3T3 cells affected the primary cilia growth, which was rescued by coexpression of a alpha-tubulin1 transgene. Furthermore, fluorescent recovery after photobleach analysis in the olfactory cilia of Drosophila indicated that tubulin is transported in a non-particulate form requiring kinesin-2. These results provide additional new insight into the mechanisms underlying selective tubulin isoform enrichment in the cilia. PMID- 27976832 TI - Clinical characteristics of doxorubicin-associated alopecia in 28 dogs. AB - BACKGROUND: Chemotherapy-induced alopecia (CIA) is common in humans, but there are limited reports describing the clinical features of CIA in dogs. OBJECTIVES: To describe the epidemiological and clinical characteristics of doxorubicin associated alopecia (DAA) in canine patients at a teaching hospital from 2012 to 2014. ANIMALS: Signalment, diagnosis, treatment protocols and clinical examination findings were recorded in 150 dogs treated with doxorubicin from 2012 to 2014. METHODS: Medical records were searched retrospectively for the keywords "alopecia" and "hypotrichosis." Dogs were excluded if the causal link of hair loss was unclear. RESULTS: Doxorubicin-associated alopecia was reported in 28 of 150 dogs (19%). Two parameters were statistically associated with the development of DAA: coat-type and cumulative doxorubicin dose. Dogs with curly or wire-haired coat-type were significantly more likely to develop DAA than dogs with straight haired coat-type [chi2 (1, N = 147) = 30, P < 0.0001]. After adjusting for sex, weight and doxorubicin dose, the odds of dogs with curly or wire-haired coat-type developing DAA were 22 times higher than those with straight-haired coat-type (P < 0.0001). Dogs that developed DAA received a significantly higher median cumulative doxorubicin dose (103.0 versus 84.5 mg/m2 ; P = 0.0039) than those that did not develop DAA. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs treated with doxorubicin may be at risk for developing DAA. This risk increases as the cumulative dose of doxorubicin increases, and with a curly or wire-haired coat type. PMID- 27976833 TI - Once-weekly dulaglutide 1.5 mg restores insulin secretion in response to intravenous glucose infusion. AB - AIMS: To evaluate the effects of dulaglutide 1.5 mg on first- and second-phase insulin secretion in response to an intravenous (i.v.) glucose bolus challenge, in subjects with type 2 diabetes mellitus (T2DM; primary objective) and in healthy subjects. MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled, 2-period crossover study, subjects received a single subcutaneous injection of dulaglutide 1.5 mg or placebo on day 1 of each period. On day 3, subjects underwent a 6-hour insulin infusion, followed by an i.v. glucose bolus and a glucagon challenge during hyperglycaemia. Areas under the concentration-time curve and maximum concentrations for first- (AUC0-10 and Cmax0 10 ) and second-phase secretion (AUC10-180 and Cmax10-180 ) were calculated for insulin and C-peptide. The glucose disappearance constant (Kg ) and homeostasis model assessment of beta-cell function (HOMA-beta) were assessed. RESULTS: In 20 subjects with T2DM, dulaglutide increased mean insulin AUC0-10 by 7.92-fold and Cmax0-10 by 5.40-fold vs placebo, and mean AUC10-180 and Cmax10-180 by 2.44- and 3.78- fold, respectively. In 10 healthy subjects, dulaglutide increased the mean insulin AUC0-10 by 3.09-fold and Cmax0-10 by 2.96-fold vs placebo, and mean AUC10 180 and Cmax10-180 by 2.04- and 4.15-fold, respectively. The corresponding C peptide values also increased. Mean Kg and HOMA-beta were higher after dulaglutide compared with placebo. CONCLUSIONS: In subjects with T2DM, a single dulaglutide 1.5-mg dose restored the first-phase insulin secretion in response to an i.v. glucose bolus, increased the second-phase insulin response and enhanced beta-cell function. PMID- 27976834 TI - Autophagy and the endo/exosomal pathways in health and disease. AB - Cell homeostasis requires the concerted action of cellular pathways involved in degradation, trafficking and intercellular communication, which are interlinked to satisfy the cell's needs upon demand. Defects in these pathways instigate the development of several age-related pathologies, such as neurodegenerative and chronic inflammatory diseases. Autophagy is an evolutionarily conserved and tightly regulated process of degrading cellular constituents. The endosomal and vesicular trafficking pathways contribute to this regulation and share common features with the autophagic process. Recently, autophagy has been implicated in the endosome/exosome secretory pathway. Importantly, current technological advances allow the manipulation of exosomes as drug nanocarriers in pharmaceutical intervention strategies. Here, we survey emerging findings relevant to the crosstalk between autophagy and the endo/exosomal vesicular trafficking pathways. In addition, we discuss novel methodologies that have recently been developed, which allow the utilization of these pathways for targeted drug delivery in disease. PMID- 27976835 TI - Sunlight-Dependent Hydrogen Production by Photosensitizer/Hydrogenase Systems. AB - We report a sustainable in vitro system for enzyme-based photohydrogen production. The [FeFe]-hydrogenase HydA1 from Chlamydomonas reinhardtii was tested for photohydrogen production as a proton-reducing catalyst in combination with eight different photosensitizers. Using the organic dye 5-carboxyeosin as a photosensitizer and plant-type ferredoxin PetF as an electron mediator, HydA1 achieves the highest light-driven turnover number (TONHydA1 ) yet reported for an enzyme-based in vitro system (2.9*106 mol(H2 ) mol(cat)-1 ) and a maximum turnover frequency (TOFHydA1 ) of 550 mol(H2 ) mol(HydA1)-1 s-1 . The system is fueled very effectively by ambient daylight and can be further simplified by using 5-carboxyeosin and HydA1 as a two-component photosensitizer/biocatalyst system without an additional redox mediator. PMID- 27976836 TI - Soluble thrombomodulin in bronchoalveolar lavage fluid is an independent predictor of severe drug-induced lung injury. AB - BACKGROUND AND OBJECTIVE: Drug-induced lung injury (DLI) can result from a vast number of agents, and sometimes presents findings similar to those of acute respiratory distress syndrome (ARDS). Previous studies have reported that circulating levels of soluble thrombomodulin (TM) reflect endothelial injuries, which play key roles in the development of ARDS. We hypothesized that endothelial injuries are an important aspect of pathogenesis in severe DLI. The primary aim of this study was to examine the associations between soluble TM and disease severity in DLI patients. METHODS: Of the 2580 patients who underwent a bronchoalveolar lavage (BAL) procedure at Tosei General Hospital between May 2007 and February 2015, we retrospectively analysed the data of 68 DLI patients. Soluble TM in plasma and BAL fluid (BALF), and other biomarkers were included in our analysis. RESULTS: At the time of diagnosis, 39 patients (57%) had respiratory failure (partial pressure of oxygen/inspiratory oxygen fraction ratio, PaO2 /FiO2 ratio < 300). There was a significant negative linear correlation between the PaO2 /FiO2 ratio and soluble TM in BALF (r = -0.448, P < 0.001). In a stepwise multiple regression analysis, soluble TM in BALF and surfactant protein D (SP-D) were the only independent determinants of the PaO2 /FiO2 ratio. Additionally, in a multivariate logistic regression model, soluble TM in BALF (adjusted OR (aOR): 7.48, 95% CI: 1.60-34.98) and SP-D (aOR: 5.31, 95% CI: 1.40-20.15) was an independent predictor of respiratory failure (PaO2 /FiO2 ratio < 300). CONCLUSION: Soluble TM in BALF is an independent predictor of severe DLI. These findings underscore the importance of pulmonary endothelial injuries in the pathogenesis of severe DLI. PMID- 27976837 TI - Acid rain recovery may help to mitigate the impacts of climate change on thermally sensitive fish in lakes across eastern North America. AB - From the 1970s to 1990s, more stringent air quality regulations were implemented across North America and Europe to reduce chemical emissions that contribute to acid rain. Surface water pH slowly increased during the following decades, but biological recovery lagged behind chemical recovery. Fortunately, this situation is changing. In the past few years, northeastern US fish populations have begun to recover in lakes that were historically incapable of sustaining wild fish due to acidic conditions. As lake ecosystems across the eastern United States recover from acid deposition, the stress to the most susceptible populations of native coldwater fish appears to be shifting from acidification effects to thermal impacts associated with changing climate. Extreme summer temperature events - which are expected to occur with increasing frequency in the coming century - can stress and ultimately kill native coldwater fish in lakes where thermal stratification is absent or highly limited. Based on data from northeastern North America, we argue that recovery from acid deposition has the potential to improve the resilience of coldwater fish populations in some lakes to impacts of climate change. This will occur as the amount of dissolved organic carbon (DOC) in the water increases with increasing lake pH. Increased DOC will reduce water clarity and lead to shallower and more persistent lake thermoclines that can provide larger areas of coldwater thermal refuge habitat. Recovery from acidification will not eliminate the threat of climate change to coldwater fish, but secondary effects of acid recovery may improve the resistance of coldwater fish populations in lakes to the effects of elevated summer temperatures in historically acidified ecosystems. This analysis highlights the importance of considering the legacy of past ecosystem impacts and how recovery or persistence of those effects may interact with climate change impacts on biota in the coming decades. PMID- 27976838 TI - Switched Photocurrent on Tin Sulfide-Based Nanoplate Photoelectrodes. AB - A new type of SnS2 nanoplate photoelectrode is prepared by using a mild wet chemical method. Depending on the calcination temperatures, SnS2 -based photoelectrodes can either retain their n-type nature with greatly enhanced anodic photocurrent density (ca. 1.2 mA cm-2 at 0.8 V vs. Ag/AgCl) or be completely converted into p-type SnS to generate approximately 0.26 mA cm-2 cathodic photocurrent density at -0.8 V vs. Ag/AgCl. The dominance of sulfur and tin vacancies are found to account for the dramatically different photoelectrochemical behaviors of n-type SnS2 and p-type SnS photoelectrodes. In addition, the band structures of n-type SnS2 and p-type SnS photoelectrodes are also deduced, which may provide an effective strategy for developing SnS2 /SnS films with controllable energy-band levels through a simple calcination treatment. PMID- 27976841 TI - Nanoscience and Nanotechnology Research Activities at NANO-CIC and FUNSOM in Suzhou. PMID- 27976840 TI - Toward Scalable Flexible Nanomanufacturing for Photonic Structures and Devices. AB - Continuous and scalable nanopatterning over flexible substrates is highly desirable for both commercial and scientific interests, but is difficult to realize with traditional photolithographic processes. The recent advancements in nanofabrication methodologies enable light management with photonic structures on flexible materials, providing an increasingly popular strategy to control the light harvesting in the optoelectronic devices of photovoltaics, and in organic and inorganic light-emitting diodes. Here, the current status of nanopatterning technologies for the fabrication of optoelectronic devices is summarized. Scalable nanopatterning technologies for nanomanufacturing on flexible materials are emphasized. Critical challenges in various patterning techniques when considering the resolution, scalability, processing throughput, and the use of masks and resists are addressed. The integration of flexible nanopatterned substrates with light manipulation in organic optoelectronic devices is also discussed; this enables the control of light flux and spectra. Finally, potential development directions are highlighted. PMID- 27976839 TI - Limited HLA sequence variation outside of antigen recognition domain exons of 360 10 of 10 matched unrelated hematopoietic stem cell transplant donor-recipient pairs. AB - Traditional DNA-based typing focuses primarily on interrogating the exons of human leukocyte antigen (HLA) genes that form the antigen recognition domain (ARD). The relevance of mismatching donor and recipient for HLA variation outside the ARD on hematopoietic stem cell transplantation (HSCT) outcomes is unknown. This study was designed to evaluate the frequency of variation outside the ARD in 10 of 10 (HLA-A, -B, -C, -DRB1, -DQB1) matched unrelated donor transplant pairs (n = 360). Next-generation DNA sequencing was used to characterize both HLA exons and introns for HLA-A, -B, -C alleles; exons 2, 3 and the intervening intron for HLA-DRB1 and exons only for HLA-DQA1 and -DQB1. Over 97% of alleles at each locus were matched for their nucleotide sequence outside of the ARD exons. Of the 4320 allele comparisons overall, only 17 allele pairs were mismatched for non-ARD exons, 41 for noncoding regions and 9 for ARD exons. The observed variation between donor and recipient usually involved a single nucleotide difference (88% of mismatches); 88% of the non-ARD exon variants impacted the amino acid sequence. The impact of amino acid sequence variation caused by substitutions in exons outside ARD regions in D-R pairs will be difficult to assess in HSCT outcome studies because these mismatches do not occur very frequently. PMID- 27976842 TI - Work-Function and Surface Energy Tunable Cyanoacrylic Acid Small-Molecule Derivative Interlayer on Planar ZnO Nanorods for Improved Organic Photovoltaic Performance. AB - The issue of work-function and surface energy is fundamental to "decode" the critical inorganic/organic interface in hybrid organic photovoltaics, which influences important photovoltaic events like exciton dissociation, charge transfer, photocurrent (Jsc), open-circuit voltage (Voc), etc. We demonstrate that by incorporating an interlayer of cyanoacrylic acid small molecular layer (SML) on solution-processed, spin-coated, planar ZnO nanorods (P-ZnO NRs), higher photovoltaic (PV) performances were achieved in both inverted organic photovoltaic (iOPV) and hybrid organic photovoltaic (HOPV) devices, where ZnO acts as an "electron-transporting layer" and as an "electron acceptor", respectively. For the tuned range of surface energy from 52.5 to 33 mN/m, the power conversion efficiency (PCE) in bulk heterojunction (BHJ) iOPVs based on poly(3-hexylthiophene) (P3HT) and phenyl-C60-butyric acid methyl ester (PC60BM) increases from 3.16% to 3.68%, and that based on poly[4,8-bis(5-(2 ethylhexyl)thiophen-2-yl)benzo[1,2-b;4,5b']dithiophene-2,6-diyl-alt-(4-(2 ethylhexyl)-3-fluorothieno[3,4-b]thiophene)-2-carboxylate-2-6-diyl)] (PTB7:Th):[6,6]-phenyl C71 butyric acid methyl ester (PC71BM) photoactive BHJ increases from 6.55% to 8.0%, respectively. The improved PV performance in iOPV devices is majorly attributed to enhanced photocurrents achieved as a result of reduced surface energy and greater electron affinity from the covalent attachment of the strong electron-withdrawing cyano moiety, while that in HOPV devices, where PCE increases from 0.21% to 0.79% for SML-modified devices, is ascribed to a large increase in Voc benefitted due to reduced work function effected from the presence of strong dipole moment in SML that points away from P-ZnO NRs. PMID- 27976843 TI - Rational Design of Self-Supported Ni3S2 Nanosheets Array for Advanced Asymmetric Supercapacitor with a Superior Energy Density. AB - We report a rationally designed two-step method to fabricate self-supported Ni3S2 nanosheet arrays. We first used 2-methylimidazole (2-MI), an organic molecule commonly served as organic linkers in metal-organic frameworks (MOFs), to synthesize an alpha-Ni(OH)2 nanosheet array as a precursor, followed by its hydrothermal sulfidization into Ni3S2. The resulting Ni3S2 nanosheet array demonstrated superior supercapacitance properties, with a very high capacitance of about 1,000 F g-1 being delivered at a high current density of 50 A g-1 for 20,000 charge-discharge cycles. This performance is unparalleled by other reported nickel sulfide-based supercapacitors and is also advantageous compared to other nickel-based materials such as NiO and Ni(OH)2. An asymmetric supercapacitor was then established, exhibiting a very stable capacitance of about 200 F g-1 at a high current density of 10 A g-1 for 10,000 cycles and a surprisingly high energy density of 202 W h kg-1. This value is comparable to that of the lithium-ion batteries, i.e., 180 W h kg-1. The potential of the material for practical applications was evaluated by building a quasi-solid-state asymmetric supercapacitor which showed good flexibility and power output, and two of these devices connected in series were able to power up 18 green light emitting diodes. PMID- 27976844 TI - Constructing Straight Polyionic Liquid Microchannels for Fast Anhydrous Proton Transport. AB - Polymeric ionic liquids (PILs) have triggered great interest as all solid-state flexible electrolytes because of safety and superior thermal, chemical, and electrochemical stability. It is of great importance to fabricate highly conductive electrolyte membranes capable to operate above 120 degrees C under anhydrous conditions and in the absence of mineral acids, without sacrificing the mechanical behavior. Herein, the diminished dimensional and mechanical stability of poly[1-(3H-imidazolium)ethylene]bis(trifluoromethanesulfonyl)imide has been improved thanks to its infiltration on a polybenzimidale (PBI) support with specific pore architecture. Our innovative solution is based on the synergic combination of an emerging class of materials and sustainable large-scale manufacturing techniques (UV polymerization and replication by microtransfer molding). Following this approach, the PIL plays the proton conduction role, and the PBI microsieve (SPBI) mainly provides the mechanical reinforcement. Among the resulting electrolyte membranes, conductivity values above 50 mS.cm-1 at 200 degrees C and 10.0 MPa as tensile stress are shown by straight microchannels of poly[1-(3H-imidazolium)ethylene]bis(trifluoromethanesulfonyl)imide cross-linked with 1% of dyvinylbenzene embedded in a PBI microsieve with well-defined porosity (36%) and pore diameter (17 MUm). PMID- 27976845 TI - High Consistency Perovskite Solar Cell with a Consecutive Compact and Mesoporous TiO2 Film by One-Step Spin-Coating. AB - Generally, in classic mesoscopic perovskite solar cells (PSCs), the compact blocking layer and mesoporous scaffold layer prepared by two steps or more will inevitably form an interface between them. It is undoubted that the interface contact is not conducive to electron transport and would increase the recombination in the device, resulting in the inferior performance of PSCs. In this work, we constructed a consecutive compact and mesoporous (CCM) TiO2 film to substitute the compact blocking layer and scaffold layer for mesoscopic PSCs. The bottom of the CCM TiO2 film was dense and the top was mesoporous with large uniform macropores. The two parts of the film were consecutive, which could promote the electron transport rate and decrease the charge recombination effectively. Moreover, due to the existence of macropores in the CCM TiO2 film, it was propitious to the deposition of perovskite and charge separation for the perovskite layer. Over 15.0% of average power conversion efficiency (PCE) with high consistency photovoltaic performances was achieved for the CCM TiO2 film based mesoscopic PSCs, which is higher than that with a classic mesoporous structure. PMID- 27976847 TI - Enhanced Wear Resistance of Transparent Epoxy Composite Coatings with Vertically Aligned Halloysite Nanotubes. AB - The influence of nanoparticle orientation on wear resistance of transparent composite coatings has been studied. Using a nozzle spray coating method, halloysite nanotubes (HNTs) were aligned in the in-plane and out-of-plane directions and in various randomly oriented states. Nanoscratching, falling sand, and Taber Abrasion tests were used to characterize the wear resistance at different length scales. Composites consistently displayed better wear resistance than pure epoxy. Samples with out-of-plane particle orientations exhibited better wear-resistant behavior than those with in-plane particle distributions. In nanoscratching tests, the out-of-plane orientation decreases the normalized scratch volume by as much as 60% compared to pure epoxy. In the falling sand and Taber Abrasion tests, out-of-plane aligned halloysite particles resulted in surfaces with smaller roughness based on stylus profilometry and SEM observations. The decrease in roughness values after these wear tests can be as large as 67% from pure epoxy to composites. Composites with higher out-of-plane particle orientation factors exhibited better light transmittance after sand impingements and other wear tests. This study suggests a useful strategy for producing material systems with enhanced mechanical durability and more durable optical properties. PMID- 27976846 TI - Engineering Hydrophobic Organosilica Nanoparticle-Doped Nanofibers for Enhanced and Fouling Resistant Membrane Distillation. AB - Engineering and scaling-up new materials for better water desalination are imperative to find alternative fresh water sources to meet future demands. Herein, the fabrication of hydrophobic poly(ether imide) composite nanofiber membranes doped with novel ethylene-pentafluorophenylene-based periodic mesoporous organosilica nanoparticles is reported for enhanced and fouling resistant membrane distillation. Novel organosilica nanoparticles were homogeneously incorporated into electrospun nanofiber membranes depicting a proportional increase of hydrophobicity to the particle contents. Direct contact membrane distillation experiments on the organosilica-doped membrane with only 5% doping showed an increase of flux of 140% compared to commercial membranes. The high porosity of organosilica nanoparticles was further utilized to load the eugenol antimicrobial agent which produced a dramatic enhancement of the antibiofouling properties of the membrane of 70% after 24 h. PMID- 27976848 TI - Chestnut-Like TiO2@alpha-Fe2O3 Core-Shell Nanostructures with Abundant Interfaces for Efficient and Ultralong Life Lithium-Ion Storage. AB - Transition metal oxides caused much attention owing to the scientific interests and potential applications in energy storage systems. In this study, a free standing three-dimensional (3D) chestnut-like TiO2@alpha-Fe2O3 core-shell nanostructure (TFN) is rationally synthesized and utilized as a carbon-free electrode for lithium-ion batteries (LIBs). Two new interfaces between anatase TiO2 and alpha-Fe2O3 are observed and supposed to provide synergistic effect. The TiO2 microsphere framework significantly improves the mechanical stability, while the alpha-Fe2O3 provides large capacity. The abundant boundary structures offer the possibility for interfacial lithium storage and electron transport. The as prepared TFN delivers a high capacity of 820 mAh g-1 even after 1000 continuous cycles with a Coulombic efficiency of ca. 99% at a current of 500 mA g-1, which is better than the works reported previously. A thin gel-like SEI (solid electrolyte interphase) film and Fe0 phase yielded during charge/discharge cycling have been confirmed which makes it possible to alleviate the volumetric change and enhance the electronic conductivity. This confirmation is helpful for understanding the mechanism of lithium-ion storage in alpha-Fe2O3-based materials. The as-prepared free-standing TFN with excellent stability and high capacity can be an appropriate candidate for carbon-free anode material in LIBs. PMID- 27976849 TI - Partial-Redox-Promoted Mn Cycling of Mn(II)-Doped Heterogeneous Catalyst for Efficient H2O2-Mediated Oxidation. AB - The development of a heterogeneous catalyst with high catalytic activity and durability for H2O2-mediated oxidation is one of the most important industrial and environmental issues. In this study, a Mn(II)-doped TiO2 heterogeneous catalyst was developed for H2O2-mediated oxidation. The TiO2 substrate-dependent partial-redox behavior of Mn was identified on the basis of our density functional theory simulations. This unique redox cycle was induced by a moderate electron transfer from Ti to Mn, which compensated for the electron loss of Mn and finally resulted in a high-efficiency cycling of Mn between its oxidized and reduced forms. In light of the theoretical results, a Mn(II)-doped TiO2 composite with well-defined morphology and large surface area (153.3 m2 g-1) was elaborately fabricated through incorporating Mn(II) ions into a TiO2 nanoflower, and further tested as the catalyst for oxidative degradation of organic pollutants in the presence of H2O2. Benefiting from the remarkable textural features and excellent Mn cycling property, this composite exhibited superior catalytic performance for organic pollutant degradation. Moreover, it could retain 98.40% of its initial activity even in the fifth cycle. Our study provides an effective strategy for designing heterogeneous catalytic systems for H2O2 mediated oxidations. PMID- 27976850 TI - Cell Adhesion Induced Using Surface Modification with Cell-Penetrating Peptide Conjugated Poly(ethylene glycol)-Lipid: A New Cell Glue for 3D Cell-Based Structures. AB - We synthesized a novel material, cell-penetrating peptide-conjugated poly(ethylene glycol)-lipid (CPP-PEG-lipid), that can induce the adhesion of floating cells. Firm cell adhesion with spreading could be induced by cell surface modification with the CPP-PEG-lipids. Cell adhesion was induced by CPPs but not by any other cationic short peptides we tested. Here, we demonstrated adherence using the floating cell line CCRF-CEM as well as primary human T cells, B cells, erythrocytes, and hepatocytes. As compared to cells grown in suspension, adherent cells were more rapidly induced to attach to substrates with the cell surface modification. The critical factor for attachment was localization of CPPs at the cell membrane by PEG-lipids with PEG > 20 kDa. These cationic CPPs on PEG chains were able to interact with substrate surfaces such as polystyrene (PS) surfaces, glass surfaces, and PS microfibers that are negatively charged, inducing firm cell adhesion and cell spreading. Also, as opposed to normal cationic peptides that interact strongly with cell membranes, CPPs were less interactive with the cell surfaces because of their cell-penetrating property, making them more available for adhering cells to the substrate surface. No effects on cell viability or cell proliferation were observed after the induction of cell adhesion. With this technique, cells could be easily immobilized onto PS microfibers, an important step in fabricating 3D cell-based structures. Cells immobilized onto 3D PS microfibers were alive, and human hepatocytes showed normal production of urea and albumin on the microfibers. This method is novel in inducing firm cell adhesion via a one-step treatment. PMID- 27976851 TI - Three-Dimensional Elemental Imaging of Nantan Meteorite via Femtosecond Laser Ionization Time-of-Flight Mass Spectrometry. AB - Femtosecond laser ionization time-of-flight mass spectrometry (fs-LI-TOFMS) is introduced for the three-dimensional elemental analysis of a Nantan meteorite. Spatially resolved multielemental imaging of major and minor compositions in a meteorite are presented with a lateral resolution of 50 MUm and a depth resolution of 7 MUm. Distinct 3D distributions of siderophile, lithophile, and chalcophile elements are revealed. Co and Ni are highly siderophile (Iron loving), mainly enriched in the metal phase. Cr, Cu, V, and Mn are enriched in the sulfide for their chalcophile (S-loving) tendency. S, P, and C aggregate together in the analytical volume. Silicate inclusion, containing lithophile elements of Al, Ca, Mg, K, and so on, is embedded within the metal phase for the immiscibility between silicate inclusion and the melted metal phase. These 3D distributions of elements aid the exploration of the formation and evolution of the meteorite. They also reveal the feasibility of fs-LI-TOFMS as a versatile tool for 3D imaging. PMID- 27976852 TI - Four-Dimensional Ultrafast Electron Microscopy: Insights into an Emerging Technique. AB - Four-dimensional ultrafast electron microscopy (4D-UEM) is a novel analytical technique that aims to fulfill the long-held dream of researchers to investigate materials at extremely short spatial and temporal resolutions by integrating the excellent spatial resolution of electron microscopes with the temporal resolution of ultrafast femtosecond laser-based spectroscopy. The ingenious use of pulsed photoelectrons to probe surfaces and volumes of materials enables time-resolved snapshots of the dynamics to be captured in a way hitherto impossible by other conventional techniques. The flexibility of 4D-UEM lies in the fact that it can be used in both the scanning (S-UEM) and transmission (UEM) modes depending upon the type of electron microscope involved. While UEM can be employed to monitor elementary structural changes and phase transitions in samples using real-space mapping, diffraction, electron energy-loss spectroscopy, and tomography, S-UEM is well suited to map ultrafast dynamical events on materials surfaces in space and time. This review provides an overview of the unique features that distinguish these techniques and also illustrates the applications of both S-UEM and UEM to a multitude of problems relevant to materials science and chemistry. PMID- 27976854 TI - Polymeric Quaternary Ammonium-Containing Coatings with Potential Dual Contact Based and Release-Based Antimicrobial Activity. AB - In the present work, reactive blending of copolymers with complementary functional groups was applied to control their antimicrobial activity and antifouling action in real conditions. For this purpose, two series of copolymers, poly(4-vinylbenzyl chloride-co-acrylic acid), P(VBC-co-AAx), and poly(sodium 4-styrenesulfonate-co-glycidyl methacrylate), P(SSNa-co-GMAx), were synthesized via free radical copolymerization and further modified by the incorporation of biocidal units either covalently (4-vinyl benzyl dimethylhexadecylammonium chloride, VBCHAM) or electrostatically bound (cetyltrimethylammonium 4-styrenesulfonate, SSAmC16). The cross-linking reaction of the carboxylic group of acrylic acid (AA) with the epoxide group of glycidyl methacrylate (GMA) of these two series of reactive antimicrobial copolymers was explored in blends obtained through solution casting after curing at various temperatures. The combined results from the ATR-FTIR characterization of the membranes, solubility tests, turbidimetry, and TEM suggest that the reaction occurs already at 80 degrees C, leading mostly to graft samples, while at higher curing temperatures (120 or 150 degrees C) insoluble cross-linked samples are usually obtained. Controlled release experiments of selected membranes were performed in pure water and aqueous 1 M NaCl solutions for a period of two months. The released material was followed through gravimetry and TOC/TN measurements, while the evolution of the integrity and the morphology of the membranes were followed visually and through SEM, respectively. Antimicrobial tests also revealed that the cross-linked membranes presented strong antimicrobial activity against S. aureus and P. aeruginosa. Finally, a specific blend combination was applied on aquaculture nets and cured at 80 degrees C. The modified nets, emerged in the sea for 15 and 35 days, exhibited high antifouling action as compared to blank nets. PMID- 27976853 TI - Structural Basis for the Species-Selective Binding of N,C-Capped Dipeptides to the Mycobacterium tuberculosis Proteasome. AB - The Mycobacterium tuberculosis (Mtb) 20S proteasome is vital for the pathogen to survive under nitrosative stress in vitro and to persist in mice. To qualify for drug development, inhibitors targeting Mtb 20S must spare both the human constitutive proteasome (c-20S) and immunoproteasome (i-20S). We recently reported members of a family of noncovalently binding dipeptide proteasome inhibitors that are highly potent and selective for Mtb 20S over human c-20S and i-20S. To understand the structural basis of their potency and selectivity, we have studied the structure-activity relationship of six derivatives and solved their cocrystal structures with Mtb 20S. The dipeptide inhibitors form an antiparallel beta-strand with the active site beta-strands. Selectivity is conferred by several features of Mtb 20S relative to its mouse counterparts, including a larger S1 pocket, additional hydrogen bonds in the S3 pocket, and hydrophobic interactions in the S4 pocket. Serine-20 and glutamine-22 of Mtb 20S interact with the dipeptides and confer Mtb-specific inhibition over c-20S and i 20S. The Mtb 20S and mammalian i-20S have a serine-27 that interacts strongly with the dipeptides, potentially explaining the higher inhibitory activity of the dipeptides toward i-20S over c-20S. This detailed structural knowledge will aid in optimizing the dipeptides as anti-tuberculosis drugs. PMID- 27976856 TI - Unveiling the Pathogenic Molecular Mechanisms of the Most Common Variant (p.K329E) in Medium-Chain Acyl-CoA Dehydrogenase Deficiency by in Vitro and in Silico Approaches. AB - Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common genetic disorder affecting the mitochondrial fatty acid beta-oxidation pathway. The mature and functional form of human MCAD (hMCAD) is a homotetramer assembled as a dimer of dimers (monomers A/B and C/D). Each monomer binds a FAD cofactor, necessary for the enzyme's activity. The most frequent mutation in MCADD results from the substitution of a lysine with a glutamate in position 304 of mature hMCAD (p.K329E in the precursor protein). Here, we combined in vitro and in silico approaches to assess the impact of the p.K329E mutation on the protein's structure and function. Our in silico results demonstrated for the first time that the p.K329E mutation, despite lying at the dimer-dimer interface and being deeply buried inside the tetrameric core, seems to affect the tetramer surface, especially the beta-domain that forms part of the catalytic pocket wall. Additionally, the molecular dynamics data indicate a stronger impact of the mutation on the protein's motions in dimer A/B, while dimer C/D remains similar to the wild type. For dimer A/B, severe disruptions in the architecture of the pockets and in the FAD and octanoyl-CoA binding affinities were also observed. The presence of unaffected pockets (C/D) in the in silico studies may explain the decreased enzymatic activity determined for the variant protein (46% residual activity). Moreover, the in silico structural changes observed for the p.K329E variant protein provide an explanation for the structural instability observed experimentally, namely, the disturbed oligomeric profile, thermal stability, and conformational flexibility, with respect to the wild-type. PMID- 27976857 TI - Quantitative Nanomechanical Properties of Multilayer Films Made of Polysaccharides through Spray Assisted Layer-by-Layer Assembly. AB - Nanomechanical properties of alginate/chitosan (Alg/Chi) multilayer films, obtained through spray assisted layer-by-layer assembly, were studied by means of PeakForce quantitative nanomechanical mapping atomic force microscopy (PF-QNM AFM). Prepared at two different alginate concentrations (1.0 and 2.5 mg/mL) and a fixed chitosan concentration (1.0 mg/mL), Alg/Chi films have an exponential growth in thickness with a transition to a linear growth toward a plateau by increasing the number of deposited bilayers. Height, elastic modulus, deformation, and adhesion maps were simultaneously recorded depending on the number of deposited bilayers. The elastic modulus of Alg/Chi films was found to be related to the mechanism of growth in contrast to the adhesion and deformation. A comparison of the nanomechanical properties obtained for non-cross linked and thermally cross-linked Alg/Chi films revealed an increase of the elastic modulus after cross-linking regardless alginate concentration. The incorporation of iron oxide nanoparticles (NPs), during the spray preparation of the films, gave rise to nanocomposite Alg/Chi films with increased elastic moduli with the number of incorporated NPs layers. Deformation maps of the films strongly suggested the presence of empty spaces associated with the method of preparation. Finally, adhesion measurements point out to a significant role of NPs on the increase of the adhesion values found for nanocomposite films. PMID- 27976858 TI - Voltammetric Thin-Layer Ionophore-Based Films: Part 1. Experimental Evidence and Numerical Simulations. AB - Voltammetric thin layer (~200 nm) ionophore-based polymeric films of defined ion exchange capacity have recently emerged as a promising approach to acquire multi ion information about the sample, in analogy to performing multiple potentiometric measurements with individual membranes. They behave under two different regimes that are dependent on the ion concentration. A thin layer control (no mass transport limitation of the polymer film or solution) is identified for ion concentrations of >10 MUM, in which case the peak potential serves as the readout signal, in analogy to a potentiometric sensor. On the other hand, ion transfer at lower concentrations is chiefly controlled by diffusional mass transport from the solution to the sensing film, resulting in an increase of peak current with ion concentration. This concentration range is suitable for electrochemical ion transfer stripping analysis. Here, the transition between the two mentioned scenarios is explored experimentally, using a highly silver selective membrane as a proof-of-concept under different conditions (variation of ion concentration in the sample from 0.1 MUM to 1 mM, scan rate from 25 mV s-1 to 200 mV s-1, and angular frequency from 100 rpm to 6400 rpm). Apart from experimental evidence, a numerical simulation is developed that considers an idealized conducting polymer behavior and permits one to predict experimental behavior under diffusion or thin-layer control. PMID- 27976859 TI - Plasmonic Nanosensors for the Determination of Drug Effectiveness on Membrane Receptors. AB - We demonstrate the potential of the NanoSPR (nanoscale surface plasmon resonance sensors) method as a simple and cheap tool for the quantitative study of membrane protein-protein interactions. We use NanoSPR to determine the effectiveness of two potential drug candidates that inhibit the protein complex formation between FtsA and ZipA at initial stages of bacterial division. As the NanoSPR method relies on individual gold nanorods as sensing elements, there is no need for fluorescent labels or organic cosolvents, and it provides intrinsically high statistics. NanoSPR could become a powerful tool in drug development, drug delivery, and membrane studies. PMID- 27976860 TI - Voltammetric Thin-Layer Ionophore-Based Films: Part 2. Semi-Empirical Treatment. AB - This work reports on a semiempirical treatment that allows one to rationalize and predict experimental conditions for thin-layer ionophore-based films with cation exchange capacity read out with cyclic voltammetry. The transition between diffusional mass transport and thin-layer regime is described with a parameter (alpha), which depends on membrane composition, diffusion coefficient, scan rate, and electrode rotating speed. Once the thin-layer regime is fulfilled (alpha = 1), the membrane behaves in some analogy to a potentiometric sensor with a second discrimination variable (the applied potential) that allows one to operate such electrodes in a multianalyte detection mode owing to the variable applied ion transfer potentials. The limit of detection of this regime is defined with a second parameter (beta = 2) and is chosen in analogy to the definition of the detection limit for potentiometric sensors provided by the IUPAC. The analytical equations were validated through the simulation of the respective cyclic voltammograms under the same experimental conditions. While simulations of high complexity and better accuracy satisfactorily reproduced the experimental voltammograms during the forward and backward potential sweeps (companion paper 1), the semiempirical treatment here, while less accurate, is of low complexity and allows one to quite easily predict relevant experimental conditions for this emergent methodology. PMID- 27976855 TI - Analytical Methods for Imaging Metals in Biology: From Transition Metal Metabolism to Transition Metal Signaling. PMID- 27976861 TI - Probing the Energetics of Dynactin Filament Assembly and the Binding of Cargo Adaptor Proteins Using Molecular Dynamics Simulation and Electrostatics-Based Structural Modeling. AB - Dynactin, a large multiprotein complex, binds with the cytoplasmic dynein-1 motor and various adaptor proteins to allow recruitment and transportation of cellular cargoes toward the minus end of microtubules. The structure of the dynactin complex is built around an actin-like minifilament with a defined length, which has been visualized in a high-resolution structure of the dynactin filament determined by cryo-electron microscopy (cryo-EM). To understand the energetic basis of dynactin filament assembly, we used molecular dynamics simulation to probe the intersubunit interactions among the actin-like proteins, various capping proteins, and four extended regions of the dynactin shoulder. Our simulations revealed stronger intersubunit interactions at the barbed and pointed ends of the filament and involving the extended regions (compared with the interactions within the filament), which may energetically drive filament termination by the capping proteins and recruitment of the actin-like proteins by the extended regions, two key features of the dynactin filament assembly process. Next, we modeled the unknown binding configuration among dynactin, dynein tails, and a number of coiled-coil adaptor proteins (including several Bicaudal-D and related proteins and three HOOK proteins), and predicted a key set of charged residues involved in their electrostatic interactions. Our modeling is consistent with previous findings of conserved regions, functional sites, and disease mutations in the adaptor proteins and will provide a structural framework for future functional and mutational studies of these adaptor proteins. In sum, this study yielded rich structural and energetic information about dynactin and associated adaptor proteins that cannot be directly obtained from the cryo-EM structures with limited resolutions. PMID- 27976862 TI - Thioether-Bonded Fluorescent Probes for Deciphering Thiol-Mediated Exchange Reactions on the Cell Surface. AB - Study on the processes of the thiol-mediated disulfide exchange reactions on the cell surface is not only important to our understanding of extracellular natural bioreduction processes but to the development of novel strategies for the intracellular delivery of synthetic bioactive molecules. However, disulfide bonded probes have their intrinsic inferiority in exploring the detailed exchange pathway because of the bidirectional reactivity of disulfide bonds toward reactive thiols. In this work, we developed thioether-bonded fluorescent probes that enable us to explore thiol-mediated thioether (and disulfide) exchange reactions on the cell surface through fluorescence recovery and/or cell imaging. We demonstrated that our thioether-bonded probes can be efficiently cleaved through thiol-thioether exchanges with exofacial protein thiols and/or glutathione (GSH) efflux. The exchanges mainly take place on the cell surface, and GSH efflux-mediated exchange reactions can take place without the requirement of pre-exchanges of the probes with cell surface-associated protein thiols. On the basis of our founder methodology, for the first time we demonstrated the interplay of exofacial protein thiols and GSH efflux on the cleavage of external thioether-bonded compounds. Moreover, given that an understanding of the process of GSH efflux and the mechanism on which it relies is crucial to our understanding of the cellular redox homeostasis and the mechanism of multidrug resistance, we expect that our thioether-bonded probes and strategies would greatly benefit the fundamental study of GSH efflux in living cells. PMID- 27976863 TI - Development of Highly Selective Fluorescent Probe Enabling Flow-Cytometric Isolation of ALDH3A1-Positive Viable Cells. AB - Aldehyde dehydrogenase (ALDH) is overexpressed in some subpopulations of stem cells and cancer cells. We have designed and synthesized the first selective fluorescent probe for class 3 ALDH (ALDH3A1). This probe enabled the visualization of ALDH3A1-positive cells by fluorescence microscopy as well as flow-cytometric isolation of ALDH3A1-positive viable cells from a human Caucasian esophageal squamous cell line (OE21) that heterogeneously expresses ALDH3A1. PMID- 27976864 TI - Flexible and Disposable Sensing Platforms Based on Newspaper. AB - The flexible sensing platform is a key component for the development of smart portable devices targeting healthcare, environmental monitoring, point-of-care diagnostics, and personal electronics. Herein, we demonstrate a simple, scalable, and cost-effective strategy for fabrication of a sensing electrode based on a waste newspaper with conformal coating of parylene C (P-paper). Thin polymeric layers over cellulose fibers allow the P-paper to possess improved mechanical and chemical stability, which results in high-performance flexible sensing platforms for the detection of pathogenic E. coli O157:H7 based on DNA hybridization. Moreover, P-paper electrodes have the potential to serve as disposable, flexible sensing platforms for point-of-care testing biosensors. PMID- 27976865 TI - Self-Referenced Smartphone-Based Nanoplasmonic Imaging Platform for Colorimetric Biochemical Sensing. AB - Colorimetric sensors usually suffer due to errors from variation in light source intensity, the type of light source, the Bayer filter algorithm, and the sensitivity of the camera to incoming light. Here, we demonstrate a self referenced portable smartphone-based plasmonic sensing platform integrated with an internal reference sample along with an image processing method to perform colorimetric sensing. Two sensing principles based on unique nanoplasmonics enabled phenomena from a nanostructured plasmonic sensor, named as nanoLCA (nano Lycurgus cup array), were demonstrated here for colorimetric biochemical sensing: liquid refractive index sensing and optical absorbance enhancement sensing. Refractive indices of colorless liquids were measured by simple smartphone imaging and color analysis. Optical absorbance enhancement in the colorimetric biochemical assay was achieved by matching the plasmon resonance wavelength with the chromophore's absorbance peak wavelength. Such a sensing mechanism improved the limit of detection (LoD) by 100 times in a microplate reader format. Compared with a traditional colorimetric assay such as urine testing strips, a smartphone plasmon enhanced colorimetric sensing system provided 30 times improvement in the LoD. The platform was applied for simulated urine testing to precisely identify the samples with higher protein concentration, which showed potential point-of care and early detection of kidney disease with the smartphone plasmonic resonance sensing system. PMID- 27976866 TI - Highly Selective Fluorescent Probe for Imaging H2Se in Living Cells and in Vivo Based on the Disulfide Bond. AB - Hydrogen selenide (H2Se) is an important metabolite of dietary Se compounds and has been implicated in various pathological and physiological processes. The development of highly sensitive and selective methods for the sensing of H2Se is therefore very important. Herein, we developed a fluorescent probe (hemicyanine (Hcy)-H2Se) for detecting H2Se based on a new H2Se-specific receptor unit, 1,2 dithiane-4,5-diol. Hcy-H2Se showed high selectivity toward H2Se over thiols (RSH), hydrogen sulfide (H2S), and selenocysteine (Sec) and was further exploited for the fluorescence imaging of H2Se both in living cells and in vivo. Furthermore, with the aid of Hcy-H2Se, we demonstrated that H2Se can be generated and gradually accumulated in HepG2 cells under hypoxic conditions and in the solid tumor after treatment with Na2SeO3. PMID- 27976867 TI - Uniform Fe3O4/Nitrogen-Doped Mesoporous Carbon Spheres Derived from Ferric Citrate-Bonded Melamine Resin as an Efficient Synergistic Catalyst for Oxygen Reduction. AB - Developing a facile strategy to synthesize an efficient and inexpensive catalyst for the oxygen reduction reaction (ORR) is critical to the commercialization of many sustainable energy storage and conversion techniques. Herein, a novel and convenient strategy was presented to prepare Fe3O4 embedded into nitrogen-doped mesoporous carbon spheres (Fe3O4/N-MCS) by the polycondensation between methylolmelamines and ammonium ferric citrate (AFC) and subsequent pyrolysis process. In particular, the polycondensation reaction was completely finished within a very short time (6.5 min), and the iron contents can be adjusted and had a great influence on the microstructure. Moreover, the Fe3O4/N-MCS can be used as a robust catalyst for the ORR in alkaline media, and the catalyst with the iron content of 3.35 wt % exhibited excellent electrochemical performance in terms of more positive onset potential (E0 = 1.036 V vs RHE) and half-wave potential (E1/2 = 0.861 V) and much better methanol tolerance and long-term durability, in comparison with that of 20% Pt/C. The remarkable performance was ascribed to the characteristics of large specific surface area, mesoporous structure, high contents of pyridinic N and graphitic N, as well as strong electronic interaction between Fe3O4 and protective N-doped graphitic layers. PMID- 27976868 TI - Thermodynamics of the Purine Nucleoside Phosphorylase Reaction Revealed by Computer Simulations. AB - Enzymes are able to catalyze chemical reactions by reducing the activation free energy, yielding significant increases in the reaction rates. This can thermodynamically be accomplished by either reducing the activation enthalpy or increasing the activation entropy. The effect of remote mutations on the thermodynamic activation parameters of human purine nucleoside phosphorylase is examined using extensive molecular dynamics and free energy simulations. More than 2700 independent reaction free energy profiles for six different temperatures have been calculated to obtain high-precision computational Arrhenius plots. On the basis of these, the activation enthalpies and entropies were computed from linear regression of the plots with DeltaG? as a function of 1/T, and the obtained thermodynamic activation parameters are in very good agreement with those from experiments. The Arrhenius plots immediately show that the 6-oxopurines (INO and GUO) have identical slopes, whereas the 6-aminopurine (ADO) has a significantly different slope, indicating that the substrate specificity is related to the difference in thermodynamic activation parameters. Furthermore, the calculations show that the human PNP specificity for 6 oxopurines over 6-aminopurines originates from significant differences in electrostatic preorganization. The effect of the remote double mutation, K22E and H104R (E:R), has also been examined, as it alters human PNP toward the bovine PNP. These residues are situated on the protein surface, 28-35 A from the active site, and the mutation alters the enthalpy-entropy balance with little effect on the catalytic rates. It is thus quite remarkable that the empirical valence bond method can reproduce the enthalpies and entropies induced by these long-range mutations. PMID- 27976869 TI - Mitigation of Biofilm Development on Thin-Film Composite Membranes Functionalized with Zwitterionic Polymers and Silver Nanoparticles. AB - We demonstrate the functionalization of thin-film composite membranes with zwitterionic polymers and silver nanoparticles (AgNPs) for combating biofouling. Combining hydrophilic zwitterionic polymer brushes and biocidal AgNPs endows the membrane with dual functionality: antiadhesion and bacterial inactivation. An atom transfer radical polymerization (ATRP) reaction is used to graft zwitterionic poly(sulfobetaine methacrylate) (PSBMA) brushes to the membrane surface, while AgNPs are synthesized in situ through chemical reduction of silver. Two different membrane architectures (Ag-PSBMA and PSBMA-Ag TFC) are developed according to the sequence AgNPs, and PSBMA brushes are grafted on the membrane surface. A static adhesion assay shows that both modified membranes significantly reduced the adsorption of proteins, which served as a model organic foulant. However, improved antimicrobial activity is observed for PSBMA-Ag TFC (i.e., AgNPs on top of the polymer brush) in comparison to the Ag-PSBMA TFC membrane (i.e., polymer brush on top of AgNPs), indicating that architecture of the antifouling layer is an important factor in the design of zwitterion-silver membranes. Confocal laser scanning microscopy (CLSM) imaging indicated that PSBMA Ag TFC membranes effectively inhibit biofilm formation under dynamic cross-flow membrane biofouling tests. Finally, we demonstrate the regeneration of AgNPs on the membrane after depletion of silver from the surface of the PSBMA-Ag TFC membrane. PMID- 27976870 TI - Disruption of the Prostaglandin Metabolome and Characterization of the Pharmaceutical Exposome in Fish Exposed to Wastewater Treatment Works Effluent As Revealed by Nanoflow-Nanospray Mass Spectrometry-Based Metabolomics. AB - Fish can be exposed to a complex mixture of chemical contaminants, including pharmaceuticals, present in discharges of wastewater treatment works (WwTWs) effluents. There is little information on the effects of effluent exposure on fish metabolism, especially the small molecule signaling compounds which are the biological target of many pharmaceuticals. We applied a newly developed sensitive nanoflow-nanospray mass spectrometry nontargeted profiling technique to identify changes in the exposome and metabolome of roach (Rutilus rutilus) exposed to a final WwTWs effluent for 15 days. Effluent exposure resulted in widespread reduction (between 50% and 90%) in prostaglandin (PG) profiles in fish tissues and plasma with disruptions also in tryptophan/serotonin, bile acid and lipid metabolism. Metabolite disruptions were not explained by altered expression of genes associated with the PG or tryptophan metabolism. Of the 31 pharmaceutical metabolites that were detected in the effluent exposome of fish, 6 were nonsteroidal anti-inflammatory drugs but with plasma concentrations too low to disrupt PG biosynthesis. PGs, bile acids, and tryptophan metabolites are important mediators regulating a diverse array of physiological systems in fish and the identity of wastewater contaminants disrupting their metabolism warrants further investigation on their exposure effects on fish health. PMID- 27976872 TI - Evaluating the Potential of Marginal Land for Cellulosic Feedstock Production and Carbon Sequestration in the United States. AB - Land availability for growing feedstocks at scale is a crucial concern for the bioenergy industry. Feedstock production on land not well-suited to growing conventional crops, or marginal land, is often promoted as ideal, although there is a poor understanding of the qualities, quantity, and distribution of marginal lands in the United States. We examine the spatial distribution of land complying with several key marginal land definitions at the United States county, agro ecological zone, and national scales, and compare the ability of both marginal land and land cover data sets to identify regions for feedstock production. We conclude that very few land parcels comply with multiple definitions of marginal land. Furthermore, to examine possible carbon-flow implications of feedstock production on land that could be considered marginal per multiple definitions, we model soil carbon changes upon transitions from marginal cropland, grassland, and cropland-pastureland to switchgrass production for three marginal land-rich counties. Our findings suggest that total soil organic carbon changes per county are small, and generally positive, and can influence life-cycle greenhouse gas emissions of switchgrass ethanol. PMID- 27976871 TI - Metabolism of the Tobacco Carcinogen 2-Amino-9H-pyrido[2,3-b]indole (AalphaC) in Primary Human Hepatocytes. AB - 2-Amino-9H-pyrido[2,3-b]indole (AalphaC) is the most abundant carcinogenic heterocyclic aromatic amine (HAA) formed in mainstream tobacco smoke. AalphaC is a liver carcinogen in rodents, but its carcinogenic potential in humans is not known. To obtain a better understanding of the genotoxicity of AalphaC in humans, we have investigated its metabolism and its ability to form DNA adducts in human hepatocytes. Primary human hepatocytes were treated with AalphaC at doses ranging from 0.1-50 MUM, and the metabolites were characterized by ultra-performance LC/ion trap multistage mass spectrometry (UPLC/MSn). Six major metabolites were identified: a ring-oxidized doubly conjugated metabolite, N2-acetyl-2-amino-9H pyrido[2,3-b]indole-6-yl-oxo-(beta-d-glucuronic acid) (N2-acetyl-AalphaC-6-O Gluc); two ring-oxidized glucuronide (Gluc) conjugates: 2-amino-9H-pyrido[2,3 b]indol-3-yl-oxo-(beta-d-glucuronic acid) (AalphaC-3-O-Gluc) and 2-amino-9H pyrido[2,3-b]indol-6-yl-oxo-(beta-d-glucuronic acid) (AalphaC-6-O-Gluc); two sulfate conjugates, 2-amino-9H-pyrido[2,3-b]indol-3-yl sulfate (AalphaC-3-O-SO3H) and 2-amino-9H-pyrido[2,3-b]indol-6-yl sulfate (AalphaC-6-O-SO3H); and the Gluc conjugate, N2-(beta-d-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AalphaC-N2 Gluc). In addition, four minor metabolites were identified: N2-acetyl-9H pyrido[2,3-b]indol-3-yl sulfate (N2-acetyl-AalphaC-3-O-SO3H), N2-acetyl-9H pyrido[2,3-b]indol-6-yl sulfate (N2-acetyl-AalphaC-6-O-SO3H), N2-acetyl-2-amino 9H-pyrido[2,3-b]indol-3-yl-oxo-(beta-d-glucuronic acid) (N2-acetyl-AalphaC-3-O Gluc), and O-(beta-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AalphaC-HN2-O-Gluc). The latter metabolite, AalphaC-HN2-O-Gluc is a reactive intermediate that binds to DNA to form the covalent adduct N-(2'-deoxyguanosin-8 yl)-2-amino-9H-pyrido[2,3-b]indole (dG-C8-AalphaC). Preincubation of hepatocytes with furafylline, a selective mechanism-based inhibitor of P450 1A2, resulted in a strong decrease in the formation of AalphaC-HN2-O-Gluc and a concomitant decrease in DNA adduct formation. Our findings describe the major pathways of metabolism of AalphaC in primary human hepatocytes and reveal the importance of N acetylation and glucuronidation in metabolism of AalphaC. P450 1A2 is a major isoform involved in the bioactivation of AalphaC to form the reactive AalphaC-HN2 O-Gluc conjugate and AalphaC-DNA adducts. PMID- 27976874 TI - Computational Insights on the Mechanism of H2 Activation at Ir2S2(PPh3)4: A Combination of Multiple Reaction Pathways Involving Facile H Migration Processes. AB - The complex Ir2S2(PPh3)4 (1) is known to react with 1 and 2 equivalents of H2 leading to [Ir(H)(PPh3)2]2(MU-S)2 (2) and Ir2(MU-S)(MU-SH)(MU-H)H2(PPh3)4 (4), respectively ( Linck , R. C. ; Pafford , R. J. ; Rauchfuss , T. B. J. Am. Chem. Soc. 2001 , 123 , 8856 - 8857 ). Herein, the results of a thorough computational (DFT) study of these formally homo- and heterolytic H2 activation processes, respectively, are presented. These indicate that 2 is formed in a two-step process whereby the oxidative addition of H2 at a single IrII center of 1 generates an intermediate (A) that rearranges into 2 by means of a facile H migration to the neighboring Ir center. Activation of the second equivalent of H2 most likely occurs at the bridging sulfur ligands of 2 leading to a reaction intermediate (3aa) that features two (MU-SH) ligands. Intermediate 3aa present two isomers that differ only on the stereochemistry of the (MU-SH) ligands, and both of them can further evolve into 4 via H migration from (MU-SH) to bridging (MU-H). Nevertheless, an alternative mechanism based on the initial isomerization of 2 into A, and followed by H2 coordination and activation steps at a single Ir center cannot be completely ruled out. In general, the results herein show that the mechanisms for the activation of H2 at 1 and 2 involve facile H migration processes, in agreement with the experimentally observed intermetallic hydride exchange in 2 and the exchange between IrH and SH centers in 4, which proceed with computed free energy barriers of ca. 19-23 kcal mol-1. PMID- 27976873 TI - Molecular Fractionation of Dissolved Organic Matter in a Shallow Subterranean Estuary: The Role of the Iron Curtain. AB - Iron that precipitates under aerobic conditions in natural aquatic systems scavenges dissolved organic matter (DOM) from solution. Subterranean estuaries (STEs) are of major importance for land-ocean biogeochemical fluxes. Their specific redox boundaries, coined the "iron curtain" due to the abundance of precipitated iron(III) (oxy)hydroxides, are hot spots for the removal and redissolution of iron, associated nutrients, and DOM. We used ultra-high resolution electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry to molecularly characterize the iron-coagulating fractions of 32 groundwater and seawater DOM samples along a salinity gradient from a shallow STE on Spiekeroog Island, North Sea, Germany, and linked our findings to trace metal and nutrient concentrations. We found systematic iron coagulation of large (>450 Da), oxygen-rich, and highly aromatic DOM molecules of terrestrial origin. The extent of coagulation increased with growing terrestrial influence along the salinity gradient. Our study is the first to show that the iron curtain may be capable of retaining terrigenous DOM fractions in marine sediments. We hypothesize that the iron curtain serves as an inorganic modulator for the supply of DOM from groundwaters to the sea, and that the STE has the potential to act as a temporal storage or even sink for terrigenous aromatic DOM compounds. PMID- 27976875 TI - Chiral-Substituted Poly-N-vinylpyrrolidinones and Bimetallic Nanoclusters in Catalytic Asymmetric Oxidation Reactions. AB - A new class of poly-N-vinylpyrrolidinones containing an asymmetric center at C5 of the pyrrolidinone ring were synthesized from l-amino acids. The polymers, particularly 17, were used to stabilize nanoclusters such as Pd/Au for the catalytic asymmetric oxidations of 1,3- and 1,2-cycloalkanediols and alkenes, and Cu/Au was used for C-H oxidation of cycloalkanes. It was found that the bulkier the C5 substituent in the pyrrolidinone ring, the greater the optical yields produced. Both oxidative kinetic resolution of (+/-)-1,3- and 1,2-trans cycloalkanediols and desymmetrization of meso cis-diols took place with 0.15 mol % Pd/Au (3:1)-17 under oxygen atmosphere in water to give excellent chemical and optical yields of (S)-hydroxy ketones. Various alkenes were oxidized with 0.5 mol % Pd/Au (3:1)-17 under 30 psi of oxygen in water to give the dihydroxylated products in >93% ee. Oxidation of (R)-limonene at 25 degrees C occurred at the C 1,2-cyclic alkene function yielding (1S,2R,4R)-dihydroxylimonene 49 in 92% yield. Importantly, cycloalkanes were oxidized with 1 mol % Cu/Au (3:1)-17 and 30% H2O2 in acetonitrile to afford chiral ketones in very good to excellent chemical and optical yields. Alkene function was not oxidized under the reaction conditions. Mechanisms were proposed for the oxidation reactions, and observed stereo- and regio-chemistry were summarized. PMID- 27976876 TI - Mixed Ligated Tris(amidinate)dimolybdenum Complexes as Catalysts for Radical Addition of CCl4 to 1-Hexene: Leaving Ligand Lability Controls Catalyst Activity. AB - We synthesized a series of mixed ligated tris(amidinate)dimolybdenum complexes, namely, [Mo2(DAniF)3(L)] [DAniF = N,N'-di(p-anisyl)formamidinate; L = acetate (OAc; 1a), m-diphenylphosphino benzoate (m-PPh2Bz; 1b), nicotinate (Nico; 1c), benzoate (Bz; 1d), 3-furoate (3-Furo; 1e), isonicotinate (IsoNico; 1f), and trifluoromethanesulfonate (OTf; 1g)], which served as catalysts for radical addition of CCl4 to 1-hexene to give 1,1,1,3-tetrachloroheptane. These mixed ligated complexes 1a-g afforded the higher yield of the radical addition product than a homoleptic DAniF complex, [Mo2(DAniF)4] (2). Among them, complexes 1a and 1g gave the radical addition product quantitatively after 9 h with a short induction period. When complexes 1a and 1g were treated with CCl4, we detected the mixed-valence Mo2(II/III) complex, [Mo2(DAniF)3Cl2] (4), in electrospray ionization mass spectrometry measurements, indicating that the leaving nature of the L ligands was a crucial factor for initiating the catalytic reaction: the catalytic activity of the carboxylate-bridged complex 1a and the triflate-bridged complex 1g in the initial 30 min highly depended on the ligand-exchange rate of L, as estimated by monitoring the reaction with CCl4 in pyridine, giving the pyridine adduct complex, [Mo2(DAniF)3Cl(py)] (3). PMID- 27976877 TI - Fabrication of GaAs, InxGa1-xAs and Their ZnSe Core/Shell Colloidal Quantum Dots. AB - We first report the GaAs/ZnSe and InxGa1-xAs/ZnSe core/shell structured colloidal quantum dots (CQDs). GaAs based CQD, which are hard to obtain by the chemical synthetic method, can be prepared successfully using the acetylacetonate complex of indium and gallium as cationic precursors. We control the indium contents, and the photoluminescence emission is tuned from orange to deep red. In0.2Ga0.8As/ZnSe core/shell QDs show the best quantum yield of 25.6%. A ZnSe outer shell protects the core and improves quantum yield, and it shows a large red shift owing to the quasi-type-I band structure. PMID- 27976878 TI - Worldwide Occurrence of Mycotoxins in Cereals and Cereal-Derived Food Products: Public Health Perspectives of Their Co-occurrence. AB - Cereal grains and their processed food products are frequently contaminated with mycotoxins. Among many, five major mycotoxins of aflatoxins, ochratoxins, fumonisins, deoxynivalenol, and zearalenone are of significant public health concern as they can cause adverse effects in humans. Being airborne or soilborne, the cosmopolitan nature of mycotoxigenic fungi contribute to the worldwide occurrence of mycotoxins. On the basis of the global occurrence data reported during the past 10 years, the incidences and maximum levels in raw cereal grains were 55% and 1642 MUg/kg for aflatoxins, 29% and 1164 MUg/kg for ochratoxin A, 61% and 71,121 MUg/kg for fumonisins, 58% and 41,157 MUg/kg, for deoxynivalenol, and 46% and 3049 MUg/kg for zearalenone. The concentrations of mycotoxins tend to be lower in processed food products; the incidences varied depending on the individual mycotoxins, possibly due to the varying stability during processing and distribution of mycotoxins. It should be noted that more than one mycotoxin, produced by a single or several fungal species, may occur in various combinations in a given sample or food. Most studies reported additive or synergistic effects, suggesting that these mixtures may pose a significant threat to public health, particularly to infants and young children. Therefore, information on the co occurrence of mycotoxins and their interactive toxicity is summarized in this paper. PMID- 27976879 TI - Oxide Ion Conductivity in the Hexagonal Perovskite Derivative Ba3MoNbO8.5. AB - Oxide ion conductors are important materials with a range of technological applications and are currently used as electrolytes for solid oxide fuel cells and solid oxide electrolyzer cells. Here we report the crystal structure and electrical properties of the hexagonal perovskite derivative Ba3MoNbO8.5. Ba3MoNbO8.5 crystallizes in a hybrid of the 9R hexagonal perovskite and palmierite structures. This is a new and so far unique crystal structure that contains a disordered distribution of (Mo/Nb)O6 octahedra and (Mo/Nb)O4 tetrahedra. Ba3MoNbO8.5 shows a wide stability range and exhibits predominantly oxide ion conduction over a pO2 range from 10-20 to 1 atm with a bulk conductivity of 2.2 * 10-3 S cm-1 at 600 degrees C. The high level of conductivity in a new structure family suggests that further study of hexagonal perovskite derivatives containing mixed tetrahedral and octahedral geometry could open up new horizons in the design of oxygen conducting electrolytes. PMID- 27976880 TI - Hiding in Plain Sight: The Bimetallic Magnesium Covalent Bond in Enzyme Active Sites. AB - The transfer of phosphate groups is an essential function of many intracellular biological enzymes. The transfer is in many cases facilitated by a protein scaffold involving two closely spaced magnesium "ions". It has long been a mystery how these "ions" can retain their closely spaced positions throughout enzymatic phosphate transfer: Coulomb's law would dictate large repulsive forces between these ions at the observed distances. Here we show, however, that the electron density can be borrowed from nearby electron-rich oxygens to populate a bonding molecular orbital that is largely localized between the magnesium "ions". The result is that the Mg-Mg core of these phosphate transfer enzymes is surprisingly similar to a metastable [Mg2]2+ ion in the gas phase, an ion that has been identified experimentally and studied with high-level quantum-mechanical calculations. This similarity is confirmed by comparative computations of the electron densities of [Mg2]2+ in the gas phase and the Mg-Mg core in the structures derived from QM/MM studies of high-resolution X-ray crystal structures. That there is a level of covalent bonding between the two Mg "ions" at the core of these enzymes is a novel concept that enables an improved vision of how these enzymes function at the molecular level. The concept is broader than magnesium-other biologically relevant metals (e.g., Mn and Zn) can also form similar stabilizing covalent Me-Me bonds in both organometallic and inorganic crystals. PMID- 27976882 TI - A Natural Component-Based Oxygen Indicator with In-Pack Activation for Intelligent Food Packaging. AB - Intelligent food packaging can provide consumers with reliable and correct information on the quality and safety of packaged foods. One of the key constituents in intelligent packaging is a colorimetric oxygen indicator, which is widely used to detect oxygen gas involved in food spoilage by means of a color change. Traditional oxygen indicators consisting of redox dyes and strong reducing agents have two major problems: they must be manufactured and stored under anaerobic conditions because air depletes the reductant, and their components are synthetic and toxic. To address both of these serious problems, we have developed a natural component-based oxygen indicator characterized by in pack activation. The conventional oxygen indicator composed of synthetic and artificial components was redesigned using naturally occurring compounds (laccase, guaiacol, and cysteine). These natural components were physically separated into two compartments by a fragile barrier. Only when the barrier was broken were all of the components mixed and the function as an oxygen indicator was begun (i.e., in-pack activation). Depending on the component concentrations, the natural component-based oxygen indicator exhibited different response times and color differences. The rate of the color change was proportional to the oxygen concentration. This novel colorimetric oxygen indicator will contribute greatly to intelligent packaging for healthier and safer foods. PMID- 27976883 TI - Biasing Simulations of DNA Base Pair Parameters with Application to Propellor Twisting in AT/AT, AA/TT, and AC/GT Steps and Their Uracil Analogs. AB - An accurate and efficient implementation of the six DNA base pair parameters as order parameters for enhanced sampling simulations is presented. The parameter definitions are defined by vector algebra operations on a reduced atomic set of the base pair, and correlate very well with standard definitions. Application of the model is illustrated by umbrella sampling simulations of propeller twisting within AT/AT, AA/TT, and AC/GT steps and their uracil analogs. Strong correlations are found between propeller twisting and a number of conformational parameters, including buckle, opening, BI/BII backbone configuration, and sugar puckering. The thymine methyl group is observed to notably alter the local conformational free energy landscape, with effects within and directly upstream of the thymine containing base pair. PMID- 27976881 TI - Photodynamic Therapy Mediated by Nontoxic Core-Shell Nanoparticles Synergizes with Immune Checkpoint Blockade To Elicit Antitumor Immunity and Antimetastatic Effect on Breast Cancer. AB - An effective, nontoxic, tumor-specific immunotherapy is the ultimate goal in the battle against cancer, especially the metastatic disease. Checkpoint blockade based immunotherapies have been shown to be extraordinarily effective but benefit only the minority of patients whose tumors have been pre-infiltrated by T cells. Here, we show that Zn-pyrophosphate (ZnP) nanoparticles loaded with the photosensitizer pyrolipid (ZnP@pyro) can kill tumor cells upon irradiation with light directly by inducing apoptosis and/or necrosis and indirectly by disrupting tumor vasculature and increasing tumor immunogenicity. Furthermore, immunogenic ZnP@pyro photodynamic therapy (PDT) treatment sensitizes tumors to checkpoint inhibition mediated by a PD-L1 antibody, not only eradicating the primary 4T1 breast tumor but also significantly preventing metastasis to the lung. The abscopal effects on both 4T1 and TUBO bilateral syngeneic mouse models further demonstrate that ZnP@pyro PDT treatment combined with anti-PD-L1 results in the eradication of light-irradiated primary tumors and the complete inhibition of untreated distant tumors by generating a systemic tumor-specific cytotoxic T cell response. These findings indicate that nanoparticle-mediated PDT can potentiate the systemic efficacy of checkpoint blockade immunotherapies by activating the innate and adaptive immune systems in tumor microenvironment. PMID- 27976885 TI - Ethylenediamine Promotes Cu Nanowire Growth by Inhibiting Oxidation of Cu(111). AB - The synthesis of metal nanostructures usually requires a capping agent that is generally thought to cause anisotropic growth by blocking the addition of atoms to specific crystal facets. This work uses a series of electrochemical measurements with a quartz crystal microbalance and single-crystal electrodes to elucidate the facet-selective chemistry occurring in the synthesis of Cu nanowires. Contrary to prevailing hypotheses, ethylenediamine, a so-called capping agent in the synthesis of Cu nanowires, causes anisotropic growth by increasing the rate of atomic addition to (111) facets at the end of a growing nanowire relative to (100) facets on the sides of a nanowire. Ethylenediamine increases the reduction rate of Cu(OH)2- on a Cu(111) surface relative to Cu(100) by selectively inhibiting the formation of Cu oxide on Cu(111). This work demonstrates how studying facet-selective electrochemistry can improve the understanding of the processes by which atoms assemble to form anisotropic metal nanostructures. PMID- 27976884 TI - Synthesis and Herbicidal Activities of p-Menth-3-en-1-amine and Its Schiff Base Derivatives. AB - p-Menth-3-en-1-amine, 4, and its Schiff base derivatives, 5a-l, were designed and synthesized. They were characterized by FT-IR, ESI+-MS, HRMS, 1H NMR, and 13C NMR spectral analyses, and their pre-emergence herbicidal activities against ryegrass were evaluated. All of the compounds showed excellent herbicidal activity. The Schiff bases showed stronger herbicidal activities than the original amine 4. These compounds showed herbicidal activities comparable to that of glyphosate. The herbicidal activities of 5k and 5l against ryegrass shoot growth were 78.3 and 355.6% higher than that of glyphosate, respectively. Furthermore, the introduction of a chlorine or bromine atom into the Schiff base derivatives containing a furan or benzene ring was beneficial to increase the activity. However, the herbicidal activities were not clearly affected when the heteroatom of the five-membered heterocyclic Schiff base or the position of the substituent on pyridine Schiff base was altered. PMID- 27976886 TI - MIB: Metal Ion-Binding Site Prediction and Docking Server. AB - The structure of a protein determines its biological function(s) and its interactions with other factors; the binding regions tend to be conserved in sequence and structure, and the interacting residues involved are usually in close 3D space. The Protein Data Bank currently contains more than 110 000 protein structures, approximately one-third of which contain metal ions. Identifying and characterizing metal ion-binding sites is thus essential for investigating a protein's function(s) and interactions. However, experimental approaches are time-consuming and costly. The web server reported here was built to predict metal ion-binding residues and to generate the predicted metal ion bound 3D structure. Binding templates have been constructed for regions that bind 12 types of metal ion-binding residues have been used to construct binding templates. The templates include residues within 3.5 A of the metal ion, and the fragment transformation method was used for structural comparison between query proteins and templates without any data training. Through the adjustment of scoring functions, which are based on the similarity of structure and binding residues. Twelve kinds of metal ions (Ca2+, Cu2+, Fe3+, Mg2+, Mn2+, Zn2+, Cd2+, Fe2+, Ni2+, Hg2+, Co2+, and Cu+) binding residues prediction are supported. MIB also provides the metal ions docking after prediction. The MIB server is available at http://bioinfo.cmu.edu.tw/MIB/ . PMID- 27976887 TI - A Dye-Sensitized Photoelectrochemical Tandem Cell for Light Driven Hydrogen Production from Water. AB - Tandem junction photoelectrochemical water-splitting devices, whereby two light absorbing electrodes targeting separate portions of the solar spectrum generate the voltage required to convert water to oxygen and hydrogen, enable much higher possible efficiencies than single absorber systems. We report here on the development of a tandem system consisting of a dye-sensitized photoelectrochemical cell (DSPEC) wired in series with a dye-sensitized solar cell (DSC). The DSPEC photoanode incorporates a tris(bipyridine)ruthenium(II) type chromophore and molecular ruthenium based water oxidation catalyst. The DSPEC was tested with two more-red absorbing DSC variations, one utilizing N719 dye with an I3-/I- redox mediator solution and the other D35 dye with a tris(bipyridine)cobalt ([Co(bpy)3]3+/2+) based mediator. The tandem configuration consisting of the DSPEC and D35/[Co(bpy)3]3+/2+ based DSC gave the best overall performance and demonstrated the production of H2 from H2O with the only energy input from simulated solar illumination. PMID- 27976888 TI - Magnetic Properties of a Dinuclear Nickel(II) Complex with 2,6-Bis[(2 hydroxyethyl)methylaminomethyl]-4-methylphenolate. AB - Magnetic properties of dinuclear nickel(II) complex [Ni2(sym hmp)2](BPh4)2.3.5DMF.0.5(2-PrOH) (1), where (sym-hmp)- is 2,6-bis[(2 hydroxyethyl)methylaminomethyl]-4-methylphenolate anion and DMF indicates dimethylformamide, were investigated using high-frequency and -field electron paramagnetic resonance (HFEPR). To magnetically characterize the mononuclear nickel(II) species forming the dimer, its two dinuclear zinc(II) analogues, [Zn2(sym-hmp)2](BPh4)2.3.5DMF.0.5(2-PrOH) (2) and [Zn2(sym hmp)2](BPh4)2.2acetone.2H2O (2'), were prepared. One of them (2') was structurally characterized by X-ray diffractometry and doped with 5% mol nickel(II) ions to prepare a mixed crystal 3. From the HFEPR results on complex 1 obtained at 40 K, the spin Hamiltonian parameters of the first excited spin state (S = 1) of the dimer were accurately determined as |D1| = 9.99(2) cm-1, |E1| = 1.62(1) cm-1, and g1 = [2.25(1), 2.19(2), 2.27(2)], and for the second excited spin state (S = 2) at 150 K estimated as |D2| ~ 3.5 cm-1. From these numbers, the single-ion zero-field splitting (ZFS) parameter of the Ni(II) ions forming the dimer was estimated as |DNi| ~ 10-10.5 cm-1. The HFEPR spectra of 3 yielded directly the single-ion parameters for DNi = +10.1 cm-1, |ENi| = 3.1 cm-1, and giso = 2.2. On the basis of the HFEPR results, the previously obtained magnetic data (Sakiyama, H.; Tone, K.; Yamasaki, M.; Mikuriya, M. Inorg. Chim. Acta 2011, 365, 183) were reanalyzed, and the isotropic interaction parameter between the Ni(II) ions was determined as J = -70 cm-1 (Hex = -J SA.SB). Finally, density functional theory calculations yielded the J value of -90 cm-1 in a qualitative agreement with the experiment. PMID- 27976889 TI - Trends in Food Enzymology. PMID- 27976890 TI - Synthesis, Acaricidal Activity, and Structure-Activity Relationships of Pyrazolyl Acrylonitrile Derivatives. AB - A series of novel pyrazolyl acrylonitrile derivatives was designed, targeting Tetranychus cinnabarinus, and synthesized. Their structures were identified by combination of 1H NMR, 13C NMR, and MS spectra. The structures of compounds 18 and 19 were further confirmed by X-ray diffraction. Extensive greenhouse bioassays indicated that compound 19 exhibits excellent acaricidal activity against all developmental stages of T. cinnabarinus, which is better than the commercialized compounds cyenopyrafen and spirodiclofen. It was shown that the acute toxicity of compounds 19 to mammals is quite low. The structure-activity relationships are also discussed. PMID- 27976891 TI - Multifold C-C Coupling and Unorthodox Cyclization Catalysis for Selective Synthesis of Indolotriarylmethanes, Indolocarbazoles, and Their Analogues: A Control Experiment Study. AB - The selective construction of medicinally and synthetically important indole based unsymmetrical triarylmethanes using indoles and aldehydes is challenging because the significant nucleophilicity of indole leads to C-C coupling with an azafulvene intermediate to build up the alternative bis(indolyl)methane products, which may be useful synthons. A new, straightforward, ligand-free CuII catalytic strategy for easy syntheses of unsymmetrical indolotriarylmethanes and new bisindolylbenzoyl analogues is established through the dual C-C coupling of an assembly of three reaction partners comprising aldehydes, indoles, and arylboronic acids. More importantly, this approach is exploited for multifold C-C coupling cyclization reactions with C-C cleavage using symmetrical bisindolylbenzoylmethanes in the presence of an organic base and aerial molecular oxygen as a stoichiometric oxidant. In contrast to the formation of a simple cyclocondensation product indolocarbazole, it undergoes unprecedented selective pseudo-four-component tandem oxidative cyclization with fragmentation from a 1,3 dicarbonyl compound to produce valuable fused 5,7-dihydroindolo[2,3-b]carbazoles through the functionalization of two indole C(sp2)-H and one C(sp3)-H bond of the active methylene residue. For a better understanding of the new reactions, we have studied various competition experiments and ESI-MS and 3D Mid-IR-ATR spectral analyses of the ongoing reactions. The predicted DFT transition state model is also in agreement with the experimental results. PMID- 27976893 TI - Palladium-Catalyzed Synthesis of Indoles and Isoquinolines with in Situ Generated Phosphinimine. AB - A palladium-catalyzed synthesis of polysubstituted indoles and isoquinolines through the coupling of aryl bromides with 2-alkynyl arylazides or 2-alkynyl benzylazides has been developed. This method provides straightforward access to indoles and isoquinolines with high efficiency and excellent functional group compatibility. In this transformation, the iminophosphorane in situ generated from azides is served as the nucleophile that attacks the alkyne moiety in the cyclization process. PMID- 27976892 TI - Fatty Acid Cysteamine Conjugates as Novel and Potent Autophagy Activators That Enhance the Correction of Misfolded F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). AB - A depressed autophagy has previously been reported in cystic fibrosis patients with the common F508del-CFTR mutation. This report describes the synthesis and preliminary biological characterization of a novel series of autophagy activators involving fatty acid cysteamine conjugates. These molecular entities were synthesized by first covalently linking cysteamine to docosahexaenoic acid. The resulting conjugate 1 synergistically activated autophagy in primary homozygous F508del-CFTR human bronchial epithelial (hBE) cells at submicromolar concentrations. When conjugate 1 was used in combination with the corrector lumacaftor and the potentiator ivacaftor, it showed an additive effect, as measured by the increase in the chloride current in a functional assay. In order to obtain a more stable form for oral dosing, the sulfhydryl group in conjugate 1 was converted into a functionalized disulfide moiety. The resulting conjugate 5 is orally bioavailable in the mouse, rat, and dog and allows a sustained delivery of the biologically active conjugate 1. PMID- 27976894 TI - Discovery of 2H-Chromen-2-one Derivatives as G Protein-Coupled Receptor-35 Agonists. AB - A family of 2H-chromen-2-one derivatives were identified as G protein-coupled receptor-35 (GPR35) agonists using dynamic mass redistribution assays in HT-29 cells. The compounds with 1H-tetrazol-5-yl in 3-substituted position displayed higher potency than the corresponding carboxyl analogs, and the hydroxyl group in the 7-position also played an important role in GPR35 agonistic activity. 6-Bromo 7-hydroxy-8-nitro-3-(1H-tetrazol-5-yl)-2H-chromen-2-one (50) was found to be the most potent GPR35 agonist with an EC50 of 5.8 nM. Calculating the physicochemical properties of compounds with moderate to high potency suggested that compounds 30, 50, and 51 showed good druggability. This study provides a novel series of GPR35 agonists, and compound 50 may be a powerful tool to study GPR35. PMID- 27976895 TI - Angiogenesis Inhibitors and Anti-Inflammatory Agents from Phoma sp. NTOU4195. AB - Seven new polyketides, phomaketides A-E (1-5) and pseurotins A3 (6) and G (7), along with the known compounds FR-111142, pseurotins A, A1, A2, D, and F2, 14 norpseurotin A, alpha-carbonylcarbene, tyrosol, cyclo(-l-Pro-l-Leu), and cyclo(-l Pro-l-Phe), were purified from the fermentation broth and mycelium of the endophytic fungal strain Phoma sp. NTOU4195 isolated from the marine red alga Pterocladiella capillacea. The structures were established through interpretation of spectroscopic data. The antiangiogenic and anti-inflammatory effects of 1-7 and related analogues were evaluated using human endothelial progenitor cells (EPCs) and lipopolysaccharide (LPS)-activated murine macrophage RAW264.7 cells, respectively. Of the compounds tested, compound 1 exhibited the most potent antiangiogenic activity by suppressing the tube formation of EPCs with an IC50 of 8.1 MUM, and compound 3 showed the most selective inhibitory activity of LPS induced NO production in RAW264.7 macrophages with an IC50 value of 8.8 MUM. PMID- 27976896 TI - Molecular Structure and Conformational Analysis of 1-Phenyl-1-X-1 Silacyclohexanes (X = F, Cl) by Electron Diffraction, Low-Temperature NMR, and Quantum Chemical Calculations. AB - The molecular structure and conformational preferences of 1-phenyl-1-X-1 silacyclohexanes C5H10Si(Ph,X) (X = F (3), Cl (4)) were studied by gas-phase electron diffraction, low-temperature NMR spectroscopy, and high-level quantum chemical calculations. In the gas phase only three (3) and two (4) stable conformers differing in the axial or equatorial location of the phenyl group and the angle of rotation about the Si-CPh bond (axi and axo denote the Ph group lying in or out of the X-Si-CPh plane) contribute to the equilibrium. In 3 the ratio Pheq:Phaxo:Phaxi is 40(12):55(24):5 and 64:20:16 by experiment and theory, respectively. In 4 the ratio Pheq:Phaxo is 79(15):21(15) and 71:29 by experiment and theory (M06-2X calculations), respectively. The gas-phase electron diffraction parameters are in good agreement with those obtained from theory at the M06-2X/aug-ccPVTZ and MP2/aug-cc-pVTZ levels. Unlike the case for M06-2X, MP2 calculations indicate that 3-Pheq conformer lies 0.5 kcal/mol higher than the 3 Phaxo conformer. As follows from QTAIM analysis, the phenyl group is more stable when it is located in the axial position but produces destabilization of the silacyclohexane ring. By low-temperature NMR spectroscopy the six-membered-ring interconversion could be frozen at 103 K and the present conformational equilibria of 3 and 4 could be determined. The ratio of the conformers is 3 Pheq:3-Phax = (75-77):(23-25) and 4-Pheq:4-Phax = 82:18. PMID- 27976898 TI - Polycyclic Ring Formation Using Bis-diazolactams for Cascade Stitching. AB - The chemoselective reaction of donor/acceptor (D/A) and acceptor/acceptor (A/A) diazo moieties in the same molecule was examined using 3-diazo-1-(ethyl 2 diazomalonyl)indolin-2-one under rhodium(II) catalysis. The metallo carbenoid derived from the D/A diazo group is preferentially formed and undergoes selective CH, NH, and OH insertion reactions, cyclopropanation, cyclopropenation, sulfur ylide formation/2,3-sigmatropic rearrangement, as well as nitrogen ylide formation followed by azetidine ring expansion. The initial reaction can be paired with a subsequent tandem cascade sequence involving dipole formation/cycloaddition in either an intra- or intermolecular sense to generate polycyclic N-heterocycles in one pot, with the formation up to three new rings in a single operation. Excellent diastereoselectivity was observed in the intramolecular cycloaddition reaction producing 5 to 7-membered rings. PMID- 27976897 TI - Potent, Selective, Allosteric Inhibition of Human Plasmin by Sulfated Non Saccharide Glycosaminoglycan Mimetics. AB - Although plasmin inhibitors could be used in multiple disorders, their use has been restricted to preventing blood loss in hemostatic dysregulation because of poor efficacy and adverse effects of current agents. We reasoned that a new class of direct inhibitors that offer better efficacy, selectivity, and safety could be discovered by exploiting allosterism in plasmin, a protease homologous to other allosteric serine proteases. We report on the synthesis, biological activity, and mechanism of action of a group of small molecules, called non-saccharide glycosaminoglycan mimetics (NSGMs), as direct allosteric plasmin inhibitors. Our results show that distinct NSGMs selectively inhibit human full-length plasmin. The molecule inhibited clot lysis, alluding to its promise as an allosteric regulator of plasmin. We show that direct allosteric inhibition of plasmin could led to new antifibrinolytic agent(s) that may exhibit better efficacy, potency, selectivity, and safety in comparison to current therapy. PMID- 27976899 TI - Ab Initio Multiple Spawning Photochemical Dynamics of DMABN Using GPUs. AB - The ultrafast decay dynamics of 4-(N,N-dimethylamino)benzonitrile (DMABN) following photoexcitation was studied with the ab initio multiple spawning (AIMS) method, combined with GPU-accelerated linear-response time-dependent density functional theory (LR-TDDFT). We validate the LR-TDDFT method for this case and then present a detailed analysis of the first ~200 fs of DMABN excited-state dynamics. Almost complete nonadiabatic population transfer from S2 (the initially populated bright state) to S1 takes place in less than 50 fs, without significant torsion of the dimethylamino (DMA) group. Significant torsion of the DMA group is only observed after the nuclear wavepacket reaches S1 and acquires locally excited electronic character. Our results show that torsion of the DMA group is not prerequisite for nonadiabatic transitions in DMABN, although such motion is indeed relevant on the lowest excited state (S1). PMID- 27976901 TI - Multicomposition EPSR: Toward Transferable Potentials To Model Chalcogenide Glass Structures. AB - The structure of xAs40Se60-(1 - x)As40S60 glasses, where x = 1.000, 0.667, 0.500, 0.333, 0.250, and 0.000, is investigated using a combination of neutron and X-ray diffraction coupled with computational modeling using multicomposition empirical potential structure refinement (MC-EPSR). Traditional EPSR (T-EPSR) produces a set of empirical potentials that drive a structural model of a particular composition to agreement with diffraction experiments. The work presented here establishes the shortcomings in generating such a model for a ternary chalcogenide glass composition. In an enhancement to T-EPSR, MC-EPSR produces a set of pair potentials that generate robust structural models across a range of glass compositions. The structures obtained vary with composition in a much more systematic way than those taken from T-EPSR. For example, the average arsenic sulfur bonding distances vary between 2.28 and 2.46 A in T-EPSR but are 2.29 +/- 0.02 A in MC-EPSR. Similarly, the arsenic-selenium bond lengths from T-EPSR vary between 2.28 and 2.43 A but are consistently 2.40 +/- 0.02 A in the MC-EPSR results. Analysis of these models suggests that the average separation of the chalcogen (S or Se) atoms is the structural origin of the changes in nonlinear refractive index with glass composition. PMID- 27976900 TI - A Rhodium(III) Complex as an Inhibitor of Neural Precursor Cell Expressed, Developmentally Down-Regulated 8-Activating Enzyme with in Vivo Activity against Inflammatory Bowel Disease. AB - We report herein the identification of the rhodium(III) complex [Rh(phq)2(MOPIP)]+ (1) as a potent and selective ATP-competitive neural precursor cell expressed, developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) inhibitor. Structure-activity relationship analysis indicated that the overall organometallic design of complex 1 was important for anti-inflammatory activity. Complex 1 showed promising anti-inflammatory activity in vivo for the potential treatment of inflammatory bowel disease. PMID- 27976902 TI - Synthesis of gamma-Lactams by Mild, o-Benzoquinone-Induced Oxidation of Pyrrolidines Containing Oxidation-Sensitive Functional Groups. AB - The late-stage oxidation of substituted pyrrolidines offers good flexibility for the construction of gamma-lactam libraries, and especially in recent years the methods for functionalization of pyrrolidine have been available. We reported a new strategy for oxidation of pyrrolidines to gamma-lactams: reaction of pyrrolidine with an o-benzoquinone gives an N,O-acetal by direct oxidation of the alpha-C-H bond of the pyrrolidine ring, and then the N,O-acetal is further oxidized by the o-benzoquinone to the gamma-lactam. Because the first oxidation occurs selectively at the alpha-C-H of the pyrrolidine ring, oxidation-sensitive functional groups (allyl-, vinyl-, hydroxyl-, and amino groups) on pyrrolidine ring are unaffected. The synthetic utility of this novel method was demonstrated by the facile syntheses of (S)-vigabatrin and two analogues. PMID- 27976903 TI - Synthesis and Evaluation of Amyloid beta Derived and Amyloid beta Independent Enhancers of the Peroxidase-like Activity of Heme. AB - Labile heme has been suggested to have an impact in several severe diseases. In the context of Alzheimer's disease (AD), however, decreased levels of free heme have been reported. Therefore, we were looking for an assay system that can be used for heme concentration determination. From a biochemical point of view the peroxidase activity of the Abeta-heme complex seemed quite attractive to pursue this goal. As a consequence, a peptide that is able to increase the readout even in the case of a low heme concentration is favorable. The examination of Abeta- and non-Abeta-derived peptides in complex with heme revealed that the peroxidase like activity significantly depends on the peptide sequence and length. A 23mer His-based peptide derived from human fatty acyl-CoA reductase 1 in complex with heme exhibited a significantly higher peroxidase activity than Abeta(40)-heme. Structural modeling of both complexes demonstrated that heme binding via a histidine can be supported by hydrogen bond interactions of a basic residue near the propionate carboxyl function of protoporphyrin IX. Furthermore, the interplay of Abeta-heme and the lipoprotein LDL as a potential physiological effector of Abeta was examined. PMID- 27976905 TI - Structure and Electronic Transitions of C7H4O2+ and C7H5O2+ Ions: Neon Matrix and Theoretical Studies. AB - C7H4O2+ and C7H5O2+ ions and the respective neutrals have been investigated by absorption spectroscopy in neon matrixes following mass selection of ions produced from salicylic acid. Three electronic transitions starting at 649.6, 431.0, and 372.0 nm are detected for C7H4O2+ and assigned on the basis of CASPT2 energies and Franck-Condon simulations as the excitations from the X 2A" to the 1 2A", 2 2A", and 3 2A" electronic states of 6-(oxomethylene)-2,4-cyclohexadien-1 one ion (A+). Absorptions commencing at 366.4 nm are observed for C7H5O2+ and assigned to the 1 2A' <- X 2A' electronic transition of (2 hydroxyphenyl)methanone ion (J+). Neutralization of J+ leads to the appearance of four absorption systems attributed to the 4 2A", 3 2A", 2 2A", and 1 2A" <- X 2A" transitions of J with origin bands 291.3, 361.2, 393.8, and 461.2 nm. PMID- 27976906 TI - A One-Pot Synthesis of 2-Aminopyrimidines from Ketones, Arylacetylenes, and Guanidine. AB - The three-component reaction of ketones, arylacetylenes, and guanidine catalyzed by the KOBut/DMSO system leads to 2-aminopyrimidines in up to 80% yield. Depending on structure of the starting ketones, the aromatization of intermediate dihydropyrimidines occurs either with loss of hydrogen molecules or methylbenzenes. The latter process takes place in the ketones, in which one of the substituents is not a methyl group. The reaction conditions are tolerable for dialkyl-, aryl(hetaryl) alkyl-, and cycloalkyl ketones. PMID- 27976904 TI - Distinguishing Isomeric Peptides: The Unimolecular Reactivity and Structures of (LeuPro)M+ and (ProLeu)M+ (M = Alkali Metal). AB - The unimolecular chemistries and structures of gas-phase (ProLeu)M+ and (LeuPro)M+ complexes when M = Li, Na, Rb, and Cs have been explored using a combination of SORI-CID, IRMPD spectroscopy, and computational methods. CID of both (LeuPro)M+ and (ProLeu)M+ showed identical fragmentation pathways and could not be differentiated. Two of the fragmentation routes of both peptides produced ions at the same nominal mass as (Pro)M+ and (Leu)M+, respectively. For the litiated peptides, experiments revealed identical IRMPD spectra for each of the m/z 122 and 138 ions coming from both peptides. Comparison with computed IR spectra identified them as the (Pro)Li+ and (Leu)Li+, and it is concluded that both zwitterionic and canonical forms of (Pro)Li+ exist in the ion population from CID of both (ProLeu)Li+ and (LeuPro)Li+. The two isomeric peptide complexes could be distinguished using IRMPD spectroscopy in both the fingerprint and the CH/NH/OH regions. The computed IR spectra for the lowest energy structures of each charge solvated complexes are consistent with the IRMPD spectra in both regions for all metal cation complexes. Through comparison between the experimental spectra, it was determined that in lithiated and sodiated ProLeu, metal cation is bound to both carbonyl oxygens and the amine nitrogen. In contrast, the larger metal cations are bound to the two carbonyls, while the amine nitrogen is hydrogen bonded to the amide hydrogen. In the lithiated and sodiated LeuPro complexes, the metal cation is bound to the amide carbonyl and the amine nitrogen while the amine nitrogen is hydrogen bonded to the carboxylic acid carbonyl. However, there is no hydrogen bond in the rubidiated and cesiated complexes; the metal cation is bound to both carbonyl oxygens and the amine nitrogen. Details of the position of the carboxylic acid C?O stretch were especially informative in the spectroscopic confirmation of the lowest energy computed structures. PMID- 27976907 TI - Four- and Five-Component Syntheses and Photophysical Properties of Emission Solvatochromic 3-Aminovinylquinoxalines. AB - 3-Aminovinylquinoxalines are readily accessible from (hetero)aryl glyoxylic acids or heterocyclic pi-nucleophiles by consecutive four- and five-component syntheses in the sense of an activation-alkynylation-cyclocondensation-addition sequence or glyoxylation-alkynylation-cyclocondensation-addition sequence in good yields. The title compounds are highly fluorescent with pronounced emission solvatochromicity and protochromic fluorescence quenching. Time-resolved fluorescence spectroscopy furnishes radiative and nonradiative fluorescence decay rates in various solvent polarities. The electronic structure is corroborated by DFT and TD-DFT calculations rationalizing the observed spectroscopic effects. PMID- 27976908 TI - Weak Selectivity Predicted for Modeled Bundles of Viral Channel-Forming Protein E5 of Human Papillomavirus-16. AB - Protein E5 is a polytopic 83 amino acid membrane protein with three transmembrane domains (TMDs), encoded by high-risk human papillomavirus-16 (HPV-16). HPV-16 is found to be the causative agent for cervical cancer. Protein E5, among other proteins (e.g., E6, E7), is expressed at an "early" (E) stage when the cell turns malignant. It has been experimentally found that E5 forms hexameric assemblies, which show the characteristics of the class of so-called channel-forming proteins by rendering lipid membranes permeable to ions and small molecules. Protein E5 is used to achieve structural models of the protein in assembled bundles using a force field-based docking approach. Extended molecular dynamics simulations of selected bundles in fully hydrated lipid bilayers suggest the second TMD to be pore-lining, allowing for water columns to exist within the lumen of the pore. Full correlation analysis indicates asymmetric dynamics within the monomers of the bundle. Potential of mean force calculations of a snapshot structure of the putative open pore of the protein bundle propose low selectivity. PMID- 27976909 TI - Introduction of Quinolines and Isoquinolines onto Nonactivated alpha-C-H Bond of Tertiary Amides through a Radical Pathway. AB - Treatment of quinolines and isoquinolines with benzoyl peroxide in tertiary amides, such as N,N-dimethylacetamide, N,N-dimethylpropionamide, and N acetylpyrrolidine, etc., under irradiation with a Hg lamp in the temperature range of 35 degrees C to 40 degrees C gave C-C-bonded quinolines and isoquinolines bearing amide groups with high regioselectivity in good to moderate yields, respectively, under transition-metal-free conditions. PMID- 27976910 TI - Density Functional Investigations on the Selective Binding of an endo Functionalized Bis-urea Macrocycle. AB - The preferential binding of syn and anti configurational isomers of endo functionalized bis-urea molecular receptor to 1,2-dinitrobenzene (G1) and 1,4 dioxane (G2) guests has been explained using dispersion-corrected M06-2X-based density functional theory. The host-guest binding is facilitated via hydrogen bonding, C-H...pi, dipole-dipole, C...C and O...O (chalcogen-chalcogen) interactions. The formation of an inclusion complex is spontaneous and thermodynamically favorable. The molecular electrostatic potential and quantum theory of atoms in molecules in conjunction with the noncovalent interactions reduced density gradient have been employed to characterize the noncovalent interactions. The encapsulation of G1 or G2 within the pi-electron-rich cavity of the bis-urea macrocycle reflects the frequency shift of the characteristic N-H and C-H vibrations of their vibrational spectra. It has also been shown that binding of the bis-urea isomers to G1 and G2 emerges with a signature in the upfield signals of the guest protons confined to the host cavity in 1H NMR spectra. PMID- 27976911 TI - Accelerated Sedimentation Velocity Assessment for Nanowires Stabilized in a Non Newtonian Fluid. AB - In this work, the long-term stability of titanium oxide nanowire suspensions was accessed by an accelerated sedimentation with centrifugal forces. Titanium oxide (TiO2) nanoparticle (NP) and nanowire (NW) dispersions were prepared, and their sizes were carefully characterized. To replace the time-consuming visual observation, sedimentation velocities of the TiO2 NP and NW suspensions were measured using an analytical centrifuge. For an aqueous TiO2 NP suspension, the measured sedimentation velocities were linearly dependent on the relative centrifugal forces (RCF), as predicted by the classical Stokes law. A similar linear relationship was also found in the case of TiO2 NW aqueous suspensions. However, NWs preferred to settle parallel to the centrifugal direction under high RCF because of the lower flow resistance along the long axis. Thus, the extrapolated sedimentation velocity under regular gravity can be overestimated. Finally, a stable TiO2 NW suspension was formulated with a shear thinning fluid and showed great stability for weeks using visual observation. A theoretical analysis was deduced with rheological shear-thinning parameters to describe the nonlinear power-law dependence between the measured sedimentation velocities and RCF. The good agreement between the theoretical predictions and measurements suggested that the sedimentation velocity can be properly extrapolated to regular gravity. In summary, this accelerated assessment on a theoretical basis can yield quantitative information about long-term stability within a short time (a few hours) and can be further extended to other suspension systems. PMID- 27976912 TI - How Picky Eating Becomes an Illness-Marketing Nutrient-Enriched Formula Milk in a Chinese Society. AB - The essential adaptive food selection behavior of young children has become increasingly medicalized as a kind of disease-the "picky-eating" syndrome in Hong Kong. The researcher used the multiple case studies approach with data collected from in-depth interviews and advertisements to examine the process of the medicalization of picky-eating disorder, which demonstrates how an essential adaptive human behavior can be redefined by the market and medical system as a deviant, abnormal behavior that needs to be eliminated and how the resulting health risks can be resolved by modern medicine produced by this pharmaceutical nexus. PMID- 27976913 TI - Social support and mental health status of older people: a population-based study in Iran-Tehran. AB - OBJECTIVES: To investigate direct and stress-buffering associations between social support from family and the mental health of older people in Iran, a country which has recently undergone an exceptionally fast fertility transition and is consequently experiencing rapid population ageing. METHOD: A cross sectional stratified random survey of 800 people aged 60+ years resident in Tehran was conducted. In total, 644 people responded. The Social Provisions Scale and the General Health Questionnaire were used to measure perceived social support and mental health, respectively. Multilevel mixed-effects models were used to examine the hypotheses. RESULTS: The findings supported the hypothesis of a direct association between perceived and received social support and mental health. However, we did not find strong evidence to suggest that social support buffered the effects of stress arising from limitations of physical functioning. Lack of help doing paperwork was associated with worse mental health for women but not men. Source of support did not seem to be important. CONCLUSION: Our results indicated that in Tehran, as in Western settings, social support is important for the mental well-being of older people. Recommendations for policy and further research priorities based on the study findings were provided. PMID- 27976915 TI - Closed reduction of femoral fractures using an L-shaped arm retainer. PMID- 27976914 TI - Using a surgical spoon for safe thoracotomy closure in minimally invasive direct coronary artery bypass surgery. PMID- 27976916 TI - Dietary Diversity and Vegetable and Fruit Consumption of Households in a Resource Poor Peri-Urban South Africa Community Differ by Food Security Status. AB - Sociodemographic, living standard measure, consumption of vegetables and fruit, and dietary diversity in relation to household food security were assessed. Using a hunger score, households were categorized as food secure (n = 125) or food insecure (n = 273). Food secure respondents had a higher mean dietary diversity score (3.98; 95%CI [3.79, 4.18] versus 3.65; 95% [CI 3.53, 3.77]), were more likely to eat vitamin A-rich foods (OR 1.15; 95% CI [1.05, 1.26]), a more varied diet (DDS >= 4, OR 1.90; 95% CI [1.19, 3.13]), and vegetables daily (OR 3.37; 95% CI [2.00, 5.76]). Cost limited daily vegetable/fruit consumption in food insecure households. Respondents with >= 8 years of schooling were more likely (OR 2.07; 95% CI [1.22, 3.53]) and households receiving social grants were less likely (OR 0.37; 95% CI [0.19, 0.72]) to be food secure. Results highlight the association between dietary diversity and household food security. PMID- 27976917 TI - A relationship-focused investigation of spousal psychological adjustment to dual sensory loss. AB - OBJECTIVES: The relationship intimacy model of psychosocial adjustment to illness indicates that a patient's willingness to communicate about their illness, as perceived by the spouse, is a strong predictor of spouse relational and psychological well-being. Inspired by the relationship intimacy model, the current study examined the psychological adjustment of spouses of individuals with dual-sensory loss (DSL), a disability where interpersonal communication is of particular concern. METHOD: Surveys were sent to all known individuals and their partners who were 50 years of age or older and were enrolled in services for acquired DSL in Denmark. A total of 65 spouses met the inclusion criteria of which 45 (69%) returned a partner survey. RESULTS: Results showed a significant association between couples' sensory loss-related communication, relationship satisfaction, perceived support and psychological well-being. Perceived support significantly mediated the association between couples' sensory loss communication and spouse psychological well-being. CONCLUSION: The current study's findings provide support for a relationship-focused perspective of spousal psychological adjustment in the context of DSL. Further, couples' sensory loss-related communication is presented as a potential intervention target to enhance spouse perceived support and psychological well-being. PMID- 27976919 TI - By My Side: The University's First Service Dogs. PMID- 27976918 TI - Unraveling the Sikasso Paradox: Agricultural Change and Malnutrition in Sikasso, Mali. AB - When cash cropping leads to agricultural and livelihood changes in the Global South, concern about food security is common among policy makers. This is indeed the case in the Sikasso region of Mali, where many have suggested that the ubiquitous cash crop cotton is a cause of the unexpectedly high rates of malnutrition in the region. Using household and forest surveys, we found little evidence that cotton cultivation is associated with malnutrition or decreased food security at a household level, but we did find evidence of a coassociation between cotton cultivation, loss of natural capital, and malnutrition at the village level. PMID- 27976920 TI - Understanding informal carers' experiences of caring for older people with a hip fracture: a systematic review of qualitative studies. AB - PURPOSE: This systematic review aimed to reconceptualize experiences from a variety of papers to provide direction for research, policy and practice. METHOD: Meta-ethnography was used to inform the review, and 21 studies were included. FINDINGS: The analysis identified a core theme of "engaging in care: struggling through", as carers, who wanted to be involved in caring, learnt to live with the intense and stressful impact of caring and changes to their life. The core theme is represented through three themes (1) Helping another to live, (2) Adapting ways of living and (3) Negotiating the unknown. CONCLUSIONS: The discussion identified a focus on carers of people suffering from a hip fracture, the willingness of informal carers to engage in caring and the intense experience of adapting to changes in relationships and dependency alongside a steep experiential learning curve. Tensions exist in negotiations with complex health care systems as carers do not feel their expertise is valued and struggle to find and understand information. Implications for Rehabilitation Including relatives/carers in the umbrella of care within a family-centred approach. Involving relatives/carers within shared decision-making about care requirements and rehabilitation goals. Utilizing forms of experiential learning to help the development of relatives/carers skills in relation to their role as carer. Providing opportunities for carers to explore ways of sustaining their own health through self-compassion. PMID- 27976921 TI - Clash of the Primary Motivations: Motivated Processing of Emotionally Experienced Content in Fear Appeals About Obesity Prevention. AB - This study examined individuals' physiological and cognitive responses to different types of emotionally experienced content located in obesity prevention fear appeals. Results suggested that experienced valence impacted individuals' attention and memory as a function of experienced arousal level. Local content that created coactive highly arousing experiences received the most attention, though visual recognition suggested these messages were more difficult to encode. Local content that created negative moderately arousing experiences was best encoded. Global message evaluation data suggest that moderately arousing messages with a change in experienced valence may prove to be most effective, as they ensure attention and good memory while keeping high self-reported interest, and a high level of perceived severity of obesity. Implications and suggestions for future research are discussed. PMID- 27976922 TI - Texting Under the Influence: Emotional Regulation as a Moderator of the Association Between Binge Drinking and Drunk Texting. AB - Texting and alcohol have each been noted to increase perceptions of control, decrease behavioral inhibition, and modulate unpleasant emotions. While drunk texting is a well-known cultural phenomenon, it has received almost no attention in research. In a sample of 211 young adult women, and using a new measure to operationalize drunk texting, difficulty accessing strategies during moments of distress moderated the relationship between binge drinking and drunk texting. Difficulties accessing emotion regulation strategies were associated with drunk texting among those who reported binge drinking. Among nonbinge drinkers, deficits in emotion regulation strategies were not associated with drunk texting. In addition, drunk texting was associated with sex in bivariate correlations. Given the lack of research on the antecedents and consequences of drunk texting, this study suggests that drunk texting may be used as a strategy for emotional regulation and may be predictive of sexual behavior. Results inform several avenues for further inquiry into the motivations and expectations underlying drunk texting and also imply potential routes for intervention. PMID- 27976923 TI - Promoting Mental Health Help-Seeking Behavior Among First-Year College Students. AB - Awareness and utilization of mental health services on college campuses is a salient issue, particularly for first-year students as they transition into college life. The current study uses focus groups and surveys to test help seeking messages for first-year students. In this formative research, Phase 1 focus-group participants (N = 47) discussed four message concepts related to awareness of symptoms of mental health problems and services available to students. Phase 2 participants (N = 292) viewed one of three message concepts and then completed items that measured their perceptions of the message. Focus-group results helped prioritize likely effectiveness of messages based on responses to message features and provided an understanding of mental health help-seeking perceptions among college students. The quantitative results indicate the messages have potential for increasing awareness of mental health issues, as well as promoting availability of campus resources. Implications for tailoring campaign messages to first-year students are discussed. PMID- 27976924 TI - Quality of life for post-polio syndrome: a patient derived, Rasch standard scale. AB - OBJECTIVE: To design a disease-specific quality of life (QoL) questionnaire for people with post-polio syndrome (PPS). METHODS: Qualitative interviews were conducted with 45 people with PPS to identify themes and derive potential items reflecting impact upon QoL. After cognitive debriefing, these were made into a questionnaire pack along with comparative questionnaires and posted to 319 patients. The 271 (85%) returned questionnaires were subjected to exploratory factor analysis (EFA) and Rasch analysis. RESULTS: A 25 item scale, the post polio quality of life scale (PP-QoL), showed good fit to the Rasch model (conditional chi-square p = 0.156), unidimensionality (% t-tests 2.0: CI 0.7 3.8), and Cronbach's alpha of 0.87. With the latent estimate transformed to a 0 100 scale, the mean score was 56.9 (SD 18.5) with only 3.3% of respondents at the floor or ceiling of the scale. Test-retest reliability showed an intraclass correlation coefficient (ICC) (2.1) of 0.916, and correlation of 0.85. CONCLUSION: The disease-specific PP-QoL demonstrated excellent reliability, appropriate concurrent validity, and satisfied the standards of the Rasch model. It enables examination of the impact of health status upon perceived QoL, and the impact of rehabilitation interventions. The scale is freely available for academic or not-for-profit users to improve research in this neglected, disabling condition. Implications for Rehabilitation In post-polio syndrome (PPS), existing work examines aspects of health-related quality of life (HRQoL), such as activity limitations. A disease-specific QoL measure would enable researchers to model the impact of health status, such as fatigue or mobility restrictions, upon QoL in PPS. The post-polio quality of life scale (PP-QoL) is based on the patients' lived experience, meets Rasch standards and is free for use for academic and not for-profit researchers. The raw score is reliable for individual use in clinical settings, and interval scale transformation is available for parametric applications and the calculation of change scores. PMID- 27976925 TI - Previvors' Uncertainty Management Strategies for Hereditary Breast and Ovarian Cancer. AB - Individuals with a genetic predisposition to develop hereditary breast and ovarian cancer (HBOC), but who have not been diagnosed with cancer, are referred to as previvors. Although genetic testing may reduce previvors' worries about whether or not they have a high genetic cancer risk, testing positive produces negative emotions and long-term uncertainty-thus requiring the management of uncertainty. Existing research indicates family, friends, and social support networks are limited in their assistance for previvors' uncertainty management. Therefore, this study examined how health care providers may assist previvors in uncertainty management by asking: What strategies do BRCA-positive previvors enact with their health care providers to help manage their uncertainty about HBOC? Purposive sampling was employed to recruit participants via online social media. The final sample consisted of 34 BRCA-positive women. Interviews revealed four uncertainty management strategies-seeking health care providers as informational sources, seeking health care providers as partners for decision making, seeking health care providers for supportive communication, and seeking referrals from health care providers for social support networks. Findings indicate that health care providers who are knowledgeable about BRCA, provide information, answer questions, check understanding, and provide additional resources assist previvors in managing their uncertainties by distinguishing options and fostering meaning. PMID- 27976926 TI - Experiences of using information and communication technology within the first year after stroke - a grounded theory study. AB - PURPOSE: The purpose of this study was to identify how people 6-12 months after stroke were using and integrating information and communication technology (ICT) in their everyday lives. METHOD: To capture the participants' experiences, one focus group and 14 individual interviews were carried out in Sweden and Denmark regarding the use of ICT in everyday life. The participants comprised 11 men and seven women aged 41-79 years. A grounded theory approach was used throughout the study and a constant comparative method was used in the analysis. RESULTS: Five categories were identified from the analysis of the interviews with the participants: 1) Using the mobile phone to feel safe, 2) Staying connected with others, 3) Recreating everyday life, 4) A tool for managing everyday life, and 5) Overcoming obstacles for using ICT. From these categories one core category emerged: The drive to integrate ICT in everyday life after stroke. CONCLUSIONS: People with stroke had a strong drive to integrate ICT in order to manage and bring meaning to their everyday lives, although sometimes they needed support and adaptations. It is not only possible but also necessary to start using ICT in rehabilitation in order to support people's recovery and promote participation in everyday life after stroke. Implications for rehabilitation People with stroke have a strong drive for using information and communication technology in their everyday lives, although support and adaptations are needed. The recovery process of people with stroke could benefit from the use of ICT in the rehabilitation and ICT could possibly contribute to independence and promote participation in everyday life. Knowledge from this study can be used in the development of an ICT based stroke rehabilitation model. PMID- 27976927 TI - Interview with Sanofi's Dr Tunde Falode. AB - Dr Tunde Falode speaks to Elena Conroy, Commissioning Editor: Dr Tunde Falode is General Manager for the Diabetes and Cardiovascular Business Unit in the UK and Ireland at Sanofi, a global pharmaceutical company. Following graduation from the University of Jos Medical School in Nigeria, he secured a basic surgical training post through Guy's and St Thomas' hospitals in London, eventually specializing in cardiac and thoracic surgery, before changing his career path. In addition to his current role at Sanofi, he recently completed his specialist training in pharmaceutical medicine and has a keen interest in sports. PMID- 27976928 TI - Post-acute care referral and inpatient rehabilitation admission criteria for persons with brain injury across two Canadian provinces. AB - PURPOSE: Investigate health care providers' perceptions of referral and admission criteria to brain injury inpatient rehabilitation in two Canadian provinces. METHODS: Health care providers (n = 345) from brain injury programs (13 acute care and 16 rehabilitation facilities) participated in a cross-sectional web based survey. The participants rated the likelihood of patients (traumatic brain injury and cerebral hypoxia) to be referred/admitted to rehabilitation and the influence of 19 additional factors (e.g., tracheostomy). The participants reported the perceived usefulness of referral/admission policies and assessment tools used. RESULTS: Ninety-one percent acute care and 98% rehabilitation participants reported the person with traumatic brain injury would likely or very likely be referred/admitted to rehabilitation compared to respectively 43% and 53% for the patient with hypoxia. Two additional factors significantly decreased the likelihood of referral/admission: older age and the combined presence of minimal learning ability, memory impairment and physical aggression. Some significant inter-provincial variations in the perceived referral/admission procedure were observed. Most participants reported policies were helpful. Similar assessment tools were used in acute care and rehabilitation. CONCLUSIONS: Health care providers appear to consider various factors when making decisions regarding referral and admission to rehabilitation. Variations in the perceived likelihood of referral/admission suggest a need for standardized referral/admission practices. Implications for Rehabilitation Various patient characteristics influence clinicians' decisions when selecting appropriate candidates for inpatient rehabilitation. In this study, acute care clinicians were less likely to refer patients that their rehabilitation counter parts would likely have admitted and a patient with hypoxic brain injury was less likely to be referred or admitted in rehabilitation than a patient with a traumatic brain injury. Such discrepancies suggest that policy-makers, managers and clinicians should work together to develop and implement more standardized referral practices and more specific admission criteria in order to ensure equitable access to brain injury rehabilitation services. PMID- 27976929 TI - Folate, homocysteine and selected vitamins and minerals status in infertile women. AB - OBJECTIVES: Diet has been recognised as a crucial factor influencing fetal and maternal health. Adequate levels of substances such as homocysteine, folate and vitamin B12 have been associated with a higher rate of success in infertility treatments. Few data, however, are available on the average levels of micronutrients in the blood of reproductive-aged women, and specific values for adequate levels are not available. The aim of this cross-sectional study was to measure levels of folate, homocysteine and selected vitamins and minerals in women attending the infertility unit of an academic hospital for in vitro fertilisation (IVF). METHODS: Fasting venous blood samples were taken in the morning during routine screening before IVF in order to measure: serum folate, red blood cell (RBC) folate, total plasma homocysteine, vitamin B12, vitamin A, vitamin E, serum iron and serum ferritin. RESULTS: Among 269 women aged 37 +/- 4 years, only 69% and 44% showed adequate levels of homocysteine and vitamin B12, respectively. Serum folate was appropriate in 78% of the study participants, but only a minority (12%) had a concentration of RBC folate regarded as optimal for the prevention of fetal neural tube defects. Serum levels of vitamin A, vitamin E, iron and ferritin were, however, appropriate in the vast majority of participants (>80%). CONCLUSION: Folate levels were largely inadequate among women attending an infertility clinic for IVF. Vitamin B12 levels were also found to be inadequate. PMID- 27976930 TI - Predicting length of stay in specialist neurological rehabilitation. AB - AIMS: A retrospective case series was performed to determine which measures of complexity, dependency and function most accurately predict inpatient neurorehabilitation length of stay for individuals with post-acute neurological disorders. METHODS: Sociodemographic, medical and functional variables were extracted from data submitted to the UK Rehabilitation Outcomes Collaborative. Length of stay was calculated as the total number of inpatient days, functional status was measured using Barthel Index, rehabilitation complexity was measured using Extended Rehabilitation Complexity Scale, and nursing dependency was measured using the Northwick Park Dependency Scale. RESULTS: The mean rehabilitation length of stay was 70.9 days, with length of stay being 35.1 days higher in inpatients with acquired brain injury than inpatients with spinal cord injury. Diagnostic category, Barthel Index scores, Extended Rehabilitation Complexity Scale scores and Northwick Park Dependency Scale scores at admission independently predicted length of stay. Multiple regressions including diagnostic group, Barthel Index, Extended Rehabilitation Complexity Scale and Northwick Park Dependency Scale statistically significantly predicted 37.9% of the variability in length of stay (p < 0.005). Northwick Park Dependency Scale on admission was most closely correlated with inpatient length of stay. CONCLUSIONS: In conclusion, inpatient length of stay is predicted by diagnostic category, Extended Rehabilitation Complexity Scale, Northwick Park Dependency Scale and Barthel Index. The most influential predictor of rehabilitation length of stay was Northwick Park Dependency Scale score at admission. These results may help facilitate rehabilitation resource planning and implementation of effective commissioning plans. Implications for Rehabilitation The most accurate predicting variable for length of stay in inpatient neurological rehabilitation was nursing need as measured by the Northwick Park Dependency Scale score on admission. Service users and commissioners can be provided with more realistic predictions of length of stay derived from admission variables that can be used in planning inpatient rehabilitation. Age and gender do not seem to have an effect on the total length of stay in rehabilitation. PMID- 27976931 TI - A novel LC-MS/MS method for mepivacaine determination and pharmacokinetic study in a single-dose two-period crossover in healthy subjects. AB - The objective of this work was to develop a simple, selective, and sensitive LC MS/MS method for the quantitation of the mepivacaine in Chinese biological matrix. The calibration curve of mepivacaine ranged from 0.5 to 2000 ng/mL with the lower limit of quantitation being 0.5 ng/mL. This sensitivity was high enough to describe the profile of blood mepivacaine level versus time. Thereby it was very desirable for the pharmacokinetic study because of its high sensitivity and accuracy. The study used a single-dose two-period crossover design principle. For the pharmacokinetic analysis of plasma, the mean (SD) values obtained were as follows: t1/2, 1.63 (0.43) h; Cmax, 435.3 (67.4) ng/ml; AUC0-t, 1546.9 (339.7) ng/ml.h; AUC0-infinity, 1982.3 (421.4) ng/ml.h; Tmax, 0.62 (0.31) h. The validated method has been successfully applied to assess the pharmacokinetic study of mepivacaine after a single administration to Chinese volunteers. PMID- 27976932 TI - Effects of controlled whole-body vibration training in improving fall risk factors among individuals with multiple sclerosis: A pilot study. AB - PURPOSE: The purpose of this study was to systematically examine the effect of an 8-week controlled whole-body vibration training on improving fall risk factors and the bone mineral density among people with multiple sclerosis (PwMS). METHODS: This study adopted a single group pre-test-post-test design. Twenty-five PwMS (50.3 years SD 14.1) received vibration training on a side-alternating vibration platform. Each training session was repeated three times every week for 8 weeks. Prior to and following the 8-week training course, a battery of fall risk factors were evaluated: the body balance, functional mobility, muscle strength, range of motion, and fear of falling. Bone density at both calcanei was also assessed. RESULTS: Twenty-two participants completed the study. Compared with pre-test, almost all fall risk factors and the bone density measurement were significantly improved at post-test, with moderate to large effect sizes varying between 0.571 and 1.007. CONCLUSIONS: The 8-week vibration training was well accepted by PwMS and improved their fall risk factors. The important findings of this study were that vibration training may increase the range of motion of ankle joints on the sagittal plane, lower the fear of falling, and improve bone density. IMPLICATIONS FOR REHABILITATION An 8-week vibration training course could be well-accepted by people with multiple sclerosis (MS). Vibration training improves the risk factors of falls in people living with MS. Vibration training could be a promising rehabilitation intervention in individuals with MS. PMID- 27976933 TI - Treatment of pain following cancer: applying neuro-immunology in rehabilitation practice. AB - AIM: Pain is the second most frequent persistent symptom following cancer treatment. This article aims at explaining how the implementation of contemporary pain neuroscience can benefit rehabilitation for adults following cancer treatment within an evidence-based perspective. MATERIALS AND METHODS: Narrative review. RESULTS: First, pain education is an effective but underused strategy for treating cancer related pain. Second, our neuro-immunological understanding of how stress can influence pain highlights the importance of integrating stress management into the rehabilitation approach for patients having cancer-related pain. The latter is supported by studies that have examined the effectiveness of various stress management programmes in this population. Third, poor sleep is common and linked to pain in patients following cancer treatment. Sleep deprivation results in a low-grade inflammatory response and consequent increased sensitivity to pain. Cognitive behavioural therapy for sleep difficulties, stress management and exercise therapy improves sleep in patients following cancer treatment. Finally, exercise therapy is effective for decreasing pain in patients following cancer treatment, and may even decrease pain-related side effects of hormone treatments commonly used in cancer survivors. CONCLUSIONS: Neuro immunology has increased our understanding of pain and can benefit conservative pain treatment for adults following cancer treatment. Implications for Rehabilitation Pain education is effective for improving cancer pain; implementation of contemporary pain neuroscience into the educational programme seems warranted. Various types of stress management are effective for treating patients following cancer treatment. Poor sleep is common in patients following cancer treatment, and rehabilitation specialists can address this by providing exercise therapy, sleep hygiene, and/or cognitive behavioural therapy. Exercise therapy is effective for decreasing pain in patients following cancer treatment, including the treatment of pain as a common side effect of hormone treatments for breast cancer survivors. PMID- 27976934 TI - When Virtual Muscularity Enhances Physical Endurance: Masculinity Threat and Compensatory Avatar Customization Among Young Male Adults. AB - Masculinity-threatened men attempt to resolve the negative states caused by the threat through compensatory behavior such as public display of muscularity, which constitutes one way in which men physically establish masculinity. Avatars serve as a key means for self-presentation in technology-mediated environments, and compensatory motives can drive avatar customization. Noting this, the present research examined whether masculinity-threatened young men engage in compensatory avatar customization and whether such customization can be self-affirming. Specifically, we conducted a laboratory experiment to investigate the effects of masculinity threat on customization of avatar muscularity and physical endurance on a task that represents behavioral self-regulation. Data from 238 male college students revealed that masculinity-threatened young men customized their avatar to have greater muscle definition than did their nonthreatened counterparts, and greater muscle definition of the customized avatar predicted greater physical endurance on a handgrip task. Furthermore, muscle definition of the customized avatar significantly mediated the relationship between masculinity threat and physical endurance. None of these effects were moderated by masculine norm conformity, which suggested that the effects overrode individual differences in the extent to which participants conformed to masculine norms and expectations. Theoretical and practical implications of these findings are discussed. PMID- 27976935 TI - Oculomotor Abnormalities in Children with Attention-Deficit/Hyperactivity Disorder Are Improved by Methylphenidate. AB - BACKGROUND: There are relatively few studies of saccadic eye movements in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to examine inhibitory abilities of eye movements in children with ADHD and to explore the effect of methylphenidate (MPH) on eye movement performance. METHODS: Thirty-one children with ADHD (mean age 9.9 +/- 0.4 years) and 31 sex-, age-, and IQ-matched children with normal development were examined. Saccades elicited not only by the gap, step, overlap, and antisaccade paradigms but also a simple fixation paradigm have been recorded using an eye tracker. The latency of each type of saccade, the error rate of antisaccades, and the number of saccades made during fixation have been measured. RESULTS: Children with ADHD and naive to treatment with respect to controls showed significantly shorter mean latency of voluntary saccades (overlap paradigm), more frequent errors during the antisaccade paradigm, and higher number of saccades made during fixation. After 1 month of MPH treatment, all these parameters changed significantly and reached control values. CONCLUSION: Taken together, these results suggest that oculomotor abilities are poor in children with ADHD, which may correlate with deficits in inhibitory mechanisms. Treatment with MPH improves oculomotor performances through adaptive strategies, which may involve brain structures related to cognitive inhibition. PMID- 27976936 TI - Lost in Trans-IL-6 Signaling: Alveolar Type II Cell Death in Emphysema. PMID- 27976937 TI - Can Dead Space Ventilation Really Be Measured without PaCO2? PMID- 27976938 TI - Omalizumab Is Associated with Reduced Acute Severity of Rhinovirus-triggered Asthma Exacerbation. PMID- 27976939 TI - Reply: Can Dead Space Ventilation Really Be Measured without PaCO2? PMID- 27976940 TI - Subclinical Interstitial Lung Abnormalities: Toward the Early Detection of Idiopathic Pulmonary Fibrosis? PMID- 27976942 TI - Can Extreme Air Pollution Events Provide a Window into Incident Asthma? PMID- 27976941 TI - Validation of Administrative Definitions of Invasive Mechanical Ventilation across 30 Intensive Care Units. PMID- 27976943 TI - Intensive Care Unit Physician Discretion in Pediatric Critical Care. Polarized, Evaluated, and Reframed. PMID- 27976944 TI - Using a Home Ventilator with a Child. PMID- 27976945 TI - New Evidence for the Complexity of the Population Structure of Mycobacterium tuberculosis Increases the Diagnostic and Biologic Challenges. PMID- 27976946 TI - Were Antibody Titers the Right Parameter When Immunologically Comparing Pneumococcal Vaccines? PMID- 27976947 TI - Can Genes Control Asthmatic Lung Function Patterns? PMID- 27976951 TI - Recruiting Adolescent Research Participants: In-Person Compared to Social Media Approaches. AB - Recruiting adolescent participants for research is challenging. The purpose of this study was to compare traditional in-person recruitment methods to social media recruitment. We recruited adolescents aged 14-18 years for a pilot physical activity intervention study, including a wearable physical activity tracking device and a Facebook group. Participants were recruited (a) in person from a local high school and an adolescent medicine clinic and (b) through social media, including Facebook targeted ads, sponsored tweets on Twitter, and a blog post. Data collected included total exposure (i.e., reach), engagement (i.e., interaction), and effectiveness. Effectiveness included screening and enrollment for each recruitment method, as well as time and resources spent on each recruitment method. In-person recruitment reached a total of 297 potential participants of which 37 enrolled in the study. Social media recruitment reached a total of 34,272 potential participants of which 8 enrolled in the study. Social media recruitment methods utilized an average of 1.6 hours of staff time and cost an average of $40.99 per participant enrolled, while in-person recruitment methods utilized an average of 0.75 hours of staff time and cost an average of $19.09 per participant enrolled. Social media recruitment reached more potential participants, but the cost per participant enrolled was higher compared to traditional methods. Studies need to consider benefits and downsides of traditional and social media recruitment methods based on study goals and population. PMID- 27976952 TI - Challenges in molecular targeted therapy for gastric cancer: considerations for efficacy and safety. AB - INTRODUCTION: The Cancer Genome Atlas Research Network recently proposed a molecular classification for gastric cancer (GC) into four subtypes based on comprehensive evaluation. While the mechanisms of molecular targeted therapies in GC were confirmed by multiple clinical studies, only a limited number of therapeutics for GC have been approved to date. Areas covered: In this systematic review of the available literature, we discuss the completed and ongoing clinical trials of molecular targeted therapies in patients with GC, with a focus on their efficacy and safety profiles. Expert opinion: Results of recent studies clearly demonstrated that trastuzumab and ramucirumab, monoclonal antibodies (mAbs) against human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF), respectively, improved overall survival (OS) in GC with manageable safety profiles. Careful surveillance of ongoing clinical trials and timely profiling and monitoring of genetic signatures are imperative to establish a strong foundation for precision medicine in GC. PMID- 27976954 TI - Acknowledgment of Reviewers: 2016. PMID- 27976953 TI - Improving Psychosocial Well-Being of Older Adults Through Exergaming: The Moderation Effects of Intergenerational Communication and Age Cohorts. AB - OBJECTIVE: Exergaming is one way to foster social interaction among older adults and to improve their psychosocial well-being, which is a crucial component of healthy aging. This study examined how exergaming affects older adults' social anxiousness, sociability, and loneliness, and it further analyzed differences in the exergaming effects across different types of game play and between different aging cohorts. METHOD: A 2 (pre-test vs. post-test) * 2 (young-old vs. old-old) * 3 (play alone vs. play with elderly vs. play with youths) mixed quasi-experiment (N = 89) was conducted in Singapore, and three-way MANOVAs were executed. RESULTS: Results showed a significant three-way interaction effect among exergaming, play type, and age group on older adults' psychosocial well-being. There was a significant decline in social anxiousness and an increase in sociability for young-old participants playing with youths. The sociability improved significantly for old-old participants playing with their peers. There was also a significant decrease in loneliness after exergaming, but little differences were found across different play types or age groups. DISCUSSION: The findings made contributions to aging research and shed light on our understanding about how to foster social interaction among older adults and, thus, promote healthy and active aging. PMID- 27976955 TI - Interactive Digital e-Health Game for Heart Failure Self-Management: A Feasibility Study. AB - OBJECTIVE: To develop and test the prototype of a serious digital game for improving community-dwelling older adults' heart failure (HF) knowledge and self management behaviors. The serious game innovatively incorporates evidence-based HF guidelines with contemporary game technology. MATERIALS AND METHODS: The study included three phases: development of the game prototype, its usability assessment, and evaluation of the game's functionality. Usability testing included researchers' usability assessment, followed by research personnel's observations of participants playing the game, and participants' completion of a usability survey. Next, in a pretest-post-test design, validated instruments-the Atlanta Heart Failure Knowledge Test and the Self Care for Heart Failure Index were used to measure improvement in HF self-management knowledge and behaviors related to HF self-maintenance, self-management, and self-efficacy, respectively. A postgame survey assessed participants' perceptions of the game. RESULTS: During usability testing, with seven participants, 100%, 100%, and 86% found the game easy to play, enjoyable, and helpful for learning about HF, respectively. In the subsequent functionality testing, with 19 participants, 89% found the game interesting, enjoyable, and easy to play. Playing the game resulted in a significant improvement in HF self-management knowledge, a nonsignificant improvement in self-reported behaviors related to HF self-maintenance, and no difference in HF self-efficacy scores. Participants with lower education level and age preferred games to any other medium for receiving information. CONCLUSION: It is feasible to develop a serious digital game that community dwelling older adults with HF find both satisfying and acceptable and that can improve their self-management knowledge. PMID- 27976957 TI - ? PMID- 27976956 TI - ? PMID- 27976958 TI - ? PMID- 27976959 TI - ? PMID- 27976960 TI - ? PMID- 27976961 TI - ? PMID- 27976963 TI - ? PMID- 27976962 TI - ? PMID- 27976964 TI - ? PMID- 27976965 TI - ? PMID- 27976966 TI - ? PMID- 27976967 TI - The ethics of withdrawal: the case of follow-up from first-in-human clinical trials. AB - This paper aims to analyze whether patients should be allowed to veto research related use of medical data collected during routine follow-ups after their withdrawal from first-in-human clinical trials. Forms of withdrawal are identified and it is argued that the right to withdraw might be limited to some of these. The paper concludes that if veto right is denied, then: the research participant should be informed about the potential use of his/her follow-up data in case of his/her withdrawal and consent to it; follow-up should not be initiated for research purposes; compulsory use of follow-up data should imply the use of data anyway collected, requiring no additional effort from the patient; and before deciding about the veto right, investigation of concerned patients' value preferences is needed. PMID- 27976968 TI - A FGFR1 inhibitor patent review: progress since 2010. AB - INTRODUCTION: FGFR1 is a well known molecular target for anticancer therapy. Many studies have proved that the regulation of FGFR1 activity is a promising therapeutic approach to treat a series of cancers. Therefore, the development of potent inhibitors has consequently become a key focus in the present drug discovery, and it is encouraging that several highly selective FGFR1 inhibitors have been identified from various sources in recent years. Areas covered: This article reviews patents and patent applications related to selective FGFR1 inhibitors published from 2010 to 2016. This summary highlights about 15 patents from different pharmaceutical companies and academic research groups. We used Baidu and NCBI search engines to find relevant patents as a search term. Expert opinion: In the past few years, considerable progress has been made in the identification and development of selective FGFR1 inhibitors in use. At present, at least 10 inhibitors of FGFR1 are in clinical trials, and several agents have shown encouraging results under experimental conditions. Given the fact that FGFR1 plays a crucial role in the regulation of cancer and other diseases, we hope that it will gain further attraction from pharmaceutical companies and encourage development of more novel, safe and efficient FGFR1 inhibitors in the future. PMID- 27976969 TI - Maternal mortality cases from pulmonary embolism: A nation-wide study in Turkey. AB - The aim of the study was to evaluate the maternal mortality cases attributed to pulmonary embolism (PE). PE constituted 7.58% of maternal deaths in 2013. Risk factors for PE were present in 15 (88.2%) of the women. Five women (29.4%) were overweight, and 5 (29.4%) were obese. Four women (23.5%) had cardiac diseases. PE occurred in the postpartum period after caesarean delivery in 9 (52.9%) patients. Eleven (64.7%) of the maternal deaths were recognised as preventable. More deaths attributed to PE occurred in the postpartum period (n = 11) than the antepartum period (n = 5). One other maternal mortality case was after therapeutic abortion. Caesarean section, obesity and cardiac diseases were important risk factors. It can be suggested that monitoring all risk factors and timely recognition of related symptoms and signs with initiation of appropriate management have paramount importance for reducing maternal mortality rate related to pulmonary embolism. Increasing awareness of healthcare professionals as well as the public, and continuously reviewing the cases are also important tools for achieving this goal. PMID- 27976971 TI - Thiadiazole inhibitors: a patent review. AB - INTRODUCTION: Four isomeric structures of thiadiazole motifs have outstanding pharmacological inhibitory applications are reported in this review. Thiadiazole nucleus is present in several biologically active natural products and commercial drugs. Most of thiadiazoles reported herein are emphasized to have broad spectrum of medicinal activities. Areas covered: This review represents the recent inhibitory activities of thiadiazole isomeric scaffolds and their broad-spectrum biological applications published as full texts during 2010-2016 as well as the patents published during 2005-2016. The inhibition areas covered included anti inflammatory, antimicrobial, antitumor, antioxidant, antitubercular, antiviral, antileishmanial, anticonvulsant, herbicidal and algicidal activities in addition to enzymes, human platelet aggregation and neuroprotective inhibitors. Expert opinion: This survey revealed very interesting data about the applications of thiadiazoles, where some synthetic or natural thiadiazole derivatives were components of drugs available in the market. Many thiadiazole derivatives can be considered as lead compounds for drug synthesis. The most inhibitory active 1,3,4 thiadiazole compounds are those incorporating secondary alkyl(aryl)amido- and/or benzylthio(mercapto) groups at positions 2 and 5. Several thiadiazole derivatives demonstrated higher antibacterial, antitumor and antiviral activities than the standard drugs. Some thiadiazole derivatives exhibited high selective enzymes inhibitory activities based on the electronic properties of the substituents at positions 2 or 5. PMID- 27976970 TI - Comparison of survival outcome of patients with primary peritoneal and fallopian tube carcinoma treated with neoadjuvant chemotherapy versus primary debulking surgery. AB - This study examines the overall survival of primary peritoneal cancer (PPC), in those patients who had primary debulking surgery (PDS) followed by six cycles of chemotherapy versus those who had neoadjuvant chemotherapy (NACT). This was a prospective observational study performed at Oxford Gynaecological Cancer Centre, over a 5-year period. Eighty-seven patients were clinically suspected of having PPC. Histology confirmed that 64 of these were PPC, with the balance being tubal in origin. PDS was performed in 31 cases. Although NACT was planned in 56 patients, 4 patients didn't receive NACT and therefore excluded from the survival analysis. The overall median survival was 34 months. However, the 5-year survival was 12%. Survival in the PDS group was 46 months versus 24 months in the NACT (p = .011). The conclusion drawn from this study is that patients affected by PPC, selected for PDS have a greater survival advantage than those who had NACT. PMID- 27976972 TI - The Protective Effects of Probiotic Bacteria on Cadmium Toxicity in Rats. AB - One of the useful properties of probiotic bacteria is their capacity to bind different targets, thus eliminating them through feces. It is supposed that one of these targets could be cadmium, a widespread environmental toxicant that causes various disturbances in biological systems. This study examined the protective effects of probiotic supplementation against cadmium-induced toxicity in the rat. The experiment was conducted in the course of 5 weeks. Animals were divided into four groups: (1) controls, (2) probiotics treated, (3) cadmium treated, and (4) probiotics + cadmium treated. The cadmium concentration was measured in the blood, liver, kidney, and feces, as well as the blood alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as biomarkers of the liver function. Histomorphological changes in the liver and kidney were also determined. Our results revealed that probiotics combined with cadmium increase this metal concentration in feces. As a result, blood, liver, and kidney Cd levels, as well as blood ALT and AST activities were lessened compared to the rat group treated with cadmium only. Besides, probiotics consumed simultaneously with cadmium attenuated histomorphological changes in the liver and kidney caused by cadmium. The rise in lactobacilli number in feces of rats treated simultaneously with cadmium and probiotics results in strong correlation with the increase of Cd concentration in their feces and the decrease of Cd concentration in their blood. We speculate that probiotics actively contribute to cadmium excretion through feces, probably, by its binding to their bacterial cell wall. PMID- 27976973 TI - Elevated rates of memory impairment in military service-members and veterans with posttraumatic stress disorder. AB - INTRODUCTION: Studies investigating the neurocognitive effects of posttraumatic stress disorder (PTSD) routinely find "deficits" in various cognitive domains. However, the rate of cognitive impairment in individuals with PTSD remains unclear, as studies have focused on null hypothesis testing (NHT) and inferring patterns of impairment rather than empirically determining the rate of cognitive impairment in this sample. METHOD: This study examined rates of cognitive impairment using a domain-specific approach in non-treatment-seeking Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn service members and veterans with (n = 92) and without (n = 79) PTSD and without substance abuse/dependence who passed a performance validity measure and were matched on age, education, estimated IQ, and ethnicity. Chi-square analyses were used to compare the rate of cognitive impairment across groups based on normative scores using three cutoffs (-1, -1.5, and -2 SDs). NHT was also used to compare performances across groups. RESULTS: Individuals with PTSD showed higher rates of impairment in memory (-1-SD cutoff) than controls, but equivalent rates of impairment in attention, processing speed, and executive functioning; no significant differences were found on NHT. Impairment in any domain was also more prevalent in PTSD (-1-, -1.5-, and -2-SD cutoffs). No differences were found on NHT or rates of impairment in individuals with PTSD with (n = 34) and without (n = 58) depression. CONCLUSIONS: Patients with PTSD were more likely to meet criteria for memory impairment and to show impairment in any domain than controls. Patients with PTSD and comorbid depression were no more likely to be impaired in any cognitive domain or to have lower scores on individual cognitive tasks than patients with PTSD alone. Clinicians noting cognitive impairment in individuals with PTSD should exercise caution before ascribing that impairment to another etiology if deficits are limited to memory. PMID- 27976974 TI - Predictive values of anti-mullerian hormone, antral follicle count and ovarian response prediction index (ORPI) for assisted reproductive technology outcomes. AB - This prospective study was performed from June 2012 to June 2014 at Royan Institute to compare the predictive values of serum anti-mullerian hormone (AMH), antral follicle count (AFC) and ovarian response prediction index (ORPI) ([AFC * AMH]/age) for in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycle outcomes. Five hundred and fifty women included in the study with male factor and unexplained infertility were the first candidates for IVF/ICSI cycles. Serum AMH level was measured by a commercial ELISA kit and AFC was calculated by a transvaginal ultrasonography on day 2-3 of the menstrual cycle before starting ovarian stimulation. All women underwent IVF/ICSI cycles using a long standard protocol with gonadotropin-releasing hormone agonist. The receiver operating characteristic curves (ROC) analysis showed that both AMH and AFC were good predictors of ovarian response with an area under the curves (AUC) > 0.75; even it seems that AFC was being a better predictor. Combining these variables is necessary as ORPI will not improve the prediction value. All the variables had poor predictive ability (AUC <0.60) for clinical pregnancy and live birth rates. Logistic regression analysis showed the AMH less than 0.4 ng/ml and quality of transferred embryos were significant predictors for clinical pregnancy rate. PMID- 27976975 TI - Going wireless and booth-less for hearing testing in industry. AB - OBJECTIVE: To assess the test-retest variability of hearing thresholds obtained with an innovative, mobile wireless automated hearing-test system (WAHTS) with enhanced sound attenuation to test industrial workers at a worksite as compared to standardised automated hearing thresholds obtained in a mobile trailer sound booth. DESIGN: A within-subject repeated-measures design was used to compare air conducted threshold tests (500-8000 Hz) measured with the WAHTS in six workplace locations, and a third test using computer-controlled audiometry obtained in a mobile trailer sound booth. Ambient noise levels were measured in all test environments. STUDY SAMPLE: Twenty workers served as listeners and 20 workers served as operators. RESULTS: On average, the WAHTS resulted in equivalent thresholds as the mobile trailer audiometry at 1000, 2000, 3000 and 8000 Hz and thresholds were within +/-5 dB at 500, 4000 and 6000 Hz. CONCLUSIONS: Comparable performance may be obtained with the WAHTS in occupational audiometry and valid thresholds may be obtained in diverse test locations without the use of sound attenuating enclosures. PMID- 27976976 TI - Antiadipogenic Effects and Mechanisms of Combinations of Genistein, Epigallocatechin-3-Gallate, and/or Resveratrol in Preadipocytes. AB - Natural bioactive compounds are considered an excellent alternative strategy for developing effective, safe, and cost-effective antiobesity agents. The aim of this study was to investigate if combinations of soy bean genistein (G), green tea epigallocatechin-3-gallate (E), and/or grape resveratrol (R) at low dosages synergistically inhibit preadipocyte differentiation both in 3T3-L1 cells and human primary preadipocytes (HPAs). Our results show that combinations of G, E, and/or R additively inhibited preadipocyte differentiation (39-56% of control) both in 3T3-L1 cells at 30 MUM and HPAs at 15 MUM, while the individual compounds have no antiadipogenic effect at the selected concentrations. We also observed similar patterns that combinations of G, E, and/or R additively reduced protein expressions of peroxisome proliferator-activated receptor gamma (PPAR-gamma) and CCAAT binding proteins alpha (C/EBP-alpha), the two key preadipocyte differentiation regulators, both in differentiated 3T3-L1 cells and HPAs. Moreover, combined G, E, and/or R attenuated protein expressions of fatty acid binding protein 4 and perilipin, two PPAR-gamma/C/EBP-alpha downstream molecules in fat drop development in a very similar pattern, in inhibiting differentiation in preadipocytes. This combined antiadipogenic effect of G + E + R is additive, not synergistic according to our results and the Median-Effect Principle. In addition, we found that a lower concentration (15 MUM) of G, E, and/or R is required in HPAs than the concentration (30 MUM) needed in 3T3-L1 cells, to exert the combined antiadipogenic effect. These data suggest that combinations of G, E, and/or R intake or soy bean, green tea, and/or grape simultaneous consumption may prevent obesity in human being. PMID- 27976977 TI - Generation of endoderm lineages from pluripotent stem cells. AB - Definitive endoderm is the cellular precursor to respiratory- and digestive related organs such as lungs, stomach, liver, pancreas and intestine. Endodermal lineage cells derived from pluripotent stem cells (PSCs) in vitro are a potentially unlimited resource for regenerative medicine. These cells are useful tools for studying the physiology, pathogenesis and medical therapies involving these tissues, and great progress has been achieved in PSCs differentiation protocols. In this review, we will focus on the most common and/or advanced differentiation strategies currently used in generating endodermal lineage cells from PSCs. A brief discussion about the effect of early definitive endoderm differentiation on the final development products will follow. PMID- 27976978 TI - Pharmacogenetic considerations in the treatment of HIV. AB - After the introduction of highly active antiretroviral therapy in the 1990s, the perception of the diagnosis of HIV infection gradually shifted from a 'death sentence' to a chronic disease requiring long-term treatment. The host genetic variability has been shown to play a relevant role in both antiretroviral drugs bioavailability and adverse effects susceptibility. Knowledge about pharmacogenetics role in HIV infection treatment has largely increased over the last years, and is reviewed in the present report, as well as future perspectives for the inclusion of pharmacogenetics information in the directing of HIV infection treatment. PMID- 27976979 TI - Vocal function after transoral videolaryngoscopic surgery (TOVS) for hypopharyngeal and supraglottic cancer. AB - CONCLUSION: The resection of the medial and lateral pyriform sinus was associated with post-operative voice impairment after TOVS. Scar contracture around the cricoarytenoid joint lead to arytenoid fixation toward lateral position, and this wound healing process caused insufficient glottis closure. Although oncological and functional outcomes of TOVS was satisfactory, surgeons should mention the risk of post-operative voice impairment in pre-operative counseling. OBJECTIVES: Transoral surgery is a minimally invasive treatment option for hypopharyngeal and supraglottic cancer. Post-operative vocal function was satisfactory in most cases, but in some cases vocal cord was fixed and occasionally voice impairment persists. METHODS: Vocal function of 55 patients who underwent transoral videolaryngoscopic surgery (TOVS) for hypopharyngeal and supraglottic cancers was evaluated by the GRBAS perceptive scale, aerodynamic tests and acoustic analyses, and the Voice Handicap Index questionnaire. The risk factors for voice impairment were identified. RESULTS: Voice impairment (G score ?2) was found in 16 cases (29.1%). Univariate analysis revealed that the resection of medial and lateral pyriform sinus (p = .0018) and neck dissection (p = .0421) were associated with post-operative voice impairment. Multivariate analysis revealed that the resection of medial and lateral pyriform sinus (p = .0021) was associated with post-operative voice impairment. PMID- 27976980 TI - Gender differences in public office workers' satisfaction, subjective symptoms and musculoskeletal complaints in workplace and office environments. AB - This study investigates differences between male and female public office workers' satisfaction levels, sick building syndrome (SBS) symptoms and musculoskeletal disorder (MSD) complaints in workplace and office environments. Questionnaire surveys were performed in 30 offices from 15 public institutions. Male and female workers of the same age were coupled and selected from each office, gathering a total of 120 male and 120 female subjects. The results show that differences exist between genders in noise and lighting satisfaction levels, SBS-related symptoms (eye, nose, skin) and MSD complaints of hand/wrist/finger, while there is no difference in overall satisfaction level of office environments. The study also suggests that office design for public office workers should take into account gender differences in preventing MSDs and also SBS. The findings of this study are expected to serve as basic data for designing effective public office environments. PMID- 27976982 TI - Patent eligibility of stem cells in Europe: where do we stand after 8 years of case law? AB - Since 2006, some of the highest ranking European Courts have issued decisions related to the patent eligibility of human embryonic stem cells. The question of patent eligibility of human embryonic stem cells remains, however, still erratic, at least in some aspects. This article will give a short comprehensive overview of the case history, and discuss questions still unsolved. PMID- 27976983 TI - Community health workers improving diabetes outcomes in a rural Appalachian population. AB - Community health workers (CHWs) play a key role in the emerging health infrastructure. They are successful in identifying individual or family needs and matching resources to help overcome the social determinants of health, and the lack of trust in the health care system. This study captures the CHW experience as research assistants and evaluates the effectiveness of CHWs' health coaching and support in improving diabetes health outcomes. By being immersed in the culture and values of the population, CHWs offer research support to assure more representative client samples, increased adherence to study protocols, and in reducing attrition rates. PMID- 27976981 TI - Hepatitis B Virus e Antigen Regulates Monocyte Function and Promotes B Lymphocyte Activation. AB - Hepatitis B virus (HBV) e (HBe) antigen is a nonstructural virus component with great immune regulation roles. It regulates adaptive immunity response and participates in persistent infection development. However, its roles on monocytes and B lymphocytes were rarely studied. Herein, we studied HBe roles on U937 and Hmy2.CIR by creating HBe stably transfected cells using lentivirus. We detected the motility of HBe-U937 through transwell migration assay. Cytokines that primarily produced by monocytes, including BAFF, B-cell activating factor (BAFF), interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-alpha, and A proliferation inducing ligand (APRIL), were measured in culture supernatants of transfected U937, and serum BAFF, IL-6, and IL-10 were detected in HBe-positive and HBe negative HBV-infected patients. Among these, BAFF mRNA and membrane-bound BAFF were further detected. Activation and inhibition markers of B lymphocytes on HBe Hmy2.CIR and proliferation of transfected Hmy2.CIR after coculture with transfected U937 were also detected. We found that U937 migration was inhibited by HBe. BAFF expression was increased in HBe-U937, however, membrane-bound BAFF on HBe-U937 was decreased. In addition, Serum BAFF in HBe-positive patients was higher than in HBe-negative patients. IL-6 and IL-10 were increased in HBe-U937 after being stimulated by lipopolysaccharide (LPS), however, serum IL-6 and IL-10 were not associated with HBe status in patients. Besides, TNF-alpha and APRIL expression were basically the same in GV166-U937 and HBe-U937. B lymphocyte activation markers CD86 and Tspan33 were raised in HBe-Hmy2.CIR. However, inhibition markers Lyn and CD32b had no differences between HBe-Hmy2.CIR and control. Proliferation of transfected Hmy2.CIR was not affected by coculture with transfected U937, however, HBe transfection itself enhanced Hmy2.CIR proliferation. Altogether, these revealed that HBe can inhibit U937 migration and promote cytokines, including BAFF, IL-6, and IL-10, production in U937. Besides, HBe enhances BAFF release from U937 and increases BAFF concentration in vivo. In addition, HBe antigen facilitates Hmy2.CIR activation and proliferation through direct induction. PMID- 27976985 TI - Analysis of elbow muscle strength parameters in Brazilian jiu-jitsu practitioners. AB - Upper-body dynamic and isometric maximum strength are essential components for success in Brazilian jiu-jitsu (BJJ). This study was aimed at analysing strength parameters in the elbow flexor and extensor muscles of BJJ practitioners. Participants (n = 28) performed maximum isometric contractions of elbow flexors and extensors to determine peak torque (PT), rate of force development (RFD), and the torque-angle (T-A) relationship at elbow angles of 45 degrees , 60 degrees , 75 degrees , 90 degrees , 105 degrees , and 120 degrees . Additionally, concentric and eccentric PTs were measured at 1.04 rad.s-1. Student t-test and ANOVA were performed using alpha = 0.05. Elbow flexors were stronger isometrically (P < 0.001, ES = 1.23) but weaker concentrically (P < 0.05, ES = 0.54) than extensor muscles, possibly because of the extensive grip disputes and pushing of opponents in BJJ. The T-A relationship had an inverted "U"-shape. Torque differences across elbow angles were moderate (ES = 0.62) for the extensor and large (ES = 0.92) for the flexor muscles. Isometric torque was greatest for elbow angles of 105 degrees and 75 degrees and smallest for 45 degrees and 120 degrees for extensor and flexor muscles, respectively. Elbow flexors had a greater RFD than extensors, regardless of elbow angle. The present study provides comprehensive results for elbow muscle strength in BJJ practitioners. PMID- 27976984 TI - Retirement Planning Among Hispanics: In God's Hands? AB - We conducted a qualitative study on retirement preparedness among middle-aged and older low-income Hispanics in Los Angeles. Data were derived from four focus groups conducted in the greater Los Angeles area. Findings demonstrate how behavioral and cultural factors-family experiences, religiosity, and denial of retirement-explain the lack of savings and preparedness for retirement. Findings also indicate that the majority of participants want to be economically independent and to keep working until they are unable to do so. Participants helped their parents financially but did not feel comfortable asking their own children for help. Instead, participants placed their survival in retirement "in God's hands." PMID- 27976986 TI - Mutations and/or Overexpressions of ERG4 and ERG11 Genes in Clinical Azoles Resistant Isolates of Candida albicans. AB - OBJECTIVE: We aimed to investigate whether mutations and/or overexpressions of ERG4 and ERG11 genes were involved in drug resistance to azoles in Candida albicans. METHODS: Totally, 34 clinical isolates of C. albicans were included in this study. Antimicrobial susceptibility tests, including 5-fluorocytosine (5 FC), amphotericin B (AMB), fluconazole (FCA), itraconazole (ITR), and voriconazole (VRC), were performed by broth microdilution method. Mutations in the ERG4 and ERG11 genes sequence were detected. The messenger RNA (mRNA) levels of ERG4 and ERG11 were measured by quantitative real-time polymerase chain reaction. The correlation of the expression levels of ERG4 with ERG11 genes in susceptible isolates and resistant isolates was analyzed by Pearson's correlation analysis. RESULTS: Among 34 C. albicans isolates, 52.94%, 70.59%, and 50.00% isolates were resistant to FCA, ITR, and VRC, respectively. Sequencing results revealed that only 2 silent mutations were found in ERG4 gene, while 10 amino acid substitutions, including 6 reported previously and 4 new identified, were frequently found in ERG11 gene. The mRNA levels of ERG4 and ERG11 genes were significantly elevated in resistant compared with susceptible C. albicans isolates. Furthermore, the mRNA level of ERG4 was positively correlated with ERG11 in susceptible but not resistant C. albicans isolates. CONCLUSIONS: The resistance to azoles may be associated with the mutations in ERG11 but not ERG4 gene in C. albicans isolates. In addition, overexpressed ERG4 and ERG11 genes are found in resistant C. albicans isolates, and the mRNA levels of ERG4 may be irrelevant to ERG11 in resistant C. albicans isolates. PMID- 27976987 TI - Prediction of atorvastatin plasmatic concentrations in healthy volunteers using integrated pharmacogenetics sequencing. AB - AIM: To use variants found by next-generation sequencing to predict atorvastatin plasmatic concentration profiles (AUC) in healthy volunteers. SUBJECTS & METHODS: A total of 60 healthy Mexican volunteers were enrolled in this study. We used variants with a predicted functional effect across 20 genes involved in atorvastatin metabolism to construct a regression model using a support vector approach with a radial basis function kernel to predict AUC refining it afterwards in order to explain a greater extent of the variance. RESULTS: The final support vector regression model using 60 variants (including six novel variants) explained 94.52% of the variance in atorvastatin AUC. CONCLUSION: An integrated analysis of several genes known to intervene in the different steps of metabolism is required to predict atorvastatin's AUC. PMID- 27976988 TI - Support for Marijuana Legalization and Predictors of Intentions to Use Marijuana More Often in Response to Legalization Among U.S. Young Adults. AB - BACKGROUND: As of 2015, more than half of U.S. states have legalized, medicalized, or decriminalized marijuana. OBJECTIVE: This study examined the prevalence and correlates of support for marijuana legalization in a national sample of young adults and the intention to use marijuana more frequently if it were legalized. METHODS: Data were from Wave 7 (weighted N = 3532) of the Truth Initiative Young Adult Cohort, a national sample of men and women aged 18-34. We assessed demographics, past 30-day substance (alcohol, tobacco, marijuana, other drug use), depression and anxiety, social smoking, marijuana harm perceptions (relative to cigarettes), and state-level marijuana policies as correlates of support for marijuana legalization and intentions to use marijuana more often if it were legalized. Multivariable models of correlates of support for legalization and intentions to use marijuana were conducted separately for the full sample and for nonmarijuana users. RESULTS: Weighted estimates showed that 39% of the full sample and 9% of nonmarijuana users supported marijuana legalization. Multivariable models showed that lower marijuana harm perceptions and lifetime and past 30-day tobacco use were common predictors of support for marijuana legalization and intentions to use marijuana among non-users of marijuana. Conclusions/Importance: Over a third of the sample supported marijuana legalization. Tobacco use and perceptions that marijuana is less harmful than cigarettes were robust risk correlates of support for marijuana legalization and intentions to use more frequently among nonusers. Public health campaigns should target these factors to deter marijuana-related harm in susceptible young adults. PMID- 27976990 TI - The Place and Future of Social Work in Palliative Care Services in Turkey: State of the Art. AB - Palliative care, which is a special type of care including alleviation of physical and psychosocial symptoms of individuals with life-limiting serious diseases, has long been neglected in Turkey. This has also affected the activity of social work and social workers in the presentation of health services. In the present study, the present status of social work in palliative care services in Turkey was analyzed. It has also been attempted to explain the historical place of social work in palliative care services from 2002 on under the guidance of the World Health Organization and Ministry of Health. In the present study, an analysis is carried out of stages social work profession went through in social care services, its strong and weak aspects, and its future perspectives. It is thought that the experience gained and accumulation of knowledge in this process as it has occurred in Turkey may serve as guidance for other countries that have only recently started to implement palliative care services, which are evaluated in the context of human rights at present. PMID- 27976989 TI - A breath ammonia analyser for monitoring patients with end-stage renal disease on haemodialysis. AB - OBJECTIVE: Breath ammonia measurement has attracted increasing interest for clinical diagnosis and metabolic status monitoring. This pilot study aims to evaluate a simple detection method to measure breath ammonia levels in haemodialysis patients. MATERIALS AND METHODS: The study group comprised 44 adults undergoing haemodialysis and a control group of 44 age- and sex-matched individuals with a glomerular filtration rate >90 mL/min. To measure breath ammonia concentration, we designed a device based on that used to monitor atmospheric air, which uses a specific colorimetric tube. A single operator took two readings from each haemodialysis patient (one predialysis and one postdialysis) and one reading from each control. The results were compared with the urea concentrations in blood and saliva. RESULTS: Breath ammonia concentration correlated significantly with blood urea both predialysis (P < 0.001; R2 = 0.55) and postdialysis (P = 0.009; R2 = 0.25), as well as with predialysis saliva urea concentration (P < 0.001; R2 = 0.24). Ammonia was not detectable in breath of any of the control group. CONCLUSIONS: The collection of breath samples in polyvinyl fluoride bags and their subsequent analysis using colorimetric tubes is a simple, noninvasive method that enables variations in breath ammonia concentration to be measured rapidly in haemodialysis patients. Using this method, we found that the breath ammonia concentration correlated significantly with the blood urea concentration before and after haemodialysis. PMID- 27976992 TI - Conversion of coal-fired bottom ash to fuel and construction materials. AB - In this study, solid wastes taken from Seyitomer coal-fired power plant bottom ashes were subjected to experimental research to obtain a carbon-rich fraction. The possible recycling opportunities of remaining inorganic fraction in the cement and concrete industry was also investigated. Flotation technique was used to separate unburned carbon from inorganic bottom ashes. Collector type, collector, dispersant and frother amounts, and pulp density are the most important variables in the flotation technique. A number of flotation collectors were tested in the experiments including new era flotation reactives. Optimum collector, dispersant and frother dosages as well as optimum pulp density were also determined. After experimental work, an inorganic fraction was obtained, which included 5.41% unburned carbon with 81.56% weight yield. These properties meets the industrial specifications for the cement and concrete industry. The carbon content of the concentrate fraction, obtained in the same experiment, was enhanced to 49.82%. This fraction accounts for 18.44% of the total amount and can be mixed to the power plant fuel. Therefore total amount of the solid waste can possibly be recycled according to experimental results. PMID- 27976993 TI - Journal of Agromedicine "Leader in the Field" 2017: William J. Nelson. PMID- 27976996 TI - The Help We Need. PMID- 27976991 TI - Relationship between JAK2V617F mutation, allele burden and coagulation function in Ph-negative myeloproliferative neoplasms. AB - OBJECTIVES: Our aim was to explore the relationship between JAK2V617F mutation allele burden and hematological parameters especially in coagulation function in Chinese population. METHODS: This study included 133 Ph-negative myeloproliferative neoplasms (MPNs) patients between 2013 and 2016. All the clinical and experimental data of patients were collected at the time of the diagnosis without any prior treatment, including blood parameters, coagulation function, splenomegaly, vascular events and chromosome karyotype. PCR and qPCR were used to detect JAK2V617F mutation and JAK2V617F mutation allele burden. RESULTS: In polycythemia vera patients, a positive correlation between the allele burden of JAK2V617F mutation and PLT counts was found; in essential thrombocythemia (ET) patients, WBC counts, RBC counts, HB, and HCT were higher in mutated patients than in wild-type patients. Furthermore, PT-INR was higher in ET and PMF mutated patients. In addition, a positive correlation between the allele burden of JAK2V617F mutation and activated partial thromboplastin time (APTT) was observed in JAK2V617F mutated ET patients. CONCLUSIONS: Higher hematologic parameters including counts of WBC, RBC, and PLT are closely associated with JAK2V617F mutation and its burden in Ph-negative MPNs; importantly, PT-INR, APTT are also related to JAK2V617F mutation and allele burden. Thus, our data indicate that JAK2V617F mutation allele burden might not only represent the burden of MPN but also alter the coagulation function. PMID- 27976997 TI - Stereotyped responses of Drosophila peptidergic neuronal ensemble depend on downstream neuromodulators. AB - Neuropeptides play a key role in the regulation of behaviors and physiological responses including alertness, social recognition, and hunger, yet, their mechanism of action is poorly understood. Here, we focus on the endocrine control ecdysis behavior, which is used by arthropods to shed their cuticle at the end of every molt. Ecdysis is triggered by ETH (Ecdysis triggering hormone), and we show that the response of peptidergic neurons that produce CCAP (crustacean cardioactive peptide), which are key targets of ETH and control the onset of ecdysis behavior, depends fundamentally on the actions of neuropeptides produced by other direct targets of ETH and released in a broad paracrine manner within the CNS; by autocrine influences from the CCAP neurons themselves; and by inhibitory actions mediated by GABA. Our findings provide insights into how this critical insect behavior is controlled and general principles for understanding how neuropeptides organize neuronal activity and behaviors. PMID- 27976998 TI - Acetylated tubulin is essential for touch sensation in mice. AB - At its most fundamental level, touch sensation requires the translation of mechanical energy into mechanosensitive ion channel opening, thereby generating electro-chemical signals. Our understanding of this process, especially how the cytoskeleton influences it, remains unknown. Here we demonstrate that mice lacking the alpha-tubulin acetyltransferase Atat1 in sensory neurons display profound deficits in their ability to detect mechanical stimuli. We show that all cutaneous afferent subtypes, including nociceptors have strongly reduced mechanosensitivity upon Atat1 deletion, and that consequently, mice are largely insensitive to mechanical touch and pain. We establish that this broad loss of mechanosensitivity is dependent upon the acetyltransferase activity of Atat1, which when absent leads to a decrease in cellular elasticity. By mimicking alpha tubulin acetylation genetically, we show both cellular rigidity and mechanosensitivity can be restored in Atat1 deficient sensory neurons. Hence, our results indicate that by influencing cellular stiffness, alpha-tubulin acetylation sets the force required for touch. PMID- 27976999 TI - Clec11a/osteolectin is an osteogenic growth factor that promotes the maintenance of the adult skeleton. AB - Bone marrow stromal cells maintain the adult skeleton by forming osteoblasts throughout life that regenerate bone and repair fractures. We discovered that subsets of these stromal cells, osteoblasts, osteocytes, and hypertrophic chondrocytes secrete a C-type lectin domain protein, Clec11a, which promotes osteogenesis. Clec11a-deficient mice appeared developmentally normal and had normal hematopoiesis but reduced limb and vertebral bone. Clec11a-deficient mice exhibited accelerated bone loss during aging, reduced bone strength, and delayed fracture healing. Bone marrow stromal cells from Clec11a-deficient mice showed impaired osteogenic differentiation, but normal adipogenic and chondrogenic differentiation. Recombinant Clec11a promoted osteogenesis by stromal cells in culture and increased bone mass in osteoporotic mice in vivo. Recombinant human Clec11a promoted osteogenesis by human bone marrow stromal cells in culture and in vivo. Clec11a thus maintains the adult skeleton by promoting the differentiation of mesenchymal progenitors into mature osteoblasts. In light of this, we propose to call this factor Osteolectin. PMID- 27977000 TI - Spinal microcircuits comprising dI3 interneurons are necessary for motor functional recovery following spinal cord transection. AB - The spinal cord has the capacity to coordinate motor activities such as locomotion. Following spinal transection, functional activity can be regained, to a degree, following motor training. To identify microcircuits involved in this recovery, we studied a population of mouse spinal interneurons known to receive direct afferent inputs and project to intermediate and ventral regions of the spinal cord. We demonstrate that while dI3 interneurons are not necessary for normal locomotor activity, locomotor circuits rhythmically inhibit them and dI3 interneurons can activate these circuits. Removing dI3 interneurons from spinal microcircuits by eliminating their synaptic transmission left locomotion more or less unchanged, but abolished functional recovery, indicating that dI3 interneurons are a necessary cellular substrate for motor system plasticity following transection. We suggest that dI3 interneurons compare inputs from locomotor circuits with sensory afferent inputs to compute sensory prediction errors that then modify locomotor circuits to effect motor recovery. PMID- 27977002 TI - Supporting Heart Failure Patient Transitions From Acute to Community Care With Home Telemonitoring Technology: A Protocol for a Provincial Randomized Controlled Trial (TEC4Home). AB - BACKGROUND: Seniors with chronic diseases such as heart failure have complex care needs. They are vulnerable to their condition deteriorating and, without timely intervention, may require multiple emergency department visits and/or repeated hospitalizations. Upon discharge, the transition from the emergency department to home can be a vulnerable time for recovering patients with disruptions in the continuity of care. Remote monitoring of heart failure patients using home telemonitoring, coupled with clear communication protocols between health care professionals, can be effective in increasing the safety and quality of care for seniors with heart failure discharged from the emergency department. OBJECTIVE: The aim of the Telehealth for Emergency-Community Continuity of Care Connectivity via Home Telemonitoring (TEC4Home) study is to generate evidence through a programmatic evaluation and a clinical trial to determine how home telemonitoring may improve care and increase patient safety during the transition of care and determine how it is best implemented to support patients with heart failure within this context. METHODS: This 4-year project consists of 3 studies to comprehensively evaluate the outcomes and effectiveness of TEC4Home. Study 1 is a feasibility study with 90 patients recruited from 2 emergency department sites to test implementation and evaluation procedures. Findings from the feasibility study will be used to refine protocols for the larger trial. Study 2 is a cluster randomized controlled trial that will include 30 emergency department sites and 900 patients across British Columbia. The primary outcome of the randomized controlled trial will be emergency department revisits and hospital readmission rates. Secondary outcomes include health care resource utilization/costs, communication between members of the care team, and patient quality of life. Study 3 will run concurrently to study 2 and test the effectiveness of predictive analytic software to detect patient deterioration sooner. RESULTS: It is hypothesized that TEC4Home will be a cost-effective strategy to decrease 90-day emergency department revisits and hospital admission rates and improve comfort and quality of life for seniors with heart failure. The results from this project will also help establish an innovation pathway for rapid and rigorous introduction of innovation into the health system. CONCLUSIONS: While there is some evidence about the effectiveness of home telemonitoring for some patients and conditions, the TEC4Home project will be one of the first protocols that implements and evaluates the technology for patients with heart failure as they transition from the emergency department to home care. The results from this research are expected to inform the full scale and spread of the home monitoring approach throughout British Columbia and Canada and to other chronic diseases. CLINICALTRIAL: ClinicalTrials.gov NCT02821065; https://clinicaltrials.gov/ct2/show/NCT02821065 (Archived by WebCite at http://www.webcitation.org/6ml2iwKax). PMID- 27977001 TI - Relief of autoinhibition by conformational switch explains enzyme activation by a catalytically dead paralog. AB - Catalytically inactive enzyme paralogs occur in many genomes. Some regulate their active counterparts but the structural principles of this regulation remain largely unknown. We report X-ray structures of Trypanosoma brucei S adenosylmethionine decarboxylase alone and in functional complex with its catalytically dead paralogous partner, prozyme. We show monomeric TbAdoMetDC is inactive because of autoinhibition by its N-terminal sequence. Heterodimerization with prozyme displaces this sequence from the active site through a complex mechanism involving a cis-to-trans proline isomerization, reorganization of a beta-sheet, and insertion of the N-terminal alpha-helix into the heterodimer interface, leading to enzyme activation. We propose that the evolution of this intricate regulatory mechanism was facilitated by the acquisition of the dimerization domain, a single step that can in principle account for the divergence of regulatory schemes in the AdoMetDC enzyme family. These studies elucidate an allosteric mechanism in an enzyme and a plausible scheme by which such complex cooperativity evolved. PMID- 27977003 TI - Single-stage endovascular treatment of multiple intracranial aneurysms with combined endovascular techniques: is it safe to treat all at once? AB - BACKGROUND AND PURPOSE: Multiple aneurysms have a high reported incidence, but the optimal treatment strategy is not clear. The aim of this study was to evaluate the safety and effectiveness of single-stage endovascular treatment of multiple aneurysms with a combination of various endovascular techniques. MATERIALS AND METHODS: Fifty-three consecutive patients with multiple intracranial aneurysms who underwent single-stage endovascular treatment for >=2 aneurysms from June 2011 to May 2016 were included in the study. Patient and aneurysm characteristics, treatment technique, complications, clinical and angiographic outcomes were retrospectively evaluated. RESULTS: 125 of 128 aneurysms (97.6%) were treated by the following endovascular techniques: simple coiling in 19, balloon-assisted coiling in 27, stent-assisted coiling in 33, flow diverters in 43, intrasaccular flow modifiers in 2, and a neck-bridging device in 1. Overall mortality and mortality directly related to the single-stage treatment was 15% (8/53) and 3.7% (2/53), respectively. Clinical and angiographic follow-up was available in 44 (83%) patients for 104 (83.2%) aneurysms for a mean duration of 16.2 months (range 3-51 months). According to the last angiographic follow-up, overall occlusion rates were complete in 85 (81.7%), near complete in 8 (7.6%), and incomplete in 11 (10.5%) aneurysms. CONCLUSIONS: Single-stage endovascular treatment of multiple aneurysms with combined endovascular techniques is technically feasible and increases the treatment possibility of all detected aneurysms. However, the safety of the procedure is controversial due to relatively high complication rates. In particular, in patients with bilateral internal carotid artery aneurysms, staged therapy may be used instead of simultaneous treatment with flow diverters to avoid thromboembolic events. PMID- 27977004 TI - Room-temperature CO Thermoelectric Gas Sensor based on Au/Co3O4 Catalyst Tablet. AB - A carbon monoxide (CO) thermoelectric (TE) gas sensor was fabricated by affixing a Au/Co3O4 catalyst tablet on a TE film layer. The Au/Co3O4 catalyst tablet was prepared by a co-precipitation and tablet compression method and its possible catalytic mechanism was discussed by means of x-ray diffraction, field emission scanning electron microscopy, high resolution transmission electron microscopy, x ray photoelectron spectroscopy, temperature-programmed reduction of hydrogen, Fourier transform infrared spectroscopy and Brunauer-Emmett-Teller analysis. The optimal catalyst, with a Au content of 10 wt%, was obtained at a calcination temperature between 200 and 300 degrees C. The small size of the Au nanoparticles, high specific surface, the existence of Co3+ and water-derived species contributed to high catalytic activity. Based on the optimal Au/Co3O4 catalyst tablet, the CO TE gas sensor worked at room temperature and showed a response voltage signal (DeltaV) of 23 mV, high selectivity among hydrogen and methane, high stability, and a fast response time of 106 s for 30 000 ppm CO/air. In addition, a CO concentration in the range of 5000-30 000 ppm could obviously be detected and exhibited a linear relationship with DeltaV. The CO TE gas sensor provides a promising option for the detection of CO gas at room temperature. PMID- 27977005 TI - Hopping conduction and random telegraph signal in an exfoliated multilayer MoS2 field-effect transistor. AB - We investigate the hopping conduction and random telegraph signal caused by various species of interface charge scatterers in a MoS2 multilayer field-effect transistor. The temperature dependence of the channel resistivity shows that at low temperatures and low carrier densities the carrier transport is via Mott variable range hopping with a hopping length changing from 41 to 80 nm. The hopping conduction was due to electron tunneling through localized band tail states formed by the scatterers located in the vicinity of the MoS2 layer. In the temperature range of 40-70 K, we observed random telegraph signal (RTS) that is caused by the capture and emission of a carrier by the interface traps that are located away from the layer. These traps form strong potential that interact with the layer and change the potential profile of the electron system. The characteristics of RTS depend strongly on gate bias and temperature, as well as the application of a magnetic field. PMID- 27977006 TI - Public variant databases: liability? AB - Public variant databases support the curation, clinical interpretation, and sharing of genomic data, thus reducing harmful errors or delays in diagnosis. As variant databases are increasingly relied on in the clinical context, there is concern that negligent variant interpretation will harm patients and attract liability. This article explores the evolving legal duties of laboratories, public variant databases, and physicians in clinical genomics and recommends a governance framework for databases to promote responsible data sharing.Genet Med advance online publication 15 December 2016. PMID- 27977007 TI - The value of genetic testing: beyond clinical utility. AB - OBJECTIVE: To assess the value of genetic testing from the perspective of the Department of Veterans Affairs (VA) clinical leadership. METHODS: We administered an Internet-based survey to VA clinical leaders nationwide. Respondents rated the value (on a 5-point scale) of each of six possible reasons for genetic testing. Bivariate and linear regressions identified associations between value ratings and environmental, organizational, provider, patient, and encounter characteristics. RESULTS: Respondents (n = 353; 63% response rate) represented 92% of VA medical centers. Tests that inform clinical management had the highest value rating (58.6%), followed by tests that inform disease prevention (56.4%), reproductive options (50.1%), life planning (43.9%), and a suspected (39.9%) or established (32.3%) diagnosis. Factors positively associated with high value included a culture that fosters adoption of genomics, specialist versus primary care provider, genetic tests available on laboratory menus, availability of genetic testing guidelines, clinicians knowing when to request genetics referrals, and availability of genetics professionals. CONCLUSION: Our results demonstrate the varied value of genetic testing from the perspective of clinical leadership within a health-care system. Engaging organizational leadership in understanding the various reasons for genetic testing and its value beyond clinical utility may increase adoption of genetic tests to support patient centered care.Genet Med advance online publication 15 December 2016. PMID- 27977009 TI - Downregulated expression of microRNA-124 in pediatric intestinal failure patients modulates macrophages activation by inhibiting STAT3 and AChE. AB - Intestinal inflammation plays a critical role in the pathogenesis of intestinal failure (IF). The macrophages are essential to maintain the intestinal homeostasis. However, the underlying mechanisms of intestinal macrophages activation remain poorly understood. Since microRNAs (miRNAs) have pivotal roles in regulation of immune responses, here we aimed to investigate the role of miR 124 in the activation of intestinal macrophages. In this study, we showed that the intestinal macrophages increased in pediatric IF patients and resulted in the induction of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). The miRNA fluorescence in situ hybridization analysis showed that the expression of miR-124 significantly reduced in intestinal macrophages in IF patients. Overexpression of miR-124 was sufficient to inhibit intestinal macrophages activation by attenuating production of IL-6 and TNF-alpha. Further studies showed that miR-124 could directly target the 3'-untranslated region of both signal transducer and activator of transcription 3 (STAT3) and acetylcholinesterase (AChE) mRNAs, and suppress their protein expressions. The AChE potentially negates the cholinergic anti-inflammatory signal by hydrolyzing the acetylcholine. We here showed that intestinal macrophages increasingly expressed the AChE and STAT3 in IF patients when compared with controls. The inhibitors against to STAT3 and AChE significantly suppressed the lipopolysaccharides-induced IL-6 and TNF-alpha production in macrophages. Taken together, these findings highlight an important role for miR-124 in the regulation of intestinal macrophages activation, and suggest a potential application of miR-124 in pediatric IF treatment regarding as suppressing intestinal inflammation. PMID- 27977008 TI - The recurrent architecture of tumour initiation, progression and drug sensitivity. AB - Recent studies across multiple tumour types are starting to reveal a recurrent regulatory architecture in which genomic alterations cluster upstream of functional master regulator (MR) proteins, the aberrant activity of which is both necessary and sufficient to maintain tumour cell state. These proteins form small, hyperconnected and autoregulated modules (termed tumour checkpoints) that are increasingly emerging as optimal biomarkers and therapeutic targets. Crucially, as their activity is mostly dysregulated in a post-translational manner, rather than by mutations in their corresponding genes or by differential expression, the identification of MR proteins by conventional methods is challenging. In this Opinion article, we discuss novel methods for the systematic analysis of MR proteins and of the modular regulatory architecture they implement, including their use as a valuable reductionist framework to study the genetic heterogeneity of human disease and to drive key translational applications. PMID- 27977010 TI - TRAP1 downregulation in human ovarian cancer enhances invasion and epithelial mesenchymal transition. AB - Ovarian cancer (OC) is the second leading cause of gynecological cancer death worldwide. Although the list of biomarkers is still growing, molecular mechanisms involved in OC development and progression remain elusive. We recently demonstrated that lower expression of the molecular chaperone TRAP1 in OC patients correlates with higher tumor grade and stage, and platinum resistance. Herein we show that TRAP1 is often deleted in high-grade serous OC patients (N=579), and that TRAP1 expression is correlated with the copy number, suggesting this could be one of the driving mechanisms for the loss of TRAP1 expression in OC. At molecular level, downregulation of TRAP1 associates with higher expression of p70S6K, a kinase frequently active in OC with emerging roles in cell migration and tumor metastasis. Indeed, TRAP1 silencing in different OC cells induces upregulation of p70S6K expression and activity, enhancement of cell motility and epithelial-mesenchymal transition (EMT). Consistently, in a large cohort of OC patients, TRAP1 expression is reduced in tumor metastases and directly correlates with the epithelial marker E-Cadherin, whereas it inversely correlates with the transcription factor Slug and the matrix metallopeptidases 2 and 9. Strikingly, pharmacological inhibition of p70S6K reverts the high motility phenotype of TRAP1 knock-down cells. However, although p70S6K inhibition or silencing reduces the expression of the transcription factors Snail and Slug, thus inducing upregulation of E-Cadherin expression, it is unable to revert EMT induced by TRAP1 silencing; furthermore, p70S6K did not show any significant correlation with EMT genes in patients, nor with overall survival or tumor stage, suggesting an independent and predominant role for TRAP1 in OC progression. Altogether, these results may provide novel approaches in OC with reduced TRAP1 expression, which could be resistant to therapeutic strategies based on the inhibition of the p70S6K pathway, with potential future intervention in OC invasion and metastasis. PMID- 27977011 TI - Severe intraventricular hemorrhage and withdrawal of support in preterm infants. AB - OBJECTIVE: The objective of the study was to determine whether withdrawal of support in severe 'intraventricular hemorrhage' (IVH), that is, IVH grade 3 and periventricular hemorrhagic infarction (PVHI), has decreased after publication of studies that show improved prognosis and to examine cranial ultrasonograms, including PVHI territories defined by Bassan. STUDY DESIGN: Retrospective cohort of preterm infants from 23 0/7 to 28 6/7 weeks' gestation in 1993 to 2013. RESULTS: Among the 1755 infants, 1494 had no bleed, germinal matrix hemorrhage (GMH) or IVH grade 2, 137 had grade 3 IVH and 124 had PVHI. The odds of withdrawal of support, adjusted for severity of GMH-IVH and baseline variables, did not decrease after publications showing better prognosis. Among 82 patients who died with PVHI, 76 had life support withdrawn, including 34 without another contributing cause of death. The median number of PVHI territories involved was three. CONCLUSION: Withdrawal of support adjusted for severity of GMH-IVH did not significantly change after publications showing better prognosis. PMID- 27977012 TI - Alarm safety and oxygen saturation targets in the Vermont Oxford Network iNICQ 2015 collaborative. AB - OBJECTIVES: To assess progress of neonatal intensive care units (NICUs) participating in the Vermont Oxford Network iNICQ 2015: Alarm Safety Collaborative in achieving Joint Commission 2014 alarm safety goals with respect to oximeters, and to compare patient-level oxygen saturation (SpO2) and oximeter alarm data to local policies. STUDY DESIGN: Prospective multicenter audits in February and August 2015 assessed implementation of policies addressing Joint Commission 2014 Alarm Safety goals, and ascertained SpO2 targets, oximeter alarm settings and compliance with policy-specified SpO2 targets and alarms. RESULTS: Eighty-six NICUs completed both audits. Of 13 policies addressing mandated goals, median (interquartile range) 8 (5, 9) policies were implemented at audit 1 and 9 (6, 11) at audit 2 (P=0.004). At audit 1, 28 NICUs had implemented ?9 policies versus 47 at audit 2. For 794 infants <31 weeks gestation, <36 weeks postmenstrual age, and on supplemental oxygen, median SpO2 target lower limit was 88% (interquartile range 87%, 90%; range 75% to 94%), upper limit 95% (interquartile range 94%, 96%; range 85% to 100%). High oximeter alarm was set according to local policy for 63% of infants, for whom SpO2 >97% was less frequent than when high alarm was not set to policy (10.1% vs 21.5%, P=0.006). CONCLUSIONS: Participating NICUs showed significant progress between audits in their implementation of Joint Commission Alarm Safety goals for oximeter monitoring. Oximeter high alarm not set per local policy is associated with increased hyperoxemia in preterm infants. Recommendations to standardize oxygen saturation targets for infants at risk for oxygenation-related outcomes have not been widely adopted. PMID- 27977014 TI - Biometry of the corpus callosum assessed by 3D ultrasound and its correlation to neurodevelopmental outcome in very low birth weight infants. AB - OBJECTIVE: Several studies have shown a relation between the size of corpus callosum (CC) and outcome in preterm infants. Three-dimensional ultrasound (3D US) offers new perspectives in cerebral imaging. To establish reference values for biometry of the CC in very low birth weight infants and to correlate these measurements to neurodevelopmental outcome at 5 years of age. STUDY DESIGN: Forty three preterm infants with a gestational age <32 weeks were included. Transfontanellar 3D-US measurements were obtained at nine different timepoints. RESULTS: 3D-US-based reference values for size, length, circumference and surface area of the CC could be established. Measurements at term-equivalent age showed a correlation to neurodevelopment outcome. CONCLUSION: Reliable biometric data of the CC can be established in preterm infants by 3D-US and correlate with neurodevelopmental outcome. PMID- 27977013 TI - Acupuncture in the neonatal intensive care unit-using ancient medicine to help today's babies: a review. AB - Acupuncture has been used for thousands of years in Eastern medicine for a variety of conditions and illnesses, including pain. Neonatal intensive care, on the other hand, is a relatively new branch of medicine that has emerged as the pivotal influence in increasing survival of critically ill newborn infants only within the last 50 years. Unfortunately, pain is an inevitable part of treatment in a neonatal intensive care unit (NICU). The control and prevention of pain remains a major issue for clinicians despite recognition and understanding of the myriad of short- and long-term problems that are associated with both pain and its treatment within the NICU environment. In this review, we examine the potential role of acupuncture to decrease and treat pain in babies requiring neonatal intensive care and discuss future therapeutic and research implications for the use of this ancient therapy within the modern environment of the NICU. PMID- 27977015 TI - The relationship between three signs of fetal magnetic resonance imaging and severity of congenital diaphragmatic hernia. AB - OBJECTIVE: To seek a simple approach for prenatally classifying congenital diaphragmatic hernia (CDH) severity using fetal magnetic resonance imaging (MRI) markers. STUDY DESIGN: A retrospective, multicenter study using questionnaires to investigate fetal MRI findings. We included fetuses prenatally diagnosed with isolated left-sided CDH and delivered after 36 weeks of gestation. We focused on three fetal MRI morphological signs: incomplete pulmonary baseline (IPB), liver up (LU) and retrocardiac stomach (RCS). We also evaluated the fetal MRI score defined as the total number of positive signs; the primary outcome was survival at discharge. RESULTS: In 256 patients (from 56 institutions), IPB, LU and RCS findings correlated with lower survival: odds ratio (95% confidence interval), 0.16 (0.08 to 0.33); 0.24 (0.12 to 0.51); and 0.14 (0.07 to 0.28); respectively. Patients with higher fetal MRI scores had a higher mortality rate. CONCLUSION: IPB, LU and RCS on fetal MRI are related to CDH severity. PMID- 27977016 TI - Heart sounds at home: feasibility of an ambulatory fetal heart rhythm surveillance program for anti-SSA-positive pregnancies. AB - OBJECTIVE: Fetuses exposed to anti-SSA (Sjogren's) antibodies are at risk of developing irreversible complete atrioventricular block (CAVB), resulting in death or permanent cardiac pacing. Anti-inflammatory treatment during the transition period from normal heart rhythm (fetal heart rhythm (FHR)) to CAVB (emergent CAVB) can restore sinus rhythm, but detection of emergent CAVB is challenging, because it can develop in ?24 h. We tested the feasibility of a new technique that relies on home FHR monitoring by the mother, to surveil for emergent CAVB. STUDY DESIGN: We recruited anti-SSA-positive mothers at 16 to 18 weeks gestation (baseline) from 8 centers and instructed them to monitor FHR two times a day until 26 weeks, using a Doppler device at home. FHR was also surveilled by weekly or every other week fetal echo. If FHR was irregular, the mother underwent additional fetal echo. We compared maternal stress/anxiety before and after monitoring. Postnatally, infants underwent a 12-lead electrocardiogram. RESULTS: Among 133 recruited, 125 (94%) enrolled. Among those enrolled, 96% completed the study. Reasons for withdrawal (n=5) were as follows: termination of pregnancy, monitoring too time consuming or moved away. During home monitoring, 9 (7.5%) mothers detected irregular FHR diagnosed by fetal echo as normal (false positive, n=2) or benign atrial arrhythmia (n=7). No CAVB was undetected or developed after monitoring. Questionnaire analysis indicated mothers felt comforted by the experience and would monitor again in future pregnancies. CONCLUSION: These data suggest ambulatory FHR surveillance of anti SSA-positive pregnancies is feasible, has a low false positive rate and is empowering to mothers. PMID- 27977017 TI - Effect of genetic variants of bilirubin metabolism on the degree of hyperbilirubinemia in African-American newborns. AB - OBJECTIVE: The objective of our study was to measure the effect of genetic variants of these two enzymes, UGT1A1 and SLCO1B1, in the bilirubin metabolic pathway on the degree of hyperbilirubinemia in a cohort of African-American (AA) infants from our well-baby nursery. In addition, a second objective was to document the types and frequencies of genetic variations of these enzymes in our cohort. STUDY DESIGN: A prospective study of 180 AA infants from the Well Baby Nursery of an inner city community hospital, all of whose mothers were type O pos. Sixty infants were ABO-incompatible direct antiglobulin test (DAT) pos, 60 were ABO-incompatible DAT neg and 60 were type O+. Blood for carboxyhemoglobin (COHb) and variants of the enzymes uridine diphosphoglucuronosyltransferase 1A1 and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) was drawn at the time of the infants' initial bilirubin, and the infants' precise percentile on the Bhutani nomogram was calculated. RESULTS: Variants in the two enzymes studied were quite common. In total, 21.1% were positive for a Gilbert phenotype, whereas an additional 42.4% were heterozygous for the *28 or *37 variant of UGT1A1. In total, 67.2% were homozygous for the *60 variant of the phenobarbital responsive enhancer module. In total, 41.1% were homozygous for the *1b variant of SLCO1B1, whereas an additional 12.7% were positive for the *4 variant of this gene. In total, 20.6% of infants had variations in both genes. Using logistic regression when COHbc was assessed with each of the different variants, only COHbc (P<0.0001 to 0.0004) was significantly associated with the level of hyperbilirubinemia as defined by the Bhutani nomogram. CONCLUSION: Although we have found quite a large number of genetic variants of the UGT1A1 and SLCO1B1 genes in the AA population, it does not appear that they have a significant impact on the incidence of hyperbilirubinemia among this group of infants. PMID- 27977018 TI - Postpartum hemorrhage following vaginal delivery: risk factors and maternal outcomes. AB - OBJECTIVE: Limited understanding of risk factors exists for postpartum hemorrhage (PPH) post-vaginal delivery. The aim of this study was to identify risk factors for PPH post-vaginal delivery within a contemporary obstetric cohort. STUDY DESIGN: Retrospective case-control study. PPH was classified by an estimated blood loss ?500 ml. Risk factors for PPH were identified using univariable and multivariable logistic regression. We secondarily investigated maternal outcomes and medical and surgical interventions for PPH management. RESULTS: The study cohort comprised 159 cases and 318 controls. Compared with a second-stage duration <2 h, a second stage?3 h was associated with PPH (adjusted odds ratio=2.3; 95% CI=1.2 to 4.6). No other clinical or obstetric variables were identified as independent risk factors for PPH. Among cases, 4% received red blood cells and 1% required intensive care admission. CONCLUSION: Although PPH related morbidity may be uncommon after vaginal delivery, PPH should be anticipated for women after a second stage ?3 h. PMID- 27977020 TI - DNA Methylation Identifies Loci Distinguishing Hereditary Nonpolyposis Colorectal Cancer Without Germ-Line MLH1/MSH2 Mutation from Sporadic Colorectal Cancer. AB - OBJECTIVES: Roughly half of hereditary nonpolyposis colorectal cancer (HNPCC) cases are Lynch syndrome and exhibit germ-line mutations in DNA mismatch repair (MMR) genes; the other half are familial colorectal cancer (CRC) type X (FCCTX) and are MMR proficient. About 70% of Lynch syndrome tumors have germ-line MLH1 or MSH2 mutations. The clinical presentation, histopathological features, and carcinogenesis of FCCTX resemble those of sporadic MMR-proficient colorectal tumors. It is of interest to obtain biomarkers that distinguish FCCTX from sporadic microsatellite stable (MSS) CRC, to develop preventive strategies. METHODS: The tumors and adjacent normal tissues of 40 patients with HNPCC were assayed using the Illumina Infinium HumanMethylation27 (HM27) BeadChip to assess the DNA methylation level at about 27,000 loci. The germ-line mutation status of MLH1 and MSH2 and the microsatellite instability status in these patients were obtained. Genome-wide DNA methylation measurements of three groups of patients with general CRC were downloaded from public domain databases. Probes with DNA methylation levels that differed significantly between patients with sporadic MSS CRC and FCCTX were examined, to explore their potential as biomarkers. RESULTS: We found that MSS HNPCC tumors were overwhelmingly hypomethylated compared with those from patient groups with other types of CRC, including germ-line MLH1/MSH2 mutated HNPCC and sporadic MSS CRC. Five gene-marker panels that exhibited a sensitivity of 100% and a specificity higher than 90% in both discovery and validation cohorts were proposed to distinguish MSS HNPCC tumors from sporadic MSS CRC. CONCLUSIONS: Our results warrant further investigation and validation. The loci identified here may become useful biomarkers for distinguishing between FCCTX and sporadic MSS CRC tumors. PMID- 27977022 TI - Capture and sequencing of NAD-capped RNA sequences with NAD captureSeq. AB - Here we describe a protocol for NAD captureSeq that allows for the identification of nicotinamide-adenine dinucleotide (NAD)-capped RNA sequences in total RNA samples from different organisms. NAD-capped RNA is first chemo-enzymatically biotinylated with high efficiency, permitting selective capture on streptavidin beads. Then, a highly efficient library preparation protocol tailored to immobilized, 5'-modified RNA is applied, with adaptor ligation to the RNA's 3' terminus and reverse transcription (RT) performed on-bead. Then, cDNA is released into solution, tailed, ligated to a second adaptor and PCR-amplified. After next generation sequencing (NGS) of the DNA library, enriched sequences are identified by comparison with a control sample in which the first step of chemo-enzymatic biotinylation is omitted. Because the downstream protocol does not necessarily rely on NAD-modified but on 'clickable' or biotin-modified RNA, it can be applied to other RNA modifications or RNA-biomolecule interactions. The central part of this protocol can be completed in ~7 d, excluding preparatory steps, sequencing and bioinformatic analysis. PMID- 27977019 TI - The iron status at birth of neonates with risk factors for developing iron deficiency: a pilot study. AB - OBJECTIVE: Small-for-gestational-age (SGA) neonates, infants of diabetic mothers (IDM) and very-low-birth weight premature neonates (VLBW) are reported to have increased risk for developing iron deficiency and possibly associated neurocognitive delays. STUDY DESIGN: We conducted a pilot study to assess iron status at birth in at-risk neonates by measuring iron parameters in umbilical cord blood from SGA, IDM, VLBW and comparison neonates. RESULTS: Six of the 50 infants studied had biochemical evidence of iron deficiency at birth. Laboratory findings consistent with iron deficiency were found in one SGA, one IDM, three VLBW, and one comparison infant. None of the infants had evidence of iron deficiency anemia. CONCLUSIONS: Evidence of biochemical iron deficiency at birth was found in 17% of screened neonates. Studies are needed to determine whether these infants are at risk for developing iron-limited erythropoiesis, iron deficiency anemia or iron-deficient neurocognitive delay. PMID- 27977023 TI - Direct, long-term intrathecal application of therapeutics to the rodent CNS. AB - Systemic application of therapeutics to the CNS tissue often results in subtherapeutic drug levels, because of restricted and selective penetration through the blood-brain barrier (BBB). Here, we give a detailed description of a standardized technique for intrathecal drug delivery in rodents, analogous to the technique used in humans. The intrathecal drug delivery method bypasses the BBB and thereby offers key advantages over oral or intravenous administration, such as maximized local drug doses with minimal systemic side effects. We describe how to deliver antibodies or drugs over several days or weeks from a s.c. minipump and a fine catheter inserted into the subdural space over the spinal cord (20 min operative time) or into the cisterna magna (10 min operative time). Drug levels can be sampled by quick and minimally invasive cerebrospinal fluid (CSF) collection from the cisterna magna (5 min procedure time). These techniques enable targeted application of any compound to the CNS for therapeutic studies in a wide range of CNS disease rodent models. Basic surgery skills are helpful for carrying out the procedures described in this protocol. PMID- 27977024 TI - Correction: A highly flexible inorganic framework with amphiphilic amine assemblies as templates. AB - Correction for 'A highly flexible inorganic framework with amphiphilic amine assemblies as templates' by Hui-Lin Huang et al., Dalton Trans., 2017, DOI: 10.1039/c6dt04165e. PMID- 27977021 TI - Correlated fluorescence microscopy and cryo-electron tomography of virus-infected or transfected mammalian cells. AB - Correlative light and electron microscopy (CLEM) combines spatiotemporal information from fluorescence light microscopy (fLM) with high-resolution structural data from cryo-electron tomography (cryo-ET). These technologies provide opportunities to bridge knowledge gaps between cell and structural biology. Here we describe our protocol for correlated cryo-fLM, cryo-electron microscopy (cryo-EM), and cryo-ET (i.e., cryo-CLEM) of virus-infected or transfected mammalian cells. Mammalian-derived cells are cultured on EM substrates, using optimized conditions that ensure that the cells are spread thinly across the substrate and are not physically disrupted. The cells are then screened by fLM and vitrified before acquisition of cryo-fLM and cryo-ET images, which is followed by data processing. A complete session from grid preparation through data collection and processing takes 5-15 d for an individual experienced in cryo-EM. PMID- 27977026 TI - Structures and magnetic properties of dysprosium complexes: the effect of crystallization temperature. AB - Two new dysprosium complexes, [Dy(H5L)(NO3)2(CH3OH)2].4CH3OH (1) and [Dy2(H5L)2(NO3)4(H2O)2].10CH3OH (2), were isolated from the reaction of a novel 1,8-naphthalenediol-based ligand N,N'-((1,8-dihydroxynaphthalene-2,7 diyl)bis(methanylylidene))bis(2-hydroxybenzohydrazide), H6L with dysprosium(iii) nitrate upon crystallization at different temperatures. Because of a low symmetrical coordination environment, both complexes display only field-induced single molecular magnetic (SMM) behavior. Interestingly, complex 2 containing two dysprosium ions shows field-induced multiple relaxation processes, whereas only one relaxation process is observed for complex 1. The remarkably different behavior observed in 2 is mainly ascribed to the weak intra- or intermolecular interactions between the two DyIII centres in this complex. PMID- 27977025 TI - Selective synthesis of iridium(iii)-derived molecular Borromean rings, [2]catenane and ring-in-ring macrocycles via coordination-driven self-assembly. AB - This paper reports the formation of unprecedented iridium(iii)-derived topological macrocycles. Discrete molecular Borromean rings 1 and 3 in pure form are synthesized via coordination-driven self-assembly of an acceptor [(Cp*Ir)2(OO?OO)](OTf)2 (Cp* = pentamethylcyclopentadienyl, OO?OO = 6,11-dioxido 5,12-naphthacenedione) (A) with dipyridyl donors 1,4-bis(4 pyridinylethynyl)benzene (L1) and 2,5-bis(4-pyridinylethynyl)thiophene (L2) respectively in methanol. Self-assembly using the same acceptor under similar conditions with two other donors 9,10-bis(4-pyridinylethynyl)anthracene (L3) and 1,4-di(4-pyridinylethynyl)buta-1,3-diyne (L4) resulted in [2]catenane 5 and non catenane ring-in-ring topological macrocycle 7 respectively. Rectangular macrocycles 2, 4, 6, and 8 were respectively obtained when the self-assembly of acceptor A with one of the donors L1-L4 was carried out under dilute conditions in nitromethane or methanol. All these new macrocycles were characterized by 1H and 13C NMR, 2D NMR, ESI-MS and elemental analyses. Single crystal X-ray structures of Borromean rings 1 and 3, and ring-in-ring macrocycle 7 revealed that the length and functionality of donors enabling CHpi and pipi interactions govern the topology. PMID- 27977027 TI - The effect of limb amputation on standing weight distribution in the remaining three limbs in dogs. AB - Despite the fact that limb amputation is a commonly performed procedure in veterinary medicine, quantitative data regarding outcomes are lacking. The intention of this study was to evaluate the effect of limb amputation on weight distribution to the remaining three limbs at a stance in dogs. Ten dogs with a prior forelimb amputation and ten dogs with a prior hindlimb amputation; all of which had no history of orthopaedic or neural disease in the remaining three limbs were included in the study. Standing weight bearing was evaluated with a commercial stance analyzer in all dogs. Five valid trials were obtained and a mean percentage of weight bearing was calculated for each remaining limb. The dogs with a previous forelimb amputation, and also those with a previous hindlimb amputation, had the largest mean increase in weight bearing in the contralateral forelimb. In conclusion, proactive monitoring of orthopaedic disease in the contralateral forelimb may be advisable in dogs with a previous limb amputation. In addition, when determining candidacy for a limb amputation, disease of the contralateral forelimb should be thoroughly evaluated. PMID- 27977028 TI - Surgical management of dorsal scapular luxation in three dogs. AB - Scapular luxation is an uncommon cause of forelimb lameness in dogs and cats. Traumatic rupture of the serratus ventralis muscle allows the scapula to displace dorsally during weight-bearing. Specific documentation regarding clinical presentation and surgical techniques is limited, with no medium- to long-term results of surgical intervention in dogs described. Presented here are three cases of scapular luxation in dogs, treated with a modified surgical technique. Clinical outcome was considered good to excellent, with resolution of lameness and abnormal scapular motion in all three dogs. Medium- and long-term outcomes were assessed in two of the dogs, with an excellent outcome in both cases. PMID- 27977030 TI - Myeloid Sarcoma in the Orbit. AB - The authors describe a case of myeloid sarcoma of the orbit in a pediatric patient. An 8-month-old male infant presented to the ophthalmology clinic with a left orbital mass, which had been increasing in size over the previous 2 months. The mass was initially diagnosed at another clinic as an infantile hemangioma, and had been treated with a topical formulation of timolol. In the ophthalmology clinic, orbital magnetic resonance imaging showed a solid enhancing mass. A biopsy was performed, and histopathology revealed myeloid sarcoma. The disease responded well to a standard chemotherapy regimen. Myeloid sarcoma is a rare, extra-medullary presentation that can occur as an isolated tumor, concurrently with or at relapse of acute myeloid leukemia. Because few cases of myeloid sarcoma in the orbit have been reported, this case report aids in the management of myeloid sarcoma in pediatric patients. The report describes an 8-month-old male infant, the youngest patient to develop myeloid sarcoma without preexisting acute myeloid leukemia. [J Pediatr Ophthalmol Strabismus. 2016;53:e64-e68.]. PMID- 27977029 TI - Painful Acute Corneal Ulceration and Anterior Stromal Keratitis in an Adolescent With Reactive Arthritis. AB - Reactive arthritis is occasionally associated with conjunctivitis and uveitis, but rarely keratitis. The authors describe a patient with paracentral anterior stromal keratitis with overlying epithelial erosion and multiple satellite subepithelial infiltrates. The initial appearance and the severe pain were suggestive of an infectious process. Recovery was rapid following introduction of topical steroid, with features suggesting an immune process in the recovery phase. The authors suggest that a history of arthritis and/or recent enteritis should be sought in the work-up of an atypical keratitis with or without epithelial defect. [J Pediatr Ophthalmol Strabismus. 2016;53:e61-e63.]. PMID- 27977031 TI - Ultra-wide Field Imaging and Swept Source Optical Coherence Tomography of Ocular Electrical Injury in a Child. AB - History of trauma in children may be obscured and physicians often rely on signs for diagnosis. The authors discuss a case of electrical injury where ocular signs led to diagnosis of the cause of macular atrophy. A high index of suspicion must always be maintained in such atypical cases, and the setting of electrical injury to the body requires meticulous ocular examination. [J Pediatr Ophthalmol Strabismus. 2016;53:e69-e71.]. PMID- 27977032 TI - Multiple Pathological Ocular Findings in a Patient With PHACE Syndrome. AB - The authors describe a 2-year-old girl diagnosed as having posterior fossa malformations, hemangiomas, arterial anomalies, cardiac anomalies, and eye abnormalities (PHACE) syndrome that presented with a large facial hemangioma of the forehead and eyelid, ptosis, microphthalmia, persistent pupillary membrane and pupillary ectopia, congenital oculomotor nerve palsy of the affected eye, and bilateral optic disc dysplasia. [J Pediatr Ophthalmol Strabismus. 2016;53:e72 e74.]. PMID- 27977033 TI - Medical Management of Blepharokeratoconjunctivitis in Children: A Delphi Consensus. AB - PURPOSE: To describe a pragmatic approach to the medical management of blepharokeratoconjunctivitis in children, based on published evidence and clinical experience. METHODS: The authors used the Delphi consensus method to explore the preferred management patterns of four senior clinicians at one institution to reach agreement on indications and dosage schedules for commonly used treatments. Four iterations were created, with electronic questionnaires distributed via an online survey platform. Initial questions were based on recent systematic reviews and clinical experience. After each round, a facilitator summarized the responses and fed these back to the expert participants, together with an invitation to complete the next round of questions. RESULTS: Typical and specific eyelid, corneal, and conjunctival disease features influenced management decisions, and treatments were targeted toward specific findings in these tissues rather than to overall disease severity. Active keratitis was considered the main indication for high potency steroids, systemic antibiotics, and possibly systemic immunomodulators. Other indications for systemic antibiotics were chronic active blepharitis and recurrent troublesome chalazia. Oral antibiotics were used for their anti-inflammatory and antimicrobial properties. There was little agreement on the role of dietary modification, topical lubricants, and preference for oral or topical antibiotics. CONCLUSIONS: Detailed clinical assessment of eyelids and ocular surface allows targeted treatment. Research is needed to clarify disease mechanisms and to optimize treatment strategies. [J Pediatr Ophthalmol Strabismus. 2017;54(3):156-162.]. PMID- 27977034 TI - Factors Predictive of Success in Probing for Congenital Nasolacrimal Duct Obstruction. AB - PURPOSE: To report the success rate of children undergoing probing for congenital nasolacrimal duct obstruction (CNLDO) and the factors relating to the failure of the procedure. METHODS: This retrospective case series included 88 eyes of 62 patients, aged 1 to 138 months, who underwent probing between January 2008 and December 2014 in the Pediatric Ophthalmology Unit of Centro Hospitalar Sao Joao. The procedure was performed in the operating room under general anesthesia. Surgical success was defined as successful lacrimal irrigation in-traoperatively and resolution of epiphora at the follow-up visit 1 month after surgery. RESULTS: The overall success rate after first probing was 77.3% (68 of 88 eyes). No differences were found regarding age (P = .546), gender (P = .740), surgical experience (P = .611), or laterality (P = .328) between children who were cured and not cured. The surgical success rate decreased in children older than 4 years, although not to a statistically significant degree (P = .190). Surgical success after second probing was 85.7% (12 of 14 eyes), and the median interval between the two procedures was 3 months (range: 2 to 54 months). In 30% (7 of 20 eyes, 4 of 13 patients) of children with persistent obstruction, otorhinolaryngology evaluation evinced an adenoid hypertrophy requiring surgical correction. CONCLUSIONS: The success rate of nasolacrimal probing for CNLDO was not related to age, gender, laterality, or the surgeon's experience. Otorhinolaryngology evaluation is recommended for unresponsive patients. [J Pediatr Ophthalmol Strabismus. 2017;54(2):123-127.]. PMID- 27977035 TI - Detecting High Hyperopia: The Plus Lens Test and the Spot Vision Screener. AB - PURPOSE: To evaluate the usefulness of the Plus Lens (Goodlite Company, Elgin, IL) test and the Spot Vision Screener (Welch Allyn, Skaneateles Falls, NY) in detecting high hyperopia in a pediatric population. METHODS: Between June and August 2015, patients were screened with the Spot Vision Screener and the Plus Lens test prior to a scheduled pediatric ophthalmology visit. The following data were analyzed: demographic data, Plus Lens result, Spot Vision Screener result, cycloplegic refraction, and examination findings. Sensitivity/specificity and positive/negative predictive values were calculated for the Plus Lens test and Spot Vision Screener in detecting hyperopia as determined by the "gold-standard" cycloplegic refraction. RESULTS: A total of 109 children (average age: 82 months) were included. Compared to the ophthalmologist's cycloplegic refraction, the Spot Vision Screener sensitivity for +3.50 diopters (D) hyperopia was 31.25% and the specificity was 100%. The Plus Lens sensitivity for +3.50 D hyperopia was 43.75% and the specificity was 89.25%. Spot Vision Screener sensitivity increased with higher degrees of hyperopia. CONCLUSIONS: In this preliminary study, the Plus Lens test and the Spot Vision Screener demonstrated moderate sensitivity with good specificity in detecting high hyperopia. [J Pediatr Ophthalmol Strabismus. 2017;54(3):163-167.]. PMID- 27977036 TI - Changing Strabismus Surgery Distribution at Shanxi Province Eye Hospital in Central China. AB - PURPOSE: To investigate whether there has been a changing trend of strabismus surgery in a provincial eye hospital in the central part of China over the past decade. METHODS: This was a retrospective analysis of data on all strabismus surgery performed in Shanxi Province Eye Hospital in China during the past 10 years. Recorded characteristics included patient demographics, type of strabismus, age, and gender. RESULTS: A total of 12,327 patients received strabismus surgery in the eye hospital from 2005 to 2014. The number of surgeries increased steadily from 800 in 2005 to 1,723 in 2014 (P < .01). Constant exotropia was the most common type among all types of strabismus. Superior oblique muscle palsy was the most common type of paralytic strabismus. Exotropia oblique A- and V-pattern type was the most common type of special strabismus. CONCLUSIONS: The amount of strabismus surgery increased during the past decade. The proportion of patients with intermittent exotropia increased over time compared to those with other types of strabismus. [J Pediatr Ophthalmol Strabismus. 2017;54(2):112-116.]. PMID- 27977038 TI - Clinical Presentation and Outcomes of Stage III or Stage IV Retinoblastoma in 80 Asian Indian Patients. AB - PURPOSE: To describe the clinical features and outcomes of patients with stage III or IV retinoblastoma. METHODS: This was a retrospective study of 80 patients. RESULTS: Based on the International Retinoblastoma Staging System (IRSS), the tumors (n = 81) belonged to stage IIIa (n = 38, 47%), IIIb (n = 1, 1%), IVa2 (n = 10, 12%), IVb1 (n = 14, 17%), and IVb3 (n = 18, 22%). Of 80 patients, 42 (53%) were compliant to treatment and 38 (47%) were non-compliant. All 38 patients who were non-compliant to treatment died of the disease at a mean duration of 13 months from diagnosis. Of the 42 patients compliant to treatment, 22 (52%) died before completion of treatment. Twenty patients with stage III disease (25%) could complete the multimodal treatment and 17 (71%) were alive and well at a median follow-up duration of 77 months. CONCLUSIONS: Compliant multimodality treatment is beneficial in patients with IRSS stage III disease. IRSS stage IV retinoblastoma has poor prognosis despite treatment. [J Pediatr Ophthalmol Strabismus. 2017;54(3):177-184.]. PMID- 27977037 TI - A High Prevalence of Exotropia in Patients With Duane Retraction Syndrome in a Tertiary Eye Care Center in South India. AB - PURPOSE: To determine the prevalence and clinical characteristics of patients with Duane retraction syndrome presenting with exotropia in a tertiary eye care center. METHODS: Medical records of 140 patients with Duane retraction syndrome and exotropia (of the total 441 patients with Duane retraction syndrome) seen from 2000 to 2009 were reviewed. Characteristics studied included age at presentation, gender, laterality, manifest primary position, abnormal head posture, ocular motility, and overshoots. Data were collected regarding associated ocular or systemic abnormalities and amblyopia. RESULTS: The mean age of the patients at presentation was 16.96 +/- 15.09 years (range: 1 to 70 years). Of the 140 patients with Duane retraction syndrome and exotropia, 59 (42%) were male. Unilateral type I Duane retraction syndrome accounted for 118 (84.2%), type II for 7 (5%), and type III for 10 (7.1%) patients, whereas 5 (3.6%) had Duane retraction syndrome and bilateral exotropia. Duane retraction syndrome was seen in the left eye, right eye, and both eyes in 97 (69%), 37 (26%), and 6 (4%) patients, respectively. Exotropia ranged from 10 to 60 prism diopters. An abnormal head posture was noted in 101 (72%) and upshoot in 26 (18.6%) patients. Reported ocular and systemic abnormalities in these patients included cataract (6), aniridia (1), nasolacrimal duct block (1), and retinal breaks (1). CONCLUSIONS: This is an exclusive study on a large series of patients with Duane retraction syndrome and exotropia. Almost one-third of patients with Duane retraction syndrome patients might have exotropia. Although patients with Duane retraction syndrome and exotropia had clinical characteristics and associations similar to those with Duane retraction syndrome and esotropia, there was an increased propensity for overshoots and face turn opposite to the affected eye, which the authors hypothesize to be due to a tight or short lateral rectus muscle. [J Pediatr Ophthalmol Strabismus. 2017;54(2):117-122.]. PMID- 27977039 TI - Thermal Conductivity of Human Bone in Cryoprobe Freezing as Related to Density. AB - Cryoprobes create localized cell destruction through freezing. Bone is resistant to temperature flow but is susceptible to freezing necrosis at warmer temperatures than tumor cells. Few studies have determined the thermal conductivity of human bone. No studies have examined conductivity as related to density. The study goal was to examine thermal conductivity in human bone while comparing differences between cancellous and cortical bone. An additional goal was to establish a relationship between bone density and thermal conductivity. Six knee joints from 5 cadavers were obtained. The epiphyseal region was sliced in half coronally prior to inserting an argon-circulating cryoprobe directed away from the joint line. Thermistor thermometers were placed perpendicularly at measured increments, and the freezing cycle was recorded until steady-state conditions were achieved. For 2 cortical samples, the probe was placed intramedullary in metaphyseal samples and measurements were performed radially from the central axis of each sample. Conductivity was calculated using Fournier's Law and then plotted against measured density of each sample. Across samples, density of cancellous bone ranged from 0.86 to 1.38 g/mL and average thermal conductivity ranged between 0.404 and 0.55 W/mK. Comparatively, cortical bone had a density of 1.70 to 1.86 g/mL and thermal conductivity of 0.0742 to 0.109 W/mK. A strong 2-degree polynomial correlation was seen (R2=0.8226, P<.001). Bone is highly resistant to temperature flow. This resistance varies and inversely correlates strongly with density. This information is clinically relevant to maximize tumor ablation while minimizing morbidity through unnecessary bone loss and damage to surrounding structures. [Orthopedics. 2017; 40(2):90-94.]. PMID- 27977040 TI - Anterior Cervical Corpectomy and Fusion Using a Synthetic Hydroxyapatite Graft for Ossification of the Posterior Longitudinal Ligament. AB - The significant complication rate associated with harvesting autologous iliac bone or fibula has encouraged development of alternative graft substitutes. In this study, the authors investigated the efficacy and safety of synthetic porous hydroxyapatite (HA) combined with local vertebral bone graft for use in anterior cervical corpectomy and fusion (ACCF) for the treatment of patients with ossification of the posterior longitudinal ligament (OPLL). Since 2006, twenty five OPLL patients underwent ACCF using HA blocks (HA group). Hydroxyapatite blocks with 40% porosity were used for the 1-level ACCFs, and HA blocks with 15% porosity were used for the 2-level ACCFs. Clinical and radiological evaluation was performed with a minimum of 2-year follow-up. Outcomes were compared with those of 25 OPLL patients who underwent ACCFs using auto-fibula grafts at the authors' institution before 2006 (FBG group). Patients' demographic data were similar in the HA and FBG groups. Both groups demonstrated significant neurological improvements postoperatively. No difference was observed in operating time, whereas the intraoperative blood loss was significantly less in the HA group. The fusion rates in the HA group were comparable to those in the FBG group. The incidences of general complications were similar in the 2 groups; however, prolonged donor-site pain was observed in 9 (36.0%) cases in the FBG group. Based on the results of this study, ACCF using HA is a safe and efficacious method for the treatment of patients with OPLL as an alternative to conventional ACCF using autologous fibula bone grafting. [Orthopedics. 2017; 40(2):e334-e339.]. PMID- 27977041 TI - Risperidone versus placebo for schizophrenia. AB - BACKGROUND: Risperidone is the first new-generation antipsychotic drug made available in the market in its generic form. OBJECTIVES: To determine the clinical effects, safety and cost-effectiveness of risperidone compared with placebo for treating schizophrenia. SEARCH METHODS: On 19th October 2015, we searched the Cochrane Schizophrenia Group Trials Register, which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. We checked the references of all included studies and contacted industry and authors of included studies for relevant studies and data. SELECTION CRITERIA: Randomised clinical trials (RCTs) comparing oral risperidone with placebo treatments for people with schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies, assessed the risk of bias of included studies and extracted data. For dichotomous data, we calculated the risk ratio (RR), and the 95% confidence interval (CI) on an intention-to-treat basis. For continuous data, we calculated mean differences (MD) and the 95% CI. We created a 'Summary of findings table' using GRADE (Grading of Recommendations Assessment, Development and Evaluation). MAIN RESULTS: The review includes 15 studies (N = 2428). Risk of selection bias is unclear in most of the studies, especially concerning allocation concealment. Other areas of risk such as missing data and selective reporting also caused some concern, although not affected on the direction of effect of our primary outcome, as demonstrated by sensitivity analysis. Many of the included trials have industry sponsorship of involvement. Nonetheless, generally people in the risperidone group are more likely to achieve a significant clinical improvement in mental state (6 RCTs, N = 864, RR 0.64, CI 0.52 to 0.78, very low-quality evidence). The effect withstood, even when three studies with >50% attrition rate were removed from the analysis (3 RCTs, N = 589, RR 0.77, CI 0.67 to 0.88). Participants receiving placebo were less likely to have a clinically significant improvement on Clinical Global Impression scale (CGI) than those receiving risperidone (4 RCTs, N = 594, RR 0.69, CI 0.57 to 0.83, very low-quality evidence). Overall, the risperidone group was 31% less likely to leave early compared to placebo group (12 RCTs, N = 2261, RR 0.69, 95% CI 0.62 to 0.78, low-quality evidence), but Incidence of significant extrapyramidal side effect was more likely to occur in the risperidone group (7 RCTs, N = 1511, RR 1.56, 95% CI 1.13 to 2.15, very low-quality evidence).When risperidone and placebo were augmented with clozapine, there is no significant differences between groups for clinical response as defined by a less than 20% reduction in PANSS/BPRS scores (2 RCTs, N = 98, RR 1.15, 95% CI 0.93 to 1.42, low quality evidence) and attrition (leaving the study early for any reason) (3 RCTs, N = 167, RR 1.13, 95% CI 0.53 to 2.42, low quality evidence). One study measured clinically significant responses using the CGI, no effect was evident (1 RCT, N = 68, RR 1.12 95% CI 0.87 to 1.44, low quality evidence). No data were available for extrapyramidal adverse effects. AUTHORS' CONCLUSIONS: Based on low quality evidence, risperidone appears to be benefitial in improving mental state compared with placebo, but it also causes more adverse events. Eight out of the 15 included trials were funded by pharmaceutical companies. The currently available evidence isvery low to low quality. PMID- 27977042 TI - Medical practice driven by legislators rather than by regulators. PMID- 27977043 TI - Perceived Burdensomeness in Older and Younger Adults: Evaluation of the Psychometric Properties of the Interpersonal Needs Questionnaire. AB - OBJECTIVES: We evaluated measurement invariance of the Interpersonal Needs Questionnaire (INQ-15) Perceived Burdensomeness subscale across younger and older adult age groups as well as the construct validity of the Perceived Burdensomeness subscale by comparing nomological networks across age groups. METHOD: We used nested multigroup confirmatory factor analyses to address measurement invariance and Fisher's r-to-z transformations to compare correlations between perceived burdensomeness and other constructs in younger and older samples. RESULTS: Results generally supported measurement invariance, but signals of differences in fit in older adults were present. The INQ-15 Perceived Burdensomeness subscale exhibited a significantly lower correlation with depressive symptoms in older adults compared to younger adults. Correlations between perceived burdensomeness and all other constructs were similar across age groups. CONCLUSION: This study provides marginal support for measurement invariance of the INQ-15 Perceived Burdensomeness subscale across younger and older adults, but results also suggest age differences in the perceived burdensomeness construct. PMID- 27977044 TI - Li18 P6 N16 -A Lithium Nitridophosphate with Unprecedented Tricyclic [P6 N16 ]18- Ions. AB - Li18 P6 N16 was synthesized by reaction of LiPN2 and Li7 PN4 at 5.5 GPa and 1273 K employing the multi-anvil technique. It is the first lithium nitridophosphate obtained by high-pressure synthesis. Moreover, it is the first example received by reaction of two ternary lithium nitrides. The combination of high-pressure conditions with a Li3 N flux enabled a complete structure determination using single-crystal X-ray diffraction. The hitherto unknown tricyclic [P6 N16 ]18- anion is composed of six vertex-sharing PN4 tetrahedra forming one vierer- and two additional dreier-rings. To confirm the structure, Rietveld refinement, 7 Li and 31 P solid-state NMR spectroscopy, FTIR spectroscopy and EDX measurements were carried out. To validate the ionic properties, the migration pathways of the Li+ ions were evaluated, and the conductivity and its temperature dependence were determined by impedance spectroscopy measurements. In order to obtain a clearer picture of the formation mechanism of this compound class, different synthetic approaches were compared, enabling targeted syntheses of unprecedented P/N-anion topologies with intriguing properties. PMID- 27977045 TI - Relationship between obstructive sleep apnoea syndrome and sleep bruxism: a systematic review. AB - Obstructive sleep apnoea syndrome (OSAS) is a clinical risk factor for sleep bruxism (SB). Both OSAS and SB are reported to be associated with sleep-related arousal reactions, although no clear causative link has been established. An electronic literature search was conducted of the MEDLINE, ScienceDirect, Wiley Online Library, SAGE Journals and EBSCOhost databases covering the period January 2006 and September 2016. Sequential screenings at the title, abstract and full text levels were performed. The review included observational studies in the English language with a clearly established aim to assess the relationship between OSAS and SB using full-night PSG. The seven-item quality-assessment tool for experimental bruxism studies was used to assess the methodology across the studies. After a comprehensive screening of titles, abstracts and full texts, only three studies that met the pre-defined criteria were finally included in this systematic review. Two studies gave evidence that OSAS is associated with the occurrence of SB events: (i) SB events frequently occur during micro-arousal events consequent on apnoea-hypopnoea (AH) events and (ii) most SB events occur in temporal conjunction with AH events termination. However, one study did not report a strong association between AH and SB events. It can be concluded that there are not enough scientific data to define a clear causative link between OSAS and SB. However, they appear to share common clinical features. Further studies should focus on the intermediate mechanisms between respiratory and SB events. PMID- 27977046 TI - The prognostic factors and outcomes of primary fetal hydrothorax with the effects of fetal intervention. AB - OBJECTIVES: This study aims to determine the prognostic factors and outcomes of primary fetal hydrothorax (FHT) and investigate the effects of fetal therapy. METHODS: A nationwide survey was conducted on fetuses with primary FHT delivered after 22 weeks of gestation between January 2007 and December 2011 at perinatal centers. RESULTS: Among the 287 cases of primary FHT, the survival rates for those with and without hydrops were 58.0% (113/195) and 97.8% (90/92), respectively. The survival rates in the no-therapy, thoracocentesis, and thoracoamniotic shunting (TAS) groups in the hydropic cases and the non-hydropic cases were 59.7% (40/67), 51.5% (35/68), and 63.3% (38/60) and 98.1% (53/54), 96.3% (26/27), and 100% (11/11), respectively. The crude relative risk for death was 2.1 (p = 0.005) for fetuses diagnosed at 26 to 30 weeks of gestational age (vs >=30 weeks), 2.3 (p = 0.001) for both skin edema and ascites, and 3.1 (p = 0.02) for bilateral pleural effusion. TAS was associated with a significant risk reduction for death in hydropic cases [adjusted relative risk 0.61, p = 0.01 (vs no fetal therapy)]. CONCLUSIONS: Hydrops and an early gestational age at diagnosis (<30 weeks of gestation), skin edema with ascites, and bilateral effusion predicted a poor prognosis in primary FHT cases. TAS was associated with a higher survival rate. (c) 2016 John Wiley & Sons, Ltd. PMID- 27977047 TI - Basolateral amygdala supports the maintenance of value and effortful choice of a preferred option. AB - The basolateral amygdala (BLA) is known to be involved in appetitive behavior, yet its role in cost-benefit choice of qualitatively different rewards (more/less preferred), beyond magnitude differences (larger/smaller), is poorly understood. We assessed the effects of BLA inactivations on effortful choice behavior. Rats were implanted with cannulae in BLA and trained to stable lever pressing for sucrose pellets on a progressive ratio schedule. Rats were then introduced to a choice: chow was concurrently available while they could work for the preferred sucrose pellets. Rats were infused with either vehicle control (aCSF) or baclofen/muscimol prior to test. BLA inactivations produced a significant decrease in lever presses for sucrose pellets compared to vehicle, and chow consumption was unaffected. Inactivation had no effect on sucrose pellet preference when both options were freely available. Critically, when lab chow was not concurrently available, BLA inactivations had no effect on the number of lever presses for sucrose pellets, indicating that primary motivation in the absence of choice remains intact with BLA offline. After a test under specific satiety for sucrose pellets, BLA inactivation rendered animals less sensitive to devaluation relative to control. The effects of BLA inactivations in our task are not mediated by decreased appetite, an inability to perform the task, a change in food preference, or decrements in primary motivation. Taken together, BLA supports the specific value and effortful choice of a preferred option. PMID- 27977049 TI - A Ring-Opening Metathesis Polymerization Catalyst That Exhibits Redox-Switchable Monomer Selectivities. AB - A ring-opening metathesis polymerization catalyst supported by a redox-active N heterocyclic carbene was synthesized and found to undergo reversible reduction. In its neutral form, the catalyst polymerized 1,5-cis,cis-cyclooctadiene at a higher rate than that of a norbornene derivative; however, upon reduction, the selectivity was found to reverse. Utilizing this oxidation state dependent selectivity, a series of copolymers with controlled compositions, microstructures, and physical properties were prepared by redox-switching the catalyst over the course of a series of polymerization reactions. PMID- 27977048 TI - Expanding Water/Base Tolerant Frustrated Lewis Pair Chemistry to Alkylamines Enables Broad Scope Reductive Aminations. AB - Lower Lewis acidity boranes demonstrate greater tolerance to combinations of water/strong Bronsted bases than B(C6 F5 )3 , this enables Si-H bond activation by a frustrated Lewis pair (FLP) mechanism to proceed in the presence of H2 O/alkylamines. Specifically, BPh3 has improved water tolerance in the presence of alkylamines as the Bronsted acidic adduct H2 O-BPh3 does not undergo irreversible deprotonation with aliphatic amines in contrast to H2 O-B(C6 F5 )3 . Therefore BPh3 is a catalyst for the reductive amination of aldehydes and ketones with alkylamines using silanes as reductants. A range of amines inaccessible using B(C6 F5 )3 as catalyst, were accessible by reductive amination catalysed by BPh3 via an operationally simple methodology requiring no purification of BPh3 or reagents/solvent. BPh3 has a complementary reductive amination scope to B(C6 F5 )3 with the former not an effective catalyst for the reductive amination of arylamines, while the latter is not an effective catalyst for the reductive amination of alkylamines. This disparity is due to the different pKa values of the water-borane adducts and the greater susceptibility of BPh3 species towards protodeboronation. An understanding of the deactivation processes occurring using B(C6 F5 )3 and BPh3 as reductive amination catalysts led to the identification of a third triarylborane, B(3,5-Cl2 C6 H3 )3 , that has a broader substrate scope being able to catalyse the reductive amination of both aryl and alkyl amines with carbonyls. PMID- 27977050 TI - The promise of chimeric antigen receptor T cells (CARTs) in leukaemia. AB - The success of genetically engineered T cells that express chimeric antigen receptors (CARTs) has been a momentous step forward in harnessing the potent cancer fighting abilities of the immune system. The efficacy seen in relapsed/refractory (r/r) acute lymphoblastic leukaemia (ALL), not only by inducing remission, but also in maintaining long-term disease control, has been unprecedented. While the foundation for this approach has been firmly set in place, continued development will improve the efficacy, toxicity and applicability to other malignancies of this new class of 'living drugs'. In this review, we provide a comprehensive overview of the most current clinical trial data in both acute and chronic leukaemias, and discuss some of the potential ways to enhance the activity and safety of CART therapy going forward. PMID- 27977051 TI - Parallel activation of prospective motor plans during visually-guided sequential saccades. AB - Behavioural evidences suggest that sequential saccades to multiple stimuli are planned in parallel. However, it remains unclear whether such parallel programming reflects concurrent processing of goals or whether multiple motor plans coexist, unfolding subsequently during execution. Here we use midway saccades, directed at intermediate locations between two targets, as a probe to address this question in a novel double-step adaptation task. The task consisted of trials where subjects had to follow the appearance of two targets presented in succession with two sequential saccades. In some trials, the second target predictably jumped to a new location during the second saccade. Initially, the second saccade was aimed at the final target's location before the jump. As subjects adapted to the target jump, saccades were aimed to the second target's new location. We tested whether the spatial distribution of midway saccades could be explained as an interaction between two concurrent saccade goals, each directed at the two target locations, or between the initial motor plan to the first target location and a prospective motor plan directed from the initial to the final target location. A shift in the midway saccades' distribution towards the jumped location of the second target following adaptation indicated that the brain can make use of prospective motor plans to guide sequential eye movements. Furthermore, we observed that the spatiotemporal pattern of endpoints of midway saccades can be well explained by a motor addition model. These results provide strong evidence of parallel activation of prospective motor plans during sequential saccades. PMID- 27977052 TI - Addition of suberoylanilide hydroxamic acid (Vorinostat) to azacitidine for patients with higher risk myelodysplastic syndromes and azacitidine failure: a phase II add-on study from the Groupe Francophone des Myelodysplasies. PMID- 27977055 TI - Erratum: Zebrafish vasa is required for germ-cell differentiation and maintenance. PMID- 27977056 TI - Toxic embryos? Oh my.... PMID- 27977053 TI - Protease-modulating matrix treatments for healing venous leg ulcers. AB - BACKGROUND: Venous leg ulcers (VLUs) are open skin wounds on the lower leg that occur because of poor blood flow in the veins of the leg; leg ulcers can last from weeks to years, and are both painful and costly. Prevalence in the UK is about 2.9 cases per 10,000 people. First-line treatment for VLUs is compression therapy, but around 60% of people have unhealed ulcers after 12 weeks' treatment and about 40% after 24 weeks; therefore, there is scope for further improvement. Limited evidence suggests non-healing leg ulcers may have persisting elevated levels of proteases, which is thought to deter the later stages of healing; thus, timely protease-modulating matrix (PMM) treatments may improve healing by physically removing proteases from the wound fluid. OBJECTIVES: To determine the effects of protease-modulating matrix (PMM) treatments on the healing of venous leg ulcers, in people managed in any care setting. SEARCH METHODS: In September 2016 we searched: the Cochrane Wounds Specialised Register; CENTRAL; Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: We searched for published or unpublished randomised controlled trials (RCTs) that evaluated PMM treatments for VLUs. We defined PMM treatments as those with a purposeful intent of reducing proteases. Wound healing was the primary endpoint. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: We included 12 studies (784 participants) in this review; sample sizes ranged from 10 to 187 participants (median 56.5). One study had three arms that were all relevant to this review and all the other studies had two arms. One study was a within-participant comparison. All studies were industry funded. Two studies provided unpublished data for healing.Nine of the included studies compared PMM treatments with other treatments and reported results for the primary outcomes. All treatments were dressings. All studies also gave the participants compression bandaging. Seven of these studies were in participants described as having 'non-responsive' or 'hard to-heal' ulcers. Results, reported at short, medium and long durations and as time-to-event data, are summarised for the comparison of any dressing regimen incorporating PMM versus any other dressing regimen. The majority of the evidence was of low or very low certainty, and was mainly downgraded for risk of bias and imprecision.It is uncertain whether PMM dressing regimens heal VLUs quicker than non-PMM dressing regimens (low-certainty evidence from 1 trial with 100 participants) (HR 1.21, 95% CI 0.74 to 1.97).In the short term (four to eight weeks) it is unclear whether there is a difference between PMM dressing regimens and non-PMM dressing regimens in the probability of healing (very low-certainty evidence, 2 trials involving 207 participants).In the medium term (12 weeks), it is unclear whether PMM dressing regimens increase the probability of healing compared with non-PMM dressing regimens (low-certainty evidence from 4 trials with 192 participants) (RR 1.28, 95% CI 0.95 to 1.71). Over the longer term (6 months), it is also unclear whether there is a difference between PMM dressing regimens and non-PMM dressing regimens in the probability of healing (low certainty evidence, 1 trial, 100 participants) (RR 1.06, 95% CI 0.80 to 1.41).It is uncertain whether there is a difference in adverse events between PMM dressing regimens and non-PMM dressing regimens (low-certainty evidence from 5 trials, 363 participants) (RR 1.03, 95% CI 0.75 to 1.42). It is also unclear whether resource use is lower for PMM dressing regimens (low-certainty evidence, 1 trial involving 73 participants), or whether mean total costs in a German healthcare setting are different (low-certainty evidence, 1 trial in 187 participants). One cost effectiveness analysis was not included because effectiveness was not based on complete healing. AUTHORS' CONCLUSIONS: The evidence is generally of low certainty, particularly because of risk of bias and imprecision of effects. Within these limitations, we are unclear whether PMM dressing regimens influence venous ulcer healing relative to dressing regimens without PMM activity. It is also unclear whether there is a difference in rates of adverse events between PMM and non-PMM treatments. It is uncertain whether either resource use (products and staff time) or total costs associated with PMM dressing regimens are different from those for non-PMM dressing regimens. More research is needed to clarify the impact of PMM treatments on venous ulcer healing. PMID- 27977058 TI - Can evidence-based medicine be applied to the theory of reference intervals? PMID- 27977060 TI - Erratum. PMID- 27977057 TI - Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia. AB - Otlertuzumab (TRU-016) is a humanized anti-CD37 protein therapeutic that triggers direct caspase-independent apoptosis of malignant B cells and induces antibody dependent cell-mediated cytotoxicity. Patients with relapsed chronic lymphocytic leukaemia (CLL) received either otlertuzumab (20 mg/kg) weekly by IV infusion for two 28-day cycles then every 14 days for four 28-day cycles and IV bendamustine (70 mg/m2 ) on Days 1 and 2 of each cycle for up to six 28-day cycles or bendamustine alone. Thirty-two patients were treated with otlertuzumab and bendamustine and 33 with bendamustine alone. Overall response rate according to the International Workshop on Chronic Lymphocytic Leukaemia criteria was 69% in the otlertuzumab and bendamustine arm and 39% in the bendamustine alone arm (P = 0.025). Median progression-free survival (PFS) was 15.9 months in the otlertuzumab and bendamustine arm and 10.2 months in the bendamustine alone arm (P = 0.0192). There was a higher incidence of pyrexia (34% vs. 12%) and neutropenia (59% vs. 39%) with the combination but this did not result in a higher incidence of severe (grade 3/4) infections (13% vs. 27%). This combination significantly increased the response rate and prolonged the PFS over single agent bendamustine in patients with relapsed or refractory CLL. PMID- 27977061 TI - Erratum. PMID- 27977059 TI - Comparison of a rapid immunochromatographic assay with an immunofluorescent antibody test for detection of Leishmania infantum antibodies in dogs. AB - BACKGROUND: Identification of Leishmania infantum-infected dogs is crucial for control of canine leishmaniosis. In particular, in areas where access to specialized laboratories is limited, the availability of reliable and rapid in clinic serologic tests may support immediate diagnosis in suspected cases and permit detection of asymptomatic canine carriers of L infantum infection. OBJECTIVE: The purpose of the study was to validate the immunochromatographic test (ICT) Anigen Rapid Leishmania Ab Test kit for detection of L infantum antibodies in naturally exposed dogs in comparison with the immunofluorescence antibody test (IFAT). METHODS: Serum samples from 66 dogs, including 20 healthy control dogs and 46 dogs suspected or confirmed with canine leishmaniosis, were measured by both tests. Anti-Leishmania IgG titers >= 1:40 by IFAT were considered positive. Kappa statistic with a 95% CI was calculated to evaluate agreement between the 2 testing methods, and sensitivity, specificity, and positive and negative likelihood ratio were calculated. RESULTS: Anti-L infantum IgG antibodies were found in 35 of 66 samples using the IFAT test (titers 1:40 1:5120). Thirty-one out of 66 samples tested positive with the qualitative ICT. Four IFAT-positive (titers < 1:80) samples were ICT-negative. The Kappa value of 0.853 demonstrated very good agreement between the 2 tests. CONCLUSION: The Anigen Rapid Leishmania Ab Test kit reliably identified canine sera with anti-L infantum IgG antibody titers >= 1:40. The ICT requires neither special preparation of the serum nor specialized equipment and can be stored at ambient temperature. The test is applicable as a field test because it is easy to use and provides rapid results. PMID- 27977062 TI - Comparison of hematology, plasma biochemistry, and blood gas variables between 2 venipuncture sites in Southern Stingrays (Dasyatis americana). AB - BACKGROUND: The Southern Stingray (Dasyatis americana) is a batoid elasmobranch frequently exhibited in zoological institutions. Blood is commonly collected from the caudal hemal arch at the tail base in stingrays for the purpose of health assessment and clinical pathology tests. An alternative site that allows a dorsal or ventral approach without necessitating puncture of a cartilaginous structure has been identified between the cartilaginous pectoral fin rays (ceratotrichia). OBJECTIVES: The purpose of the study was to compare CBC, plasma biochemistry analytes, and blood gas variables between blood samples collected from the caudal and pectoral fin vasculature sites of the Southern Stingray. METHODS: Fifteen captive Southern Stingrays (10 females, 5 males) from 4 zoo and aquarium facilities were sampled. Lithium heparinized blood samples were collected from the caudal and pectoral venipuncture sites of each animal. Values from estimated total and differential leukocyte counts, plasma biochemistry analytes, and blood gas variables were compared. RESULTS: There were no statistically significant differences between venipuncture sites for the measured analytes except for CK activity, which was statistically significantly higher in the pectoral site samples. Levels of agreement between sites were good or moderate for 22 analytes and poor for ALT, AST, CK, pO2 , lactate, monocytes, and eosinophils. CONCLUSIONS: The good agreement between sampling sites for the majority of the measured analytes and the lack of differences that would alter clinical interpretation support the use of the pectoral site as an alternative to the traditional caudal fin venipuncture site in Southern Stingrays. PMID- 27977063 TI - Different output properties of perisomatic region-targeting interneurons in the basal amygdala. AB - The perisomatic region of principal neurons in cortical regions is innervated by three types of GABAergic interneuron, including parvalbumin-containing basket cells (PVBCs) and axo-axonic cells (AACs), as well as cholecystokinin and type 1 cannabinoid receptor-expressing basket cells (CCK/CB1BCs). These perisomatic inhibitory cell types can also be found in the basal nucleus of the amygdala, however, their output properties are largely unknown. Here, we performed whole cell recordings in morphologically identified interneurons in slices prepared from transgenic mice, in which the GABAergic cells could be selectively targeted. Investigating the passive and active membrane properties of interneurons located within the basal amygdala revealed that the three interneuron types have distinct single-cell properties. For instance, the input resistance, spike rate, accommodation in discharge rate, or after-hyperpolarization width at the half maximal amplitude separated the three interneuron types. Furthermore, we performed paired recordings from interneurons and principal neurons to uncover the basic features of unitary inhibitory postsynaptic currents (uIPSCs). Although we found no difference in the magnitude of responses measured in the principal neurons, the uIPSCs originating from the distinct interneuron types differed in rise time, failure rate, latency, and short-term dynamics. Moreover, the asynchronous transmitter release induced by a train of action potentials was typical for the output synapses of CCK/CB1BCs. Our results suggest that, despite the similar uIPSC magnitudes originating from the three perisomatic inhibitory cell types, their distinct release properties together with the marked differences in their spiking characteristics may contribute to accomplish specific functions in amygdala network operation. PMID- 27977064 TI - Anti-vascular endothelial growth factor for choroidal neovascularisation in people with pathological myopia. AB - BACKGROUND: Choroidal neovascularisation (CNV) is a common complication of pathological myopia. Once developed, most eyes with myopic CNV (mCNV) experience a progression to macular atrophy, which leads to irreversible vision loss. Anti vascular endothelial growth factor (anti-VEGF) therapy is used to treat diseases characterised by neovascularisation and is increasingly used to treat mCNV. OBJECTIVES: To assess the effects of anti-vascular endothelial growth factor (anti-VEGF) therapy for choroidal neovascularisation (CNV), compared with other treatments, sham treatment or no treatment, in people with pathological myopia. SEARCH METHODS: We searched a number of electronic databases including CENTRAL and Ovid MEDLINE, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP). We did not use any date or language restrictions in the electronic searches for trials. Electronic databases were last searched on 16 June 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing anti-VEGF therapy with another treatment (e.g. photodynamic therapy (PDT) with verteporfin, laser photocoagulation, macular surgery, another anti-VEGF), sham treatment or no treatment in participants with mCNV. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two authors independently screened records, extracted data, and assessed risk of bias. We contacted trial authors for additional data. We analysed outcomes as risk ratios (RRs) or mean differences (MDs). We graded the certainty of the evidence using GRADE. MAIN RESULTS: The present review included six studies which provided data on the comparison between anti-VEGF with PDT, laser, sham treatment and another anti-VEGF treatment, with 594 participants with mCNV. Three trials compared bevacizumab or ranibizumab with PDT, one trial compared bevacizumab with laser, one trial compared aflibercept with sham treatment, and two trials compared bevacizumab with ranibizumab. Pharmaceutical companies conducted two trials. The trials were conducted at multiple clinical centres across three continents (Europe, Asia and North America). In all these six trials, one eye for each participant was included in the study.When compared with PDT, people treated with anti-VEGF agents (ranibizumab (one RCT), bevacizumab (two RCTs)), were more likely to regain vision. At one year of follow-up, the mean visual acuity (VA) in participants treated with anti-VEGFs was -0.14 logMAR better, equivalent of seven Early Treatment Diabetic Retinopathy Study (ETDRS) letters, compared with people treated with PDT (95% confidence interval (CI) -0.20 to -0.08, 3 RCTs, 263 people, low-certainty evidence). The RR for proportion of participants gaining 3+ lines of VA was 1.86 (95% CI 1.27 to 2.73, 2 RCTs, 226 people, moderate-certainty evidence). At two years, the mean VA in people treated with anti-VEGFs was -0.26 logMAR better, equivalent of 13 ETDRS letters, compared with people treated with PDT (95% CI -0.38 to -0.14, 2 RCTs, 92 people, low-certainty evidence). The RR for proportion of people gaining 3+ lines of VA at two years was 3.43 (95% CI 1.37 to 8.56, 2 RCTs, 92 people, low-certainty evidence). People treated with anti-VEGFs showed no obvious reduction (improvement) in central retinal thickness at one year compared with people treated with PDT (MD -17.84 MUm, 95% CI -41.98 to 6.30, 2 RCTs, 226 people, moderate-certainty evidence). There was low certainty evidence that people treated with anti-VEGF were more likely to have CNV angiographic closure at 1 year (RR 1.24, 95% CI 0.99 to 1.54, 2 RCTs, 208 people). One study allowed ranibizumab treatment as of month 3 in participants randomised to PDT, which may have led to an underestimate of the benefits of anti VEGF treatment.When compared with laser photocoagulation, there was more improvement in VA among bevacizumab-treated people than among laser-treated people after one year (MD -0.22 logMAR, equivalent of 11 ETDRS letters, 95% CI 0.43 to -0.01, 1 RCT, 36 people, low-certainty evidence) and after two years (MD 0.29 logMAR, equivalent of 14 ETDRS letters, 95% CI -0.50 to -0.08, 1 RCT, 36 people, low-certainty evidence).When compared with sham treatment, people treated with aflibercept had better vision at one year (MD -0.19 logMAR, equivalent of 9 ETDRS letters, 95% CI -0.27 to -0.12, 1 RCT, 121 people, moderate-certainty evidence). The fact that this study allowed for aflibercept treatment at 6 months in the control group might cause an underestimation of the benefit with anti VEGF.People treated with ranibizumab had similar improvement in VA recovery compared with people treated with bevacizumab after one year (MD -0.02 logMAR, equivalent of 1 ETDRS letter, 95% CI -0.11 to 0.06, 2 RCTs, 80 people, moderate certainty evidence).Of the included six studies, two studies reported no adverse events in either group and two industry-sponsored studies reported both systemic and ocular adverse events. In the control group, there were no systemic or ocular adverse events reported in 149 participants. Fifteen people reported systemic serious adverse events among 359 people treated with anti-VEGF agents (15/359, 4.2%). Five people reported ocular adverse events among 359 people treated with anti-VEGF agents (5/359, 1.4%). The number of adverse events was low, and the estimate of RR was uncertain regarding systemic serious adverse events (4 RCTs, 15 events in 508 people, RR 4.50, 95% CI 0.60 to 33.99, very low-certainty evidence) and serious ocular adverse events (4 RCTs, 5 events in 508 people, RR 1.82, 95% CI 0.23 to 14.71, very low-certainty evidence). There were no reports of mortality or cases of endophthalmitis or retinal detachment.There was sparse reporting of data for vision-related quality of life (in favour of anti-VEGF) in only one trial at one year of follow-up. The studies did not report data for other outcomes, such as percentage of participants with newly developed chorioretinal atrophy. AUTHORS' CONCLUSIONS: There is low to moderate-certainty evidence from RCTs for the efficacy of anti-VEGF agents to treat mCNV at one year and two years. Moderate-certainty evidence suggests ranibizumab and bevacizumab are equivalent in terms of efficacy. Adverse effects occurred rarely and the trials included here were underpowered to assess these. Future research should be focused on the efficacy and safety of different drugs and treatment regimens, the efficacy on different location of mCNV, as well as the effects on practice in the real world. PMID- 27977066 TI - SINGLE-SHOT TURBO SPIN ECHO PULSE SEQUENCE FINDINGS IN DOGS WITH AND WITHOUT PROGRESSIVE MYELOMALACIA. AB - Progressive myelomalacia is an uncommon type of ischemic, hemorrhagic spinal cord infarction. Diagnosis can be difficult, but prompt recognition is important. We hypothesized that cerebrospinal fluid signal attenuation on magnetic resonance (MR) images would be more extensive in dogs that developed progressive myelomalacia vs. control dogs. A retrospective analytic cohort study was designed. Dogs were included if they presented for acute paraplegia and loss of deep pain perception and had undergone MR imaging using both sagittal single-shot turbo spin echo (SSTSE) and standard sagittal T2-weighted fast spin echo (T2W) pulse sequences. Dogs were divided into progressive myelomalacia and control groups for comparisons. All MR examinations were evaluated by three reviewers blinded to patient outcome. Length of cerebrospinal fluid attenuation was recorded as a ratio to the length of the L2 vertebral body in SSTSE and T2W sequences (CSF:L2SSTSE and CSF:L2T2 , respectively). Length of intramedullary spinal cord hyperintensity was recorded as a ratio to the length of the L2 vertebral body in T2W sequences. A total of 21 dogs were included (five in the progressive myelomalacia group and 16 in the control group). The mean CSF:L2SSTSE attenuation value was significantly higher in dogs that developed progressive myelomalacia (CSF:L2SSTSE = 10.7) compared to controls (CSF:L2SSTSE = 5.4; P = 0.015). A cut off ratio of attenuation >7.4 provided optimal differentiation between groups in this study. Findings supported the conclusion that dogs with CSF:L2SSTSE <= 7.4 are unlikely to develop progressive myelomalacia while dogs with CSF:L2SSTSE > 7.4 are indeterminate for progressive myelomalacia. PMID- 27977065 TI - Experiences of patients undergoing dialysis who are from ethnic and racial minorities. AB - BACKGROUND: Approximately 500,000 people in the United States are affected by end stage kidney disease (ESKD), 53% of whom are Black or Latino. ESKD significantly impacts psychosocial health and quality of life. However, few studies address the psychosocial aspects of ESKD, especially among black and Latino adults. This study sought to understand the psychosocial context of living with ESKD among black and Latino adults who reside in a medically underserved community. STUDY DESIGN: A qualitative study. SETTING AND PARTICIPANTS: Participants were recruited from a dialysis centre in East New York, Brooklyn, a medically underserved community. METHODOLOGY: Descriptive phenomenology was used as a qualitative approach for capturing the experiences of patients who received dialysis in this community. ANALYTICAL APPROACH: Open-ended interviews were audio taped, transcribed, coded and analysed using standard qualitative techniques. RESULTS: Data saturation was achieved at 36 participants. The following five themes emerged: the transition to dialysis is abrupt and unexpected; denial is often an initial response; dialysis is the new normal and in order to survive one must forget the past and press forward; dialysis changes everything and impacts the entire family; strength was often found in faith and family. LIMITATIONS: This study was conducted in one setting and may need to be expanded to other sites to capture the experiences of patients cared for in other settings. CONCLUSION: These findings have practical implications for informing patient centered models of care that are more responsive to the psychosocial needs of patients with ESKD living in medically underserved communities. PMID- 27977067 TI - Morphology Engineering: A Route to Highly Reproducible and High Efficiency Perovskite Solar Cells. AB - Despite the rapid increase in the performance of perovskite solar cells (PSC), they still suffer from low lab-to-lab or people-to-people reproducibility. Aiming for a universal condition to high-performance devices, we investigated the morphology evolution of a composite perovskite by tuning annealing temperature and precursor concentration of the perovskite film. Here, we introduce thermal annealing as a powerful tool to generate a well-controlled excess of PbI2 in the perovskite formulation and show that this benefits the photovoltaic performance. We demonstrated the correlation between the film microstructure and electronic property and device performance. An optimized average grain size/thickness aspect ratio of the perovskite crystallite is identified, which brings about a highly reproducible power conversion efficiency (PCE) of 19.5 %, with a certified value of 19.08 %. Negligible hysteresis and outstanding morphology stability are observed with these devices. These findings lay the foundation for further boosting the PCE of PSC and can be very instructive for fabrication of high quality perovskite films for a variety of applications, such as light-emitting diodes, field-effect transistors, and photodetectors. PMID- 27977068 TI - Development of a repository of individual participant data from randomized controlled trials of therapists delivered interventions for low back pain. AB - BACKGROUND: Individual patient data (IPD) meta-analysis of existing randomized controlled trials (RCTs) is a promising approach to achieving sufficient statistical power to identify sub-groups. We created a repository of IPD from multiple low back pain (LBP) RCTs to facilitate a study of treatment moderators. Due to sparse heterogeneous data, the repository needed to be robust and flexible to accommodate millions of data points prior to any subsequent analysis. METHODS: We systematically identified RCTs of therapist delivered intervention for inclusion to the repository. Some were obtained through project publicity. We requested both individual items and aggregate scores of all baseline characteristics and outcomes for all available time points. The repository is made up of a hybrid database: entity-attribute-value and relational database which is capable of storing sparse heterogeneous datasets. We developed a bespoke software program to extract, transform and upload the shared data. RESULTS: There were 20 datasets with more than 3 million data points from 9328 participants. All trials collected covariates and outcomes data at baseline and follow-ups. The bespoke standardized repository is flexible to accommodate millions of data points without compromising data integrity. Data are easily retrieved for analysis using standard statistical programs. CONCLUSIONS: The bespoke hybrid repository is complex to implement and to query but its flexibility in supporting datasets with varying sets of responses and outcomes with different data types is a worthy trade off. The large standardized LBP dataset is also an important resource useable by other LBP researchers. SIGNIFICANCE: A flexible adaptive database for pain studies that can easily be expanded for future researchers to map, transform and upload their data in a safe and secure environment. The data are standardized and harmonized which will facilitate future requests from other researchers for secondary analyses. PMID- 27977069 TI - Biological mechanism of post-herpetic neuralgia: Evidence from multiple patho psychophysiological measures. AB - BACKGROUND: Post-herpetic neuralgia (PHN), which develops after the resolution of a herpes zoster eruption, is an exceptionally drug-resistant neuropathic pain. The unsatisfactory management of PHN partly results from the difficulty in dissecting out its contributing factors due to the complexity of PHN mechanism. METHODS: Here, to elaborate our understanding of the PHN mechanism and to establish a basis for effective therapeutic strategies, we comprehensively investigated the contributions of multiple factors to PHN severity. RESULTS: Based on the comparison of somatosensory detection thresholds (C, Adelta and Abeta fibre thresholds) between affected and unaffected sides, 16 PHN patients with significant sensory deficits and 13 PHN patients without significant sensory deficits were identified and assigned to different groups. The different extents of lesions in the nociceptive system between patients with and without sensory deficits were confirmed using laser-evoked brain responses. Moreover, patients with sensory deficits had more severe pain and psychological disorders, e.g. anxiety and depression. Importantly, chronic pain severity was significantly influenced by various psychophysiological factors (sleep disturbances, psychological disorders and hypothalamic-pituitary-adrenal axis dysfunction) for patients with sensory deficits. CONCLUSIONS: Our findings demonstrated the contribution of multiple patho-psychophysiological factors to PHN severity, which could help establish a basis for the development of a rational, patient-centred therapeutic strategy. SIGNIFICANCE: This study revealed the contribution of multiple patho-psychophysiological factors to PHN severity, which expanded our understanding of the underlying PHN mechanism, and helped develop a rational, patient-centred therapeutic strategy targeting towards the corresponding etiology and psychophysiological disorders for individual patient. PMID- 27977070 TI - Role of transient receptor potential ankyrin 1 receptors in rodent models of meningeal nociception - Experiments in vitro. AB - BACKGROUND: The TRP channel ankyrin type 1 (TRPA1) is a nonselective cation channel known to be activated by environmental irritants, cold and endogenous mediators of inflammation. Activation of TRPA1 in trigeminal afferents innervating meningeal structures has recently been suggested to be involved in the generation of headaches. METHODS: Two in vitro models of meningeal nociception were employed using the hemisected rodent head preparation, (1) recording of single meningeal afferents and (2) release of calcitonin gene related peptide (CGRP) from the cranial dura mater. The role of TRPA1 was examined using the TRPA1 agonists acrolein and mustard oil (MO). BCTC, an inhibitor of TRP vanilloid type 1 receptor channels (TRPV1), and the TRPA1 inhibitor HC030031 as well as mice with genetically deleted TRPA1 and TRPV1 proteins, were used to differentiate between effects. RESULTS: Acrolein did not cause discharge activity in meningeal Adelta- or C-fibres but increased the electrical activation threshold. Acrolein was also effective in releasing CGRP from the dura of TRPV1-/- but not of TRPA1-/- mice. MO increased the discharge activity of afferent fibres from rat as well as C57 wild-type and TRPA1-/- but not TRPV1-/- mice. The effect was higher in C57 compared to TRPA1-/- mice. CONCLUSION: Sole TRPA1 receptor channel activation releases CGRP and increases the activation threshold of meningeal afferents but does not generate propagated activity, and so would be capable of causing local effects like vasodilatation but not pain generation. In contrast, combined TRPA1 and TRPV1 activation may be rather pronociceptive supporting headache generation. SIGNIFICANCE: Sole activation of TRPA1 receptor channels increases the activation threshold but does not cause propagated action potentials in meningeal afferents. TRPA1 agonists cause CGRP release from rodent dura mater. Peripheral TRPA1 receptors may have a pronociceptive function in trigeminal nociception only in combination with TRPV1. PMID- 27977072 TI - Mechanical pinprick pain in patients with unilateral spatial neglect: The influence of space representation on the perception of nociceptive stimuli. AB - BACKGROUND: Crossing the hands over the midline can reduce the perceived intensity of nociceptive stimuli applied onto the hands. It remains unclear to what extent intact representation of peripersonal space influences this effect. Here we used the crossed-hands paradigm in patients with unilateral spatial neglect, a neuropsychological condition characterized by the inability to detect, attend and respond to contralesional (most often left) stimuli, and spared ability to process stimuli in the non-affected space. METHODS: Sixteen post stroke patients without unilateral neglect and 11 patients with unilateral spatial neglect received punctate mechanical pinprick stimuli onto their crossed or uncrossed hands. We tested: (i) whether deficits in space representation reduce the possibility of observing 'crossed-hands analgesia', and; (ii) whether placing the contralesional hand, normally lying in the affected space in the healthy space would increase the number of detected stimuli. RESULTS: Our results showed that neglect patients did not exhibit 'crossed-hands' analgesia, but did not provide strong evidence for an improvement in the number of detected stimuli when the contralesional hand was in the healthy space. CONCLUSION: These findings uphold the notion that the perception of nociceptive stimuli is modulated by the relative position of the hands in space, but raise questions about the conditions under which these effects may arise. SIGNIFICANCE: We show that deficits in space representation can influence the processing of mechanical pinprick stimuli. Our results raise several questions on the mechanisms underlying these effects, which are relevant for the clinical practice. PMID- 27977071 TI - Efficacy and safety of high-dose dual therapy for Helicobacter pylori rescue therapy: A systematic review and meta-analysis. AB - OBJECTIVE: Although some studies have reported >90% success with high-dose dual proton pump inhibitor (PPI)-amoxicillin dual therapy for Helicobacter pylori (H. pylori) eradication, the efficacy of this therapy remains controversial. We aimed to re-evaluate the efficacy and safety of high-dose dual therapy on H. pylori eradication. METHODS: We searched PubMed, the Cochrane Library, and EMBASE for randomized clinical trials (RCTs) evaluating the efficacy of high-dose PPI amoxicillin dual therapy as the rescue therapy on H. pylori eradication. Treatment effect was determined with a fixed-effect model using the inverse variance method and was expressed as risk ratio (RR) with 95% confidence interval (CI). RESULTS: Because of significant statistical heterogeneity (chi2 15.98, I2 = 69%) among the six studies that qualified, four RCTs that included 473 patients with H. pylori infection after eradication failure were assessed. The meta analysis showed that high-dose dual therapy and guideline-recommended rescue therapies achieved similar efficacy (81.3% vs 81.5%, RR 1.00 [95% CI 0.93-1.08], intention-to-treat analysis), compliance (95.3% vs 95.4%, RR 1.00 [95% CI 0.97 1.03]), and side effects (17.9% vs 19.7%, RR 0.88 [95% CI 0.62-1.25]). CONCLUSIONS: High-dose PPI-amoxicillin dual therapy is comparable to recommended rescue therapies for H. pylori infection. More researches are needed to determine the efficacy of high-dose dual therapy as a first-line therapy. PMID- 27977074 TI - The efficacy of prazosin for the treatment of posttraumatic stress disorder nightmares in U.S. military veterans. AB - BACKGROUND AND PURPOSE: Nightmares associated with posttraumatic stress disorder (PTSD) are a hallmark symptom among U.S. military veterans who have seen combat. Management of combat-related nightmares can be difficult and current pharmacologic options are limited and tend to have adverse side effects. The aim of this review is to explore recent literature regarding the efficacy of prazosin for the treatment of nightmare disorder in the veteran population. METHODS: Recent literature consisting of three systematic reviews was reviewed, as well as current clinical guidelines published by The Department of Veterans Affairs (VA) and The Department of Defense (DoD) and the American Academy of Sleep Medicine (AASM). CONCLUSIONS: Prazosin has been shown to be effective in the treatment of PTSD trauma-related nightmares. As a result of its low side effect profile and abilities to improve both sleep and reduce trauma nightmares, prazosin has been recommended as an adjunct therapy. IMPLICATIONS FOR PRACTICE: Prazosin should be initiated as an adjunctive treatment to promote sleep in those suffering from PTSD nightmares. It should be initiated at 1 mg and then titrated upward until absence or desired reduction of nightmares is achieved, with a maximum dosage recommendation of 20 mg at bedtime and 5 mg midmorning. PMID- 27977076 TI - ABP Directory. PMID- 27977073 TI - Preoperative sleep quality predicts postoperative pain after planned caesarean delivery. AB - BACKGROUND: Severe post-caesarean pain remains an important issue associated with persistent pain and postpartum depression. Women's sleep quality prior to caesarean delivery and its influence on postoperative pain and analgesic intake have not been evaluated yet. METHODS: Women undergoing caesarean delivery with spinal anaesthesia (bupivacaine 12 mg, fentanyl 20 MUg, morphine 100 MUg) were evaluated preoperatively for sleep quality using the Pittsburgh Sleep Quality Index (PSQI) questionnaire (PSQI 0-5 indicating good sleep quality, PSQI 6-21 poor sleep quality). Peak and average postoperative pain scores at rest, movement and uterine cramping were evaluated during 24 h using a verbal numerical pain score (VNPS; 0 indicating no pain and 100 indicating worst pain imaginable), and analgesic intake was recorded. Primary outcome was peak pain upon movement during the first 24 h. RESULTS: Seventy-eight of 245 women reported good sleep quality (31.2%; average PSQI 3.5 +/- 1.2) and 167 poor sleep quality (68.2%; average PSQI 16.0 +/- 3.4; p < 0.001). Women with poor sleep quality had significantly higher peak pain scores upon movement (46.7 +/- 28.8 vs. 36.2 +/- 25.6, respectively; p = 0.006). With multivariable logistic regression analysis, poor sleep quality significantly increased the risk for severe peak pain upon movement (VNPS >=70; OR 2.64; 95% CI 1.2-6.0; p = 0.02). DISCUSSION: A significant proportion of women scheduled for caesarean delivery were identified preoperatively as having poor sleep quality, which was associated with more severe pain and increased analgesic intake after delivery. The PSQI score may therefore be a useful tool to predict increased risk for acute post-caesarean pain and higher analgesic requirements, and help tailor anaesthetic management. SIGNIFICANCE: Multiple studies have evaluated predictors for severe acute pain after caesarean delivery that may be performed in a clinical setting, however, sleep quality prior to delivery has not been included in predictive models for post-caesarean pain. The PSQI questionnaire, a simple test to administer preoperatively, identified that up to 70% of women report poor sleep quality before delivery, and poor sleep quality was associated with increased post-caesarean pain scores and analgesic intake, indicating that PSQI could help identify preoperatively women at risk for severe pain after caesarean delivery. PMID- 27977075 TI - A Reinterpretation of Cell Transplantation: GFP Transfer From Donor to Host Photoreceptors. AB - The utilization of fluorescent reporter transgenes to discriminate donor versus host cells has been a mainstay of photoreceptor transplantation research, the assumption being that the presence of reporter+ cells in outer nuclear layer (ONL) of transplant recipients represents the integration of donor photoreceptors. We previously reported that GFP+ cells in the ONL of cone-GFP transplanted retinas exhibited rod-like characteristics, raising the possibility that GFP signal in recipient tissue may not be a consequence of donor cell integration. To investigate the basis for this mismatch, we performed a series of transplantations using multiple transgenic donor and recipient models, and assessed cell identity using nuclear architecture, immunocytochemistry, and DNA prelabeling. Our results indicate that GFP+ cells in the ONL fail to exhibit hallmark elements of donor cells, including nuclear hetero/euchromatin architecture. Furthermore, GFP signal does not appear to be a consequence of classic donor/host cell fusion or transfating post-transplant, but is most likely due to material exchange between donor and host photoreceptors. This transfer can be mediated by rods and cones, is bidirectional between donor and host cells, requires viable photoreceptors, occurs preferentially at sites of outer limiting membrane disruption and can be detected in second-order retinal neurons and Muller glia. Collectively, these data warrant re-evaluation of the use of lineage tracing fluorescent reporters in transplantation studies involving the retina and other CNS tissues. Furthermore, the reinterpretation of previous functional rescue data, based on material exchange, rather than cell integration, may offer a novel approach to vision rescue. Stem Cells 2017;35:932-939. PMID- 27977077 TI - American Board of Prosthodontics. PMID- 27977080 TI - An Inside Look at Cancer Cytopathology. PMID- 27977081 TI - Aggregation-Induced Emission: A New Research Frontier. PMID- 27977082 TI - Conjugates of Benzoxazole and GFP Chromophore with Aggregation-Induced Enhanced Emission: Influence of the Chain Length on the Formation of Particles and on the Dye Uptake by Living Cells. AB - Six conjugates of benzoxazole and green fluorescent protein chromophore that differ by the length of their alkyl chain (from C1 to C16) are investigated. They exhibit rigidofluorochromism and clear aggregation-induced emission enhancement (AIEE) behavior with emission in the orange-red that is specific to the solid state. A preparation method based on solvent exchange is used to prepare particles. The self-association properties of these molecules depend on the length of the alkyl chain. Microfibers, platelets, and rounded microparticles are successively obtained by increasing the chain length. The same method is used to prepare nanoparticles (NPs) that are fully characterized. In particular, homogeneous populations of stable NPs measuring around 70 nm are obtained with the analogs whose chains contain four to eight carbon atoms. The behavior with respect to living cells is also influenced by the nature of the compounds. Only the dyes with intermediate hydrophobicity are efficiently uptaken by both normal and tumor cells, and fluorescence only originates from dispersed dye molecules. There is no evidence for incorporation of NPs into cells. This work shows that small variations of the chemical structure must be taken into account for making the best use of AIEE compounds in view of precise applications. PMID- 27977083 TI - The 2014 Survey on Living with Chronic Diseases in Canada on Mood and Anxiety Disorders: a methodological overview. AB - INTRODUCTION: There is a paucity of information about the impact of mood and anxiety disorders on Canadians and the approaches used to manage them. To address this gap, the 2014 Survey on Living with Chronic Diseases in Canada-Mood and Anxiety Disorders Component (SLCDC-MA) was developed. The purpose of this paper is to describe the methodology of the 2014 SLCDC-MA and examine the sociodemographic characteristics of the final sample. METHODS: The 2014 SLCDC-MA is a cross-sectional follow-up survey that includes Canadians from the 10 provinces aged 18 years and older with mood and/or anxiety disorders diagnosed by a health professional that are expected to last, or have already lasted, six months or more. The survey was developed by the Public Health Agency of Canada (PHAC) through an iterative, consultative process with Statistics Canada and external experts. Statistics Canada performed content testing, designed the sampling frame and strategies and collected and processed the data. PHAC used descriptive analyses to describe the respondents' sociodemographic characteristics, produced nationally representative estimates using survey weights provided by Statistics Canada, and generated variance estimates using bootstrap methodology. RESULTS: The final 2014 SLCDC-MA sample consists of a total of 3361 respondents (68.9% response rate). Among Canadian adults with mood and/or anxiety disorders, close to twothirds (64%) were female, over half (56%) were married/in a common-law relationship and 60% obtained a post-secondary education. Most were young or middle-aged (85%), Canadian born (88%), of non Aboriginal status (95%), and resided in an urban setting (82%). Household income was fairly evenly distributed between the adequacy quintiles; however, individuals were more likely to report a household income adequacy within the lowest (23%) versus highest (17%) quintile. Forty-five percent reported having a mood disorder only, 24% an anxiety disorder only and 31% both kinds of disorder. CONCLUSION: The 2014 SLCDC-MA is the only national household survey to collect information on the experiences of Canadians living with a professionally diagnosed mood and/or anxiety disorder. The information collected offers insights into areas where additional support or interventions may be needed and provides baseline information for future public health research in the area of mental illness. PMID- 27977084 TI - Health status, activity limitations, work-related restrictions and level of disability among Canadians with mood and/or anxiety disorders. AB - INTRODUCTION: This study provides the first overview of the perceived general and mental health, activity limitations, work-related restrictions and level of disability, as well as factors associated with disability severity, among Canadian adults with mood and/or anxiety disorders, using a population-based household sample. METHODS: We used data from the 2014 Survey on Living with Chronic Diseases in Canada- Mood and Anxiety Disorders Component. The sample consists of Canadians aged 18 years and older with self-reported mood and/or anxiety disorders from the 10 provinces (n = 3361; response rate 68.9%). We conducted descriptive and multinomial multivariate logistic regression analyses. RESULTS: Among Canadian adults with mood and/or anxiety disorders, over one quarter reported "fair/poor" general (25.3%) and mental (26.1%) health; more than one-third (36.4%) reported one or more activity limitations; half (50.3%) stated a job modification was required to continue working; and more than one-third (36.5%) had severe disability. Those with concurrent mood and anxiety disorders reported poorer outcomes: 56.4% had one or more activity limitations; 65.8% required a job modification and 49.6% were severely disabled. Upon adjusting for individual characteristics, those with mood and/or anxiety disorders who were older, who had a household income in the lowest or lower-middle adequacy quintile or who had concurrent disorders were more likely to have severe disability. CONCLUSION: Findings from this study affirm that mood and/or anxiety disorders, especially concurrent disorders, are associated with negative physical and mental health outcomes. Results support the role of public health policy and programs aimed at improving the lives of people living with these disorders, in particular those with concurrent disorders. PMID- 27977086 TI - Report summary - Mood and Anxiety Disorders in Canada, 2016. AB - Mood and Anxiety Disorders in Canada, 2016 is the first publication to include administrative health data from the Canadian Chronic Disease Surveillance System (CCDSS) for the national surveillance of mood and anxiety disorders among Canadians aged one year and older. It features nationally complete CCDSS data up to fiscal year 2009/10, as well as trend data spanning over a decade (1996/97 to 2009/10). The data presented in this report, and subsequent updates, can be accessed via the Public Health Agency of Canada's Chronic Disease Infobase Data Cubes at www.infobase.phac-aspc.gc.ca. Data Cubes are interactive databases that allow users to quickly create tables and graphs using their Web browser. The report demonstrates the Public Health Agency of Canada's commitment to improving data collection and reporting about mental illness, as recommended within Changing Directions, Changing Lives - The Mental Health Strategy for Canada. PMID- 27977085 TI - Correlates of well-being among Canadians with mood and/or anxiety disorders. AB - INTRODUCTION: Our objective was to examine variables associated with well-being as measured by high self-rated mental health (SRMH) and life satisfaction (LS), among Canadian adults (aged 18+) living with a mood and/or an anxiety disorder. METHODS: We used nationally representative data from the 2014 Survey on Living with Chronic Diseases in Canada-Mood and Anxiety Disorders Component (SLCDC-MA) to describe the association between well-being and self-management behaviours (physical activity, sleep and meditation) as well as perceived stress, coping and social support. We used multivariate logistic regression to model the relationship between these factors and measures of well-being. RESULTS: Approximately one in three individuals with mood and/or anxiety disorders reported high SRMH. The logistic regression models demonstrated that several characteristics such as being older, and reporting higher self-rated general health, fewer functional limitations, lower levels of perceived life stress, higher levels of perceived coping and higher levels of perceived social support were associated with higher levels of wellbeing. Self-management behaviours (including starting physical activity, meditation, adopting good sleep habits and attaining a certain number of hours of nightly sleep) were not significantly associated with measures of well-being in our multivariate model. CONCLUSION: Canadian adults with mood and/or anxiety disorders who reported lower levels of perceived stress and higher levels of social support and coping were more likely to report high levels of well-being. This study contributes evidence from a representative population-based sample indicating well-being is achievable, even in the presence of a mood and/or an anxiety disorder. PMID- 27977087 TI - Emergency department presentations for hoverboard-related injuries: the electronic Canadian Hospitals Injury Reporting and Prevention Program, 2015 to 2016. PMID- 27977112 TI - Multicolor Emission from Poly(p-Phenylene)/Nanoporous ZnMnO Organic-Inorganic Hybrid Light-Emitting Diode. AB - The voltage-tunable multicolor emission was realized in a poly(p phenylene)/nanoporous ZnMnO organic-inorganic hybrid light-emitting diode. Red, green, and blue (RGB) colors sequentially appeared with increasing magnitude of the bias voltage (i.e., R -> RG -> RGB with V?). At a higher voltage (>2.4 V), eventually, the device emitted the visible light with a mixture of colors including RGB. These unique features may move us a step closer to the application of organic-inorganic hybrid solid-state lighting devices for the full-color display and/or the electrical-to-optical data converter for multivalue electronic signal processes. In-depth analyses on electrical and optical properties are presented, and voltage-controllable multicolor-emission mechanisms are discussed. PMID- 27977114 TI - In-Situ-Activated N-Doped Mesoporous Carbon from a Protic Salt and Its Performance in Supercapacitors. AB - Protic salts have been recently recognized to be an excellent carbon source to obtain highly ordered N-doped carbon without the need of tedious and time consuming preparation steps that are usually involved in traditional polymer based precursors. Herein, we report a direct co-pyrolysis of an easily synthesized protic salt (benzimidazolium triflate) with calcium and sodium citrate at 850 degrees C to obtain N-doped mesoporous carbons from a single calcination procedure. It was found that sodium citrate plays a role in the final carbon porosity and acts as an in situ activator. This results in a large surface area as high as 1738 m2/g with a homogeneous pore size distribution and a moderate nitrogen doping level of 3.1%. X-ray photoelectron spectroscopy (XPS) measurements revealed that graphitic and pyridinic groups are the main nitrogen species present in the material, and their content depends on the amount of sodium citrate used during pyrolysis. Transmission electron microscopy (TEM) investigation showed that sodium citrate assists the formation of graphitic domains and many carbon nanosheets were observed. When applied as supercapacitor electrodes, a specific capacitance of 111 F/g in organic electrolyte was obtained and an excellent capacitance retention of 85.9% was observed at a current density of 10 A/g. At an operating voltage of 3.0 V, the device provided a maximum energy density of 35 W h/kg and a maximum power density of 12 kW/kg. PMID- 27977113 TI - Effective Schottky Barrier Height Lowering of Metal/n-Ge with a TiO2/GeO2 Interlayer Stack. AB - A perfect ohmic contact formation technique for low-resistance source/drain (S/D) contact of germanium (Ge) n-channel metal-oxide-semiconductor field-effect transistors (MOSFETs) is developed. A metal-interlayer-semiconductor (M-I-S) structure with an ultrathin TiO2/GeO2 interlayer stack is introduced into the contact scheme to alleviate Fermi-level pinning (FLP), and reduce the electron Schottky barrier height (SBH). The TiO2 interlayer can alleviate FLP by preventing formation of metal-induced gap states (MIGS) with its very low tunneling resistance and series resistance and can provide very small electron energy barrier at the metal/TiO2 interface. The GeO2 layer can induce further alleviation of FLP by reducing interface state density (Dit) on Ge which is one of main causes of FLP. Moreover, the proposed TiO2/GeO2 stack can minimize interface dipole formation which induces the SBH increase. The M-I-S structure incorporating the TiO2/GeO2 interlayer stack achieves a perfect ohmic characteristic, which has proved unattainable with a single interlayer. FLP can be perfectly alleviated, and the SBH of the metal/n-Ge can be tremendously reduced. The proposed structure (Ti/TiO2/GeO2/n-Ge) exhibits 0.193 eV of effective electron SBH which achieves 0.36 eV of SBH reduction from that of the Ti/n-Ge structure. The proposed M-I-S structure can be suggested as a promising S/D contact technique for nanoscale Ge n-channel transistors to overcome the large electron SBH problem caused by severe FLP. PMID- 27977116 TI - Systematic Generation, Analysis, and Characterization of 3D Micro-architected Metamaterials. AB - Controlling the unit-cell topology of microlattice structures can enable the customization of effective anisotropic material properties. A wide range of properties can be obtained by varying connectivity within the unit cell, which then can be further used to optimize structures specific to applications. A methodology for a systematic generation of microlattice structures is presented that focuses on controlling discrete topology instead of average porosity (as is done in conventional porous media). An algorithm is developed to create valid lattice structures without redundancies from a given set of template nodes. A set of possible permutations of structures from an eight-node cubic octant of a unit cell are generated for evaluation of the degree of anisotropy. Generic models are developed to calculate the effective thermal and mechanical properties as an effect of topology and porosity of the micro-architected structure. The thermal and mechanical anisotropies are investigated for the effective properties of micro-architected materials. A few of the structured materials are fabricated using 3D printing technology and their effective properties characterized. Structures are represented as graphs in the form of adjacency matrices. Effective thermal conductivity is analyzed using a resistance network model, and effective stiffness is evaluated using a self-consistent elastic model, respectively. A total of 160 000 structures are generated and compared to porous-metal foams in which porosity is one of the design variables. The results show that it is possible to obtain a wide range of properties spanning more than an order of magnitude in comparison to porous-metal structures. Structures with a maximum anisotropy ratios of 7.1 and 8.2 are observed for thermal and mechanical properties, respectively. Preliminary experimental results validated the anisotropy ratio for the thermal conductivity and stiffness. PMID- 27977115 TI - LSD1 Substrate Binding and Gene Expression Are Affected by HDAC1-Mediated Deacetylation. AB - Lysine Specific Demethylase 1 (LSD1) catalyzes the demethylation of histone 3 to regulate gene expression. With a fundamental role in gene regulation, LSD1 is involved in multiple cellular processes, including embryonic development, cell proliferation, and metastasis. Significantly, LSD1 is overexpressed in multiple cancers and has emerged as a potential anticancer drug target. LSD1 is typically found in association with another epigenetic enzyme, histone deacetylase (HDAC). HDAC and LSD1 inhibitor compounds have been tested as combination anticancer agents. However, the functional link between LSD1 and HDAC has yet to be understood in detail. Here, we used a substrate trapping strategy to identify cellular substrates of HDAC1. Using inactive HDAC1 mutants, we identified LSD1 as an HDAC1 substrate. HDAC1 mediated deacetylation of LSD1 at K374 in the substrate binding lobe, which affected the histone 3 binding and gene expression activity of LSD1. The mechanistic link between HDAC1 and LSD1 established here suggests that HDAC inhibitors influence LSD1 activity, which will ultimately guide drug design targeting epigenetic enzymes. PMID- 27977117 TI - Novel Bake-in-Salt Method for the Synthesis of Mesoporous Mn3O4@C Networks with Superior Cycling Stability and Rate Performance. AB - The commercial applications of Mn3O4 in lithium ion batteries (LIBs) are greatly restricted because of the low electrical conductivity and poor cycling stability at high current density. To overcome these drawbacks, mesoporous Mn3O4@C networks were designed and synthesized via an improved bake-in-salt method using NaCl as the assistant salt, and without the protection of inert gas. The added NaCl plays a versatile role during the synthetic process, including the heat conducting medium, removable hard template and protective layer. Because of the homogeneous distribution of Mn3O4 nanoparticles within the carbon matrix, the as-prepared Mn3O4@C networks show excellent cycling stability in LIBs. After cycling for 950 times at a current density of 1 A g-1, the discharge capacity of the as-prepared Mn3O4@C networks is determined to be 754.4 mA h g-1, showing superior cycling stability as compared to its counterparts. The valuable and promising method, simple synthetic procedure and excellent cycling stability of the as-prepared Mn3O4@C networks makes it a promising candidate as the potential anode material for LIBs. PMID- 27977119 TI - Immobilization of Anodophilic Biofilms for Use in Aerotolerant Bioanodes of Microbial Fuel Cells. AB - The anodophilic bacteria in the anodes of microbial fuel cells (MFCs) used to catalyze carbon oxidation are anaerobes and require anaerobic conditions; their bioelectrocatalytic activity will be greatly suppressed upon direct exposure to O2. In this study, an aerotolerant bioanode was fabricated for the first time by immobilization of anodophilic bacteria for use in MFCs operating under aerobic conditions. The fabrication of the aerotolerant bioanode was realized through the electrochemically induced penetration and propagation of anodophilic bacteria in a three-dimensional hydrogel scaffold. Under the protection of the hydrogel scaffold, the anodophilic bacteria exhibited excellent bioelectrocatalytic activity under continuous O2 aeration and delivered a current density comparable to that under anaerobic conditions. The MFC equipped with the aerotolerant bioanode has the potential to be applied to traditionally aerobic wastewater treatment (WWT) technology. This study offers new insight into the application of MFCs for WWT. PMID- 27977120 TI - Kinetically Controlled Synthesis of Pt-Based One-Dimensional Hierarchically Porous Nanostructures with Large Mesopores as Highly Efficient ORR Catalysts. AB - Rational design and construction of Pt-based porous nanostructures with large mesopores have triggered significant considerations because of their high surface area and more efficient mass transport. Hydrochloric acid-induced kinetically controlled reduction of metal precursors in the presence of soft template F-127 and hard template tellurium nanowires has been successfully demonstrated to construct one-dimensional hierarchical porous PtCu alloy nanostructures with large mesopores. Moreover, the electrochemical experiments demonstrated that the PtCu hierarchically porous nanostructures synthesized under optimized conditions exhibit enhanced electrocatalytic performance for oxygen reduction reaction in acid media. PMID- 27977121 TI - Amidation of Polyesters Is Slow in Nonaqueous Solvents: Efficient Amidation of Poly(ethylene terephthalate) with 3-Aminopropyltriethoxysilane in Water for Generating Multifunctional Surfaces. AB - This paper describes surface functionalization of poly(ethylene terephthalate) (PET) films by transamidation of the ester groups with primary amines. The use of water as a solvent improves tremendously the reaction rate and yield compared to conventionally used alcohols. In this study, PET films were exposed to an aqueous solution of 3-aminopropyltriethoxysilane (APTES), which resulted in ester-to amide reactions on the surface of the film. Hydrolysis of the resulting ethoxy moieties in APTES creates hydroxyl groups that can be used as anchoring points for further modification of PET films. This scheme offers an alternative approach to modify polyesters using water as the solvent. PMID- 27977118 TI - Rapid Chagas Disease Drug Target Discovery Using Directed Evolution in Drug Sensitive Yeast. AB - Recent advances in cell-based, high-throughput phenotypic screening have identified new chemical compounds that are active against eukaryotic pathogens. A challenge to their future development lies in identifying these compounds' molecular targets and binding modes. In particular, subsequent structure-based chemical optimization and target-based screening require a detailed understanding of the binding event. Here, we use directed evolution and whole-genome sequencing of a drug-sensitive S. cerevisiae strain to identify the yeast ortholog of TcCyp51, lanosterol-14-alpha-demethylase (TcCyp51), as the target of MMV001239, a benzamide compound with activity against Trypanosoma cruzi, the etiological agent of Chagas disease. We show that parasites treated with MMV0001239 phenocopy parasites treated with another TcCyp51 inhibitor, posaconazole, accumulating both lanosterol and eburicol. Direct drug-protein binding of MMV0001239 was confirmed through spectrophotometric binding assays and X-ray crystallography, revealing a binding site shared with other antitrypanosomal compounds that target Cyp51. These studies provide a new probe chemotype for TcCyp51 inhibition. PMID- 27977122 TI - Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine. AB - The regulation of brain monoamine levels is paramount for cognitive functions, and the monoamine oxidase (MAO A and B) enzymes play a central role in these processes. The aim of this study was to evaluate whether the procognitive properties exerted by propargylamine N-(furan-2-ylmethyl)-N-methylprop-2-yn-1 amine (F2MPA) are related to changes in monoamine content via MAO inhibition. In vivo microdialysis and ex vivo amine metabolite measurement demonstrated region specific alterations in monoamine metabolism that differ from both of the classic MAO A and MAO B inhibitors, clorgyline and l-deprenyl, respectively. Although all the inhibitors (1 and 4 mg/kg) increased cortical serotonin tissue content, only F2MPA increased the levels of cortical noradrenaline. In the striatum, clorgyline (1 mg/kg), but not F2MPA (1 mg/kg), reduced extracellular levels of dopamine metabolites at rest or stimulated by the intrastriatal application of the MAO substrate 3-methoxytyramine. In vitro, F2MPA exhibited a low affinity toward MAO B and MAO A. Nonetheless, it modified the B form of MAO, forming a flavin adduct structurally similar to that with deprenyl. F2MPA was rapidly metabolized in the presence of rat but not human microsomes, producing a hydroxylated derivative. In conclusion, the effect of F2MPA on cognition may arise from monoaminergic changes in the cortex, but the role of MAO in this process is likely to be negligible, consistent with the poor affinity of F2MPA for MAO. PMID- 27977123 TI - Profiling Protease Specificity: Combining Yeast ER Sequestration Screening (YESS) with Next Generation Sequencing. AB - An enzyme engineering technology involving yeast endoplasmic reticulum (ER) sequestration screening (YESS) has been recently developed. Here, a new method is established, in which the YESS platform is combined with NextGen sequencing (NGS) to enable a comprehensive survey of protease specificity. In this approach, a combinatorial substrate library is targeted to the yeast ER and transported through the secretory pathway, interacting with any protease(s) residing in the ER. Multicolor FACS screening is used to isolate cells labeled with fluorophore conjugated antibodies, followed by NGS to profile the cleaved substrates. The YESS-NGS method was successfully applied to profile the sequence specificity of the wild-type and an engineered variant of the tobacco etch mosaic virus protease. Proteolysis in the yeast secretory pathway was also mapped for the first time in vivo revealing a major cleavage pattern of Ali/Leu-X-Lys/Arg-Arg. Here Ali is any small aliphatic residue, but especially Leu. This pattern was verified to be due to the well-known endogenous protease Kex2 after comparison to a newly generated Kex2 knockout strain as well as cleavage of peptides with recombinant Kex2 in vitro. This information is particularly important for those using yeast display technology, as library members with Ali/Leu-X-Lys/Arg-Arg patterns are likely being removed from screens via Kex2 cleavage without the researcher's knowledge. PMID- 27977124 TI - An Enhanced High-Rate Na3V2(PO4)3-Ni2P Nanocomposite Cathode with Stable Lifetime for Sodium-Ion Batteries. AB - Herein, we report on a high-discharge-rate Na3V2(PO4)3-Ni2P/C (NVP-NP/C) composite cathode prepared using a polyol-based pyro synthesis for Na-ion battery applications. X-ray diffraction and electron microscopy studies established the presence of Na3V2(PO4)3 and Ni2P, respectively, in the NVP-NP/C composite. As a cathode material, the obtained NVP-NP/C composite electrode exhibits higher discharge capacities (100.8 mAhg-1 at 10.8 C and 73.9 mAhg-1 at 34 C) than the NVP/C counterpart electrode (62.7 mAhg-1 at 10.8 C and 4.7 mAhg-1 at 34 C), and the composite electrode retained 95.3% of the initial capacity even after 1500 cycles at 16 C. The enhanced performance could be attributed to the synergetic effect of the Ni2P phase and nanoscale NVP particles, which ultimately results in noticeably enhancing the electrical conductivity of the composite. The present study thus demonstrates that the Na3V2(PO4)3-Ni2P/C nanocomposite is a prospective candidate for NIB with a high power/energy density. PMID- 27977125 TI - Large, Linear, and Tunable Positive Magnetoresistance of Mechanically Stable Graphene Foam-Toward High-Performance Magnetic Field Sensors. AB - Here, we present the first observation of magneto-transport properties of graphene foam (GF) composed of a few layers in a wide temperature range of 2-300 K. Large room-temperature linear positive magnetoresistance (PMR ~ 171% at B ~ 9 T) has been detected. The largest PMR (~213%) has been achieved at 2 K under a magnetic field of 9 T, which can be tuned by the addition of poly(methyl methacrylate) to the porous structure of the foam. This remarkable magnetoresistance may be the result of quadratic magnetoresistance. The excellent magneto-transport properties of GF open a way toward three-dimensional graphene based magnetoelectronic devices. PMID- 27977126 TI - Penta-graphene: A Promising Anode Material as the Li/Na-Ion Battery with Both Extremely High Theoretical Capacity and Fast Charge/Discharge Rate. AB - Recently, a new two-dimensional (2D) carbon allotrope named penta-graphene was theoretically proposed ( Zhang , S. ; et al. Proc. Natl. Acad. Sci. U.S.A. 2015 , 112 , 2372 ) and has been predicted to be the promising candidate for broad applications due to its intriguing properties. In this work, by using first principles simulation, we have further extended the potential application of penta-graphene as the anode material for a Li/Na-ion battery. Our results show that the theoretical capacity of Li/Na ions on penta-graphene reaches up to 1489 mAh.g-1, which is much higher than that of most of the previously reported 2D anode materials. Meanwhile, the calculated low open-circuit voltages (from 0.24 to 0.60 V), in combination with the low diffusion barriers (<=0.33 eV) and the high electronic conductivity during the whole Li/Na ions intercalation processes, further show the advantages of penta-graphene as the anode material. Particularly, molecular dynamics simulation (300 K) reveals that Li ion could freely diffuse on the surface of penta-graphene, and thus the ultrafast Li ion diffusivity is expected. Superior performance of penta-graphene is further confirmed by comparing with the other 2D anode materials. The light weight and unique atomic arrangement (with isotropic furrow paths on the surface) of penta graphene are found to be mainly responsible for the high Li/Na ions storage capacity and fast diffusivity. In this regard, except penta-graphene, many other recently proposed 2D metal-free materials with pentagonal Cairo-tiled structures may be the potential candidates as the Li/Na-ion battery anodes. PMID- 27977127 TI - Flower-like Cobalt Hydroxide/Oxide on Graphitic Carbon Nitride for Visible-Light Driven Water Oxidation. AB - Direct water oxidation via photocatalysis is a four-electron and multiple-proton process which requires high extra energy input to produce free dioxygen gas, making it exacting, especially under visible light irradiation. To improve the oxygen evolution reaction rates (OERs) and utilize more visible light, flower like cobalt hydroxide/oxide (Fw-Co(OH)2/Fw-Co3O4) photocatalysts were prepared and loaded onto graphitic carbon nitride (g-C3N4) by a facile coating method in this work. Influenced by the unique three-dimensional morphologies, the synthesized Fw-Co(OH)2 or Fw-Co3O4/g-C3N4 hybrids reveal favorable combination and synergism reflected by the modified photoelectric activities and the improved OER performances. Attributed to its prominent hydrotalcite structure, Fw-Co(OH)2 shows better cocatalytic activity for g-C3N4 modification compared with that of Fw-Co3O4. Specifically, 7 wt % Fw-Co(OH)2/g-C3N4 photocatalyst exhibits photocurrent density 4 times higher and OER performance 5 times better than pristine g-C3N4. This work unambiguously promotes the application of sustainable g-C3N4 in water oxidation. PMID- 27977129 TI - Superhydrophobic Copper Surfaces with Anticorrosion Properties Fabricated by Solventless CVD Methods. AB - Due to continuous miniaturization and increasing number of electrical components in electronics, copper interconnections have become critical for the design of 3D integrated circuits. However, corrosion attack on the copper metal can affect the electronic performance of the material. Superhydrophobic coatings are a commonly used strategy to prevent this undesired effect. In this work, a solventless two steps process was developed to fabricate superhydrophobic copper surfaces using chemical vapor deposition (CVD) methods. The superhydrophobic state was achieved through the design of a hierarchical structure, combining micro-/nanoscale domains. In the first step, O2- and Ar-plasma etchings were performed on the copper substrate to generate microroughness. Afterward, a conformal copolymer, 1H,1H,2H,2H-perfluorodecyl acrylate-ethylene glycol diacrylate [p(PFDA-co-EGDA)], was deposited on top of the metal via initiated CVD (iCVD) to lower the surface energy of the surface. The copolymer topography exhibited a very characteristic and unique nanoworm-like structure. The combination of the nanofeatures of the polymer with the microroughness of the copper led to achievement of the superhydrophobic state. AFM, SEM, and XPS were used to characterize the evolution in topography and chemical composition during the CVD processes. The modified copper showed water contact angles as high as 163 degrees and hysteresis as low as 1 degrees . The coating withstood exposure to aggressive media for extended periods of time. Tafel analysis was used to compare the corrosion rates between bare and modified copper. Results indicated that iCVD-coated copper corrodes 3 orders of magnitude slower than untreated copper. The surface modification process yielded repeatable and robust superhydrophobic coatings with remarkable anticorrosion properties. PMID- 27977128 TI - Oncolytic Adenovirus Complexes Coated with Lipids and Calcium Phosphate for Cancer Gene Therapy. AB - Oncolytic adenovirus (OncoAd) is a promising therapeutic agent for treating cancer. However, the therapeutic potential of OncoAd is hindered by hepatic sequestration and the host immune response in vivo. Here, we constructed a PEG/Lipids/calcium phosphate (CaP)-OncoAd (PLC-OncoAd) delivery system for ZD55 IL-24, an oncolytic adenovirus that carries the IL-24 gene. The negatively charged PLC-ZD55-IL-24 were disperse and resisted serum-induced aggregation. Compared to naked ZD55-IL-24, the systemic administration of PLC-ZD55-IL-24 in BALB/c mice resulted in reduced liver sequestration and systemic toxicity and evaded the innate immune response. In addition, masking the surface of OncoAd protected it from neutralization by pre-existing neutralizing antibody. PLC OncoAd achieved efficient targeted delivery in Huh-7-bearing nude mice, and intravenous administration of a high dose of PLC-ZD55-IL-24 increased therapeutic efficacy without inducing toxicity. The developed PLC-OncoAd delivery system represents a promising improvement for oncolytic adenovirus-based cancer gene therapy in vivo. PMID- 27977130 TI - High Pseudocapacitance in FeOOH/rGO Composites with Superior Performance for High Rate Anode in Li-Ion Battery. AB - Capacitive storage has been considered as one type of Li-ion storage with fast faradaic surface redox reactions to offer high power density for electrochemical applications. However, it is often limited by low extent of energy contribution during the charge/discharge process, providing insufficient influences to total capacity of Li-ion storage in electrodes. In this work, we demonstrate a pseudocapacitance predominated storage (contributes 82% of the total capacity) from an in-situ pulverization process of FeOOH rods on rGO (reduced graphene oxide) sheets for the first time. Such high extent of pseudocapacitive storage in the FeOOH/rGO electrode achieves high energy density with superior cycling performance over 200 cycles at different current densities (1135 mAh/g at 1 A/g and 783 mAh/g at 5 A/g). It is further revealed that the in-situ pulverization process is essential for the high pseudocapacitance in this electrode, because it not only produces a porous structure for high exposure of tiny FeOOH crystallites to electrolyte but also maintains stable electrochemical contact during ultrahigh rate charge transfer with high energy density in the battery. The utilization of in-situ pulverization in an Fe-based anode to realize high surface pseudocapacitance with superior performance may inspire future design of electrode structures in Li-ion batteries. PMID- 27977131 TI - The Striosome and Matrix Compartments of the Striatum: A Path through the Labyrinth from Neurochemistry toward Function. AB - The striatum is a heterogeneous structure with a diverse range of neuron types and neuromodulators. Three decades of anatomical and biochemical studies have established that the neurochemical organization of striatum is not uniformly heterogeneous, but rather, can be differentiated into neurochemically discrete compartments known as striosomes (also known as patches) and matrix. These compartments are well understood to differ in their expression of neurochemical markers, with some differences in afferent and efferent connectivity and have also been suggested to have different involvement in a range of neurological diseases. However, the functional outcomes of striosome-matrix organization are poorly understood. Now, recent findings and new experimental tools are beginning to reveal that the distinctions between striosomes and matrix have distinct consequences for striatal synapse function. Here, we review recent findings that suggest there can be distinct regulation of neural function in striosome versus matrix compartments, particularly compartment-specific neurochemical interactions. We highlight that new transgenic and viral tools are becoming available that should now accelerate the pace of advances in understanding of these long-mysterious striatal compartments. PMID- 27977132 TI - MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/beta-Catenin Signaling in Parkinsonian Rats. AB - Adult hippocampal neurogenesis is directly involved in regulation of stress, anxiety, and depression that are commonly observed nonmotor symptoms in Parkinson's disease (PD). These symptoms do not respond to pharmacological dopamine replacement therapy. Excitotoxic damage to neuronal cells by N-methyl-d aspartate (NMDA) receptor activation is also a major contributing factor in PD development, but whether it regulates hippocampal neurogenesis and nonmotor symptoms in PD is yet unexplored. Herein, for the first time, we studied the effect of MK-801, an NMDA receptor antagonist, on adult hippocampal neurogenesis and behavioral functions in 6-OHDA (6-hydroxydopamine) induced rat model of PD. MK-801 treatment (0.2 mg/kg, ip) increased neural stem cell (NSC) proliferation, self-renewal capacity, long-term survival, and neuronal differentiation in the hippocampus of rat model of PD. MK-801 potentially enhanced long-term survival, improved dendritic arborization of immature neurons, and reduced 6-OHDA induced neurodegeneration via maintaining the NSC pool in hippocampus, leading to decreased anxiety and depression-like phenotypes in the PD model. MK-801 inhibited glycogen synthase kinase-3beta (GSK-3beta) through up-regulation of Wnt 3a, which resulted in the activation of Wnt/beta-catenin signaling leading to enhanced hippocampal neurogenesis in PD model. Additionally, MK-801 treatment protected the dopaminergic (DAergic) neurons in the nigrostriatal pathway and improved motor functions by increasing the expression of Nurr-1 and Pitx-3 in the PD model. Therefore, MK-801 treatment serves as a valuable tool to enhance hippocampal neurogenesis in PD, but further studies are needed to revisit the role of MK-801 in the neurodegenerative disorder before proposing a potential therapeutic candidate. PMID- 27977133 TI - Hybrid of g-C3N4 Assisted Metal-Organic Frameworks and Their Derived High Efficiency Oxygen Reduction Electrocatalyst in the Whole pH Range. AB - A highly active electrocatalyst in the whole pH range for oxygen reduction reaction (ORR) is produced by employing the g-C3N4 assisted metal-organic frameworks (MOF) of C3N4@NH2-MIL-101 as the precursor. By pyrolyzing the hybrid at 700 degrees C, the C3N4@NH2-MIL-101 could be easily transformed into an abundant iron and nitrogen codoped porous carbon skeleton. The selective use of g C3N4 as a support template plays a critical role in facilitating the formation of the architecture with high surface area and rich N content. The obtained catalyst of C3N4@NH2-MIL-101-700 manifested remarkable oxygen reduction activity over the pH 0-14. Noteworthy, the catalyst displayed outstanding ORR activity with more positive half-wave potential than that of the commercial Pt/C catalyst in both alkaline and neutral conditions. Additionally, the optimal C3N4@NH2-MIL-101-700 also exhibited prominent ORR activity which is almost equal to that of commercial Pt/C in acidic electrolyte with high selectivity and very low H2O2 yield. Most importantly, the better methanol tolerance and much higher stability than the commercial Pt/C of C3N4@NH2-MIL-101-700 no matter under alkaline, neutral, or acid conditions further demonstrate the catalyst to be a promising candidate for practical electrocatalytic applications. PMID- 27977134 TI - Aloe vera Derived Activated High-Surface-Area Carbon for Flexible and High-Energy Supercapacitors. AB - Materials which possess high specific capacitance in device configuration with low cost are essential for viable application in supercapacitors. Herein, a flexible high-energy supercapacitor device was fabricated using porous activated high-surface-area carbon derived from aloe leaf (Aloe vera) as a precursor. The A. vera derived activated carbon showed mesoporous nature with high specific surface area of ~1890 m2/g. A high specific capacitance of 410 and 306 F/g was achieved in three-electrode and symmetric two-electrode system configurations in aqueous electrolyte, respectively. The fabricated all-solid-state device showed a high specific capacitance of 244 F/g with an energy density of 8.6 Wh/kg. In an ionic liquid electrolyte, the fabricated device showed a high specific capacitance of 126 F/g and a wide potential window up to 3 V, which results in a high energy density of 40 Wh/kg. Furthermore, it was observed that the activation temperature has significant role in the electrochemical performance, as the activated sample at 700 degrees C showed best activity than the samples activated at 600 and 800 degrees C. The electron microscopic images (FE-SEM and HR-TEM) confirmed the formation of pores by the chemical activation. A fabricated supercapacitor device in ionic liquid with 3 V could power up a red LED for 30 min upon charging for 20s. Also, it is shown that the operation voltage and capacitance of flexible all-solid-state symmetric supercapacitors fabricated using aloe-derived activated carbon could be easily tuned by series and parallel combinations. The performance of fabricated supercapacitor devices using A. vera derived activated carbon in all-solid-state and ionic liquid indicates their viable applications in flexible devices and energy storage. PMID- 27977136 TI - Direct Observation of Domain Motion Synchronized with Resistive Switching in Multiferroic Thin Films. AB - The room-temperature resistive switching characteristics of ferroelectric, ferroelastic, and multiferroic materials are promising for application in nonvolatile memory devices. These resistive switching characteristics can be accompanied by a change in the ferroic order parameters via applied external electric and magnetic excitations. However, the dynamic evolution of the order parameters between two electrodes, which is synchronized with resistive switching, has rarely been investigated. In this study, for the first time, we directly monitor the ferroelectric/ferroelastic domain switching dynamics between two electrodes in multiferroic BiFeO3 (BFO) planar devices, which cause resistive switching, using piezoresponse force microscopy. It is demonstrated that the geometrical relationship between the ferroelectric domain and electrode in BFO planar capacitors with only 71 degrees domain walls significantly affects both the ferroelectric domain dynamics and the resistive switching. The direct observation of domain dynamics relevant to resistive switching in planar devices may pave the way to a controllable combination of ferroelectric characteristics and resistive switching in multiferroic materials. PMID- 27977135 TI - Characterization of Two Late-Stage Enzymes Involved in Fosfomycin Biosynthesis in Pseudomonads. AB - The broad-spectrum phosphonate antibiotic fosfomycin is currently in use for clinical treatment of infections caused by both Gram-positive and Gram-negative uropathogens. The antibiotic is biosynthesized by various streptomycetes, as well as by pseudomonads. Notably, the biosynthetic strategies used by the two genera share only two steps: the first step in which primary metabolite phosphoenolpyruvate (PEP) is converted to phosphonopyruvate (PnPy) and the terminal step in which 2-hydroxypropylphosphonate (2-HPP) is converted to fosfomycin. Otherwise, distinct enzymatic paths are employed. Here, we biochemically confirm the last two steps in the fosfomycin biosynthetic pathway of Pseudomonas syringae PB-5123, showing that Psf3 performs the reduction of 2 oxopropylphosphonate (2-OPP) to (S)-2-HPP, followed by the Psf4-catalyzed epoxidation of (S)-2-HPP to fosfomycin. Psf4 can also accept (R)-2-HPP as a substrate but instead performs an oxidation to make 2-OPP. We show that the combined activities of Psf3 and Psf4 can be used to convert racemic 2-HPP to fosfomycin in an enantioconvergent process. X-ray structures of each enzyme with bound substrates provide insights into the stereospecificity of each conversion. These studies shed light on the reaction mechanisms of the two terminal enzymes in a distinct pathway employed by pseudomonads for the production of a potent antimicrobial agent. PMID- 27977137 TI - Confined Water in Layered Silicates: The Origin of Anomalous Thermal Expansion Behavior in Calcium-Silicate-Hydrates. AB - Water, under conditions of nanoscale confinement, exhibits anomalous dynamics, and enhanced thermal deformations, which may be further enhanced when such water is in contact with hydrophilic surfaces. Such heightened thermal deformations of water could control the volume stability of hydrated materials containing nanoconfined structural water. Understanding and predicting the thermal deformation coefficient (TDC, often referred to as the CTE, coefficient of thermal expansion), which represents volume changes induced in materials under conditions of changing temperature, is of critical importance for hydrated solids including: hydrogels, biological tissues, and calcium silicate hydrates, as changes in their volume can result in stress development, and cracking. By pioneering atomistic simulations, we examine the physical origin of thermal expansion in calcium-silicate-hydrates (C-S-H), the binding agent in concrete that is formed by the reaction of cement with water. We report that the TDC of C S-H shows a sudden increase when the CaO/SiO2 (molar ratio; abbreviated as Ca/Si) exceeds 1.5. This anomalous behavior arises from a notable increase in the confinement of water contained in the C-S-H's nanostructure. We identify that confinement is dictated by the topology of the C-S-H's atomic network. Taken together, the results suggest that thermal deformations of hydrated silicates can be altered by inducing compositional changes, which in turn alter the atomic topology and the resultant volume stability of the solids. PMID- 27977138 TI - Drugging the Undruggable: Therapeutic Potential of Targeting Protein Tyrosine Phosphatases. AB - Protein tyrosine phosphatases (PTPs) are essential signaling enzymes that, together with protein tyrosine kinases, regulate tyrosine phosphorylation inside the cell. Proper level of tyrosine phosphorylation is important for a diverse array of cellular processes, such as proliferation, metabolism, motility, and survival. Aberrant tyrosine phosphorylation, resulting from alteration of PTP expression, misregulation, and mutation, has been linked to the etiology of many human ailments including cancer, diabetes/obesity, autoimmune disorders, and infectious diseases. However, despite the fact that PTPs have been garnering attention as compelling drug targets, they remain a largely underexploited resource for therapeutic intervention. Indeed, PTPs have been widely dismissed as "undruggable", due to concerns that (1) the highly conserved active site (i.e., pTyr-binding pocket) makes it difficult to achieve inhibitor selectivity among closely related family members, and (2) the positive-charged active site prefers negatively charged molecules, which usually lack cell permeability. To address the issue of selectivity, we advanced a novel paradigm for the acquisition of highly potent and selective PTP inhibitors through generation of bivalent ligands that interact with both PTP active site and adjacent unique peripheral pockets. To overcome the bioavailability issue, we have identified nonhydrolyzable pTyr mimetics that are sufficiently polar to bind the PTP active site, yet still capable of efficiently penetrating cell membranes. We show that these pTyr mimetics interact in the desired inhibitory fashion with the PTP active site and tethering them to appropriate molecular fragments to engage less conserved interactions outside of PTP active site can increase PTP inhibitor potency and selectivity. We demonstrate through three pTyr mimetics fragment-based approaches that it is completely feasible to obtain highly potent and selective PTP inhibitors with robust in vivo efficacy in animal models of oncology, diabetes/obesity, autoimmune disorders, and tuberculosis. We hope that these results will help dispel concerns about the druggability of PTPs and entice further effort in fostering a PTP-based drug discovery enterprise. Well characterized, potent, selective and bioactive inhibitors are essential tools for functional interrogation of PTPs in disease biology and target validation. They will also play a critical role in illuminating the druggability of PTPs and provide the groundwork for new therapies for the treatment of human diseases. PMID- 27977139 TI - Condensation in One-Dimensional Dead-End Nanochannels. AB - Phase change at the nanoscale is at the heart of many biological and geological phenomena. The recent emergence and global implications of unconventional oil and gas production from nanoporous shale further necessitate a higher understanding of phase behavior at these scales. Here, we directly observe condensation and condensate growth of a light hydrocarbon (propane) in discrete sub-100 nm (~70 nm) channels. Two different condensation mechanisms at this nanoscale are distinguished, continuous growth and discontinuous growth due to liquid bridging ahead of the meniscus, both leading to similar net growth rates. The growth rates agree well with those predicted by a suitably defined thermofluid resistance model. In contrast to phase change at larger scales (~220 and ~1000 nm cases), the rate of liquid condensate growth in channels of sub-100 nm size is found to be limited mainly by vapor flow resistance (~70% of the total resistance here), with interface resistance making up the difference. The condensation-induced vapor flow is in the transitional flow regime (Knudsen flow accounting for up to 13% of total resistance here). Collectively, these results demonstrate that with confinement at sub-100 nm scales, such as is commonly found in porous shale and other applications, condensation conditions deviate from the microscale and larger bulk conditions chiefly due to vapor flow and interface resistances. PMID- 27977141 TI - Decabrominated Diphenyl Ethers (BDE-209) in Chinese and Global Air: Levels, Gas/Particle Partitioning, and Long-Range Transport: Is Long-Range Transport of BDE-209 Really Governed by the Movement of Particles? AB - In this paper, we report air concentrations of BDE-209 in both gas- and particle phases across China. The annual mean concentrations of BDE-209 were from below detection limit (BDL) to 77.0 pg.m-3 in the gas-phase and 1.06-728 pg.m-3 in the particle-phase. Among the nine PBDEs measured, BDE-209 is the dominant congener in Chinese atmosphere in both gas and particle phases. We predicted the partitioning behavior of BDE-209 in air using our newly developed steady state equation, and the results matched the monitoring data worldwide very well. It was found that the logarithm of the partition quotient of BDE-209 is a constant, and equal to -1.53 under the global ambient temperature range (from -50 to +50 degrees C). The gaseous fractions of BDE-209 in air depends on the concentration of total suspended particle (TSP). The most important conclusion derived from this study is that, BDE-209, like other semivolatile organic compounds (SVOCs), cannot be sorbed entirely to atmospheric particles; and there is a significant amount of gaseous BDE-209 in global atmosphere, which is subject to long-range atmospheric transport (LRAT). Therefore, it is not surprising that BDE-209 can enter the Arctic through LRAT mainly by air transport rather than by particle movement. This is a significant advancement in understanding the global transport process and the pathways entering the Arctic for chemicals with low volatility and high octanol-air partition coefficients, such as BDE-209. PMID- 27977140 TI - In Vivo Monitoring of Amino Acid Biomarkers from Inguinal Adipose Tissue Using Online Microdialysis-Capillary Electrophoresis. AB - We have developed an online, high-throughput, microdialysis-capillary electrophoresis (MD-CE) assay for measuring the in vivo dynamics of amino acid biomarkers of metabolism in adipose tissue. Microdialysis probes were implanted into the inguinal adipose tissue depot of C57BL6 mice. The probe location and integrity were verified following each experiment, demonstrating our ability to accurately target the inguinal adipose tissue depot without damaging the probe. The relative concentrations of small molecule bioamines were measured in adipose tissue every 22 s. Arginine, lysine, isoleucine, leucine, methionine, phenylalanine, valine, GABA, glutamine, alanine, glycine and taurine were separated and detected at concentrations significantly higher than the assay LOD. The relative abundances of these analytes were found to be reproducible between mice. The capability of the online MD-CE assay to record dynamic, in vivo changes was assessed by administering an insulin stimulation via tail vein injection. Valine concentrations increased by 40% in response to insulin exposure, while alanine increased by 46% and taurine increased by 37%. Following the initial increase, the amino acid concentrations remained significantly elevated for an extended period (p < 0.001). PMID- 27977142 TI - Ratiometric Sensing and Imaging of Intracellular pH Using Polyethylenimine-Coated Photon Upconversion Nanoprobes. AB - Measurement of changes of pH at various intracellular compartments has potential to solve questions concerning the processing of endocytosed material, regulation of the acidification process, and also acidification of vesicles destined for exocytosis. To monitor these events, the nanosized optical pH probes need to provide ratiometric signals in the optically transparent biological window, target to all relevant intracellular compartments, and to facilitate imaging at subcellular resolution without interference from the biological matrix. To meet these criteria we sensitize the surface conjugated pH sensitive indicator via an upconversion process utilizing an energy transfer from the nanoparticle to the indicator. Live cells were imaged with a scanning confocal microscope equipped with a low-energy 980 nm laser excitation, which facilitated high resolution and penetration depth into the specimen, and low phototoxicity needed for long-term imaging. Our upconversion nanoparticle resonance energy transfer based sensor with polyethylenimine-coating provides high colloidal stability, enhanced cellular uptake, and distribution across cellular compartments. This distribution was modulated with membrane integrity perturbing treatment that resulted into total loss of lysosomal compartments and a dramatic pH shift of endosomal compartments. These nanoprobes are well suited for detection of pH changes in in vitro models with high biological background fluorescence and in in vivo applications, e.g., for the bioimaging of small animal models. PMID- 27977143 TI - Magnetite Nanoparticles for Stem Cell Labeling with High Efficiency and Long-Term in Vivo Tracking. AB - Superparamagnetic iron oxide nanoparticles (SPIO-PAA), ultrasmall iron oxide nanoparticles (USPIO-PAA), and glucosamine-modified iron oxide nanoparticles (USPIO-PAA-GlcN) were studied as mesenchymal stem cell (MSCs) labels for cell tracking applications by magnetic resonance imaging (MRI). Pronounced differences were found in the labeling performance of the three samples in terms of cellular dose and labeling efficiency. In combination with polylysine, SPIO-PAA showed nonhomogeneous cell internalization, while for USPIO-PAA no uptake was found. On the contrary, USPIO-PAA-GlcN featured high cellular uptake and biocompatibility, and sensitive detection in both in vitro and in vivo experiments was found by MRI, showing that glucosamine functionalization can be an efficient strategy to increase cell uptake of ultrasmall iron oxide nanoparticles by MSCs. PMID- 27977144 TI - One-Step Fabrication of Biocompatible Multifaceted Nanocomposite Gels and Nanolayers. AB - Nanocomposite gels are a fascinating class of polymeric materials with an integrative assembly of organic molecules and organic/inorganic nanoparticles, offering a unique hybrid network with synergistic properties. The mechanical properties of such networks are similar to those of natural tissues, which make them ideal biomaterial candidates for tissue engineering applications. Existing nanocomposite gel systems, however, lack many desirable gel properties, and their suitability for surface coatings is often limited. To address this issue, this article aims at generating multifunctional nanocomposite gels that are injectable with an appropriate time window, functional with bicyclononynes (BCN), biocompatible and slowly degradable, and possess high mechanical strength. Further, the in situ network-forming property of the proposed system allows the fabrication of ultrathin nanocomposite coatings in the submicrometer range with tunable wettability and roughness. Multifunctional nanocomposite gels were fabricated under cytocompatible conditions (pH 7.4 and T = 37 degrees C) using laponite clays, isocyanate (NCO)-terminated sP(EO-stat-PO) macromers, and clickable BCN. Several characterization techniques were employed to elucidate the structure-property relationships of the gels. Even though the NCO-sP(EO-stat-PO) macromers could form a hydrogel network in situ on contact with water, the incorporation of laponite led to significant improvement of the mechanical properties. BCN motifs with carbamate links were used for a metal-free click ligation with azide-functional molecules, and the subsequent gradual release of the tethered molecules through the hydrolysis of carbamate bonds was shown. The biocompatibility of the hydrogels was examined through murine macrophages, showing that the material composition strongly affects cell behavior. PMID- 27977145 TI - Spatial Organization of Functional Groups on Bioactive Supramolecular Glycopeptide Nanofibers for Differentiation of Mesenchymal Stem Cells (MSCs) to Brown Adipogenesis. AB - Spatial organization of bioactive moieties in biological materials has significant impact on the function and efficiency of these systems. Here, we demonstrate the effect of spatial organization of functional groups including carboxylate, amine, and glucose functionalities by using self-assembled peptide amphiphile (PA) nanofibers as a bioactive scaffold. We show that presentation of bioactive groups on glycopeptide nanofibers affects mesenchymal stem cells (MSCs) in a distinct manner by means of adhesion, proliferation, and differentiation. Strikingly, when the glutamic acid is present in the glycopeptide backbone, the PA nanofibers specifically induced differentiation of MSCs into brown adipocytes in the absence of any differentiation medium as shown by lipid droplet accumulation and adipogenic gene marker expression analyses. This effect was not evident in the other glycopeptide nanofibers, which displayed the same functional groups but with different spatial organization. Brown adipocytes are attractive targets for obesity treatment and are found in trace amounts in adults, which also makes this specific glycopeptide nanofiber system an attractive tool to study molecular pathways of brown adipocyte formation. PMID- 27977146 TI - Coordination to Imidazole Ring Switches on Phosphorescence of Platinum Cyclometalated Complexes: The Route to Selective Labeling of Peptides and Proteins via Histidine Residues. AB - In this study, we have shown that substitution of chloride ligand for imidazole (Im) ring in the cyclometalated platinum complex Pt(phpy)(PPh3)Cl (1; phpy, 2 phenylpyridine; PPh3, triphenylphosphine), which is nonemissive in solution, switches on phosphorescence of the resulting compound. Crystallographic and nuclear magnetic resonance (NMR) spectroscopic studies of the substitution product showed that the luminescence ignition is a result of Im coordination to give the [Pt(phpy)(Im)(PPh3)]Cl complex. The other imidazole-containing biomolecules, such as histidine and histidine-containing peptides and proteins, also trigger luminescence of the substitution products. The complex 1 proved to be highly selective toward the imidazole ring coordination that allows site specific labeling of peptides and proteins with 1 using the route, which is orthogonal to the common bioconjugation schemes via lysine, aspartic and glutamic acids, or cysteine and does not require any preliminary modification of a biomolecule. The utility of this approach was demonstrated on (i) site-specific modification of the ubiquitin, a small protein that contains only one His residue in its sequence, and (ii) preparation of nonaggregated HSA-based Pt phosphorescent probe. The latter particles easily internalize into the live HeLa cells and display a high potential for live-cell phosphorescence lifetime imaging (PLIM) as well as for advanced correlation PLIM and FLIM experiments. PMID- 27977147 TI - Surface-Induced Dissociation of Protein Complexes in a Hybrid Fourier Transform Ion Cyclotron Resonance Mass Spectrometer. AB - Mass spectrometry continues to develop as a valuable tool in the analysis of proteins and protein complexes. In protein complex mass spectrometry studies, surface-induced dissociation (SID) has been successfully applied in quadrupole time-of-flight (Q-TOF) instruments. SID provides structural information on noncovalent protein complexes that is complementary to other techniques. However, the mass resolution of Q-TOF instruments can limit the information that can be obtained for protein complexes by SID. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) provides ultrahigh resolution and ultrahigh mass accuracy measurements. In this study, an SID device was designed and successfully installed in a hybrid FT-ICR instrument in place of the standard gas collision cell. The SID-FT-ICR platform has been tested with several protein complex systems (homooligomers, a heterooligomer, and a protein-ligand complex, ranging from 53 to 85 kDa), and the results are consistent with data previously acquired on Q-TOF platforms, matching predictions from known protein interface information. SID fragments with the same m/z but different charge states are well resolved based on distinct spacing between adjacent isotope peaks, and the addition of metal cations and ligands can also be isotopically resolved with the ultrahigh mass resolution available in FT-ICR. PMID- 27977148 TI - Cationic Stannylenes: In Situ Generation and NMR Spectroscopic Characterization. AB - The reaction of MeNHC (MeNHC = 1,3,4,5-tetramethylimidazolylidene, where NHC = N heterocyclic carbene) adducts to organotin(II) hydrides Ar*SnH and Ar'SnH [Ar* = 2,6-Trip2C6H3, where Trip = 2,4,6-triisopropylphenyl; Ar' = 2,6-Mes2C6H3, where Mes = 2,4,6-trimethylphenyl)] with Lewis acids such as B(C6F5)3 or [CPh3]+ allows the abstraction of hydride and thus the generation of cationic, dicoordinate bis(sigma-C)-substituted stannylenes [ArSn(NHC)]+. The supposedly dicoordinate constitution of this cationic stannylene was investigated by NMR spectroscopy and further supported by density functional theory computations. For Ar'SnH(MeNHC), the generated cation was found to be inadequately sterically encumbered, allowing the formation of an adduct, [Ar'(NHC)Sn-Sn(H)(NHC)Ar']+, which can be described as the protonated bis(NHC) adduct to the formal 1,2-distannyne. PMID- 27977149 TI - Paramagnetic Resonance of Cobalt(II) Trispyrazolylmethanes and Counterion Association. AB - Paramagnetic resonance studies (EPR, ESEEM, ENDOR, and NMR) of a series of cobalt(II) bis-trispyrazolylmethane tetrafluoroborates are presented. The complexes studied include the parent, unsubstituted ligand (Tpm), two pyrazole substituted derivatives (4Me and 3,5-diMe), and tris(1-pyrazolyl)ethane (Tpe), which includes a methyl group on the apical carbon atom. NMR and ENDOR establish the magnitude of 1H hyperfine couplings, while ESEEM provides information on the coordinated 14N. The data show that the pyrazole 3-position is more electron rich in the Tpm analogues, that the geometry about the apical atom influences the magnetic resonance, and that apical atom geometry appears more fixed in Tpm than in Tp. NMR and ENDOR establish that the BF4- counterion remains associated in fluid solution. In the case of the Tpm3,5Me complex, it appears to associate in solution, in the same position it occupies in the X-ray structure. PMID- 27977150 TI - Magnetic Excitations in Polyoxotungstate-Supported Lanthanoid Single-Molecule Magnets: An Inelastic Neutron Scattering and ab Initio Study. AB - Inelastic neutron scattering (INS) has been used to investigate the crystal field (CF) magnetic excitations of the analogs of the most representative lanthanoid polyoxometalate single-molecule magnet family: Na9[Ln(W5O18)2] (Ln = Nd, Tb, Ho, Er). Ab initio complete active space self-consistent field/restricted active space state interaction calculations, extended also to the Dy analog, show good agreement with the experimentally determined low-lying CF levels, with accuracy better in most cases than that reported for approaches based only on simultaneous fitting to CF models of magnetic or spectroscopic data for isostructural Ln families. In this work we demonstrate the power of a combined spectroscopic and computational approach. Inelastic neutron scattering has provided direct access to CF levels, which together with the magnetometry data, were employed to benchmark the ab initio results. The ab initio determined wave functions corresponding to the CF levels were in turn employed to assign the INS transitions allowed by selection rules and interpret the observed relative intensities of the INS peaks. Ultimately, we have been able to establish the relationship between the wave function composition of the CF split LnIII ground multiplets and the experimentally measured magnetic and spectroscopic properties for the various analogs of the Na9[Ln(W5O18)2] family. PMID- 27977151 TI - Correction to Bacteria Inactivation via X-ray-Induced UVC Radioluminescence: Toward in Situ Biofouling Prevention in Membrane Modules. PMID- 27977152 TI - Life Cycle Analysis of Bitumen Transportation to Refineries by Rail and Pipeline. AB - Crude oil is currently transported primarily by pipelines and rail from extraction sites to refineries around the world. This research evaluates energy use and greenhouse gas (GHG) emissions for three scenarios (synthetic crude oil and dilbit with and without diluent return) in which 750 000 bpd of Alberta's bitumen is transported 3000 km to determine which method has a lower environmental impact. Each scenario has a pipeline and rail pathway, and the dilbit without diluent return scenario has an additional heated bitumen pathway, which does not require diluent. An Excel based bottom-up model is developed using engineering first-principles to calculate mass and energy balances for each process. Results show that pipeline transportation produced between 61% and 77% fewer GHG emissions than by rail. The GHG emissions decreased by 15% and 73% for rail and pipelines as the capacity increased from 100 000 to 800 000 bpd. A Monte Carlo simulation was performed to determine the uncertainty in the emissions and found that the uncertainty was larger for pipelines (up to +/-73%) and smaller for rail (up to +/-28%). The uncertainty ranges do not overlap, thus confirming that pipelines have lower GHG emissions, which is important information for policy makers conducting pipeline reviews. PMID- 27977153 TI - Characterization of the Major Purine and Pyrimidine Adducts Formed after Incubations of 1-Chloro-3-buten-2-one with Single-/Double-Stranded DNA and Human Cells. AB - We have previously shown that 1-chloro-3-buten-2-one (CBO), a potential reactive metabolite of 1,3-butadiene (BD), exhibits potent cytotoxicity and genotoxicity that have been attributed in part to its reactivity toward DNA. In an effort to identify the DNA adducts of CBO, we characterized the CBO reactions with 2' deoxyguanosine (dG), 2'-deoxycytidine (dC), and 2'-deoxyadenosine (dA) under in vitro physiological conditions (pH 7.4, 37 degrees C). In the present study, we investigated the CBO reaction with 2'-deoxythymidine (dT) and compared the rate constants of the reactions of CBO with dA, dC, dG, and dT at both individual- and mixed-nucleosides levels. We also investigated the reactions of CBO with single- and double-stranded DNA using HPLC with UV detection after adducts were released by either acid or enzymatic hydrolysis of DNA. Consistent with the results from the nucleoside reactions and the rate constant experiments, 1,N6-(1-hydroxy-1 chloromethylpropan-1,3-diyl)adenine (A-2D) was identified as the major DNA adduct detected after acid hydrolysis, followed by N7-(4-chloro-3-oxobutyl)guanine (CG 2H) and a small amount of 1,N6-(1-hydroxy-1-hydroxymethylpropan-1,3-diyl)adenine (A-1D). After enzymatic hydrolysis, 1,N6-(1-hydroxy-1-hydroxymethylpropan-1,3 diyl)-2'-dexoyadenosine (dA-1), 3,N4-(1-hydroxy-1-hydroxymethylpropan-1,3-diyl) 2'-deoxycytidine (dC-1/2), and 1,N2-(3-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2' dexoyguanosine (CG-1) were detected, with dA-1 being the major product, followed by dC-1/2. When a nontoxic concentration of CBO (1 MUM) was incubated with HepG2 cells, no adducts could be detected by LC-MS. However, pretreatment of cells with l-buthionine sulfoximine to deplete GSH levels allowed A-2D to be consistently detected in cellular DNA. These results may contribute to a better understanding of the role of the DNA adducts in CBO genotoxicity and mutagenicity. It also suggests that A-2D could be developed as a biomarker of CBO formation after BD exposure in vivo. PMID- 27977154 TI - In Silico Identification of Bioremediation Potential: Carbamazepine and Other Recalcitrant Personal Care Products. AB - Emerging contaminants are principally personal care products not readily removed by conventional wastewater treatment and, with an increasing reliance on water recycling, become disseminated in drinking water supplies. Carbamazepine, a widely used neuroactive pharmaceutical, increasingly escapes wastewater treatment and is found in potable water. In this study, a mechanism is proposed by which carbamazepine resists biodegradation, and a previously unknown microbial biodegradation was predicted computationally. The prediction identified biphenyl dioxygenase from Paraburkholderia xenovorans LB400 as the best candidate enzyme for metabolizing carbamazepine. The rate of degradation described here is 40 times greater than the best reported rates. The metabolites cis-10,11-dihydroxy 10,11-dihydrocarbamazepine and cis-2,3-dihydroxy-2,3-dihydrocarbamazepine were demonstrated with the native organism and a recombinant host. The metabolites are considered nonharmful and mitigate the generation of carcinogenic acridine products known to form when advanced oxidation methods are used in water treatment. Other recalcitrant personal care products were subjected to prediction by the Pathway Prediction System and tested experimentally with P. xenovorans LB400. It was shown to biodegrade structurally diverse compounds. Predictions indicated hydrolase or oxygenase enzymes catalyzed the initial reactions. This study highlights the potential for using the growing body of enzyme-structural and genomic information with computational methods to rapidly identify enzymes and microorganisms that biodegrade emerging contaminants. PMID- 27977155 TI - Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle Internalization. AB - The transferrin receptor (TfR) is a promising target in cancer therapy owing to its overexpression in most solid tumors and on the blood-brain barrier. Nanostructures chemically derivatized with transferrin are employed in TfR targeting but often lose their functionality upon injection in the bloodstream. As an alternative strategy, we rationally designed a peptide coating able to bind transferrin on suitable pockets not involved in binding to TfR or iron by using an iterative multiscale-modeling approach coupled with quantitative structure activity and relationship (QSAR) analysis and evolutionary algorithms. We tested that selected sequences have low aspecific protein adsorption and high binding energy toward transferrin, and one of them is efficiently internalized in cells with a transferrin-dependent pathway. Furthermore, it promotes transferrin mediated endocytosis of gold nanoparticles by modifying their protein corona and promoting oriented adsorption of transferrin. This strategy leads to highly effective nanostructures, potentially useful in diagnostic and therapeutic applications, which exploit (and do not suffer) the protein solvation for achieving a better targeting. PMID- 27977156 TI - Synthesis of a Ternary Thiostannate with 3D Channel Decorated by Hydronium for High Proton Conductivity. AB - Metal chalcogenides with various channel structures feature a number of interesting properties including fast-ion conductivity and selective ion exchange. Most of these compounds are popularly prepared based on the templates of organic amines that play the part of a structure directing agent and even structure-building units, while it still remains a challenge as to the organotemplate-free synthesis for these compounds. Here, a new ternary thiostannate (H3O)4Cu8Sn3S12 was synthesized through a facile, efficient, and organotemplate-free route under hydrothermal conditions. The framework of (H3O)4Cu8Sn3S12 consists of [Cu8Sn6S24]8- building units and possesses a 3D interconnected 8-ring channel structure decorated by pure hydroniums, which not only balance the charges but also facilitate the proton conductivity. The proton conductivity reaches as high as 1.03 * 10-3 S cm-1 at 393 K under anhydrous conditions, which is 2 orders of magnitude higher than that of (H3O)2(enH2)Cu8Sn3S12, a similar channel structure compound prepared by using ethylenediamine as an organic template. PMID- 27977157 TI - Using Benchmarking To Strengthen the Assessment of Persistence. AB - Chemical persistence is a key property for assessing chemical risk and chemical hazard. Current methods for evaluating persistence are based on laboratory tests. The relationship between the laboratory based estimates and persistence in the environment is often unclear, in which case the current methods for evaluating persistence can be questioned. Chemical benchmarking opens new possibilities to measure persistence in the field. In this paper we explore how the benchmarking approach can be applied in both the laboratory and the field to deepen our understanding of chemical persistence in the environment and create a firmer scientific basis for laboratory to field extrapolation of persistence test results. PMID- 27977158 TI - Enhanced Performance of Ceria-Based NOx Reduction Catalysts by Optimal Support Effect. AB - CeO2-based catalysts have attracted widespread attention in environmental protection applications, including selective catalytic reduction (SCR) of NO by NH3, and their catalytic performance is often intimately associated with the supports used. However, the issue of how to choose the supports of such catalysts still remains unresolved. Herein, we systematically study the support effect in SCR over CeO2-based catalysts by using three representative supports, Al2O3, TiO2, and hexagonal WO3 (HWO), with different acidic and redox properties. HWO, with both acidic and reducible properties, achieves an optimal support effect; that is, CeO2/HWO exhibits higher catalytic activity than CeO2 supported on acidic Al2O3 or reducible TiO2. Transmission electron microscopy and X-ray diffraction techniques demonstrate that acidic supports (HWO and Al2O3) are favorable for the dispersion of CeO2 on their surfaces. X-ray photoelectron spectroscopy coupled with theoretical calculations reveals that reducible supports (HWO and TiO2) facilitate strong electronic CeO2-support interactions. Hence, the excellent catalytic performance of CeO2/HWO is mainly ascribed to the high dispersion of CeO2 and the optimal electronic CeO2-support interactions. This work shows that abundant Bronsted acid sites and excellent redox ability of supports are two critical requirements for the design of efficient CeO2-based catalysts. PMID- 27977159 TI - Oxygen Insertion Reactions within the One-Dimensional Channels of Phases Related to FeSb2O4. AB - The structure of the mineral schafarzikite, FeSb2O4, has one-dimensional channels with walls comprising Sb3+ cations; the channels are separated by edge-linked FeO6 octahedra that form infinite chains parallel to the channels. Although this structure provides interest with respect to the magnetic and electrical properties associated with the chains and the possibility of chemistry that could occur within the channels, materials in this structural class have received very little attention. Here we show, for the first time, that heating selected phases in oxygen-rich atmospheres can result in relatively large oxygen uptakes (up to ~2% by mass) at low temperatures (ca. 350 degrees C) while retaining the parent structure. Using a variety of structural and spectroscopic techniques, it is shown that oxygen is inserted into the channels to provide a structure with the potential to show high one-dimensional oxide ion conductivity. This is the first report of oxygen-excess phases derived from this structure. The oxygen insertion is accompanied not only by oxidation of Fe2+ to Fe3+ within the octahedral chains but also Sb3+ to Sb5+ in the channel walls. The formation of a defect cluster comprising one 5-coordinate Sb5+ ion (which is very rare in an oxide environment), two interstitial O2- ions, and two 4-coordinate Sb3+ ions is suggested and is consistent with all experimental observations. To the best of our knowledge, this is the first example of an oxidation process where the local energetics of the product dictate that simultaneous oxidation of two different cations must occur. This reaction, together with a wide range of cation substitutions that are possible on the transition metal sites, presents opportunities to explore the schafarzikite structure more extensively for a range of catalytic and electrocatalytic applications. PMID- 27977160 TI - Long-Term Nickel Contamination Increases the Occurrence of Antibiotic Resistance Genes in Agricultural Soils. AB - Heavy metal contamination is assumed to be a selection pressure on antibiotic resistance, but to our knowledge, evidence of the heavy metal-induced changes of antibiotic resistance is lacking on a long-term basis. Using quantitative PCR array and Illumina sequencing, we investigated the changes of a wide spectrum of soil antibiotic resistance genes (ARGs) following 4-5 year nickel exposure (0-800 mg kg-1) in two long-term experimental sites. A total of 149 unique ARGs were detected, with multidrug and beta-lactam resistance as the most prevailing ARG types. The frequencies and abundance of ARGs tended to increase along the gradient of increasing nickel concentrations, with the highest values recorded in the treatments amended with 400 mg nickel kg-1 soil. The abundance of mobile genetic elements (MGEs) was significantly associated with ARGs, suggesting that nickel exposure might enhance the potential for horizontal transfer of ARGs. Network analysis demonstrated significant associations between ARGs and MGEs, with the integrase intI1 gene having the most frequent interactions with other co occurring ARGs. The changes of ARGs were mainly driven by nickel bioavailability and MGEs as revealed by structural equation models. Taken together, long-term nickel exposure significantly increased the diversity, abundance, and horizontal transfer potential of soil ARGs. PMID- 27977162 TI - Synthesis of Barium Titanate Using Deep Eutectic Solvents. AB - Novel synthetic routes to prepare functional oxides at lower temperatures are an increasingly important area of research. Many of these synthetic routes, however, use water as the solvent and rely on dissolution of the precursors, precluding their use with, for example, titanates. Here we present a low-cost solvent system as a means to rapidly create phase-pure ferroelectric barium titanate using a choline chloride-malonic acid deep eutectic solvent. This solvent is compatible with alkoxide precursors and allows for the rapid synthesis of nanoscale barium titanate powders at 950 degrees C. The phase and morphology were determined, along with investigation of the synthetic pathway, with the reaction proceeding via BaCl2 and TiO2 intermediates. The powders were also used to create sintered ceramics, which exhibit a permittivity maximum corresponding to a tetragonal cubic transition at 112 degrees C, as opposed to the more conventional temperature of ~120 degrees C. The lower-than-expected value for the ferro- to para-electric phase transition is likely due to undetectable levels of contaminants. PMID- 27977161 TI - Rapid Destruction of Tetrabromobisphenol A by Iron(III)-Tetraamidomacrocyclic Ligand/Layered Double Hydroxide Composite/H2O2 System. AB - Iron(III)-tetraamidomacrocyclic ligand (Fe(III)-TAML) activators have received widespread attentions for their abilities to activate hydrogen peroxide to oxidize many organic pollutants. In this study, Fe(III)-TAML/layered double hydroxide (LDH) composite was developed by intercalating Fe(III)-TAML into the interlayer of LDH. Electrostatic interaction and hydrogen bonding might account for the adsorption of Fe(III)-TAML on LDH. The newly synthesized Fe(III)-TAML/LDH composite showed superior reactivity as indicated by efficient decomposition of tetrabromobisphenol A (TBBPA) in the presence of hydrogen peroxide, which can be fully degraded within 20 s and the degradation rate increased up to 8 times compared to free Fe(III)-TAML. In addition, the toxicity of the system was significantly reduced after the reaction. The higher reactivity of Fe(III) TAML/LDH system is attributed to the enhanced adsorption of TBBPA on LDH, which could increase the contact possibility between Fe(III)-TAML and TBBPA. On the basis of the analysis of reaction intermediates, beta-scission at the middle carbon atom and C-Br bond cleavage in phenyl ring of TBBPA were involved in the degradation process. Furthermore, our results demonstrated that the Fe(III) TAML/LDH composite can be reused several times, which could lower the overall cost for environmental implication and render Fe(III)-TAML/LDH as the potential environmentally friendly catalyst for future wastewater treatment under mild reaction conditions. PMID- 27977163 TI - Discovering Hidden Painted Images: Subsurface Imaging Using Microscale Spatially Offset Raman Spectroscopy. AB - We demonstrate for the first time the mapping capability of micro-spatially offset Raman spectroscopy (micro-SORS). The technique enables to form noninvasive images of thin sublayers through highly turbid overlayers. The approach is conceptually demonstrated on recovering overpainted images in situations where conventional Raman microscopy was unable to visualize the sublayer. The specimens mimic real situations encountered in Cultural Heritage that deal, for example, with hidden paintings vandalized with graffiti or covered by superimposed painted layers or whitewash. Additionally, using a letter as a hidden image, we demonstrated the micro-SORS potential to reconstruct also a hidden writing covered, for example, with paper sheets that cannot be easily removed. Potential applications could also include other disciplines such as polymers, biological, catalytic, and forensic sciences where thin, highly turbid layers mask chemically distinct subsurface structures. PMID- 27977165 TI - Correction to Selective Carbon Dioxide Adsorption by Two Robust Microporous Coordination Polymers. PMID- 27977164 TI - A Single Point Mutation in Mitochondrial Hsp70 Cochaperone Mge1 Gains Thermal Stability and Resistance. AB - Mge1, a yeast homologue of Escherichia coli GrpE, is an evolutionarily conserved homodimeric nucleotide exchange factor of mitochondrial Hsp70. Temperature dependent reversible structural alteration from a dimeric to a monomeric form is critical for Mge1 to act as a thermosensor. However, very limited information about the structural component or amino acid residue(s) that contributes to thermal sensing of Mge1/GrpE is available. In this report, we have identified a single point mutation, His167 to Leu (H167L), within the hinge region of Mge1 that confers thermal resistance to yeast. Circular dichroism, cross-linking, and refolding studies with recombinant proteins show that the Mge1 H167L mutant has increased thermal stability compared to that of wild-type Mge1 and also augments Hsp70-mediated protein refolding activity. While thermal denaturation studies suggest flexibility in the mutant, ionic quenching studies and limited proteolysis analysis reveal a relatively more rigid structure compared to that of the wild type. Intriguingly, Thermus thermophilus GrpE has a leucine at the corresponding position akin to the Mge1 mutant, and thermophilus proteins are well-known for their rigidity and hydrophobicity. Taken together, our results show that the yeast Mge1 H167L mutant functionally and structurally mimics T. thermophilus GrpE. PMID- 27977167 TI - Near-Field Raman Spectroscopy with Aperture Tips. AB - In this paper, we review nano-Raman techniques based on aperture scanning near field optical microscopy (SNOM). Fundamentals of SNOM and aperture-tip-based near field Raman spectroscopy and their applications in key technical issues, including Raman signal intensity and collection time, are introduced. Recent advances in the tip design are discussed, and applications of the aperture-SNOM based nano-Raman technique are presented. We attempt to identify the most pressing open questions in this field. We believe that, by improving the power transmission efficiency and combining the local field enhancing technique with the tip-enhanced spectroscopy, the performance of aperture-SNOM can be significantly improved. Its nanometer-scale excitation volume and the consequent low background make the aperture-tip technique feasible for many important samples that cannot be measured by other optical nanospectroscopies. PMID- 27977166 TI - xMSannotator: An R Package for Network-Based Annotation of High-Resolution Metabolomics Data. AB - Improved analytical technologies and data extraction algorithms enable detection of >10 000 reproducible signals by liquid chromatography-high-resolution mass spectrometry, creating a bottleneck in chemical identification. In principle, measurement of more than one million chemicals would be possible if algorithms were available to facilitate utilization of the raw mass spectrometry data, especially low-abundance metabolites. Here we describe an automated computational framework to annotate ions for possible chemical identity using a multistage clustering algorithm in which metabolic pathway associations are used along with intensity profiles, retention time characteristics, mass defect, and isotope/adduct patterns. The algorithm uses high-resolution mass spectrometry data for a series of samples with common properties and publicly available chemical, metabolic, and environmental databases to assign confidence levels to annotation results. Evaluation results show that the algorithm achieves an F1 measure of 0.8 for a data set with known targets and is more robust than previously reported results for cases when database size is much greater than the actual number of metabolites. MS/MS evaluation of a set of randomly selected 210 metabolites annotated using xMSannotator in an untargeted metabolomics human data set shows that 80% of features with high or medium confidence scores have ion dissociation patterns consistent with the xMSannotator annotation. The algorithm has been incorporated into an R package, xMSannotator, which includes utilities for querying local or online databases such as ChemSpider, KEGG, HMDB, T3DB, and LipidMaps. PMID- 27977169 TI - Modulating Single-Molecule Magnetic Behavior of a Dinuclear Erbium(III) Complex by Solvent Exchange. AB - [Er2(thd)4Pc].2C6H6 (1) (Hthd = 2,2,6,6-tetramethylheptanedione), obtained as green crystals from the reaction of [Er(thd)3].2H2O with lithium phthalocyanine, Li2Pc, is a stable dinuclear complex with two ErIII centers. Its lattice benzene solvent can be exchanged by soaking the crystals in dichloromethane to give [Er2(thd)4Pc].2CH2Cl2 (2). The magnetic susceptibility data suggest different coupling interactions for the two complexes. While 1 exhibits fast relaxation and an estimated energy barrier of Ea = 2.6 cm-1 under 600 Oe dc field, the single molecule magnet behavior of 2 is field-induced and the energy barrier is higher at 34.3 cm-1. Ab initio calculations were performed to understand the nature of the coupling interaction between two ErIII ions bridged by the phthalocyanine and the origin of different magnetic behavior. Importantly, the single-molecule magnetic properties can be reversibly tuned through the exchange of solvent molecules, confirmed by further measurements on the reverse solvated complexes 1 re and 2-re. This subtle control of relaxation by lattice solvents is rarely observed in single-molecule magnets, especially for ErIII-based complexes. PMID- 27977168 TI - Spectral and Hydrodynamic Analysis of West Nile Virus RNA-Protein Interactions by Multiwavelength Sedimentation Velocity in the Analytical Ultracentrifuge. AB - Interactions between nucleic acids and proteins are critical for many cellular processes, and their study is of utmost importance to many areas of biochemistry, cellular biology, and virology. Here, we introduce a new analytical method based on sedimentation velocity (SV) analytical ultracentrifugation, in combination with a novel multiwavelength detector to characterize such interactions. We identified the stoichiometry and molar mass of a complex formed during the interaction of a West Nile virus RNA stem loop structure with the human T cell restricted intracellular antigen-1 related protein. SV has long been proven as a powerful technique for studying dynamic assembly processes under physiological conditions in solution. Here, we demonstrate, for the first time, how the new multiwavelength technology can be exploited to study protein-RNA interactions, and show how the spectral information derived from the new detector complements the traditional hydrodynamic information from analytical ultracentrifugation. Our method allows the protein and nucleic acid signals to be separated by spectral decomposition such that sedimentation information from each individual species, including any complexes, can be clearly identified based on their spectral signatures. The method presented here extends to any interacting system where the interaction partners are spectrally separable. PMID- 27977170 TI - Modeling the Photochromism of S-Doped Sodalites Using DFT, TD-DFT, and SAC-CI Methods. AB - S-doped sodalite minerals of the Na8Al6Si6O24(Cl,S)2 formula, also known as hackmanites, are computationally investigated for the first time, in order to understand their photochromic properties. With combined periodic boundary conditions and embedded cluster-type approaches, this paper brings a theoretical overview of the photochromism mechanism, also called tenebrescence in geology. Time-dependent density functional theory (TD-DFT) calculations of sodalite systems containing electrons trapped in Cl vacancies showed an absorption spectrum and a simulated color in agreement with experiment. This modeling highlights the huge effect of the F center's environment such as the direct contribution of the beta cage on the trapped electron and a strong vibronic coupling of the absorption spectrum. TD-DFT and post-Hartree-Fock (SAC-CI) calculations were also operated on S22--containing systems in order to determine the exact mechanism of coloration and discoloration, supporting that the key step is a direct through-space charge transfer between the S22- ion and a Cl vacancy. The geometry modification induced by this charge transfer leads to a large electronic reorganization stabilizing the F center, thus explaining the high stability of the colored state of the mineral. PMID- 27977171 TI - Reductive Activation of O2 by Non-Heme Iron(II) Benzilate Complexes of N4 Ligands: Effect of Ligand Topology on the Reactivity of O2-Derived Oxidant. AB - A series of iron(II) benzilate complexes (1-7) with general formula [(L)FeII(benzilate)]+ have been isolated and characterized to study the effect of supporting ligand (L) on the reactivity of metal-based oxidant generated in the reaction with dioxygen. Five tripodal N4 ligands (tris(2-pyridylmethyl)amine (TPA in 1), tris(6-methyl-2-pyridylmethyl)amine (6-Me3-TPA in 2), N1,N1-dimethyl-N2,N2 bis(2-pyridylmethyl)ethane-1,2-diamine (iso-BPMEN in 3), N1,N1-dimethyl-N2,N2 bis(6-methyl-2-pyridylmethyl)ethane-1,2-diamine (6-Me2-iso-BPMEN in 4), and tris(2-benzimidazolylmethyl)amine (TBimA in 7)) along with two linear tetradentate amine ligands (N1,N2-dimethyl-N1,N2-bis(2-pyridylmethyl)ethane-1,2 diamine (BPMEN in 5) and N1,N2-dimethyl-N1,N2-bis(6-methyl-2-pyridylmethyl)ethane 1,2-diamine (6-Me2-BPMEN in 6)) were employed in the study. Single-crystal X-ray structural studies reveal that each of the complex cations of 1-3 and 5 contains a mononuclear six-coordinate iron(II) center coordinated by a monoanionic benzilate, whereas complex 7 contains a mononuclear five-coordinate iron(II) center. Benzilate binds to the iron center in a monodentate fashion via one of the carboxylate oxygens in 1 and 7, but it coordinates in a bidentate chelating mode through carboxylate oxygen and neutral hydroxy oxygen in 2, 3, and 5. All of the iron(II) complexes react with dioxygen to exhibit quantitative decarboxylation of benzilic acid to benzophenone. In the decarboxylation pathway, dioxygen becomes reduced on the iron center and the resulting iron-oxygen oxidant shows versatile reactivity. The oxidants are nucleophilic in nature and oxidize sulfide to sulfoxide and sulfone. Furthermore, complexes 2 and 4-6 react with alkenes to produce cis-diols in moderate yields with the incorporation of both the oxygen atoms of dioxygen. The oxygen atoms of the nucleophilic oxidants do not exchange with water. On the basis of interception studies, nucleophilic iron(II) hydroperoxides are proposed to generate in situ in the reaction pathways. The difference in reactivity of the complexes toward external substrates could be attributed to the geometry of the O2-derived iron-oxygen oxidant. DFT calculations suggest that, among all possible geometries and spin states, high-spin side-on iron(II) hydroperoxides are energetically favorable for the complexes of 6-Me3-TPA, 6-Me2-iso-BPMEN, BPMEN, and 6-Me2-BPMEN ligands, while high spin end-on iron(II) hydroperoxides are favorable for the complexes of TPA, iso-BPMEN, and TBimA ligands. PMID- 27977172 TI - Guest-Induced Modulation of the Energy Transfer Process in Porphyrin-Based Artificial Light Harvesting Dendrimers. AB - A series of dendritic multiporphyrin arrays (PZnTz-nPFB; n = 2, 4, 8) comprising a triazole-bearing focal zinc porphyrin (PZn) with a different number of freebase porphyrin (PFB) wings has been synthesized, and their photoinduced energy transfer process has been evaluated. UV/vis absorption, emission, and time resolved fluorescence measurements indicated that efficient excitation energy transfer takes place from the focal PZn to PFB wings in PZnTz-nPFB's. The triazole-bearing PZn effectively formed host-guest complexes with anionic species by means of axial coordination with the aid of multiple C-H hydrogen bonds. By addition of various anionic guests to PZnTz and PZnTz-nPFB's, strong bathochromic shifts of PZn absorption were observed, indicating the HOMO-LUMO gap (DeltaEHOMO LUMO) of PZn decreased by anion binding. Time-resolved fluorescence measurements revealed that the fluorescence emission predominantly takes place from PZn in PZnTz-nPFB's after the addition of CN-. This change was reversible because a treatment with a silver strip to remove CN- fully recovered the original energy transfer process from the focal PZn to PFB wings. PMID- 27977173 TI - Studies on a "Disappearing Polymorph": Thermal and Magnetic Characterization of alpha-p-NCC6F4CNSSN*. AB - The alpha-and beta-phases of the thiazyl radical p-NCC6F4CNSSN* (1) can be selectively prepared by careful control of the sublimation conditions, with the alpha-phase crystallizing preferentially when the substrate temperature is maintained below -10 degrees C, whereas the beta-phase is isolated when the substrate temperature is maintained at or above ambient temperature. Differential scanning calorimatry studies reveal that the alpha-phase converts to the beta phase upon warming over the range 111-117 degrees C (DeltaH = +4 kJ.mol-1) via a melt-recrystallization process, with the beta-phase itself melting at 167-170 degrees C (DeltaHfus = 27 kJ.mol-1). IR and Raman spectroscopy can be used to clearly discriminate between 1alpha and 1beta. The alpha-phase shows a broad maximum in the magnetic susceptibility around 8 K that, coupled with a broad maximum in the heat capacity, is indicative of short-range order. Some field dependence of the susceptibility below 3 K is observed, but the lack of features in the ac susceptibility, M vs H plots, or heat capacity mitigates against long range order in 1alpha. PMID- 27977175 TI - Defining Noncovalent Ubiquitin Homodimer Interfacial Interactions through Comparisons with Covalently Linked Diubiquitin. AB - Covalently linked diubiquitin (diUbq) is known to adopt specific interfacial interactions owing to steric hindrance induced by the covalent tether. K48-linked diUbq preferentially forms hydrophobic interfacial interactions between the two I44 faces under physiological conditions, whereas K63-linked diUbq preferentially forms electrostatic interfacial interactions. Here, we show using collision induced unfolding ion mobility-mass spectrometry that the recently reported noncovalent dimer of ubiquitin exhibits structural preferences and interfacial interactions that are most similar to that of K48-linked diUbq. PMID- 27977174 TI - Carbon Dots as Versatile Photosensitizers for Solar-Driven Catalysis with Redox Enzymes. AB - Light-driven enzymatic catalysis is enabled by the productive coupling of a protein to a photosensitizer. Photosensitizers used in such hybrid systems are typically costly, toxic, and/or fragile, with limited chemical versatility. Carbon dots (CDs) are low-cost, nanosized light-harvesters that are attractive photosensitizers for biological systems as they are water-soluble, photostable, nontoxic, and their surface chemistry can be easily modified. We demonstrate here that CDs act as excellent light-absorbers in two semibiological photosynthetic systems utilizing either a fumarate reductase (FccA) for the solar-driven hydrogenation of fumarate to succinate or a hydrogenase (H2ase) for reduction of protons to H2. The tunable surface chemistry of the CDs was exploited to synthesize positively charged ammonium-terminated CDs (CD-NHMe2+), which were capable of transferring photoexcited electrons directly to the negatively charged enzymes with high efficiency and stability. Enzyme-based turnover numbers of 6000 mol succinate (mol FccA)-1 and 43,000 mol H2 (mol H2ase)-1 were reached after 24 h. Negatively charged carboxylate-terminated CDs (CD-CO2-) displayed little or no activity, and the electrostatic interactions at the CD-enzyme interface were determined to be essential to the high photocatalytic activity observed with CD NHMe2+. The modular surface chemistry of CDs together with their photostability and aqueous solubility make CDs versatile photosensitizers for redox enzymes with great scope for their utilization in photobiocatalysis. PMID- 27977176 TI - Engineering Interfacial Charge Transfer in CsPbBr3 Perovskite Nanocrystals by Heterovalent Doping. AB - Since compelling device efficiencies of perovskite solar cells have been achieved, investigative efforts have turned to understand other key challenges in these systems, such as engineering interfacial energy-level alignment and charge transfer (CT). However, these types of studies on perovskite thin-film devices are impeded by the morphological and compositional heterogeneity of the films and their ill-defined surfaces. Here, we use well-defined ligand-protected perovskite nanocrystals (NCs) as model systems to elucidate the role of heterovalent doping on charge-carrier dynamics and energy level alignment at the interface of perovskite NCs with molecular acceptors. More specifically, we develop an in situ doping approach for colloidal CsPbBr3 perovskite NCs with heterovalent Bi3+ ions by hot injection to precisely tune their band structure and excited-state dynamics. This synthetic method allowed us to map the impact of doping on CT from the NCs to different molecular acceptors. Using time-resolved spectroscopy with broadband capability, we clearly demonstrate that CT at the interface of NCs can be tuned and promoted by metal ion doping. We found that doping increases the energy difference between states of the molecular acceptor and the donor moieties, subsequently facilitating the interfacial CT process. This work highlights the key variable components not only for promoting interfacial CT in perovskites, but also for establishing a higher degree of precision and control over the surface and the interface of perovskite molecular acceptors. PMID- 27977177 TI - Synthesis and Fluorescent Behaviour of 2-Aryl-4,5-dihydro-1H-1,2,4-triazoles. AB - A series of new 4,5-dihydro-1H-1,2,4-triazoles was synthesized from amidrazones and acetylenedicarboxylic acid esters in the presence of pyridine in toluene. The synthesized compounds were characterized by 1H, 13C NMR, FT-IR spectral analyses and XRD data. Optical studies revealed that most of the compounds reported here exhibited emission of blue or green-yellow light upon irradiation in acetone and showed Stokes shifts in the region of 70-96 nm and quantum yields of up to 45%. The interpretation of the experimental findings was supported by state-of-the-art quantum mechanical calculations. PMID- 27977178 TI - Dual Heterogeneous Catalyst Pd-Au@Mn(II)-MOF for One-Pot Tandem Synthesis of Imines from Alcohols and Amines. AB - A new Mn(II) metal-organic framework (MOF) 1 was synthesized by the combination of 4,4,4-trifluoro-1-(4-(pyridin-4-yl)phenyl)butane-1,3-dione (L) and Mn(OAc)2 in solution. 1 features a threefold-interpenetrating NbO net containing honeycomb like channels, in which the opposite Mn(II)...Mn(II) distance is 23.5075(10) A. Furthermore, 1 can be an ideal platform to support Pd-Au bimetallic alloy nanoparticles to generate a composite catalytic system of Pd-Au@Mn(II)-MOF (2). 2 can be a highly active bifunctional heterogeneous catalyst for the one-pot tandem synthesis of imines from benzyl alcohols and anilines and from benzyl alcohols and benzylamines. PMID- 27977179 TI - Predicting and Understanding the Reactivity of Aza[60]fullerenes. AB - The Diels-Alder reactivity of C59NH azafullerene has been explored computationally. The regioselectivity of the process and the factors controlling the reduced reactivity of this system with respect to the parent C60 fullerene have been analyzed in detail by using the activation strain model of reactivity and the energy decomposition analysis method. It is found that the presence of the nitrogen atom and the CH fragment in the fullerene reduces the interaction between the deformed reactants along the entire reaction coordinate. PMID- 27977180 TI - A Limonoid Kihadanin B from Immature Citrus unshiu Peels Suppresses Adipogenesis through Repression of the Akt-FOXO1-PPARgamma Axis in Adipocytes. AB - Citrus limonoids are secondary metabolites and exhibit a variety of biological activities. In this study, we elucidated the suppression of adipogenesis by a Citrus limonoid kihadanin B and determined its molecular mechanism in mouse 3T3 L1 adipocytes. Kihadanin B was purified from the peels of immature Citrus unshiu by HPLC, and its chemical structure was determined by NMR and mass spectrometry. Kihadanin B reduced the lipid accumulation with the reduction of the expression levels of the adipogenic and lipogenic genes, but did not affect lipolysis in adipocytes. Phosphorylation levels of Akt and a forkhead transcriptional factor, FOXO1, a repressor of PPARgamma, were lowered by kihadanin B. Furthermore, kihadanin B increased the binding level of FOXO1 to the PPARgamma gene promoter in adipocytes. These results indicate that a Citrus limonoid kihadanin B repressed the adipogenesis by decreasing lipid accumulation through the suppression of the Akt-FOXO1-PPARgamma axis in 3T3-L1 adipocytes. PMID- 27977181 TI - An Orally Active Bradykinin B1 Receptor Antagonist Engineered as a Bifunctional Chimera of Sunflower Trypsin Inhibitor. AB - An orally active and metabolically stable peptide TIBA was successfully engineered as a chimera by fusing an analgesic bradykinin receptor antagonist peptide and the trypsin inhibitory loop of sunflower trypsin inhibitor-1. As a fusion cyclic peptide, the metabolically labile analgesic peptide is protected from degradation by exopeptidases as well as the endopeptidases, and its serum half-life extended from <5 min to >6 h as a chimera. Moreover, the chimera TIBA was also found to be orally active in an animal pain model using a hot plate assay. PMID- 27977182 TI - Effects of Fungicide Treatment on Free Amino Acid Concentration and Acrylamide Forming Potential in Wheat. AB - Acrylamide forms from free asparagine and reducing sugars during frying, baking, roasting, or high-temperature processing, and cereal products are major contributors to dietary acrylamide intake. Free asparagine concentration is the determining factor for acrylamide-forming potential in cereals, and this study investigated the effect of fungicide application on free asparagine accumulation in wheat grain. Free amino acid concentrations were measured in flour from 47 varieties of wheat grown in a field trial in 2011-2012. The wheat had been supplied with nitrogen and sulfur and treated with growth regulators and fungicides. Acrylamide formation was measured after the flour had been heated at 180 degrees C for 20 min. Flour was also analyzed from 24 (of the 47) varieties grown in adjacent plots that were treated in identical fashion except that no fungicide was applied, resulting in visible infection by Septoria tritici, yellow rust, and brown rust. Free asparagine concentration in the fungicide-treated wheat ranged from 1.596 to 3.987 mmol kg-1, with a significant (p < 0.001 to p = 0.006, F test) effect of variety for not only free asparagine but all of the free amino acids apart from cysteine and ornithine. There was also a significant (p < 0.001, F test) effect of variety on acrylamide formation, which ranged from 134 to 992 MUg kg-1. There was a significant (p < 0.001, F test) correlation between free asparagine concentration and acrylamide formation. Both free asparagine concentration and acrylamide formation increased in response to a lack of fungicide treatment, the increases in acrylamide ranging from 2.7 to 370%. Free aspartic acid concentration also increased, whereas free glutamic acid concentration increased in some varieties but decreased in others, and free proline concentration decreased. The study showed disease control by fungicide application to be an important crop management measure for mitigating the problem of acrylamide formation in wheat products. PMID- 27977183 TI - CO2 Plant Extracts Reduce Cholesterol Oxidation in Fish Patties during Cooking and Storage. AB - Cholesterol oxidation products (COPs) in foods may pose risks for human health. Suitable antioxidants can reduce the formation of COPs in industrial products. Consumer awareness of food additives has brought a need for more natural alternatives. This is the first study on the effects of supercritical CO2 extracts of rosemary, oregano, and an antimicrobial blend of seven herbs, tested at two levels (1 and 3 g/kg fish), against cholesterol oxidation in patties made of a widely consumed fish species, Atlantic salmon (Salmo salar), during baking and storage. Cholesterol oxidation was reduced by the extracts as indicated by lowered levels of 7alpha-hydroxycholesterol, 7beta-hydroxycholesterol, and 7 ketocholesterol, which were quantified by GC-MS. The total amount of COPs was smaller in all of the cooked samples containing the plant extracts (<1 MUg/g extracted fat) than in the cooked control (14 MUg/g). Furthermore, the plant extracts exhibited protective effects also during cold storage for up to 14 days. PMID- 27977184 TI - Unexpected Efficient Synthesis of Millimeter-Scale Single-Wall Carbon Nanotube Forests Using a Sputtered MgO Catalyst Underlayer Enabled by a Simple Treatment Process. AB - An unexpected 5000% increase in growth efficiency and high (95%) single-wall selectivity synthesis of vertically aligned carbon nanotubes (CNTs) was shown from Fe catalysts supported on a sputtered MgO underlayer from a simple underlayer treatment, i.e., annealing treatment. In this way, millimeter-scale single-wall carbon nanotube "forests" could be synthesized in a 10 min time, which has never been previously reported for MgO catalyst underlayer or any underlayer besides Al2O3. This level of efficiency and characterized SWCNT properties were similar to those grown using Al2O3 underlayers. Spectroscopic and microscopic analyses revealed that the treatment improved stability of the catalyst nanoparticle array by the suppressing catalyst subsurface diffusion and retaining the metallic state of the surface Fe atoms. Taken together, these results reveal a new route in achieving highly efficient SWCNT synthesis. PMID- 27977185 TI - Strengthening of the Coordination Shell by Counter Ions in Aqueous Th4+ Solutions. AB - The presence of counterions in solutions containing highly charged metal cations can trigger processes such as ion-pair formation, hydrogen bond breakages and subsequent re-formation, and ligand exchanges. In this work, it is shown how halide (Cl-, Br-) and perchlorate (ClO4-) anions affect the strength of the primary solvent coordination shells around Th4+ using explicit-solvent and finite temperature ab initio molecular dynamics modeling methods. The 9-fold solvent geometry was found to be the most stable hydration structure in each aqueous solution. Relative to the dilute aqueous solution, the presence of the counterions did not significantly alter the geometry of the primary hydration shell. However, the free energy analyses indicated that the 10-fold hydrated states were thermodynamically accessible in dilute and bromide aqueous solutions within 1 kcal/mol. Analysis of the results showed that the hydrogen bond lifetimes were longer and solvent exchange energy barriers were larger in solutions with counterions in comparison with the solution with no counterions. This implies that the presence of the counterions induces a strengthening of the Th4+ hydration shell. PMID- 27977186 TI - What Is the Actual Local Crystalline Structure of Uranium Dioxide, UO2? A New Perspective for the Most Used Nuclear Fuel. AB - Up to now, uranium dioxide, the most used nuclear fuel, was said to have a Fm3m crystalline structure from 30 to 3000 K, and its behavior was modeled under this assumption. However, recently X-ray diffraction experiments provided atomic pair distribution functions of UO2, in which UO distance was shorter than the expected value for the Fm3m space group. Here we show neutron diffraction results that confirm this shorter UO bond, and we also modeled the corresponding pair distribution function showing that UO2 has a local Pa3 symmetry. The existence of a local lower symmetry in UO2 could explain some unexpected properties of UO2 that would justify UO2 modeling to be reassessed. It also deserves more study from an academic point of view because of its good thermoelectric properties that may originate from its particular crystalline structure. PMID- 27977187 TI - Effect of Linear-Hyperbranched Amphiphilic Phosphate Esters on Collagen Fibers. AB - The surfactants of the linear-hyperbranched phosphate esters (PAMAMGn-3-Ps) have been constructed through random multibranching esterification of lauroyl chloride and phosphate ester as a branching agent. Subsequently, a series of surfactant products were obtained. Benefiting from the amphiphilic structure with the hydrophilic core and many hydrophobic tails, PAMAMGn-3-Ps were able to self assemble into nanomicelles in aqueous media. Importantly, the polymers show low critical micelle concentrations (CMCs) and small particle sizes. Here, PAMAMG1-3 P was applied in the collagen fibers of leather to improve the fibers' distance and mechanical property of collagen fibers. Additionally, the polymers display significant flexibility, which could replace ordinary fatliquor in the future. The result provides a new application of using linear-hyperbranched amphiphilic phosphate esters into traditional leather materials to enhance the performance of collagen fibers. PMID- 27977188 TI - Exchange-Hole Dipole Dispersion Model for Accurate Energy Ranking in Molecular Crystal Structure Prediction. AB - Accurate energy ranking is a key facet to the problem of first-principles crystal structure prediction (CSP) of molecular crystals. This work presents a systematic assessment of B86bPBE-XDM, a semilocal density functional combined with the exchange-hole dipole moment (XDM) dispersion model, for energy ranking using 14 compounds from the first five CSP blind tests. Specifically, the set of crystals studied comprises 11 rigid, planar compounds and 3 co-crystals. The experimental structure was correctly identified as the lowest in lattice energy for 12 of the 14 total crystals. One of the exceptions is 4-hydroxythiophene-2-carbonitrile, for which the experimental structure was correctly identified once a quasi harmonic estimate of the vibrational free-energy contribution was included, evidencing the occasional importance of thermal corrections for accurate energy ranking. The other exception is an organic salt, where charge-transfer error (also called delocalization error) is expected to cause the base density functional to be unreliable. Provided the choice of base density functional is appropriate and an estimate of temperature effects is used, XDM-corrected density functional theory is highly reliable for the energetic ranking of competing crystal structures. PMID- 27977189 TI - Label-free Imaging and Characterization of Cancer Cell Responses to Polymethoxyflavones Using Raman Microscopy. AB - We determined the cellular responses of human colon cancer HT29 and HCT116 cells to the treatments of nobiletin (NBT) and 5-demethylnobiletin (5DN) using Raman microscopy. Evaluation at both single cell and cell population levels revealed found that NBT induced more changes in the peak intensity of nucleic acid than 5DN, whereas 5DN induced more changes in the peak intensity of localized lipid than NBT. This result indicates the different modes of inhibitory action of these two PMFs against colon cancer cells. Between the two colon cancer cells tested, HCT116 cells were more sensitive to both PMFs than HT29 cells. The Raman data were generally in a good agreement with the flow cytometry data. Our results demonstrate that Raman microscopy is able to provide macromolecular information on cellular responses to anticancer treatments. PMID- 27977190 TI - Tri- and Tetrasubstituted Pyridinylimidazoles as Covalent Inhibitors of c-Jun N Terminal Kinase 3. AB - The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffold varying several structural features in order to deduce crucial structure-activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole-N1 position increased the activity and reduced the number of off targets. The most promising covalent inhibitor, the tetrasubstituted imidazole 3 acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5 yl)pyridin-2-yl)amino)phenyl)benzamide (7) inhibits the JNK3 in the subnanomolar range (IC50 = 0.3 nM), shows high metabolic stability in human liver microsomes, and displays excellent selectivity in a screening against a panel of 410 kinases. Covalent bond formation to Cys-154 was confirmed by incubation of the inhibitors with wild-type JNK3 and JNK3-C154A mutant followed by mass spectrometry. PMID- 27977191 TI - Hydrolysis of Dicaffeoylquinic Acids from Ilex kudingcha Happens in the Colon by Intestinal Microbiota. AB - Monocaffeoylquinic acids (mono-CQAs) can be hydrolyzed or metabolized by pancreatin, intestinal brush border esterase, and microbiota in the colon. Data about the conversion of dicaffeoylquinic acids (diCQAs) in digestion are scarce. The diCQA-rich fraction including 3,4-, 3,5-, and 4,5-diCQAs was prepared from Ilex kudingcha, and the conversion in simulated gastricintestine was investigated. Artificial saliva, gastric and pancreatic fluids, Caco-2 monolayer cells, and anaerobic fermentation model were utilized to mimic digestions of the oral cavity, stomach, small intestine, and colon in vitro. The results revealed that diCQAs remained intact in simulated saliva, gastric, and pancreatic fluids and within Caco-2 cells. In anaerobic fermentation with human fecal slurry, diCQAs were hydrolyzed to mono-CQAs and caffeic acid, which were further metabolized to caffeic acid and dihydrocaffeic acid, respectively. The hydrolysis of diCQAs depended on the chemical structures, carbohydrates in the culture medium, and microbial compositions. Our research demonstrated that hydrolysis of diCQAs happened in the colon by intestinal microbiota. PMID- 27977192 TI - Atomic Recombination in Dynamic Secondary Ion Mass Spectrometry Probes Distance in Lipid Assemblies: A Nanometer Chemical Ruler. AB - The lateral organization of biological membranes is thought to take place on the nanometer length scale. However, this length scale and the dynamic nature of small lipid and protein domains have made characterization of such organization in biological membranes and model systems difficult. Here we introduce a new method for measuring the colocalization of lipids in monolayers and bilayers using stable isotope labeling. We take advantage of a process that occurs in dynamic SIMS called atomic recombination, in which atoms on different molecules combine to form diatomic ions that are detected with a NanoSIMS instrument. This process is highly sensitive to the distance between molecules. By measuring the efficiency of the formation of 13C15N- ions from 13C and 15N atoms on different lipid molecules, we measure variations in the lateral organization of bilayers even though these heterogeneities occur on a length scale of only a few nm, well below the diameter of the primary ion beam of the NanoSIMS instrument or even the best super-resolution fluorescence methods. Using this technique, we provide direct evidence for nanoscale phase separation in a model membrane, which may provide a better model for the organization of biological membranes than lipid mixtures with microscale phase separation. We expect this technique to be broadly applicable to any assembly where very short scale proximity is of interest or unknown, both in chemical and biological systems. PMID- 27977193 TI - Importance of Reducing Vapor Atmosphere in the Fabrication of Tin-Based Perovskite Solar Cells. AB - Tin-based halide perovskite materials have been successfully employed in lead free perovskite solar cells, but the tendency of these materials to form leakage pathways from p-type defect states, mainly Sn4+ and Sn vacancies, causes poor device reproducibility and limits the overall power conversion efficiencies (PCEs). Here, we present an effective process that involves a reducing vapor atmosphere during the preparation of Sn-based halide perovskite solar cells to solve this problem, using MASnI3, CsSnI3, and CsSnBr3 as the representative absorbers. This process enables the fabrication of remarkably improved solar cells with PCEs of 3.89%, 1.83%, and 3.04% for MASnI3, CsSnI3, and CsSnBr3, respectively. The reducing vapor atmosphere process results in more than 20% reduction of Sn4+/Sn2+ ratios, which leads to greatly suppressed carrier recombination, to a level comparable to their lead-based counterparts. These results mark an important step toward a deeper understanding of the intrinsic Sn based halide perovskite materials, paving the way to the realization of low-cost and lead-free Sn-based halide perovskite solar cells. PMID- 27977194 TI - Hyperconjugative, Secondary Orbital, Electrostatic, and Steric Effects on the Reactivities and Endo and Exo Stereoselectivities of Cyclopropene Diels-Alder Reactions. AB - The factors controlling the reactivities and stereoselectivities in the Diels Alder reactions of substituted cyclopropenes with butadiene were explored with M06-2X density functional theory. Differences in reactivities result from differences in the hyperconjugative aromaticities and antiaromaticities of the cyclopropenes. When the 3-substituent is a sigma-donor, the ground state is destabilized, and the reactivity is enhanced. Acceptors have the opposite effect. Electrostatic, secondary orbital, and steric effects are all found to influence stereoselectivities. PMID- 27977195 TI - Improved Potency of Indole-Based NorA Efflux Pump Inhibitors: From Serendipity toward Rational Design and Development. AB - The NorA efflux pump is a potential drug target for reversal of resistance to selected antibacterial agents, and recently we described indole-based inhibitor candidates. Herein we report a second class of inhibitors derived from them but with significant differences in shape and size. In particular, compounds 13 and 14 are very potent inhibitors in that they demonstrated the lowest IC50 values (2 MUM) ever observed among all indole-based compounds we have evaluated. PMID- 27977196 TI - Direct Observation of a Charge-Transfer State Preceding High-Yield Singlet Fission in Terrylenediimide Thin Films. AB - Singlet exciton fission (SF) in organic chromophore assemblies results in the conversion of one singlet exciton (S1) into two triplet excitons (T1), provided that the overall process is exoergic, i.e., E(S1) > 2E(T1). We report on SF in thin polycrystalline films of two terrylene-3,4:11,12-bis(dicarboximide) (TDI) derivatives 1 and 2, which crystallize into two distinct pi-stacked structures. Femtosecond transient absorption spectroscopy (fsTA) reveals a charge-transfer state preceding a 190% T1 yield in films of 1, where the pi-stacked TDI molecules are rotated by 23 degrees along an axis perpendicular to their pi systems. In contrast, when the TDI molecules are slip-stacked along their N-N axes in films of 2, fsTA shows excimer formation, followed by a 50% T1 yield. PMID- 27977197 TI - Disulfide Bond-Containing Ajoene Analogues As Novel Quorum Sensing Inhibitors of Pseudomonas aeruginosa. AB - Since its discovery 22 years ago, the bacterial cell-to-cell communication system, termed quorum sensing (QS), has shown potential as antipathogenic target. Previous studies reported that ajoene from garlic inhibits QS in opportunistic human pathogen Pseudomonas aeruginosa. In this study, screening of an in-house compound library revealed two sulfur-containing compounds which possess structural resemblance with ajoene and inhibit QS in bioreporter assay. Following a quantitative structure-activity relationship (SAR) study, 25 disulfide bond containing analogues were synthesized and tested for QS inhibition activities. SAR study indicated that the allyl group could be replaced with other substituents, with the most active being benzothiazole derivative (IC50 = 0.56 MUM). The compounds were able to reduce QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin) and successfully inhibit P. aeruginosa infection in murine model of implant-associated infection. Altogether, the QS inhibition activity of the synthesized compounds is encouraging for further exploration of novel analogues in antimicrobial drug development. PMID- 27977198 TI - All The Catalytic Active Sites of MoS2 for Hydrogen Evolution. AB - MoS2 presents a promising low-cost catalyst for the hydrogen evolution reaction (HER), but the understanding about its active sites has remained limited. Here we present an unambiguous study of the catalytic activities of all possible reaction sites of MoS2, including edge sites, sulfur vacancies, and grain boundaries. We demonstrate that, in addition to the well-known catalytically active edge sites, sulfur vacancies provide another major active site for the HER, while the catalytic activity of grain boundaries is much weaker. The intrinsic turnover frequencies (Tafel slopes) of the edge sites, sulfur vacancies, and grain boundaries are estimated to be 7.5 s-1 (65-75 mV/dec), 3.2 s-1 (65-85 mV/dec), and 0.1 s-1 (120-160 mV/dec), respectively. We also demonstrate that the catalytic activity of sulfur vacancies strongly depends on the density of the vacancies and the local crystalline structure in proximity to the vacancies. Unlike edge sites, whose catalytic activity linearly depends on the length, sulfur vacancies show optimal catalytic activities when the vacancy density is in the range of 7-10%, and the number of sulfur vacancies in high crystalline quality MoS2 is higher than that in low crystalline quality MoS2, which may be related with the proximity of different local crystalline structures to the vacancies. PMID- 27977199 TI - Origin of Substituent Effect on Tautomeric Behavior of 1,2,4-Triazole Derivatives: Combined Spectroscopic and Theoretical Study. AB - The reaction of 2-aryl-[1,2,4]triazolo[1,5-c]quinazolines with nucleophilic reagents (hydrazine hydrate, sodium hydroxide, sodium methoxide, hydrochloric acid) under acidic conditions leads to formation of compounds that tend to tautomerize. The products of the transformation are distinguished by the position (ortho-, meta-, para-) of the OCH3 group in the aryl moiety. To assign their structures we used the combined approach: experiment and theoretical modeling. The procedure included calculation of the relative stability for possible tautomers, simulation of UV/vis spectra for the most stable forms, and comparison of the resulting curves with the experimental spectral data taking into account the Boltzmann weighting. Through computations, we showed that the orientation of OCH3 substituent remarkably impacts on the tautomeric behavior of triazoles. In the case of ortho-OCH3 it is controlled by formation of the intramolecular hydrogen bond while for meta- and para- derivatives the degree of conjugation plays the decisive role. In order to balance the accuracy and cost of calculations we evaluated the performance of selected DFT methods and 6-31G*, 6 311++G**, and STO##-3Gel basis sets. The last one is a physically justified basis set previously constructed in our group, and its combination with PBE1PBE approach is shown to be the best choice for UV/vis simulations in the frame of the current research. PMID- 27977200 TI - Platinum as a HOI/I2 Redox Electrode and Its Mixed Potential in the Oscillatory Briggs-Rauscher Reaction. AB - Pt is a common redox electrode used to follow oscillations qualitatively in the Briggs-Rauscher (BR) and the Bray-Liebhafsky (BL) reactions from the time of their discovery. Although the potential oscillations of the electrode reflect the temporal pattern of the reaction properly, there is no general agreement as to how that potential is determined by the components of the reaction mixture. In this article, first we investigate how iodine species in different oxidation states affect the potential of a Pt electrode. It was found that I(+3) and I(+5) species do not affect the potential; only I-, I2, and HOI may have an influence. Although the latter three species are always present simultaneously as participants of the rapid iodine hydrolysis equilibrium, it was found that below and above the so-called hydrolysis limit potential (HLP, where the iodide and HOI concentrations are equal) the actual potential determining redox couple is different. Below the HLP, it is the traditional I2/I- redox couple, but above the HLP, it is the HOI/I2 redox pair that determines the potential of a Pt electrode. That change in the potential control mechanism was proven experimentally by exchange current measurements. In addition, from the potential response of the Pt electrode below and above the HLP, it was possible to calculate the equilibrium constant of the iodine hydrolysis as K degrees H = (4.97 +/- 0.20) * 10-13 M2, in rather good agreement with earlier measurements. We also studied the perturbing effect of H2O2 on the previously mentioned potentials. The concentration of H2O2 was 0.66 M, as in the BR reaction studied here. It was found that below the HLP, the perturbing effect of H2O2 was minimal but above the HLP, H2O2 shifted the mixed potential considerably down toward the HLP. In our experiments with the BR reaction, the potential oscillations of the Pt electrode crossed the HLP, indicating that from time to time the HOI concentration exceeds that of the iodide. We can conclude that although the perturbing effect of H2O2 prevents the calculation of concentrations from Pt potentials above the HLP, [I-]/[I2]1/2 ratios can be calculated as a good approximation from Pt potentials below the HLP. PMID- 27977201 TI - Quantum Halo States in Helium Tetramers. AB - The universality of quantum halo states enables a comparison of systems from different fields of physics, as demonstrated in two- and three-body clusters. In the present work, we studied weakly bound helium tetramers in order to test whether some of these four-body realistic systems qualify as halos. Their ground state binding energies and structural properties were thoroughly estimated using the diffusion Monte Carlo method with pure estimators. Helium tetramer properties proved to be less sensitive on the potential model than previously evaluated trimer properties. We predict the existence of realistic four-body halo 4He23He2, whereas 4He4 and 4He33He are close to the border and thus can be used as prototypes of quasi-halo systems. Our results could be tested by the experimental determination of the tetramers' structural properties using a setup similar to the one developed for the study of helium trimers. PMID- 27977203 TI - Color in Bridge-Substituted Cyanines. AB - Theories of color in cyanine dyes have evolved around the idea of a "resonance" of structures with distinct bonding and charge localization. Understanding the emergence of resonance models from the underlying many-electron problem remains a central issue for these systems. Here, the issue is addressed using a maximum entropy approach to valence-bond representations of state-averaged complete active space self-consistent field models. The approach allows calculation of energies and couplings of high-energy valence-bond structures that mediate superexchange couplings and chemical bonding. A series of valence-bond Hamiltonians for a series of bridge-substituted derivatives of Michler's hydrol blue (a monomethine cyanine) is presented. The Hamiltonians are approximated with a simple linear model parametrized by the Brown-Okamoto sigmap+ parameter of the bridge substituent. A quantitative lower bound on sigmap+, beyond which a resonant cyanine-like ground state will not exist, is presented. The large effective coupling in two-state resonance models emerges from superexchange associated with either covalent bonding or charge-carrier delocalization, with the former contribution significantly the stronger. The results provide ab initio justification for empirical diabatic-state models of methine optical response. They are of general interest for understanding the optoelectronic response in cyanines. PMID- 27977202 TI - Correlation Patterns in Experimental Data Are Affected by Normalization Procedures: Consequences for Data Analysis and Network Inference. AB - Normalization is a fundamental step in data processing to account for the sample to-sample variation observed in biological samples. However, data structure is affected by normalization. In this paper, we show how, and to what extent, the correlation structure is affected by the application of 11 different normalization procedures. We also discuss the consequences for data analysis and interpretation, including principal component analysis, partial least-squares discrimination, and the inference of metabolite-metabolite association networks. PMID- 27977204 TI - Irreversible Adsorption Controls Crystallization in Vapor-Deposited Polymer Thin Films. AB - Matrix-assisted pulsed laser evaporation (MAPLE) provides a gentle means for the quasi-vapor deposition of macromolecules. It offers a unique opportunity for the bottom-up control of polymer crystallization as film growth and crystallization occur simultaneously. Surprisingly, with increasing deposition time, it has been shown that crystallization becomes prohibited despite the availability of polymer via continuous deposition. In this Letter, we investigate the molecular origins of suppressed crystallization in poly(ethylene oxide) films deposited by MAPLE atop silicon substrates. We find that suppressed crystallization results from the formation of an irreversibly adsorbed polymer nanolayer at the substrate that forms during deposition. Substrate temperature is shown to influence the stability of the irreversibly adsorbed nanolayer and, hence, polymer thin film crystallization. Our investigation offers new insight into how temperature and interfacial interactions can serve as a new toolbox to tune polymer film morphology in bottom-up deposition. PMID- 27977205 TI - Role of Adsorption Phenomena in Cubic Tricalcium Aluminate Dissolution. AB - The workability of fresh Portland cement (PC) concrete critically depends on the reaction of the cubic tricalcium aluminate (C3A) phase in Ca- and S-rich pH >12 aqueous solution, yet its rate-controlling mechanism is poorly understood. In this article, the role of adsorption phenomena in C3A dissolution in aqueous Ca-, S-, and polynaphthalene sulfonate (PNS)-containing solutions is analyzed. The zeta potential and pH results are consistent with the isoelectric point of C3A occurring at pH ~12 and do not show an inversion of its electric double layer potential as a function of S or Ca concentration, and PNS adsorbs onto C3A, reducing its zeta potential to negative values at pH >12. The S and Ca K-edge X ray absorption spectroscopy (XAS) data obtained do not indicate the structural incorporation or specific adsorption of SO42- on the partially dissolved C3A solids analyzed. Together with supporting X-ray ptychography and scanning electron microscopy results, a model for C3A dissolution inhibition in hydrated PC systems is proposed whereby the formation of an Al-rich leached layer and the complexation of Ca-S ion pairs onto this leached layer provide the key inhibiting effect(s). This model reconciles the results obtained here with the existing literature, including the inhibiting action of macromolecules such as PNS and polyphosphonic acids upon C3A dissolution. Therefore, this article advances the understanding of the rate-controlling mechanism in hydrated C3A and thus PC systems, which is important to better controlling the workability of fresh PC concrete. PMID- 27977207 TI - Photon-by-Photon Hidden Markov Model Analysis for Microsecond Single-Molecule FRET Kinetics. AB - The function of biological macromolecules involves large-scale conformational dynamics spanning multiple time scales, from microseconds to seconds. Such conformational motions, which may involve whole domains or subunits of a protein, play a key role in allosteric regulation. There is an urgent need for experimental methods to probe the fastest of these motions. Single-molecule fluorescence experiments can in principle be used for observing such dynamics, but there is a lack of analysis methods that can extract the maximum amount of information from the data, down to the microsecond time scale. To address this issue, we introduce H2MM, a maximum likelihood estimation algorithm for photon-by photon analysis of single-molecule fluorescence resonance energy transfer (FRET) experiments. H2MM is based on analytical estimators for model parameters, derived using the Baum-Welch algorithm. An efficient and effective method for the calculation of these estimators is introduced. H2MM is shown to accurately retrieve the reaction times from ~1 s to ~10 MUs and even faster when applied to simulations of freely diffusing molecules. We further apply this algorithm to single-molecule FRET data collected from Holliday junction molecules and show that at low magnesium concentrations their kinetics are as fast as ~104 s-1. The new algorithm is particularly suitable for experiments on freely diffusing individual molecules and is readily incorporated into existing analysis packages. It paves the way for the broad application of single-molecule fluorescence to study ultrafast functional dynamics of biomolecules. PMID- 27977206 TI - CanProVar 2.0: An Updated Database of Human Cancer Proteome Variation. AB - Identification and annotation of the mutations involved in oncogenesis and tumor progression are crucial for both cancer biology and clinical applications. Previously, we developed a public resource CanProVar, a human cancer proteome variation database for storing and querying single amino acid alterations in the human cancers. Since the publication of CanProVar, extensive cancer genomics efforts have revealed the enormous genomic complexity of various types of human cancers. Thus, there is an overwhelming need for comprehensive annotation of the genomic alterations at the protein level and making such knowledge easily accessible. Here, we describe CanProVar 2.0, a significantly expanded version of CanProVar, in which the amount of cancer-related variations and noncancer specific variations was increased by about 10-fold as compared to the previous version. To facilitate the interpretation of the variations, we added to the database functional data on potential impact of the cancer-related variations on 3D protein interaction and on the differential expression of the variant-bearing proteins between cancer and normal samples. The web interface allows for flexible queries based on gene or protein IDs, cancer types, chromosome locations, or pathways. An integrated protein sequence database containing variations that can be directly used for proteomics database searching can be downloaded. PMID- 27977208 TI - Understanding How Charged Nanoparticles Electrostatically Assemble and Distribute in 1-D. AB - The effects of increasing the driving forces for a 1-D assembly of nanoparticles onto a surface are investigated with experimental results and models. Modifications, which take into account not only the particle-particle interactions but also particle-surface interactions, to previously established extended random sequential adsorption simulations are tested and verified. Both data and model are compared against the heterogeneous random sequential adsorption simulations, and finally, a connection between the two models is suggested. The experiments and models show that increasing the particle-surface interaction leads to narrower particle distribution; this narrowing is attributed to the surface interactions compensating against the particle-particle interactions. The long-term advantage of this work is that the assembly of nanoparticles in solution is now understood as controlled not only by particle particle interactions but also by particle-surface interactions. Both particle particle and particle-surface interactions can be used to tune how nanoparticles distribute themselves on a surface. PMID- 27977209 TI - Greatly Suppressed Shuttle Effect for Improved Lithium Sulfur Battery Performance through Short Chain Intermediates. AB - The high solubility of long-chain lithium polysulfides and their infamous shuttle effect in lithium sulfur battery lead to rapid capacity fading along with low Coulombic efficiency. To address above issues, we propose a new strategy to suppress the shuttle effect for greatly enhanced lithium sulfur battery performance mainly through the formation of short-chain intermediates during discharging, which allows significant improvements including high capacity retention of 1022 mAh/g with 87% retention for 450 cycles. Without LiNO3 containing electrolytes, the excellent Coulombic efficiency of ~99.5% for more than 500 cycles is obtained, suggesting the greatly suppressed shuttle effect. In situ UV/vis analysis of electrolyte during cycling reveals that the short-chain Li2S2 and Li2S3 polysulfides are detected as main intermediates, which are theoretically verified by density functional theory (DFT) calculations. Our strategy may open up a new avenue for practical application of lithium sulfur battery. PMID- 27977211 TI - Stereospecific Copper-Catalyzed Domino Ring Opening and sp3 C-H Functionalization of Activated Aziridines with N-Alkylanilines. AB - Copper efficiently catalyzed nucleophilic ring opening, sp3 C-H functionalization, and C-N bond formation in the presence of tert-butyl hydroperoxide to afford functionalized imidazolidines starting from N sulfonylaziridines and N-alkylanilines. The products were obtained in high optical purities (95 -> 99% ee) with excellent functional group tolerance. PMID- 27977210 TI - Colloidal Nanocrystal-Based BaTiO3 Xerogels as Green Bodies: Effect of Drying and Sintering at Low Temperatures on Pore Structure and Microstructures. AB - Although aerogels prepared by the colloidal assembly of nanoparticles are a rapidly emerging class of highly porous and low-density materials, their ambient dried counterparts, namely xerogels, have hardly been explored. Here we report the use of nanoparticle-based BaTiO3 xerogels as green bodies, which provide a versatile route to ceramic materials under the minimization of organic additives with a significant reduction of the calcination temperature compared to that of conventional powder sintering. The structural changes of the xerogels are investigated during ambient drying by carefully analyzing the microstructure at different drying stages. For this purpose, the shrinkage was arrested by a supercritical drying step under full preservation of the intermediate microstructure, giving unprecedented insight into the structural changes during ambient drying of a nanoparticle-based gel. In a first step, the large macropores shrink because of capillary forces, followed by the collapse of residual mesopores until a dense xerogel is obtained. The whole process is accompanied by a volume shrinkage of 97% and a drop in surface area from 300 to 220 m2 g-1. Finally, the xerogels are sintered, causing another shrinkage of up to 8% with a slight increase in the average pore and crystal sizes. At temperatures higher than 700 degrees C, an unexpected phase transition to BaTi2O5 is observed. PMID- 27977213 TI - Enantioselective Oxidative Ring-Opening Reaction of Aziridines with alpha Nitroesters Using Cinchona Alkaloid Amide/Nickel(II) Catalysts. AB - The enantioselective oxidative ring-opening reaction of aziridines with alpha nitroacetates has been developed. Good yields and enantioselectivity were observed for the reaction of various aziridines using a novel cinchona alkaloid amide/NiBr2 catalyst. Both enantiomers of products could be obtained by using pseudoenantiomeric chiral catalysts. This process offers an efficient route for the synthesis of alpha-aminoketones. PMID- 27977212 TI - Distinguishing between Mechanical and Electrostatic Interaction in Single Pass Multi Frequency Electrostatic Force Microscopy Measurements on a Molecular Material. AB - Single-pass electrostatic force microscopy is postulated as one of the most advanced techniques in terms of spatial resolution and fastness in data acquisition for the study of electrostatic phenomena at the nanoscale. However, crosstalk anomalies, in which mechanical interactions combine with tip-sample electrostatic forces, are still a major issue to overcome, specifically in soft and biological samples. In this paper we propose a novel method based on bimodal atomic force microscopy to distinguish mechanical crosstalk from electrostatic images. The method is based in the comparison of bimodal AFM images with electrostatic ones, where pure mechanical interaction can be discerned from a mixture of mechanical and electrostatic interactions. The proposed method is optimized and demonstrated using a supramolecular charge transfer material. Finally, the method is used as a tool to depict different crosstalk levels in tetrathiafulvalene-based (TTF) assemblies, discerning between electrical and mechanical interactions. This kind of observation is important for obtaining accurate descriptions of charge distribution in samples made from organic and molecular layers and materials. PMID- 27977214 TI - Interactions of Colloidal Particles and Droplets with Water-Oil Interfaces Measured by Total Internal Reflection Microscopy. AB - Total internal reflection microscopy (TIRM) is a well-known technique to measure weak forces between colloidal particles suspended in a liquid and a solid surface by using evanescent light scattering. In contrast to typical TIRM experiments, which are carried out at liquid-solid interfaces, here we extend this method to liquid-liquid interfaces. Exemplarily, we demonstrate this concept by investigating the interactions of micrometer-sized polystyrene particles and oil droplets near a flat water-oil interface for different concentrations of added salt and ionic surfactant (SDS). We find that the interaction is well described by the superposition of van der Waals and double layer forces. Interestingly, the interaction potentials are, within the SDS concentration range studied here, rather independent of the surfactant concentration, which suggests a delicate counter play of different interactions at the oil-water interface and provides interesting insights into the mechanisms relevant for the stability of emulsions. PMID- 27977215 TI - 31P and 1H NMR Studies of the Molecular Organization of Lipids in the Parallel Artificial Membrane Permeability Assay. AB - The parallel artificial membrane permeability assay (PAMPA) has emerged as a widely used primary in vitro screen for passive permeability of potential drug candidates. However, the molecular structure of the permeation barrier (consisting of a filter-supported dodecane-egg lecithin mixture) has never been characterized. Here, we investigated the long-range order of phospholipids in the PAMPA barrier by means of 31P static solid-state NMR. Diffusion constants of PAMPA membrane components were derived from liquid state NMR and, in addition, drug distribution between the PAMPA lipid phase and buffer (log DPAMPA at pH 7.4) was systematically investigated. Increasing concentration of n-dodecane to the system egg lecithin-water (lamellar phase, Lalpha) induces formation of inverted hexagonal (Hii) and isotropic phases. At n-dodecane concentrations matching those used in PAMPA (9%, w/v) a purely "isotropic" phase was observed corresponding to lipid aggregates with a diameter in the range 4-7 nm. Drug distribution studies indicate that these reverse micelles facilitate the binding to, and in turn the permeation across, the PAMPA dodecane barrier, in particular for amphiphilic solutes. The proposed model for the molecular architecture and function of the PAMPA barrier provides a fundamental, hitherto missing framework to evaluate the scope but also limitations of PAMPA for the prediction of in vivo membrane permeability. PMID- 27977216 TI - Inhalation of Respirable Crystalline Rifapentine Particles Induces Pulmonary Inflammation. AB - Rifapentine is an anti-tuberculosis (anti-TB) drug with a prolonged half-life, but oral delivery results in low concentrations in the lungs because of its high binding (98%) to plasma proteins. We have shown that inhalation of crystalline rifapentine overcomes the limitations of oral delivery by significantly enhancing and prolonging the drug concentration in the lungs. The delivery of crystalline particles to the lungs may promote inflammation. This in vivo study characterizes the inflammatory response caused by pulmonary deposition of the rifapentine particles. The rifapentine powder was delivered to BALB/c mice by intratracheal insufflation at a dose of 20 mg/kg. The inflammatory response in the lungs and bronchoalveolar lavage (BAL) was examined at 12 h, 24 h, and 7 days post treatment by flow cytometry and histopathology. At 12 and 24 h post-treatment, there was a significant influx of neutrophils into the lungs, and this returned to normal by day 7. A significant recruitment of macrophages occurred in the BAL at 24 h. Consistent with these findings, histopathological analysis demonstrated pulmonary vascular congestion and significant macrophage recruitment at 12 and 24 h post-treatment. In conclusion, the pulmonary delivery of crystalline rifapentine caused a transient neutrophil-associated inflammatory response in the lungs that resolved over 7 days. This observation may limit pulmonary delivery of rifapentine to once a week at a dose of 20 mg/kg or less. The effectiveness of weekly dosing with inhalable rifapentine will be assessed in murine Mycobacterium tuberculosis infection. PMID- 27977217 TI - Identification and Characterization of Trimethylamine-N-oxide Uptake and Efflux Transporters. AB - Trimethylamine-N-oxide (TMAO) is a recently identified predictor of cardiovascular and chronic kidney disease. TMAO is primarily generated through gut-microbiome mediated conversion of dietary choline and carnitine to TMA, which is converted to TMAO by hepatic flavin monooxygenase 3 (FMO3) and subsequently undergoes renal elimination. We investigated the role of uptake and efflux drug transporters in TMAO disposition in vitro and in vivo. After screening a large array of uptake transporters, we show organic cation transporter 2 (OCT2) is the key transporter for TMAO cellular uptake. In Oct1/2 knockout mice, we observed increased plasma TMAO levels with reduced renal retention, suggesting the importance of Oct2 in facilitating the uptake of TMAO into renal tubular cells in vivo. Multiple transporters of the ATP-binding cassette (ABC) family, including ABCG2 (BCRP) and ABCB1 (MDR1), were capable of TMAO efflux. In human subjects, clinical, dietary, and pharmacogenetic covariates were evaluated for contribution to TMAO levels in a cohort of dyslipidemic patients (n = 405). Interestingly, genetic variation in ABCG2, but not other transporters, appeared to play a role in modulating TMAO exposure. PMID- 27977219 TI - Speaking about feelings: Further evidence for multidirectional age differences in anger and sadness. AB - This study investigated age differences in anger and sadness in a sample of 82 younger (Mage = 26, SDage = 4.05) and 80 older (Mage = 70, SDage = 3.95) adults. Participants were instructed to first relive a personal memory that was characterized by either anger or sadness and to subsequently think aloud about this memory. Across different emotional response systems (i.e., subjective feelings, verbal expressions, facial behaviors, physiological arousal), older adults reacted with less anger than did their younger counterparts, whereas age differences in sadness were less pronounced. Together the findings corroborate the idea that age differences in negative emotional reactivity are multidirectional and suggest that a discrete emotions approach may complement dimensional approaches to emotional aging. (PsycINFO Database Record PMID- 27977218 TI - Framing matters: Effects of framing on older adults' exploratory decision-making. AB - We examined framing effects on exploratory decision-making. In Experiment 1 we tested older and younger adults in two decision-making tasks separated by one week, finding that older adults' decision-making performance was preserved when maximizing gains, but it declined when minimizing losses. Computational modeling indicates that younger adults in both conditions, and older adults in gains maximization, utilized a decreasing threshold strategy (which is optimal), but older adults in losses were better fit by a fixed-probability model of exploration. In Experiment 2 we examined within-subject behavior in older and younger adults in the same exploratory decision-making task, but without a time separation between tasks. We replicated the older adult disadvantage in loss minimization from Experiment 1 and found that the older adult deficit was significantly reduced when the loss-minimization task immediately followed the gains-maximization task. We conclude that older adults' performance in exploratory decision-making is hindered when framed as loss minimization, but that this deficit is attenuated when older adults can first develop a strategy in a gains-framed task. (PsycINFO Database Record PMID- 27977220 TI - How distinctive are morningness and eveningness from the Big Five factors of personality? A meta-analytic investigation. AB - This study explores relations between measures of individuals' circadian preferences and the Big Five. To this end, we compared a model of circadian preferences that acknowledges morningness (M) and eveningness (E) as separate dimensions to that of a model that places M and E on a single continuum (M-E). Analyses of 620 correlations from 44 independent samples (N = 16,647) revealed weak to modest relations between both dimensions of circadian preferences and the Big Five personality traits. The strongest observed relation was found between Conscientiousness and M (rho = .37). In the next step, regression analyses revealed that personality traits accounted for between 10.9% and 16.4% of the variance in circadian preferences. Of all the Big Five dimensions, Conscientiousness exhibited the strongest unique relation with M (beta = .32), E (beta = -.26), and M-E (beta = .32). Extraversion and Openness exhibited moderate unique relations with E (beta = .23 and beta = .17, respectively), whereas relations with M (beta = .00 and beta = .04), and M-E (beta = -.05 and beta = .06) were relatively weak. Neuroticism exhibited a modest unique and negative relation with M (beta = -.16), and Agreeableness was largely unrelated to all circadian preference variables. To determine whether these findings translated into anything of applied significance, we explored relations between circadian preference and academic performance. M and E incremented slightly over the Big Five factors in predicting grade-point average. Theoretical and practical implications of these findings are discussed. (PsycINFO Database Record PMID- 27977221 TI - The invisibility cloak illusion: People (incorrectly) believe they observe others more than others observe them. AB - Whether at a coffee shop, in a waiting room, or riding the bus, people frequently observe the other people around them. Yet they often fail to realize how much other people engage in the same behavior, and that they, therefore, also are being observed. Because it is logically impossible that people, on average, are the subjects of observation more than they are objects of it, the belief that one watches others more than one is watched is an illusion. Several studies show that people incorrectly believe that they observe others more than other people observe them. We call this mistaken belief the "invisibility cloak illusion." People believe that they observe others more than do other people and that they are generally observed less than are others (Studies 1-3, 5, 6). The illusion persists both among strangers in the same vicinity (Study 2) and among friends interacting with one another (Study 3), and it cannot be explained away as yet another general better-than-average bias nor is it the result of believing one has more thoughts, in general, than do other people (Studies 2-3). The illusion is supported by a failure to catch others watching oneself (Studies 1b, 4) and it is manifest in the specific contents of people's thoughts about one another (Studies 5 and 6). Finally, rendering a feature of one's appearance salient to oneself fails to interrupt the illusion despite increasing one's belief that others are paying more attention specifically to that salient feature (Study 6). (PsycINFO Database Record PMID- 27977222 TI - Preserving guilt in the "age of psychology": The curious career of O. Hobart Mowrer. AB - O. Hobart Mowrer had one of the most productive and curious careers of any psychologist in the 20th century, despite struggling with severe mental illness and anxiety about his sexuality. Early in his career, he was one of the country's leading experimental psychologists. During the mid-1940s, he became interested in religion and argued that anxiety was caused by repressed guilt that came from real wrongdoing. By the late 1950s, he had abandoned mainstream psychology, arguing that religion had been corrupted by its embrace of psychology and psychiatry. He claimed that sin was responsible for nearly all psychological problems and that ethical living and confession of wrongdoing could prevent mental illness. During his religious period, Mowrer received an astonishing amount of fawning press attention and was embraced by a public desirous of a path to mental health that did not require jettisoning traditional conceptions of sin, guilt, and human nature. This article examines Mowrer's life and career and situates him among other mid-century skeptics of psychology and psychiatry. Other historians have argued that by the 1950s, the conflict between religion and psychiatry/psychology in the United States had largely abated, with both sides adapting to each other. Mowrer's life and the reception of his work demonstrate that this narrative is overly simplistic; widespread conservative and religious distrust of psychology persisted even into the 1960s. (PsycINFO Database Record PMID- 27977223 TI - Randomized controlled trial to dismantle exposure, relaxation, and rescripting therapy (ERRT) for trauma-related nightmares. AB - OBJECTIVE: The aim of this study was to conduct a preliminary dismantling study of exposure, relaxation, and rescripting therapy (ERRT) for nightmares. METHOD: Participants (N = 70) were randomized to 1 of 2 conditions: ERRT with nightmare exposure and rescripting (full protocol; EX) or ERRT without nightmare exposure and rescripting (NEX). Participants completed follow-ups at 1 week, 3 months, and 6 months posttreatment. RESULTS: Both conditions yielded statistically significant improvements with medium to large effect sizes on primary outcomes related to nightmares (i.e., nights with nightmares, nightmares per week, and nightmare severity). Both conditions also yielded statistically significant improvements on secondary outcomes with medium to large effect sizes on fear of sleep, sleep quality, insomnia severity, daytime sleepiness, posttraumatic stress disorder symptom severity, and depression severity. The conditions did not differ at any time point. CONCLUSIONS: Findings indicate that ERRT with and without nightmare exposure and rescripting can significantly alleviate nightmares and related distress. The addition of nightmare exposure and rescription did not contribute incrementally to outcomes in this sample. It is possible that the dose of exposure was not sufficient to result in group differences or that the treatment components included in both conditions (i.e., psychoeducation about trauma, nightmares, and sleep; sleep habit modification; and relaxation training) may adequately treat factors that maintain nightmares for some individuals. Theoretical implications of findings are discussed. The reduction of symptoms of other conditions following this brief intervention provides further evidence for the primary role of nightmares and sleep disturbances posttrauma. (PsycINFO Database Record PMID- 27977224 TI - Scientific thinking in elementary school: Children's social cognition and their epistemological understanding promote experimentation skills. AB - Do social cognition and epistemological understanding promote elementary school children's experimentation skills? To investigate this question, 402 children (ages 8, 9, and 10) in 2nd, 3rd, and 4th grades were assessed for their experimentation skills, social cognition (advanced theory of mind [AToM]), epistemological understanding (understanding the nature of science), and general information-processing skills (inhibition, intelligence, and language abilities) in a whole-class testing procedure. A multiple indicators multiple causes model revealed a significant influence of social cognition (AToM) on epistemological understanding, and a McNemar test suggested that children's development of AToM is an important precursor for the emergence of an advanced, mature epistemological understanding. Children's epistemological understanding, in turn, predicted their experimentation skills. Importantly, this relation was independent of the common influences of general information processing. Significant relations between experimentation skills and inhibition, and between epistemological understanding, intelligence, and language abilities emerged, suggesting that general information processing contributes to the conceptual development that is involved in scientific thinking. The model of scientific thinking that was tested in this study (social cognition and epistemological understanding promote experimentation skills) fitted the data significantly better than 2 alternative models, which assumed nonspecific, equally strong relations between all constructs under investigation. Our results support the conclusion that social cognition plays a foundational role in the emergence of children's epistemological understanding, which in turn is closely related to the development of experimentation skills. Our findings have significant implications for the teaching of scientific thinking in elementary school and they stress the importance of children's epistemological understanding in scientific-thinking processes. (PsycINFO Database Record PMID- 27977225 TI - The role of mental health and specific responsivity in juvenile justice rehabilitation. AB - Understanding the role that mental health issues play in justice-involved youth poses challenges for research, policy, and practice. While mental health problems are generally not risk factors for criminal behavior according to the risk-needs responsivity (RNR) framework of correctional psychology practice, prevalence rates are very high and RNR principles suggest that mental health as a responsivity variable may moderate the success of interventions targeted to criminogenic needs. In this study we investigated the relationships among mental health status, criminogenic needs treatment, and recidivism in a sample of 232 youth referred for court-ordered assessments and followed through their community supervision sentence (probation). Youth with mental health needs were no more likely than youth without these needs to reoffend, regardless of whether those needs were treated. Youth who received mental health treatment also more frequently had their criminogenic needs matched across several domains, suggesting an association between mental health treatment and intermediate treatment targets. However, mental health did not moderate the effect of criminogenic needs treatment: youth who had a greater proportion of criminogenic needs targeted through appropriate services were less likely to reoffend, regardless of mental health status. Findings are consistent with the RNR stance that, within a correctional context in which the primary goal of intervention is preventing recidivism, treatment for mental health needs should be in addition to criminogenic needs treatment, not in replacement of it. They also point to the need for continued research to understand precisely how mental health treatment interacts with intervention targeting criminogenic needs. (PsycINFO Database Record PMID- 27977226 TI - Does early onset of criminal behavior differentiate for whom serious mental illness has a direct or indirect effect on recidivism? AB - The involvement of people with serious mental illness (SMI) with the justice system may be a direct result of their disruptive/unsafe expression of psychiatric symptoms being responded to by law enforcement. SMI may also indirectly contribute to justice involvement, through exposure to environmental and social learning processes that place people with SMI at risk for criminal behavior. This study addresses the question: For whom does SMI directly or indirectly relate to criminal behavior? Mediation and conditional effects testing were used to examine the potential of early onset of criminal behavior to distinguish those groups for whom SMI displays a direct effect or an indirect effect on criminal recidivism. This study utilized a disproportionate random sample of 379 inmates released from New Jersey Department of Corrections; 190 of whom had SMI and 189 of whom did not have SMI. Data were collected from clinical and administrative records. Results indicate that criminal risk mediated the relationship between SMI and recidivism. This indirect effect was conditioned by whether the individual had a juvenile conviction. Specifically, for early start offenders, criminal risk was positively related to recidivism while this relationship was not observed for late start offenders. Juvenile criminal onset did not condition the direct effects of SMI on recidivism. A juvenile history of criminal involvement may signal the presence of heightened criminogenic need among adults with SMI. This simple indicator could function to differentiate for clinicians those adults who are good candidates for exploring further, and targeting for amelioration, criminogenic needs to reduce further criminal involvement. (PsycINFO Database Record PMID- 27977227 TI - Charting the expansion of strategic exploratory behavior during adolescence. AB - Although models of exploratory decision making implicate a suite of strategies that guide the pursuit of information, the developmental emergence of these strategies remains poorly understood. This study takes an interdisciplinary perspective, merging computational decision making and developmental approaches to characterize age-related shifts in exploratory strategy from adolescence to young adulthood. Participants were 149 12-28-year-olds who completed a computational explore-exploit paradigm that manipulated reward value, information value, and decision horizon (i.e., the utility that information holds for future choices). Strategic directed exploration, defined as information seeking selective for long time horizons, emerged during adolescence and maintained its level through early adulthood. This age difference was partially driven by adolescents valuing immediate reward over new information. Strategic random exploration, defined as stochastic choice behavior selective for long time horizons, was invoked at comparable levels over the age range, and predicted individual differences in attitudes toward risk taking in daily life within the adolescent portion of the sample. Collectively, these findings reveal an expansion of the diversity of strategic exploration over development, implicate distinct mechanisms for directed and random exploratory strategies, and suggest novel mechanisms for adolescent-typical shifts in decision making. (PsycINFO Database Record PMID- 27977228 TI - Preventing empathic distress and social stressors at work through nonviolent communication training: A field study with health professionals. AB - One major source of mental health problems in health professionals are personally demanding encounters at work. Thus, a crucial prevention focus is the development of emotional and social skills necessary to effectively manage interactions with clients, colleagues, and supervisors. The aim of our pre-post intervention field study was to evaluate an employee training in nonviolent communication (NVC) within a public health organization. A training group participated in a 3-day NVC training and completed questionnaires before and 3 months after training. Changes in NVC skills, empathic distress, empathy, and social stressors at work were compared with data from a control group without training. Additionally, we observed NVC-trained participants' communication behavior immediately before and after the intervention. We found a promotion of communication skills in training participants as evidenced by increased emotion verbalization behavior and enhanced use of NVC at work. Empathic distress declined, and an increase of social stressors at work was prevented by enhanced emotion verbalization. The findings demonstrate that NVC training can be an effective means to foster emotional and interpersonal skills and to prevent empathic distress and social stressors at work in individuals working in socioemotionally challenging settings. Possible causal mechanisms explaining the training effects are discussed. (PsycINFO Database Record PMID- 27977230 TI - Time-out for conflict monitoring theory: Preventing rhythmic biases eliminates the list-level proportion congruent effect. AB - The proportion congruent (PC) effect is the observation that congruency effects are smaller when most trials are incongruent rather than congruent. The list level PC (LLPC) effect is the finding that a PC effect can transfer from biased inducer items to unbiased diagnostic items. Such effects are generally interpreted as resulting from conflict monitoring and attentional adaptation. An alternative view proposes that PC effects result from simple learning biases unrelated to conflict. The temporal learning account proposes that LLPC effects stem from a different task rhythm in the mostly congruent and mostly incongruent conditions. Two prime-probe experiments provide a critical test of this notion. In both, half of the participants were forced to withhold responding for a short period of time on inducer trials. This equates the task rhythm in the mostly congruent and mostly incongruent lists, while still maintaining differing levels of conflict. Consistent with the temporal learning account, but inconsistent with the conflict monitoring account, the LLPC effect was eliminated when rhythms were equated. (PsycINFO Database Record PMID- 27977229 TI - Environmental adversity and children's early trajectories of problem behavior: The role of harsh parental discipline. AB - This study was performed to examine the role of harsh parental discipline in mediating and moderating the effects of environmental adversity (family socioeconomic disadvantage and adverse life events) on emotional and behavioral problems across early-to-middle childhood. The sample included 16,916 children (48% female; 24% non-White) from the U.K.'s Millennium Cohort Study. We analyzed trajectories of conduct, hyperactivity, and emotional problems, measured at ages 3, 5, and 7 years, using growth curve models. Harsh parental discipline was measured at these ages with parent-reported items on the frequency of using the physical and verbal discipline tactics of smacking, shouting at, and "telling off" the child. As expected, family socioeconomic disadvantage and adverse life events were significantly associated with emotional and behavioral problems. Harsh parental discipline was related to children's trajectories of problems, and it moderated, but did not explain, the effect of environmental risk on these trajectories. High-risk children experiencing harsh parental discipline had the highest levels of conduct problems and hyperactivity across the study period. In addition, harsh parental discipline predicted an increase in emotional symptoms over time in high-risk children, unseen in their counterparts experiencing low levels of harsh parental discipline. However, children in low-risk families were also negatively affected by harsh parental discipline concurrently and over time. In conclusion, harsh parental discipline predicted emotional and behavioral problems in high- and low-risk children and moderated the effects of family poverty and adversity on these problems. (PsycINFO Database Record PMID- 27977231 TI - African American Dementia Caregiver Problem Inventory: Descriptive analysis and initial psychometric evaluation. AB - OBJECTIVES: The primary objectives of the present study were: (a) to develop the African American Dementia Caregiver Problem Inventory (DCPI-A) that assesses the types and frequency of problems reported by African American dementia caregivers seeking cognitive-behavioral intervention, (b) to evaluate the intercoder reliability of the DCPI-A, and (c) to measure the perceived severity of common problems reported by this caregiver population. METHOD: The development of the DCPI-A was divided into 3 major steps: (a) creating an initial sample pool of caregiver problems derived from 2 parent randomized clinical trials, (b) formulating a preliminary version of the DCPI-A, and (c) finalizing the development of the DCPI-A that includes 20 problem categories with explicit coding rules, definitions, and illustrative examples. RESULTS: The most commonly reported caregiver problems fell into 5 major categories: (a) communication problems with care recipients, family members, and/or significant others, (b) problems with socialization, recreation, and personal enhancement time; (c) problems with physical health and health maintenance, (d) problems in managing care recipients' activities of daily living; and (e) problems with care recipients' difficult behaviors. Intercoder reliability was moderately high for both percent agreement and Cronbach's kappa. A similar positive pattern of results was obtained for the analysis of coder drift. CONCLUSIONS: The descriptive analysis of the types and frequency of problems of African American dementia caregivers coupled with the outcomes of the psychometric evaluation bode well for the adoption of the DCPI-A in clinical settings. (PsycINFO Database Record PMID- 27977233 TI - Awards for Distinguished Scientific Contributions. AB - The Awards for Distinguished Scientific Contributions are presented to persons who, in the opinion of the Committee on Scientific Awards, have made distinguished theoretical or empirical contributions to basic research in psychology. The 2016 recipients of the APA Scientific Contribution Awards were recognized by the 2015 Board of Scientific Affairs and selected by the 2015 Committee on Scientific Awards. Members of the committee were Scott M. Monroe, PhD (Chair); Susan Goldin-Meadow, PhD; James Grau, PhD; Hazel R. Markus, PhD; Karen A. Matthews, PhD; and Linda Smith, PhD. (PsycINFO Database Record PMID- 27977234 TI - Award for Distinguished Scientific Contributions: Dedre Gentner. AB - The American Psychological Association (APA) Awards for Distinguished Scientific Contributions are presented to persons who, in the opinion of the Committee on Scientific Awards, have made distinguished theoretical or empirical contributions to basic research in psychology. One of the 2016 award winners is Dedre Gentner, who received this award for her "achievements in research and theory in cognitive psychology and cognitive development, especially for developing the structure mapping theory of analogy and similarity." Her award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977235 TI - Language as cognitive tool kit: How language supports relational thought. AB - The extreme version of the Whorfian hypothesis-that the language we learn determines how we view the world-has been soundly rejected by linguists and psychologists alike. However, more moderate versions of the idea that language may influence thought have garnered recent empirical support. This article defends 1 such view. I propose that language serves as a cognitive tool kit that allows us to represent and reason in ways that would be impossible without such a symbol system. I present evidence that learning and using relational language can foster relational reasoning-a core capacity of higher order cognition. In essence, language makes one smarter. (PsycINFO Database Record PMID- 27977232 TI - Interpersonal callousness and co-occurring anxiety: Developmental validity of an adolescent taxonomy. AB - Growing evidence suggests heterogeneity within interpersonal-callous (IC) youth based on co-occurring anxiety. The developmental validity of this proposed taxonomy remains unclear however, as most previous research is cross-sectional and/or limited to adolescence. We aimed to identify low-anxiety (IC/ANX-) and high-anxiety (IC/ANX+) IC variants, and compare these groups on (a) early risk exposures, (b) psychiatric symptoms from midchildhood to early adolescence, and (c) school-based functioning. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective epidemiological birth cohort, model-based cluster analysis was performed on children with complete age-13 IC and anxiety scores (n = 6,791). Analysis of variance was used to compare resulting clusters on (a) prenatal and postnatal family adversity and maternal psychopathology, and harsh parenting; (b) developmental differences in attention-deficit/hyperactivity disorder (ADHD), conduct disorder (CD), oppositional defiant disorder (ODD), emotional difficulties, and low pro-social behavior at 7, 10, and 13 years; and (c) teacher-reported discipline problems, along with standardized test performance. We identified a 4-cluster solution: "typical," "low," "IC/ANX-", and "IC/ANX+." IC/ANX+ youth showed the highest prenatal and postnatal levels of family adversity and maternal psychopathology, highest levels of ADHD, CD, ODD, and emotional difficulties, greatest discipline problems, and lowest national test scores (all p < .001). IC/ANX+ also showed a distinct pattern of increasing psychopathology from age 7 to 13 years. Adolescent IC subtypes were successfully validated in ALSPAC across multiple raters using prenatal and early postnatal risk, repeated measures of psychopathology, and school-based outcomes. Greater prenatal environmental risk among IC/ANX+ youth suggests an important target for early intervention. (PsycINFO Database Record PMID- 27977236 TI - Award for Distinguished Scientific Contributions: Terrie E. Moffitt and Avshalom Caspi. AB - The APA Awards for Distinguished Scientific Contributions are presented to persons who, in the opinion of the Committee on Scientific Awards, have made distinguished theoretical or empirical contributions to basic research in psychology. Two of the 2016 award winners are Terrie E. Moffitt and Avshalom Caspi, who received this shared award for "innovative research and theory on mental health and human development," in which they have demonstrated "how early life experiences shape health disparities and how genetic factors shape and are shaped by environmental factors." Moffitt's and Caspi's shared award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977237 TI - Award for Distinguished Scientific Contributions: Terry E. Robinson. AB - The APA Awards for Distinguished Scientific Contributions are presented to persons who, in the opinion of the Committee on Scientific Awards, have made distinguished theoretical or empirical contributions to basic research in psychology. One of the 2016 award winners is Terry E. Robinson, who received this award for "outstanding contributions to understanding the psychological and neural mechanisms underlying stimulant drug responses." Robinson's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977238 TI - Award for Distinguished Scientific Contributions: Kent C. Berridge. AB - The APA Awards for Distinguished Scientific Contributions are presented to persons who, in the opinion of the Committee on Scientific Awards, have made distinguished theoretical or empirical contributions to basic research in psychology. One of the 2016 award winners is Kent C. Berridge, who received this award for "outstanding contributions to the understanding of the psychological and neural basis of motivation." Berridge's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977240 TI - Award for Distinguished Scientific Applications of Psychology. AB - The Award for Distinguished Scientific Applications of Psychology is presented to a person who, in the opinion of the Committee on Scientific Awards, has made distinguished theoretical or empirical advances leading to the understanding or amelioration of important practical problems. The 2016 recipients of the APA Scientific Contribution Awards were recognized by the 2015 Board of Scientific Affairs and selected by the 2015 Committee on Scientific Awards. Members of the committee were Scott M. Monroe, PhD (Chair); Susan Goldin-Meadow, PhD; James Grau, PhD; Hazel R. Markus, PhD; Karen A. Matthews, PhD; and Linda Smith, PhD. (PsycINFO Database Record PMID- 27977241 TI - Award for Distinguished Contributions to the Applications of Psychology: James W. Pennebaker. AB - The APA Award for Distinguished Scientific Applications of Psychology is presented to a person who, in the opinion of the Committee on Scientific Awards, has made distinguished theoretical or empirical advances leading to the understanding or amelioration of important practical problems. The 2016 recipient is James W. Pennebaker, whose research on the therapeutic benefits of expressive writing and the computer-based analysis of everyday language have affected most theoretical and applied areas of psychology. His award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977242 TI - Awards for Distinguished Scientific Early Career Contributions to Psychology. AB - The Early Career Awards, given for the first time in 1974, recognize the large number of psychologists who demonstrate excellence early in their careers. Recipients of this award may not have held a doctoral degree for more than nine years. For purposes of this award, psychology has been divided into 10 areas: animal learning and behavior, comparative; developmental; health; cognition/human learning; psychopathology; behavioral and cognitive neuroscience; perception/motor performance; social; applied research; and individual differences. Five areas are considered each year, with areas rotated in two-year cycles. The areas considered in 2016 were animal learning and behavior, comparative; developmental; health; cognition/human learning; and psychopathology. Each year, panels are selected for the areas under consideration, and these panels recommend nominees to the Committee on Scientific Awards. The 2016 recipients of the APA Scientific Contribution Awards were recognized by the 2015 Board of Scientific Affairs and selected by the 2015 Committee on Scientific Awards. Members of the committee were Scott M. Monroe, PhD (Chair); Susan Goldin-Meadow, PhD; James Grau, PhD; Hazel R. Markus, PhD; Karen A. Matthews, PhD; and Linda Smith, PhD. (PsycINFO Database Record PMID- 27977239 TI - Liking, wanting, and the incentive-sensitization theory of addiction. AB - Rewards are both "liked" and "wanted," and those 2 words seem almost interchangeable. However, the brain circuitry that mediates the psychological process of "wanting" a particular reward is dissociable from circuitry that mediates the degree to which it is "liked." Incentive salience or "wanting," a form of motivation, is generated by large and robust neural systems that include mesolimbic dopamine. By comparison, "liking," or the actual pleasurable impact of reward consumption, is mediated by smaller and fragile neural systems, and is not dependent on dopamine. The incentive-sensitization theory posits the essence of drug addiction to be excessive amplification specifically of psychological "wanting," especially triggered by cues, without necessarily an amplification of "liking." This is because of long-lasting changes in dopamine-related motivation systems of susceptible individuals, called "neural sensitization." A quarter century after its proposal, evidence has continued to grow in support the incentive-sensitization theory. Further, its scope is now expanding to include diverse behavioral addictions and other psychopathologies. (PsycINFO Database Record PMID- 27977243 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Adriana Galvan. AB - APA's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers and have held a doctoral degree for no more than 9 years. One of the 2016 award winners is Adriana Galvan, whose "scientific discoveries have delineated neurobiological determinants of adolescent behavior that promote the transition from dependence on caregivers to autonomy." Galvan's award citation, biography, and bibliography are presented here. (PsycINFO Database Record PMID- 27977244 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Greg Hajcak. AB - APA's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers. One of the 2016 award winners is Greg Hajcak, whose "groundbreaking contributions applying psychophysiological methods to the affective neuroscience of anxiety, depression, psychosis, and related traits" and whose work "has identified promising risk biomarkers and intervention targets and has illuminated the development of, and mechanisms associated with, these disorders." Hajcak's award citation, biography, and bibliography are presented here. (PsycINFO Database Record PMID- 27977245 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Nathan M. Holmes. AB - The American Psychological Association's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers. One of the 2016 award winners is Nathan M. Holmes, whose work "has helped to elucidate the role of error correction mechanisms in extinction, how extinguished and counter-conditioned fear responses are regulated by context and time, and how motivational states (such as fear) alter the content and neural substrates of associative formation." Holmes's award citation, biography, and selected bibliography are presented here. (PsycINFO Database Record PMID- 27977246 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Tania Lombrozo. AB - APA's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers. One of the 2016 award winners is Tania Lombrozo, whose "groundbreaking studies have shown just how, and why, explanations are so important to people." Lombrozo's award citation, biography, and bibliography are presented here. (PsycINFO Database Record PMID- 27977247 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Katie A. McLaughlin. AB - APA's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers. One of the 2016 award winners is Katie A. McLaughlin, who has "has articulated important distinctions among the effects of early neglect and abuse and has uncovered specific processes that are disrupted by early adverse environmental experiences." McLaughlin's award citation, biography, and bibliography are presented here. (PsycINFO Database Record PMID- 27977248 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Fabian A. Soto. AB - APA's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers. One of the 2016 award winners is Fabian A. Soto, whose work "has shed fresh light on a broad range of fundamental psychological issues, including basic associative conditioning, causal judgment, categorization, visual object recognition, and face processing." Soto's award citation, biography, and selected bibliography are presented here. (PsycINFO Database Record PMID- 27977249 TI - Award for Distinguished Scientific Early Career Contributions to Psychology: Kate Sweeny. AB - APA's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize psychologists who have demonstrated excellence early in their careers. One of the 2016 award winners is Kate Sweeny, whose formulation of "crisis decision theory, the bad news response model, the uncertainty navigation model," and other theories and models demonstrate her capacity to provide "order and sense to unfocused and confusing research domains." Sweeny's award citation, biography, and bibliography are presented here. (PsycINFO Database Record PMID- 27977250 TI - Awards for Distinguished Contributions to Psychology in the Public Interest. AB - The Awards for Distinguished Contributions to Psychology in the Public Interest recognize persons who have advanced psychology as a science and/or profession by a single extraordinary achievement or a lifetime of outstanding contributions in the public interest. Two awards are given: one to a senior psychologist and a second to a psychologist who has made a significant contribution to the public interest in the early stages of his or her career. The 2016 recipients of the APA Awards for Psychology in the Public Interest were selected by the 2015 Committee on Psychology in the Public Interest Awards. Members of the committee were M. Dolores Cimini, PhD (Chair); Toni Antonucci, PhD; Allen M. Omoto, PhD; and Michael E. Lamb, PhD. (PsycINFO Database Record PMID- 27977251 TI - Difficulties translating research on forensic interview practices to practitioners: Finding water, leading horses, but can we get them to drink? AB - Over the last 3 decades, researchers have elucidated the cognitive and motivational conditions that affect the capacity and willingness of young alleged victims to describe their experiences to forensic interviewers. Applied researchers have also studied the contents and features of training programs designed to help interviewers take advantage of the research on developmentally appropriate interviewing. The latter studies have highlighted a knowledge transfer problem-scientists understand best-practice techniques well, many interviewers believe that they both understand and employ those practices, but widespread training has had a limited impact on the actual quality of interviews conducted in the field. There is now clear evidence that improvements in interviewing practice occur reliably only when training courses involve multiple modules, distributed over time, with repeated opportunities for interviewers to consolidate learning and to obtain feedback on the quality of the interviews they do conduct. Barriers to the implementation of such training are discussed. (PsycINFO Database Record PMID- 27977252 TI - Award for Distinguished Senior Career Contributions to Psychology in the Public Interest: Faye Z. Belgrave. AB - The APA Awards for Distinguished Contributions to Psychology in the Public Interest recognize persons who have advanced psychology as a science and/or profession by a single extraordinary achievement or a lifetime of outstanding contributions in the public interest. The 2016 recipient of the Award for Distinguished Senior Career Contributions to Psychology in the Public Interest is Faye Z. Belgrave. She was selected for her "extensive service contributions to her profession, her university, and the community," evidenced in her "focused research agenda that informs and shapes her teaching, her mentoring, and the community programs, workshops, and trainings she has designed." Dr. Belgrave's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977253 TI - Reducing disparities and achieving equity in African American women's health. AB - The colloquial phrase "Black Don't Crack" refers to perceptions of African American women retaining youthful features over time and seemingly defying the aging process. This conjecture appears to only be skin deep, as across almost every health indicator, African American women fare worse than women in other racial/ethnic groups. African American women experience excess morbidity in obesity, diabetes, and adverse birth outcomes, and are more likely than women of other ethnic groups to die from breast and cervical cancer, cardiovascular disease, and HIV/AIDS. This article provides an overview of social, biological, psychological, and cultural factors that contribute to African American women's health. Attention is directed to cultural factors that are both protective and risky for African American women's health. There is a need to garner a better understanding of the complex nature of health disparities experienced by African American women in order to move the field forward in making progress toward achieving health equity for this population. This article addresses this need and offers recommendations for translating science in this area into meaningful population level impact. (PsycINFO Database Record PMID- 27977254 TI - Award for Distinguished Senior Career Contributions to Psychology in the Public Interest: Jose Toro-Alfonso. AB - The APA Awards for Distinguished Contributions to Psychology in the Public Interest recognize persons who have advanced psychology as a science and/or profession by a single extraordinary achievement or a lifetime of outstanding contributions in the public interest. The 2016 corecipient of the Award for Distinguished Senior Career Contributions to Psychology in the Public Interest is Jose Toro-Alfonso, who was posthumously given this award for his commitment to "issues of inequity, diversity, and to the alleviation of human suffering particularly among Latino/Latina and LGBTQ communities." He "pioneered HIV/AIDS related services for youth, women, gay, and transgender populations," and Toro Alfonso's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977255 TI - Award for Distinguished Early Career Contributions to Psychology in the Public Interest: Mark L. Hatzenbuehler. AB - The APA Awards for Distinguished Contributions to Psychology in the Public Interest recognize persons who have advanced psychology as a science and/or profession by a single extraordinary achievement or a lifetime of outstanding contributions in the public interest. The 2016 corecipient of the Award for Distinguished Early Career Contributions to Psychology in the Public Interest is Mark L. Hatzenbuehler. The Award recognizes Dr. Hatzenbuehler's advancements in understanding stigma, particularly "the stigma experience of being gay or bisexual at the psychological level in terms of rumination, secret keeping, and the like; at the social level in terms of stigma-imbued social interactions; and at the structural level in terms of policies such as the presence or absence of anti-bullying interventions in schools or gay marriage prohibitions at the level of states." Hatzenbuehler's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977257 TI - Award for Distinguished Early Career Contributions to Psychology in the Public Interest: Anneliese A. Singh. AB - The APA Awards for Distinguished Contributions to Psychology in the Public Interest recognize persons who have advanced psychology as a science and/or profession by a single extraordinary achievement or a lifetime of outstanding contributions in the public interest. The 2016 corecipient of the Award for Distinguished Early Career Contributions to Psychology in the Public Interest is Anneliese A. Singh. Dr. Singh's scholarship "has promoted major advancements in LBGT studies and intersectionality of multiple identities." Singh's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977256 TI - Structural stigma: Research evidence and implications for psychological science. AB - Psychological research has provided essential insights into how stigma operates to disadvantage those who are targeted by it. At the same time, stigma research has been criticized for being too focused on the perceptions of stigmatized individuals and on microlevel interactions, rather than attending to structural forms of stigma. This article describes the relatively new field of research on structural stigma, which is defined as societal-level conditions, cultural norms, and institutional policies that constrain the opportunities, resources, and well being of the stigmatized. I review emerging evidence that structural stigma related to mental illness and sexual orientation (a) exerts direct and synergistic effects on stigma processes that have long been the focus of psychological inquiry (e.g., concealment, rejection sensitivity), (b) serves as a contextual moderator of the efficacy of psychological interventions, and (c) contributes to numerous adverse health outcomes for members of stigmatized groups ranging from dysregulated physiological stress responses to premature mortality indicating that structural stigma represents an underrecognized mechanism producing health inequalities. Each of these pieces of evidence suggests that structural stigma is relevant to psychology and therefore deserves the attention of psychological scientists interested in understanding and ultimately reducing the negative effects of stigma. (PsycINFO Database Record PMID- 27977259 TI - Award for Distinguished Contributions to Research in Public Policy. AB - The Award for Distinguished Contributions to Research in Public Policy is given to a psychologist who has made a distinguished empirical and/or theoretical contribution to research in public policy, either through a single extraordinary achievement or a lifetime of work. This contribution may consist of such factors as research leading others to view specific national policies differently; research demonstrating the importance of the application of psychological methods and theory to public policy; or research clarifying the ways in which scientific knowledge of human behavior informs public policy. The 2016 recipients of the APA Awards for Psychology in the Public Interest were selected by the 2015 Committee on Psychology in the Public Interest Awards. Members of the committee were M. Dolores Cimini, PhD (Chair); Toni Antonucci, PhD; Allen M. Omoto, PhD; and Michael E. Lamb, PhD. (PsycINFO Database Record PMID- 27977258 TI - Moving from affirmation to liberation in psychological practice with transgender and gender nonconforming clients. AB - While affirmative approaches with transgender and gender nonconforming (TGNC) clients are gaining momentum within psychological practice (American Counseling Association, 2010; American Psychological Association, 2015), there is a simultaneous and pressing need to move beyond TGNC-affirmative to TGNC-liberatory approaches to more fully address how societal gender binaries influence both psychologist and client. Psychologists may use the lens of liberation psychology (Martin-Baro, 1996) to transform the ways they work with TGNC clients. Using this perspective, psychologists can reflect on their own gender journey and experiences, identify how cisgender privilege influences counseling and psychological practice, and advocate for TGNC people to be better served in the settings in which they work. Psychologists are then able to engage in social change on behalf of, and in collaboration with, TGNC people in ways that simultaneously liberate psychologists from their own gender oppression experiences. (PsycINFO Database Record PMID- 27977261 TI - Leveraging school-based research to inform bullying prevention and policy. AB - School-based bullying and other forms of school violence have been the topic of over 40 years of research in the U.S. and internationally. Within the last 2 decades, research has increasingly informed bullying prevention, policy, and legislative efforts. The purpose of this article is to highlight several critical research areas on bullying and other forms of school violence that have shaped prevention efforts and policy over the last 2 decades. As the recipient of the 2016 Award for Distinguished Contributions to Research in Public Policy, the discussion here will focus largely on research findings from The Espelage Lab and collaborators, but these studies and findings will be situated in the larger literature. Topics covered include conceptualization of bullying from a social ecological framework, developmental considerations of bullying and associated forms of aggression, identification of populations at heightened risk for bullying, and efficacy of bullying prevention programs. Recommendations are provided for the next generation of scholars, practitioners, and policymakers focused on bullying prevention. (PsycINFO Database Record PMID- 27977260 TI - Award for Distinguished Contributions to Research in Public Policy: Dorothy L. Espelage. AB - APA's Award for Distinguished Contributions to Research in Public Policy is given to a psychologist who has made a distinguished empirical and/or theoretical contribution to research in public policy, either through a single extraordinary achievement or a lifetime of work. Dorothy L. Espelage is the 2016 recipient of this award for her exceptional work on bullying, gender, and school violence. "She is an outstanding rigorous researcher who uses the most sophisticated methods in assessing the effects of interventions designed to improve the social and emotional lives of children both within and outside of school." Espelage's citation, biography, and selected bibliography are presented here. (PsycINFO Database Record PMID- 27977262 TI - Award for Distinguished Contributions to Education and Training in Psychology. AB - This award is given by the Board of Educational Affairs in recognition of the efforts of psychologists who have made distinguished contributions to education and training, who have produced imaginative innovations, or who have been involved in the developmental phases of programs in education and training in psychology. These contributions might include important research on education and training; the development of effective materials for instruction; the establishment of workshops, conferences, or networks of communication for education and training; achievement and leadership in administration that facilitates education and training; or activity in professional organizations that promote excellence. The Award for Distinguished Contributions to Education and Training in psychology recognizes a specific contribution to education and training. The Career designation is added to the award at the discretion of the Education and Training Awards Committee to recognize continuous significant contributions made over a lifelong career in psychology. This year the Education and Training Awards Committee selected a psychologist for the Career designation. The 2016 recipients of the APA Education and Training Contributions Awards were selected by the 2015 Education and Training Awards Committee appointed by the Board of Educational Affairs (BEA). Members of the 2015 Education and Training Awards Committee were Sharon L. Berry, PhD (Chair); Arthur C. Graesser, PhD; and Thomas R. Kratochwill, PhD; Erica Wise, PhD (Chair-Elect); Ron Rozensky, PhD; and Jane Halonen, PhD. (PsycINFO Database Record PMID- 27977263 TI - Award for Distinguished Career Contributions to Education and Training in Psychology: Roger P. Greenberg. AB - The Award for Distinguished Career Contributions to Education and Training in Psychology is given in recognition of the efforts of psychologists who have made distinguished contributions to education and training, who have produced imaginative innovations, or who have been involved in the developmental phases of programs in education and training in psychology. The Career designation is added to the award at the discretion of the Education and Training Awards Committee to recognize continuous significant contributions made over a lifelong career in psychology. The 2016 recipient of this award is Roger P. Greenberg, whose "scholarship has generated important evidence on psychotherapy process and outcome, personality theories, psychosomatic conditions, and the comparative effectiveness of psychological and biological treatments for mental disorders." Greenberg's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977265 TI - Award for Distinguished Contributions of Applications of Psychology to Education and Training. AB - The Board of Educational Affairs is pleased to bestow the Award for Distinguished Contributions of Applications of Psychology to Education and Training. This award acknowledges psychologists who contribute to new teaching methods or solutions to learning problems through the use of research findings or evidence-based practices. Particular emphasis is placed on the use of psychological knowledge to improve learning in educational settings, including prekindergarten to Grade 12, or in communities. The 2016 recipients of the APA Education and Training Contributions Awards were selected by the 2015 Education and Training Awards Committee appointed by the Board of Educational Affairs (BEA). Members of the 2015 Education and Training Awards Committee were Sharon L. Berry, PhD (Chair); Arthur C. Graesser, PhD; and Thomas R. Kratochwill, PhD; Erica Wise, PhD (Chair Elect); Ron Rozensky, PhD; and Jane Halonen, PhD. (PsycINFO Database Record PMID- 27977264 TI - The rebirth of psychosocial importance in a drug-filled world. AB - In the United States, the public is heavily lobbied to accept medications as the main answer for dealing with mental maladies like depression. However, examination of the empirical evidence reveals that even when drugs are the primary treatments, findings of benefit are often more dependent on psychosocial, interpersonal factors than commonly believed. This article highlights the reemerging worth of psychotherapeutic relationships in quelling emotional discomfort. It also touches on the roles of business and research bias in overselling the idea of unique merits and specificity of gains derived purely from psychopharmacological solutions. (PsycINFO Database Record PMID- 27977266 TI - Award for Distinguished Contributions of Applications of Psychology to Education and Training: Cindy Lee Juntunen. AB - The Award for Distinguished Contributions of Applications of Psychology to Education and Training acknowledges psychologists who contribute to new teaching methods or solutions to learning problems through the use of research findings or evidence-based practices. The 2016 recipient is Cindy Lee Juntunen. She is recognized for "her steadfast commitment to the training of future counseling psychologists, for her leadership in key national organizations focused on education and training, and for her contributions to training competencies and practice guidelines within counseling psychology." Juntunen's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977267 TI - Psi Chi/APA Edwin B. Newman Graduate Research Award. AB - The Edwin B. Newman Graduate Research Award is sponsored jointly by Psi Chi, the national honor society in psychology, and the APA. The award is presented annually to the psychology graduate student who submits the best research paper that was published or presented at a national, regional, or state psychological association conference during the past calendar year. The Edwin B. Newman Graduate Research Award is given jointly by Psi Chi and APA. Members of the 2016 Edwin B. Newman Award Committee were Shawn Carlton, PhD, Psi Chi representative; Christina Frederick-Recascino, PhD; John Norcross, PhD, APA representative; Karenna Malavanti, PhD, Psi Chi representative; Steven Kohn, PhD, Psi Chi representative; Warren Fass, PhD, Psi Chi representative; Chris Lovelace, PhD, Psi Chi representative; and Cathy Epkins, PhD, APA representative. (PsycINFO Database Record PMID- 27977268 TI - APA/Psi Chi Edwin B. Newman Graduate Research Award: Meghan H. Puglia. AB - The Edwin B. Newman Graduate Research Award is given jointly by Psi Chi and APA. The award was established to recognize young researchers at the beginning of their professional lives and to commemorate both the 50th anniversary of Psi Chi and the 100th anniversary of psychology as a science (dating from the founding of Wundt's laboratory). The 2016 recipient is Meghan H. Puglia, who was chosen for "an outstanding foundational research paper that establishes a relationship between a functional epigenetic modification to the oxytocin receptor gene (OXTR) and neural response during social perception." Puglia's award citation, biography, and bibliography are presented here. (PsycINFO Database Record PMID- 27977269 TI - Award for Distinguished Professional Contributions to Independent Practice. AB - This award is intended to recognize outstanding independent practitioners in psychology. Nominations are considered for psychologists working in any area of clinical specialization, health services provision, or consulting, and services provided to any patient population or professional clientele in an independent setting. Services provided to diverse client groups or patient populations, including but not limited to children/adolescents/adults/older adults, urban/rural/frontier populations, minority populations, and persons with serious mental illness are considered. Contributions are judged distinguished by virtue of peer recognition, advancement of the public's recognition of psychology as a profession, relevant professional association honors, or other meritorious accomplishments denoting excellence as a practitioner, including advancement of the profession. The 2016 recipients of the APA Professional Contributions Awards were selected by the 2015 Board of Professional Affairs (BPA). Members of the 2015 BPA were Patricia Arredondo, EdD; Helen L. Coons, PhD, ABPP; Vickie M. Mays, PhD, MSPH; Linda A. Reddy, PhD; Lois O. Condie, PhD; Antonette M. Zeiss, PhD; Timothy A. Cavell, PhD; Robert T. Kinscherff, PhD, JD; and Jared L. Skillings, PhD, ABPP. (PsycINFO Database Record PMID- 27977270 TI - Award for Distinguished Professional Contributions to Independent Practice: Sam J. Tsemberis. AB - The Award for Distinguished Professional Contributions to Independent Practice is intended to recognize outstanding independent practitioners in psychology. The award is given to a psychologist working in an area of clinical specialization, health services provision, or consulting, and services provided to any patient population or professional clientele in an independent setting. The 2016 recipient is Sam J. Tsemberis, who "has applied the best of psychological practice and science to address the complex social, health, and economic factors involved in chronic homelessness among persons diagnosed with mental illness and addictions." Tsemberis's award citation, biography, and bibliography are presented here. (PsycINFO Database Record PMID- 27977271 TI - Award for Distinguished Professional Contributions to Institutional Practice. AB - This award is intended to recognize outstanding practitioners in psychology. Nominations are considered for psychologists working in a wide variety of institutional practice settings (e.g., schools, military, state hospital, Department of Veterans Affairs). Services provided to diverse client groups or patient populations, including but not limited to children/adolescents/ adults/older adults, urban/rural/frontier populations, minority populations, and persons with serious mental illness, are considered. Contributions are judged distinguished by virtue of peer recognition, advancement of the public's recognition of psychology as a profession, relevant professional association honors, or other meritorious accomplishments denoting excellence as a practitioner, including improvement of institutional service delivery systems or development of psychologically informed public policy. The 2016 recipients of the APA Professional Contributions Awards were selected by the 2015 Board of Professional Affairs (BPA). Members of the 2015 BPA were Patricia Arredondo, EdD; Helen L. Coons, PhD, ABPP; Vickie M. Mays, PhD, MSPH; Linda A. Reddy, PhD; Lois O. Condie, PhD; Antonette M. Zeiss, PhD; Timothy A. Cavell, PhD; Robert T. Kinscherff, PhD, JD; and Jared L. Skillings, PhD, ABPP. (PsycINFO Database Record PMID- 27977272 TI - Award for Distinguished Professional Contributions to Institutional Practice: John E. Carr. AB - The APA Awards for Distinguished Professional Contributions to Institutional Practice are intended to recognize outstanding practitioners in psychology. The 2016 award winner is John E. Carr, whose "clinical, research, teaching, administrative, and consultative work has been transformative; he has brought about substantial changes in academic medical centers for his colleagues and generations of medical school psychologists." Carr's award citation, biography, and bibliography are presented here. (PsycINFO Database Record PMID- 27977273 TI - APA/APAGS Award for Distinguished Graduate Student in Professional Psychology. AB - The APA/APAGS Award for Distinguished Graduate Student in Professional Psychology is awarded on an annual basis by the APA Board of Professional Affairs (BPA) and the American Psychological Association of Graduate Students (APAGS) to a graduate student who has demonstrated outstanding practice and application of psychology. A qualified candidate must demonstrate exemplary performance in working with an underserved population in an applied setting or have developed an innovative method for delivering health services to an underserved population. The 2016 recipient of the APA/APAGS Award for Distinguished Graduate Student in Professional Psychology was selected by the 2015 Board of Professional Affairs (BPA) and the 2015 APAGS Scholarship and Awards Selection Committee. Members of the 2015 BPA were Patricia Arredondo, EdD; Helen L. Coons, PhD, ABPP; Vickie Mays, PhD, MSPH; Linda A. Reddy, PhD; Lois O. Condi, PhD; Antonette M. Zeiss, PhD; Timothy A. Cavell, PhD; Robert T. Kinscherff, PhD, JD; and Jared L. Skillings, PhD, ABPP. Members of the 2015 APAGS Scholarship and Awards Selection Committee were Emily Voelkel, PhD; Blaire Schembari; and Yolanda Perkins-Volk. (PsycINFO Database Record PMID- 27977274 TI - APA/APAGS Award for Distinguished Graduate Student in Professional Psychology: Luz Maria Garcini. AB - The APA/APAGS Award for Distinguished Graduate Student in Professional Psychology is awarded on an annual basis by the APA Board of Professional Affairs (BPA) and the American Psychological Association of Graduate Students (APAGS) to a graduate student who has demonstrated outstanding practice and application of psychology. The 2016 award winners is Luz Maria Garcini, whose commitment to the health and mental health of those recently immigrated has led to research and service that "have greatly benefited the lives of undocumented individuals in the border area of southern California." Garcini's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977275 TI - Award for Distinguished Contributions to the International Advancement of Psychology. AB - This award is given to individuals who have made sustained and enduring contributions to international cooperation and the advancement of knowledge in psychology. The 2016 recipient of the APA Award for Distinguished Contributions to the International Advancement of Psychology was selected by the 2015 Committee on International Relations in Psychology (CIRP). The members of the 2015 CIRP were Rehman Abdulrehman, PhD (Chair); Gonzalo Bacigalupe, EdD; Silvia S. Canetto, PhD; Amanda Clinton, PhD; Melissa L. Morgan Consoli, PhD; Chryse G. Hatzichristou, PhD; Arpana G. Inman, PhD; Lori Foster Thompson, PhD; and Danny Wedding, PhD. Dr. Abdulrehman, Dr. Morgan Consoli, Dr. Thompson, and Dr. Wedding were members of the subcommittee for the 2016 award. (PsycINFO Database Record PMID- 27977276 TI - 2016 Award for Distinguished Contributions to the International Advancement of Psychology: Hector Fernandez-Alvarez. AB - The Award for Distinguished Contributions to the International Advancement of Psychology is given to individuals who have made sustained and enduring contributions to international cooperation and the advancement of knowledge in psychology. The 2016 award winner is Hector Fernandez-Alvarez, who "has woven a sophisticated network of international cooperation in psychotherapy research, training, and service provision throughout Latin America, Europe, and the United States." He was selected for his outstanding, innovative contributions to psychotherapy integration, clinical supervision, and the personal style of the therapist. Dr. Fernandez-Alvarez's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977278 TI - International Humanitarian Award. AB - The International Humanitarian Award recognizes extraordinary humanitarian services and activism by psychologists, including professional and volunteer work conducted primarily in the field with underserved populations. Award recipients are psychologists who, by their extraordinary service at a difficult time, improve the lives and contribute to the well-being of people in a large or small geographic area anywhere in the world. The 2016 recipient of the APA International Humanitarian Award was selected by the 2015 Committee on International Relations in Psychology (CIRP). The members of the 2015 CIRP were Rehman Abdulrehman, PhD (Chair); Gonzalo Bacigalupe, EdD; Silvia S. Canetto, PhD; Amanda Clinton, PhD; Melissa L. Morgan Consoli, PhD; Chryse G. Hatzichristou, PhD; Arpana G. Inman, PhD; Lori Foster Thompson, PhD; and Danny Wedding, PhD. Dr. Abdulrehman, Dr. Morgan Consoli, Dr. Thompson, and Dr. Wedding were members of the subcommittee for the 2016 award. (PsycINFO Database Record PMID- 27977277 TI - Integration in psychotherapy: Reasons and challenges. AB - Although integration has been formally influencing the field of psychotherapy since the 1930s, its impact gained significant momentum during the 1980s. Practical, theoretical, and scientific reasons help to explain the growing influence of integration in psychotherapy. The field of psychotherapy is characterized by many challenges which integration may change into meaningful opportunities. Nonetheless, many obstacles remain when seeking to advance integration. To appreciate the strength of integration in psychotherapy we describe an integrative, comprehensive approach to service delivery, research, and training. We then discuss the role of integration in the future of psychotherapy. (PsycINFO Database Record PMID- 27977279 TI - International Humanitarian Award: Alan Poling. AB - The International Humanitarian Award recognizes extraordinary humanitarian services and activism by psychologists, including professional and volunteer work conducted primarily in the field with underserved populations. The 2016 award winner is Alan Poling, who "has used his expertise in behavioral psychology to make unique and significant contributions to public health in developing nations." He received this award for his work in concert with a Belgian nongovernmental organization, in which he has tested and refined the ability of African pouched rats to detect land mines as well as tuberculosis in Africa and Asia. Poling's award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record PMID- 27977280 TI - Using pouched rats to help people: Notes from the field. AB - For several years, my students and I have assisted colleagues at Anti Persoonsmijnen Ontmijnende Product Ontwikkeling, a Belgian Nongovernmental Organization headquartered in Tanzania, in conducting research designed to evaluate and improve the performance of scent-detecting pouched rats used for humanitarian purposes. Findings indicate that the rats are accurate landmine detection animals and more sensitive than microscopy, the standard diagnostic in resource-poor areas, in detecting tuberculosis. When used for second-line screening of sputum samples initially evaluated by microscopy, the rats increase new-case detections of tuberculosis by about 40%. Studies have shown that several variables affect their performance, and knowledge of those variables has been used to improve the rats' performance when they are used operationally. Research has also demonstrated that the rats can detect Salmonella, cigarettes, and people trapped under rubble, but they are not presently used operationally for those purposes. This work illustrates that people who understand behavior and the variables that affect it can act to improve the world in ways outside the boundaries of conventional psychology. (PsycINFO Database Record PMID- 27977281 TI - What children think about their rights and their well-being: A cross-national comparison. AB - Recent years have brought a growing social and public commitment to the promotion of children's rights and children's well-being around the world, and these have become important goals of all those striving to improve children's lives. In spite of the intimate ideological connection between the concepts of children's rights and children's well-being, they have evolved separately both theoretically and empirically. In the current article, we present a study exploring the empirical association between these 2 concepts based on data from the International Survey on Children's Well-Being. This unique survey explores children's own perspectives on their well-being (subjective well-being), their perceptions and knowledge of their rights, and their reports on their right to participation. It includes data from more than 54,000 children aged 8-12 from 16 countries around the world. Our results showed clear cross-national differences between children's knowledge and perceptions of their rights and their reports on participation. Also, children's participation in different contexts in their lives showed an association with their subjective well-being; a weaker association was found between children's knowledge and perceptions of their rights. These results indicate that children's right to participation and, to some degree, their knowledge and thinking about their rights is an indicator of their well-being. (PsycINFO Database Record PMID- 27977282 TI - Individual and neighborhood stressors, sleep problems, and symptoms of anxiety and depression among Latino youth. AB - Limited research has examined the relation between exposure to stressors and internalizing symptoms among Latino adolescents, including factors that account for this relation. This study examined whether sleep played a role in the relation between exposure to neighborhood- (i.e., neighborhood disadvantage) and individual-level (i.e., negative life events) stressors and symptoms of anxiety and depression among a sample of 144 low-income, Latino adolescents (54% males, mean age = 16.25, SD = 1.46) attending a charter high school in a large, Midwestern city. The bias corrected bootstrap method was used to evaluate indirect effects. Significant findings indicated an indirect effect via sleep problems in the link between negative life events and anxiety. Alternative models were also explored. Results suggest that sleep problems are important to consider for interventions among Latino youth, particularly those exposed to neighborhood and individual stressors, as this may also have implications for reducing internalizing symptoms among this population. (PsycINFO Database Record PMID- 27977283 TI - Examining the effects of emotional and cognitive desensitization to community violence exposure in male adolescents of color. AB - The current study examined pathways in a model of desensitization, the Pathologic Adaptation Model, in adolescent males of color. Specifically, the current study examined depressive symptoms and deviant beliefs as mediators of the association between community violence exposure and subsequent violent behavior. The current study included 250 African-American (67%) and Latino (33%) male adolescents (T1 mean age = 15.32) from the Chicago Youth Development Study. Consistent with the Pathologic Adaptation Model, results demonstrated that depressive symptoms mediated the association between the quadratic violence exposure term in middle adolescence and violent behaviors in late adolescence, but the direction of the mediation effect was dependent upon the levels of violence exposure in middle adolescence. However, deviant beliefs were not found to be a significant mediator. Emotional desensitization effects may increase the likelihood of violence perpetration in adolescent males exposed to community violence, and the implications for future research and intervention efforts are discussed. (PsycINFO Database Record PMID- 27977285 TI - General practitioners' beliefs about people with schizophrenia and whether they should be subject to discriminatory treatment when in medical hospital: The mediating role of dangerousness perception. AB - This study explored the relationships between General Practitioners' (GPs) beliefs about People With Schizophrenia (PWS) and GPs' recommendations regarding restrictions for such people when in medical (nonpsychiatric) hospital, and whether these relationships were mediated by dangerousness perception. There were 322 randomly selected Italian GPs who completed a questionnaire measuring beliefs about PWS. Structural Equation Model (SEM) was used to explore the effects of these beliefs on the GPs' views about the need for restrictive rules in hospital. Thirty-1 percent of GPs firmly believed that, in medical wards, PWS should be supervised and 18% that they should be separated from other patients. SEM revealed that belief in such differential treatment was positively related to a belief that PWS need medication for the rest of their lives, and to perceptions of others' need for social distance, and of dangerousness. Dangerousness was, in turn, positively related to the belief that PWS need medication for their lives, and to a perception of the need for social distance, but negatively related to perceived capacity to report health problems. Analyses of indirect effects showed that the relationships of belief in discriminatory treatment with belief in medication for life and with perceived social distance were mediated by perceived dangerousness. GPs' attitudes about PWS appear closely with their beliefs on discriminatory behaviors in hospital, and the mediating role of dangerousness perceptions. Providing GPs with education about schizophrenia treatments and prognosis, and countering stereotypes about dangerousness, could be helpful to reduce GPs' beliefs in the need for discriminatory treatment of PWS. (PsycINFO Database Record PMID- 27977284 TI - Adaptation and implementation of a trauma-focused cognitive behavioral intervention for girls in child welfare. AB - This study describes the process of adapting and implementing Girls Aspiring toward Independence (GAIN), a trauma-focused, group-based therapy adapted from Cognitive Behavioral Intervention for Trauma in Schools (CBITS) for girls in child welfare. Descriptive data were examined on 3 outcomes: posttraumatic stress disorder (PTSD), depression, and social problem-solving skills among adolescent girls in the child welfare system. Qualitative and quantitative methods were utilized to inform the adaptation of the CBITS intervention, evaluate feasibility, treatment fidelity, and acceptability, and to test the effects of the intervention. Girls ages 12 to 18 (N = 27) were randomly assigned to the experimental and usual care conditions. Participants' symptoms of PTSD and depression and social problem-solving skills were evaluated at pre, post- (3 months), and follow-up (6 months) assessments. Adaptations for GAIN were primarily related to program structure. Data indicated that the program was receptive to girls in child welfare and that it was feasible to recruit, randomize, assess outcomes, and implement with adequate fidelity. Retention was more successful among younger girls. Descriptive initial data showed greater reductions in the percentage of girls with PTSD and depression, and modest increases in social problem-solving skills in the experimental versus usual care condition. Despite the growth of knowledge in dissemination and implementation research, the application of trauma-focused empirically supported treatment to child welfare populations lags behind. A large-scale RCT is needed to determine if GAIN is effective in reducing mental health problems and social problem solving in the child welfare population. (PsycINFO Database Record PMID- 27977286 TI - Present, protective, and promotive: Mentors' roles in the lives of young adults in residential care. AB - Mentoring relationships are considered among the most significant relationships with nonparental figures and a protective factor against a wide range of negative outcomes. This exploratory study explored mentoring relationships in the lives of 140 care leavers, and the way those relationships influenced their life course. Findings showed that most of the mentors were known to the young adults from their former care placement for 3 years and above. Thematic analysis revealed 2 main "types" of mentor: (1) a present, accessible and supportive mentor, who is mainly characterized as a parental figure and a role model, a life coach who is also a confidant; (2) a motivating and catalyzing mentor, who is characterized as promoting adaptive coping with life stressors, and leading the young adults to set and achieve their goals and change their behavioral and mental status for the better. The discussion addresses the contribution of mentoring relationships to the young adults' resilience in reference to social support and attachment theories. It discusses the importance of promoting a "mentoring policy" within the residential care settings, to enable youth to continue their relationships with their mentors during their challenging transition to emerging adulthood. (PsycINFO Database Record PMID- 27977287 TI - Strengths and weaknesses of the Young Black Men, Masculinities, and Mental Health (YBMen) Facebook project. AB - The Young Black Men, Masculinities, and Mental Health (YBMen) project is a Facebook-based intervention that provides mental health education and social support to young Black men. The YBMen project was created to better understand and address the pressures and needs of young Black men, particularly with regard to issues related to their conceptualization of masculinity and mental health. Black men from a 2-year liberal arts college in the Midwest (United States) enrolled in the YBMen pilot project. The purpose of this study is to report what participants in the YBMen pilot project liked and disliked about the intervention, along with their suggestions for improvement. Qualitative results from the 8 Black men who actively participated in the YBMen Facebook intervention and completed the postintervention interview are reported. A systematic analysis identified 9 subthemes that described participants' reactions to different components and characteristics of the Facebook intervention. Results indicated that opportunities for relationship building and connectivity, coupled with engaging popular culture references used in the intervention encouraged young Black men to actively participate in the YBMen Facebook intervention. The YBMen project has potential to improve the health and well-being of young Black men by providing nontraditional resources that are easily accessible, culturally sensitive, and gender-specific. Implications of the YBMen project as an effective Internet-based program that promotes mental health and increases social support among young Black men are discussed. (PsycINFO Database Record PMID- 27977288 TI - Our continuing exploration of medically unexplained symptoms. AB - In this issue, the reader will find three articles examining different but converging perspectives on medically unexplained symptoms (MUS). In the first article, Gates, Petterson, Wingrove, Miller, and Klink (2016) examined 110,000 office visits to primary care providers between 2002 and 2010. In the second article, Clarke (2016), an internist and gastroenterologist, presents a model for diagnosing and treating MUS. The person most referenced in the first two articles and author of the landmark study-Kroenke (2016) writes the third article, an invited commentary. Kroenke eloquently reviews the major issues confronting health care clinicians dealing with MUS. We hope that readers of the three articles on MUS in this issue will reflect on their own practice, share these articles and their impressions with colleagues, and consider ways to improve the service and consultation designs in their practice settings. Those who teach behavioral health clinicians and physicians will surely be reinforced or reinvigorated to focus on ways to help patients and colleagues. (PsycINFO Database Record PMID- 27977289 TI - Somatic symptoms deserve our attention. AB - This commentary focuses on two articles in this issue which provide important insights regarding the diagnosis and management of medically unexplained symptoms (MUS). Up to half of all outpatient visits are prompted by a physical/somatic complaint of which at least a third are MUS. Analyzing data from the National Ambulatory Care Medical Survey, Gates, Petterson, Wingrove, Miller, and Klink (2016) confirmed the common finding that depression and anxiety in patients presenting with somatic symptoms are underrecognized. Only 1-4% of such patients received a diagnosis of depression or anxiety, a rate that should have been at least four- to sixfold greater. optimize the care of chronic somatic symptoms. In the second article, Clarke draws upon clinical experience spanning several decades and thousands of patients to delineates a pragmatic approach to managing MUS. His six-step strategy augmented by illustrative cases makes more tangible the process of caring for patients with chronic symptoms. (PsycINFO Database Record PMID- 27977291 TI - Talk to her. AB - The author presents a poem that was inspired by the compassionate care provided by a physician to a comatose person in the ICU, whose family member felt helpless in finding a way to care for her. The doctor's humanity revealed a dimension of care that was healing to all those present. (PsycINFO Database Record PMID- 27977290 TI - Implementation of an acceptance- and mindfulness-based group for depression and anxiety in primary care: Initial outcomes. AB - INTRODUCTION: Depression and anxiety disorders are highly prevalent among primary care patients. Group visits provide a way of delivering interventions to multiple patients at the same time. Group visits for depression and anxiety present an opportunity to expand the reach of behavioral health services for primary care patients. The goal of the current study was to evaluate the implementation of an acceptance and mindfulness-based group for primary care patients with depression and anxiety. METHODS: Adult family medicine patients with Patient Health Questionnaire-9 (PHQ-9) and/or Generalized Anxiety Disorder Scale-7 (GAD-7) scores > 5 were eligible for the group. The group was held biweekly in the family medicine practice with rolling enrollment. The PHQ-9 and GAD-7 were administered at every visit, and changes in depression and anxiety symptoms were analyzed using multilevel modeling. We evaluated feasibility, acceptability/satisfaction, penetration, and sustainability. RESULTS: Over the course of 19 months, 50 patients were referred to the group, and 29 enrolled. The median number of visits attended was four among those who attended more than one group visit. Results revealed that depression and anxiety symptoms decreased significantly over the first four visits attended (d = -.26 and -.19, respectively). Patients who attended more than one group reported high satisfaction. The group was sustainable after the research funding ended; however, penetration was low. DISCUSSION: A rolling enrollment group for patients with depression and anxiety that utilized mindfulness- and acceptance-based treatment principles is feasible to implement in a primary care setting but is not without challenges. Recommendations for ways to enhance implementation and future research are provided. (PsycINFO Database Record PMID- 27977292 TI - Better together: Collaborative family healthcare association and the promise of team-based care. AB - In this presidential column is a personal introduction of the new president of the Collaborative Family Healthcare Association (CFHA), Christine Runyan. As president she hopes to continue to support the existing organizational initiatives. CFHA remains a preeminent organization of experts to advocate for meaningful, patient-centered quality metrics and to educate, train, mentor, consult, and realize the vision we have been asserting for 25 years. (PsycINFO Database Record PMID- 27977293 TI - Development of a Sleep Telementorship Program for Rural Department of Veterans Affairs Primary Care Providers: Sleep Veterans Affairs Extension for Community Healthcare Outcomes. AB - RATIONALE: Primary care providers (PCPs) frequently encounter sleep complaints, especially in regions with limited specialty care access. OBJECTIVES: The U.S. Department of Veterans Affairs Extension for Community Healthcare Outcomes (VA ECHO) program (based on Project ECHO) has successfully provided rural PCP education in subspecialty areas, including hepatitis C. We describe the feasibility of an ECHO program for sleep medicine. METHODS: ECHO creates a virtual learning community through video-teleconferencing, combining didactics with individualized clinical case review. We invited multidisciplinary providers to attend up to 10 stand-alone, 1-hour sessions. Invitees completed a needs assessment, which guided curriculum development. After program completion, we examined participant characteristics and self-reported changes in practice and comfort with managing sleep complaints. We surveyed participation barriers among invitees with low/no attendance. MEASUREMENTS AND MAIN RESULTS: Of the 39 program participants, 38% worked in rural healthcare. Participants included nurse practitioners (26%), registered nurses (21%), and physicians (15%). Seventeen (44%) completed the summative program evaluation. Respondents anticipated practice change from the program, especially in patient education about sleep disorders (93% of respondents). Respondents reported improved comfort managing sleep complaints, especially sleep-disordered breathing, insomnia, and sleep in post-traumatic stress disorder (80% of respondents each). A follow-up survey of program invitees who attended zero to two sessions reported scheduling conflicts (62%) and lack of protected time (52%) as major participation barriers. CONCLUSIONS: Participants in a pilot sleep medicine VA-ECHO program report practice change and increased comfort managing common sleep complaints. Future work is needed to identify objective measures of return on investment and address participation barriers. PMID- 27977295 TI - Research progress in tofu processing: From raw materials to processing conditions. AB - As a traditional soybean product with good quality and a healthy food with many functional components, tofu is increasingly consumed in people's daily life. Traditional tofu processing consists of numerous steps, including the soaking and grinding of soybean seeds, heating of the soybean slurry, filtering, and addition of coagulants, and others. The properties of soybean seeds, processing scale, soaking and heating conditions, type and concentration of coagulant, and other factors collectively impact the processing steps and the final tofu quality. The generation of whole soybean tofu with more nutritive value comparing with traditional tofu has been successfully reported by several studies. As one of the most important functional component, isoflavones and their presence in tofu are also influenced by the above-mentioned factors, which influence the nutritive value of tofu. Research investigating the influence of tofu processing conditions on the quality and isoflavone profiles of tofu are the subject of this review. Issues that should be further studied to investigate the influence of processing conditions on the quality and nutritive value of tofu are also introduced. PMID- 27977294 TI - House Dust Endotoxin Levels Are Associated with Adult Asthma in a U.S. Farming Population. AB - RATIONALE: Endotoxin initiates a proinflammatory response from the innate immune system. Studies in children suggest that endotoxin exposure from house dust may be an important risk factor for asthma, but few studies have been conducted in adult populations. OBJECTIVES: To investigate the association of house dust endotoxin levels with asthma and related phenotypes (wheeze, atopy, and pulmonary function) in a large U.S. farming population. METHODS: Dust was collected from the bedrooms (n = 2,485) of participants enrolled in a case-control study of current asthma (927 cases) nested within the Agricultural Health Study. Dust endotoxin was measured by Limulus amebocyte lysate assay. Outcomes were measured by questionnaire, spirometry, and blood draw. We evaluated associations using linear and logistic regression. MEASUREMENTS AND MAIN RESULTS: Endotoxin was significantly associated with current asthma (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.14-1.47), and this relationship was modified by early life farm exposure (born on a farm: OR, 1.18; 95% CI, 1.02-1.37; not born on a farm: OR, 1.67; 95% CI, 1.26-2.20; Interaction P = 0.05). Significant positive associations were seen with both atopic and nonatopic asthma. Endotoxin was not related to either atopy or wheeze. Higher endotoxin was related to lower FEV1/FVC in asthma cases only (Interaction P = 0.01). For asthma, there was suggestive evidence of a gene-by-environment interaction for the CD14 variant rs2569190 (Interaction P = 0.16) but not for the TLR4 variants rs4986790 and rs4986791. CONCLUSIONS: House dust endotoxin was associated with current atopic and nonatopic asthma in a U.S. farming population. The degree of the association with asthma depended on early-life farm exposures. Furthermore, endotoxin was associated with lower pulmonary function in patients with asthma. PMID- 27977297 TI - Integrated system of phytodepuration and water reclamation: A comparative evaluation of four municipal wastewater treatment plants. AB - In dry regions, water resources have become increasingly limited, and the use of alternative sources is considered one of the main strategies in sustainable water management. A highly viable alternative to commonly used water resources is treated municipal wastewater, which could strongly benefit from advanced and low cost techniques for depuration, such as the integrated system of phytodepuration (ISP). The current manuscript investigates four Italian case studies with different sizes and characteristics. The raw wastewaters and final effluents were sampled on a monthly basis over a period of up to five years, allowing the quantification of the ISP performances. The results obtained show that the investigated plants are characterized by an average efficiency value of approximately 83% for chemical oxygen demand removal, 84% for biochemical oxygen demand, 89% for total nitrogen, 91% for total phosphorus, and 85% for total suspended solids. Moreover, for three of the case studies, the ISP final effluent is suitable for irrigation, and in the fourth case study, the final effluent can be released in surface water. PMID- 27977296 TI - Phosphoinositide 3-Kinase in Asthma: Novel Roles and Therapeutic Approaches. AB - Asthma manifests as airway hyperresponsiveness and inflammation, including coughing, wheezing, and shortness of breath. Immune cells and airway structural cells orchestrate asthma pathophysiology, leading to mucus secretion, airway narrowing, and obstruction. Phosphoinositide 3-kinase, a lipid kinase, plays a crucial role in many of the cellular and molecular mechanisms driving asthma pathophysiology and represents an attractive therapeutic target. Here, we summarize the diverse roles of phosphoinositide 3-kinase in the pathogenesis of asthma and discuss novel therapeutic approaches to treatment. PMID- 27977298 TI - The Chemical Chaperone Phenylbutyrate Rescues MCT8 Mutations Associated With Milder Phenotypes in Patients With Allan-Herndon-Dudley Syndrome. AB - Mutations in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) prevent appropriate entry of thyroid hormones into brain cells during development and cause severe mental retardation in affected patients. The current treatment options are thyromimetic compounds that enter the brain independently of MCT8. Some MCT8-deficient patients (e.g., those carrying MCT8delF501) will not be as severely affected as most others. We have shown that the MCT8delF501 protein has decreased protein stability but important residual function once it reaches the plasma membrane. We were able to rescue protein expression and the function of MCT8delF501 in a Madin-Darby canine kidney cell model by application of the chemical chaperone sodium phenylbutyrate (NaPB), a drug that has been used to treat patients with cystic fibrosis and urea cycle defects for extended periods of time. In the present study, we have extended our previous study and report on the NaPB-dependent rescue of a series of other pathogenic MCT8 mutants associated with milder patient phenotypes. We show that NaPB can functionally rescue the expression and activities of Ser194Phe, Ser290Phe, Leu434Trp, Arg445Cys, Leu492Pro, and Leu568Pro mutations in MCT8 in a dose-dependent manner. The soy isoflavone genistein, a dietary supplement, which was effective in MCT8delF501, was also effective in increasing the expression and transport of these MCT8 mutants; however, the effect size differed among mutants. Kinetic analyses revealed that the Michaelis constants of the mutants toward the primary substrate 3,3',5-triiodothyronine were not much different from the wild-type value, suggesting that these mutants are not impaired in their interaction with substrate but rather destabilized by the mutation and degraded. PMID- 27977299 TI - Feed can be a source of Campylobacter jejuni infection in broilers. AB - 1. The aim was to determine the importance of a contaminated diet as a possible cause of Campylobacter jejuni infection in broilers. 2. This study evaluated the viability of C. jejuni in both starter and finisher diets and the interference from other mesophilic bacteria in this viability. 3. Starter and finisher samples of broiler diet were deliberately contaminated with 3 or 5 log CFU.g-1 of C. jejuni (NCTC 11351) and then maintained at two different storage temperatures (25 degrees C or 37 degrees C) for 3 or 5 d. 4. C. jejuni survived during this period and, when inoculated at 103 CFU.g-1, multiplied with greater proliferation at a storage temperature of 37 degrees C. There was no relationship between the amount of mesophilic bacteria and C. jejuni viability. 5. This study highlights the importance of the diet in the epidemiology of C. jejuni in broilers. PMID- 27977300 TI - Preventive Neuromuscular Training for Young Female Athletes: Comparison of Coach and Athlete Compliance Rates. AB - CONTEXT: Fewer athletic injuries and lower anterior cruciate ligament injury incidence rates were noted in studies of neuromuscular-training (NMT) interventions that had high compliance rates. However, several groups have demonstrated that preventive NMT interventions were limited by low compliance rates. OBJECTIVE: To descriptively analyze coach and athlete compliance with preventive NMT and compare the compliance between study arms as well as among school levels and sports. DESIGN: Randomized, controlled clinical trial. SETTING: Middle and high school athletic programs. Participants or Other Participants: A total of 52 teams, comprising 547 female athletes, were randomly assigned to the experimental or control group and followed for 1 athletic season. INTERVENTION(S): The experimental group (n = 30 teams [301 athletes]: 12 basketball teams [125 athletes], 6 soccer teams [74 athletes], and 12 volleyball teams [102 athletes]) participated in an NMT program aimed at reducing traumatic knee injuries through a trunk-stabilization and hip-strengthening program. The control group (n = 22 teams [246 athletes]: 11 basketball teams [116 athletes], 5 soccer teams [68 athletes], and 6 volleyball teams [62 athletes]) performed a resistive rubber-band running program. MAIN OUTCOME MEASURE(S): Compliance with the assigned intervention protocols (3 times per week during the preseason [mean = 3.4 weeks] and 2 times per week in-season [mean = 11.9 weeks] of coaches [coach compliance] and athletes [athlete compliance]) was measured descriptively. Using an independent t test, we compared coach and athlete compliance between the study arms. A 2-way analysis of variance was calculated to compare differences between coach and athlete compliance by school level (middle and high schools) and sport (basketball, soccer, and volleyball). RESULTS: The protocols were completed at a mean rate of 1.3 +/- 1.1 times per week during the preseason and 1.2 +/- 0.5 times per week in-season. A total of 88.4% of athletes completed 2/3 of the intervention sessions. Coach compliance was greater in the experimental group than in the control group (P = .014). Coach compliance did not differ by sport but was greater at the high school than the middle school (P = .001) level. Athlete compliance did not differ by study arm, sport, or school level. CONCLUSIONS: Athletes received instruction in about 50% of each protocol. Nearly 90% of athletes performed more than 2/3 of the assigned NMT interventions. The assigned intervention was performed more often in the experimental arm compared with the control arm. Coaches at the high school level complied with the given protocol more than middle school coaches did. Athletes complied well with the protocol, but coaches did not, especially at the middle school level. PMID- 27977302 TI - Organizational Infrastructure in the Collegiate Athletic Training Setting, Part III: Benefits of and Barriers in the Medical and Academic Models. AB - CONTEXT: Academic and medical models are emerging as alternatives to the athletics model, which is the more predominant model in the collegiate athletic training setting. Little is known about athletic trainers' (ATs') perceptions of these models. OBJECTIVE: To investigate the perceived benefits of and barriers in the medical and academic models. DESIGN: Qualitative study. SETTING: National Collegiate Athletic Association Divisions I, II, and III. PATIENTS OR OTHER PARTICIPANTS: A total of 16 full-time ATs (10 men, 6 women; age = 32 +/- 6 years, experience = 10 +/- 6 years) working in the medical (n = 8) or academic (n = 8) models. DATA COLLECTION AND ANALYSIS: We conducted semistructured telephone interviews and evaluated the qualitative data using a general inductive approach. Multiple-analyst triangulation and peer review were completed to satisfy data credibility. RESULTS: In the medical model, role congruency and work-life balance emerged as benefits, whereas role conflict, specifically intersender conflict with coaches, was a barrier. In the academic model, role congruency emerged as a benefit, and barriers were role strain and work-life conflict. Subscales of role strain included role conflict and role ambiguity for new employees. Role conflict stemmed from intersender conflict with coaches and athletics administrative personnel and interrole conflict with fulfilling multiple overlapping roles (academic, clinical, administrative). CONCLUSIONS: The infrastructure in which ATs provide medical care needs to be evaluated. We found that the medical model can support better alignment for both patient care and the wellbeing of ATs. Whereas the academic model has perceived benefits, role incongruence exists, mostly because of the role complexity associated with balancing teaching, patient-care, and administrative duties. PMID- 27977301 TI - Organizational Infrastructure in the Collegiate Athletic Training Setting, Part II: Benefits of and Barriers in the Athletics Model. AB - CONTEXT: The athletics model, in which athletic training clinical programs are part of the athletics department, is the predominant model in the collegiate athletic training setting. Little is known about athletic trainers' (ATs') perceptions of this model, particularly as it relates to organizational hierarchy. OBJECTIVE: To explore the perceived benefits of and barriers in the athletics model. DESIGN: Qualitative study. SETTING: National Collegiate Athletic Association Divisions I and III. PATIENTS OR OTHER PARTICIPANTS: Eight full-time ATs (5 men, 3 women; age = 41 +/- 13 years, time employed at the current institution = 14 +/- 14 years, experience as a certified AT = 18 +/- 13 years) working in the collegiate setting using the athletics model. DATA COLLECTION AND ANALYSIS: We conducted semistructured interviews via telephone or in person and used a general inductive approach to analyze the qualitative data. Multiple-analyst triangulation and peer review established trustworthiness. RESULTS: Two benefits and 3 barriers emerged from the data. Role identity emerged as a benefit that occurred with role clarity, validation, and acceptance of the collegiate AT personality. Role congruence emerged as a benefit of the athletics model that occurred with 2 lower-order themes: relationship building and physician alignment and support. Role strain, staffing concerns, and work life conflict emerged as barriers in the athletics model. Role strain occurred with 2 primary lower-order themes: role incongruity and role conflict. CONCLUSIONS: The athletics model is the most common infrastructure for employing ATs in collegiate athletics. Participants expressed positive experiences via character identity, support, trust relationships, and longevity. However, common barriers remain. To reduce role strain, misaligning values, and work-life conflict, ATs working in the athletics model are encouraged to evaluate their relationships with coaches and their supervisor and consider team physician alignment. Moreover, measures to increase quality athletic training staff from a care rather than a coverage standpoint should be considered. PMID- 27977303 TI - Tyrosyl-tRNA synthetase inhibitors: a patent review. AB - INTRODUCTION: Bacterial infection has been a consistent and relentless threat to human health because of emerging resistance to existing antibiotics. Therefore, much of the research has been focused on the design of new potent antibacterial agents. Tyrosyl-tRNA synthetase (TyrRS), as a member of aminoacyl-tRNA synthetase family, could recognize the information including the coincident tRNA molecules and the amino acids' structures, which are essential in translating the coded information into protein structures in nucleic acids. Therefore, the discovery and application of tyrosyl-tRNA synthetase inhibitors might be a potential strategy to control these diseases in humans. Areas covered: This review covers 1999 to 2016 wherein several new analogues were claimed as TyrRS inhibitors based on their chemical structures. Xiao, Z.P. et al patented two Chinese patents related to TyrRS inhibitors which are included. Expert opinion: Due to the pivotal role in translation, tyrosyl-tRNA synthetase has been recognized as a promising target for a new generation of antibiotics with selectivity and specificity. However, while some of the TyrRS inhibitors showed encouraging results, there is an urgent need to develop novel TyrRS inhibitors with higher activity and selectivity. Based on the published SAR results, selective tyrosyl tRNA synthetase inhibitors could be designed and developed as the next generation of antibacterial agents. PMID- 27977304 TI - Pharmacodynamics of combined estrogen-progestin oral contraceptives: 1. Effects on metabolism. AB - INTRODUCTION: The risk-benefit profile of any pharmacologic agent must be evaluated against risks connected with the events to be avoided. This is especially true in the case of hormonal contraception, not intended to combat a disease. Over the six decades during which their use has progressively expanded, the risk-benefit profile of combined oral contraceptives (COC) has substantially changed, with new combinations, dosages and mode of administration appearing on the market. Area covered: In a series of articles, recent information on the complex issue of COC risks and benefits will be reviewed in the hope of providing an updated picture. The present article reviews metabolic changes occurring during use of modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), often compared to classic compounds, such as levonorgestrel. Three categories of metabolic effects in healthy women are detailed: on carbohydrates, lipid and bone mineral content. Expert commentary: Overall, the picture is reassuring: the new generations of progestins are basically devoid of androgenic, estrogenic or glucocorticoid related side-effects. This should result in an improved safety profile, although past history teaches us that that large comparative and surveillance studies are required before firm conclusions can be drawn. At any rate, available evidence indicates that metabolic effects of third and fourth generation progestins, especially when they are combined with natural estrogens, are minimal and, if used in healthy women, should not cause concern. PMID- 27977305 TI - What is the role of sutureless aortic valves in today's armamentarium? AB - INTRODUCTION: Sutureless and rapid-deployment aortic bioprostheses represent an emerging and promising technology for the treatment of aortic valve stenosis. Unlike traditional aortic bioprostheses, these devices are not hand-sewn, thus allowing a significant reduction in operative times, while facilitating minimally invasive surgery and complex cardiac interventions. Sutureless aortic valve replacement represents a less invasive treatment option and an excellent alternative to conventional aortic valve replacement in elderly and higher risk patients. Areas covered: This review summarizes the current literature on sutureless and rapid-deployment aortic bioprostheses, focusing on their hemodynamic and clinical performance. Moreover, we highlight clinical caveats associated with these devices and report the current recommendations for their use, as advocated by experts in the field. Expert commentary: Finally, we summarize our group's technical modification with regards to positioning of these bioprostheses and propose some technical aspects which could decrease post procedural permanent pacemaker requirement. PMID- 27977306 TI - Nasal and Olfactory Deposition with Normal and Bidirectional Intranasal Delivery Techniques: In Vitro Tests and Numerical Simulations. AB - BACKGROUND: Intranasal delivery protocols that can effectively deposit drugs to the olfactory region are severely lacking. Furthermore, it is still challenging to quantify nasal deposition on a regional or local basis, which is crucial in assessing the performance of targeted olfactory drug delivery. OBJECTIVES: To visually and quantitatively compare drug depositions in the nose and olfactory region with normal and bidirectional breathing patterns with vibrating mesh and jet nebulizers. METHODS: A sectional nose cast was developed based on an anatomically accurate nasal airway model to visualize deposition patterns and quantify regional doses. Sar-Gel was used to visualize the deposition pattern inside the nose and the delivered doses were measured using a high precision scale. Numerical modeling was performed to understand the underlying mechanisms in both the normal and bidirectional deliveries. RESULTS: Results show that the bidirectional technique yielded higher deposition in both the nasal cavity and the olfactory region for both nebulizers. However, the vibrating mesh nebulizer was found to be more responsive to the bidirectional breathing and elicited more increase in the olfactory delivery than the PARI Sinus. The deposition patterns under the bidirectional breathing are highly different between the two nasal passages, with more dispersed distributions in the nasal passage with exiting flows. For both nebulizers, reducing the inhalation flow rates increased the nasal dose, but decreased the olfactory dose, which was consistent between in vitro measurements and numerical simulations. CONCLUSIONS: The bi directional technique with a vibrating mesh nebulizer is recommended for both nasal systematic and olfactory drug deliveries. The Sar-Gel based method in combination with sectional nasal casts appears to be a practical approach to visualize local depositions. PMID- 27977307 TI - Crisis Management for Biobanks. AB - All organizations are subject to risk and uncertainty. Adverse events may disrupt normal organizational activity and may even cause complete failure of business operations. Biorepositories are also at risk and there have been instances where multiple samples or entire collections have been destroyed. Biobank guidelines accordingly recommend the establishment of contingency plans to reduce risk to an acceptable level. In this review article, we will use general theory on risk management and illustrate how such principles can be used to establish a practical crisis management plan for any biobank organization. PMID- 27977308 TI - Zika and Flaviviruses Phylogeny Based on the Alignment-Free Natural Vector Method. AB - Zika virus (ZIKV) is a mosquito-borne flavivirus. It was first isolated from Uganda in 1947 and has become an emergent event since 2007. However, because of the inconsistency of alignment methods, the evolution of ZIKV remains poorly understood. In this study, we first use the complete protein and an alignment free method to build a phylogenetic tree of 87 Zika strains in which Asian, East African, and West African lineages are characterized. We also use the NS5 protein to construct the genetic relationship among 44 Zika strains. For the first time, these strains are divided into two clades: African 1 and African 2. This result suggests that ZIKV originates from Africa, then spread to Asia, Pacific islands, and throughout the Americas. We also perform the phylogeny analysis for 53 viruses in genus Flavivirus to which ZIKV belongs using complete proteins. Our conclusion is consistent with the classification by the hosts and transmission vectors. PMID- 27977309 TI - Drug Delivery in Asthmatic Children Following Coordinated and Uncoordinated Inhalation Maneuvers: A Randomized Crossover Trial. AB - BACKGROUND: Valved holding chambers (VHCs) are used in children to deliver pressurized metered dose inhalers (pMDI). In vitro data suggest that uncoordinated use decreases the amount of drug available for inhalation. We hypothesize that in an ex vivo study, the coordinated maneuver will deliver more drug than the uncoordinated one. PATIENTS AND METHODS: Thirty-two clinically stable asthmatic children, ages 5-8 years, completed the study. An aerosol filter was interposed between a small-volume nonelectrostatic VHC and a mouthpiece to capture the drug emitted by one puff of Flovent(r) 220 mcg during tidal breathing. Inhalation and actuation parameters were measured by an electronic monitor, and the number of breaths required to empty the VHC was calculated. Subjects completed three coordinated and three uncoordinated (actuation at the beginning of inhalation and exhalation, respectively) runs in random order. Drug content from the filter and VHC was measured by high-performance liquid chromatography and expressed as percentage of emitted dose. RESULTS: [mean (99% confidence interval)] Filter dose was higher during coordinated technique 46% (43%-50%) than during uncoordinated technique 41% (37%-44%) (p < 0.001). Peak inspiratory flow and tidal volume were 23.2 L/min (21.3-25.1 L/min) and 281 mL (251-311 mL), respectively. Subjects required three breaths to empty the VHC in 96% of the tests. CONCLUSIONS: Actuating the pMDI into a small-volume nonelectrostatic VHC during exhalation reduced by 11% the amount of fluticasone captured at the exit of the VHC. Asthmatic children (5-8 years old) need three or less breaths to empty the small-volume VHC (NCT01714063). PMID- 27977310 TI - Therapeutic approaches to asthma-chronic obstructive pulmonary disease overlap. AB - INTRODUCTION: Patients with features of both asthma and chronic obstructive pulmonary disease (COPD) ('asthma-COPD overlap') experience greater symptom burden and higher risk of adverse health outcomes than those with asthma or COPD alone. However, virtually no pharmacotherapy studies have been performed in this overlap population, leading to confusion amongst clinicians regarding therapeutic approaches. Areas covered: A pragmatic approach is suggested to identify patients with typical asthma, typical COPD, and those with overlap features. Interim clinical guidance on the treatment of asthma-COPD overlap is provided, acknowledging that these recommendations are based on expert opinion given the paucity of available evidence. Expert commentary: There is an urgent need for new studies in patients with asthma-COPD overlap to evaluate the efficacy and safety of existing pharmacotherapeutic options. Multiple underlying mechanisms are likely to contribute to the development of asthma-COPD overlap and a greater understanding of these mechanisms may allow a personalised approach to therapy in the future. PMID- 27977311 TI - Flurbiprofen-loaded niosomes-in-gel system improves the ocular bioavailability of flurbiprofen in the aqueous humor. AB - The present work aimed to prolong the contact time of flurbiprofen (FBP) in the ocular tissue to improve the drug anti-inflammatory activity. Different niosome systems were fabricated adopting thin-film hydration technique and using the nonionic surfactant Span 60. The morphology of the prepared niosomes was characterized by scanning electron microscopy (SEM). Physical characterization by differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy were conducted for the optimized formula (F5) that was selected on the basis of percent entrapment efficiency, vesicular size and total lipid content. F5 was formulated as 1% w/w Carpobol 934 gel. Pharmacokinetic parameters of FBP were investigated following ocular administration of F5-loaded gel system, F5 niosome dispersion or the corresponding FBP ocular drops to albino rabbits dispersion. Anti-inflamatory effect of F5-loaded carbopol gel was investigated by histopathological examination of the corneal tissue before and after the treatment of inflamed rabbit eye with the system. Results showed that cholesterol content, surfactant type. and total lipid contents had an apparent impact on the vesicle size of the formulated niosomes. Physical characterization revealed reduced drug crystallinity and incidence of interaction with other niosome contents. F5-loaded gel showed higher Cmax, area under the curve (AUC0 12), and thus higher ocular bioavailability than those of the corresponding FBP ocular solution. F5-loaded gel showed a promising rapid anti-inflammatory effect in the inflamed rabbit eye. These findings will eradicate the necessity for frequent ocular drug instillation and thus, improve patient compliance. PMID- 27977312 TI - Factors impacting time to acceptance and publication for peer-reviewed publications. AB - OBJECTIVE: Timely publication of data is important for the medical community and provides a valuable contribution to data disclosure. The objective of this study was to identify and evaluate times to acceptance and publication for peer reviewed manuscripts, reviews, and letters to the editor. RESEARCH DESIGN AND METHODS: Key publication metrics for published manuscripts, reviews, and letters to the editor were identified by eight Amgen publications professionals. Data for publications submitted between 1 January 2013 and 1 November 2015 were extracted from a proprietary internal publication-tracking database. Variables included department initiating the study, publication type, number of submissions per publication, and the total number of weeks from first submission to acceptance, online publication, and final publication. RESULTS: A total of 337 publications were identified, of which 300 (89%) were manuscripts. Time from submission to acceptance and publication was generally similar between clinical and real-world evidence (e.g. observational and health economics studies) publications. Median (range) time from first submission to acceptance was 23.4 (0.2-226.2) weeks. Median (range) time from first submission to online (early-release) publication was 29.7 (2.4-162.6) weeks. Median (range) time from first submission to final (print) publication was 36.2 (2.8-230.8) weeks. Time from first submission to acceptance, online publication, and final publication increased accordingly with number of submissions required for acceptance, with similar times noted between each subsequent submission. CONCLUSIONS: Analysis of a single-company publication database showed that the median time for manuscripts to be fully published after initial submission was 36.2 weeks, and time to publication increased accordingly with the number of submissions. Causes for multiple submissions and time from clinical trial completion to first submission were not assessed; these were limitations of the study. Nonetheless, publication planners should consider these results when evaluating timelines and identifying potential journals early in the publication planning process. PMID- 27977313 TI - Thioredoxin reductase inhibitors: a patent review. AB - INTRODUCTION: Mammalian thioredoxin reductases (TrxRs) are selenocysteine containing homodimeric flavin enzymes that catalyze the NADPH-dependent reduction of oxidized thioredoxins. Increasing evidence indicates that TrxRs are potential targets for anticancer drug development. This review summarizes patented inhibitors of mammalian TrxRs with an emphasis on those having potential applications in treatment of cancer. Areas covered: A background introduction of TrxR as well as the relevance of TrxR and cancer is provided in the first part of this review. Then, a brief discussion of TrxR assays is followed in the second part. The patented TrxRs' inhibitors that were categorized into four classes, i. e., metal complexes, Michael acceptors, sulfur/selenium-containing compounds and others, are summarized in the third part of the review. Expert opinion: There is currently no clinical anticancer drug that specifically targets TrxR. One major hurdle in finding a successful TrxR inhibitor as a therapeutic drug is the specific inhibition of TrxR by an inhibitor. As most inhibitors described in literature and patents target the selenol group in the C-terminus of TrxR enzymes, it is hard to avoid cross interactions of such inhibitors with thiols. Novel strategies are proposed to achieve discovery of highly selective inhibitors of TrxR enzymes. PMID- 27977314 TI - Diabetes and kidney disease: the role of sodium-glucose cotransporter-2 (SGLT-2) and SGLT-2 inhibitors in modifying disease outcomes. AB - Patients with type 2 diabetes (T2D) often have coexisting chronic kidney disease (CKD). However, healthy renal function is crucial in maintaining glucose homeostasis, assuring that almost all of the filtered glucose is reabsorbed by the sodium glucose cotransporters (SGLTs) SGLT-1 and SGLT-2. In diabetes, an increased amount of glucose is filtered by the kidneys and SGLT-2 is upregulated, leading to increased glucose absorption and worsening hyperglycemia. Prolonged hyperglycemia contributes to the development of CKD by inducing metabolic and hemodynamic changes in the kidneys. Due to the importance of SGLT-2 in regulating glucose levels, investigation into SGLT-2 inhibitors was initiated as a glucose dependent mechanism to control hyperglycemia, and there are three agents currently approved for use in the United States: dapagliflozin, canagliflozin, and empagliflozin. SGLT-2 inhibitors have been shown to reduce glycated hemoglobin (A1C), weight, and blood pressure, which not only affects glycemic control, but may also help slow the progression of renal disease by impacting the underlying mechanisms of kidney injury. In addition, SGLT-2 inhibitors have shown reductions in albuminuria, uric acid, and an increase in magnesium. Caution is advised when prescribing SGLT-2 inhibitors to patients with moderately impaired renal function and those at risk for volume depletion and hypotension. Published data on slowing of the development, as well as progression of CKD, is a hopeful indicator for the possible renal protection potential of this drug class. This narrative review provides an in-depth discussion of the interplay between diabetes, SGLT-2 inhibitors, and factors that affect kidney function. PMID- 27977315 TI - Antibody-siRNA conjugates: drugging the undruggable for anti-leukemic therapy. AB - INTRODUCTION: Generating effective RNAi-based therapies with the potential to achieve leukemia remission remains critical unmet need. Despite a growing number of leukemia clinical trials, tissue specific delivery of therapeutic siRNA is a major roadblock in translating its clinical potential. The most recent reports in the antibody-siRNA-conjugates (ARCs) field add new dimensions to leukemic therapy, where a covalently ligated therapeutic antisense-RNA with the potential to repress the oncogenic transcript is selectively delivered into the cancer cells. Despite ARC localization to leukemic cells due to high affinity antigen antibody interactions, multiple challenges exist to unlock the therapeutic potential of siRNA targeting. Areas covered: This review focuses on antibody and siRNA-based therapies for leukemia as well as potential antibody engineering based strategies to generate an optimal ARC platform. Expert opinion: In vitro and clinical results have revealed that non-targeted delivery and inefficient cellular internalization of therapeutic siRNA are major contributing factors for the lack of efficacy in leukemia patients. Rational antibody design and selective protein engineering with the potential to neutralize siRNA charge, stabilize ARC complex, restrict off-targeted delivery, optimize endosomal escape, and extend serum half-life will generate clinically relevant leukemic therapies that are safe, selective, and effective. PMID- 27977316 TI - Comparative binder efficiency modeling of dry granulation binders using roller compaction. AB - Roller compaction parameters' impact on granules and tableting properties of coprocessed Avicel(r) DG [ADG], a physical mixture of the two components at the same composition present in ADG [PADCP], and microcrystalline cellulose and Kollidon(r) VA-64 Fine physical mixture [KVA64] was quantified by analysis of variance (ANOVA) and multivariate methods. Roller force, roller gap, and roller speed levels were selected for evaluation. A 33 full-factorial experimental design with three center points for roller force, roller gap, and roller speed was used. The response parameters studied were granule-to-fines (GF) ratio, compressibility index (CI), tablet thickness (TT), tablet friability (TF), tablet breaking force (TBF) and disintegration time (DT). A model acetaminophen tablet formulation was roller granulated and tableted at 10 kg scale. Principal component analysis of ADG and PADCP formulations were separated from KVA64 formulations, indicating different granule and tableting properties were binder dependent. This difference in binder performance was also confirmed by ANOVA. The ANOVA also showed that there were no statistical performance differences between coprocessed ADG and its comparable physical blend with the exception of TT. Principal component regression (PCR) analyses of ADG and PADCP revealed that these excipients exhibited a statistically significant negative effect on granules-to-fine (GF) ratio, TT, TBF, and DT. KVA64 demonstrated a positive effect on these parameters. The KVA64 physical mixture demonstrated an overall better performance and binding capability. This study strongly suggests that there is no performance advantage of coprocessed Avicel(r) DG when compared to a physical mixture of the two components at the same composition. PMID- 27977317 TI - Disproportionality analysis of buprenorphine transdermal system and cardiac arrhythmia using FDA and WHO postmarketing reporting system data. AB - OBJECTIVE: Positive-controlled clinical studies have shown a dose dependent effect of buprenorphine transdermal system on QTc interval prolongation. This study provides assessment of the buprenorphine transdermal system and cardiac arrhythmia using US FDA and WHO postmarketing reporting databases. METHODS: Disproportionality analysis of spontaneously reported adverse events to assess whether the reporting rate of cardiac arrhythmia events was disproportionately elevated relative to expected rates of reporting in both FDA and WHO databases. Cardiac arrhythmia events were identified using the standardized Medical Dictionary for Regulatory Activities query for torsade de pointes and/or QT prolongation (TdP/QTP). The threshold for a signal of disproportionate adverse event reporting was defined as the lower 90% confidence limit >= 2 of the Empiric Bayes geometric mean in FDA database and as the lower 95% confidence limit of the Informational Component >0 in WHO database. RESULTS: There were 124 (<1%) and 77 (2%) cardiac arrhythmia event cases associated with buprenorphine transdermal as compared to 3206 (12%) and 2913 (14%) involving methadone in the FDA and WHO databases, respectively. In the FDA database methadone was associated with a signal of disproportionate reporting for TdP/QTP (EB05 3.26); however, buprenorphine transdermal was not (EB05 0.33). In the WHO database methadone was associated with a signal of disproportionate reporting for TdP/QTP (IC025 2.66); however, buprenorphine transdermal was not (IC025 -0.88). Similar trends were observed in sensitivity analyses by age, gender, and specific terms related to ventricular arrhythmia. CONCLUSIONS: The signal identified in the transdermal buprenorphine thorough QTc study, which led to a dose limitation in its US label, does not translate into a signal of increased risk for cardiac arrhythmia in real world use, as assessed by this method of analyzing post-market surveillance data. PMID- 27977318 TI - Nebulized Recombinant Human Tissue Factor Pathway Inhibitor Attenuates Coagulation and Exerts Modest Anti-inflammatory Effects in Rat Models of Lung Injury. AB - BACKGROUND: Critically ill patients are at a constant risk of direct (e.g., by pneumonia) or indirect lung injury (e.g., by sepsis). Excessive alveolar fibrin deposition is a prominent feature of lung injury, undermining pulmonary integrity and function. METHODS: We examined the effect of local administration of recombinant human tissue factor pathway inhibitor (rh-TFPI), a natural anticoagulant, in two well-established models of lung injury in rats. Rats received intratracheal instillation of Pseudomonas aeruginosa, causing direct lung injury, or they received an intravenous injection of Escherichia coli lipopolysaccharide (LPS), causing indirect lung injury. Rats were randomized to local treatment with rh-TFPI or placebo through repeated nebulization. RESULTS: Challenge with P. aeruginosa or LPS was associated with increased coagulation and decreased fibrinolysis in bronchoalveolar lavage fluid (BALF) and plasma. Rh-TFPI levels in BALF increased after nebulization, whereas plasma rh-TFPI levels remained low and systemic TFPI activity was not affected. Nebulization of rh-TFPI attenuated pulmonary and systemic coagulation in both models, without affecting fibrinolysis. Nebulization of rh-TFPI modestly reduced the inflammatory response and bacterial growth of P. aeruginosa in the alveolar compartment. CONCLUSIONS: Local treatment with rh-TFPI does not alter systemic TFPI activity; however, it attenuates both pulmonary and systemic coagulopathy. Furthermore, nebulized rh TFPI modestly reduces the pulmonary inflammatory response and allows increased bacterial clearance in rats with direct lung injury caused by P. aeruginosa. PMID- 27977319 TI - The relationship between thiamine and two symbioses: Root nodule symbiosis and arbuscular mycorrhiza. AB - Lotus japonicus THIC is expressed in all organs, and the encoded protein catalyzes thiamine biosynthesis. Loss of function produces chlorosis, a typical thiamine-deficiency phenotype, and mortality. To investigate thiamine's role in symbiosis, we focused on THI1, a thiamine-biosynthesis gene expressed in roots, nodules, and seeds. The thi1 mutant had green leaves, but formed small nodules and immature seeds. These phenotypes were rescued by THI1 complementation and by exogenous thiamine. Thus, THI1 is required for nodule enlargement and seed maturation. On the other hand, colonization by arbuscular mycorrhiza (AM) fungus Rhizophagus irregularis was not affected in the thi1 mutant or by exogenous thiamine. However, spores of R. irregularis stored more thiamine than the source (host plants), despite lacking thiamine biosynthesis genes. Therefore, disturbance of the thiamine supply would affect progeny phenotypes such as spore formation and hyphal growth. Further investigation will be required to elucidate thiamine's effect on AM. PMID- 27977321 TI - Comparative Study on the Size Distributions, Respiratory Deposition, and Transport of Particles Generated from Commonly Used Medical Nebulizers. AB - BACKGROUND: Medical nebulizers are widely and conveniently used to deliver medication to the lungs as an inhalable mist; however, the deposition of nebulized particles in the human respiratory system and the transport of the nebulized particles in the environment have not been studied in detail. METHODS: Five medical nebulizers of three different types (constant output, breath enhanced, and dosimetric) were evaluated. The size distribution functions (SDFs) and respiratory deposition of the particles generated from the nebulizers were characterized. The SDFs were obtained with an aerodynamic particle sizer (APS; TSI, Inc., St. Paul) after data correction, and the respiratory deposition was calculated according to the model developed by the International Commission on Radiological Protection. The evaporation, Brownian diffusion, and convective movement are further calculated based on aerosol properties. RESULTS AND CONCLUSIONS: The SDFs measured by the APS indicated that most of the generated particles were in the size range of 1-8 MUm. The operating pressure and flow rate affected the number-based SDF of the nebulized particles. Although different values of mean aerodynamic diameter (MAD) were obtained for the nebulizers, the mass median aerodynamic diameter did not differ significantly from each other (between 4 and 5 MUm). According to calculation, the deposition of particles in the head airways region accounted for the most of the particle mass collected by the respiratory system. Convective movement was the dominant mechanism for the transport of particles in the size ranges investigated. Relative humidity dependent evaporation can significantly decrease the size of the emitted particles, resulting in a different respiratory deposition pattern such that the amount of particles deposited in the alveolar region is greatly enhanced. Appropriate protection from these particles should be considered for those persons for whom the medication is not intended (e.g., healthcare workers, family members). PMID- 27977320 TI - Selection of High-Quality Spermatozoa May Be Promoted by Activated Vitamin D in the Woman. AB - Context: The vitamin D receptor (VDR) and enzymes involved in activation (CYP2R1, CYP27B1) and inactivation (CYP24A1) of vitamin D are expressed in ovary, testes, and spermatozoa. Objective: Determine responsiveness to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in spermatozoa from normal and infertile men, and identify the site of exposure and how 1,25(OH)2D3 influences sperm function. Design: Spermatozoa expressing VDR, CYP2R1, CYP27B1, and CYP24A1 were analyzed in normal and infertile men. 25-Hydroxyvitamin D (25-OHD), 24,25-dihydroxyvitamin D [24,25(OH)2D3], and 1,25(OH)2D3 were measured in serum, seminal fluid, cervical secretions, and ovarian follicular fluid. 1,25(OH)2D3 was tested on human spermatozoa. Setting: Tertiary center for fertility. Participants: Protein expression in spermatozoa and semen quality were assessed in 230 infertile and 114 healthy men. Vitamin D metabolites were measured in fluids from 245 men and 13 women, while 74 oocytes and 17 semen donors were used for sperm-function tests. Main Outcome Measures: VDR and CYP24A1 expressions in spermatozoa, fluid concentrations of 25-OHD, 24,25(OH)2D3, and 1,25(OH)2D3, and 1,25(OH)2D3-induced effects on intracellular calcium concentration ([Ca2+]i) and sperm-oocyte binding in vitro. Results: VDR and CYP24A1 were expressed in a >2-fold higher fraction of spermatozoa from normal than infertile men (P < 0.01). Concentrations of 25-OHD, 24,25(OH)2D, and 1,25(OH)2D3 were undetectable in seminal fluid but high in ovarian follicular fluid. Follicular concentrations of 1,25(OH)2D3 induced a modest increase in [Ca2+]i and sperm-oocyte binding in vitro (P < 0.05). Conclusion: Presence of VDR and CYP24A1 mainly in spermatozoa of higher quality supports that 1,25(OH)2D3 available in the female reproductive tract may promote selection of the best gametes for fertilization. PMID- 27977324 TI - Special Issue of Journal of Biopharmaceutical Statistics dedicated to 2016 Trends and Innovations in Clinical Trial Statistics (TICTS) Conference. PMID- 27977323 TI - Sexual Activity and Midlife Women: The Paradigm Shift from Traditional to Biopsychosocial. PMID- 27977322 TI - Blue Maize Extract Improves Blood Pressure, Lipid Profiles, and Adipose Tissue in High-Sucrose Diet-Induced Metabolic Syndrome in Rats. AB - The effect of blue maize extract in factors related to metabolic syndrome (MS) in Wistar rats was investigated. Total polyphenols, monomeric anthocyanins, and antioxidant activity were analyzed in blue maize. MS was induced in Wistar rats fed with high-sucrose (HS) diet for 12 weeks. During a period of 4 weeks, blue maize extract was administrated to HS groups fed with high-sucrose and high cholesterol-high-sucrose (HS+C) diets. In the blue maize extract administered by orogastric cannulation, the levels of total polyphenols and anthocyanins were 9.97 and 2.92 mg/kg of weight, respectively. HS diet administered during a period of 12 weeks increased significantly systolic blood pressure, serum triglycerides, and decreased high-density lipoprotein cholesterol (HDL-C), alterations related to the MS. Abdominal adipose tissue was only increased in the HS + C group. Blue maize extract administration enhanced HDL-C and decreased systolic blood pressure, serum triglycerides, total cholesterol, and epididymal adipose tissue weight. The blue maize may represent a promising nutraceutical option for the treatment of MS. PMID- 27977325 TI - Guest editor's note: Special issue on biosimilarity assessment. PMID- 27977326 TI - Development of statistical methods for analytical similarity assessment. AB - To evaluate the analytical similarity between the proposed biosimilar product and the US-licensed reference product, a working group at Food and Drug Administration (FDA) developed a tiered approach. This proposed tiered approach starts with a criticality determination of quality attributes (QAs) based on risk ranking of their potential impact on product quality and the clinical outcomes. Those QAs characterize biological products in terms of structural, physicochemical, and functional properties. Correspondingly, we propose three tiers of statistical approaches based on the levels of stringency in requirements. The three tiers of statistical approaches will be applied to QAs based on the criticality ranking and other factors. In this article, we discuss the statistical methods applicable to the three tiers of QA. We further provide more details for the proposed equivalence test as the Tier 1 approach. We also provide some discussion on the statistical challenges of the proposed equivalence test in the context of analytical similarity assessment. PMID- 27977327 TI - tDCS potentiation provides no evidence for a link between right dorsal-lateral prefrontal cortical activity and empathic responding. AB - Previous studies suggest the dorsolateral prefrontal cortex (DLPFC) is involved in processing of empathic concern. This has not been experimentally tested to date. We tested the hypotheses that electrical potentiation in the right DLPFC would be associated with increased empathic concern and prosocial behavior. Participants were randomly allocated to one of three transcranial Direct Current Stimulation (tDCS) conditions: (a) relative right potentiation, (b) relative left potentiation, and (c) sham. Participants viewed images of African children in distressing circumstances, and completed measures of empathic concern pre- and post-tDCS manipulation. Contrary to our prediction, neither effects, nor interactions of heightened empathic concern were observed. These results conflict with previous studies using this bilateral tDCS montage. Explanations could be that stimulation used in this study had been simply too weak (1.5 mA). Alternatively, the area of the DLPFC involved in emotion regulation is closer to the cortex than the area involved in empathic concern, and more easily potentiated by tDCS. Therefore, the DLPFC potentiation in the present study may have linked empathic concern with adaptive emotion regulation strategies. Future research could examine this possibility using measures of emotion regulation and higher fidelity neurostimulation (e.g., repetitive Transcranial Magnetic Stimulation [rTMS]). PMID- 27977329 TI - Reducing Artifacts during Arterial Phase of Gadoxetate Disodium-enhanced MR Imaging: Dilution Method versus Reduced Injection Rate. AB - Purpose To compare two contrast material-administration protocols (dilution vs slow injection) in terms of their effectiveness in arterial phase artifact reduction at gadoxetic acid-enhanced magnetic resonance (MR) imaging. Materials and Methods This HIPAA-compliant retrospective case-controlled cohort study was approved by the institutional review board, with a waiver of informed patient consent. A total of 318 consecutive patients undergoing gadoxetic acid-enhanced MR imaging were placed into one of two subcohorts of 159 consecutive patients each: the dilution subcohort (gadoxetic acid was diluted 1:1 with saline and injected at a rate of 2.0 mL/sec) and the slow injection subcohort (gadoxetic acid was not diluted and was injected at a rate of 1.0 mL/sec). Eighty-nine patients in the dilution subcohort also underwent follow-up MR imaging with the slow injection method, and 34 patients in the slow injection subcohort underwent follow-up MR imaging with the dilution method. Both patient- and image-based analyses, as well as intraindividual analysis, were used to compare two parameters-mean artifact score rated by two observers using a five-point scale and frequency of severe artifact-between the dilution and slow injection subcohorts with the Wilcoxon Mann-Whitney test, chi2 test, and generalized estimating equation. Results In both patient- and image-based analyses, the mean artifact score and frequency of severe artifact were lower in the dilution subcohort (mean, 1.46% and 3.8% [six of 159]) than in the slow injection subcohort (mean, 1.95% and 15.1% [24 of 159]) (P <= .001 and P < .001, respectively). In intraindividual analysis, both variables were also decreased in the dilution subcohort (P = .007 and P = .001, respectively). We found the two variables to be significantly increased in the slow injection subcohort when compared with that in the dilution subcohort for three different MR platforms (P < .05). Conclusion In comparison with slow injection of undiluted contrast material at a rate of 1.0 mL/sec, gadoxetic acid diluted to 50% and injected at a rate of 2 mL/sec had a significantly less severe ghosting artifact in the arterial phase of gadoxetic acid-enhanced MR imaging. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27977328 TI - Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression. AB - AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer. These findings were significant in light of our recent observation that androgens promoted prostate cancer cell growth in part through the induction of autophagy. Expression of these 5 genes was essential for maximal androgen-mediated autophagy and cell proliferation. In addition, expression of each of these 5 genes alone or in combination was sufficient to increase prostate cancer cell growth independent of AR activity. Further, bioinformatic analysis demonstrated that the expression of these genes correlated with disease progression in 3 separate clinical cohorts. Collectively, these findings demonstrate a functional role for increased autophagy in prostate cancer progression, provide a mechanism for how autophagy is augmented, and highlight the potential of targeting this process for the treatment of advanced prostate cancer. PMID- 27977330 TI - Hmga1 deficiency: "SAC-King" the SAC genes to incite chromosomal instability. PMID- 27977331 TI - Cell therapies administered in the chronic phase after stroke: a meta-analysis examining safety and efficacy. AB - AIM: To assess the safety and efficacy of cell therapies for chronic stroke. METHODOLOGY: Five databases were searched for treatments administered >90 days post-stroke. Reporting quality, adherence to research guidelines, treatment safety (risk ratios/pooled incidence rates) and neurological/functional efficacy (Hedge's g) were all evaluated. RESULTS: Twenty-three studies examined 17 treatments. Reporting quality scores were medium to high, but adherence to recommended guidelines was lower. Three treatments resulted in serious adverse events; four improved outcomes more than standard care. However, many studies were under-powered and individual patients varied in their response to some treatments. CONCLUSION: Preliminary findings suggest that some cell therapies may be relatively safe and effective, but larger double-blinded placebo-controlled studies are needed to establish the long-term risks and benefits. PMID- 27977333 TI - Molecular mechanism of BjCHI1-mediated plant defense against Botrytis cinerea infection. AB - Plant chitinases are a group of proteins associated with defense against pathogen attack. BjCHI1 is the first characterized chitinase containing two chitin binding domains (CBDs). Investigations have shown that BjCHI1 inhibits growth of fungal phytopathogens and agglutinates Gram-negative bacteria. Our recent studies revealed that expression of BjCHI1 mRNA is largely induced upon infection of Botrytis cinerea via a R2R3-MYB transcription factor BjMYB1 interacting with a W box-like element (Wbl-4) in the BjCHI1 promoter. The enhanced expression pattern of BjMYB1 was similar to that of BjCHI1 and associated with resistant phenotype against B. cinerea. These findings suggest that BjCHI1 is involved in host defense against fungal attack through interaction with BjMYB1. Here, we review the recent studies on BjCHI1 and propose a model of BjCHI1-mediated plant defense against fungal attack. PMID- 27977332 TI - Clinical impact of the CYP3A5 6986A>G allelic variant on kidney transplantation outcomes. AB - AIM: Meta-analyses and large cohort studies provide confusing results on the association of the CYP3A5 6986A>G allelic variant and adverse outcomes in kidney transplant recipients under tacrolimus-based immunosuppressive regimen. A residual effect of CYP3A5 recipient genotype is unexpected if kidney transplant recipients have similar exposure of tacrolimus. PATIENTS & METHODS: We have undertaken a population-based, observational study, to investigate all the consecutive patients who received a kidney transplant at the Necker hospital between 2005 and 2015, who were treated with tacrolimus and for whom the CYP3A5 genotype was available. RESULTS & CONCLUSION: We analyzed 577 patients followed for up to 5 years. We found a significant association of CYP3A5 genotypes with tacrolimus daily dose as well as with tacrolimus dose-adjusted concentrations. We however found no association of CYP3A5 genotypes with histology scores on biopsies, measured renal function, biopsy-proven acute rejection episodes and graft survival. PMID- 27977334 TI - Pharmacogenetics of ustekinumab in patients with moderate-to-severe plaque psoriasis. AB - : Aim/Materials & methods: Few studies have evaluated the influence of pharmacogenetics in psoriatic patients treated with ustekinumab. We evaluated 121 polymorphisms to study a possible association between these SNPs and the response to ustekinumab (PASI75 at 4 months; n = 69). RESULTS/CONCLUSION: The adjusted results (false discovery rate) showed an association between five SNPs in TNFRSF1A, HTR2A, NFKBIA, ADAM33 and IL13 genes, and poor response to ustekinumab. Furthermore, six SNPs in CHUK, C17orf51, ZNF816A, STAT4, SLC22A4 and Corf72 genes were associated with better response to ustekinumab. However, there was no significant association between response to ustekinumab and SNPs in HLA-C as it has been recently described. Finally, a higher weight was obtained in nonresponders than responders (p = 0.018). Further studies would be necessary to be closer to personalized medicine. PMID- 27977336 TI - Posthumous degree for 'inspiring' student. AB - The family of a nursing student who was killed in a car crash paid tribute to their 'inspiring and caring' daughter as they accepted her posthumous degree. PMID- 27977337 TI - UK could train nurses abroad to fill NHS posts. AB - A global partnership could see the UK fund the training of nurses in developing countries to plug skills gaps in the NHS and overseas. PMID- 27977339 TI - Helpline nursing. AB - Viewed by some as a backwater, only attracting those in the twilight of their career, the nurse's role on specialist health helplines is often misunderstood and undervalued. A new framework, written by senior staff at charities that employ information nurses, is set to challenge these unwarranted perceptions. 'It dignifies what we're doing,' says Cancer Research UK head information nurse Martin Ledwick, who manages a team of eight. 'And it gives nurses an idea of what we expect from them.' PMID- 27977340 TI - Beginning testosterone treatment increases risk of blood clots. AB - Starting testosterone treatment is associated with an increased risk of venous thromboembolism (VTE) that peaks within six months then gradually declines, a study suggests. PMID- 27977335 TI - Fatty acid amide hydrolase-morphine interaction influences ventilatory response to hypercapnia and postoperative opioid outcomes in children. AB - AIM: Fatty acid amide hydrolase (FAAH) degrades anandamide, an endogenous cannabinoid. We hypothesized that FAAH variants will predict risk of morphine related adverse outcomes due to opioid-endocannabinoid interactions. PATIENTS & METHODS: In 101 postsurgical adolescents receiving morphine analgesia, we prospectively studied ventilatory response to 5% CO2 (HCVR), respiratory depression (RD) and vomiting. Blood was collected for genotyping and morphine pharmacokinetics. RESULTS: We found significant FAAH-morphine interaction for missense (rs324420) and several regulatory variants, with HCVR (p < 0.0001) and vomiting (p = 0.0339). HCVR was more depressed in patients who developed RD compared with those who did not (p = 0.0034), thus FAAH-HCVR association predicts risk of impending RD from morphine use. CONCLUSION: FAAH genotypes predict risk for morphine-related adverse outcomes. PMID- 27977341 TI - Enabling patients to manage altered body image. AB - The author presented a model in the 1990s to explain altered body image, which has been used to characterise the difficulties encountered by patients who experience body change as a result of illness, injury or disability. However, it remains a challenge for nurses to establish care plans that can assist patients to manage the psychological adjustments associated with disfigurement. This article presents some simple questions to help patients narrate their psychological experiences and needs, and proposes a model of psychological change, based on the work of Kubler-Ross, to enable nurses to anticipate patient requirements that might arise at different stages of the individual's recovery and rehabilitation. Body-image rehabilitation may be protracted. Therefore, it is essential for nurses to understand what the patient is thinking and feeling throughout the rehabilitation process and which stage of psychological change the patient is working through. PMID- 27977342 TI - One You Drinks Tracker. AB - The festive season is looming, and for many this means plenty of food, socialising and alcohol. PMID- 27977344 TI - Cut intake of saturated fats to stave off coronary heart disease. AB - Replacing major saturated fatty acids with unsaturated fats, whole grain carbohydrates or plant proteins is an effective way to prevent coronary heart disease, say researchers. PMID- 27977345 TI - We must develop NHS leaders of the future. AB - Nurses and midwives face many daily challenges, particularly at this time of year, with what we traditionally refer to as 'winter pressures'. PMID- 27977346 TI - Developing person-centred practice in hip fracture care for older people. AB - AIM: To facilitate a multidisciplinary collaborative approach to developing person-centred practice in hip fracture care for older people. METHOD: Collaborative inquiry, a form of action research, was used to collect data for this study. It involved exploration of dilemmas, questions and problems that are part of human experience. Clinical leaders from different disciplines (n=16), who work with older people with hip fractures at different stages of the care pathway, participated in a series of facilitated action meetings. The practice development techniques used in this study included: identifying the strengths and limitations of the current service, values clarification, creating a shared vision, sharing clinical stories, reviewing case records, and reflecting on the experiences of three older people and two caregivers. FINDINGS: Hip fracture care was based on meeting service targets, national guidelines and audits. Care was fragmented across different service delivery units, with professional groups working independently. This resulted in suboptimal communication between members of the multidisciplinary group of clinical leaders and care that was process driven rather than person-centred. Spending time away from clinical practice enabled the multidisciplinary group to collaborate to understand care from the patients' and caregivers' perspectives, and to reflect critically on the care experience as a whole. CONCLUSION: To develop a person-centred workplace culture, the multidisciplinary team requires facilitated time for reflection. Ongoing facilitative leadership would enable the multidisciplinary team to collaborate effectively to deliver safe, effective person-centred practice in hip fracture care for older people. PMID- 27977347 TI - Time to raise a glass? AB - There is no Nursing and Midwifery Council rule that states you cannot have a drink at work, but this would be covered by your overall responsibility to maintain a professional standard and be fit and competent to practise safely. PMID- 27977348 TI - Shambolic staffing has a price. AB - Your analysis about the Nursing and Midwifery Council (NMC) report revealing too many black and minority ethnic (BME) nurses and men being referred to the regulator (analysis, 7 December) is the tip of the iceberg. PMID- 27977349 TI - Students buy essays as they can't afford to fail. AB - Nursing has changed almost beyond recognition in the past 50 years. While nurses are still expected to have a hands-on approach, they often take on duties that were once carried out by doctors, such as writing prescriptions or providing specialist care for conditions including heart disease and diabetes. As a result, training programmes have become more sophisticated, and many more nurses now hold a degree. PMID- 27977351 TI - When badges are no help. AB - Thank you for your 'advent calendar' article on how to introduce yourself to patients. PMID- 27977350 TI - Let's hear it for 12-hour shifts. AB - In response to your online story about a study that found nurses are more likely to experience emotional exhaustion when working 12-hour shifts or longer, I prefer 12-hour shifts. PMID- 27977352 TI - Are NHS recruitment issues to blame? AB - Are a disproportionate number of BME nurses and men being referred to the NMC? PMID- 27977353 TI - I'm not a computer person. AB - What a wonderful charity nurse Marcus McGilvray has set up for youngsters with or at risk of becoming infected with HIV (feature, 30 November). I was moved and would like to donate, but the excellent article only gave the computer address at the end. PMID- 27977354 TI - Fall in screening risks lives. AB - Figures released last month show cervical screening coverage in England has dropped again, and is now at 72.7%. This means that 1.12 million of the 4.2 million women invited for screening during 2015-16 did not attend, significantly increasing their risk of cervical cancer. PMID- 27977355 TI - Community staff told: surrender some of your AfC terms if you want to keep NHS pension. AB - Community nurses in South Yorkshire have been forced to take on inferior terms and conditions after their jobs were transferred to a local authority, say unions. PMID- 27977356 TI - Student life - Your first clinical placement: prepare well and ask for help. AB - Your first clinical placement as a nursing student will be an exciting experience, but it may also be somewhat overwhelming. PMID- 27977357 TI - Coeliac disease. AB - Essential facts [Figure: see text] Coeliac disease is a lifelong autoimmune condition where the body reacts to eating gluten, a protein found in wheat, rye and barley. This leads to chronic inflammation of the small intestine and can result in malabsorption of nutrients. PMID- 27977361 TI - Midwives on a mission. AB - [Figure: see text] The nurses of Nonnatus House are swapping a white Christmas in east London for a mission to South Africa in the Christmas special of Call the Midwife, pictured. PMID- 27977360 TI - Giving someone the 'right' death. AB - Before I started training to be a nurse, I had no experience of caring. Other than my nephew, I'd never washed someone, nor helped them to the toilet or fed them. PMID- 27977362 TI - Using online essay mills 'may put patients at risk'. AB - Patient safety could be at risk if nursing students cheat by passing off as their own work essays bought online, a higher education watchdog has warned. PMID- 27977363 TI - 'Rebecca made us feel that she was fighting for our daughter'. AB - Our daughter Ellie was born with complex congenital heart disease and was transferred to the Royal Brompton Hospital in London the day she was born. PMID- 27977364 TI - 'In palliative care we help children make memories'. AB - The charity Together for Short Lives has launched a campaign to encourage nurses to consider a role in children's palliative care in the voluntary sector, to prevent any further reduction in services for this already vulnerable group. PMID- 27977365 TI - Patient's Choice Award - a chance to say thank you. AB - 'Winning the Patient's Choice Award has been the highlight of my career so far. And having been nominated by a patient and then voted for by the public, it has reinforced that what I do does make a difference,' says lead bowel function clinical nurse specialist Kelly Stackhouse. PMID- 27977366 TI - Identifying learning styles. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article explored different learning styles and outlined some of the models that can be used to identify them. It discussed the limitations of these models, indicating that although they can be helpful in identifying a student's preferred learning style, this is not 'fixed' and might change over time. Learning is also influenced by other factors, such as culture and age. PMID- 27977367 TI - Reflect on your successes in 2016. AB - The introduction of revalidation has brought a greater emphasis on learning from your own practice. Through reflection, you discover who you are as a nurse, including your strengths and weaknesses. PMID- 27977369 TI - Health visitors feel brunt of ongoing budget cuts. AB - Health visitors in England are feeling the impact of public health budget cuts, with 85% saying their workload has increased. PMID- 27977368 TI - Accentuate the positive: nursing's challenge for 2017. AB - Few of us will forget the momentous events of 2016 - a remarkable year on so many fronts. Brexit, a new prime minister and the election of Donald Trump as US president stand out as defining events, but there have also been less dramatic developments that will have a profound impact on the future of nursing. PMID- 27977370 TI - From The Boss to The Big Short: highlights of 2016. AB - Viv Bennett, Public Health England's chief nurse As a lifelong (or do I mean ageing?) rocker and Bruce Springsteen fan, it was with great excitement that I saw he was touring the UK this year. PMID- 27977372 TI - 'I love having the time to talk'. AB - Barbara Stephenson qualified at Westminster Hospital in London 40 years ago. She was a medical ward sister, then a practice nurse, and has taught the diabetes X pert programme to patients. Her current role is asthma nurse specialist at Asthma UK. PMID- 27977373 TI - What will 2017 hold for the nursing profession? AB - Education and training Nurse education will see huge changes in 2017. Most radical is the controversial end to bursaries for nursing students in England. From September, funding will come through the tuition fees and student loans system instead, a government move that led to mass protests in 2016. PMID- 27977374 TI - Readers' panel - Should sugary drinks be banned from NHS hospitals? AB - Our experts consider a hot topic of the day. PMID- 27977376 TI - Paloma Faith sings the praises of NHS staff after the birth of her child. AB - Singer Paloma Faith has applauded 'incredible' NHS nurses, midwives and doctors after the birth of her first child. PMID- 27977375 TI - 'Tis the season to be jolly. AB - Our local theatre is putting on 'relaxed performances' of its pantomime this season, for people with conditions such as dementia and autism. PMID- 27977378 TI - Nurses come top in survey of trustworthiness. AB - Nursing is the most trusted profession in the UK, according to a new poll. PMID- 27977381 TI - Review of 2016: A year of challenges and triumphs for nurses. AB - January [Figure: see text] Thousands of people marched on Downing Street in protest against Whitehall plans to scrap nursing students' bursaries and replace them with loans. Anger against the government continued as the Department of Health argued that annual pay rises for NHS nurses in England should be capped at 1%. Many nurses pledged support for their medical colleagues as junior doctors went on the first of several unprecedented strikes over pay and conditions. PMID- 27977382 TI - Lack of supporting evidence for claims about fertility treatments. AB - Fertility clinics in the UK are making unsubstantiated claims about the benefits of treatment beyond standard IVF procedures, say researchers from the University of Oxford's Centre for Evidence-Based Medicine. PMID- 27977383 TI - Benzodiazepine use increases risk of hip fracture in people with Alzheimer's disease. AB - The use of benzodiazepines and related drugs raises the risk of hip fracture by 43% in people with Alzheimer's disease, say researchers from the University of Eastern Finland. PMID- 27977384 TI - No proof that vitamin D supplements prevent disease. AB - Evidence does not support the use of vitamin D supplements to prevent disease, say researchers from the University of Aberdeen and the University of Auckland in New Zealand. PMID- 27977385 TI - It's more than money: policy options to secure medical specialist workforce for regional centres. AB - Objectives Regional centres and their rural hinterlands support significant populations of non-metropolitan Australians. Despite their importance in the settlement hierarchy and the key medical services provided from these centres, little research has focused on their issues of workforce supply and long-term service requirements. In addition, they are a critical component of the recent growth of 'regional' hub-and-spoke specialist models of service delivery. Methods The present study interviewed 62 resident specialists in four regional centres, seeking to explore recruitment and retention factors important to their location decision making. The findings were used to develop a framework of possible evidence-informed policies. Results This article identifies key professional, social and locational factors, several of which are modifiable and amenable to policy redesign, including work variety, workplace culture, sense of community and spousal employment; these factors that can be targeted through initiatives in selection, training and incentives. Conclusions Commonwealth, state and local governments in collaboration with communities and specialist colleges can work synergistically, with a multiplicity of interdigitating strategies, to ensure a positive approach to the maintenance of a critical mass of long-term rural specialists. What is known about the topic? Rural origin increases likelihood of long-term retention to rural locations, with rural clinical school training associated with increased rural intent. Recruitment and retention policy has been directed at general practitioners in rural communities, with little focus on regional centres or medical specialists. What does this study add? Rural origin is associated with regional centre recruitment. Professional, social and locational factors are all moderately important in both recruitment and retention. Specialist medical training for regional centres ideally requires both generalist and subspecialist skills sets. Workforce policy needs to address modifiable factors with four groups, namely commonwealth and state governments, specialist medical colleges and local communities, all needing to align their activities for achievement of long-term medical workforce outcomes. What are the implications for practitioners? Modifiable factors affecting recruitment and retention must be addressed to support specialist models of care in regional centres. Modifiable factors relate to maintenance of a critical mass of practitioners, training a fit-for-purpose workforce and coordinated effort between stakeholders. Although remuneration is important, the decision to stay relates primarily to non-financial factors. PMID- 27977386 TI - Stigma, gay men and biomedical prevention: the challenges and opportunities of a rapidly changing HIV prevention landscape. AB - Improvements in biomedical technologies, combined with changing social attitudes to sexual minorities, provide new opportunities for HIV prevention among gay and other men who have sex with men (GMSM). The potential of these new biomedical technologies (biotechnologies) to reduce HIV transmission and the impact of HIV among GMSM will depend, in part, on the degree to which they challenge prejudicial attitudes, practices and stigma directed against gay men and people living with HIV (PLHIV). At the structural level, stigma regarding gay men and HIV can influence the scale-up of new biotechnologies and negatively affect GMSM's access to and use of these technologies. At the personal level, stigma can affect individual gay men's sense of value and confidence as they negotiate serodiscordant relationships or access services. This paper argues that maximising the benefits of new biomedical technologies depends on reducing stigma directed at sexual minorities and people living with HIV and promoting positive social changes towards and within GMSM communities. HIV research, policy and programs will need to invest in: (1) responding to structural and institutional stigma; (2) health promotion and health services that recognise and work to address the impact of stigma on GMSM's incorporation of new HIV prevention biotechnologies; (3) enhanced mobilisation and participation of GMSM and PLHIV in new approaches to HIV prevention; and (4) expanded approaches to research and evaluation in stigma reduction and its relationship with HIV prevention. The HIV response must become bolder in resourcing, designing and evaluating programs that interact with and influence stigma at multiple levels, including structural-level stigma. PMID- 27977388 TI - General practitioner management of chronic diseases in adults with severe mental illness: a community intervention trial. AB - Objective The aim of the present study was to assess the effects of a community intervention aimed at general practitioners (GPs) by comparing Medicare claims data from patients with severe mental illness (SMI) of GPs exposed to the intervention and controls that were not. Methods A comparison was made of primary care consultation and pathology data of people with SMI from intervention and control areas. Negative binomial regression models were used to compare the frequency and length of GP consultations, as well as the number and type of pathology examinations. Results Records of 103 people from intervention area and 98 controls were obtained. Intervention and control areas were not different at baseline in terms of age and claims data, but females had higher consultation rates. After adjusting for gender, people from intervention areas had more GP consultations, especially long consultations (adjusted incidence rate ratio 1.56; 95% confidence interval 1.28-1.91). They also had more pathology screening for chronic diseases, in accordance with implemented guideline recommendations. These benefits persisted after the end of the intervention. Conclusion These findings suggest that the ACTIVATE program aimed at training GPs to screen and better manage chronic diseases in adults with SMI had a positive effect up to 6 months after the trial, with demonstrated desired changes in medical management practices by GPs in the intervention area during that time. What is known about the topic? People with an SMI have higher mortality and poorer physical health than the general population. What does this paper add? The community intervention had a significant and sustained effect, with demonstrated desired changes in screening and medical management by GPs for adults with SMI in the intervention area. What are the implications for practitioners? GPs are ideally placed to assist in the prevention and better management of health conditions, thereby reducing avoidable illness and deaths in vulnerable populations, such as adults with SMI. Ongoing professional training and dissemination of clinical guidelines are critical for raising awareness about the physical and oral health care needs of people with SMI. PMID- 27977389 TI - Gel-coated tubes extend above-freezing storage of honey bee (Apis mellifera) semen to 439 days with production of fertilised offspring. AB - Honey bees are an important agricultural species; however, relatively little work has been done to improve artificial reproductive technologies for this animal. The collection and distribution of germplasm for breeding and conservation is critical for improving managed honey bee populations and conserving threatened subspecies. The most efficient method of controlling breeding in honey bees is by artificial insemination. The collection of semen for insemination requires the use of antibiotics, which is especially critical if semen is to be stored for any length of time. The introduction of antibiotics is normally done through a balanced salt solution. In this study we compare, at two temperatures, the storage of undiluted semen in antibiotic-gel-coated capillary tubes with storage of semen diluted in a balanced salt solution containing antibiotics. Live-dead cell staining and artificial insemination of honey bee queens were performed at 45, 99 and 439 days after collection of the semen. In every case the antibiotic gel-coated tube storage method at 14 degrees C produced a higher percentage of fertilised offspring. This study demonstrates the longest period of time spermatozoa have been stored above freezing while maintaining fertilisation capacity. PMID- 27977387 TI - Exploring the role of sex-seeking apps and websites in the social and sexual lives of gay, bisexual and other men who have sex with men: a cross-sectional study. AB - : Background The objective of this study was to explore the relationship between online sex-seeking, community/social attachment and sexual behaviour. METHODS: Respondent-driven sampling was used to recruit 774 sexually active gay and bisexual men in Vancouver, Canada, aged >=16 years. Multivariable logistic regression compared men who had used online sex-seeking apps/websites in the past 6 months (n=586) with those who did not (n=188). RESULTS: Multivariable results showed that online sex seekers were more likely to be younger [adjusted odds ratio (aOR)=0.95, 95% CI: (0.93-0.96)], college educated [aOR=1.60, 95% CI: (1.07, 2.40)], have more Facebook friends [aOR=1.07, 95% CI: (1.01, 1.13)], spend more social time with other gay men [aOR=1.99, 95% CI: (1.33-2.97)], and were less likely to identify emotionally with the gay community [aOR=0.93, 95% CI: (0.86-1.00)]. Further, they had displayed high sensation-seeking behaviour [aOR=1.08, 95% CI: (1.03-1.13)], were more likely to engage in serodiscordant/unknown condomless anal sex [aOR=2.34, 95% CI: (1.50-3.66)], use strategic positioning [aOR=1.72, 95% CI: (1.08-2.74)], ask their partner's HIV status prior to sex [aOR=2.06, 95% CI: (1.27-3.37)], and have ever been tested for HIV [aOR=4.11, 95% CI: (2.04-8.29)]. CONCLUSION: These findings highlight the online and offline social behaviour exhibited by gay and bisexual men, pressing the need for pro-social interventions to promote safe-sex norms online. We conclude that both Internet and community-based prevention will help reach app/web users. PMID- 27977390 TI - Development of a Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): Study Protocol. AB - BACKGROUND: Individual pharmacokinetic assessment is a critical component of tailored prophylaxis for hemophilia patients. Population pharmacokinetics allows using individual sparse data, thus simplifying individual pharmacokinetic studies. Implementing population pharmacokinetics capacity for the hemophilia community is beyond individual reach and requires a system effort. OBJECTIVE: The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project aims to assemble a database of patient pharmacokinetic data for all existing factor concentrates, develop and validate population pharmacokinetics models, and integrate these models within a Web-based calculator for individualized pharmacokinetic estimation in patients at participating treatment centers. METHODS: Individual pharmacokinetic studies on factor VIII and IX concentrates will be sourced from pharmaceutical companies and independent investigators. All factor concentrate manufacturers, hemophilia treatment centers (HTCs), and independent investigators (identified via a systematic review of the literature) having on file pharmacokinetic data and willing to contribute full or sparse pharmacokinetic data will be eligible for participation. Multicompartmental modeling will be performed using a mixed-model approach for derivation and Bayesian forecasting for estimation of individual sparse data. NONMEM (ICON Development Solutions) will be used as modeling software. RESULTS: The WAPPS-Hemo research network has been launched and is currently joined by 30 HTCs from across the world. We have gathered dense individual pharmacokinetic data on 878 subjects, including several replicates, on 21 different molecules from 17 different sources. We have collected sparse individual pharmacokinetic data on 289 subjects from the participating centers through the testing phase of the WAPPS-Hemo Web interface. We have developed prototypal population pharmacokinetics models for 11 molecules. The WAPPS-Hemo website (available at www.wapps-hemo.org, version 2.4), with core functionalities allowing hemophilia treaters to obtain individual pharmacokinetic estimates on sparse data points after 1 or more infusions of a factor concentrate, was launched for use within the research network in July 2015. CONCLUSIONS: The WAPPS-Hemo project and research network aims to make it easier to perform individual pharmacokinetic assessments on a reduced number of plasma samples by adoption of a population pharmacokinetics approach. The project will also gather data to substantially enhance the current knowledge about factor concentrate pharmacokinetics and sources of its variability in target populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT02061072; https://clinicaltrials.gov/ct2/show/NCT02061072 (Archived by WebCite at http://www.webcitation.org/6mRK9bKP6). PMID- 27977392 TI - Impact of Empagliflozin on Blood Pressure in Patients With Type 2 Diabetes Mellitus and Hypertension by Background Antihypertensive Medication. AB - : In the EMPA-REG BP trial, empagliflozin 10 mg and 25 mg once daily reduced glycohemoglobin, blood pressure (BP), and weight versus placebo in patients with type 2 diabetes mellitus and hypertension. Patients received placebo (n=271), empagliflozin 10 mg (n=276), or empagliflozin 25 mg (n=276) for 12 weeks (n=full analysis set). This present analysis investigated changes from baseline to week 12 in mean 24-hour systolic BP (SBP) and diastolic BP (DBP) in patients receiving 0, 1, or >=2 antihypertensive medications and patients receiving/not receiving diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Compared with placebo, empagliflozin 10 mg and 25 mg reduced mean 24 hour SBP/DBP in patients receiving 0 (10 mg: -3.89/-2.58 mm Hg; 25 mg: -3.77/ 2.45 mm Hg), 1 (10 mg: -4.74/-1.97 mm Hg; 25 mg: -4.27/-1.81 mm Hg), or >=2 (10 mg: -2.36/-0.68 mm Hg; 25 mg: -4.17/-1.54 mm Hg) antihypertensives. The effect of empagliflozin was not significantly different between subgroups by number of antihypertensives for changes in SBP (interaction P value 0.448) or DBP (interaction P value 0.498). Empagliflozin reduced 24-hour mean SBP/DBP irrespective of diuretic or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, with no significant difference between subgroups by use/no use of diuretics (interaction P values 0.380 [systolic]; 0.240 [diastolic]) or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (interaction P values 0.900 [systolic]; 0.359 [diastolic]). In conclusion, in patients with type 2 diabetes mellitus and hypertension, empagliflozin for 12 weeks reduced SBP and DBP versus placebo, irrespective of the number of antihypertensives and use of diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT01370005. PMID- 27977394 TI - Correction. PMID- 27977395 TI - Correction. PMID- 27977396 TI - Influence of isoform-specific Ras lipidation motifs on protein partitioning and dynamics in model membrane systems of various complexity. AB - The partitioning of the lipidated signaling proteins N-Ras and K-Ras4B into various membrane systems, ranging from single-component fluid bilayers, binary fluid mixtures, heterogeneous raft model membranes up to complex native-like lipid mixtures (GPMVs) in the absence and presence of integral membrane proteins have been explored in the last decade in a combined chemical-biological and biophysical approach. These studies have revealed pronounced isoform-specific differences regarding the lateral distribution in membranes and formation of protein-rich membrane domains. In this context, we will also discuss the effects of lipid head group structure and charge density on the partitioning behavior of the lipoproteins. Moreover, the dynamic properties of N-Ras and K-Ras4B have been studied in different model membrane systems and native-like crowded milieus. Addition of crowding agents such as Ficoll and its monomeric unit, sucrose, gradually favors clustering of Ras proteins in forming small oligomers in the bulk; only at very high crowder concentrations association is disfavored. PMID- 27977397 TI - ATP-driven processes of peroxisomal matrix protein import. AB - In peroxisomal matrix protein import two processes directly depend on the binding and hydrolysis of ATP, both taking place at the late steps of the peroxisomal import cycle. First, ATP hydrolysis is required to initiate a ubiquitin-transfer cascade to modify the import (co-)receptors. These receptors display a dual localization in the cytosol and at the peroxisomal membrane, whereas only the membrane bound fraction receives the ubiquitin modification. The second ATP dependent process of the import cycle is carried out by the two AAA+-proteins Pex1p and Pex6p. These ATPases form a heterohexameric complex, which is recruited to the peroxisomal import machinery by the membrane anchor protein Pex15p. The Pex1p/Pex6p complex recognizes the ubiquitinated import receptors, pulls them out of the membrane and releases them into the cytosol. There the deubiquitinated receptors are provided for further rounds of import. ATP binding and hydrolysis are required for Pex1p/Pex6p complex formation and receptor export. In this review, we summarize the current knowledge on the peroxisomal import cascade. In particular, we will focus on the ATP-dependent processes, which are so far best understood in the model organism Saccharomyces cerevisiae. PMID- 27977398 TI - Highlight: the transporter colloquium - spotlight on membrane proteins. PMID- 27977399 TI - Effect of integrated school-based nutrition education on optimal dietary practices and nutritional status of school adolescents in Southwest of Ethiopia: a quasi-experimental study. AB - BACKGROUND: Malnutrition and infection are major barriers to educational access and achievement in low-income countries and also work in conjunction with each other in deteriorating wellness and productivity of school adolescents. METHODS: A quasi-experimental design was used to evaluate the effectiveness of school based nutrition education using a peer-led approach, health promotion through school media and health clubs. Data were collected at baseline, midline and end line from sampled participants. To account for the effect of time trend, the difference was measured using a repeated measure analysis. Variables that have p<=0.25 in the bivariate analyses were entered into multivariables to determine the independent effect of interventions. RESULTS: There is a significant difference in food variety between food secure and insecure households (p<0.01). A significant improvement of animal source dietary intake was observed among intervention schools (p<0.001) that was significantly associated with an intervention [adjusted odds ratio (AOR)=0.26, confidence interval (CI): 0.16, 0.42], male gender (AOR=0.48, CI: 0.31, 0.73) and household economic status (AOR=1.69, CI: 1.01, 2.84). The control group had high body mass index (BMI) at baseline, but a significant improvement was observed among the intervention schools, which positively associated with male gender (AOR=4.13, CI: 2.38, 7.15) and having a middle-income family (AOR=2.93, CI: 1.92, 6.15). CONCLUSION: This study showed that by integrating a dietary intervention into school-based activities, there might be significant improvements in dietary intake of primary school adolescents. Therefore, school-based nutrition education programs should be a part of comprehensive school health programs to reach the students and potentially their families. PMID- 27977400 TI - Gastrointestinal dysfunction and autism: caution with misdiagnoses as many mysteries remain to be unraveled! PMID- 27977401 TI - Pre-aesculapian messages from ancient archives of Mesopotamia: the Epic of Gilgamesh and the library of Ashurbanipal. PMID- 27977402 TI - Sibling abuse: a Cadmean victory for societal indifference! PMID- 27977403 TI - Clinical and molecular characterization of Beckwith-Wiedemann syndrome in a Chinese population. AB - BACKGROUND: The objective of this study was to examine the clinical and molecular features, genotype-phenotype correlation and the efficacy of different diagnostic criteria for predicting a positive molecular test in Chinese Beckwith-Wiedemann syndrome (BWS) patients. METHODS: A retrospective tertiary-wide study was performed in Hong Kong with 27 molecularly confirmed BWS patients between January 2010 and September 2015. RESULTS: It was observed that 48.1% of the BWS cases were caused by loss of methylation at differentially methylated region 2 (DMR2 LoM) of the 11p15.5 region, 11.1% by gain of methylation at differentially methylated region 1 (DMR1-GoM) of the 11p15.5 region, 33.3% by paternal uniparental disomy 11 [upd (11)pat] and 7.5% by CDKN1C mutation. Two out of 27 (7.4%) had embryonal tumors. Both belonged to the DMR1-GoM subtype with one Wilm's tumor diagnosed at 3 months of age and the other, hepatoblastoma, diagnosed at 6 months of age. However, no genotype-phenotype correlation can be concluded by this cohort study. Finally, for different clinical diagnostic criteria, the Debaun and Tucker criteria and the Ibrahim et al. weighing score system have the best performance for predicting a positive molecular test in our Chinese BWS cohort. CONCLUSIONS: It is the largest study of molecularly confirmed BWS in the Chinese. Their clinical and epigenetic features are comparable with other ethnic populations. PMID- 27977393 TI - Impact of Hypertension on Cognitive Function: A Scientific Statement From the American Heart Association. AB - BACKGROUND: Age-related dementia, most commonly caused by Alzheimer disease or cerebrovascular factors (vascular dementia), is a major public health threat. Chronic arterial hypertension is a well-established risk factor for both types of dementia, but the link between hypertension and its treatment and cognition remains poorly understood. In this scientific statement, a multidisciplinary team of experts examines the impact of hypertension on cognition to assess the state of the knowledge, to identify gaps, and to provide future directions. METHODS: Authors with relevant expertise were selected to contribute to this statement in accordance with the American Heart Association conflict-of-interest management policy. Panel members were assigned topics relevant to their areas of expertise, reviewed the literature, and summarized the available data. RESULTS: Hypertension disrupts the structure and function of cerebral blood vessels, leads to ischemic damage of white matter regions critical for cognitive function, and may promote Alzheimer pathology. There is strong evidence of a deleterious influence of midlife hypertension on late-life cognitive function, but the cognitive impact of late-life hypertension is less clear. Observational studies demonstrated a cumulative effect of hypertension on cerebrovascular damage, but evidence from clinical trials that antihypertensive treatment improves cognition is not conclusive. CONCLUSIONS: After carefully reviewing the literature, the group concluded that there were insufficient data to make evidence-based recommendations. However, judicious treatment of hypertension, taking into account goals of care and individual characteristics (eg, age and comorbidities), seems justified to safeguard vascular health and, as a consequence, brain health. PMID- 27977404 TI - Sensitivity and specificity of different methods for cystic fibrosis-related diabetes screening: is the oral glucose tolerance test still the standard? AB - BACKGROUND: Cystic fibrosis-related diabetes (CFRD) is a late cystic fibrosis (CF)-associated comorbidity whose prevalence is increasing sharply lifelong. Guidelines for glucose metabolism (GM) monitoring rely on the oral glucose tolerance test (OGTT). However, this test is neither sensitive nor specific. The aim of this study was to compare sensitivity and specificity of different methods for GM monitoring in children and adolescents with CF. METHODS: Continuous glucose monitoring system (CGMS), used as the reference method, was compared with the OGTT, intravenous glucose tolerance test (IGTT), homeostasis model assessment index of insulin resistance (HOMA-IR), homeostasis model assessment index of beta cell function (HOMA-%B) and glycated haemoglobin A1C. Patients were classified into three groups according to CGMS: normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes mellitus (DM). RESULTS: Twenty-nine patients (median age: 13.1 years) were recruited. According to CGMS, 11 had DM, 12 IGT and six NGT, whereas OGTT identified three patients with DM and five with IGT. While 13 of 27 had insulin deficiency according to IGTT, there was 19 of 28 according to HOMA-%B. According to HOMA-IR, 12 of 28 had insulin resistance. HOMA-%B was the most sensitive method for CFRD screening [sensitivity 91% (95% CI), specificity 47% (95% CI) and negative predictive value 89% (95% CI)]. CONCLUSIONS: OGTT showed the weak capacity to diagnose DM in CF and should no longer be considered as the reference method for CFRD screening in patients with CF. In our study, HOMA-%B showed promising metrics for CFRD screening. Finally, CGMS revealed that pathological glucose excursions were frequent even early in life. PMID- 27977405 TI - Monitoring steroid replacement therapy in children with congenital adrenal hyperplasia. AB - BACKGROUND: The objective of this study was to compare the analysis of 17 hydroxyprogesterone (17-OHP) by radio-immunoassay (RIA) in serum with analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) on dried blood spot samples (DBSS) for monitoring therapy in children with congenital adrenal hyperplasia (CAH), and to investigate differences in 17-OHP values during the day. METHODS: Fourteen children (8 females), median age 4.2 (0.3-16.0) years, were studied. Serum samples and DBSS were drawn before hydrocortisone dosing. RESULTS: 17-OHP by LC-MS/MS in DBSS were highly correlated to 17-OHP by RIA in serum, r=0.956, p<0.01. A total of 26 three-time-point series were investigated. Using only the afternoon 17-OHP values to determine the hydrocortisone doses would have led to overdosing seven times and underdosing six times. CONCLUSIONS: Good agreement was demonstrated between 17-OHP determination by RIA in serum and LC-MS/MS on DBSS. Multiple 17-OHP measurements per day are required to ensure sufficient hydrocortisone dose adjustment. PMID- 27977406 TI - Vitamin D supplementation, the metabolic syndrome and oxidative stress in obese children. AB - BACKGROUND: Previous studies suggest that vitamin D may play a role in cardiovascular and metabolic health. Oxidative stress has also been implicated in the development of cardiovascular disease. Evidence suggests that vitamin D deficiency may contribute to the occurrence of oxidative stress. This study aimed to determine whether treatment and correction of vitamin D deficiency in obese children led to changes in their metabolic profile, independent of changes in adiposity. In addition, we aimed to determine whether vitamin D deficiency and oxidative stress are causally related in obese children. METHODS: In the retrospective arm, chart review identified 32 obese children who experienced normalization of vitamin D deficiency or insufficiency with vitamin D supplementation. We then correlated laboratory and anthropometric data with vitamin D levels. In the prospective arm of the study, urinary 8-isoprostane and hydrogen peroxide were measured before and after correction of vitamin D deficiency/insufficiency and correlated to vitamin D levels in seven patients. RESULTS: In our predominantly Hispanic population of obese children in an urban setting, we demonstrated a cause-effect relationship between vitamin D deficiency and oxidative stress. In contrast, we found no association between vitamin D status, adiposity, and markers of insulin sensitivity, nor any effect of vitamin D treatment on the same parameters. CONCLUSIONS: These discordant findings suggest a differential effect of vitamin D on cardiovascular risk factors such as oxidative stress and insulin resistance. To confirm these findings, further prospective studies with larger sample size and longer follow-up are warranted. PMID- 27977408 TI - Use of translabial three-dimensional power Doppler ultrasound for cervical assessment before labor induction. AB - OBJECTIVE: To compare translabial three-dimensional (3D) power Doppler ultrasound with Bishop score and transvaginal ultrasound measurements for cervical assessment before induction of labor with dinoprostone or cervical ripening balloon. MATERIALS AND METHODS: Translabial cervical volume and length, vascularization indices and transvaginal cervical length were measured. Results were compared among women who had vaginal delivery at 24 h or less and more than 24 h after the insertion of the dinoprostone vaginal insert or cervical ripening balloon and among women who had vaginal delivery and cesarean delivery for failure to go into labor or failure to progress. RESULTS: There was no correlation between the time to delivery after a ripening agent was applied and translabial cervical volume, translabial cervical length, vascularization index (VI), flow index (FI), vascularization flow index (VFI), transvaginal cervical length and Bishop scores. The ultrasonographic measurements were no different among women who had vaginal delivery at 24 h or less and more than 24 h and among women who had vaginal delivery and cesarean delivery for failure to go into labor or failure to progress. CONCLUSION: In this study, we failed to demonstrate the superiority of translabial 3D ultrasonography over Bishop score and transvaginal ultrasonography for predicting the success of induction of labor. PMID- 27977407 TI - Usefulness of non-fasting lipid parameters in children. AB - BACKGROUND: This study assessed whether non-fasting lipid markers could be substituted for fasting markers in screening for dyslipidemia, whether direct measurement of non-fasting low-density lipoprotein cholesterol [LDL-C (D)] could be substituted for the calculation of fasting LDL-C [LDL-C (F)], and the utility of measuring non-high-density lipoprotein cholesterol (non-HDL-C). METHODS: In 33 children, the lipid profile was measured in the non-fasting and fasting states within 24 h. Correlations were examined between non-fasting LDL-C (D) or non-HDL C levels and fasting LDL-C (F) levels. RESULTS: Non-fasting triglyceride (TG), total cholesterol (TC), HDL-C, LDL-C (D), and non-HDL-C levels were all significantly higher than the fasting levels, but the mean difference was within 10% (except for TG). Non-fasting LDL-C (D) and non-HDL-C levels were strongly correlated with the fasting LDL-C (F) levels. CONCLUSIONS: In conclusion, except for TG, non-fasting lipid parameters are useful when screening children for dyslipidemia. Direct measurement of non-fasting LDL-C and calculation of non fasting non-HDL-C could replace the calculation of fasting LDL-C because of convenience. PMID- 27977409 TI - YKL-40 expression in abnormal invasive placenta cases. AB - OBJECTIVE: YKL-40 is a secreted glycoprotein and has been implicated in the proliferation and differentiation of malignant cells, extracellular tissue remodelling, neovascularisation, inhibition of cancer cell apoptosis and stimulation of tumour-associated fibroblasts. The purpose of this study was to evaluate YKL-40 tissue expression in extravillous trophoblast invasion and its possible implication in placenta creta. METHODS: A total of 35 placenta creta cases and six control cases were included in the study, of which eight cases were placenta accreta, 12 were increta and 15 were percreta. Histological YKL-40 staining was scored in tissue as weak (1), medium (2) and strong (3). RESULTS: YKL-40 immunoreactivity intensity in the percreta group was significantly higher compared to the increta and accreta groups (2.47+/-0.74, 1.33+/-0.49 and 1.37+/ 0.52, respectively; P=0.000). YKL-40 immunoreactivity intensity was positively correlated with creta (r=0.6; P=0.000), depth of invasion (r=0.49; P=0.003) and depth of invasion to full thickness ratio (r=0.58; P=0.000). CONCLUSION: This study demonstrated that YKL-40 is strongly expressed in placenta percreta and is correlated with extravillous trophoblast invasion. These findings may be informative for understanding the pathophysiology of placenta creta. PMID- 27977410 TI - How serious are health impacts in one of the most polluted regions of Central Europe? AB - BACKGROUND: The long-term exposure to pollutants in ambient air is associated with higher mortality and occurrence of respiratory and cardiopulmonary diseases. The longitudinal cross-section study focuses on the associations between long term exposures to carcinogenic and non-carcinogenic pollutants and the prevalence and incidence of such specific diseases including immunodeficiencies. METHODS: The data on health status from industrial and non-industrial regions were obtained from health documentation for a 5-year period from 2007 to 2011 and represent the whole population living in polluted (1,249,323 inhabitants) and unpolluted (631,387 inhabitants) regions. The data on concentrations of PM10, PM2,5, NO2, SO2, benzene and benzo[a]pyrene were collected. The concentrations of pollutants were estimated from measured data by using dispersion models. The average population-weighted concentration of pollutants, which is representative for a defined geographic area and time period from 2007 to 2011, was calculated from the obtained data. The logistic regression and the Mantel-Haenszel chi2 test were used to determine the odds ratios (OR) and p-values for a linear trend. Moreover, the relative risks of mortality and morbidity to specific diseases were calculated according to theoretical dose-response association published by World Health Organization (WHO). RESULTS: The probability of incidence of chronic obstructive pulmonary disease and bronchial asthma is statistically significantly higher in the population living in the polluted region compared to the population living in the unpolluted region. The association between long-term exposure to pollutants and the prevalence of immunodeficiency with predominantly antibody defects (D80) was confirmed. The strongest association was found for exposures to particulate matter (PM2,5). The prevalence of immunodeficiency with predominantly antibody defects was also observed in both regions depending on the age of the population and statistically significant difference was only found in the group of adults (20 and over). CONCLUSION: These associations encourage the hypothesis, that the long-term exposure to PM2.5 might cause the activation of cellular immune response. Further research is needed to explore the correlative immunoregulatory mechanism linking PM2.5 (or other pollutants - SO2) and immune cells. Nowadays, it is also believed that these associations are important in the increase of incidence of immune inflammatory response which is proven risk factor for cardiovascular disease (atherosclerotic disease, coronary heart disease and sudden cardiac death). Positive association between long-term exposure and prevalence of bronchial asthma and chronic obstructive pulmonary disease might be skewed due to important socio-economic factors (especially smoking). PMID- 27977411 TI - Dolutegravir monotherapy: when should clinical practice be clinical research? PMID- 27977412 TI - Design and application of a structured phantom for detection performance comparison between breast tomosynthesis and digital mammography. AB - This paper introduces and applies a structured phantom with target objects for the comparison of detection performance of digital breast tomosynthesis (DBT) against full field digital mammography (FFDM). The phantom consists of a 48 mm thick breast-shaped polymethyl methacrylate (PMMA) container filled with water and PMMA spheres of different diameters. Three-dimensionally (3D) printed spiculated masses (diameter range: 3.8-9.7 mm) and non-spiculated masses (1.6-6.2 mm) along with microcalcifications (90-250 um) were inserted as targets. Reproducibility of the phantom application was studied on a single system using 30 acquisitions. Next, the phantom was evaluated on five different combined FFDM & DBT systems and target detection was compared for FFDM and DBT modes. Ten phantom images in both FFDM and DBT modes were acquired on these 5 systems using automatic exposure control (AEC). Five readers evaluated target detectability. Images were read with the four-alternative forced-choice (4-AFC) paradigm, with always one segment including a target and 3 normal background segments. The percentage of correct responses (PC) was assessed based on 10 trials of each reader for each object type, size and modality. Additionally, detection threshold diameters at 62.5 PC were assessed via non-linear regression fitting of the psychometric curve. The reproducibility study showed no significant differences in PC values. Evaluation of target detection in FFDM showed that microcalcification detection thresholds ranged between 110 and 118 um and were similar compared to the detection in DBT (range of 106-158 um). In DBT, detection of both mass types increased significantly (p=0.0001 and p=0.0002 for non spiculated and spiculated masses respectively) compared to FFDM, achieving almost 100% detection for all spiculated mass diameters. In conclusion, a structured phantom with inserted targets was able to show evidence for detectability differences between FFDM and DBT modes for five commercial systems. This phantom has potential for application in task-based assessment at acceptance and commissioning testing of DBT systems. PMID- 27977413 TI - A high-performance nanobridged MoO3 UV photodetector based on nanojunctions with switching characteristics. AB - Ultraviolet photodetectors (UVPDs) were fabricated via the in situ growth of orthorhombic MoO3 nanobelts among interdigital electrodes. Two types of nanojunction, touching and interpenetration, were formed between neighboring nanobelts at different growth conditions. The photoresponse mechanism of the UVPDs greatly depends on the type of nanojunction. Nanojunctions formed with touching nanobelts possess switching characteristics due to the barrier height variation along with the UV illumination. The UVPD with the touching structure exhibits low noise, high UV sensitivity and fast speed, having a dark current of 1.4 nA, an on/off ratio of over 100 and a response time of below 1 s, at an applied voltage of 10 V. The enhanced performance can be attributed to the switching characteristics of the touching nanojunction. PMID- 27977414 TI - Two-dimensional WS2 nanoribbon deposition by conversion of pre-patterned amorphous silicon. AB - We present a method for area selective deposition of 2D WS2 nanoribbons with tunable thickness on a dielectric substrate. The process is based on a complete conversion of a pre-patterned, H-terminated Si layer to metallic W by WF6, followed by in situ sulfidation by H2S. The reaction process, performed at 450 degrees C, yields nanoribbons with lateral dimension down to 20 nm and with random basal plane orientation. The thickness of the nanoribbons is accurately controlled by the thickness of the pre-deposited Si layer. Upon rapid thermal annealing at 900 degrees C under inert gas, the WS2 basal planes align parallel to the substrate. PMID- 27977415 TI - Practical experiences in the transfer of clinical protocols between CT scanners with different ATCM systems. AB - Automatic tube current modulation (ATCM) systems to aid in optimizing dose and image noise have become standard on computed tomography (CT) scanners over the last decade. ATCM systems of the main vendors modulate tube current in slightly different ways, with some using a control parameter related to image noise (e.g. Toshiba, GE) while others use a quality reference image mAs (e.g. Siemens). The translation of clinical protocols including ATCM operation between CT scanners from different manufacturers in order to obtain similar levels of image quality with optimized exposure variables has become an important issue. In this study, cylindrical phantoms of different sizes representing small, average and large patients, have been combined into one phantom, which has been scanned on Siemens, Toshiba and GE CT scanners with the full ranges of ATCM image quality settings. The volume weighted CT dose index (CTDIvol) and image noise over each section of the phantom were recorded for every setting. Relationships between the image quality level settings, and CTDIvol and measured image noise were analysed in order to investigate ATCM performance. Equations were developed from fits of the data to enable CTDIvol and image noise to be expressed in terms of the image quality parameters for different size phantoms on each scanner. The Siemens scanner protocol was chosen as the reference, as it avoided high doses for large patients, while allowing full modulation of tube current for patients of all sizes, and so was considered to provide optimized performance. The equations derived were used to equate the noise parameters on Toshiba and GE scanners to the quality reference mAs on the Siemens scanner, so that clinical protocols incorporating similar levels of optimization could be obtained on the three CT scanners. PMID- 27977416 TI - Novel fluorescent CdTe quantum dot-thymine conjugate-synthesis, properties and possible application. AB - Novel, highly fluorescent cadmium telluride quantum dots conjugated with thymine and stabilized with thioglycolic acid were obtained and characterized. Successful formation of the conjugate was confirmed by elemental analysis, and UV-vis, fluorescence and Fourier transform infrared spectroscopies. Crystal structure and composition of the conjugates were characterized with xray diffraction and x-ray photoelectron spectroscopy. The size of the conjugates was 4-6 nm as demonstrated using atomic force microscopy and high resolution transmission electron microscopy imaging. The plasmon resonance fluorescence band at 540 nm on excitation at 351 nm was observed for these nanoparticles. The intensity of this band increased with the increase in the amount of conjugated thymine with no shift in its position. Based on the fluorescence measurements it was found that the CdTe-thymine conjugate interacted efficiently and selectively not only with adenine, a nucleobase complementary to thymine, but also with adenine-containing modified nucleosides, i.e., 5'-deoxy-5'-(methylthio)adenosine and 2'-O methyladenosine, the urinary tumor markers which allow monitoring of the disease progression. To the best of our knowledge, as yet, there have been no studies presented in literature on that type of the interaction with CdTe-thymine conjugates. Therefore, the system presented can be considered as a working component of a selective adenine/adenosine biosensor with potential application in cancer diagnosis. PMID- 27977417 TI - Bioresponsive polymer coated drug nanorods for breast cancer treatment. AB - Ineffective drug release at the target site is among the top challenges for cancer treatment. This reflects the facts that interaction with the physiological condition can denature active ingredients of drugs, and low delivery to the disease microenvironment leads to poor therapeutic outcomes. We hypothesize that depositing a thin layer of bioresponsive polymer on the surface of drug nanoparticles would not only protect drugs from degradation but also allow the release of drugs at the target site. Here, we report a one-step process to prepare bioresponsive polymer coated drug nanorods (NRs) from liquid precursors using the solvent diffusion method. A thin layer (10.3 +/- 1.4 nm) of poly(epsilon-caprolactone) (PCL) polymer coating was deposited on the surface of camptothecin (CPT) anti-cancer drug NRs. The mean size of PCL-coated CPT NRs was 500.9 +/- 91.3 nm length * 122.7 +/- 10.1 nm width. The PCL polymer coating was biodegradable at acidic pH 6 as determined by Fourier transform infrared spectroscopy. CPT drugs were released up to 51.5% when PCL coating dissolved into non-toxic carboxyl and hydroxyl groups. Trastuzumab (TTZ), a humanized IgG monoclonal antibody, was conjugated to the NR surface for breast cancer cell targeting. Combination treatments using CPT and TTZ decreased the HER-2 positive BT-474 breast cancer cell growth by 66.9 +/- 5.3% in vitro. These results suggest effective combination treatments of breast cancer cells using bioresponsive polymer coated drug delivery. PMID- 27977418 TI - Very thin ITO/metal mesh hybrid films for a high-performance transparent conductive layer in GaN-based light-emitting diodes. AB - In this paper, we introduce very thin Indium tin oxide (ITO) layers (5, 10, and 15 nm) hybridized with a metal mesh to produce high-performance transparent conductive layers (TCLs) in near-ultraviolet light-emitting diodes (NUV LEDs). Using UV-vis-IR spectrometry, Hall measurement, and atomic force microscopy, we found that 10 nm was the optimal thickness for the very thin ITO layers in terms of outstanding transmittance and sheet resistance values as well as stable contact properties when hybridized with the metal mesh. The proposed layers showed a value of 4.56 Omega/? for sheet resistance and a value of 89.1% for transmittance. Moreover, the NUV LEDs fabricated with the hybrid TCLs achieved ~140% enhanced light output power compared to that of 150 nm thick ITO layers. Finally, to verify the practical usage of the TCLs for industrial applications, we packaged the NUV LED chips and obtained improved turn-on voltage (3.48 V) and light output power (~116%) performance. PMID- 27977420 TI - Enhanced room-temperature NO2 gas sensing with TeO2/SnO2 brush- and bead-like nanowire hybrid structures. AB - We have synthesized two highly sensitive, room-temperature operating TeO2/SnO2 gas sensors with hierarchical nanowire structures. One is a brush-like nanostructure, from a two-step thermal vapor-transport route, and the other one is a TeO2/SnO2 bead-like nanostructure, from annealing of the former. The TeO2/SnO2 nanostructures exhibit a greatly enhanced room-temperature gas-sensing response compared to pristine TeO2 nanowires in the sequence: TeO2/SnO2 bead-like structure > brush-like structure > pristine TeO2 nanowire. The response of the TeO2/SnO2 bead-like structure is in a range of 10 to 20 against NO2 gas of ppm levels (3-100 ppm) at room temperature. This compares favorably to the response, smaller than 2, for the pristine TeO2 nanowires. Interestingly, the TeO2/SnO2 bead-like structure exhibits a typical n-type gas-sensing behavior, in contrast to the p-type behavior from the brush-like and the pristine TeO2 structures. Possible hybrid growth and sensing mechanisms are discussed. PMID- 27977419 TI - A computational model that predicts behavioral sensitivity to intracortical microstimulation. AB - OBJECTIVE: Intracortical microstimulation (ICMS) is a powerful tool to investigate the neural mechanisms of perception and can be used to restore sensation for patients who have lost it. While sensitivity to ICMS has previously been characterized, no systematic framework has been developed to summarize the detectability of individual ICMS pulse trains or the discriminability of pairs of pulse trains. APPROACH: We develop a simple simulation that describes the responses of a population of neurons to a train of electrical pulses delivered through a microelectrode. We then perform an ideal observer analysis on the simulated population responses to predict the behavioral performance of non-human primates in ICMS detection and discrimination tasks. MAIN RESULTS: Our computational model can predict behavioral performance across a wide range of stimulation conditions with high accuracy (R 2 = 0.97) and generalizes to novel ICMS pulse trains that were not used to fit its parameters. Furthermore, the model provides a theoretical basis for the finding that amplitude discrimination based on ICMS violates Weber's law. SIGNIFICANCE: The model can be used to characterize the sensitivity to ICMS across the range of perceptible and safe stimulation regimes. As such, it will be a useful tool for both neuroscience and neuroprosthetics. PMID- 27977421 TI - Subcellular distribution and cellular self-repair ability of fluorescent quantum dots emitting in the visible to near-infrared region. AB - Semiconductor II-VI quantum dots (QDs), as high-performance fluorescent biological probes, have garnered significant attention due to their superior optical properties. To enable QDs for wide-ranging bioapplications, concerns about their in vitro behavior need to be fully addressed. Herein, for the first time, cellular behaviors of aqueous synthesized-QDs (aqQDs), whose maximum emission wavelength (lambda emission) covers the visible to near-infrared spectral window, are systematically investigated. Our results demonstrate that three different sized aqQDs feature distinct cellular distributions, i.e. aqQD530 (aqQDs whose lambda emission is 530 nm) and aqQD620 (aqQDs whose lambda emission is 620 nm) mainly distribute in the cytoplasm and nucleus, while aqQD730 (aqQDs whose lambda emission is 730 nm) mainly accumulates in the cytoplasm. Most significantly, the phenomenon that cellular self-repair ability is dependent on diameters of aqQDs is revealed for the first time. In particular, small-sized QDs (e.g. aqQD530 and aqQD620) severely deteriorate cellular self-repair ability, leading to an irreversible decrease in cell viability. In striking contrast, large-sized QDs (e.g. aqQD730) have little effect on cellular self-repair ability, and the cell viability is restored after removal of aqQD730 from the culture medium. Our results provide invaluable information for QD-relevant biosafety analysis, as well as suggest available guidance for the design of biocompatible QDs for wide utilization in biological and biomedical studies. PMID- 27977423 TI - Commentary on "Insurance Status, Not Race, is Associated With Use of Minimally Invasive Surgical Approach for Rectal Cancer". PMID- 27977424 TI - A new case series of Crisponi syndrome in a Turkish family and review of the literature. AB - Crisponi syndrome/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder with a complex phenotype, reported in the neonatal period for CS and in the evolutive one for CISS. The syndrome usually manifests at birth. The aim of this study was to report on three new patients with CS and review the Turkish patients. We report here on three patients from two related families harboring a homozygous mutation in the cytokine receptor-like factor-1 (CRLF1) gene. DNA samples of the three patients and their parents were subjected to a mutational analysis of the CRLF1 gene at the Institute of Biomedical and Genetic Research - National Research Council, Cagliari (Italy). Direct sequencing of the nine coding exons and surrounding intronic regions of CRLF1 was performed using specific primers. All three patients were found to be homozygotes for the mutation c.708_709delinsT, which leads to a frameshift in the second fibronectin type III domain (p.Pro238Argfs*6). CS should be considered in the differential diagnosis of newborns with muscle contractions, feeding and swallowing difficulties, dysmorphic facial findings, camptodactyly, and hypertermia. Neonatologists must be aware of this syndrome that, although very rare worldwide, has a higher prevalence in Turkey. PMID- 27977425 TI - Sensory Symptom Profiles of Patients With Neuropathic Pain After Spinal Cord Injury. AB - AIM: Individuals experiencing neuropathic pain (NP) after spinal cord injury (SCI) present with a variety of pain descriptors in different combinations and at different intensities. These sensory features form distinct patterns, known as sensory symptom profiles. METHODS: In the present cross-sectional study, we have used a multivariate statistical method (multiple correspondence analysis) to categorize the sensory symptom profiles of a cohort of 338 patients with at-level or below-level NP after SCI. We also investigated possible associations between positive neuropathic symptoms and features of the neurological lesion. RESULTS: The majority of participants had a combination of pain descriptors, with 59% presenting with 3 or 4 pain subtypes. No significant associations were found between specific pain profiles and etiology or clinical degree of the neurological lesion. Furthermore, similar symptom profiles were seen in patients with at-level and below-level NP. The most frequent pattern observed in patients with cervical SCI consisted predominantly of electric shocks and tingling, without burning, pressure pain, or allodynia. CONCLUSIONS: Classification of SCI NP patients into the 5 groups identified in the present study based on their distinct sensory symptom profiles may allow identification of those most likely to respond to a specific analgesic approach. PMID- 27977426 TI - Symptoms of Depression and Risk of Low Back Pain: A Prospective Co-Twin Study. AB - OBJECTIVES: To investigate whether symptoms of depression increase the risk of low back pain (LBP), after adjusting for genetic and environmental influences. METHODS: Baseline data of 1607 twins from the Murcia Twin Registry (Spain) were collected in 2009 to 2011 and follow-up data in 2013. Twins answered questions on depression-related symptomatology and LBP. Only participants not reporting chronic LBP (pain >6 mo) at baseline were included. The association between symptoms of depression and LBP was investigated using logistic regression analysis including the complete sample. Subsequent matched within-pair case control analyses were performed with all complete dizygotic twin pairs discordant for LBP, followed by monozygotic twins. RESULTS: In the total sample analysis, symptoms of depression did not significantly increase the risk of chronic LBP (odds ratio [OR]=1.40; 95% confidence interval [CI], 0.96-2.03), LBP care seeking (OR=1.21; 95% CI, 0.81-1.81), or activity-limiting LBP (OR=1.09; 95% CI, 0.69 1.72). State depression (participants' symptoms at the moment of the interview) was significantly associated with future care seeking (OR=1.06; 95% CI, 1.01 1.12) and activity-limiting LBP (OR=1.07; 95% CI, 1.01-1.14). A significant association was found between trait depression and activity-limiting LBP (OR=1.05; 95% CI, 1.01-1.10), but not for the other LBP outcomes. No significant association was observed in any of the subsequent case-control analyses. DISCUSSION: The magnitude of the association between depression and LBP seems to be small and may be confounded by genetic and early shared environment influences, although firm conclusions could not be made due to small sample size in the case-control analysis. In addition, the observed association is dependent on the method of assessment used for both conditions. PMID- 27977427 TI - Therapeutic Effects of Nurse Telephone Follow-up for Lung Cancer Patients in Turkey. AB - BACKGROUND: Patients with lung cancer can encounter many difficulties as they adjust to the side effects of chemotherapy treatments. OBJECTIVE: The aim of this study is to determine the therapeutic effects of nurse telephone follow-up for lung cancer patients. METHODS: In this quasi-experimental study, the sample consisted of 60 patients with lung cancer assigned to an intervention group (n = 30) and a control group (n = 30). The control group participants were sequentially enrolled first and then the intervention group participants were enrolled. The data were collected using the Patient Information Form, Eastern Cooperative Oncology Group Performance Status, the Edmonton Symptom Assessment Scale, and the Functional Living Index-Cancer. The Nursing Care Guide was created by the nurse researchers' team and given to both the intervention and control groups. Telephone follow-up calls were conducted with intervention patients within the first week after their chemotherapy session. The Kolmogorov-Smirnov, Pearson chi, Fisher exact, Mann-Whitney U, and Friedman test and descriptive statistics were used to evaluate the data. RESULTS: Patients in the intervention group demonstrated significantly better adjustment to the symptoms secondary to chemotherapy and higher social functioning quality of life scores compared with reported scores in the control group. CONCLUSION: Nurse telephone follow-up can reduce chemotherapy-related symptoms for lung cancer patients and improve participants' social functioning. IMPLICATIONS FOR PRACTICE: Nurse telephone follow-up is an acceptable and feasible form of patient contact and is a convenient and efficient way to offer patients the support and continuity of care they need. PMID- 27977428 TI - Breaking down the complement system: a review and update on novel therapies. AB - PURPOSE OF REVIEW: The complement system represents one of the more primitive forms of innate immunity. It has increasingly been found to contribute to pathologies in the native and transplanted kidney. We provide a concise review of the physiology of the complement cascade, and discuss current and upcoming complement-based therapies. RECENT FINDINGS: Current agents in clinical use either bind to complement components directly or prevent complement from binding to antibodies affixed to the endothelial surface. These include C1 esterase inhibitors, anti-C5 mAbs, anti-CD20 mAbs, and proteasome inhibitors. Treatment continues to show efficacy in the atypical hemolytic uremic syndrome and antibody mediated rejection. Promising agents not currently available include CCX168, TP10, AMY-101, factor D inhibitors, coversin, and compstatin. Several new trials are targeting complement inhibition to treat antineutrophilic cystoplasmic antibody (ANCA)-associated vasculitis, C3 glomerulopathy, thrombotic microangiopathy, and IgA nephropathy. New agents for the treatment of the atypical hemolytic uremic syndrome are also in development. SUMMARY: Complement based therapies are being considered for targeted therapy in the atypical hemolytic uremic syndrome and antibody-mediated rejection, C3 glomerulopathy, and ANCA-associated vasculitis. A few agents are currently in use as orphan drugs. A number of other drugs are in clinical trials and, overall, are showing promising preliminary results. PMID- 27977429 TI - Fish consumption and omega-3 fatty acid supplementation for prevention or treatment of cognitive decline, dementia or Alzheimer's disease in older adults - any news? AB - PURPOSE OF REVIEW: Twenty years of research indicates that fish and n-3 fatty acids (FAs), for example docosahexaenoic acid, may attenuate cognitive decline including Alzheimer's disease in older people. This review concerns reports during 2015-2016 in humans. RECENT FINDINGS: One prospective cohort study showed that seafood consumption was related to less neuritic plaques and neurofibrillary tangles in brain autopsies from elderly care residents. In a large 5-year intervention no effects on cognition could be shown either in n-3 FA supplemented or in control patients. Two meta-analyses in community-dwelling patients support preservation of cognition with higher fish intake. Older adults with memory complaints may improve cortical blood flow during memory challenges by n-3 FA supplementation. Recalculations from a report in Alzheimer's disease patients indicated a dose-response pattern between increments of serum n-3 FAs and cognitive improvement. Still, a Cochrane review (using three randomized control trials) concluded that n-3 FAs cannot provide any 6-month benefit in patients with mild/moderate Alzheimer's disease. SUMMARY: The accumulated knowledge indicates that healthy populations may have preventive benefits from fish and docosahexaenoic acid intake, like older adults with memory complaints/mild cognitive impairment, and maybe subgroups of patients with mild/moderate Alzheimer's disease may also show such benefits. Still, more studies are needed. PMID- 27977430 TI - Long-term consequences of acute kidney injury in the perioperative setting. AB - PURPOSE OF REVIEW: Recent studies indicate that acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected syndromes. Although the majority of patients who suffer an episode of AKI will recover laboratory indices suggesting complete or near complete recovery of renal function, a significant portion of post-AKI survivors will develop major kidney events, including development of late-stage CKD, need for renal replacement therapies, and death. RECENT FINDINGS: Our review highlights epidemiology of adverse post-AKI events, association of AKI with late development of nonrenal adverse outcomes, use of bedside equations that facilitate prognostication of adverse renal outcomes of AKI, and how variability in serum creatinine values in individual patients, even among those with normal baseline renal function may indicate risk for the development of CKD. Use of common laboratory parameters such as serum creatinine and albumin, along with certain clinical and demographic markers, individualize patients at high risk of complications and in need of close postdischarge follow up. Evidence that 'organ crosstalk' following a major AKI episode may increase the risk of heart failure, stroke, and hypertension, places its survivors in a special patient category deserving active efforts to minimize risk for cardiovascular events. SUMMARY: AKI is a major cause for acute in-hospital mortality and development of both late-stage CKD and cardiovascular events. Perioperative care to prevent AKI must challenge the notion that a single normal point of contact serum creatinine value substantially reduces the likelihood of its occurrence. PMID- 27977431 TI - Effectiveness of Extracorporeal Shock Wave Therapy Without Local Anesthesia in Patients With Recalcitrant Plantar Fasciitis: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: The objective of this meta-analysis was to investigate the efficacy of extracorporeal shock wave therapy in the treatment of recalcitrant plantar fasciitis without local anesthesia. METHODS: The Cochrane Library, EMBASE, PubMed, and Web of Science databases were searched from inception to September 2015 for randomized controlled trials comparing ESWT without local anesthesia versus placebo for treatment of plantar fasciitis in adults. The primary outcome was the 12-week post-intervention success rate of reducing the visual analog scale score by 60% from baseline at the first step in the morning, reducing the VAS score by 60% from baseline during daily activities, reducing the Roles and Maudsley score, reducing overall heel pain, and reducing pain after applying a force meter. RESULTS: Nine studies were included in the meta-analysis. Compared with placebo, ESWT significantly improved the success rate of reducing overall heel pain, reducing the VAS score by 60% at the first step in the morning and during daily activities, improving the Roles and Maudsley score to excellent or good, and reducing heel pain after application of a pressure meter. CONCLUSIONS: ESWT seems to be particularly effective in relieving pain associated with RPF. ESWT should be considered when traditional treatments have failed. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to (1) understand the recovery rates for nonsurgical treatment of plantar fasciitis, (2) understand the role of extracorporeal shockwave therapy (ESWT) in the treatment of recalcitrant plantar fasciitis, and (3) understand the indications to incorporate ESWT in the treatment plan of recalcitrant plantar fasciitis. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. PMID- 27977432 TI - The Effects of Early Exercise on Motor, Sense, and Memory Recovery in Rats With Stroke. AB - OBJECTIVE: Exercise is an effective, inexpensive, home-based, and accessible intervention strategy for stroke treatment, and early exercise after stroke has attracted a great deal of attention in recent years. However, the effects of early exercise on comprehensive functional recovery remain poorly understood. The present study investigated the effect of early exercise on motor, sense, balance, and spatial memory recovery. DESIGN: Adult Sprague-Dawley rats were subjected to unilateral middle cerebral artery occlusion (MCAO) and were randomly divided into early exercise group (EE), non-exercise group (NE), and sham group. EE group received 2 weeks of exercise training initiated at 24 hours after operation. The recovery of motor, sense, and balance function was evaluated every 3 days after MCAO. Spatial memory recovery was detected from 21 to 25 days after MCAO. RESULTS: The results showed that early exercise significantly promoted the motor and spatial memory recovery with statistical differences. The rats in EE group have a better recovery in sense and balance function, but there is no statistically significant difference about these results. CONCLUSION: Our results showed that early moderate exercise can significantly promote motor and spatial memory recovery, but not the sense and balance functions. PMID- 27977436 TI - Pitfalls With the New American College of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy. AB - The American College of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy was created to evaluate the existing literature, develop practice guidelines, and identify areas for future research focus. Several issues were identified that may not have been initially obvious during the process of developing this document, including limited practical use, a lack of high quality literature, conflicting recommendations, a potential for high resource utilization, need for continually updated information, and little headway in research that is clinically useful. The purpose of this review was to make suggestions to improving these guidelines' overall usefulness and consistency for the busy clinician. PMID- 27977437 TI - Novel Therapy for the Treatment of Early-Onset Preeclampsia. AB - Preeclampsia is a multisystem disorder affecting 2% to 8% of pregnancies and a leading cause of maternal and perinatal morbidity and mortality worldwide. Recent investigations have improved our understanding of the pathogenesis of this potentially life-threatening disease, especially in its early-onset form of manifestation. Despite these advances, therapeutic options are still limited and no effective pharmacologic interventions are currently available. Ongoing lines of research indicate some potential novel treatments targeting specific pathogenic steps. In this article we provide an updated overview of the multiple therapeutic approaches under preclinical and clinical assessment for the treatment of early-onset preeclampsia. PMID- 27977433 TI - Phase I dose-escalation study of plitidepsin in combination with sorafenib or gemcitabine in patients with refractory solid tumors or lymphomas. AB - This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer and lymphoma patients. The study included two treatment arms: a sorafenib/plitidepsin (S/P) and a gemcitabine/plitidepsin (G/P) arm. In the S/P arm, patients were treated orally with sorafenib continuous dosing at two dose levels (DL1: 200 mg twice daily and DL2: 400 mg twice daily) combined with plitidepsin (1.8 mg/m, day 1, day 8, day 15, and, q4wk, intravenously). In the G/P arm, patients with solid tumors or lymphoma were treated at four different DLs with a combination of gemcitabine (DL1: 750 mg/m, DL2-DL4: 1000 mg/m) and plitidepsin (DL1-DL2: 1.8 mg/m; DL3: 2.4 mg/m; DL4: 3 mg/m). Both agents were administered intravenously on day 1, day 8, day 15, and, q4wk. Forty-four patients were evaluable for safety and toxicity. The safety of the combination of plitidepsin with sorafenib or gemcitabine was manageable. Most adverse events (AEs) were mild; no grade 4 treatment-related AEs were reported in any of the groups (except for one grade 4 thrombocytopenia in the gemcitabine arm). The most frequently reported study drug-related (or of unknown relationship) AEs were palmar-plantar erythrodysesthesia, erythema, nausea, vomiting, and fatigue in the S/P arm and nausea, fatigue, and vomiting in the G/P arm. In the S/P arm, one dose-limiting toxicity occurred in two out of six patients treated at the maximum dose tested (DL2): palmar-plantar erythrodysesthesia and grade 2 aspartate aminotransferase/alanine aminotransferase increase that resulted in omission of days 8 and 15 plitidepsin infusions. In the G/P arm, one dose-limiting toxicity occurred in two out of six patients at DL4: grade 2 alanine aminotransferase increase resulted in omission of days 8 and 15 plitidepsin infusions and grade 4 thrombocytopenia. The recommended dose for the combination of plitidepsin with sorafenib was not defined because of a sponsor decision (no expansion cohort to confirm) and for plitidepsin with gemcitabine, it was 2.4 mg/m plitidepsin with 1000 mg/m gemcitabine. In the S/P group, objective disease responses were not observed; however, disease stabilization (>=3months) was observed in four patients. In the gemcitabine group, two lymphoma patients showed an objective response (partial response and complete response) and nine patients showed disease stabilization (>=3months). Combining plitidepsin with gemcitabine and sorafenib is feasible for advanced cancer patients; some objective responses were observed in heavily pretreated lymphoma patients. PMID- 27977438 TI - Improvement of sleep architecture parameters in cirrhotic patients with recurrent hepatic encephalopathy with the use of rifaximin. AB - BACKGROUND AND AIM: Sleep disorders are frequently reported in patients with cirrhosis and hepatic encephalopathy (HE). This study assessed the effect of rifaximin on sleep architecture parameters in patients with recurrent HE. PATIENTS AND METHODS: This sequential, prospective, and exploratory study involved all patients with cirrhosis and recurrent HE admitted between June 2014 and September 2015. HE was assessed according to the West-Haven Classification. Patients underwent 24-h polysomnography (PSG) and 7-day actigraphy. Rapid eye movement (REM) sleep was considered to be an indicator of good sleep quality. Patients completed questionnaires assessing the quality of sleep and sleepiness. After a 28-day course of rifaximin, the same assessment was repeated. RESULTS: Fifteen patients were included (nine men, mean age: 57+/-11 years). Child-Pugh scores ranged from B7 to C15. Before rifaximin, the mean HE score was 2.7+/-0.7. Data from PSG analysis indicated long total sleep time (TST): 571+/-288 min, and limited REM sleep: 2.5% TST (0-19). Seven-day actigraphy showed an impaired number of steps: 1690/24 h (176-6945). Questionnaires indicated that patients experienced impaired sleep quality and excessive daytime sleepiness. After rifaximin, HE scores decreased to 1.7+/-0.6 (P<0.001). REM sleep increased to 8.5% TST (0-25) (P=0.003). No changes were observed for TST, number of steps, and on questionnaires. CONCLUSION: Patients with recurrent HE suffer from poor sleep quality and excessive daytime sleepiness. On 24-h PSG, rifaximin improves objective sleep architecture parameters with no changes in the subjective quality of sleep and sleepiness. PMID- 27977440 TI - BMP Use and the Risk of Revision Surgery After Long Posterolateral Fusions in the Elderly. AB - STUDY DESIGN: Retrospective database review. OBJECTIVE OF THE STUDY: The objective of the study was to assess whether bone morphogenetic protein (BMP) decreases the risk of revision surgery in elderly patients treated with 3-7 level or 8 or greater level fusions. SUMMARY OF BACKGROUND DATA: Revision spine surgery in the elderly is a complex undertaking, highlighting the importance of discovering methods to decrease the risk of repeat procedures. The role of BMP in modulating risk of future revision surgery is not well studied in the elderly. MATERIALS AND METHODS: The PearlDiver database (2005-2012) was queried for elderly adult spinal deformity patients treated with a primary thoracolumbar posterolateral fusion of 3 or more levels. To compare how BMP modifies revision surgery rates in 3-7 level versus 8 level or greater fusions, 4 mutually exclusive cohorts were created and matched to one another: 1043 patients treated with 8 or greater level fusions with BMP; 1111 patients with 8 or greater level fusions without BMP; 2813 patients with 3-7 level fusions with BMP; and 4770 patients with 3-7 level fusions without BMP. Revision and complication rates were compared. Complications included seroma formation, heterotopic ossification, and postoperative neuritis within 90 days. RESULTS: Patients treated with BMP during an 8 or greater level fusion were significantly less likely to require a revision surgery than matched controls (relative risk, 0.75, P=0.015). BMP use was not associated with a decreased risk of revision surgery in 3-7 level fusions (relative risk, 0.89, P=0.20). Patients treated with BMP during 3-7 level fusions were significantly less likely to develop any of the assessed complications (P=0.02). There were no other significant differences in pairwise comparisons of subcohorts of each of the fusion lengths. CONCLUSIONS: BMP use decreases revision rates in elderly adult spinal deformity patients treated with 8 or greater level fusions, but not in those treated with 3-7 level fusions. LEVEL OF EVIDENCE: Level III. PMID- 27977439 TI - Bilateral sternal infusion of ropivacaine and length of stay in ICU after cardiac surgery with increased respiratory risk: A randomised controlled trial. AB - BACKGROUND: The continuous bilateral infusion of a local anaesthetic solution around the sternotomy wound (bilateral sternal) is an innovative technique for reducing pain after sternotomy. OBJECTIVE: To assess the effects of the technique on the need for intensive care in cardiac patients at increased risk of respiratory complications. DESIGN: Randomised, observer-blind controlled trial. SETTING: Single centre, French University Hospital. PATIENTS: In total, 120 adults scheduled for open-heart surgery, with one of the following conditions: age more than 75 years, BMI >30 kg m, chronic obstructive pulmonary disease, active smoking habit. INTERVENTION: Either a bilateral sternal infusion of 0.2% ropivacaine (3 ml h through each catheter; 'intervention' group), or standardised care only ('control' group). Analgesia was provided with paracetamol and self administered intravenous morphine. MAIN OUTCOME MEASURES: The length of time to readiness for discharge from ICU, blindly assessed by a committee of experts. RESULTS: No effect was found between groups for the primary outcome (P = 0.680, intention to treat); the median values were 42.4 and 37.7 h, respectively for the control and intervention groups (P = 0.873). Similar nonsignificant trends were noted for other postoperative delays. Significant effects favouring the intervention were noted for dynamic pain, patient satisfaction, occurrence of nausea and vomiting, occurrence of delirium or mental confusion and occurrence of pulmonary complications. In 12 patients, although no symptoms actually occurred, the total ropivacaine plasma level exceeded the lowest value for which neurological symptoms have been observed in healthy volunteers. CONCLUSION: Because of a small size effect, and despite significant analgesic effects, this strategy failed to reduce the time spent in ICU. TRIAL REGISTRATION: EudraCT (N degrees : 2012-005225-69); ClinicalTrials.gov (NCT01828788). PMID- 27977441 TI - Fluoroscopic Confirmation of Sacral Pedicle Screw Placement Utilizing Pelvic Inlet and Outlet Technique: Technical Note. AB - Minimally invasive surgical techniques may decrease length of stay, operative duration and blood loss, and postoperative pain. Numerous technical challenges and concerns surround the placement of percutaneous pedicle screws at the lumbosacral level. Maximization of screw triangulation, bicortical purchase, and rostral bias toward the sacral promontory has been shown repeatedly to stabilize lumbosacral segment instrumentation and maximize pullout strength. Because of the unique anatomy, conventional anteroposterior (AP) and lateral radiographic views are relatively less reliable at determining screw depth and penetration of the sacral cortex. Percutaneous sacral pedicle fixation using AP and lateral 2 dimensional fluoroscopy is complicated by the variable contour of the sacral alae and promontory. The pelvic inlet view is ideal for visualization of the ventral screw extent and is obtained by directing 45-degree cephalad and 0-degree mediolateral, with adjustments aligning the patient's pelvic brim. The modified pelvic outlet view is obtained with the trajectory axis being directed 45-degree caudal from the AP plane. This aligns the pubic symphysis with the second sacral vertebrae providing visualization of the superior boundary of the S1-bony neural foramen and any inferior wall pedicle breaches. The authors describe this reliable fluoroscopic technique and their clinical experience with percutaneous S1-screw placement. PMID- 27977442 TI - The Assessment of Upright Cervical Spinal Alignment Using Supine MRI Studies. AB - STUDY DESIGN: This is a prospective, single-centre study. OBJECTIVE: The purpose of this study is researching whether there is a correlation or not between the cervical alignment in the examinations of magnetic resonance imaging (MRI) in lying position and the alignment in the cervical direct radiography and whether the cervical alignment in standing position could be estimated or not through MRI measurements in the supine position. SUMMARY OF BACKGROUND DATA: Cervical spinal alignment is a parameter required for deciding the surgical procedure particularly in patients with cervical myelopathy and deformity. However, cervical alignment angles change according to lying and standing positions. Therefore, the direct standing radiograph is taken as basis for this examination. METHODS: Cervical alignments were measured with 3 different methods with the standing lateral radiographies and lying MRI of 51 patients with cervical disorder. RESULTS: A high correlation was found between the measurements in standing and lying positions for the spinal alignments measured through the Cobb angle and posterior tangent method. It was found that standing Cobb angle (in plain graphy)=Cobb angle (in MRI)*0.489+7.13 and posterior tangent angle (in plain graphy)=posterior tangent angle (in MRI)*0.54+9.37. CONCLUSIONS: It is possible to estimate the spinal alignment in standing position with the measurements of cervical spinal alignment in the MRI at supine position. And this may render having cervical graphy in standing position unnecessary. PMID- 27977443 TI - Anterior Versus Posterior Approaches for Odontoid Fracture Stabilization in Patients Older Than 65 Years: 30-day Morbidity and Mortality in a National Database. AB - STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: To compare 30-day perioperative clinical outcomes of surgical odontoid stabilization by an anterior or posterior operative approach in elderly patients. SUMMARY OF BACKGROUND DATA: Surgical stabilization of odontoid fractures is superior to nonoperative management in geriatric patients. How elderly patients with odontoid fractures fare after anterior and posterior approaches, however, is not well defined. MATERIALS AND METHODS: Retrospective review of the prospectively collected American College of Surgeons National Surgical Quality Improvement Program database (2005-2013). Elderly patients (>=65 y) with odontoid fractures who underwent odontoid stabilization through anterior or posterior approaches were identified by International Classification of Diseases 9th Revision/Common Procedure Terminology codes. Exclusion criteria included concomitant subaxial spine surgery, instrumentation noncontiguous with the atlantoaxial interval, and combined approaches. Baseline demographics and perioperative details were compared. Adverse events, mortality, reoperation, discharge, and readmission rates within 30 days of operation were compared using bivariate and multivariate generalized linear regressions. RESULTS: One hundred forty-one patients (male-81; female-60; average age: 77.8+/-6.5 y; anterior approach-48; posterior approach 93) were analyzed. Patients scheduled to have a posterior approach had significantly more nonunions preoperatively and higher body mass indices. Operative times for posterior surgeries were significantly longer. Age, comorbidities, functional dependence, time to surgery, and length of hospital stay were similar between groups. There were no significant differences in the relative risk (RR) of the composite outcome of "any adverse event" after adjusting for differences in baseline characteristics. Patients who underwent an anterior approach were more likely to have an unplanned hospital readmission (RR=8.95; 95% confidence interval, 2.21-36.29; P=0.002) and have significantly more revision operations (RR=19.51; 95% confidence interval, 2.49-152.62; P=0.005) than patients who had a posterior operation. CONCLUSIONS: An anterior approach for odontoid fracture stabilization in patients >=65 years old were associated with shorter operative times and greater RRs of unplanned readmissions and revision operations within 30 days of surgery relative to a posterior approach. PMID- 27977444 TI - Outcome of Decompression Alone for Foraminal/Extraforaminal Entrapment of L5 Nerve Root Through Wiltse Paraspinal Approach. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE OF THE STUDY: The objective of the study was to present the surgical outcome and analyze the prognostic factors for postoperative leg pain after posterior decompression alone for foraminal/extraforaminal L5 entrapment at L5-S1 segment (LSS). SUMMARY OF BACKGROUND DATA: Disk extrusion, hypertrophy of facet joint, osteophyte of vertebral body, thickened lumbosacral ligament, and collapsed disk lead to form the lumbosacral tunnel which compresses the L5 exiting nerve root. There are few reports discussing the outcome and prognostic factors of posterior decompression alone. MATERIALS AND METHODS: One hundred two consecutive patients underwent posterior decompressive surgery through Wiltse approach for foraminal/extraforaminal entrapment at LSS, performed by 2 surgeons. Demography and preoperative radiograph were analyzed for 6 parameters: age, pathology, disk height, relative disk height ratio, depth of L5 vertebrae within the pelvis, and coronal wedging angle of the segment. Clinical outcomes were assessed by the Visual Analog Scale score for back and leg pain, Oswestry Disability Index, and modified Macnab criteria. The incidence of medications of anticonvulsants, opioids, epidural nerve root block and revisional surgery at index level were also examined. RESULTS: This study included 93 patients. The mean follow-up period was 40.6+/-19.7 months. Thirty-six patients had disk herniation and 57 had stenosis. Preoperative Visual Analog Scale score and Oswestry Disability Index significantly improved at the final follow-up. On the basis of the modified Macnab criteria, 83% of the patients had good outcomes at follow-up. The mean duration of the medications of anticonvulsants or opioids is 27.2+/-37.4 days (0 210 d). 5 patients (5.4%) were reoperated. Relative disk height ratio <0.8 was associated with worsening of postoperative leg pain (P<0.01). CONCLUSIONS: Decompression as the only method for foraminal/extraforminal lesion of LSS through Wiltse paraspinal approach provided good clinical results. A large difference of disk height between standing and supine positions is associated with poor clinical outcomes. PMID- 27977454 TI - Images in Anesthesiology: Mirror Image: A Patient with Situs Inversus Totalis. PMID- 27977456 TI - Who Is Really the Communicator of Adverse Outcomes-And When? PMID- 27977457 TI - In Reply. PMID- 27977458 TI - Complexities of Bleeding During Spine Surgery: It'll Take Your (Mechanical) Breath Away. PMID- 27977459 TI - In Reply. PMID- 27977461 TI - Peripheral Nerve Blockade for Primary Total Knee Arthroplasty: A Population-based Cohort Study of Outcomes and Resource Utilization. AB - BACKGROUND: Although peripheral nerve blocks decrease pain after total knee arthroplasty, the population-level impact of nerve blocks on arthroplasty resource utilization is unknown. METHODS: We conducted a population-based cohort study using linked administrative data from Ontario, Canada. We identified all adults having their first primary knee arthroplasty between 2002 and 2013. Using propensity scores to adjust for measureable confounders, we matched nerve block patients to a patient who did not receive a block. Within the matched cohort, we estimated the independent association of blocks with outcomes (length of hospital stay [primary]; and readmissions, emergency department visits, and falls [secondary]). RESULTS: One hundred seventy-eight thousand two hundred fourteen patients were identified; 61,588 (34.6%) had a block. The mean hospital stay was 4.6 days with a block compared to 4.8 without. After matching, there was a statistically significant decrease in the length of stay in the block group (relative risk, 0.98; 95% CI, 0.97 to 0.99; P < 0.001). Blocks were associated with a significant decrease in readmissions (relative risk, 0.87; 95% CI, 0.79 to 0.88; P < 0.001) but not emergency department visits (relative risk, 1.02; 95% CI, 0.98 to 1.05) or falls (relative risk, 1.37; 95% CI, 0.90 to 2.08). The association of blocks with length of stay after 2008 was inconsistent; overall, they were associated with longer stays; however, single-shot blocks were associated with shorter stays, while continuous techniques prolonged the length of stay. CONCLUSIONS: Nerve blocks in total knee arthroplasty patients were associated with statistically significant reductions in length of stay and readmissions, but not emergency department visits or falls. The significance of these findings at the patient level and in contemporary practice requires further exploration in prospective randomized studies at low risk of indication bias. PMID- 27977462 TI - A Feedback and Evaluation System That Provokes Minimal Retaliation by Trainees. AB - BACKGROUND: Grade inflation is pervasive in educational settings in the United States. One driver of grade inflation may be faculty concern that assigning lower clinical performance scores to trainees will cause them to retaliate and assign lower teaching scores to the faculty member. The finding of near-zero retaliation would be important to faculty members who evaluate trainees. METHODS: The authors used a bidirectional confidential evaluation and feedback system to test the hypothesis that faculty members who assign lower clinical performance scores to residents subsequently receive lower clinical teaching scores. From September 1, 2008, to February 15, 2013, 177 faculty members evaluated 188 anesthesia residents (n = 27,561 evaluations), and 188 anesthesia residents evaluated 204 faculty members (n = 25,058 evaluations). The authors analyzed the relationship between clinical performance scores assigned by faculty members and the clinical teaching scores received using linear regression. The authors used complete dyads between faculty members and resident pairs to conduct a mixed effects model analysis. All analyses were repeated for three different epochs, each with different administrative attributes that might influence retaliation. RESULTS: There was no relationship between mean clinical performance scores assigned by faculty members and mean clinical teaching scores received in any epoch (P >= 0.45). Using only complete dyads, the authors' mixed effects model analysis demonstrated a very small retaliation effect in each epoch (effect sizes of 0.10, 0.06, and 0.12; P <= 0.01). CONCLUSIONS: These results imply that faculty members can provide confidential evaluations and written feedback to trainees with near zero impact on their mean teaching scores. PMID- 27977460 TI - Perioperative Outcomes and Management in Pediatric Complex Cranial Vault Reconstruction: A Multicenter Study from the Pediatric Craniofacial Collaborative Group. AB - BACKGROUND: The Pediatric Craniofacial Collaborative Group established the Pediatric Craniofacial Surgery Perioperative Registry to elucidate practices and outcomes in children with craniosynostosis undergoing complex cranial vault reconstruction and inform quality improvement efforts. The aim of this study is to determine perioperative management, outcomes, and complications in children undergoing complex cranial vault reconstruction across North America and to delineate salient features of current practices. METHODS: Thirty-one institutions contributed data from June 2012 to September 2015. Data extracted included demographics, perioperative management, length of stay, laboratory results, and blood management techniques employed. Complications and outlier events were described. Outcomes analyzed included total blood donor exposures, intraoperative and perioperative transfusion volumes, and length of stay outcomes. RESULTS: One thousand two hundred twenty-three cases were analyzed: 935 children aged less than or equal to 24 months and 288 children aged more than 24 months. Ninety-five percent of children aged less than or equal to 24 months and 79% of children aged more than 24 months received at least one transfusion. There were no deaths. Notable complications included cardiac arrest, postoperative seizures, unplanned postoperative mechanical ventilation, large-volume transfusion, and unplanned second surgeries. Utilization of blood conservation techniques was highly variable. CONCLUSIONS: The authors present a comprehensive description of perioperative management, outcomes, and complications from a large group of North American children undergoing complex cranial vault reconstruction. Transfusion remains the rule for the vast majority of patients. The occurrence of numerous significant complications together with large variability in perioperative management and outcomes suggest targets for improvement. PMID- 27977464 TI - Clinical utility of the 6-min walk test for patients with moderate Parkinson's disease. AB - The aim of this study was to test the clinical utility of the 6-min walk test (6MWT) for patients with moderate Parkinson's disease (PD) through a determination of factors related to this test. This was a descriptive, observational study carried out at a General Hospital, in-patients. Twenty-four patients with moderate PD were studied. We used Hoehn and Yahr stage ratings (HY stage), Unified Parkinson Disease Rating Scales (UPDRS) motor examination score, 6MWT, Berg Balance scale, Timed 'Up & Go' test (TUG), 10-m walk test (10-m walk speed, 10-m walk steps and cadence), and the energy cost of walking (Ec). The average HY stage was 3.1+/-0.5 and 6MWT was 340.8+/-110.9 m. TUG (r=-0.68, P<0.01) and Ec (r=-0.65, P<0.01) were correlated significantly with 6MWT. Multiple regression analysis with age, HY stage, TUG, cadence, and Ec as variables indicated a significant degree of variability in the 6MWT results (R=0.77, P<0.001). The TUG (beta=-0.47, P<0.01) and Ec (beta=-0.4, P<0.01) were correlated independently with the 6MWT results. In contrast, age, HY stage, and cadence were not independently correlated. The 6MWT is a simple tool for assessing walking capacity for patients with PD. In this study, we confirmed the convergent validity and clinical utility of the 6MWT for patients with moderate PD. The 6MWT is useful for clinical assessment to guide the planning of rehabilitation treatment for patients with moderate PD. PMID- 27977463 TI - Breast cancer: updates and advances in 2016. AB - PURPOSE OF REVIEW: Approximately 1 in 8 US women (12%) will develop invasive breast cancer over the course of her lifetime. In 2016, an estimated 246,660 new cases of invasive breast cancer are expected to be diagnosed and approximately 40,450 would die as a result of it. The global burden of breast cancer exceeds all other cancers and the incidence is increasing. The heterogeneity of breast cancer makes it a challenging solid tumor to diagnose and treat. This review focuses on the recent advances in breast cancer therapy including hormonal treatment of metastatic breast cancer, targeting cyclin-dependent kinases (CDK) 4/6 in breast cancer, updates in targeting human epidermal growth factor receptor 2 (HER2) positive breast cancer, adaptive randomization trial design and cancer genetic risk assessment. RECENT FINDINGS: Breast cancer is a heterogeneous disease and targeted therapy is improving the outcomes of women. The use of cyclin-dependent kinase inhibitors (CDK) 4/6 have demonstrated a substantial improvement in progression-free survival in the first line setting of metastatic hormone receptor positive breast cancer. And newer agents directed at HER2 continue to revolutionize HER2-positive breast cancer treatment. SUMMARY: This review highlights the recent updates in breast cancer treatment, new concepts in clinical trial design and provides a current overview of cancer genetic risk assessment. PMID- 27977465 TI - Effectiveness of repetitive transcranial magnetic stimulation in patients with fibromyalgia: a meta-analysis. AB - Even though repetitive transcranial magnetic stimulation (rTMS) has been used for a decade for the treatment of fibromyalgia, evidence of its effectiveness has not been definitely presented. The aim of this study was to investigate whether there is evidence of rTMS being effective in decreasing the severity of pain among patients with fibromyalgia. CENTRAL, MEDLINE, EMBASE, CINAHL, SCOPUS, WEB OF SCIENCE, and relevant references of the identified studies were searched. Randomized controlled studies on adults with fibromyalgia were included. The outcome studied was change in pain severity. Methodological quality was assessed using the scale introduced in the Guidelines for Systematic Reviews in the Cochrane Collaboration Back Review Group. A random-effects meta-analysis was carried out with a test for heterogeneity using the I and pooled estimate as a nonstandardized mean of difference in change in pain severity measures by a numeric rating scale. The search resulted in 791 records, eight relevant, and meta-analyses on seven trials. The risk of bias was considered low for seven studies. Pain severity before and after the last stimulation decreased by -1.2 points on 0-10 numeric rating scale (95% confidence interval: -1.7 to -0.8). Pain severity before and 1 week to 1 month after the last stimulation decreased by 0.7 points (95% confidence interval: -1.0 to -0.3). Both pooled results were below the minimal clinically important difference of 1.5 points. There is moderate evidence that rTMS is not more effective than sham in reducing the severity of pain in fibromyalgia patients, questioning the routine recommendation of this method for fibromyalgia treatment. PMID- 27977466 TI - Extremely Small Pseudoparamagnetic Iron Oxide Nanoparticle as a Novel Blood Pool T1 Magnetic Resonance Contrast Agent for 3 T Whole-Heart Coronary Angiography in Canines: Comparison With Gadoterate Meglumine. AB - OBJECTIVE: The aim of this study was to evaluate an extremely small pseudoparamagnetic iron oxide nanoparticle (ESPIO), KEG3, as a potential blood pool agent in 3 T coronary magnetic resonance angiography (MRA) in canine models and compare its efficacy to that of a gadolinium-based contrast agent. MATERIALS AND METHODS: Nine mongrel dogs were subjected to whole-heart coronary MRA in 2 separate sessions at 7-day intervals with a 3 T scanner using the FLASH sequence with either gadoterate meglumine (Gd-DOTA) or the ESPIO (KEG3). Coronary MRA was performed twice at each MR examination: the first scan during the administration of the contrast agent and the subsequent second scan at 15 minutes after contrast injection. Objective measurements of the Gd-DOTA and ESPIO images, including the signal-to-noise ratios (SNRs) for the coronary arteries and cardiac veins, contrast-to-noise ratios (CNRs) between the vessels and fat (CNRfat) and the vessels and the myocardium (CNRmyocardium), and subjective image quality scores on a 4-point scale were evaluated and compared. RESULTS: The mean SNRs and CNRs of all vascular regions in the ESPIO images were similar to those of the corresponding regions in the Gd-DOTA images in the first scan (98.1 +/- 32.5 vs 79.1 +/- 38.4 for SNR of coronary arteries, P = 0.3; 74.2 +/- 30.1 vs 61.4 +/- 38.5 for CNR, P = 0.7) and more than 2 times higher than the latter in the second scan (95.2 +/- 31.3 vs 32.1 +/- 8.1 for SNR of coronary arteries, P = 0.008; 76.1 +/- 35.8 vs 17.6 +/- 19.2 for CNR, P 0.008). Similarly, the mean values of the subjective measurements of the ESPIO images were similar to those of the Gd-DOTA images (3.9 +/- 0.3 vs 3.3 +/- 0.8 for coronary arteries, P = 0.1) in the first scan and significantly better than the latter in the second scan (3.9 +/- 0.2 vs 2.1 +/- 0.6 for coronary arteries, P = 0.007). CONCLUSIONS: The experimental blood pool agent KEG3 offers equivalent image quality for whole-heart coronary MRA at 3 T upon contrast administration and persistent better quality in the subsequent scans, compared with a traditional extracellular gadolinium-based contrast agent. PMID- 27977467 TI - Time to Discontinuation of Second-Generation Antipsychotics Versus Haloperidol and Sulpiride in People With Schizophrenia: A Naturalistic, Comparative Study. AB - PURPOSE: A retrospective study was conducted to evaluate the time to discontinuation (TTD) of the first- (FGAs) and second-generation antipsychotics (SGAs). METHODS: In total, 918 treatment episodes of patients with schizophrenia, initiated on one of the investigated drugs on an outpatient basis during 2004 2006, were entered into the study. The primary outcome was the duration of the investigated treatment episode. Discontinuation was defined when either patients were admitted or the investigated drug had been stopped for more than 28 days. We used the Cox proportional hazard model to compare hazards of discontinuations among 8 SGAs versus 2 FGAs (haloperidol and sulpiride). The follow-up period was up to 18 months. RESULTS: During the follow-up period, clozapine had the highest rate of continuous treatment in the primary analysis: clozapine, 40.6%; olanzapine, 23.4%; aripiprazole, 22.9%; amisulpride, 21.9%; zotepine, 21.3%; sulpiride, 17.0%; risperidone, 12.8%; quetiapine, 12.5%; haloperidol, 10.6%; and ziprasidone, 10.4%. Compared with haloperidol, 5 SGAs had significantly longer TTD (adjusted hazard ratios and 95% confidence intervals): clozapine (0.403, 0.267-0.607), olanzapine (0.611, 0.439-0.849), aripiprazole (0.570, 0.407-0.795), amisulpride (0.680, 0.487-0.947), and zotepine (0.687, 0.497-0.948), but only clozapine had significantly longer TTD compared with sulpiride (0.519, 0.342 0.786). The sensitivity analysis showed similar results. IMPLICATIONS/CONCLUSIONS: The current findings suggested that SGAs or FGAs are not homogeneous groups. Clozapine has the highest rate of continuous treatment among SGAs, and haloperidol is not the representative drug for all FGAs. Furthermore, antipsychotics dropout rate is high in naturalistic situation. A good service model needs to be constructed to enhance antipsychotic treatment adherence of people with schizophrenia. PMID- 27977468 TI - A Case of Asperger Syndrome With Comorbidity of Posttraumatic Stress Disorder and Selective Mutism: Significant Remission With the Combination of Aripiprazole and Eye Movement Desensitization and Reprocessing. PMID- 27977469 TI - Efficacy and Tolerability of High-Dose Escitalopram in Posttraumatic Stress Disorder. AB - BACKGROUND: Open-label trials suggest that escitalopram (up to 20 mg/d) is an effective treatment for some, but not all posttraumatic stress disorder (PTSD) patients. Higher doses of escitalopram effectively reduced major depression symptoms in patients who had not responded to regular doses. The current study examines the efficacy, tolerability, and adherence to high-dose escitalopram in PTSD. METHODS: Forty-five PTSD patients received 12 weeks of gradually increasing doses of escitalopram reaching 40 mg daily at 4 weeks. Among those, 12 participants received regular doses of antidepressants at study onset including escitalopram (n = 7). The Clinician-Administered PTSD Scale (CAPS) evaluated PTSD symptoms severity before treatment, at 3 months (upon treatment termination), and at 6 months (maintenance effect). A 20% reduction in CAPS scores was deemed clinically significant. RESULTS: Adverse events and medication adherence were monitored at each clinical session. Linear mixed-models analysis showed a significant reduction of mean CAPS scores (11.5 +/- 18.1 points) at 3 months and maintenance of gains by 6 months (F2,34.56 = 8.15, P = 0.001). Eleven participants (34.3%) showed clinically significant improvement at 3 months. Only 9 participants (20%) left the study. There were no serious adverse events and few mild ones with only 2 adverse events (diarrhea, 11.1%; drowsiness, 11.1%) reported by more than 10% of participants. CONCLUSION: High doses of escitalopram are tolerable and well adhered to in PTSD. Their beneficial effect at a group level is due to a particularly good response in a subset of patients.Variability in prior pharmacological treatment precludes a definite attribution of the results to high doses of escitalopram. PMID- 27977470 TI - The Utility of Low-Dose Aripiprazole for the Treatment of Bipolar II and Bipolar NOS Depression. AB - BACKGROUND: Despite initial reports of efficacy in bipolar depression, multicenter trials did not show aripiprazole to be better than placebo, possibly because the doses used were too high, leading to lower efficacy and high dropout rates. This study evaluated the effects of low-dose aripiprazole. Extensive clinical experience has suggested that doses beyond 5 mg are rarely efficacious. METHODS: Data were gathered from patients with bipolar II or bipolar not otherwise specified depression using a retrospective chart review. Efficacy was assessed with the Clinical Global Impression-Improvement score. Patients who had at least 2 trials of aripiprazole were included in a retrospective off-on-off-on experimental design. All patients were on other medications when aripiprazole was started. Patients were treated with doses of 1 to 5 mg. FINDINGS: On average, patients were rated improved or very much improved compared with baseline. Sixteen of 211 patients worsened or experienced no change. Forty-four patients (21%) discontinued due to adverse effects. The group of patients who underwent off-on-off-on trials experienced statistically significant improvement when they started and restarted aripiprazole, and statistically significant worsening when they discontinued it. CONCLUSIONS: When treating bipolar II or bipolar not otherwise specified depression, low doses of aripiprazole, 5 mg or less, may be more effective and better tolerated than higher ones. Clinicians should start treatment with a very low dose and give patients time to respond. PMID- 27977472 TI - Cost-effectiveness of nitrendipine and hydrochlorothiazide or metoprolol to treat hypertension in rural community health centers in China. AB - OBJECTIVES: The objective of this article is to compare blood pressure (BP) lowing effects of nitrendipine and hydrochlorothiazide and nitrendipine and metoprolol, and estimate the economic effect of these therapies on hypertension. METHODS: Outpatients (N = 793) 18-70 years of age with stage 2 or severe hypertension (SBP >= 160 mmHg and/or DBP >= 100 mmHg) were recruited from four randomly selected rural community health centers in Beijing and Jilin. After drug wash out, they were randomly divided into nitrendipine and hydrochlorothiazide group or nitrendipine and metoprolol group. The costs of drug treatment for hypertension were calculated and general estimation, whereas effectiveness was measured as a reduction in SBP and DBP at the end of a 24-week study period. RESULTS: Overall, 623 patients were eligible for the study and after a 24-week follow-up, SBP and DBP were 131.2/82.2 mmHg for the nitrendipine and hydrochlorothiazide group and 131.4/82.9 mmHg for the nitrendipine and metoprolol group and these were not significantly different (P = 0.7974 SBP and P = 0.1166 DBP). Comparing with nitrendipine and metoprolol, the cost of nitrendipine and hydrochlorothiazide was less, and its effectiveness was similar. The cost/effect ratio (US$/mmHg) was 1.4 for SBP and 2.8 for DBP for the nitrendipine and hydrochlorothiazide group, and 1.9 and 3.8 for the nitrendipine and metoprolol group's SBP and DBP values, respectively. The incremental cost per patient for achieving target BP was 5.1. Adverse events were mild or moderate and there were no differences between treatment groups. CONCLUSION: Treating hypertension with nitrendipine and hydrochlorothiazide was cost-effective than nitrendipine and metoprolol, and these data will allow more reasonable and efficient allocation of limited resources in low-income countries. PMID- 27977474 TI - Referral to Low Vision Services for Glaucoma Patients: Referral Patterns and Characteristics of Those Who Refer. AB - PURPOSE: To identify characteristics of ophthalmologists and practices who refer glaucoma patients to low vision services (LVS). MATERIALS AND METHODS: An online survey was distributed to members of the American Glaucoma Society. The survey queried demographics of responders and their clinical practices, criteria and barriers to referral to LVS. Survey responders were categorized as high referrers if they reported referring >5 patients to LVS and low referrers if they referred <=5. chi and Fischer exact tests were used to compare characteristics between high and low referrers. Logistic regression analyses were used to calculate odds ratios and 95% confidence intervals and determine factors associated with referrer status. RESULTS: High referrers to LVS tended to have >10 patients per month who had already seen a low vision provider (53% vs. 10%, P<0.001), reported following the American Academy of Ophthalmology's Preferred Practice Pattern (PPP) recommendations for LVS referrals (38% vs. 18%, P=0.011), and expressed satisfaction with their current referral practices (86% vs. 70%, P=0.049). In the fully adjusted model those who followed PPP were 2.5 times more likely to report being a high referrer as compared with a low referrer (95% confidence interval, 1.1-5.3). However, only 22% of ophthalmologists reported following these guidelines in their practice. The number of years in practice, practice location or type, volume of patients seen each week, and distance to a low vision clinic were not associated with referral. CONCLUSIONS: Familiarity with PPP guidelines may positively influence LVS referral practices. PMID- 27977473 TI - Usefulness of ambulatory blood pressure monitoring to assess the melanocortin receptor agonist bremelanotide. AB - BACKGROUND: Melanocortin receptor agonists that bind to the melanocortin receptor 4 may cause increases in blood pressure (BP). Bremelanotide is an on-demand, subcutaneous melanocortin-receptor agonist that binds to the melanocortin receptor 4 and is being developed for the treatment of female sexual dysfunction. METHODS: We studied the effects of bremelanotide administration on ambulatory BP and heart rate (HR), in a randomized, double-blind, placebo-controlled, and parallel-arm trial of three doses of bremelanotide (0.75, 1.25, and 1.75 mg) in 397 premenopausal women with female sexual dysfunction with normotension or controlled hypertension. Pharmacokinetic exposure was assessed in conjunction with ambulatory BP measurements. RESULTS: Increases in ambulatory SBP relative to placebo of 2.4 and 3.0 mmHg (1.25 mg; P values: 0.029 and 0.076) and 3.1 and 3.2 mmHg (1.75 mg; P values: 0.006 and 0.027), respectively, occurred following two doses, separated by 24 h at the 0 to 4-h postdose interval; peak increases typically lasted less than 15 min. Similar increases in the DBP were observed. Increases in BP were accompanied by reductions in HR during the 0-4-h interval for the 1.75-mg dose (-4.6 to -4.7 bpm; P < 0.001). Twenty-six participants discontinued after randomization due to prespecified increases in BP but the proportions were similar among the four treatment groups. CONCLUSION: These data show that ambulatory monitoring was a useful methodology to detect small, transient increases in ambulatory BP accompanied by reductions in HR following bremelanotide. Results of this trial led to appropriate in-clinic BP monitoring during the larger clinical development trials of this agent for female sexual dysfunction. PMID- 27977475 TI - Trabecular Micro-Bypass Stent Use in Necrotizing Scleritis. AB - PURPOSE: In this case report, we describe the successful implantation of multiple trabecular micro-bypass iStents in a patient with necrotizing scleritis. DESIGN: The study design is a case report. PARTICIPANTS: The participant was a patient who underwent multiple micro-bypass iStent surgery. METHODS: A 71-year-old man with primary open-angle glaucoma, diagnosed with necrotizing scleritis and treated with steroids consequently resulting in significantly elevated intraocular pressure in the right eye. RESULTS: Following uncomplicated surgery, IOP was reduced from 42 to 12 mm Hg 18 months after surgery on 2 drops and prednisone 40 mg daily CONCLUSIONS:: iStents may be considered as a possible intervention to lower IOP in patients with necrotizing scleritis in whom traditional glaucoma surgery is challenging or contraindicated. PMID- 27977476 TI - 24-Hour Intraocular Pressure Rhythm in Patients With Untreated Primary Open Angle Glaucoma and Effects of Selective Laser Trabeculoplasty. AB - PURPOSE OF THE STUDY: The purpose of the study was to evaluate the 24-hour nyctohemeral rhythm of intraocular pressure (IOP) in patients with untreated primary open angle glaucoma using a contact lens sensor. To evaluate the effect of selective laser trabeculoplasty (SLT) on the 24-hour rhythm of IOP. MATERIALS AND METHODS: Prospective study conducted in a chronobiology center. Fourteen patients with primary open angle glaucoma underwent three 24-hour IOP measurement sessions after a complete wash-out of the medical treatment: before SLT and 1 and 6 months after, using the contact lens sensor Triggerfish (SENSIMED, Lausanne, Switzerland). IOP and the main parameters of nyctohemeral rhythm (existence of a rhythm, acrophase, bathyphase, midline estimating statistic of rhythm, amplitude, and range) before SLT were compared with the same parameters measured 1 and 6 months later. RESULTS: IOP increased from 16.3+/-3.7 to 22.1+/-8.4 mm Hg (5.8 mm Hg; 95% confidence interval (CI), 2.41-12.71; P=0.009) after the wash-out procedure. After SLT, IOP significantly decreased by 3.4 mm Hg (95% CI, 0.09 7.89; P=0.041) (14.9%) at 1 month and 1.9 mm Hg (95% CI 0.10-3.84; P=0.044) (8.1%) at 6 months. After medication wash-out, 100% of the subjects had a nyctohemeral IOP rhythm with nocturnal acrophase (01:57+/-3:32 AM, 01:22+/-3:01 AM, and 03:17+/-2:12 AM at inclusion, 1 and 6 mo, respectively). SLT did not significantly change the characteristics of the 24-hour IOP pattern, notably the amplitude and the type of rhythm (persistence of nocturnal acrophase). CONCLUSIONS: After medical treatment wash-out, patients with open angle glaucoma consistently had a significant 24-hour IOP rhythm with nocturnal acrophase. SLT reduces the absolute IOP value but does not modify the nyctohemeral IOP rhythm. PMID- 27977477 TI - Iridocorneal Endothelial Syndrome Presenting With Large Diurnal Intraocular Pressure Fluctuation. AB - PURPOSE OF THE STUDY: The purpose of the study was to report a case of iridocorneal endothelial syndrome with an initial presentation of a large diurnal fluctuation of intraocular pressure (IOP) which peaked early in the morning. METHODS: A 31-year-old white man had transient blurry vision oculus sinister (OS) upon awakening in the morning for the past 2 months. The blurry vision improved within 1 to 2 hours. Clinical examination, diurnal IOP measurements, and specular microscopy were performed to investigate the cause of his transient blurry vision. RESULTS: At 6 AM, IOP OS was 38 mm Hg with corneal edema and visual acuity of 20/30. At 8 AM, IOP OS decreased to 25 mm Hg with clear cornea and visual acuity of 20/20. Diurnal IOP measurements revealed a large fluctuation OS (18 mm Hg). Specular microscopy revealed pleomorphism, polymegathism, light peripheral borders and light/dark reversal of the corneal endothelium OS. IOP oculus dexter remained within normal limits with clear cornea and stable visual acuity throughout the diurnal measurements. CONCLUSIONS: In patients with consistent daily episodes of transient blurry vision, clinicians should suspect a large diurnal IOP fluctuation with high peak IOP. If symptoms and signs are unilateral, iridocorneal endothelial syndrome should be included in the differential diagnosis and corneal specular microscopy should be obtained. PMID- 27977478 TI - Corneal Biomechanical Changes After Trabeculectomy and the Impact on Intraocular Pressure Measurement. AB - PURPOSE: To evaluate corneal biomechanical changes induced by trabeculectomy and their impact on intraocular pressure (IOP) measurements. MATERIALS AND METHODS: In total, 35 eyes of 35 consecutive glaucoma patients undergoing first-time trabeculectomy with mitomycin C were enrolled in this prospective interventional case series. Goldmann applanation tonometry (GAT) IOP, central corneal thickness, axial length, and Ocular Response Analyzer measurements [Goldmann-correlated IOP (IOPg), corneal-compensated IOP (IOPcc), corneal hysteresis (CH), and corneal resistance factor (CRF)] were assessed before and 6 months after uncomplicated trabeculectomy. Linear mixed models were used to compare the parameters before and after surgery. RESULTS: IOP, central corneal thickness, and axial length showed a strong correlation with CH and CRF preoperatively and postoperatively. After adjusting for these influencing factors, CH changed from 7.75+/-1.46 to 7.62+/-1.66 mm Hg (P=0.720) and CRF from 8.67+/-1.18 to 8.52+/-1.35 mm Hg (P=0.640) after trabeculectomy, but these changes were not statistically significant. IOP decreased statistically significantly with all IOP measurements (P=0.001). IOPcc was statistically significantly higher than GAT (4.82+/-5.24 mm Hg; P=0.001) and IOPg (2.92+/-1.74 mm Hg; P=0.001) preoperatively and postoperatively (GAT, 3.29+/-3.36 mm Hg; P=0.001; IOPg, 3.35+/-1.81 mm Hg; P=0.001). The difference between IOPcc and GAT (P=0.5) and IOPcc and IOPg (P=0.06) did not change significantly before or after trabeculectomy. CONCLUSIONS: Despite a marked IOP reduction and a possible weakening of the ocular walls after trabeculectomy, corneal structural tissue properties are not altered, and therefore, the accuracy of IOP measurements is not changed postoperatively. It seems likely, however, that Goldmann-correlated IOP measurements are underestimated in glaucoma patients before and after surgery. PMID- 27977479 TI - Pilot Study of Lamina Cribrosa Intensity Measurements in Glaucoma Using Swept Source Optical Coherence Tomography. AB - PURPOSE: To compare the lamina cribrosa (LC) intensity in glaucoma-suspect eyes and eyes with mild to moderate glaucoma using swept-source optical coherence tomography. METHODS: Optic disc volume scans were collected using swept-source optical coherence tomography in 19 clinically defined glaucoma-suspect eyes and 29 eyes with mild to moderate glaucoma. LC intensity was measured using Image J software, and the resultant values were normalized using the retinal pigment epithelium and vitreous signal. RESULTS: Mean age was 53.7+/-18.5 years in the glaucoma-suspect eyes and 63.0+/-16.1 years in the eyes with mild to moderate glaucoma (P=0.161). Significant differences in LC intensity were observed between the 2 groups, with median LC intensity values of 0.96 and 0.86 units in the glaucoma-suspect and the mild to moderate glaucoma groups, respectively (P<0.001). A weak positive correlation was found between mean deviation and normalized LC intensity (r=0.344; P=0.018). CONCLUSIONS: Intensity measurement of the LC is a potential novel parameter which warrants further study in the setting of glaucoma. PMID- 27977480 TI - Comparing the Performance of Compass Perimetry With Humphrey Field Analyzer in Eyes With Glaucoma. AB - PURPOSE: To evaluate the reliability indices [fixation losses, false negative response rates (FN) and false positive response rates] and threshold sensitivities obtained from glaucoma patients with a Compass perimeter and to compare the same with the Humphrey field analyzer (HFA). METHODS: In a cross sectional study, 97 eyes of 58 subjects (64 glaucoma and 33 glaucoma suspect eyes) underwent visual field examination with Compass and HFA. Any test with a fixation losses, FN or FP of >20% was considered unreliable. Reliability indices and threshold sensitivities between the 2 instruments were compared and the agreement evaluated using Bland and Altman analysis. RESULTS: In total, 37 tests (38%) with Compass and 17 (18%) with HFA were unreliable. The number of unreliable tests due to high FN (>20%) was significantly more (P=0.005) with Compass (n=27) than HFA (n=3). The mean difference [95% limits of agreement (LoA)] in mean sensitivity between Compass and HFA in the 51 eyes with reliable Compass and HFA results was -0.7 dB (-5.6, 4.3 dB). The point-wise threshold sensitivities with Compass were lower than that with HFA in central and temporal but higher in the nasal field. The 95% LoA ranged from -8 to +5 dB at one of the central points to -20 to +20 dB at one of the peripheral points. CONCLUSIONS: The numbers of unreliable tests were higher with Compass compared with HFA. The LoA between Compass and HFA for point-wise threshold sensitivities as well as the global indices were wide, implying that the instruments cannot be used interchangeably. PMID- 27977471 TI - Sources of inaccuracy in the measurement of adult patients' resting blood pressure in clinical settings: a systematic review. AB - BACKGROUND: To interpret blood pressure (BP) data appropriately, healthcare providers need to be knowledgeable of the factors that can potentially impact the accuracy of BP measurement and contribute to variability between measurements. METHODS: A systematic review of studies quantifying BP measurement inaccuracy. Medline and CINAHL databases were searched for empirical articles and systematic reviews published up to June 2015. Empirical articles were included if they reported a study that was relevant to the measurement of adult patients' resting BP at the upper arm in a clinical setting (e.g. ward or office); identified a specific source of inaccuracy; and quantified its effect. Reference lists and reviews were searched for additional articles. RESULTS: A total of 328 empirical studies were included. They investigated 29 potential sources of inaccuracy, categorized as relating to the patient, device, procedure or observer. Significant directional effects were found for 27; however, for some, the effects were inconsistent in direction. Compared with true resting BP, significant effects of individual sources ranged from -23.6 to +33 mmHg SBP and -14 to +23 mmHg DBP. CONCLUSION: A single BP value outside the expected range should be interpreted with caution and not taken as a definitive indicator of clinical deterioration. Where a measurement is abnormally high or low, further measurements should be taken and averaged. Wherever possible, BP values should be recorded graphically within ranges. This may reduce the impact of sources of inaccuracy and reduce the scope for misinterpretations based on small, likely erroneous or misleading, changes. PMID- 27977481 TI - Is Autophagy Dysfunction a Key to Exfoliation Glaucoma? AB - In this short report we review previous work toward the identification of the protein and cellular sources of exfoliation glaucoma and described our recent finding on dysfunction of autophagy in Tenon capsule fibroblasts obtained from exfoliation syndrome glaucoma patients at the time of surgery and discuss the potential implications of these findings for understanding the cellular sources of the disease. PMID- 27977482 TI - A Modified Approach to Extensive Oromandibular Reconstruction Using Free Fibula Flaps. AB - In select patients with advanced disease resulting in large composite tissue defects, consideration is often given to multiple flap reconstruction. The authors propose an alternative option. Using virtual surgical planning the authors demonstrate how modest sacrifice in projection translates into a substantial decrease in the volume and surface area of soft tissue needed, in turn maximizing soft tissue coverage with a single fibula free flap. The authors used 3-dimensional virtual surgery to simulate angle-to-angle reconstructions using free fibula flaps. The reference 3-segment reconstruction was done using symphyseal projection to the plane perpendicular to the anterior nasal spine, a customary landmark. Additional simulations were then performed using recessed projections 0.5 mm, 1 cm, 1.5 cm, and 2 cm posterior to anterior nasal spine plane. Program analytics were used to calculate the surface area and volume of the floor of mouth. With projection recessed by 1 cm, surface area decreased 22% to 14 cm. With projection recessed by 2 cm, surface area decreased 44% to 10 cm. With a 3-segment construct converted to a 2-segment construct, surface area decreased 22% to 14 cm. This demonstrates for the first time an official analysis of an intraoperative modification that sacrifices little and gains a lot. Ultimately, 1 compound flap can be used in extensive reconstructions with increased confidence that it will not be overly stressed. PMID- 27977484 TI - Are Three-Dimensional Monitors More Appropriate Than Two-Dimensional Monitors in the Three-Dimensional Analysis? AB - In orthognathic surgery, three-dimensional (3D) program-based analysis of 3D reconstructions of computed tomography (CT) images is commonly used, and images viewed on a monitor. The authors compared the coordinates of facial landmarks on images in a 3D program displayed on a two-dimensional (2D) (standard) or 3D monitor. Facial bone CT data from 30 patients were reconstructed in 3D. Four researchers identified 33 facial landmarks, 3 times each on 2D and 3D monitors, for each patient, by their x-, y-, and z-coordinates. The time taken to complete these identifications was measured.For each set of coordinates, the average intraclass coefficient was >0.8 for 2D and 3D analyses, as well as among 4 readers. It took on average of 2 minutes 46 seconds to identify the landmarks on the 2D monitor, compared with 2 minutes 25 seconds on the 3D monitor. The variance of individual coordinates differed when measured on 2D or 3D monitor. The landmarks affected were located near the median region of the facial area, and are important for setting the reference sagittal plane during diagnosis for orthognathic surgery. Therefore, identifying facial landmarks using 3D monitors may be helpful for conducting accurate facial diagnoses. PMID- 27977486 TI - Assessment of the Postoperative Stability of Mandibular Orthognathic Surgery for Correction of Class III Skeletal Malocclusion. AB - To assess the stability of mandible position after orthognathic surgery for correction of class III skeletal malocclusion. Twenty adult males, aged 18 to 40 years, with Angle class III skeletal malocclusion underwent preoperative orthodontic treatment for elimination of dental compensations followed by combined maxillomandibular surgery with rigid internal fixation. Lateral cephalograms from each patient, obtained in the natural head position before surgery, immediately after surgery, and at 6-month follow-up, were retrieved from the files of the Pontifical Catholic University of Rio Grande do Sul outpatient Oral and Maxillofacial Surgery clinic and compared. Comparison of craniometric landmark measurements showed that the precision of mandibular setback was compromised in the horizontal plane, with a mean mandibular relapse of 37.75% at point B and 45.85% at point Pg. Improved intercuspation and adaptation of the musculature to the new position of the jaws after orthognathic surgery lead to counterclockwise rotation of the mandible, ultimately displacing the mandible more anteriorly than desired. PMID- 27977487 TI - Anatomical Study and Locating Nasolacrimal Duct on Computed Topographic Image. AB - PURPOSE: We performed a novel anatomical and radiological investigation to understand the structure of nasolacrimal duct (NLD) and to provide data to help surgeons locate the openings of NLD efficiently based on landmarks. MATERIALS AND METHODS: We examined the NLD region using computed tomography images of 133 individuals and 6 dry skull specimens. Multiplanar reconstruction of the computed tomography images was performed, and the anatomical features of the NLD were studied in the coronal, sagittal, and axial planes. The long and short diameters of NLD were measured along its cross-section. The position of NLD was localized using the nostril, concha nasalis media, and medial orbital corner as landmarks. The free and open source software, 3D Slicer, was used for the segmentation of the NLD and 3D visualization of the superior and inferior openings of the NLD. RESULTS: The length, angle, and diameter of NLD were significantly influenced by the age in females compared to those in males. The inferior opening of the NLD could be located efficiently using the nostril and the midsagittal line while the superior opening of NLD could be located using the medial orbital corner. Third, 3D Slicer enabled us to measure the distance between the skin and the bony structure in the image. CONCLUSION: Our study indicates that the sex and age of the patient should be considered while selecting the optimal NLD stent for a patient, and that the precise location of NLD in reference to landmarks can simplify the surgical difficulties and reduce the risk of injury during the transnasal operation. PMID- 27977485 TI - Off-Label Use of Bone Morphogenetic Protein 2 in the Reconstructions of Mandibular Continuity Defects. AB - This paper describes 3 patients of off-label use of bone morphogenetic protein 2 (rhBMP-2) in the reconstruction of mandibular continuity defects. In the first patient, rhBMP-2 was associated with iliac crest bone graft for late mandibular reconstruction after resection of osteosarcoma. In the 2 other patients, rhBMP-2 was used alone. In 1 patient the mandibular continuity defect was due to resection for treatment of osteomyelitis and in the other patient a continuity defect was created by unsuccessful osteogenic distraction for correction of mandibular hypoplasia. Despite the good results in those patients, the off-label use of rhBMP-2 is associated with increased rate of complications, so more studies are needed to assess the predictability of the use of rhBMP-2 in mandibular continuity defects. Therefore, at the moment the off-label use of rhBMP-2 should be restricted to complicated bone defects in which the conventional alternatives of reconstruction were unsuccessful. PMID- 27977488 TI - The Need for Overcorrection When Using a Suborbital Cervicofacial Hike Flap. AB - BACKGROUND: The senior author has previously described a deep-plane cervicofacial hike flap as a workhorse for reconstruction mid-cheek defects. One important modification commonly used involves overcorrection of the defect in order to reduce the incidence of ectropion. This report outlines the senior author's experience in surgical treating complex cheek defects with an overcorrected deep plane cervicofacial hike flap. METHODS: The authors performed a retrospective review of the senior author's patients with cheek and eyelid reconstruction. The authors initially identified all patients who had undergone a deep-plane cervicofacial hike flap, then filtered those charts for patients who had overcorrection of their deformity in order to prevent ectropion. RESULTS: A total of 3 patients had an overcorrected flap. Overcorrection was accomplished either by cheek advancement with suture fixation to the deep temporal fascia, or by placement of drill holes and bone anchors. Lower eyelid malposition was avoided in all 3 patients. Patient satisfaction at long term follow-up was very high, and no revision surgery was needed. CONCLUSION: If gravitational or cicatricial forces can potentially distort the eyelid in patients with cheek or eyelid reconstruction, it is necessary to overcorrect the cheek flap. This modification of the deep-plane cervicofacial flap is an important tool in reconstructing defects in this area. PMID- 27977489 TI - Conjoined Twin Separation: Integration of Three-Dimensional Modeling for Optimization of Surgical Planning. AB - Conjoined twinning is a rare anomaly, with an incidence of approximately 1 in 100,000 live births. There is a high perinatal mortality rate, but twins who survive pose reconstructive challenges that require meticulous preoperative planning. The authors describe the senior surgeon's career experience with conjoined twin separation, and the evolution of medical modeling and 3 dimensional imaging as a critical component in presurgical planning.The authors performed a retrospective review of all consecutive patients of conjoined twin separation at a single institution from January 2004 to December 2013. Data were collected related to patient demographics, comorbidities, operative technique, perioperative complications, survival, long-term outcomes, and the type of medical modeling system used for preoperative planning.Five sets of conjoined twins underwent separation during the 10-year study period. There were 3 sets of thoraco-omphalopagus twins, 1 set of pyopagus twins, and 1 set of ischiopagus tetrapus twins. The mean age at separation was 70 days, with a mean of 3.5 surgical procedures performed per patient during the first year of life. One set of twins experienced postseparation complications that warranted immediate return to the operating room. The overall survival rate after separation was 70%. The imaging methods used were computed tomography scan with 3-dimensional reconstruction, plaster molds, medical modeling with composite printing, and virtual surgical planning.The use of imaging and medical modeling in presurgical planning has proven to be an important element in optimizing the outcomes for patients with this rare anomaly. PMID- 27977490 TI - Mandibular Contouring During Orthognathic Surgery Using the Modified Hunsuck Technique. AB - Square face or prominent mandibular angle is a major concern in Asian women. In class III patients, mandibular setback may lead to a wider lower face that is not preferred in Asian culture. In order to achieve better aesthetic outcomes, simultaneous mandibular contouring to reduce the width of the lower face is required for some patients. This article details the authors' procedures modified from Hunsuck techniques of sagittal split osteotomy. This modified Hunsuck technique provides an alternative option to obtain a desirable mandibular outline. The long-term stability is also comparable to traditional methods. PMID- 27977491 TI - Could Calcified Triglyceride Bone Cement Be an Alternative Graft Material in Maxillary Sinus Augmentation? AB - The ideal graft material for maxillary sinus augmentation is still a matter of controversy and the search for a more appropriate bone substitute for use continues. The aim of this study was to evaluate bone formation as a sign of the regeneration following maxillary sinus augmentation in rabbits using 3 different biomaterials, one of which is a newly developed graft material; calcified triglyceride bone cement (CTBC).Twenty-one New Zealand rabbits were used and randomly divided into 3 groups. Bilateral maxillary sinus augmentation was carried out and autogenous bone (AB), bovine hydroxyapatite (BHA), and CTBC were administered. Maxillary sinuses were dissected after fourth and eighth weeks of the operation. The bone formation was evaluated by stereological and histopathological analysis and the data were analyzed statistically.When the volume of primary bone is compared, statistically significant differences were found among all groups at both of the fourth and eighth weeks. The highest value was obtained from AB applied group. In BHA and CTBC applied groups, active bone formation, osseointegration of graft materials were observed at both fourth and eighth weeks. In CTBC applied group, primary bone formation was only seen as linked to the continuation of parent sinus bony wall.The efficiency of primary bone formation of CTBC was found less than AB and BHA. Of the 3 graft materials tested, BHA is the strongest alternative to AB graft for maxillary sinus augmentation. PMID- 27977492 TI - Analysis of Anatomical Characteristics and Morphometric Aspects of Infraorbital and Accessory Infraorbital Foramina. AB - OBJECTIVE: This study aimed to perform a morphological and morphometric study of the characteristics of the infraorbital foramen (IOF) and accessory infraorbital foramen (AIOF) in Brazilian skulls. METHODS: A sample calculation determined a total of 94 human skulls to be evaluated by a trained examiner for number, shape, diameters, and location of IOF in relation to anatomical landmarks. Number, size, shape, diameters, location, orientation, position, and distances in relation to anatomical landmarks were evaluated for the AIOF. Descriptive analysis, paired t test, Wilcoxon test, Pearson and Spearman correlations were used. RESULTS: A total of 188 IOFs and 48 AIOFs were found. Circular outline was the predominant shape for both IOFs and AIOFs. Infraorbital foramens presented in left sides had a significantly greater transverse diameter and distance from medial margin of the orbit when compared with IOFs located on the right sides (P <0.001). Accessory infraorbital foramens were most frequently found on the left sides of the skulls and had a superomedial position in relation to the IOFs. Accessory infraorbital foramens located on right sides had a significantly greater distance to anterior nasal spine when compared with AIOFs located on the left sides (P <0.001). CONCLUSIONS: The results of this solid methodology-based study can help guide surgeons in accurately locating the IOF and AIOF, and consequently, their neurovascular bundles to perform safe procedures during maxillofacial interventions. PMID- 27977493 TI - A Rare Patient with Facial Duplication. AB - Facial duplication, in whole or in part, is a very rare malformation. It may be symmetrical or asymmetric. Those cases that have been reported in the literature constitute a spectrum extending from simple nasal duplication to complete separation of 2 faces. Up to now there are some reports of eye, nose, mandible, or maxilla duplication separately. But there is no report of oral orifice or lips duplication. The present article reports a case of a newborn girl who presented with 2 mouths and also duplication of zygoma and maxilla. Then, we describe her stages of treatment from birth through now that she has 20 years. PMID- 27977495 TI - Invasive Aspergillosis Mimicking Sphenoid Wing Meningioma. PMID- 27977494 TI - Microsurgical Forehead Reconstruction. AB - Reconstruction of the forehead remains challenging. Especially in cases of large or even complete forehead defects, local flaps and skin grafting may not be an option, necessitating free flap coverage. The aim of this retrospective case series was to develop an algorithmic surgical approach as well as to evaluate surgical and aesthetic outcomes of microvascular-based forehead reconstructions, using gracilis muscle or anterolateral thigh flaps in 15 cases. The mean size of the defects was 84.6 (range: 25-160, +/-44.1) cm, all with significant area of bone exposure. The free flap reconstructions included 7 gracilis muscle flaps, covered with 1.2-mm-thick unmeshed split-thickness skin grafts, and 8 anterolateral thigh flaps with a mean size of the free flaps of 160 (range: 56 300, +/-78.6) cm. In all patients, wound healing at the donor site was uneventful. Minor complications occurred in 3 patients and required small revision procedures. This case series demonstrates that microsurgical reconstruction of multiple entities of forehead defects poses a reliable method, especially in large and complex defects. In our opinion, given low risks for major complications and superior aesthetic results, the gracilis muscle flap covered with unmeshed split-thickness skin graft is ideally suited to reconstruct the forehead and should be one of first choices. PMID- 27977496 TI - New-onset third-degree atrioventricular block because of autoimmune-induced myositis under treatment with anti-programmed cell death-1 (nivolumab) for metastatic melanoma. AB - There has been considerable progress in treating malignant melanoma over the last few years. The immune-checkpoint-inhibitors nivolumab and pembrolizumab have been approved by the Food and Drug Administration in 2014 for the therapy of metastatic melanoma. Anti-programmed cell death-1-blocking antibodies are known to cause immune-related adverse events. Physicians should be aware of common and rare side effects and pay attention to new ones. We therefore report a severe and life-threatening side effect of anti-programmed cell death-1 immunotherapy with nivolumab that has not been previously reported: the development of a third degree atrioventricular block. After a second infusion with nivolumab, our patient developed a troponin I-positive and autoantibody-positive myositis and a few days later a new-onset third-degree atrioventricular block. This is most likely because of an autoimmune-induced myositis with a cardiac impairment in terms of a myocarditis, which led to an impairment of the conduction of cardiac electrical stimuli. PMID- 27977497 TI - Internal Rotation Stress Testing Improves Radiographic Outcomes of Type 3 Supracondylar Humerus Fractures. AB - BACKGROUND: The purpose of this study was to determine if routine use of an intraoperative internal rotation stress test (IRST) for type 3 supracondylar humerus fractures will safely improve maintenance of reduction. METHODS: An intraoperative protocol for type 3 supracondylar humerus fractures was adopted at our institution, consisting of fracture reduction, placement of 2 laterally based divergent pins, and then an IRST to determine the need for additional fixation with a medial column pin placed through a small open approach. Fractures treated with the prospective IRST protocol were compared with a retrospective cohort before adoption of the protocol (pre-IRST). The primary outcomes were differences in Baumann's angle, lateral humerocapitellar angle, and the rotation index between final intraoperative fluoroscopic images and radiographs at final follow up. Secondary outcomes were complications such as iatrogenic nerve injury, loss of fixation, or need for reoperation. RESULTS: There were 78 fractures in the retrospective cohort (pre-IRST) and 49 in the prospective cohort (IRST). Overall rotational loss of reduction (>6%), measured by lateral rotation percentage, and major rotational loss of reduction (>12%) were less common in the IRST cohort (6/49 vs. 27/78, P=0.007 overall; 0/49 vs. 8/78, P=0.02 major loss). There were no major losses of reduction for Baumann's angle (>12 degrees) in either cohort. There were 5 subjects in the pre-IRST cohort (6.4%) with a major loss of reduction of the humerocapitellar angle (>12 degrees) and none in the IRST cohort (P=0.16) Loss of proximal fixation with need for reoperation occurred in 3 fractures in the pre-IRST cohort, and none in the IRST cohort (P=0.28). There were no postoperative nerve injuries in either group. CONCLUSIONS: Intraoperative IRST after placement of 2 lateral pins assists with the decision for additional fixation in type 3 supracondylar humerus fractures. This method improved the final radiographic rotational alignment, and was safely performed using a mini open approach for medial pin placement. LEVEL OF EVIDENCE: Level III-prospective cohort compared with a retrospective cohort. PMID- 27977498 TI - Evaluation of Pediatric Questions on the Orthopaedic In-Training Examination-An Update. AB - BACKGROUND: Pediatric orthopaedics is tested frequently on the Orthopaedic In Training Examination (OITE). The most recent data on the pediatrics section of the OITE were generated from content 10 years old. The purpose of this study is to assess the pediatric orthopaedic questions on the 2011 to 2014 OITE, and to compare question categories and cognitive taxonomy with previous data. METHODS: Four years (2011 to 2014) of OITE questions, answers, and references were reviewed. The number of pediatric questions per year was recorded, as well as presence of a clinical photo or imaging modality. Each question was categorized and assigned a cognitive taxonomy level. Categories included: knowledge; knowledge-treatment modalities; diagnosis; diagnosis/recognition of associated conditions; diagnosis/further studies; and diagnosis/treatment. Cognitive taxonomy levels included: simple recall, interpretation of data, and advanced problem-solving. RESULTS: The 3 most commonly covered topics were upper extremity trauma (17.4%), scoliosis (10.1%), and developmental dysplasia of the hip (5.7%). Compared with previous data, the percentage of pediatric questions was constant (13% vs. 14%). Categorically, the more recent OITE examinations contained significantly fewer questions testing simple knowledge (19% vs. 39%, P=0.0047), and significantly more questions testing knowledge of treatment modalities (17% vs. 9%, P=0.016) and diagnosis with associated conditions (19% vs. 9%, P=0.0034). Regarding cognitive taxonomy, there was a significant increase in the average number of questions that required advanced problem-solving (57% vs. 46%, P=0.048). Significantly more questions utilized clinical photographs and imaging studies (62% vs. 48%, P=0.012). The most common reference materials provided to support correct responses included Lovell and Winter's Pediatric Orthopaedics (25.7%) and the Journal of Pediatric Orthopaedics (23.4%). CONCLUSIONS: Although the percentage of pediatric questions on the OITE has remained essentially constant, the percentage of questions requiring advanced problem-solving or interpretation of images has increased significantly in the past 10 years. Knowledge of question type and content may be helpful for those involved in resident education and in the development of didactic pediatric orthopaedic curricula. LEVEL OF EVIDENCE: Level IV. PMID- 27977499 TI - Development of an Interprofessional Teaching Grand Rounds. PMID- 27977500 TI - Violent Extremism, Community-Based Violence Prevention, and Mental Health Professionals. AB - New community-based initiatives being developed to address violent extremism in the United States are utilizing mental health services and leadership. This article reviews current approaches to preventing violent extremism, the contribution that mental illness and psychosocial problems can make to violent extremism, and the rationale for integrating mental health strategies into preventing violent extremism. The authors describe a community-based targeted violence prevention model and the potential roles of mental health professionals. This model consists of a multidisciplinary team that assesses at-risk individuals with comprehensive threat and behavioral evaluations, arranges for ongoing support and treatment, conducts follow-up evaluations, and offers outreach, education, and resources for communities. This model would enable mental health professionals in local communities to play key roles in preventing violent extremism through their practice and leadership. PMID- 27977502 TI - Work stress and menopausal symptoms. PMID- 27977503 TI - Chronic Stress and C-Reactive Protein in Mothers During the First Postpartum Year. AB - OBJECTIVE: Elevated levels of C-reactive protein (CRP) are associated with increased risk of cardiovascular and metabolic disease. The current study tested associations between psychosocial stress and CRP in a large sample of women during the first postpartum year. METHODS: We analyzed data collected by the five site Community Child Health Network study, which studied a predominately poor population. Participants (n = 1206 women; 54% African American, 23% white, 23% Hispanic/Latina) were recruited shortly after the birth of a child. Multiple linear regression analyses tested associations of psychosocial stress in several life domains (financial, neighborhood, family, coparenting, partner relationship, discrimination, and interpersonal violence) with log-transformed CRP concentrations at 6-month and 1-year postpartum. RESULTS: Forty-eight percent of participants showed evidence of elevated CRP (>=3 mg/L) at 6-month postpartum, and 46% had elevated CRP at 12-month postpartum. Chronic financial stress at 1 month postpartum predicted higher levels of CRP at 6- (b = .15, SE = .05, p = .006) and 12-month postpartum (b = .15, SE = .06, p = .007) adjusting for race/ethnicity, income, education, parity, health behaviors, and chronic health conditions, though associations became nonsignificant when adjusted for body mass index. CONCLUSIONS: In this low-income and ethnic/racially diverse sample of women, higher financial stress at 1-month postbirth predicted higher CRP. Study findings suggest that perceived financial stress stemming from socioeconomic disadvantage may be a particular deleterious form of stress affecting maternal biology during the year after the birth of a child. PMID- 27977504 TI - Cross Section of Legislative Approaches to Reducing Indoor Dampness and Mold. AB - Exposure to indoor dampness and mold is associated with numerous adverse respiratory conditions, including asthma. While no quantitative health-based threshold currently exists for mold, the conditions that support excessive dampness and mold are known and preventable; experts agree that controlling these conditions could lead to substantial savings in health care costs and improvement in public health. This article reviews a sample of state and local policies to limit potentially harmful exposures. Adoption of laws to strengthen building codes, specify dampness and mold in habitability laws, regulate mold contractors, and other legislative approaches are discussed, as are key factors supporting successful implementation. Communicating these lessons learned could accelerate the process for other jurisdictions considering similar approaches. Information about effectiveness of legislation as prevention is lacking; thus, evaluation could yield important information to inform the development of model state or local laws that significantly address mold as a public health concern. PMID- 27977505 TI - Unusual Presentations of Childhood Systemic Lupus Erythematosus to the Emergency Department. AB - INTRODUCTION: Systemic lupus erythematosus (SLE) is a multisystemic autoinflammatory disease that can involve any organ system; therefore, diagnosis can be challenging. Hereby, we present 4 cases that presented to pediatric emergency department with unusual clinical pictures of SLE. CASES: Case 1 presented with inability to walk or talk for the last 1 week as well as intermittent pain and swelling in her joints. Case 2 presented with generalized edema and severe dyspnea. Case 3 and 4 presented to pediatric emergency department with rashes on the legs. DISCUSSION: Systemic lupus erythematosus may mimic many clinical entities, and differential diagnosis may be difficult, especially if presentation is atypical. In every emergency physician, right diagnosis and prompt treatment are very important especially in life-threatening conditions such as cardiac involvement in SLE. PMID- 27977506 TI - Management of Pediatric Acute Mastoiditis in Israel: Nationwide Survey Among Otorhinolaryngologists and Emergency Pediatricians. AB - INTRODUCTION: Acute mastoiditis (AM) is a medical emergency that mandates prompt diagnosis and treatment. Nevertheless, its management often differs between otorhinolaryngologists (ORLs) and pediatricians (PEDs) working in emergency departments. We sought to characterize the similarities and differences between management protocols of these 2 disciplines. MATERIALS AND METHODS: A voluntary electronic questionnaire, including 17 items pertaining to pediatric AM management, was sent to all the 20 otorhinolaryngology and their corresponding pediatric emergency departments nationwide. Each department sent 1 filled out questionnaire. The response rate was 100%. RESULTS: Eighteen (90%) ORLs are notified when a child with suspected AM arrives. Medical history collected by both disciplines was similar-previous otologic history (100%), previous antibiotic use (100%), and pneumococcal conjugate vaccination status (60%) whereas acute otitis media risk factors were more important to PEDs (13 [65%] PEDs, 10 [50%] ORLs). According to 85% to 90% of ORLs and PEDs, imaging was not mandatory upon admission. According to 14 (70%) PEDs and 16 (80%) ORLs, imaging was overall performed in less than 50% of patients during hospitalization. Intravenous ceftriaxone and cefuroxime were the most common first-line antibiotic treatments (8 [40%] ORLs, 10 [50%] PEDs), with a mean treatment duration of 7 to 10 days. Eighteen (90%) of the ORLs, compared with 15 (75%) PEDs, reported that myringotomy (with or without ventilating tube insertion) was performed upon diagnosis (P = 0.05). CONCLUSIONS: The management of pediatric AM is generally similar by both disciplines. The use of imaging studies is mild-moderate. We call for a national registry and encourage the publication of guidelines. PMID- 27977507 TI - Neuroendocrine Gastroenteropancreatic Tumors: Where Are We? AB - AIMS: Neuroendocrine gastroenteropancreatic tumors are infrequently found neoplasms. Our objective was to analyze the survival rates for all sites that they occur in by studying different variables. MATERIALS AND METHODS: A retrospective study was carried out using records for a 7-year period from January 1, 2008 to December 31, 2014 on neuroendocrine gastroenteropancreatic tumors patients diagnosed at the Pontevedra-Salnes Hospital Complex. The variables used were as follows: age at diagnosis, tumor size, presence or absence of metastases at diagnosis, cell proliferation index, Ki-67 of each tumor, treatments received, postdiagnosis survival time, existence or not of tumor progression, and time from diagnosis to progression and from diagnosis to mortality. In relation to treatments, the information recorded was whether the treatment was endoscopic, surgical, or pharmacological. RESULTS: Ninety-three neuroendocrine tumors made up a ratio of 4.42 cases per 100,000 inhabitants per annum. The median patient follow-up time was 44 months. The overall 5-year survival rate for patients who were followed up for a minimum of 60 months (49 patients) was 65.3%. The progression-free survival was 75.6% for 41 patients who were followed up for a minimum of 60 months. The survival rate for patients receiving endoscopic treatment was 100%, as there was no patient mortality recorded for those treated by endoscopic resection during the follow-up period. CONCLUSION: Pancreatic neuroendocrine tumors may be managed conservatively in elderly patients by either monitoring them with imaging studies or treating them with somatostatin analogs. In the case of digestive tract tumors (stomach, duodenum, and rectum) that meet the criteria for endoscopic resection, this is a reliable and safe technique in the long term. PMID- 27977508 TI - Open Versus Hand-assisted Laparoscopic Total Gastric Resection With D2 Lymph Node Dissection for Adenocarcinoma: A Case-Control Study. AB - OBJECTIVE: A case-control study was conducted to investigate the feasibility and safety of hand-assisted laparoscopic total gastrectomy (HALTG) with D2 lymphadenectomy for gastric cancer as opposed to traditional open total gastrectomy (OTG). METHODS: One hundred fifty-four patients suffering cardia, upper, middle, or whole gastric cancer operated in our department from February 2009 to February 2012 were divided into 2 groups: the open total gastrectomy group (the OTG group) and the hand-assisted laparoscopic total gastrectomy group (the HALTG group). Operative time, estimated blood loss, number of lymph node retrieval, time to the first flatus, and postoperative hospital stay were compared between the 2 groups. RESULTS: HALTG was associated with significantly less operative blood loss, shorter time to the first flatus and shorter postoperative hospital stay, but longer operative time, compared with OTG. There were no significant differences in tumor size, retrieved lymph nodes, American Joint Committee on Cancer/Union International Control Cancer staging and tumor location between the 2 groups. Negative resection margins were obtained in all patients who had undergone a hand-assisted laparoscopic gastrectomy (100%) and in all but 2 patients in the open group (97.6%). The overall observed 5-year survival rate was 56.5% in the HALTG group and 51.8% in the OTG group (P=0.0001, log-rank test). CONCLUSIONS: HALTG is a safe, feasible, and oncologically sound procedure and has advantages over ODG. PMID- 27977509 TI - The International Pressure Ulcer PrevalenceTM Survey: 2006-2015: A 10-Year Pressure Injury Prevalence and Demographic Trend Analysis by Care Setting. AB - PURPOSE: Measurement of pressure injury (PI) prevalence allows benchmarking within and across facilities; the International Pressure Ulcer PrevalenceTM (IPUP) Survey includes a variety of care settings. The purpose of this study is to present 10 years of US prevalence and limited demographic data (2006-2015) by care setting. METHODS: Facilities volunteer to participate in the IPUP Survey. Internal clinical teams collect data during a predetermined 24-hour period that includes pressure injury prevalence, demographics, and other pertinent clinical information. Aggregate data was analyzed for this study. RESULTS: The sample for this study was 918,621 patients in the United States; data collection spanned 2006 to 2015. The overall prevalence (OP) of PI in all facilities declined from 13.5% (2006) to 9.3% (2015). Facility-acquired prevalence (FAP) declined from 6.2% (2006) to a range of 3.1% to 3.4% (2013-2015). Acute care OP was 13.3% in 2006 and declined to a range of 8.8% to 9.3% (2012-2015). Facility-acquired prevalence in acute care declined from 6.4% (2006) to 2.9% in 2015, with 2008 2009 showing the most aggressive decline. Long-term acute care (LTAC) had the highest OP at 32.9% in 2006; it declined to 28.8% in 2015. The LTAC-FAP was 9.0% in 2006; it declined to 5.6% in 2015. Recently, the long-term care (LTC) FAP rose from 3.8% in 2013 to 5.4% in 2015. The rehabilitation facility FAP was 2.6% to 2.8% over the last 3 years. Average patient age declined in all care settings with the exception of LTAC and LTC. Braden Scale risk scores remained constant and weight increased in all care settings with the exception of LTC. CONCLUSIONS: The OP and FAP in acute care and rehabilitation have declined significantly over this 10-year period. Analysis of OP and FAP in LTC and LTACs varied without any clear-cut directional trends. General facility demographic trends indicate that mean patient age has decreased, Braden Scale scores for pressure injury risk has remained constant, and weight has increased in most care settings.VIDEO ABSTRACT available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JWOCN/A37). PMID- 27977510 TI - A comprehensive contribution of genes for aryl hydrocarbon receptor signaling pathway to hypertension susceptibility. AB - OBJECTIVE: The present study was designed to investigate whether genetic polymorphisms of the aryl hydrocarbon receptor (AHR) signaling pathway are involved in the molecular basis of essential hypertension (EH). METHODS: A total of 2160 unrelated Russian individuals comprising 1341 EH patients and 819 healthy controls were recruited into the study. Seven common AHR pathway single nucleotide polymorphisms (SNPs) such as rs2066853, rs2292596, rs2228099, rs1048943, rs762551, rs1056836, and rs1800566 were genotyped by TaqMan-based allele discrimination assays. RESULTS: We found that SNP rs2228099 of ARNT is associated with an increased risk of EH (odds ratio=1.20 95% confidence interval: 1.01-1.44, P=0.043) in a dominant genetic model, whereas polymorphism rs762551 of CYP1A2 showed an association with a decreased risk of disease in a recessive genetic model (odds ratio=0.68, 95% confidence interval: 0.52-0.89, P=0.006). A log-likelihood ratio test enabled identification of epistatic interaction effects on EH susceptibility for all SNPs. MB-MDR analysis showed that cigarette smoking, rs1048943, rs762551, rs1056836, and rs2228099 were significant contributing factors in 19, 18, 13, 13, and 11 interaction models, respectively. The best MDR model associated with EH risk included rs1048943, rs762551, rs1056836, and cigarette smoking (cross-validation consistency 100%, prediction error 45.7%, Ppermutation<0.0001). The mRNA expression and in-silico function prediction analyses have confirmed a regulatory potential for a majority of SNPs associated with EH susceptibility. CONCLUSION: Our pilot study was the first to show that gene-gene and gene-environment interactions in the AHR signaling pathway represent important determinants for the development of EH, and the pathway may become an attractive target for a pharmacological intervention in hypertensive patients in the future. PMID- 27977511 TI - Rituximab response in follicular lymphoma is associated with the rs20575 polymorphism in TRAILR1 extrinsic apoptosis trigger. AB - OBJECTIVE: Rituximab in combination with chemotherapy has been proven to increase progression-free and overall survival in follicular lymphoma (FL), but there is considerable interindividual variability in the response. Extrinsic pathway apoptosis triggered by death receptors seems to be involved in the mechanism of action of monoclonal antibodies. This study aimed to assess the association between TRAILR1/TRAIL polymorphisms (rs20575, rs20576, rs2230229, rs12488654) and rituximab response and the relationship with FASL rs763110, previously found to be associated with rituximab response. PATIENTS AND METHODS: Polymorphisms were determined in a study cohort of 125 FL patients treated with rituximab as first line treatment and correlated with response, which was scored according to the International Working Group Consensus Revised as complete response, partial response, stable disease, and progressive disease. RESULTS: No significant association with response was found for rs20576, rs2230229, and rs12488654 polymorphisms. In contrast, rs20575 GC/GG carriers were more partial/nonresponders (88.2%) than complete responders (72.5%), showing a trend toward statistical significance (P=0.064). In a multivariable setting, we found that female sex [odds ratio=0.355, 95% confidence interval (CI): 0.137-0.922, P=0.033] and the TRAILR1 rs20575 CC genotype (odds ratio=0.162, 95% CI: 0.035 0.757, P=0.021) were independent positive predictive factors of complete clinical response to rituximab, constructing a parsimonious model with good calibration [chi of 5.719 (d.f.=6, P=0.455)] and discrimination (C-statistic=0.739, 95% CI: 0.636-0.842). CONCLUSION: After studying the pharmacogenetic role of TRAILR1/TRAIL polymorphisms in rituximab-treated FL patients, we found that the rs20575 CC genotype is an independent predictive factor of better rituximab response, indicating the possible involvement of death receptors in anti-CD20 mechanisms of action. PMID- 27977512 TI - Schisandrin B inhibits the proliferation and invasion of glioma cells by regulating the HOTAIR-micoRNA-125a-mTOR pathway. AB - Glioma is one of the most common malignant central nervous system tumors in humans. Schisandrin B (Sch B) has been confirmed to cause the proliferation and invasion of glioma cells. In the present study, the potential mechanism underlying the antitumor effect of Sch B on glioma cells was investigated. The glioma cell lines, U251 and U87, were exposed to Sch B, and the cell viability, apoptosis, migration, and invasion were determined using the MTT assay, flow cytometry, and transwell assay, respectively. Then, the effects of HOTAIR and miR 125a on tumor biology and the mammalian target of rapamycin (mTOR) protein expression in cell lines exposed to Sch B were investigated. The results showed that Sch B decreased HOTAIR expression and increased miR-125a-5p expression. HOTAIR overexpression decreased miR-125a expression and increased mTOR expression in cells with the treatment of Sch B. The miR-125a inhibitor reversed the effects of HOTAIR downregulation on cell proliferation and migration. On co-incubation with rapamycin, a specific mTOR inhibitor, the cell viability, migration, and invasion were decreased and cell apoptosis was increased in two cell lines exposed to Sch B after the treatment of pcDNA-HOTAIR. In conclusion, Sch B played an inhibitory role in the proliferation and invasion of glioma cells by regulating the HOTAIR-micoRNA-125a-mTOR pathway. PMID- 27977513 TI - Short-duration therapeutic massage reduces postural upper trapezius muscle activity. AB - Massage therapy has historically been used as a therapeutic treatment to help reduce pain and promote relaxation. The aim of this study was to investigate the effect of therapeutic massage on the upper trapezius muscles, which are commonly associated with increased muscle tension. This was a randomized crossover study. Seventeen healthy individuals (nine women; 24.5+/-4.0 years) participated in the study. All individuals participated in two sessions that were held 24 h apart. In one of the sessions, the participants received a moderate pressure massage applied to the shoulders and neck. In the other session, participants sat quietly. The order of the sessions was counterbalanced across participants. Muscle activity, as measured by surface electromyography, of the upper trapezius muscles was recorded. The amount of muscle activity change following massage was compared with the change in muscle activity following quiet sitting. Muscle activity of the upper trapezius reduced significantly (19.3%; P=0.004) following massage compared with muscle activity following quiet sitting (1.0%). Our findings suggest that short-duration moderate pressure massage leads to a reduction in upper trapezius muscle activity. This result has potential implications for clinical populations such as those with chronic neck pain. PMID- 27977515 TI - The New NIH Rehabilitation Research Plan: Priorities and Potential for Progress in Neurorehabilitation Research. PMID- 27977514 TI - Neural correlates of brain state in chronic ischemia and stroke: combined resting state electroencephalogram and transcranial Doppler ultrasonographic study. AB - Clinical neurology is constantly searching for reliable indices of ischemic brain damage to prevent a possible development of stroke. We suggest that resting state electroencephalogram (rsEEG) with respect to other clinical data may provide important information about the severity of ischemia. We carried out correlation analysis of rsEEG, data of transcranial Doppler ultrasonography of head vessels, and clinical assessment scores collected from healthy volunteers and four groups of patients with mild chronic microvascular ischemia (CMI-1), moderate CMI (CMI 2), severe atrophy of the cerebral hemisphere, ischemic stroke in the left middle cerebral artery stroke, and ischemic stroke in the right middle cerebral artery stroke. Using independent component analysis and k-mean clustering of EEG data, we observed prominent changes in rsEEG reflected in specific distributions of spectral peaks in all groups of patients. We found a significant correlation of EEG spectral distribution and the blood flow velocity in coronal arteries, which was also affected by the severity of ischemia and the localization of stroke. Moreover, EEG spectral distribution was more indicative of early stages of ischemia than the blood flow velocity. Our data support the hypothesis that rsEEG may reflect altered neural activity caused by ischemic brain damage. PMID- 27977517 TI - Commentary on: "Considerations for the Selection of Time-Limited Walk Tests Poststroke: A Systematic Review of Test Protocols and Measurement Properties". PMID- 27977516 TI - Considerations for the Selection of Time-Limited Walk Tests Poststroke: A Systematic Review of Test Protocols and Measurement Properties. AB - BACKGROUND AND PURPOSE: Systematic reviews of research evidence describing the quality and methods for administering standardized outcome measures are essential to developing recommendations for their clinical application. The purpose of this systematic review was to synthesize the research literature describing test protocols and measurement properties of time-limited walk tests in people poststroke. METHODS: Following an electronic search of 7 bibliographic data bases, 2 authors independently screened titles and abstracts. One author identified eligible articles, and performed quality appraisal and data extraction. RESULTS: Of 12 180 records identified, 43 articles were included. Among 5 walk tests described, the 6-minute walk test (6MWT) was most frequently evaluated (n = 36). Only 5 articles included participants in the acute phase (<1 month) poststroke. Within tests, protocols varied. Walkway length and walking aid, but not turning direction, influenced 6MWT performance. Intraclass correlation coefficients for reliability were 0.68 to 0.71 (12MWT) and 0.80 to 1.00 (2-, 3-, 5- and 6MWT). Minimal detectable change values at the 90% confidence level were 11.4 m (2MWT), 24.4 m (5MWT), and 27.7 to 52.1 m (6MWT; n = 6). Moderate-to-strong correlations (>=0.5) between 6MWT distance and balance, motor function, walking speed, mobility, and stair capacity were consistently observed (n = 33). Moderate-to-strong correlations between 5MWT performance and walking speed/independence (n = 1), and between 12MWT performance and balance, motor function, and walking speed (n = 1) were reported. DISCUSSION AND CONCLUSIONS: Strong evidence of the reliability and construct validity of using the 6MWT poststroke exists; studies in the acute phase are lacking. Because protocol variations influence performance, a standardized 6MWT protocol poststroke for use across the care continuum is needed.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A150). PMID- 27977519 TI - A Cross-sectional Analysis of the Characteristics of Individuals With Parkinson Disease Who Avoid Activities and Participation Due to Fear of Falling. AB - BACKGROUND AND PURPOSE: Avoidance behavior can have deleterious consequences on health and quality of life for persons with Parkinson disease (PD); for this reason, it is important to identify potentially mitigable characteristics. We compared the characteristics of individuals with PD who exhibit fear of falling (FOF) avoidance behavior with those who do not. METHODS: Fifty-nine participants with PD were classified as avoiders (n = 27) or nonavoiders (n = 32) by using the Fear of Falling Avoidance Behavior Questionnaire and compared across 5 domains: demographic characteristics; PD-specific symptoms (subtype, Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS], Hoehn and Yahr Scale, Parkinson's Disease Questionnaire-39 [PDQ-39]); balance and falls (fall history, Berg Balance Scale [BBS], Activities-Specific Balance Confidence [ABC] Scale, Impact of Events Scale, Consequences of Falling Questionnaire [CoFQ]); physical performance (30 Second Sit-to-Stand Test, Timed Up and Go Test, physical activity monitoring); and psychological factors (Zung Anxiety Scale, Beck Depression Inventory [BDI]). RESULTS: There were no differences between avoiders and nonavoiders for demographic characteristics and fall history (Ps > 0.272). Avoiders had worse MDS-UPDRS (Ps < 0.014) and PDQ-39 scores (Ps < 0.028). Avoiders had poorer balance performance (BBS, P = 0.003), lower balance confidence (ABC, P < 0.001), and more fall catastrophization (CoFQ, P < 0.001). Avoiders reported more depression (P = 0.015) and anxiety (P = 0.028). DISCUSSION AND CONCLUSIONS: PD FOF avoiders had more involved symptoms and scored lower on balance and physical performance measures. In addition, they reported greater psychological stress. Several potentially mitigable characteristics of those with FOF avoidance behavior were identified.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A153). PMID- 27977518 TI - Effects of 2 Years of Exercise on Gait Impairment in People With Parkinson Disease: The PRET-PD Randomized Trial. AB - BACKGROUND AND PURPOSE: This study presents a secondary analysis from the Progressive Resistance Exercise Training in Parkinson Disease (PRET-PD) trial investigating the effects of progressive resistance exercise (PRE) and a Parkinson disease (PD)-specific multimodal exercise program, modified Fitness Counts (mFC), on spatial, temporal, and stability-related gait impairments in people with PD. METHODS: Forty-eight people with PD were randomized to participate in PRE or mFC 2 times a week for 24 months; 38 completed the study. Gait velocity, stride length, cadence, and double-support time were measured under 4 walking conditions (off-/on-medication, comfortable/fast speed). Ankle strength was also measured off- and on-medication. Twenty-four healthy controls provided comparison data at one time point. RESULTS: At 24 months, there were no significant differences between exercise groups. Both groups improved fast gait velocity off-medication, cadence in all conditions, and plantarflexion strength off-/on-medication. Both groups with PD had more gait measures that approximated the healthy controls at 24 months than at baseline. Plantarflexion strength was significantly associated with gait velocity and stride length in people with PD at baseline and 24 months, but changes in strength were not associated with changes in gait. DISCUSSION AND CONCLUSIONS: Twenty-four months of PRE and mFC were associated with improved off-medication fast gait velocity and improved cadence in all conditions, which is important because temporal gait measures can be resistant to medications. Spatial and stability-related measures were resistant to long-term improvements, but did not decline over 24 months. Strength gains did not appear to transfer to gait.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A161). PMID- 27977520 TI - Reliability and Concurrent Validity of the Narrow Path Walking Test in Persons With Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: About 90% of people with multiple sclerosis (PwMS) have gait instability and 50% fall. Reliable and clinically feasible methods of gait instability assessment are needed. The study investigated the reliability and validity of the Narrow Path Walking Test (NPWT) under single-task (ST) and dual task (DT) conditions for PwMS. METHODS: Thirty PwMS performed the NPWT on 2 different occasions, a week apart. Number of Steps, Trial Time, Trial Velocity, Step Length, Number of Step Errors, Number of Cognitive Task Errors, and Number of Balance Losses were measured. Intraclass correlation coefficients (ICC2,1) were calculated from the average values of NPWT parameters. Absolute reliability was quantified from standard error of measurement (SEM) and smallest real difference (SRD). Concurrent validity of NPWT with Functional Reach Test, Four Square Step Test (FSST), 12-item Multiple Sclerosis Walking Scale (MSWS-12), and 2 Minute Walking Test (2MWT) was determined using partial correlations. RESULTS: Intraclass correlation coefficients (ICCs) for most NPWT parameters during ST and DT ranged from 0.46-0.94 and 0.55-0.95, respectively. The highest relative reliability was found for Number of Step Errors (ICC = 0.94 and 0.93, for ST and DT, respectively) and Trial Velocity (ICC = 0.83 and 0.86, for ST and DT, respectively). Absolute reliability was high for Number of Step Errors in ST (SEM % = 19.53%) and DT (SEM % = 18.14%) and low for Trial Velocity in ST (SEM % = 6.88%) and DT (SEM % = 7.29%). Significant correlations for Number of Step Errors and Trial Velocity were found with FSST, MSWS-12, and 2MWT. DISCUSSION AND CONCLUSIONS: In persons with PwMS performing the NPWT, Number of Step Errors and Trial Velocity were highly reliable parameters. Based on correlations with other measures of gait instability, Number of Step Errors was the most valid parameter of dynamic balance under the conditions of our test.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A159). PMID- 27977521 TI - Exploring the Effects of Using an Oral Appliance to Reduce Movement Dysfunction in an Individual With Parkinson Disease: A Single-Subject Design Study. AB - BACKGROUND AND PURPOSE: Clinical reports suggest that wearing an oral appliance can improve the gait and balance of an individual with Parkinson disease (PD). Our primary purpose was to systematically explore this effect using a single subject study design and quantitative motion analysis. Secondarily, we sought to examine the quality-of-life outcomes following 1-month of routine oral appliance wear. METHODS: The participant was a 73-year-old ambulatory man with mid-stage PD. Using an A-B-A design, for which a custom-made oral appliance served as the intervention, kinematic and kinetic data were captured during performance of Four Square Step Test, serpentine walk, and tandem walk tasks. Grip strength was quantified with a dynamometer. Quality-of-life outcomes were collected after 1 month of appliance wear using the Parkinson Disease Questionnaire-39 (PDQ-39). Perceived changes in balance, mobility, and quality of life were captured from the participant using an 11-point Global Rate of Change (GRC) scale. RESULTS: Changes in mobility, postural control, and grip strength during appliance wear were suggestive of reduced movement dysfunction. The PDQ-39 revealed a significant improvement in quality of life, primarily related to increased emotional well-being, decreased stigma, and increased communication. GRC scores indicated a clinically significant improvement in ease of movement in the community (+3), ease of movement during the performance of activities of daily living (+4), and in standing balance while performing activities of daily living (+4). DISCUSSION AND CONCLUSIONS: Study findings provided quantitative evidence supporting the effectiveness of oral appliance wear for reducing movement dysfunction in a patient with mid-stage PD.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A155). PMID- 27977524 TI - Academy of Neurologic Physical Therapy Programming 2017 Combined Sections Meeting: Tuesday, February 14 to Saturday, February 18, 2017 Preliminary Program Schedule. PMID- 27977523 TI - A Career Influenced by the STEP Conferences. PMID- 27977522 TI - The Interface of Clinical Decision-Making With Study Protocols for Knowledge Translation From a Walking Recovery Trial. AB - BACKGROUND AND PURPOSE: Despite efforts to translate knowledge into clinical practice, barriers often arise in adapting the strict protocols of a randomized, controlled trial (RCT) to the individual patient. The Locomotor Experience Applied Post-Stroke (LEAPS) RCT demonstrated equal effectiveness of 2 intervention protocols for walking recovery poststroke; both protocols were more effective than usual care physical therapy. The purpose of this article was to provide knowledge-translation tools to facilitate implementation of the LEAPS RCT protocols into clinical practice. METHODS: Participants from 2 of the trial's intervention arms: (1) early Locomotor Training Program (LTP) and (2) Home Exercise Program (HEP) were chosen for case presentation. The two cases illustrate how the protocols are used in synergy with individual patient presentations and clinical expertise. Decision algorithms and guidelines for progression represent the interface between implementation of an RCT standardized intervention protocol and clinical decision-making. OUTCOMES: In each case, the participant presents with a distinct clinical challenge that the therapist addresses by integrating the participant's unique presentation with the therapist's expertise while maintaining fidelity to the LEAPS protocol. Both participants progressed through an increasingly challenging intervention despite their own unique presentation. SUMMARY: Decision algorithms and exercise progression for the LTP and HEP protocols facilitate translation of the RCT protocol to the real world of clinical practice. The two case examples to facilitate translation of the LEAPS RCT into clinical practice by enhancing understanding of the protocols, their progression, and their application to individual participants.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A147). PMID- 27977525 TI - Academy of Neurologic Physical Therapy 2017 Combined Sections Meeting Platform Presentations: (Abstracts are published on-line at www.JNPT.org). PMID- 27977526 TI - Academy of Neurologic Physical Therapy 2017 Combined Sections Meeting Poster Presentations: (Abstracts are published on-line at www.JNPT.org). PMID- 27977527 TI - Call for Academy of Neurologic Physical Therapy Leadership Nominations. PMID- 27977530 TI - A Survey Assessment of Perceived Importance and Methods of Maintenance of Critical Procedural Skills in Pediatric Emergency Medicine. AB - OBJECTIVE: The aim of this study was to delineate pediatric emergency medicine provider opinions regarding the importance of, and to ascertain existing processes by which practitioners maintain, the following critical procedural skills: oral endotracheal intubation, intraosseous line placement, pharmacologic and electrical cardioversion, tube thoracostomy, and defibrillation. METHODS: A customized survey was administered to all members of the Listserv for the American Academy of Pediatrics Section on Emergency Medicine. Perceived importance of maintaining critical pediatric procedural skills was measured using a 5-point Likert-type scale. Secondary outcomes included presence and type of mandatory training, availability of on-site backup, and perceived barriers to maintenance of skills. RESULTS: Two hundred sixty-two members (25%) responded representing 106 different institutions, 70% of freestanding children's hospitals that received graduate medical education payments in 2014, and 68% of pediatric emergency medicine fellowship programs. More than 90% of respondents felt it was either very or extremely important to maintain competency for 5 of the 6 critical procedures, but no more than 49% of respondents felt that clinical care alone provided opportunity to maintain skills. The proportion of respondents indicating no mandatory training for each critical procedural skill was as follows: oral endotracheal intubation (23%), intraosseous line placement (30%), pharmacologic cardioversion (32%), electrical cardioversion (32%), tube thoracostomy (40%), and defibrillation (32%). CONCLUSIONS: Critical procedural skills are perceived by emergency providers who care for children as extremely important to maintain. Direct care of pediatric patients likely does not provide sufficient opportunity to maintain these skills. There are widespread deficiencies relating to mandatory maintenance of critical procedural skill training. PMID- 27977528 TI - In-Play Cooling Interventions for Simulated Match-Play Tennis in Hot/Humid Conditions. AB - PURPOSE: This study aimed to assess the efficacy of different in-play cooling strategies for mitigating heat strain during simulated tennis match-play activity in a hot/humid environment representing the most extreme conditions during the US Open (36 degrees C, 50% relative humidity). METHODS: On three occasions, nine males completed an intermittent treadmill protocol with an exercise intensity and activity profile simulating a four-set tennis match, with 90-s breaks between odd numbered games and 120-s breaks between sets, according to International Tennis Federation rules. During breaks, 1) the currently used cooling strategy-an ice filled damp towel around the neck and a cold-damp towel on the head and thighs (ICE); 2) wetting of arms, neck, face, and lower legs with a sponge in front of an electric fan (FANwet); or 3) no cooling (CON) were applied. Rectal (Tre) and mean skin (Tsk) temperature and HR were measured throughout. Thermal sensation and RPE were assessed during breaks. Trials were terminated upon reaching a Tre >= 39.5 degrees C or volitional exhaustion. RESULTS: Seven, five, and one participant completed FANwet, ICE, and CON, respectively. By end set 1, DeltaTre was lower in FANwet (0.92 degrees C +/- 0.15 degrees C) compared with CON (1.09 degrees C +/- 0.09 degrees C, P = 0.01), and by end set 2, DeltaTre was lower (P < 0.001) in FANwet (1.55 degrees C +/- 0.23 degrees C) and ICE (1.59 degrees C +/ 0.17 degrees C) compared with CON (1.99 degrees C +/- 0.19 degrees C). Mean RPE (FANwet = 13.9 +/- 2.2, ICE = 13.6 +/- 1.8, CON = 16.6 +/- 1.8), HR (FANwet = 163 +/- 21, ICE 164 +/- 22, CON = 175 +/- 19 bpm), Tsk (FANwet = 36.56 degrees C +/- 0.69 degrees C, ICE 36.12 degrees C +/- 0.44 degrees C, CON = 37.21 degrees C +/- 0.42 degrees C), and thermal sensation were lower in FANwet and ICE (P < 0.05) compared with CON by end set 2. CONCLUSIONS: The currently recommended ICE strategy successfully mitigates thermal strain during simulated tennis match play in hot/humid conditions. The FANwet intervention is an equally effective alternative that may be more practical in limited resource settings. PMID- 27977531 TI - Is Fixing Pediatric Nail Bed Injuries With Medical Adhesives as Effective as Suturing?: A Review of the Literature. AB - OBJECTIVES: Nail bed injuries are common in children, with nail bed damage accounting for 15% to 24% of fingertip injuries. Our objective was to see whether medical adhesives, the cyanoacrylates including Histoacryl and Dermabond, could be used to fix nail bed lacerations as opposed to doing a primary repair with sutures, thus potentially being a quicker method for repair in the emergency department for these injuries. METHODS: We conducted a literature review using the search engines MEDLINE, PubMed, Web of Science, and Google Scholar, and the references within these articles were also integrated. All articles in English were searched. Search terms included "nail bed repair," "nail bed laceration repair," and "cyanoacrylate." RESULTS: A total of 6 articles were found using the previously mentioned search terms. Four articles using 2-octyl cyanoacrylate or Dermabond for the repair of nail bed injuries were found, with 2 additional articles describing the use of Histoacryl-n-butyl-2-cyanoacrylate-for nail injury repairs. CONCLUSIONS: The 6 articles discussed in this article include approximately 118 patients' worth of data including a mix of adult and pediatric patients. Despite the small numbers and variety of types of study, it is encouraging that there are so many positive results. Cryoacrylates such as Dermabond or Histoacryl maybe useful to assist with nail injuries in children. Therefore, we feel that using a medical adhesive is as effective as suturing nail bed injuries in children. PMID- 27977529 TI - Physical Activity and Adiposity-related Inflammation: The MESA. AB - PURPOSE: Physical activity is associated with decreased adiposity-related inflammation in adults. Whether this association is independent of central obesity is unknown but important for understanding the mechanisms associated with reducing cardiometabolic disease risk through physical activity. This study examined whether associations of physical activity and obesity-related inflammatory markers were independent of central adiposity. METHODS: Between 2002 and 2005, 1970 participants from the Multi-Ethnic Study of Atherosclerosis completed detailed health history and physical activity questionnaires, underwent physical measurements including computed tomography to quantify abdominal visceral and subcutaneous fat, and measurements of adiponectin, leptin, interleukin-6, tumor necrosis factor-alpha, and resistin. Statistical analyses included analysis of covariance and multivariable-adjusted regression. RESULTS: The mean (range) age of participants was 64.7 (55-84) yr and 50% were women. After adjustment for age and sex, and compared with the lowest quartile, inflammatory markers in the highest quartile of moderate-to-vigorous physical activity were 16% higher for adiponectin and 30%, 26%, and 9% lower for leptin, interleukin-6, and resistin, respectively (P < 0.05 for all). In linear regression adjusted for demographics, dyslipidemia, hypertension, diabetes, smoking, glomerular filtration rate, renin, and aldosterone, each standard deviation increment of moderate-to-vigorous physical activity was associated with significantly higher levels of adiponectin (beta = 0.04) and lower levels of leptin (beta = -0.06), interleukin-6 (beta = -0.08), and resistin (beta = -0.05, P < 0.05 for all). The associations with leptin, interleukin-6, and resistin were independent of total and central adiposity (P < 0.05), whereas the association between moderate-to-vigorous physical activity and adiponectin was attenuated by central adiposity (P > 0.05). There were no significant interactions by race/ethnicity or sex. CONCLUSIONS: Moderate-to-vigorous physical activity was associated with a more favorable profile of inflammatory markers, independent of relevant cardiometabolic disease risk factors including central obesity. PMID- 27977532 TI - Reliability of the Faces, Legs, Activity, Cry, and Consolability Scale in Assessing Acute Pain in the Pediatric Emergency Department. AB - OBJECTIVES: The Faces, Legs, Activity, Cry, and Consolability (FLACC) scale is one of the most widely utilized observational pain assessment scales in clinical practice. Although designed and validated to assess postoperative pain, the tool is currently applied to assess acute pain in multiple settings, including the emergency department. Scarce literature exists evaluating the reliability of the FLACC scale in the nonsurgical population and none in the emergency department. We sought to investigate the reliability of the FLACC scale in assessing acute pain in the pediatric emergency department and to examine the sensitivity of FLACC scores after the administration of analgesia. METHODS: In phase 1 of this prospective study, a series of 2 independent evaluators, blinded to each other's evaluations, scored 66 patients using the FLACC tool. Degree of concordance among the 6 dyads was used to measure interrater reliability. In phase 2, FLACC scores were obtained just before the administration of analgesia in 35 patients and measured at 30 and at 60 minutes after administration. RESULTS: Among the 6 dyads of evaluators, Kendall W demonstrated a strong concordance (27 of 30 measures; range, 0.63-1.00) for individual components of the scale and for the composite scores (range, 0.85-0.96). Significant mean reductions from preanalgesia FLACC scores [5.54; 95% confidence interval (CI), 4.79-6.30] were seen at 30 minutes (2.00; 95% CI, 1.61-2.39) and 60 minutes (1.14; 95% CI, 0.79-1.50) postanalgesia (P < 0.0001 for all comparisons). CONCLUSIONS: The FLACC scale demonstrated high interrater reliability for both individual FLACC items and total scores in a convenience sample of patients aged 6 months to 5 years in a pediatric emergency department. It seems to be an appropriate observational tool to assess acute pain in this population. PMID- 27977533 TI - Successful Management of Fulminant Guillain-Barre Syndrome and Its Complications. AB - A 3-year-old girl presented with muscle weakness of her limbs and trunk 6 days after developing symptoms of common cold. Two days later, she experienced respiratory arrest with a Glasgow Coma Scale score of 3, necessitating endotracheal intubation. Therefore, she was transferred to our hospital with suspected acute encephalopathy. Although no abnormalities were observed on brain and spinal magnetic resonance imaging and electroencephalography, peripheral nerve conduction velocity tests failed to evoke motor and sensory nerve action potentials. Thus, we gave a diagnosis of fulminant Guillain-Barre syndrome and initiated immunoglobulin therapy. On day 3 of admission, she developed sinus tachycardia that induced circulatory failure and oliguria, which was successfully treated with landiolol. Subsequently, we performed plasmapheresis followed by immunoglobulin and steroid pulse therapies. She was weaned off the mechanical ventilator by day 20 of admission, was ambulatory by day 44, and had completely recovered without any adverse sequelae by day 55. In conclusion, landiolol was effective for treating acute sinus tachycardia-induced circulatory failure and played a key role in saving the life of this patient. PMID- 27977534 TI - Acute Mercury Poisoning in a Group of School Children. AB - OBJECTIVE: Elemental mercury is a toxic liquid element that is used widely in the home, medicine, agriculture, and industry. It is readily vaporized and inhaled at room temperature. Thereby, inhalation can cause acute or chronic poisoning. Mercury can be found in environmental naturally find but some dangers sources give rise to contaminations. It can be very dangerous to all living organisms, especially children. METHODS: This study presents the features of mercury poisoning in a group of pediatric cases. Data were obtained for 29 pediatric cases exposed to elemental mercury in a high school chemistry laboratory in Turkey. Patients with a blood mercury level exceeding 10 MUg/L or a urine mercury level exceeding 15 MUg/L were considered to have mercury poisoning. The patients were treated with 2,3-dimercaptopropane sulfonic acid or D-penicillamine. RESULTS: Twenty-nine children with mercury poisoning were admitted to the hospital. The median duration of exposure was 58 (range, 15-120) minutes. Ten (29%) children were asymptomatic. Physical and neurological examinations were normal in 19 (65.5%) children. The most common presenting complaint was headache. The most common neurological abnormality, partly dilated/dilated pupils, was present in 9 (31%) children. Mercury levels were measured in blood samples every 5 days, and the median blood mercury level was 51.98 (range, 24.9-86.4) MUg/L. There was a positive correlation between the duration of exposure and maximum blood/urine mercury levels (P = 0.001). CONCLUSIONS: Elemental mercury exposure is potentially toxic; its symptomatology varies, especially in children. Secure storage of mercury and other toxic substances and provision of information about this subject to individuals who might be exposed to mercury and their families might help to prevent mercury poisoning. PMID- 27977535 TI - The ideal dual-isotope imaging combination in evaluating patients with suspected infection of pelvic pressure ulcers. AB - INTRODUCTION: The successful management of infected pelvic pressure ulcer patients (PPUP) depends on the distinction between infections limited to soft tissue (STI) and those with underlying osteomyelitis (OM), which can be difficult to determine clinically. Dual-isotope (DI) comprehensive imaging has excellent accuracy in localizing diabetic foot infection and differentiating OM from STI with SPECT/CT utilization. In this study, we assess the accuracy and confidence of the different DI SPECT/CT imaging steps in PPUP with confirmed diagnoses. PATIENTS AND METHODS: Pelvic flow and blood pool imaging were followed by labeled white blood cell reinjection and Tc-99m hydroxymethylene-diphosphonate bone (bone scan) and In-111-leukocytes (white blood cell scan) DI planar and SPECT/CT (step 1) acquisitions. Tc-99m sulfur colloid (bone marrow scan)/WBCS SPECT/CT (step 2) images were obtained on the following day. DI step 1 planar, step 1 SPECT/CT, step 2 SPECT/CT, and combined step 1/step 2 SPECT/CT were reviewed separately for diagnosis and diagnosis confidence. The final diagnosis was confirmed by culture/pathology in 21 patients and clinical/imaging follow-up in 12 patients. RESULTS: There were 19 OM patients, three STI patients, and 11 patients with no infection. The final diagnosis agreement to DI combined step 1/step 2 SPECT/CT was higher than DI step 2 or step 1 SPECT/CT alone, or DI step 1 planar, as assessed by lambda and error reduction %, respectively. Combined DI step 1/step 2 SPECT/CT was more sensitive than DI step 2 SPECT/CT and more specific than DI step 1 SPECT/CT, and showed higher diagnostic confidence than both imaging techniques. CONCLUSION: DI SPECT/CT is highly useful in evaluating PPUP with suspected infection. DI step 1 is more sensitive, whereas step 2 is more specific. Both step 1 and step 2 DI SPECT/CT images are needed to accurately and confidently assess for infection and distinguish OM from STI, which are crucial for optimal management. PMID- 27977536 TI - Incidence of a single subsegmental mismatched perfusion defect in single-photon emission computed tomography and planar ventilation/perfusion scans. AB - OBJECTIVE: This study aims to compare the incidence of ventilation/perfusion (V/Q) scans interpreted as indeterminate for the diagnosis of pulmonary embolism (PE) using single-photon emission computed tomography (SPECT) versus planar scintigraphy and to consider the effect of variable interpretation of single subsegmental V/Q mismatch (SSM). METHODS: A total of 1300 consecutive V/Q scans were retrospectively reviewed. After exclusion and matching for age and sex, 542 SPECT and 589 planar scans were included in the analysis. European Association of Nuclear Medicine guidelines were used to interpret the V/Q scans, initially interpreting SSM as negative scans. Patients with SSM were followed up for 3 months and further imaging for PE was collected. RESULTS: Indeterminate scans were significantly fewer in the SPECT than the planar group on the basis of the initial report (7.7 vs. 12.2%, P<0.05). This is irrespective of classification of SSM as a negative scan (4.6 vs. 12.1%, P<0.0001) or an indeterminate scan (8.3 vs. 12.2%, P<0.05). Of the 21 patients who had SSM, 19 underwent computer tomography pulmonary angiogram and embolism was found in one patient. None of these patients died at the 3-month follow-up. CONCLUSION: V/Q SPECT has greater diagnostic certainty of PE, with a 41% reduction in an indeterminate scan compared with planar scintigraphy. This is irrespective of the clinician's interpretation of SSM as negative or intermediate probability. Patients with SSM would not require further computer tomography pulmonary angiogram imaging. PMID- 27977537 TI - Pretreatment metabolic parameters measured by 18F-FDG-PET to predict the outcome of first-line chemotherapy in extensive-stage small-cell lung cancer. AB - OBJECTIVE: Patients' pretreatment metabolic burden, as measured by radiotracer fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT), has been shown to predict treatment outcome in various malignancies. However, its predictive role in extensive-stage small cell lung cancer (SCLC) has not been definitively determined. This retrospective study investigated the viability of using common pretreatment metabolic parameters, obtained through F-FDG-PET/CT, to predict outcomes of first-line chemotherapy in extensive-stage SCLC. PARTICIPANTS AND METHODS: The study population comprised 154 consecutive patients with extensive-stage SCLC who underwent a pretreatment F-FDG-PET/CT scan and received standard first-line chemotherapy between January 2011 and December 2015. RESULTS: Ten (6.5%) and 66 (42.9%) patients achieved a complete or a partial response, respectively (considered an objective response); 35 (22.7%) and 43 (27.9%) experienced stable or progressive disease. The metabolic tumor volume (MTV) was a significant factor for predicting an objective response. For predicting disease control (objective response or stable disease), MTV and total lesion glycolysis (TLG) were nonindependent factors. CONCLUSION: Greater MTV and TLG could indicate a poorer response to first-line chemotherapy for patients with extensive-stage SCLC, but the predictive efficiency was not high enough for routine reliance. For patients who are not suitable to receive first-line chemotherapy, MTV and TLG may help guide clinical decisions. PMID- 27977538 TI - Continuous Venovenous Hemofiltration in Children Less Than or Equal to 10 kg: A Single-Center Experience. AB - OBJECTIVES: The aim of this study was to review the data from patients with a body weight less than or equal to 10 kg who required continuous venovenous hemofiltration, to assess the feasibility and problems associated with continuous venovenous hemofiltration in this population and compare the results with the current literature. DESIGN: Retrospective study design. SETTING: PICU in a single tertiary pediatric referral center. PATIENTS: Children less than or equal to 10 kg who received continuous venovenous hemofiltration between January 2008 and July 2014 were included in the study. INTERVENTIONS: Clinical data from these children were analyzed, and the differences between survivors and nonsurvivors were evaluated and compared with results from current literature. In a subgroup analysis of children less than or equal to 5 kg compared with children between 5 and 10 kg, the survival rate, indications for continuous venovenous hemofiltration, and continuous venovenous hemofiltration characteristics were assessed. MEASUREMENTS AND MAIN RESULTS: In total, 71 continuous renal replacement therapy episodes in 70 children were included in the study. Children in our cohort had a survival rate of 57.7% (41/71). Survivors had less frequent need for vasopressor support prior to continuous venovenous hemofiltration, lower oxygen requirement and percent fluid overload at continuous venovenous hemofiltration initiation. Survival rate was not significantly different in children less than or equal to 5 kg compared with 5-10 kg. However, in children less than or equal to 5 kg, metabolic manipulation was a significantly more frequent indication for continuous venovenous hemofiltration, heparin use was lower and maximal blood flow rate was higher. CONCLUSIONS: We have shown that continuous venovenous hemofiltration can be performed with good outcomes in children less than or equal to 10 kg using relatively high blood flow rates and with the current equipment available. PMID- 27977540 TI - EMpowerment of PArents in THe Intensive Care Questionnaire: Translation and Validation in Italian PICUs. AB - OBJECTIVES: To translate and validate the EMpowerment of PArents in THe Intensive Care questionnaire to measure parent satisfaction and experiences in Italian PICUs. DESIGN: Prospective, multicenter study. SETTING: Four medical/surgical Italian PICUs in three tertiary hospitals. PATIENTS: Families of children, 0-16 years old, admitted to the PICUs were invited to participate. Inclusion criteria were PICU length of stay greater than 24 hours and good comprehension of Italian language by parents/guardians. Exclusion criteria were readmission within 6 months and parents of a child who died in the PICU. INTERVENTIONS: Distribution, at PICU discharge, of the EMpowerment of PArents in THe Intensive Care questionnaire with 65 items divided into five domains and a six-point rating scale: 1 " certainly no" to 6 "certainly yes." MEASUREMENTS AND MAIN RESULTS: Back and forward translations of the EMpowerment of PArents in THe Intensive Care questionnaire between Dutch (original version) and Italian languages were deployed. Cultural adaptation of the instrument was confirmed by a consultation with a representative parent group (n = 10). Totally, 150 of 190 parents (79%) participated in the study. On item level, 12 statements scored a mean below 5.0. The Cronbach's alpha, measured for internal consistency, on domain level was between 0.67 and 0.96. Congruent validity was measured by correlating the five domains with four gold standard satisfaction measures and showed adequate correlations (rs, 0.41-0.71; p < 0.05). No significant differences occurred in the nondifferential validity testing between three children's characteristics and the domains; excepting parents with a child for a surgical and planned admission were more satisfied on information and organization issues. CONCLUSIONS: The Italian version of the EMpowerment of PArents in THe Intensive Care questionnaire has satisfactory reliability and validity estimates and seems to be appropriate for Italian PICU setting. It is an important instrument providing benchmark data to be used in the process of quality improvement toward the development of a family-centered care philosophy within Italian PICUs. PMID- 27977539 TI - Delirium in Children After Cardiac Bypass Surgery. AB - OBJECTIVES: To describe the incidence of delirium in pediatric patients after cardiac bypass surgery and explore associated risk factors and effect of delirium on in-hospital outcomes. DESIGN: Prospective observational single-center study. SETTING: Fourteen-bed pediatric cardiothoracic ICU. PATIENTS: One hundred ninety four consecutive admissions following cardiac bypass surgery, 1 day to 21 years old. INTERVENTIONS: Subjects were screened for delirium daily using the Cornell Assessment of Pediatric Delirium. MEASUREMENTS AND MAIN RESULTS: Incidence of delirium in this sample was 49%. Delirium most often lasted 1-2 days and developed within the first 1-3 days after surgery. Age less than 2 years, developmental delay, higher Risk Adjustment for Congenital Heart Surgery 1 score, cyanotic disease, and albumin less than three were all independently associated with development of delirium in a multivariable model (all p < 0.03). Delirium was an independent predictor of prolonged ICU length of stay, with patients who were ever delirious having a 60% increase in ICU days compared with patients who were never delirious (p < 0.01). CONCLUSIONS: In our institution, delirium is a frequent problem in children after cardiac bypass surgery, with identifiable risk factors. Our study suggests that cardiac bypass surgery significantly increases children's susceptibility to delirium. This highlights the need for heightened, targeted delirium screening in all pediatric cardiothoracic ICUs to potentially improve outcomes in this vulnerable patient population. PMID- 27977541 TI - Loop Electrosurgical Excision Procedure Instead of Cold-Knife Conization for Cervical Intraepithelial Neoplasia in Women With Unsatisfactory Colposcopic Examinations: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: This meta-analysis compared loop electrosurgical excision procedure (LEEP) with cold-knife conization (CKC) for treating cervical intraepithelial neoplasia (CIN) in patients with unsatisfactory colposcopic examinations. MATERIAL AND METHODS: A literature search on MEDLINE, EMBASE, Cochrane Systematic Reviews, CENTRAL, Web of Science, and Scopus databases was conducted from inception until April 2015. We included clinical trials and cohort studies comparing CKC with LEEP for treating CIN. The primary outcome was a combined end point of persistent CIN (<6 months after conization) and recurrent CIN (>6 months). Secondary outcomes included procedural, pathologic, and long-term outcomes. Pooled relative risk (RR) and weighted mean difference (WMD) were used to report binary and continuous outcomes, respectively. RESULTS: Among 26 studies, the incidence of persistent and recurrent disease after LEEP was comparable with that after CKC (15.6% vs 7.38%; RR = 1.35; 95% CI = 1.00-1.81). Loop electrosurgical excision procedure was faster, caused less intraoperative bleeding, and resulted in shorter hospital stay (WMD, 9.5 minutes [95% CI = 6.4 12.6 minutes]; WMD, 42.4 mL [95% CI = 21.3-106 mL]; and WMD, 1.5 days [95% CI = 1.1-1.8 days], respectively). Loop electrosurgical excision procedure cones were shallower with overall less volume and weight than CKC (WMD, 5.1 mm [95% CI = 3.2 7.1 mm]; 2.6 mm [95% CI = 0.6-5.7 mm]; and 2.6 g [95% CI = 1.4-3.7 g], respectively). During follow-up, LEEP was associated with less cervical stenosis and fewer unsatisfactory examinations; however, this was not statistically significant (RR, 0.5 [95% CI = 0.1-1.5]; RR, 0.7 [95% CI = 0.4-1.2], respectively). CONCLUSIONS: Loop electrosurgical excision procedure is an acceptable alternative to CKC in women with CIN and unsatisfactory colposcopic examinations. Close follow-up is necessary for prompt detection and treatment of persistent or recurrent disease. PMID- 27977542 TI - Early Diagnosis of Labial Fusion in Women After Allogeneic Hematopoietic Cell Transplant Enables Outpatient Treatment. AB - OBJECTIVE: The aim of the study was to describe the presentation and successful treatment of labial fusion in women after allogeneic hematopoietic cell transplantation (HCT). MATERIALS AND METHODS: During routine posttransplant gynecologic evaluation, labial fusion was identified in 5 female patients. Clinical data were collected regarding underlying disease, transplant regimen, genital symptoms, systemic sites of chronic graft-versus-host disease (cGvHD) and treatment, and follow-up. RESULTS: At presentation, women had a median age of 40 years (range = 35-50) and were 23-month to 8-year post-HCT. Four of the 5 patients with labial fusion had evidence of active cGvHD; 3 patients had severe sclerotic cGvHD, and 1 patient had bronchiolitis obliterans. One had rheumatoid arthritis and had recently stopped taking etanercept, but had no sites of cGvHD. One patient presented with only a pinpoint opening for passage of urine. Her complete labial fusion was lysed under general anesthesia. Three of the 4 others presented with dyspareunia. Their labia were fused between the clitoris and urethra narrowing the vaginal opening without obstructing the urethra. These labial adhesions were successfully lysed during an office procedure. Once the labial mucosa healed, the patients applied topical clobetasol and estrogen to prevent reagglutination. On follow-up, 1 month to 1 year later, all women were significantly improved. CONCLUSIONS: These patients highlight the importance of asking women who have undergone allogeneic HCT, especially those with severe cGvHD, about dyspareunia and dysuria. Those with genital symptoms warrant referral to a gynecologist. These cases illustrate that labial fusion, if diagnosed early enough, may be treated successfully with an office procedure and medical therapy. PMID- 27977543 TI - Preinvasive and Invasive Cervical Adenocarcinoma: Preceding Low-Risk or Negative Pap Result Increases Time to Diagnosis. AB - OBJECTIVES: The aims of the study were to investigate screening histories of women with adenocarcinoma in situ (AIS) and adenocarcinoma (AdCa) of the cervix and to further evaluate screening for glandular disease. MATERIALS AND METHODS: Screening histories were retrospectively collected for patients with AIS or AdCa at a single large-volume academic institution from 2005 to 2015. Fisher exact and Wilcoxon rank sum tests were used to compare AIS with AdCa patient characteristics, distribution of preceding Pap (i.e., trigger Pap) results, and high-risk human papillomavirus testing. The association between Pap result and time to diagnosis was evaluated. RESULTS: Eighty-seven cases, 50 AIS and 37 AdCa, met study criteria; median age was 31 and 43 years, respectively. Among the AIS cohort, 52.0% had a negative or low-risk trigger Pap result versus 24.3% of those with AdCa (p = .001). The time to diagnosis of AIS ranged from 8.4 to 18.8 weeks for those with high- versus low-risk or negative trigger Pap results, respectively (p = .002). The time to diagnosis of AdCa ranged from 14.6 to 44.7 weeks for those with high- versus low-risk or negative trigger Pap results, respectively (p = .003). Among those with high-risk human papillomavirus testing, 89.7% tested positive at the time of trigger Pap with 100% positivity among those with low-risk or negative trigger Pap results. CONCLUSIONS: Cervical AIS and AdCa affect many young nulliparous women and commonly preceded by low-risk or negative Pap testing. The interval to diagnosis increases with low-risk and negative Pap results, and therefore, further investigation into optimal screening for glandular lesions is needed. PMID- 27977544 TI - Outcomes From Pediatric Gastroenterology Maintenance of Certification Using Web based Modules. AB - OBJECTIVES: Beginning in 2013, the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) sponsored and developed subspecialty field-specific quality improvement (QI) activities to provide Part 4 Maintenance of Certification (MOC) credit for ongoing certification of pediatric gastroenterologists by the American Board of Pediatrics. Each activity was a Web based module that measured clinical practice data repeatedly over at least 3 months as participants implemented rapid cycle change. Here, we examine existing variations in clinical practice among participating pediatric gastroenterologists and determine whether completion of Web-based MOC activities improves patient care processes and outcomes. METHODS: We performed a cross-sectional and prospective analysis of physician and parent-reported clinical practice data abstracted from Web-based MOC modules on the topics of upper endoscopy, colonoscopy, and informed consent collected from pediatric gastroenterologists from North America from 2013 to 2016. RESULTS: Among 134 participating pediatric gastroenterologists, 56% practitioners practiced at an academic institution and most (94%) were NASPGHAN members. Participating physicians reported data from 6300 procedures. At baseline, notable practice variation across measured activities was demonstrated. Much of the rapid cycle changes implemented by participants involved individual behaviors, rather than system/team-based improvement activities. Participants demonstrated significant improvements on most targeted process and quality care outcomes. CONCLUSIONS: Pediatric gastroenterologists and parents reported baseline practice variation, and improvement in care processes and outcomes measured during NASPGHAN-sponsored Web based MOC QI activities. Subspecialty-oriented Web-based MOC QI activities can reveal targets for reducing unwarranted variation in clinical pediatric practice, and can effectively improve care and patient outcomes. PMID- 27977545 TI - Endoscopic Ultrasound-guided Drainage of Walled-off Necrosis in Children With Fully Covered Self-expanding Metal Stents. AB - OBJECTIVES: Endoscopic ultrasound (EUS)-guided drainage with fully covered self expanding metallic stents (FCSEMS) has been successfully used in adult patients. The utility of FCSEMS in children with walled-off necrosis (WON) is, however, unknown. The aim of present study was to evaluate the feasibility, safety, and efficacy of EUS drainage of WON using FCSEMS in children. METHODS: We retrospectively evaluated the data of children (18 years or younger) who underwent EUS drainage of WON using FCSEMS at our institution. All FCSEMS were removed between 1 and 3 months. Feasibility, safety, and efficacy were analysed. RESULTS: Twenty-one children (20 boys, mean age 14.9 +/- 2.34 years, range 9-18 years) underwent EUS-guided drainage of WON with FCSEMS. The median size of WON was 88 mm (55-148 mm). The median interval between onset of acute pancreatitis and EUS guided drainage was 58 days (range 30-288 days). The technical and clinical success rates were 100% and 95%, respectively. Nasocystic tube was placed in 3 children for lavage. Endoscopic necrosectomy was not required in any of the children. There were no major complications. Minor complications included bleeding (2), stent migration (1), and difficulty in removal of stent (1). After a median follow-up of 360 days (range: 30-1020 days), there was 1 recurrence of WON. CONCLUSIONS: EUS drainage of WON using specially designed FCSEMS is safe and efficacious in children. The utility of FCSEMS in children should be further explored and compared with plastic stents. PMID- 27977546 TI - Consensus Review of Best Practice of Transanal Irrigation in Children. AB - Pediatric patients with either functional or organic bowel dysfunction may suffer from constipation and fecal incontinence and represent a complex group in whom management is often difficult. Many noninvasive and invasive treatments have been proposed, with variable efficacy and adverse effects. Transanal irrigation (TAI) is now an accepted alternative, in both children and adults, for bowel dysfunction that has not responded to conservative and medical therapies. There is, however, still some uncertainty about the use of TAI in pediatric populations. Hence, a group of specialists from different nations and pediatric disciplines, all with long-standing experience of bowel management in children, performed a literature search and had round table discussions to determine the best-practice use of TAI in the pediatric patient population. Based on these findings, this article provides best-practice recommendations on indications, patient selection, important considerations before treatment, patient and family training, treatment regimens, troubleshooting, and practical aspects of TAI. We conclude that careful patient selection, a tailored approach, directly supervised training, and sustained follow-up are key to optimize outcomes with TAI in children with functional or organic bowel dysfunction. PMID- 27977547 TI - Erysipelothrix rhusiopathiae Suppurative Arthritis in a 12-year-old Boy After an Unusual Fresh Water Exposure. AB - We report the case of a 12-year-old boy who experienced recurrent suppurative arthritis of the distal interphalangeal joint after near simultaneous exposure to a frog, a dog bite and lake water. Anaerobic cultures of synovial fluid obtained during operative debridement grew small round gray colonies ultimately identified as Erysipelothrix rhusiopathiae by routine laboratory tests and mass spectrometry. PMID- 27977548 TI - Update on Zika: What You Need to Know. PMID- 27977549 TI - Infant Respiratory Tract Infections or Wheeze and Maternal Vitamin D in Pregnancy: A Systematic Review. AB - BACKGROUNDS: Respiratory tract infections (RTIs) are a common cause of morbidity and mortality in young children and can be associated with wheeze. Vitamin D can have a protective role against RTI. MATERIALS AND METHODS: A systematic search of PubMed, Embase and the Cochrane library was performed. Titles and abstracts were evaluated, and selected articles were reviewed by 2 authors. We included randomized controlled trials (RCTs) investigating the effect of vitamin D supplementation during pregnancy on RTIs or wheeze in children of 5 years of age or younger. Observational studies on the association between serum 25 hydroxyvitamin D during pregnancy, or at birth, and RTIs and/or wheeze were included. The protocol was registered on PROSPERO (Registration number: CRD42015019183). RESULTS: Of 4 RCTs, 1 showed a protective effect of a high daily dose (2000 IU) of vitamin D during pregnancy on offspring RTI doctor visits (P = 0.004; the RCT also included 800 IU/d supplement to the infants until 6 months). Meta-analysis of 3 RCTs showed a reduced relative risk for offspring wheeze when mothers were supplemented with vitamin D during pregnancy [relative risk: 0.81 (95% confidence interval: 0.68-0.97), P = 0.025]. In 3 of 4 strong-quality, and 5 of 10 moderate-quality observational studies, an inverse association between pregnancy and cord 25-hydroxyvitamin D and subsequent wheeze and/or RTI was seen. CONCLUSION: Growing evidence supports a preventive role of vitamin D during pregnancy on offspring wheeze and/or RTI. Recommendations in future intervention studies may need to exceed current recommendations of vitamin D supplementation during pregnancy to show benefit against childhood wheeze or infections. PMID- 27977550 TI - Evaluation of Teicoplanin Trough Values After the Recommended Loading Dose in Children With Associated Safety Analysis. AB - BACKGROUND: This study evaluated whether the recommended teicoplanin loading dose (3 loading doses of 10 mg/kg every 12 hours) achieves a 15-30 MUg/mL trough levels in 26 children (2-16 years). In addition, we examined the incidences of renal impairment and hepatic dysfunction in children treated with teicoplanin. METHODS: This retrospective study was conducted between October 2008 and March 2014. RESULTS: The percentage of patients with a trough level <10 and <15 MUg/mL were 15.4% (4/26) and 46.2% (12/26), respectively. There were significant correlations between age and concentration/cumulative loading dose (C/D) ratio (P = 0.045), serum creatinine and C/D ratio (P < 0.001) and estimated glomerular filtration rate and C/D ratio (P = 0.005). Serum creatinine was significantly lower when trough levels were <15 MUg/mL compared with >=15 MUg/mL. The incidences of renal impairment and hepatic dysfunction were 2.3% and 5.8%, respectively, with no significant difference between <20 and >=20 MUg/mL trough level groups. CONCLUSIONS: The recommended loading dose may be insufficient to achieve 15-30 MUg/mL in children with normal renal function. In addition, the target trough level >=20 MUg/mL for deep-seated infections seems to be safe in children. PMID- 27977551 TI - Meningoradiculopathy Associated with Human Herpesvirus 7-A Virus with Potential to Cause Severe Neurologic Disease with Sequelae. AB - We present a case report of a meningoradiculopathy associated with human herpesvirus 7, with long-term motor neurologic sequelae. It is important to consider human herpesvirus 7 as a potential pathogen of severe neurologic disease and sequelae in immunocompetent children, especially in older patients presenting neurologic signs. PMID- 27977552 TI - Lack of Pertussis Protective Antibodies in Healthcare Providers Taking Care of Neonates and Infants in a Children's Hospital. AB - Contact tracing and seroepidemiologic studies were done after a premature baby contracted pertussis in a children's hospital. No infection source was confirmed. Four (3.5%) healthcare providers were positive for anti-pertussis IgM, while only 23% (26/113) were positive for IgG in a following survey. Pertussis vaccination for healthcare providers is needed. PMID- 27977553 TI - The Association Between Fecal Biomarkers of Environmental Enteropathy and Rotavirus Vaccine Response in Nicaraguan Infants. AB - BACKGROUND: Environmental enteropathy (EE) is a common intestinal condition among children living in low- and middle-income countries and is associated with diminished enteric immunity to gastrointestinal pathogens, and possibly to oral vaccine antigens. The goal of this study was to examine associations between biomarkers of EE and immunogenicity to the pentavalent rotavirus vaccine (RV5). METHODS: Infants were recruited 1 day before their first RV5 immunization in Leon, Nicaragua, from public health rosters. Infants provided a preimmunization blood and stool sample, and a second blood sample 1 month after receipt of RV5. We measured immunoglobin A (IgA) seroconversion to the first dose of RV5 and concentrations of 4 previously identified fecal biomarkers of EE (alpha-1 antitrypsin, neopterin, myeloperoxidase and calprotectin). We then assessed associations between concentrations of these biomarkers, both individually and as combined scores, and seroconversion to the first dose of RV5. RESULTS: Of the 43 enrolled infants, 24 (56%) seroconverted after the first dose of RV5. As compared with infants who seroconverted, those who did not seroconvert had higher median concentrations of both myeloperoxidase (3.1 vs. 1.1 ug/mL, P = 0.002) and calprotectin (199.1 vs. 156.2 ug/mL, P = 0.03). Further, those who did not seroconvert had a higher median combined score of the 4 biomarkers as compared with those who seroconverted (6.5 vs. 4.5, P = 0.017). CONCLUSIONS: We found an association between biomarkers of EE and seroconversion to the first dose of RV5. It is possible that interventions that prevent or ameliorate EE may also improve oral rotavirus vaccine response. PMID- 27977554 TI - Neonatal Cutaneous Invasive Aspergillosis Accompanied by Hemophagocytic Lymphohistocytosis. AB - We describe a 6-week-old female infant with cutaneous invasive aspergillosis accompanied with hemophagocytic lymphohistocytosis. Aspergillus flavus was isolated from biopsies of necrotic skin lesions on the forehead and scalp; morphologic identification was confirmed by molecular analysis. In vitro antifungal susceptibility testing showed that amphotericin B and triazoles had potent activity. The patient responded well to treatment with intravenous amphotericin B combined with oral posaconazole and local wound care. The hemophagocytic lymphohistocytosis abated after treatment of cutaneous aspergillosis. Both cutaneous invasive aspergillosis and hemophagocytic lymphohistocytosis are severe disorders with high morbidity and mortality requiring prompt diagnosis and treatment. PMID- 27977556 TI - Pediatric Prostatic Abscess Caused by Methicillin-susceptible Staphylococcus aureus. AB - Prostatic abscesses are infrequently encountered in adults and are exceedingly rare in the pediatric population. We present the case of an 11-year-old boy with a methicillin-susceptible Staphylococcus aureus prostatic abscess and bacteremia. PMID- 27977555 TI - Recurrent Clostridium difficile Infection in Children: Patient Risk Factors and Markers of Intestinal Inflammation. AB - BACKGROUND: The management of Clostridium difficile infection (CDI) in children is complicated by recurrence rates of 20%-30%. The identification of risk factors associated with recurrent disease might allow early recognition of those children at highest risk. METHODS: Pediatric patients with CDI were identified through clinical laboratory records at 2 tertiary-care children's hospitals from March 2013 through May 2014. Subjects were enrolled and followed for 60 days to assess for recurrent CDI (rCDI). Blood samples were obtained at enrollment to evaluate host interleukin (IL)-8 polymorphisms and anti-toxin A antibody levels; stool samples were obtained for inflammatory markers (lactoferrin, calprotectin, IL-8) and C. difficile ribotype 027 strain status. Thirty days post enrollment, another serum sample was obtained to compare antibody responses. RESULTS: Of the 28 pediatric patients enrolled, 27 completed follow-up and 8 (30%) experienced rCDI. At enrollment, children with malignancy had significantly lower stool calprotectin, lactoferrin and IL-8 than those without malignancy. There was a trend toward increased stool inflammatory markers in those who later developed rCDI. The IL-8 A/A genotype was not associated with recurrent disease. No patients were found to have ribotype 027 or an antibody increase to toxin A. CONCLUSIONS: The rate of rCDI in our pediatric cohort was 30%. Children with rCDI had a trend toward higher fecal inflammatory markers with the initial infection, and these values were lower in children with malignancy. Fecal lactoferrin, calprotectin and IL-8 should be further studied to determine their value in predicting the risk of rCDI in children. PMID- 27977557 TI - Safety of High-dose Acyclovir in Infants With Suspected and Confirmed Neonatal Herpes Simplex Virus Infections. AB - BACKGROUND: Acyclovir is used to treat herpes simplex virus disease in infants. Treatment with high-dose acyclovir, 60 mg/kg/d, is recommended; however, the safety of this dosage has not been assessed in the past 15 years, and this dosage is not currently approved for infants by the US Food and Drug Administration. METHODS: We included infants with neonatal herpes simplex virus disease treated with >=14 days of intravenous acyclovir starting in the first 120 days of life admitted to 1 of 42 neonatal intensive care units managed by the Pediatrix Medical Group between 2002 and 2012. We determined the frequency and proportion of infants with clinical and laboratory adverse events (AEs) as well as the number and proportion of infant days with laboratory AEs occurring during acyclovir exposure. RESULTS: We identified 89 infants during the study period with 1658 days of acyclovir exposure. Almost all received high-dose acyclovir therapy (79/89, 89%). The most common clinical AEs were hypotension and seizure, both occurring in 9% of infants. Thrombocytopenia was the most common laboratory AE occurring in 25% of infants and on 9% of infant-days. Elevated creatinine occurred in 2% of infants and 0.2% of infant-days and no infants developed renal failure requiring dialysis. Overall, 45% of infants had >=1 AE. CONCLUSIONS: In this cohort of infants treated during the high-dose acyclovir era, AEs were common but usually not severe. Many of the AEs reported in this cohort may be related to the underlying infection rather than due to acyclovir exposure. PMID- 27977558 TI - Intensive Care Admissions for Children With Enterovirus and Human Parechovirus Infections in the United Kingdom and The Republic of Ireland, 2010-2014. AB - Enteroviruses and human parechoviruses usually cause mild, self-limiting illnesses in children but can occasionally cause severe disease. During 2010 2014, 104 children in the United Kingdom and the Republic of Ireland were admitted to a pediatric intensive care unit with severe enterovirus and human parechovirus infection; 40% had neurologic symptoms, 20% respiratory failure, 16% cardiac complications and 11% septic shock. Annual number of cases and incidence increased in the 5-year period, from 0.6/1000 pediatric intensive care unit admissions (12 cases) in 2010 to 1.8/1000 (36 cases) in 2014. Most cases (n = 86, 83%) were younger than 1 year; 77% (n = 80) required invasive ventilation, 40% (n = 42) inotropic support, 4% (n = 4) renal dialysis and 3% (n = 3) extracorporeal membrane oxygenation. Eight children (8%) died, including 4 with cardiac complications. PMID- 27977559 TI - Methicillin-resistant Staphylococcus aureus as a Cause of Lemierre's Syndrome. AB - Lemierre's syndrome (LS) or jugular vein suppurative thrombophlebitis is well described in literature. The organisms most often responsible are Fusobacterium necrophorum or anaerobic flora. We present a case of LS with an atypical microbiologic cause, methicillin-resistant Staphylococcus aureus. We also present retrospective review of all LS cases from our institution and identified 2 additional children with LS caused by methicillin-resistant S. aureus. PMID- 27977561 TI - Risk Factors for Hypoxia and Tachypnea Among Adolescents With Vertically-acquired HIV in Nairobi. AB - BACKGROUND: Chronic lung diseases are increasingly recognized complications of vertically-acquired HIV among adolescents in sub-Saharan Africa and may manifest with hypoxia or tachypnea. We sought to determine the prevalence of and risk factors for hypoxia and tachypnea among adolescents with vertically-acquired HIV in Nairobi, Kenya. METHODS: We performed a cross-sectional analysis of 258 adolescents with vertically-acquired HIV who were initiating care at the Coptic Hope Center for Infectious Diseases. Adolescents with documented pneumonia were excluded. Hypoxia was defined as resting oxygen saturation <=92%, and tachypnea was based on the 99th percentile of age-appropriate respiratory rates. Logistic regression models adjusted for demographics, and HIV severity estimated odds ratios for risk of hypoxia and tachypnea associated with potential risk factors. RESULTS: Overall, 11% of adolescents had hypoxia and 55% had tachypnea. Advanced HIV [adjusted odds ratio (aOR): 2.41] and low CD4 (aOR: 1.74) were associated with greater hypoxia risk, but confidence intervals (CIs) were wide and included the null (95% CI: 0.93-6.23 and 0.69-4.39, respectively). Low CD4 (aOR: 2.45, 95% CI: 1.39-4.32), current antiretroviral therapy use (aOR: 0.48, 95% CI: 0.27-0.86) and stunted growth (aOR: 3.46, 95% CI: 1.94-6.18) were associated with altered tachypnea risk. CONCLUSIONS: Hypoxia and tachypnea are common among adolescents with vertically-acquired HIV. There was a suggestion that advanced HIV and low CD4 were associated with greater hypoxia risk. Low CD4, lack of antiretroviral therapy use and stunted growth are risk factors for tachypnea. Our findings highlight the chronic lung disease burden in this population and may inform diagnostic algorithms. PMID- 27977562 TI - Appealing the Editor's Decision: When and How. PMID- 27977563 TI - Pathways From Socioeconomic Status to Prenatal Smoking: A Test of the Reserve Capacity Model. AB - BACKGROUND: Low-income, unemployed women with low levels of education are more likely to smoke during pregnancy compared to their higher-income, employed, and well-educated counterparts. The reserve capacity model (RCM) offers a theoretical framework to explain how psychosocial factors may serve as pathways connecting socioeconomic status (SES) to health behaviors. Research supports the link between prenatal smoking and several psychosocial variables such as chronic stressors, depressive symptoms, and social support. How these variables interrelate to explain the predominance of prenatal smoking in lower socioeconomic groups of pregnant women has not been fully elucidated. OBJECTIVE: The aim of this study was to test the RCM to evaluate the roles of early pregnancy levels of chronic stress, quality of the primary intimate relationship, and depressive symptoms in explaining the relationship between SES and persistent prenatal smoking. METHODS: A secondary analysis of data from 370 pregnant nonsmokers, spontaneous quitters, and persistent prenatal smokers was conducted. On the basis of the RCM, chronic stressors, depressive symptoms, and the quality of the primary intimate relationship were evaluated as potential mediating variables linking SES with persistent prenatal smoking using path analysis. RESULTS: Path analyses indicated that a simple model with all three psychosocial variables as mediators of the relationship between SES and persistent prenatal smoking provided the best fit. DISCUSSION: Findings indicated that chronic stressors, depressive symptoms, and the quality of the primary intimate relationship play important roles in the pathway from SES to prenatal smoking status. This knowledge can assist in the development of prevention and intervention strategies to target these variables and ultimately reduce prenatal smoking. PMID- 27977565 TI - Emergency Department Weekend Presentation and Mortality in Patients With Acute Myocardial Infarction. AB - BACKGROUND: Patients admitted to acute care hospitals on weekends have poorer outcomes than those admitted on weekdays, and patients admitted to hospitals for acute myocardial infarction (AMI) on weekends have a higher mortality rate than those admitted during the week. Very few studies have examined weekend presentation for patients with AMI with respect to mortality in the emergency department (ED). OBJECTIVE: The purpose of this research was to determine if weekend and holiday presentation is associated with increased mortality in EDs among patients with AMI in New Jersey. METHODS: A retrospective cohort and three data sources representing all hospitals in New Jersey, including patients 18-90 years of age who presented to the ED with symptoms of AMI from January 1, 2008 to January 31, 2010, were used. "Weekend" was defined as Saturday and Sunday, and "holiday" was defined as one of the six major U.S. holidays. Propensity score matching with probit regression was used to estimate the unbiased treatment effect of weekend/holiday presentation on mortality in the ED. RESULTS: A total of 1,343 patients with a diagnosis of AMI presented to 73 EDs in New Jersey. Of these, 382 (28%) presented on a weekend/holiday and 961 (72%) during weekday hours. After propensity score matching and using probit regression, weekend/holiday presentation was significantly associated with mortality (b = 0.30, 95% CI [0.03, 0.57]). Other statistically significant covariates include patient age (b = 0.03, 95% CI [0.02, 0.04], hospital technology status (b = 0.75, 95% CI [0.20, 1.30]), and nurse staffing (b = -0.08, 95% CI [-0.13, -0.04]). DISCUSSION: Weekend/holiday presentation to the ED for AMI was associated with increased mortality. The effect may be related to the limited availability of resources on weekend/holidays compared to weekdays. Future studies should examine potential variations of resources, nursing workload, and education and expertise of healthcare providers in the ED during the weekend. PMID- 27977564 TI - Vector Autoregressive Models and Granger Causality in Time Series Analysis in Nursing Research: Dynamic Changes Among Vital Signs Prior to Cardiorespiratory Instability Events as an Example. AB - BACKGROUND: Patients undergoing continuous vital sign monitoring (heart rate [HR], respiratory rate [RR], pulse oximetry [SpO2]) in real time display interrelated vital sign changes during situations of physiological stress. Patterns in this physiological cross-talk could portend impending cardiorespiratory instability (CRI). Vector autoregressive (VAR) modeling with Granger causality tests is one of the most flexible ways to elucidate underlying causal mechanisms in time series data. PURPOSE: The purpose of this article is to illustrate the development of patient-specific VAR models using vital sign time series data in a sample of acutely ill, monitored, step-down unit patients and determine their Granger causal dynamics prior to onset of an incident CRI. APPROACH: CRI was defined as vital signs beyond stipulated normality thresholds (HR = 40-140/minute, RR = 8-36/minute, SpO2 < 85%) and persisting for 3 minutes within a 5-minute moving window (60% of the duration of the window). A 6-hour time segment prior to onset of first CRI was chosen for time series modeling in 20 patients using a six-step procedure: (a) the uniform time series for each vital sign was assessed for stationarity, (b) appropriate lag was determined using a lag-length selection criteria, (c) the VAR model was constructed, (d) residual autocorrelation was assessed with the Lagrange Multiplier test, (e) stability of the VAR system was checked, and (f) Granger causality was evaluated in the final stable model. RESULTS: The primary cause of incident CRI was low SpO2 (60% of cases), followed by out-of-range RR (30%) and HR (10%). Granger causality testing revealed that change in RR caused change in HR (21%; i.e., RR changed before HR changed) more often than change in HR causing change in RR (15%). Similarly, changes in RR caused changes in SpO2 (15%) more often than changes in SpO2 caused changes in RR (9%). For HR and SpO2, changes in HR causing changes in SpO2 and changes in SpO2 causing changes in HR occurred with equal frequency (18%). DISCUSSION: Within this sample of acutely ill patients who experienced a CRI event, VAR modeling indicated that RR changes tend to occur before changes in HR and SpO2. These findings suggest that contextual assessment of RR changes as the earliest sign of CRI is warranted. Use of VAR modeling may be helpful in other nursing research applications based on time series data. PMID- 27977566 TI - Students' Perceptions of Characteristics of Victims and Perpetrators of Bullying in Public Schools in Jordan. AB - BACKGROUND: School bullying is the most common school violence among adolescents and has become a global concern. Little is known about the characteristics associated with bullies and victims among Jordanian students. OBJECTIVES: The aim of the study was to examine student perceptions of school bullying-specifically, the characteristics of perpetrators and victims and how to stop bullying-and assess differences in perceptions between boys and girls. METHODS: Cross sectional study, using self-reported questionnaires, was employed to collect data from eighth-grade students (N = 913; 51% male) from a mixed rural and suburban area in northern of Jordan during the 2013-2014 school year. Descriptive statistics were used to summarize item responses. Chi-squared tests were performed to compare responses between the male and female students. RESULTS: Most of the students described a bully as one who is a coward underneath (78.9%), lacks respect for other people (70%), wants to show power (67.5%), wants to impress others (60.8%), and wants to feel superior (59.6%). Students perceived victims of bullying as having low self-esteem (68.2%), talking or sounding different than others (50.9%), shy (35%), and having no friends (27.1%). Students suggested that, to stop bullying, the victim should stand up for himself (75.4%), should become psychologically stronger (75.1%), and should involve adults (teachers, family, or others; 45.9%). There was a significant gender difference, in which boys and girls were describing victims and bullies differently. DISCUSSION: A significant percentage of students relate bullying and victimization characteristics to psychosocial characteristics and less to physical characteristics. The results offer valuable information necessary to design and implement school bullying prevention and intervention programs. PMID- 27977567 TI - Near-Falls in Elderly Community-Dwelling Blacks From Two Out-Patient Clinics in Harlem. AB - BACKGROUND: Near-falls are a frequent, but not commonly studied, occurrence in the elderly Black population and may be related to prospective falls. OBJECTIVES: The purpose of this paper is to examine the relationship of near-falls to demographic characteristics, use of assistive devices, gait, and physical activity levels in elderly Blacks. METHODS: Community-dwelling, elderly Black patients aging 65 and older and attending two clinics of the Mount Sinai Hospital in Harlem in New York City were recruited. The number of near-falls during the past year was self-reported using the Elderly Falls Screening Test. The Rapid Assessment of Physical Activity was used to assess aerobic and anaerobic activity levels. Backward stepwise logistic regression was used to identify predictors of near-falls. RESULTS: A total of 120 elderly Black adults took part in the study. Prevalence of occasional or frequent near-falls was 52.5%. In the final trimmed model, time of the 5-m observed walk (OR = 1.41, p = .001) and being male (OR = 3.68, p = .02) were significant predictors of near-fall experiences. DISCUSSION: Future research needs to be done in elderly Black populations to determine what factors may contribute to men experiencing more near-falls and on the relation between near-falls and falls. PMID- 27977568 TI - Intervention Fidelity: Monitoring Drift, Providing Feedback, and Assessing the Control Condition. AB - BACKGROUND: Measurement of intervention fidelity is an essential component of any scientifically sound intervention trial. However, few papers have proposed ways to integrate intervention fidelity data into the execution of these trials. OBJECTIVE: The purpose of this article is to describe the intervention fidelity process used in a randomized controlled trial of a human patient simulator intervention and how these data were used to monitor drift and provide feedback to improve the consistency of both intervention and control delivery over time in a multisite education intervention for parents of children with newly diagnosed Type 1 diabetes. METHODS: Intervention fidelity was measured for both the intervention and control condition by direct observation, self-report of interventionist delivery, and parent participant receipt of educational information. Intervention fidelity data were analyzed after 50%, 75%, and 100% of the participants had been recruited and compared by group (treatment and control) and research site. RESULTS: The sample included 191 parents of young children newly diagnosed with Type 1 diabetes. Observations scores in both intervention and control groups indicated a high level of intervention fidelity. Treatment receipt was also high and did not differ by treatment group. The teaching session attendance rates by site and session were significantly different at Time Point 1 (50% enrollment); following study staff retraining and reinforcement, there were no significant differences at Time Point 3 (100% enrollment). IMPLICATIONS: Results demonstrate the importance of monitoring intervention fidelity in both the intervention and control condition over time and using these data to correct drift during the course of a multisite clinical trial. PMID- 27977570 TI - Hypokalemia associated with a solitary pulmonary nodule: A case report. AB - BACKGROUND: Differential diagnosis of hypokalemia and adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome often presents challenging in endocrinology and requires careful clinical, biochemical, radiological, and pathological investigations. Hypokalemia is a common abnormality and systematic approach is required to avoid delays in diagnosis of important underlying causes. CASE SUMMARY & CONCLUSION: A 49-year-old woman presented with moderate hypokalemia. Further evaluation showed hypercortisolism due to ectopic ACTH secretion.Chest computed tomography (CT) revealed a peripheral solitary pulmonary nodule. Excision biopsy of the nodule showed carcinoid tumor. After excision biopsy, all of the patient's symptoms improved and electrolytes and ACTH levels also became normal.Carciniod tumors should be considered as a differential diagnosis in patients presenting with hypokalemia and ectopic ACTH syndrome. Carcinoid tumor often present as solitary pulmonary nodule and excision biopsy can be curative. PMID- 27977569 TI - Intraoperative radiation therapy (IORT) in head and neck cancer: A systematic review. AB - BACKGROUND: Multimodality therapy constitutes the standard treatment of advanced and recurrent head and neck cancer. Since locoregional recurrence comprises a major obstacle in attaining cure, the role of intraoperative radiation therapy (IORT) as an add-on in improving survival and local control of the disease has been investigated. IORT allows delivery of a single tumoricidal dose of radiation to areas of potential residual microscopic disease while minimizing doses to normal tissues. Advantages of IORT include the conformal delivery of a large dose of radiation in an exposed and precisely defined tumor bed, minimizing the risk of a geographic miss creating the potential for subsequent dose reduction of external beam radiation therapy (EBRT). This strategy allows for shortening overall treatment time and dose escalation. The aim of this review is to summarize recent published work on the use of IORT as an adjuvant modality to treat common head and neck cancer in the primary or recurrent setting. METHODS: We searched the Medline, Scopus, Ovid, Cochrane, Embase, and ISI Web of Science databases for articles published from 1980 up to March 2016. RESULTS: Based on relevant publications it appears that including IORT in the multimodal treatment may contribute to improved local control. However, the benefit in overall survival is not so clear. CONCLUSION: IORT seems to be a safe, promising adjunct in the management of head and neck cancer and yet further well organized clinical trials are required to determine its role more precisely. PMID- 27977571 TI - Percutaneous endoscopic transforaminal lumbar spinal canal decompression for lumbar spinal stenosis. AB - This study aimed to evaluate the safety and curative effect of percutaneous endoscopic transforaminal lumbar spinal canal decompression in the treatment of lumbar spinal stenosis.This retrospective study recruited 64 patients with lumbar spinal stenosis who underwent percutaneous endoscopic lumbar spinal canal decompression via surgical approach of posterolateral intervertebral foramen. The postoperation neurological function and pain status were evaluated by the visual analog scale (VAS) score of pain and the Oswestry disability index (ODI), and the patient satisfaction was evaluated according to the MacNab outcome criteria. The data, including preoperative comorbidities, operation time, the quantity of bleeding, bed rest time, and intraoperative and postoperative complications, were recorded.The mean operation time was 78 min, the mean quantity of bleeding was 20 mL and bed rest time was 6 h to 3 days. All patients were followed-up for 4 months to 5 years. The mean preoperative VAS score was 7.7 +/- 1.2, while postoperative 3 months, 6 months, and final follow-up VAS scores were 2.8 +/- 0.7, 2.1 +/- 0.6, and 0.8 +/- 0.6, respectively (P < 0.001). The mean preoperative ODI score was 72.4 +/- 1.2, while postoperative 3 months, 6 months, and final follow-up ODI scores were 29.7 +/- 4.9, 23.9 +/- 4.0, and 12.5 +/- 3.9, respectively (P < 0.001). The excellent and good rate reached 73.4% at the final follow-up.The percutaneous endoscopic transforaminal lumbar spinal canal decompression is an easy, safe, and effective minimally invasive surgery for patients with lumbar spinal stenosis. PMID- 27977572 TI - Three-dimensional intracranial EEG monitoring in presurgical assessment of MRI negative frontal lobe epilepsy. AB - Magnetic resonance imaging (MRI)-negative epilepsy is associated with poor clinical outcomes prognosis. The present study was aimed to assess whether intracranial 3D interictal and ictal electroencephalography (EEG) findings, a combination of EEG at a different depth, in addition to clinical, scalp EEG, and positron emission tomography-computed tomography (PETCT) data help to predict outcome in a series of patients with MRI-negative frontal lobe epilepsy (FLE) after surgery.Patients with MRI-negative FLE who were presurgically evaluated by 3D-intracranial EEG (3D-iEEG) recording were included. Outcome predictors were compared in patients with seizure freedom (group 1) and those with recurrent seizures (group 2) at least 24 months after surgery.Forty-seven patients (15 female) were included in this study. MRI was found normal in 38 patients, whereas a focal or regional hypometabolism was observed in 33 cases. Twenty-three patients (48.9%) were seizure-free (Engel class I), and 24 patients (51.1%) continued to have seizures (12 were class II, 7 were class III, and 5 were class IV). Detailed analysis of intracranial EEG revealed widespread (>2 cm) (17.4%:75%; P = 0.01) in contrast to focal seizure onset as well as shorter latency to onset of seizure spread (5.9 +/- 7.1 s; 1.4 +/- 2.9 s; P = 0.016) and to ictal involvement of brain structures beyond the frontal lobe (21.8 +/- 20.3 s; 4.9 +/- 5.1 s; P = 0.025) in patients without seizure freedom.The results suggest that presurgical evaluation using 3D-iEEG monitoring lead to a better surgical outcome as seizure free in MRI-negative FLE patients. PMID- 27977574 TI - Rituximab shows no effect on remission in patients with refractory nephrotic syndrome: A MOOSE-compliant meta-analysis. AB - To assess the efficacy of rituximab in treatment of refractory nephrotic syndrome (NS) compared with other agents.Studies were searched from Web of Science, PubMed, and CNKI up to April 2016. The standardized mean difference or relative risk or odds ratio and 95% confidence intervals were used to assess the efficacy of rituximab treatment compared with other agents in refractory NS.Totally, 8 studies were included. The present study showed that there was a significant higher relapse-free survival rate in rituximab group than that in the other agents group. Compared with other agents, rituximab did not significantly improve the complete and overall remission rate, serum albumin levels. Rituximab also did not decrease the serum creatinine, urinary protein, and serum cholesterol levels. However, compared with other agents, the adult patients had a higher serum cholesterol levels after treatment with rituximab.Rituximab promised to be a new agent in the treatment of refractory NS; it also could be used as an alternative to conventional immunosuppressive drugs-dependent or drugs-resistant. However, more high-quality, large sample, and multicenter randomized controlled trials are needed to further confirm the efficacy of rituximab in treatment of refractory NS. PMID- 27977573 TI - The efficacy and safety of panitumumab plus irrinotecan-based chemotherapy in the treatment of metastatic colorectal cancer: A meta-analysis. AB - BACKGROUND: Panitumumab, a fully human monoclonal antibody targeting epidermal growth factor receptor, is used in combination with chemotherapy for patients with metastatic colorectal cancer (mCRC). However, the effects of panitumumab in combination with irrinotecan-based chemotherapy remain uncertain. Therefore, we conducted this meta-analysis to assess the efficacy and safety of combination treatment of panitumumab plus chemotherapy in the treatment of mCRC. METHODS: By searching electronic databases (PubMed, Embase, and Web of Science), all clinical trials which assessed the effects of panitumumab plus irrinotecan-based chemotherapy in mCRC would be included. Main outcome measures included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and adverse events. Pooled estimates were calculated by a fixed-effects model or random-effects model, according to the heterogeneity among the included studies. RESULTS: Eleven trials with a total number of 1338 patients met the inclusion criteria and were included in this meta-analysis. The combination treatment of panitumumab and irrinotecan-based chemotherapy was associated with a median PFS of 5.83 months, OS of 11.15 months, and ORR of 33%. Subgroup analysis showed that, in the first-line and second-line treatment, the combination therapy for PFS was 9.27 and 5.01 months, for OS was 8.87 and 11.68 months, and for ORR was 61% and 26%, respectively. In the wild-type and mutant KRAS populations, the combination therapy for PFS was 5.76 and 5.27 months, for OS was 11.15 and 10.64 months, and for ORR was 37% and 18%, respectively. Moreover, combination therapy also induced an incidence of 56% treatment-related adverse events. CONCLUSION: Panitumumab plus irrinotecan-based chemotherapy is effective and well-tolerated in the treatment of patients with mCRC, especially in those with wild-type KRAS tumors. PMID- 27977575 TI - A systematic review of treatment response rates in Pakistani hepatitis C virus patients; current prospects and future challenges. AB - BACKGROUND: The estimated hepatitis C virus (HCV) carriers are approximately 10 million in Pakistan which usually progresses to chronic hepatitis, with rare cases of spontaneous viral eradication. The present article reviews the treatment status of HCV infection in Pakistani population and various factors associated with the treatment response rates. METHODS: Literature on anti-HCV therapy was searched in PubMed, Google Scholar and PakMediNet. Thirty three different studies representing different geographic regions of Pakistan published from 2002 to 2016 were included in the present review. Weighted mean, standard error estimates (SE) and standard deviation (SD) were determined for each population group. RESULTS: Mean value for sustained virological response (SVR) for standard IFN plus ribavirin (RBV) combination therapy was 68.38% +/- 14.13% (range 33.8%-87.10%; SE 3.08) and pegylated-IFN plus RBV combination therapy 64.38% +/- 8.68% (range 55.0%-76.00%; SE 3.88). The lowest value for SVR has been reported to be 24.3% (for genotype 1; administering INF-alpha 2b 3MU 3 times/week and RBV 1000-1200 mg/day for 48 weeks) while highest of 87.5% (genotype 3a; INF-alpha 2a 3MU 3 times/week and RBV 1000-1200 mg/day for 24 weeks). The mean value for rapid virological response (RVR) was found to be 48.18% +/- 29.20% (SE 9.73). As PEG interferon and direct acting antivirals (DAAs) are relatively expensive, interferon-alfa (IFN-alpha) and RBV combination therapy have been used widely to treat HCV infected patients in Pakistan for the last one and half decade. On average, 2.45% of the patients discontinued treatment due to severe side effects. CONCLUSION: We encourage further studies on understanding host and viral factors associated with specific focus on harder to treat viral variants (relapsers and nonresponders). These variants are currently rising in the country. PMID- 27977576 TI - Outcome of primary trabeculotomy ab interno (Trabectome) surgery in patients with steroid-induced glaucoma. AB - To determine the efficacy and safety of Trabectome surgery on patients with steroid response, ranging from ocular hypertension refractory to maximal medical therapy to the development of steroid-induced glaucoma.A nonrandomized, nonblinded, retrospective study of 20 subjects with steroid response was conducted. All 20 eyes underwent Trabectome surgery alone. Nine subjects had steroid response with unremarkable visual field, 3 had mild steroid-induced glaucoma, and 8 had advanced steroid-induced glaucoma. Outcome measures included intraocular pressure (IOP), number of glaucoma medications, need for secondary glaucoma surgery, and steroid regimen. Mann-Whitney U test was used to compare postoperative IOP and number of medications to preoperative IOP and number of medications. Kaplan-Meier was used for survival analysis, and success was defined as: IOP reduced by 20% or more on any 2 consecutive visits after 3 months; IOP <=21 mm Hg on any 2 consecutive visits after 3 months; and no secondary glaucoma surgery.The average preoperative IOP was 33.8 +/- 6.9 mm Hg and average preoperative glaucoma medication usage was 3.85 +/- 0.75 medications. At 12 months, the IOP was reduced to 15.00 +/- 3.46 mm Hg (P = 0.03) and glaucoma medication was reduced to 2.3 +/- 1.4 (P < 0.01). The survival rate at 12 months was 93%. At 12 months, 10 patients were continued on their preoperative steroid treatments, 5 were on tapered steroid treatments, and 5 had ceased steroid treatments entirely. One patient required secondary glaucoma surgery (glaucoma drainage device). No other complications were noted.The Trabectome procedure is safe and highly effective for steroid-response glaucoma, even in the context of continued steroid treatment. PMID- 27977577 TI - Negative pressure wound therapy aids recovery following surgical debridement due to severe bacterial cellulitis with abdominal abscess post-cesarean: A case report (CARE-Compliant). AB - INTRODUCTION: Bacterial cellulitis post-Cesarean section is rare. Negative pressure wound therapy (NPWT) is widely used in various medical specialities; its effectiveness in obstetrics however remains the topic of debate-used predominantly as an adjunct to secondary intention specific to high-risk patient groups. Its application in the treatment of actively infected wounds post Cesarean is not well documented. Here, we document NPWT in the treatment of an unusually severe case of bacterial cellulitis with abdominal abscess postpartum. We provide a unique photographic timeline of wound progression following major surgical debridement, documenting the effectiveness of 2 different NPWT systems (RENASYS GO and PICO, Smith & Nephew). We report problems encountered using these NPWT systems and "ad-hoc" solutions to improve efficacy and patient experience.A 34-year-old primiparous Caucasian female with no prior history or risk factors for infection and a normal body mass index (BMI) presented with severe abdominal pain, swelling, and extensive abdominal redness 7 days postemergency Cesarean section. Examination revealed extensive cellulitis with associated abdominal abscess. Staphylococcus aureus was identified in wound exudates and extensive surgical debridement undertaken day 11 postnatally due to continued febrile episodes and clinical deterioration, despite aggressive intravenous antibiotic therapy. Occlusive NPWT dressings were applied for a period of 3 weeks before discharge, as well as a further 5 weeks postdischarge into the community.NPWT was well tolerated and efficacious in infection clearance and wound healing during bacterial cellulitis. Wound healing averaged 1 cm per week before NPWT withdrawal; cessation of NPWT before full wound closure resulted in significantly reduced healing rate, increased purulent discharges, and skin irritation, highlighting the efficacy of NPWT. Five-month follow-up in the clinic found the wound to be fully healed with no additional scarring beyond the boundaries of the original Cesarean incision. The patient was pleased with treatment outcomes, reporting no lasting pain or discomfort from the scar. CONCLUSIONS: This report represents the first documented use of NPWT to aid healing of an actively infected, open wound following extensive surgical debridement 10 days post Cesarean section, confirming both the efficacy and tolerability of NPWT for the treatment of severe bacterial cellulitis in obstetric debridement. PMID- 27977578 TI - Nonmotor symptoms in patients with Parkinson disease: A cross-sectional observational study. AB - Parkinson disease (PD) is usually accompanied by numerous nonmotor symptoms (NMS), such as neuropsychiatric symptoms, sleep disorders, autonomic dysfunctions, and sensory disturbances. However, it is not clear that the factors influencing the occurrence of NMS and its sequence with motor symptoms (MS).We conducted comprehensive assessments of NMS by using 13 scales in 1119 PD patients.A total of 70.8% PD patients present NMS. Olfactory dysfunction tends to occur in PD patients with older age, more severe depression, sleep problems, and autonomic dysfunctions. Older patients are more likely to have olfactory dysfunction before MS than younger patients. Rapid eye movement behavior disorder is more prone to happen in patients with older age, older onset age, more severe depression, sleep problems, and autonomic dysfunctions. Patients with rapid eye movement behavior disorder before MS are older in onset age than after group.Olfactory dysfunction, constipation, rapid eye movement behavior disorder, and depression, as early warning NMSs of PD, connected to each other. There is a clinical heterogeneity that older patients are more likely to have NMS before MS, while younger patients are opposite. PMID- 27977579 TI - The association of serum magnesium and mortality outcomes in heart failure patients: A systematic review and meta-analysis. AB - BACKGROUND: Low serum magnesium (Mg) has been independently shown to increase risk of heart failure (HF), but data on the association between serum Mg concentration and the outcome of patients with HF are conflicting. The purpose of this systematic review and meta-analysis was to estimate the prognostic effects of hypermagnesemia and hypomagnesemia on cardiovascular (CV) mortality and all cause mortality (ACM) of patients with HF. METHODS: Relevant studies were identified from Medline and Scopus databases. Included and excluded criteria were defined. Effects (i.e., log [risk ratio [RR]]) of hypomagnesemia and hypermagnesemia versus normomagnesemia were estimated using Poisson regression, and then a multivariate meta-analysis was applied for pooling RRs across studies. Heterogeneity was explored using a meta-regression and subgroup analysis. RESULTS: On analysis, 7 eligible prospective studies yielded a total of 5172 chronic HF patients with 913 and 1438 deaths from CV and ACM, respectively. Most participants were elderly men with left ventricular (LV) ejection fraction <=40%. Those patients with baseline hypermagnesemia had a significantly higher risk of CV mortality (RR, 1.38; 95% confidence interval [CI], 1.07-1.78) or ACM (RR, 1.35; 95% CI, 1.18-1.54) than those with baseline normomagnesemia. However, baseline hypomagnesemia was not associated with the risk of CV mortality (RR, 1.11; 95% CI, 0.79-1.57) and ACM (RR, 1.11; 95% CI, 0.87-1.41). A subgroup analysis by Mg cutoff suggested a dose-response trend for hypermagnesemia effects, that is, the pooled RRs for CV mortality were 1.28 (95% CI, 1.05-1.55) and 1.92 (95% CI, 1.00-3.68) for the cutoff of 0.89 to 1.00 and 1.05 to 1.70 mmol/L, respectively. CONCLUSION: The present systematic review and meta-analysis suggested that, in HF patients, hypermagnesemia with serum Mg >= 1.05 mmol/L was associated with an increased risk of CV mortality and ACM but this was not observed for hypomagnesemia. This finding was limited to the elderly patients with chronic HF who had reduced LV systolic function. PMID- 27977581 TI - Sagittal spinopelvic parameters in 2-level lumbar degenerative spondylolisthesis: A retrospective study. AB - The purpose of our study is to evaluate sagittal parameters in 2-level lumbar degenerative spondylolisthesis (DS) (TLDS).A total of 15 patients with TLDS, 40 patients with single-level DS (SLDS), and 30 normal volunteers as control were included in our study. All subjects performed on full spine X-ray. Two categorized data were analyzed: patient characteristics-age, sex, body mass index, radiographic parameters-pelvic incidence (PI), pelvic tilt (PT), lumbar lordosis (LL), sacral slope (SS), PI-LL, Cobb between the fifth thoracic vertebral and 12th thoracic vertebral (T5-T12), sagittal vertical axis (SVA) Cobb angle of spondylolisthesis level (CSL), ratio of PT to SS (PT/SS), CSL/LL, variation trend of SS over PI, and LL over PI.The PI (73.1 degrees vs 52.9 degrees ), SS (50.8 degrees vs 32.2 degrees ), LL (53.1 degrees vs 46.9 degrees ), SVA (66.1 vs 22.0 mm), PI-LL (20.0 degrees vs 6.0 degrees ), and CSL (23.6 degrees vs 20.0 degrees ) in TLDS were significantly larger than these in SLDS. The PI (73.1 degrees vs 40.6 degrees ), PT (22.3 degrees vs 17.1 degrees ), SS (50.8 degrees vs 23.5 degrees ), LL (53.1 degrees vs 32.5 degrees ), PI-LL (20.0 degrees vs 8.1 degrees ), and SVA (66.1 vs 17.0 mm) in TLDS were significantly larger than those in the normal group (NG). The PI (52.9 degrees vs 40.6 degrees ), PT (21.0 degrees vs 17.1 degrees ), SS (32.2 degrees vs 23.5 degrees ), LL (46.9 degrees vs 32.5 degrees ), and SVA (22.0 vs 17.0 mm) in SLDS were significantly higher than those in NG. However, PT/SS (44.0%), LL over PI (y = 0.39x + 24.25), SS over PI (y = 10.79 + 0.55x) were lower in TLDS than these in SLDS (63.8%, y = 0.41x + 25, y = 0.65x - 2.09, respectively), and the similar tend between SLDS and NG (74.0%, y = 0.49x + 13.09, y = 0.67x - 3.9, respectively).Our results showed that 2-level lumbar DS, which was caused by multiple-factors, has a severe sagittal imbalance, but single-level has not any. When we plan for surgical selection for 2-level lumbar DS, global sagittal balance must be considered. PMID- 27977580 TI - Ideal cardiovascular health and incident hypertension: The longitudinal community based Kailuan study. AB - Ideal cardiovascular health (CVH) has been defined by the American Heart Association as the absence of disease and presence of 7 key health factors. Since it is unknown whether cumulative exposure to CVH reduces the risk of developing arterial hypertension, we prospectively examined the potential association between cumulative CVH (cumCVH) score (except for blood pressure metrics) and incident hypertension.Of the 101,510 participants with an age range of 18 to 98 years in this longitudinal community-based Kailuan study, our cohort included those 15,014 participants without hypertension at baseline and who had follow-up examinations 2, 4, and 6 years later. CumCVH was calculated as the summed CVH score for each examination multiplied by the time between the 2 examinations (points * year). Based on the cumCVH score, the study population was stratified into groups of <44 points, 44 to 48 points, 49 to 54 points, 55 to 59 points, and >=60 points.Incidence of hypertension ranged from 16.76% in the lowest cumCVH category to 11.52% in the highest cumCVH category. After adjusting for age, sex, education level, income level, high-sensitivity C-reactive protein concentration, uric acid concentration, resting heart rate, parental history of hypertension at baseline, and medication usage before the third follow-up examination, participants in the highest cumCVH category had a significantly reduced risk of incident hypertension compared with those in the lowest cumCVH category (adjusted odds ratio 0.60, 95% confidence interval 0.50-0.71). For every increase in category based on the cumCVH score, the risk of hypertension decreased by approximately 2% (odds ratio 0.98, 95% confidence interval 0.97-0.98). The effect was consistent across sex and age groups.A higher cumCVH score is associated with a lower risk of incident hypertension. PMID- 27977582 TI - Spine malformation complex in 3 diverse syndromic entities: Case reports. AB - RATIONALE: Clinical and radiographic phenotypic characterizations were the base line tool of diagnosis in 3 syndromic disorders in which congenital cervico thoracic kyphosis was the major deformity. PATIENTS CONCERNS: Directing maximal care toward the radiographic analysis is not only the axial malformation but also toward the appendicular abnormalities was our main concern. We fully documented the diversity of the spine phenotypic malformation complex via the clinical and radiographic phenotypes. DIAGNOSES: We established the diagnosis via phenotypic/genotypic confirmation in 3 diverse syndromic entities namely acampomelic campomelic dysplasia, Larsen syndrome and Morquio syndrome type A (mucopolysaccharidosis type IV A). INTERVENTIONS: Surgical interventions have been carried out in the Larsen syndrome and Morquio syndrome type A, resepectively. OUTCOMES: The earliest the diagnosis is, the better the results are. The necessity to diagnose children in their first year of life has many folds, firstly the management would be in favor of the child's growth and development and secondly, the prognosis could be clearer to the family and the medical staff as well. Our current paper is to sensitize paediatricians, physicians and orthopedic surgeons regarding the necessity to detect the aetiological understanding in every child who manifests a constellation of malformation complex. LESONS: Scoliosis and kyphosis/kyphoscoliosis are not a diagnosis in themselves. Such deformities are mostly a symptom complex correlated to dozens of types of syndromic associations. The rate curve progression and the final severity of congenital spine tilting are related to 3 factors: (a) the type of vertebral malformation present, (b) the patient's phenotype, and PMID- 27977583 TI - Injury of the lower ascending reticular activating system in patients with pontine hemorrhage: Diffusion tensor imaging study. AB - Many studies have reported about injury of the ascending reticular activating system (ARAS) in patients with various brain pathologies, using diffusion tensor tractography (DTT); however, little is known about injury of the ARAS in patients with pontine hemorrhage. In this study, using DTT, we attempted to investigate injury of the lower ventral and dorsal ARAS in patients with pontine hemorrhage. Twenty-three consecutive patients with pontine hemorrhage and 14 control subjects were recruited into this study. The patients were classified into 2 subgroups on the basis of the preservation of arousal: subgroup A (14 patients)-intact arousal, subgroup B (9 patients)-impaired arousal. The lower ventral and dorsal ARAS between the pontine reticular formation with hypothalamus and thalamic intralaminar nucleus were reconstructed. Fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) values were measured. The TVs of the lower ventral and dorsal ARAS were significantly lower in subgroup B than in the subgroup A and control group (P < 0.05). In terms of FA value, the lower dorsal ARAS were significantly lower in subgroup A and subgroup B than in the control group (P < 0.05). In conclusion, injury of the lower ventral and dorsal ARAS was demonstrated in patients with impaired arousal following pontine hemorrhage. We believe that analysis of the ARAS using DTT would be helpful in evaluation of patients with impaired consciousness after pontine hemorrhage. PMID- 27977584 TI - Impact of lifestyle and psychological stress on the development of early onset breast cancer. AB - The present study aimed to investigate risk factors for early onset breast cancer that are related to lifestyle and psychological stress. A comparative case control study was performed among patients from the Department of Breast Surgery in Shanghai Cancer Center of Fudan University. The information regarding risk factors associated with the development of early onset breast cancer was collected using a questionnaire in a face-to-face interview. The distribution of the risk factors associated with the development of early onset breast cancer between the patient group and the control group was analyzed with logistic regression. A total of 582 cases of young patients (<=40 years old) with breast cancer and 540 controls of young patients (<=40 years old) with benign breast disease were included in this study. The risk factors for breast cancer in young women include age at first birth (odds ratio [OR] = 0.93, 95% confidence interval [CI]: 0.88-0.98), history of breast cancer in an immediate family member (OR = 2.36, 95% CI: 1.14-4.89), history of genital surgery (OR = 2.11, 95% CI: 1.16 3.82), active and passive smoking in daily life or the environment (OR = 1.64, 95% CI: 1.19-2.25), weekly intake of soy products (OR = 1.24, 95% CI: 1.02-1.49), use of household cooking oil (OR = 2.04, 95% CI: 1.04-4.00), disharmonious marital status (OR = 1.16, 95% CI: 1.06-1.26), frequent depression (OR = 1.32, 95% CI: 1.00-1.75), and negative emotional experiences (OR = 1.15, 95% CI: 1.03 1.29). Our study could provide the basis for risk assessment and preventive interventions for early onset breast cancer. PMID- 27977585 TI - Neurocognitive performance and physical function do not change with physical cognitive-mindfulness training in female laboratory technicians with chronic musculoskeletal pain: Randomized controlled trial. AB - BACKGROUND: Cognitive and physical performance can be negatively affected by chronic pain. This study evaluates the effect of combined physical-, cognitive-, and mindfulness training (PCMT) on cognitive and physical performance. METHODS: From a large pharmaceutical company in Denmark we randomly allocated 112 female laboratory technicians with chronic upper limb pain to group-based PCMT at the worksite or a reference group for 10 weeks. Neurocognitive performance was measured by the computerized central nervous system vital signs neurocognitive assessment battery. Physical function was assessed in terms of shoulder external rotation strength and rate of force development in a custom-made dynamometer setup. RESULTS: No between-group differences (least square means [95% confidence interval]) from baseline to follow-up could be detected in any of the neurocognitive domains as measured by the central nervous system vital signs neurocognitive assessment battery, for example, Psychomotoer Speed 1.9 (-1.0 to 4.7), Reaction Time -4.0 (-19.5 to 11.6), Complex Attention -0.3 (-1.9 to 1.4), and Executive Function -0.2 (-3.5 to 3.0). Similarly, we found no change in maximal voluntary isometric strength -0.63 (-4.8 to 3.6), or rate of force development 14.8 (-12.6 to 42.2) of the shoulder external rotators. Finally, test retest reliability of maximal voluntary contraction and rate of force development shoulder external rotation showed high reliability at 0 to 30 ms, 0 to 50 ms, 0 to 100 ms, and 0 to 200 ms with ICCs at 0.95, 0.92, 0.93, 0.92, and 0.91, respectively. CONCLUSION: Ten weeks of PCMT did not improve neurocognitive or physical performance. PMID- 27977586 TI - Application of a 3-dimensional printed navigation template in Bernese periacetabular osteotomies: A cadaveric study. AB - The aim of the present study was to describe the application of 3D printed templates for intraoperative navigation and simulation of periacetabular osteotomies (PAOs) in a cadaveric model.Five cadaveric specimens (10 sides) underwent thin-slice computed tomographic scans of the ala of ilium downwards to the proximal end of femoral shaft. Bernese PAO was performed. Using Mimics v10.1 software (Materialise, Leuven, Belgium), 3D computed tomographic reconstructions were created and the 4 standard PAO bone cuts-ischial, pubic, anterior, and posterior aspects of the ilium-as well as rotation of the dislocated acetabular bone blocks were simulated for each specimen. Using these data, custom 3D printed bone-drilling templates of the pelvis were manufactured, to guide surgical placement of the PAO bone cuts. An angle fix wedge was designed and printed, to help accurately achieve the predetermined rotation angle of the acetabular bone block. Each specimen underwent a conventional PAO. Preoperative, postsimulation, and postoperative lateral center-edge angles, acetabular indices, extrusion indices, and femoral head coverage were measured and compared; P and t values were calculated for above-mentioned measurements while comparing preoperative and postoperative data, and also in postsimulation and postoperative data comparison.All 10 PAO osteotomies were successfully completed using the 3D printed bone-drilling template and angle fix wedge. No osteotomy entered the hip joint and a single posterior column fracture was observed. Comparison of preoperative and postoperative measurements of the 10 sides showed statistically significant changes, whereas no statistically significant differences between postsimulation and postoperative values were noted, demonstrating the accuracy and utility of the 3D printed templates.The application of patient-specific 3D printed bone-drilling and rotation templates in PAO is feasible and may facilitate improved clinical outcomes, through the use of precise presurgical planning and reduced surgical complications with the precisely guided bone drilling. PMID- 27977587 TI - Levodopa reverse stridor and prevent subsequent endotracheal intubation in Parkinson disease patients with bilateral vocal cord palsy: A case report. AB - BACKGROUND: Respiratory abnormalities are often overlooked; however, because of their potential comorbidity, they must be analyzed to determine the most effective treatment for patients with Parkinson disease (PD). Among various theories on respiratory abnormalities in PD, "upper airway obstruction" and "restrictive respiratory disorders" are 2 of the most accepted etiologies; both appear to be related to basal ganglia dysfunction. Complex vocal cord muscle dysfunction contributes to stridor, which can be a manifestation of nigrostriatal dopaminergic dysfunction. Stridor is a lethal form of upper airway obstruction in PD patients; its most frequent causes are bilateral vocal cord palsy, laryngeal spasms, and dystonia of the supra-laryngeal muscle. Several previous studies have suggested that levodopa administration induces a significant improvement of both lung function and symptoms of parkinsonian syndrome. CASE SUMMARY: We reported a 77-year-old gentleman PD patient admitted for acute levodopa-responsive stridor resulting from bilateral vocal cord palsy. Dopaminergic therapy prevented the need for subsequent endotracheal intubation and tracheostomy treatment. CONCLUSION: It is vital to understand that complex vocal cord muscle dysfunction may be related to nigrostriatal dopaminergic dysfunction in PD patients. The strategy of levodopa up-titration should be considered an option because it may be beneficial in relieving both stridor and parkinsonian syndrome, and in preventing respiratory failure. PMID- 27977588 TI - Clinical characteristics of immune thrombocytopenia associated with autoimmune disease: A retrospective study. AB - To clarify clinical characteristics of immune thrombocytopenia (ITP) subsets associated with autoimmune diseases (AIDs).Five thousand five hundred twenty patients were reviewed retrospectively. One hundred four ITP patients were included for analysis. Clinical manifestations at first thrombocytopenic episode were recorded.Systemic lupus erythematosus (SLE) and primary Sjogren syndrome (pSS) accounted for a large part in AIDs associated with secondary ITP. SLE-ITP, pSS-ITP, and primary ITP (pITP) patients were different in several aspects in clinical and immunological characteristics. A subgroup of patients in pITP patients with some obvious autoimmune features (defined as AIF-ITP) such as positive ANA but failing to meet the diagnosis criteria now used for a specific kind of connective tissue diseases were also different with other pITP patients in some immunological features, indicating the difference in the pathogenesis mechanism of those autoimmune featured ITP patients.ITP patients were heterogeneous in clinical characteristics. Further study about the different pathogenesis of ITP subsets especially those AIF-ITP patients who only presented with thrombocytopenia will help us have a better understanding of pathogenesis of ITP and a better management of ITP patients. PMID- 27977589 TI - Sex-specific association between serum uric acid and prolonged corrected QT interval: Result from a general rural Chinese population. AB - Recently, it has been found that high level of serum uric acid (SUA) is causally related to sudden cardiac death (SCD). We examined the sex-specific associations of SUA with prolonged heart rate-corrected QT (QTc) interval in a general Chinese population.A large sample of 11,206 Chinese research participants aged 35 years and older was recruited from rural areas of Liaoning Province during 2012 to 2013. SUA were divided into quartiles separated for males and females. Prolonged QTc interval, assessed by the Bazett formula, was defined as cut points of 460 ms or longer in females and 450 ms or longer in males. Mean (+/- standard deviation) QTc intervals were 422.1 +/- 24.2 ms among 5104 males and 436.1 +/- 23.5 ms among 6102 females, respectively. In both sexes, SUA showed significant correlations with QTc interval (both P < 0.001). Among male participants, the highest quartile of SUA (>379 MUmol/L) was related to an increased risk for prolonged QTc interval (odds ratios: 1.402, 95% confidence interval: 1.073-1.831) compared to the lowest quartile (<=276 MUmol/L) after fully adjustment. However, there were no significant relationships between SUA and prolonged QTc interval among females in all the models.Males with high SUA are prone to a higher risk for prolonged QTc interval. This study provides novel explanation for population-based findings on SUA and SCD, as well as important implications for management strategies for hyperuricemic patients in clinical practice. PMID- 27977590 TI - Intravenous versus topical tranexamic acid in primary total hip replacement: A meta-analysis. AB - BACKGROUND: As the prevalence of total hip arthroplasty (THA) is increasing, it is usually associated with considerable blood loss. Tranexamic acid (TXA) has been reported to reduce perioperative blood loss in hip joint arthroplasty. But the best route of TXA administration continues to be controversial. So, we conducted a meta-analysis that integrated all data from the 7 included trials to compare the effectiveness and safety of topical and intravenous TXA administration in primary THA. The endpoints assessed in this meta-analysis include the comparisons of total blood loss, postoperative hemoglobin decline, transfusion rates, the incidence rate of deep vein thrombosis (DVT), pulmonary embolisms (PE), and wound infection. METHODS: Literature searches of PubMed, EMBASE, the Cochrane Library, the Chinese Biomedical Literature database, the CNKI database, and Wan Fang Data were performed up to August 30, 2016. Randomized controlled trials (RCTs) were included in our meta-analysis if they compared the efficiency and safety of intravenous versus topical administration of TXA in patients who underwent primary THA. The endpoints included the comparisons of total blood loss, postoperative hemoglobin decline, transfusion rates, the incidence rate of DVT, PE, and wound infection. A meta-analysis was performed following the guidelines of the Cochrane Reviewer's Handbook and the PRISMA statement. The pooling of data was carried out by using RevMan 5.3, Denmark. RESULTS: Seven RCTs involving 964 patients met the inclusion criteria. Our meta analysis indicated that there were no significant differences in the 2 groups in terms of total blood loss ([mean difference (MD) = -14.74, 95% confidence interval (CI): -89.21 to 59.74, P = 0.7], transfusion rates [RD = -0.02, 95% CI: 0.05 to 0.02, P = 0.39]; no significant differences were found regarding the incidence of adverse effects such as deep venous thrombosis [DVT] [RD = 0.00, 95% CI: -0.01 to 0.01, P = 1.00], PE [RD = 0.00, 95% CI: -0.01 to 0.01, P = 0.71], or wound infection [RD = -0.01, 95% CI: -0.06 to 0.04, P = 0.66]). The pooled results showed that the intravenous groups had a lower postoperative hemoglobin decline (MD = -0.47, 95% CI: -0.74 to -0.20, P = 0.0006). It was probably due to insufficient data and the varied reporting of outcomes. There was some inherent heterogeneity due to the small sample size of each primary study. CONCLUSION: The topical and intravenous administrations of TXA have a similar effect on the decrease of blood loss without an increased risk of complications (DVT, PE, and wound infection). Intravenous TXA administration may have a maximum efficacy. Topical TXA administration may be preferred in patients who with high risk of thromboembolic events. However, larger, high-quality RCTs are required to explore the optimal regimen, dosage, timing still in the future in order to recommend TXA widespread use in total joint arthroplasty. PMID- 27977591 TI - Relationship between nephrotoxicity and long-term adefovir dipivoxil therapy for chronic hepatitis B: A meta-analysis. AB - BACKGROUND: To assess the relationship between adefovir dipivoxil and renal function after anti-hepatitis B virus therapy and elucidate the risk factors involved. METHODS: Based on the requirements of the Cochrane systematic review methodology, 21 observational articles on adefovir dipivoxil-associated renal dysfunction were obtained by searching various databases, between January 1, 1995 and July 1, 2016. The Newcastle Ottawa Scale was used to evaluate risk bias. Parameters for 4276 chronic hepatitis B patients were analyzed by Review Manager and R software, and glomerular filtration rate, creatinine clearance, and serum creatinine values were extracted to evaluate renal function. RESULTS: Renal dysfunction was more likely to occur in patients receiving the adefovir dipivoxil therapy (odds ratio [OR] 1.98, 95% confidence interval [CI] 1.40-2.80) than the none-adefovir dipivoxil group. Subgroup analysis showed that renal function predictive value is higher for glomerular filtration rate (OR 2.42, 95% CI 1.34 3.14), compared with serum creatinine levels (OR 1.51, 95% CI 0.75-3.04). The rate of adefovir dipivoxil-associated renal dysfunction was 12% (95% CI 0.08 0.16). Older patients and patients with renal insufficiency, hypertension, and diabetes mellitus were more prone to developing adefovir dipivoxil-associated renal dysfunction; however, integrated raw data were insufficient for further detailed analysis. CONCLUSION: Long-term adefovir dipivoxil therapy is connected to renal dysfunction in chronic hepatitis B, necessitating the monitoring of kidney function. PMID- 27977592 TI - Comparing the clinical outcomes in patients with atrial fibrillation receiving dual antiplatelet therapy and patients receiving an addition of an anticoagulant after coronary stent implantation: A systematic review and meta-analysis of observational studies. AB - BACKGROUND: Data regarding the clinical outcomes in patients with atrial fibrillation (AF) receiving dual antiplatelet therapy (DAPT) and an anticoagulant in addition to DAPT (DAPT + vitamin K antagonist [VKA]) after coronary stent implantation are still controversial. Therefore, in order to solve this issue, we aim to compare the adverse clinical outcomes in AF patients receiving DAPT and DAPT + VKA after percutaneous coronary intervention and stenting (PCI-S). METHODS: Observational studies comparing the adverse clinical outcomes such as major bleeding, major adverse cardiovascular events, stroke, myocardial infarction, all-cause mortality, and stent thrombosis (ST) in AF patients receiving DAPT + VKA therapy, and DAPT after PCI-S have been searched from Medline, EMBASE, and PubMed databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to express the pooled effect on discontinuous variables, and the pooled analyses were performed with RevMan 5.3. RESULTS: Eighteen studies consisting of a total of 20,456 patients with AF (7203 patients received DAPT + VKA and 13,253 patients received DAPT after PCI-S) were included in this meta-analysis. At a mean follow-up period of 15 months, the risk of major bleeding was significantly higher in DAPT + VKA group, with OR 0.62 (95% CI 0.50 0.77, P < 0.0001). There was no significant differences in myocardial infarction and major adverse cardiovascular event between DAPT + VKA and DAPT, with OR 1.27 (95% CI 0.92-1.77, P = 0.15) and OR 1.17 (95% CI 0.99-1.39, P = 0.07), respectively. However, the ST, stroke, and all-cause mortality were significantly lower in the DAPT + VKA group, with OR 1.98 (95% CI 1.03-3.81, P = 0.04), 1.59 (95% CI 1.08-2.34, P = 0.02), and 1.41 (95% CI 1.03-1.94, P = 0.03), respectively. CONCLUSION: At a mean follow-up period of 15 months, DAPT + VKA was associated with significantly lower risk of stroke, ST, and all-cause mortality in AF patients after PCI-S compared with DAPT group. However, the risk of major bleeding was significantly higher in the DAPT + VKA group. PMID- 27977593 TI - Comparing efficacy and safety of 2 methods of tranexamic acid administration in reducing blood loss following total knee arthroplasty: A meta-analysis. AB - BACKGROUND: The purpose of this systematic review and meta-analysis of randomized controlled trials (RCTs) were to gather data to evaluate the efficacy and safety of topical tranexamic acid (TXA) versus intravenous (IV) TXA for blood loss after a total knee arthroplasty (TKA). METHODS: Electronic databases: Pubmed, Web of Science, Cochrane library, and Embase from inception to June 2016 were searched. RCTs that comparing topical with IV TXA for blood loss control in patients prepared for TKA were included in this meta-analysis. The Cochrane risk of bias tool was used to appraise risk of bias. The primary outcomes were needed for transfusion, total blood loss, and blood loss in drainage. Secondary outcomes are hemoglobin (Hb) value at 24-hour post TKA and complication (deep venous thrombosis [DVT] and infection). The efficacy of blood loss was tested by total blood loss, drainage volume, Hb drop, and the Hb value at 24 hours after TKA. The safety was measured by the occurrence of DVT and infection. Continuous outcomes were expressed as the mean difference with the respective 95% confidence intervals (CIs). Discontinuous outcomes were expressed as the relative risk with 95% CIs. Stata 12.0 software (Stata Corp., College Station, TX) was used for the meta-analysis. RESULTS: A total of 14 articles involving 1390 patients were finally included for this meta-analysis. The pooled results revealed that there were no significant difference between the need for transfusion, total blood loss, blood loss in drainage, Hb value at 24-hour post TKA, the occurrence of complications (infection and DVT) between topical administration of TXA and IV TXA. CONCLUSION: Topical TXA has similar efficacy for blood loss control to IV TXA without sacrificing safety in TKA. However, the dose of topical TXA and IV TXA is different, thus, optimal timing and dose of TXA are still needed to explore the maximum effect of TXA. PMID- 27977594 TI - Severe ataxia due to injuries of neural tract detected by diffusion tensor tractography in a patient with pontine hemorrhage: A case report. AB - RATIONALE: We examined injuries of the dentato-rubro-thalamic tract (DRTT), cortico-ponto-cerebellar tract (CPCT), dorsal spinocerebellar tract (SCT), and inferior cerebellar peduncle (ICP) in a patient with severe ataxia following bilateral tegmental pontine hemorrhage (PH), using diffusion tensor tractography (DTT). PATIENT CONCERNS: A 75-year-old female patient underwent conservative management for bilateral tegmental PH. She presented with moderate motor weakness, severe resting and intentional tremor on both hands, and severe truncal ataxia (Scale for Assessment and Rating of Ataxia [25 points/0-40 points: a higher score indicates a worse state]), and she was not able to sit independently. DIAGNOSES AND OUTCOMES: On DTT taken at 2 weeks after initial presentation, both DRTTs and the left dorsal SCT were not reconstructed, whereas the CPCTs showed thinning of the entire pathways between the primary sensorimotor cortex and cerebellum in both hemispheres. The right ICP was discontinued at the transverse cerebellar branch of the ICP and thinning of the left ICP was observed in the vertical and transverse cerebellar branch of the ICP. LESSONS: Using DTT, concurrent injuries of the DRTT, CPCT, dorsal SCT, and ICP were demonstrated in a patient with severe ataxia following PH. Our result suggests the necessity of evaluation of these neural tracts in patients who develop ataxia after brain injury. PMID- 27977595 TI - Predicting emergency departments visit rates from septicemia in Taiwan using an age-period-cohort model, 1998 to 2012. AB - The aim of this study was to determine the age-period-cohort (APC) effects on the rate of infection-related emergency department (ED) visits from septicemia for predicting the same in recent periods.In our study, we investigated the longitudinal trends in septicemia-related visit rates. Using an APC model to decompose the septicemia visit rates into the effects of age, time period, and cohort, and examine whether their effects varied by sex.The septicemia ED visit rate was classified as the International Classification of Disease Code 038 by primary and secondary diagnosis between 1998 and 2012.In both males and females, the visit rate of septicemia showed an increase from 2003 through 2012. An increase in septicemia visit rate after 2003 was observed in all age groups. An APC model indicated a reversal increasing period effect, which increased prominently from 2003 to 2012 in both males and females. The age effect showed an increasing trend. The cohort effect tended to show a slight oscillation from 1913 to 1988. With reference to the prediction of the logarithms of the age-specific 5 year visit rates, we observed that the younger cohorts exhibited a slightly increasing trend, as compared to the older cohorts.The period effect can explain the increase in septicemia visit rates, suggesting the role of screening for septicemia. Furthermore, it is well known that aging is a relevant risk variable for infectious diseases. The present study concludes that the aged population exhibited a strong increasing future trend for septicemia-related ED visit rates. PMID- 27977597 TI - Posterior decompression and internal fixation in treatment of hypertrophy of posterior longitudinal ligament at C1-2 level accompanied with lower cervical spinal stenosis: A case report. AB - RATIONALE: Hypertrophy of posterior longitudinal ligament (HPLL) at C1-2 level accompanied with lower cervical spinal stenosis is rare in clinic. No reports have described HPLL at C1-2 level accompanied with lower cervical spinal stenosis treated by posterior decompression, combined with internal fixation in 1 stage. PATIENT CONCERNS: A 70-year-old Chinese female complained of numbness and paralysis in both her hands and right leg for 1.5 years; Cervical vertebra x-rays and magnetic resonance imaging revealed a HPLL at C1-2 and cervical spinal stenosis at C3-6. DIAGNOSES: She was diagnosed with cervical spondylotic myelopathy (CSM). INTERVENTIONS: The patient underwent posterior decompression from C1 to C5 level, and fixed with C1-2 vertebral pedicle and C3-5 lateral mass of screw. OUTCOMES: One week after operation, the patient showed significant improvement in the numbness of her hands. A follow-up cervical vertebra computed tomography showed good location of internal fixation device and correction of cervical spinal stenosis. Twelve months after surgery, the patient showed improvement in preoperative clumsiness and gait disturbance, and no recurrence of the clinical symptoms occurred. LESSONS: HPLL at C1-2 level accompanied with lower cervical spinal stenosis caused myelopathy is rare. Cervical posterior decompression and internal fixation is an effective treatment. The surgical outcome is satisfactory. PMID- 27977596 TI - The efficacy and safety of platinum plus gemcitabine (PG) chemotherapy with or without molecular targeted agent (MTA) in first-line treatment of non-small cell lung cancer (NSCLC). AB - BACKGROUND: Trials investigating the efficacy and safety of combining molecular targeted agent (MTA) with platinum-gemcitabine (PG) in first-line treatment of advanced non-small cell lung cancer (NSCLC) have shown inconsistent findings. This meta-analysis aimed to explore whether the addition of MTAs to PG in NSCLC could provide a survival benefit with a tolerable toxicity. METHODS: Web of knowledge, PubMed, Ovid, Embase, and Cochrane Library were searched to identify relevant studies and extract data on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and common grade 3 or 4 adverse events. Subgroup analyses were conducted on the basis of race and the type of MTA. RESULTS: Twelve trials with a total of 6143 patients were included in this meta-analysis. Compared with PG chemotherapy, combination therapy of MTA with PG did not improve OS (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.90 1.01) but improved PFS (HR = 0.77, 95% CI = 0.66-0.89) and ORR (risk ratio [RR] = 1.33, 95% CI = 1.11-1.60). Subanalysis indicated that there was more incidence of grade 3 or 4 rash (RR = 11.20, 95% CI = 6.07-20.68), anemia (RR = 1.21, 95% CI = 1.01-1.46), diarrhea (RR = 2.62, 95% CI = 1.21-5.65), and anorexia (RR = 2.08, 95% CI = 1.12-3.88) in combining epidermal growth factor receptor targeted therapy group compared to PG group. An increased risk of grade 3 or 4 rash (RR = 5.08, 95% CI = 1.53-16.79), thrombocytopenia (RR = 1.50, 95% CI = 1.03-2.18), and hypertension (RR = 2.36, 95% CI = 1.05-5.32) was observed in sorafenib combination group. CONCLUSION: The combination of PG plus MTA was superior to PG alone in terms of PFS and ORR but not in OS. The combination chemotherapy also showed a higher frequency of grade 3 or higher toxic effects in patients with advanced NSCLC than PG chemotherapy. PMID- 27977599 TI - CD44v6: A metastasis-associated biomarker in patients with gastric cancer?: A comprehensive meta-analysis with heterogeneity analysis. AB - BACKGROUND: The diagnostic and prognostic value of CD44v6 in patients with gastric cancer remains unclear. Therefore, a quantitative meta-analysis was conducted to determine the clinical value of CD44v6 in patients with gastric cancer. METHODS: Sixteen studies with 2177 patients were included. Pooled odds ratios (ORs) and hazard ratio (HR) with 95% confidence intervals (CIs) were calculated to estimate the impact of CD44v6 in patients with gastric cancer on clinicopathological features and 5-year overall survival (OS). Sensitivity analysis, subgroup analysis, and regression analysis were introduced to evaluate the heterogeneity across the studies. Publication bias was also explored among the studies. RESULTS: The meta-analysis showed that the upregulated CD44v6 was associated with lymph node metastasis (OR 1.91, 95% CI 1.19-3.08; P = 0.007), distant metastasis (OR 3.41, 95% CI 2.01-5.78; P = 0.000), high TNM stage (OR 2.29, 95% CI 1.10-4.75; P = 0.026), lymphatic vessel invasion (OR 1.59, 95% CI 1.21-2.09; P = 0.001), and vascular invasion (OR 1.57, 95% CI 1.19-2.07; P = 0.001). When excluded 1 study based on sensitivity analysis, pooled HR indicated that CD44v6 positive expression was correlated poor 5-year OS (OR 1.76, 95% CI 1.30-2.39; P = 0.000), meanwhile, heterogeneity was eliminated. The heterogeneity of Lauren type mainly existed in the big sample size subgroup. Different region and publication year might contribute to the heterogeneity of differentiation type. While the heterogeneity of lymph node mainly existed in Asian and big sample size group. Publication bias was observed among 12 studies on lymph node metastasis (Ppublication bias = 0.041), and 5 studies on TNM stage (Ppublication bias = 0.026). CONCLUSION: Taken together, CD44v6 overexpression might be correlated to the characteristics of tumor metastasis in gastric cancer, consisting with many mechanism studies. Therefore, CD44v6 might present a metastasis-associated biomarker in patients with gastric cancer. PMID- 27977598 TI - EGFR-TKIs versus taxanes agents in therapy for nonsmall-cell lung cancer patients: A PRISMA-compliant systematic review with meta-analysis and meta regression. AB - BACKGROUND: Currently, the nonsmall-cell lung cancer (NSCLC) is a worldwide disease, which has very poor influence on life quality, whereas the therapeutic effects of drugs for it are not satisfactory. The aim of our PRISMA-compliant systematic review and meta-analysis was to compare the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with Taxanes in patients with lung tumors. METHODS: We collected randomized controlled trials (RCTs) of EGFR-TKIs (gefitinib, erlotinib) versus Taxanes (docetaxel, paclitaxel) for the treatment of NSCLC by searching PubMed, EMbase, and the Cochrane library databases until April, 2016. The extracted data on progression free survival (PFS), progression-free survival rate (PFSR), overall survival (OS), overall survival rate (OSR), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and adverse event rates (AEs) were pooled. Disease-relevant outcomes were evaluated using RevMan 5.3.5 software and STATA 13.0 software. RESULTS: We systematically searched 26 RCTs involving 11,676 patients. The results showed that EGFR-TKIs could significantly prolong PFS (hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.66-0.92) and PFSR (risk ratio [RR] = 2.10, 95% CI: 1.17-3.77), and improve ORR (RR = 1.62, 95% CI: 1.38-1.91) and QoL. EGFR-TKIs had similar therapeutic effects to taxanes with respect to OS (HR = 1.00, 95% CI: 0.95-1.05) and OSR (RR = 1.03, 95% CI: 0.94 1.14). Furthermore, there were no significant differences between them in DCR (RR = 0.95, 95% CI: 0.88-1.03). Finally, EGFR-TKIs were superior to taxanes in most of all grades or grade >=3 AEs. CONCLUSION: In the efficacy and safety evaluation, EGFR-TKIs had an advantage in the treatment of NSCLC, especially for patients with EGFR mutation-positive. The project was prospectively registered with PROSPERO database of systematic reviews, with number CRD42016038700. PMID- 27977600 TI - Evaluation of dexmedetomidine in combination with sufentanil or butorphanol for postoperative analgesia in patients undergoing laparoscopic resection of gastrointestinal tumors: A quasi-experimental trial. AB - The aim of this study was to evaluate the efficacy of dexmedetomidine in combination with sufentanil or butorphanol for postoperative analgesia in patients undergoing laparoscopic resection of a gastrointestinal tumor.This quasi experimental trial was conducted in Nanchang, China, from January 2014 to December 2015. Eighty patients (age 27-70 years, American Society of Anesthesiologists physical status I-II) undergoing laparoscopic resection of a gastrointestinal tumor were randomized into 4 groups and offered intravenous patient-controlled analgesia for pain control after surgery. The patients received sufentanil 2.0 MUg/kg in combination with dexmedetomidine 1.5 MUg/kg (group S1) or 2.0 MUg/kg (group S2), or butorphanol 0.15 mg/kg in combination with dexmedetomidine 1.5 0 MUg/kg (group N1) or 2.0 MUg/kg (group N2). Oxygen saturation, mean arterial pressure (MAP), heart rate, visual analog scale score, and Ramsay sedation score were recorded at enrollment (T0), at extubation (T1), and 4 (T2), 8 (T3), 12 (T4), 24 (T5), and 48 (T6) hours thereafter. Side effects and satisfaction scores were evaluated after surgery.MAP increased in all groups at T1 but not significantly so when compared with T0. Heart rate decreased significantly in group S2 when compared with the other groups at T1-T5 (P < 0.05). MAP decreased significantly in group S2 when compared with group S1 at T4 T6 (P < 0.05). MAP increased significantly in group N1 when compared with group N2 at T4-T5 (P < 0.05). There was a statistically significant decrease in mean visual analog scale score in group S2 when compared with group S1 at T2 (P < 0.05) and group N2 at T1-T2 (P < 0.05). Two patients in group S1 had vomiting. There were no reports of drowsiness, respiratory depression, or other complications. The satisfaction score was higher in group S2 than in the other groups.Dexmedetomidine in combination with sufentanil or butorphanol can be used safely and effectively for postoperative analgesia in patients undergoing laparoscopic resection of a gastrointestinal tumor. The combination of dexmedetomidine 2.0 MUg/kg and sufentanil is particularly beneficial in these patients. PMID- 27977601 TI - Three polymorphisms of tumor necrosis factor-alpha and hepatitis B virus related hepatocellular carcinoma: A meta-analysis. AB - BACKGROUND: To assess the association between tumor necrosis factor-alpha (TNF alpha) G308A, G238A and C863T polymorphisms and hepatitis B virus related hepatocellular carcinoma (HBV-HCC) susceptibility. METHODS: We interrogated the databases of Pubmed, Sciencedirect and Viley online library up to March 8, 2016. Odds ratios (ORs) and corresponding 95% confidence intervals (95%CIs) were calculated in a fixed-effects model or a random-effects model when appropriate. RESULTS: In total, 12 case-control studies which containing 1580 HBV-HCC cases, 2033 HBV carrier controls, 395 HBV spontaneously recovered (SR) controls and 1116 healthy controls were included. Compared with GG genotype, the genotypes GA/AA of G308A were associated with a significantly increased HBV-HCC risk when the controls were all healthy individuals (AA vs. GG, OR 2.483, 95%CI 1.243 to 4.959; GA vs. GG, OR 1.383, 95%CI 1.028 to 1.860; GA/AA vs. GG, OR 1.381, 95%CI 1.048 to 1.820). Meanwhile, only the AA vs. GG model of G238A and HBV-HCC showed a statistic significance when the controls were healthy individuals (OR 4.776, 95%CI 1.280 to 17.819). CT genotype of TNF-alpha C863T could increase HBV-HCC risk whenever the controls were healthy individuals, HBV carriers or HBV recovers. CONCLUSION: This meta-analysis shows that AA genotype in TNF-alpha G308A and TNF-alpha G238A and CT genotype in TNF-alpha C863T may increase HBV-HCC risk. Therefore, HBV infection seemed to be a more important factor for tumorigenesis of HCC than genetic predisposition in G308A of TNF-alpha, and interaction between TNF-alpha C863T polymorphisms and HBV infection might be associated with increased HCC risk. PMID- 27977602 TI - Scarce information about breast cancer screening: An Italian websites analysis. AB - Although the public should have complete and correct information about risk/benefit ratio of breast cancer screening, public knowledge appears generally scarce and oriented to overestimate benefits, with little awareness of possible disadvantages of the screening.We evaluated any document specifically addressed to the general female public and posted on internet by Italian public health services. The presence of false positive, false positive after biopsy, false negative, interval cancer, overdiagnosis, lead-time bias, exposure to irradiation, and mortality reduction was analyzed.Of the 255 websites consulted, 136 (53.3%) had sites addressed to the female public. The most commonly reported information points were the false-positive (30.8% of sites) and radiation exposure (29.4%) rates. Only 11 documents mentioned overdiagnosis, 2 mentioned risk of false positive with biopsy, and only 1 mentioned lead-time bias. Moreover, only 15 sites (11.0%) reported quantitative data for any risk variables.Most documents about breast cancer screening published on the web for the female public contained little or no information about risk/benefit ratio and were biased in favor of screening. PMID- 27977603 TI - Diagnostic performance of convex probe EBUS-TBNA in patients with mediastinal and coexistent endobronchial or peripheral lesions. AB - To compare the performance of convex probe endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) with conventional endobronchial biopsy (EBB) or transbronchial lung biopsy (TBLB) in patients with mediastinal, and coexisting endobronchial or peripheral lesions.Retrospective review of records of patients undergoing diagnostic EBUS-TBNA and conventional bronchoscopy in 2014.A total of 74 patients had mediastinal, and coexisting endobronchial or peripheral lesions. The detection rate of EBUS-TBNA for mediastinal lesion >1 cm in short axis, EBB for visible exophytic type of endobronchial lesion, and TBLB for peripheral lesion with bronchus sign were 71%, 75%, and 86%, respectively. In contrast, the detection rate of EBUS-TBNA for mediastinal lesion <=1 cm in short axis, EBB for mucosal hyperemia type of endobronchial lesion, and TBLB for peripheral lesion without bronchus sign were 25%, 63%, and 38%, and improved to 63%, 88%, and 62% respectively by adding EBB or TBLB to EBUS-TBNA, and EBUS-TBNA to EBB or TBLB. Postprocedure bleeding was significantly more common in patients undergoing EBB and TBLB 8 (40%) versus convex probe EBUS-TBNA 2 patients (2.7%, P = 0.0004).EBUS-TBNA is a safer single diagnostic technique compared with EBB or TBLB in patients with mediastinal lesion of >1 cm in size, and coexisting exophytic type of endobronchial lesion, or peripheral lesion with bronchus sign. However, it requires combining with EBB or TBLB and vice versa to optimize yield when mediastinal lesion is <=1 cm in size, and coexisting endobronchial and peripheral lesions lack exophytic nature, and bronchus sign, respectively. PMID- 27977604 TI - The importance of IgG4 screening in patients diagnosed with primary sclerosing cholangitis in the past: A case rediagnosed as IgG4-SC after 10 years. AB - RATIONALE: While primary sclerosing cholangitis (PSC) has been recognized for decades, immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) has been correctly diagnosed only in recent years. PSC and IgG4-SC show similar clinical symptoms, serologic markers, and imaging results, but the treatment strategies and prognosis of patients differ. PATIENT CONCERNS: Here, we present the case report of a patient diagnosed with PSC for 10 years and rediagnosed with IgG4-SC recently, to emphasize the importance of screening serum IgG4 levels in patients with previous diagnosis of PSC. DIAGNOSES: A 57-year-old woman with 10-year history of PSC was hospitalized due to pruritus. In 2004, the patient underwent cholecystectomy and cholangioenterostomy because of unexplained jaundice with pancreatic swelling. In the last 10 years, her liver enzyme levels were continuously elevated. The latest liver function profile showed elevated alanine aminotransferase, aspartate aminotransferase, and total bilirubin. IgG4 was 3.69 (0.03-2.01 g/L). Immunohistochemical staining of the surgical specimen showed >10 IgG4-positive plasma cells per high-power field, and IgG4+/IgG+ plasma cells >40%. INTERVENTIONS AND OUTCOMES: She was treated with prednisone 40 mg once daily and the dose was gradually tapered. The patient remains well after 18 months. LESSONS SUBSECTIONS: Patients with IgG4-SC may be misdiagnosed as PSC due to lack of IgG4 screening. It is important to perform IgG4 screening in patients diagnosed as PSC. Steroid is effective to prevent disease progression in these patients. PMID- 27977605 TI - Burnout in the intensive care unit professionals: A systematic review. AB - BACKGROUND: Burnout has been described as a prolonged response to chronic emotional and interpersonal stress on the job that is often the result of a period of expending excessive effort at work while having too little recovery time. Healthcare workers who work in a stressful medical environment, especially in an intensive care unit (ICU), may be particularly susceptible to burnout. In healthcare workers, burnout may affect their well-being and the quality of professional care they provide and can, therefore, be detrimental to patient safety. The objectives of this study were: to determine the prevalence of burnout in the ICU setting; and to identify factors associated with burnout in ICU professionals. METHODS: The original articles for observational studies were retrieved from PubMed, MEDLINE, and Web of Science in June 2016 using the following MeSH terms: "burnout" and "intensive care unit". Articles that were published in English between January 1996 and June 2016 were eligible for inclusion. Two reviewers evaluated the abstracts identified using our search criteria prior to full text review. To be included in the final analysis, studies were required to have employed an observational study design and examined the associations between any risk factors and burnout in the ICU setting. RESULTS: Overall, 203 full text articles were identified in the electronic databases after the exclusion of duplicate articles. After the initial review, 25 studies fulfilled the inclusion criteria. The prevalence of burnout in ICU professionals in the included studies ranged from 6% to 47%. The following factors were reported to be associated with burnout: age, sex, marital status, personality traits, work experience in an ICU, work environment, workload and shift work, ethical issues, and end-of-life decision-making. CONCLUSIONS: The impact of the identified factors on burnout remains poorly understood. Nevertheless, this review presents important information, suggesting that ICU professionals may suffer from a high level of burnout, potentially threatening patient care. Future work should address the effective management of the factors negatively affecting ICU professionals. PMID- 27977606 TI - Clinical outcomes of elderly patients (>=70 years) with resectable esophageal squamous cell carcinoma who underwent esophagectomy or chemoradiotherapy: A retrospective analysis from a single cancer institute. AB - A retrospective analysis was conducted to investigate outcomes of elderly patients with resectable esophageal squamous cell carcinoma (ESCC) who underwent surgery or chemoradiotherapy (CRT).We performed a retrospective review of the records of elderly patients (>=70 years) with resectable ESCC who underwent esophagectomy or CRT between January 2009 and March 2013. According to the main treatment strategy, patients were allocated into either surgery group or CRT group. Overall survival (OS), cancer-specific survival and progression-free survival were calculated by the Kaplan-Meier method. Univariate and multivariate survival analyses were performed by the Kaplan-Meier method and Cox proportional hazards model, respectively.A total of 188 patients were enrolled. Eighty-eight patients underwent esophagectomy, and 100 patients underwent CRT. The median age of the patients was 73 years (range, 70-81 years) in the surgery group and 76 years (range, 70-88 years) in the CRT group. The median survival time (MST) for the whole cohort was 25.6 months, and 1-, 3-, and 5-year survival rates were 69.2%, 36.1%, and 21.9%, respectively. The MST in the surgery group and the CRT group was 36 months and 15 months, respectively. The 1-, 3-, and 5-year survival rates in the surgery group were 82.4%, 49.0%, and 33.3%, compared to 58.0%, 24.1%, and 7.8% in the CRT group (P < 0.0001). Multivariate analysis revealed that lymph node status (hazard ratio [HR] = 0.598, P = 0.011) and treatment strategies (HR = 0.538, P = 0.001) were independent and significant prognostic factors for OS in elderly patients.Surgery was the main treatment strategy for elderly patients with ESCC. Advanced age and comorbidities should not be the cause for elderly patients to avoid aggressive regimens. Delivered therapeutic approaches should be individualized on the basis of carefully evaluating the balance of benefits, risks, and life expectancy. PMID- 27977607 TI - Assessment of duration until initial treatment and its determining factors among newly diagnosed oral cancer patients: A population-based retrospective cohort study. AB - Few studies have focused on the early treatment stages of cancer, and the impact of treatment delay on oncologic outcomes is poorly defined. We used oral cancer as an example to investigate the distribution of durations until initial treatment.This study was conducted using the National Health Insurance Research Database, which is linked to Taiwan's Cancer Registry and Death Registry databases. We defined "cutoff points for first-time treatment" according to a weekly schedule and sorted the patients into 2 groups based on whether their duration until initial treatment was longer or shorter than each cutoff. We then calculated the Kaplan-Meier estimator to determine the difference in survival rates between the 2 groups and performed logistic regression to identify determining factors.The average time between diagnosis and initial treatment was approximately 22.45 days. The average survival duration was 1363 days (standard deviation: 473.06 days). Oral cancer patients had no statistically significant differences in survival until a cutoff point of 3 weeks was used (with survival duration 71 days longer if initial treatment was received within 3 weeks). Patients with higher incomes or higher Charlson comorbidity index scores and patients treated at a hospital in a region with medium urbanization had lower likelihoods of treatment delay, whereas older patients were at higher risk of treatment delay.The attitudes, beliefs, and social contexts of oral cancer patients influence the treatment-seeking behaviors of these patients. Therefore, the government should advocate the merits of the referral system for cancer treatment or improve quality assurance for cancer diagnoses across different types of hospitals. Health authorities should also educate patients or use a case manager to encourage prompt treatment within 3 weeks and should provide screening and prevention services, particularly for high-risk groups, to reduce mortality risk. PMID- 27977608 TI - Risk factors and management for pyloric stenosis occurred after endoscopic submucosal dissection adjacent to pylorus. AB - Endoscopic submucosal dissection (ESD) has been widely accepted as a curative treatment for gastric neoplasm. Pyloric stenosis is a chronic complication that can be caused by ESD. The aim of this study is to clarify the risk factors and management for pyloric stenosis. From January 2004 to January 2014, a total of 126 patients who underwent ESD adjacent to pylorus were reviewed retrospectively. Pyloric mucosal defect was defined as when any resection margin of ESD was involved in the pyloric ring. Pyloric stenosis was defined as when a conventional endoscope could not be passed to the duodenum. Among the 126 patients, pyloric stenosis was identified in 9. In a univariate analysis, pyloric stenosis was more common in older patients (P < 0.05) and in lesions with resections over 75% of the pyloric ring circumference (P < 0.001). In a multivariate analysis, the factor that was associated with pyloric stenosis was the extent of the pyloric ring dissection (P < 0.001). Four of the 9 patients with pyloric stenosis had mild dyspepsia, and the others had gastric outlet obstruction symptoms. The 5 symptomatic patients underwent endoscopic balloon dilation (EBD), and the frequency of EBD was 1 to 8 times. The asymptomatic patients were treated conservatively. The incidence of pyloric stenosis was higher in lesions with resections over 75% of the pyloric ring circumference. Although EBD was an effective treatment for pyloric stenosis, conservative management was also helpful in patients who had mild symptoms. PMID- 27977609 TI - Serum apolipoprotein E concentration and polymorphism influence serum lipid levels in Chinese Shandong Han population. AB - Apolipoprotein E (ApoE), which has been shown to influence serum lipid parameters, can bind to multiple types of lipids and plays an important role in the metabolism and homeostasis of lipids and lipoproteins. A previous study showed that ApoE concentration significantly affects serum lipid levels independently of ApoE polymorphism. The serum lipid levels were also closely correlated with dietary habits, and Shandong cuisine is famous for its high salt and oil contents, which widely differ among the different areas in China. Therefore, studying the effect of ApoE polymorphism on ApoE concentration and serum lipid levels in Shandong province is very important.A total of 815 subjects including 285 men and 530 women were randomly selected and studied from Jinan, Shandong province. In order to evaluate the association of ApoE polymorphism and serum level on lipid profiles, the ApoE genotypes, as well as levels of fasting serum ApoE and other lipid parameters, were detected in all subjects.The frequency of the ApoE E3 allele was highest (83.1%), while those of E2 and E4 were 9.4% and 7.5%, respectively, which are similar to those in other Asian populations. ApoE2 allele carriers showed significantly increased ApoE levels but lower levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and Apolipoprotein B (ApoB).We found that ApoE level is influenced by ApoE polymorphism in a gene-dependent manner. The ApoE polymorphism showed different influences on serum lipid parameters with increasing age and body mass index (BMI) in our Shandong Han population. PMID- 27977610 TI - A meta-analytic review of prevalence for Brugada ECG patterns and the risk for death. AB - BACKGROUND: The prevalence of Brugada ECG pattern (BrEP) is different in different regions, and its mean prevalence over the world is unknown. The risk of people with BrEP for death remains unknown. We performed a meta-analysis to determine the prevalence of BrEP and risk ratio (RR) for death. METHODS: Relevant studies published between July 1, 2000 and August 20, 2016, which contain prevalence and RR for all-cause death and cardiac death, were included. The prevalence and RR are analyzed using meta-analysis. RESULTS: We finally retrieved 24 studies of the prevalence for BrEP and 5 studies of the RR for all-cause death and cardiac death. The worldwide mean prevalence of BrEP is 0.4%, with highest in Asia (0.9%) and lowest in North America (0.2%). Additionally, the mean prevalence in male is 0.9%, whereas it is 0.1% in female. The RR of BrEP for all-cause death is 0.78 (95% confidence interval 0.45-1.37), and for cardiac death it is 0.92 (95% confidence interval 0.23-3.66). CONCLUSION: The prevalence of BrEP is about 0.4% around the world with different prevalence in region and sex. Our study shows that BrEP may not be taken as a predictor of all-cause death and cardiac death. PMID- 27977611 TI - Risk factors analysis of consecutive exotropia: Oblique muscle overaction may play an important role. AB - To evaluate clinical factors associated with the onset of consecutive exotropia (XT) following esotropia surgery.By a retrospective nested case-control design, we reviewed the medical records of 193 patients who had undergone initial esotropia surgery between 2008 and 2015, and had follow-up longer than 6 months. The probable risk factors were evaluated between groups 1 (consecutive XT) and 2 (non-consecutive exotropia). Pearson chi-square test and Mann-Whitney U test were used for univariate analysis, and conditional logistic regression model was applied for exploring the potential risk factors of consecutive XT.Consecutive exotropia occurred in 23 (11.9%) of 193 patients. Patients who had undergone large bilateral medial rectus recession (BMR) (P = 0.017) had a high risk of developing consecutive XT. Oblique dysfunction (P = 0.001), adduction limitation (P = 0.000) were associated with a high risk of consecutive XT, which was confirmed in the conditional logistic regression analysis. In addition, large amount of BMR (6 mm or more) was associated with higher incidence of adduction limitation (P = 0.045). The surgical methods and preoperative factors did not appear to influence the risk of developing consecutive XT (P > 0.05).The amount of surgery could be optimized to reduce the risk of consecutive XT. The presence of oblique overaction and postoperative adduction limitation may be associated with a high risk of consecutive XT, which may require close supervision, and/or even earlier operation intervention. PMID- 27977612 TI - Coexistence of MSI with KRAS mutation is associated with worse prognosis in colorectal cancer. AB - Kristen rat sarcoma viral oncogene homolog (KRAS) and microsatellite instability (MSI) are prognostic markers of colorectal cancer (CRC). However, the clinical value is still not fully understood, when giving the consideration to both the molecular makers. Five hundred fifty-one patients with CRC were retrospectively assessed by determining their clinicopathological features. KRAS mutations were detected by polymerase chain reaction. MSI, a defect in the mismatch repair (MMR) system, was detected by immunohistochemistry. The prognostic value of KRAS in combination with MSI was studied. Among 551 CRC patients, mutations in KRAS codon 12 and KRAS codon 13 were detected in 34.5% and 10.5% of patients, respectively. Four hundred one tumors were randomly selected to detect for MMR proteins expression. In this analysis, 30 (7.5%) tumors that had at least 1 MMR protein loss were defined as MMR protein-deficient (MMR-D), and the remaining tumors were classed as MMR protein-intact (MMR-I). According to KRAS mutation and MSI status, CRC was classified into 4 groups: Group 1, KRAS-mutated and MMR-I; Group 2, KRAS mutated and MMR-D; Group 3, KRAS wild and MMR-I; and Group 4, KRAS wild and MMR D. We found that patients in Group4 had the best prognosis. In conclusion, combination status of KRAS and MSI status may be used as a prognostic biomarker for CRC patient, if validated by larger studies. PMID- 27977614 TI - Association between pterygium and obesity status in a South Korean population. AB - This study examined the association between pterygium and obesity status by examining a nationally representative sample of South Korean adults.This population-based, cross-sectional study comprised 16,234 adults (aged >=19 years) who had participated in the fifth annual Korea National Health and Nutrition Examination Survey from 2010 to 2012. The enrolled subjects underwent interviews, clinical examinations, and laboratory investigations. We compared body mass index (BMI) and waist circumference (WC), according to the presence of pterygium. Multiple logistic regression analysis was conducted to examine the associations of each obesity parameter with pterygium after adjusting for age, smoking status, alcohol consumption, physical activities, educational levels, outdoor occupation, area of residence, and daily sun exposure duration.The prevalence rate of pterygium tended to increase as the BMI increased only in women, and both male and female subjects with higher WC were likely to have more pterygium in both sexes. In the multivariate analysis, overweight women had an odd ratio (OR) (95% confidence interval (CI)) of 1.16 (0.86-1.55) and obese women had an OR (95% CI) of 1.35 (1.02-1.77) compared to women with normal weight (P for trend for ORs = 0.04). Compared to women without abdominal obesity, abdominally obese women had an OR (95% CI) of 1.26 (1.01-1.58). There was no significant association between obesity and pterygium in men.The present study provides epidemiologic evidence of an association between obesity and pterygium in women. Further studies are needed to examine the sex difference in the pathogenesis of pterygium. PMID- 27977613 TI - Acid-reducing vagotomy is associated with reduced risk of subsequent ischemic heart disease in complicated peptic ulcer: An Asian population study. AB - Persistent exacerbation of a peptic ulcer may lead to a complicated peptic ulcer (perforation or/and bleeding). The management of complicated peptic ulcers has shifted from acid-reducing vagotomy, drainage, and gastrectomy to simple local suture or non-operative (endoscopic/angiographic) hemostasis. We were interested in the long-term effects of this trend change. In this study, complicated peptic ulcer patients who received acid-reducing vagotomy were compared with those who received simple suture/hemostasis to determine the risk of ischemic heart disease (IHD).This retrospective cohort study analyzed 335,680 peptic ulcer patients recorded from 2000 to 2006 versus 335,680 age-, sex-, comorbidity-, and index year matched comparisons. Patients with Helicobacter pylori (HP) infection were excluded. In order to identify the effect of vagus nerve severance, patients who received gastrectomy or antrectomy were also excluded. The incidence of IHD in both cohorts, and in the complicated peptic ulcer patients who received acid reducing vagotomy versus those who received simple suture or hemostasis was evaluated.The overall incidence of IHD was higher in patients with peptic ulcer than those without peptic ulcer (17.00 vs 12.06 per 1000 person-years), with an adjusted hazard ratio (aHR) of 1.46 based on multivariable Cox proportional hazards regression analysis controlling for age, sex, Charlson's comorbidity index, and death (competing risk). While comparing peptic ulcer patients with acid-reducing vagotomy to those with simple suture/hemostasis or those without surgical treatment, the aHR (0.58) was the lowest in the acid-reducing vagotomy group.Patients with peptic ulcer have an elevated risk of IHD. However, complicated peptic ulcer patients who received acid-reducing vagotomy were associated with reduced risk of developing IHD. PMID- 27977615 TI - Total revascularization for an epsilon right coronary artery and severe left main disease combined with profound cardiogenic shock: A case report. AB - RATIONALE: Severe left main disease combined with right coronary artery occlusion was rarely encountered in our daily practice. Percutaneous coronary intervention in these patients was most challenging due to high probability of hemodynamic changes. PATIENT CONCERNS: Here, we report a 67-year-old man with Non-ST-Segment Elevation Myocardial Infarction (NSTEMI) and profound cardiogenic shock and we attempted coronary intervention with total revisualization for severe left main (LM) disease and angulated epsilon right coronary artery total occlusion. He was treated successfully under intra-aortic balloon pump (IABP) and extracorporeal membrane oxygenation (ECMO) support. DIAGNOSES: NSTEMI and profound cardiogenic shock. INTERVENTIONS: Coronary intervention with total revisualization was performed for severe LM disease and angulated epsilon right coronary artery total occlusion under IABP and ECMO support. OUTCOMES: IABP and ECMO were removed until cardiac contractile function improved to left ventricular ejection fraction over 40 percentage 1 week later. The patient was discharged after 2 months and had survival for 5 years. LESSONS: Coronary intervention could be performed safely in this cardiogenic shock patient with severe LM and triple vessel disease who was supported by IABP and ECMO. Stent deployment for extremely angulated coronary artery was required multiple combination techniques to facilitate the final success. PMID- 27977616 TI - Clinical study of right ventricular longitudinal strain for assessing right ventricular dysfunction and hemodynamics in pulmonary hypertension. AB - This study aimed to appraise the application of right ventricular longitudinal strain for assessing right ventricular dysfunction and severe hemodynamic changes in pulmonary hypertension. The study included 53 patients clinically diagnosed with PH. Tissue Doppler-derived tricuspid lateral annular systolic velocity (s'), early diastolic peak velocity (e'), late diastolic peak velocity (a'), tricuspid annular plane systolic excursion (TAPSE), RV index of myocardial performance (RIMP), and right ventricular fractional area change (FAC) were determined. The STI parameter was RV free wall longitudinal peak systolic strain (RV LPSS). The patients were assigned into two groups based on a RV LPSS value of - 19%.RV LPSS, s', TAPSE, RIMP, FAC, a' and e'/a' showed significant differences. PH patients with an RV LPSS>= -19% exhibited a lower RV function (P < 0.05). RV LPSS was negatively correlated with TAPSE (r = -0.326, P < 0.05) and FAC (r = -0.495, P < 0.001) and positively correlated with RIMP (r = 0.508, P < 0.001). The optimal cut-off value of RV LPSS to reveal an mPAP >= 45 mmHg defined based on the receiver operating characteristic curve analysis was - 19.26% with a sensitivity of 83.9% and a specificity of 73.4%.Distinguishing the degree of RV dysfunction by 2D-STI may help physicians to determine the state of cardiac function and degree of PH in patients and offer a basis for subsequent clinical diagnosis and therapy. Our study demonstrates the superiority of RV LPSS for uncovering severe PH over the traditional echocardiographic parameters. PMID- 27977617 TI - The association between various indices of obesity and severity of atherosclerosis in adults in the north of Iran. AB - Recent observational studies have reported controversial results for the association between different anthropometric indices of obesity and severity of atherosclerosis. The aim of the current study is to determine the associations between anthropometric indices with severity of atherosclerosis in adult population in north of Iran.The cross-sectional study was performed on 610 participants, who were admitted to a hospital for elective angiographyin Rasht, Iran, Anthropometric indices, including waist circumference (WC), waist-to-height ratio (WHtR), conicity index (CI), body mass index (BMI), and hematological factors, were measured using the standard methods. According to angiography reports, severity of atherosclerosis was determined.Sixty-two percent of participants had moderate to severe atherosclerosis. According to BMI, 44% were overweight and 25.8% were obese. Based on WHtR and WC, 90%, and 57% were obese, respectively. The prevalence of moderate to severe atherosclerosis in centrally obese women was significantly higher than in centrally nonobese women (52% vs 28% P = 0.02). According to multivariate adjustment analysis, age, sex, systolic blood pressure, hemoglobin A1c, uric acid, and triglyceride were independently associated with severity of atherosclerosis. BMI, WC, CI, and WHtR had no significant association with severity of atherosclerosis.Our findings showed that anthropometric indices reflective of general and abdominal obesity were not independently related to the severity of atherosclerosis in adults, in northern Iran. PMID- 27977618 TI - Covered TIPS for secondary prophylaxis of variceal bleeding in liver cirrhosis: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: In the era of bare stents, transjugular intrahepatic portosystemic shunt (TIPS) is the second-line choice of therapy for the prevention of variceal rebleeding in liver cirrhosis. In the era of covered stents, the role of TIPS should be re-evaluated. AIM: The aim of the study was to compare the outcomes of covered TIPS versus the traditional first-line therapy (i.e, drug plus endoscopic therapy) for the prevention of variceal rebleeding in liver cirrhosis. METHODS: All relevant randomized controlled trials were searched via the PubMed, EMBASE, and Cochrane Library databases. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) and P values were calculated for the cumulative risk and overall risk, respectively. Heterogeneity among studies was also calculated. RESULTS: Three of 111 retrieved papers were eligible. Among them, the proportion of patients who were switched from drug plus endoscopic therapy to TIPS was 16% to 25%. The risk of bias was relatively low in all included randomized controlled trials. Meta-analyses demonstrated that the covered TIPS group had a similar overall survival (HR = 0.84, 95% CI = 0.55-1.28, P = 0.41; OR = 1.00, 95% CI = 0.59-1.69, P = 0.99), a significantly lower risk of variceal rebleeding (HR = 0.30, 95% CI = 0.18-0.48, P < 0.00001; OR = 0.24, 95% CI = 0.12 0.46, P < 0.0001), and a similar risk of hepatic encephalopathy (HR = 1.35, 95% CI = 0.72-2.53, P = 0.36; OR = 1.28, 95% CI = 0.54-3.04, P = 0.57). In most of meta-analyses, the heterogeneity among studies was not statistically significant. CONCLUSIONS: Compared with drug plus endoscopic therapy, covered TIPS had a significant benefit of preventing from variceal rebleeding, but did not increase the overall survival or risk of hepatic encephalopathy. PMID- 27977619 TI - Active case finding strategy for chronic obstructive pulmonary disease with handheld spirometry. AB - The early detection and diagnosis of chronic obstructive pulmonary disease (COPD) is critical to providing appropriate and timely treatment. We explored a new active case-finding strategy for COPD using handheld spirometry.We recruited subjects over 40 years of age with a smoking history of more than 10 pack-years who visited a primary clinic complaining of respiratory symptoms. A total of 190 of subjects were enrolled. Medical information was obtained from historical records and physical examination by general practitioners. All subjects had their pulmonary function evaluated using handheld spirometry with a COPD-6 device. Because forced expiratory volume in 6 seconds (FEV6) has been suggested as an alternative to FVC, we measured forced expiratory volume in 1 second (FEV1)/FEV6 for diagnosis of airflow limitation. All subjects were then referred to tertiary referral hospitals to complete a "Could it be COPD?" questionnaire, handheld spiromtery, and conventional spirometry. The results of each instrument were compared to evaluate the efficacy of both handheld spirometry and the questionnaire.COPD was newly diagnosed in 45 (23.7%) patients. According to our receiver-operating characteristic (ROC) curve analysis, sensitivity and specificity were maximal when the FEV1/FEV6 ratio was less than 77%. The area under the ROC curve was 0.759. The sensitivity, specificity, positive predictive value, and negative predictive value were 72.7%, 77.1%, 50%, and 90%, respectively. The area under the ROC curve of respiratory symptoms listed on the questionnaire ranged from 0.5 to 0.65, which indicates that there is almost no difference compared with the results of handheld spirometry.The present study demonstrated the efficacy of handheld spirometry as an active case-finding tool for COPD in a primary clinical setting. This study suggested that physicians should recommend handheld spirometry for people over the age of 40, who have a smoking history of more than 10 pack-years, regardless of respiratory symptoms. Furthermore, people who have abnormal results, determined using the FEV1/FEV6 <=0.77 cut-off, should be referred for further conventional spirometry to confirm the diagnosis of COPD. However, further studies within the general population are necessary to establish efficacy in the public. PMID- 27977620 TI - Changes of quality of life and cognitive function in individuals with Internet gaming disorder: A 6-month follow-up. AB - Internet gaming disorder (IGD) contributes to poor quality of life (QOL) and cognitive dysfunction and is increasingly recognized as a social problem in various countries. However, no evidence exists to determine whether QOL and cognitive dysfunction stabilize after appropriate management. The present study addressed improvement in QOL and cognitive functioning associated with changes in addiction symptoms following outpatient management for IGD. A total of 84 young males (IGD group: N = 44, mean age: 19.159 +/- 5.216 years; healthy control group: N = 40, mean age: 21.375 +/- 6.307 years) participated in this study. We administered self-report questionnaires at baseline to assess clinical and psychological characteristics, and conducted traditional and computerized neuropsychological tests. Nineteen patients with IGD completed follow-up tests in the same manner after 6 months of outpatient treatment, which included pharmacotherapy with selective serotonin reuptake inhibitors. A baseline comparison of patients with IGD against the healthy control group showed that the IGD patients had more symptoms of depression and anxiety, higher degrees of impulsiveness and anger/aggression, higher levels of distress, poorer QOL, and impaired response inhibition. After 6 months of treatment, patients with IGD showed significant improvements in the severity of IGD, as well as in QOL, response inhibition, and executive functioning. Additionally, a stepwise multiple regression analysis revealed a favorable prognosis for IGD patients with low working memory functioning and high executive functioning at baseline. These results provide evidence regarding longitudinal changes in QOL and cognitive function following psychiatric intervention for IGD. Furthermore, it appears that response inhibition may be an objective state marker underlying the pathophysiology of IGD. PMID- 27977622 TI - Chronic obstructive pulmonary disease: the impact of gender. AB - PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a widely prevalent and potentially preventable cause of death worldwide. The purpose of this review is to summarize the influence of gender on various attributes of this disease, which will help physicians provide more personalized care to COPD patients. RECENT FINDINGS: Cultural trends in smoking have morphed the epidemiology of this traditionally male disease. There is an increasing 'disease burden' among women with COPD as suggested by the higher prevalence and slower decline in death rates as compared with men. Biologic differences between the genders account for some, but not all of these differences. In women, distinct features need to be considered to boost success of therapeutic interventions such as smoking cessation, addressing comorbidities, and attendance to pulmonary rehabilitation. SUMMARY: COPD in women is distinct from that in men with respect to phenotype, symptom burden, and comorbidities. Women are more predisposed to develop chronic bronchitis, have more dyspnea, and suffer more frequently from coexistent anxiety or depression. They may be more subject than men to misdiagnoses and/or underdiagnoses of COPD, often as a result of physician bias. Knowledge of these gender differences can lead to more effective tailored care of the COPD patient. PMID- 27977621 TI - Lung cancer development in patients with connective tissue disease-related interstitial lung disease: A retrospective observational study. AB - Previous studies have reported that patients with idiopathic pulmonary fibrosis occasionally develop lung cancer (LC). However, in connective tissue disease (CTD)-related interstitial lung disease (ILD), there are few data regarding the LC development. The aim of the present study was to evaluate the clinical significance of LC development in patients with CTD-ILD. A retrospective review of our database of 562 patients with ILD between 2000 and 2014 identified 127 patients diagnosed with CTD-ILD. The overall and cumulative incidences of LC were calculated. In addition, the risk factors and prognostic impact of LC development were evaluated. The median age at the ILD diagnosis was 63 years (range 37-84 years), and 73 patients (57.5%) were female. The median follow-up period from the ILD diagnosis was 67.4 months (range 10.4-322.1 months). During the period, 7 out of the 127 patients developed LC (overall incidence 5.5%). The cumulative incidences at 1, 3, and 5 years were 0.0%, 1.8%, and 2.9%, respectively. The risk of LC development was significantly higher in patients with higher smoking pack year (odds ratio [OR] 1.028; 95% confidence interval [CI] 1.008-1.049; P = 0.007) and emphysema on chest high-resolution computed tomography (OR 14.667; 95% CI 2.871-74.926; P = 0.001). The median overall survival time after developing LC was 7.0 months (95% CI 4.9-9.1 months), and the most common cause of death was LC, not ILD. According to the Cox proportional hazard model analysis with time dependent covariates, patients who developed LC showed significantly poorer prognosis than those who did not (hazard ratio 87.86; 95% CI 19.56-394.67; P < 0.001). In CTD-ILD, clinicians should be careful with the risk of LC development in patients with a heavy smoking history and subsequent emphysema. Although not so frequent, the complication could be a poor prognostic determinant. PMID- 27977623 TI - The contribution of autoantibodies to post-translationally modified proteins to inflammatory arthritis. AB - PURPOSE OF REVIEW: This article provides an overview of the recent findings present in the field of antimodified protein antibodies and their relevance for rheumatic disease, with a focus on rheumatoid arthritis. RECENT FINDINGS: Next to anticitrullinated protein antibodies, also other antimodified protein antibodies such as anticarbamylated protein antibodies or antiacetylated protein antibodies are emerging. Likewise, their possible pathological contributions are getting detailed attention. Their possible relation to disease, both from a clinical as well as biological perspective will be summarized. SUMMARY: Current evidence is pointing to the notion that especially a combination of antimodified protein antibodies associates best with clinical phenotype and outcome. PMID- 27977625 TI - Exosome-Mediated Intercellular Communication Between Stellate Cells and Cancer Cells in Pancreatic Ductal Adenocarcinoma. PMID- 27977624 TI - Continuous Regional Arterial Infusion of Protease Inhibitors Has No Efficacy in the Treatment of Severe Acute Pancreatitis: A Retrospective Multicenter Cohort Study. AB - OBJECTIVE: The aim of this study is to assess the effectiveness of continuous regional arterial infusion (CRAI) of protease inhibitors in patients with severe acute pancreatitis (SAP) including acute necrotizing pancreatitis. METHODS: This retrospective study was conducted among 44 institutions in Japan from 2009 to 2013. Patients 18 years or older diagnosed with SAP according to the criteria of the Japanese Ministry of Health, Labour and Welfare study group (2008) were consecutively enrolled. We evaluated the association between CRAI of protease inhibitors and mortality, incidence of infection, and the need for surgical intervention using multivariable logistic regression analysis. RESULTS: Of 1159 patients admitted, 1097 patients with all required data were included for analysis. Three hundred and seventy-four (34.1%) patients underwent CRAI of protease inhibitors and 723 (65.9%) did not. In multivariable analysis, CRAI of protease inhibitors was not associated with a reduction in mortality, infection rate, or need for surgical intervention (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.47-1.32, P = 0.36; OR 0.97, 95% CI 0.61-1.54, P = 0.89; OR 0.76, 95% CI 0.50-1.15, P = 0.19; respectively). CONCLUSIONS: Continuous regional arterial infusion of protease inhibitors was not efficacious in the treatment of patients with SAP. PMID- 27977626 TI - Benign Pancreatic Hyperenzymemia: Lights on a Clinical Challenge. PMID- 27977627 TI - Somatostatin: One of the Rare Multifunctional Inhibitors of Mammalian Species. AB - This review article has for major main objectives to give an overlook of the major physiological effects of somatostatin on different organs. It will cover first the general aspect of the hormone, its cDNA and its protein maturation process, as well as its characterization in various organs. This aspect will be followed by the factors involved in the control of its secretion, its intracellular mode of action, and its general action on physiological processes. Secondly, the review will focus on the pancreas, looking at its in vivo and in vitro actions with special attention on its effects on normal pancreas growth and pancreatic tumors. PMID- 27977628 TI - Percutaneous Irreversible Electroporation for Pancreatic VIPoma: A Case Report. AB - The purpose of this study was to investigate the safety and efficacy of irreversible electroporation (IRE) for the management of unresectable pancreatic vasoactive intestinal peptide tumor (VIPoma) in a 34-year-old male patient. The initial symptom was watery diarrhea, which could not be stopped by fasting. Laboratory tests revealed high vasoactive intestinal peptide (VIP) hormone levels, hypokalemia, and metabolic acidosis. Computed tomography examination showed a 6.0 * 5.0-cm, contrast-enhanced lesion in the neck and body of the pancreas and obliteration of the portal vein. Pathological and immunohistochemical findings were indicative of pancreatic VIPoma. The patient was treated with octreotide and IRE, and had no obvious IRE-related complications, except for moderate pain at the puncture sites. The patient reported that the watery diarrhea had decreased gradually; moreover, the VIP hormone level was normalized 15 days after IRE. Computed tomography scans showed a large area of necrosis in the pancreatic lesion. The findings from this case indicated that IRE could be a feasible and safe technique in controlling pancreatic VIPoma; however, additional follow-up and findings from more cases are required to further confirm the efficacy of IRE ablation therapy for pancreatic VIPoma. PMID- 27977629 TI - A Different Viewpoint on the Size Criterion for Surgical Resection of Branch-Duct Intraductal Papillary Mucinous Neoplasm. PMID- 27977630 TI - Reply. PMID- 27977631 TI - Follow-up After Surgery for Pancreatic Ductal Adenocarcinoma: Steps Toward an International Consensus. PMID- 27977632 TI - Hyperlipidemic Acute Pancreatitis and the Apolipoprotein E4 Allele. PMID- 27977633 TI - Scavenging Endothelium of Pancreatic Islets: Differential Expression of Stabilin 1 and Stabilin-2 in Mice and Humans. PMID- 27977634 TI - KRAS Mutations With No GNAS Mutations in an Intraductal Papillary Mucinous Neoplasm: Are There Common Pathways With Pancreatic Ductal Adenocarcinoma? Lessons From an Extended IPMN, Covering the Entire Pancreas. PMID- 27977635 TI - Pancreatic Neuroendocrine Tumor Abnormally Secreting Procalcitonin. PMID- 27977636 TI - Autoimmune Pancreatitis Complicated With Pancreatic Ascites, Pancreatic Ductal Leakage, and Multiple Pseudocyst. PMID- 27977638 TI - Resurgence of Progressive Massive Fibrosis in Coal Miners - Eastern Kentucky, 2016. AB - Coal workers' pneumoconiosis, also known as "black lung disease," is an occupational lung disease caused by overexposure to respirable coal mine dust. Inhaled dust leads to inflammation and fibrosis in the lungs, and coal workers' pneumoconiosis can be a debilitating disease. The Federal Coal Mine Health and Safety Act of 1969 (Coal Act),* amended in 1977, established dust limits for U.S. coal mines and created the National Institute for Occupational Safety and Health (NIOSH)-administered Coal Workers' Health Surveillance Program with the goal of reducing the incidence of coal workers' pneumoconiosis and eliminating its most severe form, progressive massive fibrosis (PMF),? which can be lethal. The prevalence of PMF fell sharply after implementation of the Coal Act and reached historic lows in the 1990s, with 31 unique cases identified by the Coal Workers' Health Surveillance Program during 1990-1999. Since then, a resurgence of the disease has occurred, notably in central Appalachia (Figure 1) (1,2). This report describes a cluster of 60 cases of PMF identified in current and former coal miners at a single eastern Kentucky radiology practice during January 2015-August 2016. This cluster was not discovered through the national surveillance program. This ongoing outbreak highlights an urgent need for effective dust control in coal mines to prevent coal workers' pneumoconiosis, and for improved surveillance to promptly identify the early stages of the disease and stop its progression to PMF. PMID- 27977639 TI - Leading Causes of Cancer Mortality - Caribbean Region, 2003-2013. AB - Cancer is one of the leading causes of deaths worldwide (1); in 2012, an estimated 65% of all cancer deaths occurred in the less developed regions of the world (2). In the Caribbean region, cancer is the second leading cause of mortality, with an estimated 87,430 cancer-related deaths reported in 2012 (3). The Pan American Health Organization defines the Caribbean region as a group of 27 countries that vary in size, geography, resources, and surveillance systems.* CDC calculated site- and sex-specific proportions of cancer deaths and age standardized mortality rates (ASMR) for 21 English- and Dutch-speaking Caribbean countries, the United States, and two U.S. territories (Puerto Rico and the U.S. Virgin Islands [USVI]), using the most recent 5 years of mortality data available from each jurisdiction during 2003-2013. The selection of years varied by availability of the data from the countries and territories in 2015. ASMR for all cancers combined ranged from 46.1 to 139.3 per 100,000. Among males, prostate cancers were the leading cause of cancer deaths, followed by lung cancers; the percentage of cancer deaths attributable to prostate cancer ranged from 18.4% in Suriname to 47.4% in Dominica, and the percentage of cancer deaths attributable to lung cancer ranged from 5.6% in Barbados to 24.4% in Bermuda. Among females, breast cancer was the most common cause of cancer deaths, ranging from 14.0% of cancer deaths in Belize to 29.7% in the Cayman Islands, followed by cervical cancer. Several of the leading causes of cancer deaths in the Caribbean can be reduced through primary and secondary preventions, including prevention of exposure to risk factors, screening, early detection, and timely and effective treatment. PMID- 27977637 TI - Genetic Polymorphism of CYP2C19 and Inhibitory Effects of Ticagrelor and Clopidogrel Towards Post-Percutaneous Coronary Intervention (PCI) Platelet Aggregation in Patients with Acute Coronary Syndromes. AB - BACKGROUND The aim of this study was to observe the effects of genetic polymorphism of CYP2C19 on inhibitory effects of ticagrelor (Tic) and clopidogrel (Clo) towards post-percutaneous coronary intervention (PCI) platelet aggregation (IPA) and major cardiovascular events (MACE) in patients with acute coronary syndromes (ACS). MATERIAL AND METHODS From August 2013 to March 2014, 166 patients with ACS undergoing PCI were selected. The patients were randomly grouped into the Tic group and the Clo group. IPA was detected by thromboelastography (TEG) at 1 week after taking the pills. Genotyping of CYP2C19 gene was determined by analysis of gene sequence detection. Patients were followed up for 1 month and MACE was observed. RESULTS The total IPA in the Clo group was significantly increased compared with the Tic group (P<0.05). The IPAs in the 3 subgroups of Clo group were all significantly increased compared with the 3 subgroups of the Tic group (all P<0.05). MACE was not significantly different between Clo and Tic groups (P>0.05). MACE had no significant difference among the 3 subgroups of the Tic group (P>0.05). MACE in the low metabolism subgroup of the Clo group was significantly increased compared with the fast metabolism subgroup and middle metabolism subgroup of Clo group (P<0.05). MACE was not significant different between the fast metabolism subgroup and the middle metabolism subgroup of the Clo group (P>0.05). MACE in the low metabolism subgroup of the Tic group was significantly decreased compared with the low metabolism subgroup of the Clo group (P<0.05). CONCLUSIONS Ticagrelor has a better effect on inhibition platelet aggregation than Clopidogrel in ACS patients undergoing PCI. PMID- 27977640 TI - Notes from the Field: New Delhi Metallo-beta-Lactamase-Producing Carbapenem Resistant Enterobacteriaceae Identified in Patients Without Known Health Care Risk Factors - Colorado, 2014-2016. PMID- 27977642 TI - QuickStats: Use of Equipment or Assistance* for Getting Around Among Persons Aged >=50 Years - National Health Interview Survey, 2014-2015?. AB - In 2014-2015, 13.9% of persons aged >=50 years used equipment or received assistance for getting around. Specifically, 9.6% of persons aged >=50 years used a cane or walking stick, 5.8% used a walker or Zimmer frame, and 5.3% had assistance from another person. Wheelchairs or scooters were used by 3.5%, crutches by 0.7%, and artificial limbs by 0.6%. PMID- 27977641 TI - Monitoring of Persons with Risk for Exposure to Ebola Virus - United States, November 3, 2014-December 27, 2015. AB - During November 3, 2014-December 27, 2015, CDC implemented guidance on movement and monitoring of persons in the United States with potential exposure to Ebola virus (Ebola) (1). Monitoring was concluded in December 2015. After CDC modified the guidance for monitoring travelers from Guinea (the last country for which monitoring of travelers was recommended) in late December 2015, jurisdictional reports were no longer collected by CDC. This report documents the number of persons monitored as part of the effort to isolate, test, and, if necessary, treat symptomatic travelers and other persons in the United States who had risk for exposure to Ebola during the period the guidance was in effect. Sixty jurisdictions, including all 50 states, two local jurisdictions, and eight territories and freely associated states, reported a total of 29,789 persons monitored, with >99% completing 21-day monitoring with no loss to follow-up exceeding 48 hours. No confirmed cases of imported Ebola were reported once monitoring was initiated. This landmark public health response demonstrates the robust infrastructure and sustained monitoring capacity of local, state, and territorial health authorities in the United States as a part of a response to an international public health emergency. PMID- 27977643 TI - Use of a 2-Dose Schedule for Human Papillomavirus Vaccination - Updated Recommendations of the Advisory Committee on Immunization Practices. AB - Vaccination against human papillomavirus (HPV) is recommended to prevent HPV infections and HPV-associated diseases, including cancers. Routine vaccination at age 11 or 12 years has been recommended by the Advisory Committee on Immunization Practices (ACIP) since 2006 for females and since 2011 for males (1,2). This report provides recommendations and guidance regarding use of HPV vaccines and updates ACIP HPV vaccination recommendations previously published in 2014 and 2015 (1,2). This report includes new recommendations for use of a 2-dose schedule for girls and boys who initiate the vaccination series at ages 9 through 14 years. Three doses remain recommended for persons who initiate the vaccination series at ages 15 through 26 years and for immunocompromised persons. PMID- 27977644 TI - Assessing Change in Avian Influenza A(H7N9) Virus Infections During the Fourth Epidemic - China, September 2015-August 2016. AB - Since human infections with avian influenza A(H7N9) virus were first reported by the Chinese Center for Disease Control and Prevention (China CDC) in March 2013 (1), mainland China has experienced four influenza A(H7N9) virus epidemics. Prior investigations demonstrated that age and sex distribution, clinical features, and exposure history of A(H7N9) virus human infections reported during the first three epidemics were similar (2). In this report, epidemiology and virology data from the most recent, fourth epidemic (September 2015-August 2016) were compared with those from the three earlier epidemics. Whereas age and sex distribution and exposure history in the fourth epidemic were similar to those in the first three epidemics, the fourth epidemic demonstrated a greater proportion of infected persons living in rural areas, a continued spread of the virus to new areas, and a longer epidemic period. The genetic markers of mammalian adaptation and antiviral resistance remained similar across each epidemic, and viruses from the fourth epidemic remained antigenically well matched to current candidate vaccine viruses. Although there is no evidence of increased human-to-human transmissibility of A(H7N9) viruses, the continued geographic spread, identification of novel reassortant viruses, and pandemic potential of the virus underscore the importance of rigorous A(H7N9) virus surveillance and continued risk assessment in China and neighboring countries. PMID- 27977647 TI - Choose Wisely-is more always better? PMID- 27977645 TI - Preliminary Report of Microcephaly Potentially Associated with Zika Virus Infection During Pregnancy - Colombia, January-November 2016. AB - In Colombia, approximately 105,000 suspected cases of Zika virus disease (diagnosed based on clinical symptoms, regardless of laboratory confirmation) were reported during August 9, 2015-November 12, 2016, including nearly 20,000 in pregnant women (1,2). Zika virus infection during pregnancy is a known cause of microcephaly and serious congenital brain abnormalities and has been associated with other birth defects related to central nervous system damage (3). Colombia's Instituto Nacional de Salud (INS) maintains national surveillance for birth defects, including microcephaly and other central nervous system defects. This report provides preliminary information on cases of congenital microcephaly identified in Colombia during epidemiologic weeks 5-45 (January 31-November 12) in 2016. During this period, 476 cases of microcephaly were reported, compared with 110 cases reported during the same period in 2015. The temporal association between reported Zika virus infections and the occurrence of microcephaly, with the peak number of reported microcephaly cases occurring approximately 24 weeks after the peak of the Zika virus disease outbreak, provides evidence suggesting that the period of highest risk is during the first trimester of pregnancy and early in the second trimester of pregnancy. Microcephaly prevalence increased more than fourfold overall during the study period, from 2.1 per 10,000 live births in 2015 to 9.6 in 2016. Ongoing population-based birth defects surveillance is essential for monitoring the impact of Zika virus infection during pregnancy on birth defects prevalence and measuring the success in preventing Zika virus infection and its consequences, including microcephaly. PMID- 27977646 TI - How 'modifiable' are 'modifiable risk factors' for cancer? PMID- 27977648 TI - Modifiable lifestyle factors that could reduce the incidence of colorectal cancer in New Zealand. AB - AIM: To estimate population attributable fractions for modifiable lifestyle factors and colorectal cancer in New Zealand. METHOD: Relative risks for lifestyle risk factors for colorectal cancer, and population data on the prevalence of exposure in New Zealand, were used to estimate the population attributable fraction (PAF) for each risk factor. RESULTS: Six modifiable lifestyle risk factors were identified. The PAFs for these risk factors were 9% for obesity, 7% for alcohol, 4% for physical inactivity, 3% for smoking, 5% for consumption of red meat and 3% for processed meat. PAFs differed by ethnic group and sex. In women, the highest PAFs were 19% for obesity in Pacific women, 14% for obesity in Maori women, 7% for physical inactivity in Asian women, and 8% for obesity in European/other women. In men, the highest PAFs were 17% for obesity in Pacific men, 14% for high alcohol consumption in Maori men, 5% for physical inactivity in Asian men and 9% for high alcohol consumption in European/other men. CONCLUSION: If obesity, alcohol consumption, smoking and consumption of red and processed meats could be reduced, and physical activity could be increased among New Zealanders, it would reduce the risk of colorectal cancer considerably. PMID- 27977649 TI - Medicines information in New Zealand: current services and future potential. AB - AIM: To determine the current availability and role of medicines information services in New Zealand. METHOD: A 36-question online survey was used to collect quantitative data about four areas of medicines information service provision: structure, availability, users and governance. The pharmacy service leader of each of the 29 public hospitals was invited by e-mail to participate. If considered appropriate, another member of the pharmacy staff could be nominated to complete the survey on their behalf. RESULTS: The response rate was 93% (n=27). All respondents accept medicines information questions from health professionals within their local hospital, with a large proportion (85%) also accepting questions from health professionals from primary care. However, active promotion of medicines information services is rare, and health professionals within local hospitals are the most frequent service users. Although six hospitals have a formal service with dedicated staff, medicines information provision by hospital pharmacists in New Zealand is predominantly informal. CONCLUSION: The full potential of formal medicines information services is yet to be realised in New Zealand. Greater national co-ordination could enhance access to medicines information support and contribute positively to the safe and effective use of medicines across the health system. PMID- 27977650 TI - Key informant views on biobanking and genomic research with Maori. AB - The aim of the Te Mata Ira project was to explore Maori views on biobanking and genomic research, and to identify ways to address Maori concerns over the collection and use of human tissue. Key informant interviews and workshops were conducted with Maori to identify Maori views in relation to biobanking and genomic research; and, informed by these views, interviews and workshops were conducted with Maori and non-Maori key informants (Indigenous Advisory Panel (IAP) members and science communities) to explore key issues in relation to Maori participation in biobanking and genomic research. Maori key informants identified the following as key deliberations: (1) the tension for Maori between previous well-publicised negative experiences with genomic research and the potential value for whanau and communities as technologies develop, (2) protection of Maori rights and interest, (3) focus on Maori health priorities, (4) control of samples and data, (5) expectations of consultation and consent and (6) a desire for greater feedback and communication. Maori and non-Maori key informants highlighted the need to enhance levels of Maori participation in the governance of genomic research and biobanking initiatives, and acknowledged that only by increasing the level of transparency and accountability in relation to these activities will Maori communities feel that their whakapapa, rights and interests are being appropriately protected. PMID- 27977651 TI - Socio-demographic characteristics of New Zealand adult smokers, ex-smokers and non-smokers: results from the 2013 Census. AB - AIM: To describe the smoking prevalence by key socio-demographic characteristics (age, gender, ethnicity, education, labour status, income and socioeconomic deprivation) in New Zealand in 2013 and make comparisons with 2006. METHOD: Data on cigarette smoking and key socio-demographics variables were obtained from the 2013 New Zealand Census of Population and Dwellings. Age standardised smoking prevalence rates were calculated by gender, ethnicity and socioeconomic deprivation using the WHO Population Standard. Results were compared against 2006 Census data to identify changes in smoking prevalence. RESULTS: In 2013, around one in seven (15.1%) of New Zealand adults aged 15 years and older reported that they were regular smokers (smoked one or more cigarettes per day), a 5.6% absolute decrease in the smoking prevalence since the previous Census in 2006. The number of regular adult smokers dropped from 597,792 in 2006 to 463,194 in 2013, a 22.5% decrease. Falls in smoking prevalence occurred among all demographic sub-groups, including Maori and young adults. There were substantial disparities in smoking by age, ethnicity and socio-economic status. Maori continue to have the highest age-standardised smoking prevalence (32.4%), with the highest prevalence (43.1%) among young Maori women aged 25 to 29 years. Decreases in smoking prevalence were greater between 2006 and 2013 than between 1996 and 2006. CONCLUSION: The findings suggest that the decline in smoking prevalence is accelerating in New Zealand, including among high priority groups like Maori, Pacific peoples and young adults. This study confirms the value of census data for understanding patterns of tobacco use in New Zealand, to inform effective intervention development and monitoring progress towards the Smokefree 2025 goal. PMID- 27977652 TI - Auckland: city of syphilis? AB - AIMS: To briefly report on the large increase in cases of syphilis managed at Auckland Regional Sexual Health Service (ARSHS) in 2015. To raise awareness of syphilis as an emerging significant public health issue in Auckland. METHOD: A search was conducted of the electronic patient management system at ARSHS for cases of syphilis diagnosed between 1st of January 2015 and 31st of December 2015. Those that fitted the Institute of Environmental Science and Research Ltd (ESR) case definitions for infectious syphilis were included and demographic, clinical and behavioural characteristics were described. RESULTS: One hundred and fifty-two cases of infectious syphilis were managed at ARSHS in 2015, which was a 78% increase from the previous year. The crude incidence rate was 9.5 cases per 100,000 head of population. As in previous years, the majority of cases were male (92%) and most of these were gay or bisexual men (GBM). Thirty-nine percent of cases were asymptomatic and 22% of cases were diagnosed with another STI. Twenty eight percent of GBM were co-infected with HIV. While the overall number of heterosexual cases was small (n=35); there was a 3.8-fold increase from the numbers diagnosed in 2014 (n=9). CONCLUSION: The largest number of syphilis cases in recent decades was managed by the Auckland Regional Sexual Health Service in 2015. The increase in numbers is concerning as syphilis can enhance transmission and acquisition of HIV. Furthermore, other countries have noted increases in congenital syphilis cases when incidence in females has increased. It is important that all persons at risk of STI are tested for syphilis and that sexually active GBM in particular are tested regularly. Health professionals need to be made aware of who and when to test, and to refer or discuss any suspected cases with a specialist service as management of syphilis requires significant expertise. PMID- 27977653 TI - Elective surgical outcomes of patients in Christchurch, New Zealand. AB - AIM: Most studies assessing mortality after surgery have been undertaken in major public hospitals or are procedure specific. The aim of this study was to determine mortality after elective surgery at a total community level with inclusion of all patients undergoing elective surgery. METHOD: This was a prospective study of all patients that underwent elective surgery in Christchurch, New Zealand, within a calendar month. For each patient, we collected demographic data, American Society of Anaesthesiologists physical status classification (ASA), type of anaesthetic and surgical specialty. The primary outcome was 30-day mortality and the secondary outcome was 90-day mortality. RESULTS: Four thousand seven hundred and fifteen patients were included in this study. Two thousand five hundred and seventy-eight (55%) were female and the median age was 56 years (range 0-99 years). Three thousand one hundred and forty-two (67%) patients had a general anaesthetic. By day 30, 11 (0.2%) patients had died and by day 90, 27 (0.6%) patients had died. Of the 27 deaths within 90 days after surgery, one was possibly anaesthesia-related (0.02%), while the majority were due to progression of disease (18). CONCLUSION: This study shows a lower mortality than what has previously been reported for elective surgical procedures when the denominator is the total community number of operations. PMID- 27977654 TI - The New Zealand Health Strategy 2016: whither health equity? AB - New Zealand's core health policy document-the New Zealand Health Strategy (NZHS) was released in its final form in April 2016. This paper provides a critique of the strategy in particular, as it relates to health equity particularly for Maori. We introduce the five NZHS themes of-people powered, closer to home, value and high performance, one team and smart system-to focus on the aspirational goal of eliminating health inequities. Our critical framework is informed by Te Tiriti o Waitangi. We identified that the NZHS relies on the isolated efforts of committed individuals and organisations to achieve health equity and Te Tiriti engagement, rather than through a planned systems viewpoint. Evidence on health equity and Te Tiriti application suggests efforts need to be sustained, systematic and multi-levelled to be successful, rather than ad hoc and piecemeal. PMID- 27977655 TI - Financing the Canterbury Health System post-disaster. AB - The Canterbury Health System has invested substantially in its transformation to a patient-centred, integrated system, enabling improved performance despite the significant and long-term impacts of the Christchurch earthquakes in 2010 and 2011. Questions have been raised about whether this transformation is sustainable and affordable. We argue that there is a need for a post-disaster health funding strategy that takes into account the challenge of following population movements after a large natural disaster, and higher costs resulting from the disruption and the effect on the population. Such a strategy should also provide stability in an unstable environment. However, funding for health in Canterbury has followed a 'business as usual' model using the population-based funding formula, which we view as problematic. Additionally, increases in funding using that formula have been below the national average, which we believe is perverse. Canterbury has received an additional $84 million government in deficit funding since 2010/11, and this has covered part of the extra cost attributable to the earthquake. However, without system-wide integration and innovation that was underway before, and that has continued since the earthquakes, it is likely the Canterbury Health System would not have been able to meet the health needs of its population. If health funding for Canterbury had continued to increase at the average rate applied across New Zealand over the past five years, deficit funding would not have been required. PMID- 27977656 TI - Tenosynovitis due to pseudogout. AB - A 93-year-old woman acutely developed fever associated with pain and swelling around her left wrist. Physical examination revealed fusiform symmetric swelling of the entire digits, digits held in partial flexion, tenderness along the flexor tendon sheath and pain along the tendon with passive digits extension. Gram stain of collected fluid showed the presence of calcium pyrophosphate dihydrate crystals. PMID- 27977657 TI - Delayed recovery of adipsic diabetes insipidus (ADI) caused by elective clipping of anterior communicating artery and left middle cerebral artery aneurysms. AB - Adipsic diabetes insipidus (ADI) is an extremely rare complication following microsurgical clipping of anterior communicating artery aneurysm (ACoA) and left middle cerebral artery (MCA) aneurysm. It poses a significant challenge to manage due to an absent thirst response and the co-existence of cognitive impairment in our patient. Recovery from adipsic DI has hitherto been reported only once. A 52 year-old man with previous history of clipping of left posterior communicating artery aneurysm 20 years prior underwent microsurgical clipping of ACoA and left MCA aneurysms without any intraoperative complications. Shortly after surgery, he developed clear features of ADI with adipsic severe hypernatraemia and hypotonic polyuria, which was associated with cognitive impairment that was confirmed with biochemical investigations and cognitive assessments. He was treated with DDAVP along with a strict intake of oral fluids at scheduled times to maintain eunatremia. Repeat assessment at six months showed recovery of thirst and a normal water deprivation test. Management of ADI with cognitive impairment is complex and requires a multidisciplinary approach. Recovery from ADI is very rare, and this is only the second report of recovery in this particular clinical setting. PMID- 27977658 TI - A case of bariatric surgery during pregnancy. PMID- 27977659 TI - Prevalence of post-menopausal hormone use in New Zealand women. PMID- 27977660 TI - Urinary alkalisers for cystitis-fact or fiction? PMID- 27977661 TI - Response to-Combating antimicrobial resistance demands nationwide action and global governance. PMID- 27977662 TI - Global governance is a key part of the solution to antimicrobial resistance (response to Gravatt). PMID- 27977663 TI - Getting Road Expansion on the Right Track: A Framework for Smart Infrastructure Planning in the Mekong. AB - The current unprecedented expansion of infrastructure promises to enhance human wellbeing but risks causing substantial harm to natural ecosystems and the benefits they provide for people. A framework for systematically and proactively identifying the likely benefits and costs of such developments is badly needed. Here, we develop and test at the subregional scale a recently proposed global scheme for comparing the potential gains from new roads for food production with their likely impact on biodiversity and ecosystem services. Working in the Greater Mekong-an exceptionally biodiverse subregion undergoing rapid development we combined maps of isolation from urban centres, yield gaps, and the current area under 17 crops to estimate where and how far road development could in principle help to increase food production without the need for cropland expansion. We overlaid this information with maps summarising the importance of remaining habitats to terrestrial vertebrates and (as examples of major ecosystem services) to global and local climate regulation. This intersection revealed several largely converted yet relatively low-yielding areas (such as central, eastern, and northeastern Thailand and the Ayeyarwady Delta), where narrowing yield gaps by improving transport links has the potential to substantially increase food production at relatively limited environmental cost. Concentrating new roads and road improvements here while taking strong measures to prevent their spread into areas which are still extensively forested (such as northern Laos, western Yunnan, and southwestern Cambodia) could thus enhance rural livelihoods and regional food production while helping safeguard vital ecosystem services and globally significant biological diversity. PMID- 27977665 TI - Hierarchical Post-transcriptional Regulation of Colicin E2 Expression in Escherichia coli. AB - Post-transcriptional regulation of gene expression plays a crucial role in many bacterial pathways. In particular, the translation of mRNA can be regulated by trans-acting, small, non-coding RNAs (sRNAs) or mRNA-binding proteins, each of which has been successfully treated theoretically using two-component models. An important system that includes a combination of these modes of post transcriptional regulation is the Colicin E2 system. DNA damage, by triggering the SOS response, leads to the heterogeneous expression of the Colicin E2 operon including the cea gene encoding the toxin colicin E2, and the cel gene that codes for the induction of cell lysis and release of colicin. Although previous studies have uncovered the system's basic regulatory interactions, its dynamical behavior is still unknown. Here, we develop a simple, yet comprehensive, mathematical model of the colicin E2 regulatory network, and study its dynamics. Its post transcriptional regulation can be reduced to three hierarchically ordered components: the mRNA including the cel gene, the mRNA-binding protein CsrA, and an effective sRNA that regulates CsrA. We demonstrate that the stationary state of this system exhibits a pronounced threshold in the abundance of free mRNA. As post-transcriptional regulation is known to be noisy, we performed a detailed stochastic analysis, and found fluctuations to be largest at production rates close to the threshold. The magnitude of fluctuations can be tuned by the rate of production of the sRNA. To study the dynamics in response to an SOS signal, we incorporated the LexA-RecA SOS response network into our model. We found that CsrA regulation filtered out short-lived activation peaks and caused a delay in lysis gene expression for prolonged SOS signals, which is also seen in experiments. Moreover, we showed that a stochastic SOS signal creates a broad lysis time distribution. Our model thus theoretically describes Colicin E2 expression dynamics in detail and reveals the importance of the specific regulatory components for the timing of toxin release. PMID- 27977666 TI - Lack of Ecological and Life History Context Can Create the Illusion of Social Interactions in Dictyostelium discoideum. AB - Studies of social microbes often focus on one fitness component (reproductive success within the social complex), with little information about or attention to other stages of the life cycle or the ecological context. This can lead to paradoxical results. The life cycle of the social amoeba Dictyostelium discoideum includes a multicellular stage in which not necessarily clonal amoebae aggregate upon starvation to form a possibly chimeric (genetically heterogeneous) fruiting body made of dead stalk cells and spores. The lab-measured reproductive skew in the spores of chimeras indicates strong social antagonism that should result in low genotypic diversity, which is inconsistent with observations from nature. Two studies have suggested that this inconsistency stems from the one-dimensional assessment of fitness (spore production) and that the solution lies in tradeoffs between multiple life-history traits, e.g.: spore size versus viability; and spore-formation (via aggregation) versus staying vegetative (as non-aggregated cells). We develop an ecologically-grounded, socially-neutral model (i.e. no social interactions between genotypes) for the life cycle of social amoebae in which we theoretically explore multiple non-social life-history traits, tradeoffs and tradeoff-implementing mechanisms. We find that spore production comes at the expense of time to complete aggregation, and, depending on the experimental setup, spore size and viability. Furthermore, experimental results regarding apparent social interactions within chimeric mixes can be qualitatively recapitulated under this neutral hypothesis, without needing to invoke social interactions. This allows for simple potential resolutions to the previously paradoxical results. We conclude that the complexities of life histories, including social behavior and multicellularity, can only be understood in the appropriate multidimensional ecological context, when considering all stages of the life cycle. PMID- 27977664 TI - Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity. AB - Neurodegenerative lysosomal storage disorders (LSDs) are severe and untreatable, and mechanisms underlying cellular dysfunction are poorly understood. We found that toxic lipids relevant to three different LSDs disrupt multiple lysosomal and other cellular functions. Unbiased drug discovery revealed several structurally distinct protective compounds, approved for other uses, that prevent lysosomal and cellular toxicities of these lipids. Toxic lipids and protective agents show unexpected convergence on control of lysosomal pH and re-acidification as a critical component of toxicity and protection. In twitcher mice (a model of Krabbe disease [KD]), a central nervous system (CNS)-penetrant protective agent rescued myelin and oligodendrocyte (OL) progenitors, improved motor behavior, and extended lifespan. Our studies reveal shared principles relevant to several LSDs, in which diverse cellular and biochemical disruptions appear to be secondary to disruption of lysosomal pH regulation by specific lipids. These studies also provide novel protective strategies that confer therapeutic benefits in a mouse model of a severe LSD. PMID- 27977667 TI - Universal or Specific? A Modeling-Based Comparison of Broad-Spectrum Influenza Vaccines against Conventional, Strain-Matched Vaccines. AB - Despite the availability of vaccines, influenza remains a major public health challenge. A key reason is the virus capacity for immune escape: ongoing evolution allows the continual circulation of seasonal influenza, while novel influenza viruses invade the human population to cause a pandemic every few decades. Current vaccines have to be updated continually to keep up to date with this antigenic change, but emerging 'universal' vaccines-targeting more conserved components of the influenza virus-offer the potential to act across all influenza A strains and subtypes. Influenza vaccination programmes around the world are steadily increasing in their population coverage. In future, how might intensive, routine immunization with novel vaccines compare against similar mass programmes utilizing conventional vaccines? Specifically, how might novel and conventional vaccines compare, in terms of cumulative incidence and rates of antigenic evolution of seasonal influenza? What are their potential implications for the impact of pandemic emergence? Here we present a new mathematical model, capturing both transmission dynamics and antigenic evolution of influenza in a simple framework, to explore these questions. We find that, even when matched by per dose efficacy, universal vaccines could dampen population-level transmission over several seasons to a greater extent than conventional vaccines. Moreover, by lowering opportunities for cross-protective immunity in the population, conventional vaccines could allow the increased spread of a novel pandemic strain. Conversely, universal vaccines could mitigate both seasonal and pandemic spread. However, where it is not possible to maintain annual, intensive vaccination coverage, the duration and breadth of immunity raised by universal vaccines are critical determinants of their performance relative to conventional vaccines. In future, conventional and novel vaccines are likely to play complementary roles in vaccination strategies against influenza: in this context, our results suggest important characteristics to monitor during the clinical development of emerging vaccine technologies. PMID- 27977668 TI - Magnetic Resonance Spectroscopy for Evaluating Portal-Systemic Encephalopathy in Patients with Chronic Hepatic Schistosomiasis Japonicum. AB - Portal-systemic encephalopathy (PSE) is classified as type B hepatic encephalopathy. Portal-systemic shunting rather than liver dysfunction is the main cause of PSE in chronic hepatic schistosomiasis japonicum (HSJ) patients. Owing to lack of detectable evidence of intrinsic liver disease, chronic HSJ patients with PSE are frequently clinically undetected or misdiagnosed, especially chronic HSJ patients with covert PSE (subclinical encephalopathy). In this study, we investigated whether magnetic resonance spectroscopy (MRS) could be a useful tool for diagnosing PSE in chronic HSJ patients. Magnetic resonance (MR) T1-weighted imaging, diffusion-weighted imaging, and MRS were performed in 41 chronic HSJ patients with suspected PSE and in 21 age-matched controls. The T1 signal intensity index (T1SI) and apparent diffusion coefficient (ADC) value were obtained in the Globus pallidus. Liver function was also investigated via serum ammonia and liver function tests. Higher T1SI and ADC values, increased lactate and glutamine levels, and decreased myo-inositol were found in the bilateral Globus pallidus in chronic HSJ patients with PSE. No significantly abnormal serum ammonia or liver function tests were observed in chronic HSJ patients with PSE. On the basis of these findings, we propose a diagnostic procedure for PSE in chronic HSJ patients. This study reveals that MRS can be useful for diagnosing PSE in chronic HSJ patients. PMID- 27977670 TI - Serological Evidence of Contrasted Exposure to Arboviral Infections between Islands of the Union of Comoros (Indian Ocean). AB - A cross sectional serological survey of arboviral infections in humans was conducted on the three islands of the Union of Comoros, Indian Ocean, in order to test a previously suggested contrasted exposure of the three neighboring islands to arthropod-borne epidemics. Four hundred human sera were collected on Ngazidja (Grande Comore), Mwali (Moheli) and Ndzouani (Anjouan), and were tested by ELISA for IgM and/or IgG antibodies to Dengue (DENV), Chikungunya (CHIKV), Rift Valley fever (RVFV), West Nile (WNV), Tick borne encephalitis (TBEV) and Yellow fever (YFV) viruses and for neutralizing antibodies to DENV serotypes 1-4. Very few sera were positive for IgM antibodies to the tested viruses indicating that the sero-survey was performed during an inter epidemic phase for the investigated arbovirus infections, except for RVF which showed evidence of recent infections on all three islands. IgG reactivity with at least one arbovirus was observed in almost 85% of tested sera, with seropositivity rates increasing with age, indicative of an intense and long lasting exposure of the Comorian population to arboviral risk. Interestingly, the positivity rates for IgG antibodies to DENV and CHIKV were significantly higher on Ngazidja, confirming the previously suggested prominent exposure of this island to these arboviruses, while serological traces of WNV infection were detected most frequently on Mwali suggesting some transmission specificities associated with this island only. The study provides the first evidence for circulation of RVFV in human populations from the Union of Comoros and further suggests that the virus is currently circulating on the three islands in an inconspicuous manner. This study supports contrasted exposure of the islands of the Comoros archipelago to arboviral infections. The observation is discussed in terms of ecological factors that may affect the abundance and distribution of vector populations on the three islands as well as concurring anthropogenic factors that may impact arbovirus transmission in this diverse island ecosystem. PMID- 27977669 TI - On the Spatial Organization of mRNA, Plasmids, and Ribosomes in a Bacterial Host Overexpressing Membrane Proteins. AB - By using fluorescence imaging, we provide a time-resolved single-cell view on coupled defects in transcription, translation, and growth during expression of heterologous membrane proteins in Lactococcus lactis. Transcripts encoding poorly produced membrane proteins accumulate in mRNA-dense bodies at the cell poles, whereas transcripts of a well-expressed homologous membrane protein show membrane proximal localization in a translation-dependent fashion. The presence of the aberrant polar mRNA foci correlates with cessation of cell division, which is restored once these bodies are cleared. In addition, activation of the heat-shock response and a loss of nucleoid-occluded ribosomes are observed. We show that the presence of a native-like N-terminal domain is key to SRP-dependent membrane localization and successful production of membrane proteins. The work presented gives new insights and detailed understanding of aberrant membrane protein biogenesis, which can be used for strategies to optimize membrane protein production. PMID- 27977671 TI - Potential for Zika Virus to Establish a Sylvatic Transmission Cycle in the Americas. AB - Zika virus (ZIKV) originated and continues to circulate in a sylvatic transmission cycle between non-human primate hosts and arboreal mosquitoes in tropical Africa. Recently ZIKV invaded the Americas, where it poses a threat to human health, especially to pregnant women and their infants. Here we examine the risk that ZIKV will establish a sylvatic cycle in the Americas, focusing on Brazil. We review the natural history of sylvatic ZIKV and present a mathematical dynamic transmission model to assess the probability of establishment of a sylvatic ZIKV transmission cycle in non-human primates and/or other mammals and arboreal mosquito vectors in Brazil. Brazil is home to multiple species of primates and mosquitoes potentially capable of ZIKV transmission, though direct assessment of host competence (ability to mount viremia sufficient to infect a feeding mosquito) and vector competence (ability to become infected with ZIKV and disseminate and transmit upon subsequent feedings) of New World species is lacking. Modeling reveals a high probability of establishment of sylvatic ZIKV across a large range of biologically plausible parameters. Probability of establishment is dependent on host and vector population sizes, host birthrates, and ZIKV force of infection. Research on the host competence of New World monkeys or other small mammals to ZIKV, on vector competence of New World Aedes, Sabethes, and Haemagogus mosquitoes for ZIKV, and on the geographic range of potential New World hosts and vectors is urgently needed. A sylvatic cycle of ZIKV would make future elimination efforts in the Americas practically impossible, and paints a dire picture for the epidemiology of ZIKV and our ability to end the ongoing outbreak of congenital Zika syndrome. PMID- 27977672 TI - Unique Function of the Bacterial Chromosome Segregation Machinery in Apically Growing Streptomyces - Targeting the Chromosome to New Hyphal Tubes and its Anchorage at the Tips. AB - The coordination of chromosome segregation with cell growth is fundamental to the proliferation of any organism. In most unicellular bacteria, chromosome segregation is strictly coordinated with cell division and involves ParA that moves the ParB nucleoprotein complexes bi- or unidirectionally toward the cell pole(s). However, the chromosome organization in multiploid, apically extending and branching Streptomyces hyphae challenges the known mechanisms of bacterial chromosome segregation. The complex Streptomyces life cycle involves two stages: vegetative growth and sporulation. In the latter stage, multiple cell divisions accompanied by chromosome compaction and ParAB assisted segregation turn multigenomic hyphal cell into a chain of unigenomic spores. However, the requirement for active chromosome segregation is unclear in the absence of canonical cell division during vegetative growth except in the process of branch formation. The mechanism by which chromosomes are targeted to new hyphae in streptomycete vegetative growth has remained unknown until now. Here, we address the question of whether active chromosome segregation occurs at this stage. Applied for the first time in Streptomyces, labelling of the chromosomal replication initiation region (oriC) and time-lapse microscopy, revealed that in vegetative hyphae every copy of the chromosome is complexed with ParB, whereas ParA, through interaction with the apical protein complex (polarisome), tightly anchors only one chromosome at the hyphal tip. The anchor is maintained during replication, when ParA captures one of the daughter oriCs. During spore germination and branching, ParA targets one of the multiple chromosomal copies to the new hyphal tip, enabling efficient elongation of hyphal tube. Thus, our studies reveal a novel role for ParAB proteins during hyphal tip establishment and extension. PMID- 27977673 TI - Mutation Rate Variation is a Primary Determinant of the Distribution of Allele Frequencies in Humans. AB - The site frequency spectrum (SFS) has long been used to study demographic history and natural selection. Here, we extend this summary by examining the SFS conditional on the alleles found at the same site in other species. We refer to this extension as the "phylogenetically-conditioned SFS" or cSFS. Using recent large-sample data from the Exome Aggregation Consortium (ExAC), combined with primate genome sequences, we find that human variants that occurred independently in closely related primate lineages are at higher frequencies in humans than variants with parallel substitutions in more distant primates. We show that this effect is largely due to sites with elevated mutation rates causing significant departures from the widely-used infinite sites mutation model. Our analysis also suggests substantial variation in mutation rates even among mutations involving the same nucleotide changes. In summary, we show that variable mutation rates are key determinants of the SFS in humans. PMID- 27977676 TI - Improved Genetic Profiling of Anthropometric Traits Using a Big Data Approach. AB - Genome-wide association studies (GWAS) promised to translate their findings into clinically beneficial improvements of patient management by tailoring disease management to the individual through the prediction of disease risk. However, the ability to translate genetic findings from GWAS into predictive tools that are of clinical utility and which may inform clinical practice has, so far, been encouraging but limited. Here we propose to use a more powerful statistical approach, the use of which has traditionally been limited due to computational requirements and lack of sufficiently large individual level genotyped cohorts, but which improve the prediction of multiple medically relevant phenotypes using the same panel of SNPs. As a proof of principle, we used a shared panel of 319,038 common SNPs with MAF > 0.05 to train the prediction models in 114,264 unrelated White-British individuals for height and four obesity related traits (body mass index, basal metabolic rate, body fat percentage, and waist-to-hip ratio). We obtained prediction accuracies that ranged between 46% and 75% of the maximum achievable given the captured heritable component. For height, this represents an improvement in prediction accuracy of up to 68% (184% more phenotypic variance explained) over SNPs reported to be robustly associated with height in a previous GWAS meta-analysis of similar size. Across-population predictions in White non-British individuals were similar to those in White British whilst those in Asian and Black individuals were informative but less accurate. We estimate that the genotyping of circa 500,000 unrelated individuals will yield predictions between 66% and 82% of the SNP-heritability captured by common variants in our array. Prediction accuracies did not improve when including rarer SNPs or when fitting multiple traits jointly in multivariate models. PMID- 27977675 TI - Macrolide Antibiotics Exhibit Cytotoxic Effect under Amino Acid-Depleted Culture Condition by Blocking Autophagy Flux in Head and Neck Squamous Cell Carcinoma Cell Lines. AB - Autophagy, a self-digestive system for cytoplasmic components, is required to maintain the amino acid pool for cellular homeostasis. We previously reported that the macrolide antibiotics azithromycin (AZM) and clarithromycin (CAM) have an inhibitory effect on autophagy flux, and they potently enhance the cytocidal effect of various anticancer reagents in vitro. This suggests that macrolide antibiotics can be used as an adjuvant for cancer chemotherapy. Since cancer cells require a larger metabolic demand than normal cells because of their exuberant growth, upregulated autophagy in tumor cells has now become the target for cancer therapy. In the present study, we examined whether macrolides exhibit cytotoxic effect under an amino acid-starving condition in head and neck squamous cancer cell lines such as CAL 27 and Detroit 562 as models of solid tumors with an upregulated autophagy in the central region owing to hypovascularity. AZM and CAM induced cell death under the amino acid-depleted (AAD) culture condition in these cell lines along with CHOP upregulation, although they showed no cytotoxicity under the complete culture medium. CHOP knockdown by siRNA in the CAL 27 cells significantly suppressed macrolide-induced cell death under the AAD culture condition. CHOP-/- murine embryonic fibroblast (MEF) cell lines also attenuated AZM-induced cell death compared with CHOP+/+ MEF cell lines. Using a tet-off atg5 MEF cell line, knockout of atg5, an essential gene for autophagy, also induced cell death and CHOP in the AAD culture medium but not in the complete culture medium. This suggest that macrolide-induced cell death via CHOP induction is dependent on autophagy inhibition. The cytotoxicity of macrolide with CHOP induction was completely cancelled by the addition of amino acids in the culture medium, indicating that the cytotoxicity is due to the insufficient amino acid pool. These data suggest the possibility of using macrolides for "tumor-starving therapy". PMID- 27977674 TI - Genetic Evidence of Contemporary Dispersal of the Intermediate Snail Host of Schistosoma japonicum: Movement of an NTD Host Is Facilitated by Land Use and Landscape Connectivity. AB - BACKGROUND: While the dispersal of hosts and vectors-through active or passive movement-is known to facilitate the spread and re-emergence of certain infectious diseases, little is known about the movement ecology of Oncomelania spp., intermediate snail host of the parasite Schistosoma japonicum, and its consequences for the spread of schistosomiasis in East and Southeast Asia. In China, despite intense control programs aimed at preventing schistosomiasis transmission, there is evidence in recent years of re-emergence and persistence of infection in some areas, as well as an increase in the spatial extent of the snail host. A quantitative understanding of the dispersal characteristics of the intermediate host can provide new insights into the spatial dynamics of transmission, and can assist public health officials in limiting the geographic spread of infection. METHODOLOGY/PRINCIPAL FINDINGS: Oncomelania hupensis robertsoni snails (n = 833) were sampled from 29 sites in Sichuan, China, genotyped, and analyzed using Bayesian assignment to estimate the rate of recent snail migration across sites. Landscape connectivity between each site pair was estimated using the geographic distance distributions derived from nine environmental models: Euclidean, topography, incline, wetness, land use, watershed, stream use, streams and channels, and stream velocity. Among sites, 14.4% to 32.8% of sampled snails were identified as recent migrants, with 20 sites comprising >20% migrants. Migration rates were generally low between sites, but at 8 sites, over 10% of the overall host population originated from one proximal site. Greater landscape connectivity was significantly associated with increased odds of migration, with the minimum path distance (as opposed to median or first quartile) emerging as the strongest predictor across all environmental models. Models accounting for land use explained the largest proportion of the variance in migration rates between sites. A greater number of irrigation channels leading into a site was associated with an increase in the site's propensity to both attract and retain snails. CONCLUSIONS/SIGNIFICANCE: Our findings have important implications for controlling the geographic spread of schistosomiasis in China, through improved understanding of the dispersal capacity of the parasite's intermediate host. PMID- 27977678 TI - Variations in Soil Microbial Biomass Carbon and Soil Dissolved Organic Carbon in the Re-Vegetation of Hilly Slopes with Purple Soil. AB - Crust restoration is increasingly being done but we lack quantitative information on soil improvements. The study aimed to elucidate the dynamics involving soil microbial biomass carbon and soil dissolved organic carbon in the re-vegetation chronosequences of a hillslope land with purple soil in Hengyang, Hunan Province. The soil can cause serious disasters with both soil erosion and seasonal drought, and also becomes a typical representative of ecological disaster area in South China. Using the space-for-time method, we selected six typical sampling plots, designated as follows: grassplot community, meadow thicket community, frutex community, frutex and arbor community, arbor community, and top-level vegetation community. These plots were established to analyze the changes in soil microbial biomass carbon, soil microbial quotien, dissolved organic carbon, dissolved organic carbon/soil organic carbon, and soil basal respiration in 0-10, 10-20, and 20-40 cm soil layers. The relationships of these parameters with soils physic chemical properties were also determined. The ecological environment of the 6 plant communities is similar and typical; they denoted six different successive stages of restoration on hillslopes with purple soils in Hengyang, Hunan Province. The soil microbial biomass carbon and soil basal respiration contents decreased with increasing soil depth but increased with re-vegetation. By contrast, soil microbial quotient increased with increasing soil depth and re vegetation. From 0-10 cm soil layer to 20-40 cm soil layer, the dissolved organic carbon content decreased in different re-vegetation stages. In the process of re vegetation, the dissolved organic carbon content increased in the 0-10 and 10-20 cm soil layers, whereas the dissolved organic carbon content decreased after an initial increase in the 20-40 cm soil layers. Meanwhile, dissolved organic carbon/soil organic carbon increased with increasing soil depth but decreased with re-vegetation. Significant correlations existed among soil microbial biomass carbon, soil microbial quotient, dissolved organic carbon, soil basal respiration and soil physic-chemical properties associated with soil fertility. The results showed that re-vegetation was conducive to the soil quality improvement and the accumulation of soil organic carbon pool of the hillslope land with purple soil in Hengyang, Hunan Province. PMID- 27977677 TI - Role of Autoregulation and Relative Synthesis of Operon Partners in Alternative Sigma Factor Networks. AB - Despite the central role of alternative sigma factors in bacterial stress response and virulence their regulation remains incompletely understood. Here we investigate one of the best-studied examples of alternative sigma factors: the sigmaB network that controls the general stress response of Bacillus subtilis to uncover widely relevant general design principles that describe the structure function relationship of alternative sigma factor regulatory networks. We show that the relative stoichiometry of the synthesis rates of sigmaB, its anti-sigma factor RsbW and the anti-anti-sigma factor RsbV plays a critical role in shaping the network behavior by forcing the sigmaB network to function as an ultrasensitive negative feedback loop. We further demonstrate how this negative feedback regulation insulates alternative sigma factor activity from competition with the housekeeping sigma factor for RNA polymerase and allows multiple stress sigma factors to function simultaneously with little competitive interference. PMID- 27977679 TI - An Extended Normalization Model of Attention Accounts for Feature-Based Attentional Enhancement of Both Response and Coherence Gain. AB - Paying attention to a sensory feature improves its perception and impairs that of others. Recent work has shown that a Normalization Model of Attention (NMoA) can account for a wide range of physiological findings and the influence of different attentional manipulations on visual performance. A key prediction of the NMoA is that attention to a visual feature like an orientation or a motion direction will increase the response of neurons preferring the attended feature (response gain) rather than increase the sensory input strength of the attended stimulus (input gain). This effect of feature-based attention on neuronal responses should translate to similar patterns of improvement in behavioral performance, with psychometric functions showing response gain rather than input gain when attention is directed to the task-relevant feature. In contrast, we report here that when human subjects are cued to attend to one of two motion directions in a transparent motion display, attentional effects manifest as a combination of input and response gain. Further, the impact on input gain is greater when attention is directed towards a narrow range of motion directions than when it is directed towards a broad range. These results are captured by an extended NMoA, which either includes a stimulus-independent attentional contribution to normalization or utilizes direction-tuned normalization. The proposed extensions are consistent with the feature-similarity gain model of attention and the attentional modulation in extrastriate area MT, where neuronal responses are enhanced and suppressed by attention to preferred and non-preferred motion directions respectively. PMID- 27977680 TI - A Hox-Embedded Long Noncoding RNA: Is It All Hot Air? PMID- 27977681 TI - Evaluation of a Powered Ankle-Foot Prosthesis during Slope Ascent Gait. AB - Passive prosthetic feet lack active plantarflexion and push-off power resulting in gait deviations and compensations by individuals with transtibial amputation (TTA) during slope ascent. We sought to determine the effect of active ankle plantarflexion and push-off power provided by a powered prosthetic ankle-foot (PWR) on lower extremity compensations in individuals with unilateral TTA as they walked up a slope. We hypothesized that increased ankle plantarflexion and push off power would reduce compensations commonly observed with a passive, energy storing-returning prosthetic ankle-foot (ESR). We compared the temporal spatial, kinematic, and kinetic measures of ten individuals with TTA (age: 30.2 +/- 5.3 yrs) to matched abled-bodied (AB) individuals during 5 degrees slope ascent. The TTA group walked with an ESR and separately with a PWR. The PWR produced significantly greater prosthetic ankle plantarflexion and push-off power generation compared to an ESR and more closely matched AB values. The PWR functioned similar to a passive ESR device when transitioning onto the prosthetic limb due to limited prosthetic dorsiflexion, which resulted in similar deviations and compensations. In contrast, when transitioning off the prosthetic limb, increased ankle plantarflexion and push-off power provided by the PWR contributed to decreased intact limb knee extensor power production, lessening demand on the intact limb knee. PMID- 27977683 TI - Hotair Is Dispensible for Mouse Development. AB - Despite the crucial importance of Hox genes functions during animal development, the mechanisms that control their transcription in time and space are not yet fully understood. In this context, it was proposed that Hotair, a lncRNA transcribed from within the HoxC cluster regulates Hoxd gene expression in trans, through the targeting of Polycomb and consecutive transcriptional repression. This activity was recently supported by the skeletal phenotype of mice lacking Hotair function. However, other loss of function alleles at this locus did not elicit the same effects. Here, we re-analyze the molecular and phenotypic consequences of deleting the Hotair locus in vivo. In contrast with previous findings, we show that deleting Hotair has no detectable effect on Hoxd genes expression in vivo. In addition, we were unable to observe any significant morphological alteration in mice lacking the Hotair transcript. However, we find a subtle impact of deleting the Hotair locus upon the expression of the neighboring Hoxc11 and Hoxc12 genes in cis. Our results do not support any substantial role for Hotair during mammalian development in vivo. Instead, they argue in favor of a DNA-dependent effect of the Hotair deletion upon the transcriptional landscape in cis. PMID- 27977682 TI - PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor Suppressive Versus Tumor Promoting Properties of PERK in Melanoma. AB - The unfolded protein response (UPR) regulates cell fate following exposure of cells to endoplasmic reticulum stresses. PERK, a UPR protein kinase, regulates protein synthesis and while linked with cell survival, exhibits activities associated with both tumor progression and tumor suppression. For example, while cells lacking PERK are sensitive to UPR-dependent cell death, acute activation of PERK triggers both apoptosis and cell cycle arrest, which would be expected to contribute tumor suppressive activity. We have evaluated these activities in the BRAF-dependent melanoma and provide evidence revealing a complex role for PERK in melanoma where a 50% reduction is permissive for BrafV600E-dependent transformation, while complete inhibition is tumor suppressive. Consistently, PERK mutants identified in human melanoma are hypomorphic with dominant inhibitory function. Strikingly, we demonstrate that small molecule PERK inhibitors exhibit single agent efficacy against BrafV600E-dependent tumors highlighting the clinical value of targeting PERK. PMID- 27977685 TI - Completing the Picture: Importance of Considering Participatory Mapping for REDD+ Measurement, Reporting and Verification (MRV). AB - Remote sensing has been widely used for mapping land cover and is considered key to monitoring changes in forest areas in the REDD+ Measurement, Reporting and Verification (MRV) system. But Remote Sensing as a desk study cannot capture the whole picture; it also requires ground checking. Therefore, complementing remote sensing analysis using participatory mapping can help provide information for an initial forest cover assessment, gain better understanding of how local land use might affect changes, and provide a way to engage local communities in REDD+. Our study looked at the potential of participatory mapping in providing complementary information for remotely sensed maps. The research sites were located in different ecological and socio-economic contexts in the provinces of Papua, West Kalimantan and Central Java, Indonesia. Twenty-one maps of land cover and land use were drawn with local community participation during focus group discussions in seven villages. These maps, covering a total of 270,000ha, were used to add information to maps developed using remote sensing, adding 39 land covers to the eight from our initial desk assessment. They also provided additional information on drivers of land use and land cover change, resource areas, territory claims and land status, which we were able to correlate to understand changes in forest cover. Incorporating participatory mapping in the REDD+ MRV protocol would help with initial remotely sensed land classifications, stratify an area for ground checks and measurement plots, and add other valuable social data not visible at the RS scale. Ultimately, it would provide a forum for local communities to discuss REDD+ activities and develop a better understanding of REDD+. PMID- 27977684 TI - Loss of RMI2 Increases Genome Instability and Causes a Bloom-Like Syndrome. AB - Bloom syndrome is a recessive human genetic disorder with features of genome instability, growth deficiency and predisposition to cancer. The only known causative gene is the BLM helicase that is a member of a protein complex along with topoisomerase III alpha, RMI1 and 2, which maintains replication fork stability and dissolves double Holliday junctions to prevent genome instability. Here we report the identification of a second gene, RMI2, that is deleted in affected siblings with Bloom-like features. Cells from homozygous individuals exhibit elevated rates of sister chromatid exchange, anaphase DNA bridges and micronuclei. Similar genome and chromosome instability phenotypes are observed in independently derived RMI2 knockout cells. In both patient and knockout cell lines reduced localisation of BLM to ultra fine DNA bridges and FANCD2 at foci linking bridges are observed. Overall, loss of RMI2 produces a partially active BLM complex with mild features of Bloom syndrome. PMID- 27977686 TI - Comment on "Hotair Is Dispensable for Mouse Development". PMID- 27977687 TI - NUCLEAR FACTOR Y, Subunit A (NF-YA) Proteins Positively Regulate Flowering and Act Through FLOWERING LOCUS T. AB - Photoperiod dependent flowering is one of several mechanisms used by plants to initiate the developmental transition from vegetative growth to reproductive growth. The NUCLEAR FACTOR Y (NF-Y) transcription factors are heterotrimeric complexes composed of NF-YA and histone-fold domain (HFD) containing NF-YB/NF-YC, that initiate photoperiod-dependent flowering by cooperatively interacting with CONSTANS (CO) to drive the expression of FLOWERING LOCUS T (FT). This involves NF Y and CO binding at distal CCAAT and proximal "CORE" elements, respectively, in the FT promoter. While this is well established for the HFD subunits, there remains some question over the potential role of NF-YA as either positive or negative regulators of this process. Here we provide strong support, in the form of genetic and biochemical analyses, that NF-YA, in complex with NF-YB/NF-YC proteins, can directly bind the distal CCAAT box in the FT promoter and are positive regulators of flowering in an FT-dependent manner. PMID- 27977688 TI - Regulation of the Human Telomerase Gene TERT by Telomere Position Effect-Over Long Distances (TPE-OLD): Implications for Aging and Cancer. AB - Telomerase is expressed in early human development and then becomes silenced in most normal tissues. Because ~90% of primary human tumors express telomerase and generally maintain very short telomeres, telomerase is carefully regulated, particularly in large, long-lived mammals. In the current report, we provide substantial evidence for a new regulatory control mechanism of the rate limiting catalytic protein component of telomerase (hTERT) that is determined by the length of telomeres. We document that normal, young human cells with long telomeres have a repressed hTERT epigenetic status (chromatin and DNA methylation), but the epigenetic status is altered when telomeres become short. The change in epigenetic status correlates with altered expression of TERT and genes near to TERT, indicating a change in chromatin. Furthermore, we identified a chromosome 5p telomere loop to a region near TERT in human cells with long telomeres that is disengaged with increased cell divisions as telomeres progressively shorten. Finally, we provide support for a role of the TRF2 protein, and possibly TERRA, in the telomere looping maintenance mechanism through interactions with interstitial TTAGGG repeats. This provides new insights into how the changes in genome structure during replicative aging result in an increased susceptibility to age-related diseases and cancer prior to the initiation of a DNA damage signal. PMID- 27977689 TI - Tick-Borne Diseases in Turkey: A Review Based on One Health Perspective. AB - The importance of tick-borne diseases is increasing all over the world, including Turkey. Global warming, environmental and ecological changes and the existence of suitable habitats increase the impact of ticks and result in frequent emergence or re-emergence of tick-borne diseases (TBDs) with zoonotic characteristics. In Turkey, almost 19 TBDs have been reported in animals and men, involving four protozoa (babesiosis, theileriosis, cytauxzoonosis, hepatozoonosis), one filarial nematode (acanthocheilonemasis), ten bacterial agents (anaplasmosis, ehrlichiosis, aegyptianellosis, tick-borne typhus, Candidatus Rickettsia vini, Lyme borreliosis, tick-borne relapsing fever [TBRF], tularaemia, bartonellosis, and hemoplasmosis), and four viral infections (tick-borne encephalitis [TBE], Crimean-Congo Haemorrhagic Fever [CCHF], louping-ill [LI], and lumpy skin disease [LSD]). The growing number of TBD cases, in particular the fatal viral epidemics in humans, have led to increased public awareness and concern against TBDs in recent years. The World Health Organization (WHO) has developed a new political concept, called the "One Health" initiative, which is especially relevant for developing strategies against tick infestations and TBD control in humans and animals. It would be beneficial for Turkey to adopt this new strategy and establish specific research and control programs in coordination with international organizations like WHO, the World Organization for Animal Health (OIE), the Food and Agriculture Organization (FAO), the Centers for Disease Control and Prevention (CDC), and the European Center for Disease Prevention and Control (ECDC) to combat TBDs based on the "One Health Initiative" concept. In this article, we review the occurrence of primary TBDs in man and animals in Turkey in light of the "One Health" perspective. PMID- 27977690 TI - Suppression of ROS Production by Exendin-4 in PSC Attenuates the High Glucose Induced Islet Fibrosis. AB - Pancreatic stellate cells (PSCs) play a major role to fibrotic islet destruction observed in diabetic patients and animal model of diabetes. Exendin-4 (Ex-4) is a potent insulinotropic agent and has been approved for the treatment of type 2 diabetes. However, there have been no reports demonstrating the effects of Ex-4 on pancreatic islet fibrosis. In this study, Ex-4 treatment clearly attenuated fibrotic islet destruction and improved glucose tolerance and islet survival. GLP 1 receptor expression was upregulated during activation and proliferation of PSCs by hyperglycemia. The activation of PKA pathway by Ex-4 plays a role in ROS production and angiotensin II (Ang II) production. Exposure to high glucose stimulated ERK activation and Ang II-TGF- beta1 production in PSCs. Interestingly, Ex-4 significantly reduced Ang II and TGF-beta1 production by inhibition of ROS production but not ERK phosphorylation. Ex-4 may be useful not only as an anti-diabetic agent but also as an anti-fibrotic agent in type 2 diabetes due to its ability to inhibit PSC activation and proliferation and improve islet fibrosis in OLETF rats. PMID- 27977691 TI - Risk Factors for the Rupture of Middle Cerebral Artery Bifurcation Aneurysms Using CT Angiography. AB - BACKGROUND AND PURPOSE: To investigate the clinical and morphological characteristics associated with risk factors for the rupture of bifurcation-type middle cerebral artery aneurysms (MCAAs). METHODS: A total of 169 consecutive patients with 177 bifurcation-type MCAAs were reviewed from August 2011 to January 2016. Based on the clinical and morphologic characteristics findings, the risk factors of aneurysm rupture were assessed using statistical methods. RESULTS: Age, cerebral atherosclerosis, no hypertension, hypertension grade 2 and coronary artery disease (CAD) were negatively correlated with aneurysm rupture. The mean diameter (MD) of the parent and two daughter arteries was negatively correlated with rupture. Aneurysms with irregularity, depth, width, maximum size, aspect ratio, depth-to-width ratio, bottleneck factor, and size ratio were positively correlated with rupture. The multivariate logistic regression model revealed that irregular shape (odds ratio (OR) 2.697) and aspect ratio (OR 3.723) were significantly and positively correlated with rupture, while cerebral atherosclerosis (OR 0.033), CAD (OR 0.080), and MD (OR 0.201) were negatively correlated with rupture. Receiver operating characteristic analysis revealed that the threshold value of the aspect ratio and MD were 0.96 and 2.43 mm, respectively. CONCLUSIONS: Cerebral atherosclerosis and CAD are protective factors against rupture. Morphological characteristics such as an aneurysm with an irregular shape, a high aspect ratio (>0.96) and a small MD (<2.43 mm) are likely better predictors of rupture. PMID- 27977693 TI - Deep Reads: Favorites from a Few Different Shelves. PMID- 27977692 TI - Regional Brain Responses Are Biased Toward Infant Facial Expressions Compared to Adult Facial Expressions in Nulliparous Women. AB - Recent neuroimaging studies suggest that neutral infant faces compared to neutral adult faces elicit greater activity in brain areas associated with face processing, attention, empathic response, reward, and movement. However, whether infant facial expressions evoke larger brain responses than adult facial expressions remains unclear. Here, we performed event-related functional magnetic resonance imaging in nulliparous women while they were presented with images of matched unfamiliar infant and adult facial expressions (happy, neutral, and uncomfortable/sad) in a pseudo-randomized order. We found that the bilateral fusiform and right lingual gyrus were overall more activated during the presentation of infant facial expressions compared to adult facial expressions. Uncomfortable infant faces compared to sad adult faces evoked greater activation in the bilateral fusiform gyrus, precentral gyrus, postcentral gyrus, posterior cingulate cortex-thalamus, and precuneus. Neutral infant faces activated larger brain responses in the left fusiform gyrus compared to neutral adult faces. Happy infant faces compared to happy adult faces elicited larger responses in areas of the brain associated with emotion and reward processing using a more liberal threshold of p < 0.005 uncorrected. Furthermore, the level of the test subjects' Interest-In-Infants was positively associated with the intensity of right fusiform gyrus response to infant faces and uncomfortable infant faces compared to sad adult faces. In addition, the Perspective Taking subscale score on the Interpersonal Reactivity Index-Chinese was significantly correlated with precuneus activity during uncomfortable infant faces compared to sad adult faces. Our findings suggest that regional brain areas may bias cognitive and emotional responses to infant facial expressions compared to adult facial expressions among nulliparous women, and this bias may be modulated by individual differences in Interest-In-Infants and perspective taking ability. PMID- 27977695 TI - Design Principles of Biological Oscillators through Optimization: Forward and Reverse Analysis. AB - From cyanobacteria to human, sustained oscillations coordinate important biological functions. Although much has been learned concerning the sophisticated molecular mechanisms underlying biological oscillators, design principles linking structure and functional behavior are not yet fully understood. Here we explore design principles of biological oscillators from a multiobjective optimization perspective, taking into account the trade-offs between conflicting performance goals or demands. We develop a comprehensive tool for automated design of oscillators, based on multicriteria global optimization that allows two modes: (i) the automatic design (forward problem) and (ii) the inference of design principles (reverse analysis problem). From the perspective of synthetic biology, the forward mode allows the solution of design problems that mimic some of the desirable properties appearing in natural oscillators. The reverse analysis mode facilitates a systematic exploration of the design space based on Pareto optimality concepts. The method is illustrated with two case studies: the automatic design of synthetic oscillators from a library of biological parts, and the exploration of design principles in 3-gene oscillatory systems. PMID- 27977694 TI - Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response. AB - The role of common fragile sites (CFSs) in cancer remains controversial. Two main views dominate the discussion: one suggests that CFS loci are hotspots of genomic instability leading to inactivation of genes encoded within them, while the other view proposes that CFSs are functional units and that loss of the encoded genes confers selective pressure, leading to cancer development. The latter view is supported by emerging evidence showing that expression of a given CFS is associated with genome integrity and that inactivation of CFS-resident tumor suppressor genes leads to dysregulation of the DNA damage response (DDR) and increased genomic instability. These two viewpoints of CFS function are not mutually exclusive but rather coexist; when breaks at CFSs are not repaired accurately, this can lead to deletions by which cells acquire growth advantage because of loss of tumor suppressor activities. Here, we review recent advances linking some CFS gene products with the DDR, genomic instability, and carcinogenesis and discuss how their inactivation might represent a selective advantage for cancer cells. PMID- 27977696 TI - BRCAness as a Biomarker for Predicting Prognosis and Response to Anthracycline Based Adjuvant Chemotherapy for Patients with Triple-Negative Breast Cancer. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous tumor that encompasses many different subclasses of the disease. In this study, we assessed BRCAness, defined as the shared characteristics between sporadic and BRCA1 mutated tumors, in a large cohort of TNBC cases. METHODS: The BRCAness of 262 patients with primary TNBCs resected between January 2004 and December 2014 was determined through the isolation of DNA from tumor tissue. Classification of BRCAness was performed using multiple ligation-dependent probe amplification (MLPA). The tumor subtypes were determined immunohistochemically using resected specimens. RESULTS: Of the 262 TNBCs, the results of the MLPA assays showed that 174 (66.4%) tumors had BRCAness. Patients with BRCAness tumors were younger than patients with non-BRCAness tumors (P = 0.003). There was no significant difference between the two groups regarding their pathological stages. The BRCAness group had a significantly shorter recurrence-free survival (RFS) compared with the non-BRCAness group (P = 0.04) and had a shorter overall survival (OS) although this did not reach statistical significance. Adjuvant treatments with anthracycline-based regimens provided significantly greater benefits to the BRCAness group (P = 0.003 for RFS, and P = 0.03 for OS). Multivariate Cox proportional hazard model analysis showed that BRCAness was an independent negative prognostic factor, and the anthracycline-based adjuvant chemotherapy was an independent positive prognostic factor for both RFS and OS in TNBC. CONCLUSIONS: The 66.4% patients of TNBCs showed BRCAness. BRCAness is essential as a biomarker in the subclassification of TNBCs and might be of use for predicting their prognosis. Furthermore, this biomarker might be a predictive factor for the effectiveness of anthracycline-based adjuvant chemotherapy for patients with TNBCs. PMID- 27977697 TI - The Effects of Clinical Decision Support Systems on Medication Safety: An Overview. AB - BACKGROUND: The clinical decision support system(CDSS) has potential to improving medication safety. However, the effects of the intervention were conflicting and uncertain. Meanwhile, the reporting and methodological quality of this field were unknown. OBJECTIVE: The aim of this overview is to evaluate the effects of CDSS on medication safety and to examine the methodological and reporting quality. METHODS: PubMed, Embase and Cochrane Library were searched to August 2015. Systematic reviews (SRs) investigating the effects of CDSS on medication safety were included. Outcomes were determined in advance and assessed separately for process of care and patient outcomes. The methodological quality was assessed by Assessment of Multiple Systematic Reviews (AMSTAR) and the reporting quality was examined by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Twenty systematic reviews, consisting of 237 unique randomized controlled trials(RCTs) and 176 non-RCTs were included. Evidence that CDSS significantly impacted process of care was found in 108 out of 143 unique studies of the 16 SRs examining this effect (75%). Only 18 out of 90 unique studies of the 13 SRs reported significantly evidence that CDSS positively impacted patient outcomes (20%). Ratings for the overall scores of AMSTAR resulted in a mean score of 8.3 with a range of scores from 7.5 to 10.5. The reporting quality was varied. Some contents were particularly strong. However, some contents were poor. CONCLUSIONS: CDSS reduces medication error by obviously improving process of care and inconsistently improving patient outcomes. Larger samples and longer-term studies are required to ensure more reliable evidence base on the effects of CDSS on patient outcomes. The methodological and reporting quality were varied and some realms need to be improved. PMID- 27977698 TI - Age Effects on Hypocotyl Mechanics. AB - Numerous studies deal with composition and molecular processes involved in primary cell wall formation and alteration in Arabidopsis. However, it still remains difficult to assess the relation between physiological properties and mechanical function at the cell wall level. The thin and fragile structure of primary cell walls and their large biological variability, partly related to structural changes during growth, make mechanical experiments challenging. Since, to the best of our knowledge, there is no reliable data in the literature about how the properties of the fully elongated zone of hypocotyls change with age. We studied in a series of experiments on two different seed batches the tensile properties the region below the growth zone of 4 to 7 day old etiolated Arabidopsis hypocotyls. Additionally, we analysed geometrical parameters, hypocotyl density and cellulose content as individual traits and their relation to tissue mechanics. No significant differences of the mechanical parameters of the non-growing region between 5-7 day old plants could be found whereas in 4 day old plants both tensile stiffness and ultimate tensile stress were significantly lower than in the older plants. Furthermore hypocotyl diameters and densities remain almost the same for 5, 6 and 7 day old seedlings. Naturally, hypocotyl lengths increase with age. The evaluation whether the choice-age or length influences the mechanical properties showed that both are equally applicable sampling parameters. Additionally, our detailed study allows for the estimation of biological variability, connections between mechanics and hypocotyl age could be established and complement the knowledge on biochemistry and genetics affecting primary plant cell wall growth. The application of two different micromechanical devices for testing living Arabidopsis hypocotyls allows for emphasizing and discussing experimental limitations and for presenting a wide range of possibilities to address current and future questions related to plant cell wall mechanics, synthesis and growth in combination with molecular biology methodologies. PMID- 27977699 TI - The Everyday Moral Judge - Autobiographical Recollections of Moral Emotions. AB - Moral emotions are typically elicited in everyday social interactions and regulate social behavior. Previous research in the field of attribution theory identified ought (the moral standard of a given situation or intended goal), goal attainment (a goal can be attained vs. not attained) and effort (high vs. low effort expenditure) as cognitive antecedents of moral emotions. In contrast to earlier studies, mainly relying on thought experiments, we investigated autobiographical recollections of N = 312 participants by means of an online study. We analyzed a diverse range of moral emotions, i.e., admiration, anger, contempt, indignation, pride, respect, schadenfreude, and sympathy, by using a mixed-method approach. Qualitative and quantitative methods clearly corroborate the important role of ought, goal-attainment, and effort as eliciting conditions of moral emotions. Furthermore, we built categorical systems based on our participants' descriptions of real-life situations, allowing for more fine grained distinctions between seemingly similar moral emotions. We thus identify additional prerequisites explaining more subtle differences between moral emotion clusters as they emerge from our analyses (i.e., cluster 1: admiration, pride, and respect; cluster 2: anger, contempt, and indignation; cluster 3: schadenfreude and sympathy). Results are discussed in the light of attributional theories of moral emotions, and implications for future research are derived. PMID- 27977700 TI - A Quantitative Electrophysiological Biomarker of Duplication 15q11.2-q13.1 Syndrome. AB - BACKGROUND: Duplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism spectrum disorder (ASD). A distinct electrophysiological (EEG) pattern characterized by excessive activity in the beta band has been noted in clinical reports. We asked whether EEG power in the beta band, as well as in other frequency bands, distinguished children with Dup15q syndrome from those with non syndromic ASD and then examined the clinical correlates of this electrophysiological biomarker in Dup15q syndrome. METHODS: In the first study, we recorded spontaneous EEG from children with Dup15q syndrome (n = 11), age-and IQ-matched children with ASD (n = 10) and age-matched typically developing (TD) children (n = 9) and computed relative power in 6 frequency bands for 9 regions of interest (ROIs). Group comparisons were made using a repeated measures analysis of variance. In the second study, we recorded spontaneous EEG from a larger cohort of individuals with Dup15q syndrome (n = 27) across two sites and examined age, epilepsy, and duplication type as predictors of beta power using simple linear regressions. RESULTS: In the first study, spontaneous beta1 (12-20 Hz) and beta2 (20-30 Hz) power were significantly higher in Dup15q syndrome compared with both comparison groups, while delta (1-4 Hz) was significantly lower than both comparison groups. Effect sizes in all three frequency bands were large (|d| > 1). In the second study, we found that beta2 power was significantly related to epilepsy diagnosis in Dup15q syndrome. CONCLUSIONS: Here, we have identified an electrophysiological biomarker of Dup15q syndrome that may facilitate clinical stratification, treatment monitoring, and measurement of target engagement for future clinical trials. Future work will investigate the genetic and neural underpinnings of this electrophysiological signature as well as the functional consequences of excessive beta oscillations in Dup15q syndrome. PMID- 27977701 TI - Determinants of Divergent Adaptive Immune Responses after Airway Sensitization with Ligands of Toll-Like Receptor 5 or Toll-Like Receptor 9. AB - Excessive type 2 helper T cell responses to environmental antigens can cause immunopathology such as asthma and allergy, but how such immune responses are induced remains unclear. We studied this process in the airways by immunizing mice intranasally with the antigen ovalbumin together with either of two Toll like receptor (TLR) ligands. We found the TLR5 ligand flagellin promoted a type 2 helper T cell response, whereas, a TLR9 ligand CpG oligodeoxyribonucleotide (ODN) promoted a type 1 helper T cell response. CpG ODN induced mRNA encoding interleukin (IL)-12 p40, whereas, flagellin caused IL-33 secretion and induced mRNAs encoding IL-1 and thymic stromal lymphopoietin (TSLP). By using mice deficient in the TLR and IL-1R signaling molecule, myeloid differentiation primary response 88 (MyD88), in conventional dendritic cells (cDCs) and alveolar macrophages (AMs), and by cell sorting different lung populations after 2 hours of in vivo stimulation, we characterized the cell types that rapidly produced inflammatory cytokines in response to TLR stimulation. CpG ODN was likely recognized by TLR9 on cDCs and AMs, which made mRNA encoding IL-12. IL-12 was necessary for the subsequent innate and adaptive interferon-gamma production. In contrast, flagellin stimulated multiple cells of hematopoietic and non hematopoietic origin, including AMs, DCs, monocytes, and lung epithelial cells. AMs were largely responsible for IL-1alpha, whereas lung epithelial cells made TSLP. Multiple hematopoietic cells, including AMs, DCs, and monocytes contributed to other cytokines, including IL-1beta and TNFalpha. MyD88-dependent signals, likely through IL-1R and IL-33R, and MyD88-independent signals, likely from TSLP, were necessary in cDCs for promotion of the early IL-4 response by CD4 T cells in the draining lymph node. Thus, the cell types that responded to TLR ligands were a critical determinant of the innate cytokines produced and the character of the resulting adaptive immune response in the airways. PMID- 27977703 TI - A Radical Solution: The Phylogeny of the Nudibranch Family Fionidae. AB - Tergipedidae represents a diverse and successful group of aeolid nudibranchs, with approximately 200 species distributed throughout most marine ecosystems and spanning all biogeographical regions of the oceans. However, the systematics of this family remains poorly understood since no modern phylogenetic study has been undertaken to support any of the proposed classifications. The present study is the first molecular phylogeny of Tergipedidae based on partial sequences of two mitochondrial (COI and 16S) genes and one nuclear gene (H3). Maximum likelihood, maximum parsimony and Bayesian analysis were conducted in order to elucidate the systematics of this family. Our results do not recover the traditional Tergipedidae as monophyletic, since it belongs to a larger clade that includes the families Eubranchidae, Fionidae and Calmidae. This newly recovered clade is here referred to as Fionidae, the oldest name for this taxon. In addition, the present molecular phylogeny does not recover the traditional systematic relationships at a generic level, and therefore, systematic changes are required. We recognize the following clades within Fionidae: Calma, Cuthona, Cuthonella, Eubranchus, Fiona, Murmania, Tenellia, Tergipes, Tergiposacca gen. nov., Rubramoena gen. nov. and Abronica gen. nov. The type species of Tergiposacca, T. longicerata nov. sp. is described. The other two new genera have a previously described species as their type species. Most of these taxa, with the exceptions of Eubranchus, Tergipes and Fiona are composed of radically different constituent species from their traditional membership, but appear to be supported by morphological synapomorphies as well as molecular data. Aenigmastyletus, Catriona, Phestilla, Tenellia and Trinchesia are nested within other clades and, thus are here considered as synonyms of the larger clades. The phylogenetic position and validity of Myja, Guyvalvoria, Leostyletus and Subcuthona still need to be tested in future studies when material becomes available. PMID- 27977705 TI - Conflicts of Interest in GM Bt Crop Efficacy and Durability Studies. AB - Public confidence in genetically modified (GM) crop studies is tenuous at best in many countries, including those of the European Union in particular. A lack of information about the effects of ties between academic research and industry might stretch this confidence to the breaking point. We therefore performed an analysis on a large set of research articles (n = 672) focusing on the efficacy or durability of GM Bt crops and ties between the researchers carrying out these studies and the GM crop industry. We found that ties between researchers and the GM crop industry were common, with 40% of the articles considered displaying conflicts of interest (COI). In particular, we found that, compared to the absence of COI, the presence of a COI was associated with a 50% higher frequency of outcomes favorable to the interests of the GM crop company. Using our large dataset, we were able to propose possible direct and indirect mechanisms behind this statistical association. They might notably include changes of authorship or funding statements after the results of a study have been obtained and a choice in the topics studied driven by industrial priorities. PMID- 27977702 TI - Cost Effectiveness of Potential ART Adherence Monitoring Interventions in Sub Saharan Africa. AB - BACKGROUND: Interventions based around objective measurement of adherence to antiretroviral drugs for HIV have potential to improve adherence and to enable differentiation of care such that clinical visits are reduced in those with high adherence. It would be useful to understand the approximate upper limit of cost that could be considered for such interventions of a given effectiveness in order to be cost effective. Such information can guide whether to implement an intervention in the light of a trial showing a certain effectiveness and cost. METHODS: An individual-based model, calibrated to Zimbabwe, which incorporates effects of adherence and resistance to antiretroviral therapy, was used to model the potential impact of adherence monitoring-based interventions on viral suppression, death rates, disability adjusted life years and costs. Potential component effects of the intervention were: enhanced average adherence when on ART, reduced risk of ART discontinuation, and reduced risk of resistance acquisition. We considered a situation in which viral load monitoring is not available and one in which it is. In the former case, it was assumed that care would be differentiated based on the adherence level, with fewer clinic visits in those demonstrated to have high adherence. In the latter case, care was assumed to be primarily differentiated according to viral load level. The maximum intervention cost required to be cost effective was calculated based on a cost effectiveness threshold of $500 per DALY averted. FINDINGS: In the absence of viral load monitoring, an adherence monitoring-based intervention which results in a durable 6% increase in the proportion of ART experienced people with viral load < 1000 cps/mL was cost effective if it cost up to $50 per person-year on ART, mainly driven by the cost savings of differentiation of care. In the presence of viral load monitoring availability, an intervention with a similar effect on viral load suppression was cost-effective when costing $23-$32 per year, depending on whether the adherence intervention is used to reduce the level of need for viral load measurement. CONCLUSION: The cost thresholds identified suggest that there is clear scope for adherence monitoring-based interventions to provide net population health gain, with potential cost-effective use in situations where viral load monitoring is or is not available. Our results guide the implementation of future adherence monitoring interventions found in randomized trials to have health benefit. PMID- 27977704 TI - Ischemic Colitis after Cardiac Surgery: Can We Foresee the Threat? AB - INTRODUCTION: Ischemic colitis (IC) remains a great threat after cardiac surgery with use of extracorporeal circulation. We aimed to identify predictive risk factors and influence of early catecholamine therapy for this disease. METHODS: We prospectively collected and analyzed data of 224 patients, who underwent laparotomy due to IC after initial cardiac surgery with use of extracorporeal circulation during 2002 and 2014. For further comparability 58 patients were identified, who underwent bypass surgery, aortic valve replacement or combination of both. Age +/-5 years, sex, BMI +/- 5, left ventricular function, peripheral arterial disease, diabetes and urgency status were used for match-pair analysis (1:1) to compare outcome and detect predictive risk factors. Highest catecholamine doses during 1 POD were compared for possible predictive potential. RESULTS: Patients' baseline characteristics showed no significant differences. In hospital mortality of the IC group with a mean age of 71 years (14% female) was significantly higher than the control group with a mean age of 70 (14% female) (67% vs. 16%, p<0.001). Despite significantly longer bypass time in the IC group (133 +/- 68 vs. 101 +/- 42, p = 0.003), cross-clamp time remained comparable (64 +/- 33 vs. 56 +/- 25 p = 0.150). The majority of the IC group suffered low-output syndrome (71% vs. 14%, p<0.001) leading to significant higher lactate values within first 24h after operation (55 +/- 46 mg/dl vs. 31 +/- 30 mg/dl, p = 0.002). Logistic regression revealed elevated lactate values to be significant predictor for colectomy during the postoperative course (HR 1.008, CI 95% 1.003 1.014, p = 0.003). However, Receiver Operating Characteristic Curve calculates a cut-off value for lactate of 22.5 mg/dl (sensitivity 73% and specificity 57%). Furthermore, multivariate analysis showed low-output syndrome (HR 4.301, CI 95% 2.108-8.776, p<0.001) and vasopressin therapy (HR 1.108, CI 95% 1.012-1.213, p = 0.027) significantly influencing necessity of laparotomy. CONCLUSION: Patients who undergo laparotomy for IC after initial cardiac surgery have a substantial in hospital mortality risk. Early postoperative catecholamine levels do not influence the development of an IC except vasopressin. Elevated lactate remains merely a vague predictive risk factor. PMID- 27977706 TI - Development of a New Growth Standard for Breastfed Chinese Infants: What Is the Difference from the WHO Growth Standards? AB - The objectives of this longitudinal study were to examine the trajectory of breastfed infants' growth in China to update growth standards for early childhood, and to compare these updated Chinese growth standards with the growth standards recommended by the World Health Organization (WHO) in 2006.This longitudinal cohort study enrolled 1,840 healthy breastfed infants living in an "optimal" environment favorable to growth and followed up until one year of age from 2007 to 2010. The study subjects were recruited from 60 communities in twelve cities in China. A participating infant's birth weight was measured within the first hour of the infant's life, and birth length and head circumference within 24 hours after birth. Repeated weekly and monthly anthropometric measurements were also taken. Multilevel (ML) modelling via MLwiN2.25 was fitted to estimate the growth curves of weight-for-age (WFA), length-for-age (LFA), and head circumference-for-age (HFA) for the study sample as a whole and by child sex, controlling for mode of delivery, the gravidity and parity of the mother, infant's physical measurements at birth, infant's daily food intaking frequency per day, infant's medical conditions, the season when the infant's physical measurement was taken, parents' ages, heights, and attained education, and family structure and income per month. During the first four weeks after birth, breastfed infants showed an increase in weight, length, and head circumference of 1110g, 4.9 cm, and 3.2 cm, respectively, among boys, and 980 g, 4.4 cm, and 2.8 cm, respectively, among girls. Throughout infancy, the total growth for these three was 6930 g, 26.4 cm, and 12.5 cm, respectively, among boys, and 6480 g, 25.5 cm, and 11.7 cm, respectively, among girls. As expected, there was a significant sex difference in growth during the first year. In comparison with the WHO growth standards, breastfed children in our study were heavier in weight, longer in length, and bigger in head circumference, with the exception of a few age points during the first two to four months on the upper two percentile curves.Our data suggested the growth curves for breastfed infants in China were significantly different in comparison with those based on the WHO standards. The adoption of the WHO infant growth standards among Chinese infants, as well as the methods used in the development of such growth standards in China, need careful and coordinated consideration. PMID- 27977707 TI - Effect of Influenza Vaccination of Children on Infection Rate in Hutterite Communities: Follow-Up Study of a Randomized Trial. AB - BACKGROUND: An earlier cluster randomized controlled trial (RCT) of Hutterite colonies had shown that if more than 80% of children and adolescents were immunized with influenza vaccine there was a statistically significant reduction in laboratory-confirmed influenza among all unimmunized community members. We assessed the impact of this intervention for two additional influenza seasonal periods. METHODS: Follow-up data for two influenza seasonal periods of a cluster randomized trial involving 1053 Canadian children and adolescents aged 36 months to 15 years in Season 2 and 1014 in Season 3 who received the study vaccine, and 2805 community members in Season 2 and 2840 in Season 3 who did not receive the study vaccine. Follow-up for Season 2 began November 18, 2009 and ended April 25, 2010 while Season 3 extended from December 6, 2010 and ended May 27, 2011. Children were randomly assigned in a blinded manner according to community membership to receive either inactivated trivalent influenza vaccine or hepatitis A. The primary outcome was confirmed influenza A and B infection using RT-PCR assay. Due to the outbreak of 2009 H1N1 pandemic, data in Season 2 were excluded for analysis. RESULTS: For an analysis of the combined Season 1 and Season 3 data, among non-recipients (i.e., participants who did not receive study vaccines), 66 of the 2794 (2.4%) participants in the influenza vaccine colonies and 121 of the 2301 (5.3%) participants in the hepatitis A colonies had influenza confirmed by RT-PCR, for a protective effectiveness of 60% (95% CI, 6% to 83%; P = 0.04); among all study participants (i.e., including both those who received study vaccine and those who did not), 125 of the 3806 (3.3%) in the influenza vaccine colonies and 239 of the 3243 (7.4%) in the hepatitis A colonies had influenza confirmed by RT-PCR, for a protective effectiveness of 63% (95% CI, 5% to 85%; P = 0.04). CONCLUSION: Immunizing children and adolescents with inactivated influenza vaccine can offer a protective effect among unimmunized community members for influenza A and B together when considered over multiple years of seasonal influenza. TRIAL REGISTRATION: Clinicaltrials.gov NCT00877396. PMID- 27977709 TI - A Low-Cost Digital Microscope with Real-Time Fluorescent Imaging Capability. AB - This paper describes the development of a prototype of a low-cost digital fluorescent microscope built from commercial off-the-shelf (COTS) components. The prototype was tested to detect malignant tumor cells taken from a living organism in a preclinical setting. This experiment was accomplished by using Alexa Fluor 488 conjugate dye attached to the cancer cells. Our prototype utilizes a torch along with an excitation filter as a light source for fluorophore excitation, a dichroic mirror to reflect the excitation and pass the emitted green light from the sample under test and a barrier filter to permit only appropriate wavelength. The system is designed out of a microscope using its optical zooming property and an assembly of exciter filter, dichroic mirror and transmitter filter. The microscope is connected to a computer or laptop through universal serial bus (USB) that allows real-time transmission of captured florescence images; this also offers real-time control of the microscope. The designed system has comparable features of high-end commercial fluorescent microscopes while reducing cost, power, weight and size. PMID- 27977708 TI - Foot-and-Mouth Disease Virus-Associated Abortion and Vertical Transmission following Acute Infection in Cattle under Natural Conditions. AB - Foot-and-mouth disease (FMD) is a highly contagious and economically important viral disease of cloven-hoofed animals, including domestic and wild host species. During recent FMD outbreaks in India, spontaneous abortions were reported amongst FMD-affected and asymptomatic cows. The current study was an opportunistic investigation of these naturally occurring bovine abortions to assess causality of abortion and vertical transmission of FMDV from infected cows to fetuses. For this purpose, fetal tissue samples of eight abortuses (heart, liver, kidney, spleen, palatine tonsil, umbilical cord, soft palate, tongue, lungs, and submandibular lymph node) were collected and screened by various detection methods, including viral genome detection, virus isolation, and immunomicroscopy. Amongst these cases, gross pathological changes were observed in 3 abortuses. Gross pathological findings included blood-tinged peritoneal and pleural effusions and myocarditis. Hearts of infected calves had mild to moderate degeneration and necrosis of the myocardium with moderate infiltration by mixed inflammatory cells. Localization of FMDV antigen was demonstrated in lungs and soft palate by immunomicroscopy. FMDV serotype O viral genome was recovered from 7 of 8 cases. Infectious FMDV serotype O was rescued by chemical transfection of the total RNA extracted from three soft palate samples and was sequenced to confirm 100% identity of the VP1 (capsid) coding region with isolates collected from infected cattle during the acute phase of infection. Based upon these findings, it may be concluded that FMDV-associated abortion occurred among the infected pregnant cows included within this study and FMDV was subsequently transmitted vertically to fetuses. This is the first documentation of FMDV associated abortions in cattle. PMID- 27977710 TI - Characterization of Histone Modifications Associated with Inactive X-Chromosome in Trophoblast Stem Cells, eXtra-Embryonic Endoderm Cells and in In Vitro Derived Undifferentiated and Differentiated Epiblast Like Stem Cells. AB - In mouse, X-chromosome inactivation (XCI) can either be imprinted or random. Imprinted XCI (iXCI) is considered unstable and depending on continuous Xist expression, whereas random XCI (rXCI) is stably maintained even in the absence of Xist. Here we have systematically examined epigenetic modifications associated with the inactive X-chromosome (Xi) in Trophoblast Stem cells, eXtra-Embryonic Endoderm Cells, undifferentiated and differentiated Epiblast Like Stem Cells in order to understand intrinsic differences in epigenetic mechanisms involved in silencing of the inactive X-chromosome in lineages presenting iXCI and rXCI. Whereas euchromatic histone modifications are predominantly lost from the Xi territory in all cell types, the accumulation of heterochromatic modifications diverges in between the analysed cell lineages. Particularly, only the Xi of multipotent Trophoblast (iXCI) and Epiblast stem cells (rXCI) display a visible accumulation of Polycomb Repressive Complexes (PRCs), in contrast to the Xi in differentiated Epiblast Like Stem Cells and eXtra-embryonic Endoderm cells. Despite this, the histone modifications catalysed by PRCs, ubH2AK119 and H3K27me3, remain the best heterochromatic markers for the Xi in all assessed lineages. Heterochromatic chromatin modifications associated with the Xi are a reflection of the epigenetic landscape of the entire genome of the assessed cell regardless whether XCI is imprinted or random. PMID- 27977711 TI - Patients' Expectations Impact Their Satisfaction following Total Hip or Knee Arthroplasty. AB - INTRODUCTION: The objective of this study was to assess the number and magnitude of preoperative expectations and to correlate them with the degree of satisfaction expressed one year after Total Hip Arthroplasty (THA) or Total Knee Arthroplasty (TKA), in patients with severe and painful osteoarthritis (OA). MATERIALS AND METHODS: Preoperative expectations (within 20 days prior to surgery) and postoperative satisfaction (one year after the intervention) were measured using the previously validated French version of the Hospital for Special Surgery Hip or Knee Replacement Expectations Survey. Postoperative satisfaction was measured using a specific scale, following the same methodology as that used for the assessment of expectations. Prediction of the satisfaction of the patients was performed using multivariate linear regression modelling. RESULTS: A total of 138 patients (80 THA and 58 TKA) completed the two parts of the study. The expectations score (mean +/- SD) (range 0-100) was 72.58 +/- 12.63 before THA and 69.10 +/- 13.72 before TKA (p = 0.13). The number of expectations expressed was 14.34 +/- 1.32 (out of a potential maximum of 18) before THA and 14.70 +/- 2.29 (out of a potential maximum of 19) before TKA. After 1 year, THA generated a significantly higher degree of satisfaction compared to TKA (69.70 +/ 14.46 v 60.44 +/- 17.54, p<0.001) (range 0-100). The pre-operative expectations score was the single best positive predictor of the post-surgery satisfaction assessment both for TKA and THA. CONCLUSION: Patients undergoing total joint arthroplasty for end-stage OA have a high level of expectations, before both THA and TKA. While both types of interventions significantly improve essential and non-essential activities, the rate of satisfaction is significantly greater post THA. Preoperative expectations are a major contributor to the final degree of satisfaction, one year after surgery. These results re-emphasize the need for an optimal preoperative interaction between health care providers and patients, to allow patients a chance to foresee a reasonable outcome after TJA. PMID- 27977713 TI - Observations from Mortality Trends at The Children's Hospital, Accra, 2003-2013. AB - OBJECTIVE: Facility-based studies provide an unparalleled opportunity to assess interventions deployed in hospitals to reduce child mortality which is not easily captured in the national data. We examined mortality trends at the Princess Marie Louise Children's Hospital (PML) and related it to interventions deployed in the hospital and community to reduce child mortality and achieve the Millennium Development Goal 4 (MDG 4). METHODS: The study was a cross-sectional review of data on consecutive patients who died at the hospital over a period of 11 years, between 2003 and 2013. The total admissions for each year, the major hospital based and population-based interventions, which took place within the period, were also obtained. RESULTS: Out of a total of 37,012 admissions, 1,314 (3.6%) deaths occurred and admissions tripled during the period. The average annual change in mortality was -7.12% overall, -7.38% in under-fives, and -1.47% in children >=5 years. The majority of the deaths, 1,187 (90.3%), occurred in under fives. The observed decrease in under-five (and overall) mortality rate occurred in a specific and peculiar pattern. Most of the decrease occurred during the period between 2003 and 2006. After that there was a noticeable increase from 2006 to 2008. Then, the rate slowly decreased until the end of the study period in 2013. There was a concomitant decline in malaria mortality following a pattern similar to the decline observed in other parts of the continent during this period. Several interventions might have contributed to the reduction in mortality including the change in malaria treatment policy, improved treatment of malnutrition and increasing paediatric input. CONCLUSION: Under-fives mortality at PML has declined considerably; however, the reduction in mortality in older children has been minimal and thus requires special attention. Data collection for mortality reviews should be planned and commissioned regularly in hospitals to assess the effects of interventions and understand the context in which they occur. This will provide benchmarks and an impetus for improving care, identify shortfalls and ensure that the gains in child survival are maintained. PMID- 27977712 TI - Chardonnay Grape Seed Flour Ameliorates Hepatic Steatosis and Insulin Resistance via Altered Hepatic Gene Expression for Oxidative Stress, Inflammation, and Lipid and Ceramide Synthesis in Diet-Induced Obese Mice. AB - To identify differentially expressed hepatic genes contributing to the improvement of high-fat (HF) diet-induced hepatic steatosis and insulin resistance following supplementation of partially defatted flavonoid-rich Chardonnay grape seed flour (ChrSd), diet-induced obese (DIO) mice were fed HF diets containing either ChrSd or microcrystalline cellulose (MCC, control) for 5 weeks. The 2-h insulin area under the curve was significantly lowered by ChrSd, indicating that ChrSd improved insulin sensitivity. ChrSd intake also significantly reduced body weight gain, liver and adipose tissue weight, hepatic lipid content, and plasma low-density lipoprotein (LDL)-cholesterol, despite a significant increase in food intake. Exon microarray analysis of hepatic gene expression revealed down-regulation of genes related to triglyceride and ceramide synthesis, immune response, oxidative stress, and inflammation and upregulation of genes related to fatty acid oxidation, cholesterol, and bile acid synthesis. In conclusion, the effects of ChrSd supplementation in a HF diet on weight gain, insulin resistance, and progression of hepatic steatosis in DIO mice were associated with modulation of hepatic genes related to oxidative stress, inflammation, ceramide synthesis, and lipid and cholesterol metabolism. PMID- 27977714 TI - Off Target, but Sequence-Specific, shRNA-Associated Trans-Activation of Promoter Reporters in Transient Transfection Assays. AB - Transient transfection promoter reporter assays are commonly used in the study of transcriptional regulation, and can be used to define and characterize both cis acting regulatory sequences and trans-acting factors. In the process of using a variety of reporter assays designed to study regulation of the rhodopsin (rho) promoter, we discovered that rhodopsin promoter-driven reporter expression could be activated by certain species of shRNA in a gene-target-independent but shRNA sequence-specific manner, suggesting involvement of a specific shRNA associated pathway. Interestingly, the shRNA-mediated increase of rhodopsin promoter activity was synergistically enhanced by the rhodopsin transcriptional regulators CRX and NRL. Additionally, the effect was cell line-dependent, suggesting that this pathway requires the expression of cell-type specific factors. Since microRNA (miRNA) and interferon response-mediated processes have been implicated in RNAi off-target phenomena, we performed miRNA and gene expression profiling on cells transfected with shRNAs that do target a specific gene but have varied effects on rho reporter expression in order to identify transcripts whose expression levels are associated with shRNA induced rhodopsin promoter reporter activity. We identified a total of 50 miRNA species, and by microarray analysis, 320 protein-coding genes, some of which were predicted targets of the identified differentially expressed miRNAs, whose expression was altered in the presence of shRNAs that stimulated rhodopsin-promoter activity in a non-gene-targeting manner. Consistent with earlier studies on shRNA off-target effects, a number of interferon response genes were among those identified to be upregulated. Taken together, our results confirm the importance of considering off-target effects when interpreting data from RNAi experiments and extend prior results by focusing on the importance of including multiple and carefully designed controls in the design and analysis of the effects of shRNA on transient transfection-based transcriptional assays. PMID- 27977715 TI - Negative Life Events and Antenatal Depression among Pregnant Women in Rural China: The Role of Negative Automatic Thoughts. AB - BACKGROUND: Few studies have looked at the relationship between psychological and the mental health status of pregnant women in rural China. The current study aims to explore the potential mediating effect of negative automatic thoughts between negative life events and antenatal depression. METHODS: Data were collected in June 2012 and October 2012. 495 rural pregnant women were interviewed. Depressive symptoms were measured by the Edinburgh postnatal depression scale, stresses of pregnancy were measured by the pregnancy pressure scale, negative automatic thoughts were measured by the automatic thoughts questionnaire, and negative life events were measured by the life events scale for pregnant women. We used logistic regression and path analysis to test the mediating effect. RESULTS: The prevalence of antenatal depression was 13.7%. In the logistic regression, the only socio-demographic and health behavior factor significantly related to antenatal depression was sleep quality. Negative life events were not associated with depression in the fully adjusted model. Path analysis showed that the eventual direct and general effects of negative automatic thoughts were 0.39 and 0.51, which were larger than the effects of negative life events. CONCLUSIONS: This study suggested that there was a potentially significant mediating effect of negative automatic thoughts. Pregnant women who had lower scores of negative automatic thoughts were more likely to suffer less from negative life events which might lead to antenatal depression. PMID- 27977716 TI - Association between the Prevalence of Metabolic Syndrome and the Level of Coffee Consumption among Korean Women. AB - BACKGROUND: As coffee consumption is increasing remarkably over the past decade, the health effects concerning the coffee drinking has gained a wide attention across the nation. However, there is not a true consensus regarding the effects of coffee on metabolic disease. Therefore, this study aims to examine the association between coffee intake and the risk of metabolic syndrome in Korean women. METHODS: We used publicly accessible datasets collected through Korean National Health and Nutrition Examination Survey (KNHANES). Among 20,435 individuals from five consecutive years' worth of data from 2007 to 2011, only 15,691 subjects qualified for statistical analysis upon applying the exclusion criteria. We carried out the statistical analysis utilizing SPSS Statistics version 13.0 (IBM Corp., Armonk, NY.) and STATA statistical software release 13.0 (STATA Corp., College Station, TX). RESULTS: We found that the frequency of coffee intake inversely correlates with the prevalence of metabolic syndrome in women. Upon adjusting for life-style factors, socioeconomic status, and nutritional profile, the subjects from the highest coffee consumption quartile exhibited 40% lower odds of suffering from metabolic syndrome compared to those in the control (OR = 0.75; 95% CI = 0.67-0.84; P for trend < 0.001). Also, we observed that age- and BMI-adjusted HOMA-IR decreased as the coffee consumption increased (P for trend < 0.001). CONCLUSION: The findings of our study suggest that coffee consumption might be associated with reduction of metabolic syndrome in Korean women. To elucidate this cross-sectional association between coffee consumption and metabolic syndrome in women, cohort studies are warranted to confirm this relationship. PMID- 27977718 TI - Conceptions of Happiness and Unhappiness among Italian Psychology Undergraduates. AB - The present study aims at investigating the conceptions of happiness and unhappiness in a sample of Italian psychology undergraduates. Participants completed a questionnaire asking them to report the most important things that made them feel happy (happiness components) and those ones that made them feel unhappy (unhappiness components). Different measures of overall happiness and overall unhappiness were also obtained by asking respondents to assess to what extent each reported happiness and unhappiness component was present in their life, and by inviting them to provide a global judgment about their happiness and unhappiness. Results indicated that participants did not conceptualize happiness and unhappiness as perfect antonyms. Indeed, both investigated concepts encompassed a similar set of semantic components; however, the perceived salience of some of them - assessed in terms of frequency of citation and average ranking significantly varied between happiness and unhappiness. With regard to the measurement of overall happiness and unhappiness, on average, respondents considered themselves as moderately happy and only slightly unhappy. However, a judgmental asymmetry was found when comparing global and specific evaluations of unhappiness. Theoretical and empirical implications of the study are discussed. PMID- 27977717 TI - Decreased Thalamocortical Connectivity in Chronic Ketamine Users. AB - Disintegration in thalamocortical integration suggests its role in the mechanistic 'switch' from recreational to dysregulated drug seeking/addiction. In this study, we aimed to address whether thalamic nuclear groups show altered functional connectivity within the cerebral cortex in chronic ketamine users. One hundred and thirty subjects (41 ketamine users and 89 control subjects) underwent rsfMRI (resting-state functional Magnetic Resonance Imaging). Based on partial correlation functional connectivity analysis we partitioned the thalamus into six nuclear groups that correspond well with human histology. Then, in the area of each nuclear group, the functional connectivity differences between the chronic ketamine user group and normal control group were investigated. We found that the ketamine user group showed significantly less connectivity between the thalamic nuclear groups and the cortical regions-of-interest, including the prefrontal cortex, the motor cortex /supplementary motor area, and the posterior parietal cortex. However, no increased thalamic connectivity was observed for these regions as compared with controls. This study provides the first evidence of abnormal thalamocortical connectivity of resting state brain activity in chronic ketamine users. Further understanding of pathophysiological mechanisms of the thalamus in addiction (ketamine addiction) may facilitate the evaluation of much needed novel pharmacological agents for improved therapy of this complex disease. PMID- 27977719 TI - Colour Cues That Are Not Directly Attached to the Body of Males Do Not Influence the Mate Choice of Zebra Finches. AB - Mate choice decisions of female zebra finches are generally thought to rely on the assessment of male quality, which includes the specific ornamentation of males. A commonly used paradigm to experimentally manipulate a male's attractiveness is to add a coloured leg ring to the bird. Some studies have shown that female zebra finches prefer or alter their investment in males that have an additional red leg ring compared with males with green leg rings. Whether the coloured artificial ornaments need to be attached to the male's body or whether environmental colouration could have a similar effect on male attractiveness remains unclear. Here, I investigated this novel context to determine whether female choice between males is affected by environmental colour cues that are not directly attached to the male's body in four experiments involving 220 zebra finches (Taeniopygia guttata). A first experiment revealed that females chose males with red colour cues in the environmental background over males with green cues in the background. Based on this finding, I conducted follow-up experiments to obtain a deeper understanding of how environmental colour cues affect mate choice. Therefore, I examined whether female choice behaviour or male behaviour was altered in two additional experiments. Both experiments failed to show any effects of environmental colour cues on female choice or on male behaviour. Therefore, I replicated the initial experiment in a fourth experiment. Again replication failed; thus, the initial results indicating that environmental colouration affects mate choice behaviour of female zebra finches were not supported by the three subsequent experiments; thus, the outcome of the first experiment seems to be a false positive. Taking my results together, I found no robust support for the idea that environmental colour cues that are not directly attached to the body of male zebra finches affect female mate choice decisions. PMID- 27977720 TI - The Course of Neurocognitive Changes in Acute Psychosis: Relation to Symptomatic Improvement. AB - INTRODUCTION: Cognitive impairment is a core aspect of psychosis, but the course of cognitive functioning during acute psychosis remains poorly understood, as does the association between symptom change and neurocognitive change. Some studies have found cognitive improvement to be related to improvement in negative symptoms, but few have examined cognitive changes in the early acute phase, when clinical improvement mainly happens. This study's aim was to investigate the relation between cognitive and symptomatic change in clinically heterogeneous patients during the early acute phase of psychosis. METHOD: Participants (n = 84), including both first-episode and previously ill patients, were recruited from consecutive admissions to the acute psychiatric emergency ward of Haukeland University Hospital, Bergen, Norway, as part of the Bergen Psychosis Project (BPP). The RBANS neurocognitive test battery was administered on admission and again at discharge from the acute ward (mean time 4.1 weeks, SD 1.86 weeks). Symptomatic change was measured by PANSS. RESULTS: The proportion of subjects with cognitive impairment (t < 35) was 28.6% in the acute phase and 13.1% at follow-up. A sequential multiple linear regression model with RBANS change as the dependent variable found PANSS negative symptoms change to significantly predict total RBANS performance improvement (beta = -.307, p = .016). There was no significant difference between subjects with schizophrenia and those with other psychotic disorders in terms of cognitive change. CONCLUSION: The proportion of subjects with mild to moderate impairment in cognitive test performance is reduced across the acute phase of psychosis, with improvement related to amelioration of negative symptoms. PMID- 27977721 TI - The Efficacy and Safety of Miconazole Nitrate Mucoadhesive Tablets versus Itraconazole Capsules in the Treatment of Oral Candidiasis: An Open-Label, Randomized, Multicenter Trial. AB - BACKGROUND: Oral candidiasis (OC) is a common oral fungal infection. Recently, miconazole mucoadhesive tablets have been gaining attention for OC treatment. Despite trials in patients with human immunodeficiency virus and cancer, evidence of its application in the large-scale, general population with OC is lacking. This study aimed to evaluate the efficacy and safety of miconazole nitrate mucoadhesive tablets in comparison with itraconazole capsules for OC treatment. METHODS: The study was a randomized, open-label, parallel-armed, multicenter clinical trial. Totally, 343 patients diagnosed with OC, who met the inclusion criteria, were randomly assigned to either a treatment group that received miconazole nitrate mucoadhesive tablets (10 mg) once daily or a control group that received itraconazole capsules (100 mg QD) for 2 weeks, and were followed up for 2 weeks. The clinical cure, improvement of clinical symptoms/signs, mycologic cure, and safety were evaluated. RESULTS: The mucoadhesive tablets (n = 171) did not show inferiority to itraconazole (n = 172) in the treatment of OC. At the end of the 14-day treatment, the clinical cure rates were 45.29% and 41.76% in the miconazole and itraconazole groups, respectively (P = 0.3472). At the end of the 14-day follow-up, the clinical cure rates were 51.18% and 41.76% in the miconazole and itraconazole groups, respectively (P = 0.0329). Adverse events occurred in 53 subjects (33 in the miconazole group and 20 in the itraconazole group). There was no statistical difference in the safety profile between miconazole and itraconazole (P = 0.0533). Thrombocytopenic purpura, although rare, occurred in one patient in the miconazole group and was considered a drug related, severe adverse event. CONCLUSION: Miconazole nitrate mucoadhesive tablets may be as effective as systemic itraconazole capsule for OC treatment. Physicians should be cautious about thrombocytopenic purpura occurring as a rare and serious adverse event of miconazole nitrate. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR-TRC-13003935. PMID- 27977722 TI - Genome and Proteome Analysis of Rhodococcus erythropolis MI2: Elucidation of the 4,4'-Dithiodibutyric Acid Catabolism. AB - Rhodococcus erythropolis MI2 has the extraordinary ability to utilize the xenobiotic 4,4'-dithiodibutyric acid (DTDB). Cleavage of DTDB by the disulfide reductase Nox, which is the only verified enzyme involved in DTDB-degradation, raised 4-mercaptobutyric acid (4MB). 4MB could act as building block of a novel polythioester with unknown properties. To completely unravel the catabolism of DTDB, the genome of R. erythropolis MI2 was sequenced, and subsequently the proteome was analyzed. The draft genome sequence consists of approximately 7.2 Mbp with an overall G+C content of 62.25% and 6,859 predicted protein-encoding genes. The genome of strain MI2 is composed of three replicons: one chromosome and two megaplasmids with sizes of 6.45, 0.4 and 0.35 Mbp, respectively. When cells of strain MI2 were cultivated with DTDB as sole carbon source and compared to cells grown with succinate, several interesting proteins with significantly higher expression levels were identified using 2D-PAGE and MALDI-TOF mass spectrometry. A putative luciferase-like monooxygenase-class F420-dependent oxidoreductase (RERY_05640), which is encoded by one of the 126 monooxygenase encoding genes of the MI2-genome, showed a 3-fold increased expression level. This monooxygenase could oxidize the intermediate 4MB into 4-oxo-4 sulfanylbutyric acid. Next, a desulfurization step, which forms succinic acid and volatile hydrogen sulfide, is proposed. One gene coding for a putative desulfhydrase (RERY_06500) was identified in the genome of strain MI2. However, the gene product was not recognized in the proteome analyses. But, a significant expression level with a ratio of up to 7.3 was determined for a putative sulfide:quinone oxidoreductase (RERY_02710), which could also be involved in the abstraction of the sulfur group. As response to the toxicity of the intermediates, several stress response proteins were strongly expressed, including a superoxide dismutase (RERY_05600) and an osmotically induced protein (RERY_02670). Accordingly, novel insights in the catabolic pathway of DTDB were gained. PMID- 27977723 TI - Functional Validation of an Alpha-Actinin-4 Mutation as a Potential Cause of an Aggressive Presentation of Adolescent Focal Segmental Glomerulosclerosis: Implications for Genetic Testing. AB - Genetic testing in the clinic and research lab is becoming more routinely used to identify rare genetic variants. However, attributing these rare variants as the cause of disease in an individual patient remains challenging. Here, we report a patient who presented with nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) with collapsing features at age 14. Despite treatment, her kidney disease progressed to end-stage within a year of diagnosis. Through genetic testing, an Y265H variant with unknown clinical significance in alpha actinin-4 gene (ACTN4) was identified. This variant has not been seen previously in FSGS patients nor is it present in genetic databases. Her clinical presentation is different from previous descriptions of ACTN4 mediated FSGS, which is characterized by sub-nephrotic proteinuria and slow progression to end stage kidney disease. We performed in vitro and cellular assays to characterize this novel ACTN4 variant before attributing causation. We found that ACTN4 with either Y265H or K255E (a known disease-causing mutation) increased the actin bundling activity of ACTN4 in vitro, was associated with the formation of intracellular aggregates, and increased podocyte contractile force. Despite the absence of a familial pattern of inheritance, these similar biological changes caused by the Y265H and K255E amino acid substitutions suggest that this new variant is potentially the cause of FSGS in this patient. Our studies highlight that functional validation in complement with genetic testing may be required to confirm the etiology of rare disease, especially in the setting of unusual clinical presentations. PMID- 27977726 TI - Are Effects of Action on Perception Real? Evidence from Transformed Movements. AB - It has been argued that several reported non-visual influences on perception cannot be truly perceptual. If they were, they should affect the perception of target objects and reference objects used to express perceptual judgments, and thus cancel each other out. This reasoning presumes that non-visual manipulations impact target objects and comparison objects equally. In the present study we show that equalizing a body-related manipulation between target objects and reference objects essentially abolishes the impact of that manipulation so as it should do when that manipulation actually altered perception. Moreover, the manipulation has an impact on judgements when applied to only the target object but not to the reference object, and that impact reverses when only applied to the reference object but not to the target object. A perceptual explanation predicts this reversal, whereas explanations in terms of post-perceptual response biases or demand effects do not. Altogether these results suggest that body related influences on perception cannot as a whole be attributed to extra perceptual factors. PMID- 27977724 TI - Genetic Variants in CHIA and CHI3L1 Are Associated with the IgE Response to the Ascaris Resistance Marker ABA-1 and the Birch Pollen Allergen Bet v 1. AB - Helminth infections and allergic diseases are associated with IgE hyperresponsiveness but the genetics of this phenotype remain to be defined. Susceptibility to Ascaris lumbricoides infection and antibody levels to this helminth are associated with polymorphisms in locus 13q33-34. We aimed to explore this and other genomic regions to identify genetic variants associated with the IgE responsiveness in humans. Forty-eight subjects from Cartagena, Colombia, with extreme values of specific IgE to Ascaris and ABA-1, a resistance marker of this nematode, were selected for targeted resequencing. Burden analyses were done comparing extreme groups for IgE values. One-hundred one SNPs were genotyped in 1258 individuals of two well-characterized populations from Colombia and Sweden. Two low-frequency coding variants in the gene encoding the Acidic Mammalian Chitinase (CHIA rs79500525, rs139812869, tagged by rs10494133) were found enriched in high IgE responders to ABA-1 and confirmed by genetic association analyses. The SNP rs4950928 in the Chitinase 3 Like 1 gene (CHI3L1) was associated with high IgE to ABA-1 in Colombians and with high IgE to Bet v 1 in the Swedish population. CHIA rs10494133 and ABDH13 rs3783118 were associated with IgE responses to Ascaris. SNPs in the Tumor Necrosis Factor Superfamily Member 13b gene (TNFSF13B) encoding the cytokine B cell activating Factor were associated with high levels of total IgE in both populations. This is the first report on the association between low-frequency and common variants in the chitinases-related genes CHIA and CHI3L1 with the intensity of specific IgE to ABA-1 in a population naturally exposed to Ascaris and with Bet v 1 in a Swedish population. Our results add new information about the genetic influences of human IgE responsiveness; since the genes encode for enzymes involved in the immune response to parasitic infections, they could be helpful for understanding helminth immunity and allergic responses. We also confirmed that TNFSF13B has an important and conserved role in the regulation of total IgE levels, which supports potential evolutionary links between helminth immunity and allergic response. PMID- 27977725 TI - Characterization and Functional Analysis of Extracellular Vesicles and Muscle Abundant miRNAs (miR-1, miR-133a, and miR-206) in C2C12 Myocytes and mdx Mice. AB - Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder. Here, we show that the CD63 antigen, which is located on the surface of extracellular vesicles (EVs), is associated with increased levels of muscle-abundant miRNAs, namely myomiRs miR-1, miR-133a, and miR-206, in the sera of DMD patients and mdx mice. Furthermore, the release of EVs from the murine myoblast C2C12 cell line was found to be modulated by intracellular ceramide levels in a Ca2+-dependent manner. Next, to investigate the effects of EVs on cell survival, C2C12 myoblasts and myotubes were cultured with EVs from the sera of mdx mice or C2C12 cells overexpressing myomiRs in presence of cellular stresses. Both the exposure of C2C12 myoblasts and myotubes to EVs from the serum of mdx mice, and the overexpression of miR-133a in C2C12 cells in presence of cellular stress resulted in a significant decrease in cell death. Finally, to assess whether miRNAs regulate skeletal muscle regeneration in vivo, we intraperitoneally injected GW4869 (an inhibitor of exosome secretion) into mdx mice for 5 and 10 days. Levels of miRNAs and creatine kinase in the serum of GW4869-treated mdx mice were significantly downregulated compared with those of controls. The tibialis anterior muscles of the GW4869-treated mdx mice showed a robust decrease in Evans blue dye uptake. Collectively, these results indicate that EVs and myomiRs might protect the skeletal muscle of mdx mice from degeneration. PMID- 27977728 TI - Response of Bacteria Community to Long-Term Inorganic Nitrogen Application in Mulberry Field Soil. AB - The bacterial community and diversity in mulberry field soils with different application ages of inorganic nitrogen fertilizer (4Y, 4-year-old; 17Y, 17-year old; 32Y, 32-year- old) were investigated using next-generation sequencing. The results demonstrated that the application ages of nitrogen fertilizer significantly altered soil bacterial community and diversity. Soil bacterial Shannon diversity index and Chao 1 index decreased with the consecutive application of nitrogen fertilizer, and the 4Y soil exhibited the highest bacterial relative abundance and diversity. Of 45 bacterial genera (relative abundance ratio of genera greater than 0.3%), 18 were significantly affected by the plant age, and seven belong to Acidobacteria. The relative abundances of Acidobacteria Gp 1, Gp4 and Gp6 in the 4Y soil were significantly lower than that of in the 17Y and 32Y soils. However, the relative abundance of Pseudononas sp. in the 4Y soil was significantly higher than that of in the 17Y and 32Y soils. Most microbial parameters were significantly affected by soil pH and organic matter content which were significantly changed by long-term application of inorganic nitrogen fertilizer. PMID- 27977727 TI - Molecular Characterization and Functional Analysis of a Novel Calcium-Dependent Protein Kinase 4 from Eimeria tenella. AB - Eimeria tenella is an obligate intracellular parasite that actively invades cecal epithelial cells of chickens. The basis of cell invasion is not completely understood, but some key molecules of host cell invasion have been discovered. This paper investigated the characteristics of calcium-dependent protein kinase 4 (EtCDPK4), a critical molecule in E. tenella invasion of host cells. A full length EtCDPK4 cDNA was identified from E. tenella using rapid amplification of cDNA ends. EtCDPK4 had an open reading frame of 1803 bp encoding a protein of 600 amino acids. Quantitative real-time PCR and western blotting were used to explore differences in EtCDPK4 transcription and translation in four developmental stages of E. tenella. EtCDPK4 was expressed at higher levels in sporozoites, but translation was higher in second-generation merozoites. In vitro invasion inhibition assays explored whether EtCDPK4 was involved in invasion of DF-1 cells by E. tenella sporozoites. Polyclonal antibodies against recombinant EtCDPK4 (rEtCDPK4) inhibited parasite invasion, decreasing it by approximately 52%. Indirect immunofluorescence assays explored EtCDPK4 distribution during parasite development after E. tenella sporozoite invasion of DF-1 cells in vitro. The results showed that EtCDPK4 might be important in sporozoite invasion and development. To analyze EtCDPK4 functional domains according to the structural characteristics of EtCDPK4 and study the kinase activity of rEtCDPK4, an in vitro phosphorylation system was established. We verified that rEtCDPK4 was a protein kinase that was completely dependent on Ca2+ for enzyme activity. Specific inhibitors of rEtCDPK4 activity were screened by kinase activity in vitro. Some specific inhibitors were applied to assays of DF-1 cell invasion by E. tenella sporozoites to confirm that the inhibitors functioned in vitro. W-7, H-7, H-89, and myristoylated peptide inhibited DF-1 invasion by E. tenella sporozoites. The experimental results showed that EtCDPK4 may be involved in E. tenella invasion of chicken cecal epithelial cells. PMID- 27977729 TI - Interplay of Aging and Hypertension in Cardiac Remodeling: A Mathematical Geometric Model. AB - Hypertensive disorder can cause cardiac deformities. Elastic characteristic parameters, like Young's modulus of elasticity (E) derived from a traditional cylindrical model, increase significantly with aging. However, the geometric and component changes of aging hearts because of chronic hypertension remain unknown. To better describe the effects, we propose an elliptical elastic and mathematical model to evaluate myocardial stiffness. Ninety-six hypertensive patients (HTNPos) (men: 59.3%; age >= 65 years: 20.8%) were enrolled and compared with normotensive controls (HTNNeg) (n = 47, 48.9%). HTNPos patients had a thicker interventricular septum in diastole (IVSd) (HTNPos: 0.96 +/- 0.21 cm vs. HTNNeg: 0.77 +/- 0.15; p = 0.005) and higher intracardiac pressure (e/e': 9.06 +/- 4.85 cm vs. 7.76 +/- 3.41; p = 0.01), especially the elderly (> 65 years) (IVSd: 1.03 +/- 0.19 cm, e/e': 11.39 +/- 1.99; p = 0.006 and 0.01, respectively). Nevertheless, the internal dimension decreased more significantly in the HTNPos rather than in the HTNNeg elderly (5.23 +/- 0.46 vs. 4.74 +/- 0.69 cm; p = 0.02). We found different directions of cardiac remodeling with normotensive and hypertensive loads. Different from the longitudinal and circumferential strain, E and Poisson's ratio (upsilon) are values that directly present the rigidity of myocardium. E was significantly higher in the elderly (8011.92 +/- 2431.85 vs. 6052.43 +/- 3121.50; p = 0.02), whereas upsilon was significantly higher in all HTNPos patients (0.73 +/- 0.12 vs. 0.61 +/- 0.07; p < 0.001). Because E and upsilon reflected the material changes of myocardium in the HTNPos elderly, the proposed elliptical mathematical heart model better describes the geometric deformity induced by aging and hypertension. PMID- 27977730 TI - The Creation and Statistical Evaluation of a Deterministic Model of the Human Bronchial Tree from HRCT Images. AB - A quantitative description of the morphology of lung structure is essential prior to any form of predictive modeling of ventilation or aerosol deposition implemented within the lung. The human lung is a very complex organ, with airway structures that span two orders of magnitude and having a multitude of interfaces between air, tissue and blood. As such, current medical imaging protocols cannot provide medical practitioners and researchers with in-vivo knowledge of deeper lung structures. In this work a detailed algorithm for the generation of an individualized 3D deterministic model of the conducting part of the human tracheo bronchial tree is described. Distinct initial conditions were obtained from the high-resolution computed tomography (HRCT) images of seven healthy volunteers. The algorithm developed is fractal in nature and is implemented as a self-similar space sub-division procedure. The expansion process utilizes physiologically realistic relationships and thresholds to produce an anatomically consistent human airway tree. The model was validated through extensive statistical analysis of the results and comparison of the most common morphological features with previously published morphometric studies and other equivalent models. The resulting trees were shown to be in good agreement with published human lung geometric characteristics and can be used to study, among other things, structure function relationships in simulation studies. PMID- 27977731 TI - Systems Based Study of the Therapeutic Potential of Small Charged Molecules for the Inhibition of IL-1 Mediated Cartilage Degradation. AB - Inflammatory cytokines are key drivers of cartilage degradation in post-traumatic osteoarthritis. Cartilage degradation mediated by these inflammatory cytokines has been extensively investigated using in vitro experimental systems. Based on one such study, we have developed a computational model to quantitatively assess the impact of charged small molecules intended to inhibit IL-1 mediated cartilage degradation. We primarily focus on the simplest possible computational model of small molecular interaction with the IL-1 system-direct binding of the small molecule to the active site on the IL-1 molecule itself. We first use the model to explore the uptake and release kinetics of the small molecule inhibitor by cartilage tissue. Our results show that negatively charged small molecules are excluded from the negatively charged cartilage tissue and have uptake kinetics in the order of hours. In contrast, the positively charged small molecules are drawn into the cartilage with uptake and release timescales ranging from hours to days. Using our calibrated computational model, we subsequently explore the effect of small molecule charge and binding constant on the rate of cartilage degradation. The results from this analysis indicate that the small molecules are most effective in inhibiting cartilage degradation if they are either positively charged and/or bind strongly to IL-1alpha, or both. Furthermore, our results showed that the cartilage structural homeostasis can be restored by the small molecule if administered within six days following initial tissue exposure to IL 1alpha. We finally extended the scope of the computational model by simulating the competitive inhibition of cartilage degradation by the small molecule. Results from this model show that small molecules are more efficient in inhibiting cartilage degradation by binding directly to IL-1alpha rather than binding to IL-1alpha receptors. The results from this study can be used as a template for the design and development of more pharmacologically effective osteoarthritis drugs, and to investigate possible therapeutic options. PMID- 27977733 TI - Postprandial Glucose as a Risk Factor for Elevated Intraocular Pressure. AB - The aim of this study was to investigate the association between postprandial glucose and intraocular pressure in a relatively healthy population. We examined 1,439 adults getting a health check-up in a health promotion center at Tri Service General Hospital (TSGH) in Taiwan between 2012 and 2013. All participants underwent examinations to measure metabolic variables and intraocular pressure. Multiple linear regression analyses were performed to assess the relationship between postprandial glucose and intraocular pressure. The levels of postprandial glucose were divided into quartiles with subjects in the lowest quartile being regarded as the reference group to perform quartile-based analysis. Covariate adjustment was designed for three models for further analysis. Subjects with higher quartiles of postprandial glucose level had a higher systolic blood pressure, a greater waist circumference and an elevated fasting glucose level (all p < 0.001). The beta coefficient with adjusted covariates showed a significant positive association between postprandial glucose and intraocular pressure. The trends of intraocular pressure across increasing quartiles of postprandial glucose were statistically significant (all p for trend < 0.001). Thus, higher levels of postprandial glucose positively correlated with elevated intraocular pressure. PMID- 27977732 TI - The Role of Progesterone and a Novel Progesterone Receptor, Progesterone Receptor Membrane Component 1, in the Inflammatory Response of Fetal Membranes to Ureaplasma parvum Infection. AB - Ureaplasma parvum (U. parvum) is gaining recognition as an important pathogen for chorioamnionitis and preterm premature rupture of membranes. We aimed to investigate the roles of progesterone (P4) and a novel progesterone receptor, progesterone receptor membrane component 1 (PGRMC1), in the response of fetal membranes to U. parvum. Fetal membrane cells (amnion, chorion and decidua) were isolated and confirmed to be free of Mycoplasmataceae. Cells were treated with U. parvum (5x106 CFU), and adherence was quantified by qPCR. Amnion and chorion cells were transfected with scrambled siRNA or validated PGRMC1 siRNA for 72h. Cells were then treated with U. parvum for 4h with or without pretreatment with P4 (10-7 M) or ethanol for 1h. Interleukin-8 (IL-8), matrix metalloproteinase 9 (MMP9) and cyclooxygenase (COX-2) mRNA expression were quantified by qRT-PCR. Culture medium was harvested and analyzed for IL-8 and prostaglandin (PGE2) secretion by ELISA and MMP9 activity by zymography. U. parvum had a mean adherence of 15.0+/-0.6%, 16.9+/- 3.7% and 4.7+/-0.3% in cultured amnion, chorion and decidua cells, respectively. Exposure to U. parvum elicited significant inflammatory responses including induction of IL-8, COX-2, PGE2 and MMP9. A possible role of PGRMC1 was identified in the inhibition of U. parvum-stimulated COX-2 and MMP9 mRNA expression in chorion cells and MMP9 activity in amnion cells. On the other hand, it might enhance the U. parvum-stimulated IL-8 protein secretion in amnion cells. P4, mediated through PGRMC1, significantly inhibited U. Parvum-induced MMP9 mRNA and COX-2 mRNA expression in chorion cells. P4 appeared to attenuate U. parvum induced IL-8 mRNA expression in chorion cells, but this P4 effect might not mediated through PGRMC1. In summary, U. parvum preferentially adheres to and induces inflammatory responses in chorion and amnion cells. P4 and PGRMC1 appear to differentially modulate the inflammatory responses induced by U. parvum among amnion and chorion cells. PMID- 27977734 TI - Leading from the Centre: A Comprehensive Examination of the Relationship between Central Playing Positions and Leadership in Sport. AB - RESEARCH AIMS: The present article provides a comprehensive examination of the relationship between playing position and leadership in sport. More particularly, it explores links between leadership and a player's interactional centrality defined as the degree to which their playing position provides opportunities for interaction with other team members. This article examines this relationship across different leadership roles, team sex, and performance levels. RESULTS: Study 1 (N = 4443) shows that athlete leaders (and the task and motivational leader in particular) are more likely than other team members to occupy interactionally central positions in a team. Players with high interactional centrality were also perceived to be better leaders than those with low interactional centrality. Study 2 (N = 308) established this link for leadership in general, while Study 3 (N = 267) and Study 4 (N = 776) revealed that the same was true for task, motivational, and external leadership. This relationship is attenuated in sports where an interactionally central position confers limited interactional advantages. In other words, the observed patterns were strongest in sports that are played on a large field with relatively fixed positions (e.g., soccer), while being weaker in sports that are played on a smaller field where players switch positions dynamically (e.g., basketball, ice hockey). Beyond this, the pattern is broadly consistent across different sports, different sexes, and different levels of skill. CONCLUSIONS: The observed patterns are consistent with the idea that positions that are interactionally central afford players greater opportunities to do leadership-either through communication or through action. Significantly too, they also provide a basis for them to be seen to do leadership by others on their team. Thus while it is often stated that "leadership is an action, not a position," it is nevertheless the case that, when it comes to performing that action, some positions are more advantageous than others. PMID- 27977737 TI - Chinese Immigrant Wealth: Heterogeneity in Adaptation. AB - Chinese immigrants are a diverse and growing group whose members provide a unique opportunity to examine within-immigrant group differences in adaptation. In this paper, we move beyond thinking of national-origin groups as homogenous and study variation among Chinese immigrants in wealth ownership, a critical indicator of adaptation that attracts relatively little attention in the immigration literature. We develop an analytical approach that considers national origin, tenure in the U.S., and age to examine heterogeneity in economic adaptation among the immigrant generation. Our results show that variations among Chinese immigrants explain within-group differences in net worth, asset ownership, and debt. These differences also account for important variation between Chinese immigrants, natives, and other immigrant groups and provide important, new insight into the processes that lead to immigrant adaptation and long-term class stability. PMID- 27977735 TI - Genome Analysis of Streptococcus pyogenes Associated with Pharyngitis and Skin Infections. AB - Streptococcus pyogenes is a very important human pathogen, commonly associated with skin or throat infections but can also cause life-threatening situations including sepsis, streptococcal toxic shock syndrome, and necrotizing fasciitis. Various studies involving typing and molecular characterization of S. pyogenes have been published to date; however next-generation sequencing (NGS) studies provide a comprehensive collection of an organism's genetic variation. In this study, the genomes of nine S. pyogenes isolates associated with pharyngitis and skin infection were sequenced and studied for the presence of virulence genes, resistance elements, prophages, genomic recombination, and other genomic features. Additionally, a comparative phylogenetic analysis of the isolates with global clones highlighted their possible evolutionary lineage and their site of infection. The genomes were found to also house a multitude of features including gene regulation systems, virulence factors and antimicrobial resistance mechanisms. PMID- 27977736 TI - The Three Streptomyces lividans HtrA-Like Proteases Involved in the Secretion Stress Response Act in a Cooperative Manner. AB - Overproduction of Sec-proteins in S. lividans accumulates misfolded proteins outside of the cytoplasmic membrane where the accumulated proteins interfere with the correct functioning of the secretion machinery and with the correct cell functionality, triggering the expression in S. lividans of a CssRS two-component system which regulates the degradation of the accumulated protein, the so-called secretion stress response. Optimization of secretory protein production via the Sec route requires the identification and characterisation of quality factors involved in this process. The phosphorylated regulator (CssR) interacts with the regulatory regions of three genes encoding three different HtrA-like proteases. Individual mutations in each of these genes render degradation of the misfolded protein inoperative, and propagation in high copy number of any of the three proteases encoding genes results on indiscriminate alpha-amylase degradation. None of the proteases could complement the other two deficiencies and only propagation of each single copy protease gene can restore its own deficiency. The obtained results strongly suggest that the synthesis of the three HtrA-like proteases needs to be properly balanced to ensure the effective degradation of misfolded overproduced secretory proteins and, at the same time, avoid negative effects in the secreted proteins and the secretion machinery. This is particularly relevant when considering the optimisation of Streptomyces strains for the overproduction of homologous or heterologous secretory proteins of industrial application. PMID- 27977739 TI - Use of the Endophytic Fungus Daldinia cf. concentrica and Its Volatiles as Bio Control Agents. AB - Endophytic fungi are organisms that spend most of their life cycle within plant tissues without causing any visible damage to the host plant. Many endophytes were found to secrete specialized metabolites and/or emit volatile organic compounds (VOCs), which may be biologically active and assist fungal survival inside the plant as well as benefit their hosts. We report on the isolation and characterization of a VOCs-emitting endophytic fungus, isolated from an olive tree (Olea europaea L.) growing in Israel; the isolate was identified as Daldinia cf. concentrica. We found that the emitted VOCs were active against various fungi from diverse phyla. Results from postharvest experiments demonstrated that D. cf. concentrica prevented development of molds on organic dried fruits, and eliminated Aspergillus niger infection in peanuts. Gas chromatography-mass spectrometry analysis of the volatiles led to identification of 27 VOCs. On the basis of these VOCs we prepared two mixtures that displayed a broad spectrum of antifungal activity. In postharvest experiments these mixtures prevented development of molds on wheat grains, and fully eliminated A. niger infection in peanuts. In light of these findings, we suggest use of D. cf. concentrica and/or its volatiles as an alternative approach to controlling phytopathogenic fungi in the food industry and in agriculture. PMID- 27977738 TI - Small Heat Shock Protein alphaB-Crystallin Controls Shape and Adhesion of Glioma and Myoblast Cells in the Absence of Stress. AB - Cell shape and adhesion and their proper controls are fundamental for all biological systems. Mesenchymal cells migrate at an average rate of 6 to 60 MUm/hr, depending on the extracellular matrix environment and cell signaling. Myotubes, fully differentiated muscle cells, are specialized for power-generation and therefore lose motility. Cell spreading and stabilities of focal adhesion are regulated by the critical protein vinculin from immature myoblast to mature costamere of differentiated myotubes where myofibril Z-band linked to sarcolemma. The Z-band is constituted from microtubules, intermediate filaments, cell adhesion molecules and other adapter proteins that communicate with the outer environment. Mesenchymal cells, including myoblast cells, convert actomyosin contraction forces to tension through mechano-responsive adhesion assembly complexes as Z-band equivalents. There is growing evidence that microtubule dynamics are involved in the generation of contractile forces; however, the roles of microtubules in cell adhesion dynamics are not well determined. Here, we show for the first time that alphaB-crystallin, a molecular chaperon for tubulin/microtubules, is involved in cell shape determination. Moreover, knockdown of this molecule caused myoblasts and glioma cells to lose their ability for adhesion as they tended to behave like migratory cells. Surprisingly, alphaB-crystallin knockdown in both C6 glial cells and L6 myoblast permitted cells to migrate more rapidly (2.7 times faster for C6 and 1.3 times faster for L6 cells) than dermal fibroblast. On the other hand, overexpression of alphaB crystallin in cells led to an immortal phenotype because of persistent adhesion. Position of matured focal adhesion as visualized by vinculin immuno-staining, stress fiber direction, length, and density were clearly alphaB-crystallin dependent. These results indicate that the small HSP alphaB-crystallin has important roles for cell adhesion, and thus microtubule dynamics are necessary for persistent adhesion. PMID- 27977740 TI - All Trans Retinoic Acid, Transforming Growth Factor beta and Prostaglandin E2 in Mouse Plasma Synergize with Basophil-Secreted Interleukin-4 to M2 Polarize Murine Macrophages. AB - In previous studies we found that macrophages (MFs) from SH2-containing inositol 5'-phosphatase (SHIP) deficient mice are M2 polarized while their wild type (WT) counterparts are M1 polarized and that this difference in MF phenotype can be recapitulated during in vitro derivation from bone marrow if mouse plasma (MP), but not fetal calf serum, is added to standard M-CSF-containing cultures. In the current study we investigated the mechanism by which MP skews SHIP-/- but not +/+ MFs to an M2 phenotype. Our results suggest that SHIP-/- basophils constitutively secrete higher levels of IL-4 than SHIP+/+ basophils and this higher level of IL 4 is sufficient to skew both SHIP+/+ and SHIP-/- MFs to an M2 phenotype, but only when MP is present to increase the sensitivity of the MFs to this level of IL-4. MP increases the IL-4 sensitivity of both SHIP+/+ and -/- MFs not by increasing cell surface IL-4 or CD36 receptor levels, but by triggering the activation of Erk and Akt and the production of ROS, all of which play a critical role in sensitizing MFs to IL-4-induced M2 skewing. Studies to identify the factor(s) in MP responsible for promoting IL-4-induced M2 skewing suggests that all-trans retinoic acid (ATRA), TGFbeta and prostaglandin E2 (PGE2) all play a role. Taken together, these results indicate that basophil-secreted IL-4 plays an essential role in M2 skewing and that ATRA, TGFbeta and PGE2 within MP collaborate to dramatically promote M2 skewing by acting directly on MFs to increase their sensitivity to IL-4. PMID- 27977741 TI - Analysis of Sequence Variation and Risk Association of Human Papillomavirus 52 Variants Circulating in Korea. AB - INTRODUCTION: Human papillomavirus (HPV) 52 is a carcinogenic, high-risk genotype frequently detected in cervical cancer cases from East Asia, including Korea. MATERIALS AND METHODS: Sequences of HPV52 detected in 91 cervical samples collected from women attending Seoul St. Mary's Hospital were analyzed. HPV52 genomic sequences were obtained by polymerase chain reaction (PCR)-based sequencing and analyzed using Seq-Scape software, and phylogenetic trees were constructed using MEGA6 software. RESULTS: Of the 91 cervical samples, 40 were normal, 22 were low-grade lesions, 21 were high-grade lesions and 7 were squamous cell carcinomas. Four HPV52 variant lineages (A, B, C and D) were identified. Lineage B was the most frequently detected lineage, followed by lineage C. By analyzing the two most frequently detected lineages (B and C), we found that distinct variations existed in each lineage. We also found that a lineage B specific mutation K93R (A379G) was associated with an increased risk of cervical neoplasia. CONCLUSIONS: To our knowledge, we are the first to reveal the predominance of the HPV52 lineages, B and C, in Korea. We also found these lineages harbored distinct genetic alterations that may affect oncogenicity. Our findings increase our understanding on the heterogeneity of HPV52 variants, and may be useful for the development of new diagnostic assays and therapeutic vaccines. PMID- 27977742 TI - Euphorbia Kansui Reactivates Latent HIV. AB - While highly active anti-retroviral therapy has greatly improved the lives of HIV infected individuals, these treatments are unable to eradicate the virus. Current approaches to reactivate the virus have been limited by toxicity, lack of an orally available therapy, and limited responses in primary CD4+ T cells and in clinical trials. The PKC agonist ingenol, purified from Euphorbia plants, is a potent T cell activator and reactivates latent HIV. Euphorbia kansui itself has been used for centuries in traditional Chinese medicine to treat ascites, fluid retention, and cancer. We demonstrate that an extract of this plant, Euphorbia kansui, is capable of recapitulating T cell activation induced by the purified ingenol. Indeed, Euphorbia kansui induced expression of the early T cell activation marker CD69 and P-TEFb in a dose-dependent manner. Furthermore, Euphorbia kansui reactivated latent HIV in a CD4+ T cell model of latency and in HIV+ HAART suppressed PBMC. When combined with the other latency reversing agents, the effective dose of Euphorbia kansui required to reactive HIV was reduced 10-fold and resulted in synergistic reactivation of latent HIV. We conclude that Euphorbia Euphorbia kansui reactivates latent HIV and activates CD4+ T cells. When used in combination with a latency reversing agent, the effective dose of Euphorbia kansui is reduced; which suggests its application as a combination strategy to reactivate latent HIV while limiting the toxicity due to global T cell activation. As a natural product, which has been used in traditional medicine for thousands of years, Euphorbia kansui is attractive as a potential treatment strategy, particularly in resource poor countries with limited treatment options. Further clinical testing will be required to determine its safety with current anti-retroviral therapies. PMID- 27977743 TI - Spatial Variation of Soil Respiration in a Cropland under Winter Wheat and Summer Maize Rotation in the North China Plain. AB - Spatial variation of soil respiration (Rs) in cropland ecosystems must be assessed to evaluate the global terrestrial carbon budget. This study aims to explore the spatial characteristics and controlling factors of Rs in a cropland under winter wheat and summer maize rotation in the North China Plain. We collected Rs data from 23 sample plots in the cropland. At the late jointing stage, the daily mean Rs of summer maize (4.74 MUmol CO2 m-2 s-1) was significantly higher than that of winter wheat (3.77MUmol CO2 m-2 s-1). However, the spatial variation of Rs in summer maize (coefficient of variation, CV = 12.2%) was lower than that in winter wheat (CV = 18.5%). A similar trend in CV was also observed for environmental factors but not for biotic factors, such as leaf area index, aboveground biomass, and canopy chlorophyll content. Pearson's correlation analyses based on the sampling data revealed that the spatial variation of Rs was poorly explained by the spatial variations of biotic factors, environmental factors, or soil properties alone for winter wheat and summer maize. The similarly non-significant relationship was observed between Rs and the enhanced vegetation index (EVI), which was used as surrogate for plant photosynthesis. EVI was better correlated with field-measured leaf area index than the normalized difference vegetation index and red edge chlorophyll index. All the data from the 23 sample plots were categorized into three clusters based on the cluster analysis of soil carbon/nitrogen and soil organic carbon content. An apparent improvement was observed in the relationship between Rs and EVI in each cluster for both winter wheat and summer maize. The spatial variation of Rs in the cropland under winter wheat and summer maize rotation could be attributed to the differences in spatial variations of soil properties and biotic factors. The results indicate that applying cluster analysis to minimize differences in soil properties among different clusters can improve the role of remote sensing data as a proxy of plant photosynthesis in semi-empirical Rs models and benefit the acquisition of Rs in cropland ecosystems at large scales. PMID- 27977744 TI - Turkish Final Year Medical Students' Exposure to and Attitudes Concerning Drug Company Interactions: A Perspective from a Minimally Regulated Environment for Medical Students. AB - Interactions between drug companies and medical students may affect evidence based medical practice and patient safety. The aim of this study was to assess drug company-medical student interactions in a medical faculty where limited specific national or institutional regulations apply between drug companies and medical students. The objectives of the study were to determine the exposure and attitudes of final year medical students in terms of drug company-medical student and physician interactions, to identify factors affecting those attitudes and to provide data for policymakers working on the regulation of interactions between drug companies and medical students. This anonymous questionnaire-based study of 154 medical final year medical students at the Karadeniz Technical University Medical Faculty, Trabzon, Turkey, in April and May 2015 attracted a response rate of 92.2% (n/N, 154/164). Exposure to interaction with a pharmaceutical representative was reported by 90.3% (139/154) of students, and 68.8% (106/154) reported experiencing such interaction alongside a resident. In addition, 83.7% (128/153) of students reported an interaction during internship. Furthermore, 69.9% (107/153) of students agreed that interactions influence physicians' prescription preferences, while 33.1% (51/154) thought that a medical student should never accept a gift from a drug company and 24.7% (38/154) agreed with the proposition that "drug companies should not hold activities in medical faculties". Students with rational prescription training expressed greater agreement with the statement "I am skeptical concerning the information provided by drug companies during interactions" than those who had not received such training, and this finding was supported by logistic regression [O.R.(C.I), p 3.7(1.2-11.5), p = 0.022]. Acceptance of advertisement brochures was found to significantly reduce the level of agreement with the proposition that "A physician should not accept any gift from a drug company." (0.3[0.1-0.9], p = 0.030). In summary, exposure to drug companies was widespread among our final year medical students who, like students in both Western and non-Western societies, hold permissive attitudes concerning accepting gifts, and drug advertising brochures may relax those permissive attitudes still further. Rational prescription training was useful in generating rational attitudes. Policies concerning drug company-medical student relationships should be developed in Turkey as well as internationally. PMID- 27977745 TI - Barriers to Institutional Childbirth in Rumbek North County, South Sudan: A Qualitative Study. AB - BACKGROUND: South Sudan has one of the world's poorest health indicators due to a fragile health system and a combination of socio-cultural, economic and political factors. This study was conducted to identify barriers to utilisation of institutional childbirth services in Rumbek North County. METHODS: Data were collected through 14 focus group discussions with 169 women and 45 men, and 18 key informant interviews with community leaders, staff working in health facilities, traditional birth attendants, and the staff of the County Health Department. Data were analysed using inductive content analysis. RESULTS: The barriers to institutional childbirth were categorised under four main themes: 1) Issues related to access and lack of resources: long distance to health facilities, lack of transportation means, referral problems, flooding and poor roads, and payments in health facilities; 2) Issues related to the socio-cultural context and conflict: insecurity, influence of the husband, lack of birth preparedness, domestic chores of women, influence of culture; 3) Perceptions about pregnancy and childbirth: perceived benefit of institutional childbirth, low childbirth risk perception, and medicalisation of childbirth including birth being perceived to be natural, undesirable birth practices, privacy concerns, and fear of caesarean section; and 4) Perceptions about the quality of care: inadequate health facility infrastructure and perceived neglect during admission. CONCLUSIONS: Multiple factors hinder institutional childbirth in Rumbek North. Some of the factors such as insecurity and poor roads are outside the scope of the health sector and will require a multi-sectoral approach if childbirth services are to be made accessible to women. Detailed recommendations to increase utilisation of childbirth services in the county have been suggested. PMID- 27977746 TI - Two-Phase Bactericidal Mechanism of Silver Nanoparticles against Burkholderia pseudomallei. AB - Silver nanoparticles (AgNPs) have a strong antimicrobial activity against a variety of pathogenic bacteria. The killing mechanism of AgNPs involves direct physical membrane destruction and subsequent molecular damage from both AgNPs and released Ag+. Burkholderia pseudomallei is the causative agent of melioidosis, an endemic infectious disease primarily found in northern Australia and Southeast Asia. B. pseudomallei is intrinsically resistant to most common antibiotics. In this study, the antimicrobial activity and mechanism of AgNPs (10-20 nm) against B. pseudomallei were investigated. The MIC and MBC for nine B. pseudomallei strains ranged from 32-48 MUg/mL and 96-128 MUg/mL, respectively. Concentrations of AgNPs less than 256 MUg/mL were not toxic to human red blood cells. AgNPs exhibited a two-phase mechanism: cell death induction and ROS induction. The first phase was a rapid killing step within 5 min, causing the direct damage of the cytoplasmic membrane of the bacterial cells, as observed by a time-kill assay and fluorescence microscopy. During the period of 5-30 min, the cell surface charge was rapidly neutralized from -8.73 and -7.74 to 2.85 and 2.94 mV in two isolates of B. pseudomallei, as revealed by zeta potential measurement. Energy dispersive X-ray (EDX) spectroscopy showed the silver element deposited on the bacterial membrane, and TEM micrographs of the AgNP-treated B. pseudomallei cells showed severe membrane damage and cytosolic leakage at 1/5 MIC and cell bursting at MBC. During the killing effect the released Ag+ from AgNPs was only 3.9% from the starting AgNPs concentration as observed with ICP-OES experiment. In the second phase, the ROS induction occurred 1-4 hr after the AgNP treatment. Altogether, we provide direct kinetic evidence of the AgNPs killing mechanism, by which cell death is separable from the ROS induction and AgNPs mainly contributes in the killing action. AgNPs may be considered a potential candidate to develop a novel alternative agent for melioidosis treatment with fast action. PMID- 27977748 TI - Massively Parallelized Pollen Tube Guidance and Mechanical Measurements on a Lab on-a-Chip Platform. AB - Pollen tubes are used as a model in the study of plant morphogenesis, cellular differentiation, cell wall biochemistry, biomechanics, and intra- and intercellular signaling. For a "systems-understanding" of the bio-chemo-mechanics of tip-polarized growth in pollen tubes, the need for a versatile, experimental assay platform for quantitative data collection and analysis is critical. We introduce a Lab-on-a-Chip (LoC) concept for high-throughput pollen germination and pollen tube guidance for parallelized optical and mechanical measurements. The LoC localizes a large number of growing pollen tubes on a single plane of focus with unidirectional tip-growth, enabling high-resolution quantitative microscopy. This species-independent LoC platform can be integrated with micro /nano-indentation systems, such as the cellular force microscope (CFM) or the atomic force microscope (AFM), allowing for rapid measurements of cell wall stiffness of growing tubes. As a demonstrative example, we show the growth and directional guidance of hundreds of lily (Lilium longiflorum) and Arabidopsis (Arabidopsis thaliana) pollen tubes on a single LoC microscopy slide. Combining the LoC with the CFM, we characterized the cell wall stiffness of lily pollen tubes. Using the stiffness statistics and finite-element-method (FEM)-based approaches, we computed an effective range of the linear elastic moduli of the cell wall spanning the variability space of physiological parameters including internal turgor, cell wall thickness, and tube diameter. We propose the LoC device as a versatile and high-throughput phenomics platform for plant reproductive and development biology using the pollen tube as a model. PMID- 27977747 TI - Impact of NKT Cells and LFA-1 on Liver Regeneration under Subseptic Conditions. AB - BACKGROUND: Activation of the immune system in terms of subseptic conditions during liver regeneration is of paramount clinical importance. However, little is known about molecular mechanisms and their mediators that control hepatocyte proliferation. We sought to determine the functional role of immune cells, especially NKT cells, in response to partial hepatectomy (PH), and to uncover the impact of the integrin lymphocyte function-associated antigen-1 (LFA-1) on liver regeneration in a subseptic setting. METHODS: Wild-type (WT) and LFA-1-/- mice underwent a 2/3 PH and low-dose lipopolysaccharid (LPS) application. Hepatocyte proliferation, immune cell infiltration, and cytokine profile in the liver parenchyma were determined. RESULTS: Low-dose LPS application after PH results in a significant delay of liver regeneration between 48h and 72h, which is associated with a reduced number of CD3+ cells within the regenerating liver. In absence of LFA-1, an impaired regenerative capacity was observed under low-dose LPS application. Analysis of different leukocyte subpopulations showed less CD3+NK1.1+ NKT cells in the liver parenchyma of LFA-1-/- mice after PH and LPS application compared to WT controls, while CD3-NK1.1+ NK cells markedly increased. Concordantly with this observation, lower levels of NKT cell related cytokines IL-12 and IL-23 were expressed in the regenerating liver of LFA-1-/- mice, while the expression of NK cell-associated CCL5 and IL-10 was increased compared to WT mice. CONCLUSION: A subseptic situation negatively alters hepatocyte proliferation. Within this scenario, we suggest an important impact of NKT cells and postulate a critical function for LFA-1 during processes of liver regeneration. PMID- 27977749 TI - Is the Risk of Preterm Birth and Low Birth Weight Affected by the Use of Antidepressant Agents during Pregnancy? A Population-Based Investigation. AB - BACKGROUND: Untreated depression during pregnancy increases the risk of morbidity and mortality in the mother and child. Therefore, specific treatments are required for this population. OBJECTIVE: The study aimed to investigating the effect of antidepressant medication used during pregnancy with reference to the risk of preterm birth (PTB) and low birth weight (LBW). METHODS: A population based study was carried out with data provided by the healthcare utilization database of Lombardy, an Italian region with about ten million inhabitants. The study included 384,673 births from 2005 to 2010. Maternal use of antidepressants before and during pregnancy was investigated. Log-binomial regression was used to estimate the association between the use of antidepressants during pregnancy, compared to the non-use or use just before pregnancy, and the prevalence ratio of PTB and LBW. RESULTS: Women who used antidepressants during pregnancy had a 20% (95% CI: 10-40%) increased prevalence of both PTB and LBW compared to those who never used antidepressants. There was no evidence that women who used antidepressants during pregnancy had a higher prevalence of the considered outcomes compared to women who used antidepressants before pregnancy, but stopped during pregnancy. Such findings were confirmed by considering separately the effects of SSRIs and other antidepressants together. CONCLUSIONS: Our findings suggest that depression in itself, rather than antidepressant medication, might be implicated in the causal pathway of PTB and LBW. PMID- 27977750 TI - The Arabidopsis Gene zinc finger protein 3(ZFP3) Is Involved in Salt Stress and Osmotic Stress Response. AB - Plants are continuously challenged by various abiotic and biotic stresses. To tide over these adversities, plants evolved intricate regulatory networks to adapt these unfavorable environments. So far, many researchers have clarified the molecular and genetic pathways involved in regulation of stress responses. However, the mechanism through which these regulatory networks operate is largely unknown. In this study, we cloned a C2H2-type zinc finger protein gene ZFP3 from Arabidopsis thaliana and investigated its function in salt and osmotic stress response. Our results showed that the expression level of ZFP3 was highly suppressed by NaCl, mannitol and sucrose. Constitutive expression of ZFP3 enhanced tolerance of plants to salt and osmotic stress while the zfp3 mutant plants displays reduced tolerance in Arabidopsis. Gain- and Loss-of-function studies of ZFP3 showed that ZFP3 significantly changes proline accumulation and chlorophyll content. Furthermore, over-expression of ZFP3 induced the expressions of stress-related gene KIN1, RD22, RD29B and AtP5CS1. These results suggest that ZFP3 is involved in salt and osmotic stress response. PMID- 27977751 TI - Characterisation of Commensal Escherichia coli Isolated from Apparently Healthy Cattle and Their Attendants in Tanzania. AB - While pathogenic types of Escherichia coli are well characterized, relatively little is known about the commensal E. coli flora. In the current study, antimicrobial resistance in commensal E. coli and distribution of ERIC-PCR genotypes among isolates of such bacteria from cattle and cattle attendants on cattle farms in Tanzania were investigated. Seventeen E. coli genomes representing different ERIC-PCR types of commensal E. coli were sequenced in order to determine their possible importance as a reservoir for both antimicrobial resistance genes and virulence factors. Both human and cattle isolates were highly resistant to tetracycline (40.8% and 33.1%), sulphamethazole trimethoprim (49.0% and 8.8%) and ampicillin (44.9% and 21.3%). However, higher proportion of resistant E. coli and higher frequency of resistance to more than two antimicrobials was found in isolates from cattle attendants than isolates from cattle. Sixteen out of 66 ERIC-PCR genotypes were shared between the two hosts, and among these ones, seven types contained isolates from cattle and cattle attendants from the same farm, suggesting transfer of strains between hosts. Genome-wide analysis showed that the majority of the sequenced cattle isolates were assigned to phylogroups B1, while human isolates represented phylogroups A, C, D and E. In general, in silico resistome and virulence factor identification did not reveal differences between hosts or phylogroups, except for lpfA and iss found to be cattle and B1 phylogroup specific. The most frequent plasmids replicon genes found in strains from both hosts were of IncF type, which are commonly associated with carriage of antimicrobial and virulence genes. Commensal E. coli from cattle and attendants were found to share same genotypes and to carry antimicrobial resistance and virulence genes associated with both intra and extraintestinal E. coli pathotypes. PMID- 27977753 TI - Recruitment Kinetics of Tropomyosin Tpm3.1 to Actin Filament Bundles in the Cytoskeleton Is Independent of Actin Filament Kinetics. AB - The actin cytoskeleton is a dynamic network of filaments that is involved in virtually every cellular process. Most actin filaments in metazoa exist as a co polymer of actin and tropomyosin (Tpm) and the function of an actin filament is primarily defined by the specific Tpm isoform associated with it. However, there is little information on the interdependence of these co-polymers during filament assembly and disassembly. We addressed this by investigating the recovery kinetics of fluorescently tagged isoform Tpm3.1 into actin filament bundles using FRAP analysis in cell culture and in vivo in rats using intracellular intravital microscopy, in the presence or absence of the actin-targeting drug jasplakinolide. The mobile fraction of Tpm3.1 is between 50% and 70% depending on whether the tag is at the C- or N-terminus and whether the analysis is in vivo or in cultured cells. We find that the continuous dynamic exchange of Tpm3.1 is not significantly impacted by jasplakinolide, unlike tagged actin. We conclude that tagged Tpm3.1 may be able to undergo exchange in actin filament bundles largely independent of the assembly and turnover of actin. PMID- 27977754 TI - Expression of APOBEC3B mRNA in Primary Breast Cancer of Japanese Women. AB - Recent studies have identified the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3B (APOBEC3B) as a source of mutations in various malignancies. APOBEC3B is overexpressed in several human cancer types, including breast cancer. In this study, we analyzed APOBEC3B mRNA expression in 305 primary breast cancers of Japanese women using quantitative reverse transcription-PCR, and investigated the relationships between the APOBEC3B mRNA expression and clinicopathological characteristics, prognosis, and TP53 mutations. The expression of APOBEC3B mRNA was detected in 277 tumors and not detected in 28 tumors. High APOBEC3B mRNA expression was significantly correlated with ER- and PR-negativity, high grade and high Ki67 index. The APOBEC3B mRNA expression was highest in the triple negative and lowest in the hormone receptor-positive/HER2-negative subtypes. The TP53 gene was more frequently mutated in the tumors with high APOBEC3B mRNA expression. High APOBEC3B mRNA expression was significantly associated with poor recurrence-free survival in all cases and the ER-positive cases. These findings were almost consistent with the previous reports from the Western countries. In conclusion, high APOBEC3B mRNA expression was related to the aggressive phenotypes of breast cancer, high frequency of TP53 mutation and poor prognosis, especially in ER-positive tumors. PMID- 27977752 TI - GSK-3beta/NFAT Signaling Is Involved in Testosterone-Induced Cardiac Myocyte Hypertrophy. AB - Testosterone induces cardiac hypertrophy through a mechanism that involves a concerted crosstalk between cytosolic and nuclear signaling pathways. Nuclear factor of activated T-cells (NFAT) is associated with the promotion of cardiac hypertrophy, glycogen synthase kinase-3beta (GSK-3beta) is considered to function as a negative regulator, mainly by modulating NFAT activity. However, the role played by calcineurin-NFAT and GSK-3beta signaling in testosterone-induced cardiac hypertrophy has remained unknown. Here, we determined that testosterone stimulates cardiac myocyte hypertrophy through NFAT activation and GSK-3beta inhibition. Testosterone increased the activity of NFAT-luciferase (NFAT-Luc) in a time- and dose-dependent manner, with the activity peaking after 24 h of stimulation with 100 nM testosterone. NFAT-Luc activity induced by testosterone was blocked by the calcineurin inhibitors FK506 and cyclosporine A and by 11R VIVIT, a specific peptide inhibitor of NFAT. Conversely, testosterone inhibited GSK-3beta activity as determined by increased GSK-3beta phosphorylation at Ser9 and beta-catenin protein accumulation, and also by reduction in beta-catenin phosphorylation at residues Ser33, Ser37, and Thr41. GSK-3beta inhibition with 1 azakenpaullone or a GSK-3beta-targeting siRNA increased NFAT-Luc activity, whereas overexpression of a constitutively active GSK-3beta mutant (GSK-3betaS9A) inhibited NFAT-Luc activation mediated by testosterone. Testosterone-induced cardiac myocyte hypertrophy was established by increased cardiac myocyte size and [3H]-leucine incorporation (as a measurement of cellular protein synthesis). Calcineurin-NFAT inhibition abolished and GSK-3beta inhibition promoted the hypertrophy stimulated by testosterone. GSK-3beta activation by GSK-3betaS9A blocked the increase of hypertrophic markers induced by testosterone. Moreover, inhibition of intracellular androgen receptor prevented testosterone-induced NFAT Luc activation. Collectively, these results suggest that cardiac myocyte hypertrophy induced by testosterone involves a cooperative mechanism that links androgen signaling with the recruitment of NFAT through calcineurin activation and GSK-3beta inhibition. PMID- 27977755 TI - Concurrent Treatment with Taxifolin and Cilostazol on the Lowering of beta Amyloid Accumulation and Neurotoxicity via the Suppression of P-JAK2/P-STAT3/NF kappaB/BACE1 Signaling Pathways. AB - Taxifolin is a potent flavonoid that exerts anti-oxidative effect, and cilostazol increases intracellular cAMP levels by inhibiting phosphodiesterase 3 that shows antiinflammatory actions. BACE1 (beta-site APP cleaving enzyme 1) is the rate limiting enzyme responsible for the beta-cleavage of amyloid precursor proteins to Abeta peptides. In this study, endogenous Abeta and C99 accumulation was explored in N2a Swe cells exposed to 1% FBS medium. Increased Abeta and C99 levels were significantly attenuated by taxifolin alone and in combination with cilostazol. Increased phosphorylated JAK2 at Tyr1007/1008 (P-JAK), phosphorylated STAT3 at Tyr 705 (P-STAT3) expressions and increased expressions of BACE1 mRNA and protein in the activated N2a Swe cells were significantly attenuated by taxifolin (10~50 MUM), cilostazol (10~50 MUM) alone and in combination at minimum concentrations. In these cells, decreased cytosol IkappaBalpha expression was elevated, and increased nuclear NF-kappaB p65 level and nuclear NF-kappaB p65 DNA binding activity were significantly reduced by taxifolin and cilostazol in a similar manner. Following STAT3 gene (~70% reduction) knockdown in N2a cells, Abeta-induced nuclear NF-kappaB and BACE1 expressions were not observed. Taxifolin, cilostazol, or resveratrol significantly stimulated SIRT1 protein expression. In SIRT1 gene-silenced (~50%) N2a cells, taxifolin, cilostazol, and resveratrol all failed to suppress Abeta1-42-stimulated P-STAT3 and BACE1 expression. Consequently, taxifolin and cilostazol were found to significantly decrease lipopolysaccharide (1-10 MUg/ml)-induced iNOS and COX-2 expressions, and nitrite production in cultured BV-2 microglia cells and to increase N2a cell viability. In conclusion, taxifolin and cilostazol strongly inhibited amyloidogenesis in a synergistic manner by suppressing P-JAK2/P-STAT3-coupled NF kappaB-linked BACE1 expression via the up-regulation of SIRT1. PMID- 27977756 TI - Determinants of Catastrophic Dental Health Expenditure in China. AB - This study explored catastrophic health expenditure in China, due to out-of pocket payments for dental care, and its associated individual- and contextual level factors. We pooled data from 31,566 adults who participated in the third National Oral Health Survey with province-level data from different sources. We defined catastrophic dental health expenditure (CDHE) as payments for dental services and/or medication for dental problems during the last year that exceeded the 10% and 20% of the household income. The association of individual and contextual factors with catastrophic dental health expenditure was evaluated using two-level logistic regression models with individuals nested within provinces. Socioeconomic position (education and household income), household size and dental status (pain in teeth or mouth and number of teeth) were the individual-level factors associated with CDHE among the full sample of participants; and, also, among those who used dental services in the past year. Greater gross domestic product per capita was the only contextual factor associated with CDHE, and only at the lower income threshold. This study shows that out-of-pocket expenses for dental services may put a considerable, and unnecessary, burden on households' finances. Our findings also help characterise those households more likely to face catastrophic expenditure on health if they have to pay for dental services. PMID- 27977757 TI - Docosahexanoic Acid Plus Vitamin D Treatment Improves Features of NAFLD in Children with Serum Vitamin D Deficiency: Results from a Single Centre Trial. AB - BACKGROUND: There are no licensed treatments for non alcoholic fatty liver disease (NAFLD) in adults or children. In NAFLD, several studies have shown a benefit of omega-3 fatty acid treatment on lipid profile, insulin-sensitivity and hepatic steatosis and it has also been suggested that Vitamin D treatment has potential antifibrotic properties in liver disease. TRIAL DESIGN: To date, however, there are no studies that have tested the combination of Docosahexanoic acid (DHA) and vitamin D treatment which may benefit the whole spectrum of disease in NAFLD. Our aim therefore, was to test the effect of daily DHA (500 mg) plus vitamin D (800 IU) treatment, in obese children with biopsy-proven NAFLD and vitamin D deficiency, in a randomized, double-blind placebo-controlled trial. METHODS: The 41/43 patients completed the study (18-treatment, 23-placebo). At 12 months: i) the main outcome was liver histology improvement, defined by NAS; ii) the secondary outcome was amelioration of metabolic parameters. RESULTS: DHA plus vitamin D treatment reduced the NAFLD Activity Score (NAS), in the treatment group (5.4 v1.92; p<0.001 for baseline versus end of study). There was no change in fibrosis score, but a reduction of the activation of hepatic stellate cells (HSC) and fibrillar collagen content was noted (3.51+/-1.66 v. 1.59+/-1.37; p = 0.003) in treatment group. Moreover, the triglycerides (174.5 vs. 102.15 mg/dl), ALT (40.25 vs. 24.5 UI/l) and HOMA-IR (4.59 vs. 3.42) were all decreased with treatment. CONCLUSION: DHA plus vitamin D treatment improved insulin-resistance, lipid profile, ALT and NAS. There was also decreased HSC activation and collagen content with treatment. PMID- 27977758 TI - Quadri-Pulse Theta Burst Stimulation using Ultra-High Frequency Bursts - A New Protocol to Induce Changes in Cortico-Spinal Excitability in Human Motor Cortex. AB - Patterned transcranial magnetic stimulation (TMS) such as theta burst stimulation (TBS) or quadri-pulse stimulation (QPS) can induce changes in cortico-spinal excitability, commonly referred to as long-term potentiation (LTP)-like and long term depression (LTD)-like effects in human motor cortex (M1). Here, we aimed to test the plasticity-inducing capabilities of a novel protocol that merged TBS and QPS. 360 bursts of quadri-pulse TBS (qTBS) were continuously given to M1 at 90% of active motor threshold (1440 full-sine pulses). In a first experiment, stimulation frequency of each burst was set to 666 Hz to mimic the rhythmicity of the descending cortico-spinal volleys that are elicited by TMS (i.e., I-wave periodicity). In a second experiment, burst frequency was set to 200 Hz to maximize postsynaptic Ca2+ influx using a temporal pattern unrelated to I-wave periodicity. The second phase of sinusoidal TMS pulses elicited either a posterior-anterior (PA) or anterior-posterior (AP) directed current in M1. Motor evoked potentials (MEPs) were recorded before and after qTBS to probe changes in cortico-spinal excitability. PA-qTBS at 666 Hz caused a decrease in PA-MEP amplitudes, whereas AP-qTBS at 666 Hz induced an increase in mean AP-MEP amplitudes. At a burst frequency of 200 Hz, PA-qTBS and AP-qTBS produced an increase in cortico-spinal excitability outlasting for at least 60 minutes in PA- and AP-MEP amplitudes, respectively. Continuous qTBS at 666 Hz or 200 Hz can induce lasting changes in cortico-spinal excitability. Induced current direction in the brain appears to be relevant when qTBS targets I-wave periodicity, corroborating that high-fidelity spike timing mechanisms are critical for inducing bi-directional plasticity in human M1. PMID- 27977759 TI - Viscolin Inhibits In Vitro Smooth Muscle Cell Proliferation and Migration and Neointimal Hyperplasia In Vivo. AB - Viscolin, an extract of Viscum coloratum, has anti-inflammatory and anti proliferative properties against harmful stimuli. The aim of the study was to examine the anti-proliferative effects of viscolin on platelet derived growth factor-BB (PDGF)-treated human aortic smooth muscle cells (HASMCs) and identify the underlying mechanism responsible for these effects. Viscolin reduced the PDGF BB-induced HASMC proliferation and migration in vitro; it also arrested HASMCs in the G0/G1 phase by decreasing the protein expression of Cyclin D1, CDK2, Cyclin E, CDK4, and p21Cip1 as detected by Western blot analysis. These effects may be mediated by reduced PDGF-induced phosphorylation of ERK1/2, JNK, and P38, but not AKT as well as inhibition of PDGF-mediated nuclear factor (NF)-kappaB p65 and activator protein 1 (AP-1)/c-fos activation. Furthermore, viscolin pre-treatment significantly reduced neointimal hyperplasia of an endothelial-denuded femoral artery in vivo. Taken together, viscolin attenuated PDGF-BB-induced HASMC proliferation in vitro and reduced neointimal hyperplasia in vivo. Thus, viscolin may represent a therapeutic candidate for the prevention and treatment of vascular proliferative diseases. PMID- 27977760 TI - Assessing the State of Knowledge Regarding the Effectiveness of Interventions to Contain Pandemic Influenza Transmission: A Systematic Review and Narrative Synthesis. AB - BACKGROUND: Influenza pandemics occur when a novel influenza strain, to which humans are immunologically naive, emerges to cause infection and illness on a global scale. Differences in the viral properties of pandemic strains, relative to seasonal ones, can alter the effectiveness of interventions typically implemented to control seasonal influenza burden. As a result, annual control activities may not be sufficient to contain an influenza pandemic. PURPOSE: This study seeks to inform pandemic policy and planning initiatives by reviewing the effectiveness of previous interventions to reduce pandemic influenza transmission and infection. Results will inform the planning and design of more focused in depth systematic reviews for specific types of interventions, thus providing the most comprehensive and current understanding of the potential for alternative interventions to mitigate the burden of pandemic influenza. METHODS: A systematic review and narrative synthesis of existing systematic reviews and meta-analyses examining intervention effectiveness in containing pandemic influenza transmission was conducted using information collected from five databases (PubMed, Medline, Cochrane, Embase, and Cinahl/EBSCO). Two independent reviewers conducted study screening and quality assessment, extracting data related to intervention impact and effectiveness. RESULTS AND DISCUSSION: Most included reviews were of moderate to high quality. Although the degree of statistical heterogeneity precluded meta-analysis, the present systematic review examines the wide variety of interventions that can impact influenza transmission in different ways. While it appears that pandemic influenza vaccination provides significant protection against infection, there was insufficient evidence to conclude that antiviral prophylaxis, seasonal influenza cross-protection, or a range of non pharmaceutical strategies would provide appreciable protection when implemented in isolation. It is likely that an optimal intervention strategy will employ a combination of interventions in a layered approach, though more research is needed to substantiate this proposition. TRIAL REGISTRATION: PROSPERO 42016039803. PMID- 27977761 TI - First Molecular Characterization of Bovine Leukemia Virus Infections in the Caribbean. AB - Bovine leukemia virus (BLV) is a retrovirus that causes enzootic bovine leucosis. To investigate the presence and genetic variability of BLV in the Caribbean for the first time, we preformed fluorescence resonance energy transfer (FRET)-PCR for the pol of BLV on DNA from whole blood of cattle from Dominica, Montserrat, Nevis and St. Kitts. Standard PCRs with primers for the env were used for phylogenetic analysis of BLV in positive animals. We found FRET-PCR positive cattle (12.6%, 41/325) on Dominica (5.2%; 4/77) and St. Kitts (19.2%; 37/193) but not on Montserrat (0%, 0/12) or Nevis (0%, 0/43). Positive animals were cows on farms where animals were raised intensively. Phylogenetic analysis using the neighbor-joining (NJ) method on partial and full-length env sequences obtained for strains from Dominica (n = 2) and St. Kitts (n = 5) and those available in GenBank (n = 90) (genotypes 1-10) revealed the Caribbean strains belonged to genotype 1 (98-100% sequence homology). Ours is the first molecular characterization of BLV infections in the Caribbean and the first description of genotype 1 in the region. PMID- 27977762 TI - Pupil Sizes Scale with Attentional Load and Task Experience in a Multiple Object Tracking Task. AB - Previous studies have related changes in attentional load to pupil size modulations. However, studies relating changes in attentional load and task experience on a finer scale to pupil size modulations are scarce. Here, we investigated how these changes affect pupil sizes. To manipulate attentional load, participants covertly tracked between zero and five objects among several randomly moving objects on a computer screen. To investigate effects of task experience, the experiment was conducted on three consecutive days. We found that pupil sizes increased with each increment in attentional load. Across days, we found systematic pupil size reductions. We compared the model fit for predicting pupil size modulations using attentional load, task experience, and task performance as predictors. We found that a model which included attentional load and task experience as predictors had the best model fit while adding performance as a predictor to this model reduced the overall model fit. Overall, results suggest that pupillometry provides a viable metric for precisely assessing attentional load and task experience in visuospatial tasks. PMID- 27977764 TI - A Markovian Entropy Measure for the Analysis of Calcium Activity Time Series. AB - Methods to analyze the dynamics of calcium activity often rely on visually distinguishable features in time series data such as spikes, waves, or oscillations. However, systems such as the developing nervous system display a complex, irregular type of calcium activity which makes the use of such methods less appropriate. Instead, for such systems there exists a class of methods (including information theoretic, power spectral, and fractal analysis approaches) which use more fundamental properties of the time series to analyze the observed calcium dynamics. We present a new analysis method in this class, the Markovian Entropy measure, which is an easily implementable calcium time series analysis method which represents the observed calcium activity as a realization of a Markov Process and describes its dynamics in terms of the level of predictability underlying the transitions between the states of the process. We applied our and other commonly used calcium analysis methods on a dataset from Xenopus laevis neural progenitors which displays irregular calcium activity and a dataset from murine synaptic neurons which displays activity time series that are well-described by visually-distinguishable features. We find that the Markovian Entropy measure is able to distinguish between biologically distinct populations in both datasets, and that it can separate biologically distinct populations to a greater extent than other methods in the dataset exhibiting irregular calcium activity. These results support the benefit of using the Markovian Entropy measure to analyze calcium dynamics, particularly for studies using time series data which do not exhibit easily distinguishable features. PMID- 27977765 TI - Shape Variation in Neotropical Cytheridella (Ostracoda) Using Semilandmarks-Based Geometric Morphometrics: A Methodological Approach and Possible Biogeographical Implications. AB - Geometric morphometrics offer effective methods to obtain information about shape and shape variability. In ostracodology, landmark-based methods are, however, not well established. To test the applicability of geometric morphometric analyses for ostracods, we investigated shape variation among recent and fossil populations of the genus Cytheridella using a combination of landmarks and semilandmarks. The study focuses on the species' intraspecific morphological variability on a supra-regional scale, comparing living populations from Florida, Yucatan, Colombia and Brazil. We performed Generalized least-squares Procrustes Analysis on 508 adult and juvenile specimens (valves) including stages A-1 to A 4. The analyses show that the primary pattern in shape variation is ontogenetic allometry, supporting a clear separation of adults and juveniles. Shape changes are relatively small during ontogeny from A-4 to A-1. Greatest modification of valve shape occurs during the last molt phase. Insufficient differentiation of sexes is caused by females with less developed brood pouches. Disentangling size- and non-size-dependent shape changes reveals regional differences between populations of the species C. ilosvayi and supports its taxonomic distinction from a fossil relative (C. danielopoli). The distribution of regional morphotypes of C. ilosvayi in Florida, Mexico, and Brazil are congruent with fly ways of water birds. PMID- 27977763 TI - TET1 Depletion Induces Aberrant CpG Methylation in Colorectal Cancer Cells. AB - Aberrant DNA methylation is commonly observed in colorectal cancer (CRC), but the underlying mechanism is not fully understood. 5-hydroxymethylcytosine levels and TET1 expression are both reduced in CRC, while epigenetic silencing of TET1 is reportedly associated with the CpG island methylator phenotype. In the present study, we aimed to clarify the relationship between loss of TET1 and aberrant DNA methylation in CRC. Stable TET1 knockdown clones were established using Colo320DM cells, which express high levels of TET1, and HCT116 cells, which express TET1 at a level similar to that in normal colonic tissue. Infinium HumanMethylation450 BeadChip assays revealed increased levels of 5-methylcytosine at more than 10,000 CpG sites in TET1-depleted Colo320DM cells. Changes in DNA methylation were observed at various positions within the genome, including promoters, gene bodies and intergenic regions, and the altered methylation affected expression of a subset of genes. By contrast, TET1 knockdown did not significantly affect DNA methylation in HCT116 cells. However, TET1 depletion was associated with attenuated effects of 5-aza-2'-deoxycytidine on gene expression profiles in both cell lines. These results suggest that loss of TET1 may induce aberrant DNA methylation and may attenuate the effect of 5-aza-2'-deoxycytidine in CRC cells. PMID- 27977766 TI - Knockdown of Long Non-Coding RNA UCA1 Increases the Tamoxifen Sensitivity of Breast Cancer Cells through Inhibition of Wnt/beta-Catenin Pathway. AB - Acquired resistance to tamoxifen remains a major obstacle in breast cancer (BC) treatment, since the underlying mechanism has not been fully elucidated. The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been recently shown to be dysregulated and plays important roles in progression of breast cancer. In the present study, we aimed to investigate the biological role and clinical significance of UCA1 in BC drug resistance. Hence, we used quantitative PCR assay to evaluate the UCA1 expression in tissues from patients with BC as well as established tamoxifen-resistant BC cell lines in vitro. We tested the viability, invasive ability and apoptosis rate in MCF-7 and T47D cells using MTT assay, transwell assay and flow cytometry assay, respectively. The influence of UCA1 on tumorigenesis was monitored by in vivo mice xenograft model. The activation of Wnt/beta-catenin signaling pathway was evaluated by immunofluorescence assay, western blot assay and luciferase reporter assay, respectively. We found that the expression of UCA1 positively correlated with the pathological grade and mortality of breast cancer patients, moreover, expressions of UCA1 was increased significantly in the tamoxifen-resistant cell lines compared with the wild type parental cells. Ectopic expression of UCA1 promoted cell survival and resistance to tamoxifen treatment, whereas inhibition of UCA1 enhanced tamoxifen sensitivity of BC cells and induced more apoptotic cells. In addition, tamoxifen-resistant cells exhibited increased Wnt signaling activation as measured by the TOP/FOP Wnt luciferase reporter assay and beta-catenin protein level compared with parental MCF-7 and T47D cells, respectively. In line with these data, UCA1 depletion attenuated the activity of Wnt/beta-catenin pathway activation and the tumorigenicity of the tamoxifen-resistant BC cells. Taken together, our data highlights the pivotal role of UCA1-Wnt/beta-catenin signaling pathway in the tamoxifen resistance in breast cancer, which could be targeted to improve the effectiveness and efficacy of tamoxifen treatment in breast cancer. PMID- 27977767 TI - Identification of Alfalfa Leaf Diseases Using Image Recognition Technology. AB - Common leaf spot (caused by Pseudopeziza medicaginis), rust (caused by Uromyces striatus), Leptosphaerulina leaf spot (caused by Leptosphaerulina briosiana) and Cercospora leaf spot (caused by Cercospora medicaginis) are the four common types of alfalfa leaf diseases. Timely and accurate diagnoses of these diseases are critical for disease management, alfalfa quality control and the healthy development of the alfalfa industry. In this study, the identification and diagnosis of the four types of alfalfa leaf diseases were investigated using pattern recognition algorithms based on image-processing technology. A sub-image with one or multiple typical lesions was obtained by artificial cutting from each acquired digital disease image. Then the sub-images were segmented using twelve lesion segmentation methods integrated with clustering algorithms (including K_means clustering, fuzzy C-means clustering and K_median clustering) and supervised classification algorithms (including logistic regression analysis, Naive Bayes algorithm, classification and regression tree, and linear discriminant analysis). After a comprehensive comparison, the segmentation method integrating the K_median clustering algorithm and linear discriminant analysis was chosen to obtain lesion images. After the lesion segmentation using this method, a total of 129 texture, color and shape features were extracted from the lesion images. Based on the features selected using three methods (ReliefF, 1R and correlation-based feature selection), disease recognition models were built using three supervised learning methods, including the random forest, support vector machine (SVM) and K-nearest neighbor methods. A comparison of the recognition results of the models was conducted. The results showed that when the ReliefF method was used for feature selection, the SVM model built with the most important 45 features (selected from a total of 129 features) was the optimal model. For this SVM model, the recognition accuracies of the training set and the testing set were 97.64% and 94.74%, respectively. Semi-supervised models for disease recognition were built based on the 45 effective features that were used for building the optimal SVM model. For the optimal semi-supervised models built with three ratios of labeled to unlabeled samples in the training set, the recognition accuracies of the training set and the testing set were both approximately 80%. The results indicated that image recognition of the four alfalfa leaf diseases can be implemented with high accuracy. This study provides a feasible solution for lesion image segmentation and image recognition of alfalfa leaf disease. PMID- 27977768 TI - Folic Acid Supplementation Is Suboptimal in a National Cohort of Older Veterans Receiving Low Dose Oral Methotrexate. AB - OBJECTIVES: Co-prescription of folic acid in patients receiving low dose oral methotrexate is recommended because it reduces adverse events and prolongs the use of methotrexate (MTX). However, little is known about how often new users of methotrexate are co-prescribed folic acid, and what factors are associated with its use. We aimed to determine the prevalence, predictors of, and persistence of folic acid use in a population-based cohort of MTX users with rheumatic diseases. METHODS: Using a national, administrative database of patients seen through the Veterans Health Administration (VHA) that included pharmacy and laboratory data, we performed an observational cohort study of veterans over 65 years old who were new users of MTX. We used log-binomial regression to identify independent predictors of folic acid use and Kaplan Meyer survival analysis to examine persistence of folic acid over time. RESULTS: We studied 2467 incident users of MTX. 27% of patients were not prescribed folic acid through the VHA pharmacy within 30 days of MTX initiation. Patients who did not see a rheumatologist were 23% less likely to receive folic acid compared to patients who did have a rheumatologist visit during the baseline period (RR (95% CI) 0.77 (0.72, 0.82). These results remained unchanged even after adjusting for demographic, clinical, and other factors (adjusted RR (95% CI) 0.78 (0.74, 0.85)). After 20 months, only 50% of patients continued to receive folic acid. CONCLUSIONS: In a nationwide VHA cohort of new users of oral MTX, many patients did not receive folic acid or discontinued it over time. Rheumatologists were more likely to prescribe folic acid than other providers. These data highlight the need to improve patient safety for users of methotrexate by standardizing workflows for folic acid supplementation. PMID- 27977769 TI - A Scoping Review of Intimate Partner Violence Screening Programs for Health Care Professionals. AB - INTRODUCTION: Between 38 and 59 percent of women presenting to health care professionals have experienced intimate partner violence. Consequently, multiple intimate partner violence identification or screening programs within health care settings have been developed; however, substantial variations in program content and interpretation of program effectiveness has resulted in conflicting practice guidelines. The purpose of our scoping review is to broadly identify and synthesize the available literature evaluating intimate partner violence identification programs within health care settings to identify key areas for potential evidence-based recommendations and to focus research priorities in the field. MATERIALS AND METHODS: We conducted a search of MEDLINE, Embase, Cumulative Index of Nursing and Allied Health Literature, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and psycINFO. We used broad eligibility criteria to identify studies that evaluated intimate partner violence identification programs in health care settings. We completed all screening and data extraction independently and in duplicate. We used descriptive statistics to summarize all data. RESULTS: We identified 59 eligible studies evaluating intimate partner violence identification programs within health care settings. The most commonly reported outcome themes were IPV disclosure (69%, n = 35), number of patients screened (39%, n = 20), HCP opinions towards screening (37%, n = 19), and patient opinions towards screening (29%, n = 15). The majority of studies (36 studies (70.6%)) reported positive program evaluation results. DISCUSSION: The majority of studies reported positive program evaluation results. This may suggest that many different intimate partner violence identification programs are beneficial for identifying victims of abuse, however, it remains unknown as to whether identification programs prevent future episodes of abuse. Additionally, the substantial heterogeneity of the intervention characteristics, study methodology, and outcome measures assessed limits the ability to make clear recommendations as to the optimal method(s) of screening. PMID- 27977770 TI - Long-Term Quercetin Dietary Enrichment Partially Protects Dystrophic Skeletal Muscle. AB - Duchenne muscular dystrophy (DMD) results from a genetic lesion in the dystrophin gene and leads to progressive muscle damage. PGC-1alpha pathway activation improves muscle function and decreases histopathological injury. We hypothesized that mild disease found in the limb muscles of mdx mice may be responsive to quercetin-mediated protection of dystrophic muscle via PGC-1alpha pathway activation. To test this hypothesis muscle function was measured in the soleus and EDL from 14 month old C57, mdx, and mdx mice treated with quercetin (mdxQ; 0.2% dietary enrichment) for 12 months. Quercetin reversed 50% of disease-related losses in specific tension and partially preserved fatigue resistance in the soleus. Specific tension and resistance to contraction-induced injury in the EDL were not protected by quercetin. Given some functional gain in the soleus it was probed with histological and biochemical approaches, however, in dystrophic muscle histopathological outcomes were not improved by quercetin and suppressed PGC-1alpha pathway activation was not increased. Similar to results in the diaphragm from these mice, these data suggest that the benefits conferred to dystrophic muscle following 12 months of quercetin enrichment were underwhelming. Spontaneous activity at the end of the treatment period was greater in mdxQ compared to mdx indicating that quercetin fed mice were more active in addition to engaging in more vigorous activity. Hence, modest preservation of muscle function (specific tension) and elevated spontaneous physical activity largely in the absence of tissue damage in mdxQ suggests dietary quercetin may mediate protection. PMID- 27977771 TI - Tumor-Derived Factors and Reduced p53 Promote Endothelial Cell Centrosome Over Duplication. AB - Approximately 30% of tumor endothelial cells have over-duplicated (>2) centrosomes, which may contribute to abnormal vessel function and drug resistance. Elevated levels of vascular endothelial growth factor A induce excess centrosomes in endothelial cells, but how other features of the tumor environment affect centrosome over-duplication is not known. To test this, we treated endothelial cells with tumor-derived factors, hypoxia, or reduced p53, and assessed centrosome numbers. We found that hypoxia and elevated levels of bone morphogenetic protein 2, 6 and 7 induced excess centrosomes in endothelial cells through BMPR1A and likely via SMAD signaling. In contrast, inflammatory mediators IL-8 and lipopolysaccharide did not induce excess centrosomes. Finally, down regulation in endothelial cells of p53, a critical regulator of DNA damage and proliferation, caused centrosome over-duplication. Our findings suggest that some tumor-derived factors and genetic changes in endothelial cells contribute to excess centrosomes in tumor endothelial cells. PMID- 27977772 TI - Inhibition of cAMP-Dependent PKA Activates beta2-Adrenergic Receptor Stimulation of Cytosolic Phospholipase A2 via Raf-1/MEK/ERK and IP3-Dependent Ca2+ Signaling in Atrial Myocytes. AB - We previously reported in atrial myocytes that inhibition of cAMP-dependent protein kinase (PKA) by laminin (LMN)-integrin signaling activates beta2 adrenergic receptor (beta2-AR) stimulation of cytosolic phospholipase A2 (cPLA2). The present study sought to determine the signaling mechanisms by which inhibition of PKA activates beta2-AR stimulation of cPLA2. We therefore determined the effects of zinterol (0.1 MUM; zint-beta2-AR) to stimulate ICa,L in atrial myocytes in the absence (+PKA) and presence (-PKA) of the PKA inhibitor (1 MUM) KT5720 and compared these results with atrial myocytes attached to laminin (+LMN). Inhibition of Raf-1 (10 MUM GW5074), phospholipase C (PLC; 0.5 MUM edelfosine), PKC (4 MUM chelerythrine) or IP3 receptor (IP3R) signaling (2 MUM 2 APB) significantly inhibited zint-beta2-AR stimulation of ICa,L in-PKA but not +PKA myocytes. Western blots showed that zint-beta2-AR stimulation increased ERK1/2 phosphorylation in-PKA compared to +PKA myocytes. Adenoviral (Adv) expression of dominant negative (dn) -PKCalpha, dn-Raf-1 or an IP3 affinity trap, each inhibited zint-beta2-AR stimulation of ICa,L in + LMN myocytes compared to control +LMN myocytes infected with Adv-betagal. In +LMN myocytes, zint-beta2-AR stimulation of ICa,L was enhanced by adenoviral overexpression of wild-type cPLA2 and inhibited by double dn-cPLA2S505A/S515A mutant compared to control +LMN myocytes infected with Adv-betagal. In-PKA myocytes depletion of intracellular Ca2+ stores by 5 MUM thapsigargin failed to inhibit zint-beta2-AR stimulation of ICa,L via cPLA2. However, disruption of caveolae formation by 10 mM methyl-beta cyclodextrin inhibited zint-beta2-AR stimulation of ICa,L in-PKA myocytes significantly more than in +PKA myocytes. We conclude that inhibition of PKA removes inhibition of Raf-1 and thereby allows beta2-AR stimulation to act via PKCalpha/Raf-1/MEK/ERK1/2 and IP3-mediated Ca2+ signaling to stimulate cPLA2 signaling within caveolae. These findings may be relevant to the remodeling of beta-AR signaling in failing and/or aging heart, both of which exhibit decreases in adenylate cyclase activity. PMID- 27977773 TI - Identification of a Novel Homozygous Nonsense Mutation Confirms the Implication of GNAT1 in Rod-Cone Dystrophy. AB - GNAT1, encoding the transducin subunit Galpha, is an important element of the phototransduction cascade. Mutations in this gene have been associated with autosomal dominant and autosomal recessive congenital stationary night blindness. Recently, a homozygous truncating GNAT1 mutation was identified in a patient with late-onset rod-cone dystrophy. After exclusion of mutations in genes underlying progressive inherited retinal disorders, by targeted next generation sequencing, a 32 year-old male sporadic case with severe rod-cone dystrophy and his unaffected parents were investigated by whole exome sequencing. This led to the identification of a homozygous nonsense variant, c.963C>A p.(Cys321*) in GNAT1, which was confirmed by Sanger sequencing. The mother was heterozygous for this variant whereas the variant was absent in the father. c.963C>A p.(Cys321*) is predicted to produce a shorter protein that lacks critical sites for the phototransduction cascade. Our work confirms that the phenotype and the mode of inheritance associated with GNAT1 variants can vary from autosomal dominant, autosomal recessive congenital stationary night blindness to autosomal recessive rod-cone dystrophy. PMID- 27977775 TI - Fabrication of Artificial Food Bolus for Evaluation of Swallowing. AB - Simple and easy methods to evaluate swallowing are required because of the recently increased need of rehabilitation for dysphagia. "Artificial food bolus", but not "artificial food", would be a valuable tool for swallowing evaluation without considering the mastication effect which is altered according to the individual's oral condition. Thus, this study was carried out to fabricate artificial bolus resembling natural food bolus. The mechanical property and the volume change of food bolus in normal people were firstly investigated. Thirty healthy adults without dysphagia were selected and asked to chew four sample foods (rice cake, peanut, burdock, and gummy candy). The results indicated that Young's modulus of bolus before swallowing was below 150 kPa. The bolus volume before swallowing was below 400 mm3. In addition, the saliva component ratio of each bolus was approximately 30wt%, and the average saliva viscosity of research participants was approximately 10 mPa*s. Based on the obtained data, artificial food bolus was designed and fabricated by using alginate hydrogel as a visco elastic material and gelatin solution as a viscotic material with a ratio of 7:3 based on weight. Consequently, the swallowing time of fabricated artificial food bolus was measured among the same participants. The results indicated the participants swallowed fabricated food bolus with similar manner reflecting their mechanical property and volume. Thus, this artificial food bolus would be a promising tool for evaluation of swallowing. PMID- 27977774 TI - The Effect of Metformin on Diastolic Function in Patients Presenting with ST Elevation Myocardial Infarction. AB - INTRODUCTION: Diastolic dysfunction is an important predictor of poor outcome after myocardial infarction. Metformin treatment improved diastolic function in animal models and patients with diabetes. Whether metformin improves diastolic function in patients presenting with ST-segment elevation myocardial infarction (STEMI) is unknown. METHODS: The GIPS-III trial randomized STEMI patients, without known diabetes, to metformin or placebo initiated directly after PCI. The previously reported primary endpoint was left ventricular ejection fraction at 4 months, which was unaffected by metformin treatment. This is a predefined substudy to determine an effect of metformin on diastolic function. For this substudy trans-thoracic echocardiography was performed during hospitalization and after 4 months. Diastolic dysfunction was defined as having the combination of a functional alteration (i.e. decreased tissue velocity: mean of septal e' and lateral e') and a structural alteration (i.e. increased left atrial volume index (LAVI)). In addition, left ventricular mass index and transmitral flow velocity (E) to mean e' ratio (E/e') were measured to determine an effect of metformin on individual echocardiographic markers of diastolic function. RESULTS: In 237 (63%) patients included in the GIPS-III trial diastolic function was measured during hospitalization as well as at 4 months. Diastolic dysfunction was present in 11 (9%) of patients on metformin and 11 (9%) patients on placebo treatment (P = 0.98) during hospitalization. After 4 months 22 (19%) of patients with metformin and 18 (15%) patients with placebo (P = 0.47) had diastolic dysfunction. In addition, metformin did not improve any of the individual echocardiographic markers of diastolic function. CONCLUSIONS: In contrast to experimental and observational data, our randomized placebo controlled trial did not suggest a beneficial effect of short-term metformin treatment on diastolic function in STEMI patients. PMID- 27977776 TI - Inconsistency between Self-Reported Energy Intake and Body Mass Index among Urban, African-American Children. AB - BACKGROUND: To prevent obesity, it is important to assess dietary habits through self-reported energy intake (EI) in children. We investigated how EI is associated with body mass index and which elements of dietary habits and status are associated with EI among African-American (AA) children. METHODS: We assessed and included data from 218 10-14-year-old AA children in Baltimore, MD, USA. EI was calculated using a food frequency questionnaire. The basal metabolic rate (BMR) was used as the predicted minimal rate of energy expenditure of children. A fully adjusted multiple logistic regression was used to determine the prevalence of obesity (>= 95th BMI-for-age percentile) among the quartiles of EI/BMR ratio using the third quartile for the reference. The differences in the age-adjusted mean EI/BMR among the categories of dietary habits, social support, and socio economic status were analyzed using a general linear model. RESULTS: Children with the lowest EI/BMR had significantly higher adjusted odds ratio (aOR) of obesity as compared to those in the third quartile of EI/BMR (boys aOR 4.3; 95% confidence interval 1.08, 20 and girls aOR 4.1; 1.02, 21). In girls, the adjusted mean EI/BMR in the group that prepared food less than the means (3.8 times/week) was significantly lower than the group that prepared food over the means (P = 0.03). Further, the group that reported eating breakfast under 4 times/week indicated an adjusted mean EI/BMR lower than the group that ate breakfast over 5 times/week in both sexes. CONCLUSIONS: When EI was under-reported with reference to BMR, we may observe high prevalence of obesity. Further, food preparation by children and frequent consumption of breakfast may instill food cognition with usual dietary habits. Therefore, holistic assessments including dietary habits are required to examine self-reported food intake especially among overweight/obese children. PMID- 27977778 TI - Intercellular Extensions Are Induced by the Alphavirus Structural Proteins and Mediate Virus Transmission. AB - Alphaviruses are highly organized enveloped RNA viruses with an internal nucleocapsid surrounded by a membrane containing the E2 and E1 transmembrane proteins. Alphavirus budding takes place at the plasma membrane and requires the interaction of the cytoplasmic domain of E2 with the capsid protein. Here we used WT alphaviruses and Sindbis virus in which E2 was fused to a fluorescent protein to characterize virus exit from host cells. Our results show that alphavirus infection induced striking modifications of the host cell cytoskeleton and resulted in the formation of stable intercellular extensions that emanated exclusively from the infected cell. The intercellular extensions were long (> 10 MUM), contained actin and tubulin, and formed flattened contacts with neighboring cells, but did not mediate membrane or cytoplasmic continuity between cells. Receptor down-regulation studies indicated that formation of stable extensions did not require the virus receptor, and that extensions promoted cell-to-cell virus transmission to receptor-depleted cells. Virus mutant experiments demonstrated that formation of extensions required the E2-capsid interaction but not active particle budding, while intercellular transmission of infection required the production of fusion-active virus particles. Protein expression studies showed that even in the absence of virus infection, the viral structural proteins alone induced intercellular extensions, and that these extensions were preferentially targeted to non-expressing cells. Together, our results identify a mechanism for alphavirus cell-to-cell transmission and define the key viral protein interactions that it requires. PMID- 27977777 TI - Perigone Lobe Transcriptome Analysis Provides Insights into Rafflesia cantleyi Flower Development. AB - Rafflesia is a biologically enigmatic species that is very rare in occurrence and possesses an extraordinary morphology. This parasitic plant produces a gigantic flower up to one metre in diameter with no leaves, stem or roots. However, little is known about the floral biology of this species especially at the molecular level. In an effort to address this issue, we have generated and characterised the transcriptome of the Rafflesia cantleyi flower, and performed a comparison with the transcriptome of its floral bud to predict genes that are expressed and regulated during flower development. Approximately 40 million sequencing reads were generated and assembled de novo into 18,053 transcripts with an average length of 641 bp. Of these, more than 79% of the transcripts had significant matches to annotated sequences in the public protein database. A total of 11,756 and 7,891 transcripts were assigned to Gene Ontology categories and clusters of orthologous groups respectively. In addition, 6,019 transcripts could be mapped to 129 pathways in Kyoto Encyclopaedia of Genes and Genomes Pathway database. Digital abundance analysis identified 52 transcripts with very high expression in the flower transcriptome of R. cantleyi. Subsequently, analysis of differential expression between developing flower and the floral bud revealed a set of 105 transcripts with potential role in flower development. Our work presents a deep transcriptome resource analysis for the developing flower of R. cantleyi. Genes potentially involved in the growth and development of the R. cantleyi flower were identified and provide insights into biological processes that occur during flower development. PMID- 27977779 TI - Impact of Environmental Enrichment on Perineuronal Nets in the Prefrontal Cortex following Early and Late Abstinence from Sucrose Self-Administration in Rats. AB - Perineuronal nets (PNNs) are aggregates of extracellular matrix that form structures surrounding a subset of GABAergic interneurons. The staining intensity of PNNs appears to be related to plasticity. Environmental enrichment (EE) influences plasticity during adulthood: EE decreases the rewarding effects of drugs of abuse and diminishes both drug- and sucrose-seeking behavior. We determined the impact of EE on PNN intensity in the medial prefrontal cortex (mPFC) in rats trained to self-administer sucrose. We examined the number and intensity of PNNs within the prelimbic (PL), infralimbic (IL), and orbitofrontal (OF) regions of the mPFC of adult Long-Evans rats that were trained for sucrose self-administration followed by acute or chronic EE during abstinence and a cue induced reinstatement test. Rats exposed to EE prior to a cue-induced reinstatement of sucrose seeking had an increase in PNN staining compared with rats in standard housing. Conversely, naive rats given 1 day of EE had a decrease in PNN intensity in the PL, no change in the IL, and an increase in the OF. Our findings demonstrate that EE increases PNN intensity in the mPFC after sucrose training, suggesting that training enhances the ability of EE to increase PNN intensity. We further demonstrate an interaction between time of abstinence, duration of EE exposure, and cue-induced reinstatement. Our results suggest that increased PNN intensity after EE may alter the excitatory/inhibitory balance of mPFC neurons such that rats are less responsive to a sucrose cue. PMID- 27977780 TI - Pertussis Toxin Is a Robust and Selective Inhibitor of High Grade Glioma Cell Migration and Invasion. AB - In high grade glioma (HGG), extensive tumor cell infiltration of normal brain typically precludes identifying effective margins for surgical resection or irradiation. Pertussis toxin (PT) is a multimeric complex that inactivates diverse Gi/o G-protein coupled receptors (GPCRs). Despite the broad continuum of regulatory events controlled by GPCRs, PT may be applicable as a therapeutic. We have shown that the urokinase receptor (uPAR) is a major driver of HGG cell migration. uPAR-initiated cell-signaling requires a Gi/o GPCR, N-formyl Peptide Receptor 2 (FPR2), as an essential co-receptor and is thus, PT-sensitive. Herein, we show that PT robustly inhibits migration of three separate HGG-like cell lines that express a mutated form of the EGF Receptor (EGFR), EGFRvIII, which is constitutively active. PT also almost completely blocked the ability of HGG cells to invade Matrigel. In the equivalent concentration range (0.01-1.0 MUg/mL), PT had no effect on cell survival and only affected proliferation of one cell line. Neutralization of EGFRvIII expression in HGG cells, which is known to activate uPAR-initiated cell-signaling, promoted HGG cell migration. The increase in HGG cell migration, induced by EGFRvIII neutralization, was entirely blocked by silencing FPR2 gene expression or by treating the cells with PT. When U87MG HGG cells were cultured as suspended neurospheres in serum-free, growth factor supplemented medium, uPAR expression was increased. HGG cells isolated from neurospheres migrated through Transwell membranes without loss of cell contacts; this process was inhibited by PT by >90%. PT also inhibited expression of vimentin by HGG cells; vimentin is associated with epithelial-mesenchymal transition and worsened prognosis. We conclude that PT may function as a selective inhibitor of HGG cell migration and invasion. PMID- 27977781 TI - Prevalence of Echocardiography Use in Patients Hospitalized with Confirmed Acute Pulmonary Embolism: A Real-World Observational Multicenter Study. AB - BACKGROUND: Acute pulmonary embolism (PE) carries an increased risk of death. Using transthoracic echocardiography (TTE) to assist diagnosis and risk stratification is recommended in current guidelines. However, its utilization in real-world clinical practice is unknown. We conducted a retrospective observational study to delineate the prevalence of inpatient TTE use following confirmed acute PE, identify predictors for its use and its impact on patient's outcome. METHODS: Clinical details of consecutive patients (2000 to 2012) from two tertiary-referral hospitals were retrieved from dedicated PE databases. All cause and cause-specific mortality was tracked from a state-wide death registry. RESULTS: In total, 2306 patients were admitted with confirmed PE, of whom 687 (29.8%) had inpatient TTE (39.3% vs 14.4% between sites, P<0.001). Site to which patient presented, older age, cardiac failure, atrial fibrillation and diabetes were independent predictors for inpatient TTE use, while malignancy was a negative predictor. Overall mortality was 41.4% (mean follow-up 66.5+/ 49.5months). Though inpatient TTE use was not an independent predictor for all cause or cardiovascular mortality in multivariable analysis, in the inpatient TTE subgroup, right ventricle-right atrial pressure gradient (hazard ratio [HR] 1.02 per-1mmHg increase, 95% confidence interval [CI] 1.01-1.03) and moderate/severe aortic stenosis (HR 2.26, 95% CI 1.20-4.27) independently predicted all-cause mortality. CONCLUSIONS: Inpatient TTE is used infrequently in real-world clinical settings following acute PE despite its usefulness in risk stratification, prognostication and assessing comorbid cardiac pathologies. Identifying patients that will benefit most from a TTE assessment following an acute PE episode and reducing barriers in accessing TTE should be explored. PMID- 27977782 TI - Molecular Parasitic Plant-Host Interactions. PMID- 27977783 TI - Individual Differences in the Rubber Hand Illusion Are Related to Sensory Suggestibility. AB - In the rubber hand illusion (RHI), watching a rubber hand being stroked in synchrony with one's own hidden hand may induce a sense of ownership over the rubber hand. The illusion relies on bottom-up multisensory integration of visual, tactile, and proprioceptive information, and on top-down processes through which the rubber hand is incorporated into pre-existing representations of the body. Although the degree of illusory experience varies largely across individuals, the factors influencing individual differences are unknown. We investigated whether sensory suggestibility might modulate susceptibility to the RHI. Sensory suggestibility is a personality trait related to how individuals react to sensory information. Because of its sensory nature, this trait could be relevant for studies using the RHI paradigm. Seventy healthy volunteers were classified by Sensory Suggestibility Scale (SSS) scores as having high or low suggestibility and assigned to either a high- (High-SSS) or a low-suggestibility (Low-SSS) group. Two components of the RHI were evaluated in synchronous and asynchronous stroking conditions: subjective experience of sense of ownership over the rubber hand via a 9-statement questionnaire, and proprioceptive drift as measured with a ruler. The High-SSS group was generally more susceptible to the subjective component; in the synchronous condition, they rated the statement assessing the sense of ownership higher than the Low-SSS group. The scores for this statement significantly correlated with the total SSS score, indicating that the higher the sensory suggestibility, the stronger the sense of ownership. No effect of sensory suggestibility on proprioceptive drift was observed, suggesting that the effect is specific for the subjective feeling of ownership. This study demonstrates that sensory suggestibility may contribute to participants' experience of the illusion and should be considered when using the RHI paradigm. PMID- 27977784 TI - High Expression of Derlin-1 Is Associated with the Malignancy of Bladder Cancer in a Chinese Han Population. AB - Derlin-1 is overexpressed in various types of solid tumors and has an important function in cancer progression. However, its expression pattern in and association with the clinicopathological characteristics of human bladder cancer remain unclear. In the present study, 3 pairs of fresh samples of bladder cancer tissue and paracancerous tissue were first detected by liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to screen for differentially expressed proteins. Following bioinformatics analysis and assessments by qRT-PCR and western blotting, Derlin-1 was selected as a candidate protein and was then validated in samples from patients with bladder cancer by immunohistochemistry and western blotting. The results showed that the bladder cancer tissues exhibited higher levels of Derlin-1 expression than the paracancerous tissues (P < 0.05). Positive expression of Derlin-1 was significantly correlated with tumor stage, histological grade, and lymph node metastasis (P < 0.001) but was not correlated with other clinicopathological parameters including patient age (P = 0.758) and gender (P = 0.831). Besides, Derlin-1 was highly expressed in BC cell lines (um-uc-3 and T24), and the interference of Derlin-1 could reverse EMT progression, inhibit the tumor migration and invasion in T24 cells. Further, patients with positive Derlin-1 expression had shorter overall survival than those with negative expression (P < 0.001). Taken together, our results demonstrated that Derlin-1 was overexpressed in bladder cancer and was associated with the malignancy of bladder cancer. PMID- 27977786 TI - Correction: Ethnic Differences in Arterial Wave Reflection Are Mostly Explained by Differences in Body Height-Cross-Sectional Analysis of the HELIUS Study. AB - [This corrects the article DOI: 10.1371/journal.pone.0160243.]. PMID- 27977785 TI - LGR4 Is a Direct Target of MicroRNA-34a and Modulates the Proliferation and Migration of Retinal Pigment Epithelial ARPE-19 Cells. AB - The pathology of proliferative vitreoretinopathy and proliferative diabetic retinopathy is linked to proliferation, migration, and adhesion of the retinal pigment epithelium. MicroRNA-34a (miR-34a) expression modulates changes in proliferation and migration of retinal pigment epithelial cell line ARPE-19. In this study, we determined that miR-34a interacts with LGR4, identified by bioinformatics using TargetScan Human 5.0, to affect these changes. Double luciferase gene reporter assay confirmed miR-34a involvement in mediating control. miR-34a mimic transfection decreased LGR4 expression. Western blot analysis documented corresponding protein expression inhibition. MTS, Ki67 immunostaining, scratch and transwell testing, along with attachment assay showed that miR-34a upregulation inhibited ARPE-19 cell proliferation, migration and attachment partly through downregulation of LGR4 protein expression. Western blot analysis revealed that both miR-34a upregulation and LGR4 downregulation induced declines in E2F1, p-CDC2, CDK2, CDK4 and CDK6 protein expression. Taken together, miR-34a gene expression upregulation inhibits ARPE-19 cell proliferation, migration and adhesion partly by suppressing LGR4 expression. These results substantiate earlier indications that both miR-34a and LGR4 are potential drug targets to prevent fibrosis in a clinical setting. PMID- 27977788 TI - Two Different Views on the World Around Us: The World of Uniformity versus Diversity. AB - We propose that when individuals believe in fixed traits of personality (entity theorists), they are likely to expect a world of "uniformity." As such, they easily infer a population statistic from a small sample of data with confidence. In contrast, individuals who believe in malleable traits of personality (incremental theorists) are likely to presume a world of "diversity," such that they "hesitate" to infer a population statistic from a similarly sized sample. In four laboratory experiments, we found that compared to incremental theorists, entity theorists estimated a population mean from a sample with a greater level of confidence (Studies 1a and 1b), expected more homogeneity among the entities within a population (Study 2), and perceived an extreme value to be more indicative of an outlier (Study 3). These results suggest that individuals are likely to use their implicit self-theory orientations (entity theory versus incremental theory) to see a population in general as a constitution either of homogeneous or heterogeneous entities. PMID- 27977787 TI - Modulating the Biologic Activity of Mesenteric Lymph after Traumatic Shock Decreases Systemic Inflammation and End Organ Injury. AB - INTRODUCTION: Trauma/hemorrhagic shock (T/HS) causes the release of pro inflammatory mediators into the mesenteric lymph (ML), triggering a systemic inflammatory response and acute lung injury (ALI). Direct and pharmacologic vagal nerve stimulation prevents gut barrier failure and alters the biologic activity of ML after injury. We hypothesize that treatment with a pharmacologic vagal agonist after T/HS would attenuate the biologic activity of ML and prevent ALI. METHODS: ML was collected from male Sprague-Dawley rats after T/HS, trauma-sham shock (T/SS) or T/HS with administration of the pharmacologic vagal agonist CPSI 121. ML samples from each experimental group were injected into naive mice to assess biologic activity. Blood samples were analyzed for changes in STAT3 phosphorylation (pSTAT3). Lung injury was characterized by histology, permeability and immune cell recruitment. RESULTS: T/HS lymph injected in naive mice caused a systemic inflammatory response characterized by hypotension and increased circulating monocyte pSTAT3 activity. Injection of T/HS lymph also resulted in ALI, confirmed by histology, lung permeability and increased recruitment of pulmonary macrophages and neutrophils to lung parenchyma. CPSI-121 attenuated T/HS lymph-induced systemic inflammatory response and ALI with stable hemodynamics and similar monocyte pSTAT3 levels, lung histology, lung permeability and lung immune cell recruitment compared to animals injected with lymph from T/SS. CONCLUSION: Treatment with CPSI-121 after T/HS attenuated the biologic activity of the ML and decreased ALI. Given the superior clinical feasibility of utilizing a pharmacologic approach to vagal nerve stimulation, CPSI-121 is a potential treatment strategy to limit end organ dysfunction after injury. PMID- 27977790 TI - The Dynamics and Neural Correlates of Audio-Visual Integration Capacity as Determined by Temporal Unpredictability, Proactive Interference, and SOA. AB - Over 5 experiments, we challenge the idea that the capacity of audio-visual integration need be fixed at 1 item. We observe that the conditions under which audio-visual integration is most likely to exceed 1 occur when stimulus change operates at a slow rather than fast rate of presentation and when the task is of intermediate difficulty such as when low levels of proactive interference (3 rather than 8 interfering visual presentations) are combined with the temporal unpredictability of the critical frame (Experiment 2), or, high levels of proactive interference are combined with the temporal predictability of the critical frame (Experiment 4). Neural data suggest that capacity might also be determined by the quality of perceptual information entering working memory. Experiment 5 supported the proposition that audio-visual integration was at play during the previous experiments. The data are consistent with the dynamic nature usually associated with cross-modal binding, and while audio-visual integration capacity likely cannot exceed uni-modal capacity estimates, performance may be better than being able to associate only one visual stimulus with one auditory stimulus. PMID- 27977789 TI - Pregnancy-Associated Risk Factors of Postpartum Breast Cancer in Korea: A Nationwide Health Insurance Database Study. AB - Patients with postpartum breast cancer have been reported to have a poor prognosis. The present study aimed to evaluate the pregnancy-related risk factors of postpartum breast cancer in Korea. We collected patient data from the Korea National Health Insurance (KNHI) Claims Database of the Health Insurance Review and Assessment Service (HIRA) for the 2009-2013 period. We evaluated the pregnancy-related risk factors for postpartum breast cancer in two population groups. For Group 1 (women who had given birth during the 2010-2012 period), data on those who were diagnosed with breast cancer from childbirth to 1-year postpartum were extracted. For Group 2, we extracted the data of women who gave birth in 2010 and traced them until December 31, 2013. In Group 1, 1,384,551 deliveries and 317 postpartum breast cancer patients were recorded in Korea between January 1, 2010, and December 31, 2012. Women aged >=35 years (Odds Ratio [OR], 2.003; 95% Confidence Interval [CI], 1.567-2.560) and those who gave birth via cesarean delivery (OR, 1.237; 95% CI, 0.986-1.553) were considered to be at a higher risk for breast cancer. Lower risk was noted in primiparous women (OR, 0.737; 95% CI, 0.585-0.928). In Group 2, the data of 457,924 women who gave birth in 2010 were traced until December 31, 2013. Among them, 655 patients were diagnosed with breast cancer, and age >=35 years and cesarean delivery were associated with an higher risk of breast cancer, whereas primiparous status was associated with a lower risk of breast cancer. In conclusion, older age (>=35 years) and cesarean delivery are significant risk factors for postpartum breast cancer, and primiparous women have a lower risk of developing postpartum breast cancer. PMID- 27977792 TI - Chronic Low-Grade Inflammation in Childhood Obesity Is Associated with Decreased IL-10 Expression by Monocyte Subsets. AB - Chronic low-grade inflammation is related to the development of comorbidities and poor prognosis in obesity. Monocytes are main sources of cytokines and play a pivotal role in inflammation. We evaluated monocyte frequency, phenotype and cytokine profile of monocyte subsets, to determine their association with the pathogenesis of childhood obesity. Children with obesity were evaluated for biochemical and anthropometric parameters. Monocyte subsets were characterized by flow cytometry, considering cytokine production and activation/recognition molecules. Correlation analysis between clinical parameters and immunological data delineated the monocytes contribution for low-grade inflammation. We observed a higher frequency of non-classical monocytes in the childhood obesity group (CO) than normal-weight group (NW). All subsets displayed higher TLR4 expression in CO, but their recognition and antigen presentation functions seem to be diminished due to lower expression of CD40, CD80/86 and HLA-DR. All subsets showed a lower expression of IL-10 in CO and correlation analyses showed changes in IL-10 expression profile. The lower expression of IL-10 may be decisive for the maintenance of the low-grade inflammation status in CO, especially for alterations in non-classical monocytes profile. These cells may contribute to supporting inflammation and loss of regulation in the immune response of children with obesity. PMID- 27977791 TI - Peptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors. AB - Cytomegalovirus (CMV) elicits long-term T-cell immunity of unparalleled strength, which has allowed the development of highly protective CMV-based vaccine vectors. Counterintuitively, experimental vaccines encoding a single MHC-I restricted epitope offered better immune protection than those expressing entire proteins, including the same epitope. To clarify this conundrum, we generated recombinant murine CMVs (MCMVs) encoding well-characterized MHC-I epitopes at different positions within viral genes and observed strong immune responses and protection against viruses and tumor growth when the epitopes were expressed at the protein C-terminus. We used the M45-encoded conventional epitope HGIRNASFI to dissect this phenomenon at the molecular level. A recombinant MCMV expressing HGIRNASFI on the C-terminus of M45, in contrast to wild-type MCMV, enabled peptide processing by the constitutive proteasome, direct antigen presentation, and an inflation of antigen-specific effector memory cells. Consequently, our results indicate that constitutive proteasome processing of antigenic epitopes in latently infected cells is required for robust inflationary responses. This insight allows utilizing the epitope positioning in the design of CMV-based vectors as a novel strategy for enhancing their efficacy. PMID- 27977794 TI - Expanding Bicycle-Sharing Systems: Lessons Learnt from an Analysis of Usage. AB - Bike-sharing programs, with initiatives to increase bike use and improve accessibility of urban transit, have received increasing attention in growing number of cities across the world. The latest generation of bike-sharing systems has employed smart card technology that produces station-based data or trip-level data. This facilitates the studies of the practical use of these systems. However, few studies have paid attention to the changes in users and system usage over the years, as well as the impact of system expansion on its usage. Monitoring the changes of system usage over years enables the identification of system performance and can serve as an input for improving the location allocation of stations. The objective of this study is to explore the impact of the expansion of a bicycle-sharing system on the usage of the system. This was conducted for a bicycle-sharing system in Zhongshan (China), using operational usage data of different years following system expansion. To this end, we performed statistical and spatial analyses to examine the changes in both users and system usage between before and after the system expansion. The findings show that there is a big variation in users and aggregate usage following the system expansion. However, the trend in spatial distribution of demand shows no substantial difference over the years, i.e. the same high-demand and low-demand areas appear. There are decreases in demand for some old stations over the years, which can be attributed to either the negative performance of the system or the competition of nearby new stations. Expanding the system not only extends the original users' ability to reach new areas but also attracts new users to use bike-sharing systems. In the conclusions, we present and discuss the findings, and offer recommendations for the further expansion of system. PMID- 27977795 TI - Correction: Validation of the Amsterdam Dynamic Facial Expression Set - Bath Intensity Variations (ADFES-BIV): A Set of Videos Expressing Low, Intermediate, and High Intensity Emotions. AB - [This corrects the article DOI: 10.1371/journal.pone.0147112.]. PMID- 27977793 TI - Elimination of Pseudomonas aeruginosa through Efferocytosis upon Binding to Apoptotic Cells. AB - For opportunistic pathogens such as Pseudomonas aeruginosa, the mucosal barrier represents a formidable challenge. Infections develop only in patients with altered epithelial barriers. Here, we showed that P. aeruginosa interacts with a polarized epithelium, adhering almost exclusively at sites of multi-cellular junctions. In these sites, numerous bacteria attach to an extruded apoptotic cell or apoptotic body. This dead cell tropism is independent of the type of cell death, as P. aeruginosa also binds to necrotic cells. We further showed that P. aeruginosa is internalized through efferocytosis, a process in which surrounding epithelial cells engulf and dispose of extruded apoptotic cells. Intracellularly, along with apoptotic cell debris, P. aeruginosa inhabits an efferocytic phagosome that acquires lysosomal features, and is finally killed. We propose that elimination of P. aeruginosa through efferocytosis is part of a host defense mechanism. Our findings could be relevant for the study of cystic fibrosis, which is characterized by an exacerbated number of apoptotic cells and ineffective efferocytosis. PMID- 27977796 TI - Zinc Is Indispensable in Exercise-Induced Cardioprotection against Intermittent Hypoxia-Induced Left Ventricular Function Impairment in Rats. AB - In obstructive sleep apnea (OSA), recurrent obstruction of the upper airway leads to intermittent hypoxia (IH) during sleep, which can result in impairment of cardiac function. Although exercise can have beneficial effects against IH induced cardiac dysfunction, the mechanism remains unclear. This study aimed to investigate the interactions of zinc and exercise on IH-triggered left ventricular dysfunction in a rat model that mimics IH in OSA patients. Nine-week old male Sprague-Dawley rats were randomly assigned to either a control group (CON) or to a group receiving 10 weeks of exercise training (EXE). During weeks 9 and 10, half the rats in each group were subjected to IH for 8 h per day for 14 days (IHCON, IHEXE), whereas the remainder continued to breathe room air. Rats within each of the CON, IHCON, EXE, and IHEXE groups were further randomly assigned to receive intraperitoneal injections of either zinc chloride, the zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN), or injection vehicle only. IH induced a lower left ventricular fractional shortening, reduced ejection fraction, higher myocardial levels of inflammatory factors, increased levels oxidative stress, and lower levels of antioxidative capacity, all of which were abolished by zinc treatment. IHEXE rats exhibited higher levels of cardiac function and antioxidant capacity and lower levels of inflammatory factors and oxidative stress than IHCON rats; however, IHEXE rats receiving TPEN did not exhibit these better outcomes. In conclusion, zinc is required for protecting against IH-induced LV functional impairment and likely plays a critical role in exercise-induced cardioprotection by exerting a dual antioxidant and anti inflammatory effect. PMID- 27977797 TI - No Positive Association between Vitamin D Level and Immune Responses to Hepatitis B and Streptococcus pneumoniae Vaccination in HIV-Infected Adults. AB - OBJECTIVE: To assess whether higher 25-hydroxyvitamin D (25OHD) levels are associated with subsequent better immune responses to hepatitis B and Streptococcus pneumoniae vaccination in HIV-infected patients. METHODS: 25OHD was measured on stored baseline plasma samples from two randomized vaccine trials in HIV-infected adults: the ANRS HB03 VIHVAC B trial and an immunological sub-study of the ANRS 114-PNEUMOVAC trial. In ANRS HB03 VIHVAC B, participants received three or four doses of recombinant HBV vaccine strategies. Anti-HBs IgG titers were measured four weeks after the last injection. Associations between baseline 25OHD levels and ordered IgG response categories were analyzed in multivariable proportional odds models. In the ANRS 114-PNEUMOVAC sub-study, two strategies of pneumococcal vaccination were tested, cellular immune responses were measured at repeated time points, and IgG responses four weeks after the last vaccine injection. Exploratory statistical analyses were performed on this sub-study data set. RESULTS: Three hundred and thirty-nine ANRS HB03 VIHVAC B and 25 ANRS 114 PNEUMOVAC sub-study participants were included in the analyses. Median age in each of the two studies was 43 years, 68% were male, and 77-92% on antiretroviral treatment. Median 25OHD level was 18 ng/mL (IQR: 12-25) and 24 ng/mL (IQR: 13-32) in the two trial populations, respectively. In the multivariable model, there was no significant association between baseline 25OHD level and vaccine responses in ANRS HB03 VIHVAC B (proportional odds ratio 0.83 per 10 ng/mL 25OHD increase; 95% confidence interval 0.65-1.07, p = 0.14). Exploratory analyses of ANRS 114 PNEUMOVAC showed consistent results. CONCLUSION: This study does not support a positive association between 25OHD and immune responses to hepatitis B or pneumococcal vaccination in HIV-infected patients. PMID- 27977798 TI - IL-1beta/IL-6/CRP and IL-18/ferritin: Distinct Inflammatory Programs in Infections. AB - The host inflammatory response against infections is characterized by the release of pro-inflammatory cytokines and acute-phase proteins, driving both innate and adaptive arms of the immune response. Distinct patterns of circulating cytokines and acute-phase responses have proven indispensable for guiding the diagnosis and management of infectious diseases. This review discusses the profiles of acute phase proteins and circulating cytokines encountered in viral and bacterial infections. We also propose a model in which the inflammatory response to viral (IL-18/ferritin) and bacterial (IL-6/CRP) infections presents with specific plasma patterns of immune biomarkers. PMID- 27977799 TI - Enhanced Expression of Trib3 during the Development of Myelin Breakdown in dmy Myelin Mutant Rats. AB - The demyelination (dmy) rat exhibits hind limb ataxia and severe myelin breakdown in the central nervous system. The causative gene of dmy rats is the MRS2 magnesium transporter gene. Tribbles homolog 3 (Trib3) is a pseudokinase molecule that modifies certain signal pathways, and its expression is increased in response to various stresses. Here we sought to clarify the mechanism of myelin breakdown by focusing Trib3, which is remarkably up-regulated in dmy rats. The expression of Trib3 mRNA was significantly increased at 4, 5, 6, 7 and 8 weeks of age in the dmy rats, prior to the prominent myelin breakdown between 7 and 10 weeks of age. The expression level of Trib3 was increased concurrently with the progression of the clinical and pathological conditions in the dmy rats. Double immunofluorescence demonstrated that TRIB3 was mainly expressed in neurons and oligodendrocytes and localized in the Golgi apparatus. Our findings indicate that Trib3 may be associated with the pathogenic mechanism of dmy rats. PMID- 27977800 TI - Structural and Functional Characterization of the Bacterial Type III Secretion Export Apparatus. AB - Bacterial type III protein secretion systems inject effector proteins into eukaryotic host cells in order to promote survival and colonization of Gram negative pathogens and symbionts. Secretion across the bacterial cell envelope and injection into host cells is facilitated by a so-called injectisome. Its small hydrophobic export apparatus components SpaP and SpaR were shown to nucleate assembly of the needle complex and to form the central "cup" substructure of a Salmonella Typhimurium secretion system. However, the in vivo placement of these components in the needle complex and their function during the secretion process remained poorly defined. Here we present evidence that a SpaP pentamer forms a 15 A wide pore and provide a detailed map of SpaP interactions with the export apparatus components SpaQ, SpaR, and SpaS. We further refine the current view of export apparatus assembly, consolidate transmembrane topology models for SpaP and SpaR, and present intimate interactions of the periplasmic domains of SpaP and SpaR with the inner rod protein PrgJ, indicating how export apparatus and needle filament are connected to create a continuous conduit for substrate translocation. PMID- 27977802 TI - Seed Predation by the Shore Crab Carcinus maenas: A Positive Feedback Preventing Eelgrass Recovery? AB - There is an increasing interest to restore the ecosystem services that eelgrass provides, after their continuous worldwide decline. Most attempts to restore eelgrass using seeds are challenged by very high seed losses and the reasons for these losses are not all clear. We assess the impact of predation on seed loss and eelgrass establishment, and explore methods to decrease seed loss during restoration in the Swedish northwest coast. In a laboratory study we identified three previously undescribed seed predators, the shore crab Carcinus maenas, the hermit crab Pagurus bernhardus and the sea urchin Strongylocentrotus droebachiensis, of which shore crabs consumed 2-7 times more seeds than the other two species. The importance of shore crabs as seed predators was supported in field cage experiments where one enclosed crab caused 73% loss of seeds over a 1 week period on average (~ 21 seeds per day). Seedling establishment was significantly higher (14%) in cages that excluded predators over an 8-month period than in uncaged plots and cages that allowed predators but prevented seed transport (0.5%), suggesting that seed predation constitutes a major source of seed loss in the study area. Burying the seeds 2 cm below the sediment surface prevented seed predation in the laboratory and decreased predation in the field, constituting a way to decrease seed loss during restoration. Shore crabs may act as a key feedback mechanism that prevent the return of eelgrass both by direct consumption of eelgrass seeds and as a predator of algal mesograzers, allowing algal mats to overgrow eelgrass beds. This shore crab feedback mechanism could become self-generating by promoting the growth of its own nursery habitat (algal mats) and by decreasing the nursery habitat (seagrass meadow) of its dominant predator (cod). This double feedback-loop is supported by a strong increase of shore crab abundance in the last decades and may partly explain the regime shift in vegetation observed along the Swedish west coast. PMID- 27977801 TI - Incidence and Predictors of Angiographic Vasospasm, Symptomatic Vasospasm and Cerebral Infarction in Chinese Patients with Aneurysmal Subarachnoid Hemorrhage. AB - INTRODUCTION: Cerebral vasospasm (CVS) is the most common neurological complication after aneurysmal subarachnoid hemorrhage (aSAH) and associated with poor functional outcome and mortality. Reports on incidence and predictors of CVS in Chinese patients with aSAH were scarce. We aimed to estimate the incidence and predictors of angiographic vasospasm (AV), symptomatic vasospasm (SV), and cerebral infarction in Chinese patients with aSAH. METHODS: We retrospectively reviewed the medical records of 542 consecutive aSAH patients admitted to neurosurgery department of the First Affiliated Hospital of Xinjiang Medical University in Urumqi city of China between January 1, 2011 and December 31, 2015. AV, SV and cerebral infarction were defined based on clinical data and neuroimaging findings. Univariate and multivariate analyses were performed to identify predictors of AV, SV or cerebral infarction. RESULTS: 343 (63.3%) patients fulfilled the inclusion and exclusion criteria. Of them, 182(53.1%) developed AV, 99 (28.9%) developed SV, and 87 (25.4%) developed cerebral infarction. A history of hypertension, poor modified Fisher grade (3-4) and poor Hunt-Hess grade (4-5) on admission were common risk factors for AV, SV and cerebral infarction. Patients from Uyghur ethnic group or other minorities were less likely to develop AV, SV or cerebral infarction, compared to those from Han ethic group after adjustment of other potential confounders. Additionally, age >=53 years, leukocyte count >=11* 109/L on admission and being current or former smokers were independent risk factors of cerebral infarction. Leukocyte count >=11* 109/L on admission and aneurysm size >= 10 mm were independent risk factors of SV. Serum glucose level >=7.0 mmol/L on admission was an independent risk factor of AV. CONCLUSION: Risk factors of different definitions of CVS were diverse in Chinese patients with aSAH; however, risk factors of SV and cerebral infarction seem to be similar. We recommend early and aggressive therapy in these patients at-risk of CVS. PMID- 27977804 TI - Correction: Choroidal Structure in Children with Anisohypermetropic Amblyopia Determined by Binarization of Optical Coherence Tomographic Images. AB - [This corrects the article DOI: 10.1371/journal.pone.0164672.]. PMID- 27977803 TI - Distinctive Feature of Microbial Communities and Bacterial Functional Profiles in Tricholoma matsutake Dominant Soil. AB - Tricholoma matsutake, the pine mushroom, is a valuable forest product with high economic value in Asia, and plays an important ecological role as an ectomycorrhizal fungus. Around the host tree, T. matsutake hyphae generate a distinctive soil aggregating environment called a fairy ring, where fruiting bodies form. Because T. matsutake hyphae dominate the soil near the fairy ring, this species has the potential to influence the microbial community. To explore the influence of T. matsutake on the microbial communities, we compared the microbial community and predicted bacterial function between two different soil types-T. matsutake dominant and T. matsutake minor. DNA sequence analyses showed that fungal and bacterial diversity were lower in the T. matsutake dominant soil compared to T. matsutake minor soil. Some microbial taxa were significantly more common in the T. matsutake dominant soil across geographic locations, many of which were previously identified as mycophillic or mycorrhiza helper bacteria. Between the two soil types, the predicted bacterial functional profiles (using PICRUSt) had significantly distinct KEGG modules. Modules for amino acid uptake, carbohydrate metabolism, and the type III secretion system were higher in the T. matsutake dominant soil than in the T. matsutake minor soil. Overall, similar microbial diversity, community structure, and bacterial functional profiles of the T. matsutake dominant soil across geographic locations suggest that T. matsutake may generate a dominance effect. PMID- 27977805 TI - Correction: Mitochondrial Morphology and Fundamental Parameters of the Mitochondrial Respiratory Chain Are Altered in Caenorhabditis elegans Strains Deficient in Mitochondrial Dynamics and Homeostasis Processes. AB - [This corrects the article DOI: 10.1371/journal.pone.0130940.]. PMID- 27977807 TI - Correction: Technique for Early Reliability Prediction of Software Components Using Behaviour Models. AB - [This corrects the article DOI: 10.1371/journal.pone.0163346.]. PMID- 27977808 TI - Activated p53 with Histone Deacetylase Inhibitor Enhances L-Fucose-Mediated Drug Delivery through Induction of Fucosyltransferase 8 Expression in Hepatocellular Carcinoma Cells. AB - BACKGROUND: The prognosis of advanced hepatocellular carcinoma (HCC) is dismal, underscoring the need for novel effective treatments. The alpha1,6 fucosyltransferase (fucosyltransferase 8, FUT8) has been reported to accelerate malignant potential in HCC. Our study aimed to investigate the regulation of FUT8 expression by p53 and develop a novel therapeutic strategy for targeting HCC cells using L-fucose-mediated drug delivery. METHODS: Binding sites for p53 were searched for within the FUT8 promoter region. FUT8 expression was assessed by immunoblotting. Chromatin immunoprecipitation (ChIP) assays were performed to analyze p53 binding to the FUT8 promoter. The delivery of Cy5.5-encapsulated L fucose-liposomes (Fuc-Lip-Cy5.5) to a Lens Culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3)-expressing HCC cells was analyzed by flow cytometry. The induction of FUT8 by histone deacetylase inhibitor (HDACi) inducing acetylated -p53 was evaluated by immunoblotting. Flow cytometric analysis was performed to assess whether the activation of p53 by HDACi affected the uptake of Fuc-Lip-Cy5.5 by HCC cells. The cytotoxicity of an L-fucose-bound liposome carrying sorafenib (Fuc-Lip-sorafenib) with HDACi was assessed in vivo and in vitro. RESULTS: The knock down of p53 with siRNA led to decreased FUT8 expression. ChIP assays revealed p53 binds to the FUT8 promoter region. Flow cytometric analyses demonstrated the specific uptake of Fuc-Lip-Cy5.5 into AFP-L3 expressing HCC cells in a p53- and FUT8-dependent manner. HDACi upregulated the uptake of Fuc-Lip-Cy5.5 by HCC cells by increasing FUT8 via acetylated -p53. The addition of a HDACi increased apoptosis induced by Fuc-Lip-sorafenib in HCC cells. CONCLUSIONS: Our findings reveal that FUT8 is a p53 target gene and suggest that p53 activated by HDACi induces Fuc-Lip-sorafenib uptake by HCC cells, highlighting this pathway as a promising therapeutic intervention for HCC. PMID- 27977806 TI - Integrated Activity and Genetic Profiling of Secreted Peptidases in Cryptococcus neoformans Reveals an Aspartyl Peptidase Required for Low pH Survival and Virulence. AB - The opportunistic fungal pathogen Cryptococcus neoformans is a major cause of mortality in immunocompromised individuals, resulting in more than 600,000 deaths per year. Many human fungal pathogens secrete peptidases that influence virulence, but in most cases the substrate specificity and regulation of these enzymes remains poorly understood. The paucity of such information is a roadblock to our understanding of the biological functions of peptidases and whether or not these enzymes are viable therapeutic targets. We report here an unbiased analysis of secreted peptidase activity and specificity in C. neoformans using a mass spectrometry-based substrate profiling strategy and subsequent functional investigations. Our initial studies revealed that global peptidase activity and specificity are dramatically altered by environmental conditions. To uncover the substrate preferences of individual enzymes and interrogate their biological functions, we constructed and profiled a ten-member gene deletion collection of candidate secreted peptidases. Through this deletion approach, we characterized the substrate specificity of three peptidases within the context of the C. neoformans secretome, including an enzyme known to be important for fungal entry into the brain. We selected a previously uncharacterized peptidase, which we term Major aspartyl peptidase 1 (May1), for detailed study due to its substantial contribution to extracellular proteolytic activity. Based on the preference of May1 for proteolysis between hydrophobic amino acids, we screened a focused library of aspartyl peptidase inhibitors and identified four high-affinity antagonists. Finally, we tested may1Delta strains in a mouse model of C. neoformans infection and found that strains lacking this enzyme are significantly attenuated for virulence. Our study reveals the secreted peptidase activity and specificity of an important human fungal pathogen, identifies responsible enzymes through genetic tests of their function, and demonstrates how this information can guide the development of high affinity small molecule inhibitors. PMID- 27977809 TI - Multigenic Delineation of Lower Jaw Deformity in Triploid Atlantic Salmon (Salmo salar L.). AB - Lower jaw deformity (LJD) is a skeletal anomaly affecting farmed triploid Atlantic salmon (Salmo salar L.) which leads to considerable economic losses for industry and has animal welfare implications. The present study employed transcriptome analysis in parallel with real-time qPCR techniques to characterise for the first time the LJD condition in triploid Atlantic salmon juveniles using two independent sample sets: experimentally-sourced salmon (60 g) and commercially produced salmon (100 g). A total of eleven genes, some detected/identified through the transcriptome analysis (fbn2, gal and gphb5) and others previously determined to be related to skeletal physiology (alp, bmp4, col1a1, col2a1, fgf23, igf1, mmp13, ocn), were tested in the two independent sample sets. Gphb5, a recently discovered hormone, was significantly (P < 0.05) down-regulated in LJD affected fish in both sample sets, suggesting a possible hormonal involvement. In-situ hybridization detected gphb5 expression in oral epithelium, teeth and skin of the lower jaw. Col2a1 showed the same consistent significant (P < 0.05) down-regulation in LJD suggesting a possible cartilaginous impairment as a distinctive feature of the condition. Significant (P < 0.05) differential expression of other genes found in either one or the other sample set highlighted the possible effect of stage of development or condition progression on transcription and showed that anomalous bone development, likely driven by cartilage impairment, is more evident at larger fish sizes. The present study improved our understanding of LJD suggesting that a cartilage impairment likely underlies the condition and col2a1 may be a marker. In addition, the involvement of gphb5 urges further investigation of a hormonal role in LJD and skeletal physiology in general. PMID- 27977810 TI - Disrupting Mosquito Reproduction and Parasite Development for Malaria Control. AB - The control of mosquito populations with insecticide treated bed nets and indoor residual sprays remains the cornerstone of malaria reduction and elimination programs. In light of widespread insecticide resistance in mosquitoes, however, alternative strategies for reducing transmission by the mosquito vector are urgently needed, including the identification of safe compounds that affect vectorial capacity via mechanisms that differ from fast-acting insecticides. Here, we show that compounds targeting steroid hormone signaling disrupt multiple biological processes that are key to the ability of mosquitoes to transmit malaria. When an agonist of the steroid hormone 20-hydroxyecdysone (20E) is applied to Anopheles gambiae females, which are the dominant malaria mosquito vector in Sub Saharan Africa, it substantially shortens lifespan, prevents insemination and egg production, and significantly blocks Plasmodium falciparum development, three components that are crucial to malaria transmission. Modeling the impact of these effects on Anopheles population dynamics and Plasmodium transmission predicts that disrupting steroid hormone signaling using 20E agonists would affect malaria transmission to a similar extent as insecticides. Manipulating 20E pathways therefore provides a powerful new approach to tackle malaria transmission by the mosquito vector, particularly in areas affected by the spread of insecticide resistance. PMID- 27977813 TI - Papilla Reformation at Single-Tooth Implant Sites Adjacent to Teeth with Severely Compromised Periodontal Support. AB - Reformation of the lost interdental papilla remains one of the most challenging goals for clinicians. When a single tooth is replaced with an implant, the papilla between the tooth and the implant can often be maintained or predictably reformed as long as the adjacent tooth's periodontal attachment and bone are preserved. However, if the periodontal support is compromised on the neighboring natural tooth, the papilla will often be deficient or missing. The cases presented herein demonstrate long-term follow-up of successful reformation of periodontal/peri-implant tissue contours, including reconstruction of lost interproximal bone and papilla at periodontally compromised sites using a combined hard and soft tissue surgical approach. PMID- 27977811 TI - Large-Scale Phylogenomic Analysis Reveals the Complex Evolutionary History of Rabies Virus in Multiple Carnivore Hosts. AB - The natural evolution of rabies virus (RABV) provides a potent example of multiple host shifts and an important opportunity to determine the mechanisms that underpin viral emergence. Using 321 genome sequences spanning an unprecedented diversity of RABV, we compared evolutionary rates and selection pressures in viruses sampled from multiple primary host shifts that occurred on various continents. Two major phylogenetic groups, bat-related RABV and dog related RABV, experiencing markedly different evolutionary dynamics were identified. While no correlation between time and genetic divergence was found in bat-related RABV, the evolution of dog-related RABV followed a generally clock like structure, although with a relatively low evolutionary rate. Subsequent molecular clock dating indicated that dog-related RABV likely underwent a rapid global spread following the intensification of intercontinental trade starting in the 15th century. Strikingly, although dog RABV has jumped to various wildlife species from the order Carnivora, we found no clear evidence that these host jumping events involved adaptive evolution, with RABV instead characterized by strong purifying selection, suggesting that ecological processes also play an important role in shaping patterns of emergence. However, specific amino acid changes were associated with the parallel emergence of RABV in ferret-badgers in Asia, and some host shifts were associated with increases in evolutionary rate, particularly in the ferret-badger and mongoose, implying that changes in host species can have important impacts on evolutionary dynamics. PMID- 27977814 TI - Clinical Evaluation of the Influence of Connection Type and Restoration Height on the Reliability of Zirconia Abutments: A Retrospective Study on 965 Abutments with a Mean 6-Year Follow-Up. AB - This multicenter retrospective clinical study aimed to evaluate the clinical performance of zirconia abutments in anterior and posterior regions, focusing on implant-abutment connections and restoration vertical height (RVH). Six experienced prosthodontists used 965 computer-aided design/computer-assisted manufacture zirconia abutments in 601 patients. Different surgical approaches were taken according to the needs of each patient. The final restorations were all-ceramic single crowns and short-span fixed dental prostheses. Screw-retained restorations were mainly used in anterior areas, whereas cemented prostheses were chosen in cases where the implant position was not ideal. Different types of implant-abutment connections were compared: external, internal with metal components, and internal full-zirconia conical connection. All the restorations were followed up for 4 to 10 years. Technical and biologic complications were assessed in relation to several biomechanical variables, such as RVH. Differences between groups were statistically analyzed, and longevity of abutments was evaluated according to Kaplan-Meier survival analysis. Zirconia abutments resulted in overall survival and success rates of 98.9% and 94.8%, respectively. External connections reported survival and success rates of 99.7% and 94.5%, internal metal connections 99.8% and 95.5%, and internal zirconia connections 93.1% and 93.1%, respectively. Overall complication rates of 1.14%, 3.42%, and 0.62% were reported for fractures, chipping, and unscrewing, respectively. The external connection showed the longest survival while the internal zirconia connection showed the highest fracture incidence over the observation period. The clinical risk limit of RVH was identified as 14 mm. Zirconia abutments showed satisfactory clinical performance in anterior and posterior regions after 4 to 10 years. RVH and connection type influenced the clinical longevity of restorations; in particular, internal connections with secondary metallic components reduced the incidence of complications. PMID- 27977812 TI - Increased Expression of CC16 in Patients with Idiopathic Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology. The pathogenic mechanisms are unclear, but evidence indicates that aberrantly activated alveolar epithelial cells secrete a variety of mediators which induce the migration, proliferation and activation of fibroblasts and finally the excessive accumulation of extracellular matrix with the consequent destruction of the lung parenchyma. CC16 (approved symbol SCGB1A1), a putative anti-inflammatory protein produced by "club" cells in the distal airways, has not been evaluated in IPF lungs. In this study, we determined the serum and bronchoalveolar lavage (BAL) levels as well as the lung cell localization of this protein. Also, we explored the usefulness of serum levels of CC16 for the differential diagnosis of IPF (n = 85), compared with non-IPF interstitial lung diseases [chronic hypersensitivity pneumonitis (cHP; n = 85) and connective tissue diseases (CTD ILD; n = 85)]. CC16 was significantly increased in serum and BAL fluids of IPF patients and was found not only in club cells but also in alveolar epithelial cells. When compared with non-IPF patients and controls, serum levels were significantly increased (p<0.0001). Sensitivity and specificity for CC16 (cut-off 41ng/mL) were 24% and 90%, positive predictive value 56% and negative predictive value 69%. These findings demonstrate that CC16 is upregulated in IPF patients suggesting that may participate in its pathogenesis. Although higher than the serum levels of non-IPF patients it shows modest sensitivity to be useful as a potential biomarker for the differential diagnosis. PMID- 27977815 TI - A Prospective Clinical and Radiographic Assessment of Platform-Switched Laser Microchannel Implants Placed in Limited Interimplant Spaces. AB - This multicenter clinical trial of platform-switched laser-microchannel implants supports findings from a previous preclinical trial. Previous information indicated that an interimplant distance narrower than 3 mm would result in decrease in the crestal bone level, but the results of this investigation suggest that a more optimistic clinical result can be anticipated for implants and abutments with a laser-microchannel surface. PMID- 27977816 TI - Results of Computer-Guided Bone Block Harvesting from the Mandible: A Case Series. AB - Autogenous bone harvesting is a well-documented surgical procedure. Autogenous mandibular bone harvesting carries a risk of anatomical structural damage because the surgeon has no three-dimensional (3D) control of the osteotomy planes. The aim of this case series was to describe the results of mandibular bone block harvesting applying computer-guided surgery. A sample of 13 partially dentate patients presenting bone deficiencies in the horizontal and/or vertical plane were selected for autogenous mandibular bone block graft. The bone block dimension was planned through a computer-aided design (CAD) process, defining ideal bone osteotomy planes to avoid damage to anatomical structures (nerves, teeth roots, etc) and to generate a surgical guide that imposed the 3D working direction to the bone-cutting instrument. The bone block dimension was always related to the defect dimension to be compensated. A total of 13 mandibular bone blocks were harvested to treat 16 alveolar defects (9 vertical and 7 horizontal). The mean planned mesiodistal dimension of the bone block was 24.8 +/- 7.3 mm, the mean height was 8 +/- 1 mm, and the mean thickness was 4 +/- 2 mm. None of the treated patients experienced neurologic alteration of their alveolar nerve function. The preliminary data from this case series suggested that computer guided bone harvesting could be a concrete opportunity for clinicians to obtain an appropriate volume of autogenous bone in a safe manner. PMID- 27977818 TI - Response of Dental Pulp Stem Cells to Synthetic, Allograft, and Xenograft Bone Scaffolds. AB - Different degrees of clinical success have been reported for synthetic, allograft, and xenograft bone substitutes in human trials. Although these substitutes have been clinically investigated, their in vitro effects on cell differentiation remain unclear. Proliferation, differentiation, and attachment of dental pulp stem cells (DPSCs) to beta-tricalcium phosphate (beta-TCP), freeze dried bone allograft (FDBA), and deproteinized bovine bone mineral (DBBM) were compared in this study. MTT assay, measurement of total DNA, and reverse transcriptase polymerase chain reaction were performed. beta-TCP had the highest potential for DPSC attachment and proliferation, while FDBA induced osteoblastic differentiation of DPSCs. Further in vivo investigations are necessary to select a clinically appropriate scaffold. PMID- 27977817 TI - The Novel Design of Zirconium Oxide-Based Screw-Retained Restorations, Maximizing Exposure of Zirconia to Soft Peri-implant Tissues: Clinical Report After 3 Years of Follow-up. AB - Current use of zirconium oxide (ZrO2)-based screw-retained restorations does not guarantee maximum contact of soft peri-implant tissues with ZrO2, because veneering porcelain usually covers the major subgingival part of the restoration. Ceramics preclude direct interaction between zirconia and soft tissue cells, thus reducing biocompatibility and benefit to the patient. The four case reports discussed in this article describe the new design modality of the ZrO2 screw retained restorations, in which zirconia is exposed to the tissues and no veneering porcelain is located below the gingival margin. The article also shows the impact of this treatment on soft peri-implant tissues after 3 years of follow up. Soft tissue recession, vestibular contour, bleeding on probing, and probing depth were evaluated. PMID- 27977819 TI - Clinical Periodontal Response to Anterior All-Ceramic Crowns with Either Chamfer or Feather-edge Subgingival Tooth Preparations: Six-Month Results and Patient Perception. AB - Subgingival margins are often required for biologic, mechanical, or esthetic reasons. Several investigations have demonstrated that their use is associated with adverse periodontal reactions, such as inflammation or recession. The purpose of this prospective randomized clinical study was to determine if two different subgingival margin designs influence the periodontal parameters and patient perception. Deep chamfer and feather-edge preparations were compared on 58 patients with 6 months follow-up. Statistically significant differences were present for bleeding on probing, gingival recession, and patient satisfaction. Feather-edge preparation was associated with increased bleeding on probing and deep chamfer with increased recession; improved patient comfort was registered with chamfer margin design. Subgingival margins are technique sensitive, especially when feather-edge design is selected. This margin design may facilitate soft tissue stability but can expose the patient to an increased risk of gingival inflammation. PMID- 27977820 TI - Immediate Loading of Single Implants: A 2-Year Prospective Multicenter Study. AB - The aim of this prospective multicenter study was to evaluate the outcomes of single implants subjected to immediate functional loading. Inclusion criteria were single-tooth placement in postextraction sockets or fully healed sites, and sufficient bone height and width to place an implant of at least 3.5 * 10.0 mm. All implants were functionally loaded immediately after placement and followed for 2 years. Outcome measures were implant survival, complications, and peri implant marginal bone loss (MBL). A total of 57 implants (38 maxilla, 19 mandible) were placed in 46 patients (23 men, 23 women, aged 18-73 years). Of these, 10 implants were placed in postextraction sockets. One implant failed, in a healed site, giving a patient-based overall 2-year survival rate of 97.6%. The incidence of biologic complications was 1.8%; prosthetic complications amounted to 7.5%. The peri-implant MBL was 0.37 +/- 0.22 mm (healed sites: 0.4 mm +/- 0.22; postextraction sockets: 0.3 mm +/- 0.22). The immediate functional loading of single implants seems to represent a safe and successful procedure. Long-term follow-up studies on a larger sample of patients are needed to confirm these results. PMID- 27977821 TI - A Possible Link Between Rheumatoid Arthritis and Periodontitis: A Systematic Review and Meta-analysis. AB - Previous studies have shown that patients with rheumatoid arthritis (RA) have a higher susceptibility to periodontitis, but the results of individual studies remain controversial. The aim of the present meta-analysis was to comprehensively evaluate the association between RA and periodontitis. A systematic literature search was conducted in PubMed and EMBASE. Data were extracted using standardized forms, and odds ratios (OR) with 95% confidence intervals (CI) were calculated for each study. Pooled data were estimated by fixed- and random-effects models if appropriate. Eight case-control studies were included in the present study. Study size ranged from 104 to 151,569 participants. The prevalence of periodontitis in RA patients ranged from 15.5% to 100%, compared with 10.0% to 82.1% in controls. In group 1 (control) and group 2, the heterogeneity was 38% and 11%, respectively. Using fixed-effects analysis, the overall pooled estimates of the ORs for periodontitis were 4.68 (95% CI: 3.11-7.05) and 1.28 (95% CI: 1.24-1.33) in groups 1 and 2, respectively. This meta-analysis indicates that RA was significantly associated with increased overall risk of periodontitis. PMID- 27977822 TI - A New Approach for the Treatment of Lateral Periodontal Cysts with an 810-nm Diode Laser. AB - The aim of this study was to test whether the combination of diode laser therapy and surgical treatment for a lateral periodontal cyst (LPC) would result in greater clinical improvement compared with surgery alone. A total of 18 patients with LPCs were assessed for eligibility for this study. At baseline, each patient was randomly allocated to one of two regimens: diode laser plus surgery (test group) or traditional surgical treatment alone (control group). Healing parameters were assessed at 7 to 21 days to monitor short-term complications, and periodontal parameters were assessed at 3, 6, and 12 months to evaluate long-term healing. The test group demonstrated highly significant differences in both the short-term and long-term parameters compared with the control group. This study showed that diode laser treatment results in a shorter wound-healing period and could be considered valuable for the surgical treatment of LPCs. PMID- 27977823 TI - Histologic and Clinical Study of Gingival Recession Treated with Subepithelial Connective Tissue Graft: A Case Report. AB - Subepithelial connective tissue graft (SCTG) is considered the gold standard for treatment of gingival recessions. For ethical reasons, most studies report only clinical and not histologic results. A 20-year-old woman presenting with a localized gingival recession of 5 mm in the mandibular left central incisor was treated with SCTG. According to the initial treatment plan, the tooth was extracted 11 months later and a histologic study was performed, revealing new attachment of connective tissue with collagen fibers that were directly inserted in a perpendicular way into dentin areas and new cement areas (1.37 mm). PMID- 27977824 TI - Soft Tissue Closure of Grafted Extraction Sockets in the Anterior Maxilla: A Modified Palatal Pedicle Connective Tissue Flap Technique. AB - Localized ridge resorption, the consequence of socket collapse, following tooth extraction in the anterior maxilla can adversely affect esthetics, function, and future implant placement. Immediate grafting of extraction sockets may help preserve natural ridge contours, but a lack of available soft tissue can compromise the final esthetic outcome. The presented modified rotated palatal pedicle connective tissue flap is a useful technique for simultaneous soft tissue coverage and augmentation of grafted sockets to improve esthetic outcome. This article delineates its advantages through the presentation of a four-case series using this new technique. PMID- 27977825 TI - Microsurgical Instruments in Laterally Moved, Coronally Advanced Flap for Miller Class III Isolated Recession Defects: A Randomized Controlled Clinical Trial. AB - The aim of this study was to evaluate the laterally moved coronally advanced flap (LMCAF) technique in which magnified vision was used in conjunction with microsurgical instruments (LMCAF-M), and to compare the results with conventional LMCAF technique (LMCAF-C) in Miller Class III isolated recession-type defects. A total of 50 patients with recessions located at incisors and canines were treated with LMCAF-M or LMCAF-C. Outcome parameters (complete root coverage [CRC] and mean root coverage [MRC]) were assessed 6 months postoperatively. Of the 25 defects in each group, 13 in the LMCAF-M (92.0%) and 17 in the LMCAF-C group (68.0%) exhibited CRC (P < .007). MRC scores were 90.48% for the LMCAF-C group and 97.64% for the LMCAF-M group (P < .04). Patient satisfaction with esthetics and postoperative morbidity were better in the LMCAF-M group (P < .032). This study indicates that performing LMCAF with microsurgical instruments offers definite advantages in terms of CRC and MRC, decreased postoperative morbidity, and increased acceptance by patients. PMID- 27977826 TI - Xenogeneic Collagen Matrix Versus Connective Tissue Graft: Case Series of Various Gingival Recession Treatments. AB - A xenogeneic collagen matrix recently has been suggested as an alternative to connective tissue graft for the treatment of gingival recession. The matrix avoids the second surgical site, and as a consequence could decrease surgical morbidity. This new matrix was used in various clinical situations and compared to connective tissue graft (CTG) in a split-mouth design case series. A total of 17 recessions were treated with a coronally advanced flap, 9 with CTG, and 8 with the matrix. Mean recession reduction was 2.00 mm with the CTG and 2.00 mm with the matrix. No significant statistical differences between the techniques were observed in this case report. PMID- 27977827 TI - Minimally Invasive Sinus Augmentation Procedure Using a Dedicated Hydraulic Sinus Lift Implant Device: A Prospective Case Series Study on Clinical, Radiologic, and Patient-Centered Outcomes. AB - The aim of this study was to evaluate clinical and radiologic outcomes of a novel device that allows simultaneous hydraulic sinus membrane elevation, bone grafting, and implant placement. A sample of 18 consecutive participants with severe atrophy of the posterior maxilla underwent transcrestal elevation of the sinus membrane and implant placement. At the 6-month follow-up, the following parameters were assessed: implant success, any complications, marginal bone loss (MBL), three-dimensional (3D) graft measurements, implant stability quotient (ISQ), and graft density. No implants failed during follow-up (10.8 +/- 2.8 months; range: 7-14 months). No membrane tears or other adverse events were observed. Mean residual alveolar ridge height was 4.78 +/- 0.88 mm. Six months after the procedure, the mean MBL was 0.18 mm. The mean sinus membrane elevation was 12.78 +/- 2.18 mm (range: 10.7-14.23). Along the basic 3D reference planes, the dimensions of grafted bone measured around implants were as follows: axial area = 239.7 +/- 57.68 mm2; sagittal area = 257.0 +/- 60.83 mm2; coronal area = 143.3 +/- 29.46 mm2. The mean volume of the graft was 2.38 +/- 0.26 mL at baseline and 2.05 +/- 0.24 mL 6 months after graft maturation (difference: 0.33 +/- 0.29 mL, P = .0090). Graft density (in Hounsfield units [HU]), improved during healing from 322.0 +/- 100.42 HU to 1,062.0 +/- 293.7 HU; difference 740.0 +/- 295.35 HU (P = .0001). The mean ISQ value was 65.5 at implant placement, and it increased to 74.1 at the 6-month examination (P = .0014). Of 18 patients, 12 experienced no pain (66.6%) and 10 experienced no swelling (55.5%). No severe pain or swelling was reported in any of the cases. The mean number of analgesic tablets consumed was 0.78 +/- 0.67. Mean surgical time was 24.0 +/- 4.07 minutes. The iRaise Sinus Lift System may provide a new option for minimally invasive transcrestal sinus surgery with minimal patient discomfort. A physiologic contraction of 13.9% of its original volume was experienced during healing. Long term clinical studies are needed to confirm these preliminary results. PMID- 27977828 TI - Modified Lip Repositioning with Esthetic Crown Lengthening: A Combined Approach to Treating Excessive Gingival Display. AB - Lip repositioning surgery to address excessive gingival display induced by different etiologies has received major attention recently. Several techniques and variations have been reported, including myotomy or repositioning of the levator labii superioris muscle, Le Fort impaction, maxillary gingivectomies, botulinum toxin injections, and lip stabilization. This study reports a case of excessive gingival display treated by a modified combined approach. A 25-year-old woman with a 4- to 8-mm gingival display when smiling caused by a combination of short clinical crowns induced by an altered passive eruption and hypermobility of the upper lip underwent a staged esthetic crown-lengthening procedure followed by a modified lip repositioning technique. A description of the technique and a comparison with other modes of therapy is discussed. This modified approach for treating the hypermobile lip included a bilateral removal of a partial-thickness strip of mucosa from the maxillary buccal vestibule without severing the muscle, leaving the midline frenum intact and suturing the lip mucosa to the mucogingival line. The narrower vestibule and increased tooth length resulted in a symmetric and pleasing gingival display when smiling that remained stable over time. With proper diagnosis and sequence of therapy, modified lip repositioning surgery combined with esthetic crown lengthening can be used predictably to treat excessive gingival display and enhance smile esthetics. PMID- 27977830 TI - Evaluation of the Retinal and Choroidal Vasculature With OCT Angiography Versus Conventional Angiography. PMID- 27977829 TI - Effect of Lining Materials on Shear Bond Strength for Composite Restorations In Vitro. AB - This study evaluated the influence of liner agents placed under resin composite restorations on shear bond strength (SBS) to dentin. A total of 40 extracted bovine incisors were used. Enamel surfaces were ground to expose a flat dentin area of 7 mm in diameter. Teeth were divided into four groups according to tested liners: Group 1 (control) used no liner; Group 2 used a resin-modified glass ionomer cement liner (Vitrebond Plus, 3M ESPE); Group 3 used a light-activated calcium hydroxide resin liner (Ultra-Blend Plus, Ultradent); and Group 4 used a polyacrylic acid surface treatment + conventional glass-ionomer cement liner (Vidrion F, SSWhite). All groups were subjected to bonding procedures with Single Bond (3M ESPE) and 4-mm-thick buildups of resin composite were fabricated. Artificial aging was performed, and the specimens were submitted to mechanical shear testing. One-way analysis of variance (ANOVA) revealed significant differences among liners (P = .00). Group 4 showed the highest SBS. Group 1 showed significantly higher mean SBS compared with Group 3. Results showed that SBS is improved when using polyacrylic acid surface treatment + conventional glass-ionomer cement and decreased when using light-activated calcium hydroxide when compared with no liner. Polyacrylic acid surface treatment + conventional glass-ionomer cement as a liner placed under adhesion surface can improve the shear bond strength between dentin and resin, while light-activated calcium hydroxide resin should be used restrictedly in very deep cavities, because they may reduce the bond strength of the restoration submitted to masticatory forces and temperature changes in the oral environment. PMID- 27977831 TI - Spectral-Domain Optical Coherence Tomography in Older Patients With History of Retinopathy of Prematurity. AB - BACKGROUND AND OBJECTIVE: To characterize the in vivo microstructural features of patients with history of retinopathy of prematurity (ROP). PATIENTS AND METHODS: A single-center, retrospective imaging case series during which a chart review was performed of consecutive patients with history of ROP who underwent spectral domain optical coherence tomography (SD-OCT) with or without enhanced depth imaging. Eyes with time-domain OCT, no light perception, or uninterpretable SD OCT images were excluded. Main outcome measures included best-corrected visual acuity (BCVA) and exploratory SD-OCT findings. RESULTS: A total of 186 eyes of 112 patients (mean age: 31.5 years; range: 8 years to 70 years) were imaged. Mean visual acuity was 20/150 (range: 20/20 to light perception). Mean foveal thickness (MFT) and subfoveal choroidal thickness (SCT) measured 270.93 um +/- 56.40 um and 239.87 um +/- 73.00 um, respectively. There was a negative correlation between ROP stage and MFT (Rho = -0.19; P = .027), but not with SCT (Rho = -0.03; P = .748). There were negative correlations between BCVA and MFT (Rho = -0.23; P < .01) and SCT (Rho = -0.19; P = .04). Ellipsoid zone (EZ) abnormalities, inner retinal layer thickening, and presence of chorioretinal atrophy were associated with higher ROP stage (P < .001) and poorer visual acuity (Rho = 0.59; P < .001). The presence of retinoschisis (n = 36/186; 19%) was associated with poorer visual acuity (P < .001), but did not correlate with higher ROP stage (P = .17). Epiretinal membrane-like dense hyaloidal organization and vitreoretinal interface abnormalities were seen in 69% (130/186) and 33% (63/186) of eyes, respectively, but were not associated with ROP stage (P = .87) or visual acuity (P = .54). After controlling for EZ abnormalities, foveal hypoplasia, macular schisis, inner retinal thickening, chorioretinal atrophy, and ROP stage, the independent risk factors for poorer visual acuity were EZ abnormalities (Beta = 0.38; P < .001), chorioretinal atrophy (Beta = 0.18; P = .03), and ROP stage (Beta = 0.22; P < .01). CONCLUSION: SD-OCT imaging identified a variety of microstructural abnormalities present in patients with history of ROP. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1086-1094.]. PMID- 27977832 TI - Nonresponse and Recurrence of Retinopathy of Prematurity After Intravitreal Ranibizumab Treatment. AB - BACKGROUND AND OBJECTIVE: To evaluate the surgical outcome of type 1 retinopathy of prematurity (ROP) after intravitreal ranibizumab (IVR) (Lucentis; Genentech, South San Francisco, CA) treatment. PATIENTS AND METHODS: This was a prospective case series. Premature infants with treatment-requiring ROP who received IVR injections from 2013 to 2015 were included. RESULTS: Twenty-two eyes of 12 children were included in the study. Complete resolution of ROP after a single IVR was noted in 73% of eyes. Retreatment was needed in 27% of eyes due to nonresponse to IVR (18%) or recurrence of ROP (9%). After that, all treated eyes (100%) demonstrated regressed ROP with attached retina. The median visual acuity was 0.3 LogMAR (range: 0 LogMAR to 0.8 LogMAR) with a mean follow-up of 25.2 months +/- 6.8 months. CONCLUSIONS: IVR is effective and well-tolerated for patients with treatment-requiring ROP. However, nonresponse to IVR or recurrence of ROP after IVR was noted in 27% of treated eyes and required additional treatment. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1095-1105.]. PMID- 27977833 TI - Hyperreflective Choroidal Vessels in Geographic Atrophy Secondary to Age-Related Macular Degeneration. AB - BACKGROUND AND OBJECTIVE: To describe choroidal vessels in areas of geographic atrophy (GA) secondary to age-related macular degeneration that appear as hyperreflective choroidal vessels (HRCVs) on multicolor (MC) imaging. PATIENTS AND METHODS: Retrospective case series of patients with GA. Multimodal imaging evaluation was performed. RESULTS: HRCVs, which seem to be sclerotic on MC imaging, appeared as hyperautofluorescent on fundus autofluorescence, clearly distinguishable over the background of hypo-autofluorescence, and correlated with late-phase hypocyanescence areas on indocyanine green angiography. Average size of GA areas was significantly larger in eyes with (4.19 mm +/- 0.83 mm) compared to eyes without (3.22 mm +/- 1.05 mm) HRVCs (P = .0002). Similarly, mean choroidal thickness (CT) was significantly thinner in eyes with (78.5 um +/- 33.8 um) compared to eyes without (155.4 um +/- 69.8 um) HRVCs (P < .0001). CONCLUSIONS: HRCVs are more clearly distinguishable than other choroidal vessels on MC imaging in GA. HRCV identification is more frequent in eyes with larger areas of atrophy and reduced CT, and thus possibly represent a maker of more advanced GA. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1106-1114.]. PMID- 27977834 TI - High-Resolution Adaptive Optics Retinal Image Analysis at Early Stage Central Areolar Choroidal Dystrophy With PRPH2 Mutation. AB - BACKGROUND AND OBJECTIVE: To report the clinical features of Japanese patients at Stage 1 and 2 of central areolar choroidal dystrophy (CACD). PATIENTS AND METHODS: Five family members had comprehensive ophthalmic examinations including adaptive optics (AO) retinal imaging. Mutation analysis of the PRPH2 gene was performed by Sanger sequencing. The protocol conformed to the tenets of the Declaration of Helsinki and was approved by the institutional review board of The Jikei University School of Medicine. RESULTS: Four family members had a heterozygous PRPH2 mutation, p.R172Q; however, one member with a mutation did not show any ophthalmological abnormalities. Two patients had mild parafoveal retinal dystrophy and a reduction of cone density determined by AO analysis. CONCLUSION: The results indicate that the parafoveal cone photoreceptors can be affected even at the early stage of CACD. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1115 1126.]. PMID- 27977835 TI - Optical Coherence Tomography Angiography in Foveal Hypoplasia. AB - BACKGROUND AND OBJECTIVE: A retrospective case series reporting optical coherence tomography angiography (OCTA) findings in foveal hypoplasia. PATIENTS AND METHODS: Patients with foveal hypoplasia who presented to the authors' tertiary eye center. Cases of foveal hypoplasia that underwent OCTA were reviewed, and the clinical histories as well as imaging findings were summarized. RESULTS: Three patients presented to the authors' eye center for evaluation of foveal hypoplasia and underwent OCTA: a 5-year-old girl, a 40-year-old woman, and a 22-year-old man. OCTA images were taken for both eyes of all patients. Four of five eyes with foveal hypoplasia had a small but present foveal avascular zone in the deep capillary plexus, whereas all eyes had an absent or severely reduced superficial capillary plexus. CONCLUSION: OCTA can be helpful in the diagnosis of foveal hypoplasia and can aid in the anatomical characterization of disease. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1127-1131.]. PMID- 27977836 TI - Photodynamic Therapy for Pseudophakic Eyes Compared to Eyes With Cataract. AB - BACKGROUND AND OBJECTIVE: Verteporfin photodynamic therapy (vPDT) plays a role in the treatment of chorioretinal conditions. The purpose of this study was to compare vPDT outcomes between cataractous and pseudophakic eyes. PATIENTS AND METHODS: In this prospective study of consecutive patients with choroidal neovascularization (CNV) secondary to neovascular age-related macular degeneration (nAMD) treated with vPDT, cataract and pseudophakic eyes were compared for number and timing of vPDT treatments, duration of follow-up, angiographic features, and changes in best-corrected visual acuity (BCVA). RESULTS: Overall, 103 eyes (n = 95) were included in the final analysis; 44 eyes in the cataract group and 59 eyes in the pseudophakic group. No significant difference in change in BCVA (P = .19) or leakage-free CNV lesions (P = .58) was found between the groups. CONCLUSIONS: In this study of vPDT for nAMD, there was no significant difference between eyes with cataract and pseudophakic eyes. It seems that cataract does not clinically alter the effect of vPDT. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1132-1136.]. PMID- 27977837 TI - Optical Coherence Tomography Angiography in a Normal Iris. AB - BACKGROUND AND OBJECTIVE: Optical coherence tomography angiography (OCTA) is a new imaging technique for examining the macular region in many retinal diseases. The aim of this study was to assess the applicability of OCTA to detect iris vascularization. PATIENTS AND METHODS: The irises of 28 eyes of 14 patients were examined with AngioVue OCT (Optovue, Fremont, CA). The usual technique was modified using the AngioRetina mode, but with the anterior segment optical adaptor lens, and without autofocus, while making manual adjustments. OCTA scans were captured in both eyes, always by the same operator. The images were acquired in 3 * 3 and 6 * 6 volume cubes. Raw data were then exported and split using an external tool provided by Optovue to obtain three-dimensional (3-D) iris reconstruction. RESULTS: In all eyes, OCTA showed the arterial system more superficially and the venous system more deeply in 3-D reconstruction. CONCLUSION: This is the first report of a study of the vascularization and 3-D reconstruction of the normal iris with OCTA. The method detects iris vascular network and indirectly provides information on the retinal circulation in situations where this is not visible without injecting sodium fluorescein. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1138-1142.]. PMID- 27977838 TI - Multimodal Imaging Features in Acute Exudative Paraneoplastic Polymorphous Vitelliform Maculopathy. AB - An 85-year-old woman with stage IV breast cancer was referred for gradually progressive blurred vision. Dilated fundus examination revealed unifocal, yellow, round vitelliform lesions in the macular region of both eyes. The diagnosis of acute exudative paraneoplastic polymorphous vitelliform maculopathy (AEPPVM) was confirmed with swept-source optical coherence tomography (SS-OCT), fundus autofluorescence, and fluorescein angiography. SS-OCT angiography revealed normal vascular findings in both eyes. Multimodal imaging is useful in the diagnosis and monitoring of AEPPVM and may further the understanding of its pathophysiology. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1143-1146.]. PMID- 27977839 TI - MIRAgel Buckle Extrusion With Preseptal Cellulitis and Erosion Through the Eyelid Skin. AB - MIRAgel (MIRA, Waltham, MA) scleral buckle material was initially developed in the 1980s as an alternative to more traditional silicone buckles. Long-term follow-up has demonstrated complications necessitating removal due to unanticipated hydrolytic degeneration of the exoplant. Material expansion and fragmentation have led to pain, limited extraocular motility, ocular masses, infection, and eventual extrusion. Complications occur later than in other materials; most patients need removal an average of 7 years to 13 years after implantation. This case describes a previously not reported case of MIRAgel scleral buckle extrusion complicated by preseptal cellulitis and complete erosion of the material through the inferior eyelid and extrusion through the skin. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1147-1150.]. PMID- 27977840 TI - Bilateral Prefoveal Sub-Internal Limiting Membrane Hemorrhage in Autoimmune Hemolytic Anemia. AB - Severe anemia can cause multilayered retinal hemorrhages. A 65-year-old woman noted "red spheres" in the central vision of both eyes during a hospital admission for autoimmune hemolytic anemia. Examination revealed extensive multilayered retinal hemorrhages, including bilateral foveal preretinal hemorrhage. Spectral-domain optical coherence tomography localized the preretinal blood to the sub-internal limiting membrane (ILM) space. Various options are available for management of such hemorrhage, including observation for spontaneous resolution, YAG laser membranotomy, or pars plana vitrectomy with ILM peeling. In the authors' patient, the size of the sub-ILM hemorrhage spontaneously improved during the course of 1 month, with both subjective and objective visual improvement. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1151-1153.]. PMID- 27977841 TI - Polypoidal Choroidal Vasculopathy Occurring in the Context of Large Colloid Drusen. AB - The authors report, for the first time, an association between large colloid drusen (LCD) and choroidal neovascularization in a 58-year-old man. Multimodal imaging confirmed the diagnosis of LCD in both eyes and polypoidal choroidal vasculopathy in the left eye. The patient was treated with monthly intravitreal injections of aflibercept (Eylea; Regeneron, Tarrytown, NY). The authors hypothesize that these deposits are probably associated with retinal pigment epithelium dysfunction and could thus lead to delayed neovascularization and atrophy. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1154-1156.]. PMID- 27977842 TI - Optical Coherence Tomography Angiography for Detecting Choroidal Neovascularization Secondary to Punctate Inner Choroidopathy. AB - Punctate inner choroidopathy (PIC) is a relatively uncommon inflammatory multifocal chorioretinopathy that predominantly affects young, myopic women. Subfoveal choroidal neovascularization (CNV) often leads to rapid loss of sight. Fluorescein angiography (FA) and indocyanine green angiography (ICGA) remain the existing gold standards for CNV diagnosis. However, these methods are invasive and time-consuming. Recently, optical coherence tomography angiography (OCTA) has been used more frequently as an adjunct to FA/ICGA. In this report, a 38-year-old woman with PIC and idiopathic CNV presented with blurred vision despite 18/20 visual acuity. FA revealed positive staining and possible leakage, but did not provide clear evidence of CNV. OCTA detected abnormal flow in the outer retina, corresponding to type 2 CNV, that decreased following intravitreal anti-vascular endothelial growth factor (VEGF) therapy. Furthermore, OCTA could show remodeling of the choroidal capillaries after the treatment. OCTA may be helpful in the detection, follow-up, and evaluation of therapeutic strategies to treat CNV secondary to PIC. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1157-1161.]. PMID- 27977843 TI - Occult Perforating Globe Injury Caused by Intraocular Foreign Body. AB - Intraocular foreign bodies (IOFBs) may be associated with occult exit wounds. The authors present a case of a man who sustained a zipper-tooth IOFB through the cornea from a car tire explosion. CT showed an IOFB within the vitreous cavity, but the IOFB was not identified during vitrectomy. Extension of the peritomy revealed an exit wound with the foreign body lodged in the extraocular space. This case demonstrates that IOFBs can rest within the vitreous cavity after creating an exit wound, but may escape detection by being driven back out of the globe during vitrectomy due to the pressurized eye. Coexistent ocular surface and intraocular pathology often limit intraoperative visualization, but a perforating through-and-through injury should be suspected if the IOFB cannot be identified during vitrectomy. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1162-1163.]. PMID- 27977844 TI - Paracetamol (acetaminophen) or non-steroidal anti-inflammatory drugs, alone or combined, for pain relief in acute otitis media in children. AB - BACKGROUND: Acute otitis media (AOM) is one of the most common childhood infectious diseases and a significant reason for antibiotic prescriptions in children worldwide. Pain from middle ear infection and pressure behind the eardrum is the key symptom of AOM. Ear pain is central to children's and parents' experience of the illness. Because antibiotics provide only marginal benefits, analgesic treatment including paracetamol (acetaminophen) and non-steroidal anti inflammatory drugs (NSAIDs) is regarded as the cornerstone of AOM management in children. OBJECTIVES: Our primary objective was to assess the effectiveness of paracetamol (acetaminophen) or NSAIDs, alone or combined, compared with placebo or no treatment in relieving pain in children with AOM. Our secondary objective was to assess the effectiveness of NSAIDs compared with paracetamol in children with AOM. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 7, July 2016; MEDLINE (Ovid, from 1946 to August 2016), Embase (from 1947 to August 2016), CINAHL (from 1981 to August 2016), LILACS (from 1982 to August 2016) and Web of Science (from 1955 to August 2016) for published trials. We screened reference lists of included studies and relevant systematic reviews for additional trials. We searched WHO ICTRP, ClinicalTrials.gov, and the Netherlands Trial Registry (NTR) for completed and ongoing trials (search date 19 August 2016). SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing the effectiveness of paracetamol or NSAIDs, alone or combined, for pain relief in children with AOM. We also included trials of paracetamol or NSAIDs, alone or combined, for children with fever or upper respiratory tract infections (URTIs) if we were able to extract subgroup data on pain relief in children with AOM either directly or after obtaining additional data from study authors. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed methodological quality of the included trials and extracted data. We used the GRADE approach to rate the overall quality of evidence for each outcome of interest. MAIN RESULTS: We included three RCTs (327 children) which were assessed at low to moderate risk of bias.One RCT included 219 children with AOM, and used a three-arm, parallel group, double-blind design to compare paracetamol versus ibuprofen versus placebo. All children also received antibiotics and those with fever > 39 degrees C could have received paracetamol (30 mg to 60 mg) additionally to the studied treatments.Another RCT involved 156 febrile children (26 of whom had AOM). The study design was a three arm, parallel group, double-blind design and compared paracetamol versus ibuprofen versus ibuprofen plus paracetamol.The third RCT included 889 children with respiratory tract infections (82 of whom had AOM). This study applied a 3 x 2 x 2 factorial, open-label design and compared paracetamol versus ibuprofen versus ibuprofen plus paracetamol. Study participants were randomised to one of the three treatment groups as well as two dosing groups (regular versus as required) and two steam inhalation groups (steam versus no steam).Authors of two RCTs provided crude subgroup data on children with AOM. We used data from the remaining trial to inform comparison of paracetamol versus placebo (148 children) and ibuprofen versus placebo (146 children) assessments. Data from all included RCTs informed comparison of ibuprofen versus paracetamol (183 children); data from the two RCTs informed comparison of ibuprofen plus paracetamol versus paracetamol alone (71 children).We found evidence, albeit of low quality, that both paracetamol and ibuprofen as monotherapies were more effective than placebo in relieving pain at 48 hours (paracetamol versus placebo: proportion of children with pain 10% versus 25%, RR 0.38, 95% CI 0.17 to 0.85; number needed to treat to benefit (NNTB) 7; ibuprofen versus placebo: proportion of children with pain 7% versus 25%, RR 0.28, 95% CI 0.11 to 0.70; NNTB 6). Very low quality evidence suggested that adverse events did not significantly differ between children treated with either paracetamol, ibuprofen or placebo.We found insufficient evidence of a difference between ibuprofen and paracetamol in relieving ear pain at 24 hours (2 RCTs, 39 children; RR 0.83, 95% CI 0.59 to 1.18; very low quality evidence), 48 to 72 hours (3 RCTs, 183 children; RR 0.91, 95% CI 0.54 to 1.54; low quality evidence) and four to seven days (2 RCTs, 38 children; RR 0.74, 95% CI 0.17 to 3.23; very low quality evidence).Data on the effectiveness of ibuprofen plus paracetamol versus paracetamol alone came from two RCTs that provided crude subgroup data for 71 children with AOM. The small sample provided imprecise effect estimates and we were consequently unable to draw any firm conclusions (very low quality evidence). AUTHORS' CONCLUSIONS: Despite explicit guideline recommendations on its use, current evidence on the effectiveness of paracetamol or NSAIDs, alone or combined, in relieving pain in children with AOM is limited. Low quality evidence indicates that both paracetamol and ibuprofen as monotherapies are more effective than placebo in relieving short-term ear pain in children with AOM. There is insufficient evidence of a difference between ibuprofen and paracetamol in relieving short-term ear pain in children with AOM, whereas data on the effectiveness of ibuprofen plus paracetamol versus paracetamol alone were insufficient to draw any firm conclusions. Further research is needed to provide insights into the role of ibuprofen as adjunct to paracetamol, and other analgesics such as anaesthetic eardrops, for children with AOM. PMID- 27977845 TI - Stuck in Limbo: Motivational Antecedents and Consequences of Experiencing Action Crises in Personal Goal Pursuit. AB - OBJECTIVE: Action crises describe the intrapsychic conflicts individuals experience when they feel torn between further goal pursuit and goal disengagement. The present investigation introduces autonomous and controlled motivation as independent predictors of action crisis severity, beyond known personality-level predictors (action orientation) and novel personality-level predictors (Neuroticism and Conscientiousness). METHOD: Using a multi-wave prospective longitudinal design and multilevel modeling (MLM), we followed students pursuing three personal goals across an academic semester (N = 425 undergraduates; 76% female; 57% Caucasian; Mage = 20.2, SD = 2.3). In two follow up surveys, participants reported on the severity of their action crises, goal progress, and symptoms of depression. RESULTS: Results suggest that autonomous motivation shields individuals from experiencing action crises, whereas controlled motivation represents a risk factor for developing action crises beyond personality-level predictors. Furthermore, MLM revealed that autonomous motivation is a significant predictor of action crisis severity at both the within- and between-person levels of analysis. Action crises mediate both the relationship between autonomous motivation and goal progress, and the relationship between controlled motivation and symptoms of depression. CONCLUSIONS: The implications of these findings for the prevention of action crises and motivation research are discussed. PMID- 27977846 TI - Reliability of a novel ultrasound system for gray-scale analysis of muscle. AB - INTRODUCTION: Ultrasound is increasingly used as an adjunct in the diagnosis of neuromuscular disease by measuring muscle thickness and echointensity (EI). Reproducibility is limited because of variations in scanning technique and proprietary algorithms that alter EI values. METHODS: We developed a standardized scanning protocol and a portable machine without any postimaging processing. Ten subjects underwent scanning of 6 muscles by 3 sonographers on 2 separate days. One of the sonographers repeated the protocol with 4 different machine/transducer combinations. Gray-scale values were measured from each image with the use of a region of interest (ROI) box. RESULTS: Combined intraclass correlation coefficients were 0.92 (intra-rater), 0.88 (inter-rater), and 0.96 (inter system). The biceps had the highest variability (coefficient of variance [COV] 12.7%), and the medial gastrocnemius had the lowest variability (COV 7.4%). CONCLUSIONS: We demonstrate excellent reliability of a reproducible ultrasound system for gray-scale analysis of muscle that has potential applicability as a screening tool for neuromuscular disease. Muscle Nerve 56: 408-412, 2017. PMID- 27977847 TI - Sharing the Now in the Social Present: Duration of Nonverbal Synchrony Is Linked With Personality. AB - OBJECTIVE: The social present is a novel descriptor of dyadic nowness and social sharing, extending research on individual nowness (James's [1890] specious present) to the interpersonal and intersubjective domain. We wished to connect this descriptor to personality attributes. METHOD: We define the social present by the duration of significant nonverbal synchrony, based on the phenomenon of movement synchrony that generally emerges in social interactions. It is thus an implicit and objective measure that can be implemented by automated video analyses. In this study, 168 healthy participants were invited to verbal conversations in same-sex dyads. We analyzed the associations of the social present with personality attributes and interaction types (competition, cooperation, fun task). RESULTS: The average duration of the social present was 6.0 seconds, highest in competitive interactions and in male-male dyads. People with higher Openness to Experience, higher avoidant attachment, and lower narcissistic interpersonal styles showed extended social present in their interactions. CONCLUSIONS: The concept of the social present extends personality attributes to the interpersonal domain and to intersubjectivity. The social present may be computed based on movement synchrony but also prosodic or physiological synchronies. We foresee implications for health-related interactions such as psychotherapy, where therapeutic presence is an essential property of alliance. PMID- 27977848 TI - Effect of lipopolysaccharide stimulation on stem cell-associated marker expressing cells. AB - AIM: To examine the effect of inflammatory stimuli on the proliferation/migration of dental pulp stem cells by assessing the responses of stem cell-associated marker-expressing cells in rat incisors to lipopolysaccharide (LPS) stimulation in vivo. METHODOLOGY: The crowns of rat incisors were removed, and the coronal pulp chamber was instrumented. After haemostasis, an absorbent point soaked in LPS was inserted into the cavity, which was then sealed. At 3, 12, and 48 h after LPS application, pulp tissues were subjected to double-immunoperoxidase labelling using two of the antibodies against microtubule-associated protein 1B (MAP1B), CD146 and STRO-1. For gene expression analysis, total RNA was extracted, and mRNA expression levels of stem cell factor (SCF), stromal-derived factor 1 (SDF-1), CD146 and MAP1B were analysed with real-time polymerase chain reaction. SCF and SDF-1 protein levels were also assessed by Western blot. Statistical analysis was performed by Kruskal-Wallis nonparametric analysis of variance, followed by Mann Whitney U-tests with Bonferroni correction. RESULTS: The density of MAP1B+ CD146+ cells and STRO-1+ CD146+ cells in LPS-stimulated pulp tissue increased significantly at 3 h and exhibited a four- to sixfold increase at 48 h as compared with the density observed in normal pulp tissue (P < 0.05). The expression of CD146 mRNA in LPS-stimulated pulp showed significant upregulation at 3 h as compared with that observed in normal pulp tissue (P < 0.05). MAP1B, SCF and SDF-1 mRNA levels also showed significant upregulation at 3 and 72 h (P < 0.05), and Western blot analysis revealed increases in SCF and SDF-1 following LPS stimulation. CONCLUSIONS: LPS-stimulated pulp tissue exhibited upregulation of stem cell differentiation/migration markers and showed increases in the number of MAP1B+ CD146+ and STRO-1+ CD146 stem-like cells. PMID- 27977849 TI - Conservative interventions for treating middle third clavicle fractures in adolescents and adults. AB - BACKGROUND: Clavicle (collarbone) fractures account for around 4% of all fractures. Most (76%) clavicle fractures involve the middle-third section of the clavicle. Treatment of these fractures is usually non-surgical (conservative). Commonly used treatments are arm slings, strapping and figure-of-eight bandages.This is an update of a Cochrane review first published in 2009 and updated in 2014. OBJECTIVES: To evaluate the effects (benefits and harms) of different methods for conservative (non-operative) treatment for acute (treated soon after injury) middle third clavicle fractures in adolescents and adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE (from 1966), Embase (from 1980), LILACS (from 1982), trial registers, orthopaedic proceedings and reference lists of articles. We applied no language or publication restrictions. The date of the last search was 5 January 2016. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials testing conservative interventions for treating adolescents and adults with acute middle third clavicle fractures. The primary outcomes were shoulder function or disability, pain and treatment failure. DATA COLLECTION AND ANALYSIS: For this update, two review authors selected eligible trials, independently assessed risk of bias and cross-checked data extraction. We calculated risk ratios and 95% confidence intervals for dichotomous variables, and mean differences and 95% confidence intervals for continuous variables. There was very limited pooling of data. MAIN RESULTS: We included four trials in this review with 416 participants, who were aged 14 years or above. One new trial was included in this update.Very low quality evidence was available from three trials (296 participants) that compared the figure-of-eight bandage with an arm sling for treating acute middle third clavicle fractures. The three trials were underpowered and compromised by poor methodology. Shoulder function was assessed in different ways in the three trials (data for 51, 61 and 152 participants); each trial provided very low quality evidence of similar shoulder function in the two groups. Pooled data from two trials (203 participants) showed no clinical difference between groups after two weeks in pain (visual analogue scale: 0 (no pain) to 10 (worst pain); mean difference (MD) 0.43, 95% confidence interval (CI) -0.35 to 1.21; I2 = 74%; very low quality evidence). A third trial (61 participants) provided very low quality evidence based on a non-validated scoring system of more pain and discomfort during the course of treatment in the figure-of-eight group. Treatment failure, measured in terms of subsequent surgery, was not reported in two trials; the third trial (152 participants) reported one participant in the arm sling group had surgery for secondary plexus nerve palsy. There was very low quality evidence from one trial (148 participants) of little difference in time to clinical fracture healing (MD 0.2 weeks, 95% CI -0.11 to 0.51); data from four non symptomatic non-unions in the figure-of-eight group were not included. The very low evidence quality data for individual adverse outcomes (poor cosmetic appearance; change in allocated treatment due to pain and discomfort, worsened fracture position on healing; shortening > 15 mm; non-symptomatic non-union and permanent pain) did not confirm a difference between the two groups. There was no clear between group difference in the time to return to school or work activities (MD -0.12 weeks, 95% CI -0.69 to 0.45; 176 participants; very low quality evidence).Moderate quality evidence was available from one trial (120 participants; reporting data for 101 participants), which evaluated therapeutic ultrasound. This trial was at low risk of bias but was underpowered and did not report on shoulder function or quality of life. The trial found no evidence of a difference between low-intensity pulsed ultrasound and placebo in pain, treatment failure (subsequent surgery: 6/52 versus 5/49; RR 1.13, 95% CI 0.37 to 3.47), the time to clinical fracture healing (MD -0.32 days, 95% CI -5.85 to 5.21), adverse events (one case of skin irritation was reported in each group) or time to resume previous activities. AUTHORS' CONCLUSIONS: The current evidence available from randomised controlled trials is insufficient to determine which methods of conservative treatment are the most appropriate for acute middle third clavicle fractures in adolescents and adults. Further research is warranted. PMID- 27977850 TI - MicroRNA-mediated regulation of immune responses to intestinal helminth infections. AB - Intestinal helminth infections are highly prevalent in the developing world, often resulting in chronic infection and inflicting high host morbidity. With the emergence of drug-resistant parasites, a limited number of chemotherapeutic drugs available and stalling vaccine efforts, an increased understanding of antihelminth immunity is essential to provide new avenues to therapeutic intervention. MicroRNAs are a class of small, nonprotein coding RNAs which negatively regulate mRNA translation, thus providing finite control over gene expression in a plethora of biological settings. The miRNA-mediated coordinated control of gene expression has been shown to be essential in infection and immunity, in promoting and fine-tuning the appropriate immune response. This review gathers together and discusses observations of miRNA-mediated effects on the immune system and the subsequent impact on our understanding of antihelminth immunity. PMID- 27977851 TI - Implementation of treatment guidelines for specialist mental health care. AB - BACKGROUND: A huge gap exists between the production of evidence and its uptake in clinical practice settings. To fill this gap, treatment guidelines, based on explicit assessments of the evidence base, are commonly used in several fields of psychiatry, including schizophrenia and related psychotic disorders. However, it remains unclear whether treatment guidelines have any material impact on provider performance and patient outcomes, and how implementation should be conducted to maximise benefit. OBJECTIVES: The primary objective of this review was to examine the efficacy of guideline implementation strategies in improving process outcomes (performance of healthcare providers) and patient outcomes. We also explored which components of different guideline implementation strategies could influence them. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Register (March 2012 and August 2015), as well as references of included studies. SELECTION CRITERIA: Studies that examined schizophrenia-spectrum disorders to compare guideline implementation strategies with usual care or to assess the comparative efficacy of different guideline implementation strategies. DATA COLLECTION AND ANALYSIS: Review authors worked independently and in duplicate to critically appraise records from 990 studies; six individual studies met the inclusion criteria. Among the six included studies, significant heterogeneity was found in the focus of the guideline, target of the intervention, implementation strategy, and outcome measures, so meta-analysis was carried out for antipsychotic co-prescribing only. MAIN RESULTS: This review now includes six studies, with a total of 1727 participants. Of the six included studies, practitioner impact was assessed in four. Overall, risk of bias was rated as low or unclear, and all evidence in the 'Summary of findings' tables was graded as low or very low quality. Meta-analysis revealed that a combination of several guideline dissemination and implementation strategies targeting healthcare professionals did not reduce antipsychotic co-prescribing in schizophrenia outpatients (2 RCTs, N = 1082, RR 1.10 CI 0.99 to 1.23; corrected for cluster design: N = 310, RR 0.97, CI 0.75 to 1.25, very low-quality evidence). One trial, which studied a nurse-led intervention aimed at promoting cardiovascular disease screening, found a significant effect in the proportion of people receiving screening (Framingham score: N = 110, RR 0.69, 95% CI 0.55 to 0.87), although in the analysis corrected for cluster design, the effect was no longer statistically significant (N = 38, RR 0.71, 95% CI 0.48 to 1.03, very low-quality evidence).One trial reported the patient outcomes of global state, satisfaction with care, treatment adherence, and drug attitude; no effect between treatments was seen. Quality of life was not reported by any of the studies.One trial, which studied the use of re-written guideline text compared to original text, did not find a significant effect on staff receiving training (N = 68, RR 1.03, 95% CI 0.87 to 1.21, low-quality evidence), staff receiving supervision (N = 68, RR 0.86, 95% CI 0.64 to 1.17, low-quality evidence), or staff providing psychological interventions (N = 68, RR 0.86, 95% CI 0.62 to 1.18, low-quality evidence).Regarding participant outcomes, only one trial assessed the efficacy of a shared decision-making implementation strategy and found no impact on psychopathology, satisfaction with care, or drug attitude. Another single trial studied a multifaceted intervention to promote medication adherence and found no effect on adherence rates. AUTHORS' CONCLUSIONS: Considering the available evidence, it is not possible to arrive at definitive conclusions. The preliminary pattern of evidence suggests that uncertainty remains about clinically meaningful and sustainable effects of treatment guidelines on patient outcomes and how best to implement such guidelines for maximal benefit. PMID- 27977852 TI - Unequivocal evidence supporting the segregated flow intestinal model that discriminates intestine versus liver first-pass removal with PBPK modeling. AB - Merits of the segregated flow model (SFM), highlighting the intestine as inert serosa and active enterocyte regions, with a smaller fractional (fQ < 0.3) intestinal flow (QI ) perfusing the enterocyte region, are described. Less drug in the circulation reaches the enterocytes due to the lower flow (fQ QI ) in comparison with drug administered into the gut lumen, fostering the idea of route dependent intestinal removal. The SFM has been found superior to the traditional model (TM), which views the serosa and enterocytes totally as a well-mixed tissue perfused by 100% of the intestinal flow, QI . The SFM model is able to explain the lower extents of intestinal metabolism of enalapril, morphine and midazolam with i.v. vs. p.o. dosing. For morphine, the urine/bile ratio of the metabolite, morphine glucuronide MGurineMGbile for p.o. was 2.6* that of i.v. This was due to the higher proportion of intestinally formed morphine glucuronide, appearing more in urine than in bile due to its low permeability and greater extent of intestinal formation with p.o. administration. By contrast, the TM predicted the same MGurineMGbile for p.o. vs. i.v. The TM predicted that the contributions of the intestine:liver to first-pass removal were 46%:54% for both p.o. and i.v. The SFM predicted same 46%:54% (intestine:liver) for p.o., but 9%:91% for i.v. By contrast, the kinetics of codeine, the precursor of morphine, was described equally well by the SFM- and TM-PBPK models, a trend suggesting that intestinal metabolism of codeine is negligible. Fits to these PBPK models further provide insightful information towards metabolite formation: available fractions and the fractions of hepatic and total clearances that form the metabolite in question. The SFM-PBPK model is useful to identify not only the presence of intestinal metabolism but the contributions of the intestine and liver for metabolite formation. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27977853 TI - Termination of pregnancy due to renal tract abnormalities: survey of 97 fetuses from a single medical center. AB - OBJECTIVE: The article aimed to assess the spectrum of fetal renal tract abnormalities as a major finding leading to termination of pregnancy (TOP). METHOD: The study population included all pregnant women with singleton pregnancy who underwent TOP in our institute because of fetal renal tract indications between 1998 and 2015. We specifically excluded TOPs performed because of multiple pregnancies, multisystem defects, abnormal karyotype and chromosomal or genetic defect not related to renal tract abnormalities. The patients were stratified into late TOP (>=24 weeks' gestation) and early TOP (<24 weeks' gestation). RESULTS: There were 97 (3.5%) cases of TOP because of fetal renal abnormalities and are the subjects of this study. Of these cases, 19 (19.6%) were at >=24 weeks' gestation. Renal cystic disease was the leading indication for late TOP compared with early TOP group (31.8% vs 21.8%, respectively, p = 0.001). Routine prenatal care raised suspicion of abnormalities in 11 (50.9%) cases, and diagnosis was established by additional tests. Abnormal findings were either missed in one (5.3%) case or developed later in two (10.5%) cases. No routine prenatal screening was performed in the remaining five (26.3%) cases. CONCLUSIONS: We found a different distribution for fetal renal tract abnormalities leading to late versus early TOP. As many of renal tract malformations could have been diagnosed earlier (~32%), timely scanning may reduce the need for late TOPs in some cases. (c) 2016 John Wiley & Sons, Ltd. PMID- 27977854 TI - Effects of high-intensity physical training on muscle fiber characteristics in poststroke patients. AB - INTRODUCTION: Stroke is a leading cause of disability worldwide. High-intensity physical training can improve muscle strength and gait speed, but adaptive mechanisms at the muscle cellular level are largely unknown. METHODS: Outpatients with poststroke hemiparesis participated in a 3-month rehabilitation program combining high-intensity strength and body-weight supported treadmill-training. Biopsies sampled bilaterally from vastus lateralis muscles, before, after, and at 1-year follow-up after intervention, were analyzed for fiber size, type, and capillarization. RESULTS: At baseline, paretic lower limbs had smaller muscle fiber size and lower type I and IIA and higher type IIX percentages than nonparetic lower limbs. Paretic lower limbs had increased type IIA fibers after training. At follow-up, no difference between the lower limbs remained. CONCLUSIONS: Although high-intensity training appeared not to induce changes in fiber size or capillarization, increased type IIA fiber percentages may contribute to muscle power and endurance, which is crucial for functional capacity. Muscle Nerve 56: 954-962, 2017. PMID- 27977855 TI - Effect of MTA particle size on periapical healing. AB - AIM: To examine the effect of reduction in MTA particle size on dento-alveolar and osseous healing in dogs. METHODOLOGY: Root canals of 24 mandibular premolars in four 2-year-old beagles were prepared and filled with gutta-percha and sealer. Two to four weeks later, during periapical surgery, the root-end cavity preparations in these teeth were filled with either grey ProRoot MTA or modified (reduced particle sizes with faster setting time) MTA. The animals were sacrificed 4 months later. Degrees of inflammation, type of inflammatory cells, fibrous connective tissue adjacent to the root-end filling materials, cementum formation over the resected roots and root-end filling materials and bone healing were examined. Data were analysed using the McNemar test. RESULTS: No significant differences in healing of periapical tissues were found when comparing ProRoot MTA to a modified MTA containing reduced particle sizes. CONCLUSION: Reducing the particle sizes of MTA did not impact its biological properties. PMID- 27977857 TI - Influence of Cone-Beam Computed Tomography filters on diagnosis of simulated endodontic complications. AB - AIM: To evaluate the influence of cone-beam computed tomography (CBCT) filters on diagnosis of simulated endodontic complications. METHODOLOGY: Sixteen human teeth, in three mandibles, were submitted to the following simulated endodontic complications: (G1) fractured file, (G2) perforations in the canal walls, (G3) deviated cast post, and (G4) external root resorption. The mandibles were submitted to CBCT examination (I-Cat(r) Next Generation). Five oral radiologists evaluated the images independently with and without XoranCat(r) software filters. Accuracy, sensitivity and specificity were determined. ROC curves were calculated for each group with the filters, and the areas under the curves were compared using anova (one-way) test. McNemar test was applied for pair-wise agreement between all images versus the gold standard and original images versus images with filters (P < 0.05). RESULTS: G1 was the most difficult endodontic complication to diagnosis, followed by G2, G4 and G3. There were no differences between areas under the ROC curves for the filters in all groups; however, Sharpen Super Mild filter had the best results for G1 (0.47), Angio Sharpen Low 3 * 3 for G2 (0.93), Angio Sharpen Low 3 * 3, S9, Shadow and Sharpen for G3 (1.00) and Sharpen 3 * 3 for G4 (1.00). The McNemar test revealed significant differences between all filters with the gold standard (P = 0.00 for all filters) and the originals images (P = 0.00 for all filters) only in G1 group. There were no differences in the other groups. CONCLUSIONS: The filters did not improve the diagnosis of the simulated endodontic complications evaluated. Their diagnosis remains a major challenge in clinical practice. PMID- 27977858 TI - Regulation of host epithelial responses to Cryptosporidium infection by microRNAs. AB - Cryptosporidium species infect the gastrointestinal epithelium and other mucosal surfaces of vertebrate hosts. Epithelial cells provide the first line of defence against Cryptosporidium infection and play a critical role in the initiation, regulation and resolution of both innate and adaptive immune reactions. Host miRNAs in mammalian cells have been shown to play crucial roles in cellular responses to infection by diverse pathogens, including viruses, parasites and bacteria. Given the absence of RNAi machinery in Cryptosporidium, lack of miRNA expression in the parasite and minimal invasion nature of infection, Cryptosporidium infection provides an ideal model for exploring miRNA-mediated epithelial cell defence, relevant to infection of mucosal epithelial cells by pathogens in general. Increasing evidence supports that miRNAs may modulate many stages of epithelial responses following Cryptosporidium infection, including activation of the intracellular signalling pathways, production of antimicrobial molecules, expression of cytokines/chemokines, release of epithelial cell-derived exosomes and feedback regulation of immune homeostasis. On the other hand, this parasite may have developed strategies to modulate host miRNA-mediated cellular function for immune evasion. In this review, we will summarize the recent advances on miRNA regulation of epithelial responses to Cryptosporidium infection, with an emphasis on host defence and parasite immune evasion. PMID- 27977859 TI - Immune cell profile of dental pulp tissue treated with zoledronic acid. AB - AIM: To characterize the pulp immune cell profile in the teeth of rats treated with zoledronic acid (ZA). METHODOLOGY: Male Wistar rats (n = 6 per group) received four intravenous infusions of ZA at doses of 0.04, 0.20 or 1.00 mg kg-1 ZA or saline (control). On the 70th experimental day, they were euthanized. The first right molar was examined microscopically and submitted to toluidine blue reaction and immunohistochemical for CD68, tumour necrosis Factor (TNF)-alpha, interleukin (IL)-1beta, inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF-kB) and IL-18 binding protein (IL-18 bp). The presence of ectasic/dilated vessels and inflammatory cells was analysed, and mast cells and mononuclear CD68-positive cells were counted along with the intensity of immunostaining (0-3) for inflammatory markers in odontoblasts and nonodontoblasts pulp cells. The Kruskal-Wallis/Dunn's test (scores or quantitative data) and the chi-squared test (categorical data) were used (GraphPad Prism 5.0, P < 0.05). RESULTS: There was no differences in the number of animals exhibiting dilated/ectasic blood vessels (P = 0.242) and inflammatory cells (P = 0.489) or in the number of mast cells (P = 1.000). However, there was an increase in mononuclear CD68-positive cells (P = 0.026), immunostaining of TNF-alpha (P = 0.020), IL-1beta (P = 0.027) and iNOS (P = 0.001) in odontoblasts, and IL-1beta (P = 0.013) in nonodontoblast pulp cells dose-dependently. NFkB (nucleus and cytoplasm) and IL-18 bp did not differ between groups. CONCLUSION: ZA modified the immune cell profile in the dental pulp, increasing the number of macrophages and expression of pro-inflammatory markers independent of NFkB. PMID- 27977860 TI - Effect of different storage media on root dentine composition and viability of fibroblasts evaluated by several assay methods. AB - AIM: To perform multiparametric analysis of the effects of soya milk (SM), whole milk (WM) and Hank's balanced salt solution (HBSS) on the viability of fibroblasts (HGF). The study also aimed to evaluate the influence of these solutions on bovine root dentine according to OH- and PO43- on the surface. METHODOLOGY: The HGF cytotoxicity was determined according to XTT, NR and SRB assays at 1, 3 and 6 h. Root dentine fragments were assessed by Fourier infrared (FTIR) spectrophotometer before and after immersion in the solutions for the same periods. The positive control group included cells and tooth fragments maintained in Dulbecco's modified Eagle's medium (DMEM), and the negative control included tooth fragments that were kept dry. Data were analysed using anova and Tukey's test. RESULTS: No significant difference was found in cell viability evaluated by XTT (P > 0.05). Using the NR assay, WM and HBSS had significantly lower cell viability compared to the positive control group at 6 h (P < 0.05). SM had similar cell viability to the positive control group at all periods evaluated when assessed using all three tests (P > 0.05). A significant difference was found in values of OH- for the negative control group at 1 h (P = 0.002). CONCLUSIONS: Soya milk promoted better cell viability, whereas on dentine composition, the solutions behaved similarly. The association of different assay methods is promising for improving cell viability analysis. The 1-h time-point is a crucial factor in the prognosis of dental replantation because the teeth remain more hydrated and help maintain cell viability. PMID- 27977856 TI - Nematodes and human therapeutic trials for inflammatory disease. AB - Helminth infections likely provide a protective influence against some immune mediated and metabolic diseases because helminth infection dramatically decreased in developed countries shortly before the explosive rise in the prevalence of these diseases. The capacity of helminths to activate immune-regulatory circuits in their hosts and to modulate the composition of intestinal flora appears to be the mechanisms of protective action. Animal models of disease show that various helminth species prevent and/or block inflammation in various organs in a diverse range of diseases. Clinical trials have demonstrated that medicinal exposure to Trichuris suis or small numbers of Necator americanus is safe with minor, if any, reported adverse effects. This includes exposure of inflamed intestine to T. suis, asthmathic lung to N. americanus and in patients with atopy. Efficacy has been suggested in some small studies, but is absent in others. Factors that may have led to inconclusive results in some trials are discussed. To date, there have been no registered clinical trials using helminths to treat metabolic syndrome or its component conditions. However, the excellent safety profile of T. suis or N. americanus suggests that such studies should be possible. PMID- 27977861 TI - A copy number variation genotyping method for aneuploidy detection in spontaneous abortion specimens. AB - OBJECTIVE: Chromosomal abnormalities such as aneuploidy have been shown to be responsible for causing spontaneous abortion. Genetic evaluation of abortions is currently underperformed. Screening for aneuploidy in the products of conception can help determine the etiology. We designed a high-throughput ligation-dependent probe amplification (HLPA) assay to examine aneuploidy of 24 chromosomes in miscarriage tissues and aimed to validate the performance of this technique. METHODS: We carried out aneuploidy screening in 98 fetal tissue samples collected from female subjects with singleton pregnancies who experienced spontaneous abortion. The mean maternal age was 31.6 years (range: 24-43), and the mean gestational age was 10.2 weeks (range: 4.6-14.1). HLPA was performed in parallel with array comparative genomic hybridization, which is the gold standard for aneuploidy detection in clinical practices. The results from the two platforms were compared. RESULTS: Forty-nine out of ninety-eight samples were found to be aneuploid. HLPA showed concordance with array comparative genomic hybridization in diagnosing aneuploidy. CONCLUSION: High-throughput ligation-dependent probe amplification is a rapid and accurate method for aneuploidy detection. It can be used as a cost-effective screening procedure in clinical spontaneous abortions. (c) 2016 John Wiley & Sons, Ltd. PMID- 27977862 TI - Evaluation of the Ca ion release, pH and surface apatite formation of a prototype tricalcium silicate cement. AB - AIM: To evaluate the Ca2+ -releasing, alkalizing and apatite-like surface precipitate-forming abilities of a prototype tricalcium silicate cement, which was mainly composed of synthetically prepared tricalcium silicate and zirconium oxide radiopacifier. METHODOLOGY: The prototype tricalcium silicate cement, white ProRoot MTA (WMTA) and TheraCal LC (a light-cured resin-modified calcium silicate filled material) were examined. The chemical compositions were analysed with a wavelength-dispersive X-ray spectroscopy electron probe microanalyser with an image observation function (SEM-EPMA). The pH and Ca2+ concentrations of water in which the set materials had been immersed were measured, and the latter was assessed with the EDTA titration method. The surface precipitates formed on the materials immersed in phosphate-buffered saline (PBS) were analysed with SEM-EPMA and X-ray diffraction (XRD). Kruskal-Wallis tests followed by Mann-Whitney U-test with Bonferroni correction were used for statistical analysis (alpha = 0.05). RESULTS: The prototype cement contained Ca, Si and Zr as major elemental constituents, whereas it did not contain some metal elements that were detected in the other materials. The Ca2+ concentrations and pH of the immersion water samples exhibited the following order: WMTA = prototype cement > TheraCal LC (P < 0.05). All three materials produced Ca- and P-containing surface precipitates after PBS immersion, and the precipitates produced by TheraCal LC displayed lower Ca/P ratios than those formed by the other materials. XRD peaks corresponding to hydroxyapatite were detected in the precipitates produced by the prototype cement and WMTA. CONCLUSION: The prototype tricalcium silicate cement exhibited similar Ca2+ -releasing, alkalizing and apatite-like precipitate-forming abilities to WMTA. The Ca2+ -releasing, alkalizing and apatite-like precipitate-forming abilities of TheraCal LC were lower than those of the other materials. PMID- 27977863 TI - CBCT uses in clinical endodontics: the effect of CBCT on the ability to locate MB2 canals in maxillary molars. AB - AIM: To determine whether a CBCT volume can aid in the location of MB2 canals in maxillary molars. METHODOLOGY: This prospective clinical study involved 50 patients that needed RCT on a maxillary molar. The teeth where the MB2 was located upon access with the dental operating microscope received routine root canal treatment, and teeth where MB2 was not located had a CBCT volume made after instrumenting the located canals. At the second appointment, the clinician used the aid of the CBCT volume and troughing to attempt to locate MB2. RESULTS: The clinicians located MB2 upon initial access in 70% (n = 35) of teeth. In the remaining 15 teeth, CBCT and troughing located MB2 53% of the time in that group (8/15 teeth). Overall, MB2 was located in 86% of the 50 first and second maxillary molars (maxillary first molars 90% and maxillary second molars 73%). A total of 15 CBCT volumes were made, and of these teeth, 33% of MB2 canals (5/15 teeth) were visualized on the CBCT volume. CONCLUSIONS: This prospective clinical study showed that the effectiveness of using CBCT to locate additional MB2 canals in maxillary molars appears limited. The use of the dental operating microscope in conjunction with selective troughing and CBCT imaging allowed clinicians to locate 90% (maxillary first molars) and 73% (maxillary second molars) of MB2 canals. PMID- 27977864 TI - N-methyl-D-aspartate (NMDA) impairs myogenesis in C2C12 cells. AB - INTRODUCTION: N-methyl-d-aspartate (NMDA) is expressed in sensory neurons and plays important roles in peripheral pain mechanisms. The aim of this study was to examine the effects and molecular mechanisms of NMDA on C2C12 myoblast proliferation and differentiation. METHODS: Cytotoxicity and differentiation were examined by the MTT assay, reverse transcription-polymerase chain reaction, and immunofluorescence. RESULTS: NMDA had no cytotoxicity (10-500 MUM) and inhibited myoblastic differentiation of C2C12 cells, as assessed by F-actin immunofluorescence and levels of mRNAs encoding myogenic markers such as myogenin and myosin heavy-chain 2. It inhibited phosphorylation of mammalian target of rapamycin (mTOR) by inactivating mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38. It induced reactive oxygen species production. Furthermore, NMDA-suppressed expression of F-actin was reversed by adding the antioxidant N-acetylcysteine. CONCLUSIONS: Collectively, these results indicate that NMDA impairs myogenesis or myogenic differentiation in C2C12 cells through the mTOR/MAPK signaling pathways and may lead to skeletal muscle degeneration. Muscle Nerve 56: 510-518, 2017. PMID- 27977865 TI - Approach to hypersensitivity reactions from intravenous iron preparations. AB - Hypersensitivity reactions (HSRs) to intravenous iron preparations (IVIPs) are well known. With newer preparations, HSRs have become rarer; however, severe reactions may still occur. We retrospectively reviewed records of patients evaluated for HSRs to IVIPs, to determine the safety of controlled re administration (CRA). Allergological work-up included a detailed history, skin prick tests (SPTs) with IVIP, and basophil activation tests (BATs) in some patients. CRA with an IVIP was carried out if indicated. Thirty-one patients with mild to severe reactions were evaluated. SPTs and BATs were negative in all patients tested. Eighteen CRAs in 15 patients were performed. Twelve patients tolerated the procedure, including three with a previous grade IV HSR. Two developed urticaria and one developed urticaria and dyspnea. The pathophysiology of HSRs to IVIPs remains currently unclear. SPTs and BATs provided no additional information. However, in appropriate situations, CRA under surveillance can be safely performed in most patients. PMID- 27977866 TI - Effect of simulated pulpal blood flow rate on the rise in pulp chamber temperature during direct fabrication of exothermic provisional restorations. AB - AIM: To evaluate ex vivo the effect of several simulated pulpal blood flow rates on the change in pulp chamber temperature during direct fabrication of a provisional restoration using a polymethylmethacrylate (PMMA) resin. METHODOLOGY: Fifteen noncarious human premolars were prepared for complete coverage restorations. A curved needle connected to a peristaltic pump simulated the pulp blood flow. Two K-type thermocouples connected to a digital thermometer were placed in the pulp chamber, and the assembly was placed in an incubator at 37 degrees C. Three provisional crowns were made for each specimen using no water flow (group 1), a 1-mL min-1 flow rate (group 2) and a 0.5-mL/min-1 flow rate (group 3). The pulp chamber temperature was recorded continuously during polymerization until the temperature increase peaked and started to decrease and reached the baseline temperature (37 degrees C). The temperature increase was measured for the three water flow conditions. Data were analysed statistically using descriptive statistics, repeated measures one-way analysis of variance (anova) with Greenhouse-Geisser correction and Bonferroni tests. The level of significance was set at P < 0.05. RESULTS: All of the groups were associated with an increased pulp chamber temperature. Groups with flow rates at 1 and 0.5 mL min 1 had a significantly lower temperature rise when compared to the group without water flow (P < 0.001). CONCLUSIONS: Direct fabrication of provisional restorations can cause a critical increase in pulp chamber temperature. However, in the presence of simulated pulpal blood flow rates of 1 or 0.5 mL min-1 , the increase in pulp chamber temperature did not exceed the critical threshold (5.6 degrees C). PMID- 27977867 TI - Simultaneous UPLC-MS/MS determination of antiepileptic agents for dose adjustment. AB - Therapeutic drug monitoring (TDM) of anti-epileptic drugs (AED) is a routine application. Carbamazepine (CRB) is monitored as the parent drug while oxcarbazepine (OXC) and eslicarbazepine acetate (ESL) are monitored as their active metabolite (eslicarbazepine; MHD). We have developed a UPLC-MS/MS method for determining CRB, OXC, ESL and MHD in plasma or serum with a simplified extraction protocol. The developed method detects sildenafil (SLD), which clinically interferes with AED and is likely to be co-administered in epileptic patients suffering from sexual insufficiency (60%). MHD was prepared in-house. AED were simultaneously determined in presence of SLD using gatifloxacin as an internal standard (IS). Separation was achieved using acetonitrile, methanol and 100 mm ammonium acetate in water (32:3:65, v/v/v) on an Intersil(r) RP-HPLC column (250 * 4.6 mm, 5 MUm). A one-step extraction was performed by simultaneous protein and phospholipids precipitation. Detection was done by tandem mass spectrometry. No relative matrix effect was observed. The method was linear (0.5 40 MUg/mL for CRB, ESL and MHD and 0.05-4 MUg/mL for OXC), accurate and selective. Recoveries were 64.41 +/- 5.07, 45.62 +/- 1.73, 61.41 +/- 4.77 and 60.33 +/- 1.36 for CRB, OXC, ESL and MHD, respectively. The method was successfully applied for TDM of AED. PMID- 27977868 TI - Normative data for cutaneous threshold and spatial discrimination in the feet. AB - INTRODUCTION: No data are available for normative values of cutaneous threshold and spatial discrimination in the feet. We developed clinically applicable reference values in relation to the nerve distributions of the feet. METHODS: We determined foot sensation in 196 healthy individuals. Cutaneous threshold (1 point static discrimination, S1PD) was tested with monofilaments (0.008 to 300 gram) and spatial discrimination (2-point static [S2PD] and moving [M2PD] discrimination) on five locations per foot. RESULTS: There was a significant age dependent increase in S1PD, S2PD, and M2PD values (P < 0.05). No significant differences were found between both feet. S1PD values differed up to 0.8 g between genders. There were no significant differences between genders for S2PD and M2PD measurements. M2PD values were generally lower than S2PD values. CONCLUSIONS: This study provides age-related normative values for foot sensation to help clinicians assess sensory deficits in relation to aging and identify patients with underlying nerve problems. Muscle Nerve 56: 399-407, 2017. PMID- 27977869 TI - Endodontic treatment-related antibiotic prescribing patterns of South African oral health professionals. AB - AIM: To assess the antibiotic prescribing patterns of South African dentists for patients undergoing endodontic treatment. METHODOLOGY: This study used data from 2013 health insurance claims submitted by South African oral health professionals to determine the antibiotic prescribing patterns related to endodontic treatment. A logistic regression model was used to test the fully adjusted statistical significance of the association between the exploratory variables (gender, age group, event type, abscess treatment, chronic health) and the dependent variable (antibiotic prescription). Odds ratios with 95% confidence intervals (CI) are reported, and a 95% CI excluding 1 was considered statistically significant. RESULTS: Almost 10% of endodontic treatments were prescribed an antibiotic. There were no significant differences in prescribing patterns by gender, age and chronic health status. Prescriptions were more common at the preparatory stage (9.4%) of root canal treatment compared to the therapy (4.7%) and canal filling (2%) stages. Patients who received apical surgery (OR = 2.28; 95% CI 1.38-3.76) and treatment of an abscess (OR = 2.57; 95% 1.82-3.63) had a significantly increased odds of being prescribed an antibiotic. Almost three-quarters of prescriptions were for narrow spectrum antibiotics. CONCLUSION: The frequency of antibiotic prescribing by South African dental practitioners for patients undergoing endodontic treatment is relatively low and predominantly involved narrow spectrum antibiotics. It, however, remains important that antibiotics are only prescribed when clinically essential, such as when there are obvious systemic effects. These include fever above 37 degrees, malaise, lymphadenopathy, trismus, increase swelling, cellulitis, osteomyelitis and persistent infection. The wider dissemination and adherence to clear evidence-based prescribing guidelines for antibiotics in this clinical area are important. PMID- 27977870 TI - Ultrasound elastography assessment of the median nerve in leprosy patients. AB - INTRODUCTION: We sought to compare median nerve elasticity between leprosy patients (LPs) and healthy volunteers (HVs) using ultrasound elastography (UE). METHODS: Two radiologists independently measured the strain ratio of the median nerve/flexor digitorum superficialis muscle (MN/FDSM) of 18 LP and 18 HV using real-time freehand UE. Statistical analysis included intra-class correlation coefficients (ICC) and Mann-Whitney test. RESULTS: The MN/FDSM strain ratios of the LP and HV were 2.66 +/- 1.30 and 3.52 +/- 0.93, respectively (P < 0.05). We observed a significantly lower MN/FDSM strain ratio in LP with reactions (types 1 and 2 cutaneous reactions associated with or without neuritis) (2.30 +/- 0.91) compared with LP without reactions (3.60 +/- 1.70). We found no significant differences between HV and LP without reactions. The intra- and inter-observer ICCs were 0.50 (95% confidence interval [CI], 0.11-0.72) and 0.34 (95% CI, 0.28 0.52), respectively. CONCLUSIONS: MN/FDSM strain ratios were significantly lower in LP with reactions. UE may be useful for nerve elasticity evaluation in leprosy. Muscle Nerve 56: 393-398, 2017. PMID- 27977871 TI - LC-high-resolution-MS/MS analysis of chemical compounds in rat plasma after oral administration of Nao-Mai-Tong and its individual herbs. AB - Nao-Mai-Tong (NMT), a Chinese herbal formula, is used for treating ischemia cerebral apoplexy. To discover the components of NMT with potential in vivo bioactivity and investigate the differences between NMT and its single herb components, this study rigorously compared plasma samples collected from rats dosed with NMT and single-herb extracts at different times through LC-high resolution-MS/MS and data processing (Metworks). The plasma of the NMT group contained a total of 66 identified compounds (25 prototypes and 41 metabolites), including anthraquinones, triterpenoid saponins, isoflavones and phthalides. Additionally, glucuronidation, sulfation and cysteine conjugation were the major reactions through which the compounds in NMT were metabolized. The comparison of the groups revealed two metabolites that were only detected in the plasma from the NMT-dosed group, whereas seven prototype ingredients (chrysophanol-8-O glucoside, ginsenoside Rf, Rg2, Rh1, F1, F2 and chikusetsusaponin IVa) and 12 metabolites (two novel triterpenoid saponins) were only discovered in the plasma samples from the single-herb-dosed groups. Moreover, the trends in the chemical compounds detected presented marked differences between NMT-dosed rat plasma and plasma samples from the single-herb-dosed groups. The above data indicate that prescription compatibility affects the assimilation and elimination of ingredients and provides useful information for further pharmacokinetic studies. PMID- 27977872 TI - SNP-Based Heritability Estimates of Common and Specific Variance in Self- and Informant-Reported Neuroticism Scales. AB - OBJECTIVE: Our study aims to estimate the proportion of the phenotypic variance of Neuroticism and its facet scales that can be attributed to common single nucleotide polymorphisms (SNPs) in two adult populations from Estonia (EGCUT; N = 3,292) and the Netherlands (Lifelines; N = 13,383). METHOD: Genomic-relatedness matrix restricted maximum likelihood (GREML) using genome-wide complex trait analysis (GCTA) software was employed. To build upon previous research, we used self- and informant reports of the 30-facet NEO personality inventories and analyzed both the usual sum scores and the residual facet scores of Neuroticism. RESULTS: In the EGCUT cohort, the proportion of phenotypic variance explained by the additive effects of common genetic variants in self- and informant-reported Neuroticism domain scores was 15.2% (p = .070, SE = .11) and 6.2% (p = .293, SE = .12), respectively. The SNP-based heritability estimates at the level of Neuroticism facet scales differed greatly across cohorts and modes of measurement but were generally higher (a) for self- than for informant reports, and (b) for sum than for residual scores. CONCLUSIONS: Our findings indicate that a large proportion of the heritability of Neuroticism is not captured by additive genetic effects of common SNPs, with some evidence for Gene * Environment interaction across cohorts. PMID- 27977873 TI - Leigh map: A novel computational diagnostic resource for mitochondrial disease. PMID- 27977874 TI - Reply. PMID- 27977875 TI - Developmental changes in neuromagnetic rhythms and network synchrony in autism. AB - OBJECTIVE: There is gathering consensus that altered connectivity is a hallmark of the autistic brain. This includes atypical neural oscillations and their coordination across brain regions, which are understood to mediate information processing and integration. It remains unclear whether and how connectivity in various neurophysiological frequency ranges develops atypically in autism spectrum disorder (ASD). METHODS: To address this in a cross-sectional sample, we recorded resting-state magnetoencephalography from 134 children and adolescents with and without ASD, and calculated resting spectral power and inter-regional synchrony (functional connectivity). RESULTS: Although no overall group differences were observed, significant alterations in linear and nonlinear age related changes in resting oscillatory power and network synchrony were found. These differences were frequency- and region-specific and implicated brain systems thought to play a prominent role in ASD, such as the frontal cortex and cerebellum. We also found correlations between Autism Diagnostic Observation Schedule scores and the degree to which connectivity in cerebellar networks is "idiosyncratic" in an individual with autism. INTERPRETATION: We provide the first evidence that it is the curvatures of maturational changes in neurophysiological oscillations and synchrony, rather than disturbances in a particular direction, that characterize the brain function in individuals with ASD. Moreover, the patterns of idiosyncratic distortions of network synchrony relative to the group curve are associated with behavioral symptoms of ASD. Ann Neurol 2017;81:199-211. PMID- 27977876 TI - Introducing high-flow nasal cannula to the neonatal transport environment. PMID- 27977877 TI - Effects of stress appraisal on the quality of life of adult patients with multiple myeloma and their primary family caregivers in Korea. AB - BACKGROUND: Modern treatment for multiple myeloma (MM) has improved disease control and prolonged survival; thus, maintenance of quality of life (QoL) is considered a great concern for MM patients and their caregivers. The purpose of this study was to identify dyadic associations between stress appraisal and the QoL of patients with MM and their caregivers in Korea. METHODS: A total of 102 MM patient-caregiver dyads participated in this study. They independently reported their stress appraisal and QoL. The study was guided by a transactional model of stress and coping, and analyzed by using the actor-partner interdependence model. RESULTS: The results revealed good data adjustment with acceptable indices: chi2 = 6.211 (df = 6), CFI = 0.999, TLI = 0.994, RMSEA = 0.019, and SRMR = 0.043. MM patients' QoL were significantly correlated with caregivers' QoL. The stress appraisals of patients and caregivers mutually influenced each other's QoL. The patients' illness perception and the caregivers' burden were strong predictors for their QoL. The self-efficacy of patients and caregivers was also associated with their QoL. CONCLUSIONS: Our findings suggest that the way patients and caregivers perceive and respond to stress plays a significant role in their QoL during the treatment experience. Interventions designed to reconstruct negative perspectives and improve self-efficacy may help both patients and caregivers to improve their QoL. PMID- 27977878 TI - Effects of potentially functional polymorphisms in suppressor of cytokine signaling 3 (SOCS3) on the risk of head and neck squamous cancer. AB - BACKGROUND: Suppressor of cytokine signaling 3 (SOCS3) has been identified as an inhibitor of JAK/STAT pathway that plays a significant role in carcinogenesis. SOCS3 and JAK2 polymorphisms may influence the gene expression or function, contributing to the disease susceptibility; however, such effect has not been evaluated in head and neck squamous cell carcinoma (HNSCC). METHODS: A case control study was performed to test the associations of SOCS3 and JAK2 polymorphisms with risk of HNSCC in 576 cases and 1552 cancer-free controls from China. Seven potentially functional polymorphisms predicted by bioinformatics tools were genotyped using Infinium BeadChip platform. The association between genotypes and HNSCC risk was estimated by computing odds ratios (ORs) and 95% confidence intervals (CIs) in univariate and multivariate logistic regression models. RESULTS: We found that rs2280148 located at 3'-untranslated region of SOCS3 was significantly associated with an increased risk of HNSCC (additive model: adjusted OR = 1.21, 95% CI = 1.03-1.43, P = 0.021). Moreover, rs8064821 located in the promoter region of SOCS3 was linked with a decreased risk of the cancer (additive model: adjusted OR = 0.83, 95% CI = 0.71-0.97, P = 0.022). Combined analysis of these variants by the number of risk alleles showed a significant locus-dosage effect on the risk of HNSCC (Ptrend = 0.006). CONCLUSIONS: We provided the first evidence that SOCS3 polymorphisms may influence the risk of HNSCC, which could be applied as novel biomarkers to identify individuals at high risk of the disease. PMID- 27977879 TI - Longitudinal study shows that addictive Internet use during adolescence was associated with heavy drinking and smoking cigarettes in early adulthood. AB - AIM: Existing studies showing an association between substance use disorders and Internet addiction have been limited due their cross-sectional design. This longitudinal study investigated the association between addictive Internet use during adolescence and heavy drinking and cigarette smoking in early adulthood. METHODS: We focused on middle school students from the Korea Youth Panel Study who were 15 in 2003:1804 who did not drink alcohol and 2277 who did not smoke. Multivariate logistic analysis investigated the relationships between Internet use at the age of 15, with regard to location, time spent and reason for use, and drinking and smoking at the age of 20. RESULTS: Using the Internet for chatting, games and adult websites at the age of 15 had a significant association with heavy drinking at the age of 20. The Internet cafe as the location for Internet use at the age of 15 was associated with smoking behaviour at the age of 20. CONCLUSION: This study confirmed significant associations between addictive use of the Internet at the age of 15 and heavy drinking and cigarette smoking at the age of 20. The findings demonstrated the negative effects of addictive Internet use, one of the biggest problems with adolescents. PMID- 27977881 TI - Immune activation in amniotic fluid from Zika virus-associated microcephaly. AB - Recent advances in the understanding of neuropathogenesis associated with Zika virus (ZIKV) infection has led to descriptions of neonatal microcephaly cases. However, none of these reports have evaluated the humoral response during ZIKV infection. We report here polyfunctional immune activation associated with increased interferon-gamma-inducible protein 10, interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), monocyte chemoattractive protein 1 (MCP-1), and granulocyte colony-stimulating factor (G-CSF) levels in the amniotic fluid of ZIKV-positive pregnant women with neonatal microcephaly. These cytokines have been associated not only with neuronal damage, but also with differentiation and proliferation of neural progenitor cells. Our results suggested that the immune activation caused by ZIKV infection in the uterine environment could also interfere with fetal development. ANN NEUROL 2017;81:152-156. PMID- 27977882 TI - Helicobacter pylori-negative early gastric adenocarcinoma with complete intestinal mucus phenotype mimicking verrucous gastritis. PMID- 27977884 TI - Two patients with TNK2 mutations and late onset infantile spasm. PMID- 27977880 TI - Mesenchymal stem cells in the aseptic loosening of total joint replacements. AB - Peri-prosthetic osteolysis remains as the main long-term complication of total joint replacement surgery. Research over four decades has established implant wear as the main culprit for chronic inflammation in the peri-implant tissues and macrophages as the key cells mediating the host reaction to implant-derived wear particles. Wear debris activated macrophages secrete inflammatory mediators that stimulate bone resorbing osteoclasts; thus bone loss in the peri-implant tissues is increased. However, the balance of bone turnover is not only dictated by osteoclast-mediated bone resorption but also by the formation of new bone by osteoblasts; under physiological conditions these two processes are tightly coupled. Increasing interest has been placed on the effects of wear debris on the cells of the bone-forming lineage. These cells are derived primarily from multipotent mesenchymal stem cells (MSCs) residing in bone marrow and the walls of the microvasculature. Accumulating evidence indicates that wear debris significantly impairs MSC-to-osteoblast differentiation and subsequent bone formation. In this review, we summarize the current understanding of the effects of biomaterial implant wear debris on MSCs. Emerging treatment options to improve initial implant integration and treat developing osteolytic lesions by utilizing or targeting MSCs are also discussed. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1195-1207, 2017. PMID- 27977885 TI - Soluble Adhesion Molecules During Ex Vivo Lung Perfusion Are Associated With Posttransplant Primary Graft Dysfunction. AB - Ex vivo lung perfusion (EVLP) enables assessment of marginal donor lungs for transplantation. We aimed to discover biomarkers in EVLP perfusate that could predict development of primary graft dysfunction (PGD). From September 2008 to August 2013, 100 clinical EVLPs were performed. Eleven patients developed PGD grade 3 within 72 h after transplant. The non-PGD group consisted of 34 patients without PGD grade 3. Nonbilateral lung transplants or transplant after extracorporeal life support were excluded from analyses. Soluble intercellular adhesion molecule 1 (sICAM-1), soluble VCAM-1 (sVCAM-1), and soluble E selectin (sE-selectin) levels, as markers of endothelial activation, were measured in the perfusate of EVLP by enzyme-linked immunosorbent assay and were correlated with clinical outcome. Levels of sICAM-1 at 1 h and sVCAM-1 at 1 and 4 h were significantly higher in the PGD group compared with the non-PGD group. The sE selectin levels were not statistically different between the study groups. Higher levels of sVCAM-1 at 1 and 4 h were statistically significantly associated with PGD either alone or after adjustment for other PGD risk factors. These adhesion molecules may help identify donor lungs at higher risk of PGD during EVLP. PMID- 27977883 TI - A cell is more than the sum of its (dilute) parts: A brief history of quinary structure. AB - Most knowledge of protein structure and function is derived from experiments performed with purified protein resuspended in dilute, buffered solutions. However, proteins function in the crowded, complex cellular environment. Although the first four levels of protein structure provide important information, a complete understanding requires consideration of quinary structure. Quinary structure comprises the transient interactions between macromolecules that provides organization and compartmentalization inside cells. We review the history of quinary structure in the context of several metabolic pathways, and the technological advances that have yielded recent insight into protein behavior in living cells. The evidence demonstrates that protein behavior in isolated solutions deviates from behavior in the physiological environment. PMID- 27977886 TI - Self-assembled arginine-rich peptides as effective antimicrobial agents. AB - Bacteria can adapt to their ever-changing environment to develop a resistance to commonly used antibiotics. This escalating evolution of bacteria coupled with a diminished number of effective antibiotics has caused a global healthcare crisis. New antimicrobials and novel approaches to tackle this problem are urgently needed. Antimicrobial peptides are of particular interest in this endeavor due to their broad spectrum antimicrobial properties as well as ability to combat multi drug resistant bacteria. Most peptides have both hydrophobic and hydrophilic regions that enable them to be soluble in an aqueous solution, yet can insert into and subsequently disintegrate lipid rich membranes through diverse mechanisms. In this study, a novel class of cationic nanoparticles (formed by the self-assembly of an amphiphilic peptide) were shown to have strong antimicrobial properties against gram-positive bacteria, specifically Staphylococcus aureus, Staphylococcus epidermidis, and methicillin-resistant Staphylococcus aureus (MRSA) with minimal toxicity to human dermal fibroblasts. The particular self assembled structure tested here included an arginine rich nanoparticle (C17 H35 GR7RGDS or amphiphilic peptide nanoparticles, APNPs) which incorporated seven arginine residues (imparting a positive charge to improve membrane interactions), a hydrophobic block which drove the self-assembly process, and the presence of an amino acid quadruplet arginine-glycine-aspartic acid-serine (RGDS) which may render these nanoparticles capable of attracting healthy cells while competing bacterial adherence to fibronectin, an adhesive protein found on cell surfaces. As such, this in vitro study demonstrated that the presently formulated APNPs should be further studied for a wide range of antibacterial applications where antibiotics are no longer useful. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1046-1054, 2017. PMID- 27977887 TI - Modulation of hemoglobin dynamics by an allosteric effector. AB - Hemoglobin (Hb) is an extensively studied paradigm of proteins that alter their function in response to allosteric effectors. Models of its action have been used as prototypes for structure-function relationships in many proteins, and models for the molecular basis of its function have been deeply studied and extensively argued. Recent reports suggest that dynamics may play an important role in its function. Relatively little is known about the slow, correlated motions of hemoglobin subunits in various structural states because experimental and computational strategies for their characterization are challenging. Allosteric effectors such as inositol hexaphosphate (IHP) bind to both deoxy-Hb and HbCO, albeit at different sites, leading to a lowered oxygen affinity. The manner in which these effectors impact oxygen binding is unclear and may involve changes in structure, dynamics or both. Here we use neutron spin echo measurements accompanied by wide-angle X-ray scattering to show that binding of IHP to HbCO results in an increase in the rate of coordinated motions of Hb subunits relative to one another with little if any change in large scale structure. This increase of large-scale dynamics seems to be coupled with a decrease in the average magnitude of higher frequency modes of individual residues. These observations indicate that enhanced dynamic motions contribute to the functional changes induced by IHP and suggest that they may be responsible for the lowered oxygen affinity triggered by these effectors. PMID- 27977888 TI - A misfolded dimer of Cu/Zn-superoxide dismutase leading to pathological oligomerization in amyotrophic lateral sclerosis. AB - Misfolding of mutant Cu/Zn-superoxide dismutase (SOD1) is a pathological hallmark in a familial form of amyotrophic lateral sclerosis. Pathogenic mutations have been proposed to monomerize SOD1 normally adopting a homodimeric configuration and then trigger abnormal oligomerization of SOD1 proteins. Despite this, a misfolded conformation of SOD1 leading to the oligomerization at physiological conditions still remains ambiguous. Here, we show that, around the body temperature (~37 degrees C), mutant SOD1 maintains a dimeric configuration but lacks most of its secondary structures. Also, such an abnormal SOD1 dimer with significant structural disorder was prone to irreversibly forming the oligomers crosslinked via disulfide bonds. The disulfide-crosslinked oligomers of SOD1 were detected in the spinal cords of the diseased mice expressing mutant SOD1. We hence propose an alternative pathway of mutant SOD1 misfolding that is responsible for oligomerization in the pathologies of the disease. PMID- 27977890 TI - Scissor-type knife significantly improves self-completion rate of colorectal endoscopic submucosal dissection: Single-center prospective randomized trial. AB - BACKGROUND AND AIM: Colorectal endoscopic submucosal dissection (C-ESD) is recognized as a difficult procedure. Recently, scissors-type knives were launched to reduce the difficulty of C-ESD. The aim of this study was to evaluate the efficacy and safety of the combined use of a scissors-type knife and a needle type knife with a water-jet function (WJ needle-knife) for C-ESD compared with using the WJ needle-knife alone. METHODS: This was a prospective randomized controlled trial in a referral center. Eighty-five patients with superficial colorectal neoplasms were enrolled and randomly assigned to undergo C-ESD using a WJ needle-knife alone (Flush group) or a scissor-type knife-supported WJ needle knife (SB Jr group). Procedures were conducted by two supervised residents. Primary endpoint was self-completion rate by the residents. RESULTS: Self completion rate was 67% in the SB Jr group, which was significantly higher than that in the Flush group (39%, P = 0.01). Even after exclusion of four patients in the SB Jr group in whom C-ESD was completed using the WJ needle-knife alone, the self-completion rate was significantly higher (63% vs 39%; P = 0.03). Median procedure time among the self-completion cases did not differ significantly between the two groups (59 vs 51 min; P = 0.14). No fatal adverse events were observed in either group. CONCLUSIONS: In this single-center phase II trial, scissor-type knife significantly improved residents' self-completion rate for C ESD, with no increase in procedure time or adverse events. A multicenter trial would be warranted to confirm the validity of the present study. PMID- 27977889 TI - Tuning BRCA1 and BARD1 activity to investigate RING ubiquitin ligase mechanisms. AB - The tumor-suppressor protein BRCA1 works with BARD1 to catalyze the transfer of ubiquitin onto protein substrates. The N-terminal regions of BRCA1 and BARD1 that contain their RING domains are responsible for dimerization and ubiquitin ligase activity. This activity is a common feature among hundreds of human RING domain containing proteins. RING domains bind and activate E2 ubiquitin-conjugating enzymes to promote ubiquitin transfer to substrates. We show that the identity of residues at specific positions in the RING domain can tune activity levels up or down. We report substitutions that create a structurally intact BRCA1/BARD1 heterodimer that is inactive in vitro with all E2 enzymes. Other substitutions in BRCA1 or BARD1 RING domains result in hyperactivity, revealing that both proteins have evolved attenuated activity. Loss of attenuation results in decreased product specificity, providing a rationale for why nature has tuned BRCA1 activity. The ability to tune BRCA1 provides powerful tools for understanding its biological functions and provides a basis to assess mechanisms for rescuing the activity of cancer-associated variations. Beyond the applicability to BRCA1, we show the identity of residues at tuning positions that can be used to predict and modulate the activity of an unrelated RING E3 ligase. These findings provide valuable insights into understanding the mechanism and function of RING E3 ligases like BRCA1. PMID- 27977891 TI - The accommodation index measures the perturbation associated with insertions and deletions in coiled-coils: Application to understand signaling in histidine kinases. AB - Coiled-coils are essential components of many protein complexes. First discovered in structural proteins such as keratins, they have since been found to figure largely in the assembly and dynamics required for diverse functions, including membrane fusion, signal transduction and motors. Coiled-coils have a characteristic repeating seven-residue geometric and sequence motif, which is sometimes interrupted by the insertion of one or more residues. Such insertions are often highly conserved and critical to interdomain communication in signaling proteins such as bacterial histidine kinases. Here we develop the "accommodation index" as a parameter that allows automatic detection and classification of insertions based on the three dimensional structure of a protein. This method allows precise identification of the type of insertion and the "accommodation length" over which the insertion is structurally accommodated. A simple theory is presented that predicts the structural perturbations of 1, 3, 4 residue insertions as a function of the length over which the insertion is accommodated. Analysis of experimental structures is in good agreement with theory, and shows that short accommodation lengths give rise to greater perturbation of helix packing angles, changes in local helical phase, and increased structural asymmetry relative to long accommodation lengths. Cytoplasmic domains of histidine kinases in different signaling states display large changes in their accommodation lengths, which can now be seen to underlie diverse structural transitions including symmetry/asymmetry and local variations in helical phase that accompany signal transduction. PMID- 27977893 TI - In memoriam-Rainer Jaenicke. PMID- 27977892 TI - Genomic evolution of bacterial populations under coselection by antibiotics and phage. AB - Bacteria live in dynamic systems where selection pressures can alter rapidly, forcing adaptation to the prevailing conditions. In particular, bacteriophages and antibiotics of anthropogenic origin are major bacterial stressors in many environments. We previously observed that populations of the bacterium Pseudomonas fluorescens SBW25 exposed to the lytic bacteriophage SBW25Phi2 and a noninhibitive concentration of the antibiotic streptomycin (coselection) achieved higher levels of phage resistance compared to populations exposed to the phage alone. In addition, the phage became extinct under coselection while remaining present in the phage alone environment. Further, phenotypic tests indicated that these observations might be associated with increased mutation rate under coselection. In this study, we examined the genetic causes behind these phenotypes by whole-genome sequencing clones isolated from the end of the experiments. We were able to identify genetic factors likely responsible for streptomycin resistance, phage resistance and hypermutable (mutator) phenotypes. This constitutes genomic evidence in support of the observation that while the presence of phage did not affect antibiotic resistance, the presence of antibiotic affected phage resistance. We had previously hypothesized an association between mutators and elevated levels of phage resistance under coselection. However, our evidence regarding the mechanism was inconclusive, as although with phage mutators were only found under coselection, additional genomic evidence was lacking and phage resistance was also observed in nonmutators under coselection. More generally, our study provides novel insights into evolution between univariate and multivariate selection (here two stressors), as well as the potential role of hypermutability in natural communities. PMID- 27977894 TI - Synthesis and characterization of a novel scaffold for bone tissue engineering based on Wharton's jelly. AB - A composite is a material made of more than one component, and the bond between the components is on a scale larger than the atomic scale. The objective of the present study was to synthesize and perform the structural characterization and biological evaluation of a new biocomposite (BCO) based on a novel combination of an organic and an inorganic phase, for bone tissue engineering applications. The organic phase consisted of Wharton's jelly (WJ), which was obtained from embryonic tissue following a protocol developed by our laboratory. The inorganic phase consisted of bioceramic particles (BC), produced by sintering hydroxyapatite (HA) with beta- tricalcium phosphate (beta-TCP), and bioactive glass particles (BG). Each phase of the BCO was fully characterized by SEM, EDS, XRD, and FTIR. Biocompatibility was evaluated in vivo in the tibiae of Wistar rats (n = 40). Histological evaluation was performed at 0, 1, 7, 14, 30, and 60 days. XRD showed the phases corresponding to HA and beta-TCP, whereas diffractogram of BG showed it to have an amorphous structure. EDS showed mainly Si and Na, Ca, P in BG, and Ca and P in HA and beta-TCP. FTIR identified bonds between the organic and inorganic phases. From a mechanical viewpoint, the composite showed high flexural strength of 40.3 +/- 0.8 MPa. The synthesized BCO exhibited adequate biocompatibility as shown by formation of lamellar type bone linked by BG and BC particles. The biomaterial presented here showed excellent mechanical and biocompatibility properties for its potential clinical use. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1034-1045, 2017. PMID- 27977896 TI - Healing acceleration of oral mucositis induced by 5-fluorouracil with Pistacia atlantica (bene) essential oil in hamsters. AB - BACKGROUND: Oral mucositis is a common debilitating condition in patients with cancer receiving cytotoxic therapies. This study aimed to evaluate the effects of topical administrations of the essential oil extracted from hull of Pistacia atlantica fruit (bene) on healing of oral mucositis in golden hamsters. METHODS: Forty hamsters with oral mucositis induced by 5-fluorouracil administered on days 0, 5 and 10 and buccal mucosal scratching were randomly divided into four equal groups: group 1 received no additional treatment, group 2 received gel base, and groups 3 and 4 received gels containing 5% and 10% oil, respectively. From day 12, after blood sampling of all animals, a half randomly selected fraction of each group (four half groups) received once-daily topical administration of either gel type (gel base, 5% and 10%) or no treatment (control subgroup) over the buccal pouches for 3 days and the remaining halves received the same treatments for 6 days. On each final day 15 and 18, the corresponding subgroups underwent consecutively the repeated blood sampling, mucosal clinical examination and excision for histopathology. RESULTS: Comparisons on macro- and microscopical oral mucositis scorings demonstrated dose-dependent healing promotion in the subgroups receiving active gels (P < 0.05). The blood samplings revealed the chemotherapy-related pancytopenia with no significant difference among all subgroups on either end point (P > 0.05). CONCLUSIONS: The healing effect of the bene oil could mainly be local and attributed to its antioxidants and fatty acid contents present in non-saponified and saponified fractions, respectively. PMID- 27977895 TI - A Soluble Form of P Selectin Glycoprotein Ligand 1 Requires Signaling by Nuclear Factor Erythroid 2-Related Factor 2 to Protect Liver Transplant Endothelial Cells Against Ischemia-Reperfusion Injury. AB - Liver endothelial cell (LEC) damage is essential in the pathogenesis of ischemia reperfusion injury (IRI) in transplant recipients. We analyzed the mechanism of LEC resistance against IRI by using a novel recombinant soluble form of P selectin glycoprotein ligand 1, tandem P selectin glycoprotein ligand immunoglobulin (TSGL-Ig), in a mouse model of hepatic cold preservation (4 degrees C in University of Wisconsin solution for 20 h) and syngeneic orthotopic liver transplantation (OLT). Unlike controls, TSGL-Ig protected orthotopic liver transplants against ischemia-reperfusion (IR) stress, shown by depressed serum alanine aminotransferase levels, well-preserved hepatic architecture, and improved survival (42% vs. 92%). TSGL-Ig suppressed neutrophil/macrophage sequestration and proinflammatory cytokine/chemokine programs in OLT. Treatment with TSGL-Ig mitigated LEC activation (P and E selectin, VCAM-1 and intercellular adhesion molecule 1 expression). In parallel in vitro studies, TSGL-Ig diminished cellular damage in H2 O2 -stressed LEC cultures (lactic acid dehydrogenase and alanine aminotransferase levels). Increased thioredoxin, glutamate-cysteine ligase, NAD(P)H quinone dehydrogenase 1, and hypoxia-inducible factor 1alpha expression, along with transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), implied that TSGL-Ig exerts antioxidant functions in IR-stressed OLT and H2 O2 -stressed LECs. Indeed, Nrf2-deficient livers suffered fulminant IRI compared with WT despite concomitant TSGL-Ig therapy. Thus, TSGL-Ig is not only acting as a competitive antagonist blocking leukocyte migration into IR stressed liver, but it may also act directly as an agonist stimulating Nrf2 mediated cytoprotection in LECs. This study supports the role of P selectin signaling in hepatic homeostasis in OLT, with broad implications for tissue damage conditions. PMID- 27977897 TI - The membrane localization domains of two distinct bacterial toxins form a 4-helix bundle in solution. AB - Membrane localization domain (MLD) was first proposed for a 4-helix-bundle motif in the crystal structure of the C1 domain of Pasteurella multocida toxin (PMT). This structure motif is also found in the crystal structures of several clostridial glycosylating toxins (TcdA, TcdB, TcsL, and TcnA). The Ras/Rap1 specific endopeptidase (RRSP) module of the multifunctional autoprocessing repeats-in-toxins (MARTX) toxin produced by Vibrio vulnificus has sequence homology to the C1-C2 domains of PMT, including a putative MLD. We have determined the solution structure for the MLDs in PMT and in RRSP using solution state NMR. We conclude that the MLDs in these two toxins assume a 4-helix-bundle structure in solution. PMID- 27977899 TI - Individual evaluation of cardiac marker expression and self-beating during cardiac differentiation of P19CL6 cells on different culture substrates. AB - Cell-based therapies using self-beating cardiomyocytes have been attracting great attention for use in cardiac regeneration, although an effective procedure to improve cardiac differentiation and self-beating induction is required. The purpose of this study is to clarify the effect of the culture substrate on cardiac maturation by separately evaluating the cardiac differentiation step and the beating induction step in vitro. To this end, the well-studied cardiomyocyte like progenitor cell line P19CL6 and neonatal cardiomyocytes (NCMs) were selected and cultured on substrates coated with collagen type I (Col-I), gelatin (Gel), fibronectin (FN), or poly-l-lysine (PLL). It was found that the cardiac differentiation step, which was assessed using cardiac marker gene expression (GATA-binding protein 4 (GATA4), myocyte-specific enhancer factor 2D (MEF2D), and hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4)) in the P19CL6 embryonal carcinoma cells, was greatly enhanced on Col-I, Gel, and PLL. In contrast, the spontaneous beating step, which was directly assessed by counting the beating colonies and measuring contractile protein gene expression (alpha-myosin heavy chain (alpha-MHC), troponin C type 1 (TnC1), and troponin T type 2 (TnT2)) in the rat NCMs, was enhanced on the FN and PLL surfaces. In the present study, for the first time, it was found that PLL enhances both the cardiac differentiation and the beating induction steps of cardiac maturation, which can aid in preparing beating cardiomyocytes for regenerative medicine. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1166-1174, 2017. PMID- 27977900 TI - Noneligible Donors as a Strategy to Decrease the Organ Shortage. AB - Organ procurement organization (OPO) performance is generally evaluated by the number of organ procurement procedures divided by the number of eligible deaths (donation after brain death [DBD] donors aged <70 years), whereas the number of noneligible deaths (including donation after cardiac death donors and DBD donors aged >70 years) is not tracked. The present study aimed to investigate the variability in the proportion of noneligible liver donors by the 58 donor service areas (DSAs). Patients undergoing liver transplant (LT) between 2011 and 2015 were obtained from the United Network for Organ Sharing Standard Transplant Analysis and Research file. LTs from noneligible and eligible donors were compared. The proportion of noneligible liver donors by DSA varied significantly, ranging from 0% to 19.6% of total liver grafts used. In transplant programs, the proportion of noneligible liver donors used ranged from 0% to 35.3%. On linear regression there was no correlation between match Model for End-Stage Liver Disease score for programs in a given DSA and proportion of noneligible donors used from the corresponding DSA (p = 0.14). Noneligible donors remain an underutilized resource in many OPOs. Policy changes to begin tracking noneligible donors and learning from OPOs that have high noneligible donor usage are potential strategies to increase awareness and pursuit of these organs. PMID- 27977898 TI - Expansion of divergent SEA domains in cell surface proteins and nucleoporin 54. AB - SEA (sea urchin sperm protein, enterokinase, agrin) domains, many of which possess autoproteolysis activity, have been found in a number of cell surface and secreted proteins. Despite high sequence divergence, SEA domains were also proposed to be present in dystroglycan based on a conserved autoproteolysis motif and receptor-type protein phosphatase IA-2 based on structural similarity. The presence of a SEA domain adjacent to the transmembrane segment appears to be a recurring theme in quite a number of type I transmembrane proteins on the cell surface, such as MUC1, dystroglycan, IA-2, and Notch receptors. By comparative sequence and structural analyses, we identified dystroglycan-like proteins with SEA domains in Capsaspora owczarzaki of the Filasterea group, one of the closest single-cell relatives of metazoans. We also detected novel and divergent SEA domains in a variety of cell surface proteins such as EpCAM, alpha/epsilon sarcoglycan, PTPRR, collectrin/Tmem27, amnionless, CD34, KIAA0319, fibrocystin like protein, and a number of cadherins. While these proteins are mostly from metazoans or their single cell relatives such as choanoflagellates and Filasterea, fibrocystin-like proteins with SEA domains were found in several other eukaryotic lineages including green algae, Alveolata, Euglenozoa, and Haptophyta, suggesting an ancient evolutionary origin. In addition, the intracellular protein Nucleoporin 54 (Nup54) acquired a divergent SEA domain in choanoflagellates and metazoans. PMID- 27977901 TI - On the appearance of carboxylates in electrostatic potential maps. AB - Electron microscopy can provide accurate, high-resolution images of the distribution of electrostatic potential (ESP) in biological macromolecules. Careful examination of ESP maps that have been published for peptides and proteins at resolution ranging from 1.0 A to 2.9 A reveals that the negative charges of carboxylate groups have a profound effect on their appearance. It is clear that investigators must take the negative features in their experimental ESP maps into account when modeling the conformations of Asp and Glu side chains and those of the residues that surround them. PMID- 27977902 TI - Impact of molecular weight on the intrinsic immunogenic activity of poly(beta amino esters). AB - Polymeric carriers are ubiquitously studied in vaccine and drug delivery to control the encapsulation, kinetics, and targeting of cargo. Recent research reveals many polymers can cause immunostimulatory and inflammatory responses, even in the absence of other immune signals. However, the extent to which this intrinsic immunogenicity evolves during degradation is understudied. Here we synthesized a small library of poly(beta amino esters) (PBAEs) that exhibit different starting molecular weights (MWs), but with similar and rapid degradation rates. Primary dendritic cells (DCs) treated with free PBAEs, either intact or degraded to form low MW fragments, were not activated. In contrast particles formed from PBAEs at different extents of degradation caused differential expression of classical DC activation markers (for example, CD40, CD80, CD86, MHCII), as well as antigen presentation. During degradation, activation levels changed with changing physicochemical properties (for example, MW, concentration, size, charge). Of note, irrespective of starting MW, immunogenicity peaked when the MW of degrading PBAEs decreased to a range of ~1500-3000 Da. These findings could help inform design of future carriers that exploit the dynamic interactions with the immune system as materials degrade, leading to carriers that deliver cargo but also help direct the immune responses to vaccine or immunotherapy cargo. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1219-1229, 2017. PMID- 27977903 TI - Elementary, My Dear Watson-The Era of Natural Language Processing in Transplantation. PMID- 27977904 TI - Adenosine triphosphate induces P2Y2 activation and interleukin-8 release in human esophageal epithelial cells. AB - BACKGROUND AND AIM: Immune-mediated mucosal inflammation characterized by the release of interleukin (IL)-8 is associated with gastroesophageal reflux disease. ATP released by human esophageal epithelial cells (HEECs) mediates the release of cytokines through P2 nucleotide receptors that are present on various cells, including HEECs. This study characterized and identified human esophageal epithelial P2 receptors that are responsible for ATP-mediated release of IL-8 by using a human esophageal stratified squamous epithelial model. METHODS: Primary HEECs were cultured with the use of an air-liquid interface (ALI) system. The ATP analogue adenosine 5'-O-3-thiotriphosphate (ATP-gamma-S) was added to the basolateral compartment, and IL-8 release was measured. Involvement of the P2Y2 receptor was assessed with the use of selective and non-selective receptor antagonists and a P2Y2 receptor agonist. Expression of the P2Y2 receptor was assessed using western blotting and immunohistochemistry. RESULTS: Adenosine triphosphate-gamma-S induced IL-8 release through the P2Y2 receptor. A P2Y2 receptor antagonist but not a P2X3 receptor antagonist or a P2Y1 receptor antagonist blocked ATP-gamma-S-mediated IL-8 release. Conversely, a P2Y2 receptor agonist induced IL-8 release. Western blotting and immunohistochemistry of the P2Y2 receptor showed strong expression of the P2Y2 receptor on ALI-cultured HEECs and in human esophagus. Inhibition of extracellular signal-regulated kinase but not of protein kinase C blocked the ATP-mediated release of IL-8. ATP-gamma-S induced phosphorylation of extracellular signal-regulated kinase, and a P2Y2 receptor antagonist blocked this phosphorylation. CONCLUSIONS: Interleukin-8 release after purinergic stimulation in ALI-cultured HEECs is mediated through P2Y2 receptor activation. ATP-induced IL-8 release maybe involved in the pathogenesis of refractory gastroesophageal reflux disease. PMID- 27977906 TI - New insights into the effects of biomaterial chemistry and topography on the morphology of kidney epithelial cells. AB - Increasing incidence of renal pathology in the western world calls for innovative research for the development of cell-based therapies such as a bioartificial kidney (BAK) device. To fulfil the multitude of kidney functions, the core component of the BAK is a living membrane consisting of a tight kidney cell monolayer with preserved functional organic ion transporters cultured on a polymeric membrane surface. This membrane, on one side, is in contact with blood and therefore should have excellent blood compatibility, whereas the other side should facilitate functional monolayer formation. This work investigated the effect of membrane chemistry and surface topography on kidney epithelial cells to improve the formation of a functional monolayer. To achieve this, microtopographies were fabricated with high resolution and reproducibility on polystyrene films and on polyethersulfone-polyvinyl pyrrolidone (PES-PVP) porous membranes. A conditionally immortalized proximal tubule epithelial cell line (ciPTEC) was cultured on both, and subsequently, the cell morphology and monolayer formation were assessed. Our results showed that L-dopamine coating of the PES-PVP was sufficient to support ciPTEC monolayer formation. The polystyrene topographies with large features were able to align the cells in various patterns without significantly disruption of monolayer formation; however, the PES-PVP topographies with large features disrupted the monolayer. In contrast, the PES PVP membranes with small features and with large spacing supported well the ciPTEC monolayer formation. In addition, the topographical PES-PVP membranes were compatible as a substrate membrane to measure organic cation transporter activity in Transwell(r) systems. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27977905 TI - The Value of Protocol Biopsies to Identify Patients With De Novo Donor-Specific Antibody at High Risk for Allograft Loss. AB - De novo donor-specific antibody (dnDSA) is associated with antibody-mediated rejection (AMR) and allograft loss, yet the allograft histology associated with dnDSA remains unclear. The aim of this study was to examine the allograft histology associated with dnDSA in patients with serial surveillance biopsies. We retrospectively studied adult conventional solitary kidney transplant recipients from October 2007 to May 2014. The definition of dnDSA was new donor-specific antibody (DSA) with mean fluorescence intensity (MFI) >1000. The incidence of dnDSA was 7.0% (54 of 771) over mean follow-up of 4.2 +/- 1.9 years. Patients with dnDSA had reduced death-censored allograft survival (87.0% vs. 97.0% no dnDSA, p < 0.01). Moreover, 94% of patients received a biopsy after dnDSA (mean of three biopsies per patient). AMR was present in 25.0% and 52.9% of patients at dnDSA detection and at 1 year, respectively. Patients with both class I and II dnDSA had the highest rate of allograft loss. The higher the sum MFI at dnDSA detection, the higher the incidence of AMR. In conclusion, patients with dnDSA without AMR at time of detection may benefit from a follow-up biopsy within 1 year because AMR can be missed initially. In addition, the dnDSA class and sum MFI at baseline appear to be prognostic. The higher the sum MFI of dnDSA at baseline, the higher the incidence of AMR. PMID- 27977908 TI - Integrated continuous processing of proteins expressed as inclusion bodies: GCSF as a case study. AB - Affordability of biopharmaceuticals continues to be a challenge, particularly in developing economies. This has fuelled advancements in manufacturing that can offer higher productivity and better economics without sacrificing product quality in the form of an integrated continuous manufacturing platform. While platform processes for monoclonal antibodies have existed for more than a decade, development of an integrated continuous manufacturing process for bacterial proteins has received relatively scant attention. In this study, we propose an end-to-end integrated continuous downstream process (from inclusion bodies to unformulated drug substance) for a therapeutic protein expressed in Escherichia coli as inclusion body. The final process consisted of a continuous refolding in a coiled flow inverter reactor directly coupled to a three-column periodic counter-current chromatography for capture of the product followed by a three column con-current chromatography for polishing. The continuous bioprocessing train was run uninterrupted for 26 h to demonstrate its capability and the resulting output was analyzed for the various critical quality attributes, namely product purity (>99%), high molecular weight impurities (<0.5%), host cell proteins (<100 ppm), and host cell DNA (<10 ppb). All attributes were found to be consistent over the period of operation. The developed assembly offers smaller facility footprint, higher productivity, fewer hold steps, and significantly higher equipment and resin utilization. The complexities of process integration in the context of continuous processing have been highlighted. We hope that the study presented here will promote development of highly efficient, universal, end to-end, fully continuous platforms for manufacturing of biotherapeutics. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:998-1009, 2017. PMID- 27977909 TI - Television food advertising viewed by preschoolers, children and adolescents: contributors to differences in exposure for black and white youth in the United States. AB - BACKGROUND: Public health experts raise concerns about adolescents' and black youth's greater exposure to TV advertising for unhealthy foods and beverages compared with children and white youth. OBJECTIVES: Examine how television viewing patterns and rates of advertising during targeted programming contribute to this greater exposure. METHODS: Nielsen panel data provided viewing times and amount of food advertising viewed on U.S. television in 2008 and 2012. Researchers compared results by network type (black-, child- and youth-targeted), age group (preschoolers, children and adolescents) and race (black and white youth). RESULTS: Food advertising exposure increased with age for both black and white youth, but black youth viewed approximately 50% or more ads than did white youth of the same age. Higher rates of food advertising on youth-targeted networks explained greater adolescent exposure. However, greater television viewing and higher rates of advertising on youth- and black-targeted networks both contributed to black youth's greater exposure. From 2008 to 2012, increases in food-ads-per-hour increased exposure for all youth. CONCLUSIONS: Food advertisers and networks, especially those targeting adolescents and black youth, must do more to reduce advertising that negatively impacts young people's health. Furthermore, reducing commercial-television viewing by black youth may help reduce health disparities affecting their communities. PMID- 27977910 TI - Bioreactor productivity and media cost comparison for different intensified cell culture processes. AB - Process intensification in biomanufacturing has attracted a great deal of interest in recent years. Manufacturing platform improvements leading to higher cell density and bioreactor productivity have been pursued. Here we evaluated a variety of intensified mammalian cell culture processes for producing monoclonal antibodies. Cell culture operational modes including fed-batch (normal seeding density or high seeding density with N-1 perfusion), perfusion, and concentrated fed-batch (CFB) were assessed using the same media set with the same Chinese Hamster Ovary (CHO) cell line. Limited media modification was done to quickly fit the media set to different operational modes. Perfusion and CFB processes were developed using an alternating tangential flow filtration device. Independent of the operational modes, comparable cell specific productivity (fed-batch: 29.4 pg/cell/day; fed-batch with N-1 perfusion: 32.0 pg/cell/day; perfusion: 31.0 pg/cell/day; CFB: 20.1 - 45.1 pg/cell/day) was reached with similar media conditions. Continuous media exchange enabled much higher bioreactor productivity in the perfusion (up to 2.29 g/L/day) and CFB processes (up to 2.04 g/L/day), compared with that in the fed-batch processes (ranging from 0.39 to 0.49 g/L/day), largely due to the higher cell density maintained. Furthermore, media cost per gram of antibody produced from perfusion was found to be highly comparable with that from fed-batch; and the media cost for CFB was the highest due to the short batch duration. Our experimental data supports the argument that media cost for perfusion process could be even lower than that in a fed-batch process, as long as sufficient bioreactor productivity is achieved. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:867-878, 2017. PMID- 27977911 TI - Rapid classification and quantification of cocaine in seized powders with ATR FTIR and chemometrics. AB - Traditionally, fast screening for the presence of cocaine in unknown powders is performed by means of colour tests. The major drawbacks of these tests are subjective colour evaluation depending on the operator ('50 shades of blue') and a lack of selectivity. An alternative fast screening technique is Fourier Transform InfraRed (FTIR) spectrometry. This technique provides spectra that are difficult to interpret without specialized expertise and shows a lack of sensitivity for the detection of cocaine in mixtures. To overcome these limitations, a portable FTIR spectrometer using Attenuated Total Reflectance (ATR) sampling was combined with a multivariate technique, called Support Vector Machines (SVM). Representative street drug powders (n = 482), seized during the period January 2013 to July 2015, and reference powders (n = 33) were used to build and validate a classification model (n = 515) and a quantification model (n = 378). Both models were compared with the conventional chromatographic techniques. The SVM classification model showed a high sensitivity, specificity, and efficiency (99%). The SVM quantification model determined cocaine content with a root mean squared error of prediction (RMSEP) of 6% calculated over a wide working range from 4 to 99 w%. In conclusion, the developed models resulted in a clear output (cocaine detected or cocaine not detected) and a reliable estimation of the cocaine content in a wide variety of mixtures. The ATR-FTIR technique combined with SVM is a straightforward, user-friendly, and fast approach for routine classification and quantification of cocaine in seized powders. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27977907 TI - An ongoing role for Wnt signaling in differentiating melanocytes in vivo. AB - A role for Wnt signaling in melanocyte specification from neural crest is conserved across vertebrates, but possible ongoing roles in melanocyte differentiation have received little attention. Using a systems biology approach to investigate the gene regulatory network underlying stable melanocyte differentiation in zebrafish highlighted a requirement for a positive-feedback loop involving the melanocyte master regulator Mitfa. Here, we test the hypothesis that Wnt signaling contributes to that positive feedback. We show firstly that Wnt signaling remains active in differentiating melanocytes and secondly that enhanced Wnt signaling drives elevated transcription of mitfa. We show that chemical activation of the Wnt signaling pathway at early stages of melanocyte development enhances melanocyte specification as expected, but importantly that at later (differentiation) stages, it results in altered melanocyte morphology, although melanisation is not obviously affected. Downregulation of Wnt signaling also results in altered melanocyte morphology and organization. We conclude that Wnt signaling plays a role in regulating ongoing aspects of melanocyte differentiation in zebrafish. PMID- 27977913 TI - Primate empathy: three factors and their combinations for empathy-related phenomena. AB - Empathy as a research topic is receiving increasing attention, although there seems some confusion on the definition of empathy across different fields. Frans de Waal (de Waal FBM. Putting the altruism back into altruism: the evolution of empathy. Annu Rev Psychol 2008, 59:279-300. doi:10.1146/annurev.psych.59.103006.093625) used empathy as an umbrella term and proposed a comprehensive model for the evolution of empathy with some of its basic elements in nonhuman animals. In de Waal's model, empathy consists of several layers distinguished by required cognitive levels; the perception-action mechanism plays the core role for connecting ourself and others. Then, human-like empathy such as perspective-taking develops in outer layers according to cognitive sophistication, leading to prosocial acts such as targeted helping. I agree that animals demonstrate many empathy-related phenomena; however, the species differences and the level of cognitive sophistication of the phenomena might be interpreted in another way than this simple linearly developing model. Our recent studies with chimpanzees showed that their perspective-taking ability does not necessarily lead to proactive helping behavior. Herein, as a springboard for further studies, I reorganize the empathy-related phenomena by proposing a combination model instead of the linear development model. This combination model is composed of three organizing factors: matching with others, understanding of others, and prosociality. With these three factors and their combinations, most empathy-related matters can be categorized and mapped to appropriate context; this may be a good first step to discuss the evolution of empathy in relation to the neural connections in human and nonhuman animal brains. I would like to propose further comparative studies, especially from the viewpoint of Homo-Pan (chimpanzee and bonobo) comparison. WIREs Cogn Sci 2017, 8:e1431. doi: 10.1002/wcs.1431 For further resources related to this article, please visit the WIREs website. PMID- 27977912 TI - Characterization of TAP Ambr 250 disposable bioreactors, as a reliable scale-down model for biologics process development. AB - Demands for development of biological therapies is rapidly increasing, as is the drive to reduce time to patient. In order to speed up development, the disposable Automated Microscale Bioreactor (Ambr 250) system is increasingly gaining interest due to its advantages, including highly automated control, high throughput capacity, and short turnaround time. Traditional early stage upstream process development conducted in 2 - 5 L bench-top bioreactors requires high foot print, and running cost. The establishment of the Ambr 250 as a scale-down model leads to many benefits in process development. In this study, a comprehensive characterization of mass transfer coefficient (kL a) in the Ambr 250 was conducted to define optimal operational conditions. Scale-down approaches, including dimensionless volumetric flow rate (vvm), power per unit volume (P/V) and kL a have been evaluated using different cell lines. This study demonstrates that the Ambr 250 generated comparable profiles of cell growth and protein production, as seen at 5-L and 1000-L bioreactor scales, when using kL a as a scale-down parameter. In addition to mimicking processes at large scales, the suitability of the Ambr 250 as a tool for clone selection, which is traditionally conducted in bench-top bioreactors, was investigated. Data show that cell growth, productivity, metabolite profiles, and product qualities of material generated using the Ambr 250 were comparable to those from 5-L bioreactors. Therefore, Ambr 250 can be used for clone selection and process development as a replacement for traditional bench-top bioreactors minimizing resource utilization during the early stages of development in the biopharmaceutical industry. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:478-489, 2017. PMID- 27977914 TI - Analysis of Tubespins as a suitable scale-down model of bioreactors for high cell density CHO cell culture. AB - High cell density (HCD) culture increases recombinant protein productivity via higher biomass. Compared to traditional fed-batch cultures, HCD is achieved by increased nutrient availability and removal of undesired metabolic components via regular medium replenishment. HCD process development is usually performed in instrumented lab-scale bioreactors (BR) that require time and labor for setup and operation. To potentially minimize resources and cost during HCD experiments, we evaluated a 2-week 50-mL Tubespin (TS) simulated HCD process where daily medium exchanges mimic the medium replacement rate in BR. To best assess performance differences, we cultured 13 different CHO cell lines in simulated HCD as satellites from simultaneous BR, and compared growth, metabolism, productivity and product quality. Overall, viability, cell-specific productivity and metabolism in TS were comparable to BR, but TS cell growth and final titer were lower by 25 and 15% in average, respectively. Peak viable cell densities were lower in TS than BR as a potential consequence of lower pH, different medium exchange strategy and dissolved oxygen limitations. Product quality attributes highly dependent on intrinsic molecule or cell line characteristics (e.g., galactosylation, afucosylation, aggregation) were comparable in both scales. However, product quality attributes that can change extracellularly as a function of incubation time (e.g., deamidation, C-terminal lysine, fragmentation) were in general lower in TS because of shorter residence time than HCD BR. Our characterization results and two case studies show that TS-simulated HCD cultures can be effectively used as a simple scale-down model for relative comparisons among cell lines for growth or productivity (e.g., clone screening), and for investigating effects on protein galactosylation. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:490-499, 2017. PMID- 27977915 TI - Transient and stable CHO expression, purification and characterization of novel hetero-dimeric bispecific IgG antibodies. AB - IgG bispecific antibodies (BsAbs) represent one of the preferred formats for bispecific antibody therapeutics due to their native-like IgG properties and their monovalent binding to each target. Most reported studies utilized transient expression in HEK293 cells to produce BsAbs. However, the expression of biotherapeutic molecules using stable CHO cell lines is commonly used for biopharmaceutical manufacturing. Unfortunately, limited information is available in the scientific literature on the expression of BsAbs in CHO cell lines. In this study we describe an alternative approach to express the multiple components of IgG BsAbs using a single plasmid vector (quad vector). This single plasmid vector contains both heavy chain genes and both light chain genes required for the expression and assembly of the IgG BsAb, along with a selectable marker. We expressed, purified, and characterized four different IgG BsAbs or "hetero-mAbs" using transient CHO expression and stable CHO minipools. Transient CHO titers ranged from 90 to 160 mg/L. Stable CHO titers ranged from 0.4 to 2.3 g/L. Following a simple Protein A purification step, the percentage of correctly paired BsAbs ranged from 74% to 98% as determined by mass spectrometry. We also found that information generated from transient CHO expression was similar to information generated using stable CHO minipools. In conclusion, the quad vector approach represents a simple, but effective, alternative approach for the generation of IgG BsAbs in both transient CHO and stable CHO expression systems. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:469-477, 2017. PMID- 27977916 TI - Spore-displayed enzyme cascade with tunable stoichiometry. AB - Taking the advantages of inert and stable nature of endospores, we developed a biocatalysis platform for multiple enzyme immobilization on Bacillus subtilis spore surface. Among B. subtilis outer coat proteins, CotG mediated a high expression level of Clostridium thermocellum cohesin (CtCoh) with a functional display capability of ~104 molecules per spore of xylose reductase-C. thermocellum dockerin fusion protein (XR-CtDoc). By co-immobilization of phosphite dehydrogenase (PTDH) on spore surface via Ruminococcus flavefaciens cohesin-dockerin modules, regeneration of NADPH was achieved. Both xylose reductase (XR) and PTDH exhibited enhanced stability upon spore surface display. More importantly, by altering the copy numbers of CtCoh and RfCoh fused with CotG, the molar ratio between immobilized enzymes was adjusted in a controllable manner. Optimization of spore-displayed XR/PTDH stoichiometry resulted in increased yields of xylitol. In conclusion, endospore surface display presents a novel approach for enzyme cascade immobilization with improved stability and tunable stoichiometry. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:383-389, 2017. PMID- 27977917 TI - Chemically Homogeneous and Thermally Robust Ni1-xPtxSi Film Formed Under a Non Equilibrium Melting/Quenching Condition. AB - To synthesize a thermally robust Ni1-xPtxSi film suitable for ultrashallow junctions in advanced metal-oxide-semiconductor field-effect transistors, we used a continuous laser beam to carry out millisecond annealing (MSA) on a preformed Ni-rich silicide film at a local surface temperature above 1000 degrees C while heating the substrate to initiate a phase transition. The melting and quenching process by this unique high-temperature MSA process formed a Ni1-xPtxSi film with homogeneous Pt distribution across the entire film thickness. After additional substantial thermal treatment up to 800 degrees C, the noble Ni1-xPtxSi film maintained a low-resistive phase without agglomeration and even exhibited interface flattening with the underlying Si substrate. PMID- 27977918 TI - Fundamental Pathways for the Adsorption and Transport of Hydrogen on TiO2 Surfaces: Origin for Effective Sensing at about Room Temperature. AB - Effective detection of hydrogen at lowered temperature is highly desirable in promoting safety in using this abundant gas as a clean energy source. Through first-principle calculations in the framework of density functional theory, we find that the high-energy (002) surface for rutile TiO2 is significantly more effective in adsorbing hydrogen atoms through dissociating hydrogen molecules. The pathways for the dissociation of hydrogen molecules and sequential migration of hydrogen atoms are identified through searching along various transitional states. Pathways of low potential barriers indicate promise for hydrogen sensing, even close to room temperature. This has been proven through sensors made of thin films of well-aligned rutile nanorods, wherein the high-energy (002) surface dictates the top surface of the active layer of the sensors. PMID- 27977919 TI - High-Performance Aluminum-Ion Battery with CuS@C Microsphere Composite Cathode. AB - On the basis of low-cost, rich resources, and safety performance, aluminum-ion batteries have been regarded as a promising candidate for next-generation energy storage batteries in large-scale energy applications. A rechargeable aluminum-ion battery has been fabricated based on a 3D hierarchical copper sulfide (CuS) microsphere composed of nanoflakes as cathode material and room-temperature ionic liquid containing AlCl3 and 1-ethyl-3-methylimidazolium chloride ([EMIm]Cl) as electrolyte. The aluminum-ion battery with a microsphere electrode exhibits a high average discharge voltage of ~1.0 V vs Al/AlCl4-, reversible specific capacity of about 90 mA h g-1 at 20 mA g-1, and good cyclability of nearly 100% Coulombic efficiency after 100 cycles. Such remarkable electrochemical performance is attributed to the well-defined nanostructure of the cathode material facilitating the electron and ion transfer, especially for chloroaluminate ions with large size, which is desirable for aluminum-ion battery applications. PMID- 27977920 TI - Protonation Dependent Topological Dichotomy of Core Modified Hexaphyrins: Synthesis, Characterization, and Excited State Dynamics. AB - Two hitherto unknown core modified hexaphyrin analogues have been synthesized and characterized where the conformational dynamics of these macrocycles in the free base form is achieved by the rotation of thienothiophene units. Further unique property of these macrocycles is the Huckel-Mobius topological switching. The thermodynamic equilibrium and kinetics of the interconversion leading to Huckel Mobius switches have been triggered by external stimuli, such as protonation and/or temperature. We have provided a thorough solution-state spectroscopic characterization, solid-state structural evidence combined with in-depth theoretical calculations to investigate the crucial factors involved in such interconversion between Huckel and Mobius topologies for these hexaphyrins which will be useful in designing future new members to expanded porphyrin chemistry. PMID- 27977921 TI - Solvent Effects on the Structure-Property Relationship of Redox-Active Self Assembled Nanoparticle-Polyelectrolyte-Surfactant Composite Thin Films: Implications for the Generation of Bioelectrocatalytic Signals in Enzyme Containing Assemblies. AB - The search for strategies to improve the performance of bioelectrochemical platforms based on supramolecular materials has received increasing attention within the materials science community, where the main objective is to develop low-cost and flexible routes using self-assembly as a key enabling process. Important contributions to the performance of such bioelectrochemical devices have been made based on the integration and supramolecular organization of redox active polyelectrolyte-surfactant complexes on electrode supports. Here, we examine the influence of the processing solvent on the interplay between the supramolecular mesoorganization and the bioelectrochemical properties of redox active self-assembled nanoparticle-polyelectrolyte-surfactant nanocomposite thin films. Our studies reveal that the solvent used in processing the supramolecular films and the presence of metal nanoparticles not only have a substantial influence in determining the mesoscale organization and morphological characteristics of the film but also have a strong influence on the efficiency and performance of the bioelectrochemical system. In particular, a higher bioelectrochemical response is observed when nanocomposite supramolecular films were cast from aqueous solutions. These observations seem to be associated with the fact that the use of aqueous solvents increases the hydrophilicity of the film, thus favoring the access of glucose, particularly at low concentrations. We believe that these results improve our current understanding of supramolecular nanocomposite materials generated via polyelectrolyte-surfactant complexes, in order to use the processing conditions as a variable to improve the performance of bioelectrochemical devices. PMID- 27977922 TI - Proteome Analysis Is a Valuable Tool to Monitor Antigen Expression during Upstream Processing of Whole-Cell Pertussis Vaccines. AB - Physicochemical and immunochemical assays were applied to substantiate the relation between upstream processing and the quality of whole-cell pertussis vaccines. Bordetella pertussis bacteria were cultured on a chemically defined medium using a continuous cultivation process in stirred tank reactors to obtain uniform protein expression. Continuous culture favors the consistent production of proteins known as virulence factors. Magnesium sulfate was added during the steady state of the culture in order to diminish the expression of virulence proteins. Changes in gene expression and antigen composition were measured by microarrays, mass spectrometry and ELISA. Transcriptome and proteome data revealed high similarity between the biological triplicates demonstrating consistent cultivation of B. pertussis. The addition of magnesium sulfate resulted in an instant downregulation of the virulence genes in B. pertussis, but a gradual decrease of virulence proteins. The quantity of virulence proteins concurred highly with the potency of the corresponding whole-cell pertussis vaccines, which were determined by the Kendrick test. In conclusion, proteome analysis provided detailed information on the composition and proportion of virulence proteins present in the whole-cell preparations of B. pertussis. Moreover, proteome analysis is a valuable method to monitor the production process of whole-cell biomass and predict the product quality of whole-cell pertussis vaccines. PMID- 27977924 TI - High-Mobility Transport Anisotropy in Few-Layer MoO3 and Its Origin. AB - The novel two-dimensional semiconductors with high carrier mobility and excellent stability are essential to the next-generation high-speed and low-power nanoelectronic devices. Because of the natural abundance, intrinsic gap, and chemical stability, metal oxides were also recently suggested as potential candidates for electronic materials. However, their carrier mobilities are typically on the order of tens of square centimeters per volt per second, much lower than that for commonly used silicon. By using first-principles calculations and deformation potential theory, we have predicted few-layer MoO3 as chemically stable wide-band-gap semiconductors with a considerably high acoustic-phonon limited carrier mobility above 3000 cm2 V-1 s-1, which makes them promising candidates for both electron- and hole-transport applications. Moreover, we also find a large in-plane anisotropy of the carrier mobility with a ratio of about 20 30 in this unusual system. Further analysis indicates that, because of the unique charge density distribution of whole valence electrons and the states near the band edge, both the elastic modulus and deformation potential are strongly directionally dependent. Also, the predicted high-mobility transport anisotropy of few-layer MoO3 can be attributed to the synergistic effect of the anisotropy of the elastic modulus and deformation potential. Our results not only give an insightful understanding for the high carrier mobility observed in few-layer MoO3 systems but also reveal the importance of the carrier-transport direction to the device performance. PMID- 27977923 TI - Stereodivergent Allylic Substitutions with Aryl Acetic Acid Esters by Synergistic Iridium and Lewis Base Catalysis. AB - The preparation of all possible stereoisomers of a given chiral molecule bearing multiple stereocenters by a simple and unified method is a significant challenge in asymmetric catalysis. We report stereodivergent allylic substitutions with aryl acetic acid esters catalyzed synergistically by a metallacyclic iridium complex and benzotetramisole. Through permutations of the enantiomers of the two chiral catalysts, all four stereoisomers of the products bearing two adjacent stereocenters are accessible with high diastereoselectivity and enantioselectivity. The resulting chiral activated ester products can be converted readily to enantioenriched amides, unactivated esters, and carboxylic acids in a one-pot manner. PMID- 27977925 TI - Atomic Layer Deposition of In2O3:H from InCp and H2O/O2: Microstructure and Isotope Labeling Studies. AB - The atomic layer deposition (ALD) process of hydrogen-doped indium oxide (In2O3:H) using indium cyclopentadienyl (InCp) and both O2 and H2O as precursors is highly promising for the preparation of transparent conductive oxides. It yields a high growth per cycle (>0.1 nm), is viable at temperatures as low as 100 degrees C, and provides a record optoelectronic quality after postdeposition crystallization of the films ( ACS Appl. Mat. Interfaces , 2015 , 7 , 16723 - 16729 , DOI: 10.1021/acsami.5b04420 ) . Since both the dopant incorporation and the film microstructure play a key role in determining the optoelectronic properties, both the crystal growth and the incorporation of the hydrogen dopant during this ALD process are studied in this work. This has been done using transmission electron microscopy (TEM) and atom probe tomography (APT) in combination with deuterium isotope labeling. TEM studies show that an amorphous to-crystalline phase transition occurs in the low-temperature regime (100-150 degrees C), which is accompanied by a strong decrease in carrier density and an increase in carrier mobility. At higher deposition temperatures (>200 degrees C), enhanced nucleation of crystals and the incorporation of carbon impurities lead to a reduced grain size and even an amorphous phase, respectively, resulting in a strong reduction in carrier mobility. APT studies on films grown with deuterated water show that the incorporated hydrogen mainly originates from the coreactant and not from the InCp precursor. In addition, it was established that the incorporation of hydrogen decreased from ~4 atom % for amorphous growth to ~2 atom % after the transition to crystalline film growth. PMID- 27977926 TI - Dynamic Rotating Liquid Marble for Directional and Enhanced Mass Transportation in Three-Dimensional Microliter Droplets. AB - The ability of an artificial microdroplet to mimic the rotational behaviors of living systems is crucial for dynamic mass transportation but remains challenging to date. Herein, we report dynamic microdroplet rotation using a liquid marble (RLM) and achieve precise control over mass transportation and distribution in a three-dimensional (3D) microdroplet. RLM rotates synchronously with an external magnetic field, creating circular hydrodynamic flow and an outward centrifugal force. Such spin-induced phenomena direct a spiral movement of entrapped molecules and accelerate their diffusion and homogenization in the entire liquid. Moreover, we demonstrate the rotation rate-controlled (between 0 and 1300 rpm) modulation of shell-catalyzed reaction kinetics from 0.13 to 0.62 min-1. The directed acceleration of reactants toward a catalytically active shell surface is 3-fold faster than conventional stir bar-based convective flow. RLM as an efficient magnetohydrodynamics transducer will be valuable for dynamical control over mass transportation in microdroplet-based chemical, biological, and biomedical studies. PMID- 27977927 TI - Hydration Effects Turn a Highly Stretched Polymer from an Entropic into an Energetic Spring. AB - Polyethylene glycol (PEG) is a structurally simple and nontoxic water-soluble polymer that is widely used in medical and pharmaceutical applications as molecular linker and spacer. In such applications, PEG's elastic response against conformational deformations is key to its function. According to text-book knowledge, a polymer reacts to the stretching of its end-to-end separation by a decrease in entropy that is due to the reduction of available conformations, which is why polymers are commonly called entropic springs. By a combination of single-molecule force spectroscopy experiments with molecular dynamics simulations in explicit water, we show that entropic hydration effects almost exactly compensate the chain conformational entropy loss at high stretching. Our simulations reveal that this entropic compensation is due to the stretching induced release of water molecules that in the relaxed state form double hydrogen bonds with PEG. As a consequence, the stretching response of PEG is predominantly of energetic, not of entropic, origin at high forces and caused by hydration effects, while PEG backbone deformations only play a minor role. These findings demonstrate the importance of hydration for the mechanics of macromolecules and constitute a case example that sheds light on the antagonistic interplay of conformational and hydration degrees of freedom. PMID- 27977929 TI - Chiral Rhodium(III) Complex-Catalyzed Cascade Michael-Alkylation Reactions: Enantioselective Synthesis of Cyclopropanes. AB - Chiral Rh(III) complex catalyzed highly efficient enantioselective cyclopropanation of alpha,beta-unsaturated 2-acyl imidazoles or pyridine with 2 bromomalonate is developed to generate corresponding multisubstituted cyclopropanes in 70-99% yields with 93->99% enantioselectivity. The proficiency of the process is also demonstrated in gram scale reaction maintaining same reactivity and selectivity level in lower catalyst loading. Moreover, the developed methodology is applicable in challenging synthesis of biscyclopropane scaffold with 97% ee in a single operation. PMID- 27977928 TI - Etching and Chemical Control of the Silicon Nitride Surface. AB - Silicon nitride is used for many technological applications, but a quantitative knowledge of its surface chemistry is still lacking. Native oxynitride at the surface is generally removed using fluorinated etchants, but the chemical composition of surfaces still needs to be determined. In this work, the thinning (etching efficiency) of the layers after treatments in HF and NH4F solutions has been followed by using spectroscopic ellipsometry. A quantitative estimation of the chemical bonds found on the surface is obtained by a combination of infrared absorption spectroscopy in ATR mode, X-ray photoelectron spectroscopy, and colorimetry. Si-F bonds are the majority species present at the surface after silicon nitride etching; some Si-OH and a few Si-NHx bonds are also present. No Si-H bonds are present, an unfavorable feature for surface functionalization in view of the interest of such mildly reactive groups for achieving stable covalent grafting. Mechanisms are described to support the experimental results, and two methods are proposed for generating surface SiH species: enriching the material in silicon, or submitting the etched surface to a H2 plasma treatment. PMID- 27977930 TI - Role of Atomic Layer Functionalization in Building Scalable Bottom-Up Assembly of Ultra-Low Density Multifunctional Three-Dimensional Nanostructures. AB - Building three-dimensional (3D) structures from their constituent zero-, one-, and two-dimensional nanoscale building blocks in a bottom-up assembly is considered the holey grail of nanotechnology. However, fabricating such 3D nanostructures at ambient conditions still remains a challenge. Here, we demonstrate an easily scalable facile method to fabricate 3D nanostructures made up of entirely zero-dimensional silicon dioxide (SiO2) nanoparticles. By combining functional groups and vacuum filtration, we fabricate lightweight and highly structural stable 3D SiO2 materials. Further synergistic effect of material is shown by addition of a 2D material, graphene oxide (GO) as reinforcement which results in 15-fold increase in stiffness. Molecular dynamics (MD) simulations are used to understand the interaction between silane functional groups (3-aminopropyl triethoxysilane) and SiO2 nanoparticles thus confirming the reinforcement capability of GO. In addition, the material is stable under high temperature and offers a cost-effective alternative to both fire-retardant and oil absorption materials. PMID- 27977931 TI - Fluorinated Graphene Enables the Growth of Inorganic Thin Films by Chemical Bath Deposition on Otherwise Inert Substrates. AB - Chemically modified graphenes (CMGs) offer a means to tune a wide variety of graphene's exceptional properties. Critically, CMGs can be transferred onto a variety of substrates, thereby imparting functionalities to those substrates that would not be obtainable through conventional functionalization. One such application of CMGs is enabling and controlling the subsequent growth of inorganic thin films. In the current study, we demonstrated that CMGs enhance the growth of inorganic films on inert surfaces with poor growth properties. Fluorinated graphene transferred onto polyethylene enabled the dense and homogeneous deposition of a cadmium sulfide (CdS) film grown via chemical bath deposition. We showed that the coverage of the CdS film can be controlled by the degree of fluorination from less than 20% to complete coverage of the film. The approach can also be applied to other technologically important materials such as ZnO. Finally, we demonstrated that electron beam-generated plasma in a SF6 containing background could pattern fluorine onto a graphene/PE sample to selectively grow CdS films on the fluorinated region. Therefore, CMG coatings can tailor the surface properties of polymers and control the growth of inorganic thin films on polymers for the development of flexible electronics. PMID- 27977932 TI - Efficient Third Harmonic Generation and Nonlinear Subwavelength Imaging at a Higher-Order Anapole Mode in a Single Germanium Nanodisk. AB - Benefiting from large intrinsic nonlinearities, low absorption, and high field enhancement abilities, all-dielectric nanoantennas are considered essential for efficient nonlinear processes at subwavelength volumes. In particular, when the dielectric nanoantenna supports the nonradiating anapole mode, characterized by a minimum in the extinction cross section and a maximum electric energy within the material, third harmonic generation (THG) processes can be greatly enhanced. In this work, we demonstrate that a higher-order anapole mode in a 200 nm thick germanium nanodisk delivers the highest THG efficiency on the nanoscale at optical frequencies. By doubling the diameter of a disk supporting the fundamental anapole mode, we discover the emergence of an anapole mode of higher order, with a valley in the extinction cross section significantly narrower than that of the fundamental anapole. Under this condition, we observe a highly improved electric field confinement effect within the dielectric disk, leading to THG conversion efficiencies as large as 0.001% at a third harmonic wavelength of 550 nm. In addition, by mapping the THG emission across the nanodisk, we are able to unveil the anapole near-field intensity distributions, which show excellent agreement with numerical simulations. Our findings remarkably expand contemporary knowledge on localized modes in dielectric nanosystems, revealing crucial elements for the elaboration of highly efficient frequency upconversion nanodevices. PMID- 27977934 TI - Longer-term safety and tolerability of canagliflozin in patients with type 2 diabetes: a pooled analysis. AB - OBJECTIVE: To evaluate the longer-term safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS: The safety/tolerability of canagliflozin 100 and 300 mg were assessed using data pooled from seven placebo- and active-controlled studies of 52-104 weeks in duration that enrolled a broad range of patients with T2DM (N = 5598). Canagliflozin 100 and 300 mg as monotherapy or in combination with various background antihyperglycemic agents (AHAs) were compared with pooled non canagliflozin treatments (i.e. placebo, sitagliptin, glimepiride). Safety was assessed based on adverse event (AE) reports, including the incidence of AEs related to the mechanism of SGLT2 inhibition. RESULTS: Overall AE incidence was similar with canagliflozin 100 and 300 mg and non-canagliflozin (73.7%, 74.5%, and 73.7%). The incidence of AE-related discontinuations and serious AEs was low and balanced across groups. The incidence of male and female genital mycotic infections, urinary tract infections, and AEs related to osmotic diuresis or volume depletion was higher with canagliflozin versus non-canagliflozin; these AEs generally occurred early with decreased incidence over time and incidence was similar across baseline HbA1c subgroups. The incidence of fractures and diabetic ketoacidosis was low and similar across groups. Canagliflozin was associated with a low incidence of hypoglycemia when used with background AHAs that are not associated with hypoglycemia; the incidence was higher among patients on background AHAs associated with hypoglycemia (i.e. insulin, sulfonylurea, glinide). LIMITATIONS: Limitations of this analysis include its post hoc nature. While this analysis included a broad population of patients, including those with a history or risk of cardiovascular disease or chronic kidney disease, the longer term safety in these patient populations was not specifically evaluated. Ongoing outcome studies will provide data on the long-term safety of canagliflozin in these populations. CONCLUSIONS: Longer-term exposure to canagliflozin as monotherapy or in combination with other agents was generally well tolerated in patients with T2DM. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01106625, NCT01081834, NCT01106677, NCT00968812, NCT01106651, NCT01106690, NCT01137812. PMID- 27977933 TI - Influence of the Gastrointestinal Environment on the Bioavailability of Ethinyl Estradiol Sorbed to Single-Walled Carbon Nanotubes. AB - Recent evidence suggests that, because of their sorptive nature, if single-walled carbon nanotubes (SWCNTs) make their way into aquatic environments, they may reduce the toxicity of other waterborne contaminants. However, few studies have examined whether contaminants remain adsorbed following ingestion by aquatic organisms. The objective of this study was to examine the bioavailability and bioactivity of ethinyl estradiol (EE2) sorbed onto SWCNTs in a fish gastrointestinal (GI) tract. Sorption experiments indicated that SWCNTs effectively adsorbed EE2, but the chemical was still able to bind and activate soluble estrogen receptors (ERs) in vitro. However, centrifugation to remove SWCNTs and adsorbed EE2 significantly reduced ER activity compared to that of EE2 alone. Additionally, the presence of SWCNTs did not reduce the extent of EE2 driven induction of vitellogenin 1 in vivo compared to the levels in organisms exposed to EE2 alone. These results suggest that while SWCNTs adsorb EE2 from aqueous solutions, under biological conditions EE2 can desorb and retain bioactivity. Additional results indicate that interactions with gastrointestinal proteins may decrease the level of adsorption of estrogen to SWCNTs by 5%. This study presents valuable data for elucidating how SWCNTs interact with chemicals that are already present in our aquatic environments, which is essential for determining their potential health risk. PMID- 27977935 TI - Emergence of Novel Pathogenic Streptomyces Species by Site-Specific Accretion and cis-Mobilization of Pathogenicity Islands. AB - The main pathogenicity factor of Streptomyces species associated with the potato common scab disease is a nitrated diketopiperazine called thaxtomin A (ThxA). In Streptomyces scabiei (syn. S. scabies), which is thought to be the most ancient pathogenic Streptomyces species, the ThxA biosynthetic cluster is located within a mobile genomic island called the toxicogenic region (TR). Three attachment (att) sites further separate TR into two subregions (TR1 and TR2). TR1 contains the ThxA biosynthetic cluster and is conserved among several pathogenic Streptomyces species. However, TR2, an integrative and conjugative element, is missing in most pathogenic species. In our previous study, we demonstrated the mobilization of the whole TR element or TR2 alone between S. scabiei and nonpathogenic Streptomyces species. TR1 alone did not mobilize in these experiments. These data suggest that TR2 is required for the mobilization of TR1. Here, we show that TR2 can self mobilize to pathogenic Streptomyces species harboring only TR1 and integrate into the att site of TR1, leading to the tandem accretion of resident TR1 and incoming TR2. The incoming TR2 can further mobilize resident TR1 in cis and transfer to a new recipient cell. Our study demonstrated that TR1 is a nonautonomous cis-mobilizable element and that it can hijack TR2 recombination and conjugation machinery to excise, transfer, and integrate, leading to the dissemination of pathogenicity genes and emergence of novel pathogenic species. Additionally, comparative genomic analysis of 23 pathogenic Streptomyces isolates from ten species revealed that the composite pathogenicity island (PAI) formed by TR1 and TR2 is dynamic and various compositions of the island exist within the population of newly emerged pathogenic species, indicating the structural instability of this composite PAI. PMID- 27977937 TI - The long and winding road to inhaled TB therapy: not only the bug's fault. AB - Not all of the issues impacting the success of tuberculosis (TB) treatment arise from pathogen-related disease characteristics. Nowadays, there is an increasing awareness that antibiotic treatment is not the only answer to the TB problem, promoting the search for alternative administration strategies and host-directed therapies. Among all the administration routes, being the lungs the main TB focus, inhalation is conceptually a logical solution to enhance treatment effectiveness and compliance. Nevertheless, research efforts and funding are almost entirely conveyed to conventional approaches. This review will critically evaluate the reasons constraining research in this field, providing some future perspectives. The most recent advances in inhalation approaches for TB will be discussed, either at the preclinical or clinical phase, illustrating the risk of failure and chances of success. PMID- 27977936 TI - Potent inhibition of human organic cation transporter 2 (hOCT2) by beta-carboline alkaloids. AB - 1. Beta-carbolines are indole alkaloids with a wide range of pharmacological and toxicological activities. Beta-carbolines are structurally related to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), a known substrate of organic cation transporters (OCTs). The goal of this study is to determine the interaction of beta-carbolines with human OCT1, 2, and 3 (SLC22A1-3). 2. Dose dependent inhibition studies were performed for five commercially available beta carbolines using a fluorescent substrate assay in HEK293 cells stably expressing hOCT1-3. The substrate potential was evaluated by uptake assays and the impact of active transport on cellular toxicity examined. 3. All tested beta-carbolines potently inhibited hOCT2 with IC50 values in the sub- or low micromolar range. Harmaline is the most potent hOCT2 inhibitor (IC50 = 0.50 +/- 0.08 MUM). hOCT1 and hOCT3 are less sensitive to beta-carboline inhibition. Harmaline, norharmanium, and 2,9-dimethyl-4,9-dihydro-3H-beta-carbolinium accumulated 2- to 7-fold higher in cells expressing hOCT1-3. HEK293 cells expressing hOCT1-3 were 6.5- to 13-fold more sensitive to harmane and norharmanium toxicity. 4. Our data support a significant role of hOCT1-3 in tissue uptake and disposition of beta carbolines. Importantly, the potent inhibition of hOCT2 by beta-carbolines also raises the concern of potential drug interactions between naturally occurring bioactive alkaloids and drugs eliminated by hOCT2. PMID- 27978407 TI - Community Perspectives on Access to and Availability of Healthy Food in Rural, Low-Resource, Latino Communities. AB - INTRODUCTION: Attention has focused on the food environment as a result of the growing concern with obesity rates among Latinos in rural areas. Researchers have observed associations between a lack of physical access to affordable produce in areas where supermarkets and grocery stores are limited and poor dietary intake and obesity; these associations are high in rural, low-resource neighborhoods with a high population of Latino residents. We aimed to engage residents of low resource, Latino-majority neighborhoods in discussions of food access in a rural yet agricultural community setting, which is typically described as a "food desert." METHODS: We used a mixed-methods approach and conducted 3 focus groups (n = 20) and in-depth interviews (n = 59) and surveys (n = 79) with residents of a rural yet agricultural community. We used thematic analysis to explore residents' perceptions of access to healthy foods. RESULTS: Residents (n = 79; mean age, 41.6 y; 72% female; 79% Latino; 53% Spanish-speaking) reported that dollar and discount stores in this agricultural area provided access to produce; however, produce at retail stores was less affordable than produce at nonretail outlets such as fruit and vegetable stands. Gifts and trades of fruits and vegetables from neighbors and community organizations supplied no-cost or low cost healthy foods. Residents' suggestions to improve food access centered on lowering the cost of produce in existing retail outlets and seeking out nonretail outlets. CONCLUSION: Our findings contribute to understanding of the food environment in low-resource, rural yet agricultural areas. Although such areas are characterized as "food deserts," residents identified nonretail outlets as a viable source of affordable produce, while indicating that the cost of retail produce was a concern. Innovative policy solutions to increase healthy food consumption must focus on affordability as well as accessibility, and consider alternate, nonretail food outlets in agricultural areas. PMID- 27978408 TI - Differences in Food and Beverage Marketing Policies and Practices in US School Districts, by Demographic Characteristics of School Districts, 2012. AB - INTRODUCTION: Foods and beverages marketed in schools are typically of poor nutritional value. School districts may adopt policies and practices to restrict marketing of unhealthful foods and to promote healthful choices. Students' exposure to marketing practices differ by school demographics, but these differences have not yet been examined by district characteristics. METHODS: We analyzed data from the 2012 School Health Policies and Practices Study to examine how food and beverage marketing and promotion policies and practices varied by district characteristics such as metropolitan status, size, and percentage of non Hispanic white students. RESULTS: Most practices varied significantly by district size: a higher percentage of large districts than small or medium-sized districts restricted marketing of unhealthful foods and promoted healthful options. Compared with districts whose student populations were majority (>50%) non Hispanic white, a higher percentage of districts whose student populations were minority non-Hispanic white (<=50% non-Hispanic white) prohibited advertising of soft drinks in school buildings and on school grounds, made school meal menus available to students, and provided families with information on school nutrition programs. Compared with suburban and rural districts, a higher percentage of urban districts prohibited the sale of soft drinks on school grounds and used several practices to promote healthful options. CONCLUSION: Preliminary findings showing significant associations between district demographics and marketing policies and practices can be used to help states direct resources, training, and technical assistance to address food and beverage marketing and promotion to districts most in need of improvement. PMID- 27978409 TI - Pathways to Health: Association Between Trail Use, Weight Status, and Self-Rated Health Among Adults in Greenville County, South Carolina, 2014. AB - We examined associations between adults' use of a prominent rail-trail and their weight status and self-rated health. In 2014, a random-digit-dial survey of Greenville County, South Carolina, residents (n = 639) was used to collect data on trail use, height and weight, self-rated health, and demographics. Trail users were half as likely to be overweight or obese as trail nonusers (odds ratio [OR] = 0.56; 95% confidence interval [CI], 0.33-0.95). Similarly, trail users were significantly more likely to report high self-rated health than were trail nonusers (OR = 1.83; 95% CI, 1.13-2.97). Findings suggest that trail use is associated with healthier weight status and higher self-rated health and supports the development, maintenance, and promotion of trail resources. PMID- 27978410 TI - Influences and Practices in Colorectal Cancer Screening Among Health Care Providers Serving Northern Plains American Indians, 2011-2012. AB - INTRODUCTION: The epidemiology of colorectal cancer, including incidence, mortality, age of onset, stage of diagnosis, and screening, varies regionally among American Indians. The objective of the Improving Northern Plains American Indian Colorectal Cancer Screening study was to improve understanding of colorectal cancer screening among health care providers serving Northern Plains American Indians. METHODS: Data were collected, in person, from a sample of 145 health care providers at 27 health clinics across the Northern Plains from May 2011 through September 2012. Participants completed a 32-question, self administered assessment designed to assess provider practices, screening perceptions, and knowledge. RESULTS: The proportion of providers who ordered or performed at least 1 colorectal cancer screening test for an asymptomatic, average-risk patient in the previous month was 95.9% (139 of 145). Of these 139 providers, 97.1% ordered colonoscopies, 12.9% ordered flexible sigmoidoscopies, 73.4% ordered 3-card, guaiac-based, fecal occult blood tests, and 21.6% ordered fecal immunochemical tests. Nearly two-thirds (64.7%) reported performing in office guaiac-based fecal occult blood tests using digital rectal examination specimens. Providers who reported receiving a formal update on colorectal cancer screening during the previous 24 months were more likely to screen using digital rectal exam specimens than providers who had received a formal update on colorectal cancer screening more than 24 months prior (73.9% vs 56.9%, respectively, chi2 = 4.29, P = .04). CONCLUSION: Despite recommendations cautioning against the use of digital rectal examination specimens for colorectal cancer screening, the practice is common among providers serving Northern Plains American Indian populations. Accurate up-to-date, ongoing education for patients, the community, and health care providers is needed. PMID- 27978411 TI - Comparative Analysis of Five Observational Audit Tools to Assess the Physical Environment of Parks for Physical Activity, 2016. AB - We reviewed prominent audit tools used to assess the physical environment of parks and their potential to promote physical activity. To accomplish this, we manually searched the Active Living Research website (http://www.activelivingresearch.com) for published observational audit tools that evaluate the physical environment of parks, and we reviewed park audit tools used in studies included in a systematic review of observational park-based physical activity studies. We identified 5 observational audit tools for review: Bedimo-Rung Assessment Tool-Direct Observation (BRAT-DO), Community Park Audit Tool (CPAT), Environmental Assessment of Public Recreation Spaces (EAPRS) tool, Physical Activity Resource Assessment (PARA), and Quality of Public Open Space Tool (POST). All 5 tools have established inter-rater reliability estimates ranging from moderate to good. However, BRAT-DO is the only tool with published validity. We found substantial heterogeneity among the 5 in length, format, intended users, and specific items assessed. Researchers, practitioners, or community coalition members should review the goal of their specific project and match their goal with the most appropriate tool and the people who will be using it. PMID- 27978412 TI - The Potential Role of Melatonin on Memory Function: Lessons from Rodent Studies. AB - Pineal melatonin biosynthesis is regulated by the circadian clock located in the suprachiasmatic nucleus of the hypothalamus. Melatonin has been found to modulate the learning and memory process in human as well as in animals. Endogenous melatonin modulates the process of newly acquired information into long-term memory, while melatonin treatment has been found to reduce memory deficits in elderly people and in various animal models. However, the mechanisms mediating the enhancing effect of melatonin on memory remain elusive. This review intends to explore the possible mechanisms by looking at previous data on the effects of melatonin treatment on memory performance in rodents. PMID- 27978413 TI - Can Leukocyte Telomere Length Predict Survival Time in Heart Transplant Recipients over a Minimal Follow-Up of 20 years? AB - In humans, leukocyte telomere length (LTL) reduces with age and is reported to be inversely associated with ageing-related diseases. We measured LTL in leukocyte DNA using a quantitative PCR-based method from 127 blood samples of heart recipients (107 males, 20 females, age 44.1 +/- 10.5), followed for up to 30 years. Patients with coronary artery disease survived for a shorter time and also had shorter LTL (both P < 0.05 after adjustment for age and sex) than subjects with dilated cardiomyopathy. Patients with non-cardiac causes of death had shorter LTL than patients with cardiac causes (P < 0.05 after adjustment for age). An inverse correlation between LTL and age (P < 0.03) was observed in patients with non-cardiac causes of death only. Most importantly, LTL was not associated with general survival time in patients after heart transplantation. However, shorter LTL was a marker of non-cardiac causes of death. Different LTLs and survival times were determined in association with aetiology of heart failure (HF). PMID- 27978414 TI - IDH1/2 Mutation and MGMT Promoter Methylation - the Relevant Survival Predictors in Czech Patients with Brain Gliomas. AB - Gliomas are a heterogeneous group of tumours varying in prognosis, treatment approach, and overall survival. Recently, novel markers have been identified which are linked to patient prognosis and therapeutic response. Especially the mutation of the enzyme isocitrate dehydrogenase 1 or 2 (IDH1/2) gene and the O6 methylguanine-DNA methyltransferase (MGMT) promoter methylation status seem to be the most important predictors of survival. From 2012 to 2015, 94 Czech patients with primary brain tumours were enrolled into the study. The IDH1/2 mutation was detected by denaturing capillary electrophores.The methylation status of the MGMT gene and other 46 genes was revealed by MS-MLPA. In all 94 patients, the clinical data were correlated with molecular markers by Kaplan-Meier analyses and Cox regression model. The MGMT promoter methylation status was established and compared to clinical data. In our study eight different probes were used to elucidate the MGMT methylation status; hypermethylation was proclaimed if four and more probes were positive. This 3 : 5 ratio was tested and confirmed by Kaplan-Meier and Cox analyses. The study confirmed the importance of the IDH1/2 mutation and hypermethylation of the MGMT gene promoter being present in tumour tissue. Both markers are independent positive survival predictors; in the Cox model the IDH hazard ratio was 0.10 and in the case of MGMT methylation it reached 0.32. The methylation analysis of the panel of additional 46 genes did not reveal any other significant epigenetic markers; none of the candidate genes have been confirmed in the Cox regression analyses as an independent prognostic factor. PMID- 27978415 TI - Detection of Mycoplasma Contamination Directly from Culture Supernatant Using Polymerase Chain Reaction. AB - Ensuring mycoplasma-free cell culture is of prime importance as they severely affect cellular characteristics leading to experimental artefacts and spurious results. Various methods persist for mycoplasma detection; out of the whole array of methods polymerase chain reaction (PCR) is the most favoured one because it is highly sensitive, specific and quick. The PCR-based detection procedure involves three steps: cell culture supernatant collection, DNA isolation, and PCR. We have modified this procedure so that cell culture supernatant can directly be used for PCR without the need for DNA extraction. This modification makes the procedure quicker and more sensitive because loss of mycoplasma DNA is prevented and this loss becomes more significant when the level of mycoplasma contamination is very low. PMID- 27978416 TI - Apoptosis in Endomyocardial Biopsies from Patients with Dilated Cardiomyopathy. AB - Apoptosis is an active energy-consuming mechanism of cell death, which may contribute to heart failure in patients with dilated cardiomyopathy. Dilated cardiomyopathy is a common clinical outcome of many prolonged cardiac insults, and therefore is considered as the most prevalent form of cardiomyopathy. Loss of heart mass is highly correlated with the heart failure and mortality, thus the purpose of this study was to define the apoptotic index in patients with dilated cardiomyopathy. Apoptosis was detected by the TUNEL method in 30 patients. Biopsies were obtained from the left ventricle, and at least three specimens were taken. TUNEL-positive cardiomyocytes were found in 26 of 30 cases (86.7 %) and the mean apoptotic index for the entire specimen series was 5.41 +/- 1.70 %. The analysis showed that patients with dilated cardiomyopathy had significantly higher apoptotic index (P < 0.001) than healthy subjects. One subject (man, 41 years old) had a markedly elevated apoptotic index of 52.2 %. In the remaining subjects, the percentage of cardiomyocyte death ranged from 0 % to 15.5 %. The high percentage of apoptosis found in our study may be in accordance with the clinically manifested cardiac failure in patients with dilated cardiomyopathy since in most patients we recorded the left ventricular ejection fraction values below 30 %. PMID- 27978417 TI - Age-Related (Aged vs. Adult) Comparison of the Effect of Two Mild Stressors on the Nerve Growth Factor (NGF) in the Rat Hypothalamic Supraoptic Nucleus (SON) - Immunohistochemical Study. AB - The ontogenetic period of life and stress can have different effects on the nerve growth factor (NGF) in the hypothalamus. The aim of our study was to investigate the influence of two mild stressors, acute and chronic exposure to forced swim (FS) or high-light open field (HL-OF), on neurons containing NGF. Immunofluorescence staining was used to reveal the density of NGF-immunoreactive (ir) cells in the hypothalamic supraoptic nucleus (SON) in adult (postnatal day 90; P90) and aged (P720) rats. The P90 and P720 rats that were subjected to acute and chronic FS showed no differences in the density of NGF-ir neurons in the SON compared with nonstressed rats. However, a significant increase in NGF-ir cells was noted after acute but not after chronic HL-OF only in P90 rats. What is more, there were no age-related (P90 vs. P720) changes in the density of NGF-ir neurons in non-stressed and FS- or HL-OF-stressed rats. Our results indicate that acute HL-OF was the only factor inducing changes in the density of NGF-ir neurons in the SON of adult rats. This could be related to the neuroprotective role of NGF ir cells in response to acute HL-OF. The absence of age-dependent changes in the density of NGF-ir neurons may indicate that the ageing processes in SON do not generate changes in the NGF immunoreactivity of its neurons. PMID- 27978418 TI - The Potential Beneficial Effects Of Hand And Foot Bathing On Vital Signs In Women With Caesarean Section. AB - PURPOSE: Hand-foot bathing therapy is a simple technique to induce sensations of comfort and relaxation. The aim of this study was to examine the effect of hand and foot bathing therapy on vital signs in women following caesarean section. METHODS: Participants were sixty women with caesarean section. They divided to two groups: (1) study group (n=30, median age=26.67 years, SD=2.04); and, (2) control group (n=30, median age=27.75 years, SD=1.09). Vital signs were measured for 5 minutes before and for 30 minutes after the hand and foot bathing therapy. RESULTS: Pain score, systolic and diastolic blood pressures and heart and breath rates decreased after hand and foot bathing therapy. Differences between before and after therapy were statistically significantly. CONSCLUSIONS: These results indicate that hand and foot bathing therapy might be helpful to restore the vital signs in post-operative patients by decreasing anxiety and psychological stress. PMID- 27978420 TI - Can a clinical senate enhance state-wide clinician engagement? A survey study. AB - Objective Clinician engagement correlates with quality, safety and efficacy outcomes. The aim of the present study was to explore whether a clinical senate model achieves clinical input into system manager and operational health service boards. Methods A mixed-methods survey was undertaken. Participants were current or immediate past members of the Clinical Senate of Western Australia (CS). For the 124 surveys sent out, the response rate was 60%. Results Respondents stated the CS played a role in clinician engagement (95%), contributed to healthcare reform (82%), knowledge of contemporary health issues (92%), feedback to decision makers (82%), clinician networking (94%), debate on important issues (93%), enabled clinicians to work on recommendations to improve health at a state level (87%), contributed to clinician thinking on health reform (88%) and enabled clinicians to share their knowledge (91%). Four major themes emerged in the qualitative analysis: (1) the need for a strong independent clinician forum and voice at a state level; (2) the need to strengthen clinician interactions with operational healthcare boards; (3) a strong belief that clinician engagement strengthened quality and safety outcomes at a state level; and (4) that membership was important and needed to be diverse, multidisciplinary and independent, but structurally representative of clinicians in the state. Conclusion A clinical senate model can facilitate state-wide clinician engagement. What is known about the topic? High levels of clinical engagement foster a culture within healthcare organisations that is associated with the delivery of sustained high-quality, safe and efficient services. This has led to a focus on strategies to optimise clinical engagement in healthcare planning and reform. However, there is limited data exploring how to achieve clinical engagement at a state, rather than local, level within the healthcare system. What does this paper add? This survey study evaluates the effectiveness of the Western Australian clinical senate model in achieving clinical engagement at a state level with regard to the outcomes of quality and safety, planning and reform. The survey findings suggest the clinical senate model is an effective strategy for state-based clinical engagement. What are the implications for practitioners? Clinical engagement is important. It is necessary to have in place strategies that address not only local engagement within a health service, but also system-wide engagement in order to promote quality and safety, planning and reform agendas at a state level. PMID- 27978419 TI - 'Why didn't you write a not-for-cardiopulmonary resuscitation order?' Unexpected death or failure of process? AB - Objective The aim of the present study was to understand the reasons for the delivery of non-beneficial cardiopulmonary resuscitation (CPR) attempts in a tertiary private hospital over 12 months. We determined doctors' expectations of survival after CPR for their patient, whether they had considered a not-for resuscitation (NFR) order and the barriers to completion of NFR orders. Methods Anonymous questionnaires were sent to the doctors primarily responsible for a given patient's care in the hospital within 2 weeks of the unsuccessful CPR attempt. The data were analysed quantitatively where appropriate and qualitatively for themes for open-text responses Results Most doctors surveyed in the present study understood the poor outcome after CPR in the older person. Most doctors had an expectation that their own patient had a poor prognosis and a poor likely predicted outcome after CPR. This implied that the patient's death was neither unexpected nor likely to be reversible. Some doctors considered NFR orders, but multiple barriers to completion were cited, including the family's wishes, being time poor and diffusion or deferral of responsibility. Conclusions It is likely that futile CPR is provided contrary to policy and legal documents relating to end-of-life care, with the potential for harms relating to both patient and family, and members of resuscitation teams. The failure appears to relate to process rather than recognition of poor patient outcome. What is known about the topic? Mandatory CPR has been established in Australian hospitals on the premise that it will save lives. The outcome from in-hospital cardiac arrest has not improved despite significant training and resources. The outcome for those acutely hospitalised patients aged over 80 years has been repeatedly demonstrated to be poor with significant morbidity in the survivors. There is emerging literature on the extent of the delivery of non-beneficial treatments at the end of life, including futile CPR, the recognition of harms incurred by patients, families and members of the resuscitation teams and on the opportunity cost of the inappropriate use of resources. What does this paper add? This is the first study, to our knowledge, that has demonstrated that doctors understood the outcomes for CPR, particularly in those aged 80 years and older, and that failure to recognise poor outcome and prognosis in their own patients is not a barrier to writing NFR orders. What are the implications for practitioners? Recognition of the poor outcomes from CPR for the elderly patient for whom the doctor has a duty of care should result in a discussion with the patients, allowing an exploration of values and expectations of treatment. This would promote shared decision making, which includes the use of CPR. Facilitation of these discussions should be the focus of health service review. PMID- 27978421 TI - Judging arrival times of incoming traffic vehicles is not a prerequisite for safely crossing an intersection: Differential effects of vehicle size and type in passive judgment and active driving tasks. AB - Using a fixed-base driving simulator we compared the effects of the size and type of traffic vehicles (i.e., normal-sized or double-sized cars or motorcycles) approaching an intersection in two different tasks. In the perceptual judgment task, passively moving participants estimated when a traffic vehicle would reach the intersection for actual arrival times (ATs) of 1, 2, or 3s. In line with earlier findings, ATs were generally underestimated, the more so the longer the actual AT. Results revealed that vehicle size affected judgments in particular for the larger actual ATs (2 and 3s), with double-sized vehicles then being judged as arriving earlier than normal-sized vehicles. Vehicle type, on the other hand, affected judgments at the smaller actual ATs (1 and 2s), with cars then being judged as arriving earlier than motorcycles. In the behavioral task participants actively drove the simulator to cross the intersection by passing through a gap in a train of traffic. Analyses of the speed variations observed during the active intersection-crossing task revealed that the size and type of vehicles in the traffic train did not affect driving behavior in the same way as in the AT judgment task. First, effects were considerably smaller, affecting driving behavior only marginally. Second, effects were opposite to expectations based on AT judgments: driver approach speeds were smaller (rather than larger) when confronted with double-sized vehicles as compared to their normal-sized counterparts and when confronted with cars as compared to motorcycles. Finally, the temporality of the effects was different on the two tasks: vehicle size affected driver approach speed in the final stages of approach rather than early on, while vehicle type affected driver approach speed early on rather than later. Overall, we conclude that the active control of approach to the intersection is not based on successive judgments of traffic vehicle arrival times. These results thereby question the general belief that arrival time estimates are crucial for safe interaction with traffic. PMID- 27978422 TI - The distinctive role of executive functions in implicit emotion regulation. AB - Several theoretical models stress the role of executive functions in emotion regulation (ER). However, most of the previous studies on ER employed explicit regulatory strategies that could have engaged executive functions, beyond regulatory processes per se. Recently, there has been renewed interest in implicit forms of ER, believed to be closer to daily-life requirements. While various studies have shown that implicit and explicit ER engage partially overlapping neurocognitive processes, the contribution of different executive functions in implicit ER has not been investigated. In the present study, we presented participants with negatively valenced pictures of varying emotional intensity preceded by short texts describing them as either fictional or real. This manipulation was meant to induce a spontaneous emotional down-regulation. We recorded electrodermal activity (EDA) and subjective reports of emotion arousal. Executive functions (updating, switching, and inhibition) were also assessed. No difference was found between the fictional and real condition on EDA. A diminished self-reported arousal was observed, however, when pictures were described as fictional for high- and mild-intensity material, but not for neutral material. The amount of down-regulation in the fictional condition was found to be predicted by interindividual variability in updating performances, but not by the other measures of executive functions, suggesting its implication even in implicit forms of ER. The relationship between down-regulation and updating was significant only for high-intensity material. We discuss the role of updating in relation to the consciousness of one's emotional state. PMID- 27978423 TI - Addressing the Unique Needs of an Electronic Health Record in a Neonatal Intensive Care Unit. AB - Documentation in an electronic health record (EHR) should match the nurse workflow for unique patient populations and their correlated units, but pros and cons exist with such EHR customization. Integration of our NICU EHR with other units was a complex process that required nurses to customize each patient record because neonates have specific care needs. We present concepts related to EHR customization that are applicable to any unit with a unique patient population. PMID- 27978425 TI - Moving the house party to the lab: A call for experimental studies on drinking games. PMID- 27978424 TI - The role of perceived injunctive alcohol norms in adolescent drinking behavior. AB - Peers have a major influence on youth during adolescence, and perceptions about peer alcohol use (perceived norms) are often associated with personal drinking behavior among youth. Most of the research on perceived norms among adolescents focuses on perceived descriptive norms only, or perceptions about peers' behavior, and correcting these perceptions are a major focus of many prevention programs with adolescents. In contrast, perceived injunctive norms, which are personal perceptions about peers' attitudes regarding the acceptability of behaviors, have been minimally examined in the adolescent drinking literature. Yet correcting perceptions about these perceived peer attitudes may be an important component to include in prevention programs with youth. Using a sample of 2493 high school-aged youth (mean age=17.3), we assessed drinking behavior (past year use; past month frequency, quantity, and peak drinks), drinking consequences, and perceived descriptive and injunctive norms to examine the relationships of perceived injunctive and descriptive norms on adolescent drinking behavior. Findings indicated that although perceived descriptive norms were associated with some drinking outcomes (past year use; past month frequency; past month quantity; peak drinks), perceived injunctive norms were associated with all drinking outcomes, including outcomes of consequences, even after controlling for perceived descriptive norms. Findings suggest that consideration of perceived injunctive norms may be important in models of adolescent drinking. Prevention programs that do not include injunctive norms feedback may miss an important opportunity to enhance effectiveness of such prevention programs targeting adolescent alcohol use. PMID- 27978427 TI - Microbial Modulation of a Uremic Toxin. AB - In this issue of Cell Host & Microbe, Devlin et al. (2016) identify a family of tryptophanases encoded by members of the human gut microbiome and demonstrate that levels of the uremic toxin indoxyl sulfate can be modulated in vivo by altering the abundance of bacteria harboring tryptophanase activity. PMID- 27978428 TI - Pore-Forming Toxins Trigger the Purge. AB - The intestinal epithelium responds to pathogens by coordinating microbial elimination with tissue repair, both required to survive an infection. In this issue of Cell Host & Microbe, Lee et al. (2016) discover a rapid and evolutionarily conserved response to pore-forming toxins in the gut, involving cytoplasm ejection and enterocyte regrowth. PMID- 27978429 TI - DAPK1 Keeps the Peace in Antifungal Inflammation. AB - Unabated inflammation and impaired antifungal immunity underlie genetic defects in NOX-2-dependent activation of LC3-associated phagocytosis (LAP). In this issue of Cell Host & Microbe, Oikonomou et al. (2016) identify a molecular link between IFN-gamma/DAPK1 signaling, the proteosomal degradation pathway, and LAP that is critical for dampening Aspergillus-triggered immunopathology. PMID- 27978426 TI - PNF 2.0? Initial evidence that gamification can increase the efficacy of brief, web-based personalized normative feedback alcohol interventions. AB - Gamified interventions exploit the motivational characteristics of a game in order to provide prevention information and promote behavior change. Despite the modest effect sizes observed in increasingly popular web-based personalized normative feedback (PNF) alcohol interventions for college students, previous research has yet to consider how gamification might be used to enhance efficacy. This study examines whether a novel, gamified PNF intervention format, which includes a point-based reward system, the element of chance, and personal icons to visually represent users, is more effective in reducing short-term alcohol use than the standard web-based style of PNF currently used on college campuses. Two hundred and thirty-seven college students were randomly assigned to receive either a standard brief, web-based PNF alcohol intervention or the same alcohol intervention components delivered within a Facebook-connected social game called CampusGANDR (Gamified Alcohol Norm Discovery and Readjustment). In both study conditions participants answered identical questions about their perceptions of peer drinking norms and own drinking and then received the same PNF slides. Two weeks following PNF delivery, participants again reported their perceptions of peers' alcohol use and own drinking. Students in the CampusGANDR condition reported significantly reduced peer drinking norms and alcohol use at the two week follow-up relative to students who received identical PNF delivered by standard online survey. Further, a mediation model demonstrated that this effect was driven by larger reductions in perceived drinking norms among participants assigned to receive CampusGANDR, relative to control. As web-based PNF is becoming an increasingly universal prevention strategy, findings from this study suggest gamification may represent one method by which intervention efficacy could be substantially improved. The potential methodological and economic benefits associated with gamified PNF interventions are emphasized and directions for future research are discussed. PMID- 27978430 TI - HSV1 Pulls the Deamidation tRIGger. AB - Viruses have evolved a remarkable array of strategies to escape the host's innate immune responses. In this issue of Cell Host & Microbe, Zhao et al. (2016b) reveal a viral strategy to inactivate RIG-I signaling that relies on deamidation of RIG-I. PMID- 27978431 TI - HIV Latency TORn Down. AB - Combination therapy for HIV infection is effective at controlling disease but fails to eradicate the virus because a persistent reservoir of cells harbors latent HIV DNA. In this issue of Cell Host & Microbe, Besnard et al. (2016) show that the mTOR kinase is essential to reactivate HIV from latency. PMID- 27978432 TI - Retrovirus Integration: Some Assembly Required? AB - Integration is a key feature of the retroviral life cycle. This process involves packaging of the viral genome into chromatin, which is often assumed to occur as a post-integration step. In this issue of Cell Host & Microbe, Wang and colleagues (Wang et al., 2016) show that chromatinization occurs before integration, raising new questions about the role of histones in retroviral integration and transcription. PMID- 27978433 TI - Exploiting Old Pathogens to Create New Therapeutics. AB - Intestinal worms are well known for their potent immuno-modulatory capacity. In a recent study, Navarro et al. (2016) identify a secreted hookworm protein that can suppress allergic responses in both mice and humans. This represents an exciting strategy for treating chronic inflammatory disorders such as allergy. PMID- 27978434 TI - An Apicomplexan Actin-Binding Protein Serves as a Connector and Lipid Sensor to Coordinate Motility and Invasion. AB - Apicomplexa exhibit a unique form of substrate-dependent gliding motility central for host cell invasion and parasite dissemination. Gliding is powered by rearward translocation of apically secreted transmembrane adhesins via their interaction with the parasite actomyosin system. We report a conserved armadillo and pleckstrin homology (PH) domain-containing protein, termed glideosome-associated connector (GAC), that mediates apicomplexan gliding motility, invasion, and egress by connecting the micronemal adhesins with the actomyosin system. TgGAC binds to and stabilizes filamentous actin and specifically associates with the transmembrane adhesin TgMIC2. GAC localizes to the apical pole in invasive stages of Toxoplasma gondii and Plasmodium berghei, and apical positioning of TgGAC depends on an apical lysine methyltransferase, TgAKMT. GAC PH domain also binds to phosphatidic acid, a lipid mediator associated with microneme exocytosis. Collectively, these findings indicate a central role for GAC in spatially and temporally coordinating gliding motility and invasion. PMID- 27978435 TI - An E3 Ubiquitin Ligase-BAG Protein Module Controls Plant Innate Immunity and Broad-Spectrum Disease Resistance. AB - Programmed cell death (PCD) and immunity in plants are tightly controlled to promote antimicrobial defense while preventing autoimmunity. However, the mechanisms contributing to this immune homeostasis are poorly understood. Here, we isolated a rice mutant ebr1 (enhanced blight and blast resistance 1) that shows enhanced broad-spectrum bacterial and fungal disease resistance, but displays spontaneous PCD, autoimmunity, and stunted growth. EBR1 encodes an E3 ubiquitin ligase that interacts with OsBAG4, which belongs to the BAG (Bcl-2 associated athanogene) family that functions in cell death, growth arrest, and immune responses in mammals. EBR1 directly targets OsBAG4 for ubiquitination mediated degradation. Elevated levels of OsBAG4 in rice are necessary and sufficient to trigger PCD and enhanced disease resistance to pathogenic infection, most likely by activating pathogen-associated molecular patterns triggered immunity (PTI). Together, our study suggests that an E3-BAG module orchestrates innate immune homeostasis and coordinates the trade-off between defense and growth in plants. PMID- 27978437 TI - Biodegradation of waste grease by Penicillium chrysogenum for production of fatty acid. AB - The aim of present work was to effectively remediate grease waste by Penicillium chrysogenum. For efficient degradation, grease waste was pre-treated using various lipases, among them lipolase was the best. The pretreated grease was used as a substrate by P. chrysogenum resulting into the production of fatty acids. Process was optimized by response surface methodology (RSM) using four variables viz; FeCl2 (mM), spore concentration (spores/ml), time period (days) and amount of grease (g). The optimized conditions viz; FeCl2 1.25mM, culture amount 5*1011spores/ml and time period 16days led to the production of 6.6mg/g fatty acid from 10.0g of pre-treated grease mixed with 5.0g wheat bran in 10.0ml czapek dox medium under solid state fermentation. The fermented media was extracted with hexane and subjected to GCMS analysis, which showed the presence of higher amount of palmitic acid. It was purified by crystallization method and 2.8g of palmitic acid was recovered from 1.0kg grease waste in tray fermentation. PMID- 27978439 TI - Achieving nitritation in a continuous moving bed biofilm reactor at different temperatures through ratio control. AB - A ratio control strategy was implemented in a continuous moving bed biofilm reactor (MBBR) to investigate the response to different temperatures. The control strategy was designed to maintain a constant ratio between dissolved oxygen (DO) and total ammonia nitrogen (TAN) concentrations. The results revealed that a stable nitritation in a biofilm reactor could be achieved via ratio control, which compensated the negative influence of low temperatures by stronger oxygen limiting conditions. Even with a temperature as low as 6 degrees C, stable nitritation could be achieved when the controlling ratio did not exceed 0.17. Oxygen-limiting conditions in the biofilm reactor were determined by the DO/TAN concentrations ratio, instead of the mere DO concentration. This ratio control strategy allowed the achievement of stable nitritation without complete wash-out of NOB from the reactor. Through the ratio control strategy full nitritation of sidestream wastewater was allowed; however, for mainstream wastewater, only partial nitritation was recommended. PMID- 27978438 TI - Characteristics of a heterotrophic nitrogen removal bacterium and its potential application on treatment of ammonium-rich wastewater. AB - Nitrogen and organic carbon are major pollutants in wastewater causing environmental problems. Alcaligenes faecalis strain NR, isolated from activated sludge, exhibited the ability to remove ammonium and organic carbon from wastewater simultaneously under sole aerobic conditions in batch culture. Changes in carbon type, C/N ratio, oxygen concentration and inorganic ions significantly affected the treatment efficiency. Furthermore, a continuous bioreactor, solely inoculated with A. faecalis strain NR, was conducted to assess its feasibility for simultaneous nitrogen and organic matter removal in a single aerated reactor. Approximately 66.7-78.3% of NH4+-N and 85.8-92.2% of TOC were removed by using synthetic wastewater with 150-200mg/L of NH4+-N and 1350-2000mg/L of TOC. This research would be valuable to develop an innovative treatment method for ammonium rich wastewater under aerobic conditions. PMID- 27978440 TI - Experimental and numerical study of ultrasonically-assisted drilling. AB - In this study, 3D finite element simulation of ultrasonically-assisted drilling is carried out to analyze the effect of ultrasonic vibrations on common difficulties existed in conventional drilling. Influence of harmonic movement of drill bit on the formation of built-up edge is experimentally evaluated and also discussed by investigation of heat generation on the tool faces in simulation. At the end, it was revealed that intermittent movement of drill bit in vibration method causes the total time of heat transfer between workpiece and drill bit to be reduced resulting lower built-up edge formation compared to conventional drilling. Moreover, linear motion of cutting tool in the feed direction results in the increase of chip strain and consequently damage value which causes to generation of broken chips. PMID- 27978436 TI - The mTOR Complex Controls HIV Latency. AB - A population of CD4 T lymphocytes harboring latent HIV genomes can persist in patients on antiretroviral therapy, posing a barrier to HIV eradication. To examine cellular complexes controlling HIV latency, we conducted a genome-wide screen with a pooled ultracomplex shRNA library and in vitro system modeling HIV latency and identified the mTOR complex as a modulator of HIV latency. Knockdown of mTOR complex subunits or pharmacological inhibition of mTOR activity suppresses reversal of latency in various HIV-1 latency models and HIV-infected patient cells. mTOR inhibitors suppress HIV transcription both through the viral transactivator Tat and via Tat-independent mechanisms. This inhibition occurs at least in part via blocking the phosphorylation of CDK9, a p-TEFb complex member that serves as a cofactor for Tat-mediated transcription. The control of HIV latency by mTOR signaling identifies a pathway that may have significant therapeutic opportunities. PMID- 27978441 TI - Development of horseradish peroxidase-based cross-linked enzyme aggregates and their environmental exploitation for bioremediation purposes. AB - In the present study, horseradish peroxidase (HRP), in-house isolated crude cocktail enzyme, from Armoracia rusticana was cross-linked using a new type of cross-linking agent, i.e., ethylene glycol-bis [succinic acid N hydroxysuccinimide, (EG-NHS)], which is mild in nature as compared to the glutaraldehyde (GA). The HRP-immobilized cross-linked enzyme aggregates (HRP CLEAs) were developed using a wider range of EG-NHS and notably no adverse effect was observed. In a comparative evaluation, in the case of EG-NHS, a high-level stability in the residual activity was recorded, whereas a sharp decrease was observed in the case of glutaraldehyde. Following initial cross-linker evaluation, the HRP-CLEAs were tested to investigate their bio-catalytic efficacy for bioremediation purposes using a newly developed packed bed reactor system (PBRS). A maximal of 94.26% degradation of textile-based methyl orange dye was recorded within the shortest time frame, following 91.73% degradation of basic red 9, 84.35% degradation of indigo, 81.47% degradation of Rhodamin B, and 73.6% degradation of Rhodamine 6G, respectively, under the same working environment. Notably, the HRP-CLEAs retained almost 60% of its original activity after methyl orange dye degradation in seven consecutive cycles using PBRS. Furthermore, after HRP-CLEAs-mediated treatment in the PBRS, a significant toxicity reduction in the dye samples was recorded as compared to their pristine counterparts. In conclusion, the results suggest that the newly developed HRP-CLEAs have a great potential for industrial exploitation, to tackle numerous industrial dye-based emergent pollutants. PMID- 27978443 TI - Dynamically linking economic models to ecological condition for coastal zone management: Application to sustainable tourism planning. AB - While the development of the tourism industry can bring economic benefits to an area, it is important to consider the long-run impact of the industry on a given location. Particularly when the tourism industry relies upon a certain ecological state, those weighing different development options need to consider the long-run impacts of increased tourist numbers upon measures of ecological condition. This paper presents one approach for linking a model of recreational visitor behavior with an ecological model that estimates the impact of the increased visitors upon the environment. Two simulations were run for the model using initial parameters available from survey data and water quality data for beach locations in Croatia. Results suggest that the resilience of a given tourist location to the changes brought by increasing tourism numbers is important in determining its long-run sustainability. Further work should investigate additional model components, including the tourism industry, refinement of the relationships assumed by the model, and application of the proposed model in additional areas. PMID- 27978442 TI - Using nudges to reduce waste? The case of Toronto's plastic bag levy. AB - The overuse of disposable plastic bags is a major environmental problem across the globe. In recent years, numerous jurisdictions have sought to curb disposable bag use by implementing a levy or fee at the point of purchase. These levies are typically small and symbolic (around $0.05 per bag), but serve as a highly visible and continuous reminder to consumers. As such, they are consistent with nudging policies that seek to encourage broad changes in behaviour through small, non-coercive measures that influence people's thinking about an issue. While existing empirical evidence suggests that nudges are highly effective in reducing disposable bag use, we argue that many of these studies are flawed because they lack adequate temporal and geographic controls. We use longitudinal data from four waves of a major Canadian survey to analyze the effect of a disposable bag levy in the City of Toronto. Controlling for demographics and changes in social norms over time, we find that the levy increased the use of reusable shopping bags by 3.4 percentage points. Moreover, we find that the impact of the policy was highly variable across behavioural and demographic groups. The levy was highly effective in encouraging people who already used reusable bags to use them more frequently, while having no effect on infrequent users. We also find that the effects are limited to households with high socio-economic status (as measured by income, educational attainment, and housing situation). This suggests important limitations for nudging policy more generally, as people with lower socio-economic status appear to have been unaffected by this behavioural prompt. PMID- 27978444 TI - Energy input in conventional and organic paddy rice production in Missouri and Italy: A comparative case study. AB - The expected decline in availability of fossil fuels over the next several decades, either because of resource depletion or because of limits on carbon emissions, is leading to a keen interest in finding more sustainable energy sources. For this reason, it is useful to assess the energy footprint of alternative agricultural systems for crops and animal production and to identify potential transition scenarios to systems largely based on renewable energy. The present work aims to assess for the first time a comparative analysis of energy inputs in rice production systems in Southern Europe (Piemonte, Italy) and in North America (Missouri, USA). A total of twelve rice farms, either conventional or organic, were selected, collecting detailed data on direct (fuel and electricity) and indirect (machinery, fertilizers, pesticides, and seeds) energy inputs. While energy input of conventional farms ranged from 3.5 to 7 MJ/kg paddy rice, organic farming could reduce inputs by more than 50% with only 8% yield decrease. A significant reduction in fuel or electricity use can be achieved also with no till and surface irrigation. The use of renewable energy sources, as already practiced by some farms, could more than cover their electrical energy requirements. PMID- 27978445 TI - Towards the implementation of OSCE in undergraduate nursing curriculum: A qualitative study. AB - BACKGROUND: Despite the fact that Objective Structured Clinical Examination is considered to be an efficient assessment method, their implementation in the undergraduate nursing curriculum encounters difficulties. However, the initiative of the European Higher Education Area to promote competency-based assessment may represent an opportunity to introduce this instrument in undergraduate nursing curriculum. OBJECTIVE: To explore the perception of nursing faculty members regarding the implementation of the OSCE as an assessment tool in Catalan Nursing Schools. DESIGN/PARTICIPANTS/SETTING: In this qualitative study, fifteen teachers participated in semi-structured interviews in eight Catalan Nursing Schools. METHODS: Semi-structured interviews were conducted. A thematic content analysis was used to identify major themes in the interview data and collaborative analysis was undertaken to ensure rigorous results. RESULTS: The relevant aspects that are emphasized by teachers included the consideration of the dual purpose of the OSCE via its formative and evaluative facets by enhancing the feedback received by students about their performance on the OSCE. The OSCE should be administered towards the end of the degree program and should complement other methods of assessment. Despite its high cost, the OSCE was deemed to be efficient as it enables student competencies to be assessed with objective criteria, which is a difficult task with other instruments. OSCE implementation is feasible with the institutional support of and collaborative work between schools. CONCLUSIONS: The implementation of the OSCE in the Catalan undergraduate nursing degree programs is feasible if the project receives the support of all involved parties and if creative strategies are determined to reduce economic costs and optimize resources. With adequate feedback, the OSCE is an assessment tool that can provide high-impact training to students. PMID- 27978446 TI - Students' perceptions of their learning experiences: A repeat regional survey of healthcare students. AB - BACKGROUND: Student experience is an international concern and recent research has focused on initiatives to improve students' learning experiences and ultimately reduce attrition levels. OBJECTIVE: To determine similarities and differences between students' perceptions of their learning experiences between 2011 and 2015 in relation to campus-based learning, placement-based learning and personal circumstances. DESIGN: A repeat online survey in 2011 and 2015; using a questionnaire developed from thematic analysis of narrative interviews with a subsample of the target population. SETTINGS: Nine universities in the North West of England. PARTICIPANTS: A total of 1080 students completed the survey in 2011 and 1983 students in 2015 from a target population of all students studying on commissioned pre-registration healthcare education programmes. METHODS: An online survey was made available to all undergraduate students studying on Health Education funded programmes within the region and survey respondents were invited to give demographic information and rate their agreement to statements on four point Likert-type responses. RESULTS: Responses to a repeat survey of healthcare studying in the North West of England in 2015 were strikingly similar overall to those of an original 2011 survey. Although the students were positive overall about their experiences, a number were dissatisfied with some aspects of their experiences - particularly in relation to initial support on campus and whilst studying on placement. Four years on from the original survey, despite a considerable investment in improving students' experiences across the region, there appears to be little change in students' perceptions of their learning experiences CONCLUSION: In the short-term monitoring of student experience needs to be continued; and links to attrition (potential or actual) noted and acted upon. However, given that attrition from these courses has been a long-term problem and the complexity of its resolution a recurrent finding in the literature; new ways of framing and resolving the problem need to be considered. PMID- 27978447 TI - Knowing what research organizations actually do, with whom, where, how and for what purpose: Monitoring research portfolios and collaborations. PMID- 27978448 TI - Electronic structure and spectral properties of terbium(III) nitrate complex with hexamethylphosphoramide. AB - Spectral properties of terbium(III) nitrate complex with hexamethylphosphoramide have been studied by quantum-chemical methods within the density functional theory and methods of luminescent and X-ray photoelectron spectroscopy. Analysis of the luminescence excitation spectrum of the complex has indicated the absence of intramolecular transfer of electronic excitation energy from the ligand levels to the resonance levels of the rare earth central ion, so luminescence of the complex is associated with the electronic f-f-transitions of Tb3+ ion (transitions 5D4->7FJ, J=3-6). According to quantum-chemical modeling of the excited singlet and triplet levels of the complex, the excitation energy transfer from the ligands onto the central ion does not occur because of the significant difference of energies of their excited states. PMID- 27978449 TI - New highly selective turn-on fluorescence receptor for the detection of copper (II). AB - Three new receptors (1a-c) bearing a p-dimethylaminobenzamide fluorophore have been synthesized and evaluated in terms of their fluoroionophoric properties towards various metal ions. Notably, receptors 1a and 1c exhibited dramatic fluorescent enhancement towards Cu2+ in acetonitrile. Subsequent investigations revealed that the highly selective behavior of these receptors towards Cu2+ could be attributed to the Cu2+-mediated oxidative cyclization of these compounds to the corresponding 1,3,4-oxadiazoles. Solvent effects and quantum calculations indicated that 1a and 1c both possessed an intramolecular charge transfer channel, which could be obstructed by the oxidative cyclization of these receptors. Receptor 1a was successfully applied to the determination of the Cu2+ in drug sample with a low detection limit of 2.2*10-8molL-1. PMID- 27978450 TI - Musicians react faster and are better multisensory integrators. AB - The results from numerous investigations suggest that musical training might enhance how senses interact. Despite repeated confirmation of anatomical and structural changes in visual, tactile, and auditory regions, significant changes have only been reported in the audiovisual domain and for the detection of audio tactile incongruencies. In the present study, we aim at testing whether long-term musical training might also enhance other multisensory processes at a behavioural level. An audio-tactile reaction time task was administrated to a group of musicians and non-musicians. We found significantly faster reaction times with musicians for auditory, tactile, and audio-tactile stimulations. Statistical analyses between the combined uni- and multisensory reaction times revealed that musicians possess a statistical advantage when responding to multisensory stimuli compared to non-musicians. These results suggest for the first time that long term musical training reduces simple non-musical auditory, tactile, and multisensory reaction times. Taken together with the previous results from other sensory modalities, these results strongly point towards musicians being better at integrating the inputs from various senses. PMID- 27978451 TI - Assessment of thiamethoxam toxicity to Chironomus riparius. AB - The insecticide thiamethoxam (TMX) is a systemic neonicotinoid widely used for pest control in several agricultural crops. TMX mimics the action of acetylcholine causing uncontrolled muscular contraction eventually leading to insect death. TMX is being found in freshwater ecosystems at concentrations of up to 225ug/L. Still, chronic toxicity data for freshwater invertebrates is limited. Therefore, the aim of this study was to evaluate the acute and chronic effects (at organismal and biochemical levels) of TMX on the freshwater insect Chironomus riparius. C. riparius life history responses were significantly affected by TMX exposure, namely with a decrease in growth and delay in emergence. Concerning the biochemical responses, after a short exposure (48h) to TMX, our results showed that low concentrations of TMX significantly reduced CAT activity and LPO levels of C. riparius. No effects were observed in AChE, GST and ETS activities. Effects in terms of survival, development rates and biochemical responses of C. riparius exposed to low concentrations of TMX observed in this study suggest potential deleterious effects of this neonicotinoid on aquatic insects inhabiting freshwaters environments near agricultural areas. PMID- 27978452 TI - Soil concentrations of polybrominated diphenyl ethers and trace metals from an electronic waste dump site in the Greater Accra Region, Ghana: Implications for human exposure. AB - Unregulated electronic waste (e-waste) recycling operations have become a significant environmental issue as well as human health risk in developing countries across the world. The present study evaluated the extent of pollution in Agbogbloshie e-waste recycling site in Accra, Ghana. The concentrations of polybrominated diphenyl ethers (PBDEs) and some selected trace metals were determined using gas chromatography electron impact ionization mass spectrometry and flame atomic absorption spectrophotometry, respectively. The concentrations of ? PBDEs ranged from 15.6 to 96.8ngg-1 dry weight, with an overall mean of 54.8ngg-1dw. BDE-28 was the dominant congener followed by BDE-209 and BDE-47. The order of mean concentrations of the abundant trace metals was Fe>Cu>Pb?Mn, with a mean range of .531-289mgkg-1. Geoaccumulation index suggested that the surface soils deteriorated from moderate to high metal pollution, particularly for Cu, Pb and Fe. Of the trace metals analysed, Fe exhibited the highest concentration ranging from 3.97 to 918mgkg-1. Correlation and principal component analyses suggested possible interactions between PBDEs and the trace metals analysed, while source assessment suggested that PBDEs and trace metals were mostly derived from inputs from the e-waste recycling activities. Average daily dose (ADD) was estimated using concentrations corresponding to 5th percentile, median and 95th percentile. Hazard quotients of 380 and 862 were obtained for adults and children respectively, for Cu and Pb which is a cause for concern especially for local children. PMID- 27978454 TI - Electrosynthesis, physioelectrochemical and theoretical investigation of poly ortho aminophenol/magnetic functional graphene oxide nanocomposites as novel and hybrid electrodes for highly capacitive pseudocapacitors. AB - Magnetic functional graphene oxide (MFGO) has been synthesized in this work using FeCl4- magnetic anion paired with 1-methyl imidazolium cation. Hybrid poly ortho aminophenol (POAP)/MFGO films have then been prepared via POAP electropolymerization in the presence of MFGO nanosheets, serving as active electrodes for electrochemical supercapacitors. The FeCl4- functional group in MFGO plays a major part in atomic scale charge/energy transfer and consequently intramolecular electrochemical phenomena in MFGO systems, as shown by the theoretical results. POAP/MFGO composite films have been characterized by surface and electrochemical analyses. The performance of the system has been investigated by various electrochemical methods such as galvanostatic charge discharge experiments, cyclic voltammetry and electrochemical impedance spectroscopy. Novel nanocomposite compounds have been developed in this work for electrochemical redox capacitors. The advantages of these compounds include simple synthesis method, high active surface area and stability in aqueous electrolytes. PMID- 27978453 TI - Relationships of neutrophil-lymphocyte and platelet-lymphocyte ratios with the severity of major depression. AB - We aimed to evaluate the neutrophil-lymphocyte (NLR) and platelet-lymphocyte (PLR) ratios of inpatients and outpatients suffering from different levels of major depression. In total, 100 inpatients and 60 patients treated at an outpatient clinic were included the study. The presence of mood and anxiety disorders was identified with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition/Clinical Version, and the Hamilton Depression Rating Scale was used to assess the severity of major depression (MD). Inpatients and outpatients with MD did not differ in NLR or PLR. The PLRs of patients who had severe major depression with psychotic features were higher than those of patients with other types of depression, but no differences in NLRs were detected across types of depression. The PLRs were higher in patients with severe levels of major depression with psychotic features than in other patients. This parameter may be more predictive than is NLR for assessing the prognosis of major depression. PMID- 27978455 TI - Interfacial kinetics in a model emulsion polymerisation system using microelectrochemical measurements at expanding droplets (MEMED) and time lapse microscopy. AB - Physicochemical processes that take place at the oil-water interface of an epoxy amine emulsion polymerisation system influence the properties and structural morphology of the polymeric microparticles formed. Investigating these processes, such as the transport of monomers across the liquid/liquid interface brings new understanding which can be used to tune polymeric morphology. Two different approaches are used to provide new insights on these processes. Microelectrochemical measurements at expanding droplets (MEMED) is used to measure the transfer of amine from an organic phase comprised of epoxide and amine into an aqueous receptor phase. The rate of amine transfer across the liquid/liquid interface is characterised using MEMED and finite element method modelling and kinetic values are reported. Time lapse microscopy of epoxide droplets held in deionised water or an aqueous amine solution heated to different temperatures is further used to characterise epoxide dissolution into the aqueous phase. Mass-transport of epoxide into the aqueous phase is shown to be temperature-dependent. Epoxide homopolymerisation at the droplet-water interface is found to influence the rate of epoxide droplet dissolution. The rate of the epoxy-amine cure reaction is shown to be faster than the rate of the epoxide homopolymerisation reaction. The combination of methods used here is not limited to emulsion polymerisation and should find application in a myriad of processes at liquid/liquid interfaces. PMID- 27978456 TI - Effective removal of toxic metal ions from aqueous solutions: 2-Bifunctional magnetic nanocomposite base on novel reactive PGMA-MAn copolymer@Fe3O4 nanoparticles. AB - In this study, effective novel magnetic nanocomposite particles (MNCPs) were prepared based on iminodiacetic acid grafted poly (glycidylmethacrylate maleicanhydride) (PGMA-MAn) copolymer. For this purpose, firstly Fe3O4 nanoparticles reacted with 3-aminopropyl triethoxysilane for the production of magnetite nanoparticles containing amine groups (MNPs-NH2). Then iminodiacetic acid reacted with PGMA-MAn copolymer to produce iminodiacetic acid grafted PGMA MAn copolymer (ID-g-PGMA-MAn). Finally, the MNPs-NH2 reacted with the ID-g-PGMA MAn and the reaction was completed by propylenediamine (PDA) to produce MNCPs. Structure, magnetic property, size, and porosity of the prepared magnetic nanocomposite were investigated by FT-IR, XRD, VSM, EDX, SEM and BET analyses. The ability of these MNCPs for removing Pb(II) and Cd(II) from water and wastewater was studied, and the effects of different parameters (pH, adsorbent dosage, metal ion concentration, contact time and agitation) on the adsorption process were investigated. The isotherm models were used to describe adsorption equilibrium. The results showed that the best fit was achieved with the Langmuir isotherm equation, yielding maximum adsorption capacities of 53.33 and 48.53mg/g for Pb(II) and Cd(II), respectively. The kinetics equations were used for modeling of adsorption data and it was shown that pseudo-second-order kinetic equation could best describe the adsorption kinetics. Furthermore, phenol pollutant can be removed effectively by metal ions of the nanocomposite-metal complex; therefore, the synthesized adsorbent was useful not only in recovering toxic metal ions but also in the treating phenol pollutants in wastewater. PMID- 27978457 TI - Neural activations are related to body-shape, anxiety, and outcomes in adolescent anorexia nervosa. AB - Anorexia nervosa (AN) is an illness that frequently begins during adolescence and involves weight loss. Two groups of adolescent girls (AN-A, weight-recovered following AN) and (HC-A, healthy comparison) completed a functional magnetic resonance imaging task involving social evaluations, allowing comparison of neural activations during self-evaluations, friend-evaluations, and perspective taking self-evaluations. Although the two groups were not different in their whole-brain activations, anxiety and body shape concerns were correlated with neural activity in a priori regions of interest. A cluster in medial prefrontal cortex and the dorsal anterior cingulate correlated with the body shape questionnaire; subjects with more body shape concerns used this area less during self than friend evaluations. A cluster in medial prefrontal cortex and the cingulate also correlated with anxiety such that more anxiety was associated with engagement when disagreeing rather than agreeing with social terms during self evaluations. This data suggests that differences in the utilization of frontal brain regions during social evaluations may contribute to both anxiety and body shape concerns in adolescents with AN. Clinical follow-up was obtained, allowing exploration of whether brain function early in course of disease relates to illness trajectory. The adolescents successful in recovery used the posterior cingulate and precuneus more for friend than self evaluations than the adolescents that remained ill, suggesting that neural differences related to social evaluations may provide clinical predictive value. Utilization of both MPFC and the precuneus during social and self evaluations may be a key biological component for achieving sustained weight-recovery in adolescents with AN. PMID- 27978459 TI - Le Carbone, a charcoal supplement, modulates DSS-induced acute colitis in mice through activation of AMPKalpha and downregulation of STAT3 and caspase 3 dependent apoptotic pathways. AB - Le Carbone (LC) is a charcoal supplement, which contains a large amount of dietary fibers. Several studies suggested that charcoal supplement may be beneficial for stomach disorders, diarrhea, gas and indigestion. But no studies address whether LC intake would suppress inflammation, cell proliferation or disease progression in colitis. In the present study, the effect of LC on experimental colitis induced by dextran sulfate sodium (DSS) in mice and its possible mechanism of action were examined. A study was designed for 8days, using C57BL/6 female mice that were administered with 3% DSS in drinking water for 7days followed by another 1day consumption of normal water with or without treatment. LC suspension was administered daily for 7days via oral gavage using 5mg/mouse in treatment group and normal group was supplied with drinking water. LC suspension significantly attenuated the loss of body weight and shortening of colon length induced by DSS. The disease activity index, histopathologic changes were significantly reduced by LC treatment. The inflammatory mediators TNFalpha, IL-1beta, p-STAT3 and p-NF-kappaB induced in the colon by DSS were markedly suppressed by LC. The increased activation of AMPKalpha in the colon was also detected in LC group. Furthermore, the apoptotic marker protein cleaved caspase 3 was down-regulated and anti-apoptotic proteins Bcl2 and Bcl-xL were significantly up-regulated by LC treatment. Taken together, our results demonstrate the ability of LC to inhibit inflammation, apoptosis and give some evidence for its potential use as adjuvant treatment of inflammatory bowel disease. PMID- 27978458 TI - Consolidation with autologous stem cell transplantation in first remission is safe and effective in AML patients above 65 years. AB - The outcome of AML patients >=65 years remains disappointing. Current post induction strategies for elderly AML patients fit for intensive treatment involve additional cycles of chemotherapy or allogeneic transplantation. Consolidation with autologous transplantation (ASCT) is poorly studied in these patients. In this single-center retrospective analysis, we determined survival rates of AML patients >=65 years undergoing busulfan/cyclophosphamide conditioning before ASCT in first remission between 2007 and 2015. We found elderly AML patients with ASCT to have longer progression-free survival (PFS; 16.3 vs. 5.1 months, P=0.0166) and overall survival (OS; n.r. vs. 8.2 months; P=0.0255) than elderly AML patients without ASCT consolidation. In addition, elderly AML patients undergoing ASCT had comparable PFS (P=0.9462) and OS (P=0.7867) as AML patients below 65 years receiving ASCT consolidation in CR1. Our data suggest that ASCT is an option in elderly fit AML patients who appear to benefit from autologous consolidation similarly to younger AML patients. PMID- 27978460 TI - Clinical characteristics of headache or facial pain prior to the development of acute herpes zoster of the head. AB - OBJECTIVES: When physicians encounter patients with headache or facial pain (preeruptive pain) associated with acute herpes zoster of the head, especially before the appearance of characteristic skin eruptions (preeruptive phase), they typically find it difficult to make clinical impressions and apply appropriate diagnostic or therapeutic procedures. The objectives of this study were to describe the clinical characteristics of headache or facial pain associated with acute herpes zoster of the head and to elucidate the association between the manifestation of these symptoms in the preeruptive phase and incoming herpes zoster. METHODS: We retrospectively analyzed the clinical features of 152 patients with acute herpes zoster involving only the head who presented within 10days of rash onset at Chungbuk National University Hospital, a tertiary hospital in Chungcheongbuk-do in South Korea, between January 2011 and December 2015. RESULTS: The mean age of the patients was 54.3+/-19.8years. One hundred patients had herpes zoster in the trigeminal nerve, 34 in the nervus intermedius, and 18 in the upper cervical nerves. Preeruptive pain was present in 112 (73.7%) patients and had a mean duration of 3.0+/-1.3days (range, 1-6days). Severity of pain was associated with the presence of preeruptive pain (p=0.040). Headache or facial pain was limited to the ipsilateral side of the face and head in all patients, except for two who had with severe symptoms of meningitis, and was of moderate to severe intensity (90.1%). Pain of a stabbing nature was observed in 128 (84.2%) patients, and 146 (96.1%) reported experiencing this type of pain for the first time. Pain awakened 94 (61.8%) patients from sleep. Sixty-one (54.5%) of the 112 patients with preeruptive pain visited a hospital during the preeruptive phase; their preeruptive phase was significantly longer (p<0.001) and more frequently awakened them from sleep (p=0.008). Their presumptive diagnoses were as follows: tension-type headache (n=20, 32.8%); no decision (n=18, 29.5%); herpes zoster (n=5, 8.2%); migraine (n=3, 4.9%); pain associated with upper respiratory tract infection (n=3, 4.9%); parotitis (n=2, 3.3%); dry eye (n=2, 3.3%); and other (n=1 each: trigeminal neuralgia, glaucoma, pharyngitis, vestibular neuronitis, tonsillitis, teeth problems, otitis media, and occipital neuralgia). CONCLUSION: These results suggest that the typical pain of acute herpes zoster of the head has a stabbing quality, is felt unilaterally, is moderate to severe, often awakens patients from sleep, and has not been previously experienced by most patients. When encountering patients with these features accompanied by pain onset of less than one week, acute herpes zoster of the head should be considered, even without characteristic vesicles, after excluding other secondary causes by appropriate diagnostic workup. PMID- 27978461 TI - Severe bilateral subdural hematomas as a complication of diagnostic lumbar puncture for possible Alzheimer's disease. PMID- 27978462 TI - The effect of dietary supplementation with dried fruit and vegetable pomaces on production parameters and meat quality in fattening pigs. AB - The presence of biologically active substances in feed mixture is discussed to have beneficial effect on animals' health and products. The purpose of the study was to determine the effect of dietary supplementation with dried apple, chokeberry, black currant, strawberry and carrot pomaces on production parameters and meat quality in fattening pigs. The use of dried pomaces of chokeberry showed tendencies for increased feed intake and reduced fattening period. The dried pomaces had no impact on saturated and monounsaturated fatty acids profile in meat, however in some groups an elevated level of polyunsaturated fatty acids from n-3 family and a decline in total cholesterol level was observed (P<=0.05). The highest oxidative stability and vitamin E content was found after supplementation with black currant (P<=0.05). Summarizing, the used dried pomaces improved several parameters related to meat quality, what might positively influence consumers' health. PMID- 27978463 TI - Spine postural change elicits localized skin structural deformation of the trunk dorsum in vivo. AB - As the most superficial organ, the skin is the most accessible sensory system interfacing one's body and environment. With changes in posture, it is possible that the skin may undergo large deformations resulting in changes in its structural properties. The purpose of the current work was to determine the influence of spine posture on measures of trunk dorsum skin deformation, thickness and hardness in vivo. 28 young and healthy individuals were assessed while holding three static, supported spine postures (prone neutral, spine extension, and spine flexion). Skin stretch deformation was measured across each posture using an 11*9 dot matrix of 3D kinematic markers affixed to the skin of the back. Skin thickness (epidermis + dermis) was quantified using ultrasound images obtained from specific spinal levels (L4, L2, T12 and T10). Skin hardness was measured at the same specific spinal levels using a handheld Shore durometer. During the spine extension posture it was observed that the skin of the trunk dorsum relaxed/retracted on average by 12% to become both ~17% thicker and ~39% softer compared to the neutral prone posture. During the spine flexion posture the skin of the trunk dorsum stretched on average by 38% to become both ~19% thinner and ~106% harder. Additionally, in the spine flexion posture it was clear that the majority of the skin deformation occurred within the lumbar region, while deformation was more evenly distributed in the extension posture. Results also suggest that stretch distributions could be in large part determined by the intervertebral distribution of the overall spine angle, as well as in part due to the local hypodermal/subcutaneous fat and fascia distribution. With such large structural deformations of the skin of the trunk dorsum, it is suggested that corresponding changes in skin tactile sensitivity (e.g. perceptual thresholds of force necessary to elicit a sensation of touch) may be present, and should be investigated through future work. These data will aid in the development of computer models to investigate skin structural deformation (e.g. finite element models or kinematic models that track skeletal structures by accounting for soft tissue artifacts) as well as further applications pertaining to skin sensitivity, and tactile biofeedback across various body postures. PMID- 27978464 TI - Selectivity evaluation and separation of human immunoglobulin G, Fab and Fc fragments with mixed-mode resins. AB - Adsorption selectivity is critical important for mixed-mode chromatography with specially-designed ligands. Human immunoglobulin G (hIgG), Fc and Fab fragments were used in the present work to evaluate adsorption behavior and binding selectivity of four mixed-mode resins with the ligands of 4-mercatoethyl-pyridine (MEP), 2-mercapto-1-methylimidazole (MMI), 5-aminobenzimidazole (ABI) and tryptophan-5-aminobenzimidazole (W-ABI), respectively. The resins showed an obvious pH-dependent adsorption behavior. High adsorption capacities were found at neutral pH for hIgG, Fc and Fab, and almost no adsorption happened under acidic conditions. An adsorption selectivity index was proposed to evaluate separation efficiency. High specificity of hIgG/Fc was found at pH 8.9 for MEP resin, and for W-ABI resin at pH 8.0 and 8.9. In addition, isothermal titration calorimetry was used to evaluate ligand-protein interactions. Finally, the separation of hIgG and Fc (1:1) was optimized with mixed-mode resins, and the best separation performance was obtained with W-ABI-based resin. Loading at pH 8.0 resulted in the flow through of Fc with purity of 90.4% and recovery of 98.8%, while elution at pH 3.6 provided hIgG with purity of 99.7% and recovery of 86.5%. PMID- 27978465 TI - At-line hyphenation of high-speed countercurrent chromatography with Sephadex LH 20 column chromatography for bioassay-guided separation of antioxidants from vine tea (Ampelopsis grossedentata). AB - Vine tea (Ampelopsis grossedentata), a widely used healthy tea, beverage and herbal medicine, exhibited strong antioxidant activity. However, systematic purification of antioxidants, especially for those with similar structures or polarities, is a challenging work. Here, we present a novel at-line hyphenation of high-speed countercurrent chromatography with Sephadex LH-20 column chromatography (HSCCC-Sephadex LH-20 CC) for rapid and efficient separation of antioxidants from vine tea target-guided by 1,1-diphenyl-2-picryl-hydrazyl radical-high performance liquid chromatography (DPPH-HPLC) experiment. A makeup pump, a six-port switching valve and a trapping column were served as interface. The configuration had no operational time and mobile phase limitations between two dimensional chromatography and showed great flexibility without tedious sample-handling procedure. Seven targeted antioxidants were firstly separated by stepwise HSCCC using petroleum ether-ethyl acetate-methanol-water (4:9:4:9, v/v/v/v) and (4:9:5:8, v/v/v/v) as solvent systems, and then co-eluted antioxidants were on-line trapped, concentrated and desorbed to Sephadex LH-20 column for further off-line purification by methanol. It is noted that six elucidated antioxidants with purity over 95% exhibited stronger activity than ascorbic acid (VC). More importantly, this at-line hyphenated strategy could sever as a rapid and efficient pathway for systematic purification of bioactive components from complex matrix. PMID- 27978467 TI - A highly selective nanocomposite based on MIP for curcumin trace levels quantification in food samples and human plasma following optimization by central composite design. AB - A selective and rapid method was developed for quantification of curcumin in human plasma and food samples using molecularly imprinted magnetic multiwalled carbon nanotubes (MMWCNTs) which was characterized with EDX and FESEM. The role of sorbent mass, volume of eluent and sonication time on response in solid phase microextraction procedure were optimized by central composite design (CCD) combined with response surface methodology (RSM) using Statistica. Preliminary experiments reveal that among different solvents, methanol:dimethyl sulfoxide (4:1V/V) led to efficient and quantitative elution of analyte. A reversed-phase high performance liquid chromatographic technique with UV detection (HPLC-UV) was applied for detection of curcumin content. The assay procedure involves chromatographic separation on analytical Nucleosil C18 column (250*4.6mm I.D., 5MUm particle size) at ambient temperature with acetonitrile-water adjusted at pH=4.0 (20:80, v/v) as mobile phase at flow rate of 1.0mLmin-1, while UV detector was set at 420nm. Under optimized conditions, the method demonstrated linear calibration curve with good detection limit (0.028ngmL-1) and R2=0.9983. The proposed method was successfully applied to biological fluid and food samples including ginger powder, curry powder, and turmeric powder. PMID- 27978466 TI - Metabolite identification of bentysrepinine (Y101), a novel anti-HBV agent in rats using a five-step strategy based on a combined workflow with two different platforms of liquid chromatography-tandem mass spectrometry. AB - Bentysrepinine (Y101), a derivative of repensine (a compound isolated from Dichondrarepens Forst), is a novel phenyalanine dipeptide inhibiting DNA-HBV and cccDNA activities and is currently under development for the treatment of hepatitis B virus (HBV)-infected hepatitis. Our previous study implied that there might be an existence of extensive metabolism of Y101 in rats. Therefore, it is necessary to perform metabolic profiling study to further evaluate its safety and drug-like properties. In this study, the metabolism of Y101 in rats was investigated by a convincible five-step strategy to characterize metabolites in plasma and that excreted into urine, bile and feces. The five-step strategy was realized by using an combined workflow on two different MS platforms, including various scan modes of liquid chromatography with hybrid quadruple-linear ion trap mass spectrometry (LC-QTRAP-MS/MS) and various post-acquiring data mining tools of liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC QTOF-MS/MS). QTOF MS/MS was employed as a powerful complementary tool to enable high confidence of metabolites identification using its functions of accurate MS and MS/MS fragmentation. As a result, a total of 30 metabolites were detected, including 25 phase I and 5 phase II metabolites. Among them, four primary metabolites (M6-M9) were further identified by comparing with the authentic standards chemically synthesized. The possible metabolic pathways of Y101 in rats were proposed to be amide hydrolysis, monohydroxylation, dihydroxylation, N oxidation, demethylation, methylation, glucosidation and glucuronidation. This is the first study of the metabolism of Y101 in rats. The five-step strategy was successfully used to systematically characterize metabolites of Y101 in rats, and it would be generally applied for metabolite identification of new drug candidate. PMID- 27978468 TI - Effect of Panax notoginseng saponins on the pharmacokinetics of aspirin in rats. AB - Aspirin (ASA) is widely used to treat fever, pain, inflammation and cerebral infarction in clinic. Panax Notoginseng Saponins (PNS) is the extracts of Panax Notoginseng (PN)-a traditional Chinese medicine extensively used in cardiovascular diseases. Panax notoginseng saponins and ASA are both widely used to treat cerebral infarction in China. Good results in clinical practice have been achieved when the two drugs were taken together. To investigate the effect of PNS on ASA in vivo, the concentrations of salicylic acid (SA) in blood were measured after oral administration of ASA or ASA combined with PNS by UPLC-MS/MS. Sample preparation was carried out by the protein precipitation technique with an internal Saikosaponin A standard. The separation of two components was achieved by using an ACQUITY UPLC (r)BEH C18 Column (1.7MUm 2.1*100mm) by gradient elution using water (containing 0.2% formic acid) and acetonitrile (containing 0.2% formic acid) as the mobile phase at a flow rate of 0.2mL/min. The pharmacokinetic parameters were determined by using non-compartmental analysis. The results suggested that drug-drug interaction in vivo existed between PNS and ASA. The concentration of the SA was increasing when the two drugs were administered together. The transport of ASA and SA in MDCK -MDR1 cell monolayer was used to verify this conclusion. The values of apparent permeability coefficients (Papp) were significantly increased when the two drugs were used together. This result suggested PNS could increase the gastrointestinal tract absorption of ASA and SA. These findings provide more insight for wise use of two drugs to treat or prevent cardiovascular diseases. PMID- 27978469 TI - Highly sensitive LC-MS/MS methods for the determination of seven human CYP450 activities using small oral doses of probe-drugs in human. AB - Cocktails composed of several Cytochrome P450 (CYP450)-selective probe drugs have been shown of value to characterize in vivo drug-metabolism activities. Our objective was to develop and validate highly sensitive and selective LC-MS/MS assays allowing the determination of seven major human CYP450 isoenzyme activities following administration of low oral doses of a modified CYP450 probe drug cocktail in patients. The seven-drug cocktail was composed of caffeine, bupropion, tolbutamide, omeprazole, dextromethorphan, midazolam (all administered concomitantly) and chlorzoxazone (administered separately) to phenotype for CYP1A2, 2B6, 2C9, 2C19, 2D6, 3A4/5 and 2E1, respectively. Serial plasma and urine samples were collected over an 8h period. The probe-drugs and their respective metabolites were measured in both human plasma and urine, except for omeprazole (plasma only) and chlorzoxazone (urine only). Samples were analyzed by high performance liquid chromatography with heated electrospray ionization tandem mass spectrometry (HPLC-HESI-MS/MS) using a Phenomenex Luna PFP (2) analytical column (3MUm PFP(2) 150*3mm) for chromatographic separation. Optimal detection was achieved based on 3 different analytical methods; (1) isocratic elution with a mobile phase consisting of acetonitrile and water both fortified with 0.01% formic acid for the analysis of bupropion, tolbutamide, chlorzoxazone and their respective metabolites; (2) isocratic elution with a mobile phase composed of acetonitrile and ammonium formate (pH 3; 10mM) for omeprazole, dextromethorphan, midazolam and their metabolites; (3) for caffeine and paraxanthine, gradient elution using acetonitrile and 0.01% formic acid in water was used. All calibration functions were linear for all probe drugs and metabolites in both matrices over wide analytical ranges. The main advantages of our methods are the use of specific probe drugs available in most countries, the administration of small doses of probe drugs, small volume of plasma required for the analyses and simple and rapid extraction procedures. The methods met all requirements of specificity, sensitivity, linearity, precision and accuracy and stability generally accepted in bioanalytical chemistry. Determination of CYP450 phenotype in patients will permit characterization of their capacities to metabolize drugs through CYP450 under specific conditions at a definite time. This tool will be highly clinically relevant since wide intersubject variability observed in drug response is largely explained by variation in drug metabolism; it will be particularly useful in polymedicated patients with multiple comorbidities. So far, our CYP450 cocktail assays have been successfully applied to phenotype CYP450 activities in patients. PMID- 27978470 TI - The application of multiple analyte adduct formation in the LC-MS3 analysis of valproic acid in human serum. AB - LC-MS using electrospray ionisation (negative ion mode) and low-energy collision induced dissociation tandem mass spectrometric (CID-MS/MS) analysis, together with the multiple analyte adduct formation with the components of the mobile phase, were applied to analyse valproic acid in human serum with LC-MS3. The CID fragmentation of the precursor analyte adduct [M+2CH3COONa-H]- was applied in the method validation (307.1/225.1/143.0). Chromatographic separation was performed with a Luna 5MUm C18 (2) 100A, 150mm*2mm column and the elution with a mobile phase consisting of A (H2O/methanol=95/5, v/v) and B (H2O/methanol=3/97, v/v), both with 10mM ammonium acetate and 0.1% acetic acid. A binary flow pumping mode with a total flow rate of 0.400mL/min was used. The calculated limit of detection/quantification of the method calibrated in the range of 10-200MUg/mL was 0.31/1.0MUg/mL. The sample preparation based on protein precipitation with 1mL of H2O/methanol solution (3/97, v/v) with 10mM sodium acetate and 100mM acetic acid. On the basis of the experiments performed could be demonstrated, that multiple analyte adduct formation can be applied to generate MS3 quantitation of analytes with problematic fragmentation. The presented new strategy makes the analysis of small drugs, which do not produce any stable product ions at all, on the basis of LC-MS3 possible. PMID- 27978471 TI - Simple and sensitive HPLC-UV method for determination of bexarotene in rat plasma. AB - Bexarotene is currently marketed for treatment of cutaneous T-cell lymphoma and there has been growing interest in its therapeutic effectiveness for other cancers. Neuroprotective effects of bexarotene have also been reported. In this study, a simple, sensitive and cost-efficient bioanalytical method for determination of bexarotene in rat plasma was developed and fully validated. The method utilises protein precipitation with acetonitrile and liquid-liquid extraction with n-hexane-ethyl acetate (10:1, v/v). An HPLC-UV system with a Waters Atlantis C18 column and a mobile phase of acetonitrile-ammonium acetate buffer (10mM, pH 4.1) at a ratio of 75:25 (v/v), flow rate 0.2mL/min was used. Chromatograms were observed by a UV detector with wavelength set to 259nm. Intra- and inter-day validations were performed and sample stability tests were conducted at various conditions. The applicability of the method was demonstrated by a pharmacokinetic study in rats. Intravenous bolus dose of 2.5mg/kg was administered to rats and samples were obtained at predetermined time points. As a result, pharmacokinetic parameters of AUCinf (4668+/-452hng/mL), C0 (6219+/ 1068ng/mL) and t1/2 (1.15+/-0.02h) were obtained. In addition, the developed method was further applied to human and mouse plasma to assess the suitability of the method for samples from other species. PMID- 27978472 TI - Study the therapeutic mechanism of Amomum compactum in gentamicin-induced acute kidney injury rat based on a back propagation neural network algorithm. AB - Acute kidney injury (AKI) is a major global public health problems, as it causes high morbidity and serious injury to renal function. However, the etiology for AKI is not very clear. In this study, a serum metabolite profile analysis was performed to identify potential biomarkers for gentamicin-induced AKI and to investigate the mechanism of action of Amomum compactum (AC) used for treatment. A metabonomics approach by ultra-performance liquid chromatography together with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was applied to perform the analysis. Back propagation (BP) neural network models were established for classifying data from the control, model, and AC-treated groups. Accuracy rate for classification was 91.7% in positive ion mode and 87.5% in negative ion mode. By orthogonal partial least squares discriminant analysis (OPLS-DA), 29 metabolites were identified as potential biomarkers of gentamicin induced AKI. Most of them are related to phospholipid metabolism. After treatment with AC, the levels of sphingomyelin, sphingosine, phytosphingosine, and arachidonic acid were restored to normal. The results indicate that AC plays a protective role in rats with gentamicin-induced AKI via regulation of the phospholipid metabolic pathway. In this work, early biomarkers of AKI has been identified and underlying therapeutic mechanism of AC has been understood, therefore, AC can be further investigated and tested for clinical application. PMID- 27978473 TI - A validated UPLC-MS/MS method for the analysis of linezolid and a novel oxazolidinone derivative (PH027) in plasma and its application to tissue distribution study in rabbits. AB - OBJECTIVES: Linezolid is the first approved oxazolidinone antibacterial agent, whereas PH027 is a novel compound of the same class that exhibits good in vitro antibacterial activity. The objective of this study was to develop an UPLC-MS/MS assay for the analysis of linezolid and PH027 in plasma and to apply the method for comparative pharmacokinetic and tissue distribution studies of both compounds. METHOD: Plasma samples and calibrators were extracted with diethyl ether after addition of the internal standard solution. After evaporation of the ether layer, the residue was reconstituted in mobile phase and injected into UPLC MS/MS. The mobile phase consisted of 2mM ammonium acetate buffer solution and acetonitrile (70:30) at a flow rate of 0.2ml/min. Separation was achieved using UPLC BEH C18 column, and quantitative determination of the analytes was performed using multiple-reaction monitoring (MRM) scanning mode. The method was validated by analyzing quality control tissue homogenate samples, and was applied to analyze tissue homogenate samples obtained following IV injections of linezolid and PH027 in rabbits. RESULTS: The developed UPLC-MS/MS method was linear in the concentration range of 50-5000ng/ml. Validation of the method proved that the method's precision, selectivity and stability were all within the acceptable limits. Linezolid and PH027 concentrations were accurately determined in the quality control tissue homogenate samples, and analysis of samples obtained following IV administration of the two compounds showed that the tissue to plasma concentration ratio of PH027 was higher than that of linezolid probably due to its higher lipophilicity. CONCLUSIONS: The developed UPLC-MS/MS method for the analysis of linezolid and PH027 in rabbit's plasma can accurately determine the concentrations of these compounds in different tissues. PMID- 27978475 TI - Assessment of animals as a reservoir for colistin resistance: No MCR-1/MCR-2 producing Enterobacteriaceae detected in Swiss livestock. PMID- 27978474 TI - Simultaneous determination and identity confirmation of thiodicarb and its degradation product methomyl in animal-derived foodstuffs using high-performance liquid chromatography with fluorescence detection and tandem mass spectrometry. AB - A high-performance liquid chromatography-fluorescence detection method was developed for the simultaneous determination of thiodicarb and its degradation product methomyl in animal-derived food products, including chicken muscle, beef, pork, table eggs, and milk. Thiodicarb is known to degrade during analysis; therefore, a thorough investigation was carried out, revealing that thiodicarb degrades to methomyl immediately after spiking into a matrix of animal-derived food products. Consequently, thiodicarb was determined as the sum of the parent compound and methomyl. Samples were extracted with acetonitrile and sodium salts, and purified using solid-phase extraction (SPE). The limits of detection (LODs) and quantification (LOQs) were 0.0013 and 0.004mg/kg, respectively, for both analytes in various matrices. Seven-point external calibration curves were obtained, and they showed excellent linearity with determination coefficients (R2)>=0.999 for all tested matrices. The method was validated at three fortification levels (LOQ, LOQ*2, and LOQ*10) in triplicate with average recoveries ranging from 84.24 to 112.8% (for methomyl) and relative standard deviations (RSDs)<=6.5% in all matrices. The converted recoveries of thiodicarb in various matrices ranged from 74.80 to 107.80% with RSDs<=4.5%. The identities of both compounds in standard solutions and for recovery were confirmed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The developed method was further validated by accurate reproduction at another laboratory. Finally, the method was applied to market samples collected from different areas (and, in the case of milk, different brands), and none of the samples tested positive for thiodicarb or methomyl. In conclusion, the developed method can be successfully applied for a single-run analysis of thiodicarb and methomyl in livestock products. PMID- 27978476 TI - Does maternal psychological distress affect neurodevelopmental outcomes of preterm infants at a gestational age of <=32weeks. AB - BACKGROUND: There is some evidence that maternal psychological status in the prenatal and postnatal periods is associated with infants' cognitive, behavioural, and emotional functions. AIM: The aim of this study was to examine the relationships of maternal depression and anxiety with neurodevelopmental outcomes of preterm infants with a gestational age of <=32weeks, examined at a corrected age of 18 to 22months. STUDY DESIGN: Cross-sectional study. SUBJECTS: In total, 220 preterm infants with a gestational age of <=32weeks who were born from January 2008 to September 2011 and admitted to the neonatal intensive care unit were prospectively examined. OUTCOME MEASURES: Neurodevelopmental evaluation was performed at a corrected age of 18 to 22months by a developmental paediatrician using the Bayley Scales of Infant Development II (BSID-II). The Beck Depression Inventory and Beck Anxiety Inventory were used to assess maternal depression and anxiety at the same visit as the neurodevelopmental evaluation. RESULTS: The depression scores of mothers of infants with a Mental Development Index (MDI) score of <70 were significantly higher than those of mothers of infants with an MDI score of >70 (16.3+/-12.8 vs 8.8+/-7.0, p<0.001). The depression scores of mothers of infants with neurodevelopmental impairment were also significantly higher than those without neurodevelopmental impairment (12.8+/-10.5 vs 8.8+/-7.3, p=0.003). There was no relationship between the presence of cerebral palsy or a Psychomotor Developmental Index (PDI) score of <70 and the mothers' depression scores. Multiple regression analysis revealed that maternal depression and the occurrence of more than two sepsis attacks were associated with an MDI score of <70, and grade III to IV intraventricular haemorrhage was associated with neurodevelopmental impairment and a PDI score of <70. CONCLUSION: Maternal depression is negatively associated with the neurodevelopment of preterm infants at a gestational age of <=32weeks. Maternal psychological well-being should be taken into consideration during the long-term follow-up of preterm infants. PMID- 27978477 TI - Only severe malocclusion correlates with mastication deficiency. AB - OBJECTIVES: The relation between level of dentofacial deformity and extent of masticatory deficiency was studied. DESIGN: Three groups of human young adults were formed: (i) subjects needing orthodontics plus orthognathic surgery (SevDFD, n=18), (ii) subjects needing orthodontic treatment only (ModDFD, n=12), and (iii) subjects needing no treatment (NoDFD, n=12). For mastication tests, carrot boluses were collected at the deglutition time. Bolus particle size range was expressed as d50 value, which was compared with the Masticatory Normative Indicator (MNI). Index of treatment need (IOTN), global oral health assessment index (GOHAI) and chewing kinematic characteristics were also recorded. We used a general linear model univariate procedure followed by a Student-Newman-Keuls test. RESULTS: All the SevDFD subjects showed impaired mastication with MNI above the normal limit (d50 mean=7.23mm). All the ModDFD subjects but one were below this limit (d50 mean=2.54mm), and so could adapt to a low level of masticatory impairment as also indicated by kinematics. IOTN indicated a treatment need for ModDFD (3.7+/-0.5) and SevDFD (4.3+/-0.6) groups, while GOHAI values were unsatisfactory only for SevDFD (42.6+/-9.2 vs. 55.3+/-1.9). CONCLUSIONS: Our findings emphasize the need for an objective evaluation of masticatory function to discern truly deficient mastication from mild impairment allowing satisfactory adaptation of the function. However, malocclusions are known to worsen with time justifying thus their corrections as early as possible. PMID- 27978478 TI - An evaluation of pregnant women's knowledge and attitudes about newborn bloodspot screening. AB - OBJECTIVES: research suggests that information provided to parents about newborn bloodspot screening (NBS) can be inconsistent. The majority of international NBS programmes recommend that parents should receive information about NBS in the antenatal period, however prior studies have mostly focused on postnatal women's knowledge, with no quantitative study of women's knowledge in the antenatal period conducted to date. Thus, the aim of this study was to determine if antenatal women received information about NBS in the antenatal period and to evaluate their knowledge and attitudes about NBS. DESIGN/PARTICIPANTS: we conducted a cross-sectional study among antenatal attendees at three maternity hospitals in Ireland. A total of 662 antenatal women (>=36 weeks gestation) were recruited into the study (279 primiparous, 368 multiparous). Women were asked to complete a self reported knowledge and attitude questionnaire about NBS. FINDINGS: primiparity (OR 2.75; 95% CI 1.65, 4.59) lower educational status (OR 1.79; 95% CI 1.02, 3.15) and not having private health insurance (OR 1.84; 95% CI 1.19, 2.85) were independently associated with poor NBS knowledge. Fourteen per cent of antenatal women recalled receiving an information leaflet about NBS, yet over 87 % reported that they would like more information. Thirty four per cent of women agreed that they understand everything they need to know about NBS. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: the process of providing women with information about NBS in the antenatal period is inconsistent; consequently their awareness about NBS is limited. To make an informed choice about NBS women require information to be provided in a more structured format. There are many missed opportunities in the antenatal period for maternity care providers to provide women with information about NBS. Our study recommends that healthcare providers should have a more formal and structured approach with regard to the provision of information about NBS in the antenatal period. This could be achieved by incorporating NBS education into antenatal education classes or through multimedia while women are waiting in the antenatal clinic. Healthcare providers may need education about the importance and benefits of providing women with information about NBS in the antenatal period. PMID- 27978480 TI - Adult NSC diversity and plasticity: the role of the niche. AB - Adult somatic stem cells are generally defined as cells with the ability to differentiate into multiple different lineages and to self-renew during long periods of time. These features were long presumed to be represented in one single tissue-specific stem cell. Recent development of single-cell technologies reveals the existence of diversity in fate and activation state of somatic stem cells within the blood, skin and intestinal compartments [1] but also in the adult brain. Here we review how recent advances have expanded our view of neural stem cells (NSCs) as a diverse pool of cells and how the specialized microenvironment in which they reside acts to maintain this diversity. In addition, we discuss the plasticity of the system in the injured brain. PMID- 27978479 TI - oRGs and mitotic somal translocation - a role in development and disease. AB - The evolution of the human brain has been characterized by an increase in the size of the neocortex. Underlying this expansion is a significant increase in the number of neurons produced by neural stem cells during early stages of cortical development. Here we highlight recent advances in our understating of these cell populations, consisting of ventricular radial glia and outer radial glia. We highlight how gene expression studies have identified molecular signatures for radial glial cell populations and outline what has been learned about the mechanisms underlying the characteristic mode of division observed in outer radial glia cells, mitotic somal translocation. Understanding the significance of this behavior may help us explain human cortical expansion and further elucidate neurodevelopmental diseases. PMID- 27978481 TI - Division modes and physical asymmetry in cerebral cortex progenitors. AB - Neural stem cells go through a sequence of timely regulated gene expression and pattern of division mode to generate diverse neurons during brain development. During vertebrate cerebral cortex development, neural stem cells begin with proliferative symmetric divisions, subsequently undergo neurogenic asymmetric divisions, and finally gliogenic divisions. In this review, we explore the relationship between stem cell versus neural fate specification and the division mode. Specifically, we discuss recent findings on the mechanisms of asymmetric divisions, division mode, and developmental progression of neural progenitor identity. PMID- 27978482 TI - Sensitivity of the green algae Chlamydomonas reinhardtii to gamma radiation: Photosynthetic performance and ROS formation. AB - The aquatic environment is continuously exposed to ionizing radiation from both natural and anthropogenic sources, making the characterization of ecological and health risks associated with radiation of large importance. Microalgae represent the main source of biomass production in the aquatic ecosystem, thus becoming a highly relevant biological model to assess the impacts of gamma radiation. However, little information is available on the effects of gamma radiation on microalgal species, making environmental radioprotection of this group of species challenging. In this context, the present study aimed to improve the understanding of the effects and toxic mechanisms of gamma radiation in the unicellular green algae Chlamydomonas reinhardtii focusing on the activity of the photosynthetic apparatus and ROS formation. Algal cells were exposed to gamma radiation (0.49-1677mGy/h) for 6h and chlorophyll fluorescence parameters obtained by PAM fluorometry, while two fluorescent probes carboxy-H2DFFDA and DHR 123 were used for the quantification of ROS. The alterations seen in functional parameters of C. reinhardtii PSII after 6h of exposure to gamma radiation showed modifications of PSII energy transfer associated with electron transport and energy dissipation pathways, especially at the higher dose rates used. Results also showed that gamma radiation induced ROS in a dose-dependent manner under both light and dark conditions. The observed decrease in photosynthetic efficiency seems to be connected to the formation of ROS and can potentially lead to oxidative stress and cellular damage in chloroplasts. To our knowledge, this is the first report on changes in several chlorophyll fluorescence parameters associated with photosynthetic performance and ROS formation in microalgae after exposure to gamma radiation. PMID- 27978483 TI - The toxicity of plastic nanoparticles to green algae as influenced by surface modification, medium hardness and cellular adsorption. AB - To investigate processes possibly underlying accumulation and ecological effects of plastic nano-particles we have characterized their interaction with the cell wall of green algae. More specifically, we have investigated the influence of particle surface functionality and water hardness (Ca2+ concentration) on particle adsorption to algae cell walls. Polystyrene nanoparticles with different functional groups (non-functionalized, -COOH and -NH2) as well as coated (starch and PEG) gold nanoparticles were applied in these studies. Depletion measurements and atomic force microscopy (AFM) showed that adsorption of neutral and positively charged plastic nanoparticles onto the cell wall of P. subcapitata was stronger than that of negatively charged plastic particles. Results indicated that binding affinity is a function of both inter-particle and particle-cell wall interactions which are in turn influenced by the medium hardness and particle concentration. Physicochemical modelling using DLVO theory was used to interpret the experimental data, using also values for interfacial surface free energies. Our study shows that material properties and medium conditions play a crucial role in the rate and state of nanoparticle bio-adsorption for green algae. The results show that the toxicity of nanoparticles can be better described and assessed by using appropriate dose metrics including material properties, complexation/agglomeration behavior and cellular attachment and adsorption. The applied methodology provides an efficient and feasible approach for evaluating potential accumulation and hazardous effects of nanoparticles to algae caused by particle interactions with the algae cell walls. PMID- 27978484 TI - Oxcarbazepine administration and the serum levels of homocysteine, vitamin B12 and folate in epileptic patients: A systematic review and meta-analysis. AB - The objectives were to determine the influence of oxcarbazepine (OXC) monotherapy on the serum levels of total homocysteine (tHcy), vitamin B12 and folate in patient with epilepsy pooling together case-control or interventional studies. A comprehensive literature search was done through four databases including MEDLINE/PubMed, Scopus, Embase and Web of Science from January 2000 to February 2016. A random effects model (the DerSimonian-Laird estimator) was utilized to pool the effect sizes of the individual studies. The between-study variance was assessed using the Q2 test (significance level p<0.1) and quantified using the I2 test (>50% indicated evidence of heterogeneity). Overall, six studies found eligible for inclusion. The meta-analysis for tHcy revealed that the serum level of tHcy was no significant difference between patient on OXC monotherapy and healthy people [mean difference (MD) 0.31; 95% CI -1.05, 1.67, p=0.653]. The meta analysis for vitamin B12 [MD -46.51; 95% CI -113.63, 20.62, p=0.174] and folate [MD -0.48; 95% CI -1.06, 0.11, p=0.113] indicated that there was no significant difference between patients on OXC monotherapy and healthy people. In conclusion, the meta-analysis does not support the hypotheses that OXC monotherapy changes the serum levels of tHcy, vitamin B12 and folate. PMID- 27978485 TI - Nocebo effect in refractory partial epilepsy during pre-surgical monitoring: Systematic review and meta-analysis of placebo-controlled clinical trials. AB - PURPOSE: Nocebo is very prevalent among neurological diseases resulting in low adherence and treatment outcome. We sought to examine the AEs following placebo administration in Randomized Controlled Studies (RCTs) for Epilepsy. METHOD: After a systematic Medline search for RCTs for Epilepsy pharmacological treatments, we assessed the number of discontinuations because of placebo intolerance. RESULTS: Data were extracted from 4 RCTs fulfilling our search criteria. Three out of 5 placebo-treated patients (60.8%) reported at least one AE and 4.0% discontinued placebo treatment because of AEs. All patients participating in the epilepsy RCTs reported similar AEs independently of the study arm they belonged. CONCLUSION: Very limited epilepsy RCTs with pure placebo groups are available and all are in treatment resistant patients during pre surgical monitoring. However, our study indicates a significant nocebo effect in trials for epilepsy treatment adversely affecting adherence and efficacy of current treatments in clinical practice, with additional implications for trial designing. PMID- 27978486 TI - Comparing spatially static and dynamic vibrotactile take-over requests in the driver seat. AB - Vibrotactile stimuli can be effective as warning signals, but their effectiveness as directional take-over requests in automated driving is yet unknown. This study aimed to investigate the correct response rate, reaction times, and eye and head orientation for static versus dynamic directional take-over requests presented via vibrating motors in the driver seat. In a driving simulator, eighteen participants performed three sessions: 1) a session involving no driving (Baseline), 2) driving a highly automated car without additional task (HAD), and 3) driving a highly automated car while performing a mentally demanding task (N Back). Per session, participants received four directional static (in the left or right part of the seat) and four dynamic (moving from one side towards the opposite left or right of the seat) take-over requests via two 6*4 motor matrices embedded in the seat back and bottom. In the Baseline condition, participants reported whether the cue was left or right, and in the HAD and N-Back conditions participants had to change lanes to the left or to the right according to the directional cue. The correct response rate was operationalized as the accuracy of the self-reported direction (Baseline session) and the accuracy of the lane change direction (HAD & N-Back sessions). The results showed that the correct response rate ranged between 94% for static patterns in the Baseline session and 74% for dynamic patterns in the N-Back session, although these effects were not statistically significant. Steering wheel touch and steering input reaction times were approximately 200ms faster for static patterns than for dynamic ones. Eye tracking results revealed a correspondence between head/eye-gaze direction and lane change direction, and showed that head and eye-gaze movements where initiated faster for static vibrations than for dynamic ones. In conclusion, vibrotactile stimuli presented via the driver seat are effective as warnings, but their effectiveness as directional take-over requests may be limited. The present study may encourage further investigation into how to get drivers safely back into the loop. PMID- 27978487 TI - Wall teichoic acid is an essential component of Staphylococcus aureus for the induction of human dendritic cell maturation. AB - Staphylococcus aureus is a Gram-positive pathogen that can cause chronic skin inflammation, pneumonia, and septic shock. The immunomodulatory functions of wall teichoic acid (WTA), a glycopolymer abundantly expressed on the Gram-positive bacterial cell wall, are poorly understood. Here, we investigated the role of WTA in the phenotypic and functional activation of human monocyte-derived dendritic cells (DCs) treated with ethanol-killed S. aureus. WTA-deficient S. aureus mutant (DeltatagO) exhibited attenuated binding and internalization to DCs compared to the wild-type. DeltatagO induced lower expression of maturation markers on and cytokines in DCs than the wild-type S. aureus. Furthermore, autologous human peripheral blood mononuclear cells cocultured with DeltatagO-treated DCs exhibited a marked reduction in T cell proliferative activity, the expression of activation markers, and the production of cytokines compared to the wild-type S. aureus-stimulated DCs. Collectively, these results suggest that WTA is an important cell wall component of S. aureus for the induction of DC maturation and activation. PMID- 27978488 TI - Antibody-mediated targeting of antigen to C-type lectin-like receptors Clec9A and Clec12A elicits different vaccination outcomes. AB - Targeting antigen (Ag) to dendritic cell (DC) surface receptors is a potential new mode of vaccination. C-type lectin-like receptors Clec9A and Clec12A are attractive receptor targets however their targeting in vivo elicits significantly different outcomes for unknown reasons. To gain insight into the mechanisms responsible, we have examined the intrinsic capacity of Clec9A and Clec12A to elicit MHC I and MHC II Ag presentation following ex vivo targeting with primary murine DC. Both receptors exhibited high rates of internalization by CD8+ DCs, while Clec12A delivered a significantly higher Ag owing to its higher expression level. Targeting Ag to immature CD8+ DCs via both Clec9A and Clec12A failed to elicit MHC I cross-presentation above that of controls, while Clec12A was the superior receptor to target following CD8+ DC maturation. CD8- DCs were unable to elicit MHC I cross-presentation regardless of the receptor targeted. For MHC II presentation, targeting Ag to Clec12A enabled significant responses by both immature CD8+ and CD8- DCs, whereas Clec9A did not elicit significant MHC II Ag presentation by either DC subset, resting or mature. Therefore, Clec9A and Clec12A exhibit different intrinsic capacities to elicit MHC I and MHC II presentation following direct Ag targeting, though they can only elicit MHC I responses if the DC expressing the receptor is equipped with the capacity to cross-present. Our conclusions have consequences for the exploitation of these receptors for vaccination purposes, in addition to providing insight into their roles as Ag targets in vivo. PMID- 27978490 TI - Acute arsenic exposure induces inflammatory responses and CD4+ T cell subpopulations differentiation in spleen and thymus with the involvement of MAPK, NF-kB, and Nrf2. AB - Increasing lines of evidence indicate that arsenic may be associated with immune related problems, but its detailed effects on immune organs are poorly understood. The objective of this study was to explore inflammatory responses and T cell differentiation of arsenic exposure in spleen and thymus. Female C57BL/6 mice were used as a model to systemically administration 2.5, 5 and 10mg/kg NaAsO2 intra-gastrically for 24h. We found that arsenic significantly decreased the spleen and thymus weights and indices, and flow cytometry revealed that arsenic decreased the relative frequency of CD4+ T cell subpopulation and the ratios of CD4/CD8 in spleen. In contrast, serum concentration of tumor necrosis factor alpha (TNF-alpha), IL-1beta and IL-6 as well as the mRNA of key inflammatory mediators in spleen and thymus, including transforming growth factor beta (Tgf-beta), Tnf-alpha, Il-12, Il-1beta and Il-6 were significantly increased in arsenic-treated mice compared to the control as assayed by ELISA and real time PCR, respectively. In addition, arsenic increased the expression of T helper cell 1 (Th1), Th2 and regulatory T cell (Treg) -associated transcription factors and cytokines as well as decreased Th17-associated transcription factors and cytokines. Moreover, arsenic enhanced oxidative stress and induced the activation of extracellular-signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and p38 and their downstream transcription factors nuclear factor kappa B (NF-kB) and nuclear factor E2-related factor 2 (Nrf2), which comprise important mechanistic pathways involved in immune-inflammatory manifestations. Together, these results provide a novel strategy to block the arsenic-dependent impairments in immune responses. PMID- 27978489 TI - Structural, mutational and biophysical studies reveal a canonical mode of molecular recognition between immune receptor TIGIT and nectin-2. AB - In addition to antigen-specific stimulation of T cell receptor (TCR) by a peptide MHC complex, the functional outcome of TCR engagement is regulated by antigen independent costimulatory signals. Costimulatory signals are provided by an array of interactions involving activating and inhibitory receptors expressed on T cells and their cognate ligands on antigen presenting cells. T cell immunoglobulin and ITIM domain (TIGIT), a recently identified immune receptor expressed on T and NK cells, upon interaction with either of its two ligands, nectin-2 or poliovirus receptor (PVR), inhibits activation of T and NK cells. Here we report the crystal structure of the human TIGIT ectodomain, which exhibits the classic two-layer beta-sandwich topology observed in other immunoglobulin super family (IgSF) members. Biophysical studies indicate that TIGIT is monomeric in solution but can form a dimer at high concentrations, consistent with the observation of a canonical immunoglobulin-like dimer interface in the crystalline state. Based on existing structural data, we present a model of the TIGIT:nectin-2 complex and utilized complementary biochemical studies to map the nectin-binding interface on TIGIT. Our data provide important structural and biochemical determinants responsible for the recognition of nectin 2 by TIGIT. Defining the TIGIT:nectin-2 binding interface provides the basis for rational manipulation of this molecular interaction for the development of immunotherapeutic reagents in autoimmunity and cancer. PMID- 27978492 TI - Do spouse caregivers of persons with early- and late-onset dementia cope differently? A comparative study. AB - OBJECTIVES: To explore spouse caregivers' means of coping with the disease and compare them based on the age of onset of the disease in order to adapt support programs. METHODS: Interviews were conducted with 38 spouse caregivers of persons with late-onset dementia (PLOD) and 40 spouse caregivers of persons with early onset dementia (PEOD). The first step in the analysis was qualitative, using QSR N'Vivo 10 to identify the coping strategies. The second step was quantitative, comparing the coping strategies based on the age of onset of the disease with a chi2 test. RESULTS: An inventory of 26 strategies used by all caregivers was established and consolidated into two groups: acceptance strategies and avoidance strategies. The statistical results show that some strategies were used by the two groups of caregivers. However, when differences emerged, the "Planning" strategy was used by spouse caregivers of PEOD, whereas the "Re-arranging", "Humor" and "Getting away from the entourage" strategies were used by spouse caregivers of PLOD. CONCLUSION: It would be interesting to develop a support program with a common framework and specific modules depending on the age of onset of the disease. Common modules would permit developing and strengthening acceptance strategies. Specific modules for caregivers of PEOD would guide them in the acquisition of more adaptability and flexibility in the assistance provided to the PWD, which can sometimes be too rigid and controlled. Specific modules for caregivers of PLOD would help them to develop the ability to request help and identify the intervention limits of the entourage. PMID- 27978493 TI - Valence and arousal-based affective evaluations of foods. AB - We investigated the nutrient-specific and individual-specific validity of dual process models of valenced and arousal-based affective evaluations of foods across the disordered eating spectrum. 283 undergraduate women provided implicit and explicit valence and arousal-based evaluations of 120 food photos with known nutritional information on structurally similar indirect and direct affect misattribution procedures (AMP; Payne et al., 2005, 2008), and completed questionnaires assessing body mass index (BMI), hunger, restriction, and binge eating. Nomothetically, added fat and added sugar enhance evaluations of foods. Idiographically, hunger and binge eating enhance activation, whereas BMI and restriction enhance pleasantness. Added fat is salient for women who are heavier, hungrier, or who restrict; added sugar is influential for less hungry women. Restriction relates only to valence, whereas binge eating relates only to arousal. Findings are similar across implicit and explicit affective evaluations, albeit stronger for explicit, providing modest support for dual-process models of affective evaluation of foods. PMID- 27978491 TI - Validation of the self-report EXERNET questionnaire for measuring physical activity and sedentary behavior in elderly. AB - This study aims to examine the validity and reliability of the Elderly EXERNET Physical Activity Questionnaire (EEPAQ) in a sample of Spanish elderly population. A sample of 73 elderly successfully completed the EEPAQ and wore an accelerometer over 7 consecutive days. Test-retest reliability of the EEPAQ was assessed by having the participants answer the EEPAQ twice within 14 days. Criterion validity was assessed for the questionnaire against the accelerometer, as the gold standard. Results indicated that EEPAQ had adequate reliability measured by Intraclass correlation coefficient (ICC) (walking ICC=0.88; sitting ICC=0.68; household activities ICC=0.97), and good validity against the accelerometer. Walking had a significant (p<0.05) correlation with countsmin-1 (r=0.56) and moderate to vigorous physical activity (MVPA) (r=0.51), as well as a negative significant (p<0.01) correlation with sedentary minutes (r=-0.33). Sitting time was positively correlated (r=0.57; p<0.01) with sedentary time and negatively correlated with the countsmin-1 and MVPA. EEPAQ seems to be a valid and reliable tool to measure physical activity (PA) in a population of elderly living in Spain. PMID- 27978494 TI - Salidroside alleviates cigarette smoke-induced COPD in mice. AB - The present study was to evaluate the effects of salidroside (Sal) on CS (cigarette smoke)-induced COPD in mice and explore its underlying mechanisms. 50 male ICR mice were randomly assigned to five groups: control group, CS group, CS+dexamethasone (2mg/kg) group, CS+salidroside (20mg/kg) group and CS+salidroside (40mg/kg) group. The COPD mice were induced by CS exposure for 8 weeks. The results of H&E staining demonstrated that Sal alleviated CS-induced pathological injury in lungs. Besides, Sal increased the activities of superoxide dismutase (SOD), reduced the content of malondialdehyde (MDA) in serum. Sal also inhibited the generations of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) in serum and lungs. Furthermore, the administration of Sal significantly inhibited the protein levels of MAPK/NF-kappaB pathway in CS-induced mice. Our findings showed that Sal might effectively ameliorate the progression of COPD via MAPK/NF-kappaB pathway. PMID- 27978496 TI - Evaluation of hepatoprotective and antidiabetic activity of Alchemilla mollis. AB - Alchemilla mollis (Buser) Rothm aerial part and root methanolic-water extracts were evaluated for their hepatoprotective activity on carbon tetrachloride induced hepatotoxicity and hypoglycemic activity on alloxan-induced diabetic mice. None of the tested extracts exhibited effects on blood glucose levels. However hepatoprotective activity results have revealed that serum ALT levels were significantly lowered by both the aerial part and root extracts at doses of 100mg/kg and 200mg/kg. Histopathological examination showed that A. mollis aerial parts and roots induced significant recovery from cellular damage; when compared to the carbon tetrachloride group, the most significant activity was observed with A. mollis aerial part extracts at a dose of 200mg/kg. There is evidence of a hepatoprotective activity of A. mollis on the phenolic content of the plant, especially in the case of flavonoids, which have potent antioxidant properties. PMID- 27978495 TI - Brazilian red propolis improves cutaneous wound healing suppressing inflammation associated transcription factor NFkappaB. AB - The use of natural products in wound healing has been extensively studied in the context of complementary and alternative medicine. Propolis, a natural product, is a polyphenol-rich resin used for this purpose. This study aimed to investigate the effect of Brazilian Red Propolis Extract (BRPE) on inflammation and wound healing in mice, using a tissue repair model. The BRPE polyphenol content was analyzed by liquid chromatography coupled to mass spectrometry (LC/MS). A full thickness excision lesion was created, and mice were treated orally with daily doses of vehicle solution (water-alcohol solution containing 2% of ethanol, control group) or 100mg/kg of BRPE (P100 group) during nine consecutive days. BRPE chemical composition analysis showed that this complex matrix contains several phenolic compounds such as phenolic acids, phenolic terpenes and flavonoids (especially catechins, flavonols, chalcones, isoflavones, isoflavans, pterocarpans and bioflavonoids). After BRPE administration, it was observed that, when compared to the control group, P100 group presented faster wound closure (p<0.001); less neutrophils per mm2 (p<0.05) and macrophages (p<0.01) in tissue analyses, down regulation of the inflammatory transcription factor pNF-kappaB protein expression, and reduced production of inflammatory cytokine, such as TGF beta, TNF-alpha (p<0.0001), and IL-6 (p<0.001). These findings suggest a positive role of BRPE oral administration in the wound healing process via suppressing the inflammatory response during tissue repair. PMID- 27978497 TI - Magnesium Isoglycyrrhizinate attenuates lipopolysaccharide-induced depressive like behavior in mice. AB - Magnesium Isoglycyrrhizinate (MI) is a magnesium salt of 18alpha-GA stereoisomer which has been reported to exert hepatoprotective activity. The aim of the present study was to ascertain the underlying mechanisms behind the action of Magnesium Isoglycyrrhizinate on neuroinflammatation and oxidative stress in LPS stimulated mice. Mice were pretreated with Magnesium Isoglycyrrhizinate (MI, 25, 50mg/kg) as well as fluoxetine (Flu, positive control, 20mg/kg) once daily for one week before intraperitoneal injection of LPS (0.83mg/kg). Pretreatments with MI and Flu significantly improved immobility time in tail suspension test (TST) and forced swim test (FST) as well as locomotor activity in open-field test (OFT). In addition, the levels of pro-inflammatory cytokines and oxidative stress in serum and hippocampus were also suppressed effectively by MI and Flu administrations. Western blot analysis showed the up-regulated levels of p-Jak3, p-STAT3, p-NF-kappaBp65, and p-IkappaBalpha in mice exposed to LPS, while different degrees of down-regulation in these expression were observed in MI (25, 50mg/kg) and Flu (20mg/kg) groups respectively. Taken together, our obtained results demonstrated that Magnesium Isoglycyrrhizinate (MI) exhibited an antidepressant-like effect in LPS-induced mice, which might be mediated by JAK/STAT/NF-kappaB signaling pathway. PMID- 27978498 TI - Ornithine and its role in metabolic diseases: An appraisal. AB - Ornithine is a non-essential amino acid produced as an intermediate molecule in urea cycle. It is a key substrate for the synthesis of proline, polyamines and citrulline. Ornithine also plays an important role in the regulation of several metabolic processes leading to diseases like hyperorithinemia, hyperammonemia, gyrate atrophy and cancer in humans. However, the mechanism of action behind the multi-faceted roles of ornithine is yet to be unraveled completely. Several types of cancers are also characterized by excessive polyamine synthesis from ornithine by different rate limiting enzymes. Hence, in this review we aim to provide extensive insights on potential roles of ornithine in many of the disease related cellular processes and also on the structural features of ornithine interacting proteins, enabling development of therapeutic modalities. PMID- 27978499 TI - Coagulation in acutely ill patients with severe chronic liver disease: Insights from thromboelastography. AB - BACKGROUND AND AIMS: There is controversy about the true coagulation state of acutely ill patients with chronic liver disease (CLD) due to simultaneous pro- and anticoagulant factor deficits and limitations of conventional coagulation tests (CCTs). Thromboelastography (TEG) may provide more physiologically relevant insights. METHODS: In acutely ill patients with severe (Child-Pugh C) CLD, we conducted a prospective observational study of daily coagulation assessment with both CCTs and TEG. RESULTS: We studied 34 patients with CLD on a total of 109 occasions (median of 3 samples per patient), comparing findings with 157 healthy controls. Conventional coagulation tests and TEG both demonstrated clear hypocoagulability. Thromboelastography-confirmed delayed clot formation was demonstrated by longer reaction time (1.1 minutes vs 0.6 minutes on rapid TEG; P<.01), longer kinetic time (2.9 minutes vs 1.3; P<.01), more acute alpha angle (65 degrees vs 72.2 degrees ; P<.01), and longer activated clotting time (157 seconds vs 105 seconds; P<.01). Patients with CLD demonstrated weaker thrombus strength (maximum amplitude, 43.3 mm vs 61.8 mm; P<.01) and reduced clot lysis (0% vs 1% on rapid TEG; P<.01). CONCLUSIONS: In acutely ill patients with CLD, TEG demonstrates delayed clot formation and weaker thrombus strength despite decreased clot lysis. This challenges the notion that such patients experience a balanced coagulation state, highlighting the complexity of their coagulopathies. PMID- 27978500 TI - Photo-induced biosynthesis of silver nanoparticles from aqueous extract of Dunaliella salina and their anticancer potential. AB - The synthesis of silver nanoparticles (AgNPs) via green route, using biological entities is an area of interest, because one of the potential applications in the nanomedicine. In the present study, we have developed photo-induced, ecofriendly, low cost method for biosynthesis of the stable silver nanoparticles using aqueous extract of Dunaliella salina (AED) which act as both reducing as well as stabilizing agent. Biosynthesis of the AgNPs was optimized as: sunlight exposure (30min), AED (5% (v/v)) and AgNO3 (4mM). Biosynthesis of AgNPs was monitored by using UV-Vis spectroscopy which exhibited sharp SPR band at 430nm after 30min of bright sunlight exposure. SEM and TEM analyses confirmed the presence of spherical AgNPs with average size of 15.26nm. Crystalline nature of AgNPs was confirmed by SAED and XRD analyses where Braggs reflection pattern at (111), (200), (220) and (311) corresponded to face centered cubic crystal lattice of metallic silver. FTIR analysis revealed the involvement of various functional groups present in AED. AFM analysis confirmed the average surface roughness of synthesized AgNPs as 8.48nm. AgNPs were also screened for anticancer potential using assay of calcein AM/PI, Annexin/PI and cancer biomarkers against cancer cell line (MCF-7), while normal cell line (MCF-10A) were kept as control. Interestingly, anticancer potential was comparable to the known anticancer drug (Cisplatin), and was not detrimental to the normal cell line. Therefore, such green synthesized AgNPs may be explored as anticancer agent. PMID- 27978501 TI - Balancing sensory inputs: Sensory reweighting of ankle proprioception and vision during a bipedal posture task. AB - During multisensory integration, it has been proposed that the central nervous system (CNS) assigns a weight to each sensory input through a process called sensory reweighting. The outcome of this integration process is a single percept that is used to control posture. The main objective of this study was to determine the interaction between ankle proprioception and vision during sensory integration when the two inputs provide conflicting sensory information pertaining to direction of body sway. Sensory conflict was created by using bilateral Achilles tendon vibration and contracting visual flow and produced body sway in opposing directions when applied independently. Vibration was applied at 80Hz, 1mm amplitude and the visual flow consisted of a virtual reality scene with concentric rings retreating at 3m/s. Body sway elicited by the stimuli individually and in combination was evaluated in 10 healthy young adults by analyzing center of pressure (COP) displacement and lower limb kinematics. The magnitude of COP displacement produced when vibration and visual flow were combined was found to be lesser than the algebraic sum of COP displacement produced by the stimuli when applied individually. This suggests that multisensory integration is not merely an algebraic summation of individual cues. Instead the observed response might be a result of a weighted combination process with the weight attached to each cue being directly proportional to the relative reliability of the cues. The moderating effect of visual flow on postural instability produced by vibration points to the potential use of controlled visual flow for balance training. PMID- 27978503 TI - Sensory over responsivity and obsessive compulsive symptoms: A cluster analysis. AB - BACKGROUND: Several studies have examined the sensory component in Obsesseive Compulsive Disorder (OCD) and described an OCD subtype which has a unique profile, and that Sensory Phenomena (SP) is a significant component of this subtype. SP has some commonalities with Sensory Over Responsivity (SOR) and might be in part a characteristic of this subtype. Although there are some studies that have examined SOR and its relation to Obsessive Compulsive Symptoms (OCS), literature lacks sufficient data on this interplay. OBJECTIVES: First to further examine the correlations between OCS and SOR, and to explore the correlations between SOR modalities (i.e. smell, touch, etc.) and OCS subscales (i.e. washing, ordering, etc.). Second, to investigate the cluster analysis of SOR and OCS dimensions in adults, that is, to classify the sample using the sensory scores to find whether a sensory OCD subtype can be specified. Our third goal was to explore the psychometric features of a new sensory questionnaire: the Sensory Perception Quotient (SPQ). METHOD: A sample of non clinical adults (n=350) was recruited via e-mail, social media and social networks. Participants completed questionnaires for measuring SOR, OCS, and anxiety. RESULTS: SOR and OCI-F scores were moderately significantly correlated (n=274), significant correlations between all SOR modalities and OCS subscales were found with no specific higher correlation between one modality to one OCS subscale. Cluster analysis revealed four distinct clusters: (1) No OC and SOR symptoms (NONE; n=100), (2) High OC and SOR symptoms (BOTH; n=28), (3) Moderate OC symptoms (OCS; n=63), (4) Moderate SOR symptoms (SOR; n=83). The BOTH cluster had significantly higher anxiety levels than the other clusters, and shared OC subscales scores with the OCS cluster. The BOTH cluster also reported higher SOR scores across tactile, vision, taste and olfactory modalities. The SPQ was found reliable and suitable to detect SOR, the sample SPQ scores was normally distributed (n=350). CONCLUSIONS: SOR is a dimensional feature that can influence the severity of OCS and may characterize a unique sensory OCD subtype. PMID- 27978502 TI - Associations between emotion regulation difficulties, eating disorder symptoms, non-suicidal self-injury, and suicide attempts in a heterogeneous eating disorder sample. AB - BACKGROUND: This study examined the associations between specific dimensions of emotion dysregulation and eating disorder (ED) symptoms and behaviors, non suicidal self-injury (NSSI), and suicide attempts in a heterogeneous ED sample. METHODS: Participants (N=110) completed the Difficulties in Emotion Regulation Scale (DERS), the Eating Disorder Examination Questionnaire (EDE-Q), and self reported the presence of lifetime NSSI and a lifetime suicide attempt. RESULTS: The EDE-Q global score, a primarily cognitive measure of ED symptoms, was significantly positively correlated with DERS strategies, clarity, and awareness subscale scores and DERS total score (ps<0.01). Only the strategies subscale was uniquely positively associated with EDE-Q global score in a multivariate regression analysis. There was no association between the frequency of binge eating or frequency of driven exercise and any of the DERS subscale scores or total score (ps>0.01). Frequency of purging was significantly, positively associated with DERS impulse subscale score and total score (p<0.01). None of the DERS subscale scores were significantly different between those with and without NSSI or between those with and without a lifetime suicide attempt (ps>0.01). CONCLUSIONS: Findings indicate that in a heterogeneous ED sample, emotion regulation deficits are more strongly associated with cognitively-oriented symptoms of EDs than behavioral symptoms such as a binge eating, purging, driven exercise, NSSI, or suicide attempts. PMID- 27978505 TI - The first report of A. novoparasiticus, A. arachidicola and A. pseudocaelatus in Brazilian corn kernels. AB - Maize is one of the most important commercial crops cultivated throughout the world, mostly in tropical and subtropical countries. It is highly susceptible to mycotoxins, toxic secondary metabolites produced by fungi. In this study, we assessed freshly harvested corn produced in Brazil for aflatoxin contamination and the presence of Aspergillus. B type aflatoxins (AFB1+AFB2) were detected in 56% of 16 grain samples, while G type aflatoxins (AFG1+AFG2) were detected in 25%. Of the total number of grains (n=1920) evaluated for the presence of fungi species, 4.7% were infected with Aspergillus species, 74.5% and 16.7% respectively with Fusarium and Penicillium species and 4.1% with other fungi genera. In total, 89 Aspergillus isolates were identified, most (86 isolates) characterized as belonging to Aspergillus section Flavi, and the remainder to Aspergillus section Cremei (2 isolates) and Aspergillus section Terrei (1 isolate). All the isolates of section Flavi were subjected to molecular analysis. They were found to belong to six species, including Aspergillus novoparasiticus, Aspergillus arachidicola and Aspergillus pseudocaelatus, all aflatoxins B and G producing species, which are herein described for the first time infecting corn kernels. PMID- 27978506 TI - A minireview on the in vitro and in vivo experiments with anti-Escherichia coli O157:H7 phages as potential biocontrol and phage therapy agents. AB - Phage therapy is an old method of combating bacterial pathogens that has recently been taken into consideration due to the alarming spread of antibiotic resistance. Escherichia coli O157:H7 is a foodborne pathogen that causes hemorrhagic colitis and life-threatening Hemolytic Uremic Syndrome (HUS). There are several studies on isolation of specific phages against E. coli O157:H7 and more than 60 specific phages have been published so far. Although in vitro experiments have been successful in elimination or reduction of E. coli O157:H7numbers, in vivo experiments have not been as promising. This may be due to escape of bacteria to locations where phages have difficulties to enter or due to the adverse conditions in the gastrointestinal tract that affect phage viability and proliferation. To get around the latter obstacle, an alternative phage delivery method such as polymer microencapsulation should be tried. While the present time results are not very encouraging the work should be continued as more efficient phage treatment regimens might be found in future. PMID- 27978504 TI - Redox-guided axonal regrowth requires cyclic GMP dependent protein kinase 1: Implication for neuropathic pain. AB - Cyclic GMP-dependent protein kinase 1 (PKG1) mediates presynaptic nociceptive long-term potentiation (LTP) in the spinal cord and contributes to inflammatory pain in rodents but the present study revealed opposite effects in the context of neuropathic pain. We used a set of loss-of-function models for in vivo and in vitro studies to address this controversy: peripheral neuron specific deletion (SNS-PKG1-/-), inducible deletion in subsets of neurons (SLICK-PKG1-/-) and redox dead PKG1 mutants. In contrast to inflammatory pain, SNS-PKG1-/- mice developed stronger neuropathic hyperalgesia associated with an impairment of nerve regeneration, suggesting specific repair functions of PKG1. Although PKG1 accumulated at the site of injury, its activity was lost in the proximal nerve due to a reduction of oxidation-dependent dimerization, which was a consequence of mitochondrial damage in injured axons. In vitro, PKG1 deficiency or its redox insensitivity resulted in enhanced outgrowth and reduction of growth cone collapse in response to redox signals, which presented as oxidative hotspots in growing cones. At the molecular level, PKG1 deficiency caused a depletion of phosphorylated cofilin, which is essential for growth cone collapse and guidance. Hence, redox-mediated guidance required PKG1 and consequently, its deficiency in vivo resulted in defective repair and enhanced neuropathic pain after nerve injury. PKG1-dependent repair functions will outweigh its signaling functions in spinal nociceptive LTP, so that inhibition of PKG1 is no option for neuropathic pain. PMID- 27978509 TI - Nuclear functions of beta2-Spectrin in genomic stability. PMID- 27978510 TI - Optimizing Cerebral Autoregulation May Decrease Neonatal Regional Hypoxic Ischemic Brain Injury. AB - BACKGROUND: Therapeutic hypothermia provides incomplete neuroprotection for neonatal hypoxic-ischemic encephalopathy (HIE). We examined whether hemodynamic goals that support autoregulation are associated with decreased brain injury and whether these relationships are affected by birth asphyxia or vary by anatomic region. METHODS: Neonates cooled for HIE received near-infrared spectroscopy autoregulation monitoring to identify the mean arterial blood pressure with optimized autoregulatory function (MAPOPT). Blood pressure deviation from MAPOPT was correlated with brain injury on MRI after adjusting for the effects of arterial carbon dioxide, vasopressors, seizures, and birth asphyxia severity. RESULTS: Blood pressure deviation from MAPOPT related to neurologic injury in several regions independent of birth asphyxia severity. Greater duration and deviation of blood pressure below MAPOPT were associated with greater injury in the paracentral gyri and white matter. Blood pressure within MAPOPT related to lesser injury in the white matter, putamen and globus pallidus, and brain stem. Finally, blood pressures that exceeded MAPOPT were associated with reduced injury in the paracentral gyri. CONCLUSIONS: Blood pressure deviation from optimal autoregulatory vasoreactivity was associated with MRI markers of brain injury that, in many regions, were independent of the initial birth asphyxia. Targeting hemodynamic ranges to optimize autoregulation has potential as an adjunctive therapy to hypothermia for HIE. PMID- 27978512 TI - Endoscopic Valve Therapy: A New Therapeutic Approach for Otherwise Incurable Tuberculosis? PMID- 27978511 TI - Effects of Daprodustat, a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Anemia Management in Japanese Hemodialysis Subjects. AB - BACKGROUND: Daprodustat (GSK1278863) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for treatment of anemia associated with chronic kidney disease (CKD). The effect of daprodustat in Japanese CKD patients with anemia has not been previously investigated. METHODS: We evaluated the relationship between daprodustat dose and hemoglobin response in Japanese patients on hemodialysis (HD) with anemia in a 4-week, phase II, double-blind, placebo-controlled study. After interrupting their erythropoiesis-stimulating agent for between 2 and 8 weeks, subjects with hemoglobin 8.5-10.5 g/dL were randomized to placebo or daprodustat 4, 6, 8, or 10 mg orally once daily. Hemoglobin, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) levels during therapy were evaluated. RESULTS: Eighty-six of 97 randomized subjects completed the study. Mean baseline hemoglobin ranged from 9.68 to 9.92 g/dL across groups. After 4-week administration, mean hemoglobin changes were 0.28, -0.01, 0.54, and 0.97 g/dL in the 4, 6, 8, and 10 mg groups, respectively, as compared to -1.41 g/dL for placebo. Dose-dependent increase in plasma EPO concentration were observed up to 8 mg, with the 10 mg dose responses being similar to 8 mg. Plasma VEGF concentrations were minimally changed, even though 5 subjects treated with 6-10 mg reached EPO >500 mIU/mL. CONCLUSION: Daprodustat 4 10 mg once-daily produced dose-dependent increase in hemoglobin relative to placebo in Japanese HD subjects. The doses evaluated in the study have moderately increased endogenous EPO without changes in circulating VEGF levels. PMID- 27978513 TI - An Overview of Errors and Flaws of Estimated GFR versus True GFR in Patients with Diabetes Mellitus. AB - The determination of renal function is crucial in patients with type 2 diabetes (T2DM), a population at risk for chronic kidney disease (CKD). Glomerular filtration rate (GFR) can be measured (mGFR) with gold standard methods or estimated (eGFR) with formulas. Since 1957, when Effersoe published the first formula, more than 50 equations have been developed to estimate GFR. In this review, we examined the studies that compared mGFR and eGFR in patients with T2DM to analyze the performance of those formulae in this population. In cross sectional studies, the average error of eGFR was +/-30% of mGFR. Thus, in a patient with mGFR of 60 mL/min, eGFR may vary from 42 to 78 mL/min. Moreover, many patients were misclassified according to CKD stages. Formulas failed to detect glomerular hyperfiltration. In longitudinal studies, eGFR poorly reflected real GFR decline over time. All studies showed that eGFR decline was slower than mGFR decline. Notably, no major improvement in accuracy and precision has been observed since 1957 despite the use of cystatin-c. Thus, formulas are not reliable indicators of GFR in patients with T2DM. In clinical studies, where GFR is the main outcome measure of the study, eGFR should be avoided. PMID- 27978515 TI - AQP5 Variants Affect Tumoral Expression of AQP5 and Survival in Patients with Early Breast Cancer. AB - BACKGROUND: Our previous study showed the association of AQP5 upregulation with cancer proliferation and migration in breast cancer cell lines and with unfavorable prognosis in patients with early breast cancer (EBC). In the current study, we analyzed the association of AQP5 variants or their haplotypes with AQP5 expression and their prognostic impact for survival in patients with EBC. METHODS: Three AQP5 polymorphisms (rs74091166, rs3736309, and rs1964676) were selected based on the SNP database and genotyped using the Sequenom MassARRAY in 374 out of 447 patients with EBC in whom AQP5 expression had been investigated in our previous study. RESULTS: The allele frequencies of the selected variants in the current study were similar to those from Asian data previously reported. In a univariate analysis, both rs74091166 and rs1964676 were statistically associated with survival as a dominant model of minor allele. Moreover, a multivariate survival analysis revealed that the CC genotype of rs1964676 is an independent prognostic marker of survival in EBC patients, regardless of stage, tumor subtype, and adjuvant treatment [hazard ratio = 0.399, 0.384, and 0.205; p = 0.021, 0.027, and 0.016 for disease-free survival (DFS), distant DFS, and disease specific survival, respectively]. In particular, the CT/TT genotype of rs1964676 showed an association with strong expression of AQP5 (58.6 vs. 26.0%; p = 0.001), without any associations with clinical or pathological characteristics including tumor subtype, stage, or histologic grade. CONCLUSION: The current study suggests AQP5 rs1964676 as a new potential prognostic marker in patients with EBC involved in AQP5 expression. PMID- 27978516 TI - Prognostic Significance of Dementia in Older Adults with Solid Tumors. AB - BACKGROUND: The public health burden of cancer and dementia in the geriatric population is well documented. There is limited data on how dementia predicts mortality among geriatric patients with solid tumors. The objective of this study is to determine the prognostic significance of dementia on survival in patients with solid tumors. METHODS: We performed a 5-year retrospective study on elderly subjects aged >=60 years with and without dementia that were diagnosed with solid tumors. RESULTS: Among 3,460 patients with solid tumors, 132 (3.8%) patients were found to have dementia. The median age at diagnosis was 71 years. Kaplan-Meier curves demonstrated that patients with dementia had an inferior median survival compared to the nondemented group (30 vs. 56 months; log-rank p < 0.001). Cox proportional hazard regression modeling identified age >80 years, female gender, diabetes mellitus, congestive heart failure, atrial fibrillation, chronic obstructive pulmonary disease, chronic kidney disease, dementia, and radiation therapy as risk factors for decreased overall survival. CONCLUSIONS: We demonstrated that dementia is associated with shorter overall survival in elderly patients with solid tumors. PMID- 27978519 TI - The Use of Peripherally Inserted Central Catheter in Amyotrophic Lateral Sclerosis Patients at a Later Stage. AB - BACKGROUND/AIMS: To describe the use of peripherally inserted central catheter (PICC), in amyotrophic lateral sclerosis (ALS) at a later stage. METHODS: Twenty five ALS patients in the later stages of the disease underwent PICC insertion followed by parenteral nutrition (PN). For all of them, gastrostomy was non feasible. Patients were followed until death and monitored for complications. RESULTS: PICC insertion was successful in all patients. Three months after insertion, the mean body weight increased by 4.5% (p = 0.0057). PICC could be maintained until death in all but 1 patient. The mean delay between insertion and death was 4.5 months, but PN was administered for more than 1 year in 2 patients. Complications were noted in 6 patients: sepsis (n = 4), venous thrombosis (n = 1), and upper limb oedema (n = 1), none of them resulting in death. CONCLUSION: PICC insertion for PN at a later stage of ALS, in patients for whom gastrostomy is non-feasible, appears to be a useful option compared to the central venous catheter. PMID- 27978517 TI - Management of Fetal and Neonatal Graves' Disease. AB - Fetal and neonatal autoimmune hyperthyroidism is a rare, serious but transient disorder. Early diagnosis and treatment are key objectives for an optimal prognosis and the well-being of the child. This review focuses on the management of these patients during the fetal and neonatal periods. We propose a diagnostic algorithm for high-risk pregnancies in mothers with current or past hyperthyroidism related to Graves' disease, involving repeated fetal thyroid gland assessments from 20 weeks of gestation onwards and maternal serum thyroid stimulating hormone receptor antibody (TRAb) determination, with close monitoring if TRAb levels exceed 2 to 3 times the upper limit of the normal range. In fetuses with goiter, the main clinical issue is determining whether the cause is (1) maternal antithyroid drug (ATD) treatment that is appropriate for achieving normal maternal thyroid function but inappropriate and excessive for the fetus, resulting in hypothyroidism and necessitating a decrease in the ATD dose during pregnancy, or (2) the presence of TRAbs resulting in fetal thyroid stimulation and hyperthyroidism, requiring an increase in the maternal ATD dose. Methimazole/carbimazole treatment should be initiated as soon as possible during the neonatal period, carefully managed and maintained over a period of 1-3 months and then stopped when TRAb is no longer detectable in serum. PMID- 27978518 TI - High Dialysate Calcium Concentration May Cause More Sympathetic Stimulus During Hemodialysis. AB - BACKGROUND/AIMS: Acute activation of sympathetic activation during hemodialysis is essential to maintain blood pressure (BP), albeit long-term overactivity contributes to higher mortality. Low heart rate variability (HRV), a measure of autonomic nervous system activity, and abnormal ankle-brachial index (ABI) are associated with higher mortality in patients on hemodialysis. In this study, we assessed HRV and ABI pre and post dialysis in incident patients on hemodialysis using high (1.75mmol/l) and low (1.25mmol/l) dialysate calcium concentration (DCa). METHODS: HRV was measured as the ratio between low frequency and high frequency power (LF/HF). Thirty patients (age 47+/-16 years, 67% men) were studied in two consecutive mid-week hemodialysis sessions. RESULTS: Mean BP variation was positive with DCa 1.75 and negative with DCa 1.25 [4.0 (-6.0, 12.2 mmHg) vs. -3.2 (-9.8, 1.3 mmHg); p=0.050]. Reduction of ABI from pre to post HD was related to higher sympathetic activity (p=0.031). The increase in LF/HF ratio was higher with DCa 1.75 (58.3% vs. 41.7% in DCa 1.75 and 1.25, respectively, RR 2.8; p=0.026). CONCLUSION: Although higher DCa is associated with better hemodynamic tolerability during hemodialysis, this occurs at the expense of increased sympathetic activity. Higher sympathetic activity was associated with a decrease of ABI during hemodialysis. PMID- 27978520 TI - Abnormal Time Experiences in Major Depression: An Empirical Qualitative Study. AB - BACKGROUND: Phenomenological psychopathology, through theoretical and idiographic studies, conceptualizes major depressive disorder (MDD) as a disorder of time experience. Investigations on abnormal time experience (ATE) in MDD adopting methodologies requested by the standards of empirical sciences are still lacking. Our study aimed to provide a qualitative analysis, on an empirical ground and on a large scale, of narratives of temporal experiences of persons affected by MDD. METHODS: We interviewed 550 consecutive patients affected by affective and schizophrenic disorders. Clinical files were analysed by means of consensual qualitative research. RESULTS: Out of 100 MDD patients, 96 reported at least 1 ATE. The principal categories of ATE are vital retardation - the experience of a stagnation of endogenous vital processes (37 patients), the experience of present and future dominated by the past (29 patients), and the experience of the slackening of the flow oftime (25 patients). A comparison with ATE in schizophrenia patients showed that in MDD, unlike in schizophrenia, there is no disarticulation of time experience (disorder of temporal synthesis) but rather a disorder of conation or inhibition of becoming. LIMITATIONS: The interview style was not meant to make a quantitative assessment ("false negatives" cannot be excluded). CONCLUSIONS: Our findings confirm the relevance of distinctive features of ATE in MDD, support the hypothesis of an intrinsic disordered temporal structure in depressive symptoms, and may have direct implications in clinical practice, especially in relation to differential diagnosis, setting the boundaries between "true" and milder forms of depression, and neurobiological research. PMID- 27978521 TI - The Hyperfiltering Kidney in Diabetes. AB - Hyperfiltering kidney is a typical feature of diabetes. Improvement observed with regard to glucose control and blood pressure control reduces the high glomerular filtration rate and may contribute to retard the appearance and the progression of diabetic renal disease. Although the mechanism of hyperfiltration is still unclear, there is mounting evidence that the increased reabsorption of glucose and sodium by sodium glucose transporter-2 (SGLT-2) is involved in this altered renal function. There is a possibility that SGLT-2 inhibition may correct hyperfiltration in diabetes, adding a new therapeutic approach to halt renal disease in patients with diabetes. PMID- 27978523 TI - Paravalvular Regurgitation after Transcutaneous Aortic Valve Replacement: A Dynamic Lesion? PMID- 27978524 TI - Gene Network for Identifying the Entropy Changes of Different Modules in Pediatric Sepsis. AB - BACKGROUND/AIMS: Pediatric sepsis is a disease that threatens life of children. The incidence of pediatric sepsis is higher in developing countries due to various reasons, such as insufficient immunization and nutrition, water and air pollution, etc. Exploring the potential genes via different methods is of significance for the prevention and treatment of pediatric sepsis. This study aimed to identify potential genes associated with pediatric sepsis utilizing analysis of gene network and entropy. METHODS: The mRNA expression in the blood samples collected from 20 septic children and 30 healthy controls was quantified by using Affymetrix HG-U133A microarray. Two condition-specific protein-protein interaction networks (PINs), one for the healthy control and the other one for the children with sepsis, were deduced by combining the fundamental human PINs with gene expression profiles in the two phenotypes. Subsequently, distinct modules from the two conditional networks were extracted by adopting a maximal clique-merging approach. Delta entropy (DeltaS) was calculated between sepsis and control modules. RESULTS: Then, key genes displaying changes in gene composition were identified by matching the control and sepsis modules. Two objective modules were obtained, in which ribosomal protein RPL4 and RPL9 as well as TOP2A were probably considered as the key genes differentiating sepsis from healthy controls. CONCLUSION: According to previous reports and this work, TOP2A is the potential gene therapy target for pediatric sepsis. The relationship between pediatric sepsis and RPL4 and RPL9 needs further investigation. PMID- 27978522 TI - Successful Therapy of Severe Pseudomembranous Clostridium difficile Colitis Using a Combination of Fecal Microbiota Therapy and Fidaxomicin. AB - OBJECTIVE: The aim of this work was to describe the use of a combination of fidaxomicin and fecal microbiota therapy (FMT) in Clostridium difficile infection (CDI). CLINICAL PRESENTATION AND INTERVENTION: A 78-year-old female, who was admitted for surgery due to acute diverticulitis caused by postoperative complications and broad antibiotic therapy, developed CDI-induced colitis. Despite the introduction of metronidazole and vancomycin therapy, her clinical condition continued to deteriorate. She was transferred to the intensive care unit where FMT followed by fidaxomicin were performed because her C-reactive protein and leucocyte levels remained elevated. Further clinical improvement and the resolution of colitis was observed. CONCLUSION: In this case, severe CDI colitis was successfully treated with the combination of FMT and fidaxomicin. PMID- 27978525 TI - Down-Regulation of the Na+,Cl- Coupled Creatine Transporter CreaT (SLC6A8) by Glycogen Synthase Kinase GSK3beta. AB - BACKGROUND: The Na+,Cl- coupled creatine transporter CreaT (SLC6A8) is expressed in a variety of tissues including the brain. Genetic defects of CreaT lead to mental retardation with seizures. The present study explored the regulation of CreaT by the ubiquitously expressed glycogen synthase kinase GSK3beta, which contributes to the regulation of neuroexcitation. GSK3beta is phosphorylated and thus inhibited by PKB/Akt. Moreover, GSK3beta is inhibited by the antidepressant lithium. The present study thus further tested for the effects of PKB/Akt and of lithium. METHODS: CreaT was expressed in Xenopus laevis oocytes with or without wild-type GSK3beta or inactive K85RGSK3beta. CreaT and GSK3beta were further expressed without and with additional expression of wild type PKB/Akt. Creatine transport in those oocytes was quantified utilizing dual electrode voltage clamp. RESULTS: Electrogenic creatine transport was observed in CreaT expressing oocytes but not in water-injected oocytes. In CreaT expressing oocytes, co-expression of GSK3beta but not of K85RGSK3beta, resulted in a significant decrease of creatine induced current. Kinetic analysis revealed that GSK3beta significantly decreased the maximal creatine transport rate. Exposure of CreaT and GSK3beta expressing oocytes for 24 hours to Lithium was followed by a significant increase of the creatine induced current. The effect of GSK3beta on CreaT was abolished by co expression of PKB/Akt. CONCLUSION: GSK3beta down-regulates the creatine transporter CreaT, an effect reversed by treatment with the antidepressant Lithium and by co-expression of PKB/Akt. PMID- 27978526 TI - Triggering of Suicidal Erythrocyte Death by Bexarotene. AB - BACKGROUND/AIMS: The retinoid X receptor agonist bexarotene is utilized for the treatment of cutaneous T-cell lymphoma and is effective in several further malignancies. The substance counteracts tumor growth in part by triggering suicidal death or apoptosis of tumor cells. Side effects of bexarotene treatment include anemia. Theoretically, bexarotene induced anemia could be secondary to stimulation of suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling potentially stimulating eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), induction of oxidative stress, increase of ceramide abundance, as well as activation of staurosporine sensitive protein kinase C, SB203580 sensitive p38 kinase, D4476 sensitive casein kinase 1, and zVAD sensitive caspases. The present study explored, whether bexarotene induces eryptosis and, if so, whether its effect involves Ca2+ entry, oxidative stress, ceramide, kinases and/or caspases. METHODS: Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was estimated from hemoglobin concentration in the supernatant. RESULTS: A 48 hours exposure of human erythrocytes to bexarotene (>= 0.4 ug/ml) significantly increased the percentage of annexin-V-binding cells without significantly modifying forward scatter. Bexarotene significantly increased Fluo3-fluorescence and DCFDA fluorescence. Bexarotene tended to increase ceramide abundance, an effect, however, not reaching statistical significance. The effect of bexarotene on annexin-V-binding was significantly blunted by removal of extracellular Ca2+ and by addition of D4476 (10 uM), but not by addition of staurosporine (1 uM), SB203580 (2 uM), or zVAD (10 uM). CONCLUSIONS: Bexarotene triggers phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca2+ entry, oxidative stress, and activation of D4476 sensitive casein kinase. PMID- 27978527 TI - Up-Regulation of Excitatory Amino Acid Transporters EAAT3 and EAAT4 by Lithium Sensitive Glycogen Synthase Kinase GSK3beta. AB - BACKGROUND: Cellular uptake of glutamate by the excitatory amino-acid transporters (EAATs) decreases excitation and thus participates in the regulation of neuroexcitability. Kinases impacting on neuronal function include Lithium sensitive glycogen synthase kinase GSK3beta. The present study thus explored whether the activities of EAAT3 and/or EAAT4 isoforms are sensitive to GSK3beta. METHODS: cRNA encoding wild type EAAT3 (SLC1A1) or EAAT4 (SLC1A6) was injected into Xenopus oocytes without or with additional injection of cRNA encoding wild type GSK3beta or the inactive mutant K85AGSK3beta. Dual electrode voltage clamp was performed in order to determine glutamate-induced current (IEAAT). RESULTS: Appreciable IEAAT was observed in EAAT3 or EAAT4 expressing but not in water injected oocytes. IEAAT was significantly increased by coexpression of GSK3beta but not by coexpression of K85AGSK3beta. Coexpression of GSK3beta increased significantly the maximal IEAAT in EAAT3 or EAAT4 expressing oocytes, without significantly modifying apparent affinity of the carriers. Lithium (1 mM) exposure for 24 hours decreased IEAAT in EAAT3 and GSK3beta expressing oocytes to values similar to IEAAT in oocytes expressing EAAT3 alone. Lithium did not significantly modify IEAAT in oocytes expressing EAAT3 without GSK3beta. CONCLUSIONS: Lithium-sensitive GSK3beta is a powerful regulator of excitatory amino acid transporters EAAT3 and EAAT4. PMID- 27978529 TI - Effect of Temporal Fascia and Pedicle Inferior Turbinate Mucosal Flap on Repair of Large Nasal Septal Perforation via Endoscopic Surgery. AB - BACKGROUND: The repair of large nasal septal perforations (NSPs) is one of the most challenging procedures in nasal surgery. The aim of this prospective clinical study was to determine the efficacy of using a pedicle inferior turbinate mucosal flap combined with temporal fascia to repair a large NSP. METHOD: Between January 2008 and December 2015, 17 consecutive patients with large NSPs underwent septal perforation repair via an endoscopic approach using a pedicle inferior turbinate mucosal flap combined with temporal fascia. RESULTS: Complete closure of the perforation was achieved in all patients. CONCLUSION: The pedicle inferior turbinate mucosal flap combined with the temporal fascia technique can easily solve this challenging problem, and the current data from this prospective study suggest that this technique shows promising results. PMID- 27978528 TI - Drug-Eluting Balloon Technology for Native Non-Small Coronary Artery Disease: Another Crusade against Skepticism! PMID- 27978531 TI - Steroidogenic Factor-1 (SF-1, NR5A1) and?46,XX Ovotesticular Disorders of Sex Development:?One Factor, Many Phenotypes. PMID- 27978530 TI - Aquaporin Water Channels and Hydrocephalus. AB - The aquaporins (AQPs) are a family of water-transporting proteins that are broadly expressed in mammalian cells. Two AQPs in the central nervous system, AQP1 and AQP4, might play a role in hydrocephalus and are thus potential drug targets. AQP1 is expressed in the ventricular-facing membrane of choroid plexus epithelial cells, where it facilitates the secretion of cerebrospinal fluid (CSF). AQP4 is expressed in astrocyte foot processes and ependymal cells lining ventricles, where it appears to facilitate the transport of excess water out of the brain. Altered expression of these AQPs in experimental animal models of hydrocephalus and limited human specimens suggests their involvement in the pathophysiology of hydrocephalus, as do data in knockout mice demonstrating a protective effect of AQP1 deletion and a deleterious effect of AQP4 deletion in hydrocephalus. Though significant questions remain, including the precise contribution of AQP1 to CSF secretion in humans and the mechanisms by which AQP4 facilitates clearance of excess brain water, AQP1 and AQP4 have been proposed as potential drug targets to reduce ventricular enlargement in hydrocephalus. PMID- 27978532 TI - Ibuprofen plus paracetamol versus ibuprofen in acute low back pain: a randomized open label multicenter clinical study. AB - OBJECTIVE: to estimate whether combination of ibuprofen and paracetamol is more effective than ibuprofen in monotherapy, in the treatment of acute low back pain. METHODS: 80 adult patients with acute low back pain were randomized into two subgroups. In the first subgroup, 40 patients were treated with ibuprofen 400mg three times a day (TID), whilst patients in the second subgroup (n=40) were treated with a fixed-dose combination tablet of ibuprofen 200mg plus paracetamol 325mg TID, for three consecutive days. Patients were followed for another 7 days. Efficacy and tolerability of both treatment options was assessed. RESULTS: A statistically significant decrease in pain intensity, assessed using a visual analogue scale (p<0.001), as well as the 5-point Likert scale, was noticed in both subgroups of patients. However, intensity of pain on Day 4 was significantly lower in patients treated with combined therapy (t=2.05, p=0.045). Considerable improvement in mobility of the lumbar spine was noticed in both subgroup of patients (p<0.001), but at the end of the follow up period, finger-to-floor distance was lower in patients on combined therapy (4.7cm vs. 8.3cm, t=2.27, p=0.03). Improvement of functional ability on Day 4 and Day 10 was significant, regardless of treatment (p<0.001). One patient on combined therapy and two patients on ibuprofen monotherapy reported minor gastric intolerability. CONCLUSION: compared to ibuprofen monotherapy, combination of ibuprofen and paracetamol may provide faster and longer analgesia in patients with acute low back pain, with equally favorable effect on mobility and functional ability and similar tolerability. PMID- 27978533 TI - History of chronic inflammatory disorders increases the risk of Merkel cell carcinoma, but does not correlate with Merkel cell polyomavirus infection. AB - BACKGROUND: We aimed to assess the connection between chronic inflammatory disorders (CIDs) and Merkel cell carcinoma (MCC). METHODS: Merkel cell carcinoma cases diagnosed in 1978-2009 were extracted from the Finnish Cancer Registry and controls from the Population Registry. Information on reimbursed CIDs was linked to clinicopathological data including Merkel cell polyomavirus (MCV) status by qPCR and immunohistochemistry for the large T antigen of MCV (LTA), Ki-67 and tumour-infiltrating lymphocytes. RESULTS: Chronic inflammatory disorders increased the risk of MCC significantly (odds ratio (OR) 1.39, 95% confidence interval (CI) 1.03-1.88), specifically connective tissue/systemic diseases (OR 1.75, 95% CI 1.09-1.80) and diabetic conditions (OR 1.51, 95% CI 1.03-2.22). Chronic inflammatory disorders associated with larger tumour diameter (P=0.02) and higher Ki-67 expression (P=0.005). The expression of LTA was seen significantly more often in the absence of CIDs (P=0.05). CONCLUSIONS: Patients with CID are at significantly higher risk for aggressive MCC. Merkel cell polyomavirus positivity is more common in MCC patients unafflicted by CID. PMID- 27978534 TI - Leishmania infantum Induces Mild Unfolded Protein Response in Infected Macrophages. AB - The Leishmaniases are a group of parasitic diseases caused by protozoa of the Leishmania genus affecting both humans and other vertebrates. Leishmania is an intracellular pathogen able to confer resistance to apoptosis in the early phase of macrophages infection by activation of host PI3K/Akt pathway and inhibition of caspase-3 activation. Intracellular pathogens hijack organelles such as ER to facilitate survival and replication, thus eliciting ER stress and activating/modulating the unfolded protein response (UPR) in the host cell. The UPR is aimed to mitigate ER stress, thereby promoting cell survival. However, prolonged ER stress will activate the apoptotic pathway. The aim of this study was to investigate the ER stress response in Leishmania-infected macrophages to gain insights about the mechanisms underlying the apoptosis resistance in parasitized cells. Macrophages differentiated from human monocytic cell lines (U937 and THP-1) and murine primary macrophages were infected with Leishmania infantum MHOM/TN/80/IPT1 (WHO international reference strain). Several ER stress/autophagy expression markers, as well as cell survival/apoptosis markers (phospho-Akt and cleaved caspase-3) were evaluated by qPCR and/or by western blotting. As ER stress positive control, cells were treated with tunicamycin or dithiothreitol (DTT). The gene expression analyses showed a mild but significant induction of the ER stress/autophagy markers. The western blot analyses revealed that the Leishmania infection induced Akt phosphorylation and significantly inhibited the induction of caspase-3 cleavage, eIF2alpha phosphorylation and DDIT3/CHOP expression in tunicamycin and DTT treated cells. The mild but significant increase in ER stress expression markers and the delay/attenuation of the effects of ER stress inducers in infected cells support the hypothesis that L. infantum could promote survival of host cells by inducing a mild ER stress response. The host ER stress response could be not only a common pathogenic mechanism among Leishmania species but also a target for development of new drugs. PMID- 27978535 TI - Detection of Multiple Innervation Zones from Multi-Channel Surface EMG Recordings with Low Signal-to-Noise Ratio Using Graph-Cut Segmentation. AB - Knowledge of the location of muscle Innervation Zones (IZs) is important in many applications, e.g. for minimizing the quantity of injected botulinum toxin for the treatment of spasticity or for deciding on the type of episiotomy during child delivery. Surface EMG (sEMG) can be noninvasively recorded to assess physiological and morphological characteristics of contracting muscles. However, it is not often possible to record signals of high quality. Moreover, muscles could have multiple IZs, which should all be identified. We designed a fully automatic algorithm based on the enhanced image Graph-Cut segmentation and morphological image processing methods to identify up to five IZs in 60-ms intervals of very-low to moderate quality sEMG signal detected with multi-channel electrodes (20 bipolar channels with Inter Electrode Distance (IED) of 5 mm). An anisotropic multilayered cylinder model was used to simulate 750 sEMG signals with signal-to-noise ratio ranging from -5 to 15 dB (using Gaussian noise) and in each 60-ms signal frame, 1 to 5 IZs were included. The micro- and macro- averaged performance indices were then reported for the proposed IZ detection algorithm. In the micro-averaging procedure, the number of True Positives, False Positives and False Negatives in each frame were summed up to generate cumulative measures. In the macro-averaging, on the other hand, precision and recall were calculated for each frame and their averages are used to determine F1-score. Overall, the micro (macro)-averaged sensitivity, precision and F1-score of the algorithm for IZ channel identification were 82.7% (87.5%), 92.9% (94.0%) and 87.5% (90.6%), respectively. For the correctly identified IZ locations, the average bias error was of 0.02+/-0.10 IED ratio. Also, the average absolute conduction velocity estimation error was 0.41+/-0.40 m/s for such frames. The sensitivity analysis including increasing IED and reducing interpolation coefficient for time samples was performed. Meanwhile, the effect of adding power-line interference and using other image interpolation methods on the deterioration of the performance of the proposed algorithm was investigated. The average running time of the proposed algorithm on each 60-ms sEMG frame was 25.5+/-8.9 (s) on an Intel dual-core 1.83 GHz CPU with 2 GB of RAM. The proposed algorithm correctly and precisely identified multiple IZs in each signal epoch in a wide range of signal quality and is thus a promising new offline tool for electrophysiological studies. PMID- 27978536 TI - Downregulation of FBP1 Promotes Tumor Metastasis and Indicates Poor Prognosis in Gastric Cancer via Regulating Epithelial-Mesenchymal Transition. AB - BACKGROUND: Recent studies indicated that some glycolytic enzymes are complicated, multifaceted proteins rather than simple components of the glycolytic pathway. FBP1 plays a vital role in glucose metabolism, but its role in gastric cancer tumorigenesis and metastasis has not been fully understood. METHODS: The prognostic value of FBP1 was first studied in The Cancer Genome Atlas (TCGA) database and validated in in-house database. The effect of FBP1 on cell proliferation and metastasis was examined in vitro. Nonparametric test and Log-rank test were used to evaluate the clinical significance of FBP1 expression. RESULTS: In the TCGA cohort, FBP1 mRNA level were shown to be predictive of overall survival in gastric cancer (P = 0.029). In the validation cohort, FBP1 expression were inversely correlated with advanced N stage (P = 0.021) and lymphovascular invasion (P = 0.011). Multivariate Cox regression analysis demonstrated that FBP1 was an independent predictor for both overall survival (P = 0.004) and disease free survival (P<0.001). Functional studies demonstrated that ectopic FBP1 expression inhibited proliferation and invasion in gastric cancer cells, while silencing FBP1 expression had opposite effects (P<0.05). Mechanically, FBP1 serves as a tumor suppressor by inhibiting epithelial mesenchymal transition (EMT). CONCLUSIONS: Downregulation of FBP1 promotes gastric cancer metastasis by facilitating EMT and acts as a potential prognostic factor and therapeutic target in gastric cancer. PMID- 27978538 TI - Narrative Style Influences Citation Frequency in Climate Change Science. AB - Peer-reviewed publications focusing on climate change are growing exponentially with the consequence that the uptake and influence of individual papers varies greatly. Here, we derive metrics of narrativity from psychology and literary theory, and use these metrics to test the hypothesis that more narrative climate change writing is more likely to be influential, using citation frequency as a proxy for influence. From a sample of 732 scientific abstracts drawn from the climate change literature, we find that articles with more narrative abstracts are cited more often. This effect is closely associated with journal identity: higher-impact journals tend to feature more narrative articles, and these articles tend to be cited more often. These results suggest that writing in a more narrative style increases the uptake and influence of articles in climate literature, and perhaps in scientific literature more broadly. PMID- 27978537 TI - Safety, Immunogenicity and Efficacy of Prime-Boost Vaccination with ChAd63 and MVA Encoding ME-TRAP against Plasmodium falciparum Infection in Adults in Senegal. AB - Malaria transmission is in decline in some parts of Africa, partly due to the scaling up of control measures. If the goal of elimination is to be achieved, additional control measures including an effective and durable vaccine will be required. Studies utilising the prime-boost approach to deliver viral vectors encoding the pre-erythrocytic antigen ME-TRAP (multiple epitope thrombospondin related adhesion protein) have shown promising safety, immunogenicity and efficacy in sporozoite challenge studies. More recently, a study in Kenyan adults, similar to that reported here, showed substantial efficacy against P. falciparum infection. One hundred and twenty healthy male volunteers, living in a malaria endemic area of Senegal were randomised to receive either the Chimpanzee adenovirus (ChAd63) ME-TRAP as prime vaccination, followed eight weeks later by modified vaccinia Ankara (MVA) also encoding ME-TRAP as booster, or two doses of anti-rabies vaccine as a comparator. Prior to follow-up, antimalarials were administered to clear parasitaemia and then participants were monitored by PCR for malaria infection for eight weeks. The primary endpoint was time-to-infection with P. falciparum malaria, determined by two consecutive positive PCR results. Secondary endpoints included adverse event reporting, measures of cellular and humoral immunogenicity and a meta-analysis of combined vaccine efficacy with the parallel study in Kenyan adults.We show that this pre-erythrocytic malaria vaccine is safe and induces significant immunogenicity, with a peak T-cell response at seven days after boosting of 932 Spot Forming Cells (SFC)/106 Peripheral Blood Mononuclear Cells(PBMC) compared to 57 SFC/ 106 PBMCs in the control group. However, a vaccine efficacy was not observed: 12 of 57 ME-TRAP vaccinees became PCR positive during the intensive monitoring period as compared to 13 of the 58 controls (P = 0.80). This trial confirms that vaccine efficacy against malaria infection in adults may be rapidly assessed using this efficient and cost-effective clinical trial design. Further efficacy evaluation of this vectored candidate vaccine approach in other malaria transmission settings and age-de-escalation into the main target age groups for a malaria vaccine is in progress. PMID- 27978539 TI - beta1/2 or M2/3 Receptors Are Required for Different Gastrointestinal Motility Responses Induced by Acupuncture at Heterotopic or Homotopic Acupoints. AB - Acupuncture at homotopic acupoints or heterotopic acupoints is known to either inhibit or facilitate gastrointestinal motility, depending on the acupoint location. However, little effort has been made to investigate the roles of specific receptors (such as adrenergic and muscarinic acetylcholine receptors) in mediating the effects of acupuncture at heterotopic and homotopic acupoints. Different adrenergic receptor subtypes or cholinergic receptor subtypes are predominantly expressed in various sections of the gut, resulting in variations between the effects of acupuncture at heterotopic or homotopic acupoints on gastrointestinal motility. Here, we investigated the role of beta1/beta2 receptors and M2/M3 receptors in gastrointestinal motility regulated by acupuncture at ST37, a heterotopic acupoint, and ST25, a homotopic acupoint, by simultaneously recording intraluminal pressures in the distal colon and stomach or jejunum and examining fecal phenol red excretion in beta1/2 receptor-knockout mice and M2/3 receptor-knockout mice. We found that knockout of the M2/3 receptor significantly inhibited ST37 acupuncture-induced enhancement of gastric motility, jejunal motility, and colonic motility. Additionally, knocking out of the beta1/2 receptor significantly diminished the ST25 acupuncture-induced inhibition of gastric motility and jejunal motility without significantly altering the enhancement of colonic motility induced by acupuncture at ST25. Acupuncture at ST37 significantly accelerated gastrointestinal transition in beta1/2 receptor knockout mice and their wild-type littermates. However, this acceleration of gastrointestinal transition was markedly diminished in M2/3 receptor-knockout mice relative to their wild-type littermates. Acupuncture at ST25 significantly increased gastrointestinal transition in beta1/2 receptor-knockout mice and significantly decreased gastrointestinal transition in M2/3 receptor-knockout mice without altering gastrointestinal transition in wild-type littermates of either. Our study revealed that M2/3 receptors are required for the gastrointestinal motility associated with whole gastrointestinal transition enhanced by acupuncture at heterotopic acupoints, whereas beta1/2 receptors are required for the same gastrointestinal motility processes inhibited by acupuncture at homotopic acupoints. Therefore, our findings reveal important biological mechanisms underlying acupuncture treatment of disorders involving gastrointestinal motility dysfunction. PMID- 27978540 TI - Exaggerations and Caveats in Press Releases and Health-Related Science News. AB - BACKGROUND: Exaggerated or simplistic news is often blamed for adversely influencing public health. However, recent findings suggested many exaggerations were already present in university press releases, which scientists approve. Surprisingly, these exaggerations were not associated with more news coverage. Here we test whether these two controversial results also arise in press releases from prominent science and medical journals. We then investigate the influence of mitigating caveats in press releases, to test assumptions that caveats harm news interest or are ignored. METHODS AND FINDINGS: Using quantitative content analysis, we analyzed press releases (N = 534) on biomedical and health-related science issued by leading peer-reviewed journals. We similarly analysed the associated peer-reviewed papers (N = 534) and news stories (N = 582). Main outcome measures were advice to readers and causal statements drawn from correlational research. Exaggerations in press releases predicted exaggerations in news (odds ratios 2.4 and 10.9, 95% CIs 1.3 to 4.5 and 3.9 to 30.1) but were not associated with increased news coverage, consistent with previous findings. Combining datasets from universities and journals (996 press releases, 1250 news), we found that when caveats appeared in press releases there was no reduction in journalistic uptake, but there was a clear increase in caveats in news (odds ratios 9.6 and 9.5 for caveats for advice and causal claims, CIs 4.1 to 24.3 and 6.0 to 15.2). The main study limitation is its retrospective correlational nature. CONCLUSIONS: For health and science news directly inspired by press releases, the main source of both exaggerations and caveats appears to be the press release itself. However we find no evidence that exaggerations increase, or caveats decrease, the likelihood of news coverage. These findings should be encouraging for press officers and scientists who wish to minimise exaggeration and include caveats in their press releases. PMID- 27978541 TI - Effective Feature Selection for Classification of Promoter Sequences. AB - Exploring novel computational methods in making sense of biological data has not only been a necessity, but also productive. A part of this trend is the search for more efficient in silico methods/tools for analysis of promoters, which are parts of DNA sequences that are involved in regulation of expression of genes into other functional molecules. Promoter regions vary greatly in their function based on the sequence of nucleotides and the arrangement of protein-binding short regions called motifs. In fact, the regulatory nature of the promoters seems to be largely driven by the selective presence and/or the arrangement of these motifs. Here, we explore computational classification of promoter sequences based on the pattern of motif distributions, as such classification can pave a new way of functional analysis of promoters and to discover the functionally crucial motifs. We make use of Position Specific Motif Matrix (PSMM) features for exploring the possibility of accurately classifying promoter sequences using some of the popular classification techniques. The classification results on the complete feature set are low, perhaps due to the huge number of features. We propose two ways of reducing features. Our test results show improvement in the classification output after the reduction of features. The results also show that decision trees outperform SVM (Support Vector Machine), KNN (K Nearest Neighbor) and ensemble classifier LibD3C, particularly with reduced features. The proposed feature selection methods outperform some of the popular feature transformation methods such as PCA and SVD. Also, the methods proposed are as accurate as MRMR (feature selection method) but much faster than MRMR. Such methods could be useful to categorize new promoters and explore regulatory mechanisms of gene expressions in complex eukaryotic species. PMID- 27978542 TI - An Experiment with Air Purifiers in Delhi during Winter 2015-2016. AB - Particulate pollution has important consequences for human health, and is an issue of global concern. Outdoor air pollution has become a cause for alarm in India in particular because recent data suggest that ambient pollution levels in Indian cities are some of the highest in the world. We study the number of particles between 0.5MUm and 2.5MUm indoors while using affordable air purifiers in the highly polluted city of Delhi. Though substantial reductions in indoor number concentrations are observed during air purifier use, indoor air quality while using an air purifier is frequently worse than in cities with moderate pollution, and often worse than levels observed even in polluted cities. When outdoor pollution levels are higher, on average, indoor pollution levels while using an air purifier are also higher. Moreover, the ratio of indoor air quality during air purifier use to two comparison measures of air quality without an air purifier are also positively correlated with outdoor pollution levels, suggesting that as ambient air quality worsens there are diminishing returns to improvements in indoor air quality during air purifier use. The findings of this study indicate that although the most affordable air purifiers currently available are associated with significant improvements in the indoor environment, they are not a replacement for public action in regions like Delhi. Although private solutions may serve as a stopgap, reducing ambient air pollution must be a public health and policy priority in any region where air pollution is as high as Delhi's during the winter. PMID- 27978543 TI - The Proteasome Inhibitor Bortezomib Affects Chondrosarcoma Cells via the Mitochondria-Caspase Dependent Pathway and Enhances Death Receptor Expression and Autophagy. AB - High grade chondrosarcoma is characterized by its lack of response to conventional cytotoxic chemotherapy, the tendency to develop lung metastases, and low survival rates. Research within the field prioritizes the development and expansion of new treatment options for dealing with unresectable or metastatic diseases. Numerous clinical trials using the proteasome inhibitor bortezomib have shown specific efficacy as an active antitumor agent for treating a variety of solid tumors. However, as of yet the effect of bortezomib on chondrosarcoma has not been investigated. In our study, bortezomib decreased cell viability and proliferation in two different chondrosarcoma cell lines in a time- and dose dependent manner. FACS analysis, mRNA- and protein expression studies illustrated that induction of apoptosis developed through the intrinsic mitochondria-caspase dependent pathway. Furthermore, bortezomib treatment significantly increased expression of the death receptors TRAILR-1 and TRAILR-2 in chondrosarcoma cells. An increased expression of the autophagy markers Atg5/12, Beclin, and LC3BI-II supports the interpretation that bortezomib functions as a trigger for autophagy. Our results demonstrated for the first time that bortezomib reduced viability and proliferation of chondrosarcoma cells, induced apoptosis via the mitochondria caspase dependent pathway and enhanced death receptor expression and autophagy. PMID- 27978544 TI - Shifting Demographics among Research Project Grant Awardees at the National Heart, Lung, and Blood Institute (NHLBI). AB - The present study was initiated because of concerns expressed by NHLBI-funded mid career investigators regarding perceived difficulties in the renewal of their grant awards. This led us to ask: "Are mid-career investigators experiencing disproportionate difficulties in the advancement of their professional careers?" Our portfolio analysis indicates that there has been a significant and evolving shift in the demographics of research project grant (RPG) awardees at NHLBI. In 1998, mid-career (ages 41-55) investigators constituted approximately 60% of all investigators with the remaining 40% being equally divided between early-stage (ages 24-40) investigators and established (ages 56 to 70 and older) investigators. However, since 1998, the proportion of established RPG awardees has been increasing in a slowly progressive and strikingly linear fashion. At the same time the proportion of early-stage awardees fell precipitously until 2006 and then stabilized. During the same period, the proportion of mid-career awardees, which had been relatively stable through 2006, began to fall significantly. In examining potential causes of these demographic shifts we have identified certain inherent properties within the RPG award system that appear to promote an increasingly more established awardee population and a persistent decrease in the proportion of mid-career investigators. A collateral result of these demographic shifts, when combined with level or declining funding, is a significant reduction in the number of RPG awards received by NHLBI mid-career investigators and a corresponding decrease in the number of independent research laboratories. PMID- 27978546 TI - Rhinoplasty as a Significant Component of Facial Feminization and Beautification. PMID- 27978545 TI - Eosinophil Count Is a Common Factor for Complex Metabolic and Pulmonary Traits and Diseases: The LifeLines Cohort Study. AB - There is ongoing debate on the association between eosinophil count and diseases, as previous studies were inconsistent. We studied the relationship of eosinophil count with 22 complex metabolic, cardiac, and pulmonary traits and diseases. From the population-based LifeLines Cohort Study (N = 167,729), 13,301 individuals were included. We focused on relationship of eosinophil count with three classes of metabolic (7 traits, 2 diseases), cardiac (6 traits, 2 diseases), and pulmonary (2 traits, 2 diseases) outcomes. Regression analyses were applied in overall, women and men, while adjusted for age, sex, BMI and smoking. A p-value of <0.00076 was considered statistically significant. 58.2% of population were women (mean+/-SD 51.3+/-11.1 years old). In overall, one-SD higher of ln eosinophil count was associated with a 0.04 (+/-SE +/-0.002;p = 6.0*10-6) SD higher levels in ln-BMI, 0.06 (+/-0.007;p = 3.1*10-12) SD in ln-TG, 0.04 (+/ 0.003;p = 7.0*10-6) SD in TC, 0.04 (+/-0.004;p = 6.3*10-7) SD in LDL, 0.04 (+/ 0.006;p = 6.0*10-6) SD in HbA1c; and with a 0.05 (+/-0.004;p = 1.7*10-8) SD lower levels in HDL, 0.05 (+/-0.007;p = 3.4*10-23) SD in FEV1, and 0.09 (+/-0.001;p = 6.6*10-28) SD in FEV1/FVC. A higher ln-eosinophil count was associated with 1.18 (95%CI 1.09-1.28;p = 2.0*10-5) odds ratio of obesity, 1.29 (1.19-1.39;p = 1.1*10 10) of metabolic syndrome, 1.40 (1.25-1.56;p = 2.7*10-9) of COPD and 1.81 (1.61 2.03;p = 1.0*10-23) of asthma. Similar results were found in women. We found no association between ln-eosinophil count either with blood pressure indices in overall, women and men; or with BMI, LDL, HbA1c and obesity in men. In a large population based cohort, we confirmed eosinophil count as a potential factor implicated in metabolic and pulmonary outcomes. PMID- 27978547 TI - Human Induced Pluripotent Stem Cell-Derived Motor Neuron Transplant for Neuromuscular Atrophy in a Mouse Model of Sciatic Nerve Injury. AB - Importance: Human motor neurons may be reliably derived from induced pluripotent stem cells (iPSCs). In vivo transplant studies of human iPSCs and their cellular derivatives are essential to gauging their clinical utility. Objective: To determine whether human iPSC-derived motor neurons can engraft in an immunodeficient mouse model of sciatic nerve injury. Design, Setting, and Subjects: This nonblinded interventional study with negative controls was performed at a biomedical research institute using an immunodeficient, transgenic mouse model. Induced pluripotent stem cell-derived motor neurons were cultured and differentiated. Cells were transplanted into 32 immunodeficient mice with sciatic nerve injury aged 6 to 15 weeks. Tissue analysis was performed at predetermined points after the mice were killed humanely. Animal experiments were performed from February 24, 2015, to May 2, 2016, and data were analyzed from April 7, 2015, to May 27, 2016. Interventions: Human iPSCs were used to derive motor neurons in vitro before transplant. Main Outcomes and Measures: Evidence of engraftment based on immunohistochemical analysis (primary outcome measure); evidence of neurite outgrowth and neuromuscular junction formation (secondary outcome measure); therapeutic effect based on wet muscle mass preservation and/or electrophysiological evidence of nerve and muscle function (exploratory end point). Results: In 13 of the 32 mice undergoing the experiment, human iPSC derived motor neurons successfully engrafted and extended neurites to target denervated muscle. Human iPSC-derived motor neurons reduced denervation-induced muscular atrophy (mean [SD] muscle mass preservation, 54.2% [4.0%]) compared with negative controls (mean [SD] muscle mass preservation, 33.4% [2.3%]) (P = .04). No electrophysiological evidence of muscle recovery was found. Conclusions and Relevance: Human iPSC-derived motor neurons may have future use in the treatment of peripheral motor nerve injury, including facial paralysis. Level of Evidence: NA. PMID- 27978549 TI - Measurement of crosstalk in stereoscopic display systems used for vision research. AB - Studying binocular vision requires precise control over the stimuli presented to the left and right eyes. A popular technique is to segregate signals either temporally (frame interleaving), spectrally (using colored filters), or through light polarization. None of these segregation methods achieves perfect isolation, and so a degree of crosstalk is usually apparent, in which signals intended for one eye are faintly visible to the other eye. Previous studies have reported crosstalk values mostly for consumer-grade systems. Here we measure crosstalk for eight systems, many of which are intended for use in vision research. We provide benchmark crosstalk values, report a negative crosstalk effect in some LCD-based systems, and give guidelines for dealing with crosstalk in different experimental paradigms. PMID- 27978548 TI - Vitamin D Receptor Genotype, Vitamin D3 Supplementation, and Risk of Colorectal Adenomas: A Randomized Clinical Trial. AB - Importance: Despite epidemiological and preclinical evidence suggesting that vitamin D and calcium inhibit colorectal carcinogenesis, daily supplementation with these nutrients for 3 to 5 years was not found to significantly reduce the risk of recurrent colorectal adenomas in a recent randomized clinical trial. Objective: To investigate whether common variants in 7 vitamin D and calcium pathway genes (VDR, GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, and CASR) modify the effects of vitamin D3 or calcium supplementation on colorectal adenoma recurrence. Design, Setting, and Participants: We examined 41 candidate single nucleotide polymorphisms (SNPs) in 2259 participants in a randomized, double blind, placebo-controlled trial conducted at 11 clinical centers in the United States. Eligibility criteria included a recently diagnosed adenoma and no remaining colorectal polyps after complete colonoscopy. The study's treatment phase ended on August 31, 2013, and the analysis for the present study took place from July 28, 2014, to October 19, 2016. Interventions: Daily oral supplementation with vitamin D3 (1000 IU) or calcium carbonate (1200 mg elemental calcium) or both or neither. Main Outcomes and Measures: The outcomes assessed were the occurrence of 1 or more adenomas or advanced adenomas (estimated diameter, >=1 cm; or with villous histologic findings, high-grade dysplasia, or cancer) during follow-up. Treatment effects and genotype associations and interactions were estimated as adjusted risk ratios (RRs) and 95% confidence intervals (CIs). The effective number of independent SNPs was calculated to correct for multiple testing. Results: Among the 2259 participants randomized, 1702 were non-Hispanic whites who completed the trial and had genotype data for analysis (1101 men; mean [SD] age 58.1 [6.8] years). The effect of vitamin D3 supplementation on advanced adenomas, but not on adenoma risk overall, significantly varied according to genotype at 2 VDR SNPs (rs7968585 and rs731236) in linkage disequilibrium (D' = 0.98; r2 = 0.6). For rs7968585, among individuals with the AA genotype (26%), vitamin D3 supplementation reduced risk by 64% (RR, 0.36; 95% CI, 0.19-0.69; P = .002; absolute risk decreased from 14.4% to 5.1%). Among individuals with 1 or 2 G alleles (74%), vitamin D3 supplementation increased risk by 41% (RR, 1.41; 95% CI, 0.99-2.00; P = .05; absolute risk increased from 7.7% to 11.1%; P < .001 for interaction). There were no significant interactions of genotypes with calcium supplementation. Conclusions and Relevance: Our findings suggest that benefits from vitamin D3 supplementation for the prevention of advanced colorectal adenomas may vary according to vitamin D receptor genotype. Trial Registration: clinicaltrials.gov Identifier: NCT00153816. PMID- 27978552 TI - Comparison of Concurrent Use of Thoracic Radiation With Either Carboplatin Paclitaxel or Cisplatin-Etoposide for Patients With Stage III Non-Small-Cell Lung Cancer: A Systematic Review. AB - Importance: The 2 most common chemotherapy regimens used concurrently with thoracic radiation for patients with unresectable IIIA and IIIB non-small-cell lung cancer (NSCLC) are carboplatin-paclitaxel and cisplatin-etoposide. There are no prospective comparisons of these 2 regimens in this setting. Objective: To conduct a systematic review of published trials to compare outcomes and toxic effects between cisplatin-etoposide and carboplatin-paclitaxel in patients with non-small-cell lung cancer receiving thoracic radiation. Evidence Review: Studies that enrolled patients with stage III disease receiving radiotherapy (RT) with carboplatin-paclitaxel or cisplatin-etoposide were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library) and meeting abstracts. Trials were excluded if they were phase 1, enrolled less than 10 patients, or included surgical resection. A systematic analysis of extracted data was performed with software using random and fixed effect models. Clinical outcomes were compared using point estimates for weighted values of median overall survival, progression free survival, response rate, and toxic effects. A 2-tailed t test with a significance level of .05 was used for all comparisons. Findings: Overall, 3090 patients were included from 31 studies in the cisplatin-etoposide groups (median age, 61 years; 65% male; 40% squamous histology; median radiation dose, 63.0 Gy), and 3728 patients from 48 studies in carboplatin-paclitaxel groups (median age, 63 years; 65% male; 40% squamous histology; median radiation dose, 64.6 Gy). There was no significant difference in response rates between cisplatin-etoposide and carboplatin-paclitaxel (58% vs 56%; P = .26), respectively. For cisplatin etoposide vs carboplatin-paclitaxel, there was no significant difference in median progression free survival (12 months vs 9.3 months; P = .20), overall survival (19.6 months vs 18.4 months; P = .40), or 3-year survival rate (31% vs 25%; P = .50). Cisplatin-etoposide was associated with higher grade 3 to 4 hematological toxic effects compared with carboplatin-paclitaxel (eg, neutropenia [54% vs 23%; P < .001] and grade 3/4 nausea/vomiting [20% vs 11%; P = .03]), while rates of grade 3 to 4 pneumonitis (12% vs 9%; P = .12) and esophagitis (23% vs 21%; P = .27) were similar. Conclusions and Relevance: Cisplatin-etoposide and carboplatin-paclitaxel regimens were associated with comparable efficacy when used with concurrent definitive radiotherapy for patients with stage III unresectable NSCLC. The toxic effect profiles favored the carboplatin-paclitaxel regimen. PMID- 27978553 TI - Sensitized TiO2 nanocomposites through HMME linkage for photodynamic effects. AB - Although TiO2 can be used to effectively generate reactive oxygen species (ROS) for photodynamic application, its absorption in the ultraviolet range makes the excitation harmful to tissue. Based on the concept of a sensitized solar cell, TiO2 nanoparticles (NPs) are sensitized by linking with the photosensitizer, HMME, to form HMME-TiO2 nanocomposites (NCs) for demonstrating the photodynamic effects under the illumination of white light. The HMME-TiO2 NCs of different composition ratios are prepared for maximizing the generation of ROS and optimizing the inactivation effect of KB cells. The material characteristics and the ROS generation capability of the HMME-TiO2 NCs with the optimized combination ratio show their merits in a photodynamic process under white light irradiation. The application of such NCs to KB cell experiments results in a higher inactivation efficiency when compared to pure HMME of the same concentration. PMID- 27978554 TI - Technical and Clinical Considerations for Facial Feminization Surgery With Rhinoplasty and Related Procedures. AB - Importance: Together with the forehead reconstruction, feminization of the nose is one of the most common procedures in facial feminization surgery. Rhinoplasty surgical techniques, which provide correct support and stability in the midterm to long term, are essential for obtaining a predictable result. Objective: To report on the technical and clinical considerations of rhinoplasty and related procedures to feminize the nose, harmonize the nose in relation to the other modified structures (mainly the forehead and maxillomandibular complex), and achieve an aesthetic result beyond gender differences. Design, Setting, and Participants: Case series study of feminization rhinoplasties, in combination with lip-lift techniques, forehead reconstruction, and other procedures, were performed at a private practice between January 11, 2010, and May 29, 2015, in 200 consecutive male-to-female transgender patients. The mean (SD) medical follow up for patients was 32 (18.84) months (range, 12-77 months). Frontonasal angles were objectively measured. Postoperative and long-term patient satisfaction were assessed. Main Outcomes and Measures: Clinical analysis and evaluation using the 5-point Nose Feminization Scale, with 1 indicating very masculine or nose is worse and 5 indicating very feminine or exceptional result. Results: In these 200 patients, the mean (SD) age was 40.2 (12.2) years (range, 18-70 years). The mean (SE) frontonasal angle changed from 133.64 degrees (0.63 degrees ) to 149.08 degrees (0.57 degrees ) (difference in means, -15.44; 95% CI, -17.12 to -13.76; P < .001). Most patients considered their nose to appear more feminine after the surgery, and the degree of satisfaction after the rhinoplasty was 4 (much better) of 5 points on the Nose Feminization Scale. During the evaluation of feminization rhinoplasties, special attention was given to how the nose relates to other features essential to the identification of facial gender: the forehead and maxillomandibular complex. Emphasis was placed on the midterm to long-term stability of the results by reinforcing the internal structure. Conclusions and Relevance: In this case series of feminization rhinoplasties in combination with lip-lift techniques and forehead reconstruction, frontonasal angles were changed, and patient satisfaction with outcomes was high. The main goal of rhinoplasty in facial feminization surgery is to obtain feminine nasal features and the harmonization of the nose with the rest of the face. Lip-lifts and frontonasal recontouring can complement rhinoplasties associated with facial feminization surgery. Level of Evidence: 4. PMID- 27978555 TI - Ultraviolet Irradiation-Induced Volume Alteration of Corneal Epithelial Cells. AB - Purpose: The purpose of the study is to understand how extracellular stresses, such as ultraviolet (UV) irradiation, affect corneal epithelial cells. Cell volume changes, damage to corneal epithelial integrity, and cellular responses were assessed after exposure to UVC stresses. Methods: Primary human and rabbit corneal epithelial cells were exposed to UVC light in culture conditions. Ultraviolet C irradiation-induced changes in cell size and volume were measured by real-time microscopy and self-quenching of the fluorescent dye calcein, respectively. The effects of UVC irradiation on Src and focal adhesion kinase (FAK) phosphorylation and FAK-dependent integrin signaling were detected by ELISA, immunoblotting, and immunostaining. Results: Ultraviolet C irradiation induced both size and volume shifts in human and rabbit corneal epithelial cells. Ultraviolet C irradiation-induced decrease of cell volume elicited activation of Src and FAK, characterized by increased phosphorylations of SrcY416, FAKY397, and FAKY925. In addition, immunostaining studies showed UVC irradiation-induced increases in phosphorylation of FAK and formation of integrin beta5 clustering. Application of Kv channel blockers, including 4-aminopyridine (4-AP), alpha-DTX, and depressing substance-1 (BDS-1), effectively suppressed UVC irradiation induced cell volume changes, and subsequently inhibited UVC irradiation-induced phosphorylation of Src/FAK, and formation of integrin beta5 clustering, suggesting UVC irradiation-induced volume changes and Src/FAK activation. Hyperosmotic pressure-induced volume decreases were measured in comparison with effects of UVC irradiation on volume and Src/FAK activation. However, Kv channel blocker, 4-AP, had no effect on hyperosmotic pressure-induced responses. Conclusions: The present study demonstrates that UVC irradiation-induced decreases in cell volume lead to Src/FAK activation due to a rapid loss of K ions through membrane Kv channels. PMID- 27978557 TI - Understanding RPE Lipofuscin. PMID- 27978556 TI - Indoor Spatial Updating With Impaired Vision. AB - Purpose: Spatial updating is the ability to keep track of position and orientation while moving through an environment. We asked how normally sighted and visually impaired subjects compare in spatial updating and in estimating room dimensions. Methods: Groups of 32 normally sighted, 16 low-vision, and 16 blind subjects estimated the dimensions of six rectangular rooms. Updating was assessed by guiding the subjects along three-segment paths in the rooms. At the end of each path, they estimated the distance and direction to the starting location, and to a designated target. Spatial updating was tested in five conditions ranging from free viewing to full auditory and visual deprivation. Results: The normally sighted and low-vision groups did not differ in their accuracy for judging room dimensions. Correlations between estimated size and physical size were high. Accuracy of low-vision performance was not correlated with acuity, contrast sensitivity, or field status. Accuracy was lower for the blind subjects. The three groups were very similar in spatial-updating performance, and exhibited only weak dependence on the nature of the viewing conditions. Conclusions: People with a wide range of low-vision conditions are able to judge room dimensions as accurately as people with normal vision. Blind subjects have difficulty in judging the dimensions of quiet rooms, but some information is available from echolocation. Vision status has little impact on performance in simple spatial updating; proprioceptive and vestibular cues are sufficient. PMID- 27978558 TI - Nerve Growth Factor Attenuates Apoptosis and Inflammation in the Diabetic Cornea. AB - Purpose: To examine the effects of nerve growth factor (NGF) on apoptosis and inflammation in the diabetic cornea. Methods: To investigate the effects of NGF on glucose-induced apoptosis, we stained human corneal epithelial cells (HCECs) for annexin-V and propidium iodide (PI), and measured expression of cleaved caspase-3 and the Bcl-2-associated X protein (BAX). Moreover, to examine the effects of NGF on inflammation, we quantified the expression of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) using multiplex cytokine analysis, and analyzed nuclear factor-kappaB (NF-kappaB) activation and NF-kappa B inhibitor alpha (IkappaBalpha) degradation using Western blot analysis. To investigate the effects in vivo, we induced diabetes in male Sprague-Dawley rats using streptozotocin. The rats were divided into three groups: control, diabetic control, and diabetic NGF; topical NGF was applied three times daily for 3 weeks. We used the TUNEL assay to detect apoptosis in corneal tissue, and immunohistochemistry to identify cleaved caspase-3 and IL-1beta. Results: In HCECs, high glucose concentration (>=25 mM) led to reactive oxygen species (ROS) generation, apoptosis, and the release of inflammatory cytokines. Nerve growth factor markedly reduced ROS activation, annexin-PI-positive cells, and levels of cleaved caspase-3, BAX, IL-1beta, and TNF-alpha. In the diabetic rat cornea, apoptosis and inflammation were enhanced, as were levels of cleaved caspase-3 and IL-1beta. These responses were markedly reduced by NGF. Conclusions: Apoptosis and inflammation are enhanced in the diabetic cornea; NGF attenuates these responses-both in vivo and in vitro. Therefore, NGF therapy may represent a novel approach for the management of diabetic keratopathy. PMID- 27978559 TI - OCT-Leakage: A New Method to Identify and Locate Abnormal Fluid Accumulation in Diabetic Retinal Edema. AB - Purpose: To identify retinal extracellular fluid changes and their correlation with increased retinal thickness (RT) in eyes with subclinical and clinical macular edema in diabetes type 2. Methods: A cohort of 48 eyes from 48 type 2 diabetic patients with mild or moderate nonproliferative diabetic retinopathy (Early Treatment Diabetic Retinopathy Study levels 20/35) were classified as having normal RT (10), subclinical macular edema (30), or clinical macular edema (8). They were examined with Cirrus spectral-domain optical coherence tomography (OCT) at baseline visits (ClinicalTrials.gov number, NCT01145599) in the Coimbra center. Results from automated analysis of the retinal extracellular space, using our OCT-Leakage algorithm to identify sites of low optical reflectivity, were compared with those from a control group of 25 healthy eyes. Results: The highest increases in RT in the eyes with subclinical and clinical macular edema were found in the inner nuclear layer (INL). These increases were, on average, 49.9% in subclinical macular edema and 104.7% in clinical macular edema. Extracellular space increases in the INL that were identified with the OCT-Leakage algorithm showed a strong positive correlation with the increases in RT in the central subfield (r = 0.71, P < 0.001). Conclusions: Increases in number of sites with lower optical reflectivity positively correlate with the increase in RT in the initial stages of macular edema in diabetes type 2. Diabetic macular edema is represented mainly by extracellular fluid accumulation that preferentially involves the INL of the retina. PMID- 27978561 TI - Retropharyngeal Mass. PMID- 27978562 TI - Association of Malignancy Prevalence With Test Properties and Performance of the Gene Expression Classifier in Indeterminate Thyroid Nodules. AB - Importance: It is crucial for clinicians to know the malignancy prevalence within each indeterminate cytologic category to estimate the performance of the gene expression classifier (GEC). Objective: To examine the variability in the performance of the GEC. Design, Setting, and Participants: This retrospective cohort study of patients with Bethesda category III and IV thyroid nodules used single-institution data from January 1, 2013, through February 29, 2016. Expected negative predictive value (NPV) was calculated by adopting published sensitivity and specificity. Observed NPV was calculated based on the true-negative rate. Outcomes were compared with pooled data from 11 studies published January 1, 2010, to January 31, 2016. Results: A total of 145 patients with 154 thyroid nodules were included in the study (mean [SD] age, 56.0 [16.2] years; 106 females [73.1%]). Malignancy prevalence was 45%. On the basis of this prevalence, the expected NPV is 85% and the observed NPV is 69%. If the prevalence is assumed to be 25%, the expected NPV would be 94%, whereas the observed NPV would be 85%. Pooled data analysis of 11 studies comprising 1303 participants revealed a malignancy prevalence of 31% (95% CI, 29%-34%) and a pooled NPV of 92% (95% CI, 87%-96%). Conclusions and Relevance: In this study, variability in the performance of the GEC was not solely a function of malignancy prevalence and may have been attributable to intrinsic variability of the test sensitivity and specificity. The utility of the GEC in practice is elusive because of this variability. A better definition of the GEC's intrinsic properties is needed. PMID- 27978563 TI - Unilateral Optic Nerve Edema With Preserved Visual Function. PMID- 27978560 TI - Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. AB - Importance: Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined. Objective: To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. Design, Setting, and Participants: Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing. Main Outcomes and Measures: Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status. Results: In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation. Conclusions and Relevance: Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC. PMID- 27978565 TI - Demonstrating the Effectiveness of Low-Vision Rehabilitation With Outcomes of the Veterans Affairs Low Vision Intervention Trial II (LOVIT II). PMID- 27978566 TI - Lymphoma and Pregnancy-Reply. PMID- 27978567 TI - Universal Genetic Testing for Younger Patients With Colorectal Cancer. PMID- 27978564 TI - Declining Prevalence of Hearing Loss in US Adults Aged 20 to 69 Years. AB - Importance: As the US population ages, effective health care planning requires understanding the changes in prevalence of hearing loss. Objective: To determine if age- and sex-specific prevalence of adult hearing loss has changed during the past decade. Design, Setting, and Participants: We analyzed audiometric data from adults aged 20 to 69 years from the 2011-2012 cycle of the US National Health and Nutrition Examination Survey, a cross-sectional, nationally representative interview and examination survey of the civilian, noninstitutionalized population, and compared them with data from the 1999-2004 cycles. Logistic regression was used to examine unadjusted, age- and sex-adjusted, and multivariable-adjusted associations with demographic, noise exposure, and cardiovascular risk factors. Data analysis was performed from April 28 to June 3, 2016. Interventions: Audiometry and questionnaires. Main Outcomes and Measures: Speech-frequency hearing impairment (HI) defined by pure-tone average of thresholds at 4 frequencies (0.5, 1, 2, and 4 kHz) greater than 25 decibels hearing level (HL), and high-frequency HI defined by pure-tone average of thresholds at 3 frequencies (3, 4, and 6 kHz) greater than 25 decibels HL. Results: Based on 3831 participants with complete threshold measurements (1953 men and 1878 women; mean [SD] age, 43.6 [14.4] years), the 2011-2012 nationally weighted adult prevalence of unilateral and bilateral speech-frequency HI was 14.1% (27.7 million) compared with 15.9% (28.0 million) for the 1999-2004 cycles; after adjustment for age and sex, the difference was significant (odds ratio [OR], 0.70; 95% CI, 0.56-0.86). Men had nearly twice the prevalence of speech frequency HI (18.6% [17.8 million]) as women (9.6% [9.7 million]). For individuals aged 60 to 69 years, speech-frequency HI prevalence was 39.3% (95% CI, 30.7%-48.7%). In adjusted multivariable analyses for bilateral speech frequency HI, age was the major risk factor (60-69 years: OR, 39.5; 95% CI, 10.5 149.4); however, male sex (OR, 1.8; 95% CI, 1.1-3.0), non-Hispanic white (OR, 2.3; 95% CI, 1.3-3.9) and non-Hispanic Asian race/ethnicity (OR, 2.1; 95% CI, 1.1 4.2), lower educational level (less than high school: OR, 4.2; 95% CI, 2.1-8.5), and heavy use of firearms (>=1000 rounds fired: OR, 1.8; 95% CI, 1.1-3.0) were also significant risk factors. Additional associations for high-frequency HI were Mexican-American (OR, 2.0; 95% CI, 1.3-3.1) and other Hispanic race/ethnicity (OR, 2.4; 95% CI, 1.4-4.0) and the combination of loud and very loud noise exposure occupationally and outside of work (OR, 2.4; 95% CI, 1.4-4.2). Conclusions and Relevance: Adult hearing loss is common and associated with age, other demographic factors (sex, race/ethnicity, and educational level), and noise exposure. Age- and sex-specific prevalence of HI continues to decline. Despite the benefit of delayed onset of HI, hearing health care needs will increase as the US population grows and ages. PMID- 27978568 TI - Reconstructive Techniques for the Saddle Nose Deformity in Granulomatosis With Polyangiitis: A Systematic Review. AB - Importance: Repairing the saddle nose deformity in the setting of granulomatosis with polyangiitis disease is a rare but challenging situation for any surgeon. Given that the available data in the literature is based on case reports and small case series, there is little evidence available to help delineate which reconstructive techniques are optimal. Objective: To examine which techniques were most successful in reconstructive rhinoplasty for a saddle nose deformity secondary to granulomatosis with polyangiitis. Evidence Review: PubMed, MEDLINE, Cochrane Collaboration Databases, and Web of Science were searched using the terms Wegener's granulomatosis or granulomatosis with polyangiitis cross referenced with saddle nose deformity or acquired nasal deformity. These databases were supplemented with 2 cases from Boston Medical Center. Databases were queried from inception of article collection through December 14, 2015, to identify publications reporting the repair of a saddle nose deformity and granulomatosis with polyangiitis. Findings: A total of 10 studies met inclusion criteria yielding a cohort of 44 patients. The overall success rate for rhinoplasty, both primary and secondary, was 84.1% (37 of 44 patients), with a complication rate of 20%. The use of a single L-shaped graft fared better than individually placed grafts. An increased risk of graft failure was noted as the number of overall grafts increased and if nonautologous tissue was used. Conclusions and Relevance: Rhinoplasty for saddle nose deformity is a safe and effective procedure in the setting of granulomatosis with polyangiitis. In the face of this disease, reconstruction should focus on placing a robust, L-shaped strut graft with autologous tissue over individual grafts. Additionally, the use of split-calvarial bone appears to have a slightly lower complication rate over costal cartilage. PMID- 27978569 TI - Outcomes of the Veterans Affairs Low Vision Intervention Trial II (LOVIT II): A Randomized Clinical Trial. AB - Importance: Randomized clinical trials are needed to compare effectiveness and cost-effectiveness of different low-vision (LV) programs. Objective: To determine the value of adding LV rehabilitation with a therapist compared with LV services without intervention. Design, Setting, and Participants: A randomized clinical trial was conducted from September 27, 2010, to July 31, 2014, of 323 veterans with macular diseases and best-corrected distance visual acuity (BCDVAbetter-eye) of 20/50 to 20/200. Masked interviewers administered questionnaires by telephone before and after LV treatment. Using an intention-to-treat design, participants were randomized to receive LV devices with no therapy or LV devices with a rehabilitation therapist providing instruction and homework on the use of LV devices, eccentric viewing, and environmental modification. Visual ability was measured in dimensionless log odds units (logits) (0.14-logit change in visual ability corresponds to ability change expected from a 1-line change in visual acuity). Interventions: Low-vision devices without therapy and LV devices with therapy. Main Outcomes and Measures: Comparison of changes (baseline to 4 months) in overall visual ability and in 4 functional domains (reading, visual information, visual motor, and mobility) estimated from responses to the Veterans Affairs Low Vision Visual Functioning Questionnaire (higher scores indicates more ability or less difficulty in performing activities), and comparison of MNREAD changes (baseline to end of treatment) in maximum reading speed, critical print size, and reading acuity (higher number indicates lower visual acuity). Results: Of the 323 participants, 314 were male (97.2%); mean (SD) age, 80 (10.5) years. Basic LV was effective in improving visual ability. However, the LV rehabilitation group improved more in all visual function domains except mobility. Differences were 0.34-logit reading (95% CI, 0.0005 to 0.69; P = .05), 0.27-logit visual information (95% CI, 0.01 to 0.53; P = .04), 0.37-logit visual motor (95% CI, 0.08 to 0.66; P = .01), and 0.27-logit overall (95% CI, 0.06 to 0.49; P = .01). For MNREAD measures, there was more improvement in reading acuity (difference, -0.11 logMAR, 95% CI, -0.15 to -0.07; P < .001) and maximum reading speed (mean increase of 21.0 words/min; 95% CI, 6.4 to 35.5; P = .005), but not critical print size for the LV rehabilitation group (-0.06 logMAR; 95% CI, -0.12 to 0.002; P = .06). In stratified analyses, the LV rehabilitation group with BCDVAbetter-eye worse than 20/63 to 20/200 improved more in visual ability (reading, visual motor, and overall). Differences were 0.56-logit reading ability (95% CI, 0.08-1.04; P = .02), 0.40-logit visual motor (95% CI, 0.03-0.78; P = .04), 0.34-logit overall (95% CI, 0.06-0.62; P = .02). There was no significant difference between treatment groups for those with BCDVAbetter-eye of 20/50 to 20/63. Conclusions and Relevance: Both basic LV alone and combined with LV rehabilitation were effective, but the added LV rehabilitation increased the effect only for patients with BCDVAbetter-eye worse than 20/63 to 20/200. Basic LV services may be sufficient for most LV patients with mild visual impairment. Trial Registration: clinicaltrials.gov Identifier: NCT00958360. PMID- 27978570 TI - Comparison of 2 Commercially Available Next-Generation Sequencing Platforms in Oncology. PMID- 27978571 TI - Nontechnical Factors in the Simulation of Ophthalmological Procedures. PMID- 27978572 TI - Combating Cataract Blindness. PMID- 27978573 TI - Incorrect Numbers at Risk in Figure. PMID- 27978574 TI - Nasal Reconstruction in the Vasculopathic Patient-Saddle Up. PMID- 27978575 TI - Nontechnical Factors in the Simulation of Ophthalmological Procedures-Reply. PMID- 27978576 TI - Lymphoma and Pregnancy. PMID- 27978577 TI - An Aggressive Mandibular Mass. PMID- 27978578 TI - Cost and Expected Visual Effect of Interventions to Improve Follow-up After Cataract Surgery: Prospective Review of Early Cataract Outcomes and Grading (PRECOG) Study. AB - Importance: Some experts recommend increasing low rates of follow-up after cataract surgery in low- and middle-income countries using various interventions. However, little is known about the cost and effect of such interventions. Objective: To examine whether promoting follow-up after cataract surgery creates economic value. Design, Setting, and Participants: The Prospective Review of Early Cataract Outcomes and Grading (PRECOG) is a cohort study with data from patients undergoing cataract surgery from January 19, 2010, to April 18, 2012. Final follow-up was completed on August 10, 2012. Data were collected before surgery, at discharge, and at follow-up at least 40 days after surgery from 27 centers in 8 countries in Asia, Africa, and Latin America. Each center enrolled 40 to 120 consecutive patients undergoing cataract surgery. If patients did not return to the hospital for the follow-up visit, hospitals could use telephone calls or transportation subsidies to increase follow-up rate. Data were analyzed from December 2013 to January 2016. Main Outcomes and Measures: Cost of interventions (telephone calls and transportation subsidies) to increase follow up at least 40 days after surgery, visual acuity (VA) in the eye undergoing cataract surgery, presence of complications, patient and facility costs per visit, and willingness to pay for treatment or glasses if needed. The maximum incremental cost of improving VA in 1 patient (incremental cost-effect ratio [ICER]) was calculated for spontaneous follow-up (compared with no follow-up) and follow-up with the telephone and transportation interventions. Expected ICERs were estimated including only those patients willing to pay. Results: Among 2487 patients (1068 men [42.9%]; 1405 women [56.5%]; 14 missing [0.6%]; mean [SD] age, 68.4 [11.3] years), 2316 (93.1%) received follow-up, of whom 369 (16.0%) were seen in an outside facility or home and were in the cost-effectiveness analysis as unable to follow up. A grand mean (a mean of means of the different countries) of 56.3% of patients needed glasses, of whom 56.9% were willing to pay, and 1.6% had treatable complications, of whom 39.4% were willing to pay. Maximum proportions with improved VA (and corresponding ICERs) were 0.08 for no follow up, 0.45 ($151.56) for spontaneous follow-up, 0.53 ($164.46) for a telephone intervention, and 0.53 ($133.07) for a transportation intervention. These results were most sensitive to the cost of follow-up. Expected proportions (ICERs) were 0.08, 0.27 ($232.69), 0.30 ($456.22), and 0.30 ($206.47), respectively. Conclusions and Relevance: Most patients benefiting from follow-up after cataract surgery returned spontaneously when requested at discharge. Use of telephone calls or transportation subsidies to increase follow-up in low- and middle-income countries may not be cost-effective. PMID- 27978580 TI - Toilet Phobia and Toilet Refusal In Children. AB - Objective: Toilet refusal syndrome (TRS) is a common disorder in toddlers, defined by use of diapers and refusal of toilet for defecation, while toilet phobia (TP) is a rare disorder in which toilets are avoided completely. Both disorders have not been described systematically in children, yet. Therefore, the aim was to present typical case vignettes illustrating different clinical presentations of TP and TRS. Methods: 5 typical cases were selected from all patients presented at a specialized outpatient clinic for incontinence at a tertiary university hospital during the last 3 years. Results: The first case is a girl with incontinence and no behavioral comorbidities, for whom treatment was more complicated than expected because of her TP. Second, a boy with an IQ on the border to mild intellectual disability will be presented, who revealed phobias regarding the toilet. Case 3 is exemplary for a group of patients with TRS, who also have ODD and show oppositional behavior in different situations. Cases 4 and 5 show "classical" TRS with constipation following painful defecation. Similarities and differences of TRS and TP, the current state of research, diagnostic and management recommendations are presented in detail. Conclusion: TRS in preschool children is a common condition, associated with high rates of constipation and behavioral problems. In contrast, TP is rarer and harder to recognize for pediatricians, but is often accompanied with somatic and behavioral problems, as well. Although there is a paucity of studies on these pediatric disorders, pediatricians should keep them in mind. PMID- 27978581 TI - Microsurgery Fellowship Selection Criteria: A National Program Director Survey. AB - Background Desirable candidate characteristics for microsurgery fellowship applicants still remain unclear, as no data are available in the literature. This study aims to provide information on the criteria that are used to select and rank applicants for the microsurgery fellowship match. Methods A 38-question survey was sent in April 2015 to all microsurgery fellowship directors (n = 36) involved in the U.S. match, using QuestionPro Software. The survey investigated various factors used for selection of applicants, including medical school, residency training, research experience, fellowship interview, and candidate characteristics. A 5-point Likert scale was used to grade 33 influential factors from 1 ("not at all important in making my decision") to 5 ("essential in making my decision"), or for 5 controversial factors from 1 ("very negative impact in making my decision") to 5 ("very positive impact in making my decision"). Results A total of 53% (19 out of 36) of responses were received from microsurgery fellowship directors. The most important factors included letters of recommendations by microsurgeons (4.6 +/- 0.5), interactions with faculty (4.6 +/ 0.5), overall interview performance in the selection process (4.6 +/- 0.5), and professionalism and ethics (4.4 +/- 0.7). Factors that had a negative impact on the selection process included graduate from a non-U.S. plastic surgery residency program (2.1 +/- 0.9), graduate needing a visa (2.3 +/- 0.8), and graduate from a foreign medical school (2.4 +/- 1.0). Conclusion This study provides data on the microsurgery fellowship directors' perception of the criteria important for applicant selection and shows that the most valued criteria are letters of recommendation, interactions with faculty, and interview performance. PMID- 27978579 TI - Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial. AB - Importance: KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer. Objective: To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed. Design, Setting, and Participants: SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases. Interventions: Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle. Main Outcomes and Measures: The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival. Results: There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK 2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients). Conclusions and Relevance: Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX. Trial Registration: clinicaltrials.gov Identifier: NCT01658943. PMID- 27978582 TI - A Comparison of Vascularized Free Fibular Flaps and Nonvascularized Fibular Grafts for Reconstruction of Long Bone Defects after Tumor Resection. AB - Background The use of the fibula autograft has been a reliable method in the reconstruction of long bone defects after tumor resection. The objective of this study was to report the outcomes fibular grafting in terms of graft union, functional score, complications, and oncologic outcome. Methods A retrospective review of patients with fibular grafting after tumor resection was done from January 1, 1993 to December 31, 2013. The primary outcome was graft union and the revised musculoskeletal tumor society scoring system (MSTS score). The secondary outcomes were oncologic outcomes, complications, and the factors associated with graft union. Results A total of 52 patients with a mean follow-up of 42 months (SD, 33; range, 12-132 months) were included. The overall union for all fibular grafts was 37 of 52. The use of vascularized free fibula flaps had a higher union rate compared with nonvascularized fibula grafts. The use of a vascularized free fibular flap was four times likely to unite (95% CI 1.1-12.8, p = 0.039) compared with nonvascularized fibular grafts. The mean MSTS score in 36 patients was 82.5 (SD, 12.9) at 35 months from surgery (SD, 30). A total of 39 complications were present in 29 patients. On final follow-up, 45 of 52 patients were alive, six patients had died of disease and one died of other causes. Conclusion A higher union rate was achieved using vascularized free fibular flaps compared with nonvascularized fibular grafts for long bone reconstruction after tumor resection. There was no difference in terms of MSTS score between the two types of grafts. PMID- 27978583 TI - ? PMID- 27978584 TI - PPAR-gamma Agonists for the Treatment of Major Depression: A Review. AB - Introduction: Selective agonists of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) are used for the treatment of type 2 diabetes. We reviewed their efficacy and safety for the treatment of major depression and the association of their potential antidepressant effects with changes in biomarkers of metabolism and inflammation. Methods: From 8 studies, 4 open-label trials, and 4 randomized controlled trials (RCT) (3 vs. placebo and 1 vs. metformin), 448 patients with major depression were included, of which 209 patients received PPAR-gamma agonists (pioglitazone or rosiglitazone) for 6-12 weeks, either alone or in add-on therapy to conventional treatments. Results: PPAR-gamma agonists have antidepressant effects in the 4 open-label studies and in 3 out of 4 RCT. No major adverse event was reported. Improvement in depression scores was associated with improvement in 3 biomarkers of insulin resistance (homeostatic model assessment [HOMA-IR], oral glucose tolerance test, and fasting plasma glucose) and 1 biomarker of inflammation (interleukin-6) among 21 biomarkers studied. Conclusion: PPAR-gamma agonists may have antidepressant properties, which need to be assessed in further studies of major depressive episodes. PMID- 27978585 TI - [A Rare Form of Oral Leukoplakia]. PMID- 27978586 TI - [20 Years of Bilateral Cochlear Implantation - an Analysis of the Implanted Patients]. AB - Binaural hearing is essential for localization abilities and improves the speech perception in noise. Since 20 years, bilateral cochlear implantation is routinely performed to restore binaural hearing. In this cross-sectional study, we evaluated speech perception in quiet (Freiburger monosyllables, Hochmair-Schulz Moser (HSM) sentence test, each at 70 dB) and in noise (HSM test, signal-to-noise ratio 10 dB) in 103 out of 165 adult patients who were bilaterally implanted in Wurzburg between 1995 and June 2014. In almost half the patients, the second implanted side showed the better speech perception. Compared to the first implanted side, the average monosyllable scores with bilateral implants were improved from 54 to 63% and the HSM scores from 86 to 96%. In noise the speech perception improved from 47 to 65%. The speech perception of the second implanted side was independent of the time interval between the implantation of both sides in this cohort of postlingually deafened patients. This cross-sectional data underline the importance of bilateral cochlear implantation for speech understanding in quiet and even more in noise and thus, for the everyday life. For this, bilateral cochlear implantation should be the generally accepted standard in the treatment of deaf patients. PMID- 27978588 TI - Innovation in Hemophilia Therapies - "And Miles to Go, before [We] Sleep". PMID- 27978587 TI - Efficacy of Two Techniques in Anterior Cruciate Ligament Reconstruction. AB - The purpose of this study is to compare failure rate and functional outcome in young, active patients (< 25 years) with two-incision (rear-entry) versus transtibial (all-endoscopic) anterior cruciate ligament (ACL) reconstructions.Utilizing a computerized relational database (Access 2007, Microsoft Inc., Redmond, WA), 480 patients were identified that underwent ACL reconstruction, using a bone-patellar-tendon-bone autograft, by a single surgeon between January 2000 and December 2010 via a transtibial or two-incision technique. Totally, 377 (78.6%) of these patients were less than 25 years of age. Data for each patient were collected at their initial clinic visit, at the time of surgery, and at each follow-up clinic visit and entered into the computerized relational database. Overall, 274 patients (72.7%) underwent ACL reconstruction with a transtibial technique, and 103 patients (27.3%) underwent reconstruction with a two-incision technique. Failures were identified as a 2+ Lachman, 1+ or greater pivot shift, or a KT-1000 arthrometer difference of five or more.In patients < 25 years of age, there were 10 failures (9.7%) out of 103 patients undergoing a two-incision reconstruction and 28 failures (10.2%) out of 274 patients undergoing a transtibial reconstruction (p = 1.000). There was no statistical significance between the failure rate in the two different groups in regards to gender, meniscal tear, activity level, or any other factor that was analyzed.Our study showed no statistical difference between the two-incision technique and the transtibial technique for ACL reconstruction using bone patellar-tendon-bone autograft with an overall 10.1% failure rate in young, active patients (< 25 years of age). The level of evidence is level IV. PMID- 27978590 TI - Laboratory Testing for von Willebrand Disease: The Past, Present, and Future State of Play for von Willebrand Factor Assays that Measure Platelet Binding Activity, with or without Ristocetin. AB - von Willebrand disease (VWD) was first described nearly a century ago in 1924 by Erik Adolf von Willebrand. Diagnostic testing at the time was very limited and it was not until the mid to late 1900s that more tests became available to assist with the diagnosis and classification of VWD. Two of these tests are based on ristocetin, one being ristocetin-induced platelet aggregation (RIPA) and the other the von Willebrand factor (VWF) ristocetin cofactor assay (VWF:RCo). The VWF:RCo assay provides functional assessment of in vitro VWF binding to the platelet glycoprotein (Gp) complex, GPIb-IX-V. Despite some advancements and newer technologies utilizing the principles of the original VWF:RCo assay, the original assay is still referred to as the gold standard for measurement of VWF activity. This article will review the history of VWD diagnostic assays, including RIPA and VWF:RCo over the past 40 years, as well as the newer assays that measure platelet binding with or without ristocetin, and which have been developed with the aim to potentially replace platelet-based ristocetin-dependent assays. PMID- 27978589 TI - Gene Variations in the Protein C and Fibrinolytic Pathway: Relevance for Severity and Outcome in Pediatric Sepsis. AB - The host response to infection involves complex interplays between inflammation, coagulation, and fibrinolysis. Deregulation of hemostasis and fibrinolysis are major causes of critical illness and important determinants of outcome in severe sepsis. The hemostatic responses to infection vary widely between individuals, and are in part explained by polymorphisms in genes responsible for the protein C and fibrinolytic pathway. This review gives an overview of genetic polymorphisms in the protein C and fibrinolytic pathway associated with susceptibility and severity of pediatric sepsis. In addition, genetic polymorphisms associated with adult sepsis and other pediatric thromboembolic disorders are discussed, as these polymorphisms might be candidates for future molecular genetic research in pediatric sepsis. PMID- 27978591 TI - Phenotypic Parameters in Genotypically Selected Type 2B von Willebrand Disease Patients: A Large, Single-Center Experience Including a New Novel Mutation. AB - von Willebrand disease type 2B (VWD2B) expresses gain-of-function mutations that enhance binding of an individual's von Willebrand factor (VWF) to its platelet ligand, glycoprotein Ib (GPIb), and which are usually identified by increased ristocetin-induced platelet aggregation (RIPA). We describe here the phenotypic profile of 38 genotypically selected VWD2B-affected family members (AFMs) belonging to 19 unrelated families. Major bleeding was observed in 68.4% of AFMs (previous to their diagnosis and registered by lifetime interviews), with a total of 46 episodes (1.21/patient), and was found to be highly related to the individual bleeding score and presence of thrombocytopenia, but otherwise unrelated to other laboratory parameters. Excessive muco-cutaneous bleeding symptoms were often reported, the most frequent of which comprised menorrhagia, epistaxis, easy bruising, and bleeding after teeth extraction/in oral cavity. Eight unaffected family members were also studied. The prevalence of VWD2B within families was 0.826, and the penetrance of mutations was complete, making it mandatory to study entire family sets to complete diagnostic profiles. Seven heterozygous missense mutations were found, the most common being p.V1316M. In the p.R1308C group, 75% of the AFMs showed absence of RIPA at 0.5 mg/mL, 66.6% of whom had VWF:RCo < 10 IU/dL, and 50% of whom had VWF:CB < 10 IU/dL. In the p.S1310F group, none of the AFMs had VWF:RCo/VWF:Ag < 0.6 (RCo/Ag), but 100% had VWF:CB/VWF:Ag < 0.6/(CB/Ag). Patients with p.P1266L and p.R1304V were characterized as atypical VWD2B. Two de novo mutations were found in four AFMs belonging to two families. We also describe a novel mutation: p.Y1258C. Of our patients, 70.5% had O blood group. In conclusion, a normal RCo/Ag and a negative RIPA at 0.5 mg/mL do not necessarily rule out a diagnosis of VWD2B. PMID- 27978592 TI - Neurocutaneous Melanosis Associated with Prenatally Diagnosed Arachnoid Cyst. PMID- 27978593 TI - Fetal Neurosonogaphy: Ultrasound and Magnetic Resonance Imaging in Competition. AB - Both in routine diagnostics and detailed, highly specialized workups, major advances have been observed in many areas of ultrasound due to an increase in expertise and improved technology in recent years. This is particularly true in the case of fetal neurosonography 1 2 3 4. Malformations of the CNS together with fetal heart defects are among the most common congenital anomalies. From the embryonic phase to the late third trimester, the CNS undergoes extensive development and maturation processes. The diagnosis of CNS anomalies is therefore primarily dependent on the time at which the examination is performed and the experience of the examiner. The introduction of transvaginal and 3 D ultrasound for evaluating fetal brain structures has made it possible to diagnose pathological findings of the CNS with increasing accuracy 5. The detection rates for CNS anomalies are up to 90 - 95 % depending on the finding 3 5. Today, detailed fetal neurosonography also includes differential diagnostic evaluation of the posterior cranial fossa, the corpus callosum (CC), and the gyri and therefore exceeds the primarily conspicuous, non-specific diagnosis of "ventricular dilation" often occurring as an accompanying symptom 6 7 The article "Prenatal Diagnosis of Corpus Callosum Anomalies" appearing in this issue shows an increase in the frequency of diagnosis and also shows that it is possible to differentiate between complete and partial corpus callosum agenesis and hypoplasia of the corpus callosum with differentiation between isolated and non isolated cases is possible on ultrasound. In 4 of 44 cases in which both neurosonography and intrauterine MRI were performed, there was a discrepancy between the ultrasound diagnosis and the intrauterine MRI findings. In a comparison of the sonographic diagnoses and the MRI findings, additional pathologies were seen on MRI but not on ultrasound in only 3 of 44 cases. In a further case of CC hypoplasia, the sonographic diagnosis was superior to the MRI findings.Another study appearing in this issue study of CNS anomalies in fetuses with complex clubfoot also showed additionally diagnosed CNS anomalies in 4 cases on MRI. MRI yielded supplementary findings that were not visible on ultrasound in 6 cases. Although the number of cases is small, it was able to be shown, as in other studies, that a certain percentage of CNS anomalies is able to be evaluated on an additional or supplementary basis on MRI.Since intrauterine MRI has been becoming increasingly important in recent years, it is necessary to determine when MRI is indicated. There is general consensus in the literature that MRI is not a screening method for detecting fetal anomalies but should be viewed as a supplementary method to ultrasound 8 9 10. However, MRI application in pregnancy is increasing. Intrauterine MRI is most commonly used in the case of abnormal ultrasound findings regarding the CNS 11 12 13. This includes morphological evaluation of malformations and recently also of acquired hypoxic-ischemic diseases, bleeding and inflammation such as CMV infections. Thoracic and abdominal malformations are also indications for MRI for the evaluation of the lung volume in diaphragmatic defects and in the case of suspicion of esophageal atresia abnormal placentation. Further possible indications for the use of MRI include monochorial multiple pregnancies with a feto-fetal transfusion syndrome (for the evaluation of neurological development) and select cases with known diseases and syndromes 14. The majority of studies for comparing intrauterine MRI to sonographic diagnosis include a small number of cases with limited or no follow-up. Data regarding sensitivities, specificities, and positive predictive values is limited. Many studies simply calculate the difference in percentages on the basis of a small number of cases. The best available data is in regard to CNS anomalies. In one of the few meta-analyses including 34 studies and documented follow-up in 959 fetuses, intrauterine MRI was correct in 91 % of cases which was an increase of 16 % above that achieved by ultrasound 15. This means a significant diagnostic gain for specific issues. However, it must be taken into consideration that the analysis includes a period of 20 years and fetal neurosonography has made major progress in this time. The diagnostic gain would tend to be smaller today. In many studies the level of experience of the ultrasound examiners often remains unclear A possible bias is also that an examiner with less experience determines an indication for intrauterine MRI faster and more frequently and can thus gain more information compared to highly specialized, experienced ultrasound examiners in prenatal centers. Since advanced training in prenatal diagnosis is becoming increasingly difficult due to the transfer of centers to ambulatory practices, there is a certain risk that crash courses or brief internships in ultrasound will result in intrauterine MRI playing an additional role in fetal differential diagnosis and in the confirmation of findings. Because intrauterine MRI is stressful for pregnant women, indiscriminate indication for MRI cannot be recommended even if no fetal damage is to be expected provided that the appropriate safety measures are observed (examination duration of approx. 30 minutes and implementation of MRI after 18 weeks of gestation). After a properly performed ultrasound examination, little additional morphological information can be gained from MRI 16. However, in the case of an unclear sonographic finding or in the event of therapeutic consequences for the care of the fetus or for the birth, MRI is an excellent supplementary method to ultrasound. Concretely, this means ultrasound first. If the finding is not clear, intrauterine MRI can be used as an adjunct method. In this way the cost-benefit ratio can be optimized. The gains achieved by MRI compared to US depend on the quality of the examination and thus on the expertise of the examiner in both methods. The indications for fetal MRI should also follow defined standards based on a protocol adapted to the particular clinical issue 16. PMID- 27978594 TI - Treatment outcomes in patients with multidrug-resistant tuberculosis in north west Ethiopia. AB - OBJECTIVE: Multidrug-resistant tuberculosis (MDR-TB) is an emerging public health problem in Ethiopia. The aim of this study was to assess MDR-TB treatment outcomes and determine predictors of poor treatment outcomes in north-west Ethiopia. METHODS: A retrospective cohort study was conducted using all MDR-TB patients who were enrolled at Gondar University Hospital since the establishment of the MDR-TB programme in 2010. A Cox proportional hazard model was used to identify the predictors of time to poor treatment outcomes, which were defined as death or treatment failure. RESULTS: Of the 242 patients who had complete records, 131 (54%) were cured, 23 (9%) completed treatment, 31 (13%) died, four (2%) experienced treatment failure, 27 (11%) were lost to follow-up, six (2%) transferred out, and 20 (8%) were still on treatment at the time of analysis. The overall cumulative probability survival of the patients at the end of treatment (which was 24 months in duration) was 80% (95% CI: 70%, 87%). The proportion of patients with poor treatment outcomes increased over time from 6% per person-year (PY) during 2010-2012, to 12% per PY during 2013-2015. The independent predictors of time to poor treatment outcome were being anaemic [AHR = 4.2; 95% CI: 1.1, 15.9] and being a farmer [AHR = 2.2; 95% CI: 1.0, 4.9]. CONCLUSIONS: Overall, in north-west Ethiopia, the MDR-TB treatment success rate was high. However, poor treatment outcomes have gradually increased since 2012. Being a farmer and being anaemic were associated with poor treatment outcomes. It would be beneficial to assess other risk factors that might affect treatment outcomes such as co infection with malaria, poverty and other socio-economic and biological risk factors. PMID- 27978595 TI - Real-time continuous glucose monitoring in type 1 diabetes: a systematic review and individual patient data meta-analysis. AB - BACKGROUND: Real-time continuous glucose monitoring (RTCGM) may help in the management of individuals with type 1 diabetes mellitus (T1DM); however, the evidence supporting its use is unclear. The available meta-analyses on this topic use aggregate data which weaken inference. OBJECTIVE: Individual patient data were obtained from randomized controlled trials (RCTs) to conduct a meta-analysis and synthesize evidence about the effect of RTCGM on glycosylated haemoglobin (HbA1c), hypoglycaemic events and time spent in hypoglycaemia in T1DM. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus through January 2015. We included RCTs that enrolled individuals with T1DM and compared RTCGM vs control group. A two step regression model was used to pool individual patient data. RESULTS: We included 11 RCTs at moderate risk of bias. Meta-analysis suggests that the use of RTCGM is associated with a statistically significant but modest reduction in HbA1c (-0.276; 95% confidence interval -0.465 to -0.087). The improvements in HbA1c were primarily seen in individuals over age 15 years. We were unable to identify a statistically significant difference in time spent in hypoglycaemia or the number of hypoglycaemic episodes although these analyses were imprecise and warrant lower confidence. There was no difference between males and females. CONCLUSION: RTCGM in T1DM is associated with a reduction in HbA1c primarily in individuals over 15 years of age. We were unable to identify a statistically significant difference in the time spent in hypoglycaemia or the incidence of hypoglycaemic episodes. PMID- 27978597 TI - The role of emotion regulation in situational empathy-related responding and prosocial behaviour in the presence of negative affect. AB - Empathy and prosocial behaviour are crucial factors for children's positive social adjustment. Contemporary models of empathy highlight the capacity to regulate vicariously experienced emotions as a precursor to empathy-related responses (e.g., prosocial behaviour). The goal of this study was to examine the role of emotion regulation (ER) in situational empathy-related responding and prosocial behaviour. A sample of 157 children (76 boys and 81 girls; Mage = 9.94 years) participated in a two-tiered interview procedure that utilised vignettes to assess empathy and prosocial behaviour. Between both phases of the interview, a negative affect was induced to investigate the influence of ER on the change between the two phases. Results from a latent change model showed that ER strategies positively predicted change scores, that is, children with higher abilities to regulate emotions showed a higher increase in empathy and prosocial behaviour. Implications for the promotion of social-emotional learning in school are discussed. PMID- 27978596 TI - Environmental tobacco smoke exposure and periodontitis prevalence among nonsmokers in the hispanic community Health Study/Study of Latinos. AB - OBJECTIVE: To describe self-reported exposure to environmental tobacco smoke (ETS) and its association with periodontitis prevalence in a diverse group of Hispanics/Latinos. METHODS: Data came from 8675 lifetime nonsmokers in the 2008 2011 Hispanic Community Health Study/Study of Latinos. Exposure to ETS was self reported, while periodontitis was defined using the Centers for Disease Control and Prevention-American Academy of Periodontology criteria and the proportion of sites affected by clinical attachment level of >=3 mm or pocket depth of >=4 mm. Survey logistic regression estimated prevalence odds ratios (POR) and 95% confidence intervals (CI). In addition, we assessed whether greater hours of exposure to ETS in the past year was associated with greater periodontitis prevalence, and lastly, we conducted a simple sensitivity analysis of ETS misclassification. RESULTS: Age-standardized prevalence estimates (95% CI) for ETS exposure and periodontitis were 57.6% (55.9, 59.4) and 39.8% (38.1, 41.4), respectively. After adjusting for confounders and periodontitis risk factors, we estimated an overall adjusted POR (95% CI) for the ETS-periodontitis association as 1.09 (0.95-1.26) with a confidence limit ratio (CLR) of 1.34. This association varied in magnitude by Hispanic/Latino background, ranging from 1.04 (0.75, 1.43 with a CLR = 1.91) among Central Americans to 1.76 (1.16, 2.66 with a CLR = 2.29) in Puerto Ricans. CONCLUSIONS: Previously reported associations between ETS and periodontitis appear weak in this study. However, the magnitude of the association differs according to Hispanic/Latino background. PMID- 27978598 TI - The subgingival microbiome, systemic inflammation and insulin resistance: The Oral Infections, Glucose Intolerance and Insulin Resistance Study. AB - BACKGROUND: Inflammation might link microbial exposures to insulin resistance. We investigated the cross-sectional association between periodontal microbiota, inflammation and insulin resistance. METHODS: The Oral Infections, Glucose Intolerance and Insulin Resistance Study (ORIGINS) enrolled 152 diabetes-free adults (77% female) aged 20-55 years (mean = 34 +/- 10). Three hundred and four subgingival plaque samples were analysed using the Human Oral Microbe Identification Microarray to measure the relative abundances of 379 taxa. C reactive protein, interleukin-6, tumour necrosis factor-alpha and adiponectin were assessed from venous blood and their z-scores were summed to create an inflammatory score (IS). Insulin resistance was defined via the HOMA-IR. Associations between the microbiota and both inflammation and HOMA-IR were explored using multivariable linear regressions; mediation analyses assessed the proportion of the association explained by inflammation. RESULTS: The IS was inversely associated with Actinobacteria and Proteobacteria and positively associated with Firmicutes and TM7 (p-values < 0.05). Proteobacteria levels were associated with insulin resistance (p < 0.05). Inflammation explained 30-98% of the observed associations between levels of Actinobacteria, Proteobacteria or Firmicutes and insulin resistance (p-values < 0.05). Eighteen individual taxa were associated with inflammation (p < 0.05) and 22 with insulin resistance (p < 0.05). No findings for individual taxa met Bonferroni-adjusted statistical significance. CONCLUSION: Bacterial measures were related to inflammation and insulin resistance among diabetes-free adults. PMID- 27978599 TI - Impact of postprandial hyperglycemia at clinic visits on the incidence of cardiovascular events and all-cause mortality in patients with type 2 diabetes. AB - AIMS/INTRODUCTION: We evaluated the impact of postprandial hyperglycemia at clinic visits on the incidence of cardiovascular diseases (CVD) and all-cause mortality independently of mean glycosylated hemoglobin in type 2 diabetes patients in a real-world setting. MATERIALS AND METHODS: The present retrospective observational cohort study included 646 type 2 diabetes patients. All of the participants had their initial consultations at the Institute for Diabetes Care and Research, Asahi Life Foundation affiliated Marunouchi Hospital, Tokyo, Japan, during the period from 1995 to 1996, visited the clinic >=4 times, had their 2-h post-breakfast blood glucose (2h-PBBG) levels measured and were followed up for >=1 year. The 646 patients were followed up for survival. Of the 646 patients, 618 had no history of CVD at the first visit and had measured 2h PBBG until the first CVD onset or censorings. These two cohorts were followed up through June 2012, and subsequently questionnaires were mailed. Multivariate Cox proportional hazard models were used to evaluate the risk of CVD incidence and death. RESULTS: CVD occurred in 78 patients, and 56 patients died. The median follow-up periods of the CVD cohort and the mortality cohort were 15.6 and 15.9 years, respectively. The mean 2h-PBBG is a significant predictor of the CVD incidence and all-cause mortality after adjusting for the mean glycosylated hemoglobin, the number of 2h-PBBG measurements, age, sex and classical risk factors. CONCLUSIONS: Postprandial hyperglycemia represented by the mean level of 2h-PBBG at clinic visits is associated with CVD incidence and all-cause mortality independently of the mean glycosylated hemoglobin level in type 2 diabetes patients. Prospective interventional trials are warranted to confirm the present findings. PMID- 27978600 TI - Social, educational and vocational outcomes in patients with childhood-onset and young-adult-onset growth hormone deficiency. AB - OBJECTIVE: Hypopituitarism diagnosed in childhood, adolescence and young adulthood has the potential to affect growth and somatic development. Less is known about the impact of such a diagnosis on other aspects of development. DESIGN: An analysis of the KIMS database (Pfizer International Metabolic Database) was performed to explore social, educational and vocational outcomes of adult patients diagnosed in childhood, adolescence and young adulthood compared with adult-onset controls. PATIENTS: A total of 2952 adult patients diagnosed with hypothalamic pituitary conditions before the age of 25 were divided into two groups: childhood-onset [<16 years (CO)] (n = 1782) and young-adult-onset [16 to <25 years (YAO)] (n = 1170). A total of 1617 adult patients diagnosed with a nonfunctioning pituitary adenoma at the age of 25 or older formed the adult-onset control group (AO). MEASUREMENTS: KIMS Patient Life Situation Form which provided information on social, educational and vocational outcomes. RESULTS: Compared with the AO control group, CO and YAO patients were between 4.5 and 8.0 times more likely to live with their parents in adulthood; CO and YAO patients were also less likely to live in partnership and to have children. The impact on educational and vocational outcomes was less marked than on social outcomes with no significant differences compared with the AO control group. Educational and vocational outcomes showed the lowest level in male and female CO and YAO patients who had been previously diagnosed with a brain tumour. CONCLUSIONS: Social outcomes were more affected than educational and vocational outcomes. Although CO patients are more adversely affected, YAO patients were also failing to achieve social milestones. This has consequences for the delivery of endocrine care in both paediatric and adult services. PMID- 27978602 TI - Immediate versus delayed implant placement after anterior single tooth extraction: the timing randomized controlled clinical trial. AB - AIM: To compare need for bone augmentation, surgical complications, periodontal, radiographic, aesthetic and patient reported outcomes in subjects receiving implant placement at the time of extraction (Immediate Implant) or 12 weeks thereafter. METHODS: Subjects requiring single tooth extraction in the anterior and premolar areas were recruited in seven private practices. Implant position and choice of platform were restoratively driven. Measurements were performed by calibrated and masked examiners. RESULTS: IMI was unfeasible in 7.5% of cases. One hundred and 24 subjects were randomized. One implant was lost in the IMI group. IMI required bone augmentation in 72% of cases compared with 43.9% for delayed (p = 0.01), while wound failure occurred in 26.1% and 5.3% of cases, respectively (p = 0.02). At 1 year, IMI had deeper probing depths (4.1 +/- 1.2 mm versus 3.3 +/- 1.1 mm, p < 0.01). A trend for greater radiographic bone loss was observed at IMI over the initial 3-year period (p-trend < 0.01). Inadequate pink aesthetic scores were obtained in 19% of delayed and in 42% of IMI implant cases (p = 0.03). No differences in patient reported outcomes were observed. CONCLUSIONS: Immediate implant placement should not be recommended when aesthetics are important, IMI should be limited to selected cases. Longer follow up is needed to assess differences in complication rates. PMID- 27978601 TI - Cross-sectional associations of impaired glucose metabolism measures with bleeding on probing and periodontitis. AB - AIM: This study assessed the associations of pre-diabetes and insulin resistance with bleeding on probing (BOP) and periodontitis among adults. MATERIALS AND METHODS: We included 1191 Hispanic adults aged 40-65 years, free of diabetes, enrolled in San Juan Overweight Adults Longitudinal Study. Pre-diabetes was defined as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or impaired glycated haemoglobin. Impaired one-hour plasma glucose (1hPG) was defined as levels >155 mg/dl. Insulin resistance was defined using the study population-specific 75th percentile (HOMA-IR >= 3.13). High BOP was defined as percentage of teeth with bleeding >=30%. Periodontitis was defined according to the CDC/AAP definition. RESULTS: After multivariable adjustment for age, gender, education, smoking status, alcohol consumption, physical activity, obesity, HDL C, and plaque index, pre-diabetes with and without 1hPG, IFG, impaired 1hPG, IGT, and HOMA-IR were significantly associated with high BOP; pre-diabetes, IFG, and impaired 1hPG were significantly associated with severe periodontitis. Most of these associations remained significant when the analyses were restricted to non smokers. CONCLUSIONS: This study suggests associations between pre-diabetes and insulin resistance with BOP and periodontitis. Given the high prevalence of impaired glucose metabolism and periodontitis, the assessment of the temporal sequence of these associations is of utmost importance. PMID- 27978603 TI - Clinical and radiographic intra-subject comparison of implants placed with or without guided bone regeneration: 15-year results. AB - AIM: To test whether implants placed with simultaneous guided bone regeneration (GBR) differ from implants placed without GBR regarding survival rate, interproximal marginal bone level (MBL), and dimensions of buccal bone and mucosa. MATERIAL AND METHODS: Twenty-three patients treated 15 years earlier were included. Machined implants had been inserted following one of the two procedures: (i) with simultaneous GBR, which involved grafting with particulate deproteinized bovine bone mineral (DBBM), autogenous bone (AB), or a mixture of the two and defect covering with a native collagen membrane (CM) (GBR group) and (ii) standard implant placement without GBR (control group). One GBR and one control implant in each patient were selected for analysis. At 15 years, the dimensions of buccal bone and mucosa were measured with cone beam computed tomography. The interproximal MBL was evaluated at 5 and 15 years on periapical radiographs. RESULTS: The 15-year survival rate amounted to 95.6% for GBR implants and to 94.1% for control implants. At 15 years, interproximal MBL measured 1.44 +/- 0.84 mm for the GBR group and 1.69 +/- 0.84 mm for the control group. From the 5- to the 15-year examination, the loss of interproximal MBL reached 0.23 +/- 0.70 mm for the GBR group and 0.28 +/- 0.63 mm for the control group. At 15 years, buccal MBL measured 1.98 +/- 0.98 mm for GBR implants and 2.19 +/- 1.29 mm for control implants. None of these values reached statistical significant differences between the groups. In cases in which GBR involved grafting with DBBM, GBR implants achieved approximately 0.3-0.4 mm higher mean values in buccal bone dimensions and mucosal level in comparison to control implants. In contrast, when GBR was performed by grafting with AB without DBBM, implants rendered less favourable results in buccal bone and mucosa dimensions than the control implants. CONCLUSIONS: Implants placed with simultaneous GBR using particulate DBBM and/or AB in combination with CM did not significantly differ from implants completely placed into pristine bone with respect to 15-year implant survival, interproximal bone levels, and dimensions of buccal bone and mucosa. The machined-surface implants placed both into native bone and sites augmented by GBR exhibited stable interproximal bone levels. PMID- 27978604 TI - Effects of EMD liquid (Osteogain) on periodontal healing in class III furcation defects in monkeys. AB - AIM: To evaluate the effect of a novel liquid carrier system of enamel matrix derivative (Osteogain) soaked on an absorbable collagen sponge (ACS) upon periodontal wound healing/regeneration in furcation defects in monkeys. MATERIALS AND METHODS: The stability of the conventional enamel matrix derivative (Emdogain) and Osteogain adsorbed onto ACS was evaluated by ELISA. Chronic class III furcation defects were created at teeth 36, 37, 46, 47 in three monkeys (Macaca fascicularis). The 12 defects were assigned to one of the following treatments: (1) open flap debridement (OFD) + ACS, (2) OFD+Emdogain/ACS, (3) OFD+Osteogain/ACS, and (4) OFD alone. At 16 weeks following reconstructive surgery, the animals were killed for histological evaluation. RESULTS: A 20-60% significantly higher amount of total adsorbed amelogenin was found for ACS-loaded Osteogain when compared to Emdogain. The histomorphometric analysis revealed that both approaches (OFD + Emdogain/ACS and OFD + Osteogain/ACS) resulted in higher amounts of connective tissue attachment and bone formation compared to treatment with OFD + ACS and OFD alone. Furthermore, OFD + Osteogain/ACS group showed higher new attachment formation, cementum, and new bone area. CONCLUSIONS: Within their limits, the present data indicate that Osteogain possesses favourable physicochemical properties facilitating adsorption of amelogenin on ACS and may additionally enhance periodontal wound healing/regeneration when compared to Emdogain. PMID- 27978606 TI - Level of genetic differentiation affects relative performances of expressed sequence tag and genomic SSRs. AB - Microsatellites, also called simple sequence repeats (SSRs), are markers of choice to estimate relevant parameters for conservation genetics, such as migration rates, effective population size and kinship. Cross-amplification of SSRs is the simplest way to obtain sets of markers, and highly conserved SSRs have recently been developed from expressed sequence tags (EST) to improve SSR cross-species utility. As EST-SSRs are located in coding regions, the higher stability of their flanking regions reduces the frequency of null alleles and improves cross-species amplification. However, EST-SSRs have generally less allelic variability than genomic SSRs, potentially leading to differences in estimates of population genetic parameters such as genetic differentiation. To assess the potential of EST-SSRs in studies of within-species genetic diversity, we compared the relative performance of EST- and genomic SSRs following a multispecies approach on passerine birds. We tested whether patterns and levels of genetic diversity within and between populations assessed from EST- and from genomic SSRs are congruent, and we investigated how the relative efficiency of EST- and genomic SSRs is influenced by levels of differentiation. EST- and genomic SSRs ensured comparable inferences of population genetic structure in cases of strong genetic differentiation, and genomic SSRs performed slightly better than EST-SSRs when differentiation is moderate. However and interestingly, EST-SSRs had a higher power to detect weak genetic structure compared to genomic SSRs. Our study attests that EST-SSRs may be valuable molecular markers for conservation genetic studies in taxa such as birds, where the development of genomic SSRs is impeded by their low frequency. PMID- 27978605 TI - A novel method to infer the origin of polyploids from Amplified Fragment Length Polymorphism data reveals that the alpine polyploid complex of Senecio carniolicus (Asteraceae) evolved mainly via autopolyploidy. AB - Despite its evolutionary and ecological relevance, the mode of polyploid origin has been notoriously difficult to be reconstructed from molecular data. Here, we present a method to identify the putative parents of polyploids and thus to infer the mode of their origin (auto- vs. allopolyploidy) from Amplified Fragment Length Polymorphism (AFLP) data. To this end, we use Cohen's d of distances between in silico polyploids, generated within a priori defined scenarios of origin from a priori delimited putative parental entities (e.g. taxa, genetic lineages), and natural polyploids. Simulations show that the discriminatory power of the proposed method increases mainly with increasing divergence between the lower-ploid putative ancestors and less so with increasing delay of polyploidization relative to the time of divergence. We apply the new method to the Senecio carniolicus aggregate, distributed in the European Alps and comprising two diploid, one tetraploid and one hexaploid species. In the eastern part of its distribution, the S. carniolicus aggregate was inferred to comprise an autopolyploid series, whereas for western populations of the tetraploid species, an allopolyploid origin involving the two diploid species was the most likely scenario. Although this suggests that the tetraploid species has two independent origins, other evidence (ribotype distribution, morphology) is consistent with the hypothesis of an autopolyploid origin with subsequent introgression by the second diploid species. Altogether, identifying the best among alternative scenarios using Cohen's d can be straightforward, but particular scenarios, such as allopolyploid origin vs. autopolyploid origin with subsequent introgression, remain difficult to be distinguished. PMID- 27978607 TI - Neonatal 17-hydroxyprogesterone levels adjusted according to age at sample collection and birthweight improve the efficacy of congenital adrenal hyperplasia newborn screening. AB - INTRODUCTION: The primary concern related to congenital adrenal hyperplasia (CAH) newborn screening (NBS) is the high rate of false-positive results (FPR) associated with prematurity; false-negative results (FNR) can also occur due to precocious sample collection. OBJECTIVE: To determine the neonatal 17 hydroxyprogesterone (N17OHP) normal range in newborns in Sao Paulo using different references according to age and birthweight (BW) and to establish the optimal NBS cut-off levels. METHODS: Neonatal 17-hydroxyprogesterone levels from 271 810 newborns (NBs) according to sample collection time (G1: 48-<72 h and G2: >=72 h) and BW (<=1500 g, 1501-2000 g, 2001-2500 and >2500 g) were evaluated. N17OHP was measured by an fluoroimmunoassay, and serum 17OHP was measured by liquid chromatography-mass spectrometry. Affected and asymptomatic NBs with persistently increased 17OHP levels were submitted to CYP21A2-sequencing. RESULTS: Neonatal 17-hydroxyprogesterone levels in G1 were lower than G2 in all BW groups (P < 0.001). The FPR rate in G1/G2 was 0.2% using the 99.8th and 0.5% using the 99.5th percentile. The 99.8th percentile N17OHP value was the best cut off for distinguishing between unaffected and affected NBs. Forty-four salt wasters, and five simple virilisers were diagnosed; N17OHP levels ranged from 93.3 to 2209.8 nmol/l, and no affected neonates with FNR were identified. The positive predictive value in G1 and G2 using the 99.8th percentile was 5.6% and 14.1%, respectively, and 2.3% and 7%, respectively, using the 99.5th percentile. Molecular tests identified two NBs with the nonclassical form among the 29 FPR. CONCLUSION: Neonatal 17-hydroxyprogesterone levels adjusted to sample collection age and birthweight reduced the FPR, and the use of N17OHP values based upon the 99.8th percentile improved the NBS efficacy. PMID- 27978608 TI - A case of eruptive neurofibroma in a woman with neurofibromatosis during treatment with methotrexate. PMID- 27978609 TI - Mammary pigmented Paget's disease in a male: a diagnostic challenge. PMID- 27978610 TI - Raccoon eyes in amyloidosis. PMID- 27978611 TI - Rowell's Syndrome or subacute cutaneous lupus erythematosus? PMID- 27978612 TI - Neurofibromatosis type 1 and lichen sclerosus: an uncommon association. PMID- 27978613 TI - Pediatric genital lymphedema with recurrent hydrocele and late-onset secondary skin changes. PMID- 27978614 TI - Lichen Aureus associated with interferon-alfa plus ribavirin. PMID- 27978615 TI - Lichen Sclerosus in stable sexual partners: etiologic correlation or mere coincidence? PMID- 27978616 TI - Atypical exanthemas in the Emergency Department. PMID- 27978617 TI - Post-traumatic melanonychia with pseudo-Hutchinson's sign. PMID- 27978618 TI - Electrophilic Modification of PKM2 by 4-Hydroxynonenal and 4-Oxononenal Results in Protein Cross-Linking and Kinase Inhibition. AB - Rapidly proliferating cells require an increased rate of metabolism to allow for the production of nucleic acids, amino acids, and lipids. Pyruvate kinase catalyzes the final step in the glycolysis pathway, and different isoforms display vastly different catalytic efficiencies. The M2 isoform of pyruvate kinase (PKM2) is strongly expressed in cancer cells and contributes to aerobic glycolysis in what is commonly termed the Warburg effect. Here, we show that PKM2 is covalently modified by the lipid electrophiles 4-hydroxy-2-nonenal (HNE) and 4 oxo-2-nonenal (ONE). HNE and ONE modify multiple sites on PKM2 in vitro, including Cys424 and His439, which play a role in protein-protein interactions and fructose 1,6-bis-phosphate binding, respectively. Modification of these sites results in a dose-dependent decrease in enzymatic activity. In addition, high concentrations of the electrophile, most notably in the case of ONE, result in substantial protein-protein cross-linking in vitro and in cells. Exposure of RKO cells to electrophiles results in modification of monomeric PKM2 in a dose dependent manner. There is a concomitant decrease in PKM2 activity in cells upon ONE exposure, but not HNE exposure. Together, our data suggest that modification of PKM2 by certain electrophiles results in kinase inactivation. PMID- 27978619 TI - Studies via Near-Infrared Cavity Ringdown Spectroscopy and Electronic Structure Calculations of the Products of the Photolysis of Dihalomethane/N2/O2 Mixtures. AB - Near-infrared cavity ringdown spectra were recorded following the photolysis of dihalomethanes in O2/N2 mixtures. In particular, photolysis of CH2I2 under conditions previously reported to produce the simplest Criegee intermediate, CH2O2, gave a complex, structured spectrum between 6800 and 9000 cm-1, where the lowest triplet-singlet transition (a-X) of CH2O2 might be expected. To help identify the carrier of the spectrum, extensive electronic structure calculations were performed on the a and X states of CH2O2 and the lowest two doublet states of the iodomethylperoxy radical, CH2IO2, which also could be produced by the chemistry and whose A-X transition likely lies in this spectral region. The conclusion of these calculations is that the a-X transition of CH2O2 clearly falls outside the observed spectral range and would be extremely weak both because it is spin-forbidden and because of a large geometric change between the a and X states. Moreover, only a shallow well (with a barrier to dissociation of less than 1900 cm-1) is predicted on the a state, which likely precludes the existence of long-lived states. Calculations for the A-X transition of CH2IO2 are generally consistent with the observed spectrum in terms of both the electronic origin and vibrational frequencies in the A state. To confirm the carrier assignment to CH2IO2, calculations beyond the Franck-Condon approximation were carried out to explain the hot band structure of the large-amplitude, low frequency O-O-C-I torsion mode, nu12. Photolysis of other dihalomethanes produced similar spectra which were analyzed and assigned to CH2ClO2 and CH2BrO2. Experimental values for the electronic energies and frequencies for several A state vibrations and the nu12 vibration of the X state of each are reported. In addition, the observed spectra were used to follow the self-reaction of the CH2IO2 species and its reaction with SO2. The rates of these reactions are dramatically faster than those of unsubstituted alkyl peroxy radicals and approach those of the Criegee intermediate. PMID- 27978621 TI - Cheap, High-Performance, and Wearable Mn Oxide Supercapacitors with Urea-LiClO4 Based Gel Electrolytes. AB - Here we report a simple, scalable, and low-cost method to enhance the electrochemical properties of Mn oxide electrodes for highly efficient and flexible symmetrical supercapacitors. The method involving printing on a printer, pencil-drawing, and electrodeposition is established to fabricate Mn oxide/Ni nanotube/graphite/paper hybrid electrodes operating with a low-cost, novel urea LiClO4/PVA as gel electrolyte for flexible solid-state supercapacitor (FSSC) devices. The Mn oxide nanofiber/Ni-nanotube/graphite/paper (MNNGP) electrodes in urea-LiClO4/PVA gel electrolyte show specific capacitance (Csp) 960 F/g in voltage region 0.8 V at 5 mV/s and exhibit excellent rates of capacitance retention more than 85% after 5000 cycles. Moreover, the electrochemical behavior of the MNNGP electrodes in urea-LiClO4/PVA at operating temperatures 27-110 degrees C was investigated; the results show that the MNNGP electrodes in urea LiClO4/PVA exhibit outstanding performance (1100 F/g), even at 90 degrees C. The assembled FSSC devices based on the MNNGP electrodes in urea-LiClO4/PVA exhibit great Csp (380 F/g in potential region of 2.0 V at 5 mV/s, exhibiting superior energy density 211.1 W h/kg) and great cycle stability (less than 15% loss after 5000 cycles at 25 mV/s). The oxidation-state change was examined by in situ X-ray absorption spectroscopy. FSSC devices would open new opportunities in developing novel portable, wearable, and roll-up electric devices owing to the cheap, high performance, wide range of operating temperature, and simple procedures for large area fabrication. PMID- 27978620 TI - Reprogramming the Transcriptional Response to Hypoxia with a Chromosomally Encoded Cyclic Peptide HIF-1 Inhibitor. AB - The cellular response to hypoxia is orchestrated by HIF-1, a heterodimeric transcription factor composed of an alpha and a beta subunit that enables cell survival under low oxygen conditions by altering the transcription of over 300 genes. There is significant evidence that inhibition of HIF-1 would be beneficial for cancer therapy. We recently reported a cyclic hexapeptide that inhibits the HIF-1alpha/HIF-1beta protein-protein interaction in vitro and prevents HIF-1 mediated hypoxia-response signaling in cells. This cyclic peptide was identified from a library of 3.2 * 106 members generated using SICLOPPS split-intein mediated protein splicing. With a view to demonstrating the potential for encoding the production of a therapeutic agent in response to a disease marker, we have engineered human cells with an additional chromosomal control circuit that conditionally encodes the production of our cyclic peptide HIF-1 inhibitor. We demonstrate the conditional production of our HIF-1 inhibitor in response to hypoxia, and its inhibitory effect on HIF-1 dimerization and downstream hypoxia response signaling. These engineered cells are used to illustrate the synthetic lethality of inhibiting HIF-1 dimerization and glycolysis in hypoxic cells. Our approach not only eliminates the need for the chemical synthesis and targeted delivery of our HIF-1 inhibitor to cells, it also demonstrates the wider possibility that the production machinery of other bioactive compounds may be incorporated onto the chromosome of human cells. This work demonstrates the potential of sentinel circuits that produce molecular modulators of cellular pathways in response to environmental or cellular disease stimuli. PMID- 27978622 TI - Lauric Acid Stimulates Mammary Gland Development of Pubertal Mice through Activation of GPR84 and PI3K/Akt Signaling Pathway. AB - It has been demonstrated that dietary fat affects pubertal mammary gland development. However, the role of lauric acid (LA) in this process remains unclear. Thus, this study aimed to investigate the effects of LA on mammary gland development in pubertal mice and to explore the underlying mechanism. In vitro, 100 MUM LA significantly promoted proliferation of mouse mammary epithelial cell line HC11 by regulating expression of proliferative markers (cyclin D1/3, p21, PCNA). Meanwhile, LA activated the G protein-coupled receptor 84 (GPR84) and PI3K/Akt signaling pathway. In agreement, dietary 1% LA enhanced mammary duct development, increased the expression of GPR84 and cyclin D1, and activated PI3K/Akt in mammary gland of pubertal mice. Furthermore, knockdown of GPR84 or inhibition of PI3K/Akt totally abolished the promotion of HC11 proliferation induced by LA. These results showed that LA stimulated mammary gland development of pubertal mice through activation of GPR84 and PI3K/Akt signaling pathway. PMID- 27978623 TI - Microfluidic Assembly of Monodisperse Vesosomes as Artificial Cell Models. AB - Vesosomes are nested liposomal structures with high potential as advanced drug delivery vehicles, bioreactors and artificial cells. However, to date no method has been reported to prepare monodisperse vesosomes of controlled size. Here we report on a multistep microfluidic strategy for hierarchically assembling uniform vesosomes from dewetting of double emulsion templates. The control afforded by our method is illustrated by the formation of concentric, pericentric and multicompartment liposomes. The microfluidic route to vesosomes offers an exceptional platform to build artificial cells as exemplified by the in vitro transcription in "nucleus" liposomes and the mimicry of the architecture of eukaryotic cells. Finally, we show the transport of small molecules across the nucleic envelope via insertion of nanopores into the bilayers. PMID- 27978627 TI - Cobalt(III)-Catalyzed Regio- and Stereoselective alpha-Fluoroalkenylation of Arenes with gem-Difluorostyrenes. AB - A cobalt(III)-catalyzed alpha-fluoroalkenylation of different arenes with readily available gem-difluorostyrenes has been realized under mild and redox-neutral conditions. This reaction occurs via a C-H activation pathway and offers a step economical access to various 1,2-diaryl-substituted monofluoroalkenes in excellent Z selectivity in moderate to excellent yields. PMID- 27978628 TI - Radical Route to 1,4-Benzothiazine Derivatives from 2-Aminobenzenethiols and Ketones under Transition-Metal-Free Conditions. AB - Transition-metal-free radical access to 1,4-benzothiazine derivatives from o aminobenzenethiols is disclosed. This procedure is available for various ketones including alpha,beta-unsaturated, cyclic, linear, and fluoroalkyl ketones to generate a number of 1,4-benzothiazines, which exist in numerous bioactive and natural molecules, rendering this protocol attractive to both synthetic and medicinal chemistry. PMID- 27978624 TI - Neutral Loss Is a Very Common Occurrence in Phosphotyrosine-Containing Peptides Labeled with Isobaric Tags. AB - While developing a multiplexed phosphotyrosine peptide quantification assay, an unexpected observation was made: significant neutral loss from phosphotyrosine (pY) containing peptides. Using a 2000-member peptide library, we sought to systematically investigate this observation by comparing unlabeled peptides with the two highest-plex isobaric tags (iTRAQ8 and TMT10) across CID, HCD, and ETD fragmentation using high resolution high mass accuracy Orbitrap instrumentation. We found pY peptide neutral loss behavior was consistent with reduced proton mobility, and does not occur during ETD. The site of protonation at the peptide N terminus changes from a primary to a tertiary amine as a result of TMT labeling which would increase the gas phase basicity and reduce proton mobility at this site. This change in fragmentation behavior has implications during instrument method development and interpretation of MS/MS spectra, and therefore ensuing follow-up studies. We show how sites not localized to tyrosine by search and site localization algorithms can be confidently reassigned to tyrosine using neutral loss and phosphotyrosine immonium ions. We believe these findings will be of general interest to those studying pY signal transduction using isobaric tags. PMID- 27978629 TI - [2 + 2] Photocycloadditions between the Carbon-Nitrogen Double Bonds of Imines and Carbon-Carbon Double Bonds. AB - In contrast to the well-known [2 + 2] photocycloadditions between C?O and C?C bonds, the participation of C?N bonds in such reactions is relatively rare. In this paper, the unprecedented UV-light-induced [2 + 2] cycloadditions between N arylsulfonylimines and styrene derivatives or benzofurans are described. This photolytic reaction allows the highly stereoselective construction of azetidine derivatives under ambient conditions. PMID- 27978631 TI - Cu-Catalyzed Aerobic Oxidation of Di-tert-butyl Hydrazodicarboxylate to Di-tert butyl Azodicarboxylate and Its Application on Dehydrogenation of 1,2,3,4 Tetrahydroquinolines under Mild Conditions. AB - A new class of co-catalytic system was developed with homogeneous CuI and di-tert butyl azodicarboxylate for aerobic dehydrogenation of 1,2,3,4 tetrahydroquinolines under mild conditions. The developed co-catalytic system is consisting of di-tert-butyl azodicarboxylate-mediated dehydrogenation of 1,2,3,4 tetrahydroquinoline and aerobic oxidative regeneration of di-tert-butyl azodicarboxylate from di-tert-butyl hydrazodicarboxylate using molecular oxygen as a terminal oxidant. A variety of quinolines were efficiently synthesized by the developed Cu and di-tert-butyl azodicarboxylate co-catalytic system. PMID- 27978630 TI - Synthesis of Functionalized 6-Hydroxy-2-oxindole Derivatives by Phenoxide Cyclization. AB - An apparent intramolecular cross-dehydrogenative coupling of N-(3 hydroxy)monoanilide of maleic esters comprising base promoted phenoxide cyclization and subsequent base-mediated aerobic oxidation was developed to synthesize a variety of 2-(6-hydroxy-2-oxoindolin-3-ylidene)acetate derivatives. The isolation of intermediate cyclized products during the large scale reactions and their ready dehydrogenation with 1 equiv of base support this proposed two step path. PMID- 27978632 TI - Direct Esterification of Carboxylic Acids with Perfluorinated Alcohols Mediated by XtalFluor-E. AB - The direct esterification of carboxylic acids with perfluorinated alcohols mediated by XtalFluor-E is reported. The corresponding polyfluorinated esters are obtained in moderate to excellent yields with a broad range of carboxylic acids, including aromatic, heteroaromatic, aliphatic, and nonracemic chiral substrates, using only a slight excess (2 equiv) of the perfluorinated alcohol. Control experiments indicate that the reaction does not proceed through the formation of an acyl fluoride but most likely through a (diethylamino)difluoro-lambda4 sulfanyl carboxylate intermediate. PMID- 27978633 TI - Rhodium-Catalyzed beta-Selective Oxidative Heck-Type Coupling of Vinyl Acetate via C-H Activation. AB - An efficient Rh(III)-catalyzed direct ortho-C-H olefination of acetanilides with vinyl acetate was developed. This protocol provides a straightforward pathway to a series of (E)-2-acetamidostyryl acetates, giving access to indole derivatives following a simple hydrolysis/cyclization process. PMID- 27978635 TI - Chemoselective Reduction of alpha-Cyano Carbonyl Compounds: Application to the Preparation of Heterocycles. AB - beta-Aminoacrylates are reactive intermediates that are useful building blocks in synthesis. General methods for their preparation typically afford alpha and beta disubstitution patterns or beta only. Molecules with only alpha-substituents (beta-hydrogen) are much less well-known. A chemoselective reductive tautomerization of alpha-cyanoacetates, using DIBAL-H, has been developed to access these valuable synthons. alpha,beta-Unsaturated cyanoacetates and alpha cyanoketones can, also, be selectively reduced via this methodology. A series of heterocycles were prepared using these beta-enamino carbonyl compounds. PMID- 27978634 TI - Carbon Cationic Relay via Superelectrophiles: Synthesis of Spiro-diazafluorenes. AB - Superelectrophilic-initiated carbon cationic relay reactions of diazafluorenones with phenols were developed to provide strategically novel and atom-economic access to spirodiazafluorenes via tandem Friedel-Crafts reaction, nucleophilic addition, and intramolecular cyclization sequences. A range of spirodiazafluorenes that are difficult to synthesize with traditional protocols has been constructed successfully in middle to high yields using this method. PMID- 27978636 TI - Formation of Seven-Membered Carbocycles via 7-endo Mode Cyclization of Lithioheptatrienes. AB - The highly selective synthesis of triene derivatives was achieved by a zirconocene-mediated three-component coupling reaction, and the trienes were efficiently subjected to 7-endo mode cyclization. The reaction of unsymmetrical zirconacyclopentadienes prepared from two different alkynes with N bromosuccinimide (NBS) followed by treatment with allyl halides in the presence of CuCl afforded the corresponding heptatrienes in good yields. When the trienes reacted with an organolithium reagent, 7-endo mode cyclization occurred smoothly to give the corresponding cycloheptadiene. PMID- 27978637 TI - Rh(II)/Mg(OtBu)2-Catalyzed Tandem One-Pot Synthesis of 1,4-Oxazepines and 1,4 Oxazines from N-Sulfonyl-1,2,3-triazoles and Glycidols. AB - A novel, one-pot route for the synthesis of nonaromatic ring-fused 1,4-oxazepines and 1,4-oxazines has been developed. The reaction features a sequential rhodium(II)-catalyzed reaction of N-sulfonyl-1,2,3-triazoles with glycidols, followed by a regioselective Lewis acid Mg(OtBu)2-catalyzed intramolecular ring opening reaction. It has been found that the regioselectivity in the epoxide ring opening was largely determined by the substituents on the glycidols. Thus, substituted glycidols (R2 ? H) afforded seven-membered oxazepine derivatives selectively, while unsubstituted glycidols (R2 = H) afforded six-membered oxazine derivatives. Plausible reaction pathways are elucidated and supported by experiments with several glycidols bearing different substituents around the epoxide functionality. PMID- 27978638 TI - An Iminium Ion Cascade Annulation Strategy for the Synthesis of Akuammiline Alkaloid Pentacyclic Core Structures. AB - The akuammiline alkaloids are a family of indole monoterpene natural products known for their polycyclic cage-like structures. An iminium ion cascade annulation approach was developed, simultaneously synthesizing both the C and D rings of these natural products by annulation onto a protected indole ring. This reaction allowed the synthesis of a key tetracyclic intermediate toward these natural products. This tetracycle was used for the synthesis of the pentacyclic methanoquinolizidine core present in such alkaloids as akuammiline and strictamine as well as the pentacyclic furoindoline core found in pseudoakuammigine. PMID- 27978639 TI - Palladium-Catalyzed Synthesis of Aryl Vinyl Sulfides via 1,3-Oxathiolanes As Vinyl Sulfide Surrogates. AB - A nontraditional approach to synthesizing aryl vinyl sulfides is described. 2,2 Diphenyl-1,3-oxathiolane slowly liberates a vinyl sulfide anion under basic conditions. Using a Pd/Xantphos catalyst system to activate a wide range of aryl bromides, this transient sulfide species can be effectively trapped and fed into a traditional Pd0/PdII catalytic cycle. Scope and limitations of the methodology are presented along with significant discussion of a competitive C-S bond activation by this catalyst system. PMID- 27978640 TI - Regioselective Copper-Catalyzed Boracarboxylation of Vinyl Arenes. AB - Regioselective copper-catalyzed boracarboxylation of vinyl arenes with bis(pinacolato)diboron and carbon dioxide has been achieved. New boron functionalized alpha-aryl carboxylic acids, including nonsteroidal anti inflammatory drugs (NSAIDs), are obtained in moderate to excellent yields. The synthetic utility of the transformation was shown through subsequent derivatization of the carbon-boron bond yielding formal hydroxy- and fluorocarboxylation products as well as anionic difluoroboralactones. PMID- 27978641 TI - Controllable O-Nucleometalation Cyclization Strategy: Access to Divergent Ring Functionalized Molecules. AB - The vinyl moiety-assisted selective O-nucleopalladation is reported, which offers rapid constructions of cycloolefins and cyclopropanes via oxidant-induced cyclization of enynes. O2 resulted in the unexpected 6-endo-Heck cyclization, while CuCl2 led to a 5-exo-trig pathway and synergetic SN2-type C-C bond formation. Amide works as an O-transferred nucleophilic group to activate the alkyne moiety, which induced divergent annulation processes. Moreover, the regenerated amides could be used for further modifications. PMID- 27978642 TI - Synthesis of the Bioherbicidal Fungus Metabolite Macrocidin A. AB - The second total synthesis of macrocidin A afforded the bioherbicidal fungal metabolite in 16 steps starting from doubly protected l-tyrosine. The 3-octanoyl side chain with the alpha-methyl group and an omega-bromo epoxide already in place was attached to the tetramic acid via a Yoshii-Yoda acylation, and the macrocycle was eventually closed in 55% yield by a Williamson etherification between the phenolate and the epoxy bromide. PMID- 27978643 TI - 1,3-Dithianes as Acyl Anion Equivalents in Pd-Catalyzed Asymmetric Allylic Substitution. AB - A Pd-catalyzed asymmetric allylic substitution with 1,3-dithianes as acyl anion equivalents has been developed in high yields and excellent enantioselectivities. The reaction was performed on a gram scale, and the corresponding alkylated products were conveniently converted into several biologically active products. This work provides an alternative strategy utilizing electrophilic carbonyl compounds as nucleophilic species in a Pd-catalyzed allylic substitution. PMID- 27978644 TI - Directed Synthesis of All Four Pure Stereoisomers of the N,C-Coupled Naphthylisoquinoline Alkaloid Ancistrocladinium A. AB - The first preparation of the N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A and its likewise naturally occurring minor atropisomer, in an atropisomerically pure form, is described. The synthesis succeeded by resolution of the already rotationally hindered, and thus atropo-diastereomeric acetamide precursors, which were then, without major loss of stereochemical information, cyclized to the respective target molecules. The strategy was applied to the first synthesis of the regioisomeric product ancistrocladinium D, likewise in a stereochemically pure form. PMID- 27978646 TI - Ru-Catalyzed One-Pot Diannulation of Heteroaryls: Direct Access to pi-Conjugated Polycyclic Amides. AB - A novel Ru-catalyzed oxidative double annulation of heteroarenes with symmetrical and unsymmetrical alkynes is reported. A general method for the unsymmetrical annulation of heteroarenes with two distinct alkynes is showcased for the first time. Methylphenyl sulfoximine (MPS) plays an important role in the annulations of heteroarenes and allows the construction of structurally complex pi-conjugated heteroarene-fused polycyclic amide skeletons via the formation of multiple C-C and C-N bonds in a single operation. The reaction exhibits excellent substrate scope and tolerates a wide range of functional groups. PMID- 27978645 TI - Spirodalesol, an NLRP3 Inflammasome Activation Inhibitor. AB - Autoimmune and inflammatory diseases are associated with inappropriate activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, but suitable inhibitors against such improper activations remain scarce. Here, spirodalesol (1) from Daldinia eschscholzii was structurally characterized and is biosynthetically proposed as an NLRP3 inflammasome activation inhibitor with an unprecedented carbon skeleton. PMID- 27978647 TI - Controllable Rh(III)-Catalyzed Annulation between Salicylaldehydes and Diazo Compounds: Divergent Synthesis of Chromones and Benzofurans. AB - A Rh(III)-catalyzed annulation between salicylaldehydes and diazo compounds with controllable chemoselectivity is described. AgNTf2 favored benzofurans via a tandem C-H activation/decarbonylation/annulation process, while AcOH led to chromones through a C-H activation/annulation pathway. The reaction exhibited good functional group tolerance and scalability. Moreover, only a single regioisomer of benzofuran was obtained due to the in situ decarbonylation orientation effect. PMID- 27978649 TI - Organocatalytic Enantioselective Continuous-Flow Cyclopropanation. AB - A set of six solid-supported diarylprolinol catalysts (varying on the anchoring strategy and the type of polymeric support) has been prepared and applied to the enantioselective cyclopropanation reaction. The selected candidate allows implementation of a long flow experiment (48 h) and generates a library of 12 cyclopropanes by sequential flow experiments. The mildness and utility of the method have enabled a telescoped process in which the outstream is directly used in a Wittig flow reaction. PMID- 27978650 TI - TiCl4/Et3N-Mediated Condensation of Acetate and Formate Esters: Direct Access to beta-Alkoxy- and beta-Aryloxyacrylates. AB - A methodology to build (E)-beta-alkoxy- and (E)-beta-aryloxyacrylate moieties from acetate and formate esters promoted by the TiCl4/Et3N system is presented. The reaction is compatible with a broad range of structural skeletons and elapses through an unusual condensation pathway. Taking into account the obtained results, we propose a plausible mechanism involving a bimetallic titanium intermediate for this type of transformation. PMID- 27978648 TI - Reactions of Hexadehydro-Diels-Alder (HDDA)-Derived Benzynes with Thioamides: Synthesis of Dihydrobenzothiazino-Heterocyclics. AB - Reaction of thioamides (e.g., II) with benzynes generated by the hexadehydro Diels-Alder (HDDA) cycloisomerization (e.g., I) produces dihydrobenzothiazines (e.g., III). It is postulated that the reaction proceeds via benzothietene (cf. IV) and o-thiolatoaryliminium (cf. V) intermediates and that the latter undergoes intramolecular 1,3-hydrogen atom migration to produce the penultimate isomeric iminium zwitterions VI. PMID- 27978651 TI - Copper-Catalyzed C-H Oxidative Radical Functionalization and Annulation of Aniline-Linked 1,7-Enynes: Evidence for a 1,5-Hydride Shift Mechanism. AB - A new copper-catalyzed tandem C-H oxidative radical functionalization and annulation of aniline-linked 1,7-enynes with alkyl nitriles or acetone is described. This reaction allows the selective construction of 1H cyclopenta[c]quinolines and benzo[j]phenanthridin-6(5H)-ones which rely on the substitution effect at the 2-position of the acrylamide moiety. The mechanism involving a 1,5-hydride shift process is proposed according to the control deuterium-labeled experiment. PMID- 27978652 TI - Theoretical Study of Nickel-Catalyzed Proximal C-C Cleavage in Benzocyclobutenones with Insertion of 1,3-Diene: Origin of Selectivity and Role of Ligand. AB - Martin and co-workers recently developed a strategy for Ni(0)-complex-catalyzed [4 + 4] annulation of primary benzocyclobutenones (BCBs) and 1,3-dienes. A density functional theory study was performed to clarify the catalytic mechanism. The results provide insights into the origins of the chemo-, regio-, and diastereoselectivity. The calculation results explain why only P(C6H5CF3)3, among several candidates, performed well and why the [4 + 4] annulation of BCB with a 1,3-diene was achieved with a Ni(0) but not with a Rh(I) catalyst. PMID- 27978653 TI - Computational Chemistry Driven Solution to Rubriflordilactone B. AB - The structure of rubriflordilactone B (2) was determined by X-ray crystallography. However, the NMR data of the synthetic sample did not match those reported for 2. It was then suggested that the original sample contained an additional isomer of different solubility, pseudorubriflordilactone B (3), whose structure remained unknown. From theoretical calculations, reexamination of the NMR data, and biogenetic considerations, it is proposed that 3 should be the 16S,17R isomer of 2. PMID- 27978654 TI - Co(I)-Mediated Removal of Addends on the C60 Cage and Formation of the Monovalent Cobalt Complex CpCo(CO)(eta2-C60). AB - The removal of addends on the fullerene C60 cage plays an important role in the final stage for synthesizing endohedral fullerenes by the molecular surgery method. We developed a cobalt-mediated reaction to regenerate C60 from N substituted C60 derivatives (aziridinofullerene and azafulleroid). In these reactions, we found the formation of a green monovalent-cobalt complex of C60, and its structure was unambiguously determined by X-ray analysis. The characteristic electronic structure of this cobalt complex was studied by IR and UV-vis absorption spectroscopy and electrochemical analyses. PMID- 27978656 TI - Regio- and Stereoselective Alkylation of Pyridine-N-oxides: Synthesis of Substituted Piperidines and Pyridines. AB - Regio- and stereoselective addition of alkyl Grignard reagents to pyridine-N oxides gave C2-alkylated N-hydroxy-1,2,5,6-tetrahydropyridines and trans-2,3 disubstituted N-hydroxy-1,2,5,6-tetrahydropyridines in good to excellent yields. These intermediates were aromatized or alternatively reduced in one-pot methodologies for efficient syntheses of alkylpyridines or piperidines, respectively. These reactions have a broad substrate scope and short reaction times. PMID- 27978655 TI - Divergent Synthesis and Real-Time Biological Annotation of Optically Active Tetrahydrocyclopenta[c]pyranone Derivatives. AB - Sp3-rich compounds are underrepresented in libraries for probe- and drug discovery, despite their promise of extending the range of accessible molecular shapes beyond planar geometries. With this in mind, a collection of single enantiomer bicyclic, fused cyclopentenones underpinned by a complexity-generating Pauson-Khand cyclization was synthesized. A fingerprint of biological actions of these compounds was determined immediately after synthesis using real-time annotation-a process relying on multiplexed measurements of alterations in cell morphological features. PMID- 27978657 TI - Engineering Fungal Nonribosomal Peptide Synthetase-like Enzymes by Heterologous Expression and Domain Swapping. AB - A facile genetic methodology in the filamentous fungus Aspergillus nidulans allowed the exchange of various domains in nonribosomal peptide synthase (NRPS) like enzymes from Aspergillus terreus. The newly generated engineered enzymes are capable of producing compounds with different chemical structures than its parent enzyme in vivo. This work provides insight in the programing of nonribosomal peptide biosynthesis in filamentous fungi. PMID- 27978659 TI - CO2 as a C1 Source: B(C6F5)3-Catalyzed Cyclization of o-Phenylene-diamines To Construct Benzimidazoles in the Presence of Hydrosilane. AB - The catalytic construction of benzimidazoles using CO2 as a carbon source represents a facile and sustainable approach to obtaining these valuable compounds. Herein, we describe the B(C6F5)3-catalyzed synthesis of benzimidazoles via cyclization of o-phenylenediamines with CO2 and PhSiH3. This metal-free catalytic route achieves the desired products in high yield under convenient reaction conditions and is applicable to a broad substrate scope. A plausible mechanism for the reaction involving a frustrated Lewis pair pathway is proposed based on spectroscopic characterization (e.g., 13C NMR) of the reaction intermediates. PMID- 27978660 TI - Palladium-Catalyzed alpha-Arylation of Vinylogous Esters for the Synthesis of gamma,gamma-Disubstituted Cyclohexenones. AB - A palladium-catalyzed alpha-arylation of cyclic vinylogous esters to form products that are converted in one step to gamma-alkyl-gamma-aryl-substituted cyclohexenones is reported. This Pd-catalyzed reaction proceeds at room temperature, is generally high-yielding, and uses an amount of a commercially available catalyst as low as 0.25 mol %. The scope of aryl bromides is particularly broad, and alkenyl bromides can also be used. This two-step protocol, comprising alpha-arylation and reductive transposition, can be performed in one pot and is applicable to gram-scale synthesis. PMID- 27978658 TI - Stereoselective Synthesis, Docking, and Biological Evaluation of Difluoroindanediol-Based MenE Inhibitors as Antibiotics. AB - A stereoselective synthesis has been developed to provide all four side-chain stereoisomers of difluoroindanediol 2, the mixture of which was previously identified as an inhibitor of the o-succinylbenzoate-CoA synthetase MenE in bacterial menaquinone biosynthesis, having promising in vitro activity against methicillin-resistant Staphylococcus aureus and Mycobacterium tuberculosis. Only the (1R,3S)-diastereomer inhibited the biochemical activity of MenE, consistent with computational docking studies, and this diastereomer also exhibited in vitro antibacterial activity comparable to that of the mixture. However, mechanism-of action studies suggest that this inhibitor and its diastereomers may act via other mechanisms beyond inhibition of menaquinone biosynthesis. PMID- 27978661 TI - Directed Zincation with TMPZnCl.LiCl and Further Functionalization of the Tropolone Scaffold. AB - The directed zincation of tropolone derivatives was achieved using TMPZnCl.LiCl. Various functionalizations of the zincated intermediates by halogenation, acylation, allylation, and Negishi cross-coupling were successfully performed. Additionally, 1,8-conjugate addition-elimination reactions with a variety of arylmagnesium and secondary alkylzinc reagents were carried out to further elaborate the tropolone core. PMID- 27978662 TI - Nickel(II)-Catalyzed Cascade Vinylogous Mukaiyama 1,6-Michael/Michael Addition of 2-Silyloxyfuran with N-Sulfonyl-1-aza-1,3-dienes: Access to Fused Piperidine/Butyrolactone Skeletons. AB - An unprecedented and highly efficient nickel-catalyzed cascade vinylogous Mukaiyama 1,6-Michael/Michael addition of 2-silyloxyfuran with N-sulfonyl-1-aza 1,3-dienes is reported, in which 2-silyloxyfuran was successfully employed as nucleophile and electrophile sequentially. This methodology combined with subsequent reduction provides a facile access to biologically important fused piperidine/butyrolactone skeletons in good yield with exclusive diastereoselectivity under mild reaction conditions. PMID- 27978663 TI - Exploring the Reactivity of Nitro-Activated 1,3-Enynes in an Organocatalytic One Pot, Three-Component Coupling Reaction: A Tandem Catalytic Approach to a Novel 3 Nitrochroman Scaffold. AB - A tandem catalytic strategy enabling one-pot, three-component couplings of electron-rich phenols, 2-nitro 1,3-enynes, and vinyl ketones was achieved. This chemistry combined mechanistically distinct [3 + 3]-annulation and nitro-Michael addition using a single squaramide catalyst, leading to the construction of novel chiral quaternary 3-nitrochromane architecture with high chemo-, regio-, and stereoselectivity. PMID- 27978665 TI - Iron-Catalyzed 1,5-Enyne Cycloisomerization via 5-Endo-Dig Cyclization for the Synthesis of 3-(Inden-1-yl)indole Derivatives. AB - An Fe(OTf)3-catalyzed 1,5-enyne cycloisomerization via 5-endo-dig cyclization is described for the synthesis of 3-(1-indenyl)indole derivatives. Since a variety of 1,5-enynes are readily accessible via Heck-Suzuki coupling, this strategy provides a rapid and easy access to a wide range of highly substituted 3-(1 indenyl)indoles in good yields. PMID- 27978666 TI - Aryloxymethyltrifluoroborates for Rhodium-Catalyzed Asymmetric Conjugate Arylation. o-Methoxyarylation through 1,4-Rhodium Shift. AB - Reaction of potassium aryloxymethyltrifluoroborates 1 with alpha,beta-unsaturated carbonyl compounds 2 in the presence of a chiral diene-rhodium catalyst in H2O at 100 degrees C introduced 2-methoxyaryl groups at the beta-position of 2 with high enantioselectivity in high yields. The reaction is assumed to proceed through 1,4-Rh shift from aryloxymethyl-Rh intermediate to 2-methoxyaryl-Rh. The high availability of phenol derivatives makes this asymmetric conjugate arylation synthetically useful. PMID- 27978664 TI - Molecular Coplanarity and Self-Assembly Promoted by Intramolecular Hydrogen Bonds. AB - Active conformational control is realized in a conjugated system using intramolecular hydrogen bonds to achieve tailored molecular, supramolecular, and solid-state properties. The hydrogen bonding functionalities are fused to the backbone and precisely preorganized to enforce a fully coplanar conformation of the pi-system, leading to short pi-pi stacking distances, controllable molecular self-assembly, and solid-state growth of one-dimensional nano-/microfibers. This investigation demonstrates the efficiency and significance of an intramolecular noncovalent approach in promoting conformational control and self-assembly of organic molecules. PMID- 27978667 TI - Regioselective Reversal in the Cyclization of 2-Diazo-3,5-dioxo-6-ynoates (Ynones, Ynamide): Construction of gamma-Pyrones and 3(2H)-Furanones Starting from Identical Materials. AB - The AgSbF6-catalyzed cyclization of 2-diazo-3,5-dioxo-6-ynoates (ynones, ynamide) in alcoholic solvents affords gamma-pyrones, whereas the AgOAc-catalyzed cyclization in 1,2-dichloroethane (DCE) produces 3(2H)-furanones. The cyclization reactions proceeded cleanly under mild reaction conditions, and the desired gamma pyrones or 3(2H)-furanones were obtained in excellent yield. It was observed for the first time that both the catalyst and solvent play key roles in the selective formation. This unique method for the reversal of regioselectivity proved to be highly efficient except for substrates with aliphatic and Me3Si groups at the triple bond position. PMID- 27978668 TI - Aryl Ketone Catalyzed Radical Allylation of C(sp3)-H Bonds under Photoirradiation. AB - The catalytic introduction of an allyl group at nonacidic C(sp3)-H bonds was achieved under photoirradiation, in which 1,2-bis(phenylsulfonyl)-2-propene acts as an allyl source and 5,7,12,14-pentacenetetrone (PT) works as a C-H bond cleaving catalyst. A variety of substances, including alkanes, carbamates, ethers, sulfides, and alcohols, were chemoselectively allylated in a single step under neutral conditions. The present transformation is catalyzed solely by an organic molecule, PT, and proceeds smoothly even under visible light irradiation (425 nm) in the case of alkanes as a starting substance. PMID- 27978669 TI - Thiophenol-Catalyzed Visible-Light Photoredox Decarboxylative Couplings of N (Acetoxy)phthalimides. AB - We have developed visible-light photoredox decarboxylative couplings of N (acetoxy)phthalimides without an added photocatalyst in which simple and commercially available thiophenols are used as the effective organocatalysts, and 4-(trifluoromethyl)thiophenol shows optimal catalytic activity. Three representative decarboxylative examples were chosen including one amination and two C-C bond couplings to confirm efficacy of the visible-light photoredox reactions, and the results exhibited that they performed very well at room temperature. The interesting discovery should provide a novel and environmentally friendly strategy for visible-light photoredox transformation of organic molecules. PMID- 27978670 TI - Construction of Polycyclic gamma-Lactams and Related Heterocycles via Electron Catalysis. AB - Cascade radical cyclization of 1,6-enynes for the construction of biologically important polycyclic gamma-lactams and related heterocycles is reported. In these radical cascade processes, three new C-C bonds are formed and transition metals are not required to run these sequences. The mild reaction conditions, broad substrate scope, and the importance of the heterocyclic products render the approach valuable. PMID- 27978671 TI - Hypophyllins A-D, Labdane-Type Diterpenoids with Vasorelaxant Activity from Hypoestes phyllostachya "Rosea". AB - Three rearranged labdane-type diterpenoids, hypophyllins A-C (1-3), and a caged labdane diterpenoid possessing a 8,9-dioxatricyclic[4.2.1.13,7]decane moiety, hypophyllin D (4), as well as two new biogenetically related diterpernoids, hypophyllins E (5) and F (6), were isolated from the aerial parts of Hypoestes phyllostachya "Rosea". The absolute configurations of 1-4 were determined by X ray diffraction analysis. The plausible biogenetic pathway for 1-4 was also proposed. Compounds 4 and 5 showed potent vasorelaxant activity on endothelium intact thoracic aorta rings precontracted with KCl. PMID- 27978672 TI - Perfluoroalkyl Analogues of Diethylaminosulfur Trifluoride: Reagents for Perfluoroalkylthiolation of Active Methylene Compounds under Mild Conditions. AB - Trifluoromethyl diethylaminosulfur difluoride (CF3-DAST) was found to be an efficient reagent for the trifluoromethylthiolation of alpha-methylene-beta-keto esters providing alpha-trifluoromethylthio-beta-keto esters in good to high yields. alpha-Methylene-beta-keto sulfones were also accepted as substrates by CF3-DAST to furnish the corresponding alpha-trifluoromethylthio compounds. This strategy can be extended to perfluoroalkylthiolation reactions using perfluoroethyl-DAST (C2F5-DAST) and perfluoropropyl-DAST (C3F7-DAST). PMID- 27978673 TI - Amination/Cyclization Cascade by Acid-Catalyzed Activation of Indolenine for the One-Pot Synthesis of Phaitanthrin E. AB - We have developed a concise one-pot synthesis of phaitanthrin E derivatives, where simple starting materials undergo an acid-catalyzed intermolecular amination/intramolecular cyclization cascade. PMID- 27978674 TI - Transition-Metal-Free Synthesis of Tertiary Aminocyclopropanes. AB - A transition-metal-free methodology for the construction of pharmaceutically relevant tertiary aminocyclopropanes is reported. Hydrazonamides, safe and stable carbene precursors, undergo smooth cyclopropanation with vinyl arenes in the presence of a base. The reaction proceeds with stereoselectivity to favor the Z isomer and provides facile access to a variety of substitution patterns through variation of the coupling partners. PMID- 27978675 TI - An in Situ Generated Palladium on Aluminum Oxide: Applications in Gram-Scale Matsuda-Heck Reactions. AB - In situ generated palladium on aluminum oxide provides an active catalytic system for Matsuda-Heck reactions in gram-scale. The novel catalyst proceeded through a significantly higher catalytic activity compared to the classical Pd/C system. Based on the high catalytic activity the first alpha,beta,beta-triarylation of methyl acrylate in good yields could be provided in one-step. PMID- 27978676 TI - Triaryl-Substituted Divinyl Ketones Cyclization: Nazarov Reaction versus Friedel Crafts Electrophilic Substitution. AB - The acid-catalyzed cyclization of a wide range of triaryl-substituted divinyl ketones has been studied. It was found that the reaction pathway strongly depends on the nature of the aryl substituent at the alpha-position to the carbonyl group. An electron-rich aromatic substituent promotes the reaction to proceed through the intramolecular Friedel-Crafts electrophilic substitution giving dihydronaphthalene derivatives. In contrast, the presence of an electron deficient substituent is favorable for the Nazarov 4pi-conrotatory cyclization yielding triaryl-substituted cyclopentenones. The electrophilic substitution reaction was applied to thiophene and thiazole derivatives. PMID- 27978677 TI - Preparation and Reactions of Indoleninyl Halides: Scaffolds for the Synthesis of Spirocyclic Indole Derivatives. AB - The dearomatization of 2-haloindole precursors allows access to indoleninyl halides, a hitherto underexploited functional handle with broad synthetic utility. Indoleninyl iodides have been shown to react via three distinct modes: hydrolysis, nucleophilic substitution, and cross-coupling. This allows a broad array of functionalized spirocyclic indole derivatives to be generated from a common starting material. They are also useful precursors to functionalized quinolines following migratory rearrangement and subsequent derivatization reactions. PMID- 27978678 TI - A Linchpin Synthesis of 6-Hydroxyceramides from Aziridine Aldehydes. AB - A chemoselective N-oxidation/Meisenheimer rearrangement protocol was developed to generate vinylaziridine scaffolds from aziridine aldehydes. A subsequent Lewis acid-mediated aziridine ring opening with carboxylic acid nucleophiles followed by N-O bond cleavage furnishes a human skin 6-hydroxyceramide natural product in short order. The utility of this methodology is demonstrated by the preparation of a number of unnatural 6-hydroxyceramide analogues. This modular approach enables the expedient synthesis of poorly understood skin lipids, which may find application in therapeutics and cosmetics. PMID- 27978679 TI - Rotation of Aryl Groups in 9,10-Diarylphenanthrenes: Does the Rotational Barrier Become Lower as the Backbone Becomes More Crowded? AB - A series of 9,10-diarylphenanthrenes was prepared, and their structures and dynamic behaviors were both theoretically and experimentally investigated. A more twisted and crowded phenanthrene backbone was associated with a lower barrier to the rotation of an aryl group. PMID- 27978680 TI - Templated Assembly of Chiral Medium-Sized Cyclic Ethers via 8-endo-trig Nucleophilic Cyclization of Cyclopropenes. AB - An efficient approach toward enantioenriched eight-membered heterocycles via the intramolecular formal substitution of bromocyclopropanes with oxygen-based nucleophiles has been developed. The reaction proceeds via a reactive cyclopropene intermediate, which undergoes a rapid 8-endo-trig cyclization affording cis-fused [6.1.0] bicyclic products exclusively. The quaternary chiral center in the cyclopropene governs the configuration of the other two stereocenters in the final product. PMID- 27978681 TI - Asymmetric Inverse-Electron-Demand Oxa-Diels-Alder Reaction of Allylic Ketones through Dienamine Catalysis. AB - A remote beta,gamma-regioselective asymmetric inverse-electron-demand oxa-Diels Alder reaction between allylic ketones and alpha-cyano-alpha,beta-unsaturated ketones has been developed through induced extended dienamine catalysis of a cinchona-derived primary amine. A spectrum of densely substituted dihydropyran frameworks were efficiently produced with excellent enantioselectivity and fair to exclusive diastereoselectivity. PMID- 27978682 TI - Synthesis of Penta-2,4-dien-1-imines and 1,2-Dihydropyridines by Rhodium Catalyzed Reaction of N-Sulfonyl-1,2,3-triazoles with 2-(Siloxy)furans. AB - A rhodium(II)-catalyzed reaction of N-sulfonyl-1,2,3-triazoles with 2 (siloxy)furans is reported. Either open-chain penta-2,4-dien-1-imines or cyclic 1,2-dihydropyridines are selectively obtained depending on the ligand on rhodium(II). PMID- 27978683 TI - Two-Step Synthesis of Fluorescent 3-Arylated 1,3a,6a-Triazapentalenes via a Three Component Triazolization Reaction. AB - Novel 3-arylated 1,3a,6a-triazapentalenes were synthesized using a metal-free three-component triazolization reaction followed by a triflate based cyclization step. This method starts from simple commercial starting materials and provides an easy functionalization strategy for the 3-position of the triazapentalenes. By introducing electron-withdrawing groups onto this position, stable and highly fluorescent dyes could be synthesized. PMID- 27978684 TI - Synthesis of Perfluoro-tert-butyl Tyrosine, for Application in 19F NMR, via a Diazonium-Coupling Reaction. AB - A practical synthesis of the novel highly fluorinated amino acid Fmoc-perfluoro tert-butyl tyrosine was developed. The sequence proceeds in two steps from commercially available Fmoc-4-NH2-phenylalanine via diazotization followed by diazonium coupling reaction with perfluoro-tert-butanol. In peptides, perfluoro tert-butyl tyrosine was detected in 30 s by NMR spectroscopy at 500 nM peptide concentration due to nine chemically equivalent fluorines that are a sharp singlet by 19F NMR. Perfluoro-tert-butyl ether has an estimated sigmap Hammett substituent constant of +0.30. PMID- 27978685 TI - N-Heterocyclic Carbene-Catalyzed Construction of 1,3,5-Trisubstituted Benzenes from Bromoenals and alpha-Cyano-beta-methylenones. AB - A direct and efficient approach to 1,3,5-trisubstituted benzenes has been developed via N-heterocyclic carbene-catalyzed [2 + 4] annulation of alpha bromoenals and alpha-cyano-beta-methylenones. The reaction worked well for both aryl- and alkylenones. PMID- 27978686 TI - Rhodium Carbenoid Initiated O-H Insertion/Aldol/Oxy-Cope Cascade for the Stereoselective Synthesis of Functionalized Oxacycles. AB - A novel diazo-cascade approach has been developed for the synthesis of nine membered oxacycles utilizing readily accessible beta-hydroxy vinyl ketones and vinyl diazo esters. The Rh(II)-catalyzed cascade reaction begins with carbene O-H insertion followed by an intramolecular aldol cyclization to provide a substituted tetrahydrofuran intermediate that undergoes an oxy-Cope rearrangement to provide functionalized nine-membered oxacycles with complete stereoselectivity. PMID- 27978687 TI - Correction to "Synthesis of Water-Soluble Deep-Cavity Cavitands". PMID- 27978688 TI - Gold-Catalyzed Vinyl Ether Hydroalkynylation: An Alternative Pathway for the Gold Catalyzed Intermolecular Reaction of Alkenes and Alkynes. AB - In this report, the gold-catalyzed intermolecular reaction of vinyl ethers and terminal alkynes is investigated. Utilizing a triazole gold catalyst lessens gold decomposition in the presence of the vinyl ether and affords an alkynylation product instead of the [2 + 2] product. This protocol has been expanded to include glycal substrates, which undergo a one-pot alkynylation-Ferrier reaction to produce functionalized sugars in moderate to excellent yields with high diastereoselectivity. PMID- 27978689 TI - Cobalt-Catalyzed C(sp2)-C(sp3) Cross-Coupling Reactions of Diarylmanganese Reagents with Secondary Alkyl Iodides. AB - A cobalt-catalyzed cross-coupling of diarylmanganese reagents with secondary alkyl iodides using the THF-soluble salt CoCl2.2LiCl, which leads to the cross coupling products in up to 92% yield, is reported. High diastereoselectivities can be reached in these cross-couplings (dr up to 99:1). Remarkably, rearrangement of secondary alkyl iodides to unbranched products was not observed in these C-C forming reactions. PMID- 27978690 TI - Design and Synthesis of Cyclopropane Congeners of Resolvin E2, an Endogenous Proresolving Lipid Mediator, as Its Stable Equivalents. AB - Lipid chemical mediator resolvins with highly potent anti-inflammatory activity can be leads to develop novel anti-inflammatory drugs; however, they are unstable in oxygen due to their characteristic polyunsaturated structures. To solve the problem, CP-RvE2 has been designed and synthesized in which the cis-olefin of RvE2 was replaced with a cyclopropane. CP-RvE2s were much more stable than RvE2 against autoxidation and equipotent or more potent than RvE2. CP-RvE2s were successfully identified as stable equivalents of RvE2. PMID- 27978691 TI - A Synthetic Strategy for Saxitoxin Skeleton by a Cascade Bromocyclization: Total Synthesis of (+)-Decarbamoyl-alpha-saxitoxinol. AB - A new synthetic strategy for the formation of the ABC tricyclic framework of saxitoxin was developed. The BC ring moiety, including a spiro-aminal structure, was first constructed stereoselectively by a newly designed cascade bromocyclization of a readily available internal alkyne bearing guanidine and urea. The A ring was then synthesized by a guanylation of a cyclic urea, easily prepared via the oxidative cleavage of the diol of the cascade product, followed by addition of cyanide. This strategy enables the concise stereocontrolled total synthesis of (+)-decarbamoyl-alpha-saxitoxinol, which is a naturally occurring saxitoxin analogue. PMID- 27978692 TI - Catalytic Dearomatization Approach to Quinolizidine Alkaloids: Five Step Total Synthesis of (+/-)-Lasubine II. AB - A series of high-yielding silver(I)-catalyzed cyclization reactions of pyridine-, isoquinoline-, and pyrazine-ynones are described. The operationally simple and mild reaction conditions are a significant improvement over previously reported thermal cyclizations. The quinolizinone products were also used in a novel dearomatization strategy to prepare 0.53 g of the alkaloid lasubine II in five steps and 36% overall yield. PMID- 27978693 TI - C2-Symmetric Chiral Bisoxazolines as Hydrogen-Bond-Acceptor Catalysts in Enantioselective Aldol Reaction of beta-Carbonyl Acids with Trifluoroacetaldehyde Hemiacetals. AB - A simple C2-symmetric chiral bisoxazoline is demonstrated to use hydrogen bonding to catalyze an important family of aldol reactions of trifluoroacetaldehyde hemiacetals with various beta-carbonyl acids. This reaction is highly enantioselective, delivering chiral nonracemic trifluoromethylated alcohols with excellent optical purity and good isolated yields. This concept of relaying chiral information via a chiral hydrogen-bond acceptor should be applicable to a vast number of organocatalytic processes. PMID- 27978694 TI - Kinetic Resolution Driven Diastereo- and Enantioselective Synthesis of cis-beta Heteroaryl Amino Cycloalkanols by Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation. AB - The utility of tethered Ru-TsDPEN catalyst has been demonstrated for the asymmetric transfer hydrogenation of rac-alpha-heteroaryl amino cycloalkanones to construct biologically important cis-beta-heteroaryl amino cycloalkanols with two contiguous chiral centers via dynamic kinetic resolution. The stated (R,R)-Teth TsDPEN-Ru-catalyzed transformation is carried out under mild conditions using formic acid/triethylamine as a hydrogen source with excellent diastereo- and enantioselectivities. Further, this methodology has been applied for the synthesis of an antileishmanial agent and chiral ionic liquid. PMID- 27978695 TI - Pd-Catalyzed Spirocyclization via C-H Activation and Benzyne Insertion. AB - A palladium-catalyzed spirocyclization forming spirooxindoles and spirodihydrobenzofurans has been achieved. Mechanistic studies suggest that the transformation proceeds through sequential carbopalladation, C-H activation, and benzyne insertion. Both classes of spirocycles have been synthesized in good to excellent yields, and the procedure is readily scalable. PMID- 27978696 TI - Copper-Catalyzed Oxidative Cyclization of Carboxylic Acids. AB - A method for converting C-H to C-O bonds through oxidative cyclization of carboxylic acids to generate lactone products is described. The reaction employs catalytic amounts of Cu(OAc)2 and potassium persulfate as the terminal oxidant and is performed open to air in an aqueous acetic acid solvent system. Preliminary mechanistic studies suggest that substrate oxidation likely proceeds by sulfate radical anion and that the Cu catalyst has no influence on the product determining step. These conclusions differ from related investigations that propose the intermediacy of a carboxylate radical. PMID- 27978697 TI - Diastereospecific and Enantioselective Access to Dispirooxindoles from Furfurylcyclobutanols by Means of a Pd-Catalyzed Arylative Dearomatization/Ring Expansion Cascade. AB - We report a Pd-catalyzed arylative dearomatization/ring expansion cascade of furfurylcyclobutanols that involves a spiro pi-allyl palladium intermediate and affords structurally novel dispirooxindoles containing two quaternary carbon centers in good yields with high step economy, diastereospecificity, and enantioselectivity. PMID- 27978698 TI - Total Synthesis of (+)-Panacene. AB - The first total synthesis of the naturally occurring enantiomer of the marine bromoallene (+)-panacene is described. Central to this concise enantioselective synthesis was the use of a Noyori transfer hydrogenation for a Dynamic Kinetic Resolution (DKR) that set the desired absolute stereochemistry. A highly stereoselective Julia coupling was then used to install a Z-configured enyne, which enabled the biomimetic construction of the axially chiral bromoallene. PMID- 27978699 TI - Correction to "Biomimetic Total Synthesis of Paeoveitol". PMID- 27978700 TI - Enantioselective Synthesis of 2'- and 3'-Substituted Natural Flavans by Domino Asymmetric Transfer Hydrogenation/Deoxygenation. AB - A concise and highly enantioselective synthesis of the natural flavans kazinol U and (2S)-7,3'-dihydroxy-4'-methoxyflavan is reported for the first time. The key transformation is a single-step conversion of a racemic flavanone to a flavan by means of an asymmetric transfer hydrogenation/deoxygenation cascade with kinetic resolution. PMID- 27978701 TI - Synthesis of Lactones via C-H Functionalization of Nonactivated C(sp3)-H Bonds. AB - An electron-deficient amide is utilized as a directing group to functionalize nonactivated C(sp3)-H bonds through radical 1,5-hydrogen abstraction. The gamma bromoamides formed are subsequently converted to gamma-lactones under mild conditions. The method described is not limited to tertiary and secondary positions but also allows functionalization of primary nonactivated sp3 hybridized positions in a one-pot sequence. In addition, the broad functional group tolerance renders this method suitable for the late-stage introduction of gamma-lactones into complex carbon frameworks. PMID- 27978702 TI - Synthesis of Hydrazide-Containing Chroman-2-ones and Dihydroquinolin-2-ones via Photocatalytic Radical Cascade Reaction of Aroylhydrozones. AB - A general and efficient visible light photocatalytic alpha-amino carbon radical based cascade reaction of aroylhydrazones has been described. This protocol tolerates a wide array of alpha-silylamines and aroylhydrazones to afford the corresponding diversely functionalized hydrazide-containing chroman-2-ones and dihydroquinolin-2-ones in generally good yields with excellent diastereoselectivities. PMID- 27978703 TI - Diastereoselectively Complementary C-H Functionalization Enables Access to Structurally and Stereochemically Diverse 2,6-Substituted Piperidines. AB - The preparation of 2,6-substituted piperidine derivatives through diastereoselective C-H functionalization of corresponding nitrogen heterocycles represents an appealing protocol and yet remains a formidable challenge. Here, we describe a stereochemically complementary oxidative C-H functionalization of N carbamoyl tetrahydropyridines with a wide variety of building blocks, providing either the cis- or trans-2,6-substituted piperidines with diverse patterns of functionalities. The mild metal-free process exhibits excellent regio- and diastereoselectivities as well as functional group tolerance. The synthetic utilities in natural product and analogue syntheses are also described. PMID- 27978704 TI - Biomimetic Enantioselective Total Synthesis of (-)-Mycoleptodiscin A. AB - Biomimetic total synthesis of (-)-mycoleptodiscin A (1) was achieved starting from the enantiopure key intermediate, which was prepared by Friedel-Crafts reaction between 7-methoxyindole and chiral primary allylic alcohol. The crucial step in this synthesis was an intramolecular Friedel-Crafts reaction at C-4 of the indole derivative driven by the EDG/EWG within a compound that was rationally designed to prevent the cyclization reaction at the C-2 positon of indole, thereby successfully providing the complete carbon framework of 1. This intramolecular Friedel-Crafts reaction at C-4 of indole derivative could be applied for the synthesis of other C-4-substituted indole alkaloid natural products. PMID- 27978705 TI - Unconventional Passerini Reaction toward alpha-Aminoxy-amides. AB - The Passerini multicomponent reaction (P-3CR) toward the one-step synthesis of alpha-aminoxy-amide, by employing for the first time a N-hydroxamic acid component, has been reported. The sonication-accelerated, catalyst-free, simple, fast, and highly efficient Passerini reaction is used for the synthesis of diverse alpha-aminoxy-amides. The reaction is compatible with a vast range of aldehydes, isocyanides, and N-hydroxamic acids such as N-hydroxysuccinimides and phthalimides. The generated Passerini products can be easily converted into several follow-up products. PMID- 27978706 TI - ATP Recycling with Cell Lysate for Enzyme-Catalyzed Chemical Synthesis, Protein Expression and PCR. AB - E. coli lysate efficiently catalyzes acetyl phosphate-driven ATP regeneration in several important biotechnological applications. The utility of this ATP recycling strategy in enzyme-catalyzed chemical synthesis is illustrated through the conversion of uridine to UMP by the lysate from recombinant overexpression of uridine kinase with the E. coli. The UMP is further transformed into UTP through sequential phosphorylations by kinases naturally present in the lysate, in high yield. Cytidine and 5-fluorouridine also give the corresponding NMPs and NTPs with this system. Cell-free protein expression with a processed extract of lysate also proceeds readily when, instead of adding the required NTPs, all four are produced in situ from the NMPs, using acetyl phosphate and relying on endogenous kinase activity. Similarly, dNMPs can be used to produce the dNTPs necessary for DNA synthesis in PCR. These cheap alternative protocols showcase the potential of acetyl phosphate and ATP recycling with readily available cell lysate. PMID- 27978709 TI - A Malaria Transmission-Blocking (+)-Usnic Acid Derivative Prevents Plasmodium Zygote-to-Ookinete Maturation in the Mosquito Midgut. AB - The evolution of drug resistance is a recurrent problem that has plagued efforts to treat and control malaria. Recent emergence of artemisinin resistance in Southeast Asia underscores the need to develop novel antimalarials and identify new targetable pathways in Plasmodium parasites. Transmission-blocking approaches, which typically target gametocytes in the host bloodstream or parasite stages in the mosquito gut, are recognized collectively as a strategy that when used in combination with antimalarials that target erythrocytic stages will not only cure malaria but will also prevent subsequent transmission. We tested four derivatives of (+)-usnic acid, a metabolite isolated from lichens, for transmission-blocking activity against Plasmodium falciparum using the standard membrane feeding assay. For two of the derivatives, BT37 and BT122, we observed a consistent dose-response relationship between concentration in the blood meal and oocyst intensity in the midgut. To explore their mechanism of action, we used the murine model Plasmodium berghei and found that both derivatives prevent ookinete maturation. Using fluorescence microscopy, we demonstrated that in the presence of each compound zygote vitality was severely affected, and those that did survive failed to elongate and mature into ookinetes. The observed phenotypes were similar to those described for mutants of specific kinases (NEK2/NEK4) and of inner membrane complex 1 (IMC1) proteins, which are all vital to the zygote-to-ookinete transition. We discuss the implications of our findings and our high-throughput screening approach to identifying next generation, transmission-blocking antimalarials based on the scaffolds of these (+)-usnic acid derivatives. PMID- 27978710 TI - Interrogating Key Positions of Size-Reduced TALE Repeats Reveals a Programmable Sensor of 5-Carboxylcytosine. AB - Transcription-activator-like effector (TALE) proteins consist of concatenated repeats that recognize consecutive canonical nucleobases of DNA via the major groove in a programmable fashion. Since this groove displays unique chemical information for the four human epigenetic cytosine nucleobases, TALE repeats with epigenetic selectivity can be engineered, with potential to establish receptors for the programmable decoding of all human nucleobases. TALE repeats recognize nucleobases via key amino acids in a structurally conserved loop whose backbone is positioned very close to the cytosine 5-carbon. This complicates the engineering of selectivities for large 5-substituents. To interrogate a more promising structural space, we engineered size-reduced repeat loops, performed saturation mutagenesis of key positions, and screened a total of 200 repeat nucleobase interactions for new selectivities. This provided insight into the structural requirements of TALE repeats for affinity and selectivity, revealed repeats with improved or relaxed selectivity, and resulted in the first selective sensor of 5-carboxylcytosine. PMID- 27978713 TI - Synthesis and Properties of Axially Symmetrical Rigid Visible Light-Harvesting Systems Containing [60]Fullerene and Perylenebisimide. AB - Two visible light-harvesting perylenebisimide (PDI)-[60]fullerene (C60) systems, dyad P1 with one C60 unit and triad P2 with two C60 units, have been synthesized. Both systems are axially symmetrical with a rigid biphenyl linker, ensuring a relatively fixed spatial distance between the donor and acceptor, preventing through-space interaction, and enhancing energy transfer. Steady-state and transient spectroscopy, electrochemistry, as well as theoretical calculations have been used to investigate the electrochemical and photophysical properties of the two systems. Steady-state and time-resolved spectroscopy demonstrate that the excited state is featured by an efficient intramolecular energy transfer from PDI to C60. Then, the high efficient intrinsic intersystem crossing of C60 eventually leads to the production of the triplet C60. The extensive visible light absorption of PDI in the range of 400-650 nm and the final localization of the excited energy at the triplet C60 make these compounds ideal singlet oxygen inducers. Further investigation shows that the photooxidation capability for both compounds is significantly enhanced with respect to either PDI or C60 and even better than that of the commonly used triplet photosensitizer methylene blue (MB). The double C60 moieties in P2 display a better result, and the photooxidation efficiency of P2 increases 1.3- and 1.4-fold compared to that of P1 and MB, respectively. The combination of a light-harvesting unit with an intersystem crossing unit results in a highly efficient photooxidation system, which opens up a new way to triplet photosensitizer design. PMID- 27978711 TI - Probing the Catalytic Charge-Relay System in Alanine Racemase with Genetically Encoded Histidine Mimetics. AB - Histidine is a unique amino acid with an imidazole side chain in which both of the nitrogen atoms are capable of serving as a proton donor and proton acceptor in hydrogen bonding interactions. In order to probe the functional role of histidine involved in hydrogen bonding networks, fine-tuning the hydrogen bonding potential of the imidazole side chain is required but not feasible through traditional mutagenesis methods. Here, we show that two close mimetics of histidine, 3-methyl-histidine and thiazole alanine, can be genetically encoded using engineered pyrrolysine incorporation machinery. Replacement of the three histidine residues predicted to be involved in an extended charge-relay system in alanine racemase with 3-methyl-histidine or thiazole alanine shows a dramatic loss in the enzyme's catalytic efficiency, implying the role of this extended charge-relay system in activating the active site residue Y265, a general acid/base catalyst in the enzyme. PMID- 27978715 TI - Copper-Catalyzed Regioselective Ring-Opening Hydroamination of Methylenecyclopropanes. AB - A copper-catalyzed ring-opening hydroamination of methylenecyclopropanes with polymethylhydrosiloxane and O-benzoylhydroxylamines has been developed. The cyclopropane C-C bond cleavage occurs selectively at the more congested proximal position, and the corresponding homoallylamines are obtained in good to excellent yields. The umpolung electrophilic amination strategy with the hydroxylamine derivatives can provide a new reaction mode of methylenecyclopropanes in the catalytic hydroamination reaction. PMID- 27978716 TI - Visible-Light-Induced Photocatalytic Aerobic Oxidative Csp3-H Functionalization of Glycine Derivatives: Synthesis of Substituted Quinolines. AB - A visible-light induced photocatalytic aerobic oxidative dehydrogenative coupling/aromatization tandem reaction of glycine esters with unactivated alkenes has been accomplished. This visible light-driven protocol has been successfully applied to a broad scope of glycine esters and simple alkenes, giving rise to diverse substituted quinoline derivatives in 18-84% yield under mild (at room temperature under air atmosphere) and operationally simple reaction conditions. PMID- 27978714 TI - Ionic Liquid-Based Microemulsions in Catalysis. AB - The design and properties of surface-active ionic liquids that are able to form stable microemulsions with heptane and water are presented, and their promise as reaction media for thermomorphic palladium-catalyzed cross-coupling reactions is demonstrated. PMID- 27978717 TI - Synthesis of Diketohexenoic Acid Derivatives by Alkenylation of Indoles and Pyrroles with 4-Pyrones. AB - A new synthesis of functionalized (Z)-6-hetaryl-2,4-dioxo-5-hexenoic acids based on acid-catalyzed alkenylation of indoles and pyrroles with derivatives of 5 substituted 4-pyrone-2-carboxylic acid in 37-82% yields has been developed. Coupling between isochelidonic acid and indoles followed by decarboxylation afforded biologically important (E)-6-indolyl-2,4-dioxo-5-hexenoic acids. These ring-opening reactions proceed with high regioselectivity through nucleophilic attack at the C-6 position of the pyrone ring. Reactions of ethyl 6-indolyl-2,4 dioxo-5-hexenoate with nucleophiles are useful for the production of different beta-(indolyl)vinyl-containing azaheterocycles. PMID- 27978718 TI - The Cs2CO3-Catalyzed Reaction of 2-Oxindoles with Enones for the Preparation of Indolin-3-Ones and Their Further Transformation. AB - The Cs2CO3-catalyzed reaction of 2-oxindoles with enones affords 2,2 disubstituted indolin-3-ones through domino "Michael addition-oxidation-ring cleavage-C-N coupling" process. O2 acts as the sole oxidant to accomplish the oxidative process. The indolin-3-ones can be further transformed to pyridazine, azirdine-fused 3-oxindoles, 4-quinolone derivatives easily. PMID- 27978719 TI - Rhodium(III)-Catalyzed C-H Functionalization of 1-(2H)-Phthalazinones at C8. AB - The rhodium(III) catalyst tris(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate ([Cp*Rh(MeCN)3](SbF6)2) reacts with 1-(2H)-phthalazinones to promote a C-H functionalization event at C8. Preparation of a set of compounds arising from oxidative alkenylation with olefins, hydroarylation with alkynes, and iodination with N-iodosuccinimide is reported here. Oxidative alkenylation proceeds in very good yield, and the scope and limitations of the hydroarylation and halogenation reactions are discussed. Notably, this strategy enables rapid preparation of C8 substituted phthalazinones without requiring phthalazinone ring synthesis starting from a prefunctionalized arene. PMID- 27978720 TI - Competitive 1,2-C Atom Shifts in the Strained Carbene Spiro[3.3]hept-1-ylidene Explained by Distinct Ring-Puckered Conformers. AB - Spiro[3.3]hept-1-ylidene is a markedly strained carbene reaction intermediate that was generated by high-vacuum flash pyrolysis (HVFP) of the corresponding p tosylhydrazone sodium salt. Five hydrocarbons were produced from the Bamford Stevens reactant in 82% overall yield. The carbene undergoes two [1,2] sigmatropic rearrangements via competing 1,2-C atom shifts. Ring-contraction yields cyclopropylidenecyclobutane, while ring-expansion affords bicyclo[3.2.0]hept-1(5)-ene. The ring contraction is regiospecific despite the formation of some 1-methylenespiro[2.3]hexane. It does not originate from the carbene under HVFP conditions. Instead, it comes from a methylenecyclopropane type rearrangement of chemically activated cyclopropylidenecyclobutane. Similarly, some chemically activated bicyclo[3.2.0]hept-1(5)-ene rearranges to 1,2-dimethylenecyclopentane via electrocyclic ring-opening. Accounting for the conversion of primary products to secondary ones, relative yields indicate that ring-contraction within the carbene prevails over ring-expansion by a factor of 6.7:1. Computational chemistry was used to assess the structures, conformations, energies, strain energies, transition states, and activation energies of these rearrangements with the goal of explaining product selectivities. The dual-ringed carbene is predicted to assume four distinct geometric conformations that have a bearing on transition-state selection. The reactive cyclobutylidene units of two conformers are significantly puckered, like cyclobutylidene itself, while those of the other two are flatter. The selectivity of the title carbene is compared with that of spiro[2.3]hex-4-ylidene. PMID- 27978721 TI - The Chan-Evans-Lam N-Arylation of 2-Imidazolines. AB - N-Arylation of 2-imidazolines with arylboronic acids promoted by copper(II) acetate in DMSO provides an attractive alternative to the earlier reported transition metal-catalyzed approaches employing (hetero)aryl halides as it taps into the vast reagent space of commercially available boronic acids and proceeds at ambient temperature. Many of the resulting compounds are distinctly lead-like, thus positioning the method developed well within the toolbox of lead-oriented synthesis. PMID- 27978723 TI - 4-Amino-2,1,3-benzothiadiazole as a Removable Bidentate Directing Group for the Pd(II)-Catalyzed Arylation/Oxygenation of sp2/sp3 beta-C-H Bonds of Carboxamides. AB - In this paper, we report 4-amino-2,1,3-benzothiadiazole (ABTD) as a new bidentate directing group for the Pd(II)-catalyzed sp2/sp3 C-H activation/functionalization of various aliphatic/alicyclic/aromatic carboxamide systems. The Pd(II) catalyzed, ABTD-directed sp3 C-H arylation/acetoxylation of aliphatic- and alicyclic carboxamides afforded the corresponding beta-C-H arylated/acetoxylated carboxamides. The Pd(II)-catalyzed, ABTD-directed sp3 C-H arylation of cyclobutanecarboxamide with different aryl iodides afforded the corresponding bis beta-C-H arylated cyclobutanecarboxamides having all-cis stereochemistry with a high degree of stereocontrol. The Pd(II)-catalyzed, ABTD-directed arylation/benzylation/acetoxylation/alkoxylation of ortho C(sp2)-H bonds of various benzamides afforded the corresponding ortho C-H arylated/benzylated/oxygenated benzamides. The observed regio- and stereoselectivity in the Pd(II)-catalyzed, ABTD-directed arylation/benzylation of aliphatic/alicyclic carboxamides and benzamides were ascertained from the X-ray structures of representative compounds 5g (bis-beta-C(sp3)-H arylated cyclobutanecarboxamide) and 7f (ortho C(sp2)-H arylated benzamide). A brief description on the efficiency, scope, and limitations of bidentate directing group ABTD is reported. PMID- 27978722 TI - Nucleophilic 1,1-Difluoroethylation with Fluorinated Phosphonium Salt. AB - The fluorinated phosphonium salt (Ph3P+CF2CH3 BF4-) was shown to act as a nucleophilic 1,1-difluoroethylation agent to enable difluoroethylation of aldehydes and imines. PMID- 27978724 TI - Substrate-Controlled Diastereoselectivity Reversal in NHC-Catalyzed Cross-Benzoin Reactions Using N-Boc-N-Bn-Protected alpha-Amino Aldehydes. AB - The effectiveness of utilizing N-Bn-N-Boc-alpha-amino aldehydes in cross-benzoin reactions with heteroaromatic aldehydes is demonstrated. The reaction is both chemoselective and syn-selective, making it complementary to the anti-selective cross-benzoin reaction of NHBoc-alpha-amino aldehydes. Good diastereoselectivity is obtained for a variety of amino aldehydes, including nonhindered ones. A Felkin-Anh model can be used to rationalize the observed diastereoselectivity. PMID- 27978725 TI - Elaboration of Sterically Hindered delta-Lactones through Ring-Closing Metathesis: Application to the Synthesis of the C1-C27 Fragment of Hemicalide. AB - The synthesis of the C1-C27 fragment of hemicalide, a marine metabolite displaying a unique potent antiproliferative activity, has been accomplished. The synthetic approach highlights a remarkably efficient ring-closing metathesis reaction catalyzed by Nolan ruthenium indenylidene complexes to elaborate the highly substituted delta-lactone framework. PMID- 27978726 TI - Palladium-Catalyzed, Multicomponent Approach to beta-Lactams via Aryl Halide Carbonylation. AB - A palladium-catalyzed multicomponent method for the synthesis of beta-lactams from imines, aryl halides, and CO has been developed. This transformation proceeds via two tandem catalytic carbonylation reactions mediated by Pd(PtBu3)2 and provides a route to prepare these products from five separate reagents. A diverse range of polysubstituted beta-lactams can be generated by systematic variation of the substrates. This methodology can also be extended to the use of iodo-substituted imines to produce novel spirocyclic beta-lactams in good yields and selectivity. PMID- 27978727 TI - Synthesis of o-Alkenylated 2-Arylbenzoxazoles via Rh-Catalyzed Oxidative Olefination of 2-Arylbenzoxazoles: Scope Investigation, Structural Features, and Mechanism Studies. AB - 2-Arylbenzazoles are promising molecules for potential applications in medicine and material areas. Efficient protocols for direct regioselective functionalization of 2-arylbenzoxazoles are in high demand. Herein, we disclose a general method for selective ortho-olefination of 2-arylbenzo[d]oxazoles with alkenes enabled by versatile Cp*Rh(III) in high yields. This protocol features broad functional group tolerance and high regioselectivity. Intermolecular competition studies and kinetic isotope effect experiments imply that the oxidative olefination process occurs via an electrophilic C-H activation pathway. The molecular structure of the m-fluoro-substituted olefination product confirms regioselective C-H activation/olefination at the more hindered site in cases where the meta F atom or heteroatom substituent existed. Apparent torsion angles were observed in the structures of mono- and bis-olefination products, which resulted in distinct different chemical shifts of olefinic protons. Additionally, two gram-scale reactions and further transformation experiments demonstrate that this method is practical for synthesis of ortho-alkenylated 2-arylbenzoxazole derivatives. PMID- 27978728 TI - Application of the Photoredox Coupling of Trifluoroborates and Aryl Bromides to Analog Generation Using Continuous Flow. AB - A method for the coupling of aryl bromides with potassium alkyl trifluoroborates, via nickel/photoredox dual catalysis, has been developed for use in continuous flow. This operationally simple protocol is able to form Csp3-Csp2 bonds with significantly reduced reaction times and a broader substrate scope than when conducted in batch. The utility of this method for rapid analog synthesis has been demonstrated by the synthesis of a small library of alkyl-substituted quinazolines. PMID- 27978729 TI - Silver-Catalyzed Domino Reaction of ortho-Carbonylated Alkynyl-Substituted Arylaldehydes with Conjugated Dienes: Stereoselective Access to Indanone-Fused Cyclohexenes. AB - A silver-catalyzed domino reaction of ortho-carbonylated alkynyl-substituted arylaldehydes with conjugated dienes is described here. Through this reaction, the synthesis of a variety of indanone-fused cyclohexene derivatives can be achieved efficiently. The formation of these tricyclic products could involve a key Diels-Alder reaction of in situ generated indanenone dienophiles with conjugated dienes. Particularly, the products can be accomplished in a high endo/exo selective way. PMID- 27978730 TI - Application of the Solid-Supported Glaser-Hay Reaction to Natural Product Synthesis. AB - The Glaser-Hay coupling of terminal alkynes is a useful synthetic reaction for the preparation of polyynes; however, chemoselectivity issues have precluded its widespread utilization. Conducting the reaction on a solid-support provides a mechanism to alleviate the chemoselectivity issues and provide products in high purities and yields. Moreover, the polyyne core is a key component to several natural products. Herein, we describe the application of a solid-supported Glaser Hay reaction in the preparation of several natural products. These compounds were then screened for antibacterial activity, illustrating the utility of the methodology. PMID- 27978731 TI - Ruthenium(II)-Catalyzed Regioselective Ortho Amidation of Imidazo Heterocycles with Isocyanates. AB - Direct ortho amidation at the phenyl ring of 2-phenylimidazo heterocycles with aryl isocyanates has been achieved via a chelation-assisted cationic ruthenium(II) complex catalyzed mechanism. The methodology provides a straightforward, high-yielding regioselective approach toward the synthesis of an array of ortho-amidated phenylimidazo heterocycles without prior activation of C(sp2)-H. This also reports the first method for coupling of aryl isocyanates with the imidazo[1,2-a]pyridine system via a pentacyclometalated intermediate. The methodology is found to be easily scalable and could be applied toward the selective ortho amidation of 2-heteroarylimidazo[1,2-a]pyridine frameworks. PMID- 27978732 TI - Interrupting the Nazarov Cyclization with Bromine. AB - The generation of dibrominated cyclopentenones via an interrupted Nazarov cyclization is reported. The installation of two bromine atoms occurs at the alpha and alpha' positions of the cyclopentenyl scaffold via successive nucleophilic and electrophilic bromination of the 2-oxidocyclopentenyl cation and its resulting enolate. Notably, the reaction proceeds with good diastereoselectivity, favoring the symmetrical product. PMID- 27978733 TI - Synthesis of 2-Oxindoles Sharing Vicinal All-Carbon Quaternary Stereocenters via Organocatalytic Aldol Reaction. AB - An organocatalytic enantioselective aldol reaction using paraformaldehyde as C1 unit has been developed for the synthesis of 2-oxindoles sharing vicinal all carbon quaternary stereocenters. The methodology is eventually employed in the formal total synthesis of (+)-folicanthine (1b). PMID- 27978734 TI - Templated Oligosaccharide Synthesis: Driving Forces and Mechanistic Aspects. AB - We previously communicated that high alpha-selectivity that can be achieved in intramolecular glycosylations using a rigid bisphenol A template supplemented with linkers of various lengths. Herein, we present our investigation of the mechanistic aspects of the templated synthesis that helped to design an improved template-linker combination. We demonstrate that bisphenol A as the template in combination with phthaloyl linker allows for superior stereoselectivity and yields in glycosylations. Several mechanistic studies explore origins of the enhanced stereoselectivity and yields achieved using the phthaloyl linker. PMID- 27978735 TI - 6-(Aryldiazenyl)pyrazolo[1,5-a]pyrimidines as Strategic Intermediates for the Synthesis of Pyrazolo[5,1-b]purines. AB - A microwave-assisted approach for the regioselective synthesis of functionalized 6-(aryldiazenyl)pyrazolo[1,5-a]pyrimidin-7-amines from the cyclization of 3-oxo-2 (2-arylhydrazinylidene)butanenitriles with 5-amino-1H-pyrazoles under solvent free conditions has been developed. This methodology was distinguished by its broad substrate scope, operational simplicity, high atom economy, and high yielding without requiring chromatographic purification. In addition, an efficient and versatile palladium-catalyzed reductive azo cleavage is disclosed for the synthesis of diverse heteroaromatic 1,2-diamines, a valuable synthetic building block to develop new fused heteroaromatic systems. As synthetic example, several substituted pyrazolo[5,1-b]purines were synthesized in yields up to 96% by using microwave irradiation in the cyclocondensation of these 1,2-diamines with orthoesters. PMID- 27978737 TI - Access to Complex C2-Branched Glycoconjugates via Palladium-Catalyzed Aminocarbonylation Reaction of 2-Iodoglycals. AB - A convenient and straightforward synthesis of 2-amidoglycals through a palladium catalyzed aminocarbonylation reaction between 2-iodoglycal partners and diverse amines in the presence of a "CO" source has been developed. Several amines such as aliphatics, benzylics, or aromatics are compatible with our reaction conditions as well as sulfonamides. Further deprotection steps have been successfully applied, leading to glycoside mimics. This method constitutes a new route to access original glycopeptide- and glycolipid-type analogues possessing a C-C bond at the C2-position. PMID- 27978736 TI - Primary Amide Directed Regioselective ortho-C-H-Arylation of (Aryl)Acetamides. AB - An efficient and regioselective palladium(II)-catalyzed primary acetamide assisted ortho arylation of arylacetamide has been discovered. This is the first report where functionalizable primary acetamide (-CH2CONH2) is used as a directing group for C(sp2)-H activation/cross-coupling reactions, circumventing the extra steps of installation and subsequent removal of the directing groups. The synthetic utility of this transformation is demonstrated through the scale-up synthesis. In addition, the primary acetamide can be manipulated into synthetically important derivatives such as nitriles and carboxylic acids. PMID- 27978738 TI - Total Synthesis of (+)-Goniodenin. AB - Goniodenin is a lipophilic polyketide originating from plant sources and which possesses a potent cytotoxic activity against cancer cell lines. The first total synthesis of (+)-goniodenin has been achieved in 23 steps from (R)-glycidol. The synthetic sequence featured a cross metathesis for the formation of the C8-C9 bond and installation of the terminal gamma-butenolactone ring unit by the alkylation of alpha-phenylthio-gamma-butyrolactone with the corresponding C3-O triflate. The stereogenic center at C18 carbon was created by Hiyama-Fujita reduction of the corresponding ketone with high diastereoselectivity. PMID- 27978739 TI - Controlled Dimroth Rearrangement in the Suzuki-Miyaura Cross Coupling of Triazolopyridopyrimidines. AB - Polynitrogen heterocycles are often subject to Dimroth rearrangement which consists of ring opening, bond rotation, and ring closure. In this note, we report a synthesis of two new families of triazolopyridopyrimidines. Successful functionalization via a Suzuki-Miyaura coupling was performed with total control of triazole (Dimroth) isomerization based on the judicious choice of reaction conditions. PMID- 27978740 TI - Electron Transfer Mechanism in the Oxidation of Aryl 1-Methyl-1-phenylethyl Sulfides Promoted by Nonheme Iron(IV)-Oxo Complexes: The Rate of the Oxygen Rebound Process. AB - The oxidation of aryl 1-methyl-1-phenylethyl sulfides promoted by the nonheme iron(IV)-oxo complexes [(N4Py)FeIV?O]2+ and [(Bn-TPEN)FeIV?O]2+ occurs by an electron transfer-oxygen rebound (ET-OT) mechanism leading to aryl 1-methyl-1 phenylethyl sulfoxides accompanied by products derived from Calpha-S fragmentation of sulfide radical cations (2-phenyl-2-propanol and diaryl disulfides). For the first time, the rate constants for the oxygen rebound process (kOT), which are in the range of <0.8 * 104 to 3.5 * 104 s-1, were determined from the fragmentation rate constants of the radical cations (kf) and the S oxidation/fragmentation product ratios. PMID- 27978741 TI - Exploring the Reactivity of 2-Trichloromethylbenzoxazoles for Access to Substituted Benzoxazoles. AB - The reactivity of 2-trichloromethylbenzoxazoles toward various nucleophiles, under metal-free or iron-catalyzed conditions, for the synthesis of substituted benzoxazoles is described. These methods allow for selective substitution at either the 2- or 2'-position of the benzoxazoles using the same starting materials/reagents. This approach allows for the controlled synthesis of a variety of key derivatives from a single 2-trichloromethylbenzoxazole starting material. PMID- 27978742 TI - Synthesis of a Masked 2,3-Diaminoindole. AB - A three-step synthesis of masked 2,3-diaminoindole 1 from 2-iodo-3-nitro-1 (phenylsulfonyl)indole (2) has been developed. Treatment of 1 with trifluoroacetic acid generates the unstable 2,3-diamino-1-(phenylsulfonyl)indole (3), which can be trapped with alpha-dicarbonyl compounds to afford 5H pyrazino[2,3-b]indoles 7-10. PMID- 27978743 TI - Fusion and Desulfurization Reactions of Thiomorpholinochlorins. AB - An unusually nonplanar, ruffled structure that had been suspected for the previously reported [2,3-bismethylenethiomorpholinochlorinato]nickel(II) complex was confirmed by determination of its crystal structure. Treatment of this thiomorpholinochlorin with acid converts the exocyclic double bonds to direct links to the ortho-positions of both adjacent meso-phenyl groups. The crystal structure of this product indicated that the introduction of these linkages did not change the overall conformation of the macrocycle. The reactivity of the bis linked thiomorpholine moiety with respect to Raney-nickel-induced (hydro)desulfurization reactions was probed, forming a bis-phenyl-linked 2,3 dimethylchlorin, also characterized by X-ray diffraction, and a bis-indene annulated porphyrin. We also report on the synthesis of the oxygen analogue to the bis-linked thiomorpholine by reaction of a secochlorin bisketone nickel complex with Woollins' reagent. We thus introduce novel methodologies toward the synthesis of porphyrinoids carrying beta-to-ortho-phenyl fusions and expand on the scope and limits of the chemistry and interconversion of pyrrole-modified porphyrins. PMID- 27978744 TI - 9,10-Dicyanoanthracene Catalyzed Decarboxylative Alkynylation of Carboxylic Acids under Visible-Light Irradiation. AB - A metal-free, visible-light-induced photocatalytic procedure for decarboxylative alkynylation of carboxylic acids was reported. With 9,10-dicyanoanthracene as the photoredox catalyst, the reaction covered a broad scope of alpha-amino acids, alpha-oxo acids, and alpha-keto acids with blue LED irradiation at room temperature under an atmosphere of argon, delivering alkynyl products in moderate to excellent yields. Natural sun light also promoted this alkynylation strategy. This work represents the first example of an organophotocatalytic method for decarboxylative alkynylation of carboxylic acids. PMID- 27978745 TI - Study of Cascade Ring-Closing Metathesis Reactions en Route to an Advanced Intermediate of Taxol. AB - A highly functionalized intermediate in the synthesis of Taxol has been synthesized, which features the tricyclic core and the required oxygen substituents at C1, C2, C7, C10, and C13. The key step, a ring-closing dienyne metathesis (RCDEYM) reaction, has been thoroughly optimized to favor the tricyclic product over the undesired bicyclic product resulting from diene metathesis. PMID- 27978747 TI - Fifteen Years with JOC. PMID- 27978746 TI - Origins of Stereoselectivity of Chiral Vicinal Diamine-Catalyzed Aldol Reactions. AB - The sources of asymmetric induction in aldol reactions catalyzed by cinchona alkaloid-derived amines, and chiral vicinal diamines in general, have been determined by density functional theory calculations. Four vicinal diamine catalyzed aldol reactions were examined. The cyclic transition states of these reactions involve nine-membered hydrogen-bonded rings in distinct conformations. Using nomenclature from eight-membered cycloalkanes, the heavy atoms of the low energy transition states are in crown (chair-chair) and chair-boat conformations. The factors that control which of these are favored have been identified. PMID- 27978748 TI - Assembly of Polysubstituted Maleimides via Palladium-Catalyzed Cyclization Reaction of Alkynes with Isocyanides. AB - An efficient and convenient palladium-catalyzed cyclization reaction of alkynes with isocyanides is described herein. This protocol allows the practical synthesis of many valuable polysubstituted maleimide derivatives after hydrolysis with a broad scope of substrates and mild reaction conditions. C-C, C?O, and C-N bonds were constructed in this transformation with isocyanide serving as both C and N sources. PMID- 27978750 TI - Controlling the Conformational Energy of a Phenyl Group by Tuning the Strength of a Nonclassical CH...O Hydrogen Bond: The Case of 5-Phenyl-1,3-dioxane. AB - Anancomeric 5-phenyl-1,3-dioxanes provide a unique opportunity to study factors that control conformation. Whereas one might expect an axial phenyl group at C(5) of 1,3-dioxane to adopt a conformation similar to that in axial phenylcyclohexane, a series of studies including X-ray crystallography, NOE measurements, and DFT calculations demonstrate that the phenyl prefers to lie over the dioxane ring in order to position an ortho-hydrogen to participate in a stabilizing, nonclassical CH...O hydrogen bond with a ring oxygen of the dioxane. Acid-catalyzed equilibration of a series of anancomeric 2-tert-butyl-5-aryl-1,3 dioxane isomers demonstrates that remote substituents on the phenyl ring affect the conformational energy of a 5-aryl-1,3-dioxane: electron-withdrawing substituents decrease the conformational energy of the aryl group, while electron donating substituents increase the conformational energy of the group. This effect is correlated in a very linear way to Hammett substituent parameters. In short, the strength of the CH...O hydrogen bond may be tuned in a predictable way in response to the electron-withdrawing or electron-donating ability of substituents positioned remotely on the aryl ring. This effect may be profound: a 3,5-bis-CF3 phenyl group at C(5) in 1,3-dioxane displays a pronounced preference for the axial orientation. The results are relevant to broader conformational issues involving heterocyclic systems bearing aryl substituents. PMID- 27978749 TI - Tricyclic Quaternary Ammonium Salts Derived from Cinchona Alkaloids. AB - Tricyclic systems with quaternary bridgehead nitrogen atoms are rare but an interesting class of compounds. Chiral quinuclidine derivative salts with fused five and six-membered rings (X-ray) were obtained via modification of Cinchona alkaloids. The ease of ring formation was dependent on its size, while even mild activation sufficed to close the five membered ring. On the other hand the systems with fused benzene and a six-membered ring formed atropisomers separated by a barrier of ca. 15 kcal/mol, whose interconversion was studied by DFT and NMR. PMID- 27978751 TI - Pd(II)-Catalyzed Bidentate Directing Group-Aided Chemoselective Acetoxylation of Remote epsilon-C(sp2)-H Bonds in Heteroaryl-Aryl-Based Biaryl Systems. AB - In this Article, we report our successful attempt on the Pd(II)-catalyzed, bidentate directing group-aided, chemoselective acetoxylation/substitution of remote epsilon-C(sp2)-H bonds using heteroaryl-aryl-based biaryl systems. While the bidentate directing group (BDG)-aided, C-H activation, and functionalization/acetoxylation of the beta-, gamma-, and delta-C-H bonds of the appropriate carboxamide systems were well documented, there exist only rare reports dealing with the C-H activation and functionalization of remote epsilon-C H bonds of appropriate substrates. Especially, the BDG-aided chemoselective acetoxylation of the remote epsilon-C(sp2)-H bond over cyclization has not been explored well. Accordingly, in this work, the treatment of various picolinamides/oxalylamides/pyrazine-2-carboxamides 4/7/9/11, which were derived from the corresponding C-3 arylated furfurylamines or thiophen-2-ylmethanamines with PhI(OAc)2 in the presence of the Pd(OAc)2 catalyst, successfully afforded the corresponding epsilon-C-H acetoxylated products. The chemoselective acetoxylation of the epsilon-C-H bond was possible and facilitated by the biaryl substrate 4/7/9/11 and not by the biaryl substrate 2a. PMID- 27978752 TI - Copper(II)-Catalyzed Benzylic C(sp3)-H Aerobic Oxidation of (Hetero)Aryl Acetimidates: Synthesis of Aryl-alpha-ketoesters. AB - A straightforward method is developed in this paper for the synthesis of alpha ketoesters through copper-catalyzed aerobic oxidation of (hetero)aryl acetimidates using molecular oxygen as a sustainable oxidant. The reaction represents the first example of the direct synthesis of aryl-alpha-ketoesters from arylacetimidates through the aerobic oxidation of a benzylic C(sp3)-H (C?O) bond in moderate to good yield. This transformation occurs under mild reaction conditions with a wide range of substrates and utilizes a readily available oxidant and catalyst. The synthetic utility of this transformation is demonstrated through scaled-up synthesis. A plausible reaction mechanism is also proposed. PMID- 27978753 TI - Regenerable Radical-Trapping Tellurobistocopherol Antioxidants. AB - Tellurobistocopherols 9-11 were prepared by lithiation of the corresponding bromotocopherols, reaction with tellurium tetrachloride and reductive workup. Compounds 9-11 quenched linoleic-acid-derived peroxyl radicals much more efficiently than alpha-tocopherol in a chlorobenzene/water two-phase system. N Acetylcysteine or tris(2-carboxylethyl)phosphine as co-antioxidants in the aqueous phase could regenerate the tellurobistocopherols and increase their inhibition times. Antioxidant 11 inhibited peroxidation for 7-fold longer than that recorded with alpha-tocopherol. Thiol consumption in the aqueous phase was monitored and found to be inversely related to the inhibition time. PMID- 27978754 TI - Rhodium-Catalyzed NH-Indole-Directed C-H Carbonylation with Carbon Monoxide: Synthesis of 6H-Isoindolo[2,1-a]indol-6-ones. AB - An efficient synthesis of 6H-isoindolo[2,1-a]indol-6-ones through rhodium catalyzed NH-indole-directed C-H carbonylation of 2-arylindoles with carbon monoxide has been developed. Preliminary mechanistic studies revealed that this reaction proceeds via N-H bond cleavage and subsequent C-H bond cleavage. Reaction monitoring via ESI-MS was used to support the formation of five-membered rhodacycle species in the catalytic cycle. PMID- 27978755 TI - Metal-Free Domino One-Pot Decarboxylative Cyclization of Cinnamic Acid Esters: Synthesis of Functionalized Indanes. AB - Trifluoroacetic acid promoted unprecedented domino reaction for the synthesis of diverse indanes starting from simple cinnamic acid esters is described. Their formation can be explained via acid triggered decarboxylation of cinnamic acid esters and subsequent inter/intramolecular cyclization. Overall process involves in the intramolecular cleavage of two sigma-bonds (C-O and C-C) and inter/intramolecular construction of two/one C-C sigma-bond(s). Significantly, this protocol was successful without the aid of any metal salts. PMID- 27978757 TI - Copper-Catalyzed Radical-Promoted Aminocyclization of Acrylamides with N Fluorobenzenesulfonimide. AB - A facile copper-catalyzed radical aminoarylation of acrylamide with N fluorobenzenesulfonimide (NFSI) is described. In the presence of copper acetate and 1,10-phenanthroline, a range of isoquinoline-1,3-diones can be constructed in moderate to good yields using NFSI as the amination reagent. Mechanistic studies demonstrated the reaction went through a sequential radical addition and cyclization pathway, which was supported by DFT calculations. PMID- 27978756 TI - Synthesis of Succinimide-Containing Chromones, Naphthoquinones, and Xanthones under Rh(III) Catalysis: Evaluation of Anticancer Activity. AB - The weakly coordinating ketone group directed C-H functionalizations of chromones, 1,4-naphthoquinones, and xanthones with various maleimides under rhodium(III) catalysis are described. These protocols efficiently provide a range of succinimide-containing chromones, naphthoquinones, and xanthones with excellent site selectivity and functional group compatibility. All synthetic compounds were screened for in vitro anticancer activity against human breast adenocarcinoma cell lines (MCF-7). In particular, compounds 7aa and 7ca with a naphthoquinone scaffold were found to be highly cytotoxic, with an activity competitive with anticancer agent doxorubicin. PMID- 27978758 TI - Quantitative First-Principles Kinetic Modeling of the Aza-Michael Addition to Acrylates in Polar Aprotic Solvents. AB - This work presents a detailed computational study and kinetic analysis of the aza Michael addition of primary and secondary amines to acrylates in an aprotic solvent. Accurate rate coefficients for all elementary steps in the various competing mechanisms are calculated using an ONIOM-based approach in which the full system is calculated with M06-2X/6-311+G(d,p) and the core system with CBS QB3 corrected for solvation using COSMO-RS. Diffusional contributions are taken into account using the coupled encounter pair model with diffusion coefficients calculated based on molecular dynamics simulations. The calculated thermodynamic and kinetic parameters for all forward and reverse elementary reactions are fed to a microkinetic model giving excellent agreement with experimental data obtained using GC analysis. Rate analysis reveals that for primary and secondary amines, the aza-Michael addition to ethyl acrylate occurs preferentially according to a 1,2-addition mechanism, consisting of the pseudoequilibrated formation of a zwitterion followed by a rate controlling amine assisted proton transfer toward the singly substituted product. The alternative 1,4-addition becomes competitive if substituents are present on the amine or double bond of the acrylate. Primary amines react faster than secondary amines due to increased solvation of the zwitterionic intermediate and less sterically hindered proton transfer. PMID- 27978759 TI - Cu(II)-Catalyzed 6pi-Photocyclization of Dienynes. AB - The first 6pi-photocyclization of dienynes was developed, which provides a new and effective protocol for the synthesis of the phenyl ring in excellent yields with nice functional group tolerance. In this transformation, the Cu(OTf)2 catalyst plays a key role in the conversion of alkyne moiety into an alkene-type moiety, which means that the dienyne reactant is converted into a triene-type substrate. Thus, this reaction proceeds via a Cu(II)-catalyzed 6pi photocyclization of triene-type derivatives. PMID- 27978760 TI - Metal-Free Radical Oxidative Cyclization of o-Azidoaryl Acetylenic Ketones with Sulfinic Acids To Access Sulfone-Containing 4-Quinolones. AB - A novel one-pot synthesis of sulfone-containing 4-quinolones with easily available sulfinic acids as sulfonylating precursors is described. This reaction is characterized by mild reaction conditions, high functional-group tolerance and amenability to gram-scale synthesis. PMID- 27978761 TI - A One-Pot Procedure for the Synthesis of "Click-Ready" Triazoles from Ketones. AB - A practical, straightforward, and highly regioselective Zn(OAc)2-mediated method toward propargyl triazoles has been developed for the first time from commercially available enolizable ketones and propargyl amine. Postfunctionalization of this triazole leads to unique N- and C-linked bis triazoles in excellent yields. PMID- 27978762 TI - Total Syntheses of Anti-HIV Cyclodepsipeptides Aetheramides A and B. AB - A concise total synthesis of aetheramide A in an overall yield of 4.7% with a longest linear sequence of 15 steps is described. This synthetic strategy features macrocyclization via an intramolecular trapping of acylketene generated from dioxinone precursor, and stereoselective late-stage methylation of beta ketoamide. Aetheramide B could be synthesized via the ester migration of aetheramide A. PMID- 27978763 TI - Rural health service planning: the need for a comprehensive approach to costing. AB - The precipitous closure of rural maternity services in industrialized countries over the past two decades is underscored in part by assumptions of efficiencies of scale leading to cost-effectiveness. However, there is scant evidence to support this and the costing evidence that exists lacks comprehensiveness. To clearly understand the cost-effectiveness of rural services we must take the broadest societal perspective to include not only health system costs, but also those costs incurred at the family and community levels. We must consider manifest costs (hard, easily quantifiable costs, both direct and indirect) and latent costs (understood as what is sacrificed or lost), and take into account cost shifting (reallocating costs to different parts of the system) and cost downloading (passing costs on to women and families). Further, we must compare the costs of having a rural maternity service to those incurred by not having a service, a comparison that is seldom made. This approach will require determining a methodological framework for weighing all costs, one which will likely involve attention to the rich descriptions of those experiencing loss. PMID- 27978765 TI - A systematic review and checklist presenting the main challenges for health economic modeling in personalized medicine: towards implementing patient-level models. AB - INTRODUCTION: The ongoing development of genomic medicine and the use of molecular and imaging markers in personalized medicine (PM) has arguably challenged the field of health economic modeling (HEM). This study aims to provide detailed insights into the current status of HEM in PM, in order to identify if and how modeling methods are used to address the challenges described in literature. Areas covered: A review was performed on studies that simulate health economic outcomes for personalized clinical pathways. Decision tree modeling and Markov modeling were the most observed methods. Not all identified challenges were frequently found, challenges regarding companion diagnostics, diagnostic performance, and evidence gaps were most often found. However, the extent to which challenges were addressed varied considerably between studies. Expert commentary: Challenges for HEM in PM are not yet routinely addressed which may indicate that either (1) their impact is less severe than expected, (2) they are hard to address and therefore not managed appropriately, or (3) HEM in PM is still in an early stage. As evidence on the impact of these challenges is still lacking, we believe that more concrete examples are needed to illustrate the identified challenges and to demonstrate methods to handle them. PMID- 27978764 TI - National Study of Muscle Cramps in ALS in the USA. AB - The objective of this study was to describe muscle cramps in an US sample of amyotrophic lateral sclerosis (ALS) patients. Utilizing an anonymous web based questionnaire we queried ALS patients regarding the severity, frequency, time course, treatment of muscle cramps and their relationship to pain. The survey had 282 respondents with 92% reporting that they had cramps. For 20% of the sample, cramps were stated to be the presenting ALS symptom. Cramp severity was rated at a mean of 5.2/10 and the mean cramp frequency was 5.3 cramps per day. Cramp intensity and frequency did not correlate with duration or severity of ALS. Pain as measured with the Patient Reported Outcome Measurement Information System (PROMIS) pain scales was not statistically different from the US general population. Cramp severity and frequency significantly and positively correlated with the PROMIS pain scales. Patients with more severe cramps were more likely to use prescription medications for their cramps compared to patients with milder symptoms. Treatments directed at cramps were tried by 57%. In conclusion, cramps are a common symptom in ALS and it does not correlate with disease duration or severity. The severity of cramps is on average moderate and many patients try treatments. PMID- 27978766 TI - Distribution of xenobiotic metabolising enzyme genotypes in different Tunisian populations. AB - BACKGROUND: The N-acetyltransferase 2 (NAT2) and glutathione transferase enzymes play a crucial role in the metabolism of xenobiotics. Genetic polymorphisms affecting these enzymes can modify their activities with an effect on individual susceptibility for different pathologies. These metabolic phenotypes occur with varying prevalence in different populations. AIM: This study sought to analyse the prevalence of important allelic variants of NAT2, GSTM1 and GSTT1 in different Tunisian populations and compare them to other previously reported data. SUBJECTS AND METHODS: A total of 253 unrelated subjects from different Tunisian populations participated in this study. Subjects were examined with respect to the frequency of slow NAT2, GSTM1*0 and GSTT1*0 genotypes. RESULTS: The frequency of 'slow' NAT2, GSTM1*0 and GSTT1*0 genotypes in the Tunisian population were, respectively, estimated at 23.3%, 53.75% and 29.24%. The frequency of slow NAT2 and GSTM1*0 genotypes were significantly different between the North, Centre and South of Tunisia. However, this study doesn't report any significant differences in the genotype distribution between Cosmopolitan, Arab and Berber populations. CONCLUSIONS: In conclusion, these data indicate that the Tunisian population is highly heterogenic and, therefore, a strict definition of the populations involved in studies investigating the clinical effect of polymorphisms is required. PMID- 27978767 TI - Clusterin as a therapeutic target. AB - INTRODUCTION: Clusterin (CLU) is a stress-activated, ATP-independent molecular chaperone, normally secreted from cells, that is up-regulated in Alzheimer disease and in many cancers. It plays important roles in protein homeostasis/proteostasis, inhibition of cell death pathways, and modulation of pro-survival signalling and transcriptional networks. Changes in the CLU gene locus are highly associated with Alzheimer disease, and many therapy-resistant cancers over-express CLU. The extensive post-translational processing and heterogeneous oligomerization of CLU have so far prevented any definitive structure determination. This in turn has meant that targeting CLU with small molecule inhibitors is challenging. Therefore, inhibiting CLU at the gene expression level using siRNA or antisense is a valid approach to inhibit its function. Areas covered: This article reviews recent advances regarding the role of CLU in proteostasis, cellular trafficking, human diseases, and signalling pathways involved in oncogenesis. It addresses the rationale for CLU as a therapeutic target in cancer, and the current status of pre-clinical and clinical studies using CLU antisense inhibitor OGX011. Expert opinion: Discusses challenges facing the therapeutic targeting of CLU including rapid changes in the treatment landscape for prostate cancer with multiple new FDA approved drugs, selection of windows of intervention, and potential side effects when silencing CLU expression. PMID- 27978768 TI - Movement disorders and cerebrovascular diseases: from pathophysiology to treatment. AB - INTRODUCTION: Cerebrovascular diseases are one of the most common causes of secondary movement disorders. Hypokinetic or hyperkinetic movement disorders may occur after an ischemic or hemorrhagic stroke, either immediately or thereafter. Such disorders are also known to be caused by diffuse leukoaraiosis, vascular malformations and dural fistulas in the basal ganglia or other brain regions. Area covered: The aim of this review was to describe movement disorders secondary to cerebrovascular diseases, and highlight their pivotal pathophysiological aspects, clinical features, diagnostic criteria and therapeutic options. Expert commentary: Movement disorders secondary to cerebrovascular diseases remain a challenge for neurologists. These conditions share some therapeutic options with idiopathic forms, though tailored treatment may be required in certain cases. Innovative neuroimaging techniques may play a pivotal role in the early diagnosis of vascular movement disorders. Further natural history studies and good-quality clinical trials are warranted to achieve a better management of these complex disorders. PMID- 27978769 TI - Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center. AB - OBJECTIVE: To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. METHODS: Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of Sao Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses. SOD1, FUS and VAPB were also evaluated in FALS subjects. RESULTS: Mutations were identified in FALS (61.3%) and SALS (5.3%) patients. Mutations in C9orf72 (12.8%, >45 GGGGCC hexanucleotide repeats), VAPB (43.6%, P56S) and SOD1 (7.7%, L145S) were identified in FALS subjects. Pathogenic C9orf72 expansions (2.64%) were identified in some SALS patients. Similar changes of TARDBP were found in SALS (2.64%) but not in FALS subjects. No FUS mutations were seen in any FALS subjects. CONCLUSIONS: TARDBP and C9orf72 mutations in this cohort were similar to those found in other centres worldwide. VAPB mutation (P56S) was highly prevalent in Brazilian FALS patients. PMID- 27978770 TI - The 20-Year Longitudinal Trajectories of Social Functioning in Individuals With Psychotic Disorders. AB - OBJECTIVE: Social impairment is a long-recognized core feature of schizophrenia and is common in other psychotic disorders. Still, to date the long-term trajectories of social impairment in psychotic disorders have rarely been studied systematically. METHODS: Data came from the Suffolk County Mental Health Project, a 20-year prospective study of first-admission patients with psychotic disorders. A never-psychotic comparison group was also assessed. Latent class growth analysis was applied to longitudinal data on social functioning from 485 respondents with schizophrenia spectrum disorders and psychotic mood disorders, and associations of the empirically derived trajectories with premorbid social adjustment, diagnosis, and 20-year outcomes were examined. RESULTS: Four mostly stable trajectories of preserved (N=82; 59th percentile of comparison group sample distribution), moderately impaired (N=148; 17th percentile), severely impaired (N=181; 3rd percentile), and profoundly impaired (N=74; 1st percentile) functioning best described the 20-year course of social functioning across diagnoses. The outcome in the group with preserved functioning did not differ from that of never-psychotic individuals at 20 years, but the other groups functioned significantly worse. Differences among trajectories were already evident in childhood. The two most impaired trajectories started to diverge in early adolescence. Poorer social functioning trajectories were strongly associated with other real-world outcomes at 20 years. Multiple trajectories were represented within each disorder. However, more participants with schizophrenia spectrum disorders had impaired trajectories, and more with mood disorders had better functioning trajectories. CONCLUSIONS: The results highlight substantial variability of social outcomes within diagnoses-albeit overall worse social outcomes in schizophrenia spectrum disorders-and show remarkably stable long-term impairments in social functioning after illness onset across all diagnoses. PMID- 27978772 TI - Initiation of non-invasive ventilation in amyotrophic lateral sclerosis and clinical practice guidelines: Single-centre, retrospective, descriptive study in a national reference centre. AB - In amyotrophic lateral sclerosis (ALS), respiratory muscle weakness leads to respiratory failure. Non-invasive ventilation (NIV) maintains adequate ventilation in ALS patients. NIV alleviates symptoms and improves survival. In 2006, French guidelines established criteria for NIV initiation based on limited evidence. Their impact on clinical practice remains unknown. Our objective was to describe NIV initiation practices of the main French ALS tertiary referral centre with respect to guidelines. In this retrospective descriptive study, 624 patients followed in a single national reference centre began NIV between 2005 and 2013. We analysed criteria used to initiate NIV, including symptoms, PaCO2, forced vital capacity, maximal inspiratory pressures and time spent with SpO2 <90% at night. At NIV initiation, 90% of patients were symptomatic. Median PaCO2 was 48 mmHg. The main criterion to initiate NIV was 'symptoms' followed by 'hypercapnia' in 42% and 34% of cases, respectively. NIV was initiated on functional parameters in only 5% of cases. Guidelines were followed in 81% of cases. In conclusion, despite compliance with French guidelines, the majority of patients are treated at the stage of symptomatic daytime hypoventilation, which suggests that NIV is initiated late in the course of ALS. Whether this practice could be improved by changing guidelines or increasing respiratory-dedicated resources remains to be determined. PMID- 27978771 TI - The Role of Behavioral Interventions in Buprenorphine Maintenance Treatment: A Review. AB - OBJECTIVE: Although counseling is a required part of office-based buprenorphine treatment of opioid use disorders, the nature of what constitutes appropriate counseling is unclear and controversial. The authors review the literature on the role, nature, and intensity of behavioral interventions in office-based buprenorphine treatment. METHOD: The authors conducted a review of randomized controlled studies testing the efficacy of adding a behavioral intervention to buprenorphine maintenance treatment. RESULTS: Four key studies showed no benefit from adding a behavioral intervention to buprenorphine plus medical management, and four studies indicated some benefit for specific behavioral interventions, primarily contingency management. The authors examined the findings from the negative trials in the context of six questions: 1) Is buprenorphine that effective? 2) Is medical management that effective? 3) Are behavioral interventions that ineffective in this population? 4) How has research design affected the results of studies of buprenorphine plus behavioral treatment? 5) What do we know about subgroups of patients who do and those who do not seem to benefit from behavioral interventions? 6) What should clinicians aim for in terms of treatment outcome in buprenorphine maintenance? CONCLUSIONS: High-quality medical management may suffice for some patients, but there are few data regarding the types of individuals for whom medical management is sufficient. Physicians should consider a stepped-care model in which patients may begin with relatively nonintensive treatment, with increased intensity for patients who struggle early in treatment. Finally, with 6-month retention rates seldom exceeding 50% and poor outcomes following dropout, we must explore innovative strategies for enhancing retention in buprenorphine treatment. PMID- 27978774 TI - Correction to: Discovery of new heat shock protein 90 inhibitors using virtual co crystallized pharmacophore generation. PMID- 27978773 TI - A longitudinal assessment of miR-122 and GLDH as biomarkers of drug-induced liver injury in the rat. AB - CONTEXT: There is an ongoing search for specific and translational biomarkers of drug-induced liver injury (DILI). MicroRNA-122 (miR-122) has previously shown potential as a sensitive, specific, and translational biomarker of DILI in both rodent, and human studies. OBJECTIVE: To build on previous work within the field, we examined biomarker kinetics in a rat model of acetaminophen (APAP)-induced liver injury to confirm the sensitivity, and specificity of miR-122 and glutamate dehydrogenase (GLDH). MATERIALS AND METHODS: qRT-PCR and a standard enzymatic assay were used for biomarker analysis. RESULTS: Both miR-122 and GLDH were demonstrated to be more readily-detectable biomarkers of APAP-DILI than alanine aminotransferase (ALT). Peak levels for all biomarkers were detected at 2 days after APAP. At day 3, miR-122 had returned to baseline; however, other biomarkers remained elevated between 3 and 4 days. We were also able to demonstrate that, although miR-122 is present in greater quantities in exosome-free form, both exosome-bound and non-vesicle bound miR-122 are released in a similar profile throughout the course of DILI. DISCUSSION AND CONCLUSIONS: Together, this study demonstrates that both GLDH and miR-122 could be used during preclinical drug development as complementary biomarkers to ALT to increase the chance of early detection of hepatotoxicity. PMID- 27978776 TI - Short-course preoperative radiotherapy combined with chemotherapy, delayed surgery and local hyperthermia for rectal cancer: a phase II study. AB - PURPOSE: The aim of this study was to investigate the feasibility of short-course radiotherapy with oral capecitabine, hyperthermia and delayed surgery for neoadjuvant treatment of rectal cancer. METHODS: Patients with clinically staged T2-3N0-2M0 primary rectal cancer were included. All patients received short course 25 Gy in 5 Gy fractions radiotherapy with capecitabine, local hyperthermia and metronidazole. Capecitabine 1000 mg/m2 twice a day was given on days 1-14. Local hyperthermia, 41-45 degrees C for 60 min, was performed on days 3-5. Metronidazole 10 g/m2 was administered per rectum on days 3 and 5. The time interval to surgery was not less than four weeks after neoadjuvant treatment. The primary end-point was pathological complete response (pCR). Secondary end-points included neoadjuvant treatment toxicity, tumour regression, surgical and oncological outcomes. RESULTS: A total of 81 patients were included in the analysis. Ten (12.3%) patients had grade 3 toxicity and one (1.2%) patient had grade 4 toxicity. Sphincter-sparing surgery was performed for 78 (96.3%) patients. There was no postoperative mortality. Postoperative complications occurred in 11 (13.8%) patients. Sixteen (20%) patients had a pCR. The median follow-up was 40.9 months. There were no local recurrences. Nine (11.1%) patients developed distant metastases. Three-year overall survival was 97% and the three year disease-free survival was 85%. CONCLUSIONS: Short-course radiotherapy with chemotherapy, radiosensitizers and delayed surgery is a feasible treatment for rectal cancer and may lead to tumour regression rate comparable with long-course chemoradiation. PMID- 27978777 TI - Optimal weight gain during twin pregnancy in Japanese women with favorable perinatal outcomes. AB - OBJECTIVE: We examined the optimal weight gain in the healthy Japanese women with favorable perinatal outcomes of (dichorionic) twin pregnancy. METHODS: We calculated the average weight gain in the women whose height was 150-164 cm with favorable perinatal outcomes of dichorionic twin pregnancy set for this study. The women were categorized to underweight, normal, overweight and obese based on the pre-pregnancy body mass index (BMI) categories according to the Institute of Medicine (IOM) and the World Health Organization (WHO) body mass index (BMI) cutoffs. RESULTS: The average GWG in the normal-weight women with the favorable perinatal outcomes was 13.9 +/- 3.6 kg. It was significantly different from that in the underweight, overweight and obese women according to the both 2 BMI cutoffs by Student's t-test (p < 0.01). CONCLUSION: There are optimal ranges of weight gain during twin pregnancy based on the BMI classification. PMID- 27978775 TI - Can AMH levels predict the need for increased medication during IVF/ICSI in PCOS women? AB - PURPOSE: To investigate the ability of anti-Mullerian hormone (AMH) to predict the step up of human menopausal gonadotropins (HMG) dose in women with polycystic ovarian syndrome (PCOS) undergoing IVF/ICSI cycles. METHODS: AMH was drawn before ovulation induction in 976 PCOS women scheduled for IVF/ICSI. After all cycles ended, a receiver operating characteristic (ROC) curve analysis was done to investigate the ability of AMH to predict step up of the HMG. RESULTS: The area under the curve (AUC) was 0.820 95%CI (0.792-0.848), and a cutoff value of 4.6 ng/ml (sensitivity 74%, specificity 82%) for AMH was taken (p < 0.01). Cases were divided into two groups retrospectively; group (A) (AMH <=4.6 ng/ml), and group (B) (AMH >4.6 ng/ml). No difference in the mean age (p = 0.147); BMI (p = 0.411), basal FSH (p = 0.221), and starting dose (p = 0.195); however, the dose at which the first response occurred was higher in group (B) (p < 0.01). The total dose and number of days were higher in group (B) (both p < 0.01) irrespective of the PCOS subtype or androgen levels. Severe OHSS was also higher in group (B) (p = 0.026). CONCLUSIONS: PCOS with AMH >4.6 ng/ml are resistant to HMG stimulation, require dose step up during ART cycles, and are at higher risk for severe OHSS. PMID- 27978779 TI - Are changes needed in the content of general practice? PMID- 27978780 TI - Context as a drug: some consequences of placebo research for primary care. AB - OBJECTIVE: On the basis of emerging research evidence, this review aims to discuss the importance of the context surrounding the doctor-patient encounter for the success of treatment. DESIGN AND SETTING: Discussion paper based on placebo-nocebo and pain studies conducted in the western world. MAIN OUTCOME MEASURES: Literature-based theory about impact of communication elements on seriousness of symptoms in clinical practice. RESULTS: The therapeutic outcome seems to be impacted by rituals around a clinical encounter and by the doctor patient communication and relation. A warm, friendly and empathic attitude is crucial in the first contact with the practice and during the consultation as it influences the patient's perceived outcome. It is important to raise positive expectations when discussing the prognosis, conducting treatment and prescribing medications as the effect may be reduced if the physician expresses doubt about the effectiveness of the medication. Additionally, overly focus on side effects in the doctor-patient conversation about proposed treatments seems to influence the magnitude of perceived side effects in the patient. Thus, shared decision making might be a desirable tool for ensuring better expectations in the patient and successful symptom relief. CONCLUSIONS: The context of the doctor-patient interplay matters. Placebo-nocebo research provides strong evidence for this link. The therapeutic context induces biomedical processes in the patient's brain that may enhance or reduce the effects of chosen interventions. The context thus works as a drug, with real effects and side effects. KEY POINTS Increased awareness of the context drug may help GPs alleviate symptoms and better motivate patients for treatment. Treatment is affected by multiple types of context, as also confirmed by placebo-nocebo research. The therapeutic context influences the biomedical processes, which may enhance or reduce intervention effects on symptoms. The impact of context should be considered in daily general practice as it may serve as a drug, with real effects and side effects. PMID- 27978778 TI - Decoding task and stimulus representations in face-responsive cortex. AB - Observers can deliberately attend to some aspects of a face (e.g. emotional expression) while ignoring others. How do internal goals influence representational geometry in face-responsive cortex? Participants watched videos of naturalistic dynamic faces during MRI scanning. We measured multivariate neural response patterns while participants formed an intention to attend to a facial aspect (age, or emotional valence), and then attended to that aspect, and responses to the face's emotional valence, independent of attention. Distinct patterns of response to the two tasks were found while forming the intention, in left fronto-lateral but not face-responsive regions, and while attending to the face, in almost all face-responsive regions. Emotional valence was represented in right posterior superior temporal sulcus and medial prefrontal cortex, but could not be decoded when unattended. Shifting the focus of attention thus alters cortical representation of social information, probably reflecting neural flexibility to optimally integrate goals and perceptual input. PMID- 27978781 TI - Physical activity on prescription (PAP): self-reported physical activity and quality of life in a Swedish primary care population, 2-year follow-up. AB - OBJECTIVE: To study the self-reported level of physical activity (PA) and quality of life (QOL) in patients receiving physical activity on prescription (PAP) for up to 24 months. DESIGN: Observational study conducted in a regular healthcare setting. SETTING: A primary care population in Sweden receiving physical activity on prescription as part of regular care was studied alongside a reference group. SUBJECTS: The group comprised 146 patients receiving PAP at two different primary care locations (n = 96 and 50, respectively). The reference group comprised 58 patients recruited from two different primary care centres in the same region. MAIN OUTCOME MEASUREMENTS: We used two self-report questionnaires - the four level Saltin-Grimby Physical Activity Level Scale (SGPALS) to assess physical activity, and SF-36 to assess QOL. RESULTS: A significant increase in the PA level was found at six and 12 months following PAP, with an ongoing non significant trend at 24 months (p = .09). A clear improvement in QOL was seen during the period. At 24 months, significant and clinically relevant improvements in QOL persisted in four out of eight sub-scale scores (Physical Role Limitation, Bodily Pain, General Health,Vitality) and in one out of two summary scores (Physical Component Summary). CONCLUSION: Patients receiving PAP showed an increased level of self-reported PA at six and 12 months and improved QOL for up to 24 months in several domains. The Swedish PAP method seems to be a feasible method for bringing about changes in physical activity in different patient populations in regular primary healthcare. While increased physical activity (PA) is shown to improve health, the implementation of methods designed to increase activity is still being developed. Key points The present study confirms that the Swedish physical activity on prescription (PAP) method increases the self reported level of PA in the primary care setting at six and 12 months. Furthermore, this study shows that PAP recipients report a clinically relevant long-term improvement in quality of life, persisting for two years post prescription, thus extending earlier findings. These findings have clinical implications for the implementation of PAP in healthcare. PMID- 27978783 TI - In Silico Design of New Inhibitors of Guanine Phosphoribosyltransferase (GPRT) from Giardia lamblia as Antiparasitic Drug Candidates. AB - BACKGROUND: Guanine phosphoribosyltransferase (GPRT) is a very attractive target for the development of new drugs against G. lamblia because of its critical role in the synthesis of DNA and RNA. Herein we report the use of in silico approaches to identify potential G. lamblia GPRT inhibitors. METHODS: Analyses of the binding site of the enzyme accomplished through the use of several methods allowed the construction of a pharmacophore model, which was screened against a database of commercial substances. The resulting retrieved compounds were then screened against GPRT by consensus docking with two different methods, and the top 10% scored compounds had their poses visually inspected. Root Mean Square Deviation (RMSD) values <= 2.0 A were used to define a consensual pose while RMSD values between 2 and 3 A defined a partial consensus. Main toxicity endpoints were predicted through substructural analyses. RESULTS: From the 1,230 compounds retrieved in the pharmacophore-based screening, eleven had their binding modes consensually ascribed by the docking methods, suggesting a better selectivity for the parasite enzyme in comparison to the human counterpart by avoiding steric bumps with a flexible loop in the human enzyme binding site. One compound, ZINC38139588, was predicted to be totally devoid of toxicity, being perhaps the most promising of this series. CONCLUSION: Through rigorously validated docking protocols, we predicted the binding mode of these compounds in the GPRT binding site. The use of a consensus docking strategy yielded more reliable predictions of the binding modes to guide the future biological assays. PMID- 27978782 TI - A primary care lifestyle programme suitable for socioeconomically vulnerable groups - an observational study. AB - OBJECTIVE: To explore whether a primary health care (PHC) health promotion programme reaches and engages socioeconomically vulnerable groups in a community to the same extent as higher socioeconomic groups. DESIGN: Comparison of level of engagement and lifestyle improvements stratified by socioeconomic vulnerability level. SETTING: Hisingen PHC catchment area (130,000 inhabitants) Gothenburg, Sweden. PARTICIPANTS: Men and women aged 18-79, visiting any of the eight public PHC centres during an eight-month period 2007-2008, were presented with a short intervention health questionnaire and offered a health dialogue with a nurse, including a health profile, p-glucose and blood pressure check. Participants were classified according to four socioeconomic vulnerability factors: education, employment, ethnicity and living situation. RESULTS: Out of 3691 participants, 27% had low education (Hisingen community level 23%), 18% were unemployed (community level 22%), and 16% were born outside Scandinavia (community level 22%). At the one-year follow-up, 2121 (57%) attended. At baseline, 3% of the individuals in the sample had three out of four socioeconomic vulnerability factors, 17% had two vulnerability factors, 43% had one vulnerability factor, and 37% had no vulnerability factors. Improved biological markers were seen in all vulnerability groups (1-3) and odds ratios for improvement were significantly higher in the most socioeconomically vulnerable group for smoking and stress compared to the group with no vulnerability factors. CONCLUSION: Socioeconomically vulnerable groups were reached and lifestyle changes were accomplished to the same extent as in the higher socioeconomic groups in a PHC lifestyle intervention programme. KEY POINTS Primary care plays a major part in prevention of chronic diseases. However, non-pharmacological primary and secondary prevention is often less successful, especially concerning socioeconomically vulnerable groups. The health promoting intervention programme "Pro-Health" reached and engaged socioeconomically vulnerable groups. Participants from the socioeconomically vulnerable groups had comparable odds for lifestyle improvements after one year, compared to participants without vulnerability factors. PMID- 27978784 TI - Correlation between Decreased Parasympathetic Activity and Reduced Cerebrovascular Reactivity in Patients with Lacunar Infarct. AB - Reduced cerebrovascular reactivity (CVR) was found in patients with recent lacunar infarct. However, its mechanisms were controversial. The breath holding maneuver as a vasodilatory stimulus is clinically useful for an estimation of cerebrovasomotor reactivity in well co-operative patients. Patients with lacunar infarct have no higher cortical dysfunction and remain well co-operation. The breath holding maneuver is feasible and safe to perform in patients with lacunar infarct. Autonomic nervous system regulates systemic vascular activity. Regulation of autonomic function to cerebrovascular reactivity has been reported in the literature. We examined the correlation between autonomic functions with frequency and nonlinear heart rate variability (HRV) and cerebrovascular reactivity in patients with lacunar infarct by application of breath holding maneuver. Fifteen patients with lacunar infarct (8 women, age 65.6 +/- 13.61) and 16 healthy controls (11 women, age 27.33 +/- 3.85) were continuously monitored at baseline before maneuver (basal phase), during CVR induction (experimental phase) with breath holding maneuver and after maneuver (recovery phase), for arterial blood pressure (ABP), electrocardiography (EKG), mean cerebral blood flow velocity (mCBFV) of middle cerebral arteries (MCA) by transcranial doppler (TCD). The short term-one minute HRV was analyzed from EKG signals for low frequency (LF)/ high frequency (HF) ratio, nonlinear of standard deviation 1 (SD1), standard deviation 2 (SD2), cardiac Sample Entropy (SampEn) and Shannon Entropy. Significant increasing in mCBFV, LF/HF ratio, SD2/SD1, Shannon Entropy and inversely decreasing SampEn during breath holding maneuver compared with baseline were found in both groups (p<0.05). The trend of cerebrovascular reactivity is similar in both groups. However, there were differences of mCBFV, systolic blood pressure (SysBP) in the whole phases (basal, experiment and recovery) between patients and controls (p<0.05). Less scattered signals of SD1 with low value in patient group were illustrated from Poincare (p<0.05). This indicated less degree of parasympathetic drive in the patients compared to the controls. Moreover, significant positive correlation between systolic bloods pressure and mCBFV in patients suggests impact of autonomic control and cerebral blood flow on the patho-physiological mechanism of vasodilatation, triggered by hypercapnia from breath holding maneuver in patients with lacunar infarct. Reduction of cerebrovascular reactivity in patients with lacunar infarct may relate with decreased parasympathetic activity. Further study is required to demonstrate whether these findings mean mechanisms of lacunar infarct or the effect of hypertensive response. PMID- 27978785 TI - Five Pediatric Cancers - Update on Genetic Implications. AB - Pediatric cancer has undergone significant improvements in survival over the past several decades, in part due to a better understanding of the underlying genetic aberrations of each oncologic diagnosis, which has allowed for more effective targeted therapies. Pediatric brain tumors, leukemia, lymphoma, Wilms tumor, and retinoblastoma are exemplary pediatric cancers that each has specific epidemiology regarding children at risk as well as characteristic associated genetic lesions. These genetic features are more commonly being used to provide risk stratification, as well as to identify novel pathways for targeted therapy. With these advances, the overall survival of pediatric cancers continues to be improved. PMID- 27978786 TI - The Price of the Successful Treatment of Pediatric Malignancies. AB - Recent improvements in therapy of children with cancer have resulted in an increase in cure rates which lead to long-term survivorship. Assessment of short- and long-term complications and late effects of cancer therapies is accomplished by pediatric oncologists and multi-disciplinary team, including continuation of care from pediatric to adult primary care. The late complications of cancer treatment include growth and development, reproduction, vital organ function (cardiac, pulmonary, renal, gastrointestinal), dental, ocular, esthetic sequellae, and second neoplasms (benign or malignant), which are cited as the second most frequent cause of death in the Children Cancer Survivors Study cohort. Long-term follow-up guidelines for survivors of childhood cancers has been established by international specialists, the main aim is to decrease severe late complications by individualizing prevention care and treatment. Preventive measures include reduction of radiotherapy doses, or omission, introduction of new radiotherapy techniques, decrease doses of alkylating drugs, and anthracyclines, cardio protectors, fertility preservations guidelines, new surgical techniques, introduction of biological treatments. The multidisciplinary team monitors certain treatments including risk-based care not only of the tumor, but also premorbid conditions, and health behaviors. More comprehensive and high quality evaluations of survivorship programs are needed, for long term outcome, quality of life and psychosocial support. PMID- 27978787 TI - Synthesis and antiproliferative activity of new pyrazolo[3,4-c]pyridines. AB - BACKGROUND: Several pyrazolopyridines possess promising pharmacological activities, mainly attributed to their antagonistic nature towards the natural purines in many biological processes. Cytotoxicity and anticancer potential of this class of compounds is mainly related to induction of apoptotic cell death and inhibition of protein kinases. OBJECTIVES: This prompted us to design, synthesize and study the antiproliferative activity of a number of new 3,7 disubstituted pyrazolo[3,4-c] pyridines. METHODS: 2-amino-3-nitro-4-picoline was suitably modified and ring closed to provide 7-chloropyrazolo[3,4-c]pyridine. Iodination of this derivative was followed by the insertion of 3-aryl substituents via Suzuki coupling and aromatic nucleophilic substitution of the 7 chloro group by the appropriate amines. The antiproliferative activity of the target compounds was evaluated against A2058 melanoma, DU145 and PC3 prostate cancer cell lines. Flow cytometric analysis of DNA content for selected compounds was performed, after incubation of exponentially growing PC-3 cells. RESULTS: Eighteen new pyrazolopyridines have been synthesized and fully characterized. Among them, the majority of the 3-(3-fluorophenyl) derivatives exhibit interesting antiproliferative activity, with IC50 values in the range of 3.0-16.0 MUM and present reasonable SARs. Cell-cycle perturbations revealed that the most active derivative 12a blocks cells at the S phase. CONCLUSION: 3-(3-Fluorophenyl) 7-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-c]pyridine (12a) and the corresponding 1-(4-methoxybenzyl)- analogue (11a) possess interesting antiproliferative activity against all cell lines tested. Derivatives bearing this substitution pattern can be considered as useful leads for further biological evaluation. PMID- 27978788 TI - Polymer Composite Containing Carbon Nanotubes and their Applications. AB - BACKGROUND: Carbon nanotubes (CNTs) are attractive nanostructures in this regard, primarily due to their high aspect ratio coupled with high thermal and electrical conductivities. Consequently, CNT polymer composites have been extensively investigated for various applications, owing to their light weight and processibility. However, there have been several issues affecting the utilization of CNTs, such as aggregation (bundling) which leads to a non-uniform dispersion and poor interfacial bonding of the CNTs with the polymer, resulting in variation in composite performance, along with the additional issue of high cost of CNTs. DESCRIPTION: In this article, recent research and patents for polymer composites containing carbon nanomaterial are presented and summarized. In addition, a rationale for optimally designed carbon nanotube polymer composites and their applications are suggested. Above the electrical percolation threshold, a transition from insulator to conductor occurs. The percolation threshold values of CNT composite are dependent on filler shape, intrinsic properties of filler, type of polymer, CNT dispersion condition and so on. Different values of percolation threshold CNT polymer composites have been summarized. The difference in percolation threshold and conductivity of CNT composites could be explained by the degree of effective interactions between nanotubes and polymer matrix. The reaction between surface functional groups of CNTs and polymer could contribute to better dispersion of CNTs in polymer matrix. Consequently, it increased the number of electrical networks of CNTs in polymer, resulting in an enhancement of composite conductivity. In addition, to exfoliate nanotubes from heavy bundles, ultrasonication with proper solvent and three roll milling processes were used. Potential reactions of covalent bonding between functionalized CNTs and polymer were suggested based on the above rationale. CONCLUSION: Through the use of CNT functionalization, high aspect ratio CNTs, and proper fabrication, uniform dispersion of nanotubes in polymer can be achieved leading to considerable improvement in electrical conductivity and electromagnetic interference (EMI) shielding properties. PMID- 27978789 TI - Heat Shock Proteins: Therapeutic Perspectives in Inflammatory Disorders. AB - BACKGROUND: Heat shock proteins (HSPs) are highly conserved proteins present in all kingdoms of organisms. These are expressed under stress conditions in order to protect the cells from injuries. The stress induced protein denaturation is rectified by refolding and remodelling. These are intracellular proteins but can be present in extracellular fluid like serum of the patients suffering from trauma, autoimmune and inflammatory disorders. Virtually in most inflammatory diseases, immune response towards HSPs is developed. OBJECTIVE: The present review expedites the role of HSPs in inflammatory process and associated disorders, mainly in context to HSP70 and HSP90. METHOD: Commencing a thorough survey of the literature and patents available on HSPs and their role in the process of inflammation, from the authentic published resources available on Medline, Pubmed, Pubmed Central, Science Direct and other scientific databases; the information retrieved has been compiled and analyzed. RESULTS: HSPs modulate the process of inflammation by producing anti-inflammatory cytokines in chronic inflammatory disease. HSPs mediated expression of IL10 contributes in anti inflammatory role via TLR2 and TLR4-dependent mechanisms. Necroptosis, a caspase independent programmed apoptosis plays an important role in progression of several inflammatory disorders and its major components MLKL and RIPK-1 are the clients of HSP. Necroptosis is also involved in exposure of several damageassociated molecular patterns (DAMPs) including HSPs in extracellular environment leading to inflammation. Endocytosed or intracellular HSP70, is presented by MHC-II molecules and in absence of proper co stimulation, it lead to expansion of tolerogenic or regulatory T cells (Tregs) responses, which have inflammation suppressive activity by virtue of production of anti-inflammatory cytokines, suppression or killing of effector T cells or bringing the APC into tolerogenic state. HSP induced Tregs play an important role in combating autoimmunity and inflammation. CONCLUSION: Present review gives an insight towards the cause of inflammation and an account of different HSPs contributing various inflammatory disorders viz. inflammatory bowel disease (IBD), intestinal inflammation, atherosclerosis, rheumatoid arthritis (RA), multiple sclerosis etc. The importance of HSPs in handling inflammatory disorders has been depicted in recent patents also. PMID- 27978790 TI - Recent Trends in Nanotechnology-Based Drugs and Formulations for Targeted Therapeutic Delivery. AB - BACKGROUND: In the recent past, a wider spectrum of nanotechnologybased drugs or drug-loaded devices and systems has been engineered and investigated with high interests. OBJECTIVE: The key objective is to help for an enhanced/better quality of patient life in a secure way by avoiding/limiting drug abuse, or severe adverse effects of some in practice traditional therapies. METHOD: Various methodological approaches including in vitro, in vivo, and ex vivo techniques have been exploited, so far. Among them, nanoparticles-based therapeutic agents are of supreme interests for an enhanced and efficient delivery in the current biomedical sector of the modern world. RESULTS: The development of new types of novel, effective and highly reliable therapeutic drug delivery system (DDS) for multipurpose applications is essential and a core demand to tackle many human health related diseases. In this context, nanotechnology-based several advanced DDS have been engineered with novel characteristics for biomedical, pharmaceutical and cosmeceutical applications that include but not limited to the enhanced/improved bioactivity, bioavailability, drug efficacy, targeted delivery, and therapeutically safer with an extra advantage of overcoming demerits of traditional drug formulations/designs. This review work is focused on recent trends/advances in nanotechnology-based drugs and formulations designed for targeted therapeutic delivery. Moreover, information is also reviewed and given from recent patents and summarized or illustrated diagrammatically to depict a better understanding. Recent patents covering various nanotechnology-based approaches for several applications have also been reviewed. CONCLUSION: The drug loaded nanoparticles are among versatile candidates with multifunctional characteristics for potential applications in biomedical, and tissue engineering sector. PMID- 27978791 TI - Exercise Prevents Cognitive Function Decline and Demyelination in the White Matter of APP/PS1 Transgenic AD Mice. AB - BACKGROUND: Whether exercise could delay the cognitive function decline and structural changes in Alzheimer's disease (AD) are not fully understood. METHODS: 6-month-old male APP/PS1 double transgenic mice ran four months and then the effects of exercise on the cognitive function and the white matter of AD were investigated. RESULTS: The mean escape latency of the excercised group was significantly shortened when compared to that of the sedentary group. The percentage of time in target quadrant and the target zone frequency of the exercised group were significantly increased when compared to the sedentary group. The white matter volume, the myelinated fiber volume and axon volume in the white matter of the exercised group were significantly increased when compared to the sedentary group. CONCLUSION: Exercise could improve the cognitive function in AD, and the effects of exercise on the white matter of AD might be one of the structural bases for the protective effect of exercise on the cognitive function of AD. The exercise-induced protection of the white matter in AD might be due to the fact that the exercise prevented the demyelination of the myelinated fibers in the white matter of AD. PMID- 27978792 TI - Predicting Stability of Mild Cognitive Impairment (MCI): Findings of a Community Based Sample. AB - BACKGROUND: Mild Cognitive Impairment (MCI) is a risk factor for Alzheimer's disease (AD) and other forms of dementia. However, much heterogeneity concerning neuropsychological measures, prevalence and progression rates impedes distinct diagnosis and treatment implications. OBJECTIVE: Aim of the present study was the identification of specific tests providing a high certainty for stable MCI and factors that precipitate instability of MCI in a community based sample examined at three measurement points. METHOD: 130 participants were tested annually with an extensive test battery including measures of memory, language, executive functions, intelligence and dementia screening tests. Exclusion criteria at baseline comprised, severe cognitive deficits (e.g. diagnosis of dementia, psychiatric or neurological disease). Possible predictors for stability or instability of MCI-diagnosis were analyzed using Regression and Receiver Operating Characteristic (ROC) curve analysis. Age, IQ and APOE status were tested for moderating effects on the interaction of test performances and group membership. RESULTS: A high prevalence of MCI (49%) was observed at baseline with a reversion rate of 18% after two years. Stability of MCI was related to performances in four measures (VLMT: delayed recall, CERAD: recall drawings, CERAD: Boston Naming Test, Benton Visual Retention Test: number of mistakes). Conversion to MCI is associated with language functions. Reversion to 'normal' was primarily predicted by single domain impairment. There was no significant influence of demographic, medical or genetic variables. CONCLUSION: The results highlight the role of repeated measurements for a reliable identification of functional neuropsychological predictors and better diagnostic reliability. In cases of high uncertainty close monitoring over time is needed in order of estimating outcome. PMID- 27978793 TI - Generation of Alzheimer's Disease Transgenic Zebrafish Expressing Human APP Mutation Under Control of Zebrafish appb Promotor. AB - BACKGROUND: Amyloid peptide precursor (APP) as the precursor protein of peptide betaamyloid (beta-amyloid, Abeta), which is thought to play a central role in the pathogenesis of Alzheimer's disease (AD), also has an important effect on the development and progression of AD. Through knocking-in APP gene in animals, numerous transgenic AD models have been set up for the investigation of the mechanisms behind AD pathogenesis and the screening of anti-AD drugs. However, there are some limitations to these models and here is a need for such an AD model that is economic as well as has satisfactory genetic homology with human. METHODS: We generated a new AD transgenic model by knocking a mutant human APP gene (APPsw) in zebrafish with appb promoter of zebrafish to drive the expression of APPsw. RESULTS: Fluorescent image and immunochemistry stain showed and RT-PCR and western blot assay confirmed that APPsw was successfully expressed in the brain, heart, eyes and vasculature of the transgenic zebrafish. Behavioral observation demonstrated that the transgenic zebrafish had AD-like symptoms. Histopathological observation found that there were cerebral beta-amyloidosis and angiopathy (CAA), which induced neuron loss and enlarged pervascular space. CONCLUSION: These results suggest that APPsw transgenic zebrafish well simulate the pathological characters of AD and can be used as an economic AD transgenic model. Furthermore, the new model suggested that APP can express in microvasculatures and cause the Abeta generation and deposition in cerebral vessel which further destroys cerebral vascular structure resulting in the development and/or the progress of AD. PMID- 27978794 TI - Mitochondrial Dysfunctions in Bipolar Disorder: Effect of the Disease and Pharmacotherapy. AB - Exact pathophysiological mechanisms of bipolar disorder have not been sufficiently clarified. We review the evidence of mitochondrial dysfunctions on the relation between both disease and pharmacotherapy. Mitochondria produce the most of energy-rich molecules of adenosine triphosphate (ATP), apart from energy production they are involved in other functions: regulation of free radicals, antioxidant defenses, lipid peroxidation, calcium metabolism and participate in the intrinsic pathway of apoptosis. According to increasing evidence dysfunctions of mitochondria are associated with affective disorders, a hypothesis of impaired mitochondrial functions has been proposed in bipolar disorder pathogenesis. Mitochondrial DNA mutations and/or polymorphisms, impaired phospholipid metabolism and glycolytic shift, decrease in ATP production, increased oxidative stress and changes of intracellular calcium are concerned in mood disorders and effects of mood stabilizers. Recent studies have also provided data about the positive effects of chronic treatment by mood stabilizers on mitochondrial functions. PMID- 27978795 TI - Desmoteplase for Acute Ischemic Stroke: A Systematic Review and Metaanalysis of Randomized Controlled Trials. AB - INTRODUCTION: There is an unmet need to develop better treatments for acute ischemic stroke (AIS). Desmoteplase is a vampire bat saliva-derived analogue of human tissue plasminogen activator. It has higher fibrin selectivity and a longer half-life, compared to alteplase. We performed this metaanalysis to investigate the safety and efficacy of desmoteplase in AIS. METHOD: A computer literature search (PubMed, EMBASE, CENTRAL, Scopus, Web of science, and clinicaltrials.gov) was carried out. Data were extracted from eligible records and analyzed using RevMan software (version 5.3 for windows). Safety and efficacy endpoints were pooled as odds ratios (ORs) for the two groups. RESULT: Five randomized trials (n=821 patients) were pooled in the final analysis. The overall effect size favored desmoteplase over placebo in terms of reperfusion 4 to 24 hours posttreatment (OR 1.49, 95% CI [1.02, 2.19]). However, the pooled effect size did not favor either of the two groups in terms of good clinical outcome at 90 days (OR 1.16, 95% CI [0.86, 1.55]). Neither of the primary safety outcomes differed significantly between the two groups (symptomatic intracranial hemorrhage: OR 1.29, 95% CI [0.53, 3.16] and mortality within 90 days: OR 1.20, 95% CI [0.73, 1.97]). CONCLUSION: Current evidence suggests a favorable reperfusion effect for desmoteplase within 3 to 9 hours after AIS. Further large randomized trials, using a moderate dose between 90 ug/kg and 125 ug/kg, are required to translate this successful reperfusion into better clinical and quality of life outcomes for AIS patients. PMID- 27978796 TI - Neuropathic Pain and Lung Delivery of Nanoparticulate Drugs: An Emerging Novel Therapeutic Strategy. AB - Neuropathic pain is a chronic neurological disorder affecting millions of people around the world. The currently available pharmacologic agents for the treatment of neuropathic pain have limited efficacy and are associated with dose related unwanted adverse effects. Due to the limited access of drug molecules across blood-brain barrier, a small percentage of drug that is administered systematically, reaches the central nervous system in active form. These therapeutic agents also require daily treatment regimen that is inconvenient and potentially impact patient compliance. Application of nanoparticulate drugs for enhanced delivery system has been explored extensively in the last decades. Pulmonary delivery of nanomedicines for the management of various diseases has become an emerging treatment strategy that ensures the targeted delivery of drugs both for systemic and local effects with low dose and limited adverse effects. To the best of our knowledge, there are no inhaled drug products available on market for the treatment of neuropathic pain. The advantages of delivering therapeutics into deep lungs include non-invasive drug delivery, higher bioavailability with low dose, lower systemic toxicity, and potentially greater blood-brain barrier penetration. This review discusses and highlights the important issues on the application of emerging nanoparticulate lung delivery of drugs for the effective treatment of neuropathic pain. PMID- 27978797 TI - Prediction of Chemical Multi-target Profiles and Adverse Outcomes with Systems Toxicology. AB - The field of systems biology, termed systems toxicology when applied to the characterization of adverse outcomes following chemical exposure, seeks to develop biological networks to explain phenotypic responses. Ideally, these are qualitatively and quantitatively similar to the actual network of biological entities that have functional consequences in living organisms. In this review, computational tools for predicting chemicalprotein interactions of multi-target compounds are outlined. Then, we discuss how the methods of systems toxicology currently draw on those interactions to predict resulting adverse outcomes which include diseases, adverse drug reactions, and toxic endpoints. These methods are useful for predicting the safety of drugs in drug development and the toxicity of environmental chemicals (ECs) in environmental toxicology. PMID- 27978799 TI - Topoisomerases and Anthracyclines: Recent Advances and Perspectives in Anticancer Therapy and Prevention of Cardiotoxicity. AB - Topoisomerases are ubiquitous enzymes involved in maintaining genomic stability of the cell by regulating the over- or underwinding of DNA strands. Besides their customary functions, topoisomerases are important cellular targets of widely used anticancer drugs. In particular, topoisomerase IIalpha (Top2alpha) has been postulated as the primary molecular target of anthracycline's anticancer activity, whereas topoisomerase IIbeta (Top2beta), the only Top2 present in heart tissue, seems to be involved in the development of anthracycline-induced cardiotoxicity. Noteworthy, cardiotoxicity is the most frequent adverse effect of both conventional and modern anticancer targeted therapy, representing the leading noncancer-related cause of morbidity and mortality in long-term survivors. The molecular mechanisms of anthracyclineinduced cardiotoxicity have been investigated for decades and, despite the numerous mechanistic hypotheses put forward, its aetiology and pathogenesis still remain controversial. This review is aimed at focusing on the double edge sword of topoisomerase anthracycline interaction, and, in particular, on the potential role of topoisomerases in anthracyclines anticancer activity as well as in the pathogenesis of anthracycline-induced cardiotoxicity. PMID- 27978801 TI - Visual Sexual Stimulation and Erection, a Brief Review with New fMRI Data. AB - This review examines brain sites involved in sexual stimulation. New data on brain activation sites in individuals having erections concomitant with visual erotic stimulation were documented. The activation was chiefly at the midbrain around the cerebral peduncle, and in the pons centering on the tegmentum, they are indicated by blood oxygenation level dependent (BOLD) images captured by functional magnetic resonance imaging (fMRI). The cerebellum and inferior temporal lobe were activated more extensively in individuals viewing pornographic movie with a concomitant erection than those without. Similarly, individuals with erection had activations in the midbrain and pons, while drug addicts had neither erections nor any of these brainstem active sites. From our observation in the new data, we deduced three possible transmitters might be involved in erection: i) cholinergic neurons forming descending pathways and associated with motor activity ii) gamma-aminobutyric acid (GABA), directly or indirectly via decreasing pathways, modulating autonomic vascular responses in the penile vasculature causing the filling of blood iii) GABA decreases to stimulate dopamine increase in ventral tegmentum of the brain, leading to euphoric responses. PMID- 27978798 TI - Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions. AB - Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities of ICL agents, in particular platinum-based therapies, establish a "molecular landscape," i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with DDR-targeting agents. If the molecular landscape created by platinum-based agents could be better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed for the use of DDR-targeting therapies in combination/maintenance protocols for specific, clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase (PARP) inhibitors are examples of DDR-targeting therapies that could potentially increase the DNA damage and replication stress imposed by platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies have shown that the use of PARP inhibitors together with platinum-based agents is a promising therapy strategy for ovarian cancer patients with "BRCAness", i.e., a phenotypic characteristic of tumors that not only can involve loss-of-function mutations in either BRCA1 or BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis of these promising results, additional mechanism-based studies focused on the use of various DDR-targeting therapies in combination with platinum-based agents should be considered. This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that establish a molecular landscape that can be further exploited therapeutically; (2) multiple points of potential intervention after ICL agent-induced crosslinking that further predispose to cell death and can be incorporated into a systematic, therapeutic rationale for combination/ maintenance therapy using DDR-targeting agents; and (3) available agents that can be considered for use in combination/maintenance clinical protocols with platinum-based agents for patients with advanced malignancies. PMID- 27978800 TI - Comparison of Clinical Outcomes Between Genders Following Antihypertensive Therapy: A Meta-Analysis. AB - BACKGROUND: Numerous studies have reported sex and gender differences in the prevalence and treatment of cardiovascular diseases. However, sex differences in the therapy of hypertension have not been completely examined. OBJECTIVE: To estimate the gender-specific dissimilarity in outcomes among patients following antihypertensive treatment, using a meta-analysis of available studies. METHODS: A systematic literature search in Medline and SCOPUS databases was performed from January 1990 to January 2015 to find studies assessing clinical outcomes in male and female subjects after hypertension treatment, separately. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. RESULTS: the analysis included 10 studies with 16 treatment arms. Outcomes were found to be significantly more frequent in men then in women (odds ratio [OR]: 1.25, 95% confidence interval [CI]: 1.17, 1.33, p < 0.001; I2:40.17%), and this result was robust and independent. Random-effects meta-regression showed no association of outcomes with treatment duration and baseline levels. CONCLUSION: The present meta-analysis demonstrates that clinical outcomes are more frequent in men compared with women after the same treatment of hypertension. Numerous reasons, including disparities in compliance, age, and intrinsic higher risk in male, contribute to justify these findings. PMID- 27978803 TI - Magnesium in pain research: state of the art. AB - Magnesium has been shown to produce an antinociceptive effect on animal models of neuropathic and inflammatory pain. It has also been shown to exert an analgesic effect on humans in conditions presenting acute (postoperative pain) and chronic (neuropathic) pain. As it is known that magnesium is a physiological antagonist of the N-methyl-D-aspartate (NMDA) receptor ion channel, and that the NMDA receptor plays a key role in central sensitization, the primary mechanism through which magnesium produces its analgesic effect is believed to be blockade of the NMDA receptor in the spinal cord. In addition, magnesium blocks calcium channels and modulates potassium channels. The activation of the nitric oxide (NO) pathway could have an important role in the antinociceptive effects of systemic magnesium sulfate in the somatic, but not in the visceral model of inflammatory pain. Although it is known for some time that intramuscular, intravenous and subcutaneous injections of magnesium sulfate in humans, and intraperitoneal injection in rodents produce local pain sensation, the mechanism of this action was elucidated only recently. It was demonstrated that subcutaneous injection of an isotonic, pH-adjusted (7.4) solution of magnesium sulfate (6.2%) to rats produces local peripheral pain via activation of peripheral TRPA1, TRPV1, TRPV4 and NMDA receptors and peripheral production of NO. In animal models of pain, magnesium has been shown to exert both antinociceptive and pronociceptive effects by acting on different ion channels and NO pathways, however, the precise mechanisms remain to be elucidated. PMID- 27978802 TI - Novel Antibacterial Compounds and their Drug Targets - Successes and Challenges. AB - Infectious diseases are one of the most important and urgent health problems in the world. According to the World Health Organization (WHO) statistics, infectious and parasitic diseases are a cause of about 16% of all deaths worldwide and over 40% of deaths in Africa. A considerable progress that has been made during last hundred years in the fight against infectious diseases, in particular bacterial infections, can be attributed mainly to three factors: (1) the general improvement of living conditions, in particular sanitation; (2) development of vaccines and (3) development of efficient antibacterial drugs. Although considerable progress in reduction of the number of cases of bacterial infections, especially in lethal cases, has been made, continued cases and outbreaks of these diseases persist, which is caused by different contributing factors. Indeed, during last sixty years antibacterial drugs were used against various infectious diseases caused by bacterial pathogens with an undoubtable success. The most fruitful period for antibiotic development lasted from 40's to 60's of the last century and resulted in the majority of antibiotics currently on the market, which were obtained by screening actinomycetes derived from soil. Although the market for antibacterial drugs is nowadays greater than 25 billion US dollars per year, novel antibacterial drugs are still demanded due to developed resistance of many pathogenic bacteria against current antibiotics. In the last five years, one can observe a dramatic increase in cases of resistant bacteria strains (e.g. Klebsiella pneumoniae and E. coli) which are responsible for difficult to treat pneumonia and infections of urinary tract. The development of resistant bacteria strains is a side effect of antibiotic application for treatment: the infections become untreatable as a result of the existence of antibiotic-tolerant persisters. In this review, we discuss the challenges in antibacterial drug discovery, including the molecular basis of drug resistance, drug targets for novel antibacterial drugs, and new compounds (since year 2010) from different chemical classes with antibacterial activity, focusing on structure-activity relationships. PMID- 27978804 TI - Cyclodextrins Based Electrochemical Sensors for Biomedical and Pharmaceutical Analysis. AB - Electrochemical sensors are very convenient devices, as they may be used in a lot of fields starting from the food industry to environmental monitoring and medical diagnostics. They offer the values of simple design, reversible and reproducible measurements, as well as ensuring precise and accurate analytical information. Compared with other methods, electrochemical sensors are relatively simple as well as having low costs, which has led to intensive development, especially in the field of medicine and pharmaceuticals within the last decade. Recently, the number of publications covering the determination of aminoacids, dopamine, cholesterol, uric acid, biomarkers, vitamins and other pharmaceutical and biological compounds has significantly increased. Many possible types of such sensors and biosensors have been proposed: owing to the kind of the detection potentiometric voltametric, amperometry, and the materials that can be used for, e.g. designing molecular architecture of the electrode/solution interface, carbon paste, carbon nanotubes, glass carbon, graphite, graphene, PVC, conductive polymers and/or nanoparticles. The active compounds which provide the complex formation with analyte (in the case of non-current techniques) or activate biomolecules electrochemically by particle recognition and selective preconcentration of analyte on the electrode surface (in the case of current techniques) are the most recently used cyclodextrins. These macrocyclic compounds have the ability to interact with a large diversity of guest particles to form complexes of the type of guest host, for example, with particles from drugs, biomolecules, through their hydrophilic outer surface and lipophilic inner cavities. Cyclodextrins have been the subject of frequent electrochemical studies that focused mostly on both their interactions in a solid state and in solution. The process of preparing of CDs modified electrodes would, consequently, open new avenues for new electrochemical sensors and, therefore, widen their use in biomedical and drug analysis. This review presents information on manufacturing techniques and performances of these sensors and biosensors. The opportunities for these sensors to carry out biomedical and pharmaceutical researches are demonstrated. PMID- 27978805 TI - Alzheimer's disease: A review from the pathophysiology to diagnosis, new perspectives for pharmacological treatment. AB - Dementia is characterized by the impairment of cognition and behavior of people over 65 years. Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the world, as approximately 47 million people are affected by this disease and the tendency is that this number will increased 62% by 2030. Two microscopic features assist in the characterization of the disease, the amyloid plaques and neurofibrillary agglomerates. All these factors are responsible for the slow and gradual deterioration of memory that affect language, personality or cognitive control. For the AD diagnosis, neuropsychological tests are performed in different spheres of cognitive functions but since not all cognitive functions may be affected, cerebrospinal fluid biomarkers are used along with these tests. To date, cholinesterase inhibitors are used as treatment, they are the only drugs that have shown significant improvements in the cognitive functions of AD patients. Despite the proven effectiveness of cholinesterase inhibitors, an AD carrier, even while being treated, is continually subjected to progressive degeneration of the neuronal tissue. For this reason, other biochemical pathways associated with the pathophysiology of AD have been explored as alternatives to the treatment of this condition such as inhibition of beta-secretase and glycogen synthase kinase-3beta. The present study aims to conduct a review of the epidemiology, pathophysiology, symptoms, diagnosis and treatment of Alzheimer's disease, emphasizing the research and development of new therapeutic approaches. PMID- 27978806 TI - Human host defense peptides - role in maintaining human homeostasis and pathological processes. AB - The human body expresses over 100 host defense peptides and proteins (antimicrobial peptides, AMPs). The compounds are produced by tissues and mucosal surfaces, e.g. skin, the digestive and urinary tract, the ocular surface and neutrophils, and are believed to play a crucial role in defense from microbial infection. They are considered to protect the human body against microbial infections due to their antimicrobial and immunomodulatory activities. As well as having strong antimicrobial activity towards a broad spectrum of microorganisms, AMPs have been found to interact with neutrophils, monocytes and T-cells and promote the production of cytokines. They also neutralize the action of lipopolysaccharide (LPS) and play a crucial role in wound healing processes. In response to the microbial stimuli the AMPs are released in order to fight the infection, however there are several microorganisms evading the human immune system by downregulation of AMPs. Decreased or elevated expression of AMPs is associated also with several non-infectious diseases. Despite numerous studies conducted in the field of AMPs over the last few decades, their exact role in physiological and pathological processes remains to be explained. In this paper, we review the most significant human AMPs and their potential roles in maintaining human homeostasis as well as in pathological processes. PMID- 27978807 TI - Oxidative stress & FoxO transcription factors in cardiovascular aging. AB - BACKGROUND: Aging is a phenomenon in which the functions, adaptability and resistance of an organism decrease over time. With the global population aging at an accelerating pace, delaying the negative aspects of aging is vital for advancing the human life span and quality of life. The aging of multiple organs can lead to many diseases, and the cardiovascular system is no exception. Indeed, one of the primary risk factors for cardiovascular diseases is aging because of altered cardiovascular metabolism resulting in metabolic disorders and inflammation. METHODS: We attempted an organized search of bibliographic databases for peer-reviewed research papers by searching featured reviews using inclusion/exclusion criteria. The collected papers were assessed by standard tools for quality control. RESULTS: Forty-six papers were admitted to the review, and most papers featured recent research results (44) and reviewed the research field (8). We discuss these papers along with the recent progress of our work. In this review, we examine the relationship of oxidative stress with aging and the FoxO proteins, which are essential anti-aging factors in the cardiovascular system. CONCLUSION: The observations of this review suggest that anti-aging signaling mediated by FoxO proteins is important for understanding cardiovascular aging and the design of medicinal approaches. PMID- 27978808 TI - Molecular, Cellular and Pharmaceutical Aspects of Biomaterials in Dentistry and Oral and Maxillofacial Surgery. An Internationalization of Higher Education and Research Perspective. AB - In dentistry and oral and maxillofacial surgery, the development of implantable biomaterials and the understanding of their molecular, cellular and pharmaceutical aspects are currently major fields of research and education, with a considerable impact on the daily clinical practice and the evolution of therapeutic strategies. In the era of globalized economy of knowledge and science, this scientific domain needs the development of global cooperation and a paradigm evolution in the organizational culture of the dental sciences and related dental industry. Despite political pressure and theoretical efforts, the internationalization of higher education and research today in dentistry and biomaterials remains in general quite superficial and mostly dependent on the efforts of a few leaders of internationalization working through their personal networks, as it was assessed through the FAST scores (Fast Assessment Screening Test) calculated in various dental schools and groups worldwide through the ISAIAS program (Intercultural Sensitivity Academic Index &Advanced Standards). Cooperation in a multipolar multicultural community requires the development of strong intercultural competences, and this process remains limited in most institutions. These limits of international scientific cooperation can be observed through different markers, particularly the difficult and limited production of ISO standards (International Organization for Standardization) and the relatively low SCIENTI scores (Scientific Cooperation Internationalization Effort &Network Test &Index) of the specialized dental literature, particularly in comparison to the most significant medical literature. However, as an analytical tool to assess the scientific international cooperation effort between fields and periods, the SCIENTI screening system also highlighted a significant increase of the internationalization effort in the last years in the best dental biomaterials publications. Finally, an internationalization of higher education and research perspective is a very important approach to assess the evolution of the dental biomaterial science and highlights very clearly the future endeavors of this field, particularly the impact and interferences of private entities and companies in the development of this corpus of knowledge. It also reveals that the concept of independent not-for-profit Cooperation Internationalization Effort Literature (CIEL), in the various informal models that can be found worldwide around diverse leaderships, is the best perspective for a better science and understanding of molecular, cellular and pharmaceutical aspects of biomaterials in dentistry and oral and maxillofacial surgery. PMID- 27978809 TI - Antibacterial Combination of Oleoresin from Copaifera multijuga Hayne and Biogenic Silver Nanoparticles Towards Streptococcus agalactiae. AB - BACKGROUND: Streptococcus agalactiae (group B Streptococcus - GBS) remains a leading cause of neonatal infections and an important cause of invasive infections in adults with underlying conditions. METHODS: This study evaluated for the first time the effect of an oleoresin collected from Copaifera multijuga Hayne (copaiba oil) alone or in combination with silver nanoparticles produced by green synthesis using Fusarium oxysporum (AgNPbio) against planktonic and sessile cells of GBS isolated from colonized women. RESULTS: Copaiba oil showed a dose dependent bactericidal activity against planktonic GBS strains, including those resistant to erythromycin and/or clindamycin. Scanning and transmission electron microscopy of GBS treated with copaiba oil revealed morphological and ultrastructural alterations, displaying disruption of the cell wall and decreased electron density due to leakage of cytoplasmic content. Copaiba oil also exhibited antibacterial activity against biofilms of GBS strains, inhibiting their formation as well as the viability of mature biofilms. In addition, the combination of copaiba oil with AgNPbio resulted in a synergistic effect against planktonic cells and biofilm formation, reducing the minimal inhibitory concentration values of both compounds. No hemolytic activity was detected for both compounds. CONCLUSION: These results indicate the potential of copaiba oil, alone or in combination with AgNPbio, for the development of new alternative strategies for controlling GBS infections. PMID- 27978810 TI - Asymptomatic hyperuricemia is not an independent risk factor for cardiovascular events or overall mortality in the general population of the Busselton Health Study. AB - BACKGROUND: To investigate the impact of uric acid (UA) levels on cardiovascular disease and mortality at a population level. METHODS: Prospective analysis of baseline serum UA measurement and 15 year follow-up data from the Busselton Health Survey (n = 4,173), stratified by existence or absence of baseline cardiovascular disease. Outcomes were ascertained from state-wide hospital discharge and mortality registries. Cox regression produced adjusted hazard ratios (HR) for UA level as continuous and categorical (low, medium, high) predictor for cardiovascular events (CVE) and mortality. Gout was defined as a patient's self-reported history of gout. RESULTS: After age and gender adjustment each 0.1 mmol/L rise in UA level was associated with increased mortality (HR 1.19, CI 1.04-1.36), cardiovascular mortality (HR 1.27, CI 1.03-1.57) and first CVE (HR 1.28, CI 1.13-1.44) in participants with no history of CVE. Adjustment for behavioural and biomedical risk factors of cardiovascular disease attenuated these associations. Results for participants with a history of CVE and for a subset of 1,632 participants using UA levels (2-6 measurements) averaged over time were similar. The overall prevalence of hyperuricemia was 10.7%. When stratified by history of gout, UA level was significantly associated with increased risk of cardiovascular mortality only in participants with a history of CVE (HR 2.13, CI 1.03-4.43). CONCLUSIONS: Despite the considerable prevalence of hyperuricemia in 10.7% of the population, single or time averaged measures of UA were not independently predictive of incident cardiovascular disease or mortality. Hyperuricemia did associate with an increased risk of cardiovascular death only in participants with gout and existing cardiovascular disease. PMID- 27978811 TI - Disenrollment from general practitioners among chronic patients: a register-based longitudinal study of Norwegian claims data. AB - BACKGROUND: Norwegian general practitioners (GPs) consult on a variety of conditions with a mix of patient types. Patients with chronic diseases benefit from appropriate continuity of care and generally visit their GPs more often than the average patient. Our aim was to study disenrollment patterns among patients with chronic diseases in Norway, because such patterns could indicate otherwise unobserved GP quality. For instance, higher quality GPs could have both a greater share of patients with chronic diseases and lower disenrollment rates. METHODS: Data on 384,947 chronic patients and 3,974 GPs for the years 2009-2011 were obtained from national registers, including patient and GP characteristics, disenrollment data, and patient list composition. The birth cohorts from 1940 and 1970 (146,906 patients) were included for comparison. Patient and GP characteristics, comorbidity, and patient list composition were analyzed using descriptive statistics. Patients' voluntary disenrollment was analyzed using logistic regression models. RESULTS: The GPs' proportion of patients with a given chronic disease varied more than expected when the allocation was purely random. The proportions of patients with different chronic diseases were positively correlated, partly due to comorbidity. Patients tended to have lower disenrollment rates from GPs who had higher shares of patients with the same chronic disease. Disenrollment rates were generally lower from GPs with higher shares of patients with arthritis or depression, and higher from GPs who had higher shares of patients with diabetes type 1 and schizophrenia. This was the same in the comparison group. CONCLUSION: Patients with a chronic disease appeared to prefer GPs who have higher shares of patients with the same disease. High shares of patients with some diseases were also negatively associated with disenrollment for all patient groups, while other diseases were positively associated. These findings may reflect the GPs' general quality, but could alternatively result from the GPs' specialization in particular diseases. The supportive findings for the comparison group make it more plausible that high shares of chronic patients could indicate GP quality. PMID- 27978812 TI - COUSCOus: improved protein contact prediction using an empirical Bayes covariance estimator. AB - BACKGROUND: The post-genomic era with its wealth of sequences gave rise to a broad range of protein residue-residue contact detecting methods. Although various coevolution methods such as PSICOV, DCA and plmDCA provide correct contact predictions, they do not completely overlap. Hence, new approaches and improvements of existing methods are needed to motivate further development and progress in the field. We present a new contact detecting method, COUSCOus, by combining the best shrinkage approach, the empirical Bayes covariance estimator and GLasso. RESULTS: Using the original PSICOV benchmark dataset, COUSCOus achieves mean accuracies of 0.74, 0.62 and 0.55 for the top L/10 predicted long, medium and short range contacts, respectively. In addition, COUSCOus attains mean areas under the precision-recall curves of 0.25, 0.29 and 0.30 for long, medium and short contacts and outperforms PSICOV. We also observed that COUSCOus outperforms PSICOV w.r.t. Matthew's correlation coefficient criterion on full list of residue contacts. Furthermore, COUSCOus achieves on average 10% more gain in prediction accuracy compared to PSICOV on an independent test set composed of CASP11 protein targets. Finally, we showed that when using a simple random forest meta-classifier, by combining contact detecting techniques and sequence derived features, PSICOV predictions should be replaced by the more accurate COUSCOus predictions. CONCLUSION: We conclude that the consideration of superior covariance shrinkage approaches will boost several research fields that apply the GLasso procedure, amongst the presented one of residue-residue contact prediction as well as fields such as gene network reconstruction. PMID- 27978813 TI - Is upfront stereotactic radiosurgery a rational treatment option for very elderly patients with brain metastases? A retrospective analysis of 106 consecutive patients age 80 years and older. AB - BACKGROUND: Advanced age has been shown to be a factor predicting poor survival in patients with brain metastases (BM). There have been only a few studies focusing on stereotactic radiosurgery (SRS) for elderly BM patients. The present study aimed to investigate the efficacy and limitations of SRS for very elderly BM patients. METHODS: This was a retrospective observational study analyzing 106 consecutive patients (69 males/37 females) age 80 years and older who received upfront Gamma Knife SRS for BM between January 2009 and October 2015. The median age was 84 years, and the median Karnofsky performance status (KPS) was 70. Fifty two patients had a solitary BM, and others multiple BM. The median cumulative tumor volume was 3.9 mL and the median dose prescribed was 20 Gy. Overall survival (OS), neurological death rates and distant and local intracranial tumor control rates were analyzed. RESULTS: No patients were lost to follow-up. Six month and 12-month OS rates were 54% and 32%, respectively. The median OS time was 7.1 months. Competing risks analysis showed that 6-month and 12-month neurological death rates were 8% and 11%, respectively. In total, 245 / 311 tumors (79%) in 82 patients (77%) with sufficient radiological follow-up data were evaluated. Six-month and 12-month distant BM recurrence rates (per patient) after SRS were 17% and 25%, respectively. Six-month and 12-month rates of local tumor control (per lesion) were 94% and 89%, respectively. Repeat SRS, salvage WBRT and surgical resection were subsequently required in 25, 4 and 1 patient, respectively. Proportional hazard regression analysis showed that KPS >= 70 (HR: 0.444, P < .001), controlled primary disease/no extracranial metastases (HR: 0.361, P < .001) and female sex (HR: 0.569, P = 0.028) were independent factors predicting better OS. Similarly, tumor volume (>2 mL) was the only factor predicting a higher rate of local control failure (HR: 12.8, P = 0.003). CONCLUSIONS: The present study suggested an upfront SRS strategy to offer a feasible and effective treatment option for very elderly patients with limited BM. In the majority of patients, neurological death could be delayed or even prevented. PMID- 27978814 TI - SwitchFinder - a novel method and query facility for discovering dynamic gene expression patterns. AB - BACKGROUND: Biological systems and processes are highly dynamic. To gain insights into their functioning time-resolved measurements are necessary. Time-resolved gene expression data captures temporal behaviour of the genes genome-wide under various biological conditions: in response to stimuli, during cell cycle, differentiation or developmental programs. Dissecting dynamic gene expression patterns from this data may shed light on the functioning of the gene regulatory system. The present approach facilitates this discovery. The fundamental idea behind it is the following: there are change-points (switches) in the gene behaviour separating intervals of increasing and decreasing activity, whereas the intervals may have different durations. Elucidating the switch-points is important for the identification of biologically meanigfull features and patterns of the gene dynamics. RESULTS: We developed a statistical method, called SwitchFinder, for the analysis of time-series data, in particular gene expression data, based on a change-point model. Fitting the model to the gene expression time-courses indicates switch-points between increasing and decreasing activities of each gene. Two types of the model - based on linear and on generalized logistic function - were used to capture the data between the switch-points. Model inference was facilitated with the Bayesian methodology using Markov chain Monte Carlo (MCMC) technique Gibbs sampling. Further on, we introduced features of the switch-points: growth, decay, spike and cleft, which reflect important dynamic aspects. With this, the gene expression profiles are represented in a qualitative manner - as sets of the dynamic features at their onset-times. We developed a Web application of the approach, enabling to put queries to the gene expression time-courses and to deduce groups of genes with common dynamic patterns. SwitchFinder was applied to our original data - the gene expression time-series measured in neuroblastoma cell line upon treatment with all-trans retinoic acid (ATRA). The analysis revealed eight patterns of the gene expression responses to ATRA, indicating the induction of the BMP, WNT, Notch, FGF and NTRK receptor signaling pathways involved in cell differentiation, as well as the repression of the cell-cycle related genes. CONCLUSIONS: SwitchFinder is a novel approach to the analysis of biological time-series data, supporting inference and interactive exploration of its inherent dynamic patterns, hence facilitating biological discovery process. SwitchFinder is freely available at https://newbioinformatics.eu/switchfinder. PMID- 27978815 TI - Origin and diversification of Lake Ohrid's endemic acroloxid limpets: the role of geography and ecology. AB - BACKGROUND: Ancient Lake Ohrid, located on the Albania-Macedonia border, is the most biodiverse freshwater lake in Europe. However, the processes that gave rise to its extraordinary endemic biodiversity, particularly in the species-rich gastropods, are still poorly understood. A suitable model taxon to study speciation processes in Lake Ohrid is the pulmonate snail genus Acroloxus, which comprises two morphologically distinct and ecologically (vertically) separated endemic species. Using a multilocus phylogenetic framework of Acroloxus limpets from the Euro-Mediterranean subregion, together with molecular-clock and phylogeographic analyses of Ohrid taxa, we aimed to infer their geographic origin and the timing of colonization as well as the role of geography and ecology in intra-lacustrine diversification. RESULTS: In contrast to most other endemic invertebrate groups in Lake Ohrid, the phylogenetic relationships of the endemic Ohrid Acroloxus species indicate that the Balkan region probably did not serve as their ancestral area. The inferred monophyly and estimated divergence times further suggest that these freshwater limpets colonized the lake only once and that the onset of intra-lacustrine diversification coincides with the time when the lake reached deep-water conditions ca 1.3 Mya. However, the difference in vertical distribution of these two ecologically distinct species is not reflected in the phylogeographic pattern observed. Instead, western and eastern populations are genetically more distinct, suggesting a horizontal structure. CONCLUSIONS: We conclude that both geography and ecology have played a role in the intra lacustrine speciation process. Given the distinct morphology (sculptured vs. smooth shell) and ecology (littoral vs. sublittoral), and the timing of intra lacustrine diversification inferred, we propose that the onset of deep-water conditions initially triggered ecological speciation. Subsequent geographic processes then gave rise to the phylogeographic patterns observed today. However, the generally weak genetic differentiation observed suggests incipient speciation, which might be explained by the comparatively young age of the lake system and thus the relatively recent onset of intra-lacustrine diversification. PMID- 27978817 TI - Evaluation of Galleria mellonella larvae for studying the virulence of Streptococcus suis. AB - BACKGROUND: Streptococcus suis is an encapsulated Gram-positive bacterium and the leading cause of sepsis and meningitis in young pigs, resulting in considerable economic losses in the porcine industry. S. suis is considered an emerging zoonotic agent with increasing numbers of human cases over the last years. In the environment, both avirulent and virulent strains occur in pigs, with no evidence for consistent adapatation of virulent strains to the human host. Currently, there is an urgent need for a convenient, reliable and standardised animal model to rapidly assess S. suis virulence. Wax moth (Galleria mellonella) larvae have successfully been used in human and animal infectious disease studies. Here, we developed G. mellonella larvae as a model to assess virulence of S. suis strains. RESULTS: Fourteen isolates of S. suis belonging to different serotypes killed G. mellonella larvae in a dose-dependent manner. Larvae infected with the virulent serotype 2 strain, S. suis S3881/S10, were rescued by antibiotic therapy. Crucially, the observed virulence of the different serotypes and mutants was in agreement with virulence observed in piglets (Sus scrofa) and the zebrafish larval infection model. Infection with heat-inactivated bacteria or bacteria-free culture supernatants showed that in most cases live bacteria are needed to cause mortality in G. mellonella. CONCLUSIONS: The G. mellonella model is simple, cost efficient, and raises less ethical issues than experiments on vertebrates and reduces infrastructure requirements. Furthermore, it allows experiments to be performed at the host temperature (37 degrees C). The results reported here, indicate that the G. mellonella model may aid our understanding of veterinary microbial pathogens such as the emerging zoonotic pathogen S. suis and generate hypotheses for testing in the target animal host. Ultimately, this might lead to the timely introduction of new effective remedies for infectious diseases. Last but not least, use of the G. mellonella infection model to study S. suis virulence adheres to the principles of replacement, reduction and refinement (3Rs) and can potentially reduce the number of vertebrates used for experimental infection studies. PMID- 27978818 TI - Multiple and mixed methods in formative evaluation: Is more better? Reflections from a South African study. AB - BACKGROUND: Formative programme evaluations assess intervention implementation processes, and are seen widely as a way of unlocking the 'black box' of any programme in order to explore and understand why a programme functions as it does. However, few critical assessments of the methods used in such evaluations are available, and there are especially few that reflect on how well the evaluation achieved its objectives. This paper describes a formative evaluation of a community-based lay health worker programme for TB and HIV/AIDS clients across three low-income communities in South Africa. It assesses each of the methods used in relation to the evaluation objectives, and offers suggestions on ways of optimising the use of multiple, mixed-methods within formative evaluations of complex health system interventions. METHODS: The evaluation's qualitative methods comprised interviews, focus groups, observations and diary keeping. Quantitative methods included a time-and-motion study of the lay health workers' scope of practice and a client survey. The authors conceptualised and conducted the evaluation, and through iterative discussions, assessed the methods used and their results. RESULTS: Overall, the evaluation highlighted programme issues and insights beyond the reach of traditional single methods evaluations. The strengths of the multiple, mixed-methods in this evaluation included a detailed description and nuanced understanding of the programme and its implementation, and triangulation of the perspectives and experiences of clients, lay health workers, and programme managers. However, the use of multiple methods needs to be carefully planned and implemented as this approach can overstretch the logistic and analytic resources of an evaluation. CONCLUSIONS: For complex interventions, formative evaluation designs including multiple qualitative and quantitative methods hold distinct advantages over single method evaluations. However, their value is not in the number of methods used, but in how each method matches the evaluation questions and the scientific integrity with which the methods are selected and implemented. PMID- 27978816 TI - Genotype-by-sequencing facilitates genetic mapping of a stem rust resistance locus in Aegilops umbellulata, a wild relative of cultivated wheat. AB - BACKGROUND: Wild relatives of wheat play a significant role in wheat improvement as a source of genetic diversity. Stem rust disease of wheat causes significant yield losses at the global level and stem rust pathogen race TTKSK (Ug99) is virulent to most previously deployed resistance genes. Therefore, the objective of this study was to identify loci conferring resistance to stem rust pathogen races including Ug99 in an Aegilops umbelluata bi-parental mapping population using genotype-by-sequencing (GBS) SNP markers. RESULTS: A bi-parental F2:3 population derived from a cross made between stem rust resistant accession PI 298905 and stem rust susceptible accession PI 542369 was used for this study. F2 individuals were evaluated with stem rust race TTTTF followed by testing F2:3 families with races TTTTF and TTKSK. The segregation pattern of resistance to both stem rust races suggested the presence of one resistance gene. A genetic linkage map, comprised 1,933 SNP markers, was created for all seven chromosomes of Ae. umbellulata using GBS. A major stem rust resistance QTL that explained 80% and 52% of the phenotypic variations for TTTTF and TTKSK, respectively, was detected on chromosome 2U of Ae. umbellulata. CONCLUSION: The novel resistance gene for stem rust identified in this study can be transferred to commercial wheat varieties assisted by the tightly linked markers identified here. These markers identified through our mapping approach can be a useful strategy to identify and track the resistance gene in marker-assisted breeding in wheat. PMID- 27978820 TI - Variation in cyanogenic compounds concentration within a Heliconius butterfly community: does mimicry explain everything? AB - BACKGROUND: Aposematic species advertise their unpalatability using warning signals such as striking coloration. Given that predators need to sample aposematic prey to learn that they are unprofitable, prey with similar warning signals share the cost of predator learning. This reduction in predation risk drives evolutionary convergence of warning signals among chemically defended prey (Mullerian mimicry). Whether such warning signal convergence is associated to similar defence levels among co-mimics is still an open question that has rarely been tested in wild populations. We quantified variation in cyanide-based (CN) chemical protection in wild caught individuals of eight aposematic Heliconius butterfly species belonging to four sympatric mimicry rings. We then tested for correlations between chemical protection and ecological species-specific traits. RESULTS: We report significant differences in CN concentrations both within and between sympatric species, even when accounting for the phylogeny, and within and between mimicry rings, even after considering inter-specific variation. We found significant correlations between CN concentration and both hostplant specialization and gregarious behaviour in adults and larvae. However, differences in CN concentrations were not significantly linked to mimicry ring abundance, although the two most toxic species did belong to the rarest mimicry ring. CONCLUSIONS: Our results suggest that mimicry can explain the variation in the levels of chemical defence to a certain extent, although other ecological factors are also relevant to the evolution of such variability. PMID- 27978819 TI - The experiences of high school students with pulmonary tuberculosis in China: a qualitative study. AB - BACKGROUND: Clustered tuberculosis (TB) still occurred nationally in Chinese schools every year, where high school students patients accounts for the highest proportion. These young TB patients are in a critical period of physical and psychological growth. Research on their illness experience and analysis of underlying causes remains blank. The purpose of this study is to explore the overall illness experience of Chinese high school TB patients and to investigate the individual and social causes of such experience. METHODS: Twenty-two high school TB patients in a certain county of Shaanxi province were interviewed in depth twice when initial diagnosed and during intermediate treatment periods. Interview data were analyzed by framework approach. RESULTS: The high school TB patients worried about interruption of studies rather than the disease. They generally showed a lack of awareness of tuberculosis, were highly dependent on parents, and received assistance from teachers and students during the treatment. Most of them did not show obvious stigma. CONCLUSION: The unique education system and sociocultural factors in China are the root of special illness experience of high school TB patients. Huge pressure in college entrance examination leads sick students to worry about interruption of studies more than the disease itself. Their serious lack of awareness of TB, caused by the ignorance of school, parents and the students, becomes the biggest obstacle to timely diagnosis and treatment. Whether high dependence on parents is conducive to disease recovery varies with each individual. Meanwhile, patients' weak stigma could play a positive role in disease recovery. Educational and medical institutions should develop more effective TB control strategies based on these factors. PMID- 27978821 TI - Metabolic syndrome and adverse clinical outcomes in patients with bipolar disorder. AB - BACKGROUND: Metabolic syndrome (MetS) is highly prevalent among patients with bipolar disorder. MetS may cause complications in the brain, but studies investigating MetS-associated clinical psychiatric outcomes remain scant. METHODS: We enrolled clinically stable outpatients with bipolar disorder aged 18 65 years and performed anthropometric and fasting biochemical assessments to investigate MetS prevalence. We then performed clinical assessments by using the Young Mania Rating Scale for manic symptoms, the Montgomery-Asberg Depression Rating Scale for depressive symptoms, the Positive and Negative Symptom Scale for psychotic symptoms, the Involuntary Movement Scale for tardive dyskinesia, the Barnes Akathisia Rating Scale for akathisia, the Udvalg for Kliniske Undersogelser for general side effects, the Schedule for Assessment of Insight for insight, the Global Assessment of Functioning scale for global functioning, and the Wisconsin Card Sorting Test (WCST) for cognitive executive function. RESULTS: In total, 143 patients were enrolled and had a MetS prevalence of 29.4%. The patients treated with atypical antipsychotics plus mood stabilizers (36.3%) and atypical antipsychotics alone (36.0%) had a significantly higher prevalence of MetS than did those treated with mood stabilizers alone (10.5%; p = 0.012). According to multivariate regression analyses adjusted for age, sex, smoking status, bipolar disorder subtype (I or II), pharmacological treatment duration, and psychiatric medication, compared with patients without MetS, those with MetS had significantly more previous hospitalizations (p = 0.036), severer tardive dyskinesia (p = 0.030), poorer insight (p = 0.036), poorer global function (p = 0.046), and more impaired executive function (conceptual level response on the WCST; p = 0.042). CONCLUSIONS: Our results indicated that patients with comorbid bipolar disorder and MetS have more adverse clinical outcomes than those without, with more hospitalizations, severer tardive dyskinesia, poorer insight, poorer global function, and more impaired executive function. Monitoring MetS is crucial for assessing not only physical burden, but also psychiatric outcomes. PMID- 27978822 TI - Acanthamoeba containing endosymbiotic chlamydia isolated from hospital environments and its potential role in inflammatory exacerbation. AB - BACKGROUND: Environmental chlamydiae belonging to the Parachlamydiaceae are obligate intracellular bacteria that infect Acanthamoeba, a free-living amoeba, and are a risk for hospital-acquired pneumonia. However, whether amoebae harboring environmental chlamydiae actually survive in hospital environments is unknown. We therefore isolated living amoebae with symbiotic chlamydiae from hospital environments. RESULTS: One hundred smear samples were collected from Hokkaido University Hospital, Sapporo, Japan; 50 in winter (February to March, 2012) and 50 in summer (August, 2012), and used for the study. Acanthamoebae were isolated from the smear samples, and endosymbiotic chlamydial traits were assessed by infectivity, cytokine induction, and draft genomic analysis. From these, 23 amoebae were enriched on agar plates spread with heat-killed Escherichia coli. Amoeba prevalence was greater in the summer-collected samples (15/30, 50%) than those of the winter season (8/30, 26.7%), possibly indicating a seasonal variation (p = 0.096). Morphological assessment of cysts revealed 21 amoebae (21/23, 91%) to be Acanthamoeba, and cultures in PYG medium were established for 11 of these amoebae. Three amoebae contained environmental chlamydiae; however, only one amoeba (Acanthamoeba T4) with an environmental chlamydia (Protochlamydia W-9) was shown the infectious ability to Acanthamoeba C3 (reference amoebae). While Protochlamydia W-9 could infect C3 amoeba, it failed to replicate in immortal human epithelial, although exposure of HEp-2 cells to living bacteria induced the proinflammatory cytokine, IL-8. Comparative genome analysis with KEGG revealed similar genomic features compared with other Protochlamydia genomes (UWE25 and R18), except for a lack of genes encoding the type IV secretion system. Interestingly, resistance genes associated with several antibiotics and toxic compounds were identified. CONCLUSION: These findings are the first demonstration of the distribution in a hospital of a living Acanthamoeba carrying an endosymbiotic chlamydial pathogen. PMID- 27978823 TI - Salivary and serum inflammatory mediators among pre-conception women with periodontal disease. AB - BACKGROUND: There have been inconsistent conclusions regarding the levels of inflammatory mediators in saliva and serum among people with or without periodontal disease. Although pre-conception has been put forward as the optimal time for the periodontal treatment in order to improving pregnancy outcomes, few studies have been conducted to examine inflammatory mediators in saliva and serum among pre-conception women. METHODS: Pre-conception women were recruited between January 2012 and December 2014. Women were provided with an oral health examination to detect periodontal disease. Salivary and serum samples were collected at the same of examination. Inflammatory mediators includinginterleukin 1 beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNF-alpha) and beta glucuronidase (beta-glucuronidase) were tested and analyzed among women with overall periodontal disease (n = 442) or moderate/severe periodontal disease (n = 247). Results were compared to that in women with a healthy periodontium (n = 91). RESULTS: Significantly increased concentrations of inflammatory mediators of IL-1beta, IL-6, TNF-alpha and beta-glucuronidase in saliva and IL-1beta, beta glucuronidase and TNF-alpha in serum were found among pre-conception women with moderate/severe periodontal disease, compared with women without periodontal disease. Significantly increased levels were also found in all the above saliva inflammatory mediators and in serum IL-1beta and TNF-alpha among women with overall periodontal disease. The levels of all inflammatory mediators in saliva and almost all inflammatory mediators except IL-6 in serum significantly increased with severity of periodontal disease. CONCLUSION: Periodontal disease is highly associated with the elevated levels of inflammatory mediators in saliva and some mediators in serum among pre-conception women. PMID- 27978824 TI - Unspecific binding of cRNA probe to plaques in two mouse models for Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is characterized by the pathological deposition of amyloid-beta (Abeta) protein-containing plaques. Microglia and astrocytes are commonly attracted to the plaques by an unknown mechanism that may involve cell adhesion. One cell adhesion family of proteins, the cadherins, are widely expressed in the central nervous system. Therefore, our study was designed to map the expression of cadherins in AD mouse brains. A particular focus was on plaques because diverse mRNA-species were found in plaques and their surrounding area in brains of AD patients. METHODS: In this study, we used in situ hybridization to visualize cadherin expression in brains of two mouse models for AD (APP/PS1 and APP23). RESULTS: A variable number of plaques was detected in transgenic brain sections, depending on the probe used. Our first impression was that the cadherin probes visualized specific mRNA expression in plaques and that endogenous staining was unaffected. However, control experiments revealed unspecific binding with sense probes. Further experiments with variations in probe length, probe sequence, molecular tag and experimental procedure lead us to conclude that cRNA probes bind generally and in an unspecific manner to plaques. CONCLUSIONS: We demonstrate unspecific binding of cRNA probes to plaques in two mouse models for AD. The widespread and general staining of the plaques prevented us from studying endogenous expression of cadherins in transgenic brain by in situ hybridization. PMID- 27978825 TI - Using multi-year national survey cohorts for period estimates: an application of weighted discrete Poisson regression for assessing annual national mortality in US adults with and without diabetes, 2000-2006. AB - BACKGROUND: Monitoring national mortality among persons with a disease is important to guide and evaluate progress in disease control and prevention. However, a method to estimate nationally representative annual mortality among persons with and without diabetes in the United States does not currently exist. The aim of this study is to demonstrate use of weighted discrete Poisson regression on national survey mortality follow-up data to estimate annual mortality rates among adults with diabetes. METHODS: To estimate mortality among US adults with diabetes, we applied a weighted discrete time-to-event Poisson regression approach with post-stratification adjustment to national survey data. Adult participants aged 18 or older with and without diabetes in the National Health Interview Survey 1997-2004 were followed up through 2006 for mortality status. We estimated mortality among all US adults, and by self-reported diabetes status at baseline. The time-varying covariates used were age and calendar year. Mortality among all US adults was validated using direct estimates from the National Vital Statistics System (NVSS). RESULTS: Using our approach, annual all cause mortality among all US adults ranged from 8.8 deaths per 1,000 person-years (95% confidence interval [CI]: 8.0, 9.6) in year 2000 to 7.9 (95% CI: 7.6, 8.3) in year 2006. By comparison, the NVSS estimates ranged from 8.6 to 7.9 (correlation = 0.94). All-cause mortality among persons with diabetes decreased from 35.7 (95% CI: 28.4, 42.9) in 2000 to 31.8 (95% CI: 28.5, 35.1) in 2006. After adjusting for age, sex, and race/ethnicity, persons with diabetes had 2.1 (95% CI: 2.01, 2.26) times the risk of death of those without diabetes. CONCLUSION: Period-specific national mortality can be estimated for people with and without a chronic condition using national surveys with mortality follow-up and a discrete time-to-event Poisson regression approach with post-stratification adjustment. PMID- 27978826 TI - A novel real-time PCR assay for quantitative detection of Campylobacter fetus based on ribosomal sequences. AB - BACKGROUND: Campylobacter fetus is a pathogen of major concern for animal and human health. The species shows a great intraspecific variation, with three subspecies: C. fetus subsp. fetus, C. fetus subsp. venerealis, and C. fetus subsp. testudinum. Campylobacter fetus fetus affects a broad range of hosts and induces abortion in sheep and cows. Campylobacter fetus venerealis is restricted to cattle and causes the endemic disease bovine genital campylobacteriosis, which triggers reproductive problems and is responsible for major economic losses. Campylobacter fetus testudinum has been proposed recently based on genetically divergent strains isolated from reptiles and humans. Both C. fetus fetus and C. fetus testudinum are opportunistic pathogens for immune-compromised humans. Biochemical tests remain as the gold standard for identifying C. fetus but the fastidious growing requirements and the lack of reliability and reproducibility of some biochemical tests motivated the development of molecular diagnostic tools. These methods have been successfully tested on bovine isolates but fail to detect some genetically divergent strains isolated from other hosts. The aim of the present study was to develop a highly specific molecular assay to identify and quantify C. fetus strains. RESULTS: We developed a highly sensitive real-time PCR assay that targets a unique region of the 16S rRNA gene. This assay successfully detected all C. fetus strains, including those that were negative for the cstA gene-based assay used as a standard for molecular C. fetus identification. The assay showed high specificity and absence of cross-reactivity with other bacterial species. The analytical testing of the assay was determined using a standard curve. The assay demonstrated a wide dynamic range between 102 and 107 genome copies per reaction, and a good reproducibility with small intra- and inter-assay variability. CONCLUSIONS: The possibility to characterize samples in a rapid, sensitive and reproducible way makes this assay a good option to establish a new standard in molecular identification and quantification of C. fetus species. PMID- 27978827 TI - Assessing the universal health coverage target in the Sustainable Development Goals from a human rights perspective. AB - BACKGROUND: The UN's Sustainable Development Goals (SDGs), adopted in September 2015, include a comprehensive health goal, "to ensure healthy lives and promote well-being at all ages." The health goal (SDG 3) has nine substantive targets and four additional targets which are identified as a means of implementation. One of these commitments, to achieve universal health coverage (UHC), has been acknowledged as central to the achievement of all of the other health targets. As defined in the SDGs, UHC includes financial risk protection, access to quality essential health-care services, and access to safe, effective, quality and affordable essential medicines and vaccines for all. DISCUSSION: This article evaluates the extent to which the UHC target in the SDGs conforms with the requirements of the right to health enumerated in the International Covenant on Economic, Social and Cultural Rights, the Convention on the Rights of the Child, and other international human rights instruments and interpreted by international human rights bodies. It does so as a means to identify strengths and weaknesses in the framing of the UHC target that are likely to affect its implementation. While UHC as defined in the SDGs overlaps with human rights standards, there are important human rights omissions that will likely weaken the implementation and reduce the potential benefits of the UHC target. The most important of these is the failure to confer priority to providing access to health services to poor and disadvantaged communities in the process of expanding health coverage and in determining which health services to provide. Unless the furthest behind are given priority and strategies adopted to secure their participation in the development of national health plans, the SDGs, like the MDGs, are likely to leave the most disadvantaged and vulnerable communities behind. PMID- 27978828 TI - Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3. AB - BACKGROUND: STAT3 is increasingly becoming known for its non-transcriptional regulation of mitochondrial bioenergetic function upon activation of its S727 residue (S727-STAT3). Lengthy mitochondrial dysfunction can lead to cell death. We tested whether an integrin-FAK-STAT3 signaling pathway we recently discovered regulates mitochondrial function and cell survival, and treatments thereof. METHODS: Cultured mouse brain bEnd5 endothelial cells were treated with integrin, FAK or STAT3 inhibitors, FAK siRNA, as well as integrin and STAT3 activators. STAT3 null cells were transfected with mutant STAT3 plasmids. Outcome measures included oxygen consumption rate for mitochondrial bioenergetics, Western blotting for protein phosphorylation, mitochondrial membrane potential for mitochondrial integrity, ROS production, and cell counts. RESULTS: Vitronectin dependent mitochondrial basal respiration, ATP production, and maximum reserve and respiratory capacities were suppressed within 4 h by RGD and alphavbeta3 integrin antagonist peptides. Conversely, integrin ligands vitronectin, laminin and fibronectin stimulated mitochondrial function. Pharmacological inhibition of FAK completely abolished mitochondrial function within 4 h while FAK siRNA treatments confirmed the specificity of FAK signaling. WT, but not S727A functionally dead mutant STAT3, rescued bioenergetics in cells made null for STAT3 using CRISPR-Cas9. STAT3 inhibition with stattic in whole cells rapidly reduced mitochondrial function and mitochondrial pS727-STAT3. Stattic treatment of isolated mitochondria did not reduce pS727 whereas more was detected upon phosphatase inhibition. This suggests that S727-STAT3 is activated in the cytoplasm and is short-lived upon translocation to the mitochondria. FAK inhibition reduced pS727-STAT3 within mitochondria and reduced mitochondrial function in a non-transcriptional manner, as shown by co-treatment with actinomycin. Treatment with the small molecule bryostatin-1 or hepatocyte growth factor (HGF), which indirectly activate S727-STAT3, preserved mitochondrial function during FAK inhibition, but failed in the presence of the STAT3 inhibitor. FAK inhibition induced loss of mitochondrial membrane potential, which was counteracted by bryostatin, and increased superoxide and hydrogen peroxide production. Bryostatin and HGF reduced the substantial cell death caused by FAK inhibition over a 24 h period. CONCLUSION: These data suggest that extracellular matrix molecules promote STAT3-dependent mitochondrial function and cell survival through integrin-FAK signaling. We furthermore show a new treatment strategy for cell survival using S727-STAT3 activators. PMID- 27978829 TI - miR-138-5p contributes to cell proliferation and invasion by targeting Survivin in bladder cancer cells. AB - BACKGROUND: Survivin (encoded by the gene BIRC5) plays an important role in the carcinogenesis of bladder cancer. Identifying miRNAs that target Survivin in the setting of bladder cancer will help to develop Survivin-based therapies for bladder cancer. METHODS: The expression levels of miR-138-5p and Survivin protein were measured in 12 resected bladder cancer specimens. The correlation between miR-138-5p and Survivin was further examined by evaluating Survivin expression in human bladder cancer cell lines that either overexpressed or knocked down miR-138 5p. A luciferase reporter assay was performed to test the direct binding of miR 138-5p to the target gene BIRC5. We also investigated the biological role of miR 138-5p targeting to Survivin in bladder cancer cell lines both in vivo and in vitro. RESULTS: In this study, we found that the Survivin protein was either absent or weakly expressed in normal adjacent tissues and consistently up regulated in bladder cancer tissues; however, the mRNA levels did not vary as much, suggesting that a post-transcriptional mechanism was involved. Because microRNAs are powerful post-transcriptional regulators of gene expression, we used bioinformatic analyses to search for microRNAs that could potentially target BIRC5 in the setting of bladder cancer. We identified 2 specific targeting sites for miR-138-5p in the 3' untranslated region (3'-UTR) of BIRC5. We further identified an inverse correlation between miR-138-5p and Survivin protein levels in bladder cancer tissue samples. By overexpressing or knocking down miR-138-5p in bladder cancer cells, we experimentally confirmed that miR-138-5p directly recognizes the 3'-UTR of the BIRC5 transcript and regulates Survivin expression. Furthermore, the biological consequences of the targeting of BIRC5 by miR-138-5p were examined in vitro via cell proliferation and invasion assays and in vivo using a mouse xenograft tumor model. We demonstrated that BIRC5 repression by miR 138-5p suppressed the proliferative and invasive characteristics of bladder cancer cells and that miR-138-5p exerted an anti-tumor effect by negatively regulating BIRC5 in a xenograft mouse model. CONCLUSIONS: Taken together, our findings provide the first clues regarding the role of miR-138-5p as a tumor suppressor in bladder cancer by inhibiting BIRC5 translation. PMID- 27978830 TI - Angiopoietin 2 signaling plays a critical role in neural crest cell migration. AB - BACKGROUND: Collective neural crest cell migration is critical to the form and function of the vertebrate face and neck, distributing bone, cartilage, and nerve cells into peripheral targets that are intimately linked with head vasculature. The vasculature and neural crest structures are ultimately linked, but when and how these patterns develop in the early embryo are not well understood. RESULTS: Using in vivo imaging and sophisticated cell behavior analyses, we show that quail cranial neural crest and endothelial cells share common migratory paths, sort out in a dynamic multistep process, and display multiple types of motion. To better understand the underlying molecular signals, we examined the role of angiopoietin 2 (Ang2), which we found expressed in migrating cranial neural crest cells. Overexpression of Ang2 causes neural crest cells to be more exploratory as displayed by invasion of off-target locations, the widening of migratory streams into prohibitive zones, and differences in cell motility type. The enhanced exploratory phenotype correlates with increased phosphorylated focal adhesion kinase activity in migrating neural crest cells. In contrast, loss of Ang2 function reduces neural crest cell exploration. In both gain and loss of function of Ang2, we found disruptions to the timing and interplay between cranial neural crest and endothelial cells. CONCLUSIONS: Together, these data demonstrate a role for Ang2 in maintaining collective cranial neural crest cell migration and suggest interdependence with endothelial cell migration during vertebrate head patterning. PMID- 27978831 TI - The low IGFBP-3 level is associated with esophageal cancer patients: a meta analysis. AB - BACKGROUND: Esophageal cancer was a vital cause of cancer-related mortality worldwide, and the insulin-like growth factor-binding proteins (IGFBPs) has been proved to be an important factor of multiple types of tumors. There is a controversy that whether the IGFBP-3 level is associated with the clinical pathological characteristics and overall survival of esophageal cancer patients. Herein, we aimed to comprehensively assess the association between the low IGFBP 3 level and the risk, overall survival and clinical pathological characteristics of esophageal cancer. METHOD: We conducted a meta-analysis using seven eligible studies. The overall odds ratios (OR)/relative risk (RR) and their corresponding 95% confidence interval (CI) were calculated for each parameter. RESULTS: For the risk of esophageal cancer, the OR was 2.342 (p = 0.000), indicating that individuals with lower IGFBP-3 level were more likely to suffer from esophageal cancer, compared to those with relatively high IGFBP-3 level. With respect to the 3-year survival rate, the RR was 2.163 (p = 0.027), which demonstrated that esophageal cancer patients with low IGFBP-3 level had significantly lower 3-year survival rate; in terms of clinical pathological characteristics, significantly lower IGFBP-3 level was found for patients in all categories; for survival status, patients in low IGFBP-3 level are more likely to be in the dead survival status (OR = 4.480, p = 0.000). CONCLUSION: Our meta-analysis suggests that for esophageal cancer, the low IGFBP-3 level is associated with high cancer risk, poor prognosis, and unfavorable tumor stage and metastasis. PMID- 27978832 TI - Critical illness polyneuropathy (CIP) in neurological early rehabilitation: clinical and neurophysiological features. AB - BACKGROUND: Critical illness polyneuropathy (CIP) is a complex disease affecting 30-70% of critically ill patients. METHODS: Clinical (Barthel index, length of stay (LOS), morbidity, duration of mechanical ventilation, routine lab results) and neurophysiological (neurography) data of 191 patients admitted to neurological early rehabilitation and diagnosed with CIP have been analyzed retrospectively. RESULTS: CIP diagnosis was correct in 159 cases (83%). In this study, systemic inflammation, sepsis, systemic inflammatory response syndrome (SIRS), multiple organic failure (MOF), chronic renal failure, liver dysfunction, mechanical ventilation, diabetes, dyslipidemia and impaired ion homeostasis (hypocalcaemia, hypokalemia) were associated with CIP. Neurography, in particular of the peroneal, sural, tibial and median nerves, helped to identify CIP patients. Compound muscle action potential amplitude (r = -0.324, p < 0.05), as well as sensory (r = -0.389, p < 0.05) and motor conduction velocity (r = -0.347, p < 0.05) of the median nerve correlated with LOS in neurological early rehabilitation but not with outcome measures. CONCLUSIONS: In most cases, diagnosis of CIP among neurological early rehabilitation patients seems to be correct. Neurography may help to verify the diagnosis and to learn more about CIP pathophysiology, but it does not allow outcome prediction. Further studies on CIP are strongly encouraged. PMID- 27978833 TI - Expansion and diversification of the MSDIN family of cyclic peptide genes in the poisonous agarics Amanita phalloides and A. bisporigera. AB - BACKGROUND: The cyclic peptide toxins of Amanita mushrooms, such as alpha amanitin and phalloidin, are encoded by the "MSDIN" gene family and ribosomally biosynthesized. Based on partial genome sequence and PCR analysis, some members of the MSDIN family were previously identified in Amanita bisporigera, and several other members are known from other species of Amanita. However, the complete complement in any one species, and hence the genetic capacity for these fungi to make cyclic peptides, remains unknown. RESULTS: Draft genome sequences of two cyclic peptide-producing mushrooms, the "Death Cap" A. phalloides and the "Destroying Angel" A. bisporigera, were obtained. Each species has ~30 MSDIN genes, most of which are predicted to encode unknown cyclic peptides. Some MSDIN genes were duplicated in one or the other species, but only three were common to both species. A gene encoding cycloamanide B, a previously described nontoxic cyclic heptapeptide, was also present in A. phalloides, but genes for antamanide and cycloamanides A, C, and D were not. In A. bisporigera, RNA expression was observed for 20 of the MSDIN family members. Based on their predicted sequences, novel cyclic peptides were searched for by LC/MS/MS in extracts of A. phalloides. The presence of two cyclic peptides, named cycloamanides E and F with structures cyclo(SFFFPVP) and cyclo(IVGILGLP), was thereby demonstrated. Of the MSDIN genes reported earlier from another specimen of A. bisporigera, 9 of 14 were not found in the current genome assembly. Differences between previous and current results for the complement of MSDIN genes and cyclic peptides in the two fungi probably represents natural variation among geographically dispersed isolates of A. phalloides and among the members of the poorly defined A. bisporigera species complex. Both A. phalloides and A. bisporigera contain two prolyl oligopeptidase genes, one of which (POPB) is probably dedicated to cyclic peptide biosynthesis as it is in Galerina marginata. CONCLUSION: The MSDIN gene family has expanded and diverged rapidly in Amanita section Phalloideae. Together, A. bisporigera and A. phalloides are predicted to have the capacity to make more than 50 cyclic hexa , hepta-, octa-, nona- and decapeptides. PMID- 27978834 TI - Comparison of the placebo effect between different non-penetrating acupuncture devices and real acupuncture in healthy subjects: a randomized clinical trial. AB - BACKGROUND: Several studies have used placebo acupuncture methods in recent years as a way for blinding therapeutic effect of acupuncture, however placebo method selection has not followed enough methodological criteria to the point of stabilishing a consensus of what should be the best method to be used. This study aimed to evaluate the effectiveness of three different placebo acupuncture methods for blinding applied in healthy subjects. METHODS: This study was approved by the Ethics Committee of the Federal University of Sergipe with the number 47193015.5.0000.5546 and all individuals participating in the study signed a free and informed consent. For this study, 321 healthy volunteers were randomly divided into seven groups using the abdominal point stomach (ST) 25 and seven groups using the lumbar point bladder (Bl) 52 for stimulation. For real acupuncture procedure, three different methods of placebo acupuncture plus a mix between real acupuncture and placebo applied in the same individual, totaling fourteen groups in this study. Outcome assessments were performed before and immediately after applying the technique. Investigator who assessed variables had no knowledgement about the method was applied. Identification, weight and height were measured before puncture by using. At the end, subjects were asked if they believed they were receiving real or placebo acupuncture. RESULTS: There was no significant difference between groups for the perception about the type o stimulation (wheter real or placebo puncture). Percentage of subjects who reported to have received real acupuncture in the abdominal point was 69.56% in real group, 86.95% in group Park Sham, 82.60% in needle + foam, 91.30% in insertion and removal, 78.26% in real + Park Sham, 86.36% in real + needle and foam, 86.95% in real + insertion and removal, and for the lumbar point was 86.36% in real group, 86.95% in group Park Sham, 69.56% in needle + foam, 72% in insertion and removal, 86.95% in real + Park Sham, 81.81% in real + needle and foam and 78.26% in real + insertion and removal. CONCLUSION: All placebo acupuncture methods proposed in this study were equally effective for bliding the study participants using either abdominal or lumbar acupoints, and none of the placebo methods presented benefit compared to the other to be used in future clinical trials. ETHICS COMMITTEE: Federal University of Sergipe (UFS), number of approval: 47193015.5.0000.5546 TRIAL REGISTRATION: ensaiosclinicos.gov.br RBR 3w2p32 Registered in 28th January 2016. PMID- 27978835 TI - Activation of hippocampal MEK1 contributes to the cumulative antinociceptive effect of electroacupuncture in neuropathic pain rats. AB - BACKGROUND: Electroacupuncture (EA) intervention can relieve a variety of pain; however, optimal EA protocols have not been clearly determined. In addition, although central mitogen-activated protein kinase kinase (MEK) signaling has been shown to be involved in the antinociceptive effect of acupuncture stimulation, its characteristics at different time-points of EA intervention have not been fully elucidated. Therefore, the present study investigated the relationship between the effects of different numbers of EA intervention sessions and the activation of MEK1 in the hippocampus and hypothalamus in a rat model of neuropathic pain. METHODS: After ligation of the left sciatic nerve, which induces chronic constriction injury (CCI), the acupoints Zusanli (ST36) and Yanglingquan (GB34) were applied. The thermal withdrawal latency of the hind paw was used to evaluate the effect of EA on pain thresholds. Intra-hippocampus microinjection of PD98059, a MEK inhibitor, was performed to validate the involvement of MEK in EA analgesia. The hippocampus and hypothalamus were harvested to examine the phosphorylation levels of MEK (pMEK) by western blotting. RESULTS: In CCI rats, the thermal pain threshold of the affected hind paw decreased significantly relative to the control. Following subsequent daily EA interventions, CCI-induced ipsilateral hyperalgesia was markedly improved from day 4 and the analgesic effect of EA lasted 3 days after cessation of EA. Four sessions of EA markedly suppressed CCI-induced decrease of hippocampal pMEK1 (normalized to the total MEK level). In contrast, successive sessions of EA intervention gradually down-regulated the CCI-induced up-regulation of hypothalamic pMEK1 along with the increase numbers of EA intervention. However, EA did not exert the same analgesic effect after microinjection of PD98059 into the contralateral hippocampus during the first 3 days of EA intervention. CONCLUSIONS: EA intervention can induce time-dependent cumulative analgesia in neuropathic pain rats after 4 successive sessions of daily EA intervention, which is at least in part related to the activation of hippocampal MEK1. PMID- 27978836 TI - Rhodococcus aetherivorans BCP1 as cell factory for the production of intracellular tellurium nanorods under aerobic conditions. AB - BACKGROUND: Tellurite (TeO32-) is recognized as a toxic oxyanion to living organisms. However, mainly anaerobic or facultative-anaerobic microorganisms are able to tolerate and convert TeO32- into the less toxic and available form of elemental Tellurium (Te0), producing Te-deposits or Te-nanostructures. The use of TeO32--reducing bacteria can lead to the decontamination of polluted environments and the development of "green-synthesis" methods for the production of nanomaterials. In this study, the tolerance and the consumption of TeO32- have been investigated, along with the production and characterization of Te-nanorods by Rhodococcus aetherivorans BCP1 grown under aerobic conditions. RESULTS: Aerobically grown BCP1 cells showed high tolerance towards TeO32- with a minimal inhibitory concentration (MIC) of 2800 MUg/mL (11.2 mM). TeO32- consumption has been evaluated exposing the BCP1 strain to either 100 or 500 MUg/mL of K2TeO3 (unconditioned growth) or after re-inoculation in fresh medium with new addition of K2TeO3 (conditioned growth). A complete consumption of TeO32- at 100 MUg/mL was observed under both growth conditions, although conditioned cells showed higher consumption rate. Unconditioned and conditioned BCP1 cells partially consumed TeO32- at 500 MUg/mL. However, a greater TeO32- consumption was observed with conditioned cells. The production of intracellular, not aggregated and rod shaped Te-nanostructures (TeNRs) was observed as a consequence of TeO32- reduction. Extracted TeNRs appear to be embedded in an organic surrounding material, as suggested by the chemical-physical characterization. Moreover, we observed longer TeNRs depending on either the concentration of precursor (100 or 500 MUg/mL of K2TeO3) or the growth conditions (unconditioned or conditioned grown cells). CONCLUSIONS: Rhodococcus aetherivorans BCP1 is able to tolerate high concentrations of TeO32- during its growth under aerobic conditions. Moreover, compared to unconditioned BCP1 cells, TeO32- conditioned cells showed a higher oxyanion consumption rate (for 100 MUg/mL of K2TeO3) or to consume greater amount of TeO32- (for 500 MUg/mL of K2TeO3). TeO32- consumption by BCP1 cells led to the production of intracellular and not aggregated TeNRs embedded in an organic surrounding material. The high resistance of BCP1 to TeO32- along with its ability to produce Te-nanostructures supports the application of this microorganism as a possible eco-friendly nanofactory. PMID- 27978837 TI - What works for whom in pharmacist-led smoking cessation support: realist review. AB - BACKGROUND: New models of primary care are needed to address funding and staffing pressures. We addressed the research question "what works for whom in what circumstances in relation to the role of community pharmacies in providing lifestyle interventions to support smoking cessation?" METHODS: This is a realist review conducted according to RAMESES standards. We began with a sample of 103 papers included in a quantitative review of community pharmacy intervention trials identified through systematic searching of seven databases. We supplemented this with additional papers: studies that had been excluded from the quantitative review but which provided rigorous and relevant additional data for realist theorising; citation chaining (pursuing reference lists and Google Scholar forward tracking of key papers); the 'search similar citations' function on PubMed. After mapping what research questions had been addressed by these studies and how, we undertook a realist analysis to identify and refine candidate theories about context-mechanism-outcome configurations. RESULTS: Our final sample consisted of 66 papers describing 74 studies (12 systematic reviews, 6 narrative reviews, 18 RCTs, 1 process detail of a RCT, 1 cost-effectiveness study, 12 evaluations of training, 10 surveys, 8 qualitative studies, 2 case studies, 2 business models, 1 development of complex intervention). Most studies had been undertaken in the field of pharmacy practice (pharmacists studying what pharmacists do) and demonstrated the success of pharmacist training in improving confidence, knowledge and (in many but not all studies) patient outcomes. Whilst a few empirical studies had applied psychological theories to account for behaviour change in pharmacists or people attempting to quit, we found no studies that had either developed or tested specific theoretical models to explore how pharmacists' behaviour may be affected by organisational context. Because of the nature of the empirical data, only a provisional realist analysis was possible, consisting of five mechanisms (pharmacist identity, pharmacist capability, pharmacist motivation and clinician confidence and public trust). We offer hypotheses about how these mechanisms might play out differently in different contexts to account for the success, failure or partial success of pharmacy-based smoking cessation efforts. CONCLUSION: Smoking cessation support from community pharmacists and their staff has been extensively studied, but few policy-relevant conclusions are possible. We recommend that further research should avoid duplicating existing literature on individual behaviour change; seek to study the organisational and system context and how this may shape, enable and constrain pharmacists' extended role; and develop and test theory. PMID- 27978838 TI - Confidence intervals for rate ratios between geographic units. AB - BACKGROUND: Ratios of age-adjusted rates between a set of geographic units and the overall area are of interest to the general public and to policy stakeholders. These ratios are correlated due to two reasons-the first being that each region is a component of the overall area and hence there is an overlap between them; and the second is that there is spatial autocorrelation between the regions. Existing methods in calculating the confidence intervals of rate ratios take into account the first source of correlation. This paper incorporates spatial autocorrelation, along with the correlation due to area overlap, into the rate ratio variance and confidence interval calculations. RESULTS: The proposed method divides the rate ratio variances into three components, representing no correlation, overlap correlation, and spatial autocorrelation, respectively. Results applied to simulated and real cancer mortality and incidence data show that with increasing strength and scales in spatial autocorrelation, the proposed method leads to substantial improvements over the existing method. If the data do not show spatial autocorrelation, the proposed method performs as well as the existing method. CONCLUSIONS: The calculations are relatively easy to implement, and we recommend using this new method to calculate rate ratio confidence intervals in all cases. PMID- 27978839 TI - The impact of dietary risk factors on the burden of non-communicable diseases in Ethiopia: findings from the Global Burden of Disease study 2013. AB - BACKGROUND: The burden of non-communicable diseases (NCDs) has increased in sub Saharan countries, including Ethiopia. The contribution of dietary behaviours to the NCD burden in Ethiopia has not been evaluated. This study, therefore, aimed to assess diet-related burden of disease in Ethiopia between 1990 and 2013. METHOD: We used the 2013 Global Burden of Disease (GBD) data to estimate deaths, years of life lost (YLLs) and disability-adjusted life years (DALYs) related to eight food types, five nutrients and fibre intake. Dietary exposure was estimated using a Bayesian hierarchical meta-regression. The effect size of each diet disease pair was obtained based on meta-analyses of prospective observational studies and randomized controlled trials. A comparative risk assessment approach was used to quantify the proportion of NCD burden associated with dietary risk factors. RESULTS: In 2013, dietary factors were responsible for 60,402 deaths (95% Uncertainty Interval [UI]: 44,943-74,898) in Ethiopia-almost a quarter (23.0%) of all NCD deaths. Nearly nine in every ten diet-related deaths (88.0%) were from cardiovascular diseases (CVD) and 44.0% of all CVD deaths were related to poor diet. Suboptimal diet accounted for 1,353,407 DALYs (95% UI: 1,010,433 1,672,828) and 1,291,703 YLLs (95% UI: 961,915-1,599,985). Low intake of fruits and vegetables and high intake of sodium were the most important dietary factors. The proportion of NCD deaths associated with low fruit consumption slightly increased (11.3% in 1990 and 11.9% in 2013). In these years, the rate of burden of disease related to poor diet slightly decreased; however, their contribution to NCDs remained stable. CONCLUSIONS: Dietary behaviour contributes significantly to the NCD burden in Ethiopia. Intakes of diet low in fruits and vegetables and high in sodium are the leading dietary risks. To effectively mitigate the oncoming NCD burden in Ethiopia, multisectoral interventions are required; and nutrition policies and dietary guidelines should be developed. PMID- 27978841 TI - VCO2 calorimetry: stop tossing stones, it's time for building! PMID- 27978842 TI - Fast-track surgery after gynaecological oncological surgery: study protocol for a prospective randomised controlled trial. AB - BACKGROUND: Fast-track surgery (FTS), also known as enhanced recovery after surgery, is a multidisciplinary approach to accelerate recovery, reduce complications, minimise hospital stay without increasing readmission rates, and reduce health care costs, all without compromising patient safety. The advantages of FTS in abdominal surgery most likely extend to gynaecological surgery, but this is an assumption, as FTS in elective gynaecological surgery has not been well studied. No consensus guidelines have been developed for gynaecological oncological surgery although surgeons have attempted to introduce slightly modified FTS programmes for patients undergoing such surgery. To our knowledge, there are no published randomised controlled trials; however, some studies have shown that FTS in gynaecological oncological surgery leads to early hospital discharge with high levels of patient satisfaction. The aim of this study is whether FTS reduces the length of stay in hospital compared to traditional management. The secondary aim is whether FTS is associated with any increase in post-surgical complications compared to traditional management (for both open and laparoscopic surgery). METHODS/DESIGN: This trial will prospectively compare FTS and traditional management protocols. The primary endpoint is the length of post operative hospitalisation (days, mean +/- standard deviation), defined as the number of days between the date of discharge and the date of surgery. The secondary endpoints are complications in both groups (FTS versus traditional protocol) occurring during the first 3 months post-operatively including infection (wound infection, lung infection, intraperitoneal infection), post operative nausea and vomiting, ileus, post-operative haemorrhage, post-operative thrombosis, and the Acute Physiology and Chronic Health Enquiry II score. DISCUSSION: The advantages of FTS most likely extend to gynaecology, although, to our knowledge, there are no randomised controlled trials. The aim of this study is to compare the post-operative length of hospitalisation after major gynaecological or gynaecological oncological surgery and to analyse patients' post-operative complications. This trial may reveal whether FTS leads to early hospital discharge with few complications after gynaecological surgery. TRIAL REGISTRATION NUMBER: NCT02687412 . Approval Number: SCCHEC20160001. Date of registration: registered on 23 February 2016. PMID- 27978843 TI - Beam Output Audit results within the EORTC Radiation Oncology Group network. AB - Beam Output Auditing (BOA) is one key process of the EORTC radiation therapy quality assurance program. Here the results obtained between 2005 and 2014 are presented and compared to previous results.For all BOA reports the following parameters were scored: centre, country, date of audit, beam energies and treatment machines audited, auditing organisation, percentage of agreement between stated and measured dose.Four-hundred and sixty-one BOA reports were analyzed containing the results of 1790 photon and 1366 electron beams, delivered by 755 different treatment machines. The majority of beams (91.1%) were within the optimal limit of <= 3%. Only 13 beams (0.4%; n = 9 electrons; n = 4 photons), were out of the range of acceptance of <= 5%. Previous reviews reported a much higher percentage of 2.5% or more of the BOAs with >5% deviation.The majority of EORTC centres present beam output variations within the 3% tolerance cutoff value and only 0.4% of audited beams presented with variations of more than 5%. This is an important improvement compared to previous BOA results. PMID- 27978844 TI - Detection of Mycoplasma haemocanis, Mycoplasma haematoparvum, Mycoplasma suis and other vector-borne pathogens in dogs from Cordoba and Santa Fe, Argentina. AB - BACKGROUND: In Argentina, only very few reports are available for canine tick borne diseases where most are related to parasitic diseases. The objective of this survey was to investigate the prevalence of tick-borne pathogens in 70 dogs from Santa Fe and Cordoba, Argentina. METHODS: Microscopic blood smear examination as well as polymerase chain reaction (PCR) amplification using species-specific markers of Anaplasma, Babesia, Bartonella, Borrelia, Ehrlichia, Francisella, Mycoplasma (hemotropic group) and Rickettsia, followed by DNA sequencing were used to establish the prevalence of each infecting pathogen. RESULTS: Blood smear analysis showed 81% (57/70) prevalence of structures morphologically compatible with hemotropic mycoplasmas. No structures resembling either piroplasms or Anaplasma/Ehrlichia were detected. Hemotropic mycoplasma species (Mycoplasma haematoparvum, Mycoplasma haemocanis and Mycoplasma suis) were the most prevalent pathogens detected with an overall prevalence of 77.1%. Anaplasma platys was detected and identified in 11 of the 70 dogs (15.7%), meanwhile two Bartonella spp. (B. clarridgeiae and an uncharacterized Bartonella sp.) and Babesia vogeli were detected at 3 and 7% prevalence, respectively. CONCLUSIONS: The work presented here describes a high molecular prevalence for hemotropic mycoplasma species in each of the five locations selected. Three Mycoplasma spp., including Mycoplasma suis, reported for the first time in dogs have been identified by DNA amplification and sequencing. This study highlights the risk that these bacterial pathogens represent for companion animals and, due to their potential zoonotic nature, also for people. PMID- 27978845 TI - Human sex development: targeted technologies to improve diagnosis. AB - A new study of disorders of sex development presents an improved targeted next generation sequencing approach for their diagnosis.Please see related Research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1105 y . PMID- 27978846 TI - Resuscitative endovascular balloon occlusion of the aorta versus aortic cross clamping among patients with critical trauma: a nationwide cohort study in Japan. AB - BACKGROUND: Measures of aortic occlusion (AO) for resuscitation in patients with severe torso trauma remain controversial. Our aim was to characterize the current use of resuscitative endovascular balloon occlusion of the aorta (REBOA) and resuscitative open aortic cross-clamping (ACC), and to evaluate whether REBOA should be an alternative method to resuscitative open ACC. METHODS: This study was a retrospective cohort study between 2004 and 2013 from a nationwide trauma registry in Japan. Participants were selected who underwent either REBOA or ACC. Their characteristics, interventions, and outcomes were analyzed to compare REBOA and ACC directly. The primary outcome was in-hospital mortality and the secondary outcome was mortality in the emergency department. Logistic regression analysis was performed to compare the outcomes between REBOA and ACC with adjustment for severity; 1:1 propensity score matching was also performed. RESULTS: Of the 159,157 trauma patients, 903 were eligible based on the selection criteria. Overall, 405/607 patients (67%) who had REBOA died compared to 210/233 patients (90%) who had ACC. Patients with REBOA had higher revised trauma score (RTS) (mean +/- SD, 5.2 +/- 2.0 vs. 4.2 +/- 2.2; P < 0.001) but higher Injury Severity Score (ISS) (median (interquartile); 34 (25) vs. 34 (20); P < 0.001), and higher probability of survival (0.43 +/- 0.36 vs. 0.27 +/- 0.30; P < 0.001) compared to those with ACC. REBOA had an odds ratio (OR) for in-hospital mortality of 0.309 (95% confidence interval (CI) = 0.190-0.502) adjusting for trauma and injury severity score using a logistic regression model (n = 903). Similar associations were observed adjusting for RTS (OR = 0.224; 95% CI = 0.129-0.700) or adjusting for ISS (OR, 0.188; 95% CI, 0.116 to 0.303). In the propensity score-matched cohort (n = 304), REBOA was associated with lower mortality compared to ACC (OR, 0.261; 95% CI, 0.130 to 0.523). Patients with REBOA had less severe chest complications than those with ACC (Abbreviated Injury Scale thorax, 3.8 +/- 0.8 vs. 4.2 +/- 0.8; P < 0.001), although physiological severity and backgrounds were similar in this population. CONCLUSIONS: Patients who underwent AO had a high mortality. REBOA might be a favorable alternative method to resuscitative ACC for severe torso trauma although some indication bias could still remain. Further studies are needed to elucidate optimal indications. PMID- 27978840 TI - Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study. AB - BACKGROUND: Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. METHODS: Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. RESULTS: Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. CONCLUSIONS: Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. TRIAL REGISTRATION: NCT01274507 (ADEPT), registered October 28, 2010 and NCT01982162 (U-BIOPRED), registered October 30, 2013. PMID- 27978847 TI - Non-antibiotic treatments for bacterial diseases in an era of progressive antibiotic resistance. AB - The emergence of multi-drug resistant (MDR) microbial pathogens threatens the very foundation upon which standard antibacterial chemotherapy is based. We must consider non-antibiotic solutions to manage invasive bacterial infections. Transition from antibiotics to non-traditional treatments poses real clinical challenges that will not be easy to solve. Antibiotics will continue to reliably treat some infections (e.g., group A streptococci and Treponema pallidum) but will likely need adjuvant therapies or will need to be replaced for many bacterial infections in the future. PMID- 27978848 TI - Detailed statistical analysis plan for a cluster randomised controlled trial of the Healthy Lifestyles Programme (HeLP), a novel school-based intervention to prevent obesity in school children. AB - BACKGROUND: The Healthy Lifestyles Programme (HeLP) trial is being conducted to determine whether a novel school-based intervention is effective and cost effective in preventing obesity in 9-10 year-old children. This article describes the detailed statistical analysis plan for the HeLP trial, including an amendment (and rationale for amendment) made to originally planned sensitivity analyses. METHODS AND DESIGN: The HeLP trial is a definitive, pragmatic, superiority, cluster randomised controlled trial with two parallel groups and blinded outcome assessment. This update article describes in detail (1) the primary and secondary outcomes, (2) the statistical analysis principles (including which children will be included in each analysis, how the clustered nature of the study design will be accounted for, which covariates will be included in each analysis, how the results will be presented), (3) planned sensitivity analyses, planned subgroup analyses and planned adherence-adjusted analyses for the primary outcome, (4) planned analyses for the secondary outcomes and (e) planned longitudinal analyses. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) register: ISRCTN15811706 . Registered on 1 May 2012. PMID- 27978849 TI - Repair of large segmental bone defects with fascial flap-wrapped allogeneic bone. AB - BACKGROUND: The objective of this study was to investigate the therapeutic effects of the application of fascial flap-wrapped allogeneic bone for repair of large segmental tibial defects in rabbits and provide a theoretical basis for treatment of large segmental defects in weight-bearing bones. METHODS: Forty eight healthy adult New Zealand White (NZW) rabbits were randomized into two groups to establish 15-mm bone defects in the proximal tibia. Bone defects in test and control groups were repaired using allogeneic bone with and without a vascularized fascial flap from the rabbit proximal tibia, respectively. The differences in repair of bone defects between the two groups were assessed with postoperative X-ray examination, new bone quantity assessment, serum bone Gla protein (BGP) level, and biomechanical testing. RESULTS: The therapeutic effect in the test group was superior to that in the control group. CONCLUSIONS: Fascial flap-wrapped allogeneic bone is superior to allogeneic bone alone, and is ideal for the treatment of large segmental bone defects. PMID- 27978851 TI - A rare case of a double phytobezoar causing gastric and jejunum obstruction in an adult man: a case report. AB - BACKGROUND: Bezoars are an uncommon cause of mechanical intestinal occlusion. There are four different kinds of bezoars: phytobezoars, made of vegetables and fibers; trichobezoars, resulting from the ingestion of hair and frequently an expression of psychiatric disorders; lactobezoars, which are formed of milk curd; and pharmacobezoars, caused by drugs and medications. Symptoms are classically indistinguishable from one another and from more common causes of intestinal occlusion, so it can be difficult to establish a correct diagnosis in order to apply the correct treatment. We present a rare case of two different phytobezoars causing intestinal occlusion (gastric and jejunal). We also describe the correct techniques for making a correct and fast diagnosis of occlusion caused by phytobezoars, and the possible conservative and operative treatments. CASE PRESENTATION: We present the case of a double phytobezoar that was surgically treated with a double enterotomy. Our patient was a 68-year-old Caucasian man with a medical history of hypertension, a previous open appendectomy, and open repair of a perforated gastric ulcer. He was admitted with a 5-day history of abdominal pain located in his upper quadrants along with vomiting. After a preoperative examination, he was taken to the operating room. He was discharged in a good clinical condition 11 days after surgical intervention. A physical examination at 6 months demonstrated our patient was in good health. CONCLUSIONS: Diagnosing bezoars is difficult because of their rarity. However, they must be taken into consideration in a differential diagnosis because their treatment is not always surgical. In fact, it may be conservative in many cases and a correct diagnosis will guide towards the correct therapy. PMID- 27978850 TI - CT-perfusion measurements in pancreatic carcinoma with different kinetic models: Is there a chance for tumour grading based on functional parameters? AB - BACKGROUND: To evaluate the interchangeability of perfusion parameters obtained with help of models used for post-processing of perfusion-CT images in pancreatic adenocarcinoma and to determine the mean values and ranges of perfusion in different tumour gradings. METHODS: Perfusion-CT imaging was performed prospectively in 48 consecutive patients with pancreatic adenocarcinoma. In 42 patients biopsy-proven tumor grading was available (4 * G1/24 * G2/14 * G3/6* unknown). Images were post-processed using a model based on the maximum-slope (MS) approach (blood flow-BFMS) + Patlak analysis (P) (blood volume [BVP] and permeability [k-transP]), as well as a model with deconvolution-based (D) analysis (BFD, BVD and k-transD). 50 mL contrast agent were applied with a delay time of 7 s. Perfusion parameters were compared using intraclass correlation coefficient (ICC), the Wilcoxon matched-pairs test and Bland-Altman plots. RESULTS: Forty eight VOIs of tumours were outlined and analysed. Moderate to good ICC values were found for the perfusion parameters (ICC = 0.62-0.75). Wilcoxon matched-pairs revealed significantly lower values (P < .001 and 0.008), for the BF and BV values obtained using the maximum-slope approach + Patlak analysis compared to deconvolution based analysis. For k-trans measurement, deconvolution revealed significantly lower values (P < 0.001). Different histologic subgroups (G1-G3) did not show significantly different functional parameters. CONCLUSION: There were significant differences in the perfusion parameters obtained using the different calculation methods, and therefore these parameters are not directly interchangeable. However, the magnitude of pairs of parametric values is in constant relation to each other enabling the use of any of these methods. VPCT parameters did not allow for histologic classification. PMID- 27978852 TI - Phylogenetic analysis of Haemaphysalis erinacei Pavesi, 1884 (Acari: Ixodidae) from China, Turkey, Italy and Romania. AB - BACKGROUND: Haemaphysalis erinacei is one of the few ixodid tick species for which valid names of subspecies exist. Despite their disputed taxonomic status in the literature, these subspecies have not yet been compared with molecular methods. The aim of the present study was to investigate the phylogenetic relationships of H. erinacei subspecies, in the context of the first finding of this tick species in Romania. RESULTS: After morphological identification, DNA was extracted from five adults of H. e. taurica (from Romania and Turkey), four adults of H. e. erinacei (from Italy) and 17 adults of H. e. turanica (from China). From these samples fragments of the cytochrome c oxidase subunit 1 (cox1) and 16S rRNA genes were amplified via PCR and sequenced. Results showed that cox1 and 16S rRNA gene sequence divergences between H. e. taurica from Romania and H. e. erinacei from Italy were below 2%. However, the sequence divergences between H. e. taurica from Romania and H. e. turanica from China were high (up to 7.3% difference for the 16S rRNA gene), exceeding the reported level of sequence divergence between closely related tick species. At the same time, two adults of H. e. taurica from Turkey had higher 16S rRNA gene similarity to H. e. turanica from China (up to 97.5%) than to H. e. taurica from Romania (96.3%), but phylogenetically clustered more closely to H. e. taurica than to H. e. turanica. CONCLUSIONS: This is the first finding of H. erinacei in Romania, and the first (although preliminary) phylogenetic comparison of H. erinacei subspecies. Phylogenetic analyses did not support that the three H. erinacei subspecies evaluated here are of equal taxonomic rank, because the genetic divergence between H. e. turanica from China and H. e. taurica from Romania exceeded the usual level of sequence divergence between closely related tick species, suggesting that they might represent different species. Therefore, the taxonomic status of the subspecies of H. erinacei needs to be revised based on a larger number of specimens collected throughout its geographical range. PMID- 27978853 TI - Khat - a new precipitating factor for reversible cerebral vasoconstriction syndrome: a case report. AB - BACKGROUND: Postpartum reversible cerebral vasoconstriction syndrome is one of the rare reversible cerebral vasoconstriction syndromes. The clinical presentation is usually characterized by recurrent headache, focal neurological deficit, and reversible cerebral vasoconstriction seen on cerebral angiography. CASE PRESENTATION: We report a case of a 35-year-old Yemeni woman who presented with headache and focal neurological deficits that occurred 10 days after delivery, with segmental narrowing of cerebral arteries on angiography. She had significant clinical and radiological improvement on follow-up. CONCLUSIONS: The presentation of our patient's reversible cerebral vasoconstriction syndrome is unusual as she has two possible precipitating factors. In addition to being in the postpartum state, she also has a long history of chewing khat, a vasoactive substance commonly used by immigrants from Yemen. We hope that this case report will increase awareness among physicians about the use of this plant by immigrants from the horn of Africa and Yemen. PMID- 27978854 TI - Effects on and transfer across the blood-brain barrier in vitro-Comparison of organic and inorganic mercury species. AB - BACKGROUND: Transport of methylmercury (MeHg) across the blood-brain barrier towards the brain side is well discussed in literature, while ethylmercury (EtHg) and inorganic mercury are not adequately characterized regarding their entry into the brain. Studies investigating a possible efflux out of the brain are not described to our knowledge. METHODS: This study compares, for the first time, effects of organic methylmercury chloride (MeHgCl), EtHg-containing thiomersal and inorganic Hg chloride (HgCl2) on as well as their transfer across a primary porcine in vitro model of the blood-brain barrier. RESULTS: With respect to the barrier integrity, the barrier model exhibited a much higher sensitivity towards HgCl2 following basolateral incubation (brain-facing side) as compared to apical application (blood-facing side). These HgCl2 induced effects on the barrier integrity after brain side incubation are comparable to that of the organic species, although MeHgCl and thiomersal exerted much higher cytotoxic effects in the barrier building cells. Hg transfer rates following exposure to organic species in both directions argue for diffusion as transfer mechanism. Inorganic Hg application surprisingly resulted in a Hg transfer out of the brain-facing compartment. CONCLUSIONS: In case of MeHgCl and thiomersal incubation, mercury crossed the barrier in both directions, with a slight accumulation in the basolateral, brain-facing compartment, after simultaneous incubation in both compartments. For HgCl2, our data provide first evidence that the blood-brain barrier transfers mercury out of the brain. PMID- 27978856 TI - Involution of breast tissue and mammographic density. AB - BACKGROUND: Mammographic density decreases and involution of breast tissue increases with age; both are thought to be risk factors for breast cancer. The current study investigated the relationship between involution or hormone treatment (HT) and breast density among multiethnic patients with breast cancer in Hawaii. METHODS: Patients with breast cancer cases were recruited from a nested case-control study within the Multiethnic Cohort. HT use was self-reported at cohort entry and at the time of the density study. Mammographic density and involution in adjacent non-tumor breast tissue were assessed using established methods. Linear regression was applied to evaluate the correlation between involution and four density measures and to compute adjusted means by involution status while adjusting for confounders. RESULTS: In the 173 patients with breast cancer, mean percent breast density was 41.2% in mammograms taken approximately 1 year before diagnosis. The respective proportions of women with no, partial, and complete involution were 18.5, 51.4, and 30.1%, respectively and the adjusted density values for these categories were 32.5, 39.2, and 40.2% (p = 0.15). In contrast, the size of the dense area was significantly associated with involution (p = 0.001); the values ranged from 29.7 cm2 for no involution to 48.0 cm2 for complete involution. The size of the total breast area but not of the non-dense areas was also larger with progressive involution. Percent density and dense area were significantly higher in women with combined HT use. CONCLUSIONS: Contrary to previous reports, greater lobular involution was not related to lower mammographic density but to higher dense area. Possibly, percent density during the involution process depends on the timing of mammographic density assessment, as epithelial tissue is first replaced with radiographically dense stromal tissue and only later with fat. PMID- 27978855 TI - A digital enzyme-linked immunosorbent assay for ultrasensitive measurement of amyloid-beta 1-42 peptide in human plasma with utility for studies of Alzheimer's disease therapeutics. AB - BACKGROUND: Amyloid-beta 1-42 peptide (Abeta1-42) is associated with plaque formation in the brain of patients with Alzheimer's disease (AD). Pharmacodynamic studies of AD therapeutics that lower the concentrations of Abeta1-42 in peripheral blood require highly sensitive assays for its measurement. A digital enzyme-linked immunosorbent assay (ELISA) using single molecule array (Simoa) technology has been developed that provides improved sensitivity compared with conventional ELISA methods using the same antibody reagents. METHODS: A sensitive digital ELISA for measurement of Abeta1-42 using antibodies 3D6 and 21F12 was developed. Assay performance was evaluated by repeated testing of pooled human plasma and buffer diluent quality control samples to determine relative accuracy, intra- and inter-assay precision, limit of detection (LOD), lower limit of quantification (LLOQ), dilutional linearity, and spike recovery. The optimized assay was used to quantify Abeta1-42 in clinical samples from patients treated with the beta-site amyloid precursor protein cleaving enzyme 1 inhibitor LY2886721. RESULTS: The prototype assay measured Abeta1-42 with an LOD of 0.3 pg/ml and an LLOQ of 2.8 pg/ml in plasma, calibrated using an Abeta1-42 peptide standard from Fujirebio. Assay precision was acceptable with intra- and inter assay coefficients of variation both being <=10%. Dilutional linearity was demonstrated in sample diluent and immunodepleted human plasma. Analyte spike recovery ranged from 51% to 93% with a mean of 80%. This assay was able to quantify Abeta1-42 in all of the 84 clinical samples tested. A rapid reduction in levels of Abeta1-42 was detected within 1 h after drug treatment, and a dose dependent decrease of Abeta1-42 levels was also observed over the time course of sample collection. CONCLUSIONS: This digital ELISA has potential utility in clinical applications for quantification of Abeta1-42 in plasma where high sensitivity and precision are required. PMID- 27978857 TI - Process evaluation of a tailored intervention programme of cardiovascular risk management in general practices. AB - BACKGROUND: A tailored implementation programme to improve cardiovascular risk management (CVRM) in general practice had little impact on outcomes. The questions in this process evaluation concerned (1) impact on counselling skills and CVRM knowledge of practice nurses, (2) their use of the various components of the intervention programme and adoption of recommended practices and (3) patients' perceptions of counselling for CVRM. METHODS: A mixed-methods process evaluation was conducted. We assessed practice nurses' motivational interviewing skills on audio-taped consultations using Motivational Interviewing Treatment Integrity (MITI). They also completed a clinical knowledge test. Both practice nurses and patients reported on their experiences in a written questionnaire and interviews. A multilevel regression analysis and an independent sample t test were used to examine motivational interviewing skills and CVRM knowledge. Framework analysis was applied to analyse qualitative data. RESULTS: Data from 34 general practices were available, 19 intervention practices and 14 control practices. No improvements were measured on motivational interviewing skills in both groups. There appeared to be better knowledge of CVRM in the control group. On average half of the practice nurses indicated that they adopted the recommended interventions, but stated that they did not necessarily record this in patients' medical files. The tailored programme was perceived as too large. Time, follow-up support and reminders were felt to be lacking. About 20% of patients in the intervention group visited the general practice during the intervention period, yet only a small number of these patients were referred to recommended options. CONCLUSIONS: The tailored programme was only partly used by practice nurses and had little impact on either their clinical knowledge and communication skills or on patient reported healthcare. If the assumed logical model of change is valid, a more intensive programme is needed to have an impact on CVRM in general practice at all. PMID- 27978858 TI - Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention for employees through the use of an online facilitated bulletin board: study protocol for a pilot randomised controlled trial. AB - BACKGROUND: The evidence for the benefits of online cognitive behaviour therapy (CBT)-based programmes delivered in a clinical context is clear, but this evidence does not translate to online CBT-based stress management programmes delivered within a workplace context. One of the challenges to the delivery of online interventions is programme engagement; this challenge is even more acute for interventions delivered in real-world settings such as the workplace. The purpose of this pilot study is to explore the effect of an online facilitated discussion group on engagement, and to estimate the potential effectiveness of an online CBT-based stress management programme. METHODS: This study is a three-arm randomised controlled trial (RCT) comparing a minimally guided, online, CBT-based stress management intervention delivered with and without an online facilitated bulletin board, and a wait list control group. Up to 90 employees from six UK based organisations will be recruited to the study. Inclusion criteria will include age 18 years or over, elevated levels of stress (as measured on the PSS 10 scale), access to a computer or a tablet and the Internet. The primary outcome measure will be engagement, as defined by the number of logins to the site; secondary outcome measures will include further measures of engagement (the number of pages visited, the number of modules completed and self-report engagement) and measures of effectiveness (psychological distress and subjective wellbeing). Possible moderators will include measures of intervention quality (satisfaction, acceptability, credibility, system usability), time pressure, goal conflict, levels of distress at baseline and job autonomy. Measures will be taken at baseline, 2 weeks (credibility and expectancy measures only), 8 weeks (completion of intervention) and 16 weeks (follow-up). Primary analysis will be conducted on intention-to-treat principles. DISCUSSION: To our knowledge this is the first study to explore the effect of an online discussion group on the engagement and effectiveness of an online CBT-based stress management intervention. This study could provide a solution to the growing problem of poor employee psychological health and begin to address the challenge of increasing engagement with Internet-delivered health interventions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02729987 . Registered on 18 Mar 2016. PMID- 27978860 TI - Infant-directed speech (IDS) vowel clarity and child language outcomes. AB - There have been many studies examining the differences between infant-directed speech (IDS) and adult-directed speech (ADS). However, investigations asking whether mothers clarify vowel articulation in IDS have reached equivocal findings. Moreover, it is unclear whether maternal speech clarification has any effect on a child's developing language skills. This study examined vowel clarification in mothers' IDS at 0;10-11, 1;6, and 2;0, as compared to their vowel production in ADS. Relationships between vowel space, vowel duration, and vowel variability and child language outcomes at two years were also explored. Results show that vowel space and vowel duration tended to be greater in IDS than in ADS, and that one measure of vowel clarity, a mother's vowel space at 1;6, was significantly related to receptive as well as expressive child language outcomes at two years of age. PMID- 27978859 TI - Post-trial follow-up methodology in large randomized controlled trials: a systematic review protocol. AB - BACKGROUND: Clinical trials typically have a relatively short follow-up period, and may both underestimate potential benefits of treatments investigated, and fail to detect hazards, which can take much longer to emerge. Prolonged follow-up of trial participants after the end of the scheduled trial period can provide important information on both efficacy and safety outcomes. This protocol describes a systematic review to qualitatively compare methods of post-trial follow-up used in large randomized controlled trials. METHODS/DESIGN: A systematic search of electronic databases and clinical trial registries will use a predefined search strategy. All large (more than 1000 adult participants) randomized controlled trials will be evaluated. Two reviewers will screen and extract data according to this protocol with the aim of 95% concordance of papers checked and discrepancies will be resolved by a third reviewer. Trial methods, participant retention rates and prevalence of missing data will be recorded and compared. The potential for bias will be evaluated using the Cochrane Risk of Bias tool (applied to the methods used during the in-trial period) with the aim of investigating whether the quality of the post-trial follow-up methodology might be predicted by the quality of the methods used for the original trial. DISCUSSION: Post-trial follow-up can provide valuable information about the long term benefits and hazards of medical interventions. However, it can be logistically challenging and costly. The aim of this systematic review is to describe how trial participants have been followed-up post-trial in order to inform future post-trial follow-up designs. SYSTEMATIC REVIEW REGISTRATION: Not applicable for PROSPERO registration. PMID- 27978861 TI - A Prospective Analysis of Patients Presenting for Medical Attention at a Large Electronic Dance Music Festival. AB - Mass-Gathering Medicine studies have identified variables that predict greater patient presentation rates (PPRs) and transport to hospital rates (TTHRs). This is a descriptive report of patients who presented for medical attention at an annual electronic dance music festival (EDMF). At this large, single EDMF in New York City (NYC; New York, USA), the frequency of patient presentation, the range of presentations, and interventions performed were identified. This descriptive report examined consecutive patients who presented to the medical tent of a summertime EDMF held at an outdoor venue with an active, mobile, bounded crowd. Alcohol was available for sale. Entry was restricted to persons 18 years and older. The festival occurred on three consecutive days with a total cumulative attendance of 58,000. Medical staffing included two Emergency Medicine physicians, four registered nurses, and 86 Emergency Medical Services (EMS) providers. Data collected included demographics, past medical history, vital signs, physical exam, drug and alcohol use, interventions performed, and transport decisions. Eighty-four patients were enrolled over 2.5 days. Six were transported and zero died. The ages of the subjects ranged from 17 to 61 years. Forty-three (51%) were male. Thirty-eight (45%) initially presented with abnormal vital signs; four (5%) were hyperthermic. Of these latter patients, 34 (90%) reported ingestions with 3,4-methylenedioxymethamphetamine (MDMA) or other drugs. Eleven (65%) patients were diaphoretic or mydriatic. The most common prehospital interventions were intravenous normal saline (8/84; 10%), ondansetron (6/84; 7%), and midazolam (3/84; 4%). Electronic dance music festivals are a growing trend and a new challenge for Mass-Gathering Medicine as new strategies must be employed to decrease TTHR and mortality. Addressing common and expected medical emergencies at mass-gathering events through awareness, preparation, and early, focused medical interventions may decrease PPR, TTHR, and overall mortality. Friedman MS , Plocki A , Likourezos A , Pushkar I , Bazos AN , Fromm C , Friedman BW . A prospective analysis of patients presenting for medical attention at a large electronic dance music festival. Prehosp Disaster Med. 2017; 32(1):78-82. PMID- 27978862 TI - Serum C-reactive protein levels and body mass index in children and adolescents with CHD. AB - BACKGROUND: The prevalence of overweight in children with CHD is about 26.9%. Increase in adipose tissue is related to the secretion of proinflammatory markers such as C-reactive protein. Assuming that children with CHD are exposed to other inherent risk factors for heart disease, our objective was to evaluate the correlation between levels of C-reactive protein and body mass index in children and adolescents with CHD. METHODS: A cross-sectional study with 377 children and adolescents with CHD in a clinical setting of a reference hospital was carried out. C-reactive protein data were collected after 12 hours of fasting. Nutritional status was classified according to body mass index. The patients were divided into three groups: cyanotic, acyanotic, and minimal heart defects (controls). RESULTS: The mean age was 9.9+/-4.2 years, and 53.6% of the sample included males. The cyanotic group represented 22.3%, acyanotic 42.2%, and minimal defects 35.5% of the sample. The average body mass index percentile was 57.23+/-32.06. The median values of C-reactive protein were as follows: cyanotic 0.340, acyanotic with clinical repercussion 0.203, and minimal defects 0.128. There was a significant difference between the minimal defects and the cyanotic groups (p=0.023). There was a significant correlation between C-reactive protein and body mass index percentile (r=0.293, p<0.01). C-reactive protein levels were higher in girls (p=0.034). There were no significant correlations between C reactive protein and age or birth weight. CONCLUSION: The correlation between body mass index percentile and C-reactive protein was confirmed in this population. The prevention of overweight is paramount to avoid overlapping modifiable risk factors to those already inherent to the CHD. PMID- 27978863 TI - [China National Guideline of Classification, Diagnosis and Treatment for Lung Nodules (2016 Version)]. PMID- 27978864 TI - [Role of Autophagy in the Radiosensitivity of Human Lung Adenocarcinoma A549 Cells]. AB - BACKGROUND: Radiotherapy is an important treatment for lung cancer. The poor prognosis of lung cancer is largely caused by the high recurrence rate and metastasis of the tumor. Autophagy, which can be induced by radiotherapy, might be associated with DNA repair. The aim of this study is to investigate whether activating autophagy using rapamycin can enhance the radiosensitivity of lung cancer cells and clarify the association of autophagy with DNA repair. METHODS: The human adenocarcinoma A549 cell line was selected as the experimental subject. The specimens were divided into three groups: control (N), radiation (R), and Rapamycin and radiation (R+RAPA). The protein levels of gamma-H2AX, Rad51, Ku70/Ku80, p62, and LC3 were determined by Western blot. Autophagosome was observed under a transmission electron microscope, and SF was determined by colony formation assay. RESULTS: Compared with group R, the activity of autophagy and the protein expression levels of Rad51 and Ku70/80 were remarkably increased in group R+RAPA. CONCLUSIONS: The radiosensitivity of lung cancer can be promoted by activating autophagy via treatment with Rapamycin, and the process may be associated with DNA repair.?. PMID- 27978865 TI - [Synergistic Antitumor Effect of Amorphigenin Combined with Cisplatin in Human Lung Adenocarcinoma A549/DDP Cells]. AB - BACKGROUND: Amorphigenin, a rotenoid compouns, from seeds of Amorpha fruticosa, has been shown to possess anti-proliferation activities in several cancer cells. To explore the antitumor effects of amorphigenin on cisplatin-resistant human lung adenocarcinoma A549/DDP cells and explore the underlying mechanisms. METHODS: CCK-8 assay was used to measure the proliferation of A549/DDP cells; Colony formation assay was used to measure the colony formation of A549/DDP cells; Flow cytometry assay was used to detect the apoptosis rates; Western blot analysis was used to explore the expression of apoptosis-related proteins (caspase-3 protein, PARP protein) and lung resistance protein (LRP). RESULTS: Our results demonstrated that amorphigenin could inhibit the proliferation of A549/DDP cells with a inhibition concentration of 50% cell growth (IC50) at 48 h of (2.19+/-0.92) MUmol/L. Amorphigenin could inhibit the colony formation ability and induce apoptosis of A549/DDP cells; Furthermore, amorphigenin combined with cisplatin showed synergistic proliferation-inhibitory effect and apoptosis promoting effect in A549/DDP cells; reduced the expression of LRP of A549/DDP cells. CONCLUSIONS: Amorphigenin remarkably inhibits the proliferation and induces apoptosis in A549/DDP cells. Combination of amorphigenin with cisplatin had the synergistic inhibitory effect on A549/DDP cells by downregulating the expression of LRP.?. PMID- 27978866 TI - [Diagnostic Value of Folate Receptor-positive Circulating Tumor Cell in Lung Cancer: A Pilot Study]. AB - BACKGROUND: The aim of this study is to determine the efficacy and feasibility of a novel folate receptor (FR)-based circulating tumor cell (CTC) detection method in the diagnosis of lung cancer. CTCs were collected from 3 mL of blood based on negative enrichment by immunomagnetic beads and then labeled by a conjugate of a tumor-specific ligand folate and an oligonucleotide. METHODS: After washing off redundant conjugates, the bound conjugates were removed and analyzed by quantitative polymerase chain reaction. RESULTS: The CTC levels of 97 patients with lung cancer were significantly higher than that of the controls (18 patients with benign lung diseases; P<0.001). With a threshold of 8.7 Folate units, the method showed a sensitivity of 82.5% and a specificity of 72.2% in the diagnosis of lung cancer, especially a sensitivity of 86.8% in stage I disease. Compared with the existing clinical biomarkers such as neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), and CYFRA21-1, the method showed the highest diagnostic efficiency in lung cancer (area under the curve, 0.859; 95%CI: 0.779 0.939) and stage I lung cancer (area under the curve, 0.912; 95%CI: 0.829-0.994). For future work, the CTC levels of 5 lung cancer patients higher than 8.7 Folate units/3 mL in their postoperation. CONCLUSIONS: FR-positive CTCs were feasible diagnostic biomarkers in patients with lung cancer, as well as in early-stage tumors. PMID- 27978867 TI - [What is Result: Short-term Medium Chain Triglyceride Diet Effective on?Postoperative Outcome in Lung Cancer Surgery? A Prospective Randomized Study]. AB - BACKGROUND: It has been proven that medium chain triglyceride (MCT) diet was contribute to fast track recovery after surgery in patients with operation. In this study, the benefit of postoperative short term MCT diet support was investigated for non-small cell lung cancer patients who underwent anatomic resection. METHODS: A prospective study was planned with the approval of our institutional review board. 117 lung cancer patients who underwent anatomic resection in a single medical group between December 2015 and March 2016 were randomized. 62 patients were applied a MCT diet. and 55 patients in the control group who were fed with only normal diet, and the serum albumin levels, anus exhaust time, chest drainage, chest drainage time, the hospitalization time of post operation, average hospital cost were analysed. RESULTS: The mean anus exhaust time in MCT group [(27.87+/-14.38) h] was significantly shorter than that in RDG group [(45.18+/-8.62) h] (P<0.001); The mean chest tube drainage time in MCT group [(75.40+/-48.41) h] were less than that in RDG group [(110.64+/-94.19) h] (P=0.025). The mean chest tube drainage volume in MCT group [395 mL] were less than that in RDG group [590 mL] (P=0.027). The hospitalization time of post operation was (5.26+/-2.96) d in MCT group against (6.73+/-3.99) d in RGD group (P=0.030). The serum albumin levels of postoperative in MCT group [(37.26+/-2.70) g/L)] was significantly higher than that in RDG group [(35.92+/-3.12) g/L)] (P=0.023). CONCLUSIONS: The results of this study demonstrated that postoperative short term MCT diet is beneficial in postoperative gastrointestinal function fast recovered and shorten the hospitalization time in non-small cell lung cancer patients after surgery. PMID- 27978868 TI - [Application Effect of Fast Track Surgery for Patients with Lung Cancer: ?A Meta analysis]. AB - BACKGROUND: Fast track surgery (FTS) can accelerate rehabilitation and reduce postoperative hospital stay. It has been effectively applied to several surgical diseases. However, the safety and effectiveness of FTS for patients with lung cancer in China is unclear. This meta-analysis aimed to evaluate the effect of FTS undergoing lung cancer surgery in China. METHODS: Using home and abroad databases to search all documents required. The deadline of retrieval was January 31, 2016. Then the studies were screened according to the inclusion and exclusion criteria. Data were analyzed by RevMan 5.3 software. RESULTS: 8 randomized controlled trials (RCTs) and 5 clinical controlled trials (CCTs) with 1,241 patients were eligible for analysis. Compared with control group, FTS group can significantly shorten postoperative hospital time (MD=-3.61, 95%CI: -5.05--2.16, P<0.000,01) and chest tube duration (MD=-2.62, 95%CI: -3.07-2.17, P<0.000,01), reduce incidence of postoperative complications (OR=0.30, 95%CI: 0.19-0.47, P<0.000,01) and hospitalization costs (MD=-0.92, 95%CI: -1.19--0.65, P<0.000,01). CONCLUSIONS: FTS can safely and effectively accelerate the recovery of patients with lung cancer in China, it exhibits important clinical values. PMID- 27978869 TI - [Intercalated Combination of Chemotherapy and EGFR-TKIs versus Chemotherapy Alone in the First-line Treatment of Advanced Non-small Cell Lung Cancer: A Meta analysis]. AB - BACKGROUND: The combination therapy of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has attracted the attention of more and more investigators. The aim of this meta-analysis is to evaluate the clinical efficacy and safety of intercalated combination of chemotherapy and EGFR TKIs versus chemotherapy alone in the first-line therapy of advanced non-small cell lung cancer (NSCLC). METHODS: We retrieved the Cochrane Library, PubMed, EMBASE, CBM, CNKI and Wanfang databases for randomized controlled trials which involved the intercalated combination of chemotherapy and EGFR-TKIs, and chemotherapy alone in the first-line treatment of advanced NSCLC. The progression free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events were analyzed. The quality evaluation and cross-checked data were independently performed by two investigators according to the Cochrane Systematic Reviews Handbook. The Stata 12.0 software was used to conduct the meta-analysis. RESULTS: This study included 933 NSCLC patients from 6 RCTs. The meta-analysis demonstrated that the intercalated combination of chemotherapy and EGFR-TKIs significantly prolonged the PFS (HR=0.72, 95%CI: 0.53-0.98, P=0.037) of advanced NSCLC patients compared with mono-chemotherapy. However, there was no statistical difference in OS (HR=0.85, 95%CI: 0.72-1.01, P=0.060), ORR (OR=1.59, 95%CI: 0.86-2.95, P=0.142) and DCR (OR=1.09, 95%CI: 0.95-1.25, P=0.226) between the two groups. Further, the subgroup analysis showed that the intercalated combination markedly improved the PFS in female, adenocarcinoma, never smoking, EGFR mutant patients. In the aspect of safety, the main side effects of the intercalated combination therapy were rash (OR=7.81, 95%CI: 3.74-16.34, P<0.001) and diarrhea (OR=2.73, 95%CI: 1.92 3.89, P<0.001). CONCLUSIONS: The intercalated combination of chemotherapy and EGFR-TKIs significantly prolonged the PFS in the first-line therapy of advanced NSCLC patients compared with mono-chemotherapy, and the main adverse events were tolerable rash and diarrhea. Together, the intercalated combination shows promising results, and more large-scale and high-quality RCTs are still needed. PMID- 27978871 TI - [Interventional Bronchoscopies for the Treatment of 112 Cases with Complex Malignant Central Airway Diseases Involved in Bifurcation]. AB - BACKGROUND: It is very difficult to deal with the comprehensive central airway diseases, especially the malignant airway obstruction. The aim of this study is to explore the clinical effects of multiple interventional bronchoscopies for the treatment of 112 cases with comprehensive malignant central airway diseases so as to evaluate the clinical applications of thermoablation and cryosurgery. METHODS: The 112 cases with malignant airway diseases retrospectively reviewed for bronchoscopic interventions performed in more than two lesions of carina and/or bifurcation. The age was from 22 to 90 years, which including 55 cases with squamous carcinoma (SQ), 16 adenocarcinoma (AD), 15 adenocystic carcinoma (ACC), 10 metastasis tumor (MT), 8 small cell lung carcinoma (SCLC) and 8 mixed carcinoma (MC). All bronchoscopic interventions such as argon plasma coagulation (APC), cryosurgery, electronic snare and stenting were performed under rigid bronchoscopy combined with electric bronchoscopy in general anesthesia. RESULTS: The 460 bronchoscopic procedures were successfully performed in 112 cases. Cryosurgery and APC were the most used in every group. Stent was more common in patients with MT, balloon dilation was more common in patients with ACC and AD. Electric snare and radioactive seeds implantation were frequently used in cases with SCLC. Trachea stricture is more severe in MT than that in others, while bronchus stricture is more severe than that of trachea in SQ and ACC group. Karnofsky performance score (KPS) is lower and shortness of breath score (SBS) is higher in MC, MT and SCLC group. Trachea and bronchus stricture is improved after comprehensive treatment in 5 groups except of mixed group. KPS increased and SS decreased significantly in 5 groups except of adenocarcinoma. In follow-up, the overall survival time (OS) is 15 months and median survival time is 10 months, especially OS is 28.4 months in ACC and 21.7 months in AD, 8.9 months in SCLC and 7.4 months in mixed group. CONCLUSIONS: APC combination with Cryosurgery and other bronchoscopic interventions are indicated for the treatment of complex or difficult airway diseases whether they are located in trachea or bronchus. It is a safe and rapid during procedure. PMID- 27978870 TI - [Expression and Clinical Significance of PD-1 and PD-L1 in Pulmonary Carcinoids]. AB - BACKGROUND: The incidence of pulmonary carcinoid (PC) is very rare in primary lung malignant tumors, and the prognosis of this disease is closely associated with its pathological features. In this study, the expressions of programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1) in lung carcinoid cells were detected, and the correlation between the expression and corresponding clinical physiological and pathologic features was further analyzed. METHODS: The expressions of PD-1 and PD-L1 in 20 cases of PC paraffin-embedded tissue specimens were detected through immunohistochemistry. The H-score of immunohistochemical staining (range, 0-300) was employed to evaluate the expression of PD-1 and PD-L1 in the tumor tissues. RESULTS: In the 20 cases of patients with PC, 40% (8/20) showed positive expressions of PD-1, and 45% (9/20) showed positive expressions of PD-L1. Significantly higher expressions of PD-1 were observed in the smoking patients than in the nonsmoking patients (63.64% vs 11.11%, P<0.05). Furthermore, no significant relationship was found between the expressions of PD-1 and PD-L1 and the clinical characteristics of the patients, such as age, gender, pathological type, clinical stage, and metastasis (P>0.05). CONCLUSIONS: Approximately 40% of PC patients had positive expressions of PD-1or PD-L1. The positive expression rate of PD-1 in the smoking patients was significantly higher than that in the nonsmoking patients. These results suggest that the expressions of PD-1 and PD-L1 may be associated with the occurrence and development of PC. PMID- 27978872 TI - [Primary Application of Radiofrequency Ablation after Locally Progression of?EGFR TKIs in Non-small Cell Lung Cancer]. AB - BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) is one of the foundamental treatment for non-small cell lung cancer (NSCLC) with EGFR mutation, however some patients might develop locally progression in primary site. The aim of this study is to assess the clinical application of radiofrequency ablation after locally progression of NSCLC while receving EGFR TKIs. METHODS: Twenty-eight eligible NSCLC patients were enrolled. Efficacy and Safety data of radiofrequency ablation followed by EGFR-TKIs or chemotherapy were collected. RESULTS: None of patients had died during peri-operation period. The average follow-up time was 17.25 months. Locally progression rate was 10.7% (3/28), and locally progression time was 16.6 months. The average progression free survival was (24.55+/-5.36) (95%CI:14.04-35.05), and the average overall survival was (25.57+/-5.45)(95%CI:14.88-36.27). Patients were divided into EGFR TKIs group and chemotherapy group after radiofrequency ablation. The average progression-free survival of the two groups were (27.82+/-7.58)(95%CI:12.97 42.68) and (17.88+/-3.76)(95%CI:10.52-25.25)(P>0.05) respectively. The average OS (overall survival) was (29.42+/-7.68)(95%CI:14.36-44.48) and (18.44+/-3.87)(95% CI:14.89-36.27)(P>0.05) in two groups. CONCLUSIONS: Radiofrequency ablation combined with EGFR-TKIs or chemotherapy could prolong progression-free survival and overall survival of EGFR mutant NSCLC patients who had developed locally progression in primary site during EGFR-TKIs treatment. PMID- 27978873 TI - [Relationship between ID1 and EGFR-TKI Resistance ?in Non-small Cell Lung Cancer]. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) presents the highest morbidity and mortality among malignant tumors worldwide. The overall effective rate of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is 30% to 40%, and PFS (progression-free sruvival) is 12 months. However, EGFR-TKI resistance is typical in clinical observations, and this phenomenon significantly affects tumor suppression. To overcome this resistance, a new prognostic factor associated with lung cancer drug resistance should be discovered. This study investigated the relationship between the inhibitor of differentiation 1 (ID1) and non-small cell lung cancer EGFR-TKI resistance in vivo and in vitro to determine any statistical significance and discuss the underlying mechanism. METHODS: Western blot and qRT-PCR were used to quantify the expression of ID1 in lung cancer. IHC was used to detect the expression of ID1 in pathological tissues (lung cancer tissues and adjacent tissues). MTT was used to detect cell proliferation, in which the cells were treated with gefitinib after being transfected by ID1 slow virus vector. Lung cancer cells were inoculated in nude mice until the tumor diameter grew to certain measurement. Gefitinib treatment was started, and the tumor volume was estimated. RESULTS: ID1 was highly expressed in NSCLC (P<0.05). Both ID1 expression and drug resistance of EGFR-TKI in NSCLC were positively correlated (P<0.05). The treatment group with gefitinib showed obviously less expression than the control group. CONCLUSIONS: ID1 is highly expressed in NSCLC. ID1 expression was positively related to drug resistance of EGFR-TKI in NSCLC. Gefitinib can be used to effectively treat NSCLC, and the mechanism may be associated with an increased level of STAT3 phosphorylation. PMID- 27978874 TI - [Concurrent Chemoradiotherapy with Original Chemotherapy Regimens may not be Suitable for Patients Who Failed to Respond to Induction Chemotherapy?in Limited stage Small Cell Lung Cancer]. AB - BACKGROUND: The group of small cell lung cancer (SCLC) are usually highly sensitive to chemotherapy, and less than 15% of them are resistant to drugs. We respectively evaluate the correlation of the sequence and timing of radiotherapy with progression-free survival (PFS) and overall survival (OS) in patients with limited-stage SCLC (LS-SCLC), and to figure out whether concurrent chemoradiotherapy is superior to sequent chemoradiotherapy. METHODS: Sixty-seven patients diagnosed with LS-SCLC from January 2009 to June 2014 failed to respond to induction chemotherapy. According to the sequence of therapy, they were divided into concurrent chemoradiotherapy group (n=32) and sequent chemoradiotherapy group (n=35). Ninety-four percent of the patients were diagnosed with stage III, and six percent were stage Ib-IIb. Twenty-five patients were treated with prophylactic cranial irradiation (PCI). The Kaplan-Meier method was used to calculate survival time and Log-rank test was used for between-group comparisons. Between-group comparison of categorical data was made by chi2 test. RESULTS: In all patients, the 2-year OS, PFS and LC rates were 53.7%, 20.9% and 58.2%. The 2-year OS and PFS rates of concurrent chemoradiotherapy group and sequent chemoradiotherapy were 37.5% vs 54.3% (P=0.048) and 12.5% vs 28.6% (P=0.149). Hematologic toxicities were more common in concurrent group than sequent one (P=0.031), and no statistical difference was observed between the two groups in terms of grade 3 radiation esophagitis, pneumonitis and gastrointestinal reactions (9.4% vs 0, P=0.176; 12.5% vs 2.9%, P=0.318; 12.5% vs 2.9%, P=0.109). Patients treated with PCI have superior OS and PFS comparing with those not (56.0% vs 38.1%, P=0.029; 24% vs 19%, P=0.012). CONCLUSIONS: Concurrent chemoradiotherapy with original chemotherapy regimens may not be suitable for patients who failed to respond to induction chemotherapy in LS-SCLC, and second line regimens or radiotherapy alone can be used for them, but prospective trils with large sample are still needed to confirm that.?. PMID- 27978875 TI - [Endoscopic surgery and reconstruction for extensive osteoradionecrosis of skull base after radiotherapy for nasopharyngeal carcinoma]. AB - Objective: To investigate the clinical efficacy of endoscopic surgery for extensive osteoradionecrosis (ORN) of skull base in patients with nasopharyngeal carcinoma (NPC) after radiotherapy. Methods: Seventeen patients diagnosed as ORN of skull base after radiotherapy for NPC and underwent endoscopic surgery were retrospectively studied with their clinic data. Results: Based on the CT and endoscopic examination, all patients had large skull base defects with bone defects averaged 7.02 cm2 (range, 3.60 - 14.19 cm2). Excepting for curetting the sequestra, endoscopic surgery was also used to repair the wound or to protect the internal carotid artery with flap in 12 patients. No bone reconstructions were conducted in all patients with the bone defects of skull base. CT examinations were taken after endoscopic surgery when required. The postoperative follow-up ranged from 8 months to 6 years (average, 14 months). Aside from 1 patient with delayed cerebrospinal fluid (CSF), others had no related complications. Conclusions: The patients with extensive ORN can be treated with endoscopic surgery to curette the necrotic bone of skull base, and endoscopic reconstruction provides an alternative technique. It may not be necessary to reconstruct the bone defects at skull base, however, the exposed important structures of skull base, such as internal carotid artery, need to repair with soft tissue such as flap. PMID- 27978876 TI - [Application of cut needle biopsy in the diagnosis of submucosal type of nasopharyngeal neoplasms]. AB - Objective: To evaluate the efficacy of cut needle biopsy in the diagnosis of submucosal nasopharyngeal neoplasms. Methods: Cut needle biopsy performed with automatic biopsy gun was applied in 17 cases with submucosal type of nasopharyngeal neoplasms.The bleeding quantity was recorded and the pain was measured by score. Results: Adequate biopsy sample for hispathological diagnosis was received from each of the 17 patients. And the hispathological diagnosis were consistent with the follow-up visit. The bleeding quantity ranged from 1 to 5 ml ((1.9+/-0.3)ml). The scores of numerical rating scale were between 2-7 (4.0+/ 0.4). There were no serious complications such as hemorrhea. There were 3 patients of inflammation in pathological diagnosis. And These 3 patients had no tumor during the follow-up( from 6 to 33 months). There were 12 patients of undifferentiated cancer. Among the 12 patients, there were five newly diagnosed patients and seven recurrent patients. There were 2 patients of lymphoma. Conclusion: Cut needle biopsy has the advantages of minimal trauma, shorter operative time, less bleeding, light pain, and no serious complications. It is simple, safe, and worth of application clinically. PMID- 27978878 TI - [PAX3 gene mutation analysis for two Waardenburg syndrome type I families and their prenatal diagnosis]. AB - Objective: To analyze the mutations of PAX3 gene in two Waardenburg syndrome type I (WS1) pedigrees and make prenatal diagnosis for the high-risk 18-week-old fetus. Methods:PAX3 gene was first analyzed by Sanger sequencing and multiplex ligation-dependent probe amplification(MLPA) for detecting pathogenic mutation of the probands of the two pedigrees. The mutations were confirmed by MLPA and Sanger in parents and unrelated healthy individuals.Prenatal genetic diagnosis for the high-risk fetus was performed by amniotic fluid cell after genotyping. Results: A heterozygous PAX3 gene gross deletion (E7 deletion) was identified in all patients from WS1-01 family, and not found in 20 healthy individuals.Prenatal diagnosis in WS1-01 family indicated that the fetus was normal. Molecular studies identified a novel deletion mutation c. 1385_1386delCT within the PAX3 gene in all affected WS1-02 family members, but in none of the unaffected relatives and 200 healthy individuals. Conclusions:PAX3 gene mutation is etiological for two WS1 families. Sanger sequencing plus MLPA is effective and accurate for making gene diagnosis and prenatal diagnosis. PMID- 27978877 TI - [Detection and screen of pulmonary metastasis-related signature genes in nasopharyngeal carcinoma]. AB - Objective: To establish an animal model of pulmonary metastasis from nasopharyngeal carcinoma (NPC) and to investigate differential genes associated with pulmonary metastasis. Methods: CNE cell line was used to construct the stable metastasis CNE/Luc cell line which steadily expresses the fluorescent enzyme genes. The CNE/Luc cells were injected into immunodeficiency mice through tail vein, and with the in vivo imaging technology, the mice with pulmonary metastasis were filtered out. The pulmonary metastasis cells, were separated and injected into the tail vein of other nude mice to obtain the tissue-specificity metastasis cells confirmed by fluorescent imaging system. Based on the gene chip, the differential genes associated with pulmonary metastasis for NPC were found. Results: The gene expression profiles of nasopharyngeal carcinoma cell line CNE/Luc and their lung metastasis-associated subpopulation CNE/Luc-2 were constructed by gene chip technology. Ten metastasis-related genes were screened by software analysis, namely as TP53, PIK3CA, MET, KRAS, VEGFA, EDNRB, GSK3B, FOXO3, SOD2, and BIRC3. Conclusions: Some genes including TP53, PIK3CA, MET, KRAS, VEGFA, EDNRB, GSK3B, FOXO3, SOD2, and BIRC3 are indicated to have important roles in the lung metastasis of nasopharyngeal carcinoma. PMID- 27978880 TI - [Prevalence of laryngopharyngeal reflux disease in Fuzhou region of China]. AB - Objective: To assess the prevalence of laryngopharyngeal reflux disease (LPRD) in the Fuzhou region. Methods: A total of 4100 subjects who aged from 10 to 70 years derived from a random cluster sampling in fourty districts of Fuzhou region and they were asked to complete questionnaires. According to the grade standard of reflux symptom index (RSI), subjects with total score more than 13 were defined as having LPRD. The factors associated with LPRD were evaluated with corrective analysis. Results: Effective questionnaires were obtained from 4 063 of 4 100 subjects. The prevalence of LPRD was 5.00%(203/4 063). The prevalence of LPRD in subjects of 30-39 years old was significantly higher than that in subjects of 10 19 years old (chi2=8.532, P=0.003). The prevalence of LPRD in men was higher than that in women (P<0.001). There were significant difference in the prevalence of LPRD between different occupations (P<0.001). The prevalence of LPRD in industrial workers was 7.89% (24/304), higher than that in students (4/196, 3.14%). RSI was correlated with clearing throat, with a correlation coefficient of 0.687. LPRD was also correlated with dysphagia and pharyngeal foreign body sensation. Conclusions: The prevalence of LPRD in Fuzhou region is 5.00% and LPRD is closely related to age, sex, occupation, clearing throat, dysphagia and pharyngeal foreign body sensation. PMID- 27978879 TI - [Subjective and objective evaluation and correlation analysis of pre- and post- operation in patients with structural nasal obstruction]. AB - Objective: To analyze the subjective and objective results and the correlation of nasal obstruction because of nasal structural variation pre and post operation, and to provide clinical evidence for surgery and curative effect. Methods: Three groups were included in this study: group 1 were 78 patients with structural rhinitis, group 2 were 72 patients with chronic sinusitis (without nasal polyp) and group 3 were healthy controls of 75 cases. Assessment of nasal obstruction was achieved by visual analog scale (VAS), and objective measurement was achieved by rhinomanometry and acoustic rhinometry. The first two minimum cross-sectional area of nasal cavity (MCA1, MCA2), their distances from the nostrils (MD1, MD2) and the nasal volume of 5 cm depth from the nostril (NV5) were recorded. The ratio of the parameters of the two sides of the nasal cavity was calculated respectively. Nasal resistance total (RT) and calculated right-left nasal resistance ratio (Rlr) were recorded. Patients of group 1 and group 2 accepted endoscopic surgery and received the above evaluation again at three months after surgery. Three groups were compared with statistical test. Results: The preoperative values of three groups (MCA1, MD1, MCA2, MD2, NV5, RT) showed no statistical significance (F value was 0.945, 0.245, 1.380, 0.036, 0.866, 1.651, respectively; all P>0.05), while their ratio had statistical differences except MD1 (F value was 5.242, 1.726, 4.882, 4.005, 5.066, 5.316; P=0.013, 0.199, 0.019, 0.024, 0.018, 0.011, respectively). Statistical results between the ratio of values (MCA1, MD1, MCA2, MD2, NV5, RT) and VAS of nasal obstruction of group 1 and group 2 showed significant positive correlations pre operation(r of group 1 value was 0.471, 0.418, 0.260, 0.324, 0.305, 0.459, respectively; r of group 2 value was 0.373, 0.403, 0.288, 0.366, 0.402, 0.249, respectively; all P<0.05). VAS scores pre and post operation of group 1 had statistically difference (t=35.122, P<0.05). Postoperative value of MD1, MD2 and RT among three groups had no statistical difference (F value was 0.178, 0.582, 0.905, respectively; all P>0.05). Postoperative value of MCA1, MCA2, NV5 among three groups had statistical difference (F value was 4.010, 5.126, 4.901, respectively; all P<0.05). Postoperative ratio of MCA1, MD1, NV5 and Rlr among three groups had no statistical difference (F value was 1.023, 0.944, 0.524, 0.996, respectively; all P>0.05). Postoperative ratio of MCA2 and MD2 among three groups had statistical difference (F value was 4.859, 4.357, respectively; all P<0.05). Conclusion: Severity of nasal obstruction is related to structural variation of nasal cavity and the purpose of surgery is to restore structural symmetry of bilateral nasal cavity. PMID- 27978881 TI - [Reconstruction with free jejuna flap for the defect after removal of hypopharyngeal and cervical esophageal caneer: clinical analyses of 103 cases]. AB - Objective: To report our experience in reconstruction with free jejunal flap for circumferential defect following resection of hypopharygeal and cervical esophageal carcinoma. Methods: A retrospective analysis was conducted to evaluate the outcomes of reconstruction with free jejunal flaps for circumferential defects in 103 patients treated from Aug 2008 to Mar 2015. Among them, 84 were hypopharyngeal carcinoma and 19 were cervical esophageal carcinoma; 31 patients had total pharyngolaryngectomy, 70 had total pharyngolaryngectomy and cervical esophagectomy and 2 had laryngeal preservation. All patients underwent bilateral neck dissection and 84 underwent retropharyngeal lymph node dissection. Results: The 3 year overall survival rate was 51.6% and disease-specific survival rate was 50%. The 5 year overall survival rate was 39.1%. No in-hospital death, one patient had unsalvageable flap failure and underwent second reconstruction with free jejunal flap. The success rate for the free jejunal flaps was 99% (102/103). Pharyngocutanous fistula occurred in 3 patients and all healed with conservative treatment. Satisfactory oral intake was achieved in all patients. Conclusions: Oncological and functional outcomes of reconstruction with free jejunal flap for circumferential defects of hypopharynx and cervical esophagus were satisfying. Multidisciplinary cooperation is helpful to improve surgical success rate. Free jejunal flap is an ideal method for reconstruction of circumferential hypopharyngeal and cervical esophageal defects after removal of tumor. PMID- 27978882 TI - [Modified pedicled thoracoacromial artery perforator flap for the repair of complex pharyngocutaneous fistula: a retrospective review of 9 cases]. AB - Objective: To report our experience in the application of modified pedicled thoracoacromial artery perforator (TAAP) flap for the repair of complex pharyngocutaneous fistula. Methods: Between December 2011 and September 2015, modified pedicled TAAP flaps were used to repair pharyngocutaneous fistulas in 9 patients. All patients were males, and ranged in age from 28 to 72 years old. Fistula size ranged from 4.5 cm*2.5 cm to 6.5 cm*4.5 cm, and the TAAP skin paddle size ranged from 7.0 cm*4.0 cm to 8.0 cm*5.0 cm. Neck defect size ranged from 4.0 cm*3.0 cm to 6.0 cm*4.0 cm, and the TAAP skin paddle size ranged from 5.5 cm*3.5 cm to 7.0 cm*5.0 cm. Results: All 9 flaps survived smoothly and all the donor sites were closed directly, with no flap vascular crisis and necrosis. The mean hospitalization of patients was 10.4 days. Postoperative barium swallow showed no hypopharyngeal stenosis or fistula recurrence. The follow-up time ranged from 8 to 32 months. The appearance of neck was good and all patients accepted oral diet. Only linear scar was left on the donor site, with no significant impairment of the function of pectoralis major muscle. Conclusion: Modified pedicled TAAP flap is suitable for the repair of complex pharyngocutaneous fistula. PMID- 27978883 TI - [Investigation on the expression of microvessel pericyte coverage index and lymph vessel density in nasal polyps]. AB - Objective: To investigate the role of lymph vessel density (LVD) and microvessel pericyte coverage index (MPI) in the pathogenesis of nasal polyps. Methods: Using immunohistochemistry and immunofluorescence double staining method, the expressions of albumin, D2-40 and CD34-alpha-SMA in 11 specimens of normal nasal mucosa, 26 specimens of nasal polyp and 26 specimens of inferior turbinate tissue from patients with nasal polyps were investigated. The counts of microvessel density (MVD), lymph vessel density (LVD) and microvessel pericyte coverage index (MPI) were compared. SPSS 17.0 software was used to analyze the data. Results: The nasal polyp group(0.269+/-0.096) had more albumin than inferior turbinate tissue group(0.159+/-0.078) and normal nasal mucosa group(0.138+/-0.045), the differences were significant (q value was 4.873, 4.446, both P<0.05). The counts of MVD in nasal polyp group (30.52+/-4.42) were not significantly higher than those in inferior turbinate tissue group (30.33+/-6.03) and normal nasal mucosa group(28.21+/-6.84), the differences were not significant (q value was 0.130, 1.147, both P>0.05). The MPI in nasal polyp group (0.291+/-0.096) was significantly lower than those in inferior turbinate tissue group(0.432+/-0.101) and normal nasal mucosa group(0.416+/-0.071), the difference was significant (q value was 5.399, 3.680, both P<0.05). The counts of LVD in the nasal polyp group(0.245+/-0.073) were significantly lower than those in inferior turbinate tissue group (0.431+/-0.054) and normal nasal mucosa group(0.470+/-0.078), the difference was significant (q value was 10.004, 9.328, both P<0.05). MPI expression in the nasal polyp group was negetively correlated to albumin expression(r=-0.889, P<0.05). The LVD expression in the nasal polyp group was negetively correlated to albumin expression(r=-0.901, P<0.05). Conclusion: Different LVD and MIP in nasal polyp tissues and normal nasal mucosa tissues imply that microcirculatory dysfunction plays a crucial role in the pathogenesis of nasal polyps. PMID- 27978885 TI - [Two cases of bilateral pneumothorax and pneumomediastinum caused by the improper use of the Blue Line Ultra(r) tracheostomy tube]. PMID- 27978886 TI - [Evaluation of 8 cases of bilateral vocal cord paralysis by the resection of posterior part of vocal cord and vocal process using PMOD]. PMID- 27978884 TI - [Expressions of angiogenesis-related factors: CD105, EphA2 and EphrinA1 in laryngeal squamous cell carcinoma and clinical implication]. AB - Objective: To investigate the expressions of endoglin (CD105), erythropoietin producing hepatocyte receptor A2 (EphA2) and its ligand ephrinA1 proteins in laryngeal squamous cell carcinoma (LSCC) and the relationship between their expressions and the clinicopathological factors of LSCC. Methods: The expressions of CD105, EphA2 and EphrinA1 proteins were detected with immunohistochemical staining in LSCC in 76 cases and adjacent normal laryngeal tissues (ANLT) (S-P) in 25 cases.SPSS 17.0 software was used to analyze the data. Results: The mean microvessel density (MVD) value marked by CD105 staining in LSCC was 10.33+/ 2.29, which was significantly higher than that in ANLT(1.20+/-1.04, t=18.732, P<0.05). The CD105-MVD was correlated with T stage, histological grading, clinical stage, lymph node metastasis, recurrence and prognosis in LSCC (F value was 5.34, 4.79, 5.36, t value was -2.70, 2.56, all P<0.05). The positive expression rates of EphA2 and EphrinA1 in LSCC were 78.95% (60/76), and 81.85% (62/76), which were respectively significantly higher than 40% (10/25) for EphA2 expression and 44% (11/25) for EphrinA1, expression in ANLT (chi2 value was 13.41, 13.26, both P<0.05). EphA2 expression was correlated with histological grading, T stage, clinical stage, lymph node metastasis, recurrence and prognosis in LSCC (chi2 value was 6.25, 14.60, 15.11, 8.52, 5.54, all P<0.05). EphrinA1 expression was correlated with T stage, clinical stage, lymph node metastasis, recurrence and prognosis in LSCC (chi2 value was 6.44, 12.28, 16.78, 6.44, all P<0.05). The expressions of CD105, EphA2 and EphrinA1 were positively correlated with each other r value was 0.72, 0.74, 0.64, all P<0.05. Survival analysis indicated that the expressions of CD105 and EphA2, histological grading, lymph node metastasis, clinical stage and recurrence were independent factors for tumor prognosis in LSCC (P<0.05). Conclusions: The expressions of CD105, EphA2 and EphrinA1 protein were positively correlated with each other in LSCC. They may play important roles in the tumorigenesis, malignant progression and poor prognosis of LSCC. PMID- 27978887 TI - [Hemangiopericytoma from external auditory canal and middle ear: one case report]. PMID- 27978888 TI - [Treatment for intraorbital hematoma by orbital decompression after surgery of recurrent nasal polyps: a case report]. PMID- 27978889 TI - [Advances in therapy of auricular keloid]. AB - Auricularis keloids are the keloids locating on the earlobe and helix which often caused by ear piercing, burn wound and skin injury. Because of its high recurrence, the treatment of auricularis keloids is troublesome to ENT doctors. In the past, clinicians harvested some achievements by combining surgical therapy, drug therapy and physical therapy. Keloid therapies were reviewed in this article. PMID- 27978890 TI - [Speech evoked auditory brainstem response and cognitive disorders]. AB - Speech evoked auditory brainstem response(s-ABR)is evoked by compound syllable, and those stimulus are similar to the daily language which convey both semantic information and non-semantic information. Speech coding program can take place at brainstem. As a new method, s-ABR may reveal the mystery of speech coding program. Many tests have proved that s-ABR is somehow related to cognitive ability. We mainly illustrated the possibility of grading the cognitive ability using s-ABR, the abnormal test result from those cognitive disorders, and the family factors that contribute to cognitive disorder. PMID- 27978891 TI - [Advances in studies of the genes related to thyroid carcinoma]. AB - Thyroid carcinoma (TC) is the most common endocrine cancer and its incidence has been increasing globally over the past decades. With the development of the genetic technology, more and more evidences showed that many genes affect the biological behaviors of TC, making sense to early diagnosis, predicting the prognosis and targeted therapy for TC. BRAF mutation is specific to papillary thyroid carcinoma (PTC). It can not only predict the prognosis, but also have diagnosis value. RET rearrangements are identified as a specific genetic event in PTC. Though the preoperative detection of RET/PTC rearrangements has not proven useful in choosing the appropriate surgical management, new medications which are capable of inhibiting RET protein kinase activity may help to therapy the PTCs. RET mutation has specific meaning for detecting familial medullar thyroid carcinoma. Though RAS mutation can be discovered in follicular thyroid carcinoma (FTC), follicular variant of papillary thyroid carcinoma (FvPTC), poorly differentiated thyroid carcinoma (PDTC) and undifferentiated thyroid carcinoma (UTC), the relationship between RAS mutation and prognosis remains controversial. P53 can be detected in more invasive variants of PTC, PDTC and UTC. P53 can be used as a prognosis-predictor. Rescuing the function of mutant p53 (mutp53) protein is an attractive anticancer therapeutic strategy. 30%-35% FTC and 37.5% FvPTC have PAX8-PPARgamma rearrangement, which can distinguish carcinomas from adenomas in follicular neoplasms of the thyroid. Pioglitazone may have therapeutic efficacy in patients with PPFP-positive TCs. FTC and PTC have TERT promoter mutation, usually predicting poor prognosis. Other genes also influence on the biological behavior of TC, having diagnosis value and prognostic significance. Though the gene study about TC develops rapidly, many problems remain unclear. Further studies on TC-related genes are needed. PMID- 27978892 TI - [Role of narrow band imaging endoscopy in the subglottic hemangioma]. PMID- 27978894 TI - [Strategies of internal iliac artery preservation during endovascular aortic aneurysm repair]. PMID- 27978893 TI - [Current situation of endovascular abdominal aortic aneurysm repair in China]. PMID- 27978895 TI - [The progress in endovascular repair aortic diseases involved with important branches]. PMID- 27978896 TI - [Indication choice for endovascular aortic aneurysm repair and treating complex pathologies]. PMID- 27978897 TI - [Mixed cognitive impairment: a new clinical concept]. PMID- 27978898 TI - [Risk factors for long-term result of endovascular treatment for auto-immune disease related abdominal aorta pseudo-aneurysm]. AB - Objective: To summarize results of endovascular treatment for auto-immune disease related abdominal aorta pseudo-aneurysm(AIPA), and to analysis clinical predictors of long term major adverse clinical events(MACE). Methods: Retrospectively collected endovascular treatment for AIPA cases in Peking Union Medical College Hospital within 2000 to 2015. Twenty-nine cases with AIPA treated by endovascular therapy were enrolled in this study. Twenty five cases were male, range from 23 to 67 years old, mean age was (39.3+/-11.4) years old.Demographic characters, locations of aneurysms, type to auto-immune disease, immuno medical therapy, operation strategy and long term follow-up data were reported. Statistical analysis was made to verify clinical predictors of long-term MACE. Results: Among the 29 cases, 22 cases with bechet's disease, 4 cases with Takayasu's arteritis, 2 cases with systemic lupus erythematosus, 1 cases with polyarteritis nodosa. Eight cases had ruptured or pending ruptured pesudo aneurysms, the rest 21 cases had dull pain or no overt symptome. Twenty-four cases had infra-renal artery aneurysms, two were para-and supra-renal artery, two were supra-celiac artery, and the rest one had multiple aneurysms involved thoracic and abdominal aorta.All the cases received regular immune medical therapy except the three emergency cases. All the operations were under general anaesthesia. Nineteen cases underwent classical Endovascular aortic aneurysm repair (EVAR), 5 cases underwent fenestration EVAR, the rest 5 cases underwent hybrid procedure. All the 29 operations were successful, without conversion to open surgery. Major peri-operation complication included 3 incision infection, 3 pulmonary infection. No death occurred. All the cases received regular follow-up from 1 to 120 months. There were five recurrence of pseudo-aneurysm, 1 case suffered from iliac limb occlusion. 5 cases received re-intervention procedure. No occlusion of revascularizal visceral artery was found during follow-up. There were 3 deaths during follow-up, with 1 aneurysm related death, the rest died due to other reasons. Single factors logical regressions analysis showed discontinuing immune medicine therapy and age no less than 40 years significantly related long-term MACE(P<0.05). Meanwhile, type of original auto-immune disease, none classical EVAR were not significant related to MACE. Conclusions: Endovascular therapy is safe and effective for AIPA. Regular peri-operation and long-term immunotherapy is key to success. PMID- 27978899 TI - [Preliminary study of endovascular aneurysm repair using fenestration on table for abdominal aortic aneurysm with short proximal neck]. AB - Objective: To investigate the clinical value of endovascular aneurysm repair(EVAR) using fenestration on table for abdominal aortic aneurysm(AAA) with short proximal neck. Methods: A retrospective analysis of four cases with short proximal neck AAA from Aug. 2015 to May. 2016 of Tianjin Medical University General Hospital treated by EVAR using fenestration on table. Fenestrated stent grafts were designed according to the preoperative computer tomography angiography(CTA) data. All cases underwent EVAR with the fenestrated stent-grafts on table to revascularize visceral branches. Results: FEVAR was performed in all of the 4 cases successfully. Device deploying success rate was 100%. No type I endoleak was found in all of the 4 cases. Transient renal dysfunction occurred in two cases during 7 post-operative days and improved with the medical treatment. Mean follow-up period was 4.7 months(range, 1-9 months). CTA (3 cases) and ultrasonic imaging(1 case) were performed postoperatively. No endoleak was found around fenestrated stent graft and patency of visceral stent grafts were maintained in all of the 4 cases. Conclusion: EVAR using fenestration on table for short proximal neck AAA is safe and feasible, which expand the indication of EVAR for AAA, and the long-term safety and outcomes of this technique need to be assessed in the future. PMID- 27978900 TI - [A meta-analysis of totally percutaneous access versus open femoral exposure for endovascular aortic aneurysm repair]. AB - Objective: This study was aim to compare the efficacy and safety of percutaneous access and open femoral exposure for endovascular aortic aneurysm repair. Methods: Eligible studies were searched from PubMed, Embase, and Corchrane databases published in English from January 1999 to December 2015. Data extracted from each study were synthesized into overall odds ratios (OR) for technical success rates and complications. The outcomes on technical success rates and complications of both totally percutaneous access and open femoral exposure group were compared. Results: After a systematic review of English language articles, ten studies including 1 504 patients were eligible for the Meta-analysis. The technical success rates of the percutaneous endovascular aortic aneurysm repair (PEVAR) group was 95.1%, close to that of femoral exposure (FE) group (97.5%). The difference did not show significantly (OR=0.57, 95% CI: 0.31-1.04, P>0.05). However, the incidence of total postoperative complications in PEVAR group was 8%, significantly lower than that in FE group (15.9%) (OR=0.52, 95% CI: 0.37 0.42, P<0.01). Conclusion: PEVAR is associated with a similar technical success rate and lower complication incidence rate comparing with FE. Therefore, it could be as a preferred approach of endovascular aortic aneurysm repair. PMID- 27978901 TI - [Association between ultrasound screening frequency and mortality in patients with hepatocellular carcinoma]. AB - Objective: To discuss the association between ultrasound screening frequency and total mortality in patients with HCC before diagnosing HCC, and explore the optimal ultrasound screening frequency for HCC high-risk groups. Methods: Retrospectively collected clinical data of 615 cases of liver cirrhosis who developed to HCC from January 1, 2010 to December 31, 2015. Before diagnosing HCC, all patients were divided into five groups according to ultrasound screening frequency: 0-6, 7-12, 13-24, 25-36 months and not screened within 3 years (never screened). The chance to receive curative therapy, 5-year cumulative mortalities and independent factors of mortality in patients with HCC were analyzed. Results: Chances to receive curative therapy among the 0-6, 7-12, 13-24, 25-36 months and never screened groups were 38.2%, 27.2%, 25.4%, 23.8% and 19.7%, respectively (P<0.05). The 5-year overall mortality rates were 76.4%, 77.7%, 79.3%, 82.5% and 84.6%, respectively. Compared with 0-6 months, the adjusted OR of mortality for the other groups were 1.112, 1.235, 1.305 and 1.451, respectively (all P<0.05). Multivariate analysis showed that ultrasound screening frequency, curative treatment and Child-Pugh (class A/B) were the factors to affect long-term survival in patients with HCC (all P<0.05). Conclusion: For HCC high-risk groups, optimal ultrasound screening frequency is within 6 months, and high-frequency ultrasound screening can increase the chance of receiving curative treatment, reduce total mortality, and improve overall survival. PMID- 27978902 TI - [Myoclonus and it's associated factors in Creutzfeldt-Jakob disease]. AB - Objective: To analyze features and the related factors of myoclonus of 47 patients with probable or possible Creutzfeldt-Jakob disease (CJD). Methods: All patients diagnosed with"suspected CJD" and hospitalized in Xuanwu Hospital from January 2013 to November 2015 were included, and their clinical information and myoclonus features were analyzed. Age, clinical, course and manifestation, EEG, MRI, CSF14-3-3 features between myoclonus positive group and negative group were compared, and the correlation between myoclonus features and these factors was analyzed using Spearman correlation analyses. Results: (1) Occurrence rate of extrapyramidal symptoms (P=0.028), visual impairment (P=0.025) and dyssomnia (P=0.004) were higher in myoclonus positive group, the differences were significant. Spearman correlation analysis showed that myoclonus was related to extrapyramidal symptoms (P=0.024), visual impairment (P=0.030) and dyssomnia (P=0.001). (2) EEG features showed no significant difference between myoclonus positive and negative group. The 17 myoclonus positive patients were divided into three subgroups, typical EEG change group 52.94%(9/17), atypical EEG change group 23.53%(4/17) and no EEG change group 23.53%(4/17). Difference of myoclonus and other clinical manifestations were not significant among the three subgroups(P>0.05); correlation analysis also found no statistically significant correlation between myoclonus and EEG (P=0.201). Conclusions: Myoclonus often occurs after the damage of locomotor system (including pyramidal tract, extracorticospinal tract and cerebellum) among CJD patients, and it is related to extrapyramidal symptoms , visual impairment and dyssomnia . There is undefined correlation between myoclonus and periodic sharp wave complexes (PSWC) in EEG. PMID- 27978903 TI - [The value and comparison of plasma adrenocorticotropic hormone and urinary free cortisol in predicting long-term outcome after operation of Cushing's disease]. AB - Objective: To study and the value of morning plasma adrenocorticotropic hormone (ACTH) and urinary free cortisol (24 h UFC) within 3 days after operation in patients with Cushing's disease in predicting the long-term outcome. Methods: The clinical data of 140 patients with Cushing's disease who were treated in Department of Neurosurgery of PUMCH from 2012 to 2014 were analyzed retrospectively.The univariate analysis, multivariate Logistic analysis, ROC curve analysis and other statistical methods were used to study the predicting value of morning plasma ACTH and 24 h UFC in 3 days post operation. Results: Univariate analysis showed that in the two groups of the early remission and no remission, there was significant statistical difference between the preoperative ACTH, preoperative 24 h UFC, postoperative ACTH and postoperative 24 h UFC (P<0.05, <0.01, <0.01). Logistic analysis showed that ACTH and 24 h UFC after operation of two groups had significant difference (P<0.01, <0.05). ROC curve analysis showed that postoperative cutoff values of ACTH and 24 h UFC were 4.11 pmol/L (18.7 pg/ml) and 281.42 nmol (102 MUg)/24 h. ROC analysis was performed to evaluate the predicting performance of postoperative ACTH, resulting in an area under the curve (AUC) of 0.917 (95%CI: 0.858-0.957, P<0.01). In comparison, 24 h UFC had an AUC of 0.814 (95%CI: 0.739-0.875, P<0.01). The predicting value of ACTH is significantly better than that of 24 h UFC (P=0.005). Conclusion: Early morning 24 h UFC and ACTH within 3 days after operation both showed considerable accuracy in predicting the long-term outcome of Cushing's disease, and the significance of ACTH was even greater than that of 24 h UFC. PMID- 27978904 TI - [Clinical manifestations of 10 cases of imported human Zika virus disease in Jiangmen city of China]. AB - Objective: To study the clinical manifestations and detection method for imported patients of Zika virus disease. Method: The records of symptoms, signs and laboratory results were collected and analyzed. The specimen of blood, saliva and urine from patients were collected. Results: Two of ten patients had mild fever. The visible cutaneous maculopapular rash of the trunk and extremities was observed in all patients. Seven patients were observed congestive conjunctivitis and only one patient gave an account of itching. No patient had symptoms of myalgia or arthralgia. The laboratory results of patients were normal except two patients had mild leucopenia and another one had thrombocytosis. The Zika virus RNA was detected in urine samples for a longest period. The detection rates of Zika virus RNA from the samples of blood, saliva and urine that collected in seventh day after disease onset were 0, 5, 8 cases, respectively. Conclosion: Epidemiology history, maculopapular rash, congestive conjunctivitis and Zika virus RNA being detected in urine can be considered as the important clinical criterion for making a definite diagnosis as Zika virus disease. PMID- 27978905 TI - [Comparative outcomes of three kinds of transforaminal interbody fusion technique in the treatment of single segment lumbar degenerative disease]. AB - Objective: To compare the clinical outcomes among three kinds of transforaminal interbody fusion technique in the treatment of single segment lumbar degenerative disease. Methods: From October 2012 to November 2014, a total of 67 cases of lumbar degenerative disease of single segment underwent surgical intervention were retrospectively analyzed, including 19 cases by mis- transforaminal lumbar interbody fusion(TLIF), 25 cases by mini-open TLIF and 23 cases by open TLIF.Blood loss, surgical time, fluoroscopy time and hospital costs were recorded.Pre- and postoperative back pain was assessed with visual analogue scale (VAS), and lumbar function was evaluated with Oswestry disability index (ODI). Results: mis-TLIF group need more surgical time, fluoroscopy time and more hospital costs when compared to mini-open TLIF group and open TLIF group (P<0.05), but no significant difference between mini-open TLIF group and open TLIF group (P>0.05). mis-TLIF group tended to lose less blood than mini-open TLIF group(P<0.05), and mini-open TLIF group lose less blood than open TLIF group (P<0.05). There is no significant difference of the change of ODI among three groups (P>0.05). mis-TLIF group and mini-open TLIF group was superior to open TLIF group in VAS of the second day postoperative [(3.2+/-1.6) scale, (3.4+/-1.5) scale vs(5.8+/-1.4)scale](P<0.05). Conclusion: mis-TLIF, mini-open TLIF and open TLIF can all get satisfactory clinical outcomes in the treatment of single segment lumbar degenerative disease.mis-TLIF and mini-open TLIF was superior to open TLIF in blood loss, early postoperative recovery.Compared with mis-TLIF, mini-open TLIF reduce the fluoroscopy time and hospital costs, and also has a shorter learning curve. PMID- 27978906 TI - [Clinical effects of different methods of the proximal fusion for long segmental lumbar vertebrae fusion in treatment of degenerative lumbar scoliosis]. AB - Objective: To explored the clinical effects of different methods of the proximal fusion for long segmental lumbar vertebrae fusion in treatment of degenerative lumbar scoliosis(DLS). Methods: From January 2007 to March 2014 fifty-five cases of DLS treated by the posterior proximal fusion of long segmental lumbar vertebrae fusion were analyzed in Department of Orthopaedics, Shanghai general Hospital of Nanjing Medical University (35)HuaiAn The First Hospital Affiliated to Nanjing Medical University(20). According to various upper instrumented vertebra(UIV) the patients were divided into Group A(upper horizontal vertebra, UHV, n=17), Group B (upper natural vertebra, UNV n=18 ), and Group C(upper end vertebra, UEV, n=20). The VAS, ODI, spinal balance parameters and postoperative complications in each group were assessed. Results: Except for 1 case death of serious lung infection in early postoperative, 54 cases were received 2-4 years follow-up. No statistical differences in improvements and fusion rates were found among 3 groups (P>0.05). The improvements of the coronal Cobb's angle in the A group were significantly more than the C group (75.8%+/-12.8%, 69.6%+/-11.8%, 63.4%+/-15.3%, P<0.05). The incidences of early postoperative complications in A group were the highest, next in B group, and lowest C group (52.9%, 22.0%, 15.0%, P<0.05). The incidences of proximal ASD in the C group were significantly more than the A group (12.5%, 22.2%, 50.0%, P=0.045). Conclusion: UHV, UNV and UEV had similar clinical outcomes for treatment of degenerative lumbar scoliosis in short term. Correction of the coronal deformity of UHV was superior to UEV. UEV was beneficial to reduce early complications, but more likely to happen proximal adjacent segment degeneration in the long run. PMID- 27978907 TI - [Systematic evaluation of the influence of endometrial stimulation on pregnancy outcome in the patients with artificial insemination]. AB - Objective: The association between endometrial stimulation and the intrauterine insemination outcome remains to be a controversial issue, for there being all kinds of conflicting data in the existing literatures. We conducted a Meta analysis case to verify the relations between endometrial stimulation and intrauterine insemination (IUI). Methods: The articles had been searched in the following online databases: MEDLINE, CNKI, VIP, Wan Fang, EMBASE and the Cochrane Library. All of the statistics quoted for our studies have been published in English or Chinese from Jan, 2000 to May, 2016. Among the 6 studies included in this Meta-analysis, all of them used a case - control design. All the 6 studies evaluated a total of 1349 participants, including 734 cases of endometrial injury. Results: The results of the Meta-analysis showed that patients with endometrial stimulation were more likely to receive clinical pregnancy than those who did not. Compared with the control group, the clinical pregnancy rate of experiment group was higher (RR=0.88, 95% CI: 0.82-0.95, P=0.001), while the differences between their abortion rate (RR=0.72, 95% CI: 0.37-1.4, P=0.33) and multiple pregnancies rate (RR=0.78, 95% CI: 0.3-2.01, P=0.60) were insignificant. Conclusions: Endometrial stimulation could help increase the pregnancy rate in IUI cycles, while the abortion rate and multiple pregnancies rate would not be raised. PMID- 27978908 TI - [The Nobel prize and the current status of biomedical research in China]. PMID- 27978909 TI - [Certain experiences in sequential treatment of occlusal reconstruction]. AB - Occlusal reconstruction is a complex sequential treatment. The treatment may involve changes in occlusal vertical dimension and the full dental arch occlusal surface reconstruction. In this paper, we discussed the most concerned aspects of prosthodontists during the occlusal reconstruction sequential treatment, how to determine the suitable occlusal vertical dimension, rebuilding of occlusal plane, and consideratiom of temporomandibular joint disorders during reconstruction treatment. The prosthodontists should adopt the multidisciplinary collaboration mode of thinking in analysis, design, treatment, and restoration processes, regarding patients' individual characteristic through the occlusal reconstruction sequential treatment, and to reach healthy, functional, aesthetic outcome eventually. PMID- 27978910 TI - [Managing carious lesions: consensus recommendations on carious tissue removal]. PMID- 27978911 TI - [Histopathological analysis of oral lichen planus with malignant transformation]. AB - Objective: To estimate the histological features of oral lichen planus (OLP) which underwent malignant transformation and discuss the current problems in OLP pathological diagnosis. Methods: Using the modified WHO OLP criteria (2003), reevaluated the pathological changes of cases diagnosed initially as OLP and transformed into squamous cell carcinomas indicated by subsequent biopsies. Results: Among 3 721 cases of OLP clinically and pathologically diagnosed during 1984 and 2015, there were 19 cases (0.51%) having underwent malignant transformation. Reevaluation of the initial biopsies revealed that 10 cases did not meet the criteria of OLP, as without characteristic basal cell liquefaction, not exhibiting sufficient band-like lymphocytes infiltration, or presenting with epithelial dysplasia. There were 9 cases of OLP malignant transformation left after the reevaluation. Conclusions: Pathological diagnosis of OLP should fully fit the criteria i.e. basal cell liquefaction, typical band-like lymphocytes infiltration and absence of epithelial dysplasia, which is also a prerequisite for researches in malignant transformation of OLP. PMID- 27978912 TI - [A clinical evaluation of periodontal treatment effect using periodontal endoscope for patients with periodontitis: a split-mouth controlled study]. AB - Objective: To compare the clinical effects of periodontal treatment using periodontal endoscope with that of conventional treatment method for patients with periodontitis. Methods: Eleven periodontal patients with moderate to advanced periodontal destruction were recruited and treated with scaling and root planing in a split-mouth design randomly with (test group) or without (control group) periodontal endoscope. Changes of such clinical parameters as plaque index (PLI), bleeding index (BI), probing depth (PD) and attachment loss (AL) before and after treatments as well as the difference between test and control groups were examined and compared. Results: Both groups showed significant reductions in PD, BI and AL values at 6 weeks and 3 months after treatment (P <0.001). Only in the test group, for sites with PD>=6 mm at baseline, PD value ([4.0+/-1.2] mm) and AL value ([3.8+/-0.9] mm) at the end of 3 months were significantly lower than that at the end of 6 weeks (PD[4.4+/-1.3] mm, P<0.001; AL[4.1+/-1.1] mm, P< 0.05). There were no significant differences between two groups at the baseline, at the end of 6 weeks and 3 months, respectively. However, for the sites with PD>=6 mm in anterior teeth, PD value in test group at the end of 3 months was significantly lower than that in control group ([3.2+/-0.9] mm vs [3.7+/-0.9] mm, P <0.05), while AL value tend to be lower ([2.9 +/- 1.2] mm vs [3.6 +/- 1.3] mm, P=0.061). Conclusions: Periodontal treatment using endoscope is obviously effective, especially for the medium and long term prognosis of deep pockets and single rooted teeth. PMID- 27978913 TI - [Establishment and application of a digital workflow in the treatment of condylar osteochondroma and secondary dentofacial deformities using image-guided endoscopic navigation combined with orthognathic surgery]. AB - Objective: To establish a digital workflow in the treatment of mandibular condylar osteochondroma with secondary dentofacial deformities using navigation and endoscope combined with orthognathic surgery. Methods: Thirty-six patients with unilateral condylar osteochondroma were analyzed retrospectively. Preoperative planning and simulation were carried out on the digital three dimansional (3D) model in all patients. With the aid of image-guided endoscopic navigation, osteochondroma resection and condylectomy were accurately performed. Secondary dentofacial deformities were simultaneously corrected using orthognathic surgery. All patients were followed up regularly and received postoperative CT scans. The preoperative simulated model and the postoperative actual model were matched using ProPlan CMF 2.0 software. Four corresponding points were marked in the virtual and actual ostectomy plane, respectively. The intersections of mandibular sigmoid notch and posterior ramusrim with condylectomy plane were marked as the anterior point and the posterior point, respectively. The perpendicular bisector of the line from the anterior point to the posterior point was intersected with the lateral and medial margin of condylectomy plane to form the lateral point and the medial point, respectively. The straight-line distances between the corresponding points in the virtual and actual ostectomy plane were respectively measured to analyze the ostectomy discrepancy. Results: All of 36 patients obtained satisfactory clinical effects. Facial symmetry and morphology were greatly improved. Postoperative CT showed that condylar tumors were completely removed. The preoperative simulated model and the postoperative actual model were matched. The average discrepancy between the planned and actual surgical resection was minimal on the anterior points ([0.24 +/- 0.17] mm) and the mean error was maximal on the posterior points ([3.86+/-1.03] mm). The patients showed no signs of tumor recurrence in the 6 to 12 months of follow-up. Conclusions: Endoscope-assisted and navigation-guided tumor resection and condylectomy combined with simultaneous orthognathic surgery has satisfactory clinical effects in the treatment of condylar osteochondroma and secondary dentofacial deformities. The digital management workflow reported in this paper provides us a valuable option for this potentially complicated procedure. PMID- 27978914 TI - [Three dimensional reconstruction measurement study of palatal contour changes in different bone ages after rapid maxillary expansion]. AB - Objective: To compare dental and skeletal changes after rapid maxillary expansion in patients with different bone ages. Methods: Thirty-seven patients in different growth period were divided into three groups according to cervical vertebral maturation (CVM). There were 13 patients in the growth acceleration group, 13 patients in growth peak group, and 11 patients in growth deceleration group. Cone beam computed tomography (CBCT) images were segmented and reconstructed using Mimics image processing software to assess the change of palatal morphology before and after treatment. Statistical analysis was carried out using SPSS 17.0 software. Results: After the expansion the posterior teeth and alveolar bone were tilted and the mid-palatal suture was opened in all three groups. The first molar angle in the three groups decreased by 2.66 degrees +/-1.04 degrees , 3.53 degrees +/-0.81 degrees and 12.32 degrees +/-1.64 degrees , respectively and no significant difference was found between the acceleration group and the peak group (P >0.05), but the changes in the acceleration group and the peak groups were significantly less than that in the deceleration group (P<0.05). The palatal angle in the three groups increased by 6.01 degrees +/- 2.06 degrees , 4.79 degrees +/- 1.31 degrees and 6.73 degrees +/- 1.71 degrees , respectively and no significant difference was found between the acceleration group and the deceleration group (P>0.05), but the changes in the acceleration group and the deceleration group were significantly greater than that in the peak group (P<0.05). The palatal cemento-enamel junction (CEJ) width, the middle palate width and the mid-palatal suture width in the three groups increased by (7.37 +/- 1.31), (6.68 +/- 0.72) and (5.13 +/- 1.42) mm; (5.72+/-1.68), (4.82+/-1.66) and (3.42+/-1.15) mm; (3.14+/-0.45), (2.98+/-0.51) and (0.96+/-0.83) mm, respectively and no significant difference was found between the acceleration group and the peak group (P >0.05), but the changes in the acceleration group and the peak group were significantly greater than that in the deceleration group (P <0.05). Conclusions: The mid-palatal suture could be opened in patients in different CVM period. More skeletal and less dental effects were found in patients in the growth acceleration and peek group than in those in the growth deceleration group and the inclination of the alveolar bone could be avoided to a greater degree in patients in the growth peek group. PMID- 27978915 TI - [Features of facioscapulohumeral muscular dystrophy in oral and maxillofacial region and MRI analysis of facial muscles]. AB - Objective: To investigate the manifestation of facioscapulohumeral muscular dystrophy (FSHD) in oral and maxillofacial region. Methods: A total of 12 patients diagnosed as FSHD and 20 healthy volunteers were included in the study. Their medical history was collected from these patients. The decayed missing filled teeth (DMFT), calculus index-simplified (CI-S), occlusal relationship, maximal opening of mouth and maximum bite force were recorded. The impressions were taken to measure the maximal hight of palate and the width of palate. The lateral cephalometric radiographs were also taken to measure the mandibular plane frankfurt horizontal plane angle (MP-FH). They finally received oral and maxillofacial region MRI examination to observe the masseter muscle, medial pterygoid muscle and lateral pterygoid muscle. The data were analyzed by t-test or Wilcoxon signed ranks test. Results: There was no significant gender difference in FSHD group. The average age of treatment was (27.5 +/- 8.1) years and the average age of onset was (15.7+/-7.5) years. Nine patients liked to eat soft foods, 4 patients had difficulties of closing eyes, 8 patients had difficulties of cheek-bulging, 10 patients showed pouty lips and 9 patients had mesio-malocclusion. DMFT (4.0+/-2.3), CI-S (5.8+/-2.1), male maximal hight of palate (20.5+/-2.1) mm , female maximal hight of palate (17.9+/-1.6) mm, MP-FH (31.8 degrees +/-2.2 degrees ) of FSHD group were greater than those of the control group. Male width of palate (34.8+/-1.4) mm, female width of palate (33.7+/-1.5) mm, male maximum bite force (451.7 +/- 39.0) N, female maximum bite force (326.7 +/- 21.6) N, maximal opening of mouth (3.5 +/- 0.4) cm of FSHD group were less than those of the control group (P <0.05). Maxillofacial MRI showed muscle asymmetr in 11 cases of masseter and 6 cases of medial pterygoid muscle, 5 cases of lateral pterygoid, and these muscle showed mild fatty infiltration mainly concentrating in the grade 0, grade 1 and grade 2. Conclusions: The FSHD patients have poor oral hygiene, low masticatory function, limited mouth opening, high palate and narrow arch and different degree of malocclusion. The patients' masseter muscle, medial pterygoid muscles and lateral pterygoid muscles exhibit asymmetrical atrophy and fatty infiltration. PMID- 27978916 TI - [Analysis of virulence factors of Porphyromonas endodontalis based on comparative proteomics technique]. AB - Objective: To analyze the protein expression profile and the potential virulence factors of Porphyromonas endodontalis (Pe) via comparison with that of two strains of Porphyromonas gingivalis (Pg) with high and low virulences, respectively. Methods: Whole cell comparative proteomics of Pe ATCC35406 was examined and compared with that of high virulent strain Pg W83 andlow virulent strain Pg ATCC33277, respectively. Isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano liquid chromatography-tandem mass spectrometry (Nano-LC-MS/MS) were adopted to identify and quantitate the proteins of Pe and two strains of Pg with various virulences by using the methods of isotopically labeled peptides, mass spectrometric detection and bioinformatics analysis. The biological functions of similar proteins expressed by Pe ATCC35406 and two strains of Pg were quantified and analyzed. Results: Totally 1 210 proteins were identified while Pe compared with Pg W83. There were 130 proteins (10.74% of the total proteins) expressed similarly, including 89 known functional proteins and 41 proteins of unknown functions. Totally 1 223 proteins were identified when Pe compared with Pg ATCC33277. There were 110 proteins (8.99% of the total proteins) expressed similarly, including 72 known functional proteins and 38 proteins of unknown functions. The similarly expressed proteins in Pe and Pg strains with various virulences mainly focused on catalytic activity and binding function, including recombination activation gene (RagA), lipoprotein, chaperonin Dnak, Clp family proteins (ClpC and ClpX) and various iron-binding proteins. They were involved in metabolism and cellular processes. In addition, the type and number of similar virulence proteins between Pe and high virulence Pg were higher than those between Pe and low virulence Pg. Conclusions: Lipoprotein, oxygen resistance protein, iron binding protein were probably the potential virulence factors of Pe ATCC35406. It was speculated that pathogenicity of Pe was more similar to high virulence Pg than that to low virulence strain. PMID- 27978917 TI - [Comparison of surface characteristics and cytocompatibility of Ti-6Al-4V alloy fabricated with select laser melting and electron beam melting]. AB - Objective: To evaluate the surface characteristics and cytocompatibility of Ti 6Al-4V alloy fabricated using select laser melting (SLM) and electron beam melting (EBM) technique. Methods: Ti-6Al-4V alloy specimens were fabricated with SLM and EBM. A wrought form of Ti-6Al-4V alloy was used as a control. Its properties were evaluated using component analysis, contact angle test, surface roughness, surface topography, cell ultrastructure, cell attachment and proliferation observation, metal ion precipitation examination. Results: The roughness of SLM and EBM specimens was suitable for cell attachment but not the best. The character of SLM and EBM specimens was hydrophobic (>65 degrees ). The surface topography of EBM and SLM specimens were similar, but were not the best type for cell attachment. The components of Ti-alloy oxide film were detected in all the specimens. The content of Ti, Al, V ions of EBM, SLM and wrought specimens were very low and did not affect the cell attachment and proliferation. The ultrastructure of cell was normal, and the cytomembrane was intact. The number of cells was similar to each other among the three kinds of specimens and increased obviously with the culture time. Conclusions: The results of the study suggested that EBM and SLM Ti-6Al-4V specimens possessed good surface characteristics. However, the surface modification are needed further. PMID- 27978918 TI - [Effect of epigallocatechin-3-gallate on the proliferation and osteogenesis of human periodontal ligament cells]. AB - Objective: To evaluate the effect of epigallocatechin-3-gallate (EGCG) treatment on the proliferation and osteogenic differentiation of human periodontal ligament cell (hPDLC) and to explore the potential role of EGCG in promoting periodontal hard tissue regeneration. Methods: The hPDLC was isolated from periodontal ligament tissue obtained from freshly extracted human teeth. The effect of treatments with various concentrations of EGCG (0 MUmol/L, 2 MUmol/L, 4 MUmol/L, 6 MUmol/L, 8 MUmol/L and 10 MUmol/L) on cell proliferations were determined by cell counting kits (CCK) after 24-, 48- and 72-hour-incubations, respectively. Osteogenic differentiation abilities of hPDLCs were assessed by using alkaline phosphatase (ALP) activity tests after 7- and 14-day-incubations, respectively. The mineralized nodules were quantitatively examined and analyzed by using alizarin red staining after 21-day-incubation. The real-time PCR (RT-PCR) assays were conducted fordetecting the expressions of Runt related transcription factor 2 (Runx2), ALP and collagen type I (COL I) after 7-day-incubation. Results: Treatment with 4 MUmol/L EGCG increased hDPLC proliferation at 24 h, while 8 MUmol/L or 10 MUmol/L EGCG treatment groups showed inhibiting effects at 24 h and 72 h, respectively. Findings of alizarin redstaining showed orange to red colored extracellular mineralized nodules in all groups. The the A values of 2, 4, 6, 8, 10 MUmol/L EGCG groups were 0.119+/-0.001, 0.167+/-0.003, 0.173+/-0.003, 0.110+/ 0.001 and 0.083+/-0.003, respectively. A values of 2-8 MUmol/L EGCG groups were significantly higher than that of the control group, however there was no significant difference of the A values between10 MUmol/L EGCG group and the control group (0.077+/-0.001). Treatments with 2-10 MUmol/L EGCG could significantly increase the mRNA expressions of COL I and ALP with the highest values in 4-6 MUmol/L EGCG treatment groups. Although treatments with 4 and 6 MUmol/L EGCG both could increase the mRNA expressions of Runx2, the result in 4 MUmol/L group was much better than that of 6 MUmol/L group. Conclusions: Treatment of 4 MUmol/L EGCG could promote hPDLC proliferation at early stageand treatments with 4-6 MUmol/L EGCG could significantly promote the osteogenesis of hPDLCs which might play a promising role in periodontal hard tissue regeneration. PMID- 27978919 TI - [Current advance in saliva-derived exosome study]. AB - There is growing interest in the whole saliva as a diagnostic fluid because of the relatively simple and non-invasive collection. Research on salivary proteomic and genomic has greatly facilitated the diagnosis and therapy of oral diseases, also revealed the molecular mechanism of the diseases. Saliva-derived exosome as a new source, with various molecular constituents of their cells of origin, including proteins, mRNA and miRNA might serve as potential biomarker. This article reviews the biological properties of saliva exosome, its separation and other aspects associated with disease. PMID- 27978920 TI - [Research advances in dentin biomimetic remineralization]. AB - With similar characteristic as nature dentin in structure and function, regenerated dentin is considered to be the ideal material for detected dentin restoration. Accordingly, dentin regeneration is a key issue in oral medicine and biomaterial science. Biomimetic mineralizatioin and remineralization are thus considered as strategies in dentin regeneration. This review is about the research advances of dentin biomimetic remineralization. PMID- 27978921 TI - [Angiogenesis and condyle growth: review]. AB - Angiogenesis plays key roles in the process of the growth of the mandibular condyle. This article reviewed the relationship between angiogenesis, condyle growth and the role that angiogenesis plays in the condyle growth and its clinical value. PMID- 27978922 TI - [Carefully reviewing the history of diagnostic scales and paying more attention to the diagnostic value of Roussel - Uclaf causality assessment method scale for drug - induced liver injury]. AB - Currently, the diagnostic criteria for drug-induced liver injury (DILI) used in the clinical studies and related literature in China are very confusing, making it difficult to compare and extend the use of the results, conclusions, and experience of these studies. Therefore, it is necessary to carefully review the developmental history of diagnostic scales and unify the diagnostic criteria and related knowledge of DILI. Since its publication in 1993, Roussel Uclaf Causality Assessment Method (RUCAM) scale has been widely used to assess the causality between drugs and liver injury, both in DILI studies and decisions on the regulation of drugs which may cause liver injury, in order to provide a useful analytical framework for clinical physicians in the diagnosis of DILI. At present, RUCAM scale should still be used to assess causality and assist diagnosis, unless markers with diagnostic significance are found in future. PMID- 27978923 TI - [Current status of the treatment of drug-induced liver injury]. AB - In recent years, with the amazing increase in the number of prescription drugs and non-prescription drugs and the irrational use of Chinese herbal medicine and healthcare products, the incidence of drug-induced liver injury (DILI) has been increasing year by year; however, there is still a lack of effective therapeutic methods for DILI at present. Standard treatment based on timely diagnosis should be emphasized, and it is necessary to fully evaluate the severity of liver injury and primary disease, withdraw suspected drugs in time, and select appropriate drugs. Liver transplantation should be recommended to patients with severe liver failure. PMID- 27978924 TI - [Promoting translational research on drug-induced liver injury]. AB - Drug-induced liver injury (DILI) is one of the most important drug-induced diseases and an important reason for failure to obtain approval, an increase in warnings, and withdrawal from market. DILI has a complex clinical phenotype and can cause almost all types of acute, subacute, and chronic liver injury, and it may cause liver failure and even death in patients with severe conditions. The diversity of drugs involved and heterogeneity of populations are the main reasons for unpredictability of most DILI cases in clinical practice. Therefore, the prediction, diagnosis, and treatment of DILI become challenging issues in the field of liver disease, and it is of great significance to strengthen clinical translational research in this aspect, so as to transform more achievements into actual diagnostic and treatment methods. PMID- 27978925 TI - [Serological and pathological features of drug-induced liver injury and autoimmune hepatitis]. AB - Objective: To investigate the differences and similarities between drug-induced liver injury (DILI) and autoimmune hepatitis (AIH) in serum biochemical parameters and liver pathology, and to provide some thoughts for clinical diagnosis and differentiation of these two diseases. Methods: A retrospective analysis was performed for the biochemical, immunological, autoantibody, and liver pathological data of 106 DILI patients and 63 AIH patients who were hospitalized, diagnosed, and treated in our hospital from January 2012 to October 2014. The patients' general data, biochemical parameters, immunological data, Ishak score, and qualitative changes in liver tissue were analyzed and compared. The Kruskal-Wallis test was used for comparison of nonparametric data between multiple groups, the Nemenyi test was used for comparison of nonparametric data between any two groups, the Wilcoxon rank sum test was used for comparison of Ishak scores, and the chi-square test was used for comparison of constituent ratio of categorical data. Results: There were significant differences between AIH group and DILI hepatocyte injury group/mixed-type DILI group in the following serum biochemical parameters: alanine aminotransferase (187.2 U/Lvs 1 326.5 U/L and 455.6,P< 0.05), aspartate aminotransferase (172.2 U/L vs 759.5 U/L and 349.5 U/L,P<0.05), alkaline phosphatase (209.3 U/L vs 157.3 U/L and 169.4 U/L,P< 0.05), gamma-glutamyl transferase (254.8 U/L vs 176.5 U/L and 170.5 U/L,P< 0.05), total bilirubin (37.2MUmol/L vs 95.8MUmol/L and 52.6MUmol/L,P< 0.05), serum iron (18.9MUmol/L vs 36.2MUmol/L and 23.9MUmol/L,P< 0.05), serum ferritin (122.5MUmol/L vs 410.4MUmol/L and 186.5MUmol/L,P< 0.05), immunoglobulin G (18.4 g/L vs 12.6 g/L and 12.3 g/L,P< 0.05), and immunoglobulin M (1.8 g/L vs 1.3 g/L and 1.1 g/L,P< 0.05). There were also significant differences between AIH group and DILI hepatocyte injury group/mixed-type DILI group in the Ishak score for interface inflammation (2.2+/-0.8 vs 1.3+/-0.7 and 1.3+/-0.6,P< 0.05), Ishak score for portal inflammation (2.3+/-0.9 vs 1.5+/-0.7 and 1.4+/-0.8,P< 0.05), and fibrosis score (2.8+/-1.1 vs 1.5+/-0.7 and 1.3+/-0.7,P< 0.05). There were significant differences between AIH group and DILI hepatocyte injury group/mixed type DILI group in the proportion of wax-like deposition (0 vs 29.2% and 34.5%, P <0.05) and proportion of iron deposition (11.1% vs 52.1% and 25.9%,P< 0.05). Conclusion: There are differences in biochemistry, immunology, and liver histology between DILI and AIH patients. AIH patients have more serious interface inflammation and portal inflammation and a higher fibrosis degree compared with DILI patients, while DILI patients have greater proportions of wax-like deposition and iron deposition compared with AIH patients. PMID- 27978926 TI - [Current status of Chinese herbal preparations included in LiverTox database]. AB - Objective: To investigate the contents and features of drug-induced liver injury (DILI) database called LiverTox, as well as 37 herbal preparations included in this database. Methods: Firstly, the source and contents of LiverTox were briefly introduced, including the clinical features, types, severity, and causality assessment scale of DILI. Secondly, detailed information of 37 herbal preparations included in the class of "Herbals and Dietary Supplements" were extracted, including drug name, origin, efficacy, constituents, type of liver injury, and manifestations, to perform a preliminary statistical analysis. Finally, a comparative analysis was performed between such information and current knowledge of Chinese herbal medicine-induced liver injury in China. Results: LiverTox was a DILI database with open access and rich information and provided practical information on treatment, typing, causality assessment, and treatment. Among the 37 herbal preparations, 28 had the risk of liver injury. The most common indication was weight loss, followed by arthritis and constipation. The latency of hepatotoxicity ranged from 4 weeks to 6 months. Compared with the current knowledge in China, there were differences in the varieties and indications for herbal preparations with hepatotoxicity included in LiverTox, and many herbals with acknowledged hepatotoxicity in China were not included. Conclusion: LiverTox database is concise and practical, but there are certain differences between the herbal preparations included in this database and current knowledge in China. PMID- 27978927 TI - [Zinc finger E-box-binding homeobox 2 inhibits hepatitis B virus replication and expression]. AB - Objective: To investigate the effect of zinc finger E-box-binding homeobox 2 (ZEB2) on hepatitis B virus (HBV) replication and expression. Methods: HepG2, HepG2.2.15, and HepAD38 cells were cultured separately, and Western blot was used to measure the expression of ZEB2. HepG2.2.15 cells were cultured and transfected with ZEB2 expression plasmids or shRNA targeting ZEB2. Western blot was used to measure the expression of ZEB2 and HBV core proteins, quantitative real-time PCR was used to measure HBV 3.5 kb RNA and HBV DNA, Southern blot was used to measure HBV replicative intermediate, and ELISA was used to measure the expression of HBsAg and HBeAg, in order to clarify the effect of ZEB2 on HBV replication and expression. The dual-luciferase reporter system was used to analyze the effect of ZEB2 on HBV promoter, and the chromatin immunoprecipitation assay was used to detect the binding of ZEB2 to HBV promoter. The t-test was used for comparison of means between groups. Results: The expression of ZEB2 was inhibited in the cells with HBV replication. Overexpression of ZEB2 reduced the level of HBV replication and expression by about 50% (P< 0.05). After ZEB2 was downregulated by shZEB2-1 or shZEB2-2, the level of HBV replicative intermediate increased from 58.53 +/- 3.43 to 112.80 +/- 5.03, and 128.30 +/- 2.31, the relative expression level of HBV 3.5 kb RNA increased from 1.00 +/- 0.01 to 2.03 +/- 0.02 and 2.32 +/- 0.03, the level of HBsAg increased from 35.63% +/- 1.57% to 81.87% +/- 0.43% and 100.00% +/- 2.18%, and HBeAg increased from 37.00% +/- 0.70% to 88.00% +/- 2.60% and 100.00% +/- 0.75%. Furthermore, ZEB2 could bind to HBV core promoter and inhibit its transcriptional activity. Conclusion: ZEB2 inhibits HBV replication and expression through binding to HBV core promoter and inhibiting its transcriptional activity. PMID- 27978928 TI - [Changes in peripheral blood 25 - hydroxyvitamin D3, Th17 cells, and CD4+ regulatory T cells and their clinical significance in patients with primary biliary cirrhosis]. AB - Objective: To investigate the changes in peripheral blood 25-hydroxyvitamin D3[25 (OH)D3], CD4+regulatory T (Treg) cells, and Th17 cells in patients with primary biliary cirrhosis (PBC) and their mechanism of action in PBC. Methods: A total of 22 patients with PBC were enrolled and the male/female ratio was 1:21, with a mean age of 61+/-12 years. There were 7 healthy volunteers matched for age in the normal control group. Electrochemiluminescence immunoassay was used to measure the peripheral blood 25-(OH)D3level in the PBC group and normal control group, and flow cytometry was used to analyze the changes in Th17 cells and CD4+Treg cells. The t-test, rank sum test, Pearson correlation analysis, or Spearman's rank correlation analysis was used for statistical analysis according to the type of the data. Results: The PBC group had a significantly lower serum 25 (OH)D3level than the normal control group (9.49+/-3.65 vs 27.35+/-2.35 ng/ml,P< 0.01). Compared with the normal control group, the PBC group had a significantly higher percentage of Th17 cells (2.05%+/-1.17% vs 0.99%+/-0.12%,P< 0.01) and a significantly lower percentage of CD4+Treg cells (2.54%+/-1.14% vs 3.78%+/ 0.51%,P< 0.05); there was a significant difference in Th17/Treg ratio between the PBC group and the normal control group (1.00+/-0.63 vs 0.26+/-0.02,P< 0.01). In the PBC group, peripheral blood 25-(OH)D3 was not correlated with Th17 cells or Th17/Treg ratio (r= -0.062 and -0.328,P> 0.05), while it was positively correlated with the percentage of CD4+Treg cells (r= 0.468,P< 0.05). Conclusion: Patients with PBC have significant reductions in peripheral blood 25-(OH)D3and percentage of CD4+Treg cells, a significant increase in the percentage of Th17 cells, and immune unbalance of Th17 cells and CD4+Treg cells. 25-(OH)D3can upregulate the percentage of CD4+Treg cells and thus affect the development and progression of PBC, and exogenous vitamin D may improve immune function in PBC patients. PMID- 27978929 TI - [Clinical effect of polyvinyl alcohol particles combined with chemoembolization in treatment of hepatocellular carcinoma complicated by hepatic arteriovenous shunt and related and prognostic factors]. AB - Objective: To investigate the clinical effect of polyvinyl alcohol (PVA) particles combined with chemoembolization using chemotherapeutic agents or chemotherapeutic agents lipiodol emulsion (CALE) in the treatment of hepatocellular carcinoma (HCC) complicated by hepatic arteriovenous shunt (HAVS) and related prognostic factors. Methods: A retrospective analysis was performed for the clinical data of 133 patients with HCC complicated by HAVS. HAVS was classified into slow-flow HAVS, intermediate-flow HAVS, and high-flow HAVS, which were treated with 300-500MUm, 500-710MUm, and 710-1000MUm PVA particles, respectively. The patients with slow-flow and intermediate-flow HAVS underwent embolization with PVA combined with chemotherapeutic agents followed by CALE, while those with high-flow HAVS underwent the treatment with PVA combined with chemotherapeutic agents alone. The survival time, progression-free survival time, and postoperative complications were followed up and analyzed. The Kaplan-Meier method was used to calculate cumulative survival rate and the Cox proportional hazards model was used to determine prognostic factors. Results: The median overall survival (OS) of 133 patients was 9.1 months, and the 6-, 12-, and 24 month survival rates were 73.7%, 36.2%, and 10.2%, respectively. The median OS of slow-flow group (36 patients), intermediate-flow group (58 patients), and high flow group (39 patients) were 7.3, 9.1, and 10.8 months, respectively. And the 6- and 12-month survival rates were 69.2%/19.0%, 72.4%/39.2%, and 77.8%/42.7%, respectively. There was no significant difference in survival time between the patients with different types of HAVS (chi2= 2.865,P= 0.239). The incidence rates of postoperative gastroesophageal variceal bleeding and acute liver failure were 1.1% and 0.4%, respectively. The results of Cox regression analysis showed that preoperative alpha-fetoprotein level>=400 ng/ml (HR= 2.105,P= 0.006) was an independent risk factor, while multiple embolizations (HR= 0.482,P= 0.011), tumor remission (HR= 0.431,P= 0.041), and multimodality therapy (HR= 0.416,P= 0.004) were independent protective factors. Conclusion: PVA particles combined with chemotherapeutic agents or CALE is safe and effective in the treatment of HCC complicated by HAVS. Patients with multiple embolizations, tumor remission, and multimodality therapy tend to have good prognosis, while those with a high level of alpha-fetoprotein before embolization often have poor prognosis. PMID- 27978930 TI - [Value of intravoxel incoherent motion diffusion-weighted imaging in differential diagnosis of benign and malignant hepatic lesions and blood perfusion evaluation]. AB - Objective: To investigate the value of intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) in the differential diagnosis and blood perfusion evaluation of benign and malignant hepatic lesions. Methods: A retrospective analysis was performed for 86 patients (96 lesions) with pathologically or clinically confirmed hepatic lesions or hepatic lesions diagnosed based on follow up results, among whom 48 had malignant lesions (53 lesions) and 38 had benign lesions (43 lesions). The patients underwent conventional magnetic resonance (MR) plain scan, contrast-enhanced scan, and diffusion-weighted imaging (DWI) with different b values (b = 0, 50, 100, 150, 200, 400, 600, 800, 1 000, and 1 200 s/mm2) to determine the parameters of the double exponential model for intravoxel incoherent motion (IVIM): fast diffusion coefficient Dfast, slow diffusion coefficient Dslow, and percentage of fast-diffusion constituent F value. The patients were divided into groups according to the blood supply to lesions on conventional MR plain scan and contrast-enhanced scan, and there were 47 lesions in abundant blood supply group and 49 in poor blood supply group. The data for analysis were Dfast, Dslow, and F values of benign/malignant lesion groups and abundant/poor blood supply groups. The independent samples t-test was used for statistical analysis; the independent samples non-parametric test Mann-Whitney U test was used for the comparison of F value; the receiver operating characteristic (ROC) curve was used to evaluate the value of above parameters in the differentiation of benign and malignant lesions and blood supply evaluation. Results: Compared with the malignant lesion group, the benign lesion group had significantly higher Dslow, and F values (P< 0.001 orP= 0.001) and a higher Dfast value (P= 0.053). Compared with the poor blood supply group, the abundant blood supply group had significantly higher Dfast and F values (P< 0.001 orP= 0.001) and a higher Dslow value (P= 0.185). According to the ROC curve, the cut-off values of Dslow, Dfast, and F values in the diagnosis of benign/malignant hepatic lesions and evaluation of abundant/poor blood supply were 1.18*10-3mm2/s, 27.20*10-3mm2/s, 20.25%, 1.17*10-3mm2/s, 20.30*10-3mm2/s, and 17.80%, respectively, with sensitivities, specificities, accuracy, and areas under the ROC curve of 90.69%/92.45%/91.66%/0.938, 46.51%/73.58%/61.45%/0.589, 74.41%/50.94%/62.50%/0.653, 59.57%/57.14%/58.33%/0.559, 55.32%/63.26%/59.37%/0.618, and 93.61%/89.79%/90.62%/0.961, respectively. Conclusion: The parameter of the double exponential model for IVIM, Dslow value, has a certain value in the differential diagnosis of benign and malignant hepatic lesions, and F value can show blood perfusion in benign and malignant hepatic lesions without the need for contrast-enhanced scan, which provides a reference for the qualitative diagnosis of liver tumor. PMID- 27978931 TI - [Abnormal expression of insulin-like growth factor-I receptor and inhibitory effect of its transcription intervention on nude mice xenograft tumor]. AB - Objective: To investigate the expression of insulin-like growth factor-I receptor (IGF-IR) in liver cancer and the inhibitory effect of its transcription intervention on nude mice xenograft tumor. Methods: A total of 40 patients with primary liver cancer were enrolled, and 40 samples of cancer lesions, peri cancerous tissues (with a distance of 2 cm to the margin of cancer lesion), or distal liver tissues (with a distance of 5 cm to the margin of cancer lesion), with a weight of 200 mg, were collected after surgery. Some of these samples were used for pathological examination, and the rest were stored at -85 degrees C. A total of 18 BALB/c nude mice aged 4-6 weeks with a body weight of 18-20 g (9 male and 9 female mice) were randomly divided into control group, negative control group, and co-intervention group, with 6 mice in each group, and fed under specific pathogen-free conditions. The cell line was cultured in the dimethyl sulfoxide complete medium containing 10% fetal bovine serum in a CO2incubator at 37 degrees C. When the cell confluence reached 90% after cell inoculation, shRNA was divided into co-intervention group, negative control group, and untreated control group and were transfected to hepatoma cells using PolyJetTM transfection reagent. Stable cell clones obtained by G418 screening and used for the in vivo study. Immunohistochemistry, Western blotting, and quantitative real-time PCR were used to analyze the expression of IGF-IR in the human hepatoma tissue and cell line. The IGF-IR shRNA eukaryotic expression plasmids were established and screened for the most effective sequence; they were transfected to PLC/PRF/5 hepatoma cells, and the CCK-8 assay was used to analyze the changes in cell proliferation. The stable cell line screened out by G418 was inoculated to establish the subcutaneous xenograft tumor in nude mice. The tumor growth curve was plotted and histological examination was performed. Graphpad Prism 5.0 and SPSS 18.0 were used for plotting and data analysis; the variance test and Q test were used for comparison of means between multiple samples, the t-test was used for comparison of means between any two samples, the chi-square test or Fisher's exact test was used for comparison of rates between samples, and a rank correlation analysis was performed for expression intensity. Results: The liver cancer group had a significantly higher positive rate of IGF-IR than the peri cancerous group and distal tissue group (82.5% vs 42.5%/10%,chi2= 13.653 and 42.29, bothP< 0.01), as well as significantly higher expression intensity than these two groups (Z= 4.771 and 6.579, bothP< 0.01). IGF-IR was not significantly expressed in the L02 cell line and was strongly expressed in the PLC/PRF/5 hepatoma cells, and the expression intensity of IGF-IR in the PLC/PRF/5 hepatoma cells was 4 and 5 times that in Bel-7404 cells and HepG2 cells, respectively. After the PLC/PRF/5 hepatoma cells were transfected with shRNA4 with the best co intervention effect, the mean inhibition rate of tumor cell growth reached 63.9% at 72 hours, and the mean inhibition rate of IGF-IR transcription reached 59.6%. Tumor cells were arrested in G1 phase, and there was a significant increase in apoptosis rate. As for the subcutaneous hepatoma xenograft in nude mice, the intervention group had significantly slower tumor growth than the blank control group and negative control group (143+/-24 mm3 vs 372+/-46 mm3/350+/-50 mm3,t= 10.776 and 9.142, bothP< 0.01); the intervention group had significantly downregulated IGF-IR expression, which was significantly lower than that in the blank control group and negative control group (t= 11.184 and 9.450, bothP< 0.01). Conclusion: Intervention of IGF-IR transcription can effectively inhibit the growth of xenograft tumor in nude mice, suggesting that IGF-IR gene might become a new potential target for the treatment of liver cancer. PMID- 27978932 TI - [Preventive and therapeutic effects of compound ginkgo extract in rats with nonalcoholic steatohepatitis induced by high-fat, high-fructose diet]. AB - Objective: To establish a rat model of nonalcoholic steatohepatitis (NASH), and to investigate the preventative and therapeutic effects of compound ginkgo extract against NASH. Methods: A total of 60 male Sprague-Dawley rats were fed with high-fat feed and 10% fructose water for 24 weeks to establish the rat model of NASH. The general behaviors of the rats were observed, and the body weight was recorded. Blood samples from the inferior vena cava and the liver were collected after the last administration to measure serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), as well as liver function parameters. The liver index was calculated, HE staining was performed to observe liver histopathological changes, and the total lipase activity and the levels of TC, TG, and free fatty acid (FFA) in liver tissue were measured. Results: After 24 weeks, compared with the normal group, the model group had a significantly faster increase in body weight, significant increases in serum levels of TC (2.20+/-0.52 mmol/L), TG (0.87+/-0.22 mmol/L), LDL-C (1.22+/-0.50 mmol/L), alanine aminotransferase (ALT) (129.4+/-44.7 U/L), and aspartate aminotransferase (AST) (209.3+/-42.8 U/L), liver index (3.62%+/-0.28%), and the levels of TC (4.42+/ 1.39 mmol/mg.prot), TG (0.85+/-0.11 mmol/mg.prot), and FFA (644.78+/ 36.65MUmol/L) in liver tissue, and significant reductions in serum HDL-C level (0.58+/-0.11 mmol/L) and the activity of lipoprotein lipase (LPL) (9.95+/-1.64 U/mg.prot) and hepatic lipase (HL) (9.91+/-1.03 U/mg.prot) (allP< 0.01). In addition, the pathological results showed severe hepatocyte steatosis, varying degrees of inflammatory cell infiltration, exudation in the portal area, and necrosis of liver cells in the model group. After the intervention with compound ginkgo extract, there were significant reductions in serum levels of TC (1.78+/ 0.21 mmol/L), TG (0.58+/-0.07 mmol/L), LDL-C (0.84+/-0.19 mmol/L), and ALT (84.1+/-17.1 U/L), AST (155.4+/-20.9 U/L), liver index (2.71%+/-0.15%), and the levels of TC (2.24+/-1.02 mmol/mg.prot), TG (0.46+/-0.11 mmol/mg.prot), and FFA (580.56+/-50.63MUmol/L) in liver tissue, as well as significant increases in serum HDL-C level (0.68+/-0.10 mmol/L) and the activities of LPL (15.54+/-2.21 U/mg.prot) and HL (11.92+/-1.87 U/mg.prot) (P< 0.05 orP< 0.01). At the same time, it significantly reduced hepatomegaly in rats and improved fatty degeneration and degree of inflammation in liver cells. Conclusion: Compound ginkgo extract can prevent and treat NASH by correcting dyslipidemia, improving liver function and fatty degeneration in hepatocytes, and reducing the degree of inflammation, and its mechanism of action may be associated with increasing total lipase activity, reducing FFA in the liver, increasing the decomposition of TG, and reducing the synthesis of TG. PMID- 27978933 TI - [Value of antinuclear antibody combined with anti-filamentous actin antibody in diagnosis of type I autoimmune hepatitis]. PMID- 27978934 TI - [The analysis of UGT1A1 gene mutations in hereditary unconjugated hyperbilirubinemia]. PMID- 27978935 TI - [A case of hepatitis C virus related diffuse large B cell lymphoma]. PMID- 27978937 TI - [Research advances in drug-induced autoimmune hepatitis]. AB - Drug induced autoimmune hepatitis (DIAIH) refers to the liver injury mediated by drug-induced autoimmune reaction. Since it has similar clinical features as idiopathic autoimmune hepatitis, it is often difficult to make differential diagnosis in clinical practice. A deep understanding of the development, pathogenesis, related drugs, risk factors, and clinical and histological features of DIAIH helps with the correct diagnosis and treatment of DIAIH. PMID- 27978936 TI - [Current status of treatment of chronic hepatitis C and related challenges in the "Pre-DAA Era" in China]. AB - The condition of chronic hepatitis C is becoming more and more serious in China, and its disease burden and social and economic burdens are growing heavier. Currently, the standard regimen for the treatment of chronic hepatitis C in China is the PR regimen, namely pegylated interferon combined with ribavirin; however, there are still many shortcomings in this regimen. In the world, there is rapid clinical progress in direct-acting antiviral agents (DAAs) for the treatment of hepatitis C, and DAAs will soon be approved and marketed in China, ushering the "DAA Era" of hepatitis C treatment. This article reviews the disease burden of chronic hepatitis C and problems in the standard regimen in clinical treatment and briefly introduces the advantages and challenges of DAAs regimens, in order to provide a reference for the upcoming "DAA Era" of hepatitis C treatment in China. PMID- 27978938 TI - [Mechanism of action of the SIRT1-FoxO1-AdipoR2 signaling pathway in alcoholic fatty liver disease]. AB - Long-term alcohol stimulation may inhibit the expression of silent information regulator 1 in hepatocytes, which increases the acetylation level of forkhead box transcription factor O1, reduces nuclear localization, and reduces the binding capacity of DNA sequence. This further downregulates the expression of downstream adiponectin receptor 2 and microsomal triglyceride transfer protein, causes lipid metabolism disorders and triglyceride deposition in hepatocytes by affecting adiponectin signal transduction and synthesis of very-low-density lipoprotein, and finally promotes the development of alcoholic fatty liver disease. PMID- 27978939 TI - Should HIV testing for all pregnant women continue? Cost-effectiveness of universal antenatal testing compared to focused approaches across high to very low HIV prevalence settings. AB - INTRODUCTION: HIV testing is the entry point for the elimination of mother-to child transmission of HIV. Decreasing external funding for the HIV response in some low- and middle-income countries has triggered the question of whether a focused approach to HIV testing targeting pregnant women in high-burden areas should be considered. This study aimed at determining and comparing the cost effectiveness of universal and focused HIV testing approaches for pregnant women across high to very low HIV prevalence settings. METHODS: We conducted a modelling analysis on health and cost outcomes of HIV testing for pregnant women using four country-based case scenarios (Namibia, Kenya, Haiti and Viet Nam) to illustrate high, intermediate, low and very low HIV prevalence settings. We used subnational prevalence data to divide each country into high-, medium- and low burden areas, and modelled different antenatal and testing coverage in each. RESULTS: When HIV testing services were only focused in high-burden areas within a country, mother-to-child transmission rates remained high ranging from 18 to 23%, resulting in a 25 to 69% increase in new paediatric HIV infections and increased future treatment costs for children. Universal HIV testing was found to be dominant (i.e. more QALYs gained with less cost) compared to focused approaches in the Namibia, Kenya and Haiti scenarios. The universal approach was also very cost-effective compared to focused approaches, with $ 125 per quality adjusted life years gained in the Viet Nam-based scenario of very low HIV prevalence. Sensitivity analysis further supported the findings. CONCLUSIONS: Universal approach to antenatal HIV testing achieves the best health outcomes and is cost-saving or cost-effective in the long term across the range of HIV prevalence settings. It is further a prerequisite for quality maternal and child healthcare and for the elimination of mother-to-child transmission of HIV. PMID- 27978940 TI - 'They just walk away' - women's perception of being silenced by antenatal health workers: a qualitative study on women survivors of domestic violence in Nepal. AB - BACKGROUND: Domestic violence during pregnancy has detrimental effects on the health of the mother and the newborn. Antenatal care provides a 'window of opportunity' to identify and assist victims of domestic violence during pregnancy. Little is known about the experience, needs, and expectations from the women's perspective in relation to domestic violence in Nepal. OBJECTIVE: Our study aims to explore how women who have experienced domestic violence evaluate their antenatal care and their expectations and needs from health centers. DESIGN: Twelve in-depth interviews were conducted among women who had experienced domestic violence during pregnancy and utilized antenatal care. The women were recruited from two different organizations in Nepal. RESULTS: Women in our study concealed their experience of domestic violence due to fear of being insulted, discriminated, and negative attitudes of the health care providers. The women wished that the health care providers were compassionate and asked them about their experience, ensured confidentiality and privacy, and referred them to services that is free of cost. CONCLUSIONS: Findings from our study may help the health care providers to change their attitudes toward women survivors of domestic violence. Identifying and assisting these women through antenatal care could result in improved services for them and their newborns. PMID- 27978941 TI - A Real Man! PMID- 27978942 TI - Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes: The ORBIT-AF II Registry. AB - BACKGROUND: Although non-vitamin K antagonist oral anticoagulants (NOACs) do not require frequent laboratory monitoring, each compound requires dose adjustments on the basis of certain clinical criteria. OBJECTIVES: This study assessed the frequency of off-label NOAC doses among AF patients and the associations between off-label dose therapy and clinical outcomes in community practice. METHODS: We evaluated 5,738 patients treated with a NOAC at 242 ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation phase II) sites. NOAC doses were classified as either underdosed or overdosed, consistent with Food and Drug Administration labeling. Longitudinal outcomes (median follow-up: 0.99 years) included stroke or systemic embolism, myocardial infarction, major bleeding (International Society of Thrombosis and Haemostasis criteria), cause specific hospitalization, and all-cause mortality. RESULTS: Overall, 541 NOAC treated patients (9.4%) were underdosed, 197 were overdosed (3.4%), and 5,000 were dosed according to U.S. labeling (87%). Compared with patients receiving the recommended dose, those who were receiving off-label doses were older (median: 79 and 80 years of age vs. 70 years of age, respectively; p < 0.0001), more likely female (48% and 67% vs. 40%, respectively; p < 0.0001), less likely to be treated by an electrophysiologist (18% and 19% vs. 27%, respectively; p < 0.0001), and had higher CHA2DS2-VASc scores (96% and 97% >=2 vs. 86%, respectively; p < 0.0001) and higher ORBIT bleeding scores (25% and 31% >4 vs. 11%, respectively; p < 0.0001). After dose adjustment, NOAC overdosing was associated with increased all-cause mortality compared with recommended doses (adjusted hazard ratio: 1.91; 95% confidence interval [CI]: 1.02 to 3.60; p = 0.04). Underdosing was associated with increased cardiovascular hospitalization (adjusted hazard ratio: 1.26; 95% CI: 1.07 to 1.50; p = 0.007). CONCLUSIONS: A significant minority (almost 1 in 8) of U.S. patients in the community received NOAC doses inconsistent with labeling. NOAC over- and underdosing are associated with increased risk for adverse events. (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II [ORBIT AF II]; NCT01701817). PMID- 27978943 TI - Non-Vitamin K Anticoagulant Dose Selection: It's Best to Read and Follow the Directions. PMID- 27978944 TI - Bleeding Events Before Coronary Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome. AB - BACKGROUND: Upstream administration of antithrombotic drugs to patients with non ST-segment elevation acute coronary syndromes before coronary angiography is a common practice despite an incomplete understanding of the risks and benefits. OBJECTIVES: The authors analyzed the incidence of bleeding and ischemic events occurring before angiography and assessed their association with antithrombotic drugs and mortality risk. METHODS: All patients from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial with planned angiography after enrollment were included. Bleeding events were classified according to the ACUITY scale as major or nonmajor bleeding. Kaplan-Meier and Cox proportional hazards analyses were performed. RESULTS: Of 13,726 patients, 275 (2.0%) bled before angiography, including 52 (0.4%) with major bleeding. Forty four (0.3%) experienced myocardial infarction. The median time from randomization to coronary angiography was 4.5 h (interquartile ratio [IQR]: 1.7 to 19.7 h) for patients who did not bleed while waiting for angiography and 27.9 h (IQR: 21.9 to 65.6 h) for patients who bled while waiting for angiography (p < 0.001). Bleeding events accrued linearly over time, reaching 10.4% at 96 h post-randomization. Independent predictors of bleeding before angiography included age (adjusted hazard ratio [HR]: 1.03 per year of age; 95% confidence interval [CI]: 1.01 to 1.04; p < 0.001), renal insufficiency (adjusted HR: 1.48; 95% CI: 1.07 to 2.04; p = 0.02), and use of multiple antithrombotic drugs (adjusted HR: 1.33; 95% CI: 1.14 to 1.56; p < 0.001). Bleeding before coronary angiography was associated with longer hospitalization (4.8 days [IQR: 3.0 to 8.9 days] vs. 3.0 days [IQR: 1.9 to 5.9 days]; p < 0.001). Patients who bled before angiography were more likely to die within 1 year than patients who did not bleed (8.5% vs. 4.1%; p < 0.001; adjusted HR: 1.89 (95% CI: 1.23 to 2.90; p = 0.004). CONCLUSIONS: Upstream antithrombotic treatment of patients with non-ST-segment elevation acute coronary syndromes awaiting coronary angiography is associated with excess bleeding with mortality implications. Bleeding avoidance strategies before angiogram, including early angiography, may negate the need to prolong upstream antithrombotic treatment and improve the overall risk-benefit balance for these patients. (Acute Catheterization and Urgent Intervention Triage Strategy [ACUITY]; NCT00093158). PMID- 27978945 TI - Bleeding Complications Before Angiography in Non-ST-Segment Elevation Acute Coronary Syndrome Patients: Insights From ACUITY. PMID- 27978946 TI - Risk Associated With Surgery Within 12 Months After Coronary Drug-Eluting Stent Implantation. AB - BACKGROUND: Guidelines recommend postponing surgery for at least 6 months after treatment with a drug-eluting stent by percutaneous coronary intervention (DES PCI). OBJECTIVES: The goal of this study was to evaluate the surgical risk associated with DES-PCI compared with that in nonstented patients without ischemic heart disease (IHD). METHODS: Between 2005 and 2012, a total of 22,590 patients underwent DES-PCI in western Denmark. By record-linking the Western Denmark Heart Registry and the Danish National Patient Register, we evaluated 4,303 DES-PCI-treated patients with a surgical procedure and compared them with a control group of patients without previous IHD undergoing similar surgical procedures (n = 20,232). Events of interest were myocardial infarction (MI), cardiac death, and all-cause mortality within 30 days after surgery. RESULTS: Surgery in DES-PCI-treated patients was associated with an increased risk of MI (1.6% vs. 0.2%; odds ratio [OR]: 4.82; 95% confidence interval [CI]: 3.25 to 7.16) and cardiac death (1.0% vs. 0.2%; OR: 5.87; 95% CI: 3.60 to 9.58) but not all-cause mortality (3.1% vs. 2.7%; OR: 1.12; 95% CI: 0.91 to 1.38). When stratified for time from PCI to surgery, only surgery within the first month was associated with a significant increased risk of events. CONCLUSIONS: Patients requiring surgery within 12 months after DES-PCI had an increased risk of MI and cardiac death compared with patients without IHD. The increased risk was only present within the first month after DES-PCI, suggesting that surgery might be undertaken earlier than currently recommended. PMID- 27978947 TI - Surgery After DES Implantation: To Operate or Not to Operate: Is It Still a Question? PMID- 27978948 TI - Association Between Presence of a Cardiac Intensivist and Mortality in an Adult Cardiac Care Unit. AB - BACKGROUND: Dedicated intensive care unit (ICU) physician staffing is associated with a reduction in ICU mortality rates in general medical and surgical ICUs. However, limited data are available on the role of a cardiac intensivist in the cardiac intensive care unit (CICU). OBJECTIVES: This study investigated the association of cardiac intensivist-directed care with clinical outcomes in adult patients admitted to the CICU. METHODS: This study analyzed 2,431 patients admitted to the CICU at Samsung Medical Center in Seoul, South Korea, from January 2012 to December 2015. In January 2013 the CICU was changed from a low intensity staffing model to a high-intensity staffing model managed by a dedicated cardiac intensivist. Eligible patients were divided into either a low intensity management group (n = 616) or a high-intensity management group (n = 1,815). One-to-many (1:N) propensity score matching with variable matching ratios was also performed. The primary outcome was death in the CICU. RESULTS: Death in the CICU occurred in 55 patients (8.9%) in the low-intensity group versus 74 patients (4.1%) in the high-intensity group (p < 0.001). Of 135 patients who underwent extracorporeal membrane oxygenation, the CICU mortality rate in the high-intensity group was also lower than that in the low-intensity group (54.5% vs. 22.5%; p = 0.001). On propensity score matching, high-intensity staffing was found associated with a lower CICU mortality rate in the matched cohort of patients (7.5% vs. 3.7%; adjusted odds ratio: 0.53; 95% confidence interval: 0.32 to 0.86; p = 0.010). In overall and propensity-matched patients, there were no substantive differences in either median length of CICU stay or readmission rates between the 2 groups. CONCLUSIONS: The presence of a dedicated cardiac intensivist was associated with a reduction in CICU mortality rates in patients with cardiovascular disease who required critical care. PMID- 27978949 TI - Evidence-Based Redesign of the Cardiac Intensive Care Unit. PMID- 27978951 TI - Angiotensin-(1-9): New Promise for Post-Infarct Functional Therapy. PMID- 27978952 TI - Prosthetic Heart Valve Thrombosis. AB - Although surgery was the mainstay of treatment for valvular heart disease, transcatheter valve therapies have grown exponentially over the past decade. Two types of artificial heart valve exist: mechanical heart valves (MHV), which are implanted surgically, and bioprosthetic heart valves (BHV), which can be implanted via a surgical or transcatheter approach. Whereas long-term anticoagulation is required to prevent thromboembolism after MHV replacement, its value in patients receiving BHVs is uncertain. Patients undergoing transcatheter BHV replacement are at risk for thromboembolism in the first few months, and recent data suggest that the risk continues thereafter. BHV thrombosis provides a substrate for subsequent thromboembolism and may identify a reversible cause of prosthesis dysfunction. Hereafter, the authors: 1) review the data on prosthetic valve thrombosis; 2) discuss the pathophysiological mechanisms that may lead to valve thrombus formation; and 3) provide perspective on the implications of these findings in the era of transcatheter valve replacement. PMID- 27978953 TI - Natriuretic Peptides, 6-Min Walk Test, and Quality-of-Life Questionnaires as Clinically Meaningful Endpoints in HF Trials. AB - The Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions document was issued as a guidance for industry and for the Food and Drug Administration. The Expedited Access Pathway was designed as a new program for medical devices that demonstrated the potential to address unmet medical needs for life threatening or irreversibly debilitating conditions. The Food and Drug Administration would consider assessments of a device's effect on intermediate endpoints that, when improving in a congruent fashion, are reasonably likely to predict clinical benefit. The purpose of this review is to provide evidence to support the use of 3 such intermediate endpoints: natriuretic peptides, such as N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptide, the 6-min walk test distance, and health-related quality of life in heart failure. PMID- 27978950 TI - Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction. AB - BACKGROUND: Angiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter regulatory axis of the renin-angiotensin-aldosterone system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic mini-pump. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI). OBJECTIVES: The authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction. METHODS: C57BL/6 mice underwent permanent left anterior descending coronary artery ligation and cardiac function was assessed using echocardiography for 8 weeks followed by a terminal measurement of left ventricular pressure volume loops. Ang-(1-9) was delivered by adeno-associated viral vector via single tail vein injection immediately following induction of MI. Direct effects of Ang-(1-9) on cardiomyocyte excitation/contraction coupling and cardiac contraction were evaluated in isolated mouse and human cardiomyocytes and in an ex vivo Langendorff-perfused whole-heart model. RESULTS: Gene delivery of Ang-(1-9) reduced sudden cardiac death post-MI. Pressure volume measurements revealed complete restoration of end systolic pressure, ejection fraction, end-systolic volume, and the end-diastolic pressure volume relationship by Ang-(1-9) treatment. Stroke volume and cardiac output were significantly increased versus sham. Histological analysis revealed only mild effects on cardiac hypertrophy and fibrosis, but a significant increase in scar thickness. Direct assessment of Ang-(1-9) on isolated cardiomyocytes demonstrated a positive inotropic effect via increasing calcium transient amplitude and contractility. Ang-(1-9) increased contraction in the Langendorff model through a protein kinase A-dependent mechanism. CONCLUSIONS: Our novel findings showed that Ang-(1-9) gene therapy preserved left ventricular systolic function post-MI, restoring cardiac function. Furthermore, Ang-(1-9) directly affected cardiomyocyte calcium handling through a protein kinase A-dependent mechanism. These data emphasized Ang-(1-9) gene therapy as a potential new strategy in the context of MI. PMID- 27978954 TI - Copeptin and NT-proBNP as Prognostic Markers for Recurrent Ischemic Cerebrovascular Events in Ischemic Stroke Patients. PMID- 27978955 TI - 18F-Sodium Fluoride PET/MR for the Assessment of Cardiac Amyloidosis. PMID- 27978956 TI - A Bridging Protocol in High-Thrombotic Risk Mechanical Valve Bearers Undergoing Surgery or Invasive Procedures. PMID- 27978957 TI - Acute Radial Artery Injury After Instrumentation: Are Instrumented Radial Artery Conduits Ideal for CABG? PMID- 27978958 TI - Reply: Acute Radial Artery Injury After Instrumentation: Are Instrumented Radial Artery Conduits Ideal for CABG? PMID- 27978959 TI - CT Rather Than Invasive Angiography for Pregnant Patients With NSTEMI?: More Delay and More Radiation. PMID- 27978960 TI - Reply: CT Rather Than Invasive Angiography for Pregnant Patients With NSTEMI? More Delay and More Radiation. PMID- 27978961 TI - Editorial for transmural gradients issue. PMID- 27978962 TI - Single molecule imaging using X-ray free electron lasers. AB - The potential to image single molecules in action without the need for crystallisation was one of the most exciting applications promised during construction of the first XFELs. Over the past years significant progress has been made, even though the goal of molecular imaging has not yet been achieved. This article reviews the current status, and the steps required to realise X-ray single particle imaging. PMID- 27978963 TI - Introduction: Controversies in Hypertension. PMID- 27978964 TI - Prevention of premature trial discontinuation: how to counter Lasagna's law. PMID- 27978965 TI - ? PMID- 27978967 TI - ? PMID- 27978966 TI - [The six attributes of the concept of coordination in the field of care]. AB - The concept of coordination in the field of care needs to be clarified in order to improve understanding. A literature review has identified six attributes of coordination in nursing care: it is centred on the person, is characterised by pro-active planning, cross-disciplinarity, correlation, sharing and facilitation. PMID- 27978968 TI - [Physiopathology, causes and complications of obesity]. AB - Obesity is a chronic disease associated with respiratory, mechanical, cardiovascular, metabolic as well as psychological and social comorbidities. It has become increasingly prevalent over the last thirty years. The causes are multiple and interwoven, related to diet, sedentary lifestyles, psychological factors, genetics, the socio-economic context and biological factors. Management strategies must be adapted to the clinical situations and treatment must be individualised. PMID- 27978969 TI - [The place of obesity centres in the treatment of severe obesity]. AB - In 2011, as part of the Obesity Plan, the French health minister designated 37 specialist obesity centres. These centres, spread across France, are dedicated to managing severe obesity and form an important part of the organisation of the treatment of obese patients, from the provision of medical and paramedical care in the community to hospitalisation in cutting-edge units. The programme is based on a specific structure favouring the modelling and management of the individualised care pathway. PMID- 27978970 TI - [Summary]. AB - Obesity is a frequent disease, due to complex causes. Importantly, its related medical and psychosocial comorbidities are linked to its severity. Thus, the first thorough evaluation is mandatory in order to build a personalized care program, which needs to be in agreement with all the health professionals involved. This care program also needs to be reevaluated and possibly modified during the follow-up. The care objectives need to be realistic and in agreement with what the patients is expecting. PMID- 27978971 TI - [Psychological care before and after bariatric surgery]. AB - The management of an obese patient involves a multidisciplinary team. The psychological dimension often plays an important role in weight gain and must be taken into account early on in the care pathway. The support given to the patient must notably involve work on body image and how this changes as a result of bariatric surgery. PMID- 27978972 TI - [Dietary management of obese patients]. AB - As part of the complex management of obese patients, dieticians carry out a detailed analysis of their dietary behaviour. Taking into account various elements relating or not to the condition, they identify areas to work on, in particular through individual or collective therapeutic education. PMID- 27978973 TI - [The care pathway in weight loss surgery]. AB - Weight loss surgery requires multidisciplinary preparation and support. The risks of a failure in the follow-up and complications are significant. Consequently, caregivers and patients must follow a more clearly defined pathway which involves both and takes account of their expectations. PMID- 27978974 TI - [The role of the bariatric nurse coordinator]. AB - The complexity of the preparation of patients for bariatric surgery, combined with the requirement for the lifelong follow-up of all patients having undergone such a procedure, show the need for the coordination of the patient pathway by a specific healthcare professional: the bariatric nurse coordinator. A pilot experiment carried out in two integrated obesity centres provides perspectives for the care, research, training and certification of nurses involved in these programmes. PMID- 27978975 TI - [The place of bariatric surgery in the management of obesity]. AB - Surgical treatment of obesity, also called "bariatric surgery", is the reference treatment for severe and morbid forms of obesity after proper multidisciplinary medical treatment has failed. However, it is only one step in the pathway of the obese patient and should only be envisaged in the framework of lifelong nutritional care. PMID- 27978976 TI - [Management of failures and complications in weight loss surgery]. AB - The specific management of the surgical risks linked to obesity, as well as technological advances combined with the standardisation of techniques, have significantly reduced the morbidity and mortality associated with bariatric surgery over recent decades. However, as with all surgery, patients are exposed to medical and surgical failures and complications. PMID- 27978977 TI - [Nutritional follow-up after bariatric surgery]. AB - Lifelong monitoring after weight loss surgery is recommended in order to check the efficacy of the procedure and to identify complications. Particular attention must be paid to the nutritional status of pregnant women and in the event of surgical complications. Education programmes must be offered at every stage of the care pathway in order to favour the compliance required for the follow-up. PMID- 27978978 TI - [A cooperation protocol for the follow-up of patients after bariatric surgery]. AB - Professional cooperation protocols have recently been developed by the French national health authority and regional health agencies. They enable paramedical staff to perform procedures usually carried out by doctors. In the framework of bariatric surgery, the follow-up of patients after surgery is thereby assured by specialist nurses. They can make a diagnosis and prescribe vitamins, minerals and tests. PMID- 27978979 TI - [The role of patient associations in the management of obesity]. AB - Associations for obese patients and their national collective work in cooperation with health professionals and the relevant authorities to improve the overall management of obesity. They also provide patients with the support and personalised assistance they need. These actions are fully integrated into the multidisciplinary care of this chronic disease. PMID- 27978980 TI - ? PMID- 27978981 TI - Introduction to the theme 'technology - translational pharmacology'. PMID- 27978982 TI - Pharmacogenomics in the age of personalized medicine. AB - The aim of personalized medicine is to offer the right treatment to the right person at the right dose, thus maximizing efficacy and minimizing toxicity for each individual patient. Pharmacogenomic approaches attempt to refine the aim of personalized medicine by utilizing an individual's germline and somatic DNA signatures to guide treatment. In this review, we highlight the current use of pharmacogenomic based biomarker information in drug labeling. We also present several case studies on the implementation of pharmacogenomic strategies in drug discovery and development. Lastly, we comment on current challenges to implementing pharmacogenomic based testing in the clinic. PMID- 27978983 TI - Endonuclease mediated genome editing in drug discovery and development: promises and challenges. AB - Site specific genome editing has been gradually employed in drug discovery and development process over the past few decades. Recent development of CRISPR technology has significantly accelerated the incorporation of genome editing in the bench side to bedside process. In this review, we summarize examples of applications of genome editing in the drug discovery and development process. We also discuss current hurdles and solutions of genome editing. PMID- 27978984 TI - Translational PK/PD modeling to increase probability of success in drug discovery and early development. AB - In this review we present ways in which translational PK/PD modeling can address opportunities to enhance probability of success in drug discovery and early development. This is achieved by impacting efficacy and safety-driven attrition rates, through increased focus on the quantitative understanding and modeling of translational PK/PD. Application of the proposed principles early in the discovery and development phases is anticipated to bolster confidence of successfully evaluating proof of mechanism in humans and ultimately improve Phase II success. The present review is centered on the application of predictive modeling and simulation approaches during drug discovery and early development, and more specifically of mechanism-based PK/PD modeling. Case studies are presented, focused on the relevance of M&S contributions to real-world questions and the impact on decision making. PMID- 27978985 TI - Translational biomarkers: from discovery and development to clinical practice. AB - The refinement of disease taxonomy utilizing molecular phenotypes has led to significant improvements in the precision of disease diagnosis and customization of treatment options. This has also spurred efforts to identify novel biomarkers to understand the impact of therapeutically altering the underlying molecular network on disease course, and to support decision-making in drug discovery and development. However, gaps in knowledge regarding disease heterogeneity, combined with the inadequacies of surrogate disease model systems, make it challenging to demonstrate the unequivocal association of molecular and physiological biomarkers to disease pathology. This article will discuss the current landscape in biomarker research and highlight strategies being adopted to increase the likelihood of transitioning biomarkers from discovery to medical practice to enable more objective decision making, and to improve health outcome. PMID- 27978986 TI - Pharmacological considerations for predicting PK/PD at the site of action for therapeutic proteins. AB - For therapeutic proteins whose sites of action are distal to the systemic circulation, both drug and target concentrations at the tissue sites are not necessarily proportional to those in systemic circulation, highlighting the importance of understanding pharmacokinetic/pharmacodynamic (PK/PD) relationship at the sites of action. This review summarizes the pharmacological considerations for predicting local PK/PD and the importance of measuring PK and PD at site of action. Three case examples are presented to show how mechanistic and physiologically based PK/PD (PBPK/PD) models which incorporated the PK and PD at the tissue site can be used to facilitate understanding the exposure-response relationship for therapeutic proteins. PMID- 27978989 TI - Quantitative systems pharmacology: a promising approach for translational pharmacology. AB - Biopharmaceutical companies have increasingly been exploring Quantitative Systems Pharmacology (QSP) as a potential avenue to address current challenges in drug development. In this paper, we discuss the application of QSP modeling approaches to address challenges in the translational of preclinical findings to the clinic, a high risk area of drug development. Three cases have been highlighted with QSP models utilized to inform different questions in translational pharmacology. In the first, a mechanism based asthma model is used to evaluate efficacy and inform biomarker strategy for a novel bispecific antibody. In the second case study, a mitogen-activated protein kinase (MAPK) pathway signaling model is used to make translational predictions on clinical response and evaluate novel combination therapies. In the third case study, a physiologically based pharmacokinetic (PBPK) model it used to guide administration of oseltamivir in pediatric patients. PMID- 27978988 TI - Translational pharmacokinetic/pharmacodynamic analysis in cancer pharmacology: a tool to maximize the value of antitumor efficacy from tumor bearing mice. AB - Translational pharmacokinetic/pharmacodynamic (PK/PD) analysis is becoming an increasingly important tool for the identification and selection of new anticancer agents. There are two important elements of effectively using PK/PD analysis to translate preclinical antitumor efficacy from tumor bearing mice (xenografts and allografts) to cancer patients. These two sometimes overlapping elements are termed translation 'WITHIN' and 'ACROSS' species. Translating 'WITHIN' species refers to the quantitative characterization of drug action and disease behavior within tumor bearing mice using PK/PD modeling in order to use this information to make predictions of drug response in humans. Translating 'ACROSS' species refers to use of PK/PD modeling to quantify species similarities and differences in drug response in order to understand the clinical relevance of preclinical efficacy data. PMID- 27978987 TI - Translational PK/PD of anti-infective therapeutics. AB - Translational PK/PD modeling has emerged as a critical technique for quantitative analysis of the relationship between dose, exposure and response of antibiotics. By combining model components for pharmacokinetics, bacterial growth kinetics and concentration-dependent drug effects, these models are able to quantitatively capture and simulate the complex interplay between antibiotic, bacterium and host organism. Fine-tuning of these basic model structures allows to further account for complicating factors such as resistance development, combination therapy, or host responses. With this tool set at hand, mechanism-based PK/PD modeling and simulation allows to develop optimal dosing regimens for novel and established antibiotics for maximum efficacy and minimal resistance development. PMID- 27978990 TI - Perspectives in regulatory science: translational and clinical pharmacology. AB - This paper focuses on the role of clinical and translational pharmacology in the drug development and the regulatory process. Contemporary regulatory issues faced by FDA's Office of Clinical Pharmacology (OCP) in fulfilling its mission to advance the science of drug response and translate patient diversity into optimal drug therapy are discussed. Specifically current focus of the following key aspects of the drug development and regulatory science processes are discussed: the OCP vision and mission, two key OCP initiatives (i.e. guidance modernization, labeling and health communications), and translational and clinical pharmacology related regulatory science issues in (i.e. uncertainty, breakthrough therapies, individualization). PMID- 27978992 TI - Translational immunotoxicology of immunomodulatory monoclonal antibodies. AB - While immunomodulatory monoclonal antibodies (mAbs) have a wide therapeutic potential, exaggerated immunopharmacology may drive both acute and delayed immunotoxicity. The existing tools for immunotoxicity assessment do not accurately predict the full range of immunotoxicities observed in humans. New and optimized models, assays, endpoints and biomarkers in animals and humans are required to safeguard patients and allow them access to these often transformational therapies. PMID- 27978991 TI - Translational pharmacokinetics and pharmacodynamics of monoclonal antibodies. AB - Monoclonal antibodies (mAbs) are an important therapeutic class with complex pharmacology and interdependent pharmacokinetic (PK) and pharmacodynamics (PD) properties. Understanding the PK and PD of mAbs and their biological and mechanistic underpinnings are crucial in enabling their design and selection, designing appropriate efficacy and toxicity studies, translating PK/PD parameters to humans, and optimizing dose and regimen to maximize success in the clinic. Significant progress has been made in this field however many critical questions still remain. This article gives a brief overview of the PK and PD of mAbs, factors that influence them, and areas of ongoing inquiry. Current tools and translational approaches to predict the PK/PD of mAbs in humans are also discussed. PMID- 27978993 TI - Leverage nonclinical development of bispecifics by translational science. AB - Bispecific antibody constructs (Bispecifics, bsAbs) may have greater functionality compared to established monoclonal antibodies because they bind to 2 different targets or, potentially, to 2 epitopes on the same target (dual targeting). This may result in enhanced binding avidity with preferential binding to cells that express both targets or binding to targets on different cells. However, development of these next-generation biologics, including new formats, creates unique challenges due to their increased complexity. Here we review aspects of bsAbs preclinical development programs that may increase the success rates of bsAbs in clinical development. PMID- 27978995 TI - Precision Medicine with TGF-beta Inhibition Using Tumor Explants: Comment on "Patient-Specific Screening Using High-Grade Glioma Explants to Determine Potential Radiosensitization by a TGF-beta Small Molecule Inhibitor" by N. Sumru Bayin et al. AB - In a new report, Bayin et al. described an ex vivo explant model to test the patient-specific response to transforming growth factor-beta inhibition in high grade gliomas. PMID- 27978996 TI - Corrigendum to "A Potent Derivative of Indolizino[6,7-b]Indole for Treatment of Human Non-Small Cell Lung Cancer Cells" [Neoplasia 18 (2016) 199-212]. PMID- 27978997 TI - Corrigendum to "KDM4C, a H3K9me3 histone demethylase, is involved in the maintenance of human ESCC-initiating cells by epigenetically enhancing SOX2 expression" [Neoplasia 18 (2016) 594-609]. PMID- 27978994 TI - Patient-Specific Screening Using High-Grade Glioma Explants to Determine Potential Radiosensitization by a TGF-beta Small Molecule Inhibitor. AB - High-grade glioma (HGG), a deadly primary brain malignancy, manifests radioresistance mediated by cell-intrinsic and microenvironmental mechanisms. High levels of the cytokine transforming growth factor-beta (TGF-beta) in HGG promote radioresistance by enforcing an effective DNA damage response and supporting glioma stem cell self-renewal. Our analysis of HGG TCGA data and immunohistochemical staining of phosphorylated Smad2, which is the main transducer of canonical TGF-beta signaling, indicated variable levels of TGF-beta pathway activation across HGG tumors. These data suggest that evaluating the putative benefit of inhibiting TGF-beta during radiotherapy requires personalized screening. Thus, we used explant cultures of seven HGG specimens as a rapid, patient-specific ex vivo platform to test the hypothesis that LY364947, a small molecule inhibitor of the TGF-beta type I receptor, acts as a radiosensitizer in HGG. Immunofluorescence detection and image analysis of gamma-H2AX foci, a marker of cellular recognition of radiation-induced DNA damage, and Sox2, a stem cell marker that increases post-radiation, indicated that LY364947 blocked these radiation responses in five of seven specimens. Collectively, our findings suggest that TGF-beta signaling increases radioresistance in most, but not all, HGGs. We propose that short-term culture of HGG explants provides a flexible and rapid platform for screening context-dependent efficacy of radiosensitizing agents in patient-specific fashion. This time- and cost-effective approach could be used to personalize treatment plans in HGG patients. PMID- 27978998 TI - Corrigendum to "Noninvasive Multimodality Imaging of the Tumor Microenvironment: Registered Dynamic Magnetic Resonance Imaging and Positron Emission Tomography Studies of a Preclinical Tumor Model of Tumor Hypoxia" [Neoplasia 11 (2009) 247 259]. PMID- 27978999 TI - Editorial Overview. Biofuels: At the crossroads. PMID- 27979000 TI - The REAL Disparities. PMID- 27979001 TI - Installation Speech. PMID- 27979002 TI - Why Does a Man with Chronic Hypertension Post Rotor Cuff Repair Have Pulsation Over the Right Neck: MRI/MRA/MRV. PMID- 27979003 TI - Errors in Assessing Race and Ethnicity in Clinical Trial Enrollment. PMID- 27979004 TI - The Effects of Social Support on Physical Functioning in Older African Americans: Longitudinal Results from the Baltimore Study of Black Aging. AB - INTRODUCTION: Compared with other racial/ethnic groups, African Americans have higher rates of chronic conditions and suffer a disproportionate burden of disability. We aimed to examine the effects of social support on physical functioning among older African Americans. METHODS: We analyzed a sample of 448 urban, community-dwelling, older African Americans (aged 48-98 years) from the Baltimore Study of Black Aging. Baseline physical functioning was collected between 2006 and 2008 (wave 1), and change in physical functioning was collected between 2009 and 2011 (wave 2), physical functioning was assessed by self reported limitations in 7 activities of daily living-eating, dressing, grooming, walking, bathing, using the toilet, and transferring in and out of bed-using a binary variable to indicate whether the individual had difficulty performing each specific activity. Social support was measured by how frequently participants provided/received goods and services, financial assistance, transportation, companionship, advice, or encouragement (never [0], rarely [1], sometimes [2], frequently [3]). Negative binomial regression models were used to test the effects of social support given, received, and a ratio (support received/support given) on physical functioning for those who improved and those who declined in physical functioning. RESULTS: Participants reported physical functioning at wave 1 (1.24, standard deviation [SD] = 1.98) and at wave 2 (0.34, SD = 0.83). Average social support given was 7.49 (SD = 3.26), and average social support received was 7.81 (SD = 3.17). Those who improved in physical function gave less social support and had lower social support ratios; social support received had no effect. Those who remained stable or declined in physical function gave more social support; neither social support received nor social ratio had an effect. CONCLUSION: Social support given and social support received as well as the ratio should be considered when seeking to understand how physical functioning changes over time among older African Americans. PMID- 27979005 TI - Racial Disparities in HIV Care Extend to Common Comorbidities: Implications for Implementation of Interventions to Reduce Disparities in HIV Care. AB - BACKGROUND: Prior studies have described racial disparities in the quality of care for persons with HIV infection, but it is unknown if these disparities extend to common comorbid conditions. To inform implementation of interventions to reduce disparities in HIV care, we examined racial variation in a set of quality measures for common comorbid conditions among Veterans in care for HIV in the United States. METHOD: The cohort included 23,974 Veterans in care for HIV in 2013 (53.4% black; 46.6% white). Measures extracted from electronic health record and administrative data were receipt of combination antiretroviral therapy (cART), HIV viral control (serum RNA < 200 copies/ml among those on cART), hypertension control (blood pressure < 140/90 mm Hg among those with hypertension), diabetes control (hemoglobin A1C < 9% among those with diabetes), lipid monitoring, guideline-concordant antidepressant prescribing, and initiation and engagement in substance use disorder (SUD) treatment. Black persons were less likely than their white counterparts to receive cART (90.2% vs. 93.2%, p<.001), and experience viral control (84.6% vs. 91.3%, p<.001), hypertension control (61.9% vs. 68.3%, p<.001), diabetes control (85.5% vs. 89.5%, p<.001), and lipid monitoring (81.5% vs. 85.2%, p<.001). Initiation and engagement in SUD treatment were similar among blacks and whites. Differences remained after adjusting for age, comorbidity, retention in HIV care, and a measure of neighborhood social disadvantage created from census data. SIGNIFICANCE: Implementation of interventions to reduce racial disparities in HIV care should comprehensively address and monitor processes and outcomes of care for key comorbidities. PMID- 27979006 TI - Comparing Prostate Cancer Treatment Decision Making in a Resource-rich and a Resource-poor Environment: A Tale of two Hospitals. AB - OBJECTIVE: Black men with prostate cancer are diagnosed later, have poorer treatment outcomes, and higher mortality from the disease than all other racial groups. While existing literature has explored differences in the treatment decision making process between black and white men with localized prostate cancer, little is known about how environmental factors may affect the treatment decision process for men with clinically significant disease for whom treatment improves survival. The aim of this study was to compare and contrast the treatment decision process, from both patients' and treating physicians' perspectives, in a resource-rich and a resource-poor hospital. METHODS: Qualitative interviews and focus groups were conducted with patients and their treating physicians from two urban hospitals. Patients were identified through retrospective review of pathology and tumor registries; their charts abstracted to ascertain treatments. Treating physicians were identified and contacted to discuss the treatment decision process. Physicians were also asked to discuss patients who did not receive definitive treatment. Transcripts were analyzed deductively using themes from the Health Belief Model, and inductively to explore emergent themes. RESULTS: Overall, patients and physicians discussed similar factors that influenced the decision making process at both hospitals. However, a few important differences were found: providers at the resource-poor hospital discussed cost as a barrier, highlighted having limited treatment options for their patients, and noted issues with follow-up as external factors affecting treatment decisions. Patients at the resource-poor hospital expressed greater fear and anxiety, and less self-efficacy and motivation in comparison to patients treated at the hospital with greater resources. Importantly, patients at both hospitals described significant trust in their physician, yet only at the resource-poor hospital did patients suggest that they lacked knowledge regarding treatment side-effects, despite physicians at both hospitals describing their attempt to disclose all side-effects. CONCLUSION: These findings identify both medical-system factors, and practice-level factors that can help guide the development of interventions to reduce prostate cancer treatment disparities. PMID- 27979007 TI - Risk Behaviors and Testing History of African American MSM: Implications for Prevention. AB - OBJECTIVES: Knowledge of HIV status is an important step in prevention efforts especially for at risk populations like MSM. CDC recommends that MSM be tested at least annually. There is a limited information on the demographics and risk behaviors of MSM who never tested or test infrequently. This study examined the demographic characteristics, risk behaviors, and HIV status of African American MSM who reported never previously testing for HIV, testing > 12 months prior, or testing within the last 12 months from a testing evaluation study in Washington, D.C. METHODS: Eligibility requirements were: 18-64 years old; Black/African American; biologically male; and self-reported oral and/or anal sex with a man in the past six months. Descriptive statistics and logistic regression analyses were used. RESULTS: Men who never tested had greater odds of being 25-34 years old, identifying as bisexual or heterosexual and reporting condomless sex with female and male partners. In the multivariate model, men who never tested or tested > 12 months prior to the study had a greater likelihood of having a BS degree, and being age 35 or over. Being newly identified as HIV-positive was associated with never testing and testing > 12 months prior, but was significant in the multivariate model only for never testing. CONCLUSION: Results suggest prevention strategies should target risk behaviors rather than orientation and engage older men. Future studies should identify factors associated with risky sexual behaviors for men who never test or test infrequently in order to inform prevention interventions. PMID- 27979009 TI - Total Knee Arthroplasty due to Knee Osteoarthritis: Risk Factors for Persistent Postsurgical Pain. AB - OBJECTIVE: The aim of this study was to identify whether different patient characteristics and clinical factors can be risk factors in patients with persistent postsurgical pain (PPSP) after total knee arthroplasty (TKA). METHODS: Patients who underwent TKA due to knee osteoarthritis were divided into two groups: those who experienced no or mild PPSP (Numerical Rating Scale [NRS] <= 3) (group 1, n = 91) and those who experienced moderate to severe PPSP (NRS > 3) (group 2, n = 183). Information on the characteristics of patients, comorbid diseases and pre-surgical NRS scores were obtained retrospectively from hospital charts. The follow-up time; pre-surgical and last control time walking distance; and ratings on the NRS, Pain DETECT Questionnaire (PDQ) and patient satisfaction scales were recorded from the standard questionnaire presented to patients during the telephone interview. RESULTS: The mean follow-up time was 22.8 +/- 12.3 months. The rate of moderate to severe PPSP among patients amounted to 66.7% after TKA. No neuropathic pain was found in Group 1. In Group 2, 22.9% of patients experienced neuropathic pain, the results for 18% of patients were uncertain, and 59% of patients did not experience neuropathic pain. Group 2 had worse scores on the patient satisfaction scale following the last control time compared with Group 1. Being widowed, having a low education level, being a housewife, having employment that requires physical effort, pre-surgical pain intensity at rest and pre-surgical restricted walking distance are risk factors for Group 2. CONCLUSIONS: PPSP and the neuropathic component in PPSP after TKA are not underestimated for pain management and patient satisfaction. Subgroups of patients, particularly widowers, having a primary school education level or under, housewives, people with jobs that require physical effort, individuals with intense pre-surgical pain during rest and those suffering from pre-surgical restricted walking distance, are at higher risk of developing PPSP following TKA. PMID- 27979010 TI - Soul Mates: Religion, Sex, Love, and Marriage among African Americans and Latinos. AB - INTRODUCTION: This book review analyzes the complex and profound impact active religious participation has on relationships and family outcomes among African Americans and Latinos. In Soul Mates, Wilcox and Wolfinger discuss the legacy of slavery and Jim Crow laws and the resulting devastating effects on African American and Latino families despite their high religious involvement. The authors make the case that many African American men are unlikely candidates for marriage or stable relationships due to trends of family instability driven by the declining income-power of working-class men as well as entry of more women into the labor force, government penalties for low-income couples, revolt against traditional values, increased access to birth control and abortion, and the persistence of discrimination and incarceration of minority men. METHODS: The authors examine data from six national surveys as well as additional data from interviews, focus groups, ethnographic field work, and an extensive literature review. RESULTS: Wilcox and Wolfinger find evidence that when African American couples actively participate in Christian churches, the men are more likely to adhere to a "code of decency" which decreases street behaviors, such as binge drinking, having multiple sex partners, and having multi-partner fertility, which are known to inhibit family stability. CONCLUSIONS: This book will be helpful for health providers who would like to better understand and serve their African American and Latino patients. The findings suggest that health care providers can promote a healthy emotional environment for families by encouraging minority men to renew or maintain church involvement. PMID- 27979011 TI - A renewed focus on safety, efficacy, and use of inhaled corticosteroids in asthma. PMID- 27979008 TI - Association Between Perceived Medical School Diversity Climate and Change in Depressive Symptoms Among Medical Students: A Report from the Medical Student CHANGE Study. AB - PURPOSE: To determine whether perceptions of the medical school diversity climate are associated with depression symptoms among medical students. METHODS: Longitudinal web-based survey conducted in the fall of 2010 and spring of 2014 administered to a national sample of medical students enrolled in 49 schools across the U.S. (n = 3756). Negative diversity climate measured by perceptions of the institution's racial climate; exposure to negative role modeling by medical educators; frequency of witnessing discrimination in medical school. Depression symptoms measured by the PROMIS Emotional Distress-Depression Short-Form. RESULTS: 64% of students reported a negative racial climate; 81% reported witnessing discrimination toward other students at least once, and 94% reported witnessing negative role modeling. Negative racial climate, witnessed discrimination, and negative role modeling were independently and significantly associated with an increase in depression symptoms between baseline and follow up. Adjusting for students' personal experiences of mistreatment, associations between depressive symptoms and negative racial climate and negative role modeling, remained significant (.72 [.51-.93]; .33 [.12-.54], respectively). CONCLUSIONS: Among medical students, greater exposure to a negative medical school diversity climate was associated with an increase in self-reported depressive symptoms. PMID- 27979012 TI - Measuring safety of inhaled corticosteroids in asthma. AB - BACKGROUND: Despite evidence demonstrating generally excellent therapeutic ratios for inhaled corticosteroids (ICSs) in asthma treatment, many clinicians and patients have ongoing concerns regarding their safety. To frame discussions of ICS safety, it is important to understand how safety is measured. OBJECTIVE: To discuss how ICS safety is and should be measured. METHODS: Discussion is augmented by relevant articles from the literature. RESULTS: The therapeutic value of corticosteroids depends on the activation and repression of thousands of genes. However, it is not fully known which genes cause the desirable, therapeutic effects and which cause the adverse effects. The drug development process attempts to elucidate the clinically significant therapeutic effects and adverse effects of a candidate molecule and then compare them to those of currently available corticosteroids. Approaches to monitoring safety include clinical trials, retrospective comparison to historical efficacy and safety data, surrogate markers, animal models, and in vitro assays. Both preclinical and clinical data are used to compare safety among corticosteroids; however, no specific pathway or model that can robustly predict therapeutic ratios has been identified. Furthermore, variation in adverse effects is influenced by isoforms of the glucocorticoid receptor, differences in corticosteroid characteristics, differences among patients, and environmental variation. CONCLUSION: Although some preclinical and patient-based metrics have predictive value, there is a clear need for improved biomarkers of corticosteroid adverse effects. Integrated analysis of preclinical and clinical data, including long-term safety data, could be used to address this important unmet need. PMID- 27979013 TI - Pivotal efficacy trials of inhaled corticosteroids in asthma. AB - BACKGROUND: Inhaled corticosteroids (ICSs) are the mainstay of daily controller treatment for persistent and uncontrolled asthma. However, many clinicians are wary of ICSs because of safety concerns. Clinicians need to know the underlying efficacy data that support the use of ICSs to weigh efficacy against safety. OBJECTIVE: To discuss efficacy data from pivotal trials to aid clinicians in their decisions to use ICSs. METHODS: Key efficacy studies were selected to augment discussion. RESULTS: Clinical studies have revealed that ICSs are effective in reducing the risk of exacerbations in both children and adults. ICSs also reduce the risk of hospitalization and asthma-related death, improve asthma symptoms, and improve quality of life. In addition, ICSs improve lung function and airway responsiveness and reduce airway inflammation and remodeling. In young children, ICSs improve daytime and nighttime symptoms, improve lung function, reduce the risk of exacerbations, and reduce the need for rescue medications. To date, evidence is conflicting about whether intermittent ICS treatment is as effective as daily ICS treatment. The possibility of lower efficacy of intermittent therapy needs to be weighed against a reduced risk of slowed growth in children. CONCLUSION: ICSs effectively reduce the risk of exacerbations, hospitalizations, and asthma-related death and improve asthma symptoms, quality of life, lung function, and airway responsiveness. ICSs also reduce airway inflammation and remodeling. Intermittent therapy may not be as effective as daily therapy, and clinicians should weigh reduced efficacy against reduced risk of adverse effects, particularly slowed growth in children. PMID- 27979014 TI - Inhaled corticosteroids: Ocular safety and the hypothalamic-pituitary-adrenal axis. AB - BACKGROUND: Inhaled corticosteroids (ICSs) effectively deliver corticosteroids to target sites in the lungs and reduce systemic effects compared with oral corticosteroids, but long-term systemic exposure from inhaled corticosteroids remains a concern. OBJECTIVE: To discuss ICS systemic effects on the eye and the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Relevant publications were used to augment discussion. RESULTS: The most common adverse effects of exogenous corticosteroids on the eye are secondary open-angle glaucoma and posterior subcapsular cataracts. Study findings conflict about whether ICS use is associated with increased risk of glaucoma or elevated intraocular pressure, but studies might not have addressed the question in the right population. Increased risk of glaucoma may be limited to a few susceptible individuals, such as individuals with a family history of glaucoma. Large population-based studies reveal that high daily doses or high lifetime exposure of ICSs is associated with a higher risk of posterior subcapsular cataracts. More research is needed to determine the risk from low to moderate doses during long periods. For the HPA axis, there are several measures for detecting systemic effects. Short-term measures are more sensitive for detecting the systemic effects of ICSs but have less predictive value in identifying clinically important adverse effects. Several studies have found that ICSs have a dose-dependent effects on cortisol suppression that can be used to estimate equivalent dosages among ICSs. CONCLUSION: Because of systemic effects on the HPA axis, high doses of ICS should be avoided where possible. Adult patients undergoing high-dose or long-term ICS therapy should be monitored for cataracts. PMID- 27979015 TI - Inhaled corticosteroids: Effects on growth and bone health. AB - BACKGROUND: Both slowed growth in children and reduced bone mineral density (BMD) are systemic effects of corticosteroids, and there is concern about the degree to which these systemic effects affect growth and BMD. OBJECTIVE: To engage in a data-driven discussion of the effects of inhaled corticosteroids (ICSs) on growth in children and BMD. METHODS: Articles were selected based on their relevance to this review. RESULTS: Studies of ICSs in children in which growth was a secondary outcome have revealed slowed growth associated with low doses of budesonide, fluticasone propionate, and beclomethasone dipropionate. In the study of budesonide, the effect was permanent, and in the study of fluticasone propionate, the effect was long-lasting, but it is unclear whether the effect was permanent. However, the results of studies in which growth was the primary outcome were mixed. Slowed growth was detected in a study of beclomethasone dipropionate; however, slowed growth was not detected in a study of ciclesonide or flunisolide. A decrease in BMD acquisition in children was associated with high doses but not low to medium doses of ICSs. In adults, there was a dose-related effect of ICSs on BMD. Both higher daily dose and larger cumulative dose were associated with increased bone density loss. CONCLUSION: Because of the systemic effects on growth and bone health, children should be monitored for growth using stadiometry every 3 to 6 months and BMD should be monitored yearly in patients being treated with high doses of ICSs. PMID- 27979016 TI - Safety of intranasal corticosteroids. AB - BACKGROUND: Concurrent use of intranasal corticosteroids (INCSs) and inhaled corticosteroids (ICSs) is indicated for patients who are comorbid for asthma and allergic rhinitis. Clinicians need to know the data regarding INCS safety for their patients with asthma. OBJECTIVE: To discuss INCS safety data for the use of INCSs in patients with asthma and allergic rhinitis. METHODS: INCS safety studies were selected for their relevance to the discussion. RESULTS: To date, most studies regarding INCS safety are performed in patients with allergic rhinitis. These studies reveal no evidence of increased risk of nasal atrophy, and only isolated cases of septal perforation have been reported. Evidence of hypothalamic pituitary-adrenal axis suppression is inconsistent and not clinically significant. Early growth studies indicated that beclomethasone dipropionate but not other INCSs have systemic effects on growth; however, newer, larger, and better designed studies are detecting small but significant growth effects in other INCSs. INCSs do not increase the risk of cataracts or glaucoma, although there are anecdotal data on transient elevated intraocular pressure. Data on concurrent use of INCSs and ICSs are limited, but these limited data reveal no evidence of systemic effects on the hypothalamic-pituitary-adrenal axis. CONCLUSION: More studies of concurrent therapy are needed because concurrent use of ICSs and INCSs is common in practice. Clinicians might want to consider monitoring whether there are risk factors, such as a family history of glaucoma. PMID- 27979017 TI - Inhalation devices, delivery systems, and patient technique. AB - BACKGROUND: In real-life clinical settings, physicians often consider the properties of various inhaled corticosteroids (ICSs), but typically little consideration is given to the properties of different inhalers and formulations. OBJECTIVE: To discuss the effects of inhalation devices and user technique on efficacy, safety, and adherence with the aim of improving asthma management. METHODS: Relevant publications were selected to augment discussion. RESULTS: There are many types of devices available, each with advantages, disadvantages, ease of use, and rate of misuse. Aerosol particle size influences the deposition pattern of a drug in the lungs, and the optimal particle size range is 1 to 5 MUm. Retrospective reviews suggest that smaller particles (1-2 MUm) could provide improved asthma control, but randomized, prospective studies are needed. Multiple studies have demonstrated high misuse rates in patients for pressurized metered dose inhalers and dry powder inhalers. Because of this, repeated education should include physical demonstrations of using the device, checking the patient's technique, correcting the technique, and rechecking the technique. This also means that dedicated, trained staff and placebo devices should be available for instructing patients. Furthermore, the device should be selected to be cost effective and to fit the patient's preference and ability to use it correctly to enhance compliance. Asthma management guidelines and algorithms are available to guide the clinician. CONCLUSION: The choice of inhaler device should depend on cost effectiveness and the patient's preference and ability to use it correctly. Patient inhaler technique should be checked and, if necessary, corrected and rechecked, with retraining if needed, at every opportunity. PMID- 27979018 TI - Patient adherence and effective communication. AB - BACKGROUND: Poor adherence to inhaled corticosteroid medication is a critical problem for asthma because it contributes to morbidity and mortality through poor asthma control, frequent asthma exacerbations, acute care visits, and oral corticosteroid use. OBJECTIVE: To discuss evidence-based, time-efficient strategies that can be adopted by most practitioners to try to increase patient adherence. METHODS: Asthma management guidelines and other key publications are used to enhance discussion. RESULTS: Establishing patient-centered, collaborative care that permits effective patient-practitioner communication can improve adherence, thus leading to improved asthma outcomes. One critical strategy is shared decision making, in which the patient and the practitioner share relevant information, discuss risks vs benefits of various treatment options, express treatment preferences, deliberate the options, and agree on treatment. Asthma self-management education, which emphasizes self-efficacy, is also essential. The education necessary to provide those skills depends in part on consideration of the patient's health literacy. Practitioners also have at their disposal a variety of tips and techniques to improve communication and gather information not only at the patient-practitioner level but also at the practitioner practitioner level, such as within a group practice or within a health care system. CONCLUSION: To improve patient adherence, clinicians need to consider a variety of factors and implement strategies that directly target underlying issues. Strategies may include customizing and simplifying learning and intervention regimens, identifying barriers to adherence and addressing them, ensuring patient support structures are in place, and improving self-efficacy and health literacy. PMID- 27979019 TI - Management of primary antibody deficiency syndromes. PMID- 27979020 TI - Antiepilepsy drugs and the immune system. AB - OBJECTIVE: To alert physicians about the peculiar adverse effects of antiepilepsy drugs (AEDs) on the immune system. DATA SOURCES: PubMed literature during the past 25 years. STUDY SELECTIONS: Reports and review articles on the hypersensitivities of AEDs and their effect on immunity. RESULTS: AEDs have significant effects on the immune system in the form of hypersensitivity or immune suppression. IgE-mediated reactions can be urticaria, angioedema, bronchospasm, or anaphylaxis. Non-IgE-mediated reactions, more commonly associated with aromatic AEDs, can be in the form of nonspecific rashes or serious reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptom syndrome, and acute generalized exanthematous pustulosis. Because of strong genetic predispositions for certain AEDs in causing severe reactions, HLA analysis before initiation of the drug is advised in certain populations. Immunoglobulin levels can be reduced to various degrees, particularly by carbamazepine, valproate, phenytoin, levetiracetam, zonisamide, and lamotrigine. Spontaneous return to normal levels can be rapid or take months to a few years, and intravenous immunoglobulin supplementation may be needed. Cellular effects can be in the form of cytopenias, inhibition of lymphocyte function, or cytokine dysregulation. CONCLUSION: When prescribing AEDs, physicians should pay special attention to their potential adverse effects on immunity or hypersensitivity, which can be severe and even fatal. For early recognition and intervention, monitoring such patients is necessary. The cornerstone of management is discontinued use of the suspected medication and avoidance of drugs of similar structure, particularly among members of the aromatic group. PMID- 27979021 TI - Indoor tobacco legislation is associated with fewer emergency department visits for asthma exacerbation in children. AB - BACKGROUND: During the past 3 decades, numerous cities and states have adopted laws that ban smoking in public indoor spaces. The rationale for these policies has been to protect nonsmokers from the adverse health effects of secondhand smoke. OBJECTIVE: To determine whether the implementation of indoor smoking legislation is associated with a decrease in emergency department visits for asthma in children. METHODS: This retrospective analysis used a natural experiment to estimate the impact of clean indoor air legislation on the rate of emergency department admissions for asthma exacerbation in children. Data were obtained from the Pediatric Health Information System. A Poisson regression was used for analyses and controlled for age, sex, race, payer source, seasonality, and secular trends. RESULTS: Asthma emergency department visits were captured from 20 hospitals in 14 different states plus the District of Columbia from July 2000 to January 2014 (n = 335,588). Indoor smoking legislation, pooled across all cities, was associated with a decreased rate of severe asthma exacerbation (adjusted rate ratio 0.83, 95% confidence interval 0.82-0.85, P < .0001). CONCLUSION: Indoor tobacco legislation is associated with a decrease in emergency department visits for asthma exacerbation. Such legislation should be considered in localities that remain without this legislation to protect the respiratory health of their children. PMID- 27979022 TI - Association of severity of chronic rhinosinusitis with degree of comorbid asthma control. AB - BACKGROUND: Comorbid chronic rhinosinusitis (CRS) is associated with worse asthma control. However, no study has investigated whether CRS severity affects the degree of asthma control. OBJECTIVE: To determine the effect size of an association between CRS severity and asthma control. METHODS: A pilot study with a prospective cross-sectional design. Adult patients with CRS and asthma were recruited. CRS severity was measured using the 22-item Sinonasal Outcomes Test (SNOT-22), and asthma control was measured using the Asthma Control Test (ACT). Poor asthma control was defined as an ACT score of 19 or less. In addition to age and sex, we also assessed the participants' history of smoking, aeroallergen hypersensitivity, the presence of polyps, and current use of a corticosteroid containing asthma inhaler. The association between SNOT-22 and ACT was assessed using univariate and multivariable linear regression. RESULTS: A total of 40 patients were recruited. The mean (SD) SNOT-22 score was 43.6 (23.6), and the mean (SD) ACT score was 20.6 (4.8). We found that the SNOT-22 score was associated with the ACT score (adjusted beta = -0.07; 95% confidence interval [CI], -0.13 to -0.02; P = .02) and with having poor asthma control (adjusted odds ratio, 1.06; 95% CI, 1.01-1.11; P = .02). A SNOT-22 cutoff score of 45 or higher had the greatest association with uncontrolled asthma (adjusted odds ratio, 14.96; 95% CI, 1.93-115.89; P = .01). CONCLUSION: CRS severity is negatively associated with asthma control in patients with asthma and CRS. On the basis of this pilot study, further study is warranted to elucidate the effect of CRS severity on asthma control and to determine whether reduction in CRS severity translates to improvement in asthma control. PMID- 27979023 TI - Rate of recurrent anaphylaxis and associated risk factors among Olmsted County, Minnesota, residents: A population-based study. AB - BACKGROUND: The rate and risk factors for recurrence of anaphylaxis are not well known. OBJECTIVE: To measure the rate and risk factors for recurrent anaphylaxis in a population-based cohort in Olmsted County, Minnesota. METHODS: We conducted a population-based cohort study using the Rochester Epidemiology Project, a comprehensive medical records linkage system, to obtain records of patients who presented to medical centers within the Olmsted County area with anaphylaxis from January 1, 2001, through December 31, 2010. We evaluated the rate and associations of risk factors with anaphylaxis recurrence. RESULTS: Among the 611 patients with anaphylaxis, 50 (8%) experienced a total of 60 recurrences within the 10-year period, resulting in a recurrence rate of 2.6 per 100 person-years. A history of atopic dermatitis (hazard ratio [HR], 5.6; 95% confidence interval [CI], 2.0-16.1; P = .001), presenting symptoms of cough (HR, 4.7; 95% CI, 2.1 10.7; P < .001) oral pruritus (HR, 9.9; 95% CI, 4.3-23.2; P < .001), and receiving corticosteroids (HR, 5.2; 95% CI, 2.3-11.7; P < .001) were associated with an increased risk of recurrence. The cardiovascular symptom of chest pain (HR, 0.24; 95% CI, 0.07-0.79; P = .02) was associated with a decreased risk of recurrence. CONCLUSION: In this epidemiologic study, the rate of recurrence was 8% during the 10-year study period (recurrence rate of 2.6 per 100 person-years). Those with atopic dermatitis and mucocutaneous or respiratory symptoms were more likely to have a recurrent anaphylactic event. Our findings underscore the importance of early patient access to self-injectable epinephrine and referral to an allergist/immunologist for additional testing and education. PMID- 27979024 TI - Pediatric patch testing: A 10-year retrospective study. AB - BACKGROUND: Patch testing is the gold standard for diagnosing allergic contact dermatitis in children. OBJECTIVE: To present a 10-year retrospective review of pediatric patch testing at our institution. METHODS: Data from patients 18 years or younger who presented for patch testing from February 1, 2005, to May 31, 2015, were entered into a database. Patch testing was performed according to North American Contact Dermatitis Group standards. A positive reaction was defined as any allergen for which the patient had a 1+ or greater reaction and provided avoidance information. RESULTS: A total of 157 patients with a mean (SD) age of 12.3 (4.1) years were evaluated. The 2 most frequent allergens were nickel and cobalt. Most patients were referred by dermatologists for suspected allergic contact dermatitis (72.3%). Dermatitis was present for more than 2 years in most cases (n = 67 [46.2%]), from 6 months to 2 years (n = 49 [33.8%]), and for less than 6 months (n = 29 [20.0%]). Males were more likely to have a positive reaction to fragrance mix 1 compared with females (P = .02). No significant association was found between age and allergen sensitivity. Those with a history of atopy were more likely to have a positive reaction to cobalt (P = .008) and chromium (P = .03). Sixty patients (38.2%) returned for follow-up, and 37 (60.7%) reported improvement; most (n = 54 [88.5%]) were being treated with topical corticosteroids. CONCLUSION: Our study of pediatric patch testing can provide information regarding common allergens in children, which can enhance patient care. Primary care practitioners may benefit from awareness of patch testing as an alternative to prescribing systemic immunosuppressants. PMID- 27979025 TI - Atopy patch test in children with atopic dermatitis. AB - BACKGROUND: Atopic dermatitis is frequently associated with food and/or aeroallergen allergy. OBJECTIVE: To evaluate atopy patch tests (APTs) and skin prick tests (SPTs) in children with atopic dermatitis, using allergen extracts from locally lyophilized foods (cow's milk, egg white, egg yolk, wheat, soy, and shrimp), Dermatophagoides pteronyssinus, Dermatophagoides farinae, and American cockroach. METHODS: This study was a prospective, self-controlled study in children with atopic dermatitis. APTs, SPTs, and oral food challenge tests were performed in the cases with written informed consent. RESULTS: Fifty-six children with atopic dermatitis were enrolled. According to the Severity Scoring of Atopic Dermatitis Index, moderate atopic dermatitis was the most common severity (49.1%) followed by mild (20%) and severe atopic dermatitis (13.2%). APT results were positive for food allergens in 49% of participants; SPT results were positive in 54.7%. The sensitivity, specificity, positive predictive value, and negative predictive value of APTs for foods were 40%, 90.2%, 65.2%, and 76.6%, respectively. For SPTs, those values were 40%, 93.9%, 75%, and 77.3%, respectively. APT results for D farinae, D pteronyssinus, and American cockroach were positive in 33.9%, 35.8%, and 21.8% of participants, respectively. SPT results for these allergens were positive in 28.3%, 24.5%, and 9.4% of participants, respectively. No serious complications occurred. CONCLUSION: APTs with locally prepared lyophilized allergen extracts were safe and had high specificity, median positive predictive value, and low sensitivity for evaluation of suspected food allergy in children with atopic dermatitis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01164293. PMID- 27979026 TI - IL-17RB+ granulocytes are associated with airflow obstruction in asthma. AB - BACKGROUND: Interleukin (IL)-25 (IL-17E) is a proinflammatory cytokine that plays an important role in the T-helper type 2 cell pathway. The effects of IL-25 are mediated by its specific receptor, IL-17RB. Previous studies have defined an IL 17RB+ granulocyte population known as type 2 myeloid (T2M) cells that express T helper type 2 cell cytokines. The correlation of IL-17RB+ granulocytes, T2M cells, and asthma parameters is unknown. OBJECTIVE: To investigate the relation of IL-17RB+ granulocytes (and its subset, T2M cells) in patients with asthma with clinical parameters including spirometric values and the Asthma Control Test (ACT). METHODS: Peripheral blood from subjects with asthma and healthy controls was collected and analyzed by flow cytometry. Granulocytes were gated for IL 17RB+, T2M (CD11b+CD16+CD177+IL-17RB+), and eosinophil (CD16-) populations. Spirometry testing was performed on subjects with asthma. ACT scores and medical histories were collected by questionnaire and chart review. Correlations of IL 17RB+ cells and T2M cells with spirometry and ACT score were analyzed. RESULTS: Percentages of IL-17RB+ granulocytes and T2M cells were larger in subjects with asthma than in controls. Furthermore, percentages of the 2 cell populations were negatively correlated with degree of airway obstruction as measured by the ratio of percentage-predicted forced expiratory volume in 1 second to force vital capacity (r = -0.17, P = .043 for IL-17RB+ granulocytes; r = -0.32, P = .03 for T2M cells). There was no correlation with ACT score. The percentage of eosinophils was increased in subjects with asthma. However, IL-17RB+ eosinophil percentages were similar between subjects with asthma and controls and did not correlate with any clinical parameter. CONCLUSION: IL-17RB+ granulocytes and T2M cells from peripheral blood were increased in subjects with asthma, and the 2 cell types correlated with degree of airflow obstruction. PMID- 27979027 TI - Immunodominance in allergic T-cell reactivity to Japanese cedar in different geographic cohorts. AB - BACKGROUND: Japanese cedar (JC) pollen is a common trigger for allergic rhinitis in Japan. Pollen proteins targeted by IgE, including Cry j 1 and Cry j 2, and isoflavone reductase (IFR) have been identified. OBJECTIVE: To compare antigen specific IgE titers and T-cell responses to JC pollen-derived extract and peptides in cohorts with high and low pollen exposure. METHODS: Peripheral blood mononuclear cells from JC pollen allergic or nonallergic patients who have lived in Japan for at least 1 year and JC pollen allergic patients who have never been to Japan were tested for T-cell responses against JC pollen extract and peptide pools derived from Cry j 1, Cry j 2, or IFR. T-cell reactivity was assessed by interleukin 5 and interferon gamma production by ELISPOT. RESULTS: JC pollen specific T-cell reactivity and IgE titers were significantly higher in the allergic compared with the nonallergic Japanese cohort, which was also associated with different patterns of polysensitization. Interestingly, a significant overlap was observed in the hierarchy of the T-cell epitopes in the allergic Japanese cohort compared with the allergic non-Japanese cohort. In all 3 cohorts, T-cell reactivity was dominantly directed against peptides from the major allergens Cry j 1 and 2, with few T-cell responses detected against IFR. CONCLUSION: Our studies identify common denominators of T-cell reactivity in patient populations with different sensitization patterns, suggesting that generally applicable immunotherapeutic approaches might be developed irrespective of exposure modality. PMID- 27979030 TI - A real-life comparison of the Asthma Control Test and Global Initiative for Asthma asthma control grading. PMID- 27979029 TI - Chronic autoimmune urticaria as the presenting manifestation of primary hyperparathyroidism. PMID- 27979028 TI - Long-term effects of a house dust mite sublingual immunotherapy tablet in an environmental exposure chamber trial. AB - BACKGROUND: Treatment with SQ house dust mite (HDM) sublingual immunotherapy (SLIT) tablet is effective for HDM respiratory allergic disease, but data on long term effects are lacking. OBJECTIVE: Post hoc analyses were conducted to determine the long-term effect of SQ HDM SLIT-tablet on nasal, ocular, and cough symptoms 1 year after discontinuation of treatment. METHODS: Study participants underwent environmental exposure chamber (EEC) challenges at baseline and week 24 in a randomized, placebo-controlled, double-blind trial (NCT01644617) during which participants received daily 12 SQ-HDM, 6 SQ-HDM, or placebo for 24 weeks. Asthma had to be stable, well controlled, and nonsevere. The mean total asthma symptom score (TASS; sum of 3 symptoms: cough, wheeze, and dyspnea) during baseline and week 24 EEC challenge was analyzed in all participants who completed the trial (n = 106). Approximately 1 year after trial completion, another EEC challenge was conducted in a subset of participants (n = 51). Total nasal symptom score (sum of 4 symptoms), total ocular symptom score (sum of 2 symptoms), and cough were assessed. RESULTS: Compared with baseline and end-of-treatment values, sustained improvement of all symptoms assessed at the 1-year follow-up EEC challenge was evident in participants treated with 12 SQ-HDM. Results with 6 SQ HDM were less notable. After 24 weeks of 12 SQ-HDM, TASS during EEC challenge was improved 65% vs baseline; at 1-year follow-up, cough was improved 57% vs baseline. CONCLUSION: Persistent improvement of nasal and ocular symptoms was observed up to 1 year after completing 24 weeks of 12 SQ-HDM treatment. Beneficial effects on cough were also observed. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT01644617. PMID- 27979031 TI - Clinical value of post-percutaneous coronary intervention fractional flow reserve value: A systematic review and meta-analysis. AB - BACKGROUND: Fractional flow reserve (FFR) prior to percutaneous coronary intervention (PCI) is useful to guide treatment. Whether post-PCI FFR assessment might have clinical impact is controversial. The aim of this study is to evaluate the range of post-PCI FFR values and analyze the relationship between post-PCI FFR and clinical outcomes. METHODS: We systematically searched the PubMed, EMBASE, and Cochrane Library databases with cross-referencing of articles reporting post-PCI FFR and correlating post-PCI FFR values and clinical outcomes. The outcomes of interest were the immediate post-PCI FFR values and the correlations between post-PCI FFR and the incidence of repeat intervention and major adverse cardiac events (MACE). RESULTS: From 1995 to 2015, a total of 105 studies (n = 7470) were included, with 46 studies reporting post-PCI FFR and 59 studies evaluating relationship between post-PCI and clinical outcomes up to 30 months after PCI. Overall, post-PCI FFR values demonstrated a normal distribution with a mean value of 0.90 +/- 0.04. There was a positive correlation between the percentage of stent use and post-PCI FFR (P < .0001). Meta-regression analysis indicated that higher post-PCI FFR values were associated with reduced rates of repeat intervention (P < .0001) and MACE (P = .0013). A post-PCI FFR >=0.90 was associated with significantly lower risk of repeat PCI (odds ratio 0.43, 95% CI 0.34-0.56, P < .0001) and MACE (odds ratio 0.71, 95% CI 0.59-0.85, P = .0003). CONCLUSIONS: FFR measurement after PCI was associated with prognostic significance. Further investigation is required to assess the role of post-PCI FFR and validate cutoff values in contemporary clinical practice. PMID- 27979032 TI - Prevalence and outcome of thrombotic and embolic complications in adults after Fontan operation. AB - : There are limited studies of thrombotic and embolic complications (TEC) in the adult Fontan population. The purpose of the study was to determine the prevalence, risk factors, and outcomes of TECs in this population. METHODS: Retrospective review of adults with a previous Fontan operation, with follow-up at Mayo Clinic, 1994-2014. Systemic TEC was defined as intracardiac thrombus, ischemic stroke, or systemic arterial embolus. Nonsystemic TEC was defined as Fontan conduit/right atrial thrombus or pulmonary embolus. RESULTS: We identified 387 patients with a mean (SD) age of 28 (7) years and a mean follow-up of 8 (2) years. An atriopulmonary connection (APC) was done for 286 patients (74%). Atrial arrhythmias were present in 278 (72%). There were 121 TECs (systemic n=36, nonsystemic n=85) in 98 patients (25%). Risk factors for systemic TEC were atrial arrhythmia (hazard ratio 2.28, P=.001) and APC (hazard ratio 1.98, P=.02); nonsystemic TEC also had similar risk factors. All 98 patients received warfarin. Warfarin was discontinued in 10 of 98 because of bleeding, and 8 of these 10 subsequently had a second TEC. Among the 82 patients who had follow-up imaging, 16 (20%) had resolution of thrombus. In total, 24 of 98 patients had a second TEC, most of whom had inadequate anticoagulation. CONCLUSIONS: Thrombotic and embolic complication was not uncommon; risk factors for TEC were APC and atrial arrhythmias. Most patients were treated successfully with warfarin alone. A second TEC occurred in most patients whose anticoagulation was discontinued because of bleeding events. PMID- 27979033 TI - Bendopnea and risk of adverse clinical outcomes in ambulatory patients with systolic heart failure. AB - BACKGROUND: Recently, the symptom of bendopnea, that is, shortness of breath when bending forwards such as when putting on shoes, has been described in heart failure patients and found to be associated with higher ventricular filling pressures, particularly in the setting of low cardiac index. However, it is not known whether bendopnea is associated with clinical outcomes. METHODS: In a prospective convenience sample of 179 patients followed in our heart failure disease management clinic, we determined the presence of bendopnea at the time of enrollment and ascertained clinical outcomes through 1 year of follow-up. We performed univariate and stepwise multivariable modeling to test the association of bendopnea with clinical outcomes. RESULTS: Bendopnea was present in 32 of 179 (18%) subjects. At 1 year, those with versus without bendopnea were at increased risk of the composite endpoint of death, heart failure admission, inotrope initiation, left ventricular assist device implantation, or cardiac transplantation in univariate (hazard ratio [HR] 1.9, P < .05) but not multivariable (HR 1.9, P = .11) analysis. Bendopnea was more strongly associated with short-term outcomes including heart failure admission at 3 months in both univariate (HR 3.1, P < .004) and multivariable (HR 2.5, P = .04) analysis. CONCLUSIONS: Bendopnea was associated with an increased risk of adverse outcomes in ambulatory patients with heart failure, particularly heart failure admission at 3 months. PMID- 27979034 TI - Interventional left atrial appendage closure vs novel anticoagulation agents in patients with atrial fibrillation indicated for long-term anticoagulation (PRAGUE 17 study). AB - : Atrial fibrillation (AF), with a prevalence of 1% to 2%, is the most common cardiac arrhythmia. Without antithrombotic treatment, the annual risk of a cardioembolic event is 5% to 6%. The source of a cardioembolic event is a thrombus, which is usually formed in the left atrial appendage (LAA). Prevention of cardioembolic events involves treatment with anticoagulant drugs: either vitamin K antagonists or, recently, novel oral anticoagulants (NOAC). The other (nonpharmacologic) option for the prevention of a cardioembolic event involves interventional occlusion of the LAA. OBJECTIVE: To determine whether percutaneous LAA occlusion is noninferior to treatment with NOAC in AF patients indicated for long-term systemic anticoagulation. STUDY DESIGN: The trial will be a prospective, multicenter, randomized noninferiority trial comparing 2 treatment strategies in moderate to high-risk AF patients (ie, patients with history of significant bleeding, or history of cardiovascular event(s), or a with CHA2DS2VASc >=3 and HAS-BLED score >=2). Patients will be randomized into a percutaneous LAA occlusion (group A) or a NOAC treatment (group B) in a 1:1 ratio; the randomization was done using Web-based randomization software. A total of 396 study participants (198 patients in each group) will be enrolled in the study. The primary end point will be the occurrence of any of the following events within 24months after randomization: stroke or transient ischemic attack (any type), systemic cardioembolic event, clinically significant bleeding, cardiovascular death, or a significant periprocedural or device-related complications. CONCLUSION: The PRAGUE-17 trial will determine if LAA occlusion is noninferior to treatment with NOAC in moderate- to high-risk AF patients. PMID- 27979035 TI - Extending the volume-outcomes debate into the world of congenital cardiac catheterization. PMID- 27979036 TI - Relationship between hospital procedure volume and complications following congenital cardiac catheterization: A report from the IMproving Pediatric and Adult Congenital Treatment (IMPACT) registry. AB - BACKGROUND: The association between institutional volume and outcomes has been demonstrated for cardiac catheterization among adults, but less is known about this relationship for patients with congenital heart disease (CHD) undergoing cardiac catheterization. METHODS: Within the IMPACT registry, we identified all catheterizations between January 2011 and March 2015. Hierarchical logistic regression, adjusted for patient and procedural characteristics, was used to determine the association between annual catheterization lab volume and occurrence of a major adverse event (MAE). RESULTS: Of 56,453 catheterizations at 77 hospitals, an MAE occurred in 1014 (1.8%) of cases. In unadjusted analysis, a MAE occurred in 2.8% (123/4460) of cases at low-volume hospitals (<150 procedures annually), as compared with 1.5% (198/12,787), 2.0% (431/21,391), and 1.5% (262/17,815) of cases at medium- (150-299 annual procedures), high- (300-499 annual procedures), and very-high-volume (>=500 procedures annually) hospitals, respectively, P<.001. After multivariable adjustment, this significant relationship between annual procedure volume and occurrence of an MAE persisted. Compared to low-volume programs, the odds of an MAE was 0.55 (95% CI 0.35-0.86, P=.008), 0.62 (95% CI 0.41-0.95, P=.03), and 0.52 (95% CI 0.31-0.90, P=.02) at medium-, high-, and very-high-volume programs, respectively. CONCLUSIONS: Although the risk of MAE after cardiac catheterization in patients with CHD is low at all hospitals, it is higher among hospitals with fewer than 150 cases annually. These results support the notion that centers meeting this threshold volume for congenital cardiac catheterizations may achieve improved patient outcomes. PMID- 27979037 TI - Chocolate intake and incidence of heart failure: Findings from the Cohort of Swedish Men. AB - : The objective of this study was to evaluate the association of chocolate consumption and heart failure (HF) in a large population of Swedish men. METHODS: We conducted a prospective cohort study of 31,917 men 45-79 years old with no history of myocardial infarction, diabetes, or HF at baseline who were participants in the population-based Cohort of Swedish Men study. Chocolate consumption was assessed through a self-administrated food frequency questionnaire. Participants were followed for HF hospitalization or mortality from January 1, 1998, to December 31, 2011, using record linkage to the Swedish inpatient and cause-of-death registries. RESULTS: During 14 years of follow-up, 2,157 men were hospitalized (n=1,901) or died from incident HF (n=256). Compared with subjects who reported no chocolate intake, the multivariable-adjusted rate ratio of HF was 0.88 (95% CI 0.78-0.99) for those consuming 1-3 servings per month, 0.83 (95% CI 0.72-0.94) for those consuming 1-2 servings per week, 0.82 (95% CI 0.68-0.99) for those consuming 3-6 servings per week, and 1.10 (95% CI 0.84-1.45) for those consuming >=1 serving per day (P for quadratic trend=.001). CONCLUSIONS: In this large prospective cohort study, there was a J-shaped relationship between chocolate consumption and HF incidence. Moderate chocolate consumption was associated with a lower rate of HF hospitalization or death, but the protective association was not observed among individuals consuming >=1 serving per day. Journal Subject Codes: Etiology: Epidemiology, Heart failure: Congestive. PMID- 27979040 TI - Validation of an automated electronic algorithm and "dashboard" to identify and characterize decompensated heart failure admissions across a medical center. AB - BACKGROUND: We aim to validate the diagnostic performance of the first fully automatic, electronic heart failure (HF) identification algorithm and evaluate the implementation of an HF Dashboard system with 2 components: real-time identification of decompensated HF admissions and accurate characterization of disease characteristics and medical therapy. METHODS: We constructed an HF identification algorithm requiring 3 of 4 identifiers: B-type natriuretic peptide >400 pg/mL; admitting HF diagnosis; history of HF International Classification of Disease, Ninth Revision, diagnosis codes; and intravenous diuretic administration. We validated the diagnostic accuracy of the components individually (n = 366) and combined in the HF algorithm (n = 150) compared with a blinded provider panel in 2 separate cohorts. We built an HF Dashboard within the electronic medical record characterizing the disease and medical therapies of HF admissions identified by the HF algorithm. We evaluated the HF Dashboard's performance over 26 months of clinical use. RESULTS: Individually, the algorithm components displayed variable sensitivity and specificity, respectively: B-type natriuretic peptide >400 pg/mL (89% and 87%); diuretic (80% and 92%); and International Classification of Disease, Ninth Revision, code (56% and 95%). The HF algorithm achieved a high specificity (95%), positive predictive value (82%), and negative predictive value (85%) but achieved limited sensitivity (56%) secondary to missing provider-generated identification data. The HF Dashboard identified and characterized 3147 HF admissions over 26 months. CONCLUSIONS: Automated identification and characterization systems can be developed and used with a substantial degree of specificity for the diagnosis of decompensated HF, although sensitivity is limited by clinical data input. PMID- 27979038 TI - Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network "Patients with Intermittent Claudication Injected with ALDH Bright Cells" (CCTRN PACE) study. AB - BACKGROUND: Peripheral artery disease (PAD) is important to public health as a major contributor to cardiovascular morbidity and mortality. Recent developments in magnetic resonance imaging (MRI) techniques permit improved assessment of PAD anatomy and physiology, and may serve as surrogate end points after proangiogenic therapies. METHODS: The PACE study is a randomized, double-blind, placebo controlled clinical trial designed to assess the physiologic impact and potential clinical efficacy of autologous bone marrow-derived ALDHbr stem cells. The primary MRI end points of the study are as follows: (1) total collateral count, (2) calf muscle plasma volume (a measure of capillary perfusion) by dynamic contrast-enhanced MRI, and (3) peak hyperemic popliteal flow by phase-contrast MRI (PC-MRI). RESULTS: The interreader and intrareader and test-retest results demonstrated good-to-excellent reproducibility (interclass correlation coefficient range 0.61-0.98) for all magnetic resonance measures. The PAD participants (n=82) had lower capillary perfusion measured by calf muscle plasma volume (3.8% vs 5.6%) and peak hyperemic popliteal flow (4.1 vs 13.5mL/s) as compared with the healthy participants (n=16), with a significant level of collateralization. CONCLUSIONS: Reproducibility of the MRI primary end points in PACE was very good to excellent. The PAD participants exhibited decreased calf muscle capillary perfusion as well as arterial flow reserve when compared with healthy participants. The MRI tools used in PACE may advance PAD science by enabling accurate measurement of PAD microvascular anatomy and perfusion before and after stem cell or other PAD therapies. PMID- 27979039 TI - Usefulness of cell-mediated immune function in risk stratification for patients with advanced heart failure. AB - : Although heightened inflammation and autoimmune responses have been well described in patients with heart failure, the role of cell-mediated immune function in the pathogenesis and progression of heart failure is unclear. The aim of our study is to evaluate the prognostic role of cell-mediated immune function in patients with advanced heart failure. METHODS: We studied patients with advanced heart failure referred for evaluation of candidacy for advanced heart failure therapies between 2007 and 2010. Cell-mediated immune response was categorized into 3 groups-low or poor immune response (<=225 ng/mL), moderate or normal immune response (226-524 ng/mL), and strong immune response (>=525 ng/mL) using a phytohemagglutinin-stimulated T-cell response assay. RESULTS: Out of 368 patients, 41 patients (11.1%) had poor immune function, 258 patients (70.1%) had normal immune function, and 69 patients (18.7%) had strong immune function. The primary outcome of all-cause mortality or cardiac transplantation occurred in 63.4%, 45.3%, and 34.8% in the poor immunity, normal immunity, and strong immune function groups, respectively. In univariate analysis, cell-mediated immune function was strongly associated with the primary outcome (P=.014). Poor immune function portended worse prognosis (hazard ratio=2.18, 95% CI 1.01-4.70, P=.047), and strong immune function was associated with better survival (hazard ratio=0.67, 95% CI 0.43-1.04). However, when adjusted for multiple variables in multivariate analysis, immune function status lost its overall significance to predict primary outcome (P=.11), but the direction to an increased risk of primary outcome was maintained in the poor immune function group. CONCLUSIONS: Poor cell-mediated immune function measured by a clinically available assay could be associated with more adverse long-term prognosis in patients with advanced heart failure. PMID- 27979042 TI - Socioeconomic and partner status in chronic heart failure: Relationship to exercise capacity, quality of life, and clinical outcomes. AB - BACKGROUND: Prognosis in patients with heart failure (HF) is commonly assessed based on clinical characteristics. The association between partner status and socioeconomic status (SES) and outcomes in chronic HF requires further study. METHODS: We performed a post hoc analysis of HF-ACTION, which randomized 2,331 HF patients with ejection fraction <=35% to usual care +/- aerobic exercise training. We examined baseline quality of life and functional capacity and outcomes (all-cause mortality/hospitalization) by partner status and SES using adjusted Cox models and explored an interaction with exercise training. Outcomes were examined based on partner status, education level, annual income, and employment. RESULTS: Having a partner, education beyond high school, an income >$25,000, and being employed were associated with better baseline functional capacity and quality of life. Over a median follow-up of 2.5 years, higher education, higher income, being employed, and having a partner were associated with lower all-cause mortality/hospitalization. After multivariable adjustment, lower mortality was seen associated with having a partner (hazard ratio 0.91, 95% CI 0.81-1.03, P=.15) and more than a high school education (hazard ratio 0.91, CI 0.80-1.02, P=.12), although these associations were not statistically significant. There was no interaction between any of these variables and exercise training on outcomes (all P>.5). CONCLUSIONS: Having a partner and higher SES were associated with greater functional capacity and quality of life at baseline but were not independent predictors of long-term clinical outcomes in patients with chronic HF. These findings provide information that may be considered as potential variables impacting outcomes. PMID- 27979041 TI - Acute cardioversion vs a wait-and-see approach for recent-onset symptomatic atrial fibrillation in the emergency department: Rationale and design of the randomized ACWAS trial. AB - BACKGROUND: Current standard of care for patients with recent-onset atrial fibrillation (AF) in the emergency department aims at urgent restoration of sinus rhythm, although paroxysmal AF is a condition that resolves spontaneously within 24 hours in more than 70% of the cases. A wait-and-see approach with rate-control medication only and when needed cardioversion within 48 hours of onset of symptoms is hypothesized to be noninferior, safe, and cost-effective as compared with current standard of care and to lead to a higher quality of life. DESIGN: The ACWAS trial (NCT02248753) is an investigator-initiated, randomized, controlled, 2-arm noninferiority trial that compares a wait-and-see approach to the standard of care. Consenting adults with recent-onset symptomatic AF in the emergency department without urgent need for cardioversion are eligible for participation. A total of 437 patients will be randomized to either standard care (pharmacologic or electrical cardioversion) or the wait-and-see approach, consisting of symptom reduction through rate control medication until spontaneous conversion is achieved, with the possibility of cardioversion within 48 hours after onset of symptoms. Primary end point is the presence of sinus rhythm on 12 lead electrocardiogram at 4 weeks; main secondary outcomes are adverse events, total medical and societal costs, quality of life, and cost-effectiveness for 1 year. CONCLUSIONS: The ACWAS trial aims at providing evidence for the use of a wait-and-see approach for patients with recent-onset symptomatic AF in the emergency department. PMID- 27979043 TI - Switching of adenosine diphosphate receptor inhibitor after hospital discharge among myocardial infarction patients: Insights from the Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) observational study. AB - : The reasons for postdischarge adenosine diphosphate receptor inhibitor (ADPri) switching among patients with myocardial infarction (MI) are unclear. We sought to describe the incidence and patterns of postdischarge ADPri switching among patients with acute MI treated with percutaneous coronary intervention. METHODS: We used TRANSLATE-ACS (2010-2012) data to assess postdischarge ADPri switching among 8,672 MI patients discharged after percutaneous coronary intervention who remained on ADPri therapy 1 year post-MI. We examined patient-reported reasons for switching, GUSTO moderate or severe bleeding, major adverse cardiovascular events (MACEs), and definite stent thrombosis events around the time of the switch. RESULTS: Among patients still on ADPri therapy 1 year post-MI, 663 (7.6%) switched ADPri during that year. Switching occurred at a median of 50 days postdischarge and most frequently in patients discharged on ticagrelor (64/226; 28.3%), followed by prasugrel (383/2,489; 15.4%) and clopidogrel (216/5,957; 3.6%) (P < .001). Among patients discharged on prasugrel, 97.3% of switches were to clopidogrel and 87.5% of ticagrelor switches were to clopidogrel; both of these groups most often cited cost as a reason for switching (43.6% and 39.1%, respectively), whereas 60.7% who switched from clopidogrel cited physician decision as a reason. In the 7 days preceding the switch from clopidogrel, 40 (18.5%) had a MACE and 12 (5.6%) had a definite stent thrombosis event, whereas that from prasugrel or ticagrelor, a GUSTO moderate or severe bleeding event occurred in 1 (0.3%) and 0 patients, respectively. CONCLUSIONS: Postdischarge ADPri switching occurred infrequently within the first year post-MI and uncommonly was associated with MACEs or bleeding events. PMID- 27979044 TI - Serum brain-derived neurotrophic factor and risk of atrial fibrillation. AB - : Brain-derived neurotrophic factor (BDNF) is expressed by endothelial cells and can affect cardiovascular function. We examined if serum BDNF was associated with risk of incident atrial fibrillation (AF) in the Framingham Heart Study. METHODS: We studied individuals without an AF diagnosis at baseline from the Framingham original and offspring cohorts. We used age- and sex-adjusted, and multivariable adjusted Cox proportional hazards regression models to examine the association of serum BDNF concentrations with 10-year risk of incident AF. RESULTS: We studied 3,457 participants (mean age 65+/-11years, 58% women). During follow-up, 395 participants developed AF. In unadjusted analysis, higher mean serum BDNF concentration was associated with lower incidence of AF (hazard ratio 0.89 per SD, 95% CI 0.80-0.99). In multivariable-adjusted analyses, serum BDNF concentration was not significantly associated with incident AF (hazard ratio 0.98 per SD, 95% CI 0.88-1.09). Compared with the lowest quartile, BDNF levels in the other quartiles were not associated with risk of AF in multivariable-adjusted analyses. No interactions between sex or age with serum BDNF concentrations and risk of AF were found. CONCLUSIONS: In our prospective, community-based sample, we did not find a statistically significant association of serum BDNF levels with risk of incident AF. PMID- 27979045 TI - Sex differences in lipid profiles and treatment utilization among young adults with acute myocardial infarction: Results from the VIRGO study. AB - BACKGROUND: Young women with acute myocardial infarction (AMI) have higher mortality risk than similarly aged men. An adverse lipid profile is an important risk factor for cardiovascular outcomes after AMI, but little is known about whether young women with AMI have a higher-risk lipid pattern than men. We characterized sex differences in lipid profiles and treatment utilization among young adults with AMI. METHODS: A total of 2,219 adults with AMI (1,494 women) aged 18-55 years were enrolled from 103 hospitals in the United States (2008 2012). Serum lipids and lipoprotein subclasses were measured 1 month after discharge. RESULTS: More than 90% of adults were discharged on a statin, but less than half received a high-intensity dose and 12% stopped taking treatments by 1 month. For both men and women, the median of low-density lipoprotein (LDL) cholesterol was reduced to <100 mg/dL 1 month after discharge for AMI, but high density lipoprotein (HDL) cholesterol remained <40 mg/dL. Multivariate regression analyses showed that young women had favorable lipoprotein profiles compared with men: women had higher HDL cholesterol and HDL large particle, but lower total cholesterol-to-HDL cholesterol ratio and LDL small particle. CONCLUSIONS: Young women with AMI had slightly favorable lipid and lipoprotein profiles compared with men, suggesting that difference in lipid and lipoprotein may not be a major contributor to sex differences in outcomes after AMI. In both men and women, statin remained inadequately used, and low HDL cholesterol level was a major lipid abnormality. PMID- 27979046 TI - Effects of exercise and stress management training on nighttime blood pressure dipping in patients with coronary heart disease: A randomized, controlled trial. AB - INTRODUCTION: Blunted nighttime blood pressure (BP) dipping is prognostic of cardiovascular morbidity and mortality. Patients with coronary heart disease (CHD) are often characterized by a blunted nighttime BP dipping pattern. The present study compared the effects of 2 behavioral intervention programs, aerobic exercise (EX) and stress management (SM) training, with a usual care (UC) control group on BP dipping in a sample of CHD patients. METHODS: This was a secondary analysis of a randomized, controlled trial with allocation concealment and blinded outcome assessment in 134 patients with stable CHD and exercise-induced myocardial ischemia. Nighttime BP dipping was assessed by 24-hour ambulatory BP monitoring, at prerandomization baseline and after 16 weeks of one of the following treatments: usual medical care; UC plus supervised aerobic EX for 35 minutes, 3 times per week; UC plus weekly 1.5-hour sessions of SM training. RESULTS: The EX and SM groups exhibited greater improvements in systolic BP dipping (P=.052) and diastolic BP dipping (P=.031) compared with UC. Postintervention systolic BP percent-dipping means were 12.9% (SE=1.5) for SM, 11.1% (SE=1.4) for EX, and 8.6% (SE=1.4) for UC. Postintervention diastolic BP percent-dipping means were 13.3% (SE=1.9) for SM, 14.1% (SE=1.8) for EX, and 8.8% (1.8) for UC. CONCLUSIONS: For patients with stable CHD, EX or SM training resulted in improved nighttime BP dipping compared with usual medical care. These favorable effects of healthy lifestyle modifications may help reduce the risk of adverse clinical events. PMID- 27979048 TI - Introduction of Clinical Practice Update Committee Articles. PMID- 27979047 TI - Statin therapy and low-density lipoprotein cholesterol reduction in HIV-infected individuals after acute coronary syndrome: Results from the PACS-HIV lipids substudy. AB - : Knowledge about lipid interventions in secondary prevention in HIV-infected individuals is limited; studies are sparse. METHODS: A prospective observational multicenter study enrolled 282 patients on statin 1 month after first acute coronary syndrome (ACS) (95 HIV-infected individuals, 187 HIV-uninfected). Data on fasting lipids (total cholesterol [TC], low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], non-HDL-C, triglycerides, TC/HDL-C ratio) were collected over 3 years. The evolution of lipid concentrations was analyzed using mixed-effects models. Achievement of National Cholesterol Education Program Adult Treatment Panel III lipid goals and prescribed statin intensity was assessed. RESULTS: Mean age of patients was 49.0 years, and 94% were men. Baseline lipids were similar in the 2 groups. Six months after first ACS, less low-density lipoprotein cholesterol reduction was observed in the HIV infected GROUP (adjusted mean change -10.13; 95% CI -20.63 to 0.37; P=.06) than in the HIV-uninfected group (Adjusted mean change -38.51; 95% CI -46.00 to 31.04; P<.0001) Similar trends were observed for TC and non-HDL-C. After ACS, initial statin prescription for HIV-infected compared with HIV-uninfected individuals was more frequently a moderate-intensity statin (66% vs 45%) and less frequently a high-intensity statin (15% vs 45%). Over 3 years of follow-up, the proportion of HIV-infected patients receiving high-intensity statin remained persistently lower than the proportion observed in the HIV-uninfected group. CONCLUSIONS: In this observational study, HIV-infected individuals after first ACS exhibited worse lipid profiles than controls particularly during the first 6 months while receiving less potent statins. Appropriate statin intensity should be prescribed in HIV-infected individuals with awareness of potential drug-drug interactions. PMID- 27979050 TI - Comparison of the physicochemical and volatile composition of wine fractions obtained by two different dealcoholization techniques. AB - Three wines (a Rose wine, a Pelaverga and a Barbera red wines) were dealcoholized at 5% v/v ethanol with two different techniques: membrane contactor (MC) and distillation under vacuum (D). The influence of the treatments on the physicochemical composition and aromatic profile of the dealcoholized fractions was investigated. The main difference between the two techniques was the concentration grade reached by the dealcoholized fractions, which was 5-6times higher with D than with MC due to the concomitant loss of water. The main fixed compounds (organic acids, cations, polyphenols, anthocyanins) were not lost during the dealcoholization, while the losses of volatile compounds were relevant. Finally, the delta18O isotopic ratio was studied. The delta18O isotope ratio increased with D and decreased with MC. At the same time the delta18O isotope ratio fell within legal limits when the final ethanol content was adjusted to 2% by blending with dealcoholized fractions. PMID- 27979049 TI - Medical Management of Severe Alcoholic Hepatitis: Expert Review from the Clinical Practice Updates Committee of the AGA Institute. AB - The purpose of this clinical practice update is to review diagnostic criteria for severe acute alcoholic hepatitis and to determine the current best practices for this life-threatening condition. The best practices in this review are based on clinical trials, systematic reviews including meta-analysis and expert opinion to develop an approach to diagnosis and management. Best Practice Advice 1: Abstinence from drinking alcohol is the cornerstone of treatment for alcohol hepatitis (AH). Best Practice Advice 2: Patients with jaundice and suspected AH should have cultures of blood, urine, and ascites, if present, to determine the presence of bacterial infections regardless of whether they have fever. Best Practice Advice 3: Patients with AH who have jaundice should be admitted to the hospital to encourage abstinence, restore adequate nutrition, and exclude serious infections. Best Practice Advice 4: Imaging of the liver is warranted as part of the evaluation, but caution should be used in administering iodinated contrast dye, as it increases the risk of acute kidney injury (AKI). Best Practice Advice 5: Patients with AH require a diet with 1-1.5 g protein and 30-40 kcal/kg body weight for adequate recovery. If the patient is unable to eat because of anorexia or altered mental status, a feeding tube should be considered for enteral feeding. Parenteral nutrition alone is inadequate. Best Practice Advice 6: Severity and prognosis of AH should be evaluated using Maddrey Discriminant Function (MDF), Model for End-Stage Liver Disease (MELD), age, bilirubin, international normalized ratio, and creatinine (ABIC), or Glasgow scoring systems. Current treatments are based on this assessment. Best Practice Advice 7: Presence of systemic inflammatory response syndrome (SIRS) on admission is associated with an increased risk of multi-organ failure (MOF) syndrome. Development of MOF, usually due to infections developing after initial diagnosis of AH, is associated with a very high mortality rate. Best Practice Advice 8: Nephrotoxic drugs, including diuretics, should be avoided or used sparingly in patients with AH, since AKI is an early manifestation of MOF. Best Practice Advice 9: Patients with MDF > 32 or MELD score > 20 without a contraindication to glucocorticoid, such as hepatitis B viral infection, tuberculosis, or other serious infectious diseases, may be treated with methylprednisolone 32 mg daily, but the appropriate duration of treatment remains a subject of controversy. Methylprednisolone does not improve survival beyond 28 days, and the benefits for < 28 days are modest. Best Practice Advice 10: Patients with a contraindication to glucocorticoids may be treated with pentoxifylline 400 mg three times daily with meals. Data regarding the efficacy are conflicting. Best Practice Advice 11: Patients with severe AH, particularly those with a MELD score > 26 with good insight into their alcohol use disorder and good social support should be referred for evaluation for liver transplantation, as the 90-day mortality rate is very high. Best Practice Advice 12: Patients with mild to moderate AH defined by a MELD score < 20 and MDF < 32 should be referred for abstinence counseling and prescribed a high protein diet supplemented with B vitamins and folic acid. PMID- 27979051 TI - Cider fermentation process monitoring by Vis-NIR sensor system and chemometrics. AB - Optimization of a multivariate calibration process has been undertaken for a Visible-Near Infrared (400-1100nm) sensor system, applied in the monitoring of the fermentation process of the cider produced in the Basque Country (Spain). The main parameters that were monitored included alcoholic proof, l-lactic acid content, glucose+fructose and acetic acid content. The multivariate calibration was carried out using a combination of different variable selection techniques and the most suitable pre-processing strategies were selected based on the spectra characteristics obtained by the sensor system. The variable selection techniques studied in this work include Martens Uncertainty test, interval Partial Least Square Regression (iPLS) and Genetic Algorithm (GA). This procedure arises from the need to improve the calibration models prediction ability for cider monitoring. PMID- 27979052 TI - Preparation of a generic monoclonal antibody and development of a highly sensitive indirect competitive ELISA for the detection of phenothiazines in animal feed. AB - In this study, a broadly specific monoclonal antibody was prepared and a sensitive monoclonal-based indirect competitive enzyme linked immunosorbent assay (ic-ELISA) was subsequently developed to determine the phenothiazines in animal feed with a simple sample preparation procedure for the first time. The obtained antibody 3A5 was of the immunoglobulin G1 (IgG1) isotype possessing a kappa light chain, which broadly cross-reacted to nine phenothiazines. The limit of detections of the method ranged from 1.1MUgkg-1 to 15.3MUgkg-1 in the swine feed and the fish feed. The recoveries of the phenothiazines were in the range of 78.2 116.6%. The coefficient of variations were less than 16.7%. A positive correlation (r>0.9249) between the results of the ic-ELISA and the high performance liquid chromatography were also observed, which indicated that the developed ic-ELISA is reliable and can be used to monitor phenothiazines in animal feed. PMID- 27979053 TI - Induced resistance in tomato fruit by gamma-aminobutyric acid for the control of alternaria rot caused by Alternaria alternata. AB - The study investigated the effect of gamma-aminobutyric acid (GABA) on the control of alternaria rot in tomato fruit and the possible mechanism involved. Our results showed exogenous GABA could stimulate remarkable resistance to the alternaria rot, while it had no direct antifungal activity against Alternaria alternata. Moreover, the activities of antioxidant enzymes, including peroxidase, superoxide dismutase and catalase, along with the expression of these corresponding genes, were significantly induced in the GABA treatment. The obtained data suggested GABA induced resistance against the necrotrophic pathogen A. alternata, at least in part by activating antioxidant enzymes, restricting the levels of cell death caused by reactive oxygen species. Meanwhile, the key enzyme genes of GABA shunt, GABA transaminase and succinic-semialdehyde dehydrogenase, were found up-regulated in the GABA treatment. The activation of the GABA shunt might play a vital role in the resistance mechanism underpinning GABA-induced plant immunity. PMID- 27979054 TI - Effect of production system, supermarket and purchase date on the vitamin D content of eggs at retail. AB - The vitamin D content of eggs from three retail outlets was measured over five months to examine the effects of production system (organic vs. free range vs. indoor), supermarket and purchase date on the concentration of vitamin D3 and 25 hydroxyvitamin D3. Results demonstrated a higher vitamin D3 concentration in free range (57.2+/-3.1MUg/kg) and organic (57.2+/-3.2MUg/kg) compared with indoor (40.2+/-3.1MUg/kg) (P<0.001), which was perhaps related to increased vitamin D synthesis by birds having more access to sunlight, while 25-hydroxyvitamin D3 concentration was higher (P<0.05) only in organic eggs. The interaction (P<0.05) between system and supermarket for both forms of vitamin D may relate to some incorrect labelling. Concentration of 25-hydroxyvitamin D3 was higher (P<0.05) in July and September than in August. The results indicate variations in vitamin D concentrations in eggs from different sources, thus highlighting the importance of accurate labelling. PMID- 27979055 TI - Barcode DNA length polymorphisms vs fatty acid profiling for adulteration detection in olive oil. AB - The aim of this study was to compare the performance of a DNA-barcode assay with fatty acid profile analysis to authenticate the botanical origin of olive oil. To achieve this aim, we performed a PCR-capillary electrophoresis (PCR-CE) approach on olive oil: seed oil blends using the plastid trnL (UAA) intron barcode. In parallel to genomic analysis, we subjected the samples to gas chromatography analysis of fatty acid composition. While the PCR-CE assay proved equally efficient as gas chromatography analysis in detecting adulteration with soybean, palm, rapeseed, sunflower, sesame, cottonseed and peanut oils, it was superior to the widely utilized analytical chemistry approach in revealing the adulterant species and detecting small quantities of corn and safflower oils in olive oil. Moreover, the DNA-based test correctly identified all tested olive oil: hazelnut oil blends whereas it was not feasible to detect hazelnut oil adulteration through fatty acid profile analysis. Thus, the present research has shown the feasibility of a PCR-CE barcode assay to detect adulteration in olive oil. PMID- 27979056 TI - Comparison of the major polyphenols in mature Argan fruits from two regions of Morocco. AB - Previous studies have shown that Argan fruits contain a large variety of polyphenolic compounds. Recently, another class of polyphenolic compounds, namely amino phenols have been detected and identified in immature Argan fruits. The objective of this study, was to establish whether or not, these novel compounds are also present in mature Argan fruits. To this end, a comparison was made between mature fruits from two regions of Morocco. Nineteen major compounds were identified and quantitated, including amino phenols, flavonoids, and phenolic acids by chromatographic methods in mature Argan fruits from the two regions of Morocco (Essaouira and Agadir). The phenolic acids were identified as gallic acid and 3,4-dihydroxybenzoic acid; the amino phenols as Arganimide A, and argaminolics A-C, and the flavonoids as rutin pentoside, quercetin-3-O arabinoside, quercetin glycogallate, quercetin-3-O-rhamnogalactoside, rutin, quercetin-3-O-galactoside (hyperoside), quercetin-3-O-glucoside (quercitrin), quercetin-3-O-arabinoside, quercetin glycohydroxybenzoate, quercetin glycosinapate, quercetin glycoferulate, quercetin glycocoumarate and quercetin. n=145. PMID- 27979057 TI - Application of response surface methodology to optimize solid-phase microextraction procedure for chromatographic determination of aroma-active monoterpenes in berries. AB - Most of scientific papers concern the qualitative or semi-quantitative analysis of aroma-active terpenes in liquid food matrices. Therefore, the procedure based on solid-phase microextraction and two-dimensional gas chromatography-time-of flight mass spectrometry for determination of monoterpenes in fresh berries was developed. The optimal extraction conditions using divinylbenzene-carboxen polydimethylsiloxane fiber were: temperature of 50 degrees C, extraction time of 26min, equilibrium time of 29min. The developed procedure provides a high recovery (70.8-99.2%), good repeatability (CV<10.4%), high linearity (r>0.9915) and offers practical advantages over currently used methods: reliability of compounds identification, simplicity of extraction and at least one order of magnitude lower detection limits (0.10-0.011MUg/L). The method was successfully applied to determine monoterpenes in 27 berry samples of different varieties and 4 berry products. Tukey's test revealed that monoterpenes content is a reliable indicator of fruit maturity and origin. It suggests that the method may be of interest to researchers and food industry. PMID- 27979058 TI - Effect of rosmarinic acid and carnosic acid on AGEs formation in vitro. AB - This work aimed to investigate the effect of the two main components of rosemary extracts, namely rosmarinic acid (RA) and carnosic acid (CA), on the formation of advanced glycation end-products (AGEs) in vitro. In the bovine serum albumin (BSA)/glucose model, addition of RA and CA at 400MUg/mL inhibited fluorescent AGEs by more than 90%, and carboxymethyl lysine (CML) and carboxyethyl lysine (CEL) by 82.7% and 75.2%, and 71.4% and 64.2%, respectively. Moreover, the addition of RA and CA at 400MUg/mL inhibited fluorescent AGEs by more than 90% both in the BSA/glyoxal (GO) and BSA/methylglyoxal (MGO) models, the formation of CML by 64.9% and 53.9% in BSA/GO model, and CEL by 28.9% and 24.3% in BSA/MGO model, respectively. RA and CA also significantly decreased the concentration of MGO and protein carbonylation. PMID- 27979059 TI - Total polyphenols content in white wines on a microfluidic flow injection analyzer with embedded optical fibers. AB - Absorbance detection in food microdevices has not been thoroughly used due to low levels of sensitivity in measurements. Thus, it is necessary to develop microfluidic methods for improving photometric detection. For this purpose, a simple coupled-optical-fiber-polydimethylsiloxane (PDMS) microdevice was developed, to quantify polyphenols content in white wine employing the Folin Ciocalteu reaction method. A 6V and 10W halogen lamp with an optical path length of 7mm between optical fibers, which were placed into the microchip, using guides at the outlet of the flow, increased the level of sensitivity during detection. The linear range was from 0.03mmol/L to 0.18mmol/L. Thus, the corresponding equation was: Abs=4.00(+/-0.16) [tannic acid]+0.17(+/-0.017). Intra-laboratory repeatability and reproducibility percentages were 2.95% and 6.84%, respectively. Such results were compared to those obtained from applying the conventional flow injection analysis method, based on the same type of reaction. The relative error between methods was less than 13%. PMID- 27979060 TI - Effect of Rosmarinus officinalis L. essential oil combined with different packaging conditions to extend the shelf life of refrigerated beef meat. AB - Rosemary essential oil (REO) contains bioactives having antioxidant and antimicrobial properties. This work investigated the effect of REO combined with modified atmosphere packaging conditions (MAP), in our case, aerobic, vacuum or high O2, to extend the shelf life of beef. Beef slices were wrapped in special three-layer sheets of packaging material, some with a coating of REO (active packaging, AP), and some without REO (non active packaging, NAP), and stored at 4 degrees C for 20days. The use of REO proved efficacious in every storage condition, as seen in the lower counts of psychrotrophics, Brochothrix thermosphacta, Pseudomonas spp., and Enterobacteriaceae in AP meat compared to NAP meat. Sensory and colourimetric analyses showed that the best packaging conditions were high-O2 atmosphere in combination with REO. Based on microbiological data, shelf life of beef was 5-6days for AP samples packaged under aerobic conditions and 14-15days for AP samples in high-O2 conditions. PMID- 27979061 TI - Cooling treatment of olive paste during the oil processing: Impact on the yield and extra virgin olive oil quality. AB - In recent years, the temperature of processed olives in many olive-growing areas was often close to 30 degrees C, due to the global warming and an early harvesting period. Consequently, the new trends in the extraction process have to include the opportunity to cool the olives or olive paste before processing to obtain high quality EVOO. A tubular thermal exchanger was used for a rapid cooling treatment (CT) of olive paste after crushing. The results did not show a significant difference in the oil yield or any modifications in the legal parameters. The cooling process determined a significant improvement of phenolic compounds in all the three Italian cultivar EVOOs analyzed, whereas the volatile compounds showed a variability largely affected by the genetic origin of the olives with C6 aldehydes that seem to be more stable than C6 alcohols and esters. PMID- 27979062 TI - Cultivar-specific high temperature stress responses in bread wheat (Triticum aestivum L.) associated with physicochemical traits and defense pathways. AB - The increasing global temperature by 1 degrees C is estimated to reduce the harvest index in a crop by 6%, and this would certainly have negative impact on overall plant metabolism. Wheat is one of the most important crops with global annual production of over 600million tonnes. We investigated an array of physicochemical and molecular indexes to unravel differential response of nine commercial wheat cultivars to high temperature stress (HTS). The reduced rate in relative water content, higher membrane stability, slow chlorophyll degradation and increased accumulation of proline and secondary metabolites ingrained higher thermotolerance in cv. Unnat Halna, among others. The altered expression of several stress-responsive genes, particularly the genes associated with photosynthesis, heat shock proteins and antioxidants impinge on the complexity of HTS-induced responses over different genetic backgrounds and connectivity of adaptive mechanisms. This may facilitate the targeted manipulation of metabolic routes in crops for agricultural and industrial exploitation. PMID- 27979063 TI - Spectral and colorimetric characteristics of metal chelates of acylated cyanidin derivatives. AB - Colorants derived from nature are increasingly popular due to consumer demand. Anthocyanins are a class of naturally occurring pigments that produce red-purple blue hues in nature, especially when interacting with metal ions and co-pigments. The role of various acylations of cyanidin (Cy) derivatives on color expression and stability of Al3+ and Fe3+ chelates in pH 6-7 were evaluated by spectrophotometry (380-700nm) and colorimetry (CIE-L*a*b*) during dark, ambient storage (48h). Increased substitution generally increased lambdamax of Cy chelates: malonic acid monoacylationferulic-sinapic>sinapic-sinapic)>monoacylated (malonic~sinapic>ferulic>p coumaric). PMID- 27979064 TI - Effect of dietary pomegranate seed oil on laying hen performance and physicochemical properties of eggs. AB - The objective of the study was to determine the effects of pomegranate seed oil, used as a source of punicic acid (CLnA) in the diets of laying hens, on the physicochemical properties of eggs. Forty Isa Brown laying hens (26weeks old) were equally subjected to 4 dietary treatments (n=10) and fed a commercial layer diet supplying 2.5% sunflower oil (control) or three levels (0.5, 1.0 and 1.5%) of punicic acid in the diets. After 12weeks of feeding the hens, eggs collection began. Sixty eggs - randomly selected from each group - were analysed for physicochemical properties. Eggs naturally enriched with CLnA preserve their composition and conventional properties in most of the analysed parameters (including chemical composition, physical as well as organoleptic properties). Dietary CLnA had positive impact on the colour of the eggs' yolk, whereas the hardness of hard-boiled egg yolks was not affected. Additionally, increasing dietary CLnA led to an increase not only the CLnA concentrations, but also CLA in egg-yolk lipids. PMID- 27979065 TI - Development and validation of a simple and fast method for simultaneous determination of aflatoxin B1 and sterigmatocystin in grains. AB - In this study, a simple, fast, sensitive and reliable method was developed for the simultaneous determination of aflatoxin B1 (AFB1) and sterigmatocystin (STC) in rice, wheat, maize, oat, rye and barley grains based on a modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) method and liquid chromatography-tandem mass spectrometry (LC-MS/MS). AFB1 and STC were extracted using 95% acetonitrile in water and cleaned up using N-Propylethane-1,2-diamine (PSA). The method was validated according to the SANCO/12571/2013 regulation of the European Union (EU). Recoveries at three spiked levels of 0.5, 2.5 and 5.0MUg/kg ranged from 77.7% to 119.7% and the relative standard deviations (RSDs) were between 1.3% and 12.8%. Limits of detection (LOD) were 0.03 and 0.02MUg/kg for AFB1 and STC, respectively. The limit of quantification (LOQ) was 0.5MUg/kg for both AFB1 and STC. The proposed method was successfully applied to determine AFB1 and STC levels in ten non-processed rice samples from Guangdong province in China. PMID- 27979066 TI - The chemical and antioxidant stability of isolated low molecular weight phlorotannins. AB - Due to their high anti-oxidant activity, phlorotannins represent potential natural alternatives to synthetic preservatives currently used within the food industry. However, their successful integration into food products requires research into their chemical integrity, particularly when selecting appropriate storage conditions. Subsequently, this study aims to investigate the stability of low molecular weight phlorotannin fractions from Fucus vesiculosus (L.). Powder and aqueous fractions were stored under five different conditions for 10weeks. Phlorotannin stability was determined using Q-ToF-MS and UPLC-TQD-MS/MS and a DPPH assay. After 10weeks of storage, fractions suspended in an aqueous matrix underwent oxidation when exposed to continuous atmospheric oxygen and thermal degradation when exposed to a constant temperature of 50 degrees C, resulting in decreases in radical scavenging activity (p<0.001). Phlorotannins remained stable under all other storage conditions. This study highlights phlorotannins as highly stable polymers, under certain storage conditions, with an excellent capacity for scavenging radicals. PMID- 27979067 TI - Novel method for the producing area identification of Zhongning Goji berries by electronic nose. AB - High-quality Zhongning Goji berries (ZNG) are illegally adulterated in the market by adding non-ZNG (NZNG). An accurate, rapid, and effective approach for the producing area identification of ZNG is needed to protect the geographical indications of Goji berry products and to ensure fair trade. Samples from different regions were collected and their odors were detected by an electronic nose (E-nose). Principal component analysis (PCA), cluster analysis (CA), and linear discriminant analysis (LDA) were employed to build identification models. The E-nose models were further verified by gas chromatography-mass spectrometry (GC-MS). The identification rates of the PCA, CA, and LDA models were 91.0%, 98.9%, and 100%, respectively. The PCA and CA models presented good results, and the LDA model showed optimum performance. These conditions indicate the feasibility of using the E-nose technique for ZNG identification. GC-MS analysis revealed differences and similarities in total ion current chromatograms between ZNG and NZNG. PMID- 27979068 TI - Enantioselective behaviour of the herbicide fluazifop-butyl in vegetables and soil. AB - The enantioselective dissipation of the enantiomers of fluazifop-butyl in tomato, cucumber, pakchoi, rape and soil under field condition was investigated to elucidate the enantioselective environmental behaviours and chiral stability of the optical pure product. Fluazifop, the major chiral metabolite of fluazifop butyl, was also detected. Fluazifop-butyl dissipated rapidly in the vegetables and soil with the half-lives of the enantiomers ranging from 1.62 to 2.84days. Enantioselective degradations of fluazifop-butyl were found. In tomato and cucumber, S-fluazifop-butyl dissipated faster than R-enantiomer, while R fluazifop-butyl showed a faster degradation in pakchoi, rape and soil. Fluazifop was found almost immediately after the application of fluazifop-butyl and had relatively longer persistent time. When the optical pure product fluazifop-P butyl was applied, rapid degradation to R-fluazifop was found with half-lives from 1.24 to 2.28days, and no S-fluazifop-butyl or S-fluazifop was detected showing the herbicidally active fluazifop-P-butyl and R-fluazifop were configurationally stable. PMID- 27979069 TI - A novel electrochemical sensor based on a molecularly imprinted polymer for the determination of epigallocatechin gallate. AB - A novel electrochemical sensor based on the molecularly imprinted polymer (MIP) was fabricated by electrochemical polymerization of beta-cyclodextrins (beta-CD) and epigallocatechin-gallate (EGCG) on the graphene oxide (GO) modified glassy carbon (GO/GC) electrode for the first time. The MIP/GO/GC electrode exhibits an excellent ability of specific binding of EGCG and a rapid electrochemical response, high sensitivity and selectivity for determination of EGCG. This prepared MIP sensor presents distinct advantages over conventional electrochemical methods for EGCG determination because it is a one-step preparation and the template molecule can be easily removed by cyclic voltammetry scans, and no elution reagent is required. Under the optimal experimental conditions, the linear response range for EGCG concentrations by the sensor was 3*10-8mol/L to 1*10-5mol/L and the detection limit was 8.78*10-9mol/L(S/N=3). The results demonstrate that the proposed MIP sensor can be a potential alternative for the determination of EGCG in tea samples. PMID- 27979071 TI - A recyclable protein resource derived from cauliflower by-products: Potential biological activities of protein hydrolysates. AB - Cauliflower by-products (CBP) are rich in leaf protein. Every year tons of CBP will lead to environmental pollution. Therefore, this study was conducted to extract leaf protein from CBP and investigate its biological activities. Our results showed that the optimal extraction parameters were: a liquid to solid ratio of 4mL/g, a pH of 11, an ultrasonic extraction lasting 15min, and at an applied power of 175W. Under these optimized conditions, 12.066g of soluble leaf protein (SLP) was obtained from 1000g of CBP and its extraction yield was 53.07%. The obtained SLP was further hydrolysed by Alcalase and the SLP hydrolysate (SLPH) showed a potent angiotensin I-converting enzyme (ACE) inhibitory activity with an IC50 value of 138.545MUg/mL in vitro. In addition, SLPH promoted the glucose consumption and enhanced the glycogen content in HepG2 cells. Overall, our results suggested that CBP may be recycled for designing future functional foods. PMID- 27979070 TI - A new methodology capable of characterizing most volatile and less volatile minor edible oils components in a single chromatographic run without solvents or reagents. Detection of new components. AB - The possibilities offered by a new methodology to determine minor components in edible oils are described. This is based on immersion of a solid-phase microextraction fiber of PDMS/DVB into the oil matrix, followed by Gas Chromatography/Mass Spectrometry. It enables characterization and differentiation of edible oils in a simple way, without either solvents or sample modification. This methodology allows simultaneous identification and quantification of sterols, tocols, hydrocarbons of different natures, fatty acids, esters, monoglycerides, fatty amides, aldehydes, ketones, alcohols, epoxides, furans, pyrans and terpenic oxygenated derivatives. The broad information provided by this methodology is useful for different areas of interest such as nutritional value, oxidative stability, technological performance, quality, processing, safety and even the prevention of fraudulent practices. Furthermore, for the first time, certain fatty amides, gamma- and delta-lactones of high molecular weight, and other aromatic compounds such as some esters derived from cinnamic acid have been detected in edible oils. PMID- 27979072 TI - Inhibitory effect of sugarcane molasses extract on the formation of Nepsilon (carboxymethyl)lysine and Nepsilon-(carboxyethyl)lysine. AB - Molasses, the main byproduct of sugar production, is a well-known source of phenolic compounds. In this study, the effect of sugarcane molasses extract on the formation of Nepsilon-(carboxymethyl)lysine (CML) and Nepsilon (carboxyethyl)lysine (CEL) was investigated in glucose-lysine model reaction systems. Results showed that sugarcane molasses extract significantly and dose dependently inhibited the formation of CML and CEL in model reaction systems. The antiglycation activities of sugarcane molasses extract were not only brought about by its antioxidant activities but also associated with its trapping abilities of reactive carbonyl species, such as glyoxal (GO) and methylglyoxal (MGO), the key intermediate compound for the formation of CML and CEL. Besides, the presence of sugarcane molasses extract effectively reduced the extent of browning. The present study emphasized the potential health effects of sugarcane molasses and the possibility of using byproducts as effective ingredients to reduce dietary Maillard reaction end products. PMID- 27979073 TI - In vitro digestibility and IgE reactivity of enzymatically cross-linked heterologous protein polymers. AB - Homologous and heterologous cross-linked polymers of whey protein isolate (WPI), soy protein isolate (SPI) and casein (CN) and their binary mixtures, viz., WPI+SPI, WPI+CN and SPI+CN, were produced using transglutaminase, and their in vitro IgE reactivity and digestibility under simulated gastro-intestinal conditions were studied. The results showed that the IgE reactivity of protein components in heterologous polymers was significantly lower than that in homologous polymers, suggesting that each protein component masked the IgE reactive epitopes in the other protein component more effectively in heterologous polymers than in homologous polymers. In vitro digestion under simulated gastro intestinal conditions revealed that both homologous and heterologous polymers were less digestible than untreated proteins, but the peptides released during the time course of digestion were less IgE-reactive. The results of this study indicate that hypoallergenic protein products could be produced by transglutaminase-mediated heterologous polymerization of protein mixtures. PMID- 27979074 TI - Prediction of heat-induced polymerization of different globular food proteins in mixtures with wheat gluten. AB - Egg, soy or whey protein co-exists with wheat gluten in different food products. Different protein types impact each other during heat treatment. A positive co protein effect occurs when heat-induced polymerization of a mixture of proteins is more intense than that of the isolated proteins. The intrinsic protein characteristics of globular proteins which enhance polymerization in mixtures with gluten are unknown. In this report, a model was developed to predict potential co-protein effects in mixtures of gluten and globular proteins during heating at 100 degrees C. A negative co-protein effect with addition of lysozyme, no co-protein effect with soy glycinin or egg yolk and positive co-protein effects with bovine serum albumin, (S-)ovalbumin, egg white, whole egg, defatted egg yolk, wheat albumins and wheat globulins were detected. The level of accessible free sulfhydryl groups and the surface hydrophobicity of unfolded globular proteins were the main characteristics in determining the co-protein effects in gluten mixtures. PMID- 27979075 TI - Antioxidant activity of amino acids in soybean oil at frying temperature: Structural effects and synergism with tocopherols. AB - The purpose of this study was to evaluate amino acids as natural antioxidants for frying. Twenty amino acids were added to soybean oil heated to 180 degrees C, and the effects of amino acid structure on the antioxidant activity were investigated. Amino acids containing a thiol, a thioether, or an extra amine group such as arginine, cysteine, lysine, methionine, and tryptophan had the strongest antioxidant activities. At 5.5mM, these amino acids had stronger antioxidant activities than 0.02% (1.1mM) tert-butylhydroquinone (TBHQ). A functional group such as an amide, carboxylic acid, imidazole, or phenol appeared to negatively affect amino acid antioxidant activity. Synergism between amino acids and tocopherols was demonstrated, and we found that this synergistic interaction may be mostly responsible for the antioxidant activity that was observed. In a frying study with potato cubes, 5.5mM l-methionine had significantly stronger antioxidant activity than 0.02% TBHQ. PMID- 27979076 TI - The impact of protein cross-linking induced by alkali on the quality of buckwheat noodles. AB - The impact of alkali addition on the dough rheological properties and quality of buckwheat noodles was investigated. Farinograph measurements showed that the addition of alkali increased the water absorption and development time of the dough. Dynamic rheological properties analysis showed that alkali addition enhanced G' and G" of dough. In addition, the texture properties of buckwheat noodles improved by the increase of the hardness and tensile force. Furthermore, an obvious decrease in the intensity of the protein bands with lower molecular weights was observed in SDS-PAGE patterns and the extractability of protein in sodium dodecyl sulfate containing medium (SDSEP) decreased, which demonstrated that alkali addition promoted the degree of protein polymerization in the buckwheat noodles. CLSM analysis showed alkali addition produced a tight and continuous protein network in buckwheat noodles. The protein cross-linking induced by alkali improved rheological properties of dough and texture properties of buckwheat noodles. PMID- 27979077 TI - Genotypic diversity and environmental stability of starch physicochemical properties in the USDA rice mini-core collection. AB - The USDA rice mini-core collection consists of 217 accessions representative of a world-wide germplam bank. We investigated its genotypic diversity in starch physicochemical properties and the effects of genotype, environment and G*E interaction in this study. High genotypic diversity was found in all 18 measured starch quality traits in the mini-core rice in two location-years in China. Genotype, environment and G*E effects on these traits were analysed using 115 common accessions successfully produced in both environments. Thermal properties (To, Tp and Tc) were very stable whereas most other traits differed significantly between environments. However, when these accessions were divided into five subgroups based on amylose content, environment was found to have differential effects. G*E interaction also played a significant role in determining the starch traits. These findings will provide guidance for selection from the diverse genotypes in the USDA mini-core collection for cultivation and for developing cultivars with desired cooking and eating quality. PMID- 27979078 TI - Cooking impact in color, pigments and volatile composition of grapevine leaves (Vitis vinifera L. var. Malvasia Fina and Touriga Franca). AB - Grapevine leaves (Vitis vinifera L. var. Malvasia Fina and Touriga Franca) under culinary treatment (blanching and boiling at 60, 75 and 90min) were studied for their color, pigments and volatile fraction changes. Blanching and boiling caused a decrease in luminosity and a loss of green coloration in both varieties, while a yellow-brownish color arose. Significant correlations were established between the loss of green color (monochromatic variable a*) and the total chlorophylls content. The main volatiles in fresh leaves [(Z)-3-hexenal, (Z)-3-hexen-1-ol, and (Z)-3-hexenyl acetate] were drastically reduced by blanching and suppressed by boiling. Other compounds like pentanal and 6-methyl-5-hepten-2 one arose from blanching and boiling. A boiling time of 60min is adequate for the culinary process of grapevine leaves, since the product is considered edible and the pigments and volatile changes are not as drastic as observed at 75 and 90min of boiling. PMID- 27979079 TI - 1H NMR and PCA-based analysis revealed variety dependent changes in phenolic contents of apple fruit after drying. AB - Dry and fresh apples have been studied monitoring their polyphenolic profiles through 1H NMR, antioxidant capacity and total polyphenol content. Six ancient and underutilized apple varieties (Mantovana, Mora, Nesta, Cipolla, Ruggina, Sassola) and a commercial one (Golden Delicious) were dried with an air-drying system at 45 degrees C for 19h. Although some of their polyphenol constituents were lost during drying, the antioxidant capacity of some apple varieties remained higher compared to Golden Delicious. This result is very important for ancient and underutilized varieties that are not consumed on large scale as fresh product since they have low attractiveness, due to their ugly appearance. Combining quantitative NMR spectroscopy with principal component analysis we have identified and quantified several polyphenols (such as catechin, epicathechin, and chlorogenic acid) that are important to establish the nutraceutical value of the different investigated apple varieties. PMID- 27979080 TI - Distribution of YLOID in soil-grapevine system (Vitis vinifera L.) as tool for geographical characterization of agro-food products. A two years case study on different grafting combinations. AB - The knowledge of a chemistry relationship between the soil and the agricultural products is an important tool for the quality assessment of food. We studied YLOID (Y, La and lanthanoids), recognized as very useful tracers due their coherent and predictable behavior, to trace and evaluate their distribution from soil to the grape in Vitis vinifera L. Because much of the world's viticulture is based on grafting, and rootstocks have proved affect vine growth, yield, fruit and wine quality, we carried out experimental trials to analyse the YLOID distribution of two different red cultivars, grafted onto six different rootstocks, on the same soil. The YLOID amounts, the relationship Heavy vs Light YLOID and the pattern of YLOID were calculated. The results showed that the different grafting combinations were not able to induce significant differences in YLOID uptake from the soil maintaining the same fingerprint (with the exception of Eu). PMID- 27979081 TI - Determination of antioxidant capacity of diverse fruits by electron spin resonance (ESR) and UV-vis spectrometries. AB - Twenty-one kinds of fruits including strawberry, mulberry, lemon, banana, etc. were measured for antioxidant capacity based on their ability to scavenge 1,1 diphenyl-2-picryl-hydrazyl (DPPH) radical. Vitamin C equivalent antioxidant capacity (VCEAC) was used to quantify antioxidant capacity of the studied fruits. The results were expressed as mg of ascorbic acid equivalent per 100g fruit. Each fruit was divided into two parts: harvest part (fresh fruit analyzed immediately), and liquid nitrogen frozen part (fruit frozen and pulverized in liquid nitrogen). Antioxidant capacities of both fresh and frozen fruits were determined, and VCEAC values were proved to have no significant difference. For the frozen fruits, the antioxidant capacities were measured by electron spin resonance spectroscopy (ESR) and UV-vis spectrometry. VCEAC values obtained with UV-vis and ESR range from 11.48 to 345.75mg/100g and 7.01 to 366.26mg/100g. Experimental results indicated that VCEAC values obtained by two methods were highly correlated. PMID- 27979082 TI - Magnetic graphene dispersive solid phase extraction combining high performance liquid chromatography for determination of fluoroquinolones in foods. AB - In this study, a magnetic graphene-based dispersive solid phase extraction method was developed that was combined with high performance liquid chromatography to determine the residues of fluoroquinolone drugs in foods of animal origin. During the experiments, several parameters possible influencing the extraction performance were optimized (amount of magnetic graphene, sample pH, extraction time and elution solution). This extraction method showed high absorption capacities (>6800ng) and high enrichment factors (68-79-fold) for seven fluoroquinolones. Furthermore, this absorbent could be reused for at least 40 times. The limits of detection were in the range of 0.05-0.3ng/g, and the recoveries from the standards fortified blank samples (bovine milk, chicken muscle and egg) were in the range of 82.4-108.5%. Therefore, this method could be used as a simple and sensitive tool to determine the residues of fluoroquinolones in foods of animal origin. PMID- 27979083 TI - Thermal stability of oils added with avocado (Persea americana cv. Hass) or olive (Olea europaea cv. Arbequina) leaf extracts during the French potatoes frying. AB - Effect of the addition of avocado (Persea americana cv. Hass) or olive (Olea europaea cv. Arbequina) hydroalcoholic leaf extracts (AHE and OHE, respectively) on thermal stability of canola oil (CO) and high oleic sunflower oil (HOSO) during French potatoes frying at 180 degrees C was studied. The extracts were characterized by the total phenolic content, phenol chromatographic profiles and antioxidant activity. B-type trimer procyanidins were the major phenolic compounds identified in AHE. OHE showed higher phenol content, antioxidant activity regarding AHE. CO+OHE and HOSO+OHE decreased the formation of polar compounds and showed an anti-polymeric effect with respect to oils without extracts, whereas AHE extract showed a prooxidant effect on HOSO. Therefore, OHE showed an antioxidant effect on HOSO and CO under the studied conditions. In addition, all systems (CO+AHE, HOSO+AHE, CO+OHE and HOSO+OHE) increased the retention of tocopherols. These results demonstrate the potential utility of OHE as natural antioxidant for oils. PMID- 27979085 TI - Rapid, cost-effective and accurate quantification of Yucca schidigera Roezl. steroidal saponins using HPLC-ELSD method. AB - Yucca GRAS-labelled saponins have been and are increasingly used in food/feed, pharmaceutical or cosmetic industries. Existing techniques presently used for Yucca steroidal saponin quantification remain either inaccurate and misleading or accurate but time consuming and cost prohibitive. The method reported here addresses all of the above challenges. HPLC/ELSD technique is an accurate and reliable method that yields results of appropriate repeatability and reproducibility. This method does not over- or under-estimate levels of steroidal saponins. HPLC/ELSD method does not require each and every pure standard of saponins, to quantify the group of steroidal saponins. The method is a time- and cost-effective technique that is suitable for routine industrial analyses. HPLC/ELSD methods yield a saponin fingerprints specific to the plant species. As the method is capable of distinguishing saponin profiles from taxonomically distant species, it can unravel plant adulteration issues. PMID- 27979084 TI - Recent advances on determination of milk adulterants. AB - Milk adulteration is a current fraudulent practice to mask the quality parameters (e.g. protein and fat content) and increase the product shelf life. Milk adulteration includes addition of toxic substances, such as formaldehyde, hydrogen peroxide, hypochlorite, dichromate, salicylic acid, melamine, and urea. In order to assure the food safety and avoid health risks to consumers, novel analytical procedures have been proposed for detection of these adulterants. The innovations encompass sample pretreatment and improved detection and data processing, including chemometric tools. This review focuses on critical evaluation of analytical approaches for assay of milk adulteration, with emphasis on applications published after 2010. Alternatives for fast, environmentally friendly and in-situ detection of milk adulterants are highlighted. PMID- 27979086 TI - Comparison of DNA extraction methods for meat analysis. AB - Preventing adulteration of meat and meat products with less desirable or objectionable meat species is important not only for economical, religious and health reasons, but also, it is important for fair trade practices, therefore, several methods for identification of meat and meat products have been developed. In the present study, ten different DNA extraction methods, including Tris-EDTA Method, a modified Cetyltrimethylammonium Bromide (CTAB) Method, Alkaline Method, Urea Method, Salt Method, Guanidinium Isothiocyanate (GuSCN) Method, Wizard Method, Qiagen Method, Zymogen Method and Genespin Method were examined to determine their relative effectiveness for extracting DNA from meat samples. The results show that the salt method is easy to perform, inexpensive and environmentally friendly. Additionally, it has the highest yield among all the isolation methods tested. We suggest this method as an alternative method for DNA isolation from meat and meat products. PMID- 27979087 TI - Impact of gluten-friendlyTM technology on wheat kernel endosperm and gluten protein structure in seeds by light and electron microscopy. AB - The main aim of this paper was to assess the impact of Gluten-FriendlyTM (GF) technology (Italian priority patent n degrees 102015000084813 filed on 17th December 2015) on wheat kernel endosperm morphology and gluten protein structure, using SEM, light and immunofluorescent microscopy. Microscopy was combined with immunodetection with specific antibodies for gliadins, gamma-gliadins, LMW subunits and antigenic epitopes to gain a better understanding of the technology at a molecular level. The results showed significant changes to gluten proteins after GF treatment; cross-reactivity towards the antibodies recognizing almost the entire range of gluten proteins as well as the antigenic epitopes through the sequences QQSF, QQSY, PEQPFPQGC and QQPFP was significantly reduced. The present study confirms the results from our previous work and shows, for the first time, the mechanism by which a chemical-physical treatment abolishes the antigenic capacity of gluten. PMID- 27979088 TI - Kinetic stability and cellular uptake of lutein in WPI-stabilised nanoemulsions and emulsions prepared by emulsification and solvent evaporation method. AB - The particle size and lutein encapsulation efficiency of nanoemulsions prepared by emulsification and solvent evaporation method were 68.8+/-0.3nm and 80.7+/ 0.8%, respectively, whereas they were 147.3+/-0.6nm and 86.3+/-0.3% for conventional emulsions. All the emulsions had no change in their particle size during storage (28days at 5, 20 and 40 degrees C) but their lutein content and emulsion colour decreased, especially at 40 degrees C. The lutein emulsions were analysed using MTT assay on the gut enterocyte cell line Caco-2 and they showed no toxicity as the cell viability was more than 80% at 10times or higher dilution after 24h of incubation. However, there was a higher cellular uptake of lutein by Caco-2 cells in nanoemulsions (872.9+/-88.3pmol/mgprotein) than conventional emulsions (329.5+/-214.6pmol/mgprotein). The results of this study indicated that nanoemulsions can be used as a delivery system to improve the cellular uptake of lutein. PMID- 27979089 TI - Determination of oxolinic acid, danofloxacin, ciprofloxacin, and enrofloxacin in porcine and bovine meat by micellar liquid chromatography with fluorescence detection. AB - A method was developed for the determination of oxolinic acid, danofloxacin, ciprofloxacin and enrofloxacin by micellar liquid chromatography - fluorescence detection in commercial porcine and bovine meat. The samples were ultrasonicated in a micellar solution, free of organic solvent, to extract the analytes, and the supernatant was directly injected. The quinolones were resolved in <22min using a mobile phase of 0.05M SDS - 7.5% 1-propanol - 0.5% triethylamine buffered at pH 3, running through a C18 column at 1mL/min using isocratic mode. The method was validated by the in terms of: selectivity, calibration range (0.01-0.05 to 0.5mg/kg), linearity (r2>0.9998), trueness (89.3-105.1%), precision (<8.3%), decision limit (<12% over the maximum residue limit), detection capability (<21% over the maximum residue limit), ruggedness (<5.6%) and stability. The procedure was rapid, eco-friendly, safe and easy-to-handle. PMID- 27979090 TI - A study on biomimetic immunoassay-capillary electrophoresis method based on molecularly imprinted polymer for determination of trace trichlorfon residue in vegetables. AB - Pesticide residue in vegetables is a serious problem that has adverse effects on human health. In our study, we designed and synthesized a molecularly imprinted polymer that can selectively recognize trichlorfon. Using the polymer material as biomimetic antibody, we developed a biomimetic immunoassay-capillary electrophoresis method with improved sensitivity for the detection of trichlorfon. We evaluated the competitive reactions between HRP labeled trichlorfon hapten and free trichlorfon with the biomimetic antibody. Factors that affected the sensitivity of our method were tested in detail. Under optimal conditions, the limit of detection (LOD, IC15) and the sensitivity (IC50) of this method were 0.16mgL-1 and 0.13MUgL-1 for trichlorfon. We used this method to determine the trichlorfon spiked in the kidney bean and cucumber samples with recoveries ranging from 78.8% to 103%. We also detected residual trichlorfons in the leek samples, and these results were verified by gas chromatography method. PMID- 27979091 TI - A comparison of gas chromatography coupled to tandem quadrupole mass spectrometry and high-resolution sector mass spectrometry for sensitive determination of polycyclic aromatic hydrocarbons (PAHs) in cereal products. AB - Due to the high consumption level, cereals represent one of the major sources of human exposure to PAHs. Taking into account the low maximum permitted level (ML) established in the European Union (EU) for the sum of four priority PAHs (PAH4) in processed cereal-based foods, sensitive and selective analysis for very low concentrations of these carcinogenic compounds was developed and compared by applying two different analytical techniques. Elaborated methods demonstrated appropriate performance in PAHs analysis even at low contamination levels. Limits of detection (LOD) for the PAH4 varied between 0.002MUgkg-1 and 0.006MUgkg-1, recoveries were in the range of 92-103% for GC-MS/MS and 108-117% for GC-HRMS. Elaborated methods were applied for the analysis of 35 Latvian cereals and bread samples. The concentrations of PAH4 were in a range of 0.22-1.62MUgkg-1 with 14% of samples exceeding the current EU maximum permitted levels. PMID- 27979092 TI - Development and validation of a multiclass method for the quantification of veterinary drug residues in honey and royal jelly by liquid chromatography-tandem mass spectrometry. AB - The aim of this study was to develop an analytical method for the analysis of a wide range of veterinary drugs in honey and royal jelly. A modified sample preparation procedure based on the quick, easy, cheap, effective, rugged and safe (QuEChERS) method was developed, followed by liquid chromatography tandem mass spectrometry determination. Use of the single sample preparation method for analysis of 42 veterinary drugs becomes more valuable because honey and royal jelly belong to completely different complex matrices. Another main advantage of the proposed method is its ability to identify and quantify 42 veterinary drugs with higher sensitivity than reference methods of China. This work has shown that the reported method was demonstrated to be convenient and reliable for the quick monitoring of veterinary drugs in honey and royal jelly samples. PMID- 27979094 TI - Effects of boiling and roasting on proximate composition, lipid oxidation, fatty acid profile and mineral content of two sesame varieties commercialized and consumed in Far-North Region of Cameroon. AB - The aim of this study was to determine the effect of boiling and roasting on the proximate, lipid oxidation, fatty acid profile and mineral content of two sesame seeds varieties. The proximate composition was significantly affected (P<0.05) during treatments. The minerals of seeds roasting at 120 degrees C for 10min were significantly decreased. The free fatty acids content of sesame oil after processing was significantly increased (P<0.05). Iodine and peroxide value were also affected by processing. Totox and p-Anisidine values were significantly increased during processing. The fatty acids composition a little modified during processing, and roasting at 180 degrees C for 10min mostly affected the polyunsaturated fatty acids for all sesame varieties. C16:0, C18:0, C18:1 and C18:2 were quantitatively the most important fatty acids in sesame oil. Boiling appeared to be the best processing method for cooking the two sesame varieties concerning oxidative stability and fatty acid profile. PMID- 27979093 TI - Effects of the size and content of protein aggregates on the rheological and structural properties of soy protein isolate emulsion gels induced by CaSO4. AB - The effects of the size and content of soy protein isolate (SPI) aggregates on the rheological and textural properties of CaSO4-induced SPI emulsion gels were investigated. Considerable differences in the rheological, water-holding, and micro-structural properties were observed. The gels with larger and/or more SPI aggregates showed substantial increase in the elastic modulus and had lower gelation temperatures. Creep data suggested that the size of the SPI aggregates contributed more to the elastic modulus, whereas the increase of aggregate content enhanced the elastic modulus and viscous component of the gels. The water holding capacity was markedly enhanced (p<0.05) with the increase in both the size and content of SPI aggregates. Confocal laser scanning microscopy and scanning electron microscopy showed that larger and/or more SPI aggregates resulted in more homogeneous networks with smaller oil droplets. These insights provide important information for the product development in relation to soy protein-stabilized emulsions and emulsion gels. PMID- 27979095 TI - Carotenoid:beta-cyclodextrin stability is independent of pigment structure. AB - Carotenoids refer to a wide class of lipophilic pigments synthesized by plants, exert photoprotective and antioxidant properties that are lost upon carotenoid degradation. Their inclusion into hydrophilic host-molecules could improve their stability. Cyclodextrins, provide a hydrophobic cavity in the core of their structure while the outer configuration is suitable with aqueous environments. Carotenoids can accommodate into the hydrophobic core of cyclodextrins and therefore, they are protected from exogenous stress. Literature reported that carotenoid structure could modulate stability of the complexes, however no conclusions can be drawn as the studies performed so far were not completely analogous. We describe the synthesis of several carotenoids/beta-CDs inclusion complexes and provide experimental evidences that beta-CDs inclusion renders these compounds more stability towards the oxidizing agents (2,2'-azobis, 2 methylpropionamidine dihydrochloride and hydrogen peroxide). Esterified carotenoids were also used in this work to screen the influence of this particular structural configuration of xanthophylls against oxidation. PMID- 27979096 TI - Actin proteolysis during ripening of dry fermented sausages at different pH values. AB - In dry fermented sausages, myofibrillar proteins undergo intense proteolysis generating small peptides and free amino acids that play a role in flavour generation. This study aimed to identify small peptides arising from actin proteolysis, as influenced by the type of processing. Two acidification profiles were imposed, in order to mimic the pH normally obtained in southern-type and northern-type dry fermented sausages. The identification of peptides was done by liquid chromatography coupled to mass spectrometry in a data-independent positive mode of acquisition (LC-MSE). During manufacturing of the dry fermented sausages, actin was highly proteolysed, especially in nine regions of the sequence. After fermentation, 52 and 42 actin-derived peptides were identified at high and low pH, respectively, which further increased to 66 and 144 peptides, respectively, at the end of ripening. Most peptides were released at the cleavage sites of cathepsins B and D, which thus play an important role. PMID- 27979098 TI - Effect of fertilization on structural and molecular characteristics of hen egg ovalbumin. AB - Egg ovalbumin possesses high processing properties and allergenic behaviour relating to its particular molecular structure. Fertilized eggs provide a natural model for studying the structural change of ovalbumin. After fertilization, free sulfhydryl content increased from 1.03MUmol/g protein to 1.07 and 1.25MUmol/g protein on days 9 and 15 of incubation. Surface hydrophobicity of fertilized egg ovalbumin was higher than that of unfertilized egg ovalbumin (42.59), reaching 47.00 and 53.09 at 9 and 15days. A secondary structural change occurred during this period, characterized by an increase in extended-chain segments and a decrease in intermolecular beta-sheets. Hydrolysis degree of ovalbumin increased from 10.17% to 16.40% after 15days of incubation. Furthermore, new ovalbumin related proteins X and Y emerged on day 9, and then all ovalbumin spots reduced in abundance on day 15. These results warrant further research into the effect of fertilization on functional properties of ovalbumin. PMID- 27979097 TI - Infrared spectroscopy used to determine effects of chia and olive oil incorporation strategies on lipid structure of reduced-fat frankfurters. AB - This article reports an infrared spectroscopic study, using attenuated total reflectance (ATR-FTIR), on the structural characteristics of lipids in frankfurters as affected by different strategies to replace animal fat with chia flour and olive oil. Three incorporation strategies were considered: direct addition (FCO) and addition in a conventional emulsion (non-gelled) (FCE) or an emulsion gel using alginate as a gelling agent (FCEG). Reduced-fat (all-pork-fat) frankfurters (FP) were used as reference. Proximate composition and specific technological properties (pH, processing loss, texture) were also evaluated. FCE and FCEG frankfurters showed a shift to higher frequencies and the highest (p<0.05) half-bandwidth in the nuasCH2 and nusCH2 bands. These spectroscopic results could be related to the fact that the lipid chain was more disorderly in these samples, presumably because there were more lipid interactions than in the reference frankfurter. These features of lipid structure correlated significantly with processing loss and textural behaviour. PMID- 27979099 TI - Tomato cystine-knot miniproteins possessing anti-angiogenic activity exhibit in vitro gastrointestinal stability, intestinal absorption and resistance to food industrial processing. AB - The cystine-knot miniproteins present in tomato fruit (TCMPs) have been shown to exert anti-angiogenic effects by inhibiting endothelial cell migration and to display resistance to gastrointestinal proteolytic attack. To better define the pharmacological potential of TCMPs, their oral bioavailability and their resistance to industrial processing must be assessed. To explore the intestinal transport of TCMPs we used the differentiated Caco-2 cells model. After 24h incubation, 37.73+/-9.34% of TCMPs crossed the epithelium, without altering the integrity of the cell layer. To assess the effects of the industrial processing on the biochemical features and the biological activity of TCMPs, we developed a method for purifying the proteins from tomato paste. The tomato-paste purified TCMPs retained the resistance to gastrointestinal digestion and the inhibitory activity towards endothelial cell migration. Our previous and present results collectively demonstrate that TCMPs possess interesting features for drug development. PMID- 27979100 TI - Determination of phthalate esters in distillates by ultrasound-vortex-assisted dispersive liquid-liquid micro-extraction (USVADLLME) coupled with gas chromatography/mass spectrometry. AB - A method for the extraction of phthalate esters (PAEs) by Ultrasound-Vortex Assisted Dispersive Liquid-Liquid Micro-Extraction (USVADLLME) approach was optimised and applied for the first time to a historical series of brandies. These contaminants are widely spread in the environment as a consequence of about half century of use in different fields of applications. The concern about these substances and the recent legal restrictions of China in distillates import need a quick and sensitive method for their quantification. The proposed method, moreover, is environmentally oriented due to the disposal of micro-quantities of solvent required. In fact, sub-ppm-limits of detection were achieved with a solvent volume as low as 160MUL. The analysed samples were within the legal limits, except for some very ancient brandies whose contamination was probably due to a PAEs concentration effect as a consequence of long ageing and for the use of plastic pipelines no more operative. PMID- 27979101 TI - Effect of pulsed electric fields (PEF) on accumulation of selenium and zinc ions in Saccharomyces cerevisiae cells. AB - The cultures of Saccharomyces cerevisiae were treated with pulsed electric fields (PEF) in order to obtain a maximum accumulation of selenium and zinc ions (simultaneously) in the biomass. The following concentrations: 100MUgSe/ml and 150MUgZn/ml medium were assumed to be optimal for the maximum accumulation of these ions, that is 43.07mg/gd.m. for selenium and 14.48mg/gd.m. for zinc, in the cultures treated with PEF. At optimal PEF parameters: electric field strength of 3kV/cm and pulse width of 10MUs after the treatment of 20-h culture for 10min, the maximum accumulation of both ions in the yeast cells was observed. Application of PEF caused the increase of ions accumulation by 65% for selenium and 100% for zinc. Optimization of PEF parameters led to the further rise in the both ions accumulation resulting in over 2-fold and 2.5-fold higher concentration of selenium and zinc. PMID- 27979102 TI - Electrochemical methods as a tool for determining the antioxidant capacity of food and beverages: A review. AB - The growing interest in functional foods had led to the use of analytical techniques to quantify some properties, among which is the antioxidant capacity (AC). In order to identify and quantify this capacity, some techniques are used, based on synthetic radicals capture; and they are monitored by UV-vis spectrophotometry. Electrochemical techniques are emerging as alternatives, given some of the disadvantages faced by spectrophotometric methods such as the use of expensive reagent not environmentally friendly, undefined reaction time, long sample pretreatment, and low precision and sensitivity. This review focuses on the four most commonly used electrochemical techniques (cyclic voltammetry, differential pulse voltammetry, square wave voltammetry and chronoamperometry). Some of the applications to determine AC in foods and beverages are presented, as well as the correlation between both spectrophotometric and electrochemical techniques that have been reported. PMID- 27979104 TI - Solventless extraction methods for immature fruits: Evaluation of their antioxidant and cytoprotective activities. AB - In this study, extraction of immature fruits using an environmentally friendly pressurized hot water extraction (PHWE) method was compared with the traditional reflux method. Extracts were tested for their polyphenol content using the Folin Ciocalteu assay and for their antioxidant activity using the oxygen radical absorbance capacity (ORAC) assay. The highest amount of polyphenol was extracted from grape (stem) using PHWE at 100 degrees C, or reflux extraction. This was followed by reflux extraction of grape (fruit). The results were similar for the ORAC assay. All samples extracted using PHWE at 100 degrees C showed cytoprotective activity against H2O2-induced oxidative stress in Crandell-Reese feline kidney (CRFK) cells. This study demonstrated that beneficial compounds can be extracted from immature fruits without the use of organic solvents. The utilization of beneficial compounds present in immature fruits can also contribute to the reduction in agriculture waste generated. PMID- 27979103 TI - Extraction of bioactives from Orthosiphon stamineus using microwave and ultrasound-assisted techniques: Process optimization and scale up. AB - This work demonstrated the optimization and scale up of microwave-assisted extraction (MAE) and ultrasonic-assisted extraction (UAE) of bioactive compounds from Orthosiphon stamineus using energy-based parameters such as absorbed power density and absorbed energy density (APD-AED) and response surface methodology (RSM). The intensive optimum conditions of MAE obtained at 80% EtOH, 50mL/g, APD of 0.35W/mL, AED of 250J/mL can be used to determine the optimum conditions of the scale-dependent parameters i.e. microwave power and treatment time at various extraction scales (100-300mL solvent loading). The yields of the up scaled conditions were consistent with less than 8% discrepancy and they were about 91 98% of the Soxhlet extraction yield. By adapting APD-AED method in the case of UAE, the intensive optimum conditions of the extraction, i.e. 70% EtOH, 30mL/g, APD of 0.22W/mL, AED of 450J/mL are able to achieve similar scale up results. PMID- 27979105 TI - Sensitive determination of melamine in milk and powdered infant formula samples by high-performance liquid chromatography using dabsyl chloride derivatization followed by dispersive liquid-liquid microextraction. AB - A new and sensitive pre-column derivatization with dabsyl chloride followed by dispersive liquid-liquid microextraction was developed for the analysis of melamine (MEL) in raw milk and powdered infant formula samples by high performance liquid chromatography (HPLC) with visible detection. Derivatization with dabsyl chloride leads to improving sensitivity and hydrophobicity of MEL. Under optimum conditions of derivatization and microextraction steps, the method yielded a linear calibration curve ranging from 1.0 to 500MUgL-1 with a determination coefficient (R2) of 0.9995. Limit of detection and limit of quantification were 0.1 and 0.3MUgL-1, respectively. The relative standard deviation (RSD%) for intra-day (repeatability) and inter-day (reproducibility) at 25 and 100MUgL-1 levels of MEL was less than 7.0% (n=6). Finally, the proposed method was successfully applied for the preconcentration and determination of MEL in different raw milk and powdered infant formula, and satisfactory results were obtained (relative recovery ?94%). PMID- 27979106 TI - A new separation and preconcentration method for selenium in some foods using modified silica gel with 2,6-diamino-4-phenil-1,3,5-triazine. AB - A novel and simple solid phase extraction method was improved and recommended for selenium. Silica gel was modified with 2,6-diamino-4-phenil-1,3,5-triazine and characterized by FTIR, SEM and elemental analysis and used adsorbent for column solid phase extraction of selenium ions. The experimental parameters (pH, flow rates, amounts of the modified silica gel, concentration and type of eluent, volume of sample, etc.) on the recoveries of selenium were optimized. Standard reference materials were analyzed for validation of method. The present method was successfully applied to the detection of total selenium in water and microwave digested some food samples with quantitative recoveries (> 95%). The relative standard deviations were<8%. Matrix influences were not observed. The adsorption capacity of modified silica gel was 5.90mgg-1. The LOD was 0.015MUgL 1. Enrichment factor was obtained as 50 for the introduced method. PMID- 27979107 TI - Green and efficient extraction of rutin from tartary buckwheat hull by using natural deep eutectic solvents. AB - In this study, an efficient extraction technique using a combination of ultrasound and natural deep eutectic solvents (NADESs) was developed. Some basic physical properties, including viscosity, polarity, and solubility, of thirteen NADESs prepared from natural components were investigated systematically. Results show that the solubility of rutin increased in choline chloride- and glycerol based NADESs by 660-1577times compared to water. NADESs with high rutin extractability can be designed by combining NADESs components. A maximum of 9.5mg/g rutin was extracted from tartary buckwheat hull with extraction efficiencies of 95%. NADESs can be recovered and recycled. In addition, the biocompatibility and biodegradability of the tested NADESs were also evaluated. The results demonstrated that these NADESs were excellent solvents with extremely low toxicities and favorable biodegradabilities. Our findings suggest that NADESs can be used as green solvents for the extraction of bioactive ingredients. PMID- 27979108 TI - Rapid determination of trace copper in animal feed based on micro-plate colorimetric reaction and statistical partitioning correction. AB - The objective of this study was to develop a micro-plate based colorimetric assay for rapid and high-throughput detection of copper in animal feed. Copper ion in animal feed was extracted by trichloroacetic acid solution and reduced to cuprous ion by hydroxylamine. The cuprous ion can chelate with 2,2'-bicinchoninic acid to form a Cu-BCA complex which was detected with high sensitivity by micro-plate reader at 354nm. The whole assay procedure can be completed within 20min. To eliminate matrix interference, a statistical partitioning correction approach was proposed, which makes the detection of copper in complex samples possible. The limit of detection was 0.035MUg/mL and the detection range was 0.1-10MUg/mL of copper in buffer solution. Actual sample analysis indicated that this colorimetric assay produced results consistent with atomic absorption spectrometry analysis. These results demonstrated that the developed assay can be used for rapid determination of copper in animal feed. PMID- 27979109 TI - Determination of iron (III) in food, biological and environmental samples. AB - The nanodrop spectrophotometric (NDS) determination of iron (III) in water samples has been established. The proposed method is simple, selective and highly sensitive. The extraction of Fe (III)-thiocyanate complex was done by novel organic reagents such as N-phenylacetamide, N-alkylacetamide, (alkyl=butyl, hexyl and octyl group) in chloroform. The Fe (III) extract was examined in the strong acidic (HCl+H2SO4) solution. The maximum value of molar absorptivity was found to be 1.8*105Lmol-1cm-1 at lambdamax, 477nm (?9 fold enrichments) for N octylacetamide (N-OAA). The method obeys the Beers Law within the range of 0.05MUgmL-1-6.0MUgmL-1. The detection limit and RSD value of the method were found to be 5ppb and 0.5906% respectively. The correlation coefficient, slope and intercept were calculated and found to be 0.9989, 0.1112, and 0.0048, respectively. The proposed method was successfully applied to the determination of trace amount of iron (III) in food, biological and environmental samples. PMID- 27979110 TI - Sweetness prediction of natural compounds. AB - Based on the most exhaustive database of sweeteners with known sweetness values, a new quantitative structure-activity relationship model for sweetness prediction has been set up. Analysis of the physico-chemical properties of sweeteners in the database indicates that the structure of most potent sweeteners combines a hydrophobic scaffold functionalized by a limited number of hydrogen bond sites (less than 4 hydrogen bond donors and 10 acceptors), with a moderate molecular weight ranging from 350 to 450g.mol-1. Prediction of sweetness, bitterness and toxicity properties of the largest database of natural compounds have been performed. In silico screening reveals that the majority of the predicted natural intense sweeteners comprise saponin or stevioside scaffolds. The model highlights that their sweetness potency is comparable to known natural sweeteners. The identified compounds provide a rational basis to initiate the design and chemosensory analysis of new low-calorie sweeteners. PMID- 27979111 TI - Preparation and characterization of essential oil-loaded starch nanoparticles formed by short glucan chains. AB - Essential oils (EOs), including menthone, oregano, cinnamon, lavender, and citral, are natural products that have antimicrobial and antioxidant activities. However, extremely low water solubility, and easy degradation by heat, restrict their application. The aim of this work was to evaluate the enhancement in antioxidative and antimicrobial activities of EOs encapsulated in starch nanoparticles (SNPs) prepared by short glucan chains. For the first time, we have successfully fabricated menthone-loaded SNPs (SNPs-M) at different complexation temperatures (30, 60, and 90 degrees C) by an in situ nanoprecipitation method. The SNPs-M displayed spherical shapes, and the particle sizes ranged from 93 to 113nm. The encapsulation efficiency (EE) of SNPs-M increased significantly with an increase in complexation temperature, and the maximum EE was 86.6%. The SNPs-M formed at 90 degrees C had high crystallization and thermal stability. The durations of the antioxidant and antimicrobial activities of EOs was extended by their encapsulation in the SNPs. PMID- 27979112 TI - Effect of water content on thermal oxidation of oleic acid investigated by combination of EPR spectroscopy and SPME-GC-MS/MS. AB - Promotion of water to the thermal oxidation of oleic acid was detected by the combination of EPR, SPME-GC-MS/MS and GC. Spin-trapping technique was used to identify and quantify the radical species formed during thermal oxidation of oleic acid by using DMPO as electron spin trap. The most abundant radical species were identified as DMPO-alkyl radical adducts. EPR intensity plateau of the samples with 5% water content was 140% higher than the samples without water. It implies oleic acid samples with high water content had high level of oxidation rates. The proportion of aldehydes of the samples with 2% water content was the maximum about 59.97%. Among the formed products, (E,E)-2,4-decadienal has genotoxic and cytotoxic effects, whose percentage was nearly twice comparing with that of 5-0% water content. This study demonstrated that higher water content in frying systems would contribute to seriously oxidation and degradation of oleic acids. PMID- 27979113 TI - Improvement stability and performance of invertase via immobilization on to silanized and polymer brush grafted magnetic nanoparticles. AB - In this study, magnetic nanoparticles (Fe3O4) were modified sequentially with silica (Fe3O4@SiO2), glycidyl methacrylate (GMA) by surface initiated atom transfer radical polymerization (SI-ATRP) and hexamethylene diamine (as a spacer arm). The p(GMA) grafted and SA modified form (i.e., Fe3O4@SiO2@pGMA-SA-3) was used for covalent immobilization of invertase (EC 3.2.1.26). The amount of immobilized enzyme on Fe3O4@SiO2@p(GMA) and Fe3O4@SiO2@p(GMA)-SA-3 was 36.1+/-0.9 and 33.4+/-1.3mg/g, respectively. The Km and Vmax values of immobilized invertase were found to be 39.4mmol/L and 349.5mmol/L min, and not significantly changed compared with free form (34.3mmol/L and 387.2mmol/Lmin), respectively, revealed that the applied protocol did not have any detrimental effect on the retained activity of immobilized invertase. PMID- 27979114 TI - Wheat bread enriched with green coffee - In vitro bioaccessibility and bioavailability of phenolics and antioxidant activity. AB - The potential bioaccessibility and bioavailability of phenolics, caffeine and antioxidant activity of wheat bread enriched with green coffee were studied. Supplementation enhanced nutraceutical potential by improving phenolic content and lipid protecting capacity. The simulated-digestion-released phenolics (mainly caffeic acid, syringic acid and vanillic acid) from bread, also caused significant qualitative changes (chlorogenic acids were cleaved and significant amounts of caffeic acid and ferulic acid were determined). Compared to the control, for the bread with 1% and 5% of the functional component the contents of phenolics were 1.6 and 3.33 times higher. Also, an approximately 2.3-fold increase in antioxidant activity was found in bread containing 5% of the supplement. The compounds responsible for antioxidant potential have high bioaccessibility but poor bioavailability. The qualitative composition of the phenolic fraction has a key role in developing the antioxidant potential of bread; however, caffeine and synergism between antioxidants are also important considerations. PMID- 27979115 TI - Green synthesis of beta-sitostanol esters catalyzed by the versatile lipase/sterol esterase from Ophiostoma piceae. AB - beta-sitostanol esters, used as dietary complement for decreasing cholesterol absorption, have been synthesized at 28 degrees C via direct esterification or transesterification catalyzed by the versatile lipase/sterol esterase from the ascomycete fungus O. piceae. Direct esterification was conducted in biphasic isooctane: water systems containing 10mM beta-sitostanol and lauric or oleic acid as acyl donors, reaching 90% esterification in 3h with the recombinant enzyme. The use of molar excesses of the free fatty acids did not improve direct esterification rate, and the enzyme did not convert one of the two fatty acids preferentially when both were simultaneously available. On the other hand, solvent-free transesterification was an extremely efficient mechanism to synthesize beta-sitostanyl oleate, yielding virtually full conversion of up to 80mM beta-sitostanol in 2h. This process may represent a promising green alternative to the current chemical synthesis of these esters of unquestionable nutraceutical value. PMID- 27979116 TI - Technological properties of amazonian oils and fats and their applications in the food industry. AB - The application of lipids to food production is dependent on their physical, chemical, and nutritional properties. In this study, pracaxi oil, passion fruit oil, cupuassu fat, and palm stearin underwent physicochemical analyses and were combined at ratios of 40:60, 50:50, 60:40, and 70:30 to assess their potential applications in the food industry. Pracaxi oil, passion fruit oil, and cupuassu fat had interesting fatty acid profiles from a nutritional standpoint, displaying the lowest atherogenicity and thrombogenicity indices (0.02 and 0.14; 0.12 and 0.34; 0.16 and 0.65), respectively. Palm stearin had high thermal stability (7.23h). The primary applications of the blends obtained in this study are in table and functional margarine, particularly the pracaxi-stearin and passion fruit-stearin 40:60 and 50:50, pracaxi-cupuassu 60:40 and 70:30, and passion fruit-cupuassu 40:60 blends. The results suggest new industrial applications, especially for pracaxi and passion fruit oils, which are commonly applied in the cosmetic industry. PMID- 27979117 TI - Structure of starch aerogel as affected by crosslinking and feasibility assessment of the aerogel for an anti-fungal volatile release. AB - Starch suspensions were crosslinked with trisodium citrate for either 0 or 17h, gelled and then freeze-dried to corresponding aerogels. The aerogel from the 17h crosslinked suspension was loaded with the antifungal compound, trans-2-hexenal, and coated with the surfactant, sorbitan monooleate. Aerogel hardness was increased by the citrate-mediated crosslinking, whereas its adhesiveness decreased. Starch gelation decreased the crystallinity index (CrI) from 59% to ~23%; however, the pre-gelation crosslinking resulted in a higher CrI value (i.e. ~38%) for the aerogel. The voids at the internal microstructure of the 17h crosslinked aerogel were more uniform and coating with surfactant closed the surface openings. The latter accordingly resulted in a more sustained release of the volatile, trans-2-hexenal, from the crosslinked starch aerogel and led to slower lethality of Aspergillus parasiticus cells inoculated on pistachio nuts compared with the non-coated condition. PMID- 27979118 TI - Encapsulation of tea tree oil by amorphous beta-cyclodextrin powder. AB - An innovative method to encapsulate tea tree oil (TTO) by direct complexation with solid amorphous beta-cyclodextrin (beta-CD) was investigated. A beta-CD to TTO ratio of 90.5:9.5 (104.9mg TTO/g beta-CD) was used in all complexation methods. The encapsulation was performed by direct mixing, and direct mixing was followed by the addition of water (13-17% moisture content, MC) or absolute ethanol (1:1, 1:2, 1:3 and 1:4 TTO:ethanol). The direct mixing method complexed the lowest amount of TTO (60.77mg TTO/g beta-CD). Powder recrystallized using 17% MC included 99.63mg of TTO/g beta-CD. The addition of ethanol at 1:2 and 1:3 TTO:ethanol ratios resulted in the inclusion of 94.3 and 98.45mg of TTO/g beta-CD respectively, which was similar to that of TTO encapsulated in the conventional paste method (95.56mg TTO/g beta-CD), suggesting an effective solid encapsulation method. The XRD and DSC results indicated that the amorphous TTO-beta-CD complex was crystallized by the addition of water and ethanol. PMID- 27979119 TI - Evaluation of the synergism among volatile compounds in Oolong tea infusion by odour threshold with sensory analysis and E-nose. AB - Twenty-four kinds of representative aroma compounds in Oolong tea were selected to evaluate the interactions by the variation in the threshold values of these compounds before, and after, they were mixed. Result demonstrated that the ratios of the referenced threshold values of heptanal, beta-damascenone, and methional to their determined thresholds were larger, namely, 5, 3.85, and 2.5, respectively. On the other hand, the mixed compounds with similar structure and aroma mainly presented a synergistic effect and additive action. Moreover, a masking effect was found among compounds with different structures. (E)-2-hexenal was added to tea infusion at a concentration below its threshold level to investigate whether, or not, the sub-threshold compounds affected the overall odour sensation of Oolong tea by sensory analysis and electronic nose (E-nose). The result indicated that the aroma of the tea infusion with added (E)-2-hexenal had changed before, and after, they were mixed. PMID- 27979120 TI - Tunable volatile release from organogel-emulsions based on the self-assembly of beta-sitosterol and gamma-oryzanol. AB - A current challenge in the area of food emulsion is the design of microstructure that provides controlled release of volatile compounds during storage and consumption. Here, a new strategy addressed this problem at the fundamental level by describing the design of organogel-based emulsion from the self-assembly of beta-sitosterol and gamma-oryzanol that are capable of tuning volatile release. The results showed that the release rate (v0), maximum headspace concentrations (Cmax) and partition coefficients (ka/e) above structured emulsions were significantly lower than unstructured emulsions and controlled release doing undergo tunable though the self-assembled interface and core fine microstructure from internal phase under dynamic and static condition. This result provides an understanding of how emulsions can behave as delivery system to better design novel food products with enhanced sensorial and nutritional attributes. PMID- 27979121 TI - Thermoresistant xylanases from Trichoderma stromaticum: Application in bread making and manufacturing xylo-oligosaccharides. AB - The enzymes Xyl1 and Xyl2 from T. stromaticum were purified and identified by mass spectrometry (MALDI-TOF/MS). Xyl1 contained three proteins with similarity to xylanase family 10, 62 and anarabinofuranosidase of the Trichoderma genus and Xyl2 contained a protein with similarity to endo-1,4-beta-xylanase. High xylanase activity was found at 50 degrees C for Xyl1 and 60 degrees C for Xyl2 and pH 5.0 for both, retaining more than 80% of activities for one hour at 60 degrees C and pH 5-8. Ag2+ and beta-mercaptoethanol increased while SDS and EDTA inhibited the xylanase activity of both Xyl1 and Xyl2 extracts. The Km and Vmax values for purified Xyl2 were 9.6mg/mL and 28.57MUmol/min/mg, respectively. In application tests, both Xyl1 and Xyl2 were effective in degrading beechwood xylan to produce xylo-oligosaccharides. In baking, adding Xyl1 increased the softness and volume of wheat bread and whole grain bread, qualities increasingly desired by consumers in this segment. PMID- 27979122 TI - Enhanced antibacterial activity of lysozyme immobilized on chitin nanowhiskers. AB - In this paper, the contribution of chitin nanowhiskers (CHNW) to the enzymatic activity and antimicrobial activity of lysozyme adsorbed on CHNW was investigated. An activity assay showed that the lysozyme-CHNW system exhibited significant promotion potency on lysozyme activity, which was approximately 1.5 fold greater than that of free lysozyme. The molecular promotion mechanism of lysozyme immobilized by adsorption onto CHNW was investigated by ultraviolet visible spectrophotometry, fluorescence spectroscopy, and circular dichroism spectroscopy. The results indicated that changes in the secondary structure of lysozyme adsorption onto CHNW resulted in superior enzymatic activity. Furthermore, the antimicrobial assays indicated that the antimicrobial activity of the lysozyme-CHNW system was greater than that of free lysozyme, whereas its antimicrobial effect on a gram-negative bacterium was better than that on gram positive bacteria. This research provides a facile and promising approach for increasing the application of chitin-derived and enhancing the antibacterial efficiency on preservation. PMID- 27979123 TI - Impact of molecular structure on the physicochemical properties of starches isolated from different field pea (Pisum sativum L.) cultivars grown in Saskatchewan, Canada. AB - The objective of this study was to determine the molecular structure and properties of recently released cultivars of field peas [CDC Golden (CDCG), Abarth (ABAR), CDC Patrick (CDCP) and CDC Amarillo (CDCA)] grown at different locations in Saskatchewan, Canada. Starch yield (on whole seed basis), apparent amylose, total lipid and specific surface area were in the range 34-37%, 38.2 42.6%, 1.07-1.38% and 0.31-0.38m2/g, respectively. The proportion of short (DP 6 12) amylopectin chains, amylopectin branching density, molecular order, crystallinity, crystalline heterogeneity, gelatinization transition temperatures, pasting temperatures, peak viscosity, extent of acid hydrolysis, and resistant starch content were higher in CDCG and ABAR. However, amylopectin long chains (DP 13-26), average chain length and thermal stability were higher in CDCP and CDCA. The results of this study showed that differences in physicochemical properties among cultivars were mainly influenced by amylopectin chain length distribution, amylopectin branching density and co-crystallization of amylose with amylopectin. PMID- 27979124 TI - Application of cashew tree gum on the production and stability of spray-dried fish oil. AB - Evaluation of cashew gum compared to conventional materials was conducted regarding properties and oxidative stability of spray-dried fish oil. Emulsions produced with cashew gum showed lower viscosity when compared to Arabic gum. The particle size was larger (29.9MUm) when cashew gum was used, and the encapsulation efficiency reached 76%, similar to that of modified starch but higher than that for Arabic gum (60%). The oxidation process for the surface oil was conducted and a relative lower formation of oxidation compounds was observed for the cashew gum treatment. GAB model was chosen to describe the moisture adsorption isotherm behaviours. Microparticles produced using Arabic and cashew gums showed greater water adsorption when exposed to higher relative humidities. Microparticles produced using cashew gum were more hygroscopic however encapsulation efficiency were higher and surface oil oxidation were less pronounced. Cashew gum can be further explored as an encapuslant material for spray drying processes. PMID- 27979125 TI - Cellulose fibers extracted from rice and oat husks and their application in hydrogel. AB - The commercial cellulose fibers and cellulose fibers extracted from rice and oat husks were analyzed by chemical composition, morphology, functional groups, crystallinity and thermal properties. The cellulose fibers from rice and oat husks were used to produce hydrogels with poly (vinyl alcohol). The fibers presented different structural, crystallinity, and thermal properties, depending on the cellulose source. The hydrogel from rice cellulose fibers had a network structure with a similar agglomeration sponge, with more homogeneous pores compared to the hydrogel from oat cellulose fibers. The hydrogels prepared from the cellulose extracted from rice and oat husks showed water absorption capacity of 141.6-392.1% and high opacity. The highest water absorption capacity and maximum stress the compression were presented by rice cellulose hydrogel at 25 degrees C. These results show that the use of agro-industrial residues is promising for the biomaterial field, especially in the preparation of hydrogels. PMID- 27979126 TI - Novel inhibitors of tyrosinase produced by the 4-substitution of TCT. AB - We synthesized a series of 4- or 5-functionalized TCT derivatives (1-12) and investigated their inhibitory activities and mechanisms on tyrosinase by using Spectrofluorimetry, 1H and 13C NMR titration and IR spectra. The results of the fluorescence spectra and NMR titrations showed that the thiosemicarbazone moiety formed complexes with copper ions in the active center of the enzyme and played an important role in inhibiting the activities of the target compounds. The 5 functionalization decreased the inhibitory activity, but the 4-functionalization with a methoxyacetyl group enhanced the inhibitory activity, in which a strong auxiliary vicinity synergistic effect from the methoxyacetyl group strengthens and promotes the formation of complexes between the sulfur atoms of the inhibitor and the dicopper nucleus of tyrosinase. We concluded that the appropriate 4 functionalization improved the inhibitory activity of the modifier, and that 4 methoxyacetyl -TCT is promising for the inhibition of tyrosinase. PMID- 27979127 TI - Rheological and secondary structural characterization of rice flour-zein composites for noodles slit from gluten-free sheeted dough. AB - Rice flour-zein composites in a hydrated viscoelastic state were utilized to compensate for the role of wheat gluten in gluten-free sheeted dough. The use of zein above its glass transition temperature was able to form a viscoelastic protein network of non-wheat dough with rice flour. The mixing stability and development time of the rice dough were positively increased with increasing levels of zein. The protein secondary structural analysis by FTIR spectroscopy demonstrated that the rice doughs with high levels of zein showed significant increases in beta-sheet structures whose intensity was almost doubled by the use of 10% zein. The use of zein at more than 5% (w/w) successfully produced gluten free dough sheets that could be slit into thin and long noodle strands. In addition, the composites were effective in improving the rheological characteristics of gluten-free noodle strands by increasing their maximum force to extension, compared to wheat-based noodles. PMID- 27979128 TI - Molecular structure, functionality and applications of oxidized starches: A review. AB - During oxidation, the hydroxyl groups of starch molecules are first oxidized to carbonyl groups, then to carboxyl groups. The contents of the carbonyl and carboxyl groups in a starch molecule therefore indicate the extent of starch oxidation. The mechanisms of starch oxidation with different oxidizing agents, including sodium hypochlorite, hydrogen peroxide, ozone and sodium periodate, are described in this review. The effects of these oxidizing agents on the molecular, physicochemical, thermal, pasting and morphological properties of starch are described as well. In addition, the main industrial applications of oxidized starches are presented. The present review is important for understanding the effects of oxidation on starch properties, and this information may facilitate the development of novel oxidized starches for both food and non-food applications. PMID- 27979129 TI - Physicochemical properties of quinoa flour as affected by starch interactions. AB - There has been growing interest in whole grain quinoa flour for new product development due to the unique nutritional benefits. The quality of quinoa flour is much determined by the properties of its major component starch as well as non starch components. In this study, composition and physicochemical properties of whole grain flour from 7 quinoa samples have been analyzed. Flour properties have been correlated to the flour composition and the properties of isolated quinoa starches through chemometrics. Great variations in chemical composition, swelling power, water soluble index, enzyme susceptibility, pasting, gel texture, and thermal properties of the flour have been observed. Correlation analysis showed that thermal properties and enzyme susceptibility of quinoa flour are highly influenced by the starch. Interactions of starch with non-starch components, including lipids, protein, dietary fibre, phenolics, and minerals, greatly impacted the flour properties. For example, peak gelatinization temperature of the flour is positively correlated to that of the starch (r=0.948, p<0.01) and negatively correlated to the lipid content (r=-0.951, p<0.01). Understanding the roles of starch and other components in physicochemical properties of quinoa flour provides a basis for better utilization of this specialty crop. PMID- 27979130 TI - Myricetin inhibits the generation of superoxide anion by reduced form of xanthine oxidase. AB - Myricetin, a plant-derived flavonol, was found to inhibit the formation of uric acid in a mixed-type manner with IC50 value of (8.66+/-0.03)*10-6molL-1 and more potently inhibit the generation of superoxide anion (O2-) catalysed by xanthine oxidase (XOD) with IC50 value of (4.55+/-0.02)*10-6molL-1. Inhibiting O2- generation by myricetin may be attributed to the reduced form of XOD with a substantially higher reduction potential for FADH/FADH2 couple. Moreover, molecular docking verified that myricetin bound to the site around isoalloxazine ring in the flavin adenine dinucleotide (FAD) domain to block the diffusion of O2 out of the FAD site, resulting in the transfer of another electron from FADH2 to O2- to form hydrogen peroxide. This study has provided new insight into the role of myricetin in inhibiting XOD catalysis, which may be beneficial to improve myricetin's potential application in functional foods. PMID- 27979131 TI - Comparative evaluation of microbial diversity and metabolite profiles in doenjang, a fermented soybean paste, during the two different industrial manufacturing processes. AB - Two different doenjang manufacturing processes, the industrial process (IP) and the modified industrial process (mIP) with specific microbial assortments, were subjected to metabolite profiling using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). The multivariate analyses indicated that both primary and secondary metabolites exhibited distinct patterns according to the fermentation processes (IP and mIP). Microbial community analysis for doenjang using denaturing gradient gel electrophoresis (DGGE), exhibited that both bacteria and fungi contributed proportionally for each step in the process viz., soybean, steaming, drying, meju fermentation, cooling, brining, and aging. Further, correlation analysis indicated that Aspergillus population was linked to sugar metabolism, Bacillus spp. with that of fatty acids, whereas Tetragenococcus and Zygosaccharomyces were found associated with amino acids. These results suggest that the components and quality of doenjang are critically influenced by the microbial assortments in each process. PMID- 27979132 TI - Concentration of plasticizers applied during heat-moisture treatment affects properties of the modified canna starch. AB - Effects of the concentration of plasticizers applied during heat-moisture treatment (HMT) on the properties of canna starch were investigated. The modified starches were prepared by soaking starch in 0 (water), 1, 3, 5, 10, 20 and 30% w/w glycerol or sorbitol solution for 24h and adjusting the moisture content to 25% before HMT (100 degrees C, 1h). Changes in the pasting profiles of heat moisture treated starches were more obvious when glycerol solutions were used instead of water. An increase in the concentration of glycerol solution from 1% to 5% resulted in a progressive decrease in paste viscosity; paste viscosity then increased as the glycerol concentration rose from 10 to 30%. A similar trend was observed when sorbitol was used as a plasticizer, but with a lesser effect. A scheme for arrangements of the molecular structure of starch during the process of HMT was suggested. PMID- 27979133 TI - Isolation and characterization of a xylan with industrial and biomedical applications from edible acai berries (Euterpe oleraceae). AB - The chemical features of xylan largely determine its physical and biological properties and its use in the industry. In this work, we describe the occurrence, purification and partial characterization of a xylan in edible acai berries (Euterpe oleraceae), using a fairly simple and inexpensive method of purification from alkaline acai extract. A mainly linear (1->4)-beta-d-xylan was found as the majority (70%) of alkali extract and 4.2% of the dry matter acai pulp. This represents the biggest source of xylan found so far in a fruit pulp and could be suitable for applications in the industry and biomedical field. PMID- 27979134 TI - Gelation of soybean protein and polysaccharides delays digestion. AB - Xanthan gum and carrageenan, representing the medium and highly negatively charged polysaccharides, were heated respectively together with soybean protein isolate (SPI) at different biopolymer ratios. Upon mixing with simulated stomach juice (SSJ), the xanthan-SPI and carrageenan-SPI at biopolymer ratios higher than 0.01 leads to self-assembled gelation immediately. Stronger gel is formed under higher biopolymer ratios. Highly negatively charged carrageenan forms a stronger gel than that composed with xanthan gum. SDS-PAGE results show the digestibility of SPI is delayed after incorporation with the polysaccharides, which is enhanced with the increase of the biopolymer mass ratios. And the polysaccharide with higher negative charge has stronger potential in delaying the digestion of SPI. Furthermore, the microstructure of the xanthan-SPI and carrageenan-SPI gel before and after simulated stomach digestion was characterized by scanning electron microscope (SEM), which also confirms that the gel delays the digestion of soybean protein. PMID- 27979135 TI - Effects of wheat-bran arabinoxylan as partial flour replacer on bread properties. AB - Effects on physical properties of white bread of adding crude (E1) and partially purified (E2) arabinoxylans (AX) from wheat bran to partially replace flour during baking, were investigated to identify optimal dosage. The E1 and E2 had molecular weights of 620,000 and 470,000Da with arabinose to xylose ratio of 0.7 and 0.6, respectively. However, ferulic acid of 1.5mg/100g, was detectable only in E1. The AXs were added to 100g white bread formulae at dosages of 0.8-1.2% with flour removal of 2-3%(w/w). The dough increased water absorption by 2% in the specified dosage range. An optimum dosage of 0.8% with 2.5% flour removal maintained similar weight, volume, height and firmness as standard white bread. At this dosage, AX addition in white bread holds both increased health and economic benefits because of combined roles as soluble dietary fibre and flour replacer. PMID- 27979136 TI - Simultaneous quantitation of nicotinamide riboside, nicotinamide mononucleotide and nicotinamide adenine dinucleotide in milk by a novel enzyme-coupled assay. AB - Nicotinamide riboside, the most recently discovered form of vitamin B3, and its phosphorylated form nicotinamide mononucleotide, have been shown to be potent supplements boosting intracellular nicotinamide adenine dinucleotide (NAD) levels, thus preventing or ameliorating metabolic and mitochondrial diseases in mouse models. Here we report for the first time on the simultaneous quantitation of nicotinamide riboside, nicotinamide mononucleotide and NAD in milk by means of a fluorometric, enzyme-coupled assay. Application of this assay to milk from different species revealed that the three vitamers were present in human and donkey milk, while being selectively distributed in the other milks. Human milk was the richest source of nicotinamide mononucleotide. Overall, the three vitamers accounted for a significant fraction of total vitamin B3 content. Pasteurization did not affect the bovine milk content of nicotinamide riboside, whereas UHT processing fully destroyed the vitamin. In human milk, NAD levels were significantly affected by the lactation time. PMID- 27979137 TI - Acetylated rice starches films with different levels of amylose: Mechanical, water vapor barrier, thermal, and biodegradability properties. AB - Biodegradable films from native or acetylated starches with different amylose levels were prepared. The films were characterized according to the mechanical, water vapor barrier, thermal, and biodegradability properties. The films from acetylated high amylose starches had higher moisture content and water solubility than the native high amylose starch film. However, the acetylation did not affect acid solubility of the films, regardless of the amylose content. Films made from high and medium amylose rice starches were obtained; however low amylose rice starches, whether native or acetylated, did not form films with desirable characteristics. The acetylation decreased the tensile strength and increased the elongation of the films. The acetylated starch-based films had a lower decomposition temperature and higher thermal stability than native starch films. Acetylated starches films exhibited more rapid degradation as compared with the native starches films. PMID- 27979138 TI - Varieties, production, composition and health benefits of vinegars: A review. AB - Vinegars are liquid products produced from the alcoholic and subsequent acetous fermentation of carbohydrate sources. They have been used as remedies in many cultures and have been reported to provide beneficial health effects when consumed regularly. Such benefits are due to various types of polyphenols, micronutrients and other bioactive compounds found in vinegars that contribute to their pharmacological effects, among them, antimicrobial, antidiabetic, antioxidative, antiobesity and antihypertensive effects. There are many types of vinegars worldwide, including black vinegar, rice vinegar, balsamic vinegar and white wine vinegar. All these vinegars are produced using different raw materials, yeast strains and fermentation procedures, thus giving them their own unique tastes and flavours. The main volatile compound in vinegar is acetic acid, which gives vinegar its strong, sour aroma and flavour. Other volatile compounds present in vinegars are mainly alcohols, acids, esters, aldehydes and ketones. The diversity of vinegars allows extensive applications in food. PMID- 27979139 TI - Fast UPLC/PDA determination of squalene in Sicilian P.D.O. pistachio from Bronte: Optimization of oil extraction method and analytical characterization. AB - A fast reversed-phase UPLC method was developed for squalene determination in Sicilian pistachio samples that entry in the European register of the products with P.D.O. In the present study the SPE procedure was optimized for the squalene extraction prior to the UPLC/PDA analysis. The precision of the full analytical procedure was satisfactory and the mean recoveries were 92.8+/-0.3% and 96.6+/ 0.1% for 25 and 50mgL-1 level of addition, respectively. Selected chromatographic conditions allowed a very fast squalene determination; in fact it was well separated in ~0.54min with good resolution. Squalene was detected in all the pistachio samples analyzed and the levels ranged from 55.45-226.34mgkg-1. Comparing our results with those of other studies it emerges that squalene contents in P.D.O. Sicilian pistachio samples, generally, were higher than those measured for other samples of different geographic origins. PMID- 27979140 TI - Development of a laboratory technique for the evaluation of protease enzymes activity in goat and sheep milk. AB - The shelf life of milk and its products is strongly influenced by the quality of raw milk. Several bacteria present in raw milk can produce proteases: among them, those from psychotropic microorganisms (e.g. Bacillus subtilis), which produce enzymes under refrigeration, cause the most serious problem. The interaction of these enzymes with the milk proteins and the main proteolytic enzymes becomes important in determining the quality of the milk. An artificial substrate (azocasein) was used to quantify the enzyme activity through the release of a chromogenic product that was measured spectrophotometrically after clarifying the sample by the addition of trichloroacetic acid. The detection limit and quantification limit were 1.43 and 4.77mg/ml respectively for sheep milk and, 2.25 and 7.5mg/ml respectively for goat milk. This method is useful for determining the proteolytic activity in different media and its effectiveness depends on chemical-nutritional characteristics of the sample. PMID- 27979141 TI - Molecular mechanisms and in vitro antioxidant effects of Lactobacillus plantarum MA2. AB - Lactobacillus plantarum MA2 was isolated from Chinese traditional Tibetan kefir grains. The antioxidant activities in vitro of this strain were evaluated extensively. The results showed that L. plantarum MA2 can tolerate hydrogen peroxide up to 2.0mM, and its fermentate (fermented supernatant, intact cell and cell-free extract) had strong reducing capacities, lipid peroxidation inhibition capacities, Fe2+-chelating abilities, as well as various free radical scavenging capacities. Additionally, both the fermented supernatant and cell homogenate exhibited glutathione peroxidase activity and superoxide dismutase activity. In order to investigate the antioxidant mechanism of L. plantarum MA2 at the molecular level, eight antioxidant-related genes were identified, and further analyzed. Three groups of genes cat, gshR and npx, were found up-regulated under H2O2 challenge. PMID- 27979142 TI - Melatonin treatment attenuates postharvest decay and maintains nutritional quality of strawberry fruits (Fragaria*anannasa cv. Selva) by enhancing GABA shunt activity. AB - Fresh strawberry fruits as perishable commodities have a short postharvest life and are prone to postharvest fungal decay. In this study, the impact of 0, 1, 10, 100 and 1000MUmol/L melatonin on attenuating fungal decay and maintaining nutritional quality of strawberry fruits was investigated during storage at 4 degrees C for 12days. Melatonin treatment at 100MUmol/L triggered H2O2 accumulation, which result from higher superoxide dismutase (SOD) activity, associated with lower catalase (CAT) and ascorbate peroxidase (APX) activities, leading to fruits with lower decay. Higher H2O2 accumulation was concurrent with higher phenylalanine ammonia lyase (PAL) enzyme activity leading to higher total phenols and anthocyanins accumulation along with higher DPPH scavenging capacity. Also, strawberry fruits treated with melatonin exhibited higher gamma aminobutyric acid transaminase (GABA-T) enzyme activity which ensured sufficient ATP supplying leading to higher unsaturated/saturated fatty acids (unSFA/SFA) ratio. PMID- 27979143 TI - Determination of anti-oxidative histidine dipeptides in poultry by microchip capillary electrophoresis with contactless conductivity detection. AB - A home-made microchip electrophoresis (MCE) device was used to quantitate two biologically important histidine dipeptides, carnosine and anserine, using capacitively coupled contactless conductivity detection (C4D), at pH 2.7. The C4D detector exhibited a linear response to both carnosine and anserine in the range of 0-200MUM for the individual dipeptides and in the range of 0-100MUM for each dipeptide when both were present as a mixture. The limit of detections (LOD) for the dipeptides in the mixture were 0.10MUM for carnosine and 0.16MUM for anserine. Standard addition was used to detemine the accuracy of the method. For carnosine and anserine the recoveries were in the range of 96.7+/-4.9-106.0+/ 7.5% and 95.3+/-4.5-105.0+/-5.1% in thigh muscle and 97.5+/-5.1-105.0+/-7.5% and 95.3+/-5.4-97.3+/-5.6% in breast muscle, respectively. PMID- 27979144 TI - The influence of cooking procedures on doxycycline concentration in contaminated eggs. AB - Doxycycline (DC) is forbidden compound in laying hens. Most information about drug residues in eggs concern their concentrations in raw matrix and the data about the influence of cooking on antibiotics residues in eggs are limited. Thus, the residues concentration of DC in eggs after different cooking methods was investigated. Analyses of DC were assayed by liquid chromatography - tandem mass spectrometry method. The stability of DC in eggs were depended upon the type and time of cooking procedure. By microwaving DC was reduced most effective with concentrations decreased by 53% and 50.3% after 4min of microwaving without cover and microwaving with cover, respectively. In fried eggs, DC was reduced by 39.8% in 6min. By the boiling cooking, the smallest reduction was observed with the concentration decreased by 29.8% after 8min. The obtained results show that ordinary cooking does not eliminate the all DC residues present in eggs. PMID- 27979146 TI - Kinetics of browning and correlations between browning degree and pyrazine compounds in l-ascorbic acid/acidic amino acid model systems. AB - The kinetics of browning and the correlation between browning products (BPs) and pyrazine compounds were investigated by heating equimolar l-ascorbic acid (ASA)/acidic amino acids under weak alkaline conditions at 120-150 degrees C for 10-120min. The formations of BPs and pyrazine compounds from the reaction were monitored by UV-vis and SPME-GC-FID, respectively. The formation of BPs in both ASA/l-glutamic acid and ASA/l-aspartic acid model reaction systems followed zero order reaction kinetics with activation energies (Ea) of 90.13 and 93.38kJ/mol, respectively. ASA/l-aspartic acid browned at a slightly higher rate than ASA/l glutamic acid. The total concentration of pyrazine compounds was highly and positively correlated with that of BPs. Based on the observed kinetic data, the formation mechanisms of BPs and pyrazine compounds were proposed. PMID- 27979145 TI - Loading of anthocyanins on chitosan nanoparticles influences anthocyanin degradation in gastrointestinal fluids and stability in a beverage. AB - The optimal preparation parameters to create anthocyanin-loaded chitosan nanoparticles was predicted using response surface methodology (RSM). A Box Behnken design was used to determine the preparation parameters that would achieve the preferred particle size and high encapsulation efficiency. The result suggested that the optimized conditions were 2.86mg/mL carboxymethyl chitosan (CMC), 0.98mg/mL chitosan hydrochloride (CHC) and 5.97mg anthocyanins. Using the predicted amounts, the experimentally prepared particles averaged 219.53nm with 63.15% encapsulation efficiency. The result was less than 5% different than the predicted result of 214.83nm particle size and 61.80% encapsulation efficiency. Compared with the free anthocyanin solution, the anthocyanin-loaded chitosan nanoparticles showed a slowed degradation in simulated gastrointestinal fluid. Compared with the free anthocyanin solutions in a model beverage system, the stability of the anthocyanins was increased in the anthocyanin-loaded chitosan nanoparticles. PMID- 27979147 TI - Evaluation of the influence of white grape seed extracts as copigment sources on the anthocyanin extraction from grape skins previously classified by near infrared hyperspectral tools. AB - Hyperspectral imaging has been used to classify red grapes (Vitis vinifera L.) according to their predicted extractable total anthocyanin content (i.e. extractable total anthocyanin content determined by a hyperspectral method). Low, medium and high levels of predicted extractable total anthocyanin content were established. Then, grape skins were split into three parts and each part was macerated into a different model wine solution for a three-day period. Wine model solutions were made up with different concentration of copigments coming from white grape seeds. Aqueous supernatants were analyzed by HPLC-DAD and extractable anthocyanin contents were obtained. Principal component analyses and analyses of variance were carried out with the aim of studying trends related to the extractable anthocyanin contents. Significant differences were found among grapes with different levels of predicted extractable anthocyanin contents. Moreover, no significant differences were found on the extractable anthocyanin contents using different copigment concentrations in grape skin macerations. PMID- 27979148 TI - Influence of water stress and storage time on preservation of the fresh volatile profile of three basil genotypes. AB - The main goal of the present study was to describe the volatile profile of three different basil genotypes (Genovese and Green and Purple Iranian), and the impact that water stress (75% and 50% field capacity) and storage time (up to 7days) have under mild refrigerated conditions. The chromatographic profile pointed to three different chemotypes: linalool/eugenol, neral/geranial, and estragol, for Genovese, Green, and Purple genotypes, respectively. Water stress depleted the volatile profile of these three landraces, due to a reduction in the absolute concentrations of some of the components related to fresh aroma (linalool, nerol, geraniol and eugenol). The stability of the basil volatile profile during storage varied depending on the water stress that had been applied. Concentration reductions of close to 50% were quantified for most of the components identified in the Purple genotype. PMID- 27979149 TI - Characterization, phenolic compounds and functional properties of Cucumis melo L. peels. AB - The aim of this work is to investigate the phytochemical composition and functional properties of the melon peels, considered as a by-product. Melon peels (maazoun cultivar) are rich in nutritional ingredients such as carbohydrates (69.77%) and ash (3.67%). They contain significant amounts of total dietary fibers (41.69%) and antioxidants as polyphenols and flavonoids (332mg/100g extract and 95.46mg/100g extract, respectively). The identification and the quantification of the phenolic compounds of melon peels were performed by high performance liquid chromatography apparatus. The obtained results indicate that hydroxybenzoic acids and flavones constitute their main phenolic classes. 3 Hydroxybenzoic acid is the major phenolic compound in the melon peels by 33.45mg/100g, followed by apigenin-7-glycoside (29.34mg/100g). Determination of the functional properties (water and oil retention capacities) and color shows that melon peels have properties that may be useful in industrial applications. PMID- 27979151 TI - Chemical composition of Brazilian chia seeds grown in different places. AB - This study investigated and compared the occurrence and concentration of macronutrients, moisture, ash, dietary fiber, fatty acids, minerals, carotenoids, vitamins, flavonoids, phenolic compounds, antioxidant activity, phytate and tannin in Brazilian chia seeds grown in the states of Mato Grosso (MT) and Rio Grande do Sul (RS). High concentrations of lipids (31.2g.100g-1, on average), proteins (18.9g.100g-1, on average), dietary fiber (35.3g.100g-1, on average), vitamin E (8,203.6MUg.100g-1, on average) were observed. Similar values for total phenolic compounds and phytic acid in chia seeds from both regions were observed. Chia grown in RS showed higher antioxidant activity than chia grown in MT, and the tannin concentrations were higher in chia seeds grown in Mato Grosso (19.08+/ 1.08eq.catequina/gsample). In conclusion, Brazilian chia seeds showed high concentrations of lipids, proteins, total dietary fiber, minerals and vitamin E. PMID- 27979150 TI - Structural, functional and in vitro digestion characteristics of spray dried fish roe powder stabilised with gum arabic. AB - Fish roes are considered as nutritionally valuable for their high content of essential fatty acids and amino acids. However, roe lipids undergo considerable extent of oxidation during processing and storage, imparting objectionable bitter taste and rancid flavour to roe products. Hence, the objective of the study was to reconstitute the roe mass and microencapsulate lipid fraction, so that small oil droplets are entrapped within a dry matrix of roe proteins during spray drying. Prior to spray drying, the emulsion was stabilised with gum arabic as it also act as a co-wall polymer. The microscopic images indicated presence of larger aggregates in unstabilised powder (RC) compared to well-separated particles in stabilised powder (RG). Incorporation of gum arabic retarded rancidity development during storage. In vitro digestive pattern of roe powder indicated higher amount of oil release in RG. These observations highlight the potential of converting the soft textured carp roe mass into stable fish roe powder with superior storage stability and functionality. PMID- 27979152 TI - Discrimination of red and white rice bran from Indonesia using HPLC fingerprint analysis combined with chemometrics. AB - HPLC fingerprint analysis combined with chemometrics was developed to discriminate between the red and the white rice bran grown in Indonesia. The major component in rice bran is gamma-oryzanol which consisted of 4 main compounds, namely cycloartenol ferulate, cyclobranol ferulate, campesterol ferulate and beta-sitosterol ferulate. Separation of these four compounds along with other compounds was performed using C18 and methanol-acetonitrile with gradient elution system. By using these intensity variations, principal component and discriminant analysis were performed to discriminate the two samples. Discriminant analysis was successfully discriminated the red from the white rice bran with predictive ability of the model showed a satisfactory classification for the test samples. The results of this study indicated that the developed method was suitable as quality control method for rice bran in terms of identification and discrimination of the red and the white rice bran. PMID- 27979153 TI - The effects of heat treatment on the phenolic composition and antioxidant capacity of red wine pomace seasonings. AB - The impact of thermal processing on the phenolic profile and antioxidant capacity (TAC) of powdered red wine pomace seasonings (RWPSs) obtained from different sources (seedless: Sk-S; whole: W-S; seeds: Sd-S) was assessed. High contents in anthocyanins, flavonol-3-O-glycosides, phenolic acids and flavan-3-ols were found in Sk-S, whereas flavan-3-ols and phenolic acids were the main compounds identified in Sd-S. Reductions in the anthocyanidin and flavonol-3-ol contents mainly determined the effect of heat on the total phenolic contents (Sk-S: 29.4%; W-S: -28.0%; Sd-S: -5.78%), although heating affected positively the phenolic acid and flavonol aglycon contents. Slight TAC decreases were observed in the RWPS-derived extracts (classical Folin-Ciocalteu and ABTS assays). However, higher TAC reductions were detected when the powdered RWPSs were used directly as samples (QUENCHER approach). In conclusion, there is little evidence against submitting RWPSs to thermal processing, as heating affects differently each type of phenolic compound and does not induce very severe TAC decreases in these seasonings. PMID- 27979154 TI - Antioxidative effect of Assam Tea (Camellia sinesis Var. Assamica) extract on rice bran oil and its application in breakfast cereal. AB - The objectives of this research were to investigate the antioxidant effect of Assam tea extract (ATE) and whether it is fit to utilise ATE by fortification in rice bran breakfast cereal (RBC). The increasing ATE powder from 0.1 to 0.3mg/g affected to be decreased. The ATE powder at 0.3mg/g was proved to have decreased the hexanal content (0.21MUg/ml) and thiobarbituric acid reactive substances (TBARS) (2.56MUg/g) within 28days, and provided the highest antioxidant ability (EC50) (2481.44mg/kg). The fortified 0.3mg/g of ATE powder showed that increasing ATE significantly increased the total phenolic content and decreased TBARS and EC50 of breakfast cereal (p<0.05). The suitable amount ATE powder added in RBC was 0.5%. The consumer acceptance (n=200) of final product showed the sensory scores in the range of 6.3-6.8, with the percentages of acceptance and purchase intention at 98.0% and 89.0%, respectively. PMID- 27979155 TI - Hydroxytyrosol targets extracellular matrix remodeling by endothelial cells and inhibits both ex vivo and in vivo angiogenesis. AB - The health benefits of olive oil are attributed to their bioactive compounds, such as hydroxytyrosol. Previously, we demonstrated that hydroxytyrosol inhibits angiogenesis in vitro. The present study aimed to: i) get further insight into the effects of hydroxytyrosol on extracellular matrix remodeling; and ii) test whether hydroxytyrosol is able to inhibit angiogenesis ex vivo and in vivo. Hydroxytyrosol induced a shift toward inhibition of proteolysis in endothelial cells, with decreased expression of extracellular matrix remodeling-enzyme coding genes and increased levels of some of their inhibitors. Furthermore, this work demonstrated that hydroxytyrosol, at concentrations within the range of its content in virgin olive oil that can be absorbed from moderate and sustained virgin olive oil consumption, is a strong inhibitor of angiogenesis ex vivo and in vivo. These results suggest the need for translational studies to evaluate the potential use of hydroxytyrosol for angio-prevention and angiogenesis inhibition in clinical setting. PMID- 27979156 TI - Streamlining the analytical workflow for multiplex MS/MS allergen detection in processed foods. AB - Allergenic ingredients in pre-packaged foods are regulated by EU legislation mandating their inclusion on labels. In order to protect allergic consumers, sensitive analytical methods are required for detect allergen traces in different food products. As a follow-up to our previous investigations, an optimized, sensitive, label-free LC-MS/MS method for multiplex detection of five allergenic ingredients in a processed food matrix is proposed. A cookie base was chosen as a complex food matrix and home-made cookies incurred with whole egg, skimmed milk, soy flour, ground hazelnut and ground peanut were prepared at laboratory scale. In order to improve the analytical workflow both protein extraction and purification protocols were optimized and finally a sensitive streamlined SRM based analytical method for allergens detection in incurred cookies was devised. The effect of baking on the detection of selected markers was also investigated. PMID- 27979158 TI - Salting-out assisted liquid-liquid extraction coupled to ultra-high performance liquid chromatography-tandem mass spectrometry for the determination of tetracycline residues in infant foods. AB - The use of salting-out assisted liquid-liquid extraction (SALLE) combined with ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC MS/MS) has been evaluated for the determination of tetracyclines in infant foods based on meat and vegetables or in milk. To obtain satisfactory extraction efficiencies for the studied analytes, several parameters affecting the SALLE procedure were optimized. Analytical performances of the method were satisfactory, obtaining limits of quantification lower than 0.48MUgkg-1 in all cases. The precision, expressed as relative standard deviation (%, RSD) was below 11.3%. The extraction efficiency for fortified samples ranged from 89.2 to 96.8%, with RSDs lower than 7.3%. Matrix effect was evaluated for all samples studied, being lower than |21|% in all cases. In relation to the low solvent consumption, the proposed methodology could be considered rapid, cheap and environmentally friendly. Its applicability has been successfully tested in a wide range of infant foods. PMID- 27979157 TI - Changes in the arabinoxylan fraction of wheat grain during alcohol production. AB - Laboratory produced DDGS samples were compared with commercial samples from a distillery and a biofuel plant. Changes in structure, solubility and content of arabinoxylan (AX) was determined. The distillation process results in a relative increase of AX content compared to the starting material. The heating and drying processes involved in the production of DDGS lead to an increased solubility and viscosity of water-extractable AX. Production of DDGS results in structural changes to the AX. There is a decrease in 2- and 3-linked arabinose oligosaccharides, that contributes to around a 50% reduction in arabinosylation in DDGS compared with the starting grains. The current study shows that laboratory-scale DDGS provide an accurate representation of the commercial scale and that the AX composition of DDGS is consistently uniform irrespective of starting material. The uniformity of DDGS and thin stillage makes them a good potential source of AX for production of prebiotics or other novel products. PMID- 27979159 TI - Ultra-sensitive and absolute quantitative detection of Cu2+ based on DNAzyme and digital PCR in water and drink samples. AB - Here, we developed an ultra-sensitive and absolute quantitative detection method of Cu2+ based on DNAzyme and digital PCR. The binding model between DNAzyme and Cu2+ and the influence caused by the additional primer sequence were revealed to ensure quantitation independent of standard curves. The binding model of DNAzyme and Cu2+ showed that one molecular DNAzyme could bind one Cu2+ in the biosensor step. Thus, the final quantitative results, evaluated by three parallels, showed that the limit of quantitation (LOQ) was as low as 0.5pmol, while the sensitivity was evaluated as 50fmol. The specificity evaluation of our methodologies shows that extremely low crossing signal is existed within the non-specific ions. Moreover, the results of practical detection have shown that the quantitative results were stable and accurate among different food substrates. In conclusion, a flexible quantitative detection method with ultra-sensitivity was developed to detect trace amounts Cu2+ within different substrates. PMID- 27979160 TI - Laser Induced breakdown spectroscopy: A rapid tool for the identification and quantification of minerals in cucurbit seeds. AB - Laser-induced breakdown spectroscopy (LIBS) was investigated to estimate the viability as a simple and rapid method for analysis of nutrient elements in seed kernels of cucurbits. LIBS spectra were recorded in the range of 200-975nm by using Q-switched Nd:YAG laser at 532nm (4ns, 10Hz) attached to echelle spectrometer with intensified charged coupled device (ICCD). The spectral analysis revealed the presence of several elements like C, O, N, Mg, Ca, Na and K in seeds. The quantification of elements (Mg, Ca, Na and K) through LIBS was done using calibration curve method in which all calibration curve shows good linearity (r>0.95). The result obtained through LIBS was in reasonable agreement with that obtained through atomic absorption spectroscopy (AAS). Principal Component Analysis (PCA) was also applied to the LIBS data for rapid categorization of seed samples belonging to same species although samples have similar nutrient elements. PMID- 27979161 TI - Unravelling effects of flavanols and their derivatives on acrylamide formation via support vector machine modelling. AB - This study investigated the effect of flavanols and their derivatives on acrylamide formation under low-moisture conditions via prediction using the support vector regression (SVR) approach. Acrylamide was generated in a potato based equimolar asparagine-reducing sugar model system through oven heating. Both positive and negative effects were observed when the flavonoid treatment ranged 1 10,000MUmol/L. Flavanols and derivatives (100MUmol/L) suppress the acrylamide formation within a range of 59.9-78.2%, while their maximal promotion effects ranged from 2.15-fold to 2.84-fold for the control at a concentration of 10,000MUmol/L. The correlations between inhibition rates and changes in Trolox equivalent antioxidant capacity (DeltaTEAC) (RTEAC-DPPH=0.878, RTEAC-ABTS=0.882, RTEAC-FRAP=0.871) were better than promotion rates (RTEAC-DPPH=0.815, RTEAC ABTS=0.749, RTEAC-FRAP=0.841). Using DeltaTEAC as variables, an optimized SVR model could robustly serve as a new predictive tool for estimating the effect (R: 0.783-0.880), the fitting performance of which was slightly better than that of multiple linear regression model (R: 0.754-0.880). PMID- 27979162 TI - One input-class and two input-class classifications for differentiating olive oil from other edible vegetable oils by use of the normal-phase liquid chromatography fingerprint of the methyl-transesterified fraction. AB - A new method for differentiation of olive oil (independently of the quality category) from other vegetable oils (canola, safflower, corn, peanut, seeds, grapeseed, palm, linseed, sesame and soybean) has been developed. The analytical procedure for chromatographic fingerprinting of the methyl-transesterified fraction of each vegetable oil, using normal-phase liquid chromatography, is described and the chemometric strategies applied and discussed. Some chemometric methods, such as k-nearest neighbours (kNN), partial least squared-discriminant analysis (PLS-DA), support vector machine classification analysis (SVM-C), and soft independent modelling of class analogies (SIMCA), were applied to build classification models. Performance of the classification was evaluated and ranked using several classification quality metrics. The discriminant analysis, based on the use of one input-class, (plus a dummy class) was applied for the first time in this study. PMID- 27979163 TI - Development of a rapid and sensitive immunosensor for the detection of bacteria. AB - The presence of Gram-positive bacteria in foodstuffs is a chronic worldwide problem. Here, we present a cheap and simple colorimetric method for the detection of Lactobacillus species (spp.) and Staphylococcus aureus (S. aureus) using gold nanoparticles (AuNP) modified with monoclonal anti-Gram-positive bacteria to produce an immune-sensor. Detection is based on the fact that antibody-conjugated AuNPs can readily identify Gram-positive bacteria through antibody-antigen recognition, which results in a color change of AuNPs upon aggregation. The detection limit was 105CFU/ml in pure culture for Lactobacillus spp. and 120CFU/ml in pure culture for S. aureus. The method was applied successfully for detection of bacteria in samples of sugar cane, and agreed well with values obtained using other methods. These results suggested that the detection system could be used for the quantitative analysis of Gram-positive bacteria and might be applied potentially by the food industry. PMID- 27979164 TI - Dummy-surface molecularly imprinted polymers on magnetic graphene oxide for rapid and selective quantification of acrylamide in heat-processed (including fried) foods. AB - Novel nano-sized dummy-surface molecularly imprinted polymers (DSMIPs) on a magnetic graphene oxide (GO-Fe3O4) surface were developed as substrates, using propionamide as a dummy template molecule for the selective recognition and rapid pre-concentration and removal of acrylamide (AM) from food samples. These products showed rapid kinetics, high binding capacity (adsorption at 3.68mg.g-1), and selectivity (imprinting factor alpha 2.83); the adsorption processes followed the Langmuir-Freundlich isotherm and pseudo-second-order kinetic models. Excellent recognition selectivity toward acrylamide was achieved compared to structural analogs, such as propionic and acrylic acids (selectivity factor beta 2.33, and 2.20, respectively). Moreover, DSMIPs-GO-Fe3O4 was used to quantify acrylamide in food samples, yielding satisfactory recovery (86.7-94.3%) and low relative standard deviation (<4.85%). Thus, our DSMIPs-GO-Fe3O4-based procedure was demonstrated to be a convenient and practical method for the separation, enrichment, and removal of acrylamide from food samples. PMID- 27979165 TI - Enhancing the antimicrobial activity of d-limonene nanoemulsion with the inclusion of epsilon-polylysine. AB - The objective of this research was to investigate the synergism between epsilon polylysine and d-limonene and develop a novel nanoemulsion system by merging the positive effect of these two antimicrobial agents. Results from the checkerboard method showed that epsilon-polylysine and d-limonene exhibit strong synergistic and useful additive effects against Escherichia coli, Staphylococcus aureus, Bacillus subtilis and Saccharomyces cerevisiae. In addition, d-limonene nanoemulsion with the inclusion of epsilon-polylysine was successfully prepared by high pressure homogenizer technology. Its antimicrobial efficiency was compared with pure d-limonene nanoemulsion by measuring the minimal inhibitory concentration, electronic microscope observation and the leakage of the intercellular constituents. The results demonstrated a wide improvement of the antimicrobial activity of d-limonene nanoemulsion following the inclusion of epsilon-polylysine. Overall, the current study may have a valuable contribution to make in developing a more efficient antimicrobial system in the food industry. PMID- 27979166 TI - Pretreatment of flaxseed protein isolate by high hydrostatic pressure: Impacts on protein structure, enzymatic hydrolysis and final hydrolysate antioxidant capacities. AB - The effect of high hydrostatic pressure (HHP) on flaxseed protein structure and peptide profiles, obtained after protein hydrolysis, was investigated. Isolated flaxseed protein (1%, m/v) was subjected to HHP (600MPa, 5min or 20min at 20 degrees C) prior to hydrolysis with trypsin only and trypsin-pronase. The results demonstrated that HHP treatment induced dissociation of flaxseed proteins and generated higher molecular weight aggregates as a function of processing duration. Fluorescence spectroscopy showed that HHP treatment, as well as processing duration, had an impact on flaxseed protein structure since exposition of hydrophobic amino acid tyrosine was modified. Except for some specific peptides, the concentrations of which were modified, similar peptide profiles were obtained after hydrolysis of pressure-treated proteins using trypsin. Finally, hydrolysates obtained using trypsin-pronase had a greater antioxidant capacity (ORAC) than control samples; these results confirmed that HHP enhanced the generation of antioxidant peptides. PMID- 27979167 TI - Simultaneous detection of four nitrofuran metabolites in honey by using a visualized microarray screen assay. AB - A visualized microarray sensing technique has been developed and applied to the screening of honey samples for residues of banned nitrofuran antibiotics. Using a multiplexed approach, metabolites of four main nitrofuran antibiotics can be detected simultaneously. Individual antigens were spotted onto 96-well plates. An indirective competitive assay format, with visualized signal response, was employed. An extraction method, based on derivatization with 2-nitrobenzaldehyde and partition into ethyl acetate, was used for screening. The limits of detection were 0.10, 0.04, 0.04, and 0.10ngg-1 for 3-amino-5-morpholino-2-oxazolidone (AMOZ), 3-amino-2-oxazolidinone (AOZ), semicarbazide (SEM), and 1-aminohydantoin (AHD), respectively. The recovery rate ranged from 78% to 93% for the four targets. In addition, this method was easy to operate with low detection cost and fast speed. This microarray method possesses the potential to be a fit-for purpose screening technique in the arena of food safety monitoring. PMID- 27979168 TI - Differences in proteomic profiles of milk fat globule membrane in yak and cow milk. AB - Milk fat globule membrane (MFGM) is an important milk component which is rich in bioactive proteins. In this work, the isobaric tags for relative and absolute quantitation (iTRAQ) proteomic approach was used to investigate the differences in the MFGM proteins between yak and cow milk. Over 450 proteins were identified between the yak and cow MFGM. The MFGM proteins with significant differences were compared based on the relative abundance. Proteins such as Glycosylation dependent cell adhesion molecule 1 (GlyCAM1), CD59 molecule and lactadherin, were identified having a much higher abundance (4.6-10.1 fold) in yak MFGM than cow MFGM. These proteins are thought to have biological functions such as the antimicrobial and antitumor effects. This may be due to the need that yak produces high nutritive milk including high levels of bioactive compounds in order to resist the extreme high altitude environment. PMID- 27979169 TI - Rapid NMR determination of inorganic cations in food matrices: Application to mineral water. AB - A nuclear magnetic resonance (NMR) method was developed to quantify cations in mineral water. The procedure was based on integration of signals from metal ethylenediaminetetraacetic acid (EDTA) complexes at delta 2.70ppm for Mg2+ and delta 2.56ppm for Ca2+. The limits of detection were below 0.5mg/L. Lack of precision did not exceed 5%. Linearity was between 1 and 500mg/L. Correlation between NMR and a reference chromatographic method was significant (p<0.0001, R2=0.99). PLS models were also established to estimate Na+ and K+ contents. R2 was 0.85 and 0.83, respectively. Root mean square errors of cross validation (RMSECV) were 8.0mg/L and 1.9mg/L for Na+ and K+, respectively. The method was applied successfully for the analysis of 31 mineral water samples. This method is a useful tool for quantification of important cations in mineral water and might easily be adapted to other food matrices. PMID- 27979170 TI - Bioaccessibility of bioactive compounds after non-thermal processing of an exotic fruit juice blend sweetened with Stevia rebaudiana. AB - A comparative study of the bioaccessibility of bioactive compounds and antioxidant capacity in a fruit juice-Stevia rebaudiana mixture processed by pulsed electric fields (PEF), high voltage electrical discharges (HVED) and ultrasound (USN) technology at two equivalent energy inputs (32-256kJ/kg) was made using an in vitro model. Ascorbic acid was not detected following intestinal digestion, while HVED, PEF and USN treatments increased total carotenoid bioaccessibility. HVED at an energy input of 32kJ/kg improved bioaccessibility of phenolic compounds (34.2%), anthocyanins (31.0%) and antioxidant capacity (35.8%, 29.1%, 31.9%, for TEAC, ORAC and DPPH assay, respectively) compared to untreated sample. This was also observed for PEF treated samples at an energy input of 256kJ/kg (37.0%, 15.6%, 29.4%, 26.5%, 23.5% for phenolics, anthocyanins, and antioxidant capacity using TEAC, ORAC and DPPH method, respectively). Consequently, pulsed electric technologies (HVED and PEF) show good prospects for enhanced bioaccessibility of compounds with putative health benefit. PMID- 27979171 TI - Matrix-normalised real-time PCR approach to quantify soybean as a potential food allergen as affected by thermal processing. AB - The addition of soybean protein materials to meat products is a common practice in the food industry, being a potential hidden allergenic commodity. This study aimed at proposing a novel specific and highly sensitive real-time PCR system for the detection/quantification of soybean as an allergenic ingredient in processed meat products. The method achieved a limit of detection of 9.8pg of soybean DNA (8.6 copies), with adequate real-time PCR performance parameters, regardless of the soybean material (concentrate or isolate) and after thermal treatments. A normalised approach was also proposed in the range of 0.001-10% (w/w) of soybean material in pork meat, which was successfully validated and applied to processed meat products. Soybean was identified in more than 40% of tested samples of cooked ham and mortadella in the range of 0.1-4% (w/w), 3 samples not complying with labelling regulations as a result of undeclared soybean. PMID- 27979172 TI - Monoterpenoids from the traditional North Italian vegetable Aruncus dioicus (Walter) Fernald var. vulgaris (Maxim.) H.Hara (Rosaceae). AB - Investigations of young shoots of Aruncus dioicus (Walter) Fernald var. vulgaris (Maxim.) H.Hara (Rosaceae), collected from the wild and used as vegetables in alpine provinces of Italy, yielded eight monoterpenoids. Besides known compounds, aruncin A, aruncide A, and cimicifugolide, five previously undescribed substances, aruncins C, D, and E, and aruncides D and E, were identified. Based on results from the full synthesis of aruncin B, structures of aruncin A and aruncide A were revised. Structures were established by HR mass spectrometry and extensive 1D and 2D NMR spectroscopy and based on data from synthetic aruncin B. An HPLC-DAD-ESI-MS method was developed to investigate the distribution of the monoterpenoids in different organs of Aruncus dioicus var. vulgaris and in aerial parts of A. dioicus var. aethusifolius (H.Lev.) H.Hara [Syn.: Aruncus aethusifolius (H.Lev.) Nakai]. Preliminary bioactivity studies moreover indicated weak cytotoxicity for some of the compounds against human prostrate adenocarcinoma cells. PMID- 27979173 TI - Effects of high hydrostatic pressure, ultraviolet light-C, and far-infrared treatments on the digestibility, antioxidant and antihypertensive activity of alpha-casein. AB - Alpha-casein is the most important bioactive protein in processing technologies. This study investigated the digestibility, antioxidant and antihypertensive activities of alpha-casein when treated by high hydrostatic pressure (HPP), ultraviolet light-C (UV-C), and far-infrared radiation (FIR). The in vitro digestibility was modified after treatments, especially after 5min/200MPa HHP treatment. Ultra-performance liquid chromatography-tandem mass spectrometry analysis showed that one 5min/200MPa HHP treatment resulted in the highest yield of peptides. Based on the in vitro gastrointestinal digestion and antioxidant and antihypertensive activity assays, HHP increased the angiotensin converting enzyme inhibitory activity at different levels. The 15min UV-C treatment resulted in the highest antioxidant DPPH radical-scavenging activity, while the 15min UV-C and FIR treatments had higher angiotensin converting enzyme inhibitory and antioxidant activities than those of 5min treatments. This study revealed that HHP, UV-C and FIR treatments increased the antioxidant and antihypertensive activities of alpha-casein. PMID- 27979174 TI - Boiling enriches the linear polysulfides and the hydrogen sulfide-releasing activity of garlic. AB - Garlic is rich in polysulfides, and some of them can be H2S donors. This study was conducted to explore the effect of cooking on garlic's organopolysulfides and H2S-releasing activity. Garlic bulbs were crushed and boiled for a period ranging from 3 to 30min and the solvent extracts were analyzed by GC-MS/FID and HPLC. A cell-based assay was used to measure the H2S-releasing activity of the extracts. Results showed that the amounts of allyl polysulfides increased in crushed garlic boiled for 6-10min; however, prolonging the thermal treatment to 20 or 30min decreased their concentrations. Data of the H2S-releasing activity, expressed as diallyl trisulfide equivalents (DATS-E), parallel this trend, being significantly higher at 6 and 10min boiling. Our results showed enhancement of H2S-releasing activity upon moderate boiling, suggesting that shorter cooking time may maximize its health benefits as a dietary source of natural H2S donors. PMID- 27979175 TI - Impact of preharvest and postharvest alginate treatments enriched with vanillin on postharvest decay, biochemical properties, quality and sensory attributes of table grapes. AB - Alginate solution enriched with vanillin as a bioactive compound was investigated for improving preharvest and postharvest quality and safety of table grapes. Alginate treatments with or without vanillin as preharvest spray and postharvest coating were implemented on table grapes of Alphonse Lavallee and Razaki cultivars. Fungal decay, biochemical properties, quality and sensory attributes were evaluated at day of preharvest treatment, at harvesting and during 35days of storage at 4+/-2 degrees C. Alginate treatments with or without vanillin were effective in preventing weight and firmness losses. Total soluble solids, titratable acidity, and color of grapes coated with alginate coatings with or without vanillin showed minor changes compared to control grapes. Alginate coating incorporating vanillin provided significant reduction (1.73log CFU/g) in yeast-mold growth. Moreover, the coatings maintained greater total phenolic content and antioxidant activity compared to others during postharvest storage. In terms of sensory attributes, appearance was ranked as the highest for alginate coating without vanillin due to glossiness of alginate. PMID- 27979176 TI - Proteomic analysis of coffee grains exposed to different drying process. AB - Many biochemical events occur inside grains during post-harvest processes. Several methods have been developed to relate the chemical composition of the coffee grain to the beverage quality, including identification of possible molecular markers for flavor characterizing. This study was aimed at evaluating the changes in the proteomic profile of pulped and natural C. arabica grains dried in a yard or dryer at 60 degrees C. It was observed that fruits dried in a dryer at 60 degrees C showed an altered proteomic profile, with a reduction in the most abundant proteins compared to those yard-dried grains. Among the identified proteins, those involved in the metabolism of sugars and stress response were highlighted. Results have shown that post-harvest processes that impact coffee quality are related to changes in protein abundance, indicating that proteomic analysis may be effective in the identification of biochemical changes in coffee grains subjected to different post-harvest processes. PMID- 27979177 TI - Identification of phenolic antioxidants and bioactives of pomegranate seeds following juice extraction using HPLC-DAD-ESI-MSn. AB - Phenolics from free and hydrolyzed fractions of pomegranate juice (PJ) and seeds (PS) were evaluated. In general, total phenolic contents and scavenging of ABTS+, DPPH and hydroxyl radicals, as well as metal chelation of the soluble fraction from PS, were higher than those for PJ. Insoluble-bound phenolics from PS accounted for up to 27% of total scavenging capacity (free+esterified+insoluble bound). Phenolic acids (13), monomeric flavonoids (8), hydrolysable tannins (12), proanthocyanidin (1) and anthocyanins (12) were tentatively characterized using HPLC-DAD-ESI-MSn. Several compounds were identified for the first time in PJ or PS. The inhibition of DNA damage (induced by hydroxyl and peroxyl radicals), copper-induced LDL-cholesterol peroxidation, as well as alpha-glucosidase and lipase activities were demonstrated, therefore supporting the potential exploitation of PJ and PS as sources of bioactive compounds. PMID- 27979178 TI - Comparative analysis of human milk and infant formula derived peptides following in vitro digestion. AB - It has long been recognised that there are differences between human milk and infant formulas which lead to differences in health and nutrition for the neonate. In this study we examine and compare the peptide profile of human milk and an exemplar infant formula. The study identifies both similarities and differences in the endogenous and postdigestion peptide profiles of human milk and infant formula. This includes differences in the protein source of these peptides but also with the region within the protein producing the dominant proteins. Clustering of similar peptides around regions of high sequence identity and known bioactivity was also observed. Together the data may explain some of the functional differences between human milk and infant formula, while identifying some aspects of conserved function between bovine and human milks which contribute to the effectiveness of modern infant formula as a substitute for human milk. PMID- 27979179 TI - An innovative method for analysis of Pb (II) in rice, milk and water samples based on TiO2 reinforced caprylic acid hollow fiber solid/liquid phase microextraction. AB - In the present study, nano-sized titanium oxides were applied for preconcentration and determination of Pb(II) in aqueous samples using hollow fiber based solid-liquid phase microextraction (HF-SLPME) combined with flame atomic absorption spectrometry (FAAS). In this work, the nanoparticles dispersed in caprylic acid as an extraction solvent was placed into a polypropylene porous hollow fiber segment supported by capillary forces and sonification. This membrane was in direct contact with solutions containing Pb (II). The effect of experimental conditions on the extraction, such as pH, stirring rate, sample volume, and extraction time were optimized. Under the optimal conditions, the performance of the proposed method was investigated for the determination of Pb (II) in food and water samples. The method was linear in the range of 0.6 3000MUgmL-1. The relative standard deviations and relative recovery of Pb (II) was 4.9% and 99.3%, respectively (n=5). PMID- 27979180 TI - Maillard reaction and caramelization during hazelnut roasting: A multiresponse kinetic study. AB - A comprehensive kinetic model indicating the elementary steps of Maillard reaction and caramelization during hazelnut roasting was proposed based on a multi-response kinetic modeling approach. Changes in the concentrations of sucrose, fructose, glucose, amino acids, 3-deoxyglucosone, 1-deoxyglucosone, 3,4 dideoxyglucosone, glyoxal, methylglyoxal, dimethylglyoxal, and 5 hydroxymethylfurfural were examined in hazelnuts during roasting at 150, 160 and 170 degrees C for 15, 30, 60, 90, and 120min. The results suggested that 1,2 enolization was important in the interconversion of glucose and fructose, 5 hydroxymethylfurfural formation mainly proceeded via fructofuranosyl cation dehydration rather than 3-deoxglucosone, glucose contributed more than fructose and fructofuranosyl cation to the early stage of the Maillard reaction. Methylglyoxal and dimethylglyoxal were mainly formed from 1-deoxyglucosone with high reaction rate constants while glyoxal formed through glucose degradation. alpha-Dicarbonyl compounds could have a role in the formation of melanoidins. The temperature dependence of the reactions was complicated and could not be explained by the Arrhenius equation. PMID- 27979182 TI - Assessing a traceability technique in fresh oranges (Citrus sinensis L. Osbeck) with an HS-SPME-GC-MS method. Towards a volatile characterisation of organic oranges. AB - A targeted approach using HS-SPME-GC-MS was performed to compare flavour compounds of 'Navelina' and 'Salustiana' orange cultivars from organic and conventional management systems. Both varieties of conventional oranges showed higher content of ester compounds. On the other hand, higher content of some compounds related with the geranyl-diphosphate pathway (neryl and geranyl acetates) and some terpenoids were found in the organic samples. Furthermore, the partial least square discriminant analysis (PLS-DA) achieved an effective classification for oranges based on the farming system using their volatile profiles (90 and 100% correct classification). To our knowledge, it is the first time that a comparative study dealing with farming systems and orange aroma profile has been performed. These new insights, taking into account local databases, cultivars and advanced analytical tools, highlight the potential of volatile composition for organic orange discrimination. PMID- 27979181 TI - Effect of metal ions on the binding reaction of (-)-epigallocatechin gallate to beta-lactoglobulin. AB - The effects of metal ions (Cu2+, Sn2+, Zn2+, Mn2+, Al3+ and Fe3+) on the interaction between (-)-epigallocatechin-3-gallate (EGCg) and beta-lactoglobulin (beta-Lg) were investigated via fluorescence and circular dichroism (CD) spectroscopy. The results of the fluorescence titration experiment demonstrated that the addition of Cu2+ increases the quenching efficiency of EGCg to beta-Lg by more than EGCg alone, while Mn2+, Al3+ and Zn2+ decrease the quenching efficiency of EGCg to beta-Lg by less than EGCg alone. [beta-Lg-Mn], [beta-Lg Al], [beta-Lg-Zn] and [beta-Lg-Sn] obviously decreased the apparent binding affinities (Ka) of EGCg to beta-Lg by 95.53%, 81.94%, 44.66% and 38.58%, respectively, whereas [beta-Lg-Cu] significantly increased the Ka of EGCg for beta-Lg by 115.44%. The results of CD spectroscopy experiment showed the alpha helix content of beta-Lg decreased with the addition of Cu or Al, indicating that the beta-Lg-Cu and beta-Lg-Al interaction resulted in unfolding of the secondary structure of beta-Lg. PMID- 27979183 TI - Rapid determination of total protein and wet gluten in commercial wheat flour using siSVR-NIR. AB - The determination of total protein and wet gluten is of critical importance when screening commercial flour for desired processing suitability. To this end, a near-infrared spectroscopy (NIR) method with support vector regression was developed in the present study. The effects of spectral preprocessing and the synergy interval on model performance were investigated. The results showed that the models from raw spectra were not acceptable, but they were substantially improved by properly applying spectral preprocessing methods. Meanwhile, the synergy interval was validated with a good ability to improve the performance of models based on the whole spectrum. The coefficient of determination (R2), the root mean square error of prediction (RMSEP) and the standard deviation ratio (SDR) of the best models for total protein (wet gluten) were 0.906 (0.850), 0.425 (1.024) and 3.065 (2.482), respectively. These two best models have similar and lower relative errors (approximately 8.8%), which indicates their feasibility. PMID- 27979184 TI - Precooling and ozone treatments affects postharvest quality of black mulberry (Morus nigra) fruits. AB - Mulberry (Morus spp.) fruits are delicious and nutritious, but they are highly perishable and have a very short shelf-life for sale in the market. This study investigated the effect and mechanisms of 2ppm ozone and precooling treatments on the postharvest quality of mulberry fruit during refrigerated storage. The results revealed that mulberry fruit subjected to ozone and precooling treatment had higher levels of titratable acidity and total soluble solids content, better retention in firmness and color, and lower decay rate, respiratory intensity, and polyphenol oxidase activity compared to the control. From the analysis of cell ultrastructure and cell wall components of fruit, ozone and precooling treatments also induced shrinkage of the stomata in the epidermis, inhibited bacteria invasion, reduced water transpiration, and delayed the decomposition of the cell walls and the degradation of epidermal tissues. PMID- 27979185 TI - Gluten-free pasta incorporating chia (Salvia hispanica L.) as thickening agent: An approach to naturally improve the nutritional profile and the in vitro carbohydrate digestibility. AB - A gluten-free pasta was prepared adding chia at rice flour for testing the thickening and nutritional properties of this specie. Chemical analysis showed chia is a source of protein (19.52% and 15.81%, seeds and mucilage respectively), insoluble/soluble dietary fiber ratio (4.3 and 1.79 seeds and mucilage respectively), fat and ash content. The total phenolic acids content ranged from 734.5MUg/g to 923.9MUg/g for seeds and mucilage respectively. Chia was a good thickening agent and, improved the nutritional profile of enriched samples compared to CGF. After cooking TPAs increased in all samples, ranging from 5.3% in DW to 52.8% in CM5. The addition of chia seeds also increased the slowly digestible starch fraction of rice flour, commonly known to have a high glycemic index. Results suggest that chia should be added as thickening agent in the formulation of GF pasta for conferring healthier characteristics. PMID- 27979186 TI - Chemical composition and antimicrobial activity of garlic essential oils evaluated in organic solvent, emulsifying, and self-microemulsifying water based delivery systems. AB - The chemical composition of garlic essential oils (GEOs) extracted from two different cultivars has been characterized using GC-MS analysis. GEO that was extracted from the white-skin cultivar (WGO) had a lower percentage of the major constituents diallyl trisulfide and diallyl disulfide (45.76 and 15.63%) than purple-skin cultivar (PGO) which contained higher percentages (58.53 and 22.38%) of the same components, respectively. Evaluation of the antimicrobial activity of WGO and PGO delivered in organic solvent (isopropanol) showed dose-dependent antimicrobial activity against the tested pathogenic bacteria and fungi, especially with WGO. On the other hand, formulation of both GEOs in water-based emulsions totally suppressed the antimicrobial activity of GEO. Re-formulation of GEOs in water-based microemulsion (particle size 10.1nm) showed better antimicrobial activity than emulsions at the same concentration of GEOs. This study can assist in designing the proper water-based delivery system of GEO for application in food preservation. PMID- 27979187 TI - Preparation of a multiple emulsion based on pectin-whey protein complex for encapsulation of saffron extract nanodroplets. AB - The present study illustrates a simple and practical way to produce an adequate delivery system of bioactive compounds of saffron by protein-polysaccharide complex. Frist, crocin, safranal, and picrocrocin were loaded in nanodroplets (<100nm) by using water in oil (W/O) microemulsions contain 5, and 10% aqueous saffron extract as a dispersed phase. These microemulsions were then covered with whey protein concentrate (WPC)-maltodextrin or WPC-pectin-maltodextrin through water in oil in water (W/O/W) multiple emulsions. The stability and release of loaded crocin, safranal, and picrocrocin in multiple emulsions were investigated during 22days storage. The produced multiple emulsion by WPC-pectin-maltodextrin along with 5% inner aqueous phase showed a high stability and low release of encapsulated compounds over time. This emulsion also provided a high protection of crocin, safranal, and picrocrocin in the gastric condition. PMID- 27979188 TI - A sensitive high performance liquid chromatography-tandem mass spectrometry method for the detection of microbial transglutaminase in different types of restructured meat. AB - A sensitive HPLC-MS/MS-method for the detection of microbial transglutaminase (TG) from Streptomyces mobaraensis in different types of restructured meat (pork, beef, chicken, and turkey) was developed using six tryptic marker peptides (8-11 amino acids). Meat binding experiments were performed with two technical TG mixtures with and without caseinate. After optimization of the conditions of extraction and tryptic digestion, restructured meat and blank values (total samples: 62) were analyzed in a raw and heated state. By investigation of samples pre-treated with oil marinade, emulsion marinade, seasoning salt as well as breadcrumbs, only very little effects of the type of pre-treatment on the detectability of TG were found. Using four marker peptides, no false-positive or false-negative results were obtained. The limit of detection (LOD) was about a factor of 10 below the recommended amount of transglutaminase for raw as well as heated restructured meat. PMID- 27979190 TI - Chemical spoilage extent traceability of two kinds of processed pork meats using one multispectral system developed by hyperspectral imaging combined with effective variable selection methods. AB - The feasibility of hyperspectral imaging (HSI) (400-1000nm) for tracing the chemical spoilage extent of the raw meat used for two kinds of processed meats was investigated. Calibration models established separately for salted and cooked meats using full wavebands showed good results with the determination coefficient in prediction (R2P) of 0.887 and 0.832, respectively. For simplifying the calibration models, two variable selection methods were used and compared. The results showed that genetic algorithm-partial least squares (GA-PLS) with as much continuous wavebands selected as possible always had better performance. The potential of HSI to develop one multispectral system for simultaneously tracing the chemical spoilage extent of the two kinds of processed meats was also studied. Good result with an R2P of 0.854 was obtained using GA-PLS as the dimension reduction method, which was thus used to visualize total volatile base nitrogen (TVB-N) contents corresponding to each pixel of the image. PMID- 27979189 TI - Improved physicochemical properties and hepatic protection of Maillard reaction products derived from fish protein hydrolysates and ribose. AB - High amounts of waste products generated from fish-processing need to be disposed of despite their potential nutritional value. A variety of methods, such as enzymatic hydrolysis, have been developed for these byproducts. In the current study, we investigated the physicochemical, biological and antioxidative properties of fish protein hydrolysates (FPH) conjugated with ribose through the Maillard reaction. These glycated conjugates of FPH (GFPH) had more viscous rheological properties than FPH and exhibited higher heat, emulsification and foaming stability. They also protected liver HepG2 cells against t-BHP-induced oxidative stress with enhanced glutathione synthesis in vitro. Furthermore, it was shown that GFPH induced upregulation of phase II enzyme expression, such as that of HO-1 and gamma-GCL, via nuclear translocation of Nrf2 and phosphorylation of ERK. Taken together, these results demonstrate the potential of GFPH for use as a functional food ingredient with improved rheological and antioxidative properties. PMID- 27979191 TI - Molecular dimensions and structural features of neutral polysaccharides from the seed mucilage of Hyptis suaveolens L. AB - The seed mucilage of Hyptis suaveolens L. includes acid - and neutral heteropolysaccharides in a ratio of about 1:1. The anionic charged fraction responsible for swelling and viscous behaviour possesses an average molar mass of Mw=350kg/mol, Mn=255kg/mol. The neutral polysaccharide fraction shows an average molar mass of Mw=47kg/mol and Mn=28kg/mol and is composed of d-Galp-, d-Glcp- and d-Manp residues in a molar ratio of about 3:2:1. The structural features present galactoglucan (30%) and galactoglucomannan (70%) with a high level of terminal beta-linked d-Galp residues (18%). Structural details of galactoglucomannan are derived by combined enzymatic and chemical methods as well as NMR spectroscopy. Sequences of octa/nonasaccharide beta-d-Glcp-(1->4)[beta-d-Galp-(1->2)-alpha-d Galp-(1->6)]-beta-d-Manp-(1->4)-beta-d-Glcp-(1->4)-beta-d-Glcp-(1->4)[beta-d-Galp (1->2)-alpha-d-Galp-(1->6)]-beta-d-Manp and lower mass tetrasaccharide repeating units beta-d-Glcp-(1->4)[beta-d-Galp-(1->2)-alpha-d-Galp-(1->6)]-beta-d-Manp were found. The level of the prebiotic activity is related to the availability of beta linked d-Galp residues in the side chains of the molecules. PMID- 27979192 TI - Determination of neurotoxic agents as markers of common vetch adulteration in lentil by LC-MS/MS. AB - Vicia sativa (common vetch), which contains beta-cyanoalanine (BCA) and gamma glutamyl beta-cyanoalanine (gammaGBCA) is used for adulteration of lentil and have neuro toxic effects on people and animals. Therefore the determination of BCA and gammaGBCA analytes in accurate and reliable manner has high importance for human and animal health. LC-IDMS/MS method has been developed and validated for quantitative analyses of beta-cyanoalanine and 13C labeled BCA is used as an internal standard in gammaGBCA analysis. In order to validate the method, linearity, recovery, precision (repeatability), intermediate precision, limit of detection, and limit of quantification parameters were investigated. The correlation coefficient was found to be greater than 0.99 for both analytes. The recoveriess were determined as 95.8% for BCA and 97.4% for gammaGBCA. The relative expanded measurement uncertainties of beta-cyanoalanine and gamma glutamyl-beta-cyanoalanine were obtained as 4.6% and 5.8%, respectively with the coverage factor, k, is 2 and at 95% confidence level. PMID- 27979193 TI - Effects of oligomeric procyanidins on the retrogradation properties of maize starch with different amylose/amylopectin ratios. AB - The effect of oligomeric procyanidins (OPCs) on the retrogradation of maize starch with different amylose/amylopectin ratios was investigated. The apparent amylose contents in high-amylose maize (HAM), normal maize (NM), and amylopectin maize (APM) starches are 79.05%, 25.43% and 0%. Structural characterizations of retrograded maize starches in the presence of OPCs were conducted by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and nuclear magnetic resonance (NMR). The results suggest that OPCs inhibit the retrogradation of maize starches in low concentrations (1.5 2.5%) with different inhibitory effects for HAM, NM and APM starches. It may be attributed to the variations on interaction ways and binding capabilities between different types of starches and OPCs. The in vitro enzymatic digestion result indicates HAM starch and OPCs have stronger interactions with the formation of resistant structures. These findings provide a further evidence for exploring the interactions between starches and phenolic compounds. PMID- 27979194 TI - A strategy for the evaluation of an analytical approach for selected pesticide residues in complex agricultural product matrices-A case study of leek. AB - In order to choose a sensitive, selective, simple, rapid, cost-effective and reliable analytical method for a given complex sample, a strategy was proposed for the evaluation of an analytical approach to determining multi-pesticide residue in complex agricultural product matrices, using leek as an example. In this work, the matrix effect of most of pesticides were in the range of -50% to 90%. A simple thin layer chromatography (TLC) was used to evaluate the effect of cleanup. The results agree well with that of matrix effect described above. More than 91% of the investigated compounds achieved recoveries were in the range of 70-120%. The limits of detection and limits of quantification were in the range of 0.1-3.5ng/g and 0.4-11.5ng/g, respectively. The strategy can be used to analyze multi-pesticide residue or related chemicals in diverse agricultural product matrices to provide technical guidance in choosing an analytical approach. PMID- 27979195 TI - Untargeted metabolomic analysis of human serum samples associated with different levels of red meat consumption: A possible indicator of type 2 diabetes? AB - Red meat consumption has been associated with negative health effects. A study to identify biomarkers of meat consumption was undertaken using serum samples collected from combining high resolution mass spectrometry (UPLC-QTof-MS) and chemometrics. Using orthogonal partial last-squares discriminant analysis (OPLS DA), multivariate models were created for both modes of acquisition (ESI-/ESI+) and red meat intake classes (YES/NO). In the serum samples, a total 3280 and 3225 ions of interest were detected in positive and negative modes, respectively. Of these, 62 were found to be significantly different (p<0.05) between the two groups. Glycerophospholipids as well as other family lipids, such as lysophospholipids or sphingomyelin, were found significantly (p<0.05) different between yes and no red meat intake groups. This study has shown metabolomics fingerprints have the capability to identify potential biomarkers of red meat consumption, as well as possible health risk factors (e.g., key metabolic families related to the risk of development type 2 diabetes). PMID- 27979196 TI - B-vitamins, carotenoids and alpha-/gamma-tocopherol in raw and roasted nuts. AB - The concentrations of B-vitamins, carotenoids and tocopherols in nuts may differ between species and might be influenced by roasting. Thiamine, riboflavin, pyridoxine, lutein, zeaxanthin, beta-carotene and alpha-/gamma-tocopherol were determined in different varieties of raw and roasted nuts using HPLC (fluorescence/UV-vis detection). The analysis revealed remarkable concentrations of thiamine and pyridoxine in pistachios (57%, 79% of the recommended daily intake/100g (RDI), respectively) and riboflavin in almonds (119% of the RDI). Pistachios were rich in lutein/zeaxanthin and contained highest beta-carotene levels among nuts. Almonds and hazelnuts were abundant in alpha-tocopherol (>4 fold the RDI for tocopherol equivalents) while pistachios and walnuts were rich in gamma-tocopherol. Roasting had a diminishing effect on thiamine, carotenoids and tocopherols especially in almonds and walnuts. Nuts could make a valuable contribution to a healthy diet in regard to B-vitamins, lutein/zeaxanthin and tocopherols. A reduction in micronutrient content by roasting is reliant on the nut variety and specific micronutrient. PMID- 27979197 TI - Potential health benefits and quality of dried fruits: Goji fruits, cranberries and raisins. AB - Dried fruits are important snacks and additives to other foods due to their taste and nutritional advantages. Therefore there is an important goal to control the quality of the food on the market for consumer's safety. Antioxidant activity of goji fruits (Lycium barbarum), cranberries (Vaccinium macrocarpon and oxycoccus) and raisins (Vitis vinifera) were studied using the DPPH (2,2-diphenyl-1 picrylhydrazyl) and Folin-Ciocalteu assays. Cu, Mn and Ge influencing antioxidant activity were determined together with selected toxic metals (Cd, Ni and Pb). Contamination with fungi was studied by quantification of their marker - ergosterol and important mycotoxins (aflatoxins B1, B2, G1 and G2, and ochratoxin A) were also determined. Antioxidant activity of all tested dried fruits was confirmed with goji fruits being the most profitable for consumers. Contamination of the tested fruits with toxic metals and mycotoxins was low. PMID- 27979198 TI - Phytanic acid consumption and human health, risks, benefits and future trends: A review. AB - Phytanic acid is a methyl-branched fatty acid present in the human diet, derived from the enzymatic degradation of phytol and subsequently oxidized by the rumenal microbiota and certain marine organisms. Consequently, phytanic acid is carried into the human body by means of food ingestion, mostly via red meat, dairy products and fatty marine foods. This fatty acid accumulates in people with some peroxisomal disorders and is traditionally related to neurological damage. However, some benefits derived from phytanic acid intake have also been described, such as the prevention of metabolic syndrome or type 2 diabetes. The aim of this work was to conduct an overview of the literature on the phytanic acid content of foods, management of the phytanic content during food production and biochemical mechanisms of phytanic acid metabolism, as well as to assess the evidence for the health benefits and risks of phytanic acid consumption in human health. PMID- 27979199 TI - Rare earth elements in parasol mushroom Macrolepiota procera. AB - This study aimed to investigate occurrence and distribution of 16 rare earth elements (REEs) in edible saprobic mushroom Macrolepiota procera, and to estimate possible intake and risk to human consumer. Mushrooms samples were collected from sixteen geographically diverse sites in the northern regions of Poland. The results showed that for Ce as the most abundant among the RREs in edible caps, the mean concentration was at 0.18+/-0.29mgkg-1dry biomass. The mean concentration for Sigma16 REEs determined in caps of fungus was 0.50mgkg-1dry biomass and in whole fruiting bodies was 0.75mgkg-1dry biomass. From a point of view by consumer, the amounts of REEs contained in edible caps of M. procera could be considered small. Hence, eating a tasty caps of this fungus would not result in a health risk for consumer because of exposure to the REEs. PMID- 27979200 TI - Phytoglycogen improves the water solubility and Caco-2 monolayer permeation of quercetin. AB - The study examined the capability of phytoglycogen (PG) to improve the water solubility of quercetin (QC). PG-QC formulations were prepared by mixing a QC ethanol solution with a PG aqueous solution followed with vacuum drying of the supernatant. PG-QC formulations with various PG to QC ratios were prepared; the solubility of QC reached 241.76MUg/mL at PG/QC ratio of 30/1 compared with approximately 4.32MUg/mL of QC alone. The X-ray powder diffraction and FTIR analyses showed a significant reduction of QC crystallinity upon formulating with PG that was associated with the intermolecular hydrogen bonding between the hydroxyl groups of QC and PG. The Caco-2 cell monolayer permeation tests showed that PG-QC formulations resulted in substantially enhanced cellular uptake and transepithelial permeation of QC, which was related to the much-enhanced QC solubility. This study showed the potential of using PG to formulate poorly water soluble ingredients such as QC. PMID- 27979201 TI - Foam mat drying of Tommy Atkins mango: Effects of air temperature and concentrations of soy lecithin and carboxymethylcellulose on phenolic composition, mangiferin, and antioxidant capacity. AB - In this study, foam mat drying was applied to Tommy Atkins mango. Using a multifactorial design, the effect of soy lecithin (L) and carboxymethylcellulose (CMC) used as foam stabilizers (0-1.50g/100g), as well as temperature (T) (53-87 degrees C), on phenolic content and antioxidant capacity of mango were evaluated. Mango pulp contains antioxidant, such as mangiferin, that can be utilized in foods to enhance their functional properties. Our results indicated that L and T had negative effects (p<0.05) on the phenolic content and antioxidant capacity, whereas CMC had a positive effect (p<0.05). Increasing the total amount of phenolic compounds present in dried mango contributed to the higher antioxidant capacity after the drying process. This study concluded that a drying T of 80 degrees C, and a concentration of 0.30g/100g of CMC and L are optimal for increased retention of phenolic compounds and antioxidant capacity. PMID- 27979202 TI - The graphene oxide and chitosan biopolymer loads TiO2 for antibacterial and preservative research. AB - Microorganism breeding is a known cause of food spoilage and disease transmission. Aspergillus niger (A. niger) and Bacillus subtilis (B. subtilis) are examples of microorganisms that cause deterioration of fresh fruits and vegetables during storage, which can be a serious threat to human health. In this work, we synthesized a self-assembled film of graphene oxide (GO) and chitosan (CS) biopolymers with titanium dioxide (TiO2) nanoparticles embedded in its surface. We then characterized its antibacterial and preservative properties. We found that these non-cytotoxic nanometer-scale films, especially when the ratio of graphene oxide, chitosan and titanium dioxide nanoparticles in the nanocomposites is 1:20:4, exhibited high antibacterial activity against the biofilm-forming strains A. niger and B. subtilis. The preservation capacity of the nanocomposites was evaluated by enzymatic experiments. The nanocomposites did not show any cytotoxicity against mammalian somatic cells and plant cells. Altogether, this work demonstrated that the nanocomposites disrupted microbial film formation while avoiding internalization by animal and plant cells. Due to their selectivity and safety, these nanocomposites demonstrate potential as antimicrobial coatings for food preservation. PMID- 27979203 TI - Different effectiveness of two pastas supplemented with either lipophilic or hydrophilic/phenolic antioxidants in affecting serum as evaluated by the novel Antioxidant/Oxidant Balance approach. AB - Effectiveness in improving serum antioxidant status of two functional pastas was evaluated by the novel Antioxidant/Oxidant Balance (AOB) parameter, calculated as Antioxidant Capacity (AC)/Peroxide Level ratio, assessed here for the first time. In particular, Bran Oleoresin (BO) and Bran Water (BW) pastas, enriched respectively with either lipophilic (tocochromanols, carotenoids) or hydrophilic/phenolic antioxidants extracted from durum wheat bran, were studied. Notably, BO pasta was able to improve significantly (+65%) serum AOB during four hours after intake similarly to Lisosan G, a wheat antioxidant-rich dietary supplement. Contrarily, BW pasta had oxidative effect on serum so as conventional pasta and glucose, thus suggesting greater effectiveness of lipophilic than hydrophilic/phenolic antioxidants under our experimental conditions. Interestingly, no clear differences between the two pastas were observed, when AC measurements of either serum after pasta intake or pasta extracts by in vitro assays were considered, thus strengthening effectiveness and reliability of AOB approach. PMID- 27979204 TI - Production of stable food-grade microencapsulated astaxanthin by vibrating nozzle technology. AB - Astaxanthin is a carotenoid known for its strong antioxidant and health-promoting characteristics, but it is also highly degradable and thus unsuited for several applications. We developed a sustainable method for the extraction and the production of stable astaxanthin microencapsulates. Nearly 2% astaxanthin was extracted by high-pressure homogenization of dried Haematococcus pluvialis cells in soybean oil. Astaxanthin-enriched oil was encapsulated in alginate and low methoxyl pectin by Ca2+-mediated vibrating-nozzle extrusion technology. The 3% pectin microbeads resulted the best compromise between sphericity and oil retention upon drying. We monitored the stability of these astaxanthin beads under four different conditions of light, temperature and oxygen exposition. After 52weeks, the microbeads showed a total-astaxanthin retention of 94.1+/-4.1% (+4 degrees C/-light/+O2), 83.1+/-3.2% (RT/-light/-O2), 38.3+/-2.2% (RT/ light/+O2), and 57.0+/-0.4% (RT/+light/+O2), with different degradation kinetics. Refrigeration, therefore, resulted the optimal storage condition to preserve astaxanthin stability. PMID- 27979205 TI - Characterization, classification and authentication of fruit-based extracts by means of HPLC-UV chromatographic fingerprints, polyphenolic profiles and chemometric methods. AB - HPLC-UV was applied to the analysis and characterization of fruit-based and fruit processed products. A Kinetex C18 reversed-phase column was proposed under gradient elution for the determination of 17 polyphenols. Acceptable sensitivity (LODs below 0.16mg/L), and good linearity (r2 higher than 0.995), precision (RSD below 6.8%), and method trueness (relative errors below 11%) were obtained. Data corresponding to polyphenolic peak areas and HPLC-UV chromatographic fingerprints were then analyzed by exploratory principal component analysis (PCA) to extract information of the most significant variables contributing to characterization and classification of analyzed samples regarding the fruit of origin. HPLC-UV chromatographic data was further treated by partial least square (PLS) regression to determine the percentages of adulteration in cranberry-fruit extracts. It was found that even mixture samples containing low percentages of adulterants could be distinguished from genuine cranberry extracts. Highly satisfactory results were obtained, with overall errors in the quantification of adulterations below 4.3%. PMID- 27979206 TI - Identification of a cyclodextrin inclusion complex of antimicrobial peptide CM4 and its antimicrobial activity. AB - Antibacterial peptide CM4 (ABP-CM4) is a natural product isolated from the silkworm Bombyx mori. It is a small cationic peptide with broad-spectrum activities against harmful microorganisms and may be used as a novel food preservative. However, ABP-CM4 lacks tertiary structure in water-like solutions, which makes it more susceptible to proteases and labile when exposed to air. In this study, beta-cyclodextrin (beta-CD) was chosen to form an inclusion complex with ABP-CM4, which enhanced the physical and chemical properties of ABP-CM4 but did not decrease its antibacterial activity. The storage stability and susceptibility to proteinases of ABP-CM4 were apparently improved under the protection of beta-CD. This technology could also be widely applied to other AMPs as an antimicrobial system to be used in the food industry. PMID- 27979207 TI - Chemical composition and physicochemical properties of tropical red seaweed, Gracilaria changii. AB - A study on the proximate composition, minerals, vitamins, carotenoids, amino acids, fatty acids profiles and some physicochemical properties of freeze dried Gracilaria changii was conducted. It was discovered that this seaweed was high in dietary fibre (64.74+/-0.82%), low in fat (0.30+/-0.02%) and Na/K ratio (0.12+/ 0.02). The total amino acid content was 91.90+/-7.70% mainly essential amino acids (55.87+/-2.15mgg-1) which were comparable to FAO/WHO requirements. The fatty acid profiles were dominated by the polyunsaturated fatty acids particularly docosahexaenoic (48.36+/-6.76%) which led to low omega6/omega3, atherogenic, and thrombogenic index. The physicochemical properties of this seaweed namely the water holding and the swelling capacity were comparable to some commercial fibre rich products. This study suggested that G. changii could be potentially used as ingredients to improve nutritive value and texture of functional foods for human consumption. PMID- 27979208 TI - Prediction of Chinese green tea ranking by metabolite profiling using ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). AB - Metabolomics profiling provides comprehensive picture of the chemical composition in teas therefore may be used to assess tea quality objectively and reliably. In the present experiment, water and methanol extracts of green teas from China were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) with the objectives to establish a model for quality prediction and to identify potential marker metabolites. The blindly evaluated sensory score of green teas was predicted with excellent power (R2=0.87 and Q2=0.82) and accuracy (RMSEP=1.36) by a partial least-squares (PLS) regression model based on water extract. By contrast, methanol extract failed to reasonably predict the sensory scores. The levels in water extract of neotheaflavin, neotheaflavin 3-O-gallate, trigalloyl-beta-d-glucopyranose, myricetin 3,3'-digalactoside, catechin-(4alpha->8)-epigallocatechin and kaempferol were significantly larger whereas those of theogallin and gallocatechin were less in the low (score<87) than in the high score (?90) group. PMID- 27979210 TI - Mashing with unmalted sorghum using a novel low temperature enzyme system: Impacts of sorghum grain composition and microstructure. AB - Brewing lager beers from unmalted sorghum traditionally requires the use of high temperature mashing and exogenous enzymes to ensure adequate starch conversion. Here, a novel low-temperature mashing system is compared to a more traditional mash in terms of the wort quality produced (laboratory scale) from five unmalted sorghums (2 brewing and 3 non-brewing varieties). The low temperature mash generated worts of comparable quality to those resulting from a traditional energy intensive mash protocol. Furthermore, its performance was less dependant on sorghum raw material quality, such that it may facilitate the use of what were previously considered non-brewing varieties. Whilst brewing sorghums were of lower protein content, protein per se did not correlate with mashing performance. Rather, it was the way in which protein was structured (particularly the strength of protein-starch interactions) which most influenced brewing performance. RVA profile was the easiest way of identifying this characteristic as potentially problematic. PMID- 27979209 TI - Synthesis and characterization of nontoxic chitosan-coated Fe3O4 particles for patulin adsorption in a juice-pH simulation aqueous. AB - Chitosan-coated Fe3O4 particles were prepared as a magnetic adsorbent by reverse oil-in-water micro-emulsion system using Triton X-100 as the emulsifier. Coating chitosan onto the magnetic particles was confirmed by transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectra and magnetic measurements. Chitosan-coated Fe3O4 adsorbent was shown to be effective for patulin adsorption with a maximum adsorption capacity of 6.67mg/g within 5h by adding 300MUg adsorbents into 10mL 200MUg/L patulin aqueous. In addition, the recovery rate of chitosan-coated Fe3O4 adsorbent reached to 99.95% within 60min, showed its excellent recoverable performance. Moreover, in vitro cytotoxicity and acute toxicity evaluation were also conducted, the results suggested that the chitosan-coated Fe3O4 adsorbent was non-cytotoxic, and had no toxic response or histopathological changes on mice. The results of this study demonstrated that chitosan-coated Fe3O4 particles are promising adsorbents for patulin removal in fruit juice industry. PMID- 27979211 TI - Peanut protein extraction conditions strongly influence yield of allergens Ara h 1 and 2 and sensitivity of immunoassays. AB - The clinical importance of peanut (Arachis hypogaea) allergies demands standardized allergen extraction protocols. We determined the effectiveness of common extraction conditions (20 buffers, defatting reagents, extraction time/temperatures, processing, extraction repeats) on crude protein and Ara h 1 and 2 yields. Despite similar 1D-gel profiles, defatting with n-hexane resulted in significantly higher yields of crude protein, Ara h 1, and Ara h 2 than with diethyl ether. The yields were affected by the composition and pH of the extraction buffers and other conditions, but crude protein yield did not always correlate with Ara h 1 and 2 yields. Denaturants, reducing agents, acidic buffers, and thermal processing of peanuts perturbed allergen quantification in ELISAs, probably via exposure of additional epitopes. Allergen detection in 2D Western blots with PBS resulted in greater sensitivity than with TBS or Tris. We recommend that allergen extraction conditions be selected based on the research question being investigated. PMID- 27979212 TI - Static headspace analysis of odorants in commercial rice proteins. AB - Accurate identification of the odor-contributing compounds in aqueous slurries of rice proteins is necessary to improve their overall flavor characteristics. The objective of this study was to identify the primary odorants in rice protein slurries using static headspace analysis. Five commercial rice protein (RP) products, RP-G, RP-O, RP-RM, RP-RS1, and RP-RS2, were analyzed. RP-G contained the lowest levels of most of the odorants. Acetaldehyde was present in the highest amount in RP-O (0.434mg/m3). RP-RM had the highest levels of hexanal (5.907mg/m3), methanethiol (0.138mg/m3), pentanal (1.575mg/m3), and 2-pentylfuran (5.702mg/m3). Corresponding odor values were, 111, 86, 22 and 21, respectively. In RP-RS1 and RP-RS2, the predominant odorants were dimethyl disulfide, dimethyl trisulfide, and hexanal. The results showed the importance of the volatile compounds produced from amino acids, including the sulfur-containing compounds and acetaldehyde, as well as lipid oxidation derived odorants to the overall odor of rice proteins. PMID- 27979213 TI - A hybrid sorption - Spectrometric method for determination of synthetic anionic dyes in foodstuffs. AB - A sorption-spectrometric method for determination of the anionic synthetic dyes based on their sorption on silica sorbent modified with hexadecyl groups (C16) followed by measuring the diffuse reflectance spectra on the surface of the sorbent has been proposed. Adsorption of sulfonated azo dyes Tartrazine (E102), Sunset Yellow FCF (E110), Ponceau 4R (E124) reaches maximum in acidic medium (1M HCl - pH 1). For the quinophthalone type dye Quinoline Yellow (E104), the adsorption is also maximal in an acidic medium (1M HCl - pH 2). The triphenylmethane dye Fast Green FCF (E143) is absorbed in the wider area of pH (1M HCl - pH 6). Increasing concentration of the dyes in a solution led to the increase in absorption band intensity in diffuse reflectance spectra of the adsorbent, which was used for their direct determination. The proposed method was applied to the determination of dyes in beverages and pharmaceuticals. PMID- 27979214 TI - Differential responses of four biosynthetic pathways of aroma compounds in postharvest strawberry (Fragaria*ananassa Duch.) under interaction of light and temperature. AB - Light and temperature are two of the most important factors regulating postharvest strawberry aroma. To date the majority of research has been concentrated on the contribution of either light or temperature factors in isolation. In the present study, we investigated integrated effects of light and temperature on the formation of characteristic aromas during postharvest strawberry ripening process. Most volatiles including volatile esters, volatile furanones, and volatile terpenes showed increasing trends, whereas volatile benzenoids showed decreasing trends during postharvest ripening. Biosyntheses of volatile esters and volatile benzenoids were mainly affected by interaction of temperature and dark, whereas formation of volatile furanones and volatile terpenes were mostly influenced by temperature and dark, respectively. This study provided evidence of regulation of strawberry aroma by dual factors for the first time, and characterized a comprehensive profile of formations of strawberry aromas in response to light and temperature during postharvest ripening. PMID- 27979215 TI - Sun dried Corinthian currant (Vitis Vinifera L., var. Apyrena) simple sugar profile and macronutrient characterization. AB - Corinthian currant simple sugar profile was determined by high-pressure liquid chromatography coupled with refractive index detection; the content in other macroconstituents was also assessed. Corinthian currants analyzed were obtained over three consecutive crop years, while the effect of cultivation area altitude was also evaluated. Sugar extraction was optimized with respect to solvent, process, and time. Simple sugar chromatographic analysis was validated for linearity (R2>0.999), limits of detection (6.23-186.66mg/L) and quantification (18.89-565.65mg/L), precision (%RSD<2.67), and recovery (97.99-101.99%). Fructose, glucose, sucrose, maltose, and total sugar content was 32+/-1%, 32.5+/ 0.6%, 0.40+/-0.04%, 0.72+/-0.07% and 66+/-2%, respectively; moisture, ash, fat, and protein content was 13.8+/-0.5%, 2.6+/-0.7%, 0.43+/-0.06%, and 2.2+/-0.4%, respectively. Relatively small variations in sugar and other macroconstituent content were detected over the consecutive crops. Cultivation area altitude affected Corinthian currant sugar, fat, and protein content, yet with no remarkable differences. PMID- 27979216 TI - Effect of calcium-binding peptide from Pacific cod (Gadus macrocephalus) bone on calcium bioavailability in rats. AB - Bone collagen peptide with high affinity to Ca was extracted from Pacific cod (Gadus macrocephalus) bone. FTIR spectra of calcium-binding bone collagen peptide showed that band at 3381cm-1 shifted to 3361cm-1, 1455cm-1 moved to 1411cm-1, and amide II became deeper valley, compared with that of bone collagen peptide. This peptide was sequenced by Q-TOF-MS and sequences of Gly-Pro-Glu-Gly, Gly-Glu-Lys, Gly-Pro-Leu-Gly and Gly-Leu-Pro-Gly appeared repeatedly in some peptides. From SEM, after chelated with calcium, the loose and porous structure turned into granular structure. From the animal experiment, Ca apparent absorption rate, Ca retention rate and femur Ca content of calcium-binding bone collagen peptide group were significantly higher than those of model and CaCO3 groups (P<0.05), while serum ALP was significantly lower than model group (P<0.05) and similar to control group. The results suggested that calcium-binding bone collagen peptide could improve bioavailability of Ca and thus prevented Ca deficiency. PMID- 27979217 TI - Electronic nose guided determination of frying disposal time of sunflower oil using fuzzy logic analysis. AB - An electronic nose (e-nose), having 18 metal oxide semiconductor (MOS) sensors, guided determination of frying disposal time of sunflower oil is reported. The ranking and screening of MOS sensors, specific for volatile organic compounds, was performed using fuzzy logic. A correlation was examined between rancidity indices of fried oil (total polar compounds (TPC), and triglyceride dimers polymers (TGDP), among others) and e-nose based odor index. Fuzzy logic screened 6 MOS sensors (LY2/G, LY2/AA, LY2/GH, LY2/gCT1, T30/1, and P30/1) to deconvolute the rancid fried oils using hierarchical clustering on principal component space. A good relationship was noted between rancidity indices and odor index (R2>0.85). Based on maximum discard limits of rancidity indices (25% TPC and 10% TGDP), the frying disposal time of 15.2h (TPC) vs. 15.8h (e-nose) and 15.5h (TGDP) vs. 16.3h (e-nose) was determined. The demonstrated methodology holds a potential extension to different fried oils and products. PMID- 27979218 TI - Composition of Quillaja saponin extract affects lipid oxidation in oil-in-water emulsions. AB - Quillaja saponin extract comprises both, surfactants and phenolic compounds, which makes it interesting, in particular, for the formulation of sensitive functional food ingredients and its protection against oxidation. The aim of this study was to investigate the antioxidant effect of Quillaja saponin extract in oil/water emulsions. Emulsions stabilised by Quillaja saponin showed decreased oxidation stability due to naturally occurring metals but stability increased to a great extent when a chelating agent was added. Antioxidant efficiency of the saponin extract was determined photometrically by 2,2'-diphenyl-1-picrylhydrazyl (DPPH) assay and by the use of electron paramagnetic resonance spectroscopy (EPR). EPR spectroscopy applying stable hydrophilic and hydrophobic radicals is advantageous, especially for characterisation of antioxidant efficiency at the interface. The extract showed antioxidant activity towards radicals in both environments, aqueous and hydrophobic, indicating the importance of phenolic compounds for the antioxidant properties of Quillaja saponin extract and their presence at the interface facilitated by saponin molecules. PMID- 27979219 TI - Correlation of the immunostimulatory activities of honeys with their contents of identified bioactives. AB - Honeys with unique compositions and properties are worth studying for their health-promoting effects. In order to correlate bioactive content with immunostimulatory activity we compared the abilities of seventy eight New Zealand and non-New Zealand honeys to stimulate blood monocytes to release tumour necrosis factor (TNF)-alpha, and examined the compositions of selected honeys that had widely varying activities. All the honeys, except for a Malaysian "Amber honey" stimulated the release of TNF-alpha from monocytes. However, the honeys differed greatly in their immunostimulatory activity, even within the same honey type. They differed in their contents of immunostimulatory components, including apalbumins, arabinogalactan proteins, and apisimin, whose levels did not correlate exactly with immunostimulatory activities. We suggest that the immunostimulatory properties of honey may be influenced by other factors, including unidentified immunostimulatory bioactives and immunosuppressive components; the bioavailability of some bioactives may depend on unidentified factors. PMID- 27979220 TI - Controlling the potential gastrointestinal fate of beta-carotene emulsions using interfacial engineering: Impact of coating lipid droplets with polyphenol-protein carbohydrate conjugate. AB - The impact of interfacial coatings comprised of polyphenol-protein-carbohydrate conjugates on the properties of nutraceutical-fortified lipid droplets during digestion was investigated. Surface-active chlorogenic acid-lactoferrin polydextrose (CA-LF-PD) conjugate was synthesized as emulsifier to stabilize lipid droplets in beta-carotene-enriched oil-in-water emulsions. Changes in droplet size, charge, and microstructure were monitored as beta-carotene emulsions were passed through a simulated gastrointestinal tract model (mouth, stomach, small intestine). LF-coated droplets were unstable to flocculation at pH 8.0-9.0, due to the reduction in electrostatic repulsion, but CA-LF-PD conjugate coated droplets were stable. Emulsions stabilized by ternary conjugate had better stability to droplet aggregation under simulated GIT conditions than other systems, which increased beta-carotene bioaccessibility. The importance of including an oral phase in the simulated GIT model was also demonstrated. The ternary conjugate-stabilized emulsions developed in this study have potential applications as protectors and carriers of hydrophobic drugs, supplements and nutraceuticals. PMID- 27979221 TI - Inhibitory profiles of chilli pepper and capsaicin on heterocyclic amine formation in roast beef patties. AB - The inhibitory profiles of chilli pepper and capsaicin, as well as their relationship to the formation of heterocyclic amines (HAs) in roast beef patties were investigated using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) combined with principal component analysis (PCA). HAs including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-1,6 dimethylimidazo[4,5-b]pyridine (DMIP), 2-amino-1,5,6-trimethylimidazo[4,5 b]pyridine (1,5,6-TMIP), 2-amino-3-methyl-3H-imidazo[4,5-f]quinoxaline (IQx), 2 amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethyl-3H imidazo[4,5-f]quinoxaline (4,8-DiMeIQx), 1-methyl-9H-pyrido[3,4-b]indole (harman) and 9H-pyrido[3,4-b]indole (norharman) were detected and quantified in beef patties. Different levels of chilli pepper and capsaicin had different inhibitory profiles on HA formation, but had no significant (P>0.05) effect on the texture of the patties. Furthermore, all levels of chilli pepper and capsaicin reduced total HA and PhIP concentrations dose-dependently, with the highest inhibitions of 80% and 98% at 2mg of capsaicin. Moreover, capsaicin inhibited all HAs more than chilli pepper, implying that ingredients other than capsaicin in chilli pepper may promote the formation of HAs. These results could be useful for the reduction of HA, during food processing procedures, by spices. PMID- 27979222 TI - Effects of sulfur dioxide concentration on organic acids and beta-carotene in dried apricots during storage. AB - The effects of various sulfur dioxide (SO2) concentrations (0, 451, 832, 1594, 2112 and 3241mg/kg) on the profiles and contents of organic acids (OAs) and beta carotene in sulfured dried apricots (SDAs) were investigated during storage at 4, 20 and 30 degrees C for 379days. In all samples, four OAs [malic acid (MA), citric acid (CA), succinic acid (SA) and oxalic acid (OXA)] were identified. SA (13.9-31.8g/kgdw) was the major OA in SDAs containing SO2 at lower than 1594mgSO2/kg, while MA (11.7-11.7g/kgdw) was the major OA in SDAs containing SO2 at higher than 1594mgSO2/kg. As SO2 concentration increased, CA and OXA contents increased whereas MA contents decreased. Moreover, the highest stabilities of beta-carotene, MA and SO2 were determined in SDAs containing 1594mgSO2/kg at 4 degrees C. Therefore, we suggest using 1594mgSO2/kg and storing SDAs at 4 degrees C to protect OAs and beta-carotene. PMID- 27979223 TI - Effect of processing technologies and storage conditions on stability of black currant juices with special focus on phenolic compounds and sensory properties. AB - Juice was pressed from black currants without enzyme treatment (NEB=Non-Enzymatic Berry) followed by re-pressing of the residue with enzymes (EPR=Enzymatic Press Residue) and the results were compared to the conventional enzyme-aided berry pressing (EB=Enzymatic Berry). EPR-juice had 9- and 5-fold higher contents of phenolic compounds compared with the NEB- and EB-juices, respectively. Effect of the low content and stability of phenolics was noticed as loss of the visual color in the NEB-juice during storage. The decrease in monomeric anthocyanins and the increase in phenolic acids were most severe in the NEB-juice, whereas the most significant decline in hydroxycinnamic acid derivatives occurred in the enzyme-treated juices. Storage in light induced less change in the phenolic composition in EPR-juice than in the two other juices. The study gave new knowledge on changes in individual metabolites, in sensory properties and in the shelf life of berry juices. PMID- 27979224 TI - Influence of glycosylation of deamidated wheat gliadin on its interaction mechanism with resveratrol. AB - Gliadin is a main composition of wheat storage protein with unique characteristics. Polyphenol with health benefits tends to form complex with protein. In this study, glycosylation of deamidated wheat gliadin (gliadin) was carried out. Fluorescence quenching was applied to evaluate their binding mechanisms with resveratrol. Results showed that glycosylation could increase the solubility and decrease the surface hydrophobicity of gliadin. Both gliadin and glycosylated gliadin have strong affinity with resveratrol. The thermodynamic parameters of binding process indicated that complexation of resveratrol with gliadin was mainly driven by hydrophobic interaction, while by hydrogen bonds with glycosylated gliadin. The hydrosolubility of resveratrol was dramatically increased especially in the presence of glycosylated gliadin. This was consistent with the higher binding constant of glycosylated gliadin with resveratrol. Therefore, gliadin and glycosylated gliadin are both effective to carry resveratrol or other bioactive compounds, and their binding mechanisms are different due to structural difference. PMID- 27979225 TI - Simultaneous determination of main phenolic acids and flavonoids in tomato by micellar electrokinetic capillary electrophoresis. AB - A methodology for the determination of tomato phenolic acids and flavonoids has been developed combining MEKC and DAD detection. The influence on polyphenol separation of pH and background electrolyte, BGE (borax, acetonitrile, methanol and SDS concentrations), was studied and optimized using response surface methodology and weighted desirability function. Separation of polyphenols was achieved within 20min at 15 degrees C using 11.3mM borax and 11.2mM SDS adjusted to pH 8.5 as BGE. Validation was performed using standards and tomato extracts. Recoveries ranged from 77 to 106%. Acceptable repeatabilities were obtained for peak area (%RSD <3.1% and <3.7%) and migration times (%RSD <0.2% and <1.4%) for intra- and inter-day respectively. Detection limits ranged between 0.8 and 3.8mgkg-1. Five and seven of these polyphenols were determined in samples of tomato and related species. This methodology will be valuable tool in breeding programs, analyzing a large number of samples. PMID- 27979226 TI - Fractionation, enzyme inhibitory and cellular antioxidant activity of bioactives from purple sweet potato (Ipomoea batatas). AB - Sweet potato (Ipomoea batatas L.) is mainly cultivated in Asia. The deep purple color of purple sweet potato (PSP) is due to the high content of acylated anthocyanins. In the present study, PSP-derived polyphenols were identified using HPLC-PDA and HPLC-ESI-MSn analyses. After concentration of the polyphenols from PSP, preparative separation into two fractions, designated anthocyanins (AF) and copigments (CF), was carried out using adsorptive membrane chromatography. In enzyme inhibitory assays, all PSP samples inhibited the enzymes alpha-amylase, alpha-glucosidase and xanthine oxidase. Additionally, the cell signaling cellular antioxidant properties of the PSP extracts were investigated in cultured cells. PSP induced the transcription factor Nrf2, which regulates the expression of genes encoding heme oxygenase 1 (Hmox1), glutamate-cysteine ligase catalytic subunit (Gclc) and paraoxonase 1 (PON1). Furthermore, PSP enhanced cellular glutathione concentrations and decreased lipid peroxidation in cultured hepatocytes. Overall, these results suggest that PSP extracts exhibit enzyme inhibitory and cellular antioxidant properties, especially PSP CF. PMID- 27979227 TI - Phosphorus-doped helical carbon nanofibers as enhanced sensing platform for electrochemical detection of carbendazim. AB - A combined chemical vapor deposition with high-pressure annealing has been developed for the production of phosphorus-doped helical carbon nanofibers (P HCNFs). The resulting P-HCNFs have a large specific surface area, well-defined three-dimensional hierarchical helical structure and rapid apparent heterogeneous electron transfer. Based on the high electrocatalytic activity, the P-HCNFs were used to develop an amperometric sensor for carbendazim detection. The experimental results demonstrated that the sensor is promising for the determination of carbendazim in food samples due to the high sensitivity, wide linear range and low detection limit. PMID- 27979229 TI - Cloud point extraction and diffuse reflectance-Fourier transform infrared spectroscopic determination of chromium(VI): A probe to adulteration in food stuffs. AB - A new cloud point extraction (CPE) method for the determination of hexavalent chromium i.e. Cr(VI) in food samples is established with subsequent diffuse reflectance-Fourier transform infrared (DRS-FTIR) analysis. The method demonstrates enrichment of Cr(VI) after its complexation with 1,5 diphenylcarbazide. The reddish-violet complex formed showed lambdamax at 540nm. Micellar phase separation at cloud point temperature of non-ionic surfactant, Triton X-100 occurred and complex was entrapped in surfactant and analyzed using DRS-FTIR. Under optimized conditions, the limit of detection (LOD) and quantification (LOQ) were 1.22 and 4.02MUgmL-1, respectively. Excellent linearity with correlation coefficient value of 0.94 was found for the concentration range of 1-100MUgmL-1. At 10MUgmL-1 the standard deviation for 7 replicate measurements was found to be 0.11MUgmL-1. The method was successfully applied to commercially marketed food stuffs, and good recoveries (81-112%) were obtained by spiking the real samples. PMID- 27979228 TI - Identification, functional gastrointestinal stability and molecular docking studies of lentil peptides with dual antioxidant and angiotensin I converting enzyme inhibitory activities. AB - The objective was to identify peptides with dual antioxidant and angiotensin I converting enzyme (ACE) inhibitory activities released from lentil proteins by Savinase(r). The influence of gastrointestinal digestion on peptide bioactivity was also assayed. Fragments from vicilin, convicilin and legumin were the most abundant peptides identified. Peptides LLSGTQNQPSFLSGF, NSLTLPILRYL, TLEPNSVFLPVLLH showed the highest antioxidant (0.013-1.432MUmol Trolox eq./MUmol peptide) and ACE inhibitory activities (IC50=44-120MUM). Gastrointestinal digestion of peptides improved their dual activity (10-14MUmol Trolox eq./MUmol peptide; IC50=11-21MUM). In general, C-terminal heptapeptide was crucial for their dual activity. ACE inhibition relies on the formation of hydrogen bonds between C-terminal residues of lentil peptides and residues of the ACE catalytic site. The present study helps clarifying the relationship between structure and dual antioxidant/antihypertensive activity of lentil peptides opening new opportunities to food industry such as the application of lentil protein hydrolysates as ingredients for development of functional foods. PMID- 27979230 TI - Polar constituents, protection against reactive oxygen species, and nutritional value of Chinese artichoke (Stachys affinis Bunge). AB - In the present work, we studied the chemical composition of Chinese artichoke (S. affinis tubers) by analyzing its polar constituents and its macro- and micro- nutrients. A total of nine compounds were isolated from the tuber ethanolic extract and structurally elucidated by Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry (MS). The marker compounds identified were oligosaccharide stachyose and the organic acid, succinic acid, as well as phenylethanoid and iridoid glycosides. The macronutrient profile was dominated by carbohydrates (36.9% dw), whereas potassium (2.36%) was the most abundant micro nutrient. The tuber ethanolic extract was able to efficiently protect human cells (Caco-2, SHSY-5Y and K562) against t-BHP-induced oxidative damage. PMID- 27979231 TI - Comparative study on the freeze stability of yeast and chemical leavened steamed bread dough. AB - The present study comparatively evaluated the evolution of yeast and chemical leavened steamed bread dough (YLD/CLD) quality during freeze/thaw (FT) cycles. The steamed bread quality of CLD was more freeze-stable than that of the YLD after 3 FT cycles. Decreased yeast viability contributed to the loss of gassing power in YLD while no significant differences were observed for CLD during FT cycles. However, faster gas release rate in frozen CLD indicated gas retention loss due to the distortion of gluten network. Glutenin macropolymers (GMP) depolymerization via breakage of inter-chain disulfide (SS) bonds and conversions of alpha-helix and beta-turn to beta-sheet structures were the main indicators of gluten deterioration. Gluten network was more vulnerable in frozen YLD, resulting in detectable loss of viscoelasticity. The results suggested that supplement of chemical leavener contributed to a more freeze-tolerant gluten network besides its stable gassing power. PMID- 27979232 TI - Influence of storage and heating on protein glycation levels of processed lactose free and regular bovine milk products. AB - Thermal treatment preserves the microbiological safety of milk, but also induces Maillard reactions modifying for example proteins. The purpose of this study was evaluating the influence of consumer behaviors (storage and heating) on protein glycation degrees in bovine milk products. Lactosylation and hexosylation sites were identified in ultra-high temperature (UHT), lactose-free pasteurized, and lactose-free UHT milk (ULF) and infant formula (IF) using tandem mass spectrometry (electron transfer dissociation). Overall, 303 lactosylated and 199 hexosylated peptides were identified corresponding to 170 lactosylation (31 proteins) and 117 hexosylation sites (25 proteins). In quantitative terms, storage increased lactosylation up to fourfold in UHT and IF and hexosylation up to elevenfold in ULF and threefold in IF. These levels increased additionally twofold when the stored samples were heated (40 degrees C). In conclusion, storage and heating appear to influence protein glycation levels in milk at similar or even higher degrees than industrial processing. PMID- 27979233 TI - Total phenolic contents, antioxidant activities, and bioactive ingredients of juices from pomegranate cultivars worldwide. AB - Numerous recent scientific publications investigating the health benefits of pomegranate juice have greatly increased consumer interest in this fruit. The primary cause of the positive health effect of pomegranate is the unique antioxidant activity of this fruit. As a result of the increased attention given to pomegranate, the number of countries producing pomegranate has increased and new cultivars are appearing. The purpose of this review is to quantitatively establish the antioxidant activities, the total phenolic contents which are highly correlated to antioxidant activities, and the other important ingredients of pomegranate juices obtained from cultivars of different regions. Pomegranate wine, vinegar, and sour sauce obtained directly from pomegranate juice are included in this review. Comparison of aril juices with peel and seed extracts is also given. This data could be useful to the pomegranate industry in identifying and developing cultivars having commercial value. PMID- 27979234 TI - Prebiotic potential of neutral oligo- and polysaccharides from seed mucilage of Hyptis suaveolens. AB - Prebiotics are selectively fermented by the gastrointestinal microflora, resulting in benefits to human health. The seed mucilage of Hyptis suaveolens contains neutral and acidic polysaccharides in a ratio of 1:1. The neutral polysaccharides consist of galactose, glucose and mannose whereas the acidic polysaccharides contain fucose, xylose and 4-O-methylglucuronic acid -residues. The growth of probiotics in the presence of total, acidic or neutral polysaccharides and oligosaccharides was tested using turbidity measurements. The majority (11 out of 14) of the tested probiotic strains significantly grew in the neutral fraction. Growth occurred with some time delay, but may be longer lasting than with other lower molecular prebiotics. The extent of growth increased with neutral polysaccharides from H. suaveolens corresponding to the externally available galactose units (20%). In conclusion, neutral poly- and oligosaccharides from H. suaveolens have a prebiotic potential characterized by a delayed but long lasting effect. PMID- 27979235 TI - Polydiacetylene sensor interaction with food sanitizers and surfactants. AB - Polydiacetylene (PDA) vesicles are of interest as biosensors, particularly for pathogenic bacteria. As part of a food monitoring system, interaction with food sanitizers/surfactants was investigated. PDA vesicles were prepared by inkjet printing, photopolymerized and characterized by dynamic light scattering (DLS) and UV/Vis spectroscopy. The optical response of PDA vesicles at various concentrations verses a fixed sanitizer/surfactant concentration was determined using a two variable factorial design. Sanitizer/surfactant response at various concentrations over time was also measured. Results indicated that only Vigilquat and TritonX-100 interacted with PDA vesicles giving visible colour change out of 8 sanitizers/surfactants tested. PDA vesicle concentration, sanitizer/surfactant concentration, and time all had a significant (P<0.0001) effect on colour change. As they are highly sensitive to the presence of Vigilquat and TritonX-100, PDA sensors could be used to detect chemical residues as well as for detection of various contaminants in the food industry. PMID- 27979236 TI - Changes in rocket salad phytochemicals within the commercial supply chain: Glucosinolates, isothiocyanates, amino acids and bacterial load increase significantly after processing. AB - Five cultivars of Eruca sativa and a commercial variety of Diplotaxis tenuifolia were grown in the UK (summer) and subjected to commercial growth, harvesting and processing, with subsequent shelf life storage. Glucosinolates (GSL), isothiocyanates (ITC), amino acids (AA), free sugars, and bacterial loads were analysed throughout the supply chain to determine the effects on phytochemical compositions. Bacterial load of leaves increased significantly over time and peaked during shelf life storage. Significant correlations were observed with GSL and AA concentrations, suggesting a previously unknown relationship between plants and endemic leaf bacteria. GSLs, ITCs and AAs increased significantly after processing and during shelf life. The supply chain did not significantly affect glucoraphanin concentrations, and its ITC sulforaphane significantly increased during shelf life in E. sativa cultivars. We hypothesise that commercial processing may increase the nutritional value of the crop, and have added health benefits for the consumer. PMID- 27979237 TI - Densitometric TLC analysis for the control of tropane and steroidal alkaloids in Lycium barbarum. AB - Thin layer chromatographic methods for quantitative determination of nightshade specific tropane (l-hyoscyamine, scopolamine) and steroidal alkaloids (alpha solanine, alpha-chaconine) in goji berries (L. barbarum L., Solanaceae) were developed. The analysis of tropane derivatives included separation on silica gel coated HPTLC plates using mobile phase consisted of chloroform:methanol:acetone:25% ammonium hydroxide (75:15:10:1.6 v/v/v/v), derivatization with Dragendorff reagent and scanning densitometry at lambda - 520nm in reflectance/absorption mode. Steroidal alkaloid analysis employed silica gel-coated TLC plates, mobile phase composed of chloroform:methanol:water:25% ammonium hydroxide (70:30:4:2 v/v/v/v), derivatization with Carr-Price reagent and video densitometry under white light in the reflectance mode. Both methods were validated with respect to linearity, precision, accuracy and sensitivity, enabling reliable detection of tropane derivatives and alpha-solanine at 1.20 and 7.84mgper100g fresh material, respectively. None of the analyzed compounds were detected in fruits, leaves, stems and roots of three L. barbarum varieties ('No. 1', 'New Big' and 'Amber Sweet Goji'). PMID- 27979238 TI - Addition of calcium compounds to reduce soluble oxalate in a high oxalate food system. AB - Spinach (Spinacia oleracea L.) is often used as a base vegetable to make green juices that are promoted as healthy dietary alternatives. Spinach is known to contain significant amounts of oxalates, which are toxic and, if consumed regularly, can lead to the development of kidney stones. This research investigates adding 50-500mg increments of calcium carbonate, calcium chloride, calcium citrate and calcium sulphate to 100g of raw homogenates of spinach to determine whether calcium would combine with the soluble oxalate present in the spinach. Calcium chloride was the most effective additive while calcium carbonate was the least effective. The formation of insoluble oxalate after incubation at 25 degrees C for 30min is a simple practical step that can be incorporated into the juicing process. This would make the juice considerably safer to consume on a regular basis. PMID- 27979239 TI - Rapid and wide-range determination of Cd(II), Pb(II), Cu(II) and Hg(II) in fish tissues using light addressable potentiometric sensor. AB - A rapid and wide-range method, based on light addressable potentiometric sensor (LAPS), is introduced into determination of Cd(II), Pb(II), Cu(II) and Hg(II) in fish tissues. A compact LAPS module is prepared by integrating four LAPS chips specifically sensitive to target elements. Its responses in digestions from various settings are investigated to find suitable factors. Analytical properties of this method are evaluated in consequent experiments under optimized conditions. Measurement range for each target element exceeds 0.1 to 1000mgL-1, and response time is less than 10s. Accuracy, precision and selectivity of the proposed method are also well defined in measurements. It is successively performed to detect the target elements in real fish samples from 4 species, and obtained results are consistent with certified method. PMID- 27979240 TI - Preharvest Interval Periods and their relation to fruit growth stages and pesticide formulations. AB - The aim of this study was to evaluate the effect of pesticide formulations and fruit growth stages on the Pre-harvest Interval Period (PHI). Results showed that pesticide formulations did not affect the initial deposit and dissipation rate. However, the fruit growth stage at the application time showed a significant effect on the above-mentioned parameters. Fruit diameter increases in one millimeter pesticide dissipation rates were reduced in -0.033mgkg-1day-1 (R2=0.87; p<0.001) for grapes and -0.014mgkg-1day-1 (R2=0.85; p<0.001) for apples. The relation between solar radiation, air humidity and temperature, and pesticide dissipation rates were dependent on fruit type. PHI could change according to the application time, because of the initial amount of pesticide deposit in the fruits and change in the dissipation rates. Because Maximum Residue Level are becoming more restrictive, it is more important to consider the fruit growth stage effects on pesticide when performing dissipation studies to define PHI. PMID- 27979241 TI - A comparative study of triacylglycerol composition in Chinese human milk within different lactation stages and imported infant formula by SFC coupled with Q-TOF MS. AB - Triacylglycerols (TAGs) as the major component of milk fat are significant factors to ensure the healthy growth of infants. An efficient method for identifying TAGs in human milk (HM) and infant formula (IF) was established using supercritical fluid chromatograph (SFC) coupled with quadruple time-of-flight mass spectrometry (Q-TOF-MS). The results indicated the feasibility of this method with satisfactory recoveries (>80%) and correlation coefficients (r2?0.993). More than 60 TAGs in HM and 50 TAGs in IF were identified. The profiling results demonstrated that TAGs in HM were greatly affected by lactation stage. Significant differences were found between HM and IF, such as much higher medium chain TAGs and saturated TAGs in IF, indicating that the formulas developed by foreign manufacturers were not suitable for Chinese babies. This high-throughput method exhibits a huge potential for analysis of milk samples and the result may serve as an important guide for Chinese infants diet. PMID- 27979242 TI - Spectroscopic and theoretical investigations of phenolic acids in white wines. AB - Model solutions of white wines containing phenolic acids have been investigated by means of UV-vis, laser induced fluorescence and Raman spectroscopic techniques. In order to interpret the spectra, density functional theory calculations of phenolic acids have been performed. This work demonstrates that only hydroxynamic acids are in resonance with a laser excitation line with 325nm wavelength and are therefore at the origin of the strong enhancement of the Raman light scattering. Real white wines also display such resonance Raman scattering so that their content in hydroxycinnamic acids may be quite precisely determined. The analysis of the Raman spectrum of a real dry white wine reveals qualitatively the preponderance in its composition of p-coumaric and caftaric acids. PMID- 27979243 TI - Synthesis, antibacterial and antimutagenic activity of zerumbone-bicarbonyl analogues. AB - Synthesis of new zerumbone-bicarbonyl analogues by SeO2 oxidation is reported. Selective oxidation of methyl at C-13 to an aldehyde and a ketone with exo-cyclic double bond between C-13 and C-6 in zerumbone has been recognized. Both these compounds have an additional conjugated-carbonyl-functionality. They exhibited significantly higher antimutagenic activity than zerumbone against Salmonella tester strains. They are more active against Gram positive bacteria than Gram negative bacteria; however zerumbone showed highest activity against E. coli, whereas its derivatives were least effective against E. coli. PMID- 27979244 TI - Identification of phospholipids classes and molecular species in different types of egg yolk by using UPLC-Q-TOF-MS. AB - Egg phospholipids (PLs) are currently the products of greatest commercial interest with major area of importance in various fields. Therefore, in this study, duck, hen and quail egg yolk PLs were isolated by solvent extraction with chilled acetone precipitation, and subsequently separated and identified by using ultra-performance liquid chromatography with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Egg PLs were separated on hydrophilic interaction liquid chromatography (HILIC) with ethylene bridged hybrid (BEH) column by gradient elution using acetonitrile/ammonium formate as a mobile phase, and detected by mass spectrometry (MS) under electrospray ionization in positive and negative ion mode. Structural characterizations of 57 molecular species of egg yolk PLs were identified based on MS/MS fragment ion information and elemental composition in MassLynx 4.1 software. The obtained results showed that phosphatidylcholine (16:0-18:1), phosphatidylethanolamine (18:0-20:4), phosphatidylinositol (18:0-18:2), phosphatidylserine (18:0-18:2), sphingomyelin (d18:1/16:0) and lysophosphatidylcholine (16:0) were the predominant species among the different classes of egg yolk phospholipids. PMID- 27979245 TI - Formulation of yeast-leavened bread with reduced salt content by using a Lactobacillus plantarum fermentation product. AB - A Lactobacillus plantarum fermentation product (Bio21B), obtained after strain growth (14h) in a wheat flour-based medium, was applied in the bread-making process as taste enhancer, in order to obtain a yeast-leavened bread with reduced salt content (20% and 50%) with respect to a reference bread (REF) not containing the fermentation product. Sensory analysis indicated that the Bio21B bread with salt reduced by 50% had a pleasant taste similar to the salt-containing bread (REF). l-Glutamate and total free amino acid content did not differ between REF and Bio21B breads, while the acids lactic, acetic, phenyllactic, 4-OH phenyllactic and indole-3-lactic were present only in Bio21B breads. Moreover, the presence of several umami (uridine monophosphate, inosine monophosphate, adenosine, and guanosine) and kokumi (gamma-l-glutamyl-l-valine) taste-related molecules was ascertained both in REF and in Bio21B breads. Therefore, a possible role of the acidic molecules in compensating the negative perception of salt reduction can be hypothesized. PMID- 27979246 TI - Electro-activation of sweet defatted whey: Impact on the induced Maillard reaction products and bioactive peptides. AB - Electro-activation was used to add value to sweet defatted whey. This study aimed to investigate and to characterize the bioactive compounds formed under different electro-activation conditions by molecular and proteomic approaches. The effects of electric current intensity (400, 500 or 600mA) and whey concentration (7, 14 or 21% (w/v)) as a function of the electro-activation time (0, 15, 30 or 45min) were evaluated. The targeted dependent variables were the formation of Maillard reaction products (MRPs), protein hydrolysates and glycated compounds. It was shown that the MRPs derived from electro-activated whey at a concentration of 14% had the highest potential of biological activity. SDS-PAGE analyses indicated the formation of hydrolysates and glycated compounds with different molecular weight distributions. FTIR indicated the predominance of intermediate MRPs, such as the Schiff base compounds. LC-MS/MS and proteomics analysis showed the production of multi-functional bioactive peptides due to the hydrolysis of whey proteins. PMID- 27979247 TI - The structure features of umami hexapeptides for the T1R1/T1R3 receptor. AB - Umami is thought to be initiated by binding tastants to G-protein-coupled receptors in taste cells, while the structure and mechanism of the receptors are not clear. In this study, we summarized umami peptides and classified them roughly into two groups: the first group contains dipeptides and tripeptides with terminal Glu or Asp, while the second peptides comprises more amino acids without significant features. The research on the structure and taste characteristics of second group peptides are less studied, so we focus on this group. In this work, nine flavor peptides were newly identified from Takifugu obscurus, and among them, the umami hexapeptides KGRYER belong to the second group. Five hexapeptides from this study, our previous work and references were chosen to build a Three Dimensional Quantitative Structure-Activity Relationship model with q2 value as 0.964 successfully. Then the relationship between the structure and intensity of umami peptides were illustrated. PMID- 27979248 TI - Influence of lysolecithin and Tween 80 on the colloidal stability of branched chain amino acids in a nanosuspension system. AB - This study examined the influence of stabilizers on the solubility and colloidal stability of branched chain amino acids (BCAAs) nanosuspended through high pressure homogenization at 70 degrees C. Although homogenization increased the initial BCAA solubility, irrespective of pH (pH 3 or 6), homogenization alone was not sufficient to increase their long-term solubility. The incorporation of stabilizers into nanosuspensions increased the saturation concentration of BCAAs but the effect of stabilizers on the increase in the saturation concentration of BCAAs was more pronounced at pH 6.0. At pH 6, Tween 80 dramatically increased the colloidal stability of the BCAA nanosuspensions, independent of the BCAA:stabilizer ratio but not at pH 3. However, the effect of lysolecithin on the colloidal stability of nanosuspended BCAAs varied depending on pH and BCAA:lysolecithin ratio. In lysolecithin-related nanosuspensions, there was no clear relationship between the colloidal stability and nanosuspension conditions including pH and BCAA:lysolecithin ratio. This study could provide a useful information on stabilizer selection for the development of liquid or colloidal products with improved solubility and colloidal stability of nanosuspended BCAAs. PMID- 27979250 TI - alpha-Tocopherol-loaded niosome prepared by heating method and its release behavior. AB - alpha-Tocopherol-loaded niosome was developed using modified heating method. The influence of surfactants (Span60 and Tween60) in different mole ratios, presence or absence of cholesterol (Chol) and dicetyl phosphate (DCP) as well as different concentration of alpha-tocopherol (alpha-TOC) on mean size, polydispersity index, zeta potential and entrapment efficiency (EE) was evaluated. The results showed that alpha-TOC loaded niosomes exhibited a small mean size (73.85+/-0.6-186+/ 0.58nm), narrow size distribution and high EE (61.13+/-0.52-98.92+/-0.92). By decreasing the HLB, the EE and stability of the niosomes increased. The DCP and Chol improved the physicochemical properties of niosomes. 3:1 mole ratio of Span 60:Tween 60, 4mg/ml of alpha-TOC and 25:12.5:2.5 mole ratio of surfactant:Chol:DCP was the optimum formulation in the encapsulation of alpha-TOC applying niosome system. The niosomes had sustained release profile in the simulated gastric and intestinal fluid. PMID- 27979249 TI - Stable isotope dilution assay (SIDA) and HS-SPME-GCMS quantification of key aroma volatiles for fruit and sap of Australian mango cultivars. AB - Reported herein is a high throughput method to quantify in a single analysis the key volatiles that contribute to the aroma of commercially significant mango cultivars grown in Australia. The method constitutes stable isotope dilution analysis (SIDA) in conjunction with headspace (HS) solid-phase microextraction (SPME) coupled with gas-chromatography mass spectrometry (GCMS). Deuterium labelled analogues of the target analytes were either purchased commercially or synthesised for use as internal standards. Seven volatiles, hexanal, 3-carene, alpha-terpinene, p-cymene, limonene, alpha-terpinolene and ethyl octanoate, were targeted. The resulting calibration functions had determination coefficients (R2) ranging from 0.93775 to 0.99741. High recovery efficiencies for spiked mango samples were also achieved. The method was applied to identify the key aroma volatile compounds produced by 'Kensington Pride' and 'B74' mango fruit and by 'Honey Gold' mango sap. This method represents a marked improvement over current methods for detecting and measuring concentrations of mango fruit and sap volatiles. PMID- 27979251 TI - Vitamin D concentrations in fortified foods and dietary supplements intended for infants: Implications for vitamin D intake. AB - Due to potential overages to cover losses during shelf life, the actual vitamin D concentration of fortified foods and dietary supplements may deviate from the label. In this pilot study the vitamin D concentrations of fortified foods (n=29; follow-on formula, baby porridge, curd cheese dessert) and dietary supplements (n=15), both specifically intended for infants, were analytically determined. Compared to the declared values, the vitamin D content ranged from 50% to 153% for fortified foods and from 8% to 177% for supplements. In general, both instant follow-on formula and oil-based supplements had a measured vitamin D content similar to or higher than the labelled value. Ready-to-eat baby porridge was the only category in which all measured vitamin D concentrations were below the declared value (74-81%). The use of label information for fortified foods and dietary supplements may result in invalid estimations of vitamin D intake distributions of infants; both under- and overestimation may occur. PMID- 27979252 TI - Fermentation and complex enzyme hydrolysis enhance total phenolics and antioxidant activity of aqueous solution from rice bran pretreated by steaming with alpha-amylase. AB - In this study, rice bran was successively steamed with alpha-amylase, fermented with lactic acid bacteria, and hydrolyzed with complex enzymes. The changes in phenolic profiles and antioxidant activities of the corresponding aqueous solutions from three stages were investigated. Compared to the first stage, fermentation and complex enzyme hydrolysis significantly increased the total phenolics, total flavonoids, total FRAP and ORAC values by 59.2%, 56.6%, 73.6% and 45.4%, respectively. Twelve individual phenolics present in free or soluble conjugate forms were also analyzed during the processing. Ferulic acid was released in the highest amount among different phenolics followed by protocatechuic acid. Moreover, a major proportion of phenolics existed as soluble conjugates. The results showed that fermentation and complex enzyme hydrolysis enhanced total phenolics and antioxidant activities of aqueous solution from rice bran pretreated by steaming with alpha-amylase. This research could provide basis for the processing of rice bran beverage rich in phenolics. PMID- 27979253 TI - Physico-chemical characteristics and fungal profile of four Saudi fresh date (Phoenix dactylifera L.) cultivars. AB - Physico-chemical and microbial analyses of four commercial fresh date cultivars (Sukari, Barhi, Khalas and Rothana) grown in Saudi Arabia were evaluated. Colorimetric assay indicated that Sukari had the highest total sugar content of 13.21g/100gFW while the lowest was in Rothana with 7.96g/100gFW. Total phenolic content (TPC) ranged from 76.74 to 122.20mgGAE/100gFW in Barhi and Rothana respectively, whereas antioxidant activity was highest in Sukari (105.99MUgGAE/gFW) and lowest in Khalas (90.81MUgGAE/gFW). The dominant fungal genera were Aspergillus sp., Rhizopus sp., Penicillium sp. and Sarocladium sp., occurring at 37, 18, 13 and 12% respectively. The highest fungal occurrence was in Barhi (30%) followed by Sukari (29%), Khalas (26%) and Rothana (15%). The TPC had a negative correlation with fungal occurrence whilst the total sugars had a positive correlation. PMID- 27979254 TI - Binding properties of the natural red dye carthamin with human serum albumin: Surface plasmon resonance, isothermal titration microcalorimetry, and molecular docking analysis. AB - The interaction between carthamin and human serum albumin (HSA) was investigated by multiple spectroscopic analyses, surface plasmon resonance (SPR), isothermal titration microcalorimetry (ITC), and molecular docking studies. Fluorescence lifetime measurements implied that carthamin quenched the intrinsic fluorescence of HSA with the formation of a new complex via static mode. Binding affinities regarding this interaction were obtained from SPR analysis. Results demonstrated that carthamin could form a 1:1 complex with HSA at the binding affinity of KD=8.726*10-5M and that a high temperature was unfavourable for the interaction. ITC analyses and molecular docking results illustrated that HSA shaped a proper cavity (site I) to embed the whole carthamin molecule and that the complex was formed depending on intermolecular forces, including hydrophobic interaction, hydrogen bonding, and electrostatic force. Moreover, circular dichroism and 3D fluorescence demonstrated that carthamin slightly disturbed the microenvironment of amino residues and affected the secondary structure of HSA. PMID- 27979255 TI - Preparation and characterisation of Chlorogenic acid-gelatin: A type of biologically active film for coating preservation. AB - Chlorogenic acid (CGA), a type of plant polyphenol, was conjugated onto gelatin (Gel) to prepare a novel coating material for the preservation of fresh seafood. The optimal reaction molar ratio of CGA to gelatin (4:1) was determined according to the CGA content in the CGA-Gel conjugate. CGA was confirmed to be successfully conjugated onto gelatin by 1H nuclear magnetic resonance and Fourier transform infrared spectroscopy. The antioxidant activity of CGA-Gel was proven to be higher than that of the free CGA in 2,2'-azinobis-(3-ethylbenzthiazoline-6 sulphonate) radical scavenging, hydrogen peroxide scavenging, ferric ion reducing power and lipid oxidation assays. The minimum inhibitory concentrations (MIC) of CGA against Escherichia coli, Pseudomonas aeruginosa, Listeria monocytogenes and Staphylococcus aureus were 1, 1, 2 and 2mg/mL, respectively. The antibacterial activity of CGA-Gel was unaffected by conjugation. PMID- 27979256 TI - Synthesis and in vitro antioxidant and antimicrobial studies of novel structured phosphatidylcholines with phenolic acids. AB - Novel phenoylated phosphatidylcholines were synthesized from 1,2-dipalmitoyl phosphatidylcholine/egg 1,2-diacyl phosphatidylcholine and phenolic acids such as ferulic, sinapic, vanillic and syringic acids. The structures of phenoylated phosphatidylcholines were confirmed by spectral analysis. 2-acyl-1-lyso phosphatidylcholine was synthesized from phosphatidylcholine via regioselective enzymatic hydrolysis and was reacted with hydroxyl protected phenolic acids to produce corresponding phenoylated phosphatidylcholines in 48-56% yields. Deprotection of protected phenoylated phosphatidylcholines resulted in phenoylated phosphatidylcholines in 87-94% yields. The prepared compounds were evaluated for their preliminary in vitro antimicrobial and antioxidant activities. Among the active derivatives, compound 1-(4-hydroxy-3,5-dimethoxy) cinnamoyl-2-acyl-sn-glycero-3-phosphocholine exhibited excellent antioxidant activity with EC50 value of 16.43MUg/mL. Compounds 1-(4-hydroxy-3-methoxy) cinnamoyl-2-acyl-sn-glycero-3-phosphocholine and 1-(4-hydroxy-3,5-dimethoxy) cinnamoyl-2-palmitoyl-sn-glycero-3-phosphocholine exhibited good antioxidant activity with EC50 values of 36.05 and 33.35MUg/mL respectively. Compound 1-(4 hydroxy-3-methoxy) cinnamoyl-2-palmitoyl-sn-glycero-3-phosphocholine exhibited good antibacterial activity against Klebsiella planticola with MIC of 15.6MUg/mL and compound 1-(4-hydroxy-3-methoxy) benzoyl-2-acyl-sn-glycero-3-phosphocholine exhibited good antifungal activity against Candida albicans with MIC of 15.6MUg/mL. PMID- 27979257 TI - Single-step purification and characterization of an extreme halophilic, ethanol tolerant and acidophilic xylanase from Aureobasidium pullulans NRRL Y-2311-1 with application potential in the food industry. AB - An extracellular xylanase from Aureobasidium pullulans NRRL Y-2311-1 produced on wheat bran was purified by a single-step chromatographic procedure. The enzyme had a molecular weight of 21.6kDa. The optimum pH and temperature for xylanase activity were 4.0 and 30-50 degrees C, respectively. The enzyme was stable in the pH range of 3.0-8.0. The inactivation energy of the enzyme was calculated as 218kJmol-1. The xylanase was ethanol tolerant and kept complete activity in the presence of 10% ethanol. Likewise, it retained almost complete activity at a concentration range of 0-20% NaCl. In general, the enzyme was resistant to several metal ions and reagents. Mg2+, Zn2+, Cu2+, K1+, EDTA and beta mercaptoethanol resulted in enhanced xylanase activity. The Km and Vmax values on beechwood xylan were determined to be 19.43mgml-1 and 848.4Uml-1, respectively. The enzyme exhibits excellent characteristics and could, therefore, be a promising candidate for application in food and bio-industries. PMID- 27979258 TI - Carotenoids and carotenoid esters of orange- and yellow-fleshed mamey sapote (Pouteria sapota (Jacq.) H.E. Moore & Stearn) fruit and their post-prandial absorption in humans. AB - Although different genotypes of mamey sapote with distinct pulp colors are consumed in countries from Central to South America, in-depth knowledge on genotype-related differences of their carotenoid profile is lacking. Since the fruit was found to contain the potentially vitamin A-active keto-carotenoids sapotexanthin and cryptocapsin, we sought to qualitatively and quantitatively describe the carotenoid profile of different genotypes by HPLC-DAD-MSn. Sapotexanthin and cryptocapsin were present in all genotypes. Keto-carotenoids such as cryptocapsin, capsoneoxanthin, and their esters were most abundant in orange-fleshed fruit, whereas several carotenoid epoxides prevailed in yellow fleshed fruit. Differing carotenoid profiles were associated with different color hues of the fruit pulp, while the widely variable carotenoid content (3.7 8.0mg/100gFW) was mainly reflected by differences in color intensity (chroma C*). Furthermore, the post-prandial absorption of sapotexanthin to human plasma was proven for the first time. Besides sapotexanthin, cryptocapsin was found to be resorbed. PMID- 27979259 TI - A simple extraction method for the detection and quantification of polyoxin D, a nucleoside antibiotic, in butterbur using UPLC-MS/MS. AB - An effective analytical method was developed for the detection and quantification of polyoxin D in butterbur using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Samples were extracted using acidified deionised water and purified via solid-phase extraction (SPE) using an HLB cartridge. An external matrix-matched standard calibration curve was prepared, which provided an excellent linearity with a coefficient of determination (R2) ?0.999. Limits of detection (LOD) and quantification (LOQ) were 0.015 and 0.0.05MUg/g, respectively. The developed method was validated in terms of recovery performance using two fortification levels in triplicate. The storage stabilities of the various field samples were also determined. Our method provided consistent recovery (86.26-87.37%) with a relative standard deviation (RSD) of <5%, and was successfully applied to field-treated butterbur grown under greenhouse conditions and collected at various times following commercial fungicide application. As expected, a gradual degradation of polyoxin D was observed, with a half-life (t1/2) of 2.11d being recorded. Finally, we propose that the developed method can be extrapolated to other crops for routine analysis and can be used to determine the pre-harvest intervals (PHIs), thus preventing the development of antibiotic resistance genes in humans and in the environment. PMID- 27979260 TI - Determination of fourteen polyphenols in pulses by high performance liquid chromatography-diode array detection (HPLC-DAD) and correlation study with antioxidant activity and colour. AB - Pulses, which include lentils, beans, chickpeas, peas, and soybeans, provide an important source of proteins, dietary fibers, minerals and vitamins, as well as such important bioactive molecules as polyphenols. The presence of polyphenols is often related to the colour of the pulse and to its antioxidant activity. The aim of this work was to set up a new HPLC-DAD method for simultaneously analysing 14 polyphenolic compounds, including two anthocyanins, in different varieties of pulses and to correlate the polyphenol content with the seed coat colour and the antioxidant activity. The total content of the analysed polyphenols ranged from 3mg/kg for dehulled red lentils to 1630.5mg/kg for ruviotto beans. Samples with dark testa (or seed coat), namely black lentils and diavoli beans, had higher antioxidant activity than those with pale testa, and a positive correlation was found between total phenolic content (TPC) and IC50 for dark coloured varieties. PMID- 27979261 TI - Enhancing the lycopene in vitro bioaccessibility of tomato juice synergistically applying thermal and non-thermal processing technologies. AB - The influence of moderate intensity pulsed electric field pre-processing on increasing the lycopene bioaccessibility of tomato fruit, and the combined effect of blanching, ultrasonic and high intensity pulsed electric field processing on further enhancement of the lycopene bioaccessibility after juicing were investigated. Maximum total lycopene bioaccessibility (9.6%) of the tomato fruit was achieved by a 4MUs pre-processed treatment after 24h holding period and further processing results revealed that all treatments were effective to increase the total lycopene. Most of juice processing treatments decreased the release of lycopene from the tomato matrix during digestion. Only the treatment of blanching followed by high intensity pulsed electric field showed a significant release of trans-(4.01+/-0.48) and cis-(5.04+/-0.26MUg/g) lycopene, achieving 15.6% total lycopene bioaccessibility. Thus, processing of pre-blanched juice using high intensity pulsed electric field, derived from pre-processed tomato was the best overall process to achieve the highest nutritive value. PMID- 27979262 TI - Effects and detection of Nandrosol and ractopamine administration in veal calves. AB - The present study describes different effects of the selective androgen receptor modulator (SARM) nandrolone phenylpropionate (Nandrosol) and the beta-agonist ractopamine administration in veal calves, and it investigates different strategies applied to trace these molecules. Morphological changes of gonads and accessory glands attributed to androgen effects, such as testicular atrophy, seminiferous tubule diameter reduction and hyperplasia of prostate epithelium, were detected, although SARMs are not described to cause these lesions. The gene expression analysis showed an anabolic activity of Nandrosol in Longissimus dorsi muscle, where myosin heavy chain (MYH) was significantly up-regulated. An IGF1 increase was weakly significant only in Vastus lateralis muscle. In conclusion, the anatomo-histopathological observations and the MYH mRNA up-regulation in Longissimus dorsi muscle confirm the androgenic treatment in experimental animals. The biosensor assay was not enough sensitive to detect residues in urines and only the direct chemical analysis of urine samples confirmed both beta agonist and SARM treatment. PMID- 27979263 TI - Electromembrane extraction-preconcentration followed by microvolume UV-Vis spectrophotometric determination of mercury in water and fish samples. AB - Electromembrane extraction technique combined with microvolume UV-Vis spectrophotometric detection was proposed for the preconcentration-determination of mercury in water and fish samples. The optimized conditions for preconcentration step were: the applied potential 70V, bis(2-ethylhexyl) phosphate as the extractant in 1-octanol 2% v/v, extraction time 10min, stirring rate 700rpm, acceptor and donor solutions pH 3 and 7, respectively. The linear range was found to be 2.3-950.0MUgL-1 and 40-9500MUgkg-1 in water and fish samples, with corresponding detection limits of 0.7MUgL-1 and 12MUgkg-1, respectively. The method showed satisfactory repeatability and reproducibility (CV<6%). Methodological validation was performed by using cold vapor atomic absorption spectroscopy. The proposed method provided a rapid, sensitive and accurate method which is applicable for routine analysis of total mercury contents in water and fish samples. PMID- 27979264 TI - Synthesis and characterization of a molecularly imprinted polymer for the determination of spiramycin in sheep milk. AB - A series of molecularly imprinted polymers (MIPs) comprising reactionary sites which are complementary to macrolide antibiotic spiramycin (SPI) were synthetized by noncovalent bulk polymerization technique. MIPs were synthesized under different polymerization process and their recognition efficiency was evaluated in binding studies in comparison with non-imprinted polymers. The best MIP was morphologically characterized and equilibrium assays were carried out. The MIP was evaluated as a sorbent for extraction and preconcentration of SPI from aqueous and sheep milk samples, and an off-line MISPE method followed by high performance liquid chromatography with UV diode-array detection was established. Good linearity were obtained for SPI in a range of 24-965MUgkg-1 and the average recoveries at three spiked levels in milk samples were higher than 90% (RSD<5%). Limit of quantification was 24.1MUgkg-1. Cross-reactivity studies from other macrolides with similar structure were tested. The optimum imprinted polymer showed a good selectivity and affinity for SPI, demonstrating the potential of the proposed MISPE for rapid, sensitive and effective sample pretreatment for selective determination of SPI in sheep milk samples. PMID- 27979265 TI - Development of isotope dilution-liquid chromatography/tandem mass spectrometry for the accurate determination of trans- and cis-vitamin K1 isomers in infant formula. AB - A method based on isotope dilution-liquid chromatography/tandem mass spectrometry (ID-LC/MS/MS) using a C30 column has been developed for the separate and accurate determination of trans- and cis-vitamin K1 in infant formula. Vitamin K1 and the deuterium-labeled internal standard eluted at slightly different retention times experiencing different matrix effects, and this possibly resulted in biased measurement. The matrix effect profiles obtained from post-column infusion experiments showed that atmospheric pressure chemical ionization (APCI) was less susceptible to matrix effects near the retention time than electrospray ionization (ESI); therefore, APCI was used in this study. The developed method was validated by measuring fortified samples, and the results agreed with the gravimetric values. Its repeatability and reproducibly were within 2% relative standard deviation. The relative expanded uncertainty was approximately 5%, indicating that the method was of higher-order metrological quality as a reference method. PMID- 27979266 TI - Anodic stripping voltammetry with gold electrodes as an alternative method for the routine determination of mercury in fish. Comparison with spectroscopic approaches. AB - The applicability to the determination of mercury in tuna of square wave anodic stripping voltammetry (SW-ASV) conducted at both solid gold electrode (SGE) and a gold nanoparticle-modified glassy carbon electrode (AuNPs-GCE) was demonstrated. Mercury content in two certified materials and in ten samples of canned tuna was measured. The performances of the electrodes were compared with one another as well as with two spectroscopic techniques, namely cold vapour atomic absorption spectroscopy (CV-AAS) and a direct mercury analyser (DMA). The results found pointed out that both SW-ASV approaches were suitable and easy-to-use method to monitor mercury concentration in tunas, since they allowed accurate quantification at concentration values lower than the maximum admissible level in this matrix ([Hg]=1mg/kgwet weight,ww). In particular, mercury detection at the AuNPs-GCE showed a LOQ in fish-matrix of 0.1MUg/l, corresponding to 0.06mg/kgww, with performance comparable to that of DMA. PMID- 27979267 TI - Development of new NIR-spectroscopy method combined with multivariate analysis for detection of adulteration in camel milk with goat milk. AB - New NIR spectroscopy combined with multivariate analysis for detection and quantification of camel milk adulteration with goat milk was investigated. Camel milk samples were collected from Aldhahira and Sharqia regions of Sultanate of Oman and were measured using NIR spectroscopy in absorption mode in the wavelength range from 700 to 2500nm, at 2cm-1 resolution and using a 0.2mm path length CaF2 sealed cell. The multivariate methods like PCA, PLS-DA and PLS regression were used for interpretation of NIR spectral data. PLS-DA was used to detect the discrimination between the pure and adulterated milk samples. For PLSDA model the R-square value obtained was 0.974 with 0.08 RMSE. Furthermore, PLS regression model was used to quantify the levels of adulteration from, 0%, 2%, 5%, 10%, 15% and 20%. The PLS model showed the RMSEC=1.10% with R2=94%. This method is simple, reproducible, having excellent sensitivity. The limit of detection was found 0.5%, while the limit of quantification was 2%. PMID- 27979268 TI - Doped graphene/Cu nanocomposite: A high sensitivity non-enzymatic glucose sensor for food. AB - An amperometric non-enzymatic glucose sensor was developed based on nitrogen doped graphene with dispersed copper nanoparticles (Cu-NGr). The sensing element was tested in conjunction with a modified glassy carbon electrode for glucose detection. The Cu-NGr composite was prepared by one pot synthesis from a mixture of graphene oxide, copper nitrate and uric acid, followed by thermal annealing at 900 degrees C for 1h. Detailed characterizations showed homogeneous copper nanoparticle dispersion and the presence of significant proportion of graphitic nitrogen. The developed electrode presented high electrocatalytic activity towards glucose through synergetic effect of copper nanoparticles and nitrogen doped graphene. Amperometric analysis confirmed high glucose sensitivity and ultra-low detection of 10nM glucose over a linear range. The sensor was tested for direct application to detect glucose in food samples for which the sensor displayed high selectivity with excellent reproducibility and recovery in complex food materials. PMID- 27979269 TI - Magnetic solid phase extraction with CoFe2O4/oleic acid nanoparticles coupled to gas chromatography-mass spectrometry for the determination of alkylphenols in baby foods. AB - Magnetic solid phase extraction (MSPE) with cobalt ferrite nanoparticles coated with oleic acid is described for the determination of alkylphenols (APs), 4-tert butylphenol (TBP), 4-pentylphenol (PP), 4-hexylphenol (HP), 4-tert-octylphenol (TOP), 4-n-octylphenol (OP) and 4-nonylphenol (NP) in baby foods using gas chromatography with mass spectrometry (GC-MS). Prior to MSPE, the sample was treated with trichloroacetic acid, and the APs derivatized with acetic anhydride. Parameters affecting the extraction efficiency: amount of magnetic nanoparticles, extraction time and desorption conditions, were optimized. The enriched phase obtained was evaporated to dryness and the residue reconstituted in 50MUL of methanol, 1MUL of which was injected into the GC-MS. Samples were quantified applying matrix-matched calibration and using 2-chloro-5-bromoanisole as surrogate standard. The analysis of 0.5g of sample provided detection limits in the 0.4-1.7ngg-1 range. Some samples contained APs at levels of between 3ngg-1 for HP and 122ngg-1 for TOP. PMID- 27979271 TI - Fast determination of bioactive phytic acid and pyrophosphate in walnuts using microwave accelerated extraction. AB - Bioactive compounds phytic acid (IP6) and pyrophosphate (PPi) are minor components of walnuts with the ability of being inhibitors of urolithiasis, among others. Since simultaneous analysis of IP6 and PPi have known drawbacks, a new method to determine their content in walnuts has been developed with emphasis on their extraction from walnuts by microwave-assisted extraction (MAE). Acid content of extracting solvent, extraction time and temperature were optimized. After extraction, compounds were purified by selective adsorption/desorption on an anion exchange solid phase extraction and analyzed by inductive coupled plasma/mass spectrometry. A mixture of H2SO4 and HCl as solvent to extract both, IP6 and PPi, provided results slightly higher than those determined by conventional extraction with no statistical difference. The possible hydrolysis of phytic acid by MAE was analyzed. Compared with the conventional acid extraction method, significant improvement is achieved by the MAE method reducing extraction time from 3h to 10min. PMID- 27979270 TI - Enhancement of physical stability and bioaccessibility of tangeretin by soy protein isolate addition. AB - Soy protein isolate (SPI) was selected to fabricate supersaturated self emulsifying nanoemulsions, aiming to enhance physical stability and bioaccessibility of hydrophobic tangeretin. Dissolution studies demonstrated that tangeretin had the highest solubility in Tween 80, followed by oil phase solutions, and polymer solutions. Supersaturated tangeretin in oil phases easily formed crystals. That metastable zone was found to vary with its initial concentrations. After encapsulation by nanoemulsions, the addition of glycerol compressed the retention amount of tangeretin from 76% to 53%, but benefited the transparency. Whereas, the combination of glycerol and SPI could not only maintain high-loading tangeretin (>85%), but also provide high transparency for nanoemulsions. When tangeretin concentration was 4.83mM, combination of 50% glycerol and 1% SPI could maintain around 88% tangeretin in the nanoemulsion within one month. Its bioaccessibility of different systems were at 60-65%. These findings can provide useful information for protein to be a potential precipitation inhibitor. PMID- 27979272 TI - QCM-based aptamer selection and detection of Salmonella typhimurium. AB - In this study, quartz crystal microbalance (QCM) was used to select aptamers against Salmonella typhimurium. To increase the success rate of Systematic Evolution of Ligands Exponential Enrichment (SELEX), the affinity of DNA pool in each round was simultaneously tracked using QCM in order to avoid the loss of high-quality aptamers. When the frequency change reached a maximum value after several rounds of selection and counter-selection, the candidate pool was cloned and sequenced. Out of three aptamer candidates, aptamer B5 showed high specificity and binding affinity with dissociation constant (Kd value) of 58.5nM, and was chosen for further studies. Subsequently, a QCM-based aptasensor was developed to detect S. typhimurium. This aptasensor was able to detect 103CFU/mL of S. typhimurium with less than 1h. This study demonstrated QCM-based selection could be more effective selection of aptamers and QCM-based aptasensor could be more sensitive in detecting S. typhimurium. PMID- 27979273 TI - Application of graphene oxide-silica composite reinforced hollow fibers as a novel device for pseudo-stir bar solid phase microextraction of sulfadiazine in different matrices prior to its spectrophotometric determination. AB - This study presents a novel, simple and efficient pseudo-stir bar solid phase microextraction method for separation and preconcentration of sulfadiazine. To develop the method, a graphene oxide-silica composite reinforced hollow fiber was prepared via sol-gel technology and used as a novel device to extract sulfadiazine. The retained sulfadiazine was eluted using 180MUL of methanol/acetic acid (6:4) and quantified by fiber optic linear array spectrophotometry based on the formation of its azo dye with thenoyltrifluoroacetone. Under optimized conditions, the method exhibited a linear dynamic range of 5-150MUgL-1 with a detection limit of 1.5MUgL-1 and an enrichment factor of 100. The relative standard deviations of 2.9% and 5.8% (n=6) were obtained at 60MUgL-1 level of sulfadiazine for intra- and inter-day analysis respectively. The method was successfully applied to determine sulfadiazine in honey, milk, human urine and environmental water samples. PMID- 27979274 TI - Development and validation of a universal primer pair for the simultaneous detection of eight animal species. AB - In the present study, we developed a novel simplex PCR assay for the simultaneous detection of eight animal species, including goat, sheep, deer, buffalo, cattle, yak, pig and camel. A unique pair of universal primers was designed to target mitochondrial DNA variable regions in the eight animal species, generating, 787, 763, 563, 512, 507, 491, 455 and 385bp long fragments for goat, sheep, deer, buffalo, cattle, yak, pig and camel, respectively. The assay showed no cross reactivity with other common domestic animals, and was validated by sequencing and enzyme digestion. Detection limit for DNA samples from the eight animal species varied between 6 and 20pg in a 20MUl PCR mixture. Interestingly, the newly developed method successfully identified 170 commercial meat products, and is simple, fast, sensitive, specific, and cost-effective. Therefore, it could be used for the detection of goat, sheep, deer, buffalo, cattle, yak, pig, and camel species in foodstuffs. PMID- 27979275 TI - A rapid Raman detection of deoxynivalenol in agricultural products. AB - Mycotoxin results in financial damage and considerable safety risks. In this paper, the possibility of portable Raman system-based surface-enhanced Raman scattering (SERS) for a rapid detection of deoxynivalenol (DON) a mycotoxin in cereals was investigated. Under an optimized condition, SERS analysis for pure DON solution has a wide dynamic concentration range from 10-7M to 10-2M with the limit of detection (LOD) down to 100nM. Density functional theory (DFT) analysis at the level of B3LYP/6-311++G(d, p) was also preformed for vibrational assignment. For practical application, the LOD of the proposed Raman method for both DON-contaminated corns and kidney beans were validated as 10-6M and the LOD for DON-contaminated oats was 10-4M. As a perspective, the SERS-based technology could be developed into an alternatively promising assay for on-field detection of DON residues at various cereals due to it high sensitivity and selectivity. PMID- 27979276 TI - A fluorescence-quenching method for quantitative analysis of Ponceau 4R in beverage. AB - CdTe quantum dots was synthesized and used to quantitative analysis of Ponceau 4R in solution. With the excitation wavelength of 380nm the emission of CdTe quantum dots was quenched obviously by Ponceau 4R. In order to detect Ponceau 4R in mild condition the influences of fluorescence emission wavelength of CdTe quantum dots, pH value, temperature and reaction time were examined to establish the experimental condition. The linear response of the fluorescence intensity of CdTe quantum dots to Ponceau 4R allowed the quantitative analysis of Ponceau 4R in a range of 2.5-25MUg/mL, and the limit of detection for Ponceau 4R was 0.025MUg/mL. In addition, the responsive mechanism of this reaction system was investigated in detail by using the modified Stern-Volmer equation and thermodynamic calculation. Particularly, this method was used to quantitatively analyze the real sample, which indicated that this method could be more widely applied in similar samples. PMID- 27979277 TI - Optimization and validation of a method using UHPLC-fluorescence for the analysis of polycyclic aromatic hydrocarbons in cold-pressed vegetable oils. AB - Among the different food categories, the oils and fats are important sources of exposure to polycyclic aromatic hydrocarbons (PAHs), a group of organic chemical contaminants. The use of a validated method is essential to obtain reliable analytical results since the legislation establishes maximum limits in different foods. The objective of this study was to optimize and validate a method for the quantification of four PAHs [benzo(a)anthracene, chrysene, benzo(b)fluoranthene, benzo(a)pyrene] in vegetable oils. The samples were submitted to liquid-liquid extraction, followed by solid-phase extraction, and analyzed by ultra-high performance liquid chromatography. Under the optimized conditions, the validation parameters were evaluated according to the INMETRO Guidelines: linearity (r2 >0.99), selectivity (no matrix interference), limits of detection (0.08-0.30MUgkg 1) and quantification (0.25-1.00MUgkg-1), recovery (80.13-100.04%), repeatability and intermediate precision (<10% RSD). The method was found to be adequate for routine analysis of PAHs in the vegetable oils evaluated. PMID- 27979278 TI - Detection and quantification of anionic detergent (lissapol) in milk using attenuated total reflectance-Fourier Transform Infrared spectroscopy. AB - Adulteration of milk to gain economic benefit is rampant. Addition of detergent in milk can cause food poisoning and other complications. Fourier Transform Infrared spectroscopy was evaluated as rapid method for detection and quantification of anionic detergent (lissapol) in milk. Spectra of pure and artificially adulterated milk (0.2-2.0% detergent) samples revealed clear differences in wavenumber range of 4000-500cm-1. The apparent variations observed in region of 1600-995 and 3040-2851cm-1 corresponds to absorption frequencies of common constituents of detergent (linear alkyl benzene sulphonate). Principal component analysis showed discrete clustering of samples based on level of detergent (p?0.05) in milk. The classification efficiency for test samples were recorded to be >93% using Soft Independent Modelling of Class Analogy approach. Maximum coefficient of determination for prediction of detergent was 0.94 for calibration and 0.93 for validation, using partial least square regression in wavenumber combination of 1086-1056, 1343-1333, 1507-1456, 3040-2851cm-1. PMID- 27979279 TI - Molecularly imprinted polymer grafted paper-based method for the detection of 17beta-estradiol. AB - 17beta-estradiol (17beta-E2) usually is used to promote the growth of animal. Abuse of 17beta-E2 has become a global food security problem, because the residues in foods can cause endocrine disorder through the food chain. A novel molecularly imprinted polymer (MIP) grafted paper-based method for the sensitive and specific detection of 17beta-E2 was reported in this work. Results showed that the MIP's optimum synthetic conditions were as follows: 12 mL of acetonitrile was chosen as the solvent; the molar ratio of template molecule, functional monomer and cross linker was 1:12:12. MIP synthesized had a good recognition ability, the limit of detection (LOD) of established detection method for milk and human urine samples could reach 0.25MUgL-1. PMID- 27979280 TI - Simultaneous characterisation of silver nanoparticles and determination of dissolved silver in chicken meat subjected to in vitro human gastrointestinal digestion using single particle inductively coupled plasma mass spectrometry. AB - In this study, a chicken meat containing AgNPs (candidate reference material Nanolyse 14) has been used as a model matrix to study the fate and behaviour of AgNPs upon oral ingestion following an in vitro model that included saliva, gastric and intestinal digestions. The behaviour of a 40nm AgNPs standard solution during the three digestion steps was also evaluated. Sample preparation conditions were optimised to prevent AgNPs oxidation and/or aggregation and to ensure the representativeness of the reported results. Total silver released from the test sample and the evaluated AgNP standard was determined by inductively coupled plasma mass spectrometry (ICPMS). The presence of both AgNPs and dissolved silver in the extracts was confirmed by single particle (SP)-ICPMS analysis. AgNPs were sized and the particle number concentration determined in the three digestion juices. Experimental results demonstrated differentiated behaviours for AgNP from the standard solution and the meat sample highlighting the relevance of using physiological conditions for accurate risk assessment. In the most realistic scenario assayed (i.e., spiked chicken meat analysis), only 13% of the AgNPs present in the reference material would reach the intestine wall. Meanwhile, other bioaccessible dissolved forms of silver would account for as much as 44% of the silver initially spiked to the meat paste. PMID- 27979281 TI - Multiclonal plastic antibodies for selective aflatoxin extraction from food samples. AB - Herein, we focused on developing a new generation of monolithic columns for extracting aflatoxin from real food samples by combining the superior features of molecularly imprinted polymers and cryogels. To accomplish this, we designed multiclonal plastic antibodies through simultaneous imprinting of aflatoxin subtypes B1, B2, G1, and G2. We applied Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and spectrofluorimetry to characterize the materials, and conducted selectivity studies using ochratoxin A and aflatoxin M1 (a metabolite of aflatoxin B1), as well as other aflatoxins, under competitive conditions. We determined optimal aflatoxin extraction conditions in terms of concentration, flow rate, temperature, and embedded particle amount as up to 25ng/mL for each species, 0.43mL/min, 7.0, 30 degrees C, and 200mg, respectively. These multiclonal plastic antibodies showed imprinting efficiencies against ochratoxin A and aflatoxin M1 of 1.84 and 26.39, respectively, even under competitive conditions. Finally, we tested reusability, repeatability, reproducibility, and robustness of columns throughout inter- and intra-column variation studies. PMID- 27979282 TI - Comparative evaluation of an ISO 3632 method and an HPLC-DAD method for safranal quantity determination in saffron. AB - The aim of this work was a comparison of the ISO 3632 (2011) method and an HPLC DAD method for safranal quantity determination in saffron. Samples from different origins were analysed by UV-vis according to ISO 3632 (2011) and by HPLC-DAD. Both methods were compared, and there was no correlation between the safranal content obtained by UV-vis and HPLC-DAD. An over-estimation in the UV-vis experiment was observed, which was related to the cis-crocetin esters content, as well as other compounds. The results demonstrated that there was no relationship between ISO quality categories and safranal content using HPLC-DAD. Therefore, HPLC-DAD might be preferable to UV-vis for determining the safranal content and the classification of saffron for commercial purposes. In addition, HPLC-DAD was adequate for determining the three foremost parameters that define the quality of saffron (crocetin esters, picrocrocin and safranal); therefore, this approach could be included in the ISO 3632 method (2011). PMID- 27979283 TI - Improvement in shelf life of minimally processed cilantro leaves through integration of kinetin pretreatment and packaging interventions: Studies on microbial population dynamics, biochemical characteristics and flavour retention. AB - Effect of integrating optimized combination of pretreatment with packaging on shelf life of minimally processed cilantro leaves (MPCL) was appraised through analysis of their sensory attributes, biochemical characteristics, microbial population and flavour profile during storage. Minimally pretreated cilantro leaves pretreated with 50ppm kinetin and packed in 25MU polypropylene bags showed a shelf life of 21days. Optimized combination helped in efficiently maintaining sensory parameters, flavour profile, and retention of antioxidants in MPCL until 21days. Studies conducted on the effect of optimized combination on microbial population and flavour profile revealed that among different microorganisms, pectinolysers had a significant effect on spoilage of MPCL and their population of ?3.59logcfu/g was found to be acceptable. Principal component analysis of headspace volatiles revealed that (E)-2-undecenal, (E)-2-hexadecenal, (E)-2 tetradecenal & (E)-2-tetradecen-1-ol in stored samples clustered with fresh samples and therefore, could be considered as freshness indicators for MPCL. PMID- 27979284 TI - Geographical characterization by MAE-HPLC and NIR methodologies and carbonic anhydrase inhibition of Saffron components. AB - A microwave-assisted extraction method was optimised for the recovery of bioactive compounds from Crocus sativus L. stigmas with the use of water/ethanol mixture. HPLC-DAD was employed to evaluate the extraction parameters, in particular, solvent type and volume, and the duration of the procedure. Microwave assisted extraction enhanced the recovery of the active principles, limiting extraction time and solvent waste. Moreover, NIR experiments were performed in order to compare spectra in pseudo-absorbance of Saffron samples with different geographical origins through the application of the chemometric techniques. Moreover, the biological evaluation of crocin 1, safranal and its semisynthetic derivatives as selective inhibitors of five isoforms of human carbonic anhydrase was also explored. PMID- 27979285 TI - Automatic determination of coenzyme Q10 in food using cresyl violet encapsulated into magnetoliposomes. AB - A new type of magnetoliposomes (MLs), containing hydrophobic magnetic-gold nanoparticles and the long wavelength fluorophore cresyl violet, has been used for the determination of coenzyme Q10 (CoQ10). MLs were concentrated just before the detector, using a flow system and an external electromagnet device. The subsequent introduction of Triton X-100 and CoQ10 causes the MLs lysis and the cresyl violet oxidation, obtaining a decrease in the fluorescence signal. The dynamic range of the calibration graph was 0.03-0.50MUmolL-1 CoQ10, and the detection limit was 0.008MUmolL-1. The precision (relative standard deviation) was in the range of 1.3-4.5%. The method showed a sampling frequency of 12h-1 and was applied to the determination of CoQ10 in several food samples. The results were compared with those obtained using a previously described chromatographic method. Also, recovery values were in the range of 83.5-101.3%. PMID- 27979286 TI - Use of Raman spectroscopy for determining erucic acid content in canola oil. AB - This study presents a novel method to determine erucic acid in canola oil samples by using Raman spectroscopy and chemometric analysis. The oil mixtures were prepared at various concentrations of erucic acid ranging from 0% to 33.56% (w/w) through binary combinations of different oils. In order to predict erucic acid content, Raman spectroscopy and GC results were correlated by means of partial least squares analysis. High coefficient of determination values was obtained for both calibration and validation data sets, which are 0.990 and 0.982, respectively. The results of the present study reveal the potential of Raman spectroscopy for rapid determination (45s) of erucic acid in canola oil. Further research would be useful to improve the method to put it forward as an alternative to GC in the erucic acid analysis. PMID- 27979287 TI - Electromembrane extraction of diamine plastic restricted substances in soft drinks followed by capillary electrophoresis with contactless conductivity detection. AB - Ethane-1,2-diamine (EA) and hexane-1,6-diamine (HA) are two important plastic restricted substances commonly existing in food contact materials. A capillary electrophoresis with capacitively coupled contactless conductivity detection (CE C4D) method has been developed for direct determination of above analytes, and the detection sensitivity has been significantly improved based on electromembrane extraction (EME). Under the optimum conditions, EA and HA could be well separated from their aliphatic diamine homologs as well as the common inorganic cations within 25min. The limits of detection could reach sub-ng/mL level, and good linearity (r>0.998) between peak area and analyte concentration could be obtained at three orders of magnitude. This EME/CE-C4D method provided a novel application for determining these plastic restricted substances in different bottled soft drinks, providing an alternative for the sensitive analyses of diamine substances. PMID- 27979288 TI - A fast and feasible method for Br and I determination in whole egg powder and its fractions by ICP-MS. AB - A method for Br and I determination in whole egg powder and its fractions (egg white and yolk) was developed by combining microwave-induced combustion (MIC) and inductively coupled plasma mass spectrometry (ICP-MS). Using the MIC method, 350mg of whole egg powder and its fractions were efficiently digested using 50mmolL-1NH4OH as an absorbing solution. The limits of detection for Br and I using the MIC method followed by ICP-MS determination were 0.039 and 0.015MUgg-1, respectively. Using the proposed method, agreements with the reference values between 97 and 104% for Br and I were obtained by analysis of reference material NIST 8435. Finally, it was possible to observe that Br concentration (4.59 5.29MUgg-1) was higher than I (0.150-2.28MUgg-1) for all the evaluated samples. PMID- 27979289 TI - Rapid ion-pair liquid chromatographic method for the determination of fenbendazole marker residue in fermented dairy products. AB - A simple, rapid and sensitive liquid chromatographic method that allows for the quantitative determination of fenbendazole residues in fermented dairy products is described. Samples were extracted with a mixture of acetonitrile-phosphoric acid and the extracts were defatted with hexane to be further partitioned into ethyl acetate. The organic layer was evaporated to dryness and the residue was reconstituted in mobile phase. Separation of fenbendazole and its sulphoxide, sulphone, and p-hydroxylated metabolites was carried out isocratically with a mobile phase containing both positively and negatively charged pairing ions. Overall recoveries ranged from 79.8 to 88.8%, while precision data, based on within and between days variations, suggested an overall relative standard deviation of 6.3-11.0%. The detection and quantification limits were lower than 9 and 21MUg/kg, respectively. The method has been successfully applied to quantitate fenbendazole residues in Feta cheese and yoghurt made from spiked and incurred ovine milk. PMID- 27979290 TI - Development and validation of a highly sensitive quantitative/confirmatory method for the determination of ivermectin residues in bovine tissues by UHPLC-MS/MS. AB - In this work, a highly sensitive quantitative/confirmatory method was developed for the selective determination of marker residue 22,23-dihydroavermectin B1a in fat, kidney, liver and muscle bovine tissues using UHPLC-MS/MS. A QuEChERS method and a subsequent d-SPE cleaning with MgSO4 and C18 were used for samples preparation. The method was validated at three levels in each tissue (8.0, 20.0 and 80.0MUg/kg for fat, kidney and muscle, 8.0, 16.0 and 40.0MUg/kg for liver), taking into account international guidelines. Linearity and matrix effect, accuracy, within-laboratory repeatability, specificity, LOQ, LOD, Q/q relative ion intensities and uncertainty were reported. Recoveries were obtained in the range of 70-120% with within-laboratory repeatability less than 20% for the overall working range. LODs varied from 0.05 to 0.12MUg/kg. Compound identification was performed using the relative intensities of monitored transitions. The method could be applied to monitoring withdrawal period specified for ivermectin in cattle. PMID- 27979291 TI - Simultaneous determination of urea and melamine in milk powder by nonlinear chemical fingerprint technique. AB - This paper proposed a nonlinear chemical fingerprint method for simultaneous determination of urea and melamine in milk powder using "H++Ce4++BrO3-+malonic acid" as reaction system. A multiple linear relationship was obtained between the adulterants content in milk powder and inductive time of corresponding mixed milk powder. System analysis model established with classical least squares (CLS) method was then used to calculate the content of urea and melamine in milk powder. The method was successfully applied to milk powder samples and had good recoveries in the range of 99.17-100.25%, with the relative standard deviation (RSD) in the range of 0.60-4.12%. The limits of detection for urea and melamine were 0.33MUg.g-1 and 0.05MUg.g-1, respectively. The limits of quantification were 1.11MUg.g-1 and 0.18MUg.g-1, respectively. The results indicated that the new method was feasible and had the advantages of low cost, simple operation and without pretreatment of samples. PMID- 27979292 TI - Determination of cadmium and lead at sub-ppt level in soft drinks: An efficient combination between dispersive liquid-liquid microextraction and graphite furnace atomic absorption spectrometry. AB - A DLLME method for extraction and preconcentration of Cd and Pb from soft drinks and further determination by GF AAS was developed. Important parameters of DLLME such as the type and volume of dispersive and extraction solvents, concentration of DDTC (complexing agent) and pH were evaluated. Better results were obtained using 500MUL of acetone for Cd and 700MUL of acetonitrile for Pb as dispersive solvents, 60MUL of CCl4 as extraction solvent for both analytes and 500MUL of 1.5% DDTC solution. Accuracy was evaluated by recovery assays and ranged from 91 to 113% for Cd and from 95 to 108% for Pb, with RSD below 10 and 7%, respectively. The LODs were 0.006 and 0.072ngL-1 for Cd and Pb, respectively. The optimized method was applied for the determination of Cd and Pb in soft drinks with different brands and flavours. PMID- 27979293 TI - Pectin from Opuntia ficus indica: Optimization of microwave-assisted extraction and preliminary characterization. AB - Optimization of microwave-assisted extraction (MAE) of water-soluble pectin (WSP) from Opuntia ficus indica cladodes was performed using Response Surface Methodology. The effect of extraction time (X1), microwave power (X2), pH (X3) and solid-to-liquid ratio (X4) on the extraction yield was examined. The optimum conditions of MAE were as follows: X1=2.15min; X2=517W; X3=2.26 and X4=2g/30.6mL. The maximum obtained yield of pectin extraction was 12.57%. Total carbohydrate content of WSP is about 95.5% including 34.4% of Galacturonic acid. Pectin related proteins represent only the 0.66% of WSP mass. HPSEC and light scattering analyses reveal that WSP is mostly constituted of high molecular pectin and FTIR measurements show that the microwave treatment does not alter the chemical structure of WSP, in which Galacturonic acid content and yield are 34.4% and 4.33%, respectively. Overall, application of MAE can give rise to high quality pectin. PMID- 27979294 TI - Contents of capsaicinoids in chillies grown in Denmark. AB - We have studied 15 different cultivars of chillies (Capsicum var.) grown in temperate climate Denmark and determined the contents of the four major capsaicinoids: capsaicin, dihydrocapsaicin, nordihydrocapsaicin, and homocapsaicin. From these contents we have, as commonly done for chillies, calculated the so-called pungency in Scoville heat units in order to compare with previous studies from other climatical zones. For three of the investigated cultivars, Serrano, Habanero and BIH Jolokia, for which reliable pungencies has previously been reported, we have found pungencies of 34,000+/-1400, 247,000+/ 24,000 and 665,000+/-4000, respectively, which are all in the same ranges as found earlier for chillies grown in more traditional chilli growing areas. Furthermore we have found that the relative distribution of the four capsaicinoids in the 15 different cultivars is highly variable, with the content of capsaicin ranging from 31% to 71% of the total capsaicinoid content. PMID- 27979295 TI - Emulsification properties of polysaccharides from Dioscorea opposita Thunb. AB - This study investigated the emulsification properties of polysaccharides from Dioscorea opposita Thunb. Graded alcohol precipitation was used to extract Dioscorea opposita polysaccharides fractions (4 samples) in different ranges of molecular weight. Sample 3 contained more glucose and protein (80.13% and 0.34%, respectively), and molecular weight was approximately 34,790Da, distributing narrowly. The droplet sizes and stabilities of emulsions made of gum arabic (GA) and polysaccharide samples at different concentrations and ratios were measured, specifically the emulsions of GA and medium-chain-triglycerides (MCT); polysaccharides and MCT; and polysaccharides, GA and MCT (1:1:1). The results indicated that sample 2 and 3 had emulsifying properties, and the emulsions made with sample 2, GA and MCT (1:1:1) presented the best emulsification properties. Therefore, polysaccharides of Dioscorea opposita could be utilised as a natural emulsifier that can be improved synergistically with other emulsifiers, such as gum arabic. PMID- 27979296 TI - Innovative application of metal-organic frameworks for encapsulation and controlled release of allyl isothiocyanate. AB - This research investigated the technical feasibility of metal-organic frameworks (MOFs) as novel delivery systems for encapsulation and controlled release of volatile allyl isothiocyanate (AITC) molecules. We hypothesized that water vapor molecules could act as an external stimulus to trigger the release of AITC molecules encapsulated in MOFs. To test this hypothesis, three MOFs-HKUST-1, MOF 74(Zn), and RPM6-Zn-were selected based on their structural properties and AITC molecular characteristics. Results from adsorption-desorption and GC headspace analyses showed that these MOFs could encapsulate and retain AITC molecules within their pores under low (30-35%) relative humidity (RH) conditions. In contrast, the release of AITC molecules from all these MOFs was triggered under high RH (95-100%) conditions. These findings along with results from SEM, TEM, and XRPD studies support our hypothesis that water vapors could trigger the AITC release from these MOFs, indicating that development of the AITC-MOFs delivering system is technically feasible. PMID- 27979297 TI - Assessing the quality of sardine based on biogenic amines using a fuzzy logic model. AB - There is an increasing concern about the quality and quality assessment procedures of seafood. In the present study, a model to assess fish quality based on biogenic amine contents using fuzzy logic model (FLM) is proposed. The fish used was sardine (Sardinella sp.) where the production of eight biogenic amines was monitored over fifteen days of storage at 0, 3 and 10 degrees C. Based on the results, histamine, putrescine and cadaverine were selected as input variables and twelve quality grades were considered for quality of fish as output variables for the FLM. Input data were processed by rules established in the model and were then defuzzified according to defined output variables. Finally, the quality of fish was evaluated using the designed model and Pearson correlation between storage times with quality of fish showed r=0.97, 0.95 and 1 for fish stored at 0, 3 and 10 degrees C, respectively. PMID- 27979298 TI - Development of the method for identification of selected populations of torpedo scad, Megalaspis cordyla (Linnaeus, 1758), using microsatellite DNA analyses. CELFISH project - Part 4. AB - Catch and consumption of torpedo scad (Megalaspis cordyla) over the western Indian Ocean, but also the western Pacific from Japan to Australia is constantly increasing. Taking into account the degree of exploitation and missing information on the population structure of torpedo scad stocks it is crucial to provide population data. The analysis included individuals obtained in 2012 and 2013 from local markets in Madagascar, Tanzania, Vietnam and Cambodia and after successful DNA extraction fragment of the nuclear rhodopsin gene (RH1) and 9 microsatellite regions (SSRs) were amplified and analysed. Based on the obtained results it was found that there was no 100% overlap between the compared RH1 sequences and those from GenBank. In the case of the studied SSRs, the results allowed the initial characterisation and assessment of the genetic diversity of populations. Moreover, population assignment test distinguished the studied populations into two geographically distant subpopulations. PMID- 27979299 TI - Analytical optimization of a phenolic-rich herbal extract and supplementation in fermented milk containing sweet potato pulp. AB - The aims of the present study were to optimize and characterize the phenolic composition of a herbal extract composed of green mate (Ilex paraguariensis), clove (Syzygium aromaticum), and lemongrass (Cymbopogon citratus) and to propose the addition of this polyphenol-rich extract to fermented milks (FM) with/without sweet potato pulp (Ipomoea batatas). Proximate composition, pH, acidity, instrumental texture profile, total phenolic content (TPC), antioxidant activity (AA) of all formulations were measured, and sensory attributes were also investigated. The addition of a lyophilized extract (1g 100g-1) containing 87.5% clove and 12.5% green mate increased the AA and TPC, while FM with added sweet potato pulp had the best sensory acceptance. The TPC and total reducing capacity had a slight change during 21days of storage. The data showed that herbal extracts and sweet potato pulp may be used to develop new dairy foods with potential functional properties. PMID- 27979300 TI - A new exploration of licorice metabolome. AB - The roots and rhizomes of licorice plants (genus Glycyrrhiza L.) are commercially employed, after processing, in confectionery production or as sweetening and flavouring agents in the food, tobacco and beer industries. G. glabra, G. inflata and G. uralensis are the most significant licorice species, often indistinctly used for different productions. Licorice properties are directly related to its chemical composition, which determines the commercial values and the quality of the derived products. In order to better understand the characteristics and properties of each species, a chemical characterization of three species of licorice (G. glabra, G. inflata, G. uralensis) is proposed, through an untargeted metabolomic approach and using high-resolution mass spectrometry. The statistical analysis reveals new possible markers for the analyzed species, and provides a reliable identification of a high number of metabolites, contributing to the characterization of Glycyrrhiza metabolome. PMID- 27979301 TI - Bioactives of coffee cherry pulp and its utilisation for production of Cascara beverage. AB - Coffee cherry pulp is a by-product obtained during coffee production. Coffee cherry pulp contains considerable amounts of phenolic compounds and caffeine. An attempt to produce Cascara, a refreshing beverage, has been made. Six dried coffee pulp samples and a beverage called Cascara produced in Switzerland out of one of those samples were investigated. Aqueous extraction of coffee pulps revealed a content of total polyphenols between 4.9 and 9.2mg gallic acid equivalents (GAE)/gDM. The antioxidant capacity was between 51 and 92MUmol Trolox equivalents (TE)/gDM as measured by the assay with ABTS radical. Bourbon variety from Congo and maragogype variety showed highest caffeine contents with 6.5 and 6.8mg/gDM. In all samples chlorogenic acid, protocatechuic acid, gallic acid and rutin were present. The beverage Cascara contained 226mg/L of caffeine and 283mgGAE/L of total polyphenols whereas antioxidant capacity amounted to 8.9mmol TE/L. PMID- 27979302 TI - 3,6-Anhydro-l-galactose, a rare sugar from agar, a new anticariogenic sugar to replace xylitol. AB - The significance for anticariogenic sugar substitutes is growing due to increasing demands for dietary sugars and rising concerns of dental caries. Xylitol is widely used as an anticariogenic sugar substitute, but the inhibitory effects of xylitol on Streptococcus mutans, the main cause of tooth decay, are exhibited only at high concentrations. Here, the inhibitory effects of 3,6 anhydro-l-galactose (AHG), a rare sugar from red macroalgae, were evaluated on S. mutans, in comparison with those of xylitol. In the presence of 5g/l of AHG, the growth of S. mutans was retarded. At 10g/l of AHG, the growth and acid production by S. mutans were completely inhibited. However, in the presence of xylitol, at a much higher concentration (i.e., 40g/l), the growth of S. mutans still occurred. These results suggest that AHG can be used as a new anticariogenic sugar substitute for preventing dental caries. PMID- 27979303 TI - Comparing sorghum and wheat whole grain breakfast cereals: Sensorial acceptance and bioactive compound content. AB - The sensory acceptance and the content of bioactive compounds of whole-sorghum and whole-wheat breakfast cereals were compared. Sensory acceptance was assessed using the Food Action RatingScale. 3-Deoxyanthocyanidins, flavones and flavanones were determined by high-performance liquid chromatography (HPLC) with diode array detection, and vitamin E by HPLC with fluorescence detection. Total phenolics and antioxidant activity were determined by spectrophotometry. The sorghum breakfast cereal had better sensory acceptance (70.6%) than wheat breakfast cereal (41.18%). Sorghum had higher 3-deoxyanthocyanidin content (100% higher), total phenolic compounds (98.2% higher) and antioxidant activity (87.9% higher) than wheat breakfast cereal. Flavones and flavanones were not detected in both breakfast cereals. Total vitamin E content was 78.6% higher in wheat than in sorghum breakfast cereal. Thus, consumption of whole sorghum breakfast cereal should be encouraged, since it had good sensory acceptance and is a source of bioactive compounds that can promote benefits to human health. PMID- 27979306 TI - Involvement of systemic venous congestion in heart failure. AB - Systemic venous congestion has gained significant importance in the interpretation of the pathophysiology of acute heart failure, especially in the development of renal function impairment during exacerbations. In this study, we review the concept, clinical characterisation and identification of venous congestion. We update current knowledge on its importance in the pathophysiology of acute heart failure and its involvement in the prognosis. We pay special attention to the relationship between abdominal congestion, the pulmonary interstitium as filtering membrane, inflammatory phenomena and renal function impairment in acute heart failure. Lastly, we review decongestion as a new therapeutic objective and the measures available for its assessment. PMID- 27979304 TI - Determination of gossypol content in cottonseeds by near infrared spectroscopy based on Monte Carlo uninformative variable elimination and nonlinear calibration methods. AB - Near infrared (NIR) spectroscopy combined with Monte Carlo uninformative variable elimination (MC-UVE) and nonlinear calibration methods employed to determine gossypol content in cottonseeds were investigated. The reference method was performed by high performance liquid chromatography coupled to an ultraviolet detector (HPLC-UV). MC-UVE was employed to extract the effective information from the full NIR spectra. Nonlinear calibration methods were applied to establish the models compared with the linear method. The optimal model for gossypol content was obtained by MC-UVE-WLS-SVM, with root mean squares error of prediction (RMSEP) of 0.0422, coefficient of determination (R2) of 0.9331, and residual predictive deviation (RPD) of 3.8374, respectively, which was accurate and robust enough to substitute for traditional gossypol measurements. The nonlinear methods performed more reliable than linear method during the development of calibration models. Furthermore, MC-UVE could provide better and simpler calibration models than full spectra. PMID- 27979305 TI - Comparative assessment of phytochemical profiles, antioxidant and antiproliferative activities of Sea buckthorn (Hippophae rhamnoides L.) berries. AB - Phytochemical profiles, antioxidant and antiproliferative activities of berry extracts were evaluated and compared in four subspecies of Sea buckthorn (Hippophae rhamnoides L.). Among the subspecies, Hippophae rhamnoides L. subsp. sinensis exhibited highest total phenolics content (38.7+/-1.3mgGA equiv./g DW) and corresponding total antioxidant activity. Whereas maximum cellular antioxidant and antiproliferative activities were determined in Hippophae rhamnoides L. subsp. yunnanensis. Total antioxidant activity was significantly associated to total phenolics, isorhamnetin-3-rutinoside and isorhamnetin-3 glucoside. The cellular antioxidant activity and antiproliferative activity of phytochemicals were fairly correlated to phenolic acids and flavonoid aglycones. Lower median effective dose (EC50) of individual compounds against human liver cancer HepG2 cells proliferation studies confirmed the better correlation between antiproliferative activity of Sea buckthorn extracts and flavonoid aglycones, including isorhamnetin, quercetin and kaempferol. PMID- 27979307 TI - Isolated Anterior Cervical Hypertrichosis. PMID- 27979308 TI - Nodular mucinosis associated with light-chain monoclonal gammopathy of uncertain significance. PMID- 27979309 TI - Idiopathic facial aseptic granuloma: Usefulness of cutaneous ultrasound. PMID- 27979311 TI - A universal modified LMS algorithm with iteration order hybrid switching. AB - This paper presents a fractional order modified least square algorithm(FOMLMS), which involves an iteration order switch strategy. A FOMLMS scheme whose iteration order can be extended into alpha?(0,2) is investigated. The performance of FOMLMS with the iteration order in different interval (070,000 people in the United States annually, has limited therapies. ASS1 loss was identified in conventional and micropapillary urothelial carcinoma, small cell, and squamous cell carcinoma subtypes of invasive bladder cancer, as well as in T24, J82, and UM-UC-3 but not in 5637, RT112, and RT4 cell lines. ASS1-deficient cells showed preferential sensitivity to ADI-PEG 20, evidenced by decreased colony formation, reduced cell viability, and increased sub-G1 fractions. ADI-PEG 20 induced general control nonderepressible 2-dependent eukaryotic initiation factor 2alpha phosphorylation and activating transcription factor 4 and C/EBP homologous protein up-regulation, associated with caspase-independent apoptosis and autophagy. These effects were ablated with selective siRNA silencing of these proteins. ASS1 overexpression in UM-UC-3 or ASS1 silencing in RT112 cells reversed these effects. ADI-PEG 20 treatment of mice bearing contralateral flank UM-UC-3 and RT112 xenografts selectively arrested tumor growth in UM-UC-3 xenografts, which had reduced tumor size, reduced Ki-67, and increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. This suggests that ASS1 loss occurs in invasive bladder cancer and is targetable by ADI-PEG 20. PMID- 27979312 TI - Analysis, control and design of a non-inverting buck-boost converter: A bump-less two-level T-S fuzzy PI control. AB - In this paper, a new modified fuzzy Two-Level Control Scheme (TLCS) is proposed to control a non-inverting buck-boost converter. Each level of fuzzy TLCS consists of a tuned fuzzy PI controller. In addition, a Takagi-Sugeno-Kang (TSK) fuzzy switch proposed to transfer the fuzzy PI controllers to each other in the control system. The major difficulty in designing fuzzy TLCS which degrades its performance is emerging unwanted drastic oscillations in the converter output voltage during replacing the controllers. Thereby, the fuzzy PI controllers in each level of TLCS structure are modified to eliminate these oscillations and improve the system performance. Some simulations and digital signal processor based experiments are conducted on a non-inverting buck-boost converter to support the effectiveness of the proposed TLCS in controlling the converter output voltage. PMID- 27979313 TI - High resolution of racemic phenylalanine with dication imidazolium-based chiral ionic liquids in a solid-liquid two-phase system. AB - A novel solid-liquid two-phase system was developed for the chiral separation of racemic phenylalanine with new dication imidazolium-based chiral ionic liquids. Preliminary experiments showed distinct enantioselectivity in amino acid extraction with the novel solid-liquid two-phase system, more L-enantiomer of amino acid cooperatively interacted with ionic liquids and copper ions to be the solid phase. Various factors, including the alkyl chain length of cations of ionic liquids, the amount of copper acetate, the ratio of n(ILs)/n(Cu2+), the amount of water and racemic phenylalanine, the resolution time together with the resolution temperature, were systematically investigated for their influence on resolution efficiency. The results showed that, under a certain condition, the enantiomeric excess value and the yield of phenylalanine in liquid phase (mainly containing D-enantiomer) were 67.8% and 96.5%, the enantiomeric excess value and the yield of phenylalanine in solid phase (mainly containing L-enantiomer) were 99.2% and 85.2%. Finally, 2D NMR technology, infrared spectroscopy and molecular simulation method were used to study the interaction mechanism. The results indicated that L-enantiomer of phenylalanine interacts more strongly with chiral ILs and Cu2+. The novel system has characteristics of free-organic solvent, simple operation, fast separation process and very high resolution efficiency for racemic phenylalanine. This work could provide a new and alternative resolution approach for other chiral separations. PMID- 27979314 TI - Visual short-term memory binding deficits in Alzheimer's disease: a reply to Parra's commentary. PMID- 27979315 TI - Quality criteria in bariatric surgery: Consensus review and recommendations of the Spanish Association of Surgeons and the Spanish Society of Bariatric Surgery. AB - Bariatric surgery has proven to be highly effective in controlling obesity and metabolic syndrome; the results of this surgery are not only expressed in terms of weight loss, but also in terms of resolution of comorbidities, improved quality of life and complications. The different parameters used to measure these outcomes require uniformity and reference patterns. Therefore, it is essential to identify those indicators and quality criteria that are helpful in defining the "best practice" principles in bariatric surgery. In this regard, the Section of Obesity of the Spanish Association of Surgeons, in collaboration with the Spanish Society for Bariatric Surgery (SECO), present as an objective to identify the key points that define "quality" in this type of surgery. We describe the main indicators based on the published literature as well as the criteria for referral of the main comorbidities according to the evidence found and grades of recommendation. PMID- 27979316 TI - Seasonal mood changes in patients with obsessive-compulsive disorder. AB - Obsessive-compulsive disorder (OCD) is frequently associated with mood disorders. However, to date, the co-occurrence of OCD with seasonal affective disorder (SAD) has not been investigated. We have aimed to estimate the prevalence of seasonal mood changes in patients with OCD and explore the contribution of seasonality in mood to the severity of OCD. The Seasonal Pattern Assessment Questionnaire (SPAQ), the Yale-Brown Obsession and Compulsion Scale (Y-BOCS), the Hamilton Depression Rating Scale-17 Items (HDRS-17), and the Beck Anxiety Inventory (BAI) were administered to patients with OCD (n=104) and controls (n=125). The degree of seasonality was measured by the Global Seasonality Score (GSS) calculated from the SPAQ. SAD and subsyndromal seasonal affective disorder (S-SAD) were significantly more prevalent in patients with OCD (53%, n=55) than controls (25%, n=31). When patients were assessed in the season in which SAD occurs, depression and compulsions (but not obsessions, OCD or anxiety) were more severe than those assessed in a season during which SAD does not occur. SAD frequently co-occurs with OCD and, given this co-occurrence, depression symptoms in some patients with OCD might be expected to vary on a seasonal basis. PMID- 27979317 TI - Estrogen Receptor beta as a Pharmaceutical Target. AB - A major issue in clinical endocrinology today is how to use hormones to achieve the health benefits that they clearly can provide but avoid the negative side effects, that is, how to develop more precise medicines. This problem of how to use hormones is pervasive in clinical endocrinology. It is true for estrogen, progesterone, androgen, vitamin D, and thyroid hormone, and the problem is amplified in the case of new ligands for the more recently discovered nuclear receptors. Selective targeting of hormone receptor subtypes is one attractive way to harness the beneficial effects of hormones while reducing unwanted side effects. Here, we focus on estrogen receptor (ER)beta, which has promise as a selective target in hormone replacement therapy, and in breast and prostate cancers. PMID- 27979318 TI - Molecular Diagnostics of Ageing and Tackling Age-related Disease. AB - As average life expectancy increases there is a greater focus on health-span and, in particular, how to treat or prevent chronic age-associated diseases. Therapies which were able to control 'biological age' with the aim of postponing chronic and costly diseases of old age require an entirely new approach to drug development. Molecular technologies and machine-learning methods have already yielded diagnostics that help guide cancer treatment and cardiovascular procedures. Discovery of valid and clinically informative diagnostics of human biological age (combined with disease-specific biomarkers) has the potential to alter current drug-discovery strategies, aid clinical trial recruitment and maximize healthy ageing. I will review some basic principles that govern the development of 'ageing' diagnostics, how such assays could be used during the drug-discovery or development process. Important logistical and statistical considerations are illustrated by reviewing recent biomarker activity in the field of Alzheimer's disease, as dementia represents the most pressing of priorities for the pharmaceutical industry, as well as the chronic disease in humans most associated with age. PMID- 27979319 TI - Three versus six cycles of adjuvant platinum-based chemotherapy in early stage clear cell ovarian carcinoma - A multi-institutional cohort. AB - OBJECTIVES: To determine if 6 versus 3cycles of adjuvant platinum-based chemotherapy with or without taxane impacts survival in early stage ovarian clear cell carcinoma (OCCC). METHODS: We retrospectively identified all cases of stage I and II OCCC treated at 5 institutions from January 1994 through December 2011. Patients were divided into 2 groups: those who received 3 versus 6cycles of adjuvant chemotherapy. Our cohort consisted of 210 patients with stage IA-II disease, 116 of whom underwent full surgical staging. Cox proportional hazards regression and Kaplan-Meier analyses were performed to evaluate progression-free (PFS) and overall survival (OS) between groups. RESULTS: Among 210 eligible patients, the median age was 53years (range 30-88). The majority of patients were Caucasian (83.8%). All patients received adjuvant chemotherapy with 90% receiving carboplatin and paclitaxel. Thirty-eight (18.1%) patients received 3cycles, and 172 (81.9%) patients received 6cycles of adjuvant treatment. Recurrence rate was comparable between groups (18.4% vs. 27.3% for 3 vs. 6cycles, p=0.4). There was no impact of 3 versus 6cycles of chemotherapy on PFS (hazard ratio [HR] 1.4; 95% confidence interval [CI] 0.63-3.12, p=0.4) or OS (HR 1.65; 95% CI 0.59-4.65, p=0.3) on univariate analysis. There was no benefit to more chemotherapy in stratified analysis by stage nor on multivariate analysis adjusting for the impact of stage. Subgroup analysis of surgically staged patients also showed no difference in survival between 3 versus 6cycles of chemotherapy. CONCLUSIONS: Three cycles of platinum with or without taxane adjuvant chemotherapy were comparable to 6cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort. CONDENSATION: Three cycles of platinum with or without taxane adjuvant chemotherapy are comparable to 6 cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort. PMID- 27979320 TI - Locating the Seventh Cervical Spinous Process: Development and Validation of a Multivariate Model Using Palpation and Personal Information. AB - OBJECTIVE: The aim of this study was to develop and validate a multivariate prediction model, guided by palpation and personal information, for locating the seventh cervical spinous process (C7SP). METHODS: A single-blinded, cross sectional study at a primary to tertiary health care center was conducted for model development and temporal validation. One-hundred sixty participants were prospectively included for model development (n = 80) and time-split validation stages (n = 80). The C7SP was located using the thorax-rib static method (TRSM). Participants underwent chest radiography for assessment of the inner body structure located with TRSM and using radio-opaque markers placed over the skin. Age, sex, height, body mass, body mass index, and vertex-marker distance (DV-M) were used to predict the distance from the C7SP to the vertex (DV-C7). Multivariate linear regression modeling, limits of agreement plot, histogram of residues, receiver operating characteristic curves, and confusion tables were analyzed. RESULTS: The multivariate linear prediction model for DV-C7 (in centimeters) was DV-C7 = 0.986DV-M + 0.018(mass) + 0.014(age) - 1.008. Receiver operating characteristic curves had better discrimination of DV-C7 (area under the curve = 0.661; 95% confidence interval = 0.541-0.782; P = .015) than DV-M (area under the curve = 0.480; 95% confidence interval = 0.345-0.614; P = .761), with respective cutoff points at 23.40 cm (sensitivity = 41%, specificity = 63%) and 24.75 cm (sensitivity = 69%, specificity = 52%). The C7SP was correctly located more often when using predicted DV-C7 in the validation sample than when using the TRSM in the development sample: n = 53 (66%) vs n = 32 (40%), P < .001. CONCLUSIONS: Better accuracy was obtained when locating the C7SP by use of a multivariate model that incorporates palpation and personal information. PMID- 27979321 TI - Analysis of the Cochrane Review: Fibrates for secondary prevention of cardiovascular disease and stroke. AB - The influence of fibrates on cardiovascular risk has been the focus of several clinical trials. This Cochrane Collaboration Systematic Review evaluated the efficacy of fibrates for secondary prevention of cardiovascular events and stroke, analyzing 13 randomized controlled trials, in a total of 16 112 participants with a history of cardiovascular disease. Fibrates showed a protective effect for the composite outcome of non-fatal stroke, non-fatal myocardial infarction (MI) and vascular death, mainly due to reduction in the risk of non-fatal or fatal MI. Nonetheless, these results largely relied on studies including clofibrate, a drug withdrawn from the market in 2002. No statistically significant differences regarding adverse events were found between fibrates and placebo. Although insufficient to support the routine prescription of fibrates in this setting, this evidence should be taken into account when deciding on lipid-modifying therapy in dyslipidemic patients with a history of cardiovascular disease. PMID- 27979322 TI - Coronary sinus atrial septal defect in a 65-year-old woman: Diagnosis by two- and three-dimensional echocardiography. PMID- 27979323 TI - Renal denervation in heart failure: Modulating the sympathetic nervous system. PMID- 27979324 TI - Amyloidosis and its management: Amyloid neuropathies. PMID- 27979326 TI - Happy New Year! PMID- 27979325 TI - Early cognitive impairment along with decreased stress-induced BDNF in male and female patients with newly diagnosed multiple sclerosis. AB - The aim of this study was to evaluate neuroendocrine activation during stress in patients with recently diagnosed multiple sclerosis before starting the immunomodulatory therapy (EDSS score<=2.0). We verified the hypothesis that certain cognitive and affective dysfunction is present already at this early stage of the disease. The sample consisted of 38 subjects, which involved patients who were recently diagnosed multiple sclerosis and age- and sex-matched healthy volunteers. Stroop test served as mental stress model enabling measurement of cognitive performance. Present results showed increased state anxiety, depression scores and poorer performance in the Stroop test in the group of patients compared to healthy subjects. The cognitive dysfunction was particularly evident in male patients with simultaneously decreased concentrations of the brain-derived neurotrophic factor (BDNF) in plasma. The patients at this stage of the disease have not yet developed the hyperactivity of the hypothalamic-pituitary-adrenocortical axis. They showed normal levels of plasma copeptin and reduced aldosterone response to mental stress test in women only. Concentrations of plasma copeptin were higher in men compared to women. Very early stages of multiple sclerosis are accompanied by disturbances in psychological well-being, mild cognitive dysfunction and decreased plasma concentrations of BDNF, particularly in male patients. PMID- 27979327 TI - Medical Nutrition Therapy for Pediatric Kidney Stone Prevention, Part One. PMID- 27979328 TI - Corrigendum to "Methods of information theory and algorithmic complexity for network biology" [Semin. Cell Dev. Biol. 51 (2016) 32-43]. PMID- 27979329 TI - Membrane fusion: Conserved and diverse. PMID- 27979330 TI - [What surgery for recurrent Darier-Ferrand sarcoma of the chest wall?] AB - INTRODUCTION: Dermatofibrosarcoma protuberans (Darrier-Ferrand sarcoma, DFSP) is an uncommon tumor. This sarcoma has a tendency to local recurrence, requiring a wide surgical resection. OBSERVATION: We report herein two cases of patients presenting with recurrent dermatofibrosarcoma protuberans after several surgical resections. A wide surgical resection with guided tissue regenaration has been performed in one case, whereas the second case required a skin graft. CONCLUSION: Despite a short follow-up, our aim was to highlight the local aggressiveness of the DFSP and point out its therapeutic challenge, usually requiring a wide and aggressive surgery. PMID- 27979331 TI - Genome-Wide Insights into the Development and Function of Thermogenic Adipocytes. AB - Brown and brown-like adipocytes are specialized adipocytes with a high capacity to convert metabolic energy to heat. This function is not only eminent in supporting organismal thermogenesis, but may also have potential in the fight against obesity. The latter has spurred a massive interest in understanding the development and regulation of these thermogenic adipocytes. Here, we review how genome-wide studies based on next-generation sequencing have provided insight into how the chromatin and transcriptional landscapes are established in thermogenic adipocytes and how thermogenic signals can change the genomic programming of white adipocytes. Furthermore, we discuss how the integration of genomic data can be used to discover novel transcriptional pathways that may be modulated as part of therapeutic strategies for the treatment of obesity. PMID- 27979333 TI - Vocal Quality in Theater Actors. AB - OBJECTIVES: The purpose of this study was to investigate vocal quality, vocal complaints, and risk factors for developing voice disorders in theater actors. Secondly, the impact of one vocal performance on the voice was investigated by comparing objective and subjective vocal quality before and after a theater performance. STUDY DESIGN: Prospective study of the actors' voice prior to and after a performance METHODS: Speech samples of 26 theater actors (15 men, 11 women, mean age 41.9 years) were recorded before and after a theater performance of one and a half hour and analyzed using the software program Praat. Speech samples consisted of the combination of sustained phonation and continuous speech. For each speech sample, the Acoustic Voice Quality Index was calculated. Auditory perceptual evaluations were performed using the GRBASI scale. Questionnaires were used to inventory vocal symptoms and influencing factors. RESULTS: Acoustic analysis showed a mean Acoustic Voice Quality Index (AVQI) of 3.48 corresponding with a mild dysphonia. Fifty percent of the theater actors reported having (sometimes or regularly) vocal complaints after a performance. The questionnaire revealed a high presence of vocally violent behavior and poor vocal hygiene habits. Objective vocal quality, measured by the AVQI, did not change after a theater performance. The auditory perceptual evaluation of the overall grade of dysphonia showed a subtle amelioration of the vocal quality. CONCLUSIONS: The results of this study showed the presence of mild dysphonia, regular vocal complaints, and poor vocal hygiene habits in theater actors. A theater performance did not have an impact on the objective vocal quality. PMID- 27979332 TI - Polydrug use among urban adolescent cigarette smokers. AB - PURPOSE: Adolescent smokers are at increased risk for polydrug use, which is associated with more consequences than use of a single drug. Here we classified subgroups of polydrug use among urban adolescent cigarette-smokers; described the sociodemographic, smoking, and depression correlates; and identified three-year outcomes associated with subgroup membership. METHODS: Adolescent cigarette smokers (N=176; Mage=16.1; 35% male; 27% white) completed surveys assessing drug use, smoking characteristics, demographics, and depressive symptoms at baseline and 12, 24, and 36months follow-up. RESULTS: Almost all participants (96%) reported using, on average, two (SD=0.97) substances (including other tobacco products) in addition to cigarettes. Latent class analysis revealed two distinct classes of polydrug users. "Limited Range Use" (84%) class members reported current use of other tobacco, alcohol, and marijuana, as did "Extended Range Use" class members (16%) who also reported current use of "harder drugs" (i.e., cocaine/crack, hallucinogens, ecstasy, and misused prescriptions). The classes did not differ on demographics or baseline likelihood of marijuana (chi2=0.25; p<0.62) or alcohol use (chi2=3.3; p<0.07). At baseline, a larger proportion of Extended Range Use class members reported both smoking the entire cigarette and symptoms of clinical depression. Extended Range Use class membership at baseline predicted higher mean depression scores at 24 and 36months. CONCLUSION: Adolescent cigarette-smokers who reported extended range use (18%) also reported symptoms of clinical depression at baseline and follow-up. These findings indicate a need for early monitoring of depression symptoms and prevention and cessation interventions targeting this high-risk group. PMID- 27979334 TI - Quantification of weakness caused by distal median nerve lesion by dynamometry. AB - INTRODUCTION: In the assessment of hand and upper limb function, grip strength is of major importance. Use of the JAMAR dynamometer has been an accepted test of grip strength and routinely part of the physical examination. PURPOSE OF THE STUDY: The aim of this study was to determine by means of a median nerve block simulating a patient group if the measurement of different types of grip force can improve the quantification of impairment of the hand beyond the sole power grip measurements. METHODS: In 29 healthy volunteers, grip force measurement was done by the JAMAR dynamometer for power grip and by a pinch grip dynamometer for pincer grip, precision grip, pinch grip, and palmar abduction. At the power grip, the force of digit 2-5 was measured separately by a sensor glove. For each measurement, 3 trials were recorded subsequently. STUDY DESIGN: A within-subject research design was used in this prospective study. Each subject served as the control by preinjection measurements of grip and pinch strength. Subsequent measurements after median nerve block were used to examine within-subject change. RESULTS: In power grip, there was no significant reduction of maximum grip force with median nerve block compared with grip force without block. By measuring the finger forces by a sensor glove, a reduction of force at the individual fingers was found compared with the setting with no block, although significant only at the middle finger (P < .017). With median nerve block, average grip force decreased significantly 20% in pincer grip (P < .021), 29.5% in pinch grip (P < .002), 39.5% in precision grip (P < .001), and 70.7% in palmar abduction (P < .013). CONCLUSIONS: These experiments suggest a minor role of the measurement of the power grip force in the diagnostics of distal median nerve block with the dynamometer, which could not be substantially improved by the digit forces and the force distribution of the individual fingers. The assessment of other grip forms, such as pincer grasp, precision grip, pinch grip, and especially palmar abduction, leads to a relevant improvement in the diagnostics of distal median nerve lesion. LEVEL OF EVIDENCE: II. PMID- 27979335 TI - Non-lymphoid lesions that may mimic cutaneous hematopoietic neoplasms histologically. AB - This review considers neoplastic lesions that originate in the skin, and which have the potential to imitate hematopoietic proliferations at a histological level. They include lymphoepithelioma-like carcinoma, Merkel cell carcinoma, benign lymphadenoma, pseudolymphomatous angiosarcoma, lymphadenoid dermatofibroma, lymphomatoid atypical fibroxanthoma, histiocytoid (epithelioid) hemangioma, and inflamed melanocytic lesions. The clinical and pathological features of those tumors are considered. PMID- 27979337 TI - Rare advances for rare diseases. PMID- 27979336 TI - Past, present and future of cutaneous lymphomas. AB - Primary cutaneous lymphomas represent a broad group of diseases with different clinical, histopathological, phenotypic, molecular, and prognostic features. All cutaneous lymphomas share the same tropism of neoplastic lymphocytes for the skin, but precise classification is paramount for proper management of the patients. Primary cutaneous lymphomas are classified according to the schemes proposed by the European Organization for Research and Treatment of Cancer (EORTC)-Cutaneous Lymphomas Task Force together with the World Health Organization (WHO) in 2005, and the WHO classification of 2008 with the 2016 update. The recognition of organ-based lymphomas, including cutaneous lymphomas, reflects a shift in the approach to lymphoproliferative disorders, and represents one of the major advances in the WHO classification of hematological tumors. Future studies should be aimed at shedding light on the many grey areas of cutaneous lymphomas (particularly the diagnosis and nomenclature of early mycosis fungoides and variants), and at gathering more data on the disorders that are still listed as provisional entities in the WHO classification. PMID- 27979338 TI - Multiple sclerosis: the upward trajectory continues. PMID- 27979339 TI - Neuromuscular diseases: hope and hurdles in clinical trials. PMID- 27979340 TI - Paediatric neurology in 2016: a year in review. PMID- 27979341 TI - Sleep in 2016: methodological issues and progress. PMID- 27979342 TI - Neurological infections in 2016: Zika and the rest. PMID- 27979343 TI - Stroke research in 2016: when more medicine is better, and when it isn't. PMID- 27979344 TI - Alzheimer's disease pathology in synucleinopathies. PMID- 27979345 TI - Corrections. PMID- 27979346 TI - Salzburg criteria: can we extend validation to critical care? - Authors' reply. PMID- 27979347 TI - Salzburg criteria: can we extend validation to critical care? PMID- 27979348 TI - Astroglial scarring after blast exposure: unproven causality. PMID- 27979349 TI - Astroglial scarring after blast exposure: unproven causality - Authors' reply. PMID- 27979350 TI - Placebos in clinical trials: unravelling a complex phenomenon. PMID- 27979351 TI - Placebos in clinical trials: unravelling a complex phenomenon - Authors' reply. PMID- 27979352 TI - Tsuneya Ikezu. PMID- 27979353 TI - Modern diagnosis of Flaubert's death mask. PMID- 27979354 TI - Alzheimer's disease and other dementias: update on research. PMID- 27979355 TI - The most important advances in headache research in 2016. PMID- 27979357 TI - Epilepsy research in 2016: new treatment directions. PMID- 27979358 TI - DNA repair in the trinucleotide repeat disorders. AB - BACKGROUND: Inherited diseases caused by unstable repeated DNA sequences are rare, but together represent a substantial cause of morbidity. Trinucleotide repeat disorders are severe, usually life-shortening, neurological disorders caused by nucleotide expansions, and most have no disease-modifying treatments. Longer repeat expansions are associated with genetic anticipation (ie, earlier disease onset in successive generations), although the differences in age at onset are not entirely accounted for by repeat length. Such phenotypic variation within disorders implies the existence of additional modifying factors in pathways that can potentially be modulated to treat disease. RECENT DEVELOPMENTS: A genome-wide association study detected genetic modifiers of age at onset in Huntington's disease. Similar findings were seen in the spinocerebellar ataxias, indicating an association between DNA damage-response and repair pathways and the age at onset of disease. These studies also suggest that a common genetic mechanism modulates age at onset across polyglutamine diseases and could extend to other repeat expansion disorders. Genetic defects in DNA repair underlie other neurodegenerative disorders (eg, ataxia-telangiectasia), and DNA double-strand breaks are crucial to the modulation of early gene expression, which provides a mechanistic link between DNA repair and neurodegeneration. Mismatch and base excision repair are important in the somatic expansion of repeated sequences in mouse models of trinucleotide repeat disorders, and somatic expansion of the expanded CAG tract in HTT correlates with age at onset of Huntington's disease and other trinucleotide repeat disorders. WHERE NEXT?: To understand the common genetic architecture of trinucleotide repeat disorders and any further genetic susceptibilities in individual disorders, genetic analysis with increased numbers of variants and sample sizes is needed, followed by sequencing approaches to define the phenotype-modifying variants. The findings must then be translated into cell biology analyses to elucidate the mechanisms through which the genetic variants operate. Genes that have roles in the DNA damage response could underpin a common DNA repeat-based mechanism and provide new therapeutic targets (and hence therapeutics) in multiple trinucleotide repeat disorders. PMID- 27979359 TI - Movement disorders in 2016: from genes to phenotypes. PMID- 27979356 TI - Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis. AB - BACKGROUND: Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. METHODS: In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed alpha synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, alpha-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging-Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. FINDINGS: On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed alpha synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral alpha synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0.0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (beta -4.0, 95% CI -5.5 to -2.6; p<0.0001; R2 0.22, p<0.0001) and with survival (-2.0, -3.2 to -0.8; 0.003; 0.15, <0.0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral alpha synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. INTERPRETATION: Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to alpha-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-beta or alpha synuclein, and to stratify them by level of Alzheimer's disease neuropathology. FUNDING: US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke). PMID- 27979361 TI - [Warming up with endotrainer prior to laparoscopic cholecystectomy]. AB - BACKGROUND: Laparoscopic cholecystectomy is a safe and effective treatment and remains the gold standard in patients with benign disease. However it presents difficulties such as: the limited movement range of the instruments, the loss of depth perception, haptic feedback and the fulcrum effect. Previous training can optimize surgical performance in patients to master basic skills. OBJECTIVE: Assess the effectiveness of surgeons warming up with an endotrainer before performing laparoscopic cholecystectomy. MATERIAL AND METHODS: Single-blind controlled clinical trial with 16 surgeons who performed 2 laparoscopic cholecystectomies, the first according to standard practice and the second with warm-up comprising 5 MISTELS system exercises. Patient and surgeon demographics were recorded, in addition to findings and complications during and after surgery for each procedured. RESULTS: We found a decrease in surgical time of 76.88 (+/ 18.87) minutes in the group that did not warm up to prior to surgery compared with 72.81 (+/-35.5) minutes in the group with warm-up (p=0.0196). In addition, increased bleeding occurred in the procedures performed with warm-up 31.25 (+/ 30.85) ml compared with the group that had no warm-up 23.94 (+/-15.9) (p=0.0146). CONCLUSION: Performing warm up on a MISTELS system endotrainer before performing laparoscopic cholecystectomy reduces the operating time of surgery for all surgeons. Surgery bleeding increases in operations performed by surgeons with less experience in laparoscopic surgery. PMID- 27979362 TI - [Validation and clinical application of MammaPrint(r) in patients with breast cancer]. AB - BACKGROUND: In recent years, advances in molecular biology have resulted in innovations in breast cancer diagnostics and therapeutics. The development of genomics has revolutionized our understanding of this disease. MammaPrint(r) was developed as a diagnostic tool to predict risk of breast cancer recurrence using the expression of 70 genes altering the clinicopathologic paradigm of selection of patients for adjuvant cytotoxic chemotherapy. MATERIALS AND METHODS: A study of stage i-ii breast cancer patients on whom the MammaPrint(r) genomic assay was performed. RESULTS: The use of the MammaPrint(r) assay was a decisive factor for the recommendation of adjuvant treatment with chemotherapy and/or hormone therapy in patients with high risk for relapse. In our group, the patients with low-risk have not presented local or systemic recurrences DISCUSSION: The determination of the genetic characteristics and its alterations in breast cancer, is fundamentally important for a better identification of risk, as well as a better selection of cancer therapy. CONCLUSION: MammaPrint(r) is an effective study to determine risk of recurrence of in early stage breast cancer. PMID- 27979360 TI - Risk of post-procedural bleeding in children on intravenous fish oil. AB - BACKGROUND: Intestinal failure-associated liver disease (IFALD) can be treated with parenteral fish oil (FO) monotherapy, but practitioners have raised concerns about a potential bleeding risk. This study aims to describe the incidence of clinically significant post-procedural bleeding (CSPPB) in children receiving FO monotherapy. METHODS: A retrospective chart review was performed on patients at our institution treated with intravenous FO for IFALD. CSPPB was defined as bleeding leading to re-operation, transfer to the intensive care unit, re admission, or death, up to one month after any invasive procedure. RESULTS: From 244 patients reviewed, 183 underwent >=1 invasive procedure(s) (n = 732). Five (0.68%, 95% CI 0.22-1.59%) procedures resulted in CSPPB. FO therapy was never interrupted. No deaths due to bleeding occurred. CONCLUSIONS: Findings suggest that FO therapy is safe, with a CSPPB risk no greater than that reported in the general population. O3FA should not be held in preparation for procedures or in the event of bleeding. PMID- 27979363 TI - [Aplasia cutis congenita associated with epidermolysis bullosa]. AB - INTRODUCTION: Aplasia cutis congenita (ACC) is a skin condition of rare presentation, this disease is characterized by absence of skin at birth and associated with facial, skin and bone skull deformities. The diagnosis is mainly clinical. CASE REPORT: Male 5 days after birth, unique product of primigravida mother and no family history of relevance. Physical examination revealed bilateral and symmetrical skin defects of both lower extremities, the disease is characterized by skin fragility, scabs, and coated pseudomembrane ulcers, decreased interdigital space between toes of the left foot, retraction of the foot and genu varum. It was handled with allograft of epidermis cultured in vitro, general wound care and clinical follow-up. DISCUSSION: ACC associated with epidermolysis bullosa is one of the rarer forms of presentation. It is necessary to rule out other skin diseases. Clinical management is recommended with biological or synthetic skin cover, infection prevention, early treatment of complications and clinical follow. PMID- 27979364 TI - Immunotherapy and patients treated for cancer with microsatellite instability. AB - Microsatellite instability (MSI) is a tumor phenotype linked to somatic or germline (Lynch syndrome) inactivating alterations of DNA mismatch repair genes. A broad spectrum of neoplasms exhibits MSI phenotype, mainly colorectal cancer, endometrial cancer, and gastric cancer. MSI tumors are characterized by dense immune infiltration and high load of tumor neo-antigens. Growing evidence is accumulating on the efficacy of immune checkpoint inhibition for patients treated for MSI solid tumors. We present a comprehensive overview of MSI phenotype, its biological landscape and current diagnostic methods. Then we focus on MSI as a predictive biomarker of response to immune checkpoint inhibition in the context of colorectal cancer and non-colorectal tumors. PMID- 27979365 TI - Rupture of the short head component of a bifurcated distal biceps tendon. AB - BACKGROUND: Rupture of the short head component of a bifurcated distal biceps tendon is a rare injury that may be difficult to diagnose and to treat. METHODS: Three cases of patients with selective disruption of the short head of the biceps distal tendon from a single institution are reported. The presenting history, physical examination, imaging studies, operative findings, and treatment strategies are described. RESULTS: In each case, the mechanism of injury was forceful flexion of the involved elbow against an eccentric load. Notable physical examination findings included a palpable tendon in the antecubital fossa, a "reverse Popeye" deformity, and pain and weakness with resisted forearm supination and elbow flexion. Careful review of the magnetic resonance imaging studies demonstrated the classic findings for this unique injury. All 3 patients successfully returned to their baseline level of activity after anatomic repair of the short head component with or without independent repair of the long head component (depending on the degree of partial tearing seen intraoperatively). DISCUSSION/CONCLUSIONS: Rupture of the short head component of a bifurcated distal biceps tendon is a rare injury that can be easily misdiagnosed and mistreated. A meticulous physical examination and evaluation of imaging is required to differentiate this injury from a partial or complete tear of a common distal biceps tendon. Clinicians should maintain a high index of suspicion for this unusual injury pattern. When it is diagnosed appropriately, selective disruption of the short head of the biceps distal tendon may be effectively treated with anatomic repair. PMID- 27979366 TI - Does the saline load test still have a role in the orthopaedic world? A systematic review of the literature. AB - INTRODUCTION: The aim of this systematic review was to assess the efficacy of Saline load tests (SLTs) to evaluate extension of periarticular wounds into capsule in emergent settings. METHODS: We systematically reviewed the literature to evaluate the accuracy of the SLT in diagnosing penetrating joint injuries in the elbow, wrist, shoulder, knee, or ankle. RESULTS: The SLT values to determine knee arthrotomies vary from 73.8 mL to 194 mL with sensitivities ranging between 91% and 99% depending on the size of the laceration. A SLT of 30 mL in the ankle yields sensitivities ranging from 95% to 99% in assessing joint penetration. A SLT of 45 mL in the elbow yields a sensitivity of 95% in assessing joint penetration. The addition of methylene blue does not change the sensitivity of the SLT. CONCLUSION: Several studies have demonstrated the utility of the SLT as a diagnostic modality for penetrating joint injuries. However, the literature analyzed in this study was inconclusive and more studies are required to make definitive recommendations. In addition, more studies will be needed on joints other than the knee, pediatric patients, and the use of methylene blue dye in conjunction with SLT. LEVEL OF EVIDENCE: Level II, Diagnostic study. PMID- 27979367 TI - Synthesis and immunological evaluation of a low molecular weight saccharide with TLR-4 agonist activity. AB - The paucity of FDA approved adjuvants renders the synthesis, characterization, and use of new compounds as vaccine adjuvants, a necessity. For this purpose, a novel saccharide analog has been synthesized from glucosamine, pyruvylated galactose and 1,4-cyclohexanediol and its biological efficacy was determined in innate immune cells. More specifically, we assessed the production of pro inflammatory cytokines from the murine monocyte cell line, Raw 264.7 and from C57 BL/6 mouse peritoneal macrophages following exposure to the saccharide analog. Our data conclude that the novel saccharide has immunostimulatory activity on mouse macrophages as indicated by the elevated levels of IL-6 and TNF-alpha in culture supernatants. This effect was TLR-4-dependent but TLR-2-independent. Our data, suggest TLR-4 agonism; a key feature of vaccine adjuvants. PMID- 27979368 TI - Extended high frequency audiometry in users of personal listening devices. AB - PURPOSE: Noise exposure leads to high frequency hearing loss. Use of Personal Listening Devices may lead to decline in high frequency hearing sensitivity because of prolonged exposure to these devices at high volume. This study explores the changes in hearing thresholds by Extended High Frequency audiometry in users of personal listening devices. MATERIAL AND METHOD: A descriptive, hospital based observational study was performed with total 100 subjects in age group of 15-30years. Subjects were divided in two groups consisting of 30 subjects (Group A) with no history of Personal Listening Devices use and (Group B) having 70 subjects with history of use of Personal Listening Devices. Conventional pure tone audiometry with extended high frequency audiometry was performed in all the subjects. RESULT: Significant differences in hearing thresholds of Personal Listening Device users were seen at high frequencies (3kHz, 4kHz and 6kHz) and extended high frequencies (9kHz, 10kHz, 11kHz, 13kHz, 14kHz, 15kHz and 16kHz) with p value <0.05. Elevated hearing thresholds were observed in personal listening devices users which were directly proportional to volume and duration of usage. CONCLUSION: In present study no significant changes were noted in hearing thresholds in PLD users before 5years of PLD use. However, hearing thresholds were significantly increased at 3kHz, 10kHz, 13kHz in PLD users having >5years usage at high volume. Thus, it can be reasonably concluded that extended high frequencies can be used for early detection of NIHL in PLD users. PMID- 27979369 TI - Regional variability in radiation-induced lung damage can be predicted by baseline CT numbers. AB - BACKGROUND AND PURPOSE: Lung volumes are functionally heterogeneous but typically considered uniformly during radiotherapy planning. The present study aims to predict regional differences in radiation-induced lung damage based on pre treatment CT information. MATERIALS AND METHODS: For 42 lung cancer patients (including 15 from an external validation set), two 200cc lung subvolumes (low density (LD) and high-density (HD)) were auto-segmented in the ipsilateral lung of the planning CT0. After non-rigid registration of 3month follow-up CT scans, sigmoidal dose-density change (DeltaHU=HU3M-HU0) response curves were determined for all subvolumes. Predictive factors for the sigmoidal response parameters D50 and saturation level DeltaHUmax were analyzed. RESULTS: The baseline density difference between LD (mostly in the upper lobe) and HD (mostly in the lower lobe) was on average 102HU. The saturation level DeltaHUmax,LD was significantly smaller than DeltaHUmax,HD (p=0.03). Expressed as mass density increase relative to the baseline density, saturation levels were 20.7% on average irrespective of baseline density, and they could be predicted in LD and HD subvolumes (AUC=0.70 0.78). Intra-lung differences in D50 were significantly smaller than inter patient differences. CONCLUSIONS: Limited amount of damage was observed in LD subvolumes, while the relative density increase of all subvolumes was well predictable. This could allow dose redistribution preferentially targeting low density lung regions. PMID- 27979371 TI - Melatonin premedication improves quality of recovery following bariatric surgery a double blind placebo controlled prospective study. AB - BACKGROUND: Melatonin has hypnotic, sedative, analgesic, anti-inflammatory, and antioxidant properties, and is a widely used sleep agent. OBJECTIVES: Our aim was to evaluate the effect of melatonin premedication on postoperative recovery in patients undergoing bariatric surgery. SETTING: University Hospital, Israel. METHODS: Patients undergoing bariatric surgery were randomized to receive either 5 mg melatonin (M group) or placebo (P group) once on the night before surgery and again 2 hours before surgery. Quality of recovery was assessed using the QoR 15, a 15 item questionnaire on quality of recovery after surgery and anesthesia, regarding emotional state, physical comfort, psychological support, pain, and physical independence. A maximal score of 140 suggested good recovery (1 question was omitted due to irrelevance). The patients answered the questionnaire in the preanesthesia clinic, on admission to the operating room, and on the first postoperative day. RESULTS: A total of 44 patients completed the study. There was no statistical difference between M and P groups in the mean QoR-15 scores obtained before the surgery. Mean postoperative QoR-15 score was higher in the M group compared with the P group (118.3+/-12.9 versus 107.8+/-18.7, respectively; P<.01). Scores were also higher in the M group regarding pain (P<.05) and quality of sleep (P< .05). CONCLUSIONS: Use of melatonin premedication improved the quality of recovery 1 day after bariatric surgery as measured by the QoR-15, specifically the quality of sleep and pain levels. Melatonin may serve as a premedication, especially when other options, like benzodiazepines are not recommended. PMID- 27979370 TI - Optimal design and patient selection for interventional trials using radiogenomic biomarkers: A REQUITE and Radiogenomics consortium statement. AB - The optimal design and patient selection for interventional trials in radiogenomics seem trivial at first sight. However, radiogenomics do not give binary information like in e.g. targetable mutation biomarkers. Here, the risk to develop severe side effects is continuous, with increasing incidences of side effects with higher doses and/or volumes. In addition, a multi-SNP assay will produce a predicted probability of developing side effects and will require one or more cut-off thresholds for classifying risk into discrete categories. A classical biomarker trial design is therefore not optimal, whereas a risk factor stratification approach is more appropriate. Patient selection is crucial and this should be based on the dose-response relations for a specific endpoint. Alternatives to standard treatment should be available and this should take into account the preferences of patients. This will be discussed in detail. PMID- 27979372 TI - Electrophysiological abnormalities in subjects with lone atrial fibrillation - Too little, too late? PMID- 27979373 TI - Electrophysiological abnormalities in patients with paroxysmal atrial fibrillation in the absence of overt structural heart disease. AB - PURPOSE: The aim of the present study was to define the atrial electrical substrate in patients with paroxysmal atrial fibrillation (AF) occurring in the absence of overt structural heart disease and to assess if electrophysiological parameters could predict AF recurrence after radiofrequency ablation in this population. METHODS AND RESULTS: 45 consecutive patients (39 male, age 59 +/- 10 years) with paroxysmal AF and without overt structural heart disease, referred for radiofrequency catheter ablation, were prospectively enrolled. A cohort of 12 age-matched patients without a history of AF, served as a control group. Atrial electrical substrate was assessed by P-wave signal-averaging, intracardiac conduction delays and refractory periods. Total P wave duration during signal averaging was longer in patients with paroxysmal AF than in controls (140 +/- 19 ms vs 123 +/- 13 ms, p = 0.004). Patients with paroxysmal AF showed an increase in right intra-atrial (40.2 +/- 11.3 ms vs 31.7 +/- 11.8 ms, p = 0.02) and inter atrial conduction delays (87.93 +/- 22.0 ms vs 65.3 +/- 15.6 ms, p = 0.001) in sinus rhythm. Refractory periods in the right atrium were longer in patients with paroxysmal AF (265 +/- 44 ms vs 222 +/- 32 ms, p = 0.002). After ablation, 22 patients had AF recurrence but showed no differences in electrophysiological parameters compared to patients without recurrence. CONCLUSION: Electrophysiological abnormalities are present in patients with paroxysmal AF without overt structural heart disease. Neither signal-averaged P-wave duration nor intracardiac atrial electrophysiology could predict arrhythmia recurrence after pulmonary vein isolation. PMID- 27979374 TI - Identifying the predictors of hematoma after device implantation: Closing in on the suspects with an aim to prevent the menace? PMID- 27979376 TI - Hyper-uptake waists. PMID- 27979377 TI - Review: Sexual dimorphism in the formation, function and adaptation of the placenta. AB - Exposure of the embryo or fetus to perturbations in utero can result in intrauterine growth restriction, a primary risk factor for the development of adult disease. However, despite similar exposures, males and females often have altered disease susceptibility or progression from different stages of life. Fetal growth is largely mediated by the placenta, which, like the fetus is genetically XX or XY. The placenta and its associated trophoblast lineages originate from the trophectoderm (TE) of the early embryo. Rodent models (rat, mouse, spiny mouse), have been used extensively to examine placenta development and these have demonstrated the growth trajectory of the placenta in females is generally slower compared to males, and also shows altered adaptive responses to stressful environments. These placental adaptations are likely to depend on the type of stressor, duration, severity and the window of exposure during development. Here we describe the divergent developmental pathways between the male and female placenta contributing to altered differentiation of the TE derived trophoblast subtypes, placental growth, and formation of the placental architecture. Our focus is primarily genetic or environmental perturbations in rodent models which show altered placental responsiveness between sexes. We suggest that perturbations during early placental development may have greater impact on viability and growth of the female fetus whilst those occurring later in gestation may preferentially affect the male fetus. This may be of great relevance to human pregnancies which result from assisted reproductive technologies or complications such as pre-eclampsia and diabetes. PMID- 27979375 TI - Incidence, predictors and outcomes of hematoma after ICD implantation: An analysis of a nationwide database of 85,276 patients. AB - BACKGROUND: Pocket hematoma is one of the most common complications following cardiac device implantation. This study examined the impact of this complication on in-hospital outcomes following Implantable Cardioverter Defibrillator (ICD) implantation. METHODS: Data from Nationwide Inpatient Sample (NIS) 2010 was queried to identify all primary implantations of ICDs and Cardiac Resynchronization Therapy Defibrillators (CRT-D) during the year 2010 using ICD-9 codes. We then identified the patients who experienced a procedure related hematoma during the hospital stay. We compared the outcomes of the patients with and without a hematoma complication. All analyses were performed using SPSS 20 complex samples using appropriate weights to adjust for the complex sampling design of the national database. RESULTS: Out of a total of 85,276 primary ICD implantations in the year 2010, 2233 (2.6% of the implantations) were complicated by a hematoma. Increased age (p < 0.001), and comorbidities such as congestive heart failure (odds ratio (OR) - 1.86, p < 0.001), coagulopathy (OR - 2.3, p < 0.001) and renal failure (OR - 1.52, p < 0.001) were associated with an increased risk of pocket hematoma formation. Patients who developed a hematoma had a longer hospitalization (9.1 days versus 5.5 days, p < 0.001) and higher in-hospital costs ($56,545 versus $47,015, p < 0.001) compared to patients who did not have a hematoma. Overall mortality associated with ICD implantation was low (0.6%), and hematoma formation did not adversely affect mortality (0.6% versus 0.4%, p = 0.63). CONCLUSION: Hematoma occurs infrequently after ICD implantation, however, it adversely impacts the cost of procedure and length of stay. PMID- 27979378 TI - Simple additive manufacturing of an osteoconductive ceramic using suspension melt extrusion. AB - OBJECTIVE: Craniofacial bone trauma is a leading reason for surgery at most hospitals. Large pieces of destroyed or resected bone are often replaced with non resorbable and stock implants, and these are associated with a variety of problems. This paper explores the use of a novel fatty acid/calcium phosphate suspension melt for simple additive manufacturing of ceramic tricalcium phosphate implants. METHODS: A wide variety of non-aqueous liquids were tested to determine the formulation of a storable 3D printable tricalcium phosphate suspension ink, and only fatty acid-based inks were found to work. A heated stearic acid tricalcium phosphate suspension melt was then 3D printed, carbonized and sintered, yielding implants with controllable macroporosities. Their microstructure, compressive strength and chemical purity were analyzed with electron microscopy, mechanical testing and Raman spectroscopy, respectively. Mesenchymal stem cell culture was used to assess their osteoconductivity as defined by collagen deposition, alkaline phosphatase secretion and de-novo mineralization. RESULTS: After a rapid sintering process, the implants retained their pre-sintering shape with open pores. They possessed clinically relevant mechanical strength and were chemically pure. They supported adhesion of mesenchymal stem cells, and these were able to deposit collagen onto the implants, secrete alkaline phosphatase and further mineralize the ceramic. SIGNIFICANCE: The tricalcium phosphate/fatty acid ink described here and its 3D printing may be sufficiently simple and effective to enable rapid, on-demand and in-hospital fabrication of individualized ceramic implants that allow clinicians to use them for treatment of bone trauma. PMID- 27979379 TI - Social Return On Investment (SROI): Problems, solutions ... and is SROI a good investment? AB - The conclusion of this special issue on Social Return On Investment (SROI) begins with a summary of both advantages and problems of SROI, many of which were identified in preceding articles. We also offer potential solutions for some of these problems that can be derived from standard evaluation practices and that are becoming expected in SROIs that follow guidances from international SROI networks. A remaining concern about SROI is that we do not yet know if SROI itself adds sufficient benefit to programs to justify its cost. Two frameworks for this proposed metaevaluation of SROI are suggested, the first comparing benefits to costs summatively (the resource->outcome model). The second framework evaluates costs and benefits according to how much they contribute to or are caused by the different activities of SROI. This resource->activity->outcome model could enable outcomes of SROI to be maximized within resource constraints (such as budget and time limits) on SROI. Alternatively, information from this model could help minimize the costs of achieving a specific level of return on investment from conducting SROI. Possible problems with this metaevaluation of SROI are discussed. PMID- 27979380 TI - Central administration of neuropeptide Y differentially regulates monoamines and corticosterone in heat-exposed fed and fasted chicks. AB - Recently, we demonstrated that brain neuropeptide Y (NPY) mRNA expression was increased in heat exposed chicks. However, the functions of brain NPY during heat stress are unknown. This study was conducted to investigate whether centrally administered NPY affects food intake, rectal temperature, monoamines, stress hormones and plasma metabolites in chicks under high ambient temperatures (HT). Five or six-day-old chicks were centrally injected with 0, 188 or 375pmol of NPY and exposed to either HT (35+/-1 degrees C) or a control thermoneutral temperature (CT; 30+/-1 degrees C) for 3h whilst fed or fasted. NPY increased food intake under both CT and HT. NPY reduced rectal temperature 1 and 2h after central administration under CT, but not under HT. Interestingly, NPY decreased brain serotonin and norepinephrine concentrations in fed chicks, but increased concentrations of brain dopamine and its metabolites in fasted and fed chicks, respectively. Plasma epinephrine was decreased by NPY in fed chicks, but plasma concentrations of norepinephrine and epinephrine were increased significantly by NPY in fasted-heat exposed chicks. Furthermore, NPY significantly reduced plasma corticosterone concentrations in fasted chicks. Plasma glucose and triacylglycerol were increased by NPY in fed chicks, but triacylglycerol declined in fasted NPY-injected chicks. In conclusion, brain NPY may attenuate the reduction of food intake during heat stress and the increased brain NPY might be a potential regulator of the monoamines and corticosterone to modulate stress response in heat-exposed chicks. PMID- 27979381 TI - Differential effect of mass deworming and targeted deworming for soil-transmitted helminth control in children: a systematic review and meta-analysis. AB - BACKGROUND: Soil-transmitted helminth infections are a major global health issue, causing substantial morbidity in the world's poorest populations. Regular delivery of anthelmintic drugs is the mainstay for global soil-transmitted helminth control. Deworming campaigns are often targeted to school-aged children, who are at high risk of soil-transmitted-helminth-associated morbidity. However, findings from modelling studies suggest that deworming campaigns should be expanded community-wide for effective control of soil-transmitted helminth transmission. We aimed to do a systematic review and meta-analysis to compare the effect of mass (community-wide) and targeted (children only) anthelmintic delivery strategies on soil-transmitted helminth prevalence in school-aged children. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, and Web of Science for articles published on or before Nov 5, 2015, reporting soil-transmitted helminth prevalence before and after distribution of albendazole or mebendazole, either targeted to children or delivered to the whole community. We excluded studies in which drug delivery was restricted to infected individuals or to a subset of the community or school, or if follow-up time was less than 3 months or greater than 18 months after drug delivery. We extracted data on study year, country, drug administration strategy, drug dose, number of deworming rounds, treatment coverage, diagnostic method, follow-up interval, and soil-transmitted helminth prevalence before and after treatment. We used inverse variance weighted generalised linear models, with prevalence reduction as the outcome variable, to examine the effect of mass versus targeted drug administration, as well as baseline prevalence, number of drug doses, and follow-up time. This study is registered with PROSPERO, number CRD42016026929. FINDINGS: Of 10 538 studies identified, 56 studies were eligible for the systematic review and 38 of these were included in meta-analysis. Results of the regression models showed that mass deworming led to a significantly greater reduction in prevalence in children than targeted deworming, for both hookworm (odds ratio 4.6, 95% CI 1.8-11.6; p=0.0020) and Ascaris lumbricoides (16.4, 2.1-125.8; p=0.0092), with no effect seen for Trichuris trichiura. There was significant heterogeneity across studies; for targeted studies I2 was 97% for A lumbricoides and hookworm, and 96% for T trichiura, and for mass studies, I2 was 89% for A lumbricoides, 49% for hookworm, and 66% for T trichiura. INTERPRETATION: The results of this meta-analysis suggest that expanding deworming programmes community-wide is likely to reduce the prevalence of soil transmitted helminths in the high-risk group of school-aged children, which could lead to improved morbidity outcomes. These findings are in support of recent calls for re-evaluation of global soil-transmitted helminth control guidelines. FUNDING: None. PMID- 27979382 TI - Department of Error. PMID- 27979384 TI - A strengthening evidence-base for mass deworming, but questions remain. PMID- 27979385 TI - Programmed death of chemotherapy in non-small-cell lung cancer? PMID- 27979386 TI - Department of Error. PMID- 27979383 TI - Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. AB - BACKGROUND: Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non small-cell lung cancer. METHODS: We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (>=1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. FINDINGS: Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1 expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13.8 months [95% CI 11.8-15.7] vs 9.6 months [8.6-11.2]; hazard ratio [HR] 0.73 [95% CI 0.62 0.87], p=0.0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15.7 months [95% CI 12.6-18.0] with atezolizumab vs 10.3 months [8.8 12.0] with docetaxel; HR 0.74 [95% CI 0.58-0.93]; p=0.0102). Patients in the PD L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12.6 months vs 8.9 months; HR 0.75 [95% CI 0.59-0.96]). Overall survival improvement was similar in patients with squamous (HR 0.73 [95% CI 0.54-0.98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0.73 [0.60-0.89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. INTERPRETATION: To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. FUNDING: F. Hoffmann-La Roche Ltd, Genentech, Inc. PMID- 27979387 TI - Predicting and explaining behavioral intention and hand sanitizer use among US Army soldiers. AB - BACKGROUND: Using hand sanitizers can reduce bacterial contamination and is an efficient and inexpensive method of preventing infections. The purpose of this study was to explore the behavioral intention (low and absolute), attitudes, subjective norms, and perceived behavioral control of hand sanitizer use among US Army soldiers. METHODS: A questionnaire was developed following an expert panel (N = 5) review and 2 pilot studies (N = 35) to ensure questionnaire validity and clarity. Surveys were distributed among nontrainee soldiers during lunch periods. A total of 201 surveys were collected. RESULTS: Results indicated that attitudes, subjective norms, and perceived behavioral controls explained 64% of the variance in behavioral intention. Attitude remained the strongest predictor of behavior (beta = 0.70, P < .01), followed by subjective norms (beta = 0.18; P < .01), with significant differences between low and absolute intenders. CONCLUSIONS: Soldiers with absolute intention to use hand sanitizers hold significantly different behavioral and normative beliefs than low intenders. Other soldiers create negative social pressure about using hand sanitizers, indicating that if other soldiers use hand sanitizers, they will refuse to do so. Intervention to ensure use of hand sanitizer should focus on strengthening behavioral and normative beliefs among low intenders. This should increase the overall well being of the military. PMID- 27979388 TI - New case of lateral asymmetry in fishes: A new subfamily, genus and species of deep water clingfishes from Papua New Guinea, western Pacific Ocean. AB - The unusual clingfish Protogobiesox asymmetricus n. gen, n. sp. is described on the basis of four specimens collected in deep water off the north coast of Papua New Guinea in 2012. The species is characterized by its 9-10 dorsal rays, 8 anal rays, 17-24 pectoral-fin rays, 15 principal caudal-fin rays, 3 gills, third arch with 3 gill rakers, 34-35 total vertebrae, with asymmetrical lateral bending starting behind the skull, bent at an angle of 85 degrees -92 degrees ; skull asymmetrical in frontal view; skin naked, surface of head and body without striae; disc without adhesive papillae. A new subfamily Protogobiesocinae is described for this species and Lepadicyathus mendeleevi Prokofiev, 2005, which is redescribed. The new subfamily is compared within the family; keys to the subfamilies of Gobiesocidae and the species within the new subfamily are presented; its phylogenetic relationship to other gobiesocids is inferred based on a multi-locus DNA dataset. PMID- 27979389 TI - Eosinophilic esophagitis: Update in diagnosis and management. Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE). AB - Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the esophagus characterized by symptoms related to esophageal dysfunction, as well as significant esophageal eosinophilia. The entity exists worldwide but has been most extensively studied in Western countries. However, a wide range of symptoms has been noticed such as chest pain or gastro-esophageal reflux disease-like symptoms. Upper gastro-intestinal endoscopy and esophageal biopsies are crucial for the diagnosis. Endoscopy might be normal or reveal typical patterns such as rings, furrows, exudates, edema, and stricture. Two to four biopsies should be performed both in the distal and in the proximal esophagus, and 15 eosinophils per high power field within the esophageal epithelium are the minimal threshold to diagnose eosinophilic esophagitis. Allergy testing is recommended, although its impact to orient treatment remains to be demonstrated. Eosinophilic esophagitis treatment includes medical treatment, diet and endoscopic dilation. Proton pump inhibitors are the first-line therapy as up to 50% of patients respond well to proton pump inhibitors irrespective of objective evidence of GERD. Topical viscous corticosteroids or elimination diet are the treatment of choice in case of unresponsiveness to proton pump inhibitors. PMID- 27979390 TI - Universal Health Coverage-looking to the future. PMID- 27979391 TI - Building the evidence base for safety in food allergy. PMID- 27979392 TI - Dangerous disregard for the right to water. PMID- 27979393 TI - Sex-related reporting in randomised controlled trials in medical journals. PMID- 27979394 TI - Editorial policies for sex and gender analysis. PMID- 27979395 TI - Offline: Syria-ending the state of denial. PMID- 27979396 TI - Delhi looks to expand community clinic initiative. PMID- 27979397 TI - Doctors lobby for better chronic pain management. PMID- 27979398 TI - Breathing lessons: Paul Kalanithi's When Breath Becomes Air. PMID- 27979399 TI - Indigenous and tribal peoples' health. PMID- 27979400 TI - Indigenous and tribal peoples' health. PMID- 27979401 TI - Inequalities in clinical research. PMID- 27979402 TI - Indigenous and tribal peoples' health - Authors' reply. PMID- 27979403 TI - The plight of China's village doctors. PMID- 27979404 TI - Philippine drug war and impending public health crisis. PMID- 27979405 TI - Shelf life considerations as EpiPen price increases. PMID- 27979406 TI - Genomic medicine 2025: France in the race for precision medicine. PMID- 27979407 TI - Differences in Patient-Reported Outcomes Between Unicompartmental and Total Knee Arthroplasties: A Propensity Score-Matched Analysis. AB - BACKGROUND: The purpose of this study was to compare the patient-reported outcomes regarding joint awareness, function, and satisfaction after unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA). METHODS: We identified all patients who underwent a UKA or TKA at our institution between September 2011 and March 2014, with a minimum follow-up of 2 years. Propensity score matching was performed for age, gender, body mass index, operation side, and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. One hundred UKAs to 100 TKAs were matched. Each knee was evaluated according to the WOMAC score, Forgotten Joint Score (FJS), High Flexion Knee Score (HFKS) and patient's satisfaction at postoperative 2 years. RESULTS: There was no significant difference in WOMAC score at postoperative 2 years between UKA and TKA groups. However, the FJS of the UKA group was significantly higher than that of the TKA group (67.3 +/- 19.8 and 60.6 +/- 16.6, respectively; P = .011). The HFKS was also significantly higher in the UKA group compared with the TKA group (34.4 +/- 6.4 and 31.3 +/- 5.2, respectively; P < .001). Eighty-six percent of all patients who underwent UKA were satisfied compared with 71% of those who underwent TKA (P = .027). CONCLUSION: Patients who underwent UKA had higher FJS, HFKS, and satisfaction rate when compared with patients who underwent TKA, indicating that UKA facilitated less knee awareness and better function and satisfaction than TKA. PMID- 27979408 TI - Aseptic Lymphocytic-Dominated Vasculitis-Associated Lesions Scores Do Not Correlate With Metal Ion Levels or Unreadable Synovial Fluid White Blood Cell Counts. AB - BACKGROUND: Failed metal-on-metal (MoM) bearings are being increasingly encountered with little information to guide evaluation for aseptic lymphocytic dominated vasculitis-associated lesions (ALVAL). It is often assumed that elevated metal ion levels correlate with the occurrence of ALVAL. Our purpose was to determine the utility of the erythrocyte sedimentation rate, C-reactive protein, synovial white blood cell count, differential (%PMN), and serum metal ion levels in diagnosing ALVAL. METHODS: We identified 80-failed MoM total hip arthroplasties. Tissue was examined under light microscopy and graded on a scale of ALVAL severity. Mean laboratory values were compared between groups and receiver operating curves generated with an area under the curve to determine test performance and optimal cutoffs. RESULTS: ALVAL scores were graded as low in 30 (37.5%), moderate in 39 (49%), and severe in 8 (10%), with 3 being unreadable. No clear cutoff values for erythrocyte sedimentation rate, C-reactive protein, or synovial white blood cell count could be determined to reliably diagnose moderate or severe ALVAL. Furthermore, serum metal levels had no correlation with ALVAL score. The best test to diagnose ALVAL was the synovial fluid monocyte percentage with an optimal cutoff value of 39% and area under the curve of 69% (moderate testing performance). CONCLUSION: The diagnosis of ALVAL remains challenging, with most of the screening tests being unreliable. Although serum metal ion levels are typically elevated in failed MoM bearings, higher levels do not appear to correlate with ALVAL grade. Elevated synovial fluid monocytes may provide diagnostic utility for ALVAL, suggesting a possible delayed-type hypersensitivity reaction. PMID- 27979409 TI - Outcomes of Patellofemoral Arthroplasty Based on Radiographic Severity. AB - BACKGROUND: Patellofemoral arthroplasty (PFA) is increasingly performed for symptomatic patellofemoral arthritis. The purpose of this study was to evaluate the outcomes of PFA based on preoperative radiographic severity of patellofemoral arthritis. METHODS: All patients who underwent PFA for isolated patellofemoral arthritis between 2002 and 2013 and had undergone preoperative magnetic resonance imaging were identified. Radiographic severity of patellofemoral arthritis was classified according to the Iwano classification system. Groups were divided between mild (grade 0-I) and moderate to severe (grade II-IV) patellofemoral arthritis. Clinical outcomes were evaluated using the Knee Society scores (KSS), University of California at Los Angeles (UCLA) and Tegner scores. RESULTS: Seventy-five knees in 55 patients met inclusion criteria. Mean age was 51 years (range, 36 to 81), and mean follow-up was 3 years (range, 2 to 10). All patients had grade IV patellofemoral chondromalacia and/or significant subchondral cyst formation and edema on magnetic resonance imaging. On plain radiographs, there were no patients with Iwano grade 0, 21 grade I, 15 grade II, 21 grade III, and 18 grade IV patellofemoral arthritis. There was significantly more improvement in KSS pain (P = .046), KSS function (P = .02), University of California at Los Angeles (UCLA) (P = .046) and Tegner (P = .008) scores in the Iwano grade II-IV group vs the Iwano grade I group. Patient-reported pain quality improved significantly more following PFA in the grade II-IV group (P = .04). CONCLUSION: Patients with evidence of mild patellofemoral arthritis on plain radiographs demonstrated less improvement in pain and function after PFA than those with more advanced patellofemoral arthritis. Caution should be used when considering PFA for patients with minimal radiographic evidence of patellofemoral arthritis. PMID- 27979410 TI - Transcranial direct current stimulation (tDCS): Are we losing energy? PMID- 27979412 TI - Dietary tofu intake and long-term risk of death from stroke in a general population. AB - BACKGROUND & AIM: Although dietary soy intake is linked with health benefits, a relation with stroke has not been established. The present study examined the association between the intake of tofu, the richest source of dietary soy, with stroke mortality in a general population cohort of Japanese men and women. METHODS: Data comprise 9244 Japanese enrolled in the National Nutrition Survey of Japan in 1980. Participants were free of cardiovascular disease and followed for 24 years. Dietary intake was estimated from 3-day weighed food records. Multivariable Cox regression models were used to estimate hazard ratios across levels of tofu intake. RESULTS: During follow-up, there were 417 deaths due to stroke (88 cerebral hemorrhage [CH], 245 cerebral infarction [CI], and 84 of other subtypes). Among all men, and in women aged 65 years or more, tofu intake was unrelated to each form of stroke. For young women (<65 years of age), a significantly lower risk of CH in the top versus bottom quartile of tofu intake was observed (Multivariable-adjusted HR = 0.26, 95% CI: 0.08-0.85). CONCLUSIONS: In this large prospective study with long follow-up of Japanese men and women, consumption of tofu was unrelated to the risk of stroke except for CH in women <65 years of age. Whether the association in younger women is real or due to chance alone warrants further study. PMID- 27979411 TI - High School Football and Late-Life Risk of Neurodegenerative Syndromes, 1956 1970. AB - OBJECTIVE: To assess whether athletes who played American varsity high school football between 1956 and 1970 have an increased risk of neurodegenerative diseases later in life. PATIENTS AND METHODS: We identified all male varsity football players between 1956 and 1970 in the public high schools of Rochester, Minnesota, and non-football-playing male varsity swimmers, wrestlers, and basketball players. Using the medical records linkage system of the Rochester Epidemiology Project, we ascertained the incidence of late-life neurodegenerative diseases: dementia, parkinsonism, and amyotrophic lateral sclerosis. We also recorded medical record-documented head trauma during high school years. RESULTS: We identified 296 varsity football players and 190 athletes engaging in other sports. Football players had an increased risk of medically documented head trauma, especially if they played football for more than 1 year. Compared with nonfootball athletes, football players did not have an increased risk of neurodegenerative disease overall or of the individual conditions of dementia, parkinsonism, and amyotrophic lateral sclerosis. CONCLUSION: In this community based study, varsity high school football players from 1956 to 1970 did not have an increased risk of neurodegenerative diseases compared with athletes engaged in other varsity sports. This was from an era when there was a generally nihilistic view of concussion dangers, less protective equipment, and no prohibition of spearing (head-first tackling). However, the size and strength of players from previous eras may not be comparable with that of current high school athletes. PMID- 27979413 TI - A forgotten cause of wide complex tachycardia. AB - Wide complex tachycardia secondary to an acute overdose from TCA's is a well documented phenomenon. In this case we present a wide complex tachycardia after clear documentation of no acute overdose, which responded to standard treatment for TCA toxicity. These findings combined with chronic electrocardiographic abnormalities were suggestive of an acute on chronic TCA toxicity. PMID- 27979414 TI - Diagnosis and treatment of inflammatory bowel disease: First Latin American Consensus of the Pan American Crohn's and Colitis Organisation. AB - The incidence and prevalence of inflammatory bowel disease (IBD) has increased in recent years in several Latin American countries. There is a need to raise awareness in gastroenterologists and the population in general, so that early diagnosis and treatment of ulcerative colitis (UC) and Crohn's Disease (CD) can be carried out. It is important for all physicians to have homogeneous criteria regarding the diagnosis and treatment of IBD in Latin America. The Pan American Crohn's and Colitis Organisation (PANCCO) is an organization that aims to include all the countries of the Americas, but it specifically concentrates on Latin America. The present Consensus was divided into two parts for publication: 1) Diagnosis and treatment and 2) Special situations. This is the first Latin American Consensus whose purpose is to promote a perspective adapted to our Latin American countries for the diagnosis, treatment, and monitoring of patients with UC and CD. PMID- 27979415 TI - MiR-376a promotion of proliferation and metastases in ovarian cancer: Potential role as a biomarker. AB - AIMS: Ovarian cancer is the fifth most deadly cancer in women, and is usually diagnosed too late. Exploring specific and sensitive biomarkers will be helpful to early detection and will improve the survival rates of ovarian cancer patients. MAIN METHODS: Realtime PCR was used to detect the expression of miR 376a. Wound healing and transwell assays were used to examined the migration and invasion abilities of ovarian cancer cells. Tumor xenograft experiments were employed to test the in vivo malignancy of ovarian cancer cells. Western Blotting and luciferase report assays were conducted for the target genes analysis. KEY FINDINGS: Using a cohort of 32 cases of ovarian cancer and 10 cases of healthy control samples, we found that miR-376 expression is increased in ovarian cancer tissues. The serum level of miR-376a is significantly higher in ovarian cancer patients and is associated with the clinical stages of ovarian cancer. Over expression of miR-376a stimulated the proliferation, migration, and invasion of ovarian cancer cells, while inhibition of miR-376a expression blocked the proliferation, migration, and invasion. Data from nude mice further demonstrated the stimulatory role of miR-376a in ovarian cancer progression. Mechanically, miR 376a played its role by targeting KLF15 and Caspase-8. SIGNIFICANCE: Our findings enrich the knowledge of miR-376a in ovarian cancer formation and progression, providing a possibility of using miR-376a as a diagnostic and prognostic biomarker for ovarian cancer. PMID- 27979416 TI - The effect of smoking on clinical and structural damage in patients with axial spondyloarthritis: A systematic literature review. AB - OBJECTIVES: To evaluate the association between smoking and clinical parameters and structural damage in axial spondyloarthritis (axSpA). METHODS: We systematically searched MEDLINE, EMBASE and Cochrane Library till November 2015. We selected articles that analysed the smoking impact on disease activity, functional status, structural damage, physical mobility and life quality. Independent extraction of articles by 2 authors using predefined data fields was performed. Studies quality was graded according to the Oxford Level of Evidence scale. RESULTS: A total of 17 articles were selected for inclusion: 2 case control, 11 cross-sectional and 4 prospective cohort studies, which analysed 4694 patients. Weak evidence suggested a smoking effect on pain, overall assessment of health, disease activity, physical mobility and life quality in ankylosing spondylitis (AS). Moderate-good evidence revealed higher HAQ-AS among smokers (0.025units/y; 95% CI: 0.0071-0.0429; p = 0.007). Every additional unit of ASDAS resulted in an increase of 1.9 vs. 0.4 mSASSS units/2y in AS smokers vs. non smokers. Good evidence revealed that cigarette smoking and smoking intensity was associated with spinal radiographic progression in axSpA [mSASSS >=2 units/2y: OR = 2.75, 95% CI: 1.25-6.05, p=0.012; mSASSS progression in heavy smokers (>10 cigarettes/d): OR = 3.57, 95% IC: 1.33-9.60, p = 0.012]. CONCLUSIONS: Published data indicate that smoking has a dose-dependent impact on structural damage progression in axSpA. There is worse HAQ among AS smokers compared to non smokers. Respect to pain, overall assessment of health, disease activity, physical mobility and life quality, although the evidence level is poor, all evidence points in the same direction: smoking AS patients are worse than non smoking. PMID- 27979417 TI - Pheochromocytoma mimicking (or triggering?) takotsubo cardiomyopathy and hypertrophic cardiomyopathy. PMID- 27979418 TI - Variable self-reports of pain from blood pressure measurement among ED patients. PMID- 27979419 TI - Integrated locating of helicopter stations and helipads for wounded transfer under demand location uncertainty. AB - Health emergency medical service (HEMS) plays an important role in reducing injuries by providing advanced medical care in the shortest time and reducing the transfer time to advanced treatment centers. In the regions without ground relief coverage, it would be faster to transfer emergency patients to the hospital by a helicopter. In this paper, an integer nonlinear programming model is presented for the integrated locating of helicopter stations and helipads by considering uncertainty in demand points. We assume three transfer modes: (1) direct transfer by an ambulance, (2) transfer by an ambulance to a helicopter station and then to the hospital by a helicopter, (3) transfer by an ambulance to a predetermined point and then to the hospital by a helicopter. We also assume that demands occur in a square-shaped area, in which each side follows a uniform distribution. It is also assumed that demands in an area decrease errors in the distances between each two cities. The purpose of this model is to minimize the transfer time from demand points to the hospital by considering different modes. The proposed model is examined in terms of validity and applicability in Lorestan Province and a sensitivity analysis is also conducted on the total allocated budget. PMID- 27979420 TI - Procalcitonin levels in bloodstream infections caused by different sources and species of bacteria. AB - OBJECTIVE: The aim of this study was to evaluate procalcitonin (PCT) diagnostic accuracy in discriminating gram-negative (GN) from gram-positive (GP) bloodstream infections and determining the relationship between PCT levels, infection sites, and pathogen types. METHODS: Clinical and laboratory data were collected from patients with blood culture (BC)-positive sepsis between January 2014 and December 2015. PCT levels at different infection sites were compared, as was the presence of GN and GP bloodstream infection. A receiver operating characteristic (ROC) curve was generated to assess diagnostic accuracy. RESULTS: Of the 486 monomicrobial BCs, 254 (52.26%) were positive for GN bacteria (GNB), and 202 (42.18%) for GP bacteria (GPB). Median PCT levels were higher in BCs positive for GN (2.42ng/ml, IQR: 0.38-15.52) than in those positive for GPB (0.49ng/ml, IQR: 0.13-5.89) (P<0.001). In the ROC analysis to differentiate between GNB and GPB, the area under the curve was 0.628 (95% CI: 0.576-0.679). When the cutoffs for PCT were 10.335 and 15.000ng/ml, the specificity of GNB infection was 80.2% and 84.2%, respectively. PCT levels caused by GNB differed between Escherichia coli and Acinetobacter baumanni/Burkholderia cepacia, Klebsiella pneumonia and Acinetobacter baumanni. PCT levels caused by GPB differed between Staphylococcus epidermidis/Staphylococcus aureus and Staphylococcus hominis/Staphylococcus haemolyticus, Enterococcus faecium and Enterococcus faecalis/S.hominis/S. haemolyticus. Among patients with known infection sites, there were statistical differences in PCT levels between abdominal infection and pneumonia/infective endocarditis, urinary tract infection and pneumonia/catheter-related infection/infective endocarditis. CONCLUSION: PCT can distinguish between GNB and GPB infection, as well as between different bacterial species and infection sites. PMID- 27979421 TI - A comparison between evacuation from the scene and interhospital transportation using a helicopter for subarachnoid hemorrhage. AB - PURPOSE: We investigated the changes in the vital signs and the final outcomes subarachnoid hemorrhage (SAH) patients who were evacuated from the scene using the doctor-helicopter (Dr. Heli) service and those who only underwent interhospital transportation using the doctor-helicopter Dr. Heli service to investigate safety of this system. METHODS: We retrospectively investigated all of the patients with non-traumatic SAH who were transported by a Dr. Heli between January 2010 and March 2016. The subjects were divided into two groups: the Scene group included subjects who were evacuated from the scene by a Dr. Heli, while the Interhospital group included subjects who were transported by a ground ambulance to a nearby medical facility and then transported by a Dr. Heli to a single tertiary center. RESULTS: The systolic blood pressure, ratio of cardiac arrest, and Fisher classification values of the patients in the Scene group were significantly greater than those in the Interhospital group. The Glasgow Coma Scale in the Scene group was significantly lower than that in the Interhospital group. After excluding the patients with cardiac arrest, the Glasgow Coma Scale scores of the patients in the two groups did not differ to a statistically significant extent during, before or after transportation. There were no significant differences in Glasgow Outcome Scores or the survival ratio of the two groups, even when cardiac arrest patients were included. CONCLUSION: The present study indirectly suggests the safety of using a Dr. Heli to evacuate SAH patients from the scene. PMID- 27979422 TI - Treatment in carbon monoxide poisoning patients with headache: Statistical and methodological issues. PMID- 27979423 TI - Ultrasound Measurement Of Inferior Vena Cava Collapse Predicts Propofol Induced Hypotension. PMID- 27979424 TI - Comparison of phosphorus recovery from incinerated sewage sludge ash (ISSA) and pyrolysed sewage sludge char (PSSC). AB - This research compares and contrasts the physical and chemical characteristics of incinerator sewage sludge ash (ISSA) and pyrolysis sewage sludge char (PSSC) for the purposes of recovering phosphorus as a P-rich fertiliser. Interest in P recovery from PSSC is likely to increase as pyrolysis is becoming viewed as a more economical method of sewage sludge thermal treatment compared to incineration. The P contents of ISSA and PSSC are 7.2-7.5% and 5.6%, respectively. Relative to the sludge, P concentrations are increased about 8-fold in ISSA, compared to roughly 3-fold in PSSC. Both PSSC and ISSA contain whitlockite, an unusual form of calcium phosphate, with PSSC containing more whitlockite than ISSA. Acid leaching experiments indicate that a liquid/solid ratio of 10 with 30min contact time is optimal to release PO4-P into leachate for both ISSA and PSSC. The proportion of P extracted from PSSC is higher due to its higher whitlockite content. Heavy metals are less soluble from PSSC because they are more strongly incorporated in the particles. The results suggest there is potential for the development of a process to recover P from PSSC. PMID- 27979425 TI - Chemical elimination of the harmful properties of asbestos from military facilities. AB - This work presents research on the neutralization of asbestos banned from military use and its conversion to usable products. The studies showed that asbestos can be decomposed by the use of phosphoric acid. The process proved very effective when the phosphoric acid concentration was 30%, the temperature was 90 degrees C and the reaction time 60min. Contrary to the common asbestos treatment method that consists of landfilling, the proposed process ensures elimination of the harmful properties of this waste material and its transformation into inert substances. The obtained products include calcium phosphate, magnesium phosphate and silica. Chemical, microscopic and X-ray analyses proved that the products are free of harmful fibers and can be, in particular, utilized for fertilizers production. The obtained results may contribute to development of an asbestos utilization technique that fits well into the European waste policy, regulated by the EU waste management law. PMID- 27979427 TI - Re: Marko Babjuk, Andreas Bohle, Maximilian Burger, et al. EAU Guidelines on Non muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol 2017;71:447-61. PMID- 27979426 TI - Nuclear-specific AR-V7 Protein Localization is Necessary to Guide Treatment Selection in Metastatic Castration-resistant Prostate Cancer. AB - BACKGROUND: Circulating tumor cells (CTCs) expressing AR-V7 protein localized to the nucleus (nuclear-specific) identify metastatic castration-resistant prostate cancer (mCRPC) patients with improved overall survival (OS) on taxane therapy relative to the androgen receptor signaling inhibitors (ARSi) abiraterone acetate, enzalutamide, and apalutamide. OBJECTIVE: To evaluate if expanding the positivity criteria to include both nuclear and cytoplasmic AR-V7 localization ("nuclear-agnostic") identifies more patients who would benefit from a taxane over an ARSi. DESIGN, SETTING, AND PARTICIPANTS: The study used a cross-sectional cohort. Between December 2012 and March 2015, 193 pretherapy blood samples, 191 of which were evaluable, were collected and processed from 161 unique mCRPC patients before starting a new line of systemic therapy for disease progression at the Memorial Sloan Kettering Cancer Center. The association between two AR-V7 scoring criteria, post-therapy prostate-specific antigen (PSA) change (PTPC) and OS following ARSi or taxane treatment, was explored. One criterion required nuclear-specific AR-V7 localization, and the other required an AR-V7 signal but was agnostic to protein localization in CTCs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Correlation of AR-V7 status to PTPC and OS was investigated. Relationships with survival were analyzed using multivariable Cox regression and log-rank analyses. RESULTS AND LIMITATIONS: A total of 34 (18%) samples were AR-V7-positive using nuclear-specific criteria, and 56 (29%) were AR V7-positive using nuclear-agnostic criteria. Following ARSi treatment, none of the 16 nuclear-specific AR-V7-positive samples and six of the 32 (19%) nuclear agnostic AR-V7-positive samples had >=50% PTPC at 12 weeks. The strongest baseline factor influencing OS was the interaction between the presence of nuclear-specific AR-V7-positive CTCs and treatment with a taxane (hazard ratio 0.24, 95% confidence interval 0.078-0.79; p=0.019). This interaction was not significant when nuclear-agnostic criteria were used. CONCLUSIONS: To reliably inform treatment selection using an AR-V7 protein biomarker in CTCs, nuclear specific localization is required. PATIENT SUMMARY: We analyzed outcomes for patients with metastatic castration-resistant prostate cancer on androgen receptor signaling inhibitors and standard chemotherapy. Patients with circulating tumor cells that had AR-V7 protein in the cellular nuclei were very likely to survive longer on taxane-based chemotherapy, and tests unable to distinguish where the protein is located in the cell are not as predictive of benefit. PMID- 27979428 TI - Demographic trends of binge alcohol use and alcohol use disorders among older adults in the United States, 2005-2014. AB - BACKGROUND: Alcohol use is common among older adults, and this population has unique risks with alcohol consumption in even lower amounts than younger persons. No recent studies have estimated trends in alcohol use including binge alcohol use and alcohol use disorders (AUD) among older adults. METHODS: We examined alcohol use among adults age >=50 in the National Survey on Drug Use and Health (NSDUH) from 2005 to 2014. Trends of self-reported past-month binge alcohol use and AUD were estimated. Logistic regression models were used to examine correlates of binge alcohol use and AUD. RESULTS: The prevalence of both past month binge alcohol use and AUD increased significantly among adults age >=50 from 2005/2006 to 2013/2014, with a relative increase of 19.2% for binge drinking (linear trend p<0.001) and a 23.3% relative increase for AUD (linear trend p=0.035). While males had a higher prevalence of binge alcohol use and AUD compared to females, there were significant increases in both among females. In adjusted models of aggregated data, being Hispanic, male, and a smoker or illicit drug user were associated with binge alcohol use, while being male, a smoker, an illicit drug user, or reporting past-year depression or mental health treatment were associated with AUD. CONCLUSIONS: Alcohol use among older adults is increasing in the US, including past-month binge alcohol use and AUD with increasing trends among females. Providers and policymakers need to be aware of these changes to address the increase of older adults with unhealthy drinking. PMID- 27979429 TI - The Finnish experience to save asthma costs by improving care in 1987-2013. AB - The Finnish National Asthma Program 1994-2004 markedly improved asthma care in the 1990s. We evaluated the changes in costs during 26 years from 1987 to 2013. Direct and indirect costs were calculated by using data from national registries. Costs from both the societal and patient perspectives were included. The costs were based on patients with persistent, physician-diagnosed asthma verified by lung function measurements. We constructed minimum and maximum scenarios to assess the effect of improved asthma care on total costs. The number of patients with persistent asthma in the national drug reimbursement register increased from 83,000 to 247,583. Improved asthma control reduced health care use and disability, resulting in major cost savings. Despite a 3-fold increase in patients, the total costs decreased by 14%, from ?222 million to ?191 million. Costs for medication and primary care visits increased, but overall annual costs per patient decreased by 72%, from ?2656 to ?749. The theoretical total cost savings for 2013, comparing actual with predicted costs, were between ?120 and ?475 million, depending on the scenario used. The Finnish Asthma Program resulted in significant cost savings at both the societal and patient levels during a 26 year period. PMID- 27979431 TI - Prognostic Value of C-Reactive Protein and Homocysteine in Large-Artery Atherosclerotic Stroke: a Prospective Observational Study. AB - BACKGROUND: Our objective is to investigate whether C-reactive protein (CRP) and homocysteine (Hcy) levels in the acute phase of large-artery atherosclerotic stroke predict long-term functional disability and recurrent vascular events. METHODS: Patients with first-ever large-artery atherosclerotic ischemic stroke were prospectively registered in the Nanjing Stroke Registry Program between January 2012 and June 2014. Venous blood samples were collected within 2 weeks after the index stroke. Patients were followed up for 1 year. The Kaplan-Meier method was performed in survival analysis. Multiple logistic regression analysis and Cox proportional hazard model were applied to identify predictors of functional disability and recurrent vascular events, respectively. RESULTS: A total of 625 eligible patients (458 males) were evaluated. During the 1-year follow-up period, 63 patients suffered recurrent vascular events. An elevated CRP level is an independent predictor of poor functional disability at 1 year (P for trend = .002), in both males (P for trend = .017) and females (P for trend = .042). Hcy showed no relationship with functional disability. No significant relationship between CRP and Hcy levels and recurrent vascular events was found in total patients in multiple models. Stratified by sex, high Hcy levels were associated with recurrent vascular events in females (P for trend = .036) but not in males. CONCLUSIONS: Elevated CRP levels are associated with poor functional disability in patients with large-artery atherosclerotic stroke at 1 year, and Hcy is a relatively moderate predictor of recurrent vascular events in female patients with large-artery atherosclerotic stroke at 1 year. PMID- 27979432 TI - Secondary mandibular reconstruction for paediatric patients with long-term mandibular continuity defects: a retrospective study of six cases. AB - Paediatric patients with long-term mandibular continuity defects following segmental resection usually present severe functional and cosmetic deformities. Secondary mandibular reconstruction for these patients is very challenging. Literature reports on how to handle these patients are scarce. The aim of this study was to describe the authors' experience in handling those paediatric patients who have not undergone primary reconstruction, for whom the final goal of treatment is to restore a symmetrical facial appearance, masticatory function, and speech. This was a retrospective analysis of the data of six patients who underwent radical mandible resection in childhood, without immediate bone restoration, and who then underwent a secondary mandibular reconstruction procedure after reaching adulthood, during the period 2009 to 2015. The multidisciplinary treatment procedure, selection of the donor site, and reconstructive approach are discussed. Key points in relation to secondary mandibular reconstruction with the aim of achieving not only good functional and cosmetic results, but also an improvement in the paediatric patient's psychological and social outcomes, are emphasized. PMID- 27979430 TI - Classical complement pathway activation in the nasal tissue of patients with chronic rhinosinusitis. AB - BACKGROUND: Complement plays a major role in inflammatory diseases, but its involvement and mechanisms of activation in patients with chronic rhinosinusitis (CRS) are not known. OBJECTIVES: After earlier studies discovering autoantibodies in patients with CRS, we sought to investigate the nature, extent, and location of complement activation in nasal tissue of patients with CRS. Specifically, we were interested in whether antibody-mediated activation through the classical pathway was a major mechanism for complement activation in patients with CRS. METHODS: Nasal tissue was obtained from patients with CRS and control subjects. Tissue homogenates were analyzed for complement activation products (ELISA-C5b-9, C4d, activated C1, and C5a) and major complement-fixing antibodies (Luminex). Tissue sections were stained for C5b-9, C4d, and laminin. Antibodies were purified with protein A/G columns from nasal polyps (NP), matching patient serum, and control serum and assayed for basement membrane binding by means of ELISA. RESULTS: C5b-9 levels were significantly increased in NP tissue compared with uncinate tissue (UT) of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and those with chronic rhinosinusitis without nasal polyps (CRSsNP; P < .01). Similarly, C4d levels were increased in NPs compared with UT of patients with CRSwNP, patients with CRSsNP, and control subjects (P < .05). Activated C1 levels were also increased in NP tissue compared with UT of patients with CRSsNP and control subjects (P < .05) and correlated with levels of C5a (P < .01), local immunoglobulins (especially IgM, P < .0001), and anti-double-stranded DNA IgG (P < .05). Immunofluorescence showed that C5b-9 and C4d deposition occurred linearly along the epithelial basement membrane. NP tissue extracts had significantly more anti-basement membrane antibodies than sera from patients with CRSwNP and control subjects (P < .0001). CONCLUSION: Levels of C5b-9, C4d, and activated C1 were significantly increased locally in NP tissue. C5b-9 and C4d were almost universally deposited linearly along the basement membrane of NP tissue. Furthermore, activated C1 levels were best correlated with local immunoglobulin and C5a levels. Together, these data suggest that the classical pathway plays a major role in complement activation in patients with CRS. PMID- 27979433 TI - Gynecological pelvic pain as emergency pathology. AB - Acute pelvic pain is a common condition in emergency. The sources of acute pelvic pain are multifactorial, so it is important to be familiar with this type of pathologies. The purpose of this article is review the main causes of gynecological acute pelvic pain and their radiologic appearances to be able to make an accurate diagnosis and provide objective criteria for patient management. PMID- 27979434 TI - Slow growing painless mass in the lower limb. PMID- 27979435 TI - Malaria in Europe: Follow-up of autochthonous malaria in Greece and new risks. PMID- 27979437 TI - Gentamicin resistant E. coli as a cause of urinary tract infections in children. PMID- 27979436 TI - Ruminococcus gnavus infection of a metal-on-metal hip arthroplasty resembling a pseudo-tumour in a 72 year-old woman with no intestinal symptoms. PMID- 27979438 TI - Automated protein design: Landmarks and operational principles. AB - Protein design has an eventful history spanning over three decades, with handful of success stories reported, and numerous failures not reported. Design practices have benefited tremendously from improvements in computer hardware and advances in scientific algorithms. Though protein folding problem still remains unsolved, the possibility of having multiple sequence solutions for a single fold makes protein design a more tractable problem than protein folding. One of the most significant advancement in this area is the implementation of automated design algorithms on pre-defined templates or completely new folds, optimized through deterministic and heuristic search algorithms. This progress report provides a succinct presentation of important landmarks in automated design attempts, followed by brief account of operational principles in automated design methods. PMID- 27979440 TI - Introducing: The Red Journal Gray Zone. PMID- 27979439 TI - Albuminuria is associated with greater copeptin concentrations in men with type 1 diabetes: A brief report from the T1D exchange Biobank. AB - BRIEF SUMMARY: Vasopressin exerts important cardio-renal effects, but remains problematic to measure. Copeptin is a more stable peptide derived from the same precursor molecule. In this case-control study from the Type 1 Diabetes Exchange (T1DX) Biobank registry, men with T1D and albuminuria had greater copeptin concentrations than men with normoalbuminuria. PMID- 27979441 TI - The Tonsillar Fossa Battleground. PMID- 27979442 TI - Applying for Radiation Oncology Residency: Webinar-based Medical Student Mentorship Outreach. PMID- 27979444 TI - Biomathematical Optimization of Radiation Therapy in the Era of Targeted Agents. PMID- 27979443 TI - National Cancer Database Analysis of Proton Versus Photon Radiation Therapy in Non-Small Cell Lung Cancer. AB - PURPOSE: To analyze outcomes and predictors associated with proton radiation therapy for non-small cell lung cancer (NSCLC) in the National Cancer Database. METHODS AND MATERIALS: The National Cancer Database was queried to capture patients with stage I-IV NSCLC treated with thoracic radiation from 2004 to 2012. A logistic regression model was used to determine the predictors for utilization of proton radiation therapy. The univariate and multivariable association with overall survival were assessed by Cox proportional hazards models along with log rank tests. A propensity score matching method was implemented to balance baseline covariates and eliminate selection bias. RESULTS: A total of 243,822 patients (photon radiation therapy: 243,474; proton radiation therapy: 348) were included in the analysis. Patients in a ZIP code with a median income of <$46,000 per year were less likely to receive proton treatment, with the income cohort of $30,000 to $35,999 least likely to receive proton therapy (odds ratio 0.63 [95% confidence interval (CI) 0.44-0.90]; P=.011). On multivariate analysis of all patients, non-proton therapy was associated with significantly worse survival compared with proton therapy (hazard ratio 1.21 [95% CI 1.06-1.39]; P<.01). On propensity matched analysis, proton radiation therapy (n=309) was associated with better 5-year overall survival compared with non-proton radiation therapy (n=1549), 22% versus 16% (P=.025). For stage II and III patients, non-proton radiation therapy was associated with worse survival compared with proton radiation therapy (hazard ratio 1.35 [95% CI 1.10-1.64], P<.01). CONCLUSIONS: Thoracic radiation with protons is associated with better survival in this retrospective analysis; further validation in the randomized setting is needed to account for any imbalances in patient characteristics, including positron emission tomography-computed tomography staging. PMID- 27979445 TI - Highly Efficient Training, Refinement, and Validation of a Knowledge-based Planning Quality-Control System for Radiation Therapy Clinical Trials. AB - PURPOSE: To demonstrate an efficient method for training and validation of a knowledge-based planning (KBP) system as a radiation therapy clinical trial plan quality-control system. METHODS AND MATERIALS: We analyzed 86 patients with stage IB through IVA cervical cancer treated with intensity modulated radiation therapy at 2 institutions according to the standards of the INTERTECC (International Evaluation of Radiotherapy Technology Effectiveness in Cervical Cancer, National Clinical Trials Network identifier: 01554397) protocol. The protocol used a planning target volume and 2 primary organs at risk: pelvic bone marrow (PBM) and bowel. Secondary organs at risk were rectum and bladder. Initial unfiltered dose volume histogram (DVH) estimation models were trained using all 86 plans. Refined training sets were created by removing sub-optimal plans from the unfiltered sample, and DVH estimation models... and DVH estimation models were constructed by identifying 30 of 86 plans emphasizing PBM sparing (comparing protocol specified dosimetric cutpoints V10 (percentage volume of PBM receiving at least 10 Gy dose) and V20 (percentage volume of PBM receiving at least 20 Gy dose) with unfiltered predictions) and another 30 of 86 plans emphasizing bowel sparing (comparing V40 (absolute volume of bowel receiving at least 40 Gy dose) and V45 (absolute volume of bowel receiving at least 45 Gy dose), 9 in common with the PBM set). To obtain deliverable KBP plans, refined models must inform patient specific optimization objectives and/or priorities (an auto-planning "routine"). Four candidate routines emphasizing different tradeoffs were composed, and a script was developed to automatically re-plan multiple patients with each routine. After selection of the routine that best met protocol objectives in the 51-patient training sample (KBPFINAL), protocol-specific DVH metrics and normal tissue complication probability were compared for original versus KBPFINAL plans across the 35-patient validation set. Paired t tests were used to test differences between planning sets. RESULTS: KBPFINAL plans outperformed manual planning across the validation set in all protocol-specific DVH cutpoints. The mean normal tissue complication probability for gastrointestinal toxicity was lower for KBPFINAL versus validation-set plans (48.7% vs 53.8%, P<.001). Similarly, the estimated mean white blood cell count nadir was higher (2.77 vs 2.49 k/mL, P<.001) with KBPFINAL plans, indicating lowered probability of hematologic toxicity. CONCLUSIONS: This work demonstrates that a KBP system can be efficiently trained and refined for use in radiation therapy clinical trials with minimal effort. This patient-specific plan quality control resulted in improvements on protocol-specific dosimetric endpoints. PMID- 27979447 TI - Caution Must Be Exercised When Performing Deformable Dose Accumulation for Tumors Undergoing Mass Changes During Fractionated Radiation Therapy. PMID- 27979446 TI - Adverse Events Involving Radiation Oncology Medical Devices: Comprehensive Analysis of US Food and Drug Administration Data, 1991 to 2015. AB - PURPOSE: Radiation oncology relies on rapidly evolving technology and highly complex processes. The US Food and Drug Administration collects reports of adverse events related to medical devices. We sought to characterize all events involving radiation oncology devices (RODs) from the US Food and Drug Administration's postmarket surveillance Manufacturer and User Facility Device Experience (MAUDE) database, comparing these with non-radiation oncology devices. METHODS AND MATERIALS: MAUDE data on RODs from 1991 to 2015 were sorted into 4 product categories (external beam, brachytherapy, planning systems, and simulation systems) and 5 device problem categories (software, mechanical, electrical, user error, and dose delivery impact). Outcomes included whether the device was evaluated by the manufacturer, adverse event type, remedial action, problem code, device age, and time since 510(k) approval. Descriptive statistics were performed with linear regression of time-series data. Results for RODs were compared with those for other devices by the Pearson chi2 test for categorical data and 2-sample Kolmogorov-Smirnov test for distributions. RESULTS: There were 4234 ROD and 4,985,698 other device adverse event reports. Adverse event reports increased over time, and events involving RODs peaked in 2011. Most ROD reports involved external beam therapy (50.8%), followed by brachytherapy (24.9%) and treatment planning systems (21.6%). The top problem types were software (30.4%), mechanical (20.9%), and user error (20.4%). RODs differed significantly from other devices in each outcome (P<.001). RODs were more likely to be evaluated by the manufacturer after an event (46.9% vs 33.0%) but less likely to be recalled (10.5% vs 37.9%) (P<.001). Device age and time since 510(k) approval were shorter among RODs (P<.001). CONCLUSIONS: Compared with other devices, RODs may experience adverse events sooner after manufacture and market approval. Close postmarket surveillance, improved software design, and manufacturer-user training may help mitigate these events. PMID- 27979448 TI - In Regard to Perrier et al. PMID- 27979449 TI - In Reply to Escande et al. PMID- 27979450 TI - In Regard to Ramroth et al. PMID- 27979452 TI - Surgery plus PORT. PMID- 27979453 TI - Try to Avoid Tri-Modality Treatment. PMID- 27979455 TI - Transoral Robotic Surgery and the Standard of Care. PMID- 27979454 TI - Secondary Breast Cancer Risk by Radiation Volume in Women With Hodgkin Lymphoma. AB - PURPOSE: To determine whether the risk of secondary breast cancer (SBC) is reduced in women with Hodgkin lymphoma (HL) treated with smaller field radiation therapy (SFRT) versus mantle field radiation therapy (MRT). METHODS AND MATERIALS: We used the BC Cancer Agency (BCCA) Lymphoid Cancer Database to identify female patients treated for HL between January 1961 and December 2009. Radiation therapy volumes were categorized as MRT or SFRT, which included involved field, involved site, or involved nodal radiation therapy. SBC risk estimates were compared using competing risk analysis and Fine and Gray multivariable model: MRT +/- chemotherapy, SFRT +/- chemotherapy, or chemotherapy only. RESULTS: Of 734 eligible patients, 75% of the living patients have been followed up for more than 10 years, SBC has developed in 54, and 15 have died of breast cancer. The 20-year estimated risks (competing risk cumulative incidence) for SBC differed significantly: MRT 7.5% (95% confidence interval [CI] 4.4% 11.5%), SFRT 3.1% (95% CI 1.0%-7.7%), and chemotherapy-only 2.2% (95% CI 1.0% 4.8%) (P=.01). Using a Fine and Gray model to control for death and patients lost to follow-up, MRT was associated with a higher risk of SBC (hazard ratio [HR] = 2.9; 95% CI 1.4%-6.0%; P=.004) compared with chemotherapy-only and with SFRT (HR = 3.3; 95% CI 1.3%-8.4%; P=.01). SFRT was not associated with a greater risk of SBC compared with chemotherapy-only (HR = 0.87; 95% CI 0.28%-2.66%; P=.80). CONCLUSION: This study confirms that large-volume MRT is associated with a markedly increased risk of SBC; however, more modern small-volume RT is not associated with a greater risk of SBC than chemotherapy alone. PMID- 27979456 TI - Robotic Surgery plus Chemo-Radiation Therapy. PMID- 27979457 TI - Clinical Trial or Unilateral RT with Cisplatin. PMID- 27979458 TI - Zoledronic Acid in First-Line Treatment of Prostate Cancer. PMID- 27979459 TI - Residency Match Interviews: Walking the Line Requires Knowing the Line. PMID- 27979460 TI - Favorable Preliminary Outcomes for Men With Low- and Intermediate-risk Prostate Cancer Treated With 19-Gy Single-fraction High-dose-rate Brachytherapy. AB - PURPOSE: To report the toxicity and preliminary clinical outcomes of a prospective trial evaluating 19-Gy, single-fraction high-dose-rate (HDR) brachytherapy for men with low- and intermediate-risk prostate cancer. METHODS AND MATERIALS: A total of 63 patients were treated according to an institutional review board-approved prospective study of single-fraction HDR brachytherapy. Eligible patients had tumor stage <=T2a, prostate-specific antigen level <=15 ng/mL, and Gleason score <=7. Patients with a prostate gland volume >50 cm3 and baseline American Urologic Association symptom score >12 were ineligible. Patients underwent transrectal ultrasound-guided transperineal implantation of the prostate, followed by single-fraction HDR brachytherapy. Treatment was delivered using 192Ir to a dose of 19 Gy prescribed to the prostate, with no additional margin applied. RESULTS: Of the 63 patients, 58 had data available for analysis. Five patients had withdrawn consent during the follow-up period. The median follow-up period was 2.9 years (range 0.3-5.2). The median age was 61.4 years. The median gland volume at treatment was 34.8 cm3. Of the 58 patients, 91% had T1 disease, 71% had Gleason score <=6 (29% with Gleason score 7), and the median pretreatment prostate-specific antigen level was 5.1 ng/mL. The acute and chronic grade 2 genitourinary toxicity incidence was 12.1% and 10.3%, respectively. No grade 3 urinary toxicity occurred. No patients experienced acute rectal toxicity grade >=2, and 2 experienced grade >=2 chronic gastrointestinal toxicity. Three patients experienced biochemical failure, yielding a 3-year cumulative incidence estimate of 6.8%. CONCLUSIONS: Single-fraction HDR brachytherapy is well-tolerated, with favorable preliminary biochemical and clinical disease control rates. PMID- 27979462 TI - Temperature dependency of virus and nanoparticle transport and retention in saturated porous media. AB - The influence of temperature on virus (PRD1 and PhiX174) and carboxyl-modified latex nanoparticle (50 and 100nm) attachment was examined in sand-packed columns under various physiochemical conditions. When the solution ionic strength (IS) equaled 10 and 30mM, the attachment rate coefficient (katt) increased up to 109% (p<0.0002) and the percentage of the sand surface area that contributed to attachment (Sf) increased up to 160% (p<0.002) when the temperature was increased from 4 to 20 degrees C. Temperature effects at IS=10 and 30mM were also dependent on the system hydrodynamics; i.e., enhanced retention at a lower pore water velocity (0.1m/day). Conversely, this same temperature increase had a negligible influence on katt and Sf values when IS was 1mM or >50mM. An explanation for these observations was obtained from extended interaction energy calculations that considered nanoscale roughness and chemical heterogeneity on the sand surface. Interaction energy calculations demonstrated that the energy barrier to attachment in the primary minimum (?Phia) decreased with increasing IS, chemical heterogeneity, and temperature, especially in the presence of small amounts of nanoscale roughness (e.g., roughness fraction of 0.05 and height of 20nm in the zone of influence). Temperature had a negligible effect on katt and Sf when the IS=1mM because of the large energy barrier, and at IS=50mM because of the absence of an energy barrier. Conversely, temperature had a large influence on katt and Sf when the IS was 10 and 30mM because of the presence of a small ?Phia on sand with nanoscale roughness and a chemical (positive zeta potential) heterogeneity. This has large implications for setting parameters for the accurate modeling and transport prediction of virus and nanoparticle contaminants in ground water systems. PMID- 27979461 TI - Evaluating the reliability of equilibrium dissolution assumption from residual gasoline in contact with water saturated sands. AB - Understanding dissolution dynamics of hazardous compounds from complex gasoline mixtures is a key to long-term predictions of groundwater risks. The aim of this study was to investigate if the local equilibrium assumption for BTEX and TMBs (trimethylbenzenes) dissolution was valid under variable saturation in two dimensional flow conditions and evaluate the impact of local heterogeneities when equilibrium is verified at the scale of investigation. An initial residual gasoline saturation was established over the upper two-thirds of a water saturated sand pack. A constant horizontal pore velocity was maintained and water samples were recovered across 38 sampling ports over 141days. Inside the residual NAPL zone, BTEX and TMBs dissolution curves were in agreement with the TMVOC model based on the local equilibrium assumption. Results compared to previous numerical studies suggest the presence of small scale dissolution fingering created perpendicular to the horizontal dissolution front, mainly triggered by heterogeneities in the medium structure and the local NAPL residual saturation. In the transition zone, TMVOC was able to represent a range of behaviours exhibited by the data, confirming equilibrium or near-equilibrium dissolution at the scale of investigation. The model locally showed discrepancies with the most soluble compounds, i.e. benzene and toluene, due to local heterogeneities exhibiting that at lower scale flow bypassing and channelling may have occurred. In these conditions mass transfer rates were still high enough to fall under the equilibrium assumption in TMVOC at the scale of investigation. Comparisons with other models involving upscaled mass transfer rates demonstrated that such approximations with TMVOC could lead to overestimate BTEX dissolution rates and underestimate the total remediation time. PMID- 27979463 TI - Outcomes of octogenarians undergoing gastrectomy performed for malignancy. AB - BACKGROUND: Studies on perioperative outcomes of octogenarians with gastric cancer are limited by small sample size. Our aim was to determine the outcomes of gastrectomy and the variation of treatments associated with advanced age (>=80 y). METHODS: The National Surgical Quality Improvement Program database was queried from 2005 to 2011. Patients who underwent gastrectomy for malignancy were identified using International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes. RESULTS: Of 2591 cases, 487 patients were octogenarians (>=80) and 2104 were nonoctogenarians (<80). Overall, 4.9% of patients had disseminated cancer. Octogenarians had higher 30-d mortality (7.2% versus 2.5%, P < 0.01) and more major complications (31.4% versus 25.5%, P < 0.01), though fewer octogenarians underwent total gastrectomy (24.0% versus 43.2%, P < 0.01) and extended lymphadenectomy (10.1% versus 17.4%, P < 0.01) than the nonoctogenarian cohort. On multivariate analysis, age >=80 y was associated with major complications (OR, 1.3; 95% CI, 1.03-1.6; P = 0.03) and increased mortality (OR, 3.0; 95% CI, 1.9-4.9; P < 0.01). CONCLUSIONS: Advanced age (>=80 y) was associated with worse outcomes in patients undergoing gastrectomy for malignancy. Therefore, careful staging is necessary to reduce unnecessary operations in this population. Furthermore, surgeons must place greater attention on optimizing the octogenarian population before surgery. PMID- 27979464 TI - Topical vanadate enhances the repair of median laparotomy incisions. AB - BACKGROUND: There are over two million laparotomies performed in the United States each year with an incisional hernia rate between 2% and 11%. A total of 100,000 ventral hernia repairs are undertaken each year with recurrences as high as 50%. MATERIALS AND METHODS: Full thickness midline fascia incisions from the xiphoid to the pubic symphysis were made in rats. The fascia and/or muscular layer was sutured closed and a gel with 300 MUM of sodium orthovanadate or saline was placed over the suture line with the skin closed over it. On day 10, 1-cm strips from the superior, middle, and inferior regions of the abdominal wall were tested for breaking strength and processed for histology. RESULTS: The mean wound breaking strength of vanadate-treated wounds was 18.6 +/- 2.7 N compared with 9.4 +/- 3.6 N for controls (P < 0.0001). Similar quantities of granulation tissue were deposited in treated and control wounds. Fine green birefringence patterns, characteristic of immature connective tissue, were seen in control samples viewed with polarized light. In contrast, vanadate-treated wounds showed thick yellow orange birefringence patterns characteristics of more mature connective tissue. Using alpha-smooth muscle actin immunostaining, myofibroblasts were prominent in control incisions, but few were identified in vanadate-treated incisions. CONCLUSIONS: In rat laparotomy wounds, a single application of vanadate increases wound breaking strength, through enhanced connective tissue organization. These combined data suggest topical application of vanadate immediately after fascial closure will increase wound strength, possibly reducing hernia recurrences in the repaired abdominal wall. PMID- 27979465 TI - Open access phone triage for veterans with suspected malignant pleural mesothelioma. AB - BACKGROUND: Phone triaging patients with suspected malignant pleural mesothelioma (MPM) within the Veterans Healthcare Administration (VHA) system offers a model for rapid, expert guided evaluation for patients with rare and treatable diseases within a national integrated healthcare system. To assess feasibility of national open access telephone triage using evidence-based treatment recommendations for patients with MPM, measure timelines of the triage and referral process and record the impact on "intent to treat" for patients using our service. METHODS: A retrospective study. The main outcome measures were: (1) ability to perform long distance phone triage, (2) to assess the speed of access to a mesothelioma surgical specialist for patients throughout the entire VHA, and (3) to determine if access to a specialist would alter the plan of care. RESULTS: Sixty veterans were screened by our phone triage program, 38 traveled an average of 997 miles to VA Boston Healthcare system. On average, 14 d elapsed from initial phone contact until the patient was physically evaluated in our general thoracic clinic in Boston. The treatment plan was altered for 71% of patients evaluated at VA Boston Healthcare system based on 2012 International Mesothelioma Interest Group guidelines. CONCLUSIONS: Our initial experience demonstrates that in-network centralized care for Veterans with MPM is feasible within the VHA. National open access phone triage improves access to expert surgical advice and can be delivered in a timely manner for Veterans using our service. Guideline-based treatment recommendations ("intent to treat") changed the therapeutic course for the majority of patients who used our service. PMID- 27979466 TI - A method for evaluating the murine pulmonary vasculature using micro-computed tomography. AB - BACKGROUND: Significant mortality and morbidity are associated with alterations in the pulmonary vasculature. While techniques have been described for quantitative morphometry of whole-lung arterial trees in larger animals, no methods have been described in mice. We report a method for the quantitative assessment of murine pulmonary arterial vasculature using high-resolution computed tomography scanning. METHODS: Mice were harvested at 2 weeks, 4 weeks, and 3 months of age. The pulmonary artery vascular tree was pressure perfused to maximal dilation with a radio-opaque casting material with viscosity and pressure set to prevent capillary transit and venous filling. The lungs were fixed and scanned on a specimen computed tomography scanner at 8-MUm resolution, and the vessels were segmented. Vessels were grouped into categories based on lumen diameter and branch generation. RESULTS: Robust high-resolution segmentation was achieved, permitting detailed quantitation of pulmonary vascular morphometrics. As expected, postnatal lung development was associated with progressive increase in small-vessel number and arterial branching complexity. CONCLUSIONS: These methods for quantitative analysis of the pulmonary vasculature in postnatal and adult mice provide a useful tool for the evaluation of mouse models of disease that affect the pulmonary vasculature. PMID- 27979467 TI - Factors influencing delayed hospital presentation in patients with appendicitis: the APPE survey. AB - BACKGROUND: Among patients with acute appendicitis (AA), perforation is thought to be associated with symptom duration before treatment. Perforation rates vary between hospitals raising the possibility that some perforations are preventable. The factors that compel patients to present earlier or later are unknown but are critical in developing quality improvement interventions aimed at reducing perforation rates. MATERIALS AND METHODS: The Appendicitis Patient Pre-Hospital Experience (APPE) Survey is a prospective study of adults and parents of children with AA in six hospitals participating in Washington State's Comparative Effectiveness Research Translation Network (CERTAIN). The APPE survey includes questions about symptom duration before presentation (late defined as >24 h), predisposing characteristics, enabling factors, and need. RESULTS: Among 80 patients, perforation occurred more frequently in late presenters (44% versus 11%, P < 0.01). Late presenters more frequently drove themselves to the hospital (64% versus 52%, P = 0.05) as opposed to relying on friends/family members and described their health behavior as "waiting it out" when something is wrong (71% versus 46%, P = 0.03). We found similar sociodemographics, clinical characteristics, health care utilization, optimism, health care trust, and risk taking between the two cohorts. CONCLUSIONS: Late presenters described reduced social support and a tendency to "wait it out" and had higher rates of perforation than early presenters. These characteristics have not been well studied conditions but are important to understand to identify patients at high risk for delayed presentation. Future interventions might target those with low social support or those who are reluctant to seek care early to decrease rates of perforation. PMID- 27979469 TI - Review of primary extra-adrenal myelolipoma of the thorax. AB - Extra-adrenal myelolipoma happens in adrenal glands, and the thoracic location is extremely unusual. This is the first study involving 36 of patients with thoracic myelolipoma of English literature by investigating the clinical data, pathologic findings, radiological manifestation, and treatment strategy of all patients. Imageologic diagnosis including computed tomography, magnetic resonance imaging, and positron emission tomography/computed tomography scans is useful to identify the feature of extra-adrenal myelolipoma. Pathologic analysis is an effective method to clarify the diagnosis. In view of the potential progressive enlargement of the lesion, most myelolipomas are removed by surgery, and this operation has frequently been accomplished by using video-assisted thoracic surgery. PMID- 27979468 TI - Sarcopenia in emergency abdominal surgery. AB - BACKGROUND: Sarcopenia, a loss of skeletal muscle mass associated with aging, is a practical measure of frailty and has been previously identified as a predictor of outcomes in surgical cohorts including cancer resection and elderly patients. We hypothesized that sarcopenia, as measured by preoperative computerized tomography (CT) scan, predicts mortality and morbidity in emergent laparotomy. METHODS: Institutional American College of Surgeons National Surgical Quality Improvement Program data were queried for adult patients who underwent open emergency abdominal surgery between 2008 and 2013. Patients with abdominal CT scans within 30 d before surgery were included, and cross-sectional areas of the psoas muscles at vertebral level L4 were summed, normalized by patient height, and stratified by sex. The influence of this total psoas area (TPA) on postoperative morbidity and mortality was evaluated using univariate and multivariate analysis. RESULTS: Of 781 surgeries, 593 (75.9%) had appropriate preoperative CT scans. Median patient age was 61 years old, median TPA was 1719 mm2, and median body mass index was 26.7. Univariate analysis demonstrated a significant association between TPA and total postoperative morbidity (P = 0.0133), increased length of stay (<0.0001), and 90-d mortality (P = 0.0008) but not 30-d mortality (P = 0.26). In multivariate analysis, TPA lost its significance compared to more influential predictors of mortality, including American Society of Anesthesiologists classification. CONCLUSIONS: Sarcopenia, as measured by TPA, significantly predicted mortality in univariate analysis but lost significance in multivariate analysis when factors such as American Society of Anesthesiologists score were included. Because TPA is readily available at no additional risk or cost, it is a convenient additional tool for preoperative risk assessment and counseling. PMID- 27979470 TI - A simplified stratification system for venous thromboembolism risk in severely injured trauma patients. AB - BACKGROUND: The objective of this study was to re-evaluate and simplify the Greenfield risk assessment profile (RAP) for venous thromboembolism (VTE) in trauma using information readily available at the bedside. METHODS: Retrospective review of 1233 consecutive admissions to the trauma intensive care unit from August 2011-January 2015. Univariate analyses were performed to determine which RAP risk factors were significant contributors to VTE. Multivariable logistic regression was used to develop models for risk stratification. All results were considered statistically significant at P <= 0.05. RESULTS: The study population was as follows: age 44 +/- 19, 75% male, 72% blunt, injury severity score 21 +/- 13, RAP score 9 +/- 5, and 8% mortality. Groups were separated into +VTE (n = 104) and -VTE (n = 1129). They were similar in age, gender, mechanism, and mortality, but injury severity and RAP scores were higher in the +VTE group (all P < 0.0001). The +VTE group had more transfusions and longer time to prophylaxis (all P < 0.05). Receiving four or more transfusions in the first 24 h (odds ratio [OR], 2.60; 95% confidence interval [CI], 1.64-4.13), Glasgow coma score <8 for >4 h (OR, 2.13; 95% CI, 1.28-3.54), pelvic fracture (OR, 2.26; 95% CI, 1.44 3.57), age 40-59 y (OR, 1.70; 95% CI, 1.10-2.63), and >2-h operation (OR, 1.80; 95% CI, 1.14-2.85) predicted VTE with an area under the receiver operator curve of 0.729, which was comparable with 0.740 for the RAP score alone. CONCLUSIONS: VTE risk in trauma can be easily assessed using only five risk factors, which are all readily available at the bedside (transfusion, Glasgow coma scale, pelvic fracture, prolonged operation, and age). This simplified model provides similar predictive ability to the more complicated RAP score. Prospective validation of a simplified risk assessment score is warranted. PMID- 27979472 TI - Regulation of myocardial stromal cell-derived factor 1alpha/CXCL12 by tumor necrosis factor signaling. AB - BACKGROUND: Global myocardial ischemia-reperfusion (I/R) occurs during cardiac operations. This I/R injury leads to increased production of tumor necrosis factor alpha (TNF) instantly and upregulated expression of stromal cell-derived factor 1 alpha (SDF-1). On the basis of the published data from our laboratory and other groups, locally produced TNF contributes to cardiac dysfunction mainly via binding to its receptor (tumor necrosis factor receptor 1 [TNFR1]), whereas ischemia-induced myocardial SDF-1 mediates cardioprotection. Although TNF has been shown to work as an upstream initiator for induction of other cytokines and chemokines, there is no information regarding the interaction among TNF, TNFRs, and myocardial SDF-1 expression. In this study, given that TNF downregulated SDF 1 in vascular endothelial cells, we therefore hypothesized that TNF would have a negative effect on myocardial SDF-1 production, which is attributable to TNFR initiated actions. METHODS: Using a Langendorff model, isolated male mouse hearts were infused with TNF for 45 min. Male adult mouse hearts from wild type, TNFR1 knockout (TNFR1KO), TNFR2KO, and TNFR1/2KO were subjected to global I/R. H9c2 cells with small interfering RNA transfection were used as an in vitro model. The levels of SDF-1 (protein and messenger RNA) were detected by enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction . Protein kinases of IkappaB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha) and c-jun N-terminal kinase were also determined using Western blot assay. RESULTS: TNF infusion downregulated myocardial SDF-1 production in a dose-dependent manner in the hearts. In addition, using TNF significantly decreased SDF-1 expression in cardiomyoblasts (H9c2 cells), which was associated with reduced IkappaB level. Knockdown of TNFR1 or TNFR2 by small interfering RNAs neutralized TNF-suppressed SDF-1 in H9c2 cells. Furthermore, deletion of TNFR1/2 or TNFR2 increased SDF-1 production in the hearts after I/R. CONCLUSIONS: Our study represents the initial evidence showing that TNF plays an inhibitory role in modulating myocardial SDF-1 production and blockade of TNF signaling by ablation of TNFR1 and TNFR2 genes increased SDF-1 expression in the heart. These data expand on TNF signaling initiated mechanisms in myocardium, which may lend a more complete understanding of SDF-1 and TNFR-derived actions in hopes of advancing ischemic heart injury treatments. PMID- 27979471 TI - Changes in kidney perfusion and renal cortex metabolism in septic shock: an experimental study. AB - BACKGROUND: The etiology of renal dysfunction in sepsis is currently attributed to altered perfusion, microcirculatory abnormalities and cellular alterations. To clarify these mechanisms, we characterized the changes in renal perfusion and cortex metabolism in a large animal model of sepsis. METHODS: We studied 12 adult female sheep randomized to peritonitis-induced sepsis (n = 8) or to sham procedure (n = 4). A flow probe was positioned around the renal artery to measure renal blood flow (RBF). Laser Doppler was used to measure regional flow in the kidney cortex and medulla. A microdialysis probe was inserted into the renal cortex to measure cortical glucose, lactate, and pyruvate. Fluid resuscitation was provided to keep pulmonary artery occlusion pressure at baseline levels. All animals were observed for 18 h. RESULTS: Hypotension occurred after 9 h in the septic animals (P = 0.02 versus baseline). RBF and cortical flow were significantly lower than at baseline from 12 h in the septic animals (P = 0.01 and P = 0.03, respectively). Cortical lactate and pyruvate levels increased in the septic animals from 3 and from 6 h, respectively (both P = 0.02 versus baseline), and the L/P ratio from 15 h (P = 0.01). There was a correlation between cortical flow and cortical L/P ratio after shock onset (r = -0.60, P = 0.002) but not before. CONCLUSIONS: In this peritonitis model, sepsis was associated with metabolic alterations that may reflect early induction of cortical glycolysis. Septic shock was associated with reduced renal perfusion and decreased cortical and medullary blood flow, followed by signs of anaerobic metabolism in the cortex when flow reductions became critical. PMID- 27979473 TI - Lazaroid U-74389G for cardioplegia-related ischemia-reperfusion injury: an experimental study. AB - BACKGROUND: The adverse effects of myocardial ischemia and reperfusion during cardiopulmonary bypass (CPB) have been thoroughly described. Lazaroid U-74389G, a 21 aminosteroid, has been shown to attenuate ischemia and reperfusion injury and improve recovery in a variety of experimental models. METHODS: Sixteen male swine were randomly divided in two groups. All animals underwent 45 min of ischemic cardioplegic arrest, with U-74389G addition to the standard cardioplegic solution, whereas controls underwent the same procedure without U-74389G. Creatine kinase-MB isoenzyme (CK-MB) and cardiac troponin T levels were measured immediately before CPB (time point 0), during the ischemic period (time point 1) and 30 (time point 2), 60 (time point 3), and 120 (time point 4) min after reperfusion. Myocardial biopsies were obtained at time points 0 and 4. RESULTS: CK-MB levels (in U/L) at time points 0-4 were 205 (186-235) versus 219 (196-269; P = 0.72), 215 (167-248) versus 253 (193-339; P = 0.23), 234 (198-255) versus 338 (249-441; P = 0.02), 244 (217-272) versus 354 (269-496; P = 0.01), and 285 (230 321) versus 439 (432-530; P < 0.01) in lazaroid-treated animals versus controls, respectively. Cardiac troponin T levels (in ng/L) at time points 0-4 were 58 (26 287) versus 237 (26-395; P = 0.72), 129 (61-405) versus 265 (145-525; P = 0.23), 261 (123-467) versus 474 (427-1604; P = 0.04), 417 (204-750) versus 841 (584 1818; P = 0.11), and 643 (353-1259) versus 1600 (1378-2313; P < 0.01), respectively. Necrosis grades at time point 4 were 0.0 (0.0-1.0) versus 1.5 (1.0 2.0; P < 0.01) in lazaroid-treated animals versus controls, respectively. CONCLUSIONS: The present study, in addition to reconfirming the well-described adverse effects of CPB, demonstrates the efficacy of the newer generation lazaroid U-74389G in alleviating these effects. PMID- 27979474 TI - Primary appendiceal lymphoma: clinical characteristics and outcomes of 116 patients. AB - BACKGROUND: Primary appendiceal lymphoma (PAL) is extremely rare with limited data available in literature. In this study, we sought to describe clinical features and identify factors affecting survival in patients with PAL using a large population cohort. METHODS: Surveillance, Epidemiology, and End Results database was queried for patients with PAL between 1973 and 2012. Patient demographics, tumor characteristics, and outcomes were assessed. RESULTS: One hundred sixteen patients with PAL were included. The mean age (standard deviation) at diagnosis was 48 y (+/-22). PAL primarily afflicted males and white race. Diffuse large B-cell lymphoma was the most common histologic subtype (34.5%). Patients with Burkitt lymphoma presented at an earlier age compared with follicular lymphoma and diffuse large B-cell lymphoma (33 versus 59 and 53 y, respectively, [P < 0.001]). Mean overall survival (OS) for the whole cohort was 185 mo with a 5-y survival rate of 67%. No statistically significant survival difference was observed between gender, race and histologic subtypes. Right hemicolectomy conferred no survival benefit over appendectomy and/or partial colectomy (P = 0.501). In multivariate analysis, increasing age at diagnosis (P < 0.001) was associated with increased hazards of death while gender, race, tumor histology, disease stage, and nature of resection were not significantly associated with OS. CONCLUSIONS: This is the largest series of PALs. Our results demonstrate that age at diagnosis is an independent predictor of poor survival. Gender, race, histologic subtypes have no effect on OS, and hemicolectomy provides no survival benefit over appendectomy and/or partial colectomy. Additional prospective, multicenter studies including details about chemotherapy and immunotherapy are needed to guide management. PMID- 27979475 TI - Ginsenoside Rg1 protects against sepsis-associated encephalopathy through beclin 1-independent autophagy in mice. AB - BACKGROUND: Sepsis-associated encephalopathy (SAE), a commonly complicated syndrome, is associated with increased mortality in patients with sepsis. Currently, no specific diagnostic test or effective intervention exists to improve long-term consequences on cerebral function. Ginsenoside Rg1 (Rg1), a major component in ginseng, was reported to have pleiotropic properties including anti-inflammation and neuroprotection. The aim of our study was to investigate the protective effect of Rg1 on SAE and the potential mechanism. MATERIALS AND METHODS: SAE model was prepared by inducing cecal ligation and puncture (CLP) in mice. Rg1 was injected 1 h before the CLP operation. Survival rate within 7 d after operation was analyzed. Surviving mice were subjected to Morris water maze tests and the brains were collected for histopathologic evaluation and immunohistochemistry. The hippocampus was obtained for Western blot, real time polymerase chain reaction, and enzyme-linked immunosorbent assay analysis. RESULTS: Rg1 improved the postoperative survival rate and protected against sepsis-associated learning and memory impairments (Morris water maze). Besides, Rg1 was able to attenuate brain histopathologic changes (hematoxylin and eosin staining), suppress Iba1 activation, decrease the expressions of inflammatory cytokines (tumor necrosis factor alpha, interleukin 1beta, and interleukin 6), and reduce neuronal apoptosis (cleaved caspase 3 activation) in hippocampus. Furthermore, the mechanism study showed that Rg1 suppressed the expressions of light chain 3-II and p62 in hippocampus but not beclin 1. CONCLUSIONS: These findings suggested that Rg1 improved the survival rate and ameliorated cognitive impairments partially through regulating cerebral inflammation and apoptosis. In addition, the action mechanism might be noncanonical beclin 1-independent autophagy pathway. Rg1 may be a promising treatment strategy for SAE. PMID- 27979476 TI - "I got it on Ebay!": cost-effective approach to surgical skills laboratories. AB - BACKGROUND: Surgical education is witnessing a surge in the use of simulation. However, implementation of simulation is often cost-prohibitive. Online shopping offers a low budget alternative. The aim of this study was to implement cost effective skills laboratories and analyze online versus manufacturers' prices to evaluate for savings. MATERIALS AND METHODS: Four skills laboratories were designed for the surgery clerkship from July 2014 to June 2015. Skills laboratories were implemented using hand-built simulation and instruments purchased online. Trademarked simulation was priced online and instruments priced from a manufacturer. Costs were compiled, and a descriptive cost analysis of online and manufacturers' prices was performed. Learners rated their level of satisfaction for all educational activities, and levels of satisfaction were compared. RESULTS: A total of 119 third-year medical students participated. Supply lists and costs were compiled for each laboratory. A descriptive cost analysis of online and manufacturers' prices showed online prices were substantially lower than manufacturers, with a per laboratory savings of: $1779.26 (suturing), $1752.52 (chest tube), $2448.52 (anastomosis), and $1891.64 (laparoscopic), resulting in a year 1 savings of $47,285. Mean student satisfaction scores for the skills laboratories were 4.32, with statistical significance compared to live lectures at 2.96 (P < 0.05) and small group activities at 3.67 (P < 0.05). CONCLUSIONS: A cost-effective approach for implementation of skills laboratories showed substantial savings. By using hand built simulation boxes and online resources to purchase surgical equipment, surgical educators overcome financial obstacles limiting the use of simulation and provide learning opportunities that medical students perceive as beneficial. PMID- 27979477 TI - Maximizing efficiency on trauma surgeon rounds. AB - BACKGROUND: Rounding by trauma surgeons is a complex multidisciplinary team-based process in the inpatient setting. Implementation of lean methodology aims to increase understanding of the value stream and eliminate nonvalue-added (NVA) components. We hypothesized that analysis of trauma rounds with education and intervention would improve surgeon efficacy. MATERIALS AND METHODS: Level 1 trauma center with 4300 admissions per year. Average non-intensive care unit census was 55. Five full-time attending trauma surgeons were evaluated. Value added (VA) and NVA components of rounding were identified. The components of each patient interaction during daily rounds were documented. Summary data were presented to the surgeons. An action plan of improvement was provided at group and individual interventions. Change plans were presented to the multidisciplinary team. Data were recollected 6 mo after intervention. RESULTS: The percent of interactions with NVA components decreased (16.0% to 10.7%, P = 0.0001). There was no change between the two periods in time of evaluation of individual patients (4.0 and 3.5 min, P = 0.43). Overall time to complete rounds did not change. There was a reduction in the number of interactions containing NVA components (odds ratio = 2.5). CONCLUSIONS: The trauma surgeons were able to reduce the NVA components of rounds. We did not see a decrease in rounding time or individual patient time. This implies that surgeons were able to reinvest freed time into patient care, or that the NVA components were somehow not increasing process time. Direct intervention for isolated improvements can be effective in the rounding process, and efforts should be focused upon improving the value of time spent rather than reducing time invested. PMID- 27979478 TI - Risk factors for superficial surgical site infection after elective rectal cancer resection: a multivariate analysis of 8880 patients from the American College of Surgeons National Surgical Quality Improvement Program database. AB - BACKGROUND: Superficial surgical site infection (sSSI) is one of the most common complications after colorectal resection. The goal of this study was to determine the comorbidities and operative characteristics that place patients at risk for sSSI in patients who underwent rectal cancer resection. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried (via diagnosis and Current Procedural Terminology codes) for patients with rectal cancer who underwent elective resection between 2005 and 2012. Patients for whom data concerning 27 demographic factors, comorbidities, and operative characteristics were available were eligible. A univariate and multivariate analysis was performed to identify possible risk factors for sSSI. RESULTS: A total of 8880 patients met the entry criteria and were included. sSSIs were diagnosed in 861 (9.7%) patients. Univariate analysis found 14 patients statistically significant risk factors for sSSI. Multivariate analysis revealed the following risk factors: male gender, body mass index (BMI) >30, current smoking, history of chronic obstructive pulmonary disease (COPD), American Society of Anesthesiologists III/IV, abdominoperineal resection (APR), stoma formation, open surgery (versus laparoscopic), and operative time >217 min. The greatest difference in sSSI rates was noted in patients with COPD (18.9 versus 9.5%). Of note, 54.2% of sSSIs was noted after hospital discharge. With regard to the timing of presentation, univariate analysis revealed a statistically significant delay in sSSI presentation in patients with the following factors and/or characteristics: BMI <30, previous radiation therapy (RT), APR, minimally invasive surgery, and stoma formation. Multivariate analysis suggested that only laparoscopic surgery (versus open) and preoperative RT were risk factors for delay. CONCLUSIONS: Rectal cancer resections are associated with a high incidence of sSSIs, over half of which are noted after discharge. Nine patient and operative characteristics, including smoking, BMI, COPD, APR, and open surgery were found to be significant risk factors for SSI on multivariate analysis. Furthermore, sSSI presentation in patients who had laparoscopic surgery and those who had preoperative RT is significantly delayed for unclear reasons. PMID- 27979479 TI - Falciform ligament wrap for prevention of gastroduodenal artery bleed after pancreatoduodenectomy. AB - BACKGROUND: The present study aims to assess the effectiveness and current evidence of a pedicled falciform ligament wrap around the gastroduodenal artery stump for prevention of erosion hemorrhage after pancreatoduodenectomy (PD). METHODS: Retrospective data were pooled for meta-analysis. At the own center, patients who underwent PD between 2012 and 2015 were retrospectively analyzed based on the intraoperative performance of the wrap. A systematic literature review and meta-analysis was performed that combined the published and the obtained original data. The following databases were searched: Medline, Embase, Web of Science, and the Cochrane Library. RESULTS: At the own center, a falciform ligament wrap was performed in 39 of 196 PDs (20%). The wrap group contained more ampullary neoplasms, but the pancreatic fistula rate was not significantly different from the nonwrap group (28% versus 32%). In median, erosion hemorrhage occurred after 21.5 d, and it was lethal in 39% of the patients. Its incidence was not significantly lower in the wrap group (incidence: 7.7% versus 9.6% in the nonwrap group). The systematic literature search yielded four retrospective studies with a high risk of bias; only one study was controlled. When the five data sets of published and own cases with a falciform ligament wrap were pooled, the incidence of erosion hemorrhage was 5 of 533 cases (0.9%) compared with 24 of 297 cases (8.1%) without the wrap. CONCLUSIONS: The reported incidence of erosion hemorrhage after the falciform ligament wrap is low, but there are still insufficient controlled data to support its general use. PMID- 27979481 TI - Postoperative delirium is associated with increased intensive care unit and hospital length of stays after liver transplantation. AB - BACKGROUND: Delirium is increasingly recognized as a common and important postoperative complication that significantly hinders surgical recovery. However, there is a paucity of data examining the incidence and impact of delirium after liver transplantation. METHODS: Retrospective case series in a tertiary care center examining all (n = 144) adult patients who underwent liver transplantation during a 6-y period. RESULTS: Delirium occurred in 25% of the patients with an average duration of 4.56 d. Patients who developed delirium were older (P = 0.007), had higher preoperative model for end-stage liver disease score (P = 0.019) and longer pretransplant hospital length of stay (LOS; P = 0.003). Patients with delirium were also more likely to have alcohol ingestion as an etiology of the liver failure (P = 0.033). Delirious patients had a trend toward increased ventilator days (P = 0.235) and significantly longer postoperative hospital (P = 0.001) and intensive care unit LOS (P = 0.001). Delirium was also associated with an increased frequency of hospital acquired infections including urinary tract infections (P = 0.005) and pneumonias (P = 0.001). CONCLUSIONS: Delirium is a common occurrence among liver transplant patients associated with increased complications and LOSs. Further prospective studies are needed to determine the specific risk factors in this complex population and to determine if delirium has an impact on long-term outcomes. PMID- 27979480 TI - Location of abnormal parathyroid glands: lessons from 810 parathyroidectomies. AB - BACKGROUND: Primary hyperparathyroidism (pHPT) is commonly treated with targeted parathyroidectomy (PTX) guided by preoperative imaging and intraoperative parathormone monitoring. Despite advanced imaging techniques, failure of parathyroid localization still occurs. This study determines the anatomical distribution of single abnormal parathyroid glands, which may help direct the surgeon in PTX when preoperative localization is unsuccessful. METHODS: A retrospective review of prospectively collected data of 810 patients with pHPT who underwent initial PTX at a tertiary medical center was performed. All patients had biochemically confirmed pHPT and single-gland disease. Abnormal parathyroid gland localization was determined at time of operation, correlated with operative and pathology reports, and confirmed by operative success defined as eucalcemia for >=6 mo after PTX. Patients with multiple endocrine neoplasia, secondary, tertiary, or familial hyperparathyroidism, multiglandular disease, parathyroid cancer, and ectopic glands were excluded. Data were analyzed by chi square and Z-test analyses. RESULTS: Among 810 patients who underwent PTX for pHPT, single abnormal parathyroid glands were unequally distributed among the four eutopic locations (left superior, 15.7%; left inferior, 31.3%; right superior, 15.8%; right inferior, 37.2%; P < 0.01). Abnormal inferior parathyroid glands (68.5%) were significantly more common than abnormal superior glands (31.5%), respectively (P < 0.01). In men, the most common location for single abnormal parathyroid glands was the right inferior position (43.4%, P < 0.01). Overall, there was no significant difference in laterality. CONCLUSIONS: This large series of patients suggests that single eutopic abnormal parathyroid glands are more likely to be inferior. In men, moreover, if an abnormal parathyroid gland is not localized preoperatively, the right inferior location should be explored first. Nevertheless, successful PTX remains predicated on knowledge of parathyroid anatomy, experience, and judgment of the surgeon. PMID- 27979482 TI - Type I/type III collagen ratio associated with diverticulitis of the colon in young patients. AB - BACKGROUND: The incidence of diverticulitis in young patients is rising, whereas the type I:III collagen ratio of the colon decreases with age. Perhaps a lower type I:III collagen ratio in younger patients may predispose these patients to the development of the disease. METHOD: The purpose of this study was to evaluate the collagen content and type I:III collagen ratio in patients with diverticulitis versus a control group. Patients who underwent a colon resection were identified. Three groups of patients were created for analysis: those with diverticulitis aged <50 y, >50 y, and a control group. Tissue samples were stained with Sirius red/fast green and photographed. Photos analysis was performed to quantify the amount of type I collagen and type III collagen. The type I:III collagen ratio was calculated for each patient and compared. RESULTS: The quantity of type I collagen and type III collagen was higher in patients with diverticulitis aged >50 y (P = 0.04 and P < 0.0001, respectively); however, the collagen ratio was greatest in those patients with diverticulitis aged <50 y (P = 0.01). Further analysis demonstrated a significant higher type I:III ratio in all patients aged less than 50 y compared with all patients aged over 50 y (P = 0.04). CONCLUSIONS: Our study demonstrated that diverticulitis in the younger patient was not associated with a lower type I:III collagen ratio. It appears that the decrease in collagen ratio of the colon with age is associated with an increase in type III collagen deposition. PMID- 27979483 TI - Minimally invasive follicular thyroid cancer: treat as a benign or malignant lesion? AB - BACKGROUND: Follicular thyroid cancer is the second most common thyroid cancer, accounting for 10%-15% of all cases. Follicular thyroid carcinomas (FTCs) can be classified into two subtypes: classic (C), which exhibit both vascular and capsular invasion and minimally invasive (MI), which only has limited capsular invasion. Both types, like most well-differentiated thyroid cancers, are traditionally treated the same: a completion thyroidectomy usually followed by radioiodine ablation. We hypothesize that MI-FTC may behave more like a benign follicular adenoma rather than C-FTC and may not require total thyroidectomy and radioiodine. METHODS: A prospective thyroid database was screened for patients with follicular cell tumors. Data on recurrence rates, disease-free survival, and requirement for follow-up surgery and/or radioiodine were compared. Disease-free survival was determined by the Kaplan-Meier method. Analysis of variance and chi square test were used to evaluate other factors. RESULTS: In total, there were 419 benign adenomas (87%), 21 MI-FTCs (4.5%), and 41 C-FTCs (8.5%). Patients with adenomas were younger (P = 0.035) and were more likely to be female (P = 0.001). Importantly, the 16-y disease-free survival was 100% in the adenoma group, 100% in the MI-FTC group, and 36.6% in the C-FTC group (P < 0.0001). CONCLUSIONS: MI FTCs behave similar to adenomas with 100% disease-free survival with up to 16 y of follow-up. These data suggest MI-FTCs could be potentially treated by thyroid lobectomy alone like follicular adenomas and perhaps should be classified as a distinct clinical entity. PMID- 27979484 TI - MicroRNA-125b as a new potential biomarker on diagnosis of renal ischemia reperfusion injury. AB - BACKGROUND: Acute renal failure is commonly seen in the perioperative period. Ischemia-reperfusion (IR) injury plays a major role in acute renal failure and delayed graft function. MicroRNAs (miRs), which are pivotal modulators of cell activities, offer a major opportunity for affective diagnosis and treatment strategies because they are tissue specific and in the center of gene expression modulation. The effect of bardoxolone methyl (BM) on miR-21, miR-223-5p, and miR 125b in renal IR injury was evaluated in this study. METHODS: Wistar-Albino rats (12-16 wk old, weighing 300-350 g) were used in the study. Rats (n = 6) were randomized into three groups (control, IR, and BM + IR). Tissue levels of miRs were analyzed with reverse transcription polymerase chain reaction. RESULTS: Significant reduction of urea and total oxidant status, increase of total antioxidant status, and oxidative stress index were identified in the IR + BM group compared with the IR group. Significant increases of miR-21 (2842.82-fold) and miR-125b (536.8-fold) were identified in the IR group compared with the control group; however, miR-223-5p levels did not show any significant difference. Also, miR-21 and miR-125b were significantly reduced in the IR + BM group compared with the IR group. Reduced histopathologic changes were observed in the IR + BM group. A significant decrease in the number of tunel-positive cells was identified in the IR + BM group compared with the IR group. CONCLUSIONS: miR-125b was significantly increased in IR injury; thus, miR-125b can be a potential novel marker that can be used in diagnosis and treatment of renal IR injury. BM reduces miR-21 and miR-125b in case of IR injury and makes functional and histopathologic repairs. PMID- 27979485 TI - Discharge destination and readmission rates in older trauma patients. AB - BACKGROUND: In older trauma patients, the impact of discharge destination on readmission rates is not known. The objective of this study was to evaluate the association between the discharge destination and the 30-day readmission rate in older trauma patients. MATERIALS AND METHODS: A previously validated database of all patients aged 45 years or older undergoing trauma evaluation at our level 1 trauma center between January 1, 2008 and December 31, 2008 was analyzed to retrospectively compare the incidences of 30-day readmission between patients discharged to home, to inpatient rehabilitation facilities, and to other extended care facilities (ECFs). Demographic information including age and gender and potentially confounding factors including injury severity, trauma activation level, comorbidities, medications, and preinjury functional status were included. Univariate analysis was undertaken using chi-square testing. Multiple logistic regression was performed with potential confounding variables to evaluate for independent contribution to readmission risk. RESULTS: A total of 960 patients were evaluated; 81 patients (8.4%) were excluded, leaving 879 patients included in the analysis. Seventy-six patients (8.6%) were readmitted within 30 d of discharge. Overall, 6% of those discharged to home, 13% of those discharged to ECF, and 16% of those discharged to rehabilitation were readmitted (P < 0.01 on univariate analysis). Overall, 866 (98.5%) patients had data recorded for all variables analyzed using multiple logistic regression; among these, only discharge destination was independently associated with the rate of readmission (P < 0.01). CONCLUSIONS: Discharge to ECFs and inpatient rehabilitation facilities appear to be an independent risk factor for hospital readmissions in this population despite controlling for injury severity and comorbidities. Recognition of this risk factor may aid in the disposition planning of these patients and suggests the need for further evaluation of this correlation at other US medical centers. PMID- 27979486 TI - Platelet-rich plasma: a biomimetic approach to enhancement of surgical wound healing. AB - Platelets are small anucleate cytoplasmic cell bodies released by megakaryocytes in response to various physiologic triggers. Traditionally thought to be solely involved in the mechanisms of hemostasis, platelets have gained much attention due to their involvement wound healing, immunomodulation, and antiseptic properties. As the field of surgery continues to evolve so does the need for therapies to aid in treating the increasingly complex patients seen. With over 14 million obstetric, musculoskeletal, and urological and gastrointestinal surgeries performed annually, the healing of surgical wounds continues to be of upmost importance to the surgeon and patient. Platelet-rich plasma, or platelet concentrate, has emerged as a possible adjuvant therapy to aid in the healing of surgical wounds and injuries. In this review, we will discuss the wound healing properties of platelet-rich plasma and various surgical applications. PMID- 27979487 TI - Hydrophobically modified chitosan gauze: a novel topical hemostat. AB - BACKGROUND: Currently, the standard of care for treating severe hemorrhage in a military setting is Combat Gauze (CG). Previous work has shown that hydrophobically modified chitosan (hm-C) has significant hemostatic capability relative to its native chitosan counterpart. This work aims to evaluate gauze coated in hm-C relative to CG as well as ChitoGauze (ChG) in a lethal in vivo hemorrhage model. METHODS: Twelve Yorkshire swine were randomized to receive either hm-C gauze (n = 4), ChG (n = 4), or CG (n = 4). A standard hemorrhage model was used in which animals underwent a splenectomy before a 6-mm punch arterial puncture of the femoral artery. Thirty seconds of free bleeding was allowed before dressings were applied and compressed for 3 min. Baseline mean arterial pressure was preserved via fluid resuscitation. Experiments were conducted for 3 h after which any surviving animal was euthanized. RESULTS: hm-C gauze was found to be at least equivalent to both CG and ChG in terms of overall survival (100% versus 75%), number of dressing used (6 versus 7), and duration of hemostasis (3 h versus 2.25 h). Total post-treatment blood loss was lower in the hm-C gauze treatment group (4.7 mL/kg) when compared to CG (13.4 mL/kg) and ChG (12.1 mL/kg) groups. CONCLUSIONS: hm-C gauze outperformed both CG and ChG in a lethal hemorrhage model but without statistical significance for key endpoints. Future comparison of hm-C gauze to CG and ChG will be performed on a hypothermic, coagulopathic model that should allow for outcome significance to be differentiated under small treatment groups. PMID- 27979488 TI - Testosterone replacement attenuates intimal hyperplasia development in an androgen deficient model of vascular injury. AB - BACKGROUND: Androgen deficiency (AD) is associated with increased risk of vascular disease. Dysfunctional remodeling of the vessel wall and atypical proliferative potential of vascular smooth muscle cells (VSMCs) are fundamental processes in the development of intimal hyperplasia (IH). We have demonstrated an inverse relationship between dihydrotestosterone (DHT) levels, matrix metalloproteinase activity, and VSMC migration and proliferation in vitro. Here, we investigated the role of AD and testosterone (TST) replacement in IH development in an animal model of vascular injury to elucidate mechanisms modulated by AD that could be playing a role in the development of vascular pathogenesis. METHODS: Aged orchiectomized male rats underwent TST supplementation via controlled release pellet (0.5-35 mg). Young adult and middle age adult intact (MI) and orchiectomized placebo (Plac) groups served as controls. All groups underwent balloon angioplasty of the left common carotid at a 14-d post-TST. Carotid tissue was collected at a 14-d post-balloon angioplasty and subjected to morphologic and immunohistochemical analyses. Human male VSMCs were treated with DHT (0-3000 nM) for 24 h then subjected to quantitative PCR for gene expression analyses and costained for F-actin and G-actin for visualization of cytoskeletal organization. RESULTS: I:M ratio was increased in Plac, subphysiological, low-physiological, and high pharmacologic level TST animals compared with MI controls but was decreased with high-physiological TST supplementation. Injury-induced expression of previously defined matrix metalloproteinase remodeling enzymes was not significantly affected by TST status. Urotensin (UTS) receptor (UTSR) staining was low in injured vessels of all young adult intact, MI, and Plac controls but was significantly upregulated in all groups receiving exogenous TST supplementation, irrespective of dose. In vitro DHT exposure increased the expression of UTSR in VSMCs in a dose-dependent manner. However, this did not correlate with any change in proliferative markers. F:G actin staining revealed that DHT-induced cytoskeletal organization in a dose dependent manner. CONCLUSIONS: AD increased IH development in response to vascular injury, whereas physiological TST replacement attenuated this effect. AD induced IH occurs independent of matrix remodeling mechanisms known to be heavily involved in vascular dysfunction, and AD alone does not affect the UTS and/or UTSR mechanism. Exogenous TST and/or DHT increases UTSR pathway signaling in vitro and in vivo. This modulation correlates to a shift in cytoskeletal organization and may exacerbate vasoconstrictive pathogenesis. While physiological TST replacement attenuates AD-modulated IH development, its UTS mediated effect on vasotone may prove deleterious to overall vascular function. PMID- 27979490 TI - Is OM-3 synergistic with GLP-2 in intestinal failure? AB - INTRODUCTION: Glucagon-like peptide-2 (GLP-2) is a known intestinal growth factor that enhances mucosal mass and function in residual small intestine after massive small bowel resection (MSBR). Luminal omega-3 (OM-3) has been shown to have some growth factor properties. It is possible that their mechanisms of action differ. Thus, we hypothesized that administering these two substances together may have a synergistic effect. METHODS: A total of 60 adult female Sprague-Dawley rats underwent 80% MSBR and divided as follows (n = 15/group): Saline (Control) + regular feeds; GLP-2 + regular feeds; Saline + OM-3 enriched feeds; and GLP-2 + OM-3 enriched feeds. Five animals per group were sacrificed at 7, 14, and 28 days. Small intestine mucosa was harvested. DNA and protein content were measured (mucosal mass markers) at all three time points. Galactose and Glycine absorption were measured (functional capacity markers) at 28 days. Statistical analysis was done by ANOVA with post hoc Tukey's HSD test. RESULTS: At all three time points, DNA was increased in all treatment groups compared to control (P < 0.05), but GLP 2 + OM-3 group did not have increased DNA content when compared to either treatments alone. At 7 and 14 d, all three treatment groups had increased protein content compared to control (P < 0.05). At 28 d, GLP-2 + OM-3 did not have increased protein content compared to control or individual treatments (P < 1.0). All three treatment groups had increased absorption of galactose and glycine compared to control (P < 0.05) but not each other. CONCLUSIONS: Individually, GLP 2 and OM-3 are very effective in enhancing the adaptive process by increasing mucosal mass and function, at all three time points. More importantly, clinically, GLP-2 and OM-3 increase substrate absorption in a rat model of intestinal failure. However, the combination is not synergistic. PMID- 27979489 TI - Changes in cholinergic and nitrergic systems of defunctionalized colons after colostomy in rabbits. AB - BACKGROUND: This study was designed to assess smooth muscle function and motility in defunctionalized colonic segments and subsequent changes in pathways responsible for gastrointestinal motility. METHODS: Two-month-old New Zealand rabbits were randomly allocated into control and study groups. Sigmoid colostomies were performed in the study group. After a 2-month waiting period, colonic segments were harvested in both groups. For the in vitro experiment, the isolated circular muscle strips which were prepared from the harvested distal colon were used. First, contraction responses were detected using KCl and carbachol; relaxation responses were detected using papaverine, sodium nitroprusside, sildenafil, and l-arginine. The neurologic responses of muscle strips to electrical field stimulation (EFS) were evaluated in an environment with guanethidine and indomethacin. EFS studies were then repeated with atropine, Nomega-nitro-l-arginine methyl ester, atropine, and Nomega-nitro-l-arginine methyl ester-added environments. RESULTS: Although macroscopic atrophy had developed in the distal colonic segment of the colostomy, the contraction and relaxation capacity of the smooth muscle did not change. EFS-induced nitrergic peptidergic, cholinergic-peptidergic, and noncholinergic nonnitrergic responses significantly decreased at all frequencies (0.5-32 Hz) in the study group compared with those in the control group (P < 0.05). CONCLUSIONS: Although the contraction capacity of the smooth muscle was not affected, the motility of the distal colon deteriorated owing to the defective secretion of presynaptic neurotransmitters such as acetylcholine, nitric oxide, and neuropeptides. PMID- 27979491 TI - Postoperative urinary retention in colorectal surgery within an enhanced recovery pathway. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) guidelines for colorectal surgery suggest routine transurethral bladder drainage with early removal to prevent urinary tract infection (UTI). The aim of this study was to identify risk factors for urinary retention (UR). METHODS: This retrospective analysis included all colorectal patients since ERAS implementation in May 2011-November 2014. From the prospective ERAS database, over 100 items related to demographics, surgery, compliance, and outcome were analyzed. Risk factors for UR were identified by multiple logistic regressions; then, UR was correlated to functional outcomes and UTI and acute kidney injury rates. RESULTS: The study cohort consisted of 513 consecutive patients. Of these, 73 patients (14%) presented with UR. Multivariate analysis identified male gender (odds ratio 1.4; 95% CI, 1-1.8; P = 0.045) and postoperative thoracic epidural analgesia (EDA; odds ratio 2.6; 95% CI, 1.6-4.3; P <= 0.001) as independent risk factors for postoperative UR. Functional recovery was impeded in patients with UR, who were less mobile (mobilization day 1 >4 h: 57% versus 70%, P = 0.024) and gained more weight (2.8 +/- 2.5 kg versus 1.6 +/-3 kg on day 1, P = 0.001) due to fluid overload. Furthermore, patients with urinary catheters reported more pain (visual analog scales day 3: 3.1 +/- 2.5 versus 2.2 +/- 2.4, P = 0.002) and depended longer on intravenous fluid administration (termination of intravenous fluids later than day 1: 53% versus 39%, P = 0.021). Ten of 73 patients (14%) developed UTI in patients with UR and 42 of 440 (10%) in patients without UR (P = 0.276). Six of 73 patients (8%) developed acute kidney injury in patients with UR and 36 of 440 (8%) in patients without UR (P = 0.991). CONCLUSIONS: Male gender and EDA were independent risk factors for postoperative UR which appeared to be a significant impediment for functional recovery. PMID- 27979492 TI - Blood volume measured by ultrasound and radioisotope dilution in critically ill subjects. AB - BACKGROUND: Accurate bedside assessment of circulating blood volume (BV) continues to challenge clinicians in their attempt to implement goal-directed therapy in the critically ill subject. The aim of this investigation was to comparatively evaluate BV measurements obtained by ultrasound and radioisotope dilution methodologies in adult subjects admitted to a surgical intensive care unit. MATERIALS AND METHODS: Fifty subjects with concurrent central venous catheters and peripheral arterial lines underwent measurement of BV using both ultrasound and radioisotope dilution (BV-RD) methods. The ultrasound dilution method was performed using a 30-mL injectate (BV-UD30) and a 60-mL injectate (BV UD60) of isotonic saline. RESULTS: There were 24 paired data points for the BV UD30 and 40 paired data points for the BV-UD60 measurements. Spearman's rank order correlation demonstrated a positive relationship comparing both the BV-UD30 (r = 0.46, P = 0.0249) and the BV-UD60 (r = 0.80, P < 0.0001) to values obtained by radioisotope measurements. Bland-Altman analysis showed a mean bias of 1329 mL with limits of agreement (LOA) +/- 2559 mL comparing BV-RD and BV-UD30, and a mean bias of 62 mL with LOA +/-1353 mL for BV-RD and BV-UD60. CONCLUSIONS: This preliminary investigation shows that the BV-UD60 had better agreement with BV-RD, compared with the BV-UD30, but its utility appears limited by a large LOA. As this technology continues to evolve, the ultrasound dilution approach may potentially become a feasible means to calculate BV in critically ill surgical subjects. PMID- 27979493 TI - Curcumin attenuates blood-brain barrier disruption after subarachnoid hemorrhage in mice. AB - BACKGROUND: Early brain injury, one of the most important mechanisms underlying subarachnoid hemorrhage (SAH), comprises edema formation and blood-brain barrier (BBB) disruption. Curcumin, an active extract from the rhizomes of Curcuma longa, alleviates neuroinflammation by as yet unknown neuroprotective mechanisms. In this study, we examined whether curcumin treatment ameliorates SAH-induced brain edema and BBB permeability changes, as well as the mechanisms underlying this phenomenon. METHODS: We induced SAH in mice via endovascular perforation, administered curcumin 15 min after surgery and evaluated neurologic scores, brain water content, Evans blue extravasation, Western blot assay results, and immunohistochemical analysis results 24 h after surgery. RESULTS: Curcumin significantly improved neurologic scores and reduced brain water content in treated mice compared with SAH mice. Furthermore, curcumin decreased Evans blue extravasation, matrix metallopeptidase-9 expression, and the number of Iba-1 positive microglia in treated mice compared with SAH mice. At last, curcumin treatment increased the expression of the tight junction proteins zonula occludens-1 and occludin in treated mice compared with vehicle-treated and sample SAH mice. CONCLUSIONS: We demonstrated that curcumin inhibits microglial activation and matrix metallopeptidase-9 expression, thereby reducing brain edema and attenuating post-SAH BBB disruption in mice. PMID- 27979495 TI - Supporting Siblings of Neonatal Intensive Care Unit Patients: A NICU Social StoryTM as an Innovative Approach. PMID- 27979494 TI - Viability of randomized skin flaps-an experimental study in rats. AB - BACKGROUND: Randomized skin flaps are extensively used in plastic surgery, but the possibility of necrosis has challenged their use. Several studies have been conducted aiming to find ways to reduce the occurrence of necrosis. We evaluated the effects of pentoxifylline (PTX) and hyaluronidase (HLD), each alone or combined, on randomized rat skin flaps. MATERIALS AND METHODS: Fifty male Wistar rats were divided into five groups of 10 animals each: control I, control II, PTX, HLD, PTX-HLD. Substances were administered from the first to the 14th postoperative day. The necrotic area was measured on the seventh and 14th postoperative day; the animals were killed on the 14th day, when samples were collected for histologic and immunohistochemical examination. RESULTS: On the seventh day, percentage of the necrotic area was significantly reduced in PTX, HLD, and PTX-HLD animals compared with control groups. On 14th day, percentage of the necrotic area in PTX, HDL, and PTX-HLD groups was also significantly reduced compared with control groups. PTX and PTX-HLD showed a significant reduction in dermis cellularity, VV of macrophages, and myofibroblasts compared with control groups; PTX showed a significant enhancement of LV of blood vessels compared with all other groups. CONCLUSIONS: The use of each substance alone or combined increased flap viability compared with control groups. On the seventh day, PTX exhibited lower viability than HLD, whereas on the 14th day there was no difference between treated groups. PTX alone enhanced the LV of blood vessels, whereas PTX-HLD did not. However, PTX-HLD was more effective in decreasing the dermis cellularity and macrophage VV than HLD alone. PMID- 27979496 TI - Evidence-based Practice in Action: Ensuring Quality of Pediatric Assessment Frequency. AB - : Optimal frequency of head-to-toe assessment in hospitalized pediatric patients is unknown. An alteration in head-to-toe assessment frequency was proposed at a Midwestern regional hospital. The purpose of this descriptive study was to evaluate patient safety and staff satisfaction following a change in head-to-toe assessment frequency. METHOD: Chart audits were performed on all patients upon discharge and after any change in level of care to assess the risk to patient safety following the change in head-to-toe assessment frequency. Nurses were surveyed to determine satisfaction with the change. RESULTS: A total of 421 patients were included in the study. After the change, there was no increase in the number of unplanned transfers to the intensive care unit from the previous year. Registered nurses (N=15) perceived no decrease in patient safety following the change. Registered nurses were satisfied with the change in assessment frequency noting they perceived more time to provide direct patient care. CONCLUSIONS: The change in head-to-toe assessment frequency did not impact patient safety, but had a positive impact on nurse satisfaction. Following the study period, the unit policy was changed to reflect the new evidence based head to-toe assessment interval. Further research is needed with a larger, more diverse sample of pediatric patients and pediatric nurses. PMID- 27979497 TI - Societal Norms and Conditions and Their Influence on Daily Life in Children With Type 1 Diabetes in the West Bank in Palestine. AB - PURPOSE: To explore the experiences of daily life in children with type 1 diabetes (T1D) and their parents living in the West Bank in Palestine. DESIGN AND METHODS: A qualitative study using thematic interviews was performed with 10 children with T1D and their parents (n=10). Content analysis was performed with the assistance of NVIVO 10. RESULTS: The overall theme was facing the social reality of diabetes. This was underpinned by two themes: stigmatization and social constraints. Facing the social reality of diabetes described children and their parents' everyday life attempts to place themselves within the context of the disease and social context. Children and their parents described how stigmatization and social constraints impacted their daily life as a result of fear of disclosing the disease, which could affect their social status. CONCLUSION: These findings highlighted how daily life in children with T1D and their parents was highly affected by cultural impacts, especially as stigma related to the illness affected social interactions of female and male children/adolescents. Lack of knowledge and misunderstandings about T1D in society lead to negative consequences like poorer management of diabetes, and this becomes mediated by gender. PRACTICAL IMPLICATIONS: The findings suggest health care providers need to be aware of the cultural and social impact of T1D on children's and parents' daily life in order to meet their needs and challenges by providing appropriate interventions, strategies and support. PMID- 27979498 TI - On p53 revival using system oriented drug dosage design. AB - We propose a new paradigm in the drug design for the revival of the p53 pathway in cancer cells. It is shown that the current strategy of using small molecule based Mdm2 inhibitors is not enough to adequately revive p53 in cancerous cells, especially when it comes to the extracting pulsating behavior of p53. This fact has come to notice when a novel method for the drug dosage design is introduced using system oriented concepts. As a test case, small molecule drug Mdm2 repressor Nutlin 3a is considered. The proposed method determines the dose of Nutlin to revive p53 pathway functionality. For this purpose, PBK dynamics of Nutlin have also been integrated with p53 pathway model. The p53 pathway is the focus of researchers for the last thirty years for its pivotal role as a frontline cancer suppressant protein due to its effect on cell cycle checkpoints and cell apoptosis in response to a DNA strand break. That is the reason for finding p53 being absent in more than 50% of tumor cancers. Various drugs have been proposed to revive p53 in cancer cells. Small molecule based drugs are at the foremost and are the subject of advanced clinical trials. The dosage design of these drugs is an important issue. We use control systems concepts to develop the drug dosage so that the cancer cells can be treated in appropriate time. We investigate by using a computational model how p53 protein responds to drug Nutlin 3a, an agent that interferes with the MDM2-mediated p53 regulation. The proposed integrated model describes in some detail the regulation network of p53 including the negative feedback loop mediated by MDM2 and the positive feedback loop mediated by Mdm2 mRNA as well as the reversible represses of MDM2 caused by Nutlin. The reported PBK dynamics of Nutlin 3a are also incorporated to see the full effect. It has been reported that p53 response to stresses in two ways. Either it has a sustained (constant) p53 response, or there are oscillations in p53 concentration. The claimed dosage strategy achieves the p53 response in the first case. However, for the induction of oscillations, it is shown through bifurcation analysis that to achieve oscillating behavior of p53 inhibition of Mdm2 is not enough, rather antirepression of the p53-Mdm2 complex is also needed which leads to the need of a new drug design paradigm. PMID- 27979499 TI - The DSF Family of Quorum Sensing Signals: Diversity, Biosynthesis, and Turnover. AB - The diffusible signaling factor (DSF)-based quorum sensing (QS) system has emerged as a widely conserved cell-cell communication mechanism in Gram-negative bacteria. Typically, signals from the DSF family are cis-2-unsaturated fatty acids which regulate diverse biological functions. Recently, substantial progress has been made on the characterization of new members of this family of signals. There have also been new developments in the understanding of the biosynthesis of these molecules where dual enzymatic activities of the DSF synthase and the use of various substrates have been described. The recent discovery of a naturally occurring DSF turnover mechanism and its regulation provides a new dimension in our understanding of how DSF-dependent microorganisms modulate virulence gene expression in response to changes in the surrounding environment. PMID- 27979500 TI - Clinical experience with ceftazidime/avibactam in patients with severe infections, including meningitis and lung abscesses, caused by extensively drug resistant Pseudomonas aeruginosa. PMID- 27979501 TI - Amphotericin B nebulisation for invasive pulmonary aspergillosis prophylaxis: the conflict of ideality and reality. PMID- 27979502 TI - Digital PCR quantification of miR-30c and miR-181a as serum biomarkers for Duchenne muscular dystrophy. AB - Circulating microRNAs (miRs/miRNAs) are being used as non-invasive biomarkers for diagnosis, prognosis and efficiency of clinical trials. However, to exploit their potential it is necessary to improve and standardize their detection. In a previous study, we identified two microRNAs, miR-30c and miR-181a, that appear to be key regulators of muscular dystrophy. We hypothesized that they could represent useful biomarkers of Duchenne and Becker muscular dystrophies (DMD and BMD). The objective of this study was to assess the absolute levels of miR-30c and miR-181a in sera of DMD and BMD patients using digital PCR (a robust technique for precise and direct quantification of small amounts of nucleic acids without standard curves and external references), and investigate the correlation between miR-30c and miR-181a expressions and several clinical parameters. Our results show that the serum levels of miR-30c and miR-181a increased 7- and 6 fold respectively in DMD patients (n = 21, 2-14 years, ambulant), and 7-fold in BMD patients (n = 5, 9-15 years) compared to controls (n = 22, 2-14 years). No association between miRNA levels and age or corticosteroid treatment was detected in DMD. However, there was a trend towards higher levels of miR-30c in DMD patients with better preserved motor function according to various motor scales and timed tests. We demonstrate that digital PCR is a useful technique for accurate absolute quantification of microRNAs in sera of DMD/BMD patients. We propose miR-30c and miR-181a as reliable serum diagnostic biomarkers for DMD and BMD and miR-30c as a potential novel biomarker to assess disease severity in DMD. PMID- 27979503 TI - Effect of physical training on the recovery of acute exercise, among patients with cardiovascular disease. AB - INTRODUCTION: Physical training programs (PTP) have shown several beneficial effects for patients with cardiovascular disease (CVD), particularly by increasing survival and quality of life. Physiological response during the effort and recovery phases of an exercise testing, is one of the strongest prognostic markers among patients with CVD. A reasonable mechanism that explains those training effects on survival is through the adaptations seen on heart rate recovery (HRR) and oxygen uptake kinetics at the post-exertional phase (RVO2). OBJECTIVE: Compare the HRR and RVO2 values before and after a PTP in patients with CVD. METHODS: We studied a cohort of patients included in a cardiac rehabilitation program, whom performed a cardiopulmonary exercise testing (CPX). Then, risk stratification and an individualized exercise training program were performed. The exercise training program included 20 sessions of aerobic exercise, 30min a day, five times a week, at moderate intensity. Finally, a second CPX was performed. RESULTS: A total of 215 patients were included. Peak oxygen uptake values rose 2.2+/-5.2ml/kg/min (p<0.001), HRR increased 1.6+/-10bpm (p<0.05) and RVO2 improved -21+/-98s (p<0.001). A post-hoc analysis show that the percentage of maximum heart rate remained statistically associated with HRR increment. Furthermore, diabetes and sedentarism were strongly related to RVO2 improvement. No correlation between HRR and RVO2 was found (R2=0.002). CONCLUSION: Physical exercise was associated with a beneficial effect on HRR and RVO2. Nevertheless, both variables were statistically unrelated. PMID- 27979504 TI - [Histopatological study of stented coronary artery treated with the electrodeposition technique]. PMID- 27979505 TI - Re: Five-Year Biochemical Results, Toxicity, and Patient-Reported Quality of Life after Delivery of Dose-Escalated Image Guided Proton Therapy for Prostate Cancer. PMID- 27979507 TI - Re: Robot-Assisted Laparoscopic Prostatectomy versus Open Radical Retropubic Prostatectomy: Early Outcomes from a Randomised Controlled Phase 3 Study. PMID- 27979506 TI - Re: HSD3B1 and Resistance to Androgen-Deprivation Therapy in Prostate Cancer: A Retrospective, Multicohort Study. PMID- 27979508 TI - Re: Efficacy and Safety of Enzalutamide versus Bicalutamide for Patients with Metastatic Prostate Cancer (TERRAIN): A Randomised, Double-Blind, Phase 2 Study. PMID- 27979509 TI - Re: Can Radiologic Staging with Multiparametric MRI Enhance the Accuracy of the Partin Tables in Predicting Organ-Confined Prostate Cancer? PMID- 27979511 TI - Re: A Comparison of Web-Based versus Print-Based Decision Aids for Prostate Cancer Screening: Participants' Evaluation and Utilization. PMID- 27979510 TI - Re: Treatment Preferences for Active Surveillance versus Active Treatment among Men with Low-Risk Prostate Cancer. PMID- 27979512 TI - Re: Resistance to Docetaxel in Prostate Cancer is Associated with Androgen Receptor Activation and Loss of KDM5D Expression. PMID- 27979513 TI - Re: Trends in Prostate Cancer in Elderly in Denmark, 1980-2012. PMID- 27979515 TI - Re: Integrating Geriatric Assessment into Decision-Making after Prostatectomy: Adjuvant Radiotherapy, Salvage Radiotherapy, or None? PMID- 27979514 TI - Re: Clinical Outcomes in Octogenarians Treated with Docetaxel as First-Line Chemotherapy for Castration-Resistant Prostate Cancer. PMID- 27979516 TI - Re: Survival after Conservative Management versus External Beam Radiation Therapy in Elderly Patients with Localized Prostate Cancer. PMID- 27979517 TI - Re: First-Line Treatment in Senior Adults with Metastatic Castration-Resistant Prostate Cancer: A Prospective International Registry. PMID- 27979518 TI - Re: Conditional Survival of Patients with Metastatic Testicular Germ Cell Tumors Treated with First-Line Curative Therapy. PMID- 27979519 TI - Re: Abnormal Urinalysis Results are Common, Regardless of Specimen Collection Technique, in Women without Urinary Tract Infections. PMID- 27979521 TI - Re: Postoperative Urinary Retention in Men is Common after Carotid Endarterectomy and is Associated with Advanced Age and Prior Urinary Tract Infection. PMID- 27979520 TI - Re: Escherichia coli Isolates from Patients with Bacteremic Urinary Tract Infection are Genetically Distinct from Those Derived from Sepsis following Prostate Transrectal Biopsy. PMID- 27979522 TI - Re: Bacteriuria and Urinary Tract Infection after Female Urodynamic Studies: Risk Factors and Microbiological Analysis. PMID- 27979523 TI - Re: Acute Oxalate Nephropathy Associated with Orlistat. PMID- 27979524 TI - Re: Can the Presence of Crystalluria Predict Stone Formation in Patients with Cystinuria? PMID- 27979525 TI - Re: The Use of Apnea During Ureteroscopy. PMID- 27979526 TI - Re: Ureteric Stents on Extraction Strings: A Systematic Review of Literature. PMID- 27979527 TI - Re: Best Stent Length Predicted by Simple CT Measurement Rather Than Patient Height. PMID- 27979528 TI - Re: Carbapenem-Resistant Enterobacteriaceae and Endoscopy: An Evolving Threat. PMID- 27979529 TI - Re: Defining the Rate of Primary Ureteroscopic Failure in Unstented Patients: A Multi-Institutional Study. PMID- 27979530 TI - Re: Pulsed versus Continuous Mode Fluoroscopy during PCNL: Safety and Effectiveness Comparison in a Case Series Study. PMID- 27979531 TI - Re: Ultrasonography Significantly Overestimates Stone Size When Compared to Low Dose, Noncontrast Computed Tomography. PMID- 27979532 TI - Re: Comparison of Minimally Invasive Percutaneous Nephrolithotomy and Flexible Ureteroscopy for the Treatment of Intermediate Proximal Ureteral and Renal Stones in the Elderly. PMID- 27979533 TI - Re: Urethroplasty Improves Overactive Bladder Symptoms in Men with Anterior Urethral Strictures. PMID- 27979534 TI - Re: Outpatient Ultrasound Urethrogram for Assessment of Anterior Urethral Stricture: Early Experience. PMID- 27979536 TI - Re: Heparin and Alkalinized Lidocaine versus Alkalinized Lidocaine for Treatment of Interstitial Cystitis Symptoms. PMID- 27979535 TI - Re: Rapid Excision of Massive Localized Lymphedema of the Male Genitalia with Vessel Sealing Device. PMID- 27979537 TI - Re: ICIQ Symptom and Quality of Life Instruments Measure Clinically Relevant Improvements in Women with Stress Urinary Incontinence. PMID- 27979538 TI - Re: Prospective Randomized Crossover Trial Comparing Continuous and Cyclic Stimulation in InterStim Therapy. PMID- 27979539 TI - Re: Tibial Nerve Stimulation for Treating Neurogenic Lower Urinary Tract Dysfunction: A Systematic Review. PMID- 27979540 TI - Re: Conjoint Urological Society of Australia and New Zealand (USANZ) and Urogynaecological Society of Australasia (UGSA) Guidelines on the Management of Adult Non-Neurogenic Overactive Bladder. PMID- 27979541 TI - Re: Does Defective Volume Sensation Contribute to Detrusor Underactivity? PMID- 27979542 TI - Re: Bladder Function in Mice with Inducible Smooth Muscle-Specific Deletion of the Manganese Superoxide Dismutase Gene. PMID- 27979543 TI - Re: Can Metabolic Disorders in Aging Men Contribute to Prostatic Hyperplasia Eligible for Transurethral Resection of the Prostate (TURP)? PMID- 27979544 TI - Re: Clinical Significance of Peripheral Zone Thickness in Men with Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia. PMID- 27979545 TI - Re: Finasteride, Not Tamsulosin, Increases Severity of Erectile Dysfunction and Decreases Testosterone Levels in Men with Benign Prostatic Hyperplasia. PMID- 27979546 TI - Re: Aquablation-Image-Guided Robot-Assisted Waterjet Ablation of the Prostate: Initial Clinical Experience. PMID- 27979547 TI - Re: Development and Evaluation of an Immunochromatographic Strip for Rapid Screening of Sildenafil-Type Compounds as Illegal Additives in Functional Foods. PMID- 27979548 TI - Re: Sexual Function and Mortality in Older Men: The Concord Health and Ageing in Men Project. PMID- 27979549 TI - Re: PDE5A Polymorphisms Influence on Sildenafil Treatment Success. PMID- 27979550 TI - Re: Are Medical Students Interested in Sexual Health Education? A Nationwide Survey. PMID- 27979551 TI - Re: Increased Risk of Incident Chronic Medical Conditions in Infertile Men: Analysis of United States Claims Data. PMID- 27979552 TI - Re: Undergraduate Training in Human Sexuality-Evaluation of the Impact on Medical Doctors' Practice Ten Years after Graduation. PMID- 27979553 TI - Re: Oral Enclomiphene Citrate Raises Testosterone and Preserves Sperm Counts in Obese Hypogonadal Men, Unlike Topical Testosterone: Restoration Instead of Replacement. PMID- 27979554 TI - Re: Increased Body Mass Index in Men with Varicocele is Associated with Larger Spermatic Vein Diameters when Supine. PMID- 27979555 TI - Re: Scrotal Cooling to Protect against Cisplatin-Induced Spermatogenesis Toxicity: Preliminary Outcome of an Experimental Controlled Trial. PMID- 27979556 TI - Re: Is the Epididymis a Series of Organs Placed Side by Side? PMID- 27979557 TI - Re: Early Impact of Medicare Accountable Care Organizations on Cancer Surgery Outcomes. PMID- 27979558 TI - Re: Urologist Participation in Medicare Shared Savings Program Accountable Care Organizations (ACOs). PMID- 27979559 TI - Re: Public Perceptions on Robotic Surgery, Hospitals with Robots, and Surgeons That Use Them. PMID- 27979560 TI - Re: Liking Health Reform but Turned Off by Toxic Politics. PMID- 27979561 TI - Re: Financial Neutrality for Living Organ Donors: Reasoning, Rationale, Definitions, and Implementation Strategies. PMID- 27979562 TI - Re: Plastibell Circumcision of 2,276 Male Infants: A Multi-Centre Study. PMID- 27979563 TI - Re: Do Adult Men with Untreated Ventral Penile Curvature Have Adverse Outcomes? PMID- 27979564 TI - Re: The Effect of Parenteral Testosterone Administration prior to Hypospadias Surgery: A Prospective, Randomized and Controlled Study. PMID- 27979565 TI - Re: Is Routine Excision of Testicular Remnants in Testicular Regression Syndrome Indicated? PMID- 27979566 TI - Re: Clinically Localized Type 1 and 2 Papillary Renal Cell Carcinomas Have Similar Survival Outcomes following Surgery. PMID- 27979567 TI - Re: Comprehensive Analysis of Differentially Expressed Profiles of lncRNAs and circRNAs with Associated Co-Expression and ceRNA Networks in Bladder Carcinoma. PMID- 27979568 TI - Re: Infiltrating Macrophages Increase RCC Epithelial Mesenchymal Transition (EMT) and Stem Cell-Like Populations via AKT and mTOR Signaling. PMID- 27979569 TI - Re: Long-Term Follow-up of TaG1 Non-Muscle-Invasive Bladder Cancer. PMID- 27979570 TI - Re: The Effect of Broader, Directed Antimicrobial Prophylaxis Including Fungal Coverage on Perioperative Infectious Complications after Radical Cystectomy. PMID- 27979571 TI - Re: PET/Computed Tomography in Renal, Bladder, and Testicular Cancer. PMID- 27979572 TI - A Fourteen-Year Experience with Vascular Anomalies Encountered during Transaxillary Rib Resection for Thoracic Outlet Syndrome. AB - BACKGROUND: Transaxillary approach to first rib resection and scalenectomy (TAFRRS) is a well-established technique for treatment of thoracic outlet syndrome (TOS). Although anatomic features encountered during TAFRRS are in general constant, vascular anomalies may be encountered but have not been described to date. Herein we describe vascular abnormalities encountered during TAFRRS. METHODS: We performed a retrospective review of a prospective practice database of 224 operations for TOS performed in 172 patients from March 2000 to March 2014. We excluded 10 patients with missing operative reports, 3 reoperations on the same patient, and 8 non-transaxillary resections. We recorded vascular anomalies identified in operative reports and reviewed computed tomography imaging to delineate the nature of these abnormalities. RESULTS: The overall incidence of vascular anomalies was 11% (22 of 203 TAFRRS). Most patients with anomalies had venous TOS (vTOS) (9 patients, 41%), followed by 7 (32%) with neurogenic TOS (nTOS). The remainder of the patients had arterial TOS (aTOS) (6 patients, 27%). Seven patients (32%) had an abnormal subclavian artery (SCA) with 5 (23%) having an abnormal arterial course in the anterior scalene muscle (ASM); 6 patients (27%) had an abnormal internal mammary artery (IMA) originating from distal SCA; 4 (18%) had abnormalities in the supreme thoracic artery (bifurcation or duplication); 2 (9%) had an abnormal branch from the SCA with anomalous location in the operative field; and 3 (14%) had an abnormal large venous branch penetrating the ASM. In the 19 patients with arterial anomalies, 8 (42%) were recognized as arterial branches penetrating the ASM, and 11 (58%) were noticed as they had anomalous arterial locations within the operative field. Most arterial anomalies were seen in vTOS (9, 45%), followed by nTOS (7, 35%). No intraoperative vascular complications occurred. Perioperative complications included 1 occurrence of postoperative transfusion for bleeding following axillary drain discontinuation and 2 Horner's syndromes. One aberrant IMA was electively ligated to allow complete thoracic outlet decompression. CONCLUSIONS: Arterial anomalies during TAFRRS are encountered in 11% of operations, and may present with vessel locations in unusual areas within the operative field, or as abnormal vessels penetrating the ASM, thus making scalenectomy precarious. Careful attention must be paid to possible abnormal locations of vessels in the thoracic outlet to avoid bleeding complications. PMID- 27979574 TI - Apelin/APJ system: A bifunctional target for cardiac hypertrophy. AB - Apelin acts as the endogenous ligand of G protein coupled receptors APJ. The apelin/APJ system is responsible for the occurrence and development of cardiovascular diseases. In recent years, apelin/APJ has been considered to play an important role in cardiac hypertrophy, but whether that role is beneficial or aggravating remains controversial. Apelin/APJ alleviates cardiac hypertrophy which is triggered by angiotensin II, oxidative stress and exercise. However, central administration of apelin induces cardiac hypertrophy. Peripheral administration of apelin also promotes the development of cardiac hypertrophy under non-pathological conditions. Furthermore, our laboratory discovers that apelin/APJ is able to induce hypertrophy of cardiomyocytes in vitro. The exact mechanism of apelin/APJ's dual effects in cardiac hypertrophy requires further study. In this paper, we review the controversies associated with apelin/APJ in cardiac hypertrophy and we elaborate the role of apelin/APJ in cardiac hypertrophy related-diseases including obesity, diabetes, hypertension, myocarditis and myocardial infarction. We conclude that further studies should emphasize more about the relationship between apelin/APJ and pathological hypertrophy especially in clinical patients. Moreover, apelin/APJ can be a promising therapeutic target for cardiac hypertrophy. PMID- 27979576 TI - Reply to the letter to editor "Autophagy may be impelled by collected fatty acids in type 2 diabetic myocardial cells". PMID- 27979575 TI - The right atrium and tricuspid annulus are cardinal structures in tricuspid regurgitation with or without pulmonary hypertension. AB - BACKGROUND: Right heart structural abnormalities occur in both tricuspid regurgitation (TR) and pulmonary hypertension (PH). They may occur independently or together, but their joint effects on cardiac structure are incompletely described. This study examined the interactions of TR severity and PH on right heart structural changes. METHODS: The study evaluated 455 patients undergoing both echocardiography and CT angiography (CTA). Cases were divided into 3 groups by TR severity: trace (n=217), mild (n=174), and significant (moderate or severe, n=64). Each TR level was subdivided into two groups by PH absent or present. Cardiac structural measurements included tricuspid annulus area (TAA), right atrial (RA) and right ventricular volume (RV) indexed to body surface area. RESULTS: Analysis by TR and PH showed that indexed RA Volume and TAA were very sensitive to TR severity. RA volume was most affected by pulmonary hypertension when TR was trace or mild, while PH had less effect on TAA. In significant TR, neither RA volume nor TAA were changed by PH. Indexed RV volume was insensitive to trace and mild TR, and PH similarly had little effect. CONCLUSIONS: RA volume and tricuspid annulus area enlarge in proportion to TR severity, trace through significant. PH impacts RA volume but only in trace and mild TR. RA volume best reflects TR impact on right heart structure, both with and without PH. Right atrial volume and tricuspid annulus area are the cardinal indices of TR-induced right heart structural disease et al.l severities. ULTRAMINI ABSTRACT: Right heart structural effects of TR and PH were examined in this study. Patients were evaluated by echo and CTA, and grouped by TR severity as trace, mild, and significant, and were subdivided by PH absence/presence. Analysis by TR severity and PH showed that Indexed RA volume is the parameter most sensitive to TR severity, and PH causes incremental RA volume increases in trace/mild TR. Indexed tricuspid annulus area (TAA) similarly increases with TR severity, but was unaffected by PH at any TR severity. RV volume is insensitive to TR severity and PH. Indexed right atrial volume and tricuspid annulus area are cardinal indices for TR-induced right heart structural disease and increase proportionally to TR severity. RA volume is more sensitive to PH than is tricuspid annular area. TR severity may be more accurately assessed by increased RA volume and annulus area. PERSPECTIVE STATEMENT: The right atrium (RA) and tricuspid annulus (TA) are the cardinal cardiac structures affected by tricuspid regurgitation (TR). They each enlarge with TR severity. The right ventricle exhibits minimal change across TR severity. Pulmonary hypertension (PH) enhances TR-mediated RA and TA dilation, but only in trace and mild TR. PH has no effect on RA, TA, or RV size in significant TR. CENTRAL MESSAGE: Right atrial volume and tricuspid annulus area are the most sensitive to TR severity, and are also sensitive to pulmonary hypertension. PMID- 27979573 TI - Extracellular Vesicles: Unique Intercellular Delivery Vehicles. AB - Extracellular vesicles (EVs) are a heterogeneous collection of membrane-bound carriers with complex cargoes including proteins, lipids, and nucleic acids. While the release of EVs was previously thought to be only a mechanism to discard nonfunctional cellular components, increasing evidence implicates EVs as key players in intercellular and even interorganismal communication. EVs confer stability and can direct their cargoes to specific cell types. EV cargoes also appear to act in a combinatorial manner to communicate directives to other cells. This review focuses on recent findings and knowledge gaps in the area of EV biogenesis, release, and uptake. In addition, we highlight examples whereby EV cargoes control basic cellular functions, including motility and polarization, immune responses, and development, and contribute to diseases such as cancer and neurodegeneration. PMID- 27979577 TI - Vitamin D measurement standardization: The way out of the chaos. AB - Substantial variability is associated with laboratory measurement of serum total 25-hydroxyvitamin D [25(OH)D]. The resulting chaos impedes development of consensus 25(OH)D values to define stages of vitamin D status. As resolving this situation requires standardized measurement of 25(OH)D, the Vitamin D Standardization Program (VDSP) developed methodology to standardize 25(OH)D measurement to the gold standard reference measurement procedures of NIST, Ghent University and CDC. Importantly, VDSP developed protocols for standardizing 25(OH)D values from prior research based on availability of stored serum samples. The effect of such retrospective standardization on prevalence of "low" vitamin D status in national studies reported here for The Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) and the German Health Interview and Examination Survey for Children and Adolescents (KIGGS, 2003-2006) was such that in NHANES III 25(OH)D values were lower than original values while higher in KIGGS. In NHANES III the percentage with values below 30, 50 and 75 nmol/L increased from 4% to 6%, 22% to 31% and 55% to 71%, respectively. Whereas in KIGGS after standardization the percentage below 30, 50, and 70 nmol/L decreased from 28% to 13%, 64% to 47% and 87% to 85% respectively. Moreover, in a hypothetical example, depending on whether the 25(OH)D assay was positively or negatively biased by 12%, the 25(OH)D concentration which maximally suppressed PTH could vary from 20 to 35ng/mL. These examples underscore the challenges (perhaps impossibility) of developing vitamin D guidelines using unstandardized 25(OH)D data. Retrospective 25(OH)D standardization can be applied to old studies where stored serum samples exist. As a way forward, we suggest an international effort to identify key prior studies with stored samples for re-analysis and standardization initially to define the 25(OH)D level associated with vitamin D deficiency (rickets/osteomalacia). Subsequent work could focus on defining inadequacy. Finally, examples reported here highlight the importance of suspending publication of meta-analyses based on unstandardized 25(OH)D results. PMID- 27979579 TI - Liraglutide in an Adolescent Population with Obesity: A Randomized, Double-Blind, Placebo-Controlled 5-Week Trial to Assess Safety, Tolerability, and Pharmacokinetics of Liraglutide in Adolescents Aged 12-17 Years. AB - OBJECTIVES: To investigate the safety, tolerability, and pharmacokinetics of liraglutide in adolescents with obesity. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled trial. Twenty-one subjects, aged 12-17 years and Tanner stage 2-5, with obesity (body mass index [BMI] corresponding to both a BMI >=95th percentile for age and sex and to a BMI of >=30 kg/m2 for adults; additionally, BMI was <=45 kg/m2) were randomized (2:1) to receive 5 weeks of treatment with liraglutide (0.6 mg with weekly dose increase to a maximum of 3.0 mg for the last week) (n = 14) or placebo (n = 7). The primary endpoint was number of treatment-emergent adverse events (TEAEs). Secondary endpoints included safety measures, and pharmacokinetic and pharmacodynamic endpoints. RESULTS: All participants receiving liraglutide, and 4 receiving placebo (57.1%), had at least 1 TEAE. The most common TEAEs were gastrointestinal disorders. No severe TEAEs, TEAE-related withdrawals, or deaths occurred. Twelve hypoglycemic episodes occurred in 8 participants receiving liraglutide and 2 in 1 participant receiving placebo. No severe hypoglycemic episodes were reported. Liraglutide exposure in terms of trough concentration increased with dose, although dose proportionality was confounded by unexpectedly low trough concentration values at the 2.4 mg dose. Exposure in terms of model-derived area under the plasma concentration time curve from 0 to 24 hours after dose in steady state was similar to that in adults with obesity. CONCLUSIONS: Liraglutide had a similar safety and tolerability profile compared with adults when administered to adolescents with obesity, with no unexpected safety/tolerability issues. Results suggest that the dosing regimen approved for weight management in adults may be appropriate for use in adolescents. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01789086. PMID- 27979578 TI - Safety and Short-Term Outcomes of Therapeutic Hypothermia in Preterm Neonates 34 35 Weeks Gestational Age with Hypoxic-Ischemic Encephalopathy. AB - OBJECTIVE: To evaluate the safety and short-term outcomes of preterm neonates born at 34-35 weeks gestation with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia. STUDY DESIGN: Medical records of preterm neonates born at 34-35 weeks gestational age with HIE treated with therapeutic hypothermia were retrospectively reviewed. Short-term safety outcomes and the presence, severity (mild, moderate, severe), and patterns of brain injury on magnetic resonance imaging were reviewed using a standard scoring system, and compared with a cohort of term neonates with HIE treated with therapeutic hypothermia. RESULTS: Thirty-one preterm and 32 term neonates were identified. Therapeutic hypothermia-associated complications were seen in 90% of preterm infants and 81.3% of term infants (P = .30). In the preterm infants, hyperglycemia (58.1% vs31.3%, P = .03) and rewarming before completion of therapeutic hypothermia (19.4% vs 0.0%, P = .009) were more likely compared with term infants. All deaths occurred in the preterm group (12.9% vs 0%, P = .04). Neuroimaging showed the presence of injury in 80.6% of preterm infants and 59.4% of term infants (P = .07), with no differences in injury severity. Injury to the white matter was more prevalent in preterm infants compared with term infants (66.7% vs 25.0%, P = .001). CONCLUSIONS: Therapeutic hypothermia in infants born at 34-35 weeks gestational age appears feasible. Risks of mortality and side effects warrant caution with use of therapeutic hypothermia in preterm infants. PMID- 27979580 TI - A Case Report of Reversible Takotsubo Cardiomyopathy after Amphetamine/Dextroamphetamine Ingestion in a 15-Year-Old Adolescent Girl. AB - Stimulant medications are used in the treatment of attention deficit hyperactivity disorder and serious cardiac complications can occur when these medications are abused. We present a 15-year-old adolescent girl who was found to have a Takotsubo cardiomyopathy after acute amphetamine/dextroamphetamine ingestion. PMID- 27979581 TI - The Edematous and Erythematous Airway Does Not Denote Pathologic Gastroesophageal Reflux. AB - OBJECTIVE: To determine if the reflux finding score (RFS), a validated score for airway inflammation, correlates with gastroesophageal reflux measured by multichannel intraluminal impedance (MII) testing, endoscopy, and quality of life scores. STUDY DESIGN: We performed a prospective, cross-sectional cohort study of 77 children with chronic cough undergoing direct laryngoscopy and bronchoscopy, esophagogastroduodenoscopy, and MII testing with pH (pH-MII) between 2006 and 2011. Airway examinations were videotaped and reviewed by 3 blinded otolaryngologists each of whom assigned RFS to the airways. RFS were compared with the results of reflux testing (endoscopy, MII, symptom scores). An intraclass correlation coefficient was calculated for the degree of agreement between otolaryngologists' RFS. Receiver operating characteristic curves were created to determine the sensitivity of the RFS. Spearman correlation was calculated between the RFS and reflux measurements by pH-MII. RESULTS: The mean +/- SD RFS was 12 +/- 4. There was no correlation between pH-MII variables and mean RFS (|r| < 0.15). The concordance correlation coefficient for RFS between otolaryngologists was low (intraclass correlation coefficient = 0.32). Using pH metry as a gold standard, the positive predictive value for the RFS was 29%. Using MII as the gold standard, the positive predictive value for the RFS was 40%. There was no difference in the mean RFS in patients with (12 +/- 4) and without (12 +/- 3) esophagitis (P = .9). There was no correlation between RFS and quality of life scores (|r| < 0.15, P > .3). CONCLUSIONS: The RFS cannot predict pathologic gastroesophageal reflux and an airway examination should not be used as a basis for prescribing gastroesophageal reflux therapies. PMID- 27979582 TI - Differences in Infant Care Practices and Smoking among Hispanic Mothers Living in the United States. AB - OBJECTIVE: To assess the association between maternal birth country and adherence to the American Academy of Pediatrics safe sleep recommendations in a national sample of Hispanic mothers, given that data assessing the heterogeneity of infant care practices among Hispanics are lacking. STUDY DESIGN: We used a stratified, 2 stage, clustered design to obtain a nationally representative sample of mothers from 32 US intrapartum hospitals. A total of 907 completed follow-up surveys (administered 2-6 months postpartum) were received from mothers who self identified as Hispanic/Latina, forming our sample, which we divided into 4 subpopulations by birth country (US, Mexico, Central/South America, and Caribbean). Prevalence estimates and aORs were determined for infant sleep position, location, breastfeeding, and maternal smoking. RESULTS: When compared with US-born mothers, we found that mothers born in the Caribbean (aOR 4.56) and Central/South America (aOR 2.68) were significantly more likely to room share without bed sharing. Caribbean-born mothers were significantly less likely to place infants to sleep supine (aOR 0.41). Mothers born in Mexico (aOR 1.67) and Central/South America (aOR 2.57) were significantly more likely to exclusively breastfeed; Caribbean-born mothers (aOR 0.13) were significantly less likely to do so. Foreign-born mothers were significantly less likely to smoke before and during pregnancy. CONCLUSIONS: Among US Hispanics, adherence to American Academy of Pediatrics safe sleep recommendations varies widely by maternal birth country. These data illustrate the importance of examining behavioral heterogeneity among ethnic groups and have potential relevance for developing targeted interventions for safe infant sleep. PMID- 27979583 TI - Abdominal Pain-Associated Functional Gastrointestinal Disorder Prevalence in Children and Adolescents with Celiac Disease on Gluten-Free Diet: A Multinational Study. AB - OBJECTIVE: To test the hypothesis that children with celiac disease (CD) on gluten-free diet are at increased risk of abdominal pain (AP) associated functional gastrointestinal disorders (FGIDs). STUDY DESIGN: This was a multinational cross-sectional study performed from 2014 to 2015. Patients 4-18 years of age with CD on gluten-free diet for longer than 6 months were recruited from pediatric CD clinics in US and Italy. Control groups included siblings of children with CD (with normal tissue transglutaminase levels) and unrelated controls. Subjects or parents completed the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III. RESULTS: Children (n = 289) were recruited (55% US, 45% Italy): 96 children with CD, 96 sibling controls, and 97 unrelated controls. Chronic AP was present in 30 (30.9%) subjects with CD, 22 (22.7%) sibling controls, and 21 (21.6%) unrelated controls (P = .26 patients with CD vs siblings; P = .18 patients with CD vs unrelated; P = .96 siblings vs unrelated). AP-FGIDs were present in 8 (8.2%) subjects with CD, 8 (8.2%) sibling controls, and 2 (2.1%) unrelated controls (P = 1.00 subjects with CD vs sibling controls; P = .06 subjects with CD vs unrelated controls; P = .06 sibling controls vs unrelated controls). CONCLUSION: This multinational study evaluated the prevalence of chronic abdominal pain and AP-FGIDs in the pediatric population with CD. We found that subjects with CD and controls have a similar prevalence of chronic AP and AP-FGIDs. This suggests that not all types of gastrointestinal inflammation result in AP-FGIDs in children. PMID- 27979584 TI - Impact of Chronic Conditions on Emergency Department Visits of Children Using Medicaid. AB - OBJECTIVE: To assess the impact of chronic conditions on children's emergency department (ED) use. STUDY DESIGN: Retrospective analysis of 1 850 027 ED visits in 2010 by 3 250 383 children ages 1-21 years continuously enrolled in Medicaid from 10 states included in the Truven Marketscan Medicaid Database. The main outcome was the annual ED visit rate not resulting in hospitalization per 1000 enrollees. We compared rates by enrollees' characteristics, including type and number of chronic conditions, and medical technology (eg, gastrostomy, tracheostomy), using Poisson regression. To assess chronic conditions, we used the Agency for Healthcare Research and Quality's Chronic Condition Indicator system, assigning chronic conditions with ED visit rates >=75th percentile as having the "highest" visit rates. RESULTS: The overall annual ED visit rate was 569 per 1000 enrollees. As the number of the children's chronic conditions increased from 0 to >=3, visit rates increased by 180% (from 376 to 1053 per 1000 enrollees, P < .001). Rates were 174% higher in children assisted with vs without medical technology (1546 vs 565, P < .001). Sickle cell anemia, epilepsy, and asthma were among the chronic conditions associated with the highest ED visit rates (all >=1003 per 1000 enrollees). CONCLUSIONS: The highest ED visit rates resulting in discharge to home occurred in children with multiple chronic conditions, technology assistance, and specific conditions such as sickle cell anemia. Future studies should assess the preventability of ED visits in these populations and identify opportunities for reducing their ED use. PMID- 27979585 TI - The differential expression of protease activated receptors contributes to functional differences between dark and fair keratinocytes. AB - BACKGROUND: Dark skin has different properties in comparison to fair skin. Melanocytes have been shown to partly contribute to these differences, however, the involvement of keratinocytes from dark or fair skin is not well demonstrated. OBJECTIVES: This study investigated the proliferation and barrier function of dark keratinocytes (DK) and fair keratinocytes (FK), and the role of protease activated receptor (PAR)1 and PAR2. METHODS: DK and FK were isolated from human neonatal foreskins. Cells were treated with PAR1/PAR2 agonists or antagonists, proliferation was measured by BrdU assay; permeability by the flux of FITC dextran; protein expression by immunostaining or western blot. RESULTS: When compared to FK, DK proliferated significantly slower; had higher cell permeability; expressed less phosphorylated (P)-ERK/ERK, caspase-14, E-cadherin, tissue growth factor (TGF)-beta3 and PAR1; and expressed more PAR2, and matrix metalloproteinase (MMP)-9. Activation of PAR1 or inhibition of PAR2 stimulated cell proliferation and ERK activation, and in concordance inhibition of PAR1 or activation of PAR2 suppressed cell proliferation and ERK activation in both DK and FK. Inhibition of PAR2 decreased and inhibition of PAR1 increased cell permeability. In foreskin sections, the epidermis of dark foreskin expressed less caspase-14 and the same level but different distribution of E-cadherin, when compared to fair foreskin. CONCLUSIONS: These data highlight functional differences in proliferation and barrier integrity between HK and FK that are partly associated with their differential expression of PAR1 and PAR2. PMID- 27979586 TI - Hydrazone linkages in pH responsive drug delivery systems. AB - Stimuli-responsive polymeric drug delivery systems using various triggers to release the drug at the sites have become a major focus area. Among various stimuli-responsive materials, pH-responsiveness has been studied extensively. The materials used for fabricating pH-responsive drug delivery systems include a specific chemical functionality in their structure that can respond to changes in the pH of the surrounding environment. Various chemical functionalities, for example, acetal, amine, ortho ester, amine and hydrazone, have been used to design materials that are capable of releasing their payload at the acidic pH conditions of the tumor or infection sites. Hydrazone linkages are significant synthons for numerous transformations and have gained importance in pharmaceutical sciences due to their various biological and clinical applications. These linkages have been employed in various drug delivery vehicles, such as linear polymers, star shaped polymers, dendrimers, micelles, liposomes and inorganic nanoparticles, for pH-responsive drug delivery. This review paper focuses on the synthesis and characterization methods of hydrazone bond containing materials and their applications in pH-responsive drug delivery systems. It provides detailed suggestions as guidelines to materials and formulation scientists for designing biocompatible pH-responsive materials with hydrazone linkages and identifying future studies. PMID- 27979587 TI - Deciphering lymphoma pathogenesis via state-of-the-art mass spectrometry-based quantitative proteomics. AB - Mass spectrometry-based quantitative proteomics specifically applied to comprehend the pathogenesis of lymphoma has incremental value in deciphering the heterogeneity in complex deregulated molecular mechanisms/pathways of the lymphoma entities, implementing the current diagnostic and therapeutic strategies. Essential global, targeted and functional differential proteomics analyses although still evolving, have been successfully implemented to shed light on lymphoma pathogenesis to discover and explore the role of potential lymphoma biomarkers and drug targets. This review aims to outline and appraise the present status of MS-based quantitative proteomic approaches in lymphoma research, introducing the current state-of-the-art MS-based proteomic technologies, the opportunities they offer in biological discovery in human lymphomas and the related limitation issues arising from sample preparation to data evaluation. It is a synopsis containing information obtained from recent research articles, reviews and public proteomics repositories (PRIDE). We hope that this review article will aid, assimilate and assess all the information aiming to accelerate the development and validation of diagnostic, prognostic or therapeutic targets for an improved and empowered clinical proteomics application in lymphomas in the nearby future. PMID- 27979588 TI - The 2nd order focusing sector field type TOF mass analyzer with an orthogonal ion acceleration for LC-IMS-MS. AB - Original orthogonal acceleration (OA) electrostatic sector time of flight (TOF) mass analyzer is proposed those allows the second order focusing of time of flight by initial ions position. Resolving power aberration limit exceeding 80,000 FW (full width mass peak) was shown to be obtainable for mass analyzer with the total length of flight L=133.2cm, the average ion energy 3700V and the ion energy spread of 2.5% on the entrance of sector field. PMID- 27979589 TI - In vitro hydroquinone-induced instauration of histone bivalent mark on human retroelements (LINE-1) in HL60 cells. AB - Benzene is extensively used in industry despite its leukemogenic activity, representing a significant occupational hazard. We investigated if long-term treatment with low-doses hydroquinone (HQ), a benzene metabolite, might be sufficient to alter in vitro the epigenetic signature underlining LINE-1 sequences, a poorly explored step in health risks associated with benzene exposure. In HL-60 cell line, exploring the epigenetic events occurring in chromatin, we found the transient instauration of the distinctive signature combining the repressive H3Lys27 tri-methylation mark and the activating H3Lys4 tri-methylation mark (H3K27me3/H3K4me3), indicating a tendency toward a poised chromatin conformation. These alterations are lost in time after short-term treatments, while the long-term setting, performed using a concentration within the levels of total HQ in peripheral blood of benzene-exposed workers, showed a gradual increase in H3K4me3. We observed the absence of statistically significant variations in DNA methylation and expression levels of LINE-1, despite a decrease in protein levels of UHRF1, DNA methyl-transferases and histone methyl transferases. In conclusion, in vitro treatment with low-dose HQ determined the instauration of a reversible poised state of chromatin in LINE-1 sequences, suggesting that prolonged exposure could cause persistent epigenetic alterations. PMID- 27979590 TI - Development of a screening approach to detect thyroid disrupting chemicals that inhibit the human sodium iodide symporter (NIS). AB - The U.S. EPA's Endocrine Disruptor Screening Program aims to use high-throughput assays and computational toxicology models to screen and prioritize chemicals that may disrupt the thyroid signaling pathway. Thyroid hormone biosynthesis requires active iodide uptake mediated by the sodium/iodide symporter (NIS). Monovalent anions, such as the environmental contaminant perchlorate, are competitive inhibitors of NIS, yet limited information exists for more structurally diverse chemicals. A novel cell line expressing human NIS, hNIS HEK293T-EPA, was used in a radioactive iodide uptake (RAIU) assay to identify inhibitors of NIS-mediated iodide uptake. The RAIU assay was optimized and performance evaluated with 12 reference chemicals comprising known NIS inhibitors and inactive compounds. An additional 39 chemicals including environmental contaminants were evaluated, with 28 inhibiting RAIU over 20% of that observed for solvent controls. Cell viability assays were performed to assess any confounding effects of cytotoxicity. RAIU and cytotoxic responses were used to calculate selectivity scores to group chemicals based on their potential to affect NIS. RAIU IC50 values were also determined for chemicals that displayed concentration-dependent inhibition of RAIU (>=50%) without cytotoxicity. Strong assay performance and highly reproducible results support the utilization of this approach to screen large chemical libraries for inhibitors of NIS-mediated iodide uptake. PMID- 27979591 TI - Rebaudiosides T and U, minor C-19 xylopyranosyl and arabinopyranosyl steviol glycoside derivatives from Stevia rebaudiana (Bertoni) Bertoni. AB - Two diterpene glycosides were isolated from a commercial Stevia rebaudiana leaf extract. One was found to be 13-[(2-O-beta-d-glucopyranosyl-3-O-beta-d glucopyranosyl-beta-d-glucopyranosyl)oxy]ent-kaur-16-en-19-oic acid-(2-O-beta-d xylopyranosyl-3-O-beta-d-glucopyranosyl- beta-d-glucopyranosyl) ester (rebaudioside T), whereas the other was determined to be 13-[(2-O-beta-d glucopyranosyl-3-O-beta-d-glucopyranosyl-beta-d-glucopyranosyl)oxy]ent-kaur-16-en 19-oic acid-(6-O-alpha-l-arabinopyranosyl-beta-d-glucopyranosyl) ester (rebaudioside U). In addition, five C-19 sugar free derivatives were prepared and identified as follows: 13-[(2-O-alpha-l-rhamnopyranosyl-beta-d glucopyranosyl)]oxy]kaur-16-en-19-oic acid (dulcoside A1); 13-[(2-O-beta-d xylopyranosy-3-O-beta-d-glucopyranosyl-beta-d-glucopyranosyl)oxy]kaur-16-en-19 oic acid; 13-[(2-O-beta-d-xylopyranosyl-beta-d-glucopyranosyl-)oxy]kaur-16-en-19 oic acid; 13-[(2-O-beta-d-glucopyranosyl-3-O-beta-d-glucopyranosyl-beta-d xylopyranosyl-)oxy]kaur-16-en-19-oic acid (rebaudioside R1) and 13-[(2-O-6-deoxy beta-d-glucopyranosyl-3-O-beta-d-glucopyranosyl-beta-d-glucopyranosyl)oxy]kaur-16 en-19-oic acid, respectively. Chemical structures were determined by NMR experiments. HPLC analyses were also useful to differentiate different steviol C13 sugar substituent patterns by elution position. PMID- 27979592 TI - Synthesis and antiproliferative activity of 2-chlorophenyl carboxamide thienopyridines. AB - 3-Amino-2-arylcarboxamide-thieno[2,3-b]pyridines are a known class of antiproliferative compounds with activity against the phospholipase C enzyme. To further investigate the structure activity relationships of these derivatives a series of analogues were prepared modifying key functional groups. It was determined that modification of the 3-amino and 2-aryl carboxamide functionalities resulted in complete elimination of activity, whilst modification at C-5 allowed compounds of greater activity to be prepared. PMID- 27979593 TI - Antiproliferative activity and SARs of caffeic acid esters with mono-substituted phenylethanols moiety. AB - A series of CAPE derivatives with mono-substituted phenylethanols moiety were synthesized and evaluated by MTT assay on growth of 4 human cancer cell lines (Hela, DU-145, MCF-7 and ECA-109). The substituent effects on the antiproliferative activity were systematically investigated for the first time. It was found that electron-donating and hydrophobic substituents at 2'-position of phenylethanol moiety could significantly enhance CAPE's antiproliferative activity. 2'-Propoxyl derivative, as a novel caffeic acid ester, exhibited exquisite potency (IC50=0.4+/-0.02 & 0.6+/-0.03MUM against Hela and DU-145 respectively). PMID- 27979594 TI - Synthesis and in vitro antiviral evaluation of 4-substituted 3,4 dihydropyrimidinones. AB - A series of 4-substituted 3,4-dihydropyrimidine-2-ones (DHPM) was synthesized, characterized by IR, 1H NMR, 13C NMR and HRMS spectra. The compounds were evaluated in vitro for their antiviral activity against a broad range of DNA and RNA viruses, along with assessment for potential cytotoxicity in diverse mammalian cell lines. Compound 4m, which possesses a long lipophilic side chain, was found to be a potent and selective inhibitor of Punta Toro virus, a member of the Bunyaviridae. For Rift Valley fever virus, which is another Bunyavirus, the activity of 4m was negligible. DHPMs with a C-4 aryl moiety bearing halogen substitution (4b, 4c and 4d) were found to be cytotoxic in MT4 cells. PMID- 27979595 TI - Imidazopyridyl compounds as aldosterone synthase inhibitors. AB - The inhibition of aldosterone synthase (CYP11B2) may be an effective treatment of hypertension and heart failure, among other ailments. Previously reported benzimidazole CYP11B2 inhibitors led the way for bioisosteric imidazopyridines that are both potent and selective over CYP11B1. PMID- 27979596 TI - Percutaneous Cryoablation for the Treatment of Recurrent Malignant Pleural Mesothelioma: Safety, Early-Term Efficacy, and Predictors of Local Recurrence. AB - PURPOSE: To determine safety and early-term efficacy of CT-guided cryoablation for treatment of recurrent mesothelioma and assess risk factors for local recurrence. MATERIALS AND METHODS: During the period 2008-2012, 24 patients underwent 110 cryoablations for recurrent mesothelioma tumors in 89 sessions. Median patient age was 69 years (range, 48-82 y). Median tumor size was 30 mm (range, 9-113 mm). Complications were graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Recurrence was diagnosed on CT or positron emission tomography/CT by increasing size, nodular enhancement, or hypermetabolic activity and analyzed using the Kaplan-Meier method. Cox proportional hazards model was used to determine covariates associated with local tumor recurrence. RESULTS: Median duration of follow-up was 14.5 months. Complications occurred in 8 of 110 cryoablations (7.3%). All but 1 complication were graded CTCAE v4.0 1 or 2. No procedure-related deaths occurred. Freedom from local recurrence was observed in 100% of cases at 30 days, 92.5% at 6 months, 90.8% at 1 year, 87.3% at 2 years, and 73.7% at 3 years. Tumor recurrence was diagnosed 4.5-24.5 months after cryoablation (mean 5.7 months). Risk of tumor recurrence was associated with a smaller ablative margin from the edge of tumor to iceball ablation margin (multivariate hazard ratio 0.68, CI 0.48-0.95, P = .024). CONCLUSIONS: CT-guided cryoablation is safe for local control of recurrent mesothelioma, with a low rate of complications and promising early-term efficacy. A smaller ablative margin may predispose to tumor recurrence. PMID- 27979598 TI - How successful is the transition to adult urology care in spina bifida? A single center 7-year experience. AB - INTRODUCTION: Rates of successful transition from adolescent to adult spina bifida (SB) care are unknown. OBJECTIVE: We aimed to assess rates and predictors of successful transition from a multidisciplinary SB clinic to a transitional urology clinic (TUC), or a pediatric or adult urologist. STUDY DESIGN: We retrospectively reviewed patients discharged from a multidisciplinary SB clinic (2006-2012), collecting demographic and clinical data. At transition, all patients/families were given instructions to arrange an appointment within 12 months. Patients who followed-up within 2 years were classified as transitioned. Logistic regression was used for analysis. RESULTS: Of 77 patients discharged at a mean age of 19.1 years, 31 (40.3%) successfully transitioned (mean follow-up 4.7 years). Only 20/41 (48.8%) with prior bladder augmentation, urinary channel, and MACE transitioned. There was no significant change in patients transitioning over time or late catch-up presentations (p = 0.41 see Figure). Transitioned and non-transitioned groups were similar in age, gender, home-to-clinic distance, insurance, ambulation, shunt status, prior non-adherence, emergency room visits, neurosurgery appointments, hospitalizations, and surgeries (including genitourinary reconstruction) before discharge (p = 0.22). Transitioned patients had more pre-discharge appointments with services outside the SB clinic (p = 0.01) and radiographic studies (p < 0.001), but these were not significant on multivariate analysis (p = 0.16). Among those who did not transition, five (6.5%) presented after 2 years, rarely with new complaints (20.0%). Patients without urological follow-up were most likely to visit the emergency room (p = 0.03). DISCUSSION: To facilitate continued care and a smooth transition, the TUC was opened across the corridor from the multidisciplinary SB clinic. To our surprise, a low percentage of patients actually transitioned to adult care over the last 7 years. It is a sobering fact that despite offering three different transition models, <50% of patients took advantage of any of them. While none of the predictors we anticipated to be important in a successful transition were statistically significant, potentially because of low statistical power, perhaps others, such as insufficient time to coordinate care, wait times, and lack of adult coordinated care programs, may be more important. We were unable to compare the urologic health of those who did and did not transition, as we relied on medical record data. CONCLUSIONS: Only 40% of patients transitioned successfully from a multidisciplinary SB clinic and few presented after 2 years. Patients who transitioned tended to have more active health issues and more radiographic tests prior to discharge. Those followed by a urologist are less likely to use emergency room services. PMID- 27979600 TI - US 21st Century Cures Act secures health-care research funding. PMID- 27979597 TI - Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho. AB - Fibrosis is an exaggerated form of tissue repair that occurs with serious damage or repetitive injury and ultimately leads to organ failure due to the excessive scarring. Increased calcium ion entry through the TRPC6 channel has been associated with the pathogenesis of heart and glomerular diseases, but its role in renal interstitial fibrosis is unknown. We studied this by deletion of Trpc6 in mice and found it decreased unilateral ureteral obstruction-induced interstitial fibrosis and blunted increased mRNA expression of fibrosis-related genes in the ureteral obstructed kidney relative to that in the kidney of wild type mice. Administration of BTP2, a pyrazol derivative known to inhibit function of several TRPC channels, also ameliorated obstruction-induced renal fibrosis and gene expression in wild-type mice. BTP2 inhibited carbachol-activated TRPC3 and TRPC6 channel activities in HEK293 cells. Ureteral obstruction caused over a 10 fold increase in mRNA expression for TRPC3 as well as TRPC6 in the kidneys of obstructed relative to the sham-operated mice. The magnitude of protection against obstruction-induced fibrosis in Trpc3 and Trpc6 double knockout mice was not different from that in Trpc6 knockout mice. Klotho, a membrane and soluble protein predominantly produced in the kidney, is known to confer protection against renal fibrosis. Administration of soluble klotho significantly reduced obstruction-induced renal fibrosis in wild-type mice, but not in Trpc6 knockout mice, indicating that klotho and TRPC6 inhibition act in the same pathway to protect against obstruction-induced renal fibrosis. Thus klotho and TRPC6 may be pharmacologic targets for treating renal fibrosis. PMID- 27979599 TI - Estimation of tumour regression and growth rates during treatment in patients with advanced prostate cancer: a retrospective analysis. AB - BACKGROUND: We applied mathematical models to clinical trial data available at Project Data Sphere LLC (Cary, NC, USA), a non-profit universal access data sharing warehouse. Our aim was to assess the rates of cancer growth and regression using the comparator groups of eight randomised clinical trials that enrolled patients with metastatic castration-resistant prostate cancer. METHODS: In this retrospective analysis, we used data from eight randomised clinical trials with metastatic castration-resistant prostate cancer to estimate the growth (g) and regression (d) rates of disease burden over time. Rates were obtained by applying mathematical models to prostate-specific antigen levels as the representation of tumour quantity. Rates were compared between study interventions (prednisone, mitoxantrone, and docetaxel) and off-treatment data when on-study treatment had been discontinued to understand disease behaviour during treatment and after discontinuation. Growth (g) was examined for association with a traditional endpoint (overall survival) and for its potential use as an endpoint to reduce sample size in clinical trials. FINDINGS: Estimates for g, d, or both were obtained in 2353 (88%) of 2678 patients with data available for analysis; g differentiated docetaxel (a US Food and Drug Administration-approved therapy) from prednisone and mitoxantrone and was predictive of overall survival in a landmark analysis at 8 months. A simulated sample size analysis, in which g was used as the endpoint, compared docetaxel data with mitoxantrone data and showed that small sample sizes were sufficient to achieve 80% power (16, 47, and 25 patients, respectively, in the three docetaxel comparator groups). Similar results were found when the mitoxantrone data were compared with the prednisone data (41, 39, and 41 patients in the three mitoxantrone comparator groups). Finally, after discontinuation of docetaxel therapy, median tumour growth (g) increased by nearly five times. INTERPRETATION: The application of mathematical models to existing clinical data allowed estimation of rates of growth and regression that provided new insights in metastatic castration-resistant prostate cancer. The availability of clinical data through initiatives such as Project Data Sphere, when combined with innovative modelling techniques, could greatly enhance our understanding of how cancer responds to treatment, and accelerate the productivity of clinical development programmes. FUNDING: None. PMID- 27979601 TI - Can modelling of PSA dynamics accelerate drug development for prostate cancer? PMID- 27979603 TI - Cases That Haunt Us: The Rashomon Effect and Moral Distress on the Consult Service. PMID- 27979602 TI - Association between serum SPan-1 and lymph node metastasis in invasive intraductal papillary mucinous neoplasm of the pancreas. AB - BACKGROUND AND AIM: Lymph node metastasis predicts poorer prognoses in patients with invasive intraductal papillary mucinous neoplasms of the pancreas (IPMNs). Factors associated with lymph node metastasis of invasive IPMN remain unclear. Therefore, this study aimed to define factors associated with lymph node metastasis of invasive IPMN. METHODS: Between June 2000 to August 2015, 156 consecutive patients with IPMN underwent surgical resection at Kobe University Hospital, and were enrolled in this study. The relationship between lymph node metastasis and clinical characteristics, including imaging studies and serum tumor markers, was evaluated. A multivariate logistic regression analysis was performed to assess the relationship between serum tumor markers and the presence of lymph node metastasis of IPMN, adjusted for clinical characteristics. RESULTS: Lymph node metastasis was observed in 7.7% (12/156) of IPMNs via a pathological examination. The multivariate logistic regression analysis revealed that serum SPan-1 was associated with the presence of lymph node metastasis of IPMN (odds ratio [OR] = 7.32; 95% confidence interval [CI] = 1.10 to 56.0; P = 0.04). In addition, survival was poorer among serum SPan-1-positive patients than SPan-1 negative patients (Log-rank test; P = 0.0002). Lymph node enlargement was detected preoperatively on computed tomography scans in only 16.7% (2/12) of cases that were positive for lymph node metastasis. CONCLUSIONS: Elevated serum SPan-1 was associated with lymph node metastasis in this cohort of patients who underwent resection for invasive IPMN. PMID- 27979604 TI - Differences in Behavior and Brain Activity during Hypothetical and Real Choices. AB - Real behaviors are binding consequential commitments to a course of action, such as harming another person, buying an Apple watch, or fleeing from danger. Cognitive scientists are generally interested in the psychological and neural processes that cause such real behavior. However, for practical reasons, many scientific studies measure behavior using only hypothetical or imagined stimuli. Generalizing from such studies to real behavior implicitly assumes that the processes underlying the two types of behavior are similar. We review evidence of similarity and differences in hypothetical and real mental processes. In many cases, hypothetical choice tasks give an incomplete picture of brain circuitry that is active during real choice. PMID- 27979605 TI - [Reflections on underdiagnosis and primary HIV infection]. PMID- 27979606 TI - Pretreatment with IL-1beta enhances proliferation and chondrogenic potential of synovium-derived mesenchymal stem cells. AB - BACKGROUND AIMS: Synovial mesenchymal stem cells (MSCs) are an attractive cell source for cartilage regeneration because of their high proliferative ability and chondrogenic potential. We have performed clinical trials using synovial MSCs to regenerate articular cartilage. To achieve good clinical outcomes for cell transplantation therapy, it is important to control both quantity (cell number) and quality (pluripotency or chondrogenic potential) of the cells for transplantation. Interleukin (IL)-1beta is a pro-inflammatory cytokine with significant pro-proliferative potential for mesenchymal cells. However, the effects of IL-1beta on synovial MSCs remain unknown. We investigated the effects of pretreatment with IL-1beta on synovial MSCs. METHODS: Human synovial tissue was harvested during total knee arthroplasty. Nucleated cells were plated and cultured in the absence or presence of IL-1beta at 10-13, 10-12, 10-11, 10-10, 10 9 or 10-8 g/mL for 14 days. RESULTS: The number of synovial MSCs increased in a concentration-dependent manner. When cultured for 21 days in chondrogenic medium after pretreatment with 10-8 g/mL IL-1beta, pellet aggregation was observed, whereas pretreatment with 10-12, 10-11 or 10-10 g/mL IL-1beta significantly increased the weight of cartilage pellets (P <0.01). Surface markers for adhesion ability and pluripotency were reduced with high concentrations of IL-1beta. IL-6 and IL-8 expression increased, but no changes in the expression level of growth factors were indicated by cytokine array. CONCLUSIONS: We have demonstrated that pretreatment of IL-1beta increased the proliferation and chondrogenic potential of synovial MSCs, which may promote the regenerative potential of synovial MSCs. PMID- 27979607 TI - Psychometric properties of the Management of Aggression and Violence Attitude Scale in Hong Kong's emergency care setting. AB - BACKGROUND: Emergency unit is one of the most high-risk areas for patient violence. However, in Hong Kong, little research has been test psychometric properties of assessment tool of Emergency unit nurses' attitude toward violence. METHODS: The Management of Aggression and Violence Attitude Scale's (MAVASs) Scale- and Item-Content Validity Index were established by 5-experts panel. A convenience sample of 123 nurses working in 4 public Emergency Department in Hong Kong was recruited. The construct validity was tested using exploratory factor analysis and the reliability was assessed by Cronbach's alpha and test-retest reliability. RESULTS: The Scale-Content Validity Index was 97.0% and the Item Content Validity Indexes ranged from 80.0% to 100.0%. Exploratory factor analysis indicated 4-factors solution (i.e., "importance of communication with patients", "perceived effectiveness of interventions", "pitfalls of interventions" and "perceived need for intervention"). Its' internal consistency was satisfactory (Cronbach's alphas=0.40-0.77) across the 4 subscales and test-retest reliability over 4-week interval was satisfactory (Pearson's coefficient=0.85). CONCLUSION: MAVAS was found to be a valid and reliable tool to examine nurses' attitudes towards patients' violence in emergency care setting, and provides useful information to those developing training and intervention programmes for management of aggression. PMID- 27979608 TI - Early Mobilization Reduces Duration of Mechanical Ventilation and Intensive Care Unit Stay in Patients With Acute Respiratory Failure. AB - OBJECTIVE: To evaluate the effects of a quality improvement program to introduce early mobilization on the outcomes of patients with mechanical ventilation (MV) in the intensive care unit (ICU). DESIGN: A retrospective observational study. SETTING: Nineteen-bed ICU at a medical center. PARTICIPANTS: Adults patients with MV (N=153) admitted to a medical ICU. INTERVENTIONS: A multidisciplinary team (critical care nurse, nursing assistant, respiratory therapist, physical therapist, patient's family) initiated the protocol within 72 hours of MV when patients become hemodynamically stable. We did early mobilization twice daily, 5d/wk during family visits (30min each time), and cooperated with family, if possible. MAIN OUTCOME MEASURES: MV duration, rate of successful weaning, and length of ICU and hospital stay. RESULTS: We enrolled 63 patients in the before protocol group and 90 in the after protocol group. The 2 groups were well matched in age, sex, body height, body weight, body mass index, disease severity, cause of intubation, number of comorbidities, and most underlying diseases. After protocol group patients had shorter MV durations (4.7d vs 7.5d; P<.001) and ICU stays (6.9d vs 9.9d; P=.001) than did before protocol group patients. Early mobilization was negatively associated with the duration of MV (beta=-.269; P<.002; 95% confidence interval [CI], -4.767 to -1.072), and the risk of MV for >=7 days was lower in patients who underwent early mobilization (odds ratio, .082; 95% CI, .021-.311). CONCLUSIONS: The introduction of early mobilization for patients with MV in the ICU shortened MV durations and ICU stays. A multidisciplinary team that includes the patient's family can work together to improve the patient's clinical outcomes. PMID- 27979609 TI - Tinnitus therapy using tailor-made notched music delivered via a smartphone application and Ginko combined treatment: A pilot study. AB - OBJECTIVE: Notched music therapy has been suggested to be effective for relieving tinnitus. We have developed a smartphone application using tailor-made notched music for tinnitus patients. This study aimed to evaluate the effect of this smartphone application on reducing tinnitus. In addition, we investigated the predictive factors for tinnitus treatment outcome using this smartphone application. METHODS: A total of 26 patients who were chronically distressed by tinnitus with a >=18 Tinnitus Handicap Inventory (THI) score were recruited from March 2013 to March 2015 (National Clinical Trial (NCT) Identifier Number 01663467). Patients were instructed to listen to tailor-made notched music through our smartphone application for 30-60min per day and were prescribed Ginkgo biloba for 3 months. Treatment outcome was evaluated using the THI, a visual analogue scale that measures the effects of tinnitus in terms of loudness, noticeable time, annoyance, and disruption of daily life. Demographic data, including age, sex, duration of tinnitus, and pre-treatment scores on questionnaires such as the Beck Depression Inventory (BDI), State Trait Anxiety Inventory (TAI), and Pittsburgh Sleep Quality Index (PSQI) scores were compared between the effective and non-effective groups according to the differences between their pre- and post-treatment THI scores. RESULTS: Smartphone application delivered notched music therapy and Ginko combined treatment improved the THI score from 33.9+/-18.9 to 23.1+/-15.2; the effect was particularly marked for the emotional score of the THI. Improvement in the THI score was positively correlated with the initial THI score (P=0.001, adjusted estimated value=0.49, 95% confidence interval=0.25-0.73). CONCLUSION: Chronic tinnitus patients who underwent smartphone application-delivered notched music therapy and Ginko combined treatment showed improved THI scores, particularly the emotional score of the THI. A smartphone application-delivered therapy and Ginko combined treatment may be more effective in tinnitus patients who have had a higher initial THI. PMID- 27979610 TI - Salivary bypass tube placement in esophageal stricture: A technical note and report of three cases. AB - Hypopharyngeal and cervical esophageal strictures can be caused by advanced malignancies, ingestion of caustic materials, or can follow surgery or radiation therapy. They cause marked dysphagia and consequently patients need nasogastric or gastrostomy tube feeding, with a remarkable impact on quality of life. To restore oral feeding, the stenosis can be progressively dilated by using rubber bougies of increasing diameter, and a Montgomery(r) Salivary Bypass Tube can then be inserted to maintain the obtained calibre. However, while its flexibility makes it easy to tolerate, it has the drawback of making insertion difficult because the tube tends to bend. The aim of this paper is to present a possible solution to this problem. A Montgomery(r) Salivary Bypass Tube was distally sutured to a Cook Airway Exchange Catheter(r) to simplify its initial insertion through a laryngoscope and following replacements. The catheter was then easily removed leaving the bypass tube in the correct position. In our experience, this innovative approach proved effective in facilitating Montgomery(r) Salivary Bypass Tube insertion in three patients, without risks for the patient, additional operative time or increase in costs. PMID- 27979611 TI - Unilateral posterior canal-plugging surgery for intractable bilateral posterior canal-type benign paroxysmal positional vertigo. AB - OBJECTIVE: To investigate the effectiveness of unilateral posterior semicircular canal (PSCC)-plugging surgery for patients with intractable bilateral PSCC-type benign paroxysmal positional vertigo (P-BPPV). METHODS: From July 2011 to December 2015, we diagnosed 136 patients with P-BPPV. Of these, 3 patients had bilateral P-BPPV, and in 2 of the 3, the condition had been refractory to conservative treatment for more than 1 year. We planned a staged PSCC-plugging surgery for these 2 patients; initially one side was treated, and the contralateral side was treated 6 months later. RESULTS: After the first surgery, both patients experienced improvement in symptoms of vertigo and nystagmus on the operated side and no change on the non-operated side. Patients underwent the Epley maneuver for the non-operated side. In one case, the non-operated side was cured. In the other case, although the P-BPPV was not completely resolved, the patient was satisfied with the result of unilateral surgery because he was now able to turn in bed to the operated side without vertigo. Before surgery, he had experienced vertigo when turning even slightly in bed. CONCLUSION: We propose that even unilateral PSCC-plugging surgery is effective for some patients with intractable bilateral P-BPPV. PMID- 27979612 TI - Long-term cilostazol administration ameliorates memory decline in senescence accelerated mouse prone 8 (SAMP8) through a dual effect on cAMP and blood-brain barrier. AB - Phosphodiesterases (PDEs), which hydrolyze and inactivate 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP), play an important role in synaptic plasticity that underlies memory. Recently, several PDE inhibitors were assessed for their possible therapeutic efficacy in treating cognitive disorders. Here, we examined how cilostazol, a selective PDE3 inhibitor, affects brain functions in senescence-accelerated mouse prone 8 (SAMP8), an animal model of age-related cognitive impairment. Long-term administration of cilostazol restored the impaired context-dependent conditioned fear memory of SAMP8 to match that in normal aging control substrain SAMR1. Cilostazol also increased the number of cells containing phosphorylated cAMP responsive element binding protein (CREB), a downstream component of the cAMP pathway. Finally, cilostazol improves blood-brain barrier (BBB) integrity, demonstrated by reduced extravasation of 2-deoxy-2-18F-fluoro-d-glucose and Evans Blue dye in the brains of SAMP8. This improvement in BBB integrity was associated with an increased amount of zona occludens protein 1 (ZO-1) and occludin proteins, components of tight junctions integral to the BBB. The results suggest that long-term administration of cilostazol exerts its beneficial effects on age related cognitive impairment through a dual mechanism: by enhancing the cAMP system in the brain and by maintaining or improving BBB integrity. PMID- 27979614 TI - Oyster reef restoration in controlling coastal pollution around India: A viewpoint. AB - Coastal waters receive large amounts of nutrients and pollutants from different point and nonpoint sources through bays and estuaries. Excess supply of nutrients in coastal waters may have detrimental effects, leading to hypoxia and anoxia from eutrophication. Reduction in concentrations of excess nutrients/pollutants in bays/estuarine system is must for healthy coastal ecosystem functioning. Conservations of bays, estuaries and coastal zones are must for sustainable development in any maritime country. Excellent ability of oyster in removing and controlling the concentrations of nutrients, pollutants, suspended particulate matters from bays and estuarine waters stimulated me to provide a viewpoint on oyster reef restoration in controlling nutrient/heavy metals fluxes and marine coastal pollution around India. Oyster reefs restoration may decrease nutrient and heavy metals fluxes in coastal waters and reduce the intensity of oxygen depletion in the coastal Arabian Sea (seasonal) and Bay of Bengal. However, extensive research is recommended to understand the impact of oyster reef restoration in controlling coastal pollution which is essential for sustainable development around India. PMID- 27979616 TI - Ocean acidification: One potential driver of phosphorus eutrophication. AB - Harmful algal blooms which may be limited by phosphorus outbreak increases currently and ocean acidification worsens presently, which implies that ocean acidification might lead to phosphorus eutrophication. To verify the hypothesis, oxic sediments were exposed to seawater with different pH 30days. If pH was 8.1 and 7.7, the total phosphorus (TP) content in sediments was 1.52+/-0.50 and 1.29+/-0.40mg/g. The inorganic phosphorus (IP) content in sediments exposed to seawater with pH8.1 and 7.7 was 1.39+/-0.10 and 1.06+/-0.20mg/g, respectively. The exchangeable phosphorus (Ex-P) content in sediments was 4.40+/-0.45 and 2.82+/-0.15MUg/g, if seawater pH was 8.1 and 7.7. Ex-P and IP contents in oxic sediments were reduced by ocean acidification significantly (p<5%). The reduced phosphorus in sediments diffused into water, which implied that ocean acidification was one potential facilitator of phosphorus eutrophication in oxic conditions. PMID- 27979615 TI - Assessing environmental health using ecological indices for soft bottom in sewage affected rocky shores: The case of the largest seaside resort of SW Atlantic. AB - Efficient ecological indices can reflect the differences between impacted and nonimpacted sites, leading to significant variations at the contamination spatial scale. Here, we evaluated the spatial-temporal variability of 3 ecological indices (AMBI, M-AMBI, and BENTIX) in response to the distinct levels of sewage contamination. The indices were evaluated in two different ways: including Brachidontes rodriguezii (IBR) and excluding B. rodriguezii (EBR). The fact that mussel beds create a secondary infaunal habitat allows us to test these indices for soft bottoms in areas with rocky bottoms. The effectiveness and the level of agreement of these indices were increased when they were calculated with EBR. BENTIX and M-AMBI produced under- and overestimations of the ecological status of the studied sites. AMBI (EBR) seems to be better suited for environmental quality assessment in the study area. This index reduces the processing time of samples; thus, the AMBI (EBR) index could be used as a robust management tool for monitoring programs in areas with hard substrate. PMID- 27979617 TI - The iconic Torrey Canyon oil spill of 1967 - Marking its legacy. AB - March 2017 marks the 50th anniversary of the SS Torrey Canyon oil spill and cleanup, off the Cornwall coast in the English Channel. It was the world's first major supertanker disaster. It was a signature event in the marine pollution field, especially related to oil spill response and the initiation of scientific studies of monitoring and researching the fate and effects of oil in the sea. This paper recalls this event, notes our growing understanding of marine pollution and global efforts for cleaner seas, and encourages further work on both oil and the many emerging environmental issues affecting the marine environment. PMID- 27979619 TI - Human Subject Effects on Torsion Pendulum Oscillations: Importance of Establishing the Contribution of Thermal Convection Air Currents. PMID- 27979618 TI - Assessing and ameliorating the influence of the electron beam on carbon nanotube oxidation in environmental transmission electron microscopy. AB - In this work, we examine how the imaging electron beam can induce damage in carbon nanotubes (CNTs) at varying oxygen gas pressures and electron dose rates using environmental transmission electron microscopy (ETEM). Our studies show that there is a threshold cumulative electron dose which brings about damage in CNTs in oxygen - through removal of their graphitic walls - which is dependent on O2 pressure, with a 4-5 fold decrease in total electron dose per decade increase at a lower pressure range (10-6 to 10-5mbar) and approximately 1.3 -fold decrease per decade increase at a higher pressure range (10-3 to 100mbar). However, at a given pressure, damage in CNTs was found to occur even at the lowest dose rate utilized, suggesting the absence of a lower limit for the latter parameter. This study provides guidelines on the cumulative dose required to damage nanotubes in the 10-7mbar to 100mbar pressure regimes, and discusses the role of electron dose rate and total electron dose on beam-induced CNT degradation experiments. PMID- 27979613 TI - Mucopolysaccharidosis IVA and glycosaminoglycans. AB - Mucopolysaccharidosis IVA (MPS IVA; Morquio A: OMIM 253000) is a lysosomal storage disease with an autosomal recessive trait caused by the deficiency of N acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to accumulation of specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS). C6S and KS are mainly produced in the cartilage. Therefore, the undegraded substrates are stored primarily in cartilage and in its extracellular matrix (ECM), leading to a direct impact on cartilage and bone development, and successive systemic skeletal dysplasia. Chondrogenesis, the earliest phase of skeletal formation, is maintained by cellular interactions with the ECM, growth and differentiation factors, signaling pathways, and transcription factors in a temporal-spatial manner. In patients with MPS IVA, the cartilage is disrupted at birth as a consequence of abnormal chondrogenesis and/or endochondral ossification. The unique skeletal features are distinguished by a disproportional short stature, odontoid hypoplasia, spinal cord compression, tracheal obstruction, pectus carinatum, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity of joints. In spite of many descriptions of these unique clinical features, delay of diagnosis still happens. The pathogenesis and treatment of systemic skeletal dysplasia in MPS IVA remains an unmet challenge. In this review article, we comprehensively describe historical aspect, property of GAGs, diagnosis, screening, pathogenesis, and current and future therapies of MPS IVA. PMID- 27979620 TI - Assessing the influence of migration barriers and feeding ecology on total mercury concentrations in Dolly Varden (Salvelinus malma) from a glaciated and non-glaciated stream. AB - Assimilation of mercury (Hg) into food webs is directly influenced by ecological factors such as local habitat characteristics, species feeding behavior, and movement patterns. Total Hg concentrations ([THg]) in biota from Subarctic latitudes are driven both by broad spatial processes such as long-range atmospheric transport and more local influences such as biovectors and geology. Thus, even relatively pristine protected lands such as national parks are experiencing Hg accumulation. We analyzed [THg] and stable isotopes of carbon (delta13C) and nitrogen (delta15N) in 104 Dolly Varden (Salvelinus malma) collected from two rivers in southeastern Alaska, upstream and downstream of apparent anadromous migration barriers in watersheds with and without glacial coverage. To assess the potential magnitude of marine-derived THg returning to freshwater, we analyzed [THg] in ten adult pink salmon from each study system. There were no differences in Dolly Varden mean [THg] between sites after the data were standardized for fork length, but unadjusted [THg] varied relative to fish size and delta15N values. While previous studies generally show that [THg] increases with higher delta15N values, we found that Dolly Varden below migration barriers and foraging on salmon eggs had the highest delta15N values among all sampled individuals, but the lowest [THg]. Dolly Varden residing below anadromous barriers had delta13C values consistent with marine influence. Since salmon eggs typically have low [Hg], our results suggest that abundant salmon populations and the dietary subsidy they provide may reduce the annual exposure to [Hg] in egg eating stream fishes such as Dolly Varden. In addition to identifying a suitable species for freshwater Hg monitoring in southeastern Alaska, our study more broadly implies that river characteristics, location within a river, fish size, and feeding ecology are important factors influencing Hg accumulation. PMID- 27979621 TI - Recent regional climate cooling on the Antarctic Peninsula and associated impacts on the cryosphere. AB - The Antarctic Peninsula (AP) is often described as a region with one of the largest warming trends on Earth since the 1950s, based on the temperature trend of 0.54 degrees C/decade during 1951-2011 recorded at Faraday/Vernadsky station. Accordingly, most works describing the evolution of the natural systems in the AP region cite this extreme trend as the underlying cause of their observed changes. However, a recent analysis (Turner et al., 2016) has shown that the regionally stacked temperature record for the last three decades has shifted from a warming trend of 0.32 degrees C/decade during 1979-1997 to a cooling trend of -0.47 degrees C/decade during 1999-2014. While that study focuses on the period 1979 2014, averaging the data over the entire AP region, we here update and re-assess the spatially-distributed temperature trends and inter-decadal variability from 1950 to 2015, using data from ten stations distributed across the AP region. We show that Faraday/Vernadsky warming trend is an extreme case, circa twice those of the long-term records from other parts of the northern AP. Our results also indicate that the cooling initiated in 1998/1999 has been most significant in the N and NE of the AP and the South Shetland Islands (>0.5 degrees C between the two last decades), modest in the Orkney Islands, and absent in the SW of the AP. This recent cooling has already impacted the cryosphere in the northern AP, including slow-down of glacier recession, a shift to surface mass gains of the peripheral glacier and a thinning of the active layer of permafrost in northern AP islands. PMID- 27979622 TI - Earthworms (Eisenia fetida) demonstrate potential for use in soil bioremediation by increasing the degradation rates of heavy crude oil hydrocarbons. AB - Crude oil contamination widely impacts soil as a result of release during oil and gas exploration and production activities. The success of bioremediation methods to meet remediation goals often depends on the composition of the crude oil, the soil, and microbial community. Earthworms may enhance bioremediation by mixing and aerating the soil, and exposing soil microorganisms to conditions in the earthworm gut that lead to increased activity. In this study, the common composting earthworm Eisenia fetida was tested for utility to improve remediation of oil-impacted soil. E. fetida survival in soil contaminated with two distinct crude oils was tested in an artificial (lab-mixed) sandy loam soil, and survival compared to that in the clean soil. Crude oil with a high fraction of light weight hydrocarbons was more toxic to earthworms than the crude oil with a high proportion of heavy polyaromatic and aliphatic hydrocarbons. The heavier crude oil was added to soil to create a 30,000mg/kg crude oil impacted soil, and degradation in the presence of added earthworms and feed, feed alone, or no additions was monitored over time and compared. Earthworm feed was spread on top to test effectiveness of no mixing. TPH degradation rate for the earthworm treatments was ~90mg/day slowing by 200days to ~20mg/day, producing two phases of degradation. With feed alone, the rate was ~40mg/day, with signs of slowing after 500days. Both treatments reached the same end point concentrations, and exhibited faster degradation of aliphatic hydrocarbons C21, decreased. During these experiments, soils were moderately toxic during the first three months, then earthworms survived well, were active and reproduced with petroleum hydrocarbons present. This study demonstrated that earthworms accelerate bioremediation of crude oil in soils, including the degradation of the heaviest polyaromatic fractions. PMID- 27979623 TI - Soil microbial community composition and its role in carbon mineralization in long-term fertilization paddy soils. AB - Microbial communities are critical in mediating soil biological processes, including C mineralization; yet, the mechanism of microbial mediation for soil C mineralization remains poorly understood under the long-term fertilization. To identify the relative roles of microbes in C mineralization in the soil of rice paddies, we investigated the long-term (11years) effects of repeated N, P, and K fertilization on crop yield, soil properties and microbial communities and their relationships with C mineralization. The treatments included: no fertilization (control); normal fertilization (NPK); doubling the amount of N, P or K fertilizer (2NPK, N2PK, or NP2K); and doubling the amount of all three (2(NPK)). Long-term fertilization significantly increased rice yields by 3.4 to 4.8 times, and yield significantly improved by 23-32% with higher N fertilization. Increasing N fertilization significantly decreased total N and total P concentrations, while increasing P fertilization significantly increased soil pH, Olsen-P and total P concentrations. Increasing N and P fertilization changed soil microbial community compositions; pH and ratio of SOC and TN (C:N) were the most important contributors to the variance in microbial community composition. Increasing P fertilization decreased the abundance of Gram-positive and actinomycetes phospholipid fatty acid (PLFA) and significantly increased the ratio of fungal to bacterial PLFA. However, the alterations in soil microbial abundance and community composition did not significantly influence the C mineralization, while it significantly was determined by C:N ratio and marginally by crop yield. The results suggest that substrate quality (C:N ratio) and availability (crop yield), having a closer relationship with C mineralization compared to soil microbial communities, should be preferentially considered to predicting C mineralization under long-term fertilization. PMID- 27979625 TI - A method to identify drivers of societal change likely to affect natural assets in the future, illustrated with Australia's native biodiversity. AB - Human society has a profound adverse effect on natural assets as human populations increase and as global climate changes. We need to envisage different futures that encompass plausible human responses to threats and change, and become more mindful of their likely impacts on natural assets. We describe a method for developing a set of future scenarios for a natural asset at national scale under ongoing human population growth and climate change. The method involves expansive consideration of potential drivers of societal change, a reduction of these to form a small set of key drivers to which contrasting settings are assigned, which we use to develop a set of different scenarios. We use Australia's native biodiversity as the focus to illustrate the method. PMID- 27979624 TI - Polycyclic aromatic hydrocarbon (PAH)-containing soils from coal gangue stacking areas contribute to epithelial to mesenchymal transition (EMT) modulation on cancer cell metastasis. AB - The total accumulative stockpiles of gangue in China comprise 4.5billion metric tons, and approximately 659million tons of additional gangue are generated per year. Considering the stacking characteristics are highly heterogeneous, the potential cancer risks from the presence of polycyclic aromatic hydrocarbons (PAHs) remain elusive. This study aimed to determine whether PAH-containing soil around coal gangue stacking areas poses a potential cancer risk and contributes to cancer cell metastasis. The results indicate that eighteen PAHs, primarily originated from coal gangue, exhibited distance variations from the coal gangues to the downstream villages, and the abandoned colliery posed increased potential carcinogenic risks for humans as a result of long-term stacking of coal gangue. Furthermore, soil samples stimulated HepG2 cell migration and invasion in a PAH dependent manner, and the action was involved in PPARgamma-mediated epithelial to mesenchymal transition (EMT) modulation. These findings highlight the potential cancer risk of PAH-containing soil samples around coal gangue stacking areas, and identify important biomarkers underlying the risk and targets preventing the outcomes in polluted areas. PMID- 27979626 TI - Characterization factors for land use impacts on biodiversity in life cycle assessment based on direct measures of plant species richness in European farmland in the 'Temperate Broadleaf and Mixed Forest' biome. AB - Life Cycle Assessment (LCA) is a widely used tool to assess environmental sustainability of products. The LCA should optimally cover the most important environmental impact categories such as climate change, eutrophication and biodiversity. However, impacts on biodiversity are seldom included in LCAs due to methodological limitations and lack of appropriate characterization factors. When assessing organic agricultural products the omission of biodiversity in LCA is problematic, because organic systems are characterized by higher species richness at field level compared to the conventional systems. Thus, there is a need for characterization factors to estimate land use impacts on biodiversity in life cycle assessment that are able to distinguish between organic and conventional agricultural land use that can be used to supplement and validate the few currently suggested characterization factors. Based on a unique dataset derived from field recording of plant species diversity in farmland across six European countries, the present study provides new midpoint occupation Characterization Factors (CF) expressing the Potentially Disappeared Fraction (PDF) to estimate land use impacts on biodiversity in the 'Temperate Broadleaf and Mixed Forest' biome in Europe. The method is based on calculation of plant species on randomly selected test sites in the biome and enables the calculation of characterization factors that are sensitive to particular types of management. While species richness differs between countries, the calculated CFs are able to distinguish between different land use types (pastures (monocotyledons or mixed), arable land and hedges) and management practices (organic or conventional production systems) across countries. The new occupation CFs can be used to supplement or validate the few current CF's and can be applied in LCAs of agricultural products to assess land use impacts on species richness in the 'Temperate Broadleaf and Mixed Forest' biome. PMID- 27979627 TI - Sex differences in response to activity-based anorexia model in C57Bl/6 mice. AB - Anorexia nervosa is a severe eating disorder often associated with physical hyperactivity and is more frequently observed in female sex. Activity-Based Anorexia (ABA) model combines physical activity (PA) and reduced food intake and thus allows a better understanding of the mechanisms underlying anorexia nervosa. We aimed to assess sex differences in response to ABA model in C57Bl/6 mice. Twenty four male and 16 female C57BL/6 mice were studied. ABA mice were placed in individual cages with a continuously recorded activity wheel. ABA mice had a progressive limited food access from 6h/day (day 6) to 3h/day (day 9) until the end of the protocol (day 17). Body weight and food intake were daily measured. We studied physical activity during 24h, during the dark phase (D-PA) and the light phase (L-PA). We also evaluated the feeding anticipatory physical activity (A PA), the physical activity during food intake period (FI-PA) and the post prandial physical activity (PP-PA). We observed 16.7% of mortality in males (4 out of 24 mice) during ABA protocol while no female mice died (p=0.09). At day 17, food intake was significantly higher in females than in males (p<0.05) that was associated with a lower body weight loss than in females (p<0.05). Before limited food access, no gender differences in wheel running activity were observed. From day 9, A-PA significantly increased over time in males (p<0.05 vs females) while females exhibited higher FI-PA and PP-PA (p<0.05 vs males). Correlations between wheel running activities and, respectively, food intake and body weight loss showed gender differences, in particularly for L-PA and A-PA. Our results suggest a greater susceptibility of male mice to develop ABA, males and females exhibit different patterns of physical activity after limitation of food access. Underlying mechanisms should be further investigated. PMID- 27979628 TI - Parenting stressors and young adolescents' depressive symptoms: Does high vagal suppression offer protection? AB - Grounded in a dual-risk, biosocial perspective of developmental psychopathology, this study examined the role of higher vagal suppression in providing young adolescents protection from four parenting stressors. It was expected that lower vagal suppression would increase youth vulnerability to the deleterious effects of these parenting stressors. Depressive symptoms were examined as a central marker of socioemotional difficulties during early adolescence. The four parenting stressors examined were interparental hostility, maternal use of harsh discipline, maternal inconsistent discipline, and maternal psychological control. Participants were 68 young adolescents (Grade 6) and their mothers. Greater vagal suppression provided protection (i.e., lower depressive symptoms) from interparental hostility, harsh discipline, and maternal psychological control for boys but not for girls. PMID- 27979629 TI - Estimation of potential donors after cardiocirculatory death in Elche University General Hospital (Alicante, Spain). AB - OBJECTIVE: To evaluate the number and characteristics of potential organ donors among cardiocirculatory death cases. DESIGN AND SETTING: A retrospective observational study was made of individuals between 15-65 years of age who died in the period 2006-2014 in Elche University General Hospital (Alicante, Spain). INTERVENTION: A univariate analysis and binary logistic regression predictive model were performed to discriminate factors related to donation contraindication. VARIABLES OF INTEREST: Identification of patients with donation contraindication. RESULTS: Of the 1510 patients who died in the mentioned period, 1048 were excluded due to the application of exclusion criteria; 86 due to evolution towards brain death; and 20 due to losses. A total of 356 patients were analyzed, divided into two groups: 288 in non-heart beating donation II and 68 in non-heart beating donation III. Seventy patients were found to be potential non heart beating donation II and 10 were found to be potential non-heart beating donation III, which could increase donation activity by 8-9 donors a year. The patients died in the ICU, Resuscitation, Emergency Care, Internal Medicine, Digestive Diseases and Neurology. The following protective factors against organ donation contraindication were identified: death in Emergency Care, cardiorespiratory arrest before or during admission, and heart, respiratory and neurological disease as the cause of admission. Death in Internal Medicine was associated to an increased risk of donation contraindication. CONCLUSIONS: Implementing a non-heart beating donation protocol in our hospital could increase the donation potential by 8-9 donors a year. PMID- 27979631 TI - Indole-3-carbinol (I3C) analogues are potent small molecule inhibitors of NEDD4-1 ubiquitin ligase activity that disrupt proliferation of human melanoma cells. AB - The HECT domain-containing E3 ubiquitin ligase NEDD4-1 (Neural precursor cell Expressed Developmentally Down regulated gene 4-1) is frequently overexpressed in human cancers and displays oncogenic-like properties through the ubiquitin dependent regulation of multiple protein substrates. However, little is known about small molecule enzymatic inhibitors of HECT domain-containing ubiquitin ligases. We now demonstrate that indole-3-carbinol (I3C), a natural anti-cancer phytochemical derived from cruciferous vegetables such as cabbage and broccoli, represents a new chemical scaffold of small molecule enzymatic inhibitors of NEDD4-1. Using in vitro ubiquitination assays, I3C, its stable synthetic derivative 1-benzyl-I3C and five novel synthetic analogues were shown to directly inhibit NEDD4-1 ubiquitination activity. Compared to I3C, which has an IC50 of 284MUM, 1-benzyl-I3C was a significantly more potent NEDD4-1 enzymatic inhibitor with an IC50 of 12.3MUM. Compounds 2242 and 2243, the two indolecarbinol analogues with added methyl groups that results in a more nucleophilic benzene ring pi system, further enhanced potency with IC50s of 2.71MUM and 7.59MUM, respectively. Protein thermal shift assays that assess small ligand binding, in combination with in silico binding simulations with the crystallographic structure of NEDD4-1, showed that each of the indolecarbinol compounds bind to the purified catalytic HECT domain of NEDD4-1. The indolecarbinol compounds inhibited human melanoma cell proliferation in a manner that generally correlated with their effectiveness as NEDD4-1 enzymatic inhibitors. Taken together, we propose that I3C analogues represent a novel set of anti-cancer compounds for treatment of human melanomas and other cancers that express indolecarbinol sensitive target enzymes. PMID- 27979630 TI - Cervical Spinal Cord Injury without Computed Tomography Evidence of Trauma in Adults: Magnetic Resonance Imaging Prognostic Factors. AB - BACKGROUND: Spinal cord injury (SCI) without computed tomography evidence of trauma is underreported in adults and is considered a subtype of SCI with relatively good outcome. Despite this, few studies have been performed to determine specific imaging-related prognostic factors. Our objective is to describe the imaging characteristics of patients experiencing blunt cervical spine trauma with neurologic deficits, but without radiologic abnormalities and associated prognostic factors. METHODS: A retrospective review of all adult patients with cervical SCI admitted to the emergency room of 2 university hospitals from January 2004 to December 2013 was performed. Only patients with a magnetic resonance imaging (MRI) performed within 72 hours after trauma were included for further analysis. All patients with bony injury or traumatic malalignment were excluded. Data gathered on the remaining patients included demographics, mechanism of injury, severity of SCI, long-term patient outcome, improvement in neurologic condition, and MRI results. RESULTS: There were 48 patients who met the inclusion and exclusion criteria, and 40 who demonstrated improvement in the neurologic examination at follow-up. Disruption of either the anterior longitudinal ligament or ligamentum flavum and larger lesions in the MRI were predictors of lack of neurologic improvement. CONCLUSIONS: Early MRI has prognostic value in patients suffering SCI without computed tomography evidence of trauma. Lesion length is a powerful predictor of outcome in this subgroup of patients. Soft tissue injury plays a role in the severity of injury and the ability to recover in this subgroups of patients. PMID- 27979633 TI - Chylothorax in a Patient Receiving Hemodialysis. PMID- 27979632 TI - Cortisol and DHEA in development and psychopathology. AB - Dehydroepiandrosterone (DHEA) and cortisol are the most abundant hormones of the human fetal and adult adrenals released as end products of a tightly coordinated endocrine response to stress. Together, they mediate short- and long-term stress responses and enable physiological and behavioral adjustments necessary for maintaining homeostasis. Detrimental effects of chronic or repeated elevations in cortisol on behavioral and emotional health are well documented. Evidence for actions of DHEA that offset or oppose those of cortisol has stimulated interest in examining their levels as a ratio, as an alternate index of adrenocortical activity and the net effects of cortisol. Such research necessitates a thorough understanding of the co-actions of these hormones on physiological functioning and in association with developmental outcomes. This review addresses the state of the science in understanding the role of DHEA, cortisol, and their ratio in typical development and developmental psychopathology. A rationale for studying DHEA and cortisol in concert is supported by physiological data on the coordinated synthesis and release of these hormones in the adrenal and by their opposing physiological actions. We then present evidence that researching cortisol and DHEA necessitates a developmental perspective. Age-related changes in DHEA and cortisol are described from the perinatal period through adolescence, along with observed associations of these hormones with developmental psychopathology. Along the way, we identify several major knowledge gaps in the role of DHEA in modulating cortisol in typical development and developmental psychopathology with implications for future research. PMID- 27979634 TI - Actinomyces Meyeri Empyema. PMID- 27979635 TI - Development and co-existence of sarcoidosis with lymphoproliferative processes. PMID- 27979636 TI - Respiratory Planetary Medicine. PMID- 27979637 TI - Pulmonary Lymphoma. A Case Report. PMID- 27979638 TI - Tuberculosis Among Portuguese Living Abroad. PMID- 27979639 TI - The Use of High-Risk Criteria in Screening Patients for Blunt Cerebrovascular Injury: A Survey. AB - RATIONALE AND OBJECTIVES: Blunt cerebrovascular injury (BCVI) is uncommon, but delayed detection can have disastrous consequences. The Denver criteria are the most commonly used screening criteria. We aim to examine the utilization of screening criteria in the emergency department (ED) of our institution and assess whether patients with risk factors were imaged. MATERIALS AND METHODS: A survey questionnaire was sent out to radiologists in a large academic institution. A search was performed in the database on the use of CT angiography (CTA) and MR angiography (MRA) among patients with risk factors in the last 11 years. RESULTS: The survey was sent to 173 radiologists, with 41 responses (35 complete). Most of the physicians (30 out of 35) surveyed selected CTA as their preferred modality to screen for BCVI, whereas the remaining physicians selected MRA. None of the respondents reported routine use of Denver screening criteria or grading scale in their readouts. Only five respondents selected risk factors in the Denver criteria correctly. In the institution search, among the 1331 patients with blunt trauma and risk factors for BCVI, 537 underwent at least one angiographic study (40.3%). There was an increase in the screening rate after February 2010 in all risk factors, but only statistically significant among patients with foramen transversarium fractures and C1-C3 fractures. CONCLUSIONS: Both the Denver screening criteria and grading scale of vascular injury have been underutilized in the ED for patients with risk factors. Greater awareness and utilization of imaging can potentially result in decreased incidence of subsequent stroke in patients with blunt injury. PMID- 27979640 TI - Preoperative Imaging Does Not Predict Rupture in Acute Appendicitis. PMID- 27979641 TI - Awake Laryngoscopy in the Emergency Department. AB - BACKGROUND: Many emergency physicians gain familiarity with the laryngeal anatomy only during the brief view achieved during rapid sequence induction and intubation. Awake laryngoscopy in the emergency department (ED) is an important and clinically underutilized procedure. DISCUSSION: Providing benefit to the emergency physician through a slow, controlled, and deliberate examination of the airway, awake laryngoscopy facilitates confidence in the high-risk airway and eases the evolution to intubation, should it be required. Emergency physicians possess all the tools and skills required to effectively perform this procedure, through either the flexible endoscopic or rigid approaches. The procedure can be conducted utilizing local anesthesia with or without mild sedation, such that patients protect their airway. CONCLUSION: We discuss two clinical scenarios, indications/contraindications, patient selection, and steps to performing two approaches to awake laryngoscopy in the ED. PMID- 27979642 TI - Severe Carisoprodol Withdrawal After a 14-Year Addiction and Acute Overdose. AB - BACKGROUND: Carisoprodol, a centrally acting muscle relaxant with a high abuse potential, has barbiturate-like properties at the GABA-A receptor, leading to central nervous system depression and desired effects. Its tolerance and dependence has been previously demonstrated in an animal model, and withdrawal has been described in several recent case reports. Many cases can be effectively managed with a short course of benzodiazepines or antipsychotic agents. However, abrupt cessation in a patient with a history of long-term and high-dose carisoprodol abuse may result in symptoms that are more difficult for providers to treat. CASE REPORT: We present a case of a 34-year-old man with a long history of carisoprodol abuse who was found unresponsive after having ingested 7.5 grams of carisoprodol. He was intubated and admitted to the intensive care unit. He was given propofol, dexmedetomidine, fentanyl, ketamine, lorazepam, midazolam, quetiapine, and haloperidol, some at high-dose infusions, before his agitation and ventilator asynchrony could be controlled. His improvement coincided with the addition of carisoprodol and phenobarbital to his treatment regimen. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Trends show increasing emergency department presentations for drug-related disorders and treatment. This case highlights an uncommon case of carisoprodol withdrawal that may be encountered by emergency physicians, and demonstrates that benzodiazepines may not be sufficient to suppress severe withdrawal symptoms. Treatment with carisoprodol and phenobarbital provided additional benefit and can be considered in cases of severe carisoprodol withdrawal. PMID- 27979643 TI - Childhood Appendicitis: Is Time Really of the Essence? PMID- 27979644 TI - When Should Abdominal Computed Tomography Be Considered in Patients with Lower Rib Fractures? AB - BACKGROUND: Lower rib fractures are considered as a marker of intra-abdominal organ injury. Abdominal computed tomography (CT) is the "gold standard" examination for patients with lower rib fractures. However, the reported incidence of concomitant intra-abdominal injuries (IAI) is 20%-40%. OBJECTIVE: The purpose of this study was to evaluate the incidence of intra-abdominal organ injuries in blunt trauma patients with lower rib fractures. METHODS: Medical charts and radiology reports of patients with lower rib (from the 8th to 12th rib) fractures admitted to our center during a 6-year period were retrospectively reviewed. Patients were divided into two groups. Group I included patients with intra-abdominal injury (IAI) diagnosed either by CT or on urgent laparotomy, and Group II included those with normal abdominal CT scans. Data included demographics, mechanism of injury, laboratory tests, radiology results including number and location of fractured ribs, and incidence of IAI. RESULTS: Overall 318 patients were included in the study. Fifty-seven patients (17.9%) had 71 IAIs compared with 265 (82.1%) patients with no IAI. Logistic regression identified age younger than 55 years (relative risk [RR] = 7.2; 95% confidence interval [CI] 3.1-16.8; p = 0.001), bilateral rib fractures (RR = 3.9; 95% CI 1.1-13.5; p = 0.03) and decreased levels of hematocrit (RR = 2.4; 95% CI 1.2-4.8; p = 0.016) as independent risk factors for the presence of IAI. CONCLUSIONS: Abdominal CT should be considered in blunt trauma patients with lower rib fractures who are younger than 55 years of age and have bilateral rib fractures and decreased levels of hematocrit on admission. PMID- 27979645 TI - Abdominal Cerebrospinal Fluid Pseudocyst Masquerading as Ascites in an Adolescent Girl. PMID- 27979646 TI - A Patient with Left Flank Pain. PMID- 27979647 TI - Bioaccessibility of U, Th and Pb in solid wastes and soils from an abandoned uranium mine. AB - Bioaccessible U, Th, Pb and the 238U decay products 214Pb and 210Pb have been determined, using a modified Unified BARGE Method (UBM), in waste solids and soils from an abandoned uranium mine in South West England, UK. Maximum aqua regia extractable concentrations for U, Th and Pb were 16,200, 3.8 and 4750 MUg g 1, respectively. 238U had highest activity concentrations near the mine shaft, where the decay products214Pb and 210Pb had values of 235 and 180 Bq g-1, respectively. UBM extractions gave mean gastro-intestinal bioaccessibility factors (BAFs) for U and Pb in the waste solids of 0.05 and 0.03, respectively, whereas those for the soils were significantly higher at 0.24 and 0.17. The mean BAFs for the transient radionuclides, 214Pb and 210Pb, were similar to those for stable Pb implying that the stable and radioactive Pb isotopes were attached to similar sites on the particles. The doses arising from the ingestion of particulate 210Pb due to soil pica behaviour were in the range 0.2-65 and < 0.1 6.2 MUSv day-1 for a 1-year old child or an adult (>17 years), respectively. The results suggest that the health risk posed by abandoned uranium mines, with waste rock and tailings, throughout the world should take account of the dose due to both bioaccessible radionuclides, as well as their stable counterparts. PMID- 27979648 TI - Methylarginines within the RGG-Motif Region of hnRNP A1 Affect Its IRES Trans Acting Factor Activity and Are Required for hnRNP A1 Stress Granule Localization and Formation. AB - Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a stress granule associated RNA-binding protein that plays a role in apoptosis and cellular stress recovery. HnRNP A1 is a major non-histone target of protein arginine methyltransferase 1, which asymmetrically dimethylates hnRNP A1 at several key arginine residues within its arginine-glycine-glycine (RGG)-motif region. Although arginine methylation is known to regulate general RNA binding of hnRNP A1 in vitro, the functional role of arginine methylation in hnRNP A1 cytoplasmic activity is unknown. To test the impact of key methylarginine residues on hnRNP A1 cytoplasmic activity and stress granule association, cytoplasmically restricted Flag-tagged mutants of hnRNP A1 were generated in which key methylarginine residues within the RGG-motif region were changed to either lysine or alanine. Lysine substitution, which mimics unmethylated arginine, resulted in a 40% increase in internal ribosome entry site trans-acting factor (ITAF) activity and the protein readily associates with stress granules. Alanine substitution resulted in a loss of ITAF activity and reduced mRNA binding. The alanine mutant also displays reduced stress granule association and suppresses stress granule formation. Our data suggest that arginine residues within the RGG motif region are critical for hnRNP A1 cytoplasmic activities and that endogenous asymmetric dimethylation of the RGG-motif region suppresses hnRNP A1 ITAF activity in cells. Our findings indicate that methylarginine residues within the RGG-motif region of hnRNP A1 are important for its cytoplasmic activities and that hypomethylation and/or mutation of the RGG-motif region may contribute to the role of hnRNP A1 in diseases such as cancer. PMID- 27979649 TI - The RavA-ViaA Chaperone-Like System Interacts with and Modulates the Activity of the Fumarate Reductase Respiratory Complex. AB - Regulatory ATPase variant A (RavA) is a MoxR AAA+ protein that functions together with a partner protein that we termed VWA interacting with AAA+ ATPase (ViaA) containing a von Willebrand Factor A domain. However, the functional role of RavA ViaA in the cell is not yet well established. Here, we show that RavA-ViaA are functionally associated with anaerobic respiration in Escherichia coli through interactions with the fumarate reductase (Frd) electron transport complex. Expression analysis of ravA and viaA genes showed that both proteins are co expressed with multiple anaerobic respiratory genes, many of which are regulated by the anaerobic transcriptional regulator Fnr. Consistently, the expression of both ravA and viaA was found to be dependent on Fnr in cells grown under oxygen limiting condition. ViaA was found to physically interact with FrdA, the flavin containing subunit of the Frd complex. Both RavA and the Fe-S-containing subunit of the Frd complex, FrdB, regulate this interaction. Importantly, Frd activity was observed to increase in the absence of RavA and ViaA. This indicates that RavA and ViaA modulate the activity of the Frd complex, signifying a potential regulatory chaperone-like function for RavA-ViaA during bacterial anaerobic respiration with fumarate as the terminal electron acceptor. PMID- 27979650 TI - The search for neuroimaging and cognitive endophenotypes: A critical systematic review of studies involving unaffected first-degree relatives of individuals with bipolar disorder. AB - The phenomenology and underlying pathophysiology of bipolar disorder (BD) are heterogeneous. The identification of putative endophenotypes for BD can aid in the investigation of unique patho-etiological pathways, which may lead to the development of personalised preventative and therapeutic approaches for this multi-faceted disorder. We included original studies involving unaffected first degree relatives of BD patients (URs) and a healthy control (HC) comparison group with no first-degree family history of mental disorders, investigating: 'cold' and 'hot' cognition and functional and structural neuroimaging. Seventy-seven cross-sectional studies met the inclusion criteria. The present review revealed that URs in comparison with HCs showed: (i) widespread deficits in verbal memory, sustained attention, and executive function; (ii) abnormalities in the reactivity to and regulation of emotional information along with aberrant reward processing, and heightened attentional interference by emotional stimuli; and (iii) less consistency in the findings regarding structural and resting state neuroimaging, and electrophysiological measures. PMID- 27979651 TI - A brief historical perspective on the advent of brain oscillations in the biological and psychological disciplines. AB - We aim to review the historical evolution that has led to the study of the brain (body)-mind relationship based on brain oscillations, to outline and illustrate the principles of neuro-oscillatory dynamics using research findings. The paper addresses the relevant developments in behavioral sciences after Wundt established the science of psychology, and developments in the neurosciences after alpha and gamma oscillations were discovered by Berger and Adrian, respectively. Basic neuroscientific studies have led to a number of principles: (1) spontaneous EEG is composed of a set of oscillatory components, (2) the brain responds with oscillatory activity, (3) poststimulus oscillatory activity is a function of prestimulus activity, (4) the brain response results from a superposition of oscillatory components, (5) there are multiplicities with regard to oscillations and functions, and (6) oscillations are spatially integrated. Findings of clinical studies suggest that oscillatory responses can serve as biomarkers for neuropsychiatric disorders. However, the field of psychology is still making limited use of neuro-oscillatory dynamics for a bio-behavioral understanding of cognitive-affective processes. PMID- 27979652 TI - Long-term utility and complication profile of open craniotomy for biopsy in patients with idiopathic encephalitis. AB - Neurosurgeons are often asked to perform open biopsy for diagnosis of encephalitis after medical investigations are non-diagnostic. These patients may be critically ill with multiple comorbidities. Patients and their families often request data regarding the success rates and complication profile of biopsy, but minimal literature exists in this area. Retrospective chart review of all patients undergoing open brain biopsy (burr hole or craniotomy) for encephalitis refractory to medical diagnosis between January 2009 and December 2013 was undertaken. Pathology records and outpatient follow-up were reviewed to determine most recent clinical status of each patient. A total of 59 patients were included with mean follow up of 20months. The average age at biopsy was 55years. The most common unconfirmed diagnoses leading to biopsy were vasculitis (44%), neoplasm (27%), infection (12%), autoimmune (12%), amyloidosis (5%). Tissue pathology was diagnostic in 42% of all cases. Overall, biopsy confirmed the preoperative diagnosis in 46% of cases and refuted the preoperative leading diagnosis in 25% of cases. At last follow-up, the tissue pathology resulted in a medical treatment change in 25% of cases. There was a 14% major neurological complication rate (postoperative stroke, hemorrhage, or neurological deficit) and 9% cardiopulmonary complication rate (delayed extubation and re-intubation) attributable to surgical intervention. In this limited series, diagnostic utility of biopsy in patients with idiopathic encephalitis is less than 50% and the major complication rate is 23%. Patients and providers must be counseled accordingly and weigh the risks and benefits of open biopsy for encephalitis cautiously. PMID- 27979653 TI - Perceptual integration of faces and voices depends on the interaction of emotional content and spatial frequency. AB - The role of spatial frequencies (SF) is highly debated in emotion perception, but previous work suggests the importance of low SFs for detecting emotion in faces. Furthermore, emotion perception essentially relies on the rapid integration of multimodal information from faces and voices. We used EEG to test the functional relevance of SFs in the integration of emotional and non-emotional audiovisual stimuli. While viewing dynamic face-voice pairs, participants were asked to identify auditory interjections, and the electroencephalogram (EEG) was recorded. Audiovisual integration was measured as auditory facilitation, indexed by the extent of the auditory N1 amplitude suppression in audiovisual compared to an auditory only condition. We found an interaction of SF filtering and emotion in the auditory response suppression. For neutral faces, larger N1 suppression ensued in the unfiltered and high SF conditions as compared to the low SF condition. Angry face perception led to a larger N1 suppression in the low SF condition. While the results for the neural faces indicate that perceptual quality in terms of SF content plays a major role in audiovisual integration, the results for angry faces suggest that early multisensory integration of emotional information favors low SF neural processing pathways, overruling the predictive value of the visual signal per se. PMID- 27979654 TI - Anodal tDCS over the right dorsolateral prefrontal cortex modulates cognitive processing of emotional information as a function of trait rumination in healthy volunteers. AB - Healthy individuals reporting higher (as compared to lower) levels of trait rumination recruit more neural activity in dorso-cortical regions (mostly in the right hemisphere) when inhibiting negative information, possibly to compensate their difficulty to disengage from it. In the present study, we investigated whether these latter neural correlates are causally implicated in cognitive control in these individuals. We administered the Cued Emotional Control Task, a measure of cognitive control indexed by cognitive costs for inhibiting versus providing a habitual response for emotional information, in thirty-five healthy volunteers reporting a broad range of trait rumination levels. Participants completed the task after receiving both real and sham-placebo (counterbalanced order) anodal transcranial Direct Current Stimulation (tDCS) over the right dorsolateral prefrontal cortex (DLPFC). Results reveal that the tDCS induced effects on cognitive costs for emotional information were associated with individual differences in trait rumination: the higher the trait rumination level, the less cognitive costs following real neuromodulation of the right DLPFC. Interestingly, these effects were observed for both positive and negative stimuli, and not only negative information as hypothesized. Overall, the data suggest that the right DLPFC is causally involved in the alteration of cognitive control in healthy individuals who tend to ruminate, possibly by helping them to disengage from emotional material. PMID- 27979655 TI - IDC2 and IDC3, two genes involved in cell non-autonomous signaling of fruiting body development in the model fungus Podospora anserina. AB - Filamentous ascomycetes produce complex multicellular structures during sexual reproduction. Little is known about the genetic pathways enabling the construction of such structures. Here, with a combination of classical and reverse genetic methods, as well as genetic mosaic and graft analyses, we identify and provide evidence for key roles for two genes during the formation of perithecia, the sexual fruiting bodies, of the filamentous fungus Podospora anserina. Data indicate that the proteins coded by these two genes function cell non-autonomously and that their activity depends upon conserved cysteines, making them good candidate for being involved in the transmission of a reactive oxygen species (ROS) signal generated by the PaNox1 NADPH oxidase inside the maturing fruiting body towards the PaMpk1 MAP kinase, which is located inside the underlying mycelium, in which nutrients are stored. These data provide important new insights to our understanding of how fungi build multicellular structures. PMID- 27979657 TI - Undifferentiated connective tissue disease and interstitial lung disease: Trying to define patterns. AB - OBJECTIVES: To identify clinical or immunological features in patients with undifferentiated connective tissue disease (UCTD) associated interstitial lung disease (ILD), in order to group them and recognize different functional and high resolution computed tomography (HRCT) behavior. METHODS: Retrospective cohort study. Patients meeting Kinder criteria for UCTD were included. We defined the following predictive variables: 'highly specific' connective tissue disease (CTD) manifestations (Raynaud's phenomenon, dry eyes or arthritis), high antinuclear antibody (ANA) titer (above 1: 320), and 'specific' ANA staining patterns (centromere, cytoplasmic and nucleolar patterns). We evaluated the following outcomes: change in the percentage of the predicted forced vital capacity (FVC%) during the follow-up period, and HRCT pattern. RESULTS: Sixty-six patients were included. Twenty-nine (43.94%) showed at least one 'highly specific' CTD manifestation, 16 (28.57%) had a 'specific' ANA staining pattern and 29 (43.94%) high ANA titer. Patients with 'highly specific' CTD manifestations were younger (mean [SD] 52 years [14.58] vs 62.08 years [9.46], P<.001), were more likely men (10.34% vs 48.65%, P<.001) and showed a smaller decline of the FVC% (median [interquartile range] 1% [-1 to 10] vs -6% [-16 to -4], P<.006). In the multivariate analysis, the presence of highly specific manifestations was associated with improvement in the FVC% (B coefficient of 13.25 [95% confidence interval, 2.41 to 24.09]). No association was observed in relation to the HRCT pattern. CONCLUSION: The presence of 'highly specific' CTD manifestations was associated with female sex, younger age and better functional behavior. These findings highlight the impact of the clinical features in the outcome of patients with UCTD ILD. PMID- 27979658 TI - Sixty years old is the breakpoint of human frontal cortex aging. AB - Human brain aging is the physiological process which underlies as cause of cognitive decline in the elderly and the main risk factor for neurodegenerative diseases such as Alzheimer's disease. Human neurons are functional throughout a healthy adult lifespan, yet the mechanisms that maintain function and protect against neurodegenerative processes during aging are unknown. Here we show that protein oxidative and glycoxidative damage significantly increases during human brain aging, with a breakpoint at 60 years old. This trajectory is coincident with a decrease in the content of the mitochondrial respiratory chain complex I IV. We suggest that the deterioration in oxidative stress homeostasis during aging induces an adaptive response of stress resistance mechanisms based on the sustained expression of REST, and increased or decreased expression of Akt and mTOR, respectively, over the adult lifespan in order to preserve cell neural survival and function. PMID- 27979659 TI - Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia. AB - Quercetin, an important dietary flavonoid has been demonstrated to potentially reverse or even prevent pulmonary arterial hypertension (PAH) progression. However, the effects of quercetin on apoptosis and autophagy in pulmonary arterial smooth muscle cells (PASMCs) have not yet been clearly elucidated. The current study found that quercetin significantly induce the apoptotic and autophagic capacities of PASMCs in vitro and in vivo in hypoxia. In addition, we found that quercetin increases FOXO1 (a major mediator in autophagy regulation) expression and transcriptional activity. Moreover, FOXO1 knockdown by siRNAs inhibited the phosphorylation of mTOR and 4E-BPI, which is downstream of P70-S6K, and markedly blocked quercetin-induced autophagy. We also observed that FOXO1 mediated autophagy was achieved via SESN3 not Rictor upregulation and after mTOR suppression. Furthermore, Treatment with autophagy-specific inhibitors could markedly enhance quercetin-induced apoptosis in PASMCs under hypoxia. Finally, quercetin in combination with autophagy inhibition treatment could enhance the therapeutic effects of quercetin in hypoxia-associated PAH in vivo. Taken together, quercetin could enhance hypoxia-induced autophagy through the FOXO1 SENS3-mTOR pathway in PASMCs. Combining quercetin and autophagy inhibitors may be a novel therapeutic strategy for treating hypoxia-associated PAH. PMID- 27979660 TI - [Complementary approaches in the elderly on multiple medications: A look at the most vulnerable sectors]. PMID- 27979656 TI - Master regulators in development: Views from the Drosophila retinal determination and mammalian pluripotency gene networks. AB - Among the mechanisms that steer cells to their correct fate during development, master regulatory networks are unique in their sufficiency to trigger a developmental program outside of its normal context. In this review we discuss the key features that underlie master regulatory potency during normal and ectopic development, focusing on two examples, the retinal determination gene network (RDGN) that directs eye development in the fruit fly and the pluripotency gene network (PGN) that maintains cell fate competency in the early mammalian embryo. In addition to the hierarchical transcriptional activation, extensive positive transcriptional feedback, and cooperative protein-protein interactions that enable master regulators to override competing cellular programs, recent evidence suggests that network topology must also be dynamic, with extensive rewiring of the interactions and feedback loops required to navigate the correct sequence of developmental transitions to reach a final fate. By synthesizing the in vivo evidence provided by the RDGN with the extensive mechanistic insight gleaned from the PGN, we highlight the unique regulatory capabilities that continual reorganization into new hierarchies confers on master control networks. We suggest that deeper understanding of such dynamics should be a priority, as accurate spatiotemporal remodeling of network topology will undoubtedly be essential for successful stem cell based therapeutic efforts. PMID- 27979661 TI - [Breakthrough cancer pain in the elderly]. AB - Breakthrough pain is defined as an acute exacerbation of pain with rapid onset, short duration and moderate or high intensity, which occurs spontaneously or in connection with a predictable or unpredictable event despite there being stabilised and controlled baseline pain. However, there are doubts about the definition, terminology, epidemiology, and assessment of breakthrough pain, with no clear answers or consensus, especially in the elderly population. This non systematic review summarises the most important aspects of breakthrough pain in the elderly, based on the limited publications there are in that population group. PMID- 27979662 TI - Exploring the experiences of parents caring for infants with developmental dysplasia of the hip attending a dedicated clinic. AB - Specialised DDH (developmental dysplasion of the hip) clinics are developing around Ireland but are, however, variable in how they are operated. A DDH clinic was set up in the South-east of Ireland in 2002 with the goal of achieving an integrated care pathway between the orthopaedic surgical team and nursing team, working to an explicit protocol while also fostering a strong collaboration with the ultrasound department. This paper aims to explore the effectiveness of this dedicated clinic in the Southeast of Ireland. PMID- 27979663 TI - Sulforaphane inhibits osteoclast differentiation by suppressing the cell-cell fusion molecules DC-STAMP and OC-STAMP. AB - Sulforaphane (SFN), a kind of isothiocyanate, is derived from broccoli sprouts. It has anti-tumor, anti-inflammatory, and anti-oxidation activity. The molecular function of SFN in the inhibition of osteoclast differentiation is not well documented. In this study, we assessed the effect of SFN on osteoclast differentiation in vitro. SFN inhibited osteoclast differentiation in both bone marrow cells and RAW264.7 cells. Key molecules involved in the inhibitory effects of SFN on osteoclast differentiation were determined using a microarray analysis, which showed that SFN inhibits osteoclast-associated genes, such as osteoclast associated receptor (OSCAR), nuclear factor of activated T cells cytoplasmic-1, tartrate-resistant acid phosphatase, and cathepsin K. Moreover, the mRNA expression levels of the cell-cell fusion molecules dendritic cell specific transmembrane protein (DC-STAMP) and osteoclast stimulatory transmembrane protein (OC-STAMP) were strongly suppressed in cells treated with SFN. Furthermore, SFN increased the phosphorylation of signal transducer and activator of transcription 1 (STAT1), a regulator of macrophage and osteoclast cell fusion. Thus, our data suggested that SFN significantly inhibits the cell-cell fusion molecules DC-STAMP and OC-STAMP by inducing the phosphorylation of STAT1 (Tyr701), which might be regulated by interactions with OSCAR. PMID- 27979665 TI - Neonatal Cranial Ultrasound: Are Current Safety Guidelines Appropriate? AB - Ultrasound can lead to thermal and mechanical effects in interrogated tissues. We reviewed the literature to explore the evidence on ultrasound heating on fetal and neonatal neural tissue. The results of animal studies have suggested that ultrasound exposure of the fetal or neonatal brain may lead to a significant temperature elevation at the bone-brain interface above current recommended safety thresholds. Temperature increases between 4.3 and 5.6 degrees C have been recorded. Such temperature elevations can potentially affect neuronal structure and function and may also affect behavioral and cognitive function, such as memory and learning. However, the majority of these studies were carried out more than 25 y ago using non-diagnostic equipment with power outputs much lower than those of modern machines. New studies to address the safety issues of cranial ultrasound are imperative to provide current clinical guidelines and safety recommendations. PMID- 27979664 TI - Saponin fraction isolated from Conyza blinii H.Lev. demonstrates strong anti cancer activity that is due to its NF-kappaB inhibition. AB - CBS (Conyza blinii saponin) is the total triterpenoidal saponins of Conyza blinii H.Lev which is a type of traditional Chinese medicine (TCM). We have discovered that CBS has a profound cytostatic activity against a range of solid tumour cells in a time- and dose-dependent manner. We also confirm that the cytostatic activity of CBS originates from its apoptosis induction effect. Additionally, we use immunoblot to find out that the apoptosis induction effect of CBS is attributable to the activation of mitochondrial pathway. Mechanistic study demonstrates that CBS is an effective NF-kappaB inhibitor. It inhibits p65 nuclear translocation and NF-kappaB downstream gene expression, including XIAP, survivin, Bcl-xL, COX-2, cyclin D1, MMP-2, MMP-9 in HeLa cells. Tumour xenografted animal models verify the anti-cancer efficacy in vivo. Tumour growth is significantly repressed in two CBS-treated groups compared with the controls (P < 0.001). CBS treatment (i.g.) leads to a 48.5% and 57.0% reduction in terms of tumour weight for the 10 and 20 mg/kg dosed groups respectively. Also no apparent observable adverse effects can be seen. These results suggest that CBS obliterate tumour, at least in part due to its NF-kappaB inhibition, which creates potential for CBS to be developed as a practical cancer treatment. PMID- 27979666 TI - Cesarean Scar Pregnancy: Comparing the Efficacy and Tolerability of Treatment with High-Intensity Focused Ultrasound and Uterine Artery Embolization. AB - The aim of this study was to investigate the clinical efficacy of high-intensity focused ultrasound (HIFU) for the treatment of a cesarean scar pregnancy compared with uterine artery embolization (UAE) and intra-arterial methotrexate infusion combined with uterine curettage. In this retrospective cohort study, 31 patients were treated with HIFU (HIFU group), and 45 patients were treated with UAE (UAE group). We compared the treatment and recovery of the patients, including follow up. After UAE treatment, serum levels of the beta subunit of human chorionic gonadotropin declined significantly on the first day, and the residual lesions disappeared in 3-17 wk. One patient underwent hysterectomy; intrauterine adhesions were found by hysteroscopic examination after 6 mo in 2 patients, whose menstrual function did not return to normal. The remainder of the 42 patients recovered normal menstrual functioning during the 3- to 18-wk follow-up. In the patients who underwent HIFU treatment, serum beta-HCG levels did not decline rapidly; serum beta-HCG levels increased in many patients and then declined to normal steadily within 2-12 wk. Lesions detached in 3-14 wk in all patients, and menstrual functioning was recovered in 3-9 wk without uterine curettage. Compared with the UAE group, the HIFU group had less pain and fewer complications; the patients in the HIFU group were not hospitalized or anesthetized and had lower costs. HIFU is an efficient, tolerable and non-invasive treatment. PMID- 27979667 TI - In Vivo Validation of Volume Flow Measurements of Pulsatile Flow Using a Clinical Ultrasound System and Matrix Array Transducer. AB - The goal of this study was to evaluate the accuracy of a non-invasive C-plane Doppler estimation of pulsatile blood flow in the lower abdominal vessels of a porcine model. Doppler ultrasound measurements from a matrix array transducer system were compared with invasive volume flow measurements made on the same vessels with a surgically implanted ultrasonic transit-time flow probe. For volume flow rates ranging from 60 to 750 mL/min, agreement was very good, with a Pearson correlation coefficient of 0.97 (p < 0.0001) and a mean bias of -4.2%. The combination of 2-D matrix array technology and fast processing gives this Doppler method clinical potential, as many of the user- and system-dependent parameters of previous methods, including explicit vessel angle and diameter measurements, are eliminated. PMID- 27979668 TI - Time-Harmonic Elastography of the Liver is Sensitive to Intrahepatic Pressure Gradient and Liver Decompression after Transjugular Intrahepatic Portosystemic Shunt (TIPS) Implantation. AB - We investigated the correlation between hepatic venous pressure gradient (HVPG) and liver shear wave speed (SWS) measured by multi-frequency time-harmonic ultrasound elastography (THE) before and after transjugular intrahepatic portosystemic shunt (TIPS) implantation. Ten patients with ascites, cirrhotic liver disease and portal hypertension were prospectively examined with invasive HVPG measurement and THE before and after TIPS implantation. HVPG and SWS decreased after TIPS placement from 20.4 +/- 2.2 mmHg to 9.8 +/- 4.1 mmHg (mean +/- standard deviation) and from 3.87 +/- 0.54 m/s to 3.27 +/- 0.44 m/s. Mean reduction HVPG was -10.6 +/- 3.7 mmHg, p < 0.001; mean reduction SWS was -0.60 +/ 0.29 m/s, p < 0.001. A linear correlation was observed between HVPG and SWS (R = 0.59, p = 0.0061). THE-measured SWS is a first potential direct ultrasound marker for liver decompression following TIPS in ascites-associated cirrhotic liver disease and therefore might be suitable to non-invasively detect portal hypertension. PMID- 27979669 TI - Pulmonary infiltrate with characteristic "reversed halo" and "air crescent" signs. PMID- 27979670 TI - Trends in hospitalizations for community-acquired pneumonia in Spain: 2004 to 2013. AB - AIM: To describe trends in the incidence and outcomes of community-acquired pneumonia (CAP) hospitalizations in Spain (2004-2013). METHODS: We used national hospital discharge data to select all hospital admissions for CAP as primary diagnosis. We analyzed incidence, Charlson comorbidity index (CCI), diagnostic and therapeutic procedures, pathogens, length of hospital stay (LOHS), in hospital mortality (IHM) and readmission. RESULTS: We identified 959,465 admissions for CAP. Incidence rates of CAP increased significantly over time (from 142.4 in 2004 to 163.87 cases per 100,000 inhabitants in 2013). Time trend analyses showed significant increases in the number of comorbidities and the use of CAT of thorax, red cell transfusion, non-invasive mechanical ventilation and readmissions (all p values<0.05). S. pneumoniae was the most frequent causative agent, but its isolation decreased over time. Overall median of LOHS was 7days and it did not change significantly during the study period. Time trend analyses also showed significant decreases in mortality during admission for CAP. Factor associated with higher IHM included: older age, higher CCI, S. aureus isolated, use of red cell transfusion or mechanical ventilation and readmission. CONCLUSIONS: The incidence and mortality of CAP have changed in Spain from 2004 to 2013. Although there was an increased incidence of hospitalization for this disease over time, we saw a significant reduction in IHM. PMID- 27979671 TI - A young man with neck pain. PMID- 27979672 TI - [Neonatal expression of beta-thalassemia trait associated with hereditary spherocytosis in two monozygotic twins]. AB - The beta-thalassemia trait is a heterozygous beta-thalassemia characterized by a partial deficiency of the synthesis of beta-globin chains of hemoglobin. It is usually asymptomatic and the diagnosis is often made on the occasion of the completion of a systematic blood count or a family survey. Clinical expression during the neonatal period is impossible and its association with hereditary spherocytosis is common. We report two monozygotic twins who, on the 3rd day of life, presented intense jaundice, unconjugated bilirubin associated with anemia, without hepatosplenomegaly. Laboratory tests found nonimmune hemolytic anemia with microcytosis and hypochromia justifying iterative blood transfusions. The etiological investigation found heterozygous beta-thalassemia associated with hereditary spherocytosis. The family investigation and molecular analysis objectified the beta-thalassemic mutation IVS1nt110 (G->A) in the heterozygous state in the twins, the father, the mother, and in one of the two brothers. With any nonimmune hemolytic anemia in newborns, the etiological investigation should be systematic for early diagnosis and to plan appropriate treatment. PMID- 27979673 TI - Author's reply. PMID- 27979674 TI - A treatment strategy using subcutaneous fondaparinux followed by oral rivaroxaban is effective for treating acute venous thromboembolism. AB - BACKGROUND: The factor Xa inhibitors have been widely used for the treatment and prevention of venous thromboembolism (VTE). However, the efficacy of factor Xa inhibitors in Japanese patients with VTE has not been well examined. In this study, we investigated the effect of the sequential use of two factor Xa inhibitors in patients with acute VTE. METHODS: We conducted an observational study of 87 consecutive patients diagnosed with VTE. As an initial treatment, we administered subcutaneous fondaparinux to the patients for 7-10 days, and then switched to oral rivaroxaban. The symptoms and findings were assessed after the initial treatment and after using rivaroxaban for 7-14 days. We evaluated the deep vein thrombosis (DVT) in the legs using our own scoring system [quantitative ultrasound thrombosis (QUT) score]. RESULTS: Of the 87 patients, 33% had symptoms, half had pulmonary embolism (PE), and 95% had DVT of the legs. Out of the 87 patients, VTE worsened during the administration of fondaparinux in 4 patients. All of them had experienced malignancy, and died within 6 months. Of two patients developing bleeding, one patient required a transfusion. Eventually, this strategy was effective in 80 patients and had no change in one. The D-dimer level was significantly reduced by fondaparinux (17.8MUg/ml+/-16.0MUg/ml vs. 8.3MUg/ml+/-7.2MUg/ml, p<0.0001), followed by rivaroxaban (8.3MUg/ml+/-7.2MUg/ml vs. 5.5MUg/ml+/-4.9MUg/ml, p<0.0001). Similarly, the QUT score was improved by fondaparinux (4.7+/-2.6 vs. 2.5+/-2.5, p<0.0001), and further reduced by rivaroxaban (2.5+/-2.5 vs. 1.9+/-1.8, p<0.0001). CONCLUSIONS: A treatment strategy using subcutaneous fondaparinux followed by oral rivaroxaban is effective for treating acute VTE in Japanese patients. PMID- 27979675 TI - Temporal change of myocardial tissue character is associated with left ventricular reverse remodeling in patients with dilated cardiomyopathy: A cardiovascular magnetic resonance study. AB - BACKGROUND: Prognostic significance of temporal change in myocardial tissue characterization by cardiovascular magnetic resonance (CMR) has not been elucidated in patients with non-ischemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: Sixty-eight patients with newly-diagnosed DCM who underwent CMR including late gadolinium enhancement (LGE) both at baseline and during follow-up period were enrolled. LGE score was defined by a signal intensity of >=5 standard deviations above the remote reference myocardium mean. Left ventricular reverse remodeling (LVRR) defined as a LV ejection fraction increase of >=10% and a decrease in indexed LV end-diastolic diameter of >=10% compared to those at baseline was detected in 38% of the patients. There was no significant difference in LGE score between baseline and follow-up (5.8% vs. 7.3%; p=0.38). The change in LGE area (delta-LGE) was significantly lower in patients with LVRR than those without (-0.5%+/-3.4% vs. 3.0+/-7.4%; p=0.02). On the other hand, T2 ratio during the follow-up significantly reduced (1.95+/-0.48 vs. 1.67+/-0.56; p<0.01); however, there was no significant difference in the change in T2 ratio between patients with LVRR and those without (-0.29+/-0.73 vs. -0.27+/-0.66; p=0.88). Multivariate logistic analysis indicated that baseline LGE score [odds ratio; 0.78; 95% confidence interval (CI) 0.66 to 0.90; p<0.01] together with delta-LGE (odds ratio; 0.77; 95% CI 0.61 to 0.92; p=0.01) were independently associated with subsequent LVRR (p<0.01). CONCLUSIONS: The temporal change of LGE-CMR score during the clinical course was significantly correlated with following LVRR. PMID- 27979676 TI - Ebola virus derived G-quadruplexes: Thiazole orange interaction. AB - The Ebola and Marburg viruses are some of the deadliest viruses in the world. In this study a series of G-rich DNA sequences derived from these types of viruses which possess the potential to form G-quadruplex structures are analyzed. A set of DNA oligonucleotides derived from original viral isolates was used as a representative modeling sequence with which to demonstrate the influence of thiazole orange on circular dichroism (CD) spectral profiles. The results show the unique profile of the induced CD (ICD) signal in the visible region caused by interactions between the ligand and G-quadruplexes. This ligand was found to stabilize the G-quadruplex structure and can also induce topological changes and facilitate G-quadruplex multimerization. Thus, the ICD signatures can be used to determine whether specific unknown sequences can form G-quadruplex motifs. The viral sequences were analyzed using standard spectral and electrophoretic methods. In addition, the ability to target G-quadruplexes located in filoviruses offers researchers attractive therapeutic targets which would be of particular use in the development of novel antiviral therapies. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. PMID- 27979677 TI - Folding of guanine quadruplex molecules-funnel-like mechanism or kinetic partitioning? An overview from MD simulation studies. AB - BACKGROUND: Guanine quadruplexes (GQs) play vital roles in many cellular processes and are of much interest as drug targets. In contrast to the availability of many structural studies, there is still limited knowledge on GQ folding. SCOPE OF REVIEW: We review recent molecular dynamics (MD) simulation studies of the folding of GQs, with an emphasis paid to the human telomeric DNA GQ. We explain the basic principles and limitations of all types of MD methods used to study unfolding and folding in a way accessible to non-specialists. We discuss the potential role of G-hairpin, G-triplex and alternative GQ intermediates in the folding process. We argue that, in general, folding of GQs is fundamentally different from funneled folding of small fast-folding proteins, and can be best described by a kinetic partitioning (KP) mechanism. KP is a competition between at least two (but often many) well-separated and structurally different conformational ensembles. MAJOR CONCLUSIONS: The KP mechanism is the only plausible way to explain experiments reporting long time-scales of GQ folding and the existence of long-lived sub-states. A significant part of the natural partitioning of the free energy landscape of GQs comes from the ability of the GQ-forming sequences to populate a large number of syn-anti patterns in their G-tracts. The extreme complexity of the KP of GQs typically prevents an appropriate description of the folding landscape using just a few order parameters or collective variables. GENERAL SIGNIFICANCE: We reconcile available computational and experimental studies of GQ folding and formulate basic principles characterizing GQ folding landscapes. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. PMID- 27979678 TI - Mathematical model for path selection by ants between nest and food source. AB - Several models have been proposed to describe the behavior of ants when moving from nest to food sources. Most of these studies where based on numerical simulations with no mathematical justification. In this paper, we propose a mechanism for the formation of paths of minimal length between two points by a collection of individuals undergoing reinforced random walks taking into account not only the lengths of the paths but also the angles (connected to the preference of ants to move along straight lines). Our model involves reinforcement (pheromone accumulation), persistence (tendency to preferably follow straight directions in absence of any external effect) and takes into account the bifurcation angles of each edge (represented by a probability of willingness of choosing the path with the smallest angle). We describe analytically the results for 2 ants and different path lengths and numerical simulations for several ants. PMID- 27979679 TI - Preface. PMID- 27979680 TI - Integrating species composition and leaf nitrogen content to indicate effects of nitrogen deposition. AB - Nitrogen (N) deposition has been increasing globally and has arisen concerns of its impacts on terrestrial ecosystems. Ecological indicators play an important role in ecosystem monitoring, assessment and management in the context of an anthropogenic transformation of the global N cycle. By integrating species composition and leaf N stoichiometry, a new community N indicator was defined and validated in the understory plots of an N enrichment (as NH4NO3) experiment in an old-growth boreal forest in Northeast China. Three-year N additions showed no significant effect on the understory species richness, but an obvious shift in species composition occurred. The response of leaf N content to N additions was generally positive but varied by species. Overall, the community N indicator increased significantly with higher N addition level and soil available N content, being in the shape of a non-linear saturation response curve. The results suggest that the community N indicator could be an effective tool to indicate changes in ecosystem N availability. Critical values of the community N indicator for specific vegetation type could potentially provide useful information for nature conservation managers and policy makers. PMID- 27979682 TI - Evaluating spatial distribution and seasonal variation of phthalates using passive air sampling in southern India. AB - Usage of phthalates as plasticizers has resulted in worldwide occurrence and is becoming a serious concern to human health and environment. However, studies on phthalates in Indian atmosphere are lacking. Therefore, we studied the spatio temporal trends of six major phthalates in Tamil Nadu, southern India, using passive air samplers. Phthalates were ubiquitously detected in all the samples and the average total phthalates found in decreasing order is pre-monsoon (61 ng m-3) > summer (52 ng m-3) > monsoon (17 ng m-3). Largely used phthalates, dibutylphthalate (DBP) and diethylhexlphthalate (DEHP) were predominantly found in all the seasons with contribution of 11-31% and 59-68%, respectively. The highest total phthalates was observed in summer at an urban location (836 ng m 3). Furthermore, through principal component analysis, potential sources were identified as emissions from additives of plasticizers in the polymer industry and the productions of adhesives, building materials and vinyl flooring. Although inhalation exposure of infants was higher than other population segments (toddlers, children and adults), exposure levels were found to be safe for people belonging to all ages based on reference dose (RfD) and tolerable daily intake (TDI) values. This study first attempted to report seasonal trend based on atmospheric monitoring using passive air sampling technique and exposure risk together. PMID- 27979681 TI - Depth-resolved microbial community analyses in two contrasting soil cores contaminated by antimony and arsenic. AB - Investigation of microbial communities of soils contaminated by antimony (Sb) and arsenic (As) is necessary to obtain knowledge for their bioremediation. However, little is known about the depth profiles of microbial community composition and structure in Sb and As contaminated soils. Our previous studies have suggested that historical factors (i.e., soil and sediment) play important roles in governing microbial community structure and composition. Here, we selected two different types of soil (flooded paddy soil versus dry corn field soil) with co contamination of Sb and As to study interactions between these metalloids, geochemical parameters and the soil microbiota as well as microbial metabolism in response to Sb and As contamination. Comprehensive geochemical analyses and 16S rRNA amplicon sequencing were used to shed light on the interactions of the microbial communities with their environments. A wide diversity of taxonomical groups was present in both soil cores, and many were significantly correlated with geochemical parameters. Canonical correspondence analysis (CCA) and co occurrence networks further elucidated the impact of geochemical parameters (including Sb and As contamination fractions and sulfate, TOC, Eh, and pH) on vertical distribution of soil microbial communities. Metagenomes predicted from the 16S data using PICRUSt included arsenic metabolism genes such as arsenate reductase (ArsC), arsenite oxidase small subunit (AoxA and AoxB), and arsenite transporter (ArsA and ACR3). In addition, predicted abundances of arsenate reductase (ArsC) and arsenite oxidase (AoxA and AoxB) genes were significantly correlated with Sb contamination fractions, These results suggest potential As biogeochemical cycling in both soil cores and potentially dynamic Sb biogeochemical cycling as well. PMID- 27979683 TI - Nosocomial (Health Care-Associated) Legionnaire's Disease. AB - Nosocomial Legionnaire's disease is most frequently associated with presence of the organism in hospital water systems. Patients are often susceptible as a result of age, underlying comorbidities, or immunosuppression. Prevention focuses on reducing the reservoir within water systems and includes super heating, ultraviolent light, chlorination, silver-copper ionization, and distal filtration. This article reviews the epidemiology of health care-associated Legionnaire's disease, reviews characteristics of several health care-associated outbreaks, and discusses strategies to prevent health care-associated infection. PMID- 27979684 TI - Laboratory Tests for Legionnaire's Disease. AB - Legionella pneumophila is one of the more recently discovered bacterial pathogens of humans. The last 2 decades have seen tremendous progress in the evolution of diagnostic tests, for detection and characterization of this pathogen and for defining the host response to infection. This has generated several diagnostic tools that span the range from simple immunologic assays to modern genome sequencing. This review describes the state of affairs of this continuously evolving field regarding the diagnosis of Legionnaire's disease and covers detection, assessment of antibiotic susceptibility, and epidemiologic characterization of isolates of L pneumophila and other pathogenic species within the genus. PMID- 27979685 TI - Nervous System Abnormalities and Legionnaire's Disease. AB - Although patients with Legionnaire's disease frequently develop alterations of consciousness, this is no more frequent than in patients hospitalized with other, equally severe forms of bacterial pneumonia. Legionella meningitis occurs rarely, if ever. Patients with Legionnaire's are susceptible to critical illness polyneuropathy/myopathy, as are other critically ill patients. Legionnaire's patients may develop MRI hyperdensities in the splenium of the corpus callosum, as may other patients with severe infections. Patients with Legionnaire's may be at increased risk of, and rarely develop, immune-mediated multifocal brain (acute disseminated encephalomyelitis) or peripheral nerve disease (Guillain-Barre syndrome). PMID- 27979686 TI - Legionnaire's Disease and Immunosuppressive Drugs. AB - Immunosuppressive agents predispose patients to legionnaire's disease. Patients receiving tumor necrosis factor antagonists are generally not severely immunocompromised by the underlying disease. In patients with malignancy receiving immunosuppressive therapies, it is difficult to balance the underlying disease versus the therapy used. Transplant recipients are often on multiple drugs, including immunosuppressants. It seems that immunosuppressive drugs add to the risk for legionella infection. The index of suspicion should be high for legionella infection early during a compatible clinical syndrome. The control of Legionella species and prevention of transmission should be the foremost goal in protecting susceptible populations from Legionnaire's disease. PMID- 27979687 TI - Legionnaire's Disease Since Philadelphia: Lessons Learned and Continued Progress. AB - Legionnaire's disease has been recognized as a cause of severe community-acquired pneumonia (CAP). Legionnaire's disease has characteristic extrapulmonary findings that are the basis for a presumptive clinical diagnosis. The widespread use of Legionella culture, sputum DFA, serology, urinary antigen testing, and polymerase chain reaction have allowed earlier diagnosis of Legionnaire's disease. Excluding common source outbreaks, CAP caused by Legionnaire's disease is manifested as sporadic cases. In contrast, nosocomial Legionnaire's disease occurs in clusters or outbreaks from common Legionella species-contaminated water sources. Improved diagnostic tests have permitted accurate diagnosis. Bacterial coinfections with Legionnaire's disease are uncommon, but when present, are most often associated with bacteremia pneumococcal pneumonia. PMID- 27979688 TI - The use of the Core Outcome Measures Index (COMI) in patients undergoing total knee replacement. AB - BACKGROUND: The Core Outcome Measure Index (COMI) is a very short outcome instrument used in spine patients. The aim of this study was to examine the utility of a knee version of the COMI in patients undergoing total knee arthroplasty (TKA) by assessing the reproducibility, construct and discriminant validity, and responsiveness. METHODS: Preoperatively, 224 patients completed the Oxford Knee Score (OKS), EuroQoL (EQ-5D) and the COMI-Knee; 189 (84) % also completed the questionnaires at follow-up and 73 patients completed preoperatively the COMI-knee twice. RESULTS: The weighted kappa values for the COMI-knee single items ranged from 0.80 to 0.89 and the ICC for the COMI-knee (composite score), 0.86. The absolute SEM for COMI-knee was 0.4 points, i.e. four percent of the maximum value (10 points) and six percent of the average value (6.6 points). The Area Under the Curve derived from the Receiver Operating Characteristic method for the COMI-knee was 0.97 (95% CI, 0.93 to 0.99), with a cut-off value for indicating a "good" result of 2.3 (100% specificity, 87% sensitivity). Correlations between the COMI-knee and the OKS were -0.72 at baseline and -0.87 at six months. The correlations between the change scores for the COMI-knee and the change scores for the OKS and EQ5D index were 0.77 and 0.69, respectively. CONCLUSIONS: The measurement properties of the COMI-knee satisfy international quality criteria and hence support its use in assessing patients undergoing TKA. PMID- 27979689 TI - Effect of intraoral mechanical stress application on the expression of a force responsive prognostic marker associated with system disease progression. AB - OBJECTIVES: Malocclusion may be corrected nonsurgically by mechanical tooth movement. The plasma protein profiles of human subjects receiving the first phase of orthodontic treatment were examined to test the hypothesis that application of mechanical stresses to teeth induces systemic proteomic alterations. METHODS: Tandem mass tag-based liquid chromatography-mass spectrometry (LC-MS/MS) was used to examine systemic proteomic alterations in subjects undergoing controlled stress application (N=10) and in volunteers not receiving treatment (N=7) at 3 time intervals within 24h. Proteins differentially expressed by the tooth movement group were functionally analyzed with "Gene Ontology" (GO) and "Search Tool to Retrieve Interacting Genes/proteins" (STRING) softwares. Enzyme-Linked Immunosorbent Assay and Western-blot were used to validate the in vivo protein alterations. An in vitro model consisting of human periodontal ligament cells (hPDLCs) under compression was used to validate the force-responsive characteristics of galectin-3 binding protein (LGALS3BP). RESULTS: Sixteen out of the 294 proteins identified by LC-MS/MS were differentially expressed in the plasma of subjects receiving controlled mechanical stresses for moving teeth. Those proteins were clustered in biological processes related to acute inflammatory response and vesicle-related transportation. Serotransferrin, fibronectin and LGALS3BP were processed for confirmation in vivo; LGALS3BP was significantly increased in the tooth movement group. In vitro secretion of LGALS3BP in PDLCs was force-responsive. CONCLUSIONS: Regional application of mechanical stresses stimulates systemic proteomic changes. Because serum LGALS3BP is over-expressed in different systemic diseases, including cancer, further work is needed to examine how systemic up-regulation of LGALS3BP affects the progression of those diseases. PMID- 27979690 TI - MRI-guided breast vacuum biopsy: Localization of the lesion without contrast agent application using diffusion-weighted imaging. AB - OBJECTIVE: In magnetic resonance-guided breast vacuum biopsies, the contrast agent for targeting suspicious lesions can typically be applied only once during an intervention, due to the slow elimination of the gadolinium chelate from the extracellular fluid space. This study evaluated the feasibility of diffusion weighted imaging (DWI) for lesion targeting in vacuum assisted magnetic resonance imaging (MRI) biopsies. CONCLUSION: DWI may be used as an alternative to dynamic contrast-enhanced MRI with the advantage of reproducibility. However, the targeted lesion requires the characteristics of a mass-like lesion, substantial diffusion restriction, and a minimum size of approximately 1cm. PMID- 27979691 TI - Three new highly-oxygenated metabolites from the endophytic fungus Cytospora rhizophorae A761. AB - Cytosporaphenones A-C, one new polyhydric benzophenone and two new naphtopyrone derivatives, along with eight known ones, were isolated from Cytospora rhizophorae, an endophytic fungus from Morinda officinalis. Their structures were fully characterized by means of detailed spectroscopic analysis and X-ray single crystal diffraction. To our knowledge, the three new compounds were the most highly oxygenated metabolites of their families discovered in nature. Moreover, all of the compounds were evaluated for in vitro cytotoxic activities against MCF 7, NCI-H460, HepG-2 and SF-268 tumor cell lines, and the new compound 1 exhibited weak growth inhibitory activity against the tumor cell lines MCF-7 and HepG-2 with IC50 values of 70 and 60MUM, respectively. PMID- 27979692 TI - Therapeutic potential and limitations of cholinergic anti-inflammatory pathway in sepsis. AB - Sepsis is one of the main causes of mortality in hospitalized patients. Despite the recent technical advances and the development of novel generation of antibiotics, severe sepsis remains a major clinical and scientific challenge in modern medicine. Unsuccessful efforts have been dedicated to the search of therapeutic options to treat the deleterious inflammatory components of sepsis. Recent findings on neuronal networks controlling immunity raised expectations for novel therapeutic strategies to promote the regulation of sterile inflammation, such as autoimmune diseases. Interesting studies have dissected the anatomical constituents of the so-called "cholinergic anti-inflammatory pathway", suggesting that electrical vagus nerve stimulation and pharmacological activation of beta-2 adrenergic and alpha-7 nicotinic receptors could be alternative strategies for improving inflammatory conditions. However, the literature on infectious diseases, such as sepsis, is still controversial and, therefore, the real therapeutic potential of this neuroimmune pathway is not well defined. In this review, we will discuss the beneficial and detrimental effects of neural manipulation in sepsis, which depend on the multiple variables of the immune system and the nature of the infection. These observations suggest future critical studies to validate the clinical implications of vagal parasympathetic signaling in sepsis treatment. PMID- 27979693 TI - Event-related potentials and neural oscillations dissociate levels of cognitive control. AB - Recent models of human behavior suggest a hierarchical organization of cognitive control processes. These models assume that different sub-goals of cognitive control processes are nested in each other, such that higher-level sub-goals can only be accomplished when lower-level sub-goals have been realized. While the neuroanatomical localization of this organizational principle has already been successfully tested, the exact temporal nature remains to be explored. The present study applied event-related potentials (ERPs) and investigated neural oscillations during performance of three different nested cognitive control tasks. Results demonstrated a parametric modulation of the P300 component as well as beta-band (13-25Hz) oscillations as a function of different levels of cognitive control. Moreover, conditions requiring flexible updating of information exhibited similar alpha-band (8-13Hz) oscillations, which differed from the condition without flexible updating (low-level). These results suggest dissociable mechanisms of flexible information updating and complexity of cognitive control processes indexed by different oscillatory effects. PMID- 27979694 TI - Effect of rotation preference on spontaneous alternation behavior on Y maze and introduction of a new analytical method, entropy of spontaneous alternation. AB - Y maze has been used to test spatial working memory in rodents. To this end, the percentage of spontaneous alternation has been employed. Alternation indicates sequential entries into all three arms; e.g., when an animal visits all three arms clockwise or counterclockwise sequentially, alternation is achieved. Interestingly, animals have a tendency to rotate or turn to a preferred side. Thus, when an animal has a high rotation preference, this may influence their alternation behavior. Here, we have generated a new analytical method, termed entropy of spontaneous alternation, to offset the effect of rotation preference on Y maze. To validate the entropy of spontaneous alternation, we employed a free rotation test using a cylinder and a spatial working memory test on Y maze. We identified that mice showed 65.1% rotation preference on average. Importantly, the percentage of spontaneous alternation in the high preference group (more than 70% rotation to a preferred side) was significantly higher than that in the no preference group (<55%). In addition, there was a clear correlation between rotation preference on cylinder and turning preference on Y maze. On the other hand, this potential leverage effect that arose from rotation preference disappeared when the animal behavior on Y maze was analyzed with the entropy of spontaneous alternation. Further, entropy of spontaneous alternation significantly determined the loss of spatial working memory by scopolamine administration. Combined, these data indicate that the entropy of spontaneous alternation provides higher credibility when spatial working memory is evaluated using Y maze. PMID- 27979695 TI - Potential of marine natural products against drug-resistant fungal, viral, and parasitic infections. AB - Antibiotics have revolutionised medicine in many aspects, and their discovery is considered a turning point in human history. However, the most serious consequence of the use of antibiotics is the concomitant development of resistance against them. The marine environment has proven to be a very rich source of diverse natural products with significant antibacterial, antifungal, antiviral, antiparasitic, antitumour, anti-inflammatory, antioxidant, and immunomodulatory activities. Many marine natural products (MNPs)-for example, neoechinulin B-have been found to be promising drug candidates to alleviate the mortality and morbidity rates caused by drug-resistant infections, and several MNP-based anti-infectives have already entered phase 1, 2, and 3 clinical trials, with six approved for usage by the US Food and Drug Administration and one by the EU. In this Review, we discuss the diversity of marine natural products that have shown in-vivo efficacy or in-vitro potential against drug-resistant infections of fungal, viral, and parasitic origin, and describe their mechanism of action. We highlight the drug-like physicochemical properties of the reported natural products that have bioactivity against drug-resistant pathogens in order to assess their drug potential. Difficulty in isolation and purification procedures, toxicity associated with the active compound, ecological impacts on natural environment, and insufficient investments by pharmaceutical companies are some of the clear reasons behind market failures and a poor pipeline of MNPs available to date. However, the diverse abundance of natural products in the marine environment could serve as a ray of light for the therapy of drug-resistant infections. Development of resistance-resistant antibiotics could be achieved via the coordinated networking of clinicians, microbiologists, natural product chemists, and pharmacologists together with pharmaceutical venture capitalist companies. PMID- 27979697 TI - In ovo leptin administration modulates glucocorticoid receptor mRNA expression specifically in the hypothalamus of broiler chickens. AB - The glucocorticoid receptor (GR) is well documented to play a crucial role in the central control of energy homeostasis in mammals. However, the distribution and function of the GR in the chicken brain are less clear. Leptin is a key hormone regulating energy homeostasis in mammals, yet its action in the chicken is still under debate. In this study, the distribution of GR mRNA in the chicken brain and the effects of in ovo administration of leptin and its antagonist on early post hatch growth and GR mRNA expression in different hypothalamic nuclei were investigated via in situ hybridization (ISH) and quantitative PCR. GR mRNA was widely expressed in the chicken brain, mainly in the corpus striatum, nucleus rotundus, dorsolateral nucleus, nucleus ovoidalis, nucleus reticularis superior and the hippocampus (Hp) and in the preoptic area of the hypothalamus. High doses of leptin (5.0MUg) significantly promoted post-hatch growth, resulting in a significant high body weight increased by 24.64% at day (D) 21 of life. Meanwhile, hypothalamic expression of GR mRNA in the LL and HL groups was down regulated significantly by 7.02% and 13.65% respectively (P<0.05). ISH revealed region-specific changes: GR mRNA was found to be significantly decreased (P<0.05) in the paraventricular nucleus, periventricular nucleus and ventromedial nucleus but not in the Hp, infundibular nucleus or lateral hypothalamus of D21 broiler chickens. The leptin antagonist was able to reverse the effect of leptin on the growth rate and hypothalamic GR mRNA expression. These results provide evidence that in ovo administration of leptin influences early post-hatch growth and the hypothalamic expression of GR mRNA in broiler chickens. PMID- 27979696 TI - Acute exposure to the penconazole-containing fungicide Topas partially augments antioxidant potential in goldfish tissues. AB - Penconazole is a systemic fungicide commonly used in agriculture as the commercial preparation Topas. Although triazole fungicides are widely found in the aquatic environment, little is known about their acute toxicity on fish. In this study we assessed the effects of short-term exposure to Topas on some parameters of homeostasis of reactive oxygen species (ROS), such as the levels of markers of oxidative stress and parameters of the antioxidant defense system of goldfish (Carassius auratus L.). Gills appeared to be the main target organ of Topas toxicity, showing the greatest number of parameters affected. Gills of Topas-treated fish showed a higher content of low (L-SH) and high (H-SH) molecular mass thiols and higher activities of superoxide dismutase (SOD), catalase, glutathione reductase (GR), glutathione-S-transferase (GST), and glucose-6-phosphate dehydrogenase (G6PDH) as well as reduced carbonyl protein content (CP), as compared with those in the control group. In the liver, goldfish exposure to 15-25mgL-1 Topas resulted in a higher L-SH and H-SH content, but lower CP levels and activity of GST. In kidney, Topas exposure resulted in higher activities of glutathione peroxidase (GPx) and G6PDH, but lower L-SH content and activity of GST. The results of this study indicate that acute goldfish exposure to the triazole fungicide Topas increased efficiency of the antioxidant system in fish gills, liver, and kidney. This could indicate the development of low intensity oxidative stress which up-regulates defense mechanisms responsible for protection of goldfish against deleterious ROS effects. PMID- 27979698 TI - Social cognition and paranoia in forensic inpatients with schizophrenia: A cross sectional study. AB - BACKGROUND: People diagnosed with schizophrenia have difficulties in emotion recognition and theory of mind, and these may contribute to paranoia. The aim of this study was to determine whether this relationship is evident in patients residing in a secure forensic setting. METHOD: Twenty-seven male participants with a diagnosis of schizophrenia and a history of offending behaviour were assessed using The Awareness of Social Inference Test (TASIT), The Ambiguous Intentions Hostility Questionnaire (AIHQ) and The Green et al. Paranoid Thought Scales (G-PTS). Individuals were recruited from two medium secure and one high secure forensic hospital in Scotland. RESULTS: Correlation, logistic and multiple regression analyses did not find that emotion recognition and theory of mind were associated with indices of paranoid thinking. CONCLUSION: Social cognition did not appear to be related to indices of paranoia in this forensic sample. Although participants reported low levels of paranoia overall, the results are consistent with recent conclusions that theory of mind impairments are not specifically linked to paranoia in people diagnosed with schizophrenia. PMID- 27979699 TI - Childhood trauma and emotional processing circuits in schizophrenia: A functional connectivity study. AB - Childhood trauma strongly impacts emotional responses in schizophrenia. We have explored an association between early trauma and the amygdala functional connectivity using generalized psychophysiological interaction during an emotional task. Twenty-one schizophrenia patients and twenty-five controls were included. In schizophrenia patients, higher levels of sexual abuse and physical neglect during childhood were associated with decreased connectivity between the amygdala and the posterior cingulate/precuneus region. Additionally, patients showed decreased coupling between the amygdala and the posterior cingulate/precuneus region compared to controls. These findings suggest that early trauma could impact later connectivity in specific stress-related circuits affecting self-consciousness and social cognition in schizophrenia. PMID- 27979700 TI - Phenol-degrading anode biofilm with high coulombic efficiency in graphite electrodes microbial fuel cell. AB - A microbial fuel cell (MFC), with graphite electrodes as both the anode and cathode, was operated with a soil-free anaerobic consortium for phenol degradation. This phenol-degrading MFC showed high efficiency with a current density of 120 mA/m2 and a coulombic efficiency of 22.7%, despite the lack of a platinum catalyst cathode and inoculation of sediment/soil. Removal of planktonic bacteria by renewing the anaerobic medium did not decrease the performance, suggesting that the phenol-degrading MFC was not maintained by the planktonic bacteria but by the microorganisms in the anode biofilm. Cyclic voltammetry analysis of the anode biofilm showed distinct oxidation and reduction peaks. Analysis of the microbial community structure of the anode biofilm and the planktonic bacteria based on 16S rRNA gene sequences suggested that Geobacter sp. was the phenol degrader in the anode biofilm and was responsible for current generation. PMID- 27979701 TI - GPR40/FFAR1 deficient mice increase noradrenaline levels in the brain and exhibit abnormal behavior. AB - The free fatty acid receptor 1 (GPR40/FFAR1) is a G protein-coupled receptor, which is activated by long chain fatty acids. We have previously demonstrated that activation of brain GPR40/FFAR1 exerts an antinociceptive effect that is mediated by the modulation of the descending pain control system. However, it is unclear whether brain GPR40/FFAR1 contributes to emotional function. In this study, we investigated the involvement of GPR40/FFAR1 in emotional behavior using GPR40/FFAR1 deficient (knockout, KO) mice. The emotional behavior in wild and KO male mice was evaluated at 9-10 weeks of age by the elevated plus-maze test, open field test, social interaction test, and sucrose preference test. Brain monoamines levels were measured using LC-MS/MS. The elevated plus-maze test and open field tests revealed that the KO mice reduced anxiety-like behavior. There were no differences in locomotor activity or social behavior between the wild and KO mice. In the sucrose preference test, the KO mice showed reduction in sucrose preference and intake. The level of noradrenaline was higher in the hippocampus, medulla oblongata, hypothalamus and midbrain of KO mice. Therefore, these results suggest that brain GPR40/FFAR1 is associated with anxiety- and depression-related behavior regulated by the increment of noradrenaline in the brain. PMID- 27979703 TI - Object discrimination through active electrolocation: Shape recognition and the influence of electrical noise. AB - The weakly electric fish Gnathonemus petersii can recognise objects using active electrolocation. Here, we tested two aspects of object recognition; first whether shape recognition might be influenced by movement of the fish, and second whether object discrimination is affected by the presence of electrical noise from conspecifics. (i) Unlike other object features, such as size or volume, no parameter within a single electrical image has been found that encodes object shape. We investigated whether shape recognition might be facilitated by movement induced modulations (MIM) of the set of electrical images that are created as a fish swims past an object. Fish were trained to discriminate between pairs of objects that either created similar or dissimilar levels of MIM of the electrical images. As predicted, the fish were able to discriminate between objects up to a longer distance if there was a large difference in MIM between the objects than if there was a small difference. This supports an involvement of MIMs in shape recognition but the use of other cues cannot be excluded. (ii) Electrical noise might impair object recognition if the noise signals overlap with the EODs of an electrolocating fish. To avoid jamming, we predicted that fish might employ pulsing strategies to prevent overlaps. To investigate the influence of electrical noise on discrimination performance, two fish were tested either in the presence of a conspecific or of playback signals and the electric signals were recorded during the experiments. The fish were surprisingly immune to jamming by conspecifics: While the discrimination performance of one fish dropped to chance level when more than 22% of its EODs overlapped with the noise signals, the performance of the other fish was not impaired even when all its EODs overlapped. Neither of the fish changed their pulsing behaviour, suggesting that they did not use any kind of jamming avoidance strategy. PMID- 27979702 TI - Quercetin and baicalein suppress monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats. AB - Hepatic sinusoidal obstruction syndrome (SOS) is a rare liver disease with considerable mortality. This study is designed to observe the protection of quercetin and baicalein against monocrotaline (MCT)-induced SOS in rats and its engaged mechanism. Rats were pre-administrated with MCT (90mg/kg) to induce SOS, and 6, 30h later were orally given with quercetin and baicalein (40mg/kg) twice. Results of detecting rats with liver ascites, measuring serum transaminases, total bilirubin (TBil) and bile acids (TBA), analyzing blood cells, liver histological evaluation and scanning electron microscope observation all demonstrated the detoxification of quercetin and baicalein against MCT-induced SOS in rats. Quercetin and baicalein reduced the increased metalloproteinase-9 (MMP-9) expression, liver myeloperoxidase (MPO) activity, toll-like receptor (TLR)-2,3,6,9 expression and nuclear factor kappaB (NFkappaB) transcriptional activation induced by MCT. Quercetin and baicalein reduced MCT-induced nuclear translocation of early growth response1 (Egr1) and increased expression of Serpine1 and tissue factor (TF). Quercetin and baicalein reduced MCT-induced increased liver malondialdehyde (MDA) amount and enhanced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Quercetin and baicalein also abrogated MCT-induced activation of mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3K) signaling cascades. In conclusion, this study demonstrated the protection of quercetin and baicalein against MCT-induced SOS in rats, indicating the potential application of them for the treatment of SOS in clinic. Transcriptional factor NFkappaB, Egr1 and Nrf2 regulated inflammation, coagulation-fibrinolysis and antioxidant, and PI3K and MAPKs signaling cascades are all involved such protection. PMID- 27979704 TI - [Are the urinary dipsticks useful in urology?] PMID- 27979705 TI - Renal function and carotid atherosclerosis in adults with no known kidney disease. AB - BACKGROUND AND AIMS: A high prevalence of atherosclerotic lesions characterizes patients with chronic kidney disease, though there is little data on the relationship between kidney function and atherosclerotic changes in the healthy population or in people with no known renal impairment. The aim of our study was to analyze, in a comprehensive general population with no known kidney disease, the relationship between renal function and subclinical carotid atherosclerotic damage. METHODS AND RESULTS: A general real-life population of 611 participants (233 males and 378 females; age >=18 years) with no known kidney failure was selected for the study. The glomerular filtration rate (GFR) was estimated according to the CKD-EPI equation. Carotid intima-media thickness (c-IMT) and plaques were assessed by duplex Doppler ultrasonography of the carotid vessels. The main laboratory and metabolic parameters were evaluated in all participants. When we divided the overall study population into tertiles according to GFR values (I tertile <85; II tertile: 85-99; III tertile >99 ml/min/1.73 m2), the c IMT mean values and the prevalence of carotid plaques decreased with the increasing tertile of GFR. On univariate analysis, c-IMT was significantly correlated with eGFR (r = -0.33; p < 0.001), serum creatinine (r = 0.17; p < 0.001), and other variables such as age, systolic blood pressure, waist circumference, fasting or random glycemia, and glycated hemoglobin (HbA1c). On multiple regression analysis, serum creatinine was associated with c-IMT (beta = 0.069; p = 0.017), independent of other covariates. CONCLUSION: Our study seems to suggest the importance of early identification of people with near normal or mildly decreased renal function due to its association with carotid atherosclerosis. PMID- 27979706 TI - Energy expenditure estimates during school physical education: Potential vs. reality? AB - Schools are salient locations for addressing the high prevalence of overweight and obesity. Most US states require some physical education (PE) and the energy expended during PE has potential to positively affect energy balance. We previously used 2012 data to examine state policies for PE to calculate estimated student energy expenditure (EEE) under potential (i.e., recommendations followed) and existing conditions. Since then, data have been updated on both state policies and the conduct of PE. Based on updated data, we used PE frequency, duration, and intensity, student mass, and class size to calculate EEE for the delivery of PE under (a) national professional recommendations, (b) 2016 state policies, and (c) school-reported conditions. Although increased from four years ago, only 22 states currently have policies mandating specific PE minutes. EEE over 10years shows the enormous impact PE could have on energy balance. For the average recommended-size PE class, resultant annual EEE based on professional recommendations for min/week far exceeded those based on average state (n=22) policy for min/week by 44.5% for elementary, 62.7% for middle, and 59.5% for high schools. Since 2012 more states adopted policies for PE minutes than dropped them, however, EEE over 10years showed a net loss of 1200kcal/student. With no overall recent improvements in state PE policy and professional recommendations currently not being met, PE remains an underutilized public health resource for EEE. Strong policies, coupled with enhanced accountability of PE teachers and administrators, are needed to ensure PE exists in schools. PMID- 27979707 TI - Disrupting domain-domain interactions is indispensable for EngA-ribosome interactions. AB - EngA consists of two tandem GTPase-domains-GD1 and GD2-followed by a KH-domain. EngA was considered to be a 50S assembly factor since it was shown to bind 50S and its deletion leads to the accumulation of immature 45S ribosomal subunits. Subsequently, we demonstrated an additional ribosome bound state of EngA bound to 50S, 30S, and 70S. While the former (50S binding) is achieved upon GTP binding at both GD1 and GD2, the latter is formed upon GTP hydrolysis at GD1, which is believed to trigger a large conformational change in the protein. The present study brings out two key aspects of EngA regulation: First, that distinctly stabilized GD1-KH interfaces allows EngA to exist in different ribosome bound states, and second is the importance of these states to ribosome assembly. Our analyses suggest that distinct inter-domain (GD-KH) interfaces are stabilized by interactions arising from unique sets of motifs, conserved across EngA homologues, and seem to be mechanistically linked to GTP/GDP binding. By experimentally measuring binding affinities for several interface mutants, we show that disrupting the interface interactions is necessary to realize EngA ribosome binding. These findings are also supported by a recent cryo-EM structure of EngA bound to 50S, wherein the GD1-KH interface is completely disrupted leading to an 'extended' or 'open state' of the protein. Overall, it appears that the transition of EngA from a 'closed state' with GD1-KH forming a tight interface, to an 'open state' mediates interaction with ribosomal subunits. PMID- 27979708 TI - Allopregnanolone and its analog BR 297 rescue neuronal cells from oxidative stress-induced death through bioenergetic improvement. AB - Allopregnanolone (AP) is supposed to exert beneficial actions including anxiolysis, analgesia, neurogenesis and neuroprotection. However, although mitochondrial dysfunctions are evidenced in neurodegenerative diseases, AP actions against neurodegeneration-induced mitochondrial deficits have never been investigated. Also, the therapeutic exploitation of AP is limited by its difficulty to pass the liver and its rapid clearance after sulfation or glucuronidation of its 3-hydroxyl group. Therefore, the characterization of novel potent neuroprotective analogs of AP may be of great interest. Thus, we synthesized a set of AP analogs (ANS) and investigated their ability to counteract APP-overexpression-evoked bioenergetic deficits and to protect against oxidative stress-induced death of control and APP-transfected SH-SY5Y cells known as a reliable cellular model of Alzheimer's disease (AD). Especially, we examined whether ANS were more efficient than AP to reduce mitochondrial dysfunctions or bioenergetic decrease leading to neuronal cell death. Our results showed that the ANS BR 297 exhibits notable advantages over AP with regards to both protection of mitochondrial functions and reduction of oxidative stress. Indeed, under physiological conditions, BR 297 does not promote cell proliferation but efficiently ameliorates the bioenergetics by increasing cellular ATP level and mitochondrial respiration. Under oxidative stress situations, BR 297 treatment, which decreases ROS levels, improves mitochondrial respiration and cell survival, appears more potent than AP to protect control and APP-transfected cells against H2O2-induced death. Our findings lend further support to the neuroprotective effects of BR 297 emphasizing this analog as a promising therapeutic tool to counteract age- and AD-related bioenergetic deficits. PMID- 27979709 TI - The p7 viroporin of the hepatitis C virus contributes to liver inflammation by stimulating production of Interleukin-1beta. AB - Hepatitis C is one of the most widespread infectious diseases worldwide and hepatitis C virus (HCV)-induced chronic inflammation is highly associated with progredient liver damage. It was shown that HCV infection increases levels of pro inflammatory cytokines via activation of NOD-like receptor (NLRP3) inflammasomes, yet the underlying mechanism is still under question. We propose modulation of intracellular pH by p7, a 63 residue ion channel produced by the hepatitis C virus as a possible pathomechanism for hepatitis C-associated inflammation. Recombinant constructs corresponding to HCV genotypes 1-4 were expressed in HEK 293 and RAW 264.7 cells and changes of intracellular pH were monitored using pH sensitive fluorescent probes as well as production of inflammatory cytokines. Presence of p7 induced general loss of vesicular acidity as well as producing a significant increase in the levels of interleukin-1beta (IL-1beta). Effects showed a genotype-dependent pattern of IL-1beta production, in agreement with the pH-response profile of p7 channels corresponding to hepatitis C genotypes. Lowering the pH of the extracellular medium increased activity of p7 channels as well as production of IL-1beta for genotypes 1, 3, and 4, but less for genotype 2. Our data are in agreement with the hypothesis that p7 activity can trigger intracellular signaling cascades that are involved in HCV-associated cytopathy. PMID- 27979711 TI - Reliability of the American College of Surgeons Commission on Cancer's Quality of Care Measures for Hospital and Surgeon Profiling. AB - BACKGROUND: Efforts to improve healthcare quality involve profiling hospitals and providers. Whether cancer-specific measures can be used reliably for profiling purposes has not been reported. STUDY DESIGN: Hospitals and surgeons were profiled with 3 measures assessing the adequacy of lymphadenectomy for colon (ie at least 12 regional lymph nodes [12RLN] are removed and pathologically examined for resected colon cancer), gastric (ie at least 15 regional lymph nodes [G15RLN] are removed and pathologically examined for resected gastric cancer), and non small cell lung (ie at least 10 regional lymph nodes [10RLN] are removed and pathologically examined for American Joint Committee on Cancer stage IA, IB, IIA, and IIB resected non-small cell lung cancer) cancers using hierarchical models. National Cancer Data Base cases spanning 2010 to 2013 were included if they met measure eligibility. Reliability estimates for hospital and surgeon performance across cumulative years of data (2013, 2012 to 2013, 2011 to 2013, and 2010 to 2013) were calculated with and without risk adjustment. Surgeon caseload minimums were projected to achieve reliabilities of 0.40 and 0.70. RESULTS: Reliability estimates tended to increase with longer periods of data collection but at different rates, depending on measure, level of aggregation, and performance outlier status. Profiling hospitals using 12RLN with 2 years of data yielded a median reliability of 0.72 (interquartile range [IQR] 0.55 to 0.83); however, 4 years of data yielded a median reliability of only 0.31 (IQR 0.14 to 0.54) for surgeons. The G15RLN performance was poor overall; 10RLN had high reliability at both hospital (0.74; IQR 0.50 to 0.86) and surgeon (0.61; IQR 0.34 to 0.80) levels using 1 year of data, but the literature questions this measure's validity. Few surgeons could achieve appropriate levels of reliability regardless of increased data collection duration. CONCLUSIONS: Profiling hospitals based on measures such as these can achieve acceptable reliability in reasonable timeframes, but does not always. Either lower levels of reliability should be accepted to profile surgeons with these measures or longer timeframes should be used. PMID- 27979712 TI - Simultaneous screening and detection of pharmaceutical co-crystals by the one step DSC-FTIR microspectroscopic technique. AB - Various methods and analytical techniques for the preparation and identification of pharmaceutical co-crystals have been applied, but these operations require considerable time for the screening and preparation of co-crystals. In this review, a powerful method that combines Fourier-transform infrared (FTIR) microspectroscopy with thermal analysis is introduced. This unique one-step real time differential scanning calorimetry (DSC)-FTIR microspectroscopic approach has been successfully applied to simultaneously and directly screen and detect pharmaceutical co-crystal formation in systems such as indomethacin-saccharin, indomethacin-nicotinamide, carbamazepine-glutaric-acid, metaxalone-succinic-acid and piroxicam-saccharin. This powerful one-step DSC-FTIR combined technique provides an easy and direct method for one-step screening and qualitative detection of co-crystal formation in real time. PMID- 27979710 TI - Hotair facilitates hepatic stellate cells activation and fibrogenesis in the liver. AB - Long non-coding RNAs (lncRNAs) are increasingly recognized as major players in regulating various biological processes. LncRNA HOX transcript antisense RNA (Hotair) has been extensively studied in cancer. However, the role of Hotair in liver fibrosis remains unknown. Here we observed that Hotair expression was significantly increased in CCl4-induced mouse liver fibrosis models, human fibrotic livers and activated hepatic stellate cells (HSCs) by TGF-beta1 stimulation. Enforced expression of Hotair in LX-2 cells promoted cell proliferation and activation while inhibition of its expression had an opposite effect. Furthermore, we found that Hotair may act as an endogenous 'sponge' of miR-148b, which regulates expression of the DNMT1/MEG3/p53 pathways in HSCs. Intriguingly, Hotair enhanced polycomb repressive complex 2 (PRC2) occupancy and histone H3K27me3 repressive marks, specifically at the MEG3 promoter region. Finally, we found that Hotair forms an RNA/DNA hybrid and recruits PRC2 to MEG3 promoter. These data suggest that Hotair inhibition may represent a promising therapeutic option for suppressing liver fibrosis. PMID- 27979714 TI - Epicardial substrate ablation for Brugada syndrome. PMID- 27979715 TI - Redox Tuning in Photosystem II. AB - In photosynthesis, oxygen is liberated from water, not from CO2; however, this model has been silent on why photosynthesis requires bicarbonate. Rutherford and colleagues solve this problem elegantly: bicarbonate tunes water-oxidising photosystem II to make onward electron transfer efficient; an absence of bicarbonate retunes, redirects, and safely shuts down energy flow. PMID- 27979713 TI - The wavelength composition and temporal modulation of ambient lighting strongly affect refractive development in young tree shrews. AB - Shortly after birth, the eyes of most animals (including humans) are hyperopic because the short axial length places the retina in front of the focal plane. During postnatal development, an emmetropization mechanism uses cues related to refractive error to modulate the growth of the eye, moving the retina toward the focal plane. One possible cue may be longitudinal chromatic aberration (LCA), to signal if eyes are getting too long (long [red] wavelengths in better focus than short [blue]) or too short (short wavelengths in better focus). It could be difficult for the short-wavelength sensitive (SWS, "blue") cones, which are scarce and widely spaced across the retina, to detect and signal defocus of short wavelengths. We hypothesized that the SWS cone retinal pathway could instead utilize temporal (flicker) information. We thus tested if exposure solely to long wavelength light would cause developing eyes to slow their axial growth and remain refractively hyperopic, and if flickering short-wavelength light would cause eyes to accelerate their axial growth and become myopic. Four groups of infant northern tree shrews (Tupaia glis belangeri, dichromatic mammals closely related to primates) began 13 days of wavelength treatment starting at 11 days of visual experience (DVE). Ambient lighting was provided by an array of either long wavelength (red, 626 +/- 10 nm) or short-wavelength (blue, 464 +/- 10 nm) light emitting diodes placed atop the cage. The lights were either steady, or flickering in a pseudo-random step pattern. The approximate mean illuminance (in human lux) on the cage floor was red (steady, 527 lux; flickering, 329 lux), and blue (steady, 601 lux; flickering, 252 lux). Refractive state and ocular component dimensions were measured and compared with a group of age-matched normal animals (n = 15 for refraction (first and last days); 7 for ocular components) raised in broad spectrum white fluorescent colony lighting (100-300 lux). During the 13 day period, the refraction of the normal animals decreased from (mean +/- SEM) 5.8 +/- 0.7 diopters (D) to 1.5 +/- 0.2 D as their vitreous chamber depth increased from 2.77 +/- 0.01 mm to 2.80 +/- 0.03 mm. Animals exposed to red light (both steady and flickering) remained hyperopic throughout the treatment period so that the eyes at the end of wavelength treatment were significantly hyperopic (7.0 +/- 0.7 D, steady; 4.7 +/- 0.8 D, flickering) compared with the normal animals (p < 0.01). The vitreous chamber of the steady red group (2.65 +/- 0.03 mm) was significantly shorter than normal (p < 0.01). On average, steady blue light had little effect; the refractions paralleled the normal refractive decrease. In contrast, animals housed in flickering blue light increased the rate of refractive decrease so that the eyes became significantly myopic (-2.9 +/- 1.3 D) compared with the normal eyes and had longer vitreous chambers (2.93 +/- 0.04 mm). Upon return to colony lighting, refractions in all groups gradually returned toward emmetropia. These data are consistent both with the hypothesis that LCA can be an important visual cue for postnatal refractive development, and that short-wavelength temporal flicker provides an important cue for assessing and signaling defocus. PMID- 27979716 TI - Seed Coating: Science or Marketing Spin? AB - Seed coating is the practice of covering seeds with external materials to improve handling, protection, and, to a lesser extent, germination enhancement and plant establishment. With an annual value exceeding US$1 billion dollars, this technology is mostly the preserve of the private research sector, with few links to the scientific community. Here, we analyse the science and industry of seed coating and its contribution to seed establishment and plant performance. We posit that a closer collaboration between academia and industry is critical to realising the potential of seed coating both as a tool for enhancing plant establishment in the face of the challenges posed to agricultural systems and to propel the multibillion-dollar global push for ecological restoration of degraded ecosystems. PMID- 27979718 TI - Neonatal rotenone lesions cause onset of hyperactivity during juvenile and adulthood in the rat. AB - Attention deficit hyperactivity disorder (ADHD) is characterized by behavioral and cognitive symptoms. Longitudinal studies demonstrated that the symptoms remains clinically significant for the majority of ADHD children into adulthood. Furthermore, a population-based birth cohort provided the initial evidence of adult ADHD that lacks a history of childhood ADHD. We previously demonstrated that neonatal exposure to bisphenol A, an environmental chemical caused hyperactivity in the juvenile. Here, we extend to examine other chemical such as rotenone, a dopaminergic toxins. Oral administration of rotenone (3mg/kg) into 5 day-old male Wistar rats significantly caused hyperactivity at adulthood (8~11 weeks old; p<0.05). It was about 1.3~1.4-fold more active in the nocturnal phase after administration of rotenone than control rats. Higher dose (16mg/kg) or repeated lower dose of rotenone (1mg/kg/day for 4days) caused hyperactivity in the juvenile. Furthermore, DNA array analyses showed that neonatal exposure to rotenone altered the levels of gene expression of several molecules related to apoptosis/cell cycle, ATPase, skeletal molecule, and glioma. Bivariate normal distribution analysis indicates no correlation in gene expression between a hyperactivity disorder model and a Parkinson's disease model by rotenone. Thus, we demonstrate a rotenone models of ADHD whose onset varies during juvenile and adulthood. PMID- 27979717 TI - Perioperative Triplet Chemotherapy and Cetuximab in Patients With RAS Wild Type High Recurrence Risk or Borderline Resectable Colorectal Cancer Liver Metastases. AB - BACKGROUND: For borderline resectable colorectal cancer liver metastases (CLM), systemic treatment can help to achieve R0 resection and reduce the risk of relapse. We assessed the role of perioperative triplet chemotherapy in combination with cetuximab in patients with RAS wild type high recurrence risk and/or borderline resectable CLM. PATIENTS AND METHODS: This was a monocenter, open-label phase II study. Borderline resectability was defined technically as tumor involvement of >1 hepatic vein, or >4 hepatic segments, need for 2-stage hepatectomy or radiofrequency ablation, and/or biologically (high risk): >=4 metastatic nodules, or synchronous metastases. Patients were treated with 4 pre- and postoperative cycles of biweekly COI-E (cetuximab 500 mg/m2 and irinotecan 180 mg/m2 on day 1, oxaliplatin 85 mg/m2 on day 2, and capecitabine 1000 mg/m2 twice per day on days 2-6). The primary end point was overall response rate. RESULTS: Forty patients were enrolled. Nine patients with KRAS mutation were excluded after amendment in 2010. In an extended RAS test we did not find additional RAS mutations. The final population was comprised of 31 patients with RAS wild type CLM (technically borderline resectable 39%; synchronous 84%; >=4 metastatic nodules 29%). The overall response, R0 resection, and pathological response rates were 87%, 84%, and 33%, respectively. At a median follow-up of 4 years, median progression-free survival and overall survival were 17.8 and 62.5 months, respectively. Treatment toxicity was relevant but did not jeopardize the surgical plan. CONCLUSION: The COI-E regimen was associated with high response and R0 resection rates in patients with RAS wild type CLM with borderline resectability and/or high-risk features. PMID- 27979719 TI - Admission to acute mental health services after contact with crisis resolution and home treatment teams: an investigation in two large mental health-care providers. AB - BACKGROUND: Crisis resolution and home treatment teams (CRTs) offer an alternative to hospital admission for patients undergoing mental health crises in the UK. Few studies have been done to examine predictors of relapse and readmission after contact with CRTs. METHODS: We used the Clinical Record Interactive Search to identify all patients receiving care from CRTs in two National Health Service (NHS) mental health trusts in London: Camden and Islington NHS Foundation Trust and South London and Maudsley NHS Foundation Trust. We used Cox regression models to examine rates and predictors of admission to acute mental health services within 1 year of contact with CRTs. Sex, age, ethnicity, marital status, social deprivation, severity of psychopathology, duration of index CRT episode, first contact with services, and diagnosis were extracted and examined as predictors of admission. FINDINGS: Between Jan 1, 2008, and Aug 31, 2014, 17 666 patients were treated by CRTs-8759 patients in the Camden and Islington trust and 8907 patients in the South London and Maudsley trust. 53.9 patients per 100 person-years (95% CI 52.1-55.8) in Camden and Islington and 51.3 patients per 100 person-years (95% CI 49.6-53.1) in South London and Maudsley were admitted to acute services within 1 year of seeing the CRT. In both cohorts, non-affective psychotic disorders (adjusted hazard ratio [HR] 1.25, 95% CI 1.09-1.44 in Camden and Islington; 1.27, 1.17-1.38 in South London and Maudsley) and age older than 65 years (1.18, 1.01-1.37 in Camden and Islington; 1.32, 1.12-1.56 in South London and Maudsley) were associated with increased risk of admission, whereas first contact with services (0.57, 0.52-0.62 in Camden and Islington; 0.69, 0.63-0.75 in South London and Maudsley), anxiety disorders (0.81, 0.69-0.96 in Camden and Islington; 0.77, 0.67-0.87 in South London and Maudsley), and longer index CRT episodes (adjusted HR per day 0.996, 0.994-0.998 in Camden and Islington; 0.989, 0.987-0.991 in South London and Maudsley) were associated with reduced risk of admission. INTERPRETATION: Past use of mental health services and a diagnosis of non-affective psychosis, which are markers of severity of mental illness, and older age, which is a marker of chronicity, are all risk factors for future relapse after interactions with CRTs. These findings might help clinicians and policy makers to offer more targeted and cost-effective services to reduce relapse rates. FUNDING: None. PMID- 27979720 TI - Neurodevelopmental disorders. AB - Neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder, although most commonly considered in childhood, can be lifelong conditions. In this Personal View that is shaped by clinical experience and research, we adopt a conceptual approach. First, we discuss what disorders are neurodevelopmental and why such a grouping is useful. We conclude that both distinction and grouping are helpful and that it is important to take into account the strong overlap across neurodevelopmental disorders. Then we highlight some challenges in bridging research and clinical practice. We discuss the complexity of clinical phenotypes and the importance of the social context. We also argue the importance of viewing neurodevelopmental disorders as traits but highlight that this is not the only approach to use. Finally, we consider developmental change across the life-span. Overall, we argue strongly for a flexible approach in clinical practice that takes into consideration the high level of heterogeneity and overlap in neurodevelopmental disorders and for research to link more closely to what is observed in real-life practice. PMID- 27979721 TI - What is good crisis care? PMID- 27979722 TI - Apomorphine - pharmacological properties and clinical trials in Parkinson's disease. AB - Apomorphine is often considered an archetypal dopamine agonist used in the treatment of Parkinson's disease (PD). However, it can be clearly differentiated from most other commonly used dopamine agonists on the basis of its pharmacology and on its unique clinical profile. Like levodopa and dopamine, apomorphine acts as a potent, direct and broad spectrum dopamine agonist activating all dopamine receptor subtypes. It also has affinity for serotonin receptors, and alpha adrenergic receptors. Apomorphine is usually titrated to a dose that provides an equivalent antiparkinsonian response to that provided by levodopa, and its subcutaneous delivery allows a rapid onset of action, usually within 7-10 min. The mode of apomorphine delivery impacts on its clinical profile so as to provide two very different approaches to therapy in PD. When administered as an acute subcutaneous injection, it induces reliable and rapid relief from OFF periods underscoring its utility as a rescue medication. When given as a subcutaneous infusion, it significantly improves overall daily OFF time and there is also evidence to suggest that, in those patients who replace most or all of their oral drugs with apomorphine infusion, dyskinesia may also improve. In this paper, we review the rich pharmacology of apomorphine and review its efficacy in PD based on data from clinical trials. PMID- 27979723 TI - Pleural effusions in non-transplanted cystic fibrosis patients. AB - BACKGROUND: Pleural effusions are considered rare in cystic fibrosis (CF) patients. There is a paucity of available information in the literature concerning the nature and significance of pleural effusions in non-transplanted CF patients. METHODS: We conducted a multicenter retrospective evaluation of non transplanted adult CF patients. Given the small sample size, only descriptive statistics were performed. RESULTS: A total of 17 CF patients with pleural effusion were identified, of whom 9 patients underwent thoracentesis. The crude incidence of pleural effusion was 43 per 10,000 person-years in hospitalized CF patients at large CF centers. All sampled effusions were inflammatory in nature. All samples submitted for culture grew at least one organism. CONCLUSION: Pleural effusions are rare in adult non-transplanted CF patients. These fluid collections appear to be quite inflammatory with a higher rate of empyema than in the general population. PMID- 27979724 TI - A Peer-Reviewed Instructional Video is as Effective as a Standard Recorded Didactic Lecture in Medical Trainees Performing Chest Tube Insertion: A Randomized Control Trial. AB - OBJECTIVE: Online medical education resources are becoming an increasingly used modality and many studies have demonstrated their efficacy in procedural instruction. This study sought to determine whether a standardized online procedural video is as effective as a standard recorded didactic teaching session for chest tube insertion. DESIGN: A randomized control trial was conducted. Participants were taught how to insert a chest tube with either a recorded didactic teaching session, or a New England Journal of Medicine (NEJM) video. Participants filled out a questionnaire before and after performing the procedure on a cadaver, which was filmed and assessed by 2 blinded evaluators using a standardized tool. SETTING: Western University, London, Ontario. Level of clinical care: institutional. PARTICIPANTS: A total of 30 fourth-year medical students from 2 graduating classes at the Schulich School of Medicine & Dentistry were screened for eligibility. Two students did not complete the study and were excluded. There were 13 students in the NEJM group, and 15 students in the didactic group. RESULTS: The NEJM group's average score was 45.2% (+/-9.56) on the prequestionnaire, 67.7% (+/-12.9) for the procedure, and 60.1% (+/-7.65) on the postquestionnaire. The didactic group's average score was 42.8% (+/-10.9) on the prequestionnaire, 73.7% (+/-9.90) for the procedure, and 46.5% (+/-7.46) on the postquestionnaire. There was no difference between the groups on the prequestionnaire (Delta + 2.4%; 95% CI: -5.16 to 9.99), or the procedure (Delta 6.0%; 95% CI: -14.6 to 2.65). The NEJM group had better scores on the postquestionnaire (Delta + 11.15%; 95% CI: 3.74-18.6). CONCLUSIONS: The NEJM video was as effective as video-recorded didactic training for teaching the knowledge and technical skills essential for chest tube insertion. Participants expressed high satisfaction with this modality. It may prove to be a helpful adjunct to standard instruction on the topic. PMID- 27979725 TI - Response to Asgari. PMID- 27979726 TI - Physiochemical and biological characterization of novel exopolysaccharide produced by Bacillus tequilensis FR9 isolated from chicken. AB - Hetero-exopolysaccharide secreted by Bacillus tequilensis FR9 (BtqEPS), was produced and fractioned on DEAE-Sepharose and phenyl sepharose CL-6B column. HPLC analysis revealed the existence of five monosaccharides including glucose, galactose, mannose, arabinose and xylose. FT-IR spectroscopy confirmed the presence of carboxyl and hydroxyl groups. 1H NMR and 13C NMR spectra analysis showed the presence of alpha and beta-d-(+)-glucose residues and glycosidic linkages. The fibrous, porous nature and elemental composition (C, O, N, Cl, Na, P, S) of BtqEPS was inferred from SEM and EDX analysis. AFM proved that the micro structure of BtqEPS is compact and rough. XRD analysis confirmed the amorphous nature of BtqEPS with 15.6% crystallinity index. TGA curve indicated the degradation temperature (Td) of 239.72 degrees C. Furthermore, BtqEPS exhibited antioxidant effects by scavenging reactive oxygen species (ROS) and demonstrated strong reducing power. All the above findings on BtqEPS paves way to find novel insights of its potential applications in industries. PMID- 27979727 TI - Effects of heat pretreatment of starch on graft copolymerization reaction and performance of resulting starch-based wood adhesive. AB - In this study, effects of starch heat pretreatment at 70, 80 and 90 degrees C on graft copolymerization reaction with vinyl acetate (VAc) and the performance of the resulting starch-based wood adhesive (SWA) were investigated. It was shown that SWA pretreated at 90 degrees C achieved the best performance. At this temperature, the bonding capacity improved by 17.84% compared to the adhesive synthesized without heat pretreatment and the viscosity increased by 18.16% after 7 free-thaw cycles, much better than other samples. Scanning electron microscopy (SEM) and polarizing microscopy demonstrated that structures of starch granules were fully damaged after heat pretreatment at 90 degrees C. The reaction took place not only on the surface of starch granules, but also internally, leading to improvement in the grafting amounts and grafting efficiency by 42.86% and 39.03%, respectively. This was further confirmed by Fourier transform infrared spectroscopy (FT-IR), Confocal Raman microscopy (CRM) and X-ray photoelectron spectroscopy (XPS), which also showed better reaction homogeneity both between different starch granules and from granule surface to its internal structure. PMID- 27979728 TI - Temsirolimus induced structural transition of cancerous renal cystatin to normal form in rats: In vitro mechanistic approach underlying renal cancer prevention. AB - Globally, renal cell carcinomas (RCCs) represent a major portion of patients suffering from cancer. Temsirolimus is an anti-renal cancer drug that has already been approved in poor-risk metastatic RCC (mRCC) patients. In our present study, we have evaluated the in vitro effect of varying concentrations of temsirolimus on cancerous rat kidney cystatin; renal cancer was induced in rats making use of dimethylnitrosamine (DMN). It has already been reported that cancerous rat kidney cystatin performs its activity in an efficacious manner as compared to normal rat kidney cystatin, so here an attempt was made to see the effect of temsirolimus on this increased activity of cystatin in renal cancers. Anti-papain activity assay was utilized to see this effect and it was found that temsirolimus reduces the increased activity of cancerous rat kidney cystatin similar to that of normal rat kidney cystatin. Further, to have an insight into temsirolimus induced structural alterations in cancerous rat kidney cystatin; various spectroscopic assays viz. UV, Fluorescence, Circular dichroism (CD) and FTIR spectroscopy were employed. UV and Fluorescence spectroscopy shows cancerous rat kidney cystatin transformation to normal form in the presence of temsirolimus. FTIR and CD spectroscopy confirmed the complete structural reversion of cancerous rat kidney cystatin to normal form in the presence of 40MUM temsirolimus. Thus, it can said that temsirolimus causes renal cystatin to revert to normal form; the increased activity of renal cystatin observed in incidences of renal cancer is restored back to normal thereby halting the progression of renal cancer. PMID- 27979729 TI - Construction and amperometric biosensing performance of a novel platform containing carbon nanotubes-zinc phthalocyanine and a conducting polymer. AB - A novel glucose oxidase (GOx) based amperometric biosensor utilizing a conducting polymer (CP), multi walled carbon nanotubes (MWCNTs) and a novel water soluble zinc phthalocyanine (ZnPc) was constructed. For this purpose, a novel ZnPc was synthesized to examine the role of being a part of support material for enzyme deposition. High water solubility was achieved with the introduction of tetra quaternized imidazolyl moieties at the peripheral positions of phthalocyanine. In order to fabricate the proposed biosensor, a graphite electrode was firstly modified with poly[9,9-di-(2-ethylhexyl)- fluorenyl-2,7-diyl] end capped with N,N Bis(4- methylphenyl)-4-aniline (PFLA) and MWCNTs. Then, GOx was co-immobilized with ZnPc onto the modified surface. To the best our knowledge, a sensor design which combines conjugated polymer/MWCNTs/ZnPc was attempted for the first time and this approach resulted in improved biosensor characteristics. The constructed biosensor showed a linear response for glucose between 0.025-1.0mM with a detection limit of 0.018mM. KMapp and sensitivity values were calculated as 0.53mM and 82.18MUAmm-1cm-2, respectively. Moreover, scanning electron microscopy (SEM) and cyclic voltammetry (CV) techniques were used to investigate the surface modifications. Finally, fabricated biosensor was tested on beverages for glucose detection successfully. PMID- 27979730 TI - Differential basal and exercise-induced IGF-I system responses to resistance vs. calisthenic-based military readiness training programs. AB - OBJECTIVE: The purpose of this study was to: 1) evaluate differential responses of the IGF-I system to either a calisthenic- or resistance exercise-based program and 2) determine if this chronic training altered the IGF-I system during an acute resistance exercise protocol. DESIGN: Thirty-two volunteers were randomly assigned into a resistance exercise-based training (RT) group (n=15, 27+/-5y, 174+/-6cm, 81+/-12kg) or a calisthenic-based training group (CT) (n=17, 29+/-5y, 179+/-8cm, 85+/-10kg) and all underwent 8weeks of exercise training (1.5h/d, 5d/wk). Basal blood was sampled pre- (Week 0), mid- (Week 4) and post-training (Week 8) and assayed for IGF-I system analytes. An acute resistance exercise protocol (AREP) was conducted preand post-training consisting of 6 sets of 10 repetitions in the squat with two minutes of rest in between sets and the IGF-I system analytes measured. A repeated measures ANOVA (p<=0.05) was used for statistical analysis. RESULTS: No interaction or within-subject effects were observed for basal total IGF-I, free IGF-I, or IGFBP-1. IGFBP-2 (pre; 578.6+/ 295.7post-training; 14.3+/-1.9MUg/mL; p=0.01). An interaction was observed for the RT group as IGFBP-3 increased from pre to mid (3462.4+/-216.4 vs. 3962.2+/ 227.9ng/mL), but was not significant at the post-training time point (3770.3+/ 228.7ng/mL). AREP caused all analytes except free IGF-I (40% decrease) to increase (17-27%; p=0.001) during exercise, returning to baseline concentration into recovery. CONCLUSION: Post-training, bioavailable IGF-I recovered more rapidly post-exercise. 8wks of chronic physical training resulted in increased basal IGFBP-2 and IGFBP-3, decreased ALS, increased pre-AREP free IGF-I and a more rapid free IGF-I recovery post-AREP. While total IGF-I was insensitive to chronic physical training, changes were observed with circulating IGFBPs and bioavailable IGF-I. To glean the most robust information on the effects of exercise training, studies must move beyond relying solely on total IGF-I measures and should consider IGFBPs and bioavailable IGF-I as these components of the circulating IGF-I system are essential determinants of IGF-I physiological action. PMID- 27979732 TI - Genetic-based Risk Assessment for Hepatocellular Carcinoma in Patients with Hepatitis C: Where Do We Stand? PMID- 27979731 TI - Nucleoporin Nup358 facilitates nuclear import of Methoprene-tolerant (Met) in an importin beta- and Hsp83-dependent manner. AB - The bHLH-PAS transcription factor, Methoprene-tolerant (Met)1, functions as a juvenile hormone (JH) receptor and transduces JH signals by directly binding to E box like motifs in the regulatory regions of JH response genes. Nuclear localization of Met is crucial for its transcriptional activity. Our previous studies have shown that the chaperone protein Hsp83 facilitates JH-induced Met nuclear import in Drosophila melanogaster. However, the exact molecular mechanisms of Met nuclear transport are not fully elucidated. Using DNA affinity chromatography, we have previously detected binding of the nucleoporin Nup358, in the presence of JH, to the JH response region (JHRR) sequences isolated from the Kruppel-homolog 1 (Kr-h1) promoter. Here, we have demonstrated that Nup358 regulates JH-Hsp83-induced Met nuclear localization. RNAi-mediated knockdown of Nup358 expression in Drosophila fat body perturbs Met nuclear transport during the 3 h after initiation of wandering, when the JH titer is high. The accompanying reduced expression of the transport receptor importin beta in Nup358 RNAi flies could be one of the reasons accounting for Met mislocalization. Furthermore, a tetratricopeptide repeat (TPR) domain at the N-terminal end of Nup358 interacts with Hsp83 and is indispensable for Met nuclear localization. Overexpression of the TPR domain in Drosophila fat body prevents Met nuclear localization resulting in a decrease in JHRR-driven reporter activity and Kr-h1 expression. These data show that Nup358 facilitates JH-induced Met nuclear transport in a manner dependent on importin beta and Hsp83. PMID- 27979734 TI - Tobacco harm reduction revisited: back to the future. PMID- 27979733 TI - Preoperative Metabolic Syndrome Is Predictive of Significant Gastric Cancer Mortality after Gastrectomy: The Fujian Prospective Investigation of Cancer (FIESTA) Study. AB - Metabolic syndrome (MetS) has been shown to be associated with an increased risk of gastric cancer. However, the impact of MetS on gastric cancer mortality remains largely unknown. Here, we prospectively examined the prediction of preoperative MetS for gastric cancer mortality by analyzing a subset of data from the ongoing Fujian prospective investigation of cancer (FIESTA) study. This study was conducted among 3012 patients with gastric cancer who received radical gastrectomy between 2000 and 2010. The latest follow-up was completed in 2015. Blood/tissue specimens, demographic and clinicopathologic characteristics were collected at baseline. During 15-year follow-up, 1331 of 3012 patients died of gastric cancer. The median survival time (MST) of patients with MetS was 31.3months, which was significantly shorter than that of MetS-free patients (157.1months). The coexistence of MetS before surgery was associated with a 2.3 fold increased risk for gastric cancer mortality (P<0.001). The multivariate adjusted hazard ratios (HRs) were increased with invasion depth T1/T2 (HR=2.78, P<0.001), regional lymph node metastasis N0 (HR=2.65, P<0.001), positive distant metastasis (HR=2.53, P<0.001), TNM stage I/II (HR=3.00, P<0.001), intestinal type (HR=2.96, P<0.001), negative tumor embolus (HR=2.34, P<0.001), and tumor size <=4.5cm (HR=2.49, P<0.001). Further survival tree analysis confirmed the top splitting role of TNM stage, followed by MetS or hyperglycemia with remarkable discrimination ability. In this large cohort study, preoperative MetS, especially hyperglycemia, was predictive of significant gastric cancer mortality in patients with radical gastrectomy, especially for early stage of gastric cancer. PMID- 27979735 TI - Molecular epidemiology of Corynebacterium pseudotuberculosis isolated from horses in California. AB - Corynebacterium pseudotuberculosis biovar Equi is an important pathogen of horses. It is increasing in frequency in the United States, and is responsible for various clinical forms of infection, including external abscesses, internal abscesses of the abdominal or thoracic cavities, and ulcerative lymphangitis. The host/pathogen factors dictating the form or severity of infection are currently unknown. Our recent investigations have shown that genotyping C. pseudotuberculosis isolates using enterobacterial repetitive intergenic consensus (ERIC)-PCR is useful for understanding the evolutionary genetics of the species as well for molecular epidemiology studies. The aims of the present study were to assess (i) the genetic diversity of C. pseudotuberculosis strains isolated from horses in California, United States and (ii) the epidemiologic relationships among isolates. One hundred and seven C. pseudotuberculosis biovar Equi isolates from ninety-five horses, and two C. pseudotuberculosis biovar Ovis strains, C. pseudotuberculosis ATCC 19410T type strain and C. pseudotuberculosis 1002 vaccine strain, were fingerprinted using the ERIC 1+2-PCR. C. pseudotuberculosis isolated from horses showed a high genetic diversity, clustering in twenty-seven genotypes with a diversity index of 0.91. Minimal spanning tree showed four major clonal complexes with a pattern of temporal clustering. Strains isolated from the same horse showed identical ERIC 1+2-PCR genotype, with the exception of two strains isolated from the same animal that showed distinct genotypes, suggesting a co infection. We found no strong genetic signals related to clinical form (including internal versus external infections). However, temporal clustering of genotypes was observed. PMID- 27979736 TI - The expanding horizon of MicroRNAs in cellular reprogramming. AB - Research over the last few years in cellular reprogramming has enlightened the magical potential of microRNAs (miRNAs) in changing the cell fate from somatic to pluripotent. Recent investigations on exploring the role(s) of miRNAs in somatic cell reprogramming revealed that they target a wide range of molecules and refine their protein output. This leads to fine tuning of distinct cellular processes including cell cycle, signalling pathways, transcriptional activation/silencing and epigenetic modelling. The concerted actions of miRNA on different pathways simultaneously strengthen the transition from a differentiated to de differentiated state. Despite the well characterized transcriptional and epigenetic machinery underlying somatic cell reprogramming, the molecular circuitry for miRNA mediated cellular reprogramming is rather fragmented. This review summarizes recent findings addressing the role of miRNAs in inducing or suppressing reprogramming thus uncovering novel potentials of miRNAs as regulators of induced pluripotency maintenance, establishment and associated signalling pathways. Our bioinformatic analysis sheds light on various unexplored biological processes and pathways associated with reprogramming inducing miRNAs, thus helps in identifying roadblocks to full reprogramming. Specifically, the biological significance of highly conserved and most studied miRNA cluster, i.e. miR-302-367, in reprogramming is also highlighted. Further, roles of miRNAs in the differentiation of neurons from iPSCs are discussed. A recent approach of direct conversion or transdifferentiation of differentiated cells into neurons by miRNAs is also elaborated. This approach is now widely gaining impetus for the generation of neurological patient's brain cells directly from his/her somatic cells in an efficient and safe manner. Thus, decoding the intricate circuitry between miRNAs and other gene regulatory networks will not only uncover novel pathways in the direct reprogramming of somatic cells but will also open new avenues in stem cell biology. PMID- 27979737 TI - In vivo digestomics of milk proteins in human milk and infant formula using a suckling rat pup model. AB - Human milk is the optimal mode of infant feeding for the first several months of life, and infant formulas serve as an alternative when breast-feeding is not possible. Milk proteins have a balanced amino acid composition and some of them provide beneficial bioactivities in their intact forms. They also encrypt a variety of bioactive peptides, possibly contributing to infant health and growth. However, there is limited knowledge of how milk proteins are digested in the gastrointestinal tract and bioactive peptides are released in infants. A peptidomic analysis was conducted to identify peptides released from milk proteins in human milk and infant formula, using a suckling rat pup model. Among the major milk proteins targeted, alpha-lactalbumin and beta-casein in human milk, and beta-lactoglobulin and beta-casein in infant formula were the main sources of peptides, and these peptides covered large parts of the parental proteins' sequences. Release of peptides was concentrated to specific regions, such as residues 70-92 of beta-casein in human milk, residues 39-55 of beta lactoglobulin in infant formula, and residues 57-96 and 145-161 of beta-CN in infant formula, where resistance to gastrointestinal digestion was suggested. In the context of bioactive peptides, release of fragments containing known bioactive peptides was confirmed, such as beta-CN-derived opioid and antihypertensive peptides. It is therefore likely that these fragments are of biological significance in neonatal health and development. PMID- 27979738 TI - Chronic blockade of the AT2 receptor with PD123319 impairs insulin signaling in C57BL/6 mice. AB - The renin-angiotensin system modulates insulin action. Angiotensin type 1 receptor exerts a deleterious effects while the angiotensin type 2 receptor (AT2R) appears to have beneficial effects providing protection against insulin resistance and type 2 diabetes. Although recent reports indicate that agonism of AT2R ameliorates diabetes and insulin resistance, the phenotype of AT2R-knockout mice seems to be controversial relating this aspect. Thus, in this study we have explored the role of AT2R in the control of insulin action. To that end, C57Bl/6 mice were administered the synthetic AT2R antagonist PD123319 for 21days (10mg/kg/day ip); vehicle treated animals were used as control. Glucose tolerance, metabolic parameters, in vivo insulin signaling in main insulin-target tissues as well as levels of adiponectin, TNF-alpha, MCP-1 and IL-6 in adipose tissue were assessed. AT2R blockade with PD123319 induced a marginal effect on glucose homeostasis but an important reduction in the insulin-induced phosphorylation of the insulin receptor and Akt in both liver and adipose tissue. Insulin signaling in skeletal muscle remained unaltered after treatment with PD123319, which could explain the minimal effect on glucose homeostasis induced by PD123319. Our current results reinforce the notion that the AT2R has a physiological role in the conservation of insulin action. PMID- 27979739 TI - Genetic variants in SIRT3 transcriptional regulatory region affect promoter activity and fat deposition in three cattle breeds. AB - Sirtuin 3 (SIRT3) is a mitochondrial nicotinamide adenine dinucleotide (NAD) dependent deacetylase. It has crucial roles in regulating the respiratory chain, in adenosine triphosphate (ATP) production, and in both the citric acid and urea cycles. The aim of this study was to investigate whether SIRT3 could be used as a candidate gene in the breeding of cattle. Expression analysis by quantitative real-time polymerase chain reactions (qPCR) indicated that expression levels of SIRT3 were highest in the kidney, rumen, liver, omasum and muscle. Using sequencing technology on a total of 913 cattle representing three indigenous Chinese beef cattle breeds, three single nucleotide polymorphisms (SNPs) were identified in the promoter region of SIRT3, and five haplotypes representing five potential transcription factor compositions of polymorphic potential cis-acting elements. Association analysis indicated that the Hap3/8 diplotype performed better than other combinations in intramuscular fat content. In addition, the promoter activity with Hap1 haplotype was higher than the Hap8 haplotype, consistent with the association analysis. The results indicate that the polymorphisms in transcription factor binding sites of SIRT3 promoter may affect the transcriptional activity of SIRT3, and thus alter intramuscular fat content in beef cattle. PMID- 27979740 TI - The impact of luminance on tonic and phasic pupillary responses to sustained cognitive load. AB - Pupillary reactions independent of light conditions have been linked to cognition for a long time. However, the light conditions can impact the cognitive pupillary reaction. Previous studies underlined the impact of luminance on pupillary reaction, but it is still unclear how luminance modulates the sustained and transient components of pupillary reaction - tonic pupil diameter and phasic pupil response. In the present study, we investigated the impact of the luminance on these two components under sustained cognitive load. Fourteen participants performed a novel working memory task combining mathematical computations with a classic n-back task. We studied both tonic pupil diameter and phasic pupil response under low (1-back) and high (2-back) working memory load and two luminance levels (gray and white). We found that the impact of working memory load on the tonic pupil diameter was modulated by the level of luminance, the increase in tonic pupil diameter with the load being larger under lower luminance. In contrast, the smaller phasic pupil response found under high load remained unaffected by luminance. These results showed that luminance impacts the cognitive pupillary reaction - tonic pupil diameter (phasic pupil response) being modulated under sustained (respectively, transient) cognitive load. These findings also support the relationship between the locus-coeruleus system, presumably functioning in two firing modes - tonic and phasic - and the pupil diameter. We suggest that the tonic pupil diameter tracks the tonic activity of the locus-coeruleus while phasic pupil response reflects its phasic activity. Besides, the designed novel cognitive paradigm allows the simultaneous manipulation of sustained and transient components of the cognitive load and is useful for dissociating the effects on the tonic pupil diameter and phasic pupil response. PMID- 27979741 TI - Complex regional pain syndrome type I in children: What is new? AB - Complex regional pain syndrome type I (CRPS-I), although first described by the French surgeon Ambroise Pare as far back as the 16th century, nevertheless remains shrouded in mystery. The most common symptoms are pain in an entire hand or foot, allodynia, functional impairment induced by the pain, local oedema and skin color changes and transient sweating abnormalities. Most cases occur after a minor injury (i.e., a sprain or fracture), although there may be no identifiable triggering event, particularly in children. Primarily cold CRPS-I is by far the most common variant in children. Development of the Budapest criteria has benefited the diagnosis. These criteria are clinical and no specific diagnostic investigation is available. In vitro and in vivo studies have established that several pathogenic mechanisms can be involved concomitantly. However, there is no satisfactory explanation to the full clinical spectrum. Blood tests and imaging studies are useful for ruling out other diagnoses then monitoring the course of the condition, which may involve the development of demineralisation or osteopenia. High-resolution peripheral quantitative computed tomography may be helpful, as it provides quantitative assessments of the cortical and trabecular bone. CRPS-I has several specific characteristics in children compared to adults and whether the condition is the same entity in these two age groups is a legitimate question. The optimal management involves an early diagnosis followed by a multidisciplinary management programme of functional rehabilitation therapy and cognitive behavioral therapy. Analgesics are useful only during the phase of acute pain and to facilitate physical therapy. Studies in adults showed that bisphosphonates were effective within the first 12 months after symptom onset and calcitonin in longer-lasting cases. No high-quality clinical research studies into the aetiopathogenesis and treatment of CRPS-I in children and adolescents are available to date. PMID- 27979742 TI - Neurological deficit secondary to a pre-sacral abscess with epidural extension up to L3: A case report and literature review. AB - Isolated epidural abscesses are uncommon lesions. Surgical treatment may be difficult due to the extension of these lesions. We present a case of a pelvic abscess spreading along the path of the sciatic nerve to the gluteus muscles and the lumbar canal, causing neurological compression; requiring surgical treatment with three simultaneous approaches. PMID- 27979743 TI - Oncocytoma as a growing FDG-avid adrenal mass on serial 18F-FDG PET/CT imaging: A potential pitfall in oncological evaluation. PMID- 27979744 TI - Why are digits easier to identify than letters? AB - Beginning with Dejerine's report of pure alexia in 1892, numerous researchers have noted that individuals with acquired impairments of reading may show spared digit identification performance. This digit advantage has also been found in unimpaired adult readers across a number of tasks, and five main hypotheses have been proposed to explain how it arises. In this paper I consider these hypotheses in the context of recent theories of a unified alphanumeric character identification system, and evaluate them according to relevant empirical evidence. Despite some promising findings, none of the hypotheses currently provide a sufficient explanation of the digit advantage. Rather than developing new hypotheses to explain a categorical difference between digit and letter performance, I argue that future work should consider factors that affect identification performance specific to individual characters. PMID- 27979745 TI - The nanomechanical role of melanin granules in the retinal pigment epithelium. AB - Nanomechanical properties of cells and tissues, in particular their elasticity, play an important role in different physiological and pathological processes. Recently, we have demonstrated that melanin granules dramatically modify nanomechanical properties of melanoma cells making them very stiff and, as a result, less aggressive. Although the mechanical effect of melanin granules was demonstrated in pathological cells, it was never studied in the case of normal cells. In this work, we analyzed the impact of melanin granules on nanomechanical properties of primary retinal pigment epithelium tissue fragments isolated from porcine eyes. The obtained results clearly show that melanin granules are responsible for the exceptional nanomechanical properties of the tissue. Our findings suggest that melanin granules in the retinal pigment epithelium may play an important role in sustaining the stiffness of this single cell layer, which functions as a natural mechanical barrier separating the retina from the choroid. PMID- 27979746 TI - Evaluation of expressed prostatic secretion and serum using surface-enhanced Raman spectroscopy for the noninvasive detection of prostate cancer, a preliminary study. AB - Surface-enhanced Raman spectroscopy (SERS) involving expressed prostatic secretion (EPS) and serum was investigated; the objective was to determine if this approach could distinguish prostate cancer from benign prostatic hyperplasia. A total of 120 SERS spectra for EPS and 96 spectra for serum were gathered from patients within a prospective contemporary biopsy cohort. Significant differences in spectra between prostate cancer and benign prostatic hyperplasia were tentatively assigned to component changes in EPS and serum samples. Principal component analysis and linear discriminate analysis were utilized to evaluate the spectral data for EPS and serum, to build diagnostic algorithms. The leave-one-out cross-validation method was used to validate the diagnostic algorithms; it revealed diagnostic sensitivities of 75% and 60%, specificities of 75% and 76.5%, and accuracies of 75% and 68% for EPS and serum, respectively. The results suggest that EPS and serum SERS analysis could be a potential tool for prostate cancer detection. PMID- 27979747 TI - DNA vaccination for cervical cancer; a novel technology platform of RALA mediated gene delivery via polymeric microneedles. AB - HPV subtypes (16, 18) are associated with the development of cervical cancer, with oncoproteins E6 and E7 responsible for pathogenesis. The goal of this study was to evaluate our 'smart system' technology platform for DNA vaccination against cervical cancer. The vaccination platform brings together two main components; a peptide RALA which condenses DNA into cationic nanoparticles (NPs), and a polymeric polyvinylpyrrolidone (PVP) microneedle (MN) patch for cutaneous delivery of the loaded NPs. RALA condensed E6/E7 DNA into NPs not exceeding 100nm in diameter, and afforded the DNA protection from degradation in PVP. Sera from mice vaccinated with MN/RALA-E6/E7 were richer in E6/E7-specific IgGs, displayed a greater T-cell-mediated TC-1 cytotoxicity and contained more IFN-gamma than sera from mice that received NPs intramuscularly. More importantly, MN/RALA-E6/E7 delayed TC-1 tumor initiation in a prophylactic model, and slowed tumor growth in a therapeutic model of vaccination, and was more potent than intramuscular vaccination. PMID- 27979748 TI - Association of Transition Readiness to Intentional Self-Regulation and Hopeful Future Expectations in Youth With Illness. AB - BACKGROUND: Little is known about how transition readiness relates to other developmental skills of adolescence in youth with chronic illness. Better understanding of how transition readiness relates to these other developmental skills could lead to a broader array of tools to improve transition readiness. Intentional self-regulation (ISR) and hopeful future expectations (HFE) are 2 developmental skills of adolescence that improve with participation in developmental programming and thus are modifiable. METHODS: We explored associations between transition readiness, as measured by the Transition Readiness Assessment Questionnaire 29 (TRAQ-29) and ISR and HFE in youth with chronic illness recruited from a variety of subspecialty clinics from a major southeast medical center. RESULTS: A total of 71 adolescents with chronic illness were included in the analysis. The TRAQ-29 Self-Advocacy domain showed positive associations to both ISR (P = .03) and HFE (P = .009). In addition, the TRAQ-29 overall had positive associations to HFE (P = .04). CONCLUSIONS: The significant associations between TRAQ-29 Self-Advocacy domain scores and ISR and HFE suggest that transition readiness is developing within the context of other developmental areas in adolescence. More work is needed to see if the programming that improves these other developmental skills might also improve transition readiness. PMID- 27979749 TI - Early Childhood Risk Factors for Mealtime TV Exposure and Engagement in Low Income Families. AB - OBJECTIVE: To identify whether child and mother characteristics in early childhood predict TV exposure and engagement during mealtime in middle childhood. METHODS: A total of 220 low-income mother-child dyads participated. Children were 4.26 years old (SD = 0.51) at baseline and 5.94 years (SD = 0.68) at 2-year follow-up. Mothers completed baseline measures of child negative emotionality and parenting practices. Family mealtimes were video recorded and coded for background TV exposure and child TV engagement. Multinomial logistic regression tested whether child emotionality and parenting practices during early childhood predicted risk of child TV exposure or engagement during mealtime, relative to no TV use, 2 years later. RESULTS: Children with greater negative emotionality in early childhood were more likely to engage with TV during mealtime than to have no TV. Similarly, early parenting disciplinary practices characterized by over reactivity and laxness increased the risk for child TV engagement versus no TV during mealtime approximately 2 years later. CONCLUSIONS: We identified 2 factors that associated with an increased risk for TV viewing during meals. Helping parents manage child negative emotionality using positive parenting strategies might reduce later child TV engagement and improve the quality of family mealtimes. PMID- 27979750 TI - Identification and Validation of a Sickle Cell Disease Cohort Within Electronic Health Records. AB - OBJECTIVE: To develop and validate a computable phenotype algorithm for identifying patient populations with sickle cell disease. METHODS: In this retrospective study we used electronic health record data from the Children's Hospital of Wisconsin to develop a computable phenotype algorithm for sickle cell disease. The algorithm was on the basis of the International Classification of Diseases, Ninth Revision codes, number of visits, and hospital admissions for sickle cell disease. Using Informatics for Integrating Biology and the Bedside queries, the algorithm was refined in an iterative process. The final algorithm was verified using manual medical records review and by comparison with a gold standard set of confirmed sickle cell cases. The algorithm was then validated at Froedtert Hospital, a neighboring health system for adults. RESULTS: From the Children's Hospital of Wisconsin, our computable phenotype algorithm identified patients with confirmed sickle cell disease with a positive predictive value of 99.4% and a sensitivity of 99.4%. Additionally, using data from Froedtert, the computable phenotype algorithm identified patients with confirmed sickle cell disease with a positive predictive value of 95.8% and a sensitivity of 98.3%. CONCLUSIONS: The computable phenotype algorithm developed in this study had a high sensitivity and positive predictive value when identifying patients with sickle cell disease in the electronic health records of the Children's Hospital of Wisconsin and Froedtert, a neighboring health system for adults. Our algorithm allows us to harness data provided by the electronic health record to rapidly and accurately identify patient with sickle cell disease and is a rich resource for future clinical trials. PMID- 27979751 TI - PARP1-mediated PPARalpha poly(ADP-ribosyl)ation suppresses fatty acid oxidation in non-alcoholic fatty liver disease. AB - BACKGROUND & AIMS: PARP1 is a key mediator of cellular stress responses and critical in multiple physiological and pathophysiological processes of cells. However, whether it is involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains elusive. METHODS: We analysed PARP1 activity in the liver of mice on a high fat diet (HFD), and samples from NAFLD patients. Gain- or loss of-function approaches were used to investigate the roles and mechanisms of hepatic PARP1 in the pathogenesis of NAFLD. RESULTS: PARP1 is activated in fatty liver of HFD-fed mice. Pharmacological or genetic manipulations of PARP1 are sufficient to alter the HFD-induced hepatic steatosis and inflammation. Mechanistically we identified peroxisome proliferator-activated receptor alpha (PPARalpha) as a substrate of PARP1-mediated poly(ADP-ribosyl)ation. This poly(ADP-ribosyl)ation of PPARalpha inhibits its recruitment to target gene promoters and its interaction with SIRT1, a key regulator of PPARalpha signaling, resulting in suppression of fatty acid oxidation upregulation induced by fatty acids. Moreover, we show that PARP1 is a transcriptional repressor of PPARalpha gene in human hepatocytes, and its activation suppresses the ligand (fenofibrate) induced PPARalpha transactivation and target gene expression. Importantly we demonstrate that liver biopsies of NAFLD patients display robust increases in PARP activity and PPARalpha poly(ADP-ribosyl)ation levels. CONCLUSIONS: Our data indicate that PARP1 is activated in fatty liver, which prevents maximal activation of fatty acid oxidation by suppressing PPARalpha signaling. Pharmacological inhibition of PARP1 may alleviate PPARalpha suppression and therefore have therapeutic potential for NAFLD. LAY SUMMARY: PARP1 is activated in the non-alcoholic fatty liver of mice and patients. Inhibition of PARP1 activation alleviates lipid accumulation and inflammation in fatty liver of mice. PMID- 27979752 TI - Applying self-determination theory to the blood donation context: The blood donor competence, autonomy, and relatedness enhancement (Blood Donor CARE) trial. AB - The Blood Donor Competency, Autonomy, and Relatedness Enhancement (Blood Donor CARE) project was designed as a practical application of self-determination theory to encourage retention of first-time donors. Self-determination theory proposes that people are more likely to persist with behaviors that are internally-motivated, and that externally-motivated behavior can evolve and become internalized given the appropriate socio-environmental conditions. According to self-determination theory, motivation to engage in blood donation may become increasingly self-determined if the behavior satisfies fundamental human needs for competence (a sense of self-efficacy to achieve specific goals), autonomy (a sense of volitional control over one's behavior), and relatedness (a sense of connection to a larger group). The primary aim of this randomized controlled trial is to examine the effect of competence, autonomy, and/or relatedness interventions on donor retention. Using a full factorial design, first-time donors will be assigned to a control condition or one of seven intervention conditions. Donation competence, autonomy, and relatedness, along with additional constructs associated with return donation, will be assessed before and after the intervention using online surveys, and donation attempts will be tracked for one-year using blood center donor databases. We hypothesize that, compared to the control condition, the interventions will increase the likelihood of a subsequent donation attempt. We will also examine intervention specific increases in competence, autonomy, and relatedness as potential mediators of enhanced donor retention. By promoting first-time donor competence, autonomy, and relatedness our goal is to enhance internal motivation for giving and in so doing increase the likelihood of future donation. PMID- 27979753 TI - Healthy caregivers-healthy children (HC2) phase 2: Integrating culturally sensitive childhood obesity prevention strategies into childcare center policies. AB - OBJECTIVE: Despite the high prevalence of obesity among preschool-aged children, most states lack childcare center (CCC) nutrition and physical activity policies. The Healthy Caregivers, Healthy Children (HC) Phase 2 project is examining the relationship between the CCC nutrition and physical activity environment and child dietary intake/physical activity patterns and body mass index (BMI). PARTICIPANTS: A total of 24 "Quality Counts" (Miami Dade County, Florida's Quality Rating Improvement System [QRIS)]) CCCs serving low resource families with >=50 2-to-5year olds attending have been randomized to either intervention (n=12) or control (n=12). INTERVENTION: The HC2 intervention arm CCCs receive implementation of a daily curricula for (1) teachers/parents; (2) children; (3) snack, beverage, physical activity, and screen time policies; and (4) technical assistance with menu modifications. Control arm schools receive an attention control safety curriculum. HC2 is delivered once a month in year 1, quarterly in year 2 and will be disseminated throughout the Quality Counts network in year 3. MAIN OUTCOME MEASURES: Primary outcome measures include the Environment and Policy Assessment and Observation tool (EPAO), standardized dietary intake and physical activity patterns surveys, and child BMI. The 'Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM)' framework will guide the interpretation of outcome measures. CONCLUSIONS: CCCs are in need of evidence based standardized nutrition and physical activity policies. The intersection of RE-AIM and early childhood obesity prevention in the childcare setting could generate robust and new information to the field about potential barriers, facilitators, adoption, and sustainability in this setting. PMID- 27979754 TI - Design of the integrative medical group visits randomized control trial for underserved patients with chronic pain and depression. AB - BACKGROUND: Given the public health crisis of opioid overprescribing for pain, there is a need for evidence-based non pharmacological treatment options that effectively reduce pain and depression. We aim to examine the effectiveness of the Integrative Medical Group Visits (IMGV) model in reducing chronic pain and depressive symptoms, as well as increasing pain self-management. METHODS: This paper details the study design and implementation of an ongoing randomized controlled trial of the IMGV model as compared to primary care visits. The research aims to determine if the IMGV model is effective in achieving: a) a reduction in self-reported pain and depressive symptoms and 2) an improvement in the self-management of pain, through increasing pain self-efficacy and reducing use of self-reported pain medication. We intend to recruit 154 participants to be randomized in our intervention, the IMGV model (n=77) and to usual care (n=77). CONCLUSIONS: Usual care of chronic pain through pharmacological treatment has mixed evidence of efficacy and may not improve quality of life or functional status. We aim to conduct a randomized controlled trial to evaluate the effectiveness of the IMGV model as compared to usual care in reducing self reported pain and depressive symptoms as well as increasing pain management skills. PMID- 27979756 TI - Digesting or swimming? Integration of the postprandial metabolism, behavior and locomotion in a frequently foraging fish. AB - Fish that are active foragers usually perform routine activities while digesting their food; thus, their postprandial swimming capacity and related behavior adjustments might be ecologically important. To test whether digestion affect swimming performance and the relationships of digestion with metabolism and behavior in an active forager, we investigated the postprandial metabolic response, spontaneous swimming activities, critical swimming speed (Ucrit), and fast-start escape performance of both fasted and digesting (3h after feeding to satiation) juvenile rose bitterling (Rhodeus ocellatus). Feeding to satiation elicited a 50% increase in the oxygen consumption rate, which peaked at 3h after feeding and returned to the prefeeding state after another 3h. However, approximately 50% and 90% of individuals resumed feeding behavior at 2 and 3h postfeeding, respectively, although the meal size varied substantially. Digestion showed no effect on either steady swimming performance as suggested by the Ucrit or unsteady swimming performance indicated by the maximum linear velocity in fast start escape movement. However, digesting fish showed more spontaneous activity as indicated by the longer total distance traveled, mainly through an increased percentage of time spent moving (PTM). A further analysis found that fasting individuals with high swimming speed were more inclined to increase their PTM during digestive processes. The present study suggests that as an active forager With a small meal size and hence limited postprandial physiological and morphological changes, the swimming performance of rose bitterling is maintained during digestion, which might be crucial for its active foraging mode and anti predation strategy. PMID- 27979755 TI - EffectS of non-nutritive sWeetened beverages on appetITe during aCtive weigHt loss (SWITCH): Protocol for a randomized, controlled trial assessing the effects of non-nutritive sweetened beverages compared to water during a 12-week weight loss period and a follow up weight maintenance period. AB - BACKGROUND: Acute and medium-term intervention studies suggest that non-nutritive sweeteners (NNS) are beneficial for weight loss, however there is limited human data on the long-term effects of consuming NNS on weight loss, maintenance, and appetite. Further research is therefore required to elucidate the prolonged impact of NNS consumption on these outcome measures. METHODS/DESIGN: A randomized parallel groups design will be used to assess whether regular NNS beverage intake is equivalent to a water control in promoting weight loss over 12-weeks (weekly weight loss sessions; Phase I), then supporting weight maintenance over 40-weeks (monthly sessions; Phase II) and subsequently independent weight maintenance over 52-weeks (Phase III) in 432 participants. A subset of these participants (n=116) will complete laboratory-based appetite probe days (15 sessions; 3 sessions each at baseline, at the start of phase I and the end of each phase). A separate subset (n=50) will complete body composition scans (DXA) at baseline and at the end of each phase. All participants will regularly be weighed and will complete questionnaires and cognitive tasks to assess changes in body weight and appetitive behaviours. Measures of physical activity and biochemical markers will also be taken. DISCUSSION: The trial will assess the efficacy of NNS beverages compared to water during a behavioural weight loss and maintenance programme. We aim to understand whether the impact of NNS on weight, dietary adherence and well being are beneficial or transient and effects on prolonged successful weight loss and weight maintenance through sustained changes in appetite and eating behaviour. TRIAL REGISTRATION: Clinical Trials: NCT02591134; registered: 23.10.2015. PMID- 27979757 TI - Congenital retinal macrovessel associated with vitreous hemorrhage. AB - A "congenital retinal macrovessel" (CRM) is an aberrant retinal vessel (frequently a vein) that traverses the central macula and supplies or drains both above and below the horizontal raphe. It is an uncommon entity that is usually disclosed on routine examination and may rarely cause a compromised visual acuity. We describe the case of an adolescent girl who underwent vitrectomy for vitreous hemorrhage and was found to have a CRM with vascular abnormalities. To our knowledge, this is the first report of vitreous hemorrhage secondary to a CRM. PMID- 27979759 TI - Correspondence: Assessment of learning, memory and attention in developmental neurotoxicology. PMID- 27979758 TI - A testbed for optimizing electrodes embedded in the skull or in artificial skull replacement pieces used after injury. AB - BACKGROUND: Custom-fitted skull replacement pieces are often used after a head injury or surgery to replace damaged bone. Chronic brain recordings are beneficial after injury/surgery for monitoring brain health and seizure development. Embedding electrodes directly in these artificial skull replacement pieces would be a novel, low-risk way to perform chronic brain monitoring in these patients. Similarly, embedding electrodes directly in healthy skull would be a viable minimally-invasive option for many other neuroscience and neurotechnology applications requiring chronic brain recordings. NEW METHOD: We demonstrate a preclinical testbed that can be used for refining electrode designs embedded in artificial skull replacement pieces or for embedding directly into the skull itself. Options are explored to increase the surface area of the contacts without increasing recording contact diameter to maximize recording resolution. RESULTS: Embedding electrodes in real or artificial skull allows one to lower electrode impedance without increasing the recording contact diameter by making use of conductive channels that extend into the skull. The higher density of small contacts embedded in the artificial skull in this testbed enables one to optimize electrode spacing for use in real bone. COMPARISON WITH EXISTING METHODS: For brain monitoring applications, skull-embedded electrodes fill a gap between electroencephalograms recorded on the scalp surface and the more invasive epidural or subdural electrode sheets. CONCLUSIONS: Embedding electrodes into the skull or in skull replacement pieces may provide a safe, convenient, minimally invasive alternative for chronic brain monitoring. The manufacturing methods described here will facilitate further testing of skull-embedded electrodes in animal models. PMID- 27979760 TI - Diagnostic and prognostic challenges in Idiopathic Pulmonary Fibrosis: A patient's "Q and A" approach. AB - Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, debilitating disease of unknown etiology that leads to death nearly half of the patients within 3-3.5 years. The past 15 years, the scientific community has made tremendous progress towards standardized diagnostic and prognostic algorithms that led to the generation of the 2011 ATS/ERS/JRS/ALAT guidelines. The latest guidelines provided us with fundamental diagnostic algorithms that set the diagnosis in the majority of cases; however, they leave a significant minority of patients without diagnostic and most importantly, therapeutic umbrella. To this end current guidelines should be revisited in light of research advances, including the tools of "fibromics" and at the same time provide practical guidance to the real-world of IPF in order to address patients' needs. The scope of this review article is to summarize challenges in the everyday IPF clinical practice and make an effort to provide realistic answers to patients' questions. PMID- 27979761 TI - Crystallization of probucol from solution and the glassy state. AB - Crystallization of probucol (PBL) from both solution and glassy solid state was investigated. In the crystallization study from solution, six solvents and three methods, i.e., evaporation, addition of a poor solvent, and cooling on ice, were used to obtain various crystal forms. In addition to common two crystal forms (forms I and II), two further forms (forms III and cyclohexane-solvate) were found in this study, and their thermodynamic relationships were determined. Forms I and II are likely to be enantiotropically related with thermodynamic transition temperature below 5 degrees C. Isothermal crystallization studies revealed that PBL glass initially crystallized into form III between 25 and 50 degrees C, and then transformed to form I. The isothermal crystallization appears to be a powerful option to find uncommon crystal forms. The crystallization of PBL was identified to be pressure controlled, thus the physical stability of PBL glass is higher than that of typical compounds. PMID- 27979762 TI - The importance of the molecular weight of ethyl cellulose on the properties of aqueous-based controlled release coatings. AB - Previous investigations of aqueous based ethyl cellulose (EC) latex dispersions have mainly focused on the commercially available viscosity grade 20cps. In this study, dispersions of EC with varying viscosity grades (which correspond to molecular weights), ranging from 4 to 100 cps, were produced and characterised. The dispersions showed particle sizes around 200nm and highly negative zeta potentials (approx. -100mV), which indicated stable dispersions as confirmed by sedimentation studies. The different latexes were used to produce free-standing film coatings. We hypothesised that the different viscosity grades of EC would result in different properties of the films. We found that an increase in viscosity grade (and higher molecular weight) resulted in lower coalescence between the particles during film formation and thus to higher water permeability than in film coatings of lower molecular weight. After exposure to water the EC 4cps and 20cps film coatings had a more porous structure in the side facing the air during production and drying after immersion in water. Molecular weight is therefore a factor that should be considered when producing pharmaceutical coatings for controlled release. PMID- 27979763 TI - About the impact of water movement on the permeation behaviour of nanoparticles in mucus. AB - The purpose of this study was to establish a method to evaluate the diffusion behaviour of nanoparticles (NP) in mucus taking also the water movement into account. For this purpose, NP based on different chitosan derivatives, either thiolated or not, and marked with fluorescein diacetate were prepared by ionotropic gelation with hyaluronan. NP size and polydispersity were in the respective intervals 363.5+/-33.3-385.7+/-36.5nm, and 0.35+/-0.11-0.39+/-0.10. An in vitro study of water-assisted NP transport through mucus was realized by filling the barrel of a syringe kept in vertical position, tip down, with mucus. Then a bottom-to-surface PBS flow across the mucus layer was realized by connecting the tip of the syringe to the bottom of a vertical cylindrical vessel by a flexible tubing, filling the vessel with PBS, level with the surface of the mucus layer in the syringe, and dripping PBS into the vessel without causing any phase mixing. Although the mucoadhesive NP interact more strongly with the mucus, yet they are able to overcome this barrier with the aid of the water movement from lumen to epithelium. This new method promises to be more predictive of in vivo NP transport across the mucus than already reported methods, as it takes into account the water movement and regulates its contribution to the physiologic value. PMID- 27979764 TI - Acrylated chitosan for mucoadhesive drug delivery systems. AB - A new mucoadhesive polymer was synthesized by conjugating chitosan to poly(ethylene glycol)diacrylate (PEGDA) via the Michael type reaction. The product was characterized using NMR. Higher PEGDA grafting efficacy was observed with low molecular weight PEGDA (0.7kDa), compared to long 10kDa PEGDA. The acrylation percentage was calculated based on the reaction of ninhydrin with chitosan, and supported the qualitative NMR findings. The adhesive properties were studied by tensile test and rotating system involving detachment of polymer tablets from a fresh intestine sample. Chitosan modified with high molecular weight PEGDA presented improvement in mucoadhesive properties compared to both non-modified and thiolated chitosan. On the molecular level, rheology measurements of polymer/mucin mixtures provided additional evidence of strong interaction between modified chitosan and mucin glycoproteins. This new polymer shows promise as a useful polymeric carrier matrix for delivery systems, which could provide prolonged residence time of the vehicle on the mucosa surface. PMID- 27979765 TI - Crystalline solid dispersion-a strategy to slowdown salt disproportionation in solid state formulations during storage and wet granulation. AB - Salt disproportionation (a conversion from the ionized to the neutral state) in solid formulations is a potential concern during manufacturing or storage of products containing a salt of the active pharmaceutical ingredient (API) due to the negative ramifications on product performance. However, it is challenging to find an effective approach to prevent or mitigate this undesirable reaction in formulations. Hence, the overall objective of this study is to explore novel formulation strategies to reduce the risk of salt disproportionation in pharmaceutical products. Crystals of pioglitazone hydrochloride salt were dispersed into polymeric matrices as a means of preventing the pharmaceutical salt from direct contact with problematic excipients. It was found that the level of salt disproportionation could be successfully reduced during storage or wet granulation by embedding a crystalline salt into a polymeric carrier. Furthermore, the impact of different polymers on the disproportionation process of a salt of a weakly basic API was investigated herein. Disproportionation of pioglitazone hydrochloride salt was found to be significantly affected by the physicochemical properties of different polymers including hygroscopicity and acidity of substituents. These findings provide an improved understanding of the role of polymeric carriers on the stability of a salt in solid formulations. Moreover, we also found that introducing acidifiers into granulation fluid can bring additional benefits to retard the disproportionation of pioglitazone HCl during the wet granulation process. These interesting discoveries offer new approaches to mitigate disproportionation of API salt during storage or processing, which allow pharmaceutical scientists to develop appropriate formulations with improved drug stability. PMID- 27979766 TI - Nebulized solid lipid nanoparticles for the potential treatment of pulmonary hypertension via targeted delivery of phosphodiesterase-5-inhibitor. AB - Phosphodiesterase type 5 (PDE-5) inhibitors - among which sildenafil citrate (SC) - play a primary role in the treatment of pulmonary hypertension (PH). Yet, SC can be only administered orally or parenterally with lot of risks. Targeted delivery of SC to the lungs via inhalation/nebulization is mandatory. In this study, solid lipid nanoparticles (SLNs) loaded with SC were prepared and characterized in terms of colloidal, morphological and thermal properties. The amount of drug loaded and its release behavior were estimated as a function of formulation variables. The potential of lipid nanocarriers to retain their properties following nebulization and autoclaving was investigated. In addition, toxicity aspects of plain and loaded SLNs on A549 cells were studied with respect to concentration. Spherical SLNs in the size range (100-250nm) were obtained. Particles ensured high encapsulation efficiency (88-100%) and sustained release of the payload over 24h. Cell-based viability experiments revealed a concentration-dependant toxicity for both plain and loaded SLNs recording an IC50 of 516 and 384MUg/mL, respectively. Nebulization with jet nebulizer and sterilization via autoclaving affected neither the colloidal stability of SLNs nor the drug entrapment, proving their potential as pulmonary delivery system. Interaction of SLNs with mucin was a function of the emulsifier coating layer. Results yet seeking clinical evidence - might give promises of new therapy for PH of higher safety, better performance and higher patient compliance. PMID- 27979767 TI - Regulator of G protein signaling 2 (Rgs2) regulates neural crest development through Ppardelta-Sox10 cascade. AB - Neural crest cells are multipotent progenitors that migrate extensively and differentiate into numerous derivatives. The developmental plasticity and migratory ability of neural crest cells render them an attractive model for studying numerous aspects of cell progression. We observed that zebrafish rgs2 was expressed in neural crest cells. Disrupting Rgs2 expression by using a dominant negative rgs2 construct or rgs2 morpholinos reduced GTPase-activating protein activity, induced the formation of neural crest progenitors, increased the proliferation of nonectomesenchymal neural crest cells, and inhibited the formation of ectomesenchymal neural crest derivatives. The transcription of pparda (which encodes Ppardelta, a Wnt-activated transcription factor) was upregulated in Rgs2-deficient embryos, and Ppardelta inhibition using a selective antagonist in the Rgs2-deficient embryos repaired neural crest defects. Our results clarify the mechanism through which the Rgs2-Ppardelta cascade regulates neural crest development; specifically, Ppardelta directly binds to the promoter and upregulates the transcription of the neural crest specifier sox10. This study reveals a unique regulatory mechanism, the Rgs2-Ppardelta-Sox10 signaling cascade, and defines a key molecular regulator, Rgs2, in neural crest development. PMID- 27979768 TI - A state of delirium: Deciphering the effect of inflammation on tau pathology in Alzheimer's disease. AB - Alzheimer's disease (AD), the predominant form of dementia, is highly correlated with the abnormal hyperphosphorylation and aggregation of tau. Immune responses are key drivers of AD and how they contribute to tau pathology in human disease remains largely unknown. This review summarises current knowledge on the association between inflammatory processes and tau pathology. While, preclinical evidence suggests that inflammation can indeed induce tau hyperphosphorylation at both pre- and post-tangles epitopes, a better understanding of whether this develops into advanced pathological features such as neurofibrillary tangles is needed. Microglial cells, the immune phagocytes in the central nervous system, appear to play a key role in regulating tau pathology, but the underlying mechanisms are not fully understood. Their activation can be detrimental via the secretion of pro-inflammatory mediators, particularly interleukin-1beta, but also potentially beneficial through phagocytosis of extracellular toxic tau oligomers. Nevertheless, anti-inflammatory treatments in animal models were found protective, but whether or not they affect microglial phagocytosis of tau species is unknown. However, one major challenge to our understanding of the role of inflammation in the progression of tau pathology is the preclinical models used to address this question. They mostly rely on the use of septic doses of lipopolysaccharide that do not reflect the inflammatory conditions experienced AD patients, questioning whether the impact of inflammation on tau pathology in these models is dose-dependent and relevant to the human disease. The use of more translational models of inflammation corroborated with verification in clinical investigations are necessary to progress our understanding of the interplay between inflammation and tau pathology. PMID- 27979769 TI - The SAMP8 mouse for investigating memory and the role of insulin in the brain. AB - SAMP8 mice exhibit changes that commonly occur with normal aging late in life, but do so at a much earlier age. These changes include impairments in learning and memory as early as 8months of age and so the SAMP8 is a useful model to investigate those age-related brain changes that may affect cognition. As brain insulin signaling and memory decline with aging, the SAMP8 model is useful for investigating these changes and interventions that might prevent the decline. This review will summarize the SAMP8 mouse model, highlight changes in brain insulin signaling and its role in memory, and discuss intranasal insulin delivery in investigating effects on insulin metabolism and memory in the SAMP8 mice. PMID- 27979771 TI - Rapid and strong de novo donor-specific antibody development in a lung transplant recipient: Short communication/case report. AB - A 66-yo female patient (typed B*39:01, 44:02) underwent first left single lung transplant (typed B*81:01, 15:17) on 02/07/2016 with negative for DSA in current and historical samples. On 02/17/2016 strong de novo DSA (MFI=15,200, C1q+) to B81 were detected. The recipient has two children typed B*07:02, 44:02 B*27:03, 39:01, and had received multiple vaccinations. Twinrix, Zostavax and MMR vaccines contain viruses grown on live human lung fibroblasts (MRC-5, typed B*07:02, 44:02, and WI-38, typed B*08:01, 58:01). Each dose of vaccine used for injection is known to contain protein components of fibroblasts including HLA. Most likely rapid de novo DSA development is due to booster effect produced by five exposures to mismatched B locus alleles which share the following epitopes: 70IAQ, 65QIA, 65QIA+76esn, 69aa+80n, and 163ew+73te. The later three consist of paired non-self and self eplets. Although likelihood of bystander effect produced by multiple vaccinations is low its impact cannot be ruled out. PMID- 27979772 TI - Integration of mtDNA pseudogenes into the nuclear genome coincides with speciation of the human genus. A hypothesis. AB - Fragments of mitochondrial DNA are known to get inserted into nuclear DNA to form NUMTs, i.e. nuclear pseudogenes of the mtDNA. The insertion of a NUMT is a rare event. Hundreds of pseudogenes have been cataloged in the human genome. NUMTs are, in essence, a special type of mutation with their own internal timer, which is synchronized with an established molecular clock, the mtDNA. Thus insertion of NUMTs can be timed with respect to evolution milestones such as the emergence of new species. We asked whether NUMTs were inserted uniformly over time or preferentially during certain periods of evolution, as implied by the "punctuated evolution" model. To our surprise, the NUMT insertion times do appear nonrandom with at least one cluster positioned at around 2.8 million years ago (Ma). Interestingly, 2.8Ma closely corresponds to the time of emergence of the genus Homo, and to a well-documented period of major climate change ca. 2.9-2.5Ma. It is tempting to hypothesize that the insertion of NUMTs is related to the speciation process. NUMTs could be either "riders", i.e., their insertion could be facilitated by the overall higher genome rearrangement activity during speciation, or "drivers", i.e. they may more readily get fixed in the population due to positive selection associated with speciation. If correct, the hypothesis would support the idea that evolution of our genus may have happened in a rapid, punctuated manner. PMID- 27979770 TI - The endocrine-brain-aging triad where many paths meet: female reproductive hormone changes at midlife and their influence on circuits important for learning and memory. AB - Female mammals undergo natural fluctuations in sex steroid hormone levels throughout life. These fluctuations span from early development, to cyclic changes associated with the menstrual or estrous cycle and pregnancy, to marked hormone flux during perimenopause, and a final decline at reproductive senescence. While the transition to reproductive senescence is not yet fully understood, the vast majority of mammals experience this spontaneous, natural phenomenon with age, which has broad implications for long-lived species. Indeed, this post-reproductive life stage, and its transition, involves significant and enduring physiological changes, including considerably altered sex steroid hormone and gonadotropin profiles that impact multiple body systems, including the brain. The endocrine-brain-aging triad is especially noteworthy, as many paths meet and interact. Many of the brain regions affected by aging are also sensitive to changes in ovarian hormone levels, and aging and reproductive senescence are both associated with changes in memory performance. This review explores how menopause is related to cognitive aging, and discusses some of the key neural systems and molecular factors altered with age and reproductive hormone level changes, with an emphasis on brain regions important for learning and memory. PMID- 27979774 TI - Gene regulatory networks in differentiation and direct reprogramming of hepatic cells. AB - Liver development proceeds by sequential steps during which gene regulatory networks (GRNs) determine differentiation and maturation of hepatic cells. Characterizing the architecture and dynamics of these networks is essential for understanding how cell fate decisions are made during development, and for recapitulating these processes during in vitro production of liver cells for toxicology studies, disease modelling and regenerative therapy. Here we review the GRNs that control key steps of liver development and lead to differentiation of hepatocytes and cholangiocytes in mammals. We focus on GRNs determining cell fate decisions and analyse subcircuitry motifs that may confer specific dynamic properties to the networks. Finally, we put our analysis in the perspective of recent attempts to directly reprogram cells to hepatocytes by forced expression of transcription factors. PMID- 27979773 TI - Zinc gluconate toxicity in wild-type vs. MT1/2-deficient mice. AB - Previous studies have suggested that oral zinc supplementation can help reduce the duration of the common cold; however, the use of intranasal (IN) zinc is strongly associated with anosmia, or the loss of the sense of smell, in humans. Prior studies from this lab showed that upregulation of metallothioneins (MT) is a rapid and robust response to zinc gluconate (ZG). Therefore, we assessed the role of MT in the recovery of nasal epithelial damage resulting from IN zinc administration. The main studies in this investigation used a high dose of ZG (170mM) to ensure ablation of the olfactory mucosa, so that the progression of histological and functional recovery could be assessed. In vivo studies using wild-type, MT1/2 knockout mice (MT KO), and heterozygotes administered ZG by IN instillation showed profound loss of the olfactory mucosa in the nasal cavity. Recovery was monitored, and a lower percentage of the MT KO mice were able to smell 28 d after treatment; however, no significant difference was observed in the rate of cell proliferation in the basal layer of the olfactory epithelium between MT KO and wild-type mice. A lower concentration of ZG (33mM), equivalent to that found in homeopathic IN ZG preparations, also caused olfactory epithelial toxicity in mice. These studies suggest that the use of zinc in drug formulations intended for IN administration in humans must be carefully evaluated for their potential to cause olfactory functional deficits. PMID- 27979775 TI - A Single Nucleotide Deletion in J Encoding GmELF3 Confers Long Juvenility and Is Associated with Adaption of Tropic Soybean. PMID- 27979777 TI - Risk assessment and monitoring programme of nitrates through vegetables in the Region of Valencia (Spain). AB - This study was carried out to determine current levels of nitrate in vegetables marketed in the Region of Valencia (Spain) and to estimate the toxicological risk associated with their intake. A total of 533 samples of seven vegetable species were studied. Nitrate levels were derived from the Valencia Region monitoring programme carried out from 2009 to 2013 and food consumption levels were taken from the first Valencia Food Consumption Survey, conducted in 2010. The exposure was estimated using a probabilistic approach and two scenarios were assumed for left-censored data: the lower-bound scenario, in which unquantified results (below the limit of quantification) were set to zero and the upper-bound scenario, in which unquantified results were set to the limit of quantification value. The exposure of the Valencia consumers to nitrate through the consumption of vegetable products appears to be relatively low. In the adult population (16 95 years) the P99.9 was 3.13 mg kg-1 body weight day-1 and 3.15 mg kg-1 body weight day-1 in the lower bound and upper bound scenario, respectively. On the other hand, for young people (6-15 years) the P99.9 of the exposure was 4.20 mg kg-1 body weight day-1 and 4.40 mg kg-1 body weight day-1 in the lower bound and upper bound scenario, respectively. The risk characterisation indicates that, under the upper bound scenario, 0.79% of adults and 1.39% of young people can exceed the Acceptable Daily Intake of nitrate. This percentage could join the vegetable extreme consumers (such as vegetarians) of vegetables. Overall, the estimated exposures to nitrate from vegetables are unlikely to result in appreciable health risks. PMID- 27979776 TI - Safety assessment of genetically modified milk containing human beta-defensin-3 on rats by a 90-day feeding study. AB - In recent years, transgenic technology has been widely applied in many fields. There is concern about the safety of genetically modified (GM) products with the increased prevalence of GM products. In order to prevent mastitis in dairy cows, our group produced transgenic cattle expressing human beta-defensin-3 (HBD3) in their mammary glands, which confers resistance to the bacteria that cause mastitis. The milk derived from these transgenic cattle thus contained HBD3. The objective of the present study was to analyze the nutritional composition of HBD3 milk and conduct a 90-day feeding study on rats. Rats were divided into 5 groups which consumed either an AIN93G diet (growth purified diet for rodents recommended by the American Institute of Nutrition) with the addition of 10% or 30% HBD3 milk, an AIN93G diet with the addition of 10% or 30% conventional milk, or an AIN93G diet alone. The results showed that there was no difference in the nutritional composition of HBD3 and conventional milk. Furthermore, body weight, food consumption, blood biochemistry, relative organ weight, and histopathology were normal in those rats that consumed diets containing HBD3. No adverse effects were observed between groups that could be attributed to varying diets or gender. PMID- 27979778 TI - RIFM fragrance ingredient safety assessment, 5-Ethylidenebicyclo[2.2.1]hept-2-yl propionate, CAS Registry Number 73347-77-0. PMID- 27979779 TI - In silico prediction of genotoxicity. AB - The in silico prediction of genotoxicity has made considerable progress during the last years. The main driver for the pharmaceutical industry is the ICH M7 guideline about the assessment of DNA reactive impurities. An important component of this guideline is the use of in silico models as an alternative approach to experimental testing. The in silico prediction of genotoxicity provides an established and accepted method that defines the first step in the assessment of DNA reactive impurities. This was made possible by the growing amount of reliable Ames screening data, the attempts to understand the activity pathways and the subsequent development of computer-based prediction systems. This paper gives an overview of how the in silico prediction of genotoxicity is performed under the ICH M7 guideline. PMID- 27979780 TI - Identification and characterization of two LBP/BPI genes involved in innate immunity from Hyriopsis cumingii. AB - Lipopolysaccharide-binding protein and bactericidal permeability-increasing protein (LBP/BPI) play crucial role in modulating cellular signals in response to Gram-negative bacteria infection. In the present study, two isoforms of LBP/BPI genes, designated as HcLBP/BPI1 and HcLBP/BPI2, respectively, were cloned from the mussel Hyriopsis cumingii by RACE approach. The full-length cDNA sequences of HcLBP/BPI1 and HcLBP/BPI2 were 1887 and 2227 bp and encoded two secreted proteins of 501 and 518 amino acid residues, respectively. The deduced amino acid of HcLBP/BPI1 and HcLBP/BPI2 contained several conserved domains, such as signal peptide, two BPI/LBP and one central domain. Phylogentic analysis further supported that HcLBP/BPI1 and HcLBP/BPI2 belonged to new members of invertebrate LBP/BPI family. The mRNA transcripts of HcLBP/BPI1 and HcLBP/BPI2 were ubiquitously expressed in all examined tissues, and the expression level of HcLBP/BPI1 was higher than that of HcLBP/BPI2. The mRNA expression of HcLBP/BPI1 in hepatopancreas and hemocytes was significantly up-regulate after Aeromonas hydrophila and LPS challenge, and HcLBP/BPI2 in hepatopancreas was only up regulated at 6 and 12 h after LPS challenge and at 12 h after A. hydrophila challenge. In addition, the recombinant HcLBP/BPIs displayed antibacterial activity against Gram-negative bacteria, and the antibacterial index of HcLBP/BPI1 was higher than that of HcLBP/BPI2. These results indicated that HcLBP/BPI1 and HcLBP/BPI2 probably played distinct roles in bacterial mediating immune response in Mollusca. PMID- 27979781 TI - The binding of the bone morphogenetic protein antagonist gremlin to kidney heparan sulfate: Such binding is not essential for BMP antagonism. AB - Gremlin-1, a bone morphogenetic protein (BMP) antagonist, has essential roles in kidney and limb bone development, and is important in chronic diseases including tissue fibrosis. It also functions as an activating ligand of the vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), and binds strongly to the sulfated polysaccharide, heparin. Here we investigated the extent to which gremlin binds to the related polysaccharide heparan sulfate (HS), which unlike heparin is widely distributed spread within tissues. We determined that both highly sulfated HS and kidney HS are able to partially compete for the binding of heparin to gremlin, whereas low sulfated HS is a poor competitor. In further investigations of the interaction between gremlin and HS, we found that wild-type gremlin is able to bind broadly across the various regions of kidney in an HS dependent manner, with particularly intense binding to tubular structures in the renal cortex. In a model of chronic kidney disease, fibrotic changes in the kidney result in a loss of gremlin binding sites. Gremlin mutants with reduced affinity for heparin showed negligible binding under the same conditions. These mutants nonetheless remain functional as BMP antagonists on C2C12 myoblastic cells transfected with a Smad 1 reporter gene construct. Overall our findings indicate that on secretion, gremlin will bind to HS structures on the cell surface and in the extracellular matrix, thus providing for a localised reservoir which can modulate BMP activity in a temporospatially restricted manner. Although binding of heparin/HS to gremlin has been shown elsewhere to be necessary for gremlin activation of VEGFR2, this does not appear to be essential for BMP antagonism by gremlin. Thus these sulfated polysaccharides differentially regulate the activities of gremlin. PMID- 27979783 TI - Culture-proven early-onset neonatal sepsis in Arab states in the Gulf region: two year prospective study. AB - OBJECTIVE: To investigate the incidence and the pattern of causative organisms of culture-proven early-onset sepsis (EOS) in Arab states in the Gulf region. METHODS: Five neonatal care units participated in this 2-year prospective study in Kuwait, the United Arab Emirates, and Saudi Arabia. Data were collected prospectively using a standardized data collection form. EOS was defined as the growth of a single potentially pathogenic organism from blood or cerebrospinal fluid in infants within 72h of birth, with clinical and laboratory findings consistent with infection. RESULTS: Out of 67 474 live births, 102 cases of EOS occurred. The overall incidence of EOS was 1.5 (95% confidence interval 1.2-1.8) per 1000 live-births, ranging from 2.64 per 1000 live-births in Kuwait to 0.40 per 1000 live-births in King Abdulaziz Hospital in Saudi Arabia. The most common causative organism of EOS was group B Streptococcus (GBS; 60.0%), followed by Escherichia coli (13%). The incidence of invasive GBS disease was 0.90 per 1000 live-births overall and ranged from 1.4 per 1000 live-births in Kuwait to 0.6 per 1000 live-births in Dubai Hospital. CONCLUSIONS: The incidence of EOS and the patterns of the causative organisms in the Arab states in the Gulf region are similar to those in developed countries before the era of intrapartum antibiotic prophylaxis. Efforts should be made to improve intrapartum antibiotic prophylaxis in the Arab state setting, which could avert large numbers of GBS infections. PMID- 27979782 TI - Learning from epidemiological, clinical, and immunological studies on Mycobacterium africanum for improving current understanding of host-pathogen interactions, and for the development and evaluation of diagnostics, host directed therapies, and vaccines for tuberculosis. AB - Mycobacterium africanum comprises two phylogenetic lineages within the Mycobacterium tuberculosis complex (MTBC). M. africanum was first described and isolated in 1968 from the sputum of a Senegalese patient with pulmonary tuberculosis (TB) and it has been identified increasingly as an important cause of human TB, particularly prevalent in West Africa. The restricted geographical distribution of M. africanum, in contrast to the widespread global distribution of other species of MTBC, requires explanation. Available data indicate that M. africanum may also have important differences in transmission, pathogenesis, and host-pathogen interactions, which could affect the evaluation of new TB intervention tools (diagnostics and vaccines)-those currently in use and those under development. The unequal geographical distribution and spread of MTBC species means that individual research findings from one country or region cannot be generalized across the continent. Thus, generalizing data from previous and ongoing research studies on MTBC may be inaccurate and inappropriate. A major rethink is required regarding the design and structure of future clinical trials of new interventions. The West, Central, East, and Southern African EDCTP Networks of Excellence provide opportunities to take forward these pan-Africa studies. More investments into molecular, epidemiological, clinical, diagnostic, and immunological studies across the African continent are required to enable further understanding of host-M. africanum interactions, leading to the development of more specific diagnostics, biomarkers, host-directed therapies, and vaccines for TB. PMID- 27979784 TI - Less research on tuberculosis than HIV and malaria when research agendas are poorly coordinated: a systematic review of research outputs from Cambodia. AB - OBJECTIVE: Coordination of health interventions and research is often weak during periods of political transition and unprecedented aid inflows, which Cambodia has recently experienced. Although HIV, tuberculosis (TB), and malaria have been a focus of international funding, TB has received much less. This study compares the numbers and methodologies of studies conducted on TB, malaria, and HIV in Cambodia, identifying evidence gaps and future research needs. METHODS: Three electronic databases and the grey literature were searched for studies on HIV, TB, and malaria published between January 2000 and October 2015. Information about the disease focus and methodology was extracted from the studies included. RESULTS: A total of 2581 unique studies were screened and 712 were included in the analysis. The results of this review demonstrated that despite increasing numbers of publications, there have been fewer studies on TB (16%) than HIV (43%) and malaria (41%). Observational epidemiological studies outnumbered other methodologies (44%) for all three diseases. CONCLUSIONS: Despite substantial investments, important research areas appear to have been neglected in Cambodia; specifically, studies on TB and studies involving economic, qualitative, interventional, and genomics methods. The inter-disease disparity in published research in Cambodia identified, considered alongside disease burden, suggests that an increase in TB research may be needed to inform control strategies. PMID- 27979785 TI - Evaluating the impact of healthcare provider training to improve tuberculosis management: a systematic review of methods and outcome indicators used. AB - BACKGROUND: Developing human resources capacity is vital for tuberculosis (TB) control in low- and middle-income countries. Although investments in TB healthcare provider (HCP) training programmes have increased, it is unclear whether these are robustly evaluated. The objective of this systematic review was to synthesize the methods and outcome indicators used to assess TB HCP training programmes. METHODS: A systematic scoping review of publications reporting on evaluations of training programmes for TB HCPs - including doctors, nurses, paramedics, and lay health workers - was conducted through a search in three electronic databases, Google Scholar, and five websites of non-profit organizations. Data on the study location, population trained, outcomes assessed, and evaluation approach were extracted. RESULTS: After screening 499 unique publications, 21 were eligible for inclusion in the analysis. The majority of evaluations were conducted in Africa. The most common evaluation methods were a review of patient records (n=8, 38%) and post-training interview with trainees (n=7, 33%). In terms of outcomes, more than half of the studies (n=12, 57%) evaluated knowledge acquisition of trainees, with only six (29%) assessing on-the job behaviour change. CONCLUSIONS: Even though more funds have been invested in TB HCP training, publications from robust evaluations assessing the impact on quality of care and behaviour change are limited. PMID- 27979786 TI - Exploring tuberculosis by molecular tests on DNA isolated from smear microscopy slides. AB - Tuberculosis (TB) is an infectious disease of global public health importance caused by Mycobacterium tuberculosis complex. The disease has worsened with the emergence of multidrug-resistant (MDR)-TB strains. The timely diagnosis and treatment of TB remains a key public health priority, and laboratories have a critical role in the rapid and accurate detection of TB and drug resistance. Molecular assays based on nucleic acid amplification techniques have been developed for the rapid, sensitive, and specific diagnosis of TB, with the ability to determine the drug sensitivity status. These molecular techniques are now available or are being implemented in developing countries. However, traditional microscopy and culture methods cannot yet be replaced; the molecular assays can be applied in parallel with these tests for the diagnosis of TB or for drug susceptibility testing. Performing such molecular tests is often restricted by constraints with regard to sputum sample storage and safe transportation from remote health centres to central laboratories. Since smear slides are performed routinely for the diagnosis of TB in most TB diagnostic laboratories, they are readily available and could be the ideal tool to transport sputum for further molecular tests. The aim of this review was to provide a comprehensive survey on the use of smear slides for both TB diagnosis and the molecular test approach. Based on the literature, stained smear microscopy slides can be a safe system for the transportation of sputum specimens from remote health centres to reference TB laboratories for further molecular TB or MDR-TB detection, and could help in the rapid diagnosis and therefore timely management of TB patients. PMID- 27979787 TI - Worrisome high frequency of extended-spectrum beta-lactamase-producing Escherichia coli in community-acquired urinary tract infections: a case-control study. AB - OBJECTIVES: There has been a sustained and dramatic increase in community acquired urinary tract infections (CA-UTI) caused by extended-spectrum beta lactamase (ESBL)-producing bacteria over recent years. Despite this, no studies have been performed in low- or middle-income countries. The main objective of this case-control study was to describe ESBL CA-UTI and its risk factors. METHODS: Outpatients with CA-UTI seen at the Hospital Cayetano Heredia during 2015 were identified. Patients were contacted by telephone. After consent had been obtained, a questionnaire concerning previously identified risk factors was applied. Univariate and multivariate analyses were conducted using Stata version 13. RESULTS: The overall frequency of ESBL-producing Escherichia coli was 40.85%. Sixty-seven cases and 105 controls were included in this study. The following main risk factors were identified on multivariate analysis: previous antibiotic use (odds ratio (OR) 3.09), previous hospitalization (OR 2.92), and previous surgery (OR 2.75). Chronic corticosteroid use (OR 24.32, 95% confidence interval 2.39-246.92) was also identified as a risk factor. CONCLUSIONS: ESBL E. coli accounted for more than 40% of CA-UTIs during 2015. A history of previous hospitalization, surgery, and antibiotic use should be considered when treating this type of infection. Action should be taken to confirm these worrisome results and avoid the major consequences for public health. PMID- 27979788 TI - Multivariate dynamical modelling of structural change during development. AB - Here we introduce a multivariate framework for characterising longitudinal changes in structural MRI using dynamical systems. The general approach enables modelling changes of states in multiple imaging biomarkers typically observed during brain development, plasticity, ageing and degeneration, e.g. regional gray matter volume of multiple regions of interest (ROIs). Structural brain states follow intrinsic dynamics according to a linear system with additional inputs accounting for potential driving forces of brain development. In particular, the inputs to the system are specified to account for known or latent developmental growth/decline factors, e.g. due to effects of growth hormones, puberty, or sudden behavioural changes etc. Because effects of developmental factors might be region-specific, the sensitivity of each ROI to contributions of each factor is explicitly modelled. In addition to the external effects of developmental factors on regional change, the framework enables modelling and inference about directed (potentially reciprocal) interactions between brain regions, due to competition for space, or structural connectivity, and suchlike. This approach accounts for repeated measures in typical MRI studies of development and aging. Model inversion and posterior distributions are obtained using earlier established variational methods enabling Bayesian evidence-based comparisons between various models of structural change. Using this approach we demonstrate dynamic cortical changes during brain maturation between 6 and 22 years of age using a large openly available longitudinal paediatric dataset with 637 scans from 289 individuals. In particular, we model volumetric changes in 26 bilateral ROIs, which cover large portions of cortical and subcortical gray matter. We account for (1) puberty-related effects on gray matter regions; (2) effects of an early transient growth process with additional time-lag parameter; (3) sexual dimorphism by modelling parameter differences between boys and girls. There is evidence that the regional pattern of sensitivity to dynamic hidden growth factors in late childhood is similar across genders and shows a consistent anterior-posterior gradient with strongest impact to prefrontal cortex (PFC) brain changes. Finally, we demonstrate the potential of the framework to explore the coupling of structural changes across a priori defined subnetworks using an example of previously established resting state functional connectivity. PMID- 27979790 TI - A Diabetes Self-Management Program: 12-Month Outcome Sustainability From a Nonreinforced Pragmatic Trial. AB - BACKGROUND: Diabetes self-management education has been shown to be effective in controlled trials. The 6-week Better Choices, Better Health-Diabetes (BCBH-D) self-management program was also associated with an improvement in health outcomes in a 6-month translation study. OBJECTIVE: The objective of this study was to determine whether a national translation of the BCBH-D self-management program, offered both Web-based and face-to-face, was associated with improvements in health outcomes (including HbA1c) and health behaviors (including recommended medical tests) 1 year after intervention. METHODS: Web-based programs were administered nationally, whereas face-to-face workshops took place in Atlanta, Indianapolis, and St Louis. Self-report questionnaires were either Web based or administered by mail, at baseline and 1 year, and collected health and health-behavior measures. HbA1c blood samples were collected via mailed kits. A previous 6-month study found statistically significant improvements in 13 of 14 outcome measures, including HbA1c. For this study, paired t test compared baseline with 1-year outcomes. Subgroup analyses determined whether participants with specific conditions improved (high HbA1c, depression, hypoglycemia, nonadherence to medication, no aerobic exercise). The percentage of participants with improvements in effect size of at least 0.4 in at least 1 of the 5 measures was calculated. RESULTS: A total of 857 participants with 1-year data (69.7% of baseline participants) demonstrated statistically significant 1-year improvements in 13 of 15 outcome measures; 79.9% (685/857) of participants showed improvements in effect size of 0.4 or greater in at least 1 of the 5 criterial measures. CONCLUSIONS: Participants had small but significant benefits in multiple measures. Improvements previously noted at 6 months were maintained or amplified at 1 year. PMID- 27979789 TI - Age-related reduction of BOLD modulation to cognitive difficulty predicts poorer task accuracy and poorer fluid reasoning ability. AB - Aging is associated with reduced resources needed to perform difficult cognitive tasks, but the neural underpinnings are not well understood, especially as there is scant evidence linking functional brain differences to aging cognition. Therefore, the current study examined modulation of fMRI activation from easier to harder spatial distance judgments across a large lifespan sample (N=161; ages 20-94) to identify when in the lifespan modulation to difficulty begins to show deficits and if age-related modulation predicts cognition. Analyses revealed two sets of regions in which modulation increased with difficulty due to either more activation (positive modulation) or more deactivation (negative modulation) to difficulty. These two networks evidenced differential aging trajectories: a right lateralized fronto-parietal network that decreased in modulation to difficulty between middle- and older-age, and a network of regions in ventromedial prefrontal cortex, posterior cingulate, left angular and middle frontal gyri that showed decreased modulation at the transition from younger to middle-age. Critically, older adults who maintained negative modulation to difficulty showed higher task accuracy. Further, individuals who showed greater coupling between positive and negative modulation performed better on a fluid reasoning task. Age related preservation of coupled modulation in both cognitive control regions and regions typically associated with default network may be a salient marker of how the brain adapts to maintain cognitive function as we age. PMID- 27979791 TI - Stigma and Its Impact on Glucose Control Among Youth With Diabetes: Protocol for a Canada-Wide Study. AB - BACKGROUND: Stigma in chronic disease involves unwarranted rejection, judgement, or exclusion by others based on the chronic disease itself. OBJECTIVE: We aim to determine the prevalence of stigma among youth and young adults with type 1 diabetes in Canada, to assess associations between stigma and glycemic control, and to explore ways to address stigma related to type 1 diabetes. METHODS: The study includes 3 distinct phases: (1) refinement of survey questions, (2) assessment of test-retest reliability, and (3) a data collection and analysis phase (online survey and mailed-in capillary blood sample to assess hemoglobin A1c). A total of 380 youth and young adults (14 to 24 years old) with type 1 diabetes are being recruited through social media and clinic posters. RESULTS: Phases 1 and 2 are complete, and phase 3 is in progress. Thirty participants completed phase 2. The survey includes the Barriers to Diabetes Adherence in adolescent scale (intraclass correlation [ICC]=0.967, 95% CI 0.931-0.984), the Self-Efficacy for Diabetes Self-Management measure (ICC=0.952, 95% CI 0.899 0.977), the World Health Organization-5 Well-Being Index (ICC=0.860, 95% CI 0.705 0.933), 12 closed-ended questions, and an additional 5 open-ended questions to explore challenges and solutions developed by the team of experts, including a patient representative. CONCLUSIONS: This will be the first large-scale survey to estimate the prevalence of stigma in young people with type 1 diabetes. The results of this study will allow for an appreciation of the magnitude of the problem and the need for developing and implementing solutions. This work is intended to provide an initial understanding of youth perspectives on the challenges of living with type 1 diabetes and will serve as a foundation for future research and action to help youth improve their experience of living with diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02796248, https://clinicaltrials.gov/ct2/show/NCT02796248 (Archived at http://www.webcitation.org/6mhenww3o). PMID- 27979792 TI - The Mobile Phone Affinity Scale: Enhancement and Refinement. AB - BACKGROUND: Existing instruments that assess individuals' relationships with mobile phones tend to focus on negative constructs such as addiction or dependence, and appear to assume that high mobile phone use reflects pathology. Mobile phones can be beneficial for health behavior change, disease management, work productivity, and social connections, so there is a need for an instrument that provides a more balanced assessment of the various aspects of individuals' relationships with mobile phones. OBJECTIVE: The purpose of this research was to develop, revise, and validate the Mobile Phone Affinity Scale, a multi-scale instrument designed to assess key factors associated with mobile phone use. METHODS: Participants (N=1058, mean age 33) were recruited from Amazon Mechanical Turk between March and April of 2016 to complete a survey that assessed participants' mobile phone attitudes and use, anxious and depressive symptoms, and resilience. RESULTS: Confirmatory factor analysis supported a 6-factor model. The final measure consisted of 24 items, with 4 items on each of 6 factors: Connectedness, Productivity, Empowerment, Anxious Attachment, Addiction, and Continuous Use. The subscales demonstrated strong internal consistency (Cronbach alpha range=0.76-0.88, mean 0.83), and high item factor loadings (range=0.57 0.87, mean 0.75). Tests for validity further demonstrated support for the individual subscales. CONCLUSIONS: Mobile phone affinity may have an important impact in the development and effectiveness of mobile health interventions, and continued research is needed to assess its predictive ability in health behavior change interventions delivered via mobile phones. PMID- 27979793 TI - Lower Magnetization Transfer Ratio in the Forceps Minor Is Associated with Poorer Gait Velocity in Older Adults. AB - BACKGROUND AND PURPOSE: Gait disturbances in the elderly are disabling and a major public health issue but are poorly understood. In this multimodal MR imaging study, we used 2 voxel-based analysis methods to assess the voxelwise relationship of magnetization transfer ratio and white matter hyperintensity location with gait velocity in older adults. MATERIALS AND METHODS: We assessed 230 community-dwelling participants of the Austrian Stroke Prevention Family Study. Every participant underwent 3T MR imaging, including magnetization transfer imaging. Voxel-based magnetization transfer ratio-symptom mapping correlated the white matter magnetization transfer ratio of each voxel with gait velocity. To assess a possible relationship between white matter hyperintensity location and gait velocity, we applied voxel-based lesion-symptom mapping. RESULTS: We found a significant association between the magnetization transfer ratio within the forceps minor and gait velocity (beta = 0.134; 95% CI, 0.011 0.258; P = .033), independent of demographics, general physical performance, vascular risk factors, and brain volume. White matter hyperintensities did not significantly change this association. CONCLUSIONS: Our study provides new evidence for the importance of magnetization transfer ratio changes in gait disturbances at an older age, particularly in the forceps minor. The histopathologic basis of these findings is yet to be determined. PMID- 27979794 TI - Middle Cerebral Artery Bifurcation Aneurysms Treated by Extrasaccular Flow Diverters: Midterm Angiographic Evolution and Clinical Outcome. AB - BACKGROUND AND PURPOSE: Flow diverters have been increasingly used lately in off label, distal intracranial aneurysm treatments. Our aim was to evaluate the effectiveness of flow diverters in the treatment of middle cerebral artery bifurcation aneurysms and to analyze midterm angiographic patterns of regional flow modifications for safety and clinical outcomes. MATERIALS AND METHODS: Consecutive patients treated from January 2010 to December 2014 by the authors by using endovascular flow-diverting stents for MCA bifurcation aneurysms were evaluated retrospectively with prospectively maintained data. All patients had been followed for at least 12 months after treatment, with at least 2 control angiograms; regional flow-related angiographic modifications were registered by using a new angiographic outcome scale for flow diverters. Data were analyzed with emphasis on procedure-related events, angiographic results, and clinical outcome. RESULTS: Fifty-eight patients were included in the study, with 63 MCA bifurcation aneurysms; 13 of these were large and giant. Pretreatment mRS was 0 for 12 patients (20.7%), 1 for 41 (70.7%), and 2 for 5 patients (8.6%). Six-month control revealed mRS 0-2 for 57 (98.3%) patients and 3 for 1 (1.7%) patient. Procedure-related morbidity and mortality were 8.6% (5/58) and 0%, respectively. From 95% of still circulating immediate postprocedure angiographic outcomes, 68% progressed to aneurysm occlusion at 6 months and 95%, to occlusion at 12 months, with a 0% aneurysm rupture rate. CONCLUSIONS: Flow diverters seem to be an effective treatment alternative for complex MCA bifurcation aneurysms, with reasonable complication rates. Longer angiographic follow-ups are needed to assess the morphologic outcome; immediate subtotal occlusions do not seem to be related to rupture. PMID- 27979795 TI - Differential Interstrain Susceptibility to Vertebrobasilar Dolichoectasia in a Mouse Model. AB - BACKGROUND AND PURPOSE: Vetebrobasilar dolichoectasia is characterized by arterial elongation, dilation, and tortuosity and leads to high risks of ischemic stroke. Our aim was to investigate the differential susceptibility to elastase induced vertebrobasilar dolichoectasia induction in 2 different mouse strains. MATERIALS AND METHODS: Elastase (25 mU) was injected into the cisterna magna in C57BL/6J (n = 36) and 129/SvEv (SV129) (n = 36) mice. Control animals were injected with heat-inactivated elastase (n = 12 for each strain). At 3, 7, 14, and 28 days after elastase injection, MICROFIL polymer perfusion was performed. The arterial tortuosity index and the percentage increase in diameter were calculated for the basilar artery. Arterial samples were processed for conventional histologic examination, immunostaining, and matrix metalloproteinase expression. A >=50% increase in diameter and a tortuosity index of >=10 for the basilar artery were used to indicate success in achieving vertebrobasilar dolichoectasia. RESULTS: Successful vertebrobasilar dolichoectasia induction was noted in 67% (18 of 27) of the C57BL/6J strain versus 0% (0 of 19) of the SV129 strain (P < .001). Vertebrobasilar dolichoectasia was not observed in sham operated controls. Both the tortuosity index and diameter increase for the basilar artery were greater in the C57BL/6J strain compared with the SV129 strain (56.3% +/- 16.4% versus 21.1% +/- 21.6% for diameter, P < .001; 17.4 +/- 7.6 versus 10.4 +/- 3.8 for tortuosity index, P < .001). Expression of pro-matrix metalloproteinase-2 and pro- and active matrix metalloproteinase-9 was increased in elastase-injected C57BL/6J animals compared with elastase-injected SV129 animals (P = .029, 0.029, and 0.029, respectively). Inflammation scores were significantly higher in C57BL/6J animals versus SV129 animals (P < .001). C57BL/6J subjects demonstrated arterial wall dilation and elongation characterized by internal elastic lamina disruption, muscular layer discontinuity, inflammatory cell infiltration, and high matrix metalloproteinase expression in the media. CONCLUSIONS: C57BL/6J mice demonstrated greater susceptibility to vertebrobasilar dolichoectasia induction than SV129 mice. PMID- 27979796 TI - White Matter Microstructural Abnormalities in Type 2 Diabetes Mellitus: A Diffusional Kurtosis Imaging Analysis. AB - BACKGROUND AND PURPOSE: Increasing DTI studies have demonstrated that white matter microstructural abnormalities play an important role in type 2 diabetes mellitus-related cognitive impairment. In this study, the diffusional kurtosis imaging method was used to investigate WM microstructural alterations in patients with type 2 diabetes mellitus and to detect associations between diffusional kurtosis imaging metrics and clinical/cognitive measurements. MATERIALS AND METHODS: Diffusional kurtosis imaging and cognitive assessments were performed on 58 patients with type 2 diabetes mellitus and 58 controls. Voxel-based intergroup comparisons of diffusional kurtosis imaging metrics were conducted, and ROI-based intergroup comparisons were further performed. Correlations between the diffusional kurtosis imaging metrics and cognitive/clinical measurements were assessed after controlling for age, sex, and education in both patients and controls. RESULTS: Altered diffusion metrics were observed in the corpus callosum, the bilateral frontal WM, the right superior temporal WM, the left external capsule, and the pons in patients with type 2 diabetes mellitus compared with controls. The splenium of the corpus callosum and the pons had abnormal kurtosis metrics in patients with type 2 diabetes mellitus. Additionally, altered diffusion metrics in the right prefrontal WM were significantly correlated with disease duration and attention task performance in patients with type 2 diabetes mellitus. CONCLUSIONS: With both conventional diffusion and additional kurtosis metrics, diffusional kurtosis imaging can provide additional information on WM microstructural abnormalities in patients with type 2 diabetes mellitus. Our results indicate that WM microstructural abnormalities occur before cognitive decline and may be used as neuroimaging markers for predicting the early cognitive impairment in patients with type 2 diabetes mellitus. PMID- 27979797 TI - Feasibility and Safety of Repeat Instant Endovascular Interventions in Patients with Refractory Cerebral Vasospasms. AB - BACKGROUND AND PURPOSE: For patients with cerebral vasospasm refractory to medical and hemodynamic therapies, endovascular therapies often remain the last resort. Data from studies in large cohorts on the efficacy and safety of multiple immediate endovascular interventions are sparse. Our aim was to assess the feasibility and safety of multiple repeat instant endovascular interventions in patients with cerebral vasospasm refractory to medical, hemodynamic, and initial endovascular interventions. MATERIALS AND METHODS: This was a single-center retrospective study of prospectively collected data on patients with cerebral vasospasm refractory to therapies requiring >=3 endovascular interventions during the course of treatment following aneurysmal subarachnoid hemorrhage. The primary end point was functional outcome at last follow-up (mRS <=2). The secondary end point was angiographic response to endovascular therapies and the appearance of cerebral infarctions. RESULTS: During a 4-year period, 365 patients with aneurysmal subarachnoid hemorrhage were treated at our institution. Thirty-one (8.5%) met the inclusion criteria. In 52 (14%) patients, <=2 endovascular interventions were performed as rescue therapy for refractory cerebral vasospasm. At last follow-up, a good outcome was noted in 18 (58%) patients with >=3 interventions compared with 31 (61%) of those with <=2 interventions (P = .82). The initial Hunt and Hess score of <=2 was a significant independent predictor of good outcome (OR, 4.7; 95% CI, 1.2-18.5; P = .03), whereas infarcts in eloquent brain areas were significantly associated with a poor outcome (mRS 3-6; OR, 13.5; 95% CI, 2.3-81.2; P = .004). CONCLUSIONS: Repeat instant endovascular intervention is an aggressive but feasible last resort treatment strategy with a favorable outcome in two-thirds of patients with refractory cerebral vasospasm and in whom endovascular treatment has already been initiated. PMID- 27979798 TI - MRI Atlas-Based Measurement of Spinal Cord Injury Predicts Outcome in Acute Flaccid Myelitis. AB - BACKGROUND AND PURPOSE: Recent advances in spinal cord imaging analysis have led to the development of a robust anatomic template and atlas incorporated into an open-source platform referred to as the Spinal Cord Toolbox. Using the Spinal Cord Toolbox, we sought to correlate measures of GM, WM, and cross-sectional area pathology on T2 MR imaging with motor disability in patients with acute flaccid myelitis. MATERIALS AND METHODS: Spinal cord imaging for 9 patients with acute flaccid myelitis was analyzed by using the Spinal Cord Toolbox. A semiautomated pipeline using the Spinal Cord Toolbox measured lesion involvement in GM, WM, and total spinal cord cross-sectional area. Proportions of GM, WM, and cross sectional area affected by T2 hyperintensity were calculated across 3 ROIs: 1) center axial section of lesion; 2) full lesion segment; and 3) full cord atlas volume. Spearman rank order correlation was calculated to compare MR metrics with clinical measures of disability. RESULTS: Proportion of GM metrics at the center axial section significantly correlated with measures of motor impairment upon admission (r [9] = -0.78; P = .014) and at 3-month follow-up (r [9] = -0.66; P = .05). Further, proportion of GM extracted across the full lesion segment significantly correlated with initial motor impairment (r [9] = -0.74, P = .024). No significant correlation was found for proportion of WM or proportion of cross sectional area with clinical disability. CONCLUSIONS: Atlas-based measures of proportion of GM T2 signal abnormality measured on a single axial MR imaging section and across the full lesion segment correlate with motor impairment and outcome in patients with acute flaccid myelitis. This is the first atlas-based study to correlate clinical outcomes with segmented measures of T2 signal abnormality in the spinal cord. PMID- 27979802 TI - Commentary on "Epithelial-to-Mesenchymal Transition Contributes to Drug Resistance in Pancreatic Cancer". PMID- 27979803 TI - Correction: Autocrine Production of Interleukin-4 and Interleukin-10 Is Required for Survival and Growth of Thyroid Cancer Cells. PMID- 27979804 TI - Correction: IFN-beta Down-Regulates the Expression of DNA Repair Gene MGMT and Sensitizes Resistant Glioma Cells to Temozolomide. PMID- 27979808 TI - Innovative reporter gene imaging techniques making inroads to biology. PMID- 27979806 TI - Cytotoxic T Cells and Granzyme B Associated with Improved Colorectal Cancer Survival in a Prospective Cohort of Older Women. AB - Background: Host immune response may predict the course of colorectal cancer. We examined the survival of 468 colorectal cancer patients associated with two tumor infiltrating immune biomarkers, the number of cytotoxic T lymphocytes (CTLs), and the activated CTLs, as reflected by the number of cells expressing granzyme B (GZMB) in the prospective Iowa Women's Health Study.Methods: Using paraffin embedded tissue samples, we constructed and immunostained tumor microarrays with CD8 (for CTL) and GZMB antibodies. We scored CTL and GZMB densities in tumor epithelial and stromal tissues and also created a composite score for each biomarker (sum of the scores across tissue compartments). Cox regression estimated the HR and 95% confidence intervals (CI) for all-cause and colorectal cancer-specific death associated with each composite score.Results: CTL and GZMB composite scores were positively correlated (r = 0.65) and each biomarker was inversely correlated with stage at diagnosis. Both composite scores were higher in proximal colon tumors and tumors characterized by MSI-high, CIMP-high, or BRAF mutation status. HRs (95% CI) were 0.53 (0.38-0.75; Ptrend = 0.0004) and 0.66 (0.51-0.86; Ptrend = 0.002) for all-cause death, respectively, and 0.30 (0.18 0.51; Ptrend < 0.0001) and 0.41 (0.27-0.63; Ptrend < 0.0001) for colorectal cancer-related death, respectively. Including CTL and GZMB scores simultaneously in the model significantly improved the predictive performance of the models for all-cause and colorectal cancer-related death.Conclusions: Higher tumor infiltration with CTL and GZMB cells is associated with improved all-cause and cancer-specific survival of colorectal cancer patients.Impact: Both the number of CTLs and GZMB appear to be useful prognostic factors in colorectal cancer, irrespective of stage. Cancer Epidemiol Biomarkers Prev; 26(4); 622-31. (c)2016 AACR. PMID- 27979807 TI - Clinical and Epidemiological Implications of 24-Hour Ambulatory Blood Pressure Monitoring for the Diagnosis of Hypertension in Kenyan Adults: A Population-Based Study. AB - BACKGROUND: The clinical and epidemiological implications of using ambulatory blood pressure monitoring (ABPM) for the diagnosis of hypertension have not been studied at a population level in sub-Saharan Africa. We examined the impact of ABPM use among Kenyan adults. METHODS AND RESULTS: We performed a nested case control study of diagnostic accuracy. We selected an age-stratified random sample of 1248 adults from the list of residents of the Kilifi Health and Demographic Surveillance System in Kenya. All participants underwent a screening blood pressure (BP) measurement. All those with screening BP >=140/90 mm Hg and a random subset of those with screening BP <140/90 mm Hg were invited to undergo ABPM. Based on the 2 tests, participants were categorized as sustained hypertensive, masked hypertensive, "white coat" hypertensive, or normotensive. Analyses were weighted by the probability of undergoing ABPM. Screening BP >=140/90 mm Hg was present in 359 of 986 participants, translating to a crude population prevalence of 23.1% (95% CI 16.5-31.5%). Age standardized prevalence of screening BP >=140/90 mm Hg was 26.5% (95% CI 19.3-35.6%). On ABPM, 186 of 415 participants were confirmed to be hypertensive, with crude prevalence of 15.6% (95% CI 9.4-23.1%) and age-standardized prevalence of 17.1% (95% CI 11.0-24.4%). Age-standardized prevalence of masked and white coat hypertension were 7.6% (95% CI 2.8-13.7%) and 3.8% (95% CI 1.7-6.1%), respectively. The sensitivity and specificity of screening BP measurements were 80% (95% CI 73-86%) and 84% (95% CI 79-88%), respectively. BP indices and validity measures showed strong age-related trends. CONCLUSIONS: Screening BP measurement significantly overestimated hypertension prevalence while failing to identify ~50% of true hypertension diagnosed by ABPM. Our findings suggest significant clinical and epidemiological benefits of ABPM use for diagnosing hypertension in Kenyan adults. PMID- 27979809 TI - Natriuretic peptides and peripheral autonomic neurotransmission: back to the A, B, and C's. PMID- 27979810 TI - 'A picture is worth a thousand words': image highlights from Cardiovascular Research. PMID- 27979812 TI - Opioid manufacturer bribed doctors to prescribe fentanyl inappropriately, US says. PMID- 27979815 TI - Raising council tax to pay for social care is not acceptable, say critics. PMID- 27979816 TI - Christmas crackers: highlights from past years of The BMJ's seasonal issue. PMID- 27979811 TI - High glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature. AB - AIMS: The secretion of enzymatically active heparanase (HepA) has been implicated as an essential metabolic adaptation in the heart following diabetes. However, the regulation and function of the enzymatically inactive heparanase (HepL) remain poorly understood. We hypothesized that in response to high glucose (HG) and secretion of HepL from the endothelial cell (EC), HepL uptake and function can protect the cardiomyocyte by modifying its cell death signature. METHODS AND RESULTS: HG promoted both HepL and HepA secretion from microvascular (rat heart micro vessel endothelial cells, RHMEC) and macrovascular (rat aortic endothelial cells, RAOEC) EC. However, only RAOEC were capable of HepL reuptake. This occurred through a low-density lipoprotein receptor-related protein 1 (LRP1) dependent mechanism, as LRP1 inhibition using small interfering RNA (siRNA), receptor-associated protein, or an LRP1 neutralizing antibody significantly reduced uptake. In cardiomyocytes, which have a negligible amount of heparanase gene expression, LRP1 also participated in the uptake of HepL. Exogenous addition of HepL to rat cardiomyocytes produced a dramatically altered expression of apoptosis-related genes, and protection against HG and H2O2 induced cell death. Cardiomyocytes from acutely diabetic rats demonstrated a robust increase in LRP1 expression and levels of heparanase, a pro-survival gene signature, and limited evidence of cell death, observations that were not apparent following chronic and progressive diabetes. CONCLUSION: Our results highlight EC-to-cardiomyocyte transfer of heparanase to modulate the cardiomyocyte cell death signature. This mechanism was observed in the acutely diabetic heart, and its interruption following chronic diabetes may contribute towards the development of diabetic cardiomyopathy. PMID- 27979817 TI - Swap pension pledges for guaranteed care in older age, says NHS boss. PMID- 27979818 TI - Virtual reality compared with in vivo exposure in the treatment of social anxiety disorder: a three-arm randomised controlled trial. AB - BackgroundPeople with social anxiety disorder (SAD) fear social interactions and may be reluctant to seek treatments involving exposure to social situations. Social exposure conducted in virtual reality (VR), embedded in individual cognitive-behavioural therapy (CBT), could be an answer.AimsTo show that conducting VR exposure in CBT for SAD is effective and is more practical for therapists than conducting exposure in vivoMethodParticipants were randomly assigned to either VR exposure (n = 17), in vivo exposure (n = 22) or waiting list (n = 20). Participants in the active arms received individual CBT for 14 weekly sessions and outcome was assessed with questionnaires and a behaviour avoidance test. (Trial registration number ISRCTN99747069)ResultsImprovements were found on the primary (Liebowitz Social Anxiety Scale) and all five secondary outcome measures in both CBT groups compared with the waiting list. Conducting exposure in VR was more effective at post-treatment than in vivo on the primary outcome measure and on one secondary measure. Improvements were maintained at the 6-month follow-up. VR was significantly more practical for therapists than in vivo exposure.ConclusionsUsing VR can be advantageous over standard CBT as a potential solution for treatment avoidance and as an efficient, cost-effective and practical medium of exposure. PMID- 27979819 TI - Psychosis in autism: comparison of the features of both conditions in a dually affected cohort. AB - BackgroundThere is limited information on the presentation and characteristics of psychotic illness experienced by people with autism spectrum disorder (ASD).AimsTo describe autistic and psychotic phenomenology in a group of individuals with comorbid ASD and psychosis (ASD-P) and compare this group with populations affected by either, alone.MethodWe studied 116 individuals with ASD P. We compared features of their ASD with people with ASD and no comorbid psychosis (ASD-NP), and clinical characteristics of psychosis in ASD-P with people with psychosis only.ResultsIndividuals with ASD-P had more diagnoses of atypical psychosis and fewer of schizophrenia compared with individuals with psychosis only. People with ASD-P had fewer stereotyped interests/behaviours compared with those with ASD-NP.ConclusionsOur data show there may be a specific subtype of ASD linked to comorbid psychosis. The results support findings that psychosis in people with ASD is often atypical, particularly regarding affective disturbance. PMID- 27979820 TI - Acceptance and commitment therapy for psychosis: randomised controlled trial. AB - BACKGROUND: The efficacy of acceptance and commitment therapy (ACT) in psychosis has been reported but not for medication-resistant psychosis. AIMS: To test the efficacy of ACT in a sample of community-residing patients with persisting psychotic symptoms. (Australian New Zealand Clinical Trials Registry: ACTRN12608000210370.) METHOD: The primary outcome was overall mental state at post-therapy (Positive and Negative Syndrome Scale - total); secondary outcomes were psychotic symptom dimensions and functioning. In total, 96 patients were randomised to ACT (n = 49) or befriending (n = 47). Symptom, functioning and process measures were administered at baseline, post-therapy and 6 months later. RESULTS: There was no group difference on overall mental state. In secondary analyses the ACT group showed greater improvement in positive symptoms and hallucination distress at follow-up: Cohen's d = 0.52 (95% CI 0.07-0.98) and 0.65 (95% CI 0.24-1.06), respectively. CONCLUSIONS: Improvements reflected the treatment focus on positive symptoms; however, absence of process-measure changes suggests that the ACT intervention used did not manipulate targeted processes beyond befriending. Symptom-specific therapy refinements, improved investigation of process and attention to cognitive functioning and dose are warranted in future research. PMID- 27979821 TI - Weight-related peer-teasing moderates genetic and environmental risk and disordered eating: twin study. AB - BackgroundWeight-related peer-teasing is considered a potent prospective risk factor for development of disordered eating and clinical eating disorders. Currently, the interplay between genetic and environmental influences has yet to be elucidated.AimsTo determine whether peer-teasing moderates latent genetic and/or environmental risk for disordered eating among female adolescent twins.MethodFull quantitative gene-environment interplay modelling of longitudinal trajectory of disordered eating in 685 female twins from the Australian Twin Registry.ResultsA model permitting moderation of disordered eating by peer-teasing involving genetic and non-shared environment effects fit these data best. As levels of peer-teasing increased, both genetic and environmental influences on disordered eating strengthened; however, genetic sources increased proportionally more than environmental sources.ConclusionsWeight-related peer-teasing represents a particularly powerful trigger for disordered eating. Nevertheless, it is amenable to intervention/prevention activities spanning individual to universal levels of endeavour. PMID- 27979822 TI - Open toe sandals syndrome. PMID- 27979823 TI - In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia. AB - It is widely suspected, yet controversial, that infection plays an etiologic role in the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer and a disease with a confirmed prenatal origin in most cases. We investigated infections at diagnosis and then assessed the timing of infection at birth in children with ALL and age, gender, and ethnicity matched controls to identify potential causal initiating infections. Comprehensive untargeted virome and bacterial analyses of pretreatment bone marrow specimens (n = 127 ALL in comparison with 38 acute myeloid leukemia cases in a comparison group) revealed prevalent cytomegalovirus (CMV) infection at diagnosis in childhood ALL, demonstrating active viral transcription in leukemia blasts as well as intact virions in serum. Screening of newborn blood samples revealed a significantly higher prevalence of in utero CMV infection in ALL cases (n = 268) than healthy controls (n = 270) (odds ratio [OR], 3.71, confidence interval [CI], 1.56-7.92, P = .0016). Risk was more pronounced in Hispanics (OR=5.90, CI=1.89-25.96) than in non-Hispanic whites (OR=2.10 CI= 0.69-7.13). This is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children. Further investigation of CMV as an etiologic agent for ALL is warranted. PMID- 27979825 TI - Critical role of microbiota within cecal crypts on the regenerative capacity of the intestinal epithelium following surgical stress. AB - : Cecal crypts represent a unique niche that are normally occupied by the commensal microbiota. Due to their density and close proximity to stem cells, microbiota within cecal crypts may modulate epithelial regeneration. Here we demonstrate that surgical stress, a process that invariably involves a short period of starvation, antibiotic exposure, and tissue injury, results in cecal crypt evacuation of their microbiota. Crypts devoid of their microbiota display pathophysiological features characterized by abnormal stem cell activation as judged by leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) staining, expansion of the proliferative zone toward the tips of the crypts, and an increase in apoptosis. In addition, crypts devoid of their microbiota display loss of their regenerative capacity as assessed by their ability to form organoids ex vivo. When a four-member human pathogen community isolated from the stool of a critically ill patient is introduced into the cecum of mice with empty crypts, crypts become occupied by the pathogens and further disruption of crypt homeostasis is observed. Fecal microbiota transplantation restores the cecal crypts' microbiota, normalizes homeostasis within crypts, and reestablishes crypt regenerative capacity. Taken together, these findings define an emerging role for the microbiota within cecal crypts to maintain epithelial cell homeostasis in a manner that may enhance recovery in response to the physiological stress imposed by the process of surgery. NEW & NOTEWORTHY: This study provides novel insight into the process by which surgical injury places the intestinal epithelium at risk for colonization by pathogenic microbes and impairment of its regenerative capacity via loss of its microbiota. We show that fecal transplant restores crypt homeostasis in association with repopulation of the microbiota within cecal crypts. PMID- 27979826 TI - miR-200b inhibits TNF-alpha-induced IL-8 secretion and tight junction disruption of intestinal epithelial cells in vitro. AB - : Inflammatory bowel diseases (IBDs) are chronic, inflammatory disorders of the gastrointestinal tract with unclear etiologies. Intestinal epithelial cells (IECs), containing crypt and villus enterocytes, occupy a critical position in the pathogenesis of IBDs and are a major producer of immunoregulatory cytokines and a key component of the intact epithelial barrier. Previously, we have reported that miR-200b is involved in the progression of IBDs and might maintain the integrity of the intestinal epithelial barrier via reducing the loss of enterocytes. In this study, we further investigated the impact of miR-200b on intestinal epithelial inflammation and tight junctions in two distinct differentiated states of Caco-2 cells after TNF-alpha treatment. We demonstrated that TNF-alpha-enhanced IL-8 expression was decreased by microRNA (miR)-200b in undifferentiated IECs. Simultaneously, miR-200b could alleviate TNF-alpha-induced tight junction (TJ) disruption in well-differentiated IECs by reducing the reduction in the transepithelial electrical resistance (TEER), inhibiting the increase in paracellular permeability, and preventing the morphological redistribution of the TJ proteins claudin 1 and ZO-1. The expression levels of the JNK/c-Jun/AP-1 and myosin light chain kinase (MLCK)/phosphorylated myosin light chain (p-MLC) pathways were attenuated in undifferentiated and differentiated enterocytes, respectively. Furthermore, a dual-luciferase reporter gene detection system provided direct evidence that c-Jun and MLCK were the specific targets of miR-200b. Collectively, our results highlighted that miR-200b played a positive role in IECs via suppressing intestinal epithelial IL-8 secretion and attenuating TJ damage in vitro, which suggested that miR-200b might be a promising strategy for IBD therapy. NEW & NOTEWORTHY: This was the first time that the inhibitory role of miR-200b on intestinal epithelial inflammation and paracellular permeability has been reported. Moreover, we further divided the intestinal epithelial cells (IECs) into two differentiated conditions and investigated the distinct impacts of miR-200b. Finally, we put forward and proved that myosin light chain kinase (MLCK) was a novel target of miR-200b. PMID- 27979827 TI - Protective roles of hepatic GABA signaling in acute liver injury of rats. AB - gamma-Aminobutyric acid (GABA) is produced by various cells through the catalytic activity of glutamic acid decarboxylase (GAD). Activation of type-A GABA receptor (GABAAR) inhibits stem cell proliferation but protects differentiated cells from injures. The present study investigated hepatic GABA signaling system and the role of this system in liver physiology and pathophysiology. RT-PCR and immunoblot assays identified GAD and GABAAR subunits in rat livers and in HepG2 and Clone 9 hepatocytes. Patch-clamp recording detected GABA-induced currents in Clone 9 hepatocytes and depolarization in WITT cholangiocytes. The function of hepatic GABA signaling system in rats was examined using models of d galactosamine (GalN)-induced acute hepatocytic injury in vivo and in vitro. The expression of GAD increased whereas GABAAR subunits decreased in the liver of GalN-treated rats. Remarkably, treating rats with GABA or the GABAAR agonist muscimol, but not the GABABR agonist baclofen, protected hepatocytes against GalN toxicity and improved liver function. In addition, muscimol treatment decreased the formation of pseudobile ductules and the enlargement of hepatocytic canaliculi in GalN-treated rats. Our results revealed that a complex GABA signaling system exists in the rat liver. Activation of this intrahepatic GABAergic system protected the liver against toxic injury.NEW & NOTEWORTHY Auto- and paracrine GABAergic signaling systems exist in the rat hepatocytes and cholangiocytes. Activation of GABA signaling protects liver function from d galactosamine injury by reducing toxic impairment of hepatocytes and by decreasing cholangiocyte proliferation. PMID- 27979829 TI - Polyglutamine length-dependent toxicity from alpha1ACT in Drosophila models of spinocerebellar ataxia type 6. AB - Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that results from abnormal expansion of a polyglutamine (polyQ) repeat. SCA6 is caused by CAG triplet repeat expansion in the gene CACNA1A, resulting in a polyQ tract of 19-33 in patients. CACNA1A, a bicistronic gene, encodes the alpha1A calcium channel subunit and the transcription factor, alpha1ACT. PolyQ expansion in alpha1ACT causes degeneration in mice. We recently described the first Drosophila models of SCA6 that express alpha1ACT with a normal (11Q) or hyper-expanded (70Q) polyQ. Here, we report additional alpha1ACT transgenic flies, which express full-length alpha1ACT with a 33Q repeat. We show that alpha1ACT33Q is toxic in Drosophila, but less so than the 70Q version. When expressed everywhere, alpha1ACT33Q expressing adults die earlier than flies expressing the normal allele. alpha1ACT33Q causes retinal degeneration and leads to aggregated species in an age-dependent manner, but at a slower pace than the 70Q counterpart. According to western blots, alpha1ACT33Q localizes less readily in the nucleus than alpha1ACT70Q, providing clues into the importance of polyQ tract length on alpha1ACT localization and its site of toxicity. We expect that these new lines will be highly valuable for future work on SCA6. PMID- 27979828 TI - Conditional genetic deletion of Ano1 in interstitial cells of Cajal impairs Ca2+ transients and slow waves in adult mouse small intestine. AB - Myenteric plexus interstitial cells of Cajal (ICC-MY) in the small intestine are Kit+ electrical pacemakers that express the Ano1/TMEM16A Ca2+-activated Cl- channel, whose functions in the gastrointestinal tract remain incompletely understood. In this study, an inducible Cre-LoxP-based approach was used to advance the understanding of Ano1 in ICC-MY of adult mouse small intestine. KitCreERT2/+;Ano1Fl/Fl mice were treated with tamoxifen or vehicle, and small intestines (mucosa free) were examined. Quantitative RT-PCR demonstrated ~50% reduction in Ano1 mRNA in intestines of conditional knockouts (cKOs) compared with vehicle-treated controls. Whole mount immunohistochemistry showed a mosaic/patchy pattern loss of Ano1 protein in ICC networks. Ca2+ transients in ICC-MY network of cKOs displayed reduced duration compared with highly synchronized controls and showed synchronized and desynchronized profiles. When matched, the rank order for Ano1 expression in Ca2+ signal imaged fields of view was as follows: vehicle controls>>>cKO(synchronized)>cKO(desynchronized). Maintenance of Ca2+ transients' synchronicity despite high loss of Ano1 indicates a large functional reserve of Ano1 in the ICC-MY network. Slow waves in cKOs displayed reduced duration and increased inter-slow-wave interval and occurred in regular- and irregular-amplitude oscillating patterns. The latter activity suggested ongoing interaction by independent interacting oscillators. Lack of slow waves and depolarization, previously reported for neonatal constitutive knockouts, were also seen. In summary, Ano1 in adults regulates gastrointestinal function by determining Ca2+ transients and electrical activity depending on the level of Ano1 expression. Partial Ano1 loss results in Ca2+ transients and slow waves displaying reduced duration, while complete and widespread absence of Ano1 in ICC-MY causes lack of slow wave and desynchronized Ca2+ transients.NEW & NOTEWORTHY The Ca2+-activated Cl- channel, Ano1, in interstitial cells of Cajal (ICC) is necessary for normal gastrointestinal motility. We knocked out Ano1 to varying degrees in ICC of adult mice. Partial knockout of Ano1 shortened the widths of electrical slow waves and Ca2+ transients in myenteric ICC but Ca2+ transient synchronicity was preserved. Near-complete knockout was necessary for transient desynchronization and loss of slow waves, indicating a large functional reserve of Ano1 in ICC. PMID- 27979830 TI - Molecular insights into Adgra2/Gpr124 and Reck intracellular trafficking. AB - Adgra2, formerly known as Gpr124, is a key regulator of cerebrovascular development in vertebrates. Together with the GPI-anchored glycoprotein Reck, this adhesion GPCR (aGPCR) stimulates Wnt7-dependent Wnt/beta-catenin signaling to promote brain vascular invasion in an endothelial cell-autonomous manner. Adgra2 and Reck have been proposed to assemble a receptor complex at the plasma membrane, but the molecular modalities of their functional synergy remain to be investigated. In particular, as typically found in aGPCRs, the ectodomain of Adgra2 is rich in protein-protein interaction motifs whose contributions to receptor function are unknown. In opposition to the severe ADGRA2 genetic lesions found in previously generated zebrafish and mouse models, the zebrafish ouchless allele encodes an aberrantly-spliced and inactive receptor lacking a single leucine-rich repeat (LRR) unit within its N-terminus. By characterizing this allele we uncover that, in contrast to all other extracellular domains, the precise composition of the LRR domain determines proper receptor trafficking to the plasma membrane. Using CRISPR/Cas9 engineered cells, we further show that Adgra2 trafficking occurs in a Reck-independent manner and that, similarly, Reck reaches the plasma membrane irrespective of Adgra2 expression or localization, suggesting that the partners meet at the plasma membrane after independent intracellular trafficking events. PMID- 27979831 TI - Systematic and general method for quantifying localization in microscopy images. AB - Quantifying the localization of molecules with respect to other molecules, cell structures and intracellular regions is essential to understanding their regulation and actions. However, measuring localization from microscopy images is often difficult with existing metrics. Here, we evaluate a metric for quantifying localization termed the threshold overlap score (TOS), and show it is simple to calculate, easy to interpret, able to be used to systematically characterize localization patterns, and generally applicable. TOS is calculated by: (i) measuring the overlap of pixels that are above the intensity thresholds for two signals; (ii) determining whether the overlap is more, less, or the same as expected by chance, i.e. colocalization, anti-colocalization, or non colocalization; and (iii) rescaling to allow comparison at different thresholds. The above is repeated at multiple threshold combinations to generate a TOS matrix to systematically characterize the relationship between localization and signal intensities. TOS matrices were used to identify and distinguish localization patterns of different proteins in various simulations, cell types and organisms with greater specificity and sensitivity than common metrics. For all the above reasons, TOS is an excellent first line metric, particularly for cells with mixed localization patterns. PMID- 27979833 TI - Serum levels of endothelial glycocalyx constituents in women at 20 weeks' gestation who later develop gestational diabetes mellitus compared to matched controls: a pilot study. AB - OBJECTIVES: The aim of this pilot study was to determine the serum concentration of heparan sulfate, hyaluronan, chondroitin sulfate and syndecan-1 and if these serum concentrations can be used to identify women at 20 weeks' gestation who later develop gestational diabetes mellitus (GDM). DESIGN: Nested case-control study from Auckland, New Zealand participants in the prospective cohort Screening for Pregnancy Endpoints study. SETTING: Auckland, New Zealand. PARTICIPANTS: 20 pregnant women (70% European, 15% Indian, 10% Asian, 5% Pacific Islander) at 20 weeks' gestation without any hypertensive complications who developed GDM by existing New Zealand criteria defined as a fasting glucose >=5.5 mmol/L and/or 2 hours >=9.0 mmol/L after a 75 g Oral Glucose Tolerance Test. Women not meeting these criteria were excluded from this study. The patients with GDM were matched with 20 women who had uncomplicated pregnancies and negative screening for GDM and matched for ethnicity, maternal age and BMI. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary measures were the serum concentrations of syndecan-1, heparan sulfate, hyaluronan and chondroitin sulfate determined by quantitative ELISA. There were no secondary outcome measures. RESULTS: Binary logistic regression was performed to determine if serum concentrations of endothelial glycocalyx layer constituents in women at 20 weeks' gestation would be useful in predicting the subsequent diagnosis of GDM. The model was not statistically significant chi2=12.5, df=8, p=0.13, which indicates that the model was unable to distinguish between pregnant women at 20 weeks' gestation who later developed GDM and those who did not. CONCLUSIONS: Serum concentrations of syndecan-1, heparan sulfate, hyaluronan and chondroitin sulfate in pregnant women at 20 weeks' gestation were not associated with later development of GDM. To further explore whether there is any relationship between endothelial glycocalyx constituents and GDM, the next step is to evaluate serum concentrations at the time diagnosis of GDM. PMID- 27979832 TI - Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. AB - : Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments. SIGNIFICANCE: Many genotoxic chemotherapies have debilitating side effects and also induce cellular senescence in normal tissues. The senescent cells remain chronically present where they can promote local and systemic inflammation that causes or exacerbates many side effects of the chemotherapy. Cancer Discov; 7(2); 165-76. (c)2016 AACR.This article is highlighted in the In This Issue feature, p. 115. PMID- 27979835 TI - Population-based assessment of prevalence and causes of visual impairment in the state of Telangana, India: a cross-sectional study using the Rapid Assessment of Visual Impairment (RAVI) methodology. AB - OBJECTIVE: To assess the prevalence and causes of visual impairment (VI) among a rural population aged 40 years and older in the state of Telangana in India. DESIGN: Population-based cross-sectional study. SETTING: Districts of Adilabad and Mahbubnagar in south Indian state of Telangana, India. PARTICIPANTS: A sample of 6150 people was selected using cluster random sampling methodology. A team comprising a trained vision technician and a field worker visited the households and conducted the eye examination. Presenting, pinhole and aided visual acuity were assessed. Anterior segment was examined using a torchlight. Lens was examined using distant direct ophthalmoscopy in a semidark room. In all, 5881 (95.6%) participants were examined from 123 study clusters. Among those examined, 2723 (46.3%) were men, 4824 (82%) had no education, 2974 (50.6%) were from Adilabad district and 1694 (28.8%) of them were using spectacles at the time of eye examination. PRIMARY OUTCOME MEASURE: VI was defined as presenting visual acuity <6/18 in the better eye and it included moderate VI (<6/18 to 6/60) and blindness (<6/60). RESULTS: The age-adjusted and gender-adjusted prevalence of VI was 15.0% (95% CI 14.1% to 15.9%). On applying binary logistic regression analysis, VI was associated with older age groups. The odds of having VI were higher among women (OR 1.2; 95% CI 1.0 to 1.4). Having any education (OR 0.4; 95% CI 0.3 to 0.6) and current use of glasses (OR 0.19; 95% CI 0.1 to 0.2) were protective. VI was also higher in Mahbubnagar (OR 1.0 to 1.5) district. Cataract (54.7%) was the leading cause of VI followed by uncorrected refractive errors (38.6%). CONCLUSIONS: VI continues to remain a challenge in rural Telangana. As over 90% of the VI is avoidable, massive eye care programmes are required to address the burden of VI in Telangana. PMID- 27979834 TI - Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS): a study protocol for a double-blind, randomised, placebo-controlled, proof-of-concept study. AB - INTRODUCTION: Acute kidney injury (AKI) after cardiac surgery is common and results in increased morbidity and mortality. One possible mechanism for AKI is ischaemia-reperfusion injury caused by the extracorporeal circulation (ECC), resulting in an opening of the mitochondrial permeability transition pore (mPTP) in the kidneys, which can lead to cell injury or cell death. Ciclosporin may block the opening of mPTP if administered before the ischaemia-reperfusion injury. We hypothesised that ciclosporin given before the start of ECC in cardiac surgery can decrease the degree of AKI. METHODS AND ANALYSIS: Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS) study is an investigator initiated double-blind, randomised, placebo-controlled, parallel design, single centre study performed at a tertiary university hospital. The primary objective is to assess the safety and efficacy of ciclosporin to limit the degree of AKI in patients undergoing coronary artery bypass grafting surgery. We aim to evaluate 150 patients with a preoperative estimated glomerular filtration rate of 15-90 mL/min/1.73 m2. Study patients are randomised in a 1:1 ratio to receive study drug 2.5 mg/kg ciclosporin or placebo as an intravenous injection after anaesthesia induction but before start of surgery. The primary end point consists of relative P-cystatin C changes from the preoperative day to postoperative day 3. The primary variable will be tested using an analysis of covariance method. Secondary end points include evaluation of P-creatinine and biomarkers of kidney, heart and brain injury. ETHICS AND DISSEMINATION: The trial is conducted in compliance with the current version of the Declaration of Helsinki and the International Council for Harmonisation (ICH) Good Clinical Practice guidelines E6 (R1) and was approved by the Regional Ethical Review Board, Lund and the Swedish Medical Products Agency (MPA). Written and oral informed consent is obtained before enrolment into the study. TRIAL REGISTRATION NUMBER: NCT02397213; Pre-results. PMID- 27979836 TI - Longitudinal study of cardiometabolic risk from early adolescence to early adulthood in an ethnically diverse cohort. AB - OBJECTIVE: To examine influences of adiposity from early adolescence to early 20s on cardiovascular disease (CVD) risk in the multiethnic Determinants of young Adult Social well-being and Health (DASH) longitudinal study. METHODS: In 2002 2003, 6643 11-13-year-olds from 51 London schools participated at baseline, and 4785 were seen again at 14-16 years. Recently, 665 (97% of invited) participated in pilot follow-up at 21-23 years, with biological and psychosocial measures and blood biomarkers (only at 21-23 years). Regression models examined interplay between ethnicity, adiposity and CVD. RESULTS: At 21-23 years, ~30-40% were overweight. About half of the sample had completed a degree with little ethnic variation despite more socioeconomic disadvantage in adolescence among ethnic minorities. Regardless of ethnicity, overweight increased more steeply between 14 16 years and 21-23 years than between 11-13 years and 14-16 years. More overweight among Black Caribbean and Black African females, lower systolic blood pressure (sBP) among Indian females and Pakistani/Bangladeshi males compared with White UK peers, persisted from 11-13 years. At 21-23 years, glycated haemoglobin (HbA1c) was higher among Black Caribbean females, total cholesterol higher and high-density lipoprotein (HDL) cholesterol lower among Pakistani/Bangladeshis. Overweight was associated with a ~+2 mm Hg rise in sBP between 11-13 years and 21 23 years. Adiposity measures at 11-13 years were related to allostatic load (a cluster of several risk markers), HbA1c and HDL cholesterol at 21-23 years. Ethnic patterns in CVD biomarkers remained after adjustments. CONCLUSIONS: Adolescent adiposity posed significant risks at 21-23 years, a period in the lifespan generally ignored in cardiovascular studies, when ethnic/gender variations in CVD are already apparent. PMID- 27979837 TI - Trends in activities of daily living disability in a large sample of community dwelling Chinese older adults in Hong Kong: an age-period-cohort analysis. AB - BACKGROUND: To examine the trends in activities of daily living (ADL) disability in older Chinese adults in Hong Kong between 2001 and 2012. METHODS: Using data from the Elderly Health Centres (EHCs) of the Department of Health comprising a total of 54 808 community-dwelling Chinese adults aged >=65 years in 1 early cohort (1904-1917) and 10 3-year birth cohorts (1918-1920, 1921-1923, 1924-1926, 1927-1929, 1930-1932, 1933-1935, 1936-1938, 1939-1941, 1942-1944, 1945-1947), we examined trends in ADL disability by using age-period-cohort (APC) models. ADL disability was defined as being unable to perform at least 1 of 7 ADL activities (bathing, dressing, toileting, transferring, feeding, grooming, walking) independently. Cross-classified random-effects logistic regressions were performed for each of the APC trends with adjustment for age, period, cohort, sociodemographic, lifestyle, comorbidity and self-rated health. RESULTS: The mean age of the cohort was 70.9+/-4.7 (range 65-99) years. The prevalence rate of ADL disability was 1.6%. ADL disability increased with age (p<0.001) and the gradient of the increase was steeper in the older age groups. At the same age, women (1.7%) were more likely to report ADL disability than men (1.4%, p=0.001). For both genders, there was an increase in ADL disability between 2003 and 2012; adjustment for age, cohort and other covariates has diminished the trends observed among men. There was no cohort effect in ADL disability. CONCLUSIONS: ADL disability in older adults has increased over the last decade. Further study is required to identify possible causes behind the disability trends. PMID- 27979839 TI - Correction. PMID- 27979838 TI - Relation between carotid stiffness, cognitive performance and brain connectivity in a healthy middle-aged population: an observational neurophysiological cohort study with magnetoencephalography. AB - OBJECTIVE: Impaired blood flow of the carotid artery can result in cognitive impairment, but how these vascular impairments lead to global cognitive disturbances is largely unknown. Problems in functional connectivity between brain areas may be responsible for these widespread effects. Therefore, the aim of this study was to examine the association between carotid stiffness, functional connectivity and cognitive performance in relatively young and healthy adults before clinical vascular pathology occurs. DESIGN: The Amsterdam Growth and Health Longitudinal Study: an observational study. SETTING: Participants were included by attending 1 of the 2 selected secondary schools in The Netherlands. PARTICIPANTS: Men (n=110) and women (n=120) aged 41-44 years (42+/-0.7). PRIMARY AND SECONDARY OUTCOME MEASURES: Data were obtained with regard to local carotid stiffness captured measured with the Young's elastic modulus (YEM). All participants underwent a commonly used Dutch intelligence test and resting-state eyes-closed magnetoencephalography (MEG). Five artefact-free epochs were analysed. The phase lag index (PLI) was used as a measure of functional connectivity between all sensors and was assessed in six frequency bands (delta gamma). RESULTS: Carotid stiffness was significantly associated with increased functional connectivity in the alpha2 band in men (beta: 0.287; p=0.008). The same results were found for women in the beta band (beta: 0.216; p=0.040). Furthermore, carotid stiffness was associated with superior cognitive function in men (beta: 0.238; p=0.007). In addition, there was neither a significant association nor a consistent pattern between cognitive function and functional connectivity. CONCLUSIONS: The increased connectivity might be a maladaptive phenomenon caused by disinhibition of neurons which may explain the direction of the results. This study suggests that detection of increased (local) carotid stiffness may be promising to identify a disturbance in the organisation of the functional brain network, even before clinical vascular pathology occurs. PMID- 27979840 TI - Early Effector T Lymphocytes Coexpress Multiple Inhibitory Receptors in Primary Non-Small Cell Lung Cancer. AB - Clinical efficacy of PD-1/PD-L1 targeting relies upon the reactivation of tumor specific but functionally impaired PD-1+ T cells present before therapy. Thus, analyzing early-stage primary tumors may reveal the presence of T cells that are not yet functionally impaired. In this study, we report that activated (HLA-DR+) T cells with an effector memory (TEM) profile are enriched in such lesions. Tumor infiltrating lymphocytes coexpressed PD-1 with the inhibitory receptors TIM-3, CTLA-4, LAG-3, and TIGIT, but also displayed a recently activated, nonexhausted phenotype. We also identified a subset of CD8+PD-1+FOXP3+ T lymphocytes at the earliest phase of functional differentiation after priming, termed "early effector cells" (EEC), which also exhibited an activated nonexhausted phenotype, but was less differentiated and associated with coexpression of multiple inhibitory receptors. In response to autologous tumor, EECs upregulated CD107a, produced IL2 and IFNgamma, and were competent for differentiation. The identification of EECs marked by inhibitory receptor expression at tumor sites will enable investigations of early stages of adaptive antitumor immunity, as well as support the rationale for administering immunotherapy in early-stage non small cell lung cancer. Cancer Res; 77(4); 851-61. (c)2016 AACR. PMID- 27979841 TI - Modeling Alveolar Soft Part Sarcoma Unveils Novel Mechanisms of Metastasis. AB - Alveolar soft part sarcoma (ASPS) is a slowly growing, but highly metastatic, sarcoma that affects adolescents and young adults. Its characteristic alveolar structure is constituted by tumor cell nests and an abundant vascular network that is responsible for metastatic activities at the initial stage. Here, we have generated a new ex vivo mouse model for ASPS that well recapitulates associated angiogenic and metastatic phenotypes. In mouse ASPS, the tumor cells frequently showed tumor intravasation, with the intravascular tumor cells presenting as organoid structures covered with hemangiopericytes, which is also observed in human ASPS. High expression of glycoprotein nmb (GPNMB), a transcriptional target of ASPSCR1-TFE3, was observed at the sites of intravasation. ASPS tumor cells also demonstrated enhanced transendothelial migration activity, which was inhibited by silencing of Gpnmb, indicating that GPNMB plays an important role in tumor intravasation, a key step in cancer metastasis. The present model also enabled the evaluation of TFE/MITF family transcription factor function, which demonstrated that ASPSCR1-TFEB possessed definitive albeit less marked oncogenic activity than that of ASPSCR1-TFE3. Collectively, our mouse model provides a tool to understand oncogenic, angiogenic, and metastatic mechanisms of ASPS. It also identifies important motifs within the ASPSCR1-TFE3 fusion protein and provides a platform for developing novel therapeutic strategies for this disorder. Cancer Res; 77(4); 897-907. (c)2016 AACR. PMID- 27979842 TI - Rare case of glioblastoma multiforme located in posterior corpus callosum presenting with depressive symptoms and visual memory deficits. AB - Most of the primary brain tumours are located in the supratentorial region, and it is uncommon to see tumour growth on deep brain structures such as posterior corpus callosum (PCC). In addition, lesions in PCC are also difficult to recognise, because construction apraxia, visuospatial perception and attentional capacity impairment may be the only presenting symptoms. Here, we represent a rare case of gliobastoma multiforme located in PCC, which solely presents with depressive symptoms and visual memory deficits. Initial manifestations of primary brain tumours with psychiatric symptoms and memory disturbances, in addition to headaches and seizures, should be kept in mind. PMID- 27979843 TI - Unexplained lymphadenopathies: autoimmune lymphoproliferative syndrome in an adult patient. AB - Autoimmune lymphoproliferative syndrome (ALPS) is characterised by massive enlargement of the lymphoid organs, autoimmune cytopenias and a predisposition to develop lymphoid malignancies. The basic defect is a disturbance of the lymphocyte apoptosis, and a high number of circulating TCRab CD3+CD4-CD8- T-cells (double-negative T cells (DNT cells)). We describe a case of a 41-year-old man with fever, hepatosplenomegaly, multiple lymphadenopathy, autoimmune haemolytic anaemia and severe thrombocytopenia. Peripheral blood immunophenotyping revealed elevation of the characteristic DNT cells in 8% and high levels of interleukin 10. Histopathological analysis of lymph nodes showed lymphadenitis with paracortical hyperplasia. It was assumed as a probable diagnosis of ALPS, and the procedure was to medicate the patient with steroids. As a result, a significant clinical improvement was achieved, and he has been in remission for 2 years. To our knowledge, this is the first case reported in a Portuguese adult patient. PMID- 27979845 TI - Emphysematous pancreatitis: classic findings. PMID- 27979844 TI - Rare cause of neck pain: tumours of the posterior elements of the cervical spine. AB - Here we present two cases of primary bone tumours of the cervical spine in patients who had persistent neck pain-in one case, lasting 8 years. In each case, there was a delay in diagnosis and referral to a spine specialist was prolonged. Primary bone tumours of the spine are rare, which is in contrast to the wide prevalence of cervical neck pain. Many primary care providers may go an entire career without encountering a symptomatic primary cervical spine tumour. In this paper, we discuss the clinical course and treatment of each patient and review the current literature on primary bone tumours of the spine. Owing to the subtle roentgenographic findings of primary cervical tumours, we highlight the importance of advanced imaging in the clinical work-up of simple axial neck pain lasting >6 weeks to avoid misdiagnosis of serious pathology. PMID- 27979846 TI - Boari flap reconstruction in a male infant with solitary kidney and associated megaureter. AB - A 1-year-old male infant presented with fever and abdominal lump for 3 months with increased leucocyte count (15 300/mm3) and serum creatinine (0.83 mg%). Abdominal ultrasound and renal scan demonstrated solitary left kidney with dilated tortuous left ureter. Voiding cystourethrogram was unequivocal. Left percutaneous nephrostomy was placed after poor response to perurethral catheterisation. His serum creatinine dropped to 0.58 mg/dL. Subsequent percutaneous nephrostogram and CT nephrostogram showed dilated left pelvicalyceal system, dilated, tortuous left ureter. A diagnosis of obstructed megaureter was made and ureteric plication and reimplantation planned. Intraoperatively, there were primitive ureteral valves until proximal one-third of the ureter. The distance between the upper ureter and bladder was ~6 cm. This defect was bridged by Boari flap. The postoperative period was uneventful and now after 6 months of follow-up, he is doing fine. PMID- 27979847 TI - Concomitant multiple myeloma, gastric adenocarcinoma and Evan's syndrome in a patient presenting with anaemia. AB - An association between multiple myeloma (MM) and solid tumours has been previously described.1 Furthermore, autoimmune disorders can precede plasma cell dyscrasias, and the pathogenesis of MM maybe linked to chronic immune stimulation. 2 We describe a case of concomitant MM and gastric adenocarcinoma preceded by Evan's syndrome. A previously healthy woman presented to the emergency room with symptomatic anaemia. Her initial workup was compatible with autoimmune haemolytic anaemia and monoclonal gammopathy of undetermined significance. On progression of the anaemia and development of thrombocytopenia, she was diagnosed with Evan's syndrome. Two months later, she presented with severe back pain and her MRI revealed L4-5 vertebral collapse. The clinical picture was compatible with MM. Occult blood was repeatedly positive in stools, and she underwent oesophagogastroduodenoscopy and was found to have gastric adenocarcinoma. The patient refused surgical resection of the adenocarcinoma and refused active treatment for MM. PMID- 27979848 TI - Unusual case of bilateral maxillary fungus ball. AB - An otherwise healthy 34-year-old man was referred to our ear, nose and throat (ENT) clinic for a bilateral maxillary radiologic opacity. This condition was accidentally discovered with a panoramic radiography performed during a follow-up visit after a bilateral endodontic treatment. The patient did not report any specific sinonasal symptom such as purulent nasal discharge, loss of smell and cough, apart from an unspecific sinus pressure. The CT scans showed a bilateral inflammatory process into the maxillary-ethmoidal sinuses and an iron-like density within the maxillary sinuses, while nasal endoscopy showed purulent discharge in the ostiomeatal complex. The patient underwent functional endoscopic sinus surgery under general anaesthesia and the inflammatory material collected was histologically diagnosed as a rare case of bilateral fungus ball. The patient was dismissed the following day with no complications; there were not any sign of recurrence or symptoms during a 4 month follow-up. PMID- 27979849 TI - Pulmonary sarcoidosis: calcification within the galaxy sign. PMID- 27979850 TI - Large intraocular foreign body following a firecracker injury. PMID- 27979851 TI - Melphalan-induced cardiotoxicity: ventricular arrhythmias. PMID- 27979852 TI - The BMJ Christmas appeal 2016-17: changing children's lives through cataract surgery. PMID- 27979853 TI - Questions and answers. PMID- 27979854 TI - Erratum for van der Kooij et al., Multiplication of Legionella pneumophila Sequence Types 1, 47, and 62 in Buffered Yeast Extract Broth and Biofilms Exposed to Flowing Tap Water at Temperatures of 38 degrees C to 42 degrees C. PMID- 27979856 TI - 2016 Russell Ross Memorial Lecture in Vascular Biology: Molecular-Cellular Mechanisms in the Progression of Atherosclerosis. AB - Atherosclerosis is initiated by the subendothelial accumulation of apoB lipoproteins, which initiates a sterile inflammatory response dominated by monocyte-macrophages but including all classes of innate and adaptive immune cells. These inflammatory cells, together with proliferating smooth muscle cells and extracellular matrix, promote the formation of subendothelial lesions or plaques. In the vast majority of cases, these lesions do not cause serious clinical symptoms, which is due in part to a resolution-repair response that limits tissue damage. However, a deadly minority of lesions progress to the point where they can trigger acute lumenal thrombosis, which may then cause unstable angina, myocardial infarction, sudden cardiac death, or stroke. Many of these clinically dangerous lesions have hallmarks of defective inflammation resolution, including defective clearance of dead cells (efferocytosis), necrosis, a defective scar response, and decreased levels of lipid mediators of the resolution response. Efferocytosis is both an effector arm of the resolution response and an inducer of resolution mediators, and thus its defect in advanced atherosclerosis amplifies plaque progression. Preclinical causation/treatment studies have demonstrated that replacement therapy with exogenously administered resolving mediators can improve lesional efferocytosis and prevent plaque progression. Work in this area has the potential to potentiate the cardiovascular benefits of apoB-lipoprotein-lowering therapy. PMID- 27979858 TI - miR-34a promotes fibrosis in aged lungs by inducing alveolarepithelial dysfunctions. AB - Idiopathic pulmonary fibrosis is a well-known age-related disease. However, much less recognized has been the aging associated pathogenesis of this disorder. As we and others previously showed that dysregulation of micro-RNAs (miRNAs) was an important mechanism involved in pulmonary fibrosis, the role of these molecules in this pathology in the aged population has not been investigated (Cushing L, Kuang PP, Qian J, Shao F, Wu J, Little F, Thannickal VJ, Cardoso WV, Lu J. Am J Respir Cell Mol Biol 45: 287-294, 2011; Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, Kaminski N, Abraham E. J Exp Med 207: 1589-1597, 2010; Pandit KV, Corcoran D, Yousef H, Yarlagadda M, Tzouvelekis A, Gibson KF, Konishi K, Yousem SA, Singh M, Handley D, Richards T, Selman M, Watkins SC, Pardo A, Ben Yehudah A, Bouros D, Eickelberg O, Ray P, Benos PV, Kaminski N. Am J Respir Crit Care Med 182: 220-229, 2010). In this study, by using a lung fibrosis model established in old mice, we found that ablation of miR-34a protected aged animals from developing experimental lung fibrosis. miR-34a was upregulated in lung epithelial cells, but not in lung fibroblasts of aged mice, and miR-34a expression was further increased in epithelial cells of the fibrotic lungs of these old animals. We found that miR-34a induced dysfunctions in alveolar epithelial cells (AECs), as evidenced by increased cellular senescence and apoptosis and mitochondrial aberrations. More importantly, these abnormalities were attenuated in AECs of the fibrotic lungs of aged miR-34a-/- mice. We found that miR-34a targeted Sirt1, a master anti-aging regulator, and two key cell cycle modulators, E2F3 and cyclin E2, in lung epithelial cells, and the repression of these targets was relieved in miR-34a-deficient AECs. In summary, our data suggest that elevated AEC miR-34a plays a critical role in the pathogenesis of pulmonary fibrosis in the aged population. Our study also indicates miR-34a to be a more precise miRNA target for treating this disease that overwhelmingly affects people of advanced age. PMID- 27979859 TI - Capsaicin-induced Ca2+ signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH. AB - Capsaicin is an active component of chili pepper and a pain relief drug. Capsaicin can activate transient receptor potential vanilloid 1 (TRPV1) channels to increase cytosolic Ca2+ concentration ([Ca2+]cyt). A rise in [Ca2+]cyt in pulmonary artery smooth muscle cells (PASMCs) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. In this study, we observed that a capsaicin-induced increase in [Ca2+]cyt was significantly enhanced in PASMCs from patients with idiopathic pulmonary arterial hypertension (IPAH) compared with normal PASMCs from healthy donors. In addition, the protein expression level of TRPV1 in IPAH PASMCs was greater than in normal PASMCs. Increasing the temperature from 23 to 43 degrees C, or decreasing the extracellular pH value from 7.4 to 5.9 enhanced capsaicin-induced increases in [Ca2+]cyt; the acidity (pH 5.9)- and heat (43 degrees C)-mediated enhancement of capsaicin-induced [Ca2+]cyt increases were greater in IPAH PASMCs than in normal PASMCs. Decreasing the extracellular osmotic pressure from 310 to 200 mOsmol/l also increased [Ca2+]cyt, and the hypo-osmolarity-induced rise in [Ca2+]cyt was greater in IPAH PASMCs than in healthy PASMCs. Inhibition of TRPV1 (with 5'-IRTX or capsazepine) or knockdown of TRPV1 (with short hairpin RNA) attenuated capsaicin-, acidity-, and osmotic stretch-mediated [Ca2+]cyt increases in IPAH PASMCs. Capsaicin induced phosphorylation of CREB by raising [Ca2+]cyt, and capsaicin-induced CREB phosphorylation were significantly enhanced in IPAH PASMCs compared with normal PASMCs. Pharmacological inhibition and knockdown of TRPV1 attenuated IPAH PASMC proliferation. Taken together, the capsaicin-mediated [Ca2+]cyt increase due to upregulated TRPV1 may be a critical pathogenic mechanism that contributes to augmented Ca2+ influx and excessive PASMC proliferation in patients with IPAH. PMID- 27979860 TI - Alternative hematological and vascular adaptive responses to high-altitude hypoxia in East African highlanders. AB - Elevation of hemoglobin concentration, a common adaptive response to high altitude hypoxia, occurs among Oromo but is dampened among Amhara highlanders of East Africa. We hypothesized that Amhara highlanders offset their smaller hemoglobin response with a vascular response. We tested this by comparing Amhara and Oromo highlanders at 3,700 and 4,000 m to their lowland counterparts at 1,200 and 1,700 m. To evaluate vascular responses, we assessed urinary levels of nitrate (NO3-) as a readout of production of the vasodilator nitric oxide and its downstream signal transducer cyclic guanosine monophosphate (cGMP), along with diastolic blood pressure as an indicator of vasomotor tone. To evaluate hematological responses, we measured hemoglobin and percent oxygen saturation of hemoglobin. Amhara highlanders, but not Oromo, had higher NO3- and cGMP compared with their lowland counterparts. NO3- directly correlated with cGMP (Amhara R2 = 0.25, P < 0.0001; Oromo R2 = 0.30, P < 0.0001). Consistent with higher levels of NO3- and cGMP, diastolic blood pressure was lower in Amhara highlanders. Both highland samples had apparent left shift in oxyhemoglobin saturation characteristics and maintained total oxyhemoglobin content similar to their lowland counterparts. However, deoxyhemoglobin levels were significantly higher, much more so among Oromo than Amhara. In conclusion, the Amhara balance minimally elevated hemoglobin with vasodilatory response to environmental hypoxia, whereas Oromo rely mainly on elevated hemoglobin response. These results point to different combinations of adaptive responses in genetically similar East African highlanders. PMID- 27979862 TI - Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood. 1977;50(3):481-492. PMID- 27979861 TI - BMI-1 extends proliferative potential of human bronchial epithelial cells while retaining their mucociliary differentiation capacity. AB - Air-liquid interface (ALI) culture of primary airway epithelial cells enables mucociliary differentiation providing an in vitro model of the human airway, but their proliferative potential is limited. To extend proliferation, these cells were previously transduced with viral oncogenes or mouse Bmi-1 + hTERT, but the resultant cell lines did not undergo mucociliary differentiation. We hypothesized that use of human BMI-1 alone would increase the proliferative potential of bronchial epithelial cells while retaining their mucociliary differentiation potential. Cystic fibrosis (CF) and non-CF bronchial epithelial cells were transduced by lentivirus with BMI-1 and then their morphology, replication kinetics, and karyotype were assessed. When differentiated at ALI, mucin production, ciliary function, and transepithelial electrophysiology were measured. Finally, shRNA knockdown of DNAH5 in BMI-1 cells was used to model primary ciliary dyskinesia (PCD). BMI-1-transduced basal cells showed normal cell morphology, karyotype, and doubling times despite extensive passaging. The cell lines underwent mucociliary differentiation when cultured at ALI with abundant ciliation and production of the gel-forming mucins MUC5AC and MUC5B evident. Cilia displayed a normal beat frequency and 9+2 ultrastructure. Electrophysiological characteristics of BMI-1-transduced cells were similar to those of untransduced cells. shRNA knockdown of DNAH5 in BMI-1 cells produced immotile cilia and absence of DNAH5 in the ciliary axoneme as seen in cells from patients with PCD. BMI-1 delayed senescence in bronchial epithelial cells, increasing their proliferative potential but maintaining mucociliary differentiation at ALI. We have shown these cells are amenable to genetic manipulation and can be used to produce novel disease models for research and dissemination. PMID- 27979863 TI - Measure for measure: minimal residual disease in CLL. PMID- 27979865 TI - Macrophage precursors PLASTed INto alveolar space. PMID- 27979864 TI - Metformin: treating the cause of Fanconi anemia? PMID- 27979857 TI - Endothelial cell signaling and ventilator-induced lung injury: molecular mechanisms, genomic analyses, and therapeutic targets. AB - Mechanical ventilation is a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS). Paradoxically, mechanical ventilation also creates excessive mechanical stress that directly augments lung injury, a syndrome known as ventilator-induced lung injury (VILI). The pathobiology of VILI and ARDS shares many inflammatory features including increases in lung vascular permeability due to loss of endothelial cell barrier integrity resulting in alveolar flooding. While there have been advances in the understanding of certain elements of VILI and ARDS pathobiology, such as defining the importance of lung inflammatory leukocyte infiltration and highly induced cytokine expression, a deep understanding of the initiating and regulatory pathways involved in these inflammatory responses remains poorly understood. Prevailing evidence indicates that loss of endothelial barrier function plays a primary role in the development of VILI and ARDS. Thus this review will focus on the latest knowledge related to 1) the key role of the endothelium in the pathogenesis of VILI; 2) the transcription factors that relay the effects of excessive mechanical stress in the endothelium; 3) the mechanical stress-induced posttranslational modifications that influence key signaling pathways involved in VILI responses in the endothelium; 4) the genetic and epigenetic regulation of key target genes in the endothelium that are involved in VILI responses; and 5) the need for novel therapeutic strategies for VILI that can preserve endothelial barrier function. PMID- 27979866 TI - Neighborhood imbalances: overcoming MCL drug resistance. PMID- 27979867 TI - Interferon-induced thrombotic microangiopathy. PMID- 27979869 TI - An unusual presentation of secondary AML. PMID- 27979868 TI - Polyphosphate strikes back. PMID- 27979870 TI - Flowers blossoming in the desert heat. PMID- 27979871 TI - Thornburg CD, Files BA, Luo Z, et al. Impact of hydroxyurea on clinical events in the BABY HUG trial. Blood. 2012;120(22):4304-4310. PMID- 27979872 TI - Appropriate use of the EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis. PMID- 27979873 TI - 2016 update of the EULAR recommendations for the management of early arthritis. AB - OBJECTIVES: Since the 2007 recommendations for the management of early arthritis have been presented, considerable research has been published in the field of early arthritis, mandating an update of the 2007 European League Against Rheumatism (EULAR) recommendations for management of early arthritis. METHODS: In accordance with the 2014 EULAR Standardised Operating Procedures, the expert committee pursued an approach that was based on evidence in the literature and on expert opinion. The committee involved 20 rheumatologists, 2 patients and 1 healthcare professional representing 12 European countries. The group defined the focus of the expert committee and target population, formulated a definition of 'management' and selected the research questions. A systematic literature research (SLR) was performed by two fellows with the help of a skilled librarian. A set of draft recommendations was proposed on the basis of the research questions and the results of the SLR. For each recommendation, the categories of evidence were identified, the strength of recommendations was derived and the level of agreement was determined through a voting process. RESULTS: The updated recommendations comprise 3 overarching principles and 12 recommendations for managing early arthritis. The selected statements involve the recognition of arthritis, referral, diagnosis, prognostication, treatment (information, education, pharmacological and non-pharmacological interventions), monitoring and strategy. Eighteen items were identified as relevant for future research. CONCLUSIONS: These recommendations provide rheumatologists, general practitioners, healthcare professionals, patients and other stakeholders with an updated EULAR consensus on the entire management of early arthritis. PMID- 27979874 TI - Pilot Research as Advocacy: The Case of Sayana Press in Kinshasa, Democratic Republic of the Congo. AB - In the Democratic Republic of the Congo (DRC), the Ministry of Health authorizes only physicians and nurses to give injections, with one exception-medical and nursing students may also give injections if supervised by a clinical instructor. The emergence of the injectable contraceptive Sayana Press in some African countries prompted the DRC to test the acceptability and feasibility of distributing Sayana Press and other contraceptive methods at the community level through medical and nursing students. Sayana Press is similar in formulation to the injectable contraceptive Depo-Provera but contains a lower dose and is administered subcutaneously using a single-use syringe with a short needle called the Uniject system. The Uniject system allows Sayana Press to be administered by community health workers without clinical training or by self-injection. In this pilot, the advocacy objective was to obtain approval from the Ministry of Health to allow medical and nursing students to inject Sayana Press, as a first step toward authorization for community health workers to provide the method. The pilot described in this article documents a process whereby an innovative approach moved from concept to implementation to replication in less than 2 years. It also paved the way for testing additional progressive strategies to increase access to contraception at the community level. Because the pilot project included a research component designed to assess benefits and challenges, it provided the means to introduce the new task-shifting approach, which might not have been approved otherwise. Key pilot activities included: (1) increasing awareness of Sayana Press among family planning stakeholders at a national conference on family planning, (2) enlisting the support of key decision makers in designing the pilot, (3) obtaining marketing authorization to distribute Sayana Press in the DRC, (4) implementing the pilot from July to December 2015, (5) conducting quantitative and qualitative studies to assess acceptability and feasibility, and (6) disseminating the findings to family planning stakeholders. Before the pilot, Sayana Press was relatively unknown in the DRC, and there was no precedent for medical and nursing students providing family planning methods or giving injections at the community level. In less than 12 months, the approach gained legitimacy and acceptance. The key Ministry of Health decision maker orchestrated the closing session of the dissemination meeting on next steps, paving the way for pilot tests of 3 new task-shifting approaches: insertion of Implanon NXT by medical and nursing students, self-injection for Sayana Press with supervision by students, and injection of Sayana Press by community health workers with no formal clinical training. PMID- 27979875 TI - Predictors of Death in Contemporary Adult Patients With Eisenmenger Syndrome: A Multicenter Study. AB - BACKGROUND: Eisenmenger syndrome is associated with substantial morbidity and mortality. There is no consensus, however, on mortality risk stratification. We aimed to investigate survival and predictors of death in a large, contemporary cohort of Eisenmenger syndrome patients. METHODS: In a multicenter approach, we identified adults with Eisenmenger syndrome under follow-up between 2000 and 2015. We examined survival and its association with clinical, electrocardiographic, echocardiographic, and laboratory parameters. RESULTS: We studied 1098 patients (median age, 34.4 years; range, 16.1-84.4 years; 65.1% female; 31.9% with Down syndrome). The majority had a posttricuspid defect (n=643, 58.6%), followed by patients with a complex (n=315, 28.7%) and pretricuspid lesion (n=140, 12.7%). Over a median follow-up of 3.1 years (interquartile range, 1.4-5.9), allowing for 4361.6 patient-years observation, 278 patients died and 6 underwent transplantation. Twelve parameters emerged as significant predictors of death on univariable analysis. On multivariable Cox regression analysis, only age (hazard ratio [HR], 1.41/10 years; 95% confidence interval [CI], 1.24-1.59; P<0.001), pretricuspid shunt (HR, 1.56; 95% CI, 1.02 2.39; P=0.041), oxygen saturation at rest (HR, 0.53/10%; 95% CI, 0.43-0.65; P<0.001), presence of sinus rhythm (HR, 0.53; 95% CI, 0.32-0.88; P=0.013), and presence of pericardial effusion (HR, 2.41; 95% CI, 1.59-3.66; P<0.001) remained significant predictors of death. CONCLUSIONS: There is significant premature mortality among contemporary adults with Eisenmenger syndrome. We report, herewith, a multivariable mortality risk stratification model based on 5 simple, noninvasive predictors of death in this population. PMID- 27979877 TI - Neural Progenitor Cells in Cerebral Cortex of Epilepsy Patients do not Originate from Astrocytes Expressing GLAST. AB - Adult neurogenesis in human brain is known to occur in the hippocampus, the subventricular zone, and the striatum. Neural progenitor cells (NPCs) were reported in the cortex of epilepsy patients; however, their identity is not known. Since astrocytes were proposed as the source of neural progenitors in both healthy and diseased brain, we tested the hypothesis that NPCs in the epileptic cortex originate from reactive, alternatively, de-differentiated astrocytes that express glutamate aspartate transporter (GLAST). We assessed the capacity to form neurospheres and the differentiation potential of cells dissociated from fresh cortical tissue from patients who underwent surgical treatment for pharmacologically intractable epilepsy. Neurospheres were generated from 57% of cases (8/14). Upon differentiation, the neurosphere cells gave rise to neurons, oligodendrocytes, and astrocytes. Sorting of dissociated cells showed that only cells negative for GLAST formed neurospheres. In conclusion, we show that cells with neural stem cell properties are present in brain cortex of epilepsy patients, and that these cells are not GLAST-positive astrocytes. PMID- 27979876 TI - Circadian and feeding cues integrate to drive rhythms of physiology in Drosophila insulin-producing cells. AB - Circadian clocks regulate much of behavior and physiology, but the mechanisms by which they do so remain poorly understood. While cyclic gene expression is thought to underlie metabolic rhythms, little is known about cycles in cellular physiology. We found that Drosophila insulin-producing cells (IPCs), which are located in the pars intercerebralis and lack an autonomous circadian clock, are functionally connected to the central circadian clock circuit via DN1 neurons. Insulin mediates circadian output by regulating the rhythmic expression of a metabolic gene (sxe2) in the fat body. Patch clamp electrophysiology reveals that IPCs display circadian clock-regulated daily rhythms in firing event frequency and bursting proportion under light:dark conditions. The activity of IPCs and the rhythmic expression of sxe2 are additionally regulated by feeding, as demonstrated by night feeding-induced changes in IPC firing characteristics and sxe2 levels in the fat body. These findings indicate circuit-level regulation of metabolism by clock cells in Drosophila and support a role for the pars intercerebralis in integrating circadian control of behavior and physiology. PMID- 27979880 TI - Thank you to contributors. PMID- 27979881 TI - An update on the 'gliptins'. AB - Progressive impairment of insulin secretion in people with type 2 diabetes leads to blood glucose concentrations worsening over time, often resulting in escalation of blood glucose lowering therapy.1 In 2015/2016, more money was spent on dipeptidyl peptidase-4 (DPP-4) inhibitors ('gliptins') than on any other class of antidiabetic drug except for insulins.2 In 2008, we reviewed sitagliptin and vildagliptin.3 Here, we briefly review three other DPP-4 inhibitors, saxagliptin (Onglyza-AstraZeneca), linagliptin (Trajenta-Boehringer Ingelheim) and ?alogliptin (Vipidia-Takeda), and consider data from recent cardiovascular outcomes studies. PMID- 27979879 TI - Fibroblast growth factor 23 as novel biomarker for early risk stratification after ST-elevation myocardial infarction. AB - OBJECTIVE: Adverse left ventricular (LV) remodelling is the major determinant of heart failure and mortality in survivors of ST-elevation myocardial infarction (STEMI). The role of fibroblast growth factor 23 (FGF-23) for LV remodelling prediction after STEMI is unknown. We therefore aimed to investigate the relation between circulating FGF-23 and LV remodelling following revascularised STEMI. METHODS: In this prospective observational study, we included 88 consecutive patients with STEMI treated by primary percutaneous coronary intervention. FGF-23 concentrations were measured 2 (IQR: 2-2) days after symptom onset. Cardiac magnetic resonance was performed 2 (IQR: 1-3) days as well as 4 (IQR: 4-5) months after infarction to evaluate LV remodelling, defined as >=20% increase in LV end diastolic volume. RESULTS: Levels of FGF-23 were significantly higher in patients who developed LV remodelling (n=11, 13%) as compared with those without LV remodelling (152.6 (102.5-241.3) vs 75.8 (58.6-105.4) relative units per millilitre, p=0.002). The association between FGF-23 and LV remodelling remained significant (OR: 14.1, 95% CI 2.8 to 70.9; p=0.001) after adjustment for biomarkers reflecting myocardial necrosis (high-sensitivity cardiac troponin T (hs-cTnT)), myocardial stress (N-terminal pro B-type natriuretic peptide (NT proBNP)) and inflammatory state (high-sensitivity C reactive protein (hs-CRP)). Moreover, a multimarker approach adding FGF-23 to the established LV remodelling predictive biomarkers (hs-cTnT, NT-proBNP and hs-CRP) led to a net reclassification improvement of 0.92 (95% CI 0.44 to 1.41, p<0.001) and to an integrated discrimination improvement of 0.16 (95% CI 0.08 to 0.24, p<0.001). CONCLUSIONS: Circulating FGF-23 is independently associated with LV remodelling after reperfused STEMI. A comprehensive multimarker strategy that includes FGF-23 provides incremental prognostic value for prediction of LV remodelling. PMID- 27979882 TI - Psychological interventions for eating disorders. AB - Eating disorders, including anorexia nervosa, bulimia nervosa and binge eating disorder, are common conditions, characterised by disturbances of eating behaviours and a core psychopathology centred on food, eating and body image concerns.1,2 Eating disorders are associated with medical and psychological comorbidities; a significantly impaired health-related quality of life; a high rate of inpatient, outpatient and emergency care; significant healthcare costs; and increased mortality.3-10 Here, we focus on the evidence for non-drug interventions for eating disorders. PMID- 27979883 TI - Publisher's Note: Modulation of dorsal root ganglion development by ErbB signaling and the scaffold protein Sorbs3 by Malmquist et al. Development doi:10.1242/dev.084640. PMID- 27979885 TI - Introduction. PMID- 27979884 TI - Defective adgra2 (gpr124) splicing and function in zebrafish ouchless mutants. AB - A hitherto unidentified N-ethyl-N-nitrosourea (ENU)-induced mutation affects dorsal root ganglia (DRG) formation in ouchless mutant zebrafish larvae. In contrast to previous findings assigning the ouchless phenotypes to downregulated sorbs3 transcript levels, this work re-attributes the phenotypes to an essential splice site mutation affecting adgra2 (gpr124) splicing and function. Accordingly, ouchless mutants fail to complement previously characterized adgra2 mutants and exhibit highly penetrant cerebrovascular defects. The aberrantly spliced adgra2 transcript found in ouchless mutants encodes a receptor lacking a single leucine-rich repeat (LRR) within its N-terminus. PMID- 27979886 TI - Professional Practice Committee. PMID- 27979878 TI - Implications of telomeres and telomerase in endometrial pathology. AB - BACKGROUND: Eukaryotic chromosomal ends are linear and are protected by nucleoprotein complexes known as telomeres. The complex structural anatomy and the diverse functions of telomeres as well as the unique reverse transcriptase enzyme, telomerase that maintains telomeres are under intensive scientific scrutiny. Both are involved in many human diseases including cancer, but also in ageing and chronic disease such as diabetes. Their intricate involvement in many cellular processes and pathways is being dynamically deciphered in many organs including the endometrium. This review summarizes our current knowledge on the topic of telomeres and telomerase and their potential role in providing plausible explanations for endometrial aberrations related to common gynaecological pathologies. OBJECTIVE AND RATIONALE: This review outlines the recent major findings in telomere and telomerase functions in the context of endometrial biology. It highlights the contemporary discoveries in hormonal regulation, normal endometrial regeneration, stem cells and common gynaecological diseases such as endometriosis, infertility, recurrent reproductive failure and endometrial cancer (EC). SEARCH METHODS: The authors carried out systematic PubMed (Medline) and Ovid searches using the key words: telomerase, telomeres, telomere length, human telomerase reverse transcriptase, telomeric RNA component, with endometrium, hormonal regulation, endometrial stem/progenitor cells, endometrial regeneration, endometriosis, recurrent miscarriage, infertility, endometrial hyperplasia, EC and uterine cancer. Publications used in this review date from 1995 until 31st June 2016. OUTCOMES: The human endometrium is a unique somatic organ, which displays dynamic telomerase activity (TA) related to the menstrual cycle. Telomerase is implicated in almost all endometrial pathologies and appears to be crucial to endometrial stem cells. In particular, it is vital for normal endometrial regeneration, providing a distinct route to formulate possible curative, non-hormonal therapies to treat chronic endometrial conditions. Furthermore, our current understanding of telomere maintenance in EC is incomplete. Data derived from other malignancies on the role of telomerase in carcinogenesis cannot be extrapolated to EC because unlike in other cancers, TA is already present in proliferating healthy endometrial cells. WIDER IMPLICATIONS: Since telomerase is pivotal to endometrial regeneration, further studies elucidating the role of telomeres, telomerase, their associated proteins and their regulation in normal endometrial regeneration as well as their role in endometrial pathologies are essential. This approach may allow future development of novel treatment strategies that are not only non-hormonal but also potentially curative. PMID- 27979887 TI - Standards of Medical Care in Diabetes-2017: Summary of Revisions. PMID- 27979888 TI - 1. Promoting Health and Reducing Disparities in Populations. PMID- 27979889 TI - 2. Classification and Diagnosis of Diabetes. PMID- 27979891 TI - 4. Lifestyle Management. PMID- 27979890 TI - 3. Comprehensive Medical Evaluation and Assessment of Comorbidities. PMID- 27979892 TI - 5. Prevention or Delay of Type 2 Diabetes. PMID- 27979893 TI - 6. Glycemic Targets. PMID- 27979894 TI - 7. Obesity Management for the Treatment of Type 2 Diabetes. PMID- 27979895 TI - 8. Pharmacologic Approaches to Glycemic Treatment. PMID- 27979897 TI - 10. Microvascular Complications and Foot Care. PMID- 27979896 TI - 9. Cardiovascular Disease and Risk Management. PMID- 27979898 TI - 11. Older Adults. PMID- 27979899 TI - 12. Children and Adolescents. PMID- 27979900 TI - 13. Management of Diabetes in Pregnancy. PMID- 27979901 TI - 14. Diabetes Care in the Hospital. PMID- 27979902 TI - 15. Diabetes Advocacy. PMID- 27979905 TI - A long noncoding RNA, lincRNA-Tnfaip3, acts as a coregulator of NF-kappaB to modulate inflammatory gene transcription in mouse macrophages. AB - Long intergenic noncoding RNAs (lincRNAs) are long noncoding transcripts (>200 nt) from the intergenic regions of annotated protein-coding genes. We report here that the lincRNA gene lincRNA-Tnfaip3, located at mouse chromosome 10 proximal to the tumor necrosis factor alpha-induced protein 3 (Tnfaip3) gene, is an early primary response gene controlled by nuclear factor-kappaB (NF-kappaB) signaling in murine macrophages. Functionally, lincRNA- Tnfaip3 appears to mediate both the activation and repression of distinct classes of inflammatory genes in macrophages. Specifically, induction of lincRNA-Tnfaip3 is required for the transactivation of NF-kappaB-regulated inflammatory genes in response to bacterial LPSs stimulation. LincRNA-Tnfaip3 physically interacts with the high mobility group box 1 (Hmgb1), assembling a NF-kappaB/Hmgb1/lincRNA-Tnfaip3 complex in macrophages after LPS stimulation. This resultant NF kappaB/Hmgb1/lincRNA-Tnfaip3 complex can modulate Hmgb1-associated histone modifications and, ultimately, transactivation of inflammatory genes in mouse macrophages in response to microbial challenge. Therefore, our data indicate a new regulatory role of NF-kappaB-induced lincRNA-Tnfaip3 to act as a coactivator of NF-kappaB for the transcription of inflammatory genes in innate immune cells through modulation of epigenetic chromatin remodeling.-Ma, S., Ming, Z., Gong, A. Y., Wang, Y., Chen, X., Hu, G., Zhou, R., Shibata, A., Swanson, P. C., Chen, X. M. A long noncoding RNA, LincRNA-Tnfaip3, acts as a coregulator of NF-kappaB to modulate inflammatory gene transcription in mouse macrophages. PMID- 27979906 TI - 4E-BP is a target of the GCN2-ATF4 pathway during Drosophila development and aging. AB - Reduced amino acid availability attenuates mRNA translation in cells and helps to extend lifespan in model organisms. The amino acid deprivation-activated kinase GCN2 mediates this response in part by phosphorylating eIF2alpha. In addition, the cap-dependent translational inhibitor 4E-BP is transcriptionally induced to extend lifespan in Drosophila melanogaster, but through an unclear mechanism. Here, we show that GCN2 and its downstream transcription factor, ATF4, mediate 4E BP induction, and GCN2 is required for lifespan extension in response to dietary restriction of amino acids. The 4E-BP intron contains ATF4-binding sites that not only respond to stress but also show inherent ATF4 activity during normal development. Analysis of the newly synthesized proteome through metabolic labeling combined with click chemistry shows that certain stress-responsive proteins are resistant to inhibition by 4E-BP, and gcn2 mutant flies have reduced levels of stress-responsive protein synthesis. These results indicate that GCN2 and ATF4 are important regulators of 4E-BP transcription during normal development and aging. PMID- 27979907 TI - Watching cellular machinery in action, one molecule at a time. AB - Single-molecule manipulation and imaging techniques have become important elements of the biologist's toolkit to gain mechanistic insights into cellular processes. By removing ensemble averaging, single-molecule methods provide unique access to the dynamic behavior of biomolecules. Recently, the use of these approaches has expanded to the study of complex multiprotein systems and has enabled detailed characterization of the behavior of individual molecules inside living cells. In this review, we provide an overview of the various force- and fluorescence-based single-molecule methods with applications both in vitro and in vivo, highlighting these advances by describing their applications in studies on cytoskeletal motors and DNA replication. We also discuss how single-molecule approaches have increased our understanding of the dynamic behavior of complex multiprotein systems. These methods have shown that the behavior of multicomponent protein complexes is highly stochastic and less linear and deterministic than previously thought. Further development of single-molecule tools will help to elucidate the molecular dynamics of these complex systems both inside the cell and in solutions with purified components. PMID- 27979909 TI - Distinct cellular states determine calcium signaling response. AB - The heterogeneity in mammalian cells signaling response is largely a result of pre-existing cell-to-cell variability. It is unknown whether cell-to-cell variability rises from biochemical stochastic fluctuations or distinct cellular states. Here, we utilize calcium response to adenosine trisphosphate as a model for investigating the structure of heterogeneity within a population of cells and analyze whether distinct cellular response states coexist. We use a functional definition of cellular state that is based on a mechanistic dynamical systems model of calcium signaling. Using Bayesian parameter inference, we obtain high confidence parameter value distributions for several hundred cells, each fitted individually. Clustering the inferred parameter distributions revealed three major distinct cellular states within the population. The existence of distinct cellular states raises the possibility that the observed variability in response is a result of structured heterogeneity between cells. The inferred parameter distribution predicts, and experiments confirm that variability in IP3R response explains the majority of calcium heterogeneity. Our work shows how mechanistic models and single-cell parameter fitting can uncover hidden population structure and demonstrate the need for parameter inference at the single-cell level. PMID- 27979908 TI - Disentangling genetic and epigenetic determinants of ultrafast adaptation. AB - A major rationale for the advocacy of epigenetically mediated adaptive responses is that they facilitate faster adaptation to environmental challenges. This motivated us to develop a theoretical-experimental framework for disclosing the presence of such adaptation-speeding mechanisms in an experimental evolution setting circumventing the need for pursuing costly mutation-accumulation experiments. To this end, we exposed clonal populations of budding yeast to a whole range of stressors. By growth phenotyping, we found that almost complete adaptation to arsenic emerged after a few mitotic cell divisions without involving any phenotypic plasticity. Causative mutations were identified by deep sequencing of the arsenic-adapted populations and reconstructed for validation. Mutation effects on growth phenotypes, and the associated mutational target sizes were quantified and embedded in data-driven individual-based evolutionary population models. We found that the experimentally observed homogeneity of adaptation speed and heterogeneity of molecular solutions could only be accounted for if the mutation rate had been near estimates of the basal mutation rate. The ultrafast adaptation could be fully explained by extensive positive pleiotropy such that all beneficial mutations dramatically enhanced multiple fitness components in concert. As our approach can be exploited across a range of model organisms exposed to a variety of environmental challenges, it may be used for determining the importance of epigenetic adaptation-speeding mechanisms in general. PMID- 27979910 TI - Patterns of chlamydia testing in different settings and implications for wider STI diagnosis and care: a probability sample survey of the British population. AB - BACKGROUND: Following widespread rollout of chlamydia testing to non-specialist and community settings in the UK, many individuals receive a chlamydia test without being offered comprehensive STI and HIV testing. We assess sexual behaviour among testers in different settings with a view to understanding their need for other STI diagnostic services. METHODS: A probability sample survey of the British population undertaken 2010-2012 (the third National Survey of Sexual Attitudes and Lifestyles). We analysed weighted data on chlamydia testing (past year), including location of most recent test, and diagnoses (past 5 years) from individuals aged 16-44 years reporting at least one sexual partner in the past year (4992 women, 3406 men). RESULTS: Of the 26.8% (95% CI 25.4% to 28.2%) of women and 16.7% (15.5% to 18.1%) of men reporting a chlamydia test in the past year, 28.4% of women and 41.2% of men had tested in genitourinary medicine (GUM), 41.1% and 20.7% of women and men respectively tested in general practice (GP) and the remainder tested in other non-GUM settings. Women tested outside GUM were more likely to be older, in a relationship and to live in rural areas. Individuals tested outside GUM reported fewer risk behaviours; nevertheless, 11.0% (8.6% to 14.1%) of women and 6.8% (3.9% to 11.6%) of men tested in GP and 13.2% (10.2% to 16.8%) and 9.6% (6.5% to 13.8%) of women and men tested in other non-GUM settings reported 'unsafe sex', defined as two or more partners and no condom use with any partner in the past year. Individuals treated for chlamydia outside GUM in the past 5 years were less likely to report an HIV test in that time frame (women: 54.5% (42.7% to 65.7%) vs 74.1% (65.9% to 80.9%) in GUM; men: 23.9% (12.7% to 40.5%) vs 65.8% (56.2% to 74.3%)). CONCLUSIONS: Most chlamydia testing occurred in non-GUM settings, among populations reporting fewer risk behaviours. However, there is a need to provide pathways to comprehensive STI care to the sizeable minority at higher risk. PMID- 27979913 TI - Moving the Goalposts: Prevention of Atrial Arrhythmias After Congenital Heart Surgery. PMID- 27979912 TI - Follow-Up of a Prospective Surgical Strategy to Prevent Intra-Atrial Reentrant Tachycardia After the Fontan Operation. AB - BACKGROUND: Intra-atrial reentrant tachycardia (IART) after the Fontan operation had an early reported incidence of 10% to 35% during early and intermediate follow-up and posed substantial management challenges. METHODS AND RESULTS: To reduce the incidence of IART after the Fontan procedure, we performed a randomized, double-blind study to evaluate the impact of an incision in the right atrium joining the lateral tunnel suture line and the tricuspid valve annulus. Between March 1998 and September 2003, 134 subjects (median age: 1.8 years; range: 1.3-5.2 years; 91 men) were randomly assigned to receive the incision. All 134 patients had a form of single ventricle pathological anatomy. The clinical course, electrocardiograms, and Holter monitoring were available for review in 114 subjects at a median of 8.2-year follow-up (range: 0.9-11.9 years). There were 2 late deaths, neither subject had IART. The combined incidence of sustained IART was 3.5% (4/114). There was no difference in the occurrence of sustained IART between those subjects receiving the incision and those who did not (2 in each group) during follow-up. No patients of either group experienced short-term complications. CONCLUSIONS: Despite the fact that the primary outcome of this trial was not reached, the most significant finding was that with current management, the incidence of IART is considerably lower than the early retrospective, observational studies suggested. PMID- 27979911 TI - Atrioventricular Node Dysfunction and Ion Channel Transcriptome in Pulmonary Hypertension. AB - BACKGROUND: Heart block is associated with pulmonary hypertension, and the aim of the study was to test the hypothesis that the heart block is the result of a change in the ion channel transcriptome of the atrioventricular (AV) node. METHODS AND RESULTS: The most commonly used animal model of pulmonary hypertension, the monocrotaline-injected rat, was used. The functional consequences of monocrotaline injection were determined by echocardiography, ECG recording, and electrophysiological experiments on the Langendorff-perfused heart and isolated AV node. The ion channel transcriptome was measured by quantitative PCR, and biophysically detailed computer modeling was used to explore the changes observed. After monocrotaline injection, echocardiography revealed the pattern of pulmonary artery blood flow characteristic of pulmonary hypertension and right sided hypertrophy and failure; the Langendorff-perfused heart and isolated AV node revealed dysfunction of the AV node (eg, 50% incidence of heart block in isolated AV node); and quantitative PCR revealed a widespread downregulation of ion channel and related genes in the AV node (eg, >50% downregulation of Cav1.2/3 and HCN1/2/4 channels). Computer modeling predicted that the changes in the transcriptome if translated into protein and function would result in heart block. CONCLUSIONS: Pulmonary hypertension results in a derangement of the ion channel transcriptome in the AV node, and this is the likely cause of AV node dysfunction in this disease. PMID- 27979914 TI - New Strategies in Metastatic Hormone Receptor-Positive Breast Cancer: Searching for Biomarkers to Tailor Endocrine and Other Targeted Therapies. AB - Although major advances in our understanding of the molecular underpinnings of hormone receptor-positive (HR+) breast cancer have led to new therapies that have substantially improved patient outcomes, endocrine-resistant disease still remains a leading cause of breast cancer mortality. Comprehensive molecular profiling of breast cancers has highlighted tremendous tumor heterogeneity, and analysis of paired primary and metastatic tumors has shown the evolution that can occur during acquired resistance to systemic therapies. Novel techniques for monitoring tumor load under treatment pressure, including "liquid biopsy" techniques, such as circulating free tumor DNA (cfDNA) and circulating tumor cells, have shown promise as biomarkers to direct treatment without invasive tumor biopsies. However, more research is needed to deepen our understanding of breast cancer alterations under treatment pressure to reveal mechanisms of drug resistance and apply precision medicine in biomarker-driven clinical trials. Clin Cancer Res; 23(5); 1126-31. (c)2016 AACR. PMID- 27979915 TI - Neural Stem Cell-Based Anticancer Gene Therapy: A First-in-Human Study in Recurrent High-Grade Glioma Patients. AB - Purpose: Human neural stem cells (NSC) are inherently tumor tropic, making them attractive drug delivery vehicles. Toward this goal, we retrovirally transduced an immortalized, clonal NSC line to stably express cytosine deaminase (HB1.F3.CD.C21; CD-NSCs), which converts the prodrug 5-fluorocytosine (5-FC) to 5 fluorouracil (5-FU).Experimental Design: Recurrent high-grade glioma patients underwent intracranial administration of CD-NSCs during tumor resection or biopsy. Four days later, patients began taking oral 5-FC every 6 hours for 7 days. Study treatment was given only once. A standard 3 + 3 dose escalation schema was used to increase doses of CD-NSCs from 1 * 107 to 5 * 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU. Serial blood samples were obtained to assess systemic drug concentrations as well as to perform immunologic correlative studies.Results: Fifteen patients underwent study treatment. We saw no dose limiting toxicity (DLT) due to the CD-NSCs. There was 1 DLT (grade 3 transaminitis) possibly related to 5-FC. We did not see development of anti-CD NSC antibodies and did not detect CD-NSCs or replication-competent retrovirus in the systemic circulation. Intracerebral microdialysis revealed that CD-NSCs produced 5-FU locally in the brain in a 5-FC dose-dependent manner. Autopsy data indicate that CD-NSCs migrated to distant tumor sites and were nontumorigenic.Conclusions: Collectively, our results from this first-in-human study demonstrate initial safety and proof of concept regarding the ability of NSCs to target brain tumors and locally produce chemotherapy. Clin Cancer Res; 23(12); 2951-60. (c)2016 AACR. PMID- 27979916 TI - Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study. AB - Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5 azacitidine and entinostat in women with advanced hormone-resistant or triple negative breast cancer (TNBC).Experimental Design: Patients received 5 azacitidine 40 mg/m2 (days 1-5, 8-10) and entinostat 7 mg (days 3, 10) on a 28 day cycle. Continuation of epigenetic therapy was offered with the addition of endocrine therapy at the time of progression [optional continuation (OC) phase]. Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be >=20% against null of 5% using Simon two-stage design. At least one response was required in 1 of 13 patients per cohort to continue accrual to 27 per cohort (type I error, 4%; power, 90%).Results: There was one partial response among 27 women with hormone-resistant disease (ORR = 4%; 95% CI, 0-19), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n = 12). Mandatory tumor samples were obtained pre- and posttreatment (58% paired) with either up- or downregulation of ER observed in approximately 50% of posttreatment biopsies in the hormone-resistant, but not TNBC cohort.Conclusions: Combination epigenetic therapy was well tolerated, but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression, but further study is needed. Clin Cancer Res; 23(11); 2691-701. (c)2016 AACR. PMID- 27979918 TI - Pre-term birth and low birth weight following preimplantation genetic diagnosis: analysis of 88 010 singleton live births following PGD and IVF cycles. AB - STUDY QUESTION: Is PGD associated with the risk of adverse perinatal outcomes such as pre-term birth (PTB) and low birth weight (LBW)? SUMMARY ANSWER: There was no increase in the risk of adverse perinatal outcomes of PTB, and LBW following PGD compared with autologous IVF. WHAT IS KNOWN ALREADY: Pregnancies resulting from ART are associated with a higher risk of pregnancy complications compared with spontaneously conceived pregnancies. The possible reason of adverse obstetric outcomes following ART has been attributed to the underlying infertility itself and embryo specific epigenetic modifications due to the IVF techniques. It is of interest whether interventions such as embryo biopsy as performed in PGD affect perinatal outcomes. STUDY DESIGN, SIZE, DURATION: Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA), the statutory regulator of ART in the UK. The HFEA has collected data prospectively on all ART performed in the UK since 1991. Data from 1996 to 2011 involving a total of 88 010 singleton live births were analysed including 87 571 following autologous stimulated IVF +/- ICSI and 439 following PGD cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on all women undergoing either a stimulated fresh IVF +/- ICSI treatment cycle or a PGD cycle during the period from 1996 to 2011 were analysed to compare perinatal outcomes of PTB and LBW among singleton live births. Logistic regression analysis was performed adjusting for female age category, year of treatment, previous IVF cycles, infertility diagnosis, number of oocytes retrieved, whether IVF or ICSI was used and day of embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: There was no increase in the risk of PTB and LBW following PGD versus autologous stimulated IVF +/- ICSI treatment, unadjusted odds of PTB (odds ratio (OR) 0.68, 95% CI: 0.46-0.99) and LBW (OR 0.56, 95% CI: 0.37-0.85). After adjusting for the potential confounders, there was again no increase in the risk of the adverse perinatal outcomes following PGD: PTB (adjusted odds ratio (aOR) 0.66, 95% CI: 0.45-0.98) and LBW (aOR 0.58, 95% CI: 0.38-0.88). LIMITATIONS, REASONS FOR CAUTION: Although the analysis was adjusted for a number of important confounders, the data set had no information on confounders such as smoking, body mass index and the medical history of women during pregnancy to allow adjustment. There was no information on the stage of embryo at biopsy, whether blastomere or trophectoderm biopsy. WIDER IMPLICATIONS FOR THE FINDINGS: The demonstration that PGD is not associated with higher risk of PTB and LBW provides reassurance towards its current expanding application. STUDY FUNDING/COMPETING INTERESTS: No funding was obtained. There are no competing interests to declare. PMID- 27979917 TI - Bisphenol-A exposure and gene expression in human luteinized membrana granulosa cells in vitro. AB - STUDY QUESTION: Does bisphenol-A (BPA) affect gene expression in human membrana granulosa cells (MGC)? SUMMARY ANSWER: In vitro, short exposure to supra physiological concentrations of BPA alters human MGC gene expression. WHAT IS KNOWN ALREADY: Exposure to BPA may interfere with reproductive endocrine signaling. In vitro studies, mostly in animal models, have shown an inverse correlation between exposure to BPA and follicular growth, meiosis, and steroid hormone production in granulosa cells. STUDY DESIGN, SIZE, DURATION: Primary cultures of MGC obtained from 24 patients undergoing IVF (for PGD, male factor infertility or unexplained infertility) were exposed to various concentrations of BPA (0, 0.02, 0.2, 2 or 20 ug/ml) for 48 h. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in a university-affiliated hospital. Microarray analysis was used to identify genes exhibiting expression changes following BPA exposure. Genes significantly altered were identified based on changes greater than 2-fold relative to the control group (not treated by BPA) and a Student's t test P-value <0.05. Statistical significance was adjusted for multiple comparisons using the Benjamini-Hochberg method. Alterations in the expression of genes that are involved in the enriched functional annotations altered by BPA at the concentration of 20 ug/ml were confirmed by real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE: A distinct pattern of gene expression was observed in primary cultures of MGC exposed to the highest BPA concentration compared with untreated cells. We identified 652 genes that exhibited at least 2-fold differences in expression after BPA exposure (all P < 0.05 versus untreated). These genes were significantly enriched for annotations related to cell cycle progression, segregation of chromosomes, steroid metabolism, apoptosis, lipid synthesis, oocyte maturation and chromosomal alignment. No significant changes in gene expression were found at the lower doses of BPA most relevant to human exposure. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Human exposure to BPA in vivo occurs over long periods of time. In this in vitro model, cells were exposed to the chemical for 48 h only. Thus, the effects of BPA on the human follicle might be underestimated. WIDER IMPLICATIONS OF THE FINDINGS: As BPA exposure is ubiquitous, understanding the effects of the chemical on the ovary, specifically in women of reproductive age, has public health significance. The clinical evidence to date points to an association between BPA exposure and impaired IVF outcome, although not all studies have shown negative effects. Our study adds valuable mechanistic information showing that exposure to BPA alters granulosa cell gene expression at high and supra-physiological doses. STUDY FUNDING/COMPETING INTERESTS: This study was supported by grant number 1936/12 from the ISF. The authors have nothing to disclose. PMID- 27979919 TI - COMPI Fertility Problem Stress Scales is a brief, valid and reliable tool for assessing stress in patients seeking treatment. AB - STUDY QUESTION: Are the Copenhagen Multi-Centre Psychosocial Infertility research program Fertility Problem Stress Scales (COMPI-FPSS) a reliable and valid measure across gender and culture? SUMMARY ANSWER: The COMPI-FPSS is a valid and reliable measure, presenting excellent or good fit in the majority of the analyzed countries, and demonstrating full invariance across genders and partial invariance across cultures. WHAT IS KNOWN ALREADY: Cross-cultural and gender validation is needed to consider a measure as standard care within fertility. The present study is the first attempting to establish comparability of fertility related stress across genders and countries. STUDY DESIGN SIZE, DURATION: Cross sectional study. First, we tested the structure of the COMPI-FPSS. Then, reliability and validity (convergent and discriminant) were examined for the final model. Finally, measurement invariance both across genders and cultures was tested. PARTICIPANTS/MATERIALS, SETTING, METHODS: Our final sample had 3923 fertility patients (1691 men and 2232 women) recruited in clinical settings from seven different countries: Denmark, China, Croatia, Germany, Greece, Hungary and Sweden. Participants had a mean age of 34 years and the majority (84%) were childless. MAIN RESULTS AND THE ROLE OF CHANCE: Findings confirmed the original three-factor structure of the COMPI-FPSS, although suggesting a shortened measurement model using less items that fitted the data better than the full version model. While data from the Chinese and Croatian subsamples did not fit, all other counties presented good fit (chi2/df <= 5.4; comparative fit index >= 0.94; root-mean-square error of approximation <= 0.07; modified expected cross validation index <= 0.77). In general, reliability, convergent validity, and discriminant validity were observed in all subscales from each country (composite reliability >= 0.63; average variance extracted >= 0.38; squared correlation >= 0.13). Full invariance was established across genders, and partial invariance was demonstrated across countries. LIMITATIONS REASONS FOR CAUTION: Generalizability regarding the validation of the COMPI-FPSS cannot be made regarding infertile individuals not seeking treatment, or non-European patients. This study did not investigate predictive validity, and hence the capability of this instrument in detecting changes in fertility-specific adjustment over time and predicting the psychological impact needs to be established in future research. WIDER IMPLICATIONS OF THE FINDINGS: Besides extending knowledge on the psychometric properties of one of the most used fertility stress questionnaire, this study demonstrates both research and clinical usefulness of the COMPI-FPSS. STUDY FUNDING/COMPETING INTERESTS: This study was supported by European Union Funds (FEDER/COMPETE-Operational Competitiveness Program, and by national funds (FCT Portuguese Foundation for Science and Technology) under the projects PTDC/MHC PSC/4195/2012 and SFRH/BPD/85789/2012). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A. PMID- 27979920 TI - Molecular mechanisms that distinguish TFIID housekeeping from regulatable SAGA promoters. AB - An important distinction is frequently made between constitutively expressed housekeeping genes versus regulated genes. Although generally characterized by different DNA elements, chromatin architecture and cofactors, it is not known to what degree promoter classes strictly follow regulatability rules and which molecular mechanisms dictate such differences. We show that SAGA-dominated/TATA box promoters are more responsive to changes in the amount of activator, even compared to TFIID/TATA-like promoters that depend on the same activator Hsf1. Regulatability is therefore an inherent property of promoter class. Further analyses show that SAGA/TATA-box promoters are more dynamic because TATA-binding protein recruitment through SAGA is susceptible to removal by Mot1. In addition, the nucleosome configuration upon activator depletion shifts on SAGA/TATA-box promoters and seems less amenable to preinitiation complex formation. The results explain the fundamental difference between housekeeping and regulatable genes, revealing an additional facet of combinatorial control: an activator can elicit a different response dependent on core promoter class. PMID- 27979922 TI - Human RAD52 - a novel player in DNA repair in cancer and immunodeficiency. PMID- 27979921 TI - Complex structure of cytochrome c-cytochrome c oxidase reveals a novel protein protein interaction mode. AB - Mitochondrial cytochrome c oxidase (CcO) transfers electrons from cytochrome c (Cyt.c) to O2 to generate H2O, a process coupled to proton pumping. To elucidate the mechanism of electron transfer, we determined the structure of the mammalian Cyt.c-CcO complex at 2.0-A resolution and identified an electron transfer pathway from Cyt.c to CcO. The specific interaction between Cyt.c and CcO is stabilized by a few electrostatic interactions between side chains within a small contact surface area. Between the two proteins are three water layers with a long inter molecular span, one of which lies between the other two layers without significant direct interaction with either protein. Cyt.c undergoes large structural fluctuations, using the interacting regions with CcO as a fulcrum. These features of the protein-protein interaction at the docking interface represent the first known example of a new class of protein-protein interaction, which we term "soft and specific". This interaction is likely to contribute to the rapid association/dissociation of the Cyt.c-CcO complex, which facilitates the sequential supply of four electrons for the O2 reduction reaction. PMID- 27979923 TI - Efficacy and safety of idelalisib in patients with relapsed, rituximab- and alkylating agent-refractory follicular lymphoma: a subgroup analysis of a phase 2 study. PMID- 27979925 TI - Effects of ibrutinib treatment on murine platelet function during inflammation and in primary hemostasis. PMID- 27979927 TI - Determination of Aflatoxin B1-Lysine in Pig Serum and Plasma by Liquid Chromatography-Tandem Mass Spectrometry. AB - Aflatoxin B1 (AFB1) is a hepatocarcinogen produced by certain Aspergillus species growing on crops. After biotransformation in the liver, AFB1 generates several metabolites, one of which is AFB1 bound to lysine on serum albumin. AFB1-lysine (AFB1-lys) is a digest product of AFB1-albumin and is considered a biomarker of exposure to AFB1 in humans and animals. The objectives of this paper were to evaluate the performance characteristics of a new analytical method for determination of AFB1-lys levels in pig serum, heparinized and ethylenediaminetetraacetic acid (EDTA) plasma and to evaluate the interference of these anticoagulants in AFB1-lys quantification. Blank blood samples were obtained from eight crossbreed 91-day-old barrows fed AFB1-free diets. Pooled samples (n = 3) and individual samples of serum, EDTA and heparinized plasma collected from five pigs were enzymatically digested with pronase at 37 degrees C for 4 h. AFB1-lys was isolated by solid-phase extraction and quantified by liquid chromatography coupled to tandem mass spectrometry. The analytical method was applied for determination of AFB1-lys in serum and EDTA plasma collected from five 49-day-old crossbreed barrows fed ad libitum diets containing 1.1 mg of AFB1 per kg of feed during 7 days (three animals) or 42 days (two animals). Samples of heparinized plasma were only available from animals intoxicated for 42 days. All animals had lower levels of AFB1-lys in EDTA plasma samples (24.78-37.40 ng/mL), when compared to serum (49.32-252.07 ng/mL-1) or heparinized plasma (176.81 and 264.24 ng/mL-1). EDTA did not interfere in AFB1-lys standard detection, but our findings suggest that EDTA should be avoided during blood collection since it affects the pronase activity in AFB1-albumin adduct digestion and, consequently, causes a reduction in the AFB1-lys levels. Hence, determination of AFB1-lys in serum and heparinized plasma is an approach to assess an individual's exposure of swine to AFB1. PMID- 27979924 TI - Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients. AB - Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of IKZF1 deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of BTG1 were significantly enriched in IKZF1-deleted B-cell precursor acute lymphoblastic leukemia (P=0.007). While BTG1 deletions alone had no impact on prognosis, the combined presence of BTG1 and IKZF1 deletions was associated with a significantly lower 5-year event-free survival (P=0.0003) and a higher 5-year cumulative incidence of relapse (P=0.005), when compared with IKZF1-deleted cases without BTG1 aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as CDKN2A/B, PAX5, EBF1 or RB1, did not affect the outcome of IKZF1-deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, Btg1-deficient mice were crossed onto an Ikzf1 heterozygous background. We observed that loss of Btg1 increased the tumor incidence of Ikzf1+/- mice in a dose-dependent manner. Moreover, murine B cells deficient for Btg1 and Ikzf1+/- displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify BTG1 as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in IKZF1 deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function. PMID- 27979926 TI - CREBBP knockdown enhances RAS/RAF/MEK/ERK signaling in Ras pathway mutated acute lymphoblastic leukemia but does not modulate chemotherapeutic response. AB - Relapsed acute lymphoblastic leukemia is the most common cause of cancer-related mortality in young people and new therapeutic strategies are needed to improve outcome. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP, are particularly frequent in relapsed childhood acute lymphoblastic leukemia and associated with a hyperdiploid karyotype and KRAS mutations. To study the functional impact of CREBBP haploinsufficiency in acute lymphoblastic leukemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukemia cell lines and various primagraft acute lymphoblastic leukemia cells. We demonstrate that attenuation of CREBBP results in reduced acetylation of histone 3 lysine 18, but has no significant impact on cAMP-dependent target gene expression. Impaired induction of glucocorticoid receptor targets was only seen in 1 of 4 CREBBP knockdown models, and there was no significant difference in glucocorticoid induced apoptosis, sensitivity to other acute lymphoblastic leukemia chemotherapeutics or histone deacetylase inhibitors. Importantly, we show that CREBBP directly acetylates KRAS and that CREBBP knockdown enhances signaling of the RAS/RAF/MEK/ERK pathway in Ras pathway mutated acute lymphoblastic leukemia cells, which are still sensitive to MEK inhibitors. Thus, CREBBP mutations might assist in enhancing oncogenic RAS signaling in acute lymphoblastic leukemia but do not alter response to MEK inhibitors. PMID- 27979928 TI - LC-MS-MS Method for Analysis of Benzodiazepines in Wastewater During Football Games IV. AB - Continuing our studies for the analyses of drugs of abuse in municipal wastewater, a method was developed for the analysis of benzodiazepines in wastewater samples using liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). Ten benzodiazepines and metabolites were analyzed (structures were found), including alprazolam, alpha-OH-alprazolam (the primary urinary metabolite of alprazolam), chlordiazepoxide, flurazepam, 2-OH ethylflurazepam (the primary urinary metabolite of flurazepam), 7-NH2 flunitrazepam, nordiazepam, oxazepam, temazepam and alpha-OH-triazolam (the primary urinary metabolite of triazolam) (representative chromatograms were found). These drugs were chosen because of their widespread abuse. Wastewater samples were collected at both the Oxford Wastewater Treatment Plant (WWTP) in Oxford, Mississippi (MS) and the University WWTP in University, MS. These wastewater samples were collected on weekends in which the Ole Miss Rebel football team held home games at the Vaught-Hemingway Stadium, University, and one weekend on which there was no game. The collected samples were analyzed using a validated method and found to contain alprazolam, alpha-OH-alprazolam, nordiazepam, oxazepam and temazepam. None of the samples contained chlordiazepoxide, flurazepam, 2-hydroxyethyl-flurazepam, 7-NH2-flunitrazepam and alpha-OH-triazolam. PMID- 27979929 TI - Comparative Evaluation of Drug Deposition in Hair Samples Collected from Different Anatomical Body Sites. AB - In this study, we focused on the validation of a method for the simultaneous detection and quantification of cannabinoids, cocaine and opiates in hair as well as on the distribution of the drugs deposition in hair collected from different anatomical body sites. The proposed analytical procedure was validated for various parameters such as selectivity, linearity, limit of quantification, precision, accuracy, matrix effect and recovery. Four hundred and eighty-one samples were collected during 2010-2015 from 231 drug abusers. A 6-h ultrasonic assisted methanolic extraction was applied for the isolation of the drugs. The analysis was performed in an liquid chromatography-mass spectrometry system for the opiates and cocaine and in a gas chromatography-mass spectrometry system for the cannabinoids. Cocaine was the most frequent detected drug (68.8-80.5%) followed by cannabinoids (47.6-63.3%) and opiates (34.7-46.7%) depending on the body site that the samples were collected. The mean concentrations of Delta9 tetrahydrocannabinol (THC) were 0.63 +/- 2.11 for head, 0.54 +/- 1.03 for pubic, 0.34 +/- 0.51 for axillary and 0.18 +/- 0.18 ng/mg for chest hair samples. The values of cocaine were 6.52 +/- 15.98, 4.64 +/- 10.77, 6.96 +/- 38.21 and 3.94 +/ 6.35 ng/mg, while the values of 6-monoacetylmorphine (MAM) were 3.33 +/- 5.89, 3.06 +/- 9.33, 1.37 +/- 1.37 and 16.4 +/- 1.77 ng/mg for head, pubic, axillary and chest samples, respectively. Differences between the detected concentrations of cocaine and opiates between the hair samples of different anatomical sites, as well as the ratio of drug metabolites to the parent compounds were observed in some cases. Statistically significant differences in the mean detected levels were noticed for morphine and heroin between head and pubic hair and also for cocaine and benzoylecgonine, between head and axillary hair samples. Moreover, the ratio of MAM to morphine and THC to cannabinol seems to correlate statistically with the total opiate or cannabinoid detected concentrations. The above differences could be attributed to several parameters associated with the structure, morphology, growth rate and other characteristics of the collected hair. PMID- 27979930 TI - Draft Genome Sequences of 40 Pseudomonas aeruginosa Clinical Strains Isolated from the Sputum of a Single Cystic Fibrosis Patient Over an 8-Year Period. AB - We report draft genome sequences of 40 Pseudomonas aeruginosa strains, isolated from the sputum of a single cystic fibrosis patient over eight years. Analyses indicated a correlation between multidrug-resistant phenotypes and population structure. Our data provide new insights into the mechanisms leading to acquisition of antibiotic resistance in P. aeruginosa. PMID- 27979931 TI - Draft Genome Sequences of Itaconate-Producing Ustilaginaceae. AB - Some smut fungi of the family Ustilaginaceae produce itaconate from glucose. De novo genome sequencing of nine itaconate-producing Ustilaginaceae revealed genome sizes between 19 and 25 Mbp. Comparison to the itaconate cluster of U. maydis MB215 revealed all essential genes for itaconate production contributing to metabolic engineering for improving itaconate production. PMID- 27979932 TI - Complete Genome Sequences of Curli-Negative and Curli-Positive Isolates of Foodborne Escherichia coli O157:H7 Strain 86-24. AB - Escherichia coli O157:H7 strain 86-24 does not produce curli fimbriae, but gives rise to curli-positive isolates at a variable frequency. Here, we report the complete genome sequences of curli-negative and curli-positive isolates of strain 86-24. PMID- 27979933 TI - Complete Genome Sequence of a Copper-Resistant Bacterium from the Citrus Phyllosphere, Stenotrophomonas sp. Strain LM091, Obtained Using Long-Read Technology. AB - The Stenotrophomonas genus shows great adaptive potential including resistance to multiple antimicrobials, opportunistic pathogenicity, and production of numerous secondary metabolites. Using long-read technology, we report the sequence of a plant-associated Stenotrophomonas strain originating from the citrus phyllosphere that displays a copper resistance phenotype. PMID- 27979934 TI - Complete Genome Sequence of Type Strain Campylobacter fetus subsp. fetus ATCC 27374. AB - Campylobacter fetus subsp. fetus is a zoonotic bacterium important for animal and public health. The complete sequencing and annotation of the genome of the type strain C. fetus subsp. fetus ATCC 27374 are reported here. PMID- 27979935 TI - Draft Genome Sequence of Bacillus subtilis Ia1a, a New Strain for Poly-gamma Glutamic Acid and Exopolysaccharide Production. AB - We report here the 4.092-Mb high-quality draft genome assembly of a newly isolated poly-gamma-glutamic acid-producing strain, Bacillus subtilis Ia1a. The genome sequence is considered a critical tool to facilitate the engineering of improved production strains. Exopolysaccharides and many industrially important enzymes can be produced by this new strain utilizing different carbon sources. PMID- 27979936 TI - Complete Genome Sequences of Six Legionella pneumophila Isolates from Two Collocated Outbreaks of Legionnaires' Disease in 2005 and 2008 in Sarpsborg/Fredrikstad, Norway. AB - Here, we report the complete genome sequences of Legionella pneumophila isolates from two collocated outbreaks of Legionnaires' disease in 2005 and 2008 in Sarpsborg/Fredrikstad, Norway. One clinical and two environmental isolates were sequenced from each outbreak. The genome of all six isolates consisted of a 3.36 Mb-chromosome, while the 2005 genomes featured an additional 68 kb-episome sharing high sequence similarity with the L. pneumophila Lens plasmid. All six genomes contained multiple mobile genetic elements including novel combinations of type-IVA secretion systems. A comparative genomics study will be launched to resolve the genetic relationship between the L. pneumophila isolates. PMID- 27979937 TI - Draft Genome Sequence of Pediococcus parvulus 2.6, a Probiotic beta-Glucan Producer Strain. AB - We report here the draft genome sequence of the probiotic Pediococcus parvulus 2.6, a lactic acid bacterial strain isolated from ropy cider. The bacterium produces a prebiotic and immunomodulatory exopolysaccharide, and this is the first strain of the P. parvulus species whose genome has been characterized. PMID- 27979938 TI - Draft Genome Sequence of Extended-Spectrum-beta-Lactamase-Producing Escherichia coli Strain CCUG 62462, Isolated from a Urine Sample. AB - The draft genome sequence has been determined for an extended-spectrum-beta lactamase (ESBL)-producing (blaCTX-M-15) Escherichia coli strain (CCUG 62462), composed of 119 contigs and a total size of 5.27 Mb. This E. coli is serotype O25b and sequence type 131, a pandemic clonal group, causing worldwide antimicrobial-resistant infections. PMID- 27979939 TI - Draft Genome Sequence of Blautia faecis Strain Marseille-P328, Isolated from the Human Ascending Colon. AB - Blautia faecis strain Marseille P328 was isolated from the ascending colon of a French patient. We sequenced the 4.45-Mb genome of the strain and compared it with that of other species of the Blautia genus. PMID- 27979940 TI - Draft Genome Sequence of Enterococcus faecalis Strain UCD-PD3. AB - Here, we present the draft genome sequence of Enterococcus faecalis strain UCD PD3. The assembly contains 2,861,314 bp in 73 contigs. This strain was isolated from a feral domestic cat (Felis catus) anal sac secretion sample, as part of a project on isolating and characterizing the microbes present in feline anal sacs. PMID- 27979941 TI - Complete Genome Sequences of Enterococcus rotai LMG 26678T and Enterococcus silesiacus LMG 23085T. AB - The inclusion of molecular methods in the characterization of the novel species Enterococcus horridus necessitated the sequencing and assembly of the genomes of the closely related Enterococcus rotai and Enterococcus silesiacus Sequencing using Illumina technology in combination with optical mapping led to the generation of closed genomes for both isolates. PMID- 27979942 TI - Genome Sequence of Rheinheimera salexigens sp. nov. Isolated from a Fishing Hook off O'ahu, Hawai'i. AB - Rheinheimera salexigens KH87T is an obligately halophilic gammaproteobacterium. The strain's draft genome sequence, generated by the Roche 454 GS FLX+ platform, comprises two scaffolds of ~3.4 Mbp and ~3 kbp, with 3,030 protein-coding sequences and 58 tRNA coding regions. The G+C content is 42 mol%. PMID- 27979944 TI - Genomic Sequencing of Ranaviruses Isolated from Turbot (Scophthalmus maximus) and Atlantic Cod (Gadus morhua). AB - Ranaviruses have been isolated from Atlantic cod (Gadus morhua) and turbot (Scophthalmus maximus) in Denmark. Phylogenomic analyses revealed that these two ranaviruses are nearly identical and form a distinct clade at the base of the ranavirus tree branching off near other fish ranaviruses. PMID- 27979943 TI - High-Quality Draft Genome Sequence of the Actinobacterium Nocardia terpenica IFM 0406, Producer of the Immunosuppressant Brasilicardins, Using Illumina and PacBio Technologies. AB - The bacterium Nocardia terpenica IFM 0406 is known as the producer of the immunosuppressant brasilicardin A. Here, we report the completely sequenced genome of strain IFM 0406, which facilitates the heterologous expression of the brasilicardin biosynthetic gene cluster but also unveils the intriguing biosynthetic capacity of the strain to produce secondary metabolites. PMID- 27979945 TI - Complete Genome Sequences of Nine Enterovirus D68 Strains from Patients of the Lower Hudson Valley, New York, 2016. AB - Complete genome sequences of nine enterovirus D68 (EV-D68) strains from patients in New York were obtained in 2016 by metagenomic next-generation sequencing. Comparative genomic analysis suggests that a new subclade B3, with ~4.5% nucleotide divergence from subclade B1 strains causing the 2014 outbreak, is circulating in the United States in 2016. PMID- 27979946 TI - Draft Genome Sequences of Four Propionibacterium acnes Strains Isolated from Implant-Related Infections. AB - Propionibacterium acnes was previously described as a potential implant-related pathogen. Here, we report the draft genome sequence of four P. acnes strains, isolated from spine material, hip arthroplasty, and knee arthroplasty infections in France belonging to different sequence types (ST18, ST27, and ST36). PMID- 27979947 TI - Draft Genome Sequence of Cloacibacterium normanense NRS-1 Isolated from Municipal Wastewater. AB - Cloacibacterium normanense is a Gram-negative bacterium recovered from untreated human wastewater. Given its high abundance in wastewater and its apparent absence in human stool, it may contribute to biological phosphate removal. Here, we perform a whole-genome sequence of C. normanense NRS-1(T) and examine particular features of this draft genome. PMID- 27979948 TI - Complete Genome Sequence of Delftia tsuruhatensis CM13 Isolated from Murine Proximal Colonic Tissue. AB - We report here the complete genome sequence of Delftia tsuruhatensis CM13, isolated from murine proximal colonic tissue. The genome assembly using PacBio single-molecule real-time sequencing resulted in a single scaffold of 7.19 Mb. PMID- 27979949 TI - Genome Sequence of the Poly-3-Hydroxybutyrate Producer Clostridium acetireducens DSM 10703. AB - Here, we report the genome sequence of Clostridium acetireducens (DSM 10703T), a strictly anaerobic bacterium capable of fermenting acetate and leucine to butyrate, isovalerate, and poly-3-hydroxybutyrate. The draft genome consists of a circular chromosome with a size of 2.4 Mb and harbors 2,239 predicted protein encoding genes. PMID- 27979950 TI - Genome Sequences of Multidrug-Resistant Salmonella enterica subsp. enterica Serovar Infantis Strains from Broiler Chicks in Hungary. AB - Three strains of Salmonella enterica serovar Infantis isolated from healthy broiler chickens from 2012 to 2013 have been sequenced. Comparison of these and previously published S Infantis genome sequences of broiler origin in 1996 and 2004 will provide new insight into the genome evolution and recent spread of S Infantis in poultry. PMID- 27979951 TI - Complete Genome Sequence of Community-Acquired Klebsiella pneumoniae KP36, a Strain Isolated from a Patient with an Upper Urinary Tract Infection. AB - Here, we announce the complete genome sequence of Klebsiella pneumoniae KP36, a strain isolated from a patient with a severe community-acquired urinary tract infection. This genome provides insights into the pathogenesis of a pandemic K. pneumoniae strain from a community-acquired urinary tract infection. PMID- 27979952 TI - Complete Genome Sequence of Rhodococcus sp. Strain WMMA185, a Marine Sponge Associated Bacterium. AB - The Rhodococcus strain WMMA185 was isolated from the marine sponge Chondrilla nucula as part of ongoing drug discovery efforts. Analysis of the 4.44-Mb genome provides information regarding interspecies interactions as pertains to regulation of secondary metabolism and natural product biosynthetic potentials. PMID- 27979953 TI - Genome Sequence of "Anthococcus," a Novel Genus of the Family Streptococcaceae Isolated from Flowers. AB - Here, we report the draft whole-genome sequence of "Anthococcus," a novel genus of the family Streptococcaceae isolated from fresh flowers of a durian (Durio zibethinus) tree. The draft genome of Anthococcus sp. strain DF1 contains 2,157,756 bp, with a G+C content of 33.0%. PMID- 27979954 TI - Draft Genome Sequence of the Probiotic Bifidobacterium longum subsp. longum Strain MC-42. AB - Here, we report the draft genome sequence of Bifidobacterium longum subsp. longum strain MC-42 isolated from the feces of a healthy infant, and which was used in the commercially available probiotic product Biovestin. PMID- 27979955 TI - Draft Genome Sequence of Streptococcus anginosus BVI, a New Vaginal Pathogen Candidate. AB - Streptococcus anginosus is a pathogen implicated in urogenital and gastroinstestinal tract infections. Here, we report the draft genome sequence of S. anginosus BVI, isolated from a bacterial vaginosis patient attending a prenatal care unit in Cali, Colombia. The genome sequence of BVI consists of 2,014,025 bp, encoding 2,008 predicted proteins. PMID- 27979956 TI - Genome Sequences of Multidrug-Resistant, Colistin-Susceptible and -Resistant Klebsiella pneumoniae Clinical Isolates from Pakistan. AB - The emergence and spread of colistin resistance among multidrug-resistant (MDR) Klebsiella pneumoniae represent a critical threat to global health. Here, we report the complete genome sequences of 10 MDR, colistin-susceptible and resistant K. pneumoniae clinical isolates obtained in Pakistan between 2010 and 2013. PMID- 27979957 TI - Complete Genome Sequence of Trueperella pyogenes, Isolated from Infected Farmland Goats. AB - Trueperella pyogenes is a significant pathogen of livestock, causing diverse diseases, such as mastitis, liver abscessation, and pneumonia. In this study, we have reported the genome sequence of Trueperella pyogenes 2012CQ-ZSH. Moreover, several genes coding for virulence factors were found, such as pyolysin (PYO), nanH, nanP, cbpA, fimC, and fimE. PMID- 27979958 TI - Draft Genome Sequences of Type Strains Bacillus drentensis DSM 15600T and Bacillus novalis DSM 15603T. AB - Here, we report the draft genome sequences of Bacillus drentensis DSM 15600T and Bacillus novalis DSM 15603T with 5,305,306 bp and 5,667,584 bp, respectively, which will provide useful information for the functional gene mining and application of these two species. The average DNA G+C contents were 38.91% and 40.01%, respectively. PMID- 27979959 TI - Gestational Age Assessment by Methylation and Size Profiling of Maternal Plasma DNA: A Feasibility Study. PMID- 27979960 TI - Validation of the Use of Trinity Biotech ultra2 as a Comparative Method for Hemoglobin A1c Measurements in the Presence of HbE and HbD-Punjab Traits. PMID- 27979961 TI - RT-qPCR and RT-Digital PCR: A Comparison of Different Platforms for the Evaluation of Residual Disease in Chronic Myeloid Leukemia. AB - BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the cornerstone of successful clinical management of patients with chronic myeloid leukemia (CML). Quantitative monitoring of the percentage of the fusion transcript BCR-ABL1 (breakpoint cluster region-c-abl oncogene 1, non-receptor tyrosine kinase) BCR-ABL1IS (%BCR ABL1IS) by reverse transcription-quantitative PCR (RT-qPCR) is the gold standard strategy for evaluating patient response to TKIs and classification into prognostic subgroups. However, this approach can be challenging to perform in a reproducible manner. Reverse-transcription digital PCR (RT-dPCR) is an adaptation of this method that could provide the robust and standardized workflow needed for truly standardized patient stratification. METHODS: BCR-ABL1 and ABL1 transcript copy numbers were quantified in a total of 102 samples; 70 CML patients undergoing TKI therapy and 32 non-CML individuals. 3 commercially available digital PCR platforms (QS3D, QX200 and Raindrop) were compared with the platform routinely used in the clinic for RT-qPCR using the EAC (Europe Against Cancer) assay. RESULTS: Measurements on all instruments correlated well when the %BCR ABL1IS was >=0.1%. In patients with residual disease below this level, greater variations were measured both within and between instruments limiting comparable performance to a 4 log dynamic range. CONCLUSIONS: RT-dPCR was able to quantify low-level BCR-ABL1 transcript copies but was unable to improve sensitivity below the level of detection achieved by RT-qPCR. However, RT-dPCR was able to perform these sensitive measurements without use of a calibration curve. Adaptions to the protocol to increase the amount of RNA measured are likely to be necessary to improve the analytical sensitivity of BCR-ABL testing on a dPCR platform. PMID- 27979962 TI - Healthcare resource utilization and clinical outcomes associated with acute care and inpatient rehabilitation of stroke patients in Japan. AB - Objective: To investigate healthcare resource utilization and changes in functional status in stroke patients during hospitalization in an acute hospital and a rehabilitation hospital. Design: Retrospective cohort study. Setting: One acute and one rehabilitation hospital in Japan. Participants: Patients who were admitted to the acute hospital due to stroke onset and then transferred to the rehabilitation hospital (n = 263, 56% male, age 70 +/- 12 years). Main outcome measures: Hospitalization costs and functional independence measure (FIM) were evaluated according to stroke subtype and severity of disability at discharge from the acute hospital. Results: Median (IQR) costs at the acute hospital were dependent on the length of stay (LOS) and implementation of neurosurgery, which resulted in higher costs in subarachnoid hemorrhage [$52 413 ($49 166-$72 606) vs $14 129 ($11 169-$19 459) in cerebral infarction; and vs $15 035 ($10 920-$21 864) in intracerebral hemorrhage]. The costs at the rehabilitation hospital were dependent on LOS, and higher in patients with moderate disability than in those with mild disability [$30 026 ($18 419-$39 911) vs $18 052 ($10 631-$24 384)], while those with severe disability spent $25 476 ($13 340-$43 032). Patients with moderate disability gained the most benefits during hospitalization in the rehabilitation hospital, with a median (IQR) total FIM gain of 16 (5-24) points, compared with a modest improvement in patients with mild (6, 2-14) or severe disability (0, 0-5). Conclusions: The costs for in-hospital stroke care were substantial and the improvement in functional status varied by severity of disability. Our findings would be valuable to organize efficient post-acute stroke care. PMID- 27979963 TI - Developing online accreditation education resources for health care services: An Australian Case Study. AB - Quality problem or issue: In 2013, 'National Safety and Quality Health Service Standards' accreditation became mandatory for most health care services in Australia. Developing and maintaining accreditation education is challenging for health care services, particularly those in regional and rural settings. With accreditation imminent, there was a need to support health care services through the process. Initial assessment: A needs analysis identified limited availability of open access online resources for national accreditation education. Choice of solution: A standardized set of online accreditation education resources was the agreed solution to assist regional and rural health care services meet compulsory requirements. Implementation: Education resources were developed over 3 months with project planning, implementation and assessment based on a program logic model. Evaluation: Resource evaluation was undertaken after the first 3 months of resource availability to establish initial usage and stakeholder perceptions. From 1 January 2015 to 31 March 2015, resource usage was 20 272, comprising 12 989 downloads, 3594 course completions and 3689 page views. Focus groups were conducted at two rural and one metropolitan hospital (n = 16), with rural hospitals reporting more benefits. Main user-based recommendations for future resource development were automatic access to customizable versions, ensuring suitability to intended audience, consistency between resource content and assessment tasks and availability of short and long length versions to meet differing users' needs. Lessons learned: Further accreditation education resource development should continue to be collaborative, consider longer development timeframes and user-based recommendations. PMID- 27979965 TI - Defining Minimal Binding Regions in Regulator of Presynaptic Morphology 1 (RPM-1) Using Caenorhabditis elegans Neurons Reveals Differential Signaling Complexes. AB - The intracellular signaling protein regulator of presynaptic morphology 1 (RPM-1) is a conserved regulator of synapse formation and axon termination in Caenorhabditis elegans RPM-1 functions in a ubiquitin ligase complex with the F box protein FSN-1 and functions through the microtubule binding protein RAE-1. Using a structure-function approach and positive selection for transgenic C. elegans, we explored the biochemical relationship between RPM-1, FSN-1, and RAE 1. This led to the identification of two new domains in RPM-1 that are sufficient for binding to FSN-1, called FSN-1 binding domain 2 (FBD2) and FBD3. Furthermore, we map the RAE-1 binding domain to a much smaller region of RPM-1. Point mutations in RPM-1 that reduce binding to RAE-1 did not affect FSN-1 binding, indicating that RPM-1 utilizes different biochemical mechanisms to bind these molecules. Analysis of RPM-1 protein complexes in the neurons of C. elegans elucidated two further discoveries: FSN-1 binds to RAE-1, and this interaction is not mediated by RPM-1, and RPM-1 binding to FSN-1 and RAE-1 reduces FSN-1.RAE-1 complex formation. These results indicate that RPM-1 uses different mechanisms to recruit FSN-1 and RAE-1 into independent signaling complexes in neurons. PMID- 27979964 TI - Schwannomin-interacting Protein 1 Isoform IQCJ-SCHIP1 Is a Multipartner Ankyrin- and Spectrin-binding Protein Involved in the Organization of Nodes of Ranvier. AB - The nodes of Ranvier are essential regions for action potential conduction in myelinated fibers. They are enriched in multimolecular complexes composed of voltage-gated Nav and Kv7 channels associated with cell adhesion molecules. Cytoskeletal proteins ankyrin-G (AnkG) and betaIV-spectrin control the organization of these complexes and provide mechanical support to the plasma membrane. IQCJ-SCHIP1 is a cytoplasmic protein present in axon initial segments and nodes of Ranvier. It interacts with AnkG and is absent from nodes and axon initial segments of betaIV-spectrin and AnkG mutant mice. Here, we show that IQCJ SCHIP1 also interacts with betaIV-spectrin and Kv7.2/3 channels and self associates, suggesting a scaffolding role in organizing nodal proteins. IQCJ SCHIP1 binding requires a betaIV-spectrin-specific domain and Kv7 channel 1-5-10 calmodulin-binding motifs. We then investigate the role of IQCJ-SCHIP1 in vivo by studying peripheral myelinated fibers in Schip1 knock-out mutant mice. The major nodal proteins are normally enriched at nodes in these mice, indicating that IQCJ SCHIP1 is not required for their nodal accumulation. However, morphometric and ultrastructural analyses show an altered shape of nodes similar to that observed in betaIV-spectrin mutant mice, revealing that IQCJ-SCHIP1 contributes to nodal membrane-associated cytoskeleton organization, likely through its interactions with the AnkG/betaIV-spectrin network. Our work reveals that IQCJ-SCHIP1 interacts with several major nodal proteins, and we suggest that it contributes to a higher organizational level of the AnkG/betaIV-spectrin network critical for node integrity. PMID- 27979966 TI - Insulin-like Growth Factor 1 Receptor Signaling Is Required for Optimal ATR-CHK1 Kinase Signaling in Ultraviolet B (UVB)-irradiated Human Keratinocytes. AB - UVB wavelengths of light induce the formation of photoproducts in DNA that are potentially mutagenic if not properly removed by the nucleotide excision repair machinery. As an additional mechanism to minimize the risk of mutagenesis, UVB irradiated cells also activate a checkpoint signaling cascade mediated by the ATM and Rad3-related (ATR) and checkpoint kinase 1 (CHK1) kinases to transiently suppress DNA synthesis and cell cycle progression. Given that keratinocytes in geriatric skin display reduced activation of the insulin-like growth factor 1 receptor (IGF-1R) and alterations in DNA repair rate, apoptosis, and senescence following UVB exposure, here we used cultured human keratinocytes in vitro and skin explants ex vivo to examine how IGF-1R activation status affects ATR-CHK1 kinase signaling and the inhibition of DNA replication following UVB irradiation. We find that disruption of IGF-1R signaling with small-molecule inhibitors or IGF 1 withdrawal partially abrogates both the phosphorylation and activation of CHK1 by ATR and the accompanying inhibition of chromosomal DNA synthesis in UVB irradiated keratinocytes. A critical protein factor that mediates both ATR-CHK1 signaling and nucleotide excision repair is replication protein A, and we find that its accumulation on UVB-damaged chromatin is partially attenuated in cells with an inactive IGF-1R. These results indicate that mutagenesis and skin carcinogenesis in IGF-1-deficient geriatric skin may be caused by defects in multiple cellular responses to UVB-induced DNA damage, including through a failure to properly suppress DNA synthesis on UVB-damaged DNA templates. PMID- 27979967 TI - DAZ-interacting Protein 1 (Dzip1) Phosphorylation by Polo-like Kinase 1 (Plk1) Regulates the Centriolar Satellite Localization of the BBSome Protein during the Cell Cycle. AB - The function of the primary cilia, which is assembled in most vertebrate cells, is achieved by transport in and out of kinds of signaling receptors. The BBSome protein complex could recognize and target membrane proteins to the cilia, but how the BBSome itself is transported into the cilia is poorly understood. Here we demonstrate that the centrosome protein Dzip1 mediates the assembly of the BBSome Dzip1-PCM1 complex in the centriolar satellites (CS) at the G0 phase for ciliary translocation of the BBSome. Phosphorylation of Dzip1 at Ser-210 by Plk1 (polo like kinase 1) during the G2 phase promotes disassembly of this complex, resulting in removal of Dzip1 and the BBSome from the CS. Inhibiting the kinase activity of Plk1 maintains the CS localization of the BBSome and Dzip1 at the G2 phase. Collectively, our findings reveal the cell cycle-dependent regulation of BBSome transport to the CS and highlight a potential mechanism that the BBSome mediated signaling pathways are accordingly regulated during the cell cycle. PMID- 27979968 TI - RAG Recombinase as a Selective Pressure for Genome Evolution. AB - The RAG recombinase is a domesticated transposable element co-opted in jawed vertebrates to drive the process of the so-called V(D)J recombination, which is the hallmark of the adaptive immune system to produce antigen receptors. RAG targets, namely, the Recombination Signal Sequences (RSS), are rather long and degenerated sequences, which highlights the ability of the recombinase to interact with a wide range of target sequences, including outside of antigen receptor loci. The recognition of such cryptic targets by the recombinase threatens genome integrity by promoting aberrant DNA recombination, as observed in lymphoid malignancies. Genomes evolution resulting from RAG acquisition is an ongoing discussion, in particular regarding the counter-selection of sequences resembling the RSS and the modifications of epigenetic regulation at these potential cryptic sites. Here, we describe a new bioinformatics tool to map potential RAG targets in all jawed vertebrates. We show that our REcombination Classifier (REC) outperforms the currently available tool and is suitable for full genomes scans from species other than human and mouse. Using the REC, we document a reduction in density of potential RAG targets at the transcription start sites of genes co-expressed with the rag genes and marked with high levels of the trimethylation of the lysine 4 of the histone 3 (H3K4me3), which correlates with the retention of functional RAG activity after the horizontal transfer. PMID- 27979969 TI - Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT-beta-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated. Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis. We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens. WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-beta, cigarette smoke (CS), and cellular senescence. Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro. Lung specific WNT-5A overexpression exacerbated airspace enlargement in elastase induced emphysema in vivo. Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of beta catenin-driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD. We thus identify a novel essential mechanism involved in impaired mesenchymal-epithelial cross talk in COPD pathogenesis, which is amenable to therapy. PMID- 27979970 TI - Intergenerational social mobility and leisure-time physical activity in adulthood: a systematic review. AB - AIM: To systematically review the association between intergenerational social mobility and leisure-time physical activity (LTPA) in adulthood, in order to assess all published evidence relating to the hypothesis that adults socially mobile between childhood and adulthood will have different levels of LTPA than those in the same socioeconomic group across life. METHODS: A systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were identified by searching databases (MEDLINE, Embase, PsycINFO) and reference lists. Eligible studies examined associations between any indicator of social mobility, based on at least one measure of parental socioeconomic position (SEP) and one measure of own adult SEP, and LTPA in adulthood. RESULTS: 13 studies comprising a total of 44 000 participants from the UK, Finland, Sweden, Australia, USA and Brazil were included. Participants were aged 16-70 years and were from population-based surveys, occupational cohorts and primary care registries. Most studies (n=9) used occupational class measures to identify social mobility; education (n=4) and income (n=1) were also used. There was consistent evidence in nine of the 13 studies that stable high socioeconomic groups tended to report the highest levels of participation in LTPA and stable low socioeconomic groups the lowest. Upward and downwardly mobile groups participated in LTPA at levels between these stable groups. CONCLUSIONS: Cumulative exposure to higher SEP in childhood and adulthood was associated with higher LTPA in adulthood. Thus, a potential outcome of policies and interventions which aim to minimise exposure to socioeconomic adversity may be increased LTPA among adults. TRIAL REGISTRATION NUMBER: CRD42016036538. PMID- 27979971 TI - Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP. AB - YAP is the major downstream effector of the Hippo pathway, which controls cell growth, tissue homeostasis, and organ size. Aberrant YAP activation, resulting from dysregulation of the Hippo pathway, is frequently observed in human cancers. YAP is a transcription co-activator, and the key mechanism of YAP regulation is its nuclear and cytoplasmic translocation. The Hippo pathway component, LATS, inhibits YAP by phosphorylating YAP at Ser127, leading to 14-3-3 binding and cytoplasmic retention of YAP Here, we report that osmotic stress stimulates transient YAP nuclear localization and increases YAP activity even when YAP Ser127 is phosphorylated. Osmotic stress acts via the NLK kinase to induce YAP Ser128 phosphorylation. Phosphorylation of YAP at Ser128 interferes with its ability to bind to 14-3-3, resulting in YAP nuclear accumulation and induction of downstream target gene expression. This osmotic stress-induced YAP activation enhances cellular stress adaptation. Our findings reveal a critical role for NLK mediated Ser128 phosphorylation in YAP regulation and a crosstalk between osmotic stress and the Hippo pathway. PMID- 27979973 TI - Archiving of zebrafish lines can reduce animal experiments in biomedical research. PMID- 27979972 TI - Phosphorylation by NLK inhibits YAP-14-3-3-interactions and induces its nuclear localization. AB - Hippo signaling controls organ size by regulating cell proliferation and apoptosis. Yes-associated protein (YAP) is a key downstream effector of Hippo signaling, and LATS-mediated phosphorylation of YAP at Ser127 inhibits its nuclear localization and transcriptional activity. Here, we report that Nemo-like kinase (NLK) phosphorylates YAP at Ser128 both in vitro and in vivo, which blocks interaction with 14-3-3 and enhances its nuclear localization. Depletion of NLK increases YAP phosphorylation at Ser127 and reduces YAP-mediated reporter activity. These results suggest that YAP phosphorylation at Ser128 and at Ser127 may be mutually exclusive. We also find that with the increase in cell density, nuclear localization and the level of NLK are reduced, resulting in reduction in YAP phosphorylation at Ser128. Furthermore, knockdown of Nemo (the Drosophila NLK) in fruit fly wing imaginal discs results in reduced expression of the Yorkie (the Drosophila YAP) target genes expanded and DIAP1, while Nemo overexpression reciprocally increased the expression. Overall, our data suggest that NLK/Nemo acts as an endogenous regulator of Hippo signaling by controlling nuclear localization and activity of YAP/Yorkie. PMID- 27979974 TI - Next-generation nanotech meds: Diagnostic and therapeutic applications of non organic nanoparticles are making their way into clinical use. PMID- 27979976 TI - YAP needs Nemo to guide a Hippo. PMID- 27979975 TI - TLR3 downregulates expression of schizophrenia gene Disc1 via MYD88 to control neuronal morphology. AB - Viral infection during fetal or neonatal stages increases the risk of developing neuropsychiatric disorders such as schizophrenia and autism spectrum disorders. Although neurons express several key regulators of innate immunity, the role of neuronal innate immunity in psychiatric disorders is still unclear. Using cultured neurons and in vivo mouse brain studies, we show here that Toll-like receptor 3 (TLR3) acts through myeloid differentiation primary response gene 88 (MYD88) to negatively control Disrupted in schizophrenia 1 (Disc1) expression, resulting in impairment of neuronal development. Cytokines are not involved in TLR3-mediated inhibition of dendrite outgrowth. Instead, TLR3 signaling suppresses expression of several psychiatric disorder-related genes, including Disc1 The impaired dendritic arborization caused by TLR3 activation is rescued by MYD88 deficiency or DISC1 overexpression. In addition, TLR3 activation at the neonatal stage increases dendritic spine density, but narrows spine heads at postnatal day 21 (P21), suggesting a long-lasting effect of TLR3 activation on spinogenesis. Our study reveals a novel mechanism of TLR3 in regulation of dendritic morphology and provides an explanation for how environmental factors influence mental health. PMID- 27979977 TI - Long-Term Outcomes and Discard Rate of Kidneys by Decade of Extended Criteria Donor Age. AB - BACKGROUND AND OBJECTIVES: Extended criteria donors represent nowadays a main resource for kidney transplantation, and recovery criteria are becoming increasingly inclusive. However, the limits of this approach are not clear as well as the effects of extreme donor ages on long-term kidney transplantation outcomes. To address these issues, we performed a retrospective study on extended criteria donor kidney transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 647 consecutive extended criteria donor kidney transplantations performed over 11 years (2003-2013) were included. Donor, recipient, and procedural variables were classified according to donor age decades (group A, 50-59 years old [n=91]; group B, 60-69 years old [n=264]; group C, 70-79 years old [n=265]; and group D, >=80 years old [n=27]). Organs were allocated in single- or dual-kidney transplantation after a multistep evaluation including clinical and histologic criteria. Long-term outcomes and main adverse events were analyzed among age groups and in either single- or dual-kidney transplantation. Kidney discard rate incidence and causes were evaluated. RESULTS: Median follow-up was 4.9 years (25th; 75th percentiles: 2.7; 7.6 years); patient and graft survival were comparable among age groups (5-year patient survival: group A, 87.8%; group B, 88.1%; group C, 88.0%; and group D, 90.1%; P=0.77; graft survival: group A, 74.0%; group B, 74.2%; group C, 75.2%; and group D, 65.9%; P=0.62) and between dual-kidney transplantation and single-kidney transplantation except for group D, with a better survival for dual-kidney transplantation (P=0.04). No difference was found analyzing complications incidence or graft function over time. Kidney discard rate was similar in groups A, B, and C (15.4%, 17.7%, and 20.1%, respectively) and increased in group D (48.2%; odds ratio, 5.1 with A as the reference group; 95% confidence interval, 2.96 to 8.79). CONCLUSIONS: Discard rate and long-term outcomes are similar among extended criteria donor kidney transplantation from donors ages 50-79 years old. Conversely, discard rate was strikingly higher among kidneys from octogenarian donors, but appropriate selection provides comparable long-term outcomes, with better graft survival for dual-kidney transplantation. PMID- 27979980 TI - Heat induces interleukin-6 in skeletal muscle cells via TRPV1/PKC/CREB pathways. AB - Interleukin-6 (IL-6) is released from skeletal muscle cells and induced by exercise, heat, catecholamine, glucose, lipopolysaccharide, reactive oxygen species, and inflammation. However, the mechanism that induces release of IL-6 from skeletal muscle cells remains unknown. Thermosensitive transient receptor potential (TRP) proteins such as TRPV1-4 play vital roles in cellular functions. In this study we hypothesized that TRPV1 senses heat, transmits a signal into the nucleus, and produces IL-6. The purpose of the present study is to investigate the underlying mechanisms whereby skeletal muscle cells sense and respond to heat. When mouse myoblast cells were exposed to 37-42 degrees C for 2 h, mRNA expression of IL-6 increased in a temperature-dependent manner. Heat also increased IL-6 secretion in myoblast cells. A fura 2 fluorescence dual-wavelength excitation method showed that heat increased intracellular calcium flux in a temperature-dependent manner. Intracellular calcium flux and IL-6 mRNA expression were increased by the TRPV1 agonists capsaicin and N-arachidonoyldopamine and decreased by the TRPV1 antagonists AMG9810 and SB366791 and siRNA-mediated knockdown of TRPV1. TRPV2, 3, and 4 agonists did not change intracellular calcium flux. Western blotting with inhibitors demonstrated that heat increased phosphorylation levels of TRPV1, followed by PKC and cAMP response element binding protein (CREB). PKC inhibitors, Go6983 and staurosporine, CREB inhibitors, curcumin and naphthol AS-E, and knockdown of CREB suppressed the heat induced increases in IL-6. These results indicate that heat increases IL-6 in skeletal muscle cells through the TRPV1, PKC, and CREB signal transduction pathway.NEW & NOTEWORTHY Heat increases the release of interleukin-6 (IL-6) from skeletal muscle cells. IL-6 has been shown to serve immune responses and metabolic functions in muscle. It can be anti-inflammatory as well as proinflammatory. However, the mechanism that induces release of IL-6 from skeletal muscle cells remains unknown. Here we show that heat increases IL-6 in skeletal muscle cells through the transient receptor potential vannilloid 1, PKC, and cAMP response element-binding protein signal transduction pathway. PMID- 27979979 TI - A Comparative Effectiveness Analysis of Early Steroid Withdrawal in Black Kidney Transplant Recipients. AB - BACKGROUND AND OBJECTIVES: There is continued debate whether early steroid withdrawal is safe to use in high-immunologic risk patients, such as blacks. The goal of this study was to use comparative effectiveness methodology to elucidate the safety of early steroid withdrawal in blacks with kidney transplants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our cohort study used United Network of Organ Sharing data including all adult black kidney transplant recipients from 2000 to 2009 followed through 2014. Propensity score matching was used to equalize baseline risk between continued steroid and early steroid withdrawal groups. Interaction terms were used to assess if the effect of early steroid withdrawal on outcomes varied by baseline and post-transplant factors. Of 26,582 eligible black patients with kidney transplants (5825 [21.9%] with early steroid withdrawal), 5565 patients with early steroid withdrawal were matched to 5565 blacks on continued steroid use. RESULTS: Black patients with early steroid withdrawal had similar risk of graft loss (hazard ratio, 0.98; 95% confidence interval, 0.92 to 1.04; P=0.42) and lower risk of death (hazard ratio, 0.91; 95% confidence interval, 0.84 to 0.99; P=0.02), primarily driven by a late mortality advantage (>4 years post-transplant). Delayed graft function, cytolytic induction, tacrolimus, and mycophenolate significantly modified the effect of early steroid withdrawal on outcomes (P<0.05). Acute rejection rates were slightly higher in the continued steroid group (13.0% versus 11.3%, respectively; P<0.01), but this was not associated with graft or patient survival. CONCLUSIONS: Overall, early steroid withdrawal in black kidney transplant recipients was not associated with graft loss but seemed to be associated with better long-term patient survival. Early steroid withdrawal in blacks not receiving cytolytic induction, tacrolimus, and mycophenolate or those with delayed graft function was associated with higher risk of graft loss and death. PMID- 27979978 TI - Early Steroid Withdrawal in Black Transplant Patients: A Selective Process. PMID- 27979981 TI - Effects of different stresses on cardiac autonomic control and cardiovascular coupling. AB - The objective of this study was to investigate the impacts of different stresses on time-varying autonomic reactivity and cardiovascular coupling. In total, 25 male subjects were recruited. RR intervals (RRI), systolic and diastolic blood pressure (SBP, DBP), stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR) values were collected during rest, mental arithmetic task (MAT), and cold pressor test (CPT). Baroreflex sensitivity (BRS) was derived using the transfer function method. Continuous wavelet transformation of RRI was used to describe the time-variant patterns of autonomic neural activities. Wavelet cross correlation and phase synchronization were used to estimate the amplitude and phase coupling between RRI and SBP. MAT was characterized by increased heart rate (HR), SBP, DBP, and CO with decreased BRS attributable to prolonged parasympathetic withdrawal. Moreover, cardiovascular coupling was disrupted in MAT. These results indicated that baroreflex was depressed, and the top-down system started to take action under mental stress. In CPT, SBP, DBP, and SVR increased significantly, whereas HR and BRS remained unchanged. The increase of sympathetic activity was transient, and cardiovascular coupling did not change in CPT. Intriguingly, the frequency of the maximum cross-correlation coefficient in the low-frequency band (0.04-0.15 Hz) was significantly decreased in CPT, which may be due to the change of resonance frequency of the baroreflex loop.NEW & NOTEWORTHY The study is the first to compare the time-variant pattern of autonomic nervous activities and cardiovascular coupling between the mental arithmetic task (MAT) and the cold pressor test (CPT). Our results demonstrated that MAT and CPT elicited different time-varying patterns of autonomic neural activities and cardiovascular synchronization. Both the amplitude and phase consistency of blood pressure and heart rate decreased in MAT. CPT may affect the harmonic frequency of the baroreflex loop. PMID- 27979982 TI - Role of calpain in eccentric contraction-induced proteolysis of Ca2+-regulatory proteins and force depression in rat fast-twitch skeletal muscle. AB - The aim of this study was to examine the in vivo effects of eccentric contraction (ECC) on calpain-dependent proteolysis of Ca2+-regulatory proteins and force production in fast-twitch skeletal muscles. Rat extensor digitorum longus muscles were exposed to 200 repeated ECC in situ and excised immediately [recovery 0 (REC0)] or 3 days [recovery 3 (REC3)] after cessation of ECC. Calpain inhibitor (CI)-treated rats were intraperitoneally injected with MDL-28170 before ECC and during REC3. Tetanic force was markedly reduced at REC0 and remained reduced at REC3. CI treatment ameliorated the ECC-induced force decline but only at REC3. No evidence was found for proteolysis of dihydropyridine receptor (DHPR), junctophilin (JP)1, JP2, ryanodine receptor (RyR), sarcoplasmic reticulum Ca2+ ATPase (SERCA)1a, or junctional face protein-45 at REC0. At REC3, ECC resulted in decreases in DHPR, JP1, JP2, RyR, and SERCA1a. CI treatment prevented the decreases in DHPR, JP1, and JP2, whereas it had little effect on RyR and SERCA1a. These findings suggest that DHPR, JP1, and JP2, but not RyR and SERCA1a, undergo calpain-dependent proteolysis in in vivo muscles subjected to ECC and that impaired function of DHPR and/or JP might cause prolonged force deficits with ECC.NEW & NOTEWORTHY Calpain-dependent proteolysis is one of the contributing factors to muscle damage that occurs with eccentric contraction (ECC). It is unclear, however, whether calpains account for proteolysis of Ca2+-regulatory proteins in in vivo muscles subjected to ECC. Here, we provide evidence that dihydropyridine receptor and junctophilin, but not ryanodine receptor and sarcoplasmic reticulum Ca2+-ATPase, undergo calpain-dependent proteolysis. PMID- 27979983 TI - Accelerated deflation promotes homogeneous airspace liquid distribution in the edematous lung. AB - Edematous lungs contain regions with heterogeneous alveolar flooding. Liquid is trapped in flooded alveoli by a pressure barrier-higher liquid pressure at the border than in the center of flooded alveoli-that is proportional to surface tension, T Stress is concentrated between aerated and flooded alveoli, to a degree proportional to T Mechanical ventilation, by cyclically increasing T, injuriously exacerbates stress concentrations. Overcoming the pressure barrier to redistribute liquid more homogeneously between alveoli should reduce stress concentration prevalence and ventilation injury. In isolated rat lungs, we test whether accelerated deflation can overcome the pressure barrier and catapult liquid out of flooded alveoli. We generate a local edema model with normal T by microinfusing liquid into surface alveoli. We generate a global edema model with high T by establishing hydrostatic edema, which does not alter T, and then gently ventilating the edematous lungs, which increases T at 15 cmH2O transpulmonary pressure by 52%. Thus ventilation of globally edematous lungs increases T, which should increase stress concentrations and, with positive feedback, cause escalating ventilation injury. In the local model, when the pressure barrier is moderate, accelerated deflation causes liquid to escape from flooded alveoli and redistribute more equitably. Flooding heterogeneity tends to decrease. In the global model, accelerated deflation causes liquid escape, but-because of elevated T-the liquid jumps to nearby, aerated alveoli. Flooding heterogeneity is unaltered. In pulmonary edema with normal T, early ventilation with accelerated deflation might reduce the positive feedback mechanism through which ventilation injury increases over time.NEW & NOTEWORTHY We introduce, in the isolated rat lung, a new model of pulmonary edema with elevated surface tension. We first generate hydrostatic edema and then ventilate gently to increase surface tension. We investigate the mechanical mechanisms through which 1) ventilation injures edematous lungs and 2) ventilation with accelerated deflation might lessen ventilation injury. PMID- 27979984 TI - Hemodynamic response to muscle reflex is abnormal in patients with heart failure with preserved ejection fraction. AB - The aim of the present investigation was to assess the role of cardiac diastole on the hemodynamic response to metaboreflex activation. We wanted to determine whether patients with diastolic function impairment showed a different hemodynamic response compared with normal subjects during this reflex. Hemodynamics during activation of the metaboreflex obtained by postexercise muscle ischemia (PEMI) was assessed in 10 patients with diagnosed heart failure with preserved ejection fraction (HFpEF) and in 12 age-matched healthy controls (CTL). Subjects also performed a control exercise-recovery test to compare data from the PEMI test. The main results were that patients with HFpEF achieved a similar mean arterial blood pressure (MAP) response as the CTL group during the PEMI test. However, the mechanism by which this response was achieved was markedly different between the two groups. Patients with HFpEF achieved the target MAP via an increase in systemic vascular resistance (+389.5 +/- 402.9 vs. +80 +/- 201.9 dynes.s-1.cm-5 for HFpEF and CTL groups respectively), whereas MAP response in the CTL group was the result of an increase in cardiac preload (-1.3 +/- 5.2 vs. 6.1 +/- 10 ml in end-diastolic volume for HFpEF and CTL groups, respectively), which led to a rise in stroke volume and cardiac output. Moreover, early filling peak velocities showed a higher response in the CTL group than in the HFpEF group. This study demonstrates that diastolic function is important for normal hemodynamic adjustment to the metaboreflex. Moreover, it provides evidence that HFpEF causes hemodynamic impairment similar to that observed in systolic heart failure.NEW & NOTEWORTHY This study provides evidence that diastolic function is important for normal hemodynamic responses during the activation of the muscle metaboreflex in humans. Moreover, it demonstrates that diastolic impairment leads to hemodynamic consequences similar to those provoked by systolic heart failure. In both cases the target blood pressure is obtained mainly by means of exaggerated vasoconstriction than by a flow-mediated mechanism. PMID- 27979986 TI - Exposure-response modeling of flow-mediated dilation provides an unbiased and informative measure of endothelial function. AB - The brachial artery flow-mediated dilation (FMD) test is the most widely utilized method to evaluate endothelial function noninvasively in humans by calculating the percent change in diameter (FMD%). However, the underutilized velocity and diameter time course data, coupled with confounding influences in shear exposure, noise, and upward bias, make the FMD test less desirable. In this study, we developed an exposure-response, model-based approach that not only quantifies FMD based on the rich velocity and diameter data, it overcomes previously acknowledged challenges. FMD data were obtained from 15 apparently healthy participants, each exposed to four different cuff occlusion durations. The velocity response following cuff release was described by an exponential model with two parameters defining peak velocity and rate of decay. Shear exposure derived from velocity was used to drive the diameter response model, which consists of additive constriction and dilation terms. Three parameters describing distinct aspects of the vascular response to shear (magnitude of the initial constriction response, and magnitude and time constant of the dilation response) were estimated for both the individuals and population. These parameters are independent of shear exposure. Thus this approach produces identifiable and physiologically meaningful parameters that may provide additional information for comparing differences between experimental groups or over time, and provides a means to completely account for shear exposure.NEW & NOTEWORTHY While flow mediated dilation (FMD) is a valuable tool for evaluating endothelial function, analytical challenges include confounding influences of shear exposure, upward bias, and underutilization of rich time course data collected during FMD testing. We have developed an exposure-response, model-based approach that quantifies endothelial function based on the velocity and diameter data and fully accounts for shear exposure. It produces physiologically meaningful parameters that may provide useful information for comparing differences between experimental groups or over time. PMID- 27979985 TI - Changes in muscle fiber contractility and extracellular matrix production during skeletal muscle hypertrophy. AB - Skeletal muscle can adapt to increased mechanical loads by undergoing hypertrophy. Transient reductions in whole muscle force production have been reported during the onset of hypertrophy, but contractile changes in individual muscle fibers have not been previously studied. Additionally, the extracellular matrix (ECM) stores and transmits forces from muscle fibers to tendons and bones, and determining how the ECM changes during hypertrophy is important in understanding the adaptation of muscle tissue to mechanical loading. Using the synergist ablation model, we sought to measure changes in muscle fiber contractility, collagen content, and cross-linking, and in the expression of several genes and activation of signaling proteins that regulate critical components of myogenesis and ECM synthesis and remodeling during muscle hypertrophy. Tissues were harvested 3, 7, and 28 days after induction of hypertrophy, and nonoverloaded rats served as controls. Muscle fiber specific force (sFo), which is the maximum isometric force normalized to cross-sectional area, was reduced 3 and 7 days after the onset of mechanical overload, but returned to control levels by 28 days. Collagen abundance displayed a similar pattern of change. Nearly a quarter of the transcriptome changed over the course of overload, as well as the activation of signaling pathways related to hypertrophy and atrophy. Overall, this study provides insight into fundamental mechanisms of muscle and ECM growth, and indicates that although muscle fibers appear to have completed remodeling and regeneration 1 mo after synergist ablation, the ECM continues to be actively remodeling at this time point.NEW & NOTEWORTHY This study utilized a rat synergist ablation model to integrate changes in single muscle fiber contractility, extracellular matrix composition, activation of important signaling pathways in muscle adaption, and corresponding changes in the muscle transcriptome to provide novel insight into the basic biological mechanisms of muscle fiber hypertrophy. PMID- 27979987 TI - Altered nuclear dynamics in MDX myofibers. AB - Duchenne muscular dystrophy (DMD) is a genetic disorder in which the absence of dystrophin leads to progressive muscle degeneration and weakness. Although the genetic basis is known, the pathophysiology of dystrophic skeletal muscle remains unclear. We examined nuclear movement in wild-type (WT) and muscular dystrophy mouse model for DMD (MDX) (dystrophin-null) mouse myofibers. We also examined expression of proteins in the linkers of nucleoskeleton and cytoskeleton (LINC) complex, as well as nuclear transcriptional activity via histone H3 acetylation and polyadenylate-binding nuclear protein-1. Because movement of nuclei is not only LINC dependent but also microtubule dependent, we analyzed microtubule density and organization in WT and MDX myofibers, including the application of a unique 3D tool to assess microtubule core structure. Nuclei in MDX myofibers were more mobile than in WT myofibers for both distance traveled and velocity. MDX muscle shows reduced expression and labeling intensity of nesprin-1, a LINC protein that attaches the nucleus to the microtubule and actin cytoskeleton. MDX nuclei also showed altered transcriptional activity. Previous studies established that microtubule structure at the cortex is disrupted in MDX myofibers; our analyses extend these findings by showing that microtubule structure in the core is also disrupted. In addition, we studied malformed MDX myofibers to better understand the role of altered myofiber morphology vs. microtubule architecture in the underlying susceptibility to injury seen in dystrophic muscles. We incorporated morphological and microtubule architectural concepts into a simplified finite element mathematical model of myofiber mechanics, which suggests a greater contribution of myofiber morphology than microtubule structure to muscle biomechanical performance.NEW & NOTEWORTHY Microtubules provide the means for nuclear movement but show altered organization in the muscular dystrophy mouse model (MDX) (dystrophin-null) muscle. Here, MDX myofibers show increased nuclear movement, altered transcriptional activity, and altered linkers of nucleoskeleton and cytoskeleton complex expression compared with healthy myofibers. Microtubule architecture was incorporated in finite element modeling of passive stretch, revealing a role of fiber malformation, commonly found in MDX muscle. The results suggest that alterations in microtubule architecture in MDX muscle affect nuclear movement, which is essential for muscle function. PMID- 27979989 TI - Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study. AB - Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean age 43 years old; 41% men; 57% with the classical phenotype) from three international centers of excellence. We classified patients by phenotype on the basis of characteristic symptoms and enzyme activity. Men and women with classical Fabry disease had higher event rate than did those with nonclassical disease (hazard ratio for men, 5.63, 95% confidence interval, 3.17 to 10.00; P<0.001; hazard ratio for women, 2.88, 95% confidence interval, 1.54 to 5.40; P<0.001). Furthermore, men with classical Fabry disease had lower eGFR, higher left ventricular mass, and higher plasma globotriaosylsphingosine concentrations than men with nonclassical Fabry disease or women with either phenotype (P<0.001). In conclusion, before treatment with enzyme replacement therapy, men with classical Fabry disease had a history of more events than men with nonclassical disease or women with either phenotype; women with classical Fabry disease were more likely to develop complications than women with nonclassical disease. These data may support the development of new guidelines for the monitoring and treatment of Fabry disease and studies on the effects of intervention in subgroups of patients. PMID- 27979988 TI - Effect of acute aerobic exercise and histamine receptor blockade on arterial stiffness in African Americans and Caucasians. AB - African Americans (AA) exhibit exaggerated central blood pressure (BP) and arterial stiffness measured by pulse wave velocity (PWV) in response to an acute bout of maximal exercise compared with Caucasians (CA). However, whether potential racial differences exist in central BP, elastic, or muscular arterial distensibility after submaximal aerobic exercise remains unknown. Histamine receptor activation mediates sustained postexercise hyperemia in CA but the effect on arterial stiffness is unknown. This study sought to determine the effects of an acute bout of aerobic exercise on central BP and arterial stiffness and the role of histamine receptors, in AA and CA. Forty-nine (22 AA, 27 CA) young and healthy subjects completed the study. Subjects were randomly assigned to take either histamine receptor antagonist or control placebo. Central blood BP and arterial stiffness measurements were obtained at baseline, and at 30, 60, and 90 min after 45 min of moderate treadmill exercise. AA exhibited greater central diastolic BP, elevated brachial PWV, and local carotid arterial stiffness after an acute bout of submaximal exercise compared with CA, which may contribute to their higher risk of cardiovascular disease. Unexpectedly, histamine receptor blockade did not affect central BP or PWV in AA or CA after exercise, but it may play a role in mediating local carotid arterial stiffness. Furthermore, histamine may mediate postexercise carotid arterial dilation in CA but not in AA. These observations provide evidence that young and healthy AA exhibit an exaggerated hemodynamic response to exercise and attenuated vasodilator response compared with CA.NEW & NOTEWORTHY African Americans are at greater risk for developing cardiovascular disease than Caucasians. We are the first to show that young and healthy African Americans exhibit greater central blood pressure, elevated brachial stiffness, and local carotid arterial stiffness following an acute bout of submaximal exercise compared with Caucasians, which may contribute to their higher risk of cardiovascular disease. Furthermore, African Americans exhibit attenuated vasodilator response compared with Caucasians. PMID- 27979991 TI - Pericytes Preserve Capillary Integrity to Prevent Kidney Hypoxia. PMID- 27979990 TI - Dementia and Alzheimer's Disease among Older Kidney Transplant Recipients. AB - Older patients with ESRD who receive a kidney transplant (KT) may develop post-KT dementia and Alzheimer's disease (AD) associated with their long-standing kidney disease and/or neurotoxic immunosuppressant agents. To investigate this possibility, we studied 40,918 older (aged >=55 years) KT recipients (January 1, 1999 to December 31, 2011) linked to Medicare claims through the US Renal Data System. We estimated dementia and AD risk (cumulative incidence) and studied factors associated with these sequelae using competing risks models. We estimated the risk of death-censored graft loss and mortality after developing dementia or the AD subtype of dementia, separately, using adjusted Cox proportional hazards models. Older recipients had a 10-year dementia risk ranging from 5.1% for recipients aged 55-60 years to 17.0% for recipients aged >=75 years; 10-year AD risk ranged from 1.0% to 6.7%, respectively. The strongest predictors for dementia and AD were older recipient age and pretransplant diabetes. The 10-year graft loss risk was 28.8% for those who did not develop dementia and 43.1% for those who did, and the corresponding mortality risks were 55.7% and 89.9%, respectively. Older recipients with dementia had a 1.52-fold (95% confidence interval, 1.39 to 1.68) increased risk of graft loss and a 2.38-fold (95% confidence interval, 2.26 to 2.49) increased risk of mortality. We observed similar results for AD. We conclude that older KT recipients have a high risk of post-KT dementia and AD, and these sequelae associate with a profound effect on patient and graft survival. PMID- 27979993 TI - Caring for Children and Families With Limited English Proficiency: Current Challenges and an Agenda for the Future. PMID- 27979992 TI - Communication With Limited English-Proficient Families in the PICU. AB - OBJECTIVE: Health care disparities have been described for children of limited English-proficient (LEP) families compared with children of English-proficient (EP) families. Poor communication with the medical team may contribute to these worse health outcomes. Previous studies exploring communication in the PICU have excluded LEP families. We aimed to understand communication experiences and preferences in the 3 primary communication settings in the PICU. We also explored LEP families' views on interpreter use in the PICU. PATIENTS AND METHODS: EP and Spanish-speaking LEP families of children admitted to the PICU of a large tertiary pediatric hospital completed surveys between 24 hours and 7 days of admission. RESULTS: A total of 161 of 184 families were surveyed (88% response rate); 52 were LEP and 109 EP. LEP families were less likely to understand the material discussed on rounds (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.11-0.90), to report that PICU nurses spent enough time speaking with them (OR 0.15, 95% CI 0.05-0.41), and to report they could rely on their nurses for medical updates (OR 0.07, 95% CI 0.02-0.25) controlling for covariates, such as education, insurance type, presence of a chronic condition, PICU length of stay, and mortality index. LEP families reported 53% of physicians and 41% of nurses used an interpreter "often." CONCLUSIONS: Physician and nurse communication with LEP families is suboptimal. Communication with LEP families may be improved with regular use of interpreters and an increased awareness of the added barrier of language proficiency. PMID- 27979996 TI - Soil DNA metabarcoding and high-throughput sequencing as a forensic tool: considerations, potential limitations and recommendations. AB - Analysis of physical evidence is typically a deciding factor in forensic casework by establishing what transpired at a scene or who was involved. Forensic geoscience is an emerging multi-disciplinary science that can offer significant benefits to forensic investigations. Soil is a powerful, nearly 'ideal' contact trace evidence, as it is highly individualistic, easy to characterise, has a high transfer and retention probability, and is often overlooked in attempts to conceal evidence. However, many real-life cases encounter close proximity soil samples or soils with low inorganic content, which cannot be easily discriminated based on current physical and chemical analysis techniques. The capability to improve forensic soil discrimination, and identify key indicator taxa from soil using the organic fraction is currently lacking. The development of new DNA sequencing technologies offers the ability to generate detailed genetic profiles from soils and enhance current forensic soil analyses. Here, we discuss the use of DNA metabarcoding combined with high-throughput sequencing (HTS) technology to distinguish between soils from different locations in a forensic context. Specifically, we provide recommendations for best practice, outline the potential limitations encountered in a forensic context and describe the future directions required to integrate soil DNA analysis into casework. PMID- 27979994 TI - Drosophila poised enhancers are generated during tissue patterning with the help of repression. AB - Histone modifications are frequently used as markers for enhancer states, but how to interpret enhancer states in the context of embryonic development is not clear. The poised enhancer signature, involving H3K4me1 and low levels of H3K27ac, has been reported to mark inactive enhancers that are poised for future activation. However, future activation is not always observed, and alternative reasons for the widespread occurrence of this enhancer signature have not been investigated. By analyzing enhancers during dorsal-ventral (DV) axis formation in the Drosophila embryo, we find that the poised enhancer signature is specifically generated during patterning in the tissue where the enhancers are not induced, including at enhancers that are known to be repressed by a transcriptional repressor. These results suggest that, rather than serving exclusively as an intermediate step before future activation, the poised enhancer state may be a mark for spatial regulation during tissue patterning. We discuss the possibility that the poised enhancer state is more generally the result of repression by transcriptional repressors. PMID- 27979995 TI - Nucleosome fragility is associated with future transcriptional response to developmental cues and stress in C. elegans. AB - Nucleosomes have structural and regulatory functions in all eukaryotic DNA templated processes. The position of nucleosomes on DNA and the stability of the underlying histone-DNA interactions affect the access of regulatory proteins to DNA. Both stability and position are regulated through DNA sequence, histone post translational modifications, histone variants, chromatin remodelers, and transcription factors. Here, we explored the functional implications of nucleosome properties on gene expression and development in Caenorhabditis elegans embryos. We performed a time-course of micrococcal nuclease (MNase) digestion and measured the relative sensitivity or resistance of nucleosomes throughout the genome. Fragile nucleosomes were defined by nucleosomal DNA fragments that were recovered preferentially in early MNase-digestion time points. Nucleosome fragility was strongly and positively correlated with the AT content of the underlying DNA sequence. There was no correlation between promoter nucleosome fragility and the levels of histone modifications or histone variants. Genes with fragile nucleosomes in their promoters tended to be lowly expressed and expressed in a context-specific way, operating in neuronal response, the immune system, and stress response. In addition to DNA-encoded nucleosome fragility, we also found fragile nucleosomes at locations where we expected to find destabilized nucleosomes, for example, at transcription factor binding sites where nucleosomes compete with DNA-binding factors. Our data suggest that in C. elegans promoters, nucleosome fragility is in large part DNA-encoded and that it poises genes for future context-specific activation in response to environmental stress and developmental cues. PMID- 27980000 TI - Dimerization of the fungal defense lectin CCL2 is essential for its toxicity against nematodes. AB - Lectins are used as defense effector proteins against predators, parasites and pathogens by animal, plant and fungal innate defense systems. These proteins bind to specific glycoepitopes on the cell surfaces and thereby interfere with the proper cellular functions of the various antagonists. The exact cellular toxicity mechanism is in many cases unclear. Lectin CCL2 of the mushroom Coprinopsis cinerea was previously shown to be toxic for Caenorhabditis elegans and Drosophila melanogaster. This toxicity is dependent on a single, high-affinity binding site for the trisaccharide GlcNAc(Fucalpha1,3)beta1,4GlcNAc, which is a hallmark of nematode and insect N-glycan cores. The carbohydrate-binding site is located at an unusual position on the protein surface when compared to other beta trefoil lectins. Here, we show that CCL2 forms a compact dimer in solution and in crystals. Substitution of two amino acid residues at the dimer interface, R18A and F133A, interfered with dimerization of CCL2 and reduced toxicity but left carbohydrate-binding unaffected. These results, together with the positioning of the two carbohydrate-binding sites on the surface of the protein dimer, suggest that crosslinking of N-glycoproteins on the surface of intestinal cells of invertebrates is a crucial step in the mechanism of CCL2-mediated toxicity. Comparisons of the number and positioning of carbohydrate-binding sites among different dimerizing fungal beta-trefoil lectins revealed a considerable variability in the carbohydrate-binding patterns of these proteins, which are likely to correlate with their respective functions. PMID- 27979997 TI - Glycosyltransfer in mutants of putative catalytic residue Glu303 of the human ABO(H) A and B blood group glycosyltransferases GTA and GTB proceeds through a labile active site. AB - The homologous glycosyltransferases alpha-1,3-N-acetylgalactosaminyltransferase (GTA) and alpha-1,3-galactosyltransferase (GTB) carry out the final synthetic step of the closely related human ABO(H) blood group A and B antigens. The catalytic mechanism of these model retaining enzymes remains under debate, where Glu303 has been suggested to act as a putative nucleophile in a double displacement mechanism, a local dipole stabilizing the intermediate in an orthogonal associative mechanism or a general base to stabilize the reactive oxocarbenium ion-like intermediate in an SNi-like mechanism. Kinetic analysis of GTA and GTB point mutants E303C, E303D, E303Q and E303A shows that despite the enzymes having nearly identical sequences, the corresponding mutants of GTA/GTB have up to a 13-fold difference in their residual activities relative to wild type. High-resolution single crystal X-ray diffraction studies reveal, surprisingly, that the mutated Cys, Asp and Gln functional groups are no more than 0.8 A further from the anomeric carbon of donor substrate compared to wild type. However, complicating the analysis is the observation that Glu303 itself plays a critical role in maintaining the stability of a strained "double-turn" in the active site through several hydrogen bonds, and any mutation other than E303Q leads to significantly higher thermal motion or even disorder in the substrate recognition pockets. Thus, there is a remarkable juxtaposition of the mutants E303C and E303D, which retain significant activity despite disrupted active site architecture, with GTB/E303Q, which maintains active site architecture but exhibits zero activity. These findings indicate that nucleophilicity at position 303 is more catalytically valuable than active site stability and highlight the mechanistic elasticity of these enzymes. PMID- 27980001 TI - Exogenous thyroxine improves glucose intolerance in insulin-resistant rats. AB - Both hypothyroidism and hyperthyroidism are associated with glucose intolerance, calling into question the contribution of thyroid hormones (TH) on glucose regulation. TH analogues and derivatives may be effective treatment options for glucose intolerance and insulin resistance (IR), but their potential glucoregulatory effects during conditions of impaired metabolism are not well described. To assess the effects of thyroxine (T4) on glucose intolerance in a model of insulin resistance, an oral glucose tolerance test (oGTT) was performed on three groups of rats (n = 8): (1) lean, Long Evans Tokushima Otsuka (LETO), (2) obese, Otsuka Long Evans Tokushima Fatty (OLETF) and (3) OLETF + T4 (8.0 ug/100 g BM/day * 5 weeks). T4 attenuated glucose intolerance by 15% and decreased IR index (IRI) by 34% in T4-treated OLETF compared to untreated OLETF despite a 31% decrease in muscle Glut4 mRNA expression. T4 increased the mRNA expressions of muscle monocarboxylate transporter 10 (Mct10), deiodinase type 2 (Di2), sirtuin 1 (Sirt1) and uncoupling protein 2 (Ucp2) by 1.8-, 2.2-, 2.7- and 1.4-fold, respectively, compared to OLETF. Activation of AMP-activated protein kinase (AMPK) and insulin receptor were not significantly altered suggesting that the improvements in glucose intolerance and IR were independent of enhanced insulin-mediated signaling. The results suggest that T4 treatment increased the influx of T4 in skeletal muscle and, with an increase of DI2, increased the availability of the biologically active T3 to upregulate key factors such SIRT1 and UCP2 involved in cellular metabolism and glucose homeostasis. PMID- 27980002 TI - The role of nutrient sensing in the metabolic changes after gastric bypass surgery. AB - Taste receptors coupled to the gustatory G-protein, gustducin, on enteroendocrine cells sense nutrients to regulate gut hormone release. During Roux-en-Y gastric bypass (RYGB) surgery, the altered nutrient flow to more distal regions can affect gustducin-mediated gut hormone release and hence energy and glucose homeostasis. We studied the role of gustducin-mediated signaling in the metabolic improvements and intestinal adaptations along the gut after RYGB surgery in wild type (WT) and alpha-gustducin-/- (alpha-gust-/-) mice. RYGB surgery decreased body weight in WT and alpha-gust-/- mice, whereas food intake was only decreased in WT mice. Pair-feeding to the RYGB group improved glucose homeostasis to a similar extent in WT mice. GLP1 levels were increased in both genotypes, PYY levels in alpha-gust-/- mice and octanoyl ghrelin levels were not affected after RYGB surgery. In WT mice, nutrients act via alpha-gustducin to increase L-cell differentiation (foregut) and L-cell number (foregut and hindgut) in a region dependent manner. In alpha-gust-/- mice, the effect on gut hormone levels is probably tuned via increased peptide sensor and glucose transporter expression in the Roux limb and increased caecal butyrate and propionate levels in the hindgut that activate free fatty acid receptors. Finally, signaling via alpha-gustducin plays a role in the increased ion transport of the foregut but not in the improvement in colonic barrier function. In conclusion, RYGB surgery decreased body weight in both WT and alpha-gust-/- mice. Elevated plasma GLP1 and PYY levels might mediate this effect, although alpha-gustducin differentially affects several regulatory systems in the foregut and hindgut, tuning gut hormone release. PMID- 27980004 TI - The Power of Plasticity in Polyploid Persimmon. PMID- 27980003 TI - Growth hormone: a newly identified developmental organizer. AB - The sexually dimorphic expression of cytochromes P450 (CYP) drug-metabolizing enzymes has been reported in all species examined. These sex differences are only expressed during adulthood and are solely regulated by sex differences in circulating growth hormone (GH) profiles. Once established, however, the different male- and female-dependent CYP isoform profiles are permanent and immutable, suggesting that adult CYP expression requires imprinting. As the hormone that regulates an adult function is likely the same hormone that imprints the function, we selectively blocked GH secretion in some newborn male rats, whereas others received concurrent physiologic replacement of rat GH. The results demonstrate that adult male GH activation of the signal transduction pathway regulating expression of the principal CYP2C11 isoform is obligatorily dependent on perinatal GH imprinting, without which CYP2C11 and drug metabolism would be permanently and profoundly suppressed. As there are other adult metabolic functions also regulated by GH, pediatric drug therapy known to disrupt GH secretion could unintentionally impair adult health. PMID- 27980005 TI - Characterization of PABPN1 expansion mutations in a large cohort of Mexican patients with oculopharyngeal muscular dystrophy (OPMD). AB - Oculopharyngeal muscular dystrophy (OPMD) is an autosomal-dominant, adult-onset disorder defined by blepharoptosis, dysphagia, and proximal muscle weakness. OPMD arises from heterozygous expansions of a trinucleotide (GCN) tract situated at the 5' region of the polyadenylate RNA binding protein 1 (PABPN1) gene. The frequency of a particular (GCN) expansion in a given population of patients with OPMD is largely influenced by the occurrence of founder mutations. Analysis of large groups of patients with OPMD from different ethnic origins will help to estimate the relative contribution of each expanded allele to the disease. The purpose of this study was to characterize the type of PABPN1 expanded alleles in a large cohort of OPMD individuals from Mexico. Molecular analysis procedures included genomic DNA extraction from blood leukocytes in each patient followed by PCR amplification of PABPN1 exon 1, and direct nucleotide sequencing of PCR products. A total of 102 patients with OPMD were included in the study. Expanded PABPN1 gene alleles were demonstrated in all patients: 65% (66 out of 102) had a (GCN)15 expansion while the remaining 35% (36 out of 102) exhibited a (GCN)13 expansion. This is one of the largest series of molecularly confirmed patients with OPMD in a non-Caucasian population. Ethnic-specific differences in the prevalence of specific PABPN1 expansions must be considered for genetic screening of patients with OPMD. PMID- 27980007 TI - Patient-reported Flares in Ankylosing Spondylitis: A Cross-sectional Analysis of 234 Patients. AB - OBJECTIVE: Ankylosing spondylitis (AS) is characterized by periodic flares. The objective of this study was to assess the frequency of patient-reported flares and their related factors. METHODS: This cross-sectional study analyzed the 2004 data of a Canadian cohort. Participants had AS according to the modified New York criteria. Current flare status ("Are you experiencing a current flare"?), number of flares over the past 3 months, their average duration, the Bath Ankylosing Spondylitis Disease Activity and Functional Index (BASDAI and BASFI, respectively), and the AS Quality of Life questionnaire were assessed by self report. Univariate and multivariate regressions analyzed the factors associated with current flare. RESULTS: Among 234 analyzed patients, 169 (73.5%) were men, mean age was 45.5 (+/- 11.8) years, mean disease duration of 21.7 (+/- 11.7) years, and mean BASDAI and BASFI (0-10) of 4.4 (+/- 2.3) and 3.4 (+/- 2.6), respectively; 18 (7.7%) received antitumor necrosis factor (anti-TNF). Overall, 175 patients (74.8%) reported flares and 117 (50%) were currently in flare. Patients reporting flares had a median of 3 flares in 3 months, with a median duration of 2 weeks. Overall, the 234 patients spent a median of 25% of their time in flare. In multivariate analyses, current flare was significantly associated with higher BASDAI (OR 2.01, p = 0.01), worse quality of life (OR 1.37, p = 0.004), shorter AS duration (OR 1.19, p = 0.04), and less anti-TNF (OR 7.14, p = 0.03). CONCLUSION: In this population, before the wide use of biologics, flares were frequent and long. As expected, flare was associated with higher disease activity, suggesting the validity of the concept of patient reported flares. PMID- 27980009 TI - Understanding How the Diagnostic Delay of Spondyloarthritis Differs Between Women and Men: A Systematic Review and Metaanalysis. AB - OBJECTIVE: To identify empirical evidence of diagnostic delay in spondyloarthritis (SpA), determine whether sex-related differences persist, and conduct an analysis from that perspective of the possible causes, including the influence of quality research, in this group of inflammatory rheumatic diseases. METHODS: A systematic review was done of delay in diagnosis of SpA in MEDLINE and EMBASE and other sources. Study quality was determined in line with the Strengthening The Reporting of OBservational studies in Epidemiology (STROBE) statement. A metaanalysis of 13 papers reporting sex-disaggregated data was performed to evaluate sex-related differences in diagnostic delay. The global effect of diagnostic delay by sex was calculated using means difference (D) through a fixed effects model. RESULTS: The review included 23,883 patients (32.3% women) from 42 papers. No significant differences between the sexes were detected for symptoms at disease onset or during evolution. However, the mean for delay in diagnosis of SpA showed sex-related differences, being 8.8 years (7.4 10.1) for women and 6.5 (5.6-7.4) for men (p = 0.01). Only 40% of papers had high quality. A metaanalysis included 12,073 participants (31.2% women). The mean global effect was D = 0.6 years (0.31-0.89), indicating that men were diagnosed 0.6 year (7 months) before women. CONCLUSION: Delay in diagnosis of SpA persists, and is longer in women than in men. There are no significant sex-related differences in symptoms that could explain sex-related differences in diagnostic delay. Methodological and possible publication bias could result in sex-biased medical practice. PMID- 27980008 TI - The Pharmacodynamics, Pharmacokinetics, and Safety of Arhalofenate in Combination with Febuxostat When Treating Hyperuricemia Associated with Gout. AB - OBJECTIVE: Arhalofenate (ARH), in development for gout, has uricosuric and anti flare activities. ARH plus febuxostat (FBX) were evaluated in subjects with gout for serum uric acid (SUA) lowering, drug interaction, and safety. METHODS: Open phase II trial in gout volunteers (NCT02252835). Cohort 1 received ARH 600 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 80 mg followed by 40 mg. FBX 40 mg was continued alone for 2 weeks. Cohort 2 received ARH 800 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 40 mg followed by 80 mg. FBX 80 mg was continued alone for 2 weeks. SUA, its fractional excretion (FEUA), and plasma oxypurines were assessed. Pharmacokinetics of FBX and ARH were determined alone and in combination for cohort 2. RESULTS: Baseline mean SUA was 9.4 mg/dl for cohort 1 (n = 16) and 9.2 mg/dl for cohort 2 (n = 16). The largest SUA decrease (63%) was observed with ARH 800 mg + FBX 80 mg, with all subjects reaching SUA < 6 mg/dl and 93% < 5 mg/dl. The area under the curve (AUC)(0-t) of ARH acid + FBX/ARH acid was 108%. The AUC(0-t) of FBX + ARH acid/FBX was 87%. As expected, FBX increased oxypurines and increases were unaffected by ARH co-administration. Baseline FEUA were low (3.5%-4.6%) and ARH increased them toward normal without overexcretion of UA. ARH was well tolerated and appeared safe. CONCLUSION: ARH and FBX lowered SUA by complementary mechanisms. The combination provided greater decreases than each drug alone. The combination was well tolerated and appeared safe. TRIAL REGISTRATION: NCT02252835. PMID- 27980010 TI - Predictors of Mortality in People with Recent-onset Gout: A Prospective Observational Study. AB - OBJECTIVE: To determine mortality rates and predictors of death at baseline in people with a recent onset of gout. METHODS: People with gout disease duration < 10 years were recruited from primary and secondary care settings. Comprehensive clinical assessment was completed at baseline. Participants were prospectively followed for at least 1 year. Information about death was systematically collected from primary and secondary health records. Standardized mortality ratios (SMR) were calculated and risk factors for mortality were analyzed using Cox proportional hazard regression models. RESULTS: The mean (SD) followup duration was 5.1 (1.6) years (a total 1511 patient-yrs accrued). Of the 295 participants, 43 (14.6%) had died at the time of censorship (SMR 1.96, 95% CI 1.44-2.62). In the reduced Cox proportional hazards model, these factors were independently associated with an increased risk of death from all causes: older age (70-80 yrs: HR 9.96, 95% CI 3.30-30.03; 80-91 yrs: HR 9.39, 95% CI 2.68 32.89), Maori or Pacific ethnicity (HR 2.48, 95% CI 1.17-5.29), loop diuretic use (HR 3.99, 95% CI 2.15-7.40), serum creatinine (per 10 umol/l change; HR 1.04, 95% CI 1.00-1.07), and the presence of subcutaneous tophi (HR 2.85, 95% CI 1.49 5.44). The presence of subcutaneous tophi was the only baseline variable independently associated with both cardiovascular (CV) cause of death (HR 3.13, 95% CI 1.38-7.10) and non-CV cause of death (HR 3.48, 95% CI 1.25-9.63). CONCLUSION: People with gout disease duration < 10 years have an increased risk of death. The presence of subcutaneous tophi at baseline is an independent predictor of mortality, from both CV and non-CV causes. PMID- 27980011 TI - Mapping the Effect of Psoriatic Arthritis Using the International Classification of Functioning, Disability and Health. AB - OBJECTIVE: The effect of a disease can be categorized by a standardized reference system: the International Classification of Functioning, Disability and Health (ICF). The objective was to map the effect of psoriatic arthritis (PsA) from the patient's perspective to the ICF. METHODS: A systematic literature review was performed. Qualitative publications reporting domains of impact important for patients with PsA were identified using the following terms: ("psoriatic arthritis") AND ("quality of life" OR "impact"). Meaningful concepts were extracted from the publications, grouped into domains and linked to the ICF categories. The number of concepts linked to each ICF category and to each ICF level was calculated. The number of concepts not linkable was also calculated. RESULTS: Eleven studies (13 articles) were included in the analysis. Twenty-five domains of impact were cited, of which the ability to work/volunteer and social participation were the most cited (both by 10 studies). In total, 258 concepts were identified, of which 217 could be linked to 136 different ICF categories; 41 concepts, mostly personal factors, could not be precisely linked. The most represented ICF component was activities and participation (42.6%) rather than body structures (10.3%) or body functions (29.4%). Ten studies (90.9%) reported impairments in the ability to work/volunteer and social participation, and 7 (63.6%) reported leisure activities, family and intimacy, pain, skin problems, and body image. CONCLUSION: PsA widely affects all aspects of patients' lives, in particular aspects related to activities and participation. The ICF is a useful approach for the classification of disease effect. PMID- 27980012 TI - Baseline Shoulder Ultrasonography Is Not a Predictive Marker of Response to Glucocorticoids in Patients with Polymyalgia Rheumatica: A 12-month Followup Study. AB - OBJECTIVE: In this study, we evaluated whether ultrasound (US) subdeltoid bursitis (SB) and/or biceps tenosynovitis (BT) presence at baseline could represent a predictive marker of response to standard therapy after 12 months of followup, and whether a positive US examination could highlight the need of higher maintenance dosage of glucocorticoids (GC) at 6 and 12 months in patients with polymyalgia rheumatica (PMR). METHODS: Sixty-six consecutive patients with PMR underwent bilateral shoulder US evaluations before starting therapy and after 12 months of followup. Absence of girdle pain and morning stiffness (clinical remission) and laboratory variables were evaluated. After diagnosis, all patients were treated with prednisone. RESULTS: At baseline, SB and/or BT were present in 46 patients (70%), of whom 33 (72%) became negative while 13 (28%) remained positive at the 12-month US evaluation. All patients rapidly achieved a clinical remission, and at 6 months 26 (39%) also achieved a laboratory variable normalization. According to US positivity at baseline, no difference was found in remission or relapse rate after 12 months. Thirty patients (46%) at 6 months and 7 (11%) at 12 months were still taking more than 5 mg/day of prednisone. According to the US pattern at baseline, no difference was found in the mean GC dose at 6 and 12 months. CONCLUSION: In patients with PMR, the presence of SB and/or BT on US at diagnosis is not a predictive marker of GC response or of a higher GC dosage to maintain remission in a 12-month prospective followup study. PMID- 27980006 TI - Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis. AB - The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, "The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis" on 10-12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment. PMID- 27980013 TI - Histopathological Classification and Renal Outcome in Patients with Antineutrophil Cytoplasmic Antibodies-associated Renal Vasculitis: A Study of 186 Patients and Metaanalysis. AB - OBJECTIVE: Renal vasculitis is one of the most common manifestations of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) and renal histology is a key predictor of the outcome. A new histopathologic classification was proposed and validated, but the results are still debated. METHODS: We performed a retrospective analysis to validate the histopathologic classification and performed a metaanalysis to evaluate its predictive value. There were 186 patients with ANCA-associated renal vasculitis diagnosed at Ruijin Hospital who were enrolled in the retrospective study. The metaanalysis considered the data for 1601 patients. RESULTS: In our retrospective study, patients with focal class had the best renal outcome while patients with mixed class had the worst (p < 0.001). Metaanalysis showed that patients with focal class had better renal outcome than did those with crescentic class [risk ratio (RR) 0.23, 95% CI 0.16-0.34, p < 0.00001], with no evidence of heterogeneity (I2 = 0%, p = 0.96). Patients with crescentic class had better renal outcome than did those with sclerotic class (RR 0.52, 95% CI 0.41-0.64, p < 0.00001), with no evidence of heterogeneity (I2 = 2%, p = 0.43). We did not find statistical significance regarding renal outcome between mixed and crescentic classes (RR 1.14, 95% CI 0.91-1.43, p = 0.27), with no evidence of heterogeneity (I2 = 23%, p = 0.19). The retrospective study showed that lung and upper respiratory tract involvement were the most common extrarenal manifestations. CONCLUSION: We demonstrated the clinical utility of histopathologic classification in determining renal outcome in patients with AAV. Metaanalysis showed that patients with focal class had the best outcome while sclerotic class had the worst. PMID- 27980014 TI - Stiffness Is the Cardinal Symptom of Inflammatory Musculoskeletal Diseases, Yet Still Variably Measured: Report from the OMERACT 2016 Stiffness Special Interest Group. AB - OBJECTIVE: The objectives of the Outcome Measures in Rheumatology (OMERACT) Stiffness special interest group (SIG) are to characterize stiffness as an outcome in rheumatic disease and to identify and validate a stiffness patient reported outcome (PRO) in rheumatology. METHODS: At OMERACT 2016, international groups presented and discussed results of several concurrent research projects on stiffness: a literature review of rheumatoid arthritis (RA) stiffness PRO measures, a qualitative investigation into the RA and polymyalgia rheumatica patient perspective of stiffness, data-driven stiffness conceptual model development, development and testing of an RA stiffness PRO measure, and a quantitative work testing stiffness items in patients with RA and psoriatic arthritis. RESULTS: The literature review identified 52 individual stiffness PRO measures assessing morning or early morning stiffness severity/intensity or duration. Items were heterogeneous, had little or inconsistent psychometric property evidence, and did not appear to have been developed according to the PRO development guidelines. A poor match between current stiffness PRO and the conceptual model identifying the RA patient experience of stiffness was identified, highlighting a major flaw in PRO selection according to the OMERACT filter 2.0. CONCLUSION: Discussions within the Stiffness SIG highlighted the importance of further research on stiffness and defined a research agenda. PMID- 27980015 TI - Predicting Which Children with Juvenile Idiopathic Arthritis Will Have a Severe Disease Course: Results from the ReACCh-Out Cohort. AB - OBJECTIVE: We studied an inception cohort of children with juvenile idiopathic arthritis (JIA) to (1) identify distinct disease courses based on changes over 5 years in 5 variables prioritized by patients, parents, and clinicians; and (2) estimate the probability of a severe disease course for each child at diagnosis. METHODS: Assessments of quality of life, pain, medication requirements, patient reported side effects, and active joint counts were scheduled at 0, 6, 12, 18, 24, 36, 48, and 60 months. Patients who attended at least 6 assessments were included. Multivariable cluster analysis, r2, and silhouette statistics were used to identify distinct disease courses. One hundred candidate prediction models were developed in random samples of 75% of the cohort; their reliability and accuracy were tested in the 25% not used in their development. RESULTS: Four distinct courses were identified in 609 subjects. They differed in prioritized variables, disability scores, and probabilities of attaining inactive disease and remission. We named them Mild (43.8% of children), Moderate (35.6%), Severe Controlled (9%), and Severe Persisting (11.5%). A logistic regression model using JIA category, active joint count, and pattern of joint involvement at enrollment best predicted a severe disease course (Controlled + Persisting, c-index = 0.87); 91% of children in the highest decile of risk actually experienced a severe disease course, compared to 5% of those in the lowest decile. CONCLUSION: Children in this JIA cohort followed 1 of 4 disease courses and the probability of a severe disease course could be estimated with information available at diagnosis. PMID- 27980016 TI - Acute Low Back Pain? Do Not Blame the Weather-A Case-Crossover Study. AB - Objective: To investigate the influence of various weather parameters on the risk of developing a low back pain (LBP) episode. Design: Case-crossover study. Setting: Primary care clinics in Sydney, Australia. Subjects: 981 participants with a new episode of acute LBP. Methods: Weather parameters were obtained from the Australian Bureau of Meteorology. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived comparing two exposure variables in the case window-(1) the average of the weather variable for the day prior to pain onset and (2) the change in the weather variable from 2 days prior to 1 day prior to pain onset-with exposures in two control windows (1 week and 1 month before the case window). Results: The weather parameters of precipitation, humidity, wind speed, wind gust, wind direction, and air pressure were not associated with the onset of acute LBP. For one of the four analyses, higher temperature slightly increased the odds of pain onset. Conclusions: Common weather parameters that had been previously linked to musculoskeletal pain, such as precipitation, humidity, wind speed, wind gust, wind direction, and air pressure, do not increase the risk of onset for LBP. PMID- 27980018 TI - The absence of birthweight paradox as a marker of disadvantages faced by low maternal education children. AB - Background: This study tested the hypothesis that the birthweight paradox would not be observed when assessing the effect of maternal education on neonatal mortality in the presence of socioeconomic inequality in access to health care. Methods: Non-concurrent cohort study. Passive follow-up of live-born infants using probabilistic record linkage of birth and death records for Rio de Janeiro (2004-2010; n = 1 445 367). Maternal age, birthweight and neonatal death were evaluated according to maternal educational level strata (<4, 4-11 and >=12 years of study). We estimated the association between maternal educational level and neonatal mortality using logistical regression models adjusted for maternal age and birthweight (<2500 g and >=2500 g). Results: Neonatal mortality was 1.8 times higher in low educational level group compared with high educational level. We did not find birthweight-specific mortality curves crossing over in the stratum under 2500 g (birthweight paradox). The odds of a low birthweight child being born in facilities without neonatal intensive care units was about 70% higher in the group of low education when compared with mothers with high education. Conclusions: The absence of crossing birthweight-specific mortality curves may be a reason for concern about the severity of the disadvantages faced by low maternal education women. PMID- 27980017 TI - Nitric Oxide Modulates Histone Acetylation at Stress Genes by Inhibition of Histone Deacetylases. AB - Histone acetylation, which is an important mechanism to regulate gene expression, is controlled by the opposing action of histone acetyltransferases and histone deacetylases (HDACs). In animals, several HDACs are subjected to regulation by nitric oxide (NO); in plants, however, it is unknown whether NO affects histone acetylation. We found that treatment with the physiological NO donor S nitrosoglutathione (GSNO) increased the abundance of several histone acetylation marks in Arabidopsis (Arabidopsis thaliana), which was strongly diminished in the presence of the NO scavenger 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1 oxyl-3-oxide. This increase was likely triggered by NO-dependent inhibition of HDAC activity, since GSNO and S-nitroso-N-acetyl-dl-penicillamine significantly and reversibly reduced total HDAC activity in vitro (in nuclear extracts) and in vivo (in protoplasts). Next, genome-wide H3K9/14ac profiles in Arabidopsis seedlings were generated by chromatin immunoprecipitation sequencing, and changes induced by GSNO, GSNO/2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3 oxide or trichostatin A (an HDAC inhibitor) were quantified, thereby identifying genes that display putative NO-regulated histone acetylation. Functional classification of these genes revealed that many of them are involved in the plant defense response and the abiotic stress response. Furthermore, salicylic acid, which is the major plant defense hormone against biotrophic pathogens, inhibited HDAC activity and increased histone acetylation by inducing endogenous NO production. These data suggest that NO affects histone acetylation by targeting and inhibiting HDAC complexes, resulting in the hyperacetylation of specific genes. This mechanism might operate in the plant stress response by facilitating the stress-induced transcription of genes. PMID- 27980022 TI - Individualized Pazopanib Dosing-Letter. PMID- 27980023 TI - Individualized Pazopanib Dosing-Response. PMID- 27980020 TI - Identification of Ly2 members as antimicrobial peptides from zebrafish Danio rerio. AB - The emergence of multidrug-resistant (MDR) microbes caused by overuse of antibiotics leads to urgent demands for novel antibiotics exploration. Our recent data showed that Ly2.1-3 (a novel lymphocyte antigen 6 (Ly6) gene cluster) were proteins with cationic nature and rich in cysteine content, that are characteristic of antimicrobial peptides (AMPs) and their expression were all significantly up-regulated after challenge with lipopolysaccharide (LPS). These strongly suggested that Ly2.1-3 are potential AMPs, but firm evidence are lacking. Here, we clearly showed that the recombinant proteins of Ly2.1-3 were capable of killing Gram-negative bacteria Aeromonas hydrophila and Escherichia coli, while they had little bactericidal activity against the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis We also showed that recombinant proteins Ly2.1-3 (rLy2.1-3) were able to bind to the Gram-negative bacteria A. hydrophila, E. coli and the microbial signature molecule LPS, but not to the Gram-positive bacteria S. aureus and B. subtilis as well as the microbial signature molecule LTA. Moreover, the Scatchard analysis revealed that rLy2.1-3 could specifically bind to LPS. Finally, we found that Ly2.1-3 were not cytotoxic to mammalian cells. All these together indicate that Ly2.1-3 can function as AMPs. PMID- 27980024 TI - Individualized Tamoxifen Dose Escalation-Letter. PMID- 27980026 TI - Correction: SPARC Expression Did Not Predict Efficacy of nab-Paclitaxel plus Gemcitabine or Gemcitabine Alone for Metastatic Pancreatic Cancer in an Exploratory Analysis of the Phase III MPACT Trial. PMID- 27980025 TI - Individualized Tamoxifen Dose Escalation-Response. PMID- 27980027 TI - Correction: Activation of IL6/IGFIR Confers Poor Prognosis of HBV-Related Hepatocellular Carcinoma through Induction of OCT4/NANOG Expression. PMID- 27980028 TI - Home Visiting and Use of Infant Health Care: A Randomized Clinical Trial. AB - BACKGROUND AND OBJECTIVES: Evaluations of home visiting models have shown that they can reduce children's health care use in the first year of life. Models that exclusively use nurses as home visitors may cost more and be infeasible given nursing shortages in some locations. The goal of this study was to test whether a universal home visiting model employing a nurse-parent educator team as home visitors reduces health care use in the first year of life. METHODS: This study was a randomized controlled clinical trial of an intensive home visiting program delivered in homes of primary caregivers and their first-born children in Santa Fe, New Mexico. Intention-to-treat and contamination-adjusted intention-to-treat models were estimated, and 244 primary caregivers participated in the survey. RESULTS: In their first year of life, treatment group children were one-third less likely to visit the emergency department (control group mean, MC = 0.42, treatment group mean, MT = 0.28, P = .02) and were also 41% less likely to have visited a primary care provider >=9 times (MC = 0.49, MT = 0.29, P < .001). We found no differences between the treatment and control groups for hospitalizations or injuries requiring medical attention. The universal program reduced infant health care use for high-risk and lower-risk families. CONCLUSIONS: Children in families randomly assigned to the program had less health care use in their first year, demonstrating that a universal prevention home visiting model delivered by a nurse-parent educator team can reduce infant health care use. PMID- 27980029 TI - Risk Stratification for Opioid Misuse in Children, Adolescents, and Young Adults: A Quality Improvement Project. AB - BACKGROUND: The Pediatric Palliative and Comfort Care Team (PACT) at Cincinnati Children's Hospital Medical Center (CCHMC) provides opioids to a large population of patients in the ambulatory setting. Before this project, PACT had no reliable system to risk stratify patients for opioid misuse. METHODS: The global aim was safe opioid prescribing by the palliative care team. The specific, measurable, achievable, realistic, and timely aim was as follows: "In patients who present for follow up with PACT, we will use the "opioid bundle" to increase risk stratification for opioid misuse from 0% to 90% over 5 months." The opioid bundle includes a urine drug screen, Ohio Automated Rx Reporting System report, pill count, and screening history for drug abuse and mental health disorders. The setting was multiple CCHMC ambulatory clinics. Participants included all PACT members. RESULTS: Since implementing the new system, we have increased risk stratification for opioid misuse among outpatients from 0% to >90%. Results have been sustained for 12 months. Key processes have become reliable: obtaining informed consent and controlled substance agreements for all new patients and obtaining the opioid bundle to enable risk stratification in a consistent and timely fashion. A total of 34% of patients have been stratified as high risk, and an additional 27% have been stratified as moderate risk. CONCLUSIONS: A system to ensure safe opioid prescribing practices to all patients is critical for providers. Identifying key processes and executing them reliably has enabled the palliative care team at CCHMC to risk stratify >90% of patients receiving opioids in the ambulatory setting for opioid misuse. PMID- 27980030 TI - Present-day African analogue of a pre-European Amazonian floodplain fishery shows convergence in cultural niche construction. AB - Erickson [Erickson CL (2000) Nature 408 (6809):190-193] interpreted features in seasonal floodplains in Bolivia's Beni savannas as vestiges of pre-European earthen fish weirs, postulating that they supported a productive, sustainable fishery that warranted cooperation in the construction and maintenance of perennial structures. His inferences were bold, because no close ethnographic analogues were known. A similar present-day Zambian fishery, documented here, appears strikingly convergent. The Zambian fishery supports Erickson's key inferences about the pre-European fishery: It allows sustained high harvest levels; weir construction and operation require cooperation; and weirs are inherited across generations. However, our comparison suggests that the pre European system may not have entailed intensive management, as Erickson postulated. The Zambian fishery's sustainability is based on exploiting an assemblage dominated by species with life histories combining high fecundity, multiple reproductive cycles, and seasonal use of floodplains. As water rises, adults migrate from permanent watercourses into floodplains, through gaps in weirs, to feed and spawn. Juveniles grow and then migrate back to dry-season refuges as water falls. At that moment fishermen set traps in the gaps, harvesting large numbers of fish, mostly juveniles. In nature, most juveniles die during the first dry season, so that their harvest just before migration has limited impact on future populations, facilitating sustainability and the adoption of a fishery based on inherited perennial structures. South American floodplain fishes with similar life histories were the likely targets of the pre European fishery. Convergence in floodplain fish strategies in these two regions in turn drove convergence in cultural niche construction. PMID- 27980031 TI - Archaeointensity results spanning the past 6 kiloyears from eastern China and implications for extreme behaviors of the geomagnetic field. AB - Variations of the Earth's geomagnetic field during the Holocene are important for understanding centennial to millennial-scale processes of the Earth's deep interior and have enormous potential implications for chronological correlations (e.g., comparisons between different sedimentary recording sequences, archaeomagnetic dating). Here, we present 21 robust archaeointensity data points from eastern China spanning the past ~6 kyr. These results add significantly to the published data both regionally and globally. Taking together, we establish an archaeointensity reference curve for Eastern Asia, which can be used for archaeomagnetic dating in this region. Virtual axial dipole moments (VADMs) of the data range from a Holocene-wide low of ~27 to "spike" values of ~166 ZAm2 (Z: 1021). The results, in conjunction with our recently published data, confirm the existence of a decrease in paleointensity (DIP) in China around ~2200 BCE. These low intensities are the lowest ever found for the Holocene and have not been reported outside of China. We also report a spike intensity of 165.8 +/- 6.0 ZAm2 at ~1300 BCE (+/-300 y), which is either a prelude to or the same event (within age uncertainties) as spikes first reported in the Levant. PMID- 27980033 TI - The brain parenchyma has a type I interferon response that can limit virus spread. AB - The brain has a tightly regulated environment that protects neurons and limits inflammation, designated "immune privilege." However, there is not an absolute lack of an immune response. We tested the ability of the brain to initiate an innate immune response to a virus, which was directly injected into the brain parenchyma, and to determine whether this response could limit viral spread. We injected vesicular stomatitis virus (VSV), a transsynaptic tracer, or naturally occurring VSV-derived defective interfering particles (DIPs), into the caudate putamen (CP) and scored for an innate immune response and inhibition of virus spread. We found that the brain parenchyma has a functional type I interferon (IFN) response that can limit VSV spread at both the inoculation site and among synaptically connected neurons. Furthermore, we characterized the response of microglia to VSV infection and found that infected microglia produced type I IFN and uninfected microglia induced an innate immune response following virus injection. PMID- 27980035 TI - Music's Relevance for People Affected by Cancer: A Meta-Ethnography and Implications for Music Therapists. AB - BACKGROUND: Evidence supports music-based oncologic support interventions including music therapy. By comparison, little is understood about music-based self-care. This meta-ethnography examined five published qualitative studies to extend understanding of music's relevance, including helpfulness, for people affected by cancer; including children, adolescents, and adults with cancer, carers, and the bereaved. OBJECTIVE: To improve understanding of music's broad relevance for those affected by cancer. METHODS: Meta-ethnography strategies informed the analysis. Five studies were synthesized that included 138 participants: 26 children and 28 parents of children with cancer; 12 adolescents and young adults with cancer; 52 adults with cancer; 12 carers; and 8 bereaved. Studies' category and thematic findings were compared and integrated into third order interpretations, and a line of argument. Perspectives from the five studies that illuminated the line of argument were developed. RESULTS: Music usage can remain incidental, continue normally, and/or change because of cancer's harsh effects. Music can be a lifeline, support biopsychosocial and spiritual well being, or become elusive, that is, difficult to experience. Music helps or intrudes because it extends self-awareness and social connections, and prompts play, memories, imageries, and legacies. Music therapists may help patients and carers to recover or extend music's helpful effects. CONCLUSIONS: Cancer care can be improved through offering music-based resources/services, which give cancer patients and carers opportunities to extend music usage for personal support and, for carers, to support patients. Music therapists can advocate for such resources and educate health professionals about assessing/recognizing when patients' and carers' changed music behaviors signify additional support needs. PMID- 27980032 TI - Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators. AB - Recurrent Pseudomonas aeruginosa infections coupled with robust, damaging neutrophilic inflammation characterize the chronic lung disease cystic fibrosis (CF). The proresolving lipid mediator, 15-epi lipoxin A4 (15-epi LXA4), plays a critical role in limiting neutrophil activation and tissue inflammation, thus promoting the return to tissue homeostasis. Here, we show that a secreted P. aeruginosa epoxide hydrolase, cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), can disrupt 15-epi LXA4 transcellular biosynthesis and function. In the airway, 15-epi LXA4 production is stimulated by the epithelial derived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET). Cif sabotages the production of 15-epi LXA4 by rapidly hydrolyzing 14,15-EET into its cognate diol, eliminating a proresolving signal that potently suppresses IL-8-driven neutrophil transepithelial migration in vitro. Retrospective analyses of samples from patients with CF supported the translational relevance of these preclinical findings. Elevated levels of Cif in bronchoalveolar lavage fluid were correlated with lower levels of 15-epi LXA4, increased IL-8 concentrations, and impaired lung function. Together, these findings provide structural, biochemical, and immunological evidence that the bacterial epoxide hydrolase Cif disrupts resolution pathways during bacterial lung infections. The data also suggest that Cif contributes to sustained pulmonary inflammation and associated loss of lung function in patients with CF. PMID- 27980034 TI - QseC inhibition as an antivirulence approach for colitis-associated bacteria. AB - Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet-/-Rag2-/- IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond to microbiota-generated signals and host derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82's virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management. PMID- 27980039 TI - Intracellular Calcium Mobilization in Response to Ion Channel Regulators via a Calcium-Induced Calcium Release Mechanism. AB - Free intracellular calcium ([Ca2+]i), in addition to being an important second messenger, is a key regulator of many cellular processes including cell membrane potential, proliferation, and apoptosis. In many cases, the mobilization of [Ca2+]i is controlled by intracellular store activation and calcium influx. We have investigated the effect of several ion channel modulators, which have been used to treat a range of human diseases, on [Ca2+]i release, by ratiometric calcium imaging. We show that six such modulators [amiodarone (Ami), dofetilide, furosemide (Fur), minoxidil (Min), loxapine (Lox), and Nicorandil] initiate release of [Ca2+]i in prostate and breast cancer cell lines, PC3 and MCF7, respectively. Whole-cell currents in PC3 cells were inhibited by the compounds tested in patch-clamp experiments in a concentration-dependent manner. In all cases [Ca2+]i was increased by modulator concentrations comparable to those used clinically. The increase in [Ca2+]i in response to Ami, Fur, Lox, and Min was reduced significantly (P < 0.01) when the external calcium was reduced to nM concentration by chelation with EGTA. The data suggest that many ion channel regulators mobilize [Ca2+]i We suggest a mechanism whereby calcium-induced calcium release is implicated; such a mechanism may be important for understanding the action of these compounds. PMID- 27980045 TI - Revolution in stroke. PMID- 27980040 TI - Smoking and Mental Illness: A Bibliometric Analysis of Research Output Over Time. AB - INTRODUCTION: The prevalence of smoking among persons with a mental illness has remained unchanged, being 2-3 times higher than the general population in high income countries. Assessment of the volume and characteristics of research output over time can assist in identifying research priorities to promote progress within a field. The aim of this study was to undertake such an assessment in the field of smoking and mental illness. METHODS: A descriptive repeat cross sectional study was conducted of peer-reviewed publications in Medline and PsycINFO for the periods 1993-1995, 2003-2005, and 2013-2015. Publications were classified as data- or non-data-based; data-based publications were further categorized by study type, population, setting, and for intervention-focused publications by level of evidence and research translation phase. RESULTS: Included were 547 articles published in 1993-1995 (n = 65), 2003-2005 (n = 153), and 2013-2015 (n = 329). The number and proportion of data-based publications significantly increased over time, although their focus remained predominantly descriptive (>=83%); less than 14% of publications in any period had an intervention focus. The proportion of publications reporting on study populations with multiple diagnostic categories and recruiting from nonmental health settings, significantly increased from 1993-1995 to 2003-2005, however then plateaued by 2013-2015. The level of evidence provided by intervention-focused publications was suggested to increase over time, however there was no evident variation in translation phase. CONCLUSIONS: Research has increased over time to characterize smoking among those with a mental illness; however more is needed to inform the development and implementation of effective cessation interventions for this group. IMPLICATIONS: This is the first study to examine the volume and characteristics of research publications in the field of smoking and mental illness over time. The number of publications increased fivefold between 1993 1995 and 2013-2015. Between 1993-1995 and 2003-2005, progression was also indicated by increased: data-based publications, diagnostic diversity of samples, and variation in study settings; however further increases in such measures were not evident in 2013-2015. Notably, it continues to be the case that few intervention studies are undertaken. To achieve meaningful changes in the smoking prevalence of this group, a greater focus on research that assesses the effectiveness and implementation of tailored cessation interventions is required. PMID- 27980046 TI - PET Quantification of the Norepinephrine Transporter in Human Brain with (S,S) 18F-FMeNER-D2. AB - Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, (S,S)-11C-MRB and (S,S)-18F-FMeNER-D2, have been used for imaging NETs in the thalamus and midbrain (including locus coeruleus) using PET in humans. However, NET density in the equally important cerebral cortex has not been well quantified because of unfavorable kinetics with (S,S)-11C-MRB and defluorination with (S,S) 18F-FMeNER-D2, which can complicate NET quantification in the cerebral cortex adjacent to the skull containing defluorinated 18F radioactivity. In this study, we have established analysis methods of quantification of NET density in the brain including the cerebral cortex using (S,S)-18F-FMeNER-D2 PET. Methods: We analyzed our previous (S,S)-18F-FMeNER-D2 PET data of 10 healthy volunteers dynamically acquired for 240 min with arterial blood sampling. The effects of defluorination on the NET quantification in the superficial cerebral cortex was evaluated by establishing a time stability of NET density estimations with an arterial input 2-tissue-compartment model, which guided the less-invasive reference tissue model and area under the time-activity curve methods to accurately quantify NET density in all brain regions including the cerebral cortex. Results: Defluorination of (S,S)-18F-FMeNER-D2 became prominent toward the latter half of the 240-min scan. Total distribution volumes in the superficial cerebral cortex increased with the scan duration beyond 120 min. We verified that 90-min dynamic scans provided a sufficient amount of data for quantification of NET density unaffected by defluorination. Reference tissue model binding potential values from the 90-min scan data and area under the time activity curve ratios of 70- to 90-min data allowed for the accurate quantification of NET density in the cerebral cortex. Conclusion: We have established methods of quantification of NET densities in the brain including the cerebral cortex unaffected by defluorination using (S,S)-18F-FMeNER-D2 These results suggest that we can accurately quantify NET density with a 90-min (S,S) 18F-FMeNER-D2 scan in broad brain areas. PMID- 27980048 TI - Influence of Animal Heating on PET Imaging Quantification and Kinetics: Biodistribution of 18F-Tetrafluoroborate and 18F-FDG in Mice. AB - Different environmental conditions under anesthesia may lead to unstable homeostatic conditions in rodents and therefore may alter kinetics. In this study, the impact of different heating conditions on PET imaging quantification was evaluated. Methods: Two groups of 6 adult female BALB/c nude mice with subcutaneously implanted tumors underwent microPET imaging after injection of 18F labeled tetrafluoroborate or 18F-FDG. Dynamic scans were acquired under optimal and suboptimal heating conditions. Time-activity curves were analyzed to calculate uptake and washout time constants. Results: With 18F-labeled tetrafluoroborate, optimal animal heating led to a stable heart rate during acquisition (515 +/- 35 [mean +/- SD] beats/min), whereas suboptimal heating led to a lower heart rate and a higher SD (470 +/- 84 beats/min). Both uptake and washout time constants were faster (P < 0.01) in animals maintained with optimal heating. Conclusion: Although the difference in heart rates was slight, optimal heating yielded significantly faster uptake and washout kinetics than suboptimal heating in all organs for both tracers. PMID- 27980047 TI - Practical Immuno-PET Radiotracer Design Considerations for Human Immune Checkpoint Imaging. AB - Immune checkpoint blockade has emerged as a promising cancer treatment paradigm. Unfortunately, there are still a large number of patients and malignancies that do not respond to therapy. A major barrier to validating biomarkers for the prediction and monitoring of responders to clinical checkpoint blockade has been the lack of imaging tools to accurately assess dynamic immune checkpoint expression. Here, we sought to optimize noninvasive immuno-PET imaging of human programmed death-ligand 1 (PD-L1) expression, in a preclinical model, using a small high-affinity engineered protein scaffold (HAC-PD1). Six HAC-PD1 radiotracer variants were developed and used in preclinical imaging and biodistribution studies to assess their ability to detect human PD-L1 expression in vivo. Radiotracer design modifications included chelate, glycosylation, and radiometal. HACA-PD1 was adopted as the naming convention for aglycosylated tracer variants. NOD scid gamma-(NSG) mice were inoculated with subcutaneous tumors engineered to either be constitutively positive (CT26 hPD-L1) or be negative (DeltamPD-L1 CT26) for human PD-L1 expression. When the tumors had grown to an average size of 1 cm in diameter, mice were injected with 0.75-2.25 MBq (~10 MUg) of an engineered radiotracer variant and imaged. At 1 h after injection, organs were harvested for biodistribution. Of the practical immuno-PET tracer modifications considered, glycosylation was the most prominent design factor affecting tracer uptake, specificity, and clearance. In imaging studies, aglycosylated 64Cu-NOTA-HACA-PD1 most accurately visualized human PD-L1 expression in vivo. We reasoned that because of the scaffold's small size (14 kDa), its pharmacokinetics may be suitable for labeling with the short-lived and widely clinically available radiometal 68Ga. At 1 h after injection, 68Ga-NOTA HACA-PD1 and 68Ga-DOTA-HACA-PD1 exhibited promising target-to-background ratios in ex vivo biodistribution studies (12.3 and 15.2 tumor-to-muscle ratios, respectively). Notably, all HAC-PD1 radiotracer variants enabled much earlier detection of human PD-L1 expression (1 h after injection) than previously reported radiolabeled antibodies (>24 h after injection). This work provides a template for assessing immuno-PET tracer design parameters and supports the translation of small engineered protein radiotracers for imaging human immune checkpoints. PMID- 27980049 TI - Whole-Body 18F-FDG PET and 18F-FDG PET/CT in Patients with Suspected Paraneoplastic Syndrome: A Systematic Review and Meta-Analysis of Diagnostic Accuracy. AB - The purpose of this study was to assess the diagnostic performance of whole-body 18F-FDG PET or 18F-FDG PET/CT for detection of underlying malignancy in patients with clinically suspected neurologic and nonneurologic paraneoplastic syndromes. Methods: A systematic search was performed in PubMed (Medline), Embase, and Scopus (last updated November 2016) to identify relevant published studies reporting the performance of 18F-FDG PET or 18F-FDG PET/CT in patients with suspected paraneoplastic syndrome. Histopathologic confirmation or clinical follow-up was considered as the reference standard. Pooled estimates, with 95% confidence intervals (CIs), of sensitivity, specificity, and diagnostic odds ratio were calculated. A summary receiver-operating-characteristic curve was constructed, and the area under the curve (AUC) was determined along with the Q* index. Results: Twenty-one studies including a total of 1,293 individual patients suspected of having a paraneoplastic syndrome and who underwent 18F-FDG PET or 18F-FDG PET/CT examinations met our inclusion criteria. There was moderate to high heterogeneity among the included studies. The pooled sensitivity, specificity, and diagnostic odds ratio of 18F-FDG PET or 18F-FDG PET/CT for the detection of underlying malignancy were 0.81 (95% CI, 0.76-0.86), 0.88 (95% CI, 0.86-0.90), and 34.03 (95% CI, 18.76-61.72), respectively. The AUC and the Q* index were 0.916 (SE, 0.018) and 0.849, indicating excellent diagnostic accuracy. The diagnostic accuracy was slightly improved after studies with high applicability concerns were excluded (AUC, 0.931; SE, 0.020). In a subgroup analysis, 18F-FDG PET/CT was found to have a significantly higher specificity (0.89 vs. 0.79) than 18F-FDG PET alone, with no evidence of significant difference in the overall performance (AUC, 0.930 vs. 0.891; 2-tailed P value for difference, 0.31). Conclusion: This meta-analysis of available studies demonstrates that whole-body 18F-FDG PET or 18F-FDG PET/CT has high diagnostic accuracy and moderate to high sensitivity and specificity for detection of underlying malignancy in patients suspected of having a paraneoplastic syndrome. PMID- 27980050 TI - In Vivo PET Imaging of the Cancer Integrin alphavbeta6 Using 68Ga-Labeled Cyclic RGD Nonapeptides. AB - Expression of the cellular transmembrane receptor alphavbeta6 integrin is essentially restricted to malignant epithelial cells in carcinomas of a broad variety of lineages, whereas it is virtually absent in normal adult tissues. Thus, it is a highly attractive target for tumor imaging and therapy. Furthermore, alphavbeta6 integrin plays an important role for the epithelial mesenchymal interaction and the development of fibrosis. Methods: On the basis of the 68Ga chelators TRAP (triazacyclononane-triphosphinate) and NODAGA, we synthesized mono-, di-, and trimeric conjugates of the alphavbeta6 integrin selective peptide cyclo(FRGDLAFp(NMe)K) via click chemistry. These were labeled with 68Ga and screened regarding their suitability for in vivo imaging of alphavbeta6 integrin expression by PET and ex vivo biodistribution in severe combined immunodeficiency mice bearing H2009 tumor (human lung adenocarcinoma) xenografts. For these, alphavbeta6 integrin expression in tumor and other tissues was determined by beta6 immunohistochemistry. Results: Despite the multimers showing higher alphavbeta6 integrin affinities (23-120 pM) than the monomers (260 pM), the best results-that is, low background uptake and excellent tumor delineation-were obtained with the TRAP-based monomer 68Ga-avebehexin. This compound showed the most favorable pharmacokinetics because of its high polarity (log D = -3.7) and presence of additional negative charges (carboxylates) on the chelator, promoting renal clearance. Although tumor uptake was low (0.65% +/- 0.04% injected dose per gram tissue [%ID/g]), it was still higher than in all other organs except the kidneys, ranging from a maximum for the stomach (0.52 +/- 0.04 %ID/g) to almost negligible for the pancreas (0.07 +/- 0.01 %ID/g). A low but significant target expression in tumor, lung, and stomach was confirmed by immunohistochemistry. Conclusion: Because of highly sensitive PET imaging even of tissues with low alphavbeta6 integrin expression density, we anticipate clinical applicability of 68Ga-avebehexin for imaging of alphavbeta6 tumors and fibrosis by PET. PMID- 27980051 TI - 4-11C-Methoxy N-(2-Diethylaminoethyl) Benzamide: A Novel Probe to Selectively Target Melanoma. AB - We report the synthesis and preclinical evaluation of a 11C-labeled probe to target melanoma using PET. Methods: The target compound 4-11C-methoxy N-(2 diethylaminoethyl) benzamide (4-11C-MBZA) was prepared via the 11C-methylation of 4-hydroxy N-(2-diethylaminoethyl) benzamide (4-HBZA). The in vitro binding was performed using B16F1 (melanoma cells), MCF-10A (breast epithelial cells), and MDA-MB 231 (breast cancer cells). The internalization studies were conducted using B16F1 cells. In vivo biodistribution and small-animal PET imaging were performed in mice bearing B16F1 melanoma tumor xenografts. Results: The target compound 4-11C-MBZA was prepared in 46% +/- 7% radiochemical yields by reacting 11C-methyltriflate with 4-HBZA followed by high-performance liquid chromatography purification. The specific activity of this compound was 853 +/- 29.6 GBq/MUmol (23 +/- 0.8 Ci/MUmol). The binding of 4-11C-MBZA to B16F1, MCF-10A, and MDA-MB 231 cells was 6.41% +/- 1.28%, 1.51% +/- 0.17%, and 0.30% +/- 0.17%, respectively. Internalization studies using B16F1 melanoma cells show 60.7% of the cell-bound activity was internalized. Results from biodistribution studies show a rapid and high uptake of radioactivity in the tumor, with uptake levels reaching 5.85 +/- 0.79 and 8.13 +/- 1.46 percentage injected dose per gram at 10 and 60 min, respectively. Low uptake in normal tissues in conjunction with high tumor uptake resulted in high tumor-to-tissue ratios. On small-animal PET images, the tumor was clearly delineated soon after 4-11C-MBZA injection and tumor uptake reached 4.2 percentage injected dose per gram by 20 min. These preclinical evaluations show a high propensity of 4-11C-MBZA toward melanoma tumor. Conclusion: We successfully developed 4-11C-MBZA as a PET imaging probe, displaying properties advantageous over those for its 18F analogs. These preclinical evaluation results demonstrate the clinical potential of this probe to selectively target melanoma. PMID- 27980052 TI - Clinicopathological significance of Necl-4 expression in pancreatic ductal adenocarcinoma. AB - AIMS: The loss, or decreased expression, of nectin-like molecule 4 (Necl-4; an immunoglobulin-like cell adhesion molecule) is reported to be associated with the development and progression of certain types of cancer. We investigated the clinicopathological significance of Necl-4 expression in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Immunohistochemical analyses of Necl-4 (n=258) and E-cadherin (n=256) expression were performed using tissue microarray blocks of PDAC samples. Necl-4 expression of 38 pancreatic intraepithelial neoplasia (PanIN) lesions included in tissue microarray cores was also evaluated. Necl-4 and E-cadherin expression was considered positive if >30% of cells were stained, and negative if <=30% of cells were stained. RESULTS: Necl-4 expression was positive in 45.7% (n=118) and negative in 54.3% (n=140) of PDAC cases. Necl-4 staining was positive in 96.7% (n=29) and negative in 3.3% (n=1) of low-grade PanIN cases, and positive in 62.5% (n=5) and negative in 37.5% (n=3) of high grade PanIN cases. The number of cases with positive Necl-4 expression decreased in the order low-grade PanIN>high-grade PanIN>PDAC (p<0.001). Negative Necl-4 expression was significantly associated with a larger tumour size of >30 mm, perineural invasion, lymphatic involvement, lymph node metastasis (pN1), an advanced TNM (tumour, node, metastases) stage (stage IIB-IV), an advanced histological grade (G2/3), and shorter overall survival. E-cadherin staining was positive in 46.1% (n=118) and negative in 53.9% (n=138) of PDAC cases. Necl-4 expression correlated positively with E-cadherin expression (r=0.405, p<0.001). CONCLUSIONS: The results suggest that Necl-4 is associated with carcinogenesis and aggressiveness of PDAC. PMID- 27980053 TI - Performance of urinalysis tests and their ability in predicting results of urine cultures: a comparison between automated test strip analyser and flow cytometry in various subpopulations and types of samples. AB - AIMS: Results of urinalysis are available earlier than urine culture results. If urinalysis can predict results of culture, early decision can be made on treatment and whether urine samples should be cultured. This study sought to compare the performance of urinalysis tests by automated test strip analyser (nitrite and leucocyte esterase) with flow cytometry (bacteria and white cell count) in different subpopulations and types of samples. METHODS: Consecutive urine samples (n=2351) from a population with a median age of 45 years, 37.2% men, were tested. Sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the tests were calculated using contingency tables. The gold standard was positive urine culture with cut-off >105 CFU/mL. RESULTS: 14% of the cultures were positive (95.6% monomicrobial, 74.7% Enterobacteriaceae). Overall, nitrite test was the most specific (98.7%) but the least sensitive (43.2%). Bacteria count was the most sensitive (91.7%) and highly specific (87.5%). In infants <24 months, the sensitivity of bacteria count was reduced (86.1%), but specificity was high (95.9%). The specificity of nitrite was reduced in urine from the in-and-out procedure (81.9%). The sensitivity of bacteria count was reduced in bag specimens urine (83.3%) and in urine from indwelling catheter (84.7%). All tests showed a high NPV. The NPV of the combined flow cytometry tests was higher than those of automated test strip analyser (99.1% vs 97.4%). CONCLUSIONS: Overall, the performance of urinalysis is excellent. Flow cytometry tests performed better than automated test strip analyser in ruling out urine to be cultured. PMID- 27980054 TI - Reduced angiomotin p130 expression correlates with poor prognosis in lung adenocarcinoma. AB - AIMS: Lung cancer is the leading cause of cancer-related deaths worldwide, and it still results in a poor prognosis despite research and development of a treatment modality. Angiomotin (AMOT) was first described as a protein involved in angiogenesis, and although the oncogenic and tumour-suppressive roles of AMOT were recently reported, the biological function of AMOT has not yet been clarified. The aim of this study was thus to evaluate the relationship between reduced AMOT p130 expression and clinicopathological parameters, including patients' survival. METHODS: We enrolled 67 patients with lung adenocarcinoma in this study and measured the immunoreactivity of AMOT p130 in a tissue microarray. The data were analysed using a chi2 test, Cox regression hazards model and log rank test with Kaplan-Meier curves. RESULTS: Reduced AMOT p130 expression is related to lung adenocarcinoma developed at a young age with statistical significance, but there is no statistical significance for the other clinicopathological parameters. Kaplan-Meier curves with log-rank test showed that reduced AMOT p130 expression had significantly better survival rate compared with the retained group (p=0.002). Univariable and multivariable analyses of the disease free survival revealed that the decreased AMOT expression was an independent prognostic factor (p=0.004, p=0.008, respectively). CONCLUSIONS: Decreased AMOT p130 could be an independent indicator of poor survival in patients with lung adenocarcinoma. PMID- 27980060 TI - Quantifying deleterious effects of regulatory variants. AB - The majority of genome-wide association study (GWAS) risk variants reside in non coding DNA sequences. Understanding how these sequence modifications lead to transcriptional alterations and cell-to-cell variability can help unraveling genotype-phenotype relationships. Here, we describe a computational method, dubbed CAPE, which calculates the likelihood of a genetic variant deactivating enhancers by disrupting the binding of transcription factors (TFs) in a given cellular context. CAPE learns sequence signatures associated with putative enhancers originating from large-scale sequencing experiments (such as ChIP-seq or DNase-seq) and models the change in enhancer signature upon a single nucleotide substitution. CAPE accurately identifies causative cis-regulatory variation including expression quantitative trait loci (eQTLs) and DNase I sensitivity quantitative trait loci (dsQTLs) in a tissue-specific manner with precision superior to several currently available methods. The presented method can be trained on any tissue-specific dataset of enhancers and known functional variants and applied to prioritize disease-associated variants in the corresponding tissue. PMID- 27980062 TI - Updates in Rhea - an expert curated resource of biochemical reactions. PMID- 27980064 TI - Efficient size-independent chromosome delivery from yeast to cultured cell lines. AB - The delivery of large DNA vectors (>100 000 bp) remains a limiting step in the engineering of mammalian cells and the development of human artificial chromosomes (HACs). Yeast is commonly used to assemble genetic constructs in the megabase size range, and has previously been used to transfer constructs directly into cultured cells. We improved this method to efficiently deliver large (1.1 Mb) synthetic yeast centromeric plasmids (YCps) to cultured cell lines at rates similar to that of 12 kb YCps. Synchronizing cells in mitosis improved the delivery efficiency by 10-fold and a statistical design of experiments approach was employed to boost the vector delivery rate by nearly 300-fold from 1/250 000 to 1/840 cells, and subsequently optimize the delivery process for multiple mammalian, avian, and insect cell lines. We adapted this method to rapidly deliver a 152 kb herpes simplex virus 1 genome cloned in yeast into mammalian cells to produce infectious virus. PMID- 27980063 TI - BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells. AB - Bromodomain-containing protein 4 (BRD4) is a member of the bromo- and extraterminal (BET) domain-containing family of epigenetic readers which is under intensive investigation as a target for anti-tumor therapy. BRD4 plays a central role in promoting the expression of select subsets of genes including many driven by oncogenic transcription factors and signaling pathways. However, the role of BRD4 and the effects of BET inhibitors in non-transformed cells remain mostly unclear. We demonstrate that BRD4 is required for the maintenance of a basal epithelial phenotype by regulating the expression of epithelial-specific genes including TP63 and Grainy Head-like transcription factor-3 (GRHL3) in non transformed basal-like mammary epithelial cells. Moreover, BRD4 occupancy correlates with enhancer activity and enhancer RNA (eRNA) transcription. Motif analyses of cell context-specific BRD4-enriched regions predicted the involvement of FOXO transcription factors. Consistently, activation of FOXO1 function via inhibition of EGFR-AKT signaling promoted the expression of TP63 and GRHL3. Moreover, activation of Src kinase signaling and FOXO1 inhibition decreased the expression of FOXO/BRD4 target genes. Together, our findings support a function for BRD4 in promoting basal mammary cell epithelial differentiation, at least in part, by regulating FOXO factor function on enhancers to activate TP63 and GRHL3 expression. PMID- 27980065 TI - CRISPR-Cas type I-A Cascade complex couples viral infection surveillance to host transcriptional regulation in the dependence of Csa3b. AB - CRISPR-Cas (clustered regularly interspaced short palindromic repeats and the associated genes) constitute adaptive immune systems in bacteria and archaea and they provide sequence specific immunity against foreign nucleic acids. CRISPR-Cas systems are activated by viral infection. However, little is known about how CRISPR-Cas systems are activated in response to viral infection or how their expression is controlled in the absence of viral infection. Here, we demonstrate that both the transcriptional regulator Csa3b, and the type I-A interference complex Cascade, are required to transcriptionally repress the interference gene cassette in the archaeon Sulfolobus. Csa3b binds to two palindromic repeat sites in the promoter region of the cassette and facilitates binding of the Cascade to the promoter region. Upon viral infection, loading of Cascade complexes onto crRNA-matching protospacers leads to relief of the transcriptional repression. Our data demonstrate a mechanism coupling CRISPR-Cas surveillance of protospacers to transcriptional regulation of the interference gene cassette thereby allowing a fast response to viral infection. PMID- 27980067 TI - A high-sensitivity bi-directional reporter to monitor NF-kappaB activity in cell culture and zebrafish in real time. AB - Nuclear factor (NF)-kappaB transcription factors play major roles in numerous biological processes including development and immunity. Here, we engineered a novel bi-directional NF-kappaB-responsive reporter, pSGNluc, in which a high affinity NF-kappaB promoter fragment simultaneously drives expression of luciferase and GFP. Treatment with TNFalpha (also known as TNF) induced a strong, dose-dependent luciferase signal in cell culture. The degree of induction over background was comparable to that of other NF-kappaB-driven luciferase reporters, but the absolute level of expression was at least 20-fold higher. This extends the sensitivity range of otherwise difficult assays mediated exclusively by endogenously expressed receptors, as we show for Nod1 signaling in HEK293 cells. To measure NF-kappaB activity in the living organism, we established a transgenic zebrafish line carrying the pSGNluc construct. Live in toto imaging of transgenic embryos revealed the activation patterns of NF-kappaB signaling during embryonic development and as responses to inflammatory stimuli. Taken together, by integrating qualitative and quantitative NF-kappaB reporter activity, pSGNluc is a valuable tool for studying NF-kappaB signaling at high spatiotemporal resolution in cultured cells and living animals that goes beyond the possibilities provided by currently available reporters. PMID- 27980066 TI - pBACode: a random-barcode-based high-throughput approach for BAC paired-end sequencing and physical clone mapping. AB - Applications that use Bacterial Artificial Chromosome (BAC) libraries often require paired-end sequences and knowledge of the physical location of each clone in plates. To facilitate obtaining this information in high-throughput, we generated pBACode vectors: a pool of BAC cloning vectors, each with a pair of random barcodes flanking its cloning site. In a pBACode BAC library, the BAC ends and their linked barcodes can be sequenced in bulk. Barcode pairs are determined by sequencing the empty pBACode vectors, which allows BAC ends to be paired according to their barcodes. For physical clone mapping, the barcodes are used as unique markers for their linked genomic sequence. After multi-dimensional pooling of BAC clones, the barcodes are sequenced and deconvoluted to locate each clone. We generated a pBACode library of 94,464 clones for the flounder Paralichthys olivaceus and obtained paired-end sequence from 95.4% of the clones. Incorporating BAC paired-ends into the genome preassembly improved its continuity by over 10-fold. Furthermore, we were able to use the barcodes to map the physical locations of each clone in just 50 pools, with up to 11 808 clones per pool. Our physical clone mapping located 90.2% of BAC clones, enabling targeted characterization of chromosomal rearrangements. PMID- 27980069 TI - Multiple routes of endocytic internalization of PDGFRbeta contribute to PDGF induced STAT3 signaling. AB - Platelet-derived growth factor receptor beta (PDGFRbeta) is a receptor tyrosine kinase which upon activation by PDGF-BB stimulates cell proliferation, migration and angiogenesis. Ligand binding induces intracellular signaling cascades but also internalization of the receptor, eventually resulting in its lysosomal degradation. However, endocytic trafficking of receptors often modulates their downstream signaling. We previously reported that internalization of PDGFRbeta occurs via dynamin-dependent and -independent pathways but their further molecular determinants remained unknown. Here we show that, in human fibroblasts expressing endogenous PDGFRbeta and stimulated with 50 ng/ml PDGF-BB, ligand receptor uptake proceeds via the parallel routes of clathrin-mediated endocytosis (CME) and clathrin-independent endocytosis (CIE). CME involves the canonical AP2 complex as a clathrin adaptor, while CIE requires RhoA-ROCK, Cdc42 and galectin 3, the latter indicating lectin-mediated internalization via clathrin-independent carriers (CLICs). Although different uptake routes appear to be partly interdependent, they cannot fully substitute for each other. Strikingly, inhibition of any internalization mechanism impaired activation of STAT3 but not of other downstream effectors of PDGFRbeta. Our data indicate that multiple routes of internalization of PDGFRbeta contribute to a transcriptional and mitogenic response of cells to PDGF. PMID- 27980068 TI - PIGN prevents protein aggregation in the endoplasmic reticulum independently of its function in the GPI synthesis. AB - Quality control of proteins in the endoplasmic reticulum (ER) is essential for ensuring the integrity of secretory proteins before their release into the extracellular space. Secretory proteins that fail to pass quality control form aggregates. Here we show the PIGN-1/PIGN is required for quality control in Caenorhabditis elegans and in mammalian cells. In C. elegans pign-1 mutants, several proteins fail to be secreted and instead form abnormal aggregation. PIGN knockout HEK293 cells also showed similar protein aggregation. Although PIGN 1/PIGN is responsible for glycosylphosphatidylinositol (GPI)-anchor biosynthesis in the ER, certain mutations in C. elegans pign-1 caused protein aggregation in the ER without affecting GPI-anchor biosynthesis. These results show that PIGN 1/PIGN has a conserved and non-canonical function to prevent deleterious protein aggregation in the ER independently of the GPI-anchor biosynthesis. PIGN is a causative gene for some human diseases including multiple congenital seizure related syndrome (MCAHS1). Two pign-1 mutations created by CRISPR/Cas9 that correspond to MCAHS1 also cause protein aggregation in the ER, implying that the dysfunction of the PIGN non-canonical function might affect symptoms of MCAHS1 and potentially those of other diseases. PMID- 27980070 TI - Delta40p53alpha suppresses tumor cell proliferation and induces cellular senescence in hepatocellular carcinoma cells. AB - Splice variants of certain genes impact on genetic biodiversity in mammals. The tumor suppressor TP53 gene (encoding p53) plays an important role in the regulation of tumorigenesis in hepatocellular carcinoma (HCC). Delta40p53alpha is a naturally occurring p53 isoform that lacks the N-terminal transactivation domain, yet little is known about the role of Delta40p53alpha in the development of HCC. Here, we first report on the role of Delta40p53alpha in HCC cell lines. In the TP53+/Delta40 cell clones, clonogenic activity and cell survival dramatically decreased, whereas the percentage of senescence-associated beta galactosidase (SA-beta-gal)-positive cells and p21 (also known as WAF1, CIP1 and CDKN1A) expression significantly increased. These observations were clearly attenuated in the TP53+/Delta40 cell clones after Delta40p53alpha knockdown. In addition, exogenous Delta40p53 expression significantly suppressed cell growth in HCC cells with wild-type TP53, and in those that were mutant or null for TP53 Notably, Delta40p53alpha-induced tumor suppressor activity was markedly attenuated in cells expressing the hot-spot mutant Delta40p53alpha-R175H, which lacks the transcription factor activity of p53. Moreover, Delta40p53alpha expression was associated with increased full-length p53 protein expression. These findings enhance the understanding of the molecular pathogenesis of HCC and show that Delta40p53alpha acts as an important tumor suppressor in HCC cells. PMID- 27980071 TI - A PKM generated by calpain cleavage of a classical PKC is required for activity dependent intermediate-term facilitation in the presynaptic sensory neuron of Aplysia. AB - Atypical PKM, a persistently active form of atypical PKC, is proposed to be a molecular memory trace, but there have been few examinations of the role of PKMs generated from other PKCs. We demonstrate that inhibitors used to inhibit PKMs generated from atypical PKCs are also effective inhibitors of other PKMs. In contrast, we demonstrate that dominant-negative PKMs show isoform-specificity. A dominant-negative PKM from the classical PKC Apl I blocks activity-dependent intermediate-term facilitation (a-ITF) when expressed in the sensory neuron, while a dominant-negative PKM from the atypical PKC Apl III does not. Consistent with a specific role for PKM Apl I in activity-dependent facilitation, live imaging FRET-based cleavage assays reveal that activity leads to cleavage of the classical PKC Apl I, but not the atypical PKC Apl III in the sensory neuron varicosities of Aplysia In contrast, massed intermediate facilitation (m-ITF) induced by 10 min of 5HT is sufficient for cleavage of the atypical PKC Apl III in the motor neuron. Interestingly, both cleavage of PKC Apl I in the sensory neuron during a-ITF and cleavage of PKC Apl III in the motor neuron during m-ITF are inhibited by a dominant-negative form of a penta-EF hand containing classical calpain cloned from Aplysia Consistent with a role for PKMs in plasticity, this dominant-negative calpain also blocks both a-ITF when expressed in the sensory neuron and m-ITF when expressed in the motor neuron. This study broadens the role of PKMs in synaptic plasticity in two significant ways: (i) PKMs generated from multiple isoforms of PKC, including classical isoforms, maintain memory traces; (ii) PKMs play roles in the presynaptic neuron. PMID- 27980072 TI - Memory trace reactivation and behavioral response during retrieval are differentially modulated by amygdalar glutamate receptors activity: interaction between amygdala and insular cortex. AB - The insular cortex (IC) is required for conditioned taste aversion (CTA) retrieval. However, it remains unknown which cortical neurotransmitters levels are modified upon CTA retrieval. Using in vivo microdialysis, we observed that there were clear elevations in extracellular glutamate, norepinephrine, and dopamine in and around the center of the gustatory zone of the IC during CTA retrieval. Additionally, it has been reported that the amygdala-IC interaction is highly involved in CTA memory establishment. Therefore, we evaluated the effects of infusions of an AMPA receptor antagonist (CNQX) and a NMDA receptor antagonist (APV) into the amygdala on CTA retrieval and IC neurotransmitter levels. Infusion of APV into the amygdala impaired glutamate augmentation within the IC, whereas dopamine and norepinephrine levels augmentation persisted and a reliable CTA expression was observed. Conversely, CNQX infusion into the amygdala impaired the aversion response, as well as norepinephrine and dopamine augmentations in the IC. Interestingly, CNQX infusion did not affect glutamate elevation in the IC. To evaluate the functional meaning of neurotransmitters elevations within the IC on CTA response, we infused specific antagonists for the AMPA, NMDA, D1, and beta adrenergic receptor before retrieval. Results showed that activation of AMPA, D1, and beta-adrenergic receptors is necessary for CTA expression, whereas NMDA receptors are not involved in the aversion response. PMID- 27980073 TI - Respective role of the dorsal hippocampus and the entorhinal cortex during the recombination of previously learned olfactory-tactile associations in the rat. AB - The hippocampal formation has been extensively described as a key component for object recognition in conjunction with place and context. The present study aimed at describing neural mechanisms in the hippocampal formation that support olfactory-tactile (OT) object discrimination in a task where space and context were not taken into account. The task consisted in discriminating one baited cup among three, each of them presenting overlapping olfactory or tactile elements. The experiment tested the involvement of the entorhinal cortex (EC) and the dorsal hippocampus (DH) in the acquisition of this cross-modal task, either with new items or with familiar but recombined items. The main results showed that DH inactivation or cholinergic muscarinic blockade in the DH selectively and drastically disrupted performance in the recombination task. EC inactivation impaired OT acquisition of any OT combinations while cholinergic blockade only delayed it. Control experiments showed that neither DH nor EC inactivation impaired unimodal olfactory or tactile tasks. As a whole, these data suggest that DH-EC interactions are of importance for flexibility of cross-modal representations with overlapping elements. PMID- 27980074 TI - Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network. AB - Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic plasticity to facilitate extinction of appetitive behaviors and to reduce relapse. Rats self-administered cocaine and were given VNS during extinction. Relapse to drug-seeking was assessed in a cued reinstatement session. We used immunohistochemistry to measure changes in the expression of the phosphorylated transcription factor cAMP response-element binding protein (pCREB) in the PFC and the basolateral amygdala (BLA), which regulate cue learning and extinction. In vivo recordings of evoked field potentials measured drug- and VNS-induced changes in metaplasticity in the pathway from the PFC to the BLA. VNS-treated rats showed improved rates of extinction and reduced reinstatement. Following reinstatement, pCREB levels were reduced in the IL and BLA of VNS-treated rats. Evoked responses in the BLA were greatly reduced in VNS-treated rats, and these rats were also resistant to the induction of LTD. Taken together, these results show that VNS facilitates extinction and reduces reinstatement. Changes in the pathway between the PFC and the amygdala may contribute to these beneficial effects. PMID- 27980075 TI - Effects of context preexposure and delay until anxiety retrieval on generalization of contextual anxiety. AB - Animal studies suggest that time delay between acquisition and retrieval of contextual anxiety increases generalization. Moreover, such generalization is prevented by preexposure to the context (CTX), presumably due to an improved representation of such context. We investigated whether preexposure and time passing modulate generalization of contextual anxiety, in humans. On Day 1, 42 participants (preexposure group) explored two virtual offices, while 41 participants (no-preexposure group) explored a virtual stadium. On Day 2 (24 h later), all participants learned to associate one office (CTX+) with unpredictable unconditioned stimuli (USs), and another office (CTX-) with safety. On Day 3, either 24 h (recent test) or 2 wk (remote test) later, participants revisited CTX- and CTX+ without USs, as well as a generalization context (G-CTX). Results revealed successfully conditioned anxiety and anxiety generalization for ratings (G-CTX was as aversive as CTX+ was), while safety generalization was found for startle responses (G-CTX elicited startle attenuation as CTX- did). Time between learning and testing enhanced generalization as reflected by comparable startle responses to all three offices in the remote test. Contextual preexposure facilitated extinction of explicit conditioned anxiety assessed with ratings. These results suggest that memory trace of a context degrades with passage of time in humans like in animals and, consequently, anxiety generalization enhances. After context preexposure, high cognitive processes seem to be crucially involved in facilitating extinction (or safety) learning. PMID- 27980076 TI - Primary auditory cortex regulates threat memory specificity. AB - Distinguishing threatening from nonthreatening stimuli is essential for survival and stimulus generalization is a hallmark of anxiety disorders. While auditory threat learning produces long-lasting plasticity in primary auditory cortex (Au1), it is not clear whether such Au1 plasticity regulates memory specificity or generalization. We used muscimol infusions in rats to show that discriminatory threat learning requires Au1 activity specifically during memory acquisition and retrieval, but not during consolidation. Memory specificity was similarly disrupted by infusion of PKMzeta inhibitor peptide (ZIP) during memory storage. Our findings show that Au1 is required at critical memory phases and suggest that Au1 plasticity enables stimulus discrimination. PMID- 27980077 TI - Role of proteasome-dependent protein degradation in long-term operant memory in Aplysia. AB - We investigated the in vivo role of protein degradation during intermediate (ITM) and long-term memory (LTM) in Aplysia using an operant learning paradigm. The proteasome inhibitor MG-132 inhibited the induction and molecular consolidation of LTM with no effect on ITM. Remarkably, maintenance of steady-state protein levels through inhibition of protein synthesis using either anisomycin or rapamycin in conjunction with proteasome inhibition permitted the formation of robust 24 h LTM. Our studies suggest a primary role for proteasomal activity in facilitation of gene transcription for LTM and raise the possibility that synaptic mechanisms are sufficient to sustain 24 h memory. PMID- 27980079 TI - Scholarly gender gap extends to medical students: the case of Australasia. PMID- 27980078 TI - Reward retroactively enhances memory consolidation for related items. AB - Reward motivation has been shown to modulate episodic memory processes in order to support future adaptive behavior. However, for a memory system to be truly adaptive, it should enhance memory for rewarded events as well as for neutral events that may seem inconsequential at the time of encoding but can gain importance later. Here, we investigated the influence of reward motivation on retroactive memory enhancement selectively for conceptually related information. We found behavioral evidence that reward retroactively enhances memory at a 24-h memory test, but not at an immediate memory test, suggesting a role for post encoding mechanisms of consolidation. PMID- 27980080 TI - Difficulties in administration of oral medication formulations to pet cats: an e survey of cat owners. AB - The purpose here was to determine the problems cat owners encounter in medicating their cats with orally administered drugs at home. The study was carried out as an open e-questionnaire survey addressed to cat owners in which the authors focused on the oral administration route. A total of 46 completed questionnaires were included in the survey. In the study, 46 cats received 67 orally administered drugs. Approximately half of the drugs were registered for use in cats by the European Medicines Agency (54 per cent), and there were also off label drugs registered for human (36 per cent) and canine medication (7.4 per cent) and an ex tempore drug (3.0 per cent). The owners were unable to give the doses as prescribed for their cats for one-fourth of the medications (16/67). Drugs that were registered for feline medication were significantly more palatable than drugs registered for other species (odds ratio (OR) 4.9), and liquid formulations were significantly more palatable than solid formulations (OR 4.8). However, most of the owners (22/38) preferred a solid dosage form, while few (4/38) chose a liquid formulation. The results indicate that there is still a need for more palatable and easily administered oral drugs for cats. PMID- 27980081 TI - DDX3 directly regulates TRAF3 ubiquitination and acts as a scaffold to co ordinate assembly of signalling complexes downstream from MAVS. AB - The human DEAD-box helicase 3 (DDX3) has been shown to contribute to type I interferon (IFN) induction downstream from antiviral pattern recognition receptors. It binds to TANK-binding kinase 1 and IkappaB-kinase-epsilon (IKKepsilon), the two key kinases mediating activation of IFN regulatory factor (IRF) 3 and IRF7. We previously demonstrated that DDX3 facilitates IKKepsilon activation downstream from RIG-I and then links the activated kinase to IRF3. In the present study, we probed the interactions between DDX3 and other key signalling molecules in the RIG-I pathway and identified a novel direct interaction between DDX3 and TNF receptor-associated factor 3 (TRAF3) mediated by a TRAF-interaction motif in the N-terminus of DDX3, which was required for TRAF3 ubiquitination. Interestingly, we observed two waves of K63-linked TRAF3 ubiquitination following RIG-I activation by Sendai virus (SeV) infection, both of which were suppressed by DDX3 knockdown. We also investigated the spatiotemporal formation of endogenous downstream signalling complexes containing the mitochondrial antiviral signalling (MAVS) adaptor, DDX3, IkappaB-kinase epsilon (IKKepsilon), TRAF3 and IRF3. DDX3 was recruited to MAVS early after SeV infection, suggesting that it might mediate subsequent recruitment of other molecules. Indeed, knockdown of DDX3 prevented the formation of TRAF3-MAVS and TRAF3-IKKepsilon complexes. Based on our data, we propose that early TRAF3 ubiquitination is required for the formation of a stable MAVS-TRAF3 complex, while the second wave of TRAF3 ubiquitination mediates IRF3 recruitment and activation. Our study characterises DDX3 as a multifunctional adaptor molecule that co-ordinates assembly of different TRAF3, IKKepsilon and IRF3-containing signalling complexes downstream from MAVS. Additionally, it provides novel insights into the role of TRAF3 in RIG-I signalling. PMID- 27980082 TI - A review of prognostic scores after liver resection in hepatocellular carcinoma: the MSKCC, SLICER and SSCLIP scores. AB - Predicting prognosis in hepatocellular carcinoma (HCC) aids clinical decision making and stratifies patient follow-up plans. There are currently three prognostic scores specific to liver resection of HCC published in the literature: the MSKCC, SLICER and SSCLIP scores. In this review, we highlight the methodology employed in the construction of these scores and discuss the strengths and weaknesses of each. Current limitations to prognostic scores include the inability to differentiate between early and late recurrences of HCC, the failure to account for the impact of aetiology of HCC and the assumption that ethnicity has no impact on disease process. Further scientific discoveries in these areas will allow for improvement in prognostication. The SLICER score is currently the most comprehensive. External validation of each score in cohorts of patients with different baseline demographics and clinical characteristics will be required to examine their stability and reliability. PMID- 27980084 TI - Utility of rapid on-site cytologic evaluation during endobronchial ultrasound with a guide sheath for peripheral pulmonary lesions. AB - Objective: The utility of rapid on-site evaluation during endobronchial ultrasound with a guide sheath for peripheral pulmonary lesions is unclear. The aim of this study was to evaluate the role of rapid on-site evaluation during endobronchial ultrasound with a guide sheath for peripheral pulmonary lesions. Methods: Consecutive patients who underwent endobronchial ultrasound with a guide sheath for the diagnosis of peripheral pulmonary lesions at our hospital between September 2012 and July 2014 were included in this retrospective study. Cytology slides were air-dried, and modified Giemsa (Diff-Quik) staining was used for rapid on-site evaluation. Additional smears were prepared for Papanicolaou staining and tissue samples were placed in formalin for histologic evaluation. The results of rapid on-site evaluation were compared with the final diagnoses of endobronchial ultrasound with a guide sheath. Results: A total of 718 cases were included in the study population. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of rapid on site evaluation during endobronchial ultrasound with a guide sheath for peripheral pulmonary lesions was 88.6%, 65.9%, 81.2%, 77.7% and 80.1%, respectively. There were no procedure-related deaths. Conclusions: Rapid on-site evaluation during endobronchial ultrasound with a guide sheath had high sensitivity for peripheral pulmonary lesions. When carrying out rapid on-site evaluation of transbronchial biopsy samples from peripheral pulmonary lesions, careful interpretation and clinical correlation are necessary. PMID- 27980085 TI - The feasibility and effectiveness of robot-assisted radical cystectomy after neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer. AB - Objectives: The aim of this study was to compare 29 muscle-invasive bladder cancer patients who received neoadjuvant chemotherapy (NAC) followed by immediate robot-assisted radical cystectomy (RARC) with those who underwent minimum incision endoscopic RC (MIE-RC). Methods: We retrospectively reviewed the charts of 430 consecutive patients who underwent RC and bilateral pelvic node dissection (PLND) between May 1994 and July 2016. Our study focused on patients with MIBC who had histologically confirmed stage T2-T4aN0M0 urothelial carcinoma of the bladder and received NAC prior to surgery. Accordingly, 225 patients were included in this analysis, of whom, 29 underwent RARC (RARC group) and 196 underwent MIE-RC (MIE-RC group). The primary endpoints in this study were the positive surgical margin (PSM) rate and lymph node (LN) count. Results: In the RARC group, 20 patients underwent RARC with intracorporeal urinary diversion and nine patients underwent RARC with extracorporeal urinary diversion. The median surgical duration for RC and bilateral PLND was 125 min in the RARC group and 98 min in the MIE-RC group (P < 0.001). The rate of PSM was 0% in the RARC group and 0.5% in the MIE-RC group. The median LN counts were 15 in the RARC group and 18 in the MIE-RC group. No intra-operative complication or mortality was associated with RARC or MIE-RP. All complications were grade 2 according to the Clavien Dindo classification. Conclusions: Our initial experience with NAC followed by RARC appears to be favorable, with acceptable operative and perioperative clinical outcomes when compared with those of MIE-RC. PMID- 27980087 TI - Extensive water ice within Ceres' aqueously altered regolith: Evidence from nuclear spectroscopy. AB - The surface elemental composition of dwarf planet Ceres constrains its regolith ice content, aqueous alteration processes, and interior evolution. Using nuclear spectroscopy data acquired by NASA's Dawn mission, we determined the concentrations of elemental hydrogen, iron, and potassium on Ceres. The data show that surface materials were processed by the action of water within the interior. The non-icy portion of Ceres' carbon-bearing regolith contains similar amounts of hydrogen to those present in aqueously altered carbonaceous chondrites; however, the concentration of iron on Ceres is lower than in the aforementioned chondrites. This allows for the possibility that Ceres experienced modest ice rock fractionation, resulting in differences between surface and bulk composition. At mid-to-high latitudes, the regolith contains high concentrations of hydrogen, consistent with broad expanses of water ice, confirming theoretical predictions that ice can survive for billions of years just beneath the surface. PMID- 27980090 TI - Overview: metabolomics and lipidomics in nutrition and metabolism research. PMID- 27980089 TI - Structure of a yeast step II catalytically activated spliceosome. AB - Each cycle of precursor messenger RNA (pre-mRNA) splicing comprises two sequential reactions, first freeing the 5' exon and generating an intron lariat 3' exon and then ligating the two exons and releasing the intron lariat. The second reaction is executed by the step II catalytically activated spliceosome (known as the C* complex). Here, we present the cryo-electron microscopy structure of a C* complex from Saccharomyces cerevisiae at an average resolution of 4.0 angstroms. Compared with the preceding spliceosomal complex (C complex), the lariat junction has been translocated by 15 to 20 angstroms to vacate space for the incoming 3'-exon sequences. The step I splicing factors Cwc25 and Yju2 have been dissociated from the active site. Two catalytic motifs from Prp8 (the 1585 loop and the beta finger of the ribonuclease H-like domain), along with the step II splicing factors Prp17 and Prp18 and other surrounding proteins, are poised to assist the second transesterification. These structural features, together with those reported for other spliceosomal complexes, yield a near complete mechanistic picture on the splicing cycle. PMID- 27980088 TI - Architecture of the yeast small subunit processome. AB - The small subunit (SSU) processome, a large ribonucleoprotein particle, organizes the assembly of the eukaryotic small ribosomal subunit by coordinating the folding, cleavage, and modification of nascent pre-ribosomal RNA (rRNA). Here, we present the cryo-electron microscopy structure of the yeast SSU processome at 5.1 angstrom resolution. The structure reveals how large ribosome biogenesis complexes assist the 5' external transcribed spacer and U3 small nucleolar RNA in providing an intertwined RNA-protein assembly platform for the separate maturation of 18S rRNA domains. The strategic placement of a molecular motor at the center of the particle further suggests a mechanism for mediating conformational changes within this giant particle. This study provides a structural framework for a mechanistic understanding of eukaryotic ribosome assembly in the model organism Saccharomyces cerevisiae. PMID- 27980086 TI - CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells. AB - The human genome produces thousands of long noncoding RNAs (lncRNAs)-transcripts >200 nucleotides long that do not encode proteins. Although critical roles in normal biology and disease have been revealed for a subset of lncRNAs, the function of the vast majority remains untested. We developed a CRISPR interference (CRISPRi) platform targeting 16,401 lncRNA loci in seven diverse cell lines, including six transformed cell lines and human induced pluripotent stem cells (iPSCs). Large-scale screening identified 499 lncRNA loci required for robust cellular growth, of which 89% showed growth-modifying function exclusively in one cell type. We further found that lncRNA knockdown can perturb complex transcriptional networks in a cell type-specific manner. These data underscore the functional importance and cell type specificity of many lncRNAs. PMID- 27980091 TI - Metabolism of bile acids in the post-prandial state. AB - The modulation of energy expenditure by dietary administration of cholic acid in mice promoted interest in studying bile acid(s) (BA) as adjuvants in the treatment of metabolic diseases such as obesity and diabetes. Bile acids can modulate intermediary metabolism by acting directly on nuclear as well as G protein-coupled receptors or indirectly through changes in gut microbiota. Despite the potential of BA to affect intermediary metabolism, plasma kinetics and changes in individual BA in blood in the post-prandial state have been neglected for a long time. Minutes after ingestion of a meal (or a glucose challenge), the plasma BA concentration increases as a result of the secretion of bile into the duodenum, followed by intestinal absorption and a systemic circulation spillover. A large inter-individual variability of post-prandial kinetics of plasma BA is documented. Factors such as gender, diet composition, circadian oscillations, and individual capacities for the synthesis and transport of BA play important roles in determining this variability and are discussed in the present short review in light of new findings. PMID- 27980092 TI - Solution state nuclear magnetic resonance spectroscopy for biological metabolism and pathway intermediate analysis. AB - Using nuclear magnetic resonance (NMR) spectroscopy in the study of metabolism has been immensely popular in medical- and health-related research but has yet to be widely applied to more fundamental biological problems. This review provides some NMR background relevant to metabolism, describes why 1H NMR spectra are complex as well as introducing relevant terminology and definitions. The applications and practical considerations of NMR metabolic profiling and 13C NMR based flux analyses are discussed together with the elegant 'enzyme trap' approach for identifying novel metabolic pathway intermediates. The importance of sample preparation and data analysis are also described and explained with reference to data precision and multivariate analysis to introduce researchers unfamiliar with NMR and metabolism to consider this technique for their research interests. Finally, a brief glance into the future suggests NMR-based metabolism has room to expand in the 21st century through new isotope labels, and NMR technologies and methodologies. PMID- 27980093 TI - The application of metabolomics for herbal medicine pharmacovigilance: a case study on ginseng. AB - Herbal medicines are growing in popularity, use and commercial value; however, there remain problems with the quality and consequently safety of these products. Adulterated, contaminated and fraudulent products are often found on the market, a risk compounded by the fact that these products are available to consumers with little or no medical advice. Current regulations and quality control methods are lacking in their ability to combat these serious problems. Metabolomics is a biochemical profiling tool that may help address these issues if applied to quality control of both raw ingredients and final products. Using the example of the popular herbal medicine, ginseng, this essay offers an overview of the potential use of metabolomics for quality control in herbal medicines and also highlights where more research is needed. PMID- 27980094 TI - Adipose tissue development and the molecular regulation of lipid metabolism. AB - The production of new adipocytes is required to maintain adipose tissue mass and involves the proliferation and differentiation of adipocyte precursor cells (APCs). In this review, we outline new developments in understanding the phenotype of APCs and provide evidence suggesting that APCs differ between distinct adipose tissue depots and are affected by obesity. Post-mitotic mature adipocytes regulate systemic lipid homeostasis by storing and releasing free fatty acids, and also modulate energy balance via the secretion of adipokines. The review highlights recent advances in understanding the cellular and molecular mechanisms regulating adipocyte metabolism, with a particular focus on lipolysis regulation and the involvement of microribonucleic acids (miRNAs). PMID- 27980095 TI - Metabolomics in nutrition research-a powerful window into nutritional metabolism. AB - Metabolomics is the study of small molecules present in biological samples. In recent years it has become evident that such small molecules, called metabolites, play a key role in the development of disease states. Furthermore, metabolomic applications can reveal information about alterations in certain metabolic pathways under different conditions. Data acquisition in metabolomics is usually performed using nuclear magnetic resonance (NMR)-based approaches or mass spectrometry (MS)-based approaches with a more recent trend including the application of multiple platforms in order to maximise the coverage in terms of metabolites measured. The application of metabolomics is rapidly increasing and the present review will highlight applications in nutrition research. PMID- 27980096 TI - Homozygous and hemizygous CNV detection from exome sequencing data in a Mendelian disease cohort. AB - We developed an algorithm, HMZDelFinder, that uses whole exome sequencing (WES) data to identify rare and intragenic homozygous and hemizygous (HMZ) deletions that may represent complete loss-of-function of the indicated gene. HMZDelFinder was applied to 4866 samples in the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) cohort and detected 773 HMZ deletion calls (567 homozygous or 206 hemizygous) with an estimated sensitivity of 86.5% (82% for single-exonic and 88% for multi-exonic calls) and precision of 78% (53% single-exonic and 96% for multi exonic calls). Out of 773 HMZDelFinder-detected deletion calls, 82 were subjected to array comparative genomic hybridization (aCGH) and/or breakpoint PCR and 64 were confirmed. These include 18 single-exon deletions out of which 8 were exclusively detected by HMZDelFinder and not by any of seven other CNV detection tools examined. Further investigation of the 64 validated deletion calls revealed at least 15 pathogenic HMZ deletions. Of those, 7 accounted for 17-50% of pathogenic CNVs in different disease cohorts where 7.1-11% of the molecular diagnosis solved rate was attributed to CNVs. In summary, we present an algorithm to detect rare, intragenic, single-exon deletion CNVs using WES data; this tool can be useful for disease gene discovery efforts and clinical WES analyses. PMID- 27980097 TI - Large-scale mapping of mammalian transcriptomes identifies conserved genes associated with different cell states. AB - Distinguishing cell states based only on gene expression data remains a challenging task. This is true even for analyses within a species. In cross species comparisons, the results obtained by different groups have varied widely. Here, we integrate RNA-seq data from more than 40 cell and tissue types of four mammalian species to identify sets of associated genes as indicators for specific cell states in each species. We employ a statistical method, TROM, to identify both protein-coding and non-coding indicators. Next, we map the cell states within each species and also between species using these indicator genes. We recapitulate known phenotypic similarity between related cell and tissue types and reveal molecular basis for their similarity. We also report novel associations between several tissues and cell types with functional support. Moreover, our identified conserved associated genes are found to be a good resource for studying cell differentiation and reprogramming. Lastly, long non coding RNAs can serve well as associated genes to indicate cell states. We further infer the biological functions of those non-coding associated genes based on their co-expressed protein-coding genes. This study demonstrates that combining statistical modeling with public RNA-seq data can be powerful for improving our understanding of cell identity control. PMID- 27980100 TI - Synthetic spike-in standards for high-throughput 16S rRNA gene amplicon sequencing. AB - High-throughput sequencing of 16S rRNA gene amplicons (16S-seq) has become a widely deployed method for profiling complex microbial communities but technical pitfalls related to data reliability and quantification remain to be fully addressed. In this work, we have developed and implemented a set of synthetic 16S rRNA genes to serve as universal spike-in standards for 16S-seq experiments. The spike-ins represent full-length 16S rRNA genes containing artificial variable regions with negligible identity to known nucleotide sequences, permitting unambiguous identification of spike-in sequences in 16S-seq read data from any microbiome sample. Using defined mock communities and environmental microbiota, we characterized the performance of the spike-in standards and demonstrated their utility for evaluating data quality on a per-sample basis. Further, we showed that staggered spike-in mixtures added at the point of DNA extraction enable concurrent estimation of absolute microbial abundances suitable for comparative analysis. Results also underscored that template-specific Illumina sequencing artifacts may lead to biases in the perceived abundance of certain taxa. Taken together, the spike-in standards represent a novel bioanalytical tool that can substantially improve 16S-seq-based microbiome studies by enabling comprehensive quality control along with absolute quantification. PMID- 27980099 TI - The BioGRID interaction database: 2017 update. AB - The Biological General Repository for Interaction Datasets (BioGRID: https://thebiogrid.org) is an open access database dedicated to the annotation and archival of protein, genetic and chemical interactions for all major model organism species and humans. As of September 2016 (build 3.4.140), the BioGRID contains 1 072 173 genetic and protein interactions, and 38 559 post translational modifications, as manually annotated from 48 114 publications. This dataset represents interaction records for 66 model organisms and represents a 30% increase compared to the previous 2015 BioGRID update. BioGRID curates the biomedical literature for major model organism species, including humans, with a recent emphasis on central biological processes and specific human diseases. To facilitate network-based approaches to drug discovery, BioGRID now incorporates 27 501 chemical-protein interactions for human drug targets, as drawn from the DrugBank database. A new dynamic interaction network viewer allows the easy navigation and filtering of all genetic and protein interaction data, as well as for bioactive compounds and their established targets. BioGRID data are directly downloadable without restriction in a variety of standardized formats and are freely distributed through partner model organism databases and meta-databases. PMID- 27980101 TI - Evaluation of Nonpeptidic Ligand Conjugates for the Treatment of Hypoxic and Carbonic Anhydrase IX-Expressing Cancers. AB - The majority of tumors contain regions of hypoxia, which cause marked phenotypic changes to resident cells. This altered gene expression often leads to increased resistance to anticancer treatments. Therefore, elimination of these resistant hypoxic cells is crucial to prevent disease recurrence. Herein, we describe the selective delivery of imaging and chemotherapeutic agents to cells expressing carbonic anhydrase IX (CA IX), a highly upregulated hypoxia receptor. These agents were conjugated to a potent divalent CA IX ligand through a hydrophilic PEG linker. These conjugates are shown to bind CA IX-expressing cells in a receptor-dependent manner in vitro with mid-nanomolar affinities and in vivo with good tumor selectivity. In a mouse xenograft tumor model using HT-29 cells, a cytotoxic tubulysin B conjugate completely inhibited tumor growth. Overall, the targeting of a hypoxia marker, such as CA IX, to selectively deliver imaging or chemotherapeutic agents may lead to better treatment options for solid, hypoxic tumors. In addition, the combination of standard chemotherapeutics that are most potent in normoxic dividing cells and drugs specifically designed to eliminate hypoxic nondividing cells may elicit a superior clinical outcome. Mol Cancer Ther; 16(3); 453-60. (c)2016 AACR. PMID- 27980102 TI - Blocking the CCL2-CCR2 Axis Using CCL2-Neutralizing Antibody Is an Effective Therapy for Hepatocellular Cancer in a Mouse Model. AB - Hepatocellular carcinoma, a deadly disease, commonly arises in the setting of chronic inflammation. C-C motif chemokine ligand 2 (CCL2/MCP1), a chemokine that recruits CCR2-positive immune cells to promote inflammation, is highly upregulated in hepatocellular carcinoma patients. Here, we examined the therapeutic efficacy of CCL2-CCR2 axis inhibitors against hepatitis and hepatocellular carcinoma in the miR-122 knockout (a.k.a. KO) mouse model. This mouse model displays upregulation of hepatic CCL2 expression, which correlates with hepatitis that progress to hepatocellular carcinoma with age. Therapeutic potential of CCL2-CCR2 axis blockade was determined by treating KO mice with a CCL2-neutralizing antibody (nAb). This immunotherapy suppressed chronic liver inflammation in these mice by reducing the population of CD11highGr1+ inflammatory myeloid cells and inhibiting expression of IL6 and TNFalpha in KO livers. Furthermore, treatment of tumor-bearing KO mice with CCL2 nAb for 8 weeks significantly reduced liver damage, hepatocellular carcinoma incidence, and tumor burden. Phospho-STAT3 (Y705) and c-MYC, the downstream targets of IL6, as well as NF-kappaB, the downstream target of TNFalpha, were downregulated upon CCL2 inhibition, which correlated with suppression of tumor growth. In addition, CCL2 nAb enhanced hepatic NK-cell cytotoxicity and IFNgamma production, which is likely to contribute to the inhibition of tumorigenesis. Collectively, these results demonstrate that CCL2 immunotherapy could be an effective therapeutic approach against inflammatory liver disease and hepatocellular carcinoma. Mol Cancer Ther; 16(2); 312-22. (c)2016 AACR. PMID- 27980104 TI - The FA/BRCA Pathway Identified as the Major Predictor of Cisplatin Response in Head and Neck Cancer by Functional Genomics. AB - Patients with advanced stage head and neck squamous cell carcinoma (HNSCC) are often treated with cisplatin-containing chemoradiation protocols. Although cisplatin is an effective radiation sensitizer, it causes severe toxicity and not all patients benefit from the combination treatment. HNSCCs expectedly not responding to cisplatin may better be treated with surgery and postoperative radiation or cetuximab and radiation, but biomarkers to personalize chemoradiotherapy are not available. We performed an unbiased genome-wide functional genetic screen in vitro to identify genes that influence the response to cisplatin in HNSCC cells. By siRNA-mediated knockdown, we identified the Fanconi anemia/BRCA pathway as the predominant pathway for cisplatin response in HNSCC cells. We also identified the involvement of the SHFM1 gene in the process of DNA cross-link repair. Furthermore, expression profiles based on these genes predict the prognosis of radiation- and chemoradiation-treated head and neck cancer patients. This genome-wide functional analysis designated the genes that are important in the response of HNSCC to cisplatin and may guide further biomarker validation. Cisplatin imaging as well as biomarkers that indicate the activity of the Fanconi anemia/BRCA pathway in the tumors are the prime candidates. Mol Cancer Ther; 16(3); 540-50. (c)2016 AACR. PMID- 27980103 TI - Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome. AB - Epigenetic drugs, such as DNA methylation inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi), are approved in monotherapy for cancer treatment. These drugs reprogram gene expression profiles, reactivate tumor suppressor genes (TSG) producing cancer cell differentiation and apoptosis. Epigenetic drugs have been shown to synergize with other epigenetic drugs or various anticancer drugs. To discover new molecular entities that enhance epigenetic therapy, we performed a high-throughput screening using FDA-approved libraries in combination with DNMTi or HDACi. As a screening model, we used YB5 system, a human colon cancer cell line, which contains an epigenetically silenced CMV-GFP locus, mimicking TSG silencing in cancer. CMV-GFP reactivation is triggered by DNMTi or HDACi and responds synergistically to DNMTi/HDACi combination, which phenocopies TSG reactivation upon epigenetic therapy. GFP fluorescence was used as a quantitative readout for epigenetic activity. We discovered that 45 FDA-approved drugs (4% of all drugs tested) in our FDA-approved libraries enhanced DNMTi and HDACi activity, mainly belonging to anticancer and antiarrhythmic drug classes. Transcriptome analysis revealed that combination of decitabine (DNMTi) with the antiarrhythmic proscillaridin A produced profound gene expression reprogramming, which was associated with downregulation of 153 epigenetic regulators, including two known oncogenes in colon cancer (SYMD3 and KDM8). Also, we identified about 85 FDA-approved drugs that antagonized DNMTi and HDACi activity through cytotoxic mechanisms, suggesting detrimental drug interactions for patients undergoing epigenetic therapy. Overall, our drug screening identified new combinations of epigenetic and FDA-approved drugs, which can be rapidly implemented into clinical trials. Mol Cancer Ther; 16(2); 397-407. (c)2016 AACR. PMID- 27980105 TI - The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737. AB - The identification of novel therapeutic strategies is an important urgent requirement for the clinical management of ovarian cancer, which remains the leading cause of death from gynecologic cancer. Several studies have shown that the antiapoptotic proteins Bcl-xL and Mcl-1, as well as the proapoptotic protein Bim, are key elements to be modulated to kill ovarian cancer cells. Pharmacologic inhibition of Bcl-xL is possible by using BH3-mimetic molecules like ABT-737. However, inhibition of Mcl-1 and/or promotion of its BH3-only partners (including Bim, Puma, and Noxa) remains a challenge that may be achieved by modulating the signaling pathways upstream. This study sought whether AZD8055-induced mTOR inhibition and/or trametinib-induced MEK inhibition could modulate Mcl-1 and its partners to decrease the Mcl-1/BH3-only ratio and thus sensitize various ovarian cancer cell lines to ABT-737. AZD8055 treatment inhibited Mcl-1 and increased Puma expression but did not induce massive apoptosis in combination with ABT-737. In contrast, trametinib, which decreased the Mcl-1/BH3-only protein ratio by upregulating Puma and dephosphorylated active Bim, sensitized IGROV1-R10 and OVCAR3 cells to ABT-737. Adding AZD8055 to trametinib further reduced the Mcl 1/BH3-only protein ratio and triggered apoptosis without ABT-737 in IGROV1-R10 cells. Moreover, the AZD8055/trametinib association highly sensitized all cell lines including SKOV3 to ABT-737, the induced dephosphorylated Bim being crucial in this sensitization. Finally, the three-drug combination was also very efficient when replacing AZD8055 by the pan-Akt inhibitor MK-2206. This study thus proposes original multitargeted strategies and may have important implications for the design of novel approaches for ovarian cancer treatment. Mol Cancer Ther; 16(1); 102-15. (c)2016 AACR. PMID- 27980106 TI - Imatinib Spares cKit-Expressing Prostate Neuroendocrine Tumors, whereas Kills Seminal Vesicle Epithelial-Stromal Tumors by Targeting PDGFR-beta. AB - Prostate cancer is a leading cause of cancer-related death in males worldwide. Indeed, advanced and metastatic disease characterized by androgen resistance and often associated with neuroendocrine (NE) differentiation remains incurable. Using the spontaneous prostate cancer TRAMP model, we have shown that mast cells (MCs) support in vivo the growth of prostate adenocarcinoma, whereas their genetic or pharmacologic targeting favors prostate NE cancer arousal. Aiming at simultaneously targeting prostate NE tumor cells and MCs, both expressing the cKit tyrosine kinase receptor, we have tested the therapeutic effect of imatinib in TRAMP mice. Imatinib-treated TRAMP mice experience a partial benefit against prostate adenocarcinoma, because of inhibition of supportive MCs. However, they show an unexpected outgrowth of prostate NE tumors, likely because of defective signaling pathway downstream of cKit receptor. Also unexpected but very effective was the inhibition of epithelial-stromal tumors of the seminal vesicles achieved by imatinib treatment. These tumors normally arise in the seminal vesicles of TRAMP mice, independently of the degree of prostatic glandular lesions, and resemble phyllodes tumors found in human prostate and seminal vesicles, and in breast. In both mice and in patients, these tumors are negative for cKit but express PDGFR-beta, another tyrosine kinase receptor specifically inhibited by imatinib. Our results imply a possible detrimental effect of imatinib in prostate cancer patients but suggest a promising therapeutic application of imatinib in the treatment of recurrent or metastatic phyllodes tumors. Mol Cancer Ther; 16(2); 365-75. (c)2016 AACR. PMID- 27980107 TI - Niclosamide Inhibits Oxaliplatin Neurotoxicity while Improving Colorectal Cancer Therapeutic Response. AB - Neuropathic pain is a limiting factor of platinum-based chemotherapies. We sought to investigate the neuroprotective potential of niclosamide in peripheral neuropathies induced by oxaliplatin. Normal neuron-like and cancer cells were treated in vitro with oxaliplatin associated or not with an inhibitor of STAT3 and NF-kappaB, niclosamide. Cell production of reactive oxygen species and viability were measured by 2',7'-dichlorodihydrofluorescein diacetate and crystal violet. Peripheral neuropathies were induced in mice by oxaliplatin with or without niclosamide. Neurologic functions were assessed by behavioral and electrophysiologic tests, intraepidermal innervation, and myelination by immunohistochemical, histologic, and morphologic studies using confocal microscopy. Efficacy on tumor growth was assessed in mice grafted with CT26 colon cancer cells. In neuron-like cells, niclosamide downregulated the production of oxaliplatin-mediated H2O2, thereby preventing cell death. In colon cancer cells, niclosamide enhanced oxaliplatin-mediated cell death through increased H2O2 production. These observations were explained by inherent lower basal levels of GSH in cancer cells compared with normal and neuron-like cells. In neuropathic mice, niclosamide prevented tactile hypoesthesia and thermal hyperalgesia and abrogated membrane hyperexcitability. The teniacide also prevented intraepidermal nerve fiber density reduction and demyelination in oxaliplatin mice in this mixed form of peripheral neuropathy. Niclosamide prevents oxaliplatin-induced increased levels of IL6, TNFalpha, and advanced oxidized protein products. Niclosamide displayed antitumor effects while not abrogating oxaliplatin efficacy. These results indicate that niclosamide exerts its neuroprotection both in vitro and in vivo by limiting oxaliplatin-induced oxidative stress and neuroinflammation. These findings identify niclosamide as a promising therapeutic adjunct to oxaliplatin chemotherapy. Mol Cancer Ther; 16(2); 300-11. (c)2016 AACR. PMID- 27980108 TI - Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers. AB - Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYC-driven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD-NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYC-dependent cancers. Mol Cancer Ther; 16(2); 285-99. (c)2016 AACR. PMID- 27980109 TI - Folate-Hapten-Mediated Immunotherapy Synergizes with Vascular Endothelial Growth Factor Receptor Inhibitors in Treating Murine Models of Cancer. AB - The overexpression of folate receptors (FR) on many human cancers has led to the development of folate-linked drugs for the imaging and therapy of FR-expressing cancers. In a recent phase I clinical trial of late-stage renal cell carcinoma patients, folate was exploited to deliver an immunogenic hapten, fluorescein, to FR+ tumor cells in an effort to render the cancer cells more immunogenic. Although >50% of the patients showed prolonged stable disease, all patients eventually progressed, suggesting that the folate-hapten immunotherapy was insufficient by itself to treat the cancer. In an effort to identify a companion therapy that might augment the folate-hapten immunotherapy, we explored coadministration of two approved cancer drugs that had been previously shown to also stimulate the immune system. We report that sunitinib and axitinib (VEGF receptor inhibitors that simultaneously mitigate immune suppression) synergize with the folate-hapten-targeted immunotherapy to reduce tumor growth in three different syngeneic murine tumor models. We further demonstrate that the combination therapy not only enhances tumor infiltration of CD4+ and CD8+ effector cells, but surprisingly reduces tumor neovasculogenesis more than predicted. Subsequent investigation of the mechanism for this unexpected suppression of neovasculogenesis revealed that it is independent of elimination of any tumor cells, but instead likely derives from a reduction in the numbers of FR+ tumor-associated macrophages and myeloid-derived suppressor cells, that is, immunosuppressive cells that release significant quantities of VEGF. These data suggest that a reduction in stromal cells of myeloid origin can inhibit tumor growth by suppressing neovasculogenesis. Mol Cancer Ther; 16(3); 461-8. (c)2016 AACR. PMID- 27980120 TI - Production and characterization of functional recombinant hybrid heteropolymers of camel hepcidin and human ferritin H and L chains. AB - Hepcidin is a liver-synthesized hormone that plays a central role in the regulation of systemic iron homeostasis. To produce a new tool for its functional properties the cDNA coding for camel hepcidin-25 was cloned at the 5'end of human FTH sequence into the pASK-IBA43plus vector for expression in Escherichia coli The recombinant fusion hepcidin-ferritin-H subunit was isolated as an insoluble iron-containing protein. When alone it did not refold in a 24-mer ferritin molecule, but it did when renatured together with H- or L-ferritin chains. We obtained stable ferritin shells exposing about 4 hepcidin peptides per 24-mer shell. The molecules were then reduced and re-oxidized in a controlled manner to allow the formation of the proper hepcidin disulfide bridges. The functionality of the exposed hepcidin was confirmed by its ability to specifically bind the mouse macrophage cell line J774 that express ferroportin and to promote ferroportin degradation. This chimeric protein may be useful for studying the hepcidin-ferroportin interaction in cells and also as drug-delivery agent. PMID- 27980121 TI - Chimeric approach for narrowing a membrane-inserting region within human perforin. AB - Perforin is a pore-forming, immune protein that functions to deliver an apoptotic cocktail of proteins into a target pathogen. Recent studies of the bacterial cholesterol-dependent cytolysins (CDCs) have provided a model for perforin's pore forming mechanism. Both perforin and CDC family members share a conserved beta sheet flanked by two clusters of alpha-helices. Within the CDCs, these helices refold into two transmembrane beta-hairpins, TMH1 and TMH2. Based upon structural conservation and electron microscopy imaging, the analogous helices within perforin are predicted to also be membrane inserting; however, these regions are approximately twice the length of the CDC TMHs. To test the membrane-insertion potential of one of these regions, chimeras were created using a well characterized CDC, perfringolysin-O (PFO), as the backbone of these constructs. PFO's TMH2 region was replaced with perforin's corresponding helical region. Although hemolytic activity was observed, the chimera was poorly soluble. A second chimera contained the same region truncated to match the length of the PFO TMH2 region. The truncated chimera demonstrated improved solubility, significant hemolytic activity and the ability to form pores characteristic of those created by PFO. These results provide the first evidence that perforin's helices function as TMHs and more importantly narrows the residues responsible for membrane insertion. PMID- 27980122 TI - Modular control during incline and level walking in humans. AB - The neuromuscular control of human movement can be described by a set of muscle synergies factorized from myoelectric signals. There is some evidence that the selection, activation and flexible combination of these basic activation patterns are of a neural origin. We investigated the muscle synergies during incline and level walking to evaluate changes in the modular organization of neuromuscular control related to changes in the mechanical demands. Our results revealed five fundamental (not further factorizable) synergies for both walking conditions but with different frequencies of appearance of the respective synergies during incline compared with level walking. Low similarities across conditions were observed in the timing of the activation patterns (motor primitives) and the weightings of the muscles within the respective elements (motor modules) for the synergies associated with the touchdown, mid-stance and early push-off phase. The changes in neuromuscular control could be attributed to changes in the mechanical demands in support, propulsion and medio-lateral stabilization of the body during incline compared with level walking. Our findings provide further evidence that the central nervous system flexibly uses a consistent set of neural control elements with a flexible temporal recruitment and modifications of the relative muscle weightings within each element to provide stable locomotion under varying mechanical demands during walking. PMID- 27980123 TI - Integrating gastrocnemius force-length properties, in vivo activation and operating lengths reveals how Anolis deal with ecological challenges. AB - A central question in biology is how animals successfully behave under complex natural conditions. Although changes in locomotor behaviour, motor control and force production in relation to incline are commonly examined, a wide range of other factors, including a range of perch diameters, pervades arboreal habitats. Moving on different substrate diameters requires considerable alteration of body and limb posture, probably causing significant shifts in the lengths of the muscle-tendon units powering locomotion. Thus, how substrate shape impacts in vivo muscle function remains an important but neglected question in ecophysiology. Here, we used high-speed videography, electromyography, in situ contractile experiments and morphology to examine gastrocnemius muscle function during arboreal locomotion in the Cuban knight anole, Anolis equestris The gastrocnemius contributes more to the propulsive effort on broad surfaces than on narrow surfaces. Surprisingly, substrate inclination affected the relationship between the maximum potential force and fibre recruitment; the trade-off that was present between these variables on horizontal surfaces became a positive relationship on inclined surfaces. Finally, the biarticular nature of the gastrocnemius allows it to generate force isometrically, regardless of substrate diameter and incline, despite the fact that the tendons are incapable of stretching during cyclical locomotion. Our results emphasize the importance of considering ecology and muscle function together, and the necessity of examining both mechanical and physiological properties of muscles to understand how animals move in their environment. PMID- 27980124 TI - Right-to-left shunt has modest effects on CO2 delivery to the gut during digestion, but compromises oxygen delivery. AB - By virtue of their cardiovascular anatomy, reptiles and amphibians can shunt blood away from the pulmonary or systemic circuits, but the functional role of this characteristic trait remains unclear. It has been suggested that right-to left (R-L) shunt (recirculation of systemic blood within the body) fuels the gastric mucosa with acidified and CO2-rich blood to facilitate gastric acid secretion during digestion. However, in addition to elevating PCO2 , R-L shunt also reduces arterial O2 levels and would compromise O2 delivery during the increased metabolic state of digestion. Conversely, arterial PCO2 can also be elevated by lowering ventilation relative to metabolism (i.e. reducing the air convection requirement, ACR). Based on a mathematical analysis of the relative roles of ACR and R-L shunt on O2 and CO2 levels, we predict that ventilatory modifications are much more effective for gastric CO2 supply with only modest effects on O2 delivery. Conversely, elevating CO2 levels by means of R-L shunt would come at a cost of significant reductions in O2 levels. The different effects of altering ACR and R-L shunt on O2 and CO2 levels are explained by the differences in the effective blood capacitance coefficients. PMID- 27980125 TI - Warm preconditioning protects against acute heat-induced respiratory dysfunction and delays bleaching in a symbiotic sea anemone. AB - Preconditioning to non-stressful warming can protect some symbiotic cnidarians against the high temperature-induced collapse of their mutualistic endosymbiosis with photosynthetic dinoflagellates (Symbiodinium spp.), a process known as bleaching. Here, we sought to determine whether such preconditioning is underpinned by differential regulation of aerobic respiration. We quantified in vivo metabolism and mitochondrial respiratory enzyme activity in the naturally symbiotic sea anemone Exaiptasia pallida preconditioned to 30 degrees C for >7 weeks as well as anemones kept at 26 degrees C. Preconditioning resulted in increased Symbiodinium photosynthetic activity and holobiont (host+symbiont) respiration rates. Biomass-normalised activities of host respiratory enzymes [citrate synthase and the mitochondrial electron transport chain (mETC) complexes I and IV] were higher in preconditioned animals, suggesting that increased holobiont respiration may have been due to host mitochondrial biogenesis and/or enlargement. Subsequent acute heating of preconditioned and 'thermally naive' animals to 33 degrees C induced dramatic increases in host mETC complex I and Symbiodinium mETC complex II activities only in thermally naive E. pallida These changes were not reflected in the activities of other respiratory enzymes. Furthermore, bleaching in preconditioned E. pallida (defined as the significant loss of symbionts) was delayed by several days relative to the thermally naive group. These findings suggest that changes to mitochondrial biogenesis and/or function in symbiotic cnidarians during warm preconditioning might play a protective role during periods of exposure to stressful heating. PMID- 27980126 TI - Prevention of Stroke in Patients With Silent Cerebrovascular Disease: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. AB - Two decades of epidemiological research shows that silent cerebrovascular disease is common and is associated with future risk for stroke and dementia. It is the most common incidental finding on brain scans. To summarize evidence on the diagnosis and management of silent cerebrovascular disease to prevent stroke, the Stroke Council of the American Heart Association convened a writing committee to evaluate existing evidence, to discuss clinical considerations, and to offer suggestions for future research on stroke prevention in patients with 3 cardinal manifestations of silent cerebrovascular disease: silent brain infarcts, magnetic resonance imaging white matter hyperintensities of presumed vascular origin, and cerebral microbleeds. The writing committee found strong evidence that silent cerebrovascular disease is a common problem of aging and that silent brain infarcts and white matter hyperintensities are associated with future symptomatic stroke risk independently of other vascular risk factors. In patients with cerebral microbleeds, there was evidence of a modestly increased risk of symptomatic intracranial hemorrhage in patients treated with thrombolysis for acute ischemic stroke but little prospective evidence on the risk of symptomatic hemorrhage in patients on anticoagulation. There were no randomized controlled trials targeted specifically to participants with silent cerebrovascular disease to prevent stroke. Primary stroke prevention is indicated in patients with silent brain infarcts, white matter hyperintensities, or microbleeds. Adoption of standard terms and definitions for silent cerebrovascular disease, as provided by prior American Heart Association/American Stroke Association statements and by a consensus group, may facilitate diagnosis and communication of findings from radiologists to clinicians. PMID- 27980127 TI - Venous Thrombotic Recurrence After Cerebral Venous Thrombosis: A Long-Term Follow Up Study. AB - BACKGROUND AND PURPOSE: After cerebral venous thrombosis (CVT), the risk of venous thrombotic events was estimated at 2% to 3% for a new CVT and 3% to 8% for extracranial events. However, because of the paucity of prospective studies, the clinical course of CVT is still largely unknown. We aimed to prospectively evaluate the rate of thrombosis recurrence in a cohort of CVT patients with a long-term follow-up and to detect predisposing factors for recurrence. METHODS: Consecutive CVT patients with complete clinical, radiological, biological, and genetic data were systematically followed up. New venous thrombotic events were detected after hospital readmission and imaging confirmation. RESULTS: One hundred eighty-seven patients (mean age 45+/-18 years, 67% women) with angiographically confirmed CVT were included. Cause was found in 73% of patients. Coagulation abnormality and JAK2 gene mutation were detected in 20% and 9%, respectively. Median follow-up length was 73 months (range 1-247 months). Mean duration of the oral anticoagulant treatment was 14 months. Mortality rate was 2.5% per year, with 2% in-hospital mortality. During follow-up, CVT reoccurred in 6 patients, whereas 19 subjects had a symptomatic extracranial venous thrombotic event, with cumulative venous thrombotic recurrence rates of 3% at 1 year, 8% at 2 years, 12% at 5 years, and 18% at 10 years. A previous venous thrombotic event (hazard ratio, 2.8; P=0.018), presence of cancer or malignant hemopathies (hazard ratio, 3.2; P=0.039), and unknown CVT causes (hazard ratio, 2.81; P=0.024) were independently associated with recurrence. CONCLUSIONS: In our cohort of CVT patients followed on average for >6 years, subjects with a previous venous thrombotic event, cancer/malignant hemopathies, and unknown CVT causes were found to be at higher risk of recurrence. PMID- 27980128 TI - NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study): Randomized Controlled Contrast-Enhanced Sonothrombolysis in an Unselected Acute Ischemic Stroke Population. AB - BACKGROUND AND PURPOSE: The NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study) aimed to assess effect and safety of contrast-enhanced ultrasound treatment in an unselected acute ischemic stroke population. METHODS: Patients treated with intravenous thrombolysis within 4.5 hours after symptom onset were randomized 1:1 to either contrast-enhanced sonothrombolysis (CEST) or sham CEST. A visible arterial occlusion on baseline computed tomography angiography was not a prerequisite for inclusion. Pulse-wave 2 MHz ultrasound was given for 1 hour and contrast (SonoVue) as an infusion for ~30 minutes. Magnetic resonance imaging and angiography were performed after 24 to 36 hours. Primary study end points were neurological improvement at 24 hours defined as National Institutes of Health Stroke Scale score 0 or reduction of >=4 National Institutes of Health Stroke Scale points compared with baseline National Institutes of Health Stroke Scale and favorable functional outcome at 90 days defined as modified Rankin scale score 0 to 1. RESULTS: A total of 183 patients were randomly assigned to either CEST (93 patient) or sham CEST (90 patients). The rates of symptomatic intracerebral hemorrhage, asymptomatic intracerebral hemorrhage, or mortality were not increased in the CEST group. Neurological improvement at 24 hours and functional outcome at 90 days was similar in the 2 groups both in the intention to-treat analysis and in the per-protocol analysis. CONCLUSIONS: CEST is safe among unselected ischemic stroke patients with or without a visible occlusion on computed tomography angiography and with varying grades of clinical severity. There was, however, statistically no significant clinical effect of sonothrombolysis in this prematurely stopped trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01949961. PMID- 27980133 TI - Bovine TB: scheme to recognise farmers who practise good biosecurity. PMID- 27980129 TI - Three-Dimensional Map of Neonatal Arterial Ischemic Stroke Distribution From Early Multimodal Brain Imaging. AB - BACKGROUND AND PURPOSE: Although neonatal arterial ischemic stroke (NAIS) location has considerable impact on long-term outcome, a map showing spatial distribution of NAIS is lacking. Our aim was to generate this distribution map, based on early magnetic resonance imaging data. METHODS: Lesions from 34 consecutive neonates with NAIS from a single center were segmented using multimodal magnetic resonance imaging (median age at acquisition =5 days). Lesion masks for all subjects were registered onto a standard neonatal brain and then overlaid to generate a 3D map of NAIS distribution. RESULTS: The region posterior to the central sulcus is the most frequently affected in neonates, with 24 of the 34 neonates (71%) showing lesions in this region in at least one hemisphere. Moreover, NAIS frequency is markedly higher in the left hemisphere. CONCLUSIONS: This is the first report of an NAIS distribution map. Regions posterior to the central sulcus present increased vulnerability. Our findings suggest that motor areas are not as frequently affected as has been previously reported. By contrast, we find high NAIS vulnerability in functional areas related to language. The distribution of ischemic strokes in neonates seems to be different from that seen in adults. PMID- 27980130 TI - Insulinotropic effects of GPR120 agonists are altered in obese diabetic and obese non-diabetic states. AB - G-protein-coupled receptor 120 (GPR120) is a putative target for obesity and diabetes therapies. However, it remains controversial whether resident GPR120 plays a direct regulatory role in islet beta-cell insulin secretion. The present study examined this issue in isolated rodent islets and rat beta-cell line INS 1E, and assessed the role of GPR120 in islet insulin secretion in obese non diabetic (OND) and diabetic states. GPR120 expression was detected in rodent islet beta-cells. Docosahexaenoic acid (DHA) and synthetic GPR120 agonist GSK137647 (GSK) augmented insulin release from rat/mouse islets and INS-1E; DHA effects were partially mediated by GPR40. GPR120 knockdown and overexpression attenuated and enhanced DHA effects in INS-1E respectively. DHA and GSK improved postprandial hyperglycaemia of diabetic mice. Inhibition of calcium signalling in INS-1E reduced GPR120 activation-induced insulinotropic effects. The insulinotropic effects of DHA/GSK were amplified in OND rat islets, but diminished in diabetic rat islets. GPR120 and peroxisome proliferator-activated receptor gamma (PPARgamma) expression were elevated in OND islets and palmitic acid (PA)-treated INS-1E, but reduced in diabetic islets and high glucose-treated INS-1E. PPARgamma activation increased GPR120 expression in rat islets and INS 1E. DHA and GSK induced protein kinase B (Akt)/extracellular signal-regulated kinase (ERK) phosphorylation in rodent islets and INS-1E, and these effects were altered in OND and diabetic states. Taken together, the present study indicates that (i) GPR120 activation has an insulinotropic influence on beta-cells with the involvement of calcium signalling; (ii) GPR120 expression in beta-cells and GPR120-mediated insulinotropic effects are altered in OND and diabetic states in distinct ways, and these alterations may be mediated by PPARgamma. PMID- 27980141 TI - Big data, big opportunities. AB - The potential use of 'big data' in veterinary surveillance was highlighted by two speakers at the BVA Congress at the London Vet Show last month. Kathryn Clark reports. PMID- 27980136 TI - Veterinary academics win national teaching fellowships. PMID- 27980143 TI - Incorporating ethics into everyday practice. AB - The relevance of ethics to everyday veterinary practice and to animal welfare was explored in an interactive session during the BVA Congress at the London Vet Show last month. Kristy Ebanks reports. PMID- 27980144 TI - Mycoplasma wenyonii infection in dairy cows. AB - Mycoplasma wenyonii infection in two dairy herdsHypomagnesaemia in suckler cowsLeptospiral milk drop in dairy cowsNon-resolving orf in six-month-old lambsHepatosis dietetica in a five-month-old giltThese are among matters discussed in the disease surveillance report for September 2016 from SAC Consulting: Veterinary Services (SAC C VS). PMID- 27980146 TI - Unanswered questions on gastric dilatation/volvulus and gastropexy. PMID- 27980151 TI - EU vets and Brexit. PMID- 27980154 TI - Animal to human transmission of AMR. PMID- 27980153 TI - Bleeding disorders in calves. PMID- 27980155 TI - Empathy survey. PMID- 27980156 TI - Assessment of the unnecessary suffering offence. PMID- 27980158 TI - My working week: Hannah Jordan. AB - Hannah Jordan is a BVA policy officer, having previously been parliamentary intern to Lord Trees. She is also a triathlete. PMID- 27980157 TI - Leading a global veterinary community. AB - Canadian veterinarian Walt Ingwersen was recently elected as president of the World Small Animal Veterinary Association. Here, he describes the route his career has taken and why he became involved in the WSAVA. PMID- 27980160 TI - Science's rightful place. PMID- 27980159 TI - Mechanisms of bacterial persistence during stress and antibiotic exposure. AB - Bacterial persister cells avoid antibiotic-induced death by entering a physiologically dormant state and are considered a major cause of antibiotic treatment failure and relapsing infections. Such dormant cells form stochastically, but also in response to environmental cues, by various pathways that are usually controlled by the second messenger (p)ppGpp. For example, toxin antitoxin modules have been shown to play a major role in persister formation in many model systems. More generally, the diversity of molecular mechanisms driving persister formation is increasingly recognized as the cause of physiological heterogeneity that underlies collective multistress and multidrug tolerance of persister subpopulations. In this Review, we summarize the current state of the field and highlight recent findings, with a focus on the molecular basis of persister formation and heterogeneity. PMID- 27980161 TI - News at a glance. PMID- 27980162 TI - Antisense rescues babies from killer disease. PMID- 27980163 TI - In Canada, case spurs concern over misconduct secrecy. PMID- 27980164 TI - Cost of carbon capture drops, but does anyone want it? PMID- 27980165 TI - New bird flu strain brings death and questions. PMID- 27980166 TI - Trump team targets key climate metric. PMID- 27980167 TI - Some like it hot. PMID- 27980168 TI - After the vanishing. PMID- 27980169 TI - U.S. seafood import restriction presents opportunity and risk. PMID- 27980170 TI - How high will the seas rise? PMID- 27980171 TI - Starving the enemy. PMID- 27980172 TI - Toward sustainable fuel cells. PMID- 27980174 TI - John D. Roberts (1918-2016). PMID- 27980173 TI - Understanding induced seismicity. PMID- 27980175 TI - The calculators. PMID- 27980176 TI - The aftermath of AIDS in China. PMID- 27980177 TI - Retraction. PMID- 27980178 TI - Prioritizing good diets. PMID- 27980180 TI - Blowing harder and more often. PMID- 27980179 TI - Indirect impacts of climate change. PMID- 27980181 TI - A joint effect of bacteria and genetics. PMID- 27980182 TI - Diamonds rock their metal roots. PMID- 27980183 TI - Too many roads. PMID- 27980184 TI - Asymmetric catalysis by tuning triplets. PMID- 27980185 TI - Triggered quakes get unconventional. PMID- 27980186 TI - Volcano monitoring goes into the deep. PMID- 27980187 TI - Dueling for sugars. PMID- 27980188 TI - Getting rid of faulty mRNA. PMID- 27980189 TI - Defying the onslaught of antibiotics. PMID- 27980190 TI - An activity lift for platinum. PMID- 27980191 TI - Engineering control of cellular proteins. PMID- 27980192 TI - Rescuing stalled ribosomes. PMID- 27980193 TI - The seas will rise, but by how much? PMID- 27980195 TI - Structural insights into capsid flexibility. PMID- 27980194 TI - Preventing vascular calcification. PMID- 27980197 TI - Crawling cells need to explore. PMID- 27980196 TI - A star passing close to the solar system. PMID- 27980198 TI - Poor clock management and cancer. PMID- 27980199 TI - Crowd-sourced CRISPR-Cas responses. PMID- 27980200 TI - Inhibitor reduces heart muscle calcification. PMID- 27980202 TI - An ultrafast peek into the ultracold. PMID- 27980201 TI - Expanding access to gifted education. PMID- 27980203 TI - Enantioselective photochemistry through Lewis acid-catalyzed triplet energy transfer. AB - Relatively few catalytic systems are able to control the stereochemistry of electronically excited organic intermediates. Here we report the discovery that a chiral Lewis acid complex can catalyze triplet energy transfer from an electronically excited photosensitizer. We applied this strategy to asymmetric [2 + 2] photocycloadditions of 2'-hydroxychalcones, using tris(bipyridyl) ruthenium(II) as a sensitizer. A variety of electrochemical, computational, and spectroscopic data rule out substrate activation by means of photoinduced electron transfer and instead support a mechanism in which Lewis acid coordination dramatically lowers the triplet energy of the chalcone substrate. We expect that this approach will enable chemists to more broadly apply their detailed understanding of chiral Lewis acid catalysis to stereocontrol in reactions involving electronically excited states. PMID- 27980205 TI - Inflation-predictable behavior and co-eruption deformation at Axial Seamount. AB - Deformation of the ground surface at active volcanoes provides information about magma movements at depth. Improved seafloor deformation measurements between 2011 and 2015 documented a fourfold increase in magma supply and confirmed that Axial Seamount's eruptive behavior is inflation-predictable, probably triggered by a critical level of magmatic pressure. A 2015 eruption was successfully forecast on the basis of this deformation pattern and marked the first time that deflation and tilt were captured in real time by a new seafloor cabled observatory, revealing the timing, location, and volume of eruption-related magma movements. Improved modeling of the deformation suggests a steeply dipping prolate-spheroid pressure source beneath the eastern caldera that is consistent with the location of the zone of highest melt within the subcaldera magma reservoir determined from multichannel seismic results. PMID- 27980204 TI - Seismic constraints on caldera dynamics from the 2015 Axial Seamount eruption. AB - Seismic observations in volcanically active calderas are challenging. A new cabled observatory atop Axial Seamount on the Juan de Fuca ridge allows unprecedented real-time monitoring of a submarine caldera. Beginning on 24 April 2015, the seismic network captured an eruption that culminated in explosive acoustic signals where lava erupted on the seafloor. Extensive seismic activity preceding the eruption shows that inflation is accommodated by the reactivation of an outward-dipping caldera ring fault, with strong tidal triggering indicating a critically stressed system. The ring fault accommodated deflation during the eruption and provided a pathway for a dike that propagated south and north beneath the caldera's east wall. Once north of the caldera, the eruption stepped westward, and a dike propagated along the extensional north rift. PMID- 27980206 TI - Large gem diamonds from metallic liquid in Earth's deep mantle. AB - The redox state of Earth's convecting mantle, masked by the lithospheric plates and basaltic magmatism of plate tectonics, is a key unknown in the evolutionary history of our planet. Here we report that large, exceptional gem diamonds like the Cullinan, Constellation, and Koh-i-Noor carry direct evidence of crystallization from a redox-sensitive metallic liquid phase in the deep mantle. These sublithospheric diamonds contain inclusions of solidified iron-nickel carbon-sulfur melt, accompanied by a thin fluid layer of methane +/- hydrogen, and sometimes majoritic garnet or former calcium silicate perovskite. The metal dominated mineral assemblages and reduced volatiles in large gem diamonds indicate formation under metal-saturated conditions. We verify previous predictions that Earth has highly reducing deep mantle regions capable of precipitating a metallic iron phase that contains dissolved carbon and hydrogen. PMID- 27980207 TI - Biaxially strained PtPb/Pt core/shell nanoplate boosts oxygen reduction catalysis. AB - Compressive surface strains have been necessary to boost oxygen reduction reaction (ORR) activity in core/shell M/platinum (Pt) catalysts (where M can be nickel, cobalt, or iron). We report on a class of platinum-lead/platinum (PtPb/Pt) core/shell nanoplate catalysts that exhibit large biaxial strains. The stable Pt (110) facets of the nanoplates have high ORR specific and mass activities that reach 7.8 milliampere (mA) per centimeter squared and 4.3 ampere per milligram of platinum at 0.9 volts versus the reversible hydrogen electrode (RHE), respectively. Density functional theory calculations reveal that the edge Pt and top (bottom)-Pt (110) facets undergo large tensile strains that help optimize the Pt-O bond strength. The intermetallic core and uniform four layers of Pt shell of the PtPb/Pt nanoplates appear to underlie the high endurance of these catalysts, which can undergo 50,000 voltage cycles with negligible activity decay and no apparent structure and composition changes. PMID- 27980208 TI - A global map of roadless areas and their conservation status. AB - Roads fragment landscapes and trigger human colonization and degradation of ecosystems, to the detriment of biodiversity and ecosystem functions. The planet's remaining large and ecologically important tracts of roadless areas sustain key refugia for biodiversity and provide globally relevant ecosystem services. Applying a 1-kilometer buffer to all roads, we present a global map of roadless areas and an assessment of their status, quality, and extent of coverage by protected areas. About 80% of Earth's terrestrial surface remains roadless, but this area is fragmented into ~600,000 patches, more than half of which are <1 square kilometer and only 7% of which are larger than 100 square kilometers. Global protection of ecologically valuable roadless areas is inadequate. International recognition and protection of roadless areas is urgently needed to halt their continued loss. PMID- 27980209 TI - The cryo-EM structure of a ribosome-Ski2-Ski3-Ski8 helicase complex. AB - Ski2-Ski3-Ski8 (Ski) is a helicase complex functioning with the RNA-degrading exosome to mediate the 3'-5' messenger RNA (mRNA) decay in turnover and quality control pathways. We report that the Ski complex directly associates with 80S ribosomes presenting a short mRNA 3' overhang. We determined the structure of an endogenous ribosome-Ski complex using cryo-electron microscopy (EM) with a local resolution of the Ski complex ranging from 4 angstroms (A) in the core to about 10 A for intrinsically flexible regions. Ribosome binding displaces the autoinhibitory domain of the Ski2 helicase, positioning it in an open conformation near the ribosomal mRNA entry tunnel. We observe that the mRNA 3' overhang is threaded directly from the small ribosomal subunit to the helicase channel of Ski2, primed for ongoing exosome-mediated 3'-5' degradation. PMID- 27980210 TI - The structure and flexibility of conical HIV-1 capsids determined within intact virions. AB - HIV-1 contains a cone-shaped capsid encasing the viral genome. This capsid is thought to follow fullerene geometry-a curved hexameric lattice of the capsid protein, CA, closed by incorporating 12 CA pentamers. Current models for core structure are based on crystallography of hexameric and cross-linked pentameric CA, electron microscopy of tubular CA arrays, and simulations. Here, we report subnanometer-resolution cryo-electron tomography structures of hexameric and pentameric CA within intact HIV-1 particles. Whereas the hexamer structure is compatible with crystallography studies, the pentamer forms using different interfaces. Determining multiple structures revealed how CA flexes to form the variably curved core shell. We show that HIV-1 CA assembles both aberrant and perfect fullerene cones, supporting models in which conical cores assemble de novo after maturation. PMID- 27980213 TI - Living up to my mentors. PMID- 27980211 TI - Engineering extrinsic disorder to control protein activity in living cells. AB - Optogenetic and chemogenetic control of proteins has revealed otherwise inaccessible facets of signaling dynamics. Here, we use light- or ligand sensitive domains to modulate the structural disorder of diverse proteins, thereby generating robust allosteric switches. Sensory domains were inserted into nonconserved, surface-exposed loops that were tight and identified computationally as allosterically coupled to active sites. Allosteric switches introduced into motility signaling proteins (kinases, guanosine triphosphatases, and guanine exchange factors) controlled conversion between conformations closely resembling natural active and inactive states, as well as modulated the morphodynamics of living cells. Our results illustrate a broadly applicable approach to design physiological protein switches. PMID- 27980214 TI - The ISG15-specific protease USP18 regulates stability of PTEN. AB - The ubiquitin-like modifier interferon-stimulated gene 15 (ISG15) is implicated in both oncogenic and tumor suppressive programs. Yet, few ISGylation substrates are known and functionally validated in cancer biology. We previously found specific oncoproteins were substrates of ISGylation and were stabilized by the ISG15-specific deubiquitinase (DUB) ubiquitin specific peptidase 18 (USP18). Using reverse-phase protein arrays (RPPAs), this study reports that engineered loss of the DUB USP18 destabilized the tumor suppressor protein phosphatase and tensin homologue (PTEN) in both murine and human lung cancer cell lines. In contrast, engineered gain of USP18 expression in these same lung cancer cell lines stabilized PTEN protein. Using the protein synthesis inhibitor cycloheximide (CHX), USP18 knockdown was shown to destabilize PTEN whereas USP18 overexpression stabilized PTEN protein. Interestingly, repression of USP18 decreased cytoplasmic PTEN relative to nuclear PTEN protein levels. We sought to identify mechanisms engaged in this PTEN protein destabilization using immunoprecipitation assays and found ISG15 directly conjugated with PTEN. To confirm translational relevance of this work, USP18 and PTEN immunohistochemical expression were compared in comprehensive lung cancer arrays. There was a significant (P < 0.0001) positive correlation and association between PTEN and USP18 protein expression profiles in human lung cancers. Taken together, this study identified PTEN as a previously unrecognized substrate of the ISGylation post-translational modification pathway. The deconjugase USP18 serves as a novel regulator of PTEN stability. This indicates inhibition of ISGylation is therapeutically relevant in cancers. PMID- 27980216 TI - Characterization of IFNgamma-producing natural killer cells induced by cytomegalovirus reactivation after haploidentical hematopoietic stem cell transplantation. AB - During human cytomegalovirus (CMV) infection after umbilical cord blood or HLA matched hematopoietic stem cell transplantation (HSCT), a population of NKG2C expressing natural killer (NK) cells expand and persist. The expanded NK cells express high levels of inhibitory killer immunoglobulin-like receptors (KIR) specific for self-HLA and potently produce IFNgamma. However, it remains unknown whether similar events would occur after haploidentical HSCT (haplo-HSCT). Here, we demonstrated that IFNgamma-producing NK cells were expanded in haplo-HSCT patients with CMV reactivation. We then identified these expanded cells as a subset of CD56dim NK cells that expressed higher levels of both NKG2C and KIR, but lower level of NKG2A. Functionally, the subset of NK cells expressing NKG2C and self-KIR in patients with CMV reactivation accounted for IFNgamma production in response to K562 cells. However, these phenomena were not observed in patients without CMV reactivation. We therefore characterized a subset of NK cells with the CD56dim, NKG2C+, and self-KIR+ phenotype that expanded and were responsible for IFNgamma production during CMV infection after haplo-HSCT. Together, these findings support a notion that CMV reactivation induces expansion of more mature NK cells with memory-like features, which contributes to long-term control of both CMV infection and leukemia relapse after haplo-HSCT. PMID- 27980217 TI - The association between copper transporters and the prognosis of cancer patients undergoing chemotherapy: a meta-analysis of literatures and datasets. AB - Copper transporter 1 (CTR1), copper transporter 2 (CTR2), copper-transporting p type adenosine triphosphatase 1 and 2 (ATP7A and ATP7B) are key mediators of cellular cisplatin, carboplatin and oxaliplatin accumulation. In this meta analysis, we aimed to evaluate the relation of CTR1, CTR2, ATP7A and ATP7B to overall survival (OS), progression-free survival (PFS), disease-free survival (DFS) and treatment response (TR) of cancer patients who received chemotherapy based on published literatures, the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) datasets. Hazard ratios (HRs) and odds ratios (ORs) were pooled using random-effect models. Subgroup analysis and sensitivity analysis were conducted; heterogeneity and publication bias were assessed. Twelve literatures and eight datasets with 2149 patients were included. Our results suggested that high CTR1 expression was associated with favorable OS, PFS, DFS and TR in cancer patients who underwent chemotherapy with acceptable heterogeneity. The relationship of CTR1 to cancer prognosis remained significant in the subgroup of patients who underwent platinum-based chemotherapy, the patients with ovarian cancer and those with lung cancer. The significance of these relationships was not influenced by geological region of publication, data origin or detection method. However, there was no evidence for relation of CTR2, ATP7A or ATP7B to OS, PFS, DFS or TR. Test of publication bias and sensitivity analysis suggested a robustness of all the summary effect estimates. In conclusion, high CTR1 level predicts prolonged survival and enhanced response to chemotherapy in cancer patients who underwent chemotherapy and CTR1 might be a potential target to circumvent chemotherapy resistance. PMID- 27980215 TI - Guide to detecting epidermal growth factor receptor (EGFR) mutations in ctDNA of patients with advanced non-small-cell lung cancer. AB - Cancer treatment is evolving towards therapies targeted at specific molecular abnormalities that drive tumor growth. Consequently, to determine which patients are eligible, accurate assessment of molecular aberrations within tumors is required. Obtaining sufficient tumor tissue for molecular testing can present challenges; therefore, circulating free tumor-derived DNA (ctDNA) found in blood plasma has been proposed as an alternative source of tumor DNA. The diagnostic utility of ctDNA for the detection of epidermal growth factor receptor (EGFR) mutations harbored in tumors of patients with advanced non-small-cell lung cancer (NSCLC) is supported by the results of several large studies/meta-analyses. However, recent real-world studies suggest that the performance of ctDNA testing varies between geographic regions/laboratories, demonstrating the need for standardized guidance. In this review, we outline recommendations for obtaining an accurate result using ctDNA, relating to pre-analytical plasma processing, ctDNA extraction, and appropriate EGFR mutation detection methods, based on clinical trial results. We conclude that there are several advantages associated with ctDNA, including the potential for repeated sampling - particularly following progression after first-line tyrosine kinase inhibitor (TKI) therapy, as TKIs targeting resistance mutations (eg T790M) are now approved for use in the USA/EU/Japan (at time of writing). However, evidence suggests that ctDNA does not allow detection of EGFR mutations in all patients with known mutation-positive NSCLC. Therefore, although tumor tissue should be the first sample choice for EGFR testing at diagnosis, ctDNA is a promising alternative diagnostic approach. PMID- 27980218 TI - Performance evaluation for rapid detection of pan-cancer microsatellite instability with MANTIS. AB - In current clinical practice, microsatellite instability (MSI) and mismatch repair deficiency detection is performed with MSI-PCR and immunohistochemistry. Recent research has produced several computational tools for MSI detection with next-generation sequencing (NGS) data; however a comprehensive analysis of computational methods has not yet been performed. In this study, we introduce a new MSI detection tool, MANTIS, and demonstrate its favorable performance compared to the previously published tools mSINGS and MSISensor. We evaluated 458 normal-tumor sample pairs across six cancer subtypes, testing classification performance on variable numbers of target loci ranging from 10 to 2539. All three computational methods were found to be accurate, with MANTIS exhibiting the highest accuracy with 98.91% of samples from all six diseases classified correctly. MANTIS displayed superior performance among the three tools, having the highest overall sensitivity (MANTIS 97.18%, MSISensor 96.48%, mSINGS 76.06%) and specificity (MANTIS 99.68%, mSINGS 99.68%, MSISensor 98.73%) across six cancer types, even with loci panels of varying size. Additionally, MANTIS also had the lowest resource consumption (<1% of the space and <7% of the memory required by mSINGS) and fastest running times (49.6% and 8.7% of the running times of MSISensor and mSINGS, respectively). This study highlights the potential utility of MANTIS in classifying samples by MSI-status, allowing its incorporation into existing NGS pipelines. PMID- 27980219 TI - Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice. AB - During aging, uncontrolled epithelial cell proliferation in the uterus results in endometrial hyperplasia and/or cancer development. The mTOR signaling pathway is one of the major regulators of aging as suppression of this pathway prolongs lifespan in model organisms. Genetic alterations in this pathway via mutations and/or amplifications are often encountered in endometrial cancers. However, the exact contribution of mTOR signaling and uterine aging to endometrial pathologies is currently unclear. This study examined the role of mTOR signaling in uterine aging and its implications in the development of endometrial hyperplasia. The hyperplastic endometrium of both postmenopausal women and aged mice exhibited elevated mTOR activity as seen with increased expression of the pS6 protein. Analysis of uteri from Pten heterozygous and Pten overexpressing mice further confirmed that over-activation of mTOR signaling leads to endometrial hyperplasia. Pharmacological inhibition of mTOR signaling using rapamycin treatment suppressed endometrial hyperplasia in aged mice. Furthermore, treatment with mTOR inhibitors reduced colony size and proliferation of a PTEN negative endometrial cancer cell line in 3D culture. Collectively, this study suggests that hyperactivation of the mTOR pathway is involved in the development of endometrial hyperplasia in aged women and mice. PMID- 27980221 TI - Maintenance treatment of Uracil and Tegafur (UFT) in responders following first line fluorouracil-based chemotherapy in metastatic gastric cancer: a randomized phase II study. AB - BACKGROUND: Maintenance therapy proves to be effective in advanced lung and breast cancer after initial chemotherapy. The purpose of this phase II study was to evaluate the efficacy and safety of Uracil and Tegafur (UFT) maintenance in metastatic gastric cancer patients following the first-line fluorouracil-based chemotherapy. METHODS: Metastatic gastric cancer patients with stable disease or a better response after the completion of first-line chemotherapy were randomized to oral UFT (360mg/m2 * 2 weeks) every 3 weeks until disease progression/intolerable toxicity or to observation (OBS). The primary endpoint was progression-free survival (PFS); the secondary endpoints were overall survival (OS) and safety. RESULTS: The trial was closed after the interim analysis of the 58 enrolled (120 planned) patients. Median PFS was not improved in the UFT group compared with the OBS group (3.2 months versus 3.6 months, P = 0.752), as well as the median OS (14.2 months for both, P = 0.983). However, subgroup analysis showed that low baseline hemoglobin (< 120 g/L) was associated with poorer PFS with maintenance therapy (P = 0.032), while the normal hemoglobin patients benefit from the UFT treatment (P = 0.008). Grade 3 to 4 toxicities in the UFT group were anemia (3.4%), thrombocytopenia (3.4%) and diarrhea (6.9%). CONCLUSIONS: This trial did not show superiority of UFT maintenance in non selected patients responding to fluorouracil-based first-line chemotherapy. The normal hemoglobin level at baseline is a predictive biomarker for favorable patient subsets from the maintenance treatment. PMID- 27980222 TI - RIPK1 prevents aberrant ZBP1-initiated necroptosis. PMID- 27980220 TI - Berberine augments ATP-induced inflammasome activation in macrophages by enhancing AMPK signaling. AB - The isoquinoline alkaloid berberine possesses many pharmacological activities including antibacterial infection. Although the direct bactericidal effect of berberine has been documented, its influence on the antibacterial functions of macrophages is largely unknown. As inflammasome activation in macrophages is important for the defense against bacterial infection, we aimed to investigate the influence of berberine on inflammasome activation in murine macrophages. Our results showed that berberine significantly increased ATP-induced inflammasome activation as reflected by enhanced pyroptosis as well as increased release of caspase-1p10 and mature interleukin-1beta (IL-1beta) in macrophages. Such effects of berberine could be suppressed by AMP-activated protein kinase (AMPK) inhibitor compound C or by knockdown of AMPKalpha expression, indicating the involvement of AMPK signaling in this process. In line with increased IL-1beta release, the ability of macrophages to kill engulfed bacteria was also intensified by berberine. This was corroborated by the in vivo finding that the peritoneal live bacterial load was decreased by berberine treatment. Moreover, berberine administration significantly improved survival of bacterial infected mice, concomitant with increased IL-1beta levels and elevated neutrophil recruitment in the peritoneal cavity. Collectively, these data suggested that berberine could enhance bacterial killing by augmenting inflammasome activation in macrophages through AMPK signaling. PMID- 27980223 TI - Extracellular ATP induces apoptosis through P2X7R activation in acute myeloid leukemia cells but not in normal hematopoietic stem cells. AB - Recent studies have shown that high ATP levels exhibit direct cytotoxic effects on several cancer cells types. Among the receptors engaged by ATP, P2X7R is the most consistently expressed by tumors. P2X7R is an ATP-gated ion channel that could drive the opening of a non-selective pore, triggering cell-death signal. We previously demonstrated that acute myeloid leukemia (AML) cells express high level of P2X7R. Here, we show that P2X7R activation with high dose ATP induces AML blast cells apoptosis. Moreover, P2X7R is also expressed on leukemic stem/progenitor cells (LSCs) which are sensitive to ATP-mediated cytotoxicity. Conversely, this cytotoxic effect was not observed on normal hematopoietic stem/progenitor cells (HSCs). Notably, the antileukemic activity of ATP was also observed in presence of bone marrow stromal cells and its addition to the culture medium enhanced cytosine arabinoside cytotoxicity despite stroma-induced chemoresistance. Xenotransplant experiments confirmed ATP antineoplastic activity in vivo.Overall, our results demonstrate that P2X7R stimulation by ATP induced a therapeutic response in AML at the LSC level while the normal stem cell compartment was not affected. These results provide evidence that ATP would be promising for developing innovative therapy for AML. PMID- 27980225 TI - Melatonin protects against arsenic trioxide-induced liver injury by the upregulation of Nrf2 expression through the activation of PI3K/AKT pathway. AB - Melatonin has been demonstrated to have anti-inflammatory and antioxidant effects. The aim of this study was to investigate the protective effects of melatonin on arsenic trioxide (As2O3)-induced toxicity in liver and oxidative stress in rats. The rats were injected with 3mg/kg As2O3 on alternate days and melatonin was given with an intraperitoneal injection (i.p.) 1 h before As2O3 treatment. On the 8th days, the rats were killed to determine liver histological injury, antioxidant activities and accumulation of arsenic in liver tissues. Our results showed that melatonin attenuated As2O3-induced hepatic pathological damage, liver parameters, liver ROS level, MDA level, and the retention of arsenic in liver tissues. Melatonin also improved the antioxidant enzymes SOD, GPX, and CAT activity induced by As2O3. Furthermore, melatonin improved the expression of Nrf2 and HO-1. In addition, melatonin was found to activate PI3K/AKT pathway. In conclusion, our results indicated that melatonin protected against As2O3-induced liver injury by inducing Nrf2/HO-1 expression via upregulation of PI3K/AKT pathway. PMID- 27980226 TI - Novel phenotypes of NF1 patients from unrelated Chinese families with tibial pseudarthrosis and anemia. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder, manifested with neurofibromas and Cafe'-au-lait spots. Germline mutations in NF1 gene are associated with Neurofibromatosis type 1. NF1 gene encodes neurofibromin, a RAS-specific GTPase activating protein. In our study, we present a clinical molecular study of four Chinese probands with NF1 from four unrelated families, showing extreme phenotypic variation with rare phenotype. In family 1, the proband is a 16 months old girl with multiple cafe-au lait spots throughout her whole body. In family 2, the proband is a 6 months old girl with several cafe-au-lait spots mostly in her trunk and in lower limbs. In family 3, the proband is a 4 months old boy with several cafe-au-lait spots, tibial pseudarthrosis, and chronic iron deficiency anemia. In family 4, the proband is a 14 years old boy with multiple cafe-au-lait spots of variable sizes. Targeted exome capture based next generation sequencing and Sanger sequencing identified a novel mutation and three previously reported mutations in these four probands. These four mutations in NF1 gene were causing disease phenotypes in these four probands and was absent in unaffected family members and in healthy controls. According to the variant interpretation guideline of American College of Medical Genetics and Genomics (ACMG), these four mutations, are classified as "likely pathogenic". Our result expands the mutational spectrum of the NF1 gene associated with neurofibromatosis type1. PMID- 27980224 TI - Influence of aging on the activity of mice Sca-1+CD31- cardiac stem cells. AB - Therapeutic application of cardiac resident stem/progenitor cells (CSC/CPCs) is limited due to decline of their regenerative potential with donor age. A variety of studies have shown that the cardiac aging was the problem of the stem cells, but little is known about the impact of age on the subgroups CSC/CPCs, the relationship between subgroups CSC/CPCs ageing and age-related dysfunction. Here, we studied Sca-1+CD31- subgroups of CSCs from younger(2~3months) and older(22~24months) age mice, biological differentiation was realized using specific mediums for 14 days to induce cardiomyocyte, smooth muscle cells or endothelial cells and immunostain analysis of differentiated cell resulting were done. Proliferation and cell cycle were measured by flow cytometry assay, then used microarray to dissect variability from younger and older mice. Although the number of CSCs was higher in older mice, the advanced age significantly reduced the differentiation ability into cardiac cell lineages and the proliferation ability. Transcriptional changes in Sca-1+CD31- subgroups of CSCs during aging are related to Vitamin B6 metabolism, circadian rhythm, Tyrosine metabolism, Complement and coagulation cascades. Taking together these results indicate that Cardiac resident stem/progenitor cells have significant differences in their proliferative, pluripotency and gene profiles and those differences are age depending. PMID- 27980227 TI - miR-494-3p is a novel tumor driver of lung carcinogenesis. AB - Lung cancer is the leading cause of tumor-related death worldwide and more efforts are needed to elucidate lung carcinogenesis. Here we investigated the expression of 641 miRNAs in lung tumorigenesis in a K Ras(+/LSLG12Vgeo);RERTn(ert/ert) mouse model and 113 human tumors. The conserved miRNA cluster on chromosome 12qF1 was significantly and progressively upregulated during murine lung carcinogenesis. In particular, miR-494-3p expression was correlated with lung cancer progression in mice and with worse survival in lung cancer patients. Mechanistically, ectopic expression of miR-494-3p in A549 lung cancer cells boosted the tumor-initiating population, enhanced cancer cell motility, and increased the expression of stem cell-related genes. Importantly, miR-494-3p improved the ability of A549 cells to grow and metastasize in vivo, modulating NOTCH1 and PTEN/PI3K/AKT signaling.Overall, these data identify miR 494-3p as a key factor in lung cancer onset and progression and possible therapeutic target. PMID- 27980229 TI - IL1R1 gene polymorphisms are associated with knee osteoarthritis risk in the Chinese Han population. AB - IL1R1, encoding interleukin 1 receptor type 1, is located in the IL-1 gene cluster and is involved in the pathogenesis of hand, hip, and knee osteoarthritis (OA) in different ethnicities. However, the link between IL1R1 polymorphisms and OA risk in the Chinese Han population is unknown. We studied the association between five IL1R1 polymorphisms (rs10490571, rs12712127, rs956730, rs3917225, and rs3917318) and OA risk by analyzing the genotypes of 298 knee OA patients and 297 controls using Sequenom MassARRAY technology. Logistic regression analysis after adjusting for gender and age revealed significant differences in the allele frequencies of IL1R1 rs956730 and IL1R1 rs3917225 between patients and controls. In addition, IL1R1 rs3917225 was associated with increased risk of knee OA with or without adjustment by age and gender in the dominant model (adjusted OR= 1.47, 95%CI: 1.04-2.07, P = 0.030), the recessive model (adjusted OR= 1.75, 95%CI: 1.08 2.85, P= 0.023), and the additive model (adjusted OR= 1.40, 95%CI: 1.09-1.79, P = 0.007). This study is the first to report that IL1R1 polymorphisms are associated with knee OA susceptibility in the Northwestern Chinese Han population. PMID- 27980228 TI - Prognostic value of 18F-FDG-PET/CT in patients with nasopharyngeal carcinoma: a systematic review and meta-analysis. AB - BACKGROUND: The prognostic role of 18F-fluorodeoxyglucose positron emission tomography CT (18F-FDG PET/CT) parameters is still controversial in nasopharyngeal carcinoma patients. We sought to perform a systematic review and meta-analysis to explore the prognostic value of maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on event-free survival (EFS) and overall survival (OS) in nasopharyngeal carcinoma patients. RESULTS: Fifteen studies comprising 1,938 patients were included in this study. The combined hazard ratios (HRs) for EFS were 2.63 (95%CI 1.71-4.05) for SUVmax, 2.55 (95%CI 1.49-4.35) for MTV, and 3.32 (95%CI 1.23-8.95) for TLG. The pooled HRs for OS were 2.07 (95%CI 1.54-2.79) for SUVmax, 3.86 (95%CI 1.85 8.06) for MTV, and 2.60 (95%CI 1.55-4.34) for TLG. The prognostic role of SUVmax, MTV and TLG remained similar in the sub-group analyses. METHODS: A systematic literature search was performed to identify studies which associated 18F-FDG PET/CT to clinical survival outcomes of nasopharyngeal carcinoma patients. The summarized HRs for EFS and OS were estimated by using fixed- or random-effect models according to heterogeneity between trials. CONCLUSIONS: The present meta analysis confirms that high values of SUVmax, MTV and TLG predicted a higher risk of adverse events or death in patients with nasopharyngeal carcinoma, despite clinically heterogeneous nasopharyngeal carcinoma patients and the various methods adopted between these studies. PMID- 27980232 TI - Probing silicon quantum dots by single-dot techniques. AB - Silicon nanocrystals represent an important class of non-toxic, heavy-metal free quantum dots, where the high natural abundance of silicon is an additional advantage. Successful development in mass-fabrication, starting from porous silicon to recent advances in chemical and plasma synthesis, opens up new possibilities for applications in optoelectronics, bio-imaging, photovoltaics, and sensitizing areas. In this review basic physical properties of silicon nanocrystals revealed by photoluminescence spectroscopy, lifetime, intensity trace and electrical measurements on individual nanoparticles are summarized. The fabrication methods developed for accessing single Si nanocrystals are also reviewed. It is concluded that silicon nanocrystals share many of the properties of direct bandgap nanocrystals exhibiting sharp emission lines at low temperatures, on/off blinking, spectral diffusion etc. An analysis of reported results is provided in comparison with theory and with direct bandgap material quantum dots. In addition, the role of passivation and inherent interface/matrix defects is discussed. PMID- 27980230 TI - A childhood acute lymphoblastic leukemia-specific lncRNA implicated in prednisolone resistance, cell proliferation, and migration. AB - Childhood acute lymphoblastic leukemia (cALL) is the most common pediatric cancer and, despite an 85% cure rate, still represents a major cause of disease-related death in children. Recent studies have implicated long non-coding RNAs (lncRNAs) in cALL etiology, progression, and treatment response. However, barring some exceptions little is known about the functional impact of lncRNAs on cancer biology, which limits their potential as potential therapeutic targets. We wanted to investigate the functional role of lncRNAs identified as specifically overexpressed in pre-B cALL by whole-transcriptome sequencing. Here we report five lncRNAs specifically upregulated in pre-B cALL that had significant impacts on cancer hallmark traits such as cell proliferation, migration, apoptosis, and treatment response. In particular, silencing of the RP11-137H2.4 lncRNA effectively restored normal glucocorticoid (GC) response in a GC-resistant pre-B cALL cell line and specifically modulated expression of members of both the NRAS/BRAF/NF-kappaB MAPK cascade and cell cycle pathways. Since GC form the cornerstone of cALL chemotherapy and resistance in cALL confers a dismal prognosis, characterizing RP11-137H2.4'sexact role and function in this process will be critical to the development of new therapeutic approaches to overcome GC resistance in children treated for cALL. PMID- 27980233 TI - Carbon nanoparticle-modified multi-wall carbon nanotubes with fast adsorption kinetics for water treatment. AB - Carbon nanoparticle-modified multi-wall carbon nanotubes were prepared using a dehydration of carbohydrate compound method. The structural change was characterized by transmission electron microscopy, Raman spectroscopy, and Brunauer, Emmett and Teller measurement. Fast adsorption kinetics was observed for multi-wall carbon nanotubes with modification, as demonstrated by the adsorption of the model compound methylene blue. This work provides a novel facile engineering strategy to equip multi-wall carbon nanotubes with fast adsorption kinetics, which is promising for efficient water purification. PMID- 27980231 TI - A Novel Model for Predicting Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis B and Normal Alanine Aminotransferase Levels. AB - Background/Aims: Hepatocellular carcinoma (HCC) can develop in chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) levels. Therefore, methods that can stratify an individual's HCC risk are needed. Methods: A simple HCC risk score was developed from 971 patients with CHB who had elevated hepatitis B virus DNA levels (>2,000 IU/mL) with normal or mildly elevated ALT levels (<80 U/L). The score was validated from an independent cohort of 507 patients. Results: A 4-point risk scale was developed, with HCC risk ranging from 0% to 17.8% at 5 years for the lowest and highest risk scores. The D2AS score had high area under the receiver operating curves (AUROCs) for predicting development of HCC at 3/5 years (0.895/0.884). The calculated AUROCs to predict the development of HCC at 3/5 years were 0.889/0.876 in the validation cohort, with 5 year HCC incidence rates ranging from 0% to 13.8% at 5 years for the lowest and highest risk scores. Conclusions: The D2AS risk score can play a valuable role in risk stratification and may be useful for guiding clinical decisions for enhanced surveillance or treatment to reduce the HCC risk in CHB patients with normal or mildly elevated ALT levels. PMID- 27980235 TI - Timing of Treatment Initiation With Oral Anticoagulants for Acute Ischemic Stroke in Patients With Nonvalvular Atrial Fibrillation. AB - BACKGROUND: Only a few studies have addressed the optimal start time for oral anticoagulants (OACs) after acute ischemic stroke in patients with nonvalvular atrial fibrillation (NVAF). The aim of this retrospective study was to analyze the time of OAC administration after stroke onset.Methods and Results:This study included 300 patients with NVAF who had acute ischemic stroke and were treated with OACs between April 2012 and March 2016. We investigated the time at which OACs were started by anticoagulant type and the relationship between the time of OAC administration and stroke severity (the National Institutes of Health Stroke Scale [NIHSS] score on admission). Of the 300 patients, 114 and 186 patients received warfarin and direct-acting OACs (DOACs), respectively. Patients in the DOAC group had OAC initiated therapy significantly sooner (3 days) than in the warfarin group (7 days; P<0.001). With regard to stroke severity (NIHSS score <8, mild; 8-16, moderate; >16, severe), the median time for starting therapy was 2, 7, and 11 days for mild, moderate, and severe stroke, respectively. Hemorrhagic events occurred in 3 patients in the warfarin group; however, no hemorrhagic events occurred in the DOAC group. CONCLUSIONS: Our study revealed that neurologists began OACs earlier in patients with mild acute cerebral infarction. Even in patients with severe stroke, OACs were started earlier than expected. PMID- 27980234 TI - Effects of postural change on transesophageal echocardiography views and parameters in healthy dogs. AB - The purpose of the present study is to investigate the effect of postural change on transesophageal echocardiography (TEE) views and parameters of interest anesthesia monitoring in healthy dogs. Twelve Beagle dogs were anesthetized and randomly positioned in one of four postures: right lateral-recumbency, left lateral-recumbency, supine position and prone position. After examinations in one posture, the same examination was demonstrated in another posture and repeated in all postures. In each posture, several standard TEE views were demonstrated: longitudinal cranial-esophageal aorta long-axis-view, transverse middle esophageal mitral valve long-axis-view and transgastric middle short-axis-view. Additionally, echocardiographic parameters were attempted to measure, and direct blood pressure monitoring was performed in each view. As a result, oriented views, except for transgastric middle short-axis-view, could be obtained in all postures. Stroke volume and peak early diastolic velocity of mitral inflow were lower in supine position compared with those in right and left lateral recumbency. Heart rate (HR) and systemic vascular resistance were higher in supine position compared with those in right and left lateral-recumbency. Left ventricular pre-ejection period/left ventricular ejection time corrected and uncorrected by HR were higher in supine position compared with those in right and left lateral-recumbency. In conclusion, longitudinal cranial-esophageal aorta long-axis-view and transverse middle-esophageal mitral valve long-axis-view provide useful information of interest anesthesia monitoring, because of their views enable to certainly obtain TEE parameters in various postures. Furthermore, TEE parameters allow to detect the changes of preload, afterload and HR that occur in supine position dogs. PMID- 27980236 TI - Expression of uterine lipocalin 2 and its receptor during early- to mid-pregnancy period in mares. AB - From previous cDNA subtraction studies analyzing gene expression in equine endometrium, high lipocalin 2 (LCN2) mRNA expression was found in the gravid endometrium. In the uterus, LCN2 may transport hydrophobic molecules and siderophores with iron, or may form a complex with another protein, however, the expression of uterine LCN2 beyond day 20 of equine pregnancy and its receptor has not been characterized. To study the expression and potential roles of uterine LCN2 from pre-implantation to mid-gestation period, stage-specific endometrial samples were obtained from day 13 (day 0 = ovulation) cyclic and days 13, 19, 25, and 60 to 131 pregnant mares. Expression of LCN2 mRNA increased in day 19 gravid endometrium and was abundant from day 60 onward. The expression of LCN2 mRNA was localized to the glandular epithelium. LCN2 protein was detected in day 25 gravid endometrium and luminal fluid, and the protein was localized to the glandular epithelium and luminal cavity, whereas LCN2 receptor expression was found in luminal and glandular epithelium and trophectoderm throughout the experimental period. The presence of matrix metalloproteinase-9 (MMP9) was also examined because MMP9 is known to form a complex with LCN2. Although MMP9 and LCN2 were both found in luminal fluid from day 25 pregnant uterus, the complex of these proteins was not detected. Localization of the receptor in the trophectoderm suggests that endometrial LCN2 could play a role in carrying small substances from the mother to fetus in the equine species. PMID- 27980237 TI - Prediction of blastocyst development and implantation potential in utero based on the third cleavage and compaction times in mouse pre-implantation embryos. AB - Cytokinesis and cell division during pre-implantation embryonic development occur as an orchestrated spatiotemporal program. Cleavage, compaction, and blastulation in pre-implantation embryos are essential for successful implantation and pregnancy. Their alteration is associated with chromosomal imbalance and loss of developmental competence. In this study, we evaluated the time of cleavage and compaction as predictors for in vitro pre- and peri-implantation development and in utero implantation potential by time-lapse monitoring. Mouse 2-cell embryos were collected on 1.5 days post coitum (dpc) and were individually cultured to the outgrowth (OG) stage (7.5 dpc). Developmental stages were classified as 3 cell, 4-cell, 8-cell, morula, blastocyst, and OG. Cut-off times for successful blastocyst development were determined by receiver operating characteristic curve analysis. When cut-off times were set as 9 h for the third cleavage from the 2- to 4-cell stage, and 40 h for compaction from the 2-cell to morula stage, blastocyst and OG development rates, respectively, were significantly higher (P < 0.0001). Embryos were grouped according to the above cut-off time and transferred to the contralateral uterine horn on 3.5 dpc. Implantation rates in utero on 5.5 dpc were significantly higher in early third cleaved (<= 9 h from 2- to 4-cell) and early compacted embryos (<= 40 h from 2-cell to morula) than those in delayed embryos (P < 0.05). Therefore, the time of the third cleavage from 2- to the 4 cell stage and compaction from 2-cell to morula stage may be a useful morphokinetic parameter for predicting developmental potential, including successful implantation and pregnancy in human in vitro fertilization-embryo transfer programs. PMID- 27980238 TI - Glucose deprivation attenuates sortilin levels in skeletal muscle cells. AB - In skeletal muscle, sortilin plays a predominant role in the sorting of glucose transporter 4 (Glut4), thereby controlling glucose uptake. Moreover, our previous study suggested that the sortilin expression levels are also implicated in myogenesis. Despite the importance of sortilin in skeletal muscle, however, the regulation of sortilin expression has not been completely understood. In the present study, we analyzed if the sortilin expression is regulated by glucose in C2C12 myocytes and rat skeletal muscles in vivo. Sortilin protein expression was elevated upon C2C12 cell differentiation and was further enhanced in the presence of a high concentration of glucose. The gene expression and protein degradation of sortilin were not affected by glucose. On the other hand, rapamycin partially reduced sortilin induction by a high concentration of glucose, which suggested that sortilin translation could be regulated by glucose, at least in part. We also examined if the sortilin regulation by glucose was also observed in skeletal muscles that were obtained from fed or fasted rats. Sortilin expression in both gastrocnemius and extensor digitorum longus (EDL) muscle was significantly decreased by 17-18h of starvation. On the other hand, pathological levels of high blood glucose did not alter the sortilin expression in rat skeletal muscle. Overall, the present study suggests that sortilin protein levels are reduced under hypoglycemic conditions by post-transcriptional control in skeletal muscles. PMID- 27980239 TI - Amelioration of fatty liver index in patients with type 2 diabetes on ipragliflozin: an association with glucose-lowering effects. AB - In this study, we investigated the ameliorating effects of ipragliflozin on fatty liver in patients with type 2 diabetes. The factors that influenced the amelioration of fatty liver were also examined. Analysis included data of 21 Japanese patients with type 2 diabetes obtained from our prospective observational study. After obtaining patients' informed consent, once-daily ipragliflozin (50 mg/day) was given for 16 weeks. In addition to several clinical parameters, body composition was also compared before and after 16 weeks of treatment. The extent of fatty liver was estimated using a fatty liver index (FLI). After 16 weeks, FLI significantly decreased, from 70.1 +/- 19.4 to 60.3 +/ 25.5 (p = 0.0009) as well as levels of fasting plasma glucose (FPG), HbA1c, body weight, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and fat mass. To reveal the factors influencing the FLI changes observed on ipragliflozin treatment, correlations between changes in FLI and several other measured parameters were examined. Changes in FPG (correlation coefficient = 0.4683, p = 0.0323) and HbA1c (correlation coefficient = 0.4383, p = 0.0469) showed significant positive correlations with changes in FLI. On the other hand, no correlations of changes in FLI were observed with body weight, VAT, SAT nor fat mass. In conclusion, ipragliflozin ameliorated FLI in Japanese patients with type 2 diabetes. Improvement in FLI was associated with that of glucose intolerance. PMID- 27980240 TI - Characterization of a heat-activated retrotransposon in natural accessions of Arabidopsis thaliana. AB - Natural accessions are used for studying intraspecies genetic variation in the model plant Arabidopsis thaliana in order to address fundamental questions of evolution. Transposable elements are responsible for a wide range of mutations and play significant roles in shaping a genome over evolutionary time. In the present study, we aimed to characterize ONSEN, a heat-activated long terminal repeat (LTR) retrotransposon, in natural A. thaliana accessions. Southern blot analysis demonstrated that ONSEN was present in all the studied accessions, but the copy number was diverse. Olympia-1 contained a single ONSEN copy, located in the centromere of Chromosome 3. A premature stop codon in Olympia-1 ONSEN presumably abolishes integrase activity, which in turn presumably renders the retrotransposon non-functional. Hybridization of Col-0 with Olympia-1 showed that several ONSEN copies in Col-0 were activated by heat stress and maintained their transpositional activity in the progeny. PMID- 27980242 TI - A Novel Analytical Method of Cisplatin Using the HPLC with a Naphthylethyl Group Bonded with Silica Gel (piNAP) Column. AB - Cisplatin is the most widely used anticancer drug in the world. Mono-chloro and none-chloro complexes of cisplatin may be believed to be the activated compounds. The separation of these compounds using octa decyl silyl column or aminopropylsilyl silica gel column is difficult because of high-reactivity and structural similarity. In this study, cisplatin, hydroxo complexes, and OH-dimer were determined by HPLC using a naphthylethyl group bonded with silica gel (piNAP) column. The analytical conditions of HPLC were as follows: analytical column, piNAP column; wave length, 225 nm; column temperature, 40 degrees C; mobile phase, 0.1 M sodium perchlorate, acetonitrile, and perchloric acid (290 : 10 : 3), flow rate, 1.0 mL/min. Sample (20 uL) was injected onto the HPLC system. Retention time of cisplatin, mono-chloride, OH-dimer, and none-chloride was 3.2, 3.4, 3.6, and, 4.3-6.6 min, respectively. Measurable ranges with this method were 1*10-5 to 4*10-3 M for cisplatin. Correlation coefficient of the calibration curves of cisplatin was 0.999 (p<0.01). The within- and between-day variations of coefficient of variation (CV) were 5% or lower. In this study, injectable formulations in physiological saline solution, water for injection, 5% glucose solution, and 7% sodium bicarbonate precisely were measured the stability and compositional changes upon mixing by piNAP column rather than C18 column. We successfully determined cisplatin, hydroxo complexes, and OH-dimer by HPLC using a piNAP column. Thus the measurement of cisplatin (cis-diamminedichloro platinum(II), cis-[PtCl2(NH3)2]) (CDDP) should be done using a piNAP column rather than a C18 column or aminopropylsilyl silica gel column. PMID- 27980241 TI - Therapeutic Strategies to Attenuate Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment for Acute Ischemic Stroke. AB - This review focuses on the mechanisms and emerging concepts of stroke and therapeutic strategies for attenuating hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment for acute ischemic stroke (AIS). The therapeutic time window for tPA treatment has been extended. However, the patients who are eligible for tPA treatment are still <5% of all patients with AIS. The risk of serious or fatal symptomatic hemorrhage increases with delayed initiation of treatment. HT is thought to be caused by 1) ischemia/reperfusion injury; 2) the toxicity of tPA itself; 3) inflammation; and/or 4) remodeling factor-mediated effects. Modulation of these pathophysiologies is the basis of direct therapeutic strategies to attenuate HT after tPA treatment. Several studies have revealed that matrix metalloproteinases and free radicals are potential therapeutic targets. In addition, we have demonstrated that the inhibition of the vascular endothelial growth factor-signaling pathway and supplemental treatment with a recombinant angiopoietin-1 protein might be a promising therapeutic strategy for attenuating HT after tPA treatment through vascular protection. Moreover, single-target therapies could be insufficient for attenuating HT after tPA treatment and improving the therapeutic outcome of patients with AIS. We recently identified progranulin, which is a growth factor and a novel target molecule with multiple therapeutic effects. Progranulin might be a therapeutic target that protects the brain through suppression of vascular remodeling (vascular protection), neuroinflammation, and/or neuronal death (neuroprotection). Clinical trials which evaluate the effects of anti-VEGF drugs or PGRN-based treatment with tPA will be might worthwhile. PMID- 27980244 TI - A Clinical Study on Administration of Opioid Antagonists in Terminal Cancer Patients: 7 Patients Receiving Opioid Antagonists Following Opioids among 2443 Terminal Cancer Patients Receiving Opioids. AB - There have been few detailed reports on respiratory depression due to overdoses of opioids in terminal cancer patients. We investigated the situation of treatment with opioid antagonists for respiratory depression that occurred after administration of opioid at optimal doses in terminal cancer patients, to clarify pathological changes as well as causative factors. In 2443 terminal cancer patients receiving opioids, 7 patients (0.3%) received opioid antagonists: 6, morphine (hydrochloride, 5; sulfate, 1); 1, oxycodone. The median dosage of opioids was 13.3 mg/d, as converted to morphine injection. Respiratory depression occurred on this daily dose in 4 patients and after changed dose and route in 3 patients. Opioids were given through the vein in 6 patients and by the enteral route in 1 patient. Concomitant drugs included nonsteroidal anti-inflammatory drugs in 3 patients and zoledronic acid in 2 patients. In morphine-receiving patients, renal functions were significantly worsened at the time of administration of an opioid antagonist than the day before the start of opioid administration. These findings indicate that the proper use of opioids was safe and acceptable in almost all terminal cancer patients. In rare cases, however, a risk toward respiratory depression onset is indicated because morphine and morphine-6-glucuronide become relatively excessive owing to systemic debility due to disease progression, especially respiratory and renal dysfunctions. At the onset of respiratory depression, appropriate administration of an opioid antagonist mitigated the symptoms. Thereafter, opioid switching or continuous administration at reduced dosages of the same opioids prevented the occurrence of serious adverse events. PMID- 27980246 TI - Meta-analysis Exploring the Effectiveness of S-1-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer. AB - S-1 is a new oral fluoropyrimidine formulation that comprises tegafur, 5-chloro 2,4-dihydroxypyridine, and potassium oxonate. S-1 is designed to enhance antitumor activity and to reduce gastrointestinal toxicity. Several studies have demonstrated that both S-1 monotherapy and S-1 combination regimens showed encouraging efficacies and mild toxicities in the treatment of lung squamous cell carcinoma and adenocarcinoma. However, it is unclear whether S-1 can be used as standard care in advanced non-small cell lung cancer (NSCLC). The purpose of this meta-analysis was to assess the efficacy and safety of S-1-based chemotherapy, compared with standard chemotherapy, in patients with locally advanced or metastatic NSCLC. Thirteen randomized controlled trials (RCTs) involving 2,134 patients with a similar ratio of different pathological types were included. In first-line or second-line chemotherapy, compared with standard chemotherapy, S-1 based chemotherapy showed similar efficacy in terms of median overall survival (mOS), median progression free survival (mPFS), and objective response rate (ORR) (all P > 0.1), and significantly reduced the incidence of grade >= 3 hematological toxicities. In patients with locally advanced NSCLC receiving concurrent chemoradiotherapy, compared with standard chemoradiotherapy, significantly improved survival in the S-1-based chemotherapy was noted in terms of mOS and mPFS (risk radio [RR] = 1.289, P = 0.009; RR = 1.289, P = 0.000, respectively) with lower incidence of grade >= 3 neutropenia (RR = 0.453, P = 0.000). The present meta-analysis demonstrates that S-1-based chemotherapy shows similar benefits in advanced NSCLC and improves survival in locally advanced NSCLC, compared with standard treatment. PMID- 27980243 TI - Analysis of Serum Cholesterol Efflux Capacity in a Minipig Model of Nonischemic Heart Failure. AB - AIM: Circulating levels of high-density lipoprotein cholesterol (HDL-C) are decreased in patients with heart failure (HF). We tested whether HDL-C serum levels are associated with cardiac contractile dysfunction in a minipig HF model. METHODS: Blood samples were collected from 13 adult male minipigs: 1) before pacemaker implantation, 2) 10 days after surgery, and 3) 3 weeks after high-rate LV pacing. Serum cholesterol efflux capacity (CEC), an index of HDL functionality, was assessed through four mechanisms: ATP Binding Cassette transporter A1 (ABCA1), ATP Binding Cassette transporter G1 (ABCG1), Scavenger Receptor-Class B Type I (SR-BI) and Passive Diffusion (PD). RESULTS: HDL-C serum levels significantly decrease in minipigs with HF compared with baseline (p<0.0001). Serum CEC mediated by PD and SR-BI, but not ABCA1 or ABCG1, significantly decrease in animals with HF (p<0.05 and p<0.005, respectively). DISCUSSION: HDL-C serum levels and partial serum CEC reduction may play a pathophysiological role in the cardiac function decay sustained by high-rate LV pacing, opening new avenues to understand of the pathogenesis of nonischemic myocardial remodeling. PMID- 27980245 TI - Synthesis and Characterization of 8-Nitroguanosine 3',5'-Cyclic Monophosphorothioate Rp-Isomer as a Potent Inhibitor of Protein Kinase G1alpha. AB - Guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinases (PKG) are kinases regulating diverse physiological functions including vascular smooth muscle relaxation, neuronal synaptic plasticity, and platelet activities. Certain PKG inhibitors, such as Rp-diastereomers of derivatives of guanosine 3',5'-cyclic monophosphorothioate (Rp-cGMPS), have been designed and used to study PKG regulated cell signaling. 8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro cGMP) is an endogenous cGMP derivative formed as a result of excess production of reactive oxygen species and nitric oxide. 8-Nitro-cGMP causes persistent activation of PKG1alpha through covalent attachment of cGMP moieties to cysteine residues of the enzyme (i.e., the process called protein S-guanylation). In this study, we synthesized a nitrated analogue of Rp-cGMPS, 8-nitroguanosine 3',5' cyclic monophosphorothioate Rp-isomer (Rp-8-nitro-cGMPS), and investigated its effects on PKG1alpha activity. We synthesized Rp-8-nitro-cGMPS by reacting Rp-8 bromoguanosine 3',5'-cyclic monophosphorothioate (Rp-8-bromo-cGMPS) with sodium nitrite. Rp-8-Nitro-cGMPS reacted with the thiol compounds cysteine and glutathione to form Rp-8-thioalkoxy-cGMPS adducts to a similar extent as did 8 nitro-cGMP. As an important finding, a protein S-guanylation-like modification was clearly observed, by using Western blotting, in the reaction between recombinant PKG1alpha and Rp-8-nitro-cGMPS. Rp-8-Nitro-cGMPS inhibited PKG1alpha activity with an inhibitory constant of 22 uM in a competitive manner. An organ bath assay with mouse aorta demonstrated that Rp-8-nitro-cGMPS inhibited vascular relaxation induced by acetylcholine or 8-bromo-cGMP more than Rp-8-bromo-cGMPS did. These findings suggest that Rp-8-nitro-cGMPS inhibits PKG through induction of an S-guanylation-like modification by attaching the Rp-cGMPS moiety to the enzyme. Additional study is warranted to explore the potential application of Rp 8-nitro-cGMPS to biochemical and therapeutic research involving PKG1alpha activation. PMID- 27980247 TI - Japanese workplace health management in pneumoconiosis prevention. AB - OBJECTIVE: The Japanese government established the Pneumoconiosis Law in 1960 to protect health and promote the welfare of workers engaged in dust-exposed works. This article describes Japanese practice in workplace health management as regulated by the Pneumoconiosis Law to reduce pneumoconiosis in Japan. METHODS: We collected information addressing pneumoconiosis and the health care of dust exposed workers. We included all types of scientific papers found through a PubMed search as well as official reports, guidelines, and relevant laws published by the Ministry of Health, Labour and Welfare (MHLW) of Japan and other academic institutions. RESULTS: In the past, pneumoconiosis has been a major cause of mortality and morbidity for Japanese workers engaged in dust-exposed work. The Pneumoconiosis Law introduced a system of pneumoconiosis health examination and health supervision to protect workers' health. According to the periodic pneumoconiosis health examination reports in Japan, the prevalence of pneumoconiosis fell from the highest reported figure of 17.4% in 1982, where 265,720 examinations were conducted, to 1% in 2013 in which 243,740 workers were examined. The number of new cases of pneumoconiosis dropped from 6,842 cases in 1980 to 227 cases in 2013. One hundred and seventy two workers were diagnosed as having pneumoconiosis complications in 1980; however, the number fell to five in 2013. CONCLUSION: After reaching its peak in the 1980s, pneumoconiosis and its complications fell each year. The achievement of Japanese pneumoconiosis prevention can be credited to a comprehensive provision for worker health, regulated by a thorough legal framework. PMID- 27980248 TI - Decline of the performance of a portable axial-flow fan due to the friction and duct bending loss of a connected flexible duct. AB - OBJECTIVES: In a job site, a portable fan is often used to ventilate a confined space. When a portable fan is applied to such a space, the actual ventilation flow rate must be accurately estimated in advance because the safety level of contaminant and oxygen concentrations in the space will determine the ventilation requirements. When a portable fan is used with a flexible duct, the actual flow rate of the fan decreases due to the friction and duct bending loss of the duct. Intending to show the decline of a fan performance, the author conducted laboratory experiments and reported the quantitative effect of the friction and duct bending loss of a flexible duct to the flow rate of a portable fan. METHODS: Four commercial portable fans of different specifications were procured for the experiments, and the decline of the performance of each portable fan due to the friction loss etc. of a connected flexible duct was investigated by measuring actual flow rate. RESULTS: The flow rate showed an obvious decrease from the rated flow rate when a flexible duct was connected. Connection of a straight polyester flexible duct and a straight aluminum flexible duct reduced the flow rates to 81.2 - 52.9% and less than 50%, respectively. The flow rate decreased with an increase of the bend angle of the flexible duct. CONCLUSION: It is recommended that flow rate check of a portable fan should be diligently carried out in every job site. PMID- 27980249 TI - The practice of active rest by workplace units improves personal relationships, mental health, and physical activity among workers. AB - AIM: This study was designed to clarify the effects of active rest, with a focus on the practice of short-time group exercise by workplace units, on personal relationships, mental health, physical activity, and work ability among workers. METHODS: Fifty-nine white-collar workers (40 males and 19 females) performed our active rest (short-time exercise) program, which consists of warm-up, cognitive functional training, aerobic exercise, resistance training and cool-down for 10 minutes per day, 3 times per week during their lunch breaks for 10 weeks. Participants from a workplace unit were randomly allocated to the intervention (five workplaces, n=29) or control groups (six workplaces, n=30). The participants' anthropometric measurements, and their Profile of Mood States (POMS) 2, Brief Job Stress Questionnaire (BJSQ), physical activity levels and Work Ability Index were examined at the baseline and after the 10-week intervention. RESULTS: After 10 weeks, physical activity levels, especially the time spent in moderate and vigorous intensity, increased in the intervention group (p<0.05). The items of "vigor-activity" and "friendliness" improved in POMS 2, while "vigor," "interpersonal stress," "support from superiors, colleagues, and family/friends," and "job satisfaction" improved in BJSQ in the intervention group (p<0.05). In the intervention group, the number of exercise participation was positively correlated with the change in "vigor-activity" in POMS 2 (r=0.467, p=0.011). CONCLUSIONS: These results suggest that the practice of active rest by workplace units is important for improving personal relationships, mental health, and physical activity among workers. PMID- 27980251 TI - Preparation and Characterization of Hydroxypropyl Methylcellulose/Polycarbophil Mucoadhesive Blend Films Using a Mixture Design Approach. AB - The objectives of this study were to prepare the hydroxypropyl methylcellulose (HPMC)/polycarbophil (PC) mucoadhesive blend film and to investigate the main and interaction effect of HPMC and PC mixtures on the physicochemical and mechanical properties of blend films using a simplex lattice mixture design approach. The cubic and quadratic models were selected to analyze mucoadhesive properties in terms of work of adhesion and maximum detachment force, respectively. It was shown that HPMC/PC blend film had higher mucoadhesive properties than pure HPMC film. The suitable models for analyzing swelling index of blend films at various times were assessed. The puncture strength, % elongation and hydrophilicity of films were also examined. The pure HPMC film displayed more homogeneous and smoother structures compared with the blend film, as observed by scanning electron microscope and atomic force microscopy. Intermolecular hydrogen bonding between HPMC and PC was detected using Fourier transform infrared and X-ray diffraction. Therefore, the blend film shows high potential for use as a buccal delivery system. PMID- 27980250 TI - Comparison of single or multiple intratracheal administration for pulmonary toxic responses of nickel oxide nanoparticles in rats. AB - OBJECTIVES: In this study, we focused on the qualitative and quantitative differences of the lung lesions induced by single or multiple intratracheal administration of nickel oxide nanoparticles (NiO). METHODS: Male rats were randomized into groups receiving intratracheal administrations in a single dose or two to four divided doses of 2 mg/kg/bw. Bronchoalveolar lavage fluid (BALF) analyses were performed at 3 and 28 d post-dose. Histopathological analyses were performed at 28 and 91 d post-dose. RESULTS: BALF analyses revealed pulmonary injury, inflammation, and increases in the parameters indicating processing the foreign material in all the NiO-treated groups. Histopathological analyses showed the phagocytosis of NiO by alveolar macrophages, degeneration and necrosis of alveolar macrophages, and inflammatory responses. In the comparison between single and multiple administrations, the trend for stronger toxicity effects was observed after multiple application at 3 d post-dose, while the obvious toxicity effects were also seen in case of single administration. No particular differences of lung lesions depending on the frequency of administration at 28 and 91 d post-dose were evident. CONCLUSION: Intratracheal NiO administration induced strong toxic response thoroughly even by single administration. Therefore, single administration was concluded to be applicable to assess the inhalation toxicity of nanomaterials and can be used in the screening test. PMID- 27980252 TI - Experimental induction of necrotic enteritis in chickens by a netB-positive Japanese isolate of Clostridium perfringens. AB - Necrotic enteritis (NE) is one of the most important bacterial diseases in terms of economic losses. Clostridium perfringens necrotic enteritis toxin B, NetB, was recently proposed as a new key virulent factor for the development of NE. The goal of this work was to develop a necrotic enteritis model in chickens by using a Japanese isolate of C. perfringens. The Japanese isolate has been found to contain netB gene, which had the same nucleotide and deduced amino acid sequences as those of prototype gene characterized in Australian strain EHE-NE18, and also expressed in vitro a 33-kDa protein identified as NetB toxin by nano-scale liquid chromatographic tandem mass spectrometry. In the challenge experiment, broiler chickens fed a commercial chicken starter diet for 14 days post-hatch were changed to a high protein feed mixed 50:50 with fishmeal for 6 days. At day 21 of age, feed was withheld for 24 hr, and each chicken was orally challenged twice daily with 2 ml each of C. perfringens culture (109 to 1010 CFU) on 5 consecutive days. The gross necrotic lesions were observed in 90 and 12.5% of challenged and control chickens, respectively. To our knowledge, this is the first study that demonstrated that a netB-positive Japanese isolate of C. perfringens is able to induce the clinical signs and lesions characteristic of NE in the experimental model, which may be useful for evaluating the pathogenicity of field isolates, the efficacy of a vaccine or a specific drug against NE. PMID- 27980253 TI - Survival from an Acute Exacerbation of Idiopathic Pulmonary Fibrosis with or without Direct Hemoperfusion with a Polymyxin B-immobilized Fiber Column: A Retrospective Analysis. AB - Objective Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are fatal episodes of acute respiratory worsening of unknown etiology. Previous studies on acute respiratory distress syndrome have shown that direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) can have a beneficial effect on the respiratory status. This retrospective study investigated the prognosis and survival outcome of patients with AE-IPF who underwent PMX-DHP. Methods We examined the records of 50 patients with AE-IPF treated in our hospital. All patients received corticosteroid pulse therapy. We compared the disease outcome between 27 patients who underwent PMX-DHP (PMX group) and 23 patients who did not (non-PMX group). The independent predictors of survival were determined using Cox proportional hazards analyses. Results A multivariate analysis of all patients revealed that PMX-DHP therapy was a significant predictor of survival (HR=0.442, 95% CI 0.223-0.873; p=0.019). The 12-month survival rate was significantly higher in the PMX group than in the non-PMX group (41.7% vs. 9.8%; p=0.040). According to a subanalysis of the PMX group, the time from AE-IPF onset to PMX-DHP was a significant predictor of survival (HR=1.080, 95% CI 1.001-1.166; p=0.049). Conclusion PMX-DHP improved the prognosis of AE-IPF. The time from AE-IPF onset to PMX-DHP may therefore be informative for predicting the patient outcome. PMID- 27980254 TI - The Efficacy of an Oral Elemental Diet in Patients Undergoing Hematopoietic Stem Cell Transplantation. AB - Objective Conditioning regimens for hematopoietic stem cell transplantation (HSCT) are well known to cause severe gastrointestinal toxicities that often disturb the oral intake of the patients followed by poor nutrition and life threatening infection. An oral elemental diet (ED) is an easily consumed and assimilated form of liquid nutrients mainly composed of amino acids. It alleviates the digestive loading from the intestine and is mainly used for enteral nutritional support in patients with Crohn's disease. We herein report, for the first time, the efficacy of ED for patients undergoing HSCT. Methods We evaluated the efficacy of ED in a prospective cohort study. The primary endpoint for this study was the hospitalization period. The secondary endpoint was the occurrence of oral mucositis, nausea, diarrhea and fever. Patients A total of 73 patients were consecutively enrolled between March 2011 and March 2013. Twenty three patients underwent autologous HSCT and 50 patients underwent allogeneic HSCT. The first 21 patients did not receive ED (non-ED group; NEG) while in the successive 52 patients (ED group; EG), oral ED was started before conditioning and was continued until 28 days after transplantation. Results The patient characteristics were similar between the two groups. The mean duration of ED administration for EG was 28.7 days (range, 3-37 days), and the mean total-dose of ED administration was 1904 g (range, 240-2,960 g). The median hospitalization period was significantly shorter in EG compared to NEG, (34 days vs. 50 days; p=0.007). Grade 3-4 oral mucositis occurred less in EG than NEG (25% vs. 48%; p=0.06). Conclusion Oral ED may promote an early mucosal recovery and thereby shorten the duration of hospitalization. PMID- 27980255 TI - Regional Cerebral Blood Flow in [123]I-IMP Single-photon Emission Computed Tomography and the Wechsler Memory Scale-revised in Nondemented Elderly Subjects with Subjective Cognitive Impairment. AB - Objective Regional cerebral blood flow (rCBF) imaging with single-photon emission computed tomography (SPECT) is useful in the early diagnosis of dementia. We aimed to investigate the association between the rCBF and various domains related to the memory function in elderly subjects with subjective cognitive impairment (SCI). Methods Thirty-two subjects with SCI were included in the present study. Patients with dementia and mild cognitive impairment (MCI) were excluded based on the presence of logical memory impairment. N-isopropyl-p-[123I]-iodoamphetamine SPECT was performed and Wechsler Memory Scale-Revised (WMS-R) was administered to all subjects (mean age, 68.4 years; average Mini-Mental State Examination score, 27.6). The SPECT results were analyzed using the easy Z-score imaging system and the voxel-based stereotactic extraction estimation method. Correlation analyses were performed to investigate the correlation between the mean positive Z-scores in the decrease of the rCBF and the WMS-R indices. Results The SPECT study indicated marked hypoperfusion in some areas, including the bilateral temporal areas, the caudate, and the thalamus, in these subjects in comparison to the normal database. The decrease in the rCBF that was observed in several regions, including the left precuneus and left inferior frontal gyrus (LIFG), showed a significant negative correlation with several indices of the memory function, particularly visual memory. Conclusion The regional hypoperfusion observed in the study using the voxel-based stereotactic extraction estimation method suggest that the regional cerebral dysfunction is associated with the memory function of patients with SCI, even though the subjects in the present study were cognitively intact. The correlation analysis with the WMS-R suggested the contribution of the LIFG to the memory function and indicated the significance of visual memory dysfunction in the neuropsychological assessment to determine the stage of SCI. PMID- 27980256 TI - An Epidemiological Analysis of Summer Influenza Epidemics in Okinawa. AB - Objective This study evaluates the difference between winter influenza and summer influenza in Okinawa. Methods From January 2007 to June 2014, weekly rapid antigen test (RAT) results performed in four acute care hospitals were collected for the surveillance of regional influenza prevalence in the Naha region of the Okinawa Islands. Results An antigenic data analysis revealed that multiple H1N1 and H3N2 viruses consistently co-circulate in Okinawa, creating synchronized seasonal patterns and a high genetic diversity of influenza A. Additionally, influenza B viruses play a significant role in summer epidemics, almost every year. To further understand influenza epidemics during the summer in Okinawa, we evaluated the full genome sequences of some representative human influenza A and influenza B viruses isolated in Okinawa. Phylogenetic data analysis also revealed that multiple H1N1 and H3N2 viruses consistently co-circulate in Okinawa. Conclusion This surveillance revealed a distinct epidemic pattern of seasonal and pandemic influenza in this subtropical region. PMID- 27980257 TI - Double Extramedullary Plasmacytoma of the Stomach with a Long-term Endoscopic Follow-up. AB - A 56-year-old woman was referred to our hospital with a growing gastric submucosal tumor. An upper endoscopic examination revealed two gastric tumors, an original polypoid tumor and a newly diagnosed superficial tumor. Boring biopsied specimens of the submucosal tumor showed gastric plasmacytoma; however, the other specimens showed no malignancy. Blood diseases were ruled out using various examinations; therefore, we diagnosed the tumor as extramedullary gastric plasmacytoma. The patient underwent laparoscopic distal gastrectomy, and both tumors were thus revealed to be plasmacytomas. We experienced a rare case with two differently shaped extramedullary gastric plasmacytomas without significant morphologic change during the follow-up. PMID- 27980259 TI - Daclatasvir and Asunaprevir Combination Therapy-induced Hepatitis and Cholecystitis with Coagulation Disorder due to Hypersensitivity Reactions. AB - A 70-year-old woman with chronic hepatitis C was admitted to our hospital due to liver injury, cholecystitis, and disseminated intravascular coagulation with a fever and skin rash. She had been on a combination regimen of daclatasvir and asunaprevir for 2 weeks of a 24-week regimen. Because of the symptoms, laboratory findings, results of a drug-induced lymphocyte stimulation test, and pathological findings of liver biopsy, we diagnosed her with drug-induced liver injury. Although daclatasvir and asunaprevir combination therapy is generally well tolerated, some serious adverse effects have been reported. Our findings indicate that immunoallergic mechanisms were associated with daclatasvir and asunaprevir induced liver injury. PMID- 27980258 TI - A Rare Case of Epidermoid Cyst in the Pancreatic Tail Invaginated from the Splenic Hilum: The Long-term Changes in the Imaging Findings. AB - Epidermoid cysts arising from both the pancreas and spleen are rare. We herein report a case of a surgically resected epidermoid cyst in the pancreatic tail invaginated from the spleen. A multi-locular cyst, 2 cm in diameter, without a solid component was discovered incidentally in the pancreatic tail. During the 11 year follow-up, the emergence of satellite cystic lesions with distinct appearances was seen, and surgical resection was selected despite the lack of any associated symptoms or evidence of cytological abnormalities. Histologically, these cysts were lined with benign multi-layered flattened epithelium surrounded by a thin layer consisting of cells positive for CD8 and CD68 and connecting to the spleen. PMID- 27980261 TI - Coronary Embolization Caused by Pleomorphic Lung Carcinoma. AB - A 73-year-old man who had been transferred to our emergency room due to sudden chest pain was diagnosed with ST-segment elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention was performed. A long, white object which looked like a parasitic worm was retrieved via intracoronary aspiration and revascularization was successfully completed. Contrast computed tomography revealed a huge 7*6 cm mass in the right upper pulmonary lobe with direct pulmonary vein invasion. Histopathologic examination of the aspirated coronary object revealed pleomorphic lung carcinoma. This is an unusual case of STEMI caused by lung tumor embolization via direct pulmonary vein invasion to the left side of the heart. PMID- 27980260 TI - Coronary Spastic Angina Induced after Oral Desmopressin (DDAVP) Administration. AB - A 60-year-old man was prescribed oral desmopressin (1-deamino-8-D-arginine vasopressin acetate trihydrate; DDAVP) for nocturnal polyuria. One week after starting to take desmopressin, he frequently felt chest pain while resting. Coronary angiography revealed no organic stenosis; however, an acetylcholine provocation test showed severe coronary spasm with ST elevation. He was diagnosed with coronary spastic angina, and we stopped the oral desmopressin and added diltiazem. While DDAVP should dilate the coronary vessels in healthy subjects, it may provoke coronary vasospasm in patients with endothelial dysfunction. We should be careful to avoid triggering coronary spasm when administering DDAVP to patients that may have potential endothelial dysfunction. PMID- 27980262 TI - Expression of Extracellular Signal-regulated Kinase 5 and Ankyrin Repeat Domain 1 in Composite Pheochromocytoma and Ganglioneuroblastoma Detected Incidentally in the Adult Adrenal Gland. AB - Composite pheochromocytoma (cPC) is extremely rare, arising in the adrenal medulla as a mixture of PC and other tumors of neural origin. We herein report on a case of adrenal incidentaloma post-operatively diagnosed as cPC with ganglioneuroblastoma (GNBL). The PC component had 7 points on the PASS, a Ki-67 index of 5.1%, a focal absence of sustentacular cells, and no genetic aberrations in succinate dehydrogenase subunit B. The GNBL component exhibited no N-myc amplification. Tumor cells of both components were stained positively for extracellular signal-regulated kinase 5 and ankyrin repeat domain 1. The aberrant activation of growth signaling may play a role in the marginal malignancy of cPC. PMID- 27980263 TI - Suppression of the Hypothalamic-pituitary-adrenal Axis by Maximum Androgen Blockade in a Patient with Prostate Cancer. AB - A 78-year-old Japanese man showed suppression of the hypothalamic-pituitary adrenal axis during maximum androgen blockade (MAB) therapy including chlormadinone acetate (CMA) for prostate cancer. After stopping the MAB therapy, both the basal ACTH level and the response to CRH recovered. While no reports have indicated that CMA suppresses the hypothalamic-pituitary-adrenal axis in patients with prostate cancer, CMA has been shown to inhibit this axis in animals. These observations suggest that we must monitor the hypothalamic pituitary-adrenal axis in patients treated with CMA, especially under stressful conditions. PMID- 27980265 TI - Acute Bilateral Renal and Splenic Infarctions Occurring during Chemotherapy for Lung Cancer. AB - We herein report a rare case of acute bilateral renal and splenic infarctions occurring during chemotherapy for lung cancer. A 60-year-old man presented with acute and intensive upper abdominal and back pain during chemotherapy with cisplatin and etoposide for lung cancer. Contrast-enhanced computed tomography (CT) revealed bilateral renal and splenic infarctions. After the administration of unfractionated heparin his pain was relieved with a clearance of the infarctions in the CT findings and a recovery of renal dysfunction. Enhanced coagulation by lung cancer and arterial ischemia by chemotherapy may therefore contribute to the development of these infarctions. PMID- 27980264 TI - Antithyroid Arthritis Syndrome: A Case Report and Review of the Literature. AB - We herein report the case of a 38-year-old Japanese woman with antithyroid arthritis syndrome who experienced severe migratory polyarthritis after the initiation of thiamazole therapy. The patient's symptoms promptly disappeared without any sequelae after the withdrawal of the drug. Antithyroid arthritis syndrome is poorly characterized, and the findings from our literature review indicate that this syndrome exhibits serological features that are distinct from those of antithyroid agent-induced vasculitis syndrome. The absence of autoantibodies, especially anti-neutrophil cytoplasmic antibodies, may help characterize and diagnose antithyroid arthritis syndrome. Furthermore, physicians' awareness of this syndrome is essential for its diagnosis in clinical practice. PMID- 27980266 TI - Chylothorax Associated with Chronic Lymphocytic Leukemia. AB - An 80-year-old man who had suffered from chronic lymphocytic leukemia (CLL) and achieved complete remission was admitted to our hospital due to right pleural effusion. Thoracentesis revealed that the effusion was chyle. Lymphoscintigraphy showed an obstruction of the thoracic duct below the sternum. CD45-gated flow cytometry of the pleural effusion showed elevated numbers of CD5- and CD23 positive lymphocytes and a high serum level of soluble interleukin-2 receptor. These results suggested that the chylothorax was caused by the obstruction of the thoracic duct by the sludging of either abnormal lymphocytes of CLL or transformed malignant lymphoma cells. PMID- 27980267 TI - Two Cases of Tsunami Dust Pneumonia: Organizing Pneumonia Caused by the Inhalation of Dried Tsunami Sludge after the 2011 Great East Japan Earthquake. AB - We report two cases of organizing pneumonia (OP) secondary to the inhalation of the dried tsunami sludge which formed during the 2011 Great East Japan Earthquake and the consequent tsunami. After the disaster, both of these patients had been engaged in the restoration work. About half a month later, they developed shortness of breath and pulmonary infiltrates. These patients were diagnosed with interstitial pneumonia. Their biopsy specimens revealed multifocal peribronchiolitis and OP. An electron probe microanalysis of these specimens demonstrated the presence of elements from the earth's crust in the inflammatory lesions. These two cases indicate that exposure to dried tsunami sludge can cause OP. PMID- 27980268 TI - Pulmonary Mucosa-associated Lymphoid Tissue Lymphoma with Spontaneous Regression after Computed Tomography-guided Needle Biopsy: A Case Report and Summary of 8 Reported Cases. AB - A 72-year-old woman was admitted to our hospital with a solitary right lung nodule. She had no symptoms and no abnormal physical findings except for bladder cancer. Tumor markers were mildly elevated but no other abnormal laboratory data were found. The nodule was diagnosed to be pulmonary mucosa-associated lymphoid tissue lymphoma on computed tomography-guided needle biopsy. Thereafter, she first underwent surgery for bladder cancer. The lung nodule was found to have slightly increased at three months and then disappeared at 15 months after the biopsy. The notable clinical course of this rare disease suggests the effectiveness of a non-interventional treatment strategy. PMID- 27980269 TI - The Simultaneous Elevation of Oxidative Stress Markers and Wilms' Tumor 1 Gene during the Progression of Myelodysplastic Syndrome. AB - Oxidative stress is closely related to iron overload in myelodysplastic syndrome (MDS) and induces DNA damage. We evaluated the oxidative stress markers derivatives of reactive oxidative metabolites (dROM) and 8-hydroxy-2' deoxyguanosine (8-OHdG) during azacitidine treatment in an MDS patient. Simultaneous with an increase in the expression of Wilms' Tumor 1 (WT1) gene in the peripheral blood, the serum dROM level was elevated, and this increase was observed earlier than the increases in ferritin and 8-OHdG. Throughout the clinical course, dROM and 8-OHdG correlated significantly with WT1 and with ferritin, suggesting that changes in the oxidative stress marker levels reflect not only iron overload but also disease progression of MDS. PMID- 27980270 TI - Surgically Cured, Relapsed Pneumococcal Meningitis Due to Bone Defects, Non invasively Identified by Three-dimensional Multi-detector Computed Tomography. AB - A 43-year-old Japanese man presented with a history of bacterial meningitis (BM). He was admitted to our department with a one-day history of headache and was diagnosed with relapse of BM based on the cerebrospinal fluid findings. The conventional imaging studies showed serial findings suggesting left otitis media, a temporal cephalocele, and meningitis. Three-dimensional multi-detector computed tomography (3D-MDCT) showed left petrous bone defects caused by the otitis media, and curative surgical treatment was performed. Skull bone structural abnormalities should be considered a cause of relapsed BM. 3D-MDCT was useful for revealing the causal minimal bone abnormality and performing pre-surgical mapping. PMID- 27980272 TI - Olmesartan-induced Enteropathy Manifesting as Wernicke-Korsakoff Syndrome. AB - Cases of sprue-like enteropathy associated with olmesartan have sporadically been encountered since it was first reported in 2012, and their most characteristic manifestation is severe diarrhea. We herein report the first case of sprue-like enteropathy manifesting as Wernicke-Korsakoff syndrome due to vitamin B1 malabsorption with only minimally increased bowel movements. When patients are receiving olmesartan and they complain of nonspecific chronic gastrointestinal symptoms, it is important to consider changing the drugs before any serious malabsorption syndrome develops. PMID- 27980271 TI - Severe Thrombocytopenia and Acute Cytomegalovirus Colitis during Primary Human Immunodeficiency Virus Infection. AB - We herein report the case of a 25-year-old man who was referred to our hospital due to acute cytomegalovirus (CMV) colitis. The initial blood tests showed that the patient had concurrent primary human immunodeficiency virus (HIV) infection and severe thrombocytopenia. Raltegravir-based antiretroviral therapy (ART) was initiated without the use of ganciclovir or corticosteroids and resulted in a rapid clinical improvement. Platelet transfusions were only necessary for a short period, and subsequent colonoscopy revealed a completely healed ulcer. This case implies that ART alone could be effective for treating severe thrombocytopenia during primary HIV and CMV coinfection. PMID- 27980274 TI - Gastric Anisakiasis with a Gastric Ulcer. PMID- 27980273 TI - Stomach Dysfunction Is a Potential Risk Factor for Wernicke's Encephalopathy. PMID- 27980275 TI - Pharyngeal and Esophageal Erosions in Crohn's Disease. PMID- 27980276 TI - Multiple Deep Vein Thrombosis. PMID- 27980278 TI - Severe Fever with Thrombocytopenia Syndrome. PMID- 27980277 TI - Persistent Nephrogram. PMID- 27980279 TI - Shock Index More Sensitive Than Cardiogenic Shock in ST-Elevation Myocardial Infarction Treated by Primary Percutaneous Coronary Intervention. AB - BACKGROUND: Cardiogenic shock (CS) is a strong predictor of mortality in patients with ST-elevation myocardial infarction (STEMI), but there is evidence that shock index (SI), taking into account both blood pressure and heart rate, is a more sensitive and powerful predictor. We investigated the independent impact of SI and CS on 30-day and 1-year mortality in patients with STEMI, treated by primary percutaneous coronary intervention (PCI).Methods and Results:In 7,412 consecutive patients with STEMI treated with primary PCI, the predictive value of either SI or CS on 1-year mortality was assessed. Best cut-off value of SI, determined using receiver operating characteristic (ROC) curve, was 0.7, with an ROC AUC of 0.66 (95% CI: 0.65-0.67), compared with an ROC AUC of 0.60 (95% CI: 0.59-0.61) for CS (P<0.001). At admission, 387 patients (5.2%) had CS and 1,567 patients (21.1%) had SI >=0.7. The adjusted hazard ratio of mortality in patients with SI >=0.7 and in CS patients was, respectively, 3.3 (95% CI: 2.4-4.6) and 3.1 (95% CI: 2.1-4.6) after 30 days, and 2.3 (95% CI: 1.8-2.9) and 3.1 (95% CI: 2.2-4.2) after 1 year. CONCLUSIONS: SI identifies more patients with increased risk of mortality, and seems to be a more sensitive prognostic predictor than CS in patients with STEMI treated by primary PCI. PMID- 27980280 TI - Increased Coagulation With Aging: Importance of Homocysteine and Vitamin B12. PMID- 27980281 TI - Increased Coagulation With Aging: Importance of Homocysteine and Vitamin B12 - Reply. PMID- 27980282 TI - Successful Stent-Retriever Thrombectomy for Acute Cerebral Embolization After Transcatheter Aortic Valve Implantation. PMID- 27980283 TI - Pure Cusp Tear of Trifecta Bioprosthesis 2 Years after Aortic Valve Replacement. AB - Trifecta is a stented bioprosthetic heart valve with a bovine pericardial sheet externally mounted on a titanium stent. This valve is applied only for aortic valve replacement (AVR), providing excellent hemodynamics and extremely low incidence of structural valve deterioration (SVD). A 76-year-old woman presented with dyspnea on effort 24 months after AVR with a 21-mm Trifecta valve. Echocardiography revealed severe aortic regurgitation with prolapse of a cusp of Trifecta valve, which suggested that she developed acute heart failure due to early SVD. In the operation, Trifecta valve had a cusp tear near the commissure with circumferential fibrous pannus ingrowth only at the inflow side. There was neither calcification nor infection. The Trifecta valve was successfully replaced with a new porcine bioprosthesis. PMID- 27980284 TI - Roles of the Wada Test and Functional Magnetic Resonance Imaging in Identifying the Language-dominant Hemisphere among Patients with Gliomas Located near Speech Areas. AB - This study examined the accuracy of functional magnetic resonance imaging (fMRI) in identifying the language-dominant hemisphere and the situations in which the Wada test can be skipped among patients with gliomas located near speech areas. We examined 74 patients [48 men (64.9%); mean +/- standard deviation age of 42.7 +/- 13.6 years (range: 13 to 70 years); 71 right-handed, 2 left-handed, and 1 ambidextrous] with gliomas located near speech areas. All patients underwent the Wada test and fMRI, and 34 patients underwent awake surgery. The "last-and-first" task was administered during fMRI. The Wada test was successful in determining the language-dominant hemisphere in 73 patients (98.6%): left hemisphere in 68 patients (91.9%), right hemisphere in 4 patients (5.4%), and bilateral in 1 patient (1.4%). The dominant hemisphere for right-handed patients (n = 71) was the left hemisphere in 67 patients (94.3%), right hemisphere in 3 patients (4.2%), and undetectable in 1 patient (1.4%). The fMRI was successful in determining the language-dominant hemisphere in 53 patients (71.6%). The results of the Wada test and fMRI were inconsistent in 5 patients (8.6%), of which 3 (5.2%) exhibited dominance in opposite hemispheres. Furthermore, 2 of these 3 cases (2.7%) were contralateral false positive cases, whereby fMRI identified the right-hemisphere as language dominant for right-handed individuals with tumors in the left hemisphere. Based on these findings, we concluded that the Wada test can be skipped if language dominancy can be detected by fMRI. PMID- 27980285 TI - Convection-enhanced Delivery of Therapeutics for Malignant Gliomas. AB - Convection-enhanced delivery (CED) circumvents the blood-brain barrier by delivering agents directly into the tumor and surrounding parenchyma. CED can achieve large volumes of distribution by continuous positive-pressure infusion. Although promising as an effective drug delivery method in concept, the administration of therapeutic agents via CED is not without challenges. Limitations of distribution remain a problem in large brains, such as those of humans. Accurate and consistent delivery of an agent is another challenge associated with CED. Similar to the difficulties caused by immunosuppressive environments associated with gliomas, there are several mechanisms that make effective local drug distribution difficult in malignant gliomas. In this review, methods for local drug application targeting gliomas are discussed with special emphasis on CED. Although early clinical trials have failed to demonstrate the efficacy of CED against gliomas, CED potentially can be a platform for translating the molecular understanding of glioblastomas achieved in the laboratory into effective clinical treatments. Several clinical studies using CED of chemotherapeutic agents are ongoing. Successful delivery of effective agents should prove the efficacy of CED in the near future. PMID- 27980286 TI - A case of successful treatment with donepezil of olfactory hallucination in parkinson disease. AB - We report a 74-year-old female patient with Parkinson disease (PD). Around 2010, she developed depression and bradykinesia and was diagnosed as PD. In July 2014, she came to our hospital, of which she lived in the neighborhood. In the last part of December 2014, she felt uneasy about her fecal smell and saw a psychiatrist in the first part of January 2015. Quetiapine (25 mg/day) was added. In the last part of January, she complained of fecal smell everywhere and could not take a meal. No-one else could detect the smell. A diagnosis of olfactory hallucination was made. The next day after increasing to 75mg/day, however, she was admitted to our hospital because of refusing to take medicine. After introducing donepezil, olfactory hallucination subsided and her appetite was improved. Brain MRI showed atrophy of the bilateral temporal lobes and N isopropyl-p-(iodine-123)-iodoamphetamine single photon emission computed tomography (123I-IMP-SPECT) revealed hypoperfusion in the bilateral mesial temporal lobes. We suppose that cholinergic denervation in the mesial temporal lobes is an important determinant of her olfactory hallucination. PMID- 27980288 TI - A case of central pontine and extrapontine myelinolysis after surgery for a pituitary tumor. AB - A 21-year-old woman underwent surgery for a pituitary tumor. On the 11th postoperative day, blood examination revealed severe hyponatremia, with a serum sodium level of 111 mEq/l, and two days later this increased rapidly to 137 mEq/l. On the 20th postoperative day, the patient developed dysarthria and gait disturbance. Head MRI on the 30th postoperative day demonstrated intense high signal lesions in the pons and bilateral corpus striatum on FLAIR and DWI, and central pontine and extrapontine myelinolysis was diagnosed. The patient's symptoms improved gradually after rehabilitation and antispasticity treatment. It was suggested that the changes in serum sodium levels after pituitary surgery were due to impaired secretion of antidiuretic hormone due to degeneration of nerve terminals in the posterior pituitary. As pituitary surgery may trigger changes in serum sodium leading to myelinolysis, this possibility should always be borne in mind when treating such patients. PMID- 27980287 TI - A case of neurosyphilis presenting with limbic encephalitis. AB - A 46-year-old man presented with a history of personality change and memory disturbance for 5 months. He gradually became difficult in doing a daily job. Brain MRI showed abnormal hyperintensity within bilateral mesial temporal lobes on T2 weighted image. Therefore, viral and autoimmune limbic encephalitis was initially suspected. However, because treponemal and non-treponemal specific antibodies were positive in serum and cerebrospinal fluid (CSF), the diagnosis of neurosyphilis was made. Patients of neurosyphilis with mesiotemporal T2 weighted hyperintensity reportedly showed common features such as relatively young age, HIV-negative, subacute cognitive impairment and seizure, as seen in our patient. Neurosyphilis should be included in the differential diagnosis for mesiotemporal abnormality in patients with these features. In addition, in our patient, anti glutamate receptor epsilon2 antibody (ELISA) was strongly positive in CSF that suggested additional autoimmune pathophysiological mechanism. PMID- 27980289 TI - Epilepsy and ion channels. AB - Many mutations of genes for ion channels result in some epilepsies. Their electrophysiological studies reveal pathophysiological mechanisms underlining epilepsy and also mechanism of action of several antiepileptic drugs. In this review, We briefly summarize pathophysiology of epilepsy and the mechanisms of antiepileptic drugs. PMID- 27980291 TI - Actin cytoskeleton-modulating T3SS2 effectors and their contribution to the Vibrio parahaemolyticus-induced diarrhea. AB - To understand how bacterial pathogens cause diseases is the most important step in order to prevent the infection and develop an effective treatment. However, the past proceeding studies make us aware of quite-complicated interactions between the host and pathogenic bacteria. Vibrio parahaemolyticus, a food-born pathogen that is a subject of our study, causes inflammatory diarrhea in human upon ingestion of contaminated raw or undercooked seafood. Many virulence factors has been proposed since its discovery in Osaka around 70 years ago, while our research group has revealed that one of these virulence factors, type 3 secretion system 2 (T3SS2), is necessary for diarrhea induced by this bacterium. In addition, we recently found two novel T3SS2 effectors (VopO and VopV) that manipulate the actin cytoskeleton in infected host cells. In this article, I would like to show our findings with regard to biological activities of the effectors and their contributions to the T3SS2-induced enterotoxicity. PMID- 27980290 TI - Segmental spinal dysgenesis with caudal agenesis in a Holstein calf. AB - A rare complex dysraphic malformation, comprising segmental spinal dysgenesis with caudal agenesis, was found in a Holstein calf that was unable to stand and was slightly short at the lumbosacral spine with taillessness. The thoracolumbar and sacrococcygeal regions of the midline axial segments showed severe deformities. In the spinal cord, the thoracolumbar region showed severe constriction with myelodysplastic changes, and the sacrococcygeal region showed dorsoventral separation with connection to a neural mass. In the spine, vertebral anomalies according to the degree of the segmentation error were confirmed. The cervical and thoracic segments also showed milder dysraphic changes. These changes suggest a multisegmental causal insult impairing the early embryonic notochord. This represents the first bovine case definitively confirmed morphologically. PMID- 27980292 TI - A complete view of the Escherichia coli O-antigen biosynthesis gene cluster and the development of molecular-based O-serogrouping methods. AB - Much of what we know about Escherichia coli populations and epidemiology is defined at some level by O serogroups. Moreover, in our collective knowledge, outbreak and disease reports and elsewhere, all information of pathogenic E. coli have O serogroup records. O-serogroup diversification shows a strong association with the genetic diversity of O-antigen biosynthesis genes, and O-serogroup specific sequences can be used as genetic markers for identifying O serogroups. We sequenced all the known O-antigen biosynthesis gene clusters (O-AGCs) from the 184 E. coli defined O serogroups and determined their genetic makeup and diversity. Subsequently, based on a highly detailed analysis of O-AGCs, we developed comprehensive and practical molecular O-serogrouping platforms; PCR based "E. coli O-genotuping PCR" and in silico-based "SerotypeFinder". These simple and exhaustive systems may integrate microbial typing, genomics and evolutionary analyses. PMID- 27980294 TI - What Is the Acute Antral Lesion Size After Pulmonary Vein Isolation Using Different Balloon Ablation Technologies? AB - BACKGROUND: Clinical outcome after pulmonary vein isolation (PVI) may be linked to both durability of PVI and the antral lesion size. Data on balloon-guided technologies are scarce. We investigated the size of the isolated surface area (ISA) acutely after PVI achieved by cryoballoon (CB) or laser balloon (LB), both using voltage mapping.Methods and Results:In 40 patients (73% male, mean age 66+/ 9 years), a bipolar voltage map before and after PVI in sinus rhythm was acquired to delineate the isolated antral surface area (IASA, contiguous area of low voltage <0.5 mV) and the ISA (relative size of the low-voltage area in relation to the whole antral surface area including the posterior wall). IASA (CB: 57+/-14 cm2vs. LB: 42+/-15 cm2; P=0.002) as well as ISA (65+/-8% vs. 54+/-10%; P=0.001) were significantly larger in the CB than in the LB group. No periprocedural complications occurred. During a mean follow-up of 326+/-142 days, 4/20 and 5/20 patients experienced an AF/AT recurrence in the CB and LB groups, respectively. No differences in clinical outcome were observed between patients with a large (>=55%) or small (<55%) ISA. CONCLUSIONS: Balloon-guided PVI is associated with antral lesion formation. CB-guided PVI is associated with the largest ISA as compared with LB procedures. ISA size did not correlate with clinical outcome after a single procedure in the present study population. PMID- 27980295 TI - Insomnia and Cardiac Events in Patients With Heart Failure. PMID- 27980293 TI - The aryl hydrocarbon receptor: a multifunctional chemical sensor for host defense and homeostatic maintenance. AB - The aryl hydrocarbon receptor (AHR) is a pivotal chemical sensor that transduces extrinsic and intrinsic signals into cellular responses. AHR was originally thought to be involved in not only drug metabolism but also carcinogenic and toxicological responses against environmental contaminants, such as 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons. However, recent studies demonstrate that the AHR plays multiple intrinsic roles in host defense and homeostasis as well, including immunity, stem cell maintenance, and cell differentiation, upon binding with an increasing number of newly defined dietary, cellular, and microbe-derived ligands. In addition, AHR is a convergence point for several signaling cascades, which may be involved in the diverse diseases caused by binding of the persistent ligand TCDD with extremely high affinity to AHR. A comprehensive understanding of physiological and pathological processes initiated by endogenous AHR agonists and antagonists may allow for the therapeutic regulation of AHR activity. Thus, the AHR can be a valuable diagnostic marker and therapeutic target for human diseases. PMID- 27980296 TI - Genitourinary Hemorrhagic Complications and Malignancies in Patients Receiving Anticoagulation Therapy. PMID- 27980297 TI - Insomnia and Cardiac Events in Patients With Heart Failure - Reply. PMID- 27980298 TI - History of Japanese Society of Toxicology. AB - Founded in 1981, the Japanese Society of Toxicology (JSOT) has grown into an organization of nearly 3,000 members working together to advance the nation's scientific knowledge and understanding of toxicology through the implementation of planning that ensures a systematic and efficient expenditure of energies and resources, and is closely aligned with a strategy for accomplishing the Society's long-range plans. To promote public education in toxicology, the Society organizes public lectures during each year's annual meeting. Other activities include hosting scientific conferences, promoting continuing education, and facilitating international collaboration. Internally, the JSOT operates five standing committees: General Affairs, Educational, Editorial, Finance, and Science and Publicity to handle its necessary relationships. To bestow official recognition, the Society established its Toxicologist Certification Program in 1997, and has certified 536 members as Diplomat Toxicologists (DJSOT) as of May 1, 2016. Furthermore, on the same date, 43 JSOT members were certified as Emeritus Diplomats of the JSOT (EDJSOT). The Society has launched two official journals, the "Journal of Toxicological Sciences (JTS)" in 1981 and "Fundamental Toxicological Sciences (Fundam. Toxicol. Sci.)" in 2014. As for participation in the international organizations, the JSOT (then known as the Toxicological Research Group) joined the International Union of Toxicology as a charter member in 1980, and became a founding member of the Asian Society of Toxicology at its inauguration in 1994. Into the future, the JSOT will continue working diligently to advance knowledge and understanding of toxicology and secure its place among the interdisciplinary fields of science, humane studies, and ethics. PMID- 27980299 TI - Autologous Hematopoietic Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma. AB - High-dose chemotherapy supported by autologous stem cell support/transplantation (HDT/ASCT) has been a standard of care over the last two decades in patients with relapsed or refractory(R/R) diffuse large B-cell lymphoma (DLBCL), which is sensitive to salvage chemotherapy. HDT/ASCT for high-risk DLBCL in upfront setting remains controversial, so it is not recommended for clinical practice. Various promising salvage chemotherapy regimens have been reported in phase 2 studies; however, two large randomized phase 3 studies showed similar efficacy of R-ICE vs. R-DHAP and R-GDP vs. R-DHAP. Since the registry data shows feasibility and efficacy of HDT/ASCT in elderly R/R DLBCL patients, older age (> 65 years) itself is not a contraindication for HDT/ASCT. Rituximab maintenance failed to demonstrate a significant benefit compared with observation only after HDT/ASCT. While sensitive R/R DLBCL might be cured by HDT/ASCT even in third-line therapy, the prognosis of insensitive R/R DLBCL is extremely poor. Further study to establish treatment strategies for high-risk patients defined by prognostic factors or biomarkers, and insensitive patients is warranted. PMID- 27980300 TI - Langerhans Cell Histiocytosis and Langerhans Cell Sarcoma: Current Understanding and Differential Diagnosis. AB - Langerhans cell (LC) histiocytosis (LCH) and LC sarcoma (LCS) are proliferative processes consisting of cells having morphologic and phenotypic features of Langerhans cells (LCs), although the latter may have lost some of these features. Because neoplastic nature of LCH as well as LCS is more likely by recent studies, a category of LC hyperplasia can be better characterized. LCH and LCS are rarely seen in daily pathology practice, but it is important to accurately characterize these lesions. For this purpose, an outline covering proliferations of LC and related cells was constructed. The scheme of this outline is based especially on evaluating borderline lesions, neoplastic trans-differentiation, and degree of similarity with the normal counter-parts. In addition, the organization and update of the current classification scheme for histiocytic and dendritic-cell proliferations is presented. PMID- 27980301 TI - Six Cases of CD20-Positive Adult T-Cell Leukemia. AB - Adult T-cell leukaemia/lymphoma (ATLL) is a neoplasm originating in mature CD4+ peripheral T cells. However, rare cases of CD20+ ATLL have been reported. Here, we describe six cases of CD20+ ATLL diagnosed in our department. The median age was 79 years (range, 54-90 years); two patients were men, and four were women. Elevated lactate dehydrogenase was observed in four cases. All cases were lymphoma type and positive for human T-lymphotropic virus-1 (HTLV-1). HTLV-1 proviral DNA was detected in four cases. The Ann Arbor stage was I, II, or IV in one patient each and III in three patients. The clinical course was poor in almost all cases. Tumour cells were large in all cases, and flow cytometry revealed CD20+ lymphoma cells in five of six cases. Immunohistochemistry revealed lymphoma cells positive for CD20, CD3, CD4, and CCR4 and negative for CD8, CD79a, and PAX5 in all cases. CD20 expression was lower than that in normal B cells. One case was initially misdiagnosed as diffuse large B-cell lymphoma. Thus, combined use of an antibody panel and molecular genetic studies is important to avoid misdiagnosing ATLL as B-cell lymphoma. PMID- 27980302 TI - Cord Blood Transplantation Following Reduced-Intensity Conditioning for Epstein Barr Virus-Associated Hemophagocytic Lymphohistiocytosis during Systemic Lupus Erythematosus Treatment. AB - Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a serious disorder in which monoclonal growth of T cells infected with EBV and macrophage activation cause pancytopenia, high fever and acute liver failure. Patients with chemotherapy- or immunosuppression-resistant EBV-HLH require allogeneic hematopoietic stem cell transplantation (allo-HSCT), but patients who have no sibling donors may not have time to wait for an unrelated donor. In pediatric patients, there are some reports on allogeneic cord blood transplantation (allo-CBT) for the treatment of EBV-HLH; however, in adult patients, reports of allo-CBT for EBV-HLH are quite limited. The present case of a 20-year-old woman with chemotherapy-resistant EBV-HLH and systemic lupus erythematosus (SLE) who underwent allo-CBT following reduced-intensity conditioning (RIC-CBT). She achieved and maintained a complete donor type and the EBV-DNA load, and the titers of anti-double stranded DNA and antinuclear antibodies became negative. It is therefore considered that RIC-CBT is an effective treatment option for adult onset HLH. However, because the effectiveness of allo-HSCT for SLE remains unclear and transplant-related mortality is high, it is recommended that allo-HSCT for SLE is restricted to patients concomitant with oncohematological disease as with our present case. PMID- 27980303 TI - Isochromosome 17q; A Novel Finding in Myeloid Sarcoma. PMID- 27980304 TI - Diffuse Large B-Cell Lymphoma in 2016. PMID- 27980305 TI - Molecular Pathogenesis of Diffuse Large B-Cell Lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is divided into germinal center B-like (GCB) DLBCL and activated B-like (ABC) DLBCL. In recent years, whole genome sequencing (WGS), whole exome sequencing (WES), and transcriptome sequencing (RNA seq) have been performed for samples from many patients with DLBCL. Here, I present a review of the results of next generation sequencing data for DLBCL. Somatic mutations show a low identity between studies with only 10-20% gene overlap. DLBCL is a disease that results from various molecular pathogeneses. Mutations in genes involved in chromatin remodeling were found in the GCB subtype. Mutations in members of B-cell receptor (BCR) signaling and the NF kappaB pathway (MYD88) were found in the ABC subtype. The MYD88 L265P mutation was observed in 29% of ABC DLBCL cases. EZH2 mutations were observed in 21.7% of GCB DLBCL cases. WGS indicated that inactivating mutations in GNA13 (Galpha protein) were prevalent in GCB DLBCL cases. In addition, S1PR2 is a target of aberrant somatic hypermutation. In recent years, samples from patients with relapsed and refractory DLBCL were analyzed. The activation of the NF-kappaB pathway is associated with treatment resistance in DLBCL. Further clarification of the molecular pathogenesis of DLBCL is expected to lead to the development of individualized treatment for the disease. PMID- 27980306 TI - Treatment of Diffuse Large B-Cell Lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) comprises a heterogeneous group with pathophysiological, genetic and clinical features. Many patients can be cured with R-CHOP therapy, which is the current standard regimen. Despite recent progress in improving patient survival, the 40% survival of DLBCL patients remains poor. Therefore, the most important issue for patients with DLBCL remains the development of a new front-line therapy. Several studies have reported that intensified chemotherapy with dose-adjusted EPOCH-R or R-ACVBP was superior to R CHOP. Gene expression profiling has identified two distinct forms of DLBCL: activated B cell-like (ABC) and germinal center B-cell-like (GCB) types. ABC DLBCL exhibits a worse prognosis than GCB DLBCL by molecular diagnosis after R CHOP therapy. Next-generation sequencing has identified unique oncogenic mechanisms and genetic complexity, which has provided rational therapeutic targets. There are also a number of biomarkers, including CD5, and prognostic factors. Efforts to distinguish many biomarkers will be crucial for individualized treatment in the future. PMID- 27980307 TI - Genetic and Epigenetic Modulation of CD20 Expression in B-Cell Malignancies: Molecular Mechanisms and Significance to Rituximab Resistance. AB - CD20 is a differentiation related cell surface phosphoprotein that is expressed during early pre-B cell stages until plasma cell differentiation, and is a suitable molecular target for B-cell malignancies by monoclonal antibodies such as rituximab, ofatumumab, obinutuzumab and others. CD20 expression is confirmed in most B-cell malignancies; however, the protein expression level varies in each patient, even in de novo tumors, and down-modulation of CD20 expression after chemoimmunotherapy with rituximab, resulting in rituximab resistance, has been recognized in the clinical setting. Recent reports suggest that genetic and epigenetic mechanisms are correlated with aberrantly low CD20 expression in de novo tumors and relapsed/refractory disease after using rituximab. Furthermore, some targeting drugs, such as lenalidomide, bortezomib and ibrutinib, directly or indirectly affect CD20 protein expression. CD20-negative phenotypically-changed DLBCL after rituximab use tends to show an aggressive clinical course and poor outcome with resistance to not only rituximab, but also conventional salvage chemo-regimens. Understanding of the mechanisms of CD20-negative phenotype may contribute to establish strategies for overcoming chemo-refractory B-cell malignancies. In this manuscript, recent progress of research on molecular and clinical features of CD20 protein and CD20-negative B-cell malignancies was reviewed. PMID- 27980308 TI - Urinary Retention Associated with Stroke. AB - Patients often exhibit urinary retention following a stroke. Various neuropathological and animal studies have implicated the medulla oblongata, pons, limbic system, frontal lobe as areas responsible for micturition control, although the exact area responsible for urinary retention after stroke is not clear. The purpose of this study was to identify the stroke area responsible for urinary retention by localizing the areas where strokes occur. We assessed 110 patients with cerebral infarction and 27 patients with cerebral hemorrhage (78 men, 59 women; mean age, 73.0 years) who had been admitted to our hospital between October, 2012 and September, 2013. We used computed tomography (CT) and magnetic resonance imaging (MRI) to investigate the stroke location, and evaluated whether post-stroke urinary retention occurred. Twelve (8.8%) of the 137 patients (7 men, 5 women; mean age, 78.8 years) exhibited urinary retention after a stroke. Stroke occurred in the right/left dominant hemisphere in 7 patients; nondominant hemisphere in 1; cerebellum in 3; and brainstem in 1. Strokes in the dominant hemisphere were associated with urinary retention (P = 0.0314), particularly in the area of the insula (P < 0.01). We concluded that stroke affecting the insula of the dominant hemisphere tends to cause urinary retention. PMID- 27980309 TI - Immunohistochemical Analysis of the Effect of Dienogest on Ovarian Endometriotic Cysts. AB - Dienogest is a novel progestin with potent oral progestational activity that inhibits the clinical symptoms of endometriosis. We herein evaluated the effect of dienogest on ovarian endometriotic cysts via immunohistochemistry. Ovarian endometriotic cyst specimens were collected from 12 patients treated with dienogest and 20 patients not treated with hormones (controls). The expression of estrogen receptor (ER)-alpha, progesterone receptor A (PRA), and Ki-67 was studied by immunohistochemistry. As compared with the controls, the cell proliferation index was significantly reduced in both epithelial and stromal cells of the endometriotic cysts following the use of dienogest (P = 0.022 and P = 0.004, respectively). However, there was no significant difference between endometriotic cysts with and without the use of dienogest in the expressions of ER-alpha and PRA in the epithelial and stromal cells. Irrespective of the use of dienogest, the expression levels of ER-alpha and PRA in the epithelial cells were low (median: 32% and 8%, respectively). Conversely, the expression levels of ER alpha and PRA in the stromal cells were well preserved (median: 68% and 92%, respectively). In the controls, there was no significant difference between endometriotic cysts in the expression levels of Ki-67, ER-alpha and PRA in epithelial and stromal cells during the proliferative and secretory phases. The finding of a reduction in the cell proliferation index by the use of dienogest with no change in the expressions of hormonal receptors may not support the direct progestational effect of dienogest on ovarian endometriotic cysts. PMID- 27980310 TI - A Minimalist Analysis of English Topicalization: A Phase-Based Cartographic Complementizer Phrase (CP) Perspective. AB - Under the basic tenet that syntactic derivation offers an optimal solution to both phonological realization and semantic interpretation of linguistic expression, the recent minimalist framework of syntactic theory claims that the basic unit for the derivation is equivalent to a syntactic propositional element, which is called a phase. In this analysis, syntactic derivation is assumed to proceed at phasal projections that include Complementizer Phrases (CP). However, there have been pointed out some empirical problems with respect to the failure of multiple occurrences of discourse-related elements in the CP domain. This problem can be easily overcome if the alternative approach in the recent minimalist perspective, which is called Cartographic CP analysis, is adopted, but this may raise a theoretical issue about the tension between phasality and four kinds of functional projections assumed in this analysis (Force Phrase (ForceP), Finite Phrase (FinP), Topic Phrase (TopP) and Focus Phrase (FocP)). This paper argues that a hybrid analysis with these two influential approaches can be proposed by claiming a reasonable assumption that syntactically requisite projections (i.e., ForceP and FinP) are phases and independently constitute a phasehood with relevant heads in the derivation. This then enables us to capture various syntactic properties of the Topicalization construction in English. Our proposed analysis, coupled with some additional assumptions and observations in recent minimalist studies, can be extended to incorporate peculiar properties in temporal/conditional adverbials and imperatives. PMID- 27980311 TI - A Case of Resistance to Thyroid Hormone (RTH) with a Negative Family History with Diagnosis Based on Persistent Palpitations. AB - Approximately 140 different mutations of thyroid hormone receptor beta (TRbeta) have been identified in resistance to thyroid hormone (RTH). We report herein a middle-aged man with a negative family history who was diagnosed with RTH based on persistent palpitations. Genetic analysis showed a TRbeta mutation causing the substitution of alanine for proline 453 (P453A) in exon 10. Since treatment of RTH is different from that of Graves' disease and thyroid stimulating hormone producing adenoma (TSHoma), a genetic analysis should be performed even in patients who have a negative family history of RTH and who are free of TSHoma when they present with persistent inappropriate secretion of thyroid stimulating hormone (SITSH). PMID- 27980312 TI - Troubleshooting in the Treatment of Pseudoarthrosis After a Humeral Diaphyseal Fracture: A Case Report. AB - We report a case of a patient with a history of surgery for insufficient pseudoarthrosis after a humeral diaphyseal fracture. Although most humeral nonunions are successfully treated with a single procedure, some humeral nonunions are more difficult to heal and require multiple procedures. A-61-year old man presented at our hospital with pain and deformity in his left upper arm. The humeral diaphyseal fracture had been previously treated elsewhere with open reduction and internal fixation. Some days prior to his visit at our hospital, he had had pain in his left upper arm, without a particular cause, and was admitted to our hospital for initial evaluation. After a complete physical examination, symptoms of infection and any neurovascular deficit were ruled out. Radiographic examination revealed atrophic nonunion of the middle third of the humeral shaft associated with disuse osteopenia. Anterograde intramedullary nailing and bone grafting were performed for the resistant atrophic nonunion of the humeral diaphysis. In addition to the intramedullary nailing, additional fixation was performed for residual rotational instability. A postoperative evaluation revealed a periprosthetic fracture in the distal part of the humerus. Poor bone quality or a deficient plate technique might have lead to the facture. We performed open reduction and internal fixation (ORIF): he underwent fixation with a 2-plate construct for the nonunion of the humeral diaphyseal fracture, together with decortication, debridement, and bone grafting. Eight months after surgery, the patient's bone had healed and he had recovered flexion (110 degrees ) and extension (-30 degrees ) without complications. An orthopedic surgeon should be aware of these complications when choosing open reduction and internal fixation for the treatment of a history of insufficient pseudoarthrosis. Patients should be closely followed up for evidence of any complications such as infections and malunions. Fracture fixation in patients with pseudoarthrosis requires strategies to overcome the technical difficulties faced during the procedure. PMID- 27980313 TI - Decomposition Characteristics of Toluene Vapor Using Titanium Dioxide Photocatalyst and Zeolite Thermally Sprayed on an Aluminum Fiber Filter. AB - Decomposition characteristics of toluene vapor by titanium dioxide photocatalyst and zeolite that are prepared by thermal spraying on an aluminum fiber filter (photocatalyst filter) were investigated. Toluene vapor was injected into a small chamber made of stainless steel, and an air cleaner equipped with the photocatalyst filter was operated. The vapor concentration in the chamber decreased exponentially. The decreasing rate of toluene vapor in the chamber depended on the initial toluene concentration, and the higher the initial vapor concentration was, the lower the decreasing rate was obtained. The decreasing rate was constant during each decomposition experiment, although the concentration decreased with time. To investigate the effect of zeolite on the reduction of the vapor concentration, we compared the decreasing rates of toluene vapor by photocatalyst filters with and without zeolite.The decreasing rate of toluene concentration using the filter without zeolite was larger than that with zeolite. The reason for this would be that photocatalyst decomposed toluene not only in air but also adsorbed in zeolite. PMID- 27980314 TI - Comparison of the Time Course of Return to Work After Stroke Between Two Cohort Studies in Japan. AB - The conditions for stroke rehabilitation such as individual therapeutic procedure and medical treatment system in Japan have drastically changed over the past decade: increasing incidence of ischemic stroke, the use of intravenous recombinant tissue plasminogen activator, hospital specialization, introduction of convalescent rehabilitation wards, and public long-term care insurance. However, it is not known whether these changes have influenced the time course of return to work (RTW) after stroke. In this study we compared the time course of RTW after stroke in Japan that was reported in two cohort studies performed 20 years apart. The cumulative rate of RTW after first stroke was similar in the two studies, even though they were separated by an interval of two decades. This shows that advances in stroke rehabilitation have not impacted RTW, and we suggest that the social security system, particularly sickness benefit, has a strong influence on RTW. PMID- 27980315 TI - The Relation Between the Nurses' Difficulties About Care for People with Mental Disorder in General Wards and Their Negative Feeling About Hospitalization of the People. AB - The aim of this study was to explore the relations between nurses' difficulties in caring for persons living with mental disorders and negative feeling about hospitalization of these persons in general wards. Out of 150 nurses working in a local general hospital in Japan, 86 were eligible for this study. Exploratory factor analysis of the question items for symptoms and conditions with which the nurses had difficulty revealed two principal factors: symptoms like psychosis and neurosis. These factors were then compared in terms of the attitudes that nurses had toward hospitalizing those persons with mental disorders. The greater the negative attitudes toward hospitalizing the persons with mental disorders, the greater the difficulty in caring for them. It is thought that symptoms like psychosis were considered to be caused by schizophrenia, epilepsy, and dementia, and symptoms like neurosis were caused by mood disorder, personality disorder and depression. These principal factors seemed to be with two different difficulties. One is about dealing with their symptoms, another is to distinguish them. Non psychiatric nurses seemed to be working without confidence in caring for those with mental health disorders. We thought the workloads were increased by symptoms like psychosis and mental burdens on nurses as emotional labors were increased by symptoms like neurosis. Therefore, it is necessary for nurses working in general wards to improve the consultation support system about mental disorders. PMID- 27980316 TI - Relationship Between Oxytocin and Pain Modulation and Inflammation. AB - Oxytocin (OXT), which is a well-known neurohypophysial hormone that is synthesized in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus, is secreted from the posterior pituitary (PP) into the systemic circulation, where it plays an essential role in reproduction, especially during and after childbirth. Many recent studies have shown that OXT contributes to the modulation of several functions, such as social recognition, trust building, anti nociception, anti-inflammation, stress relief and suppression of feeding. However, little is known about the neuronal networks responsible for OXT effects. Endogenious OXT has two regulations: the 1st regulation is humoral regulation, in which OXT is delivered to target organs from PP via the bloodstream; the 2nd regulation is nerve regulations, in which OXT from parvocellular neurosecretory neurons in the PVN directly project to the central nerve system (CNS). OXT binding sites, as well as OXT receptor expression, are located in various regions of the CNS, including the dorsal horn of spinal cord in rats, where it plays an important role in nociception. We examined the response to acute and chronic nociception/-inflammation in rat models using OXT-monomeric red fluorescent protein 1 (mRFP1) transgenic rats. We used formalin test as acute nociceptive/ inflammatory rat models and adjuvant arthritis as chronic nociceptive/ inflammatory rat models. We studied the effects of acute and chronic nociception/ inflammation on OXT-mRFP1 expression in the hypothalamus, posterior pituitary and spinal cord, and examined the role that OXT plays in acute and chronic nociceptive responses in rats. This review focuses on pain modulation and anti inflammation by OXT according to previous clinical and animal research. PMID- 27980317 TI - Collection of DICOM RDSR (Digital Imaging and Communication in Medicine, Radiation Dose Structured Report) Information Aimed at Reducing Patient Exposure Dose. AB - The recent progress in angiography technology bestows benefits on patients for minimally invasive than surgery, while there has been an increase in the number of cases involving stochastic effects, such as radiation dermatitis, resulting from upgrading of the procedure because of an extension of the time for fluoroscopy and the number of shots. Recent CT equipment saves the dose data along with image data about the information management for patient exposure dose, which is used for management of individual cumulative dose and the presumed effective dose, using digital imaging and communication in medicine (DICOM). We extracted detailed information about shooting conditions and dose from the DICOM radiation dose structured report (DICOM RDSR) in the angiography area, and evaluated the trend of patient exposure dose in each procedure. As a result, we found that cases exceeding 3 Gy which needed observation in the head region were 16.7% and in the heart region were 27.3%. We also found that angiography had a higher dose of shooting than did fluoroscopy, and that the diagnosis and treatment with tumor involvement required a exposure dose than did vascular lesion. In this paper, we review the shooting conditions as a root of DICOM RDSR information and consider the possibility of planning for further reduction of the exposure dose. PMID- 27980321 TI - Beta Cell Function and Insulin Resistance After Conversion from Tacrolimus Twice Daily to Extended-Release Tacrolimus Once-Daily in Stable Renal Transplant Recipients. AB - BACKGROUND Post-transplantation diabetes mellitus is a major metabolic adverse effect of tacrolimus (TAC). The objective of this study was to determine if the conversion from tacrolimus twice-daily (TAC-BID) to extended-release tacrolimus once-daily (TAC-OD) in stable renal transplant recipients had any effect on beta cell function (HOMA-b), insulin resistance (HOMA-IR), patient preference, and expense. MATERIAL AND METHODS Twenty-eight renal transplant recipients were recruited and converted from TAC-BID to TAC-OD at the same dose. Primary outcomes were beta cell function and insulin resistance in stable renal transplant recipients at 4, 8, and 16 weeks after conversion. Secondary outcomes were patient satisfaction and expense of medication. RESULTS No significant change in the HOMA-beta and HOMA-IR was found in any of the 28 renal transplant recipients. However, HOMA-beta increased from 60 (37.33, 109.71) to 78.5 (44.3, 108.4) (p=0.02) in 15 patients who had the conversion within 4 years after renal transplantation. In multivariate regression analysis, the conversion from TAC-BID to TAC-OD significantly increased HOMA-b at 4 months at 1.21 mIU/mmol (95%CI 0.54 1.88 mIU/mmol, p=0.01) in this subgroup. The renal transplant recipients reported the conversion was more satisfactory and cost of treatment was comparable. CONCLUSIONS In short-term follow-up, conversion from TAC-BID to TAC-OD is safe in stable renal transplant recipients and might be beneficial in term of improved beta cell function in the early years after renal transplantation. The conversion caused comparable cost and was preferred by renal transplant recipients. PMID- 27980320 TI - Substance P Inhibits the Collagen Synthesis of Rat Myocardial Fibroblasts Induced by Ang II. AB - BACKGROUND The aim of this study was to explore the regulating effects of Substance P (SP) on the collagen synthesis of rat myocardial fibroblasts (CFBs) induced by angiotensin II (Ang II) and its potential mechanism. MATERIAL AND METHODS The CFBs of a neonatal SD rat were separately cultured and divided into the control group, Ang II treatment group, and treatment groups with different concentrations of SP, Ang II +; each group was given corresponding treatment respectively. RESULTS Ang II successfully induced the collagen synthesis of CFBs. Compared with the control group, the phosphorylation levels of TGF-beta, erk, and smad2/3 were higher (p<0.05). Different concentrations of SP had an effect on Ang II-induced CFBs, reduced the collagen synthesis of CFBs, and increased the expressions of SP receptors, accompanied by lowering TGF-beta protein, erk protein phosphorylation level, and smad2/3 protein phosphorylation level (p<0.05). Moreover, the higher the concentrations of SP, the more obvious of an effect it exerted. Treating the Ang II + SP group with aprepitant reduced the inhibiting effects of SP on collagen synthesis. The expression changes of collagen I and collagen III detected by immunocytochemistry were exactly in accordance with the results of qPCR and Western blotting. CONCLUSIONS SP can inhibit collagen synthesis of CFBs after Ang II inducing which may adjust the downstream signaling pathways associated protein including TGF-beta, erk and smad2/3. SP can block the progress of myocardial fibrosis and is dose dependent, which is expected to be a promising target for the treatment of myocardial fibrosis. PMID- 27980322 TI - Sirtuin1 (SIRT1) Regulates Tumor Necrosis Factor-alpha (TNF-alpha-Induced) Aquaporin-2 (AQP2) Expression in Renal Medullary Collecting Duct Cells Through Inhibiting the NF-kappaB Pathway. AB - BACKGROUND Aquaporin-2 (AQP2) plays a major role in water reabsorption in the renal collecting duct, and is involved in a variety of renal disease. Recent studies have indicate that sirtuin1 (SIRT1) exerts renoprotective properties against kidney diseases. This study aimed to determine the potential role of SIRT1 in AQP2 expression induced by tumor necrosis factor-alpha (TNF-alpha) and to disclose the underlying mechanism in renal inner medullary collecting duct (IMCD) cells. MATERIAL AND METHODS Quantitative real-time PCR and Western blotting were respectively identified mRNA and protein expression. Immunofluorescence staining was used to detect the localization of AQP2. Small interfering RNA (siRNA) was carried out for mechanism study. RESULTS Results showed that AQP2 was clearly increased in the plasma membrane and decreased in the cytoplasm of IMCD cells treated with AVP. TNF-alpha treatment in IMCD cells significantly reduced SIRT1 and AQP2 expression, and increased acetylated NF kappaBp65 protein level in time- and concentration-dependent manners. Moreover, SIRT1 overexpression or the activator SRT1720 augmented AQP2 expression and reduced the acetylation of NF-kappaBp65, which was reversed by SIRT1 siRNA or the inhibitors Ex527 and sirtinol in TNF-alpha-induced IMCD cells. Knockdown of NF kappaBp65 or NF-kappaBp65 inhibition by pyrrolidine dithiocarbamate (PDTC) enhanced AQP2 expression in IMCD cells exposed to TNF-alpha. Importantly, knockdown of NF-kBp65 augmented the up-regulation of SIRT1 on AQP2 expression in IMCD cells induced by TNF-alpha. CONCLUSIONS These findings indicate that SIRT1 increases AQP2 expression in TNF-alpha-induced IMCD cells via the NF-kappaB dependent signalling pathway, which might provide novel insight to understanding the renoprotective effects of SIRT1 in kidney diseases. PMID- 27980323 TI - Intrathecal Analgesic Drug Delivery is Effective for Analgesia in a Patient with Post-Poliomyelitis Syndrome: A Case Report. AB - BACKGROUND Post-poliomyelitis syndrome (PPS) is a progressive neuromuscular syndrome, with chronic pain being one of the most prevalent symptoms. We present a case report on intrathecal analgesic drug delivery to diminish chro-nic, refractory pain in a patient with PPS. CASE REPORT In a wheelchair-bound 45-year old female patient (Caucasian, body mass index [BMI] 20.5) with severe chronic, refractory pain, a Synchromed(r) II pump (Medtronic, Minneapolis, Minnesota, USA) was implanted after multidisciplinary consultation and a successful trial period. After 8 months, relocation of the pump due to regional pressure problems with surrounding erythema had to occur. A second pump relocation due to pressure pro blems and skin erosion was needed 18 months after the first relocation, moving from the abdominal wall to the sheath of the rectus abdominis muscle, resulting in resolution of the problems. CONCLUSIONS In patients with PPS, intrathecal analgesic drug delivery can be an option to treat chronic, refractory pain. Multidisciplinary consultation is necessary to deal with the wide variety of problems in these patients. Skin problems at the site of the pump reservoir can be challenging and time-consuming and, ultimately, can necessitate relocation (or removal) of the device. PMID- 27980324 TI - Short implants had lower survival rates in posterior jaws compared to standard implants. AB - Data sourcesPubMed/Medline, Embase and Cochrane Library databases supplemented by searches of the journals; Clinical Implant Dentistry and Related Research, Clinical Oral Implants Research, International Journal of Oral and Maxillofacial Implants, International Journal of Oral and Maxillofacial Surgery, Journal of Clinical Periodontology, Journal of Dentistry, Journal of Oral and Maxillofacial Surgery, Journal of Oral Implantology, Journal of Oral Rehabilitation, Journal of Periodontology, Periodontology 2000.Study selectionRandomised controlled trials (RCTs) and prospective studies with at least ten patients, published in the last ten years that compared short and standard implants and published in English were considered.Data extraction and synthesisA single author abstracted data with checking by a second reviewer. Methodological quality was assessed using the Jadad Scale and the Cochrane risk of bias tool. Risk ratios (RR) were calculated for implant survival rates, complications and prostheses failures and marginal bone loss was evaluated using mean difference (MD).ResultsThirteen studies consisting of ten RCTs and three prospective studies were included. The ten RCTs were considered to be of high quality. Two thousand six hundred and thirty-one implants were placed in 1269 patients (981 short and 1650 standard implants). Thirty-eight short implants failed (3.87%) and 45 standard implants (2.72%). Random effects meta-analysis found no statistically significant difference between standard implants and short implants placed in the posterior regions; RR =1.35 (95% CI; 0.82-2.22: P=0.24). Marginal bone loss was evaluated in nine studies and no differences in marginal bone loss were observed. Complications were reported by seven studies and no significant difference was seen between standard and short implants; RR= 0.54 (95% CI; 0.27-1.09: P = 0.08). There was also no significant difference in prosthesis failures between standard and short implants; RR= 0.96 (95% CI: 0.44-2.09: P = 0.92)ConclusionsShort implants showed marginal bone loss, prosthesis failures and complication rates similar to standard implants, being considered a predictable treatment for posterior jaws, especially in cases that require complementary surgical procedures. However, short implants with length less than 8 mm (4-7 mm) should be used with caution because they present greater risks for implant failures when compared to standard implants. PMID- 27980326 TI - Cone beam computed tomography in pre-surgical assessment of mandibular third molars. AB - DesignMulticentre, randomised controlled clinical trial.InterventionPatients referred for third molar removal received a digital panoramic radiograph(PR). Adults with one or more lower third molars in a close relationship with the mandibular canal were eligible for the study. Patients randomised to the cone beam computed tomography (CBCT) group received a high resolution CBCT scan in addition to the PR. All lower third molar extractions were performed under local anaesthesia without sedation and without antibiotic prophylaxis. Information on variables such as experience of the surgeon, duration of surgery and technique for third molar removal were recorded.Outcome measureThe primary outcome measure was the number of patient-reported altered sensations one week after surgery. Secondary outcomes included the number of patients with an objective IAN injury; permanent IAN injury (>6 months); occurrence of other postoperative complications (wound infection, alveolar osteitis); Oral Health Related Quality of Life-14, questionnaire responses; pain (VAS score); duration of surgery; number of emergency visits; and number of missed days of work or study.ResultsThree hundred and forty-one patients with 477 lower third molars were randomised from three centres. Two hundred and sixty-eight patients with 320 mandibular third molars were analysed according to the intention-to-treat principle for the primary and secondary outcomes. The overall incidence of patient-reported altered sensations one week after surgery was 6.3%. At one week there was no difference in subjective IAN injury between the CBCT and PR group. No significant differences were noted between the two groups for any of the secondary outcomes recorded.ConclusionsAlthough CBCT is a valuable diagnostic adjunct for identification of an increased risk for IAN injury, the use of CBCT does not translate into a reduction of IAN injury and other postoperative complications, after removal of the complete mandibular third molar. In these selected cases with a high risk for IAN injury, an alternative strategy, such as monitoring or a coronectomy, might be more appropriate. PMID- 27980327 TI - Tooth brushing frequency and risk of new carious lesions. AB - Data sourcesMedline, Embase, CINHAL and the Cochrane databases.Study selectionTwo reviewers selected studies, and case-control, prospective cohort, retrospective cohort and experimental trials evaluating the effect of toothbrushing frequency on the incidence or increment of new carious lesions were considered.Data extraction and synthesisTwo reviewers undertook data abstraction independently using pre-piloted forms. Study quality was assessed using a quality assessment tool for quantitative studies developed by the Effective Public Health Practice Project (EPHPP). Meta-analysis of caries outcomes was carried out using RefMan and meta-regressions undertaken to assess the influence of sample size, follow-up period, caries diagnosis level and study methodological quality.ResultsThirty three studies were included of which 13 were considered to be methodologically strong, 14 moderate and six weak. Twenty-five studies contributed to the quantitative analysis. Compared with frequent brushers, self-reported infrequent brushers demonstrated a higher incidence of carious lesions, OR=1.50 (95%CI: 1.34 -1.69). The odds of having carious lesions differed little when subgroup analysis was conducted to compare the incidence between >=2 times/d vs <2 times/d; OR=1.45; (95%CI; 1.21 - 1.74) and >=1 time/d vs <1 time/d brushers OR=1.56; (95%CI; 1.37 - 1.78). Brushing <2 times/day significantly caused an increment of carious lesions compared with >=2/day brushing, standardised mean difference [SMD] =0.34; (95%CI; 0.18 - 0.49). Overall, infrequent brushing was associated with an increment of carious lesions, SMD= 0.28; (95%CI; 0.13 - 0.44). Meta analysis conducted with the type of dentition as subgroups found the effect of infrequent brushing on incidence and increment of carious lesions was higher in deciduous, OR=1.75; (95%CI; 1.49 - 2.06) than permanent dentition OR=1.39; (95% CI: 1.29 -1.49). Meta-regression indicated that none of the included variables influenced the effect estimate.ConclusionsIndividuals who state that they brush their teeth infrequently are at greater risk for the incidence or increment of new carious lesions than those brushing more frequently. The effect is more pronounced in the deciduous than in the permanent dentition. A few studies indicate that this effect is independent of the presence of fluoride in toothpaste. PMID- 27980328 TI - Muscular activity may improve in edentulous patients after implant treatment. AB - Data sourcesMedline via Pubmed and the Cochrane Library were searched from January 1980 to September 2013. This was complemented by a manual search of the magazines Deutsche Zahnaerztliche Zeitung, Quintessenz, Zeitschrift fur Zahnarztliche Implantologie, Schweizerische Monatszeitschrift and Implantologie. Additionally, the list of reference s of all selected full-text articles and related reviews were further scrutinised for potential included studies in English or German.Study selectionThree review authors independently searched for clinical trials that assessed the muscular activity in the intervention groups: edentulous patients treated with implant-overdentures (IODs) and implant supported fixed dental prostheses (ISFDPs) and the comparison groups: dentates and edentulous patients treated with mucosa-borne complete removable dental prostheses (CRDPs).Data extraction and synthesisThe primary outcome was the muscular activity (measured by electromyography [EMG]) in masseter or temporalis muscle of the participants during clenching and chewing. The data extraction of each included study consisted of author, year, age range, treatment, number of participants, number of implants inserted, arch treated, opposite jaw, kind and side of the muscles that were measured. EMG gain or loss (unit measured: volt) was considered by using the effect size. For the meta-analyses only the studies that included masseter muscle measured separately from temporalis were considered. Concerning the side of measurement (right and left side measured together or right and left side measured separately), only the dominant type in each category was included.ResultsSixteen articles, out of the initial 646 retrieved abstracts, were analysed. The muscular activity of edentulous subjects increased after implant support therapy during clenching (effect size [ES]: 2.18 [95% confidence interval [CI]: 1.14, 3.23]) and during chewing (ES: 1.45 [95 % CI: 1.21, 1.69]). In addition, the pooled EMG data of IODs and ISFDPs were lower than that of dentate subjects during clenching (ES: -1.01 [95% CI: -1.37, 0.65]). However, the ISFDPs showed higher values than dentates during chewing. Among the edentulous patients the IODs and ISFDPs displayed higher pooled values during clenching (ES: 1.12 [95% CI: 0.7, 1.55]) and chewing (ES: 1.33 [95% CI: 0.57, 2.10]). Furthermore, the muscular activity during chewing correlated with the hardness of the food.ConclusionsEdentulous patients with CRDPs can achieve a greater degree of muscular activity after rehabilitation with implant supported/retained prostheses during clenching and chewing. During clenching, patients with ISFDPs achieved higher EMG-values than those with dentates. The harder the food, the more muscular activity involved. PMID- 27980329 TI - Preventative therapies and periodontal interventions for Down syndrome patients. AB - Data sourcesMedline, Embase, Cochrane CENTRAL and OpenGREY databases without language restriction until March 2016 plus manual searching of four specific journals and consideration of reference lists.Study selectionStudies evaluating different methods of periodontal treatment in Down syndrome patients measuring at least two periodontal parameters at different periods of assessment. Titles, abstracts and full texts were considered by two independent reviewers and a third where discussion did not reach consensus. Randomised controlled trials were evaluated using the Cochrane risk of bias tool. The observational studies were evaluated using an adapted version of the Newcastle-Ottawa Scale.Data extraction and synthesisData extraction was carried out independently by two reviewers and organised into evidence tables. No meta-analysis was undertaken, however a narrative synthesis was presented.ResultsNine studies met the inclusion criteria; four longitudinal studies, one prospective case series and four clinical trials which included two cross-over studies and a controlled trial. The studies showed marked heterogeneity in terms of methodology, intervention and outcome measures. All studies, however, included assessment of different plaque and gingival indices.Three studies investigated outcomes after scaling and root planing, one of which compared surgical and non-surgical approaches. Periodontal pockets of 1 3 mm were statistically significantly improved with non-surgical treatment in comparison with pockets greater than 4 mm which showed greater reduction with surgical treatment. Six studies investigated different forms and uses of chlorhexidine, three of which investigated its use as an adjuvant to mechanical debridement and one which also included plaque disclosing as an intervention. Chlorhexidine was shown to be most effective when used daily as a 1% gel for toothbrushing. The use of a plaque disclosing tablet and fluoridated tooth paste, however, showed further improved outcomes with regards to plaque control.ConclusionsEight of the nine studies included showed improvement in the primary outcomes of improved plaque and gingival bleeding indices. Professional intervention and periodontal maintenance significantly reduced plaque and gingival indices, irrespective of the treatment performed. Increased frequency of interventions was associated with better outcomes, especially in younger age groups. PMID- 27980330 TI - Patient and miniscrew implant factors influence the success of orthodontic miniscrew implants. AB - Data sourcesMedline via PubMed, Scopus and Web of Science databases were searched from January 2003 to March 2015 limited to human studies published in English. Manual searches for the relevant reference lists and a grey literature search via Google Scholar were also conducted.Study selectionProspective and retrospective studies about the stability of miniscrew implants (MIs) used for orthodontic anchorage into the posterior buccal region were considered. Two review authors independently assessed titles and abstracts, and evaluated full manuscripts for the meta-analysis.Data extraction and synthesisThe outcome measure was the success rate of MIs which had to be explicitly reported in order to enable its computation as odds ratios with regards to patient factors (age (years), < 20 vs. >= 20; sex, male vs. female; jaw of insertion, maxilla vs. mandible) and MI factors (length, < 8 mm vs. >= 1.4 mm; diameter, <= 1.4 mm vs. > 1.4 mm). The quality of the studies was assessed using the Newcastle-Ottawa Scale (NOS). The meta-analysis was expressed as combined OR and heterogeneity was evaluated (Cochran Q and I2). Subgroup meta-analysis was conducted based on study design, study quality and MIs sample size. Publication bias analysis (Begg's and Eggar's tests) and sensitivity analysis were performed.ResultsSeventeen non-randomised studies, five prospective and 12 retrospective, were included. Significantly higher success rates were observed for the maxillary MIs (14 studies odds ratio (OR), 2.32; 95% CI, 1.81-4.08), older patients (six studies OR, 1.59; 95% CI, 1.14-2.22), and for longer MIs (four studies OR, 0.56 (1/0.46= 2.17); 95% CI, 0.26-0.20) and MIs with larger diameter (four studies OR, 0.62 (1/0.62= 1.61); 95% CI, 0.40-0.97), whereas there was no difference observed between male and female patients (13 studies OR, 1.18; 95% CI, 0.92-1.51). All subgroups acquired homogeneity except for the components of study design regarding the jaw of insertion.ConclusionsThe results of this meta-analysis based on non-randomised clinical studies showed that jaw of insertion, age, MI length and MI diameter are critical risk factors to the success of MIs, whereas sex was not influential.Source of FundingThe Basic Science Research Program of the National Research Foundation of Korea was stated as the source of funding. PMID- 27980332 TI - Antibiotics in aggressive periodontitis, is there a clinical benefit? AB - Data sourcesMedline, Embase and CENTRAL databases were searched up to December 2014. Unpublished data were sought by searching a database listing unpublished studies OpenGray [http://www.opengrey.eu/], formerly OpenSIGLE.Study selectionRandomised clinical trials assessing treatment of patients with AgP comparing scaling and root planing (SRP) alone with SRP plus a single antibiotic or a combination of drugs with a minimum of three months follow-up were considered. Studies specifically designed to evaluate smokers or subjects with diabetes mellitus and HIV/AIDS were not included.Data extraction and synthesisTwo researchers independently screened titles, abstracts and full texts of the search results. The studies, which fulfilled inclusion criteria, underwent validity assessment and data extraction using a specifically designed form. The quality of included studies was assessed using the Cochranes collaboration tool for risk of bias. Only two of the 11 included trials were considered at a low risk of bias. The data extracted from ten studies was analysed by pair-wise meta-analyses and the data extracted from five studies was included in Bayesian network meta analyses pooled estimates. The six studies evaluated in the pairwise meta analyses were excluded in the pooled estimates because four studies included patients with advanced disease only and one study did not present average data for pocket depth (PD) and clinical attachment level (CAL) and another one for using a different mechanical treatment.ResultsFourteen studies reporting 11 randomised clinical trials with a total of 388 patients were included in the review. Nine of 11 studies reported a statistically significant greater gain in full mouth mean clinical attachment (CA) and reduction in probing depth (PD) when a systemic antibiotic was used. From those studies the calculated mean difference for CA gained was 1.08 mm (p < 0.0001) and for PD reduction was 1.05 mm (p< 0.00001) for SRP + Metronidazole (Mtz). For SRP + Mtz+ amoxicillin (Amx) group the mean difference was 0.45 mm for CA gained and 0.53 mm for PD reduction (p<0.00001) than SRP alone/placebo. Bayesian network meta-analysis showed some additional benefits in CA gain and PD reduction when SRP was associated with systemic antibiotics.ConclusionsThe results support a statistically significant benefit of adjunctive systemic antibiotics in the treatment of AgP. The most consistent advantages - reduction in PD and CAL gain - were attained with the use of Mtz and Mtz + Amx. Future RCTs should be designed in order to directly compare these two antibiotic protocols in the treatment of AgP. PMID- 27980334 TI - Orthodontic retention to have and to hold. AB - Data sourcesCochrane Oral Health Group's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, US National Institutes of Health Trials Registry and The World Health Organization (WHO) Clinical Trials Registry Platform, abstracts from the British Orthodontic Conference, the European Orthodontic Conference and the International Association for Dental Research (IADR) from 2011 to 2015 and the bibliographies of identified studies.Study selectionRandomised controlled trials (RCTs) involving children and adults who had had retainers fitted or adjunctive procedures undertaken to prevent relapse following orthodontic treatment with braces were considered.Data extraction and synthesisTwo reviewers independently selected studies, abstracted data and assessed study quality. For continuous data mean differences (MD) with 95% confidence intervals (CI) were calculated with ratios (RR) and 95% CI for dichotomous outcomes.ResultsFifteen studies involving a total of 1722 patients were included. Seven studies were considered to be at high risk of bias, four at low risk and four at unclear risk. For removable retainers versus fixed retainers (three studies) there was low quality evidence that thermoplastic removable retainers provided slightly poorer stability in the lower arch than multistrand fixed retainers: MD (Little's Irregularity Index, 0 mm is stable) 0.6 mm (95% CI 0.17 to 1.03) and of less gingival bleeding with removable retainers: RR 0.53 (95%CI; 0.31 to 0.88). Patients found fixed retainers more acceptable to wear, with a mean difference on a visual analogue scale (VAS; 0 to 100; 100 being very satisfied) of -12.84 (95% CI -7.09 to -18.60).For different types of fixed retainers (four studies) data from three studies (228 patients) comparing polyethylene ribbon bonded retainer versus multistrand retainer were pooled showing no evidence of a difference in failure rates. RR = 1.10 (95%CI; 0.77 to 1.57).Pooled data from two trials (174 patients) comparing the same types of upper fixed retainers, showed a similar finding: RR =1.25 (95%CI; 0.87 to 1.78).For different types of removable retainers (eight studies) one study at low risk of bias comparing upper and lower part-time thermoplastic versus full-time thermoplastic retainers showed no evidence of a difference in relapse (graded moderate quality evidence). Another study, comparing part-time and full-time wear of lower Hawley retainers, found no evidence of any difference in relapse (low quality evidence). Two studies at high risk of bias suggested that stability was better in the lower arch for thermoplastic retainers versus Hawley, and for thermoplastic full-time versus Begg (fulltime) (both low quality evidence). In one study, participants wearing Hawley retainers reported more embarrassment more often than participants wearing thermoplastic retainers: RR 2.42 (95% CI 1.30 to 4.49; one trial, 348 participants, high risk of bias, low quality evidence). They also found Hawley retainers harder to wear. There was conflicting evidence about survival rates of Hawley and thermoplastic retainers.For combination of upper thermoplastic and lower bonded versus upper thermoplastic with lower adjunctive procedures versus positioner (one study) there was no evidence of a difference in relapse between the combination of an upper thermoplastic and lower canine to canine bonded retainer and the combination of an upper thermoplastic retainer and lower interproximal stripping, without a lower retainer. Both these approaches are better than using a positioner as a retainer.ConclusionsWe did not find any evidence that wearing thermoplastic retainers fulltime provides greater stability than wearing them part-time, but this was assessed in only a small number of participants. Overall, there is insufficient high quality evidence to make recommendations on retention procedures for stabilising tooth position after treatment with orthodontic braces. Further high quality RCTs are needed. PMID- 27980335 TI - An orthodontic patient expects? AB - Data sourcesPubmed, Cochrane, Web of Science and PsychINFO databases.Study selectionExperimental studies (randomised or not, prospective, retrospective and cross sectional) with qualitative and/or quantitative analysis investigating patients' expectations of orthodontic treatment were considered. Only English language studies were included.Data extraction and synthesisTwo reviewers screened the studies with a single reviewer abstracting the data. Study quality was assessed by two reviewers using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria. Because of heterogeneity of the study designs a narrative summary was presented.ResultsFourteen papers reporting 13 studies were included. There was one RCT, one cohort study, two questionnaire-developments and ten cross-sectional studies. Seven studies summarising expectations with regards to the treatment process, experience and impact on quality of life, and six studies summarising expectations with regards to the treatment outcome and benefits were discussed.ConclusionsOrthodontics appears to have adopted various standardised questionnaires. However, most of them are poor in the quality of methodology and results analysis, which prohibits synthesising sufficient evidence to help identify which factors influence patient expectations. The evidence of 'expectations' affecting treatment outcomes is not found in current research. Future studies are needed to better understand the impact of 'expectation' on the treatment both theoretically and experimentally. PMID- 27980336 TI - In patients with shortened dental arches do removable dental prostheses improve masticatory performance? AB - Data sourcesPubMed, Medline, Cochrane Library, Embase and Science Direct.Study selectionStudies published in English providing data on patients with shortened dental arch (SDA) and extreme SDA (ESDA) and masticatory performance with removable dental prostheses (RDP) were included.Data extraction and synthesisTwo reviewers independently selected studies and abstracted data, with disagreements being resolved by discussion.ResultsEight studies were included; four reported on comminution studies, three on mixing ability and one included both. In patients with ESDA comminution or mixing ability was 28-39% lower compared to patients with a complete dentition. In two studies, comminution outcomes when chewing with an RDP ranged from 2% to 32% reduction, indicating better chewing function (smaller X50) compared to comminution without the RDP. One study reported 28-83% lower mixing ability when chewing at the RDP side than chewing at the dentulous side. Generally, more artificial teeth (or longer occlusal platform) in experimental RDPs resulted in better comminution and better mixing ability (significant in four out of five studies), indicating a 'dose-effect' relationship. Two of the eight studies reported on biting force with higher maximum occlusal force for biting with natural teeth than for biting with artificial teeth in a distal-extension RDP.ConclusionsWithin the limitations of this review it can be concluded that subjects with (E)SDA had a reduced masticatory performance in the order of 30-40%. Distal-extension RDPs compensated for this reduction only partially, namely in the order of 50%. RDP effects on chewing frequency were not conclusive. PMID- 27980337 TI - Continuous cooling mask devices reduce patient discomfort and postoperative pain and swelling in patients undergoing orofacial surgery. AB - Data sourcesThe resources searched included: Medline, PubMed, Embase, CINAHL, CAB Abstracts, the Cochrane Library and Google Scholar. The PRISMA guidelines for reporting systematic reviews were followed. Study selection was limited to the English language. Hand searching for additional references was performed. An intensive search was conducted for published articles describing the use of hilotherapy following oral and maxillofacial surgery.Study selectionInclusion criteria involved patients using hilotherapy after oral and maxillofacial surgery. Non-human studies were excluded. All articles were evaluated for study design, perioperative data, ethical suitability, follow-up data and surgical data reporting.Data extraction and synthesisTwo authors independently judged articles for suitability for the review. A kappa statistic test was used to calculate and to measure concordance in the author's final decisions to include studies. The agreement was 83% and considered moderate. Following data extraction a meta analysis was conducted. Heterogeneity was calculated due to the variability among the studies (different number of surgical procedures, patient age, duration of the device application, different methods of postoperative pain measurement and analgesics protocol). Standard mean differences (SMD) with 95% confidence interval (CI) were calculated for the continuous measurements. The studies were assessed and rated using the Oxford Centre for Evidence-Based Medicine Levels of Evidence criteria (all studies were rated as 2b). Publication bias was assessed.ResultsThe initial search identified 552 results. Twelve papers were included in the review, and five with a total of 206 patients were used for the meta-analysis. The studies analysed were prospective comparative studies of patients undergoing oral maxillofacial surgery. Hilotherapy reduced pain (ten point visual analogue scale) at 48 hrs (P <0.010) and 72 hrs (P<0.050) as well as postoperative facial oedema (P <0.010) compared to ice-cooling treatment. Trismus and facial neurological scores were also improved (P<0.08). Patients preferred hilotherapy to other cooling methods (P< 0.010).ConclusionsHilotherapy appears to be effective in reducing postoperative facial pain, oedema and trismus and in improving patient-reported outcomes. PMID- 27980338 TI - One-phase or two-phase orthodontic treatment? AB - Data sourcesMedline, Embase, Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), LILACS, BBO, ClinicalTrials.gov, the National Research Register and Pro-Quest Dissertation Abstracts and Thesis database.Study selectionRandomised controlled trials (RCTs) and controlled trials (CCTs) in children under 11 years at the beginning of treatment for interventions including; interceptive extractions, space maintenance, crossbite correction and habit dissuasion were considered.Data extraction and synthesisTwo reviewers independently extracted data and assessed study quality using the Cochrane Risk of Bias tool. Meta-analysis was possible for 11 comparisons.ResultsTwenty-two studies (18 RCTs, three CCTs) were included with 20 being considered to be at low or unclear risk of bias. For Class II correction in the short-term, meta-analyses demonstrated a statistically significant reduction in ANB (-1.4 degrees, 95 CI: -2.17, -0.64) and overjet ( 5.81mm, 95 CI: -6.37, -5.25) with both functional appliances and headgear versus control. For Class II correction in the long-term, however, statistical significance was not found for the same outcomes. Treatment duration was prolonged with both functional appliances (6.85 months, 95 CI: 3.24, 10.45) and headgear (12.47 months, 95 CI: 8.67, 16.26) compared to adolescent treatments. Meta-analyses were not possible for comparisons of other interceptive treatments due to heterogeneity and methodological limitations. The overall quality of the evidence based on the GRADE assessment suggested that the level of evidence was low to moderate.ConclusionsThe results suggest a lack of evidence to prove that early treatment carries additional benefit over and above that achieved with treatment commencing later; however, this does not imply that early treatment is ineffective. The additional cost and burden to the patient, parent and clinician may, therefore, generally negate early treatment. Further trials of high quality of evidence are required assessing the effectiveness of interceptive treatment for a range of occlusal problems, particularly those not known to hinge on growth potential, with long-term follow up to ascertain whether short-term effects are maintained once growth has ceased and to delineate the effects of intervention timing on the overall treatment duration. PMID- 27980339 TI - No confidence that success rates of self-drilling and self-tapping insertion techniques of orthodontic mini-implants are similar. AB - Data sourcesMedline, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, China National Knowledge Infrastructure (CNKI) and SIGLE.Study selectionRandomised controlled trials(RCTs), clinical controlled trials (CCTs) and cohort studies that assessed the success/failure rates of self-drilling and self-tapping mini-screws for orthodontic anchorage were considered.Data extraction and synthesisData was abstracted and assessed for quality by two reviewers independently. The Newcastle-Ottawa scale (NOS) was used to evaluate the methodological quality. Meta-analyses with subgroup analysis of different study designs, follow-up periods, participant age and immediate loading or delayed loading were conducted.ResultsThree CCTs and three cohort studies were included. These were assessed to be of high quality. Meta-analysis (six studies) showed no difference in success rates between the two types of screws; odds ratio (OR) = 0.90 (95%CI; 0.52-1.53). Meta-analysis (two studies) found no difference in the rate of root contact between the two systems; OR = 0.96 (95% CI; 0.53 1.71).ConclusionsCurrently available clinical evidence suggests that the success rates of self-tapping and self-drilling miniscrews are similar. Determination of the position and direction of placement should be more precise when self-drilling miniscrews are used in sites with narrow root proximity. PMID- 27980340 TI - Trial watch: Opportunities and challenges of the 2016 target landscape. PMID- 27980342 TI - Evaluation of a tyrosine kinase peptide microarray for tyrosine kinase inhibitor therapy selection in cancer. AB - Personalized cancer medicine aims to accurately predict the response of individual patients to targeted therapies, including tyrosine kinase inhibitors (TKIs). Clinical implementation of this concept requires a robust selection tool. Here, using both cancer cell lines and tumor tissue from patients, we evaluated a high-throughput tyrosine kinase peptide substrate array to determine its readiness as a selection tool for TKI therapy. We found linearly increasing phosphorylation signal intensities of peptides representing kinase activity along the kinetic curve of the assay with 7.5-10 MUg of lysate protein and up to 400 MUM adenosine triphosphate (ATP). Basal kinase activity profiles were reproducible with intra- and inter-experiment coefficients of variation of <15% and <20%, respectively. Evaluation of 14 tumor cell lines and tissues showed similar consistently high phosphorylated peptides in their basal profiles. Incubation of four patient-derived tumor lysates with the TKIs dasatinib, sunitinib, sorafenib and erlotinib primarily caused inhibition of substrates that were highly phosphorylated in the basal profile analyses. Using recombinant Src and Axl kinase, relative substrate specificity was demonstrated for a subset of peptides, as their phosphorylation was reverted by co-incubation with a specific inhibitor. In conclusion, we demonstrated robust technical specifications of this high-throughput tyrosine kinase peptide microarray. These features required as little as 5-7 MUg of protein per sample, facilitating clinical implementation as a TKI selection tool. However, currently available peptide substrates can benefit from an enhancement of the differential potential for complex samples such as tumor lysates. We propose that mass spectrometry-based phosphoproteomics may provide such an enhancement by identifying more discriminative peptides. PMID- 27980344 TI - A goodness-of-fit test for structural nested mean models. AB - Coarse structural nested mean models are tools to estimate treatment effects from longitudinal observational data with time-dependent confounding. There is, however, no guidance on how to specify the treatment effect model, and model misspecification can lead to bias. We derive a goodness-of-fit test based on modified overidentification restrictions tests for evaluating a treatment effect model, and show that our test statistic is doubly-robust in the sense that, with a correct treatment effect model, the test has the correct type-I error if either the treatment initiation model or a nuisance regression outcome model is correctly specified. In a simulation study we show that the test has correct type I error and can detect model misspecification. We use the test to study how the timing of antiretroviral treatment initiation after HIV infection predicts the effect of one year of treatment in HIV-positive patients with acute and early infection. PMID- 27980343 TI - IL-17A exacerbates diabetic retinopathy by impairing Muller cell function via Act1 signaling. AB - Diabetic retinopathy (DR), one of the most serious complications of diabetes, has been associated with inflammatory processes. We have recently reported that interleukin (IL)-17A, a proinflammatory cytokine, is increased in the plasma of diabetic patients. Further investigation is required to clarify the role of IL 17A in DR. Ins2Akita (Akita) diabetic mice and high-glucose (HG)-treated primary Muller cells were used to mimic DR-like pathology. Diabetes induced retinal expression of IL-17A and IL-17 receptor A (IL-17RA) in Muller cells in contrast to ganglion cells. Further evidence demonstrated that retinal Muller cells cultured in vitro increased IL-17A and IL-17RA expression as well as IL-17A secretion in the HG condition. In both the HG-treated Muller cells and Akita mouse retina, the Act1/TRAF6/IKK/NF-kappaB signaling pathway was activated. IL 17A further enhanced inflammatory signaling activation, whereas Act1 knockdown or IKK inhibition blocked the downstream signaling activation by IL-17A. HG- and diabetes-induced Muller cell activation and dysfunction, as determined by increased glial fibrillary acidic protein, vascular endothelial growth factor and glutamate levels and decreased glutamine synthetase and excitatory amino acid transporter-1 expression, were exacerbated by IL-17A; however, they were alleviated by Act1 knockdown or IKK inhibition. In addition, IL-17A intravitreal injection aggravated diabetes-induced retinal vascular leukostasis, vascular leakage and ganglion cell apoptosis, whereas Act1 silencing or anti-IL-17A monoclonal antibody ameliorated the retinal vascular damage and neuronal cell apoptosis. These findings establish that IL-17A exacerbates DR-like pathology by the promotion of Muller cell functional impairment via Act1 signaling. PMID- 27980341 TI - Induced pluripotent stem cell technology: a decade of progress. AB - Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, enormous progress has been made in stem cell biology and regenerative medicine. Human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. Novel pathological mechanisms have been elucidated, new drugs originating from iPSC screens are in the pipeline and the first clinical trial using human iPSC-derived products has been initiated. In particular, the combination of human iPSC technology with recent developments in gene editing and 3D organoids makes iPSC-based platforms even more powerful in each area of their application, including precision medicine. In this Review, we discuss the progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, and consider the remaining challenges and the emerging opportunities in the field. PMID- 27980345 TI - Task Equivalence for Model and Human-Observer Comparisons in SPECT Localization Studies. AB - While mathematical model observers are intended for efficient assessment of medical imaging systems, their findings should be relevant for human observers as the primary clinical end users. We have investigated whether pursuing equivalence between the model and human-observer tasks can help ensure this goal. A localization ROC (LROC) study tested prostate lesion detection in simulated In 111 SPECT imaging with anthropomorphic phantoms. The test images were 2D slices extracted from reconstructed volumes. The iterative OSEM reconstruction method was used with Gaussian postsmoothing. Variations in the number of iterations and the level of postfiltering defined the test strategies in the study. Human observer performance was compared with that of a visual-search (VS) observer, a scanning channelized Hotelling observer, and a scanning nonprewhitening (CNPW) observer. These model observers were applied with precise information about the target regions of interest (ROIs). ROI knowledge was a study variable for the human observers. In one study format, the humans read the SPECT image alone. With a dual-modality format, the SPECT image was presented alongside an anatomical image slice extracted from the density map of the phantom. Performance was scored by area under the LROC curve. The human observers performed significantly better with the dual-modality format, and correlation with the model observers was also improved. Given the human-observer data from the SPECT study format, the Pearson correlation coefficients for the model observers were 0.58 (VS), -0.12 (CH), and 0.23 (CNPW). The respective coefficients based on the human-observer data from the dual-modality study were 0.72, 0.27, and -0.11. These results point towards the continued development of the VS observer for enhancing task equivalence in model-observer studies. PMID- 27980346 TI - Cytotoxic gallium complexes containing thiosemicarbazones derived from 9 anthraldehyde: Molecular docking with biomolecules. AB - We have synthesized a trio of gallium complexes bearing 9-anthraldehyde thiosemicarbazones. The complexes were assessed for their anticancer activity and their biophysical reactivity was also investigated. The three complexes displayed good cytotoxic profiles against two human colon cancer cell lines, HCT-116 and Caco-2. The IC50 ranged from 4.7 - 44.1 MUM with the complex having an unsubstituted amino group on the thiosemicarbazone being the most active. This particular complex also showed a high therapeutic index. All three complexes bind strongly to DNA via intercalation with binding constants ranging from 7.46 * 104 M-1 to 3.25 * 105 M-1. The strength of the binding cannot be directly related to the level of anticancer activity. The complexes also bind strongly to human serum albumin with binding constants on the order of 104 - 105 M-1 as well. The complexes act as chemical nucleases as evidenced by their ability to cleave pBR322 plasmid DNA. The binding constants along with the cleavage results may suggest that the extent of DNA interaction is not directly correlated with anticancer activity. The results of docking studies with DNA, ribonucleotide reductase and human serum albumin, however showed that the complex with the best biological activity had the largest binding constant to DNA. PMID- 27980347 TI - Survival of ship biofouling assemblages during and after voyages to the Canadian Arctic. AB - Human-mediated vectors often inadvertently translocate species assemblages to new environments. Examining the dynamics of entrained species assemblages during transport can provide insights into the introduction risk associated with these vectors. Ship biofouling is a major transport vector of nonindigenous species in coastal ecosystems globally, yet its magnitude in the Arctic is poorly understood. To determine whether biofouling organisms on ships can survive passages in Arctic waters, we examined how biofouling assemblage structure changed before, during, and after eight round-trip military voyages from temperate to Arctic ports in Canada. Species richness first decreased (~70% loss) and then recovered (~27% loss compared to the original assemblages), as ships travelled to and from the Arctic, respectively, whereas total abundance typically declined over time (~55% total loss). Biofouling community structure differed significantly before and during Arctic transits as well as between those sampled during and after voyages. Assemblage structure varied across different parts of the hull; however, temporal changes were independent of hull location, suggesting that niche areas did not provide protection for biofouling organisms against adverse conditions in the Arctic. Biofouling algae appear to be more tolerant of transport conditions during Arctic voyages than are mobile, sessile, and sedentary invertebrates. Our results suggest that biofouling assemblages on ships generally have poor survivorship during Arctic voyages. Nonetheless, some potential for transporting nonindigenous species to the Arctic via ship biofouling remains, as at least six taxa new to the Canadian Arctic, including a nonindigenous cirripede, appeared to have survived transits from temperate to Arctic ports. PMID- 27980348 TI - Cover of coastal vegetation as an indicator of eutrophication along environmental gradients. AB - Coastal vegetation communities are important for primary production, biodiversity, coastal protection, carbon and nutrient cycling which, in combination with their sensitivity to eutrophication, render them potential indicators of environmental status for environmental policies like the EU Water and Marine Strategy Framework Directives. We evaluated one potential indicator for coastal vegetation, the cumulative cover at depths where the vegetation is light limited, by investigating its response to eutrophication along gradients in natural conditions. We used a large data set covering the Swedish coastline, spanning broad gradients in nutrient level, water clarity, seabed substrate, physical exposure and climate in addition to a salinity gradient from 0.5 to 30.5. Macroalgal cover increased significantly along gradients of declining nutrient concentration and increasing water clarity when we had accounted for diver effects, spatio-temporal sampling variability, salinity gradients, wave exposure and latitude. The developed empirical model explained 79% of the variation in algal cover across 130 areas. Based on this, we identified macroalgal cover as a promising indicator across the Baltic Sea, Kattegat and Skagerrak. A parallel analysis of soft-substrate macrophytes similarly identified significant increases in cover with decreasing concentrations of total nitrogen and increasing salinity, but the resulting empirical model explained only 52% of the variation in cover, probably due to the spatially more variable nature of soft-substrate vegetation. The identified general responses of vegetation cover to gradients of eutrophication across wide ranges in environmental settings may be useful for monitoring and management of marine vegetation in areas with strong environmental gradients. PMID- 27980349 TI - Modelling the dynamics of growth, development and lipid storage in the marine copepod Calanus finmarchicus. AB - Mechanistic models are essential tools for interpreting and predicting the consequences of a changing environment and stressors such as pollution on the life histories of marine organisms. Here, we apply the simple and generic energy budget model DEBkiss to the life history of the marine copepod Calanus finmarchicus. Model modifications were needed to accommodate the copepod life cycle, which deviates in several respects from most other animals (e.g., a sudden stop of growth after the final moult). We identified an acceleration of growth in the early copepodite stages, which could be linked to an increase in the specific feeding rate of the animals. Lipid storage, an essential element of C. finmarchicus biology, was successfully captured with the reproduction buffer of the DEBkiss model. The resulting model was fitted to a detailed data set from the literature and was able to explain growth, development and lipid storage from egg to adult, at different temperatures and food availabilities, within a single consistent framework. The parameterised model could subsequently be used to elucidate the energetic constraints on gonad maturation and reproduction. Interestingly, the overhead costs for egg production seem to be substantially higher than the default value applied in DEB-based studies. The current model provides a solid basis for applications in stress ecology, although our model analysis also identified several knowledge gaps. Specifically, further research is needed to cover the dynamics of diapause and gonad maturation, to explain the dependence of maximum body size on food and temperature, and to verify the predicted high costs for maturity maintenance. PMID- 27980350 TI - Patriotism's Impact on Cooperation with the State: An Experimental Study on Tax Compliance. AB - Although it seems reasonable to assume that activating patriotism might motivate citizens to cooperate with the state in reaching societal goals, the empirical evidence supporting this contention is based mostly on correlational rather than experimental studies. In addition, little is known on whether patriotism can be manipulated without simultaneously triggering nationalism and on the psychological processes which determine the patriotism-cooperation relation. This current article reports results of one survey and three experiments that manipulate patriotism by displaying either a national flag or national landscapes or by priming national achievements. The outcomes indicate that reported and manipulated patriotism indirectly increase tax compliance, although the national flag also increases nationalism. National achievements, on the other hand, seemingly increases trust in national public institutions and the voluntary motivation to cooperate, whereas national landscapes only increase the voluntary motivation to cooperate. Hence, it is possible to increase social capital in the form of trust and cooperation through patriotism without fostering nationalism as well. PMID- 27980351 TI - Like Mother(-in-Law) Like Daughter? Influence of the Older Generation's Fertility Behaviours on Women's Desired Family Size in Bihar, India. AB - This paper investigates the associations between preferred family size of women in rural Bihar, India and the fertility behaviours of their mother and mother-in law. Scheduled interviews of 440 pairs of married women aged 16-34 years and their mothers-in-law were conducted in 2011. Preferred family size is first measured by Coombs scale, allowing us to capture latent desired number of children and then categorized into three categories (low, medium and high). Women's preferred family size is estimated using ordered logistic regression. We find that the family size preferences are not associated with mother's fertility but with mother's education. Mother-in-law's desired number of grandchildren is positively associated with women's preferred family size. However, when the woman has higher education than her mother-in-law, her preferred family size gets smaller, suggesting that education provides women with greater autonomy in their decision-making on childbearing. PMID- 27980352 TI - Does the Impact of the Tobacco Epidemic Explain Structural Changes in the Decline of Mortality? AB - Since 1950, most developed countries have exhibited structural changes in mortality decline. This complicates extrapolative forecasts, such as the commonly used Lee-Carter model, that require the presence of a steady long-term trend. This study tests whether the impact of the tobacco epidemic explains the structural changes in mortality decline, as it is presumed in earlier studies. For this purpose, the time index of the Lee-Carter model in males was investigated in 20 developed countries between 1950 and 2011 for possible structural changes. It was found that removing the impact of smoking from mortality trends took away more than half of the 12 detected trend breaks. For the remaining trend breaks, adjusting for smoking attenuated the degree of change in mortality decline. Taking the tobacco epidemic into account should become standard procedure in mortality forecasts to avoid a misleading extrapolation of trends. Nevertheless, more research is needed to identify additional factors, such as health-care policies and innovations in medical treatment, to explain the remaining structural changes. PMID- 27980353 TI - Marriage Migration Versus Family Reunification: How Does the Marriage and Migration History Affect the Timing of First and Second Childbirth Among Turkish Immigrants in Germany? AB - Our study focuses on the fertility of first-generation female and male Turkish migrants in Germany. To evaluate whether timing effects such as fertility disruption or an interrelation of marriage, migration and childbirth occur, we examine first and second births in the years before and after immigration to Germany. The Turkish sample of the Generations and Gender Survey which was conducted in 2006 offers the unique opportunity to examine Turkish immigrants as a single immigrant category. We question the common understanding that Turkish immigrants who arrived to Germany after 1973 mainly arrived for family reunification resulting in high birth intensities immediately after immigration. To distinguish different circumstances under which male and female immigrants have arrived to Germany, we include the combined marriage and migration history of the couple. We find that first birth probabilities are elevated during the years immediately following migration. But this effect is not universal among migrants with different marriage and migration histories. It appears that the arrival effect of high birth intensities is particularly high among female immigrants and is evident only among marriage migrants, that is Turks who married a partner who already lived in Germany at the time of the wedding. By contrast, among those who immigrated for family reunification, we do not find such an arrival effect. PMID- 27980354 TI - Multi-fractal Detrended Texture Feature for Brain Tumor Classification. AB - We propose a novel non-invasive brain tumor type classification using Multi fractal Detrended Fluctuation Analysis (MFDFA) [1] in structural magnetic resonance (MR) images. This preliminary work investigates the efficacy of the MFDFA features along with our novel texture feature known as multi-fractional Brownian motion (mBm) [2]in classifying (grading) brain tumors as High Grade (HG) and Low Grade (LG). Based on prior performance, Random Forest (RF) [3] is employed for tumor grading using two different datasets such as BRATS-2013 [4] and BRATS-2014 [5]. Quantitative scores such as precision, recall, accuracy are obtained using the confusion matrix. On an average 90% precision and 85% recall from the inter-dataset cross-validation confirm the efficacy of the proposed method. PMID- 27980355 TI - Counselors' Perspectives of Positive Psychology for the Treatment of Addiction: A Mixed Methods Pilot Study. AB - Little is known about the use of positive psychology interventions (PPI) in addictions treatment. Questionnaires and interviews with alcohol and substance use disorder counselors explored theories of how PPIs might work, the degree to which they are used, and downsides. Results suggested that positive and pathology based themes were attended in equal proportion, that substance abuse treatment should help clients develop a good life in recovery; that counselors already use PPI; and that PPI might counter negative cognitions and affect. Reservations for using PPI included relying on PPI exclusively and employing PPI indiscriminately without regard to client characteristics. PMID- 27980356 TI - To Be or Not to Be in Thrall to the March of Smart Products. AB - This article explores how perceived disempowerment impacts the intention to adopt smart autonomous products. Empirically, the paper builds on three studies to show this impact. Study 1 explores the relevance of the perceived disempowerment in respect of smart autonomous products. Study 2 manipulates autonomy of smart products and finds that perceived disempowerment mediates the link between smart products' autonomy and adoption intention. Study 3 indicates that an intervention design-that is, a product design that allows consumers to intervene in the actions of an autonomous smart product-can reduce their perceived disempowerment in respect of autonomous smart products. Further, Study 3 reveals that personal innovativeness moderates the role that an intervention design plays in product adoption: an intervention design shows a positive effect on adoption intention for individuals with low personal innovativeness, but for those with high personal innovativeness no effect of an intervention design is present on adoption intention. The authors suggest that managers consider consumers' perceived disempowerment when designing autonomous smart products, because (1) perceived disempowerment reduces adoption and (2) when targeted at consumers with low personal innovativeness, an intervention design reduces their perceived disempowerment. PMID- 27980357 TI - Fermented Herbal Formulas KIOM-MA128 Ameliorate IL-6-Induced Intestinal Barrier Dysfunction in Colon Cancer Cell Line. AB - Inflammatory bowel disease (IBD) comprises Crohn's disease (CD) and ulcerative colitis (UC). IBD increases the risk of colorectal cancer (CRC), depending on the extent and duration of intestinal inflammation. Increased IL-6 expression has been reported in IBD patients, which may be associated with intestinal barrier function through discontinuous tight junction (TJ). KIOM-MA is a specific agent for allergic diseases and cancer, and it is composed of several plants; these herbs have been used in traditional oriental medicine. We fermented KIOM-MA, the product of KIOM-MA128, using probiotics to improve the therapeutic efficacy via the absorption and bioavailability of the active ingredients. In this study, we demonstrated that KIOM-MA/MA128 exhibited anticolitis effects via the modulation of TJ protein. Interleukin-6 resulted in a dose-dependent decrease in the TER and an increase in the FITC-dextran permeability; however, pretreatment with 400 ug/ml KIOM-MA/MA128 resulted in a significant increase in the TER and a decrease in the FITC-dextran permeability via IL-6 induction. Furthermore, protein and mRNA TJ levels remained stable after pretreatment with 400 ug/ml KIOM-MA/MA128. Moreover, KIOM-MA/MA128 suppressed the expression of PLCgamma1 and PKC. Taken together, these findings suggest novel information and clue of the anticolitis effects of KIOM-MA128 via regulation of tight junction. PMID- 27980359 TI - Difference of Self-identity Levels between Strabismus Patients and Normal Controls. AB - PURPOSE: To evaluate differences in self-identity in patients diagnosed with strabismus, patients who underwent strabismus surgery, and healthy control individuals. METHODS: Self-identity testing was done during a military service physical examination. There were three subject groups: subjects with strabismus (group 1), subjects who had undergone corrective strabismus surgery (group 2), and subjects free of strabismus (group 3). The self-identity test was comprised of six sub-sections (subjectivity, self-acceptance, future confidence, goal orientation, initiative, and familiarity). Statistical significance of the sub sections was compared across the three groups. Correlations in age at the time of surgery and across the six sub-sections were investigated in group 2. RESULTS: A total of 351 subjects were enrolled in the study; 96 subjects were in group 1, 108 subjects were in group 2, and 147 subjects were in group 3. Significant differences were evident in subjectivity, self-acceptance, initiative and familiarity between groups 1 and 3. No significant differences were found between groups 2 and 3. In group 2, statistical significance was evident between age at surgery and initiative and familiarity (r = -0.333, p < 0.001; r = -0.433, p < 0.001, respectively). CONCLUSIONS: Self-identity is greater in non-strabismus subjects than strabismus subjects. Correction of strabismus may increase self identity levels. PMID- 27980358 TI - Epiretinal Proliferation Associated with Macular Hole and Intraoperative Perifoveal Crown Phenomenon. AB - PURPOSE: To discuss the unique morphology and origin of epiretinal proliferation associated with macular hole (EPMH) occasionally observed in full-thickness macular hole (FT-MH) or lamellar hole (LH) and to introduce the perifoveal crown phenomenon encountered when removing this unusual proliferative tissue. METHODS: Sixteen patients showing EPMH in spectral domain-optical coherence tomography were selected from 212 patients diagnosed with MH, LH, FT-MH, impending MH, macular pseudohole, or epiretinal membrane between January 2013 and December 2014. Of the 212 patients included for clinical analysis, 33, 23, 11, 7, and 190 exhibited LH, FT-MH, impending MH, macular pseudohole, and epiretinal membrane, respectively. We reviewed visual acuity, macular morphology, and clinical course. Surgical specimens were analyzed histologically. RESULTS: EPMH presented as an amorphous proliferation starting from the defective inner/outer segment (IS/OS) junction covering the inner macula surface. Among the 16 patients with EPMH, 11 underwent vitrectomy, and all exhibited the intraoperative perifoveal crown phenomenon. EPMH tissue was sampled in three patients, one of whom had more tissue removed than intended and showed delayed recovery in visual acuity. Despite hole closure, IS/OS junction integrity was not successfully restored in four of 11 patients. Five patients were followed-up without surgical intervention. Visual acuity slightly decreased in three patients and did not change in one patient, while the remaining patient was lost during follow-up. Among the three perifoveal crown tissues obtained, two were successfully analyzed histologically. Neither tissue showed positivity to synaptophysin or S-100 protein, but one showed positivity to cytokeratin protein immunohistochemical staining. CONCLUSIONS: EPMH exhibited a distinct but common configuration in spectral domain-optical coherence tomography. An epithelial proliferation origin is plausible based on its configuration and histological analysis. Perifoveal crown phenomenon was observed when removing EPMH during vitrectomy. PMID- 27980361 TI - The Relationship between Vitamin D and Glaucoma: A Kangbuk Samsung Health Study. AB - PURPOSE: To investigate the relationship between vitamin D and glaucoma. METHODS: This retrospective, cross-sectional study included subjects who underwent a health screening at the Health Screening Center of Kangbuk Samsung Hospital from August 2012 to July 2013. All fundus photographs were reviewed by ophthalmologists. The ophthalmologists determined if an eye was glaucomatous based on the criteria set forth by the International Society of Geographical and Epidemiological Ophthalmology and by the appearance of the retinal nerve fiber layer and optic disc. If the subjects previously underwent an ophthalmologic examination, they were enrolled based on the documented history. In addition to fundus photographs, each participant underwent a systemic examination including blood sampling and sociodemographic and behavioral questionnaires. The subjects were divided into five groups according to serum 25-hydroxyvitamin D (25(OH)D) level. Multivariate logistic regression models were constructed to assess possible associations between elevated glaucoma risk and systemic factors with a p < 0.2 on univariate analysis. RESULTS: Of the 169,208 subjects older than 20 years, 123,331 were eligible for the study. There was no difference in the prevalence of glaucoma according to quintile of serum 25(OH)D level based on sex (p = 0.412 for males, p = 0.169 for females). According to the multivariable adjusted logistic analysis, the odds ratio of glaucoma for the fourth quintile was significantly lower than that of the first quintile in females (odds ratio, 0.713; 95% confidence interval, 0.520 to 0.979). CONCLUSIONS: Lower 25(OH)D level was significantly associated with an elevated risk of glaucoma in females compared with higher 25(OH)D level. Further evaluation is needed to investigate the relationship between glaucoma and vitamin D. PMID- 27980360 TI - Changes in Corneal Endothelial Cell after Ahmed Glaucoma Valve Implantation and Trabeculectomy: 1-Year Follow-up. AB - PURPOSE: To compare changes in corneal endothelial cell density (CECD) after Ahmed glaucoma valve (AGV) implantation and trabeculectomy. METHODS: Changes in corneal endothelium in patients that underwent AGV implantation or trabeculectomy were prospectively evaluated. Corneal specular microscopy was performed at the central cornea using a non-contact specular microscope before surgery and 6 months and 12 months after surgery. The CECD, hexagonality of the endothelial cells, and the coefficient of variation of the cell areas were compared between the two groups. RESULTS: Forty eyes of 40 patients with AGV implantation and 28 eyes of 28 patients with trabeculectomy were studied. Intraocular pressure in the AGV implantation group was significantly higher than that in the trabeculectomy group (p < 0.001), but there was no significant difference in other clinical variables between the two groups. In the AGV implantation group, the mean CECD significantly decreased by 9.4% at 6 months and 12.3% at 12 months compared with baseline values (both, p < 0.001), while it decreased by 1.9% at 6 months and 3.2% at 12 months in the trabeculectomy group (p = 0.027 and p = 0.015, respectively). The changes at 6 months and 12 months in the AGV implantation group were significantly higher than those in the trabeculectomy group (p = 0.030 and p = 0.027, respectively). In the AGV implantation group, there was a significant decrease in the CECD between baseline and 6 months and between 6 months and 12 months (p < 0.001 and p = 0.005, respectively). However, in the trabeculectomy group, a significant decrease was observed only between baseline and 6 months (p = 0.027). CONCLUSIONS: Both the AGV implantation group and the trabeculectomy group showed statistically significant decreases in the CECD 1 year after surgery. The decrease in CECD in the AVG implantation group was greater and persisted longer than that in the trabeculectomy group. PMID- 27980362 TI - Effectiveness of Toric Orthokeratology in the Treatment of Patients with Combined Myopia and Astigmatism. AB - PURPOSE: The purpose of this multi-institute, single-group clinical trial was to evaluate the effectiveness and safety of toric orthokeratology lenses for the treatment of patients with combined myopia and astigmatism. METHODS: A total of 44 patients were included in this clinical trial. The patients ranged in age from 7 to 49 years, with myopia of -0.75 to -6.0 diopters (D) and astigmatism of 1.25 to 4.0 D. After excluding 21 subjects, 23 subjects (39 eyes) were analyzed after toric orthokeratology lens use. The subjects underwent ophthalmologic examination after 1 day and 1, 2, 3, and 4 weeks of wearing overnight toric orthokeratology lenses. RESULTS: A total of 19 subjects (31 eyes) completed the trial after five subjects (eight eyes) dropped out. In the patients who completed the study by wearing lenses for 4 weeks, the myopic refractive error decreased significantly by 2.60 +/- 2.21 D (p < 0.001), from -3.65 +/- 1.62 to -1.05 +/- 1.64 D. The astigmatic refractive error were also significantly decreased by 0.63 +/- 0.98 D (p = 0.001), from 2.07 +/- 0.83 to 1.44 +/- 0.99 D. The mean uncorrected and corrected visual acuities before wearing the lenses were 2.14 +/- 0.80 logarithm of the logMAR (logMAR) and 0.05 +/- 0.13 logMAR, respectively, which changed to 0.12 +/- 0.30 logarithm of the logMAR (p < 0.001) and 0.01 +/- 0.04 logMAR (p = 0.156) after 4 weeks. No serious adverse reactions were reported during the clinical trial. CONCLUSIONS: Our results suggest that toric orthokeratology is an effective and safe treatment for correcting visual acuity in patients with combined myopia and astigmatism. PMID- 27980363 TI - Comparison of Long-term Clinical Outcomes between Descemet's Stripping Automated Endothelial Keratoplasty and Penetrating Keratoplasty in Patients with Bullous Keratopathy. AB - PURPOSE: To compare 2-year clinical outcomes of Descemet's stripping automated endothelial keratoplasty (DSAEK) and penetrating keratoplasty (PK) in patients with bullous keratopathy. METHODS: A retrospective chart review was performed to obtain 2 years of follow-up data of DSAEK or PK at a single center from March 2009 to September 2012. The study comprised 15 eyes of DSAEK and 11 eyes of PK. Outcome measures included best-corrected visual acuity (BCVA), spherical and keratometric changes, central corneal thickness, endothelial cell density, intraocular pressure, and postoperative complications. Graft survival rate was assessed by Kaplan-Meier survival analysis. RESULTS: There were no differences in patient baseline characteristics between the two groups. At postoperative 2 years, better BCVA of 0.69 +/- 0.51 logarithm of the minimum angle of resolution (logMAR) was found after DSAEK compared to 0.88 +/- 0.48 logMAR after PK. Refractive cylinder in DSAEK and PK was -2.60 +/- 1.53 and -6.00 +/- 1.05 diopters (D), respectively, and keratometric cylinder was 3.27 +/- 3.70 and 6.34 +/- 3.51 D, respectively, at postoperative 2 years. The difference of mean spherical equivalents between postoperative 1 month and 2 years was 0.84 D after DSAEK and 2.05 D after PK. A hyperopic shift of 1.17 D was present after 2 years of DSAEK. The mean endothelial cell density at postoperative 2 years was 1,548 +/ 456 cells/mm2 for DSAEK and 1,052 +/- 567 cells/mm2 for PK, with a cell loss of 19.96% vs. 52.38%, respectively when compared to postoperative 1 month. No significant difference in central corneal thickness was found between DSAEK and PK (592 +/- 75 vs. 563 +/- 90 um, respectively). Finally, the 2-year survival rate did not differ significantly between DSAEK and PK (93.3% vs. 81.8%, respectively, p = 0.344). CONCLUSIONS: Compared to PK, DSAEK provided more stable refractive errors with better visual outcome, lower endothelial cell loss, and a lower rate of graft rejection at postoperative 2 years in patients with bullous keratopathy. PMID- 27980364 TI - Macular Ganglion Cell Layer Assessment to Detect Glaucomatous Central Visual Field Progression. AB - PURPOSE: To investigate the use of ganglion cell inner plexiform layer (GC-IPL) thickness, as measured by spectral domain optical coherence tomography, to detect central visual field (VF) progression. METHODS: This study included 384 eyes from 384 patients (219 preperimetric and 165 perimetric glaucomatous eyes; average follow-up, 4.3 years). Photographic assessment of retinal nerve fiber layer (RNFL) and serial VF analysis were performed to detect glaucoma progression in the central (within 10 degrees ) area. Study inclusion required at least five serial spectral domain optical coherence tomography exams at different visits. The long-term test-retest variability of average GC-IPL thicknesses was calculated in 110 stable preperimetric glaucomatous eyes. The sensitivity and specificity of GC-IPL measurements for the detection of central VF progression were calculated in an event-based analysis using the calculated variability as a cut-off and were compared with those of central RNFL photographic assessment. RESULTS: The intersession test-retest variability, defined as the 95% confidence interval, was 1.76 um for average GC-IPL thickness. The sensitivity and specificity of the average GC-IPL thickness for detecting central VF progression were 60.7% and 78.9%, respectively. Among six sectors, the inferonasal GC-IPL sector showed the highest sensitivity (53.6%). The sensitivity of the >=1 sector GC-IPL to detect central VF progression was significantly higher than that of central RNFL photographic progression (p = 0.013). Other GC-IPL parameters showed comparable sensitivity and specificity to detect central VF progression compared with RNFL photographic progression. CONCLUSIONS: Serial GC-IPL measurements show comparable performance in the detection of central glaucomatous VF progression to RNFL photographic assessment. PMID- 27980365 TI - Comparison of Astigmatism Induced by Combined Inferior Oblique Anterior Transposition Procedure and Lateral Rectus Recession Alone. AB - PURPOSE: The purpose of this study is to compare the magnitude and axis of astigmatism induced by a combined inferior oblique (IO) anterior transposition procedure with lateral rectus (LR) recession versus LR recession alone. METHODS: Forty-six patients were retrospectively analyzed. The subjects were divided into two groups: those having concurrent inferior oblique muscle overaction (IOOA) and intermittent exotropia (group 1, 20 patients) and those having only intermittent exotropia as a control (group 2, 26 patients). Group 1 underwent combined anterior transposition of IO with LR recession and group 2 underwent LR recession alone. Induced astigmatism was defined as the difference between preoperative and postoperative astigmatism using double-angle vector analysis. Cylinder power, axis of induced astigmatism, and spherical equivalent were analyzed at 1 week, 1 month, and 3 months after surgery. RESULTS: Larger changes in the axis of induced astigmatism were observed in group 1, with 4.5 degrees incyclotorsion, than in group 2 at 1 week after surgery (axis, 84.5 degrees vs. 91 degrees ; p < 0.001). However, there was no statistically significant inter-group difference thereafter. Relaxation and rapid regression in the incyclotorsion of induced astigmatism were observed over-time. Spherical equivalent significantly decreased postoperatively at 1 month in both groups, indicating a myopic shift (p = 0.011 for group 1 and p = 0.019 for group 2) but did not show significant differences at 3 months after surgery (p = 0.107 for group 1 and p = 0.760 for group 2). CONCLUSIONS: Combined IO anterior transposition procedures caused an increased change in the axis of induced astigmatism, including temporary incyclotorsion, during the first week after surgery. However, this significant difference was not maintained thereafter. Thus, combined IO surgery with LR recession does not seem to produce a sustained astigmatic change, which can be a potential risk factor of postoperative amblyopia or diplopia compared with LR recession alone. PMID- 27980367 TI - Recurrent Paecilomyces Keratitis in a Patient with Jones Tube after Conjunctivodacryocystorhinostomy. PMID- 27980366 TI - Tunicamycin-induced Endoplasmic Reticulum Stress Upregulates the Expression of Pentraxin 3 in Human Retinal Pigment Epithelial Cells. AB - PURPOSE: To investigate the production of long pentraxin 3 (PTX3) in response to tunicamycin-induced endoplasmic reticulum (ER) stress and its role in ER stress associated cell death, PTX3 expression was evaluated in the human retinal pigment epithelial cell line, ARPE-19. METHODS: PTX3 production in ARPE-19 cells was analyzed in the absence or presence of tunicamycin treatment by enzyme-linked immunosorbent assay. PTX3 protein and mRNA levels were estimated using western blot analysis and real-time reverse transcription-polymerase chain reaction, respectively. Protein and mRNA levels of CCAAT-enhancer-binding protein homologous protein (CHOP) and ARPE-19 cell viability were measured in the presence of tunicamycin-induced ER stress in control or PTX3 small hairpin RNA (shRNA)-transfected ARPE-19 cells. RESULTS: The protein and mRNA levels of PTX3 were found to be significantly increased by tunicamycin treatment. PTX3 production was significantly decreased in inositol-requiring enzyme 1alpha shRNA transfected ARPE-19 cells compared to control shRNA-transfected cells. Furthermore, pretreatment with the NF-kappaB inhibitor abolished tunicamycin induced PTX3 production. Decreased cell viability and prolonged protein and mRNA expression of CHOP were observed under tunicamycin-induced ER stress in PTX3 shRNA transfected ARPE-19 cells. CONCLUSIONS: These results suggest that PTX3 production increased in the presence of tunicamycin-induced ER stress. Therefore, PTX3 could be an important protector of ER stress-induced cell death in human retinal pigment epithelial cells. Inositol-requiring enzyme 1alpha and the NF kappaB signaling pathway may serve as potential targets for regulation of PTX3 expression in the retina. Therefore, their role in PTX3 expression needs to be further investigated. PMID- 27980368 TI - Visual Outcomes Following Deep Anterior Lamellar Keratoplasty in Granular Corneal Dystrophy Types 1 and 2. PMID- 27980369 TI - Venous Occlusion in a Case of Orbital Cellulitis. PMID- 27980370 TI - Antielevation Syndrome after Bilateral Anterior Transposition of the Inferior Oblique Muscles. PMID- 27980372 TI - Simulation for Authentic Learning in Informal Education. AB - In 2011, the Museum of Science and Industry in Chicago, Illinois embarked on the creation of a program that allows middle and high school students to explore community health issues using human patient simulation. MedLab was created to engage students in an authentic exploration of medical science, biology, and human anatomy, with a particular focus on how these fields apply to learners' lives. The program content is made relevant through an emphasis on personal health, community health, and medical science career pathways. This article explores the development, implementation, use of technology, and outcomes of MedLab. PMID- 27980371 TI - Perceived Bonding by Parents Living with HIV and Their Adolescent Children. AB - This study examined the associations between parent and adolescent reports of bonding within families and the relationships among reported parental bonding, family conflict and adolescent stress. A total of 118 families from Anhui, China, were recruited for this study. Two family-level bonding scores were constructed: the average of and difference between parent and adolescent bonding scores. Study results indicated that the difference between parent and adolescent bonding reports was associated with higher levels of adolescent daily stress. A negative association was observed between average family-level bonding and the level of parent-reported conflict. Our findings highlight the importance of combining data from both parents and adolescents when studying issues related to family wellbeing. PMID- 27980373 TI - Prevention of Type 2 Diabetes Requires BOTH Intensive Lifestyle Interventions and Population-Wide Approaches. AB - More than 29 million people in the United States have diabetes, up from the previous estimate of 26 million in 2010, according to the latest report from the CDC. Another 86 million adults more than 1 in 3 have prediabetes, meaning that their blood glucose levels are higher than normal but not high enough to classify them as having type 2 diabetes mellitus (T2DM).1 Only about 10% of these people know they have prediabetes.2 The costs for treating and managing diabetes continue to rise. Besides the actual daily demands of the condition, the American Diabetes Association's estimate is $245 billion annually in direct and indirect costs.3. PMID- 27980374 TI - History and evolution of influenza control through vaccination: from the first monovalent vaccine to universal vaccines. AB - Influenza is a highly infectious airborne disease with an important epidemiological and societal burden; annual epidemics and pandemics have occurred since ancient times, causing tens of millions of deaths. A hundred years after this virus was first isolated, influenza vaccines are an important influenza prevention strategy and the preparations used display good safety and tolerability profiles. Innovative tools, such as recombinant technologies and intra-dermal devices, are currently being investigated in order to improve the immunological response. The recurring mutations of influenza strains has prompted the recent introduction of a quadrivalent inactivated vaccine. In the near future, scientific research will strive to produce a long-lasting universal vaccine containing an antigen that will offer protection against all influenza virus strains. PMID- 27980375 TI - Cross sectional study investigating the differences in knowledge and behaviors about HPV between vaccinated and non-vaccinated girls. AB - INTRODUCTION: The aim of the presents study was to compare the level of knowledge about Human Papilloma Virus (HPV) in vaccinated and non-vaccinated girls and to highlight the reasons why non-vaccinated girls refuse vaccination. METHODS: A cross-sectional study was conducted from October 2012 to June 2013 in Turin (Piemonte Region, Italy). Questionnaires were administered to girls attending secondary and high schools randomly selected. RESULTS: A total of 576 were compiled. The principle sources of information were parents and health workers. The main reported reasons for non-adherence to vaccination were the disagreement of the parents among the 11-12 years group (45.3%) and the lack of evidence on efficacy among the 18 years group (26.8%). By comparing the level of knowledge there was a statistically significant difference between groups: vaccinated girls reported higher score than the unvaccinated group in several questions (p <= 0.05). CONCLUSIONS: Our findings show a lack of information about HPV infection. Parents, school and health care workers have a central role in girl's education and choices about HPV vaccination. The communication campaign for the prevention of cervical cancer must therefore be characterised by messages able to clarify and consolidate messages that may have been partially received or misunderstood. PMID- 27980376 TI - Molecular epidemiology and genotyping of Chlamydia trachomatis infection in a cohort of young asymptomatic sexually active women (18-25 years) in Milan, Italy. AB - INTRODUCTION: Chlamydia trachomatis (Ct) is the most common bacterial cause of sexually transmitted infections (STI) and is associated with severe long-term sequelae in female populations. In Italy Ct infections are not submitted to a screening programme, and its epidemiological profile is understudied. Even scarcer information is available about the genetic diversity on ompA gene, whose sequence defines 18 different genovars. This study aims at evaluating the prevalence of Ct infection in young sexually active asymptomatic women aged 18 25, and characterizing the molecular epidemiology of the different circulating genovars in this population. METHODS: Cervical samples collected from 909 sexually-activeyoung women (mean age 21.5 years) were analyzed through molecular assay for the detection of Ct infection. Phylogenetic analysis on the ompA gene was performed on Ct positive samples to identify the circulating genovars. RESULTS: The overall prevalence of Ct-infection was 4.4% (95%CI: 3.2-5.9%): 5.3% among women aged 18-21 years and 3.5% among those aged 22-25 years. Phylogenetic analysis has identified 5 different genovars: D, E, F, G, and H. The most common genovar was the E (46%), followed by genovar F and G (18.9% each), D (13.5%), and H (2.7%). CONCLUSIONS: This study underlines the high prevalence of asymptomatic Ct-infections among young women. Overall, about half of the asymptomatic infections is sustained by genovar E. The introduction in Italy of a systematic screening program should be considered to allow a better understanding of Ct spreading and providing women with an opportunity for early treatment to protect their sexual and reproductive health. PMID- 27980377 TI - Temporal trends of healthcare associated infections and antimicrobial use in 2011 2013, observed with annual point prevalence surveys in Ferrara University Hospital, Italy. AB - INTRODUCTION: Healthcare associated infections (HAIs) and misuse of antimicrobials (AMs) represent a growing public health problem. The Point Prevalence Surveys (PPSs) find available information to be used for specific targeted interventions and evaluate their effects. The objective of this study was to estimate the prevalence of HAIs and AM use, to describe types of infections, causative pathogens and to compare data collected through three PPSs in Ferrara University Hospital (FUH), repeated in 3 different years (2011-2013). The population-based sample consists of all patients admitted to every acute care and rehabilitation Department in a single day. METHODS: ECDC Protocol and Form for PPS of HAI and AM use, Version 4.2, July 2011. Risk factor analysis was performed using logistic regression. RESULTS: 1,239 patients were observed. Overall, HAI prevalence was 9.6%; prevalence was higher in Intensive Care Units; urinary tract infections were the most common HAIs in all 3 surveys; E.coli was the most common pathogen; AM use prevalence was 51.1%; AMs most frequently administered were fluoroquinolones, combinations of penicillins and third generation cephalosporins. According to the regression model, urinary catheter (OR: 2.5) and invasive respiratory device (OR: 2.3) are significantly associated risk factors for HAIs (p < 0.05). CONCLUSIONS: PPSs are a sensitive and effective method of analysis. Yearly repetition is a useful way to maintain focus on the topic of HAIs and AM use, highlighting how changes in practices impact on the outcome of care and providing useful information to implement intervention programs targeted on specific issues. PMID- 27980378 TI - Operating room environment and surgical site infections in arthroplasty procedures. AB - BACKGROUND: The rate of surgical site infections (SSI) is strongly influenced by operating room quality, which is determined by the structural features of the facility and its systems and by the management and behavior of healthcare workers. The aim of the present study was to assess microbial contamination in the operating room during hip- and knee-replacement procedures, the behavior of operating room staff and the incidence of SSI through postdischarge surveillance. METHODS: Microbial contamination was evaluated by active and passive sampling at rest and in operating conditions. Organizational and behavioral characteristics were collected through observational assessment. The incidence of SSI was evaluated in 255 patients, and follow-up examinations were carried out 30 and 365 days after the procedure. RESULTS: The mean values of the airborne and sedimenting microbial loads were 12.90 CFU/m3 and 0.02 CFU/cm2/h, respectively. With regard to outcome, the infection rate proved to be 0.89% and was associated with knee-replacement procedures. The microorganism responsible for this superficial infection was Staphylococcus aureus. CONCLUSIONS: Clinical outcomes proved to be satisfactory, owing to the limited microbial load (in both at-rest and operating conditions), the appropriate behavior of the staff, compliance with the guidelines on preoperative antibiotic prophylaxis, and efficient management of the ventilation system. PMID- 27980379 TI - Epidemiology and biomolecular characterization of carbapenem-resistant klebsiella pneumoniae in an Italian hospital. AB - OBJECTIVE: To describe the occurrence of CRKP infections in a tertiary care hospital and to analyse the allelic profiles of the clinical strains involved and the most frequent carbapenemases. DESIGN: The study analyzed cases of infection due to CRKP in the period 2013-2014; 147 cases were recorded, most of which (82.31%) were in-hospital infections. SETTING: A hospital in northern Italy. METHODS: We retrospectively collected: data on patient characteristics and the microbiological characteristics of CRKP. Isolates from 72 of the in-hospital cases underwent molecular typing (MLST); in addition, in each isolate, a procedure for the detection of the blaKPC gene was carried out. RESULTS: The in hospital death rate was 24.0% in 2013 and 37.5% in 2014. However, the difference between these two values did not prove statistically significant (P > .05). Analysis of mortality revealed that bloodstream infections were more frequently associated with death than other infections (chi2 = 14.57, P < .001). The age adjusted Cox proportional hazard model revealed that the patients with bacteremia due to CRKP had a 3-fold higher risk of death (HR 3.11; 95% CI 1.66 - 5.84, P< .001) than those with infections of other sites. MLST revealed that the prevalent allelic profile was ST 512 (79.62%); the most frequent carbapenemase was KPC-3 (83.8%). CONCLUSIONS: Our results are in line with those of recent studies, which have shown that the spread of CRKP in Italy is a matter of concern and that further efforts have to be made to prevent the potential dissemination of carbapenemase-producing clones of K. pneumoniae, whenever possible. PMID- 27980380 TI - Prevalence and antibiotic susceptibility profiles of Listeria monocytogenes contamination of chicken flocks and meat in Oyo State, south-western Nigeria: Public health implications. AB - INTRODUCTION: Food contamination with Listeria monocytogenes is on the increase posing threats to public health with growing trends in food products recalls due to suspected Listeria contamination. METHODS: We conducted a cross-sectional study to determine the prevalence and antibiotic susceptibility profiles of Listeria monocytogenes (Lm) among 71 randomly selected poultry farms in Oyo State, Nigeria. A total of 450 samples comprising cloacal swabs (426) and randomly selected dressed chicken meat (24) were cultured for Lm isolation using BrillianceTM Selective Listeria Agar with antibiotics and microbial load count with Nutrient Agar. Further identification was done using microscopic, biochemical characterization and antibiotic sensitivity tests. Data were analysed using bivariate analysis and student t-test. RESULTS: An overall prevalence of 91.8% Lm contamination was obtained comprising 91.5% (390/426) in cloacal swabs and 95.8% (23/24) in meat. The prevalence of Lm in cloacal samples was significantly associated with poultry type (p = 0.008) and breed (p = 0.000. In addition, all the flocks had at least one positive sample yielding 100% flock prevalence. Antibiotic sensitivity test revealed that most of the isolates were resistant to common antibiotics like Ampicillin-cloxacillin and cefuroxime. CONCLUSIONS: The results revealed a high level of contamination with Lm in the poultry flock and meat and the observed resistance to most common antibiotics has implications for future disease control as well as public health. There is need to step up routine screening of food animal products for Listeria contamination as well as measures towards reducing such contaminations. PMID- 27980381 TI - Prevalence and predictors of risk factors for Brucellosis transmission by meat handlers and traditional healers' risk practices in Ibadan, Nigeria. AB - INTRODUCTION: Brucellosis is endemic in Nigeria and risk factors enhancing its transmission are prevalent. METHODS: Following serological evidence of brucellosis and isolation of B. abortus from slaughtered cattle in Ibadan, Nigeria, we administered a semi-structured questionnaire to determine the prevalence and predictors of eating and selling bovine gravid uterus among 350 meat handlers from five major meat processing facilities. We conducted key informant interview for five leading traditional healers to document its use. Data were analyzed using Stata 12. RESULTS: The prevalence of eating and selling gravid uterus were 29.7% and 40.3% respectively. Being meat/offal processor (OR=1.9, 95%CI: 1.11-3.3, P = 0.008) and not knowing that eating undercooked contaminated gravid uterus could expose humans to brucellosis (OR=19.5; 95%CI: 5.73-66.03; P = 0.000) were strong predictors of eating gravid uterus. Similarly, being adult (OR = 1.7, 95%CI: 1.08-2.57, P = 0.02) and inadequate knowledge of brucellosis as a preventable disease (OR = 0.03; 95%CI: 0.004-0.27, P = 0.001) predicted selling gravid uterus. Qualitative data from the traditional healers revealed using gravid uterus as special medicinal preparations to hasten parturition in overdue pregnancies, treat infertility and old age diseases in humans. CONCLUSIONS: We demonstrated a high prevalence of risk factors for brucellosis transmission, and some meat handlers' sociodemographic characteristics and brucellosis knowledge-based markers as predictors of these factors. The traditional healers' practices portend a challenge to the current brucellosis control strategy. These findings provide insights into designing all inclusive health programmes aimed at controlling brucellosis spread in Nigeria and other similar settings in developing countries. PMID- 27980382 TI - Factors associated with regular sunscreen use by medical students of a Peruvian university. AB - INTRODUCTION: Use of sunscreen is encouraged to reduce the risk of skin pathologies caused by radiation. It is important to acknowledge the associated factors that promote or hinder sunscreen use in young populations as to design better prevention policies. OBJECTIVE: To determine the factors associated with regular sunscreen use among first year medical students from a Peruvian university. MATERIALS AND METHODS: A cross-sectional study was performed. Our population was first-year medical students from a Peruvian university. We administrated an electronic survey to evaluate socio-demographic data, as well as student knowledge, attitudes, and practices regarding photo-protection. We used ordinal logistic regression to analyze the factors associated with sunscreen use. RESULTS: Of 420 first-year students, 299 completed our survey. We found that 53.5% of the participants were less than 18 years old, 63.2% were female, 9.3% (females more than males) responded that a sunburn was worth it to look tan, and 38.1% always or almost always used sunscreen during the summer. Factors associated with sunscreen use in the ordered logistic adjusted regression were male sex (OR = 0.50, IC95% = 0.34-0.86), participation in photo-protection workshops within the last year (OR = 2.40, IC95% = 1.28-4.37), and having somebody to remind them the use of sunscreen during the last three months (OR = 3.80, IC95% = 1.28-11.20). CONCLUSIONS: In our sample, a higher sunscreen use was more often observed among female participants, those who attended skin protection workshops, and those reminded to use sunscreen. This highlights the importance of educational and reminder activities in the adoption of protective habits, such as sunscreen use. PMID- 27980383 TI - Using the cytokinesis-block micronucleus cytome assay to evaluate chromosomal DNA damage in chronic renal patients undergoing bicarbonate haemodialysis and haemodiafiltration. AB - INTRODUCTION: Chronic Renal Failure (CRF) patients are considered to show genomic instability and are associated with a high risk of both cardiovascular diseases and cancer. We explored DNA damage due to two dialysis treatments in 20 patients undergoing bicarbonate haemodialysis (BD), 20 undergoing haemodiafiltration (HDF) and 40 healthy subjects. METHODS: The cytokinesis-block micronucleus (MN) assay was performed on peripheral blood lymphocytes to evaluate genetic damage. RESULTS: A higher frequency of MN in the dialysis groups compared with controls was found. The results do not show a relationship between genetic instability and the type, frequency and duration of haemodialysis. The average BD and HDF treatment time was respectively 3.8 +/- 6.3 and 3.7 +/- 3.9 yrs. CAT and scintigraphy was independently correlated with high levels of MN. CONCLUSIONS: Overall, the frequency of MN in CRF patients undergoing dialysis therapy was observed to be higher. Further studies need to be performed on a larger number of patients and for a longer period. PMID- 27980384 TI - Support Vector Machines Trained with Evolutionary Algorithms Employing Kernel Adatron for Large Scale Classification of Protein Structures. AB - With the increasing power of computers, the amount of data that can be processed in small periods of time has grown exponentially, as has the importance of classifying large-scale data efficiently. Support vector machines have shown good results classifying large amounts of high-dimensional data, such as data generated by protein structure prediction, spam recognition, medical diagnosis, optical character recognition and text classification, etc. Most state of the art approaches for large-scale learning use traditional optimization methods, such as quadratic programming or gradient descent, which makes the use of evolutionary algorithms for training support vector machines an area to be explored. The present paper proposes an approach that is simple to implement based on evolutionary algorithms and Kernel-Adatron for solving large-scale classification problems, focusing on protein structure prediction. The functional properties of proteins depend upon their three-dimensional structures. Knowing the structures of proteins is crucial for biology and can lead to improvements in areas such as medicine, agriculture and biofuels. PMID- 27980385 TI - Current Bacterial Gene Encoding Capsule Biosynthesis Protein CapI Contains Nucleotides Derived from Exonization. AB - Since the proposition of introns-early hypothesis, although many studies have shown that most eukaryotic ancestors possessed intron-rich genomes, evidence of intron existence in genomes of ancestral bacteria has still been absent. While not a single intron has been found in all protein-coding genes of current bacteria, analyses on bacterial genes horizontally transferred into eukaryotes at ancient time may provide evidence of intron existence in bacterial ancestors. In this study, a bacterial gene encoding capsule biosynthesis protein CapI was found in the genome of sea anemone, Nematostella vectensis. This horizontally transferred gene contains a phase 1 intron of 40 base pairs. The nucleotides of this intron have high sequence identity with those encoding amino acids in current bacterial CapI gene, indicating that the intron and the amino acid-coding nucleotides are originated from the same ancestor sequence. Moreover, 5'-splice site of this intron is located in a GT-poor region associated with a closely following AG-rich region, suggesting that deletion mutation at 5'-splice site has been employed to remove this intron and the intron-like amino acid-coding nucleotides in current bacterial CapI gene are derived from exonization. These data suggest that bacterial CapI gene contained intron(s) at ancient time. This is the first report providing the result of sequence analysis to suggest possible existence of spliceosomal introns in ancestral bacterial genes. The methodology employed in this study may be used to identify more such evidence that would aid in settlement of the dispute between introns-early and introns-late theories. PMID- 27980387 TI - Comparison of Three Information Sources for Smoking Information in Electronic Health Records. AB - OBJECTIVE: The primary aim was to compare independent and joint performance of retrieving smoking status through different sources, including narrative text processed by natural language processing (NLP), patient-provided information (PPI), and diagnosis codes (ie, International Classification of Diseases, Ninth Revision [ICD-9]). We also compared the performance of retrieving smoking strength information (ie, heavy/light smoker) from narrative text and PPI. MATERIALS AND METHODS: Our study leveraged an existing lung cancer cohort for smoking status, amount, and strength information, which was manually chart reviewed. On the NLP side, smoking-related electronic medical record (EMR) data were retrieved first. A pattern-based smoking information extraction module was then implemented to extract smoking-related information. After that, heuristic rules were used to obtain smoking status-related information. Smoking information was also obtained from structured data sources based on diagnosis codes and PPI. Sensitivity, specificity, and accuracy were measured using patients with coverage (ie, the proportion of patients whose smoking status/strength can be effectively determined). RESULTS: NLP alone has the best overall performance for smoking status extraction (patient coverage: 0.88; sensitivity: 0.97; specificity: 0.70; accuracy: 0.88); combining PPI with NLP further improved patient coverage to 0.96. ICD-9 does not provide additional improvement to NLP and its combination with PPI. For smoking strength, combining NLP with PPI has slight improvement over NLP alone. CONCLUSION: These findings suggest that narrative text could serve as a more reliable and comprehensive source for obtaining smoking-related information than structured data sources. PPI, the readily available structured data, could be used as a complementary source for more comprehensive patient coverage. PMID- 27980386 TI - Quantitative Proteomic Approach for MicroRNA Target Prediction Based on 18O/16O Labeling. AB - MOTIVATION: Among many large-scale proteomic quantification methods, 18O/16O labeling requires neither specific amino acid in peptides nor label incorporation through several cell cycles, as in metabolic labeling; it does not cause significant elution time shifts between heavy- and light-labeled peptides, and its dynamic range of quantification is larger than that of tandem mass spectrometry-based quantification methods. These properties offer 18O/16O labeling the maximum flexibility in application. However, 18O/16O labeling introduces large quantification variations due to varying labeling efficiency. There lacks a processing pipeline that warrants the reliable identification of differentially expressed proteins (DEPs). This motivates us to develop a quantitative proteomic approach based on 18O/16O labeling and apply it on Kaposi sarcoma-associated herpesvirus (KSHV) microRNA (miR) target prediction. KSHV is a human pathogenic gamma-herpesvirus strongly associated with the development of B cell proliferative disorders, including primary effusion lymphoma. Recent studies suggest that miRs have evolved a highly complex network of interactions with the cellular and viral transcriptomes, and relatively few KSHV miR targets have been characterized at the functional level. While the new miR target prediction method, photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation (PAR-CLIP), allows the identification of thousands of miR targets, the link between miRs and their targets still cannot be determined. We propose to apply the developed proteomic approach to establish such links. METHOD: We integrate several 18O/16O data processing algorithms that we published recently and identify the messenger RNAs of downregulated proteins as potential targets in KSHV miR-transfected human embryonic kidney 293T cells. Various statistical tests are employed for picking DEPs, and we select the best test by examining the enrichment of PAR-CLIP-reported targets with seed match to the miRs of interest among top ranked DEPs returned by statistical tests. Subsequently, the list of DEPs picked by the selected statistical test is filtered with the criteria that they must have downregulated gene expressions, must have reported as targets by an miR target prediction algorithm SVMcrio, and must have reported as targets by PAR-CLIP. RESULT: We test the developed approach in the problem of finding targets of KSHV miR-K1. The RNAs of three DEPs are identified as miR-K1 targets, among which RAB23 and HNRNPU are novel. Results from both Western blotting and Luciferase reporter assays confirm the novel targets. These results show that the developed quantitative approach based on 18O/16O labeling can be combined with genomic, PAR-CLIP, and target prediction algorithms for the confident identification of KSHV miR targets. The developed approach could also be applied in other applications. PMID- 27980388 TI - Asymmetric Dimethylarginine and Its Relation As a Biomarker in Nephrologic Diseases. AB - It is encouraging to observe that a search for publications on "asymmetric dimethylarginine (ADMA)" in PubMed, as updated on June 2016, yielded >2500 items, 24 years after a splendid paper published by Vallance et al in which the authors proposed that ADMA accumulation could be a cardiovascular risk factor in chronic kidney diseases. ADMA is the endogenous inhibitor of nitric oxide synthase and is related to endothelial dysfunction, which plays an important role in vascular damage elicited by various cardiometabolic risk factors. Although current knowledge suggests that ADMA has critical central roles in renal diseases, there are still unexplained details. The present article aims to provide a review on ADMA and its relation as a biomarker in nephrologic diseases. We aimed to systematize articles in which ADMA levels were assessed in order to clarify its role in many diseases and establish its reference values in different populations. PMID- 27980389 TI - Prognostic Value of MammaPrint(r) in Invasive Lobular Breast Cancer. AB - BACKGROUND: MammaPrint(r) is a microarray-based gene expression test cleared by the US Food and Drug Administration to assess recurrence risk in early-stage breast cancer, aimed to guide physicians in making neoadjuvant and adjuvant treatment decisions. The increase in the incidence of invasive lobular carcinomas (ILCs) over the past decades and the modest representation of ILC in the MammaPrint development data set calls for a stratified survival analysis dedicated to this specific subgroup. STUDY AIM: The current study aimed to validate the prognostic value of the MammaPrint test for breast cancer patients with early-stage ILCs. MATERIALS AND METHODS: Univariate and multivariate survival associations for overall survival (OS), distant metastasis-free interval (DMFI), and distant metastasis-free survival (DMFS) were studied in a study population of 217 early-stage ILC breast cancer patients from five different clinical studies. RESULTS AND DISCUSSION: A significant association between MammaPrint High Risk and poor clinical outcome was shown for OS, DMFI, and DMFS. A subanalysis was performed on the lymph node-negative study population. In the lymph node-negative study population, we report an up to 11 times higher change in the diagnosis of an event in the MammaPrint High Risk group. For DMFI, the reported hazard ratio is 11.1 (95% confidence interval = 2.3-53.0). CONCLUSION: Study results validate MammaPrint as an independent factor for breast cancer patients with early-stage invasive lobular breast cancer. Hazard ratios up to 11 in multivariate analyses emphasize the independent value of MammaPrint, specifically in lymph node-negative ILC breast cancers. PMID- 27980390 TI - The new Bruch's membrane opening - minimum rim width classification improves optical coherence tomography specificity in tilted discs. AB - BACKGROUND AND OBJECTIVE: To investigate and compare the false-positive (FP) diagnostic classification of the Bruch's membrane opening - minimum rim width (BMO-MRW) and retinal nerve fiber layer (RNFL) thickness in healthy eyes with tilted optic disc. MATERIALS AND METHODS: Fifty healthy eyes of 30 participants with tilted optic disc underwent BMO-MRW and RNFL scanning using Spectralis and macular Cirrus optical coherence tomography (OCT) scans. RESULTS: The overall FP rate was significantly lower using BMO-MRW map compared with both RNFL map by Spectralis (8% vs 62%, respectively, P<0.001) and ganglion cell analysis (GCA) map by Cirrus (8% vs 50%, respectively, P<0.001). Specificity was significantly higher using BMO-MRW than RNFL in eyes with low (89.7% vs 41.4%, P<0.001) and moderate myopia (95.2% vs 33.3%, P<0.001). CONCLUSION: OCT-derived BMO-MRW analysis provides significantly greater specificity than RNFL in tilted disc irrespectively of the refractive error, and it is more specific than GCA analysis in tilted disc with moderate myopia. PMID- 27980391 TI - Phacoemulsification without preoperative mydriasis in patients with age-related cataract associated with type 2 diabetes. AB - AIM: To study the effect of intracameral injection of preservative-free lignocaine to induce pupil dilatation, without using any preoperative dilating eyedrops or intraoperative mydriatics in patients with age-related cataract associated with type 2 diabetes mellitus. DESIGN: This was a prospective, observational, and interventional case series conducted at a tertiary eyecare center in rural India. MATERIALS AND METHODS: A total of 32 patients underwent phacoemulsification under topical anesthesia for visually significant cataract. Preoperative pupillary diameter was measured 3 days prior to surgical procedure under mydriatics (tropicamide 0.8%, phenylephrine hydrochloride 5%). Intraoperative pupillary dilatation was achieved by 1% intracameral lignocaine solution alone. Effective phacoemulsification time (EPT), total surgical time, and final pupillary diameter were recorded at the conclusion of surgery. RESULTS: The average duration of diabetes was 11.2 (range 5-25) years. There was no difference in dilatation by preoperative pupil-dilating drops (5.2+/-0.5 mm, range 3-8.3 mm) and intracameral 1% lignocaine during the surgical procedure (P=0.63). There was a negative correlation (r=-0.92) between diabetes duration and dilatation of pupils with dilating drops and intracameral lignocaine. The duration of the surgery, EPT, and phacoemulsification chop had statistically insignificant effects on mydriasis, while the grade of the nucleus had a statistically significant effect on mydriasis. Intracameral lignocaine had no significant effect on blood pressure or pulse. There were no surgical complications that could have compromised the visual outcome. None of the patients developed macular edema in a follow-up period of 3 months; 28 patients (87.5%) had best-corrected visual acuity from 20/30 to 20/20. CONCLUSION: Intracameral lignocaine 1% provides sufficient mydriasis for the safe phacoemulsification of cataract in patients with type 2 diabetes of variable duration. PMID- 27980392 TI - Increased therapeutic efficacy of a newly synthesized tyrosinase inhibitor by solid lipid nanoparticles in the topical treatment of hyperpigmentation. AB - Hyperpigmentation caused by melanin overproduction is a major skin disorder in humans. Inhibition of tyrosinase, a key regulator of melanin production, has been used as an effective strategy to treat hyperpigmentation. In this study, we investigated the use of solid lipid nanoparticles (SLNs) as a highly effective and nontoxic means to deliver a newly synthesized potent tyrosinase inhibitor, MHY498, and to target melanocytes through the skin. MHY498-loaded SLNs (MHY-SLNs) were prepared by an oil-in-water emulsion solvent-evaporation method, and their morphological and physicochemical properties were characterized. MHY-SLNs showed a prolonged drug-release profile and higher skin permeation than that of MHY solution. In an in vivo evaluation of antimelanogenic activity, MHY-SLNs showed a prominent inhibitory effect against ultraviolet B-induced melanogenesis, resulting in no change in the skin color of C57BL/6 mouse, compared with that observed in an MHY solution-treated group and an untreated control group. The antimelanogenic effect of MHY-SLNs was further confirmed through Fontana-Masson staining. Importantly, MHY-SLNs did not induce any toxic effects in the L929 cell line. Overall, these data indicate that MHY-SLNs show promise in the topical treatment of hyperpigmentation. PMID- 27980393 TI - Paracetamol sharpens reflection and spatial memory: a double-blind randomized controlled study in healthy volunteers. AB - BACKGROUND: Acetaminophen (APAP, paracetamol) mechanism for analgesic and antipyretic outcomes has been largely addressed, but APAP action on cognitive function has not been studied in humans. Animal studies have suggested an improved cognitive performance but the link with analgesic and antipyretic modes of action is incomplete. This study aims at exploring cognitive tests in healthy volunteers in the context of antinociception and temperature regulation. A double blind randomized controlled study (NCT01390467) was carried out from May 30, 2011 to July 12, 2011. METHODS: Forty healthy volunteers were included and analyzed. Nociceptive thresholds, core temperature (body temperature), and a battery of cognitive tests were recorded before and after oral APAP (2 g) or placebo: Information sampling task for predecisional processing, Stockings of Cambridge for spatial memory, reaction time, delayed matching of sample, and pattern recognition memory tests. Analysis of variance for repeated measures adapted to crossover design was performed and a two-tailed type I error was fixed at 5%. RESULTS: APAP improved information sampling task (diminution of the number of errors, latency to open boxes, and increased number of opened boxes; all P<0.05). Spatial planning and working memory initial thinking time were decreased (P=0.04). All other tests were not modified by APAP. APAP had an antinociceptive effect (P<0.01) and body temperature did not change. CONCLUSION: This study shows for the first time that APAP sharpens decision making and planning strategy in healthy volunteers and that cognitive performance and antinociception are independent of APAP effect on thermogenesis. We suggest that cognitive performance mirrors the analgesic rather than thermic cascade of events, with possibly a central role for serotonergic and cannabinoid systems that need to be explored further in the context of pain and cognition. PMID- 27980394 TI - Ethical considerations in adherence research. AB - Poor adherence to treatment is a common cause of medical treatment failure. Studying adherence is complicated by the potential for the study environment to impact adherence behavior. Studies performed without informing patients about adherence monitoring must balance the risks of deception against the potential benefits of the knowledge to be gained. Ethically monitoring a patient's adherence to a treatment plan without full disclosure of the monitoring plan requires protecting the patient's rights and upholding the fiduciary obligations of the investigator. Adherence monitoring can utilize different levels of deception varying from stealth monitoring, debriefing after the study while informing the subject that some information had been withheld in regard to the use of adherence monitoring (withholding), informed consent that discloses some form of adherence monitoring is being used and will be disclosed at the end of the study (authorized deception), and full disclosure. Different approaches offer different benefits and potential pitfalls. The approach used must balance the risk of nondisclosure against the potential for confounding the adherence monitoring data and the potential benefits that adherence monitoring data will have for the research subjects and/or other populations. This commentary aims to define various methods of adherence monitoring and to provide a discussion of the ethical considerations that accompany the use of each method and adherence monitoring in general as it is used in clinical research. PMID- 27980395 TI - Utility of the Morisky Medication Adherence Scale in gout: a prospective study. AB - BACKGROUND: The outcomes of any chronic illness often depend on patients' adherence with their treatment. A tool is lacking to assess adherence in gout that is standardized, allows real-time feedback, and is easy to understand. OBJECTIVE: We set out to evaluate the utility of the 8-item Morisky Medication Adherence Scale (MMAS-8) in monitoring medication adherence in a multiethnic Asian gout cohort on urate-lowering therapy (ULT). METHODS: This cohort study recruited patients with gout where baseline and 6-monthly clinical data, self report of adherence, and health status by Gout Impact Scale (GIS) and EuroQoL-5 dimension 3 levels were collected. Those who received at least 9 months of ULT were analyzed. Convergent and construct validities of MMAS-8 were evaluated against medication possession ratio (MPR) and known groups, clinical outcomes, and patient-reported outcomes. Internal consistency and test-retest reliability were assessed using Cronbach's alpha and intraclass correlation coefficient (ICC), respectively. RESULTS: Of 91 patients, 92.3% were male, 72.5% Chinese with mean age 53.5 years. MMAS-8 (mean 6.17) and MPR (mean 96.3%) were poorly correlated (r=0.069, P=0.521). MMAS-8 did not differ between those who did or did not achieve target serum urate (SU) <360 umol/L (P=0.852); or among those whose SU improved, stagnated, or worsened during follow-up (P=0.777). Adherence was associated with age (beta=0.256, P=0.015) and education level (P=0.011) but not comorbidities, polypharmacy, or flare frequency. Concerns for medication side effects and anxiety or depression were associated with lower MMAS-8 (P<0.005). Internal consistency was acceptable (alpha=0.725) and test-retest reliability was satisfactory (ICC =0.70, 95% confidence interval [CI] 0.36-0.88). CONCLUSION: MMAS-8 had limited construct validity in assessing medication adherence to ULT in our gout patients. Nevertheless, it identified patients bothered or worried about ULT side effects, and those with underlying anxiety or depression, for whom targeted education and coping support may be useful. PMID- 27980396 TI - The employee's productivity in the health care sector in Poland and their impact on the treatment process of patients undergoing elective laparoscopic cholecystectomy. AB - BACKGROUND: Increasing the engagement of employees in the treatment process of patients may benefit a hospital and employee productivity and may result in better patient care and satisfaction with medical services. Given this, the first step in improving the quality of patient care is better availability of doctors for patients in a hospital ward. METHODS: The research for this paper was conducted in six health care units in the Kuyavian-Pomeranian province in Poland. The research assessed how the elements relating to employees' behavior and things characteristic to medical service influence patients' willingness to recommend a hospital. RESULTS: Patients' perception of services is linked with the behavior of medical employees and their engagement in the treatment process. CONCLUSION: Our research indicates that individual employee recognition and collective recognition of hospital employees as a whole were identified as the most important factors in employee engagement in the treatment process (employee productivity) and patients' satisfaction with medical service. PMID- 27980398 TI - Altered spontaneous brain activity pattern in patients with late monocular blindness in middle-age using amplitude of low-frequency fluctuation: a resting state functional MRI study. AB - OBJECTIVE: Previous reports have demonstrated significant brain activity changes in bilateral blindness, whereas brain activity changes in late monocular blindness (MB) at rest are not well studied. Our study aimed to investigate spontaneous brain activity in patients with late middle-aged MB using the amplitude of low-frequency fluctuation (ALFF) method and their relationship with clinical features. METHODS: A total of 32 patients with MB (25 males and 7 females) and 32 healthy control (HC) subjects (25 males and 7 females), similar in age, sex, and education, were recruited for the study. All subjects were performed with resting-state functional magnetic resonance imaging scanning. The ALFF method was applied to evaluate spontaneous brain activity. The relationships between the ALFF signal values in different brain regions and clinical features in MB patients were investigated using correlation analysis. RESULTS: Compared with HCs, the MB patients had marked lower ALFF values in the left cerebellum anterior lobe, right parahippocampal gyrus, right cuneus, left precentral gyrus, and left paracentral lobule, but higher ALFF values in the right middle frontal gyrus, left middle frontal gyrus, and left supramarginal gyrus. However, there was no linear correlation between the mean ALFF signal values in brain regions and clinical manifestations in MB patients. CONCLUSION: There were abnormal spontaneous activities in many brain regions including vision and vision-related regions, which might indicate the neuropathologic mechanisms of vision loss in the MB patients. Meanwhile, these brain activity changes might be used as a useful clinical indicator for MB. PMID- 27980399 TI - Clinical factors and comorbidities affecting the cost of hospital-treated COPD. AB - PURPOSE: We aimed to assess the effects of comorbidities on COPD costs and to investigate the relationship between comorbidities and clinical variables. PATIENTS AND METHODS: All patients hospitalized with a diagnosis of COPD exacerbation between January 1, 2014, and December 31, 2014, at all state hospitals of Aydin province, a city located in the western part of Turkey, were included in this study. The costs examined in the study pertained to medications, laboratory tests, hospital stays, and other treatment-related factors, such as consumption of materials, doctor visits, and consultation fees. RESULTS: A total of 3,095 patients with 5,237 exacerbations (mean age, 71.9+/-10.5 years; 2,434 males and 661 females) were evaluated. For 880 of the patients (28.9%), or 3,852 of the exacerbations (73.1%), at least one comorbid disease was recorded. The mean cost of each exacerbation was $808.5+/-1,586, including $325.1+/-879.9 (40.7%) for hospital stays, $223.1+/-1,300.9 (27.6%) for medications, $46.3+/ 49.6 (0.9%) for laboratory expenditures, and $214+/-1,068 (26.5%) for other treatment-related factors, such as consumption of materials, doctor visits, and consultation fees. The cost of each exacerbation was $1,014.9 in patients with at least one comorbidity, whereas it was $233.6 in patients without comorbidity (P<0.001). Age >65 years, female gender, hospitalization in an intensive care unit, invasive or noninvasive mechanical ventilation, and a long duration of hospitalization were all found to be significant factors in increasing total costs during the exacerbations requiring hospitalization (P<0.05 for all). CONCLUSION: Comorbidities have an important role in the total costs of acute exacerbations of COPD. Strategies for the prevention, diagnosis, and effective management of comorbidities would decrease the overall financial burden associated with acute exacerbations of COPD. PMID- 27980400 TI - Cigarette smoke extract induces placental growth factor release from human bronchial epithelial cells via ROS/MAPK (ERK-1/2)/Egr-1 axis. AB - Etiological evidence demonstrates that there is a significant association between cigarette smoking and chronic airway inflammatory disease. Abnormal expression of placental growth factor (PlGF) has been reported in COPD, and its downstream signaling molecules have been reported to contribute to the pathogenesis of airway epithelial cell apoptosis and emphysema. However, the signaling mechanisms underlying cigarette smoke extract (CSE)-induced PlGF expression in airway microenvironment remain unclear. Herein, we investigated the effects of reactive oxygen species (ROS)-dependent activation of the mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase1/2 [ERK-1/2])/early growth response 1 (Egr-1) pathway on CSE-induced PlGF upregulation in human bronchial epithelium (HBE). The data obtained with quantitative reverse transcription polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining analyses showed that CSE-induced Egr-1 activation was mainly mediated through production of ROS and activation of the MAPK (ERK-1/2) cascade. The binding of Egr-1 to the PlGF promoter was corroborated by an ELISA based DNA binding activity assay. These results demonstrate that ROS activation of the MAPK (ERK-1/2)/Egr-1 pathway is a main player in the regulatory mechanism for CSE-induced PlGF production and that the use of an antioxidant could partly abolish these effects. Understanding the mechanisms of PlGF upregulation by CSE in the airway microenvironment may provide rational therapeutic interventions for cigarette smoking-related airway inflammatory diseases. PMID- 27980401 TI - Effects of aclidinium on determinants of COPD severity: symptoms and quality of life. AB - The pathophysiology of chronic obstructive pulmonary disease (COPD) includes persistent airflow limitation, altered gas exchange, and enhanced chronic inflammatory response. According to disease severity in individual patients, exacerbations and comorbidities frequently occur. The overall nocturnal and daily symptoms have a strong impact on patient quality of life and clinical outcomes. Bronchodilators, by targeting two important aspects of COPD pathophysiology, ie, bronchoconstriction and lung hyperinflation, are the mainstay of therapy for COPD. Aclidinium bromide in particular is an anticholinergic molecule, approved for maintenance bronchodilator treatment of stable COPD, that combines high antimuscarinic activity with strong kinetic selectivity for the M3 receptor subtype. Moreover, the elevated plasma clearance of aclidinium has been related to low systemic bioavailability and low incidence of anticholinergic adverse events, whereas the reduced residence time at M2 receptors provides good cardiovascular safety. Altogether, these characteristics result in a high safety and tolerability profile. This review aims to reappraise the contribution of symptoms and of the level of quality of life determinants on COPD severity and to evaluate how therapeutic strategies with aclidinium may positively impact on these specific determinants of disease severity. PMID- 27980397 TI - Integrating Epigenomics into the Understanding of Biomedical Insight. AB - Epigenetics is one of the most rapidly expanding fields in biomedical research, and the popularity of the high-throughput next-generation sequencing (NGS) highlights the accelerating speed of epigenomics discovery over the past decade. Epigenetics studies the heritable phenotypes resulting from chromatin changes but without alteration on DNA sequence. Epigenetic factors and their interactive network regulate almost all of the fundamental biological procedures, and incorrect epigenetic information may lead to complex diseases. A comprehensive understanding of epigenetic mechanisms, their interactions, and alterations in health and diseases genome widely has become a priority in biological research. Bioinformatics is expected to make a remarkable contribution for this purpose, especially in processing and interpreting the large-scale NGS datasets. In this review, we introduce the epigenetics pioneering achievements in health status and complex diseases; next, we give a systematic review of the epigenomics data generation, summarize public resources and integrative analysis approaches, and finally outline the challenges and future directions in computational epigenomics. PMID- 27980402 TI - Increased risk of community-acquired pneumonia in COPD patients with comorbid cardiovascular disease. AB - BACKGROUND AND OBJECTIVE: COPD patients with community-acquired pneumonia (CAP) have worse clinical outcomes, as compared to those without COPD. Cardiovascular disease (CVD) is a common comorbidity for COPD patients. Whether COPD with comorbid CVD will increase the risk of CAP is not well investigated. The incidence and factors associated with CAP in COPD patients with and without CVD were analyzed. METHODS: The medical records of patients with newly diagnosed COPD between 2007 and 2010 were reviewed. The patients' characteristics, medical history of CVD, occurrence of CAP, and type of medication were recorded. Kaplan Meier curves were used to assess the differences in cumulative incidence of CAP. Cox's proportional hazards regression model was used to determine the adjusted hazard ratios with 95% confidence intervals in relation to factors associated with CAP in COPD patients with and without CVD. RESULTS: Among 2,440 patients, 475 patients (19.5%) developed CAP during the follow-up period. COPD patients who developed CAP were significantly older, had lower forced expiratory volume in 1 second, frequent severe exacerbation and comorbid CVD, as well as received inhaled corticosteroid (ICS)-containing therapy than those without CAP. The cumulative incidence of CAP was higher in COPD patients with CVD compared to those without CVD. Patients who received ICS-containing therapy had significantly increased risk of developing CAP compared to those who did not. CONCLUSION: For patients with COPD, comorbid CVD is an independent risk factor for developing CAP. ICS-containing therapy may increase the risk of CAP among COPD patients. PMID- 27980403 TI - Systemic delivery and activation of the TRAIL gene in lungs, with magnetic nanoparticles of chitosan controlled by an external magnetic field. AB - Recently, functional therapies targeting a specific organ without affecting normal tissues have been designed. The use of magnetic force to reach this goal is studied in this work. Previously, we demonstrated that nanocarriers based on magnetic nanoparticles could be directed and retained in the lungs, with their gene expression under the control of a promoter activated by a magnetic field. Magnetic nanoparticles containing the TRAIL gene and chitosan were constructed using the ionic gelation method as a nanosystem for magnetofection and were characterized by microscopy, zeta-potential, and retention analysis. Magnetofection in the mouse melanoma cell line B16F10 in vitro induced TRAIL protein expression and was associated with morphological changes indicative of apoptosis. Systemic administration of the nanosystem in the tail vein of mice with melanoma B16F10 at the lungs produced a very significant increase in apoptosis in tumoral cells that correlated with the number of melanoma tumor foci observed in the lungs. The high levels of apoptosis detected in the lungs were partially related to mouse survival. The data presented demonstrate that the magnetofection nanosystem described here efficiently induces apoptosis and growth inhibition of melanoma B16F10 in the lungs. This new approach for systemic delivery and activation of a gene based in a nanocomplex offers a potential application in magnetic gene delivery for cancer. PMID- 27980404 TI - Biocompatibility and antibacterial activity of nitrogen-doped titanium dioxide nanoparticles for use in dental resin formulations. AB - The addition of antibacterial functionality to dental resins presents an opportunity to extend their useful lifetime by reducing secondary caries caused by bacterial recolonization. In this study, the potential efficacy of nitrogen doped titanium dioxide nanoparticles for this purpose was determined. Nitrogen doping was carried out to extend the ultraviolet absorbance into longer wavelength blue light for increased biocompatibility. Titanium dioxide nanoparticles (approximately 20-30 nm) were synthesized with and without nitrogen doping using a sol-gel method. Ultraviolet-Visible spectroscopy indicated a band of trap states, with increasing blue light absorbance as the concentration of the nitrogen dopant increased. Electron paramagnetic resonance measurements indicated the formation of superoxide and hydroxyl radicals upon particle exposure to visible light and oxygen. The particles were significantly toxic to Escherichia coli in a dose-dependent manner after a 1-hour exposure to a blue light source (480 nm). Intracellular reactive oxygen species assay demonstrated that the particles caused a stress response in human gingival epithelial cells when exposed to 1 hour of blue light, though this did not result in detectable release of cytokines. No decrease in cell viability was observed by water-soluble tetrazolium dye assay. The results show that nitrogen-doped titanium dioxide nanoparticles have antibacterial activity when exposed to blue light, and are biocompatible at these concentrations. PMID- 27980406 TI - Using hyaluronic acid-functionalized pH stimuli-responsive mesoporous silica nanoparticles for targeted delivery to CD44-overexpressing cancer cells. AB - In this study, novel hyaluronic acid-pH stimuli-responsive lipid membrane mesoporous silica nanoparticles (HA-PL-MSNs) were designed and assembled, with the chemotherapeutic agent doxorubicin (DOX) as the model drug. HA-PL-MSNs exhibited a well-defined mesostructure covered by lipid bilayer and particle size of ~150 nm. The drug loading capacity was up to ~18.2%. DOX release could be effectively retained by the lipid bilayer in pH 7.4 buffer and exhibited a pH triggered burst release in the acidic condition. Confocal laser scanning microscopy and fluorescence-activated cell sorting showed that HA-PL-MSNs exhibited higher cellular uptake efficiency via CD44 receptor-mediated endocytosis compared with PL-MSNs in HeLa cells. In vitro cytotoxicity studies demonstrated that HA-PL-MSNs could effectively enhance the targeted delivery of DOX and restrain the growth of HeLa cells. This might provide a promising alternative for the development of a targeted anticancer drug delivery system. PMID- 27980408 TI - Global economic burden of schizophrenia: letter in response. PMID- 27980407 TI - PEG-b-PCL polymeric nano-micelle inhibits vascular angiogenesis by activating p53 dependent apoptosis in zebrafish. AB - Micro/nanoparticles could cause adverse effects on cardiovascular system and increase the risk for cardiovascular disease-related events. Nanoparticles prepared from poly(ethylene glycol) (PEG)-b-poly(epsilon-caprolactone) (PCL), namely PEG-b-PCL, a widely studied biodegradable copolymer, are promising carriers for the drug delivery systems. However, it is unknown whether polymeric PEG-b-PCL nano-micelles give rise to potential complications of the cardiovascular system. Zebrafish were used as an in vivo model to evaluate the effects of PEG-b-PCL nano-micelle on cardiovascular development. The results showed that PEG-b-PCL nano-micelle caused embryo mortality as well as embryonic and larval malformations in a dose-dependent manner. To determine PEG-b-PCL nano micelle effects on embryonic angiogenesis, a critical process in zebrafish cardiovascular development, growth of intersegmental vessels (ISVs) and caudal vessels (CVs) in flk1-GFP transgenic zebrafish embryos using fluorescent stereomicroscopy were examined. The expression of fetal liver kinase 1 (flk1), an angiogenic factor, by real-time quantitative polymerase chain reaction (qPCR) and in situ whole-mount hybridization were also analyzed. PEG-b-PCL nano-micelle decreased growth of ISVs and CVs, as well as reduced flk1 expression in a concentration-dependent manner. Parallel to the inhibitory effects on angiogenesis, PEG-b-PCL nano-micelle exposure upregulated p53 pro-apoptotic pathway and induced cellular apoptosis in angiogenic regions by qPCR and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay. This study further showed that inhibiting p53 activity, either by pharmacological inhibitor or RNA interference, could abrogate the apoptosis and angiogenic defects caused by PEG-b-PCL nano-micelles, indicating that PEG-b-PCL nano-micelle inhibits angiogenesis by activating p53-mediated apoptosis. This study indicates that polymeric PEG-b-PCL nano-micelle could pose potential hazards to cardiovascular development. PMID- 27980409 TI - Categorical improvements in disease severity in patients with major depressive disorder treated with vilazodone: post hoc analysis of four randomized, placebo controlled trials. AB - BACKGROUND: In three 8-week studies of vilazodone 40 mg/d (NCT00285376, NCT00683592, and NCT01473394) and a 10-week study of vilazodone 20 or 40 mg/d (NCT01473381), adults with major depressive disorder (MDD) showed significantly greater improvement with vilazodone versus placebo in global disease severity as measured by mean change from baseline in Clinical Global Impression of Severity (CGI-S) score. To assess the proportion of patients achieving clinically meaningful improvement, a post hoc pooled analysis was conducted using categorical shifts in disease severity based on CGI-S scores at baseline and end of treatment (EOT). METHODS: Analyses were conducted in the pooled intent-to treat population (N=2,218). Definitions of categorical shifts included CGI-S >=4 (moderately ill or worse) at baseline to CGI-S <=2 (normal or borderline ill) at EOT; CGI-S >=5 (markedly ill or worse) at baseline to CGI-S <=2 at EOT; and CGI-S >=6 (severely ill or worse) at baseline to CGI-S <=3 (mildly ill or better) at EOT. RESULTS: At baseline, 2,217 patients were moderately ill or worse. The percentage who improved to normal or borderline ill was significantly higher with vilazodone than with placebo (40.0% versus 27.8%; odds ratio [OR] =1.7, P<0.001; number needed to treat [NNT] =9). In the 979 patients who were markedly ill or worse at baseline, the percentage who improved to normal or borderline ill was significantly higher with vilazodone than with placebo (36.8% versus 25.5%; OR =1.7, P<0.001; NNT =9). The small number of severely ill patients at baseline (n =43) provided inadequate power to detect statistically significant between-group differences, but an NNT =5 was found for improvement to mildly ill or better. CONCLUSION: Categorical shift analyses, defined using baseline and EOT CGI-S scores, showed that significantly higher proportions of patients had clinically meaningful improvements in global disease severity with vilazodone 20-40 mg/d versus placebo. This type of analysis may be useful for evaluating the effects of antidepressant treatment in adults with MDD. PMID- 27980405 TI - Polycaprolactone nanofibrous mesh reduces foreign body reaction and induces adipose flap expansion in tissue engineering chamber. AB - Tissue engineering chamber technique can be used to generate engineered adipose tissue, showing the potential for the reconstruction of soft tissue defects. However, the consequent foreign body reaction induced by the exogenous chamber implantation causes thick capsule formation on the surface of the adipose flap following capsule contracture, which may limit the internal tissue expansion. The nanotopographical property and architecture of nanofibrous scaffold may serve as a promising method for minimizing the foreign body reaction. Accordingly, electrospinning porous polycaprolactone (PCL) nanofibrous mesh, a biocompatible synthetic polymer, was attached to the internal surface of the chamber for the reducing local foreign body reaction. Adipose flap volume, level of inflammation, collagen quantification, capsule thickness, and adipose tissue-specific gene expression in chamber after implantation were evaluated at different time points. The in vivo study revealed that the engineered adipose flaps in the PCL group had a structure similar to that in the controls and normal adipose tissue structure but with a larger flap volume. Interleukin (IL)-1beta, IL-6, and transforming growth factor-beta expression decreased significantly in the PCL group compared with the control. Moreover, the control group had much more collagen deposition and thicker capsule than that observed in the PCL group. These results indicate that the unique nanotopographical effect of electrospinning PCL nanofiber can reduce foreign body reaction in a tissue engineering chamber, which maybe a promising new method for generating a larger volume of mature, vascularized, and stable adipose tissue. PMID- 27980410 TI - miR-455 inhibits neuronal cell death by targeting TRAF3 in cerebral ischemic stroke. AB - Ischemic stroke is one of the leading causes of brain disease, with high morbidity, disability, and mortality. MicroRNAs (miRNAs) have been identified as vital gene regulators in various types of human diseases. Accumulating evidence has suggested that aberrant expression of miRNAs play critical roles in the pathologies of ischemic stroke. Yet, the precise mechanism by which miRNAs control cerebral ischemic stroke remains unclear. In the present study, we explored whether miR-455 suppresses neuronal death by targeting TRAF3 in cerebral ischemic stroke. The expression levels of miR-455 and TRAF3 were detected by quantitative real-time polymerase chain reaction and Western blot. The role of miR-455 in cell death caused by oxygen-glucose deprivation (OGD) was assessed using Cell Counting Kit-8 (CCK-8) assay. The influence of miR-455 on infarct volume was evaluated in mouse brain after middle cerebral artery occlusion (MCAO). Bioinformatics softwares and luciferase analysis were used to find and confirm the targets of miR-455. The results showed that the expression levels of miR-455 significantly decreased in primary neuronal cells subjected to OGD and mouse brain subjected to MCAO. In addition, forced expression of miR-455 inhibited neuronal death and weakened ischemic brain infarction in focal ischemia stroked mice. Furthermore, TRAF3 was proved to be a direct target of miR-455, and miR-455 could negatively suppress TRAF3 expression. Biological function analysis showed that TRAF3 silencing displayed the neuroprotective effect in ischemic stroke and could enhance miR-455-induced positive impact on ischemic injury both in vitro and in vivo. Taken together, miR-455 played a vital role in protecting neuronal cells from death by downregulating TRAF3 protein expression. These findings may represent a novel latent therapeutic target for cerebral ischemic stroke. PMID- 27980411 TI - Age-related issues of instruments screening for autism in young children. PMID- 27980412 TI - Complete blood cell count components and coronary slow-flow phenomenon. PMID- 27980413 TI - High bone turnover elevates the risk of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis. AB - Hypocalcemia is the most common major adverse event in patients with osteoporosis receiving the bone resorption inhibitor denosumab; however, limited information is available regarding risk factors of hypocalcemia. Therefore, this study aimed to identify the risk factors of hypocalcemia induced by denosumab treatment for osteoporosis. We retrospectively reviewed the records of patients who had received initial denosumab supplemented with activated vitamin D for osteoporosis. Serum levels of the following bone turnover markers (BTMs) were measured at baseline: bone-specific alkaline phosphatase (BAP), total N-terminal propeptide of type 1 procollagen (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and urinary cross-linked N-telopeptide of type 1 collagen (NTX). Of the 85 denosumab-treated patients with osteoporosis studied, 22 (25.9%) developed hypocalcemia. Baseline serum total P1NP, TRACP-5b, and urinary NTX were significantly higher in patients with hypocalcemia than in those with normocalcemia following denosumab administration (all P<0.01). Multivariate logistic regression analysis revealed that patients with total P1NP >76.5 MUg/L, TRACP-5b >474 mU/dL, or urinary NTX >49.5 nmol bone collagen equivalent/mmol creatinine had a higher risk of hypocalcemia (P<0.01). Our study suggests that denosumab may have a greater impact on serum calcium levels in patients with postmenopausal osteoporosis with higher baseline bone turnover than in patients with postmenopausal osteoporosis with normal baseline bone turnover, because maintenance of normal serum calcium in this subgroup is more dependent on bone resorption. Close monitoring of serum calcium levels is strongly recommended for denosumab-treated patients with high bone turnover, despite supplementation with activated vitamin D and oral calcium. PMID- 27980415 TI - Tennessee's 3-Star Report: Using Available Data Systems to Reduce Missed Opportunities to Vaccinate Preteens. AB - All preteens should receive tetanus-diphtheria-pertussis vaccine (Tdap), quadrivalent meningococcal vaccine (Men-ACWY), and the human papillomavirus (HPV) cancer vaccine series. In Tennessee, HPV vaccination rates have stagnated at low levels for a decade. Three fundamental strategies to reduce missed opportunities for immunization include administering all recommended vaccines at the same visit, making strong recommendations for vaccines, and auditing and feedback. In Tennessee, during each summer, a surge of preteens visit local health departments (LHDs) to receive a required Tdap vaccine before entering seventh grade, presenting an opportunity to administer Men-ACWY and HPV. The Tennessee Immunization Program (TIP) coined the term "3-Star visit" for such encounters and developed a monthly report to track them using data from the Patient Tracking Billing Management Information System (PTBMIS) used by LHDs across Tennessee. Implementation of this quality improvement report has correlated with a substantial increase in 3-Star visits from 2013 to 2016, particularly during the summer months. PMID- 27980414 TI - Managing Maternal Substance Use in the Perinatal Period: Current Concerns and Treatment Approaches in the United States and Australia. AB - Substance use in pregnancy can have adverse effects on mother and fetus alike. Australia and the US are countries with high levels of substance use and policies advising abstinence, although the Australian approach occurs within a broader framework of harm minimization. Less attention has been paid to treatment of the mothers' substance use and what is considered gold standard. This is despite evidence that prior substance use in pregnancy is the most important factor in predicting future substance use in pregnancy. This paper draws together information from both the peer-reviewed and gray literature to provide a contemporary overview of patterns and outcomes of the three main drugs, alcohol, tobacco, and cannabis, used in Australia and the US during pregnancy and discusses what are considered gold standard screening and treatment approaches for these substances. This paper does not set out to be a comprehensive review of the area but rather aims to provide a concise summary of current guidelines for policy makers and practitioners who provide treatment for women who use substances in pregnancy. PMID- 27980416 TI - The Efficacy of Intraoperative Frozen Section Analysis During Breast-Conserving Surgery for Patients with Ductal Carcinoma In Situ. AB - INTRODUCTION: Recently, the incidence of ductal carcinoma in situ (DCIS), a noninvasive breast malignancy, has increased. This has resulted in an increase in the incidence of breast-conserving surgery (BCS). Numerous studies have suggested that intraoperative frozen section analysis (IFSA) could reduce the rate of additional excisions required to obtain adequate resection margins. However, DCIS is a known risk factor for positive margin status during BCS. Furthermore, some authors have concluded that IFSA may not be reliable for the detection of DCIS. AIM: The aim of this study was to evaluate the safety and efficacy of IFSA in patients with DCIS. METHODS: The operative and pathological reports of patients with DCIS, who underwent BCS at our institute between 2006 and 2015, were retrospectively reviewed. The results of IFSA and the pathological findings of final reanalyzed frozen tissue specimens were analyzed. RESULTS: In total, 25 patients were included in our analysis. None of the patients required additional operations. The correct diagnosis rate for IFSA was 89.6%, with a sensitivity and specificity of 60.0% and 95.8%, respectively. CONCLUSION: IFSA could be beneficial for determining safety resection margins in patients with DCIS. PMID- 27980417 TI - Clinicopathological Significance of TARBP2, APP, and ZNF395 in Breast Cancer. AB - The double-stranded RNA-binding protein TARBP2 has been suggested to act as an upstream regulator of breast cancer metastasis by destabilizing transcripts of the possible metastasis suppressors amyloid precursor protein (APP) and ZNF395. We examined this hypothesis by immunostaining of TARBP2, APP, and ZNF395 in 200 breast cancer specimens using tissue microarrays and analyzed the relationships between expression levels and clinicopathological parameters and prognosis. Increased TARBP2 overexpression was associated with shorter overall survival and disease-free survival, and increased but not reduced APP expression correlated with lower overall survival and disease-free survival. ZNF395 expression levels had no prognostic value, but reduced expression correlated with reduced lymph node metastasis. There was no significant relationship between TARBP2 overexpression and reduced APP and/or ZNF395 expression. Patients with tumors with higher TARBP2 or APP expression had unfavorable prognoses. Although reduced ZNF395 expression was significantly related to reduced lymph node metastasis, further studies are needed to clarify the role of TARBP2/APP/ZNF395 in breast cancer. PMID- 27980418 TI - Effects of Sterculia setigera Del. Stem Bark Extract on Hematological and Biochemical Parameters of Wistar Rats. AB - Africa is rich in a wide range of flora that are exploited as herbal medicines and remedies. Several diseases such as diabetes, diarrhea, dysentery and jaundice have been successfully managed using herbal medicines. Herbal decoctions or concoctions have been used as pain killers, antibiotics, and hematinics. This study evaluated the hematopoietic and biochemical properties of the stem bark of Sterculia setigera Del. in Wistar rats. Results showed that S. setigera decoction has copiously high tannin and cardiac glycoside levels. Ingestion of the decoction by rats over a 16-day period significantly (P < 0.05) increased the body weights of rats by 22.4% in the S. setigera-treated group. Hematological profiles showed raised levels of red blood cells, hemoglobin, packed cell volume, mean corpuscular volume, mean cell hemoglobin, mean cell hemoglobin concentration, and platelets, while biochemical parameters showed lower levels of alanine aminotransferase and aspartate aminotransferase, and slight increase in albumin and TP levels. We posit that the results justify the use of the stem bark of S. setigera as a hematinic by traditional medical practitioners and show its relative safety. Further experiments are needed to evaluate its safety. PMID- 27980419 TI - Patterns of Pesticide Use and Associated Factors Among the Commercial Farmers of Chitwan, Nepal. AB - Farmers in developing countries are exposed to pesticide hazards due to unsafe handling. This study was conducted to identify the prevailing practices of pesticide use and factors affecting the handling of pesticides among the farmers of Chitwan, Nepal. A cross-sectional study was conducted among 125 farmers. None of the farmers completely followed all the protective measures. About 59% disposed the empty pesticide containers to a nearby water source and 62% preferred house ceilings as a storage place. Males (aOR = 3.99, CI = 1.63-9.78) and older farmers (aOR = 6.18, CI = 2.59-14.72) were more likely to smoke or chew tobacco during the process of spray. Males (aOR = 2.42, CI = 1.03-5.67), literate farmers (aOR = 3.56, CI = 1.51-8.33), and farmers aware of color coding (aOR = 2.67, CI = 1.13-5.67) were more likely to read the labels on pesticide bottles. In spite of an extensive use of pesticides, the farmers were not following proper and safe handling practices, exposing them and the community to a potential pesticide hazard. PMID- 27980420 TI - Palliative Care and Patient Autonomy: Moving Beyond Prohibitions Against Hastening Death. AB - The National Hospice and Palliative Care Organization (NHPCO) upholds policies prohibiting practices that deliberately hasten death. We find these policies overly restrictive and unreasonable. We argue that under specified circumstances it is both reasonable and morally sound to allow for treatments that may deliberately hasten death; these treatments should be part of the NHPCO guidelines. Broadening such policies would be more consistent with the gold standard of bioethical principles, ie, respecting the autonomy of competent adults. PMID- 27980421 TI - A Mouse Model of Diet-Induced Obesity Resembling Most Features of Human Metabolic Syndrome. AB - Increased chicken-derived fat and fructose consumption in the human diet is paralleled by an increasing prevalence of obesity and metabolic syndrome (MS). Herein, we aimed at developing and characterizing a mouse model of diet-induced obesity (DIO) resembling most of the key features of the human MS. To accomplish this, we fed male C57BL/6J mice for 4, 8, 12, and 16 weeks with either a low-fat diet (LFD) or a high-chicken-fat diet (HFD) and tap water with or without 10% fructose (F). This experimental design resulted in the following four experimental groups: LFD, LFD + F, HFD, and HFD + F. Over the feeding period, and on a weekly basis, the HFD + F group had more caloric intake and gained more weight than the other experimental groups. Compared to the other groups, and at the end of the feeding period, the HFD + F group had a higher adipogenic index, total cholesterol, low-density lipoprotein cholesterol, fasting basal glycemia, insulin resistance, hypertension, and atherogenic index and showed steatohepatitis and systemic oxidative stress/inflammation. A mouse model of DIO that will allow us to study the effect of MS in different organs and systems has been developed and characterized. PMID- 27980422 TI - Progesterone Alters Kynurenine Pathway Activation in IFN-gamma-Activated Macrophages - Relevance for Neuroinflammatory Diseases. AB - We have previously demonstrated that the kynurenine pathway (KP), the major biochemical pathway for tryptophan metabolism, is dysregulated in many inflammatory disorders that are often associated with sexual dimorphisms. We aimed to identify a potential functional interaction between the KP and gonadal hormones. We have treated primary human macrophages with progesterone in the presence and absence of inflammatory cytokine interferon-gamma (interferon-gamma) that is known to be a potent inducer of regulating the KP enzyme. We found that progesterone attenuates interferon-gamma-induced KP activity, decreases the levels of the excitotoxin quinolinic acid, and increases the neuroprotective kynurenic acid levels. We also showed that progesterone was able to reduce the inflammatory marker neopterin. These results may shed light on the gender disparity in response to inflammation. PMID- 27980423 TI - Mesoporous silica nanoparticles functionalized with folic acid/methionine for active targeted delivery of docetaxel. AB - Mesoporous silica nanoparticles (MSNs) are known as carriers with high loading capacity and large functionalizable surface area for target-directed delivery. In this study, a series of docetaxel-loaded folic acid- or methionine-functionalized mesoporous silica nanoparticles (DTX/MSN-FA or DTX/MSN-Met) with large pores and amine groups at inner pore surface properties were prepared. The results showed that the MSNs were successfully synthesized, having good pay load and pH sensitive drug release kinetics. The cellular investigation on MCF-7 cells showed better performance of cytotoxicity and cell apoptosis and an increase in cellular uptake of targeted nanoparticles. In vivo fluorescent imaging on healthy BALB/c mice proved that bare MSN-NH2 are mostly accumulated in the liver but MSN-FA or MSN-Met are more concentrated in the kidney. Importantly, ex vivo fluorescent images of tumor-induced BALB/c mice organs revealed the ability of MSN-FA to reach the tumor tissues. In conclusion, DTX/MSNs exhibited a good anticancer activity and enhanced the possibility of targeted drug delivery for breast cancer. PMID- 27980424 TI - Structure-activity relationships study of mTOR kinase inhibition using QSAR and structure-based drug design approaches. AB - The discovery of clinically relevant inhibitors of mammalian target of rapamycin (mTOR) for anticancer therapy has proved to be a challenging task. The quantitative structure-activity relationship (QSAR) approach is a very useful and widespread technique for ligand-based drug design, which can be used to identify novel and potent mTOR inhibitors. In this study, we performed two-dimensional QSAR tests, and molecular docking validation tests of a series of mTOR ATP competitive inhibitors to elucidate their structural properties associated with their activity. The QSAR tests were performed using partial least square method with a correlation coefficient of r2=0.799 and a cross-validation of q2=0.714. The chemical library screening was done by associating ligand-based to structure based approach using the three-dimensional structure of mTOR developed by homology modeling. We were able to select 22 compounds from two databases as inhibitors of the mTOR kinase active site. We believe that the method and applications highlighted in this study will help future efforts toward the design of selective ATP-competitive inhibitors. PMID- 27980425 TI - Next-generation sequencing: advances and applications in cancer diagnosis. AB - Technological advances have led to the introduction of next-generation sequencing (NGS) platforms in cancer investigation. NGS allows massive parallel sequencing that affords maximal tumor genomic assessment. NGS approaches are different, and concern DNA and RNA analysis. DNA sequencing includes whole-genome, whole-exome, and targeted sequencing, which focuses on a selection of genes of interest for a specific disease. RNA sequencing facilitates the detection of alternative gene spliced transcripts, posttranscriptional modifications, gene fusion, mutations/single-nucleotide polymorphisms, small and long noncoding RNAs, and changes in gene expression. Most applications are in the cancer research field, but lately NGS technology has been revolutionizing cancer molecular diagnostics, due to the many advantages it offers compared to traditional methods. There is greater knowledge on solid cancer diagnostics, and recent interest has been shown also in the field of hematologic cancer. In this review, we report the latest data on NGS diagnostic/predictive clinical applications in solid and hematologic cancers. Moreover, since the amount of NGS data produced is very large and their interpretation is very complex, we briefly discuss two bioinformatic aspects, variant-calling accuracy and copy-number variation detection, which are gaining a lot of importance in cancer-diagnostic assessment. PMID- 27980426 TI - Mutations in hepatitis B virus small S genes predict postoperative survival in hepatocellular carcinoma. AB - Hepatitis B virus (HBV) DNA is prone to mutations due to proofreading deficiencies of HBV polymerase. We have previously identified hepatocellular carcinoma (HCC) survival-associated HBV mutations in the X, precore, and core regions. In the present study, we extended our research to assess HCC survival associated HBV mutations in the small S gene of HBV genome in 115 HCC patients including 60 patients with HBV B genotype, 52 patients with HBV C genotype, and 3 patients with other genotypes. The overfrequencies of mutations at nucleotides 529 and 735 are 8.5% and 91.5%, respectively, but the distribution frequencies of these mutations are not different between HBV genotypes B and C. Mutational sites 529 (relative risk: 3.611, 95% confidence interval [CI]: 1.414-9.221, P=0.007) and 735 (relative risk: 1.905, 95% CI: 1.101-3.297, P=0.021) were identified as statistically significant independent predictors for HCC survival by multivariate survival analysis using a Cox proportional hazards model. Moreover, the mutated 529A and 735T were associated with both short survival time and high HBV DNA load score in HCC patients. The analysis of DNA mutations in the HBV S gene may help identify HCC subgroups with poor prognosis and may provide reference for therapeutic decisions. PMID- 27980427 TI - Curcumin sensitizes human gastric cancer cells to 5-fluorouracil through inhibition of the NFkappaB survival-signaling pathway. AB - Fluorouracil (5-FU) is the most commonly used chemotherapeutic agent for gastric cancer (GC). However, the occurrence of resistance to 5-FU treatment poses a major problem for its clinical efficacy. In this study, we found that the NFkappaB-signaling pathway can mediate 5-FU resistance in GC cells. We developed a 5-FU-resistant GC cell line named SGCR/5-FU and found that the 5-FU-induced resistance increased cytosolic IkappaBalpha degradation and promoted NFkappaB nuclear translocation in GC cells. These findings were further confirmed by the activation of the NFkappaB survival-signaling pathway in clinical specimens. Curcumin, a natural compound, can reverse 5-FU resistance and inhibits proliferation in GC cells by downregulating the NFkappaB-signaling pathway. Moreover, it can also decrease the expression level of TNFalpha messenger RNA. Flow cytometry and Western blot analysis results showed that the combination of curcumin and 5-FU caused synergistic inhibition of growth and induction of potent apoptosis in the resistant cancer cell lines in vitro. In conclusion, our results demonstrate that the combination of 5-FU and curcumin could be further developed as a potential therapy for human GC. PMID- 27980428 TI - Availability, perceptions, and characteristics of antibiograms among Illinois pediatricians. AB - Despite the enormous volume of antibiotics prescribed by pediatricians, resources to promote judicious antibiotic use are primarily limited to hospitals. The primary objective of this survey was to delineate the availability, characteristics, and perceptions of antibiograms among pediatricians. As a secondary objective, we sought to delineate the availability of other infectious diseases (ID)-related educational resources among pediatricians, the perceived need for additional resources, and their general educational preferences. We developed an anonymous electronic survey using the Research Electronic Data Capture tool, and it was sent via email to all members of the Illinois Chapter of the American Academy of Pediatrics (ICAAP). Participants were excluded if they had not completed pediatrics residency or if they had not prescribed antibiotics in the past month. Of the 1,825 ICAAP members, 294 (16%) responded; of these, 239 (81%) were eligible and completed the survey. Of the 239 respondents, 139 (58%) had access to an antibiogram and 60 (25%) had access to a pediatric-specific antibiogram. Access to a pediatric-specific antibiogram was associated with subspecialty training (P=0.007) and practice location in Chicago (P<0.0001). Antibiogram access was associated with perceiving being informed about resistance patterns at the national (67% vs 54%, P=0.043) and local (76% vs 45%, P<0.0001) levels. Nearly all (95%) respondents would probably or definitely use a single antibiogram that compiled antibiotic resistance data from children with common infections throughout the region. More than 75% of respondents identified both the American Academy of Pediatrics Red Book and online medical resources among the top three most useful and most frequently accessed educational resources. In addition, 91% of respondents utilized smartphones/tablets. These data suggest that there is an unmet need for additional educational resources to guide antibiotic prescribing among Illinois pediatricians. In addition, an electronic regional antibiogram would be well received and could potentially improve knowledge of antibiotic resistance and empiric antibiotic use. PMID- 27980429 TI - Treatment effectiveness and treatment patterns among rheumatoid arthritis patients after switching from a tumor necrosis factor inhibitor to another medication. AB - OBJECTIVES: After treatment failure with a tumor necrosis factor inhibitor (TNFi), patients with rheumatoid arthritis (RA) can switch to another TNFi (TNFi cyclers) or to a targeted disease-modifying antirheumatic drug (DMARD) with a non TNFi mechanism of action (non-TNFi switchers). This study compared treatment patterns and treatment effectiveness between TNFi cyclers and non-TNFi switchers in patients with RA. METHODS: The analysis included a cohort of patients from the Truven Health Analytics MarketScan Commercial database with RA who switched from a TNFi (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) either to another TNFi or to a non-TNFi targeted DMARD (abatacept, tocilizumab, or tofacitinib) between January 1, 2010 and September 30, 2014. A claims-based algorithm was used to estimate treatment effectiveness based on six criteria (adherence, no dose increase, no new conventional therapy, no switch to another targeted DMARD, no new/increased oral glucocorticoid, and intra-articular injections on <2 days). RESULTS: The cohort included 5,020 TNFi cyclers and 1,925 non-TNFi switchers. Non-TNFi switchers were significantly less likely than TNFi cyclers to switch therapy again within 6 months (13.2% vs 19.5%; P<0.001) or within 12 months (29.7% vs 34.6%; P<0.001) and significantly more likely to be persistent on therapy at 12 months (61.8% vs 58.2%; P<0.001). Non-TNFi switchers were significantly more likely than TNFi cyclers to achieve all six of the claims based effectiveness algorithm criteria for the 12 months after the initial switch (27% vs 24%; P=0.011). CONCLUSION: Although the absolute differences were small, these results support switching to a non-TNFi targeted DMARD instead of TNFi cycling when patients with RA require another therapy after TNFi failure. PMID- 27980430 TI - Evaluation of serum ferritin and some metal elements in type 2 diabetes mellitus patients: comparative cross-sectional study. AB - BACKGROUND: The chronic hyperglycemia of diabetes has been associated with an imbalance of some trace metal elements in the blood sample of type 2 diabetes patients. AIM: To evaluate the status of serum ferritin and some selected metal elements among type 2 diabetes mellitus (T2DM) patients. METHODS: Facility-based comparative cross-sectional study was conducted from February 15, 2015 to October 30, 2015, at Jimma University Specialized Hospital, Ethiopia. A total of 428 type 2 diabetes and nondiabetes study subjects were recruited to the study. After overnight fasting, 10 mL of venous blood samples were taken for biochemical and trace metal element analysis. Data were entered into EpiData version 3.5.1 and exported to SPSS version 20 for Windows for analysis. RESULTS: Serum concentration of Zn+2, Mg+2, Cr+3, ferritin, and Fe+3 in patients with type 2 diabetes was significantly lower (p<0.0001) than nondiabetes patients. In contrast, serum Cu+2 was significantly higher (p<0.0001) in type 2 diabetes patients than nondiabetics. In addition, significant differences were not seen in both groups with regard to serum Mn+2, Ca+2, and Po4-3. Waist-to-hip ratio (WHR), serum Fe+3, ferritin, and Mn+2 were significantly higher among oral hypoglycemic agent users of type 2 diabetes patients than the injectable insulin users. Serum Zn+2 had significant positive correlation with serum Mg+2 (r=0.738), Cr+3 (r=0.233), Ca+2 (r=0.238), and Po4-3 (r=0.222). In addition, serum Zn+2 had shown significant and negative correlation with body mass index (BMI, r=-0.331), WHR (r=-0.340), and fasting blood glucose (FBG, r=-0.186). Likewise, serum Mg+2 and Po4-3 are significantly and negatively correlated with BMI, WHR, and FBG. CONCLUSION: The imbalance of trace metal elements in the blood sample of diabetes is uncertain. Thus, we recommend a prospective cohort study to find out the principal factors behind the problem. PMID- 27980431 TI - rDNA insulin glargine U300 - a critical appraisal. AB - BACKGROUND: As the first once-daily basal insulin analog, insulin glargine 100 U/mL (Gla-100; Lantus(r)) rapidly evolved into the most commonly prescribed insulin therapy worldwide. However, this insulin has clinical limitations. The approval of new basal insulin analogs in 2015 has already started to alter the prescribing landscape. OBJECTIVE: To review the available evidence on the clinical efficacy and safety of a more concentrated insulin glargine (recombinant DNA origin) injection 300 U/mL (Gla-300) compared to insulin Gla-100 in patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM). METHODS: The following electronic databases were searched: PubMed and MEDLINE (using Ovid platform), Scopus, BIOSIS, and Google Scholar through June 2016. Conference proceedings of the American Diabetes Association (2015-2016) were reviewed. We also manually searched reference lists of pertinent reviews and trials. RESULTS: A total of 6 pivotal Phase III randomized controlled trials known as the EDITION series were reviewed. All of these trials (n=3,500) were head-to-head comparisons evaluating the efficacy and tolerability of Gla-300 vs Gla-100 in a diverse population with T1DM and T2DM. These trials were of 6 months duration with a 6-month safety extension phase. CONCLUSION: Gla-300 was as effective as Gla-100 for improving glycemic control over 6 months in all studies, with a lower risk of nocturnal hypoglycemia significant only in insulin-experienced patients with T2DM. Overall, patients on Gla-300 required 10%-18% more basal insulin, but with less weight gain compared with Gla-100. PMID- 27980433 TI - Bacteremia caused by a rare pathogen - Chromobacterium violaceum: a case report from Nepal. AB - Chromobacterium violaceum is a gram negative saprophytic bacterium, prevalent in tropical and subtropical climates. Infections caused by C. violaceum are very uncommon, yet it can cause severe systemic infections with higher mortality when entered into the bloodstream through open wound. A case of symptomatic bacteremia in a woman caused by C. violaceum was identified recently at a tertiary care teaching hospital in Nepal. Timely diagnosis by microbiological methods and rapid administration of antimicrobials led to a successful treatment of this life threatening infection in this case. From this experience, we suggest to include this bacterium in the differential diagnosis of sepsis, especially when abraded skin is exposed to soil or stagnant water in tropical areas. The precise antimicrobial selection and timely administration should be considered when this infection is suspected. PMID- 27980432 TI - Absorption and safety of serum-derived bovine immunoglobulin/protein isolate in healthy adults. AB - PURPOSE: Previous studies have shown that oral administration of bovine immunoglobulin protein preparations is safe and provides nutritional and intestinal health benefits. The purpose of this study was to evaluate the plasma amino acid response following a single dose of serum-derived bovine immunoglobulin/protein isolate (SBI) and whether bovine immunoglobulin G (IgG) is present in stool or in blood following multiple doses of SBI in healthy volunteers. METHODS: A total of 42 healthy adults were administered a single dose of placebo or SBI at one of three doses (5 g, 10 g, or 20 g) in blinded fashion and then continued on SBI (2.5 g, 5 g, or 10 g) twice daily (BID) for an additional 2 weeks. Serial blood samples were collected for amino acid analysis following a single dose of placebo or SBI. Stool and blood samples were collected to assess bovine IgG levels. RESULTS: The area under the curve from time 0 minute to 180 minutes for essential and total amino acids as well as tryptophan increased following ingestion of 5 g, 10 g, or 20 g of SBI, with a significant difference between placebo and all doses of SBI (p<0.05) for essential amino acids and tryptophan but only the 10 g and 20 g doses for total amino acids. Bovine IgG was detected in the stool following multiple doses of SBI. No quantifiable levels of bovine IgG were determined in plasma samples 90 minutes following administration of a single dose or multiple doses of SBI. CONCLUSION: Oral administration of SBI leads to increases in plasma essential amino acids during transit through the gastrointestinal tract and is safe at levels as high as 20 g/day. PMID- 27980435 TI - Erratum: Humanistic and economic burden of fibromyalgia in Japan [Corrigendum]. AB - [This corrects the article on p. 967 in vol. 9, PMID: 27853390.]. PMID- 27980434 TI - TRPA1 in the spinal dorsal horn is involved in post-inflammatory visceral hypersensitivity: in vivo study using TNBS-treated rat model. AB - INTRODUCTION: The transient receptor potential ankyrin-1 (TRPA1) channel, a pain transducer and amplifier, is drawing increasing attention in the field of visceral hypersensitivity, commonly seen in irritable bowel syndrome and inflammatory bowel disease. However, the role of TRPA1 in visceral nociception during post-inflammatory states is not well defined. Here, we explore the correlation between TRPA1 expression in the spinal dorsal horn (SDH) and persistent post-inflammatory visceral hypersensitivity. METHODS: We injected rats intracolonically with 2,4,6-trinitrobenzene sulfonic acid (TNBS) or vehicle (n=12 per group). Post-inflammatory visceral hypersensitivity was assessed by recording the electromyographic activity of the external oblique muscle in response to colorectal distension. TRPA1 expression and distribution in the spinal cord and colon were examined by Western blotting and immunohistochemistry. RESULTS: Animals exposed to TNBS had more abdominal contractions than vehicle-injected controls (P<0.05), which corresponded to a lower nociceptive threshold. Expression of TRPA1 in the SDH (especially in the substantia gelatinosa) and the colon was significantly greater in the TNBS-treated group than in controls (P<0.05). In the SDH, the number of TRPA1-immunopositive neurons was 25.75+/-5.12 in the control group and 34.25+/-7.89 in the TNBS-treated group (P=0.023), and integrated optical density values of TRPA1 in the control and TNBS-treated groups were 14,544.63+/-6,525.54 and 22,532.75+/-7,608.11, respectively (P=0.041). CONCLUSION: Our results indicate that upregulation of TRPA1 expression in the SDH is associated with persistent post-inflammatory visceral hypersensitivity in the rat and provides insight into potential therapeutic targets for the control of persistent visceral hypersensitivity. PMID- 27980436 TI - An investigation of completion times on the Screener and Opioid Assessment for Patients with Pain - revised (SOAPP-R). AB - BACKGROUND: Respondents' scores to the Screener and Opioid Assessment for Patients with Pain - revised (SOAPP-R) have been shown to be predictive of aberrant drug-related behavior (ADB). However, research is lacking on whether an individual's completion time (the amount of time that he/she takes to finish the screener) has utility in predicting ADB, despite the fact that response speed has been useful in predicting behavior in other fields. The purpose of this study was to evaluate the degree to which SOAPP-R completion time is predictive of ADB. MATERIALS AND METHODS: This retrospective study analyzed completion-time data from 82 adult emergency department patients who completed the SOAPP-R on a tablet computer. The utility of SOAPP-R completion times in predicting ADB was assessed via logistic regression and the area under the curve (AUC) statistic. An external measure of ADB using Prescription Drug Monitoring Program data defined ADB to have occurred in individuals with at least four opioid prescriptions and at least four prescribers in 12 months. RESULTS: Although there was a slight trend for individuals with greater completion times to have greater odds of ADB (odds ratio 1.004 in simple logistic regression), the association between SOAPP-R completion time and ADB was not statistically significant in either simple logistic regression (P=0.307) or multiple logistic regression adjusting for SOAPP-R score (P=0.419). AUC values for the prediction of ADB using completion time alone, SOAPP-R score alone, and both completion time and SOAPP-R score were 0.63, 0.64, and 0.65, respectively. CONCLUSION: There was no significant evidence that SOAPP R completion times were predictive of ADB among emergency department patients. However, the AUC value for completion times was only slightly less than that for SOAPP-R total scores. PMID- 27980437 TI - The analgesic efficacy of intravenous lidocaine infusion after laparoscopic fundoplication: a prospective, randomized, double-blind, placebo-controlled trial. AB - This study aimed to determine if intravenous lidocaine infusion reduces postoperative pain intensity following laparoscopic fundoplication surgery and to also validate the safety of intravenous lidocaine at the dose tested. This was an equally randomized, double-blind, placebo-controlled, parallel-group, single center trial. Adult patients undergoing laparoscopic fundoplication were recruited. The intervention group received 1 mg/kg intravenous lidocaine bolus prior to induction of anesthesia, then an intravenous infusion at 2 mg/kg/h for 24 hours. The primary outcome was pain, measured using a numeric rating scale for 30 hours postoperatively. Secondary outcomes were nausea and vomiting, opioid requirements, adverse events, serum lidocaine concentration, and length of hospital stay. The study was terminated after an interim analysis of 24 patients showed evidence of futility. There was no difference in postoperative pain scores (lidocaine versus control, mean +/- standard deviation) at rest (2.0 +/- 2.7 vs 2.1 +/- 2.4, P=0.286) or with movement (2.0 +/- 2.6 vs 2.6 +/- 2.7, P=0.487). Three adverse events occurred in the lidocaine group (25% of patients). Intravenous lidocaine did not provide clinically significant analgesia to patients undergoing laparoscopic fundoplication. The serum lidocaine concentration of patients who experienced adverse events were within the therapeutic range. This trial cannot confirm the safety of intravenous lidocaine at the dose tested. PMID- 27980438 TI - Acute chest pain fast track at the emergency department: who was misdiagnosed for acute coronary syndrome? AB - BACKGROUND: Acute coronary syndrome (ACS) is a commonly treated disease in the emergency department (ED). Acute chest pain is a common presenting symptom of ACS. Acute chest pain fast track (ACPFT) is a triage to cover patients presenting with chest pain with the aims of early detection and treatment for ACS. This study aimed to assess the quality of the ACPFT with the aim of improving the quality of care for ACS patients. METHODS: This study was conducted at the ED in Mahidol University, Bangkok, Thailand. The inclusion criterion was patients presenting with acute chest pain at the ED. We retrospectively reviewed the medical records of all eligible patients. The primary outcomes of this study were to determine time from door to electrocardiogram and time from door to treatment (coronary angiogram with percutaneous coronary intervention or thrombolytic therapy in the case of ST elevation myocardial infarction). The outcome was compared between those who were in and not in the ACPFT. RESULTS: During the study period, there were 616 eligible patients who were divided into ACPFT (n=352 patients; 57.1%) and non-ACPFT (n=264 patients; 42.9%) groups. In the ACPFT group (n=352), 315 patients (89.5%) received an electrocardiogram within 10 minutes. The final diagnosis of ACS was made in 80 patients (22.7%) in the ACPFT group and 13 patients (4.9%) in the non-ACPFT group (P-value <0.01). After adjustment using multivariate logistic regression analysis, only epigastric pain was independently associated with being in the ACPFT group (adjusted odds ratio of 0.11; 95% confidence interval of 0.02, 0.56). CONCLUSION: The ACPFT at the ED facilitated the prompt work-ups and intervention for ACS. PMID- 27980439 TI - Predictors of disability-related attitudes: considering self-esteem, communication apprehension, contact, and geographic location. AB - Individuals' attitudes about persons with disability (PwD) strongly affect differently-abled persons' quality of life and position in society. Some research offers support for the ability of systematic, supported, longitudinal contact between different groups of individuals to improve attitudes. College campuses, in particular, offer a potentially useful arena in which to facilitate this type of contact. This study explored contextual factors (eg, geographic region, biological sex) and predictors of disability-related attitudes among a college student population to determine strategies for course-based intervention design (eg, as community-engaged or service-learning initiatives). Surveying participants from universities in two regions of the United States, we found that self-esteem, audience-based communication apprehension, and contact with PwD explain more than 50% of the variance in disability-related attitudes. Further, we found that geographic location affects both self-esteem and audience-based communication apprehension (communicating/interacting with PwD). We discuss the implications for community engagement and/or service learning and highlight the importance of partnerships among relevant community stakeholders, including university faculty, students, and staff. PMID- 27980440 TI - Using the failure mode and effects analysis model to improve parathyroid hormone and adrenocorticotropic hormone testing. AB - BACKGROUND: Risk management in health care systems applies to all hospital employees and directors as they deal with human life and emergency routines. There is a constant need to decrease risk and increase patient safety in the hospital environment. The purpose of this article is to review the laboratory testing procedures for parathyroid hormone and adrenocorticotropic hormone (which are characterized by short half-lives) and to track failure modes and risks, and offer solutions to prevent them. During a routine quality improvement review at the Endocrine Laboratory in Tel Hashomer Hospital, we discovered these tests are frequently repeated unnecessarily due to multiple failures. The repetition of the tests inconveniences patients and leads to extra work for the laboratory and logistics personnel as well as the nurses and doctors who have to perform many tasks with limited resources. METHODS: A team of eight staff members accompanied by the Head of the Endocrine Laboratory formed the team for analysis. The failure mode and effects analysis model (FMEA) was used to analyze the laboratory testing procedure and was designed to simplify the process steps and indicate and rank possible failures. RESULTS: A total of 23 failure modes were found within the process, 19 of which were ranked by level of severity. The FMEA model prioritizes failures by their risk priority number (RPN). For example, the most serious failure was the delay after the samples were collected from the department (RPN =226.1). CONCLUSION: This model helped us to visualize the process in a simple way. After analyzing the information, solutions were proposed to prevent failures, and a method to completely avoid the top four problems was also developed. PMID- 27980442 TI - Understanding the Outcome of Randomized Trials with Drug-Eluting Stents and Coronary Artery Bypass Graft in Patients with Multivessel Disease: A Review of a 25-Year Journey. AB - Randomized clinical trials (RCTs) with first- and second-generation drug-eluting stents (DESs) confirmed the superiority of coronary artery bypass surgery (CABG) in patients with multiple vessel disease. In spite of different DES designs, investigators in these trials used similar percutaneous coronary intervention (PCI) strategies hoping to achieve complete revascularization, meaning that all intermediate lesions would be stented. One of these studies also included small vessels in the revascularization policy. On this revision, authors searched for a potential explanation of these intriguing findings and also for solutions to this problem, not seen years ago when other RCTs compared CABG with PCI in the previous DES era. After they revised old and new scientific data, they concluded that improved DES design is not itself enough to narrow the gap between PCI and CABG and that in the future RCTs we should institute more conservative strategies avoiding unnecessary multiple DES implantation. PMID- 27980441 TI - The Monocular Duke of Urbino. AB - Federico da Montefeltro (1422-1482), the Duke of Urbino, was a well-known historical figure during the Italian Renaissance. He is the subject of a famous painting by Piero della Francesca (1416-1492), which displays the Duke from the left and highlights his oddly shaped nose. The Duke is known to have lost his right eye due to an injury sustained during a jousting tournament, which is why the painting portrays him from the left. Some historians teach that the Duke subsequently underwent nasal surgery to remove tissue from the bridge of his nose in order to expand his visual field in an attempt to compensate for the lost eye. In theory, removal of a piece of the nose may have expanded the nasal visual field, especially the "eye motion visual field" that encompasses eye movements. In addition, removing part of the nose may have reduced some of the effects of ocular parallax. Finally, shifting of the visual egocenter may have occurred, although this seems likely unrelated to the proposed nasal surgery. Whether or not the Duke actually underwent the surgery cannot be proven, but it seems unlikely that this would have substantially improved his visual function. PMID- 27980443 TI - Lujan-Fryns Syndrome (LFS): A Unique Combination of Hypernasality, Marfanoid Body Habitus, and Neuropsychiatric Issues, Presenting as Acute-Onset Dysphagia. AB - BACKGROUND: Lujan-Fryns syndrome (LFS) is an extremely rare, X-linked disorder, for which the full clinical spectrum is still unknown. Usually, it presents with neuropsychiatric problems such as learning disabilities and behavioral issues in a typical combination with marfanoid features. Often, there is a positive family history for the disorder. However, sporadic cases have also been reported in males. More interestingly, there is no case of LFS presenting with acute-onset dysphagia in the English language medical literature. CASE PRESENTATION: A 17 year-old Pakistani mentally normal school boy was admitted for the workup of acute-onset dysphagia, hypernasal speech, and nasal regurgitation of liquids. He had no neuropsychiatric issues, and his family history was unremarkable. An obvious nasal twang, facial dysmorphism, and marfanoid body habitus were found on examination. The genetic tests revealed a pathogenic missense mutation in the MED12 gene on his X-chromosome. CONCLUSION: LFS can present as acute-onset dysphagia and in the absence of any neuropsychiatric issues or positive family history of the syndrome. PMID- 27980444 TI - Natriuretic Peptide and High-Sensitive Troponin T Concentrations Correlate with Effectiveness of Short-Term CPAP in Patients with Obstructive Sleep Apnea and Coronary Artery Disease. AB - The risk of cardiovascular complications is increased in patients with obstructive sleep apnea (OSA). Continuous positive airway pressure (CPAP) is the most effective way to treat clinically significant OSA. We hypothesized that the concentrations of the cardiac risk markers N-terminal brain natriuretic peptide (NT-proBNP) and high-sensitive troponin T (hs-TropT) correlate with the effectiveness of CPAP therapy in patients with OSA and coexisting coronary artery disease (CAD). Twenty-one patients with severe OSA and coexisting CAD (group 1) and 20 control patients with severe OSA alone (group 2) were treated with CPAP and monitored by laboratory-based polysomnography. NT-proBNP and hs-TropT levels were measured before and after CPAP. Apnea-hypopnea index (AHI) and oxygen desaturation were similar in both groups. In group 1, hs-TropT levels correlated with AHI and oxygen desaturation upon CPAP. Elevated NT-proBNP levels in group 1 were significantly reduced by CPAP. NT-proBNP levels correlated with AHI and showed negative correlation with ST-segment depression. No such correlations were found in group 2. CPAP has the potential to normalize elevated NT-proBNP serum levels in patients with severe OSA and coexisting CAD. Levels of NT-proBNP and hs TropT correlated with AHI and oxygen desaturation. PMID- 27980445 TI - Idiopathic Pulmonary Fibrosis: Treatment and Prognosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a prognosis that can be worse than for many cancers. The initial stages of the condition were thought to mainly involve chronic inflammation; therefore, corticosteroids and other drugs that have anti-inflammatory and immunosuppressive actions were used. However, recently, agents targeting persistent fibrosis resulting from aberrant repair of alveolar epithelial injury have been in the spotlight. There has also been an increase in the number of available antifibrotic treatment options, starting with pirfenidone and nintedanib. These drugs prevent deterioration but do not improve IPF. Therefore, nonpharmacologic approaches such as long-term oxygen therapy, pulmonary rehabilitation, and lung transplantation must be considered as additional treatment modalities. PMID- 27980446 TI - Pediatric Weight Management Program Outcomes in a Largely Minority, Low Socioeconomic Status Population. AB - This article describes the outcomes of a pediatric weight management program for a population primarily composed of minority ethnic groups and those from a lower socioeconomic status group. As these groups are disproportionally affected by pediatric obesity and overweight complicated by higher rates of attrition and poorer response to intervention, it is important that adequate and effective treatment exists for patients in these groups. Further research is needed to analyze the outcomes and attrition in these high-risk populations. PMID- 27980447 TI - A Novel Homozygous Frameshift Mutation in Exon 2 of LEP Gene Associated with Severe Obesity: A Case Report. AB - BACKGROUND: Monogenic obesity is a rare type of obesity caused by a mutation in a single gene. Patients with monogenic obesity may develop early onset of obesity and severe metabolic abnormalities. CASE PRESENTATION: A two-and-half-year-old girl was presented to our clinic because of excessive weight gain and hyperphagia. She was born at full term, by normal vaginal delivery with birth weight of 2.82 kg and no complications during pregnancy. The patient was the second child of two healthy, non-obese Saudis with known consanguinity. She gained weight rapidly leading to obesity at the age of three months. METHODS: The demographic data and clinical features were recorded. Blood samples were collected and tested for endocrine and metabolic characteristics and genetic studies. Mutations of the LEP gene were screened. The coding exons 2 and 3 and the corresponding exon-intron boundaries were amplified by polymerase chain reaction using specific primers, analyzed by direct sequencing using an ABI sequencer 3500 xL GA (Applied Biosystems), and evaluated using the JSI SeqPilot software. The resulting sequence data were compared with the reference MM_0002302. CONCLUSION: We report a novel homozygous frameshift mutation c.144delin TAC (G1n49Thrfs*23) in exon 2 of the LEP gene associated with extreme obesity. PMID- 27980448 TI - Linagliptin Has Wide-Ranging Anti-Inflammatory Points of Action in Human Umbilical Vein Endothelial Cells. AB - BACKGROUND: Because of the potential anti-inflammatory effects, linagliptin, a therapeutic dipeptidyl peptidase-4 inhibitor, is used as an effective drug for diabetic patients for whom inflammation is a prognosis-related factor. We investigated the anti-inflammatory mechanism of linagliptin using seven markers. METHODS: We pretreated human umbilical vein endothelial cells (HUVECs), with linagliptin and lipopolysaccharide (LPS). The cytosolic fractions were evaluated for protein kinase A (PKA), protein kinase B (PKB), protein kinase C (PKC), ratio of reactive oxygen species (ROS) and Cu/Zn superoxide dismutase (SOD), activator protein 1 (AP-1), and adenosine 3',5'-cyclic monophosphate (cAMP). RESULTS: Linagliptin increased the PKA and PKC activities and the cAMP levels in LPS treated cells. However, it inhibited LPS-induced PKB phosphorylation, ratio of ROS and Cu/Zn SOD, and LPS-stimulated AP-1 nuclear translocation. CONCLUSION: We reaffirmed the anti-inflammatory and antioxidant effects of linagliptin. These effects might be related to the three protein kinases. Our findings suggest that linagliptin has a wide range of anti-inflammatory effects. PMID- 27980449 TI - Risk assessment of student performance in the International Foundations of Medicine Clinical Science Examination by the use of statistical modeling. AB - PURPOSE: The primary aim of this study was to assess the predictive validity of cumulative grade point average (GPA) for performance in the International Foundations of Medicine (IFOM) Clinical Science Examination (CSE). A secondary aim was to develop a strategy for identifying students at risk of performing poorly in the IFOM CSE as determined by the National Board of Medical Examiners' International Standard of Competence. METHODS: Final year medical students from an Australian university medical school took the IFOM CSE as a formative assessment. Measures included overall IFOM CSE score as the dependent variable, cumulative GPA as the predictor, and the factors age, gender, year of enrollment, international or domestic status of student, and language spoken at home as covariates. Multivariable linear regression was used to measure predictor and covariate effects. Optimal thresholds of risk assessment were based on receiver operating characteristic (ROC) curves. RESULTS: Cumulative GPA (nonstandardized regression coefficient [B]: 81.83; 95% confidence interval [CI]: 68.13 to 95.53) and international status (B: -37.40; 95% CI: -57.85 to -16.96) from 427 students were found to be statistically associated with increased IFOM CSE performance. Cumulative GPAs of 5.30 (area under ROC [AROC]: 0.77; 95% CI: 0.72 to 0.82) and 4.90 (AROC: 0.72; 95% CI: 0.66 to 0.78) were identified as being thresholds of significant risk for domestic and international students, respectively. CONCLUSION: Using cumulative GPA as a predictor of IFOM CSE performance and accommodating for differences in international status, it is possible to identify students who are at risk of failing to satisfy the National Board of Medical Examiners' International Standard of Competence. PMID- 27980451 TI - Socioeconomic factors associated with diarrheal diseases among under-five children of the nomadic population in northeast Ethiopia. AB - BACKGROUND: Diarrheal disease remains the leading cause of morbidity and mortality among under-five children worldwide. Every day, more than 4000 children lose their lives due to diarrhea. In Ethiopia, diarrhea is the second killer of under-five children next to pneumonia. METHODS: A cross-sectional study was conducted to assess the prevalence of under-five diarrhea and socioeconomic factors among the nomadic people in Hadaleala District. A total of 704 under-five children were included in this study, and subjects were recruited by the multistage cluster sampling technique. Data were collected by a pre-tested questionnaire. The multivariable logistic regression analysis was used to identify socioeconomic variables associated with childhood diarrhea. RESULTS: The 2-week period prevalence of diarrhea among under-five children was 26.1% (95% CI 22.9, 29.3%). The highest prevalence (37.5%) of diarrhea occurred among children aged between 12.0 and 23.0 months. The occurrence of diarrheal disease was associated with the presence of two (AOR = 4.3, p < 0.001) and three (AOR = 22.4, p < 0.001) under-five children in each household. The age of the children ranged between 6.0 and 11.0 months (AOR = 4.8, p < 0.001), 12.0 and 23.0 months (AOR = 6.0, p < 0.001), and 24.0 and 35.0 months (AOR = 2.5, p < 0.05), illiterate mothers (AOR = 2.5, p < 0.05), and poor households (AOR = 1.6, p < 0.05). CONCLUSIONS: Diarrhea prevalence was quite high among under-five children in Hadaleala District, and it was significantly concentrated among children aged between 12.0 and 23.0 months. The number of under-five children, age of children, mothers' education, and household economic status were significantly associated with childhood diarrhea. To minimize the magnitude of childhood diarrhea, implementing various prevention strategies such as health education, child care, personal hygiene, and household sanitation which can be integrated with the existing national health extension program are essential. PMID- 27980450 TI - Evaluating an undergraduate interprofessional education session for medical and pharmacy undergraduates on therapeutics and prescribing: the medical student perspective. AB - BACKGROUND: The current literature on undergraduate interprofessional education (IPE) for pharmacy and medical students highlights a range of positive outcomes, although to date IPE has focused predominantly on student views and experiences of IPE sessions with these opinions being sought at the end of the sessions. This study aimed to evaluate medical students' experiences of therapeutics and prescribing IPE, with pharmacy students, 1 year following the session. METHODS: Following ethics committee approval, 3rd year medical students at Cardiff University were invited to participate using non-probability sampling. Topic guide development was informed by the literature and research team discussions, including a review of the materials used in the IPE session. Semi-structured one to-one interviews explored experiences, prior to, during, and after the IPE session. Interviews were audio-recorded, transcribed verbatim, and analyzed thematically. RESULTS: Eighteen medical students were interviewed; 11 were females. Seven themes were identified, namely 1) refinement of pre-session preparation, 2) session value, 3) learning with a pharmacy student, 4) learning about a pharmacist, 5) learning from a pharmacy student, 6) importance and application of what was learnt into practice, and 7) suggestions for change. CONCLUSION: This study provides a valuable insight into medical students' experiences of a therapeutics and prescribing IPE session and emphasizes the value they placed on interaction with pharmacy students. Medical students were able to recall clear learning experiences from the IPE session that had taken place 12 months earlier, which itself is an indicator of the impact of the session on the students. Furthermore, they were able to describe how knowledge and skills learnt had been applied to subsequent learning activities. Those developing IPE sessions should consider the following: clarify professional roles in the session content, incorporate IPE as a series of activities, and use small groups of students to optimize student-student interaction and active learning. PMID- 27980452 TI - Documentation and communication of nutritional care for elderly hospitalized patients: perspectives of nurses and undergraduate nurses in hospitals and nursing homes. AB - BACKGROUND: Nutritional care is a basic human right for all people. Nevertheless, undernourishment is known to be a frequent and serious health care problem among elderly hospitalized patients in Western Europe. Nutritional documentation contributes to ensuring proper nutritional treatment and care. Only a few studies have explored how nurses document nutritional care in hospitals, and between hospitals and nursing homes. Available research suggests that documentation practices are unsatisfactory. The aim of this study was to explore how nurses document nutritional treatment and care for elderly patients in hospitals and how nurses and undergraduate nurses communicate information about patients' nutritional status when elderly patients are transferred between hospital and nursing homes. METHODS: A qualitative study was conducted using a phenomenological-hermeneutic approach. Data was collected in focus group interviews with 16 nurses in one large university hospital, and 11 nurses and 16 undergraduate nurses in five nursing homes associated with the university hospital. Participants from the university hospital represented a total of seven surgical and medical wards, all of which transferred patients to the associated nursing homes. The catchment area of the hospital and the nursing homes represented approximately 10% of the Norwegian population in heterogenic urban and rural municipalities. Data were coded and analysed thematically within the three contexts: self-understanding, critical common sense, and theoretical understanding. RESULTS: The results were summarized under three main themes 1) inadequate documentation of nutritional status on hospital admission, 2) inadequate and unsystematic documentation of nutritional information during hospital stay, 3) limited communication of nutritional information between hospital and nursing homes. The three main themes included seven sub-themes, which reflected the lack of nutritional screening and unsystematic documentation on admission and during hospital stay. Further the sub-themes elucidated poor exchange of information between hospital and nursing homes regarding the nutritional status of patients. CONCLUSION: Overall, the documentation of nutritional treatment and care for elderly patients was inadequate in the hospital and between health care settings. Inappropriate documentation can create a negative nutritional spiral that leads to increased risk of severe health related complications for elderly patients. Moreover, it hinders nutritional follow-up across health care settings. PMID- 27980453 TI - Feasibility of training practice nurses to deliver a psychosocial intervention within a collaborative care framework for people with depression and long-term conditions. AB - BACKGROUND: Practice nurses (PNs) deliver much of the chronic disease management in primary care and have been highlighted as appropriately placed within the service to manage patients with long-term physical conditions (LTCs) and co morbid depression. This nested qualitative evaluation within a service development pilot provided the opportunity to examine the acceptability of a Brief Behavioural Activation (BBA) intervention within a collaborative care framework. Barriers and facilitators to engaging with the intervention from the patient and clinician perspective will be used to guide future service development and research. METHODS: The study was conducted across 8 practices in one Primary Care Trust 1 in England. Through purposive sampling professionals (n = 10) taking part in the intervention (nurses, GPs and a mental health gateway worker) and patients (n = 4) receiving the intervention participated in semi structured qualitative interviews. Analysis utilised the four Normalisation Process Theory (NPT) concepts of coherence, cognitive participation, collective action and reflexive monitoring to explore the how this intervention could be implemented in practice. RESULTS: Awareness of depression and the stigma associated with the label of depression meant that, from a patient perspective a PN being available to 'listen' was perceived as valuable. Competing practice priorities, perceived lack of time and resources, and lack of engagement by the whole practice team were considered the greatest barriers to the implementation of this intervention in routine primary care. CONCLUSION: Lack of understanding of, participation in, and support from the whole practice team in the collaborative care model exacerbated the pressures perceived by PNs. The need for formal supervision of PNs to enable them to undertake the role of case manager for patients with depression and long-term conditions is emphasised. PMID- 27980455 TI - Inhibition of integrin beta3, a binding partner of kallistatin, leads to reduced viability, invasion and proliferation in NCI-H446 cells. AB - BACKGROUND: Kallistatin is a serine proteinase inhibitor and heparin-binding protein. It is considered an endogenous angiogenic inhibitor. In addition, multiple studies demonstrated that kallistatin directly inhibits cancer cell growth. However, the molecular mechanisms underlying these effects remain unclear. METHODS: Pull-down, immunoprecipitation, and immunoblotting were used for binding experiments. To elucidate the mechanisms, integrin beta3 knockdown (siRNA) or blockage (antibody treatment) on the cell surface of small the cell lung cancer NCI-H446 cell line was used. RESULTS: Interestingly, kallistatin was capable of binding integrin beta3 on the cell surface of NCI-H446 cells. Meanwhile, integrin beta3 knockdown or blockage resulted in loss of antitumor activities induced by kallistatin. Furthermore, kallistatin suppressed tyrosine phosphorylation of integrin beta3 and its downstream signaling pathways, including FAK/-Src, AKT and Erk/MAPK. Viability, proliferation and migration of NCI-H446 cells were inhibited by kallistatin, with Bcl-2 and Grb2 downregulation, and Bax, cleaved caspase-9 and caspase 3 upregulation. CONCLUSIONS: These findings reveal a novel role for kallistatin in preventing small cell lung cancer growth and mobility, by direct interaction with integrin beta3, leading to blockade of the related signaling pathway. PMID- 27980457 TI - Different clinical allergological features of Taenia solium infestation. AB - The tapeworm Taenia (T.) solium can be responsible for two different conditions: taeniasis and cysticercosis. Helminth infections in human host cause an immune response associated with elevated levels of IgE, tissue eosinophilia and mastocytosis, and with the presence of CD4+ T cells that preferentially produce IL-4, IL-5, and IL-13. Individuals exposed to helminth infections may have allergic inflammatory responses to parasites and parasite antigens. PubMed search of human cases of allergic reactions occurring during T. solium infestation was performed combining the terms (allergy, urticaria, angioedema, asthma, anaphylaxis) with T. solium. A study was considered eligible for inclusion in the review if it reported data on patients with T. solium infestation who had signs or symptoms of allergy. In literature we found six articles reporting the association between an allergic reaction and T. solium infestation: two cases of urticaria, two cases of relapsing angioedema, one case of asthma and two cases of anaphylaxis. Despite the large diffusion of T. solium infestation, we found only a few cases of concomitant allergic reaction and the presence of Taenia in the host. The association between T. solium infestation and allergic manifestations has never been clearly demonstrated, and in absence of a well-documented causality the hypotheses are merely speculative. Therefore, the association between Taenia infection and allergy needs to be thoroughly studied to better clarify if this association may really exist and which is the pathogenetic mechanism supported. PMID- 27980454 TI - Comprehensive analysis of the long noncoding RNA HOXA11-AS gene interaction regulatory network in NSCLC cells. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) are related to different biological processes in non-small cell lung cancer (NSCLC). However, the possible molecular mechanisms underlying the effects of the long noncoding RNA HOXA11-AS (HOXA11 antisense RNA) in NSCLC are unknown. METHODS: HOXA11-AS was knocked down in the NSCLC A549 cell line and a high throughput microarray assay was applied to detect changes in the gene profiles of the A549 cells. Bioinformatics analyses (gene ontology (GO), pathway, Kyoto Encyclopedia of Genes and Genomes (KEGG), and network analyses) were performed to investigate the potential pathways and networks of the differentially expressed genes. The molecular signatures database (MSigDB) was used to display the expression profiles of these differentially expressed genes. Furthermore, the relationships between the HOXA11-AS, de regulated genes and clinical NSCLC parameters were verified by using NSCLC patient information from The Cancer Genome Atlas (TCGA) database. In addition, the relationship between HOXA11-AS expression and clinical diagnostic value was analyzed by receiver operating characteristic (ROC) curve. RESULTS: Among the differentially expressed genes, 277 and 80 genes were upregulated and downregulated in NSCLC, respectively (fold change >=2.0, P < 0.05 and false discovery rate (FDR) < 0.05). According to the degree of the fold change, six upregulated and three downregulated genes were selected for further investigation. Only four genes (RSPO3, ADAMTS8, DMBT1, and DOCK8) were reported to be related with the development or progression of NSCLC based on a PubMed search. Among all possible pathways, three pathways (the PI3K-Akt, TGF-beta and Hippo signaling pathways) were the most likely to be involved in NSCLC development and progression. Furthermore, we found that HOXA11-AS was highly expressed in both lung adenocarcinoma and squamous cell carcinoma based on TCGA database. The ROC curve showed that the area under curve (AUC) of HOXA11-AS was 0.727 (95% CI 0.663-0.790) for lung adenocarcinoma and 0.933 (95% CI 0.906-0.960) for squamous cell carcinoma patients. Additionally, the original data from TCGA verified that ADAMTS8, DMBT1 and DOCK8 were downregulated in both lung adenocarcinoma and squamous cell carcinoma, whereas RSPO3 expression was upregulated in lung adenocarcinoma and downregulated in lung squamous cell carcinoma. For the other five genes (STMN2, SPINK6, TUSC3, LOC100128054, and C8orf22), we found that STMN2, TUSC3 and C8orf22 were upregulated in squamous cell carcinoma and that STMN2 and USC3 were upregulated in lung adenocarcinoma. Furthermore, we compared the correlation between HOXA11-AS and de-regulated genes in NSCLC based on TCGA. The results showed that the HOXA11-AS expression was negatively correlated with DOCK8 in squamous cell carcinoma (r = -0.124, P = 0.048) and lung adenocarcinoma (r = -0.176, P = 0.005). In addition, RSPO3, ADAMTS8 and DOCK8 were related to overall survival and disease-free survival (all P < 0.05) of lung adenocarcinoma patients in TCGA. CONCLUSIONS: Our results showed that the gene profiles were significantly changed after HOXA11-AS knock down in NSCLC cells. We speculated that HOXA11-AS may play an important role in NSCLC development and progression by regulating the expression of various pathways and genes, especially DOCK8 and TGF-beta pathway. However, the exact mechanism should be verified by functional experiments. PMID- 27980456 TI - Autophagy induced by a sulphamoylated estrone analogue contributes to its cytotoxic effect on breast cancer cells. AB - BACKGROUND: Autophagy can either be protective and confer survival to stressed cells, or it can contribute to cell death. The antimitotic drug 2-ethyl-3-O sulpamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol) is an in silico-designed 17-beta-estradiol analogue that induces both autophagy and apoptosis in cancer cells. The aim of the study was to determine the role of autophagy in ESE-15-ol exposed human adenocarcinoma breast cancer cells; knowledge that will contribute to future clinical applications of this novel antimitotic compound. By inhibiting autophagy and determining the cytotoxic effects of ESE-15-ol-exposure, deductions could be made as to whether the process may confer resistance to the drug, or alternatively, contribute to the cell death process. METHODS AND RESULTS: Spectophometrical analysis via crystal violet staining was used to perform cytotoxicity studies. Morphology studies were done using microscopic techniques namely polarization-optical transmitted light differential interference light microscopy, fluorescent microscopy using monodansylcadaverine staining and transmission electron microscopy. Flow cytometry was used to quantify the autophagy inhibition and assess cell viability. Results obtained indicated that 3 methyladenine inhibited autophagy and increased cell survival in both MCF-7 and MDA-MB-231 cell lines. CONCLUSION: This in vitro study inferred that autophagy inhibition with 3-methyladenine does not confer increased effectiveness of ESE-15 ol in inducing cell death. Thus it may be concluded that the autophagic process induced by ESE-15-ol exposure in MCF-7 and MDA-MB-231 cells plays a more significant role in cell death than conferring survival. PMID- 27980458 TI - Ethyl pyruvate is a novel anti-inflammatory agent to treat multiple inflammatory organ injuries. AB - Ethyl pyruvate (EP) is a simple derivative of pyruvic acid, which is an important endogenous metabolite that can scavenge reactive oxygen species (ROS). Treatment with EP is able to ameliorate systemic inflammation and multiple organ dysfunctions in multiple animal models, such as acute pancreatitis, alcoholic liver injury, acute respiratory distress syndrome (ARDS), acute viral myocarditis, acute kidney injury and sepsis. Recent studies have demonstrated that prolonged treatment with EP can ameliorate experimental ulcerative colitis and slow multiple tumor growth. It has become evident that EP has pharmacological anti-inflammatory effect to inhibit multiple early inflammatory cytokines and the late inflammatory cytokine HMGB1 release, and the anti-tumor activity is likely associated with its anti-inflammatory effect. EP has been tested in human volunteers and in a clinical trial of patients undergoing cardiac surgery in USA and shown to be safe at clinical relevant doses, even though EP fails to improve outcome of the heart surgery, EP is still a promising agent to treat patients with multiple inflammatory organ injuries and the other clinical trials are on the way. This review focuses on how EP is able to ameliorate multiple organ injuries and summarize recently published EP investigations. Graphical AbstractThe targets of the anti-inflammatory agent EP. PMID- 27980459 TI - Increased adipose tissue expression of TLR8 in obese individuals with or without type-2 diabetes: significance in metabolic inflammation. AB - BACKGROUND: The innate immune Toll-like receptors (TLRs) 2/4 are important players in chronic low-grade inflammation called metabolic inflammation in obesity and type-2 diabetes (T2D). While TLR2/4 expression changes associated with metabolic inflammation are known, the adipose tissue expression of endocytic TLR8, which is expressed by all major macrophage subsets, remain unclear. We, therefore, determined the TLR8 mRNA/protein expression in the adipose tissue samples from lean, overweight, and obese individuals with or without T2D. METHODS: Subcutaneous fat biopsy samples were collected from 49 non-diabetic (23 obese, 17 overweight, and nine lean) and 45 T2D (32 obese, ten overweight, and three lean) individuals. TLR8 gene expression was determined using real-time RT PCR and TLR8 protein expression was assessed by both immunohistochemistry and confocal microscopy. The changes in TLR8 expression were compared with those of macrophage markers, proinflammatory cytokines/chemokines, and surface TLRs/adapter proteins. The data were analyzed using t-test/Mann-Whitney U-test, Pearson's correlation, and multiple regression test. RESULTS: The data show that in obese non-diabetic/T2D individuals, TLR8 gene expression was significantly upregulated as compared with lean individuals which correlated with body mass index (BMI) and body fat percentage in non-diabetic population (P < 0.05). As expected, TLR8 adipose tissue protein expression in non-diabetic/T2D obese individuals was also higher than that of overweight/lean counterparts. In non diabetic/T2D individuals, TLR8 gene expression associated (P < 0.05) with the expression of CD68, CD11c, CD86, and CD163 macrophage markers. Also, in these individuals, TLR8 gene expression correlated positively (P < 0.05) with adipose tissue expression of TNF-alpha, IL-18, and IL-8 as well as with systemic CRP levels (in non-diabetics). TLR8 expression was also associated with TLR4/TLR2 and MyD88 expression in the adipose tissue. CONCLUSIONS: The elevated adipose tissue expression of TLR8 in obesity/T2D has consensus with inflammatory signatures and may thus represent an immune marker of metabolic inflammation. PMID- 27980460 TI - Informed baseline subtraction of proteomic mass spectrometry data aided by a novel sliding window algorithm. AB - BACKGROUND: Proteomic matrix-assisted laser desorption/ionisation (MALDI) linear time-of-flight (TOF) mass spectrometry (MS) may be used to produce protein profiles from biological samples with the aim of discovering biomarkers for disease. However, the raw protein profiles suffer from several sources of bias or systematic variation which need to be removed via pre-processing before meaningful downstream analysis of the data can be undertaken. Baseline subtraction, an early pre-processing step that removes the non-peptide signal from the spectra, is complicated by the following: (i) each spectrum has, on average, wider peaks for peptides with higher mass-to-charge ratios (m/z), and (ii) the time-consuming and error-prone trial-and-error process for optimising the baseline subtraction input arguments. With reference to the aforementioned complications, we present an automated pipeline that includes (i) a novel 'continuous' line segment algorithm that efficiently operates over data with a transformed m/z-axis to remove the relationship between peptide mass and peak width, and (ii) an input-free algorithm to estimate peak widths on the transformed m/z scale. RESULTS: The automated baseline subtraction method was deployed on six publicly available proteomic MS datasets using six different m/z axis transformations. Optimality of the automated baseline subtraction pipeline was assessed quantitatively using the mean absolute scaled error (MASE) when compared to a gold-standard baseline subtracted signal. Several of the transformations investigated were able to reduce, if not entirely remove, the peak width and peak location relationship resulting in near-optimal baseline subtraction using the automated pipeline. The proposed novel 'continuous' line segment algorithm is shown to far outperform naive sliding window algorithms with regard to the computational time required. The improvement in computational time was at least four-fold on real MALDI TOF-MS data and at least an order of magnitude on many simulated datasets. CONCLUSIONS: The advantages of the proposed pipeline include informed and data specific input arguments for baseline subtraction methods, the avoidance of time-intensive and subjective piecewise baseline subtraction, and the ability to automate baseline subtraction completely. Moreover, individual steps can be adopted as stand-alone routines. PMID- 27980461 TI - Pathways for outpatient management of venous thromboembolism in a UK centre. AB - It has become widely recognised that outpatient treatment may be suitable for many patients with venous thromboembolism. In addition, non-vitamin K antagonist oral anticoagulants that have been approved over the last few years have the potential to be an integral component of the outpatient care pathway, owing to their oral route of administration, lack of requirement for routine anticoagulation monitoring and simple dosing regimens. A robust pathway for outpatient care is also vital; one such pathway has been developed at Sheffield Teaching Hospitals in the UK. This paper describes the pathway and the arguments in its favour as an example of best practice and value offered to patients with venous thromboembolism. The pathway has two branches (one for deep vein thrombosis and one for pulmonary embolism), each with the same five-step process for outpatient treatment. Both begin from the point that the patient presents (in the Emergency Department, Thrombosis Clinic or general practitioner's office), followed by diagnosis, risk stratification, treatment choice and, finally, follow up. The advantages of these pathways are that they offer clear, evidence-based guidance for the identification, diagnosis and treatment of patients who can safely be treated in the outpatient setting, and provide a detailed, stepwise process that can be easily adapted to suit the needs of other institutions. The approach is likely to result in both healthcare and economic benefits, including increased patient satisfaction and shorter hospital stays. PMID- 27980462 TI - Edoxaban versus enoxaparin for the prevention of venous thromboembolism after total knee or hip arthroplasty: pooled analysis of coagulation biomarkers and primary efficacy and safety endpoints from two phase 3 trials. AB - BACKGROUND: The objective of this analysis was to assess the effects of edoxaban compared with enoxaparin on key coagulation biomarkers and present pooled primary efficacy and safety results from phase 3 STARS E-3 and STARS J-V trials for prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) or total hip arthroplasty (THA). METHODS: In the randomized, double-blind, double dummy, multicenter, STARS E-3 and STARS J-V trials, patients received edoxaban 30 mg or enoxaparin 2000 IU (20 mg) twice daily for 11 to 14 days. The studies were conducted in Japan and Taiwan; enoxaparin dosing was based on Japanese label recommendations. The primary efficacy endpoint was incidence of VTE; the safety endpoint was major or clinically relevant nonmajor (CRNM) bleeding. Blood samples were taken at presurgical evaluation, pretreatment (postsurgery), predose on day 7, predose on completion of treatment, and at a follow-up examination 25 to 35 days after the last dose of study drug for D-dimer, prothrombin fragment 1 + 2 (F1+2), and soluble fibrin monomer complex (SFMC) measurement. RESULTS: A total of 716 patients enrolled in STARS E-3 and 610 patients enrolled in STARS J-V; 1326 patients overall. This analysis included 657 patients who received edoxaban 30 mg QD and 650 patients who received enoxaparin 20 mg BID. Incidence of VTE was 5.1 and 10.7% for edoxaban and enoxaparin, respectively (P <0.001). Incidence of combined major and CRNM bleeding was 4.6 and 3.7% for edoxaban and enoxaparin, respectively (P = 0.427). On day 7, mean D-dimer (4.4 vs 5.5 MUg/mL), F1+2 (363 vs 463 pmol/L), and SFMC (5.7 vs 6.8 MUg/mL) were lower in edoxaban-treated patients relative to enoxaparin-treated patients, respectively (P <0.0001 for all). At end of treatment, mean D-dimer (5.4 vs 6.2 MUg/mL), F1+2 (292 vs 380 pmol/L), and SFMC (6.2 vs 7.2 MUg/mL) were lower in edoxaban-treated patients relative to enoxaparin-treated patients (P <0.0001 for all). CONCLUSIONS: Edoxaban was superior to enoxaparin in prevention of VTE following TKA and THA, with comparable rates of bleeding events. Relative to enoxaparin, edoxaban significantly reduced D-dimer, F1+2, and SFMC. TRIAL REGISTRATION: Clintrials.gov NCT01181102 and NCT01181167. Both registered 8/12/2010. PMID- 27980464 TI - A Model For Teaching Advanced Neuroscience Methods: A Student-Run Seminar to Increase Practical Understanding and Confidence. AB - Neuroscience doctoral students must master specific laboratory techniques and approaches to complete their thesis work (hands-on learning). Due to the highly interdisciplinary nature of the field, learning about a diverse range of methodologies through literature surveys and coursework is also necessary for student success (hands-off learning). Traditional neuroscience coursework stresses what is known about the nervous system with relatively little emphasis on the details of the methods used to obtain this knowledge. Furthermore, hands off learning is made difficult by a lack of detail in methods sections of primary articles, subfield-specific jargon and vague experimental rationales. We designed a student-taught course to enable first-year neuroscience doctoral students to overcome difficulties in hands-off learning by introducing a new approach to reading and presenting primary research articles that focuses on methodology. In our literature-based course students were encouraged to present a method with which they had no previous experience. To facilitate weekly discussions, "experts" were invited to class sessions. Experts were advanced graduate students who had hands-on experience with the method being covered and served as discussion co-leaders. Self-evaluation worksheets were administered on the first and last days of the 10-week course and used to assess students' confidence in discussing research and methods outside of their primary research expertise. These evaluations revealed that the course significantly increased the students' confidence in reading, presenting and discussing a wide range of advanced neuroscience methods. PMID- 27980463 TI - Undergraduate Neuroscience Education in the U.S.: Quantitative Comparisons of Programs and Graduates in the Broader Context of Undergraduate Life Sciences Education. AB - The impact of undergraduate neuroscience programs on the broader landscape of life sciences education has not been described. Using data from the National Center for Education Statistics, we found that the number of undergraduate neuroscience programs in the U.S. continues to grow. Within any given institution, neuroscience programs exist alongside a small number of other life sciences undergraduate programs, suggesting that neuroscience is one of few major options from which students can choose from at many institutions. Neuroscience majors constitute a substantial proportion of all life sciences graduates at many institutions, and in several cases, neuroscience majors were the majority of life sciences graduates. Thus, neuroscience programs contribute substantially to life sciences education, and neuroscience is a highly attractive major among undergraduate students where these programs are available. These data have implications for institutions with existing neuroscience programs as well as for institutions seeking to establish a new program. PMID- 27980465 TI - Simulated in vivo Electrophysiology Experiments Provide Previously Inaccessible Insights into Visual Physiology. AB - Lecture content and practical laboratory classes are ideally complementary. However, the types of experiments that have led to our detailed understanding of sensory neuroscience are often not amenable to classroom experimentation as they require expensive equipment, time-consuming surgeries, specialized experimental techniques, and the use of animals. While sometimes feasible in small group teaching, these experiments are not suitable for large cohorts of students. Previous attempts to expose students to sensory neuroscience experiments include: the use of electrophysiology preparations in invertebrates, data-driven simulations that do not replicate the experience of conducting an experiment, or simply observing an experiment in a research laboratory. We developed an online simulation of a visual neuroscience experiment in which extracellular recordings are made from a motion sensitive neuron. Students have control over stimulation parameters (direction and contrast) and can see and hear the action potential responses to stimuli as they are presented. The simulation provides an intuitive way for students to gain insight into neurophysiology, including experimental design, data collection and data analysis. Our simulation allows large cohorts of students to cost-effectively "experience" the results of animal research without ethical concerns, to be exposed to realistic data variability, and to develop their understanding of how sensory neuroscience experiments are conducted. PMID- 27980466 TI - The Influence of Assay Design, Blinding, and Gymnema sylvestre on Sucrose Detection by Humans. AB - The detection and grading of tastes corresponding to different taste modalities can be tested in engaging laboratory sessions using students themselves as test subjects. This article describes a series of experiments in which data pertaining to the detection of salty and sweet tastes are obtained, and the ability of the herb Gymnema sylvestre to disrupt the detection of sucrose is quantified. The effects of blinding and different assay designs on EC50 estimation are also investigated. The data obtained allow for substantial data analysis, including non-linear regression using fixed and free parameters to quantify dose-response relationships, and the use of often under-utilized permutation tests to determine significant differences when the underlying data display heteroscedasticity. PMID- 27980467 TI - An Undergraduate Laboratory Exercise that Demonstrates the Difference Between Peripherally and Centrally Mediated Measures. AB - One of the first concepts that students of neuroscience are exposed to is the overall organization of the nervous system and the two principle divisions of it: the Peripheral Nervous System (PNS) and the Central Nervous System (CNS). In sensory systems, this fundamental division plays a particularly prominent role in the information processing stream that integrates and processes information from the external environment to the CNS. To better understand the differences between the roles that the PNS and CNS play in information processing, we developed a relatively simple in-class laboratory exercise. The experimental methods used to determine several aspects of a subject's discriminative capacity (threshold detection, amplitude discrimination, duration discrimination) are described. These methods were used either under control conditions or after the students altered their skin sensitivity (i.e., the PNS) by cold water immersion. At the conclusion of the lab exercise, students will thoroughly understand the principle of the PNS vs. CNS, as well as a fundamental understanding of quantitative sensory testing. This fundamental understanding of sensory testing provides a foundation for students to pursue or investigate other aspects of sensory information processing in either independent studies or subsequent lab exercises. PMID- 27980468 TI - Are Electrode Caps Worth the Investment? An Evaluation of EEG Methods in Undergraduate Neuroscience Laboratory Courses and Research. AB - Electroencephalography (EEG) is a common neuroscience technique that is more accessible to undergraduate programs than expensive techniques such as fMRI and single-cell recording. The use of EEG can provide undergraduates with firsthand neuroscience research experience without taking too many financial resources away from a program. There are multiple types of EEG equipment that can be used, including individual electrodes and electrode caps. This study used surveys administered to students who were in a neuroscience laboratory course, conducting research, or participating in research in order to discern which of these two EEG setups is preferred by undergraduates. According to average reaction scores calculated from the surveys, laboratory students tended to prefer individual electrodes over electrode caps, and when explicitly asked about their overall preference, a majority of laboratory students chose individual electrodes over electrode caps. Additionally, comparable levels of improvement in learning objectives and the quality of data collected in laboratory sessions were found across methods. Student researchers' ratings revealed a marginal preference for caps over individual electrodes, and all 5 researchers surveyed chose caps on a discriminate choice question. Research participants' ratings of caps and individual electrodes, however, were not significantly different. These results do not point to a concrete recommendation of one setup over the other but rather suggest that either setup could be a viable option. Therefore, we conclude that programs can comfortably decide which to use based on their own needs and resources as well as the relative advantages and disadvantages of each setup. For example, individual electrodes may be better for programs with low budgets looking to introduce students to EEG data recording, whereas electrode caps may be better for programs looking to better prepare students for future EEG research or to perform multichannel recordings. PMID- 27980469 TI - Use of Structural Assessment of Knowledge for Outcomes Assessment in the Neuroscience Classroom. AB - Outcomes assessment of undergraduate neuroscience curricula should assess the ability to think integratively about basic neuroscience concepts based on two of the core competencies established by the Faculty for Undergraduate Neuroscience. The current study investigated whether the structural assessment of knowledge (SAK) approach, which evaluates the organization of an individual's knowledge structures, is effective for demonstrating learning of basic neuroscience concepts. Students in an introductory psychology course (n = 29), an introductory neuroscience course (n = 19), or an advanced behavioral neuroscience course (n = 15) completed SAK before and after learning gross brain anatomy and neuronal physiology. All students showed improvements in their SAK after short-term dissemination for gross brain anatomy, but not for neuronal physiology, concepts. Therefore, research is needed to determine whether the effectiveness of SAK in outcomes assessment depends on the content or teaching style. Additional research using SAK should also explore effectiveness for learning over longer time frames and correlations with student performance in the course. However, the results suggest SAK is a promising technique for outcomes assessment of undergraduate neuroscience curricula. PMID- 27980470 TI - An Inquiry-Based Approach to Study the Synapse: Student-Driven Experiments Using C. elegans. AB - Inquiry-based instruction has been well demonstrated to enhance long term retention and to improve application and synthesis of knowledge. Here we describe an inquiry-based teaching module that trains undergraduates as scientists who pose questions, design and execute hypothesis-driven experiments, analyze data and communicate their research findings. Before students design their research projects, they learn and practice several research techniques with the model organism, Caenorhabditis elegans. This nematode is an ideal choice for experimentation in an undergraduate lab due to its powerful genetics, ease and low cost of maintenance, and amenability for undergraduate training. Students are challenged to characterize an instructor-assigned "mystery mutant" C. elegans strain. The "mystery mutant" strain has a defect in cholinergic synaptic transmission. Students are well poised to experimentally test how the mutation impacts synaptic transmission. For example, students design experiments that address questions including: Does the effected gene influence acetylcholine neurotransmitter release? Does it inhibit postsynaptic cholinergic receptors? Students must apply their understanding of the synapse while using their recently acquired research skills (including aldicarb and levamisole assays) to successfully design, execute and analyze their experiments. Students prepare an experimental plan and a timeline for proposed experiments. Undergraduates work collaboratively in pairs and share their research findings in oral and written formats. Modifications to suit instructor-specific goals and courses with limited or no lab time are provided. Students have anonymously reported their surprise regarding how much can be learned from a worm and feelings of satisfaction from conducting research experiments of their own design. PMID- 27980471 TI - The Miracle Fruit: An Undergraduate Laboratory Exercise in Taste Sensation and Perception. AB - "Miracle Fruit" is a taste-altering berry that causes sour foods to be perceived as sweet. The present paper describes a laboratory exercise that uses Miracle Fruit to educate students about the sensation and perception of taste. This laboratory exercise reinforces course material pertaining to the function of sweet taste receptors covered in a Sensation and Perception course at Christopher Newport University. Here we provide a step-by-step explanation of the methodology, and an example of data collected and analyzed by one group of students who participated in this laboratory exercise. The origins of the Miracle Fruit, the structure and the physiological function of miraculin (the glycoprotein responsible for the taste-modifying effect found in the pulp of the Miracle Fruit) were discussed before the laboratory exercise. Students then sampled foods known to target different types of tastes (i.e., sweet, sour, bitter and salty) and rated their perception of taste intensity for each food item. Next, students each consumed Miracle Fruit berries, then resampled each original food item and again recorded their perception of taste intensity ratings for these foods. The data confirmed that the sour food items were perceived sweeter after the Miracle Fruit was consumed. The students also completed a written assignment to assess what they learned about the origins, structure, and physiological function of Miracle Fruit. This hands-on laboratory exercise received positive feedback from students. The exercise can be used by other neuroscience educators to teach concepts related to the sensory system of taste. PMID- 27980472 TI - The Establishment of an On-Campus Neurotraining Center at a Small University: Internship Experience Using Neuropsychological Techniques. AB - In 2015, Wilkes University's Neuroscience Program and Psychology Department established a unique training and learning center on a small liberal arts undergraduate campus - The NeuroTraining & Research Center. This paper shares the purpose of the Center, as a learning tool for Neuroscience majors who engage in internships and research opportunities, and as a means of promoting well-being on the campus by offering training in techniques such as Neurofeedback, Biofeedback and Audio-Visual Entrainment to the college community. The role that the center plays in connecting real world applications to concepts in Neuroscience, and the approach that the authors have taken to assess student learning is presented in this article. PMID- 27980473 TI - Using a Pop-Science Book to Teach Introductory Neuroscience: Advantages for Science Majors and Non-Science Majors Alike. AB - The traditional approach to teaching neuroscience often involves presenting a topic like one might present a "murder mystery"; evidence is presented serially until the final answer is revealed. Although this approach mirrors the scientific discovery process, it is not always effective at engaging students, particularly those who are less familiar with the scientific concepts being presented as evidence. By the time the answer arrives, students may be too overwhelmed to absorb it. One way to combat this is to reverse the order of presentation. By starting with the final condition and working backwards through the underlying neuroscientific concepts, students have a relatable framework in which to couch the scientific detail necessary to understand neural phenomena. It was with this approach in mind that the course, "Fundamental Neuroscience: Understanding Ourselves" was designed. Taught for the past seven years at the University of Minnesota, the course uses the best-selling book The Brain That Changes Itself by Norman Doidge in lieu of a traditional textbook. Each chapter focuses on a case study of a particular neuropsychological problem or, in some cases, the work of a particular neuroscientist. This material is then used as a launching point to delve deeper into the neurobiological mechanisms underlying the particular disorder. In our experience, the result is that students from a wide variety of academic backgrounds are able to engage with the material throughout the entire lesson and apply their new knowledge broadly across the discipline of Neuroscience. This article aims to provide an in-depth presentation of the course, including potential challenges of working with a pop-science text. Further, we extend our discussion to a newly-developed companion course using non traditional texts and how these courses fit into a Neuroscience minor. PMID- 27980474 TI - From Botox to Behavior: Neuroscience for Non-Scientists at Emory. AB - For the past six years, we have been teaching a neuroscience for non-science majors course titled "From Botox to Behavior: Neuroscience for non-scientists." The primary objectives for this course are to create science literate students using neuroscience concepts as the foundation. The evidence from our course assessments suggest that the students are learning fundamental concepts and developing skills of source evalution, using evidence in an argument and appreciating the role of neuroscience in society. While the course has been very successful as measured by student performance on assessments of content learning and student satisfaction, we have noticed a pervasive weakness in quantitative literacy. Our future directions include assessing what kinds of interventions and approaches work best to increase quanitative literacy among non-science majors. PMID- 27980475 TI - Word Origins of Common Neuroscience Terms for Use in an Undergraduate Classroom. AB - We compiled a list of nearly 300 neuroscience terms and list their language of origin (typically Latin or Greek), their literal meaning, and their pronunciation in a table. The table was distributed to students in an undergraduate neuroscience class a few weeks before the first examination. A follow-up survey asked students how long they spent with the handout, and also assessed whether they thought it helped them better understand the terms, apply the terms, and whether they thought it helped them enough to get a higher grade on the exam. Results were positive: nearly 78% of students used the table while reviewing the material, and these students overwhelmingly reported that the table helped them better understand and apply the terms. However, students were equally split on whether the handout resulted in a better grade on the first exam. It was our premise that better understanding the derivation of the words can help students make associations between the terms and their meanings/functions. This handout can be used in any undergraduate neuroscience to help students better understand the complex terminology associated with the material. PMID- 27980476 TI - Using Rubrics as a Scientific Writing Instructional Method in Early Stage Undergraduate Neuroscience Study. AB - Scientific writing is an important communication and learning tool in neuroscience, yet it is a skill not adequately cultivated in introductory undergraduate science courses. Proficient, confident scientific writers are produced by providing specific knowledge about the writing process, combined with a clear student understanding about how to think about writing (also known as metacognition). We developed a rubric for evaluating scientific papers and assessed different methods of using the rubric in inquiry-based introductory biology classrooms. Students were either 1) given the rubric alone, 2) given the rubric, but also required to visit a biology subject tutor for paper assistance, or 3) asked to self-grade paper components using the rubric. Students who were required to use a peer tutor had more negative attitudes towards scientific writing, while students who used the rubric alone reported more confidence in their science writing skills by the conclusion of the semester. Overall, students rated the use of an example paper or grading rubric as the most effective ways of teaching scientific writing, while rating peer review as ineffective. Our paper describes a concrete, simple method of infusing scientific writing into inquiry based science classes, and provides clear avenues to enhance communication and scientific writing skills in entry-level classes through the use of a rubric or example paper, with the goal of producing students capable of performing at a higher level in upper level neuroscience classes and independent research. PMID- 27980477 TI - "Social" Neuroscience: Leveraging Social Media to Increase Student Engagement and Public Understanding of Neuroscience. AB - Neuroscience is young and still developing. It is quickly adapting to a number of emerging changes in science and education. Not only have neuroscientists been at the forefront of the open access publishing movement, but many prominent neuroscientists continue to push towards making science more accessible and understandable to the broader public. Social media is a global phenomenon that is changing the way that we talk about research and education. Researchers, students, and the public alike can leverage social media to find updates in research and higher education. Social media also provides pathways to connect with experts and non-experts in a way never been seen before. Two major trends are appearing in education and social media: 1) providing more engaging teaching activities, and 2) providing opportunities for community engagement using teaching activities that leverage social media. In this article, we describe a semester long teaching activity that challenged students to use social media in their learning process. We provide initial evaluation and feedback from the students on their social media experience in class, and suggestions for how to improve the project in future implementations. PMID- 27980478 TI - The Woman Born Without a Cerebellum: A Real-Life Case Adapted for Use in an Undergraduate Developmental and Systems Neuroscience Course. AB - In 2014, the case of a 24-year-old woman who had just discovered she was born without a cerebellum made headlines around the world. The details of this case were combined with other published cases of cerebellar agenesis to create an active learning exercise for an undergraduate developmental and systems neuroscience course. By reading an intriguing narrative and answering questions in stages, students work together to apply and extend their knowledge of brain development and cerebellar function. The case can be used to introduce new information in a "flipped classroom" setting or as an interactive exam review. PMID- 27980479 TI - Professor Eric Can't See: A Project-Based Learning Case for Neurobiology Students. AB - "Professor Eric Can't See" is a semi-biographical case study written for an upper level undergraduate Neurobiology of Disease course. The case is integrated into a unit using a project-based learning approach to investigate the retinal degenerative disorder Retinitis pigmentosa and the visual system. Some case study scenes provide specific questions for student discussion and problem-based learning, while others provide background for student inquiry and related active learning exercises. The case was adapted from "'Chemical Eric' Can't See," and could be adapted for courses in general neuroscience or sensory neuroscience. PMID- 27980480 TI - A New Feature in JUNE: Sharing the Amazing Papers of Neuroscience. PMID- 27980481 TI - Student Assisted Course Design. AB - Designing a new course is an important but time-consuming task for instructors. Traditionally, the instructor researches and develops the course, launches it as a pilot class, and receives student feedback upon completion of the course. Here I suggest student participation in the initial design and development of a new course. I initiated a course design class with a few motivated, upper division students to plan an advanced neuroscience course. The students assisted me in the new course preparation and offered valuable organizational and intellectual input prior to launching the new course. The students benefited by receiving a deeper study of the course topics, developing critical analysis skills, learning about course design, and by viewing the course from the instructor's perspective. Thus, I propose that including students in the design of new courses can assist instructors in course development and can provide a unique, in depth learning experience for students. PMID- 27980482 TI - Candles in the Dark. PMID- 27980484 TI - Psychosocial Stress, Health, and the Hippocampus. AB - Psychoneuroimmunology (PNI) is an interdisciplinary field that examines the relationships between psychological factors and changes in endocrine and immune function, with possible consequences for health status. There is a growing literature suggesting that psychosocial stressors can impact negatively on health through deleterious changes in immune function. In their 2005 review, Glaser and Kiecolt-Glaser examined the mechanisms by which these changes might occur, and summarized some of the findings showing stress-related health consequences in a number of human populations. Buchanan et al. (2009) examined the cortisol response in individuals sustaining damage to the hippocampus, when challenged with a psychosocial stressor. Individuals with damage to the hippocampus, but not those with damage in other regions of the brain, showed abnormal cortisol responses to the psychosocial stressor. These papers were used successfully in an undergraduate Neuroscience course to stimulate class discussion; other possible uses for these articles are discussed. PMID- 27980483 TI - Introducing Students to Subcortical Sensory, Motor, and Cognitive Processes Associated with Saccades using a Series of Papers by Goldberg and Wurtz. AB - The ability to acquire, observe, and analyze neuronal activity in conjunction with behavior in awake, behaving organisms was a great leap forward for the field of neuroscience in the 20th century. While some of the early experiments are relayed in introductory textbooks, rarely are undergraduate students introduced to tractable primary literature that illustrates the genesis of modern techniques, includes raw data that are immediately interpretable based on their basic knowledge of cellular neuroscience and their own experience, and reinforces and/or question basic concepts in neuroscience. This classic paper review introduces four papers published in 1972 by Robert Wurtz and Michael Goldberg focusing on eye movement behavior and superior colliculus physiology that fit these criteria. Taken together these papers introduce students to fundamental concepts (e.g., receptive and movement fields) in the field of behavioral neuroscience by introducing students to visual, motor, and attentional processing using single unit neuronal recordings and lesion studies. I have attempted to provide the basic introductory information for faculty who wish to use these papers for in-class discussions in their introductory or upper level neuroscience courses. PMID- 27980485 TI - Both Genetic and Environmental Changes Can Enhance Learning and Memory. AB - This review discusses two papers from the same lab that directly compared the effects of genetic enhancement with environmental enrichment on learning and memory in mice. In the first study mice were genetically manipulated to have an increased expression of the NR2B component of the NMDA receptor, associated with learning. These transgenic (Tg) mice showed greater current flow, larger EPSPs, and improved learning and memory on a variety of tasks. In the second experiment both the Tg mice and normal wild type (Wt) mice were raised in either a standard environment or given an enriched environment for two weeks. The differences in behavior and in receptor expression were compared among the four groups. The enriched Wt mice performed as well as both Tg groups on measures of fear conditioning. For the more difficult task of novel object recognition the enriched Wt mice performed as well as the Tg raised in a standard environment, but the enriched Tg mice performed significantly better than all other groups. Environmental enrichment caused an increase in receptor expression in both the Wt and Tg groups, but the Tg enriched mice had the highest expression levels. These papers clearly demonstrated that the mice's environmental enrichment caused behavioral differences for both Wt and Tg-enriched mice - with important implications for humans. They also raise questions about how a lab animal's environment might change its brain and/or behavior, with a potential impact on the results of studies using animals raised in impoverished conditions. PMID- 27980486 TI - Cockroaches Now Evading Death by Getting Bitter about Sweeteners. AB - Here, I review the article "Changes in taste neurons support an adaptive behavior in cockroaches" by Wada-Katsumata et al. (2013). Their article elucidates the mechanism by which some cockroaches avoid eating poisoned bait: a change in the response properties of cells that transduce the tastant glucose and related sugars. Specifically, the data show that in cockroaches that avoid glucose consumption, these sugars activate the gustatory neurons that detect the presence of bitter compounds. This finding was replicated in cockroaches from several distinct populations. The article is brief but compelling. It serves as an excellent teaching tool for the topics of taste perception, neural mechanisms of behavior, and the rapid evolutionary response in terms of an adaptation of a sensory system to changing environmental conditions. Moreover, it could serve as a point of departure for a variety of in-class discussion topics. PMID- 27980487 TI - Cognitive Neuroscience and Single-Word Processing. AB - Early neuroimaging research on language-related function is useful for teaching cognitive neuroscience. In these studies, researchers used relatively simple experimental designs in an attempt to break down complex cognitive processes. In addition, the hypotheses tested in these studies were based on models derived from non-imaging observations, such as lesion studies. Thus, students at all levels may find the research accessible in its simplicity and engaging in its attempt to test existing theories in novel ways. Raichle (1996) describes a series of such studies that used what were, at the time, novel applications of relatively young imaging methods to measure brain activity related to single-word processing. In a short, readable article, he places the studies in their historical context (i.e., models of language function based largely on case studies of patients with brain lesions) and describes the methods and designs used in the research. He summarizes the results and the main takeaways from the research and its practical implications for research and medicine in the future. This paper touches on many important features of cognitive neuroscience, as well as psychology and neuroscience more broadly. It can serve as a springboard into discussion of many topics in many course contexts. PMID- 27980488 TI - Can We Say "Cure"? AB - Most of the commonly prescribed conventional drugs treat only symptoms, not the underlying causes of a patient's disease. This logically leads to a perception that much of modern medicine is about management of chronic disease and prevention of more serious sequelae-not actual cures. However, most health care professionals are attracted to medicine with the mission of curing patients leading to the cognitive discord that eventually leads them to integrative/functional medicine. Though use of the term cure has been actively discouraged except in limited types of cases, perhaps true health care reform needs to reclaim this term and concept. PMID- 27980489 TI - Intestinal Microbiome, Akkermansia muciniphila, and Medical Nutrition Therapy. AB - The gastrointestinal microbiome has become a topic of great interest in medicine in recent years. Genomic sequencing can now be done at a fraction of the cost of a few years ago, and this has allowed for the development and compilation of an extensive amount of data related to the species diversity of the human gastrointestinal microbiome.1 Studies have demonstrated that the intestinal microbiome is sensitive to the composition of the diet.2 It is also recognized that the composition of the microbiome can be altered rapidly in response to dietary changes, stress, chemical exposure, and exercise.3 Both the expanded understanding of the composition of the human microbiome and the ability to measure it through genomic analysis of the stool have resulted in clinicians frequently wanting to know what actionable conclusions can be taken away from an analysis of the gastrointestinal microbiome. PMID- 27980490 TI - The 80/20 Rule: Why Medical Insurers Are Not Interested in Cost Cutting (or Integrative Health) ... plus more. PMID- 27980491 TI - The New Food Current Good Manufacturing Practices and Their Effect on Dietary Supplement Quality: What You Need to Know. PMID- 27980492 TI - David Haase,md: Healing the Gut and Brain Through Electrophysiology. PMID- 27980493 TI - Kabran Chapek, nd: Successful Progression of Diet-and-lifestyle Therapies for Cognitive Impairment. PMID- 27980494 TI - In Vivo Osteoinduction: Evaluating 2-Beta Coxatene as an Immunoinductive Compound and Novel Ingredient for Joint Support. AB - CONTEXT: Osteoarthritis (OA) is a degenerative joint disease characterized by progressive loss of articular cartilage. Many treatments lack the ability to stimulate the growth of native cartilage tissue while they simultaneously increase joint comfort. For the past few decades, dietary supplements have been investigated for the ability to both address joint inflammation and stimulate cartilage tissue. OBJECTIVES: The present study intended to examine the supplement's in vivo osteoinductive capabilities and clinical efficacy for overall joint health. DESIGN: The research team designed a randomized, double blind, comparative clinical trial. SETTING: The study took place via telephone interviews. PARTICIPANTS: Participants had self-reported OA of a weight-bearing joint (ie, of the knee, hip, spine, or ankle). Patients were recruited using the Health Science Institute, a consumer supplement newsletter. INTERVENTION: Participants in the intervention group were blindly given 135 mg of 2-Beta Coxatene (2BCT) orally, which contained (1) a custom blend of low-dose Cyplexinol, an osteoinductive protein complex derived from bovine bone tissue, and (2) Boswellia serrata resin enriched to 65% 3-O-Acetyl-11-keto-beta-Boswellic acid. A positive control group was blindly given 1500 mg of glucosamine hydrogen chloride and 1200 mg of chondroitin sulfate. Participants took the supplements for 3 mo. OUTCOME MEASURES: A histological evaluation was performed on an athymic rat to test the supplement's in vivo osteoinductive capabilities. A negative control, commercially purchased, unhydrolyzed type 2 collagen was used for that test. Participants were evaluated for parameters of pain and joint function at baseline (day 0) and at days 7, 30, and 90 using the Western Ontario and McMaster Universities (WOMAC) OA index and a visual analogue scale (VAS). RESULTS: The histological evaluation of the athymic rat confirmed that the Cyplexinol component of the 2BCT was positive for de novo bone tissue and collagen synthesis, corroborating osteoinduction. In the clinical trial, the intervention group reported significant decreases of 57.4%, 52.5%, and 58% in normalized WOMAC scores for pain, stiffness, and joint functionality, respectively, from baseline to postintervention. The control group reported a decrease of 17.5%, 18.1%, and 23.9% for pain, stiffness, and joint functionality, respectively. For the intervention group, pain intensity and frequency, as measured by the VAS, also decreased 57.1% and 56.3%, respectively, from baseline to postintervention, whereas the control group showed a decrease in VAS scores of 18.0% and 14.8%, respectively. In total, an average of 81.2% of participants administered the 2BCT had reported a statistically significant improvement from baseline to postintervention, compared with 22.9% of participants administered glucosamine and chondroitin. CONCLUSIONS: In vivo studies confirmed that the bioactive proteins (Cyplexinol) within the 2BCT stimulated de novo bone and cartilage tissue production, demonstrating osteoinduction. The intervention group reported greater improvements in the psychometric evaluations that assessed joint comfort when compared with participants given the glucosamine and chondroitin. The results suggest that 2BCT may provide a novel and synergistic response to preserving joint homeostasis and improving quality of life. PMID- 27980496 TI - Reversal of Irritable Bowel Syndrome, Sleep Disturbance, and Fatigue With an Elimination Diet, Lifestyle Modification, and Dietary Supplements: A Case Report. AB - BACKGROUND: A 53-y-old Caucasian patient presented in August 2015 with chief complaints of irritable bowel syndrome (IBS; gas/bloating, gastroesophageal reflux), fatigue, and sleep disturbances. He also noted a history of chronic sinusitis, seasonal allergies, multiple chemical sensitivities, and right knee pain (3 surgeries). His primary care physician, in 2014, diagnosed prediabetes based on an elevated hemoglobin A1c and high-sensitivity C-reactive protein, which was treated with diet and lifestyle modification. CASE/INTERVENTION: In the course of 6 mo, the patient was treated using an elimination diet, lifestyle modifications, botanicals, and dietary supplements. By addressing the underlying cause of issues, his symptoms decreased and quality of life increased, resulting in the resolution of his IBS symptoms, improved sleep, and increased energy levels. CONCLUSION: This case illustrates the potential diagnostic importance of early testing for gut microbiome imbalances and gastrointestinal infections in the management of IBS as well as the usefulness of a systems-based approach for diagnostic assessment and management of a complex chronic case. PMID- 27980497 TI - Tracy Gaudet, md: Being an Agent of Health Care Transformation. PMID- 27980495 TI - Probiotics and Disease: A Comprehensive Summary-Part 1, Mental and Neurological Health. AB - This article series provides a literature review of the disease-specific probiotic strains studied in published clinical trials in humans and animals. The goal of the series is to provide clinically useful tools. The table designs allow for quick access to supportive data related to disease states and will be helpful as a guide for both researchers and clinicians. This first article (part 1) focuses on mental health and neurological conditions. Future articles in this series will review conditions related to cardiometabolic and fatigue syndromes; ear, nose, throat, respiratory, and infectious diseases; immune and dermatological conditions; cancer, gastrointestinal and genitourinary; followed by an article focused on food-based probiotic strains and nutritional supplements. This literature review is specific to condition, probiotic, and strain and also lists currently available products and foods in which these probiotics can be found. In part 1, we explore the role of probiotics in balancing mental health and neurological issues. Conditions in mental health include anxiety, depression, attention-deficit/hyperactivity disorder, and autism. Neurological conditions include age-related cognitive decline, hepatic encephalopathy, cerebral ischemia and reperfusion, traumatic brain injury, and multiple sclerosis. PMID- 27980498 TI - As Seen on TV. PMID- 27980499 TI - The influence of caffeine ingestion on strength and power performance in female team-sport players. AB - BACKGROUND: The aim of this study was to examine the influence of caffeine supplementation on knee flexor and knee extensor strength before, during and after intermittent running exercise in female team-sport players taking oral contraceptive steroids (OCS). METHOD: Ten healthy females (24 +/- 4 years; 59.7 +/- 3.5 kg; undertaking 2-6 training sessions per week) taking low-dose monophasic oral contraceptives of the same hormonal composition took part in a randomised, double-blind, placebo-controlled crossover-design trial. Sixty minutes following the ingestion of a capsule containing 6 mg?kg-1 body mass anhydrous caffeine or artificial sweetener (placebo), participants completed a 90 min intermittent treadmill-running protocol. Isometric strength performance and eccentric and concentric strength and power of the knee flexors and knee extensors (using isokinetic dynamometer), as well as countermovement jump (CMJ), was measured before, during and after the exercise protocol, as well as ~12 h post-exercise. Blood samples were taken before, during and post-exercise to measure glucose, insulin and free fatty acids (FFA). RESULTS: Caffeine supplementation significantly increased eccentric strength of the knee flexors (P < 0.05) and eccentric power of both the knee flexors (P < 0.05) and extensors (P < 0.05). However, there was no effect on isometric or concentric parameters, or CMJ performance. FFA was elevated with caffeine supplementation over time (P < 0.05) while levels of glucose and insulin were not affected by caffeine intake. CONCLUSION: Caffeine supplementation increased eccentric strength and power in female team-sport players taking OCS both during an intermittent running protocol and the following morning. PMID- 27980501 TI - The degradation of nucleotide triphosphates extracted under boiling ethanol conditions is prevented by the yeast cellular matrix. AB - INTRODUCTION: Boiling ethanol extraction is a frequently used method for metabolomics studies of biological samples. However, the stability of several central carbon metabolites, including nucleotide triphosphates, and the influence of the cellular matrix on their degradation have not been addressed. OBJECTIVES: To study how a complex cellular matrix extracted from yeast (Saccharomyces cerevisiae) may affect the degradation profiles of nucleotide triphosphates extracted under boiling ethanol conditions. METHODS: We present a double labelling LC-MS approach with a 13C-labeled yeast cellular extract as complex surrogate matrix, and 13C15N-labeled nucleotides as internal standards, to study the effect of the yeast matrix on the degradation of nucleotide triphosphates. RESULTS: While nucleotide triphosphates were degraded to the corresponding diphosphates in pure solutions, degradation was prevented in the presence of the yeast matrix under typical boiling ethanol extraction conditions. CONCLUSIONS: Extraction of biological samples under boiling ethanol extraction conditions that rapidly inactivate enzyme activity are suitable for labile central energy metabolites such as nucleotide triphosphates due to the stabilizing effect of the yeast matrix. The basis of this phenomenon requires further study. GRAPHICAL ABSTRACT: PMID- 27980500 TI - Cardiovascular proteomics in the era of big data: experimental and computational advances. AB - Proteomics plays an increasingly important role in our quest to understand cardiovascular biology. Fueled by analytical and computational advances in the past decade, proteomics applications can now go beyond merely inventorying protein species, and address sophisticated questions on cardiac physiology. The advent of massive mass spectrometry datasets has in turn led to increasing intersection between proteomics and big data science. Here we review new frontiers in technological developments and their applications to cardiovascular medicine. The impact of big data science on cardiovascular proteomics investigations and translation to medicine is highlighted. PMID- 27980502 TI - Granulocyte colony-stimulating factor alters the systemic metabolomic profile in healthy donors. AB - INTRODUCTION: Peripheral blood stem cells mobilized by granulocyte colony stimulating factor (G-CSF) from healthy donors are commonly used for allogeneic stem cell transplantation. The effect of G-CSF administration on global serum metabolite profiles has not been investigated before. OBJECTIVES: This study aims to examine the systemic metabolomic profiles prior to and following administration of G-CSF in healthy adults. METHODS: Blood samples were collected from 15 healthy stem cell donors prior to and after administration of G-CSF 10 ug/kg/day for 4 days. Using a non-targeted metabolomics approach, metabolite levels in serum were determined using ultrahigh performance liquid chromatography tandem mass spectrometry and gas chromatography/mass spectrometry. RESULTS: Comparison of the metabolite profiles of donors before and after G-CSF treatment revealed 239 metabolites that were significantly altered. The major changes of the metabolite profiles following G-CSF administration included alteration of several fatty acids, including increased levels of several medium and long-chain fatty acids, as well as polyunsaturated fatty acids; while there were lower levels of other lipid metabolites such as phospholipids, lysolipids, sphingolipids. Furthermore, there were significantly lower levels of several amino acids and/or their metabolites, including several amino acids with known immunoregulatory functions (methionine, tryptophan, valine). Lastly, the levels of several nucleotides and nucleotide metabolites (guanosine, adenosine, inosine) were also decreased after G-CSF administration, while methylated products were increased. Some of these altered products/metabolites may potentially have angioregulatory effects whereas others may suggest altered intracellular epigenetic regulation. CONCLUSION: Our results show that G-CSF treatment alters biochemical serum profiles, in particular amino acid, lipid and nucleotide metabolism. Additional studies are needed to further evaluate the relevance of these changes in healthy donors. PMID- 27980504 TI - The Administration of Tibetan Precious Pills: Efficacy in Historical and Ritual Contexts. AB - Precious pills represent a special kind of Tibetan drug that once was, and still is, highly sought after by Tibetan, Chinese, and Mongolian patients. Such pills are generally taken as a potent prophylactic remedy, and can be used to cure various diseases. The present study seeks to discuss the dispensation and efficacy of precious pills according to the presentations of historical Tibetan medical scholars. Several treatises dealing with these instructions will be analysed, thereby revealing their underlying concepts, and highlighting their points of both general consensus and disagreement. The analysis of these detailed instructions will reveal the fact that these precious pills were not merely given to a patient but, in order to ensure their full efficacy, involved an elaborate regimen concerning three chronological periods: (1) the time of preparation, (2) the time of dispensation, and (3) the time after dispensation. Thus the present study surveys not only the ritual empowerment of drugs in Tibetan medicine, but also the importance of social relationships between doctors and patients in Tibetan medical history. PMID- 27980503 TI - Stability of targeted metabolite profiles of urine samples under different storage conditions. AB - INTRODUCTION: Few studies have investigated the influence of storage conditions on urine samples and none of them used targeted mass spectrometry (MS). OBJECTIVES: We investigated the stability of metabolite profiles in urine samples under different storage conditions using targeted metabolomics. METHODS: Pooled, fasting urine samples were collected and stored at -80 degrees C (biobank standard), -20 degrees C (freezer), 4 degrees C (fridge), ~9 degrees C (cool pack), and ~20 degrees C (room temperature) for 0, 2, 8 and 24 h. Metabolite concentrations were quantified with MS using the AbsoluteIDQTM p150 assay. We used the Welch-Satterthwaite-test to compare the concentrations of each metabolite. Mixed effects linear regression was used to assess the influence of the interaction of storage time and temperature. RESULTS: The concentrations of 63 investigated metabolites were stable at -20 and 4 degrees C for up to 24 h when compared to samples immediately stored at -80 degrees C. When stored at ~9 degrees C for 24 h, few amino acids (Arg, Val and Leu/Ile) significantly decreased by 40% in concentration (P < 7.9E-04); for an additional three metabolites (Ser, Met, Hexose H1) when stored at ~20 degrees C reduced up to 60% in concentrations. The concentrations of four more metabolites (Glu, Phe, Pro, and Thr) were found to be significantly influenced when considering the interaction between exposure time and temperature. CONCLUSION: Our findings indicate that 78% of quantified metabolites were stable for all examined storage conditions. Particularly, some amino acid concentrations were sensitive to changes after prolonged storage at room temperature. Shipping or storing urine samples on cool packs or at room temperature for more than 8 h and multiple numbers of freeze and thaw cycles should be avoided. PMID- 27980505 TI - Introduction to the special issue on small-angle scattering. AB - This open-access collection of 11 selected articles covers a small but quite diverse and interesting part of the much wider range of scientific topics presented at the 16th International Conference on Small-Angle Scattering (SAS2015) in Berlin. The topics contained here describe the particular directions in which small-angle scattering is developing at the current moment and which will become increasingly important in the future. The virtual special issue is available at http://journals.iucr.org/special_issues/2016/sas2015/. PMID- 27980507 TI - A synchrotron X-ray diffraction deconvolution method for the measurement of residual stress in thermal barrier coatings as a function of depth. AB - The average residual stress distribution as a function of depth in an air plasma sprayed yttria stabilized zirconia top coat used in thermal barrier coating (TBC) systems was measured using synchrotron radiation X-ray diffraction in reflection geometry on station I15 at Diamond Light Source, UK, employing a series of incidence angles. The stress values were calculated from data deconvoluted from diffraction patterns collected at increasing depths. The stress was found to be compressive through the thickness of the TBC and a fluctuation in the trend of the stress profile was indicated in some samples. Typically this fluctuation was observed to increase from the surface to the middle of the coating, decrease a little and then increase again towards the interface. The stress at the interface region was observed to be around 300 MPa, which agrees well with the reported values. The trend of the observed residual stress was found to be related to the crack distribution in the samples, in particular a large crack propagating from the middle of the coating. The method shows promise for the development of a nondestructive test for as-manufactured samples. PMID- 27980506 TI - Atomistic modelling of scattering data in the Collaborative Computational Project for Small Angle Scattering (CCP-SAS). AB - The capabilities of current computer simulations provide a unique opportunity to model small-angle scattering (SAS) data at the atomistic level, and to include other structural constraints ranging from molecular and atomistic energetics to crystallography, electron microscopy and NMR. This extends the capabilities of solution scattering and provides deeper insights into the physics and chemistry of the systems studied. Realizing this potential, however, requires integrating the experimental data with a new generation of modelling software. To achieve this, the CCP-SAS collaboration (http://www.ccpsas.org/) is developing open source, high-throughput and user-friendly software for the atomistic and coarse grained molecular modelling of scattering data. Robust state-of-the-art molecular simulation engines and molecular dynamics and Monte Carlo force fields provide constraints to the solution structure inferred from the small-angle scattering data, which incorporates the known physical chemistry of the system. The implementation of this software suite involves a tiered approach in which GenApp provides the deployment infrastructure for running applications on both standard and high-performance computing hardware, and SASSIE provides a workflow framework into which modules can be plugged to prepare structures, carry out simulations, calculate theoretical scattering data and compare results with experimental data. GenApp produces the accessible web-based front end termed SASSIE-web, and GenApp and SASSIE also make community SAS codes available. Applications are illustrated by case studies: (i) inter-domain flexibility in two- to six-domain proteins as exemplified by HIV-1 Gag, MASP and ubiquitin; (ii) the hinge conformation in human IgG2 and IgA1 antibodies; (iii) the complex formed between a hexameric protein Hfq and mRNA; and (iv) synthetic 'bottlebrush' polymers. PMID- 27980508 TI - Robust background modelling in DIALS. AB - A method for estimating the background under each reflection during integration that is robust in the presence of pixel outliers is presented. The method uses a generalized linear model approach that is more appropriate for use with Poisson distributed data than traditional approaches to pixel outlier handling in integration programs. The algorithm is most applicable to data with a very low background level where assumptions of a normal distribution are no longer valid as an approximation to the Poisson distribution. It is shown that traditional methods can result in the systematic underestimation of background values. This then results in the reflection intensities being overestimated and gives rise to a change in the overall distribution of reflection intensities in a dataset such that too few weak reflections appear to be recorded. Statistical tests performed during data reduction may mistakenly attribute this to merohedral twinning in the crystal. Application of the robust generalized linear model algorithm is shown to correct for this bias. PMID- 27980509 TI - SEC-SANS: size exclusion chromatography combined in situ with small-angle neutron scattering. AB - The first implementation and use of an in situ size exclusion chromatography (SEC) system on a small-angle neutron scattering instrument (SANS) is described. The possibility of deploying such a system for biological solution scattering at the Institut Laue-Langevin (ILL) has arisen from the fact that current day SANS instruments at ILL now allow datasets to be acquired using small sample volumes with exposure times that are often shorter than a minute. This capability is of particular importance for the study of unstable biological macromolecules where aggregation or denaturation issues are a major problem. The first use of SEC-SANS on ILL's instrument D22 is described for a variety of proteins including one particularly aggregation-prone system. PMID- 27980510 TI - Contrast variation by dynamic nuclear polarization and time-of-flight small-angle neutron scattering. I. Application to industrial multi-component nanocomposites. AB - Dynamic nuclear polarization (DNP) at low temperature (1.2 K) and high magnetic field (3.3 T) was applied to a contrast variation study in small-angle neutron scattering (SANS) focusing on industrial rubber materials. By varying the scattering contrast by DNP, time-of-flight SANS profiles were obtained at the pulsed neutron source of the Japan Proton Accelerator Research Complex (J-PARC). The concentration of a small organic molecule, (2,2,6,6-tetramethylpiperidine-1 yl)oxy (TEMPO), was carefully controlled by a doping method using vapour sorption into the rubber specimens. With the assistance of microwave irradiation (94 GHz), almost full polarization of the paramagnetic electronic spin of TEMPO was transferred to the spin state of hydrogen (protons) in the rubber materials to obtain a high proton spin polarization (PH). The following samples were prepared: (i) a binary mixture of styrene-butadiene random copolymer (SBR) with silica particles (SBR/SP); and (ii) a ternary mixture of SBR with silica and carbon black particles (SBR/SP/CP). For the binary mixture (SBR/SP), the intensity of SANS significantly increased or decreased while keeping its q dependence for PH = -35% or PH = 40%, respectively. The q behaviour of SANS for the SBR/SP mixture can be reproduced using the form factor of a spherical particle. The intensity at low q (~0.01 A-1) varied as a quadratic function of PH and indicated a minimum value at PH = 30%, which can be explained by the scattering contrast between SP and SBR. The scattering intensity at high q (~0.3 A-1) decreased with increasing PH, which is attributed to the incoherent scattering from hydrogen. For the ternary mixture (SBR/SP/CP), the q behaviour of SANS was varied by changing PH. At PH = -35%, the scattering maxima originating from the form factor of SP prevailed, whereas at PH = 29% and PH = 38%, the scattering maxima disappeared. After decomposition of the total SANS according to inverse matrix calculations, the partial scattering functions were obtained. The partial scattering function obtained for SP was well reproduced by a spherical form factor and matched the SANS profile for the SBR/SP mixture. The partial scattering function for CP exhibited surface fractal behaviour according to q-3.6, which is consistent with the results for the SBR/CP mixture. PMID- 27980511 TI - Structure beyond pair correlations: X-ray cross-correlation from colloidal crystals. AB - The results of an X-ray cross-correlation analysis (XCCA) study on hard-sphere colloidal crystals and glasses are presented. The article shows that cross correlation functions can be used to extract structural information beyond the static structure factor in such systems. In particular, the powder average can be overcome by accessing the crystals' unit-cell structure. In this case, the results suggest that the crystal is of face-centered cubic type. It is demonstrated that XCCA is a valuable tool for X-ray crystallography, in particular for studies on colloidal systems. These are typically characterized by a rather poor crystalline quality due to size polydispersity and limitations in experimental resolution because of the small q values probed. Furthermore, nontrivial correlations are observed that allow a more detailed insight into crystal structures beyond conventional crystallography, especially to extend knowledge in structure formation processes and phase transitions. PMID- 27980512 TI - Small-angle scattering and morphologies of ultra-flexible microemulsions. AB - The phase diagrams of ternary mixtures of partly miscible solvents containing a hydrotropic co-solvent exhibit a variable miscibility gap and one critical point. This work investigates the entire monophasic region far from and near to the miscibility gap in octan-1-ol/ethanol/water, for which ultra-flexible micro emulsions (UFMEs) are observed by small-angle scattering techniques. SWAXS (combined small- and wide-angle X-ray scattering) allows the elucidation of these types of structure. Three distinct areas can be identified in the phase diagram, with scattering data resembling those from direct, bicontinuous and reverse local structures. These UFMEs are far more polydisperse than their surfactant-based counterparts. Water-rich and solvent-rich domains are only delimited by a small excess of hydrotrope, instead of a well defined surfactant layer of fixed area per molecule. It is shown that all scattering spectra obtained for the nanostructured compositions can be modelled by a simple unified analytical model composed of two uncorrelated contributions. The main one is the Ornstein-Zernike formula for composition fluctuations which gives information about the pseudo phase domain size. The second is a Lorentzian that captures the structure of at least one of the coexisting pseudo-phases. No Porod law can be measured in the SAXS domain. The proposed expression gives access to two characteristic sizes as well as one inter-aggregate distance. PMID- 27980513 TI - The use of haptic interfaces and web services in crystallography: an application for a 'screen to beam' interface. AB - Haptic interfaces have become common in consumer electronics. They enable easy interaction and information entry without the use of a mouse or keyboard. The work presented here illustrates the application of a haptic interface to crystallization screening in order to provide a natural means for visualizing and selecting results. By linking this to a cloud-based database and web-based application program interface, the same application shifts the approach from 'point and click' to 'touch and share', where results can be selected, annotated and discussed collaboratively. In the crystallographic application, given a suitable crystallization plate, beamline and robotic end effector, the resulting information can be used to close the loop between screening and X-ray analysis, allowing a direct and efficient 'screen to beam' approach. The application is not limited to the area of crystallization screening; 'touch and share' can be used by any information-rich scientific analysis and geographically distributed collaboration. PMID- 27980514 TI - Pushing the limits of crystallography. AB - A very serious concern of scientists dealing with crystal structure refinement, including theoretical research, pertains to the characteristic bias in calculated versus measured diffraction intensities, observed particularly in the weak reflection regime. This bias is here attributed to corrective factors for phonons and, even more distinctly, phasons, and credible proof supporting this assumption is given. The lack of a consistent theory of phasons in quasicrystals significantly contributes to this characteristic bias. It is shown that the most commonly used exponential Debye-Waller factor for phasons fails in the case of quasicrystals, and a novel method of calculating the correction factor within a statistical approach is proposed. The results obtained for model quasiperiodic systems show that phasonic perturbations can be successfully described and refinement fits of high quality are achievable. The standard Debye-Waller factor for phonons works equally well for periodic and quasiperiodic crystals, and it is only in the last steps of a refinement that different correction functions need to be applied to improve the fit quality. PMID- 27980515 TI - Multiparameter characterization of subnanometre Cr/Sc multilayers based on complementary measurements. AB - Cr/Sc multilayer systems can be used as near-normal incidence mirrors for the water window spectral range. It is shown that a detailed characterization of these multilayer systems with 400 bilayers of Cr and Sc, each with individual layer thicknesses <1 nm, is attainable by the combination of several analytical techniques. EUV and X-ray reflectance measurements, resonant EUV reflectance across the Sc L edge, and X-ray standing wave fluorescence measurements were used. The parameters of the multilayer model were determined via a particle-swarm optimizer and validated using a Markov chain Monte Carlo maximum-likelihood approach. For the determination of the interface roughness, diffuse scattering measurements were conducted. PMID- 27980516 TI - Use of small-angle X-ray scattering to resolve intracellular structure changes of Escherichia coli cells induced by antibiotic treatment. AB - The application of small-angle X-ray scattering (SAXS) to whole Escherichia coli cells is challenging owing to the variety of internal constituents. To resolve their contributions, the outer shape was captured by ultra-small-angle X-ray scattering and combined with the internal structure resolved by SAXS. Building on these data, a model for the major structural components of E. coli was developed. It was possible to deduce information on the occupied volume, occurrence and average size of the most important intracellular constituents: ribosomes, DNA and proteins. E. coli was studied after treatment with three different antibiotic agents (chloramphenicol, tetracycline and rifampicin) and the impact on the intracellular constituents was monitored. PMID- 27980517 TI - Combinatorial refinement of thin-film microstructure, properties and process conditions: iterative nanoscale search for self-assembled TiAlN nanolamellae. AB - Because of the tremendous variability of crystallite sizes and shapes in nano materials, it is challenging to assess the corresponding size-property relationships and to identify microstructures with particular physical properties or even optimized functions. This task is especially difficult for nanomaterials formed by self-organization, where the spontaneous evolution of microstructure and properties is coupled. In this work, two compositionally graded TiAlN films were (i) grown using chemical vapour deposition by applying a varying ratio of reacting gases and (ii) subsequently analysed using cross-sectional synchrotron X ray nanodiffraction, electron microscopy and nanoindentation in order to evaluate the microstructure and hardness depth gradients. The results indicate the formation of self-organized hexagonal-cubic and cubic-cubic nanolamellae with varying compositions and thicknesses in the range of ~3-15 nm across the film thicknesses, depending on the actual composition of the reactive gas mixtures. On the basis of the occurrence of the nanolamellae and their correlation with the local film hardness, progressively narrower ranges of the composition and hardness were refined in three steps. The third film was produced using an AlCl3/TiCl4 precursor ratio of ~1.9, resulting in the formation of an optimized lamellar microstructure with ~1.3 nm thick cubic Ti(Al)N and ~12 nm thick cubic Al(Ti)N nanolamellae which exhibits a maximal hardness of ~36 GPa and an indentation modulus of ~522 GPa. The presented approach of an iterative nanoscale search based on the application of cross-sectional synchrotron X-ray nanodiffraction and cross-sectional nanoindentation allows one to refine the relationship between (i) varying deposition conditions, (ii) gradients of microstructure and (iii) gradients of mechanical properties in nanostructured materials prepared as thin films. This is done in a combinatorial way in order to screen a wide range of deposition conditions, while identifying those that result in the formation of a particular microstructure with optimized functional attributes. PMID- 27980518 TI - Synchrotron-based macromolecular crystallography module for an undergraduate biochemistry laboratory course. AB - This paper describes the introduction of synchrotron-based macromolecular crystallography (MX) into an undergraduate laboratory class. An introductory 2 week experimental module on MX, consisting of four laboratory sessions and two classroom lectures, was incorporated into a senior-level biochemistry class focused on a survey of biochemical techniques, including the experimental characterization of proteins. Students purified recombinant protein samples, set up crystallization plates and flash-cooled crystals for shipping to a synchrotron. Students then collected X-ray diffraction data sets from their crystals via the remote interface of the Molecular Biology Consortium beamline (4.2.2) at the Advanced Light Source in Berkeley, CA, USA. Processed diffraction data sets were transferred back to the laboratory and used in conjunction with partial protein models provided to the students for refinement and model building. The laboratory component was supplemented by up to 2 h of lectures by faculty with expertise in MX. This module can be easily adapted for implementation into other similar undergraduate classes, assuming the availability of local crystallographic expertise and access to remote data collection at a synchrotron source. PMID- 27980519 TI - ContaMiner and ContaBase: a webserver and database for early identification of unwantedly crystallized protein contaminants. AB - Solving the phase problem in protein X-ray crystallography relies heavily on the identity of the crystallized protein, especially when molecular replacement (MR) methods are used. Yet, it is not uncommon that a contaminant crystallizes instead of the protein of interest. Such contaminants may be proteins from the expression host organism, protein fusion tags or proteins added during the purification steps. Many contaminants co-purify easily, crystallize and give good diffraction data. Identification of contaminant crystals may take time, since the presence of the contaminant is unexpected and its identity unknown. A webserver (ContaMiner) and a contaminant database (ContaBase) have been established, to allow fast MR based screening of crystallographic data against currently 62 known contaminants. The web-based ContaMiner (available at http://strube.cbrc.kaust.edu.sa/contaminer/) currently produces results in 5 min to 4 h. The program is also available in a github repository and can be installed locally. ContaMiner enables screening of novel crystals at synchrotron beamlines, and it would be valuable as a routine safety check for 'crystallization and preliminary X-ray analysis' publications. Thus, in addition to potentially saving X-ray crystallographers much time and effort, ContaMiner might considerably lower the risk of publishing erroneous data. PMID- 27980521 TI - The opinions of adults about the ban on cigarette sales to minors. AB - BACKGROUND: Selling of tobacco products to minors has been banned since 1996 by the tobacco control law in Turkey. However, it is also important for the public to support practices that prevent the access of tobacco products to minors. In addition, every individual has the responsibility of carrying out society based programs that restrict access to tobacco products especially to children and the youths. Social sensitivity is considered an important factor in the prevention of tobacco use. This study aims to learn about the opinions and attitudes of adults with regards to minors access to tobacco products. METHODS: The study was a descriptive study conducted in nine city centers in Turkey. The total number of participants reached was 3241. The questionnaire was developed by the research team and consisted of 22 questions concerning knowledge and behaviors of adults on restriction of tobacco sales to minors and their observations with regards tobacco sales to minors. Data was collected through face to face interview. Pearson chi-square test was used for the bivariate analysis whereas logistic regression was investigate the relationship between "the participant's response against tobacco sales to minors" and the following explanatory variables; "age", "educational status", "income level", "working status", "minors access to cigarettes", "smoking ratio in high school" and "sales of tobacco to minors". RESULTS: More than half of the participants (60.5%) belonged to the age group 25 44 years, 61.3% graduated from high school or university. Most of the participants were smoker (39.2%) or ex-smoker (19.1%), and 41.7% of the participants was non-smoker. A greater proportion of the participants (76.2%) believed that smoking prevalence was greater than 40% among high school students. One in four (27.8%) adults did not know that tobacco control law bans sell of tobacco products to minors in Turkey. More than half of the participants (57.1%) ever witnessed tobacco sales to minors and 63.6% of them did not act when confronted with the event. Almost all (96.8%) of the respondents thought that access of minors to tobacco products was not difficult. The results of logistic regression of participant's response against tobacco sales to minor and related factors for current smokers showed that respondents who believed smoking ratio in high school was 4-5 adolescent out of 10 (aOR: 1.59; 95% CI: 1.09-2.34) were more likely to give a warning or informing the police or other people as compared to respondents whose perception on the smoking ratio among high school students was 6-7 adolescents out of 10. The results of logistic regression of non-smokers' response against tobacco sales to minor were who are from higher educational level, higher economic status, working status and who believed smoking ratio in high school was 4-5 adolescent out of 10 and 2-3 adolescent out of 10 were more likely to give a warning or informing the police or other people as compared to the others. CONCLUSIONS: Although laws prohibiting the sale of tobacco products to the under age group is very important with regards to accessibility of minors to tobacco products, most of the study participants believed that minors can still easily access tobacco products, and more than half of the participants did not act when confronted with the event. The education, information and monitoring program most especially as it concerns salesman, should be reviewed and strengthened to obey the rules on sales of tobacco products to minors. Education program should be carried out to increase the knowledge and awareness of the community for sale of tobacco to minors. Social sensitivity is important for the prevention of tobacco use and every individual have a responsibility in carrying out this society based program, most especially as it related to prevention of tobacco usage among children and youths. PMID- 27980520 TI - Quality of care in patients with atrial fibrillation in primary care: a cross sectional study comparing clinical and claims data. AB - Objectives: Atrial fibrillation (AF) is a common cardiac arrhythmia with increased risk of thromboembolic stroke. Oral anticoagulation (OAC) reduces stroke risk by up to 68%. The aim of our study was to evaluate quality of care in patients with AF in a primary health care setting with a focus on physician guideline adherence for OAC prescription and heart rate- and rhythm management. In a second step we aimed to compare OAC rates based on primary care data with rates based on claims data. Methods: We included all GP practices in the region Vorpommern-Greifswald, Germany, which were willing to participate (N=29/182, response rate 16%). Claims data was derived from the regional association of statutory health insurance physicians. Patients with a documented AF diagnosis (ICD-10-GM-Code ICD I48.-) from 07/2011-06/2012 were identified using electronic medical records (EMR) and claims data. Stroke and bleeding risk were calculated using the CHA2DS2-VASc and HAS-BLED scores. We calculated crude treatment rates for OAC, rate and rhythm control medications and adjusted OAC treatment rates based on practice and claims data. Adjusted rates were calculated including the CHA2DS2-VASc and HAS-BLED scores and individual factors affecting guideline based treatment. Results: We identified 927 patients based on EMR and 1,247 patients based on claims data. The crude total OAC treatment rate was 69% based on EMR and 61% based on claims data. The adjusted OAC treatment rates were 90% for patients based on EMR and 63% based on claims data. 82% of the AF patients received a treatment for rate control and 12% a treatment for rhythm control. The most common reasons for non-prescription of OAC were an increased risk of falling, dementia and increased bleeding risk. Conclusion: Our results suggest that a high rate of AF patients receive a drug therapy according to guidelines. There is a large difference between crude and adjusted OAC treatment rates. This is due to individual contraindications and comorbidities which cannot be documented using ICD coding. Therefore, quality indicators based on crude EMR data or claims data would lead to a systematic underestimation of the quality of care. A possible overtreatment of low-risk patients cannot be ruled out. PMID- 27980522 TI - Ultrasound imaging in urogynecology - state of the art 2016. AB - The role of ultrasound imaging in urogynecology is not clearly defined. Despite significant developments in visualization techniques and interpretation of images, pelvic ultrasound is still more a tool for research than for clinical practice. Structures of the lower genitourinary tract and pelvic floor can be visualized from different approaches: transperineal, introital, transvaginal, abdominal or endoanal. According to contemporary guidelines and recommendations, the role of ultrasound in urogynecology is limited to the measurement of post void residue. However, in many instances, including planning and audit of surgical procedures, management of recurrences or complications, ultrasound may be proposed as the initial examination of choice. Ultrasound may be used for assessment of bladder neck mobility before anti-incontinence procedures. On rare occasions it is helpful in recognition of pathologies mimicking vaginal prolapse such as vaginal cyst, urethral diverticula or rectal intussusception. In patients subjected to suburethral slings, causes of surgery failure or postsurgical voiding dysfunctions can be revealed by imaging. Many reports link the location of a tape close to the bladder neck to unfavorable outcomes of sling surgery. Some postoperative complications, such as urinary retention, mesh malposition, hematoma, or urinary tract injury, can be diagnosed by ultrasound. On the other hand, the clinical value of some applications of ultrasound in urogynecology, for example measurement of the bladder wall thickness as a marker of detrusor overactivity, has not been proved. PMID- 27980523 TI - Assessment of levels of the tumor markers HE4 and CA125 considering staging, grading and histological types of endometrial cancer. AB - AIM OF THE STUDY: Aim of the study was to assess statistical differences of serum levels of HE4 and CA125 between certain endometrial cancer stages, grading and histological types. MATERIAL AND METHODS: A retrospective study of 52 patients admitted to our clinic for a surgical operation because of endometrial cancer was performed. HE4 and CA125 were measured for each patient. The staging was done according to FIGO. The statistical difference of serum levels of tumor markers was analyzed considering different stages, grading and histological types. RESULTS: Most of the patients (92.31%) were post-menopausal. Serum levels of tumor markers were significantly higher among patients with stage IB-IIIC than stage IA, among patients with stages II-III than stage I and among patients with stage IIIC than stage IA-IIIB. Only HE4 was significantly higher among patients with stage IB than stage IA and among patients with grading G2 and G3 than those with G1. Only CA125 was significantly higher among patients with stage IIIA and IIIB than those with stages I and II. There was no statistically significant difference in level of either tumor marker in differentiation of endometrioid from other histological endometrial cancer. CONCLUSIONS: Both tumor markers HE4 and CA125 can be useful additional tools for pre-surgical differentiation between different stages of endometrial cancer. HE4 can predict advanced histological grades. Neither HE4 nor CA125 can differentiate endometrioid from other histological types of endometrial cancer. PMID- 27980524 TI - Professional activity of Polish peri- and postmenopausal women. AB - INTRODUCTION: The menopausal transition as one of the stages in women's life can bring many ailments which complicate the accomplishment of professional duties. The situation of women on the Polish job market is determined by many barriers and stereotypes which impede women's access to jobs and professional promotions. MATERIAL AND METHODS: The aim of the study was to estimate the professional status and job satisfaction of women aged 40-65. The research was carried out by a survey method, a poll technique in the period from January to March 2016. An original questionnaire consisting of 35 questions was used as a research tool. RESULTS: The analysis of obtained results shows that the arithmetic mean of the age of women in full-time employment was 51.84 years whereas the arithmetic mean of the age of women in part-time or seasonal employment was 52.64. Women aged 45 60 were characterised by a significantly lower job satisfaction than women over 60 years of age. The highest percentage of women in full-time employment lived in large cities. The financial situation of working women determined their job satisfaction. Well-off respondents were more pleased with their jobs than women in a worse financial situation. CONCLUSIONS: There is a strong need of education about counteraction of gender and age discrimination on the Polish labour market. The struggle against discrimination requires support on each level of the state administration through the implementation of numerous regulations facilitating the final period and resumption of women's professional activity. PMID- 27980525 TI - Leiomyoma and leiomyoma cellulare of the fallopian tube: review of the literature and case reports. AB - INTRODUCTION: Leiomyoma of the fallopian tube is extremely rare, and its version leiomyoma cellulare (LC) of the fallopian tube is absolutely unique. Aim of the study was to review literature reports on leiomyomas of the fallopian tubes, and to present cases of leiomyoma and LC of the fallopian tubes in the patients operated on in our ward. MATERIAL AND METHODS: There were fewer than 100 cases of leiomyomas of the fallopian tubes discussed in the literature up to 1993. Case 1. Leiomyoma of the left fallopian tube was detected postoperatively in a 68-year old patient, G.K., on histopathological examination after laparoscopic total hysterectomy with bilateral adnexa. Case 2. A 56-year-old patient, K.T., with LC of the fallopian tube was qualified for laparoscopy. At operation, the procedure was converted to microlaparotomy due to the tumor size. The adnexa on the right side with the tumor of the fallopian tube were excised, and the left fallopian tube was excised, too. Histopathological microscopy found leiomyoma cellulare partim epithelioides. RESULTS: In the presented cases, the extent of operation was connected with the clinical picture, and in the case of LC of the right fallopian tube, with intraoperative histopathological findings. In both cases the postoperative course was uneventful. CONCLUSIONS: Diagnosis of leiomyoma and LC of the fallopian tube, like in the other organs of the female genital tract, is possible only due to results of histopathological microscopy. PMID- 27980526 TI - Men's knowledge about osteoporosis and its risk factors. AB - INTRODUCTION: Until recently osteoporosis was seen mainly as a woman's problem. However, in the last ten years there has been rising awareness in society that osteoporosis constitutes an inseparable element of getting old for men as well. The aim of the research was to evaluate men's knowledge about osteoporosis and its risk factors contributing to the development of the disease. MATERIAL AND METHODS: The study included 205 men aged 20-60. The examined men were patients of selected healthcare centres in Lublin Voivodeship. The study was conducted between September 2014 and April 2015. The research was performed by means of the survey method, using a poll technique. Purposive sampling and an original questionnaire were used. Gathered material was subjected to descriptive and statistical analysis. The Mann-Whitney U test and Kruskal-Wallis test were applied. The statistical significance level was set at alpha = 0.05. IBM SPSS Statistics software was used to perform the statistical analysis. RESULTS: The respondents' level of knowledge about osteoporosis and its risk factors can be estimated as average. The polled men showed better knowledge on osteoporosis risk factors (M = 59.78) than general osteoporosis knowledge (M = 53.71). Significant differences were found between the respondents' education and their general osteoporosis knowledge as well as between the respondents' living conditions and their knowledge about osteoporosis risk factors. CONCLUSIONS: Because of the insufficient level of knowledge about osteoporosis and its risk factors in the male population it is advisable to launch prevention programmes aimed at men focusing on this issue. PMID- 27980527 TI - The prevalence of sexual activity, and sexual dysfunction and behaviours in postmenopausal woman in Poland. AB - INTRODUCTION: Despite the aging of the population, there is limited data available about sexual life and behaviours among of postmenopausal and late postmenopausal women. Aim of the study was to assess the prevalence of sexual dysfunction, behaviours, and preferences in the Polish population in 2015. MATERIAL AND METHODS: This observational survey study involved 538 women, of whom 220 were over 50 years old. The main focus was on the differences and changes between older age groups, mainly 50-59 years and over 60 years. RESULTS: For 80.9% of the women above 50 years old, sex played at least a moderately important role in life. Sex was definitely important and very important for 40.45% of them. Most women over 50 years old (65.5%) were sexually active. Regardless of age, the respondents were more likely to have sexual intercourse several times a month. Less than half of the women over 50 years old (42.7%) realised their sexual fantasies. Women in the group of 50-59 years old statistically less often than younger women declared that the frequency of intercourse they had was too small. There was a statistical tendency showing that women up to 49 years old declared more sexual problems than older women. Women over 50 years old reported fewer problems in comparison to younger women, e.g. less often they claimed that sex is not pleasurable (p = 0.064). CONCLUSIONS: The prevalence of sexual activity declines with age, yet a substantial number of woman engage in vaginal intercourse, oral sex, and masturbation even past the seventh decade of life. PMID- 27980528 TI - Uterine angioleiomyoma - a rare variant of uterine leiomyoma: review of literature and case reports. AB - INTRODUCTION: Uterine angioleiomyoma (AL) is an extremely rare variant of uterine leiomyoma. It is composed of smooth muscle cells and thick-walled blood vessels. Angioleiomyoma usually occurs in middle-aged women, 40-60 years old. Aim of the study was to review of literature research reports on uterine AL. Discussion of nine case reports of uterine AL in the patients operated on in our ward. MATERIAL AND METHODS: The paper presents analysis of accessible research reports on uterine AL, and medical records of the patients operated on in our ward. RESULTS: Mean age of the patients with uterine AL was 47.11 +/-5.21, body mass index (BMI) 25.88 +/-3.95. All women had given birth (1-5 natural deliveries, 2.44 mean). Uterine AL occurred in 0.34% to 0.40% cases of leiomyomas. Angioleiomyoma were located intramurally and subserosally in six and three patients (respectively, 66.7% and 33.3%). Laparotomy was undertaken in seven cases (77.8%), transvaginal access in two cases (22.2%), and myomectomy in one case (11.1%). Blood transfusion was required in four cases (44.4%). CONCLUSIONS: In the group of uterine leiomyomas, uterine ALs occurred in 0.34-0.40% of cases. Angioleiomyoma cases posed a greater risk of complications threatening the patient's health and life. Preoperative differentiation of AL with ovarian tumour was more difficult due to frequent degenerative lesions in the course of uterine AL. PMID- 27980529 TI - Ten years of anti-HPV vaccinations: what do we know? AB - Human papillomavirus (HPV) is one of the most important carcinogens in humans. Vaccines against HPV are now considered the first anti-cancer vaccinations. Since 2007, in many developed countries, there have been recommendations present for preventive vaccines against HPV. At present, the degree of implementation of these recommendations depends on a number of country-specific factors such as the health care system organization or the ways of funding. HPV vaccines are primarily to prevent the development of cervical cancer and other genital cancers. Therefore, only their long-term effectiveness can be measured, when a correspondingly large cohort of vaccinated teenagers reaches the age of the greatest incidence of these cancers. However, great care should be taken in assessing the results of vaccinations due to the possibility of misinterpretation and possible erroneous data. Undoubtedly, teenagers are the target population of HPV vaccines. However, vaccinating young sexually active women is also justified from an individual point of view. A 9-valent vaccine has been registered in the USA and in Europe - including Poland - as one of the three preventive vaccines. It is recommended to vaccinate women between 13 and 26 and men between 13 and 21, previously unvaccinated. It is also recommended to vaccinate men aged 26 years or less who have sexual relations with other men and people with reduced immunity, including HIV-positive people who have not been vaccinated previously. PMID- 27980531 TI - Comment on: "The consequences of gynaecological cancer in patients and their partners from the sexual and psychological perspective". PMID- 27980530 TI - The significance of markers in the diagnosis of endometrial cancer. AB - Endometrial cancer is one of the most common cancers experienced by women throughout the world. It is also the most common malignancy within the female reproductive system, representing 37.7% of all disorders. The incidence increases with age, and is diagnosed most frequently in women between 45 and 65 years old. In the last few years, numerous studies have been performed to identify tumour biomarkers. Biomarkers include not only protein routinely used as tumour markers but also genes and chromosomes. The limiting factor in the use of markers in the diagnosis of endometrial cancer is their lack of specificity. However, specific markers for endometrial cancer are the subject of much research attention. Although moderately elevated levels of markers are present in a number of inflammatory or non-malignant diseases, significantly increased levels of markers indicate the development of cancer. Recently, research has been focused on the identification of molecular changes leading to different histological subtypes of endometrial cancer. In this paper the authors reviewed several currently investigated markers. Progress in these investigations is very important in the diagnostics and treatment of endometrial cancer. In particular, the identification of novel mutations and molecular profiles should enhance our ability to personalise adjuvant treatment with genome-guided targeted therapy. PMID- 27980532 TI - Corrigendum: Placebo Analgesia Changes Alpha Oscillations Induced by Tonic Muscle Pain: EEG Frequency Analysis Including Data during Pain Evaluation. AB - [This corrects the article on p. 45 in vol. 10, PMID: 27242501.]. PMID- 27980533 TI - Corrigendum: Predicting Essential Genes and Proteins Based on Machine Learning and Network Topological Features: A Comprehensive Review. AB - [This corrects the article on p. 75 in vol. 7, PMID: 27014079.]. PMID- 27980534 TI - Melioidosis parotitis in children. AB - A recent paper published in JVATiTD reporting a child in Hainan with parotitis caused by Burkholderia pseudomallei misleadingly described parotitis as a rare manifestation of melioidosis. In fact, it is one of the commonest forms of paediatric melioidosis seen in other parts of Southeast Asia, although interestingly not in Australia. PMID- 27980535 TI - The Capabilities and Limitations of Clinical Magnetic Resonance Imaging for Detecting Kidney Stones: A Retrospective Study. AB - The purpose of this work was to investigate the performance of currently available magnetic resonance imaging (MRI) for detecting kidney stones, compared to computed tomography (CT) results, and to determine the characteristics of successfully detected stones. Patients who had undergone both abdominal/pelvic CT and MRI exams within 30 days were studied. The images were reviewed by two expert radiologists blinded to the patients' respective radiological diagnoses. The study consisted of four steps: (1) reviewing the MRI images and determining whether any kidney stone(s) are identified; (2) reviewing the corresponding CT images and confirming whether kidney stones are identified; (3) reviewing the MRI images a second time, armed with the information from the corresponding CT, noting whether any kidney stones are positively identified that were previously missed; (4) for all stones MRI-confirmed on previous steps, the radiologist experts being asked to answer whether in retrospect, with knowledge of size and location on corresponding CT, these stones would be affirmed as confidently identified on MRI or not. In this best-case scenario involving knowledge of stones and their locations on concurrent CT, radiologist experts detected 19% of kidney stones on MRI, with stone size being a major factor for stone identification. PMID- 27980536 TI - Third-Generation Capsule Endoscopy Outperforms Second-Generation Based on the Detectability of Esophageal Varices. AB - Background and Aim. The third-generation capsule endoscopy (SB3) was shown to have better image resolution than that of SB2. The aim of this study was to compare SB2 and SB3 regarding detectability of esophageal varices (EVs). Methods. Seventy-six consecutive liver cirrhosis patients (42 men; mean age: 67 years) received SB3, and 99 (58 men; mean age, 67 years old) received SB2. All patients underwent esophagogastroduodenoscopy within 1 month prior to capsule endoscopy as gold standard for diagnosis. The diagnosis using SB3 and SB2 for EVs was evaluated regarding form (F0-F3), location (Ls, Lm, and Li), and the red color (RC) sign of EVs. Results. SB2 and SB3 did not significantly differ on overall diagnostic rates for EV. Sensitivity, specificity, positive predictive value, and negative predictive value of SB2/SB3 for EV diagnosis were, respectively, 65%/81%, 100%/100%, 100%/100%, and 70%/62%. However, the diagnostic rates for EV form F1 were 81% using SB3 and 52% using SB2 (P = 0.009). Further, the diagnostic rates for Ls/Lm varices were 79% using SB3 and 81% using SB2, and, for Li, varices were 84% using SB3 and 52% using SB2 (P = 0.02). Conclusion. SB3 significantly improved the detectability of EVs compared with SB2. PMID- 27980537 TI - Obstetricians/Gynecologists' Problems in Sickness Certification Consultations: Two Nationwide Surveys. AB - Objective. To explore experiences by physicians working in obstetrics, gynecology, or maternal healthcare (O/Gs) of problems in sickness certification consultations and differences between two years. Material and Methods. Answers by O/Gs to two Swedish nationwide surveys, in 2008 (n = 1037) and 2012 (n = 992), were analyzed for frequencies and severity of problems and organizational support in sickness certification consultations. Results. One-third of O/Gs found sickness certifications problematic every week. The most frequent problem was patients requesting sick notes for reasons other than work incapacity due to disease/injury (2008: 21%; 2012: 16%). The most problematic were assessing work capacity (2008 and 2012: 52%) and having different opinion from that of the patient about need for sick leave (2008: 51%; 2012: 46%). In 2012, 27% used the national sickness certification guidelines weekly, compared to 9% in 2008. A larger proportion in 2012 than 2008 reported that the guidelines facilitated contacts with patients and different stakeholders. Conclusions. Although O/Gs perceived sickness certification as problematic, there was less perceived severity of problems in 2012 compared to 2008, possibly because interventions regarding sickness certification have been introduced in Sweden recent years. Still, more organizational support, for example, time and supervision, are needed to enhance O/Gs' sickness certification practices. PMID- 27980538 TI - Gene mutations responsible for primary immunodeficiency disorders: A report from the first primary immunodeficiency biobank in Iran. AB - BACKGROUND: Primary immunodeficiency (PID) is a heterogeneous group of inheritable genetic disorders with increased susceptibility to infections, autoimmunity, uncontrolled inflammation and malignancy. Timely precise diagnosis of these patients is very essential since they may not be able to live with their congenital immunity defects; otherwise, they could survive with appropriate treatment. DNA biobanks of such patients could be used for molecular and genetic testing, facilitating the detection of underlying mutations in known genes as well as the discovery of novel genes and pathways. METHODS: According to the last update of the International Union of Immunological Societies (IUIS) classification, patients are registered in our biobank during a period of 15 years. All patients' data were collected via questionnaire and their blood samples were taken in order to extract and protect their DNA content. RESULTS: Our study comprised 197 patients diagnosed with PID. Antibody deficiency in 50 patients (25.4%), phagocytic defect in 47 patients (23.8%) and combined immunodeficiency with associated/syndromic feature in 19 patients (9.6%) were the most common PID diagnoses, respectively. The most common variant of PID in our study is common variable immunodeficiency, which accounted for 20 cases (10.1%), followed by chronic mucocutaneous candidiasis in 15 patients (7.9%) and congenital neutropenia in 13 patients (7%). Mean age at onset of disease was 4 years and mean age of diagnosis was 9.6 years. The average diagnostic delay was 5.5 years, with a range of 6 months to 46 years. Parental consanguinity and history of PID in family were observed in 70.2 and 48.9% of the patients, respectively. The majority of PID patients (93.3%) were from families with low socioeconomic status. CONCLUSION: This prospective study was designed to establish a PID Biobank in order to have a high quality DNA reservoir of these patients, shareable for international diagnostic and therapeutic collaborations. This article emphasizes the need to raise the awareness of society and general practitioners to achieve timely diagnosis of these patients and prevent current mismanagements. PMID- 27980539 TI - Aspergillus march: from ABPA to aspergilloma to subacute invasive aspergillosis. AB - BACKGROUND: Aspergillus is a ubiquitous fungus responsible for allergic as well as saprophytic and invasive manifestations depending on host's immune status. The following case report demonstrates progression of allergic manifestations of Aspergillus to its invasive form in an individual with decreasing immunity. This can lead to uncertainties in diagnosis and management. CASE PRESENTATION: A 28 year-old male, non smoker, known case of ABPA (allergic bronchopulmonary aspergillosis) was admitted with complaints of cough for 1 month, associated with recurrent episodes of hemoptysis for last 5 days. CT Thorax revealed homogenous dense round opacity in right upper lobe which replaced previous fibrocalcific bronchiectatic lesion with cavity and aspergilloma, bulging across the major fissure with fibrotic strands extending to periphery in all directions. Post pneumonectomy microscopic examination revealed Aspergillus hyphae invading blood vessels. CONCLUSION: There is a need for close clinical and radiologic follow up of patients with Aspergillus and our patient demonstrated overlap of complete spectrum of Aspergillus disease with march from one end to the other end. PMID- 27980540 TI - Comprehensive genetic testing for primary immunodeficiency disorders in a tertiary hospital: 10-year experience in Auckland, New Zealand. AB - BACKGROUND AND PURPOSE: New Zealand is a developed geographically isolated country in the South Pacific with a population of 4.4 million. Genetic diagnosis is the standard of care for most patients with primary immunodeficiency disorders (PIDs). METHODS: Since 2005, we have offered a comprehensive genetic testing service for PIDs and other immune-related disorders with a published sequence. Here we present results for this program, over the first decade, between 2005 and 2014. RESULTS: We undertook testing in 228 index cases and 32 carriers during this time. The three most common test requests were for X-linked lymphoproliferative (XLP), tumour necrosis factor receptor associated periodic syndrome (TRAPS) and haemophagocytic lymphohistiocytosis (HLH). Of the 32 suspected XLP cases, positive diagnoses were established in only 2 patients. In contrast, genetic defects in 8 of 11 patients with suspected X-linked agammaglobulinemia (XLA) were confirmed. Most XLA patients were initially identified from absence of B cells. Overall, positive diagnoses were made in about 23% of all tests requested. The diagnostic rate was lowest for several conditions with locus heterogeneity. CONCLUSIONS: Thorough clinical characterisation of patients can assist in prioritising which genes should be tested. The clinician-driven customised comprehensive genetic service has worked effectively for New Zealand. Next generation sequencing will play an increasing role in disorders with locus heterogeneity. PMID- 27980541 TI - Triple troubles selecting optimal therapy for atrial fibrillation patients undergoing percutaneous coronary interventions. PMID- 27980542 TI - Antithrombotic management in patients with percutaneous coronary intervention requiring oral anticoagulation. AB - The dynamic evolution of therapeutic options including the use of vitamin K antagonists (VKA), non-vitamin K oral anticoagulants (NOAC), more potent antiplatelet drugs as well as new generation drug-eluting stents could lead to the view that the current recommendations on the management of patients with percutaneous coronary intervention (PCI) requiring oral anticoagulation do not keep up with the results of several clinical studies published within the last 5 years. In the present overview, we summarize the recent advances in antithrombotic management used in atrial fibrillation patients undergoing PCI for stable coronary artery disease or acute coronary syndrome (ACS). The safety and efficacy of prasugrel and ticagrelor taken with oral anticoagulants also remain to be established in randomized trials; therefore the P2Y12 inhibitor clopidogrel on top of aspirin or without is now recommended to be used together with a VKA or NOAC. It is still unclear which dose of a NOAC in combination with antiplatelet agents and different stents should be used in this clinical setting and whether indeed NOAC are safer compared with VKA in such cardiovascular patients. Moreover, we discuss the use of anticoagulation in addition to antiplatelet therapy for secondary prevention in patients with ACS. To minimize bleeding risk in anticoagulated patients following PCI or ACS, the right agent should be prescribed to the right patient at the right dose and supported by regular clinical evaluation and laboratory testing, especially assessment of renal function when a NOAC is used. PMID- 27980543 TI - Triple anticoagulation therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention - real life assessment. AB - INTRODUCTION: Triple anticoagulation therapy (TT), comprising dual antiplatelet therapy (DAPT) and oral anticoagulation (OAC), is essential in atrial fibrillation (AF) patients after percutaneous coronary intervention (PCI), but it increases the bleeding risk. AIM: To assess TT models, in- and out-hospital bleeding and thromboembolic complications, and TT alterations. MATERIAL AND METHODS: During 12 months, consecutive AF post-PCI patients were scheduled for TT. Alterations in TT and thromboembolic events (death, myocardial infarction, ischemic stroke, in-stent thrombosis, peripheral embolization) were recorded. Major, non-major and minor bleeding episodes were assessed. RESULTS: One hundred and thirty-six out of 3171 patients, aged 73.0 +/-8.4 years (90 male), were included. Intra-hospitally, thrombotic events occurred in 9 (6.6%), while bleeding events occurred in 71 (52.2%) patients. Access-site hematoma and blood transfusions during in-hospital stay predisposed physicians to heparin administration as part of TT on discharge (p = 0.018 and p = 0.033 respectively). Eventually, DAPT plus warfarin or plus novel oral anticoagulant (NOAC) or plus low molecular weight heparin was prescribed in 72 (52.9%), 53 (39%), and 11 (8.1%) patients, respectively. HAS-BLED and CHA2DS2-VASc scores were similar between subgroups (p = 0.63 and p = 0.64 respectively). During 10.2 +/-4.2 months of follow-up, 11 (8.1%) deaths, and 9 (6.6%) non-fatal thromboembolic events occurred. Bleeding events occurred in 45 (34.6%) patients, including 14 (10.3%) major. TT was the only factor associated with increased risk of major bleeding (18.6% vs. 4.2%, p = 0.008). Early termination of any TT component, which concerned 59 (45.4%) patients, did not increase the risk of thromboembolic events (p = 0.89). CONCLUSIONS: Our study indicates that TT is associated with high mortality and bleeding rates in a relatively short period of time. Discontinuation of any TT drug did not increase the thromboembolic event rate, while it was associated with reduced risk of major bleeding. PMID- 27980544 TI - First-generation paclitaxel- vs. second-generation zotarolimus-eluting stents in small coronary arteries: the BASKET-SMALL Pilot Study. AB - INTRODUCTION: Event rates after percutaneous coronary interventions (PCI) are higher in small than large coronary vessels but may vary between different drug eluting stent (DES) types. AIM: To assess the efficacy of two different DES in small vessel disease. MATERIAL AND METHODS: Patients with small vessel PCI were randomised 1 : 1 to a first-generation paclitaxel- vs. a second-generation zotarolimus-eluting stent. The primary endpoint was a composite of cardiac death, non-fatal myocardial infarction, and target vessel revascularisation after 2 years. RESULTS: Overall, 191 patients were enrolled: 100 with a paclitaxel- and 91 with a zotarolimus-eluting stent. Baseline characteristics were similar in both groups. After 2 years, rates of the primary endpoint were numerically higher for zotarolimus- than paclitaxel-eluting stents (9.9% vs. 5.0%, hazard ratio 2.09, 95% confidence interval (CI) 0.7-6.2, p = 0.19), which was mainly driven by higher rates of target vessel revascularisation (6.6% vs. 2.0%, hazard ratio 3.39, 95% CI: 0.68-16.78, p = 0.14). Based on this, a total of 1,019 patients would be necessary to demonstrate at least non-inferiority between the DES used. CONCLUSIONS: In this pilot study, paclitaxel-eluting stents had a favourable efficacy profile in small vessel disease, although the numbers were too small to draw final conclusions. Based on the prohibitively high sample size for a randomized controlled trial between DES, other treatment options should be considered. PMID- 27980545 TI - Patient profile and periprocedural outcomes of bioresorbable vascular scaffold implantation in comparison with drug-eluting and bare-metal stent implantation. Experience from ORPKI Polish National Registry 2014-2015. AB - INTRODUCTION: There are limited data on the comparison of bioresorbable vascular scaffold (BVS) and drug-eluting stent (DES)/bare-metal stent (BMS) implantation in an unselected population of patients with coronary artery disease. AIM: To compare the periprocedural outcomes and patient profile of BVS and DES/BMS implantation in an all-comer population from the ORPKI Polish National Registry. MATERIAL AND METHODS: A total of 141,324 consecutive patients from 151 invasive cardiology centers in Poland were included in this prospective registry between January 2014 and June 2015. Periprocedural data on patients with at least one BVS (Absorb, Abbott Vascular, Santa Clara, CA, USA), DES or BMS (all available types) implantation in de novo lesions during index percutaneous coronary intervention for stable angina (SA) or acute coronary syndrome were collected. RESULTS: Bioresorbable vascular scaffold was the most often used in patients with SA, in single-vessel disease and in younger male patients. Bioresorbable vascular scaffold implantation was significantly more often associated with periprocedural administration of ticagrelor/prasugrel (6.8% vs. 3.6%; p = 0.001) and use of intravascular ultrasound and optical coherence tomography in comparison with the DES/BMS group (2.8% vs. 0.6% and 1.8% vs. 0.1%, respectively; p = 0.001 for both). The incidence of periprocedural death was significantly lower in the BVS group than the DES/BMS group (0.04% vs. 0.32%; p = 0.02), but this difference was no longer significant after adjustment for covariates. On the other hand, coronary artery perforation occurred significantly more often during BVS delivery (0.31% vs. 0.12%; p = 0.01), and BVS implantation was identified as an independent predictor of coronary artery perforation in multivariate logistic regression analysis (OR = 6.728, 95% CI: 2.394-18.906; p = 0.001). CONCLUSIONS: Patients treated with BVS implantation presented an acceptable safety and efficacy profile in comparison with the DES/BMS group. However, lower risk patients were the most frequent candidates for BVS implantation. PMID- 27980546 TI - Long-term quality of life and clinical outcomes in patients with resistant hypertension treated with renal denervation. AB - INTRODUCTION: Pharmacological treatment combined with lifestyle modifications is an effective treatment for arterial hypertension. However, there are still patients who do not respond to standard treatments. Patients with pharmacologically resistant hypertension may benefit from renal denervation (RDN). AIM: To assess long-term quality of life (QoL) after RDN and effectiveness in reduction of blood pressure (BP) in patients with resistant hypertension. MATERIAL AND METHODS: From 2011 to 2014, 12 patients with previously diagnosed resistant hypertension, treated by RDN, were included in this study. The QoL was assessed using a standardized Polish version of the Nottingham Health Profile questionnaire (NHP). RESULTS: The median age was 54 (IQR: 51-57.5) years. Mean baseline ambulatory pre-procedural systolic/diastolic BP was 188/115 +/-29.7/18 mm Hg. The mean values of systolic/diastolic BP measured perioperatively and 3, 6, 12 and 24 months postoperatively were 138/86, 138/85, 146/82, 152/86, and 157/91. All p-values for mean systolic and diastolic BP before versus successive time points after RDN were statistically significant; p-value for all comparisons < 0.05. Improvement of QoL was only observed in two sections of the NHP questionnaire: emotional reaction and sleep disturbance. The analysis of the NHP index of Distress (NHP-D) showed a lower distress level perioperatively and 3, 6, 12 and 24 months after RDN as compared to baseline. The RDN was not associated with any significant adverse events. CONCLUSIONS: Patients with pharmacologically resistant hypertension treated with RDN achieved significant reduction in BP during 24-month follow-up. Furthermore, a significant improvement in the QoL was observed in those patients. PMID- 27980547 TI - Neointima development in externally stented saphenous vein grafts. AB - INTRODUCTION: The main limitation of coronary artery bypass grafting (CABG) is rapid neointimal hyperplasia leading to graft failure. AIM: To assess plaque formation in saphenous vein grafts (SVG) covered by an external Dacron stent in comparison with the classical technique. MATERIAL AND METHODS: In the study group vein grafts covered by external stent mesh made of Dacron were implanted. An intravascular ultrasonography (IVUS) study was performed in 35 aorto-coronary SVG covered by an external Dacron stent and in 64 normal SVG during the first year after CABG. In each SVG 25 mm of good quality IVUS image, volumes of lumen, plaque (neointima), outer border of the vein graft (external SVG) and adventitia were calculated in three time periods: 0-130 days, 130-260 days and 260-390 days. RESULTS: Between the first and second time period, lumen volume (mm3) was reduced from 10.33 +/-4.4, to 6.80 +/-2.23 in the second period and 5.69 +/-1.26 in the third one. This effect was much less marked in normal grafts. The corresponding lumen volume (mm3) was: 10.90 +/-3.9, 9.15 +/-2.94 and 8.92 +/-2.93 in consecutive time periods. Plaque volume (mm3) did not change in control grafts during the course of the study, but it increased very significantly in stented grafts from 0.86 +/-1.24 in the first period to 2.70 +/-1.58 in the second and 3.29 +/-2.66 in the third one. CONCLUSIONS: The experimental technique of implanting SVG covered with an external elastic Dacron stent seems to be inferior to traditional ones. This is probably due to the more complicated process of vein implantation and higher micro-injury occurrence during the surgery. PMID- 27980548 TI - Transcatheter closure of ventricular septal defects using the Amplatzer Duct Occluder II device: a single-center experience. AB - INTRODUCTION: Off-label use of different devices has been described for percutaneous closure of ventricular septal defects (VSD) because of the unacceptable rate of post-procedure heart block associated with special VSD devices. AIM: To describe the early single-center clinical experience with closure of a VSD using the Amplatzer Duct Occluder II (ADO II) device in children. MATERIAL AND METHODS: Between May 2013 and June 2015, 26 patients between 13 days and 16 years of age underwent percutaneous closure of a VSD with an ADO II device at our institute. The decision to use the ADO II device was based primarily on lower risk of total atrioventricular block (TAVB) after VSD closure reported in the literature, reduction of the cost of the procedure and the need to close symptomatic VSDs in young patients. RESULTS: The location of the VSD was perimembranous in 21 patients, postsurgical residual in 2, midmuscular in 2 and apical muscular in 1. Complex procedures including newborn, combined procedures and postsurgical residual VSD were performed in 5 (19%) patients. The median duration of follow-up was 12 months. The complete VSD closure rate was 81% immediately after the procedure, 85% at 24 h, and 93% at the last follow-up. There was no device embolization. During the entire follow-up period, TAVB did not develop. CONCLUSIONS: The ADO II constitutes a safe and effective therapeutic alternative for morphologically varied VSDs in all pediatric age groups. A larger range of sizes and configurations of this occluder may be required to successfully occlude a wider range of VSDs. PMID- 27980549 TI - Leads dislodged into the pulmonary vascular bed in patients with cardiac implantable electronic devices. AB - INTRODUCTION: Spontaneous lead dislodgement into the pulmonary circulation is a rare complication of permanent pacing with unproven harmfulness and an indication of controversial class for transvenous lead extraction (TLE). AIM: To assess TLE safety in patients with leads dislodged into the pulmonary artery. MATERIAL AND METHODS: A retrospective analysis of a 9-year-old database of transvenous lead extraction procedures comprising 1767 TLEs was carried out, including a group of 19 (1.1%) patients with leads dislodged into the pulmonary artery (LDPA). RESULTS: Under univariate analysis the factors that increased the likelihood of the presence of an electrode in the pulmonary artery were mean lead dwelling time (increase of risk by 9% per year), total number of leads in the heart before TLE (increase of risk by 66% for one lead) and the number of abandoned leads (increase of risk by 119%). The presence of LDPA was associated with frequent occurrence of intracardiac lead abrasion (increase by 316%) and isolated lead related infective endocarditis (LRIE) (increase by 500%). There were no statistically significant differences in clinical (p = 0.3), procedural (p = 0.94) or radiological (p = 0.31) success rates in compared (LDPA and non-LDPA) groups. Long-term mortality after TLE was comparable in both groups. CONCLUSIONS: As the effectiveness and safety of TLE in patients with LDPA are comparable to those in standard TLE procedures, in our opinion, such patients should be considered TLE candidates. PMID- 27980550 TI - High prevalence of severe coronary artery disease in elderly patients with non operable chronic thromboembolic pulmonary hypertension referred for balloon pulmonary angioplasty. AB - INTRODUCTION: Balloon pulmonary angioplasty (BPA) is a new emerging catheter based alternative treatment option for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). AIM: To show that all elderly CTEPH patients referred for BPA are at higher risk of obstructive coronary artery disease and that, in daily practice, they should undergo invasive coronary angiography. MATERIAL AND METHODS: Eleven patients at the age of at least 65 years (6 males, 5 females, 77.2 +/-5.9 years) with confirmed non-operable type II or type III CTEPH, considered for BPA, underwent elective coronary angiography. Severe obstructive coronary artery disease (CAD) was diagnosed when stenosis of left main coronary artery >= 50% or stenosis of >= 70% of epicardial arteries was angiographically confirmed. We also screened for CAD consecutive age- and sex matched 114 PE survivors (52 males, 62 females, 74.8 +/-7.2 years) with excluded CTEPH. RESULTS: Severe CAD was more frequent in elderly patients with non operable type II or type III CTEPH candidates for BPA than in elderly acute PE survivors with excluded CTEPH (54.5% vs. 16.7%, p < 0.01), and therefore elderly CTEPH patients referred for BPA were at higher risk of CAD (OR = 5.9, 95% CI: 1.64-21.46, p = 0.007) when compared to elderly survivors after acute PE with excluded CTEPH. CONCLUSIONS: All elderly CTEPH patients referred for BPA are at higher risk of severe CAD and should routinely undergo invasive coronary angiography before BPA. PMID- 27980551 TI - COPeptin for diagnosis and prediction in Acute Coronary Syndrome (COPACS) Study: design and objectives. PMID- 27980552 TI - Clot injection for treatment of iatrogenic femoral arteriovenous fistula after percutaneous coronary intervention: a novel minimally invasive method. PMID- 27980553 TI - New treatment possibilities for patients with advanced coronary artery disease and critical limb ischemia - a feasibility study. PMID- 27980554 TI - Transient complete right bundle branch block following right heart catheterization in children - a report of two cases. PMID- 27980555 TI - Pentafurcation of left main coronary artery. PMID- 27980556 TI - Role of cardiac magnetic resonance in differentiating between acute coronary syndrome and apical hypertrophic cardiomyopathy. PMID- 27980557 TI - Prosthetic valve endocarditis after transcatheter CoreValve Evolut R bioprosthesis implantation. PMID- 27980559 TI - 17th Interventional Cardiology Workshop New Frontiers in Interventional Cardiology: December 8th, 2016, Krakow, Poland. PMID- 27980558 TI - Forty-two-year-old female patient with resistant hypertension, bilateral renal fibromuscular dysplasia and intracranial aneurysm. PMID- 27980560 TI - The present status of radiopharmaceuticals in the country. PMID- 27980561 TI - Terpene-loaded Liposomes and Isopropyl Myristate as Chemical Permeation Enhancers Toward Liposomal Gene Delivery in Lung Cancer cells; A Comparative Study. AB - Gene therapy is in its development stage as a novel method for cancer treatment. Liposomes look promising as gene delivery vectors; however, investigations have shown that these vesicles are not doing well in some cases. It was decided here to investigate the possibility of augmentation of liposomal gene delivery by chemical penetration enhancers. Cationic liposome containing antisense oligonucleotide (AsODN) against lung cancer was prepared by ethanol injection method. Liposomal cineole and limonene (as enhancers) were prepared by film hydration method. Isopropyl myristate (IPM) was also investigated as penetration enhancer. Liposomes were evaluated for their size, zeta potential and encapsulation efficiency. Cancer cells (A549) were pretreated with liposomal terpenes prior to treatment with liposomal antisense or scrambled oligonucleotide. Cell viability was evaluated by MTT assay. Oligonucleotide containing liposome showed particle size of about115 nm and zeta potential of 0.6 mV. Liposomal cineole significantly (P<0.05) increased specific activity of liposomal antisense but limonene didn't show such an effect. IPM increased both specific and non-specific cytotoxicity of Oligonucleotide. These results show that penetration enhancers (such as cineole) may be used for improving liposomal gene delivery and to reduce non-specific toxicity. Concentration and chemical nature of enhancer has prominent effect in their efficacy. PMID- 27980562 TI - Preparation, Properties and Preclinical Pharmacokinetics of Low Molecular Weight Heparin-modified Isoliquiritigenin-loaded Solid Lipid Nanoparticle. AB - Low molecular weight heparin-modified isoliquiritigenin-loaded solid lipid nanoparticle (LMWH-ISL-SLN) was developed for injective application. The morphological observation, particle diameter and zeta potential of LMWH-ISL-SLN were characterized using transmission electron microscopy (TEM) and a Malvern Zetasizer. Its entrapment efficiency (EE) and drug loading (DL) were determined by ultracentrifuge. The in-vitro release experiments were performed by dialysis technique. The cytotoxic effects of LMWH-ISL-SLN on Hep-G2 cell lines were determined using an MTT assay. Pharmacokinetic and tissue distribution studies were conducted in kunming mice after intravenous administration of LMWH-ISL-SLN. The average drug entrapment efficiency for LMWH-ISL-SLN was (99.80 +/- 3.27)%, drug loading was (18.68 +/- 1.51)%, mean particle size was (217.53 +/- 4.86) nm and zeta potential was (-18.24 +/- 2.47) mV. The in-vitro release experiments demonstrated isoliquiritigenin release from LMWH-ISL-SLN was in line with Weibull's distribution law. Hemolysis test and dose-related toxic effects proved that LMWH-ISL-SLN was a safe and non toxic product when given by intravenous injection. The pharmacokinetics results of LMWH-ISL-SLN showed that the area under the concentration-time curve (AUC0->infinity)of LMWH-ISL-SLN was greater than that for the isoliquiritigenin solution in plasma. Tissue distribution study indicated that ISL were mainly distributed in the liver and lung. In conclusion, low molecular weight heparin-modified SLN system is a promising carrier for the intravenous delivery of ISL. PMID- 27980563 TI - Physicochemical Evaluation of Lyophilized Formulation of p-SCN-Bn-DOTA- and p-SCN Bn-DTPA-rituximab for NHL Radio Immunotherapy. AB - Radioimmunotherapy (RIT) of Non-Hodgkin's lymphoma (NHL) is said to be more advantageous compared to unlabelled therapeutic antibodies. To this date, radiolabelled murine anti-CD20 mAbs, Zevalin(r) and Bexxar(r) have been approved for imaging and therapy. A preparation containing rituximab, chimeric mAb radio immunoconjugate suitable for Lu-177 labeling, could provide better imaging and therapeutic profile at the same time. This study was conducted to evaluate prepared lyophilized formulations of two rituximab immune conjugates, intended for immediate Lu-177 labeling, for imaging and therapy. The characterization of the conjugates and demonstration of the integrity of the protein and purity after conjugation and lyophilization was performed by SDS-PAGE, FT-IR and MALDI-TOF-MS. The results showed preserved antibody structure and average of 6.1 p-SCN-Bn-DOTA and 8.8 p-SCN-Bn-DTPA groups per antibody molecule which is suitable for successful labeling. These results support the possibility of developing a "ready to-label" rituximab immune conjugates for NHL imaging/therapy. PMID- 27980564 TI - Adsorption of Amlodipine at the Surface of Tosyl?Carbon Nanoparticles for Electrochemical Sensing. AB - The adsorption processes of amlodipine onto hydrophilic carbon nanoparticles (Emperor 2000TM) are investigated. The significant increase in voltammetric responses for pre-adsorbed amlodipine compared with those for solution confirms high affinity of amlodipine to carbon nanoparticles (possibly due to pi-pi stacking interaction between aromatic rings of amlodipine and surface-sulfonated carbon nanoparticles). To obtain the optimum of adsorption conditions, the effects of pH, agitation rate, and adsorption time are investigated. Under differential pulse voltammetry conditions, the peak current for the oxidation of amlodipine shows two linear relationships with concentration in the range from 1000 MUM to 10.0 MUM and 10.0 MUM to 10.0 nM. The limit of detection is estimated to be 1.0 nM. Determination of amlodipine in real samples such as human serum and commercial tablets is demonstrated. PMID- 27980565 TI - Synthesis and Acetylcholinesterase Inhibitory Evaluation of 4-(1,3 Dioxoisoindolin-2-yl)-N-Phenyl Benzamide Derivatives as Potential Anti-Alzheimer Agents. AB - Alzheimer?s disease is characterized by cognitive deficits, impaired long-term potentiation of learning and memory. A progressive reduction in cholinergic neurons in some areas of the brain such as cortex and hippocampus is related to the deficits in memory and cognitive function in Alzheimer's disease (AD). In the current project a new series of phthalimide derivatives were synthesized. Phthalic anhydride was reacted with 4-aminobenzoic acid in the presence of triethylamine under reflux condition. Then, the obtained acidic derivative was utilized for preparation of final compounds via an amidation reaction through a carbodiimde coupling reaction. Anti-acetylcholinesterase activity of synthesized derivatives was assessed by Ellman?s test. Compound 4g in this series exhibited the highest inhibitory potency (IC50 = 1.1 +/- 0.25 uM) compared to donepezil (IC50 = 0.41 +/- 0.12 uM) as reference drug. PMID- 27980566 TI - Synthesis and Docking Analysis of New Heterocyclic System N1, N4-bis (2 chloroquinolin-3-yl) methylene) benzene-1, 4-diamine as Potential Human AKT1 Inhibitor. AB - In recent years, the chemistry of 2-chloroquinoline-3-carbaldehydes have received considerable attention owing to their synthetic and effective biological importance which exhibits a wide variety of biological activity, N1,N4-bis((2 chloroquinolin-3-yl)methylene)benzene-1,4-diamine derivatives that synthesized from 2-chloroquinoline-3-carbaldehydes may have biological effects. As the inhibitor of AKT1 (RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1), the aforementioned compounds may have implication in preventing complications of cancers. A group of N1, N4-bis ((2-chloroquinolin 3-yl) methylene) benzene-1, 4-diamine derivatives (3a-3i) (H, 6-Me, 6-OMe, 6-OEt, 6-Cl, 7-Me, 6-Et, 6-Isopropyl, 7-Cl) were synthesized, and theoretically evaluated for their inhibitory as Potential Human AKT1 Inhibitors via docking process. The docking calculation was done in GOLD 5.2.2 software using Genetic algorithm. Compounds 3b (6-Me) and 3d (6-OEt) showed the best inhibitory potency by GOLD score value of 113.76 and 107.58 respectively. Some of the best models formed strong hydrogen bonds with Asn 49, Lys 220, Ser 157, Arg 225 and Trp 76 via quinoline moiety and nitrogen of quinolone ring (Figure 1.). pi-pi interaction between Lys 220, Trp 76, Tyr 224, Arg 225, Ile 80, and Asn 49 quinoline moiety was one of the common factor in enzyme-inhibitor junction. It was found that both hydrogen bonding and hydrophobic interactions are important in function of biological molecules, especially for inhibition in a complex. PMID- 27980567 TI - Synthesis, Characterization and Cytotoxicity of Alkylated Quercetin Derivatives. AB - Quercetin, a ubiquitous flavonol, represents a promising leading drug for development of new chemotherapeutic agents. However, its limited cytotoxicity to cancer cells hampers its clinical use. In order to obtain novel quercetin derivatives with superior cytotoxicity, seven alkylated quercetin derivatives were synthesized. Solubility of these derivatives was determined by turbidimetry. Cytotoxicity of the high-soluble derivatives against MCF-7 cells and caco-2 cells was determined using MTT assay. Among these seven products, 7-O-butylquercetin had the highest solubility in DMEM medium and 7-O-geranylquercetin had the most potent cytotoxicity. Further study on cytotoxicity of 7-O-geranylquercetin on NCI H446, A549, MGC-803 and SGC-7901 cell lines revealed potential antiproliferative effects. The 7-O-geranylquercetin is a broad spectrum cytotoxic agent and it may be a promising leading drug for cancer chemotherapy. PMID- 27980568 TI - Synthesis of Nocistatin C-terminal and it's Amide Derivatives as an Opioid Peptide. AB - A new biological active hexapeptide of C-terminal of nocistatin, contains Glu-Gln Lys-Gln-Leu-Gln sequence was synthesized according to solid phase peptide synthesis on the surface of 2-chloro tritylchloride resin and using fmoc protected amino acids in the presence of TBTU (O-(Benzotriazol-1-yl)-N,N,N',N' tetramethyl uranium tetrafluoroborate) as a coupling reagent. Then, amidation of the C-terminus of peptides was carried out using NH4Cl and alkyl ammonium chloride (RNH3Cl) in the presence of TBTU and a tertiary amine (DIPEA) as the base at room temperature in good to high yields. Cleavage of the desired peptides from the surface of the resin after the addition of TFA (1%) provided the protected peptides. All of the products were purified using preparative HPLC and structures were assigned according to MALDI-mass spectrometry data. PMID- 27980569 TI - A One-pot Condensation for Synthesis 2-methyl-4-phenylpyrano[3, 2-c] chromen 5(4H)-one and Synthesis of Warfarin by Ionic Liquid Catalysis. AB - The anticoagulant racemic warfarin is synthesized by the Michael addition of 4 hydroxycoumarin with benzalacetone in the present of equimolar amounts of imidazolium based ionic liquids [bmim] BF4 and [bmim] Br and other reaction solvents such as H2O, pyridine and ammonia in five different tests. Also synthesis of a derivative of warfarin (2-methyl-4-phenyl pyrano [3, 2-c] chromen 5(4H)-one) under solvent-free condition is reported. In this paper, we show the potential that ionic liquid have for the development of green methods for the formation of the C-C bond by reaction condensations without catalysts and organic solvents. A ?green method, according to the well-known principles, must reduce or eliminate the use or generation of unsafe substances. The work-up procedures were fairly simple and the products don>t require further purification. PMID- 27980571 TI - Simultaneous Chloramphenicol and Florfenicol Determination by A Validated DLLME HPLC-UV Method in Pasteurized Milk. AB - The antibiotic residues in milk are a well-known serious problem and pose several health hazards to consumers. We have described a simple, rapid, and inexpensive DLLME-HPLC/UV technique for the extraction of chloramphenicol and florfenicol residues in milk samples. Under the optimum conditions, linearity of the method was observed over the range 0.02-0.85 ug/L with correlation coefficients > 0.999. The proposed method has been found to have a good limit of detection (signal to noise ratio = 3) for chloramphenicol (12.5 ug/Kg) and florfenicol (12.2 ug/Kg), and precision with relative standard deviation values under 15% (RSD, n = 3). Good recoveries (69.1-79.4%) were obtained for the extraction of the target analytes in milk samples. This simple and economic method has been applied for analyses of 15 real milk samples. Among all samples only one of them was contaminated to florfenicol; 62.4 ug/Kg and contamination to chloramphenicol was not detected. PMID- 27980570 TI - A 99mTc-tricine-HYNIC-labeled Peptide Targeting the Melanocortin-1 Receptor for Melanoma Imaging. AB - Melanocortin-1 (MC1) receptor is an attractive melanoma-specific target for the development of alpha-MSH peptide based imaging and therapeutic agents. In this work a new lactam bridge alpha-MSH analogue was synthesized and radiolabeled with 99mTc via HYNIC chelator and tricine as co-ligand. Also, stability in human serum, receptor bound internalization and tissue biodistribution in tumor bearing nude mice were thoroughly investigated. Radiolabeling with 99mTc was performed at high specific activities (163MBq/nmol) with an acceptable labeling yield (>98%). The radioligand showed specific internalization into B16/F10 cells (13.35 +/- 0.9% at 4 h). In biodistribution studies, a receptor-specific uptake was observed in MC1 receptor positive organ so that after 4 h the tumor uptake was 4.51 +/- 0.11 % ID/g. Predominant renal excretion pathway with a highest accumulation of activity in tumor was observed for this radiopeptide. Obtained results show that the new designed labeled peptide conjugate can be a suitable candidate for diagnosis of metastatic melanomas. PMID- 27980572 TI - Stability Indicating HPLC Method for the Determination of Fulvestrant in Pharmaceutical Formulation in Comparison with Linear Sweep Voltammetric Method. AB - This paper describes two rapid, sensitive and specific methods for the determination of fulvestrant in pharmaceutical preparations by high performance liquid chromatography (HPLC) and linear sweep voltammetry (LSV). HPLC method was used to study the degradation behaviour. Fulvestrant was subjected to degradation under the conditions of hydrolysis (acid and alkali), oxidation (30% H2O2). The linearity was established over the concentration range of 5-50 m g mL-1 for LSV and 0.5-20 m g mL-1 for HPLC method. The intra- and inter-day relative standard deviation (RSD) was less than 3.96 and 3.07% for LSV and HPLC, respectively. Limits of quantification were determined as 5.0 and 0.50 m g mL-1 for LSV and HPLC, respectively. No interference was found from tablet excipients at the selected assay conditions. The methods were applied for the quality control of commercial fulvestrant dosage form to quantify the drug and to check the formulation content uniformity. PMID- 27980573 TI - UV-Vis Spectrophotometry and Multivariate Calibration Method for Simultaneous Determination of Theophylline, Montelukast and Loratadine in Tablet Preparations and Spiked Human Plasma. AB - Resolution of binary mixtures of theophylline (THEO), montelukast (MKST) and loratadine (LORA) with minimum sample pre-treatment and without analyte separation has been successfully achieved by multivariate spectrophotometric calibration, together with partial least-squares (PLS-1), principal component regression (PCR) and hybrid linear analysis (HLA). Data of analysis were obtained from UV-Vis spectra of three compounds. The method of central composite design was used in the ranges of 2-14 and 3-11 mg L-1 for calibration and validation sets, respectively. The models refinement procedure and their validation were performed by cross-validation. The minimum root mean square error of prediction (RMSEP) was 0.173 mg L-1 for THEO with PCR, 0.187 mg L-1 for MKST with PLS1 and 0.251 mg L-1 for LORA with HLA techniques. The limit of detection was obtained 0.03, 0.05 and 0.05 mg L-1 by PCR model for THEO, MKST and LORA, respectively. The procedure was successfully applied for simultaneous determination of the above compounds in pharmaceutical tablets and human plasma. Notwithstanding the spectral overlapping among three drugs, as well as the intrinsic variability of the latter in unknown samples, the recoveries are excellent. PMID- 27980575 TI - Assessment of AflatoxinM1 Contamination in UHT Flavored Milk Samples in Karaj, Iran. AB - This study was carried out to detect the presence of aflatoxin M1 (AFM1) in 30 UHT flavored milk samples in Karaj, Alborz province, Iran. High-performance liquid chromatography (HPLC) was applied to analyze AFM1 in the samples. The results showed that aflatoxin M1 was detected in all the UHT flavored milk samples, the AFM1 concentration ranged from 0.015 to 0.14 ug/L. Also, 10 samples (33.3%) were contaminated with more than 0.05 ug/L of European Union regulations for aflatoxin M1. Wherease, according to the proposed Iranian national standard and FDA (0.5 ug/L), none of the samples has not been contaminated more than the maximum AFM1 concentrations threshold. This is the first report discovering the fact that UHT flavored milk is an important contributor to the dietary intake of AFM1 in Iran. PMID- 27980574 TI - UHPLC-ESI-MS/MS and GC-MS Analyses on Phenolic, Fatty Acid and Essential Oil of Verbascum pinetorum with Antioxidant, Anticholinesterase, Antimicrobial and DNA Damage Protection Effects. AB - This paper is the first phytochemical and ABTS cation radical decolorisation activity, cupric reducing antioxidant capacity, anticholinesterase and DNA damage protection effect of endemic Verbascum pinetorum (Boiss.) O. Kuntze. Phenolic profile of V. pinetorum were qualified and quantified by UHPLC-ESI-MS/MS analysis. Malic acid (47250.61+/-2504.28 ug/g) and luteolin (7651.96+/-527.98 ug/g) were found as most abundant compounds for metanol and acetone extracts, respectively. Fatty acid and essential oil compositions were determined by GC-MS analysis. The main components of fatty acid were found to be palmitic (27.1%) and stearic (22.1%) acids. The main compounds of the essential oil were cineole (16.9%) and alpha-selinene (16.4%). The acetone extract was found to be more active than BHT used as a standard in beta-carotene-linoleic acid test system. In DPPH free radical scavenging activity, the acetone and methanol extracts showed higher activity than BHT at all tested concentrations. The acetone, methanol and water extracts showed strong inhibition while the acetone extract showed better activity than BHT and alpha-tocopherol which were used as standards in ABTS cation radical scavenging and cupric reducing antioxidant capacity assays, respectively. All extracts were found to be inactive in antialzheimer activity. The acetone extract exhibited moderate antimicrobial activity against C. albicans. The methanol extract of V. pinetorum were found no significant effect on DNA cleavage protection. PMID- 27980576 TI - Assessment of the Cytotoxic Effect of a Series of 1,4-Dihydropyridine Derivatives Against Human Cancer Cells. AB - Cancer is a leading cause of death worldwide. Despite the availability of several chemotherapeutic drugs, there is still a great need for more efficient agents for a better management of cancer. In this contribution, a series of 11 1,4 dihydropyridines (1,4-DHPs) (4a, 4b and 7a-i) were synthesized and evaluated for their cytotoxic effect against MCF-7, LS180 and MOLT-4 cancer cell lines using MTT assay. Synthesized 2,6-dimethyl-3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl 1,4-dihydropyridines exhibited different potencies ranging from weak to good cytotoxic activities, while no activity could be recorded for 1,4-bis(2,6 dimethyl-3,5-dialkyloxylcarbonyl,4-dihydropyridine-4-yl) benzene compounds (4a and 4b). Tested DHP derivatives were more potent against MOLT-4 cells, when compared to LS180 and MCF-7 cells. Compounds 7d (IC50 = 28.5 +/- 3.5 uM), 7a (IC50 = 29.7 +/- 4.7 uM) and 7a (IC50 = 17.4 +/- 2.0 uM) were the most potent derivatives against MCF-7, LS180 and MOLT-4 cells, respectively. It appeared that the introduction of N-thiazolyl carbamoyl group at the C3 and C5 positions of DHP ring enhanced the cytotoxic potential of these derivatives (compounds 7a-e). The findings of this study suggest that some of the thiazole substituted 1,4-DHPs may be candidates for further modifications towards the discovery of potent anticancer agents. PMID- 27980577 TI - New Aspects of Silibinin Stereoisomers and their 3-O-galloyl Derivatives on Cytotoxicity and Ceramide Metabolism in Hep G2 hepatocarcinoma Cell Line. AB - Ceramide as a second messenger is a key regulator in apoptosis and cytotoxicity. Ceramide-metabolizing enzymes are ideal target in cancer chemo-preventive studies. Neutral sphingomyelinase (NSMase), acid ceramidase (ACDase) and glucosyl ceramide synthase (GCS) are the main enzymes in ceramide metabolism. Silymarin flavonolignans are potent apoptosis inducers and silibinin is the most active component of silymarin. This study evaluated the effects of silybin A, silybin B and their 3-O-gallyl derivatives (SGA and SGB) at different concentrations (0-200 micro molar) on ceramide metabolism enzymes in Hep G2 hepatocarcinoma cell line. Cell viability, caspase-3 and 9 activities, total cell ceramide and the activities of ACDase, NSMase and GCS were evaluated. Under silibinin derivatives treatments, cell viability decreased and the activities of caspase-3 and 9 increased in a dose dependent manner among which SGB was the most effective one (P<0.05). Total cell ceramide and the activity of NSMase, the enzyme which elevates ceramide level, increased by silibinin derivatives. Furthermore, the activities of removing ceramide enzymes (ACDase and GCS) decreased efficiently. The galloyl esterification increased the activity of silibinin isomers. Consequently, this study reveals new sibilinin effects on ceramide metabolism and potential strategies to enhance the antineoplastic properties of this compound. PMID- 27980578 TI - L-Asparaginase Activity in Cell Lysates and Culture Media of Halophilic Bacterial Isolates. AB - The objective of this study was to isolate halophilic bacteria with the ability to produce intracellular or extracellular L-asparaginase. A total number of 120 halophilic bacteria were isolated from 17 different saline habitats of Iran including salt lakes, wetlands, brine springs and deserts. Among these, 68 were able to grow in the presence of 1.5 M NaCl and 52 demonstrated the ability to grow in the selection medium containing 3.5 M NaCl. None of the isolates appeared to produce appreciable amounts of extracellular L-asparaginase. Among the isolates that produced intracellular L-asparaginase, 5 moderate and 1 extreme halophiles were selected for further study based on their observed activity level. The moderately halophilic isolates were shown to belong to the genus Halomonas while the extreme halophile was identified as a member of the genus Aidingimonas. PMID- 27980579 TI - Laccase Activity in CTAB-Based Water-in-Oil Microemulsions. AB - The aim of this study was to develop a microemulsion system as a medium for laccase-catalyzed reactions. Phase behavior studies were conducted by constructing partial pseudo-ternary phase diagrams for systems comprising of cetyltrimethylammonium bromide (CTAB), various organic solvents as the oil phase (i.e., hexane, cyclohexane, heptane, octane, isooctane, toluene, isopropyl myristate), two co-surfactants (i.e., 1-butanol and 1-hexanol) and citrate buffer solution, at various surfactant/co-surfactant weight ratios (Rsm). A monophasic, transparent, non-birefringent area (designated as microemulsion domain) was seen to occur in some phase diagrams along the surfactant/organic solvent axis, the extent of which was dependent mainly upon the nature of co-surfactant and Rsm. On each phase diagram, three different water-in-oil (w/o) microemulsion systems with less than 50 wt% surfactant mixture and less than 20 wt% of aqueous phase were selected for laccase loading and activity measurements. Results revealed that the catalytic activity of laccase in CTAB-based w/o microemulsions decreased considerably, compared with its activity in the buffer solution, the extent of which depended upon the type of component and their compositions in the microemulsions. It was suggested that the conformational changes due to the electrostatic interactions between the cationic head group of CTAB and the negative enzyme might be the reason for the reduction of laccase activity, once entrapped in the microemulsion. PMID- 27980580 TI - Secondary Metabolites and Biological Activities of Talaromyces sp. LGT-2, an Endophytic Fungus from Tripterygium Wilfordii. AB - In the present study, eleven compounds (1-11) including nine alkaloids (1-9), one triterpenoid saponin (10) and one formamide (11) were isolated from Talaromyces sp. LGT-2, an endophytic fungus from Tripterygium wilfordi. Their structures were determined based on NMR and ESI-MS spectral data, as well as comparing previous literature data. This is the first report of the isolation of alkaloids (1-9) from Talaromyces genus. In the next step, all compounds were screened for their anti-monoamine oxidase, anti-acetylcholinesterase, antibacterial and antitumor activities. Compound 11 showed moderate anti-monoamine oxidase activity with IC50 value of 61 MUM; compounds 3, 4, 8 showed weaker anti-acetylcholinesterase activity; compounds 1, 3, 4, 7, 8, 9 showed moderate antibacterial activities; compounds 7, 8, 9 showed cytotoxicity against B16 cancer cell line with inhibitory rate of 86%, 82%, 78%, respectively, at the concentration of 500 MUg/mL. PMID- 27980581 TI - Developing a CoMSIA Model for Inhibition of COX-2 by Resveratrol Derivatives. AB - Design of selective cyclooxygenase-2 (COX-2) inhibitors is still a challenging task because of active site similarities between COX isoenzymes. To help with this issue, we tried to generate a 3D-QSAR (3 dimensional quantitative structure activity relationships) model that might reflect the essential features of COX-2 active sites. Compounds in a series of resveratrol derivatives inhibitors with reported biological activity against COX-2 were used to construct a predictive comparative molecular similarity indices (CoMSIA) model. A CoMSIA model with acceptable internal and external predictability was developed and employed to design new not yet synthesized molecules with improved activity and selectivity toward COX-2. Finally, molecular docking of the inhibitors in COX-2 active site demonstrated the possible ability of proposed compounds to inhibit COX-2, selectively. PMID- 27980582 TI - Chemical Constituents, Antimicrobial, Cytotoxicity, Mutagenic and Antimutagenic Effects of Artemisia ciniformis. AB - The aim of this study was to determine the chemical constituents, antimicrobial, cytotoxicity, mutagenic and anti-mutagenic activities of the essential oil of Artemisia ciniformis Krasch. & Popov ex Poljakov, against important bacterial pathogens and human cells which were unknown before. In-vitro cytotoxicity was measured using a modified MTT assay on normal human lymphocytes and tumor HeLa cells. The mutagenic and antimutagenic activities of the oil were evaluated using the Salmonellatyphimurium tester strains TA98 and TA100, together with nitrofluorene for TA98 and sodium azide for TA100 without (-S9) metabolic activation, and 2-aminoantracene for TA98 and TA100 with metabolic (+S9) activation. Oxygenated monoterpenes especially camphor (30.21%), 1,8-cineole (23.7%) and trans-Pinocarveol (12.28%) were the major components of the oil of A. ciniformis. Bactericidal kinetics of this oil indicated that Acinetobacter baumannii is the most vulnerable one (MIC = 0.02 mg/mL, MBC = 0.04 mg/mL, Dvalue = 3.57 min). The oil displayed an excellent cytotoxic action toward the human tumor cell line (IC50 = 19.64 ug/mL). The oil of A. ciniformis showed excellent antimutagenicity effect on the 2-nitrofluorene, in the strain of S. typhimurium TA98, without the presence of metabolic activation. PMID- 27980583 TI - Antiviral Profile of Brown and Red Seaweed Polysaccharides Against Hepatitis C Virus. AB - Hepatitis C virus (HCV) has infected 3% of the population worldwide and 20% of the population in Egypt. HCV infection can lead to hepatocellular carcinoma and death. The presently available treatment with interferon plus ribavirin, has limited benefits due to adverse side effects. Seaweeds have become a major source of new compounds to treat viral diseases. This work aimed to study the effect of four species of seaweeds as anti- HCV. The inhibition of lipid peroxidation was measured by evaluating the ability of seaweed extracts to scavenge the free radicals. The HepG2 cells were infected with the HCV and treated with each seaweed polysaccharide. Inhibition of viral replication was detected using the Real Time PCR (RT) qPCR. To explain the mode of the seaweed action on HCV, three modes of virus infections and seaweed polysaccharide treatments were applied. All treatments had the ability to inhibit the HCV with priority to Laurencia obtusa (82.36%), while the potentiality to scavenge the free radicals reached up to 81.5% with the Sargassumvulgare. Seaweed polysaccharide extracts may be helpful in exploring further gateways for antiviral therapy against HCV. PMID- 27980584 TI - Silymarin: A Novel Natural Agent to Restore Defective Pancreatic beta Cells in Streptozotocin (STZ)-induced Diabetic Rats. AB - This study aimed to investigate the potency of silymarin (SMN) and melatonin (MEL) on restoring the pancreatic cells in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were divided into five groups, including: control (C), untreated diabetic (D), SMN-treated diabetic (50 mg/Kg, orally), MEL-treated diabetic (10 mg/Kg, i.p.), and SMN plus MEL-treated diabetic rats. Diabetes was induced by injection of STZ (50 mg/Kg, i.p.). The blood glucose and insulin levels were measured. After the 28 days treatment period, antioxidant status was analyzed by determination of total antioxidant capacity (TAC) in the liver and serum. The histopathological changes in the pancreatic islets were examined by histochemical staining and enumeration of cells. Although none of the test compounds reduced the blood glucose level to normal concentration, however SMN alone and in combination with MEL was able to decline it significantly (P<0.05) after 28 days administration. Both SMN and MEL could recover the diabetes-reduced TAC values. Moreover, the diabetes-induced cellular vacuolation and cells depletion were improved by the SMN treatment. Our data suggest that the SMN and MEL treatment was able to normalize the antioxidant status, while only SMN administration could restore the cells of Langerhans islets in diabetic rats. PMID- 27980585 TI - Anticancer Effect of Ferulago Mughlea Pesmen (Apiaceae) on Cancer Cell Proliferation. AB - Ferulago W. Koch. (Apiaceae) genus is represented by approximately 50 taxa throughout the world. Ferulago species are known as "Caksir" or "Cagsir" in Turkey and mostly known for their aphrodisiac effects. However recent reports emphasize the activity of various Ferulago species against cancer, as well. The aim of this study was to investigate the effect of lyophilized extract of F. mughlea Pesmen, a species endemic for Turkey, on cancer cell proliferation. For this purpose human prostate (PC-3) and colorectal (SW-480) carcinoma cells were used to evaluate the antiproliferative effects of Ferulago W. Koch and the measurements were performed via MTT test. Lyophilized extracts obtained from aerial parts and the roots exhibited potent inhibitor effects on cell proliferation. Aerial part of the plant inhibited the proliferation of SW-480 cell at 48th hour with a 0.119 mg/mL IC50 value. PMID- 27980586 TI - Antiproliferative Activity and Apoptosis Inducing Mechanism of Anthocephalus cadamba on Dalton's Lymphoma Ascites Cells. AB - The purpose of this investigation was to evaluate the antiproliferative and apoptogenic mechanistic studies of methanol extract of Anthocephalus cadamba (MEAC) on Dalton's lymphoma ascites (DLA) cells treated mice. Determination of antiproliferative activity was performed by using different DLA cells (2*106 cells, i.p.) inoculated mice groups (n = 12). Groups were treated for 14 consecutive days with MEAC at the doses of 200 and 400 mg/Kg b.w. respectively. The mechanism of antiproliferation activity of MEAC was investigated through morphological studies by acridine orange (AO)/ethidium bromide (EB) double staining method. Comet assay was estimated to check the DNA damage induced apoptosis property. Furthermore, flow cytometry (FACS) was used to quantitatively detect the apoptotic rate by double labeling techniques using Annexin-V FITC/propidium iodide staining analysis and apoptotic proteins expression done by western blotting assay method. MEAC exhibited significant (p<0.01) decrease the tumor volume, viable cell count, tumor weight and elevated the life span of DLA tumor bearing mice. Analysis of AO/EB staining and flow cytometry showed that MEAC possessed apoptosis induced antitumor activity on DLA cells in a dose dependant manner. Dose dependent induction of DNA damage on DLA cells were observed after MEAC treatment, which was evident from the appearance of comet tail length. Pro-apoptotic gene, Bax was up-regulated and down-regulation of the Bcl-2/Bax ratio, suggesting that Bcl-2 family involved in the control of apoptosis. Experimental results revealed that MEAC possess potent antitumor activity via induction of cancer cell apoptosis mechanism. PMID- 27980588 TI - Evaluation of In Vitro Antimalarial Activity of Different Extracts of Eremostachys azerbaijanica Rech.f. AB - Six extracts with different polarity from aerial parts and rhizomes of Eremostachys azerbaijanica Rech.f., were screened for their antimalarial properties by cell free ??-hematin formation assay. Dichloromethane (DCM) extracts of both parts of plant showed significant antimalarial activities with IC50 values of 0.949 +/- 0.061 mg/mL in aerial parts and 0.382 +/- 0.011 mg/mL in rhizomes. Bioactivity-guided fractionation of the most potent part (DCM extract of rhizomes) by vacuum liquid chromatography (VLC) afforded seven fractions. Two fractions [100% Ethyl acetate (EtOAC) and 100% Methatol (MeOH)] showed considerable antimalarial activity with IC50 values of 0.335 +/- 0.033 mg/mL and 0.403 +/- 0.037 mg/mL, respectively. According to GC-MS analysis, the sesquiterpene, steroid and coumarin derivatives are the main constituents of the most potent fractions; therefore, it seems that the anti malarial activity of these fractions may be related to the presence of these types of compounds. PMID- 27980587 TI - Evaluation of the Antimalarial Effect of Ferulago angulata (Schlecht.) Boiss. Extract and Suberosin Epoxide Against Plasmodium berghei in Comparison with Chloroquine Using in-vivo Test. AB - Resistance to most antimalarial drugs has encouraged the development of novel drugs. An alternative source for discovering such drugs is natural products. Some Ferulago species are used in folk medicine for their sedative, tonic and anti parasitic effects. Besides, coumarins isolated from this genus found to have in vitro anti-leishmanicidal effect. The present study is aimed to evaluate the in vivo antimalarial activity of Ferulago angulata (Schlecht.) Boiss. extract and suberosin epoxide, using suarian mice. A rodent malaria parasite, Plasmodium berghei was used to inoculate healthy male Swiss Albino mice of age 6-8 weeks and weight 23-27 g. Hydro-alcoholic extract of F. angulata (20, 100, 300, 600 mg/Kg) and suberosin epoxide suspension (10, 30, 50, 100 mg/Kg) were administered subcutaneously. Parameters including percentage of parasitemia, suppression of parasitemia and mean survival time were determined using standard test such as peter?s. Chemo-protective effects were exerted by the crude extract and suberosin epoxide. Maximum effect was observed with the larger doses of the crude extract and suberosin epoxide. Suberosin epoxide increased the survival time compared to chloroquine. However, the results of this study indicate that the plant has a promising anti-plasmodial activity against plasmodium berghei. Thus, it could be considered as a potential source of new antimalarial agents. Suberosin epoxide at the dose of 100 mg/Kg possesses relatively significant antimalarial effect. Chemical derivatization of the parent compound or preparation of the modified formulation is required to improve its systemic bioavailability. PMID- 27980589 TI - Phytochemical and Biological Investigation of Clivia nobilis Flowers Cultivated in Egypt. AB - Amaryllidaceae is a well-known family for its high alkaloidal content. These alkaloids comprise a unique group of bases that have been found to occur in this family. The Amaryllidaceae alkaloids represent a large and still expanding group of isoquinoline alkaloids, the majority of which are not known to occur in any other family of plants. This article reports on the phytochemical investigation of the alkaloidal content of the flowers of clivia nobilis cultivated in Egypt which resulted in the isolation of four alkaloids; lycorine with pyrrolo{de}phenanthridine nucleus (lycorine-type) which is the common alkaloid of the amaryllidaceae family, clivatine and nobilisine, both with [2]benzopyrano (3,4-g) indole nucleus (lycorenine-type) and (+) 8-O-demethylmaritidine with 5,10b-ethanophenanthridine nucleus (crinine-type). Furthermore, the antimicrobial activity of the chloroform extract of the flowers of c. nobilis along with some of the isolated alkaloids has been studied. PMID- 27980590 TI - Study of the Effect of an Oral Formulation of Fig and Olive on Rheumatoid Arthritis (RA) Remission Indicators: A Randomized Clinical Trial. AB - This study was designed to explore the complementary effects of a combination formulation of olive oil, olive and fig fruits on RA remission indicators. A randomized controlled clinical trial was designed. Adult RA patients were randomly divided into two groups receiving routine Disease-modifying antirheumatic drugs (DMARDs) regimen (control group) and routine DMARDs regimen plus the herbal supplementary formulation of olive oil, fig and olive fruits (intervention group). Patients were followed every 4 weeks for total study period of 16 weeks. In addition to demographic and medical history of the patients, the Disease Activity Score with 28-joint counts based on Erythrocyte Sedimentation Rate (DAS28_ESR) were recorded. SPSS (version 22.0) software was used to analyze data, assuming p<0.05 as significance level. 56 patients (control = 27 and intervention = 29), with mean +/- sd age of 50.91 +/- 12.26 years completed the study. Repeated measures analysis revealed that differences between remission indicators in the two study groups were not statistically significant, however, there was a p = 0.03 for the within-subjects contrast test of the Patient Global Assessment (PtGA), approving a nonlinear change for PtGA with respect to time. No between groups differences in adjunct drug therapy pattern for disease flares were seen. In conclusion, although, non-significant changes in the study variable of DAS28_ESR is in agreement with few previous reports, nevertheless, trends in its reduction in the intervention group along with the significant delayed PtGA score improvements occurred in the intervention group convince us to suggest further investigations on the supplementary olive and fig products, with a longer follow up periods. PMID- 27980592 TI - Metoprolol Improves Endothelial Function in Patients with Cardiac Syndrome X. AB - Endothelial dysfunction which is manifested by the loss of nitric oxide bioavailability, is an increasingly recognized cause of cardiac syndrome X (CSX) and beta blockers are used for the treatment of this syndrome. Thus, the aim of this study was to investigate effects of metoprolol, as a beta blocker, on endothelial function in CSX patients. The study included 25 CSX patients (20 female/ 5 male, mean age: 55.36+/-10.31 years) who received metoprolol (50 mg BID) for one month. In addition, 25 healthy controls (20 female/ 5 male, mean age: 54.32 +/-9.27 years) were enrolled. Levels of endothelin-1, E-selectin, and vascular cell adhesion molecule-1 (VCAM-1) in controls and CSX patients were measured, both at the baseline and after the treatment, by the enzyme-linked immunosorbent assay. In CSX patients, at the baseline, levels of E-selectin and VCAM-1 were significantly higher than those of the controls. In addition, levels of these biomarkers in CSX patients after the treatment significantly decreased compared to the baseline. In spite of similar tendency, these differences were not significant for endothelin-1. In conclusion, metoprolol therapy improves endothelial function. Thus, it may be a suggested choice for CSX treatment. However, further studies are needed to confirm the clinical significance of metoprolol therapy for CSX patients. PMID- 27980591 TI - Effects of Resveratrol on Crosstalk between Canonical Beta-Catenin/Wnt and FOXO Pathways in Coronary Artery Disease Patients with Metabolic Syndrome: A Case Control Study. AB - Coronary artery disease (CAD) is the major cause of mortality and morbidity worldwide. The aim of this study was to explore the effect of resveratrol (RES) on Canonical beta-catenin/Wnt and forkhead box O (FOXO) pathways in CAD patients. We performed this study on 10 metabolic syndrome patients with three-vessel CAD and 10 sex-aged matched healthy subjects. The effects of RES on beta-Catenin, manganese superoxide dismutase (MnSOD), and peroxisome proliferator-activated receptor delta (PPAR-delta) expression were evaluated in peripheral blood mononuclear cells (PBMCs) of participants. RES could increase the MnSOD expression in CAD patients (38%, p < 0.0001). After RES treatment, the MnSOD expression of patients is still non-significantly lower than controls. In both blank and RES treatments, a significant positive correlation between beta-catenin and MnSOD mRNA expressions was found in controls, whereas no correlation between these gene expressions was found in untreated PBMCs of CAD patients. However, RES could modestly improve this pathway in CAD. RES could increase the MnSOD activity in healthy and CAD subjects (p = 0.051 and p = 0.009, respectively). Furthermore, in both blank and RES treatments, the significant correlation was found between total beta-catenin protein and the MnSOD activity in PBMCs of the controls but not in patients. The cross-talk between beta-catenin/Wnt and FOXO pathways was impaired in PBMCs of CAD patients. RES treatment could lead to a modest increase in the MnSOD activity independent of beta-catenin/FOXO pathway. Despite a modest improvement in the beta-catenin/FOXO pathway after RES treatment, this pathway was not completely repaired in CAD patients. PMID- 27980593 TI - The Impact of the Sanctions Made Against Iran on Availability to Asthma Medicines in Tehran. AB - The impact of the international sanctions on the Central Bank of Iran in 2013 and also accessibility of medicines in this country have received a lot of media coverage. In this study we used the data collected from a group of pharmacies all located in Tehran to assess the potential effects of the banking sanctions on access to asthma medicines. Data were collected from forty community pharmacies in Tehran, using a standard methodology proposed by the WHO and Health Action International. Data were collected in two stages: first before the sanctions were made against the banking system in the summer of 2012, and second after they were in effect in the summer of 2013, and they were analyzed using univariate analysis techniques. Several imported medicines were already in shortage during 2012. As a result of the sanctions, the availability of both imported and locally manufactured asthma medicines decreased by 19% and 42%, respectively. While before the height of the sanctions 60% of the pharmacies could provide all the essential asthma medicines, this number reduced to 28% after the sanctions (p value: 0.003). While studies about "access to medicines" in Iran prior to 2011 were indicating appropriate access, our findings suggested that the availability of asthma medicines in community pharmacies was already less than ideal in 2012 and declined dramatically after the latest wave of the sanctions. Our findings show the important effects of the sanctions on availability of asthma medications in community pharmacies. PMID- 27980595 TI - Flavonoids and Sesquiterpene Lactones from Artemisia absinthium and Tanacetum parthenium against Schistosoma mansoni Worms. AB - Human schistosomiasis, caused by trematode worms of the genus Schistosoma, is one of the most significant neglected tropical diseases, affecting more than 200 million individuals worldwide and praziquantel is the only available drug to treat this disease. Artemisia absinthium L. and Tanacetum parthenium L. are species popularly used as anthelmintics. We investigated the in vitro schistosomicidal activity of crude extracts of A. absinthium (AA) and T. parthenium (TP) and their isolated compounds. AA and TP, at 200 MUg/mL, were active, causing 100% mortality of all adult worms. Chromatographic fractionation of AA leads to isolation of artemetin and hydroxypelenolide, while santin, apigenin, and parthenolide were isolated from TP. Artemetin, hydroxypelenolide, santin, and apigenin, at 100 MUM, were inactive against adult worms. Parthenolide (12.5 to 100 MUM) caused 100% mortality, tegumental alterations, and reduction of motor activity of all adult worms of S. mansoni, without affecting mammalian cells. Confocal laser scanning microscopy showed tegumental morphological alterations and changes on the numbers of tubercles of S. mansoni worms. This report provides the first evidence for the in vitro activity of parthenolide against adult worms of S. mansoni, opening the route to further schistosomicidal studies with this compound. PMID- 27980596 TI - Parameters associated with design effect of child anthropometry indicators in small-scale field surveys. AB - BACKGROUND: Cluster surveys provide rapid but representative estimates of key nutrition indicators in humanitarian crises. For these surveys, an accurate estimate of the design effect is critical to calculate a sample size that achieves adequate precision with the minimum number of sampling units. This paper describes the variability in design effect for three key nutrition indicators measured in small-scale surveys and models the association of design effect with parameters hypothesized to explain this variability. METHODS: 380 small-scale surveys from 28 countries conducted between 2006 and 2013 were analyzed. We calculated prevalence and design effect of wasting, underweight, and stunting for each survey as well as standard deviations of the underlying continuous Z-score distribution. Mean cluster size, survey location and year were recorded. To describe design effects, median and interquartile ranges were examined. Generalized linear regression models were run to identify potential predictors of design effect. RESULTS: Median design effect was under 2.00 for all three indicators; for wasting, the median was 1.35, the lowest among the indicators. Multivariable linear regression models suggest significant, positive associations of design effect and mean cluster size for all three indicators, and with prevalence of wasting and underweight, but not stunting. Standard deviation was positively associated with design effect for wasting but negatively associated for stunting. Survey region was significant in all three models. CONCLUSIONS: This study supports the current field survey guidance recommending the use of 1.5 as a benchmark for design effect of wasting, but suggests this value may not be large enough for surveys with a primary objective of measuring stunting or underweight. The strong relationship between design effect and region in the models underscores the continued need to consider country- and locality-specific estimates when designing surveys. These models also provide empirical evidence of a positive relationship between design effect and both mean cluster size and prevalence, and introduces standard deviation of the underlying continuous variable (Z-scores) as a previously unexplored factor significantly associated with design effect. The magnitude and directionality of this association differed by indicator, underscoring the need for further investigation into the relationship between standard deviation and design effect. PMID- 27980597 TI - Alpha-mangostin from mangosteen (Garcinia mangostana Linn.) pericarp extract reduces high fat-diet induced hepatic steatosis in rats by regulating mitochondria function and apoptosis. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is caused by multiple factors including hepatic oxidative stress, lipotoxicity, and mitochondrial dysfunction. Obesity is among the risk factors for NAFLD alongside type 2 diabetes mellitus and hyperlipidemia. alpha- mangostin (alpha-MG) extracts from the pericarps of mangosteen (Garcinia mangostana Linn.) may regulate high fat diet-induced hepatic steatosis; however the underlying mechanisms remain unknown. The aim of this study was to investigate the regulatory effect of alpha-MG on high fat diet-induced hepatic steatosis and the underlying mechanisms related to mitochondrial functionality and apoptosis in vivo and in vitro. METHODS: Sprague Dawley (SD) rats were fed on either AIM 93-M control diet, a high-fat diet (HFD), or high-fat diet supplemented with 25 mg/day mangosteen pericarp extract (MGE) for 11 weeks. Thereafter, the following were determined: body weight change, plasma free fatty acids, liver triglyceride content, antioxidant enzymes (superoxide dismutase, SOD; glutathione, GSH; glutathione peroxidase, GPx; glutathione reductase GRd; catalase, CAT) and mitochondrial complex enzyme activities. In the in vitro study, primary liver cells were treated with 1 mM free fatty acid (FFA) (palmitate: oleate acid = 2:0.25) to induce steatosis. Thereafter, the effects of alpha-MG (10 MUM, 20 MUM, 30 MUM) on total and mitochondria ROS (tROS, mitoROS), mitochondria bioenergetic functions, and mitochondrial pathway of apoptosis were examined in the FFA-treated primary liver cells. RESULTS: The MGE group showed significantly decreased plasma free fatty acids and hepatic triglycerides (TG) and thiorbarbituric acid reactive substances (TBARS) levels; increased activities of antioxidant enzymes (SOD, GSH, GPx, GRd, CAT); and enhanced NADH-cytochrome c reductase (NCCR) and succinate-cytochrome c reductase (SCCR) activities in the liver tissue compared with HFD group. In the in vitro study, alpha-MG significantly increased mitochondrial membrane potential, enhanced cellular oxygen consumption rate (OCR), decreased tROS (total ROS) and mitoROS (mitochondrial ROS) levels ; reduced Ca2+ and cytochrome c (cyt c) release from mitochondria, and reduced caspases 9 and 3 activities compared with control group. CONCLUSION: These findings demonstrate alpha-MG attenuated hepatic steatosis in high fat-diet fed rats potentially through enhanced cellular antioxidant capacity and improved mitochondrial functions as well as suppressed apoptosis of hepatocytes. The findings of study represent a novel nutritional approach on the use of alpha-MG in the prevention and management of NAFLD. PMID- 27980594 TI - Health-Related Aspects of Milk Proteins. AB - Milk is an important component of a balanced diet and contains numerous valuable constituents. Considerable acclaimed health benefits of milk are related to its proteins, not only for their nutritive value but also for their biological properties. Scientific evidence suggests that anticarcinogenic activities, antihypertensive properties, immune system modulation, and other metabolic features of milk, are affiliated with its proteins (intact proteins or its derivatives). In this article, the main health-related aspects of milk proteins, such as anticarcinogenic, immunomodulatory, antimicrobial, anticariogenic, antihypertensive, and hypocholesterolemic effects are reviewed. Collectively, the findings indicate the effectiveness of milk proteins on reduction of risk factors for cancer, cardiovascular diseases and overall improvement of health aspects. PMID- 27980600 TI - Rose hip supplementation increases energy expenditure and induces browning of white adipose tissue. AB - BACKGROUND: Overweight and obesity are widespread chronic disorders defined as excessive fat accumulation, and are major risk factors for several chronic diseases including type 2 diabetes, coronary heart disease, high blood pressure and fatty liver. Changes in lifestyle such as increased physical activity and a healthy diet can be crucial tools for treating obesity. Intake of rose hip, the fruit of several plants belonging to the Rosaceae family, has been shown to reduce body fat mass and prevent body weight gain. Thus, the aim of the study was to elucidate potential mechanisms through which rose hip inhibit diet-induced obesity. METHODS: C57BL/6 J mice were fed a high fat diet with (RH) or without (CTR) rose hip supplementation for three months. In vivo indirect calorimetry was monitored, as well as gene expression and protein levels of different adipose depots. RESULTS: Although no differences in energy intake were found compared to the CTR group, RH prevented body weight gain and lowered blood glucose, insulin and cholesterol levels. Indirect calorimetry showed that RH-fed mice have significantly higher EE during the dark phase, despite comparable voluntary activity. Moreover, when challenged with treadmill running, RH-fed mice exhibited higher metabolic rate. Therefore, we hypothesized that RH could stimulate the brown adipose tissue (BAT) thermogenic capacity or may induce browning of the white adipose tissue (WAT). Compared to the CTR group, gene expression and protein levels of some brown and "brite" markers, together with genes able to promote brown adipocyte differentiation and thermogenesis (such as ucp1, tbx15, bmp7, and cidea), as well as phosphorylation of AMPK, was increased in WAT (but not in BAT) of RH-fed mice. CONCLUSIONS: Taken together these results indicate that dietary rose hip prevents body weight gain by increasing whole body EE and inducing browning of WAT. Thus, it has potential therapeutic implication for treatment of obesity and related metabolic disorders. PMID- 27980601 TI - Prevention of obesity by dietary resveratrol: how strong is the evidence? AB - Obesity is a pandemic problem worldwide. Dietary polyphenolic compounds show promise in preventing obesity. Resveratrol (RSV), one of the most extensively studied polyphenol compounds, has been shown to exert anti-obesity effects in various animal studies and also in several human studies. The fat-lowering effects of RSV may result from its ability to inhibit adipogenesis, suppress lipogenesis, stimulate lipolysis, promote apoptosis, and increase fatty acid oxidation and thermogenesis, as well as the recently demonstrated induction of the browning of white adipose tissue (WAT). These anti-obesity effects of RSV likely depend on its ability to activate AMP-activated protein kinase (AMPK), a key enzyme regulating cellular energy metabolism. Consumption of fruits such as berries, grapes and nuts, which contain high levels of RSV and other polyphenols, might help to reduce obesity. PMID- 27980598 TI - Phytochemicals as novel agents for the induction of browning in white adipose tissue. AB - Obesity and its associated metabolic syndrome continue to be a health epidemic in westernized societies and is catching up in the developing world. Despite such increases, little headway has been made to reverse adverse weight gain in the global population. Few medical options exist for the treatment of obesity which points to the necessity for exploration of anti-obesity therapies including pharmaceutical and nutraceutical compounds. Defects in brown adipose tissue, a major energy dissipating organ, has been identified in the obese and is hypothesized to contribute to the overall metabolic deficit observed in obesity. Not surprisingly, considerable attention has been placed on the discovery of methods to activate brown adipose tissue. A variety of plant-derived, natural compounds have shown promise to regulate brown adipose tissue activity and enhance the lipolytic and catabolic potential of white adipose tissue. Through activation of the sympathetic nervous system, thyroid hormone signaling, and transcriptional regulation of metabolism, natural compounds such as capsaicin and resveratrol may provide a relatively safe and effective option to upregulate energy expenditure. Through utilizing the energy dissipating potential of such nutraceutical compounds, the possibility exists to provide a therapeutic solution to correct the energy imbalance that underlines obesity. PMID- 27980599 TI - Effects of controlled doses of Oxyelite Pro on physical performance in rats. AB - BACKGROUND: OxyElite Pro (OEP) is a dietary supplement to increase metabolism which contains as key stimulant the ingredient 1,3-dimethylamylamine (DMAA). Serious adverse effects have been reported after OEP consumption however, these effects are related to poisoning or overdose. To our knowledge, no one studied the effects of OEP at controlled doses. Thus, the aim of this study was to evaluate acute and chronic OEP affects, at controlled doses in Wistar rats, on physical performance, metabolic parameters, liver injury markers and oxidative stress markers and mitochondrial biogenesis in skeletal muscle. METHODS: Rats were divided in control, 4.3 mg OEP/kg, 12.9 mg OEP/kg and 25.8 mg OEP/kg. All groups were submitted to supplementation with OEP for 4 weeks and the experimental protocols were performed 30 min after the first OEP administration (acute response) and 30 min after the last OEP administration at the end of the forth week (chronic response). RESULTS: Running distance and running time increased after acute administration of 12.9 mg OEP/kg (2.6-fold) and 25.8 mg OEP/kg (2.8-fold). Since no effect on the exercise tolerance test was observed at the lower OEP dose (4.3 mg OEP/kg), this group was removed from further analyzes. On other hand, running distance and running time decreased after daily supplementation for 4 weeks also in both groups (64% in 12.9 mg OEP/kg and 72% in 25.8 mg OEP/kg). Chronic supplementation at both 12.9 and 25.8 mg OEP/kg decreased TBARS levels in soleus muscle (36 and 31%) and liver (43 and 25%). AOPP was also decreased by both doses in the liver (39 and 45%). Chronic administration of the highest dose, 25.8 mg OEP/kg, was able to reduce mRNA expression of PGC-1alpha in soleus muscle (25%). No effect was found in other analyses such as spontaneous physical activity, body weight, food and water intake, hepatic toxicity, cardiac oxidative stress and mitochondrial DNA amount. CONCLUSION: Maximum and not recommended doses of OEP ingested acutely presented stimulating effect on the ability to exercise. However, its daily consumption for 4 weeks showed antioxidant effects in soleus muscle and liver which may have decreased the PGC-1alpha mRNA expression on soleus muscle and contributed to the impaired performance in the exercise tolerance test. PMID- 27980602 TI - Size-dependent protein segregation at membrane interfaces. AB - Membrane interfaces formed at cell-cell junctions are associated with characteristic patterns of membrane protein organization, such as E-cadherin enrichment in epithelial junctional complexes and CD45 exclusion from the signaling foci of immunological synapses. To isolate the role of protein size in these processes, we reconstituted membrane interfaces in vitro using giant unilamellar vesicles decorated with synthetic binding and non-binding proteins. We show that size differences between binding and non-binding proteins can dramatically alter their organization at membrane interfaces in the absence of active contributions from the cytoskeleton, with as little as a ~5 nm increase in non-binding protein size driving its exclusion from the interface. Combining in vitro measurements with Monte Carlo simulations, we find that non-binding protein exclusion is also influenced by lateral crowding, binding protein affinity, and thermally-driven membrane height fluctuations that transiently limit access to the interface. This simple, sensitive, and highly effective means of passively segregating proteins has implications for signaling at cell-cell junctions and protein sorting at intracellular contact points between membrane-bound organelles. PMID- 27980603 TI - A diagnostic bias might be a much simpler explanation for the apparently elevated risk for nasopharyngeal cancer with respect to formaldehyde. AB - In 2009, a working group of the International Agency for Research on Cancer classified formaldehyde as carcinogenic to humans (Group 1) and concluded that formaldehyde causes cancer of the nasopharynx (NPC) and leukemia. The results of a large cohort study of industrial workers exposed to formaldehyde, conducted by the U.S. National Cancer Institute, mainly contributed to the available body of epidemiologic evidence. In their recent updated re-analysis of these cohort data published in your journal, Dr Marsh and his colleagues concluded that the results of the original analysis of NPC-risk are misleading because they are based on inappropriate regression analyses. In our view the reason for the elevated NPC risk reported in the original analysis might be also another one - a diagnostic bias. Therefore, it would be very helpful if the authors provided results for all other sub-categories (as three-digit categories of the International Classification of Diseases) of the pharynx to verify the hypothesis described and, hence, to clarify the relationship between exposure to formaldehyde and the risk of NPC. PMID- 27980604 TI - Hydrofluoric acid burns in the western Zhejiang Province of China: a 10-year epidemiological study. AB - BACKGROUND: Chemical burns caused by hydrofluoric acid (HF) frequently occur in the Western Zhejiang Province. This study aimed to investigate the epidemiological characteristics of HF burns within this region. METHODS: A 10 year retrospective analysis was conducted using data from all inpatients with HF burns. These patients were treated at the Department of Burns and Plastic Surgery at our hospital between January 2004 and December 2013. Information obtained for each patient included sex, age, occupation, burn location, burn cause, and the hazard category of the chemical which caused the burn. Data regarding wound site and size, accompanying injuries, serum electrolyte levels, operations, length of hospital stay, and mortality were also assessed. RESULTS: A total of 201 patients (189 males, 12 females; average age: 38.33 +/- 10.57 years) were admitted due to HF burns. Over the 10-year period, the morbidity of HF burns in the past 10 years showed a gradual increase, which paralleled the development of local fluoride industries. Most HF injuries were work related and distributed in working-age patients. Aqueous HF solutions, especially highly concentrated ones, were the most common chemical cause of HF burns. Moreover, inappropriate operation, machine problems, and inadequate protection were identified as the leading causes of HF burns in the workplace. The burn area was <5% of TBSA in more than 90% of patients, and the most common burn sites were the head, neck, and upper extremities. Approximately 17% of patients underwent surgical operation. Accompanying injuries should be detected and treated correctly in a timely manner. Lastly, electrolyte imbalances, such as hypocalcaemia, hypomagnesaemia, and hypokalaemia, occurred frequently in patients with HF exposure; however, hyperkalaemia was not encountered in this study. CONCLUSION: Based on the epidemiological results for HF burns in this region, the related enterprises and local authorities should be encouraged to upgrade management policies and to provide necessary occupational hazard education and safety training for high-risk occupations within high-risk working populations. Furthermore, the enhancement of hazardous chemicals management is also needed. Finally, for patients with HF exposure, early and correct pre-hospital triage, treatment and consequent in hospital treatment and procedures should also be improved. PMID- 27980605 TI - Early newborn ritual foods correlate with delayed breastfeeding initiation in rural Bangladesh. AB - BACKGROUND: Early and exclusive breastfeeding may improve neonatal survival in low resource settings, but suboptimal breastfeeding still exists in areas with high infant mortality. Prelacteal feeding, the practice of giving a non breastmilk food as a neonate's first food, has been associated with suboptimal breastfeeding practices. We examined the association of feeding a non-breastmilk food in the first three days of life (early neonatal food, or ENF) with time from birth to initiation of breastfeeding among 25,286 Bangladeshi mother-neonate pairs, in a secondary analysis of a randomized controlled trial in northwestern rural Bangladesh conducted from 2001-2007. METHODS: Trained interviewers assessed the demographic characteristics during pregnancy. At three months postpartum, the interviewers visited participants again and retrospectively assessed demographic and breastfeeding characteristics surrounding the birth. We assessed the relationship between ENF and time to initiation of breastfeeding in hours in both unadjusted and adjusted linear regression analyses. We also calculated reverse cumulative distribution curves for time to initiation of breastfeeding and analyses were stratified by an infant's ability to breastfeed normally at birth. RESULTS: The mean +/- SD time from birth to initiation of breastfeeding was 30.6 +/- 27.9 hours. Only 2,535 (10.0%) of women reported initiating breastfeeding in the first hour after birth and 10,207 (40.4%) reported initiating breastfeeding in the first 12 hours after birth. In adjusted linear regression analyses, feeding ENF was associated with a significant increase in time, in hours, to breastfeeding initiation both among children not able to breastfeed at birth (37.4; 95% CI 33.3, 41.5) and among children able to breastfeed at birth (13.3; 95% CI 12.7, 14.0). CONCLUSIONS: Feeding ENF was strongly associated with delayed initiation of breastfeeding, even after adjusting for other related factors and stratifying on the neonate's ability to suckle normally after birth. More research is needed to understand the impact of these findings on optimal breastfeeding in this setting. It is possible that ENF feeding and the ability to breastfeed immediately after birth are interrelated in their respective associations to suboptimal breastfeeding initiation. This study in a large population representative of other populations in rural South Asia, demonstrates significantly longer times to breastfeeding initiation than previously appreciated, with a possible important role of ENF feeding. TRIAL REGISTRATION: The randomized controlled trial on which this analysis is based, "Impact of Maternal Vitamin A or Beta-Carotene Supplementation on Maternal and Infant Mortality in Bangladesh", was registered with ClinicalTrials.gov as trial number ID GHS-A-00-03-00019-00 and identifier NCT00198822. The identifier was first received September 12, 2005 (retrospectively registered). The first participant was enrolled in August 2001. PMID- 27980606 TI - The Role of Parvalbumin, Sarcoplasmatic Reticulum Calcium Pump Rate, Rates of Cross-Bridge Dynamics, and Ryanodine Receptor Calcium Current on Peripheral Muscle Fatigue: A Simulation Study. AB - A biophysical model of the excitation-contraction pathway, which has previously been validated for slow-twitch and fast-twitch skeletal muscles, is employed to investigate key biophysical processes leading to peripheral muscle fatigue. Special emphasis hereby is on investigating how the model's original parameter sets can be interpolated such that realistic behaviour with respect to contraction time and fatigue progression can be obtained for a continuous distribution of the model's parameters across the muscle units, as found for the functional properties of muscles. The parameters are divided into 5 groups describing (i) the sarcoplasmatic reticulum calcium pump rate, (ii) the cross bridge dynamics rates, (iii) the ryanodine receptor calcium current, (iv) the rates of binding of magnesium and calcium ions to parvalbumin and corresponding dissociations, and (v) the remaining processes. The simulations reveal that the first two parameter groups are sensitive to contraction time but not fatigue, the third parameter group affects both considered properties, and the fourth parameter group is only sensitive to fatigue progression. Hence, within the scope of the underlying model, further experimental studies should investigate parvalbumin dynamics and the ryanodine receptor calcium current to enhance the understanding of peripheral muscle fatigue. PMID- 27980608 TI - Human papillomavirus genotypes and HPV-16 variants distribution among Tunisian women with normal cytology and squamous intraepithelial lesions. AB - BACKGROUND: Little is known about the epidemiological characteristics of papillomavirus (HPV) infection among North African countries. Herein, we conducted a molecular epidemiological study to investigate prevalence of HPV type and HPV-16 variants among cervical-screened unvaccinated Tunisian women. METHODS: Cross-sectional study was performed on 494 Tunisian women visiting Women's Healthcare Centers. HPV-DNA detection was carried out on cervical samples using real-time polymerase chain reaction. HPV genotyping and HPV-16 variants were characterized by direct sequencing of L1 viral capsid gene. RESULTS: The overall HPV prevalence was 34% (95% CI: 30-38%) with significantly higher prevalence among women with squamous intraepithelial lesions (SIL) than those with no intraepithelial lesions (NIL) 84% (95% CI: 76-92%) and 24.5% (95% CI: 20-29%) respectively. The distribution of HPV prevalence according to women's age shows a U-shaped curve and the highest HPV prevalence rates were observed among the youngest (<=25 years; 51.2%, 95% CI: 37-67%) and the oldest women (>55 years; 41.7%, 95% The HPV-16 prevalence was 32.8% (95% CI: 22-45%) among women with SIL and 9.2% (95% CI: 6-12%) among women with NIL. Whereas, the HPV-18 prevalence was 1.3% (95% CI: 0-5%) among women with SIL and 0.3% (95% CI: 0-1%) among women with NIL. Among HPV-16 positive women, European lineage (E) was identified as the predominant HPV-16 variant (85.7%, 95% CI: 76-95%). The frequency of E variant was lower among SIL than among NIL women (81%, 95% CI: 64-99%, and 88%, 95% CI: 77-100%, respectively). Conversely, the African-2 variant frequency was higher among SIL than among NIL women (18%, 95% CI: 1-36% and 6%, 95% CI: 2-14%, respectively). In multivariate analysis, young age was the only risk factor that is independently associated with HPV infection. Moreover, HPV infection and menopause were both found to be independently associated with SIL and HSIL. CONCLUSION: HPV DNA testing should be proposed to young and menopausal Tunisian women. Considering HPV prevalence, only 13% of the Tunisian women could be protected by the bivalent HPV vaccine. These results may be helpful for designing an adapted HPV testing and vaccination program in Tunisia. PMID- 27980610 TI - African Organization for Research and Training in Cancer: position and vision for cancer research on the African Continent. AB - The African Organization for Research and training in Cancer (AORTIC) bases the following position statements on a critical appraisal of the state on cancer research and cancer care in Africa including information on the availability of data on cancer burden, screening and prevention for cancer in Africa, cancer care personnel, treatment modalities, and access to cancer care. PMID- 27980609 TI - Induction of VX2 para-renal carcinoma in rabbits: generation of animal model for loco-regional treatments of solid tumors. AB - BACKGROUND: Animal models of para-renal cancer can provide useful information for the evaluation of tumor response to loco-regional therapy experiments in solid tumors. The aim of our study was to establish a rabbit para-renal cancer model using locally implanted VX2 tumors. METHODS: In order to generate a rabbit model of para-renal cancer, we established four hind limb donor rabbits by using frozen VX2 tumor samples. Following inoculation, rabbits were monitored for appetite and signs of pain. Viable tumors appeared as palpable nodules within 2 weeks of inoculation. Tumor growth was confirmed in all rabbits by high-resolution ultrasound analysis and histology. Once tumor growth was established, hind limb tumors extraction was used for tumor line propagation and para-renal tumor creation. Twenty-one rabbit models bearing para-renal cancer were established by implanting VX2 tumor into the para-renal capsula. Tumors developed into discreet 2-3 cm nodules within 1-3 weeks of implantation. Serial renal ultrasonography follow-up, starting 1 week after tumor implantation, was performed. Two weeks after tumor implantation, rabbits were euthanized and tumors and other organs were collected for histopathology. RESULTS: Tumor growth after VX2 tumor fragment implantation was confirmed in all rabbits by high-resolution ultrasound (US) imaging examinations of the para-renal regions and was measured with digital caliper. The para-renal injection of VX2 tumor fragments, achieved tumor growth in 100% of cases. All data were confirmed by histological analysis. CONCLUSIONS: We generated for the first time, a model of para-renal cancer by surgical tumor implantation of VX2 frozen tumor fragments into rabbit's para-renal region. This method minimizes the development of metastases and the use of non-necrotic tumors and will optimize the evaluation of tumor response to loco-regional therapy experiments. PMID- 27980607 TI - Effects of Na+ Current and Mechanogated Channels in Myofibroblasts on Myocyte Excitability and Repolarization. AB - Fibrotic remodeling, characterized by fibroblast phenotype switching, is often associated with atrial fibrillation and heart failure. This study aimed to investigate the effects on electrotonic myofibroblast-myocyte (Mfb-M) coupling on cardiac myocytes excitability and repolarization of the voltage-gated sodium channels (VGSCs) and single mechanogated channels (MGCs) in human atrial Mfbs. Mathematical modeling was developed from a combination of (1) models of the human atrial myocyte (including the stretch activated ion channel current, ISAC) and Mfb and (2) our formulation of currents through VGSCs (INa_Mfb) and MGCs (IMGC_Mfb) based upon experimental findings. The effects of changes in the intercellular coupling conductance, the number of coupled Mfbs, and the basic cycle length on the myocyte action potential were simulated. The results demonstrated that the integration of ISAC, INa_Mfb, and IMGC_Mfb reduced the amplitude of the myocyte membrane potential (Vmax) and the action potential duration (APD), increased the depolarization of the resting myocyte membrane potential (Vrest), and made it easy to trigger spontaneous excitement in myocytes. For Mfbs, significant electrotonic depolarizations were exhibited with the addition of INa_Mfb and IMGC_Mfb. Our results indicated that ISAC, INa_Mfb, and IMGC_Mfb significantly influenced myocytes and Mfbs properties and should be considered in future cardiac pathological mathematical modeling. PMID- 27980611 TI - Seasonality in mood and behaviours of Japanese residents in high-latitude regions: transnational cross-sectional study. AB - BACKGROUND: Daylight hours in high-latitude regions tend to be longer than those in Japan in summer, and shorter than those in Japan in winter. For example, daylight hours in London in winter are one-third those of Tokyo. Therefore, this study investigated and compared seasonal changes in mood and behaviours of Japanese individuals living in and outside Japan. METHODS: Surveys were conducted with Japanese residents in summer and winter in the UK (n = 106), Nordic countries (n = 40), Southeast Asia (n = 50), and Japan (n = 96). First, summer and winter General Health Questionnaire-28 (GHQ28) scores of each regional group were analysed. Subsequently, month-wise differences in mood and behaviours were compared across the four geographical regions. RESULTS: Summer and winter GHQ28 scores of participants living in the UK and Nordic countries differed significantly, while no seasonal differences were observed for residents in Japan and Southeast Asia. Further, in the UK and Nordic countries, summer was associated with better mood and more activity, while winter was linked to lowered mood and reduced activity. CONCLUSION: The results indicate that Japanese living in the UK and Nordic countries (high-latitude regions) experience seasonal fluctuations in depressive symptoms that may be linked to drastic seasonal environmental changes. Observed over a 12-month period, their mood and behaviour declined in winter and improved in summer. Therefore, considering the prevalence of overseas stressors that differ from those in their home country, it is necessary to investigate the effectiveness of support systems that help migrants adapt to seasonal changes in high-latitude regions. PMID- 27980612 TI - Comorbidity of depression and diabetes: an application of biopsychosocial model. AB - BACKGROUND: Type 2 diabetes (T2D) is one of the most psychologically demanding chronic medical illness in adult. Comorbidity between diabetes and depression is quite common, but most studies were based on developed country sample. Limited data exists to document biopsychosocial predictors of depressive symptoms in Ethiopian patients. Therefore, the aim of the study was to describe the association of depressive symptoms and T2D and explore the potential underlying associated biopsychosocial risk factors. METHODS: Institution based cross sectional study was conducted on 276 patient with T2D at diabetic clinic, Black Lion General Specialized Hospital in Ethiopia. Patients were selected using systematic random sampling technique. Depressive symptoms score, which constructed from a validated nine-item Patient Health Questionnaire (PHQ-9), was an outcome variable. Finally, significant associated factors were identified using multiple linear regression analysis with backward elimination procedure. Statistical Package for Social Science (SPSS) version 22.0 (IBM SPSS Corp.) was used to perform all analysis. RESULTS: Total of 264 patient data was analyzed with 95.7% response rate. Patients mean (SD) current age and age at diagnosis was 55.9 (10.9) and 43.9 (10.9) years, respectively. Patients waist circumference (mean +/- SD) was 98.9 +/- 11.1 cm. The average PHQ-9 score was 4.9 (SD 4.1) and fasting blood glucose was 166.4 (SD 73.2). Marital status (divorced), occupation (housewife), diabetic complication (nephropathy), negative life event in the last six months, and poor social support significantly associated with increased mean PHQ-9 score after adjustment for covariates. Whereas not fearing diabetic-related complication and death significantly lower mean PHQ-9 score. CONCLUSION: Biopsychosocial variables including marital status, negative life event in the last 6 months, occupation, diabetic complication, and poor social support significantly increase average depressive symptoms score. Evidence-based intervention focusing on these identified biopsychosocial factors are necessary to prevent the development of depressive symptoms. PMID- 27980615 TI - Using gene expression data to identify causal pathways between genotype and phenotype in a complex disease: application to Genetic Analysis Workshop 19. AB - We explore causal relationships between genotype, gene expression and phenotype in the Genetic Analysis Workshop 19 data. We compare the use of structural equation modeling and a Bayesian unified framework approach to infer the most likely causal models that gave rise to the data. Testing an exhaustive set of causal relationships between each single-nucleotide polymorphism, gene expression probe, and phenotype would be computationally infeasible, thus a filtering step is required. In addition to filtering based on pairwise associations, we consider weighted gene correlation network analysis as a method of clustering genes with similar function into a small number of modules. These modules capture the key functional mechanisms of genes while greatly reducing the number of relationships to test for in causal modeling. PMID- 27980613 TI - Genetic Analysis Workshop 19: methods and strategies for analyzing human sequence and gene expression data in extended families and unrelated individuals. AB - Genetic Analysis Workshop 19 provided a platform for developing and evaluating statistical methods to analyze whole-genome sequence and gene expression data from a pedigree-based sample, as well as whole-exome sequence data from a large cohort of unrelated individuals. In this article we present an overview of the data sets, the GAW experience, and summaries of the contributions arranged into nine methodological themes. PMID- 27980614 TI - Omics-squared: human genomic, transcriptomic and phenotypic data for genetic analysis workshop 19. AB - BACKGROUND: The Genetic Analysis Workshops (GAW) are a forum for development, testing, and comparison of statistical genetic methods and software. Each contribution to the workshop includes an application to a specified data set. Here we describe the data distributed for GAW19, which focused on analysis of human genomic and transcriptomic data. METHODS: GAW19 data were donated by the T2D-GENES Consortium and the San Antonio Family Heart Study and included whole genome and exome sequences for odd-numbered autosomes, measures of gene expression, systolic and diastolic blood pressures, and related covariates in two Mexican American samples. These two samples were a collection of 20 large families with whole genome sequence and transcriptomic data and a set of 1943 unrelated individuals with exome sequence. For each sample, simulated phenotypes were constructed based on the real sequence data. 'Functional' genes and variants for the simulations were chosen based on observed correlations between gene expression and blood pressure. The simulations focused primarily on additive genetic models but also included a genotype-by-medication interaction. A total of 245 genes were designated as 'functional' in the simulations with a few genes of large effect and most genes explaining < 1 % of the trait variation. An additional phenotype, Q1, was simulated to be correlated among related individuals, based on theoretical or empirical kinship matrices, but was not associated with any sequence variants. Two hundred replicates of the phenotypes were simulated. The GAW19 data are an expansion of the data used at GAW18, which included the family-based whole genome sequence, blood pressure, and simulated phenotypes, but not the gene expression data or the set of 1943 unrelated individuals with exome sequence. PMID- 27980616 TI - Genetic complexity at expression quantitative trait loci. AB - BACKGROUND: Identifying variants that regulate gene expression and delineating their genetic architecture is a critical next step in our endeavors to better understand the genetic etiology of complex diseases. The appropriate genomic tools are in place, and preliminary analytic strategies have been developed. METHODS: Here we used Genetic Analysis Workshop (GAW) 19 data to investigate the genetic complexity of expression quantitative trait loci (eQTL), chromosomal regions likely to harbor regulatory elements responsible for gene expression. For this investigation, we analyzed the lymphocyte expression profiles of 653 individuals in 20 pedigrees who were also genotyped by single nucleotide polymorphism (SNP) arrays, followed by sequencing and imputation. We used these data to examine the degree of allelic heterogeneity, a contributor to genetic complexity at eQTL, by sequentially conditioning on the most significantly associated SNPs. RESULT: SOLAR (Sequential Oligogenic Linkage Analysis Routines) MGA (measured genotype approach) and FaST-LMM (Factored Spectrally Transformed Linear Mixed Model) software allowed us to analyze pedigree data. The power and Type 1 error rates for single SNP association testing and multiple SNP sequential association testing were consistent for these programs. Sequential conditioning of the real expression data revealed substantial levels of allelic heterogeneity at the 2 eQTL examined, illustrating this feature of genetic complexity. CONCLUSIONS: eQTL exhibit substantial genetic complexity among and within pedigrees. PMID- 27980617 TI - Factors associated with heterogeneity in microarray gene expression in peripheral blood mononuclear cells from large pedigrees. AB - BACKGROUND: Genome-wide microarray expression is a rich source of functional genomic data. We examined evidence for differences in expression from peripheral blood mononuclear cells between individuals, examined some of factors that may be responsible and provide recommendations for analysis. METHODS: A total of 643 individuals from 17 large Mexican American pedigrees had microarray gene expression data generated from peripheral blood mononuclear cells. This data has previously been used to map cis- and trans-expression quantitative trait loci using genome-wide linkage analysis. We estimated both principal components and cell proportions in these data, and tested them for association with clinical factors to provide insight into causes of variation in gene expression between individuals. RESULTS: We identified that there were highly significant differences in the second principal component of gene expression between pedigrees, with 3 pedigrees being outliers. The estimated cell proportions identified 1 individual who was a gross outlier, as well as pedigrees that differed from others in their estimated proportions of helper and cytotoxic T cells. CONCLUSIONS: These phenomena could be from either pedigree-specific genetic variation, technical artefacts, or clinical factors. Incorporating factors that influence gene expression into genetic analysis, and exclusion of outliers could improve the power of genetic mapping of expression traits. PMID- 27980618 TI - Examination of previously identified associations within the Genetic Analysis Workshop 19 data. AB - We investigate the possible replication of "known" associated single-nucleotide polymorphisms (SNPs) with blood pressure and expression phenotypes. Previous studies have provided a list of 95 SNPs thought to be associated with blood pressure phenotypes, of which 44 were present in the Genetic Analysis Workshop 19 (GAW19) family-imputed genome-wide association studies (GWAS) data and 4 in the GAW19 unrelateds sequence data. Using only the real (not simulated) GAW19 data, we show through the use of statistical tests that account for family relatedness, using FaST-LMM (Factored Spectrally Transformed Linear Mixed Model), that none of our candidate SNPs yields a significant p value. Furthermore, a study of epistasis, aiming to detect statistical interactions between loci with respect to their association with transcription levels has provided a list of 30 associated interacting SNP pairs, of which 13 are present in the GAW19 family GWAS and expression data. We show for this set of results, using the program GEMMA (genome wide efficient mixed-model analysis) to account for family relatedness, that there is evidence of replication within the real GAW19 data. Two individual SNP pairs reach significance, and the set of remaining results give a combined p value of 0.017 that at least 1 of these remaining SNP pairs interacts to influence an expression phenotype. PMID- 27980619 TI - Finding potential cis-regulatory loci using allele-specific chromatin accessibility as weights in a kernel-based variance component test. AB - We present a novel approach to detect potential cis-acting regulatory loci that combines the functional potential, an empirical DNase-seq based estimate of the allele-specificity of DNase-I hypersensitivity sites, with kernel-based variance component association analyses against expression phenotypes. To test our method we used public ENCODE whole genome DNase-I sequencing data, from a single sample, to estimate the functional potentials of the subset of 10,552 noncoding heterozygous single-nucleotide polymorphisms (SNPs) that were also present in the Genetic Analysis Workshop 19 (GAW19) family-based data set. We then built two covariance kernels, one nonweighted and one weighted by the functional potentials, and conducted kernel-based variance component association analyses against the 20,527 transcript expression phenotypes in the GAW19 family-based data set. We found signals of potential cis-regulatory effects, that surpassed the Bonferroni significance threshold, for ten transcripts. Stepwise removal of the cis-located SNPs from the weighted kernel lead to the disappearance of the association signal from our top transcript hit. We found compelling evidence of allele-specific cis-regulation for four transcripts using both kernels, and our results agree with previous research that suggests the involvement of specific cis-located variants in the regulation of their neighboring gene. PMID- 27980620 TI - Association of genetic variations and gene expression in a family-based study. AB - BACKGROUND: Expression quantitative trait locus (eQTL) maps are considered a valuable resource in studying complex diseases. The availability of gene expression data from the Genetic Analysis Workshop 19 (GAW19) provides a great opportunity to investigate the association of gene expression with genetic variants in blood. METHODS: A total of 267 samples with gene expression and whole genome sequencing data were employed in this study. We used linear mixed models with genetic random effects along with a permutation procedure to create an eQTL map. The eQTL map was further tested in terms of functional implication, including the enrichment in disease-related variants and in regulatory regions. RESULTS: We identified 22,869 significant eQTLs from the GAW19 data set. These eQTLs were highly enriched with genetic loci associated with blood pressure and DNase hypersensitive regions. In addition, the majority of genes associated with eQTLs showed moderate to high heritability (h2 > 0.4). CONCLUSIONS: We successfully created an eQTL map from the GAW19 data set. Our study indicated that the eQTLs were enriched within regulatory regions, and tended to have relatively high heritability. PMID- 27980621 TI - Analysis of gene expression to predict dynamics of future hypertension incidence in type 2 diabetic patients. AB - BACKGROUND: The main focus of the Genetic Analysis Workshop 19 (GAW19) is identification of genes related to the occurrence of hypertension in the cohort of patients with type 2 diabetes mellitus (T2DM). The aim of our study was to predict dynamics of the future hypertension incidence, based on gene expression profiles, systolic and diastolic blood pressure changes in time, sex, baseline age, and cigarette smoking status. We analyzed data made available to GAW19 participants, which included gene expression profiles of peripheral blood mononuclear cells (PBMCs) from the diabetic members of 20 Mexican American families. METHODS: On the basis of mid blood pressure measurements at several time points, the coefficient of regression (slope) was calculated for each individual. We corrected the slope value in patients treated with antihypertensive medications. Feature preprocessing methods were used to remove highly correlated probes and linear dependencies between them. Subsequently, multiple linear regression model was used to associate gene expression with the regression coefficient calculated for each T2DM patient. Tenfold cross-validation was used to validate the model. We used linear mixed effects model and kinship coefficients to account for the family structure. All calculations were performed in R. RESULTS: This analysis allowed us to identify 6 well-annotated genes: RTP4, FXYD6, GDF11, IFNAR1, NOX3, and HLA-DQ2, associated with dynamics of future hypertension incidence. Two of them, IFNAR1 and NOX3 were previously implicated in pathogenesis of hypertension. CONCLUSIONS: There is no obvious mechanism that links all detected genes with dynamics of hypertension incidence. Identification of possible connection with hypertension needs further investigation. PMID- 27980622 TI - Gene coexpression network analysis for family studies based on a meta-analytic approach. AB - For a better understanding of the biological mechanisms involved in complex traits or diseases, networks are often useful tools in genetic studies: coexpression networks based on pairwise correlations between genes are commonly used. In case of a family-based design, it can be problematic when there is a large between-family variation in expression levels. We propose here a gene coexpression network analysis for family studies. We build a coexpression network for each family and then combine the results. We applied our approach to data provided for analysis in the Genetic Analysis Workshop 19 and compared it to 2 naive approaches-ignoring correlations among the expressions and decorrelating the gene expression by using the residuals of a mixed model-and a single-probe analysis. Our approach seemed to better deal with heterogeneity with regard to the naive approaches. The naive approaches did not provide any significant results, while our approach detected genes via indirect effects. It also detected more genes than the single-probe analysis. PMID- 27980623 TI - Genome-wide joint analysis of single-nucleotide variant sets and gene expression for hypertension and related phenotypes. AB - BACKGROUND: With the advance of next-generation sequencing technologies, the study of rare variants in targeted genome regions or even the whole genome becomes feasible. Nevertheless, the massive amount of sequencing data brings great computational and statistical challenges for association analyses. Aside from sequencing variants, other high-throughput omic data (eg, gene expression data) also become available, and can be incorporated into association analysis for better modeling and power improvement. This motivates the need of developing computationally efficient and powerful approaches to model the joint associations of multilevel omic data with complex human diseases. METHODS: A similarity-based weighted U approach is used to model the joint effect of sequencing variants and gene expression. Using a Mexican American sample provided by Genetic Analysis Workshop 19 (GAW19), we performed a whole-genome joint association analysis of sequencing variants and gene expression with systolic (SBP) and diastolic blood pressure (DBP) and hypertension (HTN) phenotypes. RESULTS: The whole-genome joint association analysis was completed in 80 min on a high-performance personal computer with an i7 4700 CPU and 8 GB memory. Although no gene reached statistical significance after adjusting for multiple testing, some top-ranked genes attained a high significance level and may have biological plausibility to hypertension-related phenotypes. CONCLUSIONS: The weighted U approach is computationally efficient for high-dimensional data analysis, and is capable of integrating multiple levels of omic data into association analysis. Through a real data application, we demonstrate the potential benefit of using the new approach for joint association analysis of sequencing variants and gene expression. PMID- 27980624 TI - Identifying regions of disease-related variants in admixed populations with the summation partition approach. AB - We propose a new method for identifying disease-related regions of single nucleotide variants in recently admixed populations. We use principal component analysis to derive both global and local ancestry information. We then use the summation partition approach to search for disease-related regions based on both rare variants and the local ancestral information of each region. We demonstrate this method using individuals with high systolic blood pressure from a sample of unrelated Mexican American subjects provided in the 19th Genetic Analysis Workshop. PMID- 27980625 TI - Identification of interactions using model-based multifactor dimensionality reduction. AB - BACKGROUND: Common complex traits may involve multiple genetic and environmental factors and their interactions. Many methods have been proposed to identify these interaction effects, among them several machine learning and data mining methods. These are attractive for identifying interactions because they do not rely on specific genetic model assumptions. To handle the computational burden arising from an exhaustive search, including all possible combinations of factors, filter methods try to select promising factors in advance. METHODS: Model-based multifactor dimensionality reduction (MB-MDR), a semiparametric machine learning method allowing adjustment for confounding variables and lower level effects, is applied to Genetic Analysis Workshop 19 (GAW19) data to identify interaction effects on different traits. Several filtering methods based on the nearest neighbor algorithm are assessed in terms of compatibility with MB-MDR. RESULTS: Single nucleotide polymorphism (SNP) rs859400 shows a significant interaction effect (corrected p value <0.05) with age on systolic blood pressure (SBP). We identified 23 SNP-SNP interaction effects on hypertension status (HS), 42 interaction effects on SBP, and 26 interaction effects on diastolic blood pressure (DBP). Several of these SNPs are in strong linkage disequilibrium (LD). Three of the interaction effects on HS are identified in filtered subsets. CONCLUSIONS: The considered filtering methods seem not to be appropriate to use with MB-MDR. LD pruning is further quality control to be incorporated, which can reduce the combinatorial burden by removing redundant SNPs. PMID- 27980626 TI - Comparing machine learning and logistic regression methods for predicting hypertension using a combination of gene expression and next-generation sequencing data. AB - Machine learning methods continue to show promise in the analysis of data from genetic association studies because of the high number of variables relative to the number of observations. However, few best practices exist for the application of these methods. We extend a recently proposed supervised machine learning approach for predicting disease risk by genotypes to be able to incorporate gene expression data and rare variants. We then apply 2 different versions of the approach (radial and linear support vector machines) to simulated data from Genetic Analysis Workshop 19 and compare performance to logistic regression. Method performance was not radically different across the 3 methods, although the linear support vector machine tended to show small gains in predictive ability relative to a radial support vector machine and logistic regression. Importantly, as the number of genes in the models was increased, even when those genes contained causal rare variants, model predictive ability showed a statistically significant decrease in performance for both the radial support vector machine and logistic regression. The linear support vector machine showed more robust performance to the inclusion of additional genes. Further work is needed to evaluate machine learning approaches on larger samples and to evaluate the relative improvement in model prediction from the incorporation of gene expression data. PMID- 27980627 TI - Comparison of parametric and machine methods for variable selection in simulated Genetic Analysis Workshop 19 data. AB - Current findings from genetic studies of complex human traits often do not explain a large proportion of the estimated variation of these traits due to genetic factors. This could be, in part, due to overly stringent significance thresholds in traditional statistical methods, such as linear and logistic regression. Machine learning methods, such as Random Forests (RF), are an alternative approach to identify potentially interesting variants. One major issue with these methods is that there is no clear way to distinguish between probable true hits and noise variables based on the importance metric calculated. To this end, we are developing a method called the Relative Recurrency Variable Importance Metric (r2VIM), a RF-based variable selection method. Here, we apply r2VIM to the unrelated Genetic Analysis Workshop 19 data with simulated systolic blood pressure as the phenotype. We compare the number of "true" functional variants identified by r2VIM with those identified by linear regression analyses that use a Bonferroni correction to calculate a significance threshold. Our results show that r2VIM performed comparably to linear regression. Our findings are proof-of-concept for r2VIM, as it identifies a similar number of functional and nonfunctional variants as a more commonly used technique when the optimal importance score threshold is used. PMID- 27980628 TI - A clustering approach to identify rare variants associated with hypertension. AB - With the development of the next-generation sequencing technology, the influence of rare variants on complex disease has gathered increasing attention. In this paper, we propose a clustering-based approach, the clustering sum test, to test the effects of rare variants association by using the simulated data provided by the Genetic Analysis Workshop 19 with an unbalanced case-control ratio. The control individuals are (a) clustered into several subgroups, (b) statistics of the separate subcontrol groups as compared to the case group are calculated, and (c) a combined statistic value is obtained based on a distance score. Collapsing of rare variants is used together with the proposed method. In our results, comparing the same statistical test with and without clustering, the clustering strategy increases the number of true positives identified in the top 100 markers by 17.24 %. Compared to the sequence kernel association test, the proposed method is more robust in terms of replicated frequencies in the replicates data sets. The results suggest that the clustering approach could improve the power of nonparametric tests and that the clustering sum test has the potential to serve as a practical tool when dealing with rare variants with unbalanced case-control data in genome-wide case-control studies. PMID- 27980629 TI - Homozygosity disequilibrium and its gene regulation. AB - Homozygosity disequilibrium (HD) describes a nonrandom pattern of sizable runs of homozygosity (ROH) that deviated from a random distribution of homozygotes and heterozygotes in the genome. In this study, we developed a double-weight local polynomial model for estimating homozygosity intensity. This new estimation method enables considering the local property and genetic information of homozygosity in the human genome when detecting regions of HD. By using this new method, we estimated whole-genome homozygosity intensities by analyzing real whole-genome sequencing data of 959 related individuals from 20 large pedigrees provided by Genetic Analysis Workshop 19 (GAW19). Through the analysis, we derived the distribution of HD in the human genome and provided evidence for the genetic component of natural variation in HD. Generalized estimating equation analysis for 855 related individuals was performed to identify regions of HD associated with diastolic blood pressure (DBP), systolic blood pressure, and hypertension (HTN), with concomitant adjustment for age and sex. We identified one DBP-associated and 2 HTN-associated regions of HD. We also studied the gene regulation of HD by analyzing the real whole-genome transcription data of 647 individuals. A set of gene expressions regulated by the DBP- and HTN-associated regions of HD was identified. Finally, we conducted simulation studies to evaluate the performance of our homozygosity association test. The results showed that the association test had a high power and that type 1 error was controlled. The methods have been integrated into our developed Loss-of-Heterozygosity Analysis Suite software, which can be downloaded at http://www.stat.sinica.edu.tw/hsinchou/genetics/loh/LOHAS.htm. PMID- 27980630 TI - A general method for combining different family-based rare-variant tests of association to improve power and robustness of a wide range of genetic architectures. AB - Current rare-variant, gene-based tests of association often suffer from a lack of statistical power to detect genotype-phenotype associations as a result of a lack of prior knowledge of genetic disease models combined with limited observations of extremely rare causal variants in population-based samples. The use of pedigree data, in which rare variants are often more highly concentrated than in population-based data, has been proposed as 1 possible method for enhancing power. Methods for combining multiple gene-based tests of association into a single summary p value are a robust approach to different genetic architectures when little a priori knowledge is available about the underlying genetic disease model. To date, however, little consideration has been given to combining gene based tests of association for the analysis of pedigree data. We propose a flexible framework for combining any number of family-based rare-variant tests of association into a single summary statistic and for assessing the significance of that statistic. We show that this approach maintains type I error and improves the robustness, to different genetic architectures, of the statistical power of family- and gene-based rare-variant tests through application to simulated phenotype data from Genetic Analysis Workshop 19. PMID- 27980631 TI - The impact of genetic structure on sequencing analysis. AB - BACKGROUND: Genome-wide association studies have made substantial progress in identifying common variants associated with human diseases. Despite such success, a large portion of heritability remains unexplained. Evolutionary theory and empirical studies suggest that rare mutations could play an important role in human diseases, which motivates comprehensive investigation of rare variants in sequencing studies. To explore the association of rare variants with human diseases, many statistical approaches have been developed with different ways of modeling genetic structure (ie, linkage disequilibrium). Nevertheless, the appropriate strategy to model genetic structure of sequencing data and its effect on association analysis have not been well studied. METHODS: We investigate 3 statistical approaches that use 3 different strategies to model the genetic structure of sequencing data. We proceed by comparing a burden test that assumes independence among sequencing variants, a burden test that considers pairwise linkage disequilibrium (LD), and a functional analysis of variance (FANOVA) test that models genetic data through fitting continuous curves on individuals' genotypes. RESULTS: Through simulations, we find that FANOVA attains better or comparable performance to the 2 burden tests. Overall, the burden test that considers pairwise LD has comparable performance to the burden test that assumes independence between sequencing variants. However, for 1 gene, where the disease associated variant is located in an LD block, we find that considering pairwise LD could improve the test's performance. CONCLUSIONS: The structure of sequencing variants is complex in nature and its patterns vary across the whole genome. In certain cases (eg, a disease-susceptibility variant is in an LD block), ignoring the genetic structure in the association analysis could result in suboptimal performance. Through this study, we show that a functional-based method is promising for modeling the underlying genetic structure of sequencing data, which could lead to better performance. PMID- 27980632 TI - On combining family- and population-based sequencing data. AB - Several statistical group-based approaches have been proposed to detect effects of variation within a gene for each of the population- and family-based designs. However, unified tests to combine gene-phenotype associations obtained from these 2 study designs are not yet well established. In this study, we investigated the efficient combination of population-based and family-based sequencing data to evaluate best practices using the Genetic Analysis Workshop 19 (GAW19) data set. Because one design employed whole genome sequencing and the other whole exome sequencing, we examined variants overlapping both data sets. We used the family based sequence kernel association test (famSKAT) to analyze the family- and population-based data sets separately as well as with a combined data set. These were compared against meta-analysis. Using the combined data, we showed that famSKAT has high power to detect associations between diastolic and/or systolic blood pressures and the genes that have causal variants with large effect sizes, such as MAP4, TNN, and CGN. However, when there was a considerable difference in the powers between family- and population-based data, famSKAT with the combined data had lower power than that from the population-based data alone. The famSKAT test statistic for the combined data can be influenced by sample imbalance from the 2 designs. This underscores the importance of foresight in study design as, in this situation, the greatly lower sample size in the family-based data essentially serves to dilute signal. We observed inflated type I errors in our simulation study, largely when using population-based data, which might be a result of principal components failing to completely account for population admixture in this cohort. PMID- 27980633 TI - Comparing family-based rare variant association tests for dichotomous phenotypes. AB - BACKGROUND: It has been repeatedly stressed that family-based samples suffer less from genetic heterogeneity and that association analyses with family-based samples are expected to be powerful for detecting susceptibility loci for rare disease. Various approaches for rare-variant analysis with family-based samples have been proposed. METHODS: In this report, performances of the existing methods were compared with the simulated data set provided as part of Genetic Analysis Workshop 19 (GAW19). We considered the rare variant transmission disequilibrium test (RV-TDT), generalized estimating equations-based kernel association (GEE-KM) test, an extended combined multivariate and collapsing test for pedigree data (known as Pedigree Combined Multivariate and Collapsing [PedCMC]), gene-level kernel and burden association tests with disease status for pedigree data (PedGene), and the family-based rare variant association test (FARVAT). RESULTS: The results show that PedGene and FARVAT are usually the most efficient, and the optimal test statistic provided by FARVAT is robust under different disease models. Furthermore, FARVAT was implemented with C++, which is more computationally faster than other methods. CONCLUSIONS: Considering both statistical and computational efficiency, we conclude that FARVAT is a good choice for rare-variant analysis with extended families. PMID- 27980634 TI - Comparison of multiple single-nucleotide variant association tests in a meta analysis of Genetic Analysis Workshop 19 family and unrelated data. AB - BACKGROUND: Meta-analysis has been widely used in genetic association studies to increase sample size and to improve power, both in the context of single-variant analysis, as well as for gene-based tests. Meta-analysis approaches for haplotype analysis have not been extensively developed and used, and have not been compared with other ways of jointly analysing multiple genetic variants. METHODS: We propose a novel meta-analysis approach for a gene-based haplotype association test, and compare it with an existing meta-analysis approach of the sequence kernel association test (SKAT), using the unrelated samples and family samples of the Genetic Analysis Workshop 19 data sets. We performed association tests with diastolic blood pressure and restricted our analyses to all variants in exonic regions on all odd chromosomes. RESULTS: Meta-analysis of haplotype results and SKAT identified different genes. The most significantly associated gene identified by SKAT was the ALCAM gene on chromosome 3 with a p value of 7.0 * 10- 5. Two of the most associated genes identified by the haplotype method were FPGT (p = 6.7 * 10- 8) on chromosome 1 and SPARC (p = 3.3 * 10- 7) on chromosome 5. Both genes were previously implicated in blood pressure regulation and hypertension. CONCLUSION: We compared two meta-analysis approaches to jointly analyze multiple variants: SKAT and haplotype tests. The difference in observed results may be because the haplotype method considered all observed haplotypes, whereas SKAT weighted variants inversely to their minor allele frequency, masking the effects of common variants. The two approaches identified different top genes, and appear to be complementary. PMID- 27980635 TI - A novel statistical method for rare-variant association studies in general pedigrees. AB - Both population-based and family-based designs are commonly used in genetic association studies to identify rare variants that underlie complex diseases. For any type of study design, the statistical power will be improved if rare variants can be enriched in the samples. Family-based designs, with ascertainment based on phenotype, may enrich the sample for causal rare variants and thus can be more powerful than population-based designs. Therefore, it is important to develop family-based statistical methods that can account for ascertainment. In this paper, we develop a novel statistical method for rare-variant association studies in general pedigrees for quantitative traits. This method uses a retrospective view that treats the traits as fixed and the genotypes as random, which allows us to account for complex and undefined ascertainment of families. We then apply the newly developed method to the Genetic Analysis Workshop 19 data set and compare the power of the new method with two other methods for general pedigrees. The results show that the newly proposed method increases power in most of the cases we consider, more than the other two methods. PMID- 27980636 TI - Assessing transmission ratio distortion in extended families: a comparison of analysis methods. AB - A statistical departure from Mendel's law of segregation is known as transmission ratio distortion. Although well documented in many other organisms, the extent of transmission ratio distortion and its influence in the human genome remains incomplete. Using Genetic Analysis Workshop 19 whole genome sequence data from 20 large Mexican American pedigrees, our goal was to identify potentially distorted regions in the genome using family-based association methods such as the transmission disequilibrium test, the pedigree disequilibrium test, and the family-based association test. Preliminary results showed an unusually high number of transmission ratio distortion signals identified by the transmission disequilibrium test, but this phenomenon could not be replicated by the pedigree disequilibrium test or family-based association test. Applying these tests to different subsets of the data, we found the transmission disequilibrium test to be very sensitive to imputed genotypes. Regression analysis of transmission ratio distortion test p values controlling for minor allele frequency and quality control checks showed that Hardy Weinberg p values are associated with this inflation. Although the transmission disequilibrium test appears confounded by imputation of single nucleotide polymorphisms, the pedigree disequilibrium test and family-based association test seem to offer more robust alternatives when searching for transmission ratio distortion loci in whole genome sequence data from extended families. PMID- 27980637 TI - Transmission and decorrelation methods for detecting rare variants using sequencing data from related individuals. AB - BACKGROUND: Advances in whole genome sequencing have enabled the investigation of rare variants, which could explain some of the missing heritability that genome wide association studies are unable to detect. Most methods to detect associations with rare variants are developed for unrelated individuals; however, several methods exist that utilize family studies and could have better power to detect such associations. METHODS: Using whole genome sequencing data and simulated phenotypes provided by the organizers of the Genetic Analysis Workshop 19 (GAW19), we compared family-based methods that test for associations between rare and common variants with a quantitative trait. This was done using 2 fairly novel methods: family-based association test for rare variants (FBAT-RV), which is a transmission-based method that utilizes the transmission of genetic information from parent to offspring; and Minimum p value Optimized Nuisance parameter Score Test Extended to Relatives (MONSTER), which is a decorrelation method that instead attempts to adjust for relatedness using a regression-based method. We also considered family-based association test linear combination (FBAT LC) and FBAT-Min P, which are slightly older methods that do not allow for the weighting of rare or common variants, but contrast some of the limitations of FBAT-RV. RESULTS: MONSTER had much higher overall power than FBAT-RV and FBAT-Min P. Interestingly, FBAT-LC had similar overall power as MONSTER. MONSTER had the highest power for a gene accounting for a larger percent of the phenotypic variance, whereas MONSTER and FBAT-LC both had the highest power for a gene accounting for moderate variance. FBAT-LC had the highest power for a gene accounting for the least variance. CONCLUSIONS: Based on the simulated data from GAW19, MONSTER and FBAT-LC were the most powerful of the methods assessed. However, there are limitations to each of these methods that should be carefully considered when conducting an analysis of rare variants in related individuals. This emphasizes the need for methods that can incorporate the advantages of each of these methods into 1 family-based association test for rare variants. PMID- 27980638 TI - Imputing rare variants in families using a two-stage approach. AB - BACKGROUND: Recent focus on studying rare variants makes imputation accuracy of rare variants an important issue. Many approaches have been proposed to increase imputation accuracy among rare variants, from reference panel selection to combinations of existing methods to multistage analyses. We aimed to bring the strengths of these new approaches together with our proposed two-stage imputation for family data. METHODS: Our imputation methods were tested on the region from 46.75Mb to 49.25Mb on chromosome 3. We did quality control based on the proportion of missing genotypes per variant and individual, leaving 495 individuals with 761 genome-wide association studies (GWAS) variants only, 45 with 14,077 sequence variants only, and 419 with both GWAS and sequencing data. All data were prephased using SHAPEIT2 with a duo hidden Markov model algorithm prior to performing imputation. Imputations were performed 100 times, each time masking the sequence data for 1 individual and imputing it from the GWAS data. We used well-imputed genotypes, defined as a probability of greater than 0.9, above 2 different minor allele frequency cutoffs-0.01 and 0.05-from Impute2 as input for Merlin, and compared these results to Impute2 and Merlin separately. The imputed results were evaluated using correlation measurement and the imputation quality score. RESULTS: Our method improved imputation accuracy, measured by imputation quality score, for variants with minor allele frequency between 0.01 and 0.40, but failed to improve accuracy for variants with minor allele frequency less than 0.01 when we used a minor allele frequency cutoff of 0.01 for the Impute2 results. In contrast, our 2-stage approach with a minor allele frequency cutoff of 0.05 performed the worst of all methods for variants with minor allele frequency between 0.01 and 0.40. CONCLUSIONS: This method gave promising results, but may be further improved by changing the inclusion criteria of Impute2 variants. More analyses are needed on a larger region with different inclusion thresholds to assess the accuracy of this approach. PMID- 27980639 TI - A combined association test for rare variants using family and case-control data. AB - Statistical association tests for rare variants can be classified as the burden approach and the sequence kernel association test (SKAT) approach. The burden and SKAT approaches, originally developed for case-control analysis, have also been extended to family-based tests. In the presence of both case-control and family data for a study, joint analysis for the combined data set can increase the statistical power. We extended the Combined Association in the Presence of Linkage (CAPL) test, using both case-control and family data for testing common variants, to rare variant association analysis. The burden and SKAT algorithms were applied to the CAPL test. We used simulations to verify that the CAPL tests incorporating the burden and SKAT algorithms have correct type I error rates. Power studies suggested that both tests have adequate power to identify rare variants associated with the disease. We applied the tests to the Genetic Analysis Workshop 19 data set using the combined family and case-control data for hypertension. The analysis identified several candidate genes for hypertension. PMID- 27980640 TI - A LASSO penalized regression approach for genome-wide association analyses using related individuals: application to the Genetic Analysis Workshop 19 simulated data. AB - We propose a novel LASSO (least absolute shrinkage and selection operator) penalized regression method used to analyze samples consisting of (potentially) related individuals. Developed in the context of linear mixed models, our method models the relatedness of individuals in the sample through a random effect whose covariance structure is a linear function of known matrices with elements combinations of the condensed coefficients of identity between the individuals in the sample. We implement our method to analyze the simulated family data provided by the 19th Genetic Analysis Workshop in an effort to identify loci regulating the simulated trait of systolic blood pressure. The analyses were performed with full knowledge of the simulation model. Our findings demonstrate that we can significantly reduce the rate of false positive signals by incorporating the relatedness of the study participants. PMID- 27980641 TI - Prioritization of family member sequencing for the detection of rare variants. AB - BACKGROUND: The advent of affordable sequencing has enabled researchers to discover many variants contributing to disease, including rare variants. There are methods for determining the most informative individuals for sequencing, but the application of these methods is more complex when working with families. Sets of large families can be beneficial in finding rare variants, but it may be unfeasible to sequence all members of these family sets. METHODS: Using simulated data from the Genetic Analysis Workshop 19, we apply multiple regression to identify cases and controls. To find the best controls for each case, we used kinship coefficients to match within families. Selected cases and controls were analyzed for rare variants, collapsed by gene, associated with hypertension using the family-based rare variant association test (FARVAT). RESULTS: The gene with the strongest simulated effect, MAP4, did not meet the Bonferroni corrected significance threshold. However, analysis of cases and controls using our selection method substantially improved the significance of MAP4, despite the reduction in sample size. CONCLUSIONS: Taking the additional steps to select the optimal cases and controls from large family data sets can help ensure that only informative individuals are included in analysis and may improve the ability to detect rare variants. PMID- 27980642 TI - Testing rare variants for hypertension using family-based tests with different weighting schemes. AB - Next-generation sequencing technology makes directly testing rare variants possible. However, existing statistical methods to detect common variants may not be optimal for testing rare variants because of allelic heterogeneity as well as the extreme rarity of individual variants. Recently, several statistical methods to detect associations of rare variants were developed, including population based and family-based methods. Compared with population-based methods, family based methods have more power and can prevent bias induced by population substructure. Both population-based and family-based methods for rare variant association studies are essentially testing the effect of a weighted combination of variants or its function. How to model the weights is critical for the testing power because the number of observations for any given rare variant is small and the multiple-test correction is more stringent for rare variants. We propose 4 weighting schemes for the family-based rare variants test (FBAT-v) to test for the effects of both rare and common variants across the genome. Applying FBAT-v with the proposed weighting schemes on the Genetic Analysis Workshop 19 family data indicates that the power of FBAT-v can be comparatively enhanced in most circumstances. PMID- 27980643 TI - Genome-wide QTL and eQTL analyses using Mendel. AB - Pedigree genome-wide association studies (GWAS) (Option 29) in the current version of the Mendel software is an optimized subroutine for performing large scale genome-wide quantitative trait locus (QTL) analysis. This analysis (a) works for random sample data, pedigree data, or a mix of both; (b) is highly efficient in both run time and memory requirement; (c) accommodates both univariate and multivariate traits; (d) works for autosomal and x-linked loci; (e) correctly deals with missing data in traits, covariates, and genotypes; (f) allows for covariate adjustment and constraints among parameters; (g) uses either theoretical or single nucleotide polymorphism (SNP)-based empirical kinship matrix for additive polygenic effects; (h) allows extra variance components such as dominant polygenic effects and household effects; (i) detects and reports outlier individuals and pedigrees; and (j) allows for robust estimation via the t distribution. This paper assesses these capabilities on the genetics analysis workshop 19 (GAW19) sequencing data. We analyzed simulated and real phenotypes for both family and random sample data sets. For instance, when jointly testing the 8 longitudinally measured systolic blood pressure and diastolic blood pressure traits, it takes Mendel 78 min on a standard laptop computer to read, quality check, and analyze a data set with 849 individuals and 8.3 million SNPs. Genome-wide expression QTL analysis of 20,643 expression traits on 641 individuals with 8.3 million SNPs takes 30 h using 20 parallel runs on a cluster. Mendel is freely available at http://www.genetics.ucla.edu/software. PMID- 27980644 TI - Independent test assessment using the extreme value distribution theory. AB - The new generation of whole genome sequencing platforms offers great possibilities and challenges for dissecting the genetic basis of complex traits. With a very high number of sequence variants, a naive multiple hypothesis threshold correction hinders the identification of reliable associations by the overreduction of statistical power. In this report, we examine 2 alternative approaches to improve the statistical power of a whole genome association study to detect reliable genetic associations. The approaches were tested using the Genetic Analysis Workshop 19 (GAW19) whole genome sequencing data. The first tested method estimates the real number of effective independent tests actually being performed in whole genome association project by the use of an extreme value distribution and a set of phenotype simulations. Given the familiar nature of the GAW19 data and the finite number of pedigree founders in the sample, the number of correlations between genotypes is greater than in a set of unrelated samples. Using our procedure, we estimate that the effective number represents only 15 % of the total number of independent tests performed. However, even using this corrected significance threshold, no genome-wide significant association could be detected for systolic and diastolic blood pressure traits. The second approach implements a biological relevance-driven hypothesis tested by exploiting prior computational predictions on the effect of nonsynonymous genetic variants detected in a whole genome sequencing association study. This guided testing approach was able to identify 2 promising single-nucleotide polymorphisms (SNPs), 1 for each trait, targeting biologically relevant genes that could help shed light on the genesis of the human hypertension. The first gene, PFH14, associated with systolic blood pressure, interacts directly with genes involved in calcium channel formation and the second gene, MAP4, encodes a microtubule-associated protein and had already been detected by previous genome-wide association study experiments conducted in an Asian population. Our results highlight the necessity of the development of alternative approached to improve the efficiency on the detection of reasonable candidate associations in whole genome sequencing studies. PMID- 27980645 TI - Powerful association test combining rare variant and gene expression using family data from Genetic Analysis Workshop 19. AB - BACKGROUND: Genetic association studies aim to test for disease or trait association with genetic variants, either throughout the human genome or in regions of interest. However, for most diseases and traits, the combined effects of associated genetic variants explain only a small proportion of the genetic variation. This "missing heritability" may be a result of the small effects of common variants considered in the genetic association studies. Rare variants may also play an important role in understanding the missing heritability of complex traits. METHOD: We propose a novel weight-adjustment approach to combine gene expression into rare variant analysis. Results from previous simulation studies suggested that incorporating gene expression information can lead to substantial gain in statistical power. RESULTS: Using the family data set provided through the Genetic Analysis Workshop 19, we identified susceptible genes associated with blood pressure regulation. CONCLUSIONS: These findings provide valuable information for further functional studies for blood pressure control and mechanism. PMID- 27980646 TI - Incorporating ENCODE information into association analysis of whole genome sequencing data. AB - With the rapidly decreasing cost of the next-generation sequencing technology, a large number of whole genome sequences have been generated, enabling researchers to survey rare variants in the protein-coding and regulatory regions of the genome. However, it remains a daunting task to identify functional variants associated with complex diseases from whole genome sequencing (WGS) data because of the millions of candidate variants and yet moderate sample size. We propose to incorporate the Encyclopedia of DNA Elements (ENCODE) information in the association analysis of WGS data to boost the statistical power. We use the RegulomeDB and PolyPhen2 scores as external weights in existing rare variants association tests. We demonstrate the proposed framework using the WGS data and blood pressure phenotype from the San Antonio Family Studies provided by the Genetic Analysis Workshop 19. We identified a genome-wide significant locus in gene SNUPN on chromosome 15 that harbors a rare nonsynonymous variant, which was not detected by benchmark methods that did not incorporate biological information, including the T5 burden test and sequence kernel association test. PMID- 27980647 TI - Identity-by-descent mapping for diastolic blood pressure in unrelated Mexican Americans. AB - Population-based identity by descent (IBD) mapping is a statistical method for detection of genetic loci that share an ancestral segment among "unrelated" pairs of individuals for a disease. As a complementary method to genome-wide association studies, IBD mapping is robust to allelic heterogeneity and may identify rare inherited variants when combined with sequence data. Our objective is to identify the causal genes for diastolic blood pressure (DBP). We applied a population-based IBD mapping method to 105 unrelated individuals selected from the family data provided for the Genetic Analysis Workshop 19. Using the genome wide association study data (ie, the microarray data), chromosome 3 was scanned for IBD sharing segments among all pairs of these individuals. At the chromosomal region with the most significant relationship between IBD sharing and DBP, the whole genome sequence data were examined to identify the risk variants for DBP. The most significant chromosomal region that was identified to have a relationship between the IBD sharing and DBP was at 3q12.3 (p = 0.0016), although it did not achieve the chromosome-wide significance level (p = 0.00012). This chromosomal region contains 1 gene, ZPLD1, which has been reported to be associated with cerebral cavernous malformations, a disease with enlarged small blood vessels (capillaries) in the brain. Although 24 deleterious variants were identified at this region, no significant association was found between these variants and DBP (p = 0.40). We presented a mapping strategy which combined a population-based IBD mapping method with sequence data analyses. One gene was located at a chromosomal region identified by this method for DBP. However, further study with a large sample size is needed to assess this result. PMID- 27980648 TI - Comparing strategies for combined testing of rare and common variants in whole sequence and genome-wide genotype data. AB - We used our extension of the kernel score test to family data to analyze real and simulated baseline systolic blood pressure in extended pedigrees. We compared the power for different kernels and for different weightings of genetic markers. Moreover, we compared the power of rare and common markers with 3 strategies for joint testing and on marker panels with different densities. Marker weights had much greater influence on power than the kernel chosen. Inverse minor allele frequency weights often increased power on common markers but could decrease power on rare markers. Furthermore, defining the gene region based on linkage disequilibrium blocks often yielded robust power of joint tests of rare and common markers. PMID- 27980649 TI - Incorporation of protein binding effects into likelihood ratio test for exome sequencing data. AB - Statistical association studies are an important tool in detecting novel disease genes. However, for sequencing data, association studies confront the challenge of low power because of relatively small data sample size and rare variants. Incorporating biological information that reflects disease mechanism is likely to strengthen the association evidence of disease genes, and thus increase the power of association studies. In this paper, we annotate non-synonymous single nucleotide variants according to protein binding sites (BSs) by using a more accurate BS prediction method. We then incorporate this information into association study through a statistical framework of likelihood ratio test (LRT) based on weighted burden score of single-nucleotide variants (SNVs). The strategy is applied to Genetic Analysis Workshop 19 exome-sequencing data for detecting novel genes associated to hypotension. The SNV-weighting LRT idea is empirically verified by the simulated phenotypes (336 cases and 1607 controls), and the weights based on BS annotation are applied to the real phenotypes (394 cases and 1457 controls). Such strategy of weighting the prior information on protein functional sites is shown to be superior to the unweighted LRT and serves as a good complement to the existing association tests. Several putative genes are reported; some of them are functionally related to hypertension according to the previous evidence in the literature. PMID- 27980650 TI - Integrating multiple genomic data: sparse representation based biomarker selection for blood pressure. AB - BACKGROUND: Although many genes have been implicated as hypertension candidates, to date, few studies have integrated different types of genomic data for the purpose of biomarker selection. METHODS: Applying a newly proposed sparse representation based variable selection (SRVS) method to the Genetic Analysis Workshop19 data, we analyzed a combined data set consisting of 11522 gene expressions and 354893 single-nucleotide polymorphisms (SNPs) from 397 subjects (case/control: 151/246), with the aim to identify potential biomarkers for blood pressure using both gene expression measures and SNP data. RESULTS: Among the top 1000 variables (SNPs/gene expressions = 575/425) selected, the bioinformatics analysis showed that 302 were plausibly associated with blood pressure. In addition, we identified 173 variables that were associated with body weight and 84 associated with left ventricular contractility. Together, 55.9 % of the top 1000 variables showed associations with blood pressure related phenotypes(SNP/gene expression =348/211). CONCLUSIONS: Our results support the feasibility of the SRVS algorithm in integrating multiple data sets of different structure for comprehensive analysis. PMID- 27980651 TI - Genetic association analysis based on a joint model of gene expression and blood pressure. AB - Recent work on genetic association studies suggests that much of the heritable variation in complex traits is unexplained, which indicates a need for using more biologically meaningful modeling approaches and appropriate statistical methods. In this study, we propose a biological framework and a corresponding statistical model incorporating multilevel biological measures, and illustrate it in the analysis of the real data provided by the Genetic Analysis Workshop (GAW) 19, which contains whole genome sequence (WGS), gene expression (GE), and blood pressure (BP) data. We investigate the direct effect of single-nucleotide variants (SNVs) on BP and GE, while considering the non-directional dependence between BP and GE, by using copula functions to jointly model BP and GE conditional on SNVs. We implement the method for analysis on a genome-wide scale, and illustrate it within an association analysis of 68,727 SNVs on chromosome 19 that lie in or around genes with available GE measures. Although there is no indication for inflated type I errors under the proposed method, our results show that the association tests have smaller p values than tests under univariate models for common and rare variants using single-variant tests and gene-based multimarker tests. Hence, considering multilevel biological measures and modeling the dependence structure between these measures by using a plausible graphical approach may lead to more informative findings than standard univariate tests of common variants and well-recognized gene-based rare variant tests. PMID- 27980652 TI - Identity-by-descent estimation with population- and pedigree-based imputation in admixed family data. AB - BACKGROUND: In the past few years, imputation approaches have been mainly used in population-based designs of genome-wide association studies, although both family and population-based imputation methods have been proposed. With the recent surge of family-based designs, family-based imputation has become more important. Imputation methods for both designs are based on identity-by-descent (IBD) information. Apart from imputation, the use of IBD information is also common for several types of genetic analysis, including pedigree-based linkage analysis. METHODS: We compared the performance of several family- and population-based imputation methods in large pedigrees provided by Genetic Analysis Workshop 19 (GAW19). We also evaluated the performance of a new IBD mapping approach that we propose, which combines IBD information from known pedigrees with information from unrelated individuals. RESULTS: Different combinations of the imputation methods have varied imputation accuracies. Moreover, we showed gains from the use of both known pedigrees and unrelated individuals with our IBD mapping approach over the use of known pedigrees only. CONCLUSIONS: Our results represent accuracies of different combinations of imputation methods that may be useful for data sets similar to the GAW19 pedigree data. Our IBD mapping approach, which uses both known pedigree and unrelated individuals, performed better than classical linkage analysis. PMID- 27980653 TI - Structural equation modeling with latent variables for longitudinal blood pressure traits using general pedigrees. AB - Structural equation modeling (SEM) has been used in a wide range of applied sciences including genetic analysis. The recently developed R package, strum, implements a framework for SEM for general pedigree data. We explored different SEM techniques using strum to analyze the multivariate longitudinal data and to ultimately test the association of genotypes on blood pressure traits. The quantitative blood pressure (BP) traits, systolic BP (SBP) and diastolic BP (DBP) were analyzed as the main traits of interest with age, sex, and smoking status as covariates. The single nucleotide polymorphism (SNP) genotype information from genome-wide association studies (GWAS) data was used for the test of association. The adjustment for hypertension treatment effect was done by the censored regression approach. Two different longitudinal data models, autoregressive model and latent growth curve model, were used to fit the longitudinal BP traits. The test of association for SNP was done using a novel score test within the SEM framework of strum. We found the 10 SNPs within the GWAS suggestive P value level, and among those 10, the most significant top 3 SNPs agreed in rank in both analysis models. The general SEM framework in strum is very useful to model and test for the association with massive genotype data and complex systems of multiple phenotypes with general pedigree data. PMID- 27980654 TI - Joint analysis of multiple blood pressure phenotypes in GAW19 data by using a multivariate rare-variant association test. AB - INTRODUCTION: Large-scale sequencing studies often measure many related phenotypes in addition to the genetic variants. Joint analysis of multiple phenotypes in genetic association studies may increase power to detect disease associated loci. METHODS: We apply a recently developed multivariate rare-variant association test to the Genetic Analysis Workshop 19 data in order to test associations between genetic variants and multiple blood pressure phenotypes simultaneously. We also compare this multivariate test with a widely used univariate test that analyzes phenotypes separately. RESULTS: The multivariate test identified 2 genetic variants that have been previously reported as associated with hypertension or coronary artery disease. In addition, our region based analyses also show that the multivariate test tends to give smaller p values than the univariate test. CONCLUSIONS: Hence, the multivariate test has potential to improve test power, especially when multiple phenotypes are correlated. PMID- 27980655 TI - Multipoint association mapping for longitudinal family data: an application to hypertension phenotypes. AB - It is essential to develop adequate statistical methods to fully utilize information from longitudinal family studies. We extend our previous multipoint linkage disequilibrium approach-simultaneously accounting for correlations between markers and repeat measurements within subjects, and the correlations between subjects in families-to detect loci relevant to disease through gene based analysis. Estimates of disease loci and their genetic effects along with their 95 % confidence intervals (or significance levels) are reported. Four different phenotypes-ever having hypertension at 4 visits, incidence of hypertension, hypertension status at baseline only, and hypertension status at 4 visits-are studied using the proposed approach. The efficiency of estimates of disease locus positions (inverse of standard error) improves when using the phenotypes from 4 visits rather than using baseline only. PMID- 27980656 TI - Genome-wide association of trajectories of systolic blood pressure change. AB - BACKGROUND: There is great interindividual variation in systolic blood pressure (SBP) as a result of the influences of several factors, including sex, ancestry, smoking status, medication use, and, especially, age. The majority of genetic studies have examined SBP measured cross-sectionally; however, SBP changes over time, and not necessarily in a linear fashion. Therefore, this study conducted a genome-wide association (GWA) study of SBP change trajectories using data available through the Genetic Analysis Workshop 19 (GAW19) of 959 individuals from 20 extended Mexican American families from the San Antonio Family Studies with up to 4 measures of SBP. We performed structural equation modeling (SEM) while taking into account potential genetic effects to identify how, if at all, to include covariates in estimating the SBP change trajectories using a mixture model based latent class growth modeling (LCGM) approach for use in the GWA analyses. RESULTS: The semiparametric LCGM approach identified 5 trajectory classes that captured SBP changes across age. Each LCGM identified trajectory group was ranked based on the average number of cumulative years as hypertensive. Using a pairwise comparison of these classes the heritability estimates range from 12 to 94 % (SE = 17 to 40 %). CONCLUSION: These identified trajectories are significantly heritable, and we identified a total of 8 promising loci that influence one's trajectory in SBP change across age. Our results demonstrate the potential utility of capitalizing on extant genetic data and longitudinal SBP assessments available through GAW19 to explore novel analytical methods with promising results. PMID- 27980658 TI - Network-guided interaction mining for the blood pressure phenotype of unrelated individuals in genetic analysis workshop 19. AB - Interactions between genes are an important part of the genetic architecture of complex diseases. In this paper, we use literature-guided individual genes known to be associated with type 2 diabetes (referred to as "seed genes") to create a larger list of genes that share implied or direct networks with these seed genes. This larger list of genes are known to interact with each other, but whether they interact in ways to influence hypertension in individuals presents an interesting question. Using Genetic Analysis Workshop data on individuals with diabetes, for which only case-control labels of hypertension are known, we offer a foray into identification of diabetes-related gene interactions that are associated with hypertension. We use the approach of Lo et al. (Proc Natl Acad Sci U S A 105: 12387-12392, 2008), which creates a score to identify pairwise significant gene associations. We find that the genes GCK and PAX4, formerly known to be found within similar coexpression and pathway networks but without specific direct interactions, do, in fact, show significant joint interaction effects for hypertension. PMID- 27980657 TI - Constrained multivariate association with longitudinal phenotypes. AB - BACKGROUND: The incorporation of longitudinal data into genetic epidemiological studies has the potential to provide valuable information regarding the effect of time on complex disease etiology. Yet, the majority of research focuses on variables collected from a single time point. This aim of this study was to test for main effects on a quantitative trait across time points using a constrained maximum-likelihood measured genotype approach. This method simultaneously accounts for all repeat measurements of a phenotype in families. We applied this method to systolic blood pressure (SBP) measurements from three time points using the Genetic Analysis Workshop 19 (GAW19) whole-genome sequence family simulated data set and 200 simulated replicates. Data consisted of 849 individuals from 20 extended Mexican American pedigrees. Comparisons were made among 3 statistical approaches: (a) constrained, where the effect of a variant or gene region on the mean trait value was constrained to be equal across all measurements; (b) unconstrained, where the variant or gene region effect was estimated separately for each time point; and (c) the average SBP measurement from three time points. These approaches were run for nine genetic variants with known effect sizes (>0.001) for SBP variability and a known gene-centric kernel (MAP4)-based test under the GAW19 simulation model across 200 replicates. RESULTS: When compared to results using two time points, the constrained method utilizing all 3 time points increased power to detect association. Averaging SBP was equally effective when the variant has a large effect on the phenotype, but less powerful for variants with lower effect sizes. However, averaging SBP was far more effective than either the constrained or unconstrained approaches when using a gene-centric kernel-based test. CONCLUSION: We determined that this constrained multivariate approach improves genetic signal over the bivariate method. However, this method is still only effective in those variants that explain a moderate to large proportion of the phenotypic variance but is not as effective for gene-centric tests. PMID- 27980659 TI - A variance component method for integrated pathway analysis of gene expression data. AB - BACKGROUND: The application of pathway and gene-set based analyses to high throughput data is increasingly common and represents an effort to understand underlying biology where single-gene or single-marker analyses have failed. Many such analyses rely on the a priori identification of genes associated with the trait of interest. In contrast, this variance-component-based approach creates a similarity matrix of individuals based on the expression of genes in each pathway. METHODS: We compared 16 methods of calculating similarity for positive control matrices based on probes for the genes used to model the simulated Genetic Analysis Workshop phenotypes. RESULTS: A simple correlation matrix outperforms the other methods by identifying pathways associated with the simulated phenotypes at nearly twice the rate expected based on the associations of the component transcripts and an approximate false-positive rate of 0.05. CONCLUSIONS: This method has a number of additional advantages compared to single transcript and pathway overrepresentation analyses, including the ability to estimate the proportion of variation explained by each pathway and the logistical advantage of only calculating the distance matrices once for each messenger RNA data set regardless of the number of phenotypes. Additionally, it offers a significant reduction in the multiple testing burden over individual consideration of each probe. PMID- 27980660 TI - Association of polymorphisms in the aldosterone-regulated sodium reabsorption pathway with blood pressure among Hispanics. AB - BACKGROUND: Whereas genome-wide association study (GWAS) has proven to be an important tool for discovery of variants influencing many human diseases and traits, unfortunately its performance has not been much of all-around success for some complex conditions, for example, hypertension. Because some of the existing effective pharmacotherapeutic agents act by targeting known biological pathways, pathway-based analytical approaches could lead to more success in discovery of disease-associated variants. The objective of the present study was to identify functional variants associated with blood pressure in the aldosterone-regulated sodium reabsorption pathway using the simulated and real blood pressure phenotypes provided for Genetic Analysis Workshop 19. METHODS: The present analysis included 1942 samples with exome sequencing data and for whom blood pressure phenotypes were available. Because only odd-numbered autosomes were available, we restricted analysis to 127 quality-controlled single-nucleotide polymorphisms from the aldosterone-regulated sodium reabsorption pathway. We performed pathway-based association analysis using appropriate regression models for single variant, haplotype and epistasis association analyses. To account for multiple comparisons, statistical significance was empirically derived by permutation procedure and Bonferroni correction. RESULTS: The topmost pathway based association signals were observed in PRKCA gene for diastolic blood pressure (DBP), systolic blood pressure (SBP), and mean arterial pressure (MAP) in both real and simulated data. The associations remained significant (P <0.05) after multiple testing corrections for the number of genes. Similarly, the pathway-based 2-locus epistasis analysis indicated significant interactions between INSR and PRKCG for SBP and MAP; INS and PIK3R2 for DBP; PIK3CD and ATP1B2 for hypertension in the real data set. We also observed significant within-gene interactions in INSR for SBP, DBP, and hypertension in the simulated data set. CONCLUSION: The findings from this study show that pathway-based analytical approach targeting known biological pathways can be useful in identification of disease-associated variants that are otherwise undetectable by GWAS. The approach takes advantage of the assumption of nonindependence of variants within and across pathway genes which leads to reduced penalty of multiple testing and thus less-stringent statistical significance threshold. PMID- 27980661 TI - A multistep approach to single nucleotide polymorphism-set analysis: an evaluation of power and type I error of gene-based tests of association after pathway-based association tests. AB - The aggregation of functionally associated variants given a priori biological information can aid in the discovery of rare variants associated with complex diseases. Many methods exist that aggregate rare variants into a set and compute a single p value summarizing association between the set of rare variants and a phenotype of interest. These methods are often called gene-based, rare variant tests of association because the variants in the set are often all contained within the same gene. A reasonable extension of these approaches involves aggregating variants across an even larger set of variants (eg, all variants contained in genes within a pathway). Testing sets of variants such as pathways for association with a disease phenotype reduces multiple testing penalties, may increase power, and allows for straightforward biological interpretation. However, a significant variant-set association test does not indicate precisely which variants contained within that set are causal. Because pathways often contain many variants, it may be helpful to follow-up significant pathway tests by conducting gene-based tests on each gene in that pathway to narrow in on the region of causal variants. In this paper, we propose such a multistep approach for variant-set analysis that can also account for covariates and complex pedigree structure. We demonstrate this approach on simulated phenotypes from Genetic Analysis Workshop 19. We find generally better power for the multistep approach when compared to a more conventional, single-step approach that simply runs gene-based tests of association on each gene across the genome. Further work is necessary to evaluate the multistep approach on different data sets with different characteristics. PMID- 27980662 TI - Estimating relationships between phenotypes and subjects drawn from admixed families. AB - BACKGROUND: Estimating relationships among subjects in a sample, within family structures or caused by population substructure, is complicated in admixed populations. Inaccurate allele frequencies can bias both kinship estimates and tests for association between subjects and a phenotype. We analyzed the simulated and real family data from Genetic Analysis Workshop 19, and were aware of the simulation model. RESULTS: We found that kinship estimation is more accurate when marker data include common variants whose frequencies are less variable across populations. Estimates of heritability and association vary with age for longitudinally measured traits. Accounting for local ancestry identified different true associations than those identified by a traditional approach. Principal components aid kinship estimation and tests for association, but their utility is influenced by the frequency of the markers used to generate them. CONCLUSIONS: Admixed families can provide a powerful resource for detecting disease loci, as well as analytical challenges. Allele frequencies, although difficult to adequately estimate in admixed populations, have a strong impact on the estimation of kinship, ancestry, and association with phenotypes. Approaches that acknowledge population structure in admixed families outperform those which ignore it. PMID- 27980663 TI - Association of rare haplotypes on ULK4 and MAP4 genes with hypertension. AB - Several variants have been implicated earlier on ULK4 and MAP4 genes on chromosome 3 to be associated with hypertension. As a natural follow-up step, we explore association of haplotypes in those genes. We consider the Genetic Analysis Workshop 19 real data on unrelated individuals and analyze haplotype blocks of 5 single-nucleotide polymorphisms through a sliding window approach. We apply 4 haplotype association methods-haplo.score, haplo.glm, hapassoc, and logistic Bayesian LASSO (LBL)-and for comparison, sequence kernel association test (SKAT) and its variants. We find several rare haplotype blocks to be associated. To get an idea about the false-positive proportions, we also analyzed the data after permuting the case-control status of individuals. We found that LBL, unlike the other methods, maintains low false-positive rates in presence of rare haplotypes. Thus, we conclude that the haplotypes found to be associated by LBL are more likely to be true positive. SKAT and its variants did not find significance on either gene. PMID- 27980664 TI - Comparison of 2 models for gene-environment interactions: an example of simulated gene-medication interactions on systolic blood pressure in family-based data. AB - BACKGROUND: Nearly half of adults in the United States who are diagnosed with hypertension use blood-pressure-lowering medications. Yet there is a large interindividual variability in the response to these medications. Two complementary gene-environment interaction methods have been published and incorporated into publicly available software packages to examine interaction effects, including whether genetic variants modify the association between medication use and blood pressure. The first approach uses a gene-environment interaction term to measure the change in outcome when both the genetic marker and medication are present (the "interaction model"). The second approach tests for effect-size differences between strata of an environmental exposure (the "med diff" approach). However, no studies have quantitatively compared how these methods perform with respect to 1 or 2 degree of freedom (DF) tests or in family based data sets. We evaluated these 2 approaches using simulated genotype medication response interactions at 3 single nucleotide polymorphisms (SNPs) across a range of minor allele frequencies (MAFs 0.1-5.4 %) using the Genetic Analysis Workshop 19 family sample. RESULTS: The estimated interaction effect sizes were on average larger in the interaction model approach compared to the med-diff approach. The true positive proportion was higher for the med-diff approach for SNPs less than 1 % MAF, but higher for the interaction model when common variants were evaluated (MAF >5 %). The interaction model produced lower false-positive proportions than expected (5 %) across a range of MAFs for both the 1DF and 2DF tests. In contrast, the med-diff approach produced higher but stable false-positive proportions around 5 % across MAFs for both tests. CONCLUSIONS: Although the 1DF tests both performed similarly for common variants, the interaction model estimated true interaction effects with less bias and higher true positive proportions than the med-diff approach. However, if rare variation (MAF <5 %) is of interest, our findings suggest that when convergence is achieved, the med-diff approach may estimate true interaction effects more conservatively and with less variability. PMID- 27980665 TI - Identifying rare and common variants with Bayesian variable selection. AB - BACKGROUND: Recent advances in next-generation sequencing technologies have made it possible to generate large amounts of sequence data with rare variants in a cost-effective way. Yet, the statistical aspect of testing disease association of rare variants is quite challenging as the typical assumptions fail to hold owing to low minor allele frequency (<0.5 or 1 %). METHODS: I present a Bayesian variable selection approach to detect associations with both rare and common genetic variants for quantitative traits simultaneously. In my model, I frame the problem of identifying disease-associated variants as a problem of variable selection in a sparse space, that is, how best to model the relationship between phenotypes and a set of genetic variants. By constructing a risk index score for a group of rare variants, my method can effectively consider all variants in a multivariate model. I also use a within-chain permutation to generate the empirical thresholds to detect true-positive variants. RESULTS: I apply our method to study the association between increases in baseline systolic and diastolic blood pressure (SBP and DBP, respectively) and genetic variants in the data from Genetic Analysis Workshop 19 unrelated samples. I identify several rare and common variants in the gene MAP4 that are potentially associated with SBP and DBP. CONCLUSIONS: The application shows that my method is powerful in identifying disease-associated variants even with the extreme rarity. PMID- 27980666 TI - Type I error rates of rare single nucleotide variants are inflated in tests of association with non-normally distributed traits using simple linear regression methods. AB - In this study, the effects of (a) the minor allele frequency of the single nucleotide variant (SNV), (b) the degree of departure from normality of the trait, and (c) the position of the SNVs on type I error rates were investigated in the Genetic Analysis Workshop (GAW) 19 whole exome sequence data. To test the distribution of the type I error rate, 5 simulated traits were considered: standard normal and gamma distributed traits; 2 transformed versions of the gamma trait (log10 and rank-based inverse normal transformations); and trait Q1 provided by GAW 19. Each trait was tested with 313,340 SNVs. Tests of association were performed with simple linear regression and average type I error rates were determined for minor allele frequency classes. Rare SNVs (minor allele frequency < 0.05) showed inflated type I error rates for non-normally distributed traits that increased as the minor allele frequency decreased. The inflation of average type I error rates increased as the significance threshold decreased. Normally distributed traits did not show inflated type I error rates with respect to the minor allele frequency for rare SNVs. There was no consistent effect of transformation on the uniformity of the distribution of the location of SNVs with a type I error. PMID- 27980667 TI - Identification of low frequency and rare variants for hypertension using sparse data methods. AB - Availability of genomic sequence data provides opportunities to study the role of low-frequency and rare variants in the etiology of complex disease. In this study, we conduct association analyses of hypertension status in the cohort of 1943 unrelated Mexican Americans provided by Genetic Analysis Workshop 19, focusing on exonic variants in MAP4 on chromosome 3. Our primary interest is to compare the performance of standard and sparse-data approaches for single-variant tests and variant-collapsing tests for sets of rare and low-frequency variants. We analyze both the real and the simulated phenotypes. PMID- 27980668 TI - Using next-generation DNA sequence data for genetic association tests based on allele counts with and without consideration of zero inflation. AB - The relationship between genetic variability and individual phenotypes is usually investigated by testing for association relying on called genotypes. Allele counts obtained from next-generation sequence data could be used for this purpose too. Genetic association can be examined by treating alternative allele counts (AACs) as the response variable in negative binomial regression. AACs from sequence data often contain an excess of zeros, thus motivating the use of Hurdle and zero-inflated models. Here we examine rough type I error rates and the ability to pick out variants with small probability values for 7 different testing approaches that incorporate AACs as an explanatory or as a response variable. Model comparisons relied on chromosome 3 DNA sequence data from 407 Hispanic participants in the Type 2 Diabetes Genetic Exploration by Next generation sequencing in Ethnic Samples (T2D-GENES) project 1 with complete information on diastolic blood pressure and related medication. Our results suggest that in the investigation of the relationship between AAC as response variable and individual phenotypes as explanatory variable, Hurdle-negative binomial regression has some advantages. This model showed a good ability to discriminate strongly associated variants and controlled overall type I error rates. However, probability values from Hurdle-negative binomial regression were not obtained for approximately 25 % of the investigated variants because of convergence problems, and the mass of the probability value distribution was concentrated around 1. PMID- 27980669 TI - Comparing performance of non-tree-based and tree-based association mapping methods. AB - A central goal in the biomedical and biological sciences is to link variation in quantitative traits to locations along the genome (single nucleotide polymorphisms). Sequencing technology has rapidly advanced in recent decades, along with the statistical methodology to analyze genetic data. Two classes of association mapping methods exist: those that account for the evolutionary relatedness among individuals, and those that ignore the evolutionary relationships among individuals. While the former methods more fully use implicit information in the data, the latter methods are more flexible in the types of data they can handle. This study presents a comparison of the 2 types of association mapping methods when they are applied to simulated data. PMID- 27980670 TI - Causal effect estimation in sequencing studies: a Bayesian method to account for confounder adjustment uncertainty. AB - Estimating the causal effect of a single nucleotide variant (SNV) on clinical phenotypes is of interest in many genetic studies. The effect estimation may be confounded by other SNVs as a result of linkage disequilibrium as well as demographic and clinical characteristics. Because a large number of these other variables, which we call potential confounders, are collected, it is challenging to select and adjust for the variables that truly confound the causal effect. The Bayesian adjustment for confounding (BAC) method has been proposed as a general method to estimate the average causal effect in the presence of a large number of potential confounders under the assumption of no unmeasured confounders. In this paper, we explore the application of BAC in genetic studies using Genetic Analysis Workshop 19 exome sequencing data. Our results show that BAC can efficiently estimate the causal effect of genetic variants with adjustment for confounding. Consequently, BAC may serve as a useful tool for genome-wide association studies data analysis to effectively assess the causal effect of genetic variants and the impact of potential interventions. PMID- 27980671 TI - Biorefinery cascade processing for creating added value on tomato industrial by products from Tunisia. AB - BACKGROUND: In today's consumer perception of industrial processes and food production, aspects like food quality, human health, environmental safety, and energy security have become the keywords. Therefore, much effort has been extended toward adding value to biowastes of agri-food industries through biorefinery processing approaches. This study focused, for the first time, on the valorization of tomato by-products of a Tunisian industry for the recovery of value-added compounds using biorefinery cascade processing. RESULTS: The process integrated supercritical CO2 extraction of carotenoids within the oil fractions from tomato seeds (TS) and tomato peels (TP), followed by a batch isolation of protein from the residues. The remaining lignocellulosic matter from both fractions was then submitted to a liquid hot water (LHW) hydrolysis. Supercritical CO2 experiments extracted 5.79% oleoresin, 410.53 mg lycopene/kg, and 31.38 mg beta-carotene/kg from TP and 26.29% oil, 27.84 mg lycopene/kg, and 5.25 mg beta-carotene/kg from TS, on dry weights. Protein extraction yields, nearing 30% of the initial protein contents equal to 13.28% in TP and 39.26% in TS, revealed that TP and TS are a rich source of essential amino acids. LHW treatment run at 120-200 degrees C, 50 bar for 30 min showed that a temperature of 160 degrees C was the most convenient for cellulose and hemicellulose hydrolysis from TP and TS, while keeping the degradation products low. CONCLUSIONS: Results indicated that tomato by-products are not only a green source of lycopene-rich oleoresin and tomato seed oil (TSO) and of protein with good nutritional quality but also a source of lignocellulosic matter with potential for bioethanol production. This study would provide an important reference for the concept and the feasibility of the cascade fractionation of valuable compounds from tomato industrial by-products.Graphical abstractSchema of biorefinery cascade processing of tomato industrial by-products toward isolation of valuable fractions. PMID- 27980673 TI - Erratum to: Promise of combined hydrothermal/chemical and mechanical refining for pretreatment of woody and herbaceous biomass. AB - [This corrects the article DOI: 10.1186/s13068-016-0505-2.]. PMID- 27980672 TI - Systematic engineering of pentose phosphate pathway improves Escherichia coli succinate production. AB - BACKGROUND: Succinate biosynthesis of Escherichia coli is reducing equivalent dependent and the EMP pathway serves as the primary reducing equivalent source under anaerobic condition. Compared with EMP, pentose phosphate pathway (PPP) is reducing equivalent-conserving but suffers from low efficacy. In this study, the ribosome binding site library and modified multivariate modular metabolic engineering (MMME) approaches are employed to overcome the low efficacy of PPP and thus increase succinate production. RESULTS: Altering expression levels of different PPP enzymes have distinct effects on succinate production. Specifically, increased expression of five enzymes, i.e., Zwf, Pgl, Gnd, Tkt, and Tal, contributes to increased succinate production, while the increased expression of two enzymes, i.e., Rpe and Rpi, significantly decreases succinate production. Modular engineering strategy is employed to decompose PPP into three modules according to position and function. Engineering of Zwf/Pgl/Gnd and Tkt/Tal modules effectively increases succinate yield and production, while engineering of Rpe/Rpi module decreases. Imbalance of enzymatic reactions in PPP is alleviated using MMME approach. Finally, combinational utilization of engineered PPP and SthA transhydrogenase enables succinate yield up to 1.61 mol/mol glucose, which is 94% of theoretical maximum yield (1.71 mol/mol) and also the highest succinate yield in minimal medium to our knowledge. CONCLUSIONS: In summary, we systematically engineered the PPP for improving the supply of reducing equivalents and thus succinate production. Besides succinate, these PPP engineering strategies and conclusions can also be applicable to the production of other reducing equivalent-dependent biorenewables. PMID- 27980675 TI - Is immediate weight bearing safe for periprosthetic distal femur fractures treated by locked plating? A feasibility study in 52 consecutive patients. AB - BACKGROUND: Periprosthetic distal femur fractures associated with total knee replacement are increasing in incidence. We hypothesized that a standardized management protocol would result in few implant failures and a low rate of postoperative complications. METHODS: Retrospective observational cohort study at an urban level 1 trauma center and academic level 2 trauma center. Consecutive patients with periprosthetic distal femur fractures and stable total knee arthroplasty were included between January 1, 2011 and December 31, 2014. Patients were managed by a standardized protocol of co-management by a hospitalist service, fracture fixation within 24 h of admission by less-invasive locked bridge plating, and immediate unrestricted postoperative weight bearing. The primary outcome measure was the rate of postoperative complications. Secondary outcome measures included time to surgery, intraoperative blood loss, duration of surgery, length of hospital stay, time to full weight bearing, and time to radiographic fracture healing. RESULTS: Fifty four fractures were treated in 52 patients. There were three implant failures, one deep infection, one nonunion and two patients with symptomatic malunion. One patient had knee pain due to patellar component instability associated with valgus alignment. There were ten thromboembolic complications despite consistent anticoagulation. Two patients died within 12 months of injury. Thirty-eight patients had returned to their pre-injury ambulation status at 1 year follow-up. CONCLUSION: A standardized approach of less-invasive locked plating fixation and immediate unrestricted weight bearing appears safe and feasible in the management of this vulnerable patient cohort. TRIAL REGISTRATION NUMBER: This is a retrospective observational study without a Trial registration number. PMID- 27980674 TI - Succinate production positively correlates with the affinity of the global transcription factor Cra for its effector FBP in Escherichia coli. AB - BACKGROUND: Effector binding is important for transcription factors, affecting both the pattern and function of transcriptional regulation to alter cell phenotype. Our previous work suggested that the affinity of the global transcription factor catabolite repressor/activator (Cra) for its effector fructose-1,6-bisphosphate (FBP) may contribute to succinate biosynthesis. To support this hypothesis, single-point and three-point mutations were proposed through the semi-rational design of Cra to improve its affinity for FBP. RESULTS: For the first time, a positive correlation between succinate production and the affinity of Cra for FBP was revealed in Escherichia coli. Using the best-fit regression function, a cubic equation was used to examine and describe the relationship between succinate production and the affinity of Cra for FBP, demonstrating a significant positive correlation between the two factors (coefficient of determination R2 = 0.894, P = 0.000 < 0.01). The optimal mutant strain was Tang1683, which provided the lowest mutation energy of -4.78 kcal/mol and the highest succinate concentration of 92.7 g/L, which was 34% higher than that obtained using an empty vector control. The parameters for the interaction between Cra and DNA showed that Cra bound to the promoter regions of pck and aceB to activate the corresponding genes. Normally, Cra-regulated operons under positive control are deactivated in the presence of FBP. Therefore, theoretically, the enhanced affinity of Cra for FBP will inhibit the activation of pck and aceB. However, the activation of genes involved in CO2 fixation and the glyoxylate pathway was further improved by the Cra mutant, ultimately contributing to succinate biosynthesis. CONCLUSIONS: Enhanced binding of Cra to FBP or active site mutations may eliminate the repressive effect caused by FBP, thus leading to increased activation of genes associated with succinate biosynthesis in the Cra mutant. This work demonstrates an important transcriptional regulation strategy in the metabolic engineering of succinate production and provides useful information for better understanding of the regulatory mechanisms of transcription factors. PMID- 27980676 TI - Autism and intellectual disability in a patient with two microdeletions in 6q16: a contiguous gene deletion syndrome? AB - BACKGROUND: Copy number variations play a significant role in the aetiology of developmental disabilities including non-syndromic intellectual disability and autism. CASE PRESENTATION: We describe a 19-year old patient with intellectual disability and autism for whom chromosomal microarray (CMA) analysis showed the unusual finding of two de novo microdeletions in cis position on chromosome 6q16.1q16.2 and 6q16.3. The two deletions span 10 genes, including FBXL4, POU3F2, PRDM13, CCNC, COQ3 and GRIK2. We compared phenotypes of patients with similar deletions and looked at the involvement of the genes in neuronal networks in order to determine the pathogenicity of our patient's deletions. CONCLUSIONS: We suggest that both deletions on 6q are causing his disease phenotype since they harbour several genes which are implicated in pathways of neuronal development and function. Further studies regarding the interaction between PRDM13 and GRIK2 specifically may be interesting. PMID- 27980677 TI - A 18p11.23-p11.31 microduplication in a boy with psychomotor delay, cerebellar vermis hypoplasia, chorioretinal coloboma, deafness and GH deficiency. AB - BACKGROUND: Rearrangements involving the short arm of chromosome 18 have been extensively described. Here we report a microduplication of 320.5-431.5 Kb at 18p11.31-p11.23 in a 10 year-old boy. CASE PRESENTATION: In a 10 year-old boy with moderate psychomotor delay, hypoplasia of the cerebellar vermis, chorioretinal coloboma, deafness and growth hormone deficiency (GHD), an interstitial microduplication at 18p11.31-p11.23 was identified by array-CGH. This maternally inherited microduplication, encompasses three genes, namely ARHGAP28, LINC00668 and LAMA1 (a gene involved in cerebellum and retinal development). CONCLUSIONS: The genotype-phenotype is discussed with particular attention to the LAMA1 gene, although it is difficult, as in many other similar situations, to assess the causality of the detected duplication in the absence of further studies aiming to explore the presence of co-occurring variants that could explain the incomplete penetrance. PMID- 27980678 TI - Adaptive swarm cluster-based dynamic multi-objective synthetic minority oversampling technique algorithm for tackling binary imbalanced datasets in biomedical data classification. AB - BACKGROUND: An imbalanced dataset is defined as a training dataset that has imbalanced proportions of data in both interesting and uninteresting classes. Often in biomedical applications, samples from the stimulating class are rare in a population, such as medical anomalies, positive clinical tests, and particular diseases. Although the target samples in the primitive dataset are small in number, the induction of a classification model over such training data leads to poor prediction performance due to insufficient training from the minority class. RESULTS: In this paper, we use a novel class-balancing method named adaptive swarm cluster-based dynamic multi-objective synthetic minority oversampling technique (ASCB_DmSMOTE) to solve this imbalanced dataset problem, which is common in biomedical applications. The proposed method combines under-sampling and over-sampling into a swarm optimisation algorithm. It adaptively selects suitable parameters for the rebalancing algorithm to find the best solution. Compared with the other versions of the SMOTE algorithm, significant improvements, which include higher accuracy and credibility, are observed with ASCB_DmSMOTE. CONCLUSIONS: Our proposed method tactfully combines two rebalancing techniques together. It reasonably re-allocates the majority class in the details and dynamically optimises the two parameters of SMOTE to synthesise a reasonable scale of minority class for each clustered sub-imbalanced dataset. The proposed methods ultimately overcome other conventional methods and attains higher credibility with even greater accuracy of the classification model. PMID- 27980679 TI - MISSEL: a method to identify a large number of small species-specific genomic subsequences and its application to viruses classification. AB - BACKGROUND: Continuous improvements in next generation sequencing technologies led to ever-increasing collections of genomic sequences, which have not been easily characterized by biologists, and whose analysis requires huge computational effort. The classification of species emerged as one of the main applications of DNA analysis and has been addressed with several approaches, e.g., multiple alignments-, phylogenetic trees-, statistical- and character-based methods. RESULTS: We propose a supervised method based on a genetic algorithm to identify small genomic subsequences that discriminate among different species. The method identifies multiple subsequences of bounded length with the same information power in a given genomic region. The algorithm has been successfully evaluated through its integration into a rule-based classification framework and applied to three different biological data sets: Influenza, Polyoma, and Rhino virus sequences. CONCLUSIONS: We discover a large number of small subsequences that can be used to identify each virus type with high accuracy and low computational time, and moreover help to characterize different genomic regions. Bounding their length to 20, our method found 1164 characterizing subsequences for all the Influenza virus subtypes, 194 for all the Polyoma viruses, and 11 for Rhino viruses. The abundance of small separating subsequences extracted for each genomic region may be an important support for quick and robust virus identification. Finally, useful biological information can be derived by the relative location and abundance of such subsequences along the different regions. PMID- 27980681 TI - Targeted bisulfite sequencing of the dynamic DNA methylome. AB - BACKGROUND: The ability to measure DNA methylation precisely and efficiently continues to drive our understanding of this modification in development and disease. Whole genome bisulfite sequencing has the advantage of theoretically capturing all cytosines in the genome at single-nucleotide resolution, but it has a number of significant practical drawbacks that become amplified with increasing sample numbers. All other technologies capture only a fraction of the cytosines that show dynamic regulation across cell and tissue types. RESULTS: Here, we present a novel hybrid selection design focusing on loci with dynamic methylation that captures a large number of differentially methylated gene-regulatory elements. We benchmarked this assay against matched whole genome data and profiled 25 human tissue samples to explore its ability to detect differentially methylated regions. CONCLUSIONS: Our target capture design fills a major gap left by all other assays that exist to map DNA methylation. It maintains the ability to link cytosine methylation to genetic differences, the single-base resolution and the analysis of neighboring cytosines while notably reducing the cost per sample by focusing the sequencing effort on the most informative and relevant regions of the genome. PMID- 27980680 TI - HOXA repression is mediated by nucleoporin Nup93 assisted by its interactors Nup188 and Nup205. AB - BACKGROUND: The nuclear pore complex (NPC) mediates nuclear transport of RNA and proteins into and out of the nucleus. Certain nucleoporins have additional functions in chromatin organization and transcription regulation. Nup93 is a scaffold nucleoporin at the nuclear pore complex which is associated with human chromosomes 5, 7 and 16 and with the promoters of the HOXA gene as revealed by ChIP-on-chip studies using tiling microarrays for these chromosomes. However, the functional consequences of the association of Nup93 with HOXA is unknown. RESULTS: Here, we examined the association of Nup93 with the HOXA gene cluster and its consequences on HOXA gene expression in diploid colorectal cancer cells (DLD1). Nup93 showed a specific enrichment ~1 Kb upstream of the transcription start site of each of the HOXA1, HOXA3 and HOXA5 promoters, respectively. Furthermore, the association of Nup93 with HOXA was assisted by its interacting partners Nup188 and Nup205. The depletion of the Nup93 sub-complex significantly upregulated HOXA gene expression levels. However, expression levels of a control gene locus (GLCCI1) on human chromosome 7 were unaffected. Three-dimensional fluorescence in situ hybridization (3D-FISH) analyses revealed that the depletion of the Nup93 sub-complex (but not Nup98) disengages the HOXA gene locus from the nuclear periphery, suggesting a potential role for Nup93 in tethering and repressing the HOXA gene cluster. Consistently, Nup93 knockdown increased active histone marks (H3K9ac), decreased repressive histone marks (H3K27me3) on the HOXA1 promoter and increased transcription elongation marks (H3K36me3) within the HOXA1 gene. Moreover, the combined depletion of Nup93 and CTCF (a known organizer of HOXA gene cluster) but not Nup93 alone, significantly increased GLCCI1 gene expression levels. Taken together, this suggests a novel role for Nup93 and its interactors in repressing the HOXA gene cluster. CONCLUSIONS: This study reveals that the nucleoporin Nup93 assisted by its interactors Nup188 and Nup205 mediates the repression of HOXA gene expression. PMID- 27980682 TI - "Gap hunting" to characterize clustered probe signals in Illumina methylation array data. AB - BACKGROUND: The Illumina 450k array has been widely used in epigenetic association studies. Current quality-control (QC) pipelines typically remove certain sets of probes, such as those containing a SNP or with multiple mapping locations. An additional set of potentially problematic probes are those with DNA methylation distributions characterized by two or more distinct clusters separated by gaps. Data-driven identification of such probes may offer additional insights for downstream analyses. RESULTS: We developed a procedure, termed "gap hunting," to identify probes showing clustered distributions. Among 590 peripheral blood samples from the Study to Explore Early Development, we identified 11,007 "gap probes." The vast majority (9199) are likely attributed to an underlying SNP(s) or other variant in the probe, although SNP-affected probes exist that do not produce a gap signals. Specific factors predict which SNPs lead to gap signals, including type of nucleotide change, probe type, DNA strand, and overall methylation state. These expected effects are demonstrated in paired genotype and 450k data on the same samples. Gap probes can also serve as a surrogate for the local genetic sequence on a haplotype scale and can be used to adjust for population stratification. CONCLUSIONS: The characteristics of gap probes reflect potentially informative biology. QC pipelines may benefit from an efficient data-driven approach that "flags" gap probes, rather than filtering such probes, followed by careful interpretation of downstream association analyses. Our results should translate directly to the recently released Illumina EPIC array given the similar chemistry and content design. PMID- 27980683 TI - Clinical measures of static foot posture do not agree. AB - BACKGROUND: The aim of this study was to determine the level of agreement between common clinical foot classification measures. METHODS: Static foot assessment was undertaken using the Foot Posture Index (FPI-6), rearfoot angle (RFA), medial longitudinal arch angle (MLAA) and navicular drop (ND) in 30 participants (29 +/- 6 years, 1.72 +/- 0.08 m, 75 +/- 18 kg). The right foot was measured on two occasions by one rater within the same test environment. Agreement between the test sessions was initially determined for each measure using the Weighted Kappa. Agreement between the measures was determined using Fleiss Kappa. RESULTS: Foot classification across the two test occasions was almost perfect for MLAA (Kw = .92) and FPI-6 (Kw = .92), moderate for RFA (Kw = .60) and fair for ND (Kw = .40) for comparison within the measures. Overall agreement between the measures for foot classification was moderate (Kf = .58). CONCLUSION: The findings reported in this study highlight discrepancies between the chosen foot classification measures. The FPI-6 was a reliable multi-planar measure whereas navicular drop emerged as an unreliable measure with only fair agreement across test sessions. The use of this measure for foot assessment is discouraged. The lack of strong consensus between measures for foot classification underpins the need for a consensus on appropriate clinical measures of foot structure. PMID- 27980684 TI - The relationship between foot posture index, ankle equinus, body mass index and intermetatarsal neuroma. AB - BACKGROUND: The main purpose of this study was to investigate the presence of an association between intermetatarsal neuroma and foot type, as measured by the Foot Posture Index. The study also examined whether there was a relationship between foot type and the interspace affected with intermetatarsal neuroma, and whether ankle equinus or body mass index had an effect. METHODS: In total, 100 participants were recruited from The University of Western Australia's Podiatry Clinic, 68 of whom were diagnosed with inter-metatarsal neuroma from 2009 to 2015. There were 32 control participants recruited from 2014 to 2015. The age of subjects was recorded, as were weight and height, which were used to calculate body mass index. The foot posture index and ankle dorsiflexion were measured using standard technique. Independent t-tests and Kruskal-Wallis tests were used to compare differences in foot posture index, body mass index and ankle dorsiflexion between the inter-metatarsal neuroma and control groups. Multivariable logistic regression was also used to model relationships for outcome. RESULTS: The 68 intermetatarsal neuroma subjects had a mean age of 52 years (range 20 to 74 years) and comprised of 56 females and 12 males. The 32 control subjects had a mean age of 49 years (range 24 to 67 years) with 26 females and six males. There were no significant differences between the control and the intermetatarsal neuroma groups with respect to the mean foot posture index scores of the left and right foot (p = 0.21 and 0.87, respectively). Additionally no significant differences were detected between the affected intermetatarsal neuroma interspace and foot posture index (p = 0.27 and 0.47, respectively). There was no significant difference in mean body mass index between the intermetatarsal neuroma (26.9 +/- 5.7) and control groups (26.5 +/- 4.1) (p = 0.72). There was, however, a significant difference in mean ankle dorsiflexion between the intermetatarsal neuroma and control groups (p < 0.001 for both feet). Logistic regression models, adjusted for age, sex, foot posture index and body mass index estimated that the odds of having an intermetatarsal neuroma in the right foot increased by 61% (OR 1.61; 95% CI 1.32-1.96) with each one degree reduction of ankle dorsiflexion, and in the left foot by 43% (OR 1.43; 95% CI 1.22-1.69). CONCLUSION: No relationships were found between foot posture index and body mass index with intermetatarsal neuroma, or between foot posture index and the interspaces affected. However, a strong association was demonstrated between the presence of intermetatarsal neuroma and a restriction of ankle dorsiflexion. PMID- 27980685 TI - A targeted screening method for non-invasive vascular assessment of the lower limb. AB - BACKGROUND: Podiatrists routinely perform non-invasive lower limb vascular assessment, however frequently cite time as a major barrier in performing regular assessment. The aim of this study was to develop an evidence-based vascular assessment method to guide podiatrists' decision-making processes to aid in timely vascular assessment in at risk populations. METHOD: The sample underwent brachial pressure measurement, ankle pressures, toe pressure and Doppler waveform with colour duplex ultrasound (CFDU) used as the reference standard. Both the targeted screening method and the American Heart Association (AHA) guideline for vascular screening were then applied to the data set and sensitivity and specificity of each method was calculated. RESULTS: One hundred nineteen participants were included. Sensitivity of the targeted screening method (62%, 95% CI 47.17-75.35) was higher than the AHA method (49%, 95% CI 34.75-63.40), however, specificity of the AHA method (94%, 95% CI 85.62-98.37) was higher than the targeted screening method (85%, 95% CI 74.26-92.60). Diagnostic accuracy was similar with the AHA method yielding 74% diagnostic accuracy and the targeted screening method 73%. CONCLUSION: The targeted screening method and the broad international guideline demonstrated similar accuracy, however clinicians may save time using the targeted screening method. This study highlights the difficulties in obtaining accuracy in lower limb vascular assessment in general. PMID- 27980687 TI - Alterations of the gut microbiome in Chinese patients with systemic lupus erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) in patients from Spain is associated with intestinal dysbiosis. This study explores whether the alteration of the gut microbiome in SLE patients from China is consistent with the intestinal dysbiosis of SLE patients from Spain. RESULTS: The depletion of Firmicutes and the enrichment of Bacteroidetes in SLE patients from China were consistent with the SLE patients from Spain. Furthermore, we found that nine genera of gut microbiota were SLE-related microorganisms in Chinese subjects. Genera Rhodococcus, Eggerthella, Klebsiella, Prevotella, Eubacterium, Flavonifractor and Incertae sedis were significantly enriched, while genera Dialister and Pseudobutyrivibrio were significantly depleted in SLE patients. Receiver operating characteristic analysis indicated that the nine genera have the potential to distinguish SLE patients from healthy controls. CONCLUSIONS: Comparing the dysbiosis of the gut microbiome among SLE patients from China or Spain, may indicate that the gut microbiome profiles of SLE patients are more influenced by disease than ethnicity. PMID- 27980686 TI - Clostridium difficile colonization and antibiotics response in PolyFermS continuous model mimicking elderly intestinal fermentation. AB - BACKGROUND: Clostridium difficile (CD), a spore-forming and toxin-producing bacterium, is the main cause for antibiotic-associated diarrhea in the elderly. Here we investigated CD colonization in novel in vitro fermentation models inoculated with immobilized elderly fecal microbiota and the effects of antibiotic treatments. METHODS: Two continuous intestinal PolyFermS models inoculated with different immobilized elder microbiota were used to investigate selected factors of colonization of CD in proximal (PC, model 1) and transverse distal (TDC, model 1 and 2) colon conditions. Colonization of two CD strains of different PCR ribotypes, inoculated as vegetative cells (ribotype 001, model 1) or spores (ribotypes 001 and 012, model 2), was tested. Treatments with two antibiotics, ceftriaxone (daily 150 mg L-1) known to induce CD infection in vivo or metronidazole (twice daily 333 mg L-1) commonly used to treat CD, were investigated in TDC conditions (model 2) for their effects on gut microbiota composition (qPCR, 16S pyrosequencing) and activity (HPLC), CD spore germination and colonization, and cytotoxin titer (Vero cell assay). RESULTS: CD remained undetected after inoculating vegetative cells in PC reactors of model 1, but was shown to colonize TDC reactors of both models, reaching copy numbers of up to log10 8 mL-1 effluent with stable production of toxin correlating with CD cell numbers. Ceftriaxone treatment in TDC reactors showed only small effects on microbiota composition and activity and did not promote CD colonization compared to antibiotic-free control reactor. In contrast, treatment with metronidazole after colonization of CD induced large modifications in the microbiota and decreased CD numbers below the detection limit of the specific qPCR. However, a fast CD recurrence was measured only 2 days after cessation of metronidazole treatment. CONCLUSIONS: Using our in vitro fermentation models, we demonstrated that stable CD colonization in TDC reactors can be induced by inoculating CD vegetative cells or spores without the application of ceftriaxone. Treatment with metronidazole temporarily reduced the counts of CD, in agreement with CD infection recurrence in vivo. Our data demonstrate that CD colonized an undisturbed microbiota in vitro, in contrast to in vivo observations, thus suggesting an important contribution of host-related factors in the protection against CD infection. PMID- 27980688 TI - Association of diabetic vascular complications with poor sleep complaints. AB - BACKGROUND: Literatures reported that poor sleep complaints were associated with a great deal of health outcomes. However, there are few studies on the association of poor sleep complaints with diabetic vascular complications. METHODS: Aiming on the association, a cross-sectional survey was conducted among 1220 diabetic patients in this study. Poor sleep complaints were composed of difficulty falling asleep, early final awakening, short sleep and long sleep. The diabetic vascular complications involved in the study were diagnosed according to the Standards of Medical Care in Diabetes (ADA 2016). RESULTS: Our findings indicated that short sleep remained independently associated with diabetic kidney disease (DKD) (OR > 1, P < 0.05) after the adjustments; long sleep independently associated with diabetic retinopathy (DR) (OR > 1, P < 0.05); early final awakening and short sleep independently associated with cardiovascular disease (OR > 1, P < 0.05); short sleep independently associated with peripheral arterial disease (OR > 1, P < 0.05); there was no association between poor sleep complaints and neuropathy (P > 0.05). CONCLUSIONS: The study suggests that the poor sleep complaints were distinguishably associated with diabetic vascular complications. Clinicians should take poor sleep complaints into account in diabetes treatment. PMID- 27980690 TI - The intron-enriched HERV-K(HML-10) family suppresses apoptosis, an indicator of malignant transformation. AB - BACKGROUND: Human endogenous retroviruses (HERVs) constitute 8% of the human genome and contribute substantially to the transcriptome. HERVs have been shown to generate RNAs that modulate host gene expression. However, experimental evidence for an impact of these regulatory transcripts on the cellular phenotype has been lacking. RESULTS: We characterized the previously little described HERV K(HML-10) endogenous retrovirus family on a genome-wide scale. HML-10 invaded the ancestral genome of Old World monkeys about 35 Million years ago and is enriched within introns of human genes when compared to other HERV families. We show that long terminal repeats (LTRs) of HML-10 exhibit variable promoter activity in human cancer cell lines. One identified HML-10 LTR-primed RNA was in opposite orientation to the pro-apoptotic Death-associated protein 3 (DAP3). In HeLa cells, experimental inactivation of HML-10 LTR-primed transcripts induced DAP3 expression levels, which led to apoptosis. CONCLUSIONS: Its enrichment within introns suggests that HML-10 may have been evolutionary co-opted for gene regulation more than other HERV families. We demonstrated such a regulatory activity for an HML-10 RNA that suppressed DAP3-mediated apoptosis in HeLa cells. Since HML-10 RNA appears to be upregulated in various tumor cell lines and primary tumor samples, it may contribute to evasion of apoptosis in malignant cells. However, the overall weak expression of HML-10 transcripts described here raises the question whether our result described for HeLa represent a rare event in cancer. A possible function in other cells or tissues requires further investigation. PMID- 27980691 TI - Extremity injuries and dementia disproportionately increase the risk for long term care at older age in an analysis of German Health Insurance routine data for the years 2006 to 2010. AB - BACKGROUND: Extremity injuries (EI) and dementia are important causes of long term care (LTC), but they can also cause each other and are often present concurrently. Mobility-limiting EI can increase the risk of dementia, and dementia increases the risk for falls, which are often the cause of EI. When EI and dementia are present together, they can increase their negative effect on long-term care risk. This study aims to assess the strength of this interaction and the role of different body regions and severities of EI regarding LTC risk. METHODS: We use Cox proportional-hazard models on LTC as dependent variable. EI (primarily fractures) and dementia (all types) are the central independent variables. We control for age, sex, rehabilitation and 18 relevant comorbidities. Analyses are based on health claims records for 2004-2010 for a random sample of about 122.000 insurants of Germany's largest public health insurance "AOK" aged 65+, about 25.000 of whom entered LTC. RESULTS: Without concurrent dementia, non severe EI (NSEI) of the lower and both extremities and all kinds of severe EI (SEI) increase LTC risk (HR: hazard ratio with 95% confidence interval. Lower NSEI: HR = 1.09 [1.05-1.14]; both NSEI: HR = 1.36 [1.29-1.44]. Lower SEI: HR = 1.67 [1.57-1.79]; upper SEI: HR = 1.27 [1.19-1.37]; both SEI: HR = 1.94 [1.81 2.07]). Dementia alone increases LTC risk more than fourfold (HR = 4.23 [4.11 4.35]). Taking the interaction of EI and dementia into account, the concurrent presence of EI and dementia tends to increase the LTC risk more than expected for lower as well as upper NSEI and SEI. Summarily, when lower or upper EI and dementia are both present, the LTC risk tends to be higher than expected, suggesting synergistic effects. CONCLUSIONS: EI and dementia are important independent risk factors for long-term care. When lower or upper EI and dementia are present together, the resulting long-term care risk is increased disproportionately. Since the concurrent presence of both conditions increases the risk for care need, and a working treatment for dementia is not in sight, preventing EI, lessening the impact of EI and improving the outlook after an EI could help to reduce LTC need in the coming decades. PMID- 27980689 TI - Endogenous retroviral promoter exaptation in human cancer. AB - Cancer arises from a series of genetic and epigenetic changes, which result in abnormal expression or mutational activation of oncogenes, as well as suppression/inactivation of tumor suppressor genes. Aberrant expression of coding genes or long non-coding RNAs (lncRNAs) with oncogenic properties can be caused by translocations, gene amplifications, point mutations or other less characterized mechanisms. One such mechanism is the inappropriate usage of normally dormant, tissue-restricted or cryptic enhancers or promoters that serve to drive oncogenic gene expression. Dispersed across the human genome, endogenous retroviruses (ERVs) provide an enormous reservoir of autonomous gene regulatory modules, some of which have been co-opted by the host during evolution to play important roles in normal regulation of genes and gene networks. This review focuses on the "dark side" of such ERV regulatory capacity. Specifically, we discuss a growing number of examples of normally dormant or epigenetically repressed ERVs that have been harnessed to drive oncogenes in human cancer, a process we term onco-exaptation, and we propose potential mechanisms that may underlie this phenomenon. PMID- 27980693 TI - Predictors of Informant Discrepancies Between Mother and Middle School Teacher ADHD Ratings. AB - A diagnosis of attention-deficit/hyperactivity disorder (ADHD) according to the Diagnostic and Statistical Manual, 5th Eldition (DSM-5) is assessed in youth using ratings from both a parent and a teacher. However, individual and contextual differences between informants may lead to discrepancies in these ratings. The purpose of this study was to examine predictors of discrepancies between mother and middle school teacher reports of ADHD symptoms and related impairment. In an ethnically diverse sample of middle school students with well diagnosed DSM-IV-TR ADHD (N = 112), we examined a range of mother and school setting characteristics that may contribute to informant discrepancies in this population. Hierarchical multiple regression analyses suggested that mothers with higher levels of education and psychopathology (i.e., ADHD symptom severity, parenting stress) may be most likely to report adolescent ADHD symptom severity that is higher than reported by teachers. Reports from general education teachers (vs. special education) were associated with lower symptom severity compared to mothers. Finally, a documented diagnosis of ADHD in the school was predictive of more severe reports from mothers. We discuss explanations for these findings and implications for assessment of middle school students with ADHD. PMID- 27980694 TI - A methylation PCR method determines FMR1 activation ratios and differentiates premutation allele mosaicism in carrier siblings. AB - BACKGROUND: Epigenetic modifications of the fragile X mental retardation 1 (FMR1) gene locus may impact the risk for reproductive and neurological disorders associated with expanded trinucleotide repeats and methylation status in the 5' untranslated region. FMR1 methylation is commonly assessed by Southern blot (SB) analysis, yet this method suffers a cumbersome workflow and relatively poor sizing resolution especially for premutation allele characteristic for fragile X associated disorders. In this study, a methylation PCR (mPCR) assay was used to evaluate correlations among genotype, epitype, and phenotype in fragile X premutation (PM) carrier women in order to advance the understanding of the association between molecular determinants and the presence of fragile X associated tremor and ataxia (FXTAS). RESULTS: Activation ratios (ARs) in 39 PM women were determined by mPCR and compared with SB analysis. ARs were distributed across a range of values including five samples with <20% AR and six with >80% AR. The two methods were correlated (R2 of 0.87 and F test of <0.001), indicating that mPCR can measure AR in agreement with established assays. However, mPCR was unique in identifying novel and distinct patterns of methylation mosaicism in premutation carrier women, including seven sibling pairs that were assessed using FXTAS clinical rating scales. Of note, four of six pairs with defined age of onset for neurological signs showed ARs consistent with skewed activation of the pathogenic expanded allele. One subject with severe FXTAS had a mosaic full mutation allele identified using mPCR but not detected by SB analysis. CONCLUSIONS: We utilized a repeatable and streamlined methodology to characterize FMR1 inactivation in premutation carrier women. The method was concordant with SB analysis and provided higher resolution information on allele and methylation mosaicism. This approach can facilitate the characterization of epigenetic factors influencing fragile X phenotypes in larger cohort studies that can advance understanding and treatment of fragile X-associated disorders. PMID- 27980692 TI - Wnt signaling networks in autism spectrum disorder and intellectual disability. AB - BACKGROUND: Genetic factors play a major role in the risk for neurodevelopmental disorders such as autism spectrum disorders (ASDs) and intellectual disability (ID). The underlying genetic factors have become better understood in recent years due to advancements in next generation sequencing. These studies have uncovered a vast number of genes that are impacted by different types of mutations (e.g., de novo, missense, truncation, copy number variations). ABSTRACT: Given the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling "hubs" where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function. CONCLUSIONS: We will also review evidence that pharmacological therapies and genetic mouse models further identify abnormal Wnt signaling, particularly at the synapse, as being disrupted in ASDs and contributing to disease pathology. PMID- 27980698 TI - In the beginning when the Japanese Environmental Mutagen Society was established. AB - Upon the commemoration of the 10th anniversary of the journal, "Genes and Environment", the history of sciences on environmental mutagens in Japan was reviewed. PMID- 27980695 TI - Epigenome-wide association data implicates DNA methylation-mediated genetic risk in psoriasis. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and altered keratinocyte differentiation and inflammation and is caused by the interplay of genetic and environmental factors. Previous studies have revealed that DNA methylation (DNAm) and genetic makers are closely associated with psoriasis, and strong evidences have shown that DNAm can be controlled by genetic factors, which attracted us to evaluate the relationship among DNAm, genetic makers, and disease status. METHODS: We utilized the genome wide methylation data of psoriatic skin (PP, N = 114) and unaffected control skin (NN, N = 62) tissue samples in our previous study, and we performed whole-genome genotyping with peripheral blood of the same samples to evaluate the underlying genetic effect on skin DNA methylation. Causal inference test (CIT) was used to assess whether DNAm regulate genetic variation and gain a better understanding of the epigenetic basis of psoriasis susceptibility. RESULTS: We identified 129 SNP CpG pairs achieving the significant association threshold, which constituted 28 unique methylation quantitative trait loci (MethQTL) and 34 unique CpGs. There are 18 SNPs were associated with psoriasis at a Bonferoni-corrected P < 0.05, and these 18 SNPs formed 93 SNP-CpG pairs with 17 unique CpG sites. We found that 11 of 93 SNP-CpG pairs, composed of 5 unique SNPs and 3 CpG sites, presented a methylation-mediated relationship between SNPs and psoriasis. The 3 CpG sites were located on the body of C1orf106, the TSS1500 promoter region of DMBX1 and the body of SIK3. CONCLUSIONS: This study revealed that DNAm of some genes can be controlled by genetic factors and also mediate risk variation for psoriasis in Chinese Han population and provided novel molecular insights into the pathogenesis of psoriasis. PMID- 27980696 TI - Characterization of TET and IDH gene expression in chronic lymphocytic leukemia: comparison with normal B cells and prognostic significance. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in western countries, characterized by a heterogeneous clinical course. Although genetic studies have identified chromosomal aberrations or specific mutations, epigenetic changes have been poorly characterized in CLL. METHODS: We assessed ten-eleven translocations (TET) 1, 2, and 3, isocitrate dehydrogenase (IDH) 1, and 2 messenger RNA (mRNA) expression using real-time PCR on purified leukemic B cells from 214 CLL patients (median follow-up = 75 months, range 1-380), normal peripheral blood B cells (n = 20), and umbilical cord blood B cells (n = 21). The microenvironment influence was assessed after 24 h co culture of CLL cells with bone marrow mesenchymal stromal cells (BMSC). Finally, 5-hydroxymethylcytosine level (%5-hmC) was assessed by ELISA in CLL cells alone or with microenvironment stimuli. RESULTS: TET 1 and 3 and IDH2 were decreased in CLL cells compared with healthy B cells (P = 0.0221, 0.0013, <0.0001, respectively), while IDH1 was overexpressed (P = 0.0037). TET2 and IDH1 were significantly correlated with treatment-free survival (TFS); patients with high TET2/IDH1 expression had a higher median TFS (111 months) than patients with low expression (78 months, P = 0.0071/0.0123). Moreover, TET1 expression decreased (P = 0.0371), while TET3 and IDH2 expression increased (P = 0.0273/0.0039) in co cultures. However, %5-hmC was not correlated with clinical data and was unchanged following microenvironment stimuli. CONCLUSIONS: Despite a slight deregulation in CLL cells compared with normal B cells, we identified a significant association between TET/IDH gene expression and prognosis, suggesting that epigenetic changes could potentially be associated with disease progression. Moreover, despite an identical %5-hmC, TET gene expression was influenced by contact with BMSC confirming the crucial role of the microenvironment in CLL pathogenesis. PMID- 27980697 TI - Discovery of biomarkers in rare diseases: innovative approaches by predictive and personalized medicine. AB - There are more than 8000 rare diseases (RDs) that affect >5 % of the world's population. Many of the RDs have no effective treatment and lack of knowledge creates delayed diagnosis making management difficult. The emerging concept of the personalized medicine allows for early screening, diagnosis, and individualized treatment of human diseases. In this context, the discovery of biomarkers in RDs will be of prime importance to enable timely prevention and effective treatment. Since 80 % of RDs are of genetic origin, identification of new genes and causative mutations become valuable biomarkers. Furthermore, dynamic markers such as expressed genes, metabolites, and proteins are also very important to follow prognosis and response the therapy. Recent advances in omics technologies and their use in combination can define pathophysiological pathways that can be drug targets. Biomarker discovery and their use in diagnosis in RDs is a major pillar in RD research. PMID- 27980699 TI - Development and progress for three decades in umu test systems. AB - Umu test have been widely used to predict the detection and assessment of DNA- damaging chemicals in environmental genotoxicity field for three decades. This test system is more useful with respect to simplicity, sensitivity, rapidity, and reproducibility. A review of the literature on the development of the umu test is presented in this article. The contents of this article are included a description of numerous data using the umu test. This test have been fully evaluated and used in many directions. Different genetically engineered umu systems introducing bacterial and rat or human drug metabolizing enzymes into the umu tester strains, have been successfully established and are considered as useful tools for genotoxicity assays to study the mechanisms of biotransformation in chemical carcinogenesis. Actually, we developed that two types of bacterial metabolizing enzymes and 4 types of rat and human metabolizing enzyme DNAs are expressed in these strains such as nitroreductase and O-acetyltransferase, cytochrome P450, N-acetyltransferases, sulfotransferases, and glutathione S transferases, respectively. Due to increasing numbers of minute environmental samples and new pharmaceuticals, a high-throughput umu test system using Salmonella typhimurium TA1535/pSK1002, NM2009, and NM3009 strains provides a useful for these genotoxicity screening. I also briefly describe the first attempts to incorporate such umu tester strain into photo-genotoxicity test. PMID- 27980701 TI - Closure of a Tracheocutaneous Fistula With a Local Turnover Flap Combined With Pregrafted Palatal Mucosa: A Case Report. AB - Objectives: A method of closing a large tracheocutaneous fistula by a combination of a palatal mucosal graft with a turnover adiposal flap is presented. Methods: Mucosa of the same size as the tracheal defect was harvested from the hard palate and grafted just caudal to the fistula. After the mucosal graft had taken, a local flap containing the mucosal graft was turned over the tracheal defect facing the mucosa inward of the tracheal lumen. The defect caused by harvesting the flap was closed horizontally. Results: The fistula was closed successfully, and 1 year after the operation, the patient had no airway compromise and the operative scar was inconspicuous. Conclusions: Although the described method is a 2-stage procedure, it can be used to simply and reliably reconstruct the mucosal layer of the tracheal lumen and overlying skin. PMID- 27980700 TI - Mutations induced by 8-hydroxyguanine (8-oxo-7,8-dihydroguanine), a representative oxidized base, in mammalian cells. AB - Guanine oxidation occurs in both DNA and the cellular nucleotide pool, and one of the major products is 8-hydroxyguanine (8-oxo-7,8-dihydroguanine). The mutagenic potentials of this oxidized base have been examined in various experimental systems. In this review, we summarize the mutagenicity of the base in mammalian cells. We also describe the effects of specialized DNA polymerases, DNA repair proteins, and nucleotide pool sanitization enzymes. PMID- 27980702 TI - Severe Bilateral Lower Extremity Pyoderma Gangrenosum. PMID- 27980703 TI - Management of Severe Burn Microstomia. PMID- 27980704 TI - Local allergic rhinitis: entopy or spontaneous response? AB - BACKGROUND: The existence of a local allergic rhintis was proposed on the basis of the detection of nasal IgE in the absence of a systemic sensitization. Nevertheless, the significance of this phenomenon remains still unclear. We assessed the presence of mucosal nasal IgE in patients with ascertained allergic rhinitis, nonallergic rhinitis with inflammation and in healthy controls. METHODS: Consecutive patients with a well ascertained diagnosis (clinical history, skin prick test, specific IgE assay, nasal endoscopy, nasal cytology) underwent an immunoenzymatic measurement of specific IgE to grass, cypress, parietaria and olive in nasal scrapings. RESULTS: Fifteen patients with allergic rhinitis, 12 with non allergic rhinitis and 14 healthy subjects were studied. The patients with allergic and nonallergic rhinitis had higher nasal symptoms as compared to control subjects. Systemic sensitizatition (assessed by skin test and CAP-RAST) was obviously more frequent in allergic rhinitis, than in the other two groups. Allergen-specific nasal IgE could be detected in all groups (86,7, 33,3, and 50 % positive, respectively), even more frequently in the control group than in nonallergic rhinitis patients. No difference among allergens was identified. Out of the 26 non-allergic patients (non allergic rhinitis + controls) nasal IgE were positive in 11(42 %). DISCUSSION: According to the results, the presence of nasal IgE against allergens seems to be a non-specific phenomenon, since they can be detected also in non allergic rhinitis and in healthy subjects. CONCLUSION: It can be hypothesized that the nasal IgE production represents a form of spontaneous immune response. PMID- 27980705 TI - Asthma heterogeneity and severity. AB - Asthma is a common, chronic inflammatory airways disease characterized by a clinical syndrome of bronchial hyperresponsiveness, inflammation, and reversible airflow obstruction. Individuals with asthma can vary widely in clinical presentation, severity, and pathobiology. The incident factors, pathogenesis, prognosis, and treatment of asthma remain incompletely understood. Utilizing measurable characteristics of asthmatic patients, including demographic, physiologic, and biologic markers, can however identify meaningful phenotypic categories in asthma. Identification of these phenotypes may help improve precision therapeutics targeted toward an individual's' disease, and may identify strategies for preventing progression of disease severity. PMID- 27980707 TI - A Fluorescence Polarization Biophysical Assay for the Naegleria DNA Hydroxylase Tet1. AB - The discovery of the 5-methylcytosine (5mC) oxidation by the ten-eleven translocation (Tet) protein family was an important advancement in our understanding of DNA-modified epigenetics. Potent inhibitors of these proteins are greatly desired for both the understanding of the functions of these enzymes and to serve as eventual therapeutic leads. So far, the discovery of such small molecules with high affinity has been quite limited. Original tools to screen for activity are greatly needed in order to accelerate this process. Here we present a novel fluorescent probe, and the results of a fluorescence polarization-based binding assay for Naegleria Tet1, a homologue to mammalian Tet. A fluorescence polarization-based competition assay was also established and applied to the rapid and quantitative measurement of the binding affinity of the cofactor alphaKG and several known Tet1 inhibitors. PMID- 27980706 TI - Metagenome phylogenetic profiling of microbial community evolution in a tetrachloroethene-contaminated aquifer responding to enhanced reductive dechlorination protocols. AB - Chlorinated solvent contamination of potable water supplies is a serious problem worldwide. Biostimulation protocols can successfully remediate chlorinated solvent contamination through enhanced reductive dechlorination pathways, however the process is poorly understood and sometimes stalls creating a more serious problem. Whole metagenome techniques have the potential to reveal details of microbial community changes induced by biostimulation. Here we compare the metagenome of a tetrachloroethene contaminated Environmental Protection Agency Superfund Site before and after the application of biostimulation protocols. Environmental DNA was extracted from uncultured microbes that were harvested by on-site filtration of groundwater one month prior to and five months after the injection of emulsified vegetable oil, nutrients, and hydrogen gas bioamendments. Pair-end libraries were prepared for high-throughput DNA sequencing and 90 basepairs from both ends of randomly fragmented 400 basepair DNA fragments were sequenced. Over 31 millions reads were annotated with Metagenome Rapid Annotation using Subsystem Technology representing 32 prokaryotic phyla, 869 genera, and 3,181 species. A 3.6 log2 fold increase in biomass as measured by DNA yield per mL water was measured, but there was a 9% decrease in the number of genera detected post-remediation. We apply Bayesian statistical methods to assign false discovery rates to fold-change abundance data and use Zipf's power law to filter genera with low read counts. Plotting the log-rank against the log-fold-change facilitates the visualization of the changes in the community in response to the enhanced reductive dechlorination protocol. Members of the Archaea domain increased 4.7 log2 fold, dominated by methanogens. Prior to remediation, classes Alphaproteobacteria and Betaproteobacteria dominated the community but exhibit significant decreases five months after biostimulation. Geobacter and Sulfurospirillum replace "Sideroxydans" and Burkholderia as the most abundant genera. As a result of biostimulation, Deltaproteobacteria and Epsilonproteobacteria capable of dehalogenation, iron and sulfate reduction, and sulfur oxidation increase. Matches to thermophilic, haloalkane respiring archaea is evidence for additional species involved in biodegradation of chlorinated solvents. Additionally, potentially pathogenic bacteria increase, indicating that there may be unintended consequences of bioremediation. PMID- 27980708 TI - Bioinformatics strategies for taxonomy independent binning and visualization of sequences in shotgun metagenomics. AB - One of main steps in a study of microbial communities is resolving their composition, diversity and function. In the past, these issues were mostly addressed by the use of amplicon sequencing of a target gene because of reasonable price and easier computational postprocessing of the bioinformatic data. With the advancement of sequencing techniques, the main focus shifted to the whole metagenome shotgun sequencing, which allows much more detailed analysis of the metagenomic data, including reconstruction of novel microbial genomes and to gain knowledge about genetic potential and metabolic capacities of whole environments. On the other hand, the output of whole metagenomic shotgun sequencing is mixture of short DNA fragments belonging to various genomes, therefore this approach requires more sophisticated computational algorithms for clustering of related sequences, commonly referred to as sequence binning. There are currently two types of binning methods: taxonomy dependent and taxonomy independent. The first type classifies the DNA fragments by performing a standard homology inference against a reference database, while the latter performs the reference-free binning by applying clustering techniques on features extracted from the sequences. In this review, we describe the strategies within the second approach. Although these strategies do not require prior knowledge, they have higher demands on the length of sequences. Besides their basic principle, an overview of particular methods and tools is provided. Furthermore, the review covers the utilization of the methods in context with the length of sequences and discusses the needs for metagenomic data preprocessing in form of initial assembly prior to binning. PMID- 27980709 TI - Bengali translation and characterisation of four cognitive and trait measures for autism spectrum conditions in India. AB - BACKGROUND: Autism is characterised by atypical social-communicative behaviour and restricted range of interests and repetitive behaviours. These features exist in a continuum in the general population. Behavioural measures validated across cultures and languages are required to quantify the dimensional traits of autism in these social and non-social domains. Bengali is the seventh most spoken language in the world. However, there is a serious dearth of data on standard measures of autism-related social and visual cognition in Bengali. METHODS: Bengali translations of two measures related to social-communicative functioning (the Children's Reading the Mind in the Eyes Test (RMET) and a facial emotion recognition test with stimuli taken from the Karolinska Directed Emotional Faces database), one measure of visual perceptual disembedding (the Embedded Figures Test), and a questionnaire measure (the Children's Empathy Quotient) were tested in 25 children with autism spectrum conditions (ASC) and 26 control children (mean age = 10.7 years) in Kolkata, India. Group differences were analysed by t test and multiple regression (after accounting for potential effects of gender, IQ, and age). RESULTS: Behavioural and trait measures were associated with group differences in the expected directions: ASC children scored lower on the Children's Empathy Quotient and the RMET, as well as on facial emotion recognition, but were faster and more accurate on the Embedded Figures Test. Distributional properties of these measures within groups are similar to those reported in Western countries. CONCLUSIONS: These results provide an empirical demonstration of cross-cultural generalisability and applicability of these standard behavioural and trait measures related to autism, in a major world language. PMID- 27980710 TI - Hypoxia after stroke: a review of experimental and clinical evidence. AB - BACKGROUND: Hypoxia is a common occurrence following stroke and associated with poor clinical and functional outcomes. Normal oxygen physiology is a finely controlled mechanism from the oxygenation of haemoglobin in the pulmonary capillaries to its dissociation and delivery in the tissues. In no organ is this process more important than the brain, which has a number of vascular adaptions to be able to cope with a certain threshold of hypoxia, beyond which further disruption of oxygen delivery potentially leads to devastating consequences. Hypoxia following stroke is common and is often attributed to pneumonia, aspiration and respiratory muscle dysfunction, with sleep apnoea syndromes, pulmonary embolism and cardiac failure being less common but important treatable causes. As well as treating the underlying cause, oxygen therapy is a vital element to correcting hypoxia, but excessive use can itself cause molecular and clinical harm. As cerebral vascular occlusion completely obliterates oxygen delivery to its target tissue, the use of supplemental oxygen, even when not hypoxic, would seem a reasonable solution to try and correct this deficit, but to date randomised clinical trials have not shown benefit. CONCLUSION: Whilst evidence for the use of supplemental oxygen therapy is currently lacking, it is vital to rapidly identify and treat all causes of hypoxia in the acute stroke patient, as a failure to will lead to poorer clinical outcomes. The full results of a large randomised trial looking at the use of supplemental oxygen therapy are currently pending. PMID- 27980711 TI - Comparisons of chromosome Y-substituted mouse strains reveal that the male specific chromosome modulates the effects of androgens on cardiac functions. AB - BACKGROUND: The C57BL/6J.YA/J mouse strain is a chromosome-substituted line where the original male-specific portion of chromosome Y (MSY) from C57BL/6J mice was substituted for that from A/J mice. In hearts from male C57BL/6J.YA/J and C57BL/6J mice, orchidectomy (ORX) affected in a strictly strain-specific fashion the expression a subset of genes showing enrichment for functional categories, including that of circadian rhythms and cardiac contractility. We further tested whether: (1) there were strain-specific differences in cardiac circadian rhythms; (2) strain-dependent differences in the effects of ORX on contractility genes translated into differences in cardiac functions; and (3) differential contractility responses occurred preferentially at times when circadian rhythms also showed strain-specific differences. METHODS: In hearts from the two above strains, we (1) profiled the expression levels of 15 circadian genes at 4-h intervals across a 24 h period; (2) tested the effects of either ORX or androgen replacement on expression of cardiac contractility genes, and that of ORX on myocardial functional reserve; and (3) verified whether the effects of MSY variants on cardiac contractility-related responses showed synchronicity with differences in circadian rhythms. RESULTS: Among the 15 tested circadian genes, a subset of them were affected by strain (and thus the genetic origin of MSY), which interacted with the amplitude of their peak of maximal expression at 2:00 PM. At that same time-point, ORX decreased (and androgen supplementation increased) the expression of three contractility-related genes, and decreased myocardial relaxation reserve in C57BL/6J.YA/J, but not in C57BL/6J mice. These effects were not detected at 10:00 AM, i.e., at another time-point when circadian genes showed no strain-specific differences. CONCLUSIONS: The results indicate that in mice, androgens have activational effects on cardiac circadian rhythms, contractile gene expression, and myocardial functional reserve. All effects occurred preferentially at the same time of the day, but varied as a function of the genetic origin of MSY. Androgens may therefore be necessary but not sufficient to impart male-specific characteristics to some particular cardiac functions, with genetic material from MSY being one other necessary factor to fully define their range of actions. PMID- 27980712 TI - Impact of gonadectomy on blood pressure regulation in ageing male and female rats. AB - BACKGROUND: Sexual dimorphism in blood pressure has been associated with differential expression of the angiotensin II (AII) receptors and with activity of the nervous system. It is generally accepted that ageing affects kidney function as well as autonomic nervous system and hormonal balance. Given that hypertension is more prevalent in men than women until women reach their seventh decade, we hypothesised that females would be relatively protected from adverse effects of ageing compared to males and that this would be mediated by the protective effect of ovarian steroids. METHODS: Intact and gonadectomised male and female normotensive Wistar rats aged 6, 12 and 18 months were used to study renal function, blood pressure, heart rate, and blood pressure variability. RESULTS: We observed that intact females had lower levels of proteinuria and higher (12.5%) creatinine clearance compared to intact males and that this difference was abolished by castration but not by ovariectomy. Ovariectomy resulted in a change by 9% in heart rate, resulting in similar cardiovascular parameters to those observed in males or gonadectomised males. Spectral analysis of systolic blood pressure revealed that high-frequency power spectra were significantly elevated in the females vs. males and were reduced by ovariectomy. CONCLUSIONS: Taken altogether, the results show that females are protected from age-related declining renal function and to a lesser extent from rising blood pressure in comparison to males. Whilst ovariectomy had some deleterious effects in females, the strongest effects were associated with gonadectomy in males, suggesting a damaging effect of male hormones. PMID- 27980713 TI - Sex-specific differences in fetal and infant growth patterns: a prospective population-based cohort study. AB - BACKGROUND: The objective of this study was to assess whether sex-specific differences in fetal and infant growth exist. METHODS: This study was embedded in the Generation R Study, a population-based prospective birth cohort. In total, 8556 live singleton births were included. Fetal growth was assessed by ultrasound. During the first trimester, crown-rump-length (CRL) was measured. In the second and third trimester of pregnancy head circumference (HC), abdominal circumference (AC) and femur length (FL) were assessed. Information on infant growth during the first 2 years of life was obtained from Community Health Centers and included HC, body weight and length. RESULTS: In the first trimester, male CRL was larger than female CRL (0.12 SD [95% CI 0.03,0.22]). From the second trimester onwards, HC and AC were larger in males than in females (0.30 SD [95% CI 0.26,0.34] and 0.09 SD [95% CI 0.05,0.014], respectively). However, FL in males was smaller compared to female fetuses (0.21 SD [95% CI 0.17,0.26]). Repeated measurement analyses showed a different prenatal as well as postnatal HC growth pattern between males and females. A different pattern in body weight was observed with a higher body weight in males until the age of 12 months where after females have a higher body weight. CONCLUSIONS: Sex affects both fetal as well as infant growth. Besides body size, also body proportions differ between males and females with different growth patterns. This sexual dimorphism might arise from differences in fetal programming with sex specific health differences as a consequence in later life. PMID- 27980714 TI - Pancreatic cancer risk in relation to sex, lifestyle factors, and pre-diagnostic anthropometry in the Malmo Diet and Cancer Study. AB - BACKGROUND: Lifestyle factors may influence the risk of developing pancreatic cancer. Whereas cigarette smoking is an established risk factor, the effects of high alcohol intake and obesity are more uncertain. The aim of the present study was to examine the associations of pre-diagnostic anthropometry, alcohol consumption, and smoking habits with pancreatic cancer risk in a Swedish prospective, population-based cohort, with particular reference to potential sex differences. METHODS: The studied cohort consists of 28,098 participants, including all incident cases of pancreatic cancer, in the Malmo Diet and Cancer Study up until December 31, 2013 (n = 163). Non-parametric and chi-squared tests were applied to compare the distribution of risk factors between cases and non cases. Cox regression proportional hazards models were used to estimate the relationship between investigative factors and pancreatic cancer risk. Anthropometric factors included height, weight, body mass index (BMI), waist and hip circumference, waist-hip ratio (WHR), and body fat percentage. RESULTS: BMI was not a significant risk factor for pancreatic cancer, but a higher WHR was significantly associated with an increased risk in the entire cohort (hazard ratio (HR) 2.36, 95% confidence interval (CI) 1.28-4.35, p for trend = 0.009). Regular smoking was a significant risk factor among both women (HR 2.62, 95% CI 1.61-4.27) and men (HR 3.57, 95% CI 1.70-7.47), whereas occasional smoking was a significant risk factor only in women (HR 3.29, 95% CI 1.50-7.19). Passive smoking at work for >20 years was significantly associated with an increased risk in the entire cohort (HR 1.73, 95% CI 1.15-2.58) and in women selectively (HR 2.01, 95% CI 1.21-3.31). Alcohol consumption was not a significant risk factor. A significant interaction was found between female sex and age (p = 0.045), but no other factor, in relation to pancreatic cancer risk. CONCLUSIONS: WHR was the only pre-diagnostic anthropometric factor associated with pancreatic cancer risk, with no sex-related differences. Regular smoking was confirmed as a significant risk factor in both sexes, whereas occasional and passive smoking were significant risk factors only in women. Despite the lack of a significant interaction between smoking and sex in relation with pancreatic cancer risk, potential sex differences should be considered in future epidemiological studies. PMID- 27980716 TI - Targeted genome engineering in Caenorhabditis elegans. AB - The generation of mutants and transgenes are indispensible for biomedical research. In the nematode Caenorhabditis elegans, a series of methods have been developed to introduce genome modifications, including random mutagenesis by chemical reagents, ionizing radiation and transposon insertion. In addition, foreign DNA can be integrated into the genome through microparticle bombardment approach or by irradiation of animals carrying microinjected extrachromosomal arrays. Recent research has revolutionized the genome engineering technologies by using customized DNA nucleases to manipulate particular genes and genomic sequences. Many streamlined editing strategies are developed to simplify the experimental procedure and minimize the cost. In this review, we will summarize the recent progress of the site-specific genome editing methods in C. elegans, including the Cre/LoxP, FLP/FRT, MosTIC system, zinc-finger nucleases (ZFNs), transcriptional activator-like nucleases (TALENs), and the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 nuclease. Particularly, the recent studies of CRISPR/Cas9-mediated genome editing method in C. elegans will be emphatically discussed. PMID- 27980715 TI - Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration. AB - One of the two common hallmark lesions of Alzheimer's disease (AD) brains is neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein (p-tau). NFTs are also a defining feature of other neurodegenerative disorders and have recently been identified in the brains of patients suffering from chronic traumatic encephalopathy (CTE). However, NFTs are not normally observed in traumatic brain injury (TBI) until months or years after injury. This raises the question of whether NFTs are a cause or a consequence of long-term neurodegeneration following TBI. Two conformations of phosphorylated tau, cis p tau and trans p-tau, which are regulated by the peptidyl-prolyl isomerase Pin1, have been previously identified. By generating a polyclonal and monoclonal antibody (Ab) pair capable of distinguishing between cis and trans isoforms of p tau (cis p-tau and trans p-tau, respectively), cis p-tau was identified as a precursor of tau pathology and an early driver of neurodegeneration in AD, TBI and CTE. Histological studies shows the appearance of robust cis p-tau in the early stages of human mild cognitive impairment (MCI), AD and CTE brains, as well as after sport- and military-related TBI. Notably, cis p-tau appears within hours after closed head injury and long before other known pathogenic p-tau conformations including oligomers, pre-fibrillary tangles and NFTs. Importantly, cis p-tau monoclonal antibody treatment not only eliminates cis p-tau induction and tau pathology, but also restores many neuropathological and functional outcome in TBI mouse models. Thus, cis p-tau is an early driver of tau pathology in TBI and CTE and detection of cis p-tau in human bodily fluids could potentially provide new diagnostic and prognostic tools. Furthermore, humanization of the cis p-tau antibody could ultimately be developed as a new treatment for AD, TBI and CTE. PMID- 27980717 TI - Do women prefer a female breast surgeon? AB - BACKGROUND: Patient preferences regarding the gender of their physicians is a highly sensitive issue, which can be particularly salient in intimate medical situations. Previously published studies found that women tend to prefer female physicians, especially in the case of obstetricians and gynecologists. Data regarding other intimate specialties, such as breast surgery, are scarce. The present study was undertaken to assess gender preferences of women regarding their choice of a breast surgeon. METHODS: Five hundred and fifteen consecutive women who attended breast clinics in two university-affiliated tertiary hospitals were prospectively enrolled. A 25-item anonymous questionnaire was completed by women independently and used to assess their preferences in selecting their breast surgeon. Of the 515 women, 500 (97 % response rate; mean age 50.6 +/- 15.4 years) completed the anonymous questionnaire. RESULTS: Overall, 160 (32 %) women preferred to undergo breast examination by a female breast surgeon, 296 (59 %) had no preference, and only 44 (9 %) preferred a male surgeon. A same-gender preference was significantly and independently associated with younger age of the patients (Odds Ratio = 0.978, 95 % Confidence Interval 0.962-0.994, P = 0.007) and being married (Odds Ratio = 0.563, 95 % Confidence Interval 0.347-0.916, P = 0.021). However, only small and equal numbers of patients preferred to undergo breast surgery by a female (14 %) or a male (13 %) surgeon, and most patients (73 %) had no gender preferences. Furthermore, the three most important factors, which affected in general the actual selection, were surgical ability (93 %), experience (91.2 %) and knowledge (78.6 %), rather than physician gender per se. CONCLUSIONS: Overall, about a third of women prefer a female breast surgeon for their breast examination. Embarrassment during the examination was the major reason for same-gender preference. In contrast, when it comes to breast operations, preference for a female surgeon is less pronounced, with the professional skills of the surgeons becoming the predominant consideration. The fact that almost a third of the potential patients prefer female surgeons with regard to their breast examinations emphasizes the need to increase the number of female surgeons. Such an increase can be achieved through academic and economic changes that will enable more women to specialize in general surgery. TRIAL REGISTRATION: Trial registration is not required for this type of research. PMID- 27980718 TI - Help seeking in school by Israeli Arab minority adolescents with emotional and behavioral problems: results from the Galilee Study. AB - BACKGROUND: Many distressed minority adolescents with little access to professional mental health services use teachers and school counselors as their main consultation sources. This paper presents data from the Galilee study on factors that may increase the probability of adolescents' help-seeking in school and discusses the needed linkage between the school mental health services and those provided by other agencies, in the framework of the Mental Health Reform in Israel. METHODS: This cross-sectional survey included 1639, 9th grade students living in 5 Arab localities in the Galilee in northern Israel, representative of the Muslim and Druze populations. The study was carried out in two stages: in the screening stage, the Strengths and Difficulties Questionnaire (SDQ) was completed in the classroom. During the follow-up stage 704 students were selected and interviewed at home regarding service use in school and wellbeing at home. Their mothers were interviewed as well providing information on sociodemographic traits of the family. Total response rate was 69.3 % during the screening stage and 84.4 % during the follow-up. Students were categorized according to their SDQ scores and all students in the higher 25th percentile (high risk) and a simple systematic sample without replacement of those in the lower 75 % (low risk) were included in the follow-up study. RESULTS: Significantly more high risk than low risk students reported having felt the need to seek professional help (14.0 and 6.5 % respectively) and more high risk than low risk consulted a school source (27.1 and 15.2 %, respectively). Bivariate analyses show that among Muslim adolescents more high risk than low risk consulted a school source (30 vs. 16.2 % respectively) and among high risk students more Muslim than Druze sought help from a school source (30 vs. 18 %). Higher consultation rates were found among adolescents who felt uncomfortable at home, than among those who felt very comfortable. Binary logistic regression showed that for high risk adolescents, only religion remained significantly associated with help-seeking in school: Muslim students were 2 times more likely to seek help than Druze students. In the low-risk group, students who do not feel comfortable at home were 3.3 times more likely to seek help than those who feel comfortable at home. The main sources of consultation for both risk groups were the school counselor and the grade teacher. CONCLUSIONS: A constellation of factors may be associated with help seeking in school by minority Israeli Arab adolescents: they are students at higher risk for an emotional or behavioral disorder, they have more socio economic hardship, they feel less comfortable at home and they are more likely to live in the larger Muslim cities. Adolescents with less family support and particularly those not classified as being at high risk, are more likely to seek help from school counselors and teachers. The school staff may need additional training to care for the mental health needs of students. There is a need to integrate the school mental health services with the other government agencies that provide services to children and adolescents. PMID- 27980720 TI - Ethical standards for medical research in the Israeli military - review of the changes in the last decade. AB - BACKGROUND: The Israel Defense Forces Medical Corps (IDF MC) institutional review board (IRB) is one of approximately 50 IRBs active in Israel. In addition to routine IRB considerations it must also address in its deliberations specific safeguards in place in the IDF to protect research volunteers in the military environment. In this report, we present the characteristics of the IDF IRB, including the unique circumstances that led to a 2008 change in the pre-IRB advisory and preparatory process (APP). We also present quantitative data on the IRB's throughput and outcomes, in order to provide a benchmark for other IRBs. METHODS: We reviewed all relevant IDF regulations, both historical and current, pertaining to the structure, activity and oversight of the IRB and of medical research conducted in the IDF. Additionally, we analyzed the ethical review process for all research proposals submitted to the IDF APP between January 1, 2013 and December 31, 2015. RESULTS: In 2008 the IDF implemented several major changes which have had a substantial impact on the ethical regulation of military medical research. The period following these changes has seen a rise in the number of research proposals submitted to the IDF IRB annually. During the years 2013-2015, 377 research proposals entered the APP, of which 329 were deemed appropriate for IRB deliberation. Eight study protocols were granted waivers, 19 were rejected, and the remaining 302 were authorized. Overall, 345 of the 377 research proposals submitted (92 %) were ultimately cleared for execution; 310 of 329 proposals (94 %) deliberated by the IRB were authorized. The IRB required protocol revisions for 47 % of the research proposals, one-third of which were revisions directly associated with military-specific ethical precautions. CONCLUSIONS: Guided by the principles of protecting personal autonomy in the complex military setting, the IDF has implemented several unique measures aimed at maintaining the highest ethical standards in medical research. By sharing research approval process data similar to those presented here, medical institutions can help build and support a peer-based benchmarking process through which individual IRBs can appraise their own processes and approval rates. PMID- 27980719 TI - A feasibility study to assess the validity of administrative data sources and self-reported information of breast cancer survivors. AB - BACKGROUND: Cancer survivorship has increasingly become the focus of research due to progress in early detection and advancements in the therapeutic approach, but high-quality information sources for outcomes, potential confounders and personal characteristics present a challenge. Few studies have collected breast cancer care data from mixed data sources and validated them, and to the best of our knowledge, none so far have been conducted in Israel, where National Health Insurance Law assures universal health care, delivered through four health care funds with computerized administrative, pharmaceutical and medical databases. This validation study is aimed to assess the accuracy and completeness of information on cancer care and health outcomes using several research tools, before embarking on a full-scale study aimed to evaluate the long-term treatment related health adverse outcomes in a cohort of breast cancer survivors. METHODS: One hundred twenty randomly sampled female patients diagnosed with primary breast cancer in years 2000-2010 in northern Israel, who are members of the "Leumit" healthcare fund, were included. Data sources included "Leumit" medical records, the National Cancer Registry and a self-report questionnaire. The questionnaire was completed by 99 % of the women contacted. The accuracy of the information regarding cancer care was assessed with the reference standard set as one of the research tools, varying per the characteristic being under investigation. For example: health outcomes and medical history were validated against "Leumit" medical records, while construct validity of the self-reported questionnaire served to assess the prevalence of chronic pain. Agreement, predictive values, correlations, and internal consistency were calculated. Logistic regression models were constructed to assess potential predictors of correct responses. RESULTS: The overall level of agreement (Kappa) was almost perfect for demographics and outcomes, above 0.8 for treatments and chronic pain, while only fair to moderate for most of the self-reported medical history. Correct responses of medical history were associated with Jewish ethnicity, recency of breast cancer diagnosis, and family history of cardiovascular disease. The internal consistency of the quality-of-life scale was above 0.9. CONCLUSION: In the absence of a national registry for cancer care, a mixed methodology for data collection is the most complete source. TRIAL REGISTRATION: Trial registration number Not available. This is an observational study with prospective data collection and no intervention; therefore, trial registration number is not required. PMID- 27980721 TI - Ethics and regulation of inter-country medically assisted reproduction: a call for action. AB - The proliferation of medically assisted reproduction (MAR) for the treatment of infertility has brought benefit to many individuals around the world. But infertility and its treatment continue to be a cause of suffering, and over the past decade, there has been a steady growth in a new global market of inter country medically assisted reproduction (IMAR) involving 'third-party' individuals acting as surrogate mothers and gamete donors in reproductive collaborations for the benefit of other individuals and couples who wish to have children. At the same time there is evidence of a double standard of care for third-party women involved in IMAR, violations of human rights of children and women, and extreme abuses that are tantamount to reproductive trafficking. This paper is the report of an inter-disciplinary working group of experts who convened in Israel to discuss the complex issues of IMAR. In Israel too IMAR practices have grown rapidly in recent years, mainly because of restrictions on access to domestic surrogacy for same sex couples and a chronically insufficient supply of egg cells for the treatment of couples and singles in need. Drawing upon local expertise, the paper describes documented practices that are harmful, suggests principles of good practice based on an ethic of care, and calls for action at the international, national and professional levels to establish a human rights based system of international governance for IMAR based on three regulatory models: public health monitoring, inter-country adoption, and trafficking in human beings, organs and tissues. PMID- 27980722 TI - Immunoglobulin free light chains in adult atopic dermatitis patients do not correlate with disease severity. AB - BACKGROUND: Although total IgE levels have been proposed as a biomarker for disease severity in atopic dermatitis (AD) and are increased in the majority of AD patients, they do not correlate with disease severity during short-term follow up. During the synthesis of immunoglobulins, free light chains (Ig-FLCs) are produced in excess over heavy chains. In comparison with IgE molecules, Ig-FLCs have a very short serum half-life. Therefore, Ig-FLCs might be more suitable as a biomarker for disease severity during follow-up. Recent studies showed increased serum levels of kappa Ig-FLCs in infants with AD, correlating with disease severity. The aim of this study was to investigate serum kappa Ig-FLC levels in adults with AD, and their correlation to disease severity. METHODS: Serum kappa If-FLC and total IgE levels were measured in 82 moderate to severe AD patients and 49 non-atopic controls. Blood was collected from patients before start of treatment with potent topical steroids (European classification: III-IV). 32 patients were treated during a clinical admission, and in this subpopulation a second blood sample was taken after 2 weeks of treatment. Clinical severity was determined by the Six Area Six Sign Atopic Dermatitis (SASSAD) severity score and a panel of serum biomarkers, including thymus and activation-regulated chemokine (TARC). RESULTS: Serum kappa Ig-FLCs levels in adult AD patients were not increased compared to non-atopic controls. Moreover, we observed no correlation between kappa Ig-FLC serum levels and disease severity determined by SASSAD and a panel of serum biomarkers, including TARC. Serum kappa Ig-FLC levels did also not decrease during treatment. CONCLUSION: There are no differences in serum kappa Ig FLC levels between adult patients suffering from moderate to severe AD compared to non-atopic controls. Moreover, serum levels of kappa Ig-FLCs cannot be used as a biomarker for disease severity in adult AD. PMID- 27980723 TI - The influence of anatomy app use on chiropractic students' learning outcomes: a randomised controlled trial. AB - BACKGROUND: Anatomy apps supplement traditional learning; however, it is unknown if their use can improve students' outcome. The present study examined whether the use of anatomy apps improved student performance on a neuroanatomy assessment. METHODS: Second-year anatomy students, enrolled in a Bachelor of Science with Chiropractic Major program, were randomly allocated to experimental and control groups in July 2015. Students completed the Self-Directed Learning Readiness Scale (SDLRS). The experimental group had access to iPads with four anatomy apps for three weekly classes (1.5 h each). One week after the last class, students were assessed by an online 30-question neuroanatomy test. Linear regression was used to examine the association between test scores and app use, gender, previous anatomy unit score and SDLRS scores. Students' views on apps were collected by focus group discussion immediately after the test. RESULTS: Completed questionnaires were obtained from n = 25 control and n = 25 experimental students. There was no association between app use and neuroanatomy assessment score (B = 1.75, 95 % CI: -0.340-3.840, p = 0.099). Only previous anatomy unit score (B = 0.348, 95 % CI: 0.214-0.483, p < 0.001) affected neuroanatomy assessment scores. Students favored apps with clinical images and features including identification pins, sliding bars and rotatable 3D images. CONCLUSIONS: App use did not enhance learning outcomes in a second-year anatomy unit. PMID- 27980724 TI - Effectiveness of manual therapy for cervical radiculopathy, a review. AB - Manual therapy is often used for patients with neck pain with or without radicular symptoms. There is sparse evidence on the effectiveness in cervical radiculopathy. The aim of this study was to assess current levels of evidence on the effectiveness of manual therapy interventions for patients with cervical radiculopathy. Electronic data bases were systematically searched for clinical guidelines, reviews and randomised clinical trials (RCTs) reporting on the effectiveness of manual therapy for patients with cervical radiculopathy. Eight relevant reviews, two guidelines and two recent RCTs, that had not yet been included in either, were retrieved. The overall quality of the evidence of included studies was evaluated using the GRADE method. Most interventions were only studied in one single RCT. There is low level evidence that cervical manipulation and mobilisation as unimodal interventions are effective on pain and range of motion at the immediate follow up, but no evidence on the effectiveness of thoracic manipulation or mobilisation as unimodal interventions. There is low level evidence that a combination of spinal mobilisation and motor control exercises is more effective on pain and activity limitations than separate interventions or a wait-and-see policy. There is low level evidence of the effectiveness of cervical mobilisation with a neurodynamical intent as unimodal intervention, on the effectiveness of a multimodal intervention with neurodynamic intent on pain activity limitations and global perceived effect compared to a wait-and-see policy. There is also low level evidence that a multimodal intervention consisting of spinal and neurodynamic mobilisations and specific exercises is effective on pain in patients with CR. There is low level evidence that traction is no more effective than placebo traction. PMID- 27980725 TI - Similarities and differences of a selection of key accreditation standards between chiropractic councils on education: a systematic review. AB - BACKGROUND: Councils of Chiropractic Education (CCE) indirectly influence patient care and safety through their role of ensuring the standards of training delivered by chiropractic educational institutions. This is achieved by a process of accreditation where CCEs define and assess graduate competencies and educational standards. A previous study comparing CCE graduate competencies found variations between the CCE jurisdictions. It was proffered that variations in standards may potentially compromise patient care and safety and also inter jurisdictional mutual recognition. This study continues the examination of CCEs by looking for similarities and differences in CCE accreditation standards. There were two purposes of this review. The first was to compare the accreditation standards, domains of accreditation standards, and components of the domains of accreditation standards as represented by the domains of "Mission, goals, vision, objectives", "Resources", "Faculty/Academic staff", "Educational program/curriculum". In addition, we compared the accreditation standards between CCEs and those of the widely accepted medical accreditation standards of the World Federation of Medical Education (WFME), in order to search for deficiencies and opportunities for improvements in these standards. The second purpose was to make recommendations, if significant deficiencies or variations were found. METHOD: We undertook a systematic review of the similarities and differences between five CCEs' definitions of an accreditation standard and the descriptive lists of accreditation standards they have adopted. CCE selection criteria and data selection method were undertaken in a systematic manner. This information was tabulated for a comparative analysis and took place in April 2016. RESULTS: Only two CCEs had a definition of the term "accreditation / educational standard". At the domain level there was considerably more similarities than differences. The differences became more apparent when the comparisons were made at the component level. These included intended purposes of the mission statement, standards for faculty staff, requirements for clinical training by students, program budgetary autonomy and transparency, the inclusion of chiropractic philosophy and history, and which subjects should be taught in basic, behavioural and clinical sciences. CONCLUSIONS: A series of recommendations were made. These included the need for an increased clarity of the required basic and clinical science subjects, teaching clinic student requirements, and faculty staff qualifications. These are proposed with the intention of creating uniform and high quality international accreditation standards for chiropractic education. Future research should compare the levels of CCEs inspection standards and processes to see if similarities and differences exist also there. TRIAL REGISTRATION: Not applicable. PMID- 27980726 TI - Effect of lumbar spinal manipulation on local and remote pressure pain threshold and pinprick sensitivity in asymptomatic individuals: a randomised trial. AB - BACKGROUND: The mechanisms of clinical pain relief associated with spinal manipulative therapy (SMT) are poorly understood. Our objective was to determine whether lumbar high-velocity low-amplitude SMT altered pressure pain threshold (PPT) and pinprick sensitivity (PPS) locally and remotely, how long any change lasted (up to 30 min), and whether changes related to the side of SMT. METHODS: Thirty-four asymptomatic participants (mean age 22.6 years +/-4.0) received a right- or left-sided lumbar SMT. PPT and PPS were measured bilaterally at the calf, lumbar spine, scapula, and forehead before and immediately, 10, 20, and 30 min after intervention. Data were collected between October 2014 and June 2015. RESULTS: Bilateral calf and lumbar spine PPT increased significantly after 10 - 20 min and was maintained at 30 min (7.2-11.8 % increase). PPS decreased significantly in all locations at various times (9.8 - 22.5 % decrease). At the calf and lumbar spine, PPT increased slightly more ipsilateral to the SMT than contralateral. CONCLUSIONS: Lumbar SMT reduced deep pressure sensitivity locally and in the lower limbs for at least 30 min, whereas sensitivity to pinprick was reduced systemically. These findings suggest that SMT specifically inhibits deep pressure sensitivity distally. These findings are novel compared to other lumbar SMT studies, and may reflect a local spinal or complex supraspinal analgesic mechanism. TRIAL REGISTRATION: Registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000682640). PMID- 27980727 TI - Frequency-dependent two-sex models: a new approach to sex ratio evolution with multiple maternal conditions. AB - Mothers that experience different individual or environmental conditions may produce different proportions of male to female offspring. The Trivers-Willard hypothesis, for instance, suggests that mothers with different qualities (size, health, etc.) will use different sex ratios if maternal quality differentially affects sex-specific reproductive success. Condition-dependent, or facultative, sex ratio strategies like these allow multiple sex ratios to coexist within a population. They also create complex population structure due to the presence of multiple maternal conditions. As a result, modeling facultative sex ratio evolution requires not only sex ratio strategies with multiple components, but also two-sex population models with explicit stage structure. To this end, we combine nonlinear, frequency-dependent matrix models and multidimensional adaptive dynamics to create a new framework for studying sex ratio evolution. We illustrate the applications of this framework with two case studies where the sex ratios depend one of two possible maternal conditions (age or quality). In these cases, we identify evolutionarily singular sex ratio strategies, find instances where one maternal condition produces exclusively male or female offspring, and show that sex ratio biases depend on the relative reproductive value ratios for each sex. PMID- 27980728 TI - The immunohistochemical evaluation of selected markers in the left atrium of dogs with end-stage dilated cardiomyopathy and myxomatous mitral valve disease - a preliminary study. AB - BACKGROUND: Dilated cardiomyopathy (DCM) and myxomatous mitral valve disease (MMVD) are the most common diseases noted in dogs. Although their pathogenesis varies, both include a significant enlargement of the left atrium. The study was carried out on left atrial specimens obtained from 56 dogs, including those from 34 dogs with clinically diagnosed MMVD, 15 dogs with DCM and 7 dogs without heart disease (control group). Dogs in the MMVD and the DCM groups presented with left atrial enlargement and stage D heart failure. The specimens underwent immunohistochemical examination using desmin, vimentin, periostin and caspase-3 antibodies. RESULTS: There were alterations in the expression of the studied proteins in the study groups compared to the control group. The changes included: irregularity of desmin cross-striation and desmosomes, a higher amount of vimentin-positive cells, a change in the periostin expression pattern from cytoplasmic to extracellular, and a lower expression of caspase-3. The alterations were more pronounced in the DCM group than in the MMVD group. CONCLUSIONS: During heart failure, the pattern of desmin, vimentin, periostin and caspase-3 expression alters in the left atrium, regardless of the cause. The changes are more pronounced in dogs with DCM than in dogs with MMVD and similar left atrial enlargement, suggesting that volume overload may not be the only cause of myocardial changes in DCM. PMID- 27980729 TI - Assessment of extended-spectrum beta-lactamases and integrons among Enterobacteriaceae in device-associated infections: multicenter study in north of Iran. AB - BACKGROUND: Device-associated nosocomial infections (DA-NIs), due to MDR Enterobacteriaceae, are a major threat to patient safety in ICUs. We investigated on Extended-spectrum beta-lactamases (ESBL) producing Enterobacteriaceae and incidence of integrons in these bacteria isolated from ventilator-associated pneumonia (VAP) and catheter-associated urinary tract infections (CAUTIs) in 18 governmental hospitals in the north of Iran. METHODS: In this cross-section study, the antibiotic susceptibility test was performed using the MIC method; also, phenotypically detection of ESBL-producing bacteria was carried out by the double-disk synergy (DDS) test. Presence of ESBL-related genes and integron Classes 1 and 2 was evaluated by the PCR method. RESULTS: Out of a total of 205 patients with DA-NIs, Enterobacteriaceae were responsible for (72.68%) of infections. The most common DA-NIs caused by Enterobacteriaceae were VAP (77.18%), CAUTI (19.46%), and sepsis due to VAP (3.35%). The most frequently Enterobacteriaceae were; Klebsiella pneumoniae 75 (24; 32% ESBL positive), E. coli 69 (6; 8.69% ESBL positive) and Enterobacter spp. 5 (5; 100% ESBL positive). Distribution of ESBL-related genes was as follows: bla-SHV (94.3%), bla-CTX (48.6%), bla-VEB (22.9%) and bla-GES (17.14%). The incidence rate of integron class 1 and class 2 was (82.92%) and (2.9%) respectively. Eight types of ESBL producing bacteria were observed. CONCLUSIONS: Due to the fact that the emergence rate of ESBL Enterobacteriaceae is increasing in DA-NIs, co-incidence of different types of ESBL genes with integrons in 75-100% of strains in our study is alarming for clinicians and healthcare safety managers. Therefore, regional and local molecular level estimations of ESBLs that are agents of DA-NIs are critical for better management of empiric therapy, especially for patients in ICUs. PMID- 27980730 TI - Prolonged outbreak of clonal MDR Pseudomonas aeruginosa on an intensive care unit: contaminated sinks and contamination of ultra-filtrate bags as possible route of transmission? AB - BACKGROUND: We report on an outbreak in a surgical, interdisciplinary intensive care unit (ICU) of a tertiary care hospital. We detected a cluster of ICU patients colonized or infected with multidrug-resistant Pseudomonas aeruginosa. We established an outbreak investigation team, performed an exploratory epidemiological analysis and initiated an epidemiology-based intervention. METHODS: As part of the outbreak investigation, we performed microbiological examinations of the sinks in the patient rooms and a retrospective case-control study. All patients admitted to the outbreak ICU between January 2012 and February 2014 were included. Cases were patients colonized with the outbreak strain. Controls were patients with a different Pseudomonas aeruginosa strain. Risk factors were evaluated using multivariable conditional logistic regression analysis. Strain typing was performed using the repetitive element-based polymerase chain reaction (rep-PCR) DiversiLab system. RESULTS: The outbreak strain was found in the sinks of five (of 16) patient rooms. Altogether 21 cases and 21 (randomly selected) controls were included. In the univariate analysis, there was no significant difference in baseline data of the patients. In the multivariate analysis, stay in a room with a colonized sink (Odds Ratio[OR] 11.2, p = 0.007) and hemofiltration (OR 21.9, p = 0.020) were independently associated with an elevated risk for colonization or infection by the outbreak strain. In a subsequent evaluation of the work procedures associated with hemofiltration, we found that the ultra-filtrate bags had been on average five times per day emptied in the sinks of the patient rooms and were used multiple for the same patient. We exchanged the traps of the contaminated sinks and eliminated work procedures involving sinks in patient rooms by implementation of single use bags, which are emptied outside patient rooms to reduce splash water at the sinks. In the 20 month follow-up period, the outbreak strain was detected only once, which indicated that the outbreak had been ceased (incidence 0.75% vs. 0.04%, p < 0.001) Furthermore, the incidence of Pseudonomas aeruginosa overall was significantly decreased (2.5% vs. 1.5%, p < 0.001). CONCLUSION: In ICUs, limiting work processes involving sinks results in reduced multidrug-resistant Pseudomonas aeruginosa rates. ICUs with high rates of Pseudomonas aeruginosa should consider eliminating work processes that involve sinks and potentially splash water in close proximity to patients. TRIAL REGISTRATION: All data were surveillance based data which were obtained within the German Law on Protection against Infection ("Infektionsschutzgesetz"). Therefore a trial registration was not required. PMID- 27980731 TI - Role of quality control circle in sustained improvement of hand hygiene compliance: an observational study in a stomatology hospital in Shandong, China. AB - BACKGROUND: Hand hygiene is an important element of the WHO multimodal strategy for healthcare-associated infection control, whereas compliance of hand hygiene among healthcare workers (HCWs) remains a challenge to sustain. In order to increase the hand hygiene compliance of HCWs, a quality control circle (QCC) program was carried out in our hospital, and the plan-do-check-act (PDCA) method was applied for 12 months. FINDINGS: Hand hygiene compliance rates improved over time, with significant improvement between preintervention (60.1%) and postintervention (97.2%) periods (P < 0.001). Nurses (88.3%) exhibited higher compliance than dentists (87.3%), and female (88.4%) HCWs were more likely to perform hand hygiene than males (85.6%), both P < 0.001. Overall hand hygiene compliance and observance of the five indications exhibited significant linear increases over time (P < 0.005). CONCLUSION: This study highlights the success of a multifaceted intervention, conducted by QCC program and PDCA method, which led to a significant improvement of hand hygiene compliance. Though training is the most basic intervention element, surveillance, evaluation and feedback should be explored as additional interventions to ensure that hand hygiene compliance is achieved and sustained at high levels. PMID- 27980732 TI - Weight control interventions improve therapeutic efficacy of dacarbazine in melanoma by reversing obesity-induced drug resistance. AB - BACKGROUND: Obesity-related cellular, metabolic, and molecular alterations have been shown to increase cancer risk and tumor progression and are associated with poorer therapeutic outcome in cancer patients. However, the impact of obesity and weight-control interventions on the therapeutic response in melanoma is poorly understood. METHODS: High fat diet (HFD)-induced obese mouse model was used in this study to evaluate the outcome of dacarbazine (DTIC) therapy in melanoma. We employed LC-MS/MS to determine the quantity of the drug in tumor, and in various tissues. Unique in vitro approach was used to complement in vivo findings by culturing melanoma cells in either conditioned medium (CM) obtained from differentiated adipocytes or in serum collected from experimental mice. RESULTS: We report that diet-induced obesity impairs the outcome of DTIC therapy and reduces overall survival in tumor-bearing mice. We provide evidence that obesity restricts the accessibility of DTIC to tumor tissue. Critically, upon curtailing adiposity, accumulation and efficacy of DTIC is significantly improved. Moreover, using appropriate in vitro approaches, we show that melanoma cells exhibit a drug resistant phenotype when cultured in serum collected from diet-induced obese mice or in CM collected from 3T3-L1 adipocytes. The impaired therapeutic response to DTIC in obese state is mediated by fatty acid synthase (FASN), caveolin-1 (Cav 1), and P-glycoprotein (P-gp). The response to DTIC and overall survival were improved upon employing weight control interventions in the tumor-bearing HFD-fed (obese) mice. CONCLUSIONS: This study indicates that obesity not only supports rapid melanoma progression but also impairs the outcome of chemotherapy, which can be improved upon employing weight control interventions. From clinically relevant point of view, our study exemplifies the importance of lifestyle interventions in the treatment of obesity-promoted cancers. PMID- 27980733 TI - The role of tumor metabolism as a driver of prostate cancer progression and lethal disease: results from a nested case-control study. AB - BACKGROUND: Understanding the biologic mechanisms underlying the development of lethal prostate cancer is critical for improved therapeutic and prevention strategies. In this study we explored the role of tumor metabolism in prostate cancer progression using mRNA expression profiling of seven metabolic pathways; fatty acid metabolism, glycolysis/gluconeogenesis, oxidative phosphorylation, pentose phosphate, purine metabolism, pyrimidine metabolism and the tricarboxylic acid cycle. METHODS: The study included 404 men with archival formalin-fixed, paraffin-embedded prostate tumor tissue from the prospective Health Professionals Follow-up Study and Physicians' Health Study. Lethal cases (n = 113) were men who experienced a distant metastatic event or died of prostate cancer during follow up. Non-lethal controls (n = 291) survived at least 8 years post-diagnosis without metastases. Of 404 men, 202 additionally had matched normal tissue (140 non-lethal, 62 lethal). Analyses compared expression levels between tumor and normal tissue, by Gleason grade and by lethal status. Secondary analyses considered the association with biomarkers of cell proliferation, apoptosis and angiogenesis. RESULTS: Oxidative phosphorylation and pyrimidine metabolism were identified as the most dysregulated pathways in lethal tumors (p < 0.007), and within these pathways, a number of novel differentially expressed genes were identified including POLR2K and APT6V1A. The associations were tumor specific as there was no evidence any pathways were altered in the normal tissue of lethal compared to non-lethal cases. CONCLUSIONS: The results suggest prostate cancer progression and lethal disease are associated with alterations in key metabolic signaling pathways. Pathways supporting proliferation appeared to be of particular importance in prostate tumor aggressiveness. PMID- 27980734 TI - Multidisciplinary management of breast cancer. AB - Breast cancer, with an increasing incidence, is the most frequently diagnosed cancer in women worldwide. The treatments proposed, generally a combination of surgery, radiotherapy, chemotherapy, endocrine therapy and/or targeted therapy, are constantly improving, allowing a reduction in the mortality rate, but they are still causing many side effects, not only early but also late, which leads us to consider the post-cancer period as a chronic condition. Side effects, reviewed in this commentary, may affect physical functions, psychological status, social situation, body composition, well-being and quality of life of the patient. In view of the extent of these areas in which side effects of breast cancer and of its treatments can be found, the supportive care offered at the end of treatment need to be multidisciplinary. Different supportive care interventions may be proposed to the patients such as psychological and behavioral interventions, complementary therapies, diet interventions, physical activity/rehabilitation or also physiotherapy interventions for example, all having shown some beneficial effects in the literature. The benefits of these supportive care interventions are thereby already established and they are described in this article, but others studies will be needed to clearly define indications and most optimal modalities of application to reduce side effects and improve quality of life of patients. PMID- 27980735 TI - Personality and unachieved treatment goals related to poor adherence to asthma medication in a newly developed adherence questionnaire - a population-based study. AB - BACKGROUND: Health-care professionals have a responsibility to be attentive to patients' adherence behavior but it could be difficult to identify poor adherence in the context of clinical practice. Assessment of personality could be used to identify individuals who are in need for support with their adherence behavior. To our knowledge, existing adherence questionnaires are not based on individuals reflecting asthmatics in the general population and there is limited research describing adherence with asthma medication in relation to personal goals with the treatment. The aim was to develop and validate an adherence questionnaire in adult individuals with asthma from the general population and to assess adherence in relation to personality traits and goals with the asthma medication using the developed questionnaire. METHODS: The study was conducted in three phases: 1. A preliminary postal 46-item questionnaire was refined after psychometric testing (n = 157). 2. The questionnaire was validated (n = 104). 3. The developed adherence questionnaire was analyzed in relation to personality traits and achieved goals with the asthma medication. Adult respondents with physician diagnosed asthma using asthma medications were selected from the population-based West Sweden Asthma Study. The respondents completed the Neuroticism, Extraversion and Openness to Experience Five-Factor Inventory and the Medication Adherence Report Scale and stated their goals with the asthma medication. Data were analyzed using t-tests, correlations, multiple regression and principal component analysis. RESULTS: A final questionnaire was developed consisting of ten items organized in three subscales - "medication routines", "self-adjusting the medication" and "concerns about side-effects". Two of the subscales - "medication routines" and "self-adjusting the medication" - were associated with the Medication Adherence Report Scale. The subscale "medication routines" was associated with the personality traits - Conscientiousness and Neuroticism and unachieved goals with the asthma medication. CONCLUSIONS: The developed questionnaire appears to be useful for measuring adherence to asthma medication in adult individuals with asthma. The study suggests that both individual differences and personal treatment goals need to be addressed in efforts to promote adherence to asthma medication treatment. PMID- 27980736 TI - A case of gingival cancer with pulmonary metastases that developed complete atrioventricular block and ventricular fibrillation as a result of myocardial metastases. AB - We present a rare case of gingival cancer with pulmonary metastases that developed life-threatening complete atrioventricular block and ventricular fibrillation as a result of myocardial metastases. This case suggests that implantable cardioverter defibrillators significantly improve the quality of life in these patients and maintain their performance status. PMID- 27980737 TI - Functional salivary reservoir in maxillary complete denture - technique redefined. AB - Complete dentures are poorly tolerated in patients with xerostomia. A salivary reservoir can be incorporated into a denture that provides slow, sustained, and continuous release of salivary substitute. This article describes a simple, cost effective, and innovative technique of fabrication and designing of functional maxillary salivary reservoir complete denture. PMID- 27980738 TI - Mature CD8+ T-cell clonal expansion in the oral cavity and digestive tract: a severe lymphoid malignancy that mimics Crohn's disease. AB - In patients with atypical Crohn's disease features, including severe oral ulcerations and resistance to standard treatment, the possibility of a mature clonal CD8+ T-cell lymphoproliferative disorder should be investigated. Clinicians should be aware of this differential diagnosis because CD8+ T-cell lymphoma prognosis can be remarkably favorable upon oral treatment with cyclophosphamide. PMID- 27980739 TI - Myopotential oversensing notified by Lead Integrity Alert in a patient with implantable cardioverter defibrillator with a dedicated bipolar epicardial sensing lead. AB - Although myopotential oversensing by a dedicated bipolar lead is rare, an epicardial lead on a dilated ventricle might contribute to its sensitivity. Myopotential oversensing was notified by the Lead Integrity Alert in this case. We should be aware of this possibility for the management of such patients. PMID- 27980741 TI - A case of central diabetes insipidus associated with cardiac dysfunction. AB - Central diabetes insipidus (CDI) results from a deficiency of arginine vasopressin (AVP) secretion. It is treated by replacement therapy with the synthetic AVP analogue desmopressin. To prevent heart failure in patients with CDI accompanied by cardiac dysfunction, controlling sodium and water intake is essential, using the minimum effective dose of desmopressin. PMID- 27980740 TI - Multiple primary cutaneous plasmacytoma a decade after a nasal solitary extramedullary plasmacytoma: a puzzling case. AB - Primary cutaneous plasmacytoma should be in the differential diagnosis in case of solitary or multiple erythematous-violaceous nodules or papules. The diagnosis relies on clinical, histological, and immunochemical findings, without underlying evidence of multiple myeloma. Treatment should be individualized, and agents such as bortezomib or lenalidomide have shown to be effective. PMID- 27980742 TI - Live birth in a 46-year-old woman using microdose GnRH agonist flare-up protocol combined with GnRH antagonist: a case report. AB - Few successful pregnancies after age 45 years with low ovarian reserve have been reported. We report a 46-year-old woman with basal FSH 20.36 mIU/mL and an antral follicle count of four obtained two embryos and delivered a healthy infant with IVF using a microdose GnRH-a flare-up protocol combined with GnRH-ant. PMID- 27980743 TI - Incidentally discovered low-grade appendiceal mucinous neoplasm: a precursor to pseudomyxoma peritonei. AB - Appendiceal mucoceles (AMs) infrequently arise from an underlying malignancy. Treatment has progressed toward a less aggressive approach over time; they can be managed by appendectomy-only unless pathology reveals malignancy. The ultimate goal of management is to prevent AM rupture, avoiding the syndrome of pseudomyxoma peritonei. PMID- 27980744 TI - Abdominal epilepsy, an uncommon cause of chronic and recurrent abdominal pain: a case report. AB - Abdominal epilepsy is an uncommon cause of paroxysmal abdominal pain. It is relatively common in children, but very rare in adults. We report a case of 38 year-old, who reported with recurrent abdominal pain for 2 years. Electroencephalography confirmed the diagnosis; he responded well to carbamazepine and remains symptom-free on follow-up. PMID- 27980745 TI - A case of new-onset cardiomyopathy and ventricular tachycardia in a patient receiving ibrutinib for relapsed mantle cell lymphoma. AB - Ibrutinib is a first-in-class inhibitor of Bruton's tyrosine kinase, which is approved for use in chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Although ibrutinib has been linked to an increased incidence of atrial fibrillation, this is the first report of an association with nonischemic cardiomyopathy and ventricular arrhythmia. PMID- 27980746 TI - Inflammatory myofibroblastic pancreas tumor: a case report. AB - Inflammatory myofibroblastic tumor (IMT) histologically characterized by fibroblastic and myofibroblastic proliferation with inflammatory infiltrate. The therapy adopted was Whipple's pancreaticoduodenectomy with a histological diagnosis of the inflammatory myofibroblastic tumor. The disease that should be considered as the differential diagnosis is pancreatic cancer. The diagnosis and treatment of IMT is surgical resection. PMID- 27980747 TI - Mosaic partial pericentromeric trisomy 8 and maternal uniparental disomy in a male patient with autism spectrum disorder. AB - Various chromosomal anomalies including small supernumerary marker chromosome (sSMC) and Uniparental disomy (UPD) have been described in association with intellectual disability and autism spectrum disorder. Based on our reported findings, we recommend that patients with sSMC(8) be evaluated for autism spectrum disorder (ASD) for early institution of therapy. In the presence of an identifiable sSMC, exploration of UPD is also recommended to further investigate the role of chromosome 8 UPD in ASD. PMID- 27980748 TI - Complication of venovenous extracorporeal membrane oxygenation cannulation - the significance of an inferior vena cava anomaly. AB - Physicians should be aware of possible anatomical variants during cannulation for extracorporeal membrane oxygenation (ECMO). Particular attention to ensure continual visualization of the guidewire before proceeding to final positioning of the ECMO cannulae should be paid. Alternative imaging modalities should be contemplated when uncertainties arise to minimize the risk of inadvertent vascular injuries. PMID- 27980749 TI - Glucose-6-phosphate dehydrogenase deficiency: not exclusively in males. AB - Glucose-6-phosphate (G6PD) deficiency is the most common human enzyme defect, often presenting with neonatal jaundice and/or acute hemolytic anemia, triggered by oxidizing agents. G6PD deficiency is an X-linked, hereditary disease, mainly affecting men, but should also be considered in females with an oxidative hemolysis. PMID- 27980750 TI - All-trans retinoic acid (ATRA) in non-promyelocytic acute myeloid leukemia (AML): results of combination of ATRA with low-dose Ara-C in three elderly patients with NPM1-mutated AML unfit for intensive chemotherapy and review of the literature. AB - Based upon the clinical behavior of three patients, we suggest that the combination of low-dose Ara-C and all-trans retinoic acid may potentially be effective in some elderly patients, unfit for intensive chemotherapy, affected with NPM1-mutated acute myeloid leukemia without FLT3 mutations, warranting perspective clinical studies in these selected patients. PMID- 27980751 TI - A case of veno-venous extracorporeal membrane oxygenation for severe respiratory failure in a superobese patient. AB - After risk assessment, veno-venous extracorporeal membrane oxygenation (ECMO) has been achieved in a superobese adult patient as a bridge to recovery of respiratory failure, despite the weight-related difficulties. Early v-v ECMO implantation could be considered to support and to conduct weaning both from sedation and from invasive mechanical ventilation, with the goal to perform physiokinesitherapy during awake ECMO. PMID- 27980753 TI - Noninvasive management for iatrogenic splenic injury caused by chest tube insertion: a case report. AB - Splenic injury is one of the most critical complications of chest tube insertion and often requires invasive emergency management. However, noninvasive management such as delayed removal of the malpositioned tube may be considered for a stable patient without severe adverse event. PMID- 27980752 TI - Novel compound heterozygous mutation in SACS gene leads to a milder autosomal recessive spastic ataxia of Charlevoix-Saguenay, ARSACS, in a Finnish family. AB - Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare disorder outside Quebec causing childhood-onset cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs. A Finnish family with milder form of ARSACS was found to harbor three mutations, p.E1100K, p.N1489S, and p.M1359T, in SACS gene. The mutations segregated with the disease. PMID- 27980755 TI - Unusual association of brain hemorrhage and digestive tract occlusion: about two prenatal cases. AB - We report two prenatal cases of an exceptional association of digestive tract atresia or perforation with brain hemorrhage. This combination worsens the prognosis leading to termination of pregnancy in one case. We outline the importance of a careful fetal brain examination on imaging in cases of prenatal "acute" abdominal insults. PMID- 27980754 TI - A case of basal cell carcinoma of the nictitating membrane in a dog. AB - A case of a basal cell carcinoma (BCC) of the nictitating membrane (NM) in a 9 year-old female spayed dachshund is reported. Computed tomography and resection of the NM followed by cryosurgery was performed. Although uncommon, BCC should be considered as a differential diagnosis for tumors of the NM. PMID- 27980756 TI - Diagnostic and response assessment FDG PET-CT in neurolymphomatosis. AB - FDG PET-CT is a useful imaging tool in the diagnosis and response assessment of neurolymphomatosis, especially in cases of otherwise unexplained neuropathy following conventional diagnostic work-up including lumbar puncture, CT, and MRI. The use of a novel PET reconstruction algorithm improves image quality and lesion detection through increased signal-to-noise ratio. PMID- 27980757 TI - Aneurysmal bone cyst of the mandible affecting the articular condyle: a case report. AB - Aneurysmal bone cyst (ABC) is a benign osteolytic lesion that is fast-growing, expansile, and locally destructive. The present case is of a young girl with facial asymmetry, which had become accentuated during the previous months. A conservative treatment was performed to reduce morbidity and affectation of the lower dental nerve. PMID- 27980758 TI - Diagnosis of Cushing's disease in a patient with consistently normal urinary free cortisol levels: a case report. AB - The urinary free cortisol (UFC) test is widely used for the screening of Cushing's syndrome. This case study illustrates the potential failure of the UFC test to correctly diagnose Cushing's disease (CD), indicating that the use of other complementary tests may be necessary to diagnose this disease in some cases. PMID- 27980759 TI - Extensive intracranial arterial stenoses in conjunction with the use of tyrosine kinase inhibitor Nilotinib. AB - New-generation tyrosine kinase inhibitors (TKI) are promising agents for the treatment of chronic myeloid leukemia (CML), but the linkage to vascular diseases warrants a special attention from treating physicians, as it may carry major morbidity and mortality. PMID- 27980760 TI - Double trouble: fetal diagnosis of a pulmonary artery sling and vascular ring. AB - Left pulmonary artery slings and vascular rings are rare congenital anomalies definable by fetal echocardiography. Left pulmonary artery slings are associated with high respiratory morbidity and mortality. Prenatal diagnosis of a left pulmonary artery sling should prompt delivery planning for postnatal management at a pediatric tertiary care center. PMID- 27980761 TI - Examination of Huntington's disease with atypical clinical features in a Bangladeshi family tree. AB - Atypical manifestation of Huntington's disease (HD) could inform ongoing research into HD genetic modifiers not present in the primarily European populations studied to date. This work demonstrates that expanding HD genetic testing into under-resourced healthcare settings can benefit both local communities and ongoing research into HD etiology and new therapies. PMID- 27980763 TI - Operating the blues. AB - A 63-year-old man bearing most signs and symptoms (facial pigmentation, degenerative arthritis, and dark urine) pertinent to his known history of alkaptonuria underwent aortic valve replacement for critical aortic stenosis. Although rare, aortic stenosis is the most common cardiac manifestation of alkaptonuric ochronosis. PMID- 27980762 TI - Catheter ablation of ventricular ectopy with para-hisian origin: importance of mapping both sides of the interventricular septum and understanding when to stop ablating. AB - Catheter ablation of para-Hisian premature ventricular contractions (PVCs) still represents a challenge and is a compromise between success and inadvertent AV block. We describe a possible strategy to address PVCs from this location with high-amplitude His-bundle potentials at the site of earliest activation. PMID- 27980764 TI - Palmar rash in a teenager: more than meets the eye. AB - Despite being an uncommon disease in pediatrics, the incidence of syphilis has increased in the last years both in Europe and in the United States. Upon a suggestive clinical presentation, especially if including genital lesions and palmar rash, secondary syphilis must be included in the differential diagnosis. PMID- 27980765 TI - Computed tomography anomalies associated with isolated hypoparathyroidism. AB - Hypocalcemia due to chronic hypoparathyroidism presents with nonspecific symptoms. However, if untreated, hypocalcemia may affect neurological, cognitive, muscular, and cardiac function. Computed tomography (CT) findings may confirm a diagnosis of chronic hypoparathyroidism. Although autoimmune acquired hypoparathyroidism is a rare disease, early diagnosis and treatment are critical for avoiding severe complications. PMID- 27980766 TI - Unwitnessed head trauma: the bamboo did it. AB - Unwitnessed penetrating head injuries (PHIs) are often challenging. The inability to locate a foreign body should not exclude this diagnosis nor should it delay treatment. Attempts must be made to clarify the mechanism of injury, as this may allow for a better understanding of the patient's condition. PMID- 27980767 TI - Hemoglobin SC smear recorded with a smartphone. AB - Taking photographs of microscope slides generally requires expensive equipment and a lot of effort. We demonstrate a technique to take clear, focused pictures of microscope slides with a smartphone. This could facilitate exchange of information between providers, allow for quick second opinions, and improve patient care. PMID- 27980768 TI - Double pylorus: two sides to one story. AB - It is important to recognize that "congenital" double pylorus is a benign condition, so that extensive work-up can be avoided. Also, endoscopists should be aware of the double pylorus and demonstrate extra caution during endoscopic retrograde cholangiopancreatography (ERCP). PMID- 27980769 TI - Median arcuate ligament syndrome: case presentation and video-illustrated laparoscopic management. AB - Laparoscopic release of the median arcuate ligament, to relieve symptomatic compression of the celiac trunk, is the ideal approach when performed in a specialized center, by a surgeon with the adequate experience in advanced laparoscopic surgery. PMID- 27980770 TI - Contrast-enhanced transoral carotid ultrasonography for the evaluation of a long stenotic lesion in the internal carotid artery. AB - Contrast-enhanced transoral carotid ultrasonography (CETOCU) is a novel modality for imaging the distal extracranial internal carotid artery, which is not possible with conventional carotid ultrasonography. We present a representative case that demonstrates the usefulness of CETOCU. PMID- 27980771 TI - Applying neurobiology to the treatment of adults with anorexia nervosa. AB - BACKGROUND: Anorexia nervosa is a severe, biologically based brain disorder with significant medical complications. It is critical that new, effective treatments are developed to interrupt the persistent course of the illness due to the medical and psychological sequelae. Several psychosocial, behavioral and pharmacologic interventions have been investigated in adult anorexia nervosa; however, evidence shows that their impact is weak and treatment effects are generally small. METHOD: This paper describes a new neurobiological anorexia nervosa model that shifts focus from solely external influences, such as social and family, to include internal influences that integrate genetic and neurobiological contributions, across the age span. The model serves as a theoretical structure for a new, five-day treatment, outlined in this paper, targeting anorexia nervosa temperament, which integrates neurobiological dimensions into evidence-based treatment interventions. The treatment is in two phases. Phase I is a five day, 40 hour treatment for anorexia nervosa adults. Phase II is the follow-up and is currently being developed. RESULTS: Preliminary qualitative acceptability data on 37 adults with anorexia nervosa and 60 supports (e.g., spouses, parents, aunts, friends, partners, children of anorexia nervosa adults) are promising from Phase I. Clients with anorexia nervosa and their supports report that learning neurobiological facts improved their understanding of the illness and helped equip them with better tools to manage anorexia nervosa traits and symptoms. In addition, nutritional knowledge changed significantly. CONCLUSIONS: This is the first neurobiologically based, five-day treatment for adults with anorexia nervosa and their supports. It is a new model that outlines underlying genetic and neurobiological contributions to anorexia nervosa that serves as a foundation to treat both traits and symptoms. Preliminary qualitative findings are promising, with both clients and supports reporting that the neurobiological treatment approach helped them better understand the illness, while better conceptualizing how to respond to their traits and manage their symptoms. Data in Phase I shows promise as a neurobiologically based intervention for anorexia nervosa, and it serves as a foundation for the development of Phase II. Evidence of ongoing program efficacy will be described as data are reported on Phase II. TRIAL REGISTRATION: NCT NCT02852538 Registered 1 August 2016. PMID- 27980772 TI - Risk factors for elevated liver enzymes during refeeding of severely malnourished patients with eating disorders: a retrospective cohort study. AB - BACKGROUND: There are few previous reports regarding the cause and evolution of liver injury in patients with anorexia nervosa (AN) during the refeeding process, and its management remains controversial. This study aimed to determine the risk factors for elevated liver enzymes during refeeding and their effect on the therapeutic process in severely malnourished patients with eating disorders. METHODS: In a retrospective cohort study of 167 female inpatients in a single hospital from January 2004 to March 2015, 67 who had normal alanine aminotransferase (ALT) levels on admission were divided into two groups according to the presence or absence of elevated ALT levels during refeeding, and then compared. RESULTS: The median age and body mass index (BMI) of the patients on admission were 22 [interquartile range (IQR), 16-33] years and 12.2 (IQR, 11.1 13.0) kg/m2, respectively. Compared with their cohorts, significantly more patients in the early onset age group (<15 years old) had elevated ALT levels during refeeding (67% vs. 33%, p = 0.033), as did patients with longer median time to nadir BMI (3.0 vs. 0 days, p = 0.03). In addition, onset age [odds ratio (OR): 0.274; 95% confidence interval (CI): 0.077-0.981; p = 0.047] and time to nadir BMI (OR: 1.271; 95% CI: 1.035-1.56; p = 0.022) were significantly associated with the odds of elevated ALT levels during refeeding. CONCLUSIONS: The results of this study suggest that early age at onset may be a potential risk factor for elevated ALT levels during refeeding in severely malnourished patients with eating disorders. Furthermore, elevated ALT levels during refeeding were significantly associated with delay in the start of weight gain. No significant relationship was found between the amount of initial prescribed calories and elevated ALT levels during refeeding. The median time to maximum ALT was 27 (IQR, 21-38) days after the refeeding process started. PMID- 27980773 TI - Use of yoga in outpatient eating disorder treatment: a pilot study. AB - BACKGROUND: Individuals with restrictive eating disorders present with co-morbid psychiatric disorders and many attempt to control symptoms using strenuous exercises that increase caloric expenditure. Yoga offers a safe avenue for the engagement in physical activity while providing an outlet for disease-associated symptoms. This study sought to examine use of yoga practice in an outpatient setting and its impact on anxiety, depression and body image disturbance in adolescents with eating disorders. METHODS: Twenty adolescent girls were recruited from an urban eating disorders clinic who participated in weekly yoga classes at a local studio, in addition to standard multidisciplinary care. Yoga instructors underwent training regarding this patient population. Participants completed questionnaires focused on anxiety, depression and body image disturbance prior to the first class, and following completion of 6 and 12 classes. RESULTS: In participants who completed the study, a statistically significant decrease in anxiety, depression, and body image disturbance was seen, including: Spielberger State anxiety mean scores decreased after the completion of 7-12 yoga classes [47 (95%CI 42-52) to 42 (95%CI 37-47), adj. p = 0.0316]; as did the anorexia nervosa scale [10 (95% CI 7-12) vs. 6 (95%CI 4-8), adj. p = .0004], scores on Beck depression scales [18 (95%CI 15-22) to 10 (95%CI 6-14), adj. p = .0001], and weight and shape concern scores [16 (95%CI 12-20) to 12 (95%CI 8-16), adj. p =0.0120] and [31 (95%CI 25-37) to 20 (95%CI 13-27), adj. p = 0.0034], respectively. No significant changes in body mass index were seen throughout the trial. CONCLUSIONS: Yoga practice combined with outpatient eating disorder treatment were shown to decrease anxiety, depression, and body image disturbance without negatively impacting weight. These preliminary results suggest yoga to be a promising adjunct treatment strategy, along with standard multidisciplinary care. However, whether yoga should be endorsed as a standard component of outpatient eating disorder treatment merits further study. PMID- 27980774 TI - Cofactors in allergic reactions to food: physical exercise and alcohol are the most important. AB - INTRODUCTION: Involvement of cofactors, like physical exercise, alcohol consumption and use of several types of medication, are associated with more severe food allergic symptoms. However, there is limited evidence on how often cofactors play a role in food allergic reactions. The study aimed to get more insight into the frequency of exposure to cofactors and how often cofactors are associated with more severe symptoms in food allergic patients. METHODS: A questionnaire was completed by patients visiting the Allergology outpatient clinic. Patients with food allergy were included. Outcome measures were the frequency of medication use of medication groups that might act as cofactor and the frequency that physical exercise, alcohol consumption and use of analgesics are associated with more severe food allergic symptoms. RESULTS: Four hundred ninety-six patients were included in the study. The frequency with which patients used one or more types of medication that might act as cofactors was 7.7%: antacids/acid neutralizing medication (5%), NSAIDs (2%), beta blockers (0.6%), angiotensin-converting enzyme inhibitors (0.6%), and angiotensin receptor blockers (0.2%). Of all patients, 13% reported more severe symptoms to food after involvement of one or more of the cofactors: physical exercise (10%), alcohol consumption (5%), and use of analgesics (0.6%). Sixty-five percent did not know if these cofactors caused more severe symptoms; 22% reported that these cofactors had no effect. CONCLUSIONS: Only a small percentage of patients (7.7%) used medication that might aggravate food allergic reactions. Physical exercise and alcohol consumption were the most frequently reported cofactors, but occurring still in only 10% or less. PMID- 27980775 TI - Involvement of IL-17A-producing TCR gammadelta T cells in late protective immunity against pulmonary Mycobacterium tuberculosis infection. AB - INTRODUCTION: Interleukin (IL)-17A is a cytokine originally reported to induce neutrophil-mediated inflammation and anti-microbial activity. The CD4+ T cells, which produce IL-17A, have been well characterized as Th17 cells. On the other hand, IL-17A-producing TCR gammadelta+ T cells have been reported to participate in the immune response at an early stage of infection with Listeria monocytogenes and Mycobacterium bovis in mice. However, the involvement of IL-17A in protective immunity was not clearly demonstrated in the chronic stage of M. tuberculosis infected mice. METHODS: We analyzed role of IL-17A in host defense against chronically infected M. tuberculosis using IL-17A KO mice. RESULTS: We found that TCR gammadelta+ T cells are a primary source of IL-17A, but that mycobacterial antigen-specific Th17 cells were hardly detected even at the chronic stage of M. tuberculosis infection. IL-17A-deficient mice showed a decreased survival rate, and increased bacterial burden in the lungs after the infection when compared to the wild-type mice. Furthermore, a histological analysis showed an impaired granuloma formation in the infected lungs of IL-17A-deficient mice, which was considered to be due to a decrease of IFN-gamma and TNF at the chronic stage. CONCLUSION: Our data suggest that the IL-17A-producing TCR gammadelta+ T cells, rather than the Th17 cells, in the infected lungs are an indispensable source of protective immunity against M. tuberculosis infection. PMID- 27980776 TI - Macrophagic control of the response to uropathogenic E. coli infection by regulation of iron retention in an IL-6-dependent manner. AB - INTRODUCTION: Uropathogenic Escherichia coli (UPEC), the causative agent of over 85% of urinary tract infections (UTIs), elaborate a number of siderophores to chelate iron from the host. On the other hand, the host immune imperative is to limit the availability of iron to the bacteria. Little is known regarding the mechanisms underlying this host-iron-UPEC interaction. Our objective was to determine whether macrophages, in response to UPEC infection, retain extracellular siderophore-bound and free iron, thus limiting the ability of UPEC to access iron. METHODS: Quantitative PCR, immunoblotting analysis, and gene expression analysis of wild type and IL-6-deficient macrophages was performed. RESULTS: We found that (1) macrophages upon UPEC infection increased expression of lipocalin 2, a siderophore-binding molecule, of Dmt1, a molecule that facilitates macrophage uptake of free iron, and of the intracellular iron cargo molecule ferritin, and decreased expression of the iron exporter ferroportin; (2) bladder macrophages regulate expression of genes involved in iron retention upon UPEC infection; (3) IL-6, a cytokine known to play an important role in regulating host iron homeostasis as well as host defense to UPEC, regulates this process, in part by promoting production of lipocalin 2; and finally, (4) inhibition of IL-6 signaling genetically and by neutralizing antibodies against the IL-6 receptor, promoted intra-macrophagic UPEC growth in the presence of excess iron. CONCLUSIONS: Together, our study suggests that macrophages retain siderophore-bound and free iron in response to UPEC and IL-6 signaling is necessary for macrophages to limit the growth of UPEC in the presence of excess iron. IL-6 signaling and iron regulation is one mechanism by which macrophages may mediate UPEC clearance. PMID- 27980778 TI - Basophil Activation Test identifies the patients with Chronic Spontaneous Urticaria suffering the most active disease. AB - INTRODUCTION: The basophil activation test showing CD63 up regulation could be a specific and sensitive in vitro complementary text to the in vivo autologous serum skin test for the activity assessment of the patients suffering autoimmune chronic spontaneous urticaria. The aim of this study is to define the basophil activation test as a useful tool in clinical practice in order to identify those patients with more active disease. METHODS: We screened 139 patients (96 women) diagnosed of chronic spontaneous urticaria using simultaneously autologous serum skin test and basophil activation test and their relationship with disease activity. RESULTS: Positive autologous serum skin test was found in 56.8%; from them, 31.6% were basophil activation test positive. Negative autologous serum skin test result was found in the 43.2% of the sample that showed negative CD63 expression results in all cases, except one. Patients with positive autologous serum skin test and positive CD63 by basophil activation test showed significant higher Urticaria Activity Score of 7 days (P = 0.004) and of 3 weeks (P = 0.001) than patients with positive autologous serum skin test and negative CD63 (mean +/ standard deviation [SD] 26.57 +/- 10.56 versus 18.40 +/- 12.05 for the Urticaria Activity Score of 7 days and 56.47 +/- 23.78 versus 39.88 +/- 25.44 for the Urticaria Activity Score of 3 weeks). CONCLUSIONS: The CD63 expression on basophils appears as a reliable in vitro marker, useful in clinical practice in combination with autologous serum skin test to define chronic spontaneous urticaria patients with the highest urticaria activity that impairs a normal life. PMID- 27980777 TI - Improved B cell development in humanized NOD-scid IL2Rgammanull mice transgenically expressing human stem cell factor, granulocyte-macrophage colony stimulating factor and interleukin-3. AB - INTRODUCTION: Immunodeficient mice engrafted with human immune systems support studies of human hematopoiesis and the immune response to human-specific pathogens. A significant limitation of these humanized mouse models is, however, a severely restricted ability of human B cells to undergo class switching and produce antigen-specific IgG after infection or immunization. METHODS: In this study, we have characterized the development and function of human B cells in NOD scid IL2Rgammanull (NSG) mice transgenically expressing human stem cell factor (SCF), granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-3 (NSG SGM3) following engraftment with human hematopoietic stem cells, autologous fetal liver, and thymic tissues (bone marrow, liver, thymus or BLT model). The NSG-SGM3 BLT mice engraft rapidly with human immune cells and develop T cells, B cells, and myeloid cells. RESULTS: A higher proportion of human B cells developing in NSG-SGM3 BLT mice had a mature/naive phenotype with a corresponding decrease in immature/transitional human B cells as compared to NSG BLT mice. In addition, NSG SGM3 BLT mice have higher basal levels of human IgM and IgG as compared with NSG BLT mice. Moreover, dengue virus infection of NSG-SGM3 BLT mice generated higher levels of antigen-specific IgM and IgG, a result not observed in NSG BLT mice. CONCLUSIONS: Our studies suggest that NSG-SGM3 BLT mice show improved human B cell development and permit the generation of antigen-specific antibody responses to viral infection. PMID- 27980779 TI - Distinct immunological activation profiles of dSLIM(r) and ProMune(r) depend on their different structural context. AB - INTRODUCTION: DNA-based TLR9 agonists are potent activators of the immune system. ProMune(r) and dSLIM(r) belong to different families of TLR9 agonists and both have been established as cancer immunotherapeutics in clinical proof-of-concept studies. Unfortunately, ProMune(r) failed in pivotal oncological trials. dSLIM(r), the active ingredient of Lefitolimod (MGN1703), successfully finished a double-blinded, placebo-controlled phase II study in patients with advanced colorectal cancer, exhibiting improved progression-free survival and durable disease control. METHODS: To explain the different systemic efficacies of dSLIM(r) and ProMune(r), both TLR9 agonists and chimeric molecules thereof are analyzed side-by-side in a panel of in vitro assays for immune activation. RESULTS AND CONCLUSIONS: Indeed, dSLIM(r) exposure results in an IFN-alpha dependent broad activation of immune cells whereas ProMune(r) strongly stimulates B cells. Moreover, all functional effects of dSLIM(r) strictly depend on the presence of CG-motifs within its dumbbell-shaped, covalently closed structural context. Conversely, several immunological effects of ProMune(r) like IL-8 secretion are independent of CG-motifs and could be ascribed to the phosphorothioate-modifications of its DNA backbone, which may have caused the side effects of ProMune(r) in clinical trials. Finally, we showed that the implementation of ProMune(r) (ODN2006) base sequence into the characteristic dSLIM(r) dumbbell form resulted in dSLIM2006 with all beneficial effects for immunostimulation combined from both TLR9 classes without any CG-independent effects. PMID- 27980780 TI - Hsp90 inhibition ameliorates CD4+ T cell-mediated acute Graft versus Host disease in mice. AB - INTRODUCTION: For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co-transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)-a potentially life-threatening complication. METHODS: Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD. RESULTS: Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4+ T cell transplantation with the Hsp90 inhibitor 17-(dimethylaminoethylamino) 17-demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia bearing mice after transplantation of allogeneic CD4+ and CD8+ T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4+ T cells with a relative resistance of CD4+ regulatory and CD8+ T cells toward Hsp90 inhibition. CONCLUSIONS: Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect. PMID- 27980781 TI - Critical influence of the thymus on peripheral T cell homeostasis. AB - INTRODUCTION: A tight balance between regulatory CD4+Foxp3+ (Treg) and conventional CD4+Foxp3- (Tconv) T cell subsets in the peripheral compartment, maintained stable throughout most of lifetime, is essential for preserving self tolerance along with efficient immune responses. An excess of Treg cells, described for aged individuals, may critically contribute to their reported immunodeficiency. In this work, we investigated if quantitative changes in thymus emigration may alter the Treg/Tconv homeostasis regardless of the aging status of the peripheral compartment. METHODS: We used two different protocols to modify the rate of thymus emigration: thymectomy of adult young (4-6 weeks old) mice and grafting of young thymus onto aged (18 months old) hosts. Additionally, lymphoid cells from young and aged B6 mice were intravenously transferred to B6.RAG2-/- mice. Alterations in Treg and Tconv peripheral frequencies following these protocols were investigated after 30 days by flow cytometry. RESULTS: Thymectomized young mice presented a progressive increase in the Treg cell frequency, while the grafting of a functional thymus in aged mice restored the young-like physiological Treg/Tconv proportion. Strikingly, T cells derived from young or aged splenocytes colonized the lymphopenic periphery of RAG-/- hosts to the same extent, giving rise to similarly elevated Treg cell levels irrespective of the age of the donor population. In the absence of thymus output, the Treg subset seems to survive longer, as confirmed by their lower proportion of Annexin V+ cells. CONCLUSIONS: Our data suggest that the thymus-emigrating population, harboring an adequate proportion of Treg/Tconv lymphocytes, may be essential to keep the Treg cell balance, independently of age-related shifts intrinsic to the peripheral environment or to the T cell biology. PMID- 27980782 TI - Whole genome prediction and heritability of childhood asthma phenotypes. AB - INTRODUCTION: While whole genome prediction (WGP) methods have recently demonstrated successes in the prediction of complex genetic diseases, they have not yet been applied to asthma and related phenotypes. Longitudinal patterns of lung function differ between asthmatics, but these phenotypes have not been assessed for heritability or predictive ability. Herein, we assess the heritability and genetic predictability of asthma-related phenotypes. METHODS: We applied several WGP methods to a well-phenotyped cohort of 832 children with mild to-moderate asthma from CAMP. We assessed narrow-sense heritability and predictability for airway hyperresponsiveness, serum immunoglobulin E, blood eosinophil count, pre- and post-bronchodilator forced expiratory volume in 1 sec (FEV1), bronchodilator response, steroid responsiveness, and longitudinal patterns of lung function (normal growth, reduced growth, early decline, and their combinations). Prediction accuracy was evaluated using a training/testing set split of the cohort. RESULTS: We found that longitudinal lung function phenotypes demonstrated significant narrow-sense heritability (reduced growth, 95%; normal growth with early decline, 55%). These same phenotypes also showed significant polygenic prediction (areas under the curve [AUCs] 56% to 62%). Including additional demographic covariates in the models increased prediction 4 8%, with reduced growth increasing from 62% to 66% AUC. We found that prediction with a genomic relatedness matrix was improved by filtering available SNPs based on chromatin evidence, and this result extended across cohorts. CONCLUSIONS: Longitudinal reduced lung function growth displayed extremely high heritability. All phenotypes with significant heritability showed significant polygenic prediction. Using SNP-prioritization increased prediction across cohorts. WGP methods show promise in predicting asthma-related heritable traits. PMID- 27980783 TI - Plasmodium chabaudi infection induces AID expression in transitional and marginal zone B cells. AB - INTRODUCTION: Endemic Burkitt's lymphoma (eBL) is associated with Epstein-Barr virus and repeated malaria infections. A defining feature of eBL is the translocation of the c-myc oncogene to the control of the immunoglobulin promoter. Activation-induced cytidine deaminase (AID) has been shown to be critical for this translocation. Malaria infection induces AID in germinal center B cells, but whether malaria infection more broadly affects AID activation in extrafollicular B cells is unknown. METHODS: We either stimulated purified B cells from AID-green fluorescence protein (GFP) reporter mice or infected AID-GFP mice with Plasmodium chabaudi, AID fluorescence was monitored in B cell subsets by flow cytometry. RESULTS: In vitro analysis of B cells from these mice revealed that CpG (a Toll-like receptor 9 ligand) was a potent inducer of AID in both mature and immature B cell subsets. Infection of AID-GFP mice with Plasmodium chabaudi demonstrated that AID expression occurs in transitional and marginal zone B cells during acute malaria infection. Transitional B cells were also capable of differentiating into antibody secreting cells when stimulated in vitro with CpG when isolated from a P. chabaudi-infected mouse. CONCLUSIONS: These data suggest that P. chabaudi is capable of inducing AID expression in B cell subsets that do not participate in the germinal center reaction, suggesting an alternative role for malaria in the etiology of eBL. PMID- 27980784 TI - Rapid full-wave phase aberration correction method for transcranial high intensity focused ultrasound therapies. AB - BACKGROUND: Non-invasive high-intensity focused ultrasound (HIFU) can be used to treat a variety of disorders, including those in the brain. However, the differences in acoustic properties between the skull and the surrounding soft tissue cause aberrations in the path of the ultrasonic beam, hindering or preventing treatment. METHODS: We present a method for correcting these aberrations that is fast, full-wave, and allows for corrections at multiple treatment locations. The method is simulation-based: an acoustic model is built based on high-resolution CT scans, and simulations are performed using the hybrid angular spectrum (HAS) method to determine the phases needed for correction. RESULTS: Computation of corrections for clinically applicable resolutions can be achieved in approximately 15 min. Experimental results with a plastic model designed to mimic the aberrations caused by the skull show that the method can recover 95 % of the peak pressure obtained using hydrophone-based time-reversal methods. Testing using an ex vivo human skull flap resulted in recovering up to 70 % of the peak pressure at the focus and 61 % when steering (representing, respectively, a 1.52- and 1.19-fold increase in the peak pressure over the uncorrected case). Additionally, combining the phase correction method with rapid HAS simulations allows evaluation of such treatment metrics as the effect of misregistration on resulting pressure levels. CONCLUSIONS: The method presented here is able to rapidly compute phases required to improve ultrasound focusing through the skull at multiple treatment locations. Combining phase correction with rapid simulation techniques allows for evaluation of various treatment metrics such as the effect of steering on pressure levels. Since the method computes 3D pressure patterns, it may also be suitable for predicting off-focus hot spots during treatments-a primary concern for transcranial HIFU. Additionally, the plastic-skull method presented here may be a useful tool in evaluating the effectiveness of phase correction methods. PMID- 27980787 TI - "There is not much help for mothers like me": Parenting Skills for Mothers with Borderline Personality Disorder - a newly developed group training program. AB - BACKGROUND: Dysfunctional relationships and emotion dysregulation are hallmark features of borderline personality disorder (BPD). Women with BPD are, therefore, particularly challenged when raising a child. A group training program was developed for mothers with BPD to enhance their parenting skills and help them raise their children. The program is based on cognitive-behavioral principles and skills derived from Dialectical Behavior Therapy (DBT). METHODS: N = 15 mothers with BPD who had young children (aged 0-6 years) participated in a 12-week training program. To estimate the participants' impairment, parental stress and psychological distress were assessed before the training. After the training, participants and trainers were asked to provide feedback regarding the evaluation of and the changes due to the training. RESULTS: Participants' self-reported stress related to parenting, as well as psychological distress and depressive symptoms, was high. Participants' acceptance of the program was very good. Especially role plays were rated as useful. Trainers evaluated the program as helpful and reported visible changes in participants' behavior and attitudes towards parenting. CONCLUSIONS: The results on the acceptance of the training program are promising. TRIAL REGISTRATION: NCT02935218, Unique Protocol ID: RenRos01 Initial release 80 August 2016, last release 13 October 2016; 'retrospectively registered'. PMID- 27980786 TI - Sperm DNA damage and its role in IVF and ICSI. AB - While the semen analysis has traditionally been relied upon to differentiate fertile and infertile men, its utility has been questioned in the current era of assisted reproductive technologies. The desire for more sophisticated diagnostic and predictive tools has led to increased use of sperm DNA damage in the management of male infertility. Despite the availability of numerous assays to measure sperm DNA damage, our understanding of the etiology, measurement, and clinical implications of sperm DNA damage remains incomplete. While the current evidence is fraught with heterogeneity that complicates attempts at comparison and meta-analysis, there does appear to be a role for sperm DNA damage in the development and maintenance of pregnancy in the era of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). However, as noted by the American Society for Reproductive Medicine, the routine and widespread use of sperm DNA damage testing is not yet supported. Further studies are needed to standardize the measurement of sperm DNA damage and to clarify the exact role of sperm DNA damage within the myriad of other male and female factors contributing to reproductive outcomes in IVF and ICSI. PMID- 27980785 TI - Fast and high temperature hyperthermia coupled with radiotherapy as a possible new treatment for glioblastoma. AB - BACKGROUND: A new transcranial focused ultrasound device has been developed that can induce hyperthermia in a large tissue volume. The purpose of this work is to investigate theoretically how glioblastoma multiforme (GBM) can be effectively treated by combining the fast hyperthermia generated by this focused ultrasound device with external beam radiotherapy. METHODS/DESIGN: To investigate the effect of tumor growth, we have developed a mathematical description of GBM proliferation and diffusion in the context of reaction-diffusion theory. In addition, we have formulated equations describing the impact of radiotherapy and heat on GBM in the reaction-diffusion equation, including tumor regrowth by stem cells. This formulation has been used to predict the effectiveness of the combination treatment for a realistic focused ultrasound heating scenario. Our results show that patient survival could be significantly improved by this combined treatment modality. DISCUSSION: High priority should be given to experiments to validate the therapeutic benefit predicted by our model. PMID- 27980788 TI - Heat stroke with bimodal rhabdomyolysis: a case report and review of the literature. AB - BACKGROUND: Severe heat stroke tends to be complicated with rhabdomyolysis, especially in patients with exertional heat stroke. Rhabdomyolysis usually occurs in the acute phase of heat stroke. We herein report a case of heat stroke in a patient who experienced bimodal rhabdomyolysis in the acute and recovery phases. CASE PRESENTATION: A 34-year-old male patient was found lying unconscious on the road after participating in a half marathon in the spring. It was a sunny day with a maximum temperature of 24.2 degrees C. His medical and family history was unremarkable. Upon arrival, his Glasgow Coma Scale score was 10. However, the patient's marked restlessness and confusion returned. A sedative was administered and tracheal intubation was performed. On the second day of hospitalization, a blood analysis was compatible with a diagnosis of acute hepatic failure; thus, he received fresh frozen plasma and a platelet transfusion was performed, following plasma exchange and continuous hemodiafiltration. The patient's creatinine phosphokinesis (CPK) level increased to 8832 IU/L on the fifth day of hospitalization and then showed a tendency to transiently decrease. The patient was extubated on the eighth day of hospitalization after the improvement of his laboratory data. From the ninth day of hospitalization, gradual rehabilitation was initiated. However, he felt pain in both legs and his CPK level increased again. Despite the cessation of all drugs and rehabilitation, his CPK level increased to 105,945 IU/L on the 15th day of hospitalization. Fortunately, his CPK level decreased with a fluid infusion. The patient's rehabilitation was restarted after his CPK level fell to <10,000 IU/L. On the 31st day of hospitalization, his CK level decreased to 623 IU/L and he was discharged on foot. Later, a genetic analysis revealed that he had a thermolabile genetic phenotype of carnitine palmitoyltransferase II (CPT II). CONCLUSIONS: Physicians should pay special attention to the stress of rehabilitation exercises, which may cause collapsed muscles that are injured by severe heat stroke to repeatedly flare up. PMID- 27980789 TI - Sickle-cell disease in febrile children living in a rural village of Madagascar and association with malaria and respiratory infections. AB - BACKGROUND: In Madagascar, the last study on sickle cell disease (SCD) was done in the early 1980s. The country is known as endemic for malaria and respiratory infections. The main objective of this study was to estimate the prevalence of SCD; the secondary objective was to evaluate its association with malaria and respiratory infections. METHODS: This is a cross-sectional study which was carried out in a rural village in the south east coast of Madagascar between May 2011 and November 2013. Participants were children aged between 2-59 months presenting with fever measured by axillary temperature >=37.5 degrees C at inclusion. Genotyping of haemoglobin S was done by PCR and malaria was diagnosed by Rapid Diagnostic Test. Research for viral and atypical bacterial respiratory pathogens was performed on nasopharyngeal swabs. Uni-and multivariate polytomous logistic regression was done to assess associations between microbiological results and SCD status, with HbAA phenotype as reference. RESULTS: A total of 807 children were analysed. Prevalence of SCD among febrile children was 2.4% (95% CI, 1.5-3.7%) and that of SCT was 23.8% (95% CI, 20.9-26.9%). There was no difference in the prevalence of malaria infection according to haemoglobin status (p = 0.3). Rhinovirus (22.5%), adenovirus (14.1%), and bocavirus (11.6%) were the most common respiratory pathogens detected. After univariate analysis, patients with SCD were more frequently infected by parechovirus (p = 0.01), while patients with SCT were more prone to RSV A or B infection (p = 0.01). After multivariate analysis, HbAS phenotype was associated with higher risk of RSV A and B infection compared to HbAA (adjusted OR = 1.9; 95% CI: 1.2-3.1, p = 0.009), while HbSS phenotype was associated with higher risk of parechovirus infection (adjusted OR = 6.0; 95% CI: 1.1-31.3, p = 0.03) compared to HbAA, independently of age, gender, period per quarter, and the other viruses. CONCLUSION: The prevalence of SCD among under-five children presenting with fever was high in the study population. No association was found between SCT and malaria but few viruses, especially parechovirus, seem to play an important role in the occurrence of pneumoniae among SCD patients. PMID- 27980790 TI - Incidence of back pain in adolescent athletes: a prospective study. AB - BACKGROUND: Recently, the incidence rate of back pain (BP) in adolescents has been reported at 21%. However, the development of BP in adolescent athletes is unclear. Hence, the purpose of this study was to examine the incidence of BP in young elite athletes in relation to gender and type of sport practiced. METHODS: Subjective BP was assessed in 321 elite adolescent athletes (m/f 57%/43%; 13.2 +/ 1.4 years; 163.4 +/- 11.4 cm; 52.6 +/- 12.6 kg; 5.0 +/- 2.6 training yrs; 7.6 +/ 5.3 training h/week). Initially, all athletes were free of pain. The main outcome criterion was the incidence of back pain [%] analyzed in terms of pain development from the first measurement day (M1) to the second measurement day (M2) after 2.0 +/- 1.0 year. Participants were classified into athletes who developed back pain (BPD) and athletes who did not develop back pain (nBPD). BP (acute or within the last 7 days) was assessed with a 5-step face scale (face 1-2 = no pain; face 3-5 = pain). BPD included all athletes who reported faces 1 and 2 at M1 and faces 3 to 5 at M2. nBPD were all athletes who reported face 1 or 2 at both M1 and M2. Data was analyzed descriptively. Additionally, a Chi2 test was used to analyze gender- and sport-specific differences (p = 0.05). RESULTS: Thirty-two athletes were categorized as BPD (10%). The gender difference was 5% (m/f: 12%/7%) but did not show statistical significance (p = 0.15). The incidence of BP ranged between 6 and 15% for the different sport categories. Game sports (15%) showed the highest, and explosive strength sports (6%) the lowest incidence. Anthropometrics or training characteristics did not significantly influence BPD (p = 0.14 gender to p = 0.90 sports; r2 = 0.0825). CONCLUSIONS: BP incidence was lower in adolescent athletes compared to young non-athletes and even to the general adult population. Consequently, it can be concluded that high performance sports do not lead to an additional increase in back pain incidence during early adolescence. Nevertheless, back pain prevention programs should be implemented into daily training routines for sport categories identified as showing high incidence rates. PMID- 27980791 TI - Physical inactivity among physiotherapy undergraduates: exploring the knowledge practice gap. AB - BACKGROUND: Physical inactivity is a common risk factor for several non communicable diseases (NCDs). Increasing physical activity could reduce the burden of disease due to major NCDs and increase life expectancy. Undergraduate physiotherapy students represent a group of young-adults expected to have a good knowledge of physical activity. We evaluated physical activity levels of undergraduate physiotherapy students of University of Colombo, Sri Lanka and determined their motives and barriers for participation in physical activity. METHODS: All physiotherapy undergraduates studying at the University of Colombo, Sri Lanka in 2013 were invited for the study. Phase one was a quantitative study to evaluate the physical activity levels and phase two was a qualitative study to identify motives and barriers for physical activity and sports in the same cohort. Physical activity levels (phase 1) were assessed using the interviewer administered International Physical Activity Questionnaire (long-version). The qualitative study (phase 2) was conducted in the same population using Focus Group Discussions (n = 3) and individual In-depth Interviews (n = 5). RESULTS: Sample size in phase 1 and phase 2 were 113 (response rate = 98%; [N-115]) and 87 (response rat = 97%; [N-90]) respectively. Mean age (+/-SD) of participants was 23.4 +/- 1 years. The mean weekly total MET minutes (+/-SD) of the study population was 1791.25 +/- 3097. According to the IPAQ categorical score a higher percentage of participants were 'inactive' (48.7%), while only 15.9% were in the 'Highly active' group. Lack of support and encouragement received during childhood to engage in sports activity seem to have played an important role in continuing their exercise behavior through to the adult life. Academic activities were given priority by both parents and teachers. The environment and support from teachers, family and friends were important to initiate and adhere to sports and physical activity. CONCLUSIONS: A higher percentage of participants were 'inactive', in spite of belonging to a group which is presumed to be knowledgeable regarding the benefits of physical activity. A significant negative attitude towards physical activity was observed in this cohort of young-adults. This seems to stem from earlier in life, due to lack of support and motivation for physical exercise and sports, received during primary and secondary schooling. This negative attitude has become a significant 'internal' barrier, which has not been changed in spite of their education. PMID- 27980792 TI - Bisphenol A removal from aqueous solutions using novel UV/persulfate/H2O2/Cu system: optimization and modelling with central composite design and response surface methodology. AB - BACKGROUND: Bisphenol A is a high production volume chemical widely used in manufacturing polycarbonate plastics and epoxy resins used in many industries. Due to its adverse effects on human health as an endocrine disruptor and many other effects on the various organs of the human body as well as aquatic organisms, it should be removed from the aquatic environments. This study aimed to mineralisation of BPA from aquatic environments by application of novel UV/SPS/H2O2/Cu system and optimization and modelling of its removal using central composite design (CCD) from response surface methodology (RSM). METHODS: CCD from RSM was used for modeling and optimization of operation parameters on the BPA degradation using UV/SPS/HP/Cu system. Effective operation parameters were initial persulfate, H2O2, Cu2+ and BPA concentration along with pH and reaction time, all in three levels were investigated. For analysis of obtained data ANOVA test was used. RESULTS: The results showed that a quadratic model is suitable to fit the experimental data (p < 0.0001). Analysis of response surface plots showed a considerable impact of all six selected variables which BPA and Cu2+ initial concentrations have been the highest and the least impact on the process, respectively. F-value of model was 54.74 that indicate significance of the model. The optimum values of the operation parameters were determined. The maximum removal of BPA was achieved 99.99 % in optimal conditions and in that condition TOC removal was about 70 %. Finally, validation and accuracy of the model were also evaluated by graphical residual analysis and the influential diagnostics plots. The higher relevance between actual and predicted values demonstrated the validation and applicability of the obtained equation as the model. CONCLUSIONS: According to the results, UV/SPS/HP/Cu system is an effective process in degradation and mineralisation of BPA and CCD methodology is a convenient and reliable statistical tool for optimizing BPA removal from aqueous solutions. PMID- 27980793 TI - Environmental health centers for asbestos and their health impact surveys and activities. AB - In 2009, Korea banned the import, transport, and use of asbestos, and the Asbestos Injury Relief Act (AIRA) was promulgated in 2011. Two environmental health centers for asbestos (EHCA), including Pusan National University Yangsan Hospital (PNUYH) and SoonChunHyang University Cheonan Hospital (SCHUCH), were adapted to find environmental asbestos-related diseases (ARDs) and to support the purposes of AIRA. EHCA conducted a health impact survey (HIS) on persons who resided or reside near asbestos factories or mines. A total of 13,433 persons have taken screening examinations in PNUYH EHCA, and 623 persons (4.6%) have had secondary examinations. Of the 21,014 persons who had screening examinations in SCHUCH EHCA, 2490 persons (11.8%) had secondary examinations. Some of those who tested positive for ARDs through HISs filed applications for the asbestos victims' medical pocketbook (AVMP). Approximately 116 and 612 persons received AVMPs as a result of PNUYH and SCHUCH examinees, respectively. EHCAs have conducted HISs, public relations, and education for asbestos victims, ordinary citizens, and physicians. As HISs are based on voluntary participation, they does not monitor high-risk groups. Active surveillance focusing on high-risk groups has been blocked by the personal information protection act. Although important work has been performed in finding environmental asbestos victims and increasing public awareness on asbestos, it is necessary to improve the current system and registration. PMID- 27980794 TI - Effects of shift work on abdominal obesity among 20-39-year-old female nurses: a 5-year retrospective longitudinal study. AB - BACKGROUND: This study aimed to investigate the effects of shift work on abdominal obesity among young and middle-aged female nurses during a 5-year retrospective study. METHODS: This retrospective study included female nurses (20 39 years old) who worked at a university hospital in Korea and had available health screening results from 2010-2015. Among 2,611 employees, 934 healthy 20-39 year-old female nurses were identified, and data regarding their demographic information (age and date of employment), waist circumferences (WC), and lifestyle factors (alcohol and exercise) were obtained. Abdominal obesity was defined as a WC of >=80 cm, based on the World Health Organization's Asia-West Pacific standard in 2000. The mean WC change from baseline was analyzed using the paired t test, and the association between shift work and abdominal obesity was analyzed using the generalized estimating equation. RESULTS: Compared to all day workers (both age groups), the 20-29-year-old nurses did not exhibit significant changes in WC at each follow-up. However, among the 30-39-year-old nurses, shift workers exhibited a significant change in WC (vs. baseline) during years 4 and 5, compared to day workers. After adjusting for effective confounders and stratifying the participants according to age, the 20-29-year-old nurses exhibited an odds ratio of 3.21 (95 % confidence interval: 1.29-7.98) for shift work-associated obesity, although the odds ratio for the 30-39-year-old nurses was not statistically significant. CONCLUSION: In the study population, shift work was associated with a significant change in mean WC among 30-39-year-old nurses, and the shift work-associated risk of abdominal obesity was significant among 20-29-year-old nurses. These results indicate that shift work may influence abdominal obesity differently in 20-29-year-old and 30-39-year-old female nurses. PMID- 27980795 TI - The association between severity of King's Obesity Staging Criteria scores and treatment choice in patients with morbid obesity: a retrospective cohort study. AB - BACKGROUND: The King's Obesity Staging Criteria (KOSC) comprises of a four-graded set of health related domains. We aimed to examine whether, according to KOSC, patients undergoing bariatric surgery differed from those opting for conservative treatment. METHODS: We graded 2142 consecutive patients with morbid obesity attending our centre from 2005-10 into the following KOSC domains: airway/apnoea, body mass index (BMI), cardiovascular risk (CV-risk), diabetes mellitus, economic complications, functional limitations, gonadal dysfunction, and perceived health status/body image. Both patients and physicians agreed upon treatment choice through a shared decision making process. RESULTS: A total of 1329 (62%) patients opted for lifestyle intervention and 813 (37%) for bariatric surgery as their first treatment choice. The patients treated with bariatric surgery were younger (42 vs. 44 years, p < 0.001), had a higher BMI (45.4 vs. 43.8 kg/m2, p < 0.001) and had a lower ten year estimated CV-risk (9.4 vs. 10.7%, p = 0.004) than the lifestyle intervention group. Compared with having BMI < 40 kg/m2, BMI >= 40 kg/m2 was associated with 85% increased odds of bariatric surgery (OR 1.85 [95% CI 1.48, 2.30]). Conversely, patients with >=20% ten year CV-risk, had lower odds of bariatric surgery than patients with <20% CV-risk (0.68 [0.53, 0.87]). CONCLUSION: BMI was the strongest KOSC-domain associated with subsequent bariatric surgery after a shared decision making process. Prospective studies are required to assess whether the use of KOSC can help guide patients and clinicians to identify the most appropriate choice of treatment for morbid obesity. PMID- 27980796 TI - Nutritional quality and marketing strategies of fast food children's combo meals in Guatemala. AB - BACKGROUND: Overweight and obesity prevalence in children is now on the rise in low/middle-income countries, including Guatemala. Fast food consumption is a recognized contributing factor to this rise. Fast food restaurants use health claims, toy giveaways, price incentives and fast service to promote children's combo meals. This study sought to assess the use of toy giveaways, time to delivery and price incentives as marketing strategies in fast food chain restaurants in Guatemala. In addition, we sought to compare nutritional quality of combo meals with and without health claims. METHODS: We visited one restaurant from each of the 8 major fast food chains in Guatemala and purchased all children's combo meals to assess the prevalence of toy giveaways, health claims, and difference in delivery time and price between the combo meal and each meal item purchased separately. Each item was then classified as "healthy" or "less healthy" using the UK Nutrition Profile Model. Nutrition information was collected on-site, from the restaurant website, or by calling the customer service phone number. RESULTS: We found 114 combo meals, 21 (18.4%) of which were children's combo meals. Five (24%) had nutrition information, all were classified by our analysis as "less healthy", and three had a health claim. On average, combo meals were US$1.93 less expensive than purchasing children's meal items individually (p = 0.01). Time to delivery was 1.44 min faster for combo meals compared to purchasing meal items individually (p = 0.19). CONCLUSIONS: Children's fast food combo meals in Guatemala were promoted using several marketing strategies that encourage consumption, including offering toy giveaways and price incentives. In addition, nutrition information is lacking in fast food chain restaurants. Public health advocates in Guatemala should consider a comprehensive approach to encourage healthier choices within fast food restaurants including policies that require fruit and vegetable options for meal side dishes, accessible and easy to read nutrition information, and restrict the use of toy giveaways. PMID- 27980797 TI - Erratum to: Freshman 15 in England: a longitudinal evaluation of first year university student's weight change. AB - [This corrects the article DOI: 10.1186/s40608-016-0125-1.]. PMID- 27980798 TI - Genetic testing in a gynaecological oncology care in developing countries knowledge, attitudes and perception of Nepalese clinicians. AB - BACKGROUND: Genetic testing for an inherited susceptibility to cancer is an emerging technology in medical practice. Little information is currently available about physicians' attitudes towards these tests in developing countries. METHODS: We conducted an email survey of Nepalese physicians practicing in academic and non-academic settings in Nepal, regarding knowledge, attitudes and perception towards genetic testing for gynaecologic cancer. RESULTS: Responses were received from 251 of 387 practitioners (65%). Only 46% of all respondents felt prepared to answer patients' questions about genetic testing for gynaecologic cancer, despite 80% reporting that patients had asked questions about genetic testing, and 55% being asked more than 5 times in the past year. 42% reported more than 10 of their patients having had genetic testing for cancer, the majority for BRCA1/2. Access (40%), cost (37%) and lack of physicians' information (24%) were cited as the main barriers to testing. The most commonly identified concerns regarding genetic testing were the potential for increased patient anxiety, misinterpretation of results by patients, and maintaining confidentiality of results (64%, 47% and 38% of respondents respectively). CONCLUSION: This study shows the gap among the health care providers in developing countries and the available modern scientific tools and skills in regard to the benefits of genetic testing for gynaecological cancers in a developing nation. These findings indicate the need for the introduction of further genetic counselling education and support into gynaecological care in Nepal. PMID- 27980799 TI - Analysis of in vitro chemoresponse assays in endometrioid endometrial adenocarcinoma: an observational ancillary analysis. AB - BACKGROUND: Chemotherapy plays a role in the treatment of endometrioid endometrial cancer (EEC); however, tumor grade may affect response. Our objective was to evaluate associations between tumor grade and in vitro chemoresponse. METHODS: We conducted an analysis of primary tumor samples from women with EEC undergoing in vitro chemoresponse testing. Results were classified as sensitive (S), intermediate (I), or resistant (R) to each drug tested. Correlations between tumor grade and response were examined. RESULTS: Data was collected from 159 patients: 28 with grade 1 (18%), 52 with grade 2 (32%), and 79 (50%) with grade 3 tumors. Median age of patients was 62 (range 31-92). Most patients were Caucasian (83%) with advanced disease (Stage III: 50.9%; Stage IV: 13.2%). Overall chemoresponse was similar across all grades. Fifty percent, 56 and 51% for grade 1, 2, and 3 tumors, respectively, demonstrated S results to at least 1 agent. There was no association between grade and in vitro response to chemotherapy agents (p > 0.05) except a marginal association between grade and doxorubicin response (p = 0.08). Grade 1 and 2 cancers were more likely to demonstrate R results for doxorubicin compared to grade 3 cancers (G1: 19% vs G2: 25% vs G3: 8%; p = 0.08). In a subset tested for all 7 agents, only one patient tumor was pan-R and 4 were pan-S. CONCLUSIONS: Based on our data, grades 1-3 EEC have similar in vitro chemoresponse. These findings suggest that chemotherapy may be useful in advanced low grade EECs, but further clinical correlation is needed. PMID- 27980800 TI - Association between smoking and the risk of acute mountain sickness: a meta analysis of observational studies. AB - BACKGROUND: People rapidly ascending to high altitudes (>2500 m) may suffer from acute mountain sickness (AMS). The association between smoking and AMS risk remains unclear. Therefore, we performed a meta-analysis to evaluate the association between smoking and AMS risk. METHODS: The association between smoking and AMS risk was determined according to predefined criteria established by our team. Meta-analysis was conducted according to the PRISMA guidelines. We included all relevant studies listed in the PubMed and Embase databases as of September 2015 in this meta-analysis and performed systemic searches using the terms "smoking", "acute mountain sickness" and "risk factor". The included studies were required to provide clear explanations regarding their definitions of smoking, the final altitudes reached by their participants and the diagnostic criteria used to diagnose AMS. Odds ratios (ORs) were used to evaluate the association between smoking and AMS risk across the studies, and the Q statistic was used to test OR heterogeneity, which was considered significant when P < 0.05. We also computed 95% confidence intervals (CIs). Data extracted from the articles were analyzed with Review Manager 5.3 (Cochrane Collaboration, Oxford, UK). RESULTS: We used seven case-control studies including 694 smoking patients and 1986 non-smoking controls to analyze the association between smoking and AMS risk. We observed a significant association between AMS and smoking (OR = 0.71, 95% CI 0.52-0.96, P = 0.03). CONCLUSIONS: We determined that smoking may protect against AMS development. However, we do not advise smoking to prevent AMS. More studies are necessary to confirm the role of smoking in AMS risk. PMID- 27980801 TI - Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population. AB - BACKGROUND: Methotrexate (MTX) is currently the anchor drug widely used worldwide in the treatment of rheumatoid arthritis (RA). However, the therapeutic response to MTX has been shown to vary widely among individuals, genders and ethnic groups. The reason for this has been not clarified but it is considered to be partially due to several mechanisms in the cellular pathway of MTX including single-nucleotide polymorphisms (SNPs). The purpose of this study was to investigate the allelic frequencies in different ethnic and/or population groups in the 10 polymorphisms of enzyme proteins and transporters related to the MTX response and pharmacokinetics including MTHFR, TYMS, RFC1, FPGS, GGH, ABCB1, ABCC2 and ABCG2 in unrelated healthy Japanese adults and patients with RA. METHODS: Ten polymorphisms, methylenetetrahydrofolate reductase (MTHFR) 1298, thymidylate synthase (TYMS) 3'-UTR, reduced folate carrier 1 (RFC1) 80 and-43, folypolyglutamyl synthase (FPGS) 1994, gamma-glutamyl hydrolase (GGH) 452 and 401, the ABC transporters (ABCB1 3435, ABCC2 IVS23 + 56, ABCG2 914) of enzyme proteins and transporters related to MTX response and pharmacokinetics in 299 unrelated healthy Japanese adults and 159 Japanese patients with RA were investigated to clarify their contributions to individual variations in response and safety to MTX and establish personalized MTX therapy. SNPs were evaluated using real-time polymerase chain reaction (PCR). RESULTS: Comparison of allelic frequencies in our study with other ethnic/population groups of healthy adults and RA patients showed significant differences in 10 polymorphisms among healthy adults and 7 among RA patients. Allelic frequencies of MTHFR 1298 C, FPGS 1994A and ABCB1 3435 T were lower in Japanese than in Caucasian populations and those of ABCC2 IVS23 + 56 C and ABCG2 914A were higher in Japanese than in Caucasian/European populations in both healthy adults and RA patients. Allelic frequencies of MTHFR 1298 C, GGH-401 T, ABCB1 3435 T, and ABCG2 914A were higher in healthy Japanese adults than in an African population, and those of RFC1 80A, RFC1-43C and ABCC2 IVS23 + 56 C in healthy Japanese adults were lower than in Africans. However, no significant differences were seen in the distribution of allelic frequencies between healthy Japanese adults and RA patients. CONCLUSION: The variations in allelic frequencies in different ethnic and/or population groups in healthy adults and RA patients may contribute to individual variations in MTX response and toxicity. PMID- 27980802 TI - Erratum to: Physical, morphological, and wound healing properties of a polyurethane foam-film dressing. AB - [This corrects the article DOI: 10.1186/s40824-016-0063-5.]. PMID- 27980803 TI - Erratum to: Superior absorption and retention properties of foam-film silver dressing versus other commercially available silver dressing. AB - [This corrects the article DOI: 10.1186/s40824-016-0069-z.]. PMID- 27980805 TI - Recurrent evolution of gut symbiotic bacteria in pentatomid stinkbugs. AB - BACKGROUND: Diverse animals are intimately associated with microbial symbionts. How such host-symbiont associations have evolved is a fundamental biological issue. Recent studies have revealed a variety of evolutionary relationships, such as obligatory, facultative, and free-living, of gut bacterial symbiosis within the stinkbug family Pentatomidae, although the whole evolutionary picture remains elusive. RESULTS: Here we investigated a comprehensive assembly of Japanese pentatomid stinkbugs representing 28 genera, 35 species, and 143 populations. Polymerase chain reaction (PCR), cloning, and sequencing of bacterial 16S rRNA gene from their midgut symbiotic organ consistently detected a single bacterial species from each of the insect samples, indicating a general tendency toward monosymbiotic gut association. Bacterial sequences detected from different populations of the same species were completely or nearly identical, indicating that the majority of the gut symbiotic associations are stably maintained at the species level. Furthermore, bacterial sequences detected from different species in the same genus tended to form well-supported clades, suggesting that host symbiont associations are often stable even at the genus level. Meanwhile, when we compared such sequences with published sequences available in DNA databases, we found a number of counter-examples to such stable host-symbiont relationships; i.e., symbionts from different host species in the same genus may be phylogenetically distant, and symbionts from the same host species may be phylogenetically diverse. Likewise, symbionts of diverse pentatomid species may be closely related to symbionts of other stinkbug families, and symbionts of diverse pentatomid species may even be allied to free-living bacteria. Molecular evolutionary analyses revealed that higher molecular evolutionary rates, higher AT nucleotide compositions, and smaller genome sizes tended to be associated with the pentatomid symbionts constituting the stable lineages, whereas these traits were rarely observed in the pentatomid symbionts of promiscuous type. CONCLUSIONS: These results indicate that gut symbiotic bacteria have evolved repeatedly and dynamically in the stinkbug family Pentatomidae, which have plausibly entailed frequent symbiont acquisitions, losses, replacements and transfers, while establishing a number of relatively stable host-symbiont associations. The diverse host-symbiont relationships observed in the Pentatomidae will provide an ideal arena for investigating the evolution of symbiosis experimentally and theoretically. PMID- 27980806 TI - The life of the freshwater bryozoan Stephanella hina (Bryozoa, Phylactolaemata)-a crucial key to elucidating bryozoan evolution. AB - BACKGROUND: Phylactolaemata is the earliest branch and the sister group to all extant bryozoans. It is considered a small relict group that, perhaps due to the invasion of freshwater, has retained ancestral features. Reconstruction of the ground pattern of Phylactolaemata is thus essential for reconstructing the ground pattern of all Bryozoa, and for inferring phylogenetic relationships to possible sister taxa. It is well known that Stephanella hina, the sole member of the family Stephanelllidae, is probably one of the earliest offshoots among the Phylactolaemata and shows some morphological peculiarities. However, key aspects of its biology are largely unknown. The aim of the present study was to analyze live specimens of this species, in order to both document its behavior and describe its colony morphology. RESULTS: The colony morphology of Stephanella hina consists of zooidal arrangements with lateral budding sites reminiscent of other bryozoan taxa, i.e., Steno- and Gymnolaemata. Zooids protrude vertically from the substrate and are covered in a non-rigid jelly-like ectocyst. The latter is a transparent, sticky hull that for the most part shows no distinct connection to the endocyst. Interestingly, individual zooids can be readily separated from the rest of the colony. The loose tube-like ectocyst can be removed from the animals that produces individuals that are unable to retract their lophophore, but merely shorten their trunk by contraction of the retractor muscles. CONCLUSIONS: These observations indicate that S. hina is unique among Phylactolaemata and support the notion that bryozoans evolved from worm-like ancestors. In addition, we raise several arguments for its placement into a separate family, Stephanellidae, rather than among the Plumatellidae, as previously suggested. PMID- 27980804 TI - Direct reprogramming and biomaterials for controlling cell fate. AB - Direct reprogramming which changes the fate of matured cell is a very useful technique with a great interest recently. This approach can eliminate the drawbacks of direct usage of stem cells and allow the patient specific treatment in regenerative medicine. Overexpression of diverse factors such as general reprogramming factors or lineage specific transcription factors can change the fate of already differentiated cells. On the other hand, biomaterials can provide physical and topographical cues or biochemical cues on cells, which can dictate or significantly affect the differentiation of stem cells. The role of biomaterials on direct reprogramming has not been elucidated much, but will be potentially significant to improve the efficiency or specificity of direct reprogramming. In this review, the strategies for general direct reprogramming and biomaterials-guided stem cell differentiation are summarized with the addition of the up-to-date progress on biomaterials for direct reprogramming. PMID- 27980807 TI - High-resolution forest canopy height estimation in an African blue carbon ecosystem. AB - Mangrove forests are one of the most productive and carbon dense ecosystems that are only found at tidally inundated coastal areas. Forest canopy height is an important measure for modeling carbon and biomass dynamics, as well as land cover change. By taking advantage of the flat terrain and dense canopy cover, the present study derived digital surface models (DSMs) using stereo-photogrammetric techniques on high-resolution spaceborne imagery (HRSI) for southern Mozambique. A mean-weighted ground surface elevation factor was subtracted from the HRSI DSM to accurately estimate the canopy height in mangrove forests in southern Mozambique. The mean and H100 tree height measured in both the field and with the digital canopy model provided the most accurate results with a vertical error of 1.18-1.84 m, respectively. Distinct patterns were identified in the HRSI canopy height map that could not be discerned from coarse shuttle radar topography mission canopy maps even though the mode and distribution of canopy heights were similar over the same area. Through further investigation, HRSI DSMs have the potential of providing a new type of three-dimensional dataset that could serve as calibration/validation data for other DSMs generated from spaceborne datasets with much larger global coverage. HSRI DSMs could be used in lieu of Lidar acquisitions for canopy height and forest biomass estimation, and be combined with passive optical data to improve land cover classifications. PMID- 27980808 TI - Different weak inter-actions in the crystals of three isomeric (E)-N-methyl-N' (nitro-benzyl-idene)-2-(thio-phen-2-yl)acetohydrazides. AB - The crystal structures of three isomeric (E)-N-methyl-N'-(nitro-benzyl-idene)-2 (thio-phen-2-yl)acetohydrazides (formula C14H13N3O3S) are described, with the nitro group in ortho, meta and para positions in the benzene ring. In each crystal structure, mol-ecules are linked by various weak inter-actions (C-H?O and C-H?pi bonds, and pi-pi stacking), leading to three-dimensional networks in each case, but with little similarity between them. PMID- 27980809 TI - Crystal structure of aqua-tris-{MU-N-[bis(diethyl-amino)phosphoryl]-2,2,2-tri chloroacetamidato-kappa3O,O':O}calciumsodium. AB - In the mol-ecular structure of the title compound, [CaNa(C10H20Cl3N3O2P)3(H2O)], the Ca2+ ion has a slightly distorted octa-hedral coordination environment defined by six O atoms which belong to the carbonyl and phosphoryl groups of the three coordinating ligands. Two Cl atoms of CCl3 groups and four O atoms form the coordination environment of the Na+ ion: three from the carbonyl groups of ligands and one O atom from a coordinating water mol-ecule. In the crystal, the bimetallic complexes are assembled into chains along the c-axis direction via O H?O hydrogen bonds that involve the coordinating water mol-ecules and the phosphoryl groups. PMID- 27980810 TI - Crystal structure of 3,5-di-methyl-pyridine N-oxide dihydrate. AB - In the title compound, also known as 3,5-lutidine N-oxide dihydrate, C7H9NO.2H2O, the N-O bond is weakened due to the involvement of the O atom as an acceptor of hydrogen bonds from the two water mol-ecules of crystallization present in the asymmetric unit. Fused R35(10) ring motifs based on O-H?O hydrogen bonds form chains in the [010] direction, which are further connected by weak C-H?O inter molecular contacts. As a result, the lutidine mol-ecules are stacked in an efficient manner, with pi-pi contacts characterized by a short separation of 3.569 (1) A between the benzene rings. PMID- 27980811 TI - Two di-alkyl-ammonium salts of 2-amino-4-nitro-benzoic acid: crystal structures and Hirshfeld surface analysis. AB - The crystal structures of two ammonium salts of 2-amino-4-nitro-benzoic acid are described, namely di-methyl-aza-nium 2-amino-4-nitro-benzoate, C2H8N+.C7H5N2O4-, (I), and di-butyl-aza-nium 2-amino-4-nitro-benzoate, C8H20N+.C7H5N2O4-, (II). The asymmetric unit of (I) comprises a single cation and a single anion. In the anion, small twists are noted for the carboxyl-ate and nitro groups from the ring to which they are connected, as indicated by the dihedral angles of 11.45 (13) and 3.71 (15) degrees , respectively; the dihedral angle between the substituents is 7.9 (2) degrees . The asymmetric unit of (II) comprises two independent pairs of cations and anions. In the cations, different conformations are noted in the side chains in that three chains have an all-trans [(+)-anti-periplanar] conformation, while one has a distinctive kink resulting in a (+)-synclinal conformation. The anions, again, exhibit twists with the dihedral angles between the carboxyl-ate and nitro groups and the ring being 12.73 (6) and 4.30 (10) degrees , respectively, for the first anion and 8.1 (4) and 12.6 (3) degrees , respectively, for the second. The difference between anions in (I) and (II) is that in the anions of (II), the terminal groups are conrotatory, forming dihedral angles of 17.02 (8) and 19.0 (5) degrees , respectively. In each independent anion of (I) and (II), an intra-molecular amino-N-H?O(carboxyl-ate) hydrogen bond is formed. In the crystal of (I), anions are linked into a jagged supra-molecular chain by charge-assisted amine-N-H?O(carboxyl-ate) hydrogen bonds and these are connected into layers via charge-assisted ammonium-N-H?O(carboxyl-ate) hydrogen bonds. The resulting layers stack along the a axis, being connected by nitro-N O?pi(arene) and methyl-C-H?O(nitro) inter-actions. In the crystal of (II), the anions are connected into four-ion aggregates by charge-assisted amino-N H?O(carboxyl-ate) hydrogen bonding. The formation of ammonium-N-H?O(carboxyl-ate) hydrogen bonds, involving all ammonium-N-H and carboxyl-ate O atoms leads to a three-dimensional architecture; additional C-H?O(nitro) inter-actions contribute to the packing. The Hirshfeld surface analysis confirms the importance of the hydrogen bonding in both crystal structures. Indeed, O?H/H?O inter-actions contribute nearly 50% to the entire Hirshfeld surface in (I). PMID- 27980812 TI - Bis(N,N-di-ethyl-dithio-carbamato-kappa2S,S')(3-hy-droxy-pyridine-kappaN)zinc and bis-[N-(2-hy-droxy-eth-yl)-N-methyldithio-carbamato-kappa2S,S'](3-hy-droxy pyridine-kappaN)zinc: crystal structures and Hirshfeld surface analysis. AB - The common feature of the mol-ecular structures of the title compounds, [Zn(C5H10NS2)2(C5H5NO)], (I), and [Zn(C4H8NOS2)2(C5H5NO)], (II), are NS4 donor sets derived from N-bound hy-droxy-pyridyl ligands and asymmetrically chelating di-thio-carbamate ligands. The resulting coordination geometries are highly distorted, being inter-mediate between square pyramidal and trigonal bipyramidal for both independent mol-ecules comprising the asymmetric unit of (I), and significantly closer towards square pyramidal in (II). The key feature of the mol ecular packing in (I) is the formation of centrosymmetric, dimeric aggregates sustained by pairs of hy-droxy-O-H?S(di-thio-carbamate) hydrogen bonds. The aggregates are connected into a three-dimensional architecture by methyl-ene-C H?O(hy-droxy) and methyl-C-H?pi(chelate) inter-actions. With greater hydrogen bonding potential, supra-molecular chains along the c axis are formed in the crystal of (II), sustained by hy-droxy-O-H?O(hy-droxy) hydrogen bonds, with ethyl hydroxy and pyridyl-hydroxy groups as the donors, along with ethyl-hydroxy-O H?S(di-thio-carbamate) hydrogen bonds. Chains are connected into layers in the ac plane by methyl-ene-C-H?pi(chelate) inter-actions and these stack along the b axis, with no directional inter-actions between them. An analysis of the Hirshfeld surfaces clearly distinguished the independent mol-ecules of (I) and reveals the importance of the C-H?pi(chelate) inter-actions in the packing of both (I) and (II). PMID- 27980813 TI - Crystal structure of [UO2(NH3)5]NO3.NH3. AB - Penta-ammine dioxide uranium(V) nitrate ammonia (1/1), [UO2(NH3)5]NO3.NH3, was obtained in the form of yellow crystals from the reaction of caesium uranyl nitrate, Cs[UO2(NO3)3], and uranium tetra-fluoride, UF4, in dry liquid ammonia. The [UO2]+ cation is coordinated by five ammine ligands. The resulting [UO2(NH3)5] coordination polyhedron is best described as a penta-gonal bipyramid with the O atoms forming the apices. In the crystal, numerous N-H?N and N-H?O hydrogen bonds are present between the cation, anion and solvent mol-ecules, leading to a three-dimensional network. PMID- 27980814 TI - Crystal structure of a 2:1 piroxicam-gentisic acid co-crystal featuring neutral and zwitterionic piroxicam mol-ecules. AB - A new 2:1 co-crystal of piroxicam and gentisic acid [systematic name: 4-hy-droxy 1,1-dioxo-N-(pyridin-2-yl)-2H-1lambda6,2-benzo-thia-zine-3-carboxamide-2-(4-oxido 1,1-dioxo-2H-1lambda6,2-benzo-thia-zine-3-amido)-pyridin-1-ium-2,5-di-hydroxy benzoic acid, 2C15H13N3O4S.C7H6O4] has been synthesized using a microfluidic platform and initially identified using Raman spectroscopy. In the co-crystal, one piroxicam mol-ecule is in its neutral form and an intra-molecular O-H?O hydrogen bond is observed. The other piroxicam mol-ecule is zwitterionic (proton transfer from the OH group to the pyridine N atom) and two intra-molecular N-H?O hydrogen bonds occur. The gentisic acid mol-ecule shows whole-mol-ecule disorder over two sets of sites in a 0.809 (2):0.191 (2) ratio. In the crystal, extensive hydrogen bonding between the components forms layers propagating in the ab plane. PMID- 27980815 TI - Two cadmium coordination polymers with bridging acetate and phenyl-enedi-amine ligands that exhibit two-dimensional layered structures. AB - Poly[tetra-MU2-acetato-kappa8O:O'-bis-(MU2-benzene-1,2-di-amine kappa2N:N')dicadmium], [Cd2(CH3COO)4(C6H8N2)2] n , (I), and poly[[(MU2-acetato kappa2O:O')(acetato-kappa2O,O')(MU2-benzene-1,3-di-amine-kappa2N:N')cadmium] hemihydrate], {[Cd(CH3COO)2(C6H8N2)].0.5H2O} n , (II), have two-dimensional polymeric structures in which monomeric units are joined by bridging acetate and benzenedi-amine ligands. Each of the CdII ions has an O4N2 coordination environment. The coordination geometries of the symmetry-independent CdII ions are distorted octa-hedral and distorted trigonal anti-prismatic in (I) and distorted anti-prismatic in (II). Both compounds exhibit an intra-layer hydrogen bonding network. In addition, the water of hydration in (II) is involved in inter layer hydrogen bonding. PMID- 27980817 TI - Crystal structure of N,N'-bis-(pyridin-3-ylmeth-yl)cyclo-hexane-1,4-di-ammonium dichloride. AB - The title salt, C18H26N42+.2Cl-, was obtained by the protonation of N,N-bis (pyridin-4-ylmeth-yl)cyclo-hexane-1,4-di-amine with hydro-chloric acid in ethanol. The asymmetric unit consists of one half of an N,N-bis-(pyridin-3-ylmeth yl)cyclo-hexane-1,4-di-ammonium dication, with a crystallographic inversion centre located at the centre of the cyclo-hexyl ring, and a chloride anion. The central cyclo-hexyl ring in the dication adopts a chair conformation. The two trans-(4-pyridine)-CH2-NH2- moieties at the 1- and 4-positions of the central cyclo-hexyl ring occupy equatorial sites. The terminal pyridine ring is tilted by 53.72 (6) degrees with respect to the mean plane of the central cyclo-hexyl ring (r.m.s. deviation = 0.2413 A). In the crystal, N+-H?Cl- hydrogen bonds between the dications and the chloride anions, and pi-pi stacking inter-actions between the pyridine rings of the dications afford a two-dimensional sheet extending parallel to the ab plane. These sheets are further connected through weak C-H?Cl- hydrogen bonds, resulting in the formation of a three-dimensional supra-molecular network. PMID- 27980816 TI - Crystal structure of 7-iodo-4-oxo-4H-chromene-3-carbaldehyde. AB - In the title compound, C10H5IO3, an iodinated 3-formyl-chromone derivative, the non-H atoms are essentially coplanar (r.m.s. deviation = 0.0344 A), with the largest deviation from the least-squares plane [0.101 (3) A] being found for the formyl O atom. In the crystal, mol-ecules are linked through stacking inter actions [centroid-centroid distance between the benzene rings = 3.700 (3) A] and C-H?O hydrogen bonds. Halogen bonds between the I atoms at 7-position and the formyl O atoms [I1?O3 = 3.056 (2) A, C6-I1?O3 = 173.18 (8) degrees and I1?O3-C10 = 111.12 (18) degrees ] are also formed along [110], resulting in sheets perpendicular to the c axis, constructed by C-H?O hydrogen bonds and I?O halogen bonds. PMID- 27980818 TI - Crystal structure of 1,3-bis-[(E)-4-meth-oxy-benzyl-idene-amino]-propan-2-ol. AB - The title Schiff base, C19H22N2O3, was synthesized via the condensation reaction of 1,3-di-amino-propan-2-ol with 4-meth-oxy-benzaldehyde using water as solvent. The mol-ecule exists in an E,E conformation with respect to the C=N imine bonds and the dihedral angle between the aromatic rings is 37.25 (15) degrees . In the crystal, O-H?N hydrogen bonds link the mol-ecules into infinite C(5) chains propagating along the a-axis direction. The packing of these chains is consolidated by C-H?O inter-actions and C-H?pi short contacts, forming a three dimensional network. PMID- 27980819 TI - Crystal structure of 5,7,12,14-tetra-hydro-5,14:7,12-bis-([1,2]benzeno)-penta cene-6,13-dione. AB - The lattice of 5,7,12,14-tetra-hydro-5,14:7,12-bis-([1,2]benzeno)-penta-cene-6,13 dione, C34H20O2, at 173 K has triclinic (P-1) symmetry and crystallizes with four independent half-mol-ecules in the asymmetric unit. Each mol-ecule is generated from a C17H10O substructure through an inversion center at the centroid of the central quinone ring, generating a wide H-shaped mol-ecule, with a dihedral angle between the mean planes of the terminal benzene rings in each of the two symmetry related pairs over the four mol-ecules of 68.6 (1) (A), 65.5 (4) (B), 62.3 (9) (C), and 65.8 (8) degrees (D), an average of 65.6 (1) degrees . This compound has applications in gas-separation membranes constructed from polymers of intrinsic microporosity (PIM). The title compound is a product of a double Diels Alder reaction between anthracene and p-benzo-quinone followed by de hydrogenation. It has also been characterized by cyclic voltammetry and rotating disc electrode polarography, FT-IR, high resolution mass spectrometry, elemental analysis, and 1H NMR. PMID- 27980820 TI - Crystal structures of two new carbazole derivatives: 12-(4-nitro-phen-yl)-7 phenyl-sulfonyl-7H-benzofuro[2,3-b]carbazole and 2-methyl-4-(4-nitro-phen-yl)-9 phenyl-sulfonyl-9H-thieno[2,3-b]carbazole. AB - The title compounds, C30H18N2O5S, (I), and C27H18N2O4S2, (II), are carbazole derivatives with a phenyl-sulfonyl group and a nitro-phenyl group attached to the carbazole moiety in identical positions in both mol-ecules. A benzo-furan ring system in (I) and a methyl-thio-phene ring in (II) are fused with the respective carbazole moieties on the same sides. The mean plane of the carbazole ring system makes a dihedral angle of 3.17 (7) degrees with the benzo-furan ring system in (I) and a dihedral angle of 3.39 (11) degrees with the methyl-thio-phene ring in (II), implying that both fused units are essentially planar. The mean planes of the carbazole ring systems in both the compounds are almost orthogonal to the respective nitro-substituted phenyl rings, making dihedral angles of 75.64 (10) and 77.63 (12) degrees in compounds (I) and (II), respectively. In (I), the phenyl-sulfonyl ring system is positionally disordered with a refined occupancy ratio of 0.63 (2):0.37 (2). In both compounds, the mol-ecular structures are stabilized by intra-molecular C-H?O hydrogen bonds, generating S(6) ring motifs with the sulfone group O atoms. In the crystal of compound (I), mol-ecules are linked by pairs of C-H?O hydrogen bonds, which generate R22(18) inversion dimers, and inter-connected by C(14) chains running along the c-axis direction, whereas in compound (II), the C-H?O hydrogen bonds generate R43(37) ring motifs. In the crystals of both compounds, C-H?O hydrogen-bonded sheets are formed lying parallel to (10-1). In addition, C-H?pi and offset pi-pi inter-actions [inter centroid distance = 3.7158 (14) A in (I) and 3.9040 (15) A in (II)] are also present in the crystals of both compounds. PMID- 27980821 TI - Crystal structures of three carbazole derivatives: 12-ethyl-7-phenyl-sulfonyl-7H benzofuro[2,3-b]carbazole, (1), 2-(4,5-dimeth-oxy-2-nitro-phen-yl)-4-hy-droxy-9 phenyl-sulfonyl-9H-carbazole-3-carbaldehyde, (2), and 12-phenyl-7-phenyl-sulfonyl 7H-benzofuro[2,3-b]carbazole, (3). AB - The three title compounds, C26H19NO3S, (1), C27H20N2O8S, (2), and C30H19NO3S, (3), are carbazole derivatives, where (1) and (3) are heterocycle-containing carbazoles with a benzo-furan moiety fused to a carbazole unit. In (2), a di-meth oxy-nitro-phenyl ring is attached to the carbazole moiety. In the three derivatives, a phenyl-sulfonyl group is attached to the N atom of the carbazole unit. Compound (1) crystallizes with two independent mol-ecules in the asymmetric unit (A and B). The carbazole skeleton in the three compounds is essentially planar. In compound (1), the benzene ring of the phenyl-sulfonyl moiety is almost orthogonal to the carbazole moiety, with dihedral angles of 85.42 (9) and 84.52 (9) degrees in mol-ecules A and B, respectively. The benzene ring of the phenyl sulfonyl group in compounds (2) and (3) are inclined to the carbazole moiety, making dihedral angles of 70.73 (13) and 81.73 (12) degrees , respectively. The S atom has a distorted tetra-hedral configuration in all three compounds. In the crystals, C-H?O hydrogen bonds give rise to R22(12) inversion dimers for compound (1), and to R22(24) inversion dimers and R44(40) ring motifs for compound (2). The crystal packing in (1) also features C-H?pi and pi-pi inter-actions [shortest inter-centroid distance = 3.684 (1) A], leading to supra-molecular three dimensional aggregation. In the crystal of compound (2), the combination of the various C-H?O hydrogen bonds leads to the formation of a three-dimensional network. In the crystal of compound (3), mol-ecules are linked by C-H?O hydrogen bonds, forming chains running parallel to the a axis, and the chains are linked by C-H?pi inter-actions, forming corrugated sheets parallel to the ab plane. PMID- 27980822 TI - Crystal structure of 7-hy-droxy-8-[(4-methyl-piperazin-1-yl)meth-yl]-2H-chromen-2 one. AB - In the title compound, C15H18N2O3, the coumarin ring is essentially planar, with an r.m.s. deviation of 0.012 A. An intra-molecular O-H?N hydrogen bond forms an S(6) ring motif. The piperazine ring adopts a chair conformation. In the crystal, a C-H?O hydrogen bond generates a C(4) chain motif running along the c axis. The chain structure is stabilized by a C-H?pi inter-action. The chains are linked by pi-pi inter-actions [centroid-centroid distance of 3.5745 (11) A], forming a sheet structure parallel to the bc plane. PMID- 27980823 TI - Crystal structure of a dimeric beta-diketiminate magnesium complex. AB - The solid-state structure of a dimeric beta-diketiminate magnesium(II) complex is discussed. The compound, di-MU-iodido-bis-[(-{4-amino-1,5-bis-[2,6-bis-(propan-2 yl)phen-yl]pent-3-en-2-yl-idene}aza-nido-kappa2N,N')magnesium(II)] toluene sesquisolvate, [Mg2(C29H41N2)2I2].1.5C7H8, crystallizes as two independent mol ecules, each with 2/m crystallographic site symmetry, located at Wyckoff sites 2c and 2d. These have symmetry-equivalent magnesium atoms bridged by MU-iodide ligands with very similar Mg-I distances. The two Mg atoms are located slightly below (~0.5 A) the least-squares plane defined by N-C-C-N atoms in the ligand scaffold, and are approximately tetra-hedrally coordinated. One and one-half toluene solvent mol-ecules are disordered with respect to mirror-site symmetry at Wyckoff sites 4i and 2a, respectively. In the former case, two toluene mol-ecules inter-act in an off-center parallel stacking arrangement; the shortest C to C' (pi-pi) distance of 3.72 (1) A was measured for this inter-action. PMID- 27980824 TI - Crystal structures of two solvates of (18-crown-6)potassium acetate. AB - The crystal and mol-ecular strutures of two solvated forms of [K(18c6)]OAc (18c6 = 18-crown-6 = 1,4,7,10,13,16-hexa-oxa-cyclo-octa-decane and OAc = acetate) were determined by single-crystal X-ray diffraction, namely (acetato kappa2O,O')(1,4,7,10,13,16-hexa-oxa-cyclo-octa-decane-kappa6O)potassium dihydrate, [K(CH3COO)(C12H24O6)].2H2O (1) and (acetato-kappa2O,O')aqua (1,4,7,10,13,16-hexa-oxa-cyclo-octa-decane-kappa6O)potassium acetic acid monosolvate [K(CH3COO)(C12H24O6)(H2O)].CH3COOH (2). In both compounds, the acetate anion is bonded to the potassium ion in a chelating fashion and the metal atom is consequently slightly displaced from the O6 plane of the crown ether. In the crystals, O-H?O hydrogen bonds lead to a polymeric ladder structure in the dihydrate 1, while the acetic acid hydrate 2 features inversion dimers. PMID- 27980825 TI - Crystal structures of p-substituted derivatives of 2,6-di-methyl-bromo-benzene with 1/2 <= Z' <= 4. AB - The crystal structures of four bromo-arenes based on 2,6-di-methyl-bromo-benzene are reported, which are differentiated according the functional group X placed para to the Br atom: X = CN (4-bromo-3,5-di-methyl-benzo-nitrile, C9H8BrN), (1), X = NO2 (2-bromo-1,3-dimethyl-5-nitro-benzene, C8H8BrNO2), (2), X = NH2 (4-bromo 3,5-di-methyl-aniline, C8H10BrN), (3) and X = OH (4-bromo-3,5-di-methyl-phenol, C8H9BrO), (4). The content of the asymmetric unit is different in each crystal, Z' = 1/2 (X = CN), Z' = 1 (X = NO2), Z' = 2 (X = NH2), and Z' = 4 (X = OH), and is related to the mol-ecular symmetry and the propensity of X to be involved in hydrogen bonding. In none of the studied compounds does the crystal structure feature other non-covalent inter-actions, such as pi-pi, C-H?pi or C-Br?Br contacts. PMID- 27980826 TI - Crystal structure of fac-[2-(4-methyl-5-phenyl-pyridin-2-yl)phenyl-kappa2C1,N]bis [2-(pyridin-2-yl)phenyl-kappa2C1,N]iridium(III). AB - In the title compound, [Ir(C11H8N)2(C18H14N)], the IrIII ion adopts a distorted octa-hedral coordination environment defined by three C,N-chelating ligands, one stemming from a 2-(4-phenyl-5-methyl-pyridin-2-yl)phenyl ligand and two from 2 (pyridin-2-yl)phenyl ligands, arranged in a facial manner. The IrIII ion lies almost in the equatorial plane [deviation = 0.0069 (15) A]. In the crystal, inter molecular pi-pi stacking inter-actions, as well as inter-molecular C-H?pi inter actions, are present, leading to a three-dimensional network. PMID- 27980827 TI - Crystal structures of hydrogen-bonded co-crystals as liquid crystal precursors: 4 (n-pent-yloxy)benzoic acid-(E)-1,2-bis-(pyridin-4-yl)ethene (2/1) and 4-(n-hex yloxy)benzoic acid-(E)-1,2-bis-(pyridin-4-yl)ethene (2/1). AB - The crystal structures of title hydrogen-bonded co-crystals, 2C12H16O3.C12H10N2, (I), and 2C13H18O3.C12H10N2, (II), have been determined at 93 K. In (I), the asymmetric unit consists of one 4-(n-pent-yloxy)benzoic acid mol-ecule and one half-mol-ecule of (E)-1,2-bis-(pyridin-4-yl)ethene, which lies about an inversion centre. The asymmetric unit of (II) comprises two crystallographically independent 4-(n-hex-yloxy)benzoic acid mol-ecules and one 1,2-bis-(pyridin-4 yl)ethene mol-ecule. In each crystal, the acid and base components are linked by O-H?N hydrogen bonds, forming a linear hydrogen-bonded 2:1 unit of the acid and the base. The 2:1 units are linked via C-H?pi and pi-pi inter-actions [centroid centroid distances of 3.661 (2) and 3.909 (2) A for (I), and 3.546 (2)-3.725 (4) A for (II)], forming column structures. In (II), the base mol-ecule is orientationally disordered over two sets of sites approximately around the N?N mol-ecular axis, with an occupancy ratio of 0.647 (4):0.353 (4), and the average structure of the 2:1 unit adopts nearly pseudo-C2 symmetry. Both compounds show liquid-crystal behaviour. PMID- 27980828 TI - A tetra-nuclear cubane-like nickel(II) complex with a tridentate salicyl-idene imine Schiff base ligand: tetra-kis-[MU3-4-methyl-N-(2-oxidophen yl)salicylideneiminato]tetra-kis-[methano-lnickel(II)] methanol 0.8-solvate. AB - The tetra-nuclear title complex, [Ni4(C14H11NO2)4(CH3OH)4].0.8CH3OH, has a distorted cubane topology shaped by four Schiff base ligands. The cubane [Ni4(MU3 O4)] core is formed via the O atoms from the Schiff base ligands. The octa hedrally coordinated NiII ions occupy alternating vertices of the cube. Each NiII ion is coordinated by one O,N,O'-tridentate dianionic ligand, two O atoms of oxidophenyl groups from adjacent ligands and the O atom of a coordinating methanol mol-ecule. The cubane core is stabilized via an intra-molecular O-H?O hydrogen bond between the hy-droxy group of the coordinating methanol mol-ecules and the phenolate O atom of the aldehyde Schiff base fragment. Additional stabilization is obtained via intra-molecular C-H?O hydrogen bonds involving aromatic C-H groups and the oxygen atoms of adjacent methanol mol-ecules. In the crystal, complex mol-ecules are linked into chains parallel to the c axis via weak C-H?O hydrogen bonds. The partial-occupancy disordered methanol solvent mol ecule has a site occupancy of 0.8 and is linked to the tetra-nuclear unit via an inter-molecular C-H?O hydrogen bond involving a phenolate O atom. PMID- 27980829 TI - Crystal structure of catena-poly[di-ammonium [di-MU-oxalato-cuprate(II)]]. AB - The structure of the title compound, {(NH4)2[Cu(C2O4)2]} n , at 100 K has monoclinic (P21/c) symmetry with the CuII atom on an inversion center. The compound has a polymeric structure due to long Cu?O inter-actions which create [Cu(C2O4)2] chains along the a axis. The structure also displays inter-molecular N-H?O hydrogen bonding, which links these chains into a three-dimensional network. PMID- 27980830 TI - Crystal structure of vilazodone hydro-chloride methanol monosolvate. AB - In the title compound, C26H28N5O2+.Cl-.CH3OH {systematic name: 4-(2-carbamoyl-1 benzo-furan-5-yl)-1-[4-(5-cyano-1H-indol-3-yl)but-yl]piperazin-1-ium chloride methanol monosolvate}, the protonated piperazine ring adopts a chair conformation. The indole ring plane is nearly perpendicular to the benzo-furan ring system, with a dihedral angle of 85.77 (2) degrees . In the crystal, the organic cations, Cl- anions and methanol solvent mol-ecules are linked by classical N-H?O and N-H?Cl hydrogen bonds, and weak C-H?O and C-H?pi inter actions into a three-dimensional supra-molecular architecture. PMID- 27980831 TI - Crystal and mol-ecular structures of two silver(I) amidinates, including an unexpected co-crystal with a lithium amidinate. AB - The silver(I) amidinates bis-[MU-N1,N2-bis-(propan-2-yl)benzamidinato kappa2N1:N2]disilver(I), [Ag2(C13H19N2)2] or [Ag{PhC(N i Pr)2}]2 (1), and bis-(MU N1,N2-di-cyclohexyl-3-cyclo-propyl-propynamidinato-kappa2N1:N2)disilver(I), [Ag2(C18H27N2)2] or [Ag{cyclo-C3H5-C=C-C(NCy)2}]2 (2a), exist as centrosymmetric dimers with a planar Ag2N4C2 ring and a common linear coordination of the metal atoms in the crystalline state. Moiety 2a forms a co-crystal with the related lithium amidinate, namely bis-(MU-N1,N2-di-cyclo-hexyl-3-cyclo-propyl propynamidinato-kappa2N1:N2)disilver(I) bis-(MU-N1,N2-di-cyclo-hexyl-3-cyclo propyl-propynamidinato-kappa3N1,N2:N1)bis-(tetra-hydro-furan-kappaO)lithium(I) toluene monosolvate, [Ag2(C18H27N2)2][Li2(C18H27N2)2(C4H8O)2].C7H8 or [Ag{cyclo C3H5-C=C-C(NCy)2}]2[Li{cyclo-C3H5-C=C-C(NCy)2}(THF)]2.C7H8, composed as 2a * 2b * toluene. The lithium moiety 2b features a typical ladder-type dimeric structure with a distorted tetra-hedral coordination of the metal atoms. In the silver(I) derivatives 1 and 2a, the amidinate ligand adopts a MU-kappaN:kappaN' coordination, while it is a MU-kappaN:kappaN:kappaN'-coordination in the case of lithium derivative 2b. PMID- 27980832 TI - Crystal structure of hexa-kis-(dimethyl sulfoxide-kappaO)manganese(II) tetra iodide. AB - The title salt, [Mn(C2H6OS)6]I4, is made up from discrete [Mn(DMSO)6]2+ (DMSO is dimethyl sulfoxide) units connected through non-classical hydrogen bonds to linear I42- tetra-iodide anions. The MnII ion in the cation, situated on a position with site symmetry -3., is octa-hedrally coordinated by O atoms of the DMSO mol-ecule with an Mn-O distance of 2.1808 (12) A. The I42- anion contains a neutral I2 mol-ecule weakly coordinated by two iodide ions, forming a linear centrosymmetric tetra-iodide anion. The title compound is isotypic with the Co, Ni, Cu, and Zn analogues. PMID- 27980833 TI - Crystal structure of a compact three-dimensional metal-organic framework based on Cs+ and (4,5-di-cyano-1,2-phenyl-ene)bis-(phospho-nic acid). AB - A new metal-organic framework compound, poly[[MU7-dihydrogen (4,5-di-cyano-1,2 phenyl-ene)diphospho-nato]-(oxonium)caesium], [Cs(C8H4N2O6P2)(H3O)] n (I), based on Cs+ and the organic linker 4,5-di-cyano-1,2-phenyl-ene)bis-(phospho-nic acid, (H4cpp), containing two distinct coordinating functional groups, has been prepared by a simple diffusion method and its crystal structure is reported. The coordination polymeric structure is based on a CsO8N2 complex unit comprising a monodentate hydro-nium cation, seven O-atom donors from two phospho-nium groups of the (H2cpp)2- ligand, and two N-atom donors from bridging cyano groups. The high level of connectivity from both the metal cation and the organic linker allow the formation of a compact and dense three-dimensional network without any crystallization solvent. Topologically (I) is a seven-connected uninodal network with an overall Schafli symbol of {417.64}. Metal cations form an undulating inorganic layer, which is linked by strong and highly directional O-H?O hydrogen bonding inter-actions. These metallic layers are, in turn, connected by the organic ligands along the [010] direction to form the overall three-dimensional framework structure. PMID- 27980834 TI - [N,N-Bis(2-hy-droxy-eth-yl)di-thio-carbamato-kappa2S,S']bis-(tri-phenyl-phosphane kappaP)copper(I) chloro-form monosolvate: crystal structure, Hirshfeld surface analysis and solution NMR measurements. AB - The title compound, [Cu(C5H5NO2S2)(C18H15P)2].CHCl3, features a tetra-hedrally coordinated CuI atom within a P2S2 donor set defined by two phosphane P atoms and by two S atoms derived from a symmetrically coordinating di-thio-carbamate ligand. Both intra- and inter-molecular hy-droxy-O-H?O(hydroxy) hydrogen bonding is observed: the former closes an eight-membered {?HOC2NC2O} ring, whereas the latter connects centrosymmetrically related mol-ecules into dimeric aggregates via eight-membered {?H-O?H-O}2 synthons. The complex mol-ecules are arranged to form channels along the c axis in which reside the chloro-form mol-ecules, being connected by Cl?pi(arene) and short S?Cl [3.3488 (9) A] inter-actions. The inter molecular inter-actions have been investigated further by Hirshfeld surface analysis, which shows the conventional hydrogen bonding to be very localized with the main contributors to the surface, at nearly 60%, being H?H contacts. Solution NMR studies indicate that whilst the same basic mol-ecular structure is retained in solution, the tri-phenyl-phosphane ligands are highly labile, exchanging rapidly with free Ph3P at room temperature. PMID- 27980835 TI - Synthesis and crystal structure of a new alluaudite-like iron phosphate Na2CaMnFe(PO4)3. AB - A new iron phosphate, disodium calcium manganese(II) iron(III) tris(phosphate), Na2CaMnFe(PO4)3, has been synthesized as single crystals by the flux technique. This compound crystallizes in the monoclinic space group C2/c. The structure belongs to the alluaudite structural type and thus, it obeys the X(2)X(1)M(1)M(2)2(PO4)3 general formula. Both the X(2) and X(1) sites are fully occupied by sodium, while M(1) is occupied by calcium and M(2) exhibits a statistical distribution of iron and manganese. PMID- 27980836 TI - Crystal structure of N,N'-di-benzyl-pyromellitic diimide. AB - The title compound, C24H16N2O4 [systematic name: 2,6-di-benzyl-pyrrolo-[3,4-f]iso indole-1,3,5,7(2H,6H)-tetra-one], consists of a central pyromellitic di-imide moiety with terminal benzyl groups at the N-atom positions. The mol-ecule is located about an inversion centre, so the asymmetric unit contains one half-mol ecule. In the mol-ecule, both terminal phenyl groups, tilted by 72.97 (4) degrees with respect to the mean plane of the central pyromellitic di-imide moiety (r.m.s. deviation = 0.0145 A), are oriented away from each other, forming an elongated S-shaped conformation. In the crystal, mol-ecules are connected via weak C-H?O hydrogen bonds and C-H?pi inter-actions, resulting in the formation of supra-molecular layers extending parallel to the ab plane. PMID- 27980837 TI - Synthesis and crystal structure of 4-fluoro-benzyl-ammonium di-hydrogen phosphate, [FC6H4CH2NH3]H2PO4. AB - The asymmetric unit of the title salt, [p-FC6H4CH2NH3]+.H2PO4-, contains one 4 fluoro-benzyl-ammonium cation and one di-hydrogen phosphate anion. In the crystal, the H2PO4- anions are linked by O-H?O hydrogen bonds to build corrugated layers extending parallel to the ab plane. The FC6H4CH2NH3+ cations lie between these anionic layers to maximize the electrostatic inter-actions and are linked to the H2PO4- anions through N-H?O hydrogen bonds, forming a three-dimensional supra-molecular network. Two hydrogen atoms belonging to the di-hydrogen phosphate anion are statistically occupied due to disorder along the OH?HO direction. PMID- 27980838 TI - Crystal structure of oxam-yl. AB - The title compound, C7H13N3O3S [systematic name: (Z)-methyl 2-di-methyl-amino-N (methyl-carbamo-yloxy)-2-oxoethanimido-thio-ate], is an oxime carbamate acaride, insecticide and nematicide. The asymmetric unit comprises two independent mol ecules, A and B. The dihedral angles between the mean planes [r.m.s. deviations = 0.0017 (A) and 0.0016 A (B)] of the acetamide and oxyimino groups are 88.80 (8) degrees for A and 87.05 (8) degrees for B. In the crystal, N/C-H?O hydrogen bonds link adjacent mol-ecules, forming chains along the a axis. The chains are further linked by C-H?O hydrogen bonds, resulting in a three-dimensional network with alternating rows of A and B mol-ecules in the bc plane stacked along the a axis direction. The structure was refined as an inversion twin with a final BASF parameter of 0.16 (9). PMID- 27980839 TI - 1-[(Anthracen-9-yl)carbon-yl]-2,7-di-meth-oxy-naphthalene: a chain-like structure composed of face-to-face type dimeric mol-ecular aggregates. AB - The asymmetric unit of the title compound, C27H20O3, contains two independent mol ecules (A and B). The anthracene ring system is connected to the 2,7-di-meth-oxy naphthalene core in a twisted manner, with dihedral angles of 86.38 (5) and 79.36 (8) degrees , respectively, for conformers A and B. In the crystal, face-to-face type dimeric mol-ecular aggregates of each conformer are observed. The dimer of conformer A is formed by two pairs of C-H?pi inter-actions, and that of conformer B by a pair of (sp2)C-H?O hydrogen bonds. The dimers of conformer A are linked to each other via a pi-pi stacking inter-action between the anthracene rings to form a chain along the b axis and the chains are aligned along the c axis, forming a sheet structure. The dimers of conformer B are connected to each other via a couple of C-H?pi inter-actions to form a chain along the b axis. The chains are aligned along the c axis through (sp2)C-H?O=C hydrogen bonds, forming a sheet parallel to the bc plane. The sheets of conformers A and B are alternately stacked along the a axis via two kinds of inter-molecular (sp2)C-H?O=C hydrogen bonds. PMID- 27980840 TI - Crystal structure of bis-(3,5-di-methyl-pyridine-kappaN)bis-(methanol-kappaO)bis (thio-cyanato-kappaN)cobalt(II). AB - The asymmetric unit of the title complex, [Co(NCS)2(C7H9N)2(CH3OH)2], comprises of one CoII cation located on a centre of inversion, one thio-cyanate ligand, one methanol ligand and one 3,5-di-methyl-pyridine ligand. The CoII cation is octa hedrally coordinated by two terminal N-bonding thio-cyanate anions, two methanol mol-ecules and two 3,5-di-methyl-pyridine ligands into a discrete complex. The complex mol-ecules are linked by inter-molecular O-H?S hydrogen bonding into chains that elongate in the direction parallel to the b axis. PMID- 27980841 TI - Crystal structure of trans-di-aqua-bis-(4-cyano-benzoato-kappaO)bis-(N,N-di-ethyl nicotinamide-kappaN)cadmium. AB - The mononuclear title cadmium complex, [Cd(C10H14N2O)2(C8H4NO2)2(H2O)2], is centrosymmetric and contains two water mol-ecules, two 4-cyanobenzoate (CB) ligands and two di-ethyl-nicotinamide (DENA) ligands. All the ligands are coordinated to the CdII atom in a monodentate mode. The four nearest O atoms around the CdII atom form a slightly distorted square-planar arrangement, with the distorted octa-hedral coordination sphere being completed by the two pyridine N atoms of the DENA ligands at distances of 2.3336 (13) A. The dihedral angle between the carboxyl-ate group and the adjacent benzene ring is 8.75 (16) degrees , while the benzene and pyridine rings are oriented at a dihedral angle of 57.83 (5) degrees . The water mol-ecules exhibit both intra-molecular [to the non coordinating carboxyl-ate O atom, enclosing an S(6) hydrogen-bonding motif, where O?O = 2.670 (2) A] and inter-molecular [to the amide carbonyl O atom, enclosing an R22(16) ring motif, where O?O = 2.781 (2) A] O-H?O hydrogen bonds. The latter lead to the formation of supra-molecular chains propagating along [110]. PMID- 27980842 TI - Crystal structure of di-ethyl-ammonium aniline-4-sulfonate anilinium-4-sulfonate. AB - The title compound, C4H12N+.C6H6NO3S-.C6H7NO3S, consists of an ion pair and a zwitterionic neutral mol-ecule. The cation adopts an extended conformation [C-C-N C torsion angles = 177.1 (3) and -178.4 (3) degrees ]. In the crystal, the components are linked by N-H?O and N-H?N hydrogen bonds, generating a three dimensional network, which is consolidated by weak C-H?O inter-actions. PMID- 27980843 TI - Crystal structures of two ansa-titanocene tri-fluoro-methane-sulfonate complexes bearing the Me2Si(C5Me4)2 ligand. AB - The crystal structures of two ansa-titanocene tri-fluoro-methane-sulfonate complexes bearing the Me2Si(C5Me4)2 ligand are reported, namely [di-methylbis (eta5-tetra-methyl-cyclo-penta-dien-yl)silane](tri-fluoro-methane-sulfonato kappa2O,O')titanium(III) toluene monosolvate, [Ti(CF3O3S)(C20H30Si)].C7H8, 1, and chlorido-[di-methyl-bis-(eta5-tetra-methyl-cyclo-penta-dien-yl)silane](tri-fluoro methane-sulfonato-kappaO)titanium(IV), [Ti(CF3O3S)(C20H30Si)Cl], 2. Both complexes display a bent metallocene unit, the metal atom being coordinated in a distorted tetra-hedral geometry, with the tri-fluoro-methane-sulfonate anion acting as a bidentate or monodentate ligand in 1 and 2, respectively. In 1, weak pi-pi stacking inter-actions involving the toluene solvent mol-ecules [centroid to-centroid distance = 3.9491 (11) A] are observed. PMID- 27980844 TI - Crystal structure of fluroxypyr. AB - In the title pyridine herbicide {systematic name: 2-[(4-amino-3,5-di-chloro-6 fluoro-pyridin-2-yl)-oxy]acetic acid}, C7H5Cl2FN2O3, the mean plane of the carb oxy-lic acid substituent and the pyridyl ring plane subtend a dihedral angle of 77.5 (1) degrees . In the crystal, pairs of O-H?O hydrogen bonds form inversion dimers with R22(8) ring motifs. These are extended into chains along [011] by N H?F hydrogen bonds. In addition, inter-molecular N-H?O hydrogen bonds and weak pi pi inter-actions [ring centroid separation = 3.4602 (9) A] connect these chains into a three-dimensional network. PMID- 27980845 TI - Crystal structures of three bicyclic carbohydrate derivatives. AB - The title compounds, [(1R,3R,4R,5R,6S)-4,5-bis-(acet-yloxy)-7-oxo-2-oxabi cyclo[4.2.0]octan-3-yl]methyl acetate, C14H18O8, (I), [(1S,4R,5S,6R)-5-acet-yloxy 7-hy-droxy-imino-2-oxobi-cyclo-[4.2.0]octan-4-yl acetate, C11H15NO6, (II), and [(3aR,5R,6R,7R,7aS)-6,7-bis-(acet-yloxy)-2-oxo-octa-hydro-pyrano[3,2-b]pyrrol-5 yl]methyl acetate, C14H19NO8, (III), are stable bicyclic carbohydrate derivatives. They can easily be synthesized in a few steps from commercially available glycals. As a result of the ring strain from the four-membered rings in (I) and (II), the conformations of the carbohydrates deviate strongly from the ideal chair form. Compound (II) occurs in the boat form. In the five-membered lactam (III), on the other hand, the carbohydrate adopts an almost ideal chair conformation. As a result of the distortion of the sugar rings, the configurations of the three bicyclic carbohydrate derivatives could not be determined from their NMR coupling constants. From our three crystal structure determinations, we were able to establish for the first time the absolute configurations of all new stereocenters of the carbohydrate rings. PMID- 27980846 TI - Crystal structure of (aceto-nitrile-kappaN)iodido-(2-(naphthalen-1-yl)-6-{1 [(2,4,6-tri-methyl-phen-yl)imino]ethyl}-pyridine-kappa2N,N')copper(I). AB - In the mononuclear title complex, [CuI(C2H3N)(C26H24N2)], the CuI ion has a distorted tetra-hedral coordination environment, defined by two N atoms of the chelating 2-(naphthalen-1-yl)-6-[(2,4,6-tri-methyl-phen-yl)imino]-pyridine ligand, one N atom of an aceto-nitrile ligand and one iodide ligand. Within the complex, there are weak intra-molecular C-H?N hydrogen bonds, while weak inter molecular C-H?I inter-actions between complex mol-ecules, help to facilitate a three-dimensional network. PMID- 27980848 TI - Crystal structure and computational studies of (3Z)-4-benzoyl-3-[(2,4-di-nitro phen-yl)hydrazinyl-idene]-5-phenyl-furan-2(3H)-one. AB - In the mol-ecular structure of the title compound, C23H14N4O7, the furan, di nitro-phenyl and phenyl rings are almost in the same plane (r.m.s. deviation = 0.127 A), with the benzoyl ring inclined by a dihedral angle of 56.4 (1) degrees to the three-ring system. A bifurcated intra-molecular N-H?(O,O) hydrogen bond is present. In the crystal, adjacent mol-ecules are linked by C-H?O hydrogen bonds into chains parallel to [001]. A pi-pi stacking inter-action between the benzoyl and di-nitro-phenyl moieties contributes to the crystal packing. Theoretical calculations using DFT(B3YLP) methods were used to confirm the mol-ecular structure. PMID- 27980847 TI - Crystal structure of bis-(bis-{MU3-3-methyl-3-[(4-nitro-2-oxido-benzyl idene)amino]-propane-1,3-diolato}tris-[chlorido-(dimethyl sulfoxide)-iron(III)]) dimethyl sulfoxide hepta-solvate dihydrate. AB - The title compound, [Fe3(C11H11N2O5)2Cl3(C2H6OS)3]2.7C2H6OS.2H2O, was isolated accidentally from an Fe0-NiCl2.6H2O-H3L-TEA-DMSO system [where H3L is the product of the condensation between p-nitro-salicyl-aldehyde and 2-amino-2-methyl-propane 1,3-diol and dimethyl sulfoxide (DMSO), and TEA is triethylamine]. The structure is based on a trinuclear {Fe3(MU-O)4} core, with an angular arrangement of the FeIII ions that can be explained by the geometrical restrictions of two bulky ligands, each coordinating to all of the metal cations. PMID- 27980849 TI - Crystal structure of a 2:1 co-crystal of meloxicam with acetyl-endi-carb-oxy-lic acid. AB - The pharmaceutical 2:1 co-crystal of meloxicam [MXM; systematic name: 4-hy-droxy 2-methyl-N-(5-methyl-thia-zol-2-yl)-2H-1,2-benzo-thia-zine-3-carboxamide 1,1 dioxide] with acetyl-enedi-carb-oxy-lic acid (ACA; systematic name: but-2 ynedioic acid), crystallizes with one MXM mol-ecule and half an ACA mol-ecule in the asymmetric unit, C14H13N3O4S2.0.5C4H2O4. The mid-point of the triple bond of ACA is located on an inversion centre. In the crystal, the two stereoisomers of MXM with respect to the N atom of the sulfonamide group are related by the inversion centre. The carbonyl and hy-droxy groups belonging to the MXM mol-ecule are involved in an intra-molecular O-H?O hydrogen bond. The structure-forming motif includes two MXM mol-ecules linked via an ACA conformer through N-H?O and O H?N hydrogen bonds, similar to MXM co-crystals with other di-carb-oxy-lic acids. PMID- 27980850 TI - Crystal structure of [Ag(NH3)3]2[Ag(NH3)2]2[SnF6]F2, a compound showing argentophilic inter-actions. AB - Bis[triamminesilver(I)] bis-[diamminesilver(I)] hexa-fluorido-stannate(IV) difluoride, [Ag(NH3)3]2[Ag(NH3)2]2[SnF6]F2, was obtained in the form of colourless crystals from the reaction of CsAgSnF7 in anhydrous ammonia. Two different ammine complexes of silver(I) are present in the structure, i.e. a linear diammine and a T-shaped triammine complex. The ammine silver(I) complexes show Ag?Ag distances in the range of argentophilic inter-actions. In the crystal, several N-H?F hydrogen bonds are present between the complex cations and the SbF6 and F- anions, leading to the formation of a three-dimensional network. PMID- 27980851 TI - The synthesis and crystal structure of 2-(chloro-selan-yl)pyridine 1-oxide: the first monomeric organoselenenyl chloride stabilized by an intra-molecular secondary Se?O inter-action. AB - The title compound, C5H4ClNOSe, is the product of the reaction of sulfuryl chloride and 2-selanyl-1-pyridine 1-oxide in di-chloro-methane. The mol-ecule has an almost planar geometry (r.m.s. deviation = 0.012 A), and its mol-ecular structure is stabilized by an intra-molecular secondary Se?O inter-action of 2.353 (3) A, closing a four-membered N-C-Se?O ring. The title compound represents the first monomeric organoselenenyl chloride stabilized intra-molecularly by an inter-action of this type. The non-valent attractive Se?O inter-action results in a substantial distortion of the geometry of the ipso-carbon atom. The endo-cyclic N-C-Se [102.1 (3) degrees ] and exo-cyclic C-C-Se [136.9 (3) degrees ] bond angles deviate significantly from the ideal value of 120 degrees for an sp2 hybridized carbon atom, the former bond angle being much smaller than the latter. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming zigzag chains propagating along [010]. The chains, which stack along the a-axis direction, are linked by offset pi-pi inter-actions [inter-centroid distance = 3.960 (3) A], forming corrugated sheets parallel to the ab plane. PMID- 27980852 TI - Synthesis and structure of 1-(2-bromo-phen-yl)-2-chloro-3-(2-chloracet-yl)-1H indole. AB - In the title indole derivative, C16H10BrCl2NO, the dihedral angle between the mean plane of the indole ring system and the mean plane of the disordered 2-bromo phenyl ring is 77.6 (1) degrees . The non-H atoms of the chloracetyl group are essentially coplanar with the indole core. In the crystal, pairs of mol-ecules are face-to-face embraced via two weak C-H?O hydrogen bonds, forming inversion dimers with an inter-planar distance between two parallel indole planes of 3.360 (3) A. These dimers are connected by head-to-head Cl?Cl inter-molecular contacts to build a two-dimensional mol-ecular sheet parallel to (101). Neighbouring mol ecular sheets are stacked together to construct the three-dimensional structure by further short Cl?Cl inter-molecular contacts. The atoms of the bromo-phenyl group were refined as disordered over two sets of sites with refined occupancies of 0.61 (2) and 0.39 (2). PMID- 27980853 TI - Crystal structure of trans-cyclo-hexane-1,2-di-ammonium chromate(VI) from synchrotron X-ray diffraction data. AB - The structure of the title hybrid compound, (C6H16N2)[CrO4], has been determined from synchrotron data. The organic cation adopts a chair conformation. The inorganic CrO42- anion is slightly distorted owing to its involvement in N-H?O hydrogen-bonding inter-actions with neighbouring trans-cyclo-hexane-1,2-di ammonium cations, whereby the two Cr-O bonds to the O atoms acting as acceptor atoms for two hydrogen bonds are slightly longer than the other two Cr-O bonds for which only one acceptor inter-action per O atom is observed. In the crystal, cations and anions are packed into layers parallel to (001), held together through the aforementioned N-H?O hydrogen bonds. PMID- 27980854 TI - Vitreoretinal instruments: vitrectomy cutters, endoillumination and wide-angle viewing systems. AB - There have been many advances in vitreoretinal surgery since Machemer introduced the concept of pars plana vitrectomy, in 1971. Of particular interest are the changes in the vitrectomy cutters, their fluidics interaction, the wide-angle viewing systems and the evolution of endoillumination through the past decade and notably in the last few years. The indications of 27-gauge surgery have expanded, including more complex cases. Cut rates of up to 16,000 cuts per minute are already available. New probe designs and pump technology have allowed duty cycle performances of near 100% and improved flow control. The smaller vitrectomy diameter can be positioned between narrow spaces, allowing membrane dissection and serving as a multifunctional instrument. Enhanced endoillumination safety can be achieved by changing the light source, adding light filters, increasing the working distance and understanding the potential interactions between light and vital dyes commonly used to stain the retina. Wide-angle viewing systems (contact, non-contact or a combination of both) provide a panoramic view of the retina. Non-contact systems are assistant-independent, while contact systems may be associated with better image resolution. This review will cover some current aspects on vitrectomy procedures, mainly assessing vitrectomy cutters, as well as the importance of endoillumination and the use of wide-angle viewing systems. PMID- 27980857 TI - Comparative Antibody Responses Against three Antimalarial Vaccine Candidate Antigens from Urban and Rural Exposed Individuals in Gabon. AB - The analysis of immune responses in diverse malaria endemic regions provides more information to understand the host's immune response to Plasmodium falciparum. Several plasmodial antigens have been reported as targets of human immunity. PfAMA1 is one of most studied vaccine candidates; PfRH5 and Pf113 are new promising vaccine candidates. The aim of this study was to evaluate humoral response against these three antigens among children of Lastourville (rural area) and Franceville (urban area). Malaria was diagnosed using rapid diagnosis tests. Plasma samples were tested against these antigens by enzyme-linked immunosorbent assay (ELISA). We found that malaria prevalence was five times higher in the rural area than in the urban area (p < 0.0001). The anti-PfAMA1 and PfRh5 response levels were significantly higher in Lastourville than in Franceville (p < 0.0001; p = 0.005). The anti-AMA1 response was higher than the anti-Pf113 response, which in turn was higher than the anti-PfRh5 response in both sites. Anti-PfAMA1 levels were significantly higher in infected children than those in uninfected children (p = 0.001) in Franceville. Anti-Pf113 and anti-PfRh5 antibody levels were lowest in children presenting severe malarial anemia. These three antigens are targets of immunity in Gabon. Further studies on the role of Pf113 in antimalarial protection against severe anemia are needed. PMID- 27980856 TI - Effect of RpoN, RpoS and LuxS Pathways on the Biofilm Formation and Antibiotic Sensitivity of Borrelia Burgdorferi. AB - Borrelia burgdorferi, the causative agent of Lyme disease, is capable of forming biofilm in vivo and in vitro, a structure well known for its resistance to antimicrobial agents. For the formation of biofilm, signaling processes are required to communicate with the surrounding environment such as it was shown for the RpoN-RpoS alternative sigma factor and for the LuxS quorum-sensing pathways. Therefore, in this study, the wild-type B. burgdorferi and different mutant strains lacking RpoN, RpoS, and LuxS genes were studied for their growth characteristic and development of biofilm structures and markers as well as for their antibiotic sensitivity. Our results showed that all three mutants formed small, loosely formed aggregates, which expressed previously identified Borrelia biofilm markers such as alginate, extracellular DNA, and calcium. All three mutants had significantly different sensitivity to doxycyline in the early log phase spirochete cultures; however, in the biofilm rich stationary cultures, only LuxS mutant showed increased sensitivity to doxycyline compared to the wild-type strain. Our findings indicate that all three mutants have some effect on Borrelia biofilm, but the most dramatic effect was found with LuxS mutant, suggesting that the quorum-sensing pathway plays an important role of Borrelia biofilm formation and antibiotic sensitivity. PMID- 27980859 TI - Usage of Murine T-cell Hybridoma Cells as Responder Cells Reveals Interference of Helicobacter Pylori with Human Dendritic Cell-mediated Antigen Presentation. AB - Direct effects of Helicobacter pylori (H. pylori) on human CD4+ T-cells hamper disentangling a possible bacterial-mediated interference with major histocompatibility complex class II (MHC-II)-dependent antigen presentation to these cells. To overcome this limitation, we employed a previously described assay, which enables assessing human antigen-processing cell function by using murine T-cell hybridoma cells restricted by human leukocyte antigen (HLA) alleles. HLA-DR1+ monocyte-derived dendritic cells were exposed to H. pylori and pulsed with the antigen 85B from Mycobacterium tuberculosis (M. tuberculosis). Interleukin-2 (IL-2) secretion by AG85Baa97-112-specific hybridoma cells was then evaluated as an integral reporter of cognate antigen presentation. This methodology enabled revealing of interference of H. pylori with the antigen presenting capacity of human dendritic cells. PMID- 27980858 TI - Influence of Toxoplasma Gondii Infection on Symptoms and Signs of Premenstrual Syndrome: A Cross-sectional Study. AB - Infection with Toxoplasma gondii in brain may cause some symptoms that resemble those in women with premenstrual syndrome. To determine the association of T. gondii infection with symptoms and signs of premenstrual syndrome, we examined 489 women aged 30-40 years old. Sera of participants were analyzed for the presence of anti-Toxoplasma IgG and IgM antibodies using enzyme-linked immunoassays (EIA) and T. gondii DNA by polymerase chain reaction (PCR). Anti-T. gondii IgG antibodies were found in 38 (7.8%) of the women studied. Anti-T. gondii IgM antibodies were found in 13 (34.2%) of the 38 IgG seropositive women. Logistic regression showed two variables associated with seropositivity to T. gondii: presence of diarrhea (odds ratio [OR] = 6.10; 95% confidence interval [CI]: 1.37-27.85; P = 0.01) and weight gain (OR = 2.89; 95% CI: 1.37-6.07; P = 0.005), and two variables associated with high (>150 IU/ml) levels of IgG against T. gondii: presence of diarrhea (OR = 7.40; 95% CI: 1.79-30.46; P = 0.006) and abdominal inflammation (OR = 3.38; 95% CI: 1.13-10.10; P = 0.02). Positivity to EIA IgG and PCR was positively associated with obesity and negatively associated with joint pain by bivariate analysis. Our study for the first time reveals a potential association of T. gondii infection with clinical manifestations of premenstrual syndrome. PMID- 27980860 TI - Pretransplant Factors and Associations with Postoperative Respiratory Failure, ICU Length of Stay, and Short-Term Survival after Liver Transplantation in a High MELD Population. AB - Changes in distribution policies have increased median MELD at transplant with recipients requiring increasing intensive care perioperatively. We aimed to evaluate association of preoperative variables with postoperative respiratory failure (PRF)/increased intensive care unit length of stay (ICU LOS)/short-term survival in a high MELD cohort undergoing liver transplant (LT). Retrospective analysis identified cases of PRF and increased ICU LOS with recipient, donor, and surgical variables examined. Variables were entered into regression with end points of PRF and ICU LOS > 3 days. 164 recipients were examined: 41 (25.0%) experienced PRF and 74 (45.1%) prolonged ICU LOS. Significant predictors of PRF with univariate analysis: BMI > 30, pretransplant MELD, preoperative respiratory failure, LVEF < 50%, FVC < 80%, intraoperative transfusion > 6 units, warm ischemic time > 4 minutes, and cold ischemic time > 240 minutes. On multivariate analysis, only pretransplant MELD predicted PRF (OR 1.14, p = 0.01). Significant predictors of prolonged ICU LOS with univariate analysis are as follows: pretransplant MELD, FVC < 80%, FEV1 < 80%, deceased donor, and cold ischemic time > 240 minutes. On multivariate analysis, only pretransplant MELD predicted prolonged ICU LOS (OR 1.28, p < 0.001). One-year survival among cohorts with PRF and increased ICU LOS was similar to subjects without. Pretransplant MELD is a robust predictor of PRF and ICU LOS. Higher MELDs at LT are expected to increase need for ICU utilization and modify expectations for recovery in the immediate postoperative period. PMID- 27980855 TI - Dissecting the Interplay Between Intestinal Microbiota and Host Immunity in Health and Disease: Lessons Learned from Germfree and Gnotobiotic Animal Models. AB - This review elaborates the development of germfree and gnotobiotic animal models and their application in the scientific field to unravel mechanisms underlying host-microbe interactions and distinct diseases. Strictly germfree animals are raised in isolators and not colonized by any organism at all. The germfree state is continuously maintained by birth, raising, housing and breeding under strict sterile conditions. However, isolator raised germfree mice are exposed to a stressful environment and exert an underdeveloped immune system. To circumvent these physiological disadvantages depletion of the bacterial microbiota in conventionally raised and housed mice by antibiotic treatment has become an alternative approach. While fungi and parasites are not affected by antibiosis, the bacterial microbiota in these "secondary abiotic mice" have been shown to be virtually eradicated. Recolonization of isolator raised germfree animals or secondary abiotic mice results in a gnotobiotic state. Both, germfree and gnotobiotic mice have been successfully used to investigate biological functions of the conventional microbiota in health and disease. Particularly for the development of novel clinical applications germfree mice are widely used tools, as summarized in this review further focusing on the modulation of bacterial microbiota in laboratory mice to better mimic conditions in the human host. PMID- 27980862 TI - Retinal Fibre Layer Thickness Measurement in Normal Paediatric Population in Sweden Using Optical Coherence Tomography. AB - Purpose. To evaluate the correlation between peripapillary retinal nerve fibre layer (RNFL) thickness and both age and refraction error in healthy children using optical coherence tomography (OCT). Patients and Methods. 80 healthy children with a mean age of 9.1 years (range 3.8 to 16.7 years) undergoing routine ocular examination at the orthoptic section of the Ophthalmology Department were recruited for this cross-sectional study. After applying cycloplegia, the peripapillary RNFL thickness was measured in both eyes using the Topcon 3D OCT 2000 device. Results. 138 eyes were included in the analysis. The average refractive error (SE) was +1.7 D (range -5.25 to +7.25 D). The mean total RNFL thickness was 105 MUm +/- 10.3, the mean superior RNFL thickness was 112.7 MUm +/- 16.5, and the mean inferior RNFL thickness was 132.6 MUm +/- 18.3. We found no statistically significant effect of age on RNFL thickness (ANOVA, f = 0.33, p = 0.56). Refraction was proven to have a statistically significant effect (ANOVA, f = 67.1, p < 0.05) in RNFL measurements. Conclusions. Data obtained from this study may assist in establishing a normative database for a paediatric population. Refraction error should be taken into consideration due to its statistically significant correlation with RNFL thickness. PMID- 27980861 TI - Molecular Evidence of High Proportion of Plasmodium vivax Malaria Infection in White Nile Area in Sudan. AB - Plasmodium falciparum is a predominant malaria species that infects humans in the African continent. A recent WHO report estimated 95% and 5% of P. falciparum and P. vivax malaria cases, respectively, in Sudan. However many laboratory reports from different areas in Sudan indicated otherwise. In order to verify, we selected four hundred suspected malaria cases from Aljabalain area located in the White Nile state, central Sudan, and diagnosed them with quality insured microscopy and species-specific nested PCR. Our results indicated that the proportion of P. vivax infections among suspected malaria cases was high. We found that on average 20% and 36.5% of malaria infections in both study areas were caused by P. vivax using both microscopy and PCR, respectively. This change in pattern is likely due to the recent demographic changes and high rate of immigration from neighbouring countries in the recent years. This is the first extensive clinical study of its kind that shows rising trend in P. vivax malaria cases in White Nile area, Sudan. PMID- 27980863 TI - Adjunct Intravitreous Triamcinolone Acetonide in the Treatment of Diabetic Macular Edema with Anti-VEGF Agents. AB - Aims. To compare visual and anatomic outcomes of adjunct intravitreous (IVT) triamcinolone acetonide to antivascular endothelial growth factor (VEGF) injections to IVT anti-VEGF injections alone for center-involving diabetic macular edema (DME) in treatment-naive eyes. Methods. Retrospective study of treatment-naive eyes with center-involving DME. The primary outcome was the change in best corrected visual acuity (BCVA) in eyes receiving only IVT anti VEGF (group 1) and eyes receiving IVT anti-VEGF and adjunct IVT-TA (group 2). Results. Included were 192 eyes. The mean change in BCVA was +3.5 letters in group 1 compared to -3.5 letters in group 2 (p = 0.048). Final macular thickness improved by -94 MUm in group 1 versus -68 MUm in group 2 (p = 0.26). In group 1, 5/150 eyes compared to 9/42 eyes in group 2 (3.3% versus 21%, p = 0.0005) had a IOP >10 mmHg increase. Six of 126 phakic eyes in group 1 versus 12/33 phakic eyes in group 2 underwent cataract surgery (4.7% versus 36.3%, p = 0.00009). Conclusions. IVT-TA results in no additional benefit in eyes treated with anti VEGF agents for DME. PMID- 27980864 TI - Pulsed magnetic field versus ultrasound in the treatment of postnatal carpal tunnel syndrome: A randomized controlled trial in the women of an Egyptian population. AB - The aim of this study was to compare the effects of pulsed electromagnetic field versus pulsed ultrasound in treating patients with postnatal carpal tunnel syndrome. The study was a randomized, double-blinded trial. Forty postnatal female patients with idiopathic carpal tunnel syndrome were divided randomly into two equal groups. One group received pulsed electromagnetic field, with nerve and tendon gliding exercises for the wrist, three times per week for four weeks. The other group received pulsed ultrasound and the same wrist exercises. Pain level, sensory and motor distal latencies and conduction velocities of the median nerve, functional status scale and hand grip strength were assessed pre- and post treatment. There was a significant decrease (P < 0.05) in pain level, sensory and motor distal latencies of the median nerve, and significant increase (P < 0.05) in sensory and motor conduction velocities of the median nerve and hand grip strength in both groups, with a significant difference between the two groups in favour of pulsed electromagnetic field treatment. However, the functional status scale showed intergroup no significant difference (P > 0.05). In conclusion, while the symptoms were alleviated in both groups, pulsed electromagnetic field was more effective than pulsed ultrasound in treating postnatal carpal tunnel syndrome. PMID- 27980865 TI - Role of Short Term Video Encephalography with Induction by Verbal Suggestion in Diagnosis of Suspected Paroxysmal Nonepileptic Seizure-Like Symptoms. AB - Purpose. To determine the diagnostic yield and utility of STVEEG with verbal suggestion in diagnosis of patients presenting with transient unresponsiveness and suspected psychogenic nonepileptiform seizures. Methods. A retrospective analysis of STVEEG records of patients with transient unresponsiveness and suspected PNES between 1 Jan 2009 and 28 Feb 2014 was done. Results. Amongst 155 patients [38 males, 117 females], with mean age 32 [8-67], PNES were identified in 109 [70.3%], focal epilepsy was identified in 24 [15.4%], and actual seizure was recorded in 7 [4.5%]. Nine [5.8%] patients were found to have both epilepsy and PNES. Primary generalized epilepsy was diagnosed in 2 [1.2%]. A diagnosis of other paroxysmal nonepileptiform events [tachyarrhythmia and heart block] was done in 3 [1.9%]. A normal EEG and no inducible episode and hence an uncertain diagnosis at the end of STVEEG were seen in only 17 [10.9%] patients. A STVEEG of approximately one hour duration was able to establish the diagnosis in 138 [89.1%] patients with transient unresponsiveness. Conclusion. STVEEG with verbal suggestion is a useful and cost effective diagnostic test for diagnosis of PNES. It can be a good modality for diagnosis in patients with transient abnormalities in sensorium in the outpatient settings in developing countries. PMID- 27980866 TI - Breastfeeding among Latino Families in an Urban Pediatric Office Setting. AB - Objective. To determine the breastfeeding rate of Latino infants at an urban pediatric clinic in the first six months of life and to identify factors associated with breastfeeding. Methods. Investigators conducted a retrospective chart review of infants seen at the clinic in 2014 as part of a mixed methods study. Topics reviewed included demographics, infant health data, and feeding methods at 5 points in time. Bivariate correlations and cross-tabulations explored associations between variables. Results. Most of the mothers (75%) fed their newborns with both breastfeeding and formula (las dos). At 6 months, a majority were formula-fed only (55.9%). Approximately 10% of mothers exclusively breastfed their newborns, and the trend of exclusive breastfeeding remained steady through the 6-month visit. Over time, the number of mothers who exclusively bottle-feed their infants steadily rises. There were no statistical differences among the feeding method groups with regard to birth order of child, number of adults or children in the household, vaccination rate, number of sick visits, or infants' growth. Conclusions. More targeted attention to this population and other immigrant populations with culturally tailored interventions spanning the prenatal to early infancy periods could increase exclusive breastfeeding and ultimately improve child health. PMID- 27980867 TI - Extramedullary Plasmacytoma Diagnosed in an HIV-Positive Patient by an Unusual Clinical Presentation. AB - The aim of this paper is to describe a case report of EMP in an HIV-positive patient. A 44-year-old, dark-skinned HIV-infected woman was referred to the Oral Diseases Treatment Center with a swelling at palate and left gingival fornix in the maxilla. Biopsy was taken and the oral lesion was diagnosed as EMP with well differentiated plasma cells and restriction of the lambda light-chain. Skeletal survey was performed and no radiograph alterations were observed, thus supporting the diagnosis of EMP. Patient was referred to treatment and after two months of chemo and radiotherapy, an expanding lesion was observed in L5/S1 patient's vertebrae. Biopsy of the spinal lesion was consistent with lymphoma with plasmocitary differentiation, supporting the diagnosis of multiple myeloma (MM). Regarding the medical history, the final diagnostic was an oral extramedullary plasmacytoma with rapid progression into multiple myeloma. It is crucial to emphasize the relevance of HIV infection as a risk factor for both aggressive clinical behavior and unusual clinical presentation of extramedullary plasmacytoma cases. PMID- 27980868 TI - Clinical Manifestation, Histopathology, and Imaging of Traumatic Injuries Caused by Brazilian Porcupine (Sphiggurus villosus) Quills. AB - Injuries to humans caused by porcupines are rare. However, they may occur due to the proximity of urban areas and the animal's habitat in areas such as the Floresta da Tijuca in Rio de Janeiro. Outdoor sports and leisure activities in areas close to forests or in the rain forest are also relevant for incidents of this kind and a better knowledge of the local forest fauna would prevent such undesirable accidents. Porcupine quills have microscopic barbs at their tips which facilitate skin penetration, but hampering their removal. Once the spines are lodged in tissue, the microscopic backward-facing deployable barbs at the tips cause trauma if anyone tries to remove them. Local haemorrhage and an inflammatory response to the contaminated foreign body occur. Depending on the time lapse in removing the spines either septic or sterile foreign body reactions may occur. There is also the risk of migration of the spines, where fatal cases have been reported in human and veterinary medicine. Herein we report two unusual cases of accidents involving humans and the South American porcupine. The Sphiggurus villosus spines removed from scalp skin were also documented through Scanning Electron Microscopy. PMID- 27980869 TI - Diagnostic Colonoscopy Leading to Perforated Appendicitis: A Case Report and Systematic Literature Review. AB - Introduction. Intestinal perforation is a known complication after colonoscopy. However, appendiceal involvement with inflammation and perforation is extremely rare and only 37 cases of postcolonoscopy appendicitis have been reported so far. We describe a case of perforated appendicitis 24 hours after colonoscopy that was treated successfully in our Department. Case Report. A 60-year-old female patient underwent a colonoscopy during the investigation of nontypical abdominal pain without pathologic findings. 24 hours after the examination she presented gradually increased right lower quadrant abdominal pain and a CT scan was performed, showing an inflammation of the appendiceal area with free peritoneal air. Through laparotomy, perforated appendicitis was diagnosed and an appendectomy was performed. The patient was discharged on the tenth postoperative day in good health condition. Discussion. The characteristics of all cases reported in the literature are described, including our case. Perforated appendicitis soon after a colonoscopy is a rare, but serious complication; therefore, it is crucial to be included in the differential diagnosis of postcolonoscopy acute abdominal pain. PMID- 27980870 TI - Cannabinoid Hyperemesis Syndrome: A Case Report of Cyclic Severe Hyperemesis and Abdominal Pain with Long-Term Cannabis Use. AB - Introduction. Cannabinoid Hyperemesis Syndrome (CHS) is a rare condition that includes cyclic severe vomiting in subjects who have been consuming large doses of cannabis for several years. One of the major diagnostic criteria is the alleviation of symptoms by hot showers. The syndrome was first described in 2004 and is so far neither completely understood nor well known. The latter leads to continued morbidity in concerned subjects and unnecessary expenses for futile investigations. Standard treatments of vomiting as 5-HT3 or D2-receptor antagonists have been shown to be ineffective in alleviating the symptoms. The only long-term satisfying treatment option is the complete abstinence from cannabis consumption. Case Summary. In this case report we describe a 26-year-old male Caucasian long-term cannabis consumer who repeatedly presented in our emergency room with cyclic severe nausea and vomiting ceased by hot showers and resistant to all other treatments. The final diagnosis was not established until his third visit to the ER. Conclusion. CHS is an important differential diagnosis in patients who present with cyclic vomiting and abdominal pain with a history of long-term cannabis use. Recognition of this syndrome is important in order to avoid unnecessary clinical testing and to help the patients break the cycle of drug use. PMID- 27980871 TI - Bilateral Nasoalveolar Cyst Causing Nasal Obstruction. AB - Nasoalveolar cysts, which originate from epithelial remnants of nasolacrimal duct, are nonodontogenic soft tissue lesions of the upper jaw. These cysts are thought to be developmental and are presented with fullness in the upper lip and nose, swelling on the palate, and sometimes nasal obstruction. Because of cosmetic problems, they are often diagnosed at an early stage. These lesions are mostly revealed unilaterally but also can be seen on both sides. In this case report, a patient who complained of nasal obstruction and then diagnosed with bilateral nasoalveolar cysts and treated by sublabial excision is presented and clinical features and treatment approaches are discussed with the review of literature. PMID- 27980872 TI - Human Herpesvirus 6 Infection Presenting as an Acute Febrile Illness Associated with Thrombocytopenia and Leukopenia. AB - We present an infant with acute fever, thrombocytopenia, and leukopenia, coming from an endemic region for tick-borne encephalitis, human granulocytic anaplasmosis, and hantavirus infection. The primary human herpesvirus 6 infection was diagnosed by seroconversion of specific IgM and IgG and by identification of viral DNA in the acute patient's serum. The patient did not show skin rash suggestive of exanthema subitum during the course of illness. PMID- 27980873 TI - ST Elevation Infarction after Heart Transplantation Induced by Coronary Spasms and Mural Thrombus Detected by Optical Coherence Tomography. AB - The case illustrates the possible link between coronary spasms, intraluminal thrombus formation, and widespread organized and layered thrombi in HTx patients. Furthermore, the case underlines the clinical value of OCT as a novel method for high-resolution vessel imaging in heart-transplanted (HTx) patients with coronary spasms and suspected coronary artery disease. Coronary spasms and sudden death are frequent complications after HTx. The underlying mechanisms leading to these complications are unknown. The present case displays the clinical course of a 19 year-old HTx patient who was hospitalized due to acute myocardial infarction induced by severe coronary spasms. The patients remained unstable on conservative therapy. Therefore, an optical coherence tomography (OCT) was performed and revealed massive, organized thrombi in the left main coronary artery, the circumflex coronary artery, and the left anterior descending coronary artery. The patient was stabilized after percutaneous coronary intervention. As a mural thrombus often goes undetected by coronary angiography, OCT may prove benefit in HTx patients with myocardial infarction or suspected coronary spasms. PMID- 27980874 TI - Plantar Pressure Distribution among Older Persons with Different Types of Foot and Its Correlation with Functional Reach Distance. AB - Background. Changes in biomechanical structures of human foot are common in the older person, which may lead to alteration of foot type and plantar pressure distribution. We aimed to examine how foot type affects the plantar pressure distribution and to determine the relationship between plantar pressure distribution and functional reach distance in older persons. Methods. Fifty community-dwelling older persons (age: 69.98 +/- 5.84) were categorized into three groups based on the Foot Posture Index. The plantar pressure (max?P) and contact area were analyzed using Footscan(r) RSScan platform. The Kruskal-Wallis test was used to compare the plantar pressure between foot types and Spearman's correlation coefficient was used to correlate plantar pressure with the functional reach distance. Results. There were significant differences of max?P in the forefoot area across all foot types. The post hoc analysis found significantly lower max?P in the pronated foot compared to the supinated foot. A high linear rank correlation was found between functional reach distance and max?P of the rearfoot region of the supinated foot. Conclusions. These findings suggested that types of the foot affect the plantar maximal pressure in older persons with functional reach distance showing some associations. PMID- 27980875 TI - Enantioselective Synthesis of Fluoro-Dihydroquinazolones and -Benzooxazinones by Fluorination-Initiated Asymmetric Cyclization Reactions. AB - Stereoselective synthesis of two fluorine-bearing drug-like scaffolds, dihydroquinazolone and benzooxazinone, has been accomplished through asymmetric fluorocyclization reactions initiated by the fluorination process. The reaction employs double axially chiral anionic phase-transfer catalysts to achieve high diastereo- and enantioselectivities, and a wide range of fluorine-containing dihydroquinazolones were obtained (>20:1 dr, up to 98% ee). PMID- 27980876 TI - Development of a Pediatric Visual Field Test. AB - PURPOSE: We describe a pediatric visual field (VF) test based on a computer game where software and hardware combine to provide an enjoyable test experience. METHODS: The test software consists of a platform-based computer game presented to the central VF. A storyline was created around the game as was a structure surrounding the computer monitor to enhance patients' experience. The patient is asked to help the central character collect magic coins (stimuli). To collect these coins a series of obstacles need to be overcome. The test was presented on a Sony PVM-2541A monitor calibrated from a central midpoint with a Minolta CS-100 photometer placed at 50 cm. Measurements were performed at 15 locations on the screen and the contrast calculated. Retinal sensitivity was determined by modulating stimulus in size. To test the feasibility of the novel approach 20 patients (4-16 years old) with no history of VF defects were recruited. RESULTS: For the 14 subjects completing the study, 31 +/- 15 data points were collected on 1 eye of each patient. Mean background luminance and stimulus contrast were 9.9 +/- 0.3 cd/m2 and 27.9 +/- 0.1 dB, respectively. Sensitivity values obtained were similar to an adult population but variability was considerably higher - 8.3 +/- 9.0 dB. CONCLUSIONS: Preliminary data show the feasibility of a game-based VF test for pediatric use. Although the test was well accepted by the target population, test variability remained very high. TRANSLATIONAL RELEVANCE: Traditional VF tests are not well tolerated by children. This study describes a child-friendly approach to test visual fields in the targeted population. PMID- 27980877 TI - Suprachoroidal Corticosteroid Administration: A Novel Route for Local Treatment of Noninfectious Uveitis. AB - PURPOSE: To evaluate the safety, tolerability, and preliminary efficacy of suprachoroidal injection of triamcinolone acetonide (TA) in patients with noninfectious uveitis. METHODS: In this Phase 1/2 open-label clinical study, a single suprachoroidal injection of 4-mg TA in 100 MUL was performed in the study eye of patients with noninfectious intermediate, posterior, or pan-uveitis, and follow-up obtained for 26 weeks. RESULTS: Nine individuals with chronic uveitis were enrolled. There were 38 reported adverse events (AEs); most were mild or moderate in severity. Approximately half the AEs were ocular. The most common AE was reported by four subjects who experienced ocular pain at or near the time of the injection. All systemic AEs were unrelated to study drug. No steroid-related increases in intraocular pressure (IOP) were observed and no subject required IOP lowering medication. All eight efficacy-evaluable subjects had improvements in visual acuity. Four subjects, who did not need additional therapy, had on average a greater than 2-line improvement in visual acuity through week 26. Three of four had macular edema at baseline, and two of three had at least a 20% reduction in macular edema at week 26. CONCLUSIONS: The safety and preliminary efficacy data support further investigations of suprachoroidally administered TA as a therapeutic option for the treatment of noninfectious uveitis. TRANSLATIONAL RELEVANCE: Targeted suprachoroidal administration of corticosteroid is a potential local route for the treatment of ocular inflammatory disease, which merits further investigation. (www.ClinicalTrials.gov, NCT01789320). PMID- 27980878 TI - Glaucoma and Driving Risk under Simulated Fog Conditions. AB - PURPOSE: We evaluate driving risk under simulated fog conditions in glaucoma and healthy subjects. METHODS: This cross-sectional study included 41 glaucoma patients and 25 age-matched healthy subjects who underwent driving simulation. Tests consisted of curve negotiation without and with fog preview at 30 m of distance and two controlled speeds (slow and fast). Inverse time-to-line crossing (invTLC) was used as metric to quantify risk; higher invTLC values indicating higher risk, as less time is available to avoid drifting out of the road. Piecewise regression models were used to investigate the relationship between differences in invTLC in fog and nonfog conditions and visual field loss. RESULTS: Glaucoma patients had greater increase in driving risk under fog compared to controls, as indicated by invTLC differences (0.490 +/- 0.578 s-1 and 0.208 +/- 0.106 s-1, respectively; P = 0.002). Mean deviation (MD) of the better eye was significantly associated with driving risk under fog, with a breakpoint of -9 dB identified by piecewise regression. For values below the breakpoint, each 1 dB lower MD of better eye was associated with 0.117 s-1 higher invTLC under fast speed (adjusted R2 = 57.9%; P < 0.001). CONCLUSIONS: Glaucoma patients have a steeper increase in driving risk under fog conditions when compared to healthy subjects, especially when the severity of visual field damage falls below -9 dB of MD in the better eye. TRANSLATIONAL RELEVANCE: By investigating the relationship between driving risk and disease severity breakpoint, this study may provide guidance to clinicians in recognizing glaucoma patients who may be unfit to drive in complex situations such as fog. PMID- 27980879 TI - Lower Vitamin D Level and Distinct Tear Cytokine Profile Were Observed in Patients with Mild Dry Eye Signs but Exaggerated Symptoms. AB - PURPOSE: Dry eye is associated with inflammation, pain, and discomfort. Vitamin D is known to modulate immune responses and pain. This study investigates the level of serum vitamin D and tear-inflammatory proteins with relation to exaggerated symptoms in patients with mild dry eye. METHODS: Patients with mild dry eye signs (Dry Eye Workshop [DEWS] severity grade 1) but with exaggerated symptoms and healthy controls (n = 19, each) were recruited for this cross-sectional study. Schirmer's Test I (mm), tear film break-up time (TBUT; secs), and ocular surface disease index (OSDI) score were recorded. Serum vitamin D level and tear cytokine levels were measured. RESULTS: The mean OSDI score in the patient cohort (46 +/- 3) was significantly higher than controls (8.4 +/- 1.6). TBUT was lower (7.6 +/- 0.3 secs) in patients compared with controls (11.0 +/- 0.9 secs). Mean Schirmer's Test I value in patients (19.3 +/- 1.4 mm) was lower than in controls (30.6 +/- 1.9 mm). An inverse correlation was observed between serum vitamin D levels and OSDI score (r = -0.569; P = 0.01). Significantly higher levels of interleukin (IL)-17A/F, interferon (IFN)-gamma, monocyte chemotactic protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, IL-4, IL-10, and decreased IL-2 concentrations was observed in the tears of patients compared with controls (P < 0.05). CONCLUSION: Decreased serum vitamin D was associated with exaggerated symptoms in dry eye patients with mild dry eye signs. In addition, altered tear cytokine profile was also observed in these patients. TRANSLATIONAL RELEVANCE: Vitamin D measurements would aid in the diagnosis and management of dry eye. PMID- 27980880 TI - Discrepancy Between Identification of Early-Term Elective Deliveries by Manual Chart Review and Data Vendor. AB - Elective delivery from 37 to 39 weeks gestation (early-term deliveries) is a Joint Commission National Quality Measure, and hospitals report on early-term elective delivery rates through Outcome Research Yields Excellence (ORYX) vendors. The objective of this study was to compare early-term elective deliveries, identified through ORYX vendors with those identified through manual chart review, the traditional method of medical record review. We reviewed early term labor inductions and cesarean deliveries at a single hospital from June 1, 2010 to May 31, 2012. Rates of early-term elective deliveries identified by the data vendor were compared to physician chart review. Overall, the rate of elective deliveries by ORYX was 3% compared to 2% by physician chart review (RR 1.51 [95% CI 1.12-2.03], P < .001). Of the 116 elective early-term deliveries identified by vendor and/or chart review, vendors classified significantly more inductions and cesareans as elective (P < .001) and missed nine elective deliveries. Of the 107 deliveries identified as elective by ORYX, 62 (57.9%) were verified by chart review, including 69.0% of cesareans and 36.1% of inductions. Findings from this study suggest substantial discrepancy between identification of early-term elective deliveries by data vendors and physician chart review, and indicate that vendor-derived data may overestimate the number of electively delivered patients. PMID- 27980882 TI - Impact of Helmet Use on Injury and Financial Burden of Motorcycle and Moped Crashes in Hawai'i: Analysis of a Linked Statewide Database. AB - Helmet use reduces injury severity, disability, hospital length of stay, and hospital charges in motorcycle riders. The public absorbs billions of dollars annually in hospital charges for unhelmeted, uninsured motorcycle riders. We sought to quantify, on a statewide level, the healthcare burden of unhelmeted motorcycle and moped riders. We examined 1,965 emergency medical service (EMS) reports from motorcycle and moped crashes in Hawai'i between 2007-2009. EMS records were linked to hospital medical records to assess associations between vehicle type, helmet use, medical charges, diagnoses, and final disposition. Unhelmeted riders of either type of vehicle suffered more head injuries, especially skull fractures (adjusted odds ratio (OR) of 4.48, P < .001, compared to helmeted riders). Motorcyclists without helmets were nearly three times more likely to die (adjusted OR 2.85, P = .001). Average medical charges were almost 50% higher for unhelmeted motorcycle and moped riders, with a significant (P = .006) difference between helmeted ($27,176) and unhelmeted ($40,217) motorcycle riders. Unhelmeted riders were twice as likely to self-pay (19.3%, versus 9.8% of helmeted riders), and more likely to have Medicaid or a similar income-qualifying insurance plan (13.5% versus 5.0%, respectively). Protective associations with helmet use are stronger among motorcyclists than moped riders, suggesting the protective effect is augmented in higher speed crashes. The public financial burden is higher from unhelmeted riders who sustain more severe injuries and are less likely to be insured. PMID- 27980881 TI - Obstetric Obesity is Associated with Neonatal Hyperbilirubinemia with High Prevalence in Native Hawaiians and Pacific Island Women. AB - Obesity and pregnancy both place the liver under metabolic stress, but interactions between obstetric obesity and bilirubin metabolism have not been studied. We determined associations between obesity, maternal/neonatal bilirubin levels, and uridine 5'diphosphate-glucuronosyltransferase 1A1 (UGT1A1) enzyme that eliminates bilirubin. Adult livers were analyzed for UGT1A1 expression, activity, and bilirubin clearance by pharmacokinetic modeling. Then, matched maternal and neonatal sera (N = 450) were assayed for total and unconjugated bilirubin. Associations between obesity, UGT1A1, maternal and neonatal hyperbilirubinemia were determined statistically through correlation analysis (Pearson's test) as well as binned categories (one-way ANOVA). Morbid obesity decreased hepatic UGT1A1 protein levels, activity, and bilirubin clearance (P < .001). Increasing obesity corresponded to elevated maternal unconjugated bilirubin (P < .05). Maternal obesity was also significantly positively correlated with elevated neonatal bilirubin levels (P < .01, N = 450) and this was strongest in Native Hawaiians and Pacific Islander (NHPI) women (P < .01, n = 150). Obstetric obesity is associated with maternal and neonatal hyperbilirubinemia, likely through inhibition of hepatic UGT1A1. The NHPI cohort was the most obese and had the highest levels of maternal and neonatal unconjugated bilirubin. Neonates from obese mothers may be more susceptible to jaundice and side effects from parenteral nutrition. PMID- 27980883 TI - Medical School Hotline: The Role of Mini-Medical Schools in Education. PMID- 27980884 TI - Insights in Public Health: Leveraging Pacific Laboratories to Boost Global Health Security. PMID- 27980886 TI - A Case Review Series of Christiana Care Health System's Experience with Negative Pressure Wound Therapy Instillation. AB - Acute and chronic wounds afflict a multitude of patients to varying degrees. Wound care treatment modalities span the spectrum of technological advancement and with that differ greatly in cost. Negative pressure wound therapy (NPWT) can now be combined with instillation and dwell time (NPWTi-d). This case review series of 11 patients in a community hospital setting provides support for the utilization of NPWTi-d. Additionally, current literature on the use of NPWTi-d in comparison to NPWT will be reviewed. We highlight three specific cases. The first case is a 16-year-old male who was shot in the left leg. He suffered a pseudoaneurysm and resultant compartment syndrome. This required a fasciotomy and delayed primary closure. To facilitate this, NPWTi-d was employed and resulted in a total of four operative procedures before closure 13 days after admission. Next, a 61-year-old uncontrolled diabetic female presented with necrotizing fasciitis of the lower abdomen and pelvis. She underwent extensive debridement and placement of NPWTi-d with Dakin's solution. A total of four operative procedures were performed including delayed primary closure six days after admission. Finally, a 48-year-old female suffered a crush injury with internal degloving. NPWTi-d with saline was utilized until discharge home on postoperative day 12. NPWTi-d, when compared to NPWT, has been reported to lead to a decrease in time to operative closure, hospital length of stay, as well as operative procedures required. The cost-benefit analysis in one retrospective review noted a $1,400 savings when these factors were taken into account. This mode of wound care therapy has significant benefits that warrant the development of a prospective randomized controlled trial to further define the improvement in quality-of-life provided to the patient and the reduction of potential overall healthcare costs. PMID- 27980888 TI - Cytomegalovirus Colitis in Immunocompetent Patients. AB - Cytomegalovirus colitis is common in immunocompromised patients, but rare in immunocompetent patients. The present study not only represents the colonoscopy and pathological findings, but also applies the method of diagnosing and treating cytomegalovirus colitis in immunocompetent patients. PMID- 27980887 TI - Rural Community as Context and Teacher for Health Professions Education. AB - Nepal is a low-income, landlocked country located on the Indian subcontinent between China and India. The challenge of finding human resources for rural community health care settings is not unique to Nepal. In spite of the challenges, the health sector has made significant improvement in national health indices over the past half century. However, in terms of access to and quality of health services and impact, there remains a gross urban-rural disparity. The Patan Academy of Health Sciences (PAHS) has adopted a community-based education model, termed "community based learning and education" (CBLE), as one of the principal strategies and pedagogic methods. This method is linked to the PAHS mission of improving rural health in Nepal by training medical students through real-life experience in rural areas and developing a positive attitude among its graduates towards working in rural areas. This article outlines the PAHS approach of ruralizing the academy, which aligns with the concept of community engagement in health professional education. We describe how PAHS has embedded medical education in rural community settings, encouraging the learning context to be rural, fostering opportunities for community and peripheral health workers to participate in teaching-learning as well as evaluation of medical students, and involving community people in curriculum design and implementation. PMID- 27980889 TI - Transforming an embodied conversational agent into an efficient talking head: from keyframe-based animation to multimodal concatenation synthesis. AB - BACKGROUND: Virtual humans have become part of our everyday life (movies, internet, and computer games). Even though they are becoming more and more realistic, their speech capabilities are, most of the time, limited and not coherent and/or not synchronous with the corresponding acoustic signal. METHODS: We describe a method to convert a virtual human avatar (animated through key frames and interpolation) into a more naturalistic talking head. In fact, speech articulation cannot be accurately replicated using interpolation between key frames and talking heads with good speech capabilities are derived from real speech production data. Motion capture data are commonly used to provide accurate facial motion for visible speech articulators (jaw and lips) synchronous with acoustics. To access tongue trajectories (partially occluded speech articulator), electromagnetic articulography (EMA) is often used. We recorded a large database of phonetically-balanced English sentences with synchronous EMA, motion capture data, and acoustics. An articulatory model was computed on this database to recover missing data and to provide 'normalized' animation (i.e., articulatory) parameters. In addition, semi-automatic segmentation was performed on the acoustic stream. A dictionary of multimodal Australian English diphones was created. It is composed of the variation of the articulatory parameters between all the successive stable allophones. RESULTS: The avatar's facial key frames were converted into articulatory parameters steering its speech articulators (jaw, lips and tongue). The speech production database was used to drive the Embodied Conversational Agent (ECA) and to enhance its speech capabilities. A Text-To-Auditory Visual Speech synthesizer was created based on the MaryTTS software and on the diphone dictionary derived from the speech production database. CONCLUSIONS: We describe a method to transform an ECA with generic tongue model and animation by key frames into a talking head that displays naturalistic tongue, jaw and lip motions. Thanks to a multimodal speech production database, a Text-To-Auditory Visual Speech synthesizer drives the ECA's facial movements enhancing its speech capabilities. PMID- 27980890 TI - Mimicry and expressiveness of an ECA in human-agent interaction: familiarity breeds content! AB - BACKGROUND: Two experiments investigated the effect of features of human behaviour on the quality of interaction with an Embodied Conversational Agent (ECA). METHODS: In Experiment 1, visual prominence cues (head nod, eyebrow raise) of the ECA were manipulated to explore the hypothesis that likeability of an ECA increases as a function of interpersonal mimicry. In the context of an error detection task, the ECA either mimicked or did not mimic a head nod or brow raise that humans produced to give emphasis to a word when correcting the ECA's vocabulary. In Experiment 2, presence versus absence of facial expressions on comprehension accuracy of two computer-driven ECA monologues was investigated. RESULTS: In Experiment 1, evidence for a positive relationship between ECA mimicry and lifelikeness was obtained. However, a mimicking agent did not elicit more human gestures. In Experiment 2, expressiveness was associated with greater comprehension and higher ratings of humour and engagement. CONCLUSION: Influences from mimicry can be explained by visual and motor simulation, and bidirectional links between similarity and liking. Cue redundancy and minimizing cognitive load are potential explanations for expressiveness aiding comprehension. PMID- 27980894 TI - Advanced Science - Top Science with Maximum Accessibility. PMID- 27980891 TI - A Review of Anticipatory Pleasure in Schizophrenia. AB - PURPOSE OF REVIEW: Anhedonia, traditionally defined as a diminished capacity to experience pleasure, has long been considered a core symptom of schizophrenia. However, recent research calls into question whether individuals with schizophrenia are truly anhedonic, suggesting intact subjective and neurophysiological response to rewarding stimuli in-the-moment. Despite a presumably intact capacity to experience pleasure, people with schizophrenia still engage in fewer reward-seeking behaviors. This discrepancy has been explained as a dissociation between "liking" and "wanting", with dopaminergic and prefrontal influences on incentive salience leading hedonic responses to not effectively translate into motivated behavior. In the current review, the literature on a key aspect of the wanting deficit is reviewed, anticipatory pleasure. RECENT FINDINGS: Results provide consistent evidence for impairment in some aspects of anticipatory pleasure (e.g., prospection, associative learning between reward predictive cues and outcomes), and inconsistent evidence for others (e.g., anticipatory affect and affective forecasting). SUMMARY: Mechanisms underlying anticipatory pleasure abnormalities in schizophrenia are discussed and a new model of anticipatory pleasure deficits is proposed. Findings suggest that anticipatory pleasure may be a critical component of impairments in wanting that impact motivated behavior in schizophrenia. PMID- 27980892 TI - Photomethanation of Gaseous CO2 over Ru/Silicon Nanowire Catalysts with Visible and Near-Infrared Photons. AB - Gaseous CO2 is transformed photochemically and thermochemically in the presence of H2 to CH4 at millimole per hour per gram of catalyst conversion rates, using visible and near-infrared photons. The catalyst used to drive this reaction comprises black silicon nanowire supported ruthenium. These results represent a step towards engineering broadband solar fuels tandem photothermal reactors that enable a three-step process involving i) CO2 capture, ii) gaseous water splitting into H2, and iii) reduction of gaseous CO2 by H2. PMID- 27980893 TI - High-Volume Processed, ITO-Free Superstrates and Substrates for Roll-to-Roll Development of Organic Electronics. AB - The fabrication of substrates and superstrates prepared by scalable roll-to-roll methods is reviewed. The substrates and superstrates that act as the flexible carrier for the processing of functional organic electronic devices are an essential component, and proposals are made about how the general availability of various forms of these materials is needed to accelerate the development of the field of organic electronics. The initial development of the replacement of indium-tin-oxide (ITO) for the flexible carrier materials is described and a description of how roll-to-roll processing development led to simplification from an initially complex make-up to higher performing materials through a more simple process is also presented. This process intensification through process simplification is viewed as a central strategy for upscaling, increasing throughput, performance, and cost reduction. PMID- 27980895 TI - pH-Regulated Synthesis of Multi-Shelled Manganese Oxide Hollow Microspheres as Supercapacitor Electrodes Using Carbonaceous Microspheres as Templates. AB - Multi-shelled Mn2O3 hollow microspheres have been achieved through a pH-regulated method and used as supercapacitor electrodes. The designed unique architecture allows efficient use of pseudo-capacitive Mn2O3 nanomaterials for charge storage with facilitated transport for both ions and electrons, rendering them high specific capacitance, good rate capability, and remarkable cycling performance. PMID- 27980897 TI - The Rational Design of a Single-Component Photocatalyst for Gas-Phase CO2 Reduction Using Both UV and Visible Light. AB - The solar-to-chemical energy conversion of greenhouse gas CO2 into carbon-based fuels is a very important research challenge, with implications for both climate change and energy security. Herein, the key attributes of hydroxides and oxygen vacancies are experimentally identified in non-stoichiometric indium oxide nanoparticles, In2O3-x(OH)y, that function in concert to reduce CO2 to CO under simulated solar irradiation. PMID- 27980896 TI - Electrode Nanostructures in Lithium-Based Batteries. AB - Lithium-based batteries possessing energy densities much higher than those of the conventional batteries belong to the most promising class of future energy devices. However, there are some fundamental issues related to their electrodes which are big roadblocks in their applications to electric vehicles (EVs). Nanochemistry has advantageous roles to overcome these problems by defining new nanostructures of electrode materials. This review article will highlight the challenges associated with these chemistries both to bring high performance and longevity upon considering the working principles of the various types of lithium based (Li-ion, Li-air and Li-S) batteries. Further, the review discusses the advantages and challenges of nanomaterials in nanostructured electrodes of lithium-based batteries, concerns with lithium metal anode and the recent advancement in electrode nanostructures. PMID- 27980898 TI - Fluorosurfactants-Directed Preparation of Homogeneous and Hierarchical-Porosity CMP Aerogels for Gas Sorption and Oil Cleanup. AB - Homogeneous, hierarchical-porosity and highly hydrophobic conjugated microporous polymer (CMP) aerogels are facilely prepared assisted by fluorosurfactants. The fluorosurfactants show several roles in controlling the gelation process, modulating pore structures, and raising the hydrophobicity of materials, thus giving rise to aerogels with exceptional gas sorption and oil cleanup performance. PMID- 27980899 TI - Versatile Loading of Diverse Cargo into Functional Polymer Capsules. AB - Polymer microcapsules are of particular interest for applications including self healing coatings, catalysis, bioreactions, sensing, and drug delivery. The primary way that polymer capsules can exhibit functionality relevant to these diverse fields is through the incorporation of functional cargo in the capsule cavity or wall. Diverse functional and therapeutic cargo can be loaded into polymer capsules with ease using polymer-stabilized calcium carbonate (CaCO3) particles. A variety of examples are demonstrated, including 15 types of cargo, yielding a toolbox with effectively 500+ variations. This process uses no harsh reagents and can take less than 30 min to prepare, load, coat, and form the hollow capsules. For these reasons, it is expected that the technique will play a crucial role across scientific studies in numerous fields. PMID- 27980900 TI - Nanoparticle-Hydrogel Composites: Concept, Design, and Applications of These Promising, Multi-Functional Materials. AB - New technologies rely on the development of new materials, and these may simply be the innovative combination of known components. The structural combination of a polymer hydrogel network with a nanoparticle (metals, non-metals, metal oxides, and polymeric moieties) holds the promise of providing superior functionality to the composite material with applications in diverse fields, including catalysis, electronics, bio-sensing, drug delivery, nano-medicine, and environmental remediation. This mixing may result in a synergistic property enhancement of each component: for example, the mechanical strength of the hydrogel and concomitantly decrease aggregation of the nanoparticles. These mutual benefits and the associated potential applications have seen a surge of interest in the past decade from multi-disciplinary research groups. Recent advances in nanoparticle hydrogel composites are herein reviewed with a focus on their synthesis, design, potential applications, and the inherent challenges accompanying these exciting materials. PMID- 27980901 TI - Growth of Ultrathin ZnCo2O4 Nanosheets on Reduced Graphene Oxide with Enhanced Lithium Storage Properties. AB - The growth of ultrathin ZnCo2O4 nanosheets on reduced graphene oxide (denoted as rGO/ZnCo2O4) via a facile low-temperature solution method combined with a subsequent annealing treatment is reported. With the assistance of citrate, interconnected ZnCo2O4 nanosheets can assemble into hierarchically porous overlays on both sides of rGO sheets. Such a hybrid nanostructure would effectively faciliate the charge transport and accommodate volume variation upon prolonged charge/discharge cycling for reversible lithium storage. As a result, the rGO/ZnCo2O4 nanocomposite manifests a very stable high reversible capacity of around 960 mAh g-1 over 100 cycles at a low current density of 90 mA g-1 and excellent rate capability. PMID- 27980902 TI - Paper-Based N-Doped Carbon Films for Enhanced Oxygen Evolution Electrocatalysis. AB - Cellulous-fiber papers are used as 3D structural templates for the assembly of graphene and graphitic carbon nitrate (g-C3N4) ultrathin nanosheets. The resultant materials, which possess highly active centers, rich porosity, and 3D conductive networks, can catalyze the oxygen evolution reaction with competitive activity and much better durability compared to the benchmark noble metal electrocatalysts (IrO2). PMID- 27980903 TI - Phosphorus-Graphene Nanosheet Hybrids as Lithium-Ion Anode with Exceptional High Temperature Cycling Stability. AB - A red phosphorus-graphene nanosheet hybrid is reported as an anode material for lithium-ion batteries. Graphene nanosheets form a sea-like, highly electronically conductive matrix, where the island-like phosphorus particles are dispersed. Benefiting from this structure and properties of phosphorus, the hybrid delivers high initial capacity and exhibits promising retention at 60 degrees C. PMID- 27980904 TI - Virus Nanoparticles Mediated Osteogenic Differentiation of Bone Derived Mesenchymal Stem Cells. AB - There are few methodologies that allow manipulating a biomaterial surface at nanometer scale, which controllably influence different cellular functions. In this study, virus nanoparticles with different structural features are selected to prepare 2D substrates with defined nanoscale topographies and the cellular responses are investigated. It is demonstrated that the viral nanoparticle based substrates could accelerate and enhance osteogenesis of bone derived mesenchymal stem cells as indicated by the upregulation of osteogenic markers, including bone morphogenetic protein-2, osteocalcin, and osteopontin, at both gene and protein expression levels. Moreover, alkaline phosphatase activity and calcium mineralization, both indicators for a -successful bone formation, are also increased in cells grown on these nanoscale possessed substrates. These discoveries and developments present a new paradigm for nanoscale engineering of a biomaterial surface. PMID- 27980905 TI - Ultrafast Charge Dynamics in Trap-Free and Surface-Trapping Colloidal Quantum Dots. AB - Ultrafast transient absorption spectroscopy is used to study subnanosecond charge dynamics in CdTe colloidal quantum dots. After treatment with chloride ions, these can become free of surface traps that produce nonradiative recombination. A comparison between these dots and the same dots before treatment enables new insights into the effect of surface trapping on ultrafast charge dynamics. The surface traps typically increase the rate of electron cooling by 70% and introduce a recombination pathway that depopulates the conduction band minimum of single excitons on a subnanosecond timescale, regardless of whether the sample is stirred or flowed. It is also shown that surface trapping significantly reduces the peak bleach obtained for a particular pump fluence, which has important implications for the interpretation of transient absorption data, including the estimation of absorption cross-sections and multiple exciton generation yields. PMID- 27980906 TI - A Phosphorescent Iridium(III) Complex-Modified Nanoprobe for Hypoxia Bioimaging Via Time-Resolved Luminescence Microscopy. AB - Oxygen plays a crucial role in many biological processes. Accurate monitoring of oxygen level is important for diagnosis and treatment of diseases. Autofluorescence is an unavoidable interference in luminescent bioimaging, so that an amount of research work has been devoted to reducing background autofluorescence. Herein, a phosphorescent iridium(III) complex-modified nanoprobe is developed, which can monitor oxygen concentration and also reduce autofluorescence under both downconversion and upconversion channels. The nanoprobe is designed based on the mesoporous silica coated lanthanide-doped upconversion nanoparticles, which contains oxygen-sensitive iridium(III) complex in the outer silica shell. To image intracellular hypoxia without the interferences of autofluorescence, time-resolved luminescent imaging technology and near-infrared light excitation, both of which can reduce autofluorescence effectively, are adopted in this work. Moreover, gradient O2 concentration can be detected clearly through confocal microscopy luminescence intensity imaging, phosphorescence lifetime imaging microscopy, and time-gated imaging, which is meaningful to oxygen sensing in tissues with nonuniform oxygen distribution. PMID- 27980907 TI - Controlled Synthesis of Ultrathin Sb2Se3 Nanowires and Application for Flexible Photodetectors. AB - A new solvothermal approach is introduced to synthesize ultrathin Sb2Se3 nanowires with diameters ranging from 10 to 20 nm and with length up to 30 MUm. The Sb2Se3 nanowire-based photodetectors are firstly fabricated on polyethylene terephthalate and printing paper substrates, which exhibit excellent response to visible light with fast response time (0.18 and 0.22 s), high flexibility, and durability. PMID- 27980908 TI - Improved Voltage and Cycling for Li+ Intercalation in High-Capacity Disordered Oxyfluoride Cathodes. AB - New high-capacity intercalation cathodes of Li2V x Cr1-x O2F with a stable disordered rock salt host framework allow a high operating voltage up to 3.5 V, good rate performance (960 Wh kg-1 at ~1 C), and cycling stability. PMID- 27980910 TI - High-Throughput Contact Flow Lithography. AB - High-throughput fabrication of graphically encoded hydrogel microparticles is achieved by combining flow contact lithography in a multichannel microfluidic device and a high capacity 25 mm LED UV source. Production rates of chemically homogeneous particles are improved by two orders of magnitude. Additionally, the custom-built contact lithography instrument provides an affordable solution for patterning complex microstructures on surfaces. PMID- 27980909 TI - Facet-Controlled Synthetic Strategy of Cu2O-Based Crystals for Catalysis and Sensing. AB - Shape-dependent catalysis and sensing behaviours are primarily focused on nanocrystals enclosed by low-index facets, especially the three basic facets ({100}, {111}, and {110}). Several novel strategies have recently exploded by tailoring the original nanocrystals to greatly improve the catalysis and sensing performances. In this Review, we firstly introduce the synthesis of a variety of Cu2O nanocrystals, including the three basic Cu2O nanocrystals (cubes, octahedra and rhombic dodecahedra, enclosed by the {100}, {111}, and {110} facets, respectively), and Cu2O nanocrystals enclosed by high-index planes. We then discuss in detail the three main facet-controlled synthetic strategies (deposition, etching and templating) to fabricate Cu2O-based nanocrystals with heterogeneous, etched, or hollow structures, including a number of important concepts involved in those facet-controlled routes, such as the selective adsorption of capping agents for protecting special facets, and the impacts of surface energy and active sites on reaction activity trends. Finally, we highlight the facet-dependent properties of the Cu2O and Cu2O-based nanocrystals for applications in photocatalysis, gas catalysis, organocatalysis and sensing, as well as the relationship between their structures and properties. We also summarize and comment upon future facet-related directions. PMID- 27980911 TI - Recent Progress in Electronic Skin. AB - The skin is the largest organ of the human body and can sense pressure, temperature, and other complex environmental stimuli or conditions. The mimicry of human skin's sensory ability via electronics is a topic of innovative research that could find broad applications in robotics, artificial intelligence, and human-machine interfaces, all of which promote the development of electronic skin (e-skin). To imitate tactile sensing via e-skins, flexible and stretchable pressure sensor arrays are constructed based on different transduction mechanisms and structural designs. These arrays can map pressure with high resolution and rapid response beyond that of human perception. Multi-modal force sensing, temperature, and humidity detection, as well as self-healing abilities are also exploited for multi-functional e-skins. Other recent progress in this field includes the integration with high-density flexible circuits for signal processing, the combination with wireless technology for convenient sensing and energy/data transfer, and the development of self-powered e-skins. Future opportunities lie in the fabrication of highly intelligent e-skins that can sense and respond to variations in the external environment. The rapidly increasing innovations in this area will be important to the scientific community and to the future of human life. PMID- 27980912 TI - Triple Negative Breast Cancer: Nanosolutions for a Big Challenge. AB - Triple negative breast cancer (TNBC) is a particular immunopathological subtype of breast cancer that lacks expression of estrogen and progesterone receptors (ER/PR) and amplification of the human epidermal growth factor receptor 2 (HER2) gene. Characterized by aggressive and metastatic phenotypes and high rates of relapse, TNBC is the only breast cancer subgroup still lacking effective therapeutic options, thus presenting the worst prognosis. The development of targeted therapies, as well as early diagnosis methods, is vital to ensure an adequate and timely therapeutic intervention in patients with TNBC. This review intends to discuss potentially emerging approaches for the diagnosis and treatment of TNBC patients, with a special focus on nano-based solutions that actively target these particular tumors. PMID- 27980913 TI - Polymer-Coated Metal-Oxide Nanoparticles Inhibit IgE Receptor Binding, Cellular Signaling, and Degranulation in a Mast Cell-like Cell Line. AB - Previous reports have shown that nanoparticles (NPs) can both enhance and suppress immune effector functions; however the mechanisms that dictate these responses are still unclear. Here, the effects of polyacrylic acid (PAA) functionalized metal-oxide NP are investigated on RBL-2H3 (representative mammalian granulocyte-like cell line) cell viability, cellular degranulation, immunoglobulin E (IgE) receptor binding, and cell signaling pathways related to immune function. The increasing development of PAA-NPs as pesticide dispersants and as drug carriers in therapeutics necessitates their investigation for safe production. Using two in vitro experimental approaches, this study demonstrates that pre-exposing RBL-2H3 cells, or IgE antibodies, to PAA-NPs (TiO2, CeO2, ZnO, Fe2O3, and PAA-Capsules (NP coating control) over 24 h, significantly decrease the binding capacity of IgE for Fcepsilon receptors, inhibit the phosphorylation of intracellular signaling proteins (e.g., MAPK ERK) that mediate degranulation, and inhibited RBL-2H3 cell degranulation. In addition, and unlike the other NPs tested, PAA-TiO2 significantly reduced RBL-2H3 viability, in a time (4-24 h) and dose-dependent manner (>50 MUg mL-1). Together, these data demonstrate that PAA NPs at sub-lethal doses can interact with cell surface structures, such as receptors, to suppress various stages of the RBL-2H3 degranulatory response to external stimuli, and modify immune cell functions that can impact host-immunity. PMID- 27980915 TI - "H"-like Organic Nanowire Heterojunctions Constructed from Cooperative Molecular Assembly for Photonic Applications. AB - "H"-like organic nanowire heterojunctions with two parallel 2-acetyl-6 dimethylamino-naphthalene wires vertically bridged by one 2,4,5 triphenylimidazole wire are prepared via cooperative molecular assembly in liquid phase. The exciton conversion at the junction interfaces is beneficial for the design of multichannel light-controlled photo-switches. The results provide better understanding of molecular assembly toward specific structures and open up new prospects for the creation of novel photonic materials. PMID- 27980914 TI - Rational Design of Materials Interface for Efficient Capture of Circulating Tumor Cells. AB - Originating from primary tumors and penetrating into blood circulation, circulating tumor cells (CTCs) play a vital role in understanding the biology of metastasis and have great potential for early cancer diagnosis, prognosis and personalized therapy. By exploiting the specific biophysical and biochemical properties of CTCs, various material interfaces have been developed for the capture and detection of CTCs from blood. However, due to the extremely low number of CTCs in peripheral blood, there exists a need to improve the efficiency and specificity of the CTC capture and detection. In this regard, a critical review of the numerous reports of advanced platforms for highly efficient and selective capture of CTCs, which have been spurred by recent advances in nanotechnology and microfabrication, is essential. This review gives an overview of unique biophysical and biochemical properties of CTCs, followed by a summary of the key material interfaces recently developed for improved CTC capture and detection, with focus on the use of microfluidics, nanostructured substrates, and miniaturized nuclear magnetic resonance-based systems. Challenges and future perspectives in the design of material interfaces for capture and detection of CTCs in clinical applications are also discussed. PMID- 27980917 TI - Surface Activation of Faceted Photocatalyst: When Metal Cocatalyst Determines the Nature of the Facets. AB - Pt nanoparticles with tunable size are prepared on the entire surface of facet engineered Cu2WS4 decahedral photocatalyst via a kinetic-controlled chemical reduction process. The {101} facets of the photocatalyst which featured photo oxidation, are successfully activated for photoreduction by Pt. The resulting photocatalyst shows an activity nine times higher compared to that of the only {001}-facets activated catalyst obtained by a conventional in situ photodeposition route. PMID- 27980916 TI - Self-Assembled Soft Nanomaterials Via Silver(I)-Coordination: Nanotube, Nanofiber, and Remarkably Enhanced Antibacterial Effect. AB - Silver(I)-induced instant gelation of pyridine-containing Fmoc-l-glutamate and its concentration-dependent self-assembly from nanotubes to nanofibers are investigated. The formed metallogel with nanostructure has remarkably enhanced antibacterial activities. Interestingly, the nanotube and nanofiber exhibit different antibacterial activities, and a corresponding antimicrobial mechanism is proposed. PMID- 27980918 TI - Nanochannel Electroporation as a Platform for Living Cell Interrogation in Acute Myeloid Leukemia. AB - A living cell interrogation platform based on nanochannel electroporation is demonstrated with analysis of RNAs in single cells. This minimally invasive process is based on individual cells and allows both multi-target analysis and stimulus-response analysis by sequential deliveries. The unique platform possesses a great potential to the comprehensive and lysis-free nucleic acid analysis on rare or hard-to-transfect cells. PMID- 27980919 TI - Ultra-Efficient Photocatalytic Properties in Porous Tungsten Oxide/Graphene Film under Visible Light Irradiation. AB - Recently, a growing amount of effort has been devoted to solving the widespread problem of pollution. Photocatalysts have attracted increasing attention for their widespread environmental applications. Here, a classic and simple electrospun technique is used to directly fabricate a porous a tungsten oxide nanoframework with graphene film as a photocatalyst for degradation of pollutants. The as-synthesized film simultaneously possesses substantial adsorptivity of aromatic molecules, extensive light absorption range, significant light trapping, and efficient charge carrier separation properties, which remarkably enhance photocatalytic activity. In the photodegradation of Rhodamine B, a significant photocatalytic enhancement in the reaction rate is observed, which has superior photocatalytic activity compared to other bare WO3 and TiO2 nanomaterials under visible-light irradiation. PMID- 27980920 TI - Niobium Nitride Nb4N5 as a New High-Performance Electrode Material for Supercapacitors. AB - Supercapacitors suffer either from low capacitance for carbon or derivate electrodes or from poor electrical conductivity and electrochemical stability for metal oxide or conducting polymer electrodes. Transition metal nitrides possess fair electrical conductivity but superior chemical stability, which may be desirable candidates for supercapacitors. Herein, niobium nitride, Nb4N5, is explored to be an excellent capacitive material for the first time. An areal capacitance of 225.8 mF cm-2, with a reasonable rate capability (60.8% retention from 0.5 to 10 mA cm-2) and cycling stability (70.9% retention after 2000 cycles), is achieved in Nb4N5 nanochannels electrode with prominent electrical conductivity and electrochemical activity. Faradaic pseudocapacitance is confirmed by the mechanistic studies, deriving from the proton incorporation/chemisorption reaction owing to the copious +5 valence Nb ions in Nb4N5. Moreover, this Nb4N5 nanochannels electrode with an ultrathin carbon coating exhibits nearly 100% capacitance retention after 2000 CV cycles, which is an excellent cycling stability for metal nitride materials. Thus, the Nb4N5 nanochannels are qualified for a candidate for supercapacitors and other energy storage applications. PMID- 27980922 TI - A Highly Energetic N-Rich Zeolite-Like Metal-Organic Framework with Excellent Air Stability and Insensitivity. AB - A stable N-rich aromatic ligand is employed to prepare energetic zeolite-like metal-organic frameworks. IFMC-1 shows excellent air stability, and the lowest sensitivity toward impact, friction, and electrostatic discharge and the highest predicted heat of detonation among the reported coordination polymers, and even commercial materials (such as trinitrotoluene (TNT)). PMID- 27980921 TI - Au@CdS Core-Shell Nanoparticles-Modified ZnO Nanowires Photoanode for Efficient Photoelectrochemical Water Splitting. AB - Hydrogen production from water splitting using solar energy based on photoelectrochemical (PEC) cells has attracted increasing attention because it leaves less of a carbon footprint and has economic superiority of solar and hydrogen energy. Oxide semiconductors such as ZnO possessing high stability against photocorrosion in hole scavenger systems have been widely used to build photoanodes of PEC cells but under visible light their conversion efficiencies with respect to incident-photon-to-current conversion efficiency (IPCE) measured without external bias are still not satisfied. An innovative way is presented here to significantly improve the conversion efficiency of PEC cells by constructing a core-shell structure-based photoanode comprising Au@CdS core-shell nanoparticles on ZnO nanowires (Au@CdS-ZnO). The Au core offers strong electronic interactions with both CdS and ZnO resulting in a unique nanojunction to facilitate charge transfer. The Au@CdS-ZnO PEC cell under 400 nm light irradiation without any applied bias provides an IPCE of 14.8%. Under AM1.5 light illumination with a bias of 0.4 V, the Au@CdS-ZnO PEC cell produces H2 at a constant rate of 11.5 MUmol h-1 as long as 10 h. This work provides a fundamental insight to improve the conversion efficiency for visible light in water splitting. PMID- 27980923 TI - Graphene Oxide Wrapped Amorphous Copper Vanadium Oxide with Enhanced Capacitive Behavior for High-Rate and Long-Life Lithium-Ion Battery Anodes. AB - Graphene oxide-wrapped amorphous copper vanadium oxide is fabricated through a template-engaged redox reaction followed by vacuum dehydration. This material exhibits high reversible capacity, excellent rate capability, and out standing high-rate cyclability. The outstanding performance is attributed to the fast capacitive charge storage and the in situ formed copper with enhanced electrical conductivity. PMID- 27980924 TI - Pure Single-Crystalline Na1.1V3O7.9 Nanobelts as Superior Cathode Materials for Rechargeable Sodium-Ion Batteries. AB - Pure single-crystalline Na1.1V3O7.9 nanobelts are successfully synthesized for the first time via a facile yet effective strategy. When used as cathode materials for Na-ion batteries, the novel nanobelts exhibit excellent electrochemical performance. Given the ease and effectiveness of the synthesis route as well as the very promising electrochemical performance, the results obtained may be extended to other next-generation cathode materials for Na-ion batteries. PMID- 27980925 TI - Biomimicking Topographic Elastomeric Petals (E-Petals) for Omnidirectional Stretchable and Printable Electronics. AB - Elastomeric petals directly replicated from natural rose petal are new versatile substrates for stretchable and printable electronics. Compared with conventional flat polydimethylsiloxane substrates, elastomeric petals have biomimicking topographic surfaces that can effectively inhibit the propagation of microcracks formed in the conducting layer, which is deposited on top, regardless of the type of conductive materials and the deposition methods. PMID- 27980926 TI - Carbonaceous Dye-Sensitized Solar Cell Photoelectrodes. AB - High photovoltaic efficiency is one of the most important keys to the commercialization of dye sensitized solar cells (DSSCs) in the quickly growing renewable electricity generation market. The heart of the DSSC system is a wide bandgap semiconductor based photoelectrode film that helps to adsorb dye molecules and transport the injected electrons away into the electrical circuit. However, charge recombination, poor light harvesting efficiency and slow electron transport of the nanocrystalline oxide photoelectrode film are major issues in the DSSC's performance. Recently, semiconducting composites based on carbonaceous materials (carbon nanoparticles, carbon nanotubes (CNTs), and graphene) have been shown to be promising materials for the photoelectrode of DSSCs due to their fascinating properties and low cost. After a brief introduction to development of nanocrystalline oxide based films, this Review outlines advancements that have been achieved in the application of carbonaceous-based materials in the photoelectrode of DSSCs and how these advancements have improved performance. In addition, several of the unsolved issues in this research area are discussed and some important future directions are also highlighted. PMID- 27980927 TI - An Amine-Functionalized Iron(III) Metal-Organic Framework as Efficient Visible Light Photocatalyst for Cr(VI) Reduction. AB - The photocatalytic reduction of Cr(VI) is investigated over iron(III)-based metal organic frameworks (MOFs) structured as MIL-88B. It is found that MIL-88B (Fe) MOFs, containing Fe3-MU3-oxo clusters, can be used as photocatalyst for the reduction of Cr(VI) under visible light irradiation, which is due to the direct excitation of Fe3-MU3-oxo clusters. The amine-functionalized MIL-88B (Fe) MOFs (denoted as NH2-MIL-88B (Fe)) shows much higher efficiency for the photocatalytic Cr(VI) reduction under visible-light irradiation compared with MIL-88B (Fe). It is revealed that in addition to the direct excitation of Fe3-MU3-oxo clusters, the amine functionality in NH2-MIL-88B (Fe) can also be excited and then transferred an electron to Fe3-MU3-oxo clusters, which is responsible for the enhanced photocatalytic activity for Cr(VI) reduction. The enhanced photocatalytic activity for Cr(VI) reduction is also achieved for other two amine functionalized iron(III)-based MOFs (NH2-MIL-53 (Fe) and NH2-MIL-101 (Fe)). PMID- 27980929 TI - Scale-Up Synthesis of Fragrant Nitrogen-Doped Carbon Dots from Bee Pollens for Bioimaging and Catalysis. AB - Fragrant nitrogen-doped carbon dots of gram scale can be prepared from commercial bee pollens by a hydrothermal process. These carbon dots of 1-2 nm in size show promising applications in cellular imaging and catalysis/photocatalysis. PMID- 27980928 TI - Electron Transfer Proteins as Electronic Conductors: Significance of the Metal and Its Binding Site in the Blue Cu Protein, Azurin. AB - Electron transfer (ET) proteins are biomolecules with specific functions, selected by evolution. As such they are attractive candidates for use in potential bioelectronic devices. The blue copper protein azurin (Az) is one of the most-studied ET proteins. Traditional spectroscopic, electrochemical, and kinetic methods employed for studying ET to/from the protein's Cu ion have been complemented more recently by studies of electrical conduction through a monolayer of Az in the solid-state, sandwiched between electrodes. As the latter type of measurement does not require involvement of a redox process, it also allows monitoring electronic transport (ETp) via redox-inactive Az-derivatives. Here, results of macroscopic ETp via redox-active and -inactive Az derivatives, i.e., Cu(II) and Cu(I)-Az, apo-Az, Co(II)-Az, Ni(II)-Az, and Zn(II)-Az are reported and compared. It is found that earlier reported temperature independence of ETp via Cu(II)-Az (from 20 K until denaturation) is unique, as ETp via all other derivatives is thermally activated at temperatures >~200 K. Conduction via Cu(I)-Az shows unexpected temperature dependence >~200 K, with currents decreasing at positive and increasing at negative bias. Taking all the data together we find a clear compensation effect of Az conduction around the Az denaturation temperature. This compensation can be understood by viewing the Az binding site as an electron trap, unless occupied by Cu(II), as in the native protein, with conduction of the native protein setting the upper transport efficiency limit. PMID- 27980930 TI - MoS2 Nanosheet-Pd Nanoparticle Composite for Highly Sensitive Room Temperature Detection of Hydrogen. AB - Highly sensitive hydrogen detection at room temperature can be realized by employing solution-processed MoS2 nanosheet-Pd nanoparticle composite. A MoS2-Pd composite exhibits greater sensing performance than its graphene counterpart, indicating that solvent exfoliated MoS2 holds great promise for inexpensive and scalable fabrication of highly sensitive chemical sensors. PMID- 27980931 TI - A Temperature-Responsive Smart Europium Metal-Organic Framework Switch for Reversible Capture and Release of Intrinsic Eu3+ Ions. AB - Stimuli-responsive structural transformations are emerging as a scaffold to develop a charming class of smart materials. A EuL metal-organic framework (MOF) undergoes a reversible temperature-stimulated single-crystal to single-crystal transformation, showing a specific behavior of fast capture/release of free Eu3+ in the channels at low and room temperatures. At room temperature, compound 1a is obtained with one free carboxylate group severing as further hook, featuring one dimensional square channels filled with intrinsic free europium ions. Trigged by lowering the ambient temperature, 1b is gained. In 1b, the intrinsic free europium ions can be fast captured by the carboxylate-hooks anchored in the framework, resulting in the structural change and its channel distortion. To the best of our knowledge, this is the first report of such a rapid and reversible switch stemming from dynamic control between noncovalent and covalent Eu-ligand interactions. Utilizing EuL MOF to detect highly explosive 2,4,6-trinitrophenol at room temperature and low temperature provides a glimpse into the potential of this material in fluorescence sensors. PMID- 27980932 TI - A Tetraperylene Diimides Based 3D Nonfullerene Acceptor for Efficient Organic Photovoltaics. AB - A nonfullerene acceptor based on a 3D tetraperylene diimide is developed for bulk heterojunction organic photovoltaics. The disruption of perylene diimide planarity with a 3D framework suppresses the self-aggregation of perylene diimide and inhibits excimer formation. From planar monoperylene diimide to 3D tetraperylene diimide, a significant improvement of power conversion efficiency from 0.63% to 3.54% can be achieved. PMID- 27980933 TI - Linked-Acceptor Type Conjugated Polymer for High Performance Organic Photovoltaics with an Open-Circuit Voltage Exceeding 1 V. AB - A linked-acceptor type conjugated polymer is designed and sythesized based on 4,8 bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene (BDTT) and linked-thieno[3,4-c]pyrrole-4,6-dione (LTPD). This polymer uses alkyl-substituted thiophene as a bridge. The PBDTT-LTPD includes two TPD units in one repeating unit, which can enhance acceptor density in the polymer backbone and lower the highest occupied molecular orbital (HOMO) level. By contrast, variable alkyl substitutions in the thiophene-bridges ensure the subtle regulation of polymer properties. The solar cells based on PBDTT-LTPD display an open-circuit voltage (Voc) that exceeds 1 V, and a maximum power conversion efficiency (PCE) of 7.59% is obtained. This PCE value is the highest for conventional single-junction bulk heterojunction solar cells with Voc values of up to 1 V. Given that PBDTT-LTPD exhibits a low HOMO energy level and a band gap equivalent to that of poly(3 hexylthiophene), PBDTT-LTPD/phenyl-C61-butyric acid methyl ester may be a promising candidate for the front cell in tandem polymer solar cells. PMID- 27980934 TI - Far-Red/Near-Infrared Conjugated Polymer Nanoparticles for Long-Term In Situ Monitoring of Liver Tumor Growth. AB - The design and synthesis is reported for a fluorescent conjugated polymer (CP), poly{[4,4,9,9-tetrakis(4-(octyloxy)phenyl-4,9-dihydro-s-indaceno[1,2-b:5,6 b']dithiophene)]-alt-co-[4,7-di(thiophen-2-yl)-2,1,3-benzothiadiazole]} (PIDT DBT), with absorption and emission profiles fallen within far-red/near infrared (FR/NIR) region and further demonstrate its application in long-term in vitro cell tracing and in vivo imaging of liver tumor growth. PIDT-DBT-Tat nanoparticles (NPs) have an absorption maximum at ~600 nm with an emission maximum at ~720 nm in water. In vitro cell tracing studies reveal that PIDT-DBT Tat NPs can trace HepG2 liver cancer cells over 8 d. In vivo imaging results indicate that PIDT-DBT-Tat NPs can monitor liver tumor growth for more than 27 d in a real-time manner. Both in vitro and in vivo studies demonstrate that PIDT DBT-Tat NPs are superior to commercial Qtracker 705 as fluorescent probes. This study demonstrates for the first time the feasibility for long-term in vivo imaging of tumor growth by utilizing CP-based fluorescent probes, which will encourage the development of NIR fluorescent CPs for in vivo bioimaging. PMID- 27980935 TI - A Versatile Environmental Impedimetric Sensor for Ultrasensitive Determination of Persistent Organic Pollutants (POPs) and Highly Toxic Inorganic Ions. AB - An impedimetric sensor for persistent toxic substances, including organic pollutants and toxic inorganic ions is presented. The persistent toxic substances are detected using an ultrasensitive technique that is based on electron-transfer blockage. This depends on the formation of guest-host complexes, hydrogen bonding, or a cyclodextrin (CD)-metal complex (Mm(OH)n-beta-CD) structure between the target pollutants and beta-CD. PMID- 27980937 TI - High-Performance Organic Lithium Batteries with an Ether-Based Electrolyte and 9,10-Anthraquinone (AQ)/CMK-3 Cathode. AB - Organic carbonyl electrode materials of lithium batteries have shown multifunctional molecule design and high capacity, but have the problems of poor cycling and low rate performance due to their high solubility in traditional carbonate-based electrolytes and low conductivity. High-performance organic lithium batteries with modified ether-based electrolyte (2 m LiN(CF3SO2)2 in 1,3 dioxolane/dimethoxyethane solvent with 1% LiNO3 additive (2m-DD-1%L)) and 9,10 anthraquinone (AQ)/CMK-3 (AQC) nanocomposite cathode are reported here. The electrochemical results manifest that 2m-DD-1%L electrolyte promotes the cycling performance due to the restraint of AQ dissolution in ether-based electrolyte with high Li salt concentration and formation of a protection film on the surface of the anode. Additionally, the AQC nanocomposite improves the rate performance because of the nanoconfinement effect of CMK-3 and the decrease of charge transfer impedance. In 2m-DD-1%L electrolyte, AQC nanocomposite delivers an initial discharge capacity of 205 mA h g-1 and a capacity of 174 mA h g-1 after 100 cycles at 0.2 C. Even at a high rate of 2 C, its capacity is 146 mA h g-1. This strategy is also used for other organic carbonyl compounds with quinone substructures and they maintain high stable capacities. This sheds light on the development of advanced organic lithium batteries with carbonyl electrode materials and ether-based electrolytes. PMID- 27980936 TI - Light-Induced Switching of Tunable Single-Molecule Junctions. AB - A major goal of molecular electronics is the development and implementation of devices such as single-molecular switches. Here, measurements are presented that show the controlled in situ switching of diarylethene molecules from their nonconductive to conductive state in contact to gold nanoelectrodes via controlled light irradiation. Both the conductance and the quantum yield for switching of these molecules are within a range making the molecules suitable for actual devices. The conductance of the molecular junctions in the opened and closed states is characterized and the molecular level E0, which dominates the current transport in the closed state, and its level broadening Gamma are identified. The obtained results show a clear light-induced ring forming isomerization of the single-molecule junctions. Electron withdrawing side-groups lead to a reduction of conductance, but do not influence the efficiency of the switching mechanism. Quantum chemical calculations of the light-induced switching processes correlate these observations with the fundamentally different low-lying electronic states of the opened and closed forms and their comparably small modification by electron-withdrawing substituents. This full characterization of a molecular switch operated in a molecular junction is an important step toward the development of real molecular electronics devices. PMID- 27980938 TI - Unravelling the Role of Electrochemically Active FePO4 Coating by Atomic Layer Deposition for Increased High-Voltage Stability of LiNi0.5Mn1.5O4 Cathode Material. AB - Ultrathin amorphous FePO4 coating derived by atomic layer deposition (ALD) is used to coat the 5 V LiNi0.5Mn1.5O4 cathode material powders, which dramatically increases the capacity retention of LiNi0.5Mn1.5O4. It is believed that the amorphous FePO4 layer could act as a lithium-ions reservoir and electrochemically active buffer layer during the charge/discharge cycling, helping achieve high capacities in LiNi0.5Mn1.5O4, especially at high current densities. PMID- 27980939 TI - Switching Dielectric Constant Near Room Temperature in a Molecular Crystal. AB - The organic salt bis(2-chloroethyl)amine hydrochloride shows a sharp switching of its dielectric constant at 320 K. The switching property originates from the dynamic changes of the (2-chloroethyl)ammonium cation between frozen and motional states, corresponding to a structural phase transition. PMID- 27980940 TI - Ultralong Durability of Porous alpha-Fe2O3 Nanofibers in Practical Li-Ion Configuration with LiMn2O4 Cathode. AB - Prelithiated, electrospun alpha-Fe2O3 nanofibers display an exceptional cycleability when it is paired with commercial LiMn2O4 cathode in full-cell assembly. The performance of such alpha-Fe2O3 nanofibers is mainly due to the presence of unique morphology with porous structure, appropriate mass balance, and working potential. Also, synthesis technique cannot be ruled out for the performance. PMID- 27980941 TI - Implementation of Arithmetic Functions on a Simple and Universal Molecular Beacon Platform. AB - Diverse advanced logic circuits are fabricated to implement arithmetic functions based on a simple and single molecular beacon platform, including half adder, half subtractor, full adder, full subtractor, and a digital comparator. Dual fluorescence outputs are generated in parallel and a constant threshold value is set to build all the logic circuits. The developed enzyme-free DNA system provides a novel prototype for the design of high-level molecular logic circuits on a biomolecular platform. PMID- 27980942 TI - Toward High-Efficiency Solution-Processed Planar Heterojunction Sb2S3 Solar Cells. AB - Low-cost hybrid solar cells have made tremendous steps forward during the past decade owing to the implementation of extremely thin inorganic coatings as absorber layers, typically in combination with organic hole transporters. Using only extremely thin films of these absorbers reduces the requirement of single crystalline high-quality materials and paves the way for low-cost solution processing compatible with roll-to-roll fabrication processes. To date, the most efficient absorber material, except for the recently introduced organic-inorganic lead halide perovskites, has been Sb2S3, which can be implemented in hybrid photovoltaics using a simple chemical bath deposition. Current high-efficiency Sb2S3 devices utilize absorber coatings on nanostructured TiO2 electrodes in combination with polymeric hole transporters. This geometry has so far been the state of the art, even though flat junction devices would be conceptually simpler with the additional potential of higher open circuit voltages due to reduced charge carrier recombination. Besides, the role of the hole transporter is not completely clarified yet. In particular, additional photocurrent contribution from the polymers has not been directly shown, which points toward detrimental parasitic light absorption in the polymers. This study presents a fine-tuned chemical bath deposition method that allows fabricating solution-processed low cost flat junction Sb2S3 solar cells with the highest open circuit voltage reported so far for chemical bath devices and efficiencies exceeding 4%. Characterization of back-illuminated solar cells in combination with transfer matrix-based simulations further allows to address the issue of absorption losses in the hole transport material and outline a pathway toward more efficient future devices. PMID- 27980943 TI - On-Chip Micro-Pseudocapacitors for Ultrahigh Energy and Power Delivery. AB - Microscale supercapapcitors based on hierarchical nanoporous hybrid electrodes consisting of 3D bicontinuous nanoporous gold and pseudocapacitive manganese oxide deliver an excellent stack capacitance of 99.1 F cm-3 and a high energy density of 12.7 mW h cm-3 with a retained high power density of 46.6 W cm-3. PMID- 27980944 TI - Model Membrane-Free Li-S Batteries for Enhanced Performance and Cycle Life. AB - The success of the rechargeable Li-S cell is limited in part by the dissolution of lithium-polysulfide in the electrolyte. Remarkably, it is found that removal of the conventional membrane separator in a Li-S cell improves sulfur utilization and cycling performance, whether the sulfur is initially contained in the cathode or electrolyte. An optimized cell design yields discharge capacities as high as 980 mA h g-1 after 100 cycles. PMID- 27980945 TI - Multifunctional Hydrogels with Reversible 3D Ordered Macroporous Structures. AB - Three-dimensionally ordered macroporous (3DOM) hydrogels prepared by colloidal crystals templating display highly reversible shape memory properties, as confirmed by indirect electron microscopy imaging of their inverse replicas and direct nanoscale resolution X-ray microscopy imaging of the hydrated hydrogels. Modifications of functional groups in the 3DOM hydrogels result in various materials with programmed properties for a wide range of applications. PMID- 27980946 TI - ZT > 0.1 Electron-Carrying Polymer Thermoelectric Composites with In Situ SnCl2 Microstructure Growth. AB - An n-type pyromellitic diimide polymer composite with in situ microstructure growth of the common element compound SnCl2 reaches power factor of 50-100 MUW m 1 K-2, the highest purely n-type polymer composite power factor yet reported. The composite has a gigantic Seebeck coefficient between -4000 and -5000 MUV K-1, many times higher than other polymer composites. PMID- 27980948 TI - Interface Design Principles for High-Performance Organic Semiconductor Devices. AB - Precise manipulation of organic donor-acceptor interfaces using spacer layers is demonstrated to suppress interface recombination in an organic photo-voltaic device. These strategies lead to a dramatic improvement in a model bilayer system and bulk-heterojunction system. These interface strategies are applicable to a wide variety of donor-acceptor systems, making them both fundamentally interesting and technologically relevant for achieving high efficiency organic electronic devices. PMID- 27980947 TI - Ultrathin Single-Crystalline Boron Nanosheets for Enhanced Electro-Optical Performances. AB - Large-scale single-crystalline ultrathin boron nanosheets (UBNSs, ~10 nm) are fabricated through an effective vapor-solid process via thermal decomposition of diborane. The UBNSs have obvious advantages over thicker boron nanomaterials in many aspects. Specifically, the UBNSs demonstrate excellent field emission performances with a low turn-on field, Eto, of 3.60 V MUm-1 and a good stability. Further, the dependence of (turn-on field) Eto/(threshold field) Ethr and effective work function, Phie, on temperature is investigated and the possible mechanism of temperature-dependent field emission phenomenon has been discussed. Moreover, electronic transport in a single UBNS reveals it to be an intrinsic p type semiconductor behavior with carrier mobility about 1.26 * 10-1 cm2 V-1 s-1, which is the best data in reported works. Interestingly, a multiconductive mechanism coexisting phenomenon has been explored based on the study of temperature-dependent conductivity behavior of the UBNSs. Besides, the photodetector device fabricated from single-crystalline UBNS demonstrates good sensitivity, reliable stability, and fast response, obviously superior to other reported boron nanomaterials. Such superior electronic-optical performances are originated from the high quality of single crystal and large specific surface area of the UBNSs, suggesting the potential applications of the UBNSs in field emitters, interconnects, integrated circuits, and optoelectronic devices. PMID- 27980949 TI - Inkjet-Printed Cu2ZnSn(S, Se)4 Solar Cells. AB - Cu2ZnSn(S, Se)4-based solar cells with total area (0.5 cm2) power conversion efficiency of 6.4% are demonstrated from thin film absorbers processed by inkjet printing technology of Cu-Zn-Sn-S precursor ink followed by selenization. The device performance is limited by the low fill factor, which is due to the high series resistance. PMID- 27980950 TI - Air-Stable Copper-Based P2-Na7/9Cu2/9Fe1/9Mn2/3O2 as a New Positive Electrode Material for Sodium-Ion Batteries. AB - An air-stable copper-based P2-Na7/9Cu2/9Fe1/9Mn2/3O2 is designed and synthesized by a simple solid-state method and investigated as a positive electrode material for sodium-ion batteries. The attractive long cycling stability is demonstrated by the capacity retention of 85% after 150 cycles at 1 C rate without phase transformation. The reversible Cu2+/Cu3+ redox couple in P2 phase oxides is proved for the first time. PMID- 27980951 TI - Type I Clathrates as Novel Silicon Anodes: An Electrochemical and Structural Investigation. AB - Silicon clathrates contain cage-like structures that can encapsulate various guest atoms or molecules. An electrochemical evaluation of type I silicon clathrates based on Ba8Al y Si46-y as the anode material for lithium-ion batteries is presented here. Postcycling characterization with nuclear magnetic resonance and X-ray diffraction shows no discernible structural or volume changes even after electrochemical insertion of 44 Li (~1 Li/Si) into the clathrate structure. The observed properties are in stark contrast with lithiation of other silicon anodes, which become amorphous and suffer from large volume changes. The electrochemical reactions are proposed to occur as single phase reactions at approximately 0.2 and 0.4 V versus Li/Li+ during lithiation and delithiation, respectively, distinct from diamond cubic or amorphous silicon anodes. Reversible capacities as high as 499 mAh g-1 at a 5 mA g-1 rate were observed for silicon clathrate with composition Ba8Al8.54Si37.46, corresponding to ~1.18 Li/Si. These results show that silicon clathrates could be promising durable anodes for lithium-ion batteries. PMID- 27980953 TI - A Bioinspired Swimming and Walking Hydrogel Driven by Light-Controlled Local Density. AB - A hydrogel exhibits a real-time depth-controllable swimming motion via light mediated modulation of local density to mimic the volume changes found in the bladders of fish. Moreover, other motions, e.g., rolling, somersaulting, and bipedal-like walking, can also be realized by designing or combining gel shapes, and the location of light. PMID- 27980952 TI - Enhanced Ion Current Rectification in 2D Graphene-Based Nanofluidic Devices. AB - Furthering the promise of graphene-based planar nanofluidic devices as flexible, robust, low cost, and facile large-scale alternatives to conventional nanochannels for ion transport, we show how the nonlinear current-voltage (I-V) characteristics and ion current rectification in these platforms can be enhanced by increasing the system asymmetry. Asymmetric cuts made to the 2D multilayered graphene oxide film, for example, introduces further asymmetry to that natively inherent in the structurally symmetric system, which was recently shown to be responsible for its rectification behavior due to diffusion boundary layer fore aft asymmetry. Supported by good agreement with theory, we attribute the enhancement to the decrease in the limiting current in the positive bias state in which counter-ion trapping occurs within the negatively charged graphene oxide sheets due to increased film permselectivity as its cross-section and surface charge distribution is altered on one end; these effects being shown to be sensitive to the electrolyte pH. Further, we show that an imbalance in the pH or concentration in the microreservoirs flanking the film can also increase asymmetry and hence rectification, in addition to displaying a host of other phenomena associated with the I-V characteristics of typical nanochannel electrokinetic systems. PMID- 27980954 TI - Roll-Coated Fabrication of Fullerene-Free Organic Solar Cells with Improved Stability. AB - Large area, fullerene-free organic solar cells with improved stability and efficiency of up to 1% are fabricated by the roll-coating process on indium tin oxide free and flexible substrates, under ambient conditions. PMID- 27980956 TI - Magnetic, Fluorescent, and Copolymeric Silicone Microspheres. AB - Silicone microspheres are exceedingly difficult to make. Here, polydimethylsiloxane microspheres (~1 MUm diameter) are synthesized using ultrasonic spray pyrolysis, the first demonstration of a scalable synthetic procedure for crosslinked silicone microspheres. This continuous, aerosol process is also used to directly produce fluorescent, magnetic, and copolymeric derivatives; the potential biomedical applications of these microspheres are explored. PMID- 27980955 TI - Single-Crystalline Rhodium Nanosheets with Atomic Thickness. AB - CO confinement strategy for ultrathin Rh nanosheets: CO is introduced as a confining agent to regulate the anisotropic growth of unique 2D structure. The single-crystalline Rh nanosheets have a thickness of three to five atomic layers and tunable edge length ranging from 500 to 1300 nm. By understanding the formation mechanism, surface-clean Rh nanosheets are also prepared and display better catalytic performance that their surfactant-capped nanosheets. PMID- 27980957 TI - Selectable Nanopattern Arrays for Nanolithographic Imprint and Etch-Mask Applications. AB - A parallel nanolithographic patterning method is presented that can be used to obtain arrays of multifunctional nanoparticles. These patterns can simply be converted into a variety of secondary nanopatterns that are useful for nanolithographic imprint, plasmonic, and etch-mask applications. PMID- 27980958 TI - Biomimetic "Cactus Spine" with Hierarchical Groove Structure for Efficient Fog Collection. AB - A biomimetic "cactus spine" with hierarchical groovestructure is designed and fabricated using simple electrospinning. This novel artificial cactus spine possesses excellent fog collection and water transportation ability. A model cactus equipped with artificial spines also shows a great water storage capacity. The results can be helpful in the development of water collectors and may make a contribution to the world water crisis. PMID- 27980959 TI - Achieving Highly Efficient Photoelectrochemical Water Oxidation with a TiCl4 Treated 3D Antimony-Doped SnO2 Macropore/Branched alpha-Fe2O3 Nanorod Heterojunction Photoanode. AB - Utilizing photoelectrochemical (PEC) cells to directly collecting solar energy into chemical fuels (e.g., H2 via water splitting) is a promising way to tackle the energy challenge. alpha-Fe2O3 has emerged as a desirable photoanode material in a PEC cell due to its wide spectrum absorption range, chemical stability, and earth abundant component. However, the short excited state lifetime, poor minority charge carrier mobility, and long light penetration depth hamper its application. Recently, the elegantly designed hierarchical macroporous composite nanomaterial has emerged as a strong candidate for photoelectrical applications. Here, a novel 3D antimony-doped SnO2 (ATO) macroporous structure is demonstrated as a transparent conducting scaffold to load 1D hematite nanorod to form a composite material for efficient PEC water splitting. An enormous enhancement in PEC performance is found in the 3D electrode compared to the controlled planar one, due to the outstanding light harvesting and charge transport. A facile and simple TiCl4 treatment further introduces the Ti doping into the hematite while simultaneously forming a passivation layer to eliminate adverse reactions. The results indicate that the structural design and nanoengineering are an effective strategy to boost the PEC performance in order to bring more potential devices into practical use. PMID- 27980961 TI - Tailored Near-Infrared Photoemission in Fluoride Perovskites through Activator Aggregation and Super-Exchange between Divalent Manganese Ions. AB - Biomedical imaging and labeling through luminescence microscopy requires materials that are active in the near-infrared spectral range, i.e., within the transparency window of biological tissue. For this purpose, tailoring of Mn2+ Mn2+ activator aggregation is demonstrated within the ABF3 fluoride perovskites. Such tailoring promotes distinct near-infrared photoluminescence through antiferromagnetic super-exchange across effective dimers. The crossover dopant concentrations for the occurrence of Mn2+ interaction within the first and second coordination shells comply well with experimental observations of concentration quenching of photoluminescence from isolated Mn2+ and from Mn2+-Mn2+ effective dimers, respectively. Tailoring of this procedure is achieved via adjusting the Mn-F-Mn angle and the Mn-F distance through substitution of the A+ and/or the B2+ species in the ABF3 compound. Computational simulation and X-ray absorption spectroscopy are employed to confirm this. The principle is applied to produce pure anti-Stokes near-infrared emission within the spectral range of ~760-830 nm from codoped ABF3:Yb3+,Mn2+ upon excitation with a 976 nm laser diode, challenging the classical viewpoint where Mn2+ is used only for visible photoluminescence: in the present case, intense and tunable near-infrared emission is generated. This approach is highly promising for future applications in biomedical imaging and labeling. PMID- 27980962 TI - Understanding Strain-Induced Phase Transformations in BiFeO3 Thin Films. AB - Experiments demonstrate that under large epitaxial strain a coexisting striped phase emerges in BiFeO3 thin films, which comprises a tetragonal-like (T') and an intermediate S' polymorph. It exhibits a relatively large piezoelectric response when switching between the coexisting phase and a uniform T' phase. This strain induced phase transformation is investigated through a synergistic combination of first-principles theory and experiments. The results show that the S' phase is energetically very close to the T' phase, but is structurally similar to the bulk rhombohedral (R) phase. By fully characterizing the intermediate S' polymorph, it is demonstrated that the flat energy landscape resulting in the absence of an energy barrier between the T' and S' phases fosters the above-mentioned reversible phase transformation. This ability to readily transform between the S' and T' polymorphs, which have very different octahedral rotation patterns and c/a ratios, is crucial to the enhanced piezoelectricity in strained BiFeO3 films. Additionally, a blueshift in the band gap when moving from R to S' to T' is observed. These results emphasize the importance of strain engineering for tuning electromechanical responses or, creating unique energy harvesting photonic structures, in oxide thin film architectures. PMID- 27980960 TI - Face the Edges: Catalytic Active Sites of Nanomaterials. AB - Edges are special sites in nanomaterials. The atoms residing on the edges have different environments compared to those in other parts of a nanomaterial and, therefore, they may have different properties. Here, recent progress in nanomaterial fields is summarized from the viewpoint of the edges. Typically, edge sites in MoS2 or metals, other than surface atoms, can perform as active centers for catalytic reactions, so the method to enhance performance lies in the optimization of the edge structures. The edges of multicomponent interfaces present even more possibilities to enhance the activities of nanomaterials. Nanoframes and ultrathin nanowires have similarities to conventional edges of nanoparticles, the application of which as catalysts can help to reduce the use of costly materials. Looking beyond this, the edge structures of graphene are also essential for their properties. In short, the edge structure can influence many properties of materials. PMID- 27980963 TI - Biofunctionalized Nanostructured Zirconia for Biomedical Application: A Smart Approach for Oral Cancer Detection. AB - Results of the studies are reported relating to application of the silanized nanostructured zirconia, electrophoretically deposited onto indium tin oxide (ITO) coated glass for covalent immobilization of the monoclonal antibodies (anti CYFRA-21-1). This biosensing platform has been utilized for a simple, efficient, noninvasive, and label-free detection of oral cancer via cyclic voltammetry technique. The results of electrochemical response studies conducted on bovine serum albumin (BSA)/anti-CYFRA-21-1/3-aminopropyl triethoxy silane (APTES)/ZrO2/ITO immunoelectrode reveal that this immunoelectrode can be used to measure CYFRA-21-1 (oral cancer biomarker) concentration in saliva samples, with a high sensitivity of 2.2 mA mL ng-1, a linear detection range of 2-16 ng mL-1, and stability of six weeks. The results of these studies have been validated via enzyme-linked immunosorbent assay. PMID- 27980964 TI - Leaf-Like Graphene-Oxide-Wrapped Sulfur for High-Performance Lithium-Sulfur Battery. AB - Carbon/sulfur composites are attracting extensive attention because of their improved performances for Li-S batteries. However, the achievements are generally based on the low S-content in the composites and the low S-loading on the electrode. Herein, a leaf-like graphene oxide (GO), which includes an inherent carbon nanotube midrib in the GO plane, is synthesized for preparing GO/S composites. Owing to the inherent high conductivity of carbon nanotube midribs and the abundant surface groups of GO for S-immobilization, the composite with an S-content of 60 wt% exhibits ultralong cycling stability over 1000 times with a low capacity decay of 0.033% per cycle and a high rate up to 4C. When the S content is increased to 75 wt%, the composite still shows a perfect cycling performance over 1000 cycles. Even with the high S-loading of 2.7 mg cm-2 on the electrode and the high S-content of 85 wt%, it still shows a promising cycling performance over 600 cycles. PMID- 27980965 TI - Intercalation and Push-Out Process with Spinel-to-Rocksalt Transition on Mg Insertion into Spinel Oxides in Magnesium Batteries. AB - On the basis of the similarity between spinel and rocksalt structures, it is shown that some spinel oxides (e.g., MgCo2O4, etc) can be cathode materials for Mg rechargeable batteries around 150 degrees C. The Mg insertion into spinel lattices occurs via "intercalation and push-out" process to form a rocksalt phase in the spinel mother phase. For example, by utilizing the valence change from Co(III) to Co(II) in MgCo2O4, Mg insertion occurs at a considerably high potential of about 2.9 V vs. Mg2+/Mg, and similarly it occurs around 2.3 V vs. Mg2+/Mg with the valence change from Mn(III) to Mn(II) in MgMn2O4, being comparable to the ab initio calculation. The feasibility of Mg insertion would depend on the phase stability of the counterpart rocksalt XO of MgO in Mg2X2O4 or MgX3O4 (X = Co, Fe, Mn, and Cr). In addition, the normal spinel MgMn2O4 and MgCr2O4 can be demagnesiated to some extent owing to the robust host structure of Mg1-xX2O4, where the Mg extraction/insertion potentials for MgMn2O4 and MgCr2O4 are both about 3.4 V vs. Mg2+/Mg. Especially, the former "intercalation and push out" process would provide a safe and stable design of cathode materials for polyvalent cations. PMID- 27980966 TI - Nanoporous Metal Papers for Scalable Hierarchical Electrode. AB - Nanoporous metals similar to paper in form are developed using Japanese washi paper as a template to create hierarchical porous electrodes. This method is used to create a trimodal -nanoporous Au electrode, as a well as a hierarchical NiMn electrode that achieves high electrochemical capacitance and a rapid rate of oxygen evolution. PMID- 27980967 TI - A Carbon- and Binder-Free Nanostructured Cathode for High-Performance Nonaqueous Li-O2 Battery. AB - Operation of the nonaqueous Li-O2 battery critically relies on the reversible oxygen reduction/evolution reactions in the porous cathode. Carbon and polymeric binder, widely used for the construction of Li-O2 cathode, have recently been shown to decompose in the O2 environment and thus cannot sustain the desired battery reactions. Identifying stable cathode materials is thus a major current challenge that has motivated extensive search for noncarbonaceous alternatives. Here, RuO x /titanium nitride nanotube arrays (RuO x /TiN NTA) containing neither carbon nor binder are used as the cathode for nonaqueous Li-O2 batteries. The free standing TiN NTA electrode is more stable than carbon electrode, and possesses enhanced electronic conductivity compared to TiN nanoparticle bound with polytetrafluoroethylene due to a direct contact between TiN and Ti mesh substrate. RuO x is electrodeposited into TiN NTA to form a coaxial nanostructure, which can further promote the oxygen evolution reaction. This optimized monolithic electrode can avoid the side reaction arising from carbon material, which exhibits low overpotential and excellent cycle stability over 300 cycles. These results presented here demonstrate a highly effective carbon-free cathode and further imply that the structure designing of cathode plays a critical role for improving the electrochemical performance of nonaqueous Li-O2 batteries. PMID- 27980968 TI - Morphology Evolution in High-Performance Polymer Solar Cells Processed from Nonhalogenated Solvent. AB - A new processing protocol based on non-halogenated solvent and additive is developed to produce polymer solar cells with power conversion efficiencies better than those processed from commonly used halogenated solvent-additive pair. Morphology studies show that good performance correlates with a finely distributed nanomorphology with a well-defined polymer fibril network structure, which leads to balanced charge transport in device operation. PMID- 27980969 TI - Multimetallic Mesoporous Spheres Through Surfactant-Directed Synthesis. AB - Multimetallic mesoporous spheres are successfully synthesized with ultra-large mesopores with the assistance of nonionic triblock copolymer (F127) as a structural directing agent. The kinetically controlled reduction rate of metal species and the concentration of F127 are critical to the formation of the large mesopores. PMID- 27980970 TI - Surface Engineering and Design Strategy for Surface-Amorphized TiO2@Graphene Hybrids for High Power Li-Ion Battery Electrodes. AB - Surface amorphization provides unprecedented opportunities for altering and tuning material properties. Surface-amorphized TiO2@graphene synthesized using a designed low temperature-phase transformation technique exhibits significantly improved rate capability compared to well-crystallized TiO2@graphene and bare TiO2 electrodes. These improvements facilitates lithium-ion transport in both insertion and extraction processes and enhance electrolyte absorption capability. PMID- 27980972 TI - Shape-Controlled, Self-Wrapped Carbon Nanotube 3D Electronics. AB - The mechanical flexibility and structural softness of ultrathin devices based on organic thin films and low-dimensional nanomaterials have enabled a wide range of applications including flexible display, artificial skin, and health monitoring devices. However, both living systems and inanimate systems that are encountered in daily lives are all 3D. It is therefore desirable to either create freestanding electronics in a 3D form or to incorporate electronics onto 3D objects. Here, a technique is reported to utilize shape-memory polymers together with carbon nanotube flexible electronics to achieve this goal. Temperature assisted shape control of these freestanding electronics in a programmable manner is demonstrated, with theoretical analysis for understanding the shape evolution. The shape control process can be executed with prepatterned heaters, desirable for 3D shape formation in an enclosed environment. The incorporation of carbon nanotube transistors, gas sensors, temperature sensors, and memory devices that are capable of self-wrapping onto any irregular shaped-objects without degradations in device performance is demonstrated. PMID- 27980971 TI - Multistimuli Sensitive Behavior of Novel Bodipy-Involved Pillar[5]arene-Based Fluorescent [2]Rotaxane and Its Supramolecular Gel. AB - Fluorescent [2]rotaxane BC12P5 is successfully constructed with 1,4 diethoxypillar[5]arene as wheel over a long alkyl axle with Bodipy chromophore as one stopper for the first time. NMR spectra clearly reveal its molecular shuttle nature triggered by multiple external stimuli including solvent polarity and temperature. In particular, the fluorescence nature introduced into [2]rotaxane BC12P5 renders it a good sensor for the external stimuli. Nevertheless, the supramolecular gel successfully fabricated from this novel rotaxane system via self-assembly in dimethyl sulfoxide (DMSO) also shows reversible gel-sol phase transition upon multiple external stimuli such as heating/cooling, shaking/resting, or the addition of different anions. Interestingly, exposure of the supramolecular gel film to HCl or ammonia vapor induces the change in the film fluorescence intensity, endowing this system with a potential application in gas detecting. PMID- 27980973 TI - Multifunctional Inverse Opal-Like TiO2 Electron Transport Layer for Efficient Hybrid Perovskite Solar Cells. AB - A novel multifunctional inverse opal-like TiO2 electron transport layer (IOT-ETL) is designed to replace the traditional compact layer and mesoporous scaffold layer in perovskite solar cells (PSCs). Improved light harvesting efficiency and charge transporting performance in IOT-ETL based PSCs yield high power conversion efficiency of 13.11%. PMID- 27980974 TI - High-Performance Li-O2 Batteries with Trilayered Pd/MnO x /Pd Nanomembranes. AB - Trilayered Pd/MnO x /Pd nanomembranes are fabricated as the cathode catalysts for Li-O2 batteries. The combination of Pd and MnO x facilitates the transport of electrons, lithium ions, and oxygen-containing intermediates, thus effectively decomposing the discharge product Li2O2 and significantly lowering the charge overpotential and enhancing the power efficiency. This is promising for future environmentally friendly applications. PMID- 27980975 TI - A Subambient Open Roof Surface under the Mid-Summer Sun. AB - A novel material open to warm air stays below ambient temperature under maximum solar intensities of mid-summer. It is found to be 11 degrees C cooler than a commercial white cool roof nearby. A combination of specially chosen polymers and a silver thin film yields values near 100% for both solar reflectance, and thermal emittance at infrared wavelengths from 7.9 to 13 MUm. PMID- 27980976 TI - Contact Transfer Printing of Side Edge Prefunctionalized Nanoplasmonic Arrays for Flexible microRNA Biosensor. AB - For a nanoplasmonic approach of wearable biochip platform, understanding correlation between near-field enhancement on nanostructures and sensing capability is a crucial step to improve the sensitivity in biosensing. A novel and effective method is demonstrated to increase sensitivity with the enhanced electric fields and to reduce noise with targeted functionalization enabled by transferring side edge prefunctionalized (SEPF) nanostructure arrays onto flexible substrates. Nanostructure sidewalls have selective biochemically functional terminals for the hybridization of microRNAs (miRNAs) and the immobilization of resonant nanoparticles, thus forming hetero assemblies of the nanostructure and the nanoparticles. The unique configuration has shown ultrasensitive biosensing of miRNA-21 in a 10 * 10-15 m level by a red-shift in scattering spectra induced by a plasmon coupling. This ultrasensitive SEPF nanostructure arrays are fabricated on a flexible substrate using a contact transfer printing with a release layer of trichloro(1H, 1H, 2H, 2H perfluorooctyl)silane. The introduction of the release layer at a prefunctionalizing step has proven to provide selective functionalization only on the sidewalls of the nanostructures. This reduces a background noise caused by the scattering from nonspecifically bound nanoparticles on the substrate, thus enabling reliable and precise detection. PMID- 27980977 TI - Poly(benzoquinonyl sulfide) as a High-Energy Organic Cathode for Rechargeable Li and Na Batteries. AB - In concern of resource sustainability and environmental friendliness, organic electrode materials for rechargeable batteries have attracted increasing attentions in recent years. However, for many researchers, the primary impression on organic cathode materials is the poor cycling stability and low energy density, mainly due to the unfavorable dissolution and low redox potential, respectively. Herein, a novel polymer cathode material, namely poly(benzoquinonyl sulfide) (PBQS) is reported, for either rechargeable Li or Na battery. Remarkably, PBQS shows a high energy density of 734 W h kg-1 (2.67 V * 275 mA h g 1) in Li battery, or 557 W h kg-1 (2.08 V * 268 mA h g-1) in Na battery, which exceeds those of most inorganic Li or Na intercalation cathodes. Moreover, PBQS also demonstrates excellent long-term cycling stability (1000 cycles, 86%) and superior rate capability (5000 mA g-1, 72%) in Li battery. Besides the exciting battery performance, investigations on the structure-property relationship between benzoquinone (BQ) and PBQS, and electrochemical behavior difference between Li-PBQS battery and Na-PBQS battery, also provide significant insights into developing better Li-organic and Na-organic batteries beyond conventional Li ion batteries. PMID- 27980978 TI - A Delicate Nanoscale Motor Made by Nature-The Bacterial Flagellar Motor. AB - The bacterial flagellar motor (BFM) is a molecular complex ca. 45 nm in diameter that rotates the propeller that makes nearly all bacteria swim. The motor self assembles out of ca. 20 different proteins and can not only rotate at up to 50 000 rpm, but can also switch rotational direction in milliseconds and navigate its environment to maneuver, on average, towards regions of greater benefit. The BFM is a pinnacle of evolution that informs and inspires the design of novel nanotechnology in the new era of synthetic biology. PMID- 27980979 TI - Local Versus Long-Range Diffusion Effects of Photoexcited States on Radiative Recombination in Organic-Inorganic Lead Halide Perovskites. AB - Radiative recombination in thin films of the archetypical, high-performing perovskites CH3NH3PbBr3 and CH3NH3PbI3 shows localized regions of increased emission with dimensions ~500 nm. Maps of the spectral emission line shape show narrower emission lines in high emission regions, which can be attributed to increased order. Excited states do not diffuse out of high emission regions before they decay, but are decoupled from nearby regions, either by slow diffusion rates or energetic barriers. PMID- 27980980 TI - Control of Emission Color of High Quantum Yield CH3NH3PbBr3 Perovskite Quantum Dots by Precipitation Temperature. AB - Emission color controlled, high quantum yield CH3NH3PbBr3 perovskite quantum dots are obtained by changing the temperature of a bad solvent during synthesis. The products for temperatures between 0 and 60 degrees C have good spectral purity with narrow emission line widths of 28-36 nm, high absolute emission quantum yields of 74% to 93%, and short radiative lifetimes of 13-27 ns. PMID- 27980981 TI - Vacancy-Contained Tetragonal Na3SbS4 Superionic Conductor. AB - Tetragonal Na3SbS4 is synthesized as a new sodium superionic conductor. The discovery of Na vacancies experimentally verifies previous theoretical predictions. Na vacancies, distorted cubic sulphur sublattices and large Na atomic displacement parameters lead to the ionic conductivity as high as 3 mS cm 1, a value significantly higher than those of state-of-the-art sodium sulfide electrolytes. PMID- 27980982 TI - Z-Scheme Photocatalytic Systems for Promoting Photocatalytic Performance: Recent Progress and Future Challenges. AB - Semiconductor photocatalysts have attracted increased attention due to their great potential for solving energy and environmental problems. The formation of Z scheme photocatalytic systems that mimic natural photosynthesis is a promising strategy to improve photocatalytic activity that is superior to single component photocatalysts. The connection between photosystem I (PS I) and photosystem II (PS II) are crucial for constructing efficient Z-scheme photocatalytic systems using two photocatalysts (PS I and PS II). The present review concisely summarizes and highlights recent state-of-the-art accomplishments of Z-scheme photocatalytic systems with diverse connection modes, including i) with shuttle redox mediators, ii) without electron mediators, and iii) with solid-state electron mediators, which effectively increase visible-light absorption, promote the separation and transportation of photoinduced charge carriers, and thus enhance the photocatalytic efficiency. The challenges and prospects for future development of Z-scheme photocatalytic systems are also presented. PMID- 27980983 TI - Controllable Synthesis of Graphene by Plasma-Enhanced Chemical Vapor Deposition and Its Related Applications. AB - Graphene and its derivatives hold a great promise for widespread applications such as field-effect transistors, photovoltaic devices, supercapacitors, and sensors due to excellent properties as well as its atomically thin, transparent, and flexible structure. In order to realize the practical applications, graphene needs to be synthesized in a low-cost, scalable, and controllable manner. Plasma enhanced chemical vapor deposition (PECVD) is a low-temperature, controllable, and catalyst-free synthesis method suitable for graphene growth and has recently received more attentions. This review summarizes recent advances in the PECVD growth of graphene on different substrates, discusses the growth mechanism and its related applications. Furthermore, the challenges and future development in this field are also discussed. PMID- 27980986 TI - Local Structural Distortion Induced Uniaxial Negative Thermal Expansion in Nanosized Semimetal Bismuth. AB - The corrugated layer structure bismuth has been successfully tailored into negative thermal expansion along c axis by size effect. Pair distribution function and extended X-ray absorption fine structure are combined to reveal the local structural distortion for nanosized bismuth. The comprehensive method to identify the local structure of nanomaterials can benefit the regulating and controlling of thermal expansion in nanodivices. PMID- 27980984 TI - Ultrafast, Broadband Photodetector Based on MoSe2/Silicon Heterojunction with Vertically Standing Layered Structure Using Graphene as Transparent Electrode. AB - A MoSe2/Si heterojunction photodetector is constructed by depositing MoSe2 film with vertically standing layered structure on Si substrate. Graphene transparent electrode is utilized to further enhance the separation and transport of photogenerated carriers. The device shows excellent performance in terms of wide response spectrum of UV-visible-NIR, high detectivity of 7.13 * 1010 Jones, and ultrafast response speed of ~270 ns, unveiling the great potential for the heterojunction for high-performance optoelectronic devices. PMID- 27980985 TI - A Porous Metal-Organic Framework Assembled by [Cu30] Nanocages: Serving as Recyclable Catalysts for CO2 Fixation with Aziridines. AB - Based on a novel ligand 5-(2,6-bis(4-carboxyphenyl)pyridin-4-yl)isophthalic acid (H4BCP) with large skeletons, a unique porous framework {[Cu2(BCP)(H2O)2].3DMF} n (1) assembled by nano-sized and censer-like [Cu30] cages is successfully obtained and structurally characterized. In 1, the large 1D channel in frameworks and window size in the nanocages can enrich methylene blue and capture CO2, exhibiting the promising applications in environmental protection. More importantly, the explorations on the cycloaddition reaction of CO2 and aziridines with various substituents suggest that 1 can serve as an efficient heterogeneous catalyst for CO2 conversion with aziridines in a solvent-free system, which can be reused at least ten times without any obvious loss in catalytic activity. This is the first example of metal-organic framework (MOF)-based catalysts in converting CO2 into high-value oxazolidinones through activating aziridines and CO2, further extending the applications of MOFs materials in catalysis. PMID- 27980987 TI - Engineering Intrinsically Zirconium-89 Radiolabeled Self-Destructing Mesoporous Silica Nanostructures for In Vivo Biodistribution and Tumor Targeting Studies. AB - A systematic study of in vitro and in vivo behavior of biodegradable mesoporous silica nanoparticles (bMSNs), designed to carry multiple cargos (both small and macromolecular drugs) and subsequently self-destruct following release of their payloads, is presented. Complete degradation of bMSNs is seen within 21 d of incubation in simulated body fluid. The as-synthesized bMSNs are intrinsically radiolabeled with oxophilic zirconium-89 (89Zr, t1/2 = 78.4 h) radionuclide to track their in vivo pharmacokinetics via positron emission tomography imaging. Rapid and persistent CD105 specific tumor vasculature targeting is successfully demonstrated in murine model of metastatic breast cancer by using TRC105 (an anti CD105 antibody)-conjugated bMSNs. This study serves to illustrate a simple, versatile, and readily tunable approach to potentially overcome the current challenges facing nanomedicine and further the goals of personalized nanotheranostics. PMID- 27980989 TI - Periodic Organic-Inorganic Halide Perovskite Microplatelet Arrays on Silicon Substrates for Room-Temperature Lasing. AB - Organic-inorganic metal halide perovskites have recently demonstrated outstanding efficiencies in photovoltaics as well as highly promising performances for a wide range of optoelectronic applications such as lasing, light emission, optical detectors, and even for radiation detection. Key to the realization of functional perovskite micro/nanosystems on the ubiquitous silicon optoelectronics platform is through sophisticated lithography. Despite the rapid progress made in halide perovskite lasing, direct lithographic patterning of perovskite films to form optical cavities on conventional substrates remains extremely challenging. This study realizes room-temperature high-quality factor whispering-gallery-mode lasing (Q ~ 1210) from patterned lead halide perovskite microplatelets fabricated in periodic arrays on silicon substrate with micropatterned BN film as the buffer layer. By varying the size of the platelets, modal selectivity for single mode lasing can be achieved with different cavity sizes or by simply breaking the structural symmetry of the cavity through designing the pattern. Importantly, this work demonstrates a straightforward, versatile bottom-up scalable strategy to realize high-quality periodic perovskite arrays with variable cavity sizes for large-area light-emitting and optical gain applications. PMID- 27980991 TI - Self-Templated Synthesis of Ultrathin Nanosheets Constructed TiO2 Hollow Spheres with High Electrochemical Properties. AB - TiO2 is well-known nanomaterials and mostly used as solid nanoparticles, and normal hollow spheres for photocatalysts or electrode materials. In this study, a novel self-templated method is presented to successfully fabricate high-surface area ultrathin nanosheets constructed TiO2 hollow spheres through the solvothermal treatment of the titanate-silicone composite particles combined with calcination. The uniquely structured hollow spheres exhibit excellent rate capability and good cycle stability even at a high current density of ~10 C for the anode material of Li-ion battery. PMID- 27980990 TI - High-Performance Direct Methanol Fuel Cells with Precious-Metal-Free Cathode. AB - Direct methanol fuel cells (DMFCs) hold great promise for applications ranging from portable power for electronics to transportation. However, apart from the high costs, current Pt-based cathodes in DMFCs suffer significantly from performance loss due to severe methanol crossover from anode to cathode. The migrated methanol in cathodes tends to contaminate Pt active sites through yielding a mixed potential region resulting from oxygen reduction reaction and methanol oxidation reaction. Therefore, highly methanol-tolerant cathodes must be developed before DMFC technologies become viable. The newly developed reduced graphene oxide (rGO)-based Fe-N-C cathode exhibits high methanol tolerance and exceeds the performance of current Pt cathodes, as evidenced by both rotating disk electrode and DMFC tests. While the morphology of 2D rGO is largely preserved, the resulting Fe-N-rGO catalyst provides a more unique porous structure. DMFC tests with various methanol concentrations are systematically studied using the best performing Fe-N-rGO catalyst. At feed concentrations greater than 2.0 m, the obtained DMFC performance from the Fe-N-rGO cathode is found to start exceeding that of a Pt/C cathode. This work will open a new avenue to use nonprecious metal cathode for advanced DMFC technologies with increased performance and at significantly reduced cost. PMID- 27980988 TI - Inorganic Nanocarriers Overcoming Multidrug Resistance for Cancer Theranostics. AB - Cancer multidrug resistance (MDR) could lead to therapeutic failure of chemotherapy and radiotherapy, and has become one of the main obstacles to successful cancer treatment. Some advanced drug delivery platforms, such as inorganic nanocarriers, demonstrate a high potential for cancer theranostic to overcome the cancer-specific limitation of conventional low-molecular-weight anticancer agents and imaging probes. Specifically, it could achieve synergetic therapeutic effects, demonstrating stronger killing effects to MDR cancer cells by combining the inorganic nanocarriers with other treatment manners, such as RNA interference and thermal therapy. Moreover, the inorganic nanocarriers could provide imaging functions to help monitor treatment responses, e.g., drug resistance and therapeutic effects, as well as analyze the mechanism of MDR by molecular imaging modalities. In this review, the mechanisms involved in cancer MDR and recent advances of applying inorganic nanocarriers for MDR cancer imaging and therapy are summarized. The inorganic nanocarriers may circumvent cancer MDR for effective therapy and provide a way to track the therapeutic processes for real-time molecular imaging, demonstrating high performance in studying the interaction of nanocarriers and MDR cancer cells/tissues in laboratory study and further shedding light on elaborate design of nanocarriers that could overcome MDR for clinical translation. PMID- 27980992 TI - Transition Metal-Promoted V2CO2 (MXenes): A New and Highly Active Catalyst for Hydrogen Evolution Reaction. AB - Developing alternatives to precious Pt for hydrogen production from water splitting is central to the area of renewable energy. This work predicts extremely high catalytic activity of transition metal (Fe, Co, and Ni) promoted two-dimensional MXenes, fully oxidized vanadium carbides (V2CO2), for hydrogen evolution reaction (HER). The first-principle calculations show that the introduction of transition metal can greatly weaken the strong binding between hydrogen and oxygen and engineer the hydrogen adsorption free energy to the optimal value ~0 eV by choosing the suitable type and coverage of the promoters as well as the active sites. Strain engineering on the performance of transition metal promoted V2CO2 further reveals that the excellent HER activities can maintain well while those poor ones can be modulated to be highly active. This study provides new possibilities for cost-effective alternatives to Pt in HER and for the application of 2D MXenes. PMID- 27980993 TI - All-Copper Nanocluster Based Down-Conversion White Light-Emitting Devices. AB - Most of the present-day down-conversion white light-emitting devices (WLEDs) utilize rare-earth elements, which are expensive and facing the problem of shortage in supply. WLEDs based on the combination of orange and blue emitting copper nanoclusters are introduced, which are easy to produce and low in cost. Orange emitting Cu nanoclusters (NCs) are synthesized using glutathione as both the reduction agent and stabilizer, followed by solvent induced aggregation leading to the emission enhancement. Photoluminescence quantum yields (PL QY) of 24% and 43% in solution and solid state are achieved, respectively. Blue emitting Cu nanoclusters are synthesized by reduction of polyvinylpyrrolidone supported Cu(II) ions using ascorbic acid, followed by surface treatment with sodium citrate which improves both the emission intensity and stability of the clusters, resulting in the PL QY of 14% both in solution and solid state. All-copper nanocluster based down-conversion WLEDs are fabricated by integrating powdered orange and blue emitting Cu NC samples on a commercial GaN LED chip providing 370 nm excitation. They show favorable white light characteristics with Commission Internationale de l'Eclairage color coordinates, color rendering index, and correlated color temperature of (0.36, 0.31), 92, and 4163 K, respectively. PMID- 27980994 TI - High-Performance Heterostructured Cathodes for Lithium-Ion Batteries with a Ni Rich Layered Oxide Core and a Li-Rich Layered Oxide Shell. AB - The Ni-rich layered oxides with a Ni content of >0.5 are drawing much attention recently to increase the energy density of lithium-ion batteries. However, the Ni rich layered oxides suffer from aggressive reaction of the cathode surface with the organic electrolyte at the higher operating voltages, resulting in consequent impedance rise and capacity fade. To overcome this difficulty, we present here a heterostructure composed of a Ni-rich LiNi0.7Co0.15Mn0.15O2 core and a Li-rich Li1.2-x Ni0.2Mn0.6O2 shell, incorporating the advantageous features of the structural stability of the core and chemical stability of the shell. With a unique chemical treatment for the activation of the Li2MnO3 phase of the shell, a high capacity is realized with the Li-rich shell material. Aberration-corrected scanning transmission electron microscopy (STEM) provides direct evidence for the formation of surface Li-rich shell layer. As a result, the heterostructure exhibits a high capacity retention of 98% and a discharge-voltage retention of 97% during 100 cycles with a discharge capacity of 190 mA h g-1 (at 2.0-4.5 V under C/3 rate, 1C = 200 mA g-1). PMID- 27980995 TI - Low Sound Velocity Contributing to the High Thermoelectric Performance of Ag8SnSe6. AB - Conventional strategies for advancing thermoelectrics by minimizing the lattice thermal conductivity focus on phonon scattering for a short mean free path. Here, a design of slow phonon propagation as an effective approach for high-performance thermoelectrics is shown. Taking Ag8SnSe6 as an example, which shows one of the lowest sound velocities among known thermoelectric semiconductors, the lattice thermal conductivity is found to be as low as 0.2 W m-1 K-1 in the entire temperature range. As a result, a peak thermoelectric figure of merit zT > 1.2 and an average zT as high as ~0.8 are achieved in Nb-doped materials, without relying on a high thermoelectric power factor. This work demonstrates not only a guiding principle of low sound velocity for minimal lattice thermal conductivity and therefore high zT, but also argyrodite compounds as promising thermoelectric materials with weak chemical bonds and heavy constituent elements. PMID- 27980997 TI - Encoding Magnetic States in Monopole-Like Configurations Using Superconducting Dots. AB - A large manifold of nontrivial spin textures, including the stabilization of monopole-like fields, are generated by using a completely new and versatile approach based on the combination of superconductivity and magnetism. Robust, stable, and easily controllable complex spin structures are encoded, modified, and annihilated in a continuous magnetic thin film by defining a variety of magnetic states in superconducting dots. PMID- 27980996 TI - Ultrasensitive Luminescent In Vitro Detection for Tumor Markers Based on Inorganic Lanthanide Nano-Bioprobes. AB - Ultrasensitive and accurate detection of tumor markers is of vital importance for the screening or diagnosis of cancers at their early stages and for monitoring cancer relapse after surgical resection. Inorganic lanthanide (Ln3+) nanoparticles (NPs), owing to their superior physicochemical characteristics, are regarded as a new generation of luminescent nano-bioprobes in the field of cancer diagnosis and therapy. In this progress report, a focus is set on our recent efforts on the development of inorganic Ln3+-NPs as efficient luminescent nano bioprobes for the ultrasensitive in vitro biodetection of tumor markers, with an emphasis on the dissolution-enhanced luminescent bioassay (DELBA), an emerging technique recently developed toward practical medical applications. PMID- 27980998 TI - A Flexible Platform Containing Graphene Mesoporous Structure and Carbon Nanotube for Hydrogen Evolution. AB - It is of great significance to design a platform with large surface area and high electrical conductivity for poorly conductive catalyst for hydrogen evolution reaction (HER), such as molybdenum sulfide (MoS x ), a promising and cost effective nonprecious material. Here, the design and preparation of a free standing and tunable graphene mesoporous structure/single-walled carbon nanotube (GMS/SWCNT) hybrid membrane is reported. Amorphous MoS x is electrodeposited on this platform through a wet chemical process under mild temperature. For MoS x @GMS/SWCNT hybrid electrode with a low catalyst loading of 32 MUg cm-2, the onset potential is near 113 mV versus reversible hydrogen electrode (RHE) and a high current density of ~71 mA cm-2 is achieved at 250 mV versus RHE. The excellent HER performance can be attributed to the large surface area for MoS x deposition, as well as the efficient electron transport and abundant active sites on the amorphous MoS x surface. This novel catalyst is found to outperform most previously reported MoS x -based HER catalysts. Moreover, the flexibility of the electrode facilitates its stable catalytic performance even in extremely distorted states. PMID- 27981000 TI - The Role of Local Triplet Excited States and D-A Relative Orientation in Thermally Activated Delayed Fluorescence: Photophysics and Devices. AB - Here, a comprehensive photophysical investigation of a the emitter molecule DPTZ DBTO2, showing thermally activated delayed fluorescence (TADF), with near orthogonal electron donor (D) and acceptor (A) units is reported. It is shown that DPTZ-DBTO2 has minimal singlet-triplet energy splitting due to its near rigid molecular geometry. However, the electronic coupling between the local triplet (3LE) and the charge transfer states, singlet and triplet, (1CT, 3CT), and the effect of dynamic rocking of the D-A units about the orthogonal geometry are crucial for efficient TADF to be achieved. In solvents with low polarity, the guest emissive singlet 1CT state couples directly to the near-degenerate 3LE, efficiently harvesting the triplet states by a spin orbit coupling charge transfer mechanism (SOCT). However, in solvents with higher polarity the emissive CT state in DPTZ-DBTO2 shifts below (the static) 3LE, leading to decreased TADF efficiencies. The relatively large energy difference between the 1CT and 3LE states and the extremely low efficiency of the 1CT to 3CT hyperfine coupling is responsible for the reduction in TADF efficiency. Both the electronic coupling between 1CT and 3LE, and the (dynamic) orientation of the D-A units are thus critical elements that dictate reverse intersystem crossing processes and thus high efficiency in TADF. PMID- 27980999 TI - Anti-Metastatic and Anti-Angiogenic Activities of Core-Shell SiO2@LDH Loaded with Etoposide in Non-Small Cell Lung Cancer. AB - Currently, nanoparticles have gained a great attention in the anti-tumor research area. However, to date, studies on the anti-metastasis action of core-shell SiO2@LDH (LDH: layered double hydroxide) nanoparticles remain untouched. Two emerging aspects considered are establishing research on the controlling delivery effect of SiO2@LDH combined with anti-cancer medicine from a new perspective. The fine properties synthetic SiO2@LDH-VP16 (VP16: etoposide) are practiced to exhibit the nanoparticle's suppression on migration and invasion of non-small cell lung cancer (NSCLC). Both in vitro and in vivo inspection shows that SiO2@LDH can help VP16 better function as an anti-metastasis agent. On the other hand, anti-angiogenic efficiency, co-localization, as well as western blot are investigated to explain the possible mechanism. A clear mergence of SiO2@LDH-VP16 and cytomembrane/microtubule may be observed from co-location images. Results offer evidence that SiO2@LDH-VP16 plays positions on cytomembrane and microtubules. It efficiently inhibits metastasis on NSCLC by reducing vascularization, and eliciting depression of the PI3K-AKT and FAK-Paxillin signaling pathways. SiO2@LDH-VP16, the overall particle morphology, and function on anti-metastasis and anti-angiogenic may be tuned to give new opportunities for novel strategies for cancer therapy. PMID- 27981001 TI - Capacity Fade Analysis of Sulfur Cathodes in Lithium-Sulfur Batteries. AB - Rechargeable lithium-sulfur (Li-S) batteries are receiving ever-increasing attention due to their high theoretical energy density and inexpensive raw sulfur materials. However, their rapid capacity fade has been one of the key barriers for their further improvement. It is well accepted that the major degradation mechanisms of S-cathodes include low electrical conductivity of S and sulfides, precipitation of nonconductive Li2S2 and Li2S, and poly-shuttle effects. To determine these degradation factors, a comprehensive study of sulfur cathodes with different amounts of electrolytes is presented here. A survey of the fundamentals of Li-S chemistry with respect to capacity fade is first conducted; then, the parameters obtained through electrochemical performance and characterization are used to determine the key causes of capacity fade in Li-S batteries. It is confirmed that the formation and accumulation of nonconductive Li2S2/Li2S films on sulfur cathode surfaces are the major parameters contributing to the rapid capacity fade of Li-S batteries. PMID- 27981002 TI - Boron Substituted Na3V2(P1-x B x O4)3 Cathode Materials with Enhanced Performance for Sodium-Ion Batteries. AB - The development of excellent performance of Na-ion batteries remains great challenge owing to the poor stability and sluggish kinetics of cathode materials. Herein, B substituted Na3V2P3-x B x O12 (0 <= x <= 1) as stable cathode materials for Na-ion battery is presented. A combined experimental and theoretical investigations on Na3V2P3-x B x O12 (0 <= x <= 1) are undertaken to reveal the evolution of crystal and electronic structures and Na storage properties associated with various concentration of B. X-ray diffraction results indicate that the crystal structure of Na3V2P3-x B x O12 (0 <= x <= 1/3) consisted of rhombohedral Na3V2(PO4)3 with tiny shrinkage of crystal lattice. X-ray absorption spectra and the calculated crystal structures all suggest that the detailed local structural distortion of substituted materials originates from the slight reduction of V-O distances. Na3V2P3-1/6B1/6O12 significantly enhances the structural stability and electrochemical performance, giving remarkable enhanced capacity of 100 and 70 mAh g-1 when the C-rate increases to 5 C and 10 C. Spin polarized density functional theory (DFT) calculation reveals that, as compared with the pristine Na3V2(PO4)3, the superior electrochemical performance of the substituted materials can be attributed to the emergence of new boundary states near the band gap, lower Na+ diffusion energy barriers, and higher structure stability. PMID- 27981003 TI - Symmetric Electrodes for Electrochemical Energy-Storage Devices. AB - Increasing environmental problems and energy challenges have so far attracted urgent demand for developing green and efficient energy-storage systems. Among various energy-storage technologies, sodium-ion batteries (SIBs), electrochemical capacitors (ECs) and especially the already commercialized lithium-ion batteries (LIBs) are playing very important roles in the portable electronic devices or the next-generation electric vehicles. Therefore, the research for finding new electrode materials with reduced cost, improved safety, and high-energy density in these energy storage systems has been an important way to satisfy the ever growing demands. Symmetric electrodes have recently become a research focus because they employ the same active materials as both the cathode and anode in the same energy-storage system, leading to the reduced manufacturing cost and simplified fabrication process. Most importantly, this feature also endows the symmetric energy-storage system with improved safety, longer lifetime, and ability of charging in both directions. In this Progress Report, we provide the comprehensive summary and comment on different symmetric electrodes and focus on the research about the applications of symmetric electrodes in different energy storage systems, such as the above mentioned SIBs, ECs and LIBs. Further considerations on the possibility of mass production have also been presented. PMID- 27981004 TI - Single Crystal Sub-Nanometer Sized Cu6(SR)6 Clusters: Structure, Photophysical Properties, and Electrochemical Sensing. AB - Organic ligand-protected metal nanoclusters have attracted extensively attention owing to their atomically precise composition, determined atom-packing structure and the fascinating properties and promising applications. To date, most research has been focused on thiol-stabilized gold and silver nanoclusters and their single crystal structures. Here the single crystal copper nanocluster species (Cu6(SC7H4NO)6) determined by X-ray crystallography and mass spectrometry is presented. The hexanuclear copper core is a distorted octahedron surrounded by six mercaptobenzoxazole ligands as protecting units through a simple bridging bonding motif. Density functional theory (DFT) calculations provide insight into the electronic structure and show the cluster can be viewed as an open-shell nanocluster. The UV-vis spectra are analyzed using time-dependent DFT and illustrates high-intensity transitions involving primarily ligand states. Furthermore, the as-synthesized copper clusters can serve as promising nonenzymatic sensing materials for high sensitive and selective detection of H2O2. PMID- 27981006 TI - Enabling the Triplet of Tetraphenylethene to Sensitize the Excited State of Europium(III) for Protein Detection and Time-Resolved Luminescence Imaging. AB - A tetraphenylethene (TPE) group that exhibits aggregation-induced emission is incorporated into the ligand of a Eu(III) complex (TPEEu) to sensitize the excited state of Eu(III). In steady-state measurements, TPEEu exhibits weak luminescence when dissolved in aqueous solutions even at a high concentration level, but emits strong fluorescence of TPE and phosphorescence of Eu(III) upon binding with bovine serum albumin. With a delay time of 0.05 ms and a gate time of 1.0 ms in time-resolved measurements, only phosphorescent emission of Eu(III) is observed with a high on/off ratio. Moreover, this probe is successfully used in time-resolved luminescence imaging to eliminate the background signal from biological autofluorescence without a washing process. This work provides a general strategy in designing Ln(III) complexes for detecting a broad range of biological molecules. PMID- 27981005 TI - Human-Like Sensing and Reflexes of Graphene-Based Films. AB - Humans have numerous senses, wherein vision, hearing, smell, taste, and touch are considered as the five conventionally acknowledged senses. Triggered by light, sound, or other physical stimulations, the sensory organs of human body are excited, leading to the transformation of the afferent energy into neural activity. Also converting other signals into electronical signals, graphene-based film shows its inherent advantages in responding to the tiny stimulations. In this review, the human-like senses and reflexes of graphene-based films are presented. The review starts with the brief discussions about the preparation and optimization of graphene-based film, as where as its new progress in synthesis method, transfer operation, film-formation technologies and optimization techniques. Various human-like senses of graphene-based film and their recent advancements are then summarized, including light-sensitive devices, acoustic devices, gas sensors, biomolecules and wearable devices. Similar to the reflex action of humans, graphene-based film also exhibits reflex when under thermal radiation and light actuation. Finally, the current challenges associated with human-like applications are discussed to help guide the future research on graphene films. At last, the future opportunities lie in the new applicable human like senses and the integration of multiple senses that can raise a revolution in bionic devices. PMID- 27981007 TI - Chloride-Reinforced Carbon Nanofiber Host as Effective Polysulfide Traps in Lithium-Sulfur Batteries. AB - Lithium-sulfur (Li-S) battery is one of the most promising alternatives for the current state-of-the-art lithium-ion batteries due to its high theoretical energy density and low production cost from the use of sulfur. However, the commercialization of Li-S batteries has been so far limited to the cyclability and the retention of active sulfur materials. Using co-electrospinning and physical vapor deposition procedures, we created a class of chloride-carbon nanofiber composites, and studied their effectiveness on polysulfides sequestration. By trapping sulfur reduction products in the modified cathode through both chemical and physical confinements, these chloride-coated cathodes are shown to remarkably suppress the polysulfide dissolution and shuttling between lithium and sulfur electrodes. From adsorption experiments and theoretical calculations, it is shown that not only the sulfide-adsorption effect but also the diffusivity in the vicinity of these chlorides materials plays an important role on the reversibility of sulfur-based cathode upon repeated cycles. Balancing the adsorption and diffusion effects of these nonconductive materials could lead to the enhanced cycling performance of an Li-S cell. Electrochemical analyses over hundreds of cycles indicate that cells containing indium chloride modified carbon nanofiber outperform cells with other halogenated salts, delivering an average specific capacity of above 1200 mAh g-1 at 0.2 C. PMID- 27981009 TI - Guidable Thermophoretic Janus Micromotors Containing Gold Nanocolorifiers for Infrared Laser Assisted Tissue Welding. AB - Current wound sealing systems such as nanoparticle-based gluing of tissues allow almost immediate wound sealing. The assistance of a laser beam allows the wound sealing with higher controllability due to the collagen fiber melting which is defined by loss of tertiary protein structure and restoration upon cooling. Usually one employs dyes to paint onto the wound, if water absorption bands are absent. In case of strong bleeding or internal wounds such applications are not feasible due to low welding depth in case of water absorption bands, dyes washing off, or the dyes becoming diluted within the wound. One possible solution of these drawbacks is to use autonomously movable particles composing of biocompatible gold and magnetite nanoparticles and biocompatible polyelectrolyte complexes. In this paper a proof of principle study is presented on the utilization of thermophoretic Janus particles and capsules employed as dyes for infrared laser-assisted tissue welding. This approach proves to be efficient in sealing the wound on the mouse in vivo. The temperature measurement of single particle level proves successful photothermal heating, while the mechanical characterizations of welded liver, skin, and meat confirm mechanical restoration of the welded biological samples. PMID- 27981010 TI - The Mechanism of the Interfacial Charge and Mass Transfer during Intercalation of Alkali Metal Cations. AB - Intercalation of alkali metal cations, like Li+ or Na+, follows the same three stage mechanism of the interfacial charge and mass transfer irrespective of the nature of the electrolyte, electrolyte composition or electrode material. PMID- 27981011 TI - Graphene Oxide-Based Sensor for Ultrasensitive Visual Detection of Fluoride. AB - Visual fluoride ion detection with a detection limit down to pmol L-1 is achieved through quenching/reactivating the fluorescence of N-doped graphene oxide. PMID- 27981008 TI - Booming Development of Group IV-VI Semiconductors: Fresh Blood of 2D Family. AB - As an important component of 2D layered materials (2DLMs), the 2D group IV metal chalcogenides (GIVMCs) have drawn much attention recently due to their earth abundant, low-cost, and environmentally friendly characteristics, thus catering well to the sustainable electronics and optoelectronics applications. In this instructive review, the booming research advancements of 2D GIVMCs in the last few years have been presented. First, the unique crystal and electronic structures are introduced, suggesting novel physical properties. Then the various methods adopted for synthesis of 2D GIVMCs are summarized such as mechanical exfoliation, solvothermal method, and vapor deposition. Furthermore, the review focuses on the applications in field effect transistors and photodetectors based on 2D GIVMCs, and extends to flexible devices. Additionally, the 2D GIVMCs based ternary alloys and heterostructures have also been presented, as well as the applications in electronics and optoelectronics. Finally, the conclusion and outlook have also been presented in the end of the review. PMID- 27981012 TI - Plasmonic Nanoparticles with Quantitatively Controlled Bioconjugation for Photoacoustic Imaging of Live Cancer Cells. AB - Detection and imaging of single cancer cells is critical for cancer diagnosis and understanding of cellular dynamics. Photoacoustic imaging (PAI) provides a potential tool for the study of cancer cell dynamics, but faces the challenge that most cancer cells lack sufficient endogenous contrast. Here, a type of colloidal gold nanoparticles (AuNPs) are physically fabricated and are precisely functionalized with quantitative amounts of functional ligands (i.e., polyethyleneglycol (PEG) and (Arginine(R)-Glycine(G)-Aspartic(D))4 (RGD) peptides) to serve as an exogenous contrast agent for PAI of single cells. The functionalized AuNPs, with a fixed number of PEG but different RGD densities, are delivered into human prostate cancer cells. Radioactivity and photoacoustic analyses show that, although cellular uptake efficiency of the AuNPs linearly increases along with RGD density, photoacoustic signal generation efficiency does not and only maximize at a moderate RGD density. The functionalization of the AuNPs is in turn optimized based on the experimental finding, and single cancer cells are imaged using a custom photoacoustic microscopy with high-resolution. The quantitatively functionalized AuNPs together with the high-resolution PAI system provide a unique platform for the detection and imaging of single cancer cells, and may impact not only basic science but also clinical diagnostics on a range of cancers. PMID- 27981013 TI - PLGA-PNIPAM Microspheres Loaded with the Gastrointestinal Nutrient NaB Ameliorate Cardiac Dysfunction by Activating Sirt3 in Acute Myocardial Infarction. AB - Acute myocardial infarction (AMI) is the death of cardiomyocytes caused by a lack of energy due to ischemia. Nutrients supplied by the blood are the main source of cellular energy for cardiomyocytes. Sodium butyrate (NaB), a gastrointestinal nutrient, is a short-chain fatty acid (butyric acid) that may act as an energy source in AMI therapy. Poly(lactic-co-glycolic acid)-Poly (N-isopropylacrylamide) microspheres loaded with NaB (PP-N) are synthesized to prolong the release of NaB and are injected into ischemic zones in a Sprague-Dawley rat AMI model. Here, this study shows that PP-N can significantly ameliorate cardiac dysfunction in AMI, and NaB can specially bind to Sirt3 structure, activating its deacetylation ability and inhibiting the generation of reactive oxygen species, autophagy, and angiogenesis promotion. The results indicate that NaB, acting as a nutrient, can protect cardiomyocytes in AMI. These results suggest that the gastrointestinal nutrient NaB may be a new therapy for AMI treatment, and PP-N may be the ideal therapeutic regimen. PMID- 27981014 TI - Variation in Carbohydrates between Cancer and Normal Cell Membranes Revealed by Super-Resolution Fluorescence Imaging. AB - Carbohydrate alterations on cell membranes are associated with various cancer processes, including tumorigenesis, malignant transformation, and tumor dissemination. However, variations in the distributions of cancer-associated carbohydrates are unclear at the molecular level. Herein, direct stochastic optical reconstruction microscopy is used to reveal that seven major types of carbohydrates tended to form obvious clusters on cancer cell membranes compared with normal cell membranes (both cultured and primary cells), and most types of carbohydrates present a similar distributed characteristic on various cancer cells (e.g., HeLa and Os-Rc-2 cells). Significantly, sialic acid is found to distribute in larger-sized clusters with a higher cluster coverage percentage on various cancer cells than normal cells. These findings on the aberrant distributions of cancer-associated carbohydrates can potentially serve as novel diagnostic and therapeutic targets, as well as making a contribution to clarify how abnormal glycosylations of membrane glycoconjugates participate in tumorigenesis and metastasis. PMID- 27981015 TI - Transition Metal-Involved Photon Upconversion. AB - Upconversion (UC) luminescence of lanthanide ions (Ln3+) has been extensively investigated for several decades and is a constant research hotspot owing to its fundamental significance and widespread applications. In contrast to the multiple and fixed UC emissions of Ln3+, transition metal (TM) ions, e.g., Mn2+, usually possess a single broadband emission due to its 3d5 electronic configuration. Wavelength-tuneable single UC emission can be achieved in some TM ion-activated systems ascribed to the susceptibility of d electrons to the chemical environment, which is appealing in molecular sensing and lighting. Moreover, the UC emissions of Ln3+ can be modulated by TM ions (specifically d-block element ions with unfilled d orbitals), which benefits from the specific metastable energy levels of Ln3+ owing to the well-shielded 4f electrons and tuneable energy levels of the TM ions. The electric versatility of d0 ion-containing hosts (d0 normally viewed as charged anion groups, such as MoO66- and TiO44-) may also have a strong influence on the electric dipole transition of Ln3+, resulting in multifunctional properties of modulated UC emission and electrical behaviour, such as ferroelectricity and oxide-ion conductivity. This review focuses on recent advances in the room temperature (RT) UC of TM ions, the UC of Ln3+ tuned by TM or d0 ions, and the UC of d0 ion-centred groups, as well as their potential applications in bioimaging, solar cells and multifunctional devices. PMID- 27981016 TI - Understanding the Light Soaking Effects in Inverted Organic Solar Cells Functionalized with Conjugated Macroelectrolyte Electron-Collecting Interlayers. AB - Three kinds of charged star-shaped conjugated macroelectrolytes, named as PhNBr, TPANBr, and TrNBr, are synthesized as electron-collecting interlayers for inverted polymer solar cells (i-PSCs). Based on these well-defined structured interlayer materials, the light soaking (LS) effect observed in i-PSCs was studied systematically and accurately. The general character of the LS effect is further verified by studying additional i-PSC devices functionalized with other common interlayers. The key-role of UV photons was confirmed by electrochemical impedance spectroscopy and electron-only devices. In addition, the ultraviolet photoelectron spectroscopy measurements indicate that the work function of the indium tin oxide (ITO)/interlayer cathode is significantly reduced after UV treatment. In these i-PSC devices the LS effect originates from the adsorbed oxygen on the ITO substrates when oxygen plasma is used; however, even a small amount of oxygen from the ambient is also enough for triggering the LS effect, albeit with a weaker intensity. Our results suggest that the effect of adsorbed oxygen on ITO needs to be considered with attention while preparing i-PSCs. This is an important finding that can aid the large-scale manufacturing of organic solar cells via printing technologies, which do not always ensure the full protection of the device electrode substrates from oxygen. PMID- 27981017 TI - Formation and Stability of Low-Dimensional Structures for Group VIIIB and IB Transition Metals: The Role of sd4 Hybridization. AB - A quasi-sd4 hybridization state for group VIIIB and IB face-centered cubic (FCC) transition metals in low-dimensional nanostructures is identified, in contrast to the sd5 hybridization state in bulk. For Au, a novel three-shelled nanowire is designed with a hexagonal close-packed core in the sd5 hybridization, wrapped by FCC-(111) shell that adopts the quasi-sd4 hybridization. This new nanostructure exhibits remarkable stability and electronic properties. PMID- 27981019 TI - Shaping 3D Path of Electromagnetic Waves Using Gradient-Refractive-Index Metamaterials. AB - An all-dielectric semispherical lens with functions in shaping 3D wave propagation paths is proposed and experimentally verified. When radiation sources are placed in the central region, the lens behaves as a magnifying device to resolve the sources in subwavelength scale; while when the electromagnetic waves impinge on the semispherical lens from outside, they will be guided spirally inward. PMID- 27981020 TI - Mapping of Small Nerve Trunks and Branches Using Adaptive Flexible Electrodes. AB - Selective stimulation is delivered to the sciatic nerve using different paris of contacts on a split-ring electrode, while simulatneous recordings are acquired by the neural ribbon electrodes on three different branches. Two hook electrodes are also implanted in the muscle to monitor the activated muscle responses. It shows that the high precision implantation of electrodes, increases the efficacy and reduces the incidence of side effects. PMID- 27981018 TI - Two-Dimensional Fluorinated Graphene: Synthesis, Structures, Properties and Applications. AB - Fluorinated graphene, an up-rising member of the graphene family, combines a two dimensional layer-structure, a wide bandgap, and high stability and attracts significant attention because of its unique nanostructure and carbon-fluorine bonds. Here, we give an extensive review of recent progress on synthetic methods and C-F bonding; additionally, we present the optical, electrical and electronic properties of fluorinated graphene and its electrochemical/biological applications. Fluorinated graphene exhibits various types of C-F bonds (covalent, semi-ionic, and ionic bonds), tunable F/C ratios, and different configurations controlled by synthetic methods including direct fluorination and exfoliation methods. The relationship between the types/amounts of C-F bonds and specific properties, such as opened bandgap, high thermal and chemical stability, dispersibility, semiconducting/insulating nature, magnetic, self-lubricating and mechanical properties and thermal conductivity, is discussed comprehensively. By optimizing the C-F bonding character and F/C ratios, fluorinated graphene can be utilized for energy conversion and storage devices, bioapplications, electrochemical sensors and amphiphobicity. Based on current progress, we propose potential problems of fluorinated graphene as well as the future challenge on the synthetic methods and C-F bonding character. This review will provide guidance for controlling C-F bonds, developing fluorine-related effects and promoting the application of fluorinated graphene. PMID- 27981021 TI - Effectiveness of vaccination and wearing masks on seasonal influenza in Matsumoto City, Japan, in the 2014/2015 season: An observational study among all elementary schoolchildren. AB - Measures of seasonal influenza control are generally divided into two categories: pharmaceutical and non-pharmaceutical interventions. The effectiveness of these measures remains unclear, because of insufficient study sample size and/or differences in study settings. This observational epidemiological study involved all elementary schoolchildren in Matsumoto City, Japan, with seasonal influenza during the 2014/2015 season. Questionnaires, including experiences with influenza diagnosis and socio-demographic factors, were distributed to all 29 public elementary schools, involving 13,217 children, at the end of February 2015. Data were obtained from 10,524 children and analyzed with multivariate logistic regression analysis. The result showed that vaccination (odds ratio 0.866, 95% confidence interval 0.786-0.954) and wearing masks (0.859, 0.778-0.949) had significant protective association. Hand washing (1.447, 1.274-1.644) and gargling (1.319, 1.183-1.471), however, were not associated with protection. In the natural setting, hand washing and gargling showed a negative association, which may have been due to inappropriate infection control measures or aggregating infected and non-infected children to conduct those measures. These results may indicate a pathway for influenza transmission and explain why seasonal influenza control remains difficult in school settings. The overall effectiveness of vaccination and mask wearing was 9.9% and 8.6%, respectively. After dividing children into higher (grades 4-6) and lower (grade 1-3) grade groups, the effectiveness of vaccination became greater in the lower grade group, and the effectiveness of wearing masks became greater in the higher grade group. These results may provide valuable information about designing infection control measures that allocate resources among children. PMID- 27981022 TI - Gardening is beneficial for health: A meta-analysis. AB - There is increasing evidence that gardening provides substantial human health benefits. However, no formal statistical assessment has been conducted to test this assertion. Here, we present the results of a meta-analysis of research examining the effects of gardening, including horticultural therapy, on health. We performed a literature search to collect studies that compared health outcomes in control (before participating in gardening or non-gardeners) and treatment groups (after participating in gardening or gardeners) in January 2016. The mean difference in health outcomes between the two groups was calculated for each study, and then the weighted effect size determined both across all and sets of subgroup studies. Twenty-two case studies (published after 2001) were included in the meta-analysis, which comprised 76 comparisons between control and treatment groups. Most studies came from the United States, followed by Europe, Asia, and the Middle East. Studies reported a wide range of health outcomes, such as reductions in depression, anxiety, and body mass index, as well as increases in life satisfaction, quality of life, and sense of community. Meta-analytic estimates showed a significant positive effect of gardening on the health outcomes both for all and sets of subgroup studies, whilst effect sizes differed among eight subgroups. Although Egger's test indicated the presence of publication bias, significant positive effects of gardening remained after adjusting for this using trim and fill analysis. This study has provided robust evidence for the positive effects of gardening on health. A regular dose of gardening can improve public health. PMID- 27981023 TI - Pediatrician prescriptions for outdoor physical activity among children: A pilot study. AB - Research indicates that promoting time spent in the outdoors and outdoor physical activity increases children's daily physical activity and improves health. One method showing promise is doctor prescriptions for outdoor physical activity for children; however, no empirical evidence currently exists on prescriptions for children's outdoor physical activity. A pilot study was conducted at one pediatric practice in western North Carolina during 2015 to test the feasibility and potential effectiveness of conducting an outdoor physical activity prescription program for children aged 5-13 years. Three pediatricians wrote prescriptions for children (n = 38), discussed benefits of outdoor physical activity, and provided information packets to parents on nearby places for physical activity. Parents of patients of five pediatricians served as control (n = 32). Prior to seeing a pediatrician, parents completed a baseline survey that asked height and weight, assessed their views of children's physical activity, and their personal and child's physical activity/sedentary behaviors. A nurse measured children's height and weight. Parents were emailed one-month and three month follow-up surveys that asked the questions listed above. Changes in children's physical activity, outdoor physical activity, time spent in the outdoors, and sedentary activities were not significant between intervention and control groups. About half of parents (49%) viewed prescriptions as beneficial for their children and most used the intervention materials at home (70%). A larger study is needed to assess whether prescriptions increase children's physical activity. A critical examination of the intervention, pilot study design, and suggestions for a larger future study are provided. PMID- 27981024 TI - Memorizing fruit: The effect of a fruit memory-game on children's fruit intake. AB - : Food cues of palatable food are omnipresent, thereby simulating the intake of unhealthy snack food among children. As a consequence, this might lead to a higher intake of energy-dense snacks and less fruit and vegetables, a habit that increases the risk of developing chronic diseases. The aim of this experimental study is to examine whether playing a memory game with fruit affects fruit intake among young children. We used a randomized between-subject design with 127 children (age: 7-12 y) who played a memory-game, containing either fruit (n = 64) or non-food products (n = 63). While playing the memory-game in a separate room in school during school hours, free intake of fruit (mandarins, apples, bananas, and grapes) was measured. Afterwards, the children completed self-report measures, and length and weight were assessed. The main finding is that playing a memory-game containing fruit increases overall fruit intake (P = 0.016). Children who played the fruit version of the memory-game ate more bananas (P = 0.015) and mandarins (P = 0.036) than children who played the non-food memory-game; no effects were found for apples (P > 0.05) and grapes (P > 0.05). The findings suggest that playing a memory-game with fruit stimulates fruit intake among young children. This is an important finding because children eat insufficient fruit, according to international standards, and more traditional health interventions have limited success. Healthy eating habits of children maintain when they become adults, making it important to stimulate fruit intake among children in an enjoyable way. TRIAL REGISTRATION: Nederlands Trial Register TC = 5687. PMID- 27981025 TI - Long-term effects of a weight loss intervention with or without exercise component in postmenopausal women: A randomized trial. AB - The aim of this study was to determine the long-term effects of a weight loss intervention with or without an exercise component on body weight and physical activity. Women were randomized to diet (n = 97) or exercise (N = 98) for 16 weeks. During the intervention, both groups had achieved the set goal of 5-6 kg weight loss. All women were re-contacted twelve months after study cessation for follow-up where body weight and physical activity were measured (PASE questionnaire and ActiGraph accelerometer). At follow-up, body weight and physical activity (measured by the PASE questionnaire and accelerometer) were measured again. At follow-up, both mainly exercise (- 4.3 kg, p < 0.001) and diet (- 3.4 kg, p < 0.001) showed significantly reduced body weight compared to baseline. Both the mainly exercise and diet group were significantly more physically active at one year follow-up compared to baseline (PASE: + 33%, p < 0.001 and + 12%, p = 0.040, respectively; ActiGraph: + 16%, p = 0.012. and + 2.2%, p = 0.695 moderate-to-vigorous activity, respectively). Moreover, the increase in physical activity was statistically significantly when comparing exercise to diet (+ 0.6%, p = 0.035). ActiGraph data also showed significantly less sedentary time in mainly exercise group compared to baseline (- 2.1%, p = 0.018) and when comparing exercise to diet (- 1.8%, p = 0.023). No significant within group differences were found for the diet group. This study shows largely sustained weight loss one year after completing a weight loss program with and without exercise in overweight postmenopausal women. Although the mainly exercise group maintained more physically active compared to the diet group, maintenance of weight loss did not differ between groups. PMID- 27981027 TI - Renal cell carcinoma and hematological malignancies. PMID- 27981026 TI - Social and emotional support as a protective factor against current depression among individuals with adverse childhood experiences. AB - Depression is one of the most prevalent mental health disorders among adults with adverse childhood experiences (ACE). Several studies have well documented the protective role of social support against depression in other populations. However, the impact of perceived social and emotional support (PSES) on current depression in a large community sample of adults with ACE has not been studied yet. This study tests the hypothesis that PSES is a protective factor against current depression among adults with ACE. Data from the 2010 Behavioral Risk Factor Surveillance System (BRFSS) involving adults with at least one ACE were used for the purpose of this study (n = 12.487). PSES had three categories: Always, Usually/Sometimes, and Rarely/Never. Current depression, defined based on the responses to the eight-item Patient Health Questionnaire (PHQ-8) depression scale, was treated as a binary outcome of interest: Present or absent. Logistic regression models were used for the analysis adjusting for all potential confounders. When compared to individuals who reported that they rarely/never received social and emotional support, individuals who reported that they always received were 87% less likely to report current depression (AOR: 0.13 [95% CI: 0.08-0.21]); and those who reported that they usually/sometimes received social and emotional support were 69% less likely to report current depression (AOR: 0.31 [95% CI: 0.20-0.46]). The results of this study highlight the importance of social and emotional support as a protective factor against depression in individuals with ACE. Health care providers should routinely screen for ACE to be able to facilitate the necessary social and emotional support. PMID- 27981028 TI - Regional correlations between [11C]PIB PET and post-mortem burden of amyloid-beta pathology in a diverse neuropathological cohort. AB - Imaging-pathological correlation studies show that in vivo amyloid-beta (Abeta) positron emission tomography (PET) strongly predicts the presence of significant Abeta pathology at autopsy. We sought to determine whether regional PiB-PET uptake would improve sensitivity for amyloid detection in comparison with global measures (experiment 1), and to estimate the relative contributions of different Abeta aggregates to in vivo PET signal (experiment 2). In experiment 1, 54 subjects with [11C] PiB-PET during life and postmortem neuropathologic examination (85.2% with dementia, interval from PET to autopsy 3.1 +/- 1.9 years) were included. We assessed Thal amyloid phase (N = 36) and CERAD score (N = 54) versus both global and regional PiB SUVRs. In experiment 2 (N = 42), PiB SUVR and post-mortem amyloid beta burden was analyzed in five customized regions of interest matching regions sampled at autopsy. We assessed the relative contribution of neuritic plaques (NPs), diffuse plaques (DPs) and cerebral amyloid angiopathy (CAA) to regional PIB SUVR using multi-linear regression. In experiment 1, there were no differences in Area Under the Curve for amyloid phase >= A2 and CERAD score >= C2 between global and highest regional PiB SUVR (p = 0.186 and 0.230). In experiment 2, when NPs, DPs, and/or CAA were included in the same model, moderate to severe NPs were independently correlated with PiB SUVR in all regions except for the inferior temporal and calcarine ROI (beta = 0.414 0.804, p < 0.05), whereas DPs were independently correlated with PiB SUVR in the angular gyrus ROI (beta = 0.446, p = 0.010). CAA was also associated with PiB SUVR in the inferior temporal and calcarine ROI (beta = 0.222-0.355, p < 0.05). In conclusion, global PiB-PET SUVR performed as well as regional values for amyloid detection in our cohort. The substrate-specific binding of PiB might differ among the brain specific regions. PMID- 27981029 TI - Automated white matter fiber tract identification in patients with brain tumors. AB - We propose a method for the automated identification of key white matter fiber tracts for neurosurgical planning, and we apply the method in a retrospective study of 18 consecutive neurosurgical patients with brain tumors. Our method is designed to be relatively robust to challenges in neurosurgical tractography, which include peritumoral edema, displacement, and mass effect caused by mass lesions. The proposed method has two parts. First, we learn a data-driven white matter parcellation or fiber cluster atlas using groupwise registration and spectral clustering of multi-fiber tractography from healthy controls. Key fiber tract clusters are identified in the atlas. Next, patient-specific fiber tracts are automatically identified using tractography-based registration to the atlas and spectral embedding of patient tractography. Results indicate good generalization of the data-driven atlas to patients: 80% of the 800 fiber clusters were identified in all 18 patients, and 94% of the 800 fiber clusters were found in 16 or more of the 18 patients. Automated subject-specific tract identification was evaluated by quantitative comparison to subject-specific motor and language functional MRI, focusing on the arcuate fasciculus (language) and corticospinal tracts (motor), which were identified in all patients. Results indicate good colocalization: 89 of 95, or 94%, of patient-specific language and motor activations were intersected by the corresponding identified tract. All patient-specific activations were within 3mm of the corresponding language or motor tract. Overall, our results indicate the potential of an automated method for identifying fiber tracts of interest for neurosurgical planning, even in patients with mass lesions. PMID- 27981031 TI - Probabilistic mapping of deep brain stimulation effects in essential tremor. AB - OBJECTIVE: To create probabilistic stimulation maps (PSMs) of deep brain stimulation (DBS) effects on tremor suppression and stimulation-induced side effects in patients with essential tremor (ET). METHOD: Monopolar reviews from 16 ET-patients which consisted of over 600 stimulation settings were used to create PSMs. A spherical model of the volume of neural activation was used to estimate the spatial extent of DBS for each setting. All data was pooled and voxel-wise statistical analysis as well as nonparametric permutation testing was used to confirm the validity of the PSMs. RESULTS: PSMs showed tremor suppression to be more pronounced by stimulation in the zona incerta (ZI) than in the ventral intermediate nucleus (VIM). Paresthesias and dizziness were most commonly associated with stimulation in the ZI and surrounding thalamic nuclei. DISCUSSION: Our results support the assumption, that the ZI might be a very effective target for tremor suppression. However stimulation inside the ZI and in its close vicinity was also related to the occurrence of stimulation-induced side effects, so it remains unclear whether the VIM or the ZI is the overall better target. The study demonstrates the use of PSMs for target selection and evaluation. While their accuracy has to be carefully discussed, they can improve the understanding of DBS effects and can be of use for other DBS targets in the therapy of neurological or psychiatric disorders as well. Furthermore they provide a priori information about expected DBS effects in a certain region and might be helpful to clinicians in programming DBS devices in the future. PMID- 27981030 TI - 9.4 T MR microscopy of the substantia nigra with pathological validation in controls and disease. AB - BACKGROUND: The anatomy of the substantia nigra on conventional MRI is controversial. Even using histological techniques it is difficult to delineate with certainty from surrounding structures. We sought to define the anatomy of the SN using high field spin-echo MRI of pathological material in which we could study the anatomy in detail to corroborate our MRI findings in controls and Parkinson's disease and progressive supranuclear palsy. METHODS: 23 brains were selected from the Queen Square Brain Bank (10 controls, 8 progressive supranuclear palsy, 5 Parkinson's disease) and imaged using high field 9.4 Tesla spin-echo MRI. Subsequently brains were cut and stained with Luxol fast blue, Perls stain, and immunohistochemistry for substance P and calbindin. Once the anatomy was defined on histology the dimensions and volume of the substantia nigra were determined on high field magnetic resonance images. RESULTS: The anterior border of the substantia nigra was defined by the crus cerebri. In the medial half it was less distinct due to the deposition of iron and the interdigitation of white matter and the substantia nigra. The posterior border was flanked by white matter bridging the red nucleus and substantia nigra and seen as hypointense on spin-echo magnetic resonance images. Within the substantia nigra high signal structures corresponded to confirmed nigrosomes. These were still evident in Parkinson's disease but not in progressive supranuclear palsy. The volume and dimensions of the substantia nigra were similar in Parkinson's disease and controls, but reduced in progressive supranuclear palsy. CONCLUSIONS: We present a histologically validated anatomical description of the substantia nigra on high field spin-echo high resolution magnetic resonance images and were able to delineate all five nigrosomes. In accordance with the pathological literature we did not observe changes in the nigrosome structure as manifest by volume or signal characteristics within the substantia nigra in Parkinson's disease whereas in progressive supranuclear palsy there was microarchitectural destruction. PMID- 27981034 TI - Common variation of the CYP17 gene in Iraqi women with endometriosis disease. AB - Common variants among genes coding for enzymes in sex steroid biosynthetic pathways may influence the risk of endometriosis in Iraqi women patients in the last years. Cytochrome P450c17a1 (CYP17), a gene that codes for a key enzyme (cytochrome P450c17a1) in a rate-limiting step of estrogen biosynthesis has attracted considerable attention as an important gene for endometriosis. To evaluate the relationship between common genetic variations in CYP17 and endometriosis risk and determine the main effects of those variations on the gene expression. A women-based case control study of Iraqi women aged range (23-46), the associations between selected single-nucleotide polymorphisms (SNPs) in the CYP17 gene and endometriosis diagnosis in fifty women and thirty disease-free controls were evaluated. The study found a significant association (P <= 0.01)between endometriosis and selected SNPs of CYP17 gene, with the homozygous genotype conferring decreased risk. A highly significant difference (P <= 0.01) in CYP17 gene expression from women with versus without endometriosis and increased by 1.56-fold in women with endometriosis. These findings suggest that variation in or around CYP17 may be associated with endometriosis development in the Iraqi women. PMID- 27981035 TI - Anastomotic Urethroplasty for an Obstructing Calculus Within a Bulbar Urethral Diverticulum and Urethral Stricture. AB - A 61-year-old male with prior history of endoscopic urethral calculus removal presented to the emergency room with urinary retention and a palpable perineal mass. A CT showed a large calcification within the bulbar urethra. After multiple unsuccessful attempts at foley catheter insertion, the urology service was consulted. The patient was taken to the operating room where an obstructing urethral calculus with associated urethral stricture was visualized on cystoscopy. We present an exceedingly rare case of recurrent urethrolithiasis with associated urethral stricture managed with initial suprapubic tube and delayed primary end-to-end urethroplasty, excision of urethral stricture and urethral diverticulectomy. PMID- 27981036 TI - Penile Ulceration Secondary to Nicorandil Use. AB - Nicorandil is a medication used for treatment and prevention of angina pectoris. Its mode of action involves both arterial and venous vasodilation. Although there are numerous known side effects, one of the more unusual, adverse reactions is ulceration of the external genitalia. This case reports the finding of penile preputial ulceration secondary to the use of Nicorandil. The authors make some recommendations for management. PMID- 27981032 TI - High angular resolution diffusion-weighted imaging in mild traumatic brain injury. AB - We sought to investigate white matter abnormalities in mild traumatic brain injury (mTBI) using diffusion-weighted magnetic resonance imaging (DW-MRI). We applied a global approach based on tract-based spatial statistics skeleton as well as constrained spherical deconvolution tractography. DW-MRI was performed on 102 patients with mTBI within two months post-injury and 30 control subjects. A robust global approach considering only the voxels with a single-fiber configuration was used in addition to global analysis of the tract skeleton and probabilistic whole-brain tractography. In addition, we assessed whether the microstructural parameters correlated with age, time from injury, patient's outcome and white matter MRI hyperintensities. We found that whole-brain global approach restricted to single-fiber voxels showed significantly decreased fractional anisotropy (FA) (p = 0.002) and increased radial diffusivity (p = 0.011) in patients with mTBI compared with controls. The results restricted to single-fiber voxels were more significant and reproducible than those with the complete tract skeleton or the whole-brain tractography. FA correlated with patient outcomes, white matter hyperintensities and age. No correlation was observed between FA and time of scan post-injury. In conclusion, the global approach could be a promising imaging biomarker to detect white matter abnormalities following traumatic brain injury. PMID- 27981037 TI - Development of Squamous Cell Carcinoma of Buccal Mucosa Graft Used for Urethroplasty: A Case Report. AB - Urethroplasty may involve the use of tissue substitution including buccal mucosa graft (BMG), penile fasciocutaneous flaps, or skin grafts. Stricture recurrence and fistula formation are some uncommon complications that can result from surgery. The development of squamous cell carcinoma (SCC) after BMG substitution urethroplasty is a new complication that we encountered that has not been described in the literature. We present the first reported case of a patient who developed SCC of the buccal mucosa graft used to reconstruct the urethra. PMID- 27981033 TI - Cingulate cortex functional connectivity predicts future relapse in alcohol dependent individuals. AB - Alcohol dependence is a chronic relapsing illness. Alcohol and stress cues have consistently been shown to increase craving and relapse risk in recovering alcohol dependent (AUD) patients. However, differences in functional connectivity in response to these cues have not been studied using data-driven approaches. Here, voxel-wise connectivity is used in a whole-brain investigation of functional connectivity differences associated with alcohol and stress cues and to examine whether these differences are related to subsequent relapse. In Study 1, 45, 4- to 8-week abstinent, recovering AUD patients underwent functional magnetic resonance imaging during individualized imagery of alcohol, stress, and neutral cues. Relapse measures were collected prospectively for 90 days post discharge from inpatient treatment. AUD patients showed blunted anterior (ACC), mid (MCC) and posterior cingulate cortex (PCC), voxel-wise connectivity responses to stress compared to neutral cues and blunted PCC response to alcohol compared to neutral cues. Using Cox proportional hazard regression, weaker connectivity in ACC and MCC during neutral exposure was associated with longer time to relapse (better recovery outcome). Similarly, greater connectivity in PCC during alcohol cue compared to stress cue was associated with longer time to relapse. In Study 2, a sub-group of 30 AUD patients were demographically-matched to 30 healthy control (HC) participants for group comparisons. AUD compared to HC participants showed reduced cingulate connectivity during alcohol and stress cues. Using novel data-driven approaches, the cingulate cortex emerged as a key region in the disruption of functional connectivity during alcohol and stress-cue processing in AUD patients and as a marker of subsequent alcohol relapse. PMID- 27981038 TI - Corrigendum: Hemorrhagic Fever with Renal Syndrome: Pathogenesis and Clinical Picture. AB - [This corrects the article on p. 1 in vol. 6, PMID: 26870699.]. PMID- 27981040 TI - Type II diabetes and personality; a study to explore other psychosomatic aspects of diabetes. AB - BACKGROUND: As one of the most common chronic diseases, diabetes and its control are affected by the patients' psychological and spiritual attributes. The present study investigates the relationship between glycemic control in patients with type II diabetes and personality traits, defense mechanisms and spirituality. METHOD: The present cross-sectional study was conducted on 400 Iranian patients with type II diabetes, 64% were men. Participants completed the NEO Personality Inventory, the Defense Style Questionnaire (DSQ) and the Spiritual Assessment Inventory (SAI) and then underwent a blood sampling for the assessment of HbA1C levels. RESULTS: Of the five personality traits, extraversion (r = -0.13 and P < 0.01) and conscientiousness (r = -0.13 and P < 0.01) had significant negative relationships with HbA1C HbA1C levels, while neuroticism had a significant positive relationship with HbA1C levels (r = 0.12 and P < 0.05). Of the defense styles assessed, the neurotic style was found to have a significant negative relationship with HbA1C levels (r = -0.1 and P < 0.05). Also, of the spirituality elements, impression management had significant relationship with glycemic control (r = 0.17 and P < 0.001). CONCLUSION: According to data, Extraversion and conscientiousness can help control blood sugar while anxiety and negative emotions have detrimental effects on glycemic control. As a result considering psychological counselling beside medical interventions can help to better treatment. PMID- 27981039 TI - Effects of cell seeding density on real-time monitoring of anti-proliferative effects of transient gene silencing. AB - BACKGROUND: Real-time cellular analysis systems enable impedance-based label-free and dynamic monitoring of various cellular events such as proliferation. In this study, we describe the effects of initial cell seeding density on the anti proliferative effects of transient gene silencing monitored via real-time cellular analysis. We monitored the real-time changes in proliferation of Huh7 hepatocellular carcinoma and A7r5 vascular smooth muscle cells with different initial seeding densities following transient receptor potential canonical 1 (TRPC1) silencing using xCELLigence system. Huh7 and A7r5 cells were seeded on E plate 96 at 10,000, 5000, 1250 and 5000, 2500 cells well-1, respectively, following silencing vector transfection. The inhibitory effects of transient silencing on cell proliferation monitored every 30 min for 72 h. RESULTS: TRPC1 silencing did not inhibit the proliferation rates of Huh7 cells at 10,000 cells well-1 seeding density. However, a significant anti-proliferative effect was observed at 1250 cells well-1 density at each time point throughout 72 h. Furthermore, significant inhibitory effects on A7r5 proliferation were observed at both 5000 and 2500 cells well-1 for 72 h. CONCLUSIONS: Data suggest that the effects of transient silencing on cell proliferation differ depending on the initial cell seeding density. While high seeding densities mask the significant changes in proliferation, the inhibitory effects of silencing become apparent at lower seeding densities as the entry into log phase is delayed. Using the optimal initial seeding density is crucial when studying the effects of transient gene silencing. In addition, the results suggest that TRPC1 may contribute to proliferation and phenotypic switching of vascular smooth muscle cells. PMID- 27981041 TI - Statins alone or polypill for primary prevention of cardiovascular diseases. PMID- 27981042 TI - Postpartum glucose follow-up and lifestyle management after gestational diabetes mellitus: general practitioner and patient perspectives. AB - BACKGROUND: Incidence of type 2 diabetes is high after gestational diabetes mellitus (GDM). We aimed to evaluate the adherence to follow-up six-weeks postpartum visits in secondary care after GDM and glucose monitoring in primary care longer than 12-14 months after delivery and the years thereafter. In addition, we examined the women's lifestyle after delivery. METHODS: A cross sectional follow-up survey among women with a history of GDM and their general practitioners (GP). Rates of attendance at the six-weeks postpartum visit and glucose testing were obtained from hospital records, over the period 2011-2012. Rates of annual follow-up postpartum glucose testing were assessed by a survey among their GP's. Lifestyle of the women on diet and exercise was assessed by questionnaire in 2015. RESULTS: In total 197 women were eligible for the study. Of these, 156 (79%) attended the six-weeks postpartum visit at the diabetes outpatient clinic and in 145 (93%) of these women glucose testing was performed. In total 77 (39%) women responded to the invitation to participate in this study and filled in the lifestyle questionnaire. About one third of the women met the recommendations for sufficient physical activity. A majority of them did not fulfil the Dutch guidelines on healthy diet - fruit intake 35.1%, vegetables intake 7.8%. Of the 74 invited GP's, 61 responded (82%), only 12 (20%) reported that they had performed a follow-up glucose testing within >12-14 months postpartum. Of these women, five were tested only in the first year of follow-up, five also in the second year, and two were tested for three consecutive years. CONCLUSIONS: Despite the high attendance rate of six-weeks postpartum visit and glucose testing, we observed low rates of longer-term follow-up regarding postpartum glucose testing. Moreover, we found a suboptimal adherence to healthy lifestyle for women with a history of GDM. PMID- 27981043 TI - Adding to the spectrum of insulin sensitive populations for mixed meal tolerance test glucose reliability assessment. AB - As a measure of insulin sensitivity, the mixed meal tolerance test (MMTT) is a simple technique that can provide robust results. The assay consists of examining plasma glucose, insulin and C-peptide prior to and following the consumption of a test meal. While this procedure has been used in clinical research for several years, there is no set standard protocol, and only until recently has the reliability of this assay been thoroughly evaluated in prediabetes and type 2 diabetes subjects. Interestingly, the results from this recent study demonstrated stronger MMTT reliability for the prediabetes and diabetes cohorts compared to obese controls. This finding suggests that the obese control group may have more inherent variability in glucose response during a meal challenge likely due to compensatory influences typically observed in non-diabetic insulin-resistant subjects. Furthermore, this study raises the question whether the MMTT assay is reliable in a non-obese cohort. Therefore, to promote the standardization of this technique and contribute to the band of insulin sensitive populations, we employed the same methodology and test meal as the reference study to evaluate the MMTT reliability in healthy and overweight men. Indeed, the interclass coefficient revealed high glucose response repeatability during the MMTT in insulin-sensitive men. Overall, the MMTT is a reliable test across a range of insulin sensitivity including healthy men. However, we propose further investigation may be required to fully define the utility of this methodology in obese non-diabetic insulin-resistant populations. PMID- 27981044 TI - Evaluation of biochemical recurrence in patients with high-risk prostate cancer treated with radical prostatectomy and radiotherapy plus androgen deprivation therapy. AB - OBJECTIVE: The aim of this study was to evaluate the biochemical recurrence (BCR) in patients with high-risk prostate cancer (PCa) treated with radical prostatectomy (RP) or radiotherapy (RT) plus androgen deprivation therapy (ADT). METHODS: Subjects were patients with National Comprehensive Cancer Network defined high-risk PCa treated with either RP or RT plus ADT. We calculated BCR free survival in patients with those treatments and evaluated risk factor against BCR. RESULTS: A total of 114 patients, 71 RP and 43 RT plus ADT, were evaluated. A total of 59 and 20.9% of patients experienced BCR in the RP and RT treatment groups, respectively. The 5-year BCR-free survival probabilities improved significantly for patients who received RT compared to those who received RP (81.3 vs 37.3%, P<0.001). According to the number of risk factors, 59.2% of patients in the RP and 51.2% of patients in the RT treatment groups were classified with one risk factor (P<0.014). The 5-year BCR-free survival probabilities for patients treated with RP were 46.6 and 21.7% for one and multiple risk factors, respectively (P=0.008). On univariate analysis, only the number of risk factors had a significant impact on the risk of BCR. Meanwhile, there were no significant differences in the 5-year BCR-free survival probabilities between one and multiple risk factors in patients treated with RT. CONCLUSION: Among patients treated with RP, a marked heterogeneity existed in the oncological outcomes. Based on these findings, the number of risk factors should be emphasized to decide the optimal treatments for patients with high-risk PCa. PMID- 27981045 TI - Characterization of South American Snails of the Genus Biomphalaria (Basommatophora: Planorbidae) and Schistosoma mansoni (Platyhelminthes: Trematoda) in Molluscs by PCR-RFLP. AB - The identification of snails of the genus Biomphalaria can be done using morphological characteristics which depends on the size of the snails and skill and knowledge of researcher. These methods sometimes are not adequate for identification of species. The PCR-RFLP, using the ITS region of the rDNA, has been used to identify Brazilian species of the genus Biomphalaria. Nevertheless, there is a lack of information about snails from other Latin American countries. In addition, some snails may be infected by Schistosoma mansoni and when submitted to PCR-RFLP they show molecular profiles different from those previously standardized for the other mollusc species. In this work the molecular profiles of 15 species and the subspecies were established by PCR-RFLP of ITS rDNA with the enzyme DdeI. Moreover, the molecular profiles of host species, B. glabrata, B. straminea, B. tenagophila, and B. prona, infected by S. mansoni were also established. The molluscs were dissected to permit morphological identification. These results contribute to a correct identification of snails of the genus Biomphalaria and detection of these snails infected by S. mansoni. PMID- 27981046 TI - In Vivo Detection of the Effect of Electroacupuncture on "Zusanli" Acupoint in Rats with Adjuvant-Induced Arthritis through Optical Coherence Tomography. AB - This study aimed to investigate the effect of electroacupuncture (EA) treatment through optical coherence tomography (OCT) in vivo on rats with adjuvant-induced arthritis. OCT images were obtained from the ankle of the right hind paws of the rats in control, model, and EA groups before modelling and 1 day, 8 days, 15 days, 22 days, and 29 days after modelling. Results demonstrated that the OCT signal of the ankle of the right hind paws of the rats was indistinct compared to 1 day after modelling and before modelling in the EA group. In the EA group, the light averaged attenuation coefficients of the ankle tissues decreased as treatment duration was prolonged after EA was administered (3.43, 2.96, 2.61, 2.42, and 2.29 mm-1, resp.). There was a significant difference in attenuation coefficient decrease between the 29th d and the 1st d for EA group compared with control group (P < 0.01). This condition indicated that the light absorption of the ankle of the treated rats in the EA group decreased. Therefore, OCT can be used to monitor the effect of treatment on rats with arthritis in vivo. PMID- 27981047 TI - Enhancement of Polymerase Activity of the Large Fragment in DNA Polymerase I from Geobacillus stearothermophilus by Site-Directed Mutagenesis at the Active Site. AB - The large fragment of DNA polymerase I from Geobacillus stearothermophilus GIM1.543 (Bst DNA polymerase) with 5'-3' DNA polymerase activity while in absence of 5'-3' exonuclease activity possesses high thermal stability and polymerase activity. Bst DNA polymerase was employed in isothermal multiple self-matching initiated amplification (IMSA) which amplified the interest sequence with high selectivity and was widely applied in the rapid detection of human epidemic diseases. However, the detailed information of commercial Bst DNA polymerase is unpublished and well protected by patents, which makes the high price of commercial kits. In this study, wild-type Bst DNA polymerase (WT) and substitution mutations for improving the efficiency of DNA polymerization were expressed and purified in E. coli. Site-directed substitutions of four conserved residues (Gly310, Arg412, Lys416, and Asp540) in the activity site of Bst DNA polymerase influenced efficiency of polymerizing dNTPs. The substitution of residue Gly310 by alanine or leucine and residue Asp540 by glutamic acid increased the efficiency of polymerase activity. All mutants with higher polymerizing efficiency were employed to complete the rapid detection of EV71 associated hand, foot, and mouth disease (HFMD) by IMSA approach with relatively shorter period which is suitable for the primary diagnostics setting in rural and underdeveloped areas. PMID- 27981048 TI - Examination of Calcium Silicate Cements with Low-Viscosity Methyl Cellulose or Hydroxypropyl Cellulose Additive. AB - The purpose of this study was to improve the operability of calcium silicate cements (CSCs) such as mineral trioxide aggregate (MTA) cement. The flow, working time, and setting time of CSCs with different compositions containing low viscosity methyl cellulose (MC) or hydroxypropyl cellulose (HPC) additive were examined according to ISO 6876-2012; calcium ion release analysis was also conducted. MTA and low-heat Portland cement (LPC) including 20% fine particle zirconium oxide (ZO group), LPC including zirconium oxide and 2 wt% low-viscosity MC (MC group), and HPC (HPC group) were tested. MC and HPC groups exhibited significantly higher flow values and setting times than other groups (p < 0.05). Additionally, flow values of these groups were higher than the ISO 6876-2012 reference values; furthermore, working times were over 10 min. Calcium ion release was retarded with ZO, MC, and HPC groups compared with MTA. The concentration of calcium ions was decreased by the addition of the MC or HPC group compared with the ZO group. When low-viscosity MC or HPC was added, the composition of CSCs changed, thus fulfilling the requirements for use as root canal sealer. Calcium ion release by CSCs was affected by changing the CSC composition via the addition of MC or HPC. PMID- 27981049 TI - Effect of Salinity and Alkalinity on Luciobarbus capito Gill Na+/K+-ATPase Enzyme Activity, Plasma Ion Concentration, and Osmotic Pressure. AB - We evaluated the individual and combined effects of salinity and alkalinity on gill Na+/K+-ATPase enzyme activity, plasma ion concentration, and osmotic pressure in Luciobarbus capito. Increasing salinity concentrations (5, 8, 11, and 14 g/L) were associated with an initial increase and then decrease in L. capito gill Na+/K+-ATPase activity. Activity was affected by the difference between internal and external Na+ ion concentrations and osmotic pressure (P < 0.05). Both plasma ion (Na+, K+, and Cl-) concentration and osmotic pressure increased significantly (P < 0.05). An increase in alkalinity (15, 30, 45, and 60 mM) caused a significant increase in plasma K+ and urea nitrogen concentrations (P < 0.05) but had no effect on either plasma osmotic pressure or gill filament ATPase activity. In the two-factor experiment, the saline-alkaline interaction caused a significant increase in plasma ion (Na+, Cl-, and urea nitrogen) and osmotic pressure (P < 0.05). Variance analysis revealed that salinity, alkalinity, and their interaction significantly affected osmotic pressure, with salinity being most affected, followed by alkalinity, and their interaction. Gill filament ATPase activity increased at first and then decreased; peak values were observed in the orthogonal experiment group at a salinity of 8 g/L and alkalinity of 30 mM. PMID- 27981050 TI - Minimally Invasive Treatment of Displaced Proximal Humeral Fractures in Patients Older Than 70 Years Using the Humerusblock. AB - Background. Surgical treatment of proximal humeral fractures (PHF) in osteoporotic bone of elderly patients is challenging. The aim of this retrospective study was to evaluate the clinical and radiological outcome after percutaneous reduction and internal fixation of osteoporotic PHF in geriatric patients using the semirigid Humerusblock device. Methods. In the study period from 2005 to 2010, 129 patients older than 70 years were enrolled in the study. After a mean follow-up of 23 months, a physical examination, using the Constant Murley score and the VAS pain scale, was performed. Furthermore radiographs were taken to detect signs of malunion, nonunion, and avascular necrosis. Results. The recorded Constant-Murley score was 67.7 points (87.7% of the noninjured arm) for two-part fractures, 67.9 points (90.8%) for three-part fractures, and 43.0 points (56.7%) for four-part fractures. In ten shoulders (7.8%) loss of reduction and in four shoulders (3.1%) nonunion were the reason for revision surgery. Avascular humeral head necrosis developed in eight patients (6.2%). Conclusions. In two- and three-part fractures postoperative results are promising. Sufficient ability for the activities of daily living was achieved. In four-part fractures the functional results were less satisfying regarding function and pain with a high postoperative complication rate. In those patients other treatment strategies should be considered. Study design. Therapeutic retrospective case series (evidence-based medicine (EBM) level IV). PMID- 27981051 TI - Cogels of Hyaluronic Acid and Acellular Matrix for Cultivation of Adipose-Derived Stem Cells: Potential Application for Vocal Fold Tissue Engineering. AB - Stem cells based tissue engineering has been one of the potential promising therapies in the research on the repair of tissue diseases including the vocal fold. Decellularized extracellular matrix (DCM) as a promising scaffold has be used widely in tissue engineering; however, it remained to be an important issue in vocal fold regeneration. Here, we applied the hydrogels (hyaluronic acid [HA], HA-collagen [HA-Col], and HA-DCM) to determine the effects of hydrogel on the growth and differentiation of human adipose-derived stem cells (hADSCs) into superficial lamina propria fibroblasts. hADSCs were isolated and characterized by fluorescence-activated cell sorting. The results indicated that HA-DCM hydrogel enhanced cell proliferation and prolonged cell morphology significantly compared to HA and HA-Col hydrogel. Importantly, the differentiation of hADSCs into fibroblasts was also promoted by cogels of HA-Col and HA-DCM significantly. The differentiation of hADSCs towards superficial lamina propria fibroblasts was accelerated by the secretion of HGF, IL-8, and VEGF, the decorin and elastin expression, and the synthesis of chondroitin sulfate significantly. Therefore, the cogel of HA-DCM hydrogel was shown to be outstanding in apparent stimulation of hADSCs proliferation and differentiation to vocal fold fibroblasts through secretion of important growth factors and synthesis of extracellular matrix. PMID- 27981052 TI - Detection of Natural Toxoplasma gondii Infection in Chicken in Thika Region of Kenya Using Nested Polymerase Chain Reaction. AB - The detection of Toxoplasma gondii in free-range chickens is a good indicator of possible risk to human beings. The aim of this study was to investigate the occurrence of T. gondii in free-range chicken using polymerase chain reaction (PCR). Brain samples from 105 free-range chickens from three administrative areas in Thika region, Kenya, were collected, DNA-extracted, and analyzed using PCR to detect presence of T. gondii. The overall prevalence of T. gondii in all the three areas was 79.0% (95% CI: 70.0-86.4%) and the prevalence across the three areas was not significantly different (P = 0.5088; chi2 = 1.354). Female chickens had higher (79.4%) prevalence than males (78.6%), although the difference was not significant (P = 0.922, chi2 = 0.01). However, chickens that were more than 2 years old had significantly (P = 0.003; chi2 = 11.87) higher prevalence compared to younger ones. The study indicates that there was a high occurrence of T. gondii infection in free-range chickens from Thika region and that the infection rate is age dependent. Further studies should be carried out to determine the possible role of roaming chickens in the epidemiology of the disease among humans in the area. PMID- 27981053 TI - The Use of Two Culturing Methods in Parallel Reveals a High Prevalence and Diversity of Arcobacter spp. in a Wastewater Treatment Plant. AB - The genus Arcobacter includes species considered emerging food and waterborne pathogens. Despite Arcobacter has been linked to the presence of faecal pollution, few studies have investigated its prevalence in wastewater, and the only isolated species were Arcobacter butzleri and Arcobacter cryaerophilus. This study aimed to establish the prevalence of Arcobacter spp. at a WWTP using in parallel two culturing methods (direct plating and culturing after enrichment) and a direct detection by m-PCR. In addition, the genetic diversity of the isolates was established using the ERIC-PCR genotyping method. Most of the wastewater samples (96.7%) were positive for Arcobacter and a high genetic diversity was observed among the 651 investigated isolates that belonged to 424 different ERIC genotypes. However, only few strains persisted at different dates or sampling points. The use of direct plating in parallel with culturing after enrichment allowed recovering the species A. butzleri, A. cryaerophilus, Arcobacter thereius, Arcobacter defluvii, Arcobacter skirrowii, Arcobacter ellisii, Arcobacter cloacae, and Arcobacter nitrofigilis, most of them isolated for the first time from wastewater. The predominant species was A. butzleri, however, by direct plating predominated A. cryaerophilus. Therefore, the overall predominance of A. butzleri was a bias associated with the use of enrichment. PMID- 27981055 TI - Perspectives of caregivers towards physiotherapy treatment for children with burns in Harare, Zimbabwe: A cross-sectional study. AB - BACKGROUND: Physiotherapy is an integral part of treatment for paediatric burns. In Zimbabwe, children are admitted in paediatric burn unit with their caregivers, who play important roles such as providing explanation and obtaining cooperation of the child during physiotherapy, which is often uncomfortable or painful to the patient. The aim of this study was to determine the perspectives of caregivers towards physiotherapy interventions administered to hospitalized children at central hospitals in Harare, Zimbabwe. METHODS: A descriptive cross-sectional study was conducted using self-administered questionnaires. The study was carried out at two large central hospitals (Parirenyatwa Hospital and Harare Central Hospital). The study targeted all the caregivers of children below the age of 12 years with a diagnosis of burns, irrespective of severity or area affected, who were admitted in the two paediatric burn units. Of the 34 caregivers eligible to participate, 31 (91.1 %) questionnaires had complete data and were analysed. The analyses were done using Statistica version 12.0. RESULTS: The median age of the caregivers was 28 years (IQR = 24-33 years). Female caregivers constituted 90.3 % of the sample. The majority of the caregivers (n = 26, 83.9 %) were biological mothers to the hospitalised child. The majority of children (n = 20, 64.5 %) hospitalised were between 0 and 4 years. The commonest cause of burns was scalding (n = 19, 61.2 %). The burns were mainly in the upper extremities (n = 11, 35.5 %). Physiotherapy for the burns was mainly active and passive joint range of motion exercises (n = 30, 96.8 %). The caregivers' perceptions towards physiotherapy were mainly positive (n = 20, 64.5 %) indicating that physiotherapy plays an important role in burn management. Of the 21 caregivers given a ward exercise programme, 13 (61.9 %) were not compliant. CONCLUSIONS: Caregivers' perspectives towards physiotherapy were largely positive and are similar to those found in other studies. The majority of the caregivers indicated that physiotherapy was important in the overall management of burns leading to proper healing of the wounds without complications. PMID- 27981054 TI - Complement Receptor Type 1 Suppresses Human B Cell Functions in SLE Patients. AB - Complement receptors (CRs) play an integral role in innate immunity and also function to initiate and shape the adaptive immune response. Our earlier results showed that complement receptor type 1 (CR1, CD35) is a potent inhibitor of the B cell receptor- (BCR-) induced functions of human B lymphocytes. Here we show that this inhibition occurs already at the initial steps of B cell activation since ligation of CR1 reduces the BCR-induced phosphorylation of key signaling molecules such as Syk and mitogen activated protein kinases (MAPKs). Furthermore, our data give evidence that although B lymphocytes of active systemic lupus erythematosus (SLE) patients express lower level of CR1, the inhibitory capacity of this complement receptor is still maintained and its ligand-induced clustering results in significant inhibition of the main B cell functions, similar to that found in the case of healthy individuals. Since we have found that reduced CR1 expression of SLE patients does not affect the inhibitory capacity of the receptor, our results further support the therapeutical potential of CD35 targeting the decrease of B cell activation and autoantibody production in autoimmune patients. PMID- 27981056 TI - Outcomes following operative vs. non-operative management of blunt traumatic pancreatic injuries: a retrospective multi-institutional study. AB - BACKGROUND: Traumatic pancreatic injuries are rare, and guidelines specifying management are controversial and difficult to apply in the acute clinical setting. Due to sparse data on these injuries, we carried out a retrospective review to determine outcomes following surgical or non-surgical management of traumatic pancreatic injuries. We hypothesize a higher morbidity and mortality rate in patients treated surgically when compared to patients treated non surgically. METHODS: We performed a retrospective review of data from four trauma centers in New York from 1990-2014, comparing patients who had blunt traumatic pancreatic injuries who were managed operatively to those managed non operatively. We compared continuous variables using the Mann-Whitney U test and categorical variables using the chi-square and Fisher's exact tests. Univariate analysis was performed to determine the possible confounding factors associated with mortality in both treatment groups. RESULTS: Twenty nine patients were managed operatively and 32 non-operatively. There was a significant difference between the operative and non-operative groups in median age (37.0 vs. 16.2 years, P = 0.016), grade of pancreatic injury (grade I; 30.8 vs. 85.2%, P value for all comparisons <0.0001), median injury severity score (ISS) (16.0 vs. 4.0, P = 0.002), blood transfusion (55.2 vs. 15.6%, P = 0.0012), other abdominal injuries (79.3 vs. 38.7%, P = 0.0014), pelvic fractures (17.2 vs. 0.00%, P = 0.020), intensive care unit (ICU) admission (86.2 vs. 50.0%, P = 0.003), median length of stay (LOS) (16.0 vs. 4.0 days, P <0.0001), and mortality (27.6 vs. 3.1%, P = 0.010). CONCLUSIONS: Patients with traumatic pancreatic injuries treated operatively were more severely injured and suffered greater complications than those treated non-operatively. The greater morbidity and mortality associated with these patients warrants further study to determine optimal triage strategies and which subset of patients is likely to benefit from surgery. PMID- 27981057 TI - Clinical outcomes of combined versus separate carbachol and brimonidine drops in correcting presbyopia. AB - BACKGROUND: To test and compare in a masked fashion the efficacy of using a parasympathomimetic drug (3% carbachol) and an alpha-2 agonist (0.2% brimonidine) in both combined and separate forms to create optically beneficial miosis to pharmacologically improve vision in presbyopia. METHODS: A prospective, double masked, randomized, controlled clinical trial was conducted. Ten naturally emmetropic and presbyopic subjects between 42 and 58 years old with uncorrected distance visual acuity of at least 20/20 in both eyes without additional ocular pathology were eligible for inclusion. All subjects received 3% carbachol and 0.2% brimonidine in both combined and separate forms, 3% carbachol alone and 0.2% brimonidine (control) alone in their non-dominant eye in a crossover manner with one week washout between tests. The subjects' pupil sizes and both near and distance visual acuities will be evaluated pre- and post-treatment at 1, 2, 4, and 8 h, by a masked examiner at the same room illumination. RESULTS: Statistically significant improvement in mean near visual acuity (NVA) was achieved in all subjects who received combined 3% carbachol and 0.2% brimonidine in the same formula compared with those who received separate forms or carbachol alone or brimonidine alone (P < 0.0001). CONCLUSION: Based on the data, the combined solution demonstrated greater efficacy than the other solutions that were tested. Improving the depth of focus by making the pupil small caused statistically significant improvement in near visual acuity, with no change in binocular distance vision. TRIAL REGISTRATION: ACTRN12616001565437. Registered 11 November 2016. PMID- 27981058 TI - Effects of dopamine D1 receptor blockade on the ERG b- and d-waves during blockade of ionotropic GABA receptors. AB - BACKGROUND: Some data indicate that the dopaminergic and GABAergic systems interact in the vertebrate retina, but the type of interactions is not well understood. METHODS: In this study we investigated the effect of dopamine D1 receptor blockade by 75 MUM SCH 23390 on the electroretinographic ON (b-wave) and OFF (d-wave) responses in intact frog eyecup preparations and in eyecups where the ionotropic GABA receptors were blocked by 50 MUM picrotoxin. Student's t test, One-way repeated measures ANOVA with Bonferroni post-hoc test and Two-way ANOVA were used for statistical evaluation of the data. RESULTS: We found that SCH 23390 alone significantly enhanced the amplitude of the b- and d-waves without altering their latency. The effect developed rapidly and was fully expressed within 8-11 min after the blocker application. Picrotoxin alone also markedly enhanced the amplitude of the ERG ON and OFF responses and increased their latency significantly. The effect was fully expressed within 25-27 min after picrotoxin application and remained very stable in the next 20 min. The effects of SCH 23390 and picrotoxin are similar to that reported in our previous studies. When SCH 23390 was applied on the background of the fully developed picrotoxin effect, it diminished the amplitude of the b- and d-waves in comparison to the corresponding values obtained during application of picrotoxin alone. CONCLUSION: Our results demonstrate that the enhancing effect of D1 receptor blockade on the amplitude of the ERG b- and d-waves is not evident during the ionotropic GABA receptor blockade, indicating an interaction between these neurotransmitter systems in the frog retina. We propose that the inhibitory effect of endogenous dopamine mediated by D1 receptors on the ERG ON and OFF responses in the frog retina may be due to the dopamine-evoked GABA release. PMID- 27981059 TI - Safety and effectiveness of the SUPRACOR presbyopic LASIK algorithm on hyperopic patients. AB - BACKGROUND: To evaluate the safety and effectiveness of the Supracor excimer laser algorithm to treat hyperopic presbyopic patients using laser in-situ keratomileusis (LASIK). METHODS: This is a retrospective case review of patients diagnosed with hyperopia (Sphere >= +0.0 D and presbyopia reading add >= 1.0 D) who underwent Supracor excimer laser treatment on at least one eye for presbyopia correction from year May 2011 to May 2013. Binocular vision was further analyzed after patients were subdivided into three groups: Group A (n = 22 eyes, 11 patients) had Supracor on both eyes; Group B (n = 18 eyes, 18 patients) had Supracor in one eye and hyperopic LASIK on fellow eye; and Group C (n = 29 eyes, 29 patients) had Supracor in one eye and no treatment on the fellow eye. RESULTS: This study evaluated 58 patients wherein 69 eyes underwent Supracor presbyopic LASIK. Preoperatively, mean manifest refraction spherical equivalent (MRSE) of all eyes that underwent Supracor was +1.37 +/- 0.72 D with mean uncorrected distance visual acuity (UDVA), uncorrected intermediate visual acuity (UIVA), and uncorrected near visual acuity (UNVA) of 20/50 (0.35 logMAR), 20/50 (0.35 logMAR), and J9 (0.61 logMAR), respectively. At 6 months postoperatively, mean MRSE was -0.43 +/- 0.59 D with mean UDVA, UIVA and UNVA of 20/25 (0.13 logMAR), 20/20 (0.01 logMAR), and J1 (0.05 logMAR), respectively. Loss of two lines of best-corrected distance visual acuity (BCDVA) was seen in 6% of eyes. Mean corneal steepening of 1.0 D at the 3 mm zone and 0.7 D in the 5 mm zone was observed. Mean vertical coma increased from -0.02 to +0.10 while mean 4th order spherical aberration became more negative from 0.20 to -0.14. Mean binocular UDVA, UIVA, and UNVA are 20/20, 20/20 and J1, respectively, in all treatment groups at the 6 month postoperative follow-up. No significant differences in binocular UDVA (p >= 0.36), UIVA (p >= 0.19) and UNVA (p >= 0.56) among groups were seen. CONCLUSIONS: Supracor excimer laser algorithm is safe and effective for the treatment of presbyopia in hyperopes. Monolateral and bilateral Supracor treatments yielded similarly good binocular vision outcomes. PMID- 27981060 TI - Geographic and Demographic Disparities in Late-stage Breast and Colorectal Cancer Diagnoses Across the US. AB - PROBLEM: In 2009, breast cancer was the most common cancer in women, and colorectal cancer was the third most common cancer in both men and women. Currently, the majority of colorectal and almost 1/3 of breast cancers are diagnosed at an advanced stage in the US, which results in higher morbidity and mortality than would obtain with earlier detection. The incidence of late-stage cancer diagnoses varies considerably across the US, and few analyses have examined the entire US. PURPOSE: Using the newly available US Cancer Statistics database representing 98% of the US population, we perform multilevel analysis of the incidence of late-stage cancer diagnoses and translate the findings via bivariate mapping, answering questions related to both Why and Where demographic and geographic disparities in these diagnoses are observed. METHODS: To answer questions related to Why disparities are observed, we utilize a three-level, random-intercepts model including person-, local area-, and region- specific levels of influence. To answer questions related to Where disparities are observed, we generate county level robust predictions of late-stage cancer diagnosis rates and map them, contrasting counties ranked in the upper and lower quantiles of all county predicted rates. Bivariate maps are used to spatially translate the geographic variation among US counties in the distribution of both BC and CRC late-stage diagnoses. CONCLUSIONS: Empirical modeling results show demographic disparities, while the spatial translation of empirical results shows geographic disparities that may be quite useful for state cancer control planning. Late stage BC and CRC diagnosis rates are not spatially random, manifesting as place-specific patterns that compare counties in individual states to counties across all states. Providing a relative comparison that enables assessment of how results in one state compare with others, this paper is to be disseminated to all state cancer control and central cancer registry program officials. PMID- 27981062 TI - Multiparametric photoacoustic microscopy of the mouse brain with 300-kHz A-line rate. AB - Enabling simultaneous high-resolution imaging of the total concentration of hemoglobin ([Formula: see text]), oxygen saturation of hemoglobin ([Formula: see text]), and cerebral blood flow (CBF), multiparametric photoacoustic microscopy (PAM) holds the potential to quantify the cerebral metabolic rate of oxygen at the microscopic level. However, its imaging speed has been severely limited by the pulse repetition rate of the dual-wavelength photoacoustic excitation and the scanning mechanism. To address these limitations, we have developed a new generation of multiparametric PAM. Capitalizing on a self-developed high repetition dual-wavelength pulsed laser and an optical-mechanical hybrid-scan configuration, this innovative technique has achieved an unprecedented A-line rate of 300 kHz, leading to a 20-fold increase in the imaging speed over our previously reported multiparametric PAM that is based on pure mechanical scanning. The performance of the high-speed multiparametric PAM has been examined both in vitro and in vivo. Simultaneous PAM of microvascular [Formula: see text], [Formula: see text], and CBF in absolute values over a [Formula: see text]-mm diameter brain region of interest can be accomplished within 10 min. PMID- 27981063 TI - Measurement, modeling, and prediction of temperature rise due to optogenetic brain stimulation. AB - Optogenetics is one of the most important techniques in neurophysiology, with potential clinical applications. However, the strong light needed may cause harmful temperature rises. So far, there are no methods to reliably estimate brain heating and safe limits in actual optogenetic experiments. We used thermal imaging to directly measure such temperature rises at the surface of live mouse brains during laser illumination with wavelengths and intensities typical for optogenetics. We then modeled the temperature rise with a simple logarithmic model. Our results indicate that previous finite-element models can underestimate temperature increases by an order of magnitude. We validate our empirical model by predicting the temperature rise caused by pulsed stimulation paradigms. These predictions fit closely to the empirical data and constitute a better estimate of real temperature increases. Additionally, we provide a web-based app for easy calculation that can be used as a tool for safe design of optogenetic experiments. PMID- 27981064 TI - Automatic segmentation of coronary morphology using transmittance-based lumen intensity-enhanced intravascular optical coherence tomography images and applying a localized level-set-based active contour method. AB - Lumen segmentation from clinical intravascular optical coherence tomography (IV OCT) images has clinical relevance as it provides a full three-dimensional perspective of diseased coronary artery sections. Inaccurate segmentation may occur when there are artifacts in the image, resulting from issues such as inadequate blood clearance. This study proposes a transmittance-based lumen intensity enhancement method that ensures only lumen regions are highlighted. A level-set-based active contour method that utilizes the local speckle distribution properties of the image is then employed to drive an image-specific active contour toward the true lumen boundaries. By utilizing local speckle properties, the intensity variation issues within the image are resolved. This combined approach has been successfully applied to challenging clinical IV-OCT datasets that contains multiple lumens, residual blood flow, and its shadowing artifact. A method to identify the guide-wire and interpolate the lost lumen segments has been implemented. This approach is fast and can be performed even when guide-wire boundaries are not easily identified. Lumen enhancement also makes it easy to identify vessel side branches. This automated approach is not only able to extract the arterial lumen, but also the smaller microvascular lumens that are associated with the vasa vasorum and with atherosclerotic plaque. PMID- 27981061 TI - Review on the role of AMPA receptor nano-organization and dynamic in the properties of synaptic transmission. AB - Receptor trafficking and its regulation have appeared in the last two decades to be a major controller of basal synaptic transmission and its activity-dependent plasticity. More recently, considerable advances in super-resolution microscopy have begun deciphering the subdiffraction organization of synaptic elements and their functional roles. In particular, the dynamic nanoscale organization of neurotransmitter receptors in the postsynaptic membrane has recently been suggested to play a major role in various aspects of synapstic function. We here review the recent advances in our understanding of alpha-amino-3-hydroxy-5-methyl 4-isoxazolepropionic acid subtype glutamate receptors subsynaptic organization and their role in short- and long-term synaptic plasticity. PMID- 27981065 TI - ART 3.5D: an algorithm to label arteries and veins from three-dimensional angiography. AB - Preoperative three-dimensional (3-D) visualization of brain vasculature by digital subtraction angiography from computerized tomography (CT) in neurosurgery is gaining more and more importance, since vessels are the primary landmarks both for organs at risk and for navigation. Surgical embolization of cerebral aneurysms and arteriovenous malformations, epilepsy surgery, and stereoelectroencephalography are a few examples. Contrast-enhanced cone-beam computed tomography (CE-CBCT) represents a powerful facility, since it is capable of acquiring images in the operation room, shortly before surgery. However, standard 3-D reconstructions do not provide a direct distinction between arteries and veins, which is of utmost importance and is left to the surgeon's inference so far. Pioneering attempts by true four-dimensional (4-D) CT perfusion scans were already described, though at the expense of longer acquisition protocols, higher dosages, and sensible resolution losses. Hence, space is open to approaches attempting to recover the contrast dynamics from standard CE-CBCT, on the basis of anomalies overlooked in the standard 3-D approach. This paper aims at presenting algebraic reconstruction technique (ART) 3.5D, a method that overcomes the clinical limitations of 4-D CT, from standard 3-D CE-CBCT scans. The strategy works on the 3-D angiography, previously segmented in the standard way, and reprocesses the dynamics hidden in the raw data to recover an approximate dynamics in each segmented voxel. Next, a classification algorithm labels the angiographic voxels and artery or vein. Numerical simulations were performed on a digital phantom of a simplified 3-D vasculature with contrast transit. CE-CBCT projections were simulated and used for ART 3.5D testing. We achieved up to 90% classification accuracy in simulations, proving the feasibility of the presented approach for dynamic information recovery for arteries and veins segmentation. PMID- 27981066 TI - Blood vessel extraction of diabetic retinopathy using optimized enhanced images and matched filter. AB - Accurate extraction of structural changes in the blood vessels of the retina is an essential task in diagnosis of retinopathy. Matched filter (MF) technique is the effective way to extract blood vessels, but the effectiveness is reduced due to noisy images. The concept of MF and MF with first-order derivative of Gaussian (MF-FDOG) has been implemented for retina images of the DRIVE database. The optimized particle swarm optimization (PSO) algorithm is used for enhancing the images by edgels to improve the performance of filters. The vessels were detected by the response of thresholding to the MF, whereas the threshold is adjusted in response to the FDOG. The PSO-based enhanced MF response significantly improved the performances of filters to extract fine blood vessels structures. Experimental results show that the proposed method based on enhanced images improved the accuracy to 91.1%, which is higher than that of MF and MF-FDOG, respectively. The peak signal-to-noise ratio was also found to be higher with low mean square error values in enhanced MF response. The accuracy, sensitivity, and specificity values are significantly improved among MF, MF-FDOG, and PSO-enhanced images ([Formula: see text]). PMID- 27981067 TI - Automated algorithm for actinic cheilitis diagnosis by wide-field fluorescence imaging. AB - Actinic cheilitis (AC) is a disease caused by prolonged and cumulative sun exposure that mostly affects the lower lip, which can progress to a lip squamous cell carcinoma. Routine diagnosis relies on clinician experience and training. We investigated the diagnostic efficacy of wide-field fluorescence imaging coupled to an automated algorithm for AC recognition. Fluorescence images were acquired from 57 patients with confirmed AC and 46 normal volunteers. Three different algorithms were employed: two based on the emission characteristics of local heterogeneity, entropy and intensity range, and one based on the number of objects after K-mean clustering. A classification model was obtained using a fivefold cross correlation algorithm. Sensitivity and specificity rates were 86% and 89.1%, respectively. PMID- 27981068 TI - Structure-enhanced local phase filtering using L0 gradient minimization for efficient semiautomated knee magnetic resonance imaging segmentation. AB - The segmentation of bone surfaces from magnetic resonance imaging (MRI) data has applications in the quantitative measurement of knee osteoarthritis, surgery planning for patient-specific total knee arthroplasty, and its subsequent fabrication of artificial implants. However, due to the problems associated with MRI imaging, such as low contrast between bone and surrounding tissues, noise, bias fields, and the partial volume effect, segmentation of bone surfaces continues to be a challenging operation. A framework is presented for the enhancement of knee MRI scans prior to segmentation in order to obtain high contrast bone images. During the first stage, a contrast enhanced relative total variation regularization method is used in order to remove textural noise from the bone structures and surrounding soft tissue interface. This salient bone edge information is further enhanced using a sparse gradient counting method based on [Formula: see text] gradient minimization, which globally controls how many nonzero gradients are resulted in order to approximate prominent bone structures in a structure-sparsity-management manner. The last stage of the framework involves incorporation of local phase bone boundary information in order to provide an intensity invariant enhancement of contrast between the bone and surrounding soft tissue. The enhanced images are segmented using a fast random walker algorithm. Validation against expert segmentation was performed on 20 clinical knee MRI volumes and achieved a mean dice similarity coefficient of 0.949. PMID- 27981070 TI - Database of ion temperature maps during geomagnetic storms. AB - Ion temperatures as a function of the x and y axes in the geocentric solar magnetospheric (GSM) coordinate system and time are available for 76 geomagnetic storms that occurred during the period July 2008 to December 2013 on CDAWeb. The method for mapping energetic neutral atom data from the Two Wide-angle Imaging Spectrometers (TWINS) mission to the GSM equatorial plane and subsequent ion temperature calculation are described here. The ion temperatures are a measure of the average thermal energy of the bulk ion population in the 1-40 keV energy range. These temperatures are useful for studies of ion dynamics, for placing in situ measurements in a global context, and for establishing boundary conditions for models of the inner magnetosphere and the plasma sheet. PMID- 27981071 TI - A large-scale view of Space Technology 5 magnetometer response to solar wind drivers. AB - In this data report we discuss reprocessing of the Space Technology 5 (ST5) magnetometer database for inclusion in NASA's Coordinated Data Analysis Web (CDAWeb) virtual observatory. The mission consisted of three spacecraft flying in elliptical orbits, from 27 March to 27 June 2006. Reprocessing includes (1) transforming the data into the Modified Apex Coordinate System for projection to a common reference altitude of 110 km, (2) correcting gain jumps, and (3) validating the results. We display the averaged magnetic perturbations as a keogram, which allows direct comparison of the full-mission data with the solar wind values and geomagnetic indices. With the data referenced to a common altitude, we find the following: (1) Magnetic perturbations that track the passage of corotating interaction regions and high-speed solar wind; (2) unexpectedly strong dayside perturbations during a solstice magnetospheric sawtooth oscillation interval characterized by a radial interplanetary magnetic field (IMF) component that may have enhanced the accompanying modest southward IMF; and (3) intervals of reduced magnetic perturbations or "calms," associated with periods of slow solar wind, interspersed among variable-length episodic enhancements. These calms are most evident when the IMF is northward or projects with a northward component onto the geomagnetic dipole. The reprocessed ST5 data are in very good agreement with magnetic perturbations from the Defense Meteorological Satellite Program (DMSP) spacecraft, which we also map to 110 km. We briefly discuss the methods used to remap the ST5 data and the means of validating the results against DMSP. Our methods form the basis for future intermission comparisons of space-based magnetometer data. PMID- 27981069 TI - INSIDE in-beam positron emission tomography system for particle range monitoring in hadrontherapy. AB - The quality assurance of particle therapy treatment is a fundamental issue that can be addressed by developing reliable monitoring techniques and indicators of the treatment plan correctness. Among the available imaging techniques, positron emission tomography (PET) has long been investigated and then clinically applied to proton and carbon beams. In 2013, the Innovative Solutions for Dosimetry in Hadrontherapy (INSIDE) collaboration proposed an innovative bimodal imaging concept that combines an in-beam PET scanner with a tracking system for charged particle imaging. This paper presents the general architecture of the INSIDE project but focuses on the in-beam PET scanner that has been designed to reconstruct the particles range with millimetric resolution within a fraction of the dose delivered in a treatment of head and neck tumors. The in-beam PET scanner has been recently installed at the Italian National Center of Oncologic Hadrontherapy (CNAO) in Pavia, Italy, and the commissioning phase has just started. The results of the first beam test with clinical proton beams on phantoms clearly show the capability of the in-beam PET to operate during the irradiation delivery and to reconstruct on-line the beam-induced activity map. The accuracy in the activity distal fall-off determination is millimetric for therapeutic doses. PMID- 27981072 TI - Dust deposition on the decks of the Mars Exploration Rovers: 10 years of dust dynamics on the Panoramic Camera calibration targets. AB - The Panoramic Cameras on NASA's Mars Exploration Rovers have each returned more than 17,000 images of their calibration targets. In order to make optimal use of this data set for reflectance calibration, a correction must be made for the presence of air fall dust. Here we present an improved dust correction procedure based on a two-layer scattering model, and we present a dust reflectance spectrum derived from long-term trends in the data set. The dust on the calibration targets appears brighter than dusty areas of the Martian surface. We derive detailed histories of dust deposition and removal revealing two distinct environments: At the Spirit landing site, half the year is dominated by dust deposition, the other half by dust removal, usually in brief, sharp events. At the Opportunity landing site the Martian year has a semiannual dust cycle with dust removal happening gradually throughout two removal seasons each year. The highest observed optical depth of settled dust on the calibration target is 1.5 on Spirit and 1.1 on Opportunity (at 601 nm). We derive a general prediction for dust deposition rates of 0.004 +/- 0.001 in units of surface optical depth deposited per sol (Martian solar day) per unit atmospheric optical depth. We expect this procedure to lead to improved reflectance-calibration of the Panoramic Camera data set. In addition, it is easily adapted to similar data sets from other missions in order to deliver improved reflectance calibration as well as data on dust reflectance properties and deposition and removal history. PMID- 27981073 TI - Radar signatures of snowflake riming: A modeling study. AB - The capability to detect the state of snowflake riming reliably from remote measurements would greatly expand the understanding of its global role in cloud precipitation processes. To investigate the ability of multifrequency radars to detect riming, a three-dimensional model of snowflake growth was used to generate simulated aggregate and crystal snowflakes with various degrees of riming. Three different growth scenarios, representing different temporal relationships between aggregation and riming, were formulated. The discrete dipole approximation was then used to compute the radar backscattering properties of the snowflakes at frequencies of 9.7, 13.6, 35.6, and 94 GHz. In two of the three growth scenarios, the rimed snowflakes exhibit large differences between the backscattering cross sections of the detailed three-dimensional models and the equivalent homogeneous spheroidal models, similarly to earlier results for unrimed snowflakes. When three frequencies are used simultaneously, riming appears to be detectable in a robust manner across all three scenarios. In spite of the differences in backscattering cross sections, the triple-frequency signatures of heavily rimed particles resemble those of the homogeneous spheroids, thus explaining earlier observational results that were compatible with such spheroids. PMID- 27981074 TI - Potential for a large earthquake near Los Angeles inferred from the 2014 La Habra earthquake. AB - Tectonic motion across the Los Angeles region is distributed across an intricate network of strike-slip and thrust faults that will be released in destructive earthquakes similar to or larger than the 1933 M6.4 Long Beach and 1994 M6.7 Northridge events. Here we show that Los Angeles regional thrust, strike-slip, and oblique faults are connected and move concurrently with measurable surface deformation, even in moderate magnitude earthquakes, as part of a fault system that accommodates north-south shortening and westerly tectonic escape of northern Los Angeles. The 28 March 2014 M5.1 La Habra earthquake occurred on a northeast striking, northwest dipping left-lateral oblique thrust fault northeast of Los Angeles. We present crustal deformation observation spanning the earthquake showing that concurrent deformation occurred on several structures in the shallow crust. The seismic moment of the earthquake is 82% of the total geodetic moment released. Slip within the unconsolidated upper sedimentary layer may reflect shallow release of accumulated strain on still-locked deeper structures. A future M6.1-6.3 earthquake would account for the accumulated strain. Such an event could occur on any one or several of these faults, which may not have been identified by geologic surface mapping. PMID- 27981075 TI - Establishment of the Asia Oncology Nursing Society (AONS). AB - Over the past several years, whenever an informal group of Asian oncology nurses gathered, they talked about their mutual desire to create an organization closer to their homes that would be similar to the European Oncology Nursing Society (EONS). They saw this as a means for more of their colleagues to learn about the latest in cancer nursing and to have a time and place to network among themselves. This message continued to gain strength whenever these nurses met at other international meetings such as the International Conference on Cancer Nursing (ICCN), the Multinational Association of Supportive Care in Cancer (MASCC) and the Oncology Nursing Society in US. A definite and planned step toward forming an Asian organization as the first meeting was taken on June 24 2011 when several Asian nurses were attending a MASCC meeting in Greece. The second meeting was held in Prague, Czech Republic, in conjunction with the 17th ICCN meeting on September 10 2012, where the participants of the meeting included 21 oncology nurses from Asian countries. Finally, the first official meeting of the board directors from nine countries was held on November 21 2013 in Bangkok, Thailand. Now, and in the future, sharing and collaborating in the practice, education and research for oncology nursing in Asia is needed. PMID- 27981076 TI - A report on the first Asian Oncology Nursing Society conference. AB - The first Asian Oncology Nursing Society (AONS) conference was held in Thailand from November 22 to 24 2013. It was a significant milestone in the journey of the development of the AONS. The objectives of the conference were to facilitate opportunities for networking, collaboration and exchange of ideas with renowned leaders in Oncology Nursing, to facilitate sharing and collaboration of oncology nursing in Asia and to explore innovative strategies to strengthen the implementation of evidence-based practice in oncology nursing. PMID- 27981077 TI - Web-based interventions for caregivers of cancer patients: A review of literatures. AB - Diagnosed with cancer is a traumatic event; it does not only affect the diagnosed patients, but also their caregivers. It brings along negative impacts on biopsychosocial health to the caregivers. Supportive interventions are essential for the caregivers to go through the cancer trajectory. In the past, interventions were being delivered in either face-to-face format or delivering written documents. Although Internet becomes a popular platform for delivering interventions given its substantial growth in usage, the effectiveness of this mode of intervention delivery is unclear. The aim of this review is to review existing literatures regarding efficacy of web-based interventions in psychological outcomes of cancer caregivers. A Literature search was performed in December 2012 from seven databases, including, Ovid MEDLINE, EMBASE, PsycINFO, CINHAL, ERIC, British Nursing Index and EBM Reviews. The following keywords were used in the search but were not limited to "paediatric", "parent", "caregiver", "cancer", "web-based", and "psycho education". Totally 4668 citations were identified, after excluding the duplicated and irrelevant citations; finally six studies were included in this review. A review of the literatures identified that the web-based interventions including either online support group only or a combination of informational website and online support group significantly improved coping skills, in a way reduced anxiety, stress, depression, burden, as well as negative mood and perceived bonding in cancer caregivers. It is concluded that a web-based format as a potential platform for delivering intervention to the caregivers of cancer patients for its unique advantage of easy accessibility, and no geographic or time barriers. PMID- 27981078 TI - The relationship between cancer patients' perception of nursing care and nursing attitudes towards nursing profession. AB - OBJECTIVE: The aim of this study is to evaluate the patients' perceptions of nursing care with different types of cancer in Turkey and its relationship with nursing attitudes towards nursing profession. METHODS: An exploratory approach utilizing cross-sectional design with a structured questionnaire, administered to patients nurses a face-to-face, with specific questions about demographic and health status and two standardized scales: Patient Perception of Hospital Experience with Nursing Care (PPHEN) and Attitude Scale for Nursing Profession (ASNP). This study was conducted at the Research and Application Hospital of Ataturk University in Erzurum, Turkey with a convenience sample of 100 patients who were discharged from medical and radiation oncology clinics and 30 nurses that give care to these patients. RESULTS: It was found that patients' satisfaction had low levels with nursing care and similarly the nurses' attitudes from nursing profession were negative. There was a high correlation between the scales. CONCLUSION: The nurses' attitudes towards nursing profession are affecting the nursing care of patients' perception with cancer. We suggest that the researchers must be evaluating nurse's attitudes when they determine the patient perceptions of nursing care. PMID- 27981079 TI - Validation of EORTC QLQ-C30 and QLQ-BR23 questionnaires in the measurement of quality of life of breast cancer patients in Singapore. AB - OBJECTIVE: To validate EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires and to measure the health-related quality of life (HRQOL) of women with breast cancer in Singapore during their first 4 years of post-diagnosis and treatments. METHODS: A quantitative and cross-descriptive sectional study. All of 170 subjects were recruited in a Singapore tertiary cancer center. The European Organization for Research and Treatment-QOL questionnaire and breast cancer specific module (EORTC QLQ-C30 and QLQ-BR23) were used to measure the HRQOL among women with breast cancer. All statistical tests were performed using SPSS Version 18. The reliability of the EORTC QLQ-C30 and QLQ-BR23 questionnaires was examined using Cronbach's alpha test. EORTC QLQ-C30 was validated against EuroQol Group's 5 domain questionnaires (EQ5D) by examining its concurrent validity using Pearson Product Moment Correlation to calculate the total scores. RESULTS: The Cronbach's alpha coefficient results for EORTC QLQ-C30 and QLQ BR-23 were 0.846 and 0.873 respectively which suggested relatively good internal consistency. The correlation between EORTC QLQ-C30 and EQ5D QOL instruments demonstrated a modest linear relationship (r=0.597; P<0.001) that indicated a moderately strong correlation between the two measures. The study showed that Singaporean women with breast cancer had enjoyed high levels of HRQOL during their first 4 years of survivorship but they had significant concern over the financial impact of breast cancer. One of the key findings was younger women had experienced more physical and psychosocial concerns than older women. CONCLUSION: The EORTC QLQ-C30 and QLQ BR23 questionnaires are feasible and promising instruments to measure the levels of HRQOL in Singaporean women with breast cancer in future studies. PMID- 27981080 TI - The relationship between job stress and burnout levels of oncology nurses. AB - OBJECTIVE: Job stress and burnout levels of oncology nurses increase day-by-day in connection with rapidly increasing cancer cases worldwide as well as in Turkey. The purpose of this study was to establish job stress and burnout levels of oncology nurses and the relationship in between. METHODS: The sample of this descriptive study comprised of 189 nurses that are selected by nonprobability sampling method, employed by 11 hospitals in Istanbul. Survey form of 20 questions, Job Stressors Scale and Maslach Burnout Inventory (MBI) were used during collection of data. Data were evaluated using percentage, Kruskal-Wallis, Mann-Whitney U and Spearman correlation analyses. RESULTS: In the study, there was a positively weak correlation between "Work Role Ambiguity" subdimension of Job Stressors Scale and "Emotional Exhaustion" and "Personal Accomplishment" subdimensions, whereas a positively weak and medium correlation was encountered between "Work Role Conflict" subdimension and "Emotional Exhaustion" and "Depersonalization" subdimensions. A negatively weak correlation was found between "Work Role Overload" subdimension and "Emotional Exhaustion" and "Depersonalization" subdimensions. CONCLUSION: A significant relationship was established between subdimensions of job stress level and of burnout level, that a lot of oncology nurses who have participated in the study wanted to change their units, because of the high attrition rate. PMID- 27981082 TI - Effects of nurse-led telephone follow-up for discharged patients treated with chemotherapy. AB - OBJECTIVE: Nurse-led telephone follow-up is effective in meeting information and psycho-social needs. We explored the potential effects of nurse-led telephone follow-up for patients treated with chemotherapy in China. METHODS: A quasi experimental study was employed in the research. 300 cases of cancer inpatients in a cancer hospital in Beijing during July-October 2012 were selected by convenience sampling. To compare the satisfaction and response regarding to chemotherapy adverse side effects, patients who discharged on Monday and Friday were provided with telephone follow-up. Patients who discharged on Tuesday, Wednesday and Thursday received routine care. RESULTS: Via telephone follow-up, patient satisfaction relating to nursing care increased. Moreover, their response to chemotherapy adverse side effects showed a significant difference. CONCLUSION: Telephone follow-up by specialist nurses may be a feasible option. It was well received by patients, with no physical or psychological disadvantage. PMID- 27981081 TI - Measurement of the knowledge level about breast self-exam among the female employees of a university hospital, Turkey. AB - OBJECTIVE: Periodic mammography, clinical breast examination and breast self-exam (BSE) facilitate getting a therapeutic response and improve disease prognosis, by leading to early diagnosis of the breast cancer. METHODS: The study included a total of 618 women working in Cukurova University, Faculty of Medicine, as technician, secretary, staff, midwife and doctor. They answered a 22-items questionnaire consisting of questions about general knowledge, 8 of these were about BSE. RESULTS: While it was statistically significant that the education was not correlated with the age of onset of BSE and timing of BSE, the education was significantly efficient in terms of knowing the aim of the BSE, its frequency, post-menopausal BSE time, nipple discharge properties in the case of breast cancer, diagnostic methods and the risks. While it was statistically significant that the profession was not related to age of onset of BSE and knowing the right day of the month on which BSE should be performed, the education was likely to be efficient in knowing the frequency, post-menopausal BSE time, aim of the BSE, nipple discharge properties in the case of breast cancer, diagnostic methods and the risks. When the percentage of giving right answers to the questions and educational background and professional groups were compared, it was seen that the difference of the number of right answers and professional groups was significant. CONCLUSION: Based on our results, we concluded that the education about BSE is warranted in order to increase the likelihood of female healthcare personnel to diagnose breast cancer at an earlier stage, given their role in raising the awareness of the population. PMID- 27981083 TI - Physiological problems in patients undergoing autologous and allogeneic hematopoietic stem cell transplantation. AB - OBJECTIVE: Stem cell transplantation is usually performed in an effort to extend the patient's life span and to improve their quality of life. This study was conducted to determine the postoperative physiological effects experienced by patients who had undergone autologous and allogeneic stem cell transplantation. METHODS: The research is a descriptive study conducted with a sample of 60 patients at Stem Cell Transplantation Units in Ankara. Percentile calculation and chi-square tests were used to evaluate the data. RESULTS: When a comparison was made between patients who had undergone allogeneic Hematopoietic stem cell transplantation (HSCT) and those who had undergone autologous HSCT, results indicated that problems occurred more often for the allogeneic HSCT patients. The problems included: Digestion (94.3%), dermatological (76.7%), cardiac and respiratory (66.7%), neurological (66.7%), eye (56.7%), infections (26.7%) and Graft Versus Host Disease (5 patients). Furthermore, the problems with pain (50%), numbness and tingling (40%), and speech disorders (3 patients) were observed more often in autologous BMT patients. CONCLUSION: Autologous and allogeneic patients experienced most of physical problems due to they receive high doses of chemotherapy. Therefore, it is recommended that an interdisciplinary support team approach should be usedtohelp reduce and manage the problems that may arise during patient care. PMID- 27981085 TI - A report on mutual projects related to breast cancer nursing between Israel and China. AB - Breast cancer is a major concern in women's health in the western world, and is now receiving more and more attention also in the East. In China, for example, where the incidence of breast cancer was very low, there has been a rapid increase of the disease since the last few years. This report describes how a collaborative nursing project between the Hadassah Medical Organization and the Tianjin Cancer Institute and Hospital was initiated, planned and implemented. PMID- 27981084 TI - Coping with stress of family caregivers of cancer patients in Turkey. AB - OBJECTIVE: Cancer is a disease that not only affects the individual's mental and physical integrity but also affects the functionality of the family system. Caregivers experience stress when patients cannot cope with the symptoms they are experiencing. The stress experienced by caregivers gives rise to psychological and physical symptoms. The purpose of this study is to determine the attitude of coping with stress of family caregivers of cancer patients. METHODS: This study was conducted as a descriptive research at the Medical Oncology Clinic. The study sample group comprised of 127 family caregivers. In the collection of the data, the Personel Information Form and Attitude of Coping with Stress Inventory were used. RESULTS: The coping attitude used most frequently by family caregivers was active planning, and the least used coping attitude was avoidance isolation (biochemical). There was no significant statistical difference between the coping attitude depending on the descriptive characteristics of the family caregivers (P > 0.05). CONCLUSION: Results show that family caregivers of cancer patients tend to choose effective coping methods. However, there were still caregivers that displayed ineffective coping attitudes. Therefore, it is important to support the effective coping attitudes of caregivers and intervene in order to change the ineffective coping attitudes. PMID- 27981086 TI - Israeli breast care nurses as a learning organization. AB - This article will look at the theory of a Learning Organization as described by Senge and the Israeli Breast Care Nurses as an example. A description of the theory of a Learning Organization, the role of the Breast Care Nurses in Israel and the relation between the two will be described. Since 1996, the role of the Breast Care Nurse was founded in Israel. At that time, the role with its importance was very hard to be recognized by the health care team and other professionals of the multidisciplinary team for breast cancer patients. Since the role was initiated, it had been developing all over Israel through the support given by the Israel Cancer Association. As a learning organization, the Breast Care Nurses have a few goals: To learn to give patients the most updated and relevant information; to be a part and be seen as equal as the other members of the multidisciplinary team for breast cancer patients; to have knowledge which empowers them as a working group; to enable to teach students, mainly nursing students, in basic and further education and to help continually teach a new generation of nurses. This learning organization involves some formal and informal education. Although oncology nurses do much of the ideas we have described, we suggest using a strict model to help in implementing a Learning Organization. Future research can examine the outcomes of a Learning Organization on oncology nursing. PMID- 27981087 TI - Debunking the myth: low knowledge levels of HBV infection among Asian American college students. AB - OBJECTIVE: To examine the hepatitis B virus (HBV)-related knowledge among Asian American college students and to determine whether there are significant differences in the level of HBV knowledge among Asian American subgroups. METHODS: A cross-sectional survey was self-administered to assess a sample of 258 Asian American students' knowledge about HBV at the campus of the research site. RESULTS: Knowledge regarding transmission and consequences of HBV infection was poor. Of a possible knowledge score of 14, the median number of correct answers was eight. There were no significant differences between the subgroups of Asian American college students in total knowledge of HBV infection. CONCLUSION: The findings of this study point to the fact that the lack of knowledge and awareness is not limited to community settings only but also includes higher education environment. This finding brings to the forefront the importance of HBV education for Asian American college students. PMID- 27981088 TI - Factors affecting the quality of life of cancer patients undergoing chemotherapy: A questionnaire study. AB - OBJECTIVE: This descriptive and cross-sectional study was undertaken to determine the factors affecting cancer patients' quality of life. METHODS: We collected data from 352 chemotherapy patients of an Outpatient Chemotherapy Unit in a state hospital. We included volunteered chemotherapy patients with a signed informed consent and at least 50 Karnofsky Performance Scale points. We gathered data by Personal Information Form and Nightingale Symptom Assessment Scale (N-SAS) and analyzed via basic descriptive statistics and linear regression analysis. RESULTS: Patients were women (54.8%), married (83.5%), elementary school graduates (57.1%), housewives (44.6%) and undergoing fluorouracil-based therapy (47.2%), and almost all patients had religious and cultural rituals for the disease. Women experienced worse physical and social well-being than men (P = 0.001, P = 0.0001). Singles had worse psychological and general well-being (P = 0.0001, P = 0.0001). Housewives had the worst physical and social well-being (P < 0.05). No relationship existed between education level and life quality (P > 0.05). Breast cancer and sarcoma patients had the worst social well-being than other cancer patients. The N-SAS points of patients were not affected by blessings/prays, vow/sacrifice, consulting local herbalists and visiting "ocaks (folk physicians)" (P > 0.05). Patients with bad quality of life practiced lead pouring and amulets (P < 0.05). Gender was the first factor affecting the quality of life. CONCLUSION: Advanced studies on individual quality of life factors affecting cancer would empower nurses for better personal care techniques and patients for easily overcoming the disease. PMID- 27981089 TI - Why are chemotherapy administration errors not reported? Perceptions of oncology nurses in a Nigerian tertiary health institution. AB - OBJECTIVE: The administration of chemotherapy forms a major part of the clinical role of oncology nurses. When a mistake is made during chemotherapy administration, admitting and reporting the error timely could save the lives of cancer patients. The main objective of this study was to assess the perceptions of oncology nurses about why chemotherapy administration errors are not reported. METHODS: This is a descriptive study that surveyed a convenient sample of 128 oncology nurses currently practicing in the Ogun State University Teaching Hospital, Nigeria. The tool for data collection was a structured questionnaire that consisted of two sections. The first section was for the demographic data of participants and the second section consisted of questions constructed based on the Medication Administration Error (MAE) reporting survey developed by Wakefield and his team. RESULTS: Findings showed that majority of the nurses (89.8%) have made at least one MAE in the course of their professional practice. Fear (mean = 3.63) and managerial response (mean = 2.87) were the two major barriers to MAE reporting perceived among oncology nurses. CONCLUSION: Critically analyzing why medication errors are not reported among oncology nurses is crucial to identifying strategic interventions that would promote reporting of all errors, especially those related to chemotherapy administration. It is therefore recommended that nurse managers and health care administrators should create a favorable atmosphere that does not only prevent medication errors but also supports nurses' voluntary reporting of MAEs. Education, information and communication strategies should also be put in place to train nurses on the need to report, if possible prevent, all medication errors. PMID- 27981090 TI - Familiarity, opinions, experiences and knowledge about scalp cooling: a Dutch survey among breast cancer patients and oncological professionals. AB - OBJECTIVE: Scalp cooling (SC) is applied to reduce chemotherapy-induced alopecia (CIA). The aim of this study was to investigate patients' familiarity and opinions and oncological professionals' attitude and knowledge about SC in the Netherlands. METHODS: Ex breast cancer patients, nurses and medical oncologists (MDs) from SC and non-SC hospitals filled out questionnaires. RESULTS: The majority of MDs and nurses were satisfied with the results of SC, as were SC patients. Over 33% of MDs and nurses perceived their knowledge level insufficient to inform patients about effectiveness, which was over 43% for information about safety. MDs main reason to not apply SC was doubt about effectiveness and safety. Nurses generally offered SC to a minority of eligible patients. Patients were frequently unfamiliar with SC before diagnosis. Seventy percent of SC patients with insufficient results (20/52) reported to mind it very much. With expected success rates of 35% and 50%, respectively, 36% and 54% of patients would use SC again. CONCLUSION: Room for improvement has been shown for both patients' familiarity and oncological professionals' knowledge about SC. Sharing knowledge about results, safety and patients' experiences will improve patient counseling and SC availability. The results of this survey led to the development of a national standard on CIA and SC. PMID- 27981092 TI - Medical management of oral submucous fibrosis. PMID- 27981091 TI - Associated factors with cervical pre-malignant lesions among the married fisher women community at Sadras, Tamil Nadu. AB - OBJECTIVE: To identify the associated factors of cervical pre-malignant lesions among the married fisher women residing in the coastal areas of Sadras, Tamil Nadu. METHODS: The study was conducted in five fishermen communities under Sadras, a coastal area in Tamil Nadu, India. Two hundred and fifty married fisher women residing in the area. Quantitative descriptive approach with a cross sectional study design was used. Data were collected using a structured interview schedule for identifying the associated factors and Pap smear test was performed for identifying the pre-malignant cervical lesions among the married fisher women. Data were analyzed using descriptive and inferential statistics. RESULTS: Among 250 women, about six (2.4%) of them presented with pre-cancerous lesions such as atypical squamous cell of undifferentiated significance (ASCUS) - five (2%) and mild dysplasia one (0.4%). Majority of the women, about 178 (71.2%) women, had abnormal cervical findings. Statistical analysis showed a significant association of risk factors such as advanced age, lack of education, low socioeconomic status, using tobacco, multiparity, premarital sex, extramarital relationship, using cloth as sanitary napkin, etc. CONCLUSION: The study findings clearly show the increased vulnerable state of the fisher women for acquiring cervical cancer as they had many risk factors contributing to the same. PMID- 27981094 TI - Introduction to the Guest Editor. PMID- 27981093 TI - Negating the impact of radiation in development of cancers. PMID- 27981095 TI - A longitudinal study of emotional intelligence in graduate nurse anesthesia students. AB - OBJECTIVE: Emotional intelligence (EI) is an important component not only for success in the nurse anesthesia (NA) profession, but as a NA student as well. Using the ability-based EI model, the purpose of this was to examine the difference in EI between the first semester and last semester of NA training programs. METHODS: First semester NA students completed the online Mayer-Salovey Caruso Emotional Intelligence Test V2.0 EI instrument, and then the same students repeated the instrument in their last (7th) semester. RESULTS: There was a statistically significant correlation between overall EI and long-term overall EI (P = 0.000), reasoning area and long-term reasoning area (P = 0.035), experiencing area (P = 0.000) and long-term experiencing area, perceiving branch and long-term perceiving branch (P = 0.000), using and long-term using branch (P = 0.000), and the managing branch and long-term managing branch (P = 0.026). The correlation between the understanding branch and the long-term understanding branch was not statistically significant (P < 0.157). The paired sample t-test demonstrated no statistically significant change (n = 34) in overall EI, the two areas scores, or the four-branch scores between the first semester and the last semester of a NA training program. CONCLUSIONS: This longitudinal study shows the lack of EI change in NA students over time. Thus, no change in EI occurs as a result of transitioning through a NA program based on the accrediting body's standardized curriculum, but the results helped the researcher provide useful data to inform future research on the use of EI measures as predictors of NA program success. PMID- 27981096 TI - Emotional intelligence and clinical performance/retention of nursing students. AB - OBJECTIVE: This exploratory, quantitative, descriptive study was undertaken to explore the relationship between clinical performance and anticipated retention in nursing students. METHODS: After approval by the university's Human Subjects Committee, a sample of 104 nursing students were recruited for this study, which involved testing with a valid and reliable emotional intelligence (EI) instrument and a self-report survey of clinical competencies. RESULTS: Statistical analysis revealed that although the group average for total EI score and the 6 score subsets were in the average range, approximately 30% of the individual total EI scores and 30% of two branch scores, identifying emotions correctly and understanding emotions, fell in the less than average range. This data, as well as the analysis of correlation with clinical self-report scores, suggest recommendations applicable to educators of clinical nursing students. CONCLUSIONS: Registered nurses make-up the largest segment of the ever-growing healthcare workforce. Yet, retention of new graduates has historically been a challenge for the profession. Given the projected employment growth in nursing, it is important to identify factors which correlate with high levels of performance and job retention among nurses. There is preliminary evidence that EI a nontraditional intelligence measure relates positively not only with retention of clinical staff nurses, but with overall clinical performance as well. PMID- 27981098 TI - Ability emotional intelligence of nurse managers in the Midwestern United States. AB - OBJECTIVE: The aim of this study was to describe the emotional intelligence (EI) and examine the corresponding demographic characteristics of front-line Nurse Managers in acute care settings. METHODS: This quantitative descriptive study was conducted in eight acute care hospitals in the Midwestern United States. The Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) was used to measure the EI of 87 front-line Nurse Managers. Demographic characteristics of the participants were captured on a second tool, the Nurse Manager Demographic Characteristics questionnaire. Descriptive and inferential statistics were used for analysis. RESULTS: Significant correlations were found between the perceiving and using branches of the model and total EI score and nurses certified in a specialty. No significant correlations were found between EI and graduate education, age, years in management, percentage of time in management or number of direct reports. Considerations for future research are discussed. CONCLUSIONS: Opportunity exists to develop EI in front-line Nurse Managers. PMID- 27981097 TI - Emotional intelligence levels in baccalaureate-prepared early career registered nurses. AB - OBJECTIVE: The increasing complexity of the healthcare environment calls for increasing emotional intelligence (EI) competence in nurses. This study assessed the EI competence of 164 baccalaureate nursing alumni who graduated during the years 2007-2010 from three Benedictine institutions located in the Midwestern United States to see if there was growth of EI with experience as a registered nurse (RN), and to determine if age, gender, grade point average (GPA), and years of total healthcare work experience prior to graduation predicted EI. METHODS: Participants completed the web-based Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) and a demographic survey. RESULTS: Findings indicated 79.4% of participants were competent or higher on the MSCEIT total EI score. Percentages of nurses scoring in the competent or higher range on each of the four branch scores of perceiving, using, understanding and managing emotions were 80.6%, 72.7%, 84.2%, and 84.9% respectively. There were no significant differences on EI scores between graduates with 1-2 years compared to 3-5 years of experience as a RN. Results of a linear stepwise regression indicated being female was a significant predictor on the MSCEIT total EI score (P = 0.015) and using emotions branch (P = 0.047). Findings also indicated GPA (P < 0.001) and being female (P = 0.023) were significant predictors of EI on the understanding emotions branch. CONCLUSIONS: The findings indicate there is work to be done to improve the EI competence of nursing graduates. Continued research on the topic of EI and nursing is needed to build the knowledge base on how to promote positive patient outcomes. PMID- 27981099 TI - Developing emotional intelligence in student nurse leaders: a mixed methodology study. AB - OBJECTIVE: The purpose of this mixed method, exploratory study was to measure the impact of a peer coaching program on the measured emotional intelligence (EI) of a group of student nurse leaders. METHODS: Participation in the study was offered to nurses in the Student Ambassador program. Students who consented received instruction on EI and its importance in leadership. Participants then took a preintervention EI test (The Mayer-Salovey-Caruso EI Test, version 2 [MSCEIT]) to obtain a baseline EI ability score. Students then participated in a series of peer coaching sessions across a semester. Participants then completed a postintervention MSCEIT test, and also a qualitative survey. RESULTS: The analysis of the paired sample t-test showed that there was not a statistically significant difference in the total group EI scores from pre to posttest, t (8) = 0.036 >0.05; however, 80% of participants reported perceived changes in EI ability due to the intervention and 90% reported that peer coaching was beneficial to their leadership development. CONCLUSIONS: This study contributes to the body of EI literature and research on nursing education and leadership development. PMID- 27981100 TI - Comparing traditional measures of academic success with emotional intelligence scores in nursing students. AB - OBJECTIVE: Emotional intelligence (EI) is the ability to perceive emotions, to access and generate emotions so as to assist thought, to understand emotions and emotional knowledge and to reflectively regulate emotions so as to promote emotional and intellectual growth. EI is increasingly discussed in healthcare as having a potential role in nursing. The purpose of this descriptive study was to examine the causal relationship between EI scores and the traditional academic admission criteria (GPA) and evaluation methods of a baccalaureate nursing program. METHODS: The sample included second semester upper division nursing students (n = 85). EI was measured using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). RESULTS: The results of the statistical analysis (MANOVA, ANOVA and Pearson correlational coefficient) found no significant relationships or correlations with the current methods of evaluation for admission to nursing school or the evaluation methods used once students are in the nursing program. CONCLUSIONS: These results imply that assessing a nursing student's EI is measuring a different type of intelligence than that represented by academic achievement. Based on the findings of this study and the current state of nursing education, EI abilities should be included as part of the admission criteria for nursing programs. PMID- 27981101 TI - Exploring the emotional intelligence of Florence Nightingale. AB - OBJECTIVE: Emotional intelligence (EI) within nursing appears to be a growing interest as evidenced by the expanding number of literature reviews conducted on the subject. The inquiry for this historical research is to understand the work and characteristics of Florence Nightingale and EI. METHODS: The assumption is that nurses who are emotionally intelligent are the most likely to not only survive the nursing profession but to thrive and make compassionate future leaders. Nightingale's letters, pictures and other writings were used to evaluate her viewpoints as an inspirational nurse and leader. RESULTS: Nightingale was a catalyst for change; internally motivated to be a great nurse and had the zeal to develop others as well. CONCLUSIONS: Exploring Nightingale's characteristics of EI such her confidence, determination, integrity and compassion, her teachings and beliefs can transcend time to mold successful nurses more than a century later. "The voice of a leader. It is as resounding as the heart it encourages, as far-reaching as the change it invokes. It is tuned by its keen sense of the voices around it and speaks back in a language they can understand. Its breath enters all that truly hear it, and when it no longer speaks, it can still be heard."-Mae Taylor Moss. PMID- 27981102 TI - A model for the role of emotional intelligence in patient safety. AB - Medical errors are the third leading cause of death in the USA, resulting in over 440,000 deaths/year. Although over a decade has passed since the first Institute of Medicine study that documented such horrific statistics and despite significant safety improvement efforts, serious progress has yet to be achieved. It is estimated that 80% of medical errors result from miscommunication among health care providers and between providers and patients. There is preliminary research evidence that communication skills programs can improve safety outcomes, but a systematic theoretical framework for such programs has not been identified. Because of the connection between emotional intelligence (EI) ability and communication effectiveness, EI has been called by some "one of the largest drivers of patient safety." Little literature has explored this relationship. The purpose of this article was to present a theoretical model for the relationship between EI, communication and patient safety, with conceptual and clinical illustrations used to describe such a relationship. PMID- 27981104 TI - AONS News. PMID- 27981105 TI - Special issue on information need in cancer care and prevention. PMID- 27981103 TI - The overall impact of emotional intelligence on nursing students and nursing. AB - Healthcare employers often criticize the lack of emotional competency and critical thinking skills demonstrated by newly licensed nurses. The purpose of this study was to evaluate whether emotional intelligence (EI) training for nurses improves critical thinking and emotional competence enough to justify including EI in nursing curricula. A meta-analysis was conducted inclusive of EI related nursing abilities and traits such as leadership, health, reflection, ethical behavior, nursing student performance, and job retention/satisfaction. Studies of EI constructs, test instruments, and contrary viewpoints were also examined. The analysis included 395 EI studies of approximately 65,300 participants. All the studies reported a positive correlation with EI ranging from weak to strong with a moderate cumulative effect size of r = 0.3022 across all studies. This study may contribute to positive social change by reducing employers time and cost for training newly licensed nurses, thereby decreasing the overall cost of health care to the public. PMID- 27981106 TI - A survey of Australian cancer nurses: The prevention and control of noncommunicable diseases (CanPaC study). AB - OBJECTIVE: There is global imperative to reduce the burden of noncommunicable diseases (NCD's). NCD's are the leading cause of death and disability globally. In Australia, 2010, the World Health Organization estimated cancer deaths attributable to NCD's accounted for approximately 29% of all deaths and most are preventable by modifying lifestyle associated risk factors. The International Council of Nurses (2010) identified nurses are ideally placed to contribute to prevention and control of NCD's through evidence based strategies (EBS). The aim of this study was to explore the Australian cancer nurses role, knowledge, and skills to prevent and control NCD's. METHODS: We used nonprobability snowball sampling to collect data from an online survey distributed to 899 members of the Cancer Nurses Society of Australia. RESULTS: Two hundred and fifty-seven nurses responded; >90% found it is within the scope of their role to contribute to prevention and control of NCDs, >70% assess for modifiable risk factors, >85% refer to support services, and 70% were interested in spending more time addressing prevention. Over 60% indicated they had adequate resources, appropriate personal skills, and adequate knowledge; however 73% felt they had inadequate time to incorporate strategies within their existing workload, 56% believed their physical environment was inadequate, and 48% felt a lack of culturally appropriate resources were identified as barrier to contributing to the prevention and control of NCDs. CONCLUSIONS: Australian cancer nurses want to contribute to the prevention and control of NCD's although workload, physical environment, and culturally inadequate resources hinder the implementation of EBS to combat NCD's. PMID- 27981107 TI - Oncology nurses' recognition of long-term cancer survivorship care in Japan. AB - OBJECTIVE: This study aims to assess the knowledge of definition of cancer survivors among Japanese oncology nurses and their roles in long-term cancer survivorship care. METHODS: A structured self-administered and self-report questionnaire created by the study investigators was given to members of the Japanese Society of Cancer Nursing. The subjects were 81 female oncology nurses. RESULTS: Forty-nine nurses had 11 or more years of nursing experience, while 27 nurses had cancer-related nursing certifications such as, certification in oncology nursing specialist. This study population had rather rich experience in oncology nursing. Sixty-two nurses defined a cancer survivor from the time of diagnosis, while the nurses' recognition of long-term survivorship care was poor, compared with nursing care at the time of diagnosis, during treatment, and end of life. CONCLUSIONS: The nurses were aware of the needs to recognize and address issues faced by long-term cancer survivors and for nursing study, but very few put the effective patient education and interventions into practice. It is because oncology nurses have few chances to see cancer survivors who go out of the hands of healthcare professionals. In increasing the number of long-term survivors, long-term survivorship care is needed in addition to incorporating such education into undergraduate and graduate programs. Further study on the knowledge of long-term cancer survivorship care and nursing practices are required. PMID- 27981108 TI - Treatment-related symptom severity and occurrences among oncology adults in Australia. AB - OBJECTIVE: Cancer treatments cause a range of distressing symptoms that can be well managed with pharmacological and nonpharmacological interventions. Treatment related symptom screening and management by health care professionals is required to provide appropriate guidance to help patients to complete successfully their treatment regimen and achieve the best possible outcomes for patients. The aims of this study were to explore treatment-related symptom severity and occurrences among oncology adults in Australia and compare the results with the Chinese and Filipino studies. METHODS: A cross-sectional descriptive survey of 84 adult patients over 18 years of age undergoing chemotherapy (CT) and/or radiotherapy (RT) in the Radiation Oncology and Medical Oncology Departments in one public teaching hospital in Canberra, Australia using the 25-item treatment-related symptom checklist (TRSC) was used in this study. RESULTS: Six symptom clusters emerged from combining the 25 symptoms. Patients receiving CT experienced highest fatigue symptom occurrences (95.8%) and greater symptom severity (mean = 2.59) for fatigue symptom cluster for patients receiving a combination of CT-RT. Australians treatment-related symptom severity and occurrences were higher compared with the Filipino and Chinese adult cancer patients. CONCLUSIONS: Nurses in oncology settings are uniquely placed to assess patients' therapy-related symptoms that will assist them to target education to cancer patients' individual needs. For all types of cancer, it is important to assess treatment-related symptoms and to provide the most appropriate interventions in consideration to the patients' preferences. PMID- 27981109 TI - Unmet needs and quality of life of family caregivers of cancer patients in South Korea. AB - OBJECTIVE: The purpose of this study was to investigate the levels of unmet needs and quality of life (QOL) among family caregivers (FCs) of cancer patients and to characterize the relationship between unmet needs and QOL. METHODS: A descriptive correlation design was used. Data were collected by convenience sampling during 2013 from 191 FCs of cancer patients who visited an outpatient cancer center in a general hospital in Korea. The comprehensive needs assessment tool for cancer caregivers and the Korean version of the Caregiver QOL Index-Cancer were used to measure unmet needs and QOL, respectively. RESULTS: FCs of cancer patients had a variety of unmet needs with prevalence ranged from 57.0% to 88.9%, depending on the domain. The domain with the highest prevalence of unmet needs was healthcare staff, followed by information/education. The mean QOL score was 74.62, with a possible range of 0-140. A negative correlation was found between unmet needs and QOL. Stepwise multiple regression analysis showed that unmet needs relating to health/psychological problems, practical support, family/social support, in addition to household income, cohabitation with the patient, and patient's age, explained 52.7% of the variance in QOL. The most influential factor was unmet needs relating to health/psychological problems, which accounted for 35.7% of the variance. CONCLUSIONS: The results of this study indicate that oncology professionals need to develop interventions to improve the QOL of FCs by focusing not only on information/educational needs of patient care but also on physical and psychological needs of FCs. PMID- 27981110 TI - Perspectives from older adults receiving cancer treatment about the cancer related information they receive. AB - OBJECTIVE: Cancer patients have reported that information plays a significant role in their capacity to cope with cancer and manage the consequences of treatment. This study was undertaken to identify the importance older adults receiving cancer treatment assign to selected types of cancer-related information, their satisfaction with the cancer-related information they received, and the barriers to effective information provision for this age group. METHODS: This study was conducted in two phases with separate samples. Six hundred and eighty-four older cancer patients receiving treatment completed a standardized survey and 39 completed a semi-structured interview to gather perspectives about cancer-related information. Data were analyzed for 65-79 years and 80+ year groups. RESULTS: Information topics about their medical condition, treatment options, and side effects of treatment were rated as most important by the older cancer patients. Women assigned a higher importance ratings than men to information overall (t = 4.8, P < 0.01). Although participants were generally satisfied with the information, they received many described challenges they experienced in communicating with health care professionals because of the medical language and fast pace of speaking used by the professionals. CONCLUSIONS: The older cancer patients in this study endorsed the same topics of cancer-related information as most important as has been reported in studies for other age groups. However, this older group recommended that, during their interactions with older individuals, health care professionals use fewer medical words, speak at a slower pace, and provide written information in addition to the actual conversation. PMID- 27981112 TI - Factors in the prioritization of information needs among Hong Kong Chinese breast cancer patients. AB - OBJECTIVE: The study aims to examine the prioritization of information needs in breast cancer patients, using the Information Needs Questionnaire (INQ); and to identify the demographic and clinical characteristics associated with that prioritization. METHODS: A cross-sectional exploratory study was conducted, by means of consecutive sampling. The INQ was used to examine participants' preferences on information needs. Their demographic and clinical characteristics were collected by means of a structured questionnaire and review of medical records. Backward multivariable logistic regression analysis was performed to examine the association between prioritization of patients' information needs and their demographic and clinical characteristics. RESULTS: A total of 275 breast cancer patients took part in the analysis. Of the nine INQ items, most participants ranked as their top four needs information about the likelihood of a cure (79%), extent of the disease (76%), treatment options (55%), and family risk of developing breast cancer (51%). Certain demographic and clinical characteristics-religious belief, whether living alone or not, household income, educational level, and time since cancer diagnosis-influenced patients' prioritization of information needs. CONCLUSION: Understanding and meeting the information needs of breast cancer patients are crucial to improving their quality of care. Different patients are likely to have different priorities in information needs according to their demographic and clinical characteristics. An awareness of these associated factors will allow better tailor-made educational interventions to be provided to meet patients' individual needs in a more adequate way. PMID- 27981111 TI - Do men with prostate cancer and their partners receive the information they need for optimal illness self-management in the immediate post-diagnostic phase? AB - OBJECTIVE: To (a) determine whether the information provided to men with prostate cancer and their partners in the immediate postdiagnostic phase met their needs; and (b) examine patient and partner satisfaction with the information received. METHODS: Pre-intervention survey data from a pilot randomized controlled trial of a self-directed coping skills intervention involving 42 patients with prostate cancer, and their partners were collected to examine their psychosocial concerns/needs. RESULTS: The main concerns for patients and partners were psychosocial in nature such as managing emotions, concern about the future, and losing control. Overall, patients and partners received most information about tests and treatment options. Partners reported receiving significantly less information about support services (P = 0.03) and self-care strategies (P = 0.03) compared to patients. Partners also reported being significantly less satisfied with the information they received (P = 0.007). CONCLUSIONS: Whereas medical information is routinely given, patients and partners may benefit from greater information about psychosocial issues arising from cancer. Despite increased recognition of partner's information needs these still remain unmet. PMID- 27981113 TI - Progress in diagnosis of breast cancer: Advances in radiology technology. AB - Breast cancer is the leading cause of cancer in females between the ages of 15 and 54, and the second leading cause of cancer death in women in the United States. Diagnosis begins with detection by breast examination (clinical breast exam or breast self-exam) or by radiologic studies, like mammography. Many advances in the diagnosis of breast cancer have taken place in recent years. This article will review the history of radiologic advances in the diagnosis of breast cancer. Use of technological advancements in digital breast tomosynthesis, magnetic resonance imaging, and ultrasound in breast cancer diagnosis will be presented. Advantages and disadvantages of these diagnostic interventions when compared to older, traditional X-ray films will be discussed. It is important for all nurses, including radiology and oncology nurses, to be well informed about these varied diagnostic modalities, and appreciate the fact that advances in radiologic imaging technologies can yield improved outcomes for breast cancer patients. PMID- 27981115 TI - Special issue on complementary and alternative medicine on cancer care. PMID- 27981114 TI - Using qualitative methods to develop a contextually tailored instrument: Lessons learned. AB - OBJECTIVE: To develop a population-specific instrument to inform hepatitis B virus (HBV) and human papilloma virus (HPV) prevention education and intervention based on data and evidence obtained from the targeted population of Khmer mothers reflecting their socio-cultural and health behaviors. METHODS: The principles of community-based participatory research (CBPR) guided the development of a standardized survey interview. Four stages of development and testing of the survey instrument took place in order to inform the quantitative health survey used to collect data in stage five of the project. This article reports only on Stages 1-4. RESULTS: This process created a new quantitative measure of HBV and HPV prevention behavior based on the revised Network Episode Model and informed by the targeted population. The CBPR method facilitated the application and translation of abstract theoretical ideas of HBV and HPV prevention behavior into culturally-relevant words and expressions of Cambodian Americans (CAs). CONCLUSIONS: The design of an instrument development process that accounts for distinctive socio-cultural backgrounds of CA refugee/immigrant women provides a model for use in developing future health surveys that are intended to aid minority-serving health care professionals and researchers as well as targeted minority populations. PMID- 27981117 TI - Ethnicity, traditional healing practices, and attitudes towards complementary medicine of a pediatric oncology population receiving healing touch in Hawaii. AB - OBJECTIVE: Cultural competence among healthcare providers is becoming increasingly important. Hawai'i is an ethnically diverse island state that has a high rate of traditional and complementary medicine use. We previously reported on the feasibility of delivering Healing Touch (HT) to pediatric oncology patients, and its impact on pain, distress and fatigue. Our current objective is to examine the ethnic and cultural characteristics of this patient population, including traditional health related beliefs. METHODS: Demographic data and feedback from subjects and their families from the 2009-2010 HT study conducted in Honolulu were analyzed. RESULTS: The majority of the participants were Asian American and/or Native Hawaiian or other Pacific Islander. Almost half of the participants were more than one race. Traditional cultural health related beliefs, as reported by patients and families, sometimes aligned with patient's experiences with HT, however, degree of acculturation/time living in the United States seemed to play a role as well, with younger generation perhaps being less "traditional". Common health related themes/values across the predominant cultures were 1) emphasis on family/clan and 2) mind/body connection. CONCLUSIONS: HT appeared to be well accepted by subjects from a variety of ethnic backgrounds. Several patients had attitudes/beliefs around healthcare that were rooted in their traditional cultural values, but this was not universal. Knowledge of different cultural attitudes on health, and traditional/complementary medicine, will improve patient care. Future areas of research could examine the acceptance of HT among pediatric oncology patients in geographic areas with differing cultural demographics (i.e., continentalUnited States or internationally). PMID- 27981116 TI - Integrating complementary and alternative medicine into cancer care: Canadian oncology nurses' perspectives. AB - The integration of complementary and alternative medicine (CAM) and conventional cancer care in Canada is in its nascent stages. While most patients use CAM during their cancer experience, the majority does not receive adequate support from their oncology health care professionals (HCPs) to integrate CAM safely and effectively into their treatment and care. A variety of factors influence this lack of integration in Canada, such as health care professional(HCP) education and attitudes about CAM; variable licensure, credentialing of CAM practitioners, and reimbursement issues across the country; an emerging CAM evidence base; and models of cancer care that privilege diseased-focused care at the expense of whole person care. Oncology nurses are optimally aligned to be leaders in the integration of CAM into cancer care in Canada. Beyond the respect afforded to oncology nurses by patients and family members that support them in broaching the topic of CAM, policies, and position statements exist that allow oncology nurses to include CAM as part of their scope. Oncology nurses have also taken on leadership roles in clinical innovation, research, education, and advocacy that are integral to the safe and informed integration of evidence-based CAM therapies into cancer care settings in Canada. PMID- 27981119 TI - Precis for living in limbo and speaking legibly: Reporting qualitative description of oral tongue cancer experience. PMID- 27981120 TI - Living in limbo: Being diagnosed with oral tongue cancer. AB - OBJECTIVE: Oral tongue cancer presents clinical challenges to effective diagnosis that affect patient experience. Patient experience of the diagnostic process is poorly described, making opportunities for nursing intervention unclear. METHODS: We qualitatively describe, using constant comparative analysis, oral tongue cancer diagnosis using data from a larger grounded theory study of oral tongue cancer survivorship. Using constant comparative analysis - in keeping with the methodology of the main study - we analyzed 16 survivor interviews for themes explaining the patient experience of oral tongue cancer diagnosis. RESULTS: We termed the broader diagnostic process "living in limbo." This process includes the themes describing the peri-diagnostic process itself - "self-detected lesion," "lack of concern," "seeking help," "not a straightforward diagnosis," and "hearing the diagnosis." Entry into treatment concludes "Living in Limbo" and is described by the theme "worry and trust." CONCLUSIONS: Our findings are limited by retrospective interviews and participant homogeneity among other features. Future research with prospective designs and diverse groups of people at risk for and diagnosed with oral tongue cancer, as well as targeting those who have had negative biopsies with no eventual diagnosis of oral tongue cancer, will build on our findings. Further, study of patient experience in other sociocultural context and healthcare systems is needed to inform nursing science and practice. Finally, "living in limbo" suggests that clinician and public education about oral tongue cancer diagnosis is needed. PMID- 27981118 TI - Improved sleep after Qigong exercise in breast cancer survivors: A pilot study. AB - OBJECTIVE: Sleep disorder and fatigue are among a few major concerns of breast cancer survivors across the survivorship trajectory. The purpose of this pilot study was to examine feasibility and trends in multiple outcomes after a 6-week Qigong exercise program in breast cancer survivors. METHODS: Eight female adults (mean age 55.4 +/- 9.4 years, mean time after the completion of cancer treatment 3.9 +/- 5.7 years) who had a diagnosis of breast cancer and were at least 3 months postcompletion of primary cancer treatment prior to participation in this study. Baseline evaluation was administered using subjective questionnaires on sleep quality, insomnia, fatigue, and quality of life. All subjects participated in two training sessions to learn the "Six Healing Sound" Qigong exercise and attended group Qigong sessions once per week in the following 6 weeks. In addition to the group sessions, subjects were asked to perform the Qigong exercises twice at home right before going to bed in the evening and immediately after getting up in the morning. Following the 6-week intervention, subjects were re-assessed using the same questionnaires. Pre- and post-intervention scores were analyzed for statistical significance. RESULTS: Compliance rate was 89.6% for group sessions and 78.5% (ranging from 65.6% to 90.7%) for daily home Qigong exercises. No participant reported any adverse event or side effect during the study. All participants indicated in the end-intervention questionnaire that they would highly recommend the intervention to others. Significant improvements were observed in sleeping quality score (from 10.3 +/- 3.6 to 5.4 +/- 2.3, P < 0.01), insomnia index score (from 16.2 +/- 3.2 to 6.8 +/- 4.8, P < 0.01), fatigue score (from 60.3 +/- 9.4 to 49.1 +/- 8.6, P < 0.01), and SF-36 score (from 66.8 +/- 7.7 to 80.9 +/- 3.9, P < 0.01). CONCLUSIONS: Results of this single arm pilot study showed the feasibility and potential of "Six Healing Sounds" Qigong exercise for improving sleep and other symptoms in breast cancer survivors. PMID- 27981121 TI - Speaking legibly: Qualitative perceptions of altered voice among oral tongue cancer survivors. AB - OBJECTIVE: Treatment for oral tongue cancer poses unique challenges to restoring and maintaining personally acceptable, intelligible speech. METHODS: We report how oral tongue cancer survivors describe their speech after treatment in a qualitative descriptive approach using constant comparative technique to complete a focal analysis of interview data from a larger grounded theory study of oral tongue cancer survivorship. Interviews were completed with 16 tongue cancer survivors 3 months to 12 years postdiagnosis with stage I-IV disease and treated with surgery alone, surgery and radiotherapy, or chemo-radiation. All interview data from the main study were analyzed for themes describing perceptions of speech as oral tongue cancer survivors. RESULTS: Actual speech impairments varied among survivors. None experienced severe impairments that inhibited their daily lives. However, all expressed some level of concern about speech. Concerns about altered speech began when survivors heard their treatment plans and continued through to survivorship without being fully resolved. The overarching theme, maintaining a pattern and character of speech acceptable to the survivor, was termed "speaking legibly" using one survivor's vivid in vivo statement. Speaking legibly integrate the sub-themes of "fears of sounding unusual", "learning to talk again", "problems and adjustments", and "social impact". CONCLUSIONS: Clinical and scientific efforts to further understand and address concerns about speech, personal presentation, and identity among those diagnosed with oral tongue are important to improving care processes and patient-centered experience. PMID- 27981123 TI - Study of collaboration methods between nurses and medical social workers during facility transfer of end-of-life cancer patients. AB - OBJECTIVE: The purpose of this study is to clarify how nurses and medical social workers (hereafter, MSW) collaborate in providing nursing and support to cancer patients who will transition to end-of-life care. METHODS: Informants were comprised of 18 nurses and 8 MSW working at a large hospital practicing state-of the-art cancer treatment. Interviews were conducted by forming focus groups comprised of a mix of nurses and social workers. The focus group interview survey involved the author transcribing audio recordings of these interview sessions, extracting sections relevant to the study purpose, and performing qualitative analysis. Codes relevant to the study purpose were extracted and compiled into cards. These cards were then grouped according to similarity of contents. Sentences expressing the contents of each group were composed, and small tags were appended to meaningful codes. These groups were further grouped together if similar groups were found. Large tags were appended to meaningful codes. RESULTS: Seventeen small tags and six large tags were appended. Based on the remarks of informants in the focus group interview facilitated by the author, storylines were drawn up by arranging the small tags and large tags. The storylines were then compiled into a results diagram. Even if the patient and the family were in agreement as to his care after hospital discharge, the patient himself agreed to the transfer, and good relations had been established between the nurse and patient and the MSW and patient, as collaboration between the nurses and MSW had been insufficient, there were cases in which the hospital transfer did not proceed smoothly. CONCLUSIONS: This study reflects how a transfer will not proceed smoothly simply by establishing trusting relations between the patient and nurses, and this study demonstrated that the collaboration between nurses and MSW is indispensable when it concerns transferring the patient to end-of-life care at another facility. PMID- 27981122 TI - Promoting emancipated decision-making for surgical treatment of early stage breast cancer among Jordanian women. AB - To use the critical social theory as a framework to analyze the oppression of Jordanian women with early stage breast cancer in the decision-making process for surgical treatment and suggest strategies to emancipate these women to make free choices. This is a discussion paper utilizing the critical social theory as a framework for analysis. The sexist and paternalistic ideology that characterizes Jordanian society in general and the medical establishment in particular as well as the biomedical ideology are some of the responsible ideologies for the fact that many Jordanian women with early stage breast cancer are denied the right to choose a surgical treatment according to their own preferences and values. The financial and political power of Jordanian medical organizations (e.g., Jordan Medical Council), the weakness of nursing administration in the healthcare system, and the hierarchical organization of Jordanian society, where men are first and women are second, support these oppressing ideologies. Knowledge is a strong tool of power. Jordanian nurses could empower women with early stage breast cancer by enhancing their knowledge regarding their health and the options available for surgical treatment. To successfully emancipate patients, education alone may not be enough; there is also a need for health care providers' support and unconditional acceptance of choice. To achieve the aim of emancipating women with breast cancer from the oppression inherent in the persistence of mastectomy, Jordanian nurses need to recognize that they should first gain greater power and authority in the healthcare system. PMID- 27981124 TI - Oncology nurses awareness of drug interactions. AB - OBJECTIVE: The aim of this study was to determine oncology nurses awareness of drug interactions. METHODS: This descriptive study was conducted with nurses working in the oncology clinics who are a member of Oncology Nursing Association of Turkey. A total of 115 nurses (response rate %20) were responded to the online survey that consists of 28 questions. RESULTS: The mean age of the nurses was 33 +/- 6.8. The majority of nurses work in university hospital (60%) as a clinical nurse (62.6%) and have a Bachelor Degree in Nursing (63.5%). The mean working years in oncology was 4 years. Half of them stated receiving information on drug interactions mostly through in-service education and courses/congresses in last 5 years. The majority of them (84.3%) indicated that they are considering the possibility of drug interactions when they are scheduling the medication administration time. More than half of the responders (59.1%) encountered drug interactions; however, few explored drug interactions with food, drinks, and nutritional supplements. Their practices to assess possibility of drug interactions were reviewing the drug prospectus (78.3%); consulting with their colleagues (58.3%) and searching on the available website (42.6%) and looking at the drug interaction (39.1%). More than half (65.2%) stated lack of any system to identify drug interactions in their workplace. Nearly half of them indicated to including the drug interaction into patient education mostly for food-drug (73.9%) and drug-drug (63.5%) interactions. CONCLUSIONS: Almost all indicated the needs for further education on drug interactions and suggested to have guideline/packet guide. PMID- 27981125 TI - Effect of an education program on knowledge, self-care behavior and handwashing competence on prevention of febrile neutropenia among breast cancer patients receiving Doxorubicin and Cyclophosphamide in Chemotherapy Day Centre. AB - OBJECTIVE: To evaluate the efficacy of an education program on the prevention of febrile neutropenia (FN) among breast cancer patients receiving AC regimen. METHODS: Randomized controlled trial with the repeated-measures design was conducted in a Chemotherapy Day Centre of an acute hospital in Hong Kong. Twenty five subjects in the intervention group received an individual education session followed by three follow-up sessions and routine care. Twenty-four subjects in the control group received routine care. Primary outcomes included the incidence of admission due to FN, the self-care behavior adherence, the knowledge level on prevention of FN and the self-efficacy in self-management, handwashing competence were assessed by self-designed questionnaires, Chinese version of patient activation measure, and handwashing competence checklist. RESULTS: No statistically significant difference between the intervention group and the control group on the incidence of admission due to FN, the self-efficacy in self management, and the knowledge on prevention of FN. The self-care behavior adherence was significant at cycle 4 of AC regimen in favor of the intervention group (P = 0.036). Handwashing competence improved more significantly among subjects in the intervention group than the control group (P = 0.009). CONCLUSIONS: The education program on the prevention of FN had significantly favorable effects on self-care behavior adherence and handwashing competence across time. However, the intervention did not lead to statistically significant improvement on the incidence of admission due to FN, the self-efficacy in self management and the knowledge level on prevention of FN. PMID- 27981126 TI - ICCN 2015 at Vancouver. PMID- 27981127 TI - Special Issue on Asian Oncology Nursing Society Conference 2015. PMID- 27981128 TI - Nurses of Asia: Reflection from Asian Oncology Nursing Society Conference 2015. AB - Another significant milestone from the Executive Board and the Organizing Committee of the Asian Oncology Nursing Society (AONS) transpired last November 20-21, 2015. The 2nd AONS Conference was held in Seoul, South Korea under the theme of "Flying the Spirits of Asian Oncology Nursing." A total of 687 delegates from USA, Canada, Australia, Romania, and Asian Region supported this groundbreaking event. The objective of this 2-day conference was to facilitate sharing of expertise in the field of oncology nursing from the academe to clinical practice and to research. The issues that have been discussed in this 2 day symposium were Professional Development of Oncology Nursing, Quality of Life, Putting Evidence into Practice, Nursing Research, and Health Insurance for Cancer Care in Asia. PMID- 27981129 TI - Building Capacity for Evidenced-Based Practice at the Unit Level Using Oncology Nursing Society Putting Evidence Practice. PMID- 27981130 TI - Patient Care and Outcomes: Why Cancer Care Should Screen for Distress, the 6th Vital Sign. PMID- 27981131 TI - Vision of Professional Development of Oncology Nursing in the World. PMID- 27981132 TI - Building Capacity for Cancer Nursing Research and Evidence-Based Practice: the Cancer Nursing Professorial Precinct Initiative. PMID- 27981133 TI - Creating a Culture of Professional Development for Oncology Nursing in Asia. AB - The importance of professional development of oncology nursing in Asia is growing along with growth in the cancer burden and disparity in cancer incidence and mortality between more- and less-developed regions, the latter of which includes most Asian countries. This paper proposes ways to advance the oncology nursing in terms of education, practice, and research in Asia. It also describes major challenges expected in developing and implementing a unique professional role for oncology nurses in Asia. This study will provide insights for Asian oncology nurses in developing culturally sensitive oncology nursing practices with limited health care resources. PMID- 27981134 TI - Development and Implementation of Evidence-Based Practice in Cancer Care: Challenges and Opportunities. AB - The cancer burden is a global problem, and oncology nurses should be accountable for delivering safe and effective cancer care and providing the best possible experience for patients. The development and application of evidence-based practice in cancer care is an effective strategy in achieving this goal; however, the journey in which such practice involves may encounter various challenges. In this article, the author discusses her own experience, successful and unsuccessful of such a journey. Both challenges and opportunities are identified, and suggestions put forward for making collaborative efforts. PMID- 27981135 TI - Cancer Prehabilitation for Patients Starting from Active Treatment to Surveillance. AB - The purpose of this brief summary is to introduce the concept of cancer prehabilitation and the role of oncology nurses in prehabilitation care. Cancer prehabilitation has been defined by Sliver and Baima (2013) as "a process on the cancer continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment." The evidence supports the notion that prehabilitation programs can improve physical and psychological health outcomes and decrease overall health care costs. The care model for cancer prehabilitation should include timely and efficient assessment throughout the care continuum with a focus on improving outcomes in cancer at every stage. During the cancer journey, three types of assessment with different aims are included: (1) prehabilitation assessment pretreatment, (2) rehabilitation assessment at early post treatment, and (3) health promotion assessment at the end of treatment. Specific prehabilitation assessment and interventions for treatment-related complications or major side-effects should be considered. Teaching, counseling, discharge planning, and coordination should also be part of an oncology nurse's role in cancer prehabilitation. It is suggested that cancer care managers or navigators be trained in the assessment of their patients' physical and psychological status once the cancer diagnosis has been identified and the patient has decided to receive active treatment, especially for those waiting for surgery at home. Oncology nurses could increase their competence with prehabilitation care by gaining knowledge about cancer-related treatments and their outcomes for specific cancers and by strengthening the ability to assess the functional status and psychological distress of their patients. PMID- 27981136 TI - Complementary Therapy for Cancer Survivors: Integrative Nursing Care. AB - OBJECTIVE: The number of cancer patients who survive more than 5 years after the completion of their initial treatment is increasing. Oncology nurses must consider the needs of long-term cancer survivors in addition to those of cancer patients undergoing treatment because cancer survivors experience anxiety over several issues, including the risk of recurrence and progression of cancer status and symptom management. METHODS: We tried to examine the effect of complementary therapy (CT) to reduce anxiety. The experimental study compared an intervention group (5 males and 68 females) that underwent four CTs and a control group (5 males and 56 females) that received no intervention. The intervention group practiced the CTs in their home for 20 min/day, 2 days/week, for 8 weeks, for a total of 16 times, whereas the control group performed their usual routines. Stress response scale-18 (SRS-18) scores consisting of three subscales (depression-anxiety, temper-anger, and lethargy) were compared between the groups and across time within each group. RESULTS: The intervention group reduced depression and anxiety significantly than the control group. Furthermore, the intervention group expressed the following positive feedback: "being able to relax," "being distracted from their worries and anxieties," "being able to sleep," "feeling more in-touch with reality," and "wanting to continue the practice." CONCLUSIONS: The study might accurately reflect the perspectives of women with cancer because the majority of the patients were women. Meanwhile, the result suggests that CTs might be useful for long-term cancer survivors who experience anxiety that influence their quality of life. PMID- 27981138 TI - Brief Introduction of Medical Insurance System in China. AB - China has one of the largest numbers of cancer patients. The huge expenses of medical care for cancer patients has brought heavy economic burden to the family. This paper briefly introduces the tumor medical insurance situation in China from the construction and composition of China's medical security system, the access of cancer patients to get health insurance, the challenges and developmental trend of China's medical security system, and two case studies that highlight different financial situations. PMID- 27981139 TI - Health Insurance for Cancer Care in Asia: Thailand. AB - Thailand has a universal multi-payer system with two main types of health insurance: National Health Security Office or public health insurance and private insurance. National health insurance is designed for people who are not eligible to be members of any employment-based health insurance program. Although private health insurance is also available, all Thai citizens are required to be enrolled in either national health insurance or employees' health insurance. There are many differences between the public health insurance and private insurance. Public health insurance, therefore, initiates programs that offer many sets of benefit packages for high-cost care. For cancer care, cover screening, curative treatment such as surgery, chemotherapy, radiation together with supportive and palliative care. PMID- 27981137 TI - Introduction of Situation, Background, Assessment, Recommendation into Nursing Practice: A Prospective Study. AB - OBJECTIVE: The aim of the study was to introduce and evaluate the compliance to documentation of situation, background, assessment, recommendation (SBAR) form. METHODS: Twenty nurses involved in active bedside care were selected by simple random sampling. Use of SBAR was illustrated thru self-instructional module (SIM). Content validity and reliability were established. The situation, background, assessment, recommendation (SBAR) form was disseminated for use in a clinical setting during shift handover. A retrospective audit was undertaken at 1st week (A1) and 16th week (A2), post introduction of SIM. Nurse's opinion about the SBAR form was also captured. RESULTS: Majority of nurses were females (65%) in the age group 21-30 years (80%). There was a significant association (P = 0.019) between overall audit scores and graduate nurses. Significant improvement (P = 0.043) seen in overall scores between A1 (mean: 23.20) and A2 (mean: 24.26) and also in "Situation" domain (P = 0.045) as compared to other domains. There was only a marginal improvement in documentation related to patient's allergies and relevant past history (7%) while identifying comorbidities decreased by 40%. Only 70% of nurses had documented plan of care. Most (76%) of nurses expressed that SBAR form was useful, but 24% nurses felt SBAR documentation was time consuming. The assessment was easy (53%) to document while recommendation was the difficult (53%) part. CONCLUSIONS: SBAR technique has helped nurses to have a focused and easy communication during transition of care during handover. Importance and relevance of capturing information need to be reinforced. An audit to look for reduced number of incidents related to communication failures is essential for long-term evaluation of patient outcomes. Use of standardized SBAR in nursing practice for bedside shift handover will improve communication between nurses and thus ensure patient safety. PMID- 27981140 TI - Meeting An Unmet Need in Metastatic Colorectal Carcinoma with Regorafenib. AB - Colorectal cancer is a global issue, affecting men and women equally. Over the last 25 years, advances in therapy and multidisciplinary care have led to improvements in survival for those with colorectal cancer. Despite these advances, more therapeutic options are needed for those being treated for this disease. Regorafenib is an oral drug that is a new therapeutic option for our patients. The CORRECT and CONCUR trials demonstrate the efficacy of regorafenib in the last line setting. This article summarizes some of the regorafenib clinical trial data and discusses the strategies to help manage the side effects of this drug including patient education, dose reductions and interruptions, and monitoring hypertension and liver function. PMID- 27981141 TI - Achieving Excellence in Palliative Care: Perspectives of Health Care Professionals. AB - Caring for individuals at the end of life in the hospital environment is a challenging proposition. Understanding the challenges to provide quality end of life care is an important first step in order to develop appropriate approaches to support and educate staff members and facilitate their capacity remaining "caring." Four studies were undertaken at our facility to increase our understanding about the challenges health professionals experience in caring for patients at end of life and how staff members could be supported in providing care to patients and families: (1) In-depth interviews were used with cancer nurses (n = 30) to explore the challenges talking about death and dying with patients and families; (2) Surveys were used with nurses (n = 27) and radiation therapists (n = 30) to measure quality of work life; (3) and interprofessional focus groups were used to explore what it means "to care" (five groups held); and (4) interprofessional focus groups were held to understand what "support strategies for staff" ought to look like (six groups held). In all cases, staff members confirmed that interactions concerning death and dying are challenging. Lack of preparation (knowledge and skill in palliative care) and lack of support from managers and colleagues are significant barriers. Key strategies staff members thought would be helpful included: (1) Ensuring all team members were communicating and following the same plan of care, (2) providing skill-based education on palliative care, and (3) facilitating "debriefing" opportunities (either one-on-one or in a group). For staff to be able to continue caring for patients at the end of life with compassion and sensitivity, they need to be adequately prepared and supported appropriately. PMID- 27981143 TI - Name Recognition to Identify Patients of South Asian Ethnicity within the Cancer Registry. AB - OBJECTIVE: The goal of this project was to develop a list of forenames and surnames of South Asian (SA) women that could be used to identify SA breast cancer patients within the cancer registry. This list was compiled, evaluated, and validated to ensure comprehensiveness, accuracy, and applicability of SA names. METHODS: This project was conducted by Canadian researchers who are immersed in conducting behavioral studies with SA women diagnosed with cancer in the province of British Columbia. Recruiting SA cancer patients for research can be a difficult task due to social and cultural factors. Methods used by other researchers to identify ethnicity related unique names were employed to filter surnames and forenames that were not common to this ethnic group. Co-author (Gurpreet Oshan) of SA ethnicity rigorously identified and deleted multiple lists and redundant entries along with common English forenames which resulted in a list of 16,888 SA forenames. All co-authors of Indian ethnicity (Gurpreet Oshan, Savitri Singh-Carlson, Harajit Lail) were involved in critiquing and manually reviewing the names list throughout this process. Comprehensive lists of SA surnames and women's forenames were reviewed to identify those that were unique to SA ethnicity. Accuracy was ensured by constantly filtering the redundancy by using an Excel program which helped to illustrate the number of times each name was spelled in different ways. RESULTS: The final lists included 9112 surnames and 16,888 forenames of SA ethnicity. On the basis of the surname linkage only, the sensitivity of the list was 76.6%, specificity was 62.9%, and the positive predictive value was 58.5%. On the basis of both the surname and forename linkage, the specificity of the list was 88.6%. These lists include variations in spelling forenames and surnames as well. CONCLUSIONS: The list of surnames and forenames can be useful tools to identify SA ethnic groups from large population database in healthcare-related research. Ethnicity-specific population research is important in order to help identify how cancer care should be delivered for the SA population, as well as for planning and provision of other related health services. We are willing to share this list upon request to the authors. PMID- 27981144 TI - Awareness of Skin Cancer, Prevention, and Early Detection among Turkish University Students. AB - OBJECTIVE: The aim of this study was to determine the awareness about skin cancer, prevention, and early detection among university students. METHODS: This descriptive cross-sectional study was carried out with 404 students in a university located in Ankara, the capital city of Turkey. A 35-item questionnaire was used for data collection. RESULTS: Less than half of the students (37.9%) had knowledge about skin cancer mostly through the internet (24.5%) and media (24.1%). Half of them aware of the risk factors; mostly as avoiding direct exposure to the Sun between 10 am and 4 pm (45.3%); smoking and alcohol (38.4%); having fair skin color (34.9%); and ultraviolet light exposure (25.7%). Only one third of them (32.9%) are knowledgeable about skin cancer signs and symptoms, such as a change in color and appearance of the nevus/moles (24%). The majority of the responders (77.3%) did not know about screening tests for skin cancer and only 18 (4.5%) students were practicing skin self-examination. CONCLUSIONS: This study showed a lack of knowledge about skin cancer, prevention, and early detection among university students and reported the need for educational interventions to raise awareness in this target group. PMID- 27981142 TI - New Insights into Potential Prevention and Management Options for Chemotherapy Induced Peripheral Neuropathy. AB - OBJECTIVE: Neurological complications such as chemotherapy-induced peripheral neuropathy (CIPN) and neuropathic pain are frequent side effects of neurotoxic chemotherapy agents. An increasing survival rate and frequent administration of adjuvant chemotherapy treatments involving neurotoxic agents makes it imperative that accurate diagnosis, prevention, and treatment of these neurological complications be implemented. METHODS: A consideration was undertaken of the current options regarding protective and treatment interventions for patients undergoing chemotherapy with neurotoxic chemotherapy agent or experience with CIPN. Current knowledge on the mechanism of action has also been identified. The following databases PubMed, the Cochrane Library, Science Direct, Scopus, EMBASE, MEDLINE, CINAHL, CNKI, and Google Scholar were searched for relevant article retrieval. RESULTS: A range of pharmaceutical, nutraceutical, and herbal medicine treatments were identified that either showed efficacy or had some evidence of efficacy. Duloxetine was the most effective pharmaceutical agent for the treatment of CIPN. Vitamin E demonstrated potential for the prevention of cisplatin-IPN. Intravenous glutathione for oxaliplatin, Vitamin B6 for both oxaliplatin and cisplatin, and omega 3 fatty acids for paclitaxel have shown protection for CIPN. Acetyl-L-carnitine may provide some relief as a treatment option. Acupuncture may be of benefit for some patients and Gosha-jinki-gan may be of benefit for protection from adverse effects of oxaliplatin induced peripheral neuropathy. CONCLUSIONS: Clinicians and researchers acknowledge that there are numerous challenges involved in understanding, preventing, and treating peripheral neuropathy caused by chemotherapeutic agents. New insights into mechanisms of action from chemotherapy agents may facilitate the development of novel preventative and treatment options, thereby enabling medical staff to better support patients by reducing this debilitating side effect. PMID- 27981147 TI - Cover Story. PMID- 27981146 TI - The Oncology Nurse Prescribing: A Catalonian Survey. AB - OBJECTIVE: This study identifies the capability, knowledge, and satisfaction of oncology nurses in Spain after approval of the nurse prescribing law in 2006. METHODS: A descriptive cross-sectional study was conducted among 140 nurses in three cancer centers in Catalonia, Spain, by using convenience sampling method. The principal variables of this study were nurse satisfaction, knowledge about what products nurses are allowed to prescribe, the nurses' perception of their own prescribing ability, and their opinion on education and training needs with regard to the new approved law. The secondary variables included years of professional experience, place of work, and sociodemographic variables. Data were collected during a 3 months period by using a piloted 29-item self-assessment questionnaire. RESULTS: Analyses of univariate and bivariate data showed that 82.2% of the nurses were aware of the approved law, but 94.2% indicated that they lack information about it. The mean satisfaction with the approval of the law was 6.64 +/- 1.76 (numerical scale 0-10). In addition, 68.1% and 55.1% of the nurses were prepared to prescribe medical devices and drugs, respectively. To date, 61.1% of the nurses prescribe medical devices and 66% prescribe pharmacological products daily. CONCLUSIONS: Nurses expressed general satisfaction with the approval of the Law 29/2006. Nurses currently provide prescriptions, but widespread knowledge of the allowed prescriptions is lacking. PMID- 27981145 TI - Barriers to Colorectal Cancer Screening in Primary Care Settings: Attitudes and Knowledge of Nurses and Physicians. AB - OBJECTIVE: Healthcare providers (HCPs) play a critical role in reducing colorectal cancer (CRC) related morbidity and mortality. This study aimed at exploring the attitudes and knowledge of nurses and physicians working in primary care settings regarding CRC screening. METHODS: A total of 142 HCPs (57.7% nurses and 42.3% physicians) participated in a cross-sectional survey. Data were collected using a Self-administered Questionnaire. The participants were clinically experienced (mean = 9.39 years; standard deviation [SD] = 6.13), regularly taking care of adults eligible for CRC screening (62%) and had positive attitudes toward CRC screening (83.1%). Most participants (57%) had low levels of knowledge about CRC screening (mean = 3.23; SD = 1.50). The participants were most knowledgeable about the recommended age for initiating screening (62.7%) and the procedures not recommended for screening (90.8%). RESULTS: More than 55% did not know the frequency of performing specific screening procedures, the upper age limit at which screening is not recommended, and the patients at high-risk for CRC. There were no significant differences between nurses' and physicians' attitudes and knowledge. The participants' perceptions about professional training (odds ratio [OR] = 2.17, P = 0.003), colonoscopy (OR = 2.60, P = 0.014), and double-contrast barium enema (OR = 0.53, P = 0.041), were significantly associated with knowledge about CRC screening. CONCLUSIONS: The inadequate knowledge levels among nurses and physicians may be one of the barriers affecting CRC screening. Enhancing HCPs knowledge about CRC screening should be considered a primary intervention in the efforts to promote CRC screening and prevention. PMID- 27981148 TI - Special Issue on the Impact of Cancer on Patients and Their Families. PMID- 27981149 TI - Cancer Care and the Role of Psychosocial Oncology: Where are We and Where are We Going? PMID- 27981150 TI - Raising the Awareness of Undergraduate Nurses to the Psychosocial Impact of Living with Cancer: A Consumer Engagement in Teaching Initiative. AB - This article reflects on the development and implementation of a consumer engagement in teaching initiative by the authors. The authors highlight the challenges of engaging undergraduate nursing students on the psychosocial aspects of living with cancer and other chronic illnesses when students have very limited personal and professional experiences to draw on. The authors discuss how they have responded to these challenges by integrating the voices of consumers into their classrooms. Speakers from consumer advocacy organization, Cancer Voices SA, participated in a series of tutorials in a 1st year topic in the Undergraduate Nursing Program at the School of Nursing and Midwifery, Flinders University. Student feedback from the implementation of the initiative indicated that students found consumers' stories and experiences of living with cancer, "moving and powerful" and that they encouraged students to question their assumptions about the psychosocial impacts of cancer on individuals and families. The importance of good communication in reducing patient distress was identified by students as an important element of consumers' experiences of the health care system as was the need for transparency and information sharing between health care providers across the health care system. For many students, consumers' stories and experiences had reinforced students' commitment to studying nursing and pursuing a career in nursing. The article concludes that involving consumers in the education of health care professionals encourages a much deeper understanding of and empathy for how patients experience disease, which is integral to the provision of patient-centered and holistic care. PMID- 27981151 TI - A Review on Cost-Effectiveness and Cost-Utility of Psychosocial Care in Cancer Patients. AB - Several psychosocial care interventions have been found effective in improving psychosocial outcomes in cancer patients. At present, there is increasingly being asked for information on the value for money of this type of intervention. This review therefore evaluates current evidence from studies investigating cost effectiveness or cost-utility of psychosocial care in cancer patients. A systematic search was conducted in PubMed and Web of Science yielding 539 unique records, of which 11 studies were included in the study. Studies were mainly performed in breast cancer populations or mixed cancer populations. Studied interventions included collaborative care (four studies), group interventions (four studies), individual psychological support (two studies), and individual psycho-education (one study). Seven studies assessed the cost-utility of psychosocial care (based on quality-adjusted-life-years) while three studies investigated its cost-effectiveness (based on profile of mood states [mood], Revised Impact of Events Scale [distress], 12-Item Health Survey [mental health], or Fear of Progression Questionnaire [fear of cancer progression]). One study did both. Costs included were intervention costs (three studies), intervention and direct medical costs (five studies), or intervention, direct medical, and direct nonmedical costs (three studies). In general, results indicated that psychosocial care is likely to be cost-effective at different, potentially acceptable, willingness-to-pay thresholds. Further research should be performed to provide more clear information as to which psychosocial care interventions are most cost effective and for whom. In addition, more research should be performed encompassing potential important cost drivers from a societal perspective, such as productivity losses or informal care costs, in the analyses. PMID- 27981153 TI - Integrative Review of the Supportive Care Needs of Arab People Affected by Cancer. AB - This review aimed to identify the unmet supportive care needs to conduct an integrative review of the literature, to identify the unmet supportive care needs of Arab people affected by cancer (patients and caregivers), and the impact of these needs on quality of life and psychosocial well-being. In July 2015 databases, search engines and electronic list servers were searched, with no limit on the year of publication. Reference lists of included articles and published reviews were also hand searched. Six studies met the inclusion criteria. Most studies examined the supportive care/unmet needs of Arab cancer patients and their family caregivers. Language, communication, information, and the need to get relief from dependency were the most frequently reported unmet needs among Arab cancer patients. For immigrant Arab patients, physical unmet needs were higher than other migrant groups and native Anglo-Australians. Arab caregivers' unmet needs included concerns about providing suitable care for their family member, sharing their experience with other caregivers, obtaining information, and, in the case of pediatric cancers, dealing with siblings' emotional reactions. The existing literature exploring the unmet supportive care needs of Arab people affected by cancer is limited suggesting that comprehensive studies are needed to enhance our understanding of these needs and to inform service planning. PMID- 27981152 TI - Telomeres and Stress: Promising Avenues for Research in Psycho-Oncology. AB - A cancer diagnosis and subsequent treatment is a stressful experience with the potential for long-term health consequences for both patients and their caregivers. It is now well-established that psychological stress is associated with detrimental effects on physical health. Recent studies have investigated the link between telomeres, the protective cap at the end of chromosomes, and stress, suggesting that stress potentially impacts on cellular aging through telomere shortening, with subsequent consequences for health. This review aims to familiarize the reader with the pertinent literature exploring the relationship between telomeres and psychological and behavioral factors and propose future directions for telomere research in psycho-oncology. PMID- 27981154 TI - The Effectiveness of Support Groups in Asian Breast Cancer Patients: An Integrative Review. AB - Cancer support group has been studied as an intervention to improve patient psychosocial well-being. The effectiveness of support groups among Asian breast cancer (BC) patients has been unclear and received limited attention to the evidence of its effectiveness. The social-cognitive processing theory underlies the principles of support groups and advocates that a positive, supportive social environment can improve cognitive processing. The purpose of this paper is to present an integrative review of research evidence on the effectiveness of cancer support groups with Asian BC patients. Empirical studies related to support group among Asian and Asian American BC patients published between 1982 and April 2014 are reviewed. There are 15 studies selected (12 from the Asian-Pacific region and 3 from Western countries). The review includes 1 qualitative study, 3 descriptive studies, 1 mixed method design, and 10 experimental or quasi-experimental studies. The support group intervention activities include psycho-educational program such as health education, problem-solving, and stress management. These studies support the effectiveness of support group in alleviating psychological distress and supporting quality of life of Asian BC women. Overall, there is limited research on the use and effectiveness of support groups with Asians cancer patients in Asia and in Western countries. Without accounting for Asian immigrants overseas, the Asian population is expected to grow from 4.3 to 5.3 billion by 2050. As cancer patients become more diverse due to global emigration, more rigorous studies examining the effectiveness of psychosocial intervention among transcultural cancer patients are needed. PMID- 27981155 TI - A Prospective Study of the Relationship between Psychological Factors and Breast Cancer. AB - OBJECTIVE: This cross-sectional prospective study aimed to explore the relationship between psychological factors and breast cancer incidence. METHODS: The subjects who scheduled to receive mammography screening were recruited from a medical center's outpatient department in Taiwan. Psychological factors used for measurement were stress, anxiety, and depression. RESULTS: A total of 1160 questionnaires were completed, which underwent statistical analysis using independent t-test, Chi-square test, Pearson's correlation, and multiple logistic regression. There were statistically significant differences in the average scores of the two groups with and without breast cancer for psychological factors of anxiety (t = -2.071; P = 0.039), depression (t = -3.035; P = 0.002), and stress (t = -4.087; P < 0.001). The crude odds ratio of the two groups showed that subjects with borderline anxiety were 2.576 times (P = 0.001) more likely to have breast cancer as compared to subjects with no anxiety. Subjects with depression were 4.078 times (P = 0.03) more likely to have breast cancer as compared to subjects with no depression. Every point added to the average total stress score increased the additional risk of breast cancer by 1.124 times (P < 0.001). CONCLUSIONS: After making adjustments on educational factors, the results conclude that psychological factors such as stress, anxiety, and depression can be considered predictors of breast cancer risk. To prevent and control breast cancer in women, the findings suggest that nurses should consider adding emphasis on psychological factors in women's health education. PMID- 27981156 TI - Psychological Stress and Coping in Recently Discharged Postsurgical Cancer Patients. AB - OBJECTIVE: Cancer patients and survivors need to cope with various stressful situations and problems even after treatment. In this study, we sought to investigate psychological stress and coping in recently discharged postsurgical cancer patients. METHODS: A mail-in questionnaire survey about stress response, perceived illness-related demands, and coping strategies and styles was administered to postsurgical Japanese cancer patients. The questionnaires were returned a week after the patients' discharge from the hospital. Descriptive and nonparametric statistical analyses were used. RESULTS: Forty-two patients completed the questionnaire; their average age was 58.1 years, and 61.9% were female. The stress response scale-18 (SRS-18) score was lower than that reported among the general population. The proportion of patients who were concentrating coping on social support or positive reappraisal was high. The scores for problem and emotion-focused coping were nearly identical. SRS-18 scores were weakly correlated with those for emotion-focused coping (r = 0.38, P = 0.014). The demographic data were not significantly associated with any of the stress or coping variables. However, SRS-18 scores for patients who had adjuvant therapy and physical, functional disorders were significantly higher than those for patients who did not (P = 0.004 and P = 0.008, respectively). CONCLUSIONS: Most of the patients had a low-stress response and used appropriate coping strategies. However, the findings suggest that attention must be paid to stress-coping in patients who have a physical, functional disorder as well as in those receiving adjuvant therapy. PMID- 27981157 TI - Relationships between Death Anxiety and Quality of Life in Iranian Patients with Cancer. AB - OBJECTIVE: The purpose of the study was to examine relationships between death anxiety and quality of life (QOL) parameters of patients with cancer in the Iranian sociocultural context. METHODS: A descriptive, correlational methodology was used. The sample included 330 patients. Demographics, health information, religious behaviors, death anxiety, and QOL data were collected. RESULTS: Overall death anxiety levels were moderate with satisfactory overall QOL. Death anxiety was predictive of lowered QOL. Female patients had lower QOL and higher death anxiety compared to men. CONCLUSIONS: Findings support that higher death anxiety negatively impacts QOL in an Iranian sample with cancer. Alleviation of existential concerns in vulnerable patients may palliate mental health distress associated with facing cancer and its challenging treatments. PMID- 27981158 TI - In Asian Americans, is Having a Family Member Diagnosed with Cancer Associated with Fatalistic Beliefs? AB - OBJECTIVE: Cancer can evoke long-held cultural beliefs which either facilitate or impede efforts to expand the health literacy of families. Among these beliefs is fatalism which holds that controlling ones' outcome is not possible, and that ones' outcome is predestined. Some fatalistic beliefs are broadly held within the Asian American (AA) community and may be challenged or reinforced by the experience of having a family member diagnosed with cancer. This study evaluated the relationship between having a family member diagnosed with cancer and selected demographics in AAs on fatalistic beliefs. METHODS: Data from 519 AA subjects from the Centers for Disease Control and Prevention Health Information Trends Survey were used to complete a secondary analysis. Descriptive statistics characterize fatalistic beliefs. Four models using four questions assessed fatalistic beliefs as dependent variables and independent variables of having or not having a family member diagnosed with cancer, completing college or not, sex, and age were assessed using ordinal regression. RESULTS: All of the fatalistic beliefs examined were endorsed by large portions of the subjects. When considering the role of being exposed to having a family member with cancer, it was associated with an increase in the likelihood in a belief that one is likely to get cancer, and everything can cause cancer. Being exposed to a family member diagnosed with cancer was not significantly associated with believing, there was little one could do to control their cancer risk. This belief was broadly rejected. While the belief that there are so many different recommendations about preventing cancer, it is hard to know what to do, was broadly endorsed and not associated with having a family member diagnosed with cancer. CONCLUSIONS: The major practice implications within oncology nursing suggest the importance in assessing cancer health literacy and providing corrective knowledge in families with a member diagnosed with cancer. While recognizing the need for more knowledge, cancer diagnoses may represent a significant teachable moment for family members enhancing their health knowledge and supporting behavioral change. Two beliefs were contradictory and broadly held with the AA community, thus support will be needed for further public health research. PMID- 27981159 TI - Emotional Aspects and Pranayama in Breast Cancer Patients Undergoing Radiation Therapy: A Randomized Controlled Trial. AB - OBJECTIVE: Emotional disturbances are commonly experienced by cancer patients. The aim of this study was to determine the effectiveness of certain Pranayama techniques on the emotional aspects such as impatience, worry, anxiety, and frustration among breast cancer patients undergoing radiation therapy in India. METHODS: The study was conducted as a randomized controlled trial. Patients were recruited when they were seeking radiation therapy for breast cancer. They were allocated into two groups using block randomization technique. The experimental group performed Pranayama along with radiation therapy, whereas the control group received only routine care. RESULTS: Emotional aspects of the two groups were compared at the end of the treatment. Mann-Whitney U-test was used for comparison as the data were not following normality. It showed a significant difference between the two groups with the group who performed Pranayama showing a lesser mean score for these negative emotions. CONCLUSIONS: Pranayama might help in controlling the negative emotions likely to be faced by breast cancer patients, and it can be used as a supportive therapy for breast cancer patients receiving radiation therapy. PMID- 27981161 TI - Happy Birthday: We are Two Years Old. PMID- 27981160 TI - A Brief Encounter with the Middle East: A Narrative of One Muslim Woman Diagnosed with Breast Cancer. AB - One of the major challenges the healthcare profession face is understanding the variability and different meanings of the concepts of age and aging within different cultural, social, religious, and ethical contexts. People over the age of 65 in the Middle Eastern countries are estimated to comprise 4.7% of the population and are expected to grow rapidly. In the Middle East, cancer is the leading cause of death among women aged 40-79 and one of the leading causes of death for women over 70 years of age. Many women in the Middle East live within a system of religious values and moral perceptions based on an intergenerational family structure and clear family roles. We present a singular case study describing the importance of the ability to successfully understand cross cultural issues in a clinical setting. Attention should be given to barriers and facilitators related to health and cancer education. It is recognized that personal, psychological, religious, environmental, social, and economic factors influence participation in any health programs. Cultural and religious factors, in particular, have been shown to play a vital role in women's attitudes to breast cancer screening. It has to be noted that the case presented is meant to present and demonstrates cross-cultural issues rather than to represent Muslims in the Middle East. PMID- 27981162 TI - How do Nurses "Think Family" and Support Parents Diagnosed with Cancer Who Have Dependent Children? AB - Many barriers exist regarding access to support and information for parents with cancer who are parenting dependent children and young people. There is little known about how nurses in acute settings support parents with dependent children. Many complexity factors exist which can increase the risk of behavioral problems in children when a parent has a cancer diagnosis. A recent study presented in this editorial identifies how there is a lack of confidence and skill experienced by specialist nurses in acute oncology settings regarding the needs and well being of children where there is a cancer diagnosis in the family. Recommendations are identified for developing practice in this area and on increasing awareness of the needs of children and young people. PMID- 27981163 TI - Cancer Cachexia and its Impact on Patient Dignity: What Nurses Need to Know. AB - Noted physician, Sr. William Osler, is credited with saying, "Care more particularly for the individual patient than for the special features of the disease". Osler understood that each patient for whom we care is first and foremost a person, who also happens to be living with a particular illness. In addition to understanding the nature of the patient's illness, therefore, it is also critically important that we come to understand the patient's unique story and set of circumstances. Doing so allows us to engage with patients in a way that affirms their sense of dignity and personhood. Drawing on the exemplar of cancer cachexia, this editorial reminds clinicians of the importance of Osler's sage advice to attend to patient dignity and personhood, and provides nurses with direction about how they can do that in practice. PMID- 27981164 TI - Inclusion of Palliative Care in Indian Undergraduate Physiotherapy Curriculum course Guidelines and Content. AB - According to the guidelines published by the WHO in 2010, palliative care has been defined as "an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial, and spiritual." Intervention provided as a part of the palliative care has to be by health professionals who strictly work as a part of the multidisciplinary team and have been specifically trained to an optimal level of competency in the field. Two key problem areas in palliative care which a physiotherapist deals with are poor physical function and pain. This article deals with the following issues: (1) What is palliative care education and its importance? (2) Current scenario of palliative care in medical and allied fields internationally. (3) Current scenario of palliative care education in medical and allied fields in India. (4) Proposed curriculum guidelines for palliative care in physiotherapy. PMID- 27981166 TI - Exploring Oncology Nurses' Grief: A Self-study. AB - Oncology nursing, like many other nursing fields, often provides nurses with the opportunity to get to know their patients and their families well. This familiarity allows oncology nurses to show a level of compassion and empathy that is often helpful to the patient and their family during their struggle with cancer. However, this familiarity can also lead to a profound sense of grief if the patient loses that struggle. This self-study provided me the opportunity to systematically explore my own experience with grief as an oncology nurse, helping me to identify specific stressors and also sources of stress release. PMID- 27981165 TI - Effectiveness of Physical, Psychological, Social, and Spiritual Intervention in Breast Cancer Survivors: An Integrative Review. AB - Factors affecting the health outcomes of cancer patients have gained extensive research attention considering the increasing number and prolonged longevity of cancer survivors. Breast cancer survivors experience physical, psychological, social, and spiritual challenges. This systematic literature review aims to present and discuss an overview of main issues concerning breast cancer survivors after treatment. Treatment-related symptoms as well as psychosocial and spiritual aspects of breast cancer survivors are evaluated. Moreover, the benefits of intervention for emotional, physical, social, and spiritual needs of the patient during the survivorship are investigated. This review also proposes avenues for future studies in this field and develops a new, integrated, and complete interpretation of findings on the holistic well-being of women with breast cancer. Thus, this study provides clinicians with a more comprehensive source of information compared with individual studies on symptom experiences. PMID- 27981167 TI - Nurses' Knowledge and Attitudes toward Complementary Therapies for Cancer: A Review of the Literature. AB - Complementary therapies (CTs) are nonconventional supportive therapies, which are used by the patients with cancer. The use of CTs has been known to alleviate symptoms as a result of chemotherapy and to improve quality of life. However, if CTs are inappropriately used, there may be adverse reactions or no effect resulting in poor support of the cancer treatment. Nurses play an important role in supporting patients with cancer who often seek information regarding CTs. Within their scope of practice, it is expected that nurses have sufficient knowledge about the safety and effective use of CTs, and positive attitudes toward supporting patients who wish to use CTs. This review aims to examine existing literature regarding nurses' knowledge and attitudes toward CTs for patients with cancer. English language articles obtained from recognized nursing and midwifery databases such as CINAHL, Google Scholar, Medline, ProQuest Central, and Scopus for the period between 2002 and 2015 were searched. A total of 96 articles were retrieved using the search terms with only 13 eligible articles meeting the inclusion criteria. Three major themes were identified by the thematic analysis of reviewed studies: nurses' knowledge about CTs, nurses' attitudes toward CTs, and sources information about CTs. The majority of studies investigating nurses' knowledge and attitudes toward the use of CTs for oncology was conducted in developed countries. Overall, it was identified that nurses need to improve their knowledge and skills about CTs so that they were more confident to assist patients in integrating conventional treatment and CTs for cancer management. PMID- 27981168 TI - The Experiences and Perceptions of Women Diagnosed with Breast Cancer during Pregnancy. AB - OBJECTIVE: Although much has been documented about the experience of breast cancer, the accounts of young women have been relatively neglected, despite that around 20% of the breast cancer diagnoses occur in women under the age of 50. In particular, the voices of young women diagnosed during pregnancy are missing from research. Breast cancer is the most common cancer associated with pregnancy, and it is diagnosed in about 1 in 3000 pregnancies. METHODS: This study presents data from three women drawn from a larger study of women who had been diagnosed under the age of 45 and had completed their treatment for breast cancer. Semi structured qualitative interviews were undertaken, with a methodology informed by social constructionist grounded theory and feminism. RESULTS: The findings here report the ways that having breast cancer during pregnancy disrupted taken-for granted assumptions about their pregnancies, new motherhood, and their future life course, and how this occurred within the context of gendered ideas about femininity and motherhood. CONCLUSIONS: Breast cancer during pregnancy has a far reaching impact on young women's lives, and women affected may need practical support in caring for young children, and counselling may be appropriate. Further research is needed in this important area. PMID- 27981169 TI - Challenges in Cancer Self-management of Patients with Limited English Proficiency. AB - OBJECTIVE: This paper summarizes the barriers and challenges in cancer care reported from a validation project of a self-management intervention handbook from Chinese-American cancer patients with limited English proficiency (LEP). METHODS: Seven health-care providers (HCPs) and 16 Chinese-American cancer survivors with LEP were invited to validate a self-management intervention handbook through networking sampling method. Bilingual versions were developed and validated using the repeated translation process. Online and paper-based survey and interview were conducted to collect information on the perception of barriers and experiences on cancer care. Data were analyzed by the content analysis method. RESULTS: The HCPs reported a bilingual self-management handbook which is useful and feasible for patient self-management. The challenges in giving cancer care to LEP patients included: patients do not engage in discussion, different cultural health beliefs, unable to speak to patients in their primary language, and patients are less likely to discuss emotional and social challenges during treatments. The common barriers and experiences during cancer care included: limited understanding about treatment/medication and side effects, language barriers such as unable to communicate to make the decision, unable to understand information related to resources and do not know what questions to ask, and do not know what to expect during their cancer treatment. CONCLUSIONS: The current findings highlight the need of cancer self-management support for culturally diverse LEP cancer patients. Further research can include applying the supportive intervention to all LEP cancer patients. PMID- 27981170 TI - Evaluating Sexual Nursing Care Intervention for Reducing Sexual Dysfunction in Indonesian Cervical Cancer Survivors. AB - OBJECTIVE: This study aims to describe the factors affecting successful nursing care intervention on sexuality. METHODS: A one-group pre- and post-test design was used. Fifty-three cervical cancer survivors and their spouses were administered with nursing care intervention on sexuality in three sessions and evaluated after 6 weeks. RESULTS: Sexual intervention reduced dyspareunia symptoms, improved vaginal lubrication, improved sexual satisfaction, and enhanced sexual arousal, sexual desire, and orgasm among cancer survivors and their spouses. The other influencing factors also simultaneously contributed to the success of nursing care intervention. CONCLUSIONS: Nursing care intervention on sexuality could be a part of supportive nursing care and an important aspect in standard nursing care for cancer patients in Indonesia. PMID- 27981171 TI - The Effect of Complementary Therapy for Hospital Nurses with High Stress. AB - OBJECTIVE: This study was to examine the effect of complementary therapy (CT) for nurses with high stress levels. It was taken before we employ this technique for cancer survivors because cancer patients are a heterogeneous group that requires substantial resources to investigate. METHODS: A quasi-experimental design with five groups was employed for this study. The groups were examined whether there were effects for reducing the stress and the differences in effectiveness among four intervention groups and a nonintervention group. Stress relief was measured using pulse rate and blood pressure measurements and the short form of the profile of mood states (POMS-SF). The participants practiced the therapy for 20 min twice per week for 3 weeks. A two-way factorial analysis of variance was used to analyze the data. RESULTS: The study enrolled 98 nurses (92 female and 6 male) with a mean age of 37.3 +/- 10.5 years (range: 22-60 years). Fifty-nine nurses had 10 or more years of nursing experience. There were significant differences in pulse rate and the POMS-SF scores. All groups were effective for reducing the stress level of high-stress nurses, whereas four intervention CT groups were not more effective than nonintervention group. CONCLUSIONS: The complementary therapies were useful for nurses with high stress levels. Thus, they can be used as a self-management tool for such nurses. Afterward, we will use the CT for cancer survivors to determine whether it can improve the quality of life of cancer patients. PMID- 27981172 TI - Jordanian Physicians' Attitudes toward Disclosure of Cancer Information and Patient Participation in Treatment Decision-making. AB - OBJECTIVE: This study aims to determine the attitude of Jordanian physicians toward disclosure of cancer information, comfort and use of different decision making approaches, and treatment decision making. METHODS: A descriptive, comparative research design was used. A convenience sample of 86 Jordanian medical and radiation oncologists and surgeons practicing mainly in oncology was recruited. A modified version of a structured questionnaire was used for data collection. The questionnaire is a valid measure of physicians' views of shared decision making. RESULTS: Almost 91% of all physicians indicated that the doctor should tell the patient and let him/her decide if the family should know of an early-stage cancer diagnosis. Physicians provide abundant information about the extent of the disease, the side effects and benefits of the treatment, and details of the treatment procedures. They also provided less information on the effects of treatment on the sexuality, mood, and family of the patient. Almost 48% of the participating physicians reported using shared decision making as their usual approach for treatment decision making, and 67% reported that they were comfortable with this approach. The main setting of clinical activity was the only factor associated with physicians' usual approach to medical decision making. Moreover, age, years of experience, and main setting of clinical activity were associated with physicians' comfort level with the shared approach. CONCLUSIONS: Although Jordanian physicians appreciate patient autonomy, self determination, and right to information, paternalistic decision making and underuse of the shared decision-making approach persist. Strategies that target both healthcare providers and patients must be employed to promote shared decision making in the Jordanian healthcare system. PMID- 27981173 TI - Problems of Breast Cancer Survivors Living in an Urban Area of Nepal. AB - OBJECTIVE: The main objective of this study was to identify the problems of Nepalese breast cancer survivors living in an urban area who had completed their treatment for at least 6 months. METHODS: A cross-sectional descriptive study was conducted to assess the problems of breast cancer survivors who were registered at the Nepal Cancer Support Group. Fifty-one women who were diagnosed with breast cancer (Stage 0 to III) and were currently disease-free were enrolled in the study. They were interviewed using structured interview schedule using the Breast Cancer Prevention Trial Symptom Scale. Statistical analysis was carried out with SPSS (version 16). RESULTS: The mean age of the women at the time of enrollment was 47.3 years. The most common modality of treatment they received was the combination of surgery, chemotherapy, and radiotherapy (84%). Top five symptoms experienced by the survivors on the basis of frequency and severity were tiredness (61%), lack of energy (57%), forgetfulness (57%), lack of interest in sex (52%), general body aches (49%), and feeling of worrisome and anxiousness about future (49%). Women with age <45 years at diagnosis had higher mean rank score in psychological (24.7) and social problems (23.9) in comparison to women aged >=45 years. There was a significant relationship between severe psychological (34.9 vs. 19.6; P = 0.001) and social problems (29.1 vs. 21.2; P = 0.03), with the time since primary treatment completion of <1 year. CONCLUSIONS: Nepalese breast cancer survivors were found to have multiple physical, psychological, and social problems and might require special attention during follow-up visits. PMID- 27981175 TI - AONS Executives and Committee Members 2016-2017. PMID- 27981174 TI - Healthy Eating Index/Alternative Healthy Eating Index and Breast Cancer Mortality and Survival: A Systematic Review and Meta-analysis. AB - OBJECTIVE: Breast cancer is the most common cancer in women worldwide. The effects of overall diet quality instead of single nutrients after breast cancer diagnosis on mortality have been a growing area of research interest. The aim of this systematic review was to investigate the relationship between the Healthy Eating Index (HEI)/the Alternative Healthy Eating Index (AHEI) and risk of breast cancer mortality or survival rates as a primary outcome, and some related inflammatory factors, as secondary outcomes among postdiagnosed women. METHODS: This study methodology was performed based on the Preferred Reporting Item for Systematic Review and Meta-analysis statement recommendation and had been registered at PROSPERO (registration number: CRD42015015605). The systematic search was conducted in the electronic databases including PubMed, ISI, Scopus, Cochrane, and Google before July 2016. Researches that had not reported risk of breast cancer mortality or survival rates separately were excluded from the study. Similarly, this review excluded studies which only had examined the HEI or AHEI without reporting their association with the risk of mortality or survival rates. RESULTS: After primary search, of 643 studies identified, 4 studies including eligible criteria were selected for the final assessment. All selected studies had been conducted in the USA and used self-report food-frequency questionnaire for diet quality assessment. In two studies HEI-2005, in one study AHEI, and in another study AHEI-2010 were applied. Meta-analysis result showed no significant association between these indexes and risk of breast cancer mortality/survival among women with this malignancy [relative risk: (RR) 1.04; 95% confidence interval (CI): 0.69-1.56; P = 0.87]. CONCLUSIONS: Regarding the adherence HEI/AHEI, we found no association between mentioned indexes and risk of mortality or survival from breast cancer in women with breast cancer. However, evidence in this field is limited and inconsistence and further studies are needed. PMID- 27981176 TI - Effects of aging on stress-related responses of serotonergic neurons in the dorsal raphe nucleus of male rats. AB - Responses to various stressors in the brain change with age. However, little is known about the neural mechanisms underlying age-dependent changes in stress responses. It is known that serotonin, a stress-related transmitter, is closely related with the regulation of stress responses in the brain and that serotonergic function is modulated by various factors, including estrogen, in both sexes. In the present study, to elucidate the effects of aging on stress responses in serotonergic neurons, we examined the expression levels of tryptophan hydroxylase (TPH; a marker of serotonergic neurons) in the dorsal, ventral and lateral parts of the dorsal raphe nucleus (DRN) in young and old intact male rats. In young males, repeated restraint stress significantly increased the number of TPH-positive cells in all subdivisions of the DRN. In contrast, the stress-induced increase in TPH expression was only observed in the ventral part of the DRN in old males. Pretreatment with an estrogen receptor beta antagonist had no effect on the number of TPH-positive cells in the dorsal and lateral DRN in young stressed males, whereas the antagonist decreased the number of TPH-positive cells in all DRN subdivisions in old stressed males. Our results suggest that the effects of repeated stress exposure on the expression of TPH in serotonergic neurons in the DRN change with age and that estrogenic effects via estrogen receptor beta on TPH expression in stressed old males differ from those in young males. PMID- 27981177 TI - Relations between plasma oxytocin and cortisol: The stress buffering role of social support. AB - Stress responses in humans can be attenuated by exogenous oxytocin administration, and these stress-buffering properties may be moderated by social factors. Yet, the influence of acute stressors on circulating endogenous oxytocin levels have been inconsistent, and limited information is available concerning the influence of social support in moderating this relationship. In the current investigation, undergraduate women (N = 67) were assessed in the Trier Social Stress Test (TSST) with either social support available from a close female friend or no social support being available. An additional set of women served as controls. The TSST elicited marked elevations of state anxiety and negative emotions, which were largely attenuated among women who received social support. Furthermore, baseline oxytocin levels were inversely related to women's general feelings of distrust, as well as basal plasma cortisol levels. Despite these associations, oxytocin levels were unaffected by the TSST, and this was the case irrespective of oral contraceptive use or estrogen levels. In contrast, plasma cortisol elevations were elicited by the psychosocial stressor, but only in women using oral contraceptives, an effect that was prevented when social support was available. Taken together, these data provisionally suggest that changes in plasma oxytocin might not accompany the stress attenuating effects of social support on cortisol levels. Moreover, as plasma oxytocin might not reliably reflect brain oxytocin levels, the linkage between oxytocin and prosocial behaviors remains tenuous. PMID- 27981178 TI - Biological and psychological predictors of posttraumatic stress disorder onset and chronicity. A one-year prospective study. AB - BACKGROUND: Few studies have prospectively examined risk factors for posttraumatic stress disorder (PTSD) in the aftermath of a traumatic exposure. The aim of this study is to identify the concurrent influence of psychological and biological diatheses on PTSD onset and maintenance, taking into account socio demographic factors and psychiatric antecedents. METHODS: A total of 123 civilians (61.8% of women) recruited in emergency units, were assessed using validated instruments during the first week and then at 1, 4, and 12 months post trauma. Baseline assessment included evaluation of the psychological diathesis (i.e. psychiatric history and peritraumatic distress and dissociation), and the biological diathesis [i.e. cortisol, norepinephrine, epinephrine, c-reactive protein, total cholesterol, HDL cholesterol, glycosylated haemoglobin, waist-to hip ratio (WHR), body mass index, diastolic and systolic blood pressure (SBP), and heart rate]. RESULTS: Multivariate logistic regression analyses demonstrated both psychological and biological diatheses to be independent risk factors for PTSD. Peritraumatic distress and dissociation predicted onset (1-month) and mid term PTSD (4-months), respectively. PTSD risk was associated positively with SBP and negatively with WHR, throughout the follow-up. In addition, a higher level of 12 h-overnight urinary norepinephrine independently predicted mid-term PTSD (4 months). CONCLUSIONS: This prospective study shows that peritraumatic psychological and biological markers are independent predictors of PTSD onset with specificities according to the stage of PTSD development; the psychological diathesis, i.e. peritraumatic distress and dissociation, being a better predictor of short-term dysfunction whereas biological diathesis was also predictive of development and maintenance of PTSD. PMID- 27981179 TI - Striatal dopamine D2/3 receptor regulation by stress inoculation in squirrel monkeys. AB - Intermittent mildly stressful situations provide opportunities to learn, practice, and improve coping in a process called stress inoculation. Stress inoculation also enhances cognitive control and response inhibition of impulsive motivated behavior. Cognitive control and motivation have been linked to striatal dopamine D2 and/or D3 receptors (DRD2/3) in rodents, monkeys, and humans. Here, we study squirrel monkeys randomized early in life to stress inoculation with or without maternal companionship and a no-stress control treatment condition. Striatal DRD2/3 availability in adulthood was measured in vivo by [11C]raclopride binding using positron emission tomography (PET). DRD2/3 availability was greater in caudate and putamen compared to ventral striatum as reported in PET studies of humans and other non-human primates. DRD2/3 availability in ventral striatum was also consistently greater in stress inoculated squirrel monkeys compared to no stress controls. Squirrel monkeys exposed to stress inoculation in the presence of their mother did not differ from squirrel monkeys exposed to stress inoculation without maternal companionship. Similar effects in different social contexts extend the generality of our findings and together suggest that stress inoculation increases striatal DRD2/3 availability as a correlate of cognitive control in squirrel monkeys. PMID- 27981180 TI - Enhancement of striatum-dependent memory by conditioned fear is mediated by beta adrenergic receptors in the basolateral amygdala. AB - Emotional arousal can have a profound impact on various learning and memory processes. For example, unconditioned emotional stimuli (e.g., predator odor or anxiogenic drugs) enhance dorsolateral striatum (DLS)-dependent habit memory. These effects critically depend on a modulatory role of the basolateral complex of the amygdala (BLA). Recent work indicates that, like unconditioned emotional stimuli, exposure to an aversive conditioned stimulus (CS) (i.e., a tone previously paired with shock) can also enhance consolidation of DLS-dependent habit memory. The present experiments examined whether noradrenergic activity, particularly within the BLA, is required for a fear CS to enhance habit memory consolidation. First, rats underwent a fear conditioning procedure in which a tone CS was paired with an aversive unconditioned stimulus. Over the course of the next five days, rats received training in a DLS-dependent water plus-maze task, in which rats were reinforced to make a consistent body-turn response to reach a hidden escape platform. Immediately after training on days 1-3, rats received post-training systemic (Experiment 1) or intra-BLA (Experiment 2) administration of the beta-adrenoreceptor antagonist, propranolol. Immediately after drug administration, half of the rats were re-exposed to the tone CS in the conditioning context (without shock). Post-training CS exposure enhanced consolidation of habit memory in vehicle-treated rats, and this effect was blocked by peripheral (Experiment 1) or intra-BLA (Experiment 2) propranolol administration. The present findings reveal that noradrenergic activity within the BLA is critical for the enhancement of DLS-dependent habit memory as a result of exposure to conditioned emotional stimuli. PMID- 27981182 TI - Stress-induced increases in progesterone and cortisol in naturally cycling women. AB - Studies with animals of both sexes show that the adrenal glands release progesterone in addition to cortisol in response to stress. However, little is known about the progesterone response to stress in naturally cycling women. We investigated the effect of stress on estradiol, progesterone, and cortisol levels in women during the follicular phase of the menstrual cycle. We found that physical stress (the cold pressor test) had no effect on estradiol levels, but increased progesterone and cortisol. We also found positive correlations between baseline progesterone and cortisol levels, as well as between the change in progesterone and cortisol before and after water exposure in both the stress and control sessions. Mediation analyses revealed during the stress session, the change in progesterone from baseline to 42-min post-stress onset was mediated by the magnitude of change in cortisol levels across the same time span. Overall, these findings reveal that progesterone released in response to stress as observed in animals and men extends to women during the low ovarian output follicular phase of the menstrual cycle, and that the mechanism of release may be similar to the mechanism of cortisol release. PMID- 27981181 TI - Stress potentiates decision biases: A stress induced deliberation-to-intuition (SIDI) model. AB - Humans often make decisions in stressful situations, for example when the stakes are high and the potential consequences severe, or when the clock is ticking and the task demand is overwhelming. In response, a whole train of biological responses to stress has evolved to allow organisms to make a fight-or-flight response. When under stress, fast and effortless heuristics may dominate over slow and demanding deliberation in making decisions under uncertainty. Here, I review evidence from behavioral studies and neuroimaging research on decision making under stress and propose that stress elicits a switch from an analytic reasoning system to intuitive processes, and predict that this switch is associated with diminished activity in the prefrontal executive control regions and exaggerated activity in subcortical reactive emotion brain areas. Previous studies have shown that when stressed, individuals tend to make more habitual responses than goal-directed choices, be less likely to adjust their initial judgment, and rely more on gut feelings in social situations. It is possible that stress influences the arbitration between the emotion responses in subcortical regions and deliberative processes in the prefrontal cortex, so that final decisions are based on unexamined innate responses. Future research may further test this 'stress induced deliberation-to-intuition' (SIDI) model and examine its underlying neural mechanisms. PMID- 27981183 TI - Sex differences in sleep, anhedonia, and HPA axis activity in a rat model of chronic social defeat. AB - Repeated bouts of a major stressor such as social defeat are well known to induce a depression phenotype in male rats. Despite strong evidence and acknowledgement that women have a two-fold lifetime greater risk of developing major depression compared to men, the inclusion of female rats in studies employing social defeat are very rare; their absence is attributed to less aggressive interactions. This study sought to compare in male and female rats the impact of repeated social defeat, three times per week for four weeks, on the development of changes in sleep architecture and continuity, sucrose preference as a measure of anhedonia, changes in body weight, and basal plasma corticosterone levels. We found significant reductions in rapid eye movement sleep (REMS) during the light phase in both females and males, and significant increases in numbers of vigilance state transitions during the early dark phase in females but not in males. Additionally, females exhibited significantly greater reductions in sucrose intake than males. On the other hand, no sex differences in significantly elevated basal corticosterone levels were evident, and only the males exhibited changes in body weight. Taken together these findings suggest that the inclusion of female rats in studies of social defeat may offer greater insights in studies of stress and depression. PMID- 27981184 TI - Pioglitazone, a PPARgamma agonist rescues depression associated with obesity using chronic unpredictable mild stress model in experimental mice. AB - Pioglitazone, a peroxisome proliferator activated receptor gamma (PPARgamma) agonist belonging to thiazolidinedione class, is mainly used in diabetes mellitus. Obese subjects are twice likely to become depressed than non-obese individuals. The biological mechanisms linking depression with obesity still remain poorly understood and there is immense need for better therapeutic intervention against such co-morbid disorders. The present study investigates the effect of pioglitazone on the chronic unpredictable mild stress (CUMS) induced depression in obese mice by using behavioral tests and biochemical estimations. Mice were fed with high fat diet (HFD) for 14 weeks and were further subjected to different stress procedures for 28 days to induce depressive behavior. Animals were administered orally with pioglitazone (30 mg/kg p.o.)/escitalopram (10 mg/kg p.o.)/vehicle (10 ml/kg p.o.) daily from day 15-28. Various behavioral paradigms such as sucrose preference test, forced swim test (FST), tail suspension test (TST) and elevated plus maze (EPM) were performed. Biochemical estimations including plasma glucose, total cholesterol, triglycerides, and total proteins were performed. The data obtained from behavioral assays and biochemical assessments indicated that obese animals exhibited severe depressive-like behavior compared to non-obese animals. Furthermore, obese animals subjected to CUMS worsen the depressive behavior compared to obese control animals. Repetitive treatment with pioglitazone reversed the CUMS induced behavioral and biochemical alterations in HFD fed obese mice which atleast in part may be mediated through improving altered plasma glucose. The study suggests that pioglitazone needs further attention with respect to molecular mechanisms that could provide a better therapeutic strategy against depression associated with obesity. PMID- 27981186 TI - Integrating Interleukin-6 into depression diagnosis and treatment. AB - There is growing evidence of a relationship between inflammation and psychiatric illness. In particular, the cytokine Interleukin-6 (IL-6) has been linked to stress-related disorders such as depression and anxiety. Here we discuss evidence from preclinical and clinical studies examining the role of IL-6 in mood disorders. We focus on the functional role of peripheral and central release of IL-6 on the development of stress susceptibility and depression-associated behavior. By examining the contribution of both peripheral and central IL-6 to manifestations of stress-related symptomatology, we hope to broaden the way the field thinks about diagnosing and treating mood disorders. PMID- 27981188 TI - Maternal immune activation epigenetically regulates hippocampal serotonin transporter levels. AB - Major depressive disorder (MDD) is one of the most debilitating psychiatric diseases, affecting a large percentage of the population worldwide. Currently, the underlying pathomechanisms remain incompletely understood, hampering the development of critically needed alternative therapeutic strategies, which further largely depends on the availability of suitable model systems. Here we used a mouse model of early life stress - a precipitating factor for the development of MDD - featuring infectious stress through maternal immune activation (MIA) by polyinosinic:polycytidilic acid (Poly(I:C)) to examine epigenetic modulations as potential molecular correlates of the alterations in brain structure, function and behavior. We found that in adult female MIA offspring anhedonic behavior was associated with modulations of the global histone acetylation profile in the hippocampus. Morevoer, specific changes at the promoter and in the expression of the serotonin transporter (SERT), critically involved in the etiology of MDD and pharmacological antidepressant treatment were detected. Furthermore, an accompanying reduction in hippocampal levels of histone deacetylase (HDAC) 1 was observed in MIA as compared to control offspring. Based on these results we propose a model in which the long-lasting impact of MIA on depression-like behavior and associated molecular and cellular aberrations in the offspring is brought about by the modulation of epigenetic processes and consequent enduring changes in gene expression. These data provide additional insights into the principles underlying the impact of early infectious stress on the development of MDD and may contribute to the development of new targets for antidepressant therapy. PMID- 27981185 TI - Neuroinflammation at the interface of depression and cardiovascular disease: Evidence from rodent models of social stress. AB - A large body of evidence has emerged linking stressful experiences, particularly from one's social environment, with psychiatric disorders. However, vast individual differences emerge in susceptibility to developing stress-related pathology which may be due to distinct differences in the inflammatory response to social stress. Furthermore, depression is an independent risk factor for cardiovascular disease, another inflammatory-related disease, and results in increased mortality in depressed patients. This review is focused on discussing evidence for stress exposure resulting in persistent or sensitized inflammation in one individual while this response is lacking in others. Particular focus will be directed towards reviewing the literature underlying the impact that neuroinflammation has on neurotransmitters and neuropeptides that could be involved in the pathogenesis of comorbid depression and cardiovascular disease. Finally, the theme throughout the review will be to explore the notion that stress-induced inflammation is a key player in the high rate of comorbidity between psychosocial disorders and cardiovascular disease. PMID- 27981190 TI - Stress-induced neuroinflammatory priming: A liability factor in the etiology of psychiatric disorders. AB - Stress and glucocorticoids (GCs) have universally been considered to be anti inflammatory, however in recent years, stress and GCs have been found to exert permissive effects (immunological priming) on neuroinflammatory processes. This phenomenon of priming is characterized by prior stress or GC exposure potentiating the neuroinflammatory response to a subsequent immune challenge. A considerable body of evidence is discussed here that supports this permissive effect of stress and GCs. In light of this evidence, a mechanism of neuroinflammatory priming is proposed involving a signal cascade in the brain involving danger-associated molecular patterns (HMGB-1) and inflammasomes (NLRP3), which results in an exaggerated or amplified neuroinflammatory response and subsequently, the amplification of the physiological and behavioral sequelae of this response (i.e. sickness). Finally, we explore the notion that stressor induced sensitization of the neuroimmune microenvironment may predispose individuals to psychiatric disorders, in which exaggerated innate immune/inflammatory responses in the brain are now thought to play a key role. PMID- 27981189 TI - Untangling the Gordian knot of HIV, stress, and cognitive impairment. AB - As individuals live longer with HIV, this "graying of the HIV epidemic" has introduced a new set of challenges including a growing number of age and inflammation-related diseases such as cardiovascular disease, type II diabetes, cancer, and dementia. The biological underpinnings of these complex and co-morbid diseases are not fully understood and become very difficult to disentangle in the context of HIV and aging. In the current review we examine the contributions and interactions of HIV, stress, and cognitive impairment and query the extent to which inflammation is the linchpin in these dynamic interactions. Given the inter relatedness of stress, inflammatory mechanisms, HIV, and cognitive impairment, future work will either need to address multiple dimensions simultaneously or embrace the philosophy that breaking the aberrant cycle at any one point will subsequently remedy the other related systems and processes. Such a single-point intervention may be effective in early disease states, but after perpetuation of an aberrant cycle, adaptations in an attempt to internally resolve the issue will likely lead to the need for multifaceted interventions. Acknowledging that HIV, inflammation, and stress may interact with one another and collectively impact cognitive ability is an important step in fully understanding an individual's complete clinical picture and moving towards personalized medicine. PMID- 27981191 TI - Emergence in extinction of enhanced and persistent responding to ambiguous aversive cues is associated with high MAOA activity in the prelimbic cortex. AB - There is a great deal of individual variability in the emotional outcomes of potentially traumatic events, and the underlying mechanisms are only beginning to be understood. In order to further our understanding of individual trajectories to trauma, its vulnerability and resilience, we adapted a model of fear expression to ambiguous vs perfect cues in adult male rats, and examined long term fear extinction, 2, 3, and 50 days from acquisition. After the final conditioned fear test, mitochondrial enzyme monoamine oxidase A (MAOA) function was examined. In order to identify associations between this function and behavioral expression, an a posteri median segregation approach was adopted, and animals were classified as high or low responding according to level of freezing to the ambiguous cue at remote testing, long after the initial extinction. Those individuals characterized by their higher response showed a freezing pattern that persisted from their previous extinction sessions, in spite of their acquisition levels being equivalent to the low-freezing group. Furthermore, unlike more adaptive individuals, freezing levels of high-freezing animals even increased at initial extinction, to almost double their acquisition session levels. Controlling for perfect cue response at remote extinction, greater ambiguous threat cue response was associated with enhanced prelimbic cortex MAOA functional activity. These findings underscore MAOA as a potential target for the development of interventions to mitigate the impact of traumatic experiences. PMID- 27981187 TI - The microbiome: A key regulator of stress and neuroinflammation. AB - There is a growing emphasis on the relationship between the complexity and diversity of the microorganisms that inhabit our gut (human gastrointestinal microbiota) and health/disease, including brain health and disorders of the central nervous system. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the brain, glands, gut, immune cells and gastrointestinal microbiota that communicate in a complex multidirectional manner to maintain homeostasis. Changes in this environment can lead to a broad spectrum of physiological and behavioural effects including hypothalamic-pituitary-adrenal (HPA) axis activation, and altered activity of neurotransmitter systems and immune function. While an appropriate, co-ordinated physiological response, such as an immune or stress response are necessary for survival, a dysfunctional response can be detrimental to the host contributing to the development of a number of CNS disorders. In this review, the involvement of the gastrointestinal microbiota in stress-mediated and immune-mediated modulation of neuroendocrine, immune and neurotransmitter systems and the consequential behaviour is considered. We also focus on the mechanisms by which commensal gut microbiota can regulate neuroinflammation and further aim to exploit our understanding of their role in stress-related disorders as a consequence of neuroinflammatory processes. PMID- 27981192 TI - Forced treadmill exercise can induce stress and increase neuronal damage in a mouse model of global cerebral ischemia. AB - Physical exercise is known to be a beneficial factor by increasing the cellular stress tolerance. In ischemic stroke, physical exercise is suggested to both limit the brain injury and facilitate behavioral recovery. In this study we investigated the effect of physical exercise on brain damage following global cerebral ischemia in mice. We aimed to study the effects of 4.5 weeks of forced treadmill running prior to ischemia on neuronal damage, neuroinflammation and its effect on general stress by measuring corticosterone in feces. We subjected C57bl/6 mice (n = 63) to either treadmill running or a sedentary program prior to induction of global ischemia. Anxious, depressive, and cognitive behaviors were analyzed. Stress levels were analyzed using a corticosterone ELISA. Inflammatory and neurological outcomes were analyzed using immunohistochemistry, multiplex electrochemoluminescence ELISA and Western blot. To our surprise, we found that forced treadmill running induced a stress response, with increased anxiety in the Open Field test and increased levels of corticosterone. In accordance, mice subjected to forced exercise prior to ischemia developed larger neuronal damage in the hippocampus and showed higher cytokine levels in the brain and blood compared to non-exercised mice. The extent of neuronal damage correlated with increased corticosterone levels. To compare forced treadmill with voluntary wheel running, we used a different set of mice that exercised freely on running wheels. These mice did not show any anxiety or increased corticosterone levels. Altogether, our results indicate that exercise pre-conditioning may not be beneficial if the animals are forced to run as it can induce a detrimental stress response. PMID- 27981193 TI - Acute stress does not affect risky monetary decision-making. AB - The ubiquitous and intense nature of stress responses necessitate that we understand how they affect decision-making. Despite a number of studies examining risky decision-making under stress, it is as yet unclear whether and in what way stress alters the underlying processes that shape our choices. This is in part because previous studies have not separated and quantified dissociable valuation and decision-making processes that can affect choices of risky options, including risk attitudes, loss aversion, and choice consistency, among others. Here, in a large, fully-crossed two-day within-subjects design, we examined how acute stress alters risky decision-making. On each day, 120 participants completed either the cold pressor test or a control manipulation with equal probability, followed by a risky decision-making task. Stress responses were assessed with salivary cortisol. We fit an econometric model to choices that dissociated risk attitudes, loss aversion, and choice consistency using hierarchical Bayesian techniques to both pool data and allow heterogeneity in decision-making. Acute stress was found to have no effect on risk attitudes, loss aversion, or choice consistency, though participants did become more loss averse and more consistent on the second day relative to the first. In the context of an inconsistent previous literature on risk and acute stress, our findings provide strong and specific evidence that acute stress does not affect risk attitudes, loss aversion, or consistency in risky monetary decision-making. PMID- 27981194 TI - Differences in frontal and limbic brain activation in a small sample of monozygotic twin pairs discordant for severe stressful life events. AB - Monozygotic twin pairs provide a valuable opportunity to control for genetic and shared environmental influences while studying the effects of nonshared environmental influences. The question we address with this design is whether monozygotic twins selected for discordance in exposure to severe stressful life events during development (before age 18) demonstrate differences in brain activation during performance of an emotional word-face Stroop task. In this study, functional magnetic resonance imaging was used to assess brain activation in eighteen young adult twins who were discordant in exposure to severe stress such that one twin had two or more severe events compared to their control co twin who had no severe events. Twins who experienced higher levels of stress during development, compared to their control co-twins with lower stress, exhibited significant clusters of greater activation in the ventrolateral and medial prefrontal cortex, basal ganglia, and limbic regions. The control co-twins showed only the more typical recruitment of frontoparietal regions thought to be important for executive control of attention and maintenance of task goals. Behavioral performance was not significantly different between twins within pairs, suggesting the twins with stress recruited additional neural resources associated with affective processing and updating working memory when performing at the same level. This study provides a powerful glimpse at the potential effects of stress during development while accounting for shared genetic and environmental influences. PMID- 27981197 TI - Likelihood ratio data to report the validation of a forensic fingerprint evaluation method. AB - Data to which the authors refer to throughout this article are likelihood ratios (LR) computed from the comparison of 5-12 minutiae fingermarks with fingerprints. These LRs data are used for the validation of a likelihood ratio (LR) method in forensic evidence evaluation. These data present a necessary asset for conducting validation experiments when validating LR methods used in forensic evidence evaluation and set up validation reports. These data can be also used as a baseline for comparing the fingermark evidence in the same minutiae configuration as presented in (D. Meuwly, D. Ramos, R. Haraksim,) [1], although the reader should keep in mind that different feature extraction algorithms and different AFIS systems used may produce different LRs values. Moreover, these data may serve as a reproducibility exercise, in order to train the generation of validation reports of forensic methods, according to [1]. Alongside the data, a justification and motivation for the use of methods is given. These methods calculate LRs from the fingerprint/mark data and are subject to a validation procedure. The choice of using real forensic fingerprint in the validation and simulated data in the development is described and justified. Validation criteria are set for the purpose of validation of the LR methods, which are used to calculate the LR values from the data and the validation report. For privacy and data protection reasons, the original fingerprint/mark images cannot be shared. But these images do not constitute the core data for the validation, contrarily to the LRs that are shared. PMID- 27981198 TI - Biphasic calcium phosphates (BCP) of hydroxyapatite (HA) and tricalcium phosphate (TCP) as bone substitutes: Importance of physicochemical characterizations in biomaterials studies. AB - The data presented in this article are related to the research article entitled "Biphasic calcium phosphates bioceramics (HA/TCP): Concept, physicochemical properties and the impact of standardization of study protocols in biomaterials research" [1]. This article provides in depth study of BCP bone substitutes as valuable option in the field of tissue engineering. However, there are discrepancies in the literature regarding the ideal physicochemical properties of BCP and the ideal balance between different phase compositions for enhanced bone tissue engineering (M. Ebrahimi, M.G. Botelho, S.V. Dorozhkin, 2016; M. Ebrahimi, P. Pripatnanont, S. Suttapreyasri, N. Monmaturapoj, 2014) [1,2]. This is found to be mainly because of improper characterization of BCP bioceramics in basic studies and lack of standard study protocols in in vitro and in vivo research. This data article along with original article provide the basic data required for ideal characterization of BCP and other bioceramics in an attempt to provide basic standardized protocols for future studies. PMID- 27981195 TI - Sex differences in subcellular distribution of delta opioid receptors in the rat hippocampus in response to acute and chronic stress. AB - Drug addiction requires associative learning processes that critically involve hippocampal circuits, including the opioid system. We recently found that acute and chronic stress, important regulators of addictive processes, affect hippocampal opioid levels and mu opioid receptor trafficking in a sexually dimorphic manner. Here, we examined whether acute and chronic stress similarly alters the levels and trafficking of hippocampal delta opioid receptors (DORs). Immediately after acute immobilization stress (AIS) or one-day after chronic immobilization stress (CIS), the brains of adult female and male rats were perfusion-fixed with aldehydes. The CA3b region and the dentate hilus of the dorsal hippocampus were quantitatively analyzed by light microscopy using DOR immunoperoxidase or dual label electron microscopy for DOR using silver intensified immunogold particles (SIG) and GABA using immunoperoxidase. At baseline, females compared to males had more DORs near the plasmalemma of pyramidal cell dendrites and about 3 times more DOR-labeled CA3 dendritic spines contacted by mossy fibers. In AIS females, near-plasmalemmal DOR-SIGs decreased in GABAergic hilar dendrites. However, in AIS males, near-plasmalemmal DOR-SIGs increased in CA3 pyramidal cell and hilar GABAergic dendrites and the percentage of CA3 dendritic spines contacted by mossy fibers increased to about half that seen in unstressed females. Conversely, after CIS, near-plasmalemmal DOR-SIGs increased in hilar GABA-labeled dendrites of females whereas in males plasmalemmal DOR-SIGs decreased in CA3 pyramidal cell dendrites and near plasmalemmal DOR-SIGs decreased hilar GABA-labeled dendrites. As CIS in females, but not males, redistributed DOR-SIGs near the plasmalemmal of hilar GABAergic dendrites, a subsequent experiment examined the acute affect of oxycodone on the redistribution of DOR-SIGs in a separate cohort of CIS females. Plasmalemmal DOR SIGs were significantly elevated on hilar interneuron dendrites one-hour after oxycodone (3 mg/kg, I.P.) administration compared to saline administration in CIS females. These data indicate that DORs redistribute within CA3 pyramidal cells and dentate hilar GABAergic interneurons in a sexually dimorphic manner that would promote activation and drug related learning in males after AIS and in females after CIS. PMID- 27981199 TI - Datasets for testing the performances of jump diffusion models. AB - This article contains datasets related to the research article titled a novel jump diffusion model based on SGT distribution and its applications ("A novel jump diffusion model based on SGT distribution and its applications" (W.J. Xu, G.F. Liu, H.Y. Li, 2016) [1]). The datasets contain continuous composite daily percentage return values which are computed from the daily closing prices. Firstly, we describe statistical properties of the datasets. Then, the datasets are split into two samples, the in-sample data and out-of-sample data. The datasets can be used as benchmarks for testing the performances of jump diffusion models. PMID- 27981196 TI - Social defeat stress induces depression-like behavior and alters spine morphology in the hippocampus of adolescent male C57BL/6 mice. AB - Social stress, including bullying during adolescence, is a risk factor for common psychopathologies such as depression. To investigate the neural mechanisms associated with juvenile social stress-induced mood-related endophenotypes, we examined the behavioral, morphological, and biochemical effects of the social defeat stress model of depression on hippocampal dendritic spines within the CA1 stratum radiatum. Adolescent (postnatal day 35) male C57BL/6 mice were subjected to defeat episodes for 10 consecutive days. Twenty-four h later, separate groups of mice were tested on the social interaction and tail suspension tests. Hippocampi were then dissected and Western blots were conducted to quantify protein levels for various markers important for synaptic plasticity including protein kinase M zeta (PKMzeta), protein kinase C zeta (PKCzeta), the dopamine-1 (D1) receptor, tyrosine hydroxylase (TH), and the dopamine transporter (DAT). Furthermore, we examined the presence of the alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA)-receptor subunit GluA2 as well as colocalization with the post-synaptic density 95 (PSD95) protein, within different spine subtypes (filopodia, stubby, long-thin, mushroom) using an immunohistochemistry and Golgi-Cox staining technique. The results revealed that social defeat induced a depression-like behavioral profile, as inferred from decreased social interaction levels, increased immobility on the tail suspension test, and decreases in body weight. Whole hippocampal immunoblots revealed decreases in GluA2, with a concomitant increase in DAT and TH levels in the stressed group. Spine morphology analyses further showed that defeated mice displayed a significant decrease in stubby spines, and an increase in long-thin spines within the CA1 stratum radiatum. Further evaluation of GluA2/PSD95 containing-spines demonstrated a decrease of these markers within long-thin and mushroom spine types. Together, these results indicate that juvenile social stress induces GluA2 and dopamine-associated dysregulation in the hippocampus - a neurobiological mechanism potentially underlying the development of mood-related syndromes as a consequence of adolescent bullying. PMID- 27981200 TI - Computational fluid dynamics benchmark dataset of airflow in tracheas. AB - Computational Fluid Dynamics (CFD) is fast becoming a useful tool to aid clinicians in pre-surgical planning through the ability to provide information that could otherwise be extremely difficult if not impossible to obtain. However, in order to provide clinically relevant metrics, the accuracy of the computational method must be sufficiently high. There are many alternative methods employed in the process of performing CFD simulations within the airways, including different segmentation and meshing strategies, as well as alternative approaches to solving the Navier-Stokes equations. However, as in vivo validation of the simulated flow patterns within the airways is not possible, little exists in the way of validation of the various simulation techniques. The data presented here consists of very highly resolved flow data. The degree of resolution is compared to the highest necessary resolutions of the Kolmogorov length and time scales. Therefore this data is ideally suited to act as a benchmark case to which cheaper computational methods may be compared. A dataset and solution setup for one such more efficient method, large eddy simulation (LES), is also presented. PMID- 27981201 TI - Data supporting regulating temporospatial dynamics of morphogen for structure formation of the lacrimal gland by chitosan biomaterials. AB - The lacrimal gland is responsible for tear synthesis and secretion, and is derived from the epithelia of ocular surface and generated by branching morphogenesis. The dataset presented in this article is to support the research results of the effect of chitosan biomaterials on facilitating the structure formation of the lacrimal gland by regulating temporospatial dynamics of morphogen. The embryonic lacrimal gland explants were used as the standard experimental model for investigating lacrimal gland branching morphogenesis. Chitosan biomaterials promoted lacrimal gland branching with a dose-dependent effect. It helped in vivo binding of hepatocyte growth factor (HGF) related molecules in the epithelial-mesenchymal boundary of emerging epithelial branches. When mitogen-activated protein kinase (MAPK) or protein kinase B (Akt/PKB) inhibitors applied, the chitosan effects reduced. Nonetheless, the ratios of MAPK and Akt/PKB phosphorylation were still greater in the chitosan group than the control. The data demonstrated here confirm the essential role of HGF-signaling in chitosan-promoted structure formation of the lacrimal gland. PMID- 27981202 TI - Data on the densification during sintering of binder jet printed samples made from water- and gas-atomized alloy 625 powders. AB - Binder jet printing (BJP) is a metal additive manufacturing method that manufactures parts with complex geometry by depositing powder layer-by-layer, selectively joining particles in each layer with a polymeric binder and finally curing the binder. After the printing process, the parts still in the powder bed must be sintered to achieve full densification (A. Mostafaei, Y. Behnamian, Y.L. Krimer, E.L. Stevens, J.L. Luo, M. Chmielus, 2016; A. Mostafaei, E. Stevens, E. Hughes, S. Biery, C. Hilla, M. Chmielus, 2016; A. Mostafaei, Y. Behnamian, Y.L. Krimer, E.L. Stevens, J.L. Luo, M. Chmielus, 2016) [1-3]. The collected data presents the characterization of the as-received gas- and water-atomized alloy 625 powders, BJP processing parameters and density of the sintered samples. The effect of sintering temperatures on the microstructure and the relative density of binder jet printed parts made from differently atomized nickel-based superalloy 625 powders are briefly compared in this paper. Detailed data can be found in the original published papers by authors in (A. Mostafaei, J. Toman, E.L. Stevens, E.T. Hughes, Y.L. Krimer, M. Chmielus, 2017) [4]. PMID- 27981203 TI - A corpus for mining drug-related knowledge from Twitter chatter: Language models and their utilities. AB - In this data article, we present to the data science, natural language processing and public heath communities an unlabeled corpus and a set of language models. We collected the data from Twitter using drug names as keywords, including their common misspelled forms. Using this data, which is rich in drug-related chatter, we developed language models to aid the development of data mining tools and methods in this domain. We generated several models that capture (i) distributed word representations and (ii) probabilities of n-gram sequences. The data set we are releasing consists of 267,215 Twitter posts made during the four-month period November, 2014 to February, 2015. The posts mention over 250 drug-related keywords. The language models encapsulate semantic and sequential properties of the texts. PMID- 27981204 TI - Visualization data on the freezing process of micrometer-scaled aqueous citric acid drops. AB - The visualization data (8 movies) presented in this article are related to the research article entitled "Freezing and glass transitions upon cooling and warming and ice/freeze-concentration-solution morphology of emulsified aqueous citric acid" (A. Bogdan, M.J. Molina, H. Tenhu, 2016) [1]. The movies recorded in situ with optical cryo-miscroscopy (OC-M) demonstrate for the first time freezing processes that occur during the cooling and subsequent warming of emulsified micrometer-scaled aqueous citric acid (CA) drops. The movies are made publicly available to enable critical or extended analyzes. PMID- 27981205 TI - Data files for ab initio calculations of the lattice parameter and elastic stiffness coefficients of bcc Fe with solutes. AB - We present computed datasets on changes in the lattice parameter and elastic stiffness coefficients of bcc Fe due to substitutional Al, B, Cu, Mn, and Si solutes, and octahedral interstitial C and N solutes. The data is calculated using the methodology based on density functional theory (DFT) presented in Ref. (M.R. Fellinger, L.G. Hector Jr., D.R. Trinkle, 2017) [1]. All the DFT calculations were performed using the Vienna Ab initio Simulations Package (VASP) (G. Kresse, J. Furthmuller, 1996) [2]. The data is stored in the NIST dSpace repository (http://hdl.handle.net/11256/671). PMID- 27981206 TI - Synthesis and spectral characterization of 2,2-diphenylethyl glucosinolate and HPLC-based reaction progress curve data for the enzymatic hydrolysis of glucosinolates by Sinapis alba myrosinase. AB - The data presented in this article are related to the research article, "HPLC based enzyme kinetics assay for glucosinolate hydrolysis facilitate analysis of systems with both multiple reaction products and thermal enzyme denaturation" (C.K. Klingaman, M.J. Wagner, J.R. Brown, J.B. Klecker, E.H. Pauley, C.J. Noldner, J.R. Mays,) [1]. This data article describes (1) the synthesis and spectral characterization data of a non-natural glucosinolate analogue, 2,2 diphenylethyl glucosinolate, (2) HPLC standardization data for glucosinolate, isothiocyanate, nitrile, and amine analytes, (3) reaction progress curve data for enzymatic hydrolysis reactions with variable substrate concentration, enzyme concentration, buffer pH, and temperature, and (4) normalized initial velocities of hydrolysis/formation for analytes. These data provide a comprehensive description of the enzyme-catalyzed hydrolysis of 2,2-diphenylethyl glucosinolate (5) and glucotropaeolin (6) under widely varied conditions. PMID- 27981207 TI - Dataset of total, oligomeric alpha-synuclein and hemoglobin levels in plasma in Parkinson's disease. AB - This data article presents a dataset of total, oligomeric alpha-synuclein and hemoglobin levels in plasma of drug-naive PD patients and controls. This is the first attempt to assess the effect of hemolysis rate on oligomeric alpha synuclein levels in peripheral plasma. The data are associated with the research article "Oligomeric alpha-synuclein and glucocerebrosidase activity levels in GBA associated Parkinson's disease" (Pchelina et al., 2016) [1]. PMID- 27981208 TI - Homogeneity of ball milled ceramic powders: Effect of jar shape and milling conditions. AB - This paper contains data and supporting information of and complementary to the research article entitled "Effect of jar shape on high-energy planetary ball milling efficiency: simulations and experiments" (Broseghini et al.,) [1]. Calcium fluoride (CaF2) was ground using two jars of different shape (cylindrical and half-moon) installed on a planetary ball-mill, exploring different operating conditions (jar-to-plate angular velocity ratio and milling time). Scanning Electron Microscopy (SEM) images and X-Ray Powder Diffraction data (XRPD) were collected to assess the effect of milling conditions on the end-product crystallite size. Due to the inhomogeneity of the end product, the Whole Powder Pattern Model (WPPM, (Scardi, 2008) [2]) analysis of XRPD data required the hypothesis of a bimodal distribution of sizes - respectively ground (fine fraction) and less-to-not ground (coarse fraction) - confirmed by SEM images and suggested by the previous literature (Abdellatief et al., 2013) [3,4]. Predominance of fine fraction clearly indicates optimal milling conditions. PMID- 27981210 TI - Hemorrhagic bullae of the oral mucosa. PMID- 27981209 TI - Crohn's Disease Fibroblasts Overproduce the Novel Protein KIAA1199 to Create Proinflammatory Hyaluronan Fragments. AB - BACKGROUND & AIMS: Crohn's Disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Fibrosis, a serious complication of CD, occurs when activated intestinal fibroblasts deposit excessive amounts of extracellular matrix (ECM) in affected areas. A major component of the ECM is high-molecular weight hyaluronan (HA) that, when depolymerized to low-molecular-weight fragments, becomes proinflammatory and profibrotic. Mechanisms for HA degradation are incompletely understood, but the novel protein KIAA1199 recently was discovered to degrade HA. We hypothesized that KIAA1199 protein is increased in CD colon fibroblasts and generates HA fragments that foster inflammation and fibrosis. METHODS: Fibroblasts were isolated from explants of surgically resected colon tissue from CD and non-inflammatory bowel disease control (ND) patients. Protein levels and tissue distribution of KIAA1199 were assessed by immunoblot and immunostaining, and functional HA degradation was measured biochemically. RESULTS: Increased levels of KIAA1199 protein were produced and deposited in the ECM by cultured CD fibroblasts compared with controls. Treatment of fibroblasts with the proinflammatory cytokine interleukin (IL) 6 increased deposition of KIAA1199 in the ECM. CD fibroblasts also produce significantly higher levels of IL6 compared with controls, and antibody blockade of IL6 receptors in CD colon fibroblasts decreased the level of KIAA1199 protein in the ECM. Colon fibroblasts degrade HA, however, small interfering RNA silencing of KIAA1199 abrogated that ability. CONCLUSIONS: CD fibroblasts produce increased levels of KIAA1199 primarily through an IL6-driven autocrine mechanism. This leads to excessive degradation of HA and the generation of proinflammatory HA fragments, which contributes to maintenance of gut inflammation and fibrosis. PMID- 27981211 TI - Concomitant pemphigus herpetiformis and sarcoidosis. PMID- 27981212 TI - Metastatic melanoma with spontaneous complete regression of a thick primary lesion. PMID- 27981213 TI - Development of bullous pemphigoid during nivolumab therapy. PMID- 27981214 TI - Recurrent cutaneous angiosarcoma of the ear masquerading as atypical fibroxanthoma. PMID- 27981215 TI - Linear IgA dermatosis after infliximab infusion for ulcerative colitis. PMID- 27981216 TI - Cutaneous atypical mycobacterial infection with Mycobacterium fortuitum arising after endovenous radiofrequency ablation. PMID- 27981217 TI - Multifocal eruptive cutaneous epithelioid angiomatous nodules. PMID- 27981218 TI - Sirolimus for treatment of kaposiform hemangioendothelioma associated with Kasabach-Merritt phenomenon. PMID- 27981220 TI - Clinical spectrum of phaeohyphomycosis in solid organ transplant recipients. PMID- 27981219 TI - Successful treatment of type II pityriasis rubra pilaris with secukinumab. PMID- 27981221 TI - Successful use of secukinumab in pustular psoriasis. PMID- 27981222 TI - Ecthyma associated with Moraxella and Staphylococcus epidermidis. PMID- 27981223 TI - Malignant intertrigo: A subset of toxic erythema of chemotherapy requiring recognition. PMID- 27981224 TI - Multiple palpebral syringomas occurring after initiation of BRAF inhibition therapy in a patient with metastatic melanoma. PMID- 27981226 TI - Lupus erythematosus tumidus: A case and discussion of a rare entity in black patients. PMID- 27981225 TI - Langerhans cell histiocytosis presenting as fingernail changes. PMID- 27981227 TI - Atypical fibroxanthoma of the scalp with recurrent and multiple regional cutaneous metastases. PMID- 27981228 TI - Primary cutaneous cryptococcal infection with subsequent erythema nodosum in a 10 year-old immunocompetent girl. PMID- 27981229 TI - Quantifying the "Slosh Stomach": A Novel Tool for Assessment of Exercise Associated Gastroparesis Symptoms in Endurance Athletes. AB - Introduction. We describe a novel scale and its field use for evaluation of exercise-associated gastroparesis in the endurance athlete. Methods. A scale was created based on gastroparesis tools previously described in the medical literature. Surveys of the tool were administered to runners participating in a 210 km multiday foot race in Sri Lanka. Results. Use of this novel scale was demonstrated to be useful in assessing gastroparesis severity scores of athletes and how these symptoms affected their race performance. Of the 27 race participants who completed the survey, 27 felt that the tool adequately captured their symptoms. Conclusions. This novel survey tool was able to assess the presence and severity of exercise-associated gastroparesis symptoms in endurance racers in a remote location. This tool may be helpful with further research of the identification and management of gastroparesis and other gastrointestinal upset in the endurance race environment. PMID- 27981230 TI - Identification of Barriers to Influenza Vaccination in Patients with Chronic Obstructive Pulmonary Disease: Analysis of the 2012 Behavioral Risk Factors Surveillance System. AB - INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for influenza-related morbidity and mortality. Influenza vaccination is known to decrease influenza incidence, severity, hospitalizations, and mortality. Identification of barriers to influenza vaccination among patients with COPD may aid in efforts to increase vaccination rates. This study aims to identify predictors of influenza vaccination in COPD patients. METHODS: This study used data from the 2012 Behavioral Risk Factor Surveillance System (BRFSS). Participants with self-reported COPD and receiving an influenza vaccination in the prior 12 months were identified. Independent predictors of the exposure were identified by estimating a parsimonious logistic regression model of influenza vaccination. All analyses were performed using weighted data. RESULTS: The final study sample consisted of 36,811 COPD participants, with 48.5% of COPD patients reporting having been vaccinated and 51.5% reporting being unvaccinated. A total of 15 independent predictors of influenza vaccination in COPD patients were identified. Negative predictors included predisposing factors (younger age, male gender, household children, black or non-white/non-Hispanic/non-black race/ethnicity, lower education level, heavy alcohol use, current tobacco use) and enabling factors that reflect access to medical care (insurance status, ability to afford care, having a recent check-up). Positive predictors of influenza vaccination included need factors (chronic comorbidities), being a military veteran, or being a former smoker. CONCLUSIONS: This analysis identifies multiple predictors of influenza vaccination in persons with COPD. Identification of at risk-groups provides the foundation for development of focused efforts to improve influenza vaccination rates in patients with COPD. PMID- 27981231 TI - Iron Catalysis in Organic Synthesis: A Critical Assessment of What It Takes To Make This Base Metal a Multitasking Champion. AB - The current status of homogeneous iron catalysis in organic chemistry is contemplated, as are the reasons why this particular research area only recently starts challenging the enduring dominance of the late and mostly noble metals over the field. Centered in the middle of the d-block and able to support formal oxidation states ranging from -II to +VI, iron catalysts hold the promise of being able to encompass organic synthesis at large. They are expected to serve reductive as well as oxidative regimes, can emulate "noble tasks", but are also able to adopt "early" transition metal character. Since a comprehensive coverage of this multidimensional agenda is beyond the scope of an Outlook anyway, emphasis is laid in this article on the analysis of the factors that perhaps allow one to control the multifarious chemical nature of this earth-abundant metal. The challenges are significant, not least at the analytical frontier; their mastery mandates a mindset that differs from the routines that most organic chemists interested in (noble metal) catalysis tend to cultivate. This aspect notwithstanding, it is safe to predict that homogeneous iron catalysis bears the chance to enable a responsible paradigm for chemical synthesis and a sustained catalyst economy, while potentially providing substantial economic advantages. This promise will spur the systematic and in-depth investigations that it takes to upgrade this research area to strategy-level status in organic chemistry and beyond. PMID- 27981233 TI - Temporal and Racial Differences Associated with Atopic Dermatitis Staphylococcusaureus and Encoded Virulence Factors. AB - Atopic dermatitis (AD) is an inflammatory skin condition strongly associated with Staphylococcus aureus colonization and infection. S. aureus strains shift in populations in ~10-year intervals depending on virulence factors. Shifts in S. aureus virulence factors may in part explain the racial differences observed in the levels of prevalence and severity of AD. AD S. aureus isolates collected from 2011 to 2014 (103 isolates) and in 2008 (100 isolates) were examined for the prevalence of genes encoding superantigens (SAgs). The strains from 2011 to 2014 were obtained from AD patients as a part of the National Institute of Allergy and Infectious Diseases (NIAID) Atopic Dermatitis Research Network (ADRN). The prevalence of SAg genes was investigated temporally and racially. The enterotoxin gene cluster (EGC) was more prevalent in the 2011-2014 AD isolates than in the 2008 AD isolates. The prevalences of virulence factor genes were similar in European American (EA) and Mexican American (MA) patients but differed in 6 of 22 SAg genes between EA and African American (AA) or MA and AA isolates; notably, AA isolates lacked tstH, the gene encoding toxic shock syndrome toxin 1 (TSST-1). The presence of tstH and sel-p (enterotoxin-like P) was associated with decreased clinical severity and increased blood eosinophils, respectively. The EGC is becoming more prevalent, consistent with the previously observed 10 years of cycling of S. aureus strains. Race-specific S. aureus selection may account for differences in virulence factor profiles. The lack of TSST-1-positive (TSST-1+) AD S. aureus in AA is consistent with the lack of AAs acquiring TSST-1-associated menstrual toxic shock syndrome (TSS). IMPORTANCE Monitoring pathogen emergence provides insight into how pathogens adapt in the human population. Secreted virulence factors, important contributors to infections, may differ in a manner dependent on the strain and host. Temporal changes of Staphylococcus aureus toxigenic potential, for example, in encoding toxic shock syndrome toxin 1 (TSST 1), contributed to an epidemic of TSS with significant health impact. This study monitored changes in atopic dermatitis (AD) S. aureus isolates and demonstrated both temporal and host infection differences according to host race based on secreted superantigen potential. The current temporal increase in enterotoxin gene cluster superantigen prevalence and lack of the gene encoding TSST-1 in AAs predict differences in infection types and presentations. PMID- 27981232 TI - Strain-Dependent Recognition of a Unique Degradation Motif by ClpXP in Streptococcus mutans. AB - Streptococcus mutans, a dental pathogen, has a remarkable ability to cope with environmental stresses. Under stress conditions, cytoplasmic proteases play a major role in controlling the stability of regulatory proteins and preventing accumulation of damaged and misfolded proteins. ClpXP, a well-conserved cytoplasmic proteolytic system, is crucial in maintaining cellular homeostasis in bacteria. ClpX is primarily responsible for recognition of substrates and subsequent translocation of unfolded substrates into the ClpP proteolytic compartment for degradation. In Escherichia coli, ClpX recognizes distinct motifs present at the C-terminal end of target proteins. However, recognition sequences for ClpXP in other bacteria, including S. mutans, are not known. In this study, using two-dimensional (2D) polyacrylamide gel electrophoresis (PAGE) analysis, we have identified several putative substrates for S. mutans ClpXP. SsbA, which encodes a small DNA binding protein, is one such substrate that is degraded by ClpXP. By sequential deletions, we found that the last 3 C-terminal amino acids, LPF, are sufficient for ClpXP-mediated degradation. Addition of LPF at the C terminal end of green fluorescent protein (GFP) rendered the protein completely degradable by ClpXP. Alterations of this tripeptide motif impeded ClpXP-mediated degradation. However, recognition of LPF by ClpXP is highly specific to some S. mutans strains (UA159, UA130, and N3209) since not all S. mutans strains recognize the motif. We speculate that an adaptor protein is involved in either substrate recognition or substrate degradation by ClpXP. Nevertheless, this is the first report of a unique recognition sequence for ClpXP in streptococci. IMPORTANCE Regulated proteolysis in bacteria is an important biological process that maintains protein homeostasis. ClpXP, an intracellular proteolytic complex, is the primary protease that is responsible for protein turnover. While the substrates for ClpXP were identified in Escherichia coli, the substrates for vast majority of bacteria are currently unknown. In this study, we identified a unique substrate for ClpXP-mediated degradation in Streptococcus mutans, a dental pathogen. We also found that a small motif composed of 3 amino acids is sufficient for ClpXP-mediated degradation. Identification of this motif will clearly help us to understand the pathogenesis of this organism and other related pathogens. PMID- 27981234 TI - Coordinate Regulation of Antimycin and Candicidin Biosynthesis. AB - Streptomyces species produce an incredible array of high-value specialty chemicals and medicinal therapeutics. A single species typically harbors ~30 biosynthetic pathways, but only a few them are expressed in the laboratory; thus, poor understanding of how natural-product biosynthesis is regulated is a major bottleneck in drug discovery. Antimycins are a large family of anticancer compounds widely produced by Streptomyces species, and their regulation is atypical compared to that of most other natural products. Here we demonstrate that antimycin production by Streptomyces albus S4 is regulated by FscRI, a PAS LuxR family cluster-situated regulator of the polyene antifungal agent candicidin. We report that heterologous production of antimycins by Streptomyces coelicolor is dependent on FscRI and show that FscRI activates the transcription of key biosynthetic genes. We also demonstrate through chromatin immunoprecipitation sequencing that FscRI regulation is direct, and we provide evidence that this regulation strategy is conserved and unique to short-form antimycin gene clusters. Our study provides direct in vivo evidence of the cross regulation of disparate biosynthetic gene clusters specifying unrelated natural products and expands the paradigmatic understanding of the regulation of secondary metabolism. IMPORTANCE Natural products produced by members of the phylum Actinobacteria underpin many industrially and medically important compounds; however, the majority of the ~30 biosynthetic pathways harbored by an average species are not expressed in the laboratory. Understanding the diversity of regulatory strategies controlling the expression of these pathways is therefore critical if their biosynthetic potential is to be explored for new drug leads. Our findings reveal that the candicidin cluster-situated regulator FscRI coordinately controls the biosynthesis of both candicidin and antimycin, which is the first observation of cross-regulation of disparate biosynthetic gene clusters specifying unrelated natural products. We anticipate that this will emerge as a major strategy by which members of the phylum Actinobacteria coordinately produce natural products, which will advance our understanding of how the expression of secondary metabolism is controlled and will aid the pursuit of "silent" biosynthetic pathway activation. PMID- 27981235 TI - mSphereDirect: Author-Initiated Peer Review of Manuscripts. PMID- 27981237 TI - Dipicolinic Acid Release by Germinating Clostridium difficile Spores Occurs through a Mechanosensing Mechanism. AB - Classically, dormant endospores are defined by their resistance properties, particularly their resistance to heat. Much of the heat resistance is due to the large amount of dipicolinic acid (DPA) stored within the spore core. During spore germination, DPA is released and allows for rehydration of the otherwise dehydrated core. In Bacillus subtilis, 7 proteins are encoded by the spoVA operon and are important for DPA release. These proteins receive a signal from the activated germinant receptor and release DPA. This DPA activates the cortex lytic enzyme CwlJ, and cortex degradation begins. In Clostridium difficile, spore germination is initiated in response to certain bile acids and amino acids. These bile acids interact with the CspC germinant receptor, which then transfers the signal to the CspB protease. Activated CspB cleaves the cortex lytic enzyme, pro SleC, to its active form. Subsequently, DPA is released from the core. C. difficile encodes orthologues of spoVAC, spoVAD, and spoVAE. Of these, the B. subtilis SpoVAC protein was shown to be capable of mechanosensing. Because cortex degradation precedes DPA release during C. difficile spore germination (opposite of what occurs in B. subtilis), we hypothesized that cortex degradation would relieve the osmotic constraints placed on the inner spore membrane and permit DPA release. Here, we assayed germination in the presence of osmolytes, and we found that they can delay DPA release from germinating C. difficile spores while still permitting cortex degradation. Together, our results suggest that DPA release during C. difficile spore germination occurs though a mechanosensing mechanism. IMPORTANCEClostridium difficile is transmitted between hosts in the form of a dormant spore, and germination by C. difficile spores is required to initiate infection, because the toxins that are necessary for disease are not deposited on the spore form. Importantly, the C. difficile spore germination pathway represents a novel pathway for bacterial spore germination. Prior work has shown that the order of events during C. difficile spore germination (cortex degradation and DPA release) is flipped compared to the events during B. subtilis spore germination, a model organism. Here, we further characterize the C. difficile spore germination pathway and summarize our findings indicating that DPA release by germinating C. difficile spores occurs through a mechanosensing mechanism in response to the degradation of the spore cortex. PMID- 27981236 TI - A Phylogeny-Based Global Nomenclature System and Automated Annotation Tool for H1 Hemagglutinin Genes from Swine Influenza A Viruses. AB - The H1 subtype of influenza A viruses (IAVs) has been circulating in swine since the 1918 human influenza pandemic. Over time, and aided by further introductions from nonswine hosts, swine H1 viruses have diversified into three genetic lineages. Due to limited global data, these H1 lineages were named based on colloquial context, leading to a proliferation of inconsistent regional naming conventions. In this study, we propose rigorous phylogenetic criteria to establish a globally consistent nomenclature of swine H1 virus hemagglutinin (HA) evolution. These criteria applied to a data set of 7,070 H1 HA sequences led to 28 distinct clades as the basis for the nomenclature. We developed and implemented a web-accessible annotation tool that can assign these biologically informative categories to new sequence data. The annotation tool assigned the combined data set of 7,070 H1 sequences to the correct clade more than 99% of the time. Our analyses indicated that 87% of the swine H1 viruses from 2010 to the present had HAs that belonged to 7 contemporary cocirculating clades. Our nomenclature and web-accessible classification tool provide an accurate method for researchers, diagnosticians, and health officials to assign clade designations to HA sequences. The tool can be updated readily to track evolving nomenclature as new clades emerge, ensuring continued relevance. A common global nomenclature facilitates comparisons of IAVs infecting humans and pigs, within and between regions, and can provide insight into the diversity of swine H1 influenza virus and its impact on vaccine strain selection, diagnostic reagents, and test performance, thereby simplifying communication of such data. IMPORTANCE A fundamental goal in the biological sciences is the definition of groups of organisms based on evolutionary history and the naming of those groups. For influenza A viruses (IAVs) in swine, understanding the hemagglutinin (HA) genetic lineage of a circulating strain aids in vaccine antigen selection and allows for inferences about vaccine efficacy. Previous reporting of H1 virus HA in swine relied on colloquial names, frequently with incriminating and stigmatizing geographic toponyms, making comparisons between studies challenging. To overcome this, we developed an adaptable nomenclature using measurable criteria for historical and contemporary evolutionary patterns of H1 global swine IAVs. We also developed a web-accessible tool that classifies viruses according to this nomenclature. This classification system will aid agricultural production and pandemic preparedness through the identification of important changes in swine IAVs and provides terminology enabling discussion of swine IAVs in a common context among animal and human health initiatives. PMID- 27981238 TI - New Insights into Autoinducer-2 Signaling as a Virulence Regulator in a Mouse Model of Pneumonic Plague. AB - The Enterobacteriaceae family members, including the infamous Yersinia pestis, the causative agent of plague, have a highly conserved interbacterial signaling system that is mediated by the autoinducer-2 (AI-2) quorum-sensing molecule. The AI-2 system is implicated in regulating various bacterial virulence genes in diverse environmental niches. Deletion of the gene encoding the synthetic enzyme for the AI-2 substrate, luxS, leads to either no significant change or, paradoxically, an increase in in vivo bacterial virulence. We showed that deletion of the rbsA and lsrA genes, components of ABC transport systems that interact with AI-2, synergistically disrupted AI-2 signaling patterns and resulted in a more-than-50-fold decrease in Y. pestis strain CO92 virulence in a stringent pneumonic plague mouse model. Deletion of luxS or lsrK (encoding AI-2 kinase) from the DeltarbsA DeltalsrA background strain or complementation of the DeltarbsA DeltalsrA mutant with the corresponding gene(s) reverted the virulence phenotype to that of the wild-type Y. pestis CO92. Furthermore, the administration of synthetic AI-2 in mice infected with the DeltarbsA DeltalsrA DeltaluxS mutant strain attenuated this triple mutant to a virulence phenotype similar to that of the DeltarbsA DeltalsrA strain in a pneumonic plague model. Conversely, the administration of AI-2 to mice infected with the DeltarbsA DeltalsrA DeltaluxS DeltalsrK mutant did not rescue animals from lethality, indicating the importance of the AI-2-LsrK axis in regulating bacterial virulence. By performing high-throughput RNA sequencing, the potential role of some AI-2-signaling-regulated genes that modulated bacterial virulence was determined. We anticipate that the characterization of AI-2 signaling in Y. pestis will lead to reexamination of AI-2 systems in other pathogens and that AI 2 signaling may represent a broad-spectrum therapeutic target to combat antibiotic-resistant bacteria, which represent a global crisis of the 21st century. IMPORTANCEYersinia pestis is the bacterial agent that causes the highly fatal disease plague. The organism represents a significant concern because of its potential use as a bioterror agent, beyond the several thousand naturally occurring human infection cases occurring globally each year. While there has been development of effective antibiotics, the narrow therapeutic window and challenges posed by the existence of antibiotic-resistant strains represent serious concerns. We sought to identify novel virulence factors that could potentially be incorporated into an attenuated vaccine platform or be targeted by novel therapeutics. We show here that a highly conserved quorum-sensing system, autoinducer-2, significantly affected the virulence of Y. pestis in a mouse model of pneumonic plague. We also identified steps in autoinducer-2 signaling which had confounded previous studies and demonstrated the potential for intervention in the virulence mechanism(s) of autoinducer-2. Our findings may have an impact on bacterial pathogenesis research in many other organisms and could result in identifying potential broad-spectrum therapeutic targets to combat antibiotic resistant bacteria, which represent a global crisis of the 21st century. PMID- 27981240 TI - Genomewide Dam Methylation in Escherichia coli during Long-Term Stationary Phase. AB - DNA methylation in prokaryotes is widespread. The most common modification of the genome is the methylation of adenine at the N-6 position. In Escherichia coli K 12 and many gammaproteobacteria, this modification is catalyzed by DNA adenine methyltransferase (Dam) at the GATC consensus sequence and is known to modulate cellular processes including transcriptional regulation of gene expression, initiation of chromosomal replication, and DNA mismatch repair. While studies thus far have focused on the motifs associated with methylated adenine (meA), the frequency of meA across the genome, and temporal dynamics during early periods of incubation, here we conduct the first study on the temporal dynamics of adenine methylation in E. coli by Dam throughout all five phases of the bacterial life cycle in the laboratory. Using single-molecule real-time sequencing, we show that virtually all GATC sites are significantly methylated over time; nearly complete methylation of the chromosome was confirmed by mass spectroscopy analysis. However, we also detect 66 sites whose methylation patterns change significantly over time within a population, including three sites associated with sialic acid transport and catabolism, suggesting a potential role for Dam regulation of these genes; differential expression of this subset of genes was confirmed by quantitative real-time PCR. Further, we show significant growth defects of the dam mutant during long-term stationary phase (LTSP). Together these data suggest that the cell places a high premium on fully methylating the chromosome and that alterations in methylation patterns may have significant impact on patterns of transcription, maintenance of genetic fidelity, and cell survival. IMPORTANCE While it has been shown that methylation remains relatively constant into early stationary phase of E. coli, this study goes further through death phase and long term stationary phase, a unique time in the bacterial life cycle due to nutrient limitation and strong selection for mutants with increased fitness. The absence of methylation at GATC sites can influence the mutation frequency within a population due to aberrant mismatch repair. Therefore, it is important to investigate the methylation status of GATC sites in an environment where cells may not prioritize methylation of the chromosome. This study demonstrates that chromosome methylation remains a priority even under conditions of nutrient limitation, indicating that continuous methylation at GATC sites could be under positive selection. PMID- 27981239 TI - Ionic Liquids Impact the Bioenergy Feedstock-Degrading Microbiome and Transcription of Enzymes Relevant to Polysaccharide Hydrolysis. AB - Ionic liquid (IL) pretreatment is a promising approach for the conversion of lignocellulose to biofuels. The toxicity of residual IL, however, negatively impacts the performance of industrial enzymes and microorganisms in hydrolysis and fermentation. In this study, a thermophilic microbial community was cultured on switchgrass amended with various levels of the ionic liquid 1-ethyl-3 methylimidazolium acetate. Changes in the microbial community composition and transcription of genes relevant to IL tolerance and lignocellulose hydrolysis were quantified. Increasing the level of IL to 0.1% (wt) led to increased levels of relative abundance and transcription in organisms of the phylum Firmicutes. Interestingly, IL concentrations of up to 1% (wt) also resulted in greater xylanase transcription and enzyme activity as well as increased transcription of endoglucanase, beta-glucosidase, and IL tolerance genes compared to communities without IL. IL levels above 1% (wt) resulted in decreased enzyme activity and transcription of genes involved in lignocellulose hydrolysis. The results indicate that moderate levels of IL select for thermophilic microorganisms that not only tolerate IL but also effectively hydrolyze lignocellulose from switchgrass. Discovery of IL-tolerant organisms and enzymes is critical for the development of biological processes that convert IL-pretreated biomass to biofuels and chemicals. Employing metatranscriptomic analysis of enrichment cultures can facilitate the discovery of microorganisms and enzymes that may be active in the presence of toxic compounds such as ionic liquids. IMPORTANCE Pretreatment using ionic liquids (IL) is a promising approach for the conversion of lignocellulose to biofuels. Because IL can be inhibitory to enzymes and microorganisms involved in downstream hydrolysis and fermentation steps, discovery of IL-tolerant organisms and enzymes is critical for advancing this technology. Employing metatranscriptomics in the analysis of IL-enriched cultures facilitated tracking of dynamic changes in a complex microbial community at the level of gene transcription and doing so with genome resolution. Specific organisms were discovered that could simultaneously tolerate a moderate IL concentration and transcribe a diverse array of cellulolytic enzymes. Gene sequences of cellulolytic enzymes and efflux pumps from those same organisms were also identified, providing important resources for future research on engineering IL-tolerant organisms and enzymes. PMID- 27981241 TI - High-throughput screening of clinically approved drugs that prime polyethylenimine transfection reveals modulation of mitochondria dysfunction response improves gene transfer efficiencies. AB - Nonviral gene delivery methods are advantageous over viral vectors in terms of safety, cost, and flexibility in design and application, but suffer from lower gene transfer efficiency. In addition to modifications to nucleic acid design and nonviral carriers, new tools are sought to enhance transfection. Priming is the pharmacological modulation of transfection efficiency and transgene expression, and has demonstrated transfection increase in several compounds, for example, chloroquine and glucocorticoids. To develop a library of transfection priming compounds, a high-throughput screen was performed of the NIH Clinical Collection (NCC) to identify clinical compounds that prime polyethylenimine (PEI) transfection. HEK293T cells were treated with priming compounds, then transfected with enhanced green fluorescent protein (EGFP)-encoding plasmid by PEI. After 48 hr culture, primed and transfected cells were assayed for transfection, cell proliferation, and cell viability by fluorescence measurement of EGFP reporter, Hoechst 33342 nuclei stain, and resazurin metabolic assay. From the microscope image analysis and microplate measurements, transfection fold-changes were determined, and compounds resulting in statistically significant transfection fold-change were identified. NCC compounds were clustered using PubChem fingerprint similarity by Tanimoto coefficients in ChemmineTools. Fold-changes for each compound were linked to drug clusters, from which drug classes that prime transfection were identified. Among the identified drugs classes that primed transfection increases were antioxidants, GABAA receptor modulators, and glucocorticoids. Resveratrol and piceid, stilbenoid antioxidants found in grapes, and zolpidem, a GABAA modulator, increased transfection nearly three-fold. Literature indicate interaction of the identified transfection priming drug clusters with mitochondria, which may modulate mitochondrial dysfunction known to be associated with PEI transfection. PMID- 27981243 TI - Controlling the surface-mediated release of DNA using 'mixed multilayers'. AB - We report the design of erodible 'mixed multilayer' coatings fabricated using plasmid DNA and combinations of both hydrolytically degradable and charge shifting cationic polymer building blocks. Films fabricated layer-by-layer using combinations of a model poly(beta-amino ester) (polymer 1) and a model charge shifting polymer (polymer 2) exhibited DNA release profiles that were substantially different than those assembled using DNA and either polymer 1 or polymer 2 alone. In addition, the order in which layers of these two cationic polymers were deposited during assembly had a profound impact on DNA release profiles when these materials were incubated in physiological buffer. Mixed multilayers ~225 nm thick fabricated by depositing layers of polymer 1/DNA onto films composed of polymer 2/DNA released DNA into solution over ~60 days, with multi-phase release profiles intermediate to and exhibiting some general features of polymer 1/DNA or polymer 2/DNA films (e.g., a period of rapid release, followed by a more extended phase). In sharp contrast, 'inverted' mixed multilayers fabricated by depositing layers of polymer 2/DNA onto films composed of polymer 1/DNA exhibited release profiles that were almost completely linear over ~60-80 days. These and other results are consistent with substantial interdiffusion and commingling (or mixing) among the individual components of these compound materials. Our results reveal this mixing to lead to new, unanticipated, and useful release profiles and provide guidance for the design of polymer-based coatings for the local, surface-mediated delivery of DNA from the surfaces of topologically complex interventional devices, such as intravascular stents, with predictable long-term release profiles. PMID- 27981244 TI - Evaluating side effects of nanoparticle-mediated siRNA delivery to mesenchymal stem cells using next generation sequencing and enrichment analysis. AB - RNA interference has immense potential to modulate cell functions. However, effective delivery of small interfering RNA (siRNA) while avoiding deleterious side effects has proven challenging. This study investigates both intended and unintended effects of diblock copolymer nanoparticle (NP) delivery of siRNA delivery to human mesenchymal stem cells (hMSC). Specifically, siRNA delivery was investigated at a range of NP-siRNA:hMSC ratios with a focus on the effects of NP siRNA treatment on hMSC functions. Additionally, next generation RNA sequencing (RNAseq) was used with enrichment analysis to observe side effects in hMSC gene expression. Results show NP-siRNA delivery is negatively correlated with hMSC density. However, higher NP-siRNA:hMSC ratios increased cytotoxicity and decreased metabolic activity. hMSC proliferation was largely unaffected by NP siRNA treatment, except for a threefold reduction in hMSCs seeded at 4,000 cells/cm2. Flow cytometry reveals that apoptosis is a function of NP-siRNA treatment time and seeding density; ~14% of the treated hMSCs seeded at 8,000 cells/cm2 were annexin V+-siRNA+ 24 hr after treatment, while 11% of the treated population was annexin V+-siRNA-. RNAseq shows that NP-siRNA treatment results in transcriptomic changes in hMSCs, while pathway analysis shows upregulation of apoptosis signaling and downregulation of metabolism, cell cycle, and DNA replication pathways, as corroborated by apoptosis, metabolism, and proliferation assays. Additionally, multiple innate immune signaling pathways such as toll-like receptor, RIG-I-like receptor, and nuclear factor-kappaB signaling pathways are upregulated. Furthermore, and consistent with traditional siRNA immune activation, cytokine-cytokine receptor signaling was also upregulated. Overall, this study provides insight into NP-siRNA:hMSC ratios that are favorable for siRNA delivery. Moreover, NP-siRNA delivery results in side effects across the hMSC transcriptome that suggest activation of the innate immunity that could alter MSC functions associated with their therapeutic potential. PMID- 27981242 TI - Reducing neuroinflammation by delivery of IL-10 encoding lentivirus from multiple channel bridges. AB - The spinal cord is unable to regenerate after injury largely due to growth inhibition by an inflammatory response to the injury that fails to resolve, resulting in secondary damage and cell death. An approach that prevents inhibition by attenuating the inflammatory response and promoting its resolution through the transition of macrophages to anti-inflammatory phenotypes is essential for the creation of a growth permissive microenvironment. Viral gene delivery to induce the expression of anti-inflammatory factors provides the potential to provide localized delivery to alter the host inflammatory response. Initially, we investigated the effect of the biomaterial and viral components of the delivery system to influence the extent of cell infiltration and the phenotype of these cells. Bridge implantation reduces antigen-presenting cell infiltration at day 7, and lentivirus addition to the bridge induces a transient increase in neutrophils in the spinal cord at day 7 and macrophages at day 14. Delivery of a lentivirus encoding IL-10, an anti-inflammatory factor that inhibits immune cell activation and polarizes the macrophage population towards anti-inflammatory phenotypes, reduced neutrophil infiltration at both day 7 and day 28. Though IL-10 lentivirus did not affect macrophages number, it skewed the macrophage population toward an anti-inflammatory M2 phenotype and altered macrophage morphology. Additionally, IL-10 delivery resulted in improved motor function, suggesting reduced secondary damage and increased sparing. Taken together, these results indicate that localized expression of anti-inflammatory factors, such as IL-10, can modulate the inflammatory response following spinal cord injury, and may be a key component of a combinatorial approach that targets the multiple barriers to regeneration and functional recovery. PMID- 27981246 TI - An assessment of the evaporation and condensation phenomena of lithium during the operation of a Li(d,xn) fusion relevant neutron source. AB - The flowing lithium target of a Li(d,xn) fusion relevant neutron source must evacuate the deuteron beam power and generate in a stable manner a flux of neutrons with a broad peak at 14 MeV capable to cause similar phenomena as would undergo the structural materials of plasma facing components of a DEMO like reactors. Whereas the physics of the beam-target interaction are understood and the stability of the lithium screen flowing at the nominal conditions of IFMIF (25 mm thick screen with +/-1 mm surface amplitudes flowing at 15 m/s and 523 K) has been demonstrated, a conclusive assessment of the evaporation and condensation of lithium during operation was missing. First attempts to determine evaporation rates started by Hertz in 1882 and have since been subject of continuous efforts driven by its practical importance; however intense surface evaporation is essentially a non-equilibrium process with its inherent theoretical difficulties. Hertz-Knudsen-Langmuir (HKL) equation with Schrage's 'accommodation factor' eta = 1.66 provide excellent agreement with experiments for weak evaporation under certain conditions, which are present during a Li(d,xn) facility operation. An assessment of the impact under the known operational conditions for IFMIF (574 K and 10-3Pa on the free surface), with the sticking probability of 1 inherent to a hot lithium gas contained in room temperature steel walls, is carried out. An explanation of the main physical concepts to adequately place needed assumptions is included. PMID- 27981245 TI - Integration of growth factor gene delivery with collagen-triggered wound repair cascades using collagen-mimetic peptides. AB - Growth factors (GFs) play vital roles in wound repair. Many GF therapies have reached clinical trials, but success has been hindered by safety concerns and a lack of efficacy. Previously, we presented an approach to produce protein factors in wound beds through localized gene delivery mediated by biomimetic peptides. Modification of polyethylenimine (PEI) DNA polyplexes with collagen-mimetic peptides (CMPs) enabled tailoring of polyplex release/retention and improved gene transfer activity in a cell-responsive manner. In this work, CMP-mediated delivery from collagen was shown to improve expression of platelet-derived growth factor-BB (PDGF-BB) and promote a diverse range of cellular processes associated with wound healing, including proliferation, extracellular matrix production, and chemotaxis. Collagens were pre-exposed to physiologically-simulating conditions (complete media, 37 degrees C) for days to weeks prior to cell seeding to simulate the environment within typical wound dressings. In cell proliferation studies, significant increases in cell counts were demonstrated in collagen gels containing CMP-modified polyplex versus unmodified polyplex, and these effects became most pronounced following prolonged preincubation periods of greater than a week. Collagen containing CMP-modified polyplexes also induced a twofold increase in gel contraction as well as enhanced directionality and migratory activity in response to cell-secreted PDGF-BB gradients. While these PDGF-BB triggered behaviors were observed in collagens containing unmodified polyplexes, the responses withstood much longer preincubation periods in CMP-modified polyplex samples (10 days vs. <5 days). Furthermore, enhanced closure rates in an in vitro wound model suggested that CMP-based PDGF-BB delivery may have utility in actual wound repair and other regenerative medicine applications. PMID- 27981247 TI - Aspartate-beta-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas. AB - BACKGROUND: Despite therapeutic advances, survival with glioblastoma multiforme (GBM) remains below 15 months from diagnosis due to GBM's highly infiltrative nature which precludes complete surgical resection. Patient outcomes could potentially be improved by targeting genes and pathways that drive neoplastic cell motility and invasiveness, including hypoxia-inducible factor-1 (HIF 1alpha), NOTCH, and aspartate-beta-hydroxylase (ASPH). METHODS: Human astrocytoma biopsy specimens (n = 37), WHO Grades II-IV, were analyzed for levels and distributions of ASPH and HIF-1alpha immunoreactivity by immunohistochemical staining, and ASPH, Notch, JAG, HES1, HEY1 and HIF1alpha mRNA expression by quantigene multiplex analysis. The effects of small molecule inhibitors on ASPH's catalytic activity, cell viability and directional motility were examined in vitro in established GBM cell lines and primary tumor cells from an invasive mouse model of GBM. RESULTS: The highest grade astrocytoma, i.e. GBM was associated with the highest levels of ASPH and HIF1alpha, and both proteins were more abundantly distributed in hypoxic compared with normoxic regions of tumor. Furthermore, mining of the TCGA database revealed higher levels of ASPH expression in the mesenchymal subtype of GBM, which is associated with more aggressive and invasive behavior. In contrast, lower grade astrocytomas had low expression levels of ASPH and HIF1alpha. In vitro experiments demonstrated that small molecule inhibitors targeting ASPH's catalytic activity significantly reduced GBM viability and directional motility. Similar effects occurred in GBM cells that were transduced with a lentiviral sh-ASPH construct. CONCLUSION: This study demonstrates that increased ASPH expression could serve as a prognostic biomarker of gliomas and may assist in assigning tumor grade when biopsy specimens are scant. In addition, the findings suggest that GBM treatment strategies could be made more effective by including small molecule inhibitors of ASPH. PMID- 27981248 TI - Absence of a positive correlation between CRP and leptin in rheumatoid arthritis. AB - AIMS: Rheumatoid Arthritis (RA) is a model of chronic inflammatory disease. In this study we evaluated the correlation of leptin and CRP in patients with RA and normal controls. MAIN METHODS: A total of 75 patients with RA and 40 healthy adults were recruited in this case-control study. RA patients were categorized into high (DAS-28 > 3.2) and low activity (DAS <= 3.2) group according to their DAS-28 score. KEY FINDINGS: Leptin level was significantly correlated with CRP in healthy controls (r = 0.365; p < 0.05), but this correlation was lost in RA patients (r = 0.095, p = 0.41). Patients with RA had higher serum leptin levels compared to healthy controls (P < 0.01). No difference in serum leptin level was observed between patients with high and low activity disease. Also leptin was correlated with BMI in healthy controls (r = 0.326, p = 0.037). This correlation was not present in RA patients (r = 0.039, p = 0.756). SIGNIFICANCE: We observed that the physiologic correlation between leptin and CRP and BMI and CRP was not present RA patients. This is a new study reporting the lost correlation between leptin and CRP in RA patients. PMID- 27981249 TI - Understanding molecular markers in recurrent oral squamous cell carcinoma treated with chemoradiation. AB - INTRODUCTION: Oral cancer accounts for approximately 2.1% of all cancers worldwide. In India, oral squamous cell carcinoma (OSCC) is the most common cancer with half a million new cases diagnosed every year. More than 50% of patients eventually develop local recurrence or metastasis usually within the first 2-years following completion of treatment. It is beneficial to analyze the prognostic significance of Cyclin D1, p53 and EGFR which are critical mediators in the pathogenesis of OSCC. The objective of this study was to assess the association of expression of these markers with recurrence and pattern of recurrence in OSCC patients undergoing chemoradiation. MATERIALS AND METHODS: A Total 290 OSCC cases of locally advanced stage (III, IV) oral cancer with World Health Organization (W.H.O.) performance status of grade 0/1 in the year 2009 2012 were enrolled in the study. Treatment response was assessed according to W.H.O. criteria. Cyclin D1, EGFR and p53 expression in tumor tissue was estimated by immunohistochemical (IHC) method and quantified as percentage positive nuclei. RESULTS: During the 2-years follow up, 56 (19.3%) patients recurred, out of which, 47 (83.9%) were locoregional and 9 (16.1%) distant sites. On correlating, chi2 test showed significant (P < 0.05 or P < 0.01 or P < 0.001) association of marker expressions (Cyclin D1, EGFR and p53) with recurrence. The strong positive expressions of all three markers showed significant association with early time of recurrence. The multivariate logistic regression analysis showed significant (P < 0.05 or P < 0.01 or P < 0.001) association of recurrence with primary site, differentiation, Cyclin D1 and p53 expressions indicating these as an independent predictors of recurrence in OSCC. The Cyclin D1, EGFR and p53 expressions also showed significant (P < 0.001) poor survivals (OS, DFS and RFS) in patients with positive/strong positive expressions than negative expression suggesting their prognosis in OSCC. CONCLUSION: Our results signifies that tumors over expressing Cyclin D1, EGFR and p53 are resistant to chemoradiation and are associated with increased risk of locoregional recurrence and metastasis in OSCC patients undergoing chemoradiation. PMID- 27981250 TI - The effect of absorbed hydrogen on the dissolution of steel. AB - Atomic hydrogen (H) was introduced into steel (AISI 1018 mild steel) by controlled cathodic pre-charging. The resultant steel sample, comprising about 1 ppmw diffusible H, and a reference uncharged sample, were studied using atomic emission spectroelectrochemistry (AESEC). AESEC involved potentiodynamic polarisation in a flowing non-passivating electrolyte (0.6 M NaCl, pH 1.95) with real time reconciliation of metal dissolution using on-line inductively coupled plasma-atomic emission spectroscopy (ICP-OES). The presence of absorbed H was shown to significantly increase anodic Fe dissolution, as evidenced by the enhanced detection of Fe2+ ions by ICP-OES. We discuss this important finding in the context of previously proposed mechanisms for H-effects on the corrosion of steels. PMID- 27981251 TI - Lethal Synergism between Influenza and Streptococcus pneumoniae. AB - The devastating synergism of bacterial pneumonia with influenza viral infections left its mark on the world over the last century. Although the details of pathogenesis remain unclear, the synergism is related to a variety of factors including pulmonary epithelial barrier damage which exposes receptors that influence bacterial adherence and the triggering of an exaggerated innate immune response and cytokine storm, which further acts to worsen the injury. Several therapeutics and combination therapies of antibiotics, anti-inflammatories including corticosteroids and toll-like receptor modifiers, and anti-virals are being discussed. This mini review summarizes recent developments in unearthing the pathogenesis of the lethal synergism of pneumococcal co-infection following influenza, as well as addresses potential therapeutic options and combinations of therapies currently being evaluated. PMID- 27981253 TI - Efficacy of Intrauterine infusion of granulocyte colony stimulating factor on patients with history of implantation failure: A randomized control trial. AB - BACKGROUND: Although pregnancy rate in in vitro fertilization-embryo transfer (IVF-ET) cycles has been increased over the preceding years, but the majority of IVF-ET cycles still fail. Granulocyte colony stimulating factor (GCSF) is a glycoprotein that stimulates cytokine growth factor and induces immune system which may improve pregnancy rate in women with history of implantation failure. OBJECTIVE: The aim of this study was to evaluate GCSF ability to improve pregnancy rate in women with history of implantation failure. MATERIALS AND METHODS: 0.5 ml (300 ug/ml) GCSF was infused intrauterine in intervention group. Pregnancy outcomes were assessed based on clinical pregnancy. RESULTS: The mean age of participants was 31.95+/-4.71 years old. There were no significant differences between demographic characteristics in two groups (p>0.05). The pregnancy outcome in GCSF group was improved significantly (p=0.043). CONCLUSION: GCSF can improve pregnancy outcome in patients with history of implantation failure. PMID- 27981252 TI - Thyroid hormone dysfunction during pregnancy: A review. AB - Thyroid dysfunctions such as hypothyroidism, thyrotoxicosis and thyroid nodules may develop during pregnancy leading to abortion, placental abruptions, preeclampsia, preterm delivery and reduced intellectual function in the offspring. Epidemiological data have shown the significant role of maternal thyroid hormone in fetal neurologic development and maternal health. It has been suggested that the deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neuro-intellectual development in the early life of the child. Pregnancy poses an important challenge to the maternal thyroid gland as hormone requirements are increased during gestation as a result of an increase in thyroid- binding globulin, the stimulatory effect of HCG on TSH receptors, and increased peripheral thyroid hormone requirements. Maternal thyroid dysfunction is associated with increased risk for early abortion, preterm delivery, neonatal morbidity and other obstetrical complications. Early diagnosis for thyroid dysfunction of pregnant women and treatment of thyroid dysfunction during pregnancy is important and cost effective to avoid both fetal and maternal complications secondary to thyroid dysfunction. Therefore the aim of this review was to assess the thyroid function changes occurring during pregnancy, the different disorders with their maternal and fetal implications, the laboratory diagnosis and the best ways of management of these conditions. PMID- 27981254 TI - Ginger (Zingiber officinale) induces apoptosis in Trichomonas vaginalis in vitro. AB - BACKGROUND: Trichomoniasis is the most common sexually transmitted protozoan diseases in the worldwide. Metronidazole is the choice drug for trichomoniasis treatment, however, metronidazole resistant Trichomonas vaginalis (T.vaginalis) has been reported. Natural products are the source of most new drugs, and Zingiber officinale (Ginger) is widely used ingredient in the traditional medicine. OBJECTIVE: The aim of the present study was to determine the effect of different concentrations of the ginger ethanol extract on the growth of T.vaginalis trophozoites in vitro. MATERIALS AND METHODS: In this experimental study, 970 women who were attend in Kashan health centers were examined for T. vaginalis. Of them, 23 samples were infected with T.vaginalis. Three T. vaginalis isolates were cultured in a TYI-S-33 medium. The effect of ginger ethanol extracts and its toxicity in different concentrations (25, 50, 100, 200, 400, 800 ug/ml) on mouse macrophages were measured in triplicate exam by MTT [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The effect of ginger on apoptosis induction was determined by Flow cytometry. RESULTS: The IC50 of ginger and metronidazole were 93.8 and 0.0326 ug/ml, respectively. 12, 24 and 48 hr after adding different concentrations of extract on mouse macrophages, fatality rates in maximum dose (800 ug/ml) were 0.19, 0.26 and 0.31 respectively. Flow cytometry results showed the apoptosis rate following treatment with different concentrations of the extract after 48 hr were 17, 28.5, 42.1, 58.8, 76.3 and 100% respectively, while in the control group was 2.9%. CONCLUSION: Ginger ethanol extract induces programmed death in T. vaginalis. It is recommended that due to the known teratogenic effect of metronidazole, ginger can be considered as an alternative drug for metronidazole. PMID- 27981256 TI - Adverse perinatal outcomes in borderline amniotic fluid index. AB - BACKGROUND: Normal amniotic fluid predicts normal placental function, fetal growth and fetal well-being. OBJECTIVE: To determine adverse pregnancy outcomes in borderline amniotic fluid index (AFI). MATERIALS AND METHODS: Pregnant women (37-40 wks) with diagnosis of borderline AFI between December 2012 and August 2014 were identified. Antepartum, intrapartum and neonatal data were collected and compared with those of pregnant women with normal AFI. An AFI less than 8 and more than 5 cm was defined for borderline AFI. Pregnancy outcomes included Cesarean section for non-reassuring fetal heart rate, meconium stained amniotic fluid, 5-min Apgar score <7, low birth weight, umbilical cord blood pH at term and NICU admission. RESULTS: Gestational age at delivery in pregnancies with borderline AFI was significantly lower than normal AFI. Cesarean section rate for non-reassuring fetal heart rate in women of borderline AFI was significantly higher and there was an increased incidence of birth weight less than 10th percentile for gestation age in borderline AFI group. Incidence of low Apgar score and low umbilical artery pH in pregnancies with borderline AFI was significantly higher than women with normal AFI. There were no significant difference in the rate of NICU admission and meconium staining in both groups. CONCLUSION: There are significant differences for adverse pregnancy outcomes , such as Cesarean section due to non-reassuring fetal heart rate, birth weight less than 10th percentile for gestation age, low 5 min Apgar score and low umbilical artery pH between pregnancies with borderline and normal AFI. PMID- 27981255 TI - Comparison of serum zinc concentrations and body antioxidant status between young women with premenstrual syndrome and normal controls: A case-control study. AB - BACKGROUND: Premenstrual syndrome (PMS) is one of the important health problems with high incidence in young women. The exact cause of this syndrome is not clear and some theories have been declared from hormonal factors to nutritional disorders. OBJECTIVE: We investigated the correlation between serum zinc and antioxidant status with PMS. MATERIALS AND METHODS: In this case-control study, forty eight young girls were selected from a total sample of 110 students residing at university dormitories including PMS (n=23) and healthy (n=25) groups based on PMS questionnaire. Dietary intake questionnaire and blood samples were collected from all participants. Serum total antioxidant capacity (TAC) and zinc concentrations were also measured. RESULTS: Serum TAC and zinc concentrations were lower in PMS patients compared with healthy groups (p<0.01 and p<0.05, respectively). Healthy controls consumed lower servings of hydrogenated oils (p<0.05). There were significant differences in terms of muscle mass between the PMS and healthy groups (p<0.05). Both serum TAC and zinc levels were negatively correlated to PMS scores (r=-0.39, p<0.05 and r= -0.36; p<0.05, respectively). CONCLUSION: This study shows that higher TAC and zinc serum levels are associated with lower risk of PMS. PMS cases have more hydrogenated oils than their normal counterparts. PMID- 27981258 TI - Multiplex PCR based screening for micro/partial deletions in the AZF region of Y chromosome in severe oligozoospermic and azoospermic infertile men in Iran. PMID- 27981257 TI - Assessing the efficacy of vaginal hyoscine butyl bromide on cervical ripening prior to intrauterine procedures: A double-blinded clinical trial. AB - BACKGROUND: Unripe cervix prevents entering the endometrial cavity during intrauterine procedures. Mechanical dilatation of cervical canal might cause undesirable complications. OBJECTIVE: To investigate the substitute of mechanical intervention with chemical treatment by administering hyoscine to patients. MATERIALS AND METHODS: Sixty non-pregnant women, 20-70 years of age, with a closed cervix who were scheduled for an intrauterine procedure, were randomly divided into two groups. Group A as experimental (received two doses of hyoscine) and group B, as control group (received two doses of vitamin B6) in the vagina (8 hrs and 2 hrs before procedure) and the effect of these two drugs on dilatation and consistency of cervix were studied. RESULTS: Statistics resulted from Mann Whitney U test (p=0.027) and 2(p=0.002) indicated that in premenopausal women, the priming effect of hyoscine on dilatation and consistency of uterine cervix was significant, but there were no significant benefits from giving vaginal hyoscine to menopausal women preoperatively (p=0.603). CONCLUSION: Hyoscine proved a good choice for inducing cervical priming before intrauterine procedures in premenopausal women. PMID- 27981259 TI - Assessment of Adherence to Visual Correction and Occlusion Therapy in the Infant Aphakia Treatment Study. AB - Occlusion therapy throughout early childhood is believed to be efficacious in treating deprivation amblyopia but has not been rigorously assessed in clinical trials. Further, tools to assess adherence to such therapy over an extended period of time are lacking. Using data from the Infant Aphakia Treatment Study, a randomized clinical trial of treatment for unilateral congenital cataract, we examined the use of quarterly 48-hour recall interviews and annual 7-day prospective diaries to assess reported hours of patching in 114 children throughout the first 5 years of life. Consistency of data reported was assessed using correlation coefficients and intraclass correlation coefficients. Both interview and diary data showed excellent consistency with Cronbach's Alpha's ranging from 0.69 to 0.88 for hours of patching and 0.60 to 0.73 for hours of sleep. However, caregivers reported somewhat more adherence in prospective diaries than retrospective interviews. Completion rates, on the other hand, were substantially higher for telephone interviews than prospective diaries. For example, after four years of surgery response rates to telephone interviews exceeded 75% versus completion rates of only 54% for diaries. In situations where occlusion dose monitors cannot be used for assessing adherence to occlusion therapy, such as in infants or over an extended period of time, quantitative assessments of occlusion therapy can be obtained by parental report, either as a series of prospective diaries or a series of recall interviews. PMID- 27981261 TI - 3D Near Infrared and Ultrasound Imaging of Peripheral Blood Vessels for Real-Time Localization and Needle Guidance. AB - This paper presents a portable imaging device designed to detect peripheral blood vessels for cannula insertion that are otherwise difficult to visualize beneath the skin. The device combines near infrared stereo vision, ultrasound, and real time image analysis to map the 3D structure of subcutaneous vessels. We show that the device can identify adult forearm vessels and be used to guide manual insertions in tissue phantoms with increased first-stick accuracy compared to unassisted cannulation. We also demonstrate that the system may be coupled with a robotic manipulator to perform automated, image-guided venipuncture. PMID- 27981262 TI - [Pain as the primary symptom of a malignant parotid tumour]. AB - The differential diagnosis of peri-auricular pain is comprehensive and arriving at a correct diagnosis is not always easy, which may result in a delay of treatment or even malpractice. Two patients presented themselves with facial peri auricular pain. After a period of follow-up and control this pain turned out to be related to a malignant tumor in the glandula parotidea. These two cases show the importance for the dentist to refer patients with peri-auricular pain, with or without concomitant facial nerve palsy, to a specialist in a timely manner. PMID- 27981260 TI - Once Daily High-dose Radiation (>=60 Gy) Treatment in Limited Stage Small Cell Lung Cancer. AB - BACKGROUND: To investigate outcomes and prognostic factors in patients treated with once daily high-dose (>=60 Gy) radiation therapy (HDRT) and concurrent platinum-based chemotherapy in limited stage small cell lung cancer (LS-SCLC). While we await current phase III trials to determine optimal radiation dose fractionation schemes in LS-SCLC, we report our experience in LS-SCLC with once daily HDRT. We hypothesized that HDRT would achieve similar efficacy and tolerability as twice daily therapy. METHODS: We conducted a single institution retrospective review of all patients with LS-SCLC who underwent curative intent treatment from 2005-2013. Patients treated with HDRT (>=60 Gy) and concurrent chemotherapy (cisplatin or carboplatin and etoposide) were included in our analysis. Clinicopathologic variables assessed include gender, performance status, time to treatment, response to treatment, toxicity, volumetric tumor response at 3 months, and use of prophylactic cranial irradiation (PCI). RESULTS: 42 patients with LS-SCLC who initiated concurrent chemoradiation from 2005 to 2013 were included in the analysis. 38 patients (90%) completed definitive treatment to the lung; 16 (38%) also completed PCI. Median failure free survival (FFS) and overall survival (OS) were 11.9 and 23.1 months, respectively. Two-year and 5-year OS rates were 47% (CI=30-62%) and 21% (CI=7-38%), respectively. On univariate analysis, PCI was associated with improved FFS but this was not significant (p=0.18). Gender was the only co-variate significantly associated with statistical differences in FFS (p=0.03) and OS (p=0.02). Grade 3 and 4 esophagitis were 10.5% and 2.6%, respectively. Pre-HDRT tumor volume and 3-month post-treatment tumor volume were both associated with FFS (p<0.01) but not OS. CONCLUSIONS: In this single institution series, daily HDRT demonstrated a 2-year OS of 47% in LS-SCLC. This compares well to the historical survival of daily fractionation (47%) from INT 0096 reported by Turrisi et. al. Male gender was predictive of significantly worse FFS and OS. Once daily HDRT has similar OS to twice-daily radiation schemes; however, further studies assessing once daily HDRT for LS-SCLC are warranted. PMID- 27981263 TI - [Dissertations 25 years after date 47. Third molars in the lower jaw]. AB - Mandibular third molar impaction causes many problems in the lower jaw. It has been assumed, for example, that impacted third molars are the cause of recurrent problems following orthodontic treatment. In order to prevent problems surgical removal of third molar buds, a germectomy, was proposed. An important factor was to predict the development of the third molar. In doctoral research, this was investigated. The causal relationship between the eruption of third molars and crowding of the lower front has never been proven. Therefore the preventive removal of asymptomatic impacted lower third molars is not advisable. It is, however, advisable to remove all asymptomatic partially erupted impacted third molars that are mesioangulated, distoangulated or horizontally impacted when the patient is between 18 and 25 years old. The absence of clear and clinically applicable predictions of problems relating to the eruption of third molars limits the indication of their germectomy. This doctoral research from 1990 produced a formula for predicting the eruption of third molars in the lower jaw. PMID- 27981264 TI - [Preventive dentistry 1. Fluoride toothpaste, the cornerstone of caries prevention]. AB - After the introduction of effective fluoride toothpastes in the 1970s oral health has improved significantly. Since that time, a lot of energy has gone into improving the toothpastes. An important improvement is the increased substantivity of fluoride and the increase in the duration of its effectiveness. In addition, attempts are currently being made to combine fluoride with effective re-mineralising systems, which is technically challenging. Due to a diversity of compositions, the effectiveness of toothpastes varies. It is, however, impossible to compare all available toothpastes on a 1 to 1 basis. The precise effectiveness cannot be deduced from the ingredients, nor is the dosage-response relationship between the concentration of fluoride and its effectiveness clear. The careful use of toothpaste will compensate for small differences in effectiveness. Times for tooth brushing should be chosen when there is enough time to brush carefully. After brushing, rinsing for one minute with the toothpaste slurry and a sip of water possibly increases the effectiveness of the toothpaste. PMID- 27981265 TI - [Medicines and oral healthcare 3. Insurance coverage and qualification to prescribe]. AB - On the advice of the National Health Care Institute in the Netherlands and the institute's Board of Scientific Advisors, the minister of Health, Welfare and Sport decides whether a certain drug will or will not be included in the list of drugs covered by the basic health insurance plan mandated for all Dutch citizens. In making this decision emphasis is placed on the therapeutic value of that particular drug compared to that of the standard drug for that disorder, the impact that the inclusion of the drug would have on the budget and the drug's cost-effectiveness. In the case of disorders that do not respond or respond insufficiently to the standard treatment, however, one comes up against the limitations of this system and in some cases a necessary treatment is not reimbursed. With respect to prescribing medications, dentists are qualified to prescribe, provided they are enrolled in the so-called BIG register [that recognises the qualifications of healthcare professionals in the Netherlands]. Dental hygienists, by contrast, are not qualified to prescribe and have to limit themselves to at most recommending over-the-counter medicines. In prescribing medicines, dentists are of course limited to those about which they have comprehensive knowledge and sufficient experience. If a dentist wants to prescibe a drug that is outside his or her own experience, then he or she should consult with an oral and maxillofacial surgeon, general practitioner or medical specialist to determine whether the medication can be prescribed and if so, by whom. PMID- 27981266 TI - Initial accuracy assessment of the modified S-LANSS for the detection of neuropathic orofacial pain conditions. AB - OBJECTIVE: To evaluate the accuracy of a questionnaire modified for the identification of intraoral pain with neuropathic characteristics in a clinical orofacial pain sample population. METHOD AND MATERIALS: 136 participants with at least one of four orofacial pain diagnoses (temporomandibular disorders [TMD, n = 41], acute dental pain [ADP, n = 41], trigeminal neuralgia [TN, n = 19], persistent dentoalveolar pain disorder [PDAP, n = 14]) and a group of pain-free controls (n = 21) completed the modified S-LANSS, a previously adapted version of the original questionnaire devised to detected patients suffering from intraoral pain with neuropathic characteristics. Psychometric properties (sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV]) were calculated in two analyses with two different thresholds: (1) Detection of pain with neuropathic characteristics: PDAP + TN were considered positive, and TMD + ADP + controls were considered negative per gold standard (expert opinion). (2) Detection of PDAP: PDAP was considered positive and TMD + ADP were considered negative per gold standard. For both analyses, target values for adequate sensitivity and specificity were defined as >= 80%. RESULTS: For detection of orofacial pain with neuropathic characteristics (PDAP + TN), the modified S-LANSS presented with the most optimistic threshold sensitivity of 52% (95% confidence interval [CI], 34-69), specificity of 70% (95% CI, 60-79), PPV of 35% (95% CI, 22 51), and NPV of 82% (95% CI, 72-89). For detection of PDAP only, with the most optimistic threshold sensitivity was 64% (95% CI, 35-87), specificity 63% (95% CI, 52-74), PPV 23% (95% CI, 11-39) and NPV 91% (95% CI, 81-97). CONCLUSION: Based on a priori defined criteria, the modified S-LANSS did not show adequate accuracy to detect intraoral pain with neuropathic characteristics in a clinical orofacial pain sample. PMID- 27981267 TI - Unusual maxillary osteoblastic and osteolytic lesions presenting as an initial manifestation of childhood acute myeloid leukemia: A case report. AB - Changes in facial bones may represent a manifestation of systemic disease. Dentists play an important role in the early detection of these manifestations of complex systemic diseases. A case of unusual maxillary mixed (osteoblastic and osteolytic) lesions as an initial manifestation of childhood acute myeloid leukemia (AML) is presented. A 12-year-old male patient was referred to the Department of Oral Medicine complaining of severe swelling in the right buccal region. 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) showed enhanced FDG uptake in the right maxillary sinus. In addition, PET maximum intensity projection image showed diffused FDG uptake in the entire bone marrow. Bone marrow aspiration was performed on the lumbar vertebra, and fluorescence in situ hybridization (FISH) demonstrated AML. The patient was diagnosed with AML (M5a) and treated with chemotherapy by the pediatric department. Six months later, the patient achieved complete remission. After chemotherapy, the disappearance of the osteoblastic and osteolytic lesion and 18F-FDG accumulation were confirmed by PET/CT. Dentists should be familiar with oral manifestations of leukemia because early detection of oral lesions would increase the life span of the patients and reduce the severity of complications. PMID- 27981268 TI - The effect of a triclosan/copolymer/fluoride ?toothpaste on plaque formation, gingivitis, and ?dentin hypersensitivity: A single-blinded ?randomized clinical study. AB - OBJECTIVE: The daily removal of supragingival dental plaque is a key factor in the prevention of gingivitis. The aim of the study was to compare the gingival health benefits of a triclosan/copolymer/fluoride toothpaste (Colgate Total, a fluoride toothpaste containing an antiseptic) to a commercially available toothpaste containing 0.243% sodium fluoride in a silica base (Colgate Herbal, a conventional fluoride toothpaste with herbal extracts). METHOD AND MATERIALS: A total of 50 patients with gingivitis and at least one sensitive tooth were included. The subjects were randomly stratified into two groups: Colgate Total toothpaste, and Colgate Herbal toothpaste. After a 4-week pre-experimental phase, baseline Plaque Index (Quigley-Hein Index) (PI), Gingival Index (GI), Gingival Bleeding Index (GBI), and Visual Analog Scale (VAS) were assessed. The PI, GI, GBI, and VAS were reexamined at weeks 4, 12, and 24 after the baseline. RESULTS: Fifty subjects complied with the protocol and completed the study. The conventional fluoride toothpaste with herbal extracts group and the fluoride toothpaste containing an antiseptic group exhibited significant reductions in PI, GI, GBI, and VAS over time. The amount of reduction after 6 months of the treatment was higher in the Total group compared to Herbal group (1.82 vs 1.39, P = .015 for PI; 0.67 vs 0.37, P < .005 for GI; and 56.64% vs 34.26%, P < .005 for GBI). No significant difference was seen for VAS. CONCLUSION: Twice daily brushing with a toothpaste containing 0.3% triclosan and polyvinyl methyl ether and maleic acid copolymer provides a more effective level of plaque control and gingival health with no effect on decreasing dentin hypersensitivity compared to conventional fluoride toothpaste. Toothpastes containing triclosan/copolymer, in addition to fluoride, result in a higher reduction in plaque, gingival inflammation, and gingival bleeding when compared with fluoride toothpastes without triclosan/copolymer. PMID- 27981269 TI - Dental pigmentation and hemochromatosis: A case report. AB - The causes of dental pigmentation are diverse. It can be classified in intrinsic or extrinsic depending on the origin and location of the stain in the affected tooth. This report presents an unusual case of dental pigmentation and enamel loss where the diagnosis of its origin revealed an underlying systemic pathology, unknown to the patient, which could have affected the development of the pigmentation. PMID- 27981270 TI - Retrospective evaluation of posterior composite ?resin sandwich restorations with Herculite XRV: ?18-year findings. AB - OBJECTIVE: The aim of this retrospective study was to evaluate the long-term clinical outcomes of posterior composite resin sandwich restorations, and secondarily to assess the influence of potential factors on survival and causes of failure. METHOD AND MATERIALS: Two hundred and four posterior Herculite XRV restorations due to primary caries performed between 1991 and 1997 were included. The restorations were assessed after 18 years, by two calibrated examiners, according to USPHS criteria. The survival of the restorations was estimated by the Kaplan-Meier estimator. Cox regression was applied to evaluate the influence of the cavity size, location of the tooth, caries risk, and gender on survival rate. The predictive power of the analyzed variables on survival rate was studied with multiple linear regression analysis. RESULTS: After 10 years the survival rate was 92.6%, and 82.4% at the end of the study. Thirty-six (17.6%) restorations failed during the evaluation period, 21 (10.3%) of them after more than 10 years. The most common failure was secondary caries (69.4% of the failures). There were statistically significant differences in survival rate depending on caries risk (P = .000), but not between Class I and II (P = .106), and the type and localization of the tooth (P = .115). CONCLUSION: Posterior Herculite XRV restorations due to primary caries have high long-term survival rates. Generally, failures occur by secondary caries and are more common in molars. The patient's caries risk is the variable that best predicts the survival of posterior restorations. PMID- 27981271 TI - Ultrasonography as an educational tool for students - any progress? AB - . PMID- 27981272 TI - Ultrasonography as an integrated tool in clinical decision-making in the Emergency Department. AB - AIM: The aim of this retrospective study was to identify the role of ultrasonography as a decision-making and screening tool in emergency patients with pathological changes. MATERIAL AND METHOD: The study was carried out for 28 months in the Emergency Department of the County Emergency University Hospital, Cluj-Napoca. An ultrasound examination was performed as part of the clinical algorithm within the first hour of treating non-critical patients after they had been triaged. The diagnostic decision based on the results of the ultrasound examination was compared with the final diagnosis on discharge from the Emergency Department. RESULTS: In study were included 1565 patients with a mean age of 50.61+/-19.21 years. Ultrasound changes were detected in a statistically significant number of patients from all the examined subgroups (p<=0.002). The concordance between clinical and ultrasound findings was of 54.06%. Of all the examined patients, 20.63% were referred to surgery department based on the results of the ultrasound examination. Surgery was the final therapeutic decision in 5.06% of all the patients with normal ultrasound findings. CONCLUSIONS: Ultrasonography as an integrated tool in the clinical examination algorithm allowed the identification of non-critical patients who required emergency surgery (20.63%). The integration of point-of-care ultrasound into the clinical examination allows the management of emergency patients through the ranking of decisions: hospital admission for surgery and medical treatment, other diagnostic investigations, referral to outpatient care and family physician. PMID- 27981274 TI - Noninvasive quantitative estimation of hepatic steatosis by ultrasound: a comparison of the hepato-renal index and ultrasound attenuation index. AB - AIMS: To compare the accuracy of the ultrasound attenuation index (USAI) and hepato-renal index (HRI) for the diagnosis of hepatic steatosis (HS). MATERIAL AND METHODS: Two hundred and twenty-four potential living hepatic donors underwent US and subsequent US-guided liver biopsy. The USAI was calculated from US images with an 8 MHz transducer and HRI was measured on sagittal images with a clear visualization of both the liver and kidney. Using histological degrees of HS as the reference standard, we compared the performance of USAI and HRI for diagnosing HS >= 5% and >= 30% by receiver operating characteristic curve analysis. The interobserver agreement was evaluated by using intraclass correlation coefficients (ICCs) or Bland-Altman statistics. RESULTS: Histologic degree of HS was 0-70% (median, 5%). HRI showed a tendency towards higher accuracy than USAI for diagnosing HS >= 5% (the area under the ROC curve, 0.856 vs. 0.820; p= 0.279) and >= 30% (0.937 vs. 0.909; p = 0.378) without statistical significance. There was an excellent interobserver agreement for both USAI and HRI (ICC = 0.931 and 0.973, respectively). According to the Bland-Altman method, the 95% limits of difference between two readers for HS were -8.5% to 6.6% by USAI and -4.8% to 6.2% by HRI. Most patients would have the difference of calculated HS by USAI (74.0%) and HRI (96.0%) from different operators within a range of +/-5%. CONCLUSIONS: Although statistically insignificant, HRI was superior to USAI for the diagnosis and quantitative estimation of HS in terms of diagnostic performance, including accuracy and reproducibility. PMID- 27981273 TI - The pursuit of normal reference values of pancreas stiffness by using Acoustic Radiation Force Impulse (ARFI) elastography. AB - AIM: The purpose of this study is to evaluate pancreatic stiffness by ARFI abdominal elastography. In the current literature, there are relatively few studies that have assessed the clinical utility of this technique. MATERIAL AND METHOD: A number of 37 healthy subjects were included. The data were collected in a prospective manner and afterwards included in an observational, analytical and longitudinal study. Subsequently viewing the pancreatic parenchyma in bidimensional mode (2D-US) mode, 10 shear wave velocity (SWV) measurements for each segment: head, body and tail were performed. Statistical analysis by regression models targeted also the possible influence of other factors in assessing SWV. A comparative analysis was performed regarding the statistical significance of 5 versus 10 SWV measurements for each segment. RESULTS: The pancreas was entirely evaluated in all subjects. The mean SWV from the entire parenchyma was 1.216 m/s+/-0.36 and between the three segments SWV were similar (head: 1.224 m/s, body: 1.227 m/s and tail: 1.191 m/s). A ratio of the IQR/Median >0.4 was interpreted as statistically invalid, relevant data being highlighted in the percentage of 83.78% for the head of the pancreas, 78.37% for the body, and 67.56% at the caudal level. Significant correlations were observed between the data (mean and median SWV) provided by the group with 5 measurements of the SWV versus the standard group: 93.9% for the head, 96.6% for the body, and 98.7% accordingly to the tail. CONCLUSIONS: SWV determination by percutaneous approach represents a useful imaging method for evaluating pancreatic stiffness, of course within these limitations. Because we did not observe statistically significant differences between the results obtained by 5 or 10 measurements, we suggest that it would be sufficient to perform only five measurements of the SWV per pancreatic segment. The data obtained in the normal pancreas could be used in future comparative assessments regarding the inflammatory or tumoral pathology of the pancreas. PMID- 27981275 TI - The impact of microbubble-enhanced therapeutic ultrasound combined with prothrombin on microwave ablation in the rabbit liver. AB - AIM: This study aimed to investigate the effect of microbubble-enhanced ultrasound (MEUS) combined with prothrombin on regional hepatic circulation and microwave ablation (MWA) in rabbit livers. MATERIALS AND METHODS: High pressureamplitude therapeutic ultrasound (TUS) was used to treat 52 surgically exposed livers of healthy New Zealand rabbits: 13 livers were treated with MEUS alone, 13 with MEUS and prothrombin (PMEUS), 13 with ultrasound plus normal saline and 13 with ultrasound plus prothrombin as controls. Contrast-enhanced ultrasound (CEUS) imaging was performed on the exposed livers before and after treatment, and acoustic quantification was done to assess liver perfusion. Then, the liver was divided into two parts, one was used for pathologic examination and the other was ablated with microwave (MWA) and then processedfor pathologic examination. RESULTS: The CEUS images and Peak value after treatment in the PMEUS group were significantly reduced as compared to the remaining 3 groups (p<0.05). Occasional piecemeal hemorrhage was evidenced in the pathological examination in the MEUS group. Obvious cellular degeneration and necrosis with thrombosis were observed in the PMEUS group. Electron microscopy showed endothelial damage in both the MEUS group and PMEUS group. After MWA, coagulated volumes (V) in the PMEUS group were larger than in the remaining 3 groups (p<0.05). The cell ultrastructure disorder wasmore severe in the PMEUS group than in remaining 3 groups. CONCLUSION: PMEUS promotes endothelial injury and produces more obvious thrombotic occlusion, improving the therapeutic effect of MWA on the rabbit liver. PMID- 27981276 TI - Non-mass lesions on screening breast ultrasound. AB - AIM: The purpose of this study was to determine the significance of a non-mass lesion (NML) which is recognized during screening breast ultrasound (US). MATERIALS AND METHODS: We included patients with a NML on screening breast US and no suspicious finding on mammography between March 2008 and June 2012. The final diagnoses were based on pathology results and a clinical or sonographic follow-up for more than 12 months. We calculated the incidence, likelihood of malignancy, and positive predictive value (PPV) of biopsy with a review of imaging and histopathological findings. RESULTS: A total of 17868 screening breast US were performed in 8856 asymptomatic patients. Ninety-five NMLs were detected in 88 patients (1.0%). Among the 93 lesions that were followed or confirmed histopathologically, 2 (2.2%) were malignant, 89 (95.6%) were benign, and 2 (2.2%) were high risk lesions. The likelihood of malignancy in a NML on screening breast US was 2.2% and the PPV of biopsy was 6.3% (2 of 32). CONCLUSION: The likelihood of malignancy for a NML on screening breast US was greater than 2%. It could be classified as a BI-RADS category 4a lesion and tissue diagnosis is warranted. This provides the potential management guidelines for a NML in screening patients and further prospective studies in a large, multicenter screening population are required. PMID- 27981277 TI - A dilemma at gray scale thyroid ultrasound: microcalcification or not? Differentiation with Acoustic Radiation Force Impulse Imaging-Virtual Touch Imaging. AB - AIMS: To evaluate the capacity of virtual touch imaging (VTI) of the acoustic radiation force impulse (ARFI) techniquein the differential diagnosis of micro echogenicities in thyroid nodules. MATERIAL AND METHODS: The study comprised 28patients. Gray scale and ARFI displacement maps were used during ultrasound examination.In the same session, fine needleaspiration biopsy (FNAB) samples were obtained from the dominant nodule hav-ing micro-echogenicities. Two radiologists blinded to the FNAB results and clinical data of the patients evaluated these images and rated ARFI echogenicities according to the degree of shining points on the displacement maps and classified them as isohypoechogenic, isohyperechogenic, and obvious hyperechogenic. To differentiate between benignancy and malignancy, "a new sign" was defined as follows: in the ARFI maps obtained by VTI, iso echogenic or hyper-echogenic appearance of micro-echogenic foci was evaluated as benignancy and hypo-echogenic appearance of micro-echogenic foci was evaluated as malignancy. RESULTS: The FNAB results indicated 14 cases and benign nodules in the other 14 cases. Interobserver agreement between the two radiologists was highly significant for the classification of the micro-echogenic foci (Kappa=0.659, p<0.001). When we reclassified the hyperechoic and isohyperechoic foci as "benign" and isohypoechoic foci as "malignant", the interobserver agreement between the two radiologists increased (Kappa=0.772, p<0.001). The evaluation of the first and second radiologists were highly concordant with the gold standard pathology results (Kappa=0.786, p<0.001 and Kappa=0.714, p<0.001, respectively). CONCLUSIONS: ARFI method with specific VTI features could be a very useful tool in the differentiation of malignant microcalcifications in thyroid nodules. PMID- 27981278 TI - Knee ultrasound from research to real practice: a systematic literature review of adult knee ultrasound assessment feasibility studies. AB - OBJECTIVE: To identify and analyse existing data regarding knee ultrasound (US) feasibility in clinical practice. Material and methods: A systematic literature review was performed using the terms: ("knee") AND ("ultrasound" OR "ultrasonography") AND ("feasibility" OR "pilot" OR "proof of concept"). Feasibility studies regarding knee US or US aided maneuver involving knee joint, published during 2005-2015, were selected and evaluated against a complex framework constructed around mandatory key areas for feasibility studies: acceptability, demand, implementation, practicality, adaptation, integration and expansion. RESULTS: One hundred and fifty-nine publications were identified, of which 9 were included in the final analysis: 6 dealt with the development and implementation of novel US scores, while the rest focused on implementing MSUS in clinical practice, evaluating the usefulness of articular cartilage US assessment and the feasibility of sonography for intra-articular knee injections, respectively. Six studies quantified feasibility as time spent for the evaluation, with only two addressing areassuch as acceptability, implementation and practicality, although none of these systematically assessed all feasibility domains. CONCLUSION: Knee US feasibility is still poorly addressed; the time required for US assessment is the main area addressed. This information gap should be properly addressed in future works, in order to ensure the right place for this technique. PMID- 27981279 TI - Intra-articular hyaluronic acid vs platelet-rich plasma in the treatment of hip osteoarthritis. AB - AIM: To compare the efficacy of ultrasound-guided intra-articular (IA) treatment with platelet-rich plasma (PRP) versus viscosupplementation (hyaluronic acid HA) in hip osteoarthritis. METHODS: A total of 43 patients affected by monolateral severe hip osteoarthritis (OA) were included in the study. Patients were randomized to receive either intra-articular PRP (3 ml) or HA (30 mg/2 ml; 1,000 2,900 kDa), 3 injections in total - 1/week. Clinical assessments for each patient were made at baseline (T0), 4 (T1), and 16 weeks (T2) of follow-up. The primary efficacy outcome was pain reduction as measured by VAS and by WOMAC pain subscale. RESULTS: Data analysis revealed that, compared to T0, in the PRP treated group VAS scores significantly decreased at T1 but not at T2, thereby indicating an early effect on pain which was not maintained at a longer term follow-up. In the HA group a significant decrease of both VAS and WOMAC values was registered only between T0 and T2. CONCLUSIONS: Intra-articular PRP had an immediate effect on pain that was not maintained at longer term follow-up when, on the contrary, the effects of intra-articular HA were evident. PMID- 27981281 TI - Takotsubo Cardiomyopathy presenting as ST-elevation myocardial infarction: wide triggering spectrum and specific echocardiographical pattern in a consecutive case series report. AB - We report a series of six consecutive cases of Takotsubo Cardiomyopathy (TCM) presenting as ST-elevation acute myocardial infarction and consequently addressed to the emergency coronary angiography, inside a time-frame of one year (2015). This series underlines the wide possible triggering spectrum and clinical severity of TCM and recognizes echocardiography as an essential imaging technique in the diagnosis due to its widespread availability and feasibility in the acute care setting. PMID- 27981280 TI - Diagnosis of endometriotic lesions by sonovaginography with ultrasound gel. AB - AIMS: The aim of the study was to evaluate the diagnostic ability of sonovaginography (SVG) with ultrasound gel in patients with endometriosis. MATERIAL AND METHODS: We conducted a multicentre prospective study, which included 193 patients with symptoms highly suggestive for endometriosis. All patients were investigated by transvaginal sonography and SVG with gel and afterwards underwent laparoscopic surgery. For each category of endometriotic lesions investigated, we calculated and compared the sensitivity, specificity, positive predictive value and negative predictive value of the imagisticinvestigations used. RESULTS: In the case of endometriotic lesions of the uterosacral ligaments, SVG with gel had a sensitivity of 78.5% and a specificity of 96% (p=ns). The lesions of the vagina and rectovaginal septum were diagnosed with a sensitivity of 79%, respectively 94% (p=ns), obtaining a specificity of 99%, respectively of 97% (p=0.007). The lesions of the Douglas pouch were identified with a sensitivity of 81% (p=0.015), and those of the rectosigmoid with a 94% sensitivity (p=0.010). We obtained lower sensitivity (67%) in detecting the lesions of the urinary bladder (p=ns). CONCLUSIONS: SGV with ultrasound gel represents a useful investigation tool for the evaluation of endometriotic lesions in the posterior pelvic compartment. PMID- 27981282 TI - Strain Elastography (SE) for liver fibrosis estimation - which elastic score to calculate? AB - Liver fibrosis scoring by liver biopsy has become a rarity in daily practice mainly because many non-invasive methods with similar accuracy have been developed. Among all ultrasound elastography imaging methods, Strain Elastography (SE) is the most widely available. Although SE is a qualitative and semi quantitative method, there is reliable applicability for liver fibrosis estimation and multiple ways to transform SE into a quantitative method, in order to obtain a fibrosis score. The aim of this review is to briefly introduce all these methods and to offer support in choosing the best estimation method for liver fibrosis, with SE. PMID- 27981283 TI - Lung artefacts and their use. AB - The science of lung ultrasound has grown tremendously over the last two decades and lung ultrasound has not only entered the mainstream of point of care ultrasound but has become a dominant topic. Understanding lung ultrasound signs and artifacts is critical to being able to correlate findings with actual pathology and normal anatomy and physiology. Investigators have described multiple lung ultrasound artifacts and findings and it is important to understand both the physics and anatomic basis behind them. Additionally, ultrasound machine use and transducer selection can significantly affect results obtained on patient during an examination and the provider must carefully choose the correct settings. This manuscript describes the state of the art in ultrasound artifact recognition and correlation as well as management of ultrasound technology to optimize diagnostic success. PMID- 27981284 TI - Complete atrioventricular septal defect in the era of prenatal diagnosis. AB - Complete atrioventricular septal defect (CAVSD) is a fetal cardiac malformation (5% of all cardiac malformations) that can be detected prenatally with a reserved prognosis. The diagnosis can be suspected early at the end of the first trimester using the transabdominal or transvaginal ultrasound approach. Generally, the diagnostic can be established during the mid-trimester scan at 19-24 weeks of gestation. The percentage of antenatal diagnostic of CAVSD is between 57-92%. This review aims to analyze the anatomical principles and the ultrasound techniques that can improve the prenatal diagnosis of CAVSD. We have also analyzed the structural and genetic anomalies frequently associated with CAVSD. PMID- 27981285 TI - Utility of transthoracic echocardiography (TTE) in assessing fluid responsiveness in critically ill patients - a challenge for the bedside sonographer. AB - Transthoracic echocardiography (TTE) has become one of the most important diagnostic tools in the treatment of critically ill patients. It allows clinicians to recognise potentially reversible life-threatening situations and is also very effective in the monitoring of the fluid status of patients, slowly substituting invasive methods in the intensive care unit. Hemodynamic assessment is based on a few static and dynamic parameters. Dynamic parameters change during the respiratory cycle in mechanical ventilation and the level of this change directly corresponds to fluid responsiveness. Most of the parameters cannot be used in spontaneously breathing patients. For these patients the most important test is passive leg raising, which is a good substitute for fluid bolus. Although TTE is very useful in the critical care setting, we should not forget the important limitations, not only technical ones but also caused by the critical illness itself. Unfortunately, this method does not allow continuous monitoring and every change in the patient's condition requires repeated examination. PMID- 27981286 TI - Penile masses: Shear Wave Elastography correlated with Magnetic Resonance Imagining. A two cases report. AB - Definitive diagnosis of penile masses usually depends on clinical symptoms and patient history but in some challenging cases the help of radiologic diagnostic tools is required. Although ultrasound is an effective tool for detecting penile masses, unlike magnetic resonance imagining, it is not able to differentiate benign and malignant pathologies. Shear wave elastography (SWE) is a novel method, which has the ability to differentiate malignant and benign tissues by giving quantitative information about tissue elasticity. In this paper we present two cases with penile masses to demonstrate the potential use of SWE in the differential diagnosis of penile masses. PMID- 27981287 TI - Unusual multiple metastatic localisations in adult Burkitt's lymphoma. A case report. AB - Burkitt's lymphoma is an aggressive B-cell non-Hodgkin lymphoma. It is less common in adults accounting for less than 5% of non-Hodgkin lymphoma cases. Radiological methods (ultrasonography, computed tomography) are indispensable for the initial evaluation and appreciation of organ extension; complete diagnosis is confirmed by the histopathological examination.We present the clinical case and ultrasound imaging particularities of a young patient diagnosed with multisystem involvement Burkitt's lymphoma, with rapid progressive evolution towards exitus. PMID- 27981288 TI - Schwannoma of the median nerve mimicking carpal tunnel syndrome in a pregnant patient. Case report. AB - In patients with symptoms of a peripheral neuropathy especially during pregnancy, use of imaging techniques such as Ultrasound (US) and Magnetic Resonance Imaging (MRI) may be essential for the diagnostic accomplishment. A 30-weekspregnant diabetic female attending US evaluation due to intermittent hand pain, numbness, and weakness bilaterally. Although, the US evaluation revealed the median nerve (MN) normal size, echogenicity and echo-texture within the right carpal tunnel; the US assessment applied proximally to the carpal tunnel, revealed a hypoechoic tumor-like mass and increased MN cross section area. In transverse view, the MN was detected as an eccentric, hypoechoic structure compressed by the aforementioned mass. A presence of MN schwannoma or neurofibroma was suspected. US has been proved to be extremely useful to determine location, extent as well as the type of nerve lesion. PMID- 27981289 TI - Is strain elastography beneficial for isoechoic cholangiocarcinomas? AB - . PMID- 27981290 TI - Evaluation of nasal fluid flow in fetuses by Doppler ultrasound. AB - . PMID- 27981291 TI - Contrast-enhanced ultrasonography is useful for evaluating the intraplaque neovascularization in aortic complex plaque of ischemic stroke patients. AB - . PMID- 27981292 TI - How to get ductus venosus flow velocity waveforms between 11 and 14 weeks: Candle Flame and Falling Drop Signs. AB - . PMID- 27981293 TI - Detection of arterioportal shunt on long term follow-up of a patient diagnosed with liver abscess. AB - . PMID- 27981295 TI - One-shot balloon dilation of esophageal stricture due to unusual lichen planus localization. PMID- 27981294 TI - Sonographer preference for Knox versus ballistic gelatin for the creation of deep venous thrombosis ultrasound phantoms. AB - . PMID- 27981296 TI - Massive food impaction in achalasia. PMID- 27981297 TI - Endoscopic aspect of a severe CMV colitis induced by azathioprine in a patient with ulcerative colitis. PMID- 27981298 TI - Impaired Gastric Cancer Survival in Patients with Inflammatory Bowel Disease. AB - BACKGROUND AND AIMS: Both chronic inflammation and reduced immunosurveillance contribute to malignancy development in inflammatory bowel disease (IBD). Previous literature suggests that especially Crohn's disease patients are at an increased risk for developing gastric cancer (GC). This study aimed to identify risk factors for GC development in IBD and to compare the clinical characteristics of GC in IBD to those in the general population. METHODS: We retrospectively searched the Dutch Pathology Database to identify all Dutch IBD patients with GC between January 2004 and December 2008. Two case-control studies were performed. I: to identify risk factors for GC in IBD, with controls from the IBD South Limburg (IBDSL) population-based cohort; and II: to compare GC disease course in IBD patients with the general population. General population data were obtained from the Eindhoven Cancer Registry (ECR). RESULTS: We included 59 patients with IBD and GC (cases). Cases were significantly older at IBD diagnosis than IBDSL controls (median age 61 years versus 40; p<0.01), and ulcerative colitis (UC) was more frequent in the case group (69.5% versus 51.4%; p<0.01). We found no difference in age at diagnosis, gender, tumor location and tumor differentiation between IBD GC patients and ECR controls. When corrected for confounders and TNM-stage, IBD patients showed impaired survival (p=0.035; HR 1.385). CONCLUSIONS: Survival is significantly reduced in IBD patients compared to the general population in the multivariate analysis of our study, but age at GC diagnosis and TNM-stage were comparable between IBD cases and controls. Elderly onset IBD emerged as a risk factor for GC development in IBD patients, particularly in UC. PMID- 27981299 TI - Celiac Disease in The Netherlands: Demographic Data of Members of the Dutch Celiac Society. AB - BACKGROUND AND AIMS: Celiac disease is an autoimmune disease induced by the intake of gluten with a female to male ratio of 2-4:1. Female predominance has not been recognized in serological mass screening studies. Limited data are available on gender and age distribution in the daily clinical practice of celiac disease. The aim of this study is to describe differences in gender and age at the time of celiac disease diagnosis in the Netherlands. METHODS: Data was obtained from a prospectively maintained database of members of the Dutch Celiac Society in whom celiac disease was diagnosed between 1980 and August 2015. DESIGN: retrospective database study; Setting: database of members of the Dutch Celiac Society; Participants: out of the total number of 26,986 current and ex members, the data of 7,886 members could be used for analysis. RESULTS: Age at celiac disease diagnosis ranged between 0 and 88 years; the minority (36%) were diagnosed in childhood. In children, the majority (52%) were diagnosed before the age of 4 years. Median age did not differ in children when compared for gender (3 years). In adults, median age differed between males (52 years, IQR 41-61) and females (44 years, IQR 32-56), p<0.001. Female to male ratio was 2.4:1. CONCLUSION: The majority of celiac disease patients are diagnosed during adulthood, with males diagnosed at an older age. Only one-third of the patients were diagnosed at childhood. Celiac disease is less frequently diagnosed in young adult males. PMID- 27981300 TI - Cholelithiasis in Patients with Gaucher Disease type 1: Risk Factors and the Role of ABCG5/ABCG8 Gene Variants. AB - BACKGROUND AND AIM: Patients with Gaucher disease type 1 (GD1) show an altered lipid profile and a certain degree of insulin resistance, which might contribute to cholelithiasis (CL) and could possibly be associated with ABCG5/ABCG8 gene variants. We aimed to investigate the prevalence of CL in Caucasian adult patients with GD1 and the possible risk factors, including gene variants of the ABCG5/ABCG8 genes. METHODS: 61 Caucasian patients with GD1 (38 female/23male), aged 18-62 years and 61 healthy subjects matched for age, gender and BMI, without CL, for comparison of lipid profiles. Data before start of enzyme replacement therapy (ERT) were recorded: clinical, haematological, severity parameters, splenectomy, genotype. Fasting lipid profiles before ERT, glycemia, insulinaemia, HOMA-IR at the last visit were documented. Genotyping for the gene variants D19H, Y54C, T400K, A632V (ABCG8); Q604E (ABCG5) was performed. RESULTS: CL occurred in 45.9% of patients. Risk factors were: age, family history of CL, higher BMI values, LDL-cholesterol (LDL-C), disease severity, splenectomy. A specific dyslipidemia was found in patients vs. controls. Total serum cholesterol (TC) and LDL-C were higher in patients with CL than in those without; no obvious influence of insulin-resistance to lithogenesis was found. Patients with the GG genotype of D19H and the CC genotype of T400K (ABCG8 gene) had significantly higher levels of TC and LDL-C. CONCLUSION: Patients with GD1 showed an increased prevalence of CL, which was associated with common and disease-specific risk factors. Starting ERT soon after clinical onset and avoiding splenectomy might reduce the risk of CL in GD1. PMID- 27981302 TI - Treatment Targets in Inflammatory Bowel Disease: Current Status in Daily Practice. AB - BACKGROUND AND AIMS: Recently, treatment goals in inflammatory bowel disease (IBD) in clinical trials have shifted from mainly symptom-based to more mucosa driven. Real world data on treatment priorities are lacking. We aimed to investigate the current practice and most commonly used definitions of IBD treatment targets among Dutch gastroenterologists. METHODS: Dutch gastroenterologists were asked to participate in a computer-based nation-wide survey. We asked questions on demographics, opinion and current practice regarding IBD treatment targets. RESULTS: Twenty-four percent (134/556) of the respondents completed the survey. For both Crohn's disease (CD) (47.3%, 61/129) and ulcerative colitis (UC)(45%, 58/129) the main treatment goal was to achieve and maintain deep remission, defined as clinical, biochemical and endoscopic remission. Seventy-six percent of the participants use mucosal healing (MH) as a potential treatment target for IBD, whereas 22.6% use histological remission. There is no single definition for MH in IBD. The majority use Mayo score <= 1 in UC (52%) and 'macroscopic normal mucosa' in CD (66%). CONCLUSION: More stringent and mucosa-driven treatment targets as 'deep remission' and 'mucosal healing' have found traction in clinical practice. The most commonly used definition for MH in routine practice is endoscopic MAYO score 95%) of the luminescence of the f metal ion. PMID- 27981326 TI - Ni(ii)-catalyzed asymmetric addition of arylboronic acids to cyclic imines. AB - A Ni(ii)-catalyzed asymmetric addition of arylboronic acids to cyclic aldimines and ketimines is reported. Our tropos phosphine-oxazoline biphenyl ligand is crucial for the high catalytic activity, which coordinates to Ni(ii) to form a complex with a single axial configuration. The desired chiral amine products could be prepared with excellent yields (up to 99%) and enantioselectivities (up to 99.8%) under mild reaction conditions. PMID- 27981327 TI - Lithium and boron as interstitial palladium dopants for catalytic partial hydrogenation of acetylene. AB - It is demonstrated that light elements, including lithium and boron atoms, can take residence in the octahedral (interstitial) site of a Pd lattice by modifying the electronic properties of the metal nanoparticles, and hence the adsorptive strength of a reactant. The blocking of the sub-surface sites to H in the modified materials results in significantly higher selectivity for the partial catalytic hydrogenation of acetylene to ethylene. PMID- 27981328 TI - A hybrid carbocyclic/N-heterocyclic carbene ligand. AB - We report the synthesis and characterisation of the first complex bearing a bidentate carbocyclic/N-heterocyclic carbene ligand, which represents an unprecedented combination of these two carbene classes. Starting from an unsubstituted cycloheptatrienylidene-Pd complex, the ligand was built up in an on site synthesis at the metal center. DFT calculations were employed to understand the crucial allyl-to-alkyl rearrangement of the carbocycle in this sequence and all its binding modes during the reaction cascade were crystallographically characterised. PMID- 27981329 TI - Replacement of quinolines with isoquinolines affords target metal ion switching from Zn2+ to Cd2+ in the fluorescent sensor TQLN (N,N,N',N'-tetrakis(2 quinolylmethyl)-2,6-bis(aminomethyl)pyridine). AB - A quinoline-based heptadentate ligand, N,N,N',N'-tetrakis(2-quinolylmethyl)-2,6 bis(aminomethyl)pyridine (TQLN), exhibits a Zn2+-specific fluorescence increase at 428 nm, which is assigned to excimer emission (IZn/I0 = 38, ICd/IZn = 24%, phiZn = 0.069). In contrast, the isoquinoline counterpart 1-isoTQLN exhibits a Cd2+-specific fluorescence increase at 365 nm attributable to monomer emission (ICd/I0 = 83, IZn/ICd = 19%, phiCd = 0.015). PMID- 27981330 TI - Spectroscopic evidence for origins of size and support effects on selectivity of Cu nanoparticle dehydrogenation catalysts. AB - Selective dehydrogenation catalysts that produce acetaldehyde from bio-derived ethanol can increase the efficiency of subsequent processes such as C-C coupling over metal oxides to produce 1-butanol or 1,3-butadiene or oxidation to acetic acid. Here, we use in situ X-ray absorption spectroscopy and steady state kinetics experiments to identify Cudelta+ at the perimeter of supported Cu clusters as the active site for esterification and Cu0 surface sites as sites for dehydrogenation. Correlation of dehydrogenation and esterification selectivities to in situ measures of Cu oxidation states show that this relationship holds for Cu clusters over a wide-range of diameters (2-35 nm) and catalyst supports and reveals that dehydrogenation selectivities may be controlled by manipulating either. PMID- 27981331 TI - Easy access to triazolinedione-endcapped peptides for chemical ligation. AB - An efficient and easy route towards triazolinedione (TAD) endcapped peptides is described, in which a TAD-precursor was coupled to N-terminal amines on a solid support. Modified peptides readily reacted with diene end-functionalized poly(epsilon-caprolactone) of different molecular weights. The ligation proved to be orthogonal to a variety of functional groups present in natural amino acids. PMID- 27981332 TI - Quasi-solid electrolyte: a thixotropic gel of imogolite and an ionic liquid. AB - We report a quasi-solid electrolyte comprising a transparent thixotropic gel swelled by an ionic liquid that is formed by a framework of single-walled aluminosilicate cylindrical inorganic "imogolite" nanotubes. The quasi-solid electrolyte shows moldability, thermal stability, and high ionic conductivity, and has potential applications in free-moldable conductive and anti-icing coatings, or electrolytes for batteries. PMID- 27981334 TI - NO2-controlled cargo delivery from gated silica mesoporous nanoparticles. AB - Cargo delivery from mesoporous silica nanoparticles loaded with sulforhodamine B and capped with a difluoroboron-dipyrromethene (BODIPY) derivative was triggered by a NO2-induced oxidative process. PMID- 27981333 TI - Enzymatic incorporation and utilization of an emissive 6-azauridine. AB - To display favorable fluorescent properties, the non-emissive native nucleosides need to be modified. Here we present a motif that relies on conjugating 5 membered aromatic heterocycles (e.g., thiophene) to a 6-azapyrimidine (1,2,4 triazine) core. Synthetic accessibility and desirable photophysical properties make these nucleosides attractive candidates for enzymatic incorporation and biochemical assays. While 6-azauridine triphosphate is known to be poorly tolerated by polymerases in RNA synthesis, we illustrate that conjugating a thiophene ring at position 5 overcomes such limitations, facilitating its T7 RNA polymerase-mediated in vitro transcription incorporation into RNA constructs. We further show that the modified transcripts can be ligated to longer oligonucleotides to form singly modified RNAs, as illustrated for an A-site hairpin model RNA construct, which was employed to visualize aminoglycoside antibiotics binding. PMID- 27981335 TI - DNA packaging in viral capsids with peptide arms. AB - Strong chain rigidity and electrostatic self-repulsion of packed double-stranded DNA in viruses require a molecular motor to pull the DNA into the capsid. However, what is the role of electrostatic interactions between different charged components in the packaging process? Though various theories and computer simulation models were developed for the understanding of viral assembly and packaging dynamics of the genome, long-range electrostatic interactions and capsid structure have typically been neglected or oversimplified. By means of molecular dynamics simulations, we explore the effects of electrostatic interactions on the packaging dynamics of DNA based on a coarse-grained DNA and capsid model by explicitly including peptide arms (PAs), linked to the inner surface of the capsid, and counterions. Our results indicate that the electrostatic interactions between PAs, DNA, and counterions have a significant influence on the packaging dynamics. We also find that the packed DNA conformations are largely affected by the structure of the PA layer, but the packaging rate is insensitive to the layer structure. PMID- 27981336 TI - Erratum to: Fractionated vs. single-fraction stereotactic radiotherapy in patients with vestibular schwannoma : Hearing preservation and patients' self reported outcome based on an established questionnaire. PMID- 27981337 TI - Age-related reference curves of volumetric bone density, structure, and biomechanical parameters adjusted for weight and height in a population of healthy women: an HR-pQCT study. AB - : In a cross-sectional cohort of 450 healthy women aged 20 to 85 years, data on the density, structure, and strength of the distal radius and tibia were obtained using high-resolution peripheral quantitative computed tomography (HR-pQCT) and were adjusted for age, weight, and height. Age-dependent patterns of change differed between the sites and between the trabecular and cortical compartments. In postmenopausal women, the trabecular bone remained relatively stable at the distal tibia, but the cortical compartment changed significantly. Cortical porosity exhibited a very weak correlation with stiffness. INTRODUCTION: The aim of this study is to provide information on age-related, weight-related, and height-related changes in the volumetric bone mineral density (vBMD), structure, and biomechanical parameters of the cortical and trabecular compartments in a healthy female population using HR-pQCT. METHODS: For a cross-sectional Brazilian cohort of 450 women aged 20 to 85 years, age-related reference curves of the vBMD, structure, and biomechanical parameters of the distal radius (DR) and distal tibia (DT) were constructed and adjusted for weight and height, and comparisons between premenopausal and postmenopausal women were performed. RESULTS: Reference curves were obtained for all parameters. At the DR, age related changes varied from -8.68% (cortical thickness [Ct.Th]) to 26.7% (trabecular separation [Tb.Sp]). At the DT, the changes varied from -12.4% (Ct.Th) to 26.3% (Tb.Sp). Cortical porosity (Ct.Po) exhibited the largest percent changes: 342.2% at the DR and 381.5% at the DT. In premenopausal women, Ct.Th remained constant; in postmenopausal women, structural trabecular parameters (trabecular number (Tb.N), trabecular thickness (Tb.Th), Tb.Sp) did not change, whereas cortical parameters and stiffness were significantly altered. Cortical vBMD showed the greatest absolute decrease at both sites, and the slopes were highly negative after menopause. Pearson correlations between stiffness (S) and HR-pCT parameters revealed a significant correlation between the densities and structures of the trabecular and cortical compartments. A weak correlation was observed between S and Ct.Po (DR r = -0.162, DT r = -0.273; p < 0.05). CONCLUSIONS: These data provide reference curves from healthy women and demonstrate that density and structural and biomechanical parameters differ between the radius and tibia and between the trabecular and cortical compartments. In postmenopausal women, the trabecular bone remained relatively stable at the tibia site, whereas the cortical compartment changed significantly. PMID- 27981338 TI - Seasonal association between ambient ozone and mortality in Zhengzhou, China. AB - Different seasonal health effects of ambient ozone (O3) have been reported in previous studies. This might be due to inappropriate adjustment of temperature in different seasons. We used daily data on non-accidental mortality and ambient air pollution in Zhengzhou from January 19, 2013 to June 30, 2015. Season-stratified analyses using generalized additive models were conducted to evaluate the seasonal associations with adjustment of temperature with different lagged days (lag0-1 for warm season, lag0-14 for cold season). We recorded a total of 70,443 non-accidental deaths in Zhengzhou during the study period. Significant associations were observed between ambient O3 and mortality in cold season. Every 10-MUg/m3 increment of 24-h O3 of 1-day lagged time was associated with a 1.38% (95% CI 0.60, 2.16%) increase in all cause mortality, 1.35% (95% CI 0.41, 2.30%) increase in cardiovascular mortality, and 1.78% (95% CI 0.43, 3.14%) increase in respiratory mortality. Similar associations were observed when using daily 1- and 8-h maximum concentrations of O3. No significant association was found during warm season. This study suggests a more pronounced ozone-mortality association in cold season in Zhengzhou, and we suggest that different lagged temperatures should be considered when examining the seasonal health effects of ambient ozone. PMID- 27981340 TI - A sensitive aptasensor based on molybdenum carbide nanotubes and label-free aptamer for detection of bisphenol A. AB - To specifically and sensitively identify bisphenol A (BPA) with a simple and rapid method is very important for food safety. Using an anti-BPA aptamer and Mo2C nanotubes, we developed a label-free and low-background signal biosensor for BPA detection. The anti-BPA aptamer drastically increased the fluorescence signal of N-methylmesoporphyrin IX under an assistance of Help-DNA. Additionally, BPA can interact with the anti-BPA aptamer and switch its conformation to prevent the formation of a G-quadruplex, resulting in fluorescence quenching. Simultaneously, Mo2C nanotubes can reduce the background signals due to the adsorption of Help DNA on their surface. This method shows a linear range of 2-20 nM with a detection limit of 2 nM for detecting BPA. This label-free BPA aptasensor with low background signal is inexpensive, easy to use, and can be applied to determine BPA in real water samples. Graphical Abstract A low-background and label-free biosensor was designed based on Mo2C nanotubes and aptamer for BPA detection. PMID- 27981339 TI - Climate change, heat, and mortality in the tropical urban area of San Juan, Puerto Rico. AB - Extreme heat episodes are becoming more common worldwide, including in tropical areas of Australia, India, and Puerto Rico. Higher frequency, duration, and intensity of extreme heat episodes are triggering public health issues in most mid-latitude and continental cities. With urbanization, land use and land cover have affected local climate directly and indirectly encouraging the Urban Heat Island effect with potential impacts on heat-related morbidity and mortality among urban populations. However, this association is not completely understood in tropical islands such as Puerto Rico. The present study examines the effects of heat in two municipalities (San Juan and Bayamon) within the San Juan metropolitan area on overall and cause-specific mortality among the population between 2009 and 2013. The number of daily deaths attributed to selected causes (cardiovascular disease, hypertension, diabetes, stroke, chronic lower respiratory disease, pneumonia, and kidney disease) coded and classified according to the Tenth Revision of the International Classification of Diseases was analyzed. The relations between elevated air surface temperatures on cause specific mortality were modeled. Separate Poisson regression models were fitted to explain the total number of deaths as a function of daily maximum and minimum temperatures, while adjusting for seasonal patterns. Results show a significant increase in the effect of high temperatures on mortality, during the summers of 2012 and 2013. Stroke (relative risk = 16.80, 95% CI 6.81-41.4) and cardiovascular diseases (relative risk = 16.63, 95% CI 10.47-26.42) were the primary causes of death most associated with elevated summer temperatures. Better understanding of how these heat events affect the health of the population will provide a useful tool for decision makers to address and mitigate the effects of the increasing temperatures on public health. The enhanced temperature forecast may be a crucial component in decision making during the National Weather Service Heat Watches, Advisories, and Warning process. PMID- 27981341 TI - A sensitive LC-MS/MS method for the quantification of regioisomers of epoxyeicosatrienoic and dihydroxyeicosatrienoic acids in human plasma during endothelial stimulation. AB - Epoxyeicosatrienoic acids (EETs) are vasodilating lipid mediators metabolized into dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase. We aimed to develop a LC-MS/MS method to quantify EETs and DHETs in human plasma and monitored their levels during vascular endothelial stimulation. Plasma samples, collected from 14 healthy and five hypertensive subjects at baseline and during radial artery endothelium-dependent flow-mediated dilatation, were spiked with internal standards. Lipids were then extracted by a modified Bligh and Dyer method and saponified to release bound EETs and DHETs. Samples were purified by a second liquid-liquid extraction and analyzed by LC-MS/MS. The assay allowed identification of (+/-)8(9)-epoxy-5Z,11Z,14Z-eicosatrienoic acid (8,9-EET); (+/ )11(12)-epoxy-5Z,8Z,14Z-eicosatrienoic acid (11,12-EET); (+/-)14(15)-epoxy 5Z,8Z,11Z-eicosatrienoic acid (14,15-EET); (+/-)8,9-dihydroxy-5Z,11Z,14Z eicosatrienoic acid (8,9-DHET); (+/-)11,12-dihydroxy-5Z,8Z,14Z-eicosatrienoic acid (11,12-DHET); and (+/-)14,15-dihydroxy-5Z,8Z,11Z-eicosatrienoic acid (14,15 DHET). (+/-)5(6)-epoxy-5Z,11Z,14Z-eicosatrienoic acid (5,6-EET) was virtually undetectable due to its chemical instability. The limits of quantification were 0.25 ng/mL for DHETs and 0.5 ng/mL for EETs. Intra- and inter-assay variations ranged from 1.6 to 13.2%. Heating induced a similar increase in 8,9-EET, 11,12 EET, and 14,15-EET levels and in corresponding DHET levels in healthy but not in hypertensive subjects. We validated a sensitive LC-MS/MS method for measuring simultaneously plasma EET and DHET regioisomers in human plasma and showed its interest for assessing endothelial function. PMID- 27981342 TI - Electrosteric stabilization of colloidal TiO2 nanoparticles with DNA and polyethylene glycol for selective enhancement of UV detection sensitivity in capillary electrophoresis analysis. AB - A new approach to selectively enhance the ultraviolet (UV) detection sensitivity of titania (TiO2), albeit in the presence of silica (SiO2), alumina (Al2O3), and zinc oxide (ZnO), nanoparticles in capillary electrophoresis (CE) analysis was developed. Interactions of Triton X-100 (TX-100), polyethylene glycol (PEG), and deoxyribonucleic acid (DNA) with TiO2 nanoparticles produced larger CE-UV peaks at various enhancement factors. Single-stranded DNA (ssDNA) was a more effective adsorbate than double-stranded DNA (dsDNA) due to its flexible molecular structure that participated in a stronger interaction with TiO2 nanoparticles via its sugar-phosphate backbone. Disaggregation of TiO2 nanoparticles upon DNA binding due to electrosteric stabilization was validated using dynamic light scattering. PEG coating of TiO2-DNA nanoparticles further enhanced the UV detection sensitivity in CE analysis by providing extra electrosteric stabilization. This analytical technique, which involves binding of TiO2 nanoparticles with DNA followed by coating with PEG, has allowed us to achieve progressively an enhancement factor up to 13.0 +/- 3.0 - fold in analytical sensitivity for the accurate determination of disaggregated TiO2 nanoparticles. Graphical Abstract Selective enhancement of UV detection sensitivity for TiO2 nanoparticles via electrosteric stabilization using ssDNA and PEG. PMID- 27981343 TI - Evaluation of a commercial electro-kinetically pumped sheath-flow nanospray interface coupled to an automated capillary zone electrophoresis system. AB - Capillary zone electrophoresis-electrospray ionization-mass spectrometry (CZE-ESI MS) is attracting renewed attention for proteomic and metabolomic analysis. An important reason for this interest is the maturation and commercialization of interfaces for coupling CZE with ESI-MS. One of these interfaces is an electro kinetically pumped sheath flow nanospray interface developed by the Dovichi group, in which a very low sheath flow is generated based on electroosmosis within a glass emitter. CMP Scientific has commercialized this interface as the EMASS-II ion source. In this work, we compared the performance of the EMASS-II ion source with our in-house system. The performance of the systems is equivalent. We also coupled the EMASS-II ion source with a PrinCE Next|480 capillary electrophoresis autosampler and an Orbitrap mass spectrometer, and analyzed this system's performance in terms of sensitivity, reproducibility, and separation performance for separation of tryptic digests, intact proteins, and amino acids. The system produced reproducible analysis of BSA digest; the RSDs of peptide intensity and migration time across 24 runs were less than 20 and 6%, respectively. The system produced a linear calibration curve of intensity across a 30-fold range of tryptic digest concentration. The combination of a commercial autosampler and electrospray interface efficiently separated amino acids, peptides, and intact proteins, and only required 5 MUL of sample for analysis. Graphical Abstract The commercial and locally constructed versions of the interface provide similar numbers of protein identifications from a Xenopus laevis fertilized egg digest. PMID- 27981345 TI - A systematic review of lessons learned from PET molecular imaging research in atypical parkinsonism. PMID- 27981344 TI - [Characteristics of elective hip replacement in the elderly]. AB - Due to demographic changes the number of elderly patients undergoing hip replacement surgery is increasing. In order to ensure safe treatment of elderly patients, age-specific medical factors must be taken into consideration. This article presents an overview of these factors. Furthermore, we evaluated our own patients treated between 2010 and 2015 regarding age-related treatment strategies and complication rates. Out of 3166 patients a total of 439 were over 80 years old (average age 84 years). It can be concluded from the scientific literature and from own data that elective hip replacement surgery in elderly patients is a technically safe procedure; however, the risk profile of each patient must be thoroughly analyzed so that in the event of even minor signs of potential complications countermeasures can be taken in good time. PMID- 27981348 TI - [Secondary prophylaxis after fractures is deficient]. PMID- 27981346 TI - Altered expression of apoptosis-regulating miRNAs in salivary gland tumors suggests their involvement in salivary gland tumorigenesis. AB - Salivary gland tumors comprise a heterogeneous group of lesions with different histological features and diverse clinical pathophysiology. They account for about 3% of all head and neck tumors. Apoptosis plays an important role during morphogenesis of glandular structures, including that of the salivary gland. Recent studies have demonstrated that several microRNAs (miRNAs) are involved in the control of apoptosis. The aim of the present study was to determine the expression of apoptosis-related miRNAs (miR-15a, miR-16, miR-17-5p, miR-20a, miR 21, miR-29, and miR-34) and their target mRNAs in 25 pleomorphic adenomas, 23 mucoepidermoid carcinomas, and 10 non-neoplastic salivary gland samples by real time RT-PCR. We observed upregulation of miR-15a, miR-16, miR-17-5p, miR-21, miR 29, and miR-34a in pleomorphic adenomas. The expression of miR-21 and miR-34a was upregulated in 91 and 74% of mucoepidermoid carcinomas, respectively. Downregulation of miR-20a was observed in 75% of pleomorphic adenomas and in 57% of mucoepidermoid carcinomas. APAF1, BAX, BCL2, BID, CASP2, CASP8, DIABLO , and TP53 transcripts were upregulated in both tumor types. BAD transcripts were upregulated in pleomorphic adenomas. CASP3 and CASP6 transcripts were upregulated in mucoepidermoid carcinomas. BCL2, CASP2, CASP6, and CASP8 proteins were mostly absent in mucoepidermoid carcinomas but expressed in few cells in pleomorphic adenomas. Our study provides evidence of alterations in the expression of apoptosis-regulating miRNAs in salivary gland tumors, suggesting possible involvement of these microRNAs in salivary gland tumorigenesis. PMID- 27981347 TI - Bacterial community structure within an activated sludge reactor added with phenolic compounds. AB - Biodegradation of phenolic compounds in bioreactors is well documented, but the changes in the bacterial populations dynamics during degradation were not that often. A glass bubble column used as reactor was inoculated with activated sludge, spiked with 2-chlorophenol, phenol and m-cresol after 28 days and maintained for an additional 56 days, while the 16S rRNA gene from metagenomic DNA was monitored. Proteobacteria (68.1%) dominated the inoculum, but the bacterial composition changed rapidly. The relative abundance of Bacteroidetes and Firmicutes decreased from 4.8 and 9.4 to <0.1 and 0.2% respectively, while that of Actinobacteria and TM7 increased from 4.8 and 2.0 to 19.2 and 16.1% respectively. Phenol application increased the relative abundance of Proteobacteria to 94.2% (mostly Brevundimonas 17.6%), while that of Bacteroidetes remained low (1.2%) until day 42. It then increased to 47.3% (mostly Leadbetterella 46.9%) at day 84. It was found that addition of phenolic compounds did not affect the relative abundance of the Alphaproteobacteria initially, but it decreased slowly while that of the Bacteroidetes increased towards the end. PMID- 27981349 TI - The influence of piperine on the pharmacokinetics of fexofenadine, a P glycoprotein substrate, in healthy volunteers. AB - PURPOSE: Piperine (PIP) has been found to inhibit P-glycoprotein (P-gp) function in rats, suggesting that it may have the potential to modulate P-gp-mediated drug efflux in humans. The aim of this study was to evaluate the effect of PIP on the pharmacokinetics of fexofenadine (FEX), a P-gp substrate, in healthy volunteers. METHODS: An open-label, two-period, sequential study involving 12 healthy volunteers was conducted. A single oral dose of FEX 120 mg was given to volunteers during the control phase and after the treatment phase. A once-daily oral dose of PIP 20 mg was given to volunteers during the treatment phase (10 days). Blood samples were collected at predefined time intervals, and plasma samples containing FEX were analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: Treatment with PIP significantly increased maximum plasma concentration of FEX [406.9 (control) vs. 767 ng/mL (treatment)] and area under the plasma concentration-time curve [3403.7 (control) vs. 5724.7 ng.h/mL (treatment)] when compared to the control phase. In contrast, PIP treatment significantly decreased apparent oral clearance of FEX [35.4 (control) vs. 20.7 L/h (treatment)] as compared to the control. There was no significant change observed in the half life and renal clearance of FEX between the treatment phase and control phase. CONCLUSIONS: The results suggest that altered pharmacokinetics and enhanced bioavailability of FEX might be attributed to PIP-mediated inhibition of P-gp drug efflux. Therefore, intake of PIP or dietary supplements containing PIP may potentially enhance the absorption or bioavailability of P-gp substrate drugs in addition to FEX. PMID- 27981351 TI - Superficial siderosis syndrome with progressive hearing loss and bilateral vestibular failure, 51 years after a neurosurgical procedure: diagnostic value of combined MRI and video head impulse test. PMID- 27981350 TI - The role of bone resorption in the etiopathogenesis of acquired middle ear cholesteatoma. AB - Cholesteatoma is a destructive squamous epithelial lesion of the temporal bone which gradually expands and leads to serious complications by destruction of nearby bony structures. Erosion caused by bone resorption of the ossicular chain and bony labyrinth may result in hearing loss, vestibular dysfunction, facial paralysis, labyrinthine fistulae and intracranial complications. The exact underlying cellular and molecular mechanism of bone resorption in acquired cholesteatoma still remains unexplained. Pubmed database and China National Knowledge Infrastructure were screened for articles focusing on bone resorption in acquired cholesteatoma. Osteoclast activation, pressure necrosis, acid lysis, enzyme mediation, inflammatory mediators and several newly discovered biomolecules are outlined as main theories behind bone resorption in acquired cholesteatoma, aiming to facilitate the development of potential therapeutic targets for preventing intracranial and extracranial complications caused by bone resorption in acquired middle ear cholesteatoma. PMID- 27981353 TI - Adolescents with a smartphone sleep less than their peers. AB - : Many studies have shown that the use of electronic media is related to sleep disturbance, but few have examined the impact of smartphones. The objective of this study was to assess longitudinally whether acquiring a smartphone had an effect on adolescents' sleeping duration. The study included 591 adolescents observed at baseline (T0, Spring 2012; mean age 14.3 years, 288 females) and 2 years later (T1). They were divided into owners (those owning a smartphone at T0 and T1; N = 383), new owners (those owning a smartphone at T1 but not at T0; N = 153), and non-owners (those not owning a smartphone at any time-point; N = 55). Groups were compared on sleep duration, sleep problems, and sociodemographic variables. Overall, all three groups decreased their sleeping time between T0 and T1. At T0, owners of a smartphone were found to sleep significantly less than non owners and new-owners, especially on school days, and to report significantly more sleeping problems. At T1, new-owners and owners showed no differences on sleep duration or sleeping problems. CONCLUSION: The results emphasize that owning a smartphone tends to entail sleep disturbance. Therefore, adolescents and parents should be informed about the potential consequences of smartphone use on sleep and health. What is Known: * The use of electronic media plays an important role in the life of adolescents. * Smartphone use is increasing among young people and allows them to be connected almost anytime anywhere. What is New : * Adolescents owning a smartphone sleep less hours on school days than their peers. * Smartphones seem to have an important impact on youths' sleep duration. PMID- 27981354 TI - An Assessment of Long-Term Compliance with Performance Standards in Compensatory Mitigation Wetlands. AB - Under the US Clean Water Act, wetland restoration is used to compensate for adverse impacts to wetlands. Following construction, compensation wetlands are monitored for approximately 5 years to determine if they comply with project specific performance standards. Once a compensation site complies with performance standards, it is assumed that the site will continue to meet standards indefinitely. However, there have been few assessments of long-term compliance. We surveyed, in 2012, 30 compensation sites 8-20 years after restoration to determine whether projects continued to meet performance standards. Additionally, we compared floristic quality of compensation sites to the quality of adjacent natural wetlands to determine whether wetland condition in compensation sites could be predicted based on the condition of nearby wetlands. Compensation sites met, on average, 65% of standards during the final year of monitoring and 53% of standards in 2012, a significant decrease in compliance. Although forested wetlands often failed to meet standards for planted tree survival, the temporal decrease in compliance was driven by increasing dominance by invasive plants in emergent wetlands. The presumption of continued compliance with performance standards after a 5-year monitoring period was not supported. Wetlands restored near better quality natural wetlands achieved and maintained greater floristic quality, suggesting that landscape context was an important determinant of long-term restoration outcomes. Based on our findings, we recommend that compensation wetlands should be monitored for longer time periods, and we suggest that nearby or adjacent natural wetlands provide good examples of reasonably achievable restoration outcomes in a particular landscape. PMID- 27981355 TI - Probabilistic Evaluation of Ecological and Economic Objectives of River Basin Management Reveals a Potential Flaw in the Goal Setting of the EU Water Framework Directive. AB - The biological status of European lakes has not improved as expected despite up to-date legislation and ecological standards. As a result, the realism of objectives and the attainment of related ecological standards are under doubt. This paper gets to the bottom of a river basin management plan of a eutrophic lake in Finland and presents the ecological and economic impacts of environmental and societal drivers and planned management measures. For these purposes, we performed a Monte Carlo simulation of a diffuse nutrient load, lake water quality and cost-benefit models. Simulations were integrated into a Bayesian influence diagram that revealed the basic uncertainties. It turned out that the attainment of good ecological status as qualified in the Water Framework Directive of the European Union is unlikely within given socio-economic constraints. Therefore, management objectives and ecological and economic standards need to be reassessed and reset to provide a realistic goal setting for management. More effort should be put into the evaluation of the total monetary benefits and on the monitoring of lake phosphorus balances to reduce the uncertainties, and the resulting margin of safety and costs and risks of planned management measures. PMID- 27981352 TI - The clinical heterogeneity of drug-induced myoclonus: an illustrated review. AB - A wide variety of drugs can cause myoclonus. To illustrate this, we first discuss two personally observed cases, one presenting with generalized, but facial predominant, myoclonus that was induced by amantadine; and the other presenting with propriospinal myoclonus triggered by an antibiotic. We then review the literature on drugs that may cause myoclonus, extracting the corresponding clinical phenotype and suggested underlying pathophysiology. The most frequently reported classes of drugs causing myoclonus include opiates, antidepressants, antipsychotics, and antibiotics. The distribution of myoclonus ranges from focal to generalized, even amongst patients using the same drug, which suggests various neuro-anatomical generators. Possible underlying pathophysiological alterations involve serotonin, dopamine, GABA, and glutamate-related processes at various levels of the neuraxis. The high number of cases of drug-induced myoclonus, together with their reported heterogeneous clinical characteristics, underscores the importance of considering drugs as a possible cause of myoclonus, regardless of its clinical characteristics. PMID- 27981357 TI - Overexpression of protein kinase STK25 in mice exacerbates ectopic lipid accumulation, mitochondrial dysfunction and insulin resistance in skeletal muscle. AB - AIMS/HYPOTHESIS: Understanding the molecular networks controlling ectopic lipid deposition and insulin responsiveness in skeletal muscle is essential for developing new strategies to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a critical regulator of liver steatosis, hepatic lipid metabolism and whole body glucose and insulin homeostasis. Here, we assessed the role of STK25 in control of ectopic fat storage and insulin responsiveness in skeletal muscle. METHODS: Skeletal muscle morphology was studied by histological examination, exercise performance and insulin sensitivity were assessed by treadmill running and euglycaemic hyperinsulinaemic clamp, respectively, and muscle lipid metabolism was analysed by ex vivo assays in Stk25 transgenic and wild-type mice fed a high-fat diet. Lipid accumulation and mitochondrial function were also studied in rodent myoblasts overexpressing STK25. Global quantitative phosphoproteomics was performed in skeletal muscle of Stk25 transgenic and wild-type mice fed a high fat diet to identify potential downstream mediators of STK25 action. RESULTS: We found that overexpression of STK25 in transgenic mice fed a high-fat diet increases intramyocellular lipid accumulation, impairs skeletal muscle mitochondrial function and sarcomeric ultrastructure, and induces perimysial and endomysial fibrosis, thereby reducing endurance exercise capacity and muscle insulin sensitivity. Furthermore, we observed enhanced lipid accumulation and impaired mitochondrial function in rodent myoblasts overexpressing STK25, demonstrating an autonomous action for STK25 within cells. Global phosphoproteomic analysis revealed alterations in the total abundance and phosphorylation status of different target proteins located predominantly to mitochondria and sarcomeric contractile elements in Stk25 transgenic vs wild-type muscle, respectively, providing a possible molecular mechanism for the observed phenotype. CONCLUSIONS/INTERPRETATION: STK25 emerges as a new regulator of the complex interplay between lipid storage, mitochondrial energetics and insulin action in skeletal muscle, highlighting the potential of STK25 antagonists for type 2 diabetes treatment. PMID- 27981359 TI - Evaluation of the ossification of the medial clavicle according to the Kellinghaus substage system in identifying the 18-year-old age limit in the estimation of forensic age-is it necessary? AB - The evaluation of the ossification of the medial clavicular epiphysis being part of an assigned expert approach according to standard plays an important role within civil and criminal proceedings in assessing whether a person has reached her/his 19th or 22nd year of age. Evaluation of the medial clavicular epiphysis with thin-section CT is one of the methods recommended by the Study Group on Forensic Age Diagnostics of the German Association of Forensic Medicine. In this retrospective study, we evaluated the thin-section CT (section thickness of 0.6 and 1 mm) images of 254 patients (146 male, 108 female) with an age range of 13 28 years according to the Kellinghaus substage system. The mean values of female patients were observed to be about 10 months lower for stage 2a than the mean values of the male patients, about 13 months lower for stage 2b, and about 18 months lower for stage 2c. The earliest appearance for stage 3c was at 19 years in both sexes. Our data from this study were consistent with both our previous studies and the data of other studies. We think that stage 3c is important in determining whether a person has reached the age of 18 or not and, therefore, that the Kellinghaus substage system is a requirement in the assessment of forensic age. PMID- 27981360 TI - Erratum to: 3D genomics imposes evolution of the domain model of eukaryotic genome organization. PMID- 27981358 TI - Associations of maternal BMI and insulin resistance with the maternal metabolome and newborn outcomes. AB - AIMS/HYPOTHESIS: Maternal obesity increases the risk for large-for-gestational age birth and excess newborn adiposity, which are associated with adverse long term metabolic outcomes in offspring, probably due to effects mediated through the intrauterine environment. We aimed to characterise the maternal metabolic milieu associated with maternal BMI and its relationship to newborn birthweight and adiposity. METHODS: Fasting and 1 h serum samples were collected from 400 European-ancestry mothers in the Hyperglycaemia and Adverse Pregnancy Outcome Study who underwent an OGTT at ~28 weeks gestation and whose offspring had anthropometric measurements at birth. Metabolomics assays were performed using biochemical analyses of conventional clinical metabolites, targeted MS-based measurement of amino acids and acylcarnitines and non-targeted GC/MS. RESULTS: Per-metabolite analyses demonstrated broad associations with maternal BMI at fasting and 1 h for lipids, amino acids and their metabolites together with carbohydrates and organic acids. Similar metabolite classes were associated with insulin resistance with unique associations including branched-chain amino acids. Pathway analyses indicated overlapping and unique associations with maternal BMI and insulin resistance. Network analyses demonstrated collective associations of maternal metabolite subnetworks with maternal BMI and newborn size and adiposity, including communities of acylcarnitines, lipids and related metabolites, and carbohydrates and organic acids. Random forest analyses demonstrated contribution of lipids and lipid-related metabolites to the association of maternal BMI with newborn outcomes. CONCLUSIONS/INTERPRETATION: Higher maternal BMI and insulin resistance are associated with broad-based changes in maternal metabolites, with lipids and lipid-related metabolites accounting, in part, for the association of maternal BMI with newborn size at birth. PMID- 27981361 TI - Utility of cardiac CT for evaluating delayed contrast enhancement in dilated cardiomyopathy. AB - BACKGROUND: The presence of myocardial fibrosis is associated with adverse outcome in dilated cardiomyopathy (DCM). Delayed contrast-enhanced cardiac magnetic resonance (DE-CMR) currently represents the gold standard in noninvasive evaluation of myocardial scarring. However, a significant number of patients are unable to undergo DE-CMR study for various reasons. We sought to determine the diagnostic accuracy of cardiac CT (CCT) compared with CMR in the investigation of the presence of delayed contrast enhancement (DCE) in subjects with DCM. METHODS: We prospectively enrolled 17 consecutive patients with DCM, who were initially referred to our institution because of recently manifested heart failure due to unexplained left ventricular systolic dysfunction. In all subjects, CCT and DE CMR were performed within 1 week. RESULTS: CCT and DE-CMR showed satisfactory agreement in detecting DCE (agreement in 82% cases, kappa = 0.56) with 50% sensitivity, 100% specificity, and a positive predictive value of 100%. CONCLUSION: CCT may be a valuable method for detecting DCE in patients with DCM. CCT thus might be considered as an alternative method to DE-CMR in the assessment of the presence and extent of myocardial fibrosis in subjects who are not suitable for DE-CMR examination. PMID- 27981356 TI - Chronomedicine and type 2 diabetes: shining some light on melatonin. AB - In mammals, the circadian timing system drives rhythms of physiology and behaviour, including the daily rhythms of feeding and activity. The timing system coordinates temporal variation in the biochemical landscape with changes in nutrient intake in order to optimise energy balance and maintain metabolic homeostasis. Circadian disruption (e.g. as a result of shift work or jet lag) can disturb this continuity and increase the risk of cardiometabolic disease. Obesity and metabolic disease can also disturb the timing and amplitude of the clock in multiple organ systems, further exacerbating disease progression. As our understanding of the synergy between the timing system and metabolism has grown, an interest has emerged in the development of novel clock-targeting pharmaceuticals or nutraceuticals for the treatment of metabolic dysfunction. Recently, the pineal hormone melatonin has received some attention as a potential chronotherapeutic drug for metabolic disease. Melatonin is well known for its sleep-promoting effects and putative activity as a chronobiotic drug, stimulating coordination of biochemical oscillations through targeting the internal timing system. Melatonin affects the insulin secretory activity of the pancreatic beta cell, hepatic glucose metabolism and insulin sensitivity. Individuals with type 2 diabetes mellitus have lower night-time serum melatonin levels and increased risk of comorbid sleep disturbances compared with healthy individuals. Further, reduced melatonin levels, and mutations and/or genetic polymorphisms of the melatonin receptors are associated with an increased risk of developing type 2 diabetes. Herein we review our understanding of molecular clock control of glucose homeostasis, detail the influence of circadian disruption on glucose metabolism in critical peripheral tissues, explore the contribution of melatonin signalling to the aetiology of type 2 diabetes, and discuss the pros and cons of melatonin chronopharmacotherapy in disease management. PMID- 27981362 TI - Oxidative stress and Syntax score. PMID- 27981363 TI - miR-539 as a key negative regulator of the MEK pathway in myocardial infarction. AB - BACKGROUND: Myocardial infarction is one of the most common causes of death, and the number of individuals at risk is increasing. A rapid and accurate differential diagnosis of myocardial infarction is crucial for timely interventions and for improvement of the prognosis. However, it is difficult to achieve using current methods. To better manage this condition, improved tools for risk prediction, including more accurate biomarkers, are needed. METHODS: We studied the expression of microRNA-539 (miR-539) and of MEK protein using a rat model of myocardial infarction. RESULTS: The results of our experiments demonstrated an increase in the expression of miR-539 and a decrease in the expression of MEK. Furthermore, we observed that miR-539 inhibited the expression of MEK through targeting of the 3'UTR of MEK; this led not only to suppressed proliferation but also to apoptosis and autophagy of H9C2 cells. CONCLUSION: Overexpression of miR-539 plays a role in the degree of myocardial infarction. On the basis of our results, we conclude that miR-539 may be a potential therapeutic target for myocardial infarction. PMID- 27981364 TI - Synergistic interplay of Gbetagamma and phosphatidylinositol 4,5-bisphosphate dictates Kv7.4 channel activity. AB - Kv7.4 channels are key determinants of arterial contractility and cochlear mechanosensation that, like all Kv7 channels, have an obligatory requirement for phosphatidylinositol 4,5-bisphosphate (PIP2). betagamma G proteins (Gbetagamma) have been identified as novel positive regulators of Kv7.4. The present study ascertained whether Gbetagamma increased Kv7.4 open probability through an increased sensitivity to PIP2. In HEK cells stably expressing Kv7.4, PIP2 or Gbetagamma increased open probability in a concentration dependent manner. Depleting PIP2 prevented any Gbetagamma-mediated stimulation whilst an array of Gbetagamma inhibitors prohibited any PIP2-induced current enhancement. A combination of PIP2 and Gbetagamma at sub-efficacious concentrations increased channel open probability considerably. The stimulatory effects of three Kv7.2-7.5 channel activators were also lost by PIP2 depletion or Gbetagamma inhibitors. This study alters substantially our understanding of the fundamental processes that dictate Kv7.4 activity, revealing a more complex and subtle paradigm where the reliance on local phosphoinositide is dictated by interaction with Gbetagamma. PMID- 27981365 TI - Association of worry about cancer to benefit finding and functioning in long-term cancer survivors. AB - PURPOSE: Worry about cancer recurrence or progression is associated with negative effects of cancer, such as worse physical functioning, but associations with positive changes post-cancer, such as benefit finding, are unknown. We measured the proportion of patients reporting frequent worry about cancer recurrence or progression and examined the association between worry about cancer recurrence or progression to benefit finding and functioning in cancer. METHODS: We surveyed 594 long-term (5-10 years post-diagnosis) survivors of cancer (breast, prostate, colorectal, lung, melanoma) in this cross-sectional study. The survey asked about worry about cancer recurrence/progression, negative effects of cancer on mental and physical function, and benefit finding as a result of the cancer (positive effects). Multivariate regressions estimated associations of worry about cancer with negative and positive effects of cancer. RESULTS: Worrying about cancer often or all the time was reported by 19.6% of survivors. Worry about cancer was related to worse functioning (odds ratio (OR) range 1.40 to 1.46, all p's < .01). Worry about recurrence/progression was unrelated to benefit finding (all p's > .10). CONCLUSIONS: Worry about cancer was associated with negative, but not positive, effects of cancer. Treating worry about cancer is unlikely to reduce benefit finding after cancer. Given the high prevalence of worry about cancer and relationship to negative effects of cancer, clinical care should attempt to address this worry for long-term survivors. PMID- 27981366 TI - A prospective exploration of symptom burden clusters in women with breast cancer during chemotherapy treatment. AB - PURPOSE: The aim was to prospectively map symptom clusters in patients with stage I-IIIa breast cancer during standard chemotherapy treatment in a randomised study. METHODS: Participants completed the Memorial Symptom Assessment Scale (MSAS) at baseline, day 12 after the first and third cycle of FEC 75 or FEC 100, and day 12 after the last cycle of Taxotere. Cut-off values for symptom scores, a mean value based on each individual reporting a symptom including occurrence, frequency, severity and distress for inclusion in analysis, were determined. RESULTS: The symptom burden cluster analysis was conducted in two steps and included symptoms with high frequency and high levels of distress. The factor analysis revealed three symptom clusters; physical, gastro (phys/gastro) and emotional, with core symptoms that remained stable over time. The most prevalent symptoms for the total sample during all cycles were as follows: lack of energy (range between 48 and 90%), feeling sad (48-79%), difficulty sleeping (54-78%), difficulty concentrating (53-74%), worrying (54-74%) and pain (29-67%). CONCLUSION: In summary, we have prospectively established that symptom clusters remain stable over time with a basis of core symptoms. This knowledge will aid in the development of effective core symptom-focused interventions to minimise symptom burden for patients treated with chemotherapy for breast cancer. PMID- 27981367 TI - [Cardiac causes of chest pain]. AB - Because of the life-threatening character and a high prevalence in emergency rooms, cardiac causes are important differential diagnoses of acute chest pain with the need for rapid clarification. In this context the working diagnosis "acute coronary syndrome" (ACS) plays a major role. In a synopsis of the clinical presentation, medical history, electrocardiogram and analysis of cardiac biomarkers, ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina pectoris can be specified as entities of ACS. The treatment of ACS consists of an immediate anti ischemic therapy, anti-thrombotic therapy and invasive coronary diagnostics with subsequent interventional or operative revascularization therapy. The timing of invasive management is essentially determined by the individual patient risk, with the exception of STEMI where interventional revascularization must be undertaken within 120 min of diagnosis. In this context the GRACE 2.0 and TIMI risk score have become established as reliable tools. Another rare but fatal cause of acute chest pain is aortic dissection. An abrupt onset of tearing and sharp chest pains, deficits in pulse as well as the presence of high-risk factors, such as advanced age, arterial hypertension, atherosclerosis, known collagenosis and previous aortic or coronary artery procedures are highly indicative for aortic dissection and additional diagnostic imaging and the highly sensitive D-dimer should be undertaken. Additionally, inflammatory diseases, such as pericarditis and myocarditis can be associated with chest pains and mimic the character of ACS and should also be considered in the differential diagnostics. PMID- 27981369 TI - [The interdisciplinary concept of perineal rectocele correction]. PMID- 27981368 TI - Diet and environment 1.2 million years ago revealed through analysis of dental calculus from Europe's oldest hominin at Sima del Elefante, Spain. AB - Sima del Elefante, Atapuerca, Spain contains one of the earliest hominin fragments yet known in Europe, dating to 1.2 Ma. Dental calculus from a hominin molar was removed, degraded and analysed to recover entrapped remains. Evidence for plant use at this time is very limited and this study has revealed the earliest direct evidence for foods consumed in the genus Homo. This comprises starchy carbohydrates from two plants, including a species of grass from the Triticeae or Bromideae tribe, meat and plant fibres. All food was eaten raw, and there is no evidence for processing of the starch granules which are intact and undamaged. Additional biographical detail includes fragments of non-edible wood found adjacent to an interproximal groove suggesting oral hygiene activities, while plant fibres may be linked to raw material processing. Environmental evidence comprises spores, insect fragments and conifer pollen grains which are consistent with a forested environment. PMID- 27981371 TI - [Inflammatory markers in the identification of septic complications in colorectal surgery : Results of the IMACORS study]. PMID- 27981370 TI - [First report of urinary endoscopic vacuum therapy : For large bladder defect after abdomino-perineal excision of the rectum. Video paper. German version]. AB - PURPOSE: The technique of active urinary endoscopic vacuum therapy (uEVT) is described. The surgical technique is demonstrated in detail with the help of a video of the operation and which is available online. Vesical fistulas are a rare complication following rectal surgery. The EVT technique is a novel method for treatment of gastrointestinal leakage. This endoscopic procedure has been adapted to treat a large bladder defect after abdominoperineal resection of the rectum with urine flowing out of the perineal wound. MATERIAL AND METHOD: A new open pore film drainage (OFD) catheter with an external diameter of only a few millimeters has been developed and is constructed from a very thin open-pore double-layered film and a drainage tube. The OFD was inserted into the bladder by means of flexible endoscopy and channeled out through a suprapubic incision. Continuous suction was applied with an electronic vacuum pump to actively drain the urine completely. A passive catheter drainage of urine from the renal pelvis via transurethral single J stent was carried out simultaneously during the complete duration of treatment. The healing process was monitored during and after therapy by intravesical endoscopy. RESULTS: The application of continuous negative pressure via the OFD resulted in total collapse of the bladder. The urine in the bladder was actively and permanently drained through the OFD. Urine leakage from the perineal wound stopped immediately after induction of suction. After 18 days of treatment with the uEVT the bladder defect was healed. After therapy and removal of the catheters the patient had normal micturition. CONCLUSION: A novel small-bore OFD has been developed for EVT. The OFD technique now allows endoscopic application of negative pressure in the bladder. This first successful experience proves uEVT to be a potent interventional alternative in the treatment of bladder defects. PMID- 27981372 TI - First report of urinary endoscopic vacuum therapy : For large bladder defect after abdomino-perineal excision of the rectum. Video paper. AB - PURPOSE: The technique of active urinary endoscopic vacuum therapy (uEVT) is described. The surgical technique is demonstrated in detail with the help of a video of the operation, which is available online. Vesical fistulas are a rare complication following rectal surgery. The EVT technique is a novel method for the treatment of gastrointestinal leakage. This endoscopic procedure has been adapted to treat a large bladder defect after abdomino-perineal resection of the rectum with urine flowing out of the perineal wound. MATERIALS AND METHODS: A new open-pore film drainage (OFD) catheter with an external diameter of only a few millimeters was developed and constructed from a very thin open-pore double layered film and a drainage tube. The OFD was inserted into the bladder by means of flexible endoscopy and channeled out through a suprapubic incision. Continuous suction was applied with an electronic vacuum pump to actively drain the urine completely. A passive catheter drainage of urine from the renal pelvis via a transurethral single J stent was carried out simultaneously during the complete duration of treatment. The healing process was monitored during and after therapy via intravesical endoscopy. RESULTS: The application of continuous negative pressure via the OFD resulted in total collapse of the bladder. The urine in the bladder was actively and permanently drained through the OFD. Urine leakage from the perineal wound stopped immediately after induction of suction. The bladder defect healed after 18 days of treatment with uEVT. After therapy and removal of the catheters, the patient had normal micturition. CONCLUSION: A novel small-bore OFD was developed for EVT. The OFD technique allows for endoscopic application of negative pressure in the bladder. This first successful experience proves uEVT to be a potent interventional alternative in the treatment of bladder defects. PMID- 27981373 TI - [Combined treatment of BPS with tamsulosin and finasteride : Literature review and prescription data]. AB - Combined therapy of benign prostatic syndrome (BPS) with alpha1-blockers and 5alpha-reductase (5AR)-inhibitors is recommended according to two leading studies on doxazosin/finasteride and tamsulosin/dutasteride for all 10 in Germany possible combinations (five alpha1-blockers and two 5AR inhibitors). Because tamsulosin and finasteride predominate in the treatment of BPS in Germany, the role of the combination tamsulosin/finasteride and its scientific basis from clinical studies has been investigated. A pharmacoepidemiological extrapolation from receipts of pharmacy data centres showed a strong increase of the combination tamsulosin/finasteride since 2003. As a free combination, tamsulosin/finasteride beside the fixed combination tamsulosin/dutasteride accounts to about 50% of all alpha1-blocker/5AR-inhibitor combinations today. Clinical studies on tamsulosin/finasteride have been published including controlled studies of the combination and both monotherapies. The results of improvement of lower urinary tract symptoms (LUTS), maximum urinary flow rate (Qmax), prostate volume (PV) and prostate-specific antigen (PSA) as well as adverse events and drug safety are in agreement with the leading studies. However, results due to chance cannot be excluded because of deficiencies in study design. A reliable comparison of the risk of progression between tamsulosin/finasteride and both monotherapies is lacking completely. Because of the great coherence and continuous evaluation of available data of all combinations, and with the established strong class effect of monotherapies, a continuation of the therapeutic practice with the combination tamsulosin/finasteride is possible. PMID- 27981374 TI - [On the legalization debate of non-medical cannabis consumption : Position paper of the German Association for Psychiatry, Psychotherapy and Psychosomatics]. AB - Calls are increasing for the legalization of cannabis. Some legal experts, various politicians, political parties and associations are demanding a change in drug policy. The legalization debate is lively and receiving wide coverage in the media. The German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) comments on the most important questions from a medical scientific perspective: can cannabis consumption trigger mental illnesses, what consequences would legalization have for the healthcare system and where is more research needed? PMID- 27981375 TI - [Coercive measures in German hospitals for psychiatry and psychotherapy : A pilot study by the DGPPN to evaluate a uniform assessment instrument]. AB - STUDY OBJECTIVE: A simple instrument to record case-related coercive measures was tested as part of a pilot project of the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN). METHODS: To assess coercive measures data were collected for 3 months in 8 German hospitals for psychiatry and psychotherapy. The type of measures used, the main diagnosis and the legal basis for the coercive measures were documented. RESULTS: In the sample studied, coercive measures were applied in 8% of cases. Coercive measures were most commonly used in patients with a schizophrenic disorder. The principle of justifiable necessity according to S 34 of the German Penal Code was used particularly often as the legal basis for justifying the coercive measures. CONCLUSION: Suitable measurement instruments and reliable data that enable the learning of best practices represent the basis for a reduction of coercive measures. PMID- 27981376 TI - Vitamin D deficiency is prevalent among idiopathic stone formers, but does correction pose any risk? AB - While vitamin D (vitD) deficiency is thought to contribute to poor health in a variety of ways and should be corrected, there is still concern about giving vitD supplements to patients with a history of nephrolithiasis. The aim is to study the prevalence of vitD deficiency and the effect on stone risk of cholecalciferol (vitD3) supplementation in a cohort of idiopathic stone formers (ISF). We screened for vitD deficiency and urinary measures of stone risk, comparing vitD deficient (serum 25-OH vitD <=30 nmol/L; <=12 ng/mL) with vitD insufficient (31 75 nmol/L; 13-30 ng/mL) or vitD replete (>75 nmol/L; >30 ng/mL); we investigated the effect of giving vitD3 (20,000 IU orally, weekly for 4 months) to 37 of the vitD deficients. Thirty-one percent (142/456) were vitD deficient, 57% (259/456) vitD insufficient, and the rest (12%) vitD replete (55/456). Comparison among the groups showed that baseline 24-h urinary measures related to stone risk expressed as concentration ratios over urine creatinine (Cr), such as U. Calcium/Cr, U. Oxalate/Cr, U. Citrate/Cr, and U. Uric acid/Cr were not significantly different. VitD3 supplementation did significantly increase serum 25-OH vitD levels and U. Phosphate/Cr ratios, as well as reduce serum parathyroid hormone (PTH) concentrations. Following vitD3 supplementation, there was an overall rise in 24 h urine calcium excretion, but it failed to reach statistical significance (p = 0.06). U. Calcium/Cr increased in 22 out of 37 patients (average increase +0.07 mmol/mmol), decreased in 14 (average decrease -0.13 mmol/mmol), and remained unchanged in 1; 6 out of 26 initially normocalciuric ISF developed hypercalciuria; and 6 out of 9 patients who became vitD replete were hypercalciuric after supplementation. It is appropriate to monitor urinary Ca excretion in vitD-supplemented stone formers, because it may reveal underlying hypercalciuria in some treated patients. PMID- 27981378 TI - The RIPASA score is sensitive and specific for the diagnosis of acute appendicitis in a western population. AB - AIM: The definitive diagnosis of acute appendicitis (AA) requires histopathological examination. Various clinical diagnostic scoring systems attempt to reduce negative appendectomy rates. The most commonly used in Western Europe and the USA is the Alvarado score. The Raja Isteri Pengiran Anak Saleha appendicitis (RIPASA) score achieves better sensitivity and specificity in Asian and Middle Eastern populations. We aimed to determine the diagnostic accuracy of the RIPASA score in Irish patients with AA. METHODS: All patients who presented to our institution with right iliac fossa pain and clinically suspected AA between January 1 and December 31, 2015, were indentified from our hospital inpatient enquiry database and retrospectively studied. Operating theatre records and histology reports confirmed those who underwent a non-elective operative procedure and the presence or absence of AA. SPSS version 22 was used for statistical analysis. Standard deviation is provided where appropriate. RESULTS: Two hundred eight patients were included in the study (106/51% male, mean age 22.7 +/- 9.2 years). One hundred thirty-five (64.9%) had histologically confirmed AA (mean symptom duration = 36.19 +/- 15.90 h). At a score >=7.5, the previously determined score most likely associated with AA in Eastern populations, the RIPASA scoring system demonstrated a sensitivity of 85.39%, specificity of 69.86%, positive predictive value of 84.06%, negative predictive value of 72.86% and diagnostic accuracy of 80% in our cohort. CONCLUSION: The RIPASA score is a useful tool to aid in the diagnosis of acute appendicitis in the Irish population. A score of >=7.5 provides sensitivity and specificity exceeding that previously documented for the Alvarado score in Western populations. WHAT DOES THIS PAPER ADD TO THE LITERATURE?: This is the first study evaluating the utility of the RIPASA score in predicting acute appendicitis in a Western population. At a value of 7.5, a cut-off score suggestive of appendicitis in the Eastern population, RIPASA demonstrated a high-sensitivity, specificity, positive predictive value and diagnostic accuracy in our cohort and was more accurate than the commonly used Alvarado score. PMID- 27981379 TI - Lung morphometry: the link between structure and function. AB - The study of the structural basis of gas exchange function in the lung depends on the availability of quantitative information that concerns the structures establishing contact between the air in the alveoli and the blood in the alveolar capillaries, which can be entered into physiological equations for predicting oxygen uptake. This information is provided by morphometric studies involving stereological methods and allows estimates of the pulmonary diffusing capacity of the human lung that agree, in experimental studies, with the maximal oxygen consumption. The basis for this "machine lung" structure lies in the complex design of the cells building an extensive air-blood barrier with minimal cell mass. PMID- 27981380 TI - Tissue remodelling in pulmonary fibrosis. AB - Many lung diseases result in fibrotic remodelling. Fibrotic lung disorders can be divided into diseases with known and unknown aetiology. Among those with unknown aetiology, idiopathic pulmonary fibrosis (IPF) is a common diagnosis. Because of its progressive character leading to a rapid decline in lung function, it is a fatal disease with poor prognosis and limited therapeutic options. Thus, IPF has motivated many studies in the last few decades in order to increase our mechanistic understanding of the pathogenesis of the disease. The current concept suggests an ongoing injury of the alveolar epithelium, an impaired regeneration capacity, alveolar collapse and, finally, a fibroproliferative response. The origin of lung injury remains elusive but a diversity of factors, which will be discussed in this article, has been shown to be associated with IPF. Alveolar epithelial type II (AE2) cells play a key role in lung fibrosis and their crucial role for epithelial regeneration, stabilisation of alveoli and interaction with fibroblasts, all known to be responsible for collagen deposition, will be illustrated. Whereas mechanisms of collagen deposition and fibroproliferation are the focus of many studies in the field, the awareness of other mechanisms in this disease is currently limited to biochemical and imaging studies including quantitative assessments of lung structure in IPF and animal models assigning alveolar collapse and collapse induration crucial roles for the degradation of the lung resulting in de-aeration and loss of surface area. Dysfunctional AE2 cells, instable alveoli and mechanical stress trigger remodelling that consists of collapsed alveoli absorbed by fibrotic tissue (i.e., collapse induration). PMID- 27981381 TI - Erratum to: Cementogenic genes in human periodontal ligament stem cells are downregulated in response to osteogenic stimulation while upregulated by vitamin C treatment. PMID- 27981377 TI - Myrrh exerts barrier-stabilising and -protective effects in HT-29/B6 and Caco-2 intestinal epithelial cells. AB - PURPOSE: Myrrh, the oleo-gum resin of Commiphora molmol, is well known for its anti-inflammatory properties. In different animal models, it protected against DSS-, TNBS- and oxazolone-induced colitis. To date, no information concerning the effect of myrrh on barrier properties are available. Thus, this study investigates the effect of myrrh on paracellular barrier function in the absence or presence of the pro-inflammatory cytokine TNFalpha. METHODS: Monolayers of human colon cell lines HT-29/B6 and Caco-2 were incubated with myrrh under control conditions or after challenge with the pro-inflammatory cytokine TNFalpha. Barrier function was analysed by electrophysiological and permeability measurements, Western blotting, immunostaining in combination with confocal microscopy, and freeze-fracture electron microscopy. RESULTS: In Caco-2 cells, myrrh induced an increase in transepithelial resistance (TER) which was associated with downregulation of the channel-forming tight junction (TJ) protein claudin-2 via inhibition of the PI3 kinase signalling pathway. In HT-29/B6 cells, myrrh had no effect on barrier properties under basic conditions, but protected against barrier damage induced by TNFalpha, as indicated by a decrease in TER and an increase in fluorescein permeability. The TNFalpha effect was associated with a redistribution of the sealing TJ protein claudin-1, an increase in the expression of claudin-2 and a change in TJ ultrastructure. Most importantly, all TNFalpha effects were inhibited by myrrh. The effect of myrrh on claudin-2 expression in this cell line was mediated via inhibition of the STAT6 pathway. CONCLUSIONS: This study shows for the first time that myrrh exerts barrier stabilising and TNFalpha-antagonising effects in human intestinal epithelial cell models via inhibition of PI3K and STAT6 signalling. This suggests therapeutic application of myrrh in intestinal diseases associated with barrier defects and inflammation. PMID- 27981383 TI - Management of super-super obese patients: comparison between one anastomosis (mini) gastric bypass and Roux-en-Y gastric bypass. AB - BACKGROUND: Gastric bypass can be technically challenging in super-super obese patients. Both Roux-en-Y gastric bypass (RYGB) and one anastomosis (mini) gastric bypass (OAGB/MGB) have been described in these patients, but direct comparisons are lacking. The purpose of this study was to compare the early outcomes with these two procedures in patients with body mass index (BMI) of >=60 kg/m2 in our unit. METHODS: We identified all super-super obese patients who underwent either OAGB/MGB or RYGB from our prospectively maintained database. Information was also obtained from the case notes and from hospital computerized records. We obtained data regarding patient demographics, operative details, complications, and weight loss, in both groups, and compared them using standard statistical methods. RESULTS: This study compares our results with 19 OAGB/MGB and 47 RYGB super-super obese patients performed in our unit between October 2012 and June 2015. OAGB/MGB group patients had a significantly higher weight and body mass index. There was no mortality or major complication in either group. There were two late complications in the OAGB/MGB group compared to six in the RYGB group. One patient in the OAGB/MGB group needed conversion to RYGB for persistent reflux symptoms. OAGB/MGB patients achieved a significantly higher EWL of 70.4% at 2 years compared to 57.1% in the RYGB group. The difference between TWL of 44.4 and 33.4%, respectively, was also significant at 2 years. TWL of 43.0 and 29.3%, respectively, in OAGB/MGB and RYGB groups at 18 months was also significantly different, but the difference in EWL at 18 months did not reach significance. CONCLUSION: One anastomosis (mini) gastric bypass yields superior weight loss at 18 and 24 months in comparison with Roux-en-Y gastric bypass in patients with BMI of >=60 kg/m2. Findings need confirmation in larger randomized studies. PMID- 27981382 TI - LINX(r) magnetic esophageal sphincter augmentation versus Nissen fundoplication for gastroesophageal reflux disease: a systematic review and meta-analysis. AB - BACKGROUND: The LINX(r) magnetic sphincter augmentation system (MSA) is a surgical technique with short-term evidence demonstrating efficacy in the treatment of medically refractory or chronic gastroesophageal reflux disease (GERD). Currently, the Nissen fundoplication is the gold-standard surgical treatment for GERD. We are the first to systematically review the literature and perform a meta-analysis comparing MSA to the Nissen fundoplication. METHODS: A comprehensive search of electronic databases (e.g., MEDLINE, EMBASE, SCOPUS, Web of Science and the Cochrane Library) using search terms "Gastroesophageal reflux or heartburn" and "LINX or endoluminal or magnetic" and "fundoplication or Nissen" was completed. All randomized controlled trials, non-randomized comparison study and case series with greater than 5 patients were included. Five hundred and forty-seven titles were identified through primary search, and 197 titles or abstracts were screened after removing duplicates. Meta-analysis was performed on postoperative quality of life outcomes, procedural efficacy and patient procedural satisfaction. RESULTS: Three primary studies identified a total of 688 patients, of whom 273 and 415 underwent Nissen fundoplication and MSA, respectively. MSA was statistically superior to LNF in preserving patient's ability to belch (95.2 vs 65.9%, p < 0.00001) and ability to emesis (93.5 vs 49.5%, p < 0.0001). There was no statistically significant difference between MSA and LNF in gas/bloating (26.7 vs 53.4%, p = 0.06), postoperative dysphagia (33.9 vs 47.1%, p = 0.43) and proton pump inhibitor (PPI) elimination (81.4 vs 81.5%, p = 0.68). CONCLUSION: Magnetic sphincter augmentation appears to be an effective treatment for GERD with short-term outcomes comparable to the more technically challenging and time-consuming Nissen fundoplication. Long-term comparative outcome data past 1 year are needed in order to further understand the efficacy of magnetic sphincter augmentation. PMID- 27981384 TI - Laparoscopic-assisted versus open total gastrectomy for Siewert type II and III esophagogastric junction carcinoma: a propensity score-matched case-control study. AB - BACKGROUND: Few studies have evaluated the outcomes of laparoscopic-assisted total gastrectomy (LATG) for Siewert type II and III adenocarcinoma of the esophagogastric junction (AEG). Thus, aim of this study was to investigate the surgical outcomes of LATG for Siewert type II and III AEG. METHODS: Clinical data for 700 Siewert type II and III AEG patients were analyzed retrospectively. The short- and long-term outcomes were compared between the matched groups using a propensity score matching method. RESULTS: Before matching, the comorbidities, Siewert classifications and tumor invasion depths significantly differed between the LATG and open total gastrectomy (OTG) groups. After matching, the clinicopathologic characteristics were well balanced between the two groups. In addition, after matching, decreases in the operative time, amount of blood loss, time to resumption of a semifluid diet, and length of hospital stay and an increased number of lymph nodes (LNs) retrieved were observed in the LATG group compared with the OTG group. Further, a significantly higher 3-year overall survival rate (81.3 vs 66.4%; P = 0.011) and disease-free survival rate (77.5 vs 63.8%; P = 0.040) were observed for the Siewert type II AEG patients in the LATG group compared with those in the OTG group; however, the survival rates were similar for the Siewert type III AEG patients in the two groups (P = 0.853 and P = 0.844, respectively). CONCLUSIONS: LATG is associated with better short-term outcomes for Siewert type II and III AEG. In addition, it may result in an increased number of retrieved LNs and better long-term survival for Siewert type II AEG patients in particular. PMID- 27981385 TI - [Preclinical safety evaluation of chloral hydrate after topical application using the example of psoriatic itch]. AB - BACKGROUND: Psoriasis is known today as a T-cell-mediated autoimmunological systemic disease. The chronic inflammatory processes involve neuroimmunological factors that are held responsible not only for various aspects of psychiatric neurological comorbidities but also for neurosensory problems, primarily itching. Amongst other things, the significance of GABAA receptors are often discussed in this context. The topical use of chloral hydrate in semisolid preparations for antipruritic therapy goes back to Neisser and is currently experiencing a revival in individually manufactured formulations. However, it is currently unknown whether the unwanted side effects that are described for systemic use of chloral hydrate are also relevant for topical application. OBJECTIVES: For lack of clinical safety data, preclinical tests for cutaneous cytotoxicity and calculations for systemic bioavailability after topical application have been performed. CONCLUSION: The present data cannot fully remove safety concerns for topical application of chloral hydrate in the formulation favoured by the NRF (Neues Rezepturformularium)-the so-called 1-2-3-cream. A twice daily use of the 1 2-3-cream on a maximum of 10% of the body surface can be regarded as safe. For a better assessment of harmlessness, tests for cutaneous bioavailability (concentration-time profile) on human skin and clinical studies would be necessary. PMID- 27981386 TI - [Non-viral sexually transmitted infections - Epidemiology, clinical manifestations, diagnostics and therapy : Part 1: Gonococci]. AB - Approximately 1 million people are infected per day worldwide by one or more sexually transmitted infections (STI) as estimated by the World Health Organization (WHO). Gonorrhoea represents an almost exclusively sexually transmitted infection, which predominantly affects mucous membranes of the genitourinary tract. Extragenital localization of infections is also possible, e. g. in the anorectal region. Currently, only syphilis and human immunodeficiency virus (HIV) are notifiable diseases according to the Infection Protection Act in Germany. In Saxony, an extended registration ordinance according to the German Infection Protection Act is in force, which means that besides syphilis the laboratory detection of Neisseria gonorrhoeae, Chlamydia trachomatis and genital mycoplasms are also notifiable infections. In particular, beginning in 2009 in Saxony a spectacular increase of registered infections due to N. gonorrhoeae was observed and in 2015 altogether 824 infections due to N. gonorrhoeae were reported. Alarming is the increase in resistance of N. gonorrhoeae against penicillin, doxycycline, ciprofloxacin and recently also against azithromycin and third generation cephalosporins. The so-called superbug of N. gonorrhoeae, which originated in Japan with multidrug resistance against most of the currently available oral antibiotics, has now arrived in Europe. Intramuscular or intravenous injection of ceftriaxone plus oral azithromycin, each given as single dose is the standard therapy for gonorrhoea. PMID- 27981389 TI - Pro-differentiating effects of a synthetic flavagline on human teratocarcinomal cancer stem-like cells. AB - As initiators of the carcinogenic process, cancer stem cells (CSCs) are considered as new targets for anti-cancer therapies. However, these cells are hidden in the cancer bulk and remain relatively insensitive to chemotherapy, which targets their proliferative capacities. Alternatively, growing evidences have pointed out that a differentiation therapy could adversely affect these cells, which consequently should lose their self-renewal properties and become less aggressive. In order to evaluate the differentiation potential of an emerging class of anti-cancer drugs, we used the poorly differentiated teratocarcinomal cell as a model of Oct4-expressing CSC and determined the molecular mechanisms induced by the highly active flavagline FL3. The drug, administrated at sublethal concentration and for long period, was able to downregulate the expression levels of the stemness factors Oct4 and Nanog at both transcriptional and translational levels, concomitantly with a decrease of clonogenicity. The appearance of specific neural markers further demonstrated the differentiation properties of FL3. Interestingly, an expression of active caspase 3 and an upregulation of the expression of the germ cell nuclear factor were observed in treated cells; this suggests that the suppression of Oct4 expression required for the induction of differentiation involves overlapping mechanisms of protein degradation and gene repression. Finally, this study shows that FL3, like all-trans retinoic acid (ATRA), acts as a differentiation inducer of teratocarcinomal cells. Thus, FL3 offers an alternative possibility for cancer treatment since it could target the carcinogenic process by inducing the differentiation of ATRA-resistant and Oct4-expressing CSCs, without toxic side effects on normal cells. PMID- 27981387 TI - [Non-viral sexually transmitted infections - Epidemiology, clinical manifestations, diagnostics and therapy : Part 2: Chlamydia and mycoplasma]. AB - Chlamydia trachomatis is the most common pathogen of sexually transmitted bacterial infections worldwide. Every year in Germany approximately 300,000 new infections are to be expected. Chlamydia infections occur nearly exclusively in the postpubertal period. The peak age group is 15-25 years. The infection usually runs an asymptomatic course and the diagnosis is made by nucleic acid amplification techniques (NAAT) often after chlamydial screening or if complications occur. For treatment of chlamydial infections oral doxycycline 100 mg twice daily over 7 days is initially used or alternatively oral azithromycin 1.5 g as a single dose is recommended. The sexual partner should also be investigated and treated. Genital Mycoplasma infections are caused by Ureaplasma urealyticum (pathogen of urethritis and vaginitis), Ureaplasma parvum (mostly saprophytic and rarely a cause of urethritis) and Mycoplasma hominis (facultative pathogenic). Mycoplasma genitalium represents a relatively new sexually transmitted Mycoplasma species. Doxycycline is effective in Ureaplasma infections or alternatively clarithromycin and azithromycin. Doxycycline can be ineffective in Mycoplasma hominis infections and an alternative is clindamycin. Non gonococcal and non-chlamydial urethritis due to Mycoplasma genitalium can now be diagnosed by molecular biological techniques using PCR and should be treated by azithromycin. PMID- 27981388 TI - Transcriptome portrait of cellulose-enriched flax fibres at advanced stage of specialization. AB - Functional specialization of cells is among the most fundamental processes of higher organism ontogenesis. The major obstacle to studying this phenomenon in plants is the difficulty of isolating certain types of cells at defined stages of in planta development for in-depth analysis. A rare opportunity is given by the developed model system of flax (Linum usitatissimum L.) phloem fibres that can be purified from the surrounding tissues at the stage of the tertiary cell wall deposition. The performed comparison of the whole transcriptome profile in isolated fibres and other portions of the flax stem, together with fibre metabolism characterization, helped to elucidate the general picture of the advanced stage of plant cell specialization and to reveal novel participants potentially involved in fibre metabolism regulation and cell wall formation. Down regulation of all genes encoding proteins involved in xylan and lignin synthesis and up-regulation of genes for the specific set of transcription factors transcribed during tertiary cell wall formation were revealed. The increased abundance of transcripts for several glycosyltransferases indicated the enzymes that may be involved in synthesis of fibre-specific version of rhamnogalacturonan I. PMID- 27981391 TI - Third-ventricle enterogenous cyst presentation mimicking a colloid cyst: uncommon presentation of a rare disease and literature review. AB - Enterogenous cysts (ECs) are endodermal lesions resulting from splitting anomalies in the neuroenteric canal. We report the case of a 64-year-old patient who presented with a sudden headache followed by collapse. Brain computed tomography revealed a hyperdense lesion in the anterior part of the third ventricle with obstructive hydrocephalus. A presumptive diagnosis of colloid cyst was made and he underwent a right transcortical approach for lesion resection. The histopathological examination revealed an EC. ECs are common lesions in the cervical-thoracic spine but rare in the supratentorial compartment with only two previously described cases occurring in the third ventricle. PMID- 27981390 TI - Trust and Deception in Children with Autism Spectrum Disorders: A Social Learning Perspective. AB - Previous research has demonstrated abnormal trust and deception behaviors in children with Autism Spectrum Disorders (ASD), and we aimed to examine whether these abnormalities were primarily due to their specific deficits in social learning. We tested 42 high-functioning children with ASD and 38 age- and ability matched typically developing (TD) children in trust and deception tasks and a novel condition with reduced social components. Results indicated that while TD children improved their performance with more social components, children with ASD lacked this additional performance gain, though they performed similarly as TD children in the condition with reduced social components. Our findings highlight that deficits of ASD in trust and deception are primarily associated with failure of use of social cues. PMID- 27981392 TI - Histological evidence that metformin reverses the adverse effects of diabetes on orthodontic tooth movement in rats. AB - This study evaluated the effects of metformin on orthodontic tooth movement in a rat model of type 2 diabetes mellitus. Rats were fed a high-fat diet for 4 weeks to induce fat accumulation and insulin resistance, and then injected with a low dose of streptozotocin (35 mg/kg) intraperitoneally to induce type 2 diabetes. An orthodontic appliance was placed in normoglycemic, type 2 diabetes, and type 2 diabetes with metformin-administrated rats. After 14 days, type 2 diabetes rats exhibited greater orthodontic tooth movement and had a higher number of tartrate resistant acid phosphatase-positive osteoclasts, stronger cathepsin K expression, and weaker alkaline phosphatase immunostaining than normoglycemic rats. Metformin administration resulted in normalization of osteoclast numbers, cathepsin K immunostaining, and of tooth movement as well as partly recovery of alkaline phosphatase expression in diabetic rats. Metformin also reduced sclerostin expression and improved the immunolocalization of dentin matrix protein 1 in osteocytes of type 2 diabetes rats. These results suggest that metformin administration reversed the adverse effects of diabetes on orthodontic tooth movement. PMID- 27981394 TI - Heritability of Working in a Creative Profession. AB - Creativity is the tendency to generate or recognize ideas, alternatives, or possibilities. Following a study on the genetic contribution to working in a creative profession, based on polygenic score analysis, we report the total heritability of this trait in a large sample of adult twins and their siblings registered with the Netherlands Twin Register. Data from 6755 twins and 1817 siblings were analyzed using genetic structural equation modeling. Working in a creative profession is relatively rare in our sample (2.6% of twins and 3.2% of siblings). Twin correlations (identical 0.68 and fraternal 0.40) commended a model with additive genetic factors (full model estimate 0.56), shared (full model estimate 0.12), and unique environmental factors (full model estimate 0.32). Genetic model fitting resulted in a best-fitting model existing of additive genetic factors and unique environmental factors, resulting in a heritability of 0.70. PMID- 27981393 TI - Hyperparathyroidism and increased fractional excretion of phosphate predict allograft loss in long-term kidney transplant recipients. AB - BACKGROUND: After kidney transplantation, fibroblast growth factor-23 (FGF-23) normally returns to baseline within 1 year whereas hyperparathyroidism persists in most kidney transplant (KT) recipients. As a result, serum phosphate remains relatively low in association with increased serum calcium and urinary phosphate excretion when compared to chronic kidney disease patients. The relationship between mineral metabolism and outcomes in long-term KT recipients has not been extensively studied. This study investigated whether the alteration in mineral metabolism influenced graft survival in long-term KT recipients. METHODS: This study included 273 KT recipients after 1 year of transplantation. Mineral parameters were obtained at the time of enrolment and patients were followed prospectively for an average of 71 months. RESULTS: Graft loss (death-censored) occurred in 41 (15%) patients. In univariate analysis, deceased donor transplantation, decreased serum albumin and estimated glomerular filtration rate, increased serum phosphate, parathyroid hormone (PTH), FGF-23 and fractional excretion of phosphate (FePi) predicted future allograft loss. After adjustments for cardiovascular disease risk factors, donor type, dialysis vintage, serum albumin and allograft function, only increased PTH and FePi remained associated with the outcome. Relationships between increased serum phosphate and FGF-23 with graft survival were lost after adjustments. Adjusted survival curves revealed the association between PTH > 90 pg/mL and FePi > 20% with worse graft survival. CONCLUSIONS: Hyperparathyroidism and increased FePi predicted allograft loss in long-term KT recipients. PMID- 27981395 TI - Evaluation of exposure to (ultra) high static magnetic fields during activities around human MRI scanners. AB - OBJECTIVE: To assess the individual exposure to the static magnetic field (SMF) and the motion-induced time-varying magnetic field (TVMF) generated by activities in an inhomogeneous SMF near high and ultra-high field magnetic resonance imaging (MRI) scanners. The study provides information on the level of exposure to high and ultra-high field MRI scanners during research activities. MATERIALS AND METHODS: A three-axis Hall magnetometer was used to determine the SMF and TVMF around human 3- and 7-Tesla (T) MRI systems. The 7-T MRI scanner used in this study was passively shielded and the 3-T scanner was actively shielded and both were from the same manufacturer. The results were compared with the exposure restrictions given by the International Commission on Non-Ionizing Radiation Protection (ICNIRP). RESULTS: The recorded exposure was highly variable between individuals, although they followed the same instructions for moving near the scanners. Maximum exposure values of B = 2057 mT and dB/dt = 4347 mT/s for the 3 T scanner and B = 2890 mT, dB/dt = 3900 mT/s for 7 T were recorded. No correlation was found between reporting the MRI-related sensory effects and exceeding the reference values. CONCLUSIONS: According to the results of our single-center study with five subjects, violation of the ICNIRP restrictions for max B in MRI research environments was quite unlikely at 3 and 7 T. Occasions of exceeding the dB/dt limit at 3 and 7 T were almost similar (30% of 60 exposure scenarios) and highly variable among the individuals. PMID- 27981397 TI - The Impact of Food Assistance on Dietary Diversity and Food Consumption among People Living with HIV/AIDS. AB - Little is known about the outcomes of food assistance targeted to food insecure people living with HIV/AIDS. Using primary data from Zambia, we estimated the impact of food assistance on the dietary diversity and consumption expenditures of households with HIV infected members receiving antiretroviral therapy. Propensity score matching estimates show that food assistance increased dietary diversity by 9.8 points (23%) mainly through the consumption of food items provided in the ration. Food assistance recipients were 20% points more likely to have acceptable food consumption and 15% points less likely to have poor food consumption than non-recipients. Food assistance also increased food consumption expenditures but had no significant impact on food purchases and total consumption expenditures. Overall, our findings demonstrate that food assistance can be an effective instrument for improving diets and enhancing the food security of people living with HIV/AIDS. PMID- 27981396 TI - Semi-automated myocardial segmentation of bright blood multi-gradient echo images improves reproducibility of myocardial contours and T2* determination. AB - OBJECTIVES: Early detection of iron loading is affected by the reproducibility of myocardial contour assessment. A novel semi-automatic myocardial segmentation method is presented on contrast-optimized composite images and compared to the results of manual drawing. MATERIALS AND METHODS: Fifty-one short-axis slices at basal, mid-ventricular and apical locations from 17 patients were acquired by bright blood multi-gradient echo MRI. Four observers produced semi-automatic and manual myocardial contours on contrast-optimized composite images. The semi automatic segmentation method relies on vector field convolution active contours to generate the endocardial contour. After creating radial pixel clusters on the myocardial wall, a combination of pixel-wise coefficient of variance (CoV) assessment and k-means clustering establishes the epicardial contour for each segment. RESULTS: Compared to manual drawing, semi-automatic myocardial segmentation lowers the variability of T2* quantification within and between observers (CoV of 12.05 vs. 13.86% and 14.43 vs. 16.01%) by improving contour reproducibility (P < 0.001). In the presence of iron loading, semi-automatic segmentation also lowers the T2* variability within and between observers (CoV of 13.14 vs. 15.19% and 15.91 vs. 17.28%). CONCLUSION: Application of semi-automatic myocardial segmentation on contrast-optimized composite images improves the reproducibility of T2* quantification. PMID- 27981398 TI - Identifying Resilience Resources for HIV Prevention Among Sexual Minority Men: A Systematic Review. AB - Most HIV prevention for sexual minority men and men who have sex with men targets risk behaviors (e.g., condom use) and helps <50% of participants. Bolstering resilience might increase HIV prevention's effectiveness. This systematic review identified resilience resources (protective factors) in high-risk, HIV-negative, sexual minority men. We reviewed PsycINFO, PsycARTICLES, MEDLINE, references, and Listservs for studies including sexual minority men with 1+ HIV risk factor (syndemics): childhood sexual abuse, partner abuse, substance abuse, or mental health symptoms. From 1356 articles screened, 20 articles met inclusion criteria. Across the articles, we identified and codified 31 resilience resources: socioeconomic (e.g., employment), behavioral coping strategies (e.g., mental health treatment), cognitions/emotions (e.g., acceptance), and relationships. Resilience resources were generally associated with lower HIV risk; there were 18 low-risk associations, 4 high-risk associations, 8 non-significant associations). We generated a set of empirically based resilience variables and a hypothesis to be evaluated further to improve HIV prevention. PMID- 27981399 TI - The Usefulness of the CRAFFT in Screening for Problematic Drug and Alcohol Use Among Youth Living with HIV. AB - Substance use is highly prevalent among youth living with HIV (YLWH) and negatively impacts HIV care. This study sought to determine whether the CRAFFT (Car, Relax, Alone, Forget, Friends, and Trouble), designed to screen for problematic substance use, is reliably associated with substance use behaviors among YLWH. A cross-sectional sample of 2216 youth (ages 12-26) were recruited through the adolescent medicine trials network for HIV/AIDS Interventions. Participants completed a self-administered survey. Over half screened positive on the CRAFFT (i.e., >=2). Among frequent substance users, those older in age, behaviorally infected, with history of incarceration or unstably housed were more likely to screen positive on the CRAFFT. Study findings suggest that the CRAFFT reliably identifies youth who use substances. Thus, screening measures such as the CRAFFT should be utilized routinely in HIV clinical settings for youth. PMID- 27981400 TI - Strategies and Challenges in Recruiting Black Immigrant Mothers for a Community Based Study on Child Nutritional Health in Ottawa, Canada. AB - There is a need to identify barriers to participation as well as recruitment strategies to engage minority parents of young children in health-oriented research. This paper offers insights on strategies and challenges in recruiting black immigrant mothers living in Ottawa (Canada) for a community-based health oriented research project among 6-to-12-year-old children. We recruited 259 mother-child dyads. Most participants were recruited by team members during community events, fairs, religious gatherings, etc. Other successful strategies included referral from participants, community partners, and through research team members' networks. Mass media strategies were mostly ineffective. Instant and meaningful incentives, developing community partnerships, building and ensuring study legitimacy and trust, placing convenience of participants ahead of that of research team members, doing community outreach, and taking contact information on the spot, as well as using word-of-mouth were essential to recruiting. This study clearly indicates the importance of adopting multiple recruitment strategies. PMID- 27981401 TI - Early permanent disappearance of abnormal muscle response during microvascular decompression for hemifacial spasm: a retrospective clinical study. AB - The objective of this study is to explore the cause of early abnormal muscle response (AMR) disappearance during microvascular decompression for hemifacial spasm and the clinical outcomes of these patients. Three hundred seventy-two patients received microvascular decompression (MVD) under intraoperative electrophysiological monitoring in Nanjing Drum Tower Hospital in 2014; the characteristic AMR of HFS was observed in 359 patients during the operation. And the 359 patients were divided into two groups based on whether AMR had remained before the beginning of the decompression procedure for offending vessels. Thirty three patients who showed a permanent disappearance of AMR before the beginning of decompression were regarded as group I. Dural opening and the succeeding CSF drainage produced a permanent disappearance of AMR in 13. During the dissection of lateral cerebellomedullary cistern, a permanent disappearance of AMR was found in 20 patients. Thirty-two patients were cured immediately; delayed resolution (7 days after surgery) was found in one patient. No complications were observed and no recurrence was found during the follow-up period in the 33 patients. In the other 326 patients (group II), AMR disappeared temporarily before the beginning of the decompression procedure for offending vessels in 42 patients. After decompression, AMR disappeared completely in 305 patients. Two hundred sixty seven patients were cured immediately and 57 patients got a delayed resolution (2 days to 45 weeks after surgery). The two left did not get a complete abolition of spasm. Three cases of hearing loss, one hoarseness, and nine delayed facial paralysis were observed. The reason of early abnormal muscle response disappearance may be that the degree of neurovascular compression was not serious; these patients were more likely to get an immediate cure. Continuous intraoperative electrophysiological monitoring of AMR is necessary. PMID- 27981402 TI - The response of marigold (Tagetes erecta Linn.) to ozone: impacts on plant growth and leaf physiology. AB - Progressively increasing ozone (O3) concentrations pose a potential threat to the value of marigold (Tagetes erecta Linn.), a plant widely used in urban landscaping. The response of marigold to elevated O3 has been reported earlier, but the mechanisms underlying the O3 effect have not been clearly elucidated. In the present study, we exposed marigold "Moonsong Deep Orange" plants to elevated O3, including ambient non-filtered air (NF) plus 60 ppb (NF+60) and 120 ppb (NF+120) O3, to assess visible injury and the possible physiological consequences of this pollutant. Yellow lesions appeared after 4 days under NF+120 treatment and 12 days under NF+60 treatment, with 85.6% and 36.8% of the leaves being injured at harvest time, respectively. Compared with NF, NF+60 inhibited leaf photosynthesis, stem-diameter growth, and biomass production significantly, while the parameters were decreased more by NF+120. Although the stomatal conductance decreased under elevated O3 exposure, the O3 flux into leaves increased by 28.0 104.8% under NF+60 treatment and 57.5-145.6% under NF+120 treatment. The total ascorbic acid (ASA) content increased due to elevated O3 exposure, while the reduced ASA content did not, resulting in a decreased ratio of reduced to total ASA. A lower level of jasmonic acid (JA) was observed under elevated O3 exposure. In conclusion, the impacts of elevated O3 on marigold plants may be ascribed to increased O3 flux into leaves and reduced protective capacity of leaves to convert oxidized to reduced ASA and synthesize endogenous JA. PMID- 27981403 TI - De novo transcriptome sequencing and analysis of freshwater snail (Radix balthica) to discover genes and pathways affected by exposure to oxazepam. AB - Pharmaceuticals are increasingly found in aquatic ecosystems due to the non efficiency of waste water treatment plants. Therefore, aquatic organisms are frequently exposed to a broad diversity of pharmaceuticals. Freshwater snail Radix balthica has been chosen as model to study the effects of oxazepam (psychotropic drug) on developmental stages ranging from trochophore to hatching. In order to provide a global insight of these effects, a transcriptome deep sequencing has been performed on exposed embryos. Eighteen libraries were sequenced, six libraries for three conditions: control, exposed to the lowest oxazepam concentration with a phenotypic effect (delayed hatching) (TA) and exposed to oxazepam concentration found in freshwater (TB). A total of 39,759,772 filtered raw reads were assembled into 56,435 contigs having a mean length of 1579.68 bp and mean depth of 378.96 reads. 44.91% of the contigs have at least one annotation. The differential expression analysis between the control condition and the two exposure conditions revealed 146 contigs differentially expressed of which 144 for TA and two for TB. 34.0% were annotated with biological function. There were four mainly impacted processes: two cellular signalling systems (Notch and JNK) and two biosynthesis pathways (Polyamine and Catecholamine pathways). This work reports a large-scale analysis of differentially transcribed genes of R. balthica exposed to oxazepam during egg development until hatching. In addition, these results enriched the de novo database of potential ecotoxicological models. PMID- 27981405 TI - Study of Fluorescent Imaging of Se (IV) in Living Cells Using a Turn-on Fluorescent Probe Based on a Rhodamine Spirolactame Derivative. AB - A highly selective fluorescent probe 2-(2-(2-aminoethylamino)ethyl)-3',6' bis(ethylamino)-2',7'-dimethylspiro[isoindoline-1,9'-xanthen]-3-one (ABDO) for Se (IV) had been synthesized in our earlier report. In this study, this fluorescent sensor is applied on analysis fluorescent imaging of Se (IV) in Hela cells. The experiment conditions, such as the MTT assay, different concentration of saline, incubated time of Hela cells with ABDO and Se (IV), and intracellular action position of Se (IV), are investigated. Through a series of experiments, the fluorescent image of Se (IV) in Hela cells can be observed when the cells cultured by 2 MUM ABDO and 2 MUM Se (IV) for 210 min. And the intracellular action position of Se (IV) is verified after the co-localization experiments are done. It is mitochondria. These experimental results show that ABDO will be an eagerly anticipated sensor for fluorescent imaging analysis of selenium ion in living cells. Besides, we also can use the complexes of ABDO-Se to observe morphology and distribution of mitochondria in cells like JG-B. PMID- 27981404 TI - Two New Mononuclear Copper(II)-Dipeptide Complexes of 2-(2'-Pyridyl)Benzoxazole: DNA Interaction, Antioxidation and in Vitro Cytotoxicity Studies. AB - Two new mononuclear mixed ligand copper(II) complexes [Cu(PBO)(Gly gly)(H2O)].ClO4.1.5H2O (1) and [Cu(PBO)(Gly-L-leu)(H2O)].ClO4 (2) (PBO is 2-(2' pyridyl)benzoxazole, Gly-gly and Gly-L-leu are Glycyl-glycine anion and Glycyl-L leucine anion, respectively), have been prepared and characterized by various analytical and spectral techniques. The interactions of the complexes with DNA were investigated using multi-spectroscopic methods (absorption, emission, circular dichroism), viscometry and electrochemical titration as well as molecular docking technique. The results indicated that 1 and 2 are bound to calf thymus DNA (CT-DNA) through an intercalative mode. The thermodynamic analyses revealed that the reactions between the Cu(II) complexes with DNA are spontaneous with negative Gibbs free energy (DeltaG). The positive changes of enthalpy (DeltaH) and entropy (DeltaS) suggested that the binding processes are dominated by hydrophobic interaction accompanying with endothermic. Also, the complexes exhibited efficient oxidative cleavage of pBR322 plasmid DNA in the presence of ascorbic acid, probably induced by *OH as reactive oxygen species. In addition, 1 and 2 displayed excellent antioxidant activities with the IC50 values of 0.112 and 0.191 MUM, respectively, using the mean of nitroblue tetrazolium (NBT) photochemical reduction under a nonenzymatic condition. Moreover, the complexes were screened for their in vitro cytotoxicity against three human carcinoma cell lines (HeLa, PC-3 and A549), in which 2 owns higher cytotoxicity, which was consistent with DNA binding and cleavage ability order of the complexes. This results showed the in vitro biochemical potentials of the Cu(II)-dipeptide complexes with aromatic heterocyclic, viz. effective metallopeptide-nucleases, SOD mimics and non-platinum chemotherapeutic metallopharmaceuticals and their structure-activity relationship, which may contribute to the rational molecular design of new metallopeptide based chemotherapeutic agents. PMID- 27981408 TI - Erratum to: Complete sequence of three different biotypes of tomato spotted wilt virus (wild type, tomato Sw-5 resistance-breaking and pepper Tsw resistance breaking) from Spain. PMID- 27981406 TI - Effects of Hypericum Scabrum extract on anxiety and oxidative stress biomarkers in rats fed a long-term high-fat diet. AB - The continuous and long-term consumption of a high-fat diet (HFD) leads to weight gain and obesity. A HFD and obesity increase the risks of psychiatric disorders, such as anxiety and depression. In this study, we investigated the effects of a Hypericum Scabrum (H. scabrum) extract, which is an antioxidant, on anxiety in rats fed a long-term HFD. Sixty male Wistar rats were divided into the following six groups: (1) Control (standard diet), (2) Ext100 [standard diet supplemented with extract (100 mg/kg once/day)], (3) Ext300 [standard diet supplemented with extract (300 mg/kg once/day)], (4) HFD, (HFD), (5) HFD + Ext100, and (6) HFD + Ext300. The groups were fed their diet for 3 months. Anxiety was measured with the elevated plus-maze test. At the end of the study, blood samples were taken, and biochemical parameters and oxidative stress biomarker levels were determined in the plasma. Compared to the control group, the HFD group exhibited significant decreases in both the time in the open arms and number of entries into the open arms. H. scabrum extract supplementation significantly increased these parameters in the HFD-fed groups. The HFD significantly increased serum malondialdehyde levels and significantly decreased total glutathione levels, while H. scabrum extract supplementation significantly reversed these parameters. In conclusion, these results showed that a HFD increased anxiety behavior. In contrast, H. scabrum extract supplementation had anxiolytic effects and reversed the effects of the HFD, which suggested that the effects of H. scabrum extract supplementation were due to its strong antioxidant properties. PMID- 27981407 TI - The bile duct ligated rat: A relevant model to study muscle mass loss in cirrhosis. AB - Muscle mass loss and hepatic encephalopathy (complex neuropsychiatric disorder) are serious complications of chronic liver disease (cirrhosis) which impact negatively on clinical outcome and quality of life and increase mortality. Liver disease leads to hyperammonemia and ammonia toxicity is believed to play a major role in the pathogenesis of hepatic encephalopathy. However, the effects of ammonia are not brain-specific and therefore may also affect other organs and tissues including muscle. The precise pathophysiological mechanisms underlying muscle wasting in chronic liver disease remains to be elucidated. In the present study, we characterized body composition as well as muscle protein synthesis in cirrhotic rats with hepatic encephalopathy using the 6-week bile duct ligation (BDL) model which recapitulates the main features of cirrhosis. Compared to sham operated control animals, BDL rats display significant decreased gain in body weight, altered body composition, decreased gastrocnemius muscle mass and circumference as well as altered muscle morphology. Muscle protein synthesis was also significantly reduced in BDL rats compared to control animals. These findings demonstrate that the 6-week BDL experimental rat is a relevant model to study liver disease-induced muscle mass loss. PMID- 27981409 TI - Medical Image Retrieval Using Vector Quantization and Fuzzy S-tree. AB - The aim of the article is to present a novel method for fuzzy medical image retrieval (FMIR) using vector quantization (VQ) with fuzzy signatures in conjunction with fuzzy S-trees. In past times, a task of similar pictures searching was not based on searching for similar content (e.g. shapes, colour) of the pictures but on the picture name. There exist some methods for the same purpose, but there is still some space for development of more efficient methods. The proposed image retrieval system is used for finding similar images, in our case in the medical area - in mammography, in addition to the creation of the list of similar images - cases. The created list is used for assessing the nature of the finding - whether the medical finding is malignant or benign. The suggested method is compared to the method using Normalized Compression Distance (NCD) instead of fuzzy signatures and fuzzy S-tree. The method with NCD is useful for the creation of the list of similar cases for malignancy assessment, but it is not able to capture the area of interest in the image. The proposed method is going to be added to the complex decision support system to help to determine appropriate healthcare according to the experiences of similar, previous cases. PMID- 27981410 TI - miR-106a suppresses tumor cells death in colorectal cancer through targeting ATG7. AB - Autophagy-related gene 7 (ATG7) and miR-106a play an important role in cancer cell autophagy and apoptosis, but the outcome of ATG7 and miR-106a in colorectal cancer (CRC) still remains not clear. In this study, we found that ATG7 and miR 106a expression were mutually related with cell death and prognosis in CRC patients. In addition, we also showed that ATG7 and miR-106a expression were changeable in colorectal cancer cell lines when compared with normal cell lines, but ATG7 and miR-106a mRNA level was negatively correlated. Furthermore, ATG7 protein and mRNA levels decreased after over-expression of miR-106a, whereas the suppression of ATG7 had the opposite effect. We confirmed that miR-106a down regulated ATG7 mRNA level by binding the specific sequence of ATG7 mRNA 3'UTR region. Moreover, the over-expression of ATG7 induced CRC cells death both in vitro and in vivo. Taken together, our study data demonstrated that ATG7 aggravated the cell death of CRC, which was inhibited by miR-106a. PMID- 27981411 TI - Prevalence of erosive lesions with respect to risk factors in a young adult population in Poland-a cross-sectional study. AB - OBJECTIVE: The study was conducted to investigate the prevalence of erosive lesions and related risk factors in the population of 18-year-old young adults in Poland. MATERIALS AND METHODS: Calibrated examiners measured erosive tooth wear according to Basic Erosive Wear Examination (BEWE) scoring system in 1869 patients and assessed the impact of risk factors with a questionnaire. RESULTS: Erosion was present in 42.3% of the patients. Early damage to the enamel was the most frequent finding (BEWE 1)-28.9%. More advanced lesions (BEWE 2) were observed in 12% of the patients. Advanced damage to the teeth (BEWE 3) was diagnosed rarely-1.4% of the examined population. Acidic diet, hygienic habits, and medical conditions such as asthma, eating disorders, and esophageal reflux showed statistical significance, as associated with erosion in the examined population. CONCLUSIONS: The present study indicates that dental erosion is a common oral disease in the 18-year-old population with prevalence of frequency and intensity in males. However, on the basis of observations carried out in recent years, it may be assumed that the prevalence of this type of lesion is increasing. CLINICAL RELEVANCE: Present findings support other longitudinal studies toward evaluation of the BEWE system as a valuable standard for assessing erosive and related risk factors among different populations. PMID- 27981412 TI - Survival in pediatric medulloblastoma: a population-based observational study to improve prognostication. AB - Medulloblastoma is the most common form of brain malignancy of childhood. The mainstay of epidemiological data regarding childhood medulloblastoma is derived from case series, hence population-based studies are warranted to improve the accuracy of survival estimates. To utilize a big-data approach to update survival estimates in a contemporary cohort of children with medulloblastoma. We performed a population-based retrospective observational cohort study utilizing the Surveillance, Epidemiology, and End Results Program database that captures all children, less than 20 years of age, between 1973 and 2012 in 18 geographical regions representing 28% of the US population. We included all participants with a presumed or histologically diagnosis of medulloblastoma. The main outcome of interest is survivors at 1, 5 and 10 years following diagnosis. A cohort of 1735 children with a median (interquartile range) age at diagnosis of 7 (4-11) years, with a diagnosis of medulloblastoma were identified. The incidence and prevalence of pediatric medulloblastoma has remained stable over the past 4 decades. There is a critical time point at 1990 when the overall survival has drastically improved. In the contemporary cohort (1990 onwards), the percentage of participants alive was 86, 70 and 63% at 1, 5 and 10 years, respectively. Multivariate Cox-Regression model demonstrated Radiation (HR 0.37; 95% CI 0.30 0.46, p < 0.001) and Surgery (HR 0.42; 95% CI 0.30-0.58, p < 0.001) independently predict survival. The probability of mortality from a neurological cause is <5% in patients who are alive 8 years following diagnosis. The SEER cohort analysis demonstrates significant improvements in pediatric medulloblastoma survival. In contrast to previous reports, the majority of patients survive in the modern era, and those alive 8 years following initial diagnosis are likely a long-term survivor. The importance of minimizing treatment-related toxicity is increasingly apparent given the likelihood of long-term survival. PMID- 27981413 TI - Evaluating the Impact of an Anti-stigma Intervention on Pharmacy Students' Willingness to Counsel People Living with Mental Illness. AB - Third-year pharmacy students (n = 88) participated in an anti-stigma intervention program consisting of presentations, videos, discussion and active-learning exercises. Willingness to counsel (WTC) people with mental illness (MI) was evaluated using immediate pre and post-tests comparing diabetes, depression and schizophrenia. At pre-test, WTC diabetes was highest (higher = increased WTC) while schizophrenia was the lowest. There were no statistically significant differences between pre/post-test WTC for diabetes and depression, while schizophrenia WTC increased significantly (p < 0.05). At post-test, diabetes WTC was significantly higher than depression and schizophrenia (p < 0.0001). Regression results for WTC depression showed that comfortability and gender were significant (p < 0.05) predictors. Regression results for WTC schizophrenia showed that comfortability was a significant (p < 0.05) predictor. As highly accessible healthcare providers, pharmacists have the potential to positively impact healthcare, but this depends on WTC. Colleges of pharmacy may consider instituting policies that support experiential education involving counseling people living with MI, as this may increase comfortability. PMID- 27981414 TI - MicroRNA-155: a Novel Armamentarium Against Inflammatory Diseases. AB - An increasing number of diseases are being newly closely associated with inflammation, where microRNAs seem to play a critical role in the whole disease process from initiation to development. MicroRNAs are small non-coding RNAs that govern gene expression and modulation by means of mRNA degradation or translational repression. After several profound research studies, new correlations between microRNA-155 and inflammation-related diseases are strongly emerging. Hence, we review in this paper the possible molecular mechanisms of microRNA-155 in inflammatory disorders. Furthermore, we also consider the feasibility of targeting it as a bright alternative to improve the early diagnose statistics and treatments in those diseases. MicroRNA-155 features a novel breakthrough in fine-tuning inflammatory responses and, thereby, in treating a wide spectrum of diseases with inflammation as a common denominator. PMID- 27981415 TI - Na+/H+ exchanger 3 inhibitor diminishes the amino-acid-enhanced transepithelial calcium transport across the rat duodenum. AB - Na+/H+ exchanger (NHE)-3 is important for intestinal absorption of nutrients and minerals, including calcium. The previous investigations have shown that the intestinal calcium absorption is also dependent on luminal nutrients, but whether aliphatic amino acids and glucose, which are abundant in the luminal fluid during a meal, similarly enhance calcium transport remains elusive. Herein, we used the in vitro Ussing chamber technique to determine epithelial electrical parameters, i.e., potential difference (PD), short-circuit current (Isc), and transepithelial resistance, as well as 45Ca flux in the rat duodenum directly exposed on the mucosal side to glucose or various amino acids. We found that mucosal glucose exposure led to the enhanced calcium transport, PD, and Isc, all of which were insensitive to NHE3 inhibitor (100 nM tenapanor). In the absence of mucosal glucose, several amino acids (12 mM in the mucosal side), i.e., alanine, isoleucine, leucine, proline, and hydroxyproline, markedly increased the duodenal calcium transport. An inhibitor for NHE3 exposure on the mucosal side completely abolished proline- and leucine-enhanced calcium transport, but not transepithelial transport of both amino acids themselves. In conclusion, glucose and certain amino acids in the mucosal side were potent stimulators of the duodenal calcium absorption, but only amino-acid-enhanced calcium transport was NHE3-dependent. PMID- 27981416 TI - Weight, body condition, milk production, and metabolism of Nellore cows when their calves are submitted to different supplementation levels. AB - Creep feeding has been used to reduce calves' nutritional dependence on the cow, but research results under tropical conditions have not been conclusive about the effects on the cow. Therefore, this study was conducted to evaluate the effects of high and low supplementation levels for Nellore heifer calves on performance, milk production, and metabolic profile of their mothers. Fifty multiparous Nellore cows and their respective calves were used. The following treatments were evaluated: 0-control, no supplement was fed to calves; 3-calves received supplement in the amount of 3 g/kg of body weight (BW); 6-calves received supplement in the amount of 6 g/kg of BW. There was no significant effect of level of supplementation offered to offspring on cow BW, body condition score (BCS) and subcutaneous fat thickness (P > 0.05). Level of supplementation of heifer calves did not significantly affect milk production corrected to 4% of fat (P > 0.05). Fat, protein, lactose, and total solids of the milk also did not differ among supplementation strategies (P > 0.05). Level of supplement fed to calves had no effect on cows' glucose, total cholesterol, HDL, LDL, triglycerides, total protein, and albumin levels (P > 0.05), but cows nursing calves that did not receive supplement had lower level of serum urea N (SUN; P < 0.05). We conclude that creep feeding in the amounts of 3 or 6 g/kg of BW daily has no major impact on dams' performance and metabolism. PMID- 27981417 TI - Feeding behavior of finishing goats fed diets containing detoxified castor meal, co-product of the biodiesel industry. AB - An investigation was made into the feeding behavior of goats to evaluate the effects of a detoxified castor bean meal in the diet of goats. Thirty-six 1/2 crossbred Boer goats were used, with an average weight of 20 +/- 3.2 kg. A completely randomized design was used with four treatments (diets with of 0, 100, 200, and 300 g detoxified castor bean meals/kg dry matter) and nine replicates. Castor bean meal was detoxified using calcium oxide. Diets were formulated to be isonitrogenous, and the forage:concentrate ratio was 50:50. The feeding behavior was observed on the 17th, 45th, and 70th days of the experiment. For the evaluation of feeding behavior (feeding, idle, and rumination times), the animals were observed in 5-min intervals for 24 h. The addition of detoxified castor bean meal did not change (P > 0.05) the evaluated behavioral variables. Linear reduction was observed (P < 0.05) in the efficiencies of feeding and rumination, expressed in g dry matter/h. The variables related to the time series discretization of the feeding behavior of goats did not change (P > 0.05) with the inclusion of detoxified castor bean meal. The inclusion of detoxified castor bean meal in growing goats' diets does not change the feeding, rumination, and idle times, however, decreases intake, feeding, and rumination efficiencies of dry matter. PMID- 27981421 TI - Identification of Binding Mode and Prospective Structural Features of Novel Nef Protein Inhibitors as Potential Anti-HIV Drugs. AB - Human immunodeficiency virus (HIV)-negative factor (Nef) protein is an accessory pathogenic factor, which plays a significant role in acquired immune deficiency syndrome (AIDS). Nef deficient HIV virus took a longer time to progress into AIDS. Therefore, targeting Nef protein is considered as a key strategy towards HIV/AIDS treatment. Up-to-date, only few compounds were reported as Nef inhibitors. This has prompted us to provide a first account of an integrated computational framework in order to identify more potential Nef inhibitors. Herein, using a hybrid ligand (shape similarity and pharmacophore) and structure (molecular docking) based virtual screening approaches combined with molecular dynamics as well as post dynamics analysis, potential new hits were identified as HIV-Nef inhibitors. The top ranked compounds of molecular docking from the shape similarity-based library (ZINC04177596, ? G bind= -28.7482 kcal/mol) and pharmacophore-based library (ZINC36617540, ? G bind= -20.2271 kcal/mol) possess comparatively better binding affinities than the reference molecule, B9 (? G bind = -18.0694 kcal/mol). Both these hits (ZINC04177596 and ZINC36617540) showed similar binding mode at the binding site as like the prototype, B9. Hydrophobic and electrostatic interactions seemed to be the prominent binding forces that hold these ligands at the dimer interface of Nef protein. Finally, a set of chemical structural features that can be used as a guide in the design of novel potential Nef inhibitors is also highlighted herein. We believe that the information gained from this study would be of great importance in the discovery and design of potential small molecules targeting HIV-Nef. PMID- 27981420 TI - Imaging genetics in attention-deficit/hyperactivity disorder and related neurodevelopmental domains: state of the art. AB - Joint analysis of genetic and neuroimaging data, known as Imaging Genetics (IG), offers an opportunity to deepen our knowledge of the biological mechanisms of neurodevelopmental domains. There has been exponential growth in the literature on IG studies, which challenges the standardization of analysis methods in this field. In this review we give a complete up-to-date account of IG studies on attention deficit hyperactivity disorder (ADHD) and related neurodevelopmental domains, which serves as a reference catalog for researchers working on this neurological disorder. We searched MEDLINE/Pubmed and identified 37 articles on IG of ADHD that met our eligibility criteria. We carefully cataloged these articles according to imaging technique, genes and brain region, and summarized the main results and characteristics of each study. We found that IG studies on ADHD generally focus on dopaminergic genes and the structure of basal ganglia using structural Magnetic Resonance Imaging (MRI). We found little research involving multiple genetic factors and brain regions because of the scarce use of multivariate strategies in data analysis. IG of ADHD and related neurodevelopmental domains is still in its early stages, and a lack of replicated findings is one of the most pressing challenges in the field. PMID- 27981418 TI - 17beta-Estradiol-Induced Synaptic Rearrangements Are Accompanied by Altered Ectonucleotidase Activities in Male Rat Hippocampal Synaptosomes. AB - 17beta-Estradiol (E2) rapidly, by binding to membrane estrogen receptors, activates cell signaling cascades which induce formation of new dendritic spines in the hippocampus of males as in females, but the interaction with other metabolic processes, such as extracellular adenine nucleotides metabolism, are currently unknown. Extracellular adenine nucleotides play significant roles, controlling excitatory glutamatergic synapses and development of neural circuits and synaptic plasticity. Their precise regulation in the synaptic cleft is tightly controlled by ecto-nucleoside triphosphate diphosphohydrolase (NTPDase)/ecto-5'-nucleotidase (eN) enzyme chain. Therefore, we sought to clarify whether a single systemic injection of E2 in male rats is accompanied by changes in the expression of the pre- and postsynaptic proteins and downstream kinases linked to E2-induced synaptic rearrangement as well as alterations in NTPDase/eN pathway in the hippocampal synaptosomes. Obtained data showed activation of mammalian target of rapamycin and upregulation of key synaptic proteins necessary for spine formation, 24 h after systemic E2 administration. In E2-mediated conditions, we found downregulation of NTPDase1 and NTPDase2 and attenuation of adenine nucleotide hydrolysis by NTPDase/eN enzyme chain, without changes in NTPDase3 properties and augmentation of synaptic tissue-nonspecific alkaline phosphatase (TNAP) activity. Despite reduced NTPDase activities, increased TNAP activity probably prevents toxic accumulation of ATP in the extracellular milieu and also hydrolyzes accumulated ADP due to unchanged NTPDase3 activity. Thus, our initial evaluation supports idea of specific roles of different ectonucleotidases and their coordinated actions in E2-mediated spine remodeling and maintenance. PMID- 27981422 TI - Effects of Electroporation on Tamoxifen Delivery in Estrogen Receptor Positive (ER+) Human Breast Carcinoma Cells. AB - Estrogen receptor positive breast cancer is the most common type of breast cancer and in most cases, hormone therapy is considered complementary to surgery. Tamoxifen is one of the most common drugs used in hormone therapy for treating estrogen receptor positive breast cancer cells. However, it has severe side effects depending on the duration of treating breast cancer and amount of tamoxifen used. In this study, we examined the effects of electroporation on the tamoxifen uptake in estrogen receptor positive MCF-7 breast cancer cells. The survival rate of MCF-7 cells had a negative relationship with energy dissipation in cells. Similarly, the electrical charge delivered to cells during electroporation was inversely proportional to survival rate. The combined application of electroporation and tamoxifen is much more effective than the usage of tamoxifen alone in the treatment of estrogen receptor positive breast cancer. The application of electroporation increased the uptake of tamoxifen into MCF-7 cells and reduced the minimal tamoxifen dosage which, is needed for the treatment of estrogen receptor positive breast cancer. PMID- 27981419 TI - The Novel Membrane-Bound Proteins MFSD1 and MFSD3 are Putative SLC Transporters Affected by Altered Nutrient Intake. AB - Membrane-bound solute carriers (SLCs) are essential as they maintain several physiological functions, such as nutrient uptake, ion transport and waste removal. The SLC family comprise about 400 transporters, and we have identified two new putative family members, major facilitator superfamily domain containing 1 (MFSD1) and 3 (MFSD3). They cluster phylogenetically with SLCs of MFS type, and both proteins are conserved in chordates, while MFSD1 is also found in fruit fly. Based on homology modelling, we predict 12 transmembrane regions, a common feature for MFS transporters. The genes are expressed in abundance in mice, with specific protein staining along the plasma membrane in neurons. Depriving mouse embryonic primary cortex cells of amino acids resulted in upregulation of Mfsd1, whereas Mfsd3 is unaltered. Furthermore, in vivo, Mfsd1 and Mfsd3 are downregulated in anterior brain sections in mice subjected to starvation, while upregulated specifically in brainstem. Mfsd3 is also attenuated in cerebellum after starvation. In mice raised on high-fat diet, Mfsd1 was specifically downregulated in brainstem and hypothalamus, while Mfsd3 was reduced consistently throughout the brain. PMID- 27981423 TI - Establishment and characterization of a mid-kidney cell line derived from golden pompano Trachinotus ovatus, a new cell model for virus pathogenesis and toxicology studies. AB - Golden pompano Trachinotus ovatus, a popularly cultured and commercially important marine fish worldwide, has been recognized as a promising candidate for mariculture. However, outbreaks of infectious bacterial or viral diseases and environmental deterioration have led to great economic losses in T. ovatus aquaculture recently. In our research, we established a new mid-kidney cell line, designated as TOK, from golden pompano, T. ovatus. The optimized growth temperature and working concentration of fetal bovine serum (FBS) were 28 degrees C and 10-20%, respectively. Foreign genes could express well in TOK cells. The modal number of TOK cells was 54. The TOK cells were susceptive to Singapore grouper iridovirus (SGIV) and red-spotted grouper nervous necrosis virus (RGNNV), and the virus could propagate in cells. Propagation was verified by qRT-PCR, and virions were observed under electron microscopy. Cytotoxicity analysis revealed that TOK cells were sensitive to different concentrations of extracellular products (ECPs) from Vibrio alginolyticus and V. anguillarum. Moreover, heavy metals (Cd, Cu, and Hg) also showed dose-dependent cytotoxicity to the TOK cell line. We established a mid-kidney cell line from T. ovatus which could be applied to cytotoxicity assays of heavy metals. The newly established TOK cell line possesses great application potential in genetic manipulation, virus-host interaction studies, and toxicity assays of bacterial extracellular products and heavy metals. PMID- 27981424 TI - Backbone chemical shift assignments and secondary structure analysis of the U1 protein from the Bas-Congo virus. AB - The Bas-Congo virus (BASV) is the first rhabdovirus associated with a human outbreak of acute hemorrhagic fever. The single-stranded, negative-sense RNA genome of BASV contains the five core genes present in all rhabdoviral genomes plus an additional three genes, annotated U1, U2, and U3, with weak (<21%) sequence similarity only to a handful of genes observed in a few other rhabdoviral genomes. The function of the rhabdoviral U proteins is unknown, but, they are hypothesized to play a role in viral infection or replication. To better understand this unique family of proteins, a construct containing residues 27-203 of the 216-residue U1 protein (BASV-U1*) was prepared. By collecting data in 0.5 M urea it was possible to eliminate transient association enough to enable the assignment of most of the observable 1HN, 1Halpha, 15N, 13Calpha, 13Cbeta, and 13C' chemical shifts for BASV-U1* that will provide a foundation to study its solution properties. The analyses of these chemical shifts along with 15N-edited NOESY data enabled the identification of the elements of secondary structure present in BASV-U1*. PMID- 27981426 TI - Erratum to: Return to work among self-employed cancer survivors. PMID- 27981427 TI - The Enrichment of Microbial Community for Accumulating Polyhydroxyalkanoates Using Propionate-Rich Waste. AB - Polyhydroxyalkanoates (PHAs) are promising alternatives to plastics since they have similar properties to polyolefin but are biodegradable and biocompatible. Recently, the conversion of propionate wastewater to PHAs by undefined mixed microbial cultures becomes attractive. However, how microbial community changes remains unclear during the enrichment step, which is critical for a robust PHA producing system. In this study, PHA-accumulating cultures were enriched under feast/famine condition using propionate-rich substrates. Our results showed that during the first 2 h of the enrichment, dissolved oxygen of cultures increased remarkably until saturation, and amounts of C, N, and chemical oxygen demand of cultures decreased significantly to a very low level. High-throughput sequencing revealed that bacterial populations affiliated with Alphaproteobacteria and Bacteroidetes dominated the cultures enriched. Most of these dominant populations contributed to the conversion of short-chain fatty acids to PHAs. Being fed with the substrate rich in propionate but without nitrogen, the cultures enriched could accumulate nearly 27% PHAs at 72 h with higher content of hydroxyvalerate. Our work reveals the process in which environmental microbes responded to propionate-rich condition and shifted to populations for accumulating PHAs; it also will be helpful to develop an efficient PHA-producing system using propionate-rich waste. PMID- 27981428 TI - Stiff left atrial syndrome as another cause for heart failure with preserved ejection fraction and normal BNP levels. PMID- 27981425 TI - 1H, 15N, 13C backbone resonance assignments of human soluble catechol O methyltransferase in complex with S-adenosyl-L-methionine and 3,5 dinitrocatechol. AB - Catechol O-methyltransferase (COMT) is an enzyme that plays a major role in catechol neurotransmitter deactivation. Inhibition of COMT can increase neurotransmitter levels, which provides a means of treatment for Parkinson's disease, schizophrenia and depression. COMT exists as two isozymes: a soluble cytoplasmic form (S-COMT), expressed in the liver and kidneys and a membrane bound form (MB-COMT), found mostly in the brain. Here we report the backbone 1H, 15N and 13C chemical shift assignments of S-COMT in complex with S-adenosyl-L methionine, 3,5-dinitrocatechol and Mg2+. Assignments were obtained by heteronuclear multidimensional NMR spectroscopy. In total, 97 % of all backbone resonances were assigned in the complex, with 205 out of a possible 215 residues assigned in the 1H-15N TROSY spectrum. Prediction of solution secondary structure from a chemical shift analysis using the TALOS+ webserver is in good agreement with published X-ray crystal structures. PMID- 27981429 TI - Theoretical Studies on Azaindoles as Human Aurora B Kinase Inhibitors: Docking, Pharmacophore and ADMET Studies. AB - Aurora kinases are the cell cycle mitotic regulators processing multiple functions during cell division. Altered mechanism of these mitotic kinases may contribute to genomic instability that is most often correlated with tumorigenesis, which has been reported in many human cancers. Selective blockage of the aberrantly expressed Aurora kinases has the potential therapeutic assessment to control the deregulated cell cycle machinery and their associated risks of cancer. Using a combination of docking-, ligand- and structure-based pharmacophore strategies, in the present study, we have tried to predict the anticancer potentiality of our synthesized compounds (A1 to A5 and B1 to B9) against human Aurora B kinase. The results revealed that among all the compounds, compound B7 may act as a best candidate to be an agent of the high binding affinity with a score of 113.464 kcal/mol and good pharmacophoric features with acceptable fit values of both ligand- and structure-based pharmacophore models. Consequently, ADMET properties are also calculated to predict the safer efficacy of the compounds. PMID- 27981430 TI - Comparison of Temporal Artery Thermometry with Axillary and Rectal Thermometry in Full Term Neonates. AB - OBJECTIVE: To assess the efficacy of temporal artery thermometer in febrile and hypothermic neonates in comparison to axillary thermometer. METHODS: It was a cross sectional observational study. Study participants included 210 neonates admitted in neonatal intensive care unit of a tertiary care teaching hospital, divided into three groups of 70 each, namely normothermic, febrile and hypothermic. Temperatures were measured using temporal artery, axillary and rectal thermometers in each patient. RESULTS: Mean rectal temperature was found to be comparable to mean temporal artery temperature in normothermic babies. Temporal artery thermometer had a better sensitivity to diagnose fever, than hypothermia. Also, temporal artery temperature showed a good correlation with rectal temperature in normothermic and febrile group and not in hypothermic neonates. CONCLUSIONS: Temporal artery thermometer can accurately detect temperature in febrile and normothermic fullterm neonates but not in hypothermic neonates. Further studies are required before advocating temporal artery thermometry as a replacement of rectal thermometry among this group of population. PMID- 27981431 TI - Adjusting Overall Survival Estimates after Treatment Switching: a Case Study in Metastatic Castration-Resistant Prostate Cancer. AB - BACKGROUND: If patients in oncology trials receive subsequent therapy, standard intention-to-treat (ITT) analyses may inaccurately estimate the overall survival (OS) effect of the investigational product. In this context, a post-hoc analysis of the phase 3 PREVAIL study was performed with the aim to compare enzalutamide with placebo in terms of OS, adjusting for potential confounding from switching to antineoplastic therapies that are not part of standard metastatic castration resistant prostate cancer (mCRPC) treatment pathways in some jurisdictions. METHODS: The PREVAIL study, which included 1717 chemotherapy-naive men with mCRPC randomized to treatment with enzalutamide 160 mg/day or placebo, was stopped after a planned interim survival analysis revealed a benefit in favor of enzalutamide. Data from this cutoff point were confounded by switching from both arms and so were evaluated in terms of OS using two switching adjustment methods: the two-stage accelerated failure time model (two-stage method) and inverse probability of censoring weights (IPCW). RESULTS: Following adjustment for switching to nonstandard antineoplastic therapies by 14.8 (129/872 patients) and 21.3% (180/845 patients) of patients initially randomized to enzalutamide and placebo, respectively, the two-stage and IPCW methods both resulted in numerical reductions in the hazard ratio (HR) for OS [HR 0.66, 95% confidence interval (CI) 0.57-0.81 and HR 0.63, 95% CI 0.52-0.75, respectively] for enzalutamide compared to placebo versus the unadjusted ITT analysis (HR 0.71, 95% CI 0.60-0.84). These results suggest a slightly greater effect of enzalutamide on OS than originally reported. CONCLUSION: In the PREVAIL study, switching to nonstandard antineoplastic mCRPC therapies resulted in the ITT analysis of primary data underestimating the benefit of enzalutamide on OS. PMID- 27981432 TI - The size matters: regulation of lipid storage by lipid droplet dynamics. AB - Adequate energy storage is essential for sustaining healthy life. Lipid droplet (LD) is the subcellular organelle that stores energy in the form of neutral lipids and releases fatty acids under energy deficient conditions. Energy storage capacity of LDs is primarily dependent on the sizes of LDs. Enlargement and growth of LDs is controlled by two molecular pathways: neutral lipid synthesis and atypical LD fusion. Shrinkage of LDs is mediated by the degradation of neutral lipids under energy demanding conditions and is controlled by neutral cytosolic lipases and lysosomal acidic lipases. In this review, we summarize recent progress regarding the regulatory pathways and molecular mechanisms that control the sizes and the energy storage capacity of LDs. PMID- 27981433 TI - Ambulatory Blood Pressure Monitoring in the Diagnosis and Treatment of Hypertension. AB - Clinicians should take initiatives to establish ambulatory blood pressure monitoring (ABPM) services in their own practice, or to ensure that they have access to such services elsewhere. Whenever possible, ABPM should be performed in suitable cases, where it is likely to deliver clinically useful information for making a correct diagnosis, or for tailoring the anti-hypertensive treatment regimen for each individual patient. ABPM is clinically useful, among others, for identifying people with "masked normotension", "masked hypertension", "sleep-time hypertension", and "reduced decline of sleep-time blood pressure". This review briefly outlines the rationales for the use of ABPM, interpretations of the ABPM derived parameters, and the advantages of ABPM in decision making in the management of hypertension. PMID- 27981434 TI - Novel Pathophysiological Mechanisms in Hypertension. AB - Hypertension is the most common disease affecting humans and imparts a significant cardiovascular and renal risk to patients. Extensive research over the past few decades has enhanced our understanding of the underlying mechanisms in hypertension. However, in most instances, the cause of hypertension in a given patient continues to remain elusive. Nevertheless, achieving aggressive blood pressure goals significantly reduces cardiovascular morbidity and mortality, as demonstrated in the recently concluded SPRINT trial. Since a large proportion of patients still fail to achieve blood pressure goals, knowledge of novel pathophysiologic mechanisms and mechanism based treatment strategies is crucial. The following chapter will review the novel pathophysiological mechanisms in hypertension, with a focus on role of immunity, inflammation and vascular endothelial homeostasis. The therapeutic implications of these mechanisms will be discussed where applicable. PMID- 27981435 TI - Using Webinars for the Education of Health Professionals and People Affected by Cancer: Processes and Evaluation. AB - Technology provides an opportunity to engage with a variety of audiences to provide cancer education, information and support. Webinars are one such format that allow live presentations by experts that can be accessed online, from people's homes or other convenient locations. In 2015, Cancer Council Victoria (CCV) undertook a program of work to design and evaluate the effectiveness of a suite of webinars: four designed for people affected by cancer and two for health professionals. Webinars included a series of expert presentations, a panel discussion and an interactive component where participants posed questions to the panel. Evaluation included analysis of online metrics and a post-event survey covering experience and satisfaction with the webinar, self-reported changes in knowledge of key webinar concepts and confidence to discuss concepts with health professionals or patients. A total of 438 people participated in the webinars (41.5% of 1056 registrations), and 207 post-event surveys were completed by participants (47.3%). Overall, 90.1% indicated that webinar content was relevant to their interests and needs. Self-ratings of knowledge, awareness of resources and confidence to discuss webinar topics increased after the webinar. The majority (63.9%) had not participated in a webinar before, and 92.6% were interested in participating in future webinars. Over half of respondents (52.8%) had not accessed CCV resources before. This work provided a new opportunity to consolidate consistency of delivery and evaluation of webinars, demonstrating they are an effective, acceptable, accessible and sustainable vehicle for delivering information and support to health professionals and people affected by cancer. PMID- 27981436 TI - Understanding the relation between medical students' collective and individual trajectories: an application of habitus. AB - INTRODUCTION: While medical educators typically attend to group trends, groups are made up of unique individuals. An exploration of Bourdieu's concept of habitus, defined as a system of dispositions, may help medical educators think relationally about the collective trajectory of the group and the individual trajectory of each student. METHODS: We built on our 4-year, longitudinal study which reported how field, capital, and habitus worked together to explain how medical students, as a group, navigated transitions in undergraduate medical education. In this secondary analysis, we reviewed serial collections of narratives about students' peak learning experiences in medical school (19 students, 5 narratives per student), concentrating on first-person representations of self. We then explored the relation between collective and individual trajectories in three illustrative cases. RESULTS: The social space of undergraduate medical education harmonized students' experience and helped explain the collective trajectory, as evidenced by students' consistent reports of taking initiative and staying open-minded. But individuals were not totally harmonized. They had unique dispositions that influenced their ability to access valued resources and shaped their behaviour. For example, Emily consistently spoke of being driven by her own goals; Zach focused on meeting expectations of authorities; Hilary routinely oriented toward abstract medical knowledge. DISCUSSION: Habitus provides a useful conceptual lens for thinking relationally about collective and individual trajectories of medical students. Our work may inform faculty as they seek to situate individualized learning within standardized curricula, and is a step toward researching transitions in medical training from a holistic perspective that includes, but is not limited to, individual trajectories. PMID- 27981438 TI - Interactions of emotion and anxiety on visual working memory performance. AB - It is a widely observed finding that emotion and anxiety interact; highly stressed or anxious individuals show robust attentional biases towards external negative information. More generally, research has suggested that exposure to threatening stimuli, as well as the experience of acute stress, also may impair top-down attentional control and working memory. In the current study, we investigated how the influence of emotion and anxiety may interact to influence working memory performance. Participants were required to encode the orientation of four simple shapes, eight, or four shapes while filtering out four other irrelevant shapes from memory. Before memory displays, an irrelevant neutral or fearful face cue also was presented. Memory performance was found to interact with self-reported state anxiety and cue valence; on neutral cue trials, state anxiety was negatively correlated with performance. This effect was absent following a fear cue. In addition, filtering efficiency was negatively associated with state anxiety solely following a fear cue. Our findings suggest that state anxiety's influence to visual working memory can be strongly modulated by external signals to threat. Most crucially, rather than anxious individuals having greater difficulty rejecting external threatening information, we observed that external threat may in its own right generally impair filtering efficiency in anxious individuals. PMID- 27981437 TI - Similar to the category, but not the exemplars: A study of generalization. AB - Reference point approaches have dominated the study of categorization for decades by explaining classification learning in terms of similarity to stored exemplars or averages of exemplars. The most successful reference point models are firmly grounded in the associative learning tradition-treating categorization as a stimulus generalization process based on inverse exponential distance in psychological space augmented by a dimensional selective attention mechanism. We present experiments that pose a significant challenge to popular reference point accounts which explain categorization in terms of stimulus generalization from exemplars, prototypes, or adaptive clusters. DIVA, a similarity-based alternative to the reference point framework, provides a successful account of the human data. These findings suggest that a successful psychology of categorization may need to look beyond stimulus generalization and toward a view of category learning as the induction of a richer model of the data. PMID- 27981439 TI - Development and Content Validity of the Statin Experience Assessment Questionnaire (SEAQ)(c). AB - INTRODUCTION: The National Lipid Association Statin Intolerance (SI) Panel recognized the need for better understanding of the patient SI experience. OBJECTIVE: The objective of this research was to develop a patient-reported outcome (PRO) questionnaire to assess a patient's experience with SI. METHODS: Questionnaire development was informed via a series of research activities: literature review, concept elicitation, item generation, and content evaluation. Following the literature review and concept elicitation, a draft questionnaire was constructed and subsequently modified based on feedback from therapeutic area experts and patients via cognitive debriefing interviews. RESULTS: Muscle-related symptoms were the most commonly reported symptoms associated with SI in the literature review (35 of 41 articles reviewed [85%]) and in semi-structured interviews with experts (n = 5 [100%]) and patients (n = 17 of 20 [85.0%]). Physical and other impacts of SI symptoms on daily activities were also frequently reported. A 17-item draft questionnaire was created, and cognitive debriefing with experts (n = 5) and patients (n = 15) was conducted. Overall, the items, response options, and instructions were comprehensible and positively reviewed; minor changes resulted in the 15-item Statin Experience Assessment Questionnaire (SEAQ)(c). Using a 30-day recall period, the SEAQ(c) assesses the severity and impact of six SI symptoms (muscle ache, muscle pain, muscle cramps, muscle weakness, tiredness, and joint pain) on an 11-point numeric scale. Statin discontinuation and likelihood of discontinuation due to symptoms are assessed and scored on a yes/no and five-point verbal response scale, respectively. CONCLUSION: The SEAQ PMID- 27981440 TI - Visceral fat is associated with brain structure independent of human immunodeficiency virus infection status. AB - The combined effects of human immunodeficiency virus (HIV), obesity, and elevated visceral adipose tissue (VAT) on brain structure are unknown. In a cross sectional analysis of Multicenter AIDS Cohort Study (MACS) participants, we determined associations between HIV serostatus, adiposity, and brain structure. Men (133 HIV+, 84 HIV-) in the MACS Cardiovascular 2 and magnetic resonance imaging (MRI) sub-studies with CT-quantified VAT and whole brain MRI measured within 1 year were assessed. Voxel-based morphometry analyzed brain volumes. Men were stratified by elevated (eVAT, >=100cm2) or "normal" (nVAT, <100cm2) VAT. Forward stepwise modeling determined associations between clinical and demographic variables and regional brain volumes. eVAT was present in 67% of men. Groups were similar in age and education, but eVAT men were more likely to be HIV+ and have hypertension, diabetes mellitus, body mass index >25 kg/m2, smaller gray and white matter volumes, and larger cerebrospinal fluid volume than nVAT men. In multivariate analysis, hypertension, higher adiponectin, higher interleukin-6, age, diabetes mellitus, higher body mass index, and eVAT were associated with brain atrophy (p < 0.05, ordered by increasing strength of association), but HIV serostatus and related factors were generally not. No interactions were observed. Greater VAT was associated with smaller bilateral posterior hippocampus and left mesial temporal lobe and temporal stem white matter volume. Traditional risk factors are more strongly associated with brain atrophy than HIV serostatus, with VAT having the strongest association. However, HIV+ MACS men had disproportionately greater VAT, suggesting the risk for central nervous system effects may be amplified in this population. PMID- 27981441 TI - Distribution of cellular HSV-1 receptor expression in human brain. AB - Herpes simplex virus type 1 (HSV-1) is a neurotropic virus linked to a range of acute and chronic neurological disorders affecting distinct regions of the brain. Unusually, HSV-1 entry into cells requires the interaction of viral proteins glycoprotein D (gD) and glycoprotein B (gB) with distinct cellular receptor proteins. Several different gD and gB receptors have been identified, including TNFRSF14/HVEM and PVRL1/nectin 1 as gD receptors and PILRA, MAG, and MYH9 as gB receptors. We investigated the expression of these receptor molecules in different areas of the adult and developing human brain using online transcriptome databases. Whereas all HSV-1 receptors showed distinct expression patterns in different brain areas, the Allan Brain Atlas (ABA) reported increased expression of both gD and gB receptors in the hippocampus. Specifically, for PVRL1, TNFRFS14, and MYH9, the differential z scores for hippocampal expression, a measure of relative levels of increased expression, rose to 2.9, 2.9, and 2.5, respectively, comparable to the z score for the archetypical hippocampus-enriched mineralocorticoid receptor (NR3C2, z = 3.1). These data were confirmed at the Human Brain Transcriptome (HBT) database, but HBT data indicate that MAG expression is also enriched in hippocampus. The HBT database allowed the developmental pattern of expression to be investigated; we report that all HSV1 receptors markedly increase in expression levels between gestation and the postnatal/adult periods. These results suggest that differential receptor expression levels of several HSV-1 gD and gB receptors in the adult hippocampus are likely to underlie the susceptibility of this brain region to HSV-1 infection. PMID- 27981442 TI - Graphene Oxide as a Novel Evenly Continuous Phase Matrix for TOF-SIMS. AB - Using matrix to enhance the molecular ion signals for biomolecule identification without loss of spatial resolution caused by matrix crystallization is a great challenge for the application of TOF-SIMS in real-world biological research. In this report, graphene oxide (GO) was used as a matrix for TOF-SIMS to improve the secondary ion yields of intact molecular ions ([M + H]+). Identifying and distinguishing the molecular ions of lipids (m/z >700) therefore became straightforward. The spatial resolution of TOF-SIMS imaging could also be improved as GO can form a homogeneous layer of matrix instead of crystalline domain, which prevents high spatial resolution in TOF-SIMS imaging. Lipid mapping in presence of GO revealed the delicate morphology and distribution of single vesicles with a diameter of 800 nm. On GO matrix, the vesicles with similar shape but different chemical composition could be distinguished using molecular ions. This novel matrix holds potentials in such applications as the analysis and imaging of complex biological samples by TOF-SIMS. Graphical Abstract ?. PMID- 27981443 TI - Distinct Fragmentation Pathways of Anticancer Drugs Induced by Charge-Carrying Cations in the Gas Phase. AB - With the growth of the pharmaceutical industry, structural elucidation of drugs and derivatives using tandem mass spectrometry (MS2) has become essential for drug development and pharmacokinetics studies because of its high sensitivity and low sample requirement. Thus, research seeking to understand fundamental relationships between fragmentation patterns and precursor ion structures in the gas phase has gained attention. In this study, we investigate the fragmentation of the widely used anticancer drugs, doxorubicin (DOX), vinblastine (VBL), and vinorelbine (VRL), complexed by a singly charged proton or alkali metal ion (Li+, Na+, K+) in the gas phase. The drug-cation complexes exhibit distinct fragmentation patterns in tandem mass spectra as a function of cation size. The trends in fragmentation patterns are explicable in terms of structures derived from ion mobility mass spectrometry (IM-MS) and theoretical calculations. Graphical Abstract ?. PMID- 27981445 TI - Patterns of sorafenib and TACE treatment of unresectable hepatocellular carcinoma in a Chinese population: subgroup analysis of the GIDEON study. AB - To analyze safety and efficacy of patterns of sorafenib and TACE therapy under real-life clinical practice conditions. A total of 338 Chinese patients with unresectable hepatocellular carcinoma (HCC) from the international database of the GIDEON non-interventional trial were included in this analysis. Endpoints were overall survival (OS), progression-free survival (PFS), time to progression (TTP) and safety. Two major patterns in the use of sorafenib observed in current Chinese clinical practice were: sorafenib administration subsequent to transarterial chemoembolization (TACE) treatment (n = 226, 66.9%) and sorafenib administration concomitant to TACE (n = 80, 35.4%). Patients receiving TACE prior to sorafenib had worse liver function (43.8% BCLC stage Cat diagnosis and 62.1% BCLC stage C at study entry) than those receiving TACE concomitant to sorefenib (35.0% BCLC stage C at diagnosis and 51.3% BCLC stage three at study entry). For patients undergoing prior TACE and concomitant TACE treatment, median OS time was 354 days vs. 608 days, PFS time was 168 days vs. 201 days, and TTP was 214 days vs. 205 days; and the percentage of patients who experienced drug-related adverse effects after sorafenib therapy in these two groups were 33.3 and 50.0%, respectively. Sorafenib treatment is usually administered in cases of tumor progression or poor liver function status after TACE treatment in China. Under such conditions, patients still gained a relatively satisfactory survival outcome. In addition, the present study suggests that concomitant sorafenib and TACE treatments may lead to a better prognosis, although differences in baseline characteristics may have contributed in part to the better outcomes. PMID- 27981446 TI - Comparative capability of menstrual blood versus bone marrow derived stem cells in neural differentiation. AB - In order to characterize the potency of menstrual blood stem cells (MenSCs) for future cell therapy of neurological disorders instead of bone marrow stem cells (BMSCs) as a well-known and conventional source of adult stem cells, we examined the in vitro differentiation potential of these stem cells into neural-like cells. The differentiation potential of MenSCs to neural cells in comparison with BMSCs was assessed under two step neural differentiation including conversion to neurosphere-like cells and final differentiation. The expression levels of Nestin, Microtubule-associated protein 2, gamma-aminobutyric acid type B receptor subunit 1 and 2, and Tubulin, beta 3 class III mRNA and/or protein were up regulated during development of MenSCs into neurosphere-like cells (NSCs) and neural-like cells. The up-regulation level of these markers in differentiated neural-like cells from MenSCs was comparable with differentiated cells from BMSCs. Moreover, both differentiated MenSCs and BMSCs expressed high levels of potassium, calcium and sodium channel genes developing functional channels with electrophysiological recording. For the first time, we demonstrated that MenSCs are a unique cell population with differentiation ability into neural-like cells comparable to BMSCs. In addition, we have introduced an approach to generate NSCs from MenSCs and BMSCs and their further differentiation into neural-like cells in vitro. Our results hold a promise to future stem cell therapy of neurological disorders using NSCs derived from menstrual blood, an accessible source in every woman. PMID- 27981447 TI - The Differential Effects of an Opt-Out HIV Testing Policy for Pregnant Women in Ethiopia When Accounting for Stigma: Secondary Analysis of DHS Data. AB - Individual factors associated with HIV testing have been studied across multiple populations; however, testing is not just an individual-level phenomenon. This secondary analysis of 2005 and 2011 Ethiopia Demographic and Health Survey data was conducted to determine the extent to which the 2007 institution of an opt-out policy of HIV testing during antenatal care increased testing among women, and whether effects differed by women's stigmatizing beliefs about HIV. A logit model with interaction between pre-/post-policy year and policy exposure (birth in the past year) was used to estimate the increased probability of past-year testing, which may be attributable to the policy. Results suggested the policy contributed to a nine-point increase in the probability of testing (95% CI 0.06-0.13, p < 0.0001). A three-way interaction was used to compare the effects of exposure to the policy among women holding higher and lower HIV stigmatizing beliefs. The increase in the probability of past-year testing was 16 percentage points greater among women with lower stigmatizing beliefs (95% CI 0.06-0.27, p = 0.002). Women with higher stigmatizing beliefs were less likely to report attending antenatal care (ANC), testing at their last ANC visit, or being offered a test at their last ANC visit. We encourage researchers and practitioners to explore interventions that operate at multiple levels of socio-ecological spheres of influence, addressing both stigma and structural barriers to testing, in order to achieve the greatest results in preventing HIV. PMID- 27981448 TI - Short-Term Effects on Family Communication and Adolescent Conduct Problems: Familias Unidas in Ecuador. AB - : Familias Unidas, a Hispanic/Latino-specific, parent-centered intervention, found to be efficacious in improving family functioning and reducing externalizing behaviors among youth in the USA, was recently adapted and tested for use in Ecuador. This study examined the short-term efficacy of Familias Unidas in Ecuador on parent-adolescent communication, parental monitoring of peers, and youth conduct problems. Two hundred thirty-nine youths (ages 12-14 years) and their primary care givers were randomized to either Familias Unidas or Community Practice and assessed pre- and post-intervention. There was a significant difference between Familias Unidas and Community Practice in conduct problems at 3 months (standardized beta = -.101, p = .001, effect size = .262). A significant indirect intervention effect was also detected, indicating that Familias Unidas predicted conduct problems at 3 months through parent-adolescent communication at 3 months (standardized beta = -.036, p = .016, CI 95% [-.066, .007], effect size = .265). Familias Unidas was efficacious in reducing conduct problems through improved parent-adolescent communication, relative to Community Practice. Future assessments will determine whether Familias Unidas also has an impact on substance use and sexual risk behaviors at later time points, as demonstrated in past Familias Unidas trials. The short-term effects of the intervention, family engagement, and facilitator skill in the Ecuadorian adaptation of Familias Unidas are promising. This study implies that an intervention developed for Hispanics/Latinos in the USA and culturally adapted and implemented for use by Hispanics/Latinos in a Latin American country can be efficacious in improving family functioning and reducing youth conduct problems. TRIAL REGISTRATION: MSP-DIS-2015-0055-0, Ministry of Public Health (MSP), Ecuador. PMID- 27981444 TI - Hyperglycaemia Induced by Novel Anticancer Agents: An Undesirable Complication or a Potential Therapeutic Opportunity? AB - Signalling pathways involving protein kinase, insulin-like growth factor 1, insulin receptors and the phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) system are critical in promoting oncogenesis. The use of anticancer agents that inhibit these pathways frequently results in hyperglycaemia, an on-target effect of these drugs. Hyperglycaemia induced by these agents denotes optimal inhibition of the desired pharmacological target. As hyperglycaemia can be treated successfully and effectively with metformin, managing this complication by reducing the dose of or discontinuing the anticancer drug may be counterproductive, especially if it is otherwise effective and clinically tolerated. The use of metformin to treat hyperglycaemia induced by anticancer drugs provides a valuable therapeutic opportunity of potentiating their clinical anticancer effects. Although evidence from randomised controlled trials is awaited, extensive preclinical evidence and clinical observational studies suggest that metformin has anticancer properties that improve overall survival in patients with diabetes and a variety of cancers. Metformin has also been reported to reverse resistance to epidermal growth factor receptor (EGFR) inhibiting tyrosine kinase inhibitors. This review summarises briefly the role of the above signalling pathways in oncogenesis, the causal association between inhibition of these pathways and hyperglycaemia, and the effect of metformin on clinical outcomes resulting from its anticancer properties. The evidence reviewed herein, albeit almost exclusively from observational studies, provides support for a greater use of metformin not only in patients with cancer and diabetes or drug-induced hyperglycaemia but also potentially as an anticancer drug. However, prospective randomised controlled studies are needed in all these settings to better assess the effect on clinical outcomes of adding metformin to ongoing anticancer therapy. PMID- 27981450 TI - Drug Distribution. Part 1. Models to Predict Membrane Partitioning. AB - PURPOSE: Tissue partitioning is an important component of drug distribution and half-life. Protein binding and lipid partitioning together determine drug distribution. METHODS: Two structure-based models to predict partitioning into microsomal membranes are presented. An orientation-based model was developed using a membrane template and atom-based relative free energy functions to select drug conformations and orientations for neutral and basic drugs. RESULTS: The resulting model predicts the correct membrane positions for nine compounds tested, and predicts the membrane partitioning for n = 67 drugs with an average fold-error of 2.4. Next, a more facile descriptor-based model was developed for acids, neutrals and bases. This model considers the partitioning of neutral and ionized species at equilibrium, and can predict membrane partitioning with an average fold-error of 2.0 (n = 92 drugs). CONCLUSIONS: Together these models suggest that drug orientation is important for membrane partitioning and that membrane partitioning can be well predicted from physicochemical properties. PMID- 27981449 TI - Effects of Excipient Interactions on the State of the Freeze-Concentrate and Protein Stability. AB - PURPOSE: The physical state of excipients in freeze-dried formulations directly affects the stability of the active pharmaceutical ingredient (API). Crystallization of trehalose and mannitol in frozen solutions has been shown to be a function of composition. However, to date a detailed study of the effect of concentrations of the API and other excipients on the crystallinity of mannitol and trehalose in frozen solutions has not been reported. METHODS: The crystallinity of mannitol and trehalose in frozen solutions was characterized by Differential Scanning Calorimetry, X-ray diffractometry, and FTIR spectroscopy. The secondary structure of BSA was probed by FTIR, and Circular Dichroism spectroscopy in frozen and thawed solutions, respectively. RESULTS: Trehalose crystallization was accompanied by unfolding of BSA. BSA delayed and reduced the extent of mannitol and trehalose crystallization. Similar effects were observed upon adding D2O (>=5% w/w) and low concentrations of polysorbate 20 (<=0.2% w/w) with retention of BSA in its native conformation. At high BSA to trehalose mass ratio, the protein could stabilize itself in the frozen state, but unfolded upon thawing. CONCLUSIONS: The API and other excipients, in a concentration-dependent manner, influenced the physical state of the freeze concentrate as well as the stability of the API. PMID- 27981452 TI - Analysis of complications and perioperative data after open or percutaneous dorsal instrumentation following traumatic spinal fracture of the thoracic and lumbar spine: a retrospective cohort study including 491 patients. AB - PURPOSE: The aim of the current study is to analyze perioperative data and complications of open vs. percutaneous dorsal instrumentation after dorsal stabilization in patients suffering from fractures of the thoracic or lumbar spine. METHODS: In the time period from 01/2007 to 06/2009, open surgical approach was used for dorsal stabilization. The percutaneous surgical approach was used from 05/2009 to 03/2014. In every time period, all types of fractures were treated only by open or by percutaneous approach, respectively, to avoid any selection bias. Retrospectively, epidemiological data, complications and perioperative data were documented and statistically analyzed. RESULTS: A total of 491 patients met the inclusion criteria. Open surgery procedure was carried out on 169 patients, and percutaneous surgery procedure was carried out on 322 patients. Fracture level ranged from T1 to L5, and fractures were classified types A, B, and C. In 91.4% of all patients, no complication occured following dorsal stabilization after traumatic spine fracture during their hospital stay. However, 42 complications related to dorsal stabilization have been documented during the hospital stay. The complication rate was 14.8% if open surgical approach has been used and was significantly reduced to 5.3% using percutaneous surgical approach. Post-operative hospital stay was also reduced significantly using the percutaneous surgical approach. CONCLUSIONS: According to the current study, percutaneous dorsal stabilization of the spine could also be safely used in trauma cases and is not restricted to degenerative spinal surgery. PMID- 27981453 TI - Aggressive osteoblastoma of the cervical spine involving the canal and vertebral artery: a case report. AB - OBJECTIVE: We present such a case of aggressive osteoblastoma of cervical spine. We describe its complicated clinical progression, hoping to shed light on the surgical strategy of this complex tumor. METHODS: We present such a case of aggressive osteoblastoma involving the C6-7 vertebrae. A 25-year-old man was diagnosed as aggressive osteoblastoma of the cervical spine. The lesion encroached upon the radicular foramina and was located adjacent to the canal of the vertebral artery. Preoperative embolization was performed to reduce intraoperative bleeding and to prevent intraoperative injury of the vertebral artery. RESULTS: A pathologic examination showed osteoblasts suggestive of osteoblastoma. At 2-year follow-up, bony union was achieved, and there was no evidence of recurrence on a CT scan. CONCLUSION: En bloc total resection for highly vascular osteoblastoma is ideal, but this case shows that piecemeal total resection following preoperative embolization is a surgical option for highly expansive osteoblastoma. PMID- 27981451 TI - Bromelain-Functionalized Multiple-Wall Lipid-Core Nanocapsules: Formulation, Chemical Structure and Antiproliferative Effect Against Human Breast Cancer Cells (MCF-7). AB - PURPOSE: This study was conducted a promising approach to surface functionalization developed for lipid-core nanocapsules and the merit to pursue new strategies to treat solid tumors. METHODS: Bromelain-functionalized multiple wall lipid-core nanocapsules (Bro-MLNC-Zn) were produced by self-assembling following three steps of interfacial reactions. Physicochemical and structural characteristics, in vitro proteolytic activity (casein substrate) and antiproliferative activity (breast cancer cells, MCF-7) were determined. RESULTS: Bro-MLNC-Zn had z-average diameter of 135 nm and zeta potential of +23 mV. The complex is formed by a Zn-N chemical bond and a chelate with hydroxyl and carboxyl groups. Bromelain complexed at the nanocapsule surface maintained its proteolytic activity and showed anti-proliferative effect against human breast cancer cells (MCF-7) (72.6 +/- 1.2% at 1.250 MUg mL-1 and 65.5 +/- 5.5% at 0.625 MUg mL-1). Comparing Bro-MLNC-Zn and bromelain solution, the former needed a dose 160-folds lower than the latter for a similar effect. Tripan blue dye assay corroborated the results. CONCLUSIONS: The surface functionalization approach produced an innovative formulation having a much higher anti-proliferative effect than the bromelain solution, even though both in vitro proteolytic activity were similar, opening up a great opportunity for further studies in nanomedicine. PMID- 27981454 TI - Is the duration of pre-operative conservative treatment associated with the clinical outcome following surgical decompression for lumbar spinal stenosis? A study based on the Spine Tango Registry. AB - BACKGROUND: The incidence of lumbar spinal stenosis (LSS) continues to rise, with both conservative and surgical management representing options for its treatment. The timing of surgery for LSS varies from shortly after the onset of symptoms to several months or years after conservative treatment. The aim of this study was to investigate the association between the duration of pre-operative conservative treatment and the ultimate outcome following surgical interventions for LSS. METHODS: The study was based on prospective multicentre registry data (Spine Tango). Cases of LSS with a documented duration of conservative treatment, undergoing spinal decompression with at least one post-operative patient assessment between 3 and 30 months, were included in the study. Cases of LSS with spondylolisthesis, additional spinal pathology or previous spinal surgery were excluded. Interrogation of the Spine Tango Registry listed 3478 patients meeting the prescribed inclusion criteria. This cohort was stratified into four groups: (1) no previous treatment (n = 497; 14.3%), (2) conservative treatment <6 months (n = 965; 27.8%), (3) conservative treatment between 6 and 12 months (n = 758; 21.8%), and (4) conservative treatment >12 months (n = 1258; 36.1%). Group 4 reference group in regression analysis. The inverse probability of treatment weighting (IPTW) was applied using the propensity score to balance the groups for their characteristics. Outcome measures included achievement of the minimum clinically important change (MCIC) score of 2 points for (a) back pain, (b) leg pain and (c) Core Outcome Measures Index (COMI), and (d) surgical complications, (e) general complications and (f) operation time >2 h. RESULTS: Patient group ("duration of conservative therapy") was not associated with achievement of the MCIC for post-operative relief of leg pain (p = 0.22), achievement of MCIC for the COMI score (p = 0.054), surgical complications (p = 0.11) or general complications (p = 0.14). Only MCIC for post-operative relief of back pain (p = 0.021) and operation time were significantly associated with patient group (p = 0.038). However, compared with the reference group of >12 months of conservative treatment there was no significant difference in the likelihood of achieving the MCIC for those with none, <6 or 6-12 months of conservative treatment. CONCLUSIONS: The duration of pre-operative conservative treatment was not associated with the ultimate outcome of decompression surgery. Further research is required to investigate optimal thresholds/indications for surgery and its appropriate timing in individual patients. PMID- 27981456 TI - Molecular dynamics study of nitrogen diffusion in nanocrystalline iron. AB - To obtain a deeper understanding of the production of advanced high-nitrogen steels, the diffusivity of nitrogen in bcc iron was investigated at the nanoscale by molecular dynamics (MD) simulation using the modified embedded-atom method (MEAM) interatomic potential. The diffusivity of nitrogen was calculated by mean square displacement (MSD) at different temperatures (773-1473 K) and nitrogen concentrations (0.23, 0.77, and 1.50 wt.%). The results show that the diffusion coefficient increases with temperature and decreases with increasing nitrogen concentration. The temperature dependence of the diffusion coefficient according to the Arrhenius equation was obtained. Activation energies and pre-exponential factors for different nitrogen concentrations were derived from the diffusion coefficient. PMID- 27981455 TI - Is physiotherapy integrated virtual walking effective on pain, function, and kinesiophobia in patients with non-specific low-back pain? Randomised controlled trial. AB - PURPOSE: According to literature, virtual reality was found to reduce pain and kinesiophobia in patients with chronic pain. The purpose of the study was to investigate short-term effect of the virtual reality on pain, function, and kinesiophobia in patients with subacute and chronic non-specific low-back pain METHODS: This randomised controlled study in which 44 patients were randomly assigned to the traditional physiotherapy (control group, 22 subjects) or virtual walking integrated physiotherapy (experimental group, 22 subjects). Before and after treatment, Visual Analog Scale (VAS), TAMPA Kinesiophobia Scale (TKS), Oswestry Disability Index (ODI), Nottingham Health Profile (NHP), Timed-up and go Test (TUG), 6-Minute Walk Test (6MWT), and Single-Leg Balance Test were assessed. The interaction effect between group and time was assessed by using repeated measures analysis of covariance. RESULTS: After treatment, both groups showed improvement in all parameters. However, VAS, TKS, TUG, and 6MWT scores showed significant differences in favor of the experimental group. CONCLUSION: Virtual walking integrated physiotherapy reduces pain and kinesiophobia, and improved function in patients with subacute and chronic non-specific low-back pain in short term. PMID- 27981457 TI - Bariatric Surgery Ameliorates Diabetic Cardiac Dysfunction by Inhibiting ER Stress in a Diabetic Rat Model. AB - BACKGROUND: Cardiac dysfunction is a severe complication of diabetes, with no effective treatment. Currently, bariatric surgery is more and more widely used to attenuate diabetes-associated diseases. The mechanism is not clear. Endoplasmic reticulum (ER) stress-dependent apoptosis has been observed in the progression of diabetic myocardium damage. Therefore, this research was designed to investigate the effects of different bariatric procedures on cardiac dysfunction via ER stress-induced cardiomyocyte apoptosis pathway in a diabetic rat model. METHODS: Duodenal-jejunal bypass (DJB), sleeve gastrectomy (SG), and sham surgery were performed in diabetic rats. Echocardiographic examination, H&E staining, Masson staining, and TUNEL staining were performed to measure the diabetes-caused heart damages. ER stress-associated signaling molecules like glucose-regulated protein 78 (GRP78), protein kinase RNA (PKR)-like ER protein kinase (PERK), p-PERK, inositol-requiring enzyme 1alpha (IRE1alpha), p-IRE1alpha, activating transcription factor 6 (ATF6), C/EBP homologous protein (CHOP), and caspase 12 were measured and compared among DJB group, SG group, and sham group. RESULTS: Compared with sham group, DJB and SG groups both had significantly lower GRP78, PERK, p-PERK, CHOP, and caspase 12, though there was no statistical change on IRE1alpha, p-IRE1alpha, and ATF6. DJB and SG groups also showed improved heart function and lower cardiomyocyte apoptosis in diabetic rats. CONCLUSION: DJB and SG ameliorated cardiac dysfunction by inhibiting PERK-mediated pathway. And no difference was observed on the effects of DJB and SG on ER stress-dependent myocardium damage in diabetic rats. PMID- 27981458 TI - Bariatric Surgery or Non-surgical Weight Loss for Idiopathic Intracranial Hypertension? A Systematic Review and Comparison of Meta-analyses. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is associated with obesity and weight loss by any means is considered beneficial in this condition. OBJECTIVES: This study aims to appraise bariatric surgery vs. non-surgical weight loss (medical, behavioural and lifestyle) interventions in IIH management. METHODS: A systematic review and meta-analyses of surgical and non-surgical studies. RESULTS: Bariatric surgery achieved 100% papilloedema resolution and a reduction in headache symptoms in 90.2%. Non-surgical methods offered improvement in papilloedema in 66.7%, visual field defects in 75.4% and headache symptoms in 23.2%. Surgical BMI decrease was 17.5 vs. 4.2 for non-surgical methods. CONCLUSIONS: Whilst both bariatric surgery and non-surgical weight loss offer significant beneficial effects on IIH symptomatology, future studies should address the lack of prospective and randomised trials to establish the optimal role for these interventions. PMID- 27981459 TI - Taste, Enjoyment, and Desire of Flavors Change After Sleeve Gastrectomy-Short Term Results. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) incidence continues to increase worldwide because of its efficacy and low surgical risks. This study aimed to investigate satisfaction with eating and the change in taste perception, desire, and enjoyment of flavor changes and associations with extent of percentage excess weight loss (%excess weight loss (EWL)) post-LSG. METHODS: One hundred six participants completed an online questionnaire 4 to 6 weeks as well as 6 to 8 months post-LSG bariatric surgery. The questionnaire included study-specific questions about changes in taste, desire, and enjoyment of eight major categories of flavor, as well as the Suter Quality of Alimentation Questionnaire to measure satisfaction with eating. RESULTS: The majority of participants reported a post surgery increase in the intensity of the flavor of sweet (60, 55%) and fatty (57, 70%) at both time points, respectively. Participants also reported a decreased enjoyment for sweet (77, 61%) and fatty (77, 83%) flavors and decreased desire for fatty (83, 84%) and sweet (82, 68%) flavors at both time periods. This study found an increase in intensity of flavor of all eight taste modalities and a decrease in desire and enjoyment of all taste modalities except salty and savory flavors following surgery. Participants reported an increased acuity of spicy flavors and fatty tastes over time, and the desire and enjoyment of sweet, bitter, and metallic flavors increased over time. Changes in savory enjoyment over a 6- to 8-month period post-LSG were weakly associated with extent of % EWL at 6 months post-surgery. The participants reported average (40, 37%), good (33, 42%), and excellent (15, 11%) satisfaction with eating at both time points. CONCLUSION: This preliminary study indicates that subjective changes in taste, desire, and enjoyment of flavors of eight taste modalities are very common after LSG. PMID- 27981460 TI - HER2/HER3 pathway in biliary tract malignancies; systematic review and meta analysis: a potential therapeutic target? AB - Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as "high quality" (HQ) if IHC overexpression was defined as presence of moderate/strong staining or "low quality" (LQ) where "any" expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9-34.1 %). When HQ studies were analyzed (n = 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8-27.1 %) vs. 4.8 % (95 % CI 0-14.5 %), respectively, p value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to "unselected" patients: 57.6 % (95 % CI 16.2-99 %) vs. 17.9 % (95 % CI 0.1-35.4 %), respectively, p value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7-46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials. PMID- 27981462 TI - An educational leaflet improves response to invitation for screening for arthritis in patients with psoriasis in primary care, but only in practices in the most deprived areas. AB - This study hypothesises that an educational leaflet about psoriatic arthritis (PsA) will improve psoriasis patients' attendance for screening for PsA. A random sample of patients >=18 years old with a coded diagnosis of psoriasis and no diagnosis of PsA, rheumatoid arthritis or ankylosing spondylitis were identified from five GP surgeries in Yorkshire, UK. Patients were randomised 1:1 to receive study information alone or with the educational leaflet, with an invitation to attend for a screening examination by a dermatologist and rheumatologist. Nine hundred thirty-two invitation packs were sent to recruit 191 (20.5%) participants. One hundred sixty-nine (88.5%) had current or previous psoriasis and 17 (10.1%) had previously undiagnosed PsA. The estimated prevalence of PsA was 18.1% (95% CI: 16.2, 20.1%).The response rate was lower than expected and was not significantly higher when patients received the educational leaflet (22.8 vs 18.3%, p = 0.08). Response rates varied by practice (14.7 to 30.6%). However, deprivation scores for each practice revealed a significant increase in response with the leaflet for deprivation decile of 3 (p < 0.001) but no significant differences in the other practices. An educational leaflet about PsA improves attendance for screening in primary care, but only in those practices with higher levels of socioeconomic deprivation. PMID- 27981461 TI - Plasma ficolin levels and risk of nephritis in Danish patients with systemic lupus erythematosus. AB - Given the scavenging properties of ficolins, we hypothesized that variation in the plasma concentrations of the three ficolins may be associated with development of lupus nephritis (LN), type of LN, end-stage renal disease (ESRD), and/or mortality among patients with systemic lupus erythematosus (SLE). SLE patients attending a Danish tertiary rheumatology referral center were included. Plasma concentrations of ficolin-1, ficolin-2, and ficolin-3 were determined and dichotomized by the median into high and low. LN was defined by clinical criteria; type of LN by renal biopsy; ESRD follow-up time was defined as time from onset of LN to the development of ESRD or censoring at the end of follow-up. The study included 112 SLE patients with median disease duration of 8 years of which 53 (47%) had LN at the time of inclusion. During a median follow-up of 10 years, five patients developed ESRD. Sixteen patients died. Odds ratios (ORs) of LN were 1.2 (95% CI: 0.6-2.7), 4.1 (95% CI: 1.7-9.7), and 0.9 (95% CI: 0.4-2.0) for patients with low ficolin-1, ficolin-2, and ficolin-3 plasma levels, respectively. The distribution of histological classes differed between patients with high and low plasma levels of ficolin-1 (p = 0.009). Patients with high ficolin-1 plasma levels had an increased risk of ESRD. There was no association between the levels of the analyzed plasma ficolins and mortality. Low plasma ficolin-2 levels were associated with an increased risk of having LN. High plasma levels of ficolin-1 were associated with the histological subtype of LN and development of ESRD. PMID- 27981465 TI - Area-based fuzzy membership forest cover comparison between MODIS NPP and Forest Inventory and Analysis (FIA) across eastern U.S. forest. AB - This research assessed the accuracy of the moderate resolution imaging spectroradiometer's (MODIS) land cover classification of softwood and hardwood using a fuzzy-based approach for 31 easternmost states in the U.S. Our main objective was to quantitatively evaluate spatially explicit land cover classifications of MODIS net primary product (NPP) scheme using the USDA Forest Service's (FS) field-based, tree-specific Forest Inventory Analysis (FIA). We used a grid of 648 km2 hexagons as base mapping units and interpreted our results at the USDA FS level IV ecological regions. Forest area was calculated for both MODIS and FIA and were found to be strongly correlated (Pearson's r = 0.875, p < 0.01), which suggests the two classifications are comparable. Area-based fuzzy memberships of softwood and hardwood forest were determined for both MODIS and FIA for each hexagon. We used cross-entropy (H c) to evaluate the accuracy of the MODIS classification. Our results determined that the accuracy of MODIS forest cover classification was not uniform for all ecological regions. Tree species importance values (IV) and Shannon's diversity index (H s) were calculated to examine species abundance and heterogeneity, which may partially explain discrepancies between MODIS and FIA classifications. The greatest misclassifications were due to (1) MODIS underestimating softwood forest cover and (2) MODIS confusing forest cover with other land covers such as grassland, cropland, or woody savanna. Our results provide a guideline for users to understand the degree of uncertainty of MODIS forest cover classifications in the eastern USA. PMID- 27981464 TI - Assessing coral health and disease from digital photographs and in situ surveys. AB - Methods for monitoring the status of marine communities are increasingly adopting the use of images captured in the field. However, it is not always clear how data collected from photographic images relate to historic data collected using traditional underwater visual census methods. Here, we compare coral health and disease data collected in situ by scuba divers with photographic images collected simultaneously at 12 coral reef sites. Five globally relevant coral diseases were detected on 194 colonies from in situ surveys and 79 colonies from photos, whilst 698 colonies from in situ surveys and 535 colonies from photos exhibited signs of compromised health other than disease. Comparisons of in situ surveys with photographic analyses indicated that the number of disease cases occurring in the examined coral populations (prevalence) was six times higher (4.5 vs. 0.8% of colonies), whilst compromised health was three times higher (14 vs. 4% of colonies) from in situ surveys. Skeletal eroding band disease, sponge overgrowth and presence of Waminoa flatworms were not detected in photographs, though they were identified in situ. Estimates of black band disease and abnormally pigmented coral tissues were similar between the two methods. Estimates of the bleached and healthy colonies were also similar between methods and photographic analyses were a strong predictor of bleached (r 2 = 0.8) and healthy (r 2 = 0.5) colony prevalence from in situ surveys. Moreover, when data on disease and compromised health states resulting in white or pale coral colony appearance were pooled, the prevalence of 'white' colonies from in situ (14%) and photographic analyses (11%) were statistically similar. Our results indicate that information on coral disease and health collected by in situ surveys and photographic analyses are not directly comparable, with in situ surveys generally providing higher estimates of prevalence and greater ability to identify some diseases and compromised states. Careful sampling of photographs can however identify signs of coral stress, including some coral diseases, which may be used to trigger early-warning management interventions. PMID- 27981463 TI - Interleukin (IL)-1 inhibition with anakinra and canakinumab in Behcet's disease related uveitis: a multicenter retrospective observational study. AB - This study aimed to evaluate the role of interleukin (IL)-1 inhibitors anakinra (ANA) and canakinumab (CAN) in the treatment of Behcet's disease (BD)-related uveitis. Multicenter retrospective observational study includes 19 consecutive BD patients (31 affected eyes) received treatment with anti-IL-1 agents. Data were analyzed at baseline and at 3 and 12 months. The primary endpoint is the reduction of ocular inflammatory flares (OIF). The secondary endpoints are improvement of best corrected visual acuity (BCVA); reduction of macular thickness defined by optical coherence tomography (OCT) and of vasculitis identified with fluorescein angiography (FA); evaluation of statistically significant differences between patients treated with IL-1 inhibitors as monotherapy, subjects also administered with disease modifying anti-rheumatic drugs (DMARDs) and/or corticosteroids as well as between patients administered with IL-1 inhibitors as first line biologic treatment and those previously treated with TNF-alpha inhibitors. At 12 months, OIF significantly decreased from 200 episodes/100 patients/year to 48.87 episodes/100 patients/year (p < 0.0001). The frequency of retinal vasculitis identified by FA significantly decreased between baseline and 3- and 12-month follow-up visits (p < 0.0001 and p = 0.001, respectively). OIF rate was significantly higher in patients co-administered with DMARDs (81.8 episodes/100 patients/year) than in patients undergoing IL-1 inhibitors as monotherapy (0.0 episodes/100 patients/year) (p = 0.03). No differences were identified on the basis of corticosteroid use and between patients administered with IL-1 inhibitors as first line biologic approach or second line. Steroid dosage was significantly decreased at 12-month visit compared to baseline (p = 0.02). Treatment with IL-1 inhibitors is effective in the management of BD-related uveitis and provides a long-term control of ocular inflammation in refractory and long-lasting cases. PMID- 27981466 TI - Multiple geophysical surveys for old landfill monitoring in Singapore. AB - One-dimensional boring presents limitations on mapping the refuse profile in old landfills owning to waste heterogeneity. Electrical imaging (EI) and multiple analysis of surface wave (MASW) were hereby deployed at an old dumping ground in Singapore to explore the subsurface in relation to geotechnical analysis. MASW estimated the refuse boundary with a higher precision as compared to EI, due to its endurance for moisture variation. EI and MASW transection profiles suggested spots of interest, e.g., refuse pockets and leachate mounds. 3D inversion of EI and MASW data further illustrated the transformation dynamics derived by natural attenuation, for instance the preferential infiltration pathway. Comparison of geophysical surveys at different years uncovered the subterranean landfill conditions, indicating strong impacts induced by aging, precipitation, and settlement. This study may shed light on a characterization framework of old landfills via combined geophysical models, thriving landfill knowledge with a higher creditability. PMID- 27981467 TI - Spatial distribution of soil cadmium and its influencing factors in peri-urban farmland: a case study in the Jingyang District, Sichuan, China. AB - Semi-agricultural ecosystems in peri-urban areas are susceptible to contamination. The spatial distribution and influencing factors of such pollution are unclear and poorly constrained in many areas worldwide. Therefore, studying the problems of soil pollution in peri-urban areas is critical for environmental management and agricultural production. In this paper, with cadmium (Cd) as the target pollutant, the spatiotemporal variations of soil cadmium pollution and the relative importance of the affecting factors were analyzed at a peri-urban area from the Jingyang District, Sichuan, China. Statistical results showed that the farmland in the study area could be considered moderately soil Cd-polluted, under the dual influence of natural factors and human activity. In particular, the soil Cd concentration in Tianyuan and Bajiaojing exceeded 0.5 mg kg-1, for intensive industrial enterprises are distributed in these areas. Correspondingly, the geoaccumulation index also showed that the contamination of Cd in this area was moderately polluted. Moreover, the ecological risk index was 80% in the study area, indicating that the soil Cd pollution potential risk was moderate to high. High geological background values (soil Cd = 0.29 mg kg-1), river migration, industrial enterprises, and traffic significantly influenced soil Cd pollution, with natural geological factors playing greater roles. The significant horizontal spatial effective distances away from Shiting River, Deyang-Aba Highway, and chemical plants were 200, 400, and 100 m, respectively. These results will be useful in guiding farmland cultivation and pollution remediation effectively in the peri-urban areas. PMID- 27981469 TI - Frontline Account: Reducing the Stress of Pain Management Through the Implementation of a Controlled Substance Review Group in a VA Internal Medicine Residency Clinic. PMID- 27981468 TI - The Association Between Hospital Capacity Strain and Inpatient Outcomes in Highly Developed Countries: A Systematic Review. AB - BACKGROUND: Increases in patient needs can strain hospital resources, which may worsen care quality and outcomes. This systematic literature review sought to understand whether hospital capacity strain is associated with worse health outcomes for hospitalized patients and to evaluate benefits and harms of health system interventions to improve care quality during times of hospital capacity strain. METHODS: Parallel searches were conducted in MEDLINE, CINAHL, the Cochrane Library, and reference lists from 1999-2015. Two reviewers assessed study eligibility. We included English-language studies describing the association between capacity strain (high census, acuity, turnover, or an indirect measure of strain such as delayed admission) and health outcomes or intermediate outcomes for children and adults hospitalized in highly developed countries. We also included studies of health system interventions to improve care during times of capacity strain. Two reviewers extracted data and assessed risk of bias using the Newcastle-Ottawa Score for observational studies and the Cochrane Collaboration Risk of Bias Assessment Tool for experimental studies. RESULTS: Of 5,702 potentially relevant studies, we included 44 observational and 8 experimental studies. There was marked heterogeneity in the metrics used to define capacity strain, hospital settings, and overall study quality. Mortality increased during times of capacity strain in 18 of 30 studies and in 9 of 12 studies in intensive care unit settings. No experimental studies were randomized, and none demonstrated an improvement in health outcomes after implementing the intervention. The pediatric literature is very limited; only six observational studies included children. There was insufficient study homogeneity to perform meta-analyses. DISCUSSION: In highly developed countries, hospital capacity strain is associated with increased mortality and worsened health outcomes. Evidence-based solutions to improve outcomes during times of capacity strain are needed. PMID- 27981471 TI - Metabolic Tumor Burden Assessed by Dual Time Point [18F]FDG PET/CT in Locally Advanced Breast Cancer: Relation with Tumor Biology. AB - PURPOSE: The aim of the study was to investigate the influence of dual time point 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) on the standard uptake value (SUV) and volume-based metabolic variables of breast lesions and their relation with biological characteristics and molecular phenotypes. PROCEDURES: Retrospective analysis including 67 patients with locally advanced breast cancer (LABC). All patients underwent a dual time point [18F]FDG PET/CT, 1 h (PET-1) and 3 h (PET-2) after [18F]FDG administration. Tumors were segmented following a three-dimensional methodology. Semiquantitative metabolic variables (SUVmax, SUVmean, and SUVpeak) and volume-based variables (metabolic tumor volume, MTV, and total lesion glycolysis, TLG) were obtained. Biologic prognostic parameters, such as the hormone receptors status, p53, HER2 expression, proliferation rate (Ki-67), and grading were obtained. Molecular phenotypes and risk-classification [low: luminal A, intermediate: luminal B HER2 (-) or luminal B HER2 (+), and high: HER2 pure or triple negative] were established. Relations between clinical and biological variables with the metabolic parameters were studied. The relevance of each metabolic variable in the prediction of phenotype risk was assessed using a multivariate analysis. RESULTS: SUV-based variables and TLG obtained in the PET-1 and PET-2 showed high and significant correlations between them. MTV and SUV variables (SUVmax, SUVmean, and SUVpeak) where only marginally correlated. Significant differences were found between mean SUV variables and TLG obtained in PET-1 and PET-2. High and significant associations were found between metabolic variables obtained in PET-1 and their homonymous in PET-2. Based on that, only relations of PET-1 variables with biological tumor characteristics were explored. SUV variables showed associations with hormone receptors status (p < 0.001 and p = 0.001 for estrogen and progesterone receptor, respectively) and risk classification according to phenotype (SUVmax, p = 0.003; SUVmean, p = 0.004; SUVpeak, p = 0.003). As to volume-based variables, only TLG showed association with hormone receptors status (estrogen, p < 0.001; progesterone, p = 0.031), risk-classification (p = 0.007), and grade (p = 0.036). Hormone receptor negative tumors, high-grade tumors, and high-risk phenotypes showed higher TLG values. No association was found between the metabolic variables and Ki-67, HER2, or p53 expression. CONCLUSION: Statistical differences were found between mean SUV-based variables and TLG obtained in the dual time point PET/CT. Most of PET-derived parameters showed high association with molecular factors of breast cancer. However, dual time point PET/CT did not offer any added value to the single PET acquisition with respect to the relations with biological variables, based on PET 1 SUV, and volume-based variables were predictors of those obtained in PET-2. PMID- 27981470 TI - Immunoglobulin G (IgG)-Based Imaging Probe Accumulates in M1 Macrophage Infiltrated Atherosclerotic Plaques Independent of IgG Target Molecule Expression. AB - PURPOSE: Vulnerable plaques are key factors for ischemic diseases. Thus, their precise detection is necessary for the diagnosis of such diseases. Immunoglobulin G (IgG)-based imaging probes have been developed for imaging biomolecules related to plaque formation for the diagnosis of atherosclerosis. However, IgG accumulates nonspecifically in atherosclerotic regions, and its accumulation mechanisms have not yet been clarified in detail. Therefore, we explored IgG accumulation mechanisms in atherosclerotic lesions and examined images of radiolabeled IgG for the diagnosis of atherosclerosis. PROCEDURES: Mouse IgG without specificity to biomolecules was labeled with technetium-99m via 6 hydrazinonicotinate to yield [99mTc]IgG. ApoE-/- or C57BL/6J mice were injected intravenously with [99mTc]IgG, and their aortas were excised 24 h after injection. After radioactivity measurement, serial aortic sections were autoradiographically and histopathologically examined. RAW264.7 macrophages were polarized into M1 or M2 and then treated with [99mTc]IgG. The radioactivities in the cells were measured after 1 h of incubation. [99mTc]IgG uptake in M1 macrophages was also evaluated after the pretreatment with an anti-Fcgamma receptor (FcgammaR) antibody. The expression levels of FcgammaRs in the cells were measured by western blot analysis. RESULTS: [99mTc]IgG accumulation levels in the aortas were significantly higher in apoE-/- mice than in C57BL/6J mice (5.1 +/- 1.4 vs 2.8 +/- 0.5 %ID/g, p < 0.05). Autoradiographic images showed that the accumulation areas highly correlated with the macrophage-infiltrated areas. M1 macrophages showed significantly higher levels of [99mTc]IgG than M2 or M0 (nonpolarized) macrophages [2.2 +/- 0.3 (M1) vs 0.5 +/- 0.1 (M2), 0.4 +/- 0.1 (M0) %dose/mg protein, p < 0.01] and higher expression levels of FcgammaRI and FcgammaRII. [99mTc]IgG accumulation in M1 macrophages was suppressed by pretreatment with the anti-FcgammaR antibody [2.2 +/- 0.3 (nonpretreatment) vs 1.2 +/- 0.2 (pretreatment) %ID/mg protein, p < 0.01]. CONCLUSIONS: IgG accumulated in pro-inflammatory M1 macrophages via FcgammaRs in atherosclerotic lesions. Thus, the target biomolecule-independent imaging of active inflammation should be taken into account in the diagnosis of atherosclerosis using IgG-based probes. PMID- 27981473 TI - Commentary: Proposal for an Update of the Definition and Scope of Behavioral Medicine. PMID- 27981472 TI - Neuroprotective Effects of Echinacoside on Regulating the Stress-Active p38MAPK and NF-kappaB p52 Signals in the Mice Model of Parkinson's Disease. AB - Herbal medicines have long been used to treat Parkinson's disease (PD). To systematically analyze the anti-parkinsonian activity of echinacoside (ECH) in a neurotoxic model of PD and provide a future basis for basic and clinical investigations, male C57BL/6 mice were randomized into blank control, PD model and ECH-administration groups. ECH significantly suppressed the dopaminergic neuron loss (P < 0.01) caused by MPTP and maintained dopamine content (P < 0.01) and dopamine metabolite content (P < 0.05) compared with that measured in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage. Additionally, ECH inhibited the activation of microglia and astrocytes in the substantia nigra, which suggested the involvement of neuroinflammation. The relevant cytokines were detected with a Proteome Profiler Array, which confirmed that ECH participated in the regulation of seven cytokines. Given that p38 mitogen-activated protein kinase (p38MAPK) and NF-kappaB (NF-kappaB) signals are considered to be closely related to neuroninflammation, the gene expression levels of p38MAPK and six NF-kappaB DNA-binding subunits were assessed. Western blotting analysis showed that both p38MAPK and the NF-kappaB p52 subunit were upregulated in the MPTP group and that ECH downregulated their expressions. Minocycline was administered as the positive control to inhibit neuroinflammation, and no differences were detected between the minocycline- and ECH-mediated inhibition of the p38MAPK and NF-kappaB p52 signals. In conclusion, echinacoside is a potential novel orally active compound for regulating neuroinflammation and related signals in Parkinson's disease and may provide a new prospect for clinical treatment. PMID- 27981474 TI - A cheap protocol for colour measure and for diagnostic in planning a cultural heritage restoration. Case study: main facade of Palazzo Governi (Cagliari, Sardinia, Italy). AB - Due to the bad state of conservation, "Palazzo Governi", a seventeenth-century building located in the old town district of "Stampace" in Cagliari (Sardinia, Italy), was subjected to restoration. Thus, according to the Italian Law n. 1089, the main facade colour must be reproduced, and therefore, its identification was required. The available samples looked fairly degraded, in particular as an easy plaster to crumble; so, some other analyses able to identify the degradation cause were performed. Two different approaches were adopted to attain the first goal, the visual colour assessment by a sensory panel (subjective) and the instrumental measurement by colorimetry (objective). Ion chromatography and inductively coupled plasma-optical emission spectroscopy analyses, as well as conductivity and pH measurements, were performed to evaluate the presence of water-soluble salts inside the plaster, as possible cause of degradation; the binder/aggregate ratio was also evaluated. A full mineralogical and petrographic characterisation of the materials constituting the samples, as well as the identification of their stratigraphy and some other morphologic and structural features suitable to highlight eventual forms of degradation, were performed by optical microscopy. Scanning electron microscopy coupled to X-ray microanalysis was been also used in order to confirm and/or to integrate data obtained by optical microscopy. The samples have been compared with two samples coming from two other buildings, also located in Sardinia, that looked in good conservation state. The results evidenced that the causes of degradation come from a high salt (especially sulphate) content and a scarce presence of binder in the plaster that can be imputed to a wrong initial composition and/ or to a leaching by acidic rain. PMID- 27981477 TI - Variations in root morphology among 18 herbaceous species and their relationship with cadmium accumulation. AB - This study aims to investigate whether root system morphology is involved in the interspecific variations in Cd accumulation in herbaceous plants. Biomasses, root morphology, and Cd accumulation of 18 herbaceous species were determined under 0, 2, and 10 mg kg-1 Cd conditions. Significant variations were found in biomass production, root system morphology, and Cd accumulation among the 18 species. Cd concentrations in the shoot had negative correlations with the biomass of roots and shoots in the 2 mg kg-1 Cd treatment. Total amounts of Cd in plants showed positive correlations with the biomass of roots and shoots, total root lengths, root surface areas, root volumes, and proportions of the fine roots (diameter <0.2 mm). Percentages of Cd in shoots were positively related to specific root lengths, root surface areas, and plant biomasses but negatively correlated with proportions of roots in the 0.6-0.8-mm diameter class. High-biomass species (rapeseed, Indian mustard, and four-o'clock) have high Cd uptake capacity due to their large root system. Longer and thinner roots might contribute to higher capacity for transferring Cd from roots to shoots, while coarse roots (i.e., diameter of 0.6-0.8 mm) could retain more Cd in the tissues and, consequently, reduce Cd transfer from roots to shoots. PMID- 27981476 TI - Disability-adjusted life years and economic cost assessment of the health effects related to PM2.5 and PM10 pollution in Mumbai and Delhi, in India from 1991 to 2015. AB - Particulate air pollution is becoming a serious public health concern in urban cities in India due to air pollution-related health effects associated with disability-adjusted life years (DALYs) and economic loss. To obtain the quantitative result of health impact of particulate matter (PM) in most populated Mumbai City and most polluted Delhi City in India, an epidemiology-based exposure response function has been used to calculate the attributable number of mortality and morbidity cases from 1991 to 2015 in a 5-year interval and the subsequent DALYs, and economic cost is estimated of the health damage based on unit values of the health outcomes. Here, we report the attributable number of mortality due to PM10 in Mumbai and Delhi increased to 32,014 and 48,651 in 2015 compared with 19,291 and 19,716 in year 1995. And annual average mortality due to PM2.5 in Mumbai and Delhi was 10,880 and 10,900. Premature cerebrovascular disease (CEV), ischemic heart disease (IHD), and chronic obstructive pulmonary disease (COPD) causes are about 35.3, 33.3, and 22.9% of PM2.5-attributable mortalities. Total DALYs due to PM10 increased from 0.34 million to 0.51 million in Mumbai and 0.34 million to 0.75 million in Delhi from average year 1995 to 2015. Among all health outcomes, mortality and chronic bronchitis shared about 95% of the total DALYs. Due to PM10, the estimated total economic cost at constant price year 2005 US$ increased from 2680.87 million to 4269.60 million for Mumbai City and 2714.10 million to 6394.74 million for Delhi City, from 1995 to 2015, and the total amount accounting about 1.01% of India's gross domestic product (GDP). A crucial presumption is that in 2030, PM10 levels would have to decline by 44% (Mumbai) and 67% (Delhi) absolutely to maintain the same health outcomes in year 2015 levels. The results will help policy makers from pollution control board for further cost-benefit analyses of air pollution management programs in Mumbai and Delhi. PMID- 27981475 TI - Perturbations and 3R in carbon management. AB - Perturbations in various carbon pools like biological, geological, oceanic, and missing carbon sink affect its global data, which are generally neglected or ignored in routine calculations. These natural and anthropogenic events need to be considered before projecting a sustainable carbon management plan. These plans have both general and experimental aspects. General plans should focus on (a) minimizing emission; (b) maximizing environmentally sound reuse, reduce, and recycling; (c) effective treatment; and (d) converting carbon into valuable products with atom economy. Experimental carbon management plans involving various biological and chemical techniques with limitation in terms of research level and economic feasibility. Chemical options have benefits of higher productivity and wider product range, but it suffers from its higher-energy requirements and environmental unfriendliness. In contrast to this, biological options are more selective and less energy intensive, but their productivity is very low. Hence, there is a requirement of hybrid process where the benefits of both the options, i.e., biological and chemical, can be reaped. In view of above, the proposed review targets to highlight the various perturbations in the global carbon cycle and their effects; study the currently practiced options of carbon management, specifically in light of 3R principle; and propose various new hybrid methods by compatible combinations of chemical and biological processes to develop better and safer carbon management. These methods are hypothetical so they may require further research and validations but may provide a comprehensive base for developing such management methods. PMID- 27981478 TI - Influence of transport from urban sources and domestic biomass combustion on the air quality of a mountain area. AB - The environmental influence of biomass burning for civil uses was investigated through the determination of several air toxicants in the town of Leonessa and its surroundings, in the mountain region of central Italy. Attention was focussed on PM10, polycyclic aromatic hydrocarbons (PAHs) and regulated gaseous pollutants (nitrogen dioxide, ozone and benzene). Two in-field campaigns were carried out during the summer 2012 and the winter 2013. Contemporarily, air quality was monitored in Rome and other localities of Lazio region. In the summer, all pollutants, with the exception of ozone, were more abundant in Rome. On the other hand, in the winter, PAH concentration was higher in Leonessa (15.8 vs. 7.0 ng/m3), while PM10 was less concentrated (22 vs. 34 MUg/m3). Due to lack of other important sources and to limited impact of vehicle traffic, biomass burning was identified as the major PAH source in Leonessa during the winter. This hypothesis was confirmed by PAH molecular signature of PM10 (i.e. concentration diagnostic ratios and 206 ion mass trace in the chromatograms). A similar phenomenon (i.e. airborne particulate levels similar to those of the capital city but higher PAH loads) was observed in other locations of the province, suggesting that uncontrolled biomass burning contributed to pollution across the Rome metropolitan area. PMID- 27981479 TI - Chemical quality of tap water in Madrid: multicase control cancer study in Spain (MCC-Spain). AB - Chronic consumption of water, which contains contaminants, may give rise to adverse health effects. The Madrid region, covered by the population-based multicase-control (MCC-Spain) study, includes two drinking water supply areas. The different sources of the water, coupled together with the possible differences in water management, mean that there may be differences in drinking water quality. In the context of the MCC study, our aims were to describe contaminant concentrations in tap water drawn from various sampling points distributed around the region, assess these concentrations by reference to guideline values and study possible differences between the two supply areas. Tap water samples were collected from 34 sampling points in 7 towns in the Madrid region (19-29 April 2010), and 23 contaminants (metals, nitrates, disinfection by product and Mutagen X levels) were quantified. We undertook a descriptive analysis of the contaminant concentrations in the water and compared them between the two water supply areas (Wilcoxon test). We created maps representing the distribution of the concentrations observed at water sampling points and assessed the correlations (Spearman's coefficient) between the different parameters measured. The concentrations of the contaminants were below guideline values. There were differences between the two supply areas in concentration of nitrates (p value = 0.0051) and certain disinfection by-products. While there were positive correlations (rho >0.70) among some disinfection by-products, no correlations were found in metals or nitrates. The differences in nitrate levels could be linked to differences in farming/industrial activities in the catchment areas and in disinfection by-products might be related to the existence of different treatment systems or bromine content in source waters. PMID- 27981480 TI - Volcanic ash-based geopolymer cements/concretes: the current state of the art and perspectives. AB - The progress achieved with the use of volcanic ash for geopolymer synthesis has been critically reviewed in this paper. This consists of an overview of mineralogy and chemistry of volcanic ash. The role of chemical composition and mineral contents of volcanic ash on their reactivity during geopolymerization reaction and, consequently, mechanical properties have been accessed. An attempt has been made to establish a relationship between synthesis factors and final properties. A critical assessment of some synthesis conditions has been addressed and some practical recommendations given along with suggestions of future works that have to be done. All this has shown that there are still many works such as durability tests (carbonation, freeze-thaw, resistance, etc.), life cycle analysis, etc. that need to be done in order to satisfy both suitability and sustainability criteria for a large-scale or industrial application. PMID- 27981481 TI - Methanol-enhanced removal and metabolic conversion of formaldehyde by a black soybean from formaldehyde solutions. AB - Methanol regulation of some biochemical and physiological characteristics in plants has been documented in several references. This study showed that the pretreatment of methanol with an appropriate concentration could stimulate the HCHO uptake by black soybean (BS) plants. The process of methanol-stimulated HCHO uptake by BS plants was optimized using the Central Composite Design and response surface methodology for the three variables, methanol concentration, HCHO concentration, and treatment time. Under optimized conditions, the best stimulation effect of methanol on HCHO uptake was obtained. 13C-NMR analysis indicated that the H13CHO metabolism produced H13COOH, [2-13C]Gly, and [3-13C]Ser in BS plant roots. Methanol pretreatment enhanced the metabolic conversion of H13CHO in BS plant roots, which consequently increased HCHO uptake by BS plants. Therefore, methanol pretreatment might be used to increase HCHO uptake by plants in the phytoremediation of HCHO-polluted solutions. PMID- 27981482 TI - Association of breast adipose tissue levels of polychlorinated biphenyls and breast cancer development in women from Chaoshan, China. AB - Polychlorinated biphenyls (PCBs) are implied to be potential risk factors for breast cancer in wildlife and in in vivo and in vitro studies. Epidemiological studies revealed some individual or groups of PCB congeners associated with breast cancer risk, but consistent conclusions are scarce. This study aimed to explore the association between PCB exposure and breast cancer development. Breast adipose tissues were collected, and seven PCB congeners were analyzed by gas chromatography-mass spectrometry (GC-MS). Demographic characteristics, basic clinical data, and pathological diagnosis information were obtained from medical records. The differences in PCB exposure levels among different groups and indices were compared, and the correlation among PCB congeners was evaluated. The order of congener profile by molar concentration was PCB-153 > PCB-138 > PCB-180 > PCB-118 > PCB-101 > PCB-52 > PCB-28. ?PCB level differed by occupation and residence and was significantly higher at 55-59-year-old group than at the other age groups. ?PCB level was higher in postmenopausal than in premenopausal women. Decreasing ?PCB levels were related with increasing parity among women with progesterone receptor (PR)-positive breast tumors. With increased clinical stage, the ?PCB level increased significantly. ?PCB level did not differ by tumor-node metastasis classification and PR or human epidermal growth factor receptor 2 (HER2) expression but did differ by estrogen receptor (ER) expression (P = 0.04) without a regularly increasing trend in breast adipose tissue. These results suggest a potential association between PCB exposure and breast cancer development. Further in vitro and in vivo studies are needed to confirm these findings and explain the underlying mechanisms. Graphical Abstract Total PCBs level among different clinical stages in breast cancer patients. PMID- 27981483 TI - Photo-Fenton and Fenton-like processes for the treatment of the antineoplastic drug 5-fluorouracil under simulated solar radiation. AB - In the present study, photo-Fenton and Fenton-like processes were investigated for the degradation and mineralization of the antineoplastic drug 5-fluorouracil (5-FU). For the optimization of photo-Fenton treatment under simulated solar light (SSL) radiation, the effects of several operating parameters (i.e., 5-FU concentration, Fe3+, and oxidant concentration) on the treatment efficiency were studied. According to the results, SSL/[Fe(C2Omicron4)3]3-/Eta2Omicron2 process was the most efficient, since faster degradation of 5-FU and higher mineralization percentages were achieved. All the applied processes followed quite similar transformation routes which include defluorination-hydroxylation as well as pyrimidine ring opening, as demonstrated by the transformation products identified by high resolution mass spectrometry analysis. The toxicity of the treated solutions was evaluated using the Microtox assay. In general, low toxicity was recorded for the initial solution and the solution at the end of the photocatalytic treatment, while an increase in the overall toxicity was observed only at the first stages of SSL/Fe3+/Eta2Omicron2 and SSL/Fe3+/S2O82- processes. PMID- 27981484 TI - Uric Acid Is Protective After Cerebral Ischemia/Reperfusion in Hyperglycemic Mice. AB - Hyperglycemia at stroke onset is associated with poor long-term clinical outcome in numerous studies. Hyperglycemia induces intracellular acidosis, lipid peroxidation, and peroxynitrite production resulting in the generation of oxidative and nitrosative stress in the ischemic tissue. Here, we studied the effects of acute hyperglycemia on in vivo intercellular adhesion molecule-1 (ICAM 1) expression, neutrophil recruitment, and brain damage after ischemia/reperfusion in mice and tested whether the natural antioxidant uric acid was protective. Hyperglycemia was induced by i.p. administration of dextrose 45 min before transient occlusion of the middle cerebral artery. Magnetic resonance imaging (MRI) was performed at 24 h to measure lesion volume. A group of normoglycemic and hyperglycemic mice received an i.v. injection of micron-sized particles of iron oxide (MPIOs), conjugated with either anti-ICAM-1 antibody or control IgG, followed by T2*w MRI. Neutrophil infiltration was studied by immunofluorescence and flow cytometry. A group of hyperglycemic mice received an i.v. infusion of uric acid (16 mg/kg) or the vehicle starting after 45 min of reperfusion. ICAM-1-targeted MPIOs induced significantly larger MRI contrast enhancing effects in the ischemic brain of hyperglycemic mice, which also showed more infiltrating neutrophils and larger lesions than normoglycemic mice. Uric acid reduced infarct volume in hyperglycemic mice but it did not prevent vascular ICAM-1 upregulation and did not significantly reduce the number of neutrophils in the ischemic brain tissue. In conclusion, hyperglycemia enhances stroke-induced vascular ICAM-1 and neutrophil infiltration and exacerbates the brain lesion. Uric acid reduces the lesion size after ischemia/reperfusion in hyperglycemic mice. PMID- 27981485 TI - 1H-MR spectroscopy of suspicious breast mass lesions at 3T: a clinical experience. AB - OBJECTIVES: To test 3T proton magnetic resonance spectroscopy (1H-MRS) for breast mass lesions. METHODS: Patients with BI-RADS 4-5 lesions at mammography/ultrasound were prospectively enrolled. After contrast-enhanced breast MRI, single-voxel MRS (point-resolved volume selection, PRESS); pencil beam shimming; volume of interest 1 cm3; TR/TE = 3000/135 ms) was performed. Spectra were considered reliable if the full width at half maximum (FWHM) of the water peak was <=45 Hz. A signal-to-noise ratio of the total choline (tCho) peak at 3.21 ppm >=2 was used as cutoff for malignancy. All lesions underwent needle sampling. Final pathology was available for all malignant lesions; for benign lesions the reference standard was final pathology or at least 1-year negative follow-up. RESULTS: Reliable spectra were obtained in 115/127 lesions (91%), with a mean FWHM of 32.4 Hz (range 8-45 Hz). A tCho peak SNR >=2 was detected in 66 malignant lesions (62 invasive cancers; 4 ductal carcinoma in situ) and in 3 benign lesions. Excluding lesions located <=1 cm from the skin (n = 3) or pectoral muscle (n = 11), sensitivity was 65/73 [89%, 95% confidence interval (CI): 80-95%], and specificity 25/28 (89%) (95% CI: 72-98%). Considering only invasive cancers, sensitivity reached 61/68 (90%, 95% CI: 81-96%). MRS additional time was 8 min. CONCLUSIONS: When lesions close to the skin or pectoral muscle are excluded, 3T 1H-MRS of mass lesions >=1 cm showed a high diagnostic performance, however, insufficient to avoid needle biopsy. PMID- 27981486 TI - Fiducial marker for prostate radiotherapy: comparison of 0.35- and 0.5-mm diameter computed tomography and magnetic resonance images. AB - PURPOSE: When performing intensity-modulated radiotherapy for prostate cancer, a marker is inserted into the prostate to enable the recognition of its position using cone-beam computed tomography (CT). However, it is difficult to recognize the prostatic outline using CT alone. Magnetic resonance imaging (MRI) can depict the prostatic outline better than CT. In treatment plans using CT and MRI registration, various markers are used in institutions; however, the selection of an optimal marker size is difficult. Comparison of a different fiducial marker study was conducted using phantom, but no study in vivo was found. Therefore, we prospectively investigated the effects of different marker diameter sizes using CT and MR images. METHODS: Thirty-one consecutive patients were enrolled in this study. CT and MRI were performed 3 weeks after marker placement. The 0.35-mm diameter marker was placed on the left side of the prostate, and the 0.5-mm diameter marker was placed on the right side. The length of each marker was 10 mm. The better MRI image was selected between those obtained using T2*-two dimensional weighted image (T2*2D) and T2*-three-dimensional weighted image (T2*3D). Two observers evaluated and scored the prostatic outline image quality as well as visualized the prostatic markers using CT and MRI. RESULTS: MRI was significantly superior to CT in depicting the prostatic outline. The CT artifacts were significantly lesser for the 0.35-mm-diameter marker than for the 0.5-mm diameter marker. The degree of marker recognition using MRI was significantly better with the 0.5-mm-diameter marker. CONCLUSION: The 0.5-mm-diameter fiducial marker had significantly better visualization than the 0.35-mm-diameter marker. While CT artifacts were significantly worse with the 0.5-mm-diameter marker, the artifact level was tolerable for clinical practice. Therefore, we recommend the 0.5-mm-diameter diameter marker in terms of prostatic outline and marker visualization using MRI. PMID- 27981488 TI - Erratum to: Methods for the Evaluation of the Bioactivity and Biocontrol Potential of Species of Trichoderma. PMID- 27981487 TI - Serum miR-92a-3p as a New Potential Biomarker for Diagnosis of Kawasaki Disease with Coronary Artery Lesions. AB - Recent studies have suggested that serum microRNAs (miRNAs) are novel biomarkers for many cardiovascular diseases, but their role in Kawasaki disease (KD) is still unclear. We demonstrated that serum miR-92a-3p levels were significantly higher in children with KD compared with children with fever and controls (both P < 0.05). When the disease recovered, miR-92a-3p levels returned to those of controls. Clinical and pathological data showed that high levels of miR-92a-3p were significantly associated with coronary artery lesions (CALs). Analysis of the receiver operating characteristic (ROC) curve showed that serum miR-92a-3p had a sensitivity of 81.8% and a specificity of 66.7% for distinguishing KD with CALs from KD without CALs. The area under the curve was 0.816 (P < 0.05, 95% CI 0.669-0.962). Therefore, the miRNA miR-92a-3p may be used as a potential biomarker for diagnosis of KD and KD with coronary artery lesions. PMID- 27981490 TI - Implications of an inpatient warfarin dosing nomogram on safety outcomes post discharge. AB - Many hospitals have implemented warfarin dosing nomograms to improve patient safety. To our knowledge, no study has assessed the impact inpatient warfarin initiation has in both medical and surgical patients, on safety outcomes post discharge. To evaluate the impact of a suggested institutional nomogram for the initiation of warfarin, the primary endpoint was the incidence of bleeding throughout follow up. Secondary endpoints included the composite of INR changes >=0.5/day and INR >4. Patients were followed for a period of 2 weeks post discharge. The composite endpoint was evaluated for an effect on reaching therapeutic INR, time to reach therapeutic INR, and bleeding events throughout follow up. A single center retrospective study comparing the safety of adherence vs. non-adherence to a warfarin nomogram. A total of 206 patients were included, 73 patients in the nomogram adherence vs. 133 in the nonadherence arm. There was no difference in the proportion of patients who bled throughout the follow up period, adherence 9.6% vs. nonadherence to the nomogram 13.5%, p = 0.407. There was however a statistical difference in the mean total number of bleeding events, 0.096 (7/73) in the adherence vs. 0.158 (21/133) in the non-adherence arm, p = 0.022. There was also no difference in the composite endpoint, 19.2% in the adherence vs. 28.6% in the non-adherence arm p = 0.180. A positive correlation between the inpatient composite and risk of bleeding throughout follow up was noted. The findings of this study support adherence to the nomogram as opposed to non-adherence. PMID- 27981489 TI - Influence of low-dose proton pump inhibitors administered concomitantly or separately on the anti-platelet function of clopidogrel. AB - Proton pump inhibitors (PPIs) at low doses can effectively prevent gastrointestinal bleeding due to aspirin and are widely used in Japan for gastroprotection in patients taking anti-platelet agents. We examined the influence of different PPIs at low doses administered concomitantly or separately on anti-platelet functions of clopidogrel. In 41 healthy Japanese volunteers with different CYP2C19 genotypes who took clopidogrel 75 mg in the morning alone, or with omeprazole 10 mg, esomeprazole 10 mg, lansoprazole 15 mg, or rabeprazole 10 mg, either concomitantly in the morning or separately in the evening, we measured the inhibition of platelet aggregation (IPA, %) using VerifyNow P2Y12 assay at 4 h after the last clopidogrel dose on Day 7 of each regimen. IPA by clopidogrel with rabeprazole administered at lunchtime, approximately 4 h after clopidogrel, was also measured. Mean IPAs in those concomitantly receiving omeprazole, esomeprazole, lansoprazole or rabeprazole (47.2 +/- 21.1%, 43.2 +/- 20.2%, 46.4 +/- 18.8%, and 47.3 +/- 19.2%, respectively) were significantly decreased compared with those receiving clopidogrel alone (56.0%) (all ps < 0.001). This decrease was observed when PPIs were administered separately in the evening. However, IPA by clopidogrel with rabeprazole administered at lunchtime was 51.6%, which was markedly similar to that of clopidogrel alone (p = 0.114). All tested PPIs reduce the efficacy of clopidogrel when administered concomitantly. Our preliminary data suggest that administration of rabeprazole 4 h following clopidogrel may minimize potential drug-drug interactions. PMID- 27981491 TI - Cardiovascular Abnormalities and in-Hospital All-Cause Mortality in Patients with Spontaneous Sub-Arachnoid Hemorrhage: An Observational Study. AB - INTRODUCTION: Patients with spontaneous sub-arachnoid hemorrhage (SAH) might develop various cardiac abnormalities, however; the prognostic implications of these cardiac abnormalities are not well known. This study aimed to detect the cardiac abnormality that correlates best with in-hospital all-cause mortality in patients with SAH. METHODS: In this retrospective study, all patients admitted to our institution with a primary diagnosis of SAH, and underwent a transthoracic echocardiogram (TTE) from July 2011 until May 2014, were enrolled. Data gathered included patients' demographics, Hunt and Hess clinical grading, computed tomography SAH Fisher grading, troponin T level, electrocardiographic (ECG) changes, TTE, and in-hospital all-cause mortality. Multivariate logistic regression of the cardiac abnormalities and in-hospital all-cause mortality was performed. RESULTS: A total of 247 patients were included in our analysis. In hospital all-cause mortality was 15.6% (38 patients). The presence of elevated troponin T levels, resting segmental wall motion abnormalities, reduced ejection fraction (<35%), and prolonged corrected QT interval (QTc) on ECG were associated with increased in-hospital all-cause mortality on univariate analysis. On multivariable regression, QTc prolongation was the only independent predictor for in-hospital all-cause mortality (p = 0.04). CONCLUSIONS: Prolonged QTc interval on ECG was independently associated with in-hospital all-cause mortality in patients presenting with spontaneous SAH. Whether this is a causative association or a marker of underlying severe clinical presentation of SAH remains unknown. PMID- 27981493 TI - Conversion Surgery Post-Intraperitoneal Paclitaxel and Systemic Chemotherapy for Gastric Cancer Carcinomatosis Peritonei. Are We Ready? AB - Peritoneal metastasis is common in gastric cancer. It is difficult to treat and carries a poor prognosis. Intraperitoneal (IP) delivery of chemotherapy can attain a higher drug exposure in the peritoneal cavity but with reduced systemic toxicity. Therefore, we hypothesized that IP paclitaxel with systemic chemotherapy would be clinically beneficial for gastric cancer with peritoneal metastases. Patients with unresectable and/or recurrent gastric adenocarcinoma with peritoneal dissemination and/or positive peritoneal washing cytology were recruited. They underwent eight cycles of IP paclitaxel and systemic XELOX. The primary endpoint was 1-year overall survival rate and secondary endpoints were safety, response rate, and peritoneal cytological response. Patients who subsequently had no distant metastases and two consecutive negative peritoneal cytologies underwent conversion gastrectomy if there was no macroscopic evidence of peritoneal disease at diagnostic laparoscopy. Twenty-two patients were enrolled, receiving at least one cycle of IP paclitaxel at the time of reporting (data cutoff-March 11, 2016). The median number of cycles was 7.5. The median overall survival was 18.8 months, and the 1-year survival rate was 72.2%. One patient died of neutropenic sepsis. Of 19 evaluable patients with measurable disease, 7 (36.8%) achieved PR, 8 (42.1%) achieved SD, and 4 (21.1%) experienced PD. Peritoneal cytology turned negative in 11 of 17 (64.7%) patients. Six patients underwent conversion gastrectomy (4 R0, 2 R1) with a median survival of 21.6 months (range = 8.7-29.9 months). XELOX and IP paclitaxel appears to be an effective regimen in gastric cancer with peritoneal metastases. Conversion gastrectomy may be considered in patients with a favorable response. PMID- 27981492 TI - Sphincter-Preserving Surgery for Low Rectal Cancer: Do We Overshoot the Mark? AB - PURPOSE: Intersphincteric resection (ISR) is an alternative to abdominoperineal resection (APR) for a selected subset of patients with low rectal cancer, combining equivalent oncological outcome and sphincter preservation. However, functional results are heterogeneous and often imperfect. The aim of the present investigation was to determine the long-term functional results and quality of life after ISR. METHODS: One hundred forty-three consecutive patients who underwent surgery for low rectal cancer were analysed. Sixty patients received ISR and 83 patients APR, respectively. Kaplan-Meier estimate was used to analyse patients' survival. The EORTC QLQ-C30, -C29 and the Wexner score were used to determine functional outcome and quality of life. RESULTS: ISR and APR were both associated with comparable morbidity and no mortality. Patients' disease- and recurrence-free survival after ISR and APR were similar (p = 0.2872 and p = 0.4635). Closure of ileostomy was performed in 73% of all patients after ISR. Long-term outcome showed a rate of incontinence (Wexner score >=10) in 66% of the patients. Despite this, patients' quality of life was significantly better after ISR compared to APR in terms of abdominal complaints and psycho-emotional functioning. CONCLUSIONS: ISR is technically feasible with acceptable postoperative morbidity rates. Functional results following ISR are compromised by incontinence as the most important complication. However, long-term quality of life is superior to APR, which should be considered when selecting patients for ISR. PMID- 27981494 TI - Fall Composition of Storage Lipids is Associated with the Overwintering Strategy of Daphnia. AB - Diapause, which occurs through the production of dormant eggs, is a strategy used by some zooplankton to avoid winter months of persistent low temperatures and low food availability. However, reports of active zooplankton under the ice indicate that other strategies also exist. This study was aimed at evaluating whether the composition of storage lipids in the fall differs between diapausing and active overwintering Daphnia. We assessed the quantity of storage lipids and fatty acid (FA) composition of Daphnia species, along with FA content of seston, in six boreal, alpine and subarctic lakes at the onset of winter, and evaluated the association between storage lipids and Daphnia overwintering strategy. We found that active overwintering Daphnia had >55% body fat and the highest FA concentrations. Polyunsaturated FA, especially stearidonic acid (18:4n-3; SDA) and high ratios of n-3:n-6, were preferentially retained to a greater extent in active overwintering Daphnia than in those that entered diapause. Daphnia FA composition was independent of that of the seston diet, indicating that Daphnia adjusted their storage lipids according to the physiological requirements of a given overwintering strategy. The occurrence of an active overwintering strategy has consequences for zooplankton community structure, and can have important implications for the transfer of high-quality energy at higher trophic levels. PMID- 27981495 TI - Chronic Obstructive Pulmonary Disease Individualized Therapy: Tailored Approach to Symptom Management. AB - Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality. COPD is typified by persistent, progressive airflow limitation and a range of respiratory and systemic symptoms such as breathlessness, coughing, wheezing, depression, anxiety, general fatigue, and sleeping difficulties. Despite receiving treatment for COPD, many patients suffer from regular symptoms that affect their daily lives and lead to increased morbidity. These symptoms vary in severity, frequency, and type, and can occur at any time throughout the 24-h day, with over half of patients with COPD experiencing symptoms in the morning, during the day, and at nighttime. Despite the prevalence of symptoms, patient and physician perception of the impact of COPD symptoms on patients' lives is not always in concordance. Dual bronchodilator therapy with a long acting muscarinic antagonist (LAMA) and long-acting beta agonist (LABA) has the potential to treat the symptoms of COPD in addition to improving lung function. This review therefore examines the burden of symptoms experienced throughout the day by patients with COPD and the evidence for combined LAMA/LABA treatment in terms of symptom management. As patients with COPD experience varying symptoms throughout the course of their disease, the role of tailoring treatment to the individual needs of the patient is also examined. We conclude that the symptoms of COPD are troublesome, variable, can occur during all parts of the 24-h day, and have a substantial impact on patients' health status and quality of life. In order to provide effective, patient-orientated care, patients with COPD should be evaluated on the basis of lung function, the frequency of symptoms, and patient perceived impact of symptoms on their lives. Therapy should be chosen carefully based on individualized assessment, ensuring personalization to the individual needs of the patient. PMID- 27981496 TI - A Review of Clinical Practice Guidelines for the Management of Hypertriglyceridemia: A Focus on High Dose Omega-3 Fatty Acids. AB - Cardiovascular (CV) disease remains the leading cause of preventable death in the US. Hyperlipidemia is a major modifiable risk factor for CV disease, and after numerous clinical trials have demonstrated that reductions in low-density lipoprotein (LDL) cholesterol with statin therapy can prevent major adverse CV events, statins have emerged as the drug of choice to lower LDL cholesterol and reduce CV risk. However, some statin-treated patients remain at high residual risk of CV events despite achieving low LDL cholesterol levels, especially if their triglyceride (TG) levels are elevated or their high-density lipoprotein (HDL) cholesterol levels low. Evidence from genetic and observational studies has linked elevated TG levels to an increased risk of CV events. Furthermore, very high TG levels are associated with acute pancreatitis. Consequently, several clinical practice guidelines provide recommendations for the management and treatment of high and very high TG levels. This review focuses on the clinical practice guidelines for the management of hypertriglyceridemia and the role of prescription omega-3 fatty acids in preventing pancreatitis and CV disease in individuals with high and very high TG levels. PMID- 27981497 TI - Factors Affecting Canagliflozin-Induced Transient Urine Volume Increase in Patients with Type 2 Diabetes Mellitus. AB - INTRODUCTION: Sodium glucose co-transporter 2 (SGLT2) inhibitors exhibit diuretic activity, which is a possible mechanism underlying the cardiovascular benefit of these inhibitors. However, the osmotic diuresis-induced increase in urine volume, and the risk of dehydration have been of concern with SGLT2 inhibitor treatment. This study aimed to investigate the mechanism underlying SGLT2 inhibitor canagliflozin-induced diuresis in Japanese type 2 diabetes mellitus (T2DM) patients. METHODS: Thirteen T2DM patients received a daily oral dose of 100 mg canagliflozin before breakfast for 6 days. Blood and urine samples were collected at predetermined time points. The primary endpoint was evaluation of correlations between changes from baseline in urine volume and factors that are known to affect urine volume and between actual urine volume and these factors. RESULTS: Canagliflozin transiently increased urine volume and urinary sodium excretion on Day 1 with a return to baseline levels thereafter. Canagliflozin administration increased urinary glucose excretion, which was sustained during repeated-dose administration. Plasma atrial natriuretic peptide (ANP) and N-terminal pro-b-type natriuretic peptide (NT-proBNP) levels decreased, while plasma renin activity increased. On Day 1 of treatment, changes in sodium and potassium excretion were closely correlated with changes in urine output. A post hoc multiple regression analysis showed changes in sodium excretion and water intake as factors that affected urine volume change at Day 1. Furthermore, relative to that at baseline, canagliflozin decreased blood glucose throughout the day and increased plasma total GLP-1 after breakfast. CONCLUSION: Canagliflozin induced transient sodium excretion and did not induce water intake at Day 1; hence, natriuresis rather than glucose-induced osmotic diuresis may be a major factor involved in the canagliflozin-induced transient increase in urine output. In addition, canagliflozin decreased plasma ANP and NT-proBNP levels and increased plasma renin activity, which may be a compensatory mechanism for sodium retention, leading to subsequent urine output recovery. CLINICAL TRIAL REGISTRATION: UMIN000019462. FUNDING: Mitsubishi Tanabe Pharma Corporation. PMID- 27981498 TI - Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity. AB - Myalgic encephalomyelitis (ME) is a complex, heterogeneous illness of unknown etiology. The search for biomarkers that can delineate cases from controls is one of the most active areas of ME research; however, little progress has been made in achieving this goal. In contrast to identifying biomarkers that are directly involved in the pathological process, an immunosignature identifies antibodies raised to proteins expressed during, and potentially involved in, the pathological process. Although these proteins might be unknown, it is possible to detect antibodies that react to these proteins using random peptide arrays. In the present study, we probe a custom 125,000 random 12-mer peptide microarray with sera from 21 ME cases and 21 controls from the USA and Europe and used these data to develop a diagnostic signature. We further used these peptide sequences to potentially uncover the naturally occurring candidate antigens to which these antibodies may specifically react with in vivo. Our analysis revealed a subset of 25 peptides that distinguished cases and controls with high specificity and sensitivity. Additionally, Basic Local Alignment Search Tool (BLAST) searches suggest that these peptides primarily represent human self-antigens and endogenous retroviral sequences and, to a minor extent, viral and bacterial pathogens. PMID- 27981499 TI - Direct Conversion of Somatic Cells into Induced Neurons. AB - The progressive loss and degeneration of neurons in the central nervous system (CNS), as a result of traumas or diseases including Alzheimer's, Parkinson's, Huntington's disease, stroke, and traumatic injury to the brain and spinal cord, can usually have devastating effects on quality of life. The current strategies available for treatments are described including drug delivery, surgery, electrical stimulation, and cell-based tissue engineering approaches. However, apart from cell-based therapy, other attempts are limited in improving clinical outcomes. Recently, stem cell and neural stem cell (NSC) in particular therapy has been proposed as an attractive and promising strategy for regenerative medicine due to their unique biological attributes, such as giving rise to neuronal lineage commitment in accordance with the neural development. Nevertheless, stem cell strategy still faces numerous challenges, including ethical issue, tumor formation, and graft rejection. Thus, seeking a more appropriate approach like direct reprogramming or lineage reprogramming is critical. Compared to induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), direct lineage reprogramming of somatic cells to generate induced neurons (iNs) without undergoing a state of pluripotent still has several advantages such as short induction cycle, high transdifferentiation efficiency, no ethical concerns, and risk of neoplasia. On the basis of these advantages, cell reprogramming will hold great promise for therapeutic cell replacement, disease modeling establishment, drug screening, and personalized medicine. Here, we systematically review recent advances in somatic lineage reprogramming into iNs, including the identification of novel reprogramming factors, the underlying molecular mechanisms and the concerns exist, as well as the major challenges in the future. PMID- 27981500 TI - Ethnic Inequalities in COPD Outcomes: a Register-Based Study in Copenhagen, Denmark. AB - The aim of this study was to investigate the differences in age at diagnosis and survival time after diagnosis between Chronic Obstructive Pulmonary Disease (COPD) patients with native Danish and other ethnic backgrounds. Individuals diagnosed with COPD in a hospital setting in Copenhagen in the period 2003-2007 were identified from annual hospital contact records. The cohort was restricted to COPD patients older than 35 years old at diagnosis. Follow-up was available until the end of 2010. ANOVA was conducted to test if mean age at diagnosis differed between the patient groups with different ethnicity. Kaplan-Meier estimator was used to estimate survival time after diagnosis. Cox proportional hazards models were conducted to calculate hazards of death according to ethnicity. A total of 2845 COPD patients were included; 131 (4.6%) were with non Western ethnic minority backgrounds. Patients with non-Western ethnic backgrounds were diagnosed at a younger age and had a better survival probability compared to ethnic Danish patients; hazard ratio HR (95% CI) for death during follow-up in non-Western vs. ethnic Danish patients was 0.33 (0.18-0.62). Our study showed marked differences in age at diagnosis and survival time after diagnosis between the COPD patients with different ethnic backgrounds residing in Copenhagen. Further studies are needed to find out the reasons for younger age of COPD diagnosis in non-Western minorities and for shorter survival time after diagnosis in ethnic Danish COPD patients. PMID- 27981501 TI - Theoretical Implications of Gender, Power, and Sexual Scripts for HIV Prevention Programs Aimed at Young, Substance-Using African-American Women. AB - HIV continues to be a major public health problem for African-American (AA) women, and the burden of new cases to our society is significant because each case is at risk of infecting others. Substance use worsens the risk of HIV transmission to AA women. We provide specific recommendations to move the concept of tailoring HIV prevention interventions for substance users forward by focusing on young, sexually active, substance-using AA women and applying a culturally relevant revision to existing theoretical frameworks to include the Sexual Script Theory and the Theory of Gender and Power. We encourage use of these theories to guide adaptation of interventions to demonstrate efficacy within this hard-to reach population. Consistent use of theories designed to exploit powerlessness and sexual scripts as barriers to adoption of protective sexual behaviors has potential to permeate sexual and substance use networks among African-Americans. This recommendation is being made because this theoretical framework has not been used in HIV prevention interventions targeting young, sexually active, substance using AA women. PMID- 27981502 TI - Skin targeting of resveratrol utilizing solid lipid nanoparticle-engrossed gel for chemically induced irritant contact dermatitis. AB - Irritant contact dermatitis (ICD) is a chronic and relapsing skin disease with severe eczematous lesions. Despite its growing prevalence, therapeutic treatments remain limited. Long-term topical corticosteroid treatment can induce skin atrophy, hypopigmentation, and increase in transepidermal water loss. An innovative dermal treatment is essential to reduce the side effects of corticosteroids. Topical resveratrol (RES), although effective for ICD, is a challenging molecule due to low solubility and poor bioavailability. The objective of this work was to build RES-loaded solid lipid nanoparticles (RES SLNs) with skin targeting. For this purpose, RES-SLNs were prepared using the probe ultrasonication method utilizing Precirol ATO 5 and Tween 20. The RES-SLNs were evaluated for particle size, entrapment efficiency (EE), and transmission electron microscopy (TEM) studies. Further, RES-SLNs were incorporated into Carbopol gel and investigated for ex vivo skin permeation, deposition study on human cadaver skin, and finally skin irritation study on New Zealand White rabbits. It was further assessed for possible beneficial effects on ICD using BALB/c mice. RES-SLN showed mean size below 100 nm and 68-89% EE. TEM studies confirmed spherical particles in the nanometer range. An ex vivo study of RES-SLN loaded gel exhibited controlled drug release up to 24 h; similarly, in vitro drug deposition studies showed potential of skin targeting with no skin irritation. RES-SLN gel confirmed competent suppression of ear swelling and reduction in skin water content in the BALB/c mouse model of ICD when compared to marketed gel. Thus, the formulated RES-SLN gel would be a safe and effective alternative to conventional vehicles for treatment of ICD. PMID- 27981503 TI - Lack of Evidence to Guide Deprescribing of Antihyperglycemics: A Systematic Review. AB - INTRODUCTION: Individualizing glycemic targets to goals of care and time to benefit in persons with type 2 diabetes is good practice, particularly in populations at risk of hypoglycemia and adverse outcomes relating to the use of antihyperglycemics. Guidelines acknowledge the need for relaxed targets in frail older adults, but there is little guidance on how to safely deprescribe (i.e. stop, reduce or substitute) antihyperglycemics. METHODS: The purpose of this study was to synthesize evidence from all studies evaluating the effects of deprescribing versus continuing antihyperglycemics in older adults with type 2 diabetes. To this end, we searched MEDLINE, EMBASE, and Cochrane Library (July 2015) for controlled studies evaluating the effects of deprescribing antihyperglycemics in adults with type 2 diabetes. All such studies were eligible for inclusion in our study, and two independent reviewers screened titles, abstracts and full-text articles, extracted data, and evaluated risk of bias. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment and a narrative summary were completed. RESULTS: We identified two controlled before-and-after studies, both of very low quality. One study found that an educational intervention decreased glyburide use while not compromising glucose control. The other reported that cessation of antihyperglycemics in elderly nursing home patients resulted in a non-significant increase in glycated hemoglobin (HbA1C). No significant change in hypoglycemia rate was found in the only study with this outcome measure. CONCLUSIONS: There is limited evidence available regarding deprescribing antihyperglycemic medications. Adequately powered, high-quality studies, particularly in the elderly and with clinically important outcomes, are required to support evidence-based decision-making. PROTOCOL REGISTRATION NUMBER: CRD42015017748. PMID- 27981505 TI - Erratum to: Chromatin Preparation and Chromatin Immuno-precipitation from Drosophila Embryos. PMID- 27981504 TI - Isolation, Identification and Screening of Potential Probiotic Bacteria in Milk from South African Saanen Goats. AB - This study aimed to evaluate lactic acid bacteria isolates from Saanen goats' milk for probiotic attributes, thereby determining their potential as direct-fed microbials for goats. Isolates were identified using API 50CH system, 16S rDNA sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry. All 17 isolates obtained were identified as Lactobacillus plantarum except one identified as Pediococcus acidilactici. Four isolates identified as L. plantarum (Accession numbers KJ026587.1, KM207826.1, KC83663.1 and KJ958428.1) by at least two of the techniques used and isolate 17 differently identified by all the methods used were selected as representatives and then screened for probiotic properties. These isolates displayed phenotypic probiotic attributes including tolerance to acid and bile salts, ability to adhere to intestines and possession of antagonistic activities against Proteus vulgaris, Staphylococcus aureus, Salmonella typhimurium, Pseudomonas aeruginosa and Escherichia coli. The lactic acid bacteria isolated from Saanen goats' milk showed potential to be used as sustainable probiotics in goats' industry. Successful use of probiotics in animals depends upon availability of appropriate isolates originating from the specific host animal. This study is a positive contribution towards identification of isolates with potential for formulation as direct-fed microbials for South African Saanen goats. PMID- 27981506 TI - The effects of enactment and intention accessibility on prospective memory performance. AB - The intention-superiority effect denotes faster response latencies to stimuli linked with a prospective memory task compared to stimuli linked with no prospective task or with a cancelled task. It is generally assumed that the increased accessibility of intention-related materials contributes to successful execution of prospective memory tasks at an appropriate opportunity. In two experiments we investigated the relationship between the intention-superiority effect and actual prospective memory performance under relatively realistic conditions. We also manipulated enactment versus observation encoding to further investigate the similarity in representations of enacted and to-be-enacted tasks. Additionally, Experiment 1 included a control condition to investigate the development of the intention-superiority effect over time. Participants were asked to perform prospective tasks at the end of the experiment to prepare the room for the next participant. They studied these preparatory tasks at the beginning of the experiment either by enacting them themselves or by observing the experimenter perform them. In Experiment 2, participants in a control condition did not intend to perform prospective tasks. We observed a smaller intention-superiority effect after enactment encoding than after observation encoding, but only if response latencies were assessed immediately before the prospective memory task. In addition, Experiment 2 suggested that the size of the intention-superiority effect is related to successful prospective memory performance, thus providing evidence for a functional relationship between accessibility and memory. PMID- 27981509 TI - Comment on: "Challenges in Individualizing Drug Dosage for Intensive Care Unit Patients: Is Augmented Renal Clearance What We Really Want to Know? Some Suggested Management Approaches and Clinical Software Tools". PMID- 27981508 TI - Anti-obesity effects of resveratrol: comparison between animal models and humans. AB - The prevalence of obesity has increased rapidly during recent years and has reached epidemic proportions. As a result, the scientific community is interested in active biomolecules which are naturally present in plants and foodstuffs and may be useful in body weight management. In recent years, polyphenols have made up one of the most frequently studied groups among these molecules. Numerous studies have been carried out on animals to analyse the potential anti-obesity effects of resveratrol, a non-flavonoid polyphenol, and a general consensus concerning the body-fat-lowering effect of this compound exists. By contrast, studies in humans have been few so far. Moreover, in these studies, the effectiveness of resveratrol is low. The aims of the present review are to summarize the results reported so far on this topic and to justify the differences observed between animals and humans. It seems that the reduced response to resveratrol in humans cannot be attributed to the use of lower doses in humans because the doses that induce body-fat-lowering effects in rodents are in the same range as those used in human studies. With regard to the experimental period length, treatments were longer in animal studies than in human studies. This can be one of the reasons contributing to the reduced responses observed in humans. Moreover, animals used in the reported studies are young while volunteers participating in human studies are adults, suggesting that resveratrol may be more efficient in young individuals. In addition to differences in the experimental designs, metabolic differences between animals and human cannot be discarded. PMID- 27981507 TI - Emerging diagnostic, prognostic and therapeutic biomarkers for ovarian cancer. AB - BACKGROUND: In spite of various treatment options currently available, ovarian cancer (OC) still remains a leading cause of death in women world-wide. Diagnosis at an early stage is one of the most important factors that determines survival. Current clinical diagnostic tools have, however, a limited efficacy in early OC detection. Therefore, there is a critical need for new (early) diagnostic biomarkers and tools. Through advances in genomic, proteomic and metabolomic techniques, several novel molecular OC biomarkers have recently been identified. These biomarkers are currently subject to validation. In addition, integration of genomic, proteomic and metabolomic data, in conjunction with epidemiologic and clinical data, is considered essential for obtaining useful results. Interesting recent work has already shown that specific diagnostic biomarkers, such as BRCA mutations, may have profound therapeutic implications. Here, we review the current state of OC research through literature and database searches, with a focus on various recently identified biomarkers via different technologies for the (early) diagnosis, prognosis and treatment of OC. CONCLUSIONS: Multi biomarker panels accompanied by a meticulous determination of their sensitivity and specificity, as well their validation, using multivariate analyses will be critical for its clinical application, including early OC detection and tailor made OC treatment. PMID- 27981510 TI - Aberrant CpG Methylation Mediates Abnormal Transcription of MAO-A Induced by Acute and Chronic L-3,4-Dihydroxyphenylalanine Administration in SH-SY5Y Neuronal Cells. AB - L-3,4-dihydroxyphenylalanine (L-dopa) remains the most effective drug for therapy of Parkinson's disease (PD); however, long-term use of it causes serious side effects. L-dopa-induced dyskinesia (LID) has consistently been related to L-dopa derived excessive dopamine release, but the mechanisms have not been addressed very clear. Monoamine oxidase A (MAO-A) is one of the key enzymes in dopamine metabolism and therefore may be involved in L-dopa-induced side effects. And, epigenetic modification controls MAO-A gene transcription. To investigate the effects of L-dopa on MAO-A transcription and its underlying epigenetic mechanism, neuronal SH-SY5Y cells were treated with L-dopa for 24 h (acute) and for 7-21 days (chronic). Results showed that chronic L-dopa administration resulted in a dose-dependent and time-dependent downregulation of MAO-A, whereas acute L-dopa administration induced upregulation of MAO-A transcription and expression. Meanwhile, chronic L-dopa exposure induced CpG hypermethylation in MAO-A promoter, while acute L-dopa administration caused CpG hypomethylation. And, CpG demethylation resulted in reactivation of MAO-A transcription. These results indicated that aberrant CpG methylation might play a key role in MAO-A transcriptional misregulation in L-dopa administration. In addition, results showed that acute L-dopa administration induced downregulation of DNA methyltransferase 3a (DNMT3a). Transcription of ten-eleven translocation 1 (TET1) were significantly downregulated in chronic L-dopa administration. These data indicated that in chronic L-dopa administration, TET1 downregulation might mediate CpG hypermethylation, which is responsible for the downregulation of MAO A transcription. In contrast, in acute L-dopa administration, DNMT3a downregulation might mediate hypomethylation, contributing to the MAO-A upregulation. In conclusion, our findings suggested that TET1 and DNMTs might mediate aberrant CpG methylation, associated with the misregulation of MAO-A in L dopa administration, which might contribute to dopamine release abnormally leading to the side effects of L-dopa. PMID- 27981512 TI - Reduced serum levels of oestradiol and brain derived neurotrophic factor in both diabetic women and HFD-feeding female mice. AB - The estrogen levels in the pre and post menstrual phases interact with brain derived neurotrophic factor in a complex manner, which influences the overall state of the body. To study the role of oestradiol and brain-derived neurotrophic factor in modulating obesity related type 2 diabetes and the interactions between two factors, we enrolled 15 diabetic premenopausal women and 15 diabetic postmenopausal women respectively, the same number of healthy pre and postmenopausal women were recruited as two control groups. The fasting blood glucose, insulin, lipids, estrogen, and brain-derived neurotrophic factor levels were measured through clinical tests. Additionally, we set up obese female mouse model to mimic human trial stated above, to verify the relationship between estrogen and brain-derived neurotrophic factor. Our findings revealed that there is a moderately positive correlation between brain-derived neurotrophic factor and oestradiol in females, and decreased brain-derived neurotrophic factor may worsen impaired insulin function. The results further confirmed that high fat diet-fed mice which exhibited impaired glucose tolerance, showed lower levels of oestradiol and decreased expression of brain-derived neurotrophic factor mRNA in the ventromedial hypothalamus. The level of brain-derived neurotrophic factor reduced on condition that the level of oestradiol is sufficiently low, such as women in postmenopausal period, which aggravates diabetes through feeding-related pathways. Increasing the level of brain-derived neurotrophic factor may help to alleviate the progression of the disease in postmenopausal women with diabetes. PMID- 27981513 TI - Growth hormone and the heart in growth hormone deficiency-what have we learned so far? PMID- 27981514 TI - Visceral adiposity index as an indicator of cardiometabolic risk in patients treated for craniopharyngioma. AB - PURPOSE: Craniopharyngioma is associated with metabolic alterations leading to increased cardiovascular mortality. Recently, the visceral adiposity index has been proposed as a marker of visceral adipose tissue dysfunction and of the related cardiometabolic risk. The role of the visceral adiposity index has never been explored in craniopharyngioma patients. We assessed the cardiometabolic risk on the basis of the visceral adiposity index in craniopharyngioma patients. METHODS: We evaluated data of 24 patients treated for craniopharyngioma in a single-centre. We investigated the relationship among patients' clinical and biochemical features, cardiovascular risk -assessed by the Framingham and the atherosclerotic cardiovascular disease risk scores-, visceral adiposity index and adipose tissue dysfunction severity. RESULTS: Increased visceral adiposity index was found in 8 patients (33%). Adipose tissue dysfunction resulted to be severe, moderate or mild in 5, 2 and 1 cases. Increased visceral adiposity index significantly correlated with the occurrence of metabolic syndrome (p 0.027), IRI (p 0.001), triglycerides (p < 0.001), HOMA-IR (p < 0.001) and with lower ISI Matsuda (p 0.005) and HDL-cholesterol (p < 0.001). Higher degree of adipose tissue dysfunction associated with increased insulin resistance. No gender difference was found for visceral adiposity index, adipose tissue dysfunction severity, and cardiovascular risk scores. Patients with adulthood onset craniopharyngioma showed higher Framingham risk score (p 0.004), atherosclerotic cardiovascular disease 10-year (p < 0.001) and lifetime (p 0.018) risk scores than those with childhood onset disease. CONCLUSIONS: Visceral adiposity index is increased in one third of our patients with craniopharyngioma, even if metabolic syndrome does not occur. Increased visceral adiposity index and adipose tissue dysfunction severity correlate with insulin sensitivity parameters, do not correlate with Framingham or atherosclerotic cardiovascular disease risk scores, and are not influenced by gender and age of disease onset. PMID- 27981511 TI - The emergence of levothyroxine as a treatment for hypothyroidism. AB - OBJECTIVE: To describe the historical refinements, understanding of physiology and clinical outcomes observed with thyroid hormone replacement strategies. METHODS: A Medline search was initiated using the search terms, levothyroxine, thyroid hormone history, levothyroxine mono therapy, thyroid hormone replacement, combination LT4 therapy, levothyroxine Bioequivalence. Pertinent articles of interest were identified by title and where available abstract for further review. Additional references were identified in the course of review of the literature identified. RESULTS: Physicians have intervened in cases of thyroid dysfunction for more than two millennia. Ingestion of animal thyroid derived preparations has been long described but only scientifically documented for the last 130 years. Refinements in hormone preparation, pharmaceutical production and regulation continue to this day. The literature provides documentation of physiologic, pathologic and clinical outcomes which have been reported and continuously updated. Recommendations for effective and safe use of these hormones for reversal of patho-physiology associated with hypothyroidism and the relief of symptoms of hypothyroidism has documented a progressive refinement in our understanding of thyroid hormone use. Studies of thyroid hormone metabolism, action and pharmacokinetics have allowed evermore focused recommendations for use in clinical practice. Levothyroxine mono-therapy has emerged as the therapy of choice of all recent major guidelines. CONCLUSIONS: The evolution of thyroid hormone therapies has been significant over an extended period of time. Thyroid hormone replacement is very useful in the treatment of those with hypothyroidism. All of the most recent guidelines of major endocrine societies recommend levothyroxine mono-therapy for first line use in hypothyroidism. PMID- 27981515 TI - Preliminary data of VEGF-A and VEGFR-2 polymorphisms as predictive factors of radiological response and clinical outcome in iodine-refractory differentiated thyroid cancer treated with sorafenib. PMID- 27981517 TI - The role of AIP mutations in pituitary adenomas: 10 years on. PMID- 27981516 TI - Physical activity and hypocaloric diet recovers osteoblasts homeostasis in women affected by abdominal obesity. AB - Obesity is a multifactorial disease linked to metabolic chronic disorders such as diabetes, and hypertension. Also, it has recently been associated with skeletal alterations and low bone mineral density. We previously demonstrated that exposure of osteoblasts to sera of sedentary subjects affected by obesity alters cell homeostasis in vitro, leading to disruption of intracellular differentiation pathways and cellular activity. Thus, the purpose of the present study has been to evaluate whether sera of sedentary obese women, subjected to physical activity and hypocaloric diet, could recover osteoblast homeostasis in vitro as compared to the sera of same patients before intervention protocol. To this aim, obese women were evaluated at time 0 and after 4, 6, and 12 months of individualized prescribed physical activity and hypocaloric diet. Dual-energy-X-ray absorptiometry measurements were performed at each time point, as well as blood was collected at the same points. Cells were incubated with sera of subjects before and after physical activity as described: obese at baseline and after for 4, 6, and 12 months of physical activity and nutritional protocol intervention. Osteoblasts exposed to sera of patients, who displayed increased lean and decreased fat mass (from 55.5 +/- 6.5 to 57.1 +/- 5.6% p <= 0.05; from 44.5 +/- 1.1 to 40.9 +/- 2.6% p <= 0.01 respectively), showed a time-dependent increase of Wnt/beta-catenin signaling, versus cells exposed to sera of obese patients before intervention protocol, suggesting recovery of osteoblast homeostasis upon improvement of body composition. An increase in beta-catenin nuclear accumulation and nuclear translocation was also observed, accompanied by an increase in Adiponectin receptor 1 protein expression, suggesting positive effect on cell differentiation program. Furthermore, a decrease in sclerostin amount and an increase of type 1 procollagen amino-terminal-propeptide were depicted as compared to baseline, proportionally to the time of physical activity, suggesting a recovery of bone remodeling modulation and an increase of osteoblast activity induced by improvement of body composition. In conclusion, our results show for the first time that sera of obese sedentary women who increased lean mass and decreased fat mass, by physical activity and hypocaloric diet, rescue osteoblasts differentiation and activity likely due to a reactivation of Wnt/beta-catenin pathway, suggesting that a correct life style can improve skeletal metabolic alteration induced by obesity. PMID- 27981518 TI - Leptin directly stimulates parathyroid hormone secretion. PMID- 27981519 TI - Craniopharyngiomas: a life-changing tumor. PMID- 27981521 TI - The influence of action video game playing on eye movement behaviour during visual search in abstract, in-game and natural scenes. AB - Action game playing has been associated with several improvements in visual attention tasks. However, it is not clear how such changes might influence the way we overtly select information from our visual world (i.e. eye movements). We examined whether action-video-game training changed eye movement behaviour in a series of visual search tasks including conjunctive search (relatively abstracted from natural behaviour), game-related search, and more naturalistic scene search. Forty nongamers were trained in either an action first-person shooter game or a card game (control) for 10 hours. As a further control, we recorded eye movements of 20 experienced action gamers on the same tasks. The results did not show any change in duration of fixations or saccade amplitude either from before to after the training or between all nongamers (pretraining) and experienced action gamers. However, we observed a change in search strategy, reflected by a reduction in the vertical distribution of fixations for the game-related search task in the action-game-trained group. This might suggest learning the likely distribution of targets. In other words, game training only skilled participants to search game images for targets important to the game, with no indication of transfer to the more natural scene search. Taken together, these results suggest no modification in overt allocation of attention. Either the skills that can be trained with action gaming are not powerful enough to influence information selection through eye movements, or action-game-learned skills are not used when deciding where to move the eyes. PMID- 27981522 TI - Increased experience amplifies the activation of task-irrelevant category representations. AB - Prior research has demonstrated the benefits (i.e., task-relevant attentional selection) and costs (i.e., task-irrelevant attentional capture) of prior knowledge on search for an individual target or multiple targets from a category. This study investigated whether the level of experience with particular categories predicts the degree of task-relevant and task-irrelevant activation of item and category representations. Adults with varying levels of dieting experience (measured via 3 subscales of Disinhibition, Restraint, Hunger; Stunkard & Messick, Journal of Psychosomatic Research, 29(1), 71-83, 1985) searched for targets defined as either a specific food item (e.g., carrots), or a category (i.e., any healthy or unhealthy food item). Apart from the target present trials, in the target-absent "foil" trials, when searching for a specific item (e.g., carrots), irrelevant items from the target's category (e.g., squash) were presented. The ERP (N2pc) results revealed that the activation of task relevant representations (measured via Exemplar and Category N2pc amplitudes) did not differ based on the degree of experience. Critically, however, increased dieting experience, as revealed by lower Disinhibition scores, predicted activation of task-irrelevant representations (i.e., attentional capture of foils from the target item category). Our results suggest that increased experience with particular categories encourages the rapid activation of category representations even when category information is task irrelevant, and that the N2pc in foil trials could potentially serve as an indication of experience level in future studies on categorization. PMID- 27981520 TI - Impact of pre-gestational and gestational diabetes mellitus on the expression of glucose transporters GLUT-1, GLUT-4 and GLUT-9 in human term placenta. AB - PURPOSE: Various studies in placental tissue suggest that diabetes mellitus alters the expression of glucose transporter (GLUT) proteins, with insulin therapy being a possible modulatory factor. The aim of the present study was quantitative evaluation of the expression of glucose transporters (GLUT-1, GLUT 4, GLUT-9) in the placenta of women in both, uncomplicated and diabetic pregnancy. Additionally, the effect of insulin therapy on the expression of selected glucose transporter isoforms was analyzed. METHODS: Term placental samples were obtained from healthy control (n = 25) and diabetic pregnancies, including diet-controlled gestational diabetes mellitus (GDMG1) (n = 16), insulin controlled gestational diabetes mellitus (GDMG2) (n = 6), and pre-gestational diabetes mellitus (PGDM) (n = 6). Computer-assisted quantitative morphometry of stained placental sections was performed to determine the expression of selected glucose transporter proteins. RESULTS: Morphometric analysis revealed a significant increase in the expression of GLUT-4 and GLUT-9 in insulin-dependent diabetic women (GDMG2 + PGDM) as compared to both, control and GDMG1 groups (p < .05). Significantly increased GLUT-1 expression was observed only in placental specimens from patients with PGDM (p < .05). No statistically significant differences in GLUT expression were found between GDMG1 patients and healthy controls. CONCLUSIONS: The results of the study confirmed the presence of GLUT-1, GLUT-4 and GLUT-9 proteins in the trophoblast from both, uncomplicated and diabetic pregnancies. In addition, insulin therapy may increase placental expression of GLUT-4 and GLUT-9, and partially GLUT-1, in women with GDMG2/PGDM. PMID- 27981523 TI - Two distinct patterns of interference in between-attribute Stroop matching tasks. AB - In between-attribute Stroop matching tasks, participants compare the meaning (or the color) of a Stroop stimulus with a probe color (or meaning) while attempting to ignore the Stroop stimulus's task-irrelevant attribute. Interference in this task has been explained by two competing theories: A semantic competition account and a response competition account. Recent results favor the response competition account, which assumes that interference is caused by a task-irrelevant comparison. However, the comparison of studies is complicated by the lack of a consensus on how trial types should be classified and analyzed. In this work, we review existing findings and theories and provide a new classification of trial types. We report two experiments that demonstrate the superiority of the response competition account in explaining the basic pattern of performance while also revealing its limitations. Two qualitatively distinct interference patterns are identified, resulting from different types of task-irrelevant comparisons. By finding the same interference pattern across task versions, we were additionally able to demonstrate the comparability of processes across two task versions frequently used in neurophysiological and cognitive studies. An integrated account of both types of interference is presented and discussed. PMID- 27981524 TI - Preparation of NASICON-Type Nanosized Solid Electrolyte Li1.4Al0.4Ti1.6(PO4)3 by Evaporation-Induced Self-Assembly for Lithium-Ion Battery. AB - A simple and practicable evaporation-induced self-assembly (EISA) method is introduced for the first time to prepare nanosized solid electrolyte Li1.4Al0.4Ti1.6(PO4)3 (LATP) for all-solid-state lithium-ion batteries. A pure Na+ super ion conductor (NASICON) phase is confirmed by X-ray diffraction (XRD) analysis, and its primary particle size is down to 70 nm by optimizing evaporation rate of the solvent. Excellent room temperature bulk and total lithium-ion conductivities of 2.09 * 10-3 S cm-1 and 3.63 * 10-4 S cm-1 are obtained, with an ion-hopping activation energy as low as 0.286 eV. PMID- 27981525 TI - Nymph and Adult Biology of Euschistus cornutus Dallas: a Potential Soybean Pest in the Neotropics. AB - Laboratory studies with Euschistus cornutus Dallas indicated that nymphs complete development when feeding on green bean, Phaseolus vulgaris L. pod, on soybean, Glycine max (L.) Merrill pod, and on raw shelled peanut, Arachis hypogaea L., but not on fruit (berry) of privet, Ligustrum lucidum Ait. Total mortality was lower on green bean pod (45%), and higher on soybean pod and peanut raw (75 and 80%, respectively). Nymph developmental time was significantly longer for females feeding on green bean pod (37.4 days) than on soybean pod (27 days); a single data was observed on peanut raw (32 days). Males showed no significant differences in total nymph developmental time among foods (31.3 to 33.0 days). At adult emergency, fresh body weight of females (52.2 to 68.5 mg) and males (61.9 to 71.3 mg) did not show statistical differences among foods tested nor between genders. Survivorship of E. cornutus adult after 50 days was greater on peanut raw than on green bean or soybean pod; on privet berry, the majority of males and females (>80%) were dead after 20 days. The reproductive performance data was, in general, greater on peanut raw than on green bean or soybean pod; on privet fruit, no female laid eggs. Fresh body weight gain occurred on all foods, except on privet berry, on which adults lost weight over time. Records of specimens from insect collections in Brazil indicated that E. cornutus occurs in the Southeast and South regions (19 degrees to 31 degrees S latitude). The most common host plant is soybean, suggesting a potential pest status of this stink bug on this crop in the future. PMID- 27981526 TI - Molecular mechanisms in bone mechanotransduction. AB - Bone is one of the most adaptable tissues in the body as it is continuously subjected to load bearing. In fact, mechanical loading is an important regulator of bone mass. The skeleton adjusts to load by changing its mass, shape and microarchitecture, depending on the magnitude of the strain. Mechanical stimulation is necessary for the development of the skeleton, whereas in adults physiological levels of strain help maintain bone mass by reducing bone resorption. On the other hand, an excessive level of strain or bone disuse induces bone loss. Osteocytes are long-lived cells comprising more than 90% of bone cellularity, which are embedded in the bone matrix forming a functional syncytium extending to the bone surface. These cells are considered to be the main bone cells responsible for translating mechanical strain into regulatory signals for osteoblasts and osteoclasts, leading to adapting bone responses to environmental changes. In this review, we discuss the complexity and well orchestrated events that occur in bone mechanotransduction, focusing on osteocyte viability as an important biological response in this respect. Elucidation of the molecular mechanisms of bone mechanotransduction and the key role of osteocytes is opening new avenues for the treatment of bone loss-related diseases. PMID- 27981528 TI - Clinical study on influences of enteric coated aspirin on blood pressure and blood pressure variability. AB - OBJECTIVE: We investigated the effects of oral administration of enteric coated aspirin (ASA) on blood pressure and blood pressure variability of hypertension patients before sleep. PATIENTS AND METHODS: We observed 150 hypertension cases, classified as Grade 1-2, from September 2006 to March 2008. They are divided into a control group with 30 cases, ASA I group with 60 cases and ASA II group with 60 cases randomly. Subjects in the control group had proper diets, were losing weight, exercising and maintaining a healthy mentality and were taking 30 mg Adalat orally once a day. Based on the treatment of control group, patients in ASA I group were administered 0.1 g Bayaspirin (produced by Bayer Company) at drought in the morning. Also, based on the treatment of control group, patients in ASA II group were administered 0.1 g Bayaspirin at draught before sleep. RESULTS: The course of treatment is 3 months and then after the treatment, decreasing blood pressure and blood pressure variability conditions in three groups will be compared. Through the comparison of ASA II group with the control group, they have differences in terms of systolic blood pressure (SBP), diastolic blood pressure (DBP), decreasing range of blood pressure and blood pressure variability (p < 0.05). CONCLUSIONS: The oral administration of ASA before sleep has synergistic effects on decreasing blood pressure of hypertension patients and improving blood pressure variability. PMID- 27981527 TI - Examination of the pharmacodynamics and pharmacokinetics of a diclofenac poly(lactic-co-glycolic) acid nanoparticle formulation in the rat. AB - OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are assembled into two categories; cyclooxygenase (COX-1) sparing inhibitors of COX-2 and non-selective NSAIDs. Diclofenac (DICLO) is a non-selective NSAID that has been linked to serious side effects including gastric ulcers and renal injury. In this study, we examine the effect of poly(lactic-co-glycolic) acid nanoformulation on DICLO associated adverse events and pharmacokinetics using a nanoparticle (NP) formulation previously developed in our laboratory. MATERIALS AND METHODS: Rats were administered a single dose of methylcellulose (VEH), blank NP, DICLO (10 mg/kg), or a DICLO-NP suspension equivalent to the DICLO dose. Urinary and blood parameters were measured at baseline and following treatment. Duodenal and gastric prostaglandin E2 (PGE2) and duodenal myeloperoxidase (MPO) were collected to assess inflammation at 24 hrs post-treatment. RESULTS: The mean percent change from baseline in sodium excretion rate (umol/min/100 g body weight) differed significantly from VEH in the NP (p < 0.0001), DICLO (p < 0.0001), and DICLO-NP (p = 0.0001) groups. The differences among groups did not reach significance for plasma sodium or potassium concentrations, potassium excretion rate, gastric PGE2, or intestinal biomarker concentrations. Regarding renal histopathology, DICLO produced considerably more necrosis compared to VEH; while DICLO-NP did not elicit notable differences from VEH. CONCLUSIONS: Our results suggest that over the duration and dosage examined, DICLO-NP may reduce renal necrosis without influencing other side effects or drug characteristics. PMID- 27981529 TI - Effect of regular oral intake of aspirin during pregnancy on pregnancy outcome of high-risk pregnancy-induced hypertension syndrome patients. AB - OBJECTIVE: The aim of this study is to analyze the effect of 100 mg/d regular oral intake of aspirin during pregnancy on high-risk pregnancy-induced hypertension syndrome patients. PATIENTS AND METHODS: We consecutively selected 98 cases high-risk pregnancy-induced hypertension syndrome patients. After obtaining the informed consent of the patients, we randomly divided the patients into aspirin group (50 cases) and placebo group (48 cases). The oral intake of aspirin lasted from the final diagnosis of pregnancy to antepartum time, and was taken before sleep. The bleeding index was closely detected and we stop taking aspirin when necessary. RESULTS: The comparison of clinical outcome showed that the incidents of pregnancy-induced hypertension syndrome, pre-eclampsia and eclampsia of aspirin group were significantly lower than that of the placebo group (p<0.05). Comparing the complications of fetus perinatal period, the difference was not statistically significant (p>0.05). CONCLUSIONS: 100 mg/d regular oral intake of aspirin during pregnancy is safe, effective and worthy of generalization to high-risk pregnancy-induced hypertension syndrome patients. PMID- 27981530 TI - Relationship between deficiencies in vitamin A and E and occurrence of infectious diseases among children. AB - OBJECTIVE: To investigate the relationship between vitamin A deficiency (VAD), vitamin E deficiency (VED) and infectious diseases. PATIENTS AND METHODS: We chose 684 cases of healthy children age 5 months-12 years from our hospital, measured their VA, VE from vein under the light proof condition with high pressure liquid chromatography. Thereafter, the children who get the acute respiratory tract infection (ARI) or diarrhea two weeks later were registered. RESULTS: After the two weeks trial (N=684 cases), the VA level of children with ARI was lower than that of children without ARI (0.23+/-0.02 mg/ml/0.33+/-0.01 mg/ml), p<0.05. Moreover, the VE level of children with ARI was significantly lower than that of children without ARI (p<0.05). Most interestingly, the proportion of children with diarrhea accompanied with decreased VA level in serum was higher than that of children without diarrhea, indicating that VA level <0.2 mg/L more easily affected acute respiratory tract infection. CONCLUSIONS: We were able to demonstrate that Children who presented vitamin A deficiency were easier to get the acute respiratory tract infection (ARI) and diarrhea. Children who presented vitamin E deficiency were easier to get the acute respiratory tract infection (ARI). Vitamin A and vitamin E deficiencies are one of the important factors related to occurrences of acute infectious diseases in children. PMID- 27981531 TI - miR-760 mediates chemoresistance through inhibition of epithelial mesenchymal transition in breast cancer cells. AB - OBJECTIVE: Therapeutic resistance has been a great obstacle for successful treatment of breast cancer. Our study aimed to explore the role of microRNA-760 (miR-760) in chemoresistant breast cancer cells. MATERIALS AND METHODS: Real-time PCR was performed to measure the mRNA expression of miR-760 and Nanog. Western blot was used to determine the protein expression of Nanog and mesenchymal and epithelial markers. Cell viability was measured by the CCK-8 assay. RESULTS: Our results showed that the expression of miR-760 was significantly reduced the doxorubicin (DOX)-resistant MCF-7/DOX cells and chemoresistant breast cancer tissues. Moreover, up-regulation of miR-760 sensitized breast cancer cells to the anti-cancer agents. The MCF-7/DOX cells exhibited increased expression of Snail, a mesenchymal marker, and decreased levels of E-Cadherin, an epithelial marker. In addition, overexpression of miR-760 suppressed the expression of Nanog, a transcriptional factor involved in chemoresistance, and resulted in the reversal of EMT in breast cancer cells. CONCLUSIONS: Our study demonstrated that miR-760 modulated chemoresistance through the epithelial-mesenchymal transition in breast cancer cells, providing a potential therapeutic target for treatment of drug resistant breast cancer. PMID- 27981532 TI - Rifaximin modulates 5-fluorouracil-induced gastrointestinal mucositis in rats. AB - OBJECTIVE: This study assessed the protective potential of rifaximin in 5 fluorouracil (5-FU) induced intestinal mucositis in the Wistar rats'. MATERIALS AND METHODS: Twenty-nine Wistar rats were divided into 4 interventional groups of 6 animals (A, B, C and F) and one control group (M) of 5 animals. Groups A, B and C received for three days consecutively rifaximin orally: 50 mg/kg (group A), 100 mg/kg (group B) and 200 mg/kg (group C). In the fourth day, 500 mg/kg of 5-FU was administered intraperitoneally to the groups A, B, C and F. A semi-quantitative histological assessment for duodenum, jejunum and colon were obtained by rating 11 histological characteristics of mucositis from 0 (normal) to 3 (severe). Semi quantitative grades were a measure for TLR4 immunopositive cells. Statistical comparisons used - U Test, with a Bonferroni correction for alpha (p <= 0.016). RESULTS: In the group F the most affected areas were the jejunum (median histological score 25) and the duodenum (median histological score 22). The assessment of duodenum histological lesions depicted significant difference between F and B groups (U = 1.5, p = 0.007) and between F and C groups (U = 0, p = 0.003). Graded microscopic degenerative lesions on jejunum were significantly different between F and C groups (U = 0, p = 0.004). Graded TLR4 immunopositive cells in the jejunum surface epithelium was significantly different between groups F and C (U = 2.5, p = 0.006). In the colonic mucosa, significantly differences were noted on microscopic degenerative lesions between F and A groups (U = 0, p = 0.004) and between F and C groups (U = 0, p = 0.004). CONCLUSIONS: Pretreatment with 200 mg/kg of rifaximin for 3 consecutive days proved efficient in preventing intestinal mucosal degenerative lesions induced by 5-FU. PMID- 27981533 TI - Triamcinolone acetonide reduces viability, induces oxidative stress, and alters gene expressions of human chondrocytes. AB - OBJECTIVE: Patients with knee osteoarthritis (OA) are sometimes prescribed intra articular injections of glucocorticoids (GCs), such as triamcinolone acetonide (TA). Whether GCs cause chondrotoxicity is not known. We wished to ascertain if TA induces toxicity by causing oxidative stress and alters expression of P21, growth differentiation factor (GDF)15, and cFos. PATIENTS AND METHODS: Primary chondrocytes isolated from 10 OA patients undergoing total knee replacement surgery were incubated with TA (0, 1, 5, 10 mg/ml), with or without 100 uM vitamin C for 7 and 14 days for viability assays and 48 h for oxidative stress and gene expression analyses. RESULTS: TA significantly decreased chondrocyte viability and increased the ratio of oxidized glutathione to total glutathione suggesting an increase in oxidative stress. Vitamin C significantly increased the viability and decreased the oxidative stress of cells treated with 5 mg/ml TA. Expression of P21, GDF15, and cFos increased significantly when TA was added (5.17 +/- 2.4-, 4.96 +/- 3.1-fold for P21, 9.97 +/- 2.9- and 4.2 +/- 1.6-fold for GDF15, and 6.65 +/- 4.8-, 12.96 +/- 8.3-fold for cFos at 1, and 5 mg/ml TA, respectively). CONCLUSIONS: TA induced chondrotoxicity by increasing oxidative stress and altering expressions of genes involved in cell death. The addition of vitamin C decreased oxidative stress and increased viability, suggesting that antioxidants might attenuate TA toxicity in cartilage. PMID- 27981534 TI - The anxiolitic effects of BTG1640 and BTG1675A on ultrasonic isolation calls and locomotor activity of rat pups. AB - OBJECTIVE: The aim of the present study was to evaluate the anxiolytic properties of the new isoxazoline compounds BTG1640 and BTG1675A in comparison with diazepam. MATERIALS AND METHODS: We evaluated the ultrasonic distress emission in both sexes of neonatal rat pups (which seems to be a sensitive indicator of the rat emotional reactivity and represents a valuable tool to screen compounds with expected anxiolytic properties) and the locomotor activity in 30-day old rat pups. RESULTS: We found a significant reduction in the number of emitted ultrasonic calls only after i.p. administration of diazepam 1 mg/kg, while no significant reduction have been detected after i.p. administration of BTG 1640 and BTG 1675A. Furthermore, we found a significant reduction of locomotor activity in the first 10' of the test, only in the group treated with diazepam 0.1 mg. CONCLUSIONS: The tests validating the supposed anxiolytic properties of the new isoxazoline compounds BTG1640 and BTG1675A, in comparison with diazepam, gave negative results. PMID- 27981535 TI - Remote ischemic preconditioning provides neuroprotection: impact on ketamine induced neuroapoptosis in the developing rat brain. AB - OBJECTIVE: Previous studies have demonstrated that the commonly used anesthetic ketamine can acutely increase apoptosis and have long-lasting detrimental effects on cognitive function as the animal matures. Remote ischemic preconditioning (RIPC) has been confirmed to have a cerebral protective role in animal models of brain damage. The aim of this study was to investigate whether RIPC can protect the developing brain from anesthetic-induced neurotoxicity. MATERIALS AND METHODS: To investigate the protective properties of RIPC, 60 new-born Sprague Dawley (SD) rats were randomly allocated into four groups: ketamine (20 mg/kg was diluted in saline, six times at an interval of 2 hours); RIPC (left hind row ischemia 5 min, reperfusion 5 min, a total of four cycles); ketamine + RIPC: RIPC was induced at postnatal day 5 and rats underwent the same treatment with the ketamine group after 48 hours; and saline (group vehicle). Neuronal apoptosis in the frontal cortex and hippocampal CA1 region was measured 24 h after treatment using immunohistochemistry of cleaved caspase-3. Learning and memory abilities were tested at the age of 60 days by Morris water maze test. RESULTS: The percentage of cleaved caspase-3 immunohistochemical staining positive cells in the ketamine + RIPC group showed a more marked decline in neuronal apoptosis of the CA1 region than that in the ketamine group (p < 0.05) but not in the CA1 region (p > 0.05). The mice exposed to RIPC alone showed no difference from the saline-treated mice. Moreover, RIPC significantly reversed the learning and memory deficits observed at 60 days of age. CONCLUSIONS: Our data indicate that RIPC treatment provides protection against ketamine-induced neuroapoptosis in the frontal cerebral cortex but not in the hippocampal CA1 region in developing rats and attenuates long-term behavioural deficits as the animals mature, suggesting a new possible strategy for neuroprotection. PMID- 27981536 TI - Nicotinamide phosphoribosyltransferase enhances beta cell expansion during pregnancy. AB - OBJECTIVE: Many factors contribute to the development of gestational diabetes mellitus (GDM). Among these factors, nicotinamide phosphoribosyltransferase (NAMPT) plays a critical role. Previous studies have demonstrated the effects of NAMPT on insulin resistance during GDM, while the effects of NAMPT on beta cells remain unknown. Here we addressed this question. PATIENTS AND METHODS: Mouse islets were isolated and transduced with adeno-associated vectors carrying NAMPT. Glucose-stimulated insulin secretion, beta cell proliferation, and beta cell apoptosis were analyzed in NAMPT-overexpressing islets, compared to controls. RESULTS: Overexpression of NAMPT in primary mouse islets increased glucose stimulated insulin secretion and increased beta cell expansion through augmentation of beta cell proliferation, without affecting beta cell apoptosis. CONCLUSIONS: NAMPT enhances expansion of beta cell mass during pregnancy. Inadequate NAMPT may contribute to the development of GDM partially through reduced beta cell expansion in the gestational period. PMID- 27981537 TI - Aconitine induces cell apoptosis in human pancreatic cancer via NF-kappaB signaling pathway. AB - OBJECTIVE: Pancreatic cancer is one of the leading causes of death from cancer in European countries and the United States. This study sought to investigate the effects of aconitine, a well-known aconitum plant-produced toxin, on pancreatic cancer cell growth and apoptosis and to explore the potential mechanisms. MATERIALS AND METHODS: In this study, pancreatic cancer cell lines Miacapa-2 and PANC-1 were cultured, and cell viability was examined in these two cells treated with different doses of aconitine. Moreover, cell apoptosis was also analyzed upon aconitine treatment, and the specific mechanism was examined by Western blot assay and caspase activity detection. RESULTS: The results showed that aconitine inhibited pancreatic cancer cell growth in a dose- and time-dependent manner. The administration of aconitine in Miapaca-2 and PANC-1 cells also induced cell apoptosis by upregulating the expression of pro-apoptotic factors Bax, cl-caspase 3, cl-caspase-9, and cleaved poly (ADP-ribose) polymerase 1 (PARP1), and by decreasing the anti-apoptotic Bcl-2 expression. More importantly, NF-kappaB was also decreased upon aconitine treatment. In a xenograft mouse model of pancreatic cancer, aconitine suppressed tumor growth and increased cell apoptosis. CONCLUSIONS: This study is the first report on the effects of aconitine on pancreatic cancer, and it reveals that aconitine may serve as a potent therapeutic strategy for clinical treatment of pancreatic cancer. PMID- 27981538 TI - Diagnosis and treatment of acute pharyngitis/tonsillitis: a preliminary observational study in General Medicine. AB - OBJECTIVE: According to recent observations, the insufficiently targeted use of antibiotics is creating increasingly resistant bacterial strains. In this context, it seems increasingly clear the need to resort to extreme and prudent rationalization of antibiotic therapy, especially by the physicians working in primary care units. In clinical practice, actually the general practitioner often treats multiple diseases without having the proper equipment. In particular, the use of a dedicated, easy to use diagnostic test would be one more weapon for the correct diagnosis and treatment of acute pharyngo-tonsillitis. The disease is a condition frequently encountered in clinical practice but its optimal management remains a controversial topic. In this context, the observational study is intended to demonstrate the usefulness of the rapid test (RAD: Rapid antigen detection) against group A beta-hemolytic streptococcus (GABHS) in everyday clinical practice to identify individuals with acute streptococcal pharyngo tonsillitis needing antibiotic therapy and to pursue the following objectives: (1) Getting the answer to an unmet medical need; (2) Promoting the appropriateness of the use of antibiotics; (3) Provide a means of containment in pharmaceutical spending. PATIENTS AND METHODS: 50 patients presenting sore throat associated with erythema and/or pharyngeal tonsillar exudate with or without scarlatiniform rash, fever and malaise had been subjected to perform a rapid test (RAD: Rapid antigen detection) for the search of the beta-hemolytic Streptococcus Group A (GABHS). Pharyngeal-tonsillar swabs were tested using Immunospark (relative sensitivity 97.6%, relative specificity 97.5%) according to manufacturer's instructions (runtime/reading response < 10 min). RESULTS: Of the 50 tests, 45 provided a negative response while 5 were positive for the search of the beta-hemolytic Streptococcus group A. No test result has been invalid. CONCLUSIONS: Based on the results obtained, only patients with a positive rapid test were subjected to targeted antibiotic therapy. This has resulted in a significant cost savings in pharmaceutical expenditure, without neglecting the more important and correct application of the Guidelines with performing of a clinically validated test that carries advantages for reducing the use of unnecessary and potentially harmful antibiotics and the consequent lower prevalence and incidence of antibiotic-resistant bacterial strains. PMID- 27981539 TI - Growth and adhesion to HT-29 cells inhibition of Gram-negatives by Bifidobacterium longum BB536 e Lactobacillus rhamnosus HN001 alone and in combination. AB - OBJECTIVE: The aim of this study was to test the inhibitory effect of supernatants of broth cultures of Bifidobacterium longum BB536 and Lactobacillus rhamnosus HN001, both individually and in combination, against Gram-negative strains (uropathogens, enteropathogens and a reference strain). Moreover, in vitro protection of B. longum BB536 and L. rhamnosus HN001, both individually and in combination, against pathogen adhesion to HT-29 cell line, was investigated. MATERIALS AND METHODS: The inhibitory activity was performed by the agar diffusion test and in vitro antagonistic activity against pathogen adhesion to human epithelial intestinal HT-29 cells was performed using standardized culture techniques. RESULTS: The study showed that B. longum BB536 and L. rhamnosus HN001, individually and in combination have inhibitory activity against the majority of the Gram negative strains tested. Furthermore, the results showed that both probiotic strains have a good capacity to inhibit pathogenic adhesion to HT-29 cells. Moreover, the ability of B. longum BB536 and L. rhamnosus HN001 to inhibit pathogenic adhesion increased when they were used in combination. DISCUSSION: The combination of B. longum BB536 and L. rhamnosus HN001 showed inhibitory activity against Gram-negatives and an improved ability to reduce their adhesion properties and to compete with them. CONCLUSIONS: The simultaneous presence of the two-probiotic strains could promote competitive mechanisms able to reduce the adhesion properties of pathogen strains and have an important ecological role within the highly competitive environment of the human gut. PMID- 27981540 TI - Sleeve gastrectomy: have we finally found the holy grail of bariatric surgery? A review of the literature. AB - OBJECTIVE: Laparoscopic sleeve gastrectomy has become one of the most commonly performed bariatric operations. It is essentially a restrictive bariatric operation; however, a series of hormonal changes occurring postoperatively contribute to decreased appetite and reduced food intake. PATIENTS AND METHODS: This is a literature review of recent articles published on Pubmed, Medline and Google Scholar databases in English. RESULTS: Although, laparoscopic sleeve gastrectomy is commonly performed worldwide, there is still a lack of standardization regarding the surgical technique. Standardizing the surgical technique is essential in order to minimize postoperative complications and offer patients the best long-term weight loss. CONCLUSIONS: Laparoscopic sleeve gastrectomy appears to be an effective bariatric operation. It is relatively easy to perform, well tolerated by the patients and very effective regarding long-term excessive weight loss and resolution of the comorbidities, with minimum nutritional deficiencies. PMID- 27981541 TI - Association between the resistin gene-420 C>G polymorphism and obesity: an updated meta-analysis. AB - OBJECTIVE: The aim of this study was to assess the relationship of the resistin gene (RETN)-420 C>G polymorphism and obesity susceptibility by conducting an updated meta-analysis. MATERIALS AND METHODS: The electronic databases including PubMed, Medline, Embase, China National Knowledge Infrastructure, Chinese Wanfang Database, and Chinese VIP database were searched for relevant studies published before December 2013. The fixed effect model or random effects model was used based on the heterogeneity test results. The sensitivity analysis was performed in the allelic model and the dominant genetic model, respectively. Publication bias was assessed via funnel plot. The meta-analysis was performed using the software of RevMan 5.2. RESULTS: Data were obtained from 10 included studies, involving 5,069 cases and 6,673 controls. The overall odds ratios (ORs) with its 95% confidence interval (CI) showed no association between RETN-420 C>G polymorphism and obesity in the allelic model (p = 0.09; OR = 1.10; 95% CI = 0.991.24), the dominant model (p = 0.09; OR = 1.16; 95% CI = 0.98-1.36), and the recessive model (p = 0.71; OR = 1.02; 95% CI = 0.90-1.16). Sensitivity analysis showed statistical differences of association analysis within the allelic model (p = 0.04; OR = 1.14; 95% CI = 1.01-1.28) and the dominant genetic model (p = 0.04; OR = 1.21; 95% CI = 1.01-1.45), when 1 study was omitted. No publication bias was observed. CONCLUSIONS: The RETN-420 C>G polymorphism may be related to obesity with G allele as a risk factor. PMID- 27981542 TI - Extraction of glycogen on mild condition lacks AIG fraction. AB - OBJECTIVE: Extraction of animal tissues with cold water or perchloric acid yields less glycogen than is obtained with hot-alkaline. Extraction with acid and alkaline gives two fractions, acid soluble (ASG) and insoluble glycogen (AIG). The aim of this work is to examine the hypothesis that not all liver glycogen is extractable by Tris-buffer using current techniques. MATERIALS AND METHODS: Rat liver was homogenized with Tris-buffer pH 8.3 and extracted for the glycogen fractions, ASG and AIG. The degree of homogenization was changed to remove all glycogen. RESULTS: The content of glycogen was 47.7 +/- 1.2 and 11.6 +/- 0.8 mg/g wet liver in the supernatant and pellet of the first extraction respectively. About 24% of total glycogen is lost through the first pellet. Increasing the extent of homogenization from 30 to 180 sec and from 15000 to 20000 rpm followed with 30 sec ultrasonication did not improve the extraction. ASG and AIG constitute about 77% and 23% of the pellet glycogen respectively. CONCLUSIONS: Extraction with cold Tris-buffer failed to extract glycogen completely. Increasing the extent of homogenization followed with ultrasonication also did not improve the extraction. Thus it is necessary to re-examine the previous findings obtained by extraction with cold Tris-buffer. PMID- 27981544 TI - Human umbilical cord mesenchymal stem cells ameliorate experimental cirrhosis through activation of keratinocyte growth factor by suppressing microRNA-199. AB - OBJECTIVE: Keratinocyte growth factor (KGF) has a demonstrated role in the prevention of cirrhosis during liver regeneration. Previous studies have shown that transplantation of human umbilical cord mesenchymal stem cells (HUCMSCs) reduces the development of cirrhosis after liver injury. However, whether KGF may be involved in the underlying molecular mechanisms remains unknown. Here we addressed this question. MATERIALS AND METHODS: We did HUCMSC transplantation in mice that had developed cirrhosis by carbon tetrachloride (CCl4). The effects of UCMSC transplantation on KGF levels and liver damage were examined. The level of a KGF-targeting microRNA, miR-199, was examined. The regulation of KGF by miR-199 was studied by bioinformatics analyses and luciferase reporter assay. RESULTS: HUCMSC transplantation significantly ameliorated the severity of liver fibrosis, reduced portal hypertension and sodium retention that were induced by CCl4. HUCMSC transplantation significantly increased the levels of KGF in the injured liver, seemingly through suppression of miR-199, which targeted 3'-UTR of KGF mRNA to inhibit its protein translation. CONCLUSIONS: HUCMSCs may ameliorate cirrhosis through activation of KGF by suppressing miR-199. PMID- 27981543 TI - Cognitive impairment and quality of life in patients with migraine-associated vertigo. AB - OBJECTIVE: To study the impact of migraine-associated vertigo (MV) on the cognitive state of patients and their quality of life. PATIENTS AND METHODS: A total of 120 patients were enrolled in the study, including 40 diagnosed with MV, forty with a simple migraine and 40 healthy volunteers. Cognitive assessments were done using the mini-mental state examination (MMSE), and a battery of tests for cognitive functions in performance, memory, language, space and attention during interictal periods. Also, MRI was used to detect brain white matter lesions and SF-36 for quality of life. RESULTS: The scores of cognitive tests (MMSE, tracing, memory and VFT scores) in MV cases were significantly lower than those in the simple migraine group. TMT-A and TMT-B scores in the MV group were the highest followed by those in the simple migraine group. The incidence of deep brain, peripheral lateral ventricle and total white matter lesions in the MV group was higher than that in the simple migraine group. Finally, the deep lesion and peripheral lateral ventricle scores in the MV group were significantly higher than those in the simple migraine group. The physical, social, mental and total health scores in the MV group were significantly lower than those in the simple migraine group. All the differences found between groups had statistical significance, and all the variables examined fared best in the healthy control group. CONCLUSIONS: MV patients show a more pronounced cognitive impairment than patients with a simple migraine or healthy volunteers, the incidence of brain white matter lesions is increased in them, and their quality of life is severely compromised. PMID- 27981545 TI - Long non-coding RNA MVIH acts as a prognostic marker in glioma and its role in cell migration and invasion. AB - OBJECTIVE: High expression levels of lncRNA associated with microvascular invasion in HCC (lncRNA MVIH) were found to correlate with several solid tumors. However, little is known concerning the function of MVIH in glioma. The purpose of our study is to explore the role of lncRNA MVIH in clinical glioma samples and cell lines. PATIENTS AND METHODS: The expression levels of MVIH were analyzed in glioma surgical resection tissues and cells by RT-PCR. Additionally, the associations of MVIH expression with clinicopathological features were analyzed. Survival and Cox proportional-hazards regression analyses were performed to determine the correlation between MVIH expression levels and prognosis in the patients. The cell proliferation, migration ability, invasion ability were measured successively by CKK-8 assay, transwell and wound healing assay. RESULTS: We found that MVIH was significantly upregulated in glioma cell lines and tissues. Furthermore, MVIH expression was positively correlated with KPS and WHO grade. Patients with MVIH high expression tumors had a worse overall survival compared to patients with MVIH high expression tumors. Moreover, Univariate and multivariate Cox regression analysis confirmed that MVIH was an independent risk factor for glioma. Finally, in vitro, we showed that up-regulation of MVIH expression promoted human glioma cells proliferation, invasion and migration, while down-regulation of MVIH expression suppressed human glioma cells proliferation, invasion and migration. CONCLUSIONS: Our findings indicated that MVIH expression may serve not only as a prognostic marker but also as a potential therapeutic target in glioma. PMID- 27981546 TI - LncRNA H19 is overexpressed in glioma tissue, is negatively associated with patient survival, and promotes tumor growth through its derivative miR-675. AB - OBJECTIVE: Glioma is one of the most common and invasive tumors of the central nervous system. Long non-coding (lnc) RNAs are involved in many cancers, but their function and mechanism in glioma remain largely unknown. We wished to delineate the role of lncRNA H19 and its derivative miR-675 in this tumor. PATIENTS AND METHODS: Using qPCR, we compared expression of lncRNA H19 in 35 specimens of glioma vs control tissue, and in two glioma cell lines U251 and U87 vs Normal Human Astrocyte (NHA) cells. Cell proliferation was evaluated after shRNA silencing of lncRNA H19 in glioma cell lines. The role of miR-675 was tested using antagomir and the mimic. RESULTS: LncRNA H19 was overexpressed in glioma tissue and cell lines. In tissue, higher expression levels were observed in more advanced stages of the tumor. Furthermore, lncRNA H19 was negatively associated with patient survival time. In cell culture experiments, silencing of lncRNA H19 diminished proliferation of glioma cell lines. These effects of lncRNA H19 appeared to be intermediated by miR-675. The latter was overexpressed in glioma tissue and was negatively associated with patient survival. Supporting the involvement of miR-675, its antagomir decreased proliferation of glioma cell lines, whereas its mimic increased proliferation of NHA cells. CONCLUSIONS: LncRNA H19 is overexpressed in glioma tissue, and is positively associated with the tumor grade and negatively associated with patient survival. In cell culture studies, lncRNA H19 promotes glioma cell proliferation. These tumor-promoting effects of lncRNA H19 appear to be mediated by miR-675. PMID- 27981547 TI - Circulating miR-199a-3p in plasma and its potential diagnostic and prognostic value in glioma. AB - OBJECTIVE: The present study aimed to examine the possibility of using plasma miR 199a-3p as a biomarker for glioma. PATIENTS AND METHODS: Plasma miR-199a-3p expression glioma patients and normal healthy controls were quantified by Quantitative reverse transcription PCR. Then, the associations of serum miR-199a 3p level with clinicopathological factors or survival of glioma patients were further evaluated. Receiver operating characteristics (ROC) and area under the ROC curve (AUC) were used to validate the diagnostic value of miR-199a-3p. Univariate and multivariate Cox regression analyses were finally performed to analyze the independent factors for overall survival. RESULTS: The qRT-PCR results showed that the miR-199a-3p expression was significantly downregulated in glioma tissues compared with the adjacent non-tumor tissues (p<0.01). Furthermore, plasma miR-199a-3p level was significantly lower in glioma patients when compared with healthy controls (p<0.01). ROC curve analysis showed that plasma miR-199a-3p was a useful marker for discriminating cases from healthy controls, with an area under the ROC curve (AUC) of 0.8466 (95% confidence interval (CI) 0.772 to 0.9211, p<0.001). Moreover, miR-199a-3p expression was associated with various clinicopathological parameters, including WHO grade (p=0.001) and KPS score (p=0.008). We found that glioma patients with low miR 199a-3p expression level had distinctly shorter overall survival than patients with high miR-199a-3p expression level (p=0.0067). Univariate and multivariate analysis suggested that miR-199a-3p expression was an independent predictor of poor prognosis. CONCLUSIONS: These findings indicated that the circulating miR 199a-3p could be used as a promising novel biomarker for the diagnosis and prognosis of glioma. PMID- 27981548 TI - Expression of long non-coding RNA (lncRNA) H19 in immunodeficient mice induced with human colon cancer cells. AB - OBJECTIVE: To study the expression of long non-coding RNA (lncRNA) H19 in immunodeficient mice induced with human colon cancer cells. Long non-coding RNAs (lncRNA) have a vital and regulatory role, in almost all cancers including colon cancer. In the present study, the prominent regulatory role of IncH19 RNA in immunodeficient mice induced with human colon cancer cells was identified. Interestingly, the lncH19 RNA was up-regulated in human colon cancer cells induced immunodeficient mice colon cancer samples. PATIENTS AND METHODS: The expression profile of the lnc H19 RNA in the colon cancer tissues were identified by RT-PCR and the further the data was confirmed and validated by Northern blot analysis. RESULTS: Based on the data, it was identified that lnc H19 RNA was increased significantly in immunodeficient mice induced with human colon cancer cells, when compared with controls. The data was further confirmed and validated by Northern blot analysis. CONCLUSIONS: The obtained data future potential application in colon cancer diagnosis. At the same time, lncH19 RNA may serve as a new target for anti-tumor therapy in colon cancer. Also, the obtained data is the important clue to find out the key roles of lncH19 RNA-miRNA functional network in colon cancer. PMID- 27981549 TI - Analysis of expression of cyclin E, p27kip1 and Ki67 protein in colorectal cancer tissues and its value for diagnosis, treatment and prognosis of disease. AB - OBJECTIVE: We conducted this study is to investigate the clinical application value of Cyclin E, p27kip1 and Ki67 protein expression in colorectal cancer tissues for diagnosis, treatment, and prognosis of this disease. PATIENTS AND METHODS: The positive expression of Cyclin E, p27kip1 and Ki-67 in tissues of 200 patients with colorectal cancer and 200 patients with benign colorectal tumor or inflammation were detected by immunohistochemistry PowerVision two-step method. RT-PCR was used to detect the expression level of the corresponding mRNA, as well as to analyze the association with TNM staging, pathology type, free progression survival and median survival. The sensitivity, specificity, and accuracy of diagnosis were analyzed by ROC. RESULTS: The positive expression rate and positive degree of Cyclin E and Ki-67 of observation group were higher than those of the control group, while positive expression rate and positive degree of p27kipl was lower than that of the control group; the differences were statistically significant (p<0.05). The quantitative expression levels of Cyclin E and Ki-67 mRNA of observation group were distinctly higher than those of the control group, while p27kipl was evidently lower than that of the control group; the differences were statistically significant (p<0.05). With the increase of TNM staging, the positive expression of Cyclin E and Ki-67 increased, p27kipl decreased, and the difference was statistically significant (p<0.05). With the decrease of differentiation degree, the positive expression of Cyclin E and Ki-67 increased, p27kipl decreased, and the difference was statistically significant (p<0.05). The free progression survival and median survival of positive expression and negative expression of Cyclin E and Ki-67 were shortened, p27kipl extended, and the difference was statistically significant (p<0.05). The diagnostic sensitivity of Cyclin E mRNA was 89.6%, specificity 84.5%, accuracy 0.823 and the critical value was 0.3562; The diagnostic sensitivity of p27kipl mRNA was 80.5%, specificity 76.5%, accuracy 0.802 and the critical value was 0.3023. The diagnostic sensitivity of Ki-67 mRNA was 86.5%, specificity 82.9%, accuracy 0.814 and the critical value was 0.3243. CONCLUSIONS: We discovered that Cyclin E and Ki67 protein expression of colorectal cancer tissues was upregulated and p27kipl protein expression was downregulated, which were closely related to the TNM and pathological differentiation degree. These values were also closely associated with free progression survival and median survival of prognosis. Therefore, the above indexes can be used as highly sensitive, specific and accurate markers for the diagnosis of colorectal cancer. PMID- 27981550 TI - Knockdown of tripartite motif 59 (TRIM59) inhibits tumor growth in prostate cancer. AB - OBJECTIVE: Members of the tripartite motif (TRIM) protein family contain a highly conserved N-terminal really interesting new gene (RING) domain that is involved in regulating transcriptional factors and tumor suppressors. In this study, the effects of TRIM59 expression on tumor growth were investigated in prostate cancer. MATERIALS AND METHODS: The expression of TRIM59 in prostate cancer tissues (n = 15) and prostate cancer cell lines was determined by quantitative reverse transcriptase-PCR (qRT-PCR), Western blotting, and immunohistochemistry. A specific shRNA targeting TRIM59 was employed to knockdown TRIM59 expression in the prostate cancer cell lines PC3 and DU145. The effects of TRIM59 knockdown on cell proliferation were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and colony formation assays. The effects on cell cycle progression were determined by flow cytometry, and a xenograft mouse model of prostate cancer was generated to determine the in vivo effects of TRIM59 knockdown. The effects on cell cycle regulators were determined by Western blotting. RESULTS: TRIM59 was highly expressed in prostate cancer tissues. Knockdown of TRIM59 significantly inhibited cell proliferation and colony formation, and cell cycle analysis showed that TRIM59-depleted cells accumulated in S-phase. TRIM59 knockdown was shown to inhibit tumorigenesis in mice. In addition, the cell cycle regulators CDC25A, CDC2, and cyclin B1 were decreased by TRIM59 shRNA-mediated knockdown. CONCLUSIONS: Our study suggests that TRIM59 promotes prostate cancer cell proliferation, possibly through its effects on cell cycle progression. PMID- 27981551 TI - Long non-coding RNA HNF1A-AS1 up-regulation in non-small cell lung cancer correlates to poor survival. AB - OBJECTIVE: Accumulating studies have focused on the role of the newly identified lncRNAs in the tumor. We aimed to investigate the clinical correlation between long non-coding RNA HNF1A-AS (HNF1A-AS1) expression and non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Real-time polymerase chain reaction (PCR) was employed to detect HNF1A-AS expression in NSCLC tissues and corresponding adjacent tissues. The c2-test was used to compare the clinicopathological characteristics between different groups. Survival analysis was performed using the Kaplan-Meier method. The univariate and multivariate analyses were performed to investigate the prognostic significance of HNF1A-AS for NSCLC. RESULTS: The level of HNF1A-AS was higher in tumor tissues than that in normal tissues (p < 0.01). In addition, HNF1A-AS level was significantly associated with TNM stage (p = 0.002) and Lymph node metastasis (p = 0.005). Kaplan-Meier analysis indicated that a high level of HNF1A-AS expression predicted unfavorable overall survival (p < 0.001). The univariate and multivariate analysis identified HNF1A-AS as an independent poor prognostic factor for overall survival in NSCLC patients (p < 0.05). CONCLUSIONS: These results demonstrated that overexpression of HNF1A-AS might act a poor prognosis indicator in patients with NSCLC. PMID- 27981552 TI - The effect of three-dimensional conformal radiotherapy on locally recurrent nasopharyngeal carcinoma and on the expression of succinate dehydrogenase B. AB - OBJECTIVE: Investigate the effect of three-dimensional conformal radiotherapy (3DCRT) on locally recurrent nasopharyngeal carcinoma (NPC) on the expression of succinate dehydrogenase B (SDHB). PATIENTS AND METHODS: Eighty-six patients diagnosed with locally recurrent NPC in our hospital were selected and divided into the control group (43 cases) and observation group (43 cases). Conventional two-dimensional radiotherapy was applied in the control group, and 3DCRT was adopted in the observation group. The curative effect of both groups was compared. RESULTS: The effective rate and the degree of alleviation of the observation group were higher than those of the control group, and the differences were statistically significant (p<0.05). There were no differences in the occurrence rate of complications from radiotherapy between the two groups (p>0.05). The survival rate and median survival time of the observation group were significantly higher than those of the control group (p<0.05). The positive expression rate of SDHB in the observation group after radiotherapy was significantly higher than that of the control group (p<0.05), and the median survival time of patients with positive expression of SDHB was significantly higher than patients with negative expression (p<0.05). CONCLUSIONS: 3DCRT applied for treatment of locally recurrent NPC was safe and effective. It also improved the positive expression rate of SDHB, which was associated with increased survival time. PMID- 27981553 TI - A circulating serum miRNA panel as early detection biomarkers of cervical intraepithelial neoplasia. AB - OBJECTIVE: MicroRNAs (miRNAs) have been demonstrated to play critical roles in regulating the molecular process of tumorigenesis. Therefore, the purpose of this study was to establish a panel of serum miRNA signature for early detection of cervical intraepithelial neoplasia (CIN). PATIENTS AND METHODS: One hundred and twenty-six patients with CIN and sixty healthy control subjects were recruited in this cohort study. Quantitative reverse transcript polymerase chain reaction (qRT PCR) was conducted to detect the expression level of the panel of miRNA signature (miR-9, miR-10a, miR-20a and miR-196a) in the serum samples of all the participants. The association between HPV infection status and the expression levels of miRNAs was also evaluated. In addition, Receiver Operating Characteristic (ROC) curve was used to evaluate the diagnostic value of the combination of these four serum miRNAs. RESULTS: The expression levels of the four miRNAs (miR-9, miR-10a, miR-20a and miR-196a) were all significantly upregulated in the serum samples derived from the CIN patients compared with those from the healthy controls (p < 0.01). Also, HPV infection status was significantly correlated with the expression levels of miRNAs (p < 0.01). The ROC analysis showed that this four-miRNA signature showed high accuracy in discriminating CIN individuals (AUC = 0.886, p < 0.01) from healthy controls. CONCLUSIONS: Taken together, our findings demonstrated that the panel of four serum miRNAs (miR-9, miR-10a, miR-20a and miR-196a) are useful and novel noninvasive biomarkers for early detection of CIN. PMID- 27981554 TI - Clinical significance of changes of expression of the Wnt/beta-catenin signaling pathway in renal clear cell carcinoma. AB - OBJECTIVE: To explore the changes and clinical significance of expression of beta catenin in renal carcinoma. PATIENTS AND METHODS: We selected 46 patients with renal clear cell carcinoma who were hospitalized from May 2013 to March 2016 and healthy adults (controls) matched for age and body weight, who were hospitalized in the physical examination center of our hospital during the same period. Peripheral blood of patients and controls was drawn for ELISA. After surgery, renal carcinoma and normal peritumoral tissue samples were harvested for immunohistochemical staining, Western blot analysis and qRT-PCR was used to observe changes of beta-catenin expression in renal carcinoma tissues. RESULTS: Compared with controls, ELISA showed that there were significant differences in beta-catenin levels in peripheral blood of patients with renal carcinoma (p<0.05). Western blot and qRT-PCR showed that the expression levels of beta catenin in renal carcinoma tissues were higher than in normal peritumoral tissues and the differences were statistically significant (p<0.05). Immunohistochemical staining showed that beta-catenin was increased significantly in renal carcinoma tissue compared with normal peritumoral tissues (p<0.05). CONCLUSIONS: beta catenin expression was significantly increased in the tumor tissues of patients with renal carcinoma. The measurement of beta-catenin expression levels in peripheral blood from patients could be used for early diagnosis of renal carcinoma, which is of great clinical significance. PMID- 27981555 TI - A reddish pulsatile mass beyond tympanic membrane: think before act. AB - We report a case of a 76-year-old man that referred to our hospital because of progressive mixed right hearing loss, aural fullness and pulsatile tinnitus synchronized with heart beats. Otoscopic examination revealed a reddish pulsatile mass beyond tympanic membrane. CT and MRI scans showed a class C glomus tumor. Anamnesis and a complete physical examination, with careful differential diagnosis, should be obtained to rule out highly vascularized middle ear lesion before any invasive procedure. PMID- 27981556 TI - Ethanol concentration changes in blood samples during medium-term refrigerated storage. AB - OBJECTIVE: Stability of blood alcohol concentration (BAC) in laboratory samples is of great importance when it is necessary to perform repeated analyses. MATERIALS AND METHODS: We have analyzed the stability of BAC in 50 samples, which were taken from apprehended drivers, kept at -18oC, without preserving agents. Quantitative analyses were performed using headspace sampling gas chromatography (HS-GC) with flame ionizing detection (FID). Samples were analyzed immediately after collection (C1), and after 60 (C60), 120 (C120) and 180 (C180) days. A group of 50 samples, which were kept closed for 180 days at -18oC, was utilized as a control. RESULTS: We found a significant decrease in BAC between C1 and C180 (= 0.224; SD= 0.144; t = 10.98; p<0.001), and between C1 and C60, C60 and C120, C120 and C180. There was a significant positive correlation (r=0.8) between starting concentration C1, and the value of BAC changes (DeltaC). Linear regression analysis (R2=0.64) implies the degree of validity to the proposed model of DeltaC change regarding initial BAC. There were significant changes in DeltaC between the two groups. CONCLUSIONS: These data underline the significance of air chamber percent (CA%) and ethanol evaporation due to ventilation between liquid and gas phase as a mechanism of ethanol decay. PMID- 27981558 TI - Predicting transporter-mediated drug interactions: Commentary on: "Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin and rosuvastatin" and "Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A". AB - Transporters, expressed in various tissues, govern the absorption, distribution, metabolism, and excretion of drugs, and consequently their inherent safety and efficacy profiles. Drugs may interact with a transporter as a substrate and/or an inhibitor. Understanding transporter-mediated drug-drug interactions (DDIs), in addition to enzyme-mediated DDIs, is an integral part of risk assessment in drug development and regulatory review because the concomitant use of more than one medication in patients is common. PMID- 27981557 TI - Potentially Avoidable Readmissions of Patients Discharged to Post-Acute Care: Perspectives of Hospital and Skilled Nursing Facility Staff. AB - BACKGROUND: Hospital readmissions from skilled nursing facilities (SNFs) are common. Previous research has not examined how assessments of avoidable readmissions differ between hospital and SNF perspectives. OBJECTIVES: To determine the percentage of readmissions from post-acute care that are considered potentially avoidable from hospital and SNF perspectives. DESIGN: Prospective cohort study. SETTING: One academic medical center and 23 SNFs. PARTICIPANTS: We included patients from a quality improvement trial aimed at reducing hospital readmissions among patients discharged to SNFs. We included Medicare patients who were discharged to one of 23 regional SNFs between January 2013 and January 2015, and readmitted to the hospital within 30 days. MEASUREMENTS: Hospital-based physicians and SNF-based staff performed structured root-cause analyses (RCA) on a sample of readmissions from a participating SNF to the index hospital. RCAs reported avoidability and factors contributing to readmissions. RESULTS: The 30 day unplanned readmission rate to the index hospital from SNFs was 14.5% (262 hospital readmissions of 1,808 discharges). Of the readmissions, 120 had RCA from both the hospital and SNF. The percentage of readmissions rated as potentially avoidable was 30.0% and 13.3% according to hospital and SNF staff, respectively. Hospital and SNF ratings of potential avoidability agreed for 73.3% (88 of the 120 readmissions), but readmission factors varied between settings. Diagnostic problems and improved management of changes in conditions were the most common avoidable readmission factors by hospitals and SNFs, respectively. CONCLUSION: A substantial percentage of hospital readmissions from SNFs are rated as potentially avoidable. The ratings and factors underlying avoidability differ between hospital and SNF staff. These data support the need for joint accountability and collaboration for future readmission reduction efforts between hospitals and their SNF partners. PMID- 27981559 TI - Relationships as Medicine: Quality of the Physician-Patient Relationship Determines Physician Influence on Treatment Recommendation Adherence. AB - OBJECTIVE: To determine whether quality of physician-patient relationships influences uptake of physician treatment recommendations in men with clinically localized prostate cancer (PCa). STUDY SETTING: Data were collected July 2010 to August 2014 at two cancer centers and three community facilities. STUDY DESIGN: Analyses were prospective and cross-sectional. We modeled associations between quality of the patient-physician relationship and influence of physician recommendations on treatment choice using generalized estimating equations (GEE). DATA COLLECTION: Data were collected via survey and medical record abstraction. PRINCIPAL FINDINGS: Participants (N = 1166) were 14.7 percent minority; 37.1 percent had low-, 47.5 percent had intermediate-, and 15.4 percent had high-risk PCa. Those reporting a better physician-patient relationship perceived that their physician's treatment recommendation was more influential (RR = 1.05, 95 percent CI = 1.04-1.05, p < .001) and were more likely to choose the recommended treatment (OR = 2.92, 95 percent CI = 2.39, 3.58, p < .001). A pattern of interactions emerged indicating that quality of the physician-patient relationship was more strongly associated with influence of recommendations for more, versus less aggressive treatment in those with low-risk, but not intermediate-risk disease. CONCLUSIONS: Prioritizing quality of the physician patient relationship through training, practice change, and patient feedback may increase adherence. However, strategies need to align with efforts to reduce physician recommendations for inefficacious treatments to prevent overtreatment. PMID- 27981561 TI - Plasma osmolality and oxygen consumption of perch Perca fluviatilis in response to different salinities and temperatures. AB - The present study determined the blood plasma osmolality and oxygen consumption of the perch Perca fluviatilis at different salinities (0, 10 and 15) and temperatures (5, 10 and 20 degrees C). Blood plasma osmolality increased with salinity at all temperatures. Standard metabolic rate (SMR) increased with salinity at 10 and 20 degrees C. Maximum metabolic rate (MMR) and aerobic scope was lowest at salinity of 15 at 5 degrees C, yet at 20 degrees C, they were lowest at a salinity of 0. A cost of osmoregulation (SMR at a salinity of 0 and 15 compared with SMR at a salinity of 10) could only be detected at a salinity of 15 at 20 degrees C, where it was 28%. The results show that P. fluviatilis have capacity to osmoregulate in hyper-osmotic environments. This contradicts previous studies and indicates intraspecific variability in osmoregulatory capabilities among P. fluviatilis populations or habitat origins. An apparent cost of osmoregulation (28%) at a salinity of 15 at 20 degrees C indicates that the cost of osmoregulation in P. fluviatilis increases with temperature under hyperosmotic conditions and a power analysis showed that the cost of osmoregulation could be lower than 12.5% under other environmental conditions. The effect of salinity on MMR is possibly due to a reduction in gill permeability, initiated to reduce osmotic stress. An interaction between salinity and temperature on aerobic scope shows that high salinity habitats are energetically beneficial during warm periods (summer), whereas low salinity habitats are energetically beneficial during cold periods (winter). It is suggested, therefore, that the seasonal migrations of P. fluviatilis between brackish and fresh water is to select an environment that is optimal for metabolism and aerobic scope. PMID- 27981560 TI - Role of spacer-1 in the maturation and function of GlcNAc-1-phosphotransferase. AB - The UDP-GlcNAc:lysosomal enzyme, N-acetylglucosamine-1-phosphotransferase (GlcNAc 1-PT), is an alpha2 beta2 gamma2 hexamer that mediates the initial step in the formation of the mannose 6-phosphate targeting signal on newly synthesized lysosomal acid hydrolases. The GNPTAB gene encodes the 1256 amino acid long alpha/beta precursor which is normally cleaved at K928 in the early Golgi by Site 1 protease (S1P). Here, we show that removal of the so-called 'spacer-1' domain (residues 86-322) results in cleavage almost exclusively at a second S1P consensus sequence located upstream of K928. In addition, GlcNAc-1-PT lacking spacer-1 exhibits enhanced phosphorylation of several non-lysosomal glycoproteins, while the phosphorylation of lysosomal acid hydrolases is not altered. In view of these effects on the maturation and function of GlcNAc-1-PT, we suggest renaming 'spacer-1' the 'regulatory-1' domain. PMID- 27981563 TI - Comparison of Outcomes Following a Switch From a Brand to an Authorized Versus Independent Generic Drug. AB - Authorized generics are identical in formulation to brand drugs, manufactured by the brand company but marketed as a generic. Generics, marketed by generic manufacturers, are required to demonstrate pharmaceutical and bioequivalence to the brand drug, but repetition of clinical trials is not required. This retrospective cohort study compared outcomes for generics and authorized generics, which serves as a generic vs. brand proxy that minimizes bias against generics. For the seven drugs studied between 1999 and 2014, 5,234 unique patients were on brand drugs prior to generic entry and 4,900 (93.6%) switched to a generic. During the 12 months following the brand-to-generic switch, patients using generics vs. authorized generics were similar in terms of outpatient visits, urgent care visits, hospitalizations, and medication discontinuation. The likelihood of emergency department (ED) visits was slightly higher for authorized generics compared with generics. These data suggest that generics were clinically no worse than their proxy brand comparators. PMID- 27981562 TI - The effect of embedded bonus rounds on slot machine preference. AB - Twenty-three university students completed a simulated slot machine task involving the concurrent presentation of two slot machines that were varied both in win density and the inclusion of a bonus round feature to evaluate the effect of embedded bonus rounds on participant response allocation. The results suggest that participants allocated a greater percentage of responses to machines with embedded bonus rounds across both dense (Bonus: M = 68.4, SD = 19.2; No Bonus: M = 51.2; 9.6) and lean (Bonus: M = 48.8, SD = 9.6; No Bonus: M = 31.6, SD = 19.2) reinforcement schedules, in which the overall reinforcement rate across all machines was held constant. PMID- 27981565 TI - A multicentre snapshot study of the incidence of serious procedural complications secondary to central venous catheterisation. AB - Despite the high number of central venous access devices inserted annually, there are limited data on the incidence of the associated procedural complications, many of which carry substantial clinical risk. This point was highlighted in the recently published Association of Anaesthetists of Great Britain and Ireland 'Safe vascular access 2016' guidelines. This trainee-led snapshot study aimed to identify the number of central venous catheter insertions and the incidence of serious complications across multiple hospital sites within a fixed two-week period. Secondary aims were to identify the availability of resources and infrastructure to facilitate safe central venous catheter insertion and management of potential complications. Fifteen hospital sites participated, completing an initial resource survey and daily identification of all adult central venous catheter insertions, with subsequent review of any complications detected. A total of 487 central venous catheter insertions were identified, of which 15 (3.1%) were associated with a significant procedural complication. The most common complication was failure of insertion, which occurred in seven (1.4%) cases. Facilities to enable safer central venous catheter insertion and manage complications varied widely between hospitals, with little evidence of standardisation of guidelines or protocols. PMID- 27981567 TI - National Cancer Institute Formulary: A Public-Private Partnership Providing Investigators Access to Investigational Anticancer Agents. AB - As part of the White House Cancer Moonshot Initiative, the National Cancer Institute (NCI) has developed a drug formulary to provide investigational anticancer agents to the extramural research community. This article describes how the NCI Formulary functions, how researchers may apply for access to drugs in the formulary, and the NCI's initial goals for formulary participation. Approved investigators may apply for access to formulary agents at: https://nciformulary.cancer.gov. PMID- 27981566 TI - Patient Perceptions of Care as Influenced by a Large Institutional Pharmacogenomic Implementation Program. AB - Despite growing clinical use of genomic information, patient perceptions of genomic-based care are poorly understood. We prospectively studied patient physician pairs who participated in an institutional pharmacogenomic implementation program. Trust/privacy/empathy/medical decision-making (MDM)/personalized care dimensions were assessed through patient surveys after clinic visits at which physicians had access to preemptive pharmacogenomic results (Likert scale, 1 = minimum/5 = maximum; mean [SD]). From 2012-2015, 1,261 surveys were issued to 507 patients, with 792 (62.8%) returned. Privacy, empathy, MDM, and personalized care scores were significantly higher after visits when physicians considered pharmacogenomic results. Importantly, personalized care scores were significantly higher after physicians used pharmacogenomic information to guide medication changes (4.0 [1.4] vs. 3.0 [1.6]; P < 0.001) compared with prescribing visits without genomic guidance. Multivariable modeling controlling for clinical factors confirmed personalized care scores were more favorable after visits with genomic-influenced prescribing (odds ratio [OR] = 3.26; 95% confidence interval [CI] = (1.31-8.14); P < 0.05). Physicians seem to individualize care when utilizing pharmacogenomic results and this decision making augmentation is perceived positively by patients. PMID- 27981568 TI - Portuguese self-reported oral-hygiene habits and oral status. AB - BACKGROUND: Good oral health is essential for good general health and quality of life. In Portugal, there are few studies on oral-health habits and the population's perceptions of this behaviour. OBJECTIVE: The main purpose of this study was to characterise the Portuguese population's self-reported oral-health status, habits and perceptions, as well as their demands regarding national oral health-care services. METHODS: A randomised group of 1,395 individuals, > 15 years of age, was selected as a representative sample of the Portuguese population. Face-to-face interviews were conducted, based on a structured questionnaire with closed and semi-closed questions. The data were submitted for statistical analysis using SPSS. RESULTS AND DISCUSSION: A sample of 1,102 individuals answered the questionnaire. The great majority of the sample (97.6%) brushed their teeth daily, 70.3% had lost permanent teeth and 6.4% were edentulous. The loss of permanent teeth was statistically associated with poor oral-hygiene habits (P < 0.01). Moreover, 50.1% of the participants had experienced difficulty eating and/or drinking, 18% had felt ashamed of the appearance of their teeth and 69.3% had experienced toothache or gingival pain. A reduction in visits to a dentist in the previous 12 months was identified mainly for people from a lower social class (31.2%) and older people (29.4%). CONCLUSION: Evidence suggests that oral diseases might be more prevalent in Portuguese adults than the European average. Efforts should be made to promote good oral-hygiene habits among older people and people from lower social classes. PMID- 27981569 TI - Genetic advances uncover mechanisms of chemotherapy-induced peripheral neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity experienced in 30-40% of patients undergoing treatment with various chemotherapeutics, including taxanes, vinca alkaloids, epothilones, proteasome inhibitors, and thalidomide. Importantly, CIPN significantly affects a patient's quality of life. Recent genetic association studies are enhancing our understanding of CIPN pathophysiology and serve as a foundation for identification of genetic biomarkers to predict toxicity risk and for the development of novel strategies for prevention and treatment. PMID- 27981570 TI - The effect of environmental colour on the growth, metabolism, physiology and skin pigmentation of the carnivorous freshwater catfish Lophiosilurus alexandri. AB - The growth, physiology and skin pigmentation of pacama Lophiosilurus alexandri juveniles were evaluated in an experiment using different tank colours (white, yellow, green, blue, brown and black) over an 80 day period. The tank colours did not cause significant differences to final body mass, total length, survival rate, carcass composition (moisture, crude protein, ash, ether extract, calcium, phosphorus, energy), or to plasma protein, triglyceride and cholesterol values. Haematocrit values, however, were highest for fish kept in white tanks (ANOVA P < 0.05), while the greatest haemoglobin levels were recorded for fish kept in blue and brown tanks (P < 0.01). The concentrations of cortisol (P < 0.001) and glucose (P < 0.01) were the most in fish in the black tanks. Tank colour affected skin pigmentation significantly, with fish in white tanks having the highest values of L* (brightness) and the lowest values in blue and black tanks. L*, however, decreased in all treatments throughout the experiment. C*ab increased significantly over the course of the experiment in fish kept in white tanks. Similar increases of C*ab were recorded in the other treatments but to a lesser extent. The use of black tanks during the cultivation of L. alexandri caused stress and should be avoided. Cultivation in white and yellow tanks produced individuals with a pale skin colour, while cultivation in blue and black tanks resulted in juveniles with a darker and more pigmented skin. PMID- 27981571 TI - Haematopoietic prolyl hydroxylase-1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis. AB - Prolyl hydroxylase domain-containing proteins (PHDs) regulate the adaptation of cells to hypoxia. Pan-hydroxylase inhibition is protective in experimental colitis, in which PHD1 plays a prominent role. However, it is currently unknown how PHD1 targeting regulates this protection and which cell type(s) are involved. Here, we demonstrated that Phd1 deletion in endothelial and haematopoietic cells (Phd1f/f Tie2:cre) protected mice from dextran sulphate sodium (DSS)-induced colitis, with reduced epithelial erosions, immune cell infiltration, and colonic microvascular dysfunction, whereas the response of Phd2f/+ Tie2:cre and Phd3f/f Tie2:cre mice to DSS was similar to that of their littermate controls. Using bone marrow chimeras and cell-specific cre mice, we demonstrated that ablation of Phd1 in haematopoietic cells but not in endothelial cells was both necessary and sufficient to inhibit experimental colitis. This effect relied, at least in part, on skewing of Phd1-deficient bone marrow-derived macrophages towards an anti inflammatory M2 phenotype. These cells showed an attenuated nuclear factor-kappaB dependent response to lipopolysaccharide (LPS), which in turn diminished endothelial chemokine expression. In addition, Phd1 deficiency in dendritic cells significantly reduced interleukin-1beta production in response to LPS. Taken together, our results further support the development of selective PHD1 inhibitors for ulcerative colitis, and identify haematopoietic cells as their primary target. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27981572 TI - Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy. AB - Voriconazole, a triazole antifungal agent, demonstrates wide interpatient variability in serum concentrations, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 ultrarapid metabolizers have decreased trough voriconazole concentrations, delaying achievement of target blood concentrations; whereas poor metabolizers have increased trough concentrations and are at increased risk of adverse drug events. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org). PMID- 27981575 TI - Pain hurts 2: changes over time in children and young people with cerebral palsy. PMID- 27981574 TI - Loop G in the GABAA receptor alpha1 subunit influences gating efficacy. AB - KEY POINTS: The functional importance of residues in loop G of the GABAA receptor has not been investigated. D43 and T47 in the alpha1 subunit are of particular significance as their structural modification inhibits activation by GABA. While the T47C substitution had no significant effect, non-conservative substitution of either residue (D43C or T47R) reduced the apparent potency of GABA. Propofol potentiated maximal GABA-evoked currents mediated by alpha1(D43C)beta2gamma2 and alpha1(T47R)beta2gamma2 receptors. Non-stationary variance analysis revealed a reduction in maximal GABA-evoked Popen , suggesting impaired agonist efficacy. Further analysis of alpha1(T47R)beta2gamma2 receptors revealed that the efficacy of the partial agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol) relative to GABA was impaired. GABA-, THIP- and propofol-evoked currents mediated by alpha1(T47R)beta2gamma2 receptors deactivated faster than those mediated by alpha1beta2gamma2 receptors, indicating that the mutation impairs agonist-evoked gating. Spontaneous gating caused by the beta2(L285R) mutation was also reduced in alpha1(T47R)beta2(L285R)gamma2 compared to alpha1beta2(L285R)gamma2 receptors, confirming that alpha1(T47R) impairs gating independently of agonist activation. ABSTRACT: The modification of cysteine residues (substituted for D43 and T47) by 2-aminoethyl methanethiosulfonate in the GABAA alpha1 subunit loop G is known to impair activation of alpha1beta2gamma2 receptors by GABA and propofol. While the T47C substitution had no significant effect, non-conservative substitution of either residue (D43C or T47R) reduced the apparent potency of GABA. Propofol (1 MUm), which potentiates sub-maximal but not maximal GABA-evoked currents mediated by alpha1beta2gamma2 receptors, also potentiated maximal currents mediated by alpha1(D43C)beta2gamma2 and alpha1(T47R)beta2gamma2 receptors. Furthermore, the peak open probabilities of alpha1(D43C)beta2gamma2 and alpha1(T47R)beta2gamma2 receptors were reduced. The kinetics of macroscopic currents mediated by alpha1(D43C)beta2gamma2 and alpha1(T47R)beta2gamma2 receptors were characterised by slower desensitisation and faster deactivation. Similar changes in macroscopic current kinetics, together with a slower activation rate, were observed with the loop D alpha1(F64C) substitution, known to impair both efficacy and agonist binding, and when the partial agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4 c]pyridine-3-ol) was used to activate WT or alpha1(T47R)beta2gamma2 receptors. Propofol-evoked currents mediated by alpha1(T47R)beta2gamma2 and alpha1(F64C)beta2gamma2 receptors also exhibited faster deactivation than their WT counterparts, revealing that these substitutions impair gating through a mechanism independent of orthosteric binding. Spontaneous gating caused by the introduction of the beta2(L285R) mutation was also reduced in alpha1(T47R)beta2(L285R)gamma2 compared to alpha1beta2(L285R)gamma2 receptors, confirming that alpha1(T47R) impairs gating independently of activation by any agonist. These findings implicate movement of the GABAA receptor alpha1 subunit's beta1 strand during agonist-dependent and spontaneous gating. Immobilisation of the beta1 strand may provide a mechanism for the inhibition of gating by inverse agonists such as bicuculline. PMID- 27981573 TI - Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel. AB - Genetic variants in the pharmacokinetic (PK) mechanism are the main underlying factors affecting the antiplatelet response to clopidogrel. Using a genomewide association study (GWAS) to identify new genetic loci that modify antiplatelet effects in Chinese patients with coronary heart disease, we identified novel variants in two transporter genes (SLC14A2 rs12456693, ATP-binding cassette [ABC]A1 rs2487032) and in N6AMT1 (rs2254638) associated with P2Y12 reaction unit (PRU) and plasma active metabolite (H4) concentration. These new variants dramatically improved the predictability of PRU variability to 37.7%. The associations between these loci and PK parameters of clopidogrel and H4 were observed in additional patients, and its function on the activation of clopidogrel was validated in liver S9 fractions (P < 0.05). Rs2254638 was further identified to exert a marginal risk effect for major adverse cardiac events in an independent cohort. In conclusion, new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment. PMID- 27981576 TI - Combining familiarity and landscape features helps break down the barriers between movements and home ranges in a non-territorial large herbivore. AB - Recent advances in animal ecology have enabled identification of certain mechanisms that lead to the emergence of territories and home ranges from movements considered as unbounded. Among them, memory and familiarity have been identified as key parameters in cognitive maps driving animal navigation, but have been only recently used in empirical analyses of animal movements. At the same time, the influence of landscape features on movements of numerous species and on space division in territorial animals has been highlighted. Despite their potential as exocentric information in cognitive maps and as boundaries for home ranges, few studies have investigated their role in the design of home ranges of non-territorial species. Using step selection analyses, we assessed the relative contribution of habitat characteristics, familiarity preferences and linear landscape features in movement step selection of 60 GPS-collared Mediterranean mouflon Ovis gmelini musimon * Ovis sp. monitored in southern France. Then, we evaluated the influence of these movement-impeding landscape features on the design of home ranges by testing for a non-random distribution of these behavioural barriers within sections of space differentially used by mouflon. We reveal that familiarity and landscape features are key determinants of movements, relegating to a lower level certain habitat constraints (e.g. food/cover trade off) that we had previously identified as important for this species. Mouflon generally avoid crossing both anthropogenic (i.e. roads, tracks and hiking trails) and natural landscape features (i.e. ridges, talwegs and forest edges) while moving in the opposite direction, preferentially toward familiar areas. These specific behaviours largely depend on the relative position of each movement step regarding distance to the landscape features or level of familiarity in the surroundings. We also revealed cascading consequences on the design of home ranges in which most landscape features were excluded from cores and relegated to the peripheral areas. These results provide crucial information on landscape connectivity in a context of marked habitat fragmentation. They also call for more research on the role of landscape features in the emergence of home ranges in non-territorial species using recent methodological developments bridging the gap between movements and space use patterns. PMID- 27981577 TI - Clinical Pharmacokinetics and Pharmacodynamics of Atezolizumab in Metastatic Urothelial Carcinoma. AB - Atezolizumab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting human programmed death-ligand 1 (PD-L1), is US Food and Drug Administration (FDA) approved in metastatic urothelial carcinoma (MUC) and is being investigated in various malignancies. This analysis based upon 906 patients from two phase I and one phase II MUC studies, is the first report of the clinical pharmacokinetics (PK) and pharmacodynamics (PD) of atezolizumab. Atezolizumab exhibited linear PK over a dose range of 1-20 mg/kg, including the labeled 1,200 mg dose. The clearance, volume of distribution, and terminal half-life estimates from population pharmacokinetic (PopPK) analysis of 0.200 L/day, 6.91 L, and 27 days, respectively, were as expected for an IgG1. Exposure-response analyses did not identify statistically significant relationships with either objective response rate or adverse events of grades 3-5 or of special interest. None of the statistically significant covariates from PopPK (body weight, gender, antitherapeutic antibody, albumin, and tumor burden) would require dose adjustment. PMID- 27981579 TI - Pharmacogenetic Implementation Lessons From the "Real World". AB - The manuscript "Anticoagulation Endpoints With Clinical Implementation of Warfarin Pharmacogenetic Dosing in a Real- World Setting: A Proposal for a New Pharmacogenetic Dosing Approach" describes process outcomes in an institutional program to use pharmacogenetic testing to optimize warfarin dose in a cohort of 257 patients of diverse ancestries. The strengths and weaknesses of the approach and program are discussed, along with the current and potential future status of warfarin as a model for pharmacogenetic testing. PMID- 27981578 TI - Bicarbonate sensing in mouse cortical astrocytes during extracellular acid/base disturbances. AB - KEY POINTS: The present study suggests that the electrogenic sodium-bicarbonate cotransporter, NBCe1, supported by carbonic anhydrase II, CAII, provides an efficient mechanism of bicarbonate sensing in cortical astrocytes. This mechanism is proposed to play a major role in setting the pHi responses to extracellular acid/base challenges in astrocytes. A decrease in extracellular [HCO3- ] during isocapnic acidosis and isohydric hypocapnia, or an increase in intracellular [HCO3- ] during hypercapnic acidosis, was effectively sensed by NBCe1, which carried bicarbonate out of the cells under these conditions, and caused an acidification and sodium fall in WT astrocytes, but not in NBCe1-knockout astrocytes. Isocapnic acidosis, hypercapnic acidosis and isohydric hypocapnia evoked inward currents in NBCe1- and CAII-expressing Xenopus laevis oocytes, but not in native oocytes, suggesting that NBCe1 operates in the outwardly directed mode under these conditions consistent with our findings in astrocytes. We propose that bicarbonate sensing of astrocytes may have functional significance during extracellular acid/base disturbances in the brain, as it not only alters intracellular pH/[HCO3- ]-dependent functions of astrocytes, but also modulates the extracellular pH/[HCO3- ] in brain tissue. ABSTRACT: Extracellular acid/base status of the mammalian brain undergoes dynamic changes during many physiological and pathological events. Although intracellular pH (pHi ) of astrocytes responds to extracellular acid/base changes, the mechanisms mediating these changes have remained unresolved. We have previously shown that the electrogenic sodium bicarbonate cotransporter, NBCe1, is a high-affinity bicarbonate carrier in cortical astrocytes. In the present study, we investigated whether NBCe1 plays a role in bicarbonate sensing in astrocytes, and in determining the pHi responses to extracellular acid/base challenges. We measured changes in intracellular H+ and Na+ in astrocytes from wild-type (WT) and from NBCe1-knockout (KO) mice, using ion-selective dyes, during isocapnic acidosis, hypercapnic acidosis and hypocapnia. We also analysed NBCe1-mediated membrane currents in Xenopus laevis oocytes under similar conditions. Comparing WT and NBCe1-KO astrocytes, we could dissect the contribution of NBCe1, of diffusion of CO2 across the cell membrane and, after blocking carbonic anhydrase (CA) activity with ethoxyzolamide, of the role of CA, for the amplitude and rate of acid/base fluxes. Our results suggest that NBCe1 transport activity in astrocytes, supported by CA activity, renders astrocytes bicarbonate sensors in the mouse cortex. NBCe1 carried bicarbonate into and out of the cell by sensing the variations of transmembrane [HCO3- ], irrespective of the changes in intra- and extracellular pH, and played a major role in setting pHi responses to the extracellular acid/base challenges. We propose that bicarbonate sensing of astrocytes may have potential functional significance during extracellular acid/base alterations in the brain. PMID- 27981580 TI - Electrical defects of the transverse-axial tubular system in cardiac diseases. AB - Electrical excitability is an essential feature of cardiomyocytes and the homogenous propagation of the action potential is guaranteed by a complex network of membrane invaginations called the transverse-axial tubular system (TATS). TATS structural remodelling is a hallmark of cardiac diseases and we demonstrated that this can be accompanied by electrical defects at single T-tubular level. Using a random-access multi-photon (RAMP) microscope, we found that pathological T tubules can fail to conduct action potentials, which delays local Ca2+ release. Although the underlying causes for T-tubular electrical failure are still unknown, our findings suggest that they are likely to be related to local ultrastructural alterations. Here, we first review the experimental approach that allowed us to observe and dissect the consequences of TATS electrical dysfunction and then propose two different strategies to unveil the reasons for T-tubular electrical failures. The first strategy consists in a correlative approach, in which the failing T-tubule identified with the RAMP microscope is then imaged with electron microscopy. The second approach exploits the diffusion of molecules within TATS to gain insights into the local TATS structure, even without a thorough reconstruction of the tubular network. Although challenging, the local electrical failure occurring at single T-tubules is a fundamental question that needs to be addressed and could provide novel insights in cardiac pathophysiology. PMID- 27981581 TI - Dissecting neurovascular coupling mechanisms: a role for adenosine A2A receptor: An Editorial highlight for 'Correlation of transient adenosine release and oxygen changes in the caudate-putamen'. AB - Read the highlighted article 'Correlation of transient adenosine release and oxygen changes in the caudate-putamen' on page 13. PMID- 27981582 TI - Lake sturgeon Acipenser fulvescens and shovelnose sturgeon Scaphirhynchus platorynchus environmental life history revealed using pectoral fin-ray microchemistry: implications for interjurisdictional conservation through fishery closure zones. AB - This study inferred that the majority of shovelnose sturgeon Scaphirhynchus platorynchus captured in the upper Mississippi River probably originated from locations outside the upper Mississippi River (Missouri River, middle Mississippi River); whereas, lake sturgeon Acipenser fulvescens exhibit infrequent movement outside of the upper Mississippi River, but may move throughout these interconnected large rivers at various life stages. By using pectoral fin-ray microchemistry (a non-lethal alternative to using otoliths), it is suggest that interjurisdictional cooperation will probably be needed to ensure sustainability of the S. platorynchus commercial fishery and the success of A. fulvescens reintroduction in the upper Mississippi River. Additionally, fin-ray microchemistry can provide invaluable data to make informed management decisions regarding large river fishes, that cross jurisdictional boundaries or that move outside of closure zones, without causing further mortality to compromised fish populations (e.g. threatened and endangered species). PMID- 27981583 TI - Cross-seeding between Abeta40 and Abeta42 in Alzheimer's disease. AB - Abeta42 is the major component of parenchymal plaques in the brain of Alzheimer's patients, while Abeta40 is the major component of cerebrovascular plaques. Since Abeta40 and Abeta42 coexist in the brain, understanding the interaction between Abeta40 and Abeta42 during their aggregation is important to delineate the molecular mechanism underlying Alzheimer's disease. Here, we present a rigorous and systematic study of the cross-seeding effects between Abeta40 and Abeta42. We show that Abeta40 fibril seeds can promote Abeta42 aggregation in a concentration dependent manner, and vice versa. Our results also suggest that seeded aggregation and spontaneous aggregation may be two separate pathways. These findings may partly resolve conflicting observations in the literature regarding the cross-seeding effects between Abeta40 and Abeta42. PMID- 27981584 TI - Maternal Smoking Status in Successive Pregnancies and Risk of Having a Small for Gestational Age Infant. AB - BACKGROUND: Smoking during pregnancy is linked to having a small for gestational age (SGA) baby. We estimated SGA risk among women who smoked persistently, quit smoking or started smoking during their first two pregnancies. METHODS: Data from the population-based Medical Birth Registry of Norway was used to evaluate self reported smoking at the beginning and end of two successive pregnancies among 118 355 Nordic women giving birth 1999-2014. Relative risks (RR) with 95% confidence intervals (CI) of SGA in the second pregnancy were estimated using adjusted generalised linear models with non-smokers during both pregnancies serving as referent category. RESULTS: Daily smokers throughout both pregnancies had almost threefold increased SGA risk in the second pregnancy (RR 2.9, 95% CI 2.7, 3.1). Daily smokers in the first pregnancy, who abstained in the second, had a 1.3-fold increased risk (95% CI 1.1, 1.5). Intermediate risks were found among persistent daily smokers who quit by the end of the second pregnancy (RR 2.0, 95% CI 1.6, 2.4) and non-smokers in first pregnancy who smoked daily throughout their second (RR 1.8, 95% CI 1.4, 2.3). Persistently smoking women without SGA in first pregnancy, had a 2.7-fold increased risk of SGA in second pregnancy (95% CI 2.5, 3.0). CONCLUSIONS: Smoking throughout two successive pregnancies was associated with the greatest increased SGA risk compared with non-smokers, while cessation before or during the second pregnancy reduced this risk. Women who smoked in the first pregnancy without experiencing SGA are not protected against SGA in second pregnancy if they continue smoking. PMID- 27981585 TI - Improving the water solubility of Monascus pigments under acidic conditions with gum arabic. AB - BACKGROUND: Monascus pigments (Mps) are natural food colorants and their stability in acidic solutions is important for application in the food industry. This study aimed to evaluate the use of gum arabic (GA) as a stabilizer for maintaining the solubility of Mps in an acidic aqueous solution exposed to a high temperature, and to analyze the molecular interactions between GA and Mps. RESULTS: Mps dispersed (0.2 g kg-1 ) in deionized water at pH 3.0-4.0 without GA formed precipitates but remained in a stable solution in the presence of GA (1 g kg-1 ). The significant improvement of Mps water solubility under acidic conditions was attributed to the formation of Mps-GA complexes, as indicated by a sharp increase in the fluorescence intensity. The results on particle size, zeta potential, and transmission electron microscopy further suggested that molecular binding of Mps to GA, electrostatic repulsion, and steric hindrance of GA were contributing factors to preventing the aggregation of Mps in acidic solutions. A mechanistic model was presented for GA-Mps interactions and complex structures. CONCLUSION: GA was proven to be an effective stabilizer of natural food colorants in acidic solutions. (c) 2016 Society of Chemical Industry. PMID- 27981587 TI - Inactivation of foodborne pathogenic and spoilage micro-organisms using ultraviolet-A light in combination with ferulic acid. AB - : The low energy of UV-A (315-400 nm) is insufficient for disinfection. To improve UV-A disinfection technology, we evaluated the effect of ferulic acid (FA) addition on disinfection by UV-A light-emitting diode (LED) (350-385 nm) against various food spoilers and pathogens (seven bacteria and four fungi species). Photoantimicrobial assays were performed at FA concentrations below the MIC. The MIC of the isomerized FA, consisting of 93% cis-form and 7% trans-form, was very similar to that of the commercially available FA (trans-form). Irradiation with UV-A (1.0 J cm-2 ) in the presence of 100 mg l-1 FA resulted in enhanced reducing of all of the tested bacterial strains. A combination of UV-A (10 J cm-2 ) and 1000 mg l-1 FA resulted in enhanced reducing of Saccharomyces cerevisiae and one of the tested filamentous fungi. These results demonstrated that the combination of a short-term application of UV-A and FA at a low concentration yielded synergistic enhancement of antimicrobial activity, especially against bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Microbial contamination is one of the most serious problems for foods, fruit and sugar thick juices. UV light is suitable for the nonthermal decontamination of food products by inactivating the contaminating micro-organisms. However, UV-A exposure is insufficient for disinfection. This study demonstrates that the combination of UV-A LED light (350-385 nm), which is not hazardous to human eyes and skin, and ferulic acid (FA), a known phytochemical and food additive, provides synergistic antimicrobial activity against foodborne pathogenic and spoilage micro-organisms. Therefore, FA addition to UV-A light treatment may be useful for improvement of UV-A disinfection technology to prevent food deterioration. PMID- 27981586 TI - Gaze-evoked nystagmus induced by alcohol intoxication. AB - KEY POINTS: The cerebellum is the core structure controlling gaze stability. Chronic cerebellar diseases and acute alcohol intoxication affect cerebellar function, inducing, among others, gaze instability as gaze-evoked nystagmus. Gaze evoked nystagmus is characterized by increased centripetal eye-drift. It is used as an important diagnostic sign for patients with cerebellar degeneration and to assess the 'driving while intoxicated' condition. We quantified the effect of alcohol on gaze-holding using an approach allowing, for the first time, the comparison of deficits induced by alcohol intoxication and cerebellar degeneration. Our results showed that alcohol intoxication induces a two-fold increase of centripetal eye-drift. We establish analysis techniques for using controlled alcohol intake as a model to support the study of cerebellar deficits. The observed similarity between the effect of alcohol and the clinical signs observed in cerebellar patients suggests a possible pathomechanism for gaze holding deficits. ABSTRACT: Gaze-evoked nystagmus (GEN) is an ocular-motor finding commonly observed in cerebellar disease, characterized by increased centripetal eye-drift with centrifugal correcting saccades at eccentric gaze. With cerebellar degeneration being a rare and clinically heterogeneous disease, data from patients are limited. We hypothesized that a transient inhibition of cerebellar function by defined amounts of alcohol may provide a suitable model to study gaze-holding deficits in cerebellar disease. We recorded gaze-holding at varying horizontal eye positions in 15 healthy participants before and 30 min after alcohol intake required to reach 0.60/00 blood alcohol content (BAC). Changes in ocular-motor behaviour were quantified measuring eye-drift velocity as a continuous function of gaze eccentricity over a large range (+/-40 deg) of horizontal gaze angles and characterized using a two-parameter tangent model. The effect of alcohol on gaze stability was assessed analysing: (1) overall effects on the gaze-holding system, (2) specific effects on each eye and (3) differences between gaze angles in the temporal and nasal hemifields. For all subjects, alcohol consumption induced gaze instability, causing a two-fold increase [2.21 (0.55), median (median absolute deviation); P = 0.002] of eye-drift velocity at all eccentricities. Results were confirmed analysing each eye and hemifield independently. The alcohol-induced transient global deficit in gaze-holding matched the pattern previously described in patients with late-onset cerebellar degeneration. Controlled intake of alcohol seems a suitable disease model to study cerebellar GEN. With alcohol resulting in global cerebellar hypofunction, we hypothesize that patients matching the gaze-holding behaviour observed here suffered from diffuse deficits in the gaze-holding system as well. PMID- 27981589 TI - Capillary transport of two immiscible fluids in presence of electroviscous retardation. AB - The transport of two immiscible electrolytes through a narrow confinement whose walls bear a finite surface potential is analyzed through a lumped model by considering the influence of a regulatory self-induced axial electric field, termed as streaming potential. The presence of a surface charge on the channel walls culminates in the aqueous solutions carrying a net charge so as to make the overall system (channel and fluid) electrically neutral. The advection due to pressure driven flow or capillarity in the absence of any externally imposed electric field causes a preferential transport of net charged species. Thus, in order to render a net zero current through the system, there is an induced electric field which also retards the flow as a consequence of the force acting on the charged segments of fluid due to the streaming electric field. It is shown through a lumped model that for the situation of two distinct segments of fluids, the rate of front penetration into the capillary is strongly dependent on the relative conductivities of the two fluids. The streaming electric field evolves in accordance to the net conductivity of the channel and is responsible for dynamic changes in the retarding influence on the segments of fluid. PMID- 27981588 TI - A highly specific competitive direct enzyme immunoassay for sterigmatocystin as a tool for rapid immunochemotaxonomic differentiation of mycotoxigenic Aspergillus species. AB - : A simplified method to produce specific polyclonal rabbit antibodies against sterigmatocystin (STC) was established, using a STC-glycolic acid-ether derivative (STC-GE) conjugated to keyhole limpet haemocyanin (immunogen). The competitive direct enzyme immunoassay (EIA) established for STC had a detection limit (20% binding inhibition) of 130 pg ml-1 . The test was highly specific for STC, with minor cross-reactivity with O-methylsterigmatocystin (OMSTC, 0.87%) and negligible reactivity with aflatoxins (<0.02%). STC-EIA was used in combination with a previously developed specific EIA for aflatoxins (<0.1% cross-reactivity with STC and OMSTC), to study the STC/aflatoxin production profiles of reference strains of Aspergillus species. This immunochemotaxonomic procedure was found to be a convenient tool to identify STC- or aflatoxin-producing strains. SIGNIFICANCE AND IMPACT OF THE STUDY: The carcinogenic mycotoxin sterigmatocystin (STC) is produced by several Aspergillus species, either alone or together with aflatoxins. Here, we report a very simple and straightforward procedure to obtain highly sensitive and specific anti-STC antibodies, and their use in the first ever real STC-specific competitive direct enzyme immunoassay (EIA). In combination with a previous EIA for aflatoxins, this study for the first time demonstrates the potential of a STC/aflatoxin EIA pair for what is branded as 'immunochemotaxonomic' identification of mycotoxigenic Aspergillus species. This new analytical tool enhances analytical possibilities for differential analysis of STC and aflatoxins. PMID- 27981590 TI - Dietary restriction and aerobic exercise attenuate obesity-induced lymphatic dysfunction. PMID- 27981591 TI - What prenatal ultrasound features are predictable of complex or vanishing gastroschisis? A retrospective study. AB - OBJECTIVE: To evaluate prenatal ultrasound parameters as prognostic factors for complex and vanishing gastroschisis. METHODS: Retrospective multicentre study of 200 gastroschisis over 13 years (2000-2013). Collection of prenatal ultrasound evaluation on maternal and fetal growth parameters, intra- and extra-abdominal bowel and stomach dilation, abdominal wall defect diameter and changes in bowel appearance. Correlation of these factors with the presence of mechanical intestinal complications at birth, named 'complex gastroschisis'. RESULTS: Fifty two patients (26%) had complex gastroschisis (CG), including ten vanishing gastroschisis. The presence of intra-abdominal bowel dilation at the second (T2) or third (T3) trimester ultrasound was predictive for CG, with odds ratios at 6.69 (95%CI 2.41-18.55) and 4.72 (95%CI 2.16-10.28), respectively, with a cut-off value at the last examination of >19 mm. A small abdominal wall defect diameter was also predictive for CG, with cut-off values of <9.2 mm at T2 and <12.5 mm at T3. Vanishing gastroschisis recorded earlier intra-abdominal bowel dilation diagnosis, associated with a small wall defect and no extra-abdominal dilation. CONCLUSION: Intra-abdominal bowel dilation and a small abdominal wall defect diameter accurately predict CG and could be a first sign of vanishing gastroschisis when they occur early. (c) 2016 John Wiley & Sons, Ltd. PMID- 27981592 TI - The ascending pathophysiology of cholestatic liver disease. AB - In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process. The first and early lesions are in "downstream" bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the "upstream" liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50% 60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more "tailored" use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti-inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor-ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end-stage disease. These are arguments to consider a step-wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage-defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722-738). PMID- 27981593 TI - Determination of isoflavone (genistein and daidzein) concentration of soybean seed as affected by environment and management inputs. AB - BACKGROUND: Isoflavones, such as genistein and daidzein, are produced in soybean seed [Glycine max (L.) Merr.] and may be associated with health benefits in the human diet. More research is required to determine the effect of agronomic soybean treatments on isoflavone concentration. In this study from 2012 to 2014 at Michigan State University and Breckenridge locations, we have evaluated agronomic input management systems which are marketed to increase or protect potential soybean grain yield, including: nitrogen fertilization, herbicide defoliant, foliar applied fertilizer, a biological-based foliar application, foliar applied fungicide, foliar applied insecticide, a seed applied fungicide, and a maximized seed treatment that included fungicide and insecticide as well as an inoculant and lipo-chitooligosaccharide nodulation promoter, for their effect on soybean seed genistein and daidzein concentrations. RESULTS: Paired comparisons were made between treatments receiving a designated management input and those without the input. Year and location had a significant effect on isoflavone concentrations. Agronomic management inputs impacted soybean seed daidzein concentrations in 15 of 48 field observations and genistein concentrations in 11 of 48 observations. CONCLUSION: The research supports findings that soybean seed isoflavone levels exhibit a location specific response, and the temporal variability experienced between years appears to influence changes in soybean isoflavone levels more than location. (c) 2016 Society of Chemical Industry. PMID- 27981594 TI - Enhanced yields and soil quality in a wheat-maize rotation using buried straw mulch. AB - BACKGROUND: Straw return may improve soil quality and crop yields. In a 2-year field study, a straw return method (ditch-buried straw return, DB-SR) was used to investigate the soil quality and crop productivity effects on a wheat-corn rotation system. This study consisted of three treatments, each with three replicates: (1) mineral fertilisation alone (CK0); (2) mineral fertilisation + 7500 kg ha-1 wheat straw incorporated at depth of 0-15 cm (NPKWS); and (3) mineral fertilisation + 7500 kg ha-1 wheat straw ditch buried at 15-30 cm (NPKDW). RESULTS: NPKWS and NPKDW enhanced crop yield and improved soil biotical properties compared to mineral fertilisation alone. NPKDW contributed to greater crop yields and soil nutrient availability at 15-30 cm depths, compared to NPKWS treatment. NPKDW enhanced soil microbial activity and bacteria species richness and diversity in the 0-15 cm layer. NPKWS increased soil microbial biomass, bacteria species richness and diversity at 15-30 cm. CONCLUSIONS: The comparison of the CK0 and NPKWS treatments indicates that a straw ditch buried by digging to the depth of 15-30 cm can improve crop yields and soil quality in a wheat-maize rotation system. (c) 2016 Society of Chemical Industry. PMID- 27981595 TI - An investigation of the effect of rapid slurry chilling on blown pack spoilage of vacuum-packaged beef primals. AB - : The aim of this study was to investigate if rapid slurry chilling would retard or prevent blown pack spoilage (BPS) of vacuum-packaged beef primals. Beef primals were inoculated with Clostridium estertheticum subspp. estertheticum (DSMZ 8809), C. estertheticum subspp. laramenise (DSMZ 14864) and C. gasigenes (DSMZ 12272), and vacuum-packaged with and without heat shrinkage (90 degrees C for 3 s). These packs were then subjected to immediate chilling in an ice slurry or using conventional blast chilling systems and stored at 2 degrees C for up to 100 days. The onset and progress of BPS was monitored using the following scale; 0-no gas bubbles in drip; 1-gas bubbles in drip; 2-loss of vacuum; 3-'blown'; 4 presence of sufficient gas inside the packs to produce pack distension and 5 tightly stretched, 'overblown' packs/packs leaking. Rapid slurry chilling (as compared to conventional chilling) did not significantly affect (P > 0.05) the time to the onset or progress of BPS. It was therefore concluded that rapid chilling of vacuum-packaged beef primals, using an ice slurry system, may not be used as a control intervention to prevent or retard blown pack spoilage. SIGNIFICANCE AND IMPACT OF THE STUDY: This study adds to our growing understanding of blown pack spoilage of vacuum-packaged beef primals and suggests that rapid chilling of vacuum-packaged beef primals is not a control option for the beef industry. The results suggest that neither eliminating the heat shrinkage step nor rapid chilling of vacuum-packaged beef retard the time to blown pack spoilage. PMID- 27981597 TI - Effect of pretreatment on rehydration, colour and nanoindentation properties of potato cylinders dried using a mixed-mode solar dryer. AB - BACKGROUND: Desirable quality estimation is an important consumer driver for wider acceptability of mixed-mode solar drying of potatoes in food industries. The aim of this study is to characterise rehydration, colour, texture, nanoindentaion and microstructure of dried potato samples and to establish the influence of pre-drying treatment on the above qualities. RESULTS: The water absorption capacity and rehydration ability of solar dried potato were significantly influenced by pretreatment followed by rehydration temperature and sample diameter. The redness index (a*) of pretreated dried samples was lower with simultaneous higher value of yellowness index (b*), chroma (C*) and hue angle (h*). Also, the average nanohardness (H) of pretreated samples increased significantly by 22.64% compared to that of untreated samples. The average reduced modulus (Er ) and Young's modulus (Es ) of dried potato samples were 1.865 GPa and 1.403 GPa, respectively. Moreover, creep displacement of 43.27 nm was traced in the untreated potato samples during a 20 s dwell time under a constant load of 200 uN in the nanoindentation test. Micrographs revealed more uniform pore spaces in pretreated samples. CONCLUSION: Pretreated, thinner potato samples achieved better quality dried products in terms of rehydration, colour, texture and nanohardness indices with significantly improved microstructure and creep resistance properties. (c) 2016 Society of Chemical Industry. PMID- 27981596 TI - Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements. AB - : Bile duct loss during the course of drug-induced liver injury is uncommon, but can be an indication of vanishing bile duct syndrome (VBDS). In this work, we assess the frequency, causes, clinical features, and outcomes of cases of drug induced liver injury with histologically proven bile duct loss. All cases of drug induced liver injury enrolled into a prospective database over a 10-year period that had undergone liver biopsies (n = 363) were scored for the presence of bile duct loss and assessed for clinical and laboratory features, causes, and outcomes. Twenty-six of the 363 patients (7%) with drug-, herbal-, or dietary supplement-associated liver injury had bile duct loss on liver biopsy, which was moderate to severe (<50% of portal areas with bile ducts) in 14 and mild (50% 75%) in 12. The presenting clinical features of the 26 cases varied, but the most common clinical pattern was a severe cholestatic hepatitis. The implicated agents included amoxicillin/clavulanate (n = 3), temozolomide (n = 3), various herbal products (n = 3), azithromycin (n = 2), and 15 other medications or dietary supplements. Compared to those without, those with bile duct loss were more likely to develop chronic liver injury (94% vs. 47%), which was usually cholestatic and sometimes severe. Five patients died and 2 others underwent liver transplantation for progressive cholestasis despite treatment with corticosteroids and ursodiol. The most predictive factor of poor outcome was the degree of bile duct loss on liver biopsy. CONCLUSION: Bile duct loss during acute cholestatic hepatitis is an ominous early indicator of possible VBDS, for which at present there are no known means of prevention or therapy. (Hepatology 2017;65:1267-1277). PMID- 27981598 TI - Anti-TNF-alpha for necrotizing sarcoid granulomatosis of the liver. AB - We present a case of hepatosplenic necrotizing sarcoid granulomatosis, a variant form of "classical" sarcoidosis, that became clinically apparent in the form of multiple hepatic and splenic masses mimicking malignancy. Flow cytometry of intrahepatic T cells isolated from liver biopsy led to the targeted treatment with anti-tumor necrosis factor-alpha, which was highly effective in inducing remission. (Hepatology 2017;65:1410-1412). PMID- 27981600 TI - The effect of pharmacists on ward rounds measured by the STOPP/START tool in a specialized geriatric unit. AB - WHAT IS KNOWN AND OBJECTIVE: The STOPP/START tool has been validated to assess elderly patients for potentially inappropriate prescribing. This study aimed to assess the effect of inclusion of a pharmacist on a physician-led ward round on potentially inappropriate prescribing in hospitalized elderly patients. METHODS: This was an observational study of prescribing for patients using the STOPP/START tool at three points during hospital stay; admission to hospital, on transfer to the specialized geriatric unit and on discharge from hospital. Data were collected over 4 months pre- and post-introduction of a pharmacist to a physician led ward round. Demographic and clinical data, including total number of medications and STOPP/START criteria met, were collected. The mean number of STOPP/START criteria at each time-point was compared for pre- and post introduction of a pharmacist using a Mann-Whitney U-test. The mean number of criteria for each time-point within each group was compared using a paired Student's t-test. RESULTS AND DISCUSSION: The demographic characteristics of the participants in the pre- and post-intervention groups were similar. The post intervention group had numerically less STOPP/START criteria, mean 1.18 (1.37) compared to the pre-intervention group 1.50 (1.41), P = 0.07 at discharge. The pre-intervention group had no significant change in the criteria from admission 1.78 (1.57) to geriatric unit transfer 1.72 (1.54) (P = 0.37); however, there was a significant decrease from geriatric unit transfer 1.72 (1.54) to discharge 1.50 (1.41) (P = 0.02). The post-intervention group had a significant decrease from hospital admission 2.30 (1.91) to geriatric unit transfer 1.59 (1.60) (P < 0.01) and again to discharge 1.18 (1.37) (P < 0.01). WHAT IS NEW AND CONCLUSION: Pharmacist participation on the ward round in a specialized geriatric unit resulted in a numerical improvement in prescribing quality as measured by the STOPP/START tool. PMID- 27981599 TI - Human immunodeficiency virus-infected and uninfected adults with non-genotype 3 hepatitis C virus have less hepatic steatosis than adults with neither infection. AB - : Hepatic steatosis (HS) is common in individuals with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections, but the independent contributions of HCV and HIV to HS are unclear. Magnetic resonance imaging and spectroscopy were used to measure visceral adipose tissue (VAT) and liver fat fraction (LFF) (total lipids/[total lipids + water]) in 356 adults: 57 with HCV monoinfection, 70 with HIV/HCV coinfection, 122 with HIV monoinfection, and 107 with neither infection. Participants who were infected with HCV genotype 3 were excluded because of the genotype's reported steatogenic effects. For prevalence estimates, HS was defined as LFF >= 0.05. We estimated the association of HIV and HCV status with LFF using multivariable linear regression, adjusting for demographics, lifestyle, and metabolic factors including the homeostasis model assessment estimate of insulin resistance (HOMA-IR) and liver fibrosis defined using the aspartate aminotransferase-to-platelet ratio index (APRI). The prevalence of HS was highest in the uninfected (33%) and HIV-monoinfected (28%), followed by the HCV-monoinfected (19%) and HIV/HCV-coinfected (11%) (P = 0.003 across groups). Compared with uninfected participants-and after adjusting for demographics, lifestyle, and metabolic factors-HIV monoinfection, HCV monoinfection, and HIV/HCV coinfection were associated with 19% (95% confidence interval [CI], -39% to 6%), 38% (95% CI, -55% to -12%), and 42% (95% CI, -59% to 18%) lower LFF, respectively. HCV monoinfection and HIV/HCV coinfection remained strongly associated with lower LFF after further adjusting for APRI, and results were unchanged after excluding subjects with suspected cirrhosis. Among the entire cohort, Hispanic ethnicity, male sex, VAT, and HOMA-IR were independently associated with greater LFF. CONCLUSION: Contrary to expectations, HIV/HCV coinfected and HCV-monoinfected adults had significantly less liver fat than uninfected adults, even after adjusting for demographics, lifestyle, metabolic factors, and hepatic fibrosis. Our findings suggest that non-genotype 3 HCV infection may be protective against HS. The mechanisms by which this occurs and the impact of HCV treatment on HS requires further investigation. (Hepatology 2017;65:853-863). PMID- 27981601 TI - Production of oridonin-rich extracts from Rabdosia rubescens using hyphenated ultrasound-assisted supercritical carbon dioxide extraction. AB - BACKGROUND: Among active components in Rabdosia rubescens, oridonin has been considered a key component and the most valuable compound because it has a wide range of activities beneficial to human health. To produce a high-quality oridonin extract, an alternative hyphenated procedure involving an ultrasound assisted and supercritical carbon dioxide (HSC-CO2 ) extraction method to extract oridonin from R. rubescens was developed in this study. Fictitious solubilities of oridonin in supercritical CO2 (SC-CO2 ) with ultrasound assistance were measured by using the dynamic method at temperatures ranging from 305.15 K to 342.15 K over a pressure range of 11.5 to 33.5 MPa. RESULTS: Fictitious solubilities of oridonin at different temperatures and pressures were over the range of 2.13 * 10-6 to 10.09 * 10-6 (mole fraction) and correlated well with the density-based models, including the Bartle model, the Chrastil model, the Kumar and Johnston model and the Mendez-Santiago and Teja model, with overall average absolute relative deviations (AARDs) of 6.29%, 4.39%, 3.12% and 5.07%, respectively. CONCLUSION: Oridonin exhibits retrograde solubility behaviour in the supercritical state. Fictitious solubility data were further determined and obtained a good fit with four semi-empirical models. Simultaneously, the values of the total heat of solution, vaporisation and solvation of oridonin were estimated. (c) 2016 Society of Chemical Industry. PMID- 27981603 TI - Exploring STR signal in the single- and multicopy number regimes: Deductions from an in silico model of the entire DNA laboratory process. AB - Short tandem repeat (STR) profiling from DNA samples has long been the bedrock of human identification. The laboratory process is composed of multiple procedures that include quantification, sample dilution, PCR, electrophoresis, and fragment analysis. The end product is a short tandem repeat electropherogram comprised of signal from allele, artifacts, and instrument noise. In order to optimize or alter laboratory protocols, a large number of validation samples must be created at significant expense. As a tool to support that process and to enable the exploration of complex scenarios without costly sample creation, a mechanistic stochastic model that incorporates each of the aforementioned processing features is described herein. The model allows rapid in silico simulation of electropherograms from multicontributor samples and enables detailed investigations of involved scenarios. An implementation of the model that is parameterized by extensive laboratory data is publically available. To illustrate its utility, the model was employed in order to evaluate the effects of sample dilutions, injection time, and cycle number on peak height, and the nature of stutter ratios at low template. We verify the model's findings by comparison with experimentally generated data. PMID- 27981602 TI - Prohibitin 1 suppresses liver cancer tumorigenesis in mice and human hepatocellular and cholangiocarcinoma cells. AB - : Prohibitin 1 (PHB1) is best known as a mitochondrial chaperone, and its role in cancer is conflicting. Mice lacking methionine adenosyltransferase alpha1 (MATalpha1) have lower PHB1 expression, and we reported that c-MYC interacts directly with both proteins. Furthermore, c-MYC and MATalpha1 exert opposing effects on liver cancer growth, prompting us to examine the interplay between PHB1, MATalpha1, and c-MYC and PHB1's role in liver tumorigenesis. We found that PHB1 is highly expressed in normal hepatocytes and bile duct epithelial cells and down-regulated in most human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In HCC and CCA cells, PHB1 expression correlates inversely with growth. PHB1 and MAT1A positively regulate each other's expression, whereas PHB1 negatively regulates the expression of c-MYC, MAFG, and c-MAF. Both PHB1 and MATalpha1 heterodimerize with MAX, bind to the E-box element, and repress E-box promoter activity. PHB1 promoter contains a repressive E-box element and is occupied mainly by MAX, MNT, and MATalpha1 in nonmalignant cholangiocytes and noncancerous tissues that switched to c-MYC, c-MAF, and MAFG in cancer cells and human HCC/CCA. All 8-month-old liver-specific Phb1 knockout mice developed HCC, and one developed CCA. Five-month-old Phb1 heterozygotes, but not Phb1 flox mice, developed aberrant bile duct proliferation; and one developed CCA 3.5 months after left and median bile duct ligation. Phb1 heterozygotes had a more profound fall in the expression of glutathione synthetic enzymes and higher hepatic oxidative stress following left and median bile duct ligation. CONCLUSION: We have identified that PHB1, down-regulated in most human HCC and CCA, heterodimerizes with MAX to repress the E-box and positively regulates MAT1A while suppressing c-MYC, MAFG, and c-MAF expression; in mice, reduced PHB1 expression predisposes to the development of cholestasis-induced CCA. (Hepatology 2017;65:1249-1266). PMID- 27981606 TI - Evaluation of Cutaneous Findings in Children and Adolescents with Attention Deficit Hyperactivity Disorder: A Preliminary Study. AB - Attention deficit hyperactivity disorder (ADHD) is characterized by attention, concentration, mobility, and impulse control problems and is among the most frequently seen psychiatric disorders during childhood. Our aim was to evaluate cutaneous findings in children and adolescents with ADHD. In our study we found that onychophagy, traumatic skin changes, atopy and related symptoms, certain birthmarks, and acne were frequent cutaneous findings in children with ADHD. Although a limitation is the lack of a control group, ADHD is very common, and our study suggests that further studies of cutaneous findings and ADHD are warranted. PMID- 27981605 TI - Hepatocyte autotaxin expression promotes liver fibrosis and cancer. AB - : Autotaxin (ATX) is a secreted lysophospholipase D that catalyzes the production of lysophosphatidic acid (LPA), a pleiotropic growth-factor-like lysophospholipid. Increased ATX expression has been detected in various chronic inflammatory disorders and different types of cancer; however, little is known about its role and mode of action in liver fibrosis and cancer. Here, increased ATX expression was detected in chronic liver disease (CLD) patients of different etiologies, associated with shorter overall survival. In mice, different hepatotoxic stimuli linked with the development of different forms of CLDs were shown to stimulate hepatocyte ATX expression, leading to increased LPA levels, activation of hepatic stellate cells (HSCs), and amplification of profibrotic signals. Hepatocyte-specific, conditional genetic deletion and/or transgenic overexpression of ATX established a liver profibrotic role for ATX/LPA, whereas pharmacological ATX inhibition studies suggested ATX as a possible therapeutic target in CLDs. In addition, hepatocyte ATX ablation and the consequent deregulation of lipid homeostasis was also shown to attenuate hepatocellular carcinoma (HCC) development, thus implicating ATX/LPA in the causative link of cirrhosis and HCC. CONCLUSION: ATX is a novel player in the pathogenesis of liver fibrosis and cancer and a promising therapeutic target. (Hepatology 2017;65:1369 1383). PMID- 27981604 TI - Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice. AB - : Diet-related health issues such as nonalcoholic fatty liver disease and cardiovascular disorders are known to have a major inflammatory component. However, the exact pathways linking diet-induced changes (e.g., hyperlipidemia) and the ensuing inflammation have remained elusive so far. We identified biological processes related to innate immunity and oxidative stress as prime response pathways in livers of low-density lipoprotein receptor-deficient mice on a Western-type diet using RNA sequencing and in silico functional analyses of transcriptome data. The observed changes were independent of the presence of microbiota and thus indicative of a role for sterile triggers. We further show that malondialdehyde (MDA) epitopes, products of lipid peroxidation and markers for enhanced oxidative stress, are detectable in hepatic inflammation predominantly on dying cells and stimulate cytokine secretion as well as leukocyte recruitment in vitro and in vivo. MDA-induced cytokine secretion in vitro was dependent on the presence of the scavenger receptors CD36 and MSR1. Moreover, in vivo neutralization of endogenously generated MDA epitopes by intravenous injection of a specific MDA antibody results in decreased hepatic inflammation in low-density lipoprotein receptor-deficient mice on a Western-type diet. CONCLUSION: Accumulation of MDA epitopes plays a major role during diet induced hepatic inflammation and can be ameliorated by administration of an anti MDA antibody. (Hepatology 2017;65:1181-1195). PMID- 27981607 TI - Synthesis and Docking of Novel 3-Indolylpropyl Derivatives as New Polypharmacological Agents Displaying Affinity for 5-HT1A R/SERT. AB - A series of novel 3-indolylpropyl derivatives was synthesized and evaluated for their binding affinities at the serotonin-1A receptor subtype (5-HT1A R) and the 5-HT transporter (SERT). Compounds 11b and 14b exhibited the highest affinities at the 5-HT1A R (Ki = 43 and 56 nM), whereas compounds 11c and 14a were the most potent analogs at the SERT (Ki = 34 and 17 nM). On the other hand, compounds 14b and 11d showed potent activity at both targets, displaying a profile that makes them promising leads for the search for novel potent ligands with a dual mechanism of action. Molecular docking studies in all the compounds unveiled relevant drug-target interactions, which allowed rationalizing the observed affinities. PMID- 27981608 TI - Contrasting results from molecular and pedigree-based population diversity measures in captive zebra highlight challenges facing genetic management of zoo populations. AB - Zoo conservation breeding programs manage the retention of population genetic diversity through analysis of pedigree records. The range of demographic and genetic indices determined through pedigree analysis programs allows the conservation of diversity to be monitored relative to the particular founder population for a species. Such approaches are based on a number of well documented founder assumptions, however without knowledge of actual molecular genetic diversity there is a risk that pedigree-based measures will be misinterpreted and population genetic diversity misunderstood. We examined the genetic diversity of the captive populations of Grevy's zebra, Hartmann's mountain zebra and plains zebra in Japan and the United Kingdom through analysis of mitochondrial DNA sequences. Very low nucleotide variability was observed in Grevy's zebra. The results were evaluated with respect to current and historic diversity in the wild, and indicate that low genetic diversity in the captive population is likely a result of low founder diversity, which in turn suggests relatively low wild genetic diversity prior to recent population declines. Comparison of molecular genetic diversity measures with analogous diversity indices generated from the studbook data for Grevy's zebra and Hartmann's mountain zebra show contrasting patterns, with Grevy's zebra displaying markedly less molecular diversity than mountain zebra, despite studbook analysis indicating that the Grevy's zebra population has substantially more founders, greater effective population size, lower mean kinship, and has suffered less loss of gene diversity. These findings emphasize the need to validate theoretical estimates of genetic diversity in captive breeding programs with empirical molecular genetic data. Zoo Biol. 36:87-94, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27981609 TI - The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis. AB - : Tripartite motif 8 (TRIM8), an E3 ligase ubiquitously expressed in various cells, is closely involved in innate immunity. However, its role in nonalcoholic steatohepatitis is largely unknown. Here, we report evidence that TRIM8 is a robust enhancer of steatohepatitis and its complications induced by a high-fat diet or a genetic deficiency (ob/ob). Using gain-of-function and loss-of-function approaches, we observed dramatic exacerbation of insulin resistance, hepatic steatosis, inflammation, and fibrosis by hepatocyte-specific TRIM8 overexpression, whereas deletion or down-regulation of TRIM8 in hepatocytes led to a completely opposite phenotype. Furthermore, investigations of the underlying mechanisms revealed that TRIM8 directly binds to and ubiquitinates transforming growth factor-beta-activated kinase 1, thus promoting its phosphorylation and the activation of downstream c-Jun N-terminal kinase/p38 and nuclear factor kappaB signaling. Importantly, the participation of TRIM8 in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis was verified on the basis of its dramatically increased expression in the livers of these patients, suggesting a promising development of TRIM8 disturbance for the treatment of nonalcoholic steatohepatitis-related metabolic disorders. CONCLUSION: The E3 ligase TRIM8 is a potent regulator that exacerbates steatohepatitis and metabolic disorders dependent on its binding and ubiquitinating capacity on transforming growth factor-beta-activated kinase 1. (Hepatology 2017;65:1492-1511). PMID- 27981610 TI - Assessment of behavior and space use before and after forelimb amputation in a zoo-housed chimpanzee (Pan troglodytes). AB - Primates possess great manual dexterity, and their limbs are integral to many aspects of normal functioning (e.g., climbing, feeding). As such, the loss of a limb carries the risk of significant disability and potentially harmful impairment of species-typical functioning. Limb loss is known to occur in some wild primate populations due to entanglement in hunting snares, but can also occur in captive settings due to injury that necessitates therapeutic amputation. In this study, we conducted a detailed evaluation of the behavior, travel, and space use expressed by a female zoo-housed chimpanzee (Pan troglodytes) before and following surgical amputation of her right forelimb. Overall, our results suggest that the injury did not substantively affect her daily activities. She showed no change to her vertical space use, spending equivalent proportions of her time on the ground and high in the enclosure. There was a decrease in the frequency of locomotion on the ground (P = 0.006) but also a significant increase in the overall distance travelled (P = 0.0015) following the removal of the limb. This case study provides evidence that individual chimpanzees are able to successfully adjust to significant anatomical changes when provided adequate environments in which to stay active, and highlights the importance of an effective post-surgical monitoring period-a comprehensive recovery evaluation that includes input from both veterinary and behavioral research staff is likely to provide the most holistic assessment of animal health and long-term wellbeing. Zoo Biol. 36:5-10, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27981612 TI - Cutaneous Reactions in Children Treated with the Mitogen-Activated Protein Kinase Extracellular Signal-Regulated Kinase Inhibitor Trametinib for Neural Tumors. AB - BACKGROUND: The mitogen-activated protein kinase (MAPK) pathway is a target for the treatment of a growing number of malignancies. The cutaneous reactions to medications that inhibit this pathway have not been described in children. METHODS: A retrospective chart review was completed for eight children with neural tumors treated with the MAPK extracellular signal-regulated kinase inhibitor trametinib. All children were evaluated by a pediatric dermatologist with documentation of cutaneous findings. RESULTS: All patients had at least two separate skin reactions while on treatment with trametinib. Common skin findings included xerotic dermatitis, bacterial folliculitis, acneiform eruptions, paronychia, and hair thinning. No child needed to discontinue use of trametinib due to cutaneous toxicities. CONCLUSIONS: Cutaneous reactions are common in children receiving trametinib. Identification of these reactions is the initial step in establishing treatment guidelines that will minimize skin eruptions and subsequent interruption of trametinib treatment. PMID- 27981611 TI - Growth factor receptor binding protein 14 inhibition triggers insulin-induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma. AB - : Metabolic diseases such as obesity and type 2 diabetes are recognized as independent risk factors for hepatocellular carcinoma (HCC). Hyperinsulinemia, a hallmark of these pathologies, is suspected to be involved in HCC development. The molecular adapter growth factor receptor binding protein 14 (Grb14) is an inhibitor of insulin receptor catalytic activity, highly expressed in the liver. To study its involvement in hepatocyte proliferation, we specifically inhibited its liver expression using a short hairpin RNA strategy in mice. Enhanced insulin signaling upon Grb14 inhibition was accompanied by a transient induction of S phase entrance by quiescent hepatocytes, indicating that Grb14 is a potent repressor of cell division. The proliferation of Grb14-deficient hepatocytes was cell-autonomous as it was also observed in primary cell cultures. Combined Grb14 down-regulation and insulin signaling blockade using pharmacological approaches as well as genetic mouse models demonstrated that Grb14 inhibition-mediated hepatocyte division involved insulin receptor activation and was mediated by the mechanistic target of rapamycin complex 1-S6K pathway and the transcription factor E2F1. In order to determine a potential dysregulation in GRB14 gene expression in human pathophysiology, a collection of 85 human HCCs was investigated. This revealed a highly significant and frequent decrease in GRB14 expression in hepatic tumors when compared to adjacent nontumoral parenchyma, with 60% of the tumors exhibiting a reduced Grb14 mRNA level. CONCLUSION: Our study establishes Grb14 as a physiological repressor of insulin mitogenic action in the liver and further supports that dysregulation of insulin signaling is associated with HCC. (Hepatology 2017;65:1352-1368). PMID- 27981613 TI - Induction of multiple cytotoxic T lymphocyte responses in mice by a multiepitope DNA vaccine against dengue virus serotype 1. AB - Dengue virus (DENV) is still a major threat to human health in most tropical and subtropical countries and regions. In the present study, a multi-epitope DNA vaccine that encodes 15 immunogenic and conserved HLA-A*0201-, HLA-A*1101-, HLA A*2402-restricted CTL epitopes from DENV serotype 1 (DENV-1) was constructed based on the eukaryotic expressing plasmid pcDNATM 3.1/myc-His(-) A. Immunization of HLA-A*0201, HLA-A*1101 and HLA-A*2402 transgenic mice with the recombinant plasmid pcDNATM 3.1/myc-His(-) A-DENV-1-Meg resulted in significantly greater IFN gamma-secreting T-cell responses against most (14/15) CTL epitopes than occurred in mice immunized with the empty plasmid pcDNATM 3.1/myc-His(-) A. Additionally, the epitope-specific T cells directed to some epitopes secreted not only IFN gamma but also IL-6 and/or TNF-alpha. Finally, the induced epitope-specific T cells also efficiently lysed epitope-pulsed splenocytes and DENV-1-infected splenic monocytes. The present study confirms the immunogenicity of multi-epitope DENV vaccine, suggesting that it may contribute to the development of a universal DENV vaccine. PMID- 27981614 TI - Favorable short-term outcome of hepatitis C virus-positive liver graft with bridging fibrosis: A plea for very early viral eradication. PMID- 27981616 TI - Emerging secondary syphilis presenting as syphilitic hepatitis. PMID- 27981615 TI - Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease. AB - : The cut-off point of intrahepatic triglyceride (IHTG) content to define nonalcoholic fatty liver disease (NAFLD) by proton magnetic resonance spectroscopy (1 H-MRS) was established based on the 95th percentile in a group of healthy individuals (i.e., >=5.56%). Whether this threshold correlates with metabolic and histological changes and whether a further accumulation of IHTG is associated with worsening of these parameters has not been properly assessed in a large cohort of patients. In this cross-sectional study, 352 subjects were carefully characterized with the following studies: liver 1 H-MRS; euglycemic insulin clamp with measurement of glucose turnover; oral glucose tolerance test; and a liver biopsy. Hepatic insulin sensitivity (suppression of endogenous glucose production by insulin) was affected early on after IHTG content was ~1.5% and remained uniformly impaired (~40%-45%), regardless of further IHTG accumulation. Skeletal muscle insulin sensitivity showed a gradual impairment at low degrees of IHTG accumulation, but remained unchanged after IHTG content reached the ~6 +/- 2% threshold. A similar pattern was observed for metabolic changes typically associated with NAFLD, such as hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C). In contrast, adipose tissue insulin sensitivity (suppression of free fatty acids by insulin) showed a continuous worsening across the spectrum of IHTG accumulation in NAFLD (r = -0.38; P < 0.001). Histological severity of liver disease (inflammation, ballooning, and fibrosis) was not associated with the amount of IHTG content. CONCLUSION: IHTG accumulation is strongly associated with adipose tissue insulin resistance (IR), supporting the current theory of lipotoxicity as a driver of IHTG accumulation. Once IHTG accumulation reaches ~6 +/- 2%, skeletal muscle IR, hypertriglyceridemia, and low HDL-C become fully established. Histological activity appears to have an early threshold and is not significantly influenced by increasing amounts of IHTG accumulation. (Hepatology 2017;65:1132-1144). PMID- 27981617 TI - Utility of the Hemangioma Severity Scale as a Triage Tool and Predictor of Need for Treatment. AB - BACKGROUND/OBJECTIVES: Infantile hemangiomas (IHs) are commonly encountered in primary care and most often remain asymptomatic, resolving without sequelae. Certain characteristics are associated with a greater risk of complications, associated anomalies, and disfigurement. The heterogeneous presentation poses a clinical challenge for physicians in determining the need for treatment and subspecialty referral. This study aims to evaluate the utility of the previously published Hemangioma Severity Scale (HSS) to predict the need for treatment. METHODS: This retrospective study included 106 patients with IHs seen in the Indiana University Dermatology Clinic in 2011. Data from electronic medical records and clinical photographs taken at patients' initial visits were used to score the hemangiomas using the HSS. Treatments used over 9 to 14 months of follow-up were recorded. RESULTS: Four HSS score subgroups were identified. Higher HSS scores correlated with the need for treatment; 98% of patients with HSS scores of 10 or greater received local or systemic therapy. Higher HSS scores also correlated with greater frequency of complications and risks of associated structural anomalies and permanent disfigurement. Scores did not correlate with sex, age at initial presentation, history of bleeding or pain, or IH size. CONCLUSIONS: The HSS may be a useful tool for primary care physicians in identifying high-risk IHs that may benefit from therapy. This easy-to-use scale can improve clinical outcomes by identifying which patients need intervention to minimize complications. IHs with total HSS scores of 6 or greater should be referred for subspecialty evaluation. PMID- 27981618 TI - Access to Genetic Diagnostics for Genodermatoses: Who Should Get Tested? Why? Who Pays? PMID- 27981619 TI - Familial Progressive Hyperpigmentation, Cutaneous Mastocytosis, and Gastrointestinal Stromal Tumor as Clinical Manifestations of Mutations in the c KIT Receptor Gene. AB - BACKGROUND: Familial progressive hyperpigmentation (FPH) is an autosomal dominant disorder characterized by the appearance of hyperpigmented patches on the skin from early infancy that increase in size and number with age. METHODS: We report the clinical and molecular studies of an 11-year-old boy who had areas of hyperpigmentation since birth that had spread across his body as irregular hyperpigmented macules and papules, and include relevant history in family members. RESULTS: Affected members of his family shared a mutation in the c-KIT gene. All had progressive hyperpigmentation, in some cases accompanied by gastrointestinal stromal tumors and mastocytoma. There have been few reports of familial progressive hyperpigmentation together with systemic manifestations. CONCLUSIONS: Molecular analysis of c-KIT should be considered in the presence of FPH with systemic involvement. PMID- 27981620 TI - Comparison of clinical and radiographic status around immediately loaded versus conventional loaded implants placed in patients with type 2 diabetes: 12- and 24 month follow-up results. AB - There are no studies that have compared the clinical and radiographic status around immediately loaded (IL) and conventional loaded (CL) implants placed in patients with type 2 diabetes mellitus (T2DM). The aim was to compare the clinical and radiographic status around IL and CL implants placed in T2DM patients. One hundred and eight diabetic patients [55 with IL implants (Group 1) and 53 with CL implants (Group 2)] were included in this cross-sectional study. All implants were placed in healed sites in the maxillary and mandibular premolar and molar regions and supported single restorations. All patients underwent full mouth mechanical debridement biannually. Haemoglobin A1c (HbA1c) levels, clinical [bleeding on probing (BOP) and probing depth (PD) >= 4 mm] and radiographic [crestal bone loss (CBL)] peri-implant parameters were measured for both groups at 12- and 24-month follow-up. Group comparisons were performed using the Mann Whitney U-test (P < 0.05). The mean age and duration of T2DM in groups 1 and 2 were 50.6 +/- 2.2 and 51.8 +/- 1.7 years, and 9.2 +/- 2.4 and 8.5 +/- 0.4 years, respectively. At 12- and 24-month follow-up, the mean HbA1c levels in groups 1 and 2 were 5.4% (4.8-5.5%) and 5.1% (4.7-5.4%) and 5.1% (4.7-5.2%) and 4.9% (4.5 5.2%), respectively. At 12- and 24-month follow-up, there was no statistically significant difference in peri-implant BOP, PD and CBL in both groups. It was concluded that clinical and radiographic status is comparable around IL and CL implants placed in patients with T2DM. The contribution of careful case selection, oral hygiene maintenance and glycaemic control is emphasised. PMID- 27981622 TI - Successful Treatment of Vitiligo Associated with Vogt-Koyanagi-Harada Disease. AB - Vogt-Koyanagi-Harada disease (VKH) is a rare multisystem disorder with cutaneous, ophthalmic, neurologic, and auditory manifestations. There is a paucity of published literature regarding the management of cutaneous features in VKH. We report a case of VKH-associated vitiligo responsive to topical corticosteroids and topical calcineurin inhibitors. PMID- 27981623 TI - Central Centrifugal Cicatricial Alopecia in Children: A Case Series and Review of the Literature. AB - BACKGROUND/OBJECTIVES: Central centrifugal cicatricial alopecia (CCCA) is a form of scarring hair loss most commonly seen in middle-aged African and African American women. It is rarely reported in children. The objective of the current study was to document the presence of CCCA in children and to encourage physicians to recognize early signs of CCCA in children of affected adults. METHODS: Six children presented with biopsy-proven CCCA to the Department of Dermatology at Wake Forest Baptist Health and the Nelson R. Mandela School of Medicine from 2012 to 2015. Demographic characteristics, hair styling history, and family history of CCCA were noted. Examination included complete history, skin and scalp examination, photographs of the scalp, and scalp biopsies. RESULTS: Patient ages ranged from 14 to 19 years (mean age at onset 14 years). Five patients reported scalp symptoms such as tender papules, pruritus, and scaling. Four patients reported appreciable hair loss on the vertex of the scalp. One patient had used chemical relaxers and hair dyes in the past. Five patients had a known family history of CCCA. CONCLUSION: Because CCCA is not typically seen or suspected in children, it is likely to be misdiagnosed or underreported. The findings in these cases add weight to the concept that genetic susceptibility rather than hair care practices may play a significant role in causing CCCA. PMID- 27981624 TI - Neonatal Subgaleal Hematoma from Trauma During Vaginal Delivery without Instrument Use. AB - Neonatal subgaleal hematomas (SGHs) are rare but potentially life-threatening complications of vacuum extraction deliveries. We report a rare case of four enlarging SGHs in an 11-day-old boy born without use of instruments during delivery. It is likely that trauma from the provider's fingers caused these SGHs during a normal vaginal delivery. Ultrasound findings confirmed the diagnosis of SGH, distinct from other birth trauma such as cephalohematoma or caput succedaneum. PMID- 27981621 TI - Targeting beta-catenin in hepatocellular cancers induced by coexpression of mutant beta-catenin and K-Ras in mice. AB - : Recently, we have shown that coexpression of hMet and mutant-beta-catenin using sleeping beauty transposon/transposase leads to hepatocellular carcinoma (HCC) in mice that corresponds to around 10% of human HCC. In the current study, we investigate whether Ras activation, which can occur downstream of Met signaling, is sufficient to cause HCC in association with mutant-beta-catenin. We also tested therapeutic efficacy of targeting beta-catenin in an HCC model. We show that mutant-K-Ras (G12D), which leads to Ras activation, cooperates with beta catenin mutants (S33Y, S45Y) to yield HCC in mice. Affymetrix microarray showed > 90% similarity in gene expression in mutant-K-Ras-beta-catenin and Met-beta catenin HCC. K-Ras-beta-catenin tumors showed up-regulation of beta-catenin targets like glutamine synthetase (GS), leukocyte cell-derived chemotaxin 2, Regucalcin, and Cyclin-D1 and of K-Ras effectors, including phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, phosphorylated mammalian target of rapamycin, phosphorylated eukaryotic translation initiation factor 4E, phosphorylated 4E-binding protein 1, and p-S6 ribosomal protein. Inclusion of dominant-negative transcription factor 4 at the time of K-Ras-beta-catenin injection prevented HCC and downstream beta-catenin and Ras signaling. To address whether targeting beta-catenin has any benefit postestablishment of HCC, we administered K-Ras-beta-catenin mice with EnCore lipid nanoparticles (LNP) loaded with a Dicer substrate small interfering RNA targeting catenin beta 1 (CTNNB1; CTNNB1-LNP), scrambled sequence (Scr-LNP), or phosphate-buffered saline for multiple cycles. A significant decrease in tumor burden was evident in the CTNNB1-LNP group versus all controls, which was associated with dramatic decreases in beta-catenin targets and some K-Ras effectors, leading to reduced tumor cell proliferation and viability. Intriguingly, in relatively few mice, non-GS-positive tumors, which were evident as a small subset of overall tumor burden, were not affected by beta-catenin suppression. CONCLUSION: Ras activation downstream of c-Met is sufficient to induce clinically relevant HCC in cooperation with mutant beta-catenin. beta catenin suppression by a clinically relevant modality is effective in treatment of beta-catenin-positive, GS-positive HCCs. (Hepatology 2017;65:1581-1599). PMID- 27981625 TI - Plaque-Like Myofibroblastic Tumor of Infancy: A New Case Report and Literature Review. AB - Plaque-like myofibroblastic tumor of infancy is a rare entity, with only a few reports described in the literature. Herein we present a new case of a nodular plaque-like lesion of the left lower back in an 18-month-old boy. The lesion might initially be thought to be a dermatofibroma, but the overall characteristics suggested the diagnosis of plaque-like myofibroblastic tumor of infancy. We also provide a summary of previous reports in the literature about this exceptional tumor. PMID- 27981626 TI - Regression of Nevi After Candida Injection for the Treatment of Verruca Vulgaris. AB - The most common treatment methods for verruca vulgaris are destructive methods that are often painful and treat individual verruca. Thus immune modulators, including Candida immunotherapy, are used to treat persistent recalcitrant and multiple verrucas simultaneously. Very few side effects are reported with Candida immunotherapy; they include vitiligo and now halo nevi. Physicians need to be aware of and discuss side effects with patients undergoing Candida immunotherapy. PMID- 27981628 TI - Concurrent Pemphigus Foliaceus and Graves' Disease. AB - Pemphigus foliaceus (PF) is an uncommon immunobullous disease in children. Other autoimmune diseases have rarely been reported in children with PF. We report the case of an adolescent girl who presented with concurrent PF and Graves' disease. PMID- 27981627 TI - Characteristics of Pediatric Scrub Typhus Eschar in South Indian Children. AB - BACKGROUND: Knowledge of anatomic location of eschar is useful in diagnosing scrub typhus early in children and to initiate appropriate treatment. METHODS: All children younger than 12 years of age admitted with confirmed diagnosis of scrub typhus over a 17-month period were included and the presence of eschar and other characteristics were recorded and analyzed. RESULTS: Of 107 confirmed patients with scrub typhus, 37 (34.6%) presented with eschar. The site of eschar distribution was the face, 2.7%; neck, 5.4%; axilla, 18.9%; trunk, 10.8%; inguinal, 35.1%; and genitalia and buttocks, 27%. Lymphadenopathy was associated with 67.5% of eschars. The presence of eschar did not correlate with severity, complications, or response to therapy. CONCLUSION: Careful examination for eschar in children presenting with fever, particularly in the skin folds of the groin, genitalia, and axillae, can aid in early diagnosis of scrub typhus. Lymphadenopathy should alert the clinician to the possibility of finding an eschar in the drainage area. PMID- 27981629 TI - Gold(III) Triggered Transformations of 22-Methyl-m-benziporphyrin Involving an Effective Contraction of Benzene to Cyclopentadiene. AB - A structurally prearranged carbaporphyrin, 22-methyl-m-benziporphyrin, provided the perfect macrocyclic platform to form gold(III) 22-methyl-m-benziporphyrin, which facilitates the specific m-benzene ring contraction yielding gold(III) 21 methyl 21-carbaporphyrin with remarkably high yield. PMID- 27981630 TI - Unravelling the Pathway Complexity in Conformationally Flexible N-Centered Triarylamine Trisamides. AB - Two families of C3 -symmetrical triarylamine-trisamides comprising a triphenylamine- or a tri(pyrid-2-yl)amine core are presented. Both families self assemble in apolar solvents via cooperative hydrogen-bonding interactions into helical supramolecular polymers as evidenced by a combination of spectroscopic measurements, and corroborated by DFT calculations. The introduction of a stereocenter in the side chains biases the helical sense of the supramolecular polymers formed. Compared to other C3 -symmetrical compounds, a much richer self assembly landscape is observed. Temperature-dependent spectroscopy measurements highlight the presence of two self-assembled states of opposite handedness. One state is formed at high temperature from a molecularly dissolved solution via a nucleation-elongation mechanism. The second state is formed below room temperature through a sharp transition from the first assembled state. The change in helicity is proposed to be related to a conformational switch of the triarylamine core due to an equilibrium between a 3:0 and a 2:1 conformation. Thus, within a limited temperature window, a small conformational twist results in an assembled state of opposite helicity. PMID- 27981631 TI - Optical detection of different phenolic compounds by means of a novel biosensor based on sol-gel immobilized laccase. AB - A novel sol-gel-based biosensor exploiting the optical absorption properties of sol-gel immobilized laccase has been constructed to increase enzyme specificity toward different phenolic substrates. Laccase from Trametes versicolor has been immobilized in optically transparent sol-gel matrices. Using Fourier transform infrared spectroscopy and data analysis based on a wavelet algorithm, a successful enzyme immobilization has been determined. The changes in the optical absorption spectra of laccase reaction products at 425, 375, and 400 nm have been used to determine hydroquinone, resorcinol, and catechol concentrations, respectively. Owing to the slow response time of the hydroquinone-laccase reaction, our optical biosensor has been tested with resorcinol and catechol. Linear ranges up to 1.4 and 0.2 mM, limit-of-detection (LOD) of 4.5 and 0.6 MUMU, have been evidenced for resorcinol and catechol, respectively. Data for determining the resorcinol concentration have been particularly interesting since no other biosensor device has been reported in the literature. In comparison with other biosensors using laccase from the same native source, our biosensor has been characterized by larger linear ranges, significant sensitivities, and good LODs. To challenge our biosensor with real samples, tap water samples spiked with known amount of catechol and resorcinol have been employed. PMID- 27981632 TI - Proof of Principle: Immobilisation of Robust CuII3 TbIII -Macrocycles on Small, Suitably Pre-functionalised Gold Nanoparticles. AB - In a proof-of-principle study, a soluble macrocyclic single-molecule magnet (SMM) containing a CuII3 TbIII magnetic core was covalently grafted onto small gold nanoparticles pre-functionalised with carboxylate-terminated tethers. A modified microemulsion method allowed production of the small and monodisperse nanoparticles (approximately 3.5 nm in diameter) for the chemisorption of a large amount of intact macrocyclic complexes in the hybrid system. PMID- 27981633 TI - The technological revolution, occupational therapy practice and research: How are we responding? PMID- 27981635 TI - OT AUSTRALIA Position Statement: Occupational Deprivation. PMID- 27981636 TI - A personal digital assistant intervention reduced job coaching support hours without reducing work performance among workers with autism. PMID- 27981637 TI - Occupational therapists are well placed to develop, support and embed carer programmes. PMID- 27981638 TI - Smart-home technologies were found to support some domains of independent living when ageing at home: Perspectives of older adult consumers', families, health professionals and service providers. PMID- 27981640 TI - When Political Imperatives Collide With Policy Objectives. PMID- 27981641 TI - Magnetic resonance fingerprinting using echo-planar imaging: Joint quantification of T1 and T2* relaxation times. AB - PURPOSE: To develop an implementation of the magnetic resonance fingerprinting (MRF) paradigm for quantitative imaging using echo-planar imaging (EPI) for simultaneous assessment of T1 and T2*. METHODS: The proposed MRF method (MRF-EPI) is based on the acquisition of 160 gradient-spoiled EPI images with rapid, parallel-imaging accelerated, Cartesian readout and a measurement time of 10 s per slice. Contrast variation is induced using an initial inversion pulse, and varying the flip angles, echo times, and repetition times throughout the sequence. Joint quantification of T1 and T2* is performed using dictionary matching with integrated B1+ correction. The quantification accuracy of the method was validated in phantom scans and in vivo in 6 healthy subjects. RESULTS: Joint T1 and T2* parameter maps acquired with MRF-EPI in phantoms are in good agreement with reference measurements, showing deviations under 5% and 4% for T1 and T2*, respectively. In vivo baseline images were visually free of artifacts. In vivo relaxation times are in good agreement with gold-standard techniques (deviation T1 : 4 +/- 2%, T2*: 4 +/- 5%). The visual quality was comparable to the in vivo gold standard, despite substantially shortened scan times. CONCLUSION: The proposed MRF-EPI method provides fast and accurate T1 and T2* quantification. This approach offers a rapid supplement to the non-Cartesian MRF portfolio, with potentially increased usability and robustness. Magn Reson Med 78:1724-1733, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27981642 TI - Ginseng Protein Reverses Amyloid Beta Peptide and H2 O2 Cytotoxicity in Neurons, and Ameliorates Cognitive Impairment in AD Rats Induced by a Combination of D Galactose and AlCl3. AB - Ginseng (Panax ginseng C.A. Meyer) is one of the most widely used herbal medicines worldwide. The present study evaluated the neuroprotective effects of ginseng protein (GP) and its possible mechanisms in a cellular and animal model of AD. The results demonstrated that GP (10-100 ug/mL) significantly improved the survival rate of neurons and reduced the cells' apoptosis and the mRNA expression of caspase-3 and Bax/Bcl-2. In addition, GP (0.1 g/kg) significantly shortened the escape latency, prolonged the crossing times and the percentage of residence time; reduced the level of Abeta1-42 and p-tau, the activity of T-NOS and iNOS, and the content of MDA and NO, improved the activity of SOD, the concentration of cAMP and the protein expression of p-PKA/PKA and -CREB/CREB. The results demonstrated that GP significantly inhibited Alzheimer-like pathophysiological changes induced by Abeta25-35 or H2 O2 in cells or those induced by D-gal/ Al in animals. These neuroprotective effects of GP may be associated with the cAMP/PKA/CREB pathway. Also, in combination with our previous studies, these results indicate that the anti-AD mechanism of GP was likely to activate the CREB pathway through multiple channels. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27981644 TI - Structure-Activated Copper Photosensitisers for Photocatalytic Water Reduction. AB - A series of phenanthroline-based ligands have been synthesised and their influence as bidentate nitrogen ligands in heteroleptic [Cu(P^P)(N^N)]+ photosensitisers in light-driven water reduction has been studied. In this noble metal-free Cu-Fe-based photocatalytic water reduction system, the structural effects of the nitrogen ligands have been explored, including the steric and electronic effects of substituents at the 2,9- and 4,7-positions of phenanthroline. Ligands were prepared that led to increased hydrogen generation, with turnover numbers (TONCu ) of up to 1388 being observed. All the new complexes were electrochemically and photophysically characterised. We demonstrate for the first time that the presence of fluorine in nitrogen ligands increases the efficacy of copper complexes in photocatalytic hydrogen production. PMID- 27981645 TI - Wood's lamp image of porokeratosis. PMID- 27981643 TI - UGT1A1 (TA)n genotype is not the major risk factor of cholelithiasis in sickle cell disease children. AB - OBJECTIVES: Because of the increased hemolytic rate, a significant proportion of patients with sickle cell disease (SCD) are prone to develop cholelithiasis. The present study investigated the role of several genetic factors (UGT1A1 promoter (TA)n repeat polymorphism, alpha-globin status), hematological parameters, clinical severity, and hydroxyurea (HU) therapy on the occurrence of cholelithiasis in SCD. METHODS: One hundred and fifty-eight children (2-18 yr old) regularly followed at the University Hospital of Lyon (France) were included. A multivariate Cox model was used to test the associations between cholelithiasis and the different parameters analyzed. RESULTS: We confirmed that alpha-thalassemia and low basal reticulocyte (RET) count were independent protective factors for cholelithiasis while 7/7, 8/8 and 7/8 UGT1A1 (TA)n genotypes were independent predisposing factors for this complication. We also showed for the first time that HU treatment decreased the risk for cholelithiasis while frequent vaso-occlusive crises and acute chest syndrome events increased that risk. CONCLUSIONS: Our findings demonstrate that UGT1A1 (TA)n polymorphism is not the only factor triggering gallstone formation in SCD. Cholelithiasis is also modulated by RET count, the number of deleted alpha-genes, HU therapy and the frequency of vaso-occlusive events. PMID- 27981647 TI - Synthesis, Crystal Structure, and Properties of Bi3 TeBO9 or Bi3 (TeO6 )(BO3 ): A Non-Centrosymmetric Borate-Tellurate(VI) of Bismuth. AB - Pale-yellow single crystals of the new borate tellurate(VI) Bi3 TeBO9 were obtained by reaction of stoichiometric amounts of Bi2 O3 , B2 O3 , and Te(OH)6 at 780 degrees C. The non-centrosymmetric crystal structure (P63 , Z=2, a=8.7454(16), c=5.8911(11) A, 738 refl., 43 param, R1=0.037, wR2=0.093) contains isolated trigonal-planar BO3 units and nearly undistorted TeO6 octahedra. The Bi3+ cations are located in between in octahedral voids. The BiO6 octahedra are significantly distorted to a [3+3] pattern (2.25/2.50 A) due to the ns2 configuration. According to the structural features, the formula can be written as Bi3 (TeO6 )(BO3 ). Alternatively, the structure can also be described as hcp of oxygen with TeVI and BiIII in octahedral voids and BIII in trigonal- planar voids. The vibrational spectra show the typical features of BO3 and TeO6 units with a significant 10 B/11 B isotopic splitting of the IR-active B-O valence mode (1248 and 1282 cm-1 ). The UV/Vis spectrum shows an optical band edge with an onset around 480 nm (2.6 eV). MAS-NMR spectra of 11 B show an anisotropic signal with a quadrupole coupling constant of CQ =2.55 MHz. and a very small deviation from rotational symmetry (eta=0.2). The isotropic chemical shift is 20.1 ppm. The second harmonic generation (SHG) test was positive with an activity comparable to potassium dihydrogen phosphate (KDP). Bi3 TeBO9 decomposes in air at 825 degrees C to Bi2 TeO5 . PMID- 27981646 TI - Characterisation of Kiss1r (Gpr54)-Expressing Neurones in the Arcuate Nucleus of the Female Rat Hypothalamus. AB - Kisspeptin is essential in reproduction and acts by stimulating neurones expressing gonadotrophin-releasing hormone (GnRH). Recent studies suggest that kisspeptin has multiple roles in the modulation of neuronal circuits in systems outside the hypothalamic-pituitary-gonadal axis. Our recent research using in situ hybridisation (ISH) clarified the histological distribution of Kiss1r (Gpr54)-expressing neurones in the rat brain that were presumed to be putative targets of kisspeptin. The arcuate nucleus (ARN) of the hypothalamus is one of the brain regions in which Kiss1r expression in non-GnRH neurones is prominent. However, the characteristics of Kiss1r-expressing neurones in the ARN remain unclear. The present study aimed to determine the neurochemical characteristics of Kiss1r-expressing neurones in the ARN using ISH and immunofluorescence. We revealed that the majority (approximately 63%) of Kiss1r-expressing neurones in the ARN were pro-opiomelanocortin (POMC) neurones, which have an anorexic effect in mammals. Additionally, a few Kiss1r-expressing neurones in the dorsal ARN are tuberoinfundibular dopamine (TIDA) neurones, which control milk production by inhibiting prolactin secretion from the anterior pituitary. TIDA neurones showed a relatively weak Kiss1r ISH signal compared to POMC neurones, as well as low co expression of Kiss1r (approximately 15%). We also examined the expression of Kiss1r in neuropeptide Y and kisspeptin neurones, which are reported to arise from POMC-expressing progenitor cells during development. However, the vast majority of neuropeptide Y and kisspeptin neurones in the ARN did not express Kiss1r. These results suggest that kisspeptin may directly regulate energy homeostasis and milk production by modulating the activity of POMC and TIDA neurones, respectively. Our results provide an insight into the wide variety of roles that kisspeptin plays in homeostatic and neuroendocrine functions. PMID- 27981648 TI - Elevated skin and core temperatures both contribute to reductions in tolerance to a simulated haemorrhagic challenge. AB - NEW FINDINGS: What is the central question of this study? Combined increases in skin and core temperatures reduce tolerance to a simulated haemorrhagic challenge. The aim of this study was to examine the separate and combined influences of increased skin and core temperatures upon tolerance to a simulated haemorrhagic challenge. What is the main finding and its importance? Skin and core temperatures increase during many occupational settings, including military procedures, in hot environments. The study findings demonstrate that both increased skin temperature and increased core temperature can impair tolerance to a simulated haemorrhagic challenge; therefore, a soldier's tolerance to haemorrhagic injury is likely to be impaired during any military activity that results in increased skin and/or core temperatures. Tolerance to a simulated haemorrhagic insult, such as lower-body negative pressure (LBNP), is profoundly reduced when accompanied by whole-body heat stress. The aim of this study was to investigate the separate and combined influence of elevated skin (Tskin ) and core temperatures (Tcore ) on LBNP tolerance. We hypothesized that elevations in Tskin as well as Tcore would both contribute to reductions in LBNP tolerance and that the reduction in LBNP tolerance would be greatest when both Tskin and Tcore were elevated. Nine participants underwent progressive LBNP to presyncope on four occasions, as follows: (i) control, with neutral Tskin (34.3 +/- 0.5 degrees C) and Tcore (36.8 +/- 0.2 degrees C); (ii) primarily skin hyperthermia, with high Tskin (37.6 +/- 0.2 degrees C) and neutral Tcore (37.1 +/- 0.2 degrees C); (iii) primarily core hyperthermia, with neutral Tskin (35.0 +/- 0.5 degrees C) and high Tcore (38.3 +/- 0.2 degrees C); and (iv) combined skin and core hyperthermia, with high Tskin (38.8 +/- 0.6 degrees C) and high Tcore (38.1 +/- 0.2 degrees C). The LBNP tolerance was quantified via the cumulative stress index (in millimetres of mercury * minutes). The LBNP tolerance was reduced during the skin hyperthermia (569 +/- 151 mmHg min) and core hyperthermia trials (563 +/- 194 mmHg min) relative to control conditions (1010 +/- 246 mmHg min; both P < 0.05). However, LBNP tolerance did not differ between skin hyperthermia and core hyperthermia trials (P = 0.92). The lowest LBNP tolerance was observed during combined skin and core hyperthermia (257 +/- 106 mmHg min; P < 0.05 relative to all other trials). These data indicate that elevated skin temperature, as well as elevated core temperature, can both contribute to reductions in LBNP tolerance in heat-stressed individuals. However, heat stress-induced reductions in LBNP tolerance are greatest in conditions when both skin and core temperatures are elevated. PMID- 27981649 TI - Characterisation of electrospun gelatine nanofibres encapsulated with Moringa oleifera bioactive extract. AB - BACKGROUND: Drumstick (Moringa oleifera) leaves have been used as a folk herbal medicine across many cultures since ancient times. This is most probably due to presence of phytochemicals possessing antioxidant properties, which could retard oxidative stress, and their degenerative effect. The current study deals with nanoencapsulation of Moringa oleifera (MO) leaf ethanolic extract within fish sourced gelatine matrix using electrospinning technique. RESULTS: The total phenolic and flavonoid content, radical scavenging (IC50 ) and metal reducing properties were 67.0 +/- 2.5 mg GAE g-1 sample 32.0 +/- 0.5 mg QE g-1 extract, 0.08 +/- 0.01 mg mL-1 and 510 +/- 10 umol eq Fe(II) g-1 extract, respectively. Morphological and spectroscopic analysis of the fibre mats confirmed successful nanoencapsulation of MO extract within defect free nanofibres via electrospinning process. The percentage encapsulation efficiency (EE) was between 80% and 85%. Furthermore, thermal stability of encapsulated fibres, especially at 3% and 5% of core loading content, was significantly improved. Toxicological analysis revealed that the extract in its original and encapsulated form was safe for oral consumption. CONCLUSION: Overall, the present study showed the potential of ambient temperature electrospinning process as a safe nanoencapsulation method, where MO extract retained its antioxidative capacities. (c) 2016 Society of Chemical Industry. PMID- 27981650 TI - Rosbin, a synthetic small molecule, induces A549 cells apoptosis through a ROS mediated pathway. AB - Rosbin (Thieno [2, 3-c] piperidine-3-carboxamide-2-[(3-methoxy-naphtha-lene-2 carbonyl)-amino]-6-(benzyl)-, hydrochloride), a synthetic piperidinothieno derivative compound obtained from chemical genetics screenings, significantly suppresses the viability of non-small cell lung cancer A549 cells with an IC50 of 2.05 +/- 0.31 uM. It only decreases growth of non-tumour MRC-5 cells at the doses higher than 10 uM. Rosbin induces apoptosis in a dose-dependent manner by reducing the mitochondrial membrane potential (MMP) and increasing activities of caspases-3/7 and caspase-9 in A549 cells, without affecting the activity of caspase-8. Further studies showed that reactive oxygen species (ROS) induced apoptosis of A549 in the presence of rosbin as apoptosis was inhibited by N acetyl cysteine (NAC). These results suggest that rosbin is a novel apoptosis inducer, and ROS played a significant role in the A549 apoptosis induced by rosbin. PMID- 27981652 TI - The qualitative quality conversation. PMID- 27981653 TI - Social network analysis in medical education: a methodology in search of a theory. PMID- 27981654 TI - Knowing how we know: an epistemological rationale for the medical humanities. AB - CONTEXT: Although their inclusion in medical curricula internationally is increasing, the medical humanities still face challenges to their role and place in the curriculum. Justifications supporting the inclusion of humanities content, methods and perspectives in medical curricula have generally been proposed along instrumental, intrinsic and critical lines. However, recent literature in the field has turned to 'ways of knowing' as representing an alternative, essentially epistemological, perspective on the matter. This involves the claim that the medical humanities align with and promote characteristic ways of understanding and practising medicine, which are not adequately represented in traditional disciplinary frameworks. DISCUSSION: Such epistemological arguments aim to move beyond generic claims of medicine as both an 'art' and a 'science' to explore the way in which the humanities support the ultimate objectives of a medical education, particularly in relation to claims about requisite knowledge and typical reasoning. Not only can this help focus attempts to identify and document relevant learning or clinical outcomes, but it can potentially uncover evidence from education outcomes research which may not have been the focus of previous inquiry in the medical humanities and which may in fact be associated, at least in part, with curricular activities formally associated with humanities disciplines. CONCLUSIONS: An epistemological view of the humanities in medical education offers a significant new way of conceptualising and communicating the potential role of the humanities in medical training. If clinical practice can be characterised as rational but interpretive, partly predictable yet fundamentally uncertain, and logical but also intuitive, it follows that educational training should facilitate such ways of knowing and thinking. An epistemological perspective enables the argument that the medical humanities are valuable not because they are more 'humane', but because they help constitute what it means to think like a doctor. PMID- 27981651 TI - MR spectroscopy of breast cancer for assessing early treatment response: Results from the ACRIN 6657 MRS trial. AB - PURPOSE: To estimate the accuracy of predicting response to neoadjuvant chemotherapy (NACT) in patients with locally advanced breast cancer using MR spectroscopy (MRS) measurements made very early in treatment. MATERIALS AND METHODS: This prospective Health Insurance Portability and Accountability Act (HIPAA)-compliant protocol was approved by the American College of Radiology and local-site institutional review boards. One hundred nineteen women with invasive breast cancer of >=3 cm undergoing NACT were enrolled between September 2007 and April 2010. MRS measurements of the concentration of choline-containing compounds ([tCho]) were performed before the first chemotherapy regimen (time point 1, TP1) and 20-96 h after the first cycle of treatment (TP2). The change in [tCho] was assessed for its ability to predict pathologic complete response (pCR) and radiologic response using the area under the receiver operating characteristic curve (AUC) and logistic regression models. RESULTS: Of the 119 subjects enrolled, only 29 cases (24%) with eight pCRs provided usable data for the primary analysis. Technical challenges in acquiring quantitative MRS data in a multi-site trial setting limited the capture of usable data. In this limited data set, the decrease in tCho from TP1 to TP2 had poor ability to predict either pCR (AUC = 0.53, 95% confidence interval [CI]: 0.27-0.79) or radiologic response (AUC = 0.51, 95% CI: 0.27-0.75). CONCLUSION: The technical difficulty of acquiring quantitative MRS data in a multi-site clinical trial setting led to a low yield of analyzable data, which was insufficient to accurately measure the ability of early MRS measurements to predict response to NACT. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:290-302. PMID- 27981655 TI - The interplay of text, meaning and practice: methodological considerations on discourse analysis in medical education. AB - CONTEXT: The study of discourses (i.e. verbal interactions or written accounts) is increasingly used in social sciences to gain insight into issues connected to discourse, such as meanings, behaviours and actions. This paper situates discourse analysis in medical education, based on a framework developed in organisational discourse analysis and widely deployed in other social science disciplines. OBJECTIVES: This paper aims to examine the constructs of 'discourse' and 'discourse analysis', and how various understandings of discourse and discourse analysis may play out in empirical and analytical settings, with a particular focus on the field of medical education. METHODS: The study is based on a literature analysis of discourse analysis approaches published in Medical Education. RESULTS: Findings suggest that empirical studies through discourse analysis can be heuristically understood in terms of the links between text, practices and meaning. CONCLUSIONS: Discourse analysis provides a more strongly supported argument when it is possible to defend claims on three levels: practice, using observational data; meaning, using ethnographic data, and text, using conversational and textual data. PMID- 27981656 TI - The challenges of studying visual expertise in medical image diagnosis. AB - CONTEXT: Visual expertise is the superior visual skill shown when executing domain-specific visual tasks. Understanding visual expertise is important in order to understand how the interpretation of medical images may be best learned and taught. In the context of this article, we focus on the visual skill of medical image diagnosis and, more specifically, on the methodological set-ups routinely used in visual expertise research. METHODS: We offer a critique of commonly used methods and propose three challenges for future research to open up new avenues for studying characteristics of visual expertise in medical image diagnosis. The first challenge addresses theory development. Novel prospects in modelling visual expertise can emerge when we reflect on cognitive and socio cultural epistemologies in visual expertise research, when we engage in statistical validations of existing theoretical assumptions and when we include social and socio-cultural processes in expertise development. The second challenge addresses the recording and analysis of longitudinal data. If we assume that the development of expertise is a long-term phenomenon, then it follows that future research can engage in advanced statistical modelling of longitudinal expertise data that extends the routine use of cross-sectional material through, for example, animations and dynamic visualisations of developmental data. The third challenge addresses the combination of methods. Alternatives to current practices can integrate qualitative and quantitative approaches in mixed-method designs, embrace relevant yet underused data sources and understand the need for multidisciplinary research teams. CONCLUSION: Embracing alternative epistemological and methodological approaches for studying visual expertise can lead to a more balanced and robust future for understanding superior visual skills in medical image diagnosis as well as other medical fields. PMID- 27981657 TI - When I say ... autoethnography. PMID- 27981659 TI - What's in a name? Definitional clarity and its unintended consequences. PMID- 27981658 TI - Shedding the cobra effect: problematising thematic emergence, triangulation, saturation and member checking. AB - CONTEXT: Qualitative research is widely accepted as a legitimate approach to inquiry in health professions education (HPE). To secure this status, qualitative researchers have developed a variety of strategies (e.g. reliance on post positivist qualitative methodologies, use of different rhetorical techniques, etc.) to facilitate the acceptance of their research methodologies and methods by the HPE community. Although these strategies have supported the acceptance of qualitative research in HPE, they have also brought about some unintended consequences. One of these consequences is that some HPE scholars have begun to use terms in qualitative publications without critically reflecting on: (i) their ontological and epistemological roots; (ii) their definitions, or (iii) their implications. OBJECTIVES: In this paper, we share our critical reflections on four qualitative terms popularly used in the HPE literature: thematic emergence; triangulation; saturation, and member checking. METHODS: We discuss the methodological origins of these terms and the applications supported by these origins. We reflect critically on how these four terms became expected of qualitative research in HPE, and we reconsider their meanings and use by drawing on the broader qualitative methodology literature. CONCLUSIONS: Through this examination, we hope to encourage qualitative scholars in HPE to avoid using qualitative terms uncritically and non-reflexively. PMID- 27981660 TI - Reporting quality and risk of bias in randomised trials in health professions education. AB - CONTEXT: Complete reporting of research is essential to enable consumers to accurately appraise, interpret and apply findings. Quality appraisal checklists are giving way to tools that judge the risk for bias. OBJECTIVES: We sought to determine the prevalence of these complementary aspects of research reports (completeness of reporting and perceived risk for bias) of randomised studies in health professions education. METHODS: We searched bibliographic databases for randomised studies of health professions education. We appraised two cohorts representing different time periods (2008-2010 and 2014, respectively) and worked in duplicate to apply the CONSORT guidelines and Cochrane Risk of Bias tool. We explored differences between time periods using independent-samples t-tests or the chi-squared test, as appropriate. RESULTS: We systematically identified 180 randomised studies (2008-2010, n = 150; 2014, n = 30). Frequencies of reporting of CONSORT elements within full-text reports were highly variable and most elements were reported in fewer than 50% of studies. We found a statistically significant difference in the CONSORT reporting index (maximum score: 500) between the 2008-2010 (mean +/- standard deviation [SD]: 242.7 +/- 55.6) and 2014 (mean +/- SD: 311.6 +/- 53.2) cohorts (p < 0.001). High or unclear risk for bias was most common for allocation concealment (157, 87%) and blinding of participants (147, 82%), personnel (152, 84%) and outcome assessors (112, 62%). Most risk for bias elements were judged to be unclear (range: 51-84%). Risk for bias elements significantly improved over time for blinding of participants (p = 0.007), incomplete data (p < 0.001) and the presence of other sources of bias (p < 0.001). CONCLUSIONS: Reports of randomised studies in health professions education frequently omit elements recommended by the CONSORT statement. Most reports were assessed as having a high or unclear risk for bias. Greater attention to how studies are reported at study outset and in manuscript preparation could improve levels of complete transparent reporting. PMID- 27981661 TI - What use is qualitative research? PMID- 27981662 TI - Assessing the structure of the CAST (Cannabis Abuse Screening Test) in 13 European countries using multigroup analyses. AB - Our aims are to describe and explain the structure of the Cannabis Abuse Screening Test (CAST) across countries. Standard statistical analyses fail to describe and explain several variables simultaneously while taking account of the group structure of individuals. The 2011 European School Survey Project on Alcohol and other Drugs (ESPAD): 5204 last-year cannabis users aged 15-16 from 13 European countries. Multigroup principal component analysis (mgPCA) and multigroup partial least squares (mgPLS). MgPCA shows that the CAST has a two dimensional structure (frequency of use/problems and non-recreational use/dependency symptoms). All the countries present a good concordance with the common structure, except Kosovo, Lichtenstein and Romania. MgPLS shows that three explanative variables (in a total of eight) are mainly related with the CAST (the frequencies of cannabis use in the last 12 months and in the last 30 days and the age at first cannabis use) while Kosovo, Lichtenstein and Romania also present specificities. The CAST structure appears stable in the 13 countries except for Kosovo, Lichtenstein and Romania that also show specific relationships between the CAST variables and their determinants. PMID- 27981663 TI - Determination of Polyphenolic Phytochemicals using Highly Deshielded -OH 1 H-NMR Signals. PMID- 27981664 TI - Compressed sensing for body MRI. AB - : The introduction of compressed sensing for increasing imaging speed in magnetic resonance imaging (MRI) has raised significant interest among researchers and clinicians, and has initiated a large body of research across multiple clinical applications over the last decade. Compressed sensing aims to reconstruct unaliased images from fewer measurements than are traditionally required in MRI by exploiting image compressibility or sparsity. Moreover, appropriate combinations of compressed sensing with previously introduced fast imaging approaches, such as parallel imaging, have demonstrated further improved performance. The advent of compressed sensing marks the prelude to a new era of rapid MRI, where the focus of data acquisition has changed from sampling based on the nominal number of voxels and/or frames to sampling based on the desired information content. This article presents a brief overview of the application of compressed sensing techniques in body MRI, where imaging speed is crucial due to the presence of respiratory motion along with stringent constraints on spatial and temporal resolution. The first section provides an overview of the basic compressed sensing methodology, including the notion of sparsity, incoherence, and nonlinear reconstruction. The second section reviews state-of-the-art compressed sensing techniques that have been demonstrated for various clinical body MRI applications. In the final section, the article discusses current challenges and future opportunities. LEVEL OF EVIDENCE: 5 J. Magn. Reson. Imaging 2017;45:966-987. PMID- 27981665 TI - Hip MRI: Prevalence of articular cartilage defects and labral tears in asymptomatic volunteers. A comparison with a matched population of patients with femoroacetabular impingement. AB - PURPOSE: To prospectively compare defects of the articular cartilage and labrum in asymptomatic volunteers and in patients with femoroacetabular impingement (FAI) matched for age and gender. MATERIALS AND METHODS: This cross-sectional study was institutional review board approved. A total of 63 asymptomatic volunteers and 63 patients with symptomatic FAI between 20 and 50 years underwent 1.5 Tesla MRI (coronal T1-weighted, coronal intermediate-weighted fat saturated, transverse oblique true fast imaging with steady-state precession [FISP], sagittal dual echo steady state [DESS] sequence). Two radiologists independently assessed defects of the cartilage and labrum at six positions. Statistics included Mann-Whitney U-test and Spearman's rho. RESULTS: A defect of the articular cartilage and/or labrum was present on average in 57% of asymptomatic volunteers, compared with 80% of symptomatic patients (P <= 0.028). A total of 14% of volunteers had acetabular cartilage defects, and 6% had femoral cartilage defects, compared with 47% and 30% in symptomatic patients (P <= 0.001 and P <= 0.003), respectively. Labrum defects were seen in 44% of volunteers versus 61% of patients (P <= 0.12). Both cartilage and labral defects were more commonly encountered in male volunteers than in female volunteers, with the largest difference seen for the acetabular cartilage (P <= 0.02). In all groups, the majority of cartilage and labrum defects were encountered in the anterosuperior, superior, and posterosuperior position. CONCLUSION: A substantial number of asymptomatic volunteers had labral tears, defects of the acetabular cartilage, and to a lesser degree, defects of the femoral cartilage; our data demonstrate that not all cartilage and labral defects of the hip joint are symptomatic and that a similar predilection for location of defects is found in volunteers and FAI patients. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. MAGN. RESON. IMAGING 2017;46:440-451. PMID- 27981666 TI - Skin-derived precursors possess the ability of differentiation into the epidermal progeny and accelerate burn wound healing. AB - Skin-derived precursors (SKPs) are remnants of the embryonic neural crest stem cells that reside in the dermis until adulthood. Although they possess a wide range of differentiation potentials, their differentiation into keratinocyte-like cells and their roles in skin wound healing are obscure. The present study aimed to investigate the differentiation of SKPs into keratinocyte-like cells and evaluate their role in healing of third degree burn wounds. To this aim, SKPs were differentiated into keratinocyte-like cells on tissue culture plate and collagen-chitosan scaffold prepared by freeze-drying. Their differentiation capability was detected by real-time RT-PCR and immunofluorescence. Thereafter, they were cultured on scaffold and implanted in a rat model of burn wound. Histopathological and immunohistochemical analyses were employed to examine the reconstituted skin. The research findings revealed that SKPs were able to differentiate along the epidermal lineage and this ability can be enhanced on a suitable scaffold. Additionally, the results indicated that SKPs apparently promoted wound healing process and accelerate its transition from proliferating stage to maturational phase, especially if they were differentiated into keratinocyte-like cells. Regarding the results, it is concluded that SKPs are able to differentiate into keratinocyte-like cells, particularly when they are cultured on collagen-chitosan scaffold. Moreover, they can regenerate epidermal and dermal layers including thick collagen bundles, possibly through differentiation into keratinocyte-like cells. PMID- 27981668 TI - Activation of protease-activated receptor 2 mediates cutaneous vasodilatation but not sweating: roles of nitric oxide synthase and cyclo-oxygenase. AB - NEW FINDINGS: What is the central question of this study? Protease-activated receptor 2 (PAR2) is located in the endothelial cells of skin vessels and eccrine sweat glands. However, a functional role of PAR2 in the control of cutaneous blood flow and sweating remains to be assessed in humans in vivo. What is the main finding and its importance? Our results demonstrate that in normothermic resting humans in vivo, activation of PAR2 elicits cutaneous vasodilatation partly through nitric oxide synthase-dependent mechanisms, but does not mediate sweating. These results provide important new insights into the physiological significance of PAR2 in human skin. Protease-activated receptor 2 (PAR2) is present in human skin, including keratinocytes, endothelial cells of skin microvessels and eccrine sweat glands. However, whether PAR2 contributes functionally to the regulation of cutaneous blood flow and sweating remains entirely unclear in humans in vivo. We hypothesized that activation of PAR2 directly stimulates cutaneous vasodilatation and sweating via actions of nitric oxide synthase (NOS) and cyclo-oxygenase (COX). In 12 physically active young men (29 +/- 5 years old), cutaneous vascular conductance (CVC) and sweat rate were measured at four intradermal microdialysis forearm skin sites that were treated with the following: (i) lactated Ringer's solution (control); (ii) 10 mm NG nitro-l-arginine (NOS inhibitor); (iii) 10 mm ketorolac (COX inhibitor); or (iv) a combination of both inhibitors. At all sites, a PAR2 agonist (SLIGKV-NH2 ) was co-administered in a dose-dependent fashion (0.06, 0.18, 0.55, 1.66 and 5 mm, each for 25 min). The highest dose of SLIGKV-NH2 (5 mm) increased CVC from baseline at the control site (P <= 0.05). This increase in CVC associated with PAR2 activation was attenuated by NOS inhibition regardless of the presence or absence of simultaneous COX inhibition (both P <= 0.05). However, COX inhibition alone did not affect the PAR2-mediated increase in CVC (P > 0.05). No increase in sweat rate was measured at any administered dose of SLIGKV-NH2 (all P > 0.05). We show that in normothermic resting humans in vivo, PAR2 activation does not increase sweat rate, whereas it does modulate cutaneous vasodilatation through NOS-dependent mechanisms. PMID- 27981667 TI - Assessment of pathological complete response to preoperative chemoradiotherapy by means of multiple mathematical models of diffusion-weighted MRI in locally advanced rectal cancer: A prospective single-center study. AB - PURPOSE: To assess stretched-exponential, mono-exponential and intravoxel incoherent motion (IVIM) models of diffusion-weighted MRI(DWI) in predicting pathological complete response (pCR) to neoadjuvant chemoradiotherapy (CRT) in rectal cancer patients. MATERIALS AND METHODS: This prospective study recruited 98 consecutive patients with locally advanced rectal cancer who underwent 3 Tesla MR examination before, during and after CRT. The apparent diffusion coefficient (ADC), IVIM-derived parameters (D, f, and D*), and stretched-exponential model derived parameters (DDC and alpha) were measured. The parameters and their corresponding changes during and after CRT were compared between pCR and non-pCR. Receiver-operating characteristic curve analysis was performed to evaluate the diagnostic performance. Coefficient of variations and intraclass correlation coefficient were calculated to assess reliability and agreement. RESULTS: Nineteen patients achieved pCR while 79 did not. The pCR group had higher ADC and alpha (ADC2 and alpha2 ), and their changes (DeltaADC2 , and Deltaalpha2 ) at the endpoint than non-pCR group. alpha2 and ADC2 yielded similar AUCs (P = 0.339), Deltaalpha2 and DeltaADC2 yielded similar AUCs (P = 0.263) ADC and alpha presented substantial agreement, and alpha presented the minimum CV (5.0-7.0%). CONCLUSION: ADC and alpha were useful for assessing pCR after CRT. alpha might be more useful because it demonstrated better diagnostic performance than IVIM derived parameters and better reliability than ADC. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:175-183. PMID- 27981670 TI - Understanding the alcohol harm paradox: an analysis of sex- and condition specific hospital admissions by socio-economic group for alcohol-associated conditions in England. AB - BACKGROUND AND AIMS: In many countries, conflicting gradients in alcohol consumption and alcohol-associated mortality have been observed. To understand this 'alcohol harm paradox' we analysed the socio-economic gradient in alcohol associated hospital admissions to test whether it was greater in conditions which were: (1) chronic (associated with long-term drinking) and partially alcohol attributable, (2) chronic and wholly alcohol-attributable, (3) acute (associated with intoxication) and partially alcohol-attributable and (4) acute and wholly alcohol-attributable. Our aim was to clarify how (1) drinking patterns (e.g. intoxication linked to acute admissions or dependence linked to chronic conditions) and (2) non-alcohol causes (e.g. smoking and poor diet which are risks for partially alcohol-attributable conditions) contribute to the paradox. DESIGN: Regression analysis testing the modifying effects of condition-group (1-4 above) and sex on the relationship between area-based deprivation and admissions. SETTING: England, April 2010-March 2013. PARTICIPANTS: A total of 9 239 629 English hospital admissions where a primary or secondary cause was one of 36 alcohol-associated conditions. MEASUREMENTS: Admissions by condition and deciles of Index of Multiple Deprivation (IMD). Socio-economic gradient measured as the relative index of inequality (RII, the slope of a linear regression of IMD on admissions adjusted for overall admission rate). Conditions were categorized by ICD-10 code. FINDINGS: A socio-economic gradient in hospitalizations was seen for all conditions, except partially attributable chronic conditions. The gradient was significantly steeper for conditions which were wholly attributable to alcohol and for acute conditions than for conditions partially alcohol attributable and for chronic conditions. Gradients were steeper for men than for women in cases of wholly alcohol attributable conditions. CONCLUSIONS: There is a socio-economic gradient in English hospital admission for most alcohol-associated conditions. The greatest inequalities are in conditions associated with alcohol dependence, such as liver disease and mental and behavioural conditions, and in acute conditions, such as alcohol poisoning and assault. Socio-economic differences in harmful drinking patterns (dependence and intoxication) may contribute to the 'alcohol harm paradox'. PMID- 27981669 TI - Alcohol use disorder and divorce: evidence for a genetic correlation in a population-based Swedish sample. AB - AIMS: We tested the association between alcohol use disorder (AUD) and divorce; estimated the genetic and environmental influences on divorce; estimated how much genetic and environmental influences accounted for covariance between AUD and divorce; and estimated latent genetic and environmental correlations between AUD and divorce. We tested sex differences in these effects. DESIGN: We identified twin and sibling pairs with AUD and divorce information in Swedish national registers. We described the association between AUD and divorce using tetrachorics and used twin and sibling models to estimate genetic and environmental influences on divorce, on the covariance between AUD and divorce and the latent genetic and environmental correlations between AUD and divorce. SETTING: Sweden. PARTICIPANTS: A total of 670 836 individuals (53% male) born 1940-1965. MEASUREMENTS: Life-time measures of AUD and divorce. FINDINGS: AUD and divorce were related strongly (males: rtet = +0.44, 95% CI = 0.43, 0.45; females rtet = +0.37, 95% CI = 0.36, 0.38). Genetic factors accounted for a modest proportion of the variance in divorce (males: 21.3%, 95% CI = 7.6, 28.5; females: 31.0%, 95% CI = 18.8, 37.1). Genetic factors accounted for most of the covariance between AUD and divorce (males: 52.0%, 95% CI = 48.8, 67.9; females: 53.74%, 95% CI = 17.6, 54.5), followed by non-shared environmental factors (males: 45.0%, 95% CI = 37.5, 54.9; females: 41.6%, 95% CI = 40.3, 60.2). Shared environmental factors accounted for a negligible proportion of the covariance (males: 3.0%, 95% CI = -3.0, 13.5; females: 4.75%, 95% CI = 0.0, 6.6). The AUD-divorce genetic correlations were high (males: rA = +0.76, 95% CI = 0.53, 0.90; females +0.52, 95% CI = 0.24, 0.67). The non-shared environmental correlations were modest (males: rE = +0.32, 95% CI = 0.31, 0.40; females: +0.27, 95% CI = 0.27, 0.36). CONCLUSIONS: Divorce and alcohol use disorder are correlated strongly in the Swedish population, and the heritability of divorce is consistent with previous studies. Covariation between AUD and divorce results from overlapping genetic and non-shared environmental factors. Latent genetic and non-shared environmental correlations for alcohol use disorder and divorce are high and moderate. PMID- 27981671 TI - Distinct white matter injury associated with medial temporal lobe atrophy in Alzheimer's versus semantic dementia. AB - This study aims at further understanding the distinct vulnerability of brain networks in Alzheimer's disease (AD) versus semantic dementia (SD) investigating the white matter injury associated with medial temporal lobe (MTL) atrophy in both conditions. Twenty-six AD patients, twenty-one SD patients, and thirty-nine controls underwent a high-resolution T1-MRI scan allowing to obtain maps of grey matter volume and white matter density. A statistical conjunction approach was used to identify MTL regions showing grey matter atrophy in both patient groups. The relationship between this common grey matter atrophy and white matter density maps was then assessed within each patient group. Patterns of grey matter atrophy were distinct in AD and SD but included a common region in the MTL, encompassing the hippocampus and amygdala. This common atrophy was associated with alterations in different white matter areas in AD versus SD, mainly including the cingulum and corpus callosum in AD, while restricted to the temporal lobe - essentially the uncinate and inferior longitudinal fasciculi - in SD. Complementary analyses revealed that these relationships remained significant when controlling for global atrophy or disease severity. Overall, this study provides the first evidence that atrophy of the same MTL region is related to damage in distinct white matter fibers in AD and SD. These different patterns emphasize the vulnerability of distinct brain networks related to the MTL in these two disorders, which might underlie the discrepancy in their symptoms. These results further suggest differences between AD and SD in the neuropathological processes occurring in the MTL. Hum Brain Mapp 38:1791-1800, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 27981672 TI - Performance of the neoBona test: a new paired-end massively parallel shotgun sequencing approach for cell-free DNA-based aneuploidy screening. AB - OBJECTIVE: To assess the performance of screening for fetal trisomies 21, 18 and 13 by cell-free (cf) DNA analysis of maternal blood using a new method based on paired-end massively parallel shotgun sequencing (MPSS). METHODS: This was a blinded study of plasma samples (1mL) obtained from 1000 women undergoing screening for fetal trisomies 21, 18 and 13 at 11-13 weeks' gestation. The study included 50 cases with confirmed fetal trisomy 21, 30 with trisomy 18, 10 with trisomy 13 and 910 unaffected pregnancies. Paired-end MPSS with the neoBona(r) test allowed simultaneous assessment of fetal fraction, cfDNA fragment size distribution and chromosome counting, which were integrated into a new analysis algorithm to calculate trisomy likelihood ratios (t-score) for each chromosome of interest. Each sample was classified as trisomic or unaffected using chromosome specific cut-offs set at t-score values of 1.5 for trisomy 21 and 3.0 for trisomies 18 and 13. RESULTS: Valid results were provided for 988 (98.8%) cases; 12 (1.2%) samples, from nine euploid and three trisomy 21 pregnancies, did not pass quality-control criteria and were excluded from further analysis. All 47 cases of trisomy 21, all 10 of trisomy 13, 29 of 30 with trisomy 18 and all 901 unaffected cases were classified correctly. Median fetal fraction was 10.5% (range, 0.3-33.8%) and trisomic and unaffected cases with low fetal fractions of < 1% were identified correctly. CONCLUSIONS: This novel method for cfDNA analysis of maternal plasma, which utilizes paired-end MPSS, can provide accurate prediction of fetal trisomies. Use of a new multicomponent t-score removes the need to reject samples with fetal fraction < 4%, which potentially extends the benefits of non-invasive prenatal cfDNA analysis to a larger proportion of pregnancies. (c) 2016 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. PMID- 27981673 TI - Rapid differentiation and asynchronous coevolution of male and female genitalia in stink bugs. AB - Despite claims that genitalia are among the fastest evolving phenotypes, few studies have tested this trend in a quantitative and phylogenetic framework. In systems where male and female genitalia coevolve, there is a growing effort to explore qualitative patterns of evolution and their underlying mechanisms, but the temporal aspect remains overlooked. An intriguing question is how fast male and female genitalia may change in a coevolutionary scenario. Here, we apply a series of comparative phylogenetic analyses to reveal a scenario of correlated evolution and to investigate how fast male and female external, nonhomologous and functionally integrated genitalia change in a group of stink bugs. We report three findings: the female gonocoxite 8 and the male pygophore showed a clear pattern of correlated evolution, both genitalia were estimated to evolve much faster than nongenital traits, and rates of evolution of the male genitalia were twice as fast as the female genitalia. Our results corroborate the widely held view that male genitalia evolve fast and add to the scarce evidence for rapidly evolving female genitalia. Different rates of evolution exhibited by males and females suggest either distinct forms or strengths of selection, despite their tight functional integration and coevolution. The morphological characteristics of this coevolutionary trend are more consistent with a cooperative adjustment of the genitalia, suggesting a scenario of female choice, morphological accommodation, lock-and-key or some combination of the three. PMID- 27981675 TI - Crowd control: sex ratio affects sexually selected cuticular hydrocarbons in male Drosophila serrata. AB - Although it is advantageous for males to express costly sexually selected signals when females are present, they may also benefit from suppressing these signals to avoid costly interactions with rival males. Cuticular chemical profiles frequently function as insect sexual signals; however, few studies have asked whether males alter these signals in response to their social environment. In Drosophila serrata, an Australian fly, there is sexual selection for a multivariate combination of male cuticular hydrocarbons (CHCs). Here, we show that the ratio of females to males that an adult male experiences has a strong effect on his CHC expression, with female-biased adult sex ratios eliciting greater expression of CHC profiles associated with higher male mating success. Classical models predict that male reproductive investment should be highest when there is a small but nonzero number of rivals, but we found that males expressed the most attractive combination of CHCs when there were no rivals. We found that male CHCs were highly sensitive to adult sex ratio, with males expressing higher values of CHC profiles associated with greater mating success as the ratio of females to males increased. Moreover, sex ratio has a stronger effect on male CHC expression than adult density. Finally, we explore whether sex ratio affects the variance among a group of males in their CHC expression, as might be expected if individuals respond differently to a given social environment, but find little effect. Our results reveal that subtle differences in social environment can induce plasticity in male chemical signal expression. PMID- 27981676 TI - miR-194 functions as a novel modulator of cellular senescence in mouse embryonic fibroblasts. AB - MicroRNA-194 (miR-194), a typical p53 responsive miRNA, serves as a tumor suppressor similar as p53, and has been demonstrated to play an anti proliferation role in various human cancers. In spite of the pivotal role of p53 during aging process, the knowledge of miR-194's contribution to cellular senescence is limited. We herein sought to explore the role of miR-194 in the replicative senescence and stress-induced senescence of mouse embryonic fibroblasts. Our results unraveled that, compared to young cells, miR-194 is highly expressed in senescent cells, and extra expression of miR-194 significantly triggers the replicative senescence of MEFs and H2 O2 -induced senescence of NIH/3T3 cells, while inhibition of miR-194 exhibited the opposite effect. We further unveiled that DNMT3A was a direct and authentic target of miR 194, which has been reported to be closely associated with cellular senescence. Taken together, our data suggest that miR-194 may significantly promote the development of cellular senescence in mouse embryonic fibroblasts, which potentially occurs through inhibiting the DNMT3A expression. PMID- 27981677 TI - Provoked and spontaneous confabulations in Alzheimer's disease: An examination of their prevalence and relation with general cognitive and executive functioning. AB - AIM: A dissociation can be made between confabulations that are produced when the subject is directly questioned (i.e., provoked confabulations) and context-free, unprovoked confabulations (i.e., spontaneous confabulations). Unlike provoked confabulations, there is a paucity of research on spontaneous confabulations in Alzheimer's disease (AD). Our paper assessed this issue by assessing both types of confabulation in participants with mild to moderate AD and controls. METHODS: Provoked confabulations were evaluated with questions probing personal and general knowledge, whereas spontaneous confabulations were rated by nursing and medical staff. RESULTS: Findings showed more provoked confabulations in AD participants than in controls. Only occasional appearance of spontaneous confabulations was observed in the AD participants. Further, spontaneous confabulations in AD participants were significantly correlated with general cognitive functioning, but not with executive functioning. CONCLUSION: Our findings suggest that spontaneous confabulations in AD are relatively rare, at least in the mild to moderate stage of the disease. PMID- 27981674 TI - The canonical semantic network supports residual language function in chronic post-stroke aphasia. AB - Current theories of language recovery after stroke are limited by a reliance on small studies. Here, we aimed to test predictions of current theory and resolve inconsistencies regarding right hemispheric contributions to long-term recovery. We first defined the canonical semantic network in 43 healthy controls. Then, in a group of 43 patients with chronic post-stroke aphasia, we tested whether activity in this network predicted performance on measures of semantic comprehension, naming, and fluency while controlling for lesion volume effects. Canonical network activation accounted for 22%-33% of the variance in language test scores. Whole-brain analyses corroborated these findings, and revealed a core set of regions showing positive relationships to all language measures. We next evaluated the relationship between activation magnitudes in left and right hemispheric portions of the network, and characterized how right hemispheric activation related to the extent of left hemispheric damage. Activation magnitudes in each hemispheric network were strongly correlated, but four right frontal regions showed heightened activity in patients with large lesions. Activity in two of these regions (inferior frontal gyrus pars opercularis and supplementary motor area) was associated with better language abilities in patients with larger lesions, but poorer language abilities in patients with smaller lesions. Our results indicate that bilateral language networks support language processing after stroke, and that right hemispheric activations related to extensive left hemispheric damage occur outside of the canonical semantic network and differentially relate to behavior depending on the extent of left hemispheric damage. Hum Brain Mapp 38:1636-1658, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27981678 TI - Bilateral pre-auricular papillary squamous cell carcinomas associated with papillomavirus infection in a domestic cat. AB - BACKGROUND: Cutaneous papillary squamous cell carcinomas (SCCs) are extremely rare in humans and have not been reported in any nonhuman species. In humans, oral papillary SCCs are often caused by papillomavirus infection and have a more favourable prognosis than other SCC subtypes. CASE: A 10-year-old ginger and white domestic short hair cat had a 12 month history of symmetrical, roughly circular, exophytic 2 cm diameter masses in both pre-auricular regions. Surgical excision was performed, although with only narrow margins. METHODS AND RESULTS: Histology of both masses revealed a proliferation of neoplastic keratinocytes arranged in numerous filiform projections that were supported by fibrovascular stalks. Although the cells were confined to the epidermis predominantly, nests of neoplastic cells were visible within the superficial dermis. The neoplastic cells demonstrated significant atypia with a variable nuclear:cytoplasmic ratio and a high mitotic index. A papillary subtype SCC was diagnosed. Felis catus papillomavirus type 2 (FcaPV-2) was the only papillomavirus detected in the masses and FcaPV-2 E6/E7 gene expression and p16CDKN2A protein immunostaining were detected. Six months after surgery neither recurrence nor further masses had developed. CONCLUSIONS: This is the first cutaneous papillary SCC reported in a nonhuman species. Papillary SCCs may be a rare manifestation of FcaPV-2 infection in cats. The unusual location of the SCCs suggests that both papillomavirus infection and ultraviolet light exposure could have contributed to neoplasia development. Evidence from this single case suggests that papillary SCCs may have a more favourable prognosis than conventional SCCs in cats. PMID- 27981680 TI - A Whole Proteome Inventory of Background Photocrosslinker Binding. AB - Affinity-based protein profiling (AfBPP) is a widely applied method for the target identification of bioactive molecules. Probes containing photocrosslinkers, such as benzophenones, diazirines, and aryl azides, irreversibly link the molecule of interest to its target protein upon irradiation with UV light. Despite their prevalent application, little is known about photocrosslinker-specific off-targets, affecting the reliability of results. Herein, we investigated background protein labeling by gel-free quantitative proteomics. Characteristic off-targets were identified for each photoreactive group and compiled in a comprehensive inventory. In a proof-of-principle study, H8, a protein kinase A inhibitor, was equipped with a diazirine moiety. Application of this photoprobe revealed, by alignment with the diazirine background, unprecedented insight into its in situ proteome targets. Taken together, our findings guide the identification of biologically relevant binders in photoprobe experiments. PMID- 27981679 TI - Effects of antipsychotics on intestinal motility in zebrafish larvae. AB - BACKGROUND: Antipsychotics are essential for the treatment of schizophrenia. However, due to side effects, both continuity of treatment and patients' general health can be jeopardized. Some of these drugs, especially clozapine, have a class of side effects attributed to their antimuscarinic properties, such as dysmotility, a condition in which muscles of the digestive system become impaired. Dysmotility may also alter the speed, strength or coordination of the digestive organs, causing distention, disturbing gastrointestinal transit, leading to symptoms such as bloating, nausea, vomiting, and even malnutrition. In this study, our aim was to develop an in vivo assay capable of identifying and studying the antimuscarinic effects of antipsychotics in a zebrafish model. METHODS: We performed video recordings of in vivo 5-day postfertilization (dpf) zebrafish larvae gastrointestinal tracts and analyzed the frequency of spontaneous and regular cycles of contractions of the gut. KEY RESULTS: The assay was first validated with treatment with atropine. We showed that this antimuscarinic drug reduces peristaltic cycles. Subsequently, the larvae were treated with the antipsychotics haloperidol, risperidone, and clozapine. Neither haloperidol nor risperidone reduced gut motility, but clozapine significantly reduced the frequency of cycles of contractions (P<.0001), which confirms the existing clinical data. CONCLUSIONS & INFERENCES: We conclude that this zebrafish assay efficiently identifies anticholinergic side effects of antipsychotics, and can thus be a quick and useful way to screen for this property in new drugs. PMID- 27981681 TI - Development and validation of prescribing quality indicators for patients with type 2 diabetes. AB - AIM: Quality indicators are used to measure whether healthcare professionals act according to guidelines, but few indicators focus on the quality of pharmacotherapy for diabetes. The aim of this study was to develop and validate a set of prescribing quality indicators (PQIs) for type 2 diabetes in primary care, and to apply this set in practice. To take into account the stepwise treatment of chronic disease, clinical action indicators were specifically considered. METHODS: Potential PQIs were derived from clinical practice guidelines and evaluated using the RAND/UCLA Appropriateness Method, a modified Delphi panel. Thereafter, the feasibility of calculating the PQIs was tested in two large Dutch primary care databases including >80 000 diabetes patients in 2012. RESULTS: 32 PQIs focusing on treatment with glucose, lipid, blood pressure and albuminuria lowering drugs, and on vaccination, medication safety and adherence were assessed by ten experts. After the Delphi panel, the final list of twenty PQIs was tested for feasibility. All PQIs definitions were feasible for measuring the quality of medication treatment using these databases. Indicator scores ranged from 18.8% to 90.8% for PQIs focusing on current medication use, clinical action and medication choice, and from 2.1% to 37.2% for PQIs focusing on medication safety. DISCUSSION AND CONCLUSIONS: Twenty PQIs focusing on treatment with glucose, lipid, blood pressure and albuminuria lowering drugs, and on medication safety in type 2 diabetes were developed, considered valid and operationally feasible. Results showed room for improvement, especially in initiation and intensification of treatment as measured with clinical action indicators. PMID- 27981682 TI - Rituximab in immune thrombocytopenia: gender, age, and response as predictors of long-term response. AB - OBJECTIVES: To evaluate the efficacy of a salvage treatment with rituximab (RTX) in adults with primary immune thrombocytopenia (ITP), in terms of short-term response and long-term response (LTR, i.e., probability to achieve and maintain response) and to identify biological and clinical predictors of response. METHODS: We retrospectively evaluated the outcome of patients with primary ITP treated with standard dosage RTX (375 mg/m2 * 4) as salvage therapy in five Italian centers. One hundred and three patients, median age of 46 yr, were included. The median period of observation was 59 months. RESULTS: Response (R) and complete response (CR) were documented in 57 (55%) and 37 (36%) patients, respectively. Patients younger than 40 yr had a higher probability to achieve CR (P = 0.025). Younger women (age < 40 yr) had a significantly higher probability to achieve R and CR (P = 0.039 and P = 0.009, respectively). The estimated LTR rate was 36% and 31% after 48 and 72 months, respectively; female sex (P = 0.033) and younger age (P = 0.021) were associated with better LTR. Younger women had the highest LTR rate (P = 0.006). Response duration was associated with the obtainment of CR after RTX (CR vs. partial response, P = 0.002). CONCLUSIONS: The effect of RTX salvage treatment appears higher in younger women, with LTR rate possibly approaching that of splenectomy. PMID- 27981683 TI - Use of Torulaspora delbrueckii and Saccharomyces cerevisiae in semi-industrial sequential inoculation to improve quality of Palomino and Chardonnay wines in warm climates. AB - AIMS: We have evaluated for the first time the impact of two commercial yeast strains (Torulaspora delbrueckii TD291 and Saccharomyces cerevisiae QA23) inoculated sequentially in musts of Chardonnay and Palomino Fino grape varieties grown under warm climate (South-west of Spain). METHODS AND RESULTS: Semi industrial scale alcoholic fermentations (AF) were performed during the 2011 and 2012 harvests. Implantation analyses demonstrated that T. delbrueckii is the predominant strain until the end of the AF phase. Wines with sequential inoculation (SI) resulted in the production of low levels of acetic acid (which gives wine an undesirable 'vinegary' character), low acetaldehyde in Chardonnay and high in Palomino wines. The most salient attributes that contribute to the quality of the Chardonnay and Palomino wines produced were aroma intensity, fresh and tropical fruit character. CONCLUSIONS: This study demonstrated that SI of T. delbrueckii and S. cerevisiae contribute significantly to the improvement of Chardonnay wine aromas and the creation of new styles of wine for Palomino. SIGNIFICANCE AND IMPACT OF THE STUDY: This study has generated new knowledge about the biotechnological potential of T. delbrueckii (TD219) and S. cerevisiae (QA23) for improving the organoleptic properties of Chardonnay and Palomino wines. PMID- 27981685 TI - Rural and remote research: Supporting the heart and soul of Australia. PMID- 27981686 TI - Research translation: Making a difference in rural health. PMID- 27981687 TI - AJRH would like to thank the following reviewers for their contribution in 2016. PMID- 27981684 TI - Gastrointestinal symptom severity in irritable bowel syndrome, inflammatory bowel disease and the general population. AB - BACKGROUND: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) patients report similar gastrointestinal (GI) symptoms, yet comparisons of symptom severity between groups and with the general population (GP) are lacking. METHODS: We compared Patient-Reported Outcomes Measurement Information System (PROMIS(r) ) GI symptom scales measuring gastro-esophageal reflux (GER), disrupted swallowing, diarrhea, bowel incontinence, nausea/vomiting, constipation, belly pain, and gas/bloating in: (i) USA GP sample, (ii) IBS patients, and (iii) IBD patients from tertiary care and community populations. Symptom severity scores were based on T-score metric with mean 50+/-10 (standard deviation) relative to the GP. KEY RESULTS: Of 1643 patients enrolled, there were 253 IBS patients (68% F, mean age 45+/-15 years), 213 IBD patients (46% F, mean age 41+/-14 years), and 1177 GP subjects (57% F, mean age 46+/-16 years). IBS patients reported greater severity of GER, disrupted swallowing, nausea/vomiting, belly pain, gas/bloating, and constipation symptoms than their IBD counterparts (all P<.05). Compared to the GP, IBD patients had worse belly pain, gas/bloating, diarrhea, and bowel incontinence, but less severe GER and disrupted swallowing (all P<.05), and IBS patients had more severe nausea/vomiting, belly pain, gas/bloating, and constipation (all P<.05). Women had more severe belly pain and gas/bloating than men, whereas men had more severe bowel incontinence (all P<.05). CONCLUSION & INFERENCES: IBS and IBD are associated with more severe GI symptoms compared to the GP excluding esophageal symptoms. Unlike IBD, IBS is not characterized by observable GI inflammation but patients report more severe upper and lower GI symptoms. PMID- 27981688 TI - A new graphical format to communicate treatment effects to patients-A web-based randomized controlled trial. AB - OBJECTIVE: Patients making treatment decisions require understandable evidence based information. However, evidence on graphical presentation of benefits and side-effects of medical treatments is not conclusive. The study evaluated a new space-saving format, CLARIFIG (clarifying risk figures), aiming to facilitate accuracy of comprehension. METHODS: CLARIFIG displays groups of patients with and without treatment benefits as coloured sectors of a proportional bar graph representing in total 100 patients. Supplementary icons indicate the corresponding group's actual condition. The study used an application showing effects of immunotherapy intended to slow disease progression in multiple sclerosis (MS). In a four-arm web-based randomized controlled trial, CLARIFIG was compared to the reference standard, multifigure pictographs (MFP), regarding comprehension (primary outcome) and processing time. Both formats were presented as static and animated versions. People with MS were recruited through the website of the German MS society. RESULTS: Six hundred and eighty-two patients were randomized and analysed for the primary end point. There were no differences in comprehension rates (MFPstatic =46%, CLARIFIGstatic =44%; P=.59; MFPanimated =23%, CLARIFIGanimated =30%; P=.134). Processing time for CLARIFIG was shorter only in the animated version (MFPstatic =162 seconds, CLARIFIGstatic =155 seconds; P=.653; MFPanimated =286 seconds, CLARIFIGanimated =189 seconds; P<=.001). However, both animated versions caused more wrong answers and longer processing time than static presentation (MFPstatic vs animated : P<=.001/.001, CLARIFIGstatic vs animated : P=.027/.017). CONCLUSION: Comprehension of the new format is comparable to MFP. CLARIFIG has the potential to simplify presentation in more complex contexts such as comparison of several treatment options in patient decision aids, but further studies are needed. PMID- 27981689 TI - Polymersome Popping by Light-Induced Osmotic Shock under Temporal, Spatial, and Spectral Control. AB - The light-triggered, programmable rupture of cell-sized vesicles is described, with particular emphasis on self-assembled polymersome capsules. The mechanism involves a hypotonic osmotic imbalance created by the accumulation of photogenerated species inside the lumen, which cannot be compensated owing to the low water permeability of the membrane. This simple and versatile mechanism can be adapted to a wealth of hydrosoluble molecules, which are either able to generate reactive oxygen species or undergo photocleavage. Ultimately, in a multi compartmentalized and cell-like system, the possibility to selectively burst polymersomes with high specificity and temporal precision and to consequently deliver small encapsulated vesicles (both polymersomes and liposomes) is demonstrated. PMID- 27981690 TI - Measuring changes in the optic nerve sheath diameter in patients with idiopathic normal-pressure hydrocephalus: a useful diagnostic supplement to spinal tap tests. AB - BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) removal improves clinical symptoms of many patients with idiopathic normal-pressure hydrocephalus (iNPH). The aim of this study was to investigate the correlation of changes in the optic nerve sheath diameter (ONSD) with patient responses to CSF removal. METHODS: Transorbital ultrasonography was performed to obtain ONSD measurements in 31 patients with iNPH before and after lumbar puncture. Measurements were obtained while patients were supine and upright. Changes in the ONSD between supine and upright positions [ONSD variability (ONSD-V)] were assessed and compared with those in 60 healthy volunteers. ONSD-V was correlated with relative changes in a validated iNPH severity (Boon) score. RESULTS: Mean pre-puncture ONSD-V was significantly lower in healthy volunteers and patients with no response to CSF removal (Fisher test) [0.05 +/- 0.14 mm (SD)] than in responsive patients [0.37 +/- 0.20 mm (SD), P < 0.001]. ONSD-V predicted response to the spinal tap test (odds ratio, 0.30; 95% confidence interval, 0.12-0.75 mm, P = 0.011). The higher the ONSD-V, the better the therapeutic effect (chi2 = 14.980, P < 0.001). The post-spinal tap test ONSD-V correlated significantly with clinical severity in the motor portion of the Boon score [0.16 +/- 0.23 mm (SD), P = 0.003]. CONCLUSIONS: The ONSD-V before and after spinal tap test correlated well with the clinical effects of CSF removal. Transorbital ultrasonography seems to be a reliable, safe add-on to the Fisher test and may support selection of patients for shunt intervention. PMID- 27981692 TI - Parents and carers of young people with liver transplantation: Lost in transition? PMID- 27981691 TI - The costs of crime during and after publicly funded treatment for opioid use disorders: a population-level study for the state of California. AB - BACKGROUND AND AIMS: Treatment for opioid use disorders (OUD) reduces the risk of mortality and infectious disease transmission; however, opportunities to quantify the potential economic benefits of associated decreases in drug-related crime are scarce. This paper aimed to estimate the costs of crime during and after periods of engagement in publicly funded treatment for OUD to compare total costs of crime during a hypothetical 6-month period following initiation of opioid agonist treatment (OAT) versus detoxification. DESIGN: Retrospective, administrative data based cohort study with comprehensive information on drug treatment and criminal justice systems interactions. SETTING: Publicly funded drug treatment facilities in California, USA (2006-10). PARTICIPANTS: A total of 31 659 individuals admitted for the first time to treatment for OUD, and who were linked with criminal justice and mortality data, were followed during a median 2.3 years. Median age at first treatment admission was 32, 35.8% were women and 37.1% primarily used prescription opioids. MEASUREMENTS: Daily costs of crime (US$2014) were calculated from a societal perspective and were composed of the costs of policing, court, corrections and criminal victimization. We estimated the average marginal effect of treatment engagement in OAT or detoxification adjusting for potential fixed and time-varying confounders, including drug use and criminal justice system involvement prior to treatment initiation. FINDINGS: Daily costs of crime during treatment compared with after treatment were $126 lower for OAT [95% confidence interval (CI) = $116, $136] and $144 lower for detoxification (95% CI = $135, $154). Summing the costs of crime during and after treatment over a hypothetical 6-month period using the observed median durations of OAT (161 days) and detoxification (19 days), we estimated that enrolling an individual in OAT as opposed to detoxification would save $17 550 ($16 840, $18 383). CONCLUSIONS: In publicly funded drug treatment facilities in California, USA, engagement in treatment for opioid use disorders is associated with lower costs of crime in the 6 months following initiation of treatment, and the economic benefits were far greater for individuals receiving time-unlimited treatment. PMID- 27981693 TI - Caring for an intimate stranger: parenting a child with psychosis. AB - WHAT IS KNOWN ON THE SUBJECT: The care of an adult son or daughter with psychosis is filled with overwhelming demands caused by the symptomatology and illness exacerbations. Parents display disenfranchised grief over multiple losses and report increased levels of emotional burden. Most studies use quantitative methods and rely on pre-existing theoretical frameworks to investigate, through psychometric measures, the effects of being a carer. Meaning attributions to the disorder, and changes in parent-child relations over time, are poorly understood. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE: This hermeneutic phenomenological study illuminates the subjective experience of parenting a son or daughter with psychosis, as it is lived and described by parents of young adults with psychosis. Findings suggest that the parents' perceptions of their child changes over the course of the disorder, leading to a redefinition of the parent-child relationship, causing alternations in attachment. Findings illuminate the parents' profound guilt over having contributed or not prevented the disorder, over not being 'good' parents and feeling ambivalent towards an 'intimate stranger.' Guilt is compensated by absolute dedication to the son or daughter's care, at the expense of their own well-being. WHAT ARE THE IMPLICATIONS FOR PRACTICE: Interventions for parents must be available as soon as possible, both during hospitalization and after discharge. Professionals should provide a therapeutic space, where parents could express intimate thoughts and feelings, address guilt, fear and resentment issues, be assisted in their parenting role as well as in the reconstruction of a sense of self and self-esteem. Professionals are invited to facilitate illness acceptance, provide accurate information, assist parents to redefine their relationship to the child and facilitate the integration of the traumatic experience into their personal and family narrative. Professionals must develop in depth awareness of their biases and attitudes, have an ongoing training on how to respond to the parents' needs, facilitate therapeutic change and accompany families through the course of their adult child's illness trajectory. ABSTRACT: Introduction Children who are diagnosed with psychosis often rely on their parents for prolonged care. The impact of such care is partially understood as most studies use quantitative methods and pre existing theoretical frameworks that limit their investigation to emotional burden, and emotional responses. Aim Explore the parents' lived experience of caring for a child with psychosis. Method A hermeneutic phenomenological design was used with a sample of 16 parents of children with psychotic disorders who were hospitalized or attended the outpatient clinic of a large psychiatric Greek hospital. Results Identified themes were as follows: (i) the psychosis experience, (ii) redefinition of the parent-child relationship over the course of the disorder and (iii) challenges of parenting a child with psychosis. Discussion 'Caring for an intimate stranger' reflects the parents' overall experience, involving changes in the parent-child relationship, ambivalence towards caretaking and profound guilt, compensated by self-sacrifice parenting practices. IMPLICATIONS FOR PRACTICE: Findings highlight the necessity to train mental health professionals to provide individualized information; facilitate family communication; address the parents' guilt, ambivalence, meaning attributions that compromise adjustment; and support them through the challenges of parenting a son or daughter with psychosis. PMID- 27981694 TI - Quantifying the unmet needs of caregivers of people with dementia: a critical review of the quality of measures. AB - OBJECTIVE: The array of demanding tasks carried out by caregivers of people with dementia have significant negative impacts on their physical, mental and social well-being. Needs assessment allows individuals to indicate the extent to which their needs across different areas have or have not been met, allowing for estimations of the prevalence of needs and the extent to which help is required. This approach is extremely valuable in a clinical context, as it enables identification of the areas with which caregivers report a particular desire for help and allows targeting of support and resources to those who identify high levels of unmet needs. This systematic review aimed to critically examine the psychometric properties of measures that assess unmet needs of caregivers of people with dementia. METHODS: Medline, Embase, PsycINFO and Cochrane electronic databases were searched between January 1990 and August 2015 for English-language publications describing the development or validation of measures assessing the unmet needs of adult caregivers of people with dementia. The psychometric properties of included measures were assessed against standard criteria for psychometric quality. RESULTS: Four measures met the inclusion criteria. Only half of the indices of psychometric quality were tested across measures. Three measures had adequate internal consistency reliability, of which one also showed adequate test-retest reliability. Two measures reported adequate construct validity, while criterion validity was not assessed for any measure. CONCLUSIONS: There is a clear need to develop a psychometrically rigorous instrument to identify the unmet needs of caregivers of people with dementia. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27981695 TI - Expected utility versus expected regret theory versions of decision curve analysis do generate different results when treatment effects are taken into account. AB - RATIONALE, AIMS, AND OBJECTIVES: Decision curve analysis (DCA) is a widely used method for evaluating diagnostic tests and predictive models. It was developed based on expected utility theory (EUT) and has been reformulated using expected regret theory (ERG). Under certain circumstances, these 2 formulations yield different results. Here we describe these situations and explain the variation. METHODS: We compare the derivations of the EUT- and ERG-based formulations of DCA for a typical medical decision problem: "treat none," "treat all," or "use model" to guide treatment. We illustrate the differences between the 2 formulations when applied to the following clinical question: at which probability of death we should refer a terminally ill patient to hospice? RESULTS: Both DCA formulations yielded identical but mirrored results when treatment effects are ignored; they generated significantly different results otherwise. Treatment effect has a significant effect on the results derived by EUT DCA and less so on ERG DCA. The elicitation of specific values for disutilities affected the results even more significantly in the context of EUT DCA, whereas no such elicitation was required within the ERG framework. CONCLUSION: EUT and ERG DCA generate different results when treatment effects are taken into account. The magnitude of the difference depends on the effect of treatment and the disutilities associated with disease and treatment effects. This is important to realize as the current practice guidelines are uniformly based on EUT; the same recommendations can significantly differ if they are derived based on ERG framework. PMID- 27981697 TI - Science-in-brief: Clinical highlights from BEVA Congress 2016. PMID- 27981698 TI - Equine echocardiography: Abbreviations and terminology recommended by Equine Veterinary Journal. PMID- 27981696 TI - Stereospecific Palladium-Catalyzed Acylation of Enantioenriched Alkylcarbastannatranes: A General Alternative to Asymmetric Enolate Reactions. AB - We report the development of a Pd-catalyzed process for the cross coupling of unactivated primary, secondary, and tertiary alkylcarbastannatrane nucleophiles with acyl electrophiles. Reactions involving optically active alkylcarbastannatranes occur with exceptional stereofidelity and with net retention of absolute configuration. Because the stereochemistry of the resulting products is entirely reagent-controlled, this process may be viewed as a general, alternative approach to the preparation of products typically accessed via asymmetric enolate methodologies. Additionally, we report a new method for the preparation of optically active alkylcarbastannatranes, which should facilitate their future use in stereospecific reactions. PMID- 27981699 TI - Making research accessible. PMID- 27981700 TI - Peer reviewers in 2016. PMID- 27981702 TI - Attaching meaning to the number words: contributions of the object tracking and approximate number systems. AB - Children's understanding of the quantities represented by number words (i.e., cardinality) is a surprisingly protracted but foundational step in their learning of formal mathematics. The development of cardinal knowledge is related to one or two core, inherent systems - the approximate number system (ANS) and the object tracking system (OTS) - but whether these systems act alone, in concert, or antagonistically is debated. Longitudinal assessments of 198 preschool children on OTS, ANS, and cardinality tasks enabled testing of two single-mechanism (ANS only and OTS-only) and two dual-mechanism models, controlling for intelligence, executive functions, preliteracy skills, and demographic factors. Measures of both OTS and ANS predicted cardinal knowledge in concert early in the school year, inconsistent with single-mechanism models. The ANS but not the OTS predicted cardinal knowledge later in the school year as well the acquisition of the cardinal principle, a critical shift in cardinal understanding. The results support a Merge model, whereby both systems initially contribute to children's early mapping of number words to cardinal value, but the role of the OTS diminishes over time while that of the ANS continues to support cardinal knowledge as children come to understand the counting principles. PMID- 27981704 TI - The eye of the retriever: developing episodic memory mechanisms in preverbal infants assessed through pupil dilation. AB - Studying memory in infants can be challenging, as they cannot express their subjective recollection verbally. In this study we use a novel method with which we can assess episodic recognition memory through pupillometry, using identical procedures and stimuli for infants and adults. In three experiments of 4- and 7 month-old infants, and adults we show that the adult pupillary response is larger to previously seen than to never seen items (old/new effect). Pupil dilations index subjective memory experience in adults, producing distinct pupil dilations to items judged as remembered, familiar, and new, regardless of actual previous exposure (Experiment 1). Seven-month-old infants demonstrate a clear pupillary old/new effect, very similar to that of adults (Experiment 2), whereas 4-month olds do not demonstrate such an effect (Experiment 3). Our findings suggest that the mnemonic mechanisms that serve infants' and adults' episodic recognition memory are more similar than previously asserted: they are not fully developed at 4 months of age but that there is contiguity in human episodic memory development from 7 months of age. PMID- 27981703 TI - Nickel-Catalyzed Barton Decarboxylation and Giese Reactions: A Practical Take on Classic Transforms. AB - Two named reactions of fundamental importance and paramount utility in organic synthesis have been reinvestigated, the Barton decarboxylation and Giese radical conjugate addition. N-hydroxyphthalimide (NHPI) based redox-active esters were found to be convenient starting materials for simple, thermal, Ni-catalyzed radical formation and subsequent trapping with either a hydrogen atom source (PhSiH3 ) or an electron-deficient olefin. These reactions feature operational simplicity, inexpensive reagents, and enhanced scope as evidenced by examples in the realm of peptide chemistry. PMID- 27981705 TI - Azaindoles as Zinc-Binding Small-Molecule Inhibitors of the JAMM Protease CSN5. AB - CSN5 is the zinc metalloprotease subunit of the COP9 signalosome (CSN), which is an important regulator of cullin-RING E3 ubiquitin ligases (CRLs). CSN5 is responsible for the cleavage of NEDD8 from CRLs, and blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state, thereby leading to auto ubiquitination and ultimately degradation of the substrate recognition subunits. Herein, we describe the discovery of azaindoles as a new class of CSN5 inhibitors, which interact with the active-site zinc ion of CSN5 through an unprecedented binding mode. The best compounds inhibited CSN5 with nanomolar potency, led to degradation of the substrate recognition subunit Skp2 in cells, and reduced the viability of HCT116 cells. PMID- 27981706 TI - The Crystal Structure of RosB: Insights into the Reaction Mechanism of the First Member of a Family of Flavodoxin-like Enzymes. AB - 8-demethyl-8-aminoriboflavin-5'-phosphate (AFP) synthase (RosB) catalyzes the key reaction of roseoflavin biosynthesis by forming AFP from riboflavin-5'-phosphate (RP) and glutamate via the intermediates 8-demethyl-8-formylriboflavin-5' phosphate (OHC-RP) and 8-demethyl-8-carboxylriboflavin-5'-phosphate (HO2 C-RP). To understand this reaction in which a methyl substituent of an aromatic ring is replaced by an amine we structurally characterized RosB in complex with OHC-RP (2.0 A) and AFP (1.7 A). RosB is composed of four flavodoxin-like subunits which have been upgraded with specific extensions and a unique C-terminal arm. It appears that RosB has evolved from an electron- or hydride-transferring flavoprotein to a sophisticated multi-step enzyme which uses RP as a substrate (and not as a cofactor). Structure-based active site analysis was complemented by mutational and isotope-based mass-spectrometric data to propose an enzymatic mechanism on an atomic basis. PMID- 27981707 TI - Electroencephalographic reactivity testing in unconscious patients: a systematic review of methods and definitions. AB - Electroencephalographic (EEG) reactivity testing is often presented as a clear cut element of electrophysiological testing. Absence of EEG reactivity is generally considered an indicator of poor outcome, especially in patients after cardiac arrest. However, guidelines do not clearly describe how to test for reactivity and how to evaluate the results. In a quest for clear guidelines, we performed a systematic review aimed at identifying testing methods and definitions of EEG reactivity. We systematically searched the literature between 1970 and May 2016. Methodological quality of the studies was assessed using the QUality In Prognostic Studies tool. Quality of the descriptions of stimulus protocol and reactivity definition was rated on a four-category grading scale based on reproducibility. We found that protocols for EEG reactivity testing vary greatly and descriptions of protocols are almost never replicable. Furthermore, replicable definitions of presence or absence of EEG reactivity are never provided. In order to draw firm conclusions on EEG reactivity as a prognostic factor, future studies should include a precise stimulation protocol and reactivity definition to facilitate guideline formation. PMID- 27981709 TI - Incidence of type 1 diabetes has doubled in Kuwaiti children 0-14 years over the last 20 years. AB - AIMS: This study had 2 aims: to report data on the incidence of childhood-onset type 1 diabetes in Kuwaiti children aged 0-14 years during 2011 to 2013 and to compare the recent data with those collected during 1992 to 1997. METHODS: All newly diagnosed patients were registered through the Childhood-Onset Diabetes eRegistry (CODeR) in 2011-2013, based on the DiaMond protocol used in 1992-1997. RESULTS: A total of 515 Kuwaiti children (247 boys and 268 girls) aged 0-14 years newly diagnosed with type 1 diabetes were registered from 1 January 2011 to 31 December 2013. Data ascertainment were 96.7%. The mean age +/- SD at diagnosis was 8.7 +/- 3.4 years in boys and 7.9 +/- 3.1 years in girls. The crude incidence rate (95% CI) was 40.9 (37.4-44.6) and the age standardized rate 41.7 (95% 38.1 45.4) per 100,000 per year, 39.3 (34.6-44.4) among boys and 44.1 (39.0-49.7) among girls. A statistically significant increasing trend in incidence was observed as the overall crude incidence rose from 17.7 in 1992-1994 to 40.9 per 100,000 per year in 2011-2013. The Poisson regression model depicting the trend in incidence revealed that, the incidence rates adjusted for age and sex in 2011 to 2013 was 2.3 (95% CI 1.9-2.7) times higher than 1992-1997. CONCLUSIONS: The incidence of type 1 diabetes in Kuwaiti children 0-14 years has doubled in the last 2 decades. The reasons for this increase requires further investigation. PMID- 27981710 TI - Hybrid Palladium Nanoparticles for Direct Hydrogen Peroxide Synthesis: The Key Role of the Ligand. AB - Ligand-modified palladium nanoparticles deposited on a carbon carrier efficiently catalyze the direct synthesis of H2 O2 and the unique performance is due to their hybrid nanostructure. Catalytic testing demonstrated that the selectivity increases with the HHDMA ligand content from 10 % for naked nanoparticles up to 80 %, rivalling that obtained with state-of-the-art bimetallic catalysts (HHDMA=C20 H46 NO5 P). Furthermore, it remains stable over five consecutive reaction runs owing to the high resistance towards leaching of the organic moiety, arising from its bond with the metal surface. As rationalized by density functional theory, this behavior is attributed to the adsorption mode of the reaction intermediates on the metal surface. Whereas they lie flat in the absence of the organic shell, their electrostatic interaction with the ligand result in a unique vertical configuration which prevents further dissociation and over hydrogenation. These findings demonstrate the importance of understanding substrate-ligand interactions in capped nanoparticles to develop smart catalysts for the sustainable manufacture of hydrogen peroxide. PMID- 27981708 TI - Non-Viral CRISPR/Cas Gene Editing In Vitro and In Vivo Enabled by Synthetic Nanoparticle Co-Delivery of Cas9 mRNA and sgRNA. AB - CRISPR/Cas is a revolutionary gene editing technology with wide-ranging utility. The safe, non-viral delivery of CRISPR/Cas components would greatly improve future therapeutic utility. We report the synthesis and development of zwitterionic amino lipids (ZALs) that are uniquely able to (co)deliver long RNAs including Cas9 mRNA and sgRNAs. ZAL nanoparticle (ZNP) delivery of low sgRNA doses (15 nm) reduces protein expression by >90 % in cells. In contrast to transient therapies (such as RNAi), we show that ZNP delivery of sgRNA enables permanent DNA editing with an indefinitely sustained 95 % decrease in protein expression. ZNP delivery of mRNA results in high protein expression at low doses in vitro (<600 pM) and in vivo (1 mg kg-1 ). Intravenous co-delivery of Cas9 mRNA and sgLoxP induced expression of floxed tdTomato in the liver, kidneys, and lungs of engineered mice. ZNPs provide a chemical guide for rational design of long RNA carriers, and represent a promising step towards improving the safety and utility of gene editing. PMID- 27981711 TI - Sorafenib dose escalation in treatment-naive patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study. AB - OBJECTIVE: To assess the efficacy and safety of sorafenib dose escalation in metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Intra-patient dose escalation may enhance the clinical benefit of targeted anticancer agents in metastatic disease. In this non-randomised, open-label, Phase 2b study, treatment naive patients with mRCC were initially treated with the standard oral sorafenib dose [400 mg twice daily (BID)]. Two dose escalations were planned, each 200 mg BID after 28 days at the prior level. Dose reductions, interruptions, or delayed escalations were used to manage adverse events (AEs). The primary endpoint was objective response rate (ORR) in the modified intent-to-treat (mITT) population, which comprised patients with >=6 months of treatment including >=4 months of therapy at their highest tolerated dose. Secondary endpoints included progression free survival (PFS) and safety. RESULTS: In all, 83 patients received sorafenib. The dose received for the longest duration was 400, 600, and 800 mg BID in 48.2%, 15.7%, and 24.1% of patients, respectively. The ORR was 44.4% [n = 8/18; 95% confidence interval (CI) 21.5-69.2] and 17.9% (n = 12/67; 95% CI 9.6-29.2) in the mITT and ITT populations, respectively. The median (95% CI) PFS was 7.4 (6.0 11.7) months (ITT). The most common AEs of any grade were hand-foot skin reaction (66.3%) and diarrhoea (63.9%). CONCLUSION: Sorafenib demonstrated clinical benefit in treatment-naive patients with mRCC. However, relatively few patients could sustain doses of >400 mg BID. There was evidence that, where tolerated, escalation from the standard sorafenib dose may have enhanced clinical benefit. However, this study does not support dose escalation for most patients with treatment-naive mRCC. Alternative protocols for sorafenib dose escalation could be explored. PMID- 27981712 TI - Corneal anesthetic effect and ocular tolerance of 3.5% lidocaine gel in comparison with 0.5% aqueous proparacaine and 0.5% viscous tetracaine in normal canines. AB - OBJECTIVE: To compare the degree and duration of corneal anesthesia of a novel viscous ophthalmic lidocaine hydrochloride preparation vs. two commonly used ophthalmic anesthetic preparations. METHODS: Each subject was randomly selected to receive 2 of 4 treatments at 2 different time periods separated by a 1 week washout: 3.5% lidocaine hydrochloride gel (Akten(r) ; Akorn Inc., Lake Forest, Illinois, USA), 0.5% aqueous proparacaine hydrochloride (Akorn Inc.), 0.5% viscous tetracaine hydrochloride (TetraViscTM; Ocusoft Inc., Richmond, Texas, USA), or 0.9% saline eyewash as a negative control. Corneal sensitivity was determined using a Cochet-Bonnet aesthesiometer (LuneauA(r) , Chartres Cedex, France) prior to instillation of each treatment; at 1 and 5 min post treatment; and at 5-min intervals thereafter for 90 min total. Ocular side effects were recorded on a scale of 0-3. RESULTS: Twenty-four normal dogs (48 eyes) were entered into the study. Mean duration of maximal anesthesia was significantly greater at 34.2 min with tetracaine compared to 21.5 min and 19 min with proparacaine and lidocaine respectively. Corneal sensitivity was significantly decreased from baseline for up to 70 min with tetracaine and 55 min with both proparacaine and lidocaine. All lidocaine-treated eyes had transient blepharospasm and conjunctival hyperemia. Ten out of 24 tetracaine-treated eyes had conjunctival hyperemia with 4 of these having concurrent chemosis. CONCLUSIONS: Tetracaine provided a significantly longer duration of corneal anesthesia than proparacaine or lidocaine. Tetracaine and lidocaine were associated with more ocular side effects than proparacaine, although these were mild and transient. None. PMID- 27981713 TI - The effect of inoculum source and fluid shear force on the development of in vitro oral multispecies biofilms. AB - AIMS: Saliva has been previously used as an inoculum for in vitro oral biofilm studies. However, the microbial community profile of saliva is markedly different from hard- and soft-tissue-associated oral biofilms. Here, we investigated the changes in the biofilm architecture and microbial diversity of in vitro oral biofilms developed from saliva, tongue or plaque-derived inocula under different salivary shear forces. METHODS AND RESULTS: Four inoculum types (saliva, bacteria harvested from the tongue, toothbrush and curette-harvested plaque) were collected and pooled. Biofilms (n >= 15) were grown for 20 h in cell-free human saliva flowing at three different shear forces. Stained biofilms were imaged using a confocal laser scanning microscope. Biomass, thickness and roughness were determined by image analysis and bacterial community composition analysed using Ion Torrent. All developed biofilms showed a significant reduction in observed diversity compared with their respective original inoculum. Shear force altered biofilm architecture of saliva and curette-collected plaque and community composition of saliva, tongue and curette-harvested plaque. CONCLUSIONS: Different intraoral inocula served as precursors of in vitro oral polymicrobial biofilms which can be influenced by shear. SIGNIFICANCE AND IMPACT OF THE STUDY: Inoculum selection and shear force are key factors to consider when developing multispecies biofilms within in vitro models. PMID- 27981714 TI - Divergence in brain composition during the early stages of ecological specialization in Heliconius butterflies. AB - During speciation across ecological gradients, diverging populations are exposed to contrasting sensory and spatial information that present new behavioural and perceptive challenges. These challenges may be met by heritable or environmentally induced changes in brain function which mediate behaviour. However, few studies have investigated patterns of neural divergence at the early stages of speciation, inhibiting our understanding of the relative importance of these processes. Here, we provide a novel case study. The incipient species pair, Heliconius erato and H. himera, are parapatric across an environmental and altitudinal gradient. Despite ongoing gene flow, these species have divergent ecological, behavioural and physiological traits. We demonstrate that these taxa also differ significantly in brain composition, in particular in the relative levels of investment in structures that process sensory information. These differences are not explained solely by environmentally-induced plasticity, but include heritable, nonallometric shifts in brain structure. We suggest these differences reflect divergence to meet the demands of contrasting sensory ecologies. This conclusion would support the hypothesis that the evolution of brain structure and function play an important role in facilitating the emergence of ecologically distinct species. PMID- 27981715 TI - A Robust and Broadly Applicable Cobalt-Catalyzed Cross-Coupling of Functionalized Bench-Stable Organozinc Pivalates with Unsaturated Halides. AB - We report a robust and broadly applicable CoCl2 -catalyzed cross-coupling between functionalized aryl and heteroaryl zinc pivalates and various electron-poor aryl and heteroaryl halides (X=Cl, Br, I). Couplings with (E)- or (Z)-bromo- or iodo alkenes proceed with retention of configuration. Also, alkynyl bromides react with arylzinc pivalates providing arylated alkynes. PMID- 27981716 TI - Tween 80 and respiratory growth affect metabolite production and membrane fatty acids in Lactobacillus casei N87. AB - AIMS: To evaluate the effect of cultivation (anaerobiosis vs respiration) and Tween 80 supplementation on the production of metabolites and on the composition of membrane fatty acids (FAs) in Lactobacillus casei N87. METHODS AND RESULTS: Anaerobic and respiratory growth, with or without Tween 80 supplementation, was carried out in a chemically defined medium. Production of biomass, organic acids, volatile organic compounds (VOCs), consumption of amino acids and changes in membrane FAs were investigated. Respiration altered the central metabolism rerouting pyruvate away from lactate accumulation, while Tween 80 had a minor effect on metabolic pathways. VOCs were mainly affected by growth conditions and significant amounts of diacetyl were produced by respiratory cultures. Respiration increased desaturation of membrane lipids and Tween 80 improved the production of essential polyunsaturated FAs. Palmitic acid decreased in Tween supplemented aerated cultures. CONCLUSIONS: Combination of Tween 80 and respiratory growth promoted production of biomass and aroma compounds and affected the composition of membrane FAs in Lact. casei N87. SIGNIFICANCE AND IMPACT OF THE STUDY: Respiration might be exploited in Lact. casei as a natural strategy for the enhanced production of aroma compounds. PMID- 27981717 TI - Effect of varying degrees of renal impairment on the pharmacokinetics and tolerability of taspoglutide. AB - AIM: To evaluate single-dose pharmacokinetics and tolerability of taspoglutide in people with varying degrees of renal impairment and matched healthy participants. METHODS: Participants in the present study were people with mild renal impairment (n = 10), moderate impairment (n = 10), severe impairment (n = 9), and a matched healthy control group (n = 10). Participants received a single subcutaneous injection of taspoglutide (10 mg) on day 1. Plasma and urine drug concentration, antibody formation, vital signs, ECGs and routine laboratory variables were measured frequently and adverse events (AEs) were monitored for 9 weeks. RESULTS: Taspoglutide exposure was higher among participants with moderate and severe renal impairment compared with participants with normal renal function. Mean AUClast was 13% and 38% higher in participants with moderate and severe renal impairment, respectively compared with participants with normal renal function. Likewise, mean peak plasma concentration (Cmax ) was 57% and 93% higher in participants with moderate and severe renal function impairment, respectively, compared with participants with normal renal function. Linear regression analyses showed a statistically significant inverse relationship between taspoglutide exposure parameters (AUC and Cmax ) and creatinine clearance. Higher incidences of gastrointestinal (GI) AEs were reported in participants with severe renal impairment. CONCLUSION: Renal impairment altered the pharmacokinetics of taspoglutide. The degree of renal impairment was associated with an increased exposure to taspoglutide and an increased risk of GI AEs. PMID- 27981719 TI - Prevention and Management of Postpartum Haemorrhage: Green-top Guideline No. 52. PMID- 27981720 TI - Off-licence use of once-daily maraviroc in children and adolescents with perinatally acquired HIV-1 infection. PMID- 27981718 TI - A Redox-Activatable Fluorescent Sensor for the High-Throughput Quantification of Cytosolic Delivery of Macromolecules. AB - Efficient delivery of biomacromolecules (e.g., proteins, nucleic acids) into cell cytosol remains a critical challenge for the development of macromolecular therapeutics or diagnostics. To date, most common approaches to assess cytosolic delivery rely on fluorescent labeling of macromolecules with an "always on" reporter and subcellular imaging of endolysosomal escape by confocal microscopy. This strategy is limited by poor signal-to-noise ratio and only offers low throughput, qualitative information. Herein we describe a quantitative redox activatable sensor (qRAS) for the real-time monitoring of cytosolic delivery of macromolecules. qRAS-labeled macromolecules are silent (off) inside the intact endocytic organelles, but can be turned on by redox activation after endolysosomal disruption and delivery into the cytosol, thereby greatly improving the detection accuracy. In addition to confocal microscopy, this quantitative sensing technology allowed for a high-throughput screening of a panel of polymer carriers toward efficient cytosolic delivery of model proteins on a plate reader. The simple and versatile qRAS design offers a useful tool for the investigation of new strategies for endolysosomal escape of biomacromolecules to facilitate the development of macromolecular therapeutics for a variety of disease indications. PMID- 27981721 TI - A Stereoconvergent Cyclopropanation Reaction of Styrenes. AB - The first stereoconvergent cyclopropanation reaction by means of photoredox catalysis using diiodomethane as the methylene source is described. This transformation exhibits broad functional group tolerance and it is characterized by an excellent stereocontrol en route to trans-cyclopropanes regardless of whether E- or Z-styrene substrates were utilized. PMID- 27981722 TI - Response to Bjorn Hofmann: Clarifying overdiagnosis without losing conceptual complexity. PMID- 27981724 TI - Why the mechanisms of 12-Step behaviour change should matter to clinicians. PMID- 27981723 TI - MicroRNA-155 is a biomarker of T-cell activation and immune dysfunction in HIV-1 infected patients. AB - OBJECTIVES: MicroRNA-155 (miR-155) regulates T-cell differentiation and activation. It has also been associated with HIV infection. However, it remains unclear whether miR-155 is related to the T-cell response in HIV-infected individuals (e.g. T-cell activation and exhaustion). METHODS: We performed a cross-sectional study involving 121 HIV-1-infected patients on highly active antiretroviral therapy (HAART) and 43 HAART-naive patients. MiR-155 levels in the peripheral blood were determined by quantitative reverse transcription-polymerase chain reaction (PCR). T-cell immune activation, exhaustion, and homeostasis were measured by determining the expression of CD38, programmed death 1 (PD-1) and CD127 via flow cytometry. RESULTS: The levels of miR-155 in total peripheral blood mononuclear cells, CD4 T cells and CD8 T cells from HIV-1-infected patients were increased (P < 0.01). Nonresponders and HAART-naive patients also exhibited a higher percentage of CD8+ CD38+ T cells and a lower percentage of CD4+ CD127+ and CD8+ CD127+ T cells (P < 0.05). We also found higher levels of PD-1 expression on the CD4+ and CD8+ T cells of HIV-1-infected patients (P < 0.05). CONCLUSIONS: Our findings suggest that miR-155 levels in the peripheral blood of HIV-1-infected patients are increased and associated with T-cell activation. Therefore, miR-155 is a potential biomarker of the immune response following HIV 1 infection. PMID- 27981725 TI - Development of Gold-catalyzed [4+1] and [2+2+1]/[4+2] Annulations between Propiolate Derivatives and Isoxazoles. AB - Two new gold-catalyzed annulations of isoxazoles with propiolates have been developed. Most isoxazoles follow an initial O attack on the alkyne to afford a [4+1] annulation product. This process results in a remarkable alkyne cleavage of initial propiolates. Unsubstituted isoxazoles proceed through an N attack step to yield formal [2+2+1]/[4+2] annulation products. These two annulation products arise initially from two seven-membered heterocyclic intermediates, which then lead to products. PMID- 27981726 TI - Transgenic tobacco plants constitutively expressing peanut BTF3 exhibit increased growth and tolerance to abiotic stresses. AB - Abiotic stresses limit crop growth and productivity worldwide. Cellular tolerance, an important abiotic stress adaptive trait, involves coordinated activities of multiple proteins linked to signalling cascades, transcriptional regulation and other diverse processes. Basal transcriptional machinery is considered to be critical for maintaining transcription under stressful conditions. From this context, discovery of novel basal transcription regulators from stress adapted crops like peanut would be useful for improving tolerance of sensitive plant types. In this study, we prospected a basal transcription factor, BTF3 from peanut (Arachis hypogaea L) and studied its relevance in stress acclimation by over expression in tobacco. AhBTF3 was induced under PEG-, NaCl-, and methyl viologen-induced stresses in peanut. The constitutive expression of AhBTF3 in tobacco increased plant growth under non stress condition. The transgenic plants exhibited superior phenotype compared to wild type under mannitol- and NaCl-induced stresses at seedling level. The enhanced cellular tolerance of transgenic plants was evidenced by higher cell membrane stability, reactive oxygen species (ROS) scavenging activity, seedling survival and vigour than wild type. The transgenic lines showed better in vitro regeneration capacity on growth media supplemented with NaCl than wild type. Superior phenotype of transgenic plants under osmotic and salinity stresses seems to be due to constitutive activation of genes of multiple pathways linked to growth and stress adaptation. The study demonstrated that AhBTF3 is a positive regulator of growth and stress acclimation and hence can be considered as a potential candidate gene for crop improvement towards stress adaptation. PMID- 27981727 TI - Catalysis with Chalcogen Bonds. AB - Herein, we introduce catalysts that operate with chalcogen bonds. Compared to conventional hydrogen bonds, chalcogen bonds are similar in strength but more directional and hydrophobic, thus ideal for precision catalysis in apolar solvents. For the transfer hydrogenation of quinolines and imines, rate enhancements well beyond a factor of 1000 are obtained with chalcogen bonds. Better activities with deeper sigma holes and wider bite angles, chloride inhibition and correlation with computed anion binding energies are consistent with operational chalcogen bonds. Comparable to classics, such as 2,2'-bipyrroles or 2,2'-bipyridines, dithieno[3,2-b;2',3'-d]thiophenes (DTTs), particularly their diimides, but also wide-angle cyclopentadithiazole-4-ones are identified as privileged motifs to stabilize transition states in the focal point of the sigma holes on their two co-facial endocyclic sulfur atoms. PMID- 27981728 TI - Physicians' response to sexual dysfunction presented by a younger vs. An older adult. AB - AIM: The aim of this study is to determine whether physicians have an age bias regarding sexual dysfunction presented by older vs. younger patients in terms of attributed diagnosis, etiology, proposed treatment and perceived prognosis. METHOD: An on-line survey consisting of one of two, randomly administered, case vignettes, which differed only by the age of the patient (28 or 78). In both cases, the patient was described as suffering from occasional erectile dysfunction with a clear psychosocial indication. A total of 236 physicians responded to the survey. Overall, 110 physicians received an "old" vignette and 126 physicians received a "young" vignette. RESULTS: Even though both cases presented with a clear psychosocial etiology, the "older" vignette was more likely to be diagnosed with erectile dysfunction whereas the "younger" vignette was more likely to be diagnosed with performance anxiety. The "older" vignette's dysfunction was more likely to be attributed to hormonal changes, health problems and decreased sexual desire. Physicians were more likely to recommend testosterone replacement therapy (TRT) and PDE5 inhibitors (PDE5i; such as Sildenafil; Vardenafil; Tadalafil) as well as a referral to urology to the "older" vignette. In contrast, the "younger" vignette was more often referred to a sexologist and received a more positive prognosis than the older patient. CONCLUSIONS: This study demonstrates an age bias among physicians regarding sexuality in later life. Of particular note is the tendency to prescribe PDE5i to the older patient, despite the clear psychosocial indication presented in the case vignette. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27981729 TI - The flagellar master operon flhDC is a pleiotropic regulator involved in motility and virulence of the fish pathogen Yersinia ruckeri. AB - AIMS: To investigate the function of the master flagellar operon flhDC in the fish pathogen Yersinia ruckeri and compare the effect of a constructed flhD mutation to a naturally occurring fliR mutation causing loss-of-motility in emergent biotype 2 (BT2) strains. METHODS AND RESULTS: Yersinia ruckeri flhD and fliR mutants were constructed in a motile strain. Both mutations caused loss-of motility, ablation of flagellin synthesis and phospholipase secretion, similar to naturally occurring BT2 strains. Transcriptome analysis confirmed flhDC regulation of flagellar, chemotaxis and phospholipase loci as well as other genes of diverse function. The flhD mutation confers a competitive advantage within the fish host when compared with its parent strain, while this advantage was not seen with the naturally occurring fliR mutation. CONCLUSIONS: An intact flhD is necessary for expression of the flagellar secretion system as well as other diverse loci, consistent with a role for flhD as a pleiotropic regulator. The maintenance of the flhD locus in Y. ruckeri strains suggests its importance for aspects of Y. ruckeri biology other than virulence, since the flhD mutation conferred a competitive advantage during experimental challenge of rainbow trout. SIGNIFICANCE AND IMPACT OF THE STUDY: Yersinia ruckeri is the causative agent of enteric red mouth disease, an invasive septicaemia that affects farmed salmonid fish species. Disease outbreaks can cause severe economic losses in aquaculture. BT2 variants, which have independently emerged worldwide, are an increasing threat to farmed fish production. Knowledge of mechanisms involved in virulence, conserved functions and gene regulation among strains may be exploited for the development of novel disease control strategies to prevent pathogen growth or virulence phenotypes within aquaculture. PMID- 27981730 TI - The importance of economic analyses in health care: examining the economics of preterm prelabour rupture of membranes care. PMID- 27981731 TI - Robotic salvage retroperitoneal and pelvic lymph node dissection for 'node-only' recurrent prostate cancer: technique and initial series. AB - OBJECTIVES: To describe the technique of robot-assisted high-extended salvage retroperitoneal and pelvic lymphadenectomy (sRPLND+PLND) for 'node-only' recurrent prostate cancer. PATIENTS AND METHODS: In all, 10 patients underwent robot-assisted sRPLND+PLND (09/2015-03/2016) for 'node-only' recurrent prostate cancer, as identified by 11 C-acetate positron emission tomography/computed tomography imaging. Our anatomical template extends from bilateral renal artery/vein cranially up to Cloquet's node caudally, completely excising lymphatic-fatty tissue from aorto-caval and iliac vascular trees; RPLND precedes PLND. Meticulous node-mapping assessed nodes at four prospectively assigned anatomical zones. RESULTS: The median operative time was 4.8 h, estimated blood loss 100 mL and hospital stay 1 day. No patient had an intraoperative complication, open conversion or blood transfusion. Three patients had spontaneously resolving Clavien-Dindo grade II postoperative complications. The mean (range) number of nodes excised per patient was 83 (41-132) and mean (range) number of positive nodes per patient was 23 (0-109). Seven patients (70%) had positive nodes on final pathology. Node-positive rates per anatomical level I, II, III and IV were 28%, 32%, 33% and 33%, respectively. In patients with positive nodes, the median PSA level had decreased by 83% at the 2-month follow up. CONCLUSION: The initial series of robot-assisted sRPLND+PLND is presented, wherein we duplicate open surgery with superior nodal counts and decreased morbidity. Robot-assisted technical details for an anatomical LND template up to the renal vessels are presented. Longer follow-up is necessary to assess oncological outcomes. PMID- 27981732 TI - Clinical impact of 68 Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with prostate cancer with rising prostate-specific antigen after treatment with curative intent: preliminary analysis of a multidisciplinary approach. AB - OBJECTIVE: To assess the impact of a novel molecular imaging technique, 68 Ga (HBED-CC)-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT), in the clinical management of patients with prostate cancer with rising prostate-specific antigen (PSA) after treatment with curative intent. PATIENTS AND METHODS: In all, 131 consecutive patients were referred to our centre for a 68 Ga-PSMA PET/CT in the setting of recurring prostate cancer. Of these patients, 11/131(8%) presented with persistent PSA after radical prostatectomy, while 120/131 (92%) were referred for biochemical recurrence after surgery, radiotherapy or both. The images where taken 1 h after injection of 2 MBq/kg of the 68 Ga-(HBED-CC)-PSMA ligand. All examinations were interpreted by two experienced nuclear medicine specialists. Using the results of the examination, a multidisciplinary oncology committee (MOC) reported on the treatment strategy. A positive impact on clinical management was considered if the examination determined a modification in the treatment strategy compared to the MOC decision before PSMA imaging. RESULTS: All patients completed the examination with no adverse reactions. The median (interquartile range) PSA level at the time of the examination was 2.2 (0.72-6.7) ng/mL. Overall, 68 Ga-PSMA PET/CT detected at least one lesion suspicious for prostate cancer in 98/131 (75%) patients. There was an impact on subsequent management in 99/131 patients (76%). The main modifications included continuing surveillance (withholding hormonal therapy), hormonal manipulations, stereotaxic radiotherapy, salvage radiotherapy, salvage node dissection or salvage local treatment (prostatectomy, high-intensity focussed ultrasound). CONCLUSION: Our preliminary experience suggests that performing 68 Ga-PSMA PET/CT in patients with prostate cancer with rising PSA after treatment with curative intent can be clinically useful as it changes the treatment strategy in a significant proportion of patients. However, larger prospective trials are needed to validate our present findings. PMID- 27981733 TI - High-Performance Electrolytic Oxygen Evolution in Neutral Media Catalyzed by a Cobalt Phosphate Nanoarray. AB - The topotactic conversion of cobalt phosphide nanoarray on Ti mesh into a cobalt phosphate nanoarray (Co-Pi NA) via oxidative polarization in phosphate-buffered water is presented. As a 3D oxygen evolution reaction (OER) catalyst electrode at neutral pH, the resulting Co-Pi NA/Ti shows exceptionally high catalytic activity and demands an overpotential of only 450 mV to drive a geometrical catalytic current density of 10 mA cm-2 . Notably, this catalyst also shows superior long term electrochemical stability. The excellent catalytic activity can be attributed to that such 3D nanoarray configuration allows for the exposure of more active sites and the easier diffusion of electrolytes and oxygen. PMID- 27981736 TI - Frontal theta activation associated with error detection in toddlers: influence of familial socioeconomic status. AB - Error detection is one of the functions of the executive attention network, a brain system involved in executive control that includes the anterior cingulate cortex and other prefrontal regions. Despite the key role of this function in a wide range of life outcomes, very limited research has examined the early development of the network and whether its functional efficacy is related to environmental factors. Electrophysiological studies with adults have shown oscillatory activity in theta (4-7 Hz) range arising from medial frontal cortex that follows the detection of self-committed or observed errors. In the current study, we designed a novel experimental procedure that involved a familiarization phase with simple three-pieces puzzles followed by an experimental phase in which toddlers observed the puzzles being formed either correctly or incorrectly. Observation of incorrect configurations produced increased potentials in midline channels and greater power theta activity for both toddlers (n = 56) and adults (n = 14). In addition, socioeconomic status of the family in general, and parental education in particular, contributed to individual differences in the amplitude of the error-related signal and associated theta power in toddlers, indicating that children raised in lower SES families show poorer activation of the executive attention network. These data demonstrate the influence of environmental factors at the earliest stages of development of the executive attention network. Importantly, the results show that error-detection EEG signals can be used as neural markers of the initial development of executive attention, which can be of great help for the early detection of risk for developmental disorders involving deficits in this function. PMID- 27981734 TI - Hyperemesis gravidarum and long-term mortality: a population-based cohort study. AB - OBJECTIVE: To investigate whether exposure to hyperemesis gravidarum (HG) is associated with increased maternal long-term mortality. DESIGN: Population-based cohort study. SETTING: Medical Birth Registry of Norway (1967-2002) linked to the Cause of Death Registry. POPULATION: Women in Norway with singleton births in the period 1967-2002, with and without HG. Women were followed until 2009 or death. METHODS: Cox proportional hazard regression model was applied to estimate hazard ratios (HRs) with 95% confidence interval (CI). MAIN OUTCOME MEASURES: The primary outcome was all-cause mortality during follow up. Secondary outcomes were cause-specific mortality (cardiovascular mortality, deaths due to cancer, external causes or mental and behavioural disorders). RESULTS: Of 999 161 women with singleton births, 13 397 (1.3%) experienced HG. During a median follow up of 26 years (25 902 036 person-years), 43 470 women died (4.4%). Women exposed to HG had a lower risk of long-term all-cause mortality compared with women without HG (crude HR 0.82; 95% CI 0.75-0.90). When adjusting for confounders, this reduction was no longer significant (adjusted HR 0.92; 95% CI 0.84-1.01). Women exposed to HG had a similar risk of cardiovascular death as women not exposed (adjusted HR 1.04; 95% CI 0.83-1.29), but a lower long-term risk of death from cancer (adjusted HR 0.86; 95% CI 0.75-0.98). CONCLUSION: In this large population-based cohort study, HG was not associated with an increased risk of long-term all-cause mortality. Women exposed to HG had no increase in mortality due to cardiovascular disease, but had a reduced risk of death from cancer. TWEETABLE ABSTRACT: Population-based cohort study: Hyperemesis was not associated with an increased risk of long-term mortality. PMID- 27981737 TI - Early induction of pyruvate dehydrogenase kinase 4 by retinoic acids in adipocytes. AB - SCOPE: Vitamin A and its metabolites, such as retinoic acids (RA), are related to metabolic diseases, in particular insulin resistance and obesity. Here, we studied the roles of 9-cis RA and all-trans RA on the regulation of pyruvate dehydrogenase kinase 4 (PDK4), an enzyme involved in fatty acid reesterification, which is a crucial metabolic pathway in adipose tissue (AT) lipid homeostasis. METHODS AND RESULTS: 9-cis RA and all-trans RA treatment of human and murine AT explants, as well as adipocytes (3T3-F442A cell line) induces PDK4 expression both at the mRNA and the protein level, via a transcriptional mechanism. Using site-directed mutagenesis and chomatin immuno-precipitation, we showed that this activation involves two new RA responsive elements in the Pdk4 promoter, RAREa (DR1: -125/-112) and RAREb (DR1: -86/-73), specific to AT. Furthermore, even though endogeneous Pdk4 gene was upregulated by RA in Fao cells, a rat hepatoma cell line, the induction did not occur through the newly found RAREs. CONCLUSION: In this study, we showed that adipocyte PDK4 gene is a new target of the vitamin A derived RA and might participate to the reduced fatty acid efflux from the adipocyte, a step that plays an important role in the developement of metabolic diseases. PMID- 27981739 TI - Judgments of damage to public versus private property in Chinese children at different historical times. AB - This study examined children's judgments of damage to public versus private property in China at two historical times. Participants were two cohorts (1980 and 2012) of elementary school children at ages 7, 9, and 11 years. The children were administered paired stories that described a protagonist who damaged public or private property with a good or bad intention. The results showed that children in the 2012 cohort were less likely than their counterparts in the 1980 cohort to judge damage to public property as more culpable than damage to private property. The cohort differences were more evident in older children than in younger children. The results suggest that macro-level contexts may play an important role in shaping children's judgments. PMID- 27981738 TI - Comparison of exposure response relationship of atrasentan between North American and Asian populations. AB - AIMS: The selective endothelin (ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan. MATERIALS AND METHODS: Two 12-week double-blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians (N = 77) and North Americans (N = 134). Atrasentan plasma concentration was measured in 161 atrasentan-treated patients. RESULTS: Mean albuminuria reduction in Asian, compared to North American, patients was, respectively, -34.4% vs -26.3% for 0.75 mg/d ( P = .44) and -48.0% vs -28.9% for 1.25 mg/d ( P = .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration; P = .024). Body surface area (beta = -1.09 per m2 ; P < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (beta = 0.69 per mg/dL increment; P = .010) were independent determinants of atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between Asian and North American populations. CONCLUSION: The higher exposure and albuminuria reduction of atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to atrasentan-induced sodium retention. PMID- 27981740 TI - Maternal vitamin D status during pregnancy and risk of childhood asthma: A meta analysis of prospective studies. AB - SCOPE: Mounting evidence suggests that maternal vitamin D status during pregnancy may be associated with development of childhood asthma, but the results are still inconsistent. A dose-response meta-analysis was performed to quantitatively summarize evidence on the association of maternal vitamin D status during pregnancy with the risk of childhood asthma. METHODS AND RESULTS: A systematic search was conducted to identify all studies assessing the association of maternal 25-hydroxyvitamin D (25(OH)D) during pregnancy with risk of childhood asthma. The fixed or random-effect model was selected based on the heterogeneity test among studies. Nonlinear dose-response relationship was assessed by restricted cubic spline model. Fifteen prospective studies with 12 758 participants and 1795 cases were included in the meta-analysis. The pooled relative risk of childhood asthma comparing the highest versus lowest category of maternal 25(OH)D levels was 0.87 (95% confidence interval, CI, 0.75-1.02). For dose-response analysis, evidence of a U-shaped relationship was found between maternal 25(OH)D levels and risk of childhood asthma (Pnonlinearity = 0.02), with the lowest risk at approximately 70 nmol/L of 25(OH)D. CONCLUSION: This dose response meta-analysis suggested a U-shaped relationship between maternal blood 25(OH)D levels and risk of childhood asthma. Further studies are needed to confirm the association. PMID- 27981741 TI - Lesbian and bisexual women's likelihood of becoming pregnant: a systematic review and meta-analysis. AB - BACKGROUND: Few data exist regarding pregnancy in lesbian and bisexual (LB) women. OBJECTIVES: To determine the likelihood of LB women becoming pregnant, naturally or assisted, in comparison with heterosexual women SEARCH STRATEGY: Systematic review of papers published 1 January 2000 to 23 June 2015. SELECTION CRITERIA: Studies contained details of pregnancy rates among LB women compared with heterosexual women. No restriction on study design. DATA COLLECTION AND ANALYSIS: Inclusion decisions, data extraction and quality assessment were conducted in duplicate. Meta-analyses were carried out, with subgroups as appropriate. MAIN RESULTS: Of 6859 papers identified, 104 full-text articles were requested, 30 papers (28 studies) were included. The odds ratio (OR) of ever being pregnant was 0.19 (95% CI 0.18-0.21) in lesbian women and 1.22 (95% CI 1.15 1.29) in bisexual women compared with heterosexual women. In the general population, the odds ratio for pregnancy was nine-fold lower among lesbian women and over two-fold lower among bisexual women (0.12 [95% CI 0.12-0.13] and 0.50 [95% CI 0.45-0.55], respectively). Odds ratios for pregnancy were higher for both LB adolescents (1.37 [95% CI 1.18-1.59] and 1.98 [95% CI 1.85, 2.13], respectively). There were inconsistent results regarding abortion rates. Lower rates of previous pregnancies were found in lesbian women undergoing artificial insemination (OR 0.17 [95% CI 0.11-0.26]) but there were higher assisted reproduction success rates compared with heterosexual women (OR 1.56 [95% CI 1.24 1.96]). CONCLUSIONS: Heterosexuality must not be assumed in adolescents, as LB adolescents are at greater risk of unwanted pregnancies and terminations. Clinicians should provide appropriate information to all women, without assumptions about LB patients' desire for, or rejection of, fertility and childbearing. TWEETABLE ABSTRACT: Review of likelihood of LB women becoming pregnant: LB teenagers at greater risk of unwanted pregnancies. PMID- 27981742 TI - Maternal and neonatal outcomes of pregnancies in women with Addison's disease: a population-based cohort study on 7.7 million births. AB - OBJECTIVE: To assess if pregnancies among women with Addison's disease (AD) are at higher risk of adverse maternal and neonatal outcomes. DESIGN: Population based retrospective cohort study. SETTING/POPULATION: All births in the United States' Healthcare Cost and Utilization Project-Nationwide Inpatient Sample from 2003 to 2011. METHODS: Baseline characteristics were compared between women with AD and those without, and prevalence over time was measured. Logistic regression was used to estimate the effect of AD on maternal and neonatal outcomes by calculating the crude and adjusted odds ratios (OR) and corresponding 95% confidence intervals (95% CI). RESULTS: We calculated a prevalence of AD in pregnancy of 5.5/100 000, increasing from 5.6 to 9.6/100 000 (P = 0.0001) over the 9-year study period. Compared with women without AD, women with AD were more likely to deliver preterm (OR 1.50, 95% CI 1.16-1.95), deliver by caesarean section (OR 1.32, 95% CI 1.08-1.61), have impaired wound healing (OR 4.28, 95% CI 2.55-7.18), develop infections (OR 2.44, 95% CI 1.66-3.58) and develop thromboembolism (OR 5.21, 95% CI 2.15-12.63), require transfusions (OR 6.69, 95% CI 4.69-9.54), and have prolonged postpartum hospital admissions (OR 5.71, 95% CI 4.37-7.47). Maternal mortality was significantly higher than in the comparison group (OR 22.30, 95% CI 6.82-72.96). Congenital anomalies (OR 3.62, 95% CI 2.05 6.39) and small-for-gestational age infants (OR 1.78, 95% CI 1.15-2.75) were more likely in these pregnancies. CONCLUSIONS: Addison's disease significantly increases the risk of severe adverse maternal and neonatal outcomes, so pregnant women with AD are best managed in tertiary-care centres. TWEETABLE ABSTRACT: Pregnancies complicated by Addison's disease have an increased risk of adverse maternal and neonatal outcomes. PMID- 27981743 TI - Whey protein isolate improves vitamin B12 and folate status in elderly Australians with subclinical deficiency of vitamin B12. AB - SCOPE: Whey protein isolate (WPI) contains vitamin B12 and folate. However, the efficacy of WPI as a bioavailable source of these vitamins in the elderly with low vitamin B12 was not previously tested. We investigated the effects of WPI supplementation on vitamin B12 and folate status in blood and measured changes in homocysteine (HCY), methylmalonic acid (MMA), and genome integrity biomarkers in elderly individuals with low vitamin B12 status. The effect of WPI was compared to soy protein isolate (SPI). METHODS AND RESULTS: In this randomized controlled cross-over intervention trial, 56 subclinically vitamin B12 -deficient participants received 50 g WPI or 50 g SPI as a control for 8 wk followed by 16 wk washout phase and then cross-over to alternative supplement for next 8 wk. Consumption of WPI resulted in significant increase in serum active B12 (p < 0.0001) and serum folate (p = 0.0094). MMA, HCY, and nucleoplasmic bridges increased significantly after SPI intake but not after WPI (p = 0.052; p = 0.028; p = 0.0009, respectively). CONCLUSION: Results indicate that WPI consumption improves active B12 and folate status. Unlike SPI, WPI consumption may prevent increase in MMA, HCY, and genome instability in older Australians with low vitamin B12 status. PMID- 27981744 TI - Influence of a community-based stretching intervention on the health outcomes among Korean-Chinese female migrant workers in South Korea: A randomized prospective trial. AB - AIM: To investigate the long-term effectiveness of stretching exercises on the health outcomes of Korean-Chinese female migrant workers. METHODS: This study was a randomized prospective trial. The study's participants (n = 80) were middle aged, Korean-Chinese women who had worked full-time during the previous 6 months. They were assigned randomly to an enhanced stretching intervention group or a standard stretching intervention group. Both groups were instructed to carry out a structured 6 min stretching exercise program for at least three times per day and 5 days per week. The enhanced intervention group received additional interventions to increase exercise adherence through individual phone counseling and short message service during the 12 weeks, followed by three sets of acculturation workshops during the period of weeks 13-24. Musculoskeletal fitness, symptoms, and acculturative stress were assessed at baseline, week 12, and week 24. Linear mixed-models were used to test the interventions' effects. RESULTS: The amount of stretching that was carried out, as a percentage of the recommended amount, was not significantly different between groups. There were significant improvements in flexibility of the back and work-related musculoskeletal disorder symptoms after completing the 24 week intervention but no significant difference existed between the groups. Acculturative stress decreased at week 12 but there was no significant change at week 24. CONCLUSIONS: The 24 week, community-based stretching program for the Korean-Chinese female migrant workers was effective in increasing their flexibility and decreasing work related musculoskeletal disorder symptoms. Culturally adaptive augmented interventions to increase social support are suggested in order to reduce acculturative stress. PMID- 27981745 TI - Assisted reproductive technology and severe postpartum haemorrhage: a case control study. AB - OBJECTIVE: To investigate the association between assisted reproductive technology and severe postpartum haemorrhage. DESIGN: Case-control study. SETTING: The study was conducted in Norway; Division of Gynaecology and Obstetrics at Oslo University Hospital and Department of Obstetrics and Gynaecology at Drammen Hospital. POPULATION: A source population including all women admitted for delivery at Oslo University Hospital and Drammen Hospital during the time period 1 January 2008 to 31 December 2011. The study population consisted of all cases of severe postpartum haemorrhage (n = 1064) and a random sample of controls (n = 2059). METHODS: We used an explanatory strategy in the analysis, with multivariable logistic regression. MAIN OUTCOME MEASURES: Severe postpartum haemorrhage; defined as blood loss >=1500 ml or need for blood transfusion. RESULTS: Assisted reproductive technology was associated with an increased risk of severe postpartum haemorrhage (crude OR = 2.92; 95% CI 2.18 3.92, P < 0.001). Mode of delivery and anticoagulant medication had significant confounding effects. Strong interaction was found for multiple pregnancies. After adjusting for confounding and interaction, an increased risk was observed both in the strata of multiple pregnancies (adjusted OR = 7.00, 95% CI 2.70-18.12, P < 0.001), and in the strata of single gestation (adjusted OR = 1.58, 95% CI 1.12 2.24, P = 0.010). CONCLUSIONS: Our findings warrant an increased awareness of the risk of severe postpartum haemorrhage in women conceiving with assisted reproductive technology. Furthermore, the high risk of severe postpartum haemorrhage in the presence of a twin or triplet pregnancy is an additional argument for single embryo transfer. TWEETABLE ABSTRACT: Assisted reproductive technology is associated with an increased risk of severe postpartum haemorrhage. PMID- 27981747 TI - When is balloon tamponade more likely to arrest PPH? PMID- 27981746 TI - Galectin-3 promotes caspase-independent cell death of HIV-1-infected macrophages. AB - HIV-1-infected macrophages are a key contributor to the formation of a viral reservoir and new treatment strategies focus on eliminating this pool of virus. Galectin-3 is a potent apoptosis-inducing protein that regulates diverse cellular activities. In the present study, we investigated whether galectin-3 could induce cell death in HIV-1-infected macrophages using HIV-1-infected THP1 monocytes (THP1-MNs) and THP1-derived macrophages (THP1-MPhis) as in vitro cellular models. We found that THP1-MPhis were more resistant than the THP1-MNs to HIV-1 infection induced death, and that HIV-1 infection of the THP1-MPhis increased expression of the anti-apoptotic proteins Mcl-1, Bcl-2 and Bcl-xL. Additionally, galectin-3 but not FasL, tumor necrosis factor (TNF)-related apoptosis-inducing ligand or TNF alpha, could induce cell death in HIV-1-infected THP1-MPhis. A similar result was shown for primary human monocyte-derived macrophages. Galectin-3-induced cell death was also significantly increased in macrophages obtained from SIVmac251 infected macaques compared to that of macrophages from healthy macaques. Furthermore, galectin-3-induced cell death in HIV-1-infected THP1-MPhis was caspase independent. Interestingly, endonuclease G (Endo G) was increased in the nucleus and decreased in the cytoplasm of galectin-3-treated cells; thus, galectin-3-induced cell death in HIV-1-infected THP1-MPhis is most likely related to the translocation of Endo G from the cytoplasm to the nucleus. These findings suggest that galectin-3 may potentially aid in the eradication of HIV-1/SIV infected macrophages. PMID- 27981748 TI - Acute effects of water immersion on heart rate variability in participants with heart disease. AB - BACKGROUND: Water immersion and aquatic exercise can be an important therapeutic tool in patients suffering from heart disease (HD). However, the effects of water immersion on heart rate variability (HRV) in HD participants remain unknown. METHODS: Twenty-eight volunteers in sinus rhythm within the same age range took part in this study: 18 HD and ten healthy controls (HC). Heart rhythm was collected with a heart rate monitor (sampling rate 1000 Hz) for periods of 10 min at rest in the supine position on land, standing on land (STL) and standing in water (STW) to the xiphoid process. RESULTS: Heart disease participants had the same response as HC participants to the three experimental conditions (no significant between-group differences in all HRV variables). STW (immersion) caused in both groups to increase HRV when compared to supine and STL. CONCLUSION: Heart disease participants demonstrate similar beneficial adaptations as HC participants to the effects of immersion, reinforcing the concept that immersion can be a valuable aquatic cardiac rehabilitation tool to acutely increase HRV. Approaches that improve HRV in both healthy and cardiac patients may have a positive impact on the reduction of morbidity and mortality. PMID- 27981749 TI - Motivating women and their partners to participate in childbirth education and increasing natural delivery rates in Iran. PMID- 27981750 TI - Isomeric Detergent Comparison for Membrane Protein Stability: Importance of Inter Alkyl-Chain Distance and Alkyl Chain Length. AB - Membrane proteins encapsulated by detergent micelles are widely used for structural study. Because of their amphipathic property, detergents have the ability to maintain protein solubility and stability in an aqueous medium. However, conventional detergents have serious limitations in their scope and utility, particularly for eukaryotic membrane proteins and membrane protein complexes. Thus, a number of new agents have been devised; some have made significant contributions to membrane protein structural studies. However, few detergent design principles are available. In this study, we prepared meta and ortho isomers of the previously reported para-substituted xylene-linked maltoside amphiphiles (XMAs), along with alkyl chain-length variation. The isomeric XMAs were assessed with three membrane proteins, and the meta isomer with a C12 alkyl chain was most effective at maintaining solubility/stability of the membrane proteins. We propose that interplay between the hydrophile-lipophile balance (HLB) and alkyl chain length is of central importance for high detergent efficacy. In addition, differences in inter-alkyl-chain distance between the isomers influence the ability of the detergents to stabilise membrane proteins. PMID- 27981751 TI - Liver fibrosis: Review of current imaging and MRI quantification techniques. AB - : Liver fibrosis is characterized by the accumulation of extracellular matrix proteins such as collagen in the liver interstitial space. All causes of chronic liver disease may lead to fibrosis and cirrhosis. The severity of liver fibrosis influences the decision to treat or the need to monitor hepatic or extrahepatic complications. The traditional reference standard for diagnosis of liver fibrosis is liver biopsy. However, this technique is invasive, associated with a risk of sampling error, and has low patient acceptance. Imaging techniques offer the potential for noninvasive diagnosis, staging, and monitoring of liver fibrosis. Recently, several of these have been implemented on ultrasound (US), computed tomography, or magnetic resonance imaging (MRI). Techniques that assess changes in liver morphology, texture, or perfusion that accompany liver fibrosis have been implemented on all three imaging modalities. Elastography, which measures changes in mechanical properties associated with liver fibrosis-such as strain, stiffness, or viscoelasticity-is available on US and MRI. Some techniques assessing liver shear stiffness have been adopted clinically, whereas others assessing strain or viscoelasticity remain investigational. Further, some techniques are only available on MRI-such as spin-lattice relaxation time in the rotating frame (T1 rho), diffusion of water molecules, and hepatocellular function based on the uptake of a liver-specific contrast agent-remain investigational in the setting of liver fibrosis staging. In this review, we summarize the key concepts, advantages and limitations, and diagnostic performance of each technique. The use of multiparametric MRI techniques offers the potential for comprehensive assessment of chronic liver disease severity. LEVEL OF EVIDENCE: 5 J. MAGN. RESON. IMAGING 2017;45:1276-1295. PMID- 27981752 TI - The effect of physical fatigue on oscillatory dynamics of the sensorimotor cortex. AB - AIM: While physical fatigue is known to arise in part from supraspinal mechanisms within the brain, exactly how brain activity is modulated during fatigue is not well understood. Therefore, this study examined how typical neural oscillatory responses to voluntary muscle contractions were affected by fatigue. METHODS: Eleven healthy adults (age 27 +/- 4 years) completed two experimental sessions in a randomized crossover design. Both sessions first assessed baseline maximal voluntary isometric wrist-flexion force (MVFb ). Participants then performed an identical series of fourteen test contractions (2 * 100%MVFb , 10 * 40%MVFb , 2 * 100%MVFb ) both before and after one of two interventions: forty 12-s contractions at 55%MVFb (fatigue intervention) or 5%MVFb (control intervention). Magnetoencephalography (MEG) was used to characterize both the movement-related mu and beta decrease (MRMD and MRBD) and the post-movement beta rebound (PMBR) within the contralateral sensorimotor cortex during the 40%MVFb test contractions, while the 100%MVFb test contractions were used to monitor physical fatigue. RESULTS: The fatigue intervention induced a substantial physical fatigue that endured throughout the post-intervention measurements (28.9-29.5% decrease in MVF, P < 0.001). Fatigue had a significant effect on both PMBR (anova, session * time-point interaction: P = 0.018) and MRBD (P = 0.021): the magnitude of PMBR increased following the fatigue but not the control interventions, whereas MRBD was decreased post-control but not post-fatigue. Mu oscillations were unchanged throughout both sessions. CONCLUSION: Physical fatigue resulted in an increased PMBR, and offset attenuations in MRBD associated with task habituation. PMID- 27981753 TI - Association between genetic polymorphisms involved in the hypoxia-inducible factor pathway and lung cancer risk: a case-control study in Japan. AB - AIM: Hypoxia-inducible factor (HIF) contributes to the adaptation of tumor cells to hypoxic conditions, so genetic polymorphisms involved in this pathway may affect cellular response to hypoxia and be associated with cancer risk. Thus, we examined the association between the lung cancer risk and genetic polymorphisms involved in the HIF pathway. METHODS: This case-control study consists of 462 lung cancer cases and 379 controls from Japan. We examined the effect of HIF1A rs11549467, HIF1A rs11549465, HIF1A rs2057482, HIF2A rs13419896 and vascular endothelial growth factor A (VEGFA) rs833061 on the risk of lung cancer using TaqMan real-time PCR assay. Logistic regression was used to estimate the odds ratio (OR) and its 95% confidence interval (CI) of lung cancer risk. The multiplicative and additive interactions with cigarette smoking were also examined. RESULTS: The AA genotype of HIF2A rs13419896 (OR = 0.54, 95% CI = 0.30 0.99) and the CC genotype of VEGFA rs833061 (OR = 0.42, 95% CI = 0.24-0.75) were significantly associated with a decreased risk of lung cancer after adjustment of potential covariates. Additive interactions between these two polymorphisms and cigarette smoking were also significant. CONCLUSION: HIF2A rs13419896 and VEGFA rs833061 were significantly related to lung cancer risk, with possible interaction between polymorphisms and cigarette smoking. Further studies are needed to confirm these results. PMID- 27981754 TI - Identification of Predominant Phytochemical Compounds and Cytotoxic Activity of Wild Olive Leaves (Olea europaea L. ssp. sylvestris) Harvested in South Portugal. AB - This study has been aimed at providing a qualitative and quantitative evaluation of selected phytochemicals such as phenolic acids, flavonoids, oleuropein, fatty acids profile, and volatile oil compounds, present in wild olive leaves harvested in Portugal, as well as at determining their antioxidant and cytotoxic potential against human melanoma HTB-140 and WM793, prostate cancer DU-145 and PC-3, hepatocellular carcinoma Hep G2 cell lines, as well as normal human skin fibroblasts BJ and prostate epithelial cells PNT2. Gallic, protocatechuic, p hydroxybenzoic, vanillic acids, apigenin 7-O-glucoside, luteolin 7-O-glucoside, and rutin were identified in olive leaves. The amount of oleuropein was equal to 22.64 g/kg dry weight. (E)-Anethole (32.35%), fenchone (11.89%), and (Z)-3-nonen 1-ol (8%) were found to be the main constituents of the oil volatile fraction, whereas palmitic, oleic, and alpha-linolenic acid were determined to be dominating fatty acids. Olive leaves methanol extract was observed to exerted a significant, selective cytotoxic effect on DU-145 and PC-3 cell lines. Except the essential oil composition, evaluated wild olive leaves, with regard to their quantitative and qualitative composition, do not substantially differ from the leaves of other cultivars grown for industrial purposes and they reveal considerable antioxidant and cytotoxic properties. Thus, the wild species may prove to be suitable for use in traditional medicine as cancer chemoprevention. PMID- 27981755 TI - Student perceptions of workplace-based assessment. AB - BACKGROUND: Workplace-based assessments (WBAs) have become integrated into postgraduate medical training, although there is much negativity from trainees. The objective of this study was to examine medical student understanding and perceptions towards WBAs. METHODS: A questionnaire was administered to final-year medical students at a single institution, examining experience, understanding and perceptions towards WBAs. Rating-scale responses were analysed by calculating positivity estimate values, and categorising data for subgroup comparison. Negativity was the most prevalent overall position of students towards participating in WBAs RESULTS: One hundred and fifteen of 162 (71%) students completed the questionnaire. Almost half the students had experience of WBAs and the majority (90%) reported benefiting from them; however, those with experience did not report more positive perceptions towards WBAs. In contrast, those students who seemed to demonstrate a good understanding of WBAs reported strongly positive perceptions. Interestingly, understanding and experience were not correlated. Negativity was the most prevalent overall position of students towards participating in WBAs as future trainees, with similar concerns reported by trainees, such as availability of time, trainer engagement and a feeling that they are simply 'tick-box' exercises. DISCUSSION: Medical students appear to possess negative perceptions towards WBAs. Although having experience of undertaking WBAs had little impact on their position, possessing an understanding of WBAs seemed to influence perceptions. This suggests that the manner in which medical students are exposed to WBAs should be carefully considered to ensure that it fosters the development of enthusiasm and positivity that can be carried by the students into their professional careers. PMID- 27981758 TI - The FEBS Journal in 2017: quality is its own reward. PMID- 27981756 TI - Maternal diabetes modulates offspring cell proliferation and apoptosis during odontogenesis via the TLR4/NF-kappaB signalling pathway. AB - OBJECTIVES: Maternal gestational diabetes leads to an adverse in utero environment and increases the risk of malformations during embryo organogenesis. In the present study, we analysed the effects of maternal diabetes on tooth germ cell proliferation and apoptosis in offspring, and investigated their underlying mechanisms. MATERIALS AND METHODS: A rat model of maternal diabetes was induced by intraperitoneal injection of streptozotocin and the pregnant rats were divided into three groups: controls, the diabetic group and diabetic group with insulin treatment. Offspring of the three groups were collected and cell proliferation and apoptosis in tooth germs were analysed. Primary dental papilla cells and dental epithelial stem cells were isolated and treated with high glucose in vitro, in an attempt to simulate maternal diabetes-induced hyperglycaemia in vivo. RESULTS: Maternal diabetes significantly affected cell proliferation and apoptosis in offspring tooth germs. The TLR4/NF-KB signalling pathway was activated in the tooth germs of offspring of diabetic dams. High glucose treatment activated the TLR4/NF-KB signalling pathway in primary dental papilla cells and dental epithelial stem cells in vitro, resulting in suppression of cell proliferation and enhancement of apoptosis. TLR4 knockdown significantly reduced adverse effects induced by high glucose treatment. CONCLUSIONS: Maternal gestational diabetes significantly impaired dental epithelial and mesenchymal cell proliferation and apoptosis in offspring, possibly by activation of the TLR4/NF-KB signalling pathway. PMID- 27981759 TI - Writing brilliant manuscripts. PMID- 27981757 TI - Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis. AB - AIMS: To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in people with type 2 diabetes. MATERIALS AND METHODS: We electronically searched, up to June 3, 2016, published randomized clinical trials lasting between 24 and 32 weeks that compared a GLP-1RA (albiglutide, dulaglutide, twice-daily exenatide and once-weekly exenatide, liraglutide, lixisenatide, semaglutide and taspoglutide) with placebo or another GLP-1RA. Data on cardiometabolic and safety outcomes were analysed using a mixed-treatment comparison meta-analysis. RESULTS: A total of 34 trials (14 464 participants) met the inclusion criteria; no published data for semaglutide were available. Compared with placebo, all GLP-1RAs reduced glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels (reductions ranged from -0.55% and -0.73 mmol/L, respectively, for lixisenatide to -1.21% and -1.97 mmol/L, respectively, for dulaglutide). There were no differences within short-acting (twice-daily exenatide and lixisenatide) or long-acting (albiglutide, dulaglutide, once-weekly exenatide, liraglutide and taspoglutide) groups. Compared with twice-daily exenatide, dulaglutide treatment was associated with the greatest HbA1c and FPG reduction (0.51% and 1.04 mmol/L, respectively), followed by liraglutide (0.45% and 0.93 mmol/L, respectively) and once-weekly exenatide (0.38% and 0.85 mmol/L, respectively); similar reductions were found when these 3 agents were compared with lixisenatide. Compared with placebo, all GLP-1RAs except albiglutide reduced weight and increased the risk of hypoglycaemia and gastrointestinal side effects, and all agents except dulaglutide and taspoglutide reduced systolic blood pressure. When all GLP-1RAs were compared with each other, no clinically meaningful differences were observed in weight loss, blood pressure reduction or hypoglycaemia risk. Albiglutide had the lowest risk of nausea and diarrhoea and once-weekly exenatide the lowest risk of vomiting. CONCLUSIONS: The RCTs in the present analysis show that all GLP-1RAs improve glycaemic control, reduce body weight and increase the risk of adverse gastrointestinal symptoms compared with placebo. Although there were no differences when short-acting agents were compared with each other or when long-acting agents were compared with each other, dulaglutide, liraglutide and once-weekly exenatide were superior to twice daily exenatide and lixisenatide at lowering HbA1c and FPG levels. There were no differences in hypoglycaemia between these 3 agents, whilst once-weekly exenatide had the lowest risk of vomiting. These results, along with patient's preferences and individualized targets, should be considered when selecting a GLP-1RA. PMID- 27981760 TI - Infliximab for ipilimumab-induced colitis: A series of 13 patients. AB - OBJECTIVE: To review the outcomes of metastatic melanoma patients treated with infliximab for severe steroid-refractory colitis secondary to ipilimumab therapy. BACKGROUND: Immune-related colitis is a known potential adverse effect of ipilimumab, that causes significant morbidity and extended hospital stays. There are limited outcome data for patients treated with infliximab for ipilimumab induced colitis refractory to corticosteroids. Management guidelines have been developed based on case study evidence only. DESIGN AND SETTING: A retrospective review of all patients administered infliximab for ipilimumab-induced colitis at South Australian public hospitals between October 2011 and April 2015. MAIN OUTCOME MEASURES: Resolution of colitis/diarrhea, duration of hospital stay, dosage regimen of infliximab used (single dose vs multiple dose) and surgical intervention if required. RESULTS: Between October 2011 and April 2015, 106 patients were dispensed ipilimumab from South Australian public hospitals for the treatment of metastatic melanoma. Thirteen were administered infliximab for severe, steroid-refractory colitis secondary to ipilimumab. Sixty-two percent received a single dose of infliximab only. Four patients achieved resolution of colitis symptoms at 1 month postinfliximab. Thirty-three percent required surgical intervention despite treatment with infliximab. One patient declined surgery and subsequently died due to bowel perforation. The average number of overnight bed days due to colitis was 27. CONCLUSION: This series of patients with severe ipilimumab-induced colitis suggests that despite treatment with infliximab a high proportion of patients do not achieve resolution of symptoms. Review of these cases has highlighted the absence of evidence-based guidelines to treat severe, steroid refractory colitis secondary to ipilimumab. Further prospective studies may clarify the role of infliximab for the treatment of ipilimumab-induced colitis. PMID- 27981762 TI - Corrigendum. PMID- 27981761 TI - Everolimus-induced tubular toxicity in non-renal cancer. PMID- 27981763 TI - From medical student to clinician-scientist: where is the pathway in Australia? AB - Clinician-scientists are a valuable resource and are crucial to ensuring that high-quality health and medical research is undertaken and translated to patients. Although the literature notes the global decline in clinician scientists and infers the worldwide similarity in the challenges to reverse this decline, Australia continues to lag behind in establishing an infrastructure to address the dilemma. PMID- 27981765 TI - Corrigendum. PMID- 27981764 TI - Legal and ethical issues associated with Advance Care Directives in an Australian context. AB - The need for appropriate mechanisms guiding end-of-life care is increasingly vital. This commentary compares the use of Advance Care Directives (ACD) in New South Wales and South Australia in order to highlight the inconsistency in Australian legislation, before exploring common problems, legal concerns and ethical issues associated with their application in an adult population. The benefits and detriments of statutory legislation for ACD are also evaluated. PMID- 27981766 TI - Erratum. PMID- 27981767 TI - First reported case of khat cardiomyopathy and malignant hypertension in Australia. PMID- 27981768 TI - Volume 46 contents. PMID- 27981769 TI - Documentation of consent for blood transfusion. AB - In 2012, 110 hospitals reported on consent policy against national guidelines, with 105 (95%) including a statement on blood transfusion. Of the 103 hospitals (1788 transfusion episodes) that participated in the consent practice component, 89 specified the method of consent used; 46 (52%) had a specific transfusion consent form and achieved compliance of 90% compared to 43-69% for most other methods. The consent audit shows that a specific blood consent form achieved a high rate of medical record documentation compliance. PMID- 27981770 TI - Henry Joseph Macauley Barnett, 1922-2016. PMID- 27981771 TI - Goodpasture disease as a consequence of melioidosis. AB - We describe a case of anti-glomerular basement membrane (GBM) antibody-mediated disease in association with concomitant Burkholderia pseudomallei (melioidosis) bacteraemia. The temporal profile of the illness and initial absence of circulating anti-GBM antibodies, in light of the subsequent definitive histological diagnosis of anti-GBM disease, makes this case interesting and unusual. Additionally, there have been no prior case reports suggesting melioidosis as a cause of biopsy-proven glomerulonephritis. PMID- 27981772 TI - Novel oral anticoagulant drugs and severe oesophagitis dissecans. PMID- 27981773 TI - Over-imaging in uncomplicated low back pain: a 12-month audit of a general medical unit. AB - Low back pain is frequently encountered in hospitals and is a leading cause of disability, often involving costly imaging that exposes a patient to radiation. A retrospective 12-month audit at a South Australian tertiary hospital aimed to evaluate the frequency, modality and appropriateness of imaging in patients with low back pain. Results showed that the general medical unit was unnecessarily ordering imaging in 40% of patients who exhibited no indications warranting such a procedure. A standardised protocol is required to preventing clinicians from requesting imaging solely for the purposes of self-reassurance, patient reassurance or fear of litigation. PMID- 27981774 TI - Elderly patients are at high risk of night-time admission to the intensive care unit following a rapid response team call. AB - Previous studies have shown that elderly patients (age >=65 years) are less likely to be admitted to the intensive care unit following a rapid response team call and have high hospital mortality rates. This study has shown that elderly patients have a significantly higher probability of being admitted to an intensive care unit following a rapid response team call at night than during the day. However, at no time are they at greater risk than younger patients of incomplete vital sign recording, a failure to escalate care for acute deterioration or mortality. PMID- 27981775 TI - Kimura disease in a Maori man with nephrotic syndrome. PMID- 27981776 TI - Lyme disease: why the controversy? AB - Some Australians have become convinced of the existence of locally acquired Lyme disease (LD). The history of LD, since its recognition in the early 1970s, is reviewed as a model for investigative approaches to unknown syndromes. Australian Management Guidelines for LD include the requirement for diagnostic testing by National Association of Testing Authorities-accredited laboratories using Therapeutic Goods Administration-licensed tests, which result in the efficient diagnosis of LD in overseas travellers. Despite this, patients who have not left Australia pay many thousands of dollars for non-specialist consultations and testing at overseas laboratories. Unproven long-term therapy with multiple antibiotics has resulted in serious complications, including allergies, line sepsis, pancreatitis and pseudomembranous colitis. Studies have shown that LD vectors are not found in Australia, and Lyme Borrelia has not been found in Australian vectors, animals or patients with autochthonous illnesses. I propose that (i) A non-controversial name for the chronic syndrome should be adopted, 'Australian Multisystem Disorder'. (ii) Research funding should enable the development of a consensus case definition and studies of the epidemiology of this syndrome with laboratory investigations to identify an aetiology and surrogate markers of disease. Prospective, randomised treatment studies could then be undertaken using ethical protocols. PMID- 27981777 TI - Enough is enough ... a call to action to improve ethical and governance review processes in Australia. PMID- 27981778 TI - Fibroids and IVF: retrospective studies or randomised clinical trials? PMID- 27981779 TI - Thalamic dopaminergic neurons projects to the paraventricular nucleus-rostral ventrolateral medulla/C1 neural circuit. AB - Paraventricular nuclei (PVN) projections to the rostral ventrolateral medulla (RVLM)/C1 catecholaminergic neuron group constitute the pre-autonomic sympathetic center involved in the neural control of systemic cardiovascular function. However, the role of extra-hypothalamic and thalamic dopaminergic (DA) inputs in this circuit remains underexplored. Using retrograde neuroanatomical tracing and high contrast confocal imaging methods, we investigated the projections and morphology of the discrete thalamic DA neuron groups in the dorsal hypothalamic area and their contribution to the PVN-RVLM neural circuit. We found that DA neuron subgroups in the Zona Incerta (Zi; 60%) and Reuniens thalamic nuclei (Re; 40%) were labeled comparably to the PVN (85%) after a retrograde tracer was injected into the RVLM/C1 (P < 0.01 mean +/- SEM). The Re/Zi DA neuron subgroups were characterized by angulated cell bodies, superiomedial and inferiomedial projections reaching the contralateral Re/Zi and ipsilateral PVN DA neurons respectively. Ultimately, we deduced that the DA projections of the Re/Zi to the PVN contribute to the PVN-RVLM/C1 neural circuit. As a result of these connections, the Re/Zi DA neuron groups may regulate preautonomic sympathetic events associated with the PVN-RVLM pathway. Anat Rec, 300:1307-1314, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27981780 TI - Skull Anatomy and Ontogeny of Legless Lizard Pseudopus apodus (Pallas, 1775): Heterochronic Influences on Form. AB - Pseudopus apodus (Pallas, 1775) is the largest extant legless species of the subfamily Anguinae (Anguimorpha, Anguidae) living mostly in the sub-arid territories ranging from the Balkan area in Europe to Kazakhstan in Asia. The species of other two genera live in North America, South-East Asia and North Africa (Ophisaurus) and Europe and South-West Asia (Anguis). The interrelationships of Anguinae are unresolved; this is in part the consequence of the insufficient knowledge of the cranial, postcranial and integumentary anatomy of the individual anguine species. The aim of this article is to fulfill this gap in our knowledge of the anguine anatomy. Now, in the first part of the project, the individual bones of the exocranium and visceral endocranium of the anguine legless lizard P. apodus are described in detail. In the present study, P. apodus is revealed to have autoapomorphic features of the skull which clearly distinguish it from Anguis and Ophisaurus. In addition, the study of posthatchling ontogeny of exocranium of P. apodus revealed some features, such as a nasal process of premaxilla being slightly widened in about its mid-length, that are also typical for adults of the Ophisaurus and Anguis species as well as extinct species of Pseudopus. This strongly indicates that peramorphic heterochronic process played role in the evolution of the P. apodus skull. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:460-502, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27981782 TI - Neuromuscular changes and the rapid adaptation following a bout of damaging eccentric exercise. AB - INTRODUCTION: An initial bout of eccentric exercise is known to protect against muscle damage following a repeated bout of the same exercise; however, the neuromuscular adaptations owing to this phenomenon are unknown. AIM: To determine whether neuromuscular disturbances are modulated following a repeated bout of eccentric exercise. METHODS: Following eccentric exercise performed with the elbow flexors, we measured maximal voluntary force, resting twitch force, muscle soreness, creatine kinase (CK) and voluntary activation (VA) using motor point and motor cortex stimulation at baseline, immediately post-exercise and at 1, 2, 3, 4 and 7 days post-exercise on two occasions, separated by 3 weeks. RESULTS: Significant muscle damage and fatigue were evident following the first exercise bout; maximal voluntary contraction (MVC) was reduced immediately by 35% and remained depressed at 7 days post-exercise. Soreness and CK release peaked at 3 and 4 days post-exercise respectively. Resting twitch force remained significantly reduced at 7 days (-48%), whilst VA measured with motor point and motor cortex stimulation was reduced until 2 and 3 days respectively. A repeated bout effect (RBE) was observed with attenuated soreness and CK release and a quicker recovery of MVC and resting twitch force. A similar decrement in VA was observed following both bouts; however, following the repeated bout there was a significantly smaller reduction in, and a faster recovery of, VA measured using motor cortical stimulation. CONCLUSION: Our data suggest that the RBE may be explained, partly, by a modification in motor corticospinal drive. PMID- 27981783 TI - New insights into the antiangiogenic and proangiogenic properties of dietary polyphenols. AB - Polyphenols can be found in natural products of plant origin, including vegetables, fruits, and beverages. A large number of these plant origin compounds are an integral part of the human diet and in the past decade evidence has shown their beneficial properties in human health, by acting in several cell signaling pathways. Among other beneficial effects, polyphenols have been associated with angiogenesis. Increasing evidence highlighting the ability of dietary polyphenols to influence angiogenesis by interfering with multiple signaling pathways is debated. Particular emphasis is given to the mechanisms that ultimately may induce the formation of capillary-like structures (by increasing endothelial cell proliferation, migration, and invasion) or, conversely, may inhibit the steps of angiogenesis leading to the inhibition/regress of vascular development. Dietary polyphenols can, therefore, be viewed as promising nutraceuticals but important aspects have still to be further investigated, to deep knowledge concerning their concentration-mediated effects, effect of specific polyphenols, and respective metabolites, to ensure their appropriate and effective usefulness as proangiogenic or antiangiogenic nutraceuticals. PMID- 27981781 TI - Association between dietary inflammatory index and inflammatory markers in the HELENA study. AB - BACKGROUND: Previous research has shown that diet is associated with low-grade systemic inflammation among adults. However, no study has yet been conducted to explore the association between inflammatory potential of diet and low-grade systemic inflammation among adolescents whose dietary behavior may be different from adults. METHODS AND RESULTS: We examine the predictive ability of 24-h recall-derived dietary inflammatory index (DII) scores on inflammation among 532 European adolescents in the HELENA cross-sectional study. The DII is a literature derived dietary index developed to predict inflammation. The DII was calculated per 1000 calories and was tested against C-reactive protein, ILs-1,2,4,10, TNF alpha, ICAM, vascular cell adhesion molecule (VCAM), and IFN-gamma. All inflammatory markers had nonnormal distributions and therefore were log transformed. Analyses were performed using multivariable linear regression, adjusting for age, sex, city, BMI, smoking, and physical activity. Pro inflammatory diet (higher DII scores) was associated with increased levels of various inflammatory markers: TNF-alpha, IL-1, 2, IFN-gamma, and vascular cell adhesion molecule (bDIIt3vs1 = 0.13, 95% CI: 0.001, 0.25; 0.13, 95% CI 0.001, 0.25; 0.40, 95% CI: 0.03, 0.77; 0.53, 95% CI: 0.05, 1.01; 0.07, 95% CI: 0.01, 0.13, respectively). CONCLUSION: These results reinforce the fact that diet, as a whole, plays an important role in modifying inflammation in adolescents. PMID- 27981784 TI - Microwave-Assisted Selective Hydrogenation of Furfural to Furfuryl Alcohol Employing a Green and Noble Metal-Free Copper Catalyst. AB - Green, inexpensive, and robust copper-based heterogeneous catalysts achieve 100 % conversion and 99 % selectivity in the conversion of furfural to furfuryl alcohol when using cyclopentyl-methyl ether as green solvent and microwave reactors at low H2 pressures and mild temperatures. The utilization of pressurized microwave reactors produces a 3-4 fold increase in conversion and an unexpected enhancement in selectivity as compared to the reaction carried out at the same conditions using conventional autoclave reactors. The enhancement in catalytic rate produced by microwave irradiation is temperature dependent. This work highlights that using microwave irradiation in the catalytic hydrogenation of biomass-derived compounds is a very strong tool for biomass upgrade that offers immense potential in a large number of transformations where it could be a determining factor for commercial exploitation. PMID- 27981785 TI - Morphological Study: Ultrastructural Aspects of Articular Cartilage and Subchondral Bone in Patients Affected by Post-Traumatic Shoulder Instability. AB - Post-traumatic shoulder instability is a frequent condition in active population, representing one of most disabling pathologies, due to altered balance involving joints. No data are so far available on early ultrastructural osteo-chondral damages, associated with the onset of invalidating pathologies, like osteoarthritis-OA. Biopsies of glenoid articular cartilage and sub-chondral bone were taken from 10 adult patients underwent arthroscopic stabilization. Observations were performed under Transmission Electron Microscopy-TEM in tangential, arcuate and radial layers of the articular cartilage and in the sub chondral bone. In tangential and arcuate layers chondrocytes display normal and very well preserved ultrastructure, probably due to the synovial liquid supply; otherwise, throughout the radial layer (un-calcified and calcified) chondrocytes show various degrees of degeneration; occasionally, in the radial layer evidences of apoptosis/autophagy were also observed. Concerning sub-chondral bone, osteocytes next to the calcified cartilage also show signs of degeneration, while osteocytes farther from the osteo-chondral border display normal ultrastructure, probably due to the bone vascular supply. The ultrastructural features of the osteo-chondral complex are not age-dependent. This study represents the first complete ultrastructural investigation of the articular osteo-chondral complex in shoulder instability, evaluating the state of preservation/viability of both chondrocytes and osteocytes throughout the successive layers of articular cartilage and sub-chondral bone. Preliminary observations here collected represent the morphological basis for further deepening of pathogenesis related to shoulder instability, enhancing the relationship between cell shape and microenvironment; in particular, they could be useful in understanding if the early surgical treatment in shoulder instability could avoid the onset of OA. Anat Rec, 300:1208-1218, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27981786 TI - Diagnosis of common hemoglobinopathies among South East Asian population using capillary isoelectric focusing system. AB - INTRODUCTION: We have evaluated an automated capillary isoelectric focusing (cIEF)-based Hb analyzer in diagnosis of hemoglobinopathies commonly found among South East Asian population. METHODS: Study was performed on a cohort of 665 adult Thai subjects and 13 fetal blood specimens obtained at routine thalassemia diagnostic laboratory. Hb analysis was performed using the cIEF system. Thalassemia genotypes were defined by DNA analysis. RESULTS: The system revealed satisfactorily within-run and between-run precision for quantitation of Hb A2 and Hb E (CV: 0.02-0.09%). The reference ranges of Hb A2 and Hb E were 2.6-4.0% and 25.7-33.1%, respectively. The system identified the cases of beta-thalassemia and Hb E disorders correctly. Several thalassemia genotypes and Hb variants were identifiable. However, Hb Constant Spring was separated closely to Hb A2 and Hbs Bart's and H were relatively difficult to be reported due to interfering peaks separating at the same regions. Prenatal diagnosis by fetal blood analysis was found to be accurate for Hb Bart's hydrops fetalis and Hb E-beta0 -thalassemia disease. CONCLUSIONS: The cIEF system could accurately diagnose beta-thalassemia and Hb E carriers and demonstrate many Hb variants found in the region. The system cannot report Hb A2 in the presence of Hb E whereas Hbs Lepore and F are comigrated. Diagnosis of alpha-thalassemia disease based on Hb H and Hb Bart's might be difficult. PMID- 27981787 TI - Pathogenesis, hemodynamics, and growth of intracranial aneurysms: Future directions. PMID- 27981788 TI - Plasticity in seedling morphology, biomass allocation and physiology among ten temperate tree species in response to shade is related to shade tolerance and not leaf habit. AB - Mechanisms of shade tolerance in tree seedlings, and thus growth in shade, may differ by leaf habit and vary with ontogeny following seed germination. To examine early responses of seedlings to shade in relation to morphological, physiological and biomass allocation traits, we compared seedlings of 10 temperate species, varying in their leaf habit (broadleaved versus needle-leaved) and observed tolerance to shade, when growing in two contrasting light treatments - open (about 20% of full sunlight) and shade (about 5% of full sunlight). We analyzed biomass allocation and its response to shade using allometric relationships. We also measured leaf gas exchange rates and leaf N in the two light treatments. Compared to the open treatment, shading significantly increased traits typically associated with high relative growth rate (RGR) - leaf area ratio (LAR), specific leaf area (SLA), and allocation of biomass into leaves, and reduced seedling mass and allocation to roots, and net assimilation rate (NAR). Interestingly, RGR was not affected by light treatment, likely because of morphological and physiological adjustments in shaded plants that offset reductions of in situ net assimilation of carbon in shade. Leaf area-based rates of light-saturated leaf gas exchange differed among species groups, but not between light treatments, as leaf N concentration increased in concert with increased SLA in shade. We found little evidence to support the hypothesis of a increased plasticity of broadleaved species compared to needle-leaved conifers in response to shade. However, an expectation of higher plasticity in shade intolerant species than in shade-tolerant ones, and in leaf and plant morphology than in biomass allocation was supported across species of contrasting leaf habit. PMID- 27981789 TI - Comparison of abnormal cell flagging of the hematology analyzers Sysmex XN and Sysmex XE-5000 in oncohematologic patients. AB - INTRODUCTION: Hematology analyzers should optimize flagging while minimizing false-negative results and unnecessary microscopic reviews. METHODS: We compared flagging performance of Sysmex XE-5000 and XN analyzers in oncohematologic patients. Differential counts were performed by Cellavision digital system (100 cells) and a hematologist (another 100 cells). RESULTS: First, we included 292 samples (86 with blasts): 28 acute lymphoblastic leukemia, 88 acute myeloid leukemia, 91 myelodysplastic syndromes, 45 chronic myeloproliferative neoplasms, and 40 chronic myelomonocytic leukemia. Sensitivity, specificity and efficiency to detect blasts were 59.3%, 88.3%, and 79.8% for XE-5000 analyzer and 70.9%, 91.3%, and 85.2% for the XN analyzer. Then, we included 111 lymphoid malignancies. In 55 CLL XE-5000 flagged for Abn Lympho/L_Blasts?, XN flagged for Abn Lympho?. In one-third of 19 samples with splenic marginal lymphoma, none of the analyzers flagged. In 5 Sezary syndrome cases, XE-5000 triggered the Abn Lympho/L_Blasts? flag while the flagging in XN was less consistent: Abn Lympho? Blasts? and Atypical Lympho?. In 5 hairy cell leukemias, both analyzers only flagged one sample. In 13 myelomas, XE-5000 generated Atypical Lympho? flag; XN triggered more variable flags. In other lymphoid malignancies, flags were variable. XN analyzer generates less samples with false basophilia. CONCLUSION: XN analyzer has improved blast detection in oncohematologic patients. Operators cannot rely on the blast flag alone but have to consider other flags and hemogram data. In lymphoproliferative disorders, XN analyzer yields less samples with pseudobasophilia. Both analyzers must improve flagging for hairy cell leukemia. PMID- 27981791 TI - The role of imaging in the surveillance and diagnosis of hepatocellular cancer. AB - A decision support tool has been developed as part of a suite of on-line evidence based and consensus-based guidelines Diagnostic imaging Pathways (DIP): www.imagingpathways.health.wa.gov.au) in the form of an algorithmic flow chart with supporting evidence and consensus to inform referrers to diagnostic imaging and radiologists as to the optimum strategy for surveillance and diagnosis of primary hepatocellular cancer (HCC) in those patients with risk factors of this disease. A literature review, including reference to several international consensus-based expert guidelines, has been employed to develop this tool. PMID- 27981792 TI - Comparative studies on the fermentation performance of autochthonous Saccharomyces cerevisiae strains in Chinese light-fragrant liquor during solid state or submerged fermentation. AB - AIM: To explore the metabolic characteristic of autochthonous Saccharomyces cerevisiae strains in Chinese light-fragrant liquor fermentation. METHODS AND RESULTS: Inter-delta amplification analysis was used to differentiate the S. cerevisiae strains at strain level. Twelve biotypes (I-XII) were identified among the 72 S. cerevisiae strains preselected. A comparison was conducted between solid-state fermentation (SSF) and submerged fermentation (SmF) with S. cerevisiae strains had different genotype, with a focus on the production of ethanol and the volatile compounds. The degree of ethanol ranged from 28.0 to 45.2 g l-1 in SmF and from 14.8 to 25.6 g kg-1 in SSF, and SSF was found to be more suitable for the production of ethanol with higher yield coefficient of all the S. cerevisiae strains. The metabolite profiles of each yeast strain showed obvious distinction in the two fermentations. The highest amounts of ethyl acetate in SmF and SSF were found in genotype VII (328.2 MUg l-1 ) and genotype V (672 MUg kg-1 ), respectively. In addition, the generation of some volatile compounds could be strictly related to the strain used. Compound beta-damascenone was only detected in genotypes I, II, X and XII in the two fermentation processes. Furthermore, laboratory scale fermentations were clearly divided into SSF and SmF in hierarchical cluster analysis regardless of the inoculated yeast strains, indicating that the mode of fermentation was more important than the yeast strains inoculated. CONCLUSION: The autochthonous S. cerevisiae strains in Chinese light-fragrant liquor vary considerably in terms of their volatiles profiles during SSF and SmF. SIGNIFICANCE AND IMPACT OF THE STUDY: This work facilitates a better understanding of the fermentative mechanism in the SSF process for light-fragrant liquor production. PMID- 27981790 TI - TLR4 and Caveolin-1 in Monocytes Are Associated With Inflammatory Conditions in Diabetic Neuropathy. AB - The purpose of this study was to investigate the expression of TLR4 and caveolin 1 in monocytes among healthy volunteers as well as those with type-2 diabetes mellitus (T2DM) and diabetic peripheral neuropathy (DPN). Nineteen healthy control subjects, 18 patients with T2DM, and 20 patients with DPN were enrolled. Toll-like receptor (TLR)4, caveolin-1, MyD88, phosphorylated IkappaB, and plasma TNF-alpha and interleukin (IL)-6 were measured using real-time polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay. Compared with the other two groups, the DPN group had higher expression of TLR4, MyD88, phosphorylated IkappaB, TNF-alpha, and IL-6, but significantly lower levels of caveolin-1 and total IkappaB in monocytes. Plasma concentrations of TNF-alpha and IL-6 were positively correlated with TLR4 and negatively correlated with caveolin 1 in patients with DPN. Plasma concentration of TLR4 was negatively correlated with caveolin-1 in patients with DPN. Reduced expression of caveolin-1 in monocytes could aggravate the TLR4-mediated inflammatory cascade. PMID- 27981794 TI - Reproductive Tract Histology in South American Fur Seal Pups (Arctophoca australis). AB - In the present study, a detailed histological description of the female reproductive tract of South American fur seal (Arctophoca australis) pups has been conducted. The uterine tube was covered by cuboidal to columnar epithelium; nerve fibers were present in the mesosalpinx and beneath the muscular layer. The uterus was bipartitus; the endometrial surface of the horns was lined by a simple cuboidal or columnar epithelium with deep tubular glands; caudally ("the transition area"), the epithelium changed to pseudostratified columnar, few tubular glands were present and the myometrium increased in width. A bistratified epithelium internally coated the uterine body, whereas it changed to cylindrical stratified epithelium with a highly vascularized lamina propria and a strong muscular layer in the cervix; no endometrial glands were observed in this region. From the transition area of the uterus to the vagina there were several nerve fibers and ganglia belonging to the uterovaginalis plexus. In the vestibule, hymenal folds were poorly developed; adnexa structures included the major vestibular glands and a neurovascular structure similar to the vestibular bulb. Minor vestibular glands were associated with the clitoris. The skin of the perineum was lined by a keratinized stratified epithelium, pigmented, with sebaceous glands, sweat glands and hair follicles. This is the first detailed histological description of the reproductive tract of South American fur seal pups, including the glandular adnexa and nerve structures. These results contribute to the reproductive biology in Pinniped species, and give a better understanding of the utero-placental perfusion mechanism during diving. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:600-613, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27981793 TI - Responses to romidepsin by line of therapy in patients with relapsed or refractory peripheral T-cell lymphoma. AB - Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive non Hodgkin lymphomas typically associated with poor prognosis. Most patients with PTCL receive chemotherapy as first-line treatment, but many experience rapid relapse. For patients with relapsed/refractory PTCL, responses to treatment and long-term outcomes tend to worsen with increasing lines of therapy. Romidepsin is a potent class I histone deacetylase inhibitor approved by the US Food and Drug Administration for the treatment of PTCL in patients who have received >=1 prior therapy. A pivotal phase 2 trial of romidepsin in patients with relapsed/refractory PTCL demonstrated an objective response rate of 25% (33/130), including 15% with confirmed/unconfirmed complete response, and a median duration of response of 28 months. In the analysis presented herein, romidepsin was shown to have similar responses and long-term outcomes in patients with 1, 2, and >=3 prior lines of treatment, including in patients with disease refractory to the last prior therapy. Although adverse events increased with increasing lines of treatment, the rate of dose modifications and discontinuations due to adverse events was not significantly different. These data support the use of romidepsin as salvage treatment for PTCL irrespective of the number of prior therapies. PMID- 27981796 TI - A novel HLA-A*24 allele, A*24:02:61, confirmed in a Chinese individual. AB - A novel HLA-A*24 allele, A*24:02:61, confirmed in a Chinese individual. PMID- 27981795 TI - Targeting the epigenome: Screening bioactive compounds that regulate histone deacetylase activity. AB - SCOPE: Nutrigenomics is a rapidly expanding field that elucidates the link between diet-genome interactions. Recent evidence demonstrates that regulation of the epigenome, and in particular inhibition of histone deacetylases (HDACs), impact pathogenetic mechanisms involved in chronic disease. Few studies, to date, have screened libraries of bioactive compounds that act as epigenetic modifiers. This study screened a library of 131 natural compounds to determine bioactive compounds that inhibit Zn-dependent HDAC activity. METHODS AND RESULTS: Using class-specific HDAC substrates, we screened 131 natural compounds for HDAC activity in bovine cardiac tissue. From this screen, we identified 18 bioactive compound HDAC inhibitors. Using our class-specific HDAC substrates, we next screened these 18 bioactive compounds against recombinant HDAC proteins. Consistent with inhibition of HDAC activity, these compounds were capable of inhibiting activity of individual HDAC isoforms. Lastly, we report that treatment of H9c2 cardiac myoblasts with bioactive HDAC inhibitors was sufficient to increase lysine acetylation as assessed via immunoblot. CONCLUSION: This study provided the first step in identifying multiple bioactive compound HDAC inhibitors. Taken together, this report sets the stage for future exploration of these bioactive compounds as epigenetic regulators to potentially ameliorate chronic disease. PMID- 27981797 TI - Laserpitium zernyi Hayek Flower and Herb Extracts: Phenolic Compounds, and Anti edematous, Antioxidant, and Antimicrobial Activities. AB - Phenolic compounds and different biological activities of the dry MeOH extracts of the flowers and the herb (aerial parts without flowers) of Laserpitium zernyi Hayek (Apiaceae) were investigated. The total phenolic contents in the extracts were determined spectrophotometrically using Folin-Ciocalteu reagent. In both extracts, apigenin, luteolin, their 7-O-glucosides, and chlorogenic acid were detected by HPLC. Identified phenolics were quantified in both extracts, except luteolin in L. zernyi herb extract. The extracts (p.o.) were tested for anti edematous activity in a model of carrageenan (i.pl.) induced rat paw edema. Antioxidant activity of the extracts was assessed by FRAP assay and DPPH and * OH radicals scavenging tests. Antimicrobial activity was investigated using broth microdilution test against five Gram-positive and three Gram-negative bacteria, as well as against two strains of Candida albicans. The polyphenol-richer flower extract exerted higher anti-edematous and antioxidant activities. The herb extract exhibited better antimicrobial effect against Micrococcus luteus, Enterococcus faecalis, Bacillus subtilis, and Pseudomonas aeruginosa, while against other tested microorganisms, the activity of both extracts was identical. Demonstrated biological activities of L. zernyi flower and herb extracts represent a good basis for their further investigation as potential new herbal medicinal raw materials. PMID- 27981799 TI - Expression of Epithelial and Mesenchymal Differentiation Markers in the Early Human Gonadal Development. AB - Expressions of cytokeratin 8 (CK8), vimentin, nestin, and alpha-smooth-muscle actin (alpha-SMA) were analyzed in the developing gonads of 12, 5-9 week old (W) human conceptuses by immunohistochemistry and immunofluorescence. During the investigated period, the number of CK8 positive cells increased from 56% to 92% in the gonadal surface epithelium, from 50% to 60% in the stroma, and from 23% to 42% in the medulla. In the early fetal period, the cell expression of CK8 increased in all gonadal parts, whereas primordial germ cells (PGC) remained negative. The expression of vimentin increased in the gonad stroma (gs) from 73% to 88%, and in the surface epithelium from 18% to 97% until ninth W. The medulla had the highest expression of vimentin in the seventh to eighth W (93%). Vimentin and CK8 colocalized in the somatic cells, while some PGCs showed vimentin expression only. Initially, nestin was positive in the gonad surface epithelium (8%) and stroma (52%), however during further development it decreased to 1% and 33%, respectively. In the early fetal period, the nestin positive cells decreased from 44% to 31% in the gonad medulla. Alpha-SMA was positive only in the blood vessels and mesonephros. The described pattern of expression of intermediate filaments (IF) in developing human gonads suggests their role in the control of PGC apoptosis, early differentiation of gs cells and cell migration. Both epithelial and mesenchymal origins of follicular cells and possible epithelial-to mesenchymal transition of somatic cells is proposed. Lastly, IF intensity expression varies depending on the cell type and developmental period analyzed. Anat Rec, 300:1315-1326, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 27981798 TI - Frequencies and phenotypic consequences of association of alpha- and beta thalassemia alleles with sickle-cell disease in Bahrain. AB - INTRODUCTION: Bahrain has high prevalence rates of sickle cell and thalassemia in the population. This study reports the frequencies and phenotypic characteristics of alpha- and/or beta-thalassemia associated with sickle-cell disease (SCD) in a tertiary care hospital. METHODS: Adult SCD patients (n = 200) were screened for the common alpha- and beta-thalassemia alleles prevalent in the region using molecular techniques. Results of CBC, hemoglobin analysis, and average annual frequencies of severe pain episodes and numbers of transfused red cell units were documented. RESULTS: Patients were grouped on the basis of molecular studies as sickle-cell anemia (SS, n = 131), SS/alpha-thalassemia with three normal genes (n = 27), SS/alpha-thalassemia with two normal genes (n = 11), sickle-beta thalassemia (Sbeta, n = 23), and Sbeta with co-inherited alpha-thalassemia (n = 8). Identified alpha-thalassemia determinants were -alpha3.7 (n = 52), -alpha4.2 (n = 4), alphaT-Saudi alpha (n = 1), and alphaHph alpha (n = 1). All beta thalassemia alleles were beta0 defects. Sickle-thalassemia association resulted in higher hemoglobin, hematocrit, and erythrocyte counts with reduced MCV and reticulocytes. Significant clinical associations were as follows: increased severe pain frequency with alpha-thalassemia (three-gene group); red cell transfusion with beta-thalassemia alleles and female gender. CONCLUSION: One third of patients with SCD co-inherited alpha- and/or beta-thalassemia alleles and these associations explained some of the observed phenotypic variability. A low prevalence of nondeletion alpha-thalassemia alleles was observed in these patients. The most significant disease amelioration occurred in SCD associated with two alpha-thalassemia alleles. PMID- 27981801 TI - Natural Products among Brown Algae: The Case of Cystoseira schiffneri Hamel (Sargassaceae, Phaeophyceae). AB - A chemotaxonomic study on the marine brown alga Cystoseira schiffneri collected from the Tunisian marine coast allowed us to identify kjellmanianone (1) and a new isololiolide derivative named schiffnerilolide (2). The structure elucidation and the assignment of relative configurations of the isolated natural products were based on advanced mass spectrometric and nuclear magnetic resonance techniques. This outcome suggested a close phylogenetic relationship of C. schiffneri with brown algae belonging to genus Sargassum C. Agardh. Molecular characterization using the nuclear small subunit rRNA (SSU rRNA) gene (18S) sequence as genetic marker was made. Pigment analysis showed a significant seasonal change of carotenoids, in particular of fucoxanthin and fucoxanthinol. Also galactolipids, the main constituents of the thylakoid membranes, showed remarkable seasonal changes. PMID- 27981800 TI - Identification of Glucosinolates in Seeds of Three Brassicaceae Species Known to Hyperaccumulate Heavy Metals. AB - Plants from the Brassicaceae family are known to contain secondary metabolites called glucosinolates. Our goal was to establish by LC/MS the glucosinolate profile of seeds of three Brassicaceae species known to hyperaccumulate heavy metals. We investigated Alyssum fallacinum auct. non Hausskn., Iberis intermedia Guers., and Noccaea caerulescens (J. Presl & C. Presl) F. K. Mey. Our results indicate that A. fallacinum seeds contain glucoiberin and glucoibervirin, which had not been previously identified in this plant. Furthermore, we report for the first time the presence of glucoiberin, glucoibervirin, glucotropaeolin, and sinigrin in I. intermedia. We have detected for the first time glucoconringiin in N. caerulescens. In addition, glucosinalbin, 4-hydroxyglucobrassicin, and glucomoringin were also detected. PMID- 27981802 TI - A Novel Method for Constructing Histological Section Datasets of the Basal Ganglia in Digitized Human Brain. AB - To investigate the construction of the histological section datasets in the basal ganglia of digitized human brain to provide a reference for the meso-level histological data acquisition. A fresh adult brain from a cadaver with no neurological disease was selected, and tissue blocks of the basal ganglia in the right hemisphere was extracted using the visualization method, followed by pretreatments including gradient dehydrating, gelatin-embedding and setting of calibration points. And then the tissue blocks was cryosectioned into 60-MUm thick coronal sections and the sectional images were captured simultaneously by a digital camera at a fixed position. Two series of sections (one section out of ten) were Nissl-stained with Toluidine blue and immunostained with the calbindin D-28K, respectively. Stained sections were digitized by a high resolution scanner. After alignment and registration, contours of nuclei and different nucleic function divisions in the digital images of stained sections were identified, and then were segmented and labeled using software exploited by ourselves. Datasets of one set of registrated serial sectional images and two sets of registrated histochemically stained images in basal ganglia area were obtained, which provide a histological reference for the neurosurgery and diagnostic imaging. a systematic method of cutting, slicing, staining, data acquisition and image registration of large tissue blocks was established, providing a reference for histological data acquisition on the digital human. Anat Rec, 300:1011-1021, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27981803 TI - Effects of supine rest duration on ultrasound measures of the vastus lateralis. AB - INTRODUCTION: Due to the potential for intramuscular fluid shifts from changing body position, researchers often utilize a 10- to 15-min period of supine rest as a standardizing procedure prior to ultrasound assessment of the lower limbs. However, no previous research has observed the changes in muscle morphological characteristics via ultrasonography of the lower limbs depending on the length of time of supine rest to determine whether 10-15 min of supine rest is necessary. The aim of this study was to examine changes in muscle morphology of the vastus lateralis (VL) at various time-points over the course of 15 min of supine rest. METHODS: Muscle thickness (MT), cross-sectional area (CSA) and echo intensity (EI) of the VL were assessed in 24 adults at four time-points including the following: immediately upon moving from a standing to supine position (T0), after 5 (T5), 10 (T10) and 15 min (T15) of lying in a supine position. RESULTS: CSA significantly decreased from T0 to T10 (P = 0.001) and T15 (P<0.001), with no difference between any other time-points (P = 0.055-0.666). However, the reported changes in CSA did not exceed the standard error of the measurement for this procedure. No significant differences between any time-points for MT (P = 0.726 0.966) or EI (P = 0.061-0.783) were observed. DISCUSSION: These findings suggest extended periods of supine rest may not be needed to obtain consistent muscle morphological measurements of the VL using ultrasonography. PMID- 27981805 TI - Reinhart Ahlrichs (1940-2016). AB - Reinhart Ahlrichs, Professor Emeritus of Theoretical Chemistry at the Karlsruhe Institute of Technology (KIT) and one of the leading figures of both the German and international theoretical chemistry communities, passed away aged 76 on October 12, 2016. His work shaped the field of quantum chemistry and took the interplay between theory and experiment to new levels. He was also the founder of the TURBOMOLE program package. PMID- 27981804 TI - MD-Logic overnight type 1 diabetes control in home settings: A multicentre, multinational, single blind randomized trial. AB - AIMS: To evaluate the safety, efficacy and need for remote monitoring of the MD Logic closed-loop system during short-term overnight use at home. METHODS: Seventy-five patients (38 male; aged 10-54 years; average A1c, 7.8% +/- 0.7%, 61.8 +/- 7.2 mmol/mol) were enrolled from 3 clinical sites. Patients were randomly assigned to participate in 2 overnight crossover periods, each including 4 consecutive nights, 1 under closed-loop control and 1 under sensor-augmented pump (SAP) therapy in the patient's home. Both study arms were supervised using a remote-monitoring system in a blinded manner. Primary endpoints were time spent with glucose levels below 70 mg/dL and percentage of nights in which mean overnight glucose levels were within 90 to 140 mg/dL. RESULTS: The median [interquartile range] percentage of time spent in hypoglycaemia was significantly lower on nights when MD-Logic was used, compared to SAP therapy (2.07 [0, 4.78] and 2.6 [0, 10.34], respectively; P = .004) and the percentage of individual nights with a mean overnight glucose level in target was significantly greater (75 [42, 75] and 50 [25,75], respectively; P = .008). The time spent in target range was increased by a median of 28% (P = .001), with the same amount of insulin (10.69 [7.28, 13.94] and 10.41[6.9, 14.07], respectively; P = .087). The remote monitoring triggered calls for hypoglycaemia at twice the rate during SAP therapy compared to closed-loop control (62 and 29, respectively; P = .002). CONCLUSIONS: The MD-Logic system demonstrated a safe and efficient profile during overnight use by children, adolescents and adults with type 1 diabetes and, therefore, provides an effective means of mitigating the risk of nocturnal hypoglycaemia. PMID- 27981806 TI - Interplay between Reaction and Phase Behaviour in Carbon Dioxide Hydrogenation to Methanol. AB - Condensation promotes CO2 hydrogenation to CH3 OH beyond equilibrium through in situ product separation. Although primordial for catalyst and reactor design, triggering conditions as well as the impact on sub-equilibrium reaction behaviour remain unclear. Herein we used an in-house designed micro-view-cell to gain chemical and physical insights into reaction and phase behaviour under high pressure conditions over a commercial Cu/ZnO/Al2 O3 catalyst. Raman microscopy and video monitoring, combined with online gas chromatography analysis, allowed the complete characterisation of the reaction bulk up to 450 bar (1 bar=0.1 MPa) and 350 degrees C. Dew points of typical effluent streams related to a parametric study suggest that the improving reaction performance and reverting selectivities observed from 230 degrees C strongly correlate with (i) a regime transition from kinetic to thermodynamic, and (ii) a phase transition from a single supercritical to a biphasic reaction mixture. Our results advance a rationale behind transitioning CH3 OH selectivities for an improved understanding of CO2 hydrogenation under high pressure. PMID- 27981807 TI - Does temproray bilateral balloon occlusion of the common iliac arteries reduce the need for intra-operative blood transfusion in cases of placenta accretism? AB - INTRODUCTION: Bilateral balloon occlusion has been employed as a prophylactic measure in cases of placenta accretism prior to caesarean section with the aim of reducing blood loss and its associated morbidity/mortality. There is however no clear consensus on its efficacy in the current literature. The objective of this study was to assess the efficacy of bilateral balloon occlusion of the common iliac arteries (CIA) in reducing intra-operative morbidity in cases of placenta accretism. METHODS: The databases of the pathology department and radiology interventional suite were reviewed over a nine year period. Fifty-two cases of confirmed placental accretism who underwent caesarean section with or without hysterectomy were identified and divided into two groups. Twenty-five cases had temporary occlusion of the common iliac arteries (CIA) during delivery and these were considered the study group. The reminder 27 cases did not have temporary occlusion of the CIA and were considered the control group. The two groups were compared based on gravidity, age group, post-operative haemoglobin, drop in haemoglobin, estimated blood loss (EBL), transfusion requirement and the histopathological sub-types of placenta accretism. RESULTS: There was no statistically difference between the study and the control groups regarding EBL, post-operative haemoglobin drop, transfusion requirement or in the placenta accretism histopathological subtype. Two cases in the study group had acute thromboembolic complications. Both groups had a single patient requiring a massive intra-operative transfusion. CONCLUSION: Our study was not able to detect a significant difference in blood loss or blood product requirement between patients who underwent CIA balloon in the setting of caesarean section for placenta accreta. This remains a challenging scenario requiring a multidisciplinary approach. PMID- 27981808 TI - Fluorescing fatty acids in rat fatty liver models. AB - The autofluorescence (AF) of NAD(P)H and flavins has been at the basis of many in situ studies of liver energy metabolism and functionality. Conversely, few data have been so far reported on fluorescing lipids. In this work we investigated the AF of liver lipid extracts from two fatty liver models, Wistar rats fed with MCD diet for 12 days (Wi-MCD), and obese (fa/fa) Zucker rats. Among the most abundant fatty acids in the lipid extracts, indicated by mass spectrometry, arachidonic acid (AA) exhibited higher quantum yield than the other fluorescing fatty acids (FLFA), and red shifted AF spectrum. This allowed to estimate the AA contribution to the overall emission of lipid extracts by curve fitting analysis. AA prevailed in obese Zucker livers, accounting for the different AF spectral profiles between the two models. AF and mass spectrometry indicated also a different balance between the fluorescing fraction and the overall amount of AA in the two models. The ability of AF to detect directly AA and FLFA was demonstrated, suggesting its supportive role as tool in wide-ranging applications, from the control of animal origin food, to experimental investigations on liver fat accumulation, lipotoxicity and disease progression, with potential translation to the clinics. PMID- 27981809 TI - Chicoric acid attenuate a nonalcoholic steatohepatitis by inhibiting key regulators of lipid metabolism, fibrosis, oxidation, and inflammation in mice with methionine and choline deficiency. AB - SCOPE: Nonalcoholic fatty liver diseases (NAFLD) range histopathologically from hepatic steatosis to steatohepatitis. Chicoric acid has beneficial effects on obesity and liver injury, but its effects on nonalcoholic steatohepatitis (NASH) have not yet been determined. This study examined the effects of Crepidiastrum denticulatum extract (CDE) and its active compound chicoric acid in a mouse model of NASH and fibrosis. METHODS: CDE and chicoric acid were orally administrated to mice fed a methionine- and choline-deficient (MCD) diet. HepG2 and AML-12 cells in MCD medium were incubated with chicoric acid. MCD-fed mice developed the histopathological characteristics of human NASH, including altered regulation of lipid metabolism, inflammation, fibrosis, and oxidation-associated expression, along with augmented lipoperoxidation. Administration of CDE or chicoric acid to MCD-fed mice and HepG2 and AML-12 cells in MCD medium reduced oxidative stress by upregulating antioxidant enzymes and decreased inflammation by inhibiting proinflammatory cytokines and nuclear factor-kappaB activation. In addition, CDE or chicoric acid reduced fibrosis, apoptosis, and lipogenesis-related gene expression and increased AMP Kinase activation both in vivo and in vitro. CONCLUSIONS: CDE and chicoric acid may be effective in the treatment of NAFLD and NASH. PMID- 27981811 TI - Canine Transmissible Venereal Tumor: Is Its Biological Behavior Changing? PMID- 27981810 TI - Utility of ultrasound for body fat assessment: validity and reliability compared to a multicompartment criterion. AB - Measurement of body composition to assess health risk and prevention is expanding. Accurate portable techniques are needed to facilitate use in clinical settings. This study evaluated the accuracy and repeatability of a portable ultrasound (US) in comparison with a four-compartment criterion for per cent body fat (%Fat) in overweight/obese adults. Fifty-one participants (mean +/- SD; age: 37.2 +/- 11.3 years; BMI: 31.6 +/- 5.2 kg m-2 ) were measured for %Fat using US (GE Logiq-e) and skinfolds. A subset of 36 participants completed a second day of the same measurements, to determine reliability. US and skinfold %Fat were calculated using the seven-site Jackson-Pollock equation. The Wang 4C model was used as the criterion method for %Fat. Compared to a gold standard criterion, US %Fat (36.4 +/- 11.8%; P = 0.001; standard error of estimate [SEE] = 3.5%) was significantly higher than the criterion (33.0 +/- 8.0%), but not different than skinfolds (35.3 +/- 5.9%; P = 0.836; SEE = 4.5%). US resulted in good reliability, with no significant differences from Day 1 (39.95 +/- 15.37%) to Day 2 (40.01 +/- 15.42%). Relative consistency was 0.96, and standard error of measure was 0.94%. Although US overpredicted %Fat compared to the criterion, a moderate SEE for US is suggestive of a practical assessment tool in overweight individuals. %Fat differences reported from these field-based techniques are less than reported by other single-measurement laboratory methods and therefore may have utility in a clinical setting. This technique may also accurately track changes. PMID- 27981812 TI - Take Care of the Fast-in-Human Study. PMID- 27981813 TI - B cell autoimmunity and bone damage in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic immune-inflammatory disease associated with significant bone damage. Pathological bone remodeling in RA is primarily driven by persistent inflammation. Indeed, pro-inflammatory cytokines stimulate the differentiation of bone-resorbing osteoclasts and, in parallel, suppress osteoblast function, resulting in net loss of bone. Abating disease activity thus remains the major goal of any treatment strategy in patients with RA. Autoantibody-positive patients, however, often show a rapidly progressive destructive course of the disease, disproportionate to the level of inflammation. The epidemiological association between RA-specific autoantibodies, in particular anti-citrullinated protein autoantibodies, and poor structural outcomes has recently found mechanistic explanation in the multiple roles that B cells play in bone remodeling. In this review, we will summarize the substantial progress that has been made in deciphering how B cells and autoantibodies negatively impact on bone in the course of RA, through both inflammation-dependent and independent mechanisms. PMID- 27981814 TI - Evidence-based algorithm for diagnosis and assessment in psoriatic arthritis: results by Italian DElphi in psoriatic Arthritis (IDEA). AB - Psoriatic arthritis (PsA) is a chronic inflammatory disease involving skin, peripheral joints, entheses, and axial skeleton. The disease is frequently associated with extrarticular manifestations (EAMs) and comorbidities. In order to create a protocol for PsA diagnosis and global assessment of patients with an algorithm based on anamnestic, clinical, laboratory and imaging procedures, we established a DElphi study on a national scale, named Italian DElphi in psoriatic Arthritis (IDEA). After a literature search, a Delphi poll, involving 52 rheumatologists, was performed. On the basis of the literature search, 202 potential items were identified. The steering committee planned at least two Delphi rounds. In the first Delphi round, the experts judged each of the 202 items using a score ranging from 1 to 9 based on its increasing clinical relevance. The questions posed to experts were How relevant is this procedure/observation/sign/symptom for assessment of a psoriatic arthritis patient? Proposals of additional items, not included in the questionnaire, were also encouraged. The results of the poll were discussed by the Steering Committee, which evaluated the necessity for removing selected procedures or adding additional ones, according to criteria of clinical appropriateness and sustainability. A total of 43 recommended diagnosis and assessment procedures, recognized as items, were derived by combination of the Delphi survey and two National Expert Meetings, and grouped in different areas. Favourable opinion was reached in 100% of cases for several aspects covering the following areas: medical (familial and personal) history, physical evaluation, imaging tool, second level laboratory tests, disease activity measurement and extrarticular manifestations. After performing PsA diagnosis, identification of specific disease activity scores and clinimetric approaches were suggested for assessing the different clinical subsets. Further, results showed the need for investigation on the presence of several EAMs and risk factors. In the context of any area, a rank was assigned for each item by Expert Committee members, in order to create the logical sequence of the algorithm. The final list of recommended diagnosis and assessment procedures, by the Delphi survey and the two National Expert Meetings, was also reported as an algorithm. This study shows results obtained by the combination of a DElphi survey of a group of Italian rheumatologists and two National Expert Meetings, created with the aim of establishing a clinical procedure and algorithm for the diagnosis and the assessment of PsA patients. In order to find accurate and practical diagnostic and assessment items in clinical practice, we have focused our attention on evaluating the different PsA domains. Hence, we conceived the IDEA algorithm in order to address PsA diagnosis and assessment in the context of daily clinical practice. The IDEA algorithm might eventually lead to a multidimensional approach and could represent a useful and practical tool for addressing diagnosis and for assessing the disease appropriately. However, the elaborated algorithm needs to be further investigated in daily practice, for evidencing and proving its eventual efficacy in detecting and staging PsA and its heterogeneous spectrum appropriately. PMID- 27981815 TI - The role of clinically significant antiphospholipid antibodies in systemic lupus erythematosus. AB - The objective is to investigate the role of clinically significant antiphospholipid antibodies (aPL) in a cohort of systemic lupus erythematosus (SLE) patients. All SLE patients followed for at least 5 years and with available aPL profile at the beginning of the follow-up in our center were studied. Clinically significant aPL were defined as: positive lupus anticoagulant test, anti-cardiolipin and/or anti- beta2Glycoprotein I IgG/IgM >99th percentile on two or more occasions at least 12 weeks apart. Patients with and without clinically significant aPL were compared by univariate (Chi square or Fisher's exact test for categorical variables and Student's t or Mann-Whitney test for continuous variables) and multivariate analysis (logistic regression analysis). P values <0.05 were considered significant. Among 317 SLE patients studied, 117 (37%) had a clinically significant aPL profile at baseline. Such patients showed at univariate analysis an increased prevalence of deep venous thrombosis, pulmonary embolism, cardiac valvular disease, cognitive dysfunction and antiphospholipid syndrome (APS), but a reduced prevalence of acute cutaneous lupus and anti extractable nuclear antigens (ENA) when compared with patients without clinically significant aPL. Multivariate analysis confirmed the association between clinically significant aPL and reduced risk of acute cutaneous lupus [p=0.003, odds ratio (OR) 0.43] and ENA positivity (p<0.001, OR 0.37), with increased risk of cardiac valvular disease (p=0.024, OR 3.1) and APS (p<0.0001, OR 51.12). Triple positivity was the most frequent profile and was significantly associated to APS (p<0.0001, OR 28.43). Our study showed that one third of SLE patients had clinically significant aPL, and that this is associated with an increased risk, especially for triple positive, of APS, and to a different clinical and serological pattern of disease even in the absence of APS. PMID- 27981816 TI - Risk of cytomegalovirus reactivation in patients with immune-mediated inflammatory diseases undergoing biologic treatment: a real matter? AB - The use of biological agents has grown exponentially in immune-mediated inflammatory diseases (IMID), often achieving a good control of disease progression and improving patients' quality of life. However, their use resulted in an increased risk of adverse events, including reactivation of chronic/latent infectious diseases. As for the risk of Cytomegalovirus (CMV) reactivation, very few data are available. We reviewed the literature reporting cases of CMV infection in IMID patients during biological therapy. Although the risk of CMV reactivation cannot be excluded, we concluded that there is no evidence to warrant CMV screening before starting a biological agent. PMID- 27981817 TI - Intracardiac thrombus in Behcet's disease. AB - Behcet's disease (BD) is a multisystem inflammatory disorder. Intracardiac thrombus (ICT) formation is an uncommon but important complication of BD. Of the cases of Behcet's disease, we selected those with ICT. All patients fulfilled the diagnostic criteria of the International Study Group of Behcet's disease. The ICT in each case was confirmed by ultrasonography, computed tomography and MRI. Clinical features and laboratory parameters were determined. Among our 518 patients with BD, 8 were diagnosed as having intracardiac thrombus (ICT). All were male; the mean age at the time of the ICT diagnosis was 30.8 years. The main presenting symptoms were hemoptysis, chest pain, and dyspnea. It was associated with pulmonary artery aneurysm and vena cava thrombosis in 3 cases each, pulmonary embolism, and lower limbs deep venous thrombosis in 1 case each. The coexistence of other cardiac complications was as follows: pericarditis in 2 cases, myocarditis, endomyocardial fibrosis, and coronary arteritis with consequent myocardial infarction in one case each. In all cases, echocardiography was sufficient to reach the diagnosis. Chest computed tomography performed in all cases led to the diagnosis of associated pulmonary vasculo-Behcet lesions in 4 cases. All patients received colchicine, anticoagulation, and corticosteroids. Seven patients were on immunosuppressant agents (2 patients received azathioprine and 5 cyclophosphamide). Clinical remission with ICT resolution was observed in 5 cases. Combined immunosuppressive therapy with prednisone and cyclophosphamide might be needed to treat ICT due to BD. PMID- 27981818 TI - ? AB - Paget's disease of bone (PDB) is a focal disorder of osteoclasts, leading to chaotic bone remodelling, and it is characterized by the presence of focal areas of excessive bone formation alongside with areas of focal bone resorption. The typical radiographic feature is the cotton wool appearance. To date, bisphosphonates are the mainstay of the treatment. We hereby report the case of a young woman presenting with mandible PDB, with a relevant diagnostic delay and mistakenly treated for five years with chronic oral corticosteroids. After our evaluation, the patient received treatment with intravenous neridronate (an amino bisphosphonate licensed in Italy for the treatment of this disease), with achievement of clinical remission. PMID- 27981819 TI - Successful treatment of refractory adult onset Still's disease with rituximab. AB - Adult-onset Still's disease (AOSD) is an uncommon inflammatory condition of unknown origin. In chronic disease, joint involvement is often predominant and erosions are noted in one third of patients. Therapeutic strategies derive from observational data. Corticosteroids are usually the first-line treatment. With inadequate response to corticosteroids, methotrexate appears the best choice to control disease activity and allow for tapering of steroid use. For refractory disease, biological therapy seems the most promising. We report here the case of a 38-year-old female patient with AOSD refractory to cytotoxic agents, treated by rituximab infusion therapy with favorable outcome. PMID- 27981820 TI - Aseptic HLA B27-positive spondylodiscitis: decreased 18F-FDG uptake after etanercept treatment. AB - We observed a 69-year old man suffering from HLA B27 ankylosing spondylitis with persistent night back pain. 18F-FDG-PET/CT showed an increased metabolism at the level of the spinal space of L2-L3, L3-L4 with increased uptake compatible with spondylodiscitis. He started therapy with etanercept 50 mg/week. After six months of treatment repeated testing showed no uptake of the discs and vertebral bodies. PMID- 27981821 TI - Low energy manual anal stretch: an approach in the treatment of chronic anal fissure. AB - BACKGROUND: Anal fissure is a tear in the epitelial lining of the anal canal. This is a very common anorectal disorder, but the choice of treatment is unclear. Sphincterotomy is effective but it is affected by a high risk of fecal incontinence. Manual anal stretch is aN efficacious, economic and safe maneuver. The aim of this prospective study was to assess the safety and effectiveness of anal stretch in resolving chronic anal fissures. METHODS: Twenty-five patients with a clinical diagnosis of chronic anal fissure were submitted to anal stretch. All patients were submitted to anal stretch, after clinical evaluation. All patients were studied at basal time, and at 7 days, 3, 6 and 12 months after the treatment. RESULTS: At 3 months and 6 months after the anal stretch, 88% and 94% of patients showed a resolution of anal fissures and only 12% have relapsed at 12 months, without complications, such as faecal incontinence. CONCLUSIONS: The anal stretch appears to induce better resolution of chronic anal fissure with a very low risk of fecal incontinence. PMID- 27981822 TI - Early cholecystectomy for non-severe acute gallstone pancreatitis: easier said than done. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) carried out within 3 days after an attack of non-severe acute gallstone pancreatitis (NSAGP) is recommended to reduce hospital stay and overall costs. Aim of the study was to evaluate factors that may delay a timely surgical management of NSAGP and the consequences of this deviation. METHODS: We reviewed the charts of patients admitted for NSAGP and managed by LC during the last 14 years. A total number of 316 patients entered the study, 98 of whom underwent early LC. A comparison of pre-operative and outcome data from the group of patients undergone early LC and those who received a delayed LC (>3 days since the admission) was made. RESULTS: Only 31% of patients presenting with NSAGP were managed by early LC. Respect to these, patients who received a delayed LC were significantly older and had a greater occurrence of clinical signs suggesting common bile duct stones (CBDS). Stabilization of co-morbidities and need to investigate preoperatively the common duct were the main factors associated to the surgical delay. By comparing patients undergone early LC and those who received delayed LC, differences regarding conversion to open surgery (2% vs. 1.3%), need to explore the common bile duct (18.3% vs. 25.6%), CBDS clearance rates (94.4% vs. 94.6%), morbidity (8.1% vs. 8.7%), and postoperative hospital stay (3.9 vs. 3.2 days) were however statistically not significant. CONCLUSIONS: Several reasons could delay the 3-day recommendation for surgery in NSAGP. These include the need to achieve before surgery the control of age-related co morbidities, and the workup to investigate for common duct stones. A fast track program aiming to early surgery would be advisable for patients presenting with NSAGP. Compared to delayed LC, early LC appears to shorten overall hospitalization but it does not seem to have any clinical impact on the course. PMID- 27981823 TI - Robotic single port cholecystectomy: current data and future perspectives. AB - INTRODUCTION: Minimally invasive techniques are used more and more frequently. Since conventional laparoscopic approach has been the gold standard, surgeons in their effort to further reduce the invasiveness of conventional laparoscopic cholecystectomy have adopted Single Incision approach. The widespread adoption of robotics has led to the inevitable hybridization of robotic technology with laparoendoscopic single-site surgery (LESS). As a result, employment of the da Vinci surgical system may allow greater surgical maneuverability, improving ergonomics. EVIDENCE ACQUISITION: A review of the English literature was conducted to evaluate all robotic single port cholecystectomy performed till today. Demographic data, operative parameters, postoperative outcomes and materials used for the operation were collected and assessed. EVIDENCE SYNTHESIS: A total of 12 studies, including 501 patients were analyzed. Demographics and clinical characteristics of the patients was heterogeneous, but in most studies a mean BMI <30 was recorded. Intraoperative metrics like operative time, estimated blood loss and conversion rate were comparable with those in multiport conventional laparoscopy. CONCLUSIONS: Robotic single port cholecystectomy is a safe and feasible alternative to conventional multiport laparoscopic or manual robotic approach. However, current data do not suggest a superiority of robotic SILC over other established methods. PMID- 27981825 TI - Laparo-endoscopic rendez-vous versus sequential "delayed" approach in patients with choledocholithiasis. AB - BACKGROUND: The aim of this study was to compare the efficacy and safety of synchronous laparoscopic cholecystectomy with laparo-endoscopic rendez-vous (LRV) technique vs. sequential "delayed" approach with the main goal to compare the conversion rate and postoperative complications. METHODS: Patients diagnosed as having gallstones and CBD stones or sludge were enrolled in this study. From January 2013 to June 2015, 43 consecutive patients were submitted to the sequential treatment (ERCP prior to laparoscopic cholecystectomy) and the next consecutive 46 patients were submitted to undergo the rendez-vous technique. All endoscopic procedures in both groups were performed by the same endoscopist with the same technique. Data were collected on patient age, gender, latency operation time, duration of surgery, bilio-pancreatic events, hospital stay, mortality, conversion rate and postoperative complications. RESULTS: The overall mean age was 58 years-old (25-84 years) with 43 males (48.3%) and 46 females (51.7%). The conversion rate to open surgery was 11.6% in the "sequential group" vs. 2.2% in the LRV group with a P value 0.10. The reasons for conversion included in the first group unclear anatomy (in 2 patients) and severe adhesions (in the remnant 3 patient), and in the second group unclear anatomy (in one patient). No bilio pancreatic events occurred in the waiting period for LC in the first group. No mortality was recorded in either group. Postoperative complications were seen in 7% of patients in the "sequential group" vs. 2.2% in the rendez-vous group (P value 0.35). CONCLUSIONS: LRV does not present real advantages in comparison to delayed sequential approach in terms of conversion rate and postoperative complications. However, these results require further elaboration in studies on large numbers of patients undergoing LRV approach. PMID- 27981824 TI - Reconstruction after musculoskeletal sarcomas: how to avoid a surgical trap. AB - BACKGROUND: Musculoskeletal sarcomas comprise 1% of all malignancies in adults. Unfortunately, sometimes they are addressed in non-appropriate way requiring a more invasive procedure to achieve radical surgery at a later date. Due to incomplete predictability of their extension, scheduled reconstruction cannot be performed at times, forcing plans to change or clogging up immediate reconstruction. In this paper, the authors provide an insight in the treatment of musculoskeletal sarcomas, particularly focusing on the preoperative planning of reconstructive strategies, which is crucial in order to prevent unpleasant surprises during reconstruction. METHODS: Fifty-six consecutive patients requiring reconstructive procedures following the extirpation of tumors were recruited. All data collected during the diagnostic phase were analyzed collectively during a multi-disciplinary meeting where the surgical procedure was planned. A score system was created and results were then classified into "excellent", "good", "sufficient" and "poor". RESULTS: After a minimum follow up of 12 months, we recorded the following results: excellent in 10 patients (17.9%), good in 28 patients (50%), sufficient in 12 cases (21.4%) and poor in 6 cases (10.7%). CONCLUSIONS: The improvement of treatment and the long-lasting survival in musculoskeletal sarcoma have shifted the goal of therapeutic protocol to obtaining radical tumor removal and maximum functional restoration. When facing unpredictable extension of the resections, reconstruction may be a challenging or even impossible task to fulfil. Only meticulous preoperative planning can prevent surgeons from falling into all sorts of surgical traps following wide resections. PMID- 27981826 TI - Up-regulation of Flot-2 protein is related to lymph node metastasis and poor prognosis in human solid tumors. AB - INTRODUCTION: Numerous studies showed that the Flot-2 protein expression was significantly elevated in cancerous tissues and Flot-2 played pivotal roles in the development and progression of cancers. Increased expression of Flot-2 was correlated to a poor prognosis in cancer patients. EVIDENCE ACQUISITION: Eligible literatures were collected by retrieving multiple databases, including PubMed, Web of Science, Embase, CNKI and Wanfang database. With RevMan5.3 software and Stata SE12.0, the association of Flot-2 expression level with lymph node metastasis (LNM) and overall survival (OS) were explored in cancer patients. EVIDENCE SYNTHESIS: A total of 1947 cancer patients from 13 eligible articles were included in this meta-analysis. The results indicated that patients with over-expressed Flot-2 would develop an increased risk of LNM (OR=2.58, 95% CI: 1.60-4.16, P=0.0001), as well as shorter OS (HR=1.59, 95% CI: 1.13-2.06, P=0.000), compared to those patients with lower expression of Flot-2 in tumor tissues. CONCLUSIONS: Flot-2 protein might be a novel biomarker; LNM and OS may be predicted by up-regulated expression of Flot-2 in various tumors. PMID- 27981827 TI - Novel technologies and techniques in bariatric surgery. AB - Obesity has been on the rise globally and more people are now clinically obese than ever before in the US. This issue has a significant impact on both health and cost to healthcare systems. Bariatric surgery is efficacious in treatment of obesity but only in late stages of the disease, and there is a requirement for less invasive techniques/devices to treat obesity at earlier stages. Currently a number of these are either in clinical trials or have recently been approved by the Food and Drug Administration for weight loss. This review aims to give an overview of the newer technologies and techniques being used in bariatric surgery. It will also give a glimpse into future methods and those that have fallen short in recent times. PMID- 27981828 TI - Management of post-ERCP complications. AB - Endoscopic retrograde cholangiopancreatography (ERCP) has the highest risk of complication of any endoscopic procedure routinely performed by gastroenterologists or surgeons. Adverse events are inevitable when performing ERCP, and one must learn to manage these appropriately when they occur. One avenue for a successful outcome after a complication of ERCP is to follow the "5R model" of management: recognize, react, reach out, repent, and revisit. Several case studies are used as examples of intervention after complication, especially after retroperitoneal perforation. The literature is briefly reviewed in some areas, and I draw upon my own experience extensively in others. If there is a sixth R in the model it would be to "rejoice" when a patient is successfully managed and is finally sent home in good health. PMID- 27981830 TI - MnO2 Nanofilms on Nitrogen-Doped Hollow Graphene Spheres as a High-Performance Electrocatalyst for Oxygen Reduction Reaction. AB - Platinum is commonly chosen as an electrocatalyst used for oxygen reduction reaction (ORR). In this study, we report an active catalyst composed of MnO2 nanofilms grown directly on nitrogen-doped hollow graphene spheres, which exhibits high activity toward ORR with positive onset potential (0.94 V vs RHE), large current density (5.2 mA cm-2), and perfect stability. Significantly, when it was used as catalyst for air electrode, a zinc-air battery exhibited a high power density (82 mW cm-2) and specific capacities (744 mA h g-1) comparable to that with Pt/C (20 wt %) as air cathode. The enhanced activity is ascribed to the synergistic interaction between MnO2 and the doped hollow carbon nanomaterials. This easy and cheap method paves a way of synthesizing high-performance electrocatalysts for ORR. PMID- 27981831 TI - Effect of Morphology on the Electrical Resistivity of Silver Nanostructure Films. AB - The relatively high temperatures (>200 degrees C) required to sinter silver nanoparticle inks have limited the development of printed electronic devices on low-cost, heat-sensitive paper and plastic substrates. This article explores the change in morphology and resistivity that occurs upon heating thick films of silver nanowires (of two different lengths; Ag NWs), nanoparticles (Ag NPs), and microflakes (Ag MFs) at temperatures between 70 and 400 degrees C. After heating at 70 degrees C, films of long Ag NWs exhibited a resistivity of 1.8 * 10-5 Omega cm, 4000 times more conductive than films made from Ag NPs. This result indicates the resistivity of thick films of silver nanostructures is dominated by the contact resistance between particles before sintering. After sintering at 300 degrees C, the resistivity of short Ag NWs, long Ag NWs, and Ag NPs converge to a value of (2-3) * 10-5 Omega cm, while films of Ag MFs remain ~10* less conductive (4.06 * 10-4 Omega cm). Thus, films of long Ag NW films heated at 70 degrees C are more conductive than Ag NP films sintered at 300 degrees C. Adding 10 wt % nanowires to a film of nanoparticles results in a 400-fold improvement in resistivity. PMID- 27981829 TI - Discerning the Role of the Hydroxyproline Residue in the Structure of Conantokin Rl-B and Its Role in GluN2B Subunit-Selective Antagonistic Activity toward N Methyl-d-Aspartate Receptors. AB - Conantokins (con) are short gamma-carboxyglutamate (Gla)-containing polypeptides expressed by marine snails that function as antagonists of N-methyl-d-aspartate receptor (NMDAR) ion channels. The Gla residues govern structural conformations and antagonistic activities of the conantokins. In addition to Gla, some conantokins, e.g., conRl-B, also contain a hydroxyproline (HyP or O) residue, which in this case is centrally located in the peptide at position 10. Because conRl-B specifically inhibits ion channels of GluN2B subunit-containing heterotetrameric NMDARs, we evaluated the unusual role of HyP10 in this effect. To accomplish this goal, we examined synthetic variants of conRl-B in which HyP10 was either deleted (conRl-B[DeltaO10]) or replaced with alanine (conRl-B[O10A]) or proline (conRl-B[O10P]). The solution structures of these variants were determined by nuclear magnetic resonance spectroscopy. Deletion of HyP10, or replacement of HyP10 with Ala10, attenuated the distortion in the central region of the apo-conRl-B helix and allowed Mg2+-complexed end-to-end alpha-helix formation. The inhibitory properties of these variants were assessed by measuring NMDA/Gly-stimulated intracellular Ca2+ influx in mice neurons. ConRl-B[O10P] retained its NMDAR ion channel inhibitory activity in wild-type (WT) neurons but lost its GluN2B specificity, whereas conRl-B[DeltaO10] showed overall diminished inhibitory function. ConRl-B[O10A] showed attenuated inhibitory function but retained its GluN2B specificity. Thus, HyP10 plays a critical role in maintaining the structural integrity of conRl-B, which can be correlated with its GluN2B subunit-selective inhibition. Weakened inhibition by conRl-B was also observed in neurons lacking either the GluN2C or GluN2D subunit, compared to WT neurons. This suggests that GluN2C and GluN2D are also required for inhibition by conRl-B. PMID- 27981832 TI - A First-Principles Time-Dependent Density Functional Theory Framework for Spin and Time-Resolved Angular-Resolved Photoelectron Spectroscopy in Periodic Systems. AB - We present a novel theoretical approach to simulate spin, time, and angular resolved photoelectron spectroscopy (ARPES) from first-principles that is applicable to surfaces, thin films, few layer systems, and low-dimensional nanostructures. The method is based on a general formulation in the framework of time-dependent density functional theory (TDDFT) to describe the real time evolution of electrons escaping from a surface under the effect of any external (arbitrary) laser field. By extending the so-called t-SURFF method to periodic systems one can calculate the final photoelectron spectrum by collecting the flux of the ionization current trough an analyzing surface. The resulting approach, that we named t-SURFFP, allows us to describe a wide range of irradiation conditions without any assumption on the dynamics of the ionization process allowing for pump-probe simulations on an equal footing. To illustrate the wide scope of applicability of the method we present applications to graphene, monolayer, and bilayer WSe2, and hexagonal BN (hBN) under different laser configurations. PMID- 27981834 TI - Arrays of Ultrathin CdS Nanoflakes with High-Energy Surface for Efficient Gas Detection. AB - It is fascinating and challenging to endow conventional materials with unprecedented properties. For instance, cadmium sulfide (CdS) is an important semiconductor with excellent light response; however, its potential in gas sensing was underestimated owing to relatively low chemical activity and poor electrical conductivity. Herein, we demonstrate that an ideal architecture, ultrathin nanoflake arrays (NFAs), can improve significantly gas-sensing properties of CdS material. The CdS NFAs are grown directly on the interdigitated electrode to expose large surface area. Their thickness is reduced below the double Debye length of CdS, permitting to achieve a full depletion of carriers. Particularly, the prepared CdS nanoflakes are enclosed with high-energy {0001} facets exposed, which provides more active sites for gas adsorption. Moreover, the NFAs exhibit the light-trapping effect, which further enhances their gas sensitivity. As a result, the as-prepared CdS NFAs demonstrate excellent gas sensing and light-response properties, thus being capable of dual gas and light detection. PMID- 27981833 TI - Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry. AB - The isoxazolidine ring represents one of the privileged structures in medicinal chemistry, and there have been an increasing number of studies on isoxazolidine and isoxazolidine-containing compounds. Optimization of the 1,3-dipolar cycloaddition (1,3-DC), original methods including electrophilic or palladium mediated cyclization of unsaturated hydroxylamine, has been developed to obtain isoxazolidines. Novel reactions involving the isoxazolidine ring have been highlighted to accomplish total synthesis or to obtain bioactive compounds, one of the most significant examples being probably the thermic ring contraction applied to the total synthesis of (+/-)-Gelsemoxonine. The unique isoxazolidine scaffold also exhibits an impressive potential as a mimic of nucleosides, carbohydrates, PNA, amino acids, and steroid analogs. This review aims to be a comprehensive and general summary of the different isoxazolidine syntheses, their use as starting building blocks for the preparation of natural compounds, and their main biological activities. PMID- 27981835 TI - Radiolabeled Selective Matrix Metalloproteinase 13 (MMP-13) Inhibitors: (Radio)Syntheses and in Vitro and First in Vivo Evaluation. AB - The noninvasive imaging of MMP activity in vivo could have a high impact in basic research as well as in clinical applications. This approach can be established using radiolabeled MMP inhibitors (MMPIs) as tracers for the detection of activated MMPs by means of PET. However, the complexity of diseases associated with dysregulated MMP expression necessitates the imaging of distinct MMPs or MMP subgroups to distinguish their individual role in specific diseases. To this end, selective and potent MMP-13 inhibitors based on a N,N'-bis(benzyl)pyrimidine-4,6 dicarboxamide core have been synthesized and successfully radiolabeled with carbon-11, fluorine-18, and gallium-68. Selected radiolabeled candidates were evaluated in vitro and in vivo regarding their pharmacokinetic properties and metabolic stability. PMID- 27981837 TI - The Floatability of Single Spheres versus Their Pairs on the Water Surface. AB - Particle floatability at the water surface encountered in nature and industrial systems often occurs in the presence of many particles, but the available theoretical developments are based on the flotation of single particles. Here experiments were conducted to compare the floatabilities of single and multiple spheres on the air-water interfaces. Specifically, the forces on floating single spheres and their pairs versus the depth of deformed interface were measured using a force sensor combined with high-speed video microscopy and modeled based on the 3D Young-Laplace equation which was numerically solved. The experimental and theoretical results for the vertical forces supporting the floatability of the pairs of spheres agree well. The maximum measured forces on the pairs were equal to the sum of the maximum forces measured on two single spheres individually, but the forces measured on the single spheres and their pairs at different depths of interface deformation were different. The vertical forces supporting the floatability of the sphere pairs can better tolerate the interface deformation than the same force on two single particles. This evidence is also supported by the experiments with multiple particles floating at the surface of water-ethanol mixtures. Adding ethanol into water reduced the surface tension of water and the floatability of particles at the water surface, but the floatability of multiple particles was sustainable at much lower critical surface tensions than that for single particles, invalidating the classical theories. Lateral interparticle interactions influence the floatability of particles and should be considered in its modeling. PMID- 27981836 TI - Enhanced Temporal Resolution with Ion Channel-Functionalized Sensors Using a Conductance-Based Measurement Protocol. AB - The binding of a target analyte to an ion channel (IC), which is readily detected electrochemically in a label-free manner with single-molecule selectivity and specificity, has generated widespread interest in using natural and engineered ICs as transducers in biosensing platforms. To date, the majority of developments in IC-functionalized sensing have focused on IC selectivity or sensitivity or development of suitable membrane environments and aperture geometries. Comparatively little work has addressed analytical performance criteria, particularly criteria required for temporal measurements of dynamic processes. We report a measurement protocol suitable for rapid, time-resolved monitoring (<=30 ms) of IC-modulated membrane conductance. Key features of this protocol include the reduction of membrane area and the use of small voltage steps (10 mV) and short duration voltage pulses (10 ms), which have the net effect of reducing the capacitive charging and decreasing the time required to achieve steady state currents. Application of a conductance protocol employing three sequential, 10 ms voltage steps (-10 mV, -20 mV, -30 mV) in an alternating, pyramid-like arrangement enabled sampling of membrane conductance every 30 ms. Using this protocol, dynamic IC measurements on black lipid membranes (BLMs) functionalized with gramicidin A were conducted using a fast perfusion system. BLM conductance decreased by 76 +/- 7.5% within 30 ms of switching from solutions containing 0 to 1 M Ca2+, which demonstrates the feasibility of using this approach to monitor rapid, dynamic chemical processes. Rapid conductance measurements will be broadly applicable to IC-based sensors that undergo analyte-specific gating. PMID- 27981838 TI - Signatures of Size-Dependent Structural Patterns in Hydrated Copper(I) Clusters, Cu+(H2O)n=1-10. AB - The isomers of a hydrated Cu(I) ion with n = 1-10 water molecules were investigated by using ab initio quantum chemistry and an automated isomer-search algorithm. The electronic structure and vibrational spectra of the hundreds of resulting isomers were used to analyze the source of the observed bonding patterns. A structural evolution from dominantly two-coordinate structures (n = 1 4) toward a mixture of two- and three-coordinate structures was observed at n = 5 6, where the stability provided by expanded hydrogen-bonding was competitive with the dominantly electrostatic interaction between the water ligand and remaining binding sites of the metal ion. Further hydration (n = 7-10) led to a mixture of three- and four-coordinate structures. The metal ion was found, through spectroscopic signatures, to appreciably perturb the O-H bonds of even third shell water molecules, which highlighted the ability of this nominally simple ion to partially activate the surrounding water network. PMID- 27981839 TI - Environmental Electrophiles: Protein Adducts, Modulation of Redox Signaling, and Interaction with Persulfides/Polysulfides. AB - Included among the many environmental electrophiles are aromatic hydrocarbon quinones formed during combustion of gasoline, crotonaldehyde in tobacco smoke, methylmercury accumulated in fish, cadmium contaminated in rice, and acrylamide in baked foods. These electrophiles can modify nucleophilic functions such as cysteine residues in proteins forming adducts and in the process activate cellular redox signal transduction pathways such as kinases and transcription factors. However, higher concentrations of electrophiles disrupt such signaling by nonselective covalent modification of cellular proteins. Persulfide/polysulfides produced by various enzymes appear to capture environmental electrophiles because of the formation of their sulfur adducts without electrophilicity. We therefore speculate that persulfide/polysulfides are candidates for the regulation of redox signal transduction pathways (e.g., cell survival, cell proliferation, and adaptive response) and toxicity during exposure to environmental electrophiles. PMID- 27981840 TI - Developments of Metal Phosphides as Efficient OER Precatalysts. AB - Over the last 2 years, it has been observed that metal phosphides have emerged as efficient electrocatalysts for both hydrogen and oxygen evolution reactions (HER and OER). However, while the HER has been immensely studied, the OER is limited. The chemistry in the OER is more complicated and involves irreversible surface oxidations of these materials and transforms them to their corresponding oxide/oxyhydroxide. Interestingly, these in situ changes have been widely observed generating more active catalysts with superior performance. Phosphides of Fe, Co, and Ni with different compositions have been proved as efficient catalysts for water oxidation. Considering their importance, structures, compositions, surface modifications, and also in situ transformation during electrolysis, this Perspective provides state-of-the-art views of their current developments and future prospects. PMID- 27981841 TI - Control and Switching of Aromaticity in Various All-Aza-Expanded Porphyrins: Spectroscopic and Theoretical Analyses. AB - Modification of aromaticity is regarded as one of the most interesting and important research topics in the field of physical organic chemistry. Particularly, porphyrins and their analogues (porphyrinoids) are attractive molecules for exploring various types of aromaticity because most porphyrinoids exhibit circular conjugation pathways in their macrocyclic rings with various molecular structures. Aromaticity in porphyrinoids is significantly affected by structural modification, redox chemistry, NH tautomerization, and electronic states (singlet and triplet excited states). Conversely, aromaticity significantly affects the spectroscopic properties and chemical reactivities of porphyrinoids. In this context, considerable efforts have been devoted to understanding and controlling the aromaticity and antiaromaticity of porphyrinoids. Thus, a series of porphyrinoids are in the limelight, being expected to shed light on this field because they have some advantages to demonstrate the switching of aromaticity; it is possible to control the aromaticity by lowering the temperature, adding and removing the protons of expanded porphyrins, changing the chemical environment, and switching the electronic states (triplet and singlet excited states) by photoexcitation. In this regard, this Review describes the control of aromaticity in various expanded porphyrins from the spectroscopic point of view with assistance from theoretical calculations. PMID- 27981843 TI - Radiolabeled Rhein as Small-Molecule Necrosis Avid Agents for Imaging of Necrotic Myocardium. AB - A rapid and accurate identification of necrotic myocardium is of great importance for diagnosis, risk stratification, clinical decision-making, and prognosis evaluation of myocardial infarction. Here, we explored technetium-99m labeled rhein derivatives for rapid imaging of the necrotic myocardium. Three hydrazinonicotinic acid-linker-rhein (HYNIC-linker-rhein) derivatives were synthesized, and then, these synthetic compounds were labeled with technetium-99m using ethylenediaminediacetic acid (EDDA) and tricine as coligands [99mTc(EDDA) HYNIC-linker-rhein]. The necrosis avidity of the three 99mTc-labeled rhein derivatives was tested in a mouse model of ethanol-induced muscular necrosis by gamma counting, histochemical staining, and autoradiography. A lead tracer for visualization of necrotic myocardium was assessed by single photon emission computed tomography/computed tomography (SPECT/CT) imaging in a rat model with reperfused myocardial infarction. The necrosis avidity mechanism of the tracer was explored by DNA binding studies in vitro and blocking experiments in vivo. Results showed that the uptake in necrotic muscles of the three 99mTc-compounds was higher than that in viable muscles (P < 0.001). Autoradiography and histochemical staining results were consistent with selective uptake of the radiotracer in the necrotic regions. Among the these tracers, 99mTc(EDDA)-HYNIC ethylenediamine-rhein [99mTc(EDDA)-HYNIC-2C-rhein] displayed the best distribution profiles for imaging. The necrotic myocardium lesions were clearly visualized by SPECT/CT using 99mTc(EDDA)-HYNIC-2C-rhein at 1 h after injection. The necrotic-to-viable myocardium and necrotic myocardium-to-blood uptake ratios of 99mTc(EDDA)-HYNIC-2C-rhein were 4.79 and 3.02 at 1 h after injection. DNA binding studies suggested HYNIC-linker-rhein bound to DNA through intercalation. The uptake of 99mTc(EDDA)-HYNIC-2C-rhein in necrotic muscle was significantly blocked by excessive unlabeled rhein, with 77.61% decline at 1 h after coinjection. These findings suggested 99mTc(EDDA)-HYNIC-2C-rhein emerged as a "hot spot" imaging probe that has a potential for rapid imaging of necrotic myocardium. The necrosis avidity mechanism of 99mTc(EDDA)-HYNIC-linker-rhein may be due to its interaction with exposed DNA in necrotic tissues. PMID- 27981842 TI - Measuring and Remediating Nonspecific Modifications of Gold Surfaces Using a Coupled in Situ Electrochemical Fluorescence Microscopic Methodology. AB - In surface-based biosensors, the nonspecific or undesired adsorption of the probe is an important characteristic that is typically difficult to measure and therefore to control or eliminate. A methodology for measuring and then minimizing or eliminating this problem on gold surfaces, readily applicable to many common surface modifications is presented. Combining electrochemical perturbation and fluorescence microscopy, we show that the potential at which the adsorbed species is removed can be used as an estimate of the strength of the adsorbate-surface interaction. This desorption potential can be easily measured through an increase in fluorescence intensity as the potential is manipulated. Furthermore, this method can be used to evaluate strategies for preventing or removing nonspecific adsorption. This is demonstrated for a wide variety of surface modifications, from strongly chemisorbed monolayers such as thiol self assembled monolayers (SAMs) to physisorbed monolayers as well as for complex surface structures like peptide and DNA mixed-component SAMs. The use of a coadsorption strategy or small magnitude potential-step cycles was shown to significantly decrease the amount of nonspecifically or noncovalently bound probe, creating better defined surfaces. PMID- 27981844 TI - Chemically Driven Enhancement of Oxygen Reduction Electrocatalysis in Supported Perovskite Oxides. AB - Perovskite oxides have the capacity to efficiently catalyze the oxygen reduction reaction (ORR), which is of fundamental importance for electrochemical energy conversion. While the perovskite catalysts have been generally utilized with a support, the role of the supports, regarded as inert toward the ORR, has been emphasized mostly in terms of the thermal stability of the catalyst system and as an ancillary transport channel for oxygen ions during the ORR. We demonstrate a novel approach to improving the catalytic activity of perovskite oxides for solid oxide fuel cells by controlling the oxygen-ion conducting oxide supports. Catalytic activities of (La0.8Sr0.2)0.95MnO3 perovskite thin-film placed on different oxide supports are characterized by electrochemical impedance spectroscopy and X-ray absorption spectroscopy. These analyses confirm that the strong atomic orbital interactions between the support and the perovskite catalyst enhance the surface exchange kinetics by ~2.4 times, in turn, improving the overall ORR activity. PMID- 27981845 TI - Microwave Synthesis of Chitosan Capped Silver-Dysprosium Bimetallic Nanoparticles: A Potential Nanotheranosis Device. AB - Accurate imaging of the structural and functional state of biological targets is a critical task. To amend paucities associated with individual imaging, there is high interest to develop a multifunctional theranostic devices for cancer diagnosis and therapy. Herein, chitosan coated silver/dysprosium bimetallic nanoparticles (BNPs) were synthesized through a green chemistry route and characterization results inferred that the BNPs are crystalline, spherical, and of size ~10 nm. High-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) and X-ray photoelectron spectroscopy (XPS) confirm the reduced metallic states of Ag and Dy in nanoparticles. These BNPs demonstrate high emission in a second near-infrared (NIR-II, 1000-1400 nm) biological window on excitation at 808 nm. Moreover, magnetization and magnetic resonance imaging (MRI) studies perceive the inherent paramagnetic features of Dy component that displays dark T2 contrast and high relaxivity. Due to high X-ray attenuation effect, BNPs exhibit better Hounsfield unit (HU) value than the reported contrast agents. BNPs unveil good biocompatibility and also express sturdy therapeutic effect in HeLa cells when tethered with doxorubicin. PMID- 27981846 TI - Exhaustive Qualitative LC-DAD-MSn Analysis of Arabica Green Coffee Beans: Cinnamoyl-glycosides and Cinnamoylshikimic Acids as New Polyphenols in Green Coffee. AB - Coffee is one of the most consumed beverages in the world, due to its unique aroma and stimulant properties. Although its health effects are controversial, moderate intake seems to be beneficial. The present work deals with the characterization and quantification of polyphenols and methylxanthines in four Arabica green coffee beans from different geographical origins. The antioxidant activity was also evaluated. Forty-three polyphenols (cinnamic acid, cinnamoyl amide, 5 cinammoyl-glycosides, and 36 cinnamate esters) were identified using LC MSn. Among these, cinnamate esters of six different chemical groups (including two dimethoxycinnamoylquinic acid isomers, three caffeoyl-feruloylquinic acid isomers, caffeoyl-sinapoylquinic acid, p-coumaroyl-feruloylquinic acid, two caffeoylshikimic acid isomers, and trimethoxycinnamoylshikimic acid) in addition to five isomers of cinnamoyl-glycosides called caffeoyl-2,7-anhydro-3-deoxy-2 octulopyranosic acid (CDOA) are described for the first time in Arabica green coffee beans. Moreover, 38 polyphenols (6-7% w/w) and 2 methylxanthines (1.3% w/w) were quantified by HPLC-DAD. Caffeoylquinic was the most abundant group of compounds (up to 85.5%) followed by dicaffeoylquinic and feruloylquinic acids (up to 8 and 7%, respectively) and the newly identified cinnamoyl-glycosides (CDOA) (up to 2.5%). Caffeine was the main methylxanthine (99.8%), with minimal amounts of theobromine (0.2%). African coffees (from Kenya and Ethiopia) showed higher polyphenolic content than American beans (from Brazil and Colombia), whereas methylxanthine contents varied randomly. Both phenols and methylxanthines contributed to the antioxidant capacity associated with green coffee, with a higher contribution of polyphenols. We conclude that green coffee represents an important source of polyphenols and methylxanthines, with high antioxidant capacity. PMID- 27981847 TI - Mitigation Strategies for Greenhouse Gas Emissions from Agriculture and Land-Use Change: Consequences for Food Prices. AB - The land use sector of agriculture, forestry, and other land use (AFOLU) plays a central role in ambitious climate change mitigation efforts. Yet, mitigation policies in agriculture may be in conflict with food security related targets. Using a global agro-economic model, we analyze the impacts on food prices under mitigation policies targeting either incentives for producers (e.g., through taxes) or consumer preferences (e.g., through education programs). Despite having a similar reduction potential of 43-44% in 2100, the two types of policy instruments result in opposite outcomes for food prices. Incentive-based mitigation, such as protecting carbon-rich forests or adopting low-emission production techniques, increase land scarcity and production costs and thereby food prices. Preference-based mitigation, such as reduced household waste or lower consumption of animal-based products, decreases land scarcity, prevents emissions leakage, and concentrates production on the most productive sites and consequently lowers food prices. Whereas agricultural emissions are further abated in the combination of these mitigation measures, the synergy of strategies fails to substantially lower food prices. Additionally, we demonstrate that the efficiency of agricultural emission abatement is stable across a range of greenhouse-gas (GHG) tax levels, while resulting food prices exhibit a disproportionally larger spread. PMID- 27981848 TI - Striking the Optimal Solubility-Permeability Balance in Oral Formulation Development for Lipophilic Drugs: Maximizing Carbamazepine Blood Levels. AB - The purpose of this research was to investigate the performance of cosolvent based solubility-enabling formulations in oral delivery of lipophilic drugs, accounting for the gastrointestinal tract (GIT) luminal solubilization processes, the solubility-permeability interplay, and the overall in vivo systemic absorption. The poorly soluble antiepileptic agent carbamazepine was formulated in three cosolvent-based formulations: 20%, 60%, and 100% PEG-400, and the apparent solubility and rat permeability of the drug in these formulations were evaluated. The performance of the formulations in the dynamic GIT environment was assessed utilizing the biorelevant pH-dilution method. Then, the overall in vivo drug exposure was investigated following oral administration to rats. The three formulations showed dramatic solubility and permeability differences; the 100% PEG-400 provided the highest solubility enhancement and the 20% the poorest, while the exact opposite was evident from the permeability point of view. The dissolution results indicated that the 20% PEG-400 formulation crashes quickly following oral administration, but both the 60% and the 100% PEG-400 formulations allowed full solubilization of the dose throughout the entire GIT-like journey. The best in vivo performing formulation was the 60% PEG-400 (Fsys > 90%), followed by the 100% PEG-400 (Fsys = 76%), and the 20% PEG-400 formulation (Fsys ~ 60%). In conclusion, this work demonstrates the in vivo solubility-permeability trade-off in oral delivery of lipophilic drugs; when a solubility-enabling formulation is developed, minimal threshold solubility should be targeted, that is just enough to allow solubilization of the drug dose throughout the GIT, while excess solubilizer should be avoided. PMID- 27981849 TI - Oxathiaborolium: A Type of Chiral Lewis Acid Catalyst and Its Application in Catalytic and Highly Enantioselective Diels-Alder Reactions. AB - The first reported sulfur-stabilized borenium cations were synthesized through halide abstraction of a haloborane intermediate by halophilic reagents. Different from the well-known cationic oxazaborolidines, a sulfide instead of an amine was used to not only simplify the preparation of the catalysts but also increase Lewis acidity of the boron atom. The in situ generated borenium salts showed exceptional Lewis acidity and successfully catalyzed asymmetric Diels-Alder reactions of cyclopentadiene and dienophiles in excellent yields and enantioselectivities. The NMR studies of these oxathiaborolium structures were reported as well. PMID- 27981850 TI - Wide Band Gap Semiconductor from a Hidden 2D Incommensurate Graphene Phase. AB - Producing a usable semiconducting form of graphene has plagued the development of graphene electronics for nearly two decades. Now that new preparation methods have become available, graphene's intrinsic properties can be measured and the search for semiconducting graphene has begun to produce results. This is the case of the first graphene "buffer" layer grown on SiC(0001) presented in this work. We show, contrary to assumptions of the last 40 years, that the buffer graphene layer is not commensurate with SiC. The new modulated structure we've found resolves a long-standing contradiction where ab initio calculations expect a metallic buffer, while experimentally it is found to be a semiconductor. Model calculations using the new incommensurate structure show that the semiconducting pi-band character of the buffer comes from partially hybridized graphene incommensurate boundaries surrounding unperturbed graphene islands. PMID- 27981851 TI - Molecular detection of aminoglycoside-modifying enzyme genes in Acinetobacter baumannii clinical isolates. AB - Acinetobacter baumannii is a major opportunistic pathogen in healthcare settings worldwide. In Iran, there are only few reports on the prevalence of aminoglycoside resistance genes among A. baumannii isolates. The aim of this study was to investigate the existence of aminoglycoside-modifying enzyme (AME) genes from A. baumannii strains collected at a university teaching hospital in Iran. One hundred A. baumannii strains were collected between 2014 and 2015 from hospitalized patients at Loghman Hakim Hospital, Tehran, Iran. Antimicrobial susceptibility was determined by disk diffusion method according to the Clinical and Laboratory Standards Institute recommendations. The DNA was extracted using a kit obtained from Bioneer Co. (Korea) and was used as a template for polymerase chain reaction. The most active antimicrobial agent against these strains was colistin. The rate of extended-spectrum cephalosporin resistance was 97%. The aadA1, aadB, aac(6')-Ib, and aac(3)-IIa genes were found in 85%, 77%, 72%, and 68% of A. baumannii isolates, respectively. This study showed a high prevalence rate of AME genes in A. baumannii. This prevalence rate has explained that further aminoglycoside resistance genes may have role in the resistance of clinical isolates of A. baumannii. Therefore, control and treatment of serious infections caused by this opportunistic pathogen should be given more consideration. PMID- 27981853 TI - Comparing the accuracy of high tibial osteotomies between computer navigation and conventional methods. AB - BACKGROUND: The accuracy of correction has been shown to be an important determinant in long-term outcomes of patients who were treated with a medial open wedge high tibial osteotomy (HTO) who suffer from unicompartmental osteoarthritis (OA). Computer navigation systems have the potential to improve surgical precision. The purpose of this study was to compare radiographic outcomes between patients treated with a navigation system and those treated through conventional methods of assessing alignment intra-operatively. The null hypothesis was that the method of assessing the alignment intra-operatively would make no difference in the accuracy of correction. METHODS: In this retrospective study, 107 patients with medial varus OA who were managed by open-wedge HTO were included. Of the 107 patients, 41 were treated using an intraoperative navigation system and 66 were treated using conventional methods. Pre-operative and post-operative single-leg, long-leg standing alignment films were used to determine the extent of pre operative varus deformity and the post-surgical correction achieved compared to the predetermined target range. RESULTS: The navigational system had eight instances of software malfunction (19.5%) intra-operatively and correction was determined using the cable method. These results were analyzed as part of the conventional group. Post-operative radiographic differences were significant between the two groups. In the navigation group, 75.8% of the patients were corrected within the target range compared to 66.2% in the conventional group. More patients were also under corrected (to the point of remaining in varus) using conventional methods compared to a navigation system. There was no statistically significant difference in the degree of correction in the sagittal plane between the two groups. Regardless of the method used for checking alignment intra-operatively, there was a statistically significant difference in post-operative weight-bearing measurements when the surgeon had intra-operative axial loading versus when they did not. CONCLUSION: For coronal plane corrections, the navigation system was shown to have greater success in achieving the desired correction value and in having fewer patients who were under corrected. Despite the measurement technique a surgeon chooses to assess the accuracy of correction, axial loading the extremity in order to simulate the weight-bearing film alignment post-operatively is important to maximize the accuracy of correction needed. PMID- 27981854 TI - A Prospective Randomized Study Comparing Disposable with Reusable Blades for a Morcellator Device. AB - INTRODUCTION & OBJECTIVES: Transurethral enucleation of the prostate for the management of benign prostatic obstruction (BPO) involves two steps: the enucleation and morcellation procedure. The aim of our study was to assess the efficacy of a morcellator device using disposable and reusable blades with different settings of morcellation speed. METHODS: A prospective randomized study was initiated for patients with symptomatic BPO undergoing Thulium laser enucleation of the prostate. Mechanical tissue morcellation was performed using the PiranhaTM morcellator (R. Wolf, Knittlingen, Germany) with disposable or reusable blades at 850 (n = 24) or 1500 revolutions per minute (rpm) (n = 24). Patient characteristics, intraoperative complications, and the morcellation rate (g/min) were recorded. Data are expressed as median and interquartile range (IQR). RESULTS: Forty-eight patients were randomized using disposable (n = 24) or reusable blades (n = 24). For reusable blades, the morcellation rate did not increase when changing the morcellation speed from 850 to 1500 rpm (5 vs 4.53 g/min, p = 0.843). The morcellation rate increased significantly when changing the morcellation speed from 850 to 1500 rpm using single-use blades (4.77 vs 10 g/min, p <= 0.014). The morcellation rate was not different at 850 rpm between reusable and single-use blades (5 vs 4.77 g/min, p = 0.671). Conversely, the morcellation rate was significantly different at 1500 rpm between reusable and single-use blades (4.53 vs 10 g/min, p <= 0.017). The total morcellation rate (at 850 and 1500 rpm) was significantly increased using single-use blades compared to reusable blades (7.67 vs 4.8 g/min, p <= 0.026). Interestingly, enucleated weight (g) and the morcellation rate (g/min) correlated inversely using single-use blades at 1500 rpm (r = -0.742, p <= 0.004). Only one superficial bladder injury occurred at 1500 rpm, which needed no further interventions. CONCLUSIONS: The Piranha morcellator facilitates efficient tissue removal with single-use and reusable blades. Disposable morcellator blades increase tissue removal significantly at 1500 rpm. PMID- 27981852 TI - Epigenetics, obesity and early-life cadmium or lead exposure. AB - Obesity is a complex and multifactorial disease, which likely comprises multiple subtypes. Emerging data have linked chemical exposures to obesity. As organismal response to environmental exposures includes altered gene expression, identifying the regulatory epigenetic changes involved would be key to understanding the path from exposure to phenotype and provide new tools for exposure detection and risk assessment. In this report, we summarize published data linking early-life exposure to the heavy metals, cadmium and lead, to obesity. We also discuss potential mechanisms, as well as the need for complete coverage in epigenetic screening to fully identify alterations. The keys to understanding how metal exposure contributes to obesity are improved assessment of exposure and comprehensive establishment of epigenetic profiles that may serve as markers for exposures. PMID- 27981855 TI - Individual differences in language and working memory affect children's speech recognition in noise. AB - OBJECTIVE: We examined how cognitive and linguistic skills affect speech recognition in noise for children with normal hearing. Children with better working memory and language abilities were expected to have better speech recognition in noise than peers with poorer skills in these domains. DESIGN: As part of a prospective, cross-sectional study, children with normal hearing completed speech recognition in noise for three types of stimuli: (1) monosyllabic words, (2) syntactically correct but semantically anomalous sentences and (3) semantically and syntactically anomalous word sequences. Measures of vocabulary, syntax and working memory were used to predict individual differences in speech recognition in noise. STUDY SAMPLE: Ninety-six children with normal hearing, who were between 5 and 12 years of age. RESULTS: Higher working memory was associated with better speech recognition in noise for all three stimulus types. Higher vocabulary abilities were associated with better recognition in noise for sentences and word sequences, but not for words. CONCLUSIONS: Working memory and language both influence children's speech recognition in noise, but the relationships vary across types of stimuli. These findings suggest that clinical assessment of speech recognition is likely to reflect underlying cognitive and linguistic abilities, in addition to a child's auditory skills, consistent with the Ease of Language Understanding model. PMID- 27981858 TI - Budget impact of everolimus for the treatment of progressive, well differentiated, non-functional neuroendocrine tumors of gastrointestinal or lung origin that are advanced or metastatic. AB - BACKGROUND: Advanced neuroendocrine tumors (NETs) are a rare malignancy with considerable need for effective therapies. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2016 for treatment of adults with progressive, well-differentiated, non-functional NETs of gastrointestinal (GI) or lung origin that are unresectable, locally advanced, or metastatic. OBJECTIVE: To assess the 3-year budget impact for a typical US health plan following availability of everolimus for treatment of GI and lung NETs. Methods An economic model was developed that considered two perspectives: an entire health plan and a pharmacy budget. The total budget impact included costs of drug therapies, administration, hospitalizations, physician visits, monitoring, and adverse events (AEs). The pharmacy model only considered drug costs. RESULTS: In a US health plan with 1 million members, the model estimated 66 patients with well differentiated, non-functional, and advanced or metastatic GI NETs and 20 with lung NETs undergoing treatment each year. Total budget impact in the first through third year after FDA approval ranged from $0.0568-$0.1443 per member per month (PMPM) for GI NETs and from $0.0181-$0.0355 PMPM for lung NETs. The total budget impact was lower than the pharmacy budget impact because it included cost offsets from administration and AE management for everolimus compared with alternative therapies (e.g. chemotherapies). LIMITATIONS: Because GI and lung NETs are rare diseases with limited published data, several assumptions were made that may influence interpretation of results. CONCLUSIONS: The budget impact for everolimus was minimal in this rare disease area with a high unmet need, largely due to low disease prevalence. These results should be considered in the context of significant clinical benefits potentially provided by everolimus, including significantly longer progression-free survival (PFS) for advanced GI and lung NET patients. PMID- 27981857 TI - Effective modified conservative tissue preserving protocol to treat stage I axillary hidradenitis suppurativa: a prospective cohort study of 627 patients with five years follow-up. AB - BACKGROUND: Hidradenitis suppurativa is a chronic inflammatory cutaneous disorder that involves the infundibular terminal follicles in areas rich in apocrine glands and associated with the formation of abscesses and fistulating sinus. The clinical course is variable, and definitive evidence-based guidelines for the management are not well-established. Conservative treatment is controversial, and surgical excision is the recommended method. Herein, we aim to analyze the results of a modified conservative tissue preserving management protocol for stage I axillary hidradenitis suppurativa. METHODS: A prospective cohort study of the results of 627 patients who were diagnosed and treated for stage I axillary hidradenitis suppurativa between January 2001 and December 2010 was done. Three hundred and forty nine (55.7%) were females, and 278 (44.3%) were males. The modified conservative treatment protocol consisted of three times per day washing the affected area with antibacterial soap, application of warm compresses for 10 min, followed by application of topical sodium fusidate 2% ointment (fusidic acid), with abstinence of armpits shaving during the treatment period. RESULTS: Four hundred and sixty one (73.5%) patients had complete healing within two weeks, 127 (20.3%) within three weeks, 39 (6.2%) within four weeks. The recurrence rate was 5.9% (37 patients) in which all patients were retreated conservatively and had complete healing, none required surgical intervention. CONCLUSIONS: We conclude that hidradenitis suppurativa continues to be a challenging disease for patients and physicians. Tissue preserving conservative method using the fusidic acid ointment for treating stage I axillary hidradenitis suppurativa showed a promising result. Further research should be conducted on the optimal treatment regimen. PMID- 27981856 TI - Distinct cellular and molecular environments support aging-related DNA methylation changes in the substantia nigra. AB - AIM: We aimed to couple brain region-specific changes in global DNA methylation over aging to underlying cellular and molecular environments. MATERIALS & METHODS: We measured two major forms of DNA methylation and analyzed Dnmt, Tet and metabolite levels in the striatum and substantia nigra (SN) over aging in healthy male mice. RESULTS: The ratio of 5-hydroxymethylcytosine to 5 methylcytosine increases over aging in the SN, and 5-hydroxymethylcytosine increases preferentially in dopaminergic neurons. Additionally, this age dependent alteration in methylation correlates with a reduction in the ratio of alpha-ketoglutarate to succinate in the SN. CONCLUSION: Distinct cellular and molecular environments correlate with aging-associated methylation changes in the SN, implicating this epigenetic mechanism in the susceptibility of this brain region to age-related cell loss. PMID- 27981859 TI - Ultrasound-guided drainage and sclerosis of a cystic myometrial mass. PMID- 27981860 TI - Determinants of maternal health care services utilization in Pakistan: evidence from Pakistan demographic and health survey, 2012-13. AB - The aim of this study was to determine the association between maternal utilisation of health-care services and socio-demographic factors among reproductive-age women in Pakistan. We used the sample of ever-married reproductive-age women (n = 7446) from the Pakistan Demographic and Health Survey (PDHS), 2012-13. We measured maternal utilisation of health-care services by using three dependent variables: number of antenatal care (ANC) visits, delivery assistance by a skilled health provider, and delivery in a health-care facility. Around 36.6% of women had made four or more ANC visits, 59% had received assistance from skilled health providers during delivery, and 55.3% had given birth in a health-care facility. On multivariable logistic regression, all three variables were positively associated with education and wealth, and negatively associated with birth order and women's autonomy. Policymakers and health planners may use our findings to develop efficient strategies, particularly for uneducated women and those with poor economic status, to improve the utilisation of maternal health-care services in Pakistan. PMID- 27981862 TI - Evaluation of a Novel Single-Use Flexible Ureteroscope. AB - INTRODUCTION: A novel single-use flexible ureteroscope promises the optical characteristics and maneuverability of a reusable fourth-generation flexible ureteroscope. In this study, the LithoVue Single-Use Digital flexible ureteroscope was directly compared with contemporary reusable flexible ureteroscopes, with regard to optics, deflection, and irrigation flow. METHODS: Three flexible ureteroscopes such as the LithoVue (Single Use; Boston Scientific), Flex-Xc (Karl Storz, Germany), and Cobra (Richard Wolf, Germany) were assessed in vitro for image resolution, distortion, color representation, grayscale imaging, field of view, and depth of field. Ureteroscope deflection was tested with an empty channel followed by placement of a 200 MUm laser fiber and a 1.9F wire basket, a 2.0F nanoelectric pulse lithotripsy (NPL) probe, and a 2.4F NPL probe. Ureteroscope irrigation flow was measured using normal saline at 100 cm, with an empty channel followed by a 200 MUm laser fiber, a 1.9F wire basket and a 2.0F NPL probe. RESULTS: The LithoVue showed the largest field of view, with excellent resolution, image distortion, and depth of field. No substantial difference was demonstrated in color reproducibility or in the discernment of grayscales between ureteroscopes. The LithoVue maintained full deflection ability with all instruments in the working channel, although the Flex-Xc and Cobra ureteroscopes showed loss of deflection ranging from 2 degrees to 27 degrees , depending on the instrument placed. With an empty channel, the LithoVue showed an absolute flow rate similar to the Flex-Xc ureteroscope (p = 0.003). It maintained better flow with instruments in the channel than the Flex-Xc ureteroscope. The Cobra ureteroscope has a separate 3.3F instrument channel, keeping flow rates the same with instrument insertion. CONCLUSION: The LithoVue Single-Use Digital ureteroscope has comparable optical capabilities, deflection, and flow, making it a viable alternative to standard reusable fourth-generation flexible digital and fiberoptic ureteroscopes. PMID- 27981861 TI - A comparison of two rating protocols for videofluoroscopic swallowing study by inexperienced judges. AB - PURPOSE: Videofluoroscopic swallowing study (VFSS) has been widely used in clinical settings and in research for evaluating swallowing functions. The interpretation of such studies requires subjective judgment by the raters, which may be affected by clinical experience and definitions of the rating parameters. Two methods have been proposed to improve the reliability: training and use of a coordinate mapping (CM) protocol. This study aimed at investigating the effect of training on improving the intra-and inter-rater reliabilities of VFSS analysis; and comparing the intra- and inter-rater reliabilities of a clinical evaluation (CE) protocol and a CM protocol for analysing VFSS. METHOD: Forty inexperienced judges were randomly assigned to one of two groups: a CE group or a CM group. Each group received training to perform VFSS judgments using the relevant analysis protocol. All participants were tested individually before and after training. RESULT: Results showed that training significantly improved the intra- and inter-rater reliabilities of both protocols. In addition, the CE group achieved significantly higher intra- and inter-rater reliabilities than the CM group after training. CONCLUSION: It is recommended that standard training protocols be implemented during clinical training to improve the reliability in VFSS analysis. PMID- 27981864 TI - Corrigendum. PMID- 27981863 TI - Management of pseudohypoparathyroidism in pregnancy: a case report. PMID- 27981865 TI - Healthcare resource utilization in patients receiving idarucizumab for reversal of dabigatran anticoagulation due to major bleeding, urgent surgery, or procedural interventions: interim results from the RE-VERSE ADTM study. AB - AIMS: Patients treated with anticoagulants may experience serious bleeding or require urgent surgery or intervention, and may benefit from rapid anticoagulant reversal. This exploratory analysis assessed healthcare resource utilization (HCRU) in patients treated with idarucizumab, a specific reversal agent for dabigatran etexilate. MATERIALS AND METHODS: RE-VERSE ADTM (NCT02104947), a prospective, multi-center open-label study, is evaluating idarucizumab for dabigatran reversal in patients with serious bleeding (Group A) or undergoing emergency surgery/procedures (Group B). HCRU outcome measures evaluated in the first 90 patients enrolled were use of blood products and pro-hemostatic agents, length of stay (LOS) in hospital, and LOS in intensive care unit (ICU). RESULTS: Blood products or pro-hemostatic agents were given to 63% (32/51) of patients in Group A and 23% (9/39) of patients in Group B on the day of/day after surgery. An overnight hospital stay was reported for 82% (42/51) of patients in Group A with median LOS = 7 (range = 1-71) bed-days. For Group B, 92% (36/39) had an overnight hospital stay with a median LOS = 9 (range = 1-92) bed-days. In Group A, 17 patients were admitted to the ICU for at least 1 day with median LOS = 4 (range = 1-44) days; in Group B the number was 15 with median LOS = 2 (range = 1-92) days. LIMITATIONS: The lack of a control group and the small patient numbers limit the strength of the conclusions. CONCLUSIONS: The use of idarucizumab may simplify emergency management of dabigatran-treated patients with life-threatening bleeds and reduce perioperative complications in patients undergoing emergency surgery. PMID- 27981869 TI - Contents index. PMID- 27981866 TI - Influence of videogames and musical instruments on performances at a simulator for robotic surgery. AB - OBJECTIVE: To assess if exposure to videogames, musical instrument playing, or both influence the psychomotor skills level, assessed by a virtual reality simulator for robot-assisted surgery (RAS). MATERIALS AND METHODS: A cohort of 57 medical students were recruited: playing musical instruments (group 1), videogames (group 2), both (group 3), and no activity (group 4); all students executed four exercises on a virtual simulator for RAS. RESULTS: Subjects from group 3 achieved the best performances on overall score: 527.09 +/- 130.54 vs. 493.73 +/- 108.88 (group 2), 472.72 +/- 85.31 (group 1), and 403.13 +/- 99.83 (group 4). Statistically significant differences (p < .05) between group 3 and group 4 were found for overall score (p = .009) and for time of completion (p = .044). As regards experience with the piano, subjects from group 3 outperformed those from group 1 on overall score (496.98 +/- 122.71 vs. 470.25 +/- 92.31), but without statistically significant difference (p = .646). CONCLUSIONS: The present study suggests that the level of psychomotor skills in subjects exposed to both musical instrument playing and videogames is higher than that in those practicing either one alone. The effect of videogames appears negligible in individuals playing the piano. PMID- 27981867 TI - Phenotypic and functional characterization of a bortezomib-resistant multiple myeloma cell line by flow and mass cytometry. AB - Multiple myeloma (MM) is an incurable malignant plasma cell neoplasm. Proteasome inhibitors including Bortezomib (Bz) are used to treat MM, and treatment failure due to drug resistance occurs. Bz-sensitive and -resistant MM cells have distinct immunophenotypic signatures that correlate with clinical outcome. These changes can be identified by fluorescence-based cytometry (FBC), however, FBC is rarely used in predicting Bz resistance. Mass cytometry (MC) is a recently developed variation of flow cytometry that detects heavy metal-ion tagged antibodies using time-of-flight mass spectrometry allowing for detection of up to 38 epitopes simultaneously in a single cell, without significant overlap, exceeding the dimensionality of FBC 3-4-fold. Here, we compared FBC and MC in the immunophenotypic characterization of Bz-sensitive and -resistant human MM cell line U266. We show that Bz-resistant cells are associated with the loss of CD56 and CD66a adhesion molecules as well as an activation signature. PMID- 27981871 TI - Reliability and validity of the Bowel Function Index for evaluating opioid induced constipation: translation, cultural adaptation and validation of the Portuguese version (BFI-P). AB - OBJECTIVE: The Bowel Function Index (BFI) is a simple and sound bowel function and opioid-induced constipation (OIC) screening tool. We aimed to develop the translation and cultural adaptation of this measure (BFI-P) and to assess its reliability and validity for the Portuguese language and a chronic pain population. METHODS: The BFI-P was created after a process including translation, back translation and cultural adaptation. Participants (n = 226) were recruited in a chronic pain clinic and were assessed at baseline and after one week. Internal consistency, test-retest reliability, responsiveness, construct (convergent and known groups) and factorial validity were assessed. RESULTS: Test retest reliability had an intra-class correlation of 0.605 for BFI mean score. Internal consistency of BFI had Cronbach's alpha of 0.865. The construct validity of BFI-P was shown to be excellent and the exploratory factor analysis confirmed its unidimensional structure. The responsiveness of BFI-P was excellent, with a suggested 17-19 point and 8-12 point change in score constituting a clinically relevant change in constipation for patients with and without previous constipation, respectively. CONCLUSIONS: This study had some limitations, namely, the criterion validity of BFI-P was not directly assessed; and the absence of a direct criterion for OIC precluded the assessment of the criterion based responsiveness of BFI-P. Nevertheless, BFI may importantly contribute to better OIC screening and its Portuguese version (BFI-P) has been shown to have excellent reliability, internal consistency, validity and responsiveness. Further suggestions regarding statistically and clinically important change cut-offs for this instrument are presented. PMID- 27981870 TI - Immunohistological analysis of eotaxin and RANTES in the model animal of eosinophilic otitis media. AB - BACKGROUND: The most crucial clinical problem of Eosinophilic Otitis Media (EOM) is sensorineural hearing loss. A previous report revealed that repeated antigen stimulation of middle ear causes eosinophilic inflammation not only in the middle ear but also in the inner ear. OBJECTIVE: The purpose of the present study was to elucidate the mechanism of eosinophil infiltration to the inner ear in the animal model of EOM. METHODS: Continuous OVA stimulation to the middle ear of guinea pigs was performed for 7 days, 14 days, and 28 days. Histological observation was made for eosinophil infiltration and morphological change of the inner ear. Immunostaining for eotaxin and RANTES was performed to study immunoreactivity of those chemokines. RESULTS: In the 7-day stimulation side, a few eosinophils were found in the scala tympani, without obvious morphological damage of the inner ear. Moreover, immunoreactivity of both eotaxin and RANTES was significantly higher in the OVA stimulation sides than control sides. For both eotaxin and RANTES, the number of immunopositive cells was significantly increased in the 14 day stimulation side over the 7-day stimulation side. CONCLUSIONS: Eotaxin and RANTES seem to play some important roles for the eosinophil infiltration in the middle and inner ear of model animal of EOM. PMID- 27981872 TI - French-Canadian translation and validation of four questionnaires assessing hearing impairment and handicap. AB - OBJECTIVE: Questionnaires evaluating hearing impairment are available in English but there is a need for French standardised questionnaires for researchers as well as for audiologists and other clinicians. The objective of this study is to describe the translation and validation of four questionnaires that assess different aspects of hearing impairment and handicap among elders with hearing loss, by comparing the main score and psychometric evaluation of original and French-Canadian (FC) versions of the World Health Organization Disability Assessment Scale II (WHO-DAS II), the Screening Test for Hearing Problems (STHP), the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Measure of Audiologic Rehabilitation Self-Efficacy for Hearing Aids (MARS-HA). DESIGN: Vallerand method: translation and back-translation by two translators, revision by a committee of experts and pre-tested with five bilingual older participants. STUDY SAMPLE: Participants (n = 29) were 65 years of age or older including 21 with hearing aids. RESULTS: The psychometric properties (internal consistency, temporal stability after four weeks) indicate good reliability for most of the translated questionnaires and their subscales, especially the WHO-DAS II. CONCLUSIONS: The translations in FC of two hearing loss and two hearing aid questionnaires were validated. It is recommended to pursue the demonstration for temporal stability for the STHP. PMID- 27981873 TI - Causes of Death in HIV-Infected Individuals with Immunovirologic Success in a National Prospective Survey. AB - This prospective multi-center observational survey describes causes of death and their trends from 2000 to 2010 among treated HIV-infected patients with immunovirologic success (PIVS) in France. In 90 clinical sites providing HIV care and treatment, representing a cohort of 82,000 patients in 2010, the underlying causes of death and characteristics of deceased patients were prospectively recorded in 2000, 2005, and 2010 by using a standardized form. We provide data on PIVS, define as patients with a CD4+ T cell value above 500/mm3 and a plasma HIV 1 RNA below 50 copies/ml at their last periodic checkup before death, compare them with immunovirologic uncontrolled patients, and describe trends in these data from 2000 onward. The main underlying causes of death of the 120 PIVS recorded in 2010 were: a non-AIDS/nonviral hepatitis-related malignancy (19%), suicide (12.5%), cardiovascular disease (11.5%), and liver disease (11%). Only three PIVS died of an AIDS-related event. Socioeconomic difficulty was identified in 41% of PIVS in 2010. This percentage had constantly grown since 2000 (p < .001). Median age at death also increased (40, 46, and 52 years in 2000, 2005, and 2010, respectively; p < .001). The distribution of the main causes of death of PIVS was statistically different from that of uncontrolled patients (p < .001). Although immunovirologic control is fundamental, a parallel multidisciplinary approach to care is essential to accurately detect and treat comorbidities, particularly cancer, psychiatric disorders, and cardiovascular disease. Psychosocial aspects must be considered. PMID- 27981874 TI - A tribute to Barry Ganetzky: a trainee's perspective from 1986-1992. PMID- 27981876 TI - How many different symptom combinations fulfil the diagnostic criteria for major depressive disorder? Results from the CRESCEND study. AB - BACKGROUND: The polythetic nature of major depressive disorder (MDD) in DSM- IV and DSM-5 inevitably leads to diagnostic heterogeneity. AIMS: This study aimed to identify the number of depressive symptom combinations actually fulfilling the DSM-IV diagnostic criteria that can be found in Korean MDD patients and the relative frequencies of each combination. METHODS: Using the data from the Clinical Research Center for Depression (CRESCEND) study in South Korea, we enrolled 853 MDD patients diagnosed using DSM-IV and scored as 8 or more on the Hamilton Depression Rating Scale (HAMD). Descriptive statistical analyses were performed to reveal the degree of diagnostic heterogeneity of the MDD. RESULTS: This study identified 119 different depressive symptom combinations. The most common combination consisted of all nine depressive symptom profiles, and nine different combinations were each present in more than 3% of the patients. CONCLUSION: The findings support the criticism that the diagnosis of MDD is not based on a single mental process, but on a set of 'family resemblances'. PMID- 27981875 TI - Three-dimensional imaging of Drosophila motor synapses reveals ultrastructural organizational patterns. AB - We combined cryo-preservation of intact Drosophila larvae and electron tomography with comprehensive segmentation of key features to reconstruct the complete ultrastructure of a model glutamatergic synapse in a near-to-native state. Presynaptically, we detail a complex network of filaments that connects and organizes synaptic vesicles. We link the complexity of this synaptic vesicle network to proximity to the active zone cytomatrix, consistent with the model that these protein structures function together to regulate synaptic vesicle pools. We identify a net-shaped network of electron-dense filaments spanning the synaptic cleft that suggests conserved organization of trans-synaptic adhesion complexes at excitatory synapses. Postsynaptically, we characterize a regular pattern of macromolecules that yields structural insights into the scaffolding of neurotransmitter receptors. Together, these analyses reveal an unexpected level of conservation in the nanoscale organization of diverse glutamatergic synapses and provide a structural foundation for understanding the molecular machines that regulate synaptic communication at a powerful model synapse. PMID- 27981877 TI - Performing under pressure: Exploring the psychological state underlying clutch performance in sport. AB - Clutch performance is improved performance under pressure. However, little research has examined the psychological state experienced by athletes in these situations. Therefore, this study qualitatively examined the subjective experience underlying clutch performance across a range of sports (e.g., team, individual) and standards (Olympic to recreational athletes). Sixteen athletes (Mage = 27.08 years; SD = 6.48) took part in in-depth, semi-structured interviews primarily after an exceptional performance (M = 4.38 days later; SD = 3.14). Data were analysed inductively and thematically. Clutch states involved 12 characteristics, including heightened and deliberate concentration, intense effort, and heightened awareness, which distinguished the experience of clutch from other optimal psychological states such as flow. Other characteristics, such as perceptions of control, were also reported and supported previous experimental research on clutch. These findings present in-depth qualitative insights into the psychological state underlying clutch performance, and are discussed in relation to the existing literature on optimal psychological states in sport. PMID- 27981878 TI - Xenogeneic Decellularized Scaffold: A Novel Platform for Ovary Regeneration. AB - Women younger than 40 years may face early menopause because of premature ovarian failure (POF). The cause of POF can be idiopathic or iatrogenic, especially the cancer-induced oophorectomy and chemo- or radiation therapy. The current treatments, including hormone replacement therapy (HRT) and cryopreservation techniques, have increased risk of ovarian cancer and may reintroduce malignant cells after autografting. Decellularization technique has been regarded as a novel regenerative medicine strategy for organ replacement, wherein the living cells of an organ are removed, leaving the extracellular matrix (ECM) for cellular seeding. This study aimed to produce a xenogeneic decellularized ovary (D-ovary) scaffold as a platform for ovary regeneration and transplantation. We have developed a novel decellularization protocol for porcine ovary by treatment with physical, chemical, and enzymatic methods. Using hematoxylin and eosin (H&E) staining, DAPI staining, scanning electron microscopy (SEM), and quantitative analysis, this approach proved effective in removing cellular components and preserving ECM. Furthermore, the results of biological safety evaluation demonstrated that the D-ovary tissues were noncytotoxic for rat ovarian cells in vitro and caused only a minimal immunogenic response in vivo. In addition, the D ovary tissues successfully supported rat granulosa cell penetration ex vivo and showed an improvement in estradiol (E2) hormone secretion. PMID- 27981879 TI - Inter-observer agreement of paranasal sinus computed tomography scans. AB - CONCLUSION: The study demonstrated considerable inter-observer variation in certain surgically important structures. This would indicate the significance for consultation when evaluating sinus CT scans of CRS patients for planned advanced sinus surgery. OBJECTIVES: After the failure of medical treatment of chronic rhinosinusitis (CRS), the need for surgery and the pre-operative planning of safe surgery is based on computed tomography (CT) findings. The aim of this prospective study was to compare inter-observer agreement of anatomical and surgical structures of sinus CT scans. The hypothesis was that the agreement between observers is good. METHODS: Of these 57 CRS patients, Lund-Mackay (LM) scores and 43 other structural parameters were analyzed blinded. The reproducibility of the findings between three observers, a radiologist, an Ear, nose and throat (ENT) surgeon, and an ENT resident, were compared. RESULTS: In general, there was moderate inter-observer agreement of the structures by Cohen's kappa coefficient. Poor reproducibility was observed in the following structures: optic nerve, insertion of the uncinated process, anterior ethmoidal artery, and Keros class. PMID- 27981880 TI - Transcriptome profiling of the developing male germ line identifies the miR-29 family as a global regulator during meiosis. AB - MicroRNAs are essential for spermatogenesis. However, the stage-specific requirements for particular miRNAs in the male mammalian germ line remain largely uncharacterized. The miR-34 family is, to date, the only miRNA proven to be necessary for the production of sperm in mammals, though its germline roles are poorly understood. Here, we generate and analyze paired small RNA and mRNA profiles across different stages of germline development in male mice, focusing on time points shortly before and during meiotic prophase I. We show that in addition to miR-34, miR-29 also mediates widespread repression of mRNA targets during meiotic prophase I in the male mouse germline. Furthermore, we demonstrate that predicted miR-29 target mRNAs in meiotic cells are largely distinct from those of miR-34, indicating that miR-29 performs a regulatory function independent of miR-34. Prior to this work, no germline role has been attributed to miR-29. To begin to understand roles for miR-29 in the germ line, we identify targets of miR-29 undergoing post transcriptional downregulation during meiotic prophase I, which likely correspond to the direct targets of miR-29. Interestingly, candidate direct targets of miR-29 are enriched in transcripts encoding extracellular matrix components. Our results implicate the miR-29 family as an important regulatory factor during male meiosis. PMID- 27981882 TI - Active yeast ribosome preparation using monolithic anion exchange chromatography. AB - In vitro studies of translation provide critical mechanistic details, yet purification of large amounts of highly active eukaryotic ribosomes remains a challenge for biochemists and structural biologists. Here, we present an optimized method for preparation of highly active yeast ribosomes that could easily be adapted for purification of ribosomes from other species. The use of a nitrogen mill for cell lysis coupled with chromatographic purification of the ribosomes results in 10-fold-increased yield and less variability compared with the traditional approach, which relies on sedimentation through sucrose cushions. We demonstrate that these ribosomes are equivalent to those made using the traditional method in a host of in vitro assays, and that utilization of this new method will consistently produce high yields of active yeast ribosomes. PMID- 27981881 TI - Systematic characterization of artificial small RNA-mediated inhibition of Escherichia coli growth. AB - A new screening system for artificial small RNAs (sRNAs) that inhibit the growth of Escherichia coli was constructed. In this system, we used a plasmid library to express RNAs of ~120 nucleotides, each with a random 30-nucleotide sequence that can recognize its target mRNA(s). After approximately 60,000 independent colonies were screened, several plasmids that inhibited bacterial growth were isolated. To understand the inhibitory mechanism, we focused on one sRNA, S-20, that exerted a strong inhibitory effect. A time-course analysis of the proteome of S-20 expressing E. coli and a bioinformatic analysis were used to identify potential S 20 target mRNAs, and suggested that S-20 binds the translation initiation sites of several mRNAs encoding enzymes such as peroxiredoxin (osmC), glycyl-tRNA synthetase alpha subunit (glyQ), uncharacterized protein ygiM, and tryptophan synthase beta chain (trpB). An in vitro translation analysis of chimeric luciferase-encoding mRNAs, each containing a potential S-20 target sequence, indicated that the translation of these mRNAs was inhibited in the presence of S 20. A gel shift analysis combined with the analysis of a series of S-20 mutants suggested that S-20 targets multiple mRNAs that are responsible for inhibiting E. coli growth. These data also suggest that S-20 acts like an endogenous sRNA and that E. coli can utilize artificial sRNAs. PMID- 27981883 TI - Varicose vein therapy and nerve lesions. AB - Treating varicose veins using endovenous thermal techniques - especially laser and radio frequency ablation - has emerged as an effective alternative to open surgery with stripping and high ligation. Even though these methods are very gentle and patient-friendly, they are nevertheless accompanied by risks and side effects. Compared to open surgical therapy, the risk of damage to peripheral and motor nerves is reduced; however, it still exists as a result of heat exposure and tumescent anaesthesia. Non-thermal methods that can be applied without tumescent anaesthesia have been introduced to the market. They pose a considerably lower risk of nerve lesions while proving to be much more effective. This paper investigates data on postoperative nerve damage and paraesthesia using internet research (PubMed). It analyses the current state of knowledge regarding non-thermal treatment methods and takes into account the latest developments in the use of cyanoacrylate to close insufficient saphenous veins. PMID- 27981884 TI - Quantitative characterization of the mechanism of action and impact of a 'proteolysis-permitting' anti-PCSK9 antibody. AB - A recent report described a novel mechanism of action for an anti-proprotein convertase subtilisin-kexin type 9 (PCSK9) monoclonal antibody (LY3015014, or LY), wherein the antibody has improved potency and duration of action due to the PCSK9 epitope for LY binding. Unlike other antibodies, proteolysis of PCSK9 can occur when LY is bound to PCSK9. We hypothesized that this allowance of PCSK9 cleavage potentially improves LY efficiency through two pathways, namely lack of accumulation of intact PCSK9 and reduced clearance of LY. A quantitative modeling approach is necessary to further understand this novel mechanism of action. We developed a mechanism-based model to characterize the relationship between antibody pharmacokinetics, PCSK9 and LDL cholesterol levels in animals, and used the model to better understand the underlying drivers for the improved efficiency of LY. Simulations suggested that the allowance of cleavage of PCSK9 resulting in a lack of accumulation of intact PCSK9 is the major driver of the improved potency and durability of LY. The modeling reveals that this novel 'proteolysis permitting' mechanism of LY is a means by which an efficient antibody can be developed with a total antibody dosing rate that is lower than the target production rate. We expect this engineering approach may be applicable to other targets and that the mathematical models presented herein will be useful in evaluating similar approaches. PMID- 27981885 TI - Kinematic and kinetic analysis of overhand, sidearm and underhand lacrosse shot techniques. AB - Lacrosse requires the coordinated performance of many complex skills. One of these skills is shooting on the opponents' net using one of three techniques: overhand, sidearm or underhand. The purpose of this study was to (i) determine which technique generated the highest ball velocity and greatest shot accuracy and (ii) identify kinematic and kinetic variables that contribute to a high velocity and high accuracy shot. Twelve elite male lacrosse players participated in this study. Kinematic data were sampled at 250 Hz, while two-dimensional force plates collected ground reaction force data (1000 Hz). Statistical analysis showed significantly greater ball velocity for the sidearm technique than overhand (P < 0.001) and underhand (P < 0.001) techniques. No statistical difference was found for shot accuracy (P > 0.05). Kinematic and kinetic variables were not significantly correlated to shot accuracy or velocity across all shot types; however, when analysed independently, the lead foot horizontal impulse showed a negative correlation with underhand ball velocity (P = 0.042). This study identifies the technique with the highest ball velocity, defines kinematic and kinetic predictors related to ball velocity and provides information to coaches and athletes concerned with improving lacrosse shot performance. PMID- 27981888 TI - Diabetes Mellitus and Bone Regeneration: A Systematic Review and Meta-Analysis of Animal Studies. AB - BACKGROUND: The regeneration of bone defects resulting from trauma, resection of tumors, infection, or congenital disease is a challenge, and bone grafts are utilized in a wide array of clinical settings to augment bone repair and regeneration. Diabetes mellitus (DM) is a chronic metabolic disease, which affects 8.3% of the world population, summing ~387 million individuals. The consequences of the disease, for example, hyperglycemia, have been associated to a reduced capacity to form bone and poor bone quality, influencing bone healing. Our aim was to systematically review the literature to the effect of diabetic condition on bone regeneration in animal models, when using bone substitute materials from different origins, and perform a meta-analysis to quantitatively study the effect of DM on bone regeneration. METHODS: An extensive search strategy was carried out through PubMed and EMBASE to identify the potential relevant studies published from database inception until July 1, 2015. Initially, the title and abstract of 1409 studies were screened, after which inclusion criteria sorted 29 studies for full-text evaluation. After using exclusion criteria, a final number of seven studies could be included in the review. RESULTS: The seven included studies that passed our inclusion/exclusion criteria were all type 1 diabetes, comprising a total of 189 animals and 14 intrastudy comparisons. These studies presented a consistent and reduced risk of bias and showed a significant average effect size of -6.87% of bone formation for diabetes type 1 versus healthy condition [95% confidence interval: -10.55 to -3.18; I2 = 87.4%; p = 0.0003]. INTERPRETATION: These findings prove that DM type 1 negatively influences bone formation compared with a healthy condition, irrespective of the bone substitute material used. PMID- 27981887 TI - Insertion of scFv into the hinge domain of full-length IgG1 monoclonal antibody results in tetravalent bispecific molecule with robust properties. AB - By simultaneous binding two disease mediators, bispecific antibodies offer the opportunity to broaden the utility of antibody-based therapies. Herein, we describe the design and characterization of Bs4Ab, an innovative and generic bispecific tetravalent antibody platform. The Bs4Ab format comprises a full length IgG1 monoclonal antibody with a scFv inserted into the hinge domain. The Bs4Ab design demonstrates robust manufacturability as evidenced by MEDI3902, which is currently in clinical development. To further demonstrate the applicability of the Bs4Ab technology, we describe the molecular engineering, biochemical, biophysical, and in vivo characterization of a bispecific tetravalent Bs4Ab that, by simultaneously binding vascular endothelial growth factor and angiopoietin-2, inhibits their function. We also demonstrate that the Bs4Ab platform allows Fc-engineering similar to that achieved with IgG1 antibodies, such as mutations to extend half-life or modulate effector functions. PMID- 27981886 TI - Additive Manufacturing of Vascular Grafts and Vascularized Tissue Constructs. AB - There is a great need for engineered vascular grafts among patients with cardiovascular diseases who are in need of bypass therapy and lack autologous healthy blood vessels. In addition, because of the severe worldwide shortage of organ donors, there is an increasing need for engineered vascularized tissue constructs as an alternative to organ transplants. Additive manufacturing (AM) offers great advantages and flexibility of fabrication of cell-laden, multimaterial, and anatomically shaped vascular grafts and vascularized tissue constructs. Various inkjet-, extrusion-, and photocrosslinking-based AM techniques have been applied to the fabrication of both self-standing vascular grafts and porous, vascularized tissue constructs. This review discusses the state-of-the-art research on the use of AM for vascular applications and the key criteria for biomaterials in the AM of both acellular and cellular constructs. We envision that new smart printing materials that can adapt to their environment and encourage rapid endothelialization and remodeling will be the key factor in the future for the successful AM of personalized and dynamic vascular tissue applications. PMID- 27981890 TI - Molecular dynamics simulation and molecular docking studies of 1,4 Dihydropyridines as P-glycoprotein's allosteric inhibitors. AB - P-glycoprotein (P-gp) is a main factor contributing to multidrug resistance. The effect of this transporter protein on limiting the effectiveness of chemotherapy has been shown by various studies. In a previous report, we synthesized some 14 dihydropyridine (DHP) derivatives as inhibitors of human P-gp. In the present study, a computational approach has been exploited to reveal the main interactions between DHPs and P-gp. In order to do this, homology modeling was performed to obtain a model of the protein. Then, molecular dynamics simulation was used to refine the constructed model of P-gp in the presence of the lipids bilayer. Model validation was performed with several tools. Finally, molecular docking followed by MD simulation of ligand-protein complex was employed to elucidate the binding mode and the dynamical changes of protein with/without DHPs bound. The results emphasized that interaction of the residues Gln912, Ser909, Arg905, Ser474, Val472 with DHPs play a crucial role in the inhibitory of these ligands and this was in a relatively good accordance with the results reported in the experimental studies. PMID- 27981889 TI - Percutaneous implantation of a unibody endograft to treat non-aneurysmal aortoiliac disease. AB - This case-series report describes the use of an Endologix AFX(r) stent graft for the treatment of non-aneurysmal aortic disease. Over a period of 26 months, this device was successfully implanted in six patients with aortic bifurcation < 15 mm to treat critical limb ischemia secondary to dissection, ulcer, or coarctation. PMID- 27981891 TI - LC-MS/MS methods for albendazole analysis in feed and its metabolite residues in fish fillet and a leaching study in feed after an alternative procedure for drug incorporation. AB - This paper describes the development of analytical methods for the quantification of albendazole (ABZ) in fish feed and ABZ and its main known metabolites (albendazole sulfoxide, albendazole sulfone and albendazole aminosulfone) in fish fillet employing LC-MS/MS. In order to assess the reliability of the analytical methods, evaluation was undertaken as recommended by related guides proposed by the Brazilian Ministry of Agriculture for analytical method validation. The calibration curve for ABZ quantification in feed showed adequate linearity (r > 0.99), precision (CV < 1.03%) and trueness ranging from 99% to 101%. The method for ABZ residues in fish fillet involving the QuEChERS technique for sample extraction had adequate linearity (r > 0.99) for all analytes, precision (CV < 13%) and trueness around 100%, with CCalpha < 122 ng g-1 and CCbeta < 145 ng g-1. Besides, by aiming to avoid the risk of ABZ leaching from feed into the aquatic environment during fish medication via the oral route, a promising procedure for drug incorporation in the feed involving coating feed pellets with ethyl cellulose polymer containing ABZ was also evaluated. The medicated feed had good homogeneity (CV < 3%) and a lower release of ABZ (< 0.2%) from feed to water when the medicated feed stayed in the water for up to 15 min. PMID- 27981892 TI - Phenethyl isothiocyanate suppresses the metastasis of ovarian cancer associated with the inhibition of CRM1-mediated nuclear export and mTOR-STAT3 pathway. AB - Epithelial ovarian cancer is prone to metastasizing at an early stage, but their mechanisms remain unclear. CRM1 is an important nuclear exportin and inhibitors targeting CRM1 has been explored as an anti-cancer strategy. In previous study, we observed that PEITC could combine with the hydrophobic pocket of CRM1. In this study, we focused on the effects of PEITC on EOC and its mechanisms. Results showed that IC50 values of PEITC on SKOV3 and HO8910 cell line were 42.14 MUM and 37.29 MUM, respectively. PEITC inhibits the migration and invasion of SKOV3 and HO8910 cells in vitro. Oral administration of 10 MUmol PEITC suppressed the metastasis of EOC in a xenograft mouse model in vivo. PEITC treatment decreased the expressions of CRM1 and mTOR (cargo protein of CRM1) in EOC cell lines and in xenograft mouse tissues. Moreover, CRM1-mediated nuclear export was attenuated by PEITC, mTOR accumulated in nucleus, expressions of mTORS2448 and downstream effectors STAT3S727, MMP2 and MMP9 were decreased in a dose- and time-dependent manner. Furthermore, immunohistochemical analysis showed that CRM1 and mTOR were increased in EOC tissues compared with benign ovarian tumors, and related with advanced stage, type II EOC, positive peritoneal cytology and decreased overall survival. In addition, CRM1 was positively correlated with mTOR levels. In conclusion, our data demonstrated that PEITC suppresses the metastasis of EOC through inhibiting CRM1-mediated nuclear export, subsequently suppressing the mTOR-STAT3 pathway. Both CRM1 and mTOR were increased in EOC patients, providing a rationale for further clinical investigation of PEITC in EOC treatment. PMID- 27981893 TI - Meisoindigo, but not its core chemical structure indirubin, inhibits zebrafish interstitial leukocyte chemotactic migration. AB - CONTEXT: Inflammatory disease is a big threat to human health. Leukocyte chemotactic migration is required for efficient inflammatory response. Inhibition of leukocyte chemotactic migration to the inflammatory site has been shown to provide therapeutic targets for treating inflammatory diseases. OBJECTIVE: Our study was designed to discover effective and safe compounds that can inhibit leukocyte chemotactic migration, thus providing possible novel therapeutic strategy for treating inflammatory diseases. MATERIALS AND METHODS: In this study, we used transgenic zebrafish model (Tg:zlyz-EGFP line) to visualize the process of leukocyte chemotactic migration. Then, we used this model to screen the hit compound and evaluate its biological activity on leukocyte chemotactic migration. Furthermore, western blot analysis was performed to evaluate the effect of the hit compound on the AKT or ERK-mediated pathway, which plays an important role in leukocyte chemotactic migration. RESULTS: In this study, using zebrafish-based chemical screening, we identified that the hit compound meisoindigo (25 MUM, 50 MUM, 75 MUM) can significantly inhibit zebrafish leukocyte chemotactic migration in a dose-dependent manner (p = 0.01, p = 0.0006, p < 0.0001). Also, we found that meisoindigo did not affect the process of leukocyte reverse migration (p = 0.43). Furthermore, our results unexpectedly showed that indirubin, the core structure of meisoindigo, had no significant effect on zebrafish leukocyte chemotactic migration (p = 0.6001). Additionally, our results revealed that meisoindigo exerts no effect on the Akt or Erk-mediated signalling pathway. DISCUSSION AND CONCLUSION: Our results suggest that meisoindigo, but not indirubin, is effective for inhibiting leukocyte chemotactic migration, thus providing a potential therapeutic agent for treating inflammatory diseases. PMID- 27981894 TI - Knockout of miR-221 and miR-222 reveals common and specific targets for paralogous miRNAs. AB - MicroRNAs (miRNAs) regulate the expression of mRNA through sequence-specific binding of the 3' untranslated region (UTR). The seed sequence of miRNAs is the key determinant for target site recognition. Paralogous miRNAs, which share the same seed sequences but differ in their 3' regions, are known to regulate largely overlapping groups of mRNAs. However, no study has analyzed functional differences between paralogous miRNAs with proper experimental methods. In this study, we compared the targets of paralogous miRNAs, miR-221 and miR-222. Using a nuclease-mediated genome engineering technique, we established knockout cell lines for these miRNAs, and precisely analyzed differences in target regulation. We found that miR-221 and miR-222 suppress the previously identified targets, CDKN1B and CDKN1C, differentially. Whereas both miRNAs suppressed CDKN1B, only miR-221 suppressed CDKN1C. From transcriptome analyses, we found that several different target mRNAs were regulated by each of miR-221 and miR-222 independently, although a large number of mRNAs responded commonly to miR-221 and miR-222. This is the first study to compare the mRNA regulations by paralogous miRNAs and illustrate that paralogous miRNAs with the same seed sequence also have difference in target regulation. PMID- 27981895 TI - Alternative polyadenylation in a family of paralogous EPB41 genes generates protein 4.1 diversity. AB - Alternative polyadenylation (APA) is a step in mRNA 3'-end processing that contributes to the complexity of the transcriptome by generating isoforms that differ in either their coding sequence or their 3'-untranslated regions (UTRs). The EPB41 genes, EPB41, EPB41L2, EPB41L3 and EPB41L1, encode an impressively complex array of structural adaptor proteins (designated 4.1R, 4.1G, 4.1B and 4.1N, respectively) by using alternative transcriptional promoters and tissue specific alternative pre-mRNA splicing. The great variety of 4.1 proteins mainly results from 5'-end and internal processing of the EPB41 pre-mRNAs. Thus, 4.1 proteins can vary in their N-terminal extensions but all contain a highly homologous C-terminal domain (CTD). Here we study a new group of EPB41-related mRNAs that originate by APA and lack the exons encoding the CTD characteristic of prototypical 4.1 proteins, thereby encoding a new type of 4.1 protein. For the EPB41 gene, this type of processing was observed in all 11 human tissues analyzed. Comparative genomic analysis of EPB41 indicates that APA is conserved in various mammals. In addition, we show that APA also functions for the EPB41L2, EPB41L3 and EPB41L1 genes, but in a more restricted manner in the case of the latter 2 than it does for the EPB41 and EPB41L2 genes. Our study shows alternative polyadenylation to be an additional mechanism for the generation of 4.1 protein diversity in the already complex EPB41-related genes. Understanding the diversity of EPB41 RNA processing is essential for a full appreciation of the many 4.1 proteins expressed in normal and pathological tissues. PMID- 27981896 TI - Screening of renal dysfunction among Burkitt lymphoma survivors by novel markers. AB - BACKGROUND: Burkitt lymphoma (BL) represents the most common pathological type of non-Hodgkin lymphoma in our region. Recently, high success rates have been achieved in BL treatment. Little is known about long-term renal dysfunction in this vulnerable group. In the present study, we tried to detect early chronic kidney diseases (CKD) among BL survivors by using novel screening modalities. PATIENTS AND METHODS: we investigated 53 children (aged 10 +/- 2.8 years, 34 boys) who successfully treated for Burkitt lymphoma, based on LMB96 protocol, as "patient group" and 30 children as control. All eligible participants were subjected to history taking, physical assessment, and routine laboratory investigations including urine analysis, serum creatinine. Estimated glomerular filtration rates using new Schwartz formula (GFRCKD) were calculated and chronic kidney disease prevalence was diagnosed accordingly. Also, serum Cystatin-C (Cys C) and neutrophil-gelatinase-associated Lipocalin (NGAL) were determined as novel markers aiming at early and accurate detection of CKD in BL survivors. RESULTS: After 18.3 +/- 5.2 months of BL cytotoxic therapy completion, almost one fifth of asymptomatic BL survivors showed evidence of subclinical CKD when estimated GFRCKD (16.9%), serum Cystatin-C (15%) and serum neutrophil-gelatinase-associated Lipocalin (18.8%) were used for kidney function monitoring. This prevalence was four to fivefolds higher than that detected by routine serum creatinine screening (3.7%). Significant persistent albuminuria was diagnosed at 4/53 (7.5.3%) of BL survivors and asymptomatic hypertension was reported in 1/53 (1.9%) of them compared to none of the controls. Positive correlation could be displayed between serum Cys-C and serum NGAL. Conversely, negative correlations between both of them and estimated GFRCKD were documented. CONCLUSION: Novel modalities such new Schwartz formula (GFRCKD) estimation, serum Cys-C, and serum NGAL assessment should be incorporated in the routine follow-up screening for CKD among BL survivors for accurate diagnosis of such detrimental morbidity. PMID- 27981897 TI - The Correlation Between Urinary 8-Iso-Prostaglandin F2alpha and Hydrogen Peroxide Toward Renal Function in T2DM Patients Consuming Sulfonylurea and Combination of Metformin-Sulfonylurea. AB - BACKGROUND: Renal dysfunction is a common complication in type 2 diabetes mellitus patients associated with oxidative damage which could be characterized by 8-iso-prostaglandin F2alpha and hydrogen peroxide level as oxidative stress markers. OBJECTIVE: The aim of our study is to determine if there is a difference in 8-iso-prostaglandin F2alpha and hydrogen peroxide levels between sulfonylurea and combination of metformin-sulfonylurea in diabetic patients. We also wanted to determine if these oxidative stress markers correlate with the estimated Glomerular Filtration Rate (eGFR). SUBJECTS AND METHODS: We conducted a cross sectional study with inclusion of 55 patients with type 2 diabetes mellitus in Dr. Sitanala Tangerang Hospital, Indonesia with purposive sampling. The value of eGFR was obtained by serum creatinine levels, while the level of 8-iso prostaglandin F2alpha was measured by ELISA and urinary hydrogen peroxide using FOX-1 (Ferrous Ion Oxidation Xylenol Orange 1). RESULTS: There was no difference in 8-iso-prostaglandin F2alpha and hydrogen peroxide level between the two groups (p=0.088 and p=0.848). Moreover, there was no difference in eGFR values between the two groups, measured by Cockroft-Gault, MDRD, and CKD-EPI. 8-iso prostaglandin F2alpha (n=55) was positively correlated with eGFR based on Cockroft-Gault (r=0.382; p=0.009), whereas urinary hydrogen peroxide (n=47) also generate significant positive correlation with eGFR based on the MDRD equation (r=0.326; p=0.021). Linear regression analysis showed that 8-iso-prostaglandin F2alpha is the most predictive factor and the only significant factor for eGFR in Cockroft-Gault, MDRD and also CKDEPI, even after controlled by gender, age, BMI, HbA1c, systole, and H2O2. CONCLUSION: The two treatments did not have any significant differences in antioxidant activity. However, an increase of urinary 8-iso-prostaglandin F2. and hydrogen peroxide which correlates with eGFR in the total sample may play a significant role in the pathophysiology of diabetic nephropathy. PMID- 27981898 TI - The Role of Carbonic Anhydrase in Hepatic Glucose Production. AB - BACKGROUND: Carbonic anhydrase is a ubiquitous zinc metalloenzyme in organisms that primarily catalyzes the reversible hydration of CO2 to HCO3 - and H+. It is involved in many important physiological and pathological conditions such as electrolyte secretion and biosynthetic reaction like gluconeogenesis, lipogenesis and ureagenesis. The enzyme provides HCO3 - as a substrate for pyruvate carboxylase, the first enzyme in hepatic gluconeogenesis. The present review showed that carbonic anhydrase is the main driver of hepatic gluconeogenesis. METHODS: Google scholar and Medline Embase (inception to 2015) were searched for studies on mechanism of hepatic glucose production, increased hepatic glucose production in diabetes and changes in carbonic anhydrase activity in diabetes and its treatment. RESULTS: Many studies have linked changes in carbonic anhydrase activity with the development and progression of diabetes mellitus. Carbonic anhydrase has been shown to provide HCO3 - as substrate for the first reaction of hepatic gluconeogenesis which has also been reported to increase significantly in type 2 diabetes. Increase in carbonic anhydrase activity increases the availability of these substrates and in turn increases hepatic glucose production. CONCLUSION: Carbonic anhydrase can be said to be the key factor responsible for reduction of hepatic glucose production. Thus carbonic anhydrase could serve as a new therapeutic target for reducing hepatic glucose production. PMID- 27981899 TI - High Hydrostatic Pressure-Assisted Enzymatic Treatment Improves Antioxidant and Anti-inflammatory Properties of Phosvitin. AB - BACKGROUND: Phosvitin (PV) is a highly-phosphorylated metal-binding protein in egg yolk. Phosphoserine clusters make PV resistant to enzymatic digestion, which might be nutritionally undesirable. OBJECTIVE: This study was designed to determine the effects of high hydrostatic pressure and enzymatic hydrolysis (HHP EH) on the antioxidant and anti-inflammatory properties of PV hydrolysates (PVHs). METHODS: PV was hydrolyzed by alcalase, elastase, savinase, thermolysin, and trypsin at 0.1, 50, and 100 MPa pressure levels. PVHs were evaluated for degree of hydrolysis, molecular weight distribution patterns, antioxidant and anti-inflammatory properties in chemical and cellular models. The effect of PVH on gene expression of pro-inflammatory cytokines (TNF-alpha and IL-1beta) was also evaluated using real time-PCR. The hydrolysate with most potent antioxidant and anti-inflammatory properties was subjected to LC-MS/MS analysis to identify the peptide sequence. RESULTS: Hydrolysates produced at 100 MPa exhibited higher degree of hydrolysis and greater reducing power and free radical scavenging activity compared to those obtained at atmospheric pressure. After adjusting the phosphate content, alcalase- and trypsin-digested PVHs showed superior iron chelation capacity (69-73%), regardless of pressure. Both alcalase- and trypsin digested PVHs significantly inhibited nitric oxide production by RAW264.7 macrophage cells. LPS-stimulated up-regulation of proinflammatory cytokines was also suppressed by alcalase-digested PVH. CONCLUSION: The HHP-EH method could play a promising role in the production of bioactive peptides from hydrolysis resistant proteins. HHP-assisted PVH may be useful in preparing a potential pharmaceutical with antioxidant and anti-inflammatory properties. PMID- 27981900 TI - Pharmacophore and Docking Guided Virtual Screening Study for Discovery of Type I Inhibitors of VEGFR-2 Kinase. AB - BACKGROUND: Kinase domain of VEGFR-2 displays conformational flexibility which leads to existence of two kinds of inhibitors viz. type I and type II inhibitors. They exhibit different binding modes and this necessitates the development of separate pharmacophore models for them. METHODS: The virtual screening study for discovery of type I inhibitors of VEGFR-2 kinase was done by using combined pharmacophore (generated using PHASE and validated by 3D-QSAR) and docking (Glide) based approach. Validated pharmacophore was used as preliminary filter followed by docking. ADME properties were predicted for retrieved hits using QikProp. RESULTS: ADHRR.94 with statistical parameters r2 test 0.94, r2 training 0.99, SD 0.0766, r2 0.9861, F 283.3, RMSE 0.2605, q2 0.8115 and Pearson's R 0.9723was identified as the best pharmacophore hypothesis for type I inhibitors of VEGFR-2 kinase. Virtual screening study was done for Asinex Elite Libraries comprising of 104400 molecules using ADHRR.94, HTVS docking and XP docking that resulted in twelve hits. Asinex ligand 5686 with docking score of -10.48kcal/mol was top-ranking hit. It made two hydrogen bonding interactions with Cys 919, one as an acceptor and other as a donor, which are characteristic of type I inhibitors. Additional interactions observed were pi-cation with Lys 868 and pi- pistacking with Phe 1047.Twelve hits had acceptable values for ADME properties. CONCLUSION: Twelve hits with best obtained docking scores ranging from -10.48 to 7.23 kcal/mol and mimicking characteristic type I inhibitor interactions were identified which could be probable inhibitors of VEGFR-2. PMID- 27981901 TI - Molecular Insights of CREB and MAP-K Phosphorylation by Modafinil in Wake-Related Brain Areas. AB - BACKGROUND: Modafinil (MOD) is a waking-promoting compound that is used for the treatment of sleep disorders such as sleepiness and narcolepsy. Despite its efficiency, there are missing pieces of evidence regarding the mechanism of action of MOD at molecular level. For example, current data have demonstrated that MOD induces alertness by activating several wake-related neurotransmitter receptors, including dopamine 1 (D1) receptor. Nevertheless, an intriguing point highlights that MOD might be activating intracellular elements bounded to D1 receptor, such as cAMP response element-binding (CREB) or mitogen-activated protein kinase (MAP-K) expression. OBJECTIVE: We tested whether administrations of MOD induce phosphorylation of either CREB or MAPK in wake-related brain areas, such as dorsomedial hypothalamic nucleus (DM) and tuberomammillary nucleus (TMN) in rats. METHODS: Rats that received a systemic injection of MOD (30 or 150 mg/Kg) were sacrificed and brains were processed for immunohistochemical analysis of phospho-CREB or phospho-MAP-K staining. RESULTS: MOD dose-dependently enhanced phospho-CREB and phospho-MAP-K immunoreactivity in DM and TMN. Moreover, the statistical analysis revealed that MOD increased the number of phospho- CREB and phospho-MAP-K immunoreactive neurons in these brain areas studied. CONCLUSION: These findings provide significative insights regarding the possible molecular mechanism of action of MOD engaging the activation of phospho-CREB and phospho MAP-K in wake-linked brain areas. Indeed, further studies are required to fully understand the molecular mechanism of action of MOD. PMID- 27981902 TI - A Binary Classifier for Prediction of the Types of Metabolic Pathway of Chemicals. AB - BACKGROUND: The study of metabolic pathway is one of the most important fields in biochemistry. Good comprehension of the metabolic pathway system is helpful to uncover the mechanism of some fundamental biological processes. Because chemicals are part of the main components of the metabolic pathway, correct identification of which metabolic pathways a given chemical can participate in is an important step for understanding the metabolic pathway system. Most previous methods only considered the chemical information, which tried to deal with a multilabel classification problem of assigning chemicals to proper metabolic pathways. METHODS: In this study, the pathway information was also employed, thereby transforming the problem into a binary classification problem of identifying the pair of chemicals and metabolic pathways, i.e., a chemical and a metabolic pathway was paired as a sample to be considered in this study. To construct the prediction model, the association between chemical pathway type pairs was evaluated by integrating the association between chemicals and association between pathway types. The support vector machine was adopted as the prediction engine. RESULTS: The extensive tests show that the constructed model yields good performance with total prediction accuracy around 0.878. CONCLUSION: The comparison results indicate that our model is quite effective and suitable for the identification of whether a given chemical can participate in a given metabolic pathway. PMID- 27981904 TI - Hot Topics in Pharmacotherapy for Neovascular Age-Related Macular Degeneration. AB - BACKGROUND: The preferred approach for the treatment of neovascular age-related macular degeneration (AMD) is frequent intravitreal injections of the anti vascular endothelial growth factor (VEGF) agents. However, considering the limitations of current anti-VEGF approaches, including the need for frequent injections, inadequate response in some patients, and a relatively short duration of effect, several new therapeutic modalities are under evaluation. METHODS: A comprehensive review of the literature was performed on the new treatment modalities for neovascular AMD, and the relevant studies were discussed. RESULTS: The treatment modalities for neovascular AMD include new anti-VEGF drugs, new drug delivery systems and new targets in the pathogenic cascade of choroidal neovascularization. These new modalities are in different phases of clinical development. CONCLUSION: The results of the completed studies reporting the new therapeutic modalities for neovascular AMD thus far are promising. PMID- 27981905 TI - Natural Approaches in Diabetes Management: A Review of Diet, Exercise, and Natural Products. AB - Diabetes mellitus (DM) is a highly prevalent condition that causes significant morbidity and mortality in the United States and worldwide. Conventional therapies include lifestyle modification, oral pharmacological agents, and subcutaneous insulin. Emerging data suggest that natural approaches to the treatment of DM may help supplement current therapies for further glycemic control. Herein, we review the evidence of several natural modalities for DM treatment. We describe the pathophysiology of diabetes and its complications, provide an overview of current pharmacologic treatments, and finally, discuss natural approaches to diabetes management. Specifically, we will describe on the utility of diet, physical activity, and common natural products in the treatment of DM and focus on recent, high-quality studies. Adverse effects and potential interactions of each therapy will be highlighted where applicable. PMID- 27981903 TI - Endophthalmitis Prophylaxis in Cataract Surgery: Overview of Current Practice Patterns Around the World. AB - BACKGROUND: Acute-onset postoperative endophthalmitis after cataract surgery remains a rare but important cause of visual loss. There is no global consensus regarding the optimal strategies for prophylaxis of endophthalmitis and practices vary substantially around the world, especially with respect to the use of intracameral antibiotics. The European Society of Cataract & Refractive Surgeons in a randomized clinical trial (2007) reported an approximately 5-fold reduction in endophthalmitis rates associated with the use of intracameral cefuroxime. Despite this report, the use of intracameral antibiotics has not been universally adopted. METHODS: Various endophthalmitis prophylaxis patterns around the world (including the United States, Canada, Australia/New Zealand, Japan, China, India, Indonesia, South Africa, Argentina, Russia, Sweden and Mexico) are compared. Each contributing author was asked to provide similar information, including endophthalmitis rates based on published studies, current practice patterns, and in some cases original survey data. Various methods were used to obtain this information, including literature reviews, expert commentary, and some new survey data not previously published. RESULTS: Many different practice patterns were reported from around the world, specifically with respect to the use of intracameral antibiotics. CONCLUSION: There is no worldwide consensus regarding endophthalmitis prophylaxis with cataract surgery. PMID- 27981906 TI - Locomotor Training and Factors Associated with Blood Glucose Regulation After Spinal Cord Injury. AB - BACKGROUND: Individuals with spinal cord injury (SCI) have increased rates of glucose intolerance, insulin insensitivity, and type II diabetes caused mainly by the deconditioning of paralyzed muscle. The purpose of this systematic review was to determine the effectiveness of locomotor training in individuals with SCI on blood glucose control. METHODS: We searched studies on locomotor training for individuals with SCI with outcomes of glucose, insulin, or outcomes that could change glucose handling (i.e. increases in muscle mass, shifts in muscle fiber type composition, changes in transport proteins, or enzymes involved in glucose metabolism) in PubMed and EMBASE. RESULTS: Eleven studies (10 with incomplete SCI; 1 with complete SCI) were included in our review. Locomotor training included body weight supported treadmill training (BWSTT) with manual or robotic assistance, with and without functional electrical stimulation (FES), or involved FES-assisted over ground training. Six months of locomotor training in individuals with SCI resulted in significant decreases in glucose (15%) and insulin (33%) areas under the curve during oral glucose tolerance tests. Two to twelve months of locomotor training reversed some of the muscle atrophy - with muscle being the site of most glucose consumption, this is important for glucose control. Training also increased capacity for glucose storage, enzymes involved in glucose phosphorylation (hexokinase) and oxidation (citrate synthase), and glucose transport proteins (GLUT-4). Fiber type composition shifted to a slower fiber type, which favors glucose handling. There were no effects on fat mass. CONCLUSION: Locomotor training in individuals with SCI (generally an incomplete injury) increases capacity to handle glucose and results in muscular changes that should reduce the risk of type II diabetes. PMID- 27981907 TI - The Utility of Interappendicular Connections in Bipedal Locomotion. AB - Homo sapiens constitute the only currently obligate bipedal mammals and, as it stands, upright bipedal locomotion is a defining characteristic of humans. Indeed, while the evolution to bipedalism has allowed for the upper limbs to be liberated from ground contact during ambulation, their role in locomotion is far from obsolete. Rather, there is reason to believe that arm swing offers important mechanical and neurological advantages to bipedal locomotion. In this short review, we present some compelling findings on the neural connections between the arms and legs during human locomotion. We begin with a description of the importance of arm swing during walking from a mechanical perspective. Then, we examine evidence for the existence of interappendicular connections that converge along with peripheral afferents, descending inputs, and propriospinal projections, onto the neural circuits innervating the muscles of the arms and legs. The varied effects of interappendicular coupling on the neural control of locomotion are also examined in cases of neurological injury. We use the insight gained from these collected works as well as those from our own studies on locomotor training to discuss strategies to use interappendicular connections to rehabilitate walking in individuals experiencing loss of function after debilitating spinal cord injury. PMID- 27981908 TI - Ester-Based Hydrophilic Cyclodextrin Nanosponges for Topical Ocular Drug Delivery. AB - BACKGROUND: Cyclodextrin-based nanosponges are hyper-cross-linked supramolecular architectures. Similar to the parent compound they are derived from, they have been shown to possess the ability to form inclusion and non-inclusion complexes with drugs of different polarities, enzymes, proteins, peptides and macromolecules. Cyclodextrins only form inclusion complexes with hydrophobic guest molecules, while nanosponges extend this function by forming inclusion and non-inclusion complexes with both hydrophobic and hydrophilic compounds. This host-guest interaction provides enhancement in stability, solubility and sometimes in membrane permeability. OBJECTIVE: The potential of ester-based hydrophilic nanosponges as drug carriers in topical ocular drug delivery was assessed by undertaking drug loading, drug release, phase solubility and ex vivo pig corneal drug permeation studies on the nanosponges. METHOD: The ester-based cyclodextrin-based nanosponges were synthesized through cross-linking beta cyclodextrin by pyromellitic dianhydride. Various concentrations of pyromellitic dianhydride, the cross-linker, were initially tested for their effects on the drug loading capacity of the nanosponges. Thereafter, varying ratios of drug to nanosponge complexes were studied and analyzed for their drug release kinetics, and solubility and permeation effects. RESULTS: A cyclodextrin-based nanosponge drug delivery system with potential to improve corneal permeation and drug solubility was formulated. Their ability to improve pig corneal permeation was shown; where up to 75% permeation of the model drug was achieved in the presence of the nanosponges as compared to the 28% permeation of the pure drug. The nanosponges provided drug release for approximately an hour. This is a common behavior for hydrophilic complexes due to their high solubility in aqueous media. CONCLUSION: The ester-based hydrophilic cyclodextrin-based nanosponge derivative can be used as a drug delivery system in topical ocular drug delivery, to improve stability, solubility and corneal permeation. PMID- 27981909 TI - Multiple Sclerosis and Neuroinflammation: The Overview of Current and Prospective Therapies. AB - Persistent neuroinflammation is now recognized as a chief pathological component of practically all neurodegenerative diseases. Neuroinflammation in the central nervous system (CNS), is accompanied with immune responses of glial cells. Glial cells respond to pathological stimuli through antigen presentation, and cytokine and chemokine signaling. Therefore, limiting CNS inflammation represents prospective therapeutic approach in diseases like Alzheimer's, amyotrophic lateral sclerosis, Parkinson's, ischemia, various psychiatric disorders and Multiple sclerosis (MS). As a complex disease, MS is characterized by neuroinflamation, demyelination and sequential axonal loss. Due to unknown etiology and the heterogeneous presentation of the disease, MS is hard to treat and the search for potential therapeutics is wide and meticulous. However, finding a proper antineuroinflammatory drug may bring an advance in selecting novel treatment regimens of ample of neurodegenerative diseases and neurological disorders. The present review gives the overview of the existing and potential therapies in MS, aimed to modulate neuroinflammation and ensure neuroprotection. PMID- 27981910 TI - Multilevel Analysis of Locomotion in Immature Preparations Suggests Innovative Strategies to Reactivate Stepping after Spinal Cord Injury. AB - Locomotion is one of the most complex motor behaviors. Locomotor patterns change during early life, reflecting development of numerous peripheral and hierarchically organized central structures. Among them, the spinal cord is of particular interest since it houses the central pattern generator (CPG) for locomotion. This main command center is capable of eliciting and coordinating complex series of rhythmic neural signals sent to motoneurons and to corresponding target-muscles for basic locomotor activity. For a long-time, the CPG has been considered a black box. In recent years, complementary insights from in vitro and in vivo animal models have contributed significantly to a better understanding of its constituents, properties and ways to recover locomotion after a spinal cord injury (SCI). This review discusses key findings made by comparing the results of in vitro isolated spinal cord preparations and spinal transected in vivo models from neonatal animals. Pharmacological, electrical, and sensory stimulation approaches largely used to further understand CPG function may also soon become therapeutic tools for potent CPG reactivation and locomotor movement induction in persons with SCI or developmental neuromuscular disorder. PMID- 27981911 TI - Microtubule-Directed Therapeutic Strategy for Neurodegenerative Disorders: Starting From the Basis and Looking on the Emergences. AB - Around ten years ago, the first evidence that targeting microtubule system could be a potential strategy in slowing down neurodegeneration was reported. Several teams have been working to better shape this idea and the scientific community has now the opportunity of fishing into a large amount of data coming from in vitro and in in vivo studies. Notably, these results have driven clinical trials addressing tauopathies. Unfortunately, moving such a neuroprotective strategy from mice to men has revealed unexpected concerns and results that do not fit with the promising background. Here we aim to focus the rationale for the design of a microtubule-based therapy in neurodegeneration, look at the results achieved and discuss the future perspectives. PMID- 27981912 TI - Probing the Human Spinal Locomotor Circuits by Phasic Step-Induced Feedback and by Tonic Electrical and Pharmacological Neuromodulation. AB - The mammalian lumbar spinal cord experimentally isolated from supraspinal and afferent feedback input remains capable of expressing some basic locomotor function when appropriately stimulated. This ability has been attributed to spinal neural circuits referred to as central pattern generators (CPGs). In individuals with a severe spinal cord injury, rhythmic activity in paralyzed leg muscles can be generated by phasic proprioceptive feedback during therapist- or robotic-assisted stepping on a motorized treadmill. Here, we critically review to what extent the resulting motor output represents locomotor-like activity, and whether these motor patterns are the result of activation of CPGs, as commonly suggested in the literature. Attempts will be made to further delineate the pivotal roles played by mechanisms such as spinal proprioceptive reflexes and their alterations after spinal cord injury, the central excitability level, and by neurotransmitters critical for spinal locomotor activity. We will discuss the view that the muscle activity produced during assisted passive treadmill stepping is resulting from the entrainment of spinal reflex circuits by the cyclically generated proprioceptive feedback. We suggest that the activation of CPG circuits depends rather on the presence of a sustained tonic excitatory drive, as can be provided by electrical spinal cord stimulation, or by specific combinations of dopaminergic agonists, adrenergic/ dopaminergic precursors and/or 5-HT receptor agonists. Novel rehabilitation strategies using spinal cord stimulation and rhythmic-activity producing drugs during locomotor therapy will pave the way for clinically relevant advances in restoration of motor function in people with severe spinal cord injury. PMID- 27981913 TI - Editorial (Thematic Issue: Endocrine Disorders and Cognitive Function in the Elderly). PMID- 27981914 TI - Serum Testosterone and Cognitive Function in Ageing Male: Updating the Evidence. AB - BACKGROUND: Testosterone (T) deficit, either in prepubertal or postpubertal form of hypogonadism, seems to play a key role in impairing cognitive function, including memory, attention, language and visuospatial abilities, especially in elderly men. OBJECTIVE: Several studies have recently showed the association between low serum T levels and important cognitive dysfunctions in ageing male as well as in subjects suffering from Alzheimer's disease (AD), mild cognitive impairment (MCI) and even depression, suggesting that T could exert an active neuroprotective role. METHODS: By searching PubMed and recent patents (ranging from 2010 to 2015), we identified several observational and intervention studies dealing with T and cognitive function in adult and ageing men. Findings were reviewed, thoroughly examined and, finally, summarized herein. RESULTS: Although a large number of studies have been carried out so far, conclusive evidence cannot be drawn, in particular, for cognitive disorders in males. Conversely, T supplementation has been suggested for depressive syndrome in young and ageing men. To date, no clinical data have been carried out on cognitive dysfunctions employing the quoted patents in men. CONCLUSIONS: Studies aiming to evaluate the role of serum T and its supplementation in adult and ageing men with T deficiency syndrome need to be encouraged, given that subjects affected by overt hypogonadism, either in prepubertal (i.e. Klinefelter syndrome) or postpubertal forms (chemical castration in subjects affected by prostate cancer), often complain of cognitive dysfunction, and seem to considerably benefit from T replacement therapy. PMID- 27981915 TI - Variability of antithrombotics use in patients with hypoplastic left heart syndrome and its variants following first- and second-stage palliation surgery: a national report using the National Pediatric Cardiology Quality Improvement Collaborative registry. AB - : Purpose Patients with hypoplastic left heart syndrome and its variants following palliation surgery are at risk for thrombosis. This study examines variability of antithrombotic practice, the incidence of interstage shunt thrombosis, and other adverse events following Stage I and Stage II palliation within the National Pediatric Cardiology Quality Improvement Collaborative registry. METHODS: We carried out a multicentre, retrospective review using the National Pediatric Cardiology Quality Improvement Collaborative registry including patients from 2008 to 2013 across 52 surgical sites. Antithrombotic medications used at Stage I and Stage II discharge were evaluated. Variability of antithrombotics use at the individual patient level and intersite variability, incidence of shunt thrombosis, and other adverse events such as cardiac arrest, seizure, stroke, and need for cardiac catheterisation intervention in the interstage period were identified. Antithrombotic strategies for hybrid Stage I patients were evaluated but they were excluded from the variability and outcomes analysis. RESULTS: A total of 932 Stage I and 923 Stage II patients were included in the study: 93.8% of Stage I patients were discharged on aspirin and 4% were discharged on no antithrombotics, and 77% of Stage II patients were discharged on aspirin and 17.5% were discharged on no antithrombotics. Only three patients (0.2%) presented with interstage shunt thrombosis. The majority of patients who died during interstage or required shunt dilation and/or stenting were discharged home on aspirin. CONCLUSION: Aspirin is the most commonly used antithrombotic following Stage I and Stage II palliation. There is more variability in the choice of antithrombotics following Stage II compared with Stage I. The incidence of interstage shunt thrombosis and associated adverse events was rare. PMID- 27981916 TI - Incorrect ventricular lead placement into the systemic right ventricle of a patient with D-transposition of the great vessels after Mustard procedure. AB - Incorrect pacemaker lead placement into the systemic ventricle is a complication that has rarely been described in patients with D-transposition status after atrial baffle palliation. We present a case of ventricular lead misplacement in the systemic right ventricle of a patient with D-transposition of the great arteries after Mustard procedure. This case demonstrates the challenges with proper imaging of lead placement in patients with atrial baffles and long-term management of a lead in the systemic ventricle. PMID- 27981917 TI - An observational study to assess if automated diabetic retinopathy image assessment software can replace one or more steps of manual imaging grading and to determine their cost-effectiveness. AB - BACKGROUND: Diabetic retinopathy screening in England involves labour-intensive manual grading of retinal images. Automated retinal image analysis systems (ARIASs) may offer an alternative to manual grading. OBJECTIVES: To determine the screening performance and cost-effectiveness of ARIASs to replace level 1 human graders or pre-screen with ARIASs in the NHS diabetic eye screening programme (DESP). To examine technical issues associated with implementation. DESIGN: Observational retrospective measurement comparison study with a real-time evaluation of technical issues and a decision-analytic model to evaluate cost effectiveness. SETTING: A NHS DESP. PARTICIPANTS: Consecutive diabetic patients who attended a routine annual NHS DESP visit. INTERVENTIONS: Retinal images were manually graded and processed by three ARIASs: iGradingM (version 1.1; originally Medalytix Group Ltd, Manchester, UK, but purchased by Digital Healthcare, Cambridge, UK, at the initiation of the study, purchased in turn by EMIS Health, Leeds, UK, after conclusion of the study), Retmarker (version 0.8.2, Retmarker Ltd, Coimbra, Portugal) and EyeArt (Eyenuk Inc., Woodland Hills, CA, USA). The final manual grade was used as the reference standard. Arbitration on a subset of discrepancies between manual grading and the use of an ARIAS by a reading centre masked to all grading was used to create a reference standard manual grade modified by arbitration. MAIN OUTCOME MEASURES: Screening performance (sensitivity, specificity, false-positive rate and likelihood ratios) and diagnostic accuracy [95% confidence intervals (CIs)] of ARIASs. A secondary analysis explored the influence of camera type and patients' ethnicity, age and sex on screening performance. Economic analysis estimated the cost per appropriate screening outcome identified. RESULTS: A total of 20,258 patients with 102,856 images were entered into the study. The sensitivity point estimates of the ARIASs were as follows: EyeArt 94.7% (95% CI 94.2% to 95.2%) for any retinopathy, 93.8% (95% CI 92.9% to 94.6%) for referable retinopathy and 99.6% (95% CI 97.0% to 99.9%) for proliferative retinopathy; and Retmarker 73.0% (95% CI 72.0% to 74.0%) for any retinopathy, 85.0% (95% CI 83.6% to 86.2%) for referable retinopathy and 97.9% (95% CI 94.9 to 99.1%) for proliferative retinopathy. iGradingM classified all images as either 'disease' or 'ungradable', limiting further iGradingM analysis. The sensitivity and false-positive rates for EyeArt were not affected by ethnicity, sex or camera type but sensitivity declined marginally with increasing patient age. The screening performance of Retmarker appeared to vary with patient's age, ethnicity and camera type. Both EyeArt and Retmarker were cost saving relative to manual grading either as a replacement for level 1 human grading or used prior to level 1 human grading, although the latter was less cost-effective. A threshold analysis testing the highest ARIAS cost per patient before which ARIASs became more expensive per appropriate outcome than human grading, when used to replace level 1 grader, was Retmarker L3.82 and EyeArt L2.71 per patient. LIMITATIONS: The non-randomised study design limited the health economic analysis but the same retinal images were processed by all ARIASs in this measurement comparison study. CONCLUSIONS: Retmarker and EyeArt achieved acceptable sensitivity for referable retinopathy and false-positive rates (compared with human graders as reference standard) and appear to be cost-effective alternatives to a purely manual grading approach. Future work is required to develop technical specifications to optimise deployment and address potential governance issues. FUNDING: The National Institute for Health Research (NIHR) Health Technology Assessment programme, a Fight for Sight Grant (Hirsch grant award) and the Department of Health's NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and the University College London Institute of Ophthalmology. PMID- 27981918 TI - The Expanding Role of Antibodies in Kidney Transplantation. PMID- 27981919 TI - Mortality Prediction in Patients Admitted in Surgical Intensive Care Unit by Using APACHE IV. AB - OBJECTIVE: To predict the mortality by the mean Acute Physiology and Chronic Health Evaluation (APACHE) IV score of all the patients admitted in a Surgical Intensive Care Unit (ICU) and comparing the score of the survivors and non survivors. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Surgical Intensive Care Unit, Mayo Hospital, Lahore, from June 2013 to November 2014. METHODOLOGY: All adult patients admitted in the Surgical ICU were included in this study. The demographics and other data of the patients were recorded. The APACHE IV scores of all patients were calculated at the time of admission. The scores of the survivors and the non-survivors were compared for prediction of survival and mortality. RESULTS: The age of these patients ranged from 13 to 70 (mean 38.39) years with 86 (55.48%) males and 69 (44.52%) females. The mean APACHE IV score of these patients was 34.96 +/-14.93 ranging from 11 to 63 years. Eighty-three (53.55%) patients survived and 72 (46.45%) died. With respect to gender, 41 (47.67%) males out of 86 and 31 (44.92%) females out of 69 did not survive. The mortality increased with an increase in APACHE IV score and all the patients with score more than 39 did not survive. CONCLUSION: The predicted mortality can be assessed by APACHE IV score, so it is good for application among the surgical ICU patients. PMID- 27981920 TI - In-Silico Analysis of Amotosalen Hydrochloride Binding to CD-61 of Platelets. AB - OBJECTIVE: To determine the docking of Amotosalen hydrochloride (AH) at CD-61 of platelets, and to suggest the cause of bleeding in AH treated platelets transfusion. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Medical College, Taif University, Taif, Saudi Arabia, from October 2014 to May 2015. METHODOLOGY: The study was carried out in-silico. PDB (protein data bank) code of Tirofiban bound to CD-61 was 2vdm. CD-61 was docked with Tirofiban using online docking tools, i.e. Patchdock and Firedock. Then, Amotosalen hydrochloride and CD-61 were also docked. Best docking poses to active sites of 2vdm were found. Ligplot of interactions of ligands and CD-61 were obtained. Then comparison of hydrogen bonds, hydrogen bond lengths, and hydrophobic bonds of 2vdm molecule and best poses of docking results were done. Patchdock and Firedock results of best poses were also analysed using SPSS version 16. RESULTS: More amino acids were involved in hydrogen and hydrophobic bonds in Patchdock and Firedock docking of Amotosalen hydrochloride with CD-61 than Patchdock and Firedock docking of CD-61 with Tirofiban. The binding energy was more in latter than former. CONCLUSION: Amotosalen hydrochloride binds to the active site of CD 61 with weaker binding force. Haemorrhage seen in Amotosalen hydrochloride treated platelets might be due to binding of Amotosalen hydrochloride to CD-61. PMID- 27981921 TI - Emerging Trends of Bloodstream Infections: A Six-Year Study at a Paediatric Tertiary Care Hospital in Kabul. AB - OBJECTIVE: To determine the frequency of pathogens causing bloodstream infections and evaluate their trends and antibiogram patterns among in-patients in a paediatric tertiary care centre. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: French Medical Institute for Mothers and Children (FMIC), Kabul, Afghanistan in two phases, from January 2010 to December 2015. METHODOLOGY: Results of blood cultures from suspected cases of sepsis admitted in the FMIC, from January 2010 to December 2012 (Period-1), and from January 2013 to December 2015 (Period-2) were completed. Standard microbiological methods were followed for blood culture and antibiotic sensitivity testing. RESULTS: Out of total 1,040 cases of culture proven sepsis, 528 (50.77%) Gram-negative bacilli (GNB), 474 (45.58%) Gram-positive cocci (GPC), and 38 (3.65%) Candida species were isolated during the entire study period. Out of 528 GNB isolates, 373 (70.64%) belonged to the Enterobacteriaceae and 155 (29.36%) were non-fermenters. Among Enterobacteriaceae, 168 (31.82%) were Klebsiella species (K. pneumoniae=124, K. oxytoca=44), 70 (13.26%) were Enterobacter species (E. cloacae=52, E. aerogenes=18), 65 (12.31%) were E. coli, 37 (7.01%) were Serratia marcescens and 31 (5.87%) were others. Out of 155 non-fermenters, 88 (16.67%) were Pseudomonas aeruginosa, 39 (7.39%) were Burkholderia cepacia and 18 (3.41%) were Stenotrophomonas maltophilia. There was a drop in the frequency of Enterobacteriaceae from 85% in Period-1 to 58.68% in Period-2. There was an increase in the frequency of nonfermenters from 15% to 41.32%, particularly 18 new cases of sepsis caused by Stenotrophomonas maltophilia during Period-2. Among GPC, there was an overall rise of 16.14% in the prevalence of Staphylococcus epidermidis during Period-2 and a drop of 9.64% in the frequency of Staphylococcus aureus during Period-2. The majority of Gram-negative isolates were multidrug-resistant to commonly used antibiotics. However, most of the isolates were sensitive to amikacin and imipenem (except S. maltophilia). The frequency of those producing ESBL reduced by 11.22% during the Period-2. Among Gram-positive cocci, the pattern of antibiogram did not show a significant change during both periods, and majority remained resistant to commonly used antibiotics. All Staphylococci were sensitive to vancomycin but resistant to penicillin. There was a substantial decline of 18.87% in the frequency of Methicillin-resistant Staphylococci (MRSA/MRSE) during Period-2. CONCLUSION: Staphylococci and Klebsiellae remain the most important bacteria responsible for bloodstream infections in a tertiary healthcare facility in Kabul. Yet, there has been an increase in the prevalence of Pseudomonas and Burkholderia cepacia. Moreover, Stenotrophomonas maltophilia emerged as a new hospital acquired pathogen. This study could possibly help in suggesting choices eluding the misuse of appropriate antibiotics. PMID- 27981922 TI - Caregiver Burden, Quality of Life and Vulnerability Towards Psychopathology in Caregivers of Patients with Dementia/Alzheimer's Disease. AB - OBJECTIVE: To identify caregivers' burden, evaluate quality of life in them; and predict anxiety and depression in caregivers of patients with Alzheimer's disease (AD). STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Neurology and Psychiatry Department of Lahore General Hospital (LGH), from January to December, 2013. METHODOLOGY: A purposive sample of 60 caregivers, who had been taking care of patients with AD for more than one year, were recruited from the study centre. The Zarit Burden Interview was used to assess caregiver burden. The brief version of World Health Organization Quality of Life Scale to assess quality of life and anxiety and depression subscales of symptom checklist-revised were administered to assess caregivers' vulnerability towards psychopathology. RESULTS: There were 6 males and 54 females caregivers with mean age of 37.60 +/ 14.87 years. The burden of caregiving had negative relationship (-0.57; -0.50; 0.48; and -0.50, respectively) with physical, psychological, social, and environmental domains of quality of life. Neither caregiver burden nor quality of life predicted for anxiety and depression in the caregivers. CONCLUSION: Caregiver burden may impair quality of life of caregivers but results imply the need to identify the interpersonal and intrapersonal characteristics of caregivers that buffered the adverse effects of caregiver burden and impaired the quality of life on psychological wellbeing of the patients with AD. PMID- 27981923 TI - Tumor Regression Patterns in Retinoblastoma. AB - OBJECTIVE: To observe the types of tumor regression after treatment, and identify the common pattern of regression in our patients. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Pediatric Ophthalmology and Strabismus, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan, from October 2011 to October 2014. METHODOLOGY: Children with unilateral and bilateral retinoblastoma were included in the study. Patients were referred to Pakistan Institute of Medical Sciences, Islamabad, for chemotherapy. After every cycle of chemotherapy, dilated fundus examination under anesthesia was performed to record response of the treatment. Regression patterns were recorded on RetCam II. RESULTS: Seventy-four tumors were included in the study. Out of 74 tumors, 3 were ICRB group A tumors, 43 were ICRB group B tumors, 14 tumors belonged to ICRB group C, and remaining 14 were ICRB group D tumors. Type IV regression was seen in 39.1% (n=29) tumors, type II in 29.7% (n=22), type III in 25.6% (n=19), and type I in 5.4% (n=4). All group A tumors (100%) showed type IV regression. Seventeen (39.5%) group B tumors showed type IV regression. In group C, 5 tumors (35.7%) showed type II regression and 5 tumors (35.7%) showed type IV regression. In group D, 6 tumors (42.9%) regressed to type II non-calcified remnants. CONCLUSION: The response and success of the focal and systemic treatment, as judged by the appearance of different patterns of tumor regression, varies with the ICRB grouping of the tumor. PMID- 27981924 TI - Thalidomide for Control Delayed Vomiting in Cancer Patients Receiving Chemotherapy. AB - OBJECTIVE: To explore the efficacy and safety of thalidomide for the treatment of delayed vomiting, induced by chemotherapy in cancer patients. STUDY DESIGN: Randomized, double-blind controlled study. PLACE AND DURATION OF STUDY: The Oncology Department of Affiliated Hospital of Xuzhou Medical University, Jiangsu Xuzhou, China, from January 2012 to January 2014. METHODOLOGY: A total of 78 cancer patients, who had delayed vomiting observed from 24 hours to 1 week after chemotherapy, were included in the study. Patients were divided in a treatment group (40 patients, 51.28%) and a control group (38 patients, 48.71%). The treatment group received thalidomide at an oral dose of 100 mg per night; 50 mg was added daily up to a dose of 200 mg per night, if the curative effect was suboptimal and the medicine was tolerated. Both the treatment and the control groups received a drip of 10 mg azasetron 30 minutes before chemotherapy. The control group only proportions of antiemetic effects and adverse reactions were compared using the c2 test. Antiemetic effects and adverse reactions were assessed from Odds Ratios (OR) with 95% Confidence Intervals(95% CI). RESULTS: The effective control rate of delayed vomiting in the treatment group was significantly higher than that in the control group (c2=5.174, p=0.023). No significant difference was found between the two groups in other adverse effects of chemotherapy. Karnofsky scores or the overall self-evaluation of the patients (p>0.05). CONCLUSION: Thalidomide can effectively control the delayed vomiting of cancer patients receiving chemotherapy and the adverse reactions of the agent can be tolerated. PMID- 27981925 TI - Comparison of Presentation and Outcome in 100 Pediatric Hodgkin Lymphoma Patients Treated at Children Hospital, Lahore, Pakistan and Royal Marsden Hospital, UK. AB - OBJECTIVE: To compare differences in demographics and outcomes in childhood Hodgkin lymphoma (HL) presenting at the Children's Hospital Lahore (CHL), and Royal Marsden Hospital (RMH), UK. STUDY DESIGN: An observational comparative study. PLACE AND DURATION OF STUDY: From January 2011 to February 2012 at CH, Lahore and from October 2008 to February 2012 at RMH, UK. METHODOLOGY: Consecutive HL patients (50 from each hospital) were inducted. Data regarding age, gender, staging, histopathology and outcome were analysed. Clinical and pathological staging done according to Ann-Arbor and World Health Organization classification. Treatment duration was 6-8 months. They were followed for 6 months post-treatment. Frequencies of variables were noted and compared. Chi square test was used for determining significance. RESULTS: Patients from Children's Hospital, Lahore were younger (mean 7.9 years) with male predominance (n=42, 84%). Histopathology showed Mixed Cellularity (MC) in 32 (64%), Nodular Sclerosis (NS) in 5 (10%), Lymphocyte Rich in 4 (8%) and lymphocyte depleted in 1 (2%), nodular lymphocyte predominant (NLP) in 1 (2%) each. Majority presented in stage IV (n=25,50%), or stage III (n=20,40%). Constitutional B symptoms were present in 37 (74%). Bone marrow involvement observed in 23 (46%). Remission was achieved in 42 (84%) patients; 2 (4%) relapsed, 4 (8%) expired and 2 (4%) left against medical advice. In contrast, RMH patients were older (mean 11.8 years.) and 30 (60%) were males. NS (n=40,80%) and NLP (n=6,12%) types were predominant. Two (4%) patients were in stage I, 27 (54%) in stage II, 12 (24%) in stage III and 9 (18%) presented in stage IV. Fourteen (28%) had B-symptoms. None had bone marrow disease. Event free survival was 46 (92%). Four (8%) patients relapsed. Three responded to second line therapy and one relapsed postautologous transplant. CONCLUSION: Significant differences were observed in age at presentation, stage, histopathology and extent of bone marrow involvement between the groups. Of interest is the bone marrow involvement in stage IV patients in Pakistan. Delayed diagnosis account for advanced stage but difference in pathological subtype needs further study. PMID- 27981926 TI - Stone-Free-Rate After Extracorporeal Shockwave Lithotripsy in the Management of Pediatric Renal Stones in Lower Pole and Other Locations - A Comparative Study. AB - OBJECTIVE: To determine a difference in the stone-free-rate among different renal locations in children after extracorporeal shockwave lithotripsy (ESWL). STUDY DESIGN: A descriptive study. PLACE AND DURATION OF STUDY: Urology Department, Shifa International Hospital, Islamabad, Pakistan, from January 2007 to June 2015. METHODOLOGY: The study included children who underwent ESWL, divided into three groups based on location of stones in kidney as group A (lower pole stones), group B (upper and mid pole stones) and group C (renal pelvis stone), respectively. ESWL was done by standard technique using Storz Modulith SLX lithotripter 3rd generation. Data was collected by chart review. SPSS version 16 was used for data analysis. RESULTS: Among 76 children with mean age of 7.55 +/ 4.16 years, 55 (72.4%) were males whereas 21 (27.6%) were females. Mean stone size was 1.08 +/-0.59 cm. There were 34, 17 and 25 cases in groups A, B and C, respectively. Post- ESWL stone-free-rate was 47% in lower pole stones, 70.58% in upper and mid pole stones, and 68% in renal pelvis stones. Hematuria was seen in one patient from each group, sepsis in two patients from each of the mid pole/upper pole and lower pole group, while Steinstrasse in one patient from each group. CONCLUSION: ESWL is a safe and effective way of treating renal stones in all poles in pediatric population. PMID- 27981927 TI - The Pathogenesis of Radial Ray Deficiency in Thrombocytopenia-Absent Radius (TAR) Syndrome. AB - The genetic basis of thrombocytopenia-absent radius (TAR) syndrome was recently identified to be related to the RBM8A gene. The encoded protein (known as the Y14 protein) is widely expressed in human cells (including osteoblasts) and plays several essential intracellular functions. Hence, the pathogenesis of radial ray deficiency in thrombocytopeniaabsent radius syndrome remains a mystery. The current paper reviews the pathogenesis of the clinical features of thrombocytopenia-absent radius syndrome and offers a hypothesis of pathogenesis through attenuation of the Fibroblast Growth Factor 8 signal in the mesoderm because of an increased degradation of the Fibroblast Growth Factor Receptor 1. PMID- 27981928 TI - Comparison of Direct Trocar Insertion with Other Techniques for Laparoscopy. AB - OBJECTIVE: To assess the safety of direct trocar insertion (DTI) before creating pneumoperitoneum in laparoscopic procedures. STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Combined Military Hospital (CMH) Kohat, Pakistan from November 2013 to January 2015. METHODOLOGY: All the cases undergoing laparoscopy at the study centre in the above duration were included in the study after approval from the Hospital Ethical Committee and informed written consent. Out of the 200 cases, DTI was successfully used to establish peritoneal access in 190 cases, while open Hassen's technique (OL) was used in ten cases. Body mass index (BMI) of all the patients was calculated before surgery. All the cases were performed under general anaesthesia with adequate relaxation. A 10 mm permanent re-useable sharp metallic trocar was inserted through umbilical scar after lifting the abdominal wall using towel clamps. Studied variables included age, gender, BMI, operations, history of previous surgery, number of attempts for DTI and complications. RESULTS: Mean age of the patients in DTI group was 46.58 +/-13.94 years, while 48.70 +/-10.08 years in OL group. Female to male ratio in DTI group was 1.43:1; and 2.33:1 in OL group. Increase in BMI had a relation with number of unsuccessful attempts of DTI, so obesity was the main reason of failure of DTI. CONCLUSION: DTI is a safe and effective method of peritoneal access for laparoscopy with very low failure rate related to BMI and minimal complications. PMID- 27981929 TI - Journal of the College of Physicians and Surgeons of Pakistan: Five Years Bibliometric Analysis. AB - To conduct the bibliometric analysis of the Journal of the College of Physicians and Surgeons Pakistan (JCPSP) from 2012 to 2014. The prime objectives of this report were to determine the number and percentage of articles by year, authorship pattern, gender and geographical affiliation, ranking by subject and citation analysis. A data collection instrument was developed as bibliometric form. The data was analysed using the Microsoft Excel spread sheet. Editorials and letters to editors were excluded. There were 1106 total research documents, including 721 original articles and 385 case reports. A rapid increase in number of articles per year was noticed, more original papers than case reports. Majority of the authors were male. The contribution of Balochistan and Khyber Pakhtunkhwa was less than the other provinces. JCPSP was the most cited document in the reference list of the research documents. The scholars of Khyber Pakhtunkhwa and Balochistan and female researchers should give more attention in writing quality articles eligible for consideration at this Journal. It is also suggested that writers should be compelled to address such fields of medical sciences as neurology, nephrology, anatomy and pharmacology, while writing original articles and case reports. PMID- 27981930 TI - Isolated Dorsal Pancreatic Agenesis. AB - Developmental anomalies of the pancreas have been reported; but among these, agenesis of dorsal pancreas is an extremely rare congenital pancreatic anomaly. It may be asymptomatic and incidentally detected on imaging or may be associated with diabetes mellitus or attacks of pancreatitis. We report a rare case of agenesis of dorsal pancreas that was detected incidentally on imaging and there was no other co-existing anomaly. PMID- 27981931 TI - Pleural Effusion Developing in Two Patients on Continuous Ambulatory Peritoneal Dialysis. AB - Two patients with end-stage-renal-disease on continuous ambulatory peritoneal dialysis (CAPD) presented with pleural effusions. The aspirated fluid was categorised as transudate, based on alkaline pH, low protein and lactic dehydrogenase level. A striking feature of the pleural fluid was, its very high glucose content that resulted from translocation of dextrose containing peritoneal dialysate into the pleural space via a pleuroperitoneal connection. One patient was transferred to hemodialysis, which led to complete resolution of pleural effusion. The other patient was switched to automated peritoneal dialysis, using small dwell volumes with consequent reduction in size of the pleural effusion. Pleuroperitoneal leak should always be considered in the differential diagnosis of pleural effusion in CAPD patients. Although isotopic peritoneography can demonstrate reflux of the tracer in the pleural space, measurement of pleural fluid glucose is a simpler and reliable way of diagnosing pleuroperitoneal communication. PMID- 27981933 TI - Anthropometrical Measurements of Healthy Newborn Babies in Karachi, and the Factors Affecting these Parameters. AB - The present cross-sectional study was undertaken with the aim of establishing norms for birth weight, crown heel length, and head circumference of the newborns in the population of Karachi. It was conducted in four public and private hospitals of Karachi, covering middle to low-income areas during a period of 2 years. There were 404 mothers and their babies included in this study that fulfilled the inclusion and exclusion criteria of the study. Anthropometric measurements including birth weight, crown heel length, and occipitofrontal circumference (OFC) were recorded within 24 hours of birth. Maternal age, parity, gestational age, newborn gender, Apgar score, and delivery mode were also recorded. The data entry and analysis was done on Statistical Packages of Social Sciences (SPSS) version 21.The mean birth weights of the babies were found to be 3.03 +/-0.39 kg, crown heel length were 49.2 +/-2.4 cm, and OFC were 34 +/-1.5 cm. A statistically significant difference was found between the gender of the babies (male=3.07 +/-0.4 kg versus female=3.0 +/-0.4 kg) for birth weight (p=0.02). This study provides the mean values of anthropometric measurements of the newborns in low-income areas of Karachi. PMID- 27981932 TI - G6PD Deficiency with Arnold-Chiari Malformation. AB - A neonate with glucose-6-phosphate dehydrogenase (G6PD) deficiency and Arnold Chiari Malformation (ACM) type 2 underwent lumbar meningomyelocele (MMC) repair. Patients with G6PD deficiency are prone to develop haemolysis following any kind of oxidative stress and in ACM, there is a disturbed cranio-spinal pressure relationship. The neonate was managed under general anaesthesia with propofol for induction as well as for maintenance along with fentanyl and oxygen-nitrous mixture. PMID- 27981934 TI - Ultrasound Diagnosis of Scrotal Wall Cavernous Hemangioma. PMID- 27981935 TI - Percutaneous Endoscopic Gastrostomy in Situs Inversus Totalis. PMID- 27981936 TI - Ring Chromosome 10 in a Case of Acute Promyelocytic Leukemia. PMID- 27981937 TI - Zika Virus in Pakistan: A Looming Adversity? PMID- 27981938 TI - Laparoscopic Restaging Surgery for Ovarian or Fallopian Tube Cancer. PMID- 27981939 TI - Canalicular Adenoma Arising in Buccal Mucosa. PMID- 27981940 TI - Squamous Cell Carcinoma Arising in Background of Mature Cystic Teratoma. AB - Mature cystic teratoma of ovary is a common benign adnexal tumor in females. Malignant transformation in a mature cystic teratoma of the ovary occurs in only 1 - 2% of cases. Most common malignant transformation is squamous cell carcinoma (70-80% of cases), occurring mostly in postmenopausal women with large sized cysts. Here, we report a case of 46-year lady who presented with pain in lower abdomen. Ultrasound and CT scan revealed complex adnexal mass measuring 16x9 cm. Size and older age of the patients should be regarded as important predictors of malignant transformation in mature cystic teratoma. Adequate sampling followed by histopathological examination has important role in diagnosis of such rare tumor. PMID- 27981941 TI - Baize-like CeO2 and NiO/CeO2 nanorod catalysts prepared by dealloying for CO oxidation. AB - Baize-like monolithic CeO2 and NiO/CeO2 nanorod catalysts were prepared by combined dealloying and calcination and the catalytic activities were evaluated using CO catalytic oxidation. The CeO2 catalysts were composed of nanorods and exhibited a three-dimensional supporting structure with pores. After introduction of NiO, dispersed NiO nanosheets and nanoparticles were supported on the surface of CeO2 nanorods and they were not well-crystallined due to CeO2 inhibiting the NiO crystallization. The Raman and x-ray photoelectron spectroscopy analyses revealed that the introduction of NiO species into CeO2 generated more coordinate unsaturated Ni atoms, oxygen vacancies, defects and active sites for CO catalytic reactions. The reaction activation energy of NiO/CeO2 nanorod catalyst prepared from the Al83Ce10Ni7 precursor alloy was just 31.2 kJ mol-1 and the CO conversion can reach up to 97% at 240 degrees C, which was superior to that of pure CeO2 and nanoporous NiO. The enhanced catalytic activity of baize-like NiO/CeO2 nanorods can be attributed to the strong synergistic effects between finely dispersed NiO species and surface oxygen vacancies in CeO2 nanorods. PMID- 27981942 TI - Broadband light-absorption InGaN photoanode assisted by imprint patterning and ZnO nanowire growth for energy conversion. AB - In this research, an InGaN-based photoanode with a broadband light-absorption range from ultraviolet to green, patterned by imprint lithography and branched by ZnO nanowires, has been applied to water splitting. Over the solar spectrum range, the absorbance increases due to the scattering effect of the micro structure compared to that of flat surface InGaN, which reaches a maximum of over 90% at 380 nm as ZnO nanowires are further employed in this novel photoanode. Consequently, the induced photocurrent density of the InGaN photoanode with a domelike structure and ZnO nanowires on the surface shows a remarkable enhancement of seven times that of the one with a flat surface. Further investigation indicates the wet-etching process for defect removal has an essential impact on photocurrent efficiency. This design demonstrates an innovative approach for water splitting. PMID- 27981943 TI - Spectral-distortion-free light extraction from organic light-emitting diodes using nanoscale photonic crystal. AB - Despite their generally good performance, photonic crystal (PC)-based organic light-emitting diodes (OLEDs) encounter a serious spectral distortion problem. In this study, we obtained spectral-distortion-free PC-based OLEDs by lowering the pitch (period of the PC) to less than a half the emission wavelength, using a simple and scalable nanoscale process of laser interference lithography. The demonstrated OLEDs with 200 nm pitch-size nanoscale periodic hole arrays exhibited negligible changes in the Internal Commission on Illumination 1931 color coordinate of Delta (0.0104, 0.0078) and a peak wavelength of Delta0 nm (relative to the reference), while maintaining the function of the internal light extraction layer, manifested as a 23% enhancement of the external quantum efficiency (EQE). The enhancement of the EQE reached 85% after incorporating a micro-lens array. The improved light extraction, spectral-distortion-free characteristic, and excellent color stability over a broad range of viewing angles were successfully derived by performing finite difference time domain simulations. PMID- 27981944 TI - Precise fabrication of a 5 nm graphene nanopore with a helium ion microscope for biomolecule detection. AB - We report a scalable method to fabricate high-quality graphene nanopores for biomolecule detection using a helium ion microscope (HIM). HIM milling shows promising capabilities for precisely controlling the size and shape, and may allow for the potential production of nanopores at wafer scale. Nanopores could be fabricated at different sizes ranging from 5 to 30 nm in diameter in few minutes. Compared with the current solid-state nanopore fabrication techniques, e.g. transmission electron microscopy, HIM is fast. Furthermore, we investigated the exposure-time dependence of graphene nanopore formation: the rate of pore expansion did not follow a simple linear relationship with exposure time, but a fast expansion rate at short exposure time and a slow rate at long exposure time. In addition, we performed biomolecule detection with our patterned graphene nanopore. The ionic current signals induced by 20-base single-stranded DNA homopolymers could be used as a basis for homopolymer differentiation. However, the charge interaction of homopolymer chains with graphene nanopores, and the conformations of homopolymer chains need to be further considered to improve the accuracy of discrimination. PMID- 27981945 TI - Nanoscale silicon substrate patterns from self-assembly of cylinder forming poly(styrene)-block-poly(dimethylsiloxane) block copolymer on silane functionalized surfaces. AB - Poly(styrene)-block-poly(dimethylsiloxane) (PS-b-PDMS) is an excellent block copolymer (BCP) system for self-assembly and inorganic template fabrication because of its high Flory-Huggins parameter (chi ~ 0.26) at room temperature in comparison to other BCPs, and high selective etch contrast between PS and PDMS block for nanopatterning. In this work, self-assembly in PS-b-PDMS BCP is achieved by combining hydroxyl-terminated poly(dimethylsiloxane) (PDMS-OH) brush surfaces with solvent vapor annealing. As an alternative to standard brush chemistry, we report a simple method based on the use of surfaces functionalized with silane-based self-assembled monolayers (SAMs). A solution-based approach to SAM formation was adopted in this investigation. The influence of the SAM modified surfaces upon BCP films was compared with polymer brush-based surfaces. The cylinder forming PS-b-PDMS BCP and PDMS-OH polymer brush were synthesized by sequential living anionic polymerization. It was observed that silane SAMs provided the appropriate surface chemistry which, when combined with solvent annealing, led to microphase segregation in the BCP. It was also demonstrated that orientation of the PDMS cylinders may be controlled by judicious choice of the appropriate silane. The PDMS patterns were successfully used as an on-chip etch mask to transfer the BCP pattern to underlying silicon substrate with sub-25 nm silicon nanoscale features. This alternative SAM/BCP approach to nanopattern formation shows promising results, pertinent in the field of nanotechnology, and with much potential for application, such as in the fabrication of nanoimprint lithography stamps, nanofluidic devices or in narrow and multilevel interconnected lines. PMID- 27981946 TI - Structure variation of a sidewall quantum well on a GaN nanorod. AB - A theoretical model for evaluating the height-dependent variations of quantum well (QW) thickness and In concentration in a sidewall QW of a single- or two section GaN nanorod (NR) is proposed. By reasonably choosing modeling parameter values, the obtained numerical results are quite consistent with the available experimental data. In particular, the model clearly demonstrates the increasing trends of QW thickness and In concentration with height on a sidewall of a single section NR. Also, it successfully explains the larger QW thickness and higher In concentration in the upper uniform section, when compared with the lower uniform section, in a two-section NR. In this model, three III-group adatom supply sources are considered for sidewall deposition on a single-section NR, including the downward diffusion of adatoms collected on the slant facets at the NR top, the upward diffusion of adatoms collected on the NR base, and the direct adsorption of atoms on the sidewall from the vapor phase. For a two-section NR, the upward and downward diffusions of adatoms collected on the slant facets of the tapering section between the two uniform sections serve as extra adatom supply sources. PMID- 27981947 TI - Super color purity green organic light-emitting diodes with ZrO2/zircone nanolaminates as a distributed Bragg reflector deposited by atomic layer deposition. AB - ZrO2/zircone nanolaminate thin films fabricated by atomic layer deposition were used for a distributed Bragg reflector (DBR) in green organic light-emitting diodes (OLEDs). It is found that the novel ZrO2/zircone DBR structure significantly improves the light purity of green OLEDs without interfering with intrinsic electroluminescence properties. The full width at half maximum (FWHM) of the EL spectral band for the green OLEDs decreases with respect to increasing the ZrO2/zircone pairs. The FWHMs of OLEDs with 0, 2, 4, and 6 pairs of ZrO2/zircone layers are 72 nm, 48 nm, 24 nm, and 12 nm, respectively. A super narrow FWHM of 12 nm is achieved by using six pairs of the DBR structure. The EQE is increased from 10.7% to 16.1% with four pairs of ZrO2/zircone layers. PMID- 27981948 TI - Three-dimensional donut-like gold nanorings with multiple hot spots for surface enhanced raman spectroscopy. AB - Seeking for the best possible substrates for surface-enhanced Raman spectroscopy (SERS) is of great interest for single-molecule-level detection applications. Lithographic plasmonic nanostructures are supposed to enable uniform enhancement and thus have attracted extensive interest in the past decade. In this work, we propose and demonstrate a lithographic three-dimensional (3D) donut-like gold nanoring array as a SERS substrate with an enhancement factor (EF) up to 3.84 * 107. This 3D nanoring array could be directly fabricated using electron-beam lithography-defined templates without any additional lift-off process and thus promises ultraclean metallic surfaces. Meanwhile, the 3D configuration allows multiple hot spots for improving SERS performance compared to planar counterparts with comparable plasmon resonance position. Systematic experiments and simulations were conducted to gain understanding of the origin of the improved SERS performance. The results imply that the 3D donut-like gold nanorings with multiple hot spots can serve as a promising configuration for SERS applications. PMID- 27981950 TI - High gluon densities in heavy ion collisions. AB - The early stages of heavy ion collisions are dominated by high density systems of gluons that carry each a small fraction x of the momenta of the colliding nucleons. A distinguishing feature of such systems is the phenomenon of 'saturation' which tames the expected growth of the gluon density as the energy of the collision increases. The onset of saturation occurs at a particular transverse momentum scale, the 'saturation momentum', that emerges dynamically and that marks the onset of non-linear gluon interactions. At high energy, and for large nuclei, the saturation momentum is large compared to the typical hadronic scale, making high density gluons amenable to a description with weak coupling techniques. This paper reviews some of the challenges faced in the study of such dense systems of small x gluons, and of the progress made in addressing them. The focus is on conceptual issues, and the presentation is both pedagogical, and critical. Examples where high gluon density could play a visible role in heavy ion collisions are briefly discussed at the end, for illustration purpose. PMID- 27981949 TI - Phase shifting mask modulated laser patterning on graphene. AB - A one-step graphene patterning method is developed in this paper. A phase shifting mask is used to modulate incident laser beam spatially and generate graphene patterns by laser heating. Periodic graphene nanoribbon and nanomesh structures are fabricated by employing 1D and 2D phase shifting masks, respectively. The noncontact, simple procedure, easy handling and economic properties of this method make it promising towards graphene-based device fabrication. PMID- 27981951 TI - Mechanical properties of monocrystalline and polycrystalline monolayer black phosphorus. AB - The mechanical properties of monocrystalline and polycrystalline monolayer black phosphorus (MBP) are systematically investigated using classic molecular dynamic simulations. For monocrystalline MBP, it is found that the shear strain rate, sample dimensions, temperature, atomic vacancies and applied statistical ensemble affect the shear behaviour. The wrinkled morphology is closely connected with the direction of the in-plane shear, dimensions of the samples, and applied ensembles. Particularly, small samples subjected to loading/unloading of the shear deformation along the armchair direction demonstrate a clear mechanical hysteresis loop. For polycrystalline MBP, the maximum shear stress as a function of the average grain size follows an inverse pseudo Hall-Petch type relationship under an isothermal-isobaric (NPT) ensemble, whereas under a canonical (NVT) ensemble, the maximum shear stress of polycrystalline MBP exhibits a 'flipped' behaviour. Furthermore, polycrystalline MBP subjected to uniaxial tension also exhibits a strongly grain size-dependent mechanical response, and it can fail by brittle intergranular and transgranular fractures because of its weaker grain boundary structures and the direction-dependent edge energy, respectively. These findings provide useful insight into the mechanical design of BP for nanoelectronic devices. PMID- 27981952 TI - Enhanced peroxidase activity and tumour tissue visualization by cobalt-doped magnetoferritin nanoparticles. AB - Magnetoferritin (M-HFn) is a biomimetic magnetic nanoparticle with a human heavy chain ferritin (HFn) shell, trapping a magnetite (Fe3O4) core that has inherited peroxidase-like activity. In this study, cobalt-doped M-HFn nanoparticles (M-HFn Co x Fe3-x O4) with different amounts of cobalt were successfully synthesized. Experimental results indicate that the controlled doping of a certain amount of cobalt into the magnetite cores of M-HFn nanoparticles enhances its peroxidase like catalytic activity and efficacy for visualizing tumour tissues. For example, compared with sample Co0 (without cobalt doping), the peroxidase-like activity of the cobalt-doped nanoparticle sample Co60 (with a cobalt doping molar percentage of ~34.2%) increases 1.7 times, and has the maximal reaction velocity (V max) values. Moreover, after a one-step incubation with Co60 nanoparticles, and using the peroxidase substrate 3,3'-diaminobenzidine tetrahydrochloride (DAB) for colour development, the tumour tissues of breast, colorectal, stomach and pancreas tumours showed a deeper brown colour with clear boundaries between the healthy and tumourous cells. Therefore, this suggests that the cobalt-doped magnetoferritin nanoparticles enhance peroxidase activity and tumour tissue visualization. PMID- 27981953 TI - The fabrication and thermal properties of bismuth-aluminum oxide nanothermometers. AB - Bismuth (Bi) nanowires, well controlled in length and diameter, were prepared by using an anodic aluminum oxide (AAO) template-assisted molding injection process with a high cooling rate. A high performance atomic layer deposition (ALD)-capped bismuth-aluminum oxide (Bi-Al2O3) nanothermometer is demonstrated that was fabricated via a facile, low-cost and low-temperature method, including AAO templated-assisted molding injection and low-temperature ALD-capped processes. The thermal behaviors of Bi nanowires and Bi-Al2O3 nanocables were studied by in situ heating transmission electron microscopy. Linear thermal expansion of liquid Bi within native bismuth oxide nanotubes and ALD-capped Bi-Al2O3 nanocables were evaluated from 275 degrees C to 700 degrees C and 300 degrees C to 1000 degrees C, respectively. The results showed that the ALD-capped Bi-Al2O3 nanocable possesses the highest working temperature, 1000 degrees C, and the broadest operation window, 300 degrees C-1000 degrees C, of a thermal-expanding type nanothermometer. Our innovative approach provides another way of fabricating core-shell nanocables and to further achieve sensing local temperature under an extreme high vacuum environment. PMID- 27981954 TI - Nanoindentation characterisation of human colorectal cancer cells considering cell geometry, surface roughness and hyperelastic constitutive behaviour. AB - Characterisation of the mechanical behaviour of cancer cells is an issue of crucial importance as specific cell mechanical properties have been measured and utilized as possible biomarkers of cancer progression. Atomic force microscopy certainly occupies a prominent place in the field of the mechanical characterisation devices. We developed a hybrid approach to characterise different cell lines (SW620 and SW480) of the human colon carcinoma submitted to nanoindentation measurements. An ad hoc algorithm was written that compares the force-indentation curves experimentally retrieved with those predicted by a finite element model that simulates the nanoindentation process and reproduces the cell geometry and the surface roughness. The algorithm perturbs iteratively the values of the cell mechanical properties implemented in the finite element model until the difference between the experimental and numerical force indentation curves reaches the minimum value. The occurrence of this indicates that the implemented material properties are very close to the real ones. Different hyperelastic constitutive models, such as Arruda-Boyce, Mooney-Rivlin and Neo-Hookean were utilized to describe the structural behaviour of indented cells. The algorithm was capable of separating, for all the cell lines investigated, the mechanical properties of cell cortex and cytoskeleton. Material properties determined via the algorithm were different with respect to those obtained with the Hertzian contact theory. This demonstrates that factors such as: the cell geometry/anatomy and the hyperelastic constitutive behaviour, which are not contemplated in the Hertz's theory hypotheses, do affect the nanoindentation measurements. The proposed approach represents a powerful tool that, only on the basis of nanoindentation measurements, is capable of characterising material at the subcellular level. PMID- 27981955 TI - Controllable growth of monolayer MoS2 by chemical vapor deposition via close MoO2 precursor for electrical and optical applications. AB - MoO2 is used as a new source material for the growth of large area and high optical quality monolayer MoS2. However, a systematic study of the growth parameters is still missing and large-area growth of discreet single crystals is still challenging. Hereby, we report the shape evolution of monolayer growth of MoS2 and develop a methodology to achieve centimeter-scaled discrete MoS2 by adopting MoO2 as Mo source material in an atmospheric-pressure chemical vapor deposition process. Our results indicate the growth of monolayer MoS2 could benefit from the precise control of the introduction time of sulfur and the S/MoO2 ratio in experiments. Micro-Raman and photoluminescence spectra confirm the properties of the material. E-beam lithography was utilized to make contact with the as-grown MoS2 located at the selective area. The electrical properties of MoS2 with different morphologies were compared. In the end, the persistent photoconductivity properties of monolayer MoS2 were emphasized and the underlying mechanism was proposed. These studies demonstrate a better understanding of the growth and application of MoS2-based 2D materials. PMID- 27981956 TI - A Randomized Comparison of Medication and Cognitive Behavioral Therapy for Treating Depression in Low-Income Young Minority Women. AB - BACKGROUND Longitudinal data arise frequently in biomedical science and health studies where each subject is repeatedly measured over time. We compared the effectiveness of medication and cognitive behavioral therapy on depression in predominantly low-income young minority women. MATERIAL AND METHODS The treatment effects on patients with low-level depression may differ from the treatment effects on patients with high-level depression. We used a quantile regression model for longitudinal data analysis to determine which treatment is most beneficial for patients at different stress levels over time. RESULTS The results confirm that both treatments are effective in reducing the depression score over time, regardless of the depression level. CONCLUSIONS Compared to cognitive behavioral therapy, treatment with medication more often effective, although the size of the effect differs. Thus, no matter how severe a patient's depression symptoms are, antidepressant medication is effective in decreasing depression symptoms. PMID- 27981957 TI - [The molecular genetic analysis of chromosomal DNA in burned bones]. AB - The objective of the present study was a demonstrative consideration of the debatable problem concerning the possibility of obtaining reliable genetic information by the investigation of burned bones. The bone fragments with the identifiable external features of different degree of ignition (i.e. in the carbonized, grey- and white-burnt states) were placed in the muffle furnace for the controlled thermal treatment. The analytical suitability of these burned bone objects for genotyping was estimated with the use of standard chromosomal STR loci multiplex genotyping panels. The results of the study cast serious doubts as regards the possibility of genotyping of chromosomal DNA extracted from the burned bones. It was shown that the exposure of the bone tissue to a temperature of 150 degrees Celsius during 2 hours can turn it into a material absolutely unsuitable for genotyping due to the loss of all individual genotypic traits. Characteristically the burned bone objects are externally indistinguishable from the native bone. At the same time, the material with the signs of the high temperature impact visible by the unaided eye (e.g. in the carbonized, pronounced black as well as grey and white-burnt states) is altogether unsuitable for the reliable identification of the genetic profile of chromosomal DNA. PMID- 27981959 TI - [Specific features of the injuries to the head inflicted by hits with long objects with the impact surface of various shape]. AB - The article was designed to characterize the specific features of the injuries to the head inflicted under experimental conditions by hits with long objects with the impact surfaces of various shape. The data obtained can be used to improve the conduction of forensic medical expertises for the identification purposes. A combined approach for the layer-by-layer description of head injuries is proposed to be used for the identification of morphological features of interest. PMID- 27981958 TI - [Pulmonary thromboembolism and errors of its lifetime diagnostics]. AB - The objective of the present study was the forensic medical evaluation of the importance of clinical and morphological manifestations of the venous thromboembolic complications (VTEC) for the early diagnostics of pulmonary thromboembolism. The article presents a detailed information about the VTEC morbidity rate and mortality from pulmonary artery thromboembolism (PATE) with special reference to the possible clinical variants and outcomes of this pathology. The importance of studying VTEC morbidity is substantiated. An episode from the personal expert practical work is reported to illustrate errors of lifetime diagnostics of pulmonary artery thromboembolism. Special attention is given to the necessity of the comprehensive examination of the patients presenting with VTEC for the lifetime diagnostics of pulmonary artery thromboembolism. The great value of the comprehensive pathological anatomic (forensic medical) investigation for postmortem diagnostics of VTEC is emphasized. It is concluded that the integrated approach is needed to the conduction of forensic medical expertise of the subjects presenting with the manifestations of the venous thromboembolic complications. PMID- 27981961 TI - [The possibilities for the expert assessment of the influence of the structural features of a hunting weapon barrel on the characteristics of injuries inflicted by the multi-element ammunition in a cylindrical container]. AB - The objective of the present study was to analyze the available information contained in the special literature concerning the possibilities for the expert assessment of the influence of the constructive and ballistic characteristics of hunting weapon barrels ("cylinder" versus "choke") and their regular ammunition (equipped with pellets placed in a special wad-container and without it) on the mechanisms of damage formation. It was shown that the barrel muzzle narrowing produces the well apparent effect on the process of formation and release of all the damaging factors of the shot which makes it difficult to diagnose the resultant damage. It is concluded that the use of shooting ammunition with the pellets enclosed in wad-containers creates the objective prerequisite for the differentiation between its different types. PMID- 27981960 TI - [The forensic medical aspects of the perinatal losses from intrauterine infections]. AB - The objective of the present study was to evaluate the contribution of intrauterine infections to the loss of fetuses and newborn babies and to elucidate the cause-and-effect relationships between the unfavourable outcomes of pregnancies and the actions of the attending medical personnel. The main group of the patients included in the study was comprised of 28 women whose pregnancy ended in stillbirths (13 cases) and infant death during the neonatal period (15 cases) in the association with intrauterine infections (IUI). The control group consisted of 11 practically healthy women with the physiological course of pregnancy and parturition matched to those of the main group in terms of age, parity, and social status. Special attention was given to the possibilities of prevention of neonatal deaths and the severity of harm to the health of mother and child. Examination of the patients of the main group revealed multiple infectious foci in the body affecting various organs and their systems including the urogenital tract. The premature birth occurred in 46.4% of the women presenting with fetal-placental insufficiency. They gave birth to the babies with a low weight for gestational age in the state of asphyxia that required the application of the resuscitation procedures and intensive therapy. The present study has shown that the immediate cause of fetal and neonatal deaths was multiple organ dysfunction associated with intrauterine infections. No direct relationship between the unfavourable outcomes of pregnancy and the actions of the medical personnel was documented in the majority of the cases (89.3%). It is concluded that the main factors responsible for tanatogenesis were the character and severity of the difficult to diagnose pathological process. PMID- 27981962 TI - [The identification of the AB0 blood type system by means of the single nucleotide polymorphisms analysis]. AB - The authors describe a domestically produced test-system for the determination of the AB0 blood type by means of the single nucleotide polymorphisms (SNP) analysis. The results of the trials indicate that the proposed test-system can be employed for the investigation of DNA specimens of individual origin obtained from any objects of expertise including micro-objects containing human nuclear DNA. PMID- 27981963 TI - [The point-digital interpretation and the choice of the dermatoglyphic patterns on human fingers for diagnostics of consanguineous relationship]. AB - The objective of the present study was the development of the point-digital model for the scaless interpretation of the dermatoglyphic papillary patterns on human fingers that would allow to comprehensively describe, in digital terms, the main characteristics of the traits and perform the quantitative assessment of the frequency of their inheritance. A specially developed computer program, D.glyphic. 7-14 was used to mark the dermatoglyphic patterns on the fingerprints obtained from 30 familial triplets (father + mother + child).The values of all the studied traits for kinship diagnostics were found by calculating the ratios of the sums of differences between the traits in the parent-parent pairs to those in the respective parent-child pairs. The algorithms for the point marking of the traits and reading out the digital information about them have been developed. The traditional dermatoglyphic patterns were selected and the novel ones applied for the use in the framework of the point-digital model for the interpretation of the for diagnostics of consanguineous relationship. The present experimental study has demonstrated the high level of inheritance of the selected traits and the possibility to develop the algorithms and computation techniques for the calculation of consanguineous relationship coefficients based on these traits. PMID- 27981964 TI - [The spectral analysis as an instrument for the investigation of the functional dynamic complexes of oral speech skills for the medical criminalistic identification of the speaker]. AB - The objective of the present work was the search for the theoretical foundations and the approaches to the assessment of the methodological basis for the application of the spectral analysis to the investigation of the functional dynamic complexes (FDC) of oral speech skills for the medical criminalistic identification of the speaker. The study included the analysis of the relevant literature publications, methodological proposals of the authors of the present article, and the results of their medical criminalistics investigations and laboratory experiments. The results of the study give evidence that the spectral analysis provides an acceptable tool for distinguishing the stable identification signs of a given acoustic group that characterize the functional-dynamic complexes of oral speech skills skills for the medical criminalistic identification of the speaker. PMID- 27981966 TI - [On the training of the expert and pedagogical personnel for the forensic medical services of the Republic of Kazakhstan]. AB - We undertook the analysis of the legislative acts currently in force in the Republic of Kazakhstan pertinent to the training of the expert and pedagogical personnel for the forensic medical services with special reference to their advantages and disadvantages from the standpoint of legal regulation of the activities in this sphere. The problems of staffing support of expert practice are illustrated on the example of activities of the Almaty branch of the Centre of Forensic Medicine of the Kazakh Ministry of Justice. The approaches to the solution of these problems are proposed. PMID- 27981965 TI - [The histological changes in the stomach associated with death from overcooling at the site of discovery of the corpse and at the stage of hospitalization]. AB - The objective of the present publication was the description of the histological changes in the gastric structures revealed after the death of the victims of overcooling at the site of discovery of the corpse and at the stage of hospitalization. The stomachs of the subjects found at the place of death from overcooling in the absence of concomitant pathological findings were characterized by a diagnostic complex of pathomorphological changes peculiar to this form of death. The expression of separate signs forming the diagnostic complex decreased in the subjects with chronic atrophic gastritis and the concurrent structural reorganization of the organ. The high concentration of ethyl alcohol in the blood is associated with enhanced permeability of the vessels. The analysis of the relevant literature publications and the results of original morphological studies of the cases of death from overcooling at the stage of hospitalization after cessation of the influence of cold made it possible to elucidate dynamics of histological changes in the stomach. These data taken together with information from other sources allow to evaluate the lifetime effects of cold and the duration of its action under extreme conditions as well as to prognosticate the development of pathological processes. PMID- 27981967 TI - Cooperative redox activation for carbon dioxide conversion. AB - A longstanding challenge in production chemistry is the development of catalytic methods for the transformation of carbon dioxide into useful chemicals. Silane and borane promoted reductions can be fined-tuned to provide a number of C1 building blocks under mild conditions, but these approaches are limited because of the production of stoichiometric waste compounds. Here we report on the conversion of CO2 with diaryldisilanes, which through cooperative redox activation generate carbon monoxide and a diaryldisiloxane that actively participate in a palladium-catalysed carbonylative Hiyama-Denmark coupling for the synthesis of an array of pharmaceutically relevant diarylketones. Thus the disilane reagent not only serves as the oxygen abstracting agent from CO2, but the silicon-containing 'waste', produced through oxygen insertion into the Si-Si bond, participates as a reagent for the transmetalation step in the carbonylative coupling. Hence this concept of cooperative redox activation opens up for new avenues in the conversion of CO2. PMID- 27981968 TI - Single-cell exome sequencing identifies mutations in KCP, LOC440040, and LOC440563 as drivers in renal cell carcinoma stem cells. PMID- 27981971 TI - Erratum: Molecular basis of cooperativity in pH-triggered supramolecular self assembly. PMID- 27981969 TI - Innate immune signaling and regulation in cancer immunotherapy. AB - A pre-existing T cell-inflamed tumor microenvironment has prognostic utility and also can be predictive for response to contemporary cancer immunotherapies. The generation of a spontaneous T cell response against tumor-associated antigens depends on innate immune activation, which drives type I interferon (IFN) production. Recent work has revealed a major role for the STING pathway of cytosolic DNA sensing in this process. This cascade of events contributes to the activation of Batf3-lineage dendritic cells (DCs), which appear to be central to anti-tumor immunity. Non-T cell-inflamed tumors lack chemokines for Batf3 DC recruitment, have few Batf3 DCs, and lack a type I IFN gene signature, suggesting that failed innate immune activation may be the ultimate cause for lack of spontaneous T cell activation and accumulation. With this information in hand, new strategies for triggering innate immune activation and Batf3 DC recruitment are being developed, including novel STING agonists for de novo immune priming. Ultimately, the successful development of effective innate immune activators should expand the fraction of patients that can respond to immunotherapies, such as with checkpoint blockade antibodies. PMID- 27981972 TI - What preventive care do sedated children with caries referred to specialist services need? AB - Introduction Few studies have assessed the preventive needs of children treated under conscious sedation or their parents'/guardians' views regarding oral health education.Aim To report on the profile of children who required treatment under conscious sedation. Also to obtain the views of the parents or guardians of these children on their experiences of oral health preventive services and the support they would like in order to improve their child's oral health.Method A researcher administered questionnaire was used to collect quantitative and qualitative responses from a consecutive sample of 123 parents/guardians during their child's sedation appointment at King's College Hospital.Results Caries was the main reason for the child's sedation treatment and 77.2% of them were high caries risk. Parents reported that their general dentist had given advice about sugar (80%) and tooth-brushing (74%), but few had prescribed fluoride varnish (15%), fissure sealants (12%) or a fluoride rinse (36%). Parents felt challenged by the ready availability of sugar, and others suggested difficulty in maintaining healthy oral habits in complex families. Overall, the majority of parents thought leaflets, health professionals' advice, and Internet websites could be informative, and they requested school- and hospital-based prevention programmes.Discussion The majority of children had high caries risk. They had received advice but not professional preventive treatment such as fluoride varnish and fissure sealants. Their parents requested preventive education using new technologies and media and better access through school-based and hospital prevention programmes. PMID- 27981973 TI - Dental trauma: Ho, ho, hospitalised. PMID- 27981970 TI - Time Series miRNA-mRNA integrated analysis reveals critical miRNAs and targets in macrophage polarization. AB - Polarization of macrophages is regulated through complex signaling networks. Correlating miRNA and mRNA expression over time after macrophage polarization has not yet been investigated. We used paired RNA-Seq and miRNA-Seq experiments to measure the mRNA and miRNA expression in bone marrow-derived macrophages over a time-series of 8 hours. Bioinformatics analysis identified 31 differentially expressed miRNAs between M1 and M2 polarized macrophages. The top 4 M1 miRNAs (miR-155-3p, miR-155-5p, miR-147-3p and miR-9-5p) and top 4 M2 miRNAs (miR-27a 5p, let-7c-1-3p, miR-23a-5p and miR-23b-5p) were validated by qPCR. Interestingly, M1 specific miRNAs could be categorized to early- and late response groups, in which three new miRNAs miR-1931, miR-3473e and miR-5128 were validated as early-response miRNAs. M1 polarization led to the enrichment of genes involved in immune responses and signal transduction, whereas M2 polarization enriched genes involved in cell cycle and metabolic processes. C2H2 zinc-finger family members are key targets of DE miRNAs. The integrative analysis between miRNAs and mRNAs demonstrates the regulations of miRNAs on nearly four thousand differentially expressed genes and most of the biological pathways enriched in macrophage polarization. In summary, this study elucidates the expression profiles of miRNAs and their potential targetomes during macrophage polarization. PMID- 27981974 TI - On your marks, get set... ROT! PMID- 27981978 TI - Working together to share the dental neglect. AB - This safeguarding in dentistry article encourages wider healthcare information sharing in dental neglect in children. It describes the development of a local procedure for healthcare information sharing following dental extraction in children under general anaesthetic. This appropriate information sharing may be used to inform healthcare practitioners' assessments of the health needs of the child, family support and education, or for safeguarding purposes. PMID- 27981979 TI - Oral health: Case report: Unusual sugar binge. PMID- 27981982 TI - Study examines the gingivae of gummy bears. PMID- 27981981 TI - Sugar to be stamped out of children's books. PMID- 27981992 TI - Special feature: A Christmas story for the chairside. PMID- 27981991 TI - Shortage of staff caused by Christmas party excess. PMID- 27981989 TI - Working conditions: Elfless hard labour. PMID- 27981983 TI - Shading concepts and layering techniques to master direct anterior composite restorations: an update. AB - Creating perfect direct composite restorations has been for long time a strict challenge due to many materials' limitations impacting either shade integration or surface quality, and possibly colour stability. Next to technological drawbacks, a certain complexity and lack of predictability in clinical application was inherent to the technique and made it elitist for a long time. Shading and layering concepts then progressively evolved from a simplistic, non histo-anatomical, bilaminar technique to a multi-layering approach (3 to 4 or more layers), following the Vita ClassicTM system. One of the most achieved concepts is polychromatic layering which makes use of a variable number of layers (basically VITATM or non-VITATM opacious dentin, chromatic enamel and translucent/opalescent enamel), driven by the natural tooth optical composition. In parallel with this evolution, a simplified, non-VITA shading system was developed with a reduced number of layers (basically dentin &enamel layer, plus effect shades if required) known as the natural layering concept, aiming to the same optimal esthetic integration and natural colour reproduction/emulation. The latest improvements appear all driven by the same view of improved reliability and clinical simplification. PMID- 27981994 TI - Christmas White Paper. PMID- 27981995 TI - A dentist's life: I'm not heavy, I'm a dentist. PMID- 27981996 TI - Clinical decision making - choosing between intuition, experience and scientific evidence. AB - Intuition usually results in poorer decisions than an evidence-based decision making process. However, research has shown there are certain circumstances when intuition is equivalent or superior to evidence based decision-making. The first pre-requisite is domain expertise and being a dentist is insufficient - a minimum of five years additional practicing experience is needed. Intuition allows the expert to store information in subconscious frameworks and extract that data without conscious thought at a rapid rate. Decisions that have severe time constraints, problems that are complex and ambiguous in nature, and a lack of scientific evidence are some factors that are suitable for intuition-based clinical decision-making. PMID- 27981999 TI - A new definition for oral health developed by the FDI World Dental Federation opens the door to a universal definition of oral health. AB - This article first published as an editorial in the Journal of the American Dental Association presents the FDI World Dental Federation's universal definition of oral health. This new definition was approved in September 2016 and developed as as part of the FDI's advocacy and strategic plan - Vision 2020. PMID- 27982003 TI - Tooth fairies hit by recession. PMID- 27982004 TI - Coins should be banned from Christmas puds. PMID- 27982000 TI - Gastrointestinal diseases and their oro-dental manifestations: Part 1: Crohn's disease. AB - Widely varying prevalence rates of oral lesions in patients with Crohn's disease have been reported, ranging from 0.5% to 37%. These manifestations may coincide with or precede intestinal symptoms. Oral manifestations can be classified as specific lesions, when macroscopic examination shows similar changes to those observed endoscopically in the intestine, and non-specific lesions including aphthous ulcerations. The most frequently observed oral lesions are oedema, ulcers and hyperplastic lesions on the buccal mucosa. In most patients these lesions are asymptomatic, however, some patients may experience discomfort. In this review we describe the most relevant oro-dental manifestations observed in patients with Crohn's disease and discuss the potential implications for oro dental management. PMID- 27982005 TI - What's in a name? Nominative determinism in the UK dental workforce. AB - Background Nominative determinism describes the theory that people are more likely to pursue careers that are connected to their names. Compelling research has been carried out across the medical professions that provides strong evidence for this phenomenon, but as yet its applicability to the UK dental workforce remains unknown.Aim The aim of this study was to establish the prevalence of dentally-related surnames in the UK dental workforce (dentists and dental care professionals) and compare this to the UK population.Results Dentistry may provide a surprising counter-example to prevailing theories of nominative determinism, as UK dentists are significantly less likely than the UK general population to have dentally-related surnames. This new phenomenon of 'nominative antideterminism' was not observed in the dental care professional (DCP) cohort, for whom the prevalence of dentally-related surnames was similar to that in the wider UK population. PMID- 27982009 TI - Brexism and bruxism. PMID- 27982012 TI - Infection control: Mistletoe threat. PMID- 27982007 TI - Motivational interviewing in general dental practice: A review of the evidence. AB - Objectives The objective of this study was to systematically review the evidence regarding the use of motivational interviewing in the context of general dental practice, in order that practitioners can decide whether it might be an important skill to develop within their practices.Data sources The results reported in this study form part of a larger systematic review which sought to identify whether oral health promotion within dental practice is effective and how its effects can be optimised. Here, we focus on the papers describing motivational interviewing in dental practice published since 1994. The systematic review included searches of 20 online resources (including Ovid Medline and Embase).Data selection Papers which were not about oral health promotion and did not apply the behavioural and psychological theories, which underpin motivational interviewing, were excluded.Data synthesis This review included eight papers all of which were considered to be of robust quality, in terms of their research methods and seven of which were considered to offer externally valid findings. Five described randomised controlled trials and all of these RCTs demonstrated that interventions including motivational interviewing had a positive effect on oral health and health behaviour.Conclusions This review shows that the motivational interviewing technique, which is based on the concept of autonomy support, has potential for helping patients with poor oral health. Training in motivational interviewing for dental personnel could be a very useful addition to the skill set of practitioners and dental teams. PMID- 27982013 TI - Inter-proximal enamel reduction in contemporary orthodontics. AB - Inter-proximal enamel reduction has gained increasing prominence in recent years being advocated to provide space for orthodontic alignment, to refine contact points and to potentially improve long-term stability. An array of techniques and products are available ranging from hand-held abrasive strips to handpiece mounted burs and discs. The indications for inter-proximal enamel reduction and the importance of formal space analysis, together with the various techniques and armamentarium which may be used to perform it safely in both the labial and buccal segments are outlined. PMID- 27982015 TI - Evolution of multiple cell clones over a 29-year period of a CLL patient. AB - Chronic lymphocytic leukaemia (CLL) is a frequent B-cell malignancy, characterized by recurrent somatic chromosome alterations and a low level of point mutations. Here we present single-nucleotide polymorphism microarray analyses of a single CLL patient over 29 years of observation and treatment, and transcriptome and whole-genome sequencing at selected time points. We identify chromosome alterations 13q14-, 6q- and 12q+ in early cell clones, elimination of clonal populations following therapy, and subsequent appearance of a clone containing trisomy 12 and chromosome 10 copy-neutral loss of heterogeneity that marks a major population dominant at death. Serial single-cell RNA sequencing reveals an expression pattern with high FOS, JUN and KLF4 at disease acceleration, which resolves following therapy, but reoccurs following relapse and death. Transcriptome evolution indicates complex changes in expression occur over time. In conclusion, CLL can evolve gradually during indolent phases, and undergo rapid changes following therapy. PMID- 27982014 TI - Monocyte-derived inflammatory Langerhans cells and dermal dendritic cells mediate psoriasis-like inflammation. AB - Dendritic cells (DCs) have been implicated in the pathogenesis of psoriasis but the roles for specific DC subsets are not well defined. Here we show that DCs are required for psoriasis-like changes in mouse skin induced by the local injection of IL-23. However, Flt3L-dependent DCs and resident Langerhans cells are dispensable for the inflammation. In epidermis and dermis, the critical DCs are TNF-producing and IL-1beta-producing monocyte-derived DCs, including a population of inflammatory Langerhans cells. Depleting Ly6Chi blood monocytes reduces DC accumulation and the skin changes induced either by injecting IL-23 or by application of the TLR7 agonist imiquimod. Moreover, we find that IL-23-induced inflammation requires expression of CCR6 by DCs or their precursors, and that CCR6 mediates monocyte trafficking into inflamed skin. Collectively, our results imply that monocyte-derived cells are critical contributors to psoriasis through production of inflammatory cytokines that augment the activation of skin T cells. PMID- 27982018 TI - SiO2@antisense molecules covered by nepetalactone, extracted from Nepeta gloeocephala, inhibits ILK phosphorylation and downstream PKB/AKT signaling in HeLa cells. AB - In this study, the anticancer property of SiO2@antisense molecules (SiO2@AMs) and SiO2@AM covered by nepetalactone (SiO2@AM/CN), extracted from Nepeta gloeocephala, was investigated. Here integrin-linked kinase (ILK) phosphorylation and protein kinase B/AKT (PKB/AKT) signaling was studied when HeLa cells were exposed to SiO2@AM and SiO2@AM/CN. First, N. gloeocephala was identified at the Iranian National Herbarium. Then, its essential oil (EO) was obtained by the hydrodistillation method. In the next step, 4aalpha,7alpha,7aalpha-nepetalactone was extracted from the EO, based on the spectroscopic data. To obtain SiO2@AM/CN, 1 ml of SiO2@AM was mixed with extracted nepetalactone and then strongly shaken for 30 min. Finally, serial concentrations (100, 50, 25 and 12.5 MUg ml-1) of SiO2@AM and SiO2@AM/CN were prepared and then exposed to HeLa cells (2 * 105 cells per ml) for 24 h at 37 degrees C. After incubation, 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell-cycle analysis, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and western blots were carried out. To find ILK phosphorylation and PKB/AKT signaling, the expression of threonine-173 (Thr-173), serine-246 (Ser-246), total ILK, AKT Ser473, AKT-Thr308 and total AKT was investigated. HeLa cells that were treated with SiO2@AM/CN had G2/M arrest. Based on the TUNEL assay, many apoptotic cells have been shown when they were exposed to SiO2@AM/CN. Importantly, SiO2@AM/CN decreased ILK phosphorylation at Thr-173 and Ser-246 without affecting total ILK levels. Moreover, SiO2@AM/CN decreased AKT-Ser473 and AKT-Thr308 phosphorylation without affecting total PKB/AKT protein. PMID- 27982016 TI - Exosomes and breast cancer: a comprehensive review of novel therapeutic strategies from diagnosis to treatment. AB - Exosomes are nanosized vesicles, released by various cells, which have essential roles in intercellular communication locally and systemically through transporting their contents such as proteins and lipids as well as RNA. It was clear that the element of contents in exosomes reassembled with the emerging of cancers. Over the past decade, researchers paid more attention to the role of exosomes in breast cancer. The purpose of this review was to discuss the details of the biological characteristics of exosomes in breast cancer. The discussion would focus on the role of exosomes in breast cancer development, progression, metastasis and drug resistance, as well as related therapeutic and diagnostic strategies. PMID- 27982017 TI - Extracellular vesicle-mediated suicide mRNA/protein delivery inhibits glioblastoma tumor growth in vivo. AB - Extracellular vesicles (EVs) are considered as important mediators of intercellular communication, which carry a diverse repertoire of genetic information between cells. This feature of EVs can be used and improved to advance their therapeutic potential. We have previously shown that genetically engineered EVs carrying the suicide gene mRNA and protein-cytosine deaminase (CD) fused to uracil phosphoribosyltransferase (UPRT)-inhibited schwannoma tumor growth in vivo. To further examine whether this approach can be applied to other cancer types, we established a subcutaneous xenograft glioblastoma tumor model in mice, as glioblastoma represents the most common primary brain tumor, which is highly aggressive compared with the original schwannoma tumor model. U87-MG glioblastoma cells were implanted into the flanks of nude SCID mice, and the animals were intratumorally injected with the EVs isolated from the cells expressing EGFP or CD-UPRT. After the intraperitoneal administration of the prodrug 5-fluorocytosine, the tumor growth was assessed by regular caliper measurements. Our data revealed that the treatment with the CD-UPRT-enriched EVs significantly reduced the tumor growth in mice. Taken together, our findings suggest that EVs uploaded with therapeutic CD-UPRT mRNA/protein may be a useful tool for glioblastoma treatment. PMID- 27982019 TI - The associations of TERT-CLPTM1L variants and TERT mRNA expression with the prognosis of early stage non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer-related death in the world. Several genome-wide association studies (GWAS) have identified TERT-CLPTM1L as plausible causative locus for lung cancer development. This study aimed to investigate the associations of genetic variations in TERT-CLPTM1L and the expression level of TERT with the survival of early stage non-small cell lung cancer (NSCLC) patients. We selected three single-nucleotide polymorphisms of TERT-CLPTM1L (rs2853669, rs2736108 and rs31490) and genotyped in 140 early stage NSCLC patients by TaqMan assay. Associations between these variations and survival outcome of early stage NSCLC patients were further investigated. We also used TCGA data to evaluate the associations of TERT messenger RNA (mRNA) expression and survival outcome of early stage NSCLC patients. Survival analysis showed that, compared with early NSCLC patients carrying TERT rs2853669 TT+TC genotypes, patients with rs2853669 CC genotype had significantly longer median survival time (MST=102.2 vs 52.4 months; log-rank P=0.028) and lower death risk [hazard ratio (HR) with 95% confidence interval (CI))=0.38(0.17-0.82), P=0.014]. Early NSCLC patients carrying TERT rs2736108 AA genotype had significantly shorter MST (MST=29.0 vs 63.3 months; log-rank P=0.020) and increased death risk [HR (95% CI)=2.22(1.01-5.80), P=0.046], when compared with patients carrying rs2736108 GG genotypes. TCGA data revealed that early NSCLC patients with higher expression level of TERT mRNA in lung tumor tissues had a longer MST and decreased death risk than those with low expression level of TERT mRNA [MST=54.4 vs 49.0 months; log-rank P=0.041; adjusted HR (95% CI)=0.68(0.50-0.94)]. These findings may add potential evidence to understand the prognostic value of TERT and provide a new prospect of individualized prevention and treatment for early stage NSCLC. PMID- 27982021 TI - Circulating exosomes and exosomal microRNAs as biomarkers in gastrointestinal cancer. AB - The most important biological function of exosomes is their possible use as biomarkers in clinical diagnosis. Compared with biomarkers identified in conventional specimens such as serum or urine, exosomal biomarkers provide the highest amount of sensitivity and specificity, which can be attributed to their excellent stability. Exosomes, which harbor different types of proteins, nucleic acids and lipids, are present in almost all bodily fluids. The molecular constituents of exosomes, especially exosomal proteins and microRNAs (miRNAs), are promising as biomarkers in clinical diagnosis. This discovery that exosomes also contain messenger RNAs and miRNAs shows that they could be carriers of genetic information. Although the majority of RNAs found in exosomes are degraded RNA fragments with a length of <200 nucleotides, some full-length RNAs might be present that may affect protein production in the recipient cell. In addition, exosomal miRNAs have been found to be associated with certain diseases. Several studies have pointed out miRNA contents of circulating exosomes that are similar to those of originating cancer cells. In this review, the recent advances in circulating exosomal miRNAs as biomarkers in gastrointestinal cancers are discussed. These studies indicated that miRNAs can be detected in exosomes isolated from body fluids such as saliva, which suggests potential advantages of using exosomal miRNAs as noninvasive novel biomarkers. PMID- 27982020 TI - Intrabody targeting vascular endothelial growth factor receptor-2 mediates downregulation of surface localization. AB - Angiogenesis is among the most important mechanisms that helps cancer cells to survive, grow and undergo metastasis. Therefore, inhibiting angiogenesis will suppress tumor growth. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are believed to be important players of angiogenesis. The goal of this study was to evaluate the success of a novel nanobody against VEGFR2 in tethering its target inside the endoplasmic reticulum and preventing its transport to the cell membrane. Nanobody sequence was cloned in a mammalian vector in fusion with green fluorescent protein and a KDEL retention signal. After transfection of 293KDR cells with this expression vector, surface localization of VEGFR2 was monitored by flow cytometry. This study demonstrates that our intrananobody is effective in targeting VEGFR2 receptor, and therefore, it is a powerful tool to downregulate a surface-exposed target protein, and in this capacity, it has potential to be used as a therapeutic protein to inhibit growth of tumors. PMID- 27982022 TI - How types of premises modulate the typicality effect in category-based induction: diverging evidence from the P2, P3, and LPC effects. AB - Behavioural studies have indicated that semantic typicality influences processing time and accuracy during the performance of inductive reasoning (i.e., the typicality effect). The present study examines this effect by manipulating the types of premises and conclusions (i.e., general, typical, or atypical) at an electrophysiological level using a semantic category-based induction task. With regard to behavioural results, higher inductive strength was found in typical conclusions in all premise conditions, whereas a longer response time for atypical conclusions was only found in general and typical premise conditions. The ERP results had different response patterns: in the general premise condition, a larger P2, as well as a smaller P3 and LPC (500-600 ms), were elicited by atypical conclusions relative to typical ones; in the typical premise condition, a larger P2 and LPC (600-700 ms) were found for atypical conclusions; in the atypical premise condition, however, only a larger P2 was found for atypical conclusions. The divergent evidence for the typicality effect indicated that the processing of the typicality effect in general, and specific premise conditions, might involve different cognitive processes, such as resource allocation and inference violation, which yielded new insights into the neural underpinnings of the typicality effect in a category-based induction. PMID- 27982023 TI - Spatial signalling mediated by the transforming growth factor-beta signalling pathway during tooth formation. AB - Tooth development relies on sequential and reciprocal interactions between the epithelial and mesenchymal tissues, and it is continuously regulated by a variety of conserved and specific temporal-spatial signalling pathways. It is well known that suspensions of tooth germ cells can form tooth-like structures after losing the positional information provided by the epithelial and mesenchymal tissues. However, the particular stage in which the tooth germ cells start to form tooth like structures after losing their positional information remains unclear. In this study, we investigated the reassociation of tooth germ cells suspension from different morphological stages during tooth development and the phosphorylation of Smad2/3 in this process. Four tooth morphological stages were designed in this study. The results showed that tooth germ cells formed odontogenic tissue at embryonic day (E) 14.5, which is referred to as the cap stage, and they formed tooth-like structures at E16.5, which is referred to as the early bell stage, and E18.5, which is referred to as the late bell stage. Moreover, the transforming growth factor-beta signalling pathway might play a role in this process. PMID- 27982025 TI - Morphological characterization of colorectal cancers in The Cancer Genome Atlas reveals distinct morphology-molecular associations: clinical and biological implications. AB - The Cancer Genome Atlas data on colorectal carcinoma have provided a comprehensive view of the tumor's genomic alterations and their tumorigenic roles. Tumor morphology, however, has not been fully integrated into the analysis. The aim of this study was to explore relevant associations between tumor morphology and the newly characterized genomic alterations in colorectal carcinoma. Two hundred and seven colorectal carcinomas that had undergone whole exome sequencing as part of The Cancer Genome Atlas project and had adequate virtual images in the cBioPortal for Cancer Genomics constituted our study population. Upon analysis, a tight association between 'microsatellite instability-high histology' and microsatellite instability-high (P<0.001) was readily detected and helped validate our image-based histology evaluation. Further, we showed, (1) among all histologies, the not otherwise specified type had the lowest overall mutation count (P<0.001 for entire cohort, P<0.03 for the microsatellite-instable group), and among the microsatellite-instable tumors, this type also correlated with fewer frameshift mutations in coding mononucleotide repeats of a defined set of relevant genes (P<0.01); (2) cytosine phosphate guanine island methylator phenotype-high colorectal cancers with or without microsatellite instability tended to have different histological patterns: the former more often mucinous and the latter more often not otherwise specified; (3) mucinous histology was associated with more frequent alterations in BRAF, PIK3CA, and the transforming growth factor-beta pathway when compared with non-mucinous histologies (P<0.001, P=0.01, and P<0.001, respectively); and (4) few colorectal cancers (<9%) exhibited upregulation of immune-inhibitory genes including major immune checkpoints; these tumors were primarily microsatellite-instable (up to 43%, vs <3% in microsatellite-stable group) and had distinctly non-mucinous histologies with a solid growth. These morphology molecular associations are interesting and propose important clinical implications. The morphological patterns associated with alterations of immune checkpoint genes bear the potential to guide patient selection for clinical trials that target immune checkpoints in colorectal cancer, and provide directions for future studies. PMID- 27982024 TI - Epstein-Barr virus-positive follicular lymphoma. AB - Epstein-Barr virus (EBV) -associated follicular lymphoma is only rarely reported. Herein, we report the largest series analyzing prevalence and clinicopathologic characteristics of EBV-associated follicular lymphoma occurring in unselected cases. Out of 382 analyzed cases, 10 EBV-positive follicular lymphomas were identified (prevalence=2.6%, 95% confidence interval 1.3-4.0%). All EBV-positive follicular lymphomas showed EBV-encoded small RNA-positive lymphoma cells present in a follicular distribution. Of these, eight also had tissue available for testing of expression of latent membrane protein 1 (LMP1), out of which six (75%) were positive. There was a significant association with grades 3A-3B follicular lymphoma (P<0.0001) and CD30 expression (P=0.0002). EBV-positive follicular lymphomas were otherwise morphologically and immunophenotypically indistinguishable from EBV-negative cases of similar grade. Nine of the EBV positive follicular lymphomas occurred in patients with no known history of immunosuppression, while one patient had a history of hydroxychloroquine administration for Sjogren's syndrome. The mean age in the EBV-positive and negative follicular lymphomas was 56 (range 31-83 years) and 49 years (range 25 92 years), respectively, with no statistically significant difference. Seven of the patients with EBV-positive follicular lymphoma had additional biopsies from different time points available for review, all of which showed progression of disease in the form of progression of tumor grade. Five of these progressed to diffuse large B-cell lymphoma, one of which had tissue available for testing and was EBV-positive. Our findings suggest that EBV infection may have a role in lymphomagenesis and/or disease progression in a subset of follicular lymphomas, thereby expanding the spectrum of recognized EBV-associated B-cell lymphomas. PMID- 27982026 TI - Mechanism of internal browning of pineapple: The role of gibberellins catabolism gene (AcGA2ox) and GAs. AB - Internal browning (IB), a physiological disorder (PD) that causes severe losses in harvested pineapple, can be induced by exogenous gibberellins (GAs). Over the years, studies have focused on roles of Gibberellin 2-oxidase (GA2oxs), the major GAs catabolic enzyme in plants, in the regulation of changes in morphology or biomass. However, whether GA2oxs could regulate PD has not been reported. Here, a full-length AcGA2ox cDNA was isolated from pineapple, with the putative protein sharing 23.59% to 72.92% identity with GA2oxs from five other plants. Pineapples stored at 5 degrees C stayed intact, while those stored at 20 degrees C showed severe IB. Storage at 5 degrees C enhanced AcGA2ox expression and decreased levels of a GAs (GA4) 'compared with storage at 20 degrees C. However, at 20 degrees C, exogenous application of abscisic acid (ABA) significantly suppressed IB. ABA simultaneously upregulated AcGA2ox and reduced GA4. Ectopic expression of AcGA2ox in Arabidopsis resulted in reduced GA4, lower seed germination, and shorter hypocotyls and roots, all of which were restored by exogenous GA4/7. Moreover, in pineapple, GA4/7 upregulated polyphenol oxidase, while storage at 5 degrees C and ABA downregulated it. These results strongly suggest the involvement of AcGA2ox in regulation of GAs levels and a role of AcGA2ox in regulating IB. PMID- 27982027 TI - Engineering orthogonal dual transcription factors for multi-input synthetic promoters. AB - Synthetic biology has seen an explosive growth in the capability of engineering artificial gene circuits from transcription factors (TFs), particularly in bacteria. However, most artificial networks still employ the same core set of TFs (for example LacI, TetR and cI). The TFs mostly function via repression and it is difficult to integrate multiple inputs in promoter logic. Here we present to our knowledge the first set of dual activator-repressor switches for orthogonal logic gates, based on bacteriophage lambda cI variants and multi-input promoter architectures. Our toolkit contains 12 TFs, flexibly operating as activators, repressors, dual activator-repressors or dual repressor-repressors, on up to 270 synthetic promoters. To engineer non cross-reacting cI variants, we design a new M13 phagemid-based system for the directed evolution of biomolecules. Because cI is used in so many synthetic biology projects, the new set of variants will easily slot into the existing projects of other groups, greatly expanding current engineering capacities. PMID- 27982028 TI - A molecular and neuronal basis for amino acid sensing in the Drosophila larva. AB - Amino acids are important nutrients for animals, reflected in conserved internal pathways in vertebrates and invertebrates for monitoring cellular levels of these compounds. In mammals, sensory cells and metabotropic glutamate receptor-related taste receptors that detect environmental sources of amino acids in food are also well-characterised. By contrast, it is unclear how insects perceive this class of molecules through peripheral chemosensory mechanisms. Here we investigate amino acid sensing in Drosophila melanogaster larvae, which feed ravenously to support their rapid growth. We show that larvae display diverse behaviours (attraction, aversion, neutral) towards different amino acids, which depend upon stimulus concentration. Some of these behaviours require IR76b, a member of the variant ionotropic glutamate receptor repertoire of invertebrate chemoreceptors. IR76b is broadly expressed in larval taste neurons, suggesting a role as a co-receptor. We identify a subpopulation of these neurons that displays physiological activation by some, but not all, amino acids, and which mediate suppression of feeding by high concentrations of at least a subset of these compounds. Our data reveal the first elements of a sophisticated neuronal and molecular substrate by which these animals detect and behave towards external sources of amino acids. PMID- 27982030 TI - Electron energy-loss spectroscopy of branched gap plasmon resonators. AB - The miniaturization of integrated optical circuits below the diffraction limit for high-speed manipulation of information is one of the cornerstones in plasmonics research. By coupling to surface plasmons supported on nanostructured metallic surfaces, light can be confined to the nanoscale, enabling the potential interface to electronic circuits. In particular, gap surface plasmons propagating in an air gap sandwiched between metal layers have shown extraordinary mode confinement with significant propagation length. In this work, we unveil the optical properties of gap surface plasmons in silver nanoslot structures with widths of only 25 nm. We fabricate linear, branched and cross-shaped nanoslot waveguide components, which all support resonances due to interference of counter propagating gap plasmons. By exploiting the superior spatial resolution of a scanning transmission electron microscope combined with electron energy-loss spectroscopy, we experimentally show the propagation, bending and splitting of slot gap plasmons. PMID- 27982031 TI - Harnessing the natural inhibitory domain to control TNFalpha Converting Enzyme (TACE) activity in vivo. AB - Dysregulated activity of A Disintegrin And Metalloproteinase 17 (ADAM17)/TNFalpha Converting Enzyme (TACE) is associated with inflammatory disorders and cancer progression by releasing regulatory membrane-tethered proteins like TNFalpha, IL6R and EGFR ligands. Although specific inhibition of TACE is thought to be a viable strategy for inflammatory disorders and for malignancies treatment, the generation of effective inhibitors in vivo has been proven to be challenging. Here we report on the development of a protein inhibitor that leverages the endogenous modulator of TACE. We have generated a stable form of the auto inhibitory TACE prodomain (TPD), which specifically inhibits in vitro and cell surface TACE, but not the related ADAM10, and effectively modulated TNFalpha secretion in cells. TPD significantly attenuated TACE-mediated disease models of sepsis, rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), and reduced TNFalpha in synovial fluids from RA patients. Our results demonstrate that intervening with endogenous ADAM sheddase modulatory mechanisms holds potential as a general strategy for the design of ADAM inhibitors. PMID- 27982033 TI - Zinc isotope evidence for sulfate-rich fluid transfer across subduction zones. AB - Subduction zones modulate the chemical evolution of the Earth's mantle. Water and volatile elements in the slab are released as fluids into the mantle wedge and this process is widely considered to result in the oxidation of the sub-arc mantle. However, the chemical composition and speciation of these fluids, which is critical for the mobility of economically important elements, remain poorly constrained. Sulfur has the potential to act both as oxidizing agent and transport medium. Here we use zinc stable isotopes (delta66Zn) in subducted Alpine serpentinites to decipher the chemical properties of slab-derived fluids. We show that the progressive decrease in delta66Zn with metamorphic grade is correlated with a decrease in sulfur content. As existing theoretical work predicts that Zn-SO42- complexes preferentially incorporate heavy delta66Zn, our results provide strong evidence for the release of oxidized, sulfate-rich, slab serpentinite-derived fluids to the mantle wedge. PMID- 27982029 TI - GALNT14 promotes lung-specific breast cancer metastasis by modulating self renewal and interaction with the lung microenvironment. AB - Some polypeptide N-acetyl-galactosaminyltransferases (GALNTs) are associated with cancer, but their function in organ-specific metastasis remains unclear. Here, we report that GALNT14 promotes breast cancer metastasis to the lung by enhancing the initiation of metastatic colonies as well as their subsequent growth into overt metastases. Our results suggest that GALNT14 augments the self-renewal properties of breast cancer cells (BCCs). Furthermore, GALNT14 overcomes the inhibitory effect of lung-derived bone morphogenetic proteins (BMPs) on self renewal and therefore facilitates metastasis initiation within the lung microenvironment. In addition, GALNT14 supports continuous growth of BCCs in the lung by not only inducing macrophage infiltration but also exploiting macrophage derived fibroblast growth factors (FGFs). Finally, we identify KRAS-PI3K-c-JUN signalling as an upstream pathway that accounts for the elevated expression of GALNT14 in lung-metastatic BCCs. Collectively, our findings uncover an unprecedented role for GALNT14 in the pulmonary metastasis of breast cancer and elucidate the underlying molecular mechanisms. PMID- 27982032 TI - Transport of lipophilic carboxylates is mediated by transmembrane helix 2 in multidrug transporter AcrB. AB - The deployment of multidrug efflux pumps is a powerful defence mechanism for Gram negative bacterial cells when exposed to antimicrobial agents. The major multidrug efflux transport system in Escherichia coli, AcrAB-TolC, is a tripartite system using the proton-motive force as an energy source. The polyspecific substrate-binding module AcrB uses various pathways to sequester drugs from the periplasm and outer leaflet of the inner membrane. Here we report the asymmetric AcrB structure in complex with fusidic acid at a resolution of 2.5 A and mutational analysis of the putative fusidic acid binding site at the transmembrane domain. A groove shaped by the interface between transmembrane helix 1 (TM1) and TM2 specifically binds fusidic acid and other lipophilic carboxylated drugs. We propose that these bound drugs are actively displaced by an upward movement of TM2 towards the AcrB periplasmic porter domain in response to protonation events in the transmembrane domain. PMID- 27982034 TI - A TLR9 agonist promotes IL-22-dependent pancreatic islet allograft survival in type 1 diabetic mice. AB - Pancreatic islet transplantation is a promising potential cure for type 1 diabetes (T1D). Islet allografts can survive long term in the liver parenchyma. Here we show that liver NK1.1+ cells induce allograft tolerance in a T1D mouse model. The tolerogenic effects of NK1.1+ cells are mediated through IL-22 production, which enhances allograft survival and increases insulin secretion. Increased expression of NKG2A by liver NK1.1+ cells in islet allograft transplanted mice is involved in the production of IL-22 and in the reduced inflammatory response to allografts. Vaccination of T1D mice with a CpG oligonucleotide TLR9 agonist (ODN 1585) enhances expansion of IL-22-producing CD3 NK1.1+ cells in the liver and prolongs allograft survival. Our study identifies a role for liver NK1.1+ cells, IL-22 and CpG oligonucleotides in the induction of tolerance to islet allografts in the liver parenchyma. PMID- 27982035 TI - Global repositioning of transcription start sites in a plant-fermenting bacterium. AB - Bacteria respond to their environment by regulating mRNA synthesis, often by altering the genomic sites at which RNA polymerase initiates transcription. Here, we investigate genome-wide changes in transcription start site (TSS) usage by Clostridium phytofermentans, a model bacterium for fermentation of lignocellulosic biomass. We quantify expression of nearly 10,000 TSS at single base resolution by Capp-Switch sequencing, which combines capture of synthetically capped 5' mRNA fragments with template-switching reverse transcription. We find the locations and expression levels of TSS for hundreds of genes change during metabolism of different plant substrates. We show that TSS reveals riboswitches, non-coding RNA and novel transcription units. We identify sequence motifs associated with carbon source-specific TSS and use them for regulon discovery, implicating a LacI/GalR protein in control of pectin metabolism. We discuss how the high resolution and specificity of Capp-Switch enables study of condition-specific changes in transcription initiation in bacteria. PMID- 27982036 TI - Interplay of Dirac electrons and magnetism in CaMnBi2 and SrMnBi2. AB - Dirac materials exhibit intriguing low-energy carrier dynamics that offer a fertile ground for novel physics discovery. Of particular interest is the interplay of Dirac carriers with other quantum phenomena such as magnetism. Here we report on a two-magnon Raman scattering study of AMnBi2 (A=Ca, Sr), a prototypical magnetic Dirac system comprising alternating Dirac carrier and magnetic layers. We present the first accurate determination of the exchange energies in these compounds and, by comparison with the reference compound BaMn2Bi2, we show that the Dirac carrier layers in AMnBi2 significantly enhance the exchange coupling between the magnetic layers, which in turn drives a charge gap opening along the Dirac locus. Our findings break new grounds in unveiling the fundamental physics of magnetic Dirac materials, which offer a novel platform for probing a distinct type of spin-Fermion interaction. The results also hold great promise for applications in magnetic Dirac devices. PMID- 27982039 TI - Lymphoma: Now you see it... PMID- 27982038 TI - Release of Plasmodium sporozoites requires proteins with histone-fold dimerization domains. AB - The sporozoite, the stage of the malaria parasite transmitted by the mosquito, first develops for ~2 weeks in an oocyst. Rupture of the oocyst capsule is required for release of sporozoites, which then transfer to the salivary gland where they are injected into a new host. Here we identify two parasite proteins that we call oocyst rupture proteins 1 (ORP1) and ORP2. These proteins have a histone-fold domain (HFD) that promotes heterodimer formation in the oocyst capsule at the time of rupture. Oocyst rupture is prevented in mutants lacking either protein. Mutational analysis confirms the HFD as essential for ORP1 and ORP2 function, and heterodimer formation was verified in vitro. These two proteins are potential targets for blocking transmission of the parasite in the mosquito. PMID- 27982037 TI - Proteomic analysis of scallop hepatopancreatic extract provides insights into marine polysaccharide digestion. AB - Marine polysaccharides are used in a variety of applications, and the enzymes that degrade these polysaccharides are of increasing interest. The main food source of herbivorous marine mollusks is seaweed, and several polysaccharide degrading enzymes have been extracted from mollusk digestive glands (hepatopancreases). Here, we used a comprehensive proteomic approach to examine the hepatopancreatic proteins of the Zhikong scallop (Chlamys farreri). We identified 435 proteins, the majority of which were lysosomal enzymes and carbohydrate and protein metabolism enzymes. However, several new enzymes related to polysaccharide metabolism were also identified. Phylogenetic and structural analyses of these enzymes suggest that these polysaccharide-degrading enzymes may have a variety of potential substrate specificities. Taken together, our study characterizes several novel polysaccharide-degrading enzymes in the scallop hepatopancreas and provides an enhanced view of these enzymes and a greater understanding of marine polysaccharide digestion. PMID- 27982042 TI - Parkinson disease: Could gut microbiota influence severity of Parkinson disease? PMID- 27982040 TI - Gene discovery in amyotrophic lateral sclerosis: implications for clinical management. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease predominantly affecting upper and lower motor neurons. The disease leads to relentlessly progressive weakness of voluntary muscles, with death typically resulting from diaphragmatic failure within 2-5 years. Since the discovery of mutations in SOD1, which account for ~2% of ALS cases, increasing efforts have been made to understand the genetic component of ALS risk, with the expectation that this insight will not only aid diagnosis and classification, but also guide personalized treatment and reveal the mechanisms that cause motor neuron death. In this Review, we outline previous and current efforts to characterize genes that are associated with ALS, describe current knowledge about the genetic architecture of ALS - including the relevance of family history - and the probable nature of future gene discoveries, and explore how our understanding of ALS genetics affects present and future clinical decisions. We observe that many gene variants associated with ALS have effect sizes between those of mutations that greatly increase risk and those of common variants that have a small effect on risk, and combine this observation with insights from next-generation sequencing to explore the implications for genetic counselling. PMID- 27982043 TI - Gene therapy: Gene-editing therapy for neurological disease. PMID- 27982044 TI - Clinical trials: To catch a crook, you might try statistics. PMID- 27982041 TI - Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours. AB - Standard treatment of primary and metastatic brain tumours includes high-dose megavoltage-range radiation to the cranial vault. About half of patients survive >6 months, and many attain long-term control or cure. However, 50-90% of survivors exhibit disabling cognitive dysfunction. The radiation-associated cognitive syndrome is poorly understood and has no effective prevention or long term treatment. Attention has primarily focused on mechanisms of disability that appear at 6 months to 1 year after radiotherapy. However, recent studies show that CNS alterations and dysfunction develop much earlier following radiation exposure. This finding has prompted the hypothesis that subtle early forms of radiation-induced CNS damage could drive chronic pathophysiological processes that lead to permanent cognitive decline. This Review presents evidence of acute radiation-triggered CNS inflammation, injury to neuronal lineages, accessory cells and their progenitors, and loss of supporting structure integrity. Moreover, injury-related processes initiated soon after irradiation could synergistically alter the signalling microenvironment in progenitor cell niches in the brain and the hippocampus, which is a structure critical to memory and cognition. Progenitor cell niche degradation could cause progressive neuronal loss and cognitive disability. The concluding discussion addresses future directions and potential early treatments that might reverse degenerative processes before they can cause permanent cognitive disability. PMID- 27982045 TI - A dissociation between consolidated perceptual learning and sensory adaptation in vision. AB - Perceptual learning refers to improvement in perception thresholds with practice, however, extended training sessions show reduced performance during training, interfering with learning. These effects were taken to indicate a tight link between sensory adaptation and learning. Here we show a dissociation between adaptation and consolidated learning. Participants trained with a texture discrimination task, in which visual processing time is limited by a temporal target-to-mask window defined as the Stimulus-Onset-Asynchrony (SOA). An initial training phase, previously shown to produce efficient learning, was followed by training structures with varying numbers of SOAs. Largest interference with learning was found in structures containing the largest SOA density, when SOA was gradually decreased. When SOAs were largely kept unchanged, learning was effective. All training structures yielded the same within-session performance reduction, as expected from sensory adaptation. The results point to a dissociation between within-day effects, which depend on the number of trials per se regardless of their temporal structure, and consolidation effects observed on the following day, which were mediated by the temporal structure of practice. These results add a new dimension to consolidation in perceptual learning, suggesting that the degree of its effectiveness depends on variations in temporal properties of the visual stimuli. PMID- 27982046 TI - Comprehensive phenotypic analysis of knockout mice deficient in cyclin G1 and cyclin G2. AB - Cyclin G1 (CycG1) and Cyclin G2 (CycG2) play similar roles during the DNA damage response (DDR), but their detailed roles remain elusive. To investigate their distinct roles, we generated knockout mice deficient in CycG1 (G1KO) or CycG2 (G2KO), as well as double knockout mice (DKO) deficient in both proteins. All knockouts developed normally and were fertile. Generation of mouse embryonic fibroblasts (MEFs) from these mice revealed that G2KO MEFs, but not G1KO or DKO MEFs, were resistant to DNA damage insults caused by camptothecin and ionizing radiation (IR) and underwent cell cycle arrest. CycG2, but not CycG1, co localized with gammaH2AX foci in the nucleus after gamma-IR, and gammaH2AX mediated DNA repair and dephosphorylation of CHK2 were delayed in G2KO MEFs. H2AX associated with CycG1, CycG2, and protein phosphatase 2A (PP2A), suggesting that gammaH2AX affects the function of PP2A via direct interaction with its B'gamma subunit. Furthermore, expression of CycG2, but not CycG1, was abnormal in various cancer cell lines. Kaplan-Meier curves based on TCGA data disclosed that head and neck cancer patients with reduced CycG2 expression have poorer clinical prognoses. Taken together, our data suggest that reduced CycG2 expression could be useful as a novel prognostic marker of cancer. PMID- 27982048 TI - Efficient generation of B2m-null pigs via injection of zygote with TALENs. AB - Donor major histocompatibility complex class I (MHC I) molecules are the main targets of the host immune response after organ allotransplantation. Whether and how MHC I-deficiency of pig donor tissues affects rejection after xenotransplantation has not been assessed. Beta2-microglobulin (B2M) is indispensable for the assembly of MHC I receptors and therefore provides an effective target to disrupt cell surface MHC I expression. Here, we report the one-step generation of mutant pigs with targeted disruptions in B2m by injection of porcine zygotes with B2m exon 2-specific TALENs. After germline transmission of mutant B2m alleles, we obtained F1 pigs with biallelic B2m frameshift mutations. F1 pigs lacked detectable B2M expression in tissues derived from the three germ layers, and their lymphocytes were devoid of MHC I surface receptors. Skin grafts from B2M deficient pigs exhibited remarkably prolonged survival on xenogeneic wounds compared to tissues of non-mutant littermates. Mutant founder pigs with bi-allelic disruption in B2m and B2M deficient F1 offspring did not display visible abnormalities, suggesting that pigs are tolerant to B2M deficiency. In summary, we show the efficient generation of pigs with germline mutations in B2m, and demonstrate a beneficial effect of donor MHC I-deficiency on xenotransplantation. PMID- 27982047 TI - A Clickable Analogue of Ketamine Retains NMDA Receptor Activity, Psychoactivity, and Accumulates in Neurons. AB - Ketamine is a psychotomimetic and antidepressant drug. Although antagonism of cell-surface NMDA receptors (NMDARs) may trigger ketamine's psychoactive effects, ketamine or its major metabolite norketamine could act intracellularly to produce some behavioral effects. To explore the viability of this latter hypothesis, we examined intracellular accumulation of novel visualizable analogues of ketamine/norketamine. We introduced an alkyne "click" handle into norketamine (alkyne-norketamine, A-NK) at the key nitrogen atom. Ketamine, norketamine, and A NK, but not A-NK-amide, showed acute and persisting psychoactive effects in mice. This psychoactivity profile paralleled activity of the compounds as NMDAR channel blockers; A-NK-amide was inactive at NMDARs, and norketamine and A-NK were active but ~4-fold less potent than ketamine. We incubated rat hippocampal cells with 10 MUM A-NK or A-NK-amide then performed Cu2+ catalyzed cycloaddition of azide-Alexa Fluor 488, which covalently attaches the fluorophore to the alkyne moiety in the compounds. Fluorescent imaging revealed intracellular localization of A-NK but weak A-NK-amide labeling. Accumulation was not dependent on membrane potential, NMDAR expression, or NMDAR activity. Overall, the approach revealed a correlation among NMDAR activity, intracellular accumulation/retention, and behavioral effects. Thus, we advance first generation chemical biology tools to aid in the identification of ketamine targets. PMID- 27982049 TI - Enhanced stability of freestanding lipid bilayer and its stability criteria. AB - We present a new strategy to dramatically enhance the stability of freestanding lipid bilayers. We found that an addition of a water in oil emulsion stabilizer, SPAN 80 to a solvent phase guarantees nearly millimeter-scale stable freestanding lipid bilayers. The water permeability, bilayer area, contact angle, and interfacial tension were measured as a function of time and SPAN 80-to-lipid weight ratio (PhiSPAN 80) with several different solvents. Surprisingly, the SPAN 80, instead of remaining in the bilayer, was moved out of the bilayer during the bilayer formation. Also we studied the effect of solvent on freestanding bilayer formation, and found that squalene was the only solvent that was not incorporated into the bilayer. The regime of stable bilayer formation was experimentally determined to be 3/1 < PhiSPAN 80 < 15/1, and we suggest general stability criteria for bilayer formation. This technique and the suggested stability criteria can be potentially helpful to many model membrane-based researches in life sciences, physical sciences and biomedical engineering fields. PMID- 27982051 TI - Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen. AB - High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification of 'hit' compounds. A pre-requisite to medicinal chemistry optimisation programmes required to improve the drug-like properties of a 'hit' molecule is identification of its mode of action. Herein, we have combined phenotypic screening with a biased target-specific screen. The inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 has been identified as a drugable target in Mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into lead-like molecules. This study has identified 7 new chemical series from a high throughput resistance-based phenotypic screen using Mycobacterium bovis BCG over expressing GuaB2. Hit compounds were identified in a single shot high-throughput screen, validated by dose response and subjected to further biochemical analysis. The compounds were also assessed using molecular docking experiments, providing a platform for their further optimisation using medicinal chemistry. This work demonstrates the versatility and potential of GuaB2 as an anti-tubercular drug target. PMID- 27982052 TI - Lateral optical binding between two colloidal particles. AB - An optical binding force between two nearby colloidal particles trapped by two coherent laser beams is measured by phase-sensitive detection. The binding force is long-range and spatially oscillatory. For identical linearly-polarized incident beams, the oscillation period is equal to the optical wavelength. For mutually perpendicular polarizations, a new force appears with half-wavelength periodicity, caused by double inter-particle scattering. This force is observable only with cross-polarized incident beams, for which the stronger single scattering forces are forbidden by parity. PMID- 27982050 TI - Immune Responses Induced by Recombinant Bacillus Subtilis Expressing the Hemagglutinin Protein of H5N1 in chickens. AB - To develop an effective, safe, and convenient vaccine for the prevention of highly pathogenic avian influenza (HPAI) H5N1, we have constructed a recombinant Bacillus subtilis strain (B.S.-HA) expressing the hemagglutinin (HA) protein. Then we evaluated the immune function in chicken bone marrow derived dendritic cells (BM-DCs), and the immune response after oral immunization. Our results show that the recombinant Bacillus subtilis B.S.-HA could be sampled by BM-DCs in vitro and increase the BM-DCs major histocompatibility complex (MHC) II phenotype. The weight, height of the small intestine villus, and lymphoid tissue area of the ileum increased significantly in B.S.-HA immunized chickens (P < 0.05 or P < 0.01). B.S.-HA induced the secretion of cytokines and the expression of Toll-like receptors in the trachea and small intestine (P < 0.05 or P < 0.01). In addition, B.S.-HA elevated the specific IgA titers in the trachea, IgG and HI antibody titers in serum (P < 0.05 or P < 0.01). Therefore, B.S.-HA provides a potential novel strategy and approach for developing an H5N1 vaccine. PMID- 27982055 TI - Tunable magnetic states on the zigzag edges of hydrogenated and halogenated group IV nanoribbons. AB - The magnetic and electronic properties of hydrogenated and halogenated group-IV zigzag nanoribbons (ZNRs) are investigated by first-principles density functional calculations. Fascinatingly, we find that all the ZNRs have magnetic edges with a rich variety of electronic and magnetic properties tunable by selecting the parent and passivating elements as well as controlling the magnetization direction and external strain. In particular, the electric property of the edge band structure can be tuned from the conducting to insulating with a band gap up to 0.7 eV. The last controllability would allow us to develop magnetic on-off nano-switches. Furthermore, ZNRs such as SiI, Ge, GeI and SnH, have fully spin polarized metallic edge states and thus are promising materials for spintronics. The calculated magnetocrystalline anisotropy energy can be as large as ~9 meV/edge-site, being 2*103 time greater than that of bulk Ni and Fe (~5 MUeV/atom), and thus has great potential for high density magneto-electric data storage devices. Finally, the calculated exchange coupling strength and thus magnetic transition temperature increases as the applied strain goes from -5% to 5%. Our findings thus show that these ZNRs would have exciting applications in next-generation electronic and spintronic nano-devices. PMID- 27982053 TI - Analysis of High-altitude Syndrome and the Underlying Gene Polymorphisms Associated with Acute Mountain Sickness after a Rapid Ascent to High-altitude. AB - To investigated the objective indicators and potential genotypes for acute mountain sickness (AMS). 176 male subjects were evaluated for symptoms scores and physiological parameters at 3700 m. EPAS1 gene polymorphisms were explored and verified effects of potential genotypes on pulmonary function by inhaled budesonide. The incidence of AMS was 53.98% (95/176). The individuals who suffered from headache with anxiety and greater changes in heart rate (HR), the forced vital capacity (FVC), and mean flow velocity of basilar artery (Vm-BA), all of which were likely to develop AMS. The rs4953348 polymorphism of EPAS1 gene had a significant correlation with the SaO2 level and AMS, and a significant difference in the AG and GG genotype distribution between the AMS and non-AMS groups. The spirometric parameters were significantly lower, but HR (P = 0.036) and Vm-BA (P = 0.042) significantly higher in the AMS subjects with the G allele than those with the A allele. In summary, changes in HR (>=82 beats/min), FVC (<=4.2 Lt) and Vm-BA (>=43 cm/s) levels may serve as predictors for diagnosing AMS accompanied by high-altitude syndrome. The A allele of rs4953348 is a protective factor for AMS through HR and Vm-BA compensation, while the G allele may contribute to hypoxic pulmonary hypertension in AMS. PMID- 27982054 TI - Mitochondrial-bacterial hybrids of BamA/Tob55 suggest variable requirements for the membrane integration of beta-barrel proteins. AB - beta-Barrel proteins are found in the outer membrane (OM) of Gram-negative bacteria, chloroplasts and mitochondria. The assembly of these proteins into the corresponding OM is facilitated by a dedicated protein complex that contains a central conserved beta-barrel protein termed BamA in bacteria and Tob55/Sam50 in mitochondria. BamA and Tob55 consist of a membrane-integral C-terminal domain that forms a beta-barrel pore and a soluble N-terminal portion comprised of one (in Tob55) or five (in BamA) polypeptide transport-associated (POTRA) domains. Currently the functional significance of this difference and whether the homology between BamA and Tob55 can allow them to replace each other are unclear. To address these issues we constructed hybrid Tob55/BamA proteins with differently configured N-terminal POTRA domains. We observed that constructs harboring a heterologous C-terminal domain could not functionally replace the bacterial BamA or the mitochondrial Tob55 demonstrating species-specific requirements. Interestingly, the various hybrid proteins in combination with the bacterial chaperones Skp or SurA supported to a variable extent the assembly of bacterial beta-barrel proteins into the mitochondrial OM. Collectively, our findings suggest that the membrane assembly of various beta-barrel proteins depends to a different extent on POTRA domains and periplasmic chaperones. PMID- 27982056 TI - Microstructure Imaging of Crossing (MIX) White Matter Fibers from diffusion MRI. AB - Diffusion MRI (dMRI) reveals microstructural features of the brain white matter by quantifying the anisotropic diffusion of water molecules within axonal bundles. Yet, identifying features such as axonal orientation dispersion, density, diameter, etc., in complex white matter fiber configurations (e.g. crossings) has proved challenging. Besides optimized data acquisition and advanced biophysical models, computational procedures to fit such models to the data are critical. However, these procedures have been largely overlooked by the dMRI microstructure community and new, more versatile, approaches are needed to solve complex biophysical model fitting problems. Existing methods are limited to models assuming single fiber orientation, relevant to limited brain areas like the corpus callosum, or multiple orientations but without the ability to extract detailed microstructural features. Here, we introduce a new and versatile optimization technique (MIX), which enables microstructure imaging of crossing white matter fibers. We provide a MATLAB implementation of MIX, and demonstrate its applicability to general microstructure models in fiber crossings using synthetic as well as ex-vivo and in-vivo brain data. PMID- 27982057 TI - New cell motility model observed in parasitic cnidarian Sphaerospora molnari (Myxozoa:Myxosporea) blood stages in fish. AB - Cellular motility is essential for microscopic parasites, it is used to reach the host, migrate through tissues, or evade host immune reactions. Many cells employ an evolutionary conserved motor protein- actin, to crawl or glide along a substrate. We describe the peculiar movement of Sphaerospora molnari, a myxozoan parasite with proliferating blood stages in its host, common carp. Myxozoa are highly adapted parasitic cnidarians alternately infecting vertebrates and invertebrates. S. molnari blood stages (SMBS) have developed a unique "dancing" behaviour, using the external membrane as a motility effector to rotate and move the cell. SMBS movement is exceptionally fast compared to other myxozoans, non directional and constant. The movement is based on two cytoplasmic actins that are highly divergent from those of other metazoans. We produced a specific polyclonal actin antibody for the staining and immunolabelling of S. molnari's microfilaments since we found that neither commercial antibodies nor phalloidin recognised the protein or microfilaments. We show the in situ localization of this actin in the parasite and discuss the importance of this motility for evasion from the cellular host immune response in vitro. This new type of motility holds key insights into the evolution of cellular motility and associated proteins. PMID- 27982058 TI - Shengmai Formula suppressed over-activated Ras/MAPK pathway in C. elegans by opening mitochondrial permeability transition pore via regulating cyclophilin D. AB - Since about 30% of all human cancers contain mutationally activated Ras, down regulating the over-activation of Ras/MAPK pathway represents a viable approach for treating cancers. Over-activation of Ras/MAPK pathway is accompanied by accumulation of reactive oxygen species (ROS). One approach for developing anti cancer drugs is to target ROS production and their accumulation. To test this idea, we have employed C. elegans of let-60 (gf) mutant, which contain over activated let-60 (the homolog of mammalian ras) and exhibit tumor-like symptom of multivulva phenotype, to determine whether anti-oxidants can affect their tumor like phenotype. Specifically we studied the effect of Shengmai formula (SM), a traditional Chinese medicine that has strong anti-oxidant activity, on the physiology of let-60 (gf) mutants. Unexpectedly, we found that SM treatment led to the opening of mitochondrial permeability transition pore by regulating cyclophilin D and then triggered oxidative stress and related signaling pathway activation, including p53, JNK, and p38/MAPK pathways. Finally, SM induced mitochondrial pathway of apoptosis and inhibited the tumor-like symptom of the multivulva phenotype of let-60(gf) mutants. Our results provide evidences to support that SM act as a pro-oxidant agent and could serve as a potential drug candidate for combating over-activated Ras-related cancer. PMID- 27982059 TI - The role of the unusual threonine string in the conversion of prion protein. AB - The conversion of normal prion protein (PrP) into pathogenic PrP conformers is central to prion disease, but the mechanism remains unclear. The alpha-helix 2 of PrP contains a string of four threonines, which is unusual due to the high propensity of threonine to form beta-sheets. This structural feature was proposed as the basis for initiating PrP conversion, but experimental results have been conflicting. We studied the role of the threonine string on PrP conversion by analyzing mouse Prnpa and Prnpb polymorphism that contains a polymorphic residue at the beginning of the threonine string, and PrP mutants in which threonine 191 was replaced by valine, alanine, or proline. The PMCA (protein misfolding cyclic amplification) assay was able to recapitulate the in vivo transmission barrier between PrPa and PrPb. Relative to PMCA, the amyloid fibril growth assay is less restrictive, but it did reflect certain properties of in vivo prion transmission. Our results suggest a plausible theory explaining the apparently contradictory results in the role of the threonine string in PrP conversion and provide novel insights into the complicated relationship among PrP stability, seeded conformational change, and prion structure, which is critical for understanding the molecular basis of prion infectivity. PMID- 27982060 TI - A CRISPR/Cas9 Functional Screen Identifies Rare Tumor Suppressors. AB - An enormous amount of tumor sequencing data has been generated through large scale sequencing efforts. The functional consequences of the majority of mutations identified by such projects remain an open, unexplored question. This problem is particularly complicated in the case of rare mutations where frequency of occurrence alone or prediction of functional consequences are insufficient to distinguish driver from passenger or bystander mutations. We combine genome editing technology with a powerful mouse cancer model to uncover previously unsuspected rare oncogenic mutations in Burkitt's lymphoma. We identify two candidate tumor suppressors whose loss cooperate with MYC over-expression to accelerate lymphomagenesis. Our results highlight the utility of in vivo CRISPR/Cas9 screens combined with powerful mouse models to identify and validate rare oncogenic modifier events from tumor mutational data. PMID- 27982061 TI - Multicenter evaluation of crystal violet decolorization assay (CVDA) for rapid detection of isoniazid and rifampicin resistance in Mycobacterium tuberculosis. AB - The aim of this multicenter study was to evaluate the performance of the crystal violet decolorization assay (CVDA) for detection of multidrug resistant tuberculosis (MDR-TB). This study was performed in 11 centers in two phases. A total of 156 isolates were tested for INH and RIF resistance. In the phase I, 106 clinical isolates were tested in the Center 1-7. In the phase 2, 156 clinical isolates were tested in the center 1-6, center 8-11. Eighty six of 156 tested isolates were the same in phase I. Agreements were 96.2-96.8% for INH and 98.1 98.7% for RIF in the phase I-II, respectively. Mean time to obtain the results in the phase I was 14.3 +/- 5.4 days. In the phase II, mean time to obtain the results was 11.6 +/- 3.5 days. Test results were obtained within 14days for 62.3% (66/106) of isolates in the phase I and 81.4% (127/156) of isolates in the phase II. In conclusion, CVDA is rapid, reliable, inexpensive, and easy to perform for rapid detection of MDR-TB isolates. In addition, it could be adapted for drug susceptibility testing with all drugs both in developed and developing countries. PMID- 27982064 TI - The influence of ionic strength on carbonate-based spectroscopic barometry for aqueous fluids: an in-situ Raman study on Na2CO3-NaCl solutions. AB - The Raman wavenumber of the symmetric stretching vibration of carbonate ion (nu1 CO32-) was measured in three aqueous solutions containing 2.0 mol.L-1 Na2CO3 and 0.20, 0.42, or 0.92 mol.L-1 NaCl, respectively, from 122 to 1538 MPa at 22 degrees C using a moissanite anvil cell. The nu1 Raman signal linearly shifted to higher wavenumbers with increasing pressure. Most importantly, the slope of nu1 CO32- Raman frequency shift (?nu1/?P)I was independent of NaCl concentration. Moreover, elevated ionic strength was found to shift the apparent outline of the carbonate peak toward low wavenumbers, possibly by increasing the proportion of the contact ion pair NaCO3-. Further investigations revealed no cross-interaction between the pressure effect and the ionic strength effect on the Raman spectra, possibly because the distribution of different ion-pair species in the carbonate equilibrium was largely pressure-independent. These results suggested that the ionic strength should be incorporated as an additional constraint for measuring the internal pressure of various solution-based systems. Combining the nu1-CO32- Raman frequency slope with the pressure herein with the values for the temperature or the ionic strength dependencies determined from previous studies, we developed an empirical equation that can be used to estimate the pressure of carbonate-bearing aqueous solutions. PMID- 27982063 TI - How actions shape perception: learning action-outcome relations and predicting sensory outcomes promote audio-visual temporal binding. AB - To maintain a temporally-unified representation of audio and visual features of objects in our environment, the brain recalibrates audio-visual simultaneity. This process allows adjustment for both differences in time of transmission and time for processing of audio and visual signals. In four experiments, we show that the cognitive processes for controlling instrumental actions also have strong influence on audio-visual recalibration. Participants learned that right and left hand button-presses each produced a specific audio-visual stimulus. Following one action the audio preceded the visual stimulus, while for the other action audio lagged vision. In a subsequent test phase, left and right button press generated either the same audio-visual stimulus as learned initially, or the pair associated with the other action. We observed recalibration of simultaneity only for previously-learned audio-visual outcomes. Thus, learning an action-outcome relation promotes temporal grouping of the audio and visual events within the outcome pair, contributing to the creation of a temporally unified multisensory object. This suggests that learning action-outcome relations and the prediction of perceptual outcomes can provide an integrative temporal structure for our experiences of external events. PMID- 27982062 TI - Changes in mitochondrial homeostasis and redox status in astronauts following long stays in space. AB - The effects of long-term exposure to extreme space conditions on astronauts were investigated by analyzing hair samples from ten astronauts who had spent six months on the International Space Station (ISS). Two samples were collected before, during and after their stays in the ISS; hereafter, referred to as Preflight, Inflight and Postflight, respectively. The ratios of mitochondrial (mt) to nuclear (n) DNA and mtRNA to nRNA were analyzed via quantitative PCR. The combined data of Preflight, Inflight and Postflight show a significant reduction in the mtDNA/nDNA in Inflight, and significant reductions in the mtRNA/nRNA ratios in both the Inflight and Postflight samples. The mtRNA/mtDNA ratios were relatively constant, except in the Postflight samples. Using the same samples, the expression of redox and signal transduction related genes, MnSOD, CuZnSOD, Nrf2, Keap1, GPx4 and Catalase was also examined. The results of the combined data from Preflight, Inflight and Postflight show a significant decrease in the expression of all of the redox-related genes in the samples collected Postflight, with the exception of Catalase, which show no change. This decreased expression may contribute to increased oxidative stress Inflight resulting in the mitochondrial damage that is apparent Postflight. PMID- 27982065 TI - Acute kidney injury as a risk factor for diagnostic discrepancy among geriatric patients: a pilot study. AB - Diagnostic discrepancy, defined as different admission and discharge diagnoses, could be a potential source of diagnostic error. We evaluated whether acute kidney injury (AKI) in the elderly affected their risk for diagnostic discrepancy. Patients aged >=60 years from the general medical wards were prospectively enrolled and divided according to AKI status upon admission, using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. We compared their discharge and admission diagnoses and identified patients with a diagnostic discrepancy, using multiple logistic regression analysis to evaluate the relationship between initial AKI and the presence of a diagnostic discrepancy. A total of 188 participants (mean age, 77.9 years) were recruited. Regression analysis showed that initial AKI on admission was associated with a higher risk of diagnostic discrepancy upon discharge (odds ratio [OR] 3.3; p < 0.01). In contrast, higher AKI severity was also associated with an increased risk of diagnostic discrepancy (for KDIGO grade 1, 2, and 3; OR 2.92, 3.91, and 4.32; p = 0.04, 0.03, and 0.02, respectively), suggesting that initial AKI upon admission could be an important risk factor for diagnostic discrepancy. Consequently, reducing geriatric AKI might have the potential to reduce diagnostic discrepancy among these patients. PMID- 27982066 TI - The nature of photoinduced phase transition and metastable states in vanadium dioxide. AB - Photoinduced threshold switching processes that lead to bistability and the formation of metastable phases in photoinduced phase transition of VO2 are elucidated through ultrafast electron diffraction and diffusive scattering techniques with varying excitation wavelengths. We uncover two distinct regimes of the dynamical phase change: a nearly instantaneous crossover into an intermediate state and its decay led by lattice instabilities over 10 ps timescales. The structure of this intermediate state is identified to be monoclinic, but more akin to M2 rather than M1 based on structure refinements. The extinction of all major monoclinic features within just a few picoseconds at the above-threshold-level (~20%) photoexcitations and the distinct dynamics in diffusive scattering that represents medium-range atomic fluctuations at two photon wavelengths strongly suggest a density-driven and nonthermal pathway for the initial process of the photoinduced phase transition. These results highlight the critical roles of electron correlations and lattice instabilities in driving and controlling phase transformations far from equilibrium. PMID- 27982068 TI - The Management and Prognostic Prediction of Adenocarcinoma of Appendix. AB - Malignant tumours of the appendix are quite rare, especially appendiceal adenocarcinomas, which may be difficult to detect preoperatively or intraoperatively. We collected data for 1404 patients with adenocarcinoma of the appendix from the Surveillance, Epidemiology, and End Results Program (SEER) database to explore the potential associations between clinicopathological factors and overall survival. Furthermore, a novel nomogram for predicting prognosis was developed based on our analysis of the SEER data. The nomogram prediction model included seven prognostic factors derived based on different clinical estimates. When compared with the traditional tumour-node-metastasis (TNM) staging system, the nomogram prediction model showed superior discriminatory power (Harrell's C-index, 0.741 vs. 0.686) and a greater degree of similarity to actual 5-year overall survival after calibration (Akaike Information Criterion index, 5270.781 vs. 5430.141). Finally, we provide recommendations for the management of patients with adenocarcinoma of the appendix. Notably, we found the depth of adenocarcinoma invasion may be used as an indicator to determine the optimal surgical approach. For mucinous adenocarcinomas of the appendix, because these tumours are characterized by unique biological behaviour, intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is recommended. However, whether systematic chemotherapy should be administered to patients with adenocarcinoma of the appendix requires further investigation. PMID- 27982067 TI - Brown adipogenic potential of brown adipocytes and peri-renal adipocytes from human embryo. AB - Both brown adipocytes (BAC) and beige cells hold therapeutic potential for the treatment of metabolic disorders. Unfortunately, the amount and activity of these cells are limited in adults. Although BAC marker expression has been shown in peri-renal adipose tissues in children and adults, functional assessment is lacking. Furthermore, it is entirely unknown whether adipose progenitors are present in human embryo and able to give rise to BAC in situ during evolution. Therefore, adipose tissues in the interscapular and peri-renal regions were dissected from human embryo and subcutaneous white adipose tissues (sWAT) were obtained from an adult. After subjected to differentiation in vitro, adipocyte progenitors were detected present in all these adipose tissues. When stimulated for adipogenesis, differentiated adipocytes in the intercapular and peri-renal regions showed similar features: (1) induced BAC and beige cell marker expression including UCP1 and PRDM16 and comparable mitochondrion copy number; (2) similar gene expression patterns by RNA-Seq analysis; and (3) similar maximal oxygen consumption rates examined by respirometry. Nevertheless, stimulation of adipocyte progenitors in sWAT induces neither BAC and beige cell marker expression nor any change of oxygen consumption. In conclusion, peri-renal adipocyte progenitors in human embryo hold browning potential for BAC production. PMID- 27982070 TI - Efficient DNA-Polymer Coupling in Organic Solvents: A Survey of Amide Coupling, Thiol-Ene and Tetrazine-Norbornene Chemistries Applied to Conjugation of Poly(N Isopropylacrylamide). AB - A range of chemistries were explored for the efficient covalent conjugation of DNA to poly(N-isopropylacrylamide) (poly(NIPAM)) in organic solvents. Amide coupling and thiol-ene Michael addition were found to be ineffective for the synthesis of the desired products. However, the inverse electron-demand Diels Alder (DAinv) reaction between tetrazine (Tz) and norbornene (Nb) was found to give DNA-polymer conjugates in good yields (up to 40%) in organic solvents (N,N dimethylformamide, N,N-dimethylacetamide and N-methyl-2-pyrrolidone), and without the need for a catalyst. Methods for the synthesis of Tz-and Nb- functionalised DNA were developed, along with a post-polymerisation functionalisation strategy for the production of Tz-functionalised polymers. PMID- 27982072 TI - Magnetic resonance anisotropy in CeB6: an entangled state of the art. AB - Electron spin resonance (ESR) in strongly correlated metals is an exciting phenomenon, as strong spin fluctuations in this class of materials broaden extremely the absorption line below the detection limit. In this respect, ESR observation in CeB6 provides a unique chance to inspect Ce3+ magnetic state in the antiferroquadrupole (AFQ) phase. We apply the original high frequency (60 GHz) experimental technique to extract the temperature and angular dependences of g-factor, line width and oscillating magnetization. Experimental data show unambiguously that the modern ESR theory in the AFQ phase considering the Gamma8 ground state of Ce3+ ion completely fails to predict both the g-factor magnitude and its angular dependence. Alignment of the external magnetic field along [100] axis induces a strong (more than twofold) broadening of ESR line width with respect to the other crystallographic directions and results also in the anomalous temperature dependences of the g-factor and oscillating magnetization. In this experimental geometry the latter parameter surprisingly exceeds total static magnetization by 20% at T* ~ 2.5 K. We argue that the unusual physical picture of ESR in CeB6 may be strongly affected by spin fluctuations and dynamic collective effects predominantly pronounced in [100] direction. PMID- 27982069 TI - The role of the poly(A) tract in the replication and virulence of tick-borne encephalitis virus. AB - The tick-borne encephalitis virus (TBEV) is a flavivirus transmitted to humans, usually via tick bites. The virus causes tick-borne encephalitis (TBE) in humans, and symptoms range from mild flu-like symptoms to severe and long-lasting sequelae, including permanent brain damage. It has been suggested that within the population of viruses transmitted to the mammalian host, quasispecies with neurotropic properties might become dominant in the host resulting in neurological symptoms. We previously demonstrated the existence of TBEV variants with variable poly(A) tracts within a single blood-fed tick. To characterize the role of the poly(A) tract in TBEV replication and virulence, we generated infectious clones of Toro-2003 with the wild-type (A)3C(A)6 sequence (Toro-6A) or with a modified (A)3C(A)38 sequence (Toro-38A). Toro-38A replicated poorly compared to Toro-6A in cell culture, but Toro-38A was more virulent than Toro-6A in a mouse model of TBE. Next-generation sequencing of TBEV genomes after passaging in cell culture and/or mouse brain revealed mutations in specific genomic regions and the presence of quasispecies that might contribute to the observed differences in virulence. These data suggest a role for quasispecies development within the poly(A) tract as a virulence determinant for TBEV in mice. PMID- 27982071 TI - Pan- and core- network analysis of co-expression genes in a model plant. AB - Genome-wide gene expression experiments have been performed using the model plant Arabidopsis during the last decade. Some studies involved construction of coexpression networks, a popular technique used to identify groups of co regulated genes, to infer unknown gene functions. One approach is to construct a single coexpression network by combining multiple expression datasets generated in different labs. We advocate a complementary approach in which we construct a large collection of 134 coexpression networks based on expression datasets reported in individual publications. To this end we reanalyzed public expression data. To describe this collection of networks we introduced concepts of 'pan network' and 'core-network' representing union and intersection between a sizeable fractions of individual networks, respectively. We showed that these two types of networks are different both in terms of their topology and biological function of interacting genes. For example, the modules of the pan-network are enriched in regulatory and signaling functions, while the modules of the core network tend to include components of large macromolecular complexes such as ribosomes and photosynthetic machinery. Our analysis is aimed to help the plant research community to better explore the information contained within the existing vast collection of gene expression data in Arabidopsis. PMID- 27982073 TI - Enhanced Conversion Efficiency of III-V Triple-junction Solar Cells with Graphene Quantum Dots. AB - Graphene has been used to synthesize graphene quantum dots (GQDs) via pulsed laser ablation. By depositing the synthesized GQDs on the surface of InGaP/InGaAs/Ge triple-junction solar cells, the short-circuit current, fill factor, and conversion efficiency were enhanced remarkably. As the GQD concentration is increased, the conversion efficiency in the solar cell increases accordingly. A conversion efficiency of 33.2% for InGaP/InGaAs/Ge triple-junction solar cells has been achieved at the GQD concentration of 1.2 mg/ml, corresponding to a 35% enhancement compared to the cell without GQDs. On the basis of time-resolved photoluminescence, external quantum efficiency, and work function measurements, we suggest that the efficiency enhancement in the InGaP/InGaAs/Ge triple-junction solar cells is primarily caused by the carrier injection from GQDs to the InGaP top subcell. PMID- 27982075 TI - Oxyfunctionalization of pyridine derivatives using whole cells of Burkholderia sp. MAK1. AB - Pyridinols and pyridinamines are important intermediates with many applications in chemical industry. The pyridine derivatives are in great demand as synthons for pharmaceutical products. Moreover, pyridines are used either as biologically active substances or as building blocks for polymers with unique physical properties. Application of enzymes or whole cells is an attractive strategy for preparation of hydroxylated pyridines since the methods for chemical synthesis of pyridinols, particularly aminopyridinols, are usually limited or inefficient. Burkholderia sp. MAK1 (DSM102049), capable of using pyridin-2-ol as the sole carbon and energy source, was isolated from soil. Whole cells of Burkholderia sp. MAK1 were confirmed to possess a good ability to convert different pyridin-2 amines and pyridin-2-ones into their 5-hydroxy derivatives. Moreover, several methylpyridines as well as methylated pyrazines were converted to appropriate N oxides. In conclusion, regioselective oxyfunctionalization of pyridine derivatives using whole cells of Burkholderia sp. MAK1 is a promising method for the preparation of various pyridin-5-ols and pyridin-N-oxides. PMID- 27982076 TI - Establishment of the cytoplasmic incompatibility-inducing Wolbachia strain wMel in an important agricultural pest insect. AB - The wMel Wolbachia strain was known for cytoplasmic incompatibility (CI) induction and blocking the transmission of dengue. However, it is unknown whether it can establish and induce CI in a non-dipteran host insect. Here we artificially transferred wMel from Drosophila melanogaster into the whitefly Bemisia tabaci. Fluorescence in situ hybridisation demonstrated that wMel had successfully transfected the new host. Reciprocal crossing was conducted with wMel-transfected and wild-type isofemale lines, indicating that wMel could induce a strong CI without imposing significant cost on host fecundity. We then determined the maternal transmission efficiency of wMel in the offspring generations, showing a fluctuating trend over a period of 12 generations. We thus detected the titre of wMel during different developmental stages and in different generations by using real-time quantitative PCR, revealing a similar fluctuating mode, but it was not significantly correlated with the dynamics of transmission efficiency. These results suggest that wMel can be established in B.tabaci, a distantly related pest insect of agricultural importance; moreover, it can induce a strong CI phenotype in the recipient host insect, suggesting a potential for its use in biological control of B. tabaci. PMID- 27982074 TI - An adenylyl cyclase with a phosphodiesterase domain in basal plants with a motile sperm system. AB - Adenylyl cyclase (AC), which produces the signalling molecule cAMP, has numerous important cellular functions in diverse organisms from prokaryotes to eukaryotes. Here we report the identification and characterization of an AC gene from the liverwort Marchantia polymorpha. The encoded protein has both a C-terminal AC catalytic domain similar to those of class III ACs and an N-terminal cyclic nucleotide phosphodiesterase (PDE) domain that degrades cyclic nucleotides, thus we designated the gene MpCAPE (COMBINED AC with PDE). Biochemical analyses of recombinant proteins showed that MpCAPE has both AC and PDE activities. In MpCAPE promoter-GUS lines, GUS activity was specifically detected in the male sexual organ, the antheridium, suggesting MpCAPE and thus cAMP signalling may be involved in the male reproductive process. CAPE orthologues are distributed only in basal land plants and charophytes that use motile sperm as the male gamete. CAPE is a subclass of class III AC and may be important in male organ and cell development in basal plants. PMID- 27982077 TI - Effects of Bisphenol A Metabolite 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene on Lung Function and Type 2 Pulmonary Alveolar Epithelial Cell Growth. AB - Bisphenol A (BPA) is recognized as a major pollutant worldwide. 4-Methyl-2,4 bis(4-hydroxyphenyl)pent-1-ene (MBP) is a major active metabolite of BPA. The epidemiological and animal studies have reported that BPA is harmful to lung function. The role of MBP in lung dysfunction after BPA exposure still remains unclear. This study investigated whether MBP would induce lung alveolar cell damage and evaluated the role of MBP in the BPA exposure-induced lung dysfunction. An in vitro type 2 alveolar epithelial cell (L2) model and an ex vivo isolated reperfused rat lung model were used to determine the effects of BPA or MBP on cell growth and lung function. MBP, but not BPA, dose-dependently increased the mean artery pressure (Pa), pulmonary capillary pressure (Pc), pulmonary capillary filtration coefficient (Kfc), and wet/dry weight ratio in isolated reperfused rat lungs. MBP significantly reduced cell viability and induced caspases-3/7 cleavage and apoptosis and increased AMP-activated protein kinas (AMPK) phosphorylation and endoplasmic reticulum (ER) stress-related molecules expression in L2 cells, which could be reversed by AMPK-siRNA transfection. These findings demonstrated for the first time that MBP exposure induced type 2 alveolar cell apoptosis and lung dysfunction through an AMPK regulated ER stress signaling pathway. PMID- 27982080 TI - Vibrational density of states and thermodynamics at the nanoscale: the 3D-2D transition in gold nanostructures. AB - Surface enhanced Raman scattering (SERS) is generally and widely used to enhance the vibrational fingerprint of molecules located at the vicinity of noble metal nanoparticles. In this work, SERS is originally used to enhance the own vibrational density of states (VDOS) of nude and isolated gold nanoparticles. This offers the opportunity of analyzing finite size effects on the lattice dynamics which remains unattainable with conventional techniques based on neutron or x-ray inelastic scattering. By reducing the size down to few nanometers, the role of surface atoms versus volume atoms become dominant, and the "text-book" 3D 2D transition on the dynamical behavior is experimentally emphasized. "Anomalies" that have been predicted by a large panel of simulations at the atomic scale, are really observed, like the enhancement of the VDOS at low frequencies or the occurrence of localized modes at frequencies beyond the cut-off in bulk. Consequences on the thermodynamic properties at the nanoscale, like the reduction of the Debye temperature or the excess of the specific heat, have been evaluated. Finally the high sensitivity of reminiscent bulk-like phonons on the arrangements at the atomic scale is used to access the morphology and internal disorder of the nanoparticles. PMID- 27982078 TI - A TNFRSF14-FcERI-mast cell pathway contributes to development of multiple features of asthma pathology in mice. AB - Asthma has multiple features, including airway hyperreactivity, inflammation and remodelling. The TNF superfamily member TNFSF14 (LIGHT), via interactions with the receptor TNFRSF14 (HVEM), can support TH2 cell generation and longevity and promote airway remodelling in mouse models of asthma, but the mechanisms by which TNFSF14 functions in this setting are incompletely understood. Here we find that mouse and human mast cells (MCs) express TNFRSF14 and that TNFSF14:TNFRSF14 interactions can enhance IgE-mediated MC signalling and mediator production. In mouse models of asthma, TNFRSF14 blockade with a neutralizing antibody administered after antigen sensitization, or genetic deletion of Tnfrsf14, diminishes plasma levels of antigen-specific IgG1 and IgE antibodies, airway hyperreactivity, airway inflammation and airway remodelling. Finally, by analysing two types of genetically MC-deficient mice after engrafting MCs that either do or do not express TNFRSF14, we show that TNFRSF14 expression on MCs significantly contributes to the development of multiple features of asthma pathology. PMID- 27982079 TI - Ginsenoside Rg1 attenuates ultraviolet B-induced glucocortisides resistance in keratinocytes via Nrf2/HDAC2 signalling. AB - Oxidative stress, which occurs after ultraviolet (UV) radiation, usually results in Glucocorticoid (GC) resistance and the subsequent development of skin inflammation. One approach to protecting the skin against UV radiation is the use of antioxidants. The ginsenoside Rg1 is a novel natural antioxidant isolated from the medicinal plant Panax ginseng C.A. Mey. We demonstrated that UVB exposure exacerbated inflammation and reduced both the level of the glucocorticoid receptor (GR) and the efficacy of dexamethasone (Dex) in human keratinocytes (HaCaT cells). Pretreatment with Rg1 increased the expression of GR and restored Dex responsiveness to inflammation in UVB-irradiated HaCaT cells. Mechanistically, Rg1 rescued UVB-induced HDAC2 degradation. HDAC2 knockdown partially abolished the Rg1-induced up-regulation of GR and the enhancement of GC sensitivity. In addition, Rg1 reduced the production of reactive oxygen species (ROS), which preceded the up-regulation of HDAC2, and consequent sensitization of cells to Dex. Moreover, Rg1 treatment promoted the translocation and activation of Nrf2. Nrf2 knockdown partially abolished the Rg1-induced decrease of ROS production and increase of HDAC2. Rg1 also potentiated the anti-inflammatory effects of Dex in UVB-irradiated mouse skin. In conclusion, we demonstrated that Rg1 attenuated UVB-induced GC insensitivity. Notably, these effects were partially mediated by the Nrf2/HDAC2 pathway. PMID- 27982081 TI - A cloud-based workflow to quantify transcript-expression levels in public cancer compendia. AB - Public compendia of sequencing data are now measured in petabytes. Accordingly, it is infeasible for researchers to transfer these data to local computers. Recently, the National Cancer Institute began exploring opportunities to work with molecular data in cloud-computing environments. With this approach, it becomes possible for scientists to take their tools to the data and thereby avoid large data transfers. It also becomes feasible to scale computing resources to the needs of a given analysis. We quantified transcript-expression levels for 12,307 RNA-Sequencing samples from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas. We used two cloud-based configurations and examined the performance and cost profiles of each configuration. Using preemptible virtual machines, we processed the samples for as little as $0.09 (USD) per sample. As the samples were processed, we collected performance metrics, which helped us track the duration of each processing step and quantified computational resources used at different stages of sample processing. Although the computational demands of reference alignment and expression quantification have decreased considerably, there remains a critical need for researchers to optimize preprocessing steps. We have stored the software, scripts, and processed data in a publicly accessible repository (https://osf.io/gqrz9). PMID- 27982083 TI - NetDiff - Bayesian model selection for differential gene regulatory network inference. AB - Differential networks allow us to better understand the changes in cellular processes that are exhibited in conditions of interest, identifying variations in gene regulation or protein interaction between, for example, cases and controls, or in response to external stimuli. Here we present a novel methodology for the inference of differential gene regulatory networks from gene expression microarray data. Specifically we apply a Bayesian model selection approach to compare models of conserved and varying network structure, and use Gaussian graphical models to represent the network structures. We apply a variational inference approach to the learning of Gaussian graphical models of gene regulatory networks, that enables us to perform Bayesian model selection that is significantly more computationally efficient than Markov Chain Monte Carlo approaches. Our method is demonstrated to be more robust than independent analysis of data from multiple conditions when applied to synthetic network data, generating fewer false positive predictions of differential edges. We demonstrate the utility of our approach on real world gene expression microarray data by applying it to existing data from amyotrophic lateral sclerosis cases with and without mutations in C9orf72, and controls, where we are able to identify differential network interactions for further investigation. PMID- 27982085 TI - Production of fluorescent dissolved organic matter in Arctic Ocean sediments. AB - Little is known about the production of fluorescent dissolved organic matter (FDOM) in the anoxic oceanic sediments. In this study, sediment pore waters were sampled from four different sites in the Chukchi-East Siberian Seas area to examine the bulk dissolved organic carbon (DOC) and their optical properties. The production of FDOM, coupled with the increase of nutrients, was observed above the sulfate-methane-transition-zone (SMTZ). The presence of FDOM was concurrent with sulfate reduction and increased alkalinity (R2 > 0.96, p < 0.0001), suggesting a link to organic matter degradation. This inference was supported by the positive correlation (R2 > 0.95, p < 0.0001) between the net production of FDOM and the modeled degradation rates of particulate organic carbon sulfate reduction. The production of FDOM was more pronounced in a shallow shelf site S1 with a total net production ranging from 17.9 to 62.3 RU for different FDOM components above the SMTZ depth of ca. 4.1 mbsf, which presumably underwent more accumulation of particulate organic matter than the other three deeper sites. The sediments were generally found to be the sources of CDOM and FDOM to the overlying water column, unearthing a channel of generally bio-refractory and pre aged DOM to the oceans. PMID- 27982082 TI - The involvement of dityrosine crosslinking in alpha-synuclein assembly and deposition in Lewy Bodies in Parkinson's disease. AB - Parkinson's disease (PD) is characterized by intracellular, insoluble Lewy bodies composed of highly stable alpha-synuclein (alpha-syn) amyloid fibrils. alpha synuclein is an intrinsically disordered protein that has the capacity to assemble to form beta-sheet rich fibrils. Oxidiative stress and metal rich environments have been implicated in triggering assembly. Here, we have explored the composition of Lewy bodies in post-mortem tissue using electron microscopy and immunogold labeling and revealed dityrosine crosslinks in Lewy bodies in brain tissue from PD patients. In vitro, we show that dityrosine cross-links in alpha-syn are formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress by fluorescence and confirmed using mass spectrometry. A covalently cross-linked dimer isolated by SDS-PAGE and mass analysis showed that dityrosine dimer was formed via the coupling of Y39-Y39 to give a homo dimer peptide that may play a key role in formation of oligomeric and seeds for fibril formation. Atomic force microscopy analysis reveals that the covalent dityrosine contributes to the stabilization of alpha-syn assemblies. Thus, the presence of oxidative stress induced dityrosine could play an important role in assembly and toxicity of alpha-syn in PD. PMID- 27982086 TI - Gene expression in local stroma reflects breast tumor states and predicts patient outcome. AB - The surrounding microenvironment has been implicated in the progression of breast tumors to metastasis. However, the degree to which metastatic breast tumors locally reprogram stromal cells as they disrupt tissue boundaries is not well understood. We used species-specific RNA sequencing in a mouse xenograft model to determine how the metastasis suppressor RKIP influences transcription in a panel of paired tumor and stroma tissues. We find that gene expression in metastatic breast tumors is pervasively correlated with gene expression in local stroma of both mouse xenografts and human patients. Changes in stromal gene expression elicited by tumors better predicts subtype and patient survival than tumor gene expression, and genes with coordinated expression in both tissues predict metastasis-free survival. These observations support the use of stroma-based strategies for the diagnosis and prognosis of breast cancer. PMID- 27982087 TI - An innovative concept of use of redox-active electrolyte in asymmetric capacitor based on MWCNTs/MnO2 and Fe2O3 thin films. AB - In present investigation, we have prepared a nanocomposites of highly porous MnO2 spongy balls and multi-walled carbon nanotubes (MWCNTs) in thin film form and tested in novel redox-active electrolyte (K3[Fe(CN)6] doped aqueous Na2SO4) for supercapacitor application. Briefly, MWCNTs were deposited on stainless steel substrate by "dip and dry" method followed by electrodeposition of MnO2 spongy balls. Further, the supercapacitive properties of these hybrid thin films were evaluated in hybrid electrolyte ((K3[Fe(CN)6 doped aqueous Na2SO4). Thus, this is the first proof-of-design where redox-active electrolyte is applied to MWCNTs/MnO2 hybrid thin films. Impressively, the MWCNTs/MnO2 hybrid film showed a significant improvement in electrochemical performance with maximum specific capacitance of 1012 Fg-1 at 2 mA cm-2 current density in redox-active electrolyte, which is 1.5-fold higher than that of conventional electrolyte (Na2SO4). Further, asymmetric capacitor based on MWCNTs/MnO2 hybrid film as positive and Fe2O3 thin film as negative electrode was fabricated and tested in redox-active electrolytes. Strikingly, MWCNTs/MnO2//Fe2O3 asymmetric cell showed an excellent supercapacitive performance with maximum specific capacitance of 226 Fg-1 and specific energy of 54.39 Wh kg-1 at specific power of 667 Wkg-1. Strikingly, actual practical demonstration shows lightning of 567 red LEDs suggesting "ready-to sell" product for industries. PMID- 27982088 TI - Concepts of ferrovalley material and anomalous valley Hall effect. AB - Valleytronics rooted in the valley degree of freedom is of both theoretical and technological importance as it offers additional opportunities for information storage, as well as electronic, magnetic and optical switches. In analogy to ferroelectric materials with spontaneous charge polarization, or ferromagnetic materials with spontaneous spin polarization, here we introduce a new member of ferroic family, that is, a ferrovalley material with spontaneous valley polarization. Combining a two-band k.p model with first-principles calculations, we show that 2H-VSe2 monolayer, where the spin-orbit coupling coexists with the intrinsic exchange interaction of transition-metal d electrons, is such a room temperature ferrovalley material. We further predict that such system could demonstrate many distinctive properties, for example, chirality-dependent optical band gap and, more interestingly, anomalous valley Hall effect. On account of the latter, functional devices based on ferrovalley materials, such as valley-based nonvolatile random access memory and valley filter, are contemplated for valleytronic applications. PMID- 27982084 TI - Mitochondrial Phylogenomics yields Strongly Supported Hypotheses for Ascaridomorph Nematodes. AB - Ascaridomorph nematodes threaten the health of humans and other animals worldwide. Despite their medical, veterinary and economic importance, the identification of species lineages and establishing their phylogenetic relationships have proved difficult in some cases. Many working hypotheses regarding the phylogeny of ascaridomorphs have been based on single-locus data, most typically nuclear ribosomal RNA. Such single-locus hypotheses lack independent corroboration, and for nuclear rRNA typically lack resolution for deep relationships. As an alternative approach, we analyzed the mitochondrial (mt) genomes of anisakids (~14 kb) from different fish hosts in multiple countries, in combination with those of other ascaridomorphs available in the GenBank database. The circular mt genomes range from 13,948-14,019 bp in size and encode 12 protein-coding genes, 2 ribosomal RNAs and 22 transfer RNA genes. Our analysis showed that the Pseudoterranova decipiens complex consists of at least six cryptic species. In contrast, the hypothesis that Contracaecum ogmorhini represents a complex of cryptic species is not supported by mt genome data. Our analysis recovered several fundamental and uncontroversial ascaridomorph clades, including the monophyly of superfamilies and families, except for Ascaridiidae, which was consistent with the results based on nuclear rRNA analysis. In conclusion, mt genome analysis provided new insights into the phylogeny and taxonomy of ascaridomorph nematodes. PMID- 27982089 TI - Broadband and wide-angle RCS reduction using a 2-bit coding ultrathin metasurface at terahertz frequencies. AB - A novel broadband and wide-angle 2-bit coding metasurface for radar cross section (RCS) reduction is proposed and characterized at terahertz (THz) frequencies. The ultrathin metasurface is composed of four digital elements based on a metallic double cross line structure. The reflection phase difference of neighboring elements is approximately 90 degrees over a broadband THz frequency. The mechanism of RCS reduction is achieved by optimizing the coding element sequences, which redirects the electromagnetic energies to all directions in broad frequencies. An RCS reduction of less than -10 dB bandwidth from 0.7 THz to 1.3 THz is achieved in the experimental and numerical simulations. The simulation results also show that broadband RCS reduction can be achieved at an incident angle below 60 degrees for TE and TM polarizations under flat and curve coding metasurfaces. These results open a new approach to flexibly control THz waves and may offer widespread applications for novel THz devices. PMID- 27982090 TI - Recombinant Marek's disease virus type 1 provides full protection against very virulent Marek's and infectious bursal disease viruses in chickens. AB - Marek's disease virus (MDV) is a preferred vector in the construction of recombinant vaccines. However, bivalent vaccine based on MDV that confers full protection against both very virulent Marek's and infectious bursal disease virus (IBDV) infections in chickens has not been produced. Here we developed a system utilizing overlapping fosmid DNAs transfection that rescues an MDV type 1 (MDV1) vaccine strain. Using this system, we inserted the IBDV VP2 gene at MDV1 genome sites UL41, US10 and US2. The VP2 protein was stably expressed in the recombinant MDV-infected cells and self-assembled into IBDV subviral particles. Insertion of the VP2 gene did not affect the replication phenotype of MDV in cell cultures, nor did it increase the virulence of the MDV vaccine strain in chickens. After challenge with very virulent IBDV, r814US2VP2 conferred full protection, whereas r814UL41VP2 and r814US10VP2 provided partial or no protection. All the three recombinant vaccines provided full protection against very virulent MDV challenge in chickens. These results demonstrated that r814US2VP2 could be used as a promising bivalent vaccine against both Marek's and infectious bursal diseases in chickens. PMID- 27982093 TI - Interplay of multiple synaptic plasticity features in filamentary memristive devices for neuromorphic computing. AB - Bio-inspired computing represents today a major challenge at different levels ranging from material science for the design of innovative devices and circuits to computer science for the understanding of the key features required for processing of natural data. In this paper, we propose a detail analysis of resistive switching dynamics in electrochemical metallization cells for synaptic plasticity implementation. We show how filament stability associated to joule effect during switching can be used to emulate key synaptic features such as short term to long term plasticity transition and spike timing dependent plasticity. Furthermore, an interplay between these different synaptic features is demonstrated for object motion detection in a spike-based neuromorphic circuit. System level simulation presents robust learning and promising synaptic operation paving the way to complex bio-inspired computing systems composed of innovative memory devices. PMID- 27982092 TI - Incomplete DRB4-dependence of the DCL4-mediated antiviral defense. AB - The double-stranded RNA-binding protein DRB4 of Arabidopsis was shown previously to contribute to the DICER-LIKE 4 (DCL4)-mediated biogenesis of viral small interfering RNAs (vsiRNAs) of 21 nucleotides (nt) in size. However, it is unclear whether all 21-nt vsiRNAs are dependent on this DRB4-DCL4 partnership. To resolve this question, we generated dcl2drb4 and dcl4drb4 double knockout mutants, and subjected them to infections with CPB-CC-PDS, a turnip crinkle virus mutant capable of inducing silencing of the PHYTOENE DESATURASE gene. The dcl2drb4 double knockouts caused a far smaller loss of antiviral silencing than dcl2dcl4. In addition, although both drb4 and dcl4 single mutants permitted a consistent (but small) increase in viral RNA levels, the drb4 mutant correlated with a less pronounced reduction of 21-nt vsiRNAs. Therefore, a substantial subset of DCL4 antiviral activity is DRB4-independent, and may involve other DRB proteins that compensate for loss of DRB4. PMID- 27982091 TI - A detergent-based procedure for the preparation of IgG-like bispecific antibodies in high yield. AB - Bispecific antibodies (BsAbs), with the ability to recognize two different epitopes simultaneously, offer remarkable advantages in bioassays, cancer therapy, biosensors, and enzyme electrodes. Preparation and purification of BsAbs in adequate quantities remains a major hurdle in their use in various applications. Poor yield is also the principal limitation in the preparation of BsAbs by the redox procedure. IgG with reduced inter-heavy chain disulfides do not dissociate into half molecules at neutral pH. In this study, we report that the dissociation occurs in presence of sodium dodecyl sulphate (SDS) and inclusion of the detergent during the redox procedure results in remarkable increase in the formation of the BsAbs. Exposure of antibodies to 0.1% (w/v) SDS causes only minor loss in secondary/tertiary structure and the ability to bind the antigen. The BsAbs prepared using the modified redox procedure that recognize the antigens HRP and alpha-LA were prepared and successfully employed for detecting alpha-LA in milk/dairy products by ELISA and dot blot techniques. BsAbs were also prepared from partially purified immunoglobulin gamma (IgG). This work shows for the first time that SDS, by dissociating IgG with reduced inter-heavy chain disulfides into half molecules, markedly enhances the formation of BsAbs by the redox procedure. PMID- 27982095 TI - Improved charge carrier lifetime in planar perovskite solar cells by bromine doping. AB - The charge carrier lifetime is an important parameter in solar cells as it defines, together with the mobility, the diffusion length of the charge carriers, thus directly determining the optimal active layer thickness of a device. Herein, we report on charge carrier lifetime values in bromine doped planar methylammonium lead iodide (MAPbI3) solar cells determined by transient photovoltage. The corresponding charge carrier density has been derived from charge carrier extraction. We found increased lifetime values in solar cells incorporating bromine compared to pure MAPbI3 by a factor of ~2.75 at an illumination intensity corresponding to 1 sun. In the bromine containing solar cells we additionally observe an anomalously high value of extracted charge, which we deduce to originate from mobile ions. PMID- 27982094 TI - Huangqin-tang ameliorates dextran sodium sulphate-induced colitis by regulating intestinal epithelial cell homeostasis, inflammation and immune response. AB - Huangqin-tang (HQT) is a traditional Chinese medicine (TCM) formula widely used for the treatment of inflammatory bowel disease in China. However, the molecular mechanisms by which HQT protects the colon are unclear. We studied the protective effects of HQT and the underlying mechanisms in an experimental mouse model and in vitro. In vivo, dextran sodium sulphate (DSS)-induced acute and chronic colitis were significantly ameliorated by HQT as gauged by phenotypic, histopathologic and inflammatory manifestations of the disease. Mechanistically, DSS-induced nuclear factor-kappaB (NF-kappaB) signalling was inhibited by HQT. Moreover, HQT-treated mice demonstrated significant changes in cell apoptosis, expression of apoptosis-associated genes such as caspase-3, bax, bcl-2, and intestinal permeability. HQT also increased occluding and zonula occludens-1 (ZO 1), inhibited cell proliferation (Ki67), and increased regulatory T cells numbers, protein expression of Foxp3 and IL-10 in the colonic tissue. In vitro, HQT down-regulated production of pro-inflammatory cytokines and supressed the NF kappaB signalling pathway in lipopolysaccharides-induced RAW 264.7 macrophages. Our study suggests that HQT plays a critical role in regulating intestinal epithelial cell homeostasis, inflammation and immune response in colitis and offers novel therapeutic options in the management of inflammatory bowel disease. PMID- 27982096 TI - A structural insight into the negative effects of opioids in analgesia by modulating the TLR4 signaling: An in silico approach. AB - Opioids are considered the gold standard therapy for pain. However, TLR-dependent negative effects in analgesia have highlighted the complexities in the pharmacodynamics of opioids. While successive studies have reported that morphine and Morphine-3-glucuronide (M3G) activate the TLR4 pathway, the structural details of this mechanism are lacking. Here, we have utilized various computational tools to reveal the structural dynamics of the opioid-bound TLR4/MD2 complex, and have proposed a potential TLR4 activation mechanism. Our results support previous findings, and include the novel insight that the stable binding of morphine and naloxone, but not M3G, in the MD2 cavity, is TLR4 dependent. Morphine interacts with MD2 near its Phe126 loop to induce the active conformation (MD2C); however, this binding is likely reversible, and the complex gains stability upon interaction with TLR4. M3G also induces the MD2C state, with both the Phe126 loop and the H1 loop being involved in MD2-M3G complex stability. Remarkably, naloxone, which requires TLR4 interaction for complex stability, switches the conformation of the gating loop to the inactive state (MD2 degrees ). Cumulatively, our findings suggest that ligand binding and receptor clustering occur successively in opioid-induced TLR4 signaling, and that MD2 plasticity and pocket hydrophobicity are crucial for the recognition and accommodation of ligands. PMID- 27982098 TI - ARN: Analysis and Visualization System for Adipogenic Regulation Network Information. AB - Adipogenesis is the process of cell differentiation through which preadipocytes become adipocytes. Lots of research is currently ongoing to identify genes, including their gene products and microRNAs, that correlate with fat cell development. However, information fragmentation hampers the identification of key regulatory genes and pathways. Here, we present a database of literature-curated adipogenesis-related regulatory interactions, designated the Adipogenesis Regulation Network (ARN, http://210.27.80.93/arn/), which currently contains 3101 nodes (genes and microRNAs), 1863 regulatory interactions, and 33,969 expression records associated with adipogenesis, based on 1619 papers. A sentence-based text mining approach was employed for efficient manual curation of regulatory interactions from approximately 37,000 PubMed abstracts. Additionally, we further determined 13,103 possible node relationships by searching miRGate, BioGRID, PAZAR and TRRUST. ARN also has several useful features: i) regulatory map information; ii) tests to examine the impact of a query node on adipogenesis; iii) tests for the interactions and modes of a query node; iv) prediction of interactions of a query node; and v) analysis of experimental data or the construction of hypotheses related to adipogenesis. In summary, ARN can store, retrieve and analyze adipogenesis-related information as well as support ongoing adipogenesis research and contribute to the discovery of key regulatory genes and pathways. PMID- 27982097 TI - Induction of a Cellular DNA Damage Response by Porcine Circovirus Type 2 Facilitates Viral Replication and Mediates Apoptotic Responses. AB - Cellular DNA damage response (DDR) triggered by infection of DNA viruses mediate cell cycle checkpoint activation, DNA repair, or apoptosis induction. In the present study, infection of porcine circovirus type 2 (PCV2), which serves as a major etiological agent of PCV2-associated diseases (PCVAD), was found to elicit a DNA damage response (DDR) as observed by the phosphorylation of H2AX and RPA32 following infection. The response requires active viral replication, and all the ATM (ataxia telangiectasia-mutated kinase), ATR (ATM- and Rad3-related kinase), and DNA-PK (DNA-dependent protein kinase) are the transducers of the DDR signaling events in the PCV2-infected cells as demonstrated by the phosphorylation of ATM, ATR, and DNA-PK signalings as well as reductions in their activations after treatment with specific kinase inhibitors. Inhibitions of ATM, ATR, and DNA-PK activations block viral replication and prevent apoptotic responses as observed by decreases in cleaved poly-ADP ribose polymerase (PARP) and caspase-3 as well as fragmented DNA following PCV2 infection. These results reveal that PCV2 is able to exploit the cellular DNA damage response machinery for its own efficient replication and for apoptosis induction, further extending our understanding for the molecular mechanism of PCV2 infection. PMID- 27982099 TI - Co-expression analysis and identification of fecundity-related long non-coding RNAs in sheep ovaries. AB - Small Tail Han sheep, including the FecBBFecBB (Han BB) and FecB+ FecB+ (Han++) genotypes, and Dorset sheep exhibit different fecundities. To identify novel long non-coding RNAs (lncRNAs) associated with sheep fecundity to better understand their molecular mechanisms, a genome-wide analysis of mRNAs and lncRNAs from Han BB, Han++ and Dorset sheep was performed. After the identification of differentially expressed mRNAs and lncRNAs, 16 significant modules were explored by using weighted gene coexpression network analysis (WGCNA) followed by functional enrichment analysis of the genes and lncRNAs in significant modules. Among these selected modules, the yellow and brown modules were significantly related to sheep fecundity. lncRNAs (e.g., NR0B1, XLOC_041882, and MYH15) in the yellow module were mainly involved in the TGF-beta signalling pathway, and NYAP1 and BCORL1 were significantly associated with the oxytocin signalling pathway, which regulates several genes in the coexpression network of the brown module. Overall, we identified several gene modules associated with sheep fecundity, as well as networks consisting of hub genes and lncRNAs that may contribute to sheep prolificacy by regulating the target mRNAs related to the TGF-beta and oxytocin signalling pathways. This study provides an alternative strategy for the identification of potential candidate regulatory lncRNAs. PMID- 27982101 TI - Effect of hydrothermal pretreatment on the structural changes of alkaline ethanol lignin from wheat straw. AB - Due to the enormous abundance of lignin and its unique aromatic nature, lignin has great potential for the production of industrially useful fuels, chemicals, and materials. However, the rigid and compact structure of the plant cell walls significantly blocks the separation of lignin. In this study, wheat straw was hydrothermally pretreated at different temperatures (120-200 degrees C) followed by post-treatment with 70% ethanol containing 1% NaOH to improve the isolation of lignin. Results demonstrated that the content of associated carbohydrates of the lignin fractions was gradually reduced with the increment of the hydrothermal severity. The structure of the lignins changed regularly with the increase of the pretreatment temperature from 120 to 200 degrees C. In particular, the contents of beta-O-4', beta-beta', beta-5' linkages and aliphatic OH in the lignins showed a tendency of decrease, while the content of phenolic OH and thermal stability of the lignin fractions increased steadily as the increment of the pretreatment temperature. PMID- 27982100 TI - Spontaneous Isopeptide Bond Formation as a Powerful Tool for Engineering Site Specific Antibody-Drug Conjugates. AB - Spontaneous isopeptide bond formation, a stabilizing posttranslational modification that can be found in gram-positive bacterial cell surface proteins, has previously been used to develop a peptide-peptide ligation technology that enables the polymerization of tagged-proteins catalyzed by SpyLigase. Here we adapted this technology to establish a novel modular antibody labeling approach which is based on isopeptide bond formation between two recognition peptides, SpyTag and KTag. Our labeling strategy allows the attachment of a reporting cargo of interest to an antibody scaffold by fusing it chemically to KTag, available via semi-automated solid-phase peptide synthesis (SPPS), while equipping the antibody with SpyTag. This strategy was successfully used to engineer site specific antibody-drug conjugates (ADCs) that exhibit cytotoxicities in the subnanomolar range. Our approach may lead to a new class of antibody conjugates based on peptide-tags that have minimal effects on protein structure and function, thus expanding the toolbox of site-specific antibody conjugation. PMID- 27982103 TI - Highly energetic phenomena in water electrolysis. AB - Water electrolysis performed in microsystems with a fast change of voltage polarity produces optically invisible nanobubbles containing H2 and O2 gases. In this form the gases are able to the reverse reaction of water formation. Here we report extreme phenomena observed in a millimeter-sized open system. Under a frequency of driving pulses above 100 kHz the process is accompanied by clicking sounds repeated every 50 ms or so. Fast video reveals that synchronously with the click a bubble is growing between the electrodes which reaches a size of 300 MUm in 50 MUs. Detailed dynamics of the system is monitored by means of a vibrometer by observing a piece of silicon floating above the electrodes. The energy of a single event is estimated as 0.3 MUJ and a significant part of this energy is transformed into mechanical work moving the piece. The observations are explained by the combustion of hydrogen and oxygen mixture in the initial bubble with a diameter of about 40 MUm. Unusual combustion mechanism supporting spontaneous ignition at room temperature is responsible for the process. The observed effect demonstrates a principal possibility to build a microscopic internal combustion engine. PMID- 27982102 TI - Sustained maternal hyperoxygenation improves aortic arch dimensions in fetuses with coarctation. AB - The aim was to investigate the impact of maternal hyperoxygenation (HO) on cardiac dimensions in fetuses with isolated Coarctation (CoA). Fetal echocardiography was performed serially in 48 fetuses with CoA and gestation age matched normal fetues. The Z-scores for the mitral valve (MV), tricuspid valve (TV), aortic valve (AV), ascending aorta (AAo), isthmus, pulmonary valve (PV), main pulmonary artery (MPA), and descending aorta (DAo) were measured and compared among normal fetuses, CoA fetuses with oxygen and CoA fetuses with air. In the group with oxygen, 6 L/min oxygen was administered to the mother using a face mask. Regression analyses were performed to identify potential factors for HO outcome. The left heart dimension Z-scores increased gradually during HO therapy periods, especially at 4 weeks after oxygen therapy (P < 0.05). As for the case group with air, the left heart dimension remained unchanged. The duration of HO was associated with aortic arch Z-scores (adjusted R2 = 0.199, 0.60 for AAO and isthmus, respectively). Sustained maternal middle-flow oxygenation can be safely used to improve left heart dimensions in fetuses with isolated CoA. The duration of HO were associated with treatment outcome. These findings may provide useful information for developing novel treatment strategies. PMID- 27982104 TI - Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases. AB - Protease-antiprotease imbalance and oxidative stress are considered to be major pathophysiological hallmarks of severe obstructive lung diseases including chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), but limited information is available on their direct roles in the regulation of pulmonary phenotypes. Here, we utilized betaENaC-transgenic (Tg) mice, the previously established mouse model of severe obstructive lung diseases, to produce lower-mortality but pathophysiologically highly useful mouse model by backcrossing the original line with C57/BL6J mice. C57/BL6J-betaENaC-Tg mice showed higher survival rates and key pulmonary abnormalities of COPD/CF, including mucous hypersecretion, inflammatory and emphysematous phenotypes and pulmonary dysfunction. DNA microarray analysis confirmed that protease- and oxidative stress-dependent pathways are activated in the lung tissue of C57/BL6J betaENaC-Tg mice. Treatments of C57/BL6J-betaENaC-Tg mice with a serine protease inhibitor ONO-3403, a derivative of camostat methylate (CM), but not CM, and with an anti-oxidant N-acetylcystein significantly improved pulmonary emphysema and dysfunction. Moreover, depletion of a murine endogenous antioxidant vitamin C (VC), by genetic disruption of VC-synthesizing enzyme SMP30 in C57/BL6J-betaENaC Tg mice, exaggerated pulmonary phenotypes. Thus, these assessments clarified that protease-antiprotease imbalance and oxidative stress are critical pathways that exacerbate the pulmonary phenotypes of C57/BL6J-betaENaC-Tg mice, consistent with the characteristics of human COPD/CF. PMID- 27982105 TI - Nrf2 inhibits epithelial-mesenchymal transition by suppressing snail expression during pulmonary fibrosis. AB - Epithelial-mesenchymal transition (EMT) is a phenotype conversion that plays a critical role in the development of pulmonary fibrosis (PF). It is known that snail could regulate the progression of EMT. Nuclear factor erythroid 2 related factor 2 (Nrf2), a key regulator of antioxidant defense system, protects cells against oxidative stress. However, it is not known whether Nrf2 regulates snail thereby modulating the development of PF. Here, bleomycin (BLM) was intratracheally injected into both Nrf2-knockout (Nrf2-/-) and wild-type mice to compare the development of PF. Rat type II alveolar epithelial cells (RLE-6TN) were treated with a specific Nrf2 activator sulforaphane, or transfected with Nrf2 and snail siRNAs to determine their effects on transforming growth factor beta1 (TGF-beta1)-induced EMT. We found that BLM-induced EMT and lung fibrosis were more severe in Nrf2-/- mice compared to wild-type mice. In vitro, sulforaphane treatment attenuated TGF-beta1-induced EMT, accompanied by the down regulation of snail. Inversely, silencing Nrf2 by siRNA enhanced TGF-beta1 induced EMT along with increased expression of snail. Interestingly, when snail was silenced by siRNA, sulforaphane treatment was unable to reduce the progression of EMT in RLE-6TN cells. These findings suggest that Nrf2 attenuates EMT and fibrosis process by regulating the expression of snail in PF. PMID- 27982106 TI - Protein knotting through concatenation significantly reduces folding stability. AB - Concatenation by covalent linkage of two protomers of an intertwined all-helical HP0242 homodimer from Helicobacter pylori results in the first example of an engineered knotted protein. While concatenation does not affect the native structure according to X-ray crystallography, the folding kinetics is substantially slower compared to the parent homodimer. Using NMR hydrogen deuterium exchange analysis, we showed here that concatenation destabilises significantly the knotted structure in solution, with some regions close to the covalent linkage being destabilised by as much as 5 kcal mol-1. Structural mapping of chemical shift perturbations induced by concatenation revealed a pattern that is similar to the effect induced by concentrated chaotrophic agent. Our results suggested that the design strategy of protein knotting by concatenation may be thermodynamically unfavourable due to covalent constrains imposed on the flexible fraying ends of the template structure, leading to rugged free energy landscape with increased propensity to form off-pathway folding intermediates. PMID- 27982108 TI - High maltose sensitivity of sweet taste receptors in the Japanese macaque (Macaca fuscata). AB - Taste sensitivity differs among animal species depending on feeding habitat. To humans, sucrose is one of the sweetest natural sugars, and this trait is expected to be similar in other primates. However, previous behavioral tests have shown that some primate species have equal preferences for maltose and sucrose. Because sweet tastes are recognized when compounds bind to the sweet taste receptor Tas1R2/Tas1R3, we evaluated the responses of human and Japanese macaque Tas1R2/Tas1R3 to various natural sugars using a heterologous expression system. Human Tas1R2/Tas1R3 showed high sensitivity to sucrose, as expected; however, Japanese macaque Tas1R2/Tas1R3 showed equally high sensitivity to maltose and sucrose. Furthermore, Japanese macaques showed equally high sensitivity to sucrose and maltose in a two-bottle behavioral experiment. These results indicate that Japanese macaques have high sensitivity to maltose, and this sensitivity is directly related to Tas1R2/Tas1R3 function. This is the first molecular biological evidence that for some primate species, sucrose is not the most preferable natural sugar, as it is for humans. PMID- 27982107 TI - Recent breeding programs enhanced genetic diversity in both desi and kabuli varieties of chickpea (Cicer arietinum L.). AB - In order to understand the impact of breeding on genetic diversity and gain insights into temporal trends in diversity in chickpea, a set of 100 chickpea varieties released in 14 countries between 1948 and 2012 were re-sequenced. For analysis, the re-sequencing data for 29 varieties available from an earlier study was also included. Copy number variations and presence absence variations identified in the present study have potential to drive phenotypic variations for trait improvement. Re-sequencing of a large number of varieties has provided opportunities to inspect the genetic and genomic changes reflecting the history of breeding, which we consider as breeding signatures and the selected loci may provide targets for crop improvement. Our study also reports enhanced diversity in both desi and kabuli varieties as a result of recent chickpea breeding efforts. The current study will aid the explicit efforts to breed for local adaptation in the context of anticipated climate changes. PMID- 27982109 TI - Graphene damage effects on radiation-resistance and configuration of copper graphene nanocomposite under irradiation: A molecular dynamics study. AB - Metal-graphene nanocomposite is a kind of potential radiation tolerant material. Graphene damage of the composite is inevitable within radiation environments. In this paper, two kinds of copper-graphene nanocomposite (CGNC) systems containing perfect graphene and prefabricated damage graphene, respectively, were adopted to expound the influences of graphene damage on the properties (radiation-resistance and configuration) of CGNC under irradiation by atomistic simulations. In the CGNC containing perfect graphene, the increasing graphene damage induced by the increase of the number of cascades, did not obviously impair the role of copper graphene interface in keeping the properties of CGNC. In the CGNC containing prefabricated damage graphene, the properties of CGNC would significantly deteriorate once the radius of prefabricated damage exceeds 10 A, and even stacking fault tetrahedral would occur in the CGNC. The results highlighted that prefabricated graphene damage have greater effects on the change of the properties of CGNC. Therefore, it is very necessary to maintain the structural integrity of graphene for improving the radiation-resistance and configuration of CGNC. PMID- 27982113 TI - A Jurassic wood providing insights into the earliest step in Ginkgo wood evolution. AB - The fossil record of Ginkgo leaf and reproductive organs has been well dated to the Mid-Jurassic (170 Myr). However, the fossil wood record that can safely be assigned to Ginkgoales has not yet been reported from strata predating the late Early Cretaceous (ca. 100 Myr). Here, we report a new fossil wood from the Mid Late Jurassic transition deposit (153-165 Myr) of northeastern China. The new fossil wood specimen displays several Ginkgo features, including inflated axial parenchyma and intrusive tracheid tips. Because it is only slightly younger than the oldest recorded Ginkgo reproductive organs (the Yima Formation, 170 Myr), this fossil wood very probably represents the oldest bona fide fossil Ginkgo wood and the missing ancestral form of Ginkgo wood evolution. PMID- 27982112 TI - Usefulness of CHA2DS2-VASc Scoring Systems for Predicting Risk of Perioperative Embolism in Patients of Cardiac Myxomas Underwent Surgical Treatment. AB - Cardiac myxomas are rare but manifested with risk of embolism and often cause unexpected symptoms or sudden death. We retrospectively collected the medical records of patients diagnosed of cardiac myxomas at the cardiac center of our university. Overall 465 patients were included in this study, patients in the embolism group had significantly higher CHA2DS2-VASc scores (P = 0.005). In embolic group, stroke was recorded in 110 (77.14%) patients, while embolic events in the limbs were observed in 10 (2.15%) and 9(1.93%) developed splenic infarction. Patients in embolism group had older age (P = 0.021) and higher BMI (P <0.001) than those in non-embolism group. There was no significant difference between two groups in terms of time of mechanical ventilation (P = 0.065), ICU stay (P = 0.053), hospital stay (P = 0.071) and volume of drainage (P = 0.083), blood transfusions (P = 0.060) except that patients with embolic events had significantly higher incidence of postoperative atrial fibrillation (P = 0.032) and lower survival rate (P < 0.001). Furthermore, the CHA2DS2-VASc score was a significant predictor of embolism in patients with cardiac myxomas (P = 0.015; P = 0.003) and the Kaplan-Meier analysis obtained a higher rate of embolism in patients with higher stratification of CHA2DS2-VASc scores (P = 0.002). In conclusion, CHA2DS2-VASc scoring scheme was strongly predictive of stroke and embolic events in patients with cardiac myxomas. PMID- 27982111 TI - Dual-seq transcriptomics reveals the battle for iron during Pseudomonas aeruginosa acute murine pneumonia. AB - Determining bacterial gene expression during infection is fundamental to understand pathogenesis. In this study, we used dual RNA-seq to simultaneously measure P. aeruginosa and the murine host's gene expression and response to respiratory infection. Bacterial genes encoding products involved in metabolism and virulence were differentially expressed during infection and the type III and VI secretion systems were highly expressed in vivo. Strikingly, heme acquisition, ferric-enterobactin transport, and pyoverdine biosynthesis genes were found to be significantly up-regulated during infection. In the mouse, we profiled the acute immune response to P. aeruginosa and identified the pro-inflammatory cytokines involved in acute response to the bacterium in the lung. Additionally, we also identified numerous host iron sequestration systems upregulated during infection. Overall, this work sheds light on how P. aeruginosa triggers a pro-inflammatory response and competes for iron with the host during infection, as iron is one of the central elements for which both pathogen and host fight during acute pneumonia. PMID- 27982110 TI - An effective treatment of experimental osteomyelitis using the antimicrobial titanium/silver-containing nHP66 (nano-hydroxyapatite/polyamide-66) nanoscaffold biomaterials. AB - Effective treatment of osteomyelitis remains a formidable clinical challenge. The rapid emergence of multidrug-resistant bacteria has renewed interest in developing antimicrobial biomaterials using antiseptic silver ions to treat osteomyelitis. However, inadequate local retention and severe cytotoxic effects have limited the clinical use of ionic silver for bone grafts. We recently developed novel porous nano-hydroxyapatite/polyamide 66 (nHP66)-based nanoscaffold materials containing varied concentrations of silver ions (Ag+) (TA nHAPA66) and oxidized titanium (TiO2), which was added as a second binary element to enhance antibacterial activity and biocompatibility. In this study, we establish a large cohort of rabbit model of experimental osteomyelitis and investigate the in vivo antimicrobial and therapeutic effects of TA-nHP66 biomaterials and their in vivo silver release kinetics. We find the TA-nHP66 scaffolds exhibit potent antibacterial activities against E. coli and S. aureus, support cell adhesion and cell proliferation of pre-osteoblasts, and stimulate osteogenic regulator/marker expression. Moreover, the TA2-nHP66 scaffold exerts potent antibacterial/anti-inflammation effects in vivo and promotes bone formation at the lesion site of osteomyelitis. We further demonstrate that TA2 nHP66 exhibits excellent biosafety profile without apparent systemic toxicities. Therefore, the TA-nHP66 scaffold biomaterials may be further explored as an effective adjuvant therapy for infected bone defects and/or osteomyelitis debridement. PMID- 27982114 TI - Shared and unique patterns of phenotypic diversification along a stream gradient in two congeneric species. AB - Stream ecosystems show gradual variation of various selection factors, which can result in a zonation of species distributions and gradient evolution of morphological and life-history traits within species. Identifying the selective agents underlying such phenotypic evolution is challenging as different species could show shared and/or unique (species-specific) responses to components of the river gradient. We studied a stream gradient inhabited by two mosquitofishes (genus Gambusia) in the Rio Grijalva basin in southern Mexico and found a patchy distribution pattern of both congeners along a stretch of 100 km, whereby one species was usually dominant at a given site. We uncovered both shared and unique patterns of diversification: some components of the stream gradient, including differences in piscine predation pressure, drove shared patterns of phenotypic divergence, especially in females. Other components of the gradient, particularly abiotic factors (max. annual temperature and temperature range) resulted in unique patterns of divergence, especially in males. Our study highlights the complexity of selective regimes in stream ecosystems. It exemplifies that even closely related, congeneric species can respond in unique ways to the same components of the river gradient and shows how both sexes can exhibit quite different patterns of divergence in multivariate phenotypic character suites. PMID- 27982115 TI - Generation of kidney tubular organoids from human pluripotent stem cells. AB - Recent advances in stem cell research have resulted in methods to generate kidney organoids from human pluripotent stem cells (hPSCs), which contain cells of multiple lineages including nephron epithelial cells. Methods to purify specific types of cells from differentiated hPSCs, however, have not been established well. For bioengineering, cell transplantation, and disease modeling, it would be useful to establish those methods to obtain pure populations of specific types of kidney cells. Here, we report a simple two-step differentiation protocol to generate kidney tubular organoids from hPSCs with direct purification of KSP (kidney specific protein)-positive cells using anti-KSP antibody. We first differentiated hPSCs into mesoderm cells using a glycogen synthase kinase-3beta inhibitor for 3 days, then cultured cells in renal epithelial growth medium to induce KSP+ cells. We purified KSP+ cells using flow cytometry with anti-KSP antibody, which exhibited characteristics of all segments of kidney tubular cells and cultured KSP+ cells in 3D Matrigel, which formed tubular organoids in vitro. The formation of tubular organoids by KSP+ cells induced the acquisition of functional kidney tubules. KSP+ cells also allowed for the generation of chimeric kidney cultures in which human cells self-assembled into 3D tubular structures in combination with mouse embryonic kidney cells. PMID- 27982117 TI - Galectin-3 Induces a Pro-degradative/inflammatory Gene Signature in Human Chondrocytes, Teaming Up with Galectin-1 in Osteoarthritis Pathogenesis. AB - Inflammatory chemo- and cytokines and matrix-degrading proteases underlie the progression of osteoarthritis (OA). Aiming to define upstream regulators for these disease markers, we pursued initial evidence for an upregulation of members of the adhesion/growth-regulatory galectin family. Immunohistochemical localization of galectin-3 (Gal-3) in sections of human cartilage with increasing levels of degeneration revealed a linear correlation reaching a chondrocyte positivity of 60%. Presence in situ was cytoplasmic, the lectin was secreted from OA chondrocytes in culture and binding of Gal-3 yielded lactose-inhibitable surface staining. Exposure of cells to the lectin led to enhanced gene expression and secretion of functional disease markers. Genome-wide transcriptomic analysis broadened this result to reveal a pro-degradative/inflammatory gene signature under the control of NF-kappaB. Fittingly, targeting this route of activation by inhibitors impaired the unfavourable response to Gal-3 binding, as also seen by shortening the lectin's collagen-like repeat region. Gal-3's activation profile overlaps with that of homodimeric galectin-1 (Gal-1) and also has distinctive (supplementing) features. Tested at subsaturating concentrations in a mixture, we found cooperation between the two galectins, apparently able to team up to promote OA pathogenesis. In summary, our results suggest that a network of endogenous lectins is relevant for initiating this process cascade. PMID- 27982118 TI - Brusatol inhibits HIF-1 signaling pathway and suppresses glucose uptake under hypoxic conditions in HCT116 cells. AB - Hypoxia-inducible factor-1 (HIF-1) is an important transcription factor that induces adaptive responses upon low oxygen conditions in human cancers and triggers off a poor prognostic outcome of conventional treatments. In this study, we discovered for the first time that brusatol (BRU), a quassinoid extracted from Brucea Esters, has the capability to inhibit HIF-1 signaling pathway. We found that BRU concentration-dependently down-regulated HIF-1alpha protein levels under hypoxia or CoCl2-induced mimic hypoxia in HCT116 cells without causing significant cytotoxicity. Besides, the transactivation activity of HIF-1 was suppressed by BRU under hypoxic conditions, as well as the expression of HIF-1 target genes, including VEGF, GLUT1, HK2 and LDHA. In addition, BRU can also decrease glucose consumption under hypoxia through inhibition of HIF-1 signaling pathway. Further studies revealed that the inhibitory effect of BRU on HIF-1 signaling pathway might be attributed to promoting degradation of HIF-1alpha. Interestingly, intracellular reactive oxygen species (ROS) levels and mitochondrial ROS level were both decreased by BRU treatment, indicating the involvment of mitochondrial ROS regulation in the action of BRU. Taken together, these results provided clear evidence for BRU-mediated HIF-1alpha regulation and suggested its therapeutic potential in colon tumors. PMID- 27982116 TI - A method for high-throughput functional imaging of single cells within heterogeneous cell preparations. AB - Functional characterization of individual cells within heterogeneous tissue preparations is challenging. Here, we report the development of a versatile imaging method that assesses single cell responses of various endpoints in real time, while identifying the individual cell types. Endpoints that can be measured include (but are not limited to) ionic flux (calcium, sodium, potassium and hydrogen), metabolic responsiveness (NAD(P)H, mitochondrial membrane potential), and signal transduction (H2O2 and cAMP). Subsequent to fluorescent imaging, identification of cell types using immunohistochemistry allows for mapping of cell type to their respective functional real time responses. To validate the utility of this method, NAD(P)H responses to glucose of islet alpha versus beta cells generated from dispersed pancreatic islets, followed by the construction of frequency distributions characterizing the variability in the magnitude of each individual cell responses were compared. As expected, no overlap between the glucose response frequency distributions for beta cells versus alpha cells was observed, thereby establishing both the high degree of fidelity and low rate of both false-negatives and false-positives in this approach. This novel method has the ability not only to resolve single cell level functional differences between cell types, but also to characterize functional heterogeneity within a given cell type. PMID- 27982119 TI - Declining Prevalence of Disease Vectors Under Climate Change. AB - More than half of the world population is at risk of vector-borne diseases including dengue fever, chikungunya, zika, yellow fever, leishmaniasis, chagas disease, and malaria, with highest incidences in tropical regions. In Ecuador, vector-borne diseases are present from coastal and Amazonian regions to the Andes Mountains; however, a detailed characterization of the distribution of their vectors has never been carried out. We estimate the distribution of 14 vectors of the above vector-borne diseases under present-day and future climates. Our results consistently suggest that climate warming is likely threatening some vector species with extinction, locally or completely. These results suggest that climate change could reduce the burden of specific vector species. Other vector species are likely to shift and constrain their geographic range to the highlands in Ecuador potentially affecting novel areas and populations. These forecasts show the need for development of early prevention strategies for vector species currently absent in areas projected as suitable under future climate conditions. Informed interventions could reduce the risk of human exposure to vector species with distributional shifts, in response to current and future climate changes. Based on the mixed effects of future climate on human exposure to disease vectors, we argue that research on vector-borne diseases should be cross-scale and include climatic, demographic, and landscape factors, as well as forces facilitating disease transmission at fine scales. PMID- 27982120 TI - Emotional arousal modulates oscillatory correlates of targeted memory reactivation during NREM, but not REM sleep. AB - Rapid eye movement (REM) sleep is considered to preferentially reprocess emotionally arousing memories. We tested this hypothesis by cueing emotional vs. neutral memories during REM and NREM sleep and wakefulness by presenting associated verbal memory cues after learning. Here we show that cueing during NREM sleep significantly improved memory for emotional pictures, while no cueing benefit was observed during REM sleep. On the oscillatory level, successful memory cueing during NREM sleep resulted in significant increases in theta and spindle oscillations with stronger responses for emotional than neutral memories. In contrast during REM sleep, solely cueing of neutral (but not emotional) memories was associated with increases in theta activity. Our results do not support a preferential role of REM sleep for emotional memories, but rather suggest that emotional arousal modulates memory replay and consolidation processes and their oscillatory correlates during NREM sleep. PMID- 27982121 TI - Ionizing radiation from Chernobyl affects development of wild carrot plants. AB - Radioactivity released from disasters like Chernobyl and Fukushima is a global hazard and a threat to exposed biota. To minimize the deleterious effects of stressors organisms adopt various strategies. Plants, for example, may delay germination or stay dormant during stressful periods. However, an intense stress may halt germination or heavily affect various developmental stages and select for life history changes. Here, we test for the consequence of exposure to ionizing radiation on plant development. We conducted a common garden experiment in an uncontaminated greenhouse using 660 seeds originating from 33 wild carrots (Daucus carota) collected near the Chernobyl nuclear power plant. These maternal plants had been exposed to radiation levels that varied by three orders of magnitude. We found strong negative effects of elevated radiation on the timing and rates of seed germination. In addition, later stages of development and the timing of emergence of consecutive leaves were delayed by exposure to radiation. We hypothesize that low quality of resources stored in seeds, damaged DNA, or both, delayed development and halted germination of seeds from plants exposed to elevated levels of ionizing radiation. We propose that high levels of spatial heterogeneity in background radiation may hamper adaptive life history responses. PMID- 27982122 TI - Thiol-Capped Gold Nanoparticles Swell-Encapsulated into Polyurethane as Powerful Antibacterial Surfaces Under Dark and Light Conditions. AB - A simple procedure to develop antibacterial surfaces using thiol-capped gold nanoparticles (AuNPs) is shown, which effectively kill bacteria under dark and light conditions. The effect of AuNP size and concentration on photo-activated antibacterial surfaces is reported and we show significant size effects, as well as bactericidal activity with crystal violet (CV) coated polyurethane. These materials have been proven to be powerful antibacterial surfaces against both Gram-positive and Gram-negative bacteria. AuNPs of 2, 3 or 5 nm diameter were swell-encapsulated into PU before a coating of CV was applied (known as PU-AuNPs CV). The antibacterial activity of PU-AuNPs-CV samples was tested against Staphylococcus aureus and Escherichia coli as representative Gram-positive and Gram-negative bacteria under dark and light conditions. All light conditions in this study simulated a typical white-light hospital environment. This work demonstrates that the antibacterial activity of PU-AuNPs-CV samples and the synergistic enhancement of photoactivity of triarylmethane type dyes is highly dependent on nanoparticle size and concentration. The most powerful PU-AuNPs-CV antibacterial surfaces were achieved using 1.0 mg mL-1 swell encapsulation concentrations of 2 nm AuNPs. After two hours, Gram-positive and Gram-negative bacteria were reduced to below the detection limit (>4 log) under dark and light conditions. PMID- 27982123 TI - Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis. AB - The aim of the present study is to investigate the molecular pathways underlying amyotrophic lateral sclerosis (ALS) pathogenesis within the peripheral nervous system. We analyzed gene expression changes in human motor nerve diagnostic biopsies obtained from eight ALS patients and seven patients affected by motor neuropathy as controls. An integrated transcriptomics and system biology approach was employed. We identified alterations in the expression of 815 genes, with 529 up-regulated and 286 down-regulated in ALS patients. Up-regulated genes clustered around biological process involving RNA processing and protein metabolisms. We observed a significant enrichment of up-regulated small nucleolar RNA transcripts (p = 2.68*10-11) and genes related to endoplasmic reticulum unfolded protein response and chaperone activity. We found a significant down-regulation in ALS of genes related to the glutamate metabolism. Interestingly, a network analysis highlighted HDAC2, belonging to the histone deacetylase family, as the most interacting node. While so far gene expression studies in human ALS have been performed in postmortem tissues, here specimens were obtained from biopsy at an early phase of the disease, making these results new in the field of ALS research and therefore appealing for gene discovery studies. PMID- 27982127 TI - Tuning magnetic spirals beyond room temperature with chemical disorder. AB - In the past years, magnetism-driven ferroelectricity and gigantic magnetoelectric effects have been reported for a number of frustrated magnets featuring ordered spiral magnetic phases. Such materials are of high-current interest due to their potential for spintronics and low-power magnetoelectric devices. However, their low-magnetic ordering temperatures (typically <100 K) greatly restrict their fields of application. Here we demonstrate that the onset temperature of the spiral phase in the perovskite YBaCuFeO5 can be increased by more than 150 K through a controlled manipulation of the Fe/Cu chemical disorder. Moreover, we show that this novel mechanism can stabilize the magnetic spiral state of YBaCuFeO5 above the symbolic value of 25 degrees C at zero magnetic field. Our findings demonstrate that the properties of magnetic spirals, including its wavelength and stability range, can be engineered through the control of chemical disorder, offering a great potential for the design of materials with magnetoelectric properties beyond room temperature. PMID- 27982125 TI - Imaging electric field dynamics with graphene optoelectronics. AB - The use of electric fields for signalling and control in liquids is widespread, spanning bioelectric activity in cells to electrical manipulation of microstructures in lab-on-a-chip devices. However, an appropriate tool to resolve the spatio-temporal distribution of electric fields over a large dynamic range has yet to be developed. Here we present a label-free method to image local electric fields in real time and under ambient conditions. Our technique combines the unique gate-variable optical transitions of graphene with a critically coupled planar waveguide platform that enables highly sensitive detection of local electric fields with a voltage sensitivity of a few microvolts, a spatial resolution of tens of micrometres and a frequency response over tens of kilohertz. Our imaging platform enables parallel detection of electric fields over a large field of view and can be tailored to broad applications spanning lab on-a-chip device engineering to analysis of bioelectric phenomena. PMID- 27982126 TI - Interleukin-12 bypasses common gamma-chain signalling in emergency natural killer cell lymphopoiesis. AB - Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (gammac)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted gammac deletion. Herein we identify an alternative pathway of NK-cell development driven by the proinflammatory cytokine IL-12, which can occur independently of gammac-signalling. In response to viral infection or upon exogenous administration, IL-12 is sufficient to elicit the emergence of a population of CD122+CD49b+ cells by targeting NK-cell precursors (NKPs) in the bone marrow (BM). We confirm the NK-cell identity of these cells by transcriptome-wide analyses and their ability to eliminate tumour cells. Rather than using the conventional pathway of NK-cell development, IL-12-driven CD122+CD49b+ cells remain confined to a NK1.1lowNKp46low stage, but differentiate into NK1.1+NKp46+ cells in the presence of gammac-cytokines. Our data reveal an IL-12-driven hard-wired pathway of emergency NK-cell lymphopoiesis bypassing steady-state gammac-signalling. PMID- 27982128 TI - Microwave control of the superconducting proximity effect and minigap in magnetic and normal metals. AB - We demonstrate theoretically that microwave radiation applied to superconducting proximity structures controls the minigap and other spectral features in the density of states of normal and magnetic metals, respectively. Considering both a bilayer and Josephson junction geometry, we show that microwaves with frequency omega qualitatively alters the spectral properties of the system: inducing a series of resonances, controlling the minigap size Emg, and even replacing the minigap with a strong peak of quasiparticle accumulation at zero energy when omega = Emg. The interaction between light and Cooper pairs may thus open a route to active control of quantum coherent phenomena in superconducting proximity structures. PMID- 27982124 TI - The human intestinal microbiota of constipated-predominant irritable bowel syndrome patients exhibits anti-inflammatory properties. AB - The intestinal microbiota of patients with constipated-predominant irritable bowel syndrome (C-IBS) displays chronic dysbiosis. Our aim was to determine whether this microbial imbalance instigates perturbation of the host intestinal mucosal immune response, using a model of human microbiota-associated rats (HMAR) and dextran sulfate sodium (DSS)-induced experimental colitis. The analysis of the microbiota composition revealed a decrease of the relative abundance of Bacteroides, Roseburia-Eubacterium rectale and Bifidobacterium and an increase of Enterobacteriaceae, Desulfovibrio sp., and mainly Akkermansia muciniphila in C IBS patients compared to healthy individuals. The bacterial diversity of the gut microbiota of healthy individuals or C-IBS patients was maintained in corresponding HMAR. Animals harboring a C-IBS microbiota had reduced DSS colitis with a decreased expression of pro-inflammatory cytokines from innate, Th1, and Th17 responses. The pre-treatment of conventional C57BL/6 mice or HMAR with A. muciniphila, but not with Escherichia coli, prior exposure to DSS also resulted in a reduction of colitis severity, highlighting that the anti-inflammatory effect of the gut microbiota of C-IBS patients is mediated, in part, by A. muciniphila. This work highlights a novel aspect of the crosstalk between the gut microbiota of C-IBS patients and host intestinal homeostasis. PMID- 27982129 TI - Phosphorylation of SKAP by GSK3beta ensures chromosome segregation by a temporal inhibition of Kif2b activity. AB - Chromosome segregation in mitosis is orchestrated by the dynamic interactions between the kinetochore and spindle microtubules. Our recent study shows SKAP is an EB1-dependent, microtubule plus-end tracking protein essential for kinetochore oscillations during mitosis. Here we show that phosphorylation of SKAP by GSK3beta regulates Kif2b depolymerase activity by competing Kif2b for microtubule plus-end binding. SKAP is a bona fide substrate of GSK3beta in vitro and the phosphorylation is essential for an accurate kinetochore-microtubule attachment in cells. The GSK3beta-elicited phosphorylation sites were mapped by mass spectrometry and the phosphomimetic mutant of SKAP can rescue the phenotype of chromosome missegregation in SKAP-suppressed cells. Importantly, GSK3beta elicited phosphorylation promotes SKAP binding to Kif2b to regulate its depolymerase activity at the microtubule plus-ends. Based on those findings, we reason that GSK3beta-SKAP-Kif2b signaling axis constitutes a dynamic link between spindle microtubule plus-ends and mitotic chromosomes to achieve faithful cell division. PMID- 27982132 TI - Sensitive and accurate quantification of human malaria parasites using droplet digital PCR (ddPCR). AB - Accurate quantification of parasite density in the human host is essential for understanding the biology and pathology of malaria. Semi-quantitative molecular methods are widely applied, but the need for an external standard curve makes it difficult to compare parasite density estimates across studies. Droplet digital PCR (ddPCR) allows direct quantification without the need for a standard curve. ddPCR was used to diagnose and quantify P. falciparum and P. vivax in clinical patients as well as in asymptomatic samples. ddPCR yielded highly reproducible measurements across the range of parasite densities observed in humans, and showed higher sensitivity than qPCR to diagnose P. falciparum, and equal sensitivity for P. vivax. Correspondence in quantification was very high (>0.95) between qPCR and ddPCR. Quantification between technical replicates by ddPCR differed 1.5-1.7-fold, compared to 2.4-6.2-fold by qPCR. ddPCR facilitates parasite quantification for studies where absolute densities are required, and will increase comparability of results reported from different laboratories. PMID- 27982131 TI - CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARalpha. AB - CREB3L3 is involved in fatty acid oxidation and ketogenesis in a mutual manner with PPARalpha. To evaluate relative contribution, a combination of knockout and transgenic mice was investigated. On a ketogenic-diet (KD) that highlights capability of hepatic ketogenesis, Creb3l3-/- mice exhibited reduction of expression of genes for fatty oxidation and ketogenesis comparable to Ppara-/- mice. Most of the genes were further suppressed in double knockout mice indicating independent contribution of hepatic CREB3L3. During fasting, dependency of ketogenesis on CREB3L3 is lesser extents than Ppara-/- mice suggesting importance of adipose PPARalpha for supply of FFA and hyperlipidemia in Creb3l3-/- mice. In conclusion CREB3L3 plays a crucial role in hepatic adaptation to energy starvation via two pathways: direct related gene regulation and an auto-loop activation of PPARalpha. Furthermore, as KD-fed Creb3l3-/- mice exhibited severe fatty liver, activating inflammation, CREB3L3 could be a therapeutic target for NAFLD. PMID- 27982130 TI - Lipidomic analysis enables prediction of clinical outcomes in burn patients. AB - Recent discoveries have highlighted the novel metabolic functions of adipose tissue in enhancing hypermetabolism after trauma. As the exact function and expression profiles of serum lipids and free fatty acids (FFA) are essentially unknown, we determined the lipidomic expression profile after burn in correlation to clinical outcomes to identify important lipid mediators affecting post-burn outcomes. We conducted a prospective cohort study with 46 adult burn patients and 5 healthy controls at the Ross Tilley Burn Center in Toronto, Canada. Patients were stratified based on major demographic and clinical variables, including age, burn severity, mortality, and sepsis. Serum FFAs and inflammatory markers were measured during acute hospital stay. We found that FFAs were acutely elevated post-burn and returned to baseline over time. Greater burn severity and age were associated with an impaired acute response in unsaturated FFAs and pro inflammatory cytokines. Elevations in saturated and mono-unsaturated FFAs correlated significantly to increased mortality. In summary, persistent elevation of unsaturated lipids was associated with a functionally altered inflammatory immunological milieu and worse clinical outcomes. The present lipidomic analysis indicates profound alterations in the lipid profile after burn by characterizing key lipids as potential diagnostic and outcome indicators in critically injured patients. PMID- 27982134 TI - TracMouse: A computer aided movement analysis script for the mouse inverted horizontal grid test. AB - In rodents, detection and quantification of motor impairments is difficult. The traction test (inverted grid with mice clinging to the underside) currently has no objective rating system. We here developed and validated the semi-automatic MATLAB script TracMouse for unbiased detection of video-recorded movement patterns. High precision videos were analyzed by: (i) principal identification of anatomical paw details frame-by-frame by an experimentally blinded rater; (ii) automatic retrieval of proxies by TracMouse for individual paws. The basic states of Hold and Step were discriminated as duration and frequency, and these principle parameters were converted into static and dynamic endpoints and their discriminating power assessed in a dopaminergic lesion model. Relative to hind paws, forepaws performed ~4 times more steps, they were ~20% longer, and Hold duration was ~5 times shorter in normal C57Bl/6 mice. Thus, forepaw steps were classified as exploratory, hind paw movement as locomotive. Multiple novel features pertaining to paw sequence, step lengths and exploratory touches were accessible through TracMouse and revealed subtle Parkinsonian phenotypes. Novel proxies using TracMouse revealed previously unidentified features of movement and may aid the understanding of (i) brain circuits related to motor planning and execution, and (ii) phenotype detection in experimental models of movement disorders. PMID- 27982135 TI - Antibiotic free selection for the high level biosynthesis of a silk-elastin-like protein. AB - Silk-elastin-like proteins (SELPs) are a family of genetically engineered recombinant protein polymers exhibiting mechanical and biological properties suited for a wide range of applications in the biomedicine and materials fields. They are being explored as the next generation of biomaterials but low productivities and use of antibiotics during production undermine their economic viability and safety. We have developed an industrially relevant, scalable, fed batch process for the high level production of a novel SELP in E. coli in which the commonly used antibiotic selection marker of the expression vector is exchanged for a post segregational suicide system, the separate-component stabilisation system (SCS). SCS significantly augments SELP productivity but also enhances the product safety profile and reduces process costs by eliminating the use of antibiotics. Plasmid content increased following induction but no significant differences in plasmid levels were discerned when using SCS or the antibiotic selection markers under the controlled fed-batch conditions employed. It is suggested that the absence of competing plasmid-free cells improves host cell viability and enables increased productivity with SCS. With the process developed, 12.8 g L-1 purified SELP was obtained, this is the highest SELP productivity reported to date and clearly demonstrates the commercial viability of these promising polymers. PMID- 27982133 TI - Identifying ultrasensitive HGF dose-response functions in a 3D mammalian system for synthetic morphogenesis. AB - Nonlinear responses to signals are widespread natural phenomena that affect various cellular processes. Nonlinearity can be a desirable characteristic for engineering living organisms because it can lead to more switch-like responses, similar to those underlying the wiring in electronics. Steeper functions are described as ultrasensitive, and can be applied in synthetic biology by using various techniques including receptor decoys, multiple co-operative binding sites, and sequential positive feedbacks. Here, we explore the inherent non linearity of a biological signaling system to identify functions that can potentially be exploited using cell genome engineering. For this, we performed genome-wide transcription profiling to identify genes with ultrasensitive response functions to Hepatocyte Growth Factor (HGF). We identified 3,527 genes that react to increasing concentrations of HGF, in Madin-Darby canine kidney (MDCK) cells, grown as cysts in 3D collagen cell culture. By fitting a generic Hill function to the dose-responses of these genes we obtained a measure of the ultrasensitivity of HGF-responsive genes, identifying a subset with higher apparent Hill coefficients (e.g. MMP1, TIMP1, SNORD75, SNORD86 and ERRFI1). The regulatory regions of these genes are potential candidates for future engineering of synthetic mammalian gene circuits requiring nonlinear responses to HGF signalling. PMID- 27982138 TI - Velocardiofacial Syndrome-Associated Psychiatric Illness and Response to Aripiprazole: A Case Study. PMID- 27982137 TI - Quality of life in patients with gastroschisis is comparable with the general population: A questionnaire survey. AB - AIM: To evaluate long-term quality of life and somatic growth of patients with gastroschisis and compare them with the general population. METHODS: We performed a questionnaire survey of the quality of life of our patients treated between 2004-2012. RESULTS: A questionnaire was sent to our 56 patients with gastroschisis, 38 mothers of patients (68%) responded to the questionnaire. 33 of 38 mothers claim that the quality of life of their child is very good, 4 of them responded that it is good. 1 mother confessed that the quality of life was very poor. Anthropometric data show comparable results with the standard population except for patients of 1 year of age who still have lower weight (P<0.001) and body height in the 5th percentile and patients of 3 years of age who are also significantly thinner. 13% of patients in our study group have gastrointestinal problems. 9 patients (24%) attend follow-up at the neurological center (Attention Deficit Hyperactivity Disorder n=6, mental retardation n=1, dysarthria n=2), however, overall intellectual abilities are within normal range. 7 patients underwent surgery for umbilical (n=3) or inguinal hernia (n=4), 2 patients were operated on for undescended testicles, 3 patients were operated on for an adhesive ileus. 92% of mothers are very satisfied with the cosmetic result of the scar. CONCLUSION: The study has shown that the majority of patients after operation of gastroschisis have a very good quality of life without limitation in comparison with the general population. The presented anthropometric data confirm that the development of patients with gastroschisis is favourable. PMID- 27982139 TI - A Ru-Ru pair housed in ruthenium phthalocyanine: the role of a "cage" architecture in the molecule coupling with the Ag(111) surface. AB - A number of studies have investigated the properties of monomeric and double decker phthalocyanines (Pcs) adsorbed on metal surfaces, in view of applications in spintronics devices. In a combined experimental and theoretical study, we consider here a different member of the Pcs family, the (RuPc)2 dimer, whose structure is characterized by two paired up magnetic centers embedded in a double decker architecture. For (RuPc)2 on Ag(111), we show that this architecture works as a preserving cage by shielding the Ru-Ru pair from a direct interaction with the surface atoms. In fact, while noticeable surface-to-molecule charge transfer occurs with the ensuing quenching of the molecular magnetic moment, such phenomena occur here in the absence of a direct Ru-Ag coupling or structural rearrangement, at variance with other Pcs and thanks to the above shielding effect. These unique properties of the (RuPc)2 architecture are expected to permit an easy control of the surface-to-molecule charge-transfer process as well as of the molecular magnetic properties, thus making the (RuPc)2 dimer a significant paradigm for innovative "cage" structures as well as a promising candidate for applications in spintronics nano or single-molecule devices. PMID- 27982136 TI - IL-34 is associated with the presence and severity of renal dysfunction and coronary artery disease in patients with heart failure. AB - Pro-inflammatory mediators are identified in patients with heart failure (HF), some of which may be used as biomarkers with diagnostic or prognostic value. As an additional ligand of Colony Stimulating Factor-1 Receptor (CSF-1R), interleukin-34 (IL-34) has been identified as a pro-inflammatory cytokine participating in chronic heart failure (CHF). However, the potential impact of IL 34 in CHF complications remains unknown. In order to determine the clinical significance of serum IL-34 in CHF patients, especially those with kidney dysfunction and coronary artery disease (CAD) comorbid conditions, serum IL-34 was measured in 510 consecutive patients with CHF in a cross-sectional study. The present study demonstrated that higher serum IL-34 levels were associated with poorer renal function and more severe anemia in patients with CHF. After adjusting for age, gender, conventional risk factors, and other significant covariates, IL-34 positively correlated with the presence and severity of renal dysfunction (as measured by eGFR and cystatin C) on multivariable linear and logistic regression analysis. IL-34 was also demonstrated to be an independent risk factor for CAD among HF patients. In conclusion, elevated serum IL-34 levels were demonstrated to be independently associated with renal insufficiency and CAD in patients with CHF, regardless of the systolic function. PMID- 27982140 TI - Polyoxometalates as artificial nucleases: hydrolytic cleavage of DNA promoted by a highly negatively charged ZrIV-substituted Keggin polyanion. AB - A highly negatively charged binuclear ZrIV-substituted Keggin polyoxometalate [{alpha-PW11O39Zr(MU-OH)(H2O)}2]8- (ZrK 2 : 2) has been shown to promote the hydrolytic cleavage of phosphoester bonds in the supercoiled plasmid pUC19 DNA under physiological pH and temperature, giving relaxed and linear forms of pUC19 as hydrolysis products. The interaction between ZrK 2 : 2 and DNA was experimentally proven by circular dichroism (CD) spectroscopy and 31P diffusion ordered NMR spectroscopy. PMID- 27982141 TI - Hydrogen bond dynamics governs the effective photoprotection mechanism of plant phenolic sunscreens. AB - Sinapic acid derivatives are important sunscreen species in natural plants, which could provide protection from solar UV radiation. Using a combination of ultrafast excited state dynamics, together with classical molecular dynamics studies, we demonstrate that there is direct coupling of hydrogen bond motion with excited state photoprotection dynamics as part of the basic mechanism in solution. Beyond the intra-molecular degree of freedom, the inter-molecular motions on all timescales are potentially important for the photochemical or photophysical events, ranging from the ultrafast hydrogen bond motion to solvent rearrangements. This provides not only an enhanced understanding of the anomalous experimental spectroscopic results, but also the key idea in the development of sunscreen agents with improved photo-chemical properties. We suggest that the hydrogen bond dynamics coupled excited state photoprotection mechanism may also be possible in a broad range of bio-related molecules in the condensed phase. PMID- 27982143 TI - Water aggregation and dissociation on the ZnO(101[combining macron]0) surface. AB - A comprehensive search for stable structures in the low coverage regime (0-1 ML) and at 2 ML and 3 ML using DFT revealed several new aggregation states of water on the non-polar ZnO(101[combining macron]0) surface. Ladder-like structures consisting of half-dissociated dimers, arranged side-by-side along the polar axis, constitute the most stable aggregate at low coverages (<=1 ML) with a binding energy exceeding that of the monolayer. At coverages beyond the monolayer - a regime that has hardly been studied previously - a novel type of structure with a continuous honeycomb-like 2D network of hydrogen bonds was discovered, where each surface oxygen atom is coordinated by additional H-bonding water molecules. This flat double-monolayer has a relatively high adsorption energy, every zinc and oxygen atom is 4-fold coordinated and every hydrogen atom is engaged in a hydrogen bond. Hence this honeycomb double monolayer offers no H bond donor or acceptor sites for further growth of the water film. At 3 ML coverage, the interface restructures forming a contact layer of half-dissociated water dimers and a liquid-like overlayer of water attached by hydrogen bonds. The structures and their adsorption energies are analysed to understand the driving forces for aggregation and dissociation of water on the surface. We apply a decomposition scheme based on a Born-Haber cycle, discussing difficulties that may occur in applying such an analysis to the adsorption of dissociated molecules and point out alternatives to circumvent the bias against severely stretched bonds. Water aggregation on the ZnO surface is favoured by direct water-water interactions including H-bonds and dipole-dipole interactions and surface- or adsorption-mediated interactions including enhanced water-surface interactions and reduced relaxations of the water molecules and surface. While dissociation of isolated adsorbed molecules is unfavourable, partial or even full dissociation is preferred for aggregates. Nevertheless, direct water-water interactions change very little in the dissociation reaction. Dissociation is governed by a subtle balance between strongly enhanced water-surface interactions and the large energies required for the geometric changes of the water molecule(s) and the surface. Our conclusions are discussed on the background of the current knowledge on water adsorption at metals and non-metallic surfaces. PMID- 27982142 TI - Functionalized hydrazide macrocycle ion channels showing pH-sensitive ion selectivities. AB - Transmembrane channels formed by functionalized hydrazide macrocycles are reported. The different pH values of buffer solutions have a significant effect on the K+/Cl- selectivity of the macrocycles. This unique transport behavior is mainly induced by the different distributions of charges in the tubular channels under various pH values. PMID- 27982145 TI - Conformational and entropy analyses of extended molecular dynamics simulations of alpha-, beta- and gamma-cyclodextrins and of the beta-cyclodextrin/nabumetone complex. AB - Herein, we report the results of 5.0 MUs molecular dynamics simulations of native alpha-, beta- and gamma-cyclodextrins (CDs) in explicit water solvent that are useful to describe, in a comparative manner, the distorted geometry of the CD molecules in aqueous solution, the width and fluctuations of their cavities, and the number of cavity waters. By discretizing the time evolution of the dihedral angles, the rate of conformational change of the torsional motions and the conformational entropy are calculated for the three CDs, thus allowing the analysis of the extent of the MD sampling and the entropic significance of the CD flexibility. To obtain a first estimation of the conformational and entropy changes in the host molecule upon ligand binding, the inclusion complex formed between beta-CD and nabumetone is also studied. Overall, the simulations complement previous experimental results on the structure and dynamics of native CDs, and together with the results obtained for the inclusion complex, provide insight into the entropic effects at work on the binding equilibria between CDs and guest ligands. PMID- 27982144 TI - Superfluorinated and NIR-luminescent gold nanoclusters. AB - A novel class of superfluorinated and NIR-luminescent gold nanoclusters were obtained starting from a branched thiol, bearing 27 equivalent 19F atoms per molecule. These unprecedented clusters combine in a unique nanosystem both NIR photoluminescence and 19F NMR properties, thus representing a promising multimodal platform for bioimaging applications. PMID- 27982146 TI - Pulsed Nd:YAG laser-induced photoreaction of cis,cis-1,3-cyclooctadiene at 266 nm: selective cyclization to cis-bicyclo[4.2.0]oct-7-ene. AB - Nanosecond-scale pulsed laser irradiation of cis,cis-1,3-cyclooctadiene via an Nd:YAG laser at 266 nm induced highly selective cyclization of the 1,3-diene moiety to afford cis-bicyclo[4.2.0]oct-7-ene in high yield. The pulsed Nd:YAG laser light is highly monochromatic thereby allowing efficient control of the photoreaction selectivity by controlling the photostationary state. PMID- 27982147 TI - A CoOx-modified SnNb2O6 photoelectrode for highly efficient oxygen evolution from water. AB - SnNb2O6 has arisen as a candidate for photoanodes for solar water splitting. CoOx cocatalyst-loaded SnNb2O6 showed a stable, high anodic photocurrent with an incident photon-to-current conversion efficiency (IPCE) of 18% at 0.6 VRHE and a half-cell solar-to-hydrogen (HC-STH) efficiency of 0.39% at 0.6 VRHE. PMID- 27982148 TI - Partial oxidation of the absorber layer reduces charge carrier recombination in antimony sulfide solar cells. AB - We investigate the effect of a post heat treatment of the absorber layer in air for antimony sulfide (Sb2S3) sensitized solar cells. Phenomenologically, exposing the Sb2S3 surface of sensitised solar cells to air at elevated temperatures is known to improve device performance. Here, we have investigated the detailed origins of this improvement. To this end, samples were annealed in air for different time periods and the build-up of an antimony oxide layer was monitored by XPS. A very short heat treatment resulted in an increase in power conversion efficiency from eta = 1.4% to eta = 2.4%, while longer annealing decreased the device performance. This improvement was linked to a reduction in charge carrier recombination at the interface of Sb2S3 with the organic hole conductor, arising from the oxide barrier layer, as demonstrated by intensity modulated photovoltage spectroscopy (IMVS). PMID- 27982149 TI - Decreasing amyloid toxicity through an increased rate of aggregation. AB - Amyloid beta is one of the peptides involved in the onset of Alzheimer's disease, yet the structure of the toxic species and its underlying mechanism remain elusive on account of the dynamic nature of the Abeta oligomerisation process. While it has been reported that incubation of Amyloid beta (1-42) sequences (Abeta42) lead to formation of aggregates that vary in morphology and toxicity, we demonstrate that addition of a discrete macrocyclic host molecule, cucurbit[8]uril (CB[8]), substantially reduces toxicity in the neuronal cell line SH-SY5Y. The macrocycle preferentially targets Phe residues in Abeta42 complexing them in a 2 : 1 fashion in neighboring peptide strands. A small but significant structural 'switch' occurs, which induces an increased aggregation rate, suggesting a different cell-uptake mechanism for Abeta42 in the presence of CB[8]. Dramatically increasing the rate of Abeta42 aggregation with CB[8] bypasses the toxic, oligomeric state offering an alternative approach to counter Alzheimer's disease. PMID- 27982151 TI - Cross-linker mediated formation of sulfur-functionalized V2O5/graphene aerogels and their enhanced pseudocapacitive performance. AB - The development of efficient synthesis methods for the preparation of vanadium oxide (V2O5)-graphene holds great promise considering the excellent performance of the composite in electrochemical applications. Herein, we report the cross linking of a V2O5-graphene hybrid via a vanadium-thiourea redox system, which allowed the assembly of graphene oxide functional groups with V2O5 through the reducing ability of thiourea (TU) under room conditions within an impressively short reaction time (20 min). The resulting 3D composite aerogel forms a highly porous architecture of sulfur-functionalized interconnected networks. Such sulfur functionalized transition metal oxide-graphene-based aerogels are excellent candidates in energy storage applications. When the vanadium oxide-graphene aerogel was evaluated as an electrode for a supercapacitor, a specific capacitance as high as 484.0 F g-1 at 0.6 A g-1 was obtained in a two-electrode cell configuration. This performance is much higher than that of the vanadium oxide-graphene aerogels prepared in the absence of thiourea. The vanadium oxide graphene aerogel is able to deliver a remarkable energy density of 43.0 Wh kg-1 at a power density of 0.48 kW kg-1 at 0.6 A g-1 and can hold 24.2 Wh kg-1 at a maximum power density of 9.3 kW kg-1 at 10 A g-1. The symmetric supercapacitor assembled from the aerogel can retain 80% of its initial capacitance after 10 000 cycles. PMID- 27982150 TI - Partial PEGylation of superparamagnetic iron oxide nanoparticles thinly coated with amine-silane as a source of ultrastable tunable nanosystems for biomedical applications. AB - The development of superparamagnetic iron oxide nanoparticle (SPION)-based diagnostic and therapeutic nanosystems holds a promise of revolutionizing biomedicine, helping to solve important unmet clinical needs. Such potential will only be fulfilled if appropriate methods for SPION production and for their subsequent tailoring to specific applications are established, something that remains challenging. Here, we report a simple and low cost method to fabricate structurally and colloidally ultrastable, water soluble SPIONs. We used thermal decomposition to produce SPIONs of the highest quality, which were then thinly coated with an amine-silane derivative by ligand exchange, conferring hydrophilicity and great structural stability on the nanoparticles. Subsequent partial covalent occupancy of surface amine groups with polyethyleneglycol (PEG) was carried out to give them excellent colloidal stability, whilst still leaving reactive anchoring points for further functionalization. The correct composition and physicochemical properties of our PEGylated SPIONs and their precursors were confirmed using a broad range of analytical techniques, and we also demonstrated the biocompatible character of the resulting nanoparticles, as well as their suitability as T2 MRI contrast agents in vivo. Finally, using a near infra-red fluorophore, we also confirmed that these SPIONs are amenable to further tuning, to adapt them to a wide range of applications or to optimize their performance in particular settings. In summary, our work provides a novel and robust method for the production of SPIONs that can be used as a tunable platform for the development of smart diagnostic and therapeutic nanosystems. PMID- 27982152 TI - A novel "tunnel-like" cyclopalladated arylimine catalyst immobilized on graphene oxide nano-sheet. AB - A novel "tunnel-like" cyclopalladated arylimine was prepared and immobilized on graphene oxide nano-sheet to form a hybrid catalytic material (denoted as F-GO Pd) by self-assembly. The F-GO-Pd catalyst was characterized by XRD, FTIR, Raman, XPS, SEM, and TEM. This novel hybrid catalytic material was proven to be an efficient catalyst for the Suzuki-Miyaura coupling reaction of aryl halides (I, Br, Cl) with arylboronic acids in aqueous media under mild conditions with a very low amount of catalyst (0.01 mol%) and a high turnover frequency (TOF) (>20 000 h 1). In particular, high yields also could be obtained at room temperature with prolonged time. F-GO-Pd also showed good stability and recyclability seven times with a superior catalytic activity. The heterogeneous catalytic mechanism was investigated with kinetic studies, hot filtration tests, catalyst poisoning tests, and in situ FTIR spectroscopy with a ReactIR and the deactivation mechanism of the catalysts was proposed through analysis of its chemical stability by TEM, SEM, Raman, and XRD, indicating that a heterogeneous catalytic process occurred on the surface and the changes of the catalytic activity during the recycling were related to the micro-environment of the catalyst surface. PMID- 27982153 TI - Tuning quantum electron and phonon transport in two-dimensional materials by strain engineering: a Green's function based study. AB - Novel two-dimensional (2D) materials show unusual physical properties which combined with strain engineering open up the possibility of new potential device applications in nanoelectronics. In particular, transport properties have been found to be very sensitive to applied strain. In the present work, using a density-functional based tight-binding (DFTB) method in combination with Green's function (GF) approaches, we address the effect of strain engineering of the transport setup (contact-device(scattering)-contact regions) on the electron and phonon transport properties of two-dimensional materials, focusing on hexagonal boron-nitride (hBN), phosphorene, and MoS2 monolayers. Considering unstretched contact regions, we show that the electronic bandgap displays an anomalous behavior and the thermal conductance continuously decreases after increasing the strain level in the scattering region. However, when the whole system (contact and device regions) is homogeneously strained, the bandgap for hBN and MoS2 monolayers decreases, while for phosphorene it first increases and then tends to zero with larger strain levels. Additionally, the thermal conductance shows specific strain dependence for each of the studied 2D materials. These effects can be tuned by modifying the strain level in the stretched contact regions. PMID- 27982154 TI - Electronic forces as descriptors of nucleophilic and electrophilic regioselectivity and stereoselectivity. AB - One of the main tasks of theoretical chemistry is to rationalize computational results with chemical insights. Key concepts of such nature include nucleophilicity, electrophilicity, regioselectivity, and stereoselectivity. While computational tools are available to predict barrier heights and other reactivity properties with acceptable accuracy, a conceptual framework to appreciate above quantities is still lacking. In this work, we introduce the electronic force as the fundamental driving force of chemical processes to understand and predict molecular reactivity. It has three components but only two are independent. These forces, electrostatic and steric, can be employed as reliable descriptors for nucleophilic and electrophilic regioselectivity and stereoselectivity. The advantages of using these forces to evaluate molecular reactivity are that electrophilic and nucleophilic attacks are featured by distinct characteristics in the electrostatic force and no knowledge of quantum effects included in the kinetic and exchange-correlation energies is required. Examples are provided to highlight the validity and general applicability of these reactivity descriptors. Possible applications in ambident reactivity, sigma and pi holes, frustrated Lewis pairs, and stereoselective reactions are also included in this work. PMID- 27982155 TI - Thermodynamic origins of the solvent-dependent stability of lithium polysulfides from first principles. AB - An understanding of the complex solution phase chemistry of dissolved lithium polysulfides is critical to approaches aimed at improving the cyclability and commercial viability of lithium sulfur batteries. Experimental measurements are frustrated by the versatile sulfur-sulfur bond, with spontaneous disproportionation and interconversion leading to unknown equilibrium distributions of polysulfides with varying lengths and charge states. Here, the solubility of isolated lithium polysulfides is calculated from first-principles molecular dynamics simulations. We explore the associated changes in the dissolution free energy, enthalpy and entropy in two regimes: liquid-phase monodentate solvation in dimethylformamide (DMF) and polymer-like chelation in bis(2-methoxyethyl) ether (diglyme). In both of these technologically relevant solvents, we show that the competition between enthalpy and entropy, related to specific interfacial atomic interactions, conspires to increase the relative stability of long chain dianionic species, which exist as Li+-LiSx- contact-ion pairs. Further, we propose a mechanism of radical polysulfide stabilization in simple solvents through the reorientation of the 1st shell solvent molecules to screen electrostatic fields emanating from the solute and explain nonmonotonicity of the dissolution entropy with polysulfide length in terms of a three-shell solvation model. Our analysis provides statistical dynamics insights into polylsulfide stability, useful to understand or predict the relevant chemical species present in the solvent at low concentrations. PMID- 27982156 TI - An approach to utilize the artificial high power LED UV-A radiation in photoreactors for the degradation of methylene blue. AB - Utilization of UV LED light is trending in the development of photoreactors for pollutant treatment. In this study, two different geometries were studied in the degradation of methylenebBlue (MB) using high power UVA LED as a source of light. The dosage, initial concentration, electric power, and H2O2 addition were evaluated in the two geometries: a mini CPC (Cilindrical Parabolic Collector) and a vertical cylindrical with external irradiation both coupled with LED UVA. Best degradation was obtained for 0.3 g L-1 TiO2, 40 min, and 15 ppm of MB of initial concentration in the standard batch reactor. It was found that the best system was a cpc geometry. Also, hydrogen peroxide was used as an electron acceptor and 97% degradation was obtained in 30 min with 10 mM H2O2 and 0.4 g TiO2/L. Power of the LEDs was also evaluated and it was found that 20 W m-2 is the best operational condition to achieve the best MB degradation avoiding the oxidant species recombination. PMID- 27982157 TI - Carboxylatopillar[n]arenes: a versatile class of water soluble synthetic receptors. AB - Carboxylatopillar[n]arenes (CP[n]As, n = 5, 6, 7, 9, 10) are water soluble derivatives of pillar[n]arenes. The three-dimensional pi-electron-rich cavity and carboxylate groups at the portals, enabled CP[n]A to have strong binding affinity in water, which has been successfully harnessed in fabricating responsive supramolecular assemblies from supra-amphiphiles and developing targeted drug delivery systems (DDSs). CP[n]A based supraamphiphiles have also been used for sensor applications. This review highlights the diverse applications of water soluble carboxylatopillar[n]arenes. PMID- 27982158 TI - Homogeneous cationic substitution for two-dimensional layered metal oxide nanosheets via a galvanic exchange reaction. AB - The galvanic exchange reaction of an exfoliated 2D layered metal oxide nanosheet (NS) with excess substituent metal cations enables the synthesis of a mixed metal oxide 2D NS with controllable cation compositions and physicochemical properties. The reaction of the exfoliated MnO2 NS with Fe2+ or Sn2+ ions at 90 degrees C induces the uniform galvanic replacement of Mn ions with these substituent ions, whereas the same reaction at 25 degrees C results in the intercalative restacking of the negatively-charged MnO2 NS with Fe2+ or Sn2+ cations. Upon the galvanic exchange reaction, the highly anisotropic MnO2 2D NS retains its original 2D morphology and layered structure, which is in stark contrast to 0D nanoparticles yielding hollow nanospheres via the galvanic exchange reaction. This observation is attributable to the thin thickness of the 2D NS allowing the simultaneous replacement of all the component surface-exposed metal ions. The resulting substitution of the MnO2 NS with Fe and Sn ions remarkably improves the electrode performance of the carbon-coated derivatives of the MnO2 NS for lithium ion batteries. The present study clearly demonstrates that the galvanic exchange reaction can provide an efficient method not only to tailor cation compositions but also to improve the functionalities of 2D metal oxide NSs and their carbon coated derivatives. PMID- 27982159 TI - Comparative Study between Perfusion Changes and Positive Findings on Coronary Flow Reserve. AB - BACKGROUND: Functional assessment of coronary artery obstruction is used in cardiology practice to correlate anatomic obstructions with flow decrease. Among such assessments, the study of the coronary fractional flow reserve (FFR) has become the most widely used. OBJECTIVE: To evaluate the correlation between FFR and findings of ischemia obtained by noninvasive methods including stress echocardiography and nuclear medicine and the presence of critical coronary artery obstruction. METHODS: Retrospective study of cases treated with systematized and standardized procedures for coronary disease between March 2011 and August 2014. We included 96 patients with 107 critical coronary obstructions (> 50% in the coronary trunk and/or >= 70% in other segments) estimated by quantitative coronary angiography (QCA) and intracoronary ultrasound (ICUS). All cases presented ischemia in one of the noninvasive studies. RESULTS: All 96 patients presented ischemia (100%) in one of the functional tests. On FFR study with adenosine 140 g/kg/min, 52% of the cases had values <= 0.80. On correlation analysis for FFR <= 0.80, the evaluation of sensitivity, specificity, positive and negative predictive values, accuracy, and ROC curve in relation to the stenosis degree and length, and presence of ischemia, no significant values or strong correlation were observed. CONCLUSION: Coronary FFR using a cut-off value of 0.80 showed no correlation with noninvasive ischemia tests in patients with severe coronary artery obstructions on QCA and ICUS. PMID- 27982161 TI - First Latin uterine transplantation: we can do it! PMID- 27982160 TI - Lifestyle Intervention on Metabolic Syndrome and its Impact on Quality of Life: A Randomized Controlled Trial. AB - BACKGROUND: Lifestyle intervention programs can reduce the prevalence of metabolic syndrome (MetS) and, therefore, reduce the risk for cardiac disease, one of the main public health problems nowadays. OBJECTIVE: The aim of this study was to compare the effects of three types of approach for lifestyle change programs in the reduction of metabolic parameters, and to identify its impact on the quality of life (QOL) of individuals with MetS. METHODS: A randomized controlled trial included 72 individuals with MetS aged 30-59 years. Individuals were randomized into three groups of multidisciplinary intervention [Standard Intervention (SI) - control group; Group Intervention (GI); and Individual Intervention (II)] during 12 weeks. The primary outcome was change in the metabolic parameters, and secondarily, the improvement in QOL measures at three moments: baseline, 3 and 9 months. RESULTS: Group and individual interventions resulted in a significant reduction in body mass index, waist circumference, systolic blood pressure at 3 months and the improvement of QOL, although it was significantly associated with the physical functioning domain. However, these changes did not remain 6 months after the end of intervention. Depression and anxiety were significantly associated with worse QOL, although they showed no effect on the response to intervention. CONCLUSION: Multidisciplinary intervention, especially in a group, might be an effective and economically feasible strategy in the control of metabolic parameters of MetS and improvement of QOL compared to SI, even in a dose-effect relationship. PMID- 27982162 TI - Influence of central obesity in estimating maximal oxygen uptake. AB - OBJECTIVE:: To assess the influence of central obesity on the magnitude of the error of estimate of maximal oxygen uptake in maximal cycling exercise testing. METHOD:: A total of 1,715 adults (68% men) between 18-91 years of age underwent cardiopulmonary exercise testing using a progressive protocol to volitional fatigue. Subjects were stratified by central obesity into three quartile ranges: Q1, Q2-3 and Q4. Maximal oxygen uptake [mL.(kg.min)-1] was estimated by the attained maximal workload and body weight using gender- and population-specific equations. The error of estimate [mL.(kg.min)-1] and percent error between measured and estimated maximal oxygen uptake values were compared among obesity quartile ranges. RESULTS:: The error of estimate and percent error differed (mean +/- SD) for men (Q1=1.3+/-3.7 and 2.0+/-10.4; Q2-3=0.5+/-3.1 and -0.5+/-13.0; and Q4=-0.3+/-2.8 and -4.5+/-15.8 (p<0.05)) and for women (Q1=1.6+/-3.3 and 3.6+/ 10.2; Q2-3=0.4+/-2.7 and -0.4+/-11.8; and Q4=-0.9+/-2.3 and -10.0+/-22.7 (p<0.05)). CONCLUSION:: Central obesity directly influences the magnitude of the error of estimate of maximal oxygen uptake and should be considered when direct expired gas analysis is unavailable. PMID- 27982163 TI - Mortality reduction with use of oral beta-blockers in patients with acute coronary syndrome. AB - OBJECTIVES:: Recent studies have revealed a relationship between beta-blocker use and worse prognosis in acute coronary syndrome, mainly due to a higher incidence of cardiogenic shock. However, the relevance of this relationship in the reperfusion era is unknown. The aim of this study was to analyze the outcomes of patients with acute coronary syndrome that started oral beta-blockers within the first 24 hours of hospital admission (group I) compared to patients who did not use oral beta-blockers in this timeframe (group II). METHODS:: This was an observational, retrospective and multicentric study with 2,553 patients (2,212 in group I and 341 in group II). Data regarding demographic characteristics, coronary treatment and medication use in the hospital were obtained. The primary endpoint was in-hospital all-cause mortality. The groups were compared by ANOVA and the chi-square test. Multivariate analysis was conducted by logistic regression and results were considered significant when p<0.05. RESULTS:: Significant differences were observed between the groups in the use of angiotensin-converting enzyme inhibitors, enoxaparin, and statins; creatinine levels; ejection fraction; tabagism; age; and previous coronary artery bypass graft. Significant differences were also observed between the groups in mortality (2.67% vs 9.09%, OR=0.35, p=0.02) and major adverse cardiovascular events (11% vs 29.5%, OR=4.55, p=0.02). CONCLUSIONS:: Patients with acute coronary syndrome who underwent early intervention with oral beta-blockers during the first 24 hours of hospital admission had a lower in-hospital death rate and experienced fewer major adverse cardiovascular events with no increase in cardiogenic shock or sustained ventricular arrhythmias compared to patients who did not receive oral beta blockers within this timeframe. PMID- 27982164 TI - Immunohistochemical angiogenic biomarkers in hepatocellular carcinoma and cirrhosis: correlation with pathological features. AB - OBJECTIVE: To investigate immunohistochemical markers of angiogenesis and their association with pathological prognostic features in hepatocellular carcinoma and cirrhotic liver. METHODS: Vascular endothelial growth factor, CD105, and cyclooxygenase-2 were immunohistochemically detected in 52 hepatocellular carcinoma tissue samples and 48 cirrhotic liver tissue samples. Semiquantitative measurements of vascular endothelial growth factor and cyclooxygenase-2 were evaluated considering the degree and intensity of immunostaining based on a 7 point final scoring scale. CD105 microvascular density (MVD-CD105) was measured using automated analysis. Morphological aspects evaluated in the hepatocellular carcinoma samples included size (<=2 and >2 cm), differentiation grade, and microvascular invasion. RESULTS: The mean vascular endothelial growth factor immunoreactivity score was slightly higher in the hepatocellular carcinoma samples (4.83+/-1.35) than the cirrhotic liver (4.38+/-1.28) samples. There was a significant and direct correlation between these mean scores (rs=0.645, p=0.0001). Cyclooxygenase-2 was expressed in all the cirrhotic liver samples but was only found in 78% of the hepatocellular carcinoma samples. The mean cyclooxygenase-2 score was higher in the cirrhotic liver samples (4.85+/-1.38) than the hepatocellular carcinoma samples (2.58+/-1.68), but there was no correlation between the scores (rs=0.177, p=0.23). The mean CD105 percentage in the hepatocellular carcinoma samples (11.2%) was lower than that in the cirrhotic samples (16.9%). There was an inverse relationship in MVD-CD105 expression between the hepatocellular carcinoma and cirrhotic samples (rs=-0.78, p=0.67). There were no significant associations between vascular endothelial growth factor expression and morphological characteristics. Cyclooxygenase-2 and CD105 were associated with hepatocellular carcinoma differentiation grade (p=0.003 and p=0.05, respectively). CONCLUSION: Vascular endothelial growth factor, cyclooxygenase-2, and MVD-CD105 were highly expressed in cirrhotic liver compared to hepatocellular carcinoma and might be involved in liver carcinogenesis. Additionally, cyclooxygenase-2 and CD105 might be involved in hepatocellular carcinoma differentiation grade. PMID- 27982166 TI - Randomized trial of radiofrequency ablation versus conventional surgery for superficial venous insufficiency: if you don't tell, they won't know. AB - OBJECTIVES:: This study compared radiofrequency ablation versus conventional surgery in patients who had not undergone previous treatment for bilateral great saphenous vein insufficiency, with each patient serving as his own control. METHOD:: This was a randomized controlled trial that included 18 patients and was carried out between November 2013 and May 2015. Each of the lower limbs of each patient was randomly assigned to undergo either radiofrequency ablation or conventional surgery. Clinical features (hyperpigmentation, hematoma, aesthetics, pain, skin burn, nerve injury, and thrombophlebitis) were evaluated at one week, one month, and six months postoperatively. Hemodynamic assessments (presence of resection or occlusion of the great saphenous vein and recurrent reflux in the sapheno-femoral junction and in the great saphenous vein) were performed at one month, six months, and 12 months postoperatively. The independent observer (a physician not involved in the original operation), patient, and duplex ultrasonographer were not made aware of the treatment done in each case. Clinicaltrials.gov: NCT02588911. RESULTS:: Among the clinical variables analyzed, only the aesthetic evaluation by the physicians was significant, with radiofrequency ablation being considered better than conventional surgery (average, 0.91 points higher: standard deviation: 0.31; 95% confidence interval: 1.51, -0.30; p=0.003). However, in our study, we observed primary success rates of 80% for radiofrequency ablation and 100% for conventional surgery. CONCLUSIONS:: If the physician is not required to inform the patient as to the technique being performed, the patient will not be able to identify the technique based on the signs and symptoms. Our study revealed that both techniques led to high levels of patient satisfaction, but our results favor the choice of conventional surgery over radiofrequency ablation, as patients who underwent conventional surgery had better hemodynamic assessments. PMID- 27982165 TI - Lymphocyte count as a sign of immunoparalysis and its correlation with nutritional status in pediatric intensive care patients with sepsis: A pilot study. AB - OBJECTIVES:: Developing malnutrition during hospitalization is well recognized worldwide, and children are at a relatively higher risk for malnutrition than adults. Malnutrition can lead to immune dysfunction, which is associated with a higher mortality rate due to sepsis, the most frequent cause of death in pediatric intensive care units (PICUs). The aim of this study was to investigate whether malnourished patients are more likely to have relative or absolute lymphopenia and, consequently, worse prognoses. METHODS:: We enrolled 14 consecutive patients with sepsis whose legal representatives provided written informed consent. Patients were classified as normal or malnourished based on anthropometric measurements. As an additional evaluation of nutritional status, serum albumin and zinc were measured on the 1st and 7th days of hospitalization. Lymphocyte count was also measured on the 1st and 7th days. Clinicaltrials.gov: NCT02698683. RESULTS:: Malnutrition prevalence rates were 33.3% and 42.8% based on weight and height, respectively. Laboratory analyses revealed a reduction of serum albumin in 100% of patients and reduction of zinc in 93.3% of patients. A total of 35% of patients had fewer than 500 lymphocytes/mm3 on their first day in the PICU. Lymphocyte counts and zinc concentrations significantly increased during hospitalization. CONCLUSIONS:: Nutritional evaluations, including anthropometric measurements, were not correlated with lymphocyte counts. Lymphocyte counts concomitantly increased with zinc levels, suggesting that micronutrient supplementation benefits patients with sepsis. PMID- 27982168 TI - Managing obstructive sleep apnoea in children: the role of craniofacial morphology. AB - Obstructive sleep apnoea syndrome is a type of sleep-disordered breathing that affects 1 to 5% of all children. Pharyngeal and palatine tonsil hypertrophy is the main predisposing factor. Various abnormalities are predisposing factors for obstructive sleep apnoea, such as decreased mandibular and maxillary lengths, skeletal retrusion, increased lower facial height and, consequently, increased total anterior facial height, a larger cranio-cervical angle, small posterior airway space and an inferiorly positioned hyoid bone. The diagnosis is based on the clinical history, a physical examination and tests confirming the presence and severity of upper airway obstruction. The gold standard test for diagnosis is overnight polysomnography. Attention must be paid to identify the craniofacial characteristics. When necessary, children should be referred to orthodontists and/or sleep medicine specialists for adequate treatment in addition to undergoing an adenotonsillectomy. PMID- 27982167 TI - Correlation between ultrasound velocity and densitometry in fresh and demineralized cortical bone. AB - OBJECTIVE:: To compare ultrasound propagation velocity with densitometry in the diaphyseal compact cortical bone of whole sheep metatarsals. METHODS:: The transverse ultrasound velocity and bone mineral density of 5-cm-long diaphyseal bone segments were first measured. The bone segments were then divided into four groups of 15 segments each and demineralized in an aqueous 0.5 N hydrochloric acid solution for 6, 12, 24 or 36 hours. All measurements were repeated after demineralization for each time duration and the values measured before and after demineralization were compared. RESULTS:: Ultrasound velocity and bone mineral density decreased with demineralization time, and most differences in the pre- and post-demineralization values within each group and between groups were significant: A moderate correlation coefficient (r=0.75956) together with a moderate agreement was determined between both post-demineralization parameters, detected by the Bland-Altman method. CONCLUSION:: We conclude that both ultrasound velocity and bone mineral density decrease as a result of demineralization, thus indicating that bone mineral content is of great importance for maintaining the acoustic parameters of cortical bone, as observed for cancellous bone. Ultrasound velocity can be used to evaluate both compact cortical bone quality and bone mineral density. PMID- 27982169 TI - Primordial and primary prevention programs for cardiovascular diseases: from risk assessment through risk communication to risk reduction. A review of the literature. AB - The aim of this study was to identify and reflect on the methods employed by studies focusing on intervention programs for the primordial and primary prevention of cardiovascular diseases. The PubMed, EMBASE, SciVerse Hub-Scopus, and Cochrane Library electronic databases were searched using the terms 'effectiveness AND primary prevention AND risk factors AND cardiovascular diseases' for systematic reviews, meta-analyses, randomized clinical trials, and controlled clinical trials in the English language. A descriptive analysis of the employed strategies, theories, frameworks, applied activities, and measurement of the variables was conducted. Nineteen primary studies were analyzed. Heterogeneity was observed in the outcome evaluations, not only in the selected domains but also in the indicators used to measure the variables. There was also a predominance of repeated cross-sectional survey design, differences in community settings, and variability related to the randomization unit when randomization was implemented as part of the sample selection criteria; furthermore, particularities related to measures, limitations, and confounding factors were observed. The employed strategies, including their advantages and limitations, and the employed theories and frameworks are discussed, and risk communication, as the key element of the interventions, is emphasized. A methodological process of selecting and presenting the information to be communicated is recommended, and a systematic theoretical perspective to guide the communication of information is advised. The risk assessment concept, its essential elements, and the relevant role of risk perception are highlighted. It is fundamental for communication that statements targeting other people's understanding be prepared using systematic data. PMID- 27982170 TI - Uterine transplantation: a systematic review. AB - Up to 15% of the reproductive population is infertile, and 3 to 5% of these cases are caused by uterine dysfunction. This abnormality generally leads women to consider surrogacy or adoption. Uterine transplantation, although still experimental, may be an option in these cases. This systematic review will outline the recommendations, surgical aspects, immunosuppressive drugs and reproductive aspects related to experimental uterine transplantation in women. PMID- 27982171 TI - Does Cryopreservation Affect the Biological Properties of Stem Cells from Dental Tissues? A Systematic Review. AB - This systematic review evaluated if different cryopreservation protocols could affect biological properties (Cell survival rate (CSR), proliferation, differentiation, maintenance of stem cell markers) of stem cells obtained from dental tissues (DSC) post-thaw. An electronic search was carried out within PubMed and ISI Web Science by using specific keyword. Two independent reviewers read the titles and abstracts of all reports respecting predetermined inclusion/exclusion criteria. Data were extracted considering the biological properties of previously cryopreserved DSCs and previously cryopreserved dental tissues. DSCs cryopreserved as soon as possible after their isolation presents a CSR quite similar to the non-cryopreserved DSC. Dimethyl sulfoxide (DMSO) [10%] showed good results related to cell recovery post-thaw to cryopreserve cells and tissues for periods of up to 2 years. The cryopreservation of DSC in a mechanical freezer (-80 degrees C) allows the recovery of stem cells post-thaw. The facilities producing magnetic field (MF), demand a lower concentration of cryoprotectant, but their use is not dispensable. It is possible to isolate and cryopreserve dental pulp stem cell (DPSC) from healthy and diseased vital teeth. Cryopreservation of dental tissues for late DSC isolation, combined with MF dispensability, could be valuable to reduce costs and improve the logistics to develop teeth banks. PMID- 27982172 TI - Salivary Immunoglobulins in Individuals with Common Variable Immunodeficiency. AB - Oral manifestations of common variable immunodeficiency (CVID) are rare, have rarely been studied and have given controversial results. There are few data about IgA, IgG, and IgM antibody salivary levels in the literature, and there are few papers about the clinical impact of antibody deficiencies and CVID on the oral health of such patients. The aim of this study was to measure serum and salivary IgA, IgG, and IgM levels in CVID participants and controls, and to associate immunoglobulin levels with caries and periodontal disease. This was a case-control study involving 51 CVID individuals and 50 healthy controls. All participants underwent examination for dental caries and periodontal disease. Blood and whole saliva samples were collected on the same day of the oral examination. Serum IgA, IgM, and IgG levels were measured by turbidimetry and salivary IgA, IgM, and IgG titers were assessed by enzyme-linked immunosorbent assay. Incidences of caries and gingivitis were significantly higher in the CVID group than in the control group (p<0.05). Salivary and blood IgA and IgM titers were significantly reduced in the CVID group, but there was no association of salivary immunoglobulin levels with periodontal disease or with caries incidence (p>0.05 for both). Although CVID was associated with increased susceptibility to caries and gingivitis, it was not associated with low salivary levels of IgA and IgM. PMID- 27982173 TI - ? AB - The aim of this study was to evaluate the antiplaque effect of Ocimum gratissimum (Og) by in vivo investigation. Fifteen healthy volunteers participated in a crossover, double-blind clinical study, using a 3-day partial-mouth plaque accumulation model. The participants abolished any method of mechanical oral hygiene and they were randomly assigned to initially use just the following mouthrinses: distilled water (DW solution), 0.12% chlorhexidine digluconate (CLX solution) or 10% Og (Og solution). The plaque index (PLI) was recorded in all mandibular teeth at the end of the trial and the Kruskal-Wallis (alpha=0.05) and Mann-Whitney (alpha=0.05) tests were used to estimate the difference among groups. The clinical results showed statistically significant difference among the groups (p<0.05), favoring the CLX solution and Og solution, but the first was more effective (p<0.05). The mouthrinses containing 0.12% chlorhexidine digluconate and 10% Og were able to inhibit plaque re-growth, however Og showed more limited results in comparison to CLX. PMID- 27982174 TI - Cytotoxicity Profile of Endodontic Sealers Provided by 3D Cell Culture Experimental Model. AB - The aim of the present study was to evaluate the cytotoxic effects of five endodontic sealers (AH Plus, Endomethasone N, EndoSequence BC, MTA Fillapex and Pulp Canal Sealer EWT) using a three-dimensional (3D) cell culture model. A conventional bi-dimensional (2D) cell culture model was used as reference technique for comparison. Balb/c 3T3 fibroblasts were cultured in conventional bi dimensional cell culture and in rat-tail collagen type I three-dimensional cell culture models. Then, both cell cultures were incubated with elutes of freshly mixed endodontic sealers for 24 h. Cell viability was measured by the methyl thiazol-diphenyltetrazolium assay (MTT). Data were statistically analyzed using ANOVA and the Tukey test at a significance level of p<0.05. All tested sealers exhibited cytotoxic effects; however, cytotoxic effect was culture model- and sealer-dependent. Sealers showed higher cytotoxicity in 2D than in 3D cell culture model (p<0.05). In both conditions, EndoSequence BC showed the lowest cytotoxicity (p<0.05). MTA Fillapex was much more cytotoxic than the other tested endodontic sealers (p<0.05), with the exception of AH Plus in the 2D cell culture model (p>0.05). Endomethasone N and Pulp Canal Sealer EWT showed lower cytotoxic effects than AH Plus in 2D cell culture model (p<0.05); however no statistical differences was observed among these sealers in 3D cell culture model. It may be concluded that cytotoxicity was higher in 2D cell culture compared to 3D cell culture. EndoSequence BC sealer exhibited the highest cytocompatibility and MTA Fillapex the lowest cytocompatibility. PMID- 27982175 TI - Biological Tissue Response to a New Formulation of a Silicone Based Endodontic Sealer. AB - Satisfactory biological behavior is a necessary requirement for clinical application of endodontic materials. In this study, the connective tissue responses to silicone (GuttaFlow 2), epoxy resin (AH Plus) and zinc oxide and eugenol (Endofill) based sealers were compared. Twelve Wistar rats had polyethylene tubes (four per animal) containing one of the tested sealers and empty tubes (negative control) implanted in their subcutaneous tissue. The tubes were randomly placed 2 cm from the spine and at least 2 cm apart from one another. Tissue samples with implants were processed for histological analysis after 7 or 60 days (n=6 animals per period). Inflammatory cells, fibrous condensation and abscess were scored according to their intensity. Friedman, followed by Dunn's post hoc, was used to compare sealers. Differences between the two experimental periods were verified using Mann-Witney U test (p<0.05). At 7 days, most of the histological parameters showed no significant differences amongst groups. Endofill group scored higher than the others for giant cells (o<0.05) and promoted a greater number of samples presenting abscess formation. GuttaFlow 2 tended to show a less intense inflammatory infiltrate compared to the other materials. At 60 days, there were no significant differences between groups in most of the histological parameters evaluated. However, it was observed that Endofill scored higher for macrophages (p<0.05) compared to the control group, and GuttaFlow 2 tended to present lower scores than the others for neutrophils and abscess. GuttaFlow 2 showed proper biological behavior and should be considered adequate for clinical practice. PMID- 27982176 TI - On the Causality Between Dentinal Defects and Root Canal Preparation: A Micro-CT Assessment. AB - This study aimed to evaluate the cause-effect relationship between canal preparation with ProTaper Universal (PTU) system and dentinal defects formation using micro-computed tomography (micro-CT) analysis. Forty mesial canals of mandibular molars with a type II Vertucci's canal configuration were scanned at an isotropic resolution of 14.16 um. The sample was assigned to an experimental (n = 30) and a control (n = 10) groups, and the mesial canals were prepared with PTU system up to F2 instrument. The specimens from the experimental group were scanned and the cross-section images of the mesial roots, before and after preparation, were screened to identify the presence of dentinal defects. In the control group, the specimens were sectioned perpendicularly to the long axis of the root into 1-mm-thick slices (n = 80) and examined under optical microscope. Once a dentinal defect was detected, the slice was scanned through micro-CT. In the experimental group, dentinal micro-cracks were observed in 4,828 slices (24.04%). In all cross-section images, dentinal defects identified in the postoperative images were already present in the corresponding preoperative image. In the control group, 13 out of 80 slices (16.25%) had at least one dentinal defect visualized under stereomicroscopy, which was identified after a further micro-CT scanning. Micro-CT showed reliability as similar as optical microscopy in detecting dentinal defects, adding the possibility of tracking the dentinal tissue, before and after canal preparation, and providing a clear visualization of micro-cracks. Root canal preparation with PTU system did not induce the formation of new dentinal defects. PMID- 27982177 TI - Effect of Gamma Radiation and Endodontic Treatment on Mechanical Properties of Human and Bovine Root Dentin. AB - This study evaluated the effect of gamma radiation and endodontic treatment on the microhardness and flexural strength of human and bovine root dentin. Forty single-rooted human teeth and forty bovine incisor teeth were collected, cleaned and stored in distilled water at 4 degrees C. The human and bovine teeth were divided into 4 groups (n=10) resulting from the combination of two study factors: first, regarding the endodontic treatment in 2 levels: with or without endodontic treatment; and second, radiotherapy in two levels: with or without radiotherapy by 60 Gy of Co-60 gamma radiation fractioned into 2 Gy daily doses five days per week. Each tooth was longitudinally sectioned in two parts; one-half was used for the three-point bending test and the other for the Knoop hardness test (KHN). Data were analyzed by 3-way ANOVA and Tukey HSD test (alpha=0.05). No significant difference was found for flexural strength values. The human dentin had significantly higher KHN than the bovine. The endodontic treatment and radiotherapy resulted in significantly lower KHN irrespective of tooth origin. The results indicated that the radiotherapy had deleterious effects on the microhardness of human and bovine dentin and this effect is increased by the interaction with endodontic therapy. The endodontic treatment adds additional negative effect on the mechanical properties of radiated tooth dentin; the restorative protocols should be designed taking into account this effect. PMID- 27982178 TI - Pulp Chamber Heating: An In Vitro Study Evaluating Different Light Sources and Resin Composite Layers. AB - The aim of the present in vitro study was to evaluate the temperature variation inside the pulp chamber during light-activation of the adhesive and resin composite layers with different light sources. Cavities measuring 8x10 mm were prepared on the buccal surface of bovine incisors, leaving a remaining dentin thickness of 1 mm. Specimens were placed in a 37+/-1 degrees C water bath to standardize the temperature. The temperature in the pulp chamber was measured every 10 s during 40 s of light activation of the adhesive system (SBMP-3M/ESPE) and in the three consecutive 1-mm-thick layers of resin composite (Z250-3M/ESPE). Three light source devices were evaluated: Elipar 2500 (QTH), LD Max (LED low irradiance) and VALO (LED high irradiance). The results were submitted to one-way ANOVA with repeated measures and Tukey's test, both with p<0.001. The exothermic reaction warming was observed in the Z250 increments, but not in the SBMP. The high irradiance LED showed a higher temperature average (42.7+/-1.56 degrees C), followed by the quartz-tungsten-halogen light (40.6+/-0.67 degrees C) and the lower irradiance LED (37.8+/-0.12 degrees C). Higher temperature increases were observed with the adhesive and the first resin composite increment light activation, regardless of the employed light source. From the second increment of Z250, the restorative material acted as a dispersive structure of heat, reducing temperature increases. Regardless the light source and restorative step, the temperature increased with the irradiation time. It may be concluded that the light source, irradiation time and resin composite thickness interfered in the temperature variation inside the pulp chamber. PMID- 27982179 TI - Streptococcus Mutans Biofilm Influences on the Antimicrobial Properties of Glass Ionomer Cements. AB - The aim of this study was to evaluate the in vitro antibacterial and biofilm inhibition properties of glass ionomer restorative cements. Ketac Nano, Vitremer, Ketac Molar Easymix and Fuji IX were analyzed using the following tests: a) agar plate diffusion test to evaluate the inhibitory activity of cements against S. mutans (n=8); b) S. mutans adherence test by counting colony-forming units after 2 h of material/bacteria exposure (n=10); c) biofilm wet weight after seven days of bacterial accumulation on material disks, with growth medium renewed every 48 h (n=10); d) pH and fluoride measurements from the medium aspired at 48 h intervals during the 7-day biofilm development (n=10). Data from the a, b and c tests were submitted to Kruskal-Wallis and Mann-Whitney tests and the fluoride release and pH data were submitted to two-way ANOVA and Tukey tests (a=5%). Vitremer followed by Ketac Nano showed the greatest inhibitory zone against S. mutans than the conventional ionomers. Vitremer also showed higher pH values than Ketac Nano and Fuji IX in the first 48 h and released higher fluoride amount than Ketac Nano e Ketac Molar Easymix throughout the experimental period. The chemical composition of restorative glass ionomer materials influenced the antibacterial properties. The resin modified glass ionomer (Vitremer) was more effective for inhibition of S. mutans and allowed greater neutralization of the pH in the first 48 h. However, the type of glass ionomer (resin modified or conventional) did not influence the weight and adherence of the biofilm and fluoride release. PMID- 27982180 TI - Effects of Contamination by Hemostatic Agents and Use of Cleaning Agent on Etch and-Rinse Dentin Bond Strength. AB - The aim of this study was to evaluate the influence of contamination by hemostatic agents and rinsing with chlorhexidine on bond strength between dentin and resin composite. Ninety-six bovine teeth were sectioned to expose a flat dentin surface area. A standardized cavity with 2.0 mm in thickness, superficial diameter of 4.0 mm and bottom diameter of 3.0 mm was prepared with a diamond bur in each dentin specimen. The teeth were divided into four groups according to the hemostatic employed: G1: control; G2: use of ViscoStat, Ultradent; G3: Hemosthasegel, FGM; and G4: Hemostop, Dentsply. The groups were divided into two subgroups according to the cleaning protocol method (n=12): A: without any further cleaning; and B: cleaning with chlorhexidine at 0.2%. All cavities were filled using a dentin adhesive and a resin composite, following the manufacturer's instructions. After 24 h, the specimens were aged by thermal and mechanical cycling. The bond strength was determined by the push out bond test (MPa), Statistical analysis was performed using two-way ANOVA and Tukey test (p<0.05). Statistically significant differences were detected among all groups treated with hemostatic agents and the control group. The post-hoc test showed that cleaning the cavity with chlorhexidine significantly improves the bond strength between dentin and resin composite. Our results suggested that the use of chlorhexidine can reestablish the bond strength between dentin and resin composite when a hemostatic agent was applied. PMID- 27982181 TI - Bonding of the Polymer Polyetheretherketone (PEEK) to Human Dentin: Effect of Surface Treatments. AB - Polyetheretherketone (PEEK) is a material suitable for frameworks of fixed dental prostheses. The effect of different surface treatments on the bond strength of PEEK bonded to human dentin was evaluated. One hundred PEEK cylinders (3 mm*3 mm) were divided into five groups according to surface treatment: silica coating, sandblasting with 45 MUm Al2O3 particles, etching with 98% sulfuric acid for 5, 30 and for 60 s. These cylinders were luted with resin cement onto 50 human molars. First, each tooth was embedded in epoxy resin and the buccal dentin surface was exposed. Then, two delimited dentin areas (AE:3 mm) per tooth were etched with 35% phosphoric acid and bonded with a two-step self-priming adhesive system. After the luting procedure the specimens were stored in water (24 h/37 degrees C). Shear bond strength (SBS) was tested using a universal testing machine (crosshead speed 0.5 mm/min; load cell 50 kgf) and failure types were assessed. Stress data (MPa) were analyzed using the Kruskal-Wallis test. Comparison of the proportions of different failure types was performed using the Bonferroni method (p<0.05). Kruskal-Wallis demonstrated that differences among groups were not significant (p=0.187). Mean SBS were as follows: silica coating, 2.12+/-1.12 MPa; sandblasting, 2.37+/-0.86 MPa; sulfuric acid 5 s, 2.28+/-1.75 MPa; sulfuric acid 30 s, 1.80+/-0.85 MPa; sulfuric acid 60 s, 1.67+/-0.94 MPa. Adhesive and mixed failures were predominant in all groups. Both physical and chemical surface treatments produced adhesion between PEEK, resin cement and dentin. PMID- 27982183 TI - Adhesives Doped with Bioactive Niobophosphate Micro-Filler: Degree of Conversion and Microtensile Bond Strength. AB - To evaluate the effect of incorporating niobium phosphate bioactive glass (NbG) into commercial etch-and-rinse adhesive systems, with and without silane, on their degree of conversion (DC) (%) and microtensile bond strength (MUTBS). The NbG micro-filler was added to two etch-and-rinse adhesive systems: One Step (OS) and Prime & Bond (PB) at 40% concentration. The following groups were formed: control without glass addition OS; addition of unsilanized NbG (OSNbG); addition of silanized NbG (OSNbGS); control without glass PB; addition of unsilanized NbG (PBNbG); addition of silanized NbG (PBNbGS). The DC was determined using total Fourier spectroscopy reflection (FTIR/ATR). For MUTBS testing, 48 human third molars (n=8) were restored and sliced to obtain specimens (0.8 mm2) and they were tested at two different time intervals: immediately and after 6 months. The fracture mode was evaluated with a stereoscopic loupe (40*) and by scanning electron microscopy (SEM). The data were subjected to ANOVA and Tukey tests (a=0.05). NbG addition did not compromise the adhesive system DC values (p>0.05). Furthermore, the NbG added to the adhesive systems did not affect MUTBS values (p>0.05). Fracture occurred predominantly at the dentin-adhesive interface. NbG bioactive glass did not affect the DC or microtensile bond strength results. PMID- 27982182 TI - Alkaline Peroxides Versus Sodium Hypochlorite for Removing Denture Biofilm: a Crossover Randomized Trial. AB - This study evaluated the efficacy of cleanser solutions on denture biofilm removal by a crossover randomized clinical trial. Thirty two edentulous patients were instructed to brush their dentures (specific brush and liquid soap) three times a day (after breakfast, lunch and dinner) and to soak them (>= 8 h) in: (C) control -water; (AP): alkaline peroxide; or (SH) 0.5% sodium hypochlorite. Each solution was used for 21 days (three cycles of 7 days). At the end of each cycle, the inner surfaces of maxillary dentures were disclosed (1% neutral red) and photographed (HX1 - Sony). Areas (total and stained biofilm) were measured (Image Tool software) and the percentage of biofilm calculated as the ratio between the area of the biofilm multiplied by 100 and total surface area of the internal base of the denture. Data were compared by means of generalized estimating equation (alpha=5%) and multiple comparisons (Bonferroni; alpha=1.67%). Immersion in SH reduced biofilm (%) (8.3 +/- 13.3B) compared to C (18.2 +/- 14.9A) and AP (18.2 +/- 16.6A). The 0.5% sodium hypochlorite solution was the most efficacious for biofilm removal. Alkaline peroxides may not lead to further biofilm removal in patients with adequate denture maintenance habits. PMID- 27982184 TI - Assessment of Marginal Bone Loss around Platform-Matched and Platform-Switched Implants - A Prospective Study. AB - The aim of the present study was to perform a software-assisted radiographic assessment of the effect of platform-switching on marginal bone loss (MBL) around dental implants. Forty patients requiring a dental implant in non-grafted partially edentulous mandibles were enrolled and categorized into implants receiving a platform-matched abutment (control group) or implants with a platform switched abutment (test group). Standardized digital periapical radiographs were taken at the time of implant placement (T0), at implant loading (T1) and 1-year after functional loading (T2). Software-assisted radiographic assessment of the MBL horizontal, vertical and area changes was performed and compared between time intervals (T1-T0, T2-T1 and T2-T0). Mean radiographic horizontal MBL (hMBL) and vertical MBL (vMBL) from implant placement to 1-year after implant loading (T2 T0) were significantly increased around platform-matched when compared to platform-switched abutments (1.04 mm vs 0.84 mm, p<0.05) and (0.99 mm vs 0.82 mm, p<0.05), respectively. Additionally, bone loss area (BLa) was greater (0.77 mm2 vs 0.63 mm2; p<0.05) for platform-matched compared to platform-switched abutments. Platform-switching has a positive impact upon the amount of bone modeling after loading implants with internal hexagon connection. PMID- 27982186 TI - The Effect of Hydrofluoric Acid Concentration and Heat on the Bonding to Lithium Disilicate Glass Ceramic. AB - The aim of this study was to evaluate the effects of hydrofluoric acid (HF) concentration and previous heat treatment (PHT) on the surface morphology and micro-shear bond strength (mSBS) of a lithium disilicate glass ceramic (EMX) to resin cement. One hundred four EMX specimens were randomly assigned to two groups (n=52) according to the HF concentration: 5% and 10%. A new random distribution was made according to the PHTs (n=13): control (no PHT); previously heated HF (70 degrees C); previously heated EMX surface (85 degrees C); the combination of heated HF + heated EMX surface. The etching time was set at 20 s. All EMX blocks were silanated and received a thin layer of an unfilled resin. Five resin cement cylinders were made on each EMX surface using Tygon tubes as matrices, and then stored for 24 h at 37 degrees C. One random etched EMX sample from each group was analyzed using field-emission scanning electron microscopy (FE-SEM). The data were subjected to two-way ANOVA and multiple comparisons were performed using the Tukey post hoc test (a=0.05). For the control groups, 5% HF showed statistically lower mSBS values when compared to 10% HF (p<0.05). PHT increased the mSBS values for 5% HF, yielding statistically similar results to non-PHT 10% HF (p<0.05). FE SEM images showed increased glassy matrix removal when PHT was applied to HF 5%, but not to the same degree as for 10% HF. PHT has the potential to improve the bond strength of 5% HF concentration on lithium disilicate glass ceramic. PMID- 27982185 TI - Physico-chemical and Histomorphometric Evaluation of Zinc-containing Hydroxyapatite in Rabbits Calvaria. AB - The aim of this study was to characterize the physico-chemical properties and bone repair after implantation of zinc-containing nanostructured porous hydroxyapatite scaffold (nZnHA) in rabbits' calvaria. nZnHA powder containing 2% wt/wt zinc and stoichiometric nanostructured porous hydroxyapatite (nHA - control group) were shaped into disc (8 mm) and calcined at 550 degrees C. Two surgical defects were created in the calvaria of six rabbits (nZnHA and nHA). After 12 weeks, the animals were euthanized and the grafted area was removed, fixed in 10% formalin with 0.1 M phosphate buffered saline and embedded in paraffin (n=10) for histomorphometric evaluation. In addition, one sample from each group (n=2) was embedded in methylmethacrylate for the SEM and EDS analyses. The thermal treatment transformed the nZnHA disc into a biphasic implant composed of Zn containing HA and Zn-containing beta-tricalcium phosphate (ZnHA/betaZnTCP). The XRD patterns for the nHA disc were highly crystalline compared to the ZnHA disc. Histological analysis revealed that both materials were biologically compatible and promoted osteoconduction. X-ray fluorescence and MEV-EDS of nZnHA confirmed zinc in the samples. Histomorphometric evaluation revealed the presence of new bone formation in both frameworks but without statistically significant differences (p>0.05), based on the Wilcoxon test. The current study confirmed that both biomaterials improve bone repair, are biocompatible and osteoconductive, and that zinc (2wt%) did not increase the bone repair. Additional in vivo studies are required to investigate the effect of doping hydroxyapatite with a higher Zn concentration. PMID- 27982187 TI - Effect of Acid Etching, Silane and Thermal Cycling on the Bond Strength of Metallic Brackets to Ceramic. AB - The aim of this study was to evaluate the effect of silanes, thermal cycling and acid etching on the shear bond strength (SBS) of metallic brackets to feldspathic ceramic. Feldspathic ceramic cylinders (Groups 1, 2, 5 and 6) were etched for 60 s with 10% hydrofluoric acid and Groups 3, 4, 7 and 8, without acid etching. Two layers of silane Clearfil Ceramic Primer (CCP, Groups 1 to 4) and two layers of RelyX Ceramic Primer (RCP, groups 5 to 8) were applied and dried for 60 s. Brackets were bonded to the cylinders with Transbond XT and light-activated for 40 s with Bluephase G2. All specimens were stored in deionized water at 37 degrees C for 24 h, and the specimens of groups 1, 3, 5 and 7 were submitted to 7,000 thermal cycles (5 degrees C/55 degrees C). After storage, the SBS test was performed at a crosshead speed of 1 mm/min. Data were subjected to three-way ANOVA and Tukey's post hoc test (alpha=0.05). The adhesive remnant index (ARI) was evaluated at 8x magnification. The SBS of CCP was significantly greater than of RCP (p<0.05), with or without thermal cycling. Thermal cycling significantly reduced the SBS (p<0.05). The groups submitted to acid etching showed significantly higher SBS than those without acid etching (p<0.05). In conclusion, thermal cycling reduced SBS for all groups. The best ceramic surface treatment for bracket bonding was achieved by acid etching and CCP silane. The ARI results showed predominance of score 0 for all groups. PMID- 27982188 TI - Tensile Strength of Resin Cements Used with Base Metals in a Simulating Passive Cementation Technique for Implant-Supported Prostheses. AB - The aim of this study was to analyze the tensile strength of two different resin cements used in passive cementation technique for implant-supported prosthesis. Ninety-six plastic cylinders were waxed in standardized forms, cast in commercially pure titanium, nickel-chromium and nickel-chromium-titanium alloys. Specimens were cemented on titanium cylinders using self-adhesive resin cement or conventional dual-cured resin cement. Specimens were divided in 12 groups (n=8) in accordance to metal, cement and ageing process. Specimens were immersed in distilled water at 37 degrees C for 24 h and half of them was thermocycled for 5,000 cycles. Specimens were submitted to bond strength test in a universal test machine EMIC-DL2000 at 5 mm/min speed. Statistical analysis evidenced higher tensile strength for self-adhesive resin cement than conventional dual-cured resin cement, whatever the used metal. Self-adhesive resin cement presented higher tensile strength compared to conventional dual-cured resin cement. In conclusion, metal type and ageing process did not influence the tensile strength results. PMID- 27982190 TI - Dragon's Blood Sap (Croton Lechleri) As Storage Medium For Avulsed Teeth: In Vitro Study Of Cell Viability. AB - Tooth replantation success depends on the condition of cementum periodontal ligament after tooth avulsion; which is influenced by storage medium. The dragon's blood (Croton lechleri) sap has been suggested as a promising medium because it supports collagen formation and exhibits healing, anti-inflammatory and antimicrobial properties. Thus, the aim of this study was to evaluate the efficacy of dragon's blood sap as a storage medium for avulsed teeth through evaluation of functional and metabolic cell viability. This in vitro study compared the efficacy of different storage media to maintain the viability of human peripheral blood mononuclear and periodontal ligament cells. A 10% dragon's blood sap was tested while PBS was selected as its control. Ultra pasteurized whole milk was used for comparison as a commonly used storage medium. DMEM and distilled water were the positive and negative controls, respectively. The viability was assessed through trypan blue exclusion test and colorimetric MTT assay after 1, 3, 6, 10 and 24 h of incubation. The dragon's blood sap showed promising results due to its considerable maintenance of cell viability. For trypan blue test, the dragon's blood sap was similar to milk (p<0.05) and both presented the highest viability values. For MTT, the dragon's blood sap showed better results than all storage media, even better than milk (p<0.05). It was concluded that the dragon's blood sap was as effective as milk, the gold standard for storage medium. The experimental sap preserved the membrane of all cells and the functional viability of periodontal ligament cells. PMID- 27982191 TI - Effects of Image Compression on Linear Measurements of Digital Panoramic Radiographs. AB - This study aimed to evaluate the accuracy of panoramic radiographs obtained by digital system based on charge coupled device (CCD) and a phosphor storage plate (PSP) system with two different file formats, JPEG irreversible type and BMP. Linear measurements of artificial bony defects were made in dry mandibles with a digital caliper. Measures of digital panoramic radiographs were taken in ImageJ(r) software. Each measurement was performed twice by an experienced examiner. The intra-rater agreement was considered very strong (Pearson's correlation coefficient of 0.97). There was no significant difference between the linear measurements of dry mandibles, considered the gold standard, in relation to measurements obtained from digital radiographs (p=0.47). The error of these measures for the CCD was 1.04 mm (9.97%) for JPEG images and 1.03 mm (9.99%) for those with BMP format. For the PSP images, these values were 1.48 mm (14.94%) and 1.43 mm (14.43%), respectively. Although there was no statistical difference between the images with JPEG and BMP format, for both digital systems (p=1.00 for CCD and p=0.98 for PSP system), errors made on radiographs obtained by PSP system were significantly higher than those of CCD (p<0.05). The size of the files saved in JPEG was also significantly lower (p=0.005) compared with the files saved in BMP. It may be concluded that the digital radiographs, both saved in JPEG and BMP formats, are accurate, regardless the used digital system, and JPEG images are more suitable for teleradiology. PMID- 27982189 TI - Gabapentin Differentially Modulate c-Fos Expression in Hypothalamus and Spinal Trigeminal Nucleus in Surgical Molar Extraction. AB - The study on the efficacy of oral analgesics reported that no single class of drug is effective in post-surgical dental pain. Pain following removal of third molar is most commonly used and widely accepted acute pain model for assessing the analgesic effect of drugs in humans. Reports demonstrated that analgesic efficacy in the human dental model is highly predictive. The high incidence of false-negative findings in analgesic investigations hinders the process of molecular discovery. Molecular mechanism of post-surgical pain is not known. More importantly, the animal model for postoperative dental pain is not well established. In an attempt to discover an effective post-surgical dental pain blocker with acceptable side effects, it is essential to elucidate the molecular mechanism of post-operative dental pain. The present study investigated mandibular molars extraction in rat as an animal model for the post-operative dental pain in central nervous system. Using c-Fos immunohistochemistry, we demonstrated that pre administration of GBP (150 mg/kg. i.p) significantly (p< 0.01) neutralized the surgical molar extraction induced c-Fos expression bilaterally in rat hypothalamus. Present results indicate that pain after surgical molar extraction might follow novel neural pathways therefore difficult to treat with existing anti-nociceptive drugs. PMID- 27982192 TI - Differential Impacts of Caries Classification in Children and Adults: A Comparison of ICDAS and DMF-T. AB - The aim of this study was to describe and compare findings regarding the prevalence and severity of dental caries when using ICDAS and DMFT/dmft in an epidemiological study with children and their mothers. This cross-sectional study evaluated 150 preschoolers and their mothers. Data were collected with ICDAS and then transformed into DMFT/dmft. ICDAS scores related to caries were analyzed according to three different cut-off-points: CP1 (0-healthy/1-6-caries), CP2 (0-1 healthy/2-6-caries) and CP3 (0-2-healthy/3-6-caries), representing the D/d of DMFT/dmft. ICDAS codes regarding restorations, except sealants, were considered the F/f and the code 97 as the M/m of DMFT/dmft index. Prevalence of caries and its severity with ICDAS were 92%, 84% and 31.3% in children and 97.3%, 96.6% and 80% in adults according to CP1/CP2/CP3, respectively. Admitting CP3 as the standard for data transformation of ICDAS in DMFT/dmft, it was observed that DMFT/dmft index would underestimate 60% of non-cavitated lesions in children and 16.6% in adults. The DMFT/dmft underestimated the presence of disease to disregard non-cavitated lesions for the pediatric population evaluated. The choice of which is the best index for epidemiological surveys will depend on the purpose of the research and the target population: if it is to estimate the needs of the population to determine clinical care in children and adults, the DMFT/dmft may be sufficient. However, if the objective is to have a more comprehensive diagnosis of caries at the population level in order to develop preventive strategies, to halt and reverse the disease, the detection of non cavitated-lesions becomes important, mainly in young children. PMID- 27982193 TI - Use of Feldspathic Porcelain Veneers to Improve Smile Harmony: A 3-Year Follow-up Report. AB - This case report describes an esthetic treatment to improve the shape and alignment of the anterior teeth, reestablishing smile harmony, using feldspathic porcelain veneers. Results of clinical follow up after 36 months are also presented. The advantages, disadvantages and limitations of the technique are detailed with reference to the relevant literature. This suggests that the success of treatment depends on adequate conditions of bonding between the veneers and the tooth complex, which involves parameters such as the strength and durability of the bond interface. Therefore, the clinical success of feldspathic porcelain veneers depends on the accurate selection of cases and correct execution of clinical and laboratory procedures. The rehabilitation involved from first right premolar to the left with feldspathic porcelain veneers made on refractory dies. After the 3-year follow up, excellent clinical results and patient satisfaction were achieved. PMID- 27982194 TI - Histologic and Tomographic Findings of Bone Block Allografts in a 4 Years Follow up: A Case Series. AB - The aim of this paper is to report histologic and tomographic findings of fresh frozen bone block allografts bearing dental implants in functional occlusion in a long-term follow-up. Four patients with implants functionally loaded for 4 years on augmented ridges requiring additional mucogingival surgery or implant placement were included in this case series. Cone-beam tomography scans were compared volumetrically between the baseline (first implant placement) and current images. Biopsies of the grafts were retrieved and sent to histological analysis. Volumetric reduction of the grafts varied from 2.1 to 7.7%. Histological evaluation demonstrated well-incorporated grafts with different degrees of remodeling. While data presented in this report are from a small sample size and do not allow definitive conclusions, the biopsies of the grafted sites were very similar to the host's native bone. Remodeling of the cortical portion of the allografts seems to take longer than the cancellous portion. The presence of unincorporated graft remains did not impair the implant success or the health of the surrounding tissues. This is the first time histologic and tomographic long term data of bone allograft have been made available in dentistry. PMID- 27982195 TI - Oral Adenosquamous Carcinoma Mimicking a Pyogenic Granuloma: a Challenging Diagnosis. AB - Adenosquamous carcinoma is an aggressive variant of squamous cell carcinoma. This report describes a case of adenosquamous carcinoma with clinical features of a benign lesion and discusses the differential diagnoses, especially regarding histopathological and immunohistochemical analyses. A 45-year-old male was referred to our outpatient clinic complaining about a rapid-growing enlargement in hard palate. Clinical examination revealed an erythematous and pedunculated nodule with lobulated non-ulcerated surface. Excisional biopsy was performed following clinical diagnosis of pyogenic granuloma. Histologically, the specimen consisted of areas characterizing both well-differentiated squamous cell carcinoma and true adenocarcinoma. After a broad list of immunohistochemical markers was evaluated (AE1/AE3, CEA, CK5, CK7, CK8/18, p53, p63 and Ki67), the diagnosis of adenosquamous carcinoma was rendered and the patient referred to complementary surgery. Adenosquamous carcinoma represents a challenge in diagnostic routine due to its rarity, diverse range of clinical presentations and histological features. Furthermore, classical clinical benign features may be present in malignant lesions; hence the submission of every surgical specimen to histological analysis is mandatory to provide the patient the adequate treatment. PMID- 27982197 TI - Is body mass index still a good tool for obesity evaluation? PMID- 27982196 TI - Diagnosis of acromegaly: black, white... and sometimes gray! PMID- 27982198 TI - Treatment of hypothyroidism with levothyroxine plus liothyronine: a randomized, double-blind, crossover study. AB - Objective: To compare the effects of a unique fixed combination levothyroxine/liothyronine (LT4/LT3) therapy in patients with primary hypothyroidism. Subjects and methods: This is a randomized, double-blind, crossover study. Adults with primary hypothyroidism (n = 32, age 42.6 +/- 13.3, 30 females) on stable doses of LT4 for >= 6 months (125 or 150 MUg/day) were randomized to continue LT4 treatment (G1) or to start LT4/LT3 therapy (75/15 MUg/day; G2). After 8 weeks, participants switched treatments for 8 more weeks. Thyroid function, lipid profile, plasma glucose, body weight, electrocardiogram, vital signs, and quality of life (QoL) were evaluated at weeks 0, 8 and 16. Results: Free T4 levels were significantly lower while on LT4/LT3 (G1: 1.07 +/- 0.29 vs. 1.65 +/- 0.46; G2: 0.97 +/- 0.26 vs. 1.63 +/- 0.43 ng/dL; P < 0.001). TSH and T3 levels were not affected by type of therapy. More patients on LT4/LT3 had T3 levels above the upper limit (15% vs. 3%). The combination therapy led to an increase in heart rate, with no significant changes in electrocardiogram or arterial blood pressure. Lipid profile, body weight and QoL remained unchanged. Conclusions: The combination therapy yielded significantly lower free T4 levels, with no changes in TSH or T3 levels. More patients on LT4/T3 had elevated T3 levels, with no significant alterations in the evaluated outcomes. No clear clinical benefit of the studied formulation could be observed. Future trials need to evaluate different formulations and the impact of the combined therapy in select populations with genetic polymorphisms. PMID- 27982199 TI - Elevated IGF-1 with GH suppression after an oral glucose overload: incipient acromegaly or false-positive IGF-1? AB - Objective: To report the evolution of patients with a suggestive clinical scenario and elevated serum insulin-like growth factor-1 (IGF-1), but growth hormone (GH) suppression in the oral glucose tolerance test (OGTT), in whom acromegaly was not initially excluded. Subjects and methods: Forty six patients with a suggestive clinical scenario, who had elevated IGF-1 (outside puberty and pregnancy) in two measurements, but GH < 0.4 ug/L in the OGTT, were selected. Five years after initial evaluation, the patients were submitted to clinical and laboratory (serum IGF-1) reassessment. Patients with persistently elevated IGF-1 were submitted to a new GH suppression test and magnetic resonance imaging (MRI) of the pituitary. Results: Four patients were lost to follow-up. During reassessment, 42 patients continued to show no "typical phenotype" or changes in physiognomy. Fifteen of the 42 patients had normal IGF-1. Among the 27 patients with persistently elevated IGF-1 and who were submitted to a new OGTT, GH suppression was confirmed in all. Two patients exhibited a lesion suggestive of microadenoma on pituitary MRI. In our interpretation of the results, acromegaly was ruled out in 40 patients and considered "possible" in only 2. Conclusion: Our results show that even in patients with a suggestive clinical scenario and elevated IGF-1, confirmed in a second measurement and without apparent cause, acromegaly is very unlikely in the case of GH suppression in the OGTT. PMID- 27982201 TI - Incidence and prevalence of clinically relevant pituitary adenomas: retrospective cohort study in a Health Management Organization in Buenos Aires, Argentina. AB - Objectives: The main purpose of this study was to estimate the incidence rate and prevalence of clinically relevant pituitary adenomas (PAs) within the Hospital Italiano Medical Care Program (HIMCP), a well-defined population of 150,000 members living in the urban and suburban area of the city of Buenos Aires. We defined clinically relevant PAs as those associated with endocrine dysfunction and/or mass effect. Subjects and methods: A retrospective open cohort study was conducted, including all members of the HIMCP over 18 years old, with active memberships during the period of the study, from January 1st 2003, to January 1, 2014. The incidence rates (IRs) were standardized (SIR) to the World Health Organization (WHO) 2000 standard population and were expressed per 100,000 members/year. Prevalence was estimated at January 1, 2014, and was expressed per 100,000 persons. The clinical records have been electronically managed since 2001. All lab and imaging studies were done in-house. Results: The overall SIR was 7.39/100,000/year (95% CI 4.47-10.31). Female patients had a specific IR significantly higher than male patients (5.85 vs.1.54) and represented 73% of the affected members. Regarding tumor size, 61.4% were microadenomas, and the mean age at diagnosis was 46.4 years. Prolactinomas had the highest SIR (5.41), followed by acromegaly (Acro) and non-functioning adenomas (NFAs) with overlapping 95% CIs (0.44-1.41 and 0.31-0.99, respectively). Microprolactinomas were more frequent in female (72.6%) (p < 0.01) and younger members (38 vs.60 years; p < 0.04). The overall prevalence rate was 97.76/100,000. Prolactinomas had the highest prevalence (56.29), followed by NFAs (21.48), Acro (14.07) and CD (5.93). Conclusion: Our results demonstrate that clinically relevant PAs are more common than usually suspected, especially prolactinomas and growth-hormone secreting PAs. These data highlight the need to increase the awareness of PAs, thereby enabling early diagnosis and treatment. PMID- 27982200 TI - Metabolic syndrome and sexual function in postmenopausal women. AB - Objective: The purpose of this study was to evaluate whether female sexual dysfunction (FSD) is associated with metabolic syndrome (MS) and to identify factors that contribute to FSD in postmenopausal women. Subjects and methods: This was a cross-sectional study in 111 sexually active women aged 45-65 years. We applied the Female Sexual Function Index (FSFI) to evaluate the participant's sexual function and a structured questionnaire to collect demographic, socioeconomic, clinical, anthropometric, and laboratory data. Results: The prevalences of MS and FSD were 68.5% and 70.3%, respectively. After logistic regression analysis, we identified the following variables associated with FSD: married status (prevalence ratio [PR] 1.69, 95% confidence interval [95% CI] 1.16 2.47, p < 0.01), 6-10 years elapsed since menopause (PR 1.60, 95% CI 1.22-2.09, p < 0.01), occurrence of climacteric symptoms (PR 1.01, 95% CI 1.00-1.02, p = 0.03), and history of sexual abuse (PR 1.40, 95% CI 1.12-1.73, p < 0.01). Conclusion: We found a high prevalence of MS and FSD, but no association between both. Married status, time elapsed since menopause, climacteric symptoms, and history of sexual abuse emerged as factors associated with FSD on multivariate analysis. PMID- 27982203 TI - Crosslinking enters public health armamentarium in Brazil. PMID- 27982202 TI - A boy with Prader-Willi syndrome: unmasking precocious puberty during growth hormone replacement therapy. AB - Prader-Willi syndrome (PWS) is a genetic disorder frequently characterized by obesity, growth hormone deficiency, genital abnormalities, and hypogonadotropic hypogonadism. Incomplete or delayed pubertal development as well as premature adrenarche are usually found in PWS, whereas central precocious puberty (CPP) is very rare. This study aimed to report the clinical and biochemical follow-up of a PWS boy with CPP and to discuss the management of pubertal growth. By the age of 6, he had obesity, short stature, and many clinical criteria of PWS diagnosis, which was confirmed by DNA methylation test. Therapy with recombinant human growth hormone (rhGH) replacement (0.15 IU/kg/day) was started. Later, he presented psychomotor agitation, aggressive behavior, and increased testicular volume. Laboratory analyses were consistent with the diagnosis of CPP (gonadorelin-stimulated LH peak 15.8 IU/L, testosterone 54.7 ng/dL). The patient was then treated with gonadotropin-releasing hormone analog (GnRHa). Hypothalamic dysfunctions have been implicated in hormonal disturbances related to pubertal development, but no morphologic abnormalities were detected in the present case. Additional methylation analysis (MS-MLPA) of the chromosome 15q11 locus confirmed PWS diagnosis. We presented the fifth case of CPP in a genetically-confirmed PWS male. Combined therapy with GnRHa and rhGH may be beneficial in this rare condition of precocious pubertal development in PWS. PMID- 27982204 TI - Corneal structure in tilted disc syndrome. AB - Purpose:: To evaluate the central corneal thickness (CCT), corneal volume (CV), and anterior and posterior corneal surfaces using the Scheimpflug imaging system in patients diagnosed with tilted disc syndrome (TDS). Methods:: The study group (Group 1) and the control group (Group 2) comprised 35 eyes of 35 age-, sex-, and refraction-matched cases. All cases underwent a full ophthalmic examination that included cycloplegic refraction, axial ocular length measurement, and Scheimpflug imaging. Results:: The mean age was 34.68 +/- 15.48 years in Group 1 and 34.11 +/ 12.01 years in Group 2 (p=0.864). The gender distribution was 18 males and 17 females in Group 1 and 16 males and 19 females in Group 2 (p=0.618). All subjects were Caucasian. The spherical equivalent was 3.62 +/- 1.75 D in Group 1 and 3.69 +/- 1.51 D in Group 2 (p=0.850). There was no significant difference in age, sex, race, or spherical equivalent between groups. There was no significant difference in mean keratometric value and CV3 (the CV in the central 3 mm) between groups (p=0.232 and 0.172, respectively). There were statistically significant differences in CCT, CV5, and CV7 (CV in the central 5 and 7 mm3, respectively) and total CV between groups (p=0.008, 0.003, 0.023, and 0.019, respectively). The values of all parameters were lower in the study group than in the control group. There was also a statistically significant difference in the anterior elevation parameters of the cornea between groups (p<0.05). The mean values of Group 1 were higher than those of Group 2. There were statistically significant differences in the two parameters referring to the posterior elevation of the cornea between the two groups (p<0.05). Conclusion:: The results of this study showed that eyes with TDS have thinner CCT, lower CV, and different anterior corneal curvature than normal eyes. PMID- 27982205 TI - Microbiological and epidemiological study of infectious keratitis in children and adolescents. AB - Purpose:: To analyze epidemiological and microbiological aspects of microbial keratitis in children and adolescents. Methods:: This retrospective cohort study was conducted at the Department of Ophthalmology and Visual Science, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, between July 15, 1975, and December 31, 2010. We analyzed corneal samples from 859 patients with clinical suspicion of infectious keratitis, comparing epidemiological and microbiological characteristics of bacterial keratitis with those of non bacterial and non-viral keratitis. We also compared Gram-positive and Gram negative pathogens in patients with bacterial keratitis. We created a susceptibility profile of the bacterial microorganisms studied. Results:: Of the 859 patients, 346 (40.3%) showed positive culture results for non-viral microorganisms. Teenagers (13-18 years) made up the group with the highest number of patients with keratitis (164, 47.4%). The most frequent risk factors for keratitis were trauma (33.5%) and previous ocular surgery (24.9%). Gram-positive bacteria (71.8%) were the most often isolated, with coagulase-negative Staphylococcus (23.8%) the most prevalent microorganism. Logistic regression analysis showed age (p=0.002), topical antimicrobial drug use (p=0.01), and trauma due to non-chemical burns (p=0.005) were risk factors for non-bacterial keratitis. Age (p=0.01) was also a risk factor for Gram-negative bacterial keratitis. Conclusion:: Our study showed that in the age range studied, the prevalence of keratitis caused by Gram-negative bacteria or by the non-viral microorganisms evaluated increases with age. Previous use of topical antimicrobial drug and trauma due to non-chemical burns are associated with non bacterial keratitis. Knowledge of the risk factors and the microorganisms involved may help improve treatment of keratitis in children and adolescents and minimize visual impairment. PMID- 27982206 TI - Dysfunction in the fellow eyes of strabismic and anisometropic amblyopic children assessed by visually evoked potentials. AB - Purpose:: To evaluate visual acuity and transient pattern reversal (PR) visual evoked potentials (VEPs) in the fellow eyes of children with strabismic and/or anisometropic amblyopia. Methods:: Children diagnosed with strabismic and/or anisometropic amblyopia were recruited for electrophysiological assessment by VEPs. Monocular grating and optotype acuity were measured using sweep-VEPs and an Early Treatment Diabetic Retinopathy Study chart, respectively. During the same visit, transient PR-VEPs of each eye were recorded using stimuli subtending with a visual angle of 60', 15', and 7.5'. Parameters of amplitude (in MUV) and latency (in ms) were determined from VEP recordings. Results:: A group of 40 strabismic and/or anisometropic amblyopic children (22 females: 55%, mean age= 8.7 +/- 2.2 years, median= 8 years) was examined. A control group of 19 healthy children (13 females: 68.4%, mean age= 8.2 +/- 2.6 years, median= 8 years) was also included. The fellow eyes of all amblyopes had significantly worse optotype acuity (p=0.021) than the control group, regardless of whether they were strabismic (p=0.040) or anisometropic (p=0.048). Overall, grating acuity was significantly worse in the fellow eyes of amblyopes (p=0.016) than in healthy controls. Statistically prolonged latency for visual angles of 15' and 7.5' (p=0.018 and 0.002, respectively) was found in the strabismic group when compared with the control group. For the smaller visual stimulus (7.5'), statistically prolonged latency was found among all fellow eyes of amblyopic children (p<0.001). Conclusions:: The fellow eyes of amblyopic children showed worse optotype and grating acuity, with subtle abnormalities in the PR-VEP detected as prolonged latencies for smaller size stimuli when compared with eyes of healthy children. These findings show the deleterious effects of amblyopia in several distinct visual functions, mainly those related to spatial vision. PMID- 27982207 TI - Comparison of 20% sulfur hexafluoride with air for intraocular tamponade in Descemet membrane endothelial keratoplasty (DMEK). AB - Purpose:: To compare the effect of 20% sulfur hexafluoride (SF6) with that of air on graft detachment rates for intraocular tamponade in Descemet membrane endothelial keratoplasty (DMEK). Methods:: Forty-two eyes of patients who underwent DMEK by a single surgeon (A.S.J.) at Wilmer Eye Institute between January 2012 and 2014 were identified; 21 received air for intraocular tamponade and the next consecutive 21 received SF6. The main outcome measure was the graft detachment rate; univariate and multivariate analyses were performed. Results:: The graft detachment rate was 67% in the air group and 19% in the SF6 group (p<0.05). No complete graft detachments occurred, and all partial detachments underwent intervention with injection of intraocular air. The percentages of eyes with 20/25 or better vision were not different between the groups (67% vs. 71%). Univariate analysis showed significantly higher detachment rates with air tamponade (OR, 8.50; p<0.005) and larger donor graft size (OR, 14.96; p<0.05). Multivariate analysis with gas but not graft size included showed that gas was an independent statistically significant predictor of outcome (OR, 6.65; p<0.05). When graft size was included as a covariate, gas was no longer a statistically significant predictor of detachment but maintained OR of 7.81 (p=0.063) similar to the results of univariate and multivariate analyses without graft size. Conclusion:: In comparison with air, graft detachment rates for intraocular tamponade in DMEK were significantly reduced by 20% SF6. PMID- 27982208 TI - Pattern-reversal visual evoked potentials as a diagnostic tool for ocular malingering. AB - Purpose:: To investigate the contributions of transient pattern-reversal visual evoked potentials in the diagnosis of ocular malingering at a Brazilian university hospital. Methods:: Adult patients with suspected malingering in one or both eyes were referred for visual evoked potential testing. Data from patients' medical records were reviewed and analyzed retrospectively. Data analysis included the distance optotype visual acuity based on a ETDRS retro illuminated chart and the transient pattern-reversal visual evoked potential parameters of latency (milliseconds) and amplitude (microvolts) for the P100 component, using checkerboards with visual subtenses of 15' and 60'. Motivations for malingering were noted. Results:: The 20 subjects included 11 (55%) women. Patient ages ranged from 21 to 61 years (mean= 45.05 +/- 11.76 years; median= 49 years). In 8 patients (6 women), both eyes exhibited reduced visual acuity with normal pattern-reversal visually evoked potential parameters (pure malingerers). The remaining 12 patients (7 men) exhibited reduced vision in only 1 eye, with simulated reduced vision in the contralateral eye (exaggerators). Financial motivation was noted in 18 patients (9 men). Conclusion:: Normal pattern-reversal visually evoked potential parameters with suspected ocular malingering were observed in a 20 patient cohort. This electrophysiological technique appeared to be useful as a measure of visual pathway integrity in this specific population. PMID- 27982209 TI - Subfoveal choroidal thickness changes after intravitreal bevacizumab therapy for central serous chorioretinopathy. AB - Purpose:: To evaluate subfoveal choroidal thickness (SFCT) changes after intravitreal bevacizumab (IVB) therapy for central serous chorioretinopathy (CSC) using enhanced depth imaging spectral-domain optical coherence tomography (EDI OCT). Methods:: In this retrospective study, we assessed the medical records of patients with CSC who received IVB (IVB group) or who were observed without intervention (control group). SFCT was measured using EDI-OCT. The main outcome measure was the change in SFCT. Results:: Twenty-one eyes were included in the IVB group and 16 eyes were included in the control group. All patients showed resolution of neurosensory detachment and improvement in vision. In the IVB group, the mean SFCT was 315 MUm at baseline, which decreased to 296 MUm at the most recent visit. In the control group, the mean SFCT was 307 MUm at baseline, which decreased to 266 MUm at the most recent visit. Although there was a significant decrease in the mean SFCT for the control group, the decrease was not significant for the IVB group (41 vs 19 MUm, p=0.003 vs p=0.071). Conclusions:: SFCT decreased in both groups with remission of the disease. However, the decrease was significantly greater in the control group. In terms of anatomic and functional outcomes, IVB injection is not promising. PMID- 27982210 TI - Comparison of central corneal thickness estimated by an ultrasonic pachymeter and non-contact specular microscopy. AB - Purpose:: To compare central corneal thickness (CCT) measurements of healthy individuals obtained with ultrasonic pachymetry (UP) and non-contact specular microscopy (NCSM). Method:: In total, 148 eyes of 74 subjects with no ocular or systemic diseases were included in the study. Central corneal thickness measurements of all patients performed with UP and NCCM were compared. Results:: A total of 74 subjects (38 females) were included in this study. The mean age was 45.2 +/- 18.4 (range 12-85) years. The mean central corneal thickness of all 148 eyes was 546.9 +/- 40 MUm with UP and 510.8 +/- 42 MUm with NCSM. The mean central corneal thickness measured with NCSM was 35 MUm thinner than that measured with UP (p<0.001). A high degree of agreement was found between the two methods (r=0.942, p<0.001). Conclusions:: Our results suggest that NCSM measures thinner corneas than UP and that the correction formula we identified should be applied when comparing between these two devices. PMID- 27982211 TI - Is there a relationship between outer retinal destruction and choroidal changes in cone dystrophy? AB - Purpose:: The aim of the present study was to use enhanced depth imaging optical coherence tomography (EDI-OCT) to investigate choroidal changes in patients with cone dystrophy (CD) and to correlate these findings with clinical and electroretinography (ERG) findings. Methods:: This case-control study included 40 eyes of 20 patients with CD and 40 eyes of 40 age- and refraction-matched healthy individuals. Choroidal thickness (CT) measurements were obtained under the foveal center and at 500 and 1,500 MUm from the nasal and temporal regions to the center of the fovea, respectively. EDI-OCT and ERG data were analyzed, and the correlations of CT with the best-corrected visual acuity (BCVA) and the central foveal thickness (CFT) were evaluated. Results:: The mean subfoveal CTs in the CD and control groups were 240.70 +/- 70.78 and 356.18 +/- 48.55 MUm, respectively. The subfoveal CT was significantly thinner in patients with CD than in the controls (p<0.001). The patients with CD also had significantly thinner choroids than the controls at each measurement location relative to the fovea (p<0.001). The subfoveal CT in the CD group correlated with CFT (p=0.012), but no significant correlation was found between the subfoveal CT and BCVA or photopic ERG responses. Conclusions:: The present study demonstrated a significant thinning of the choroid in patients with CD. EDI-OCT is a useful technique for describing the choroidal changes occurring in CD. Future studies investigating the association between choroidal changes and outer retinal destruction or the disease stage may provide a better understanding of the pathophysiology of CD. PMID- 27982212 TI - Evaluation of inner segment/outer segment junctions in different types of epiretinal membranes. AB - Purpose:: This study was conducted to evaluate the relationships of inner/outer segment (IS/OS) junction disruption, macular thickness, and epiretinal membrane (ERM) grade with best-corrected visual acuity (BCVA), as well as the relationship between IS/OS junction disruption and ERM grade. Methods:: Fifty-four eyes of 54 patients with different grades of ERM were retrospectively reviewed. Patients were classified into three groups by ERM grade according to retinal striae and vessel distortion: grade/group 1, visible membranes without retinal striae or vessel distortion; grade/group 2, mild to moderate macular striae or vessel straightening; and grade/group 3, moderate to severe striae and vascular straightening. Correlations of BCVA with age, central retinal thickness, ERM grade, and IS/OS disruption as well as of IS/OS disruption, central macular thickness, and BCVA with ERM grade were evaluated. Results:: Twenty-nine (53.7%) eyes exhibited IS/OS junction disruption. Groups 1 and 2 differed significantly with respect to BCVA (p=0.038), but groups 2 and 3 did not (p=0.070). Central macular thickness was significantly greater in group 2 than in group 1 (p=0.031) and in group 3 than in group 2 (p=0.033). Groups 1 and 2 differed significantly in terms of IS/OS disruption (p=0.000), but groups 2 and 3 did not (p=0.310). Conclusions:: The IS/OS junction appears to be disrupted during the early stages of ERM. Grade 3 ERM is associated with a significantly higher incidence of IS/OS disruption. PMID- 27982213 TI - Repeatability of contrast sensitivity testing in patients with age-related macular degeneration, glaucoma, and cataract. AB - Purpose:: To analyze the intrasession and intersession repeatability of contrast sensitivity (CS) measurements in patients with glaucoma, cataract, or age-related macular degeneration (AMD) and healthy controls. Methods:: CS measurements were performed using the OPTEC-Functional Vision Analyzer (FVA), which uses a standardized and closed (view-in) system. Measurements for patients with glaucoma, cataract, or AMD and healthy controls were repeated within 30 minutes (intrasession) and during two sessions (intersession), separated by one week to one month. Test-retest reliability and correlation were measured using the intraclass correlation coefficient (ICC) and coefficient of repeatability (COR). Results:: Ninety subjects (90 eyes) with visual acuity of 0.17 logMAR or higher in the cataract group or 0.00 logMAR in the other groups were included. During the first session, the ICC values were 0.87, 0.90, 0.76, and 0.69, and COR values were 0.24, 0.20, 0.38, and 0.25 for the control, glaucoma, cataract, and AMD groups, respectively. The reliability scores significantly improved during the second session, except in the glaucoma group. There was an acceptable floor effect and no ceiling effect at higher frequencies in the glaucoma and AMD groups. Conclusion:: In subjects with good visual acuity, the FVA system is useful for evaluating CS and demonstrates good repeatability, as shown by ICC and COR. Because there is no ceiling effect, this system is beneficial for evaluation of early changes in CS, particularly in patients with glaucoma or AMD. PMID- 27982214 TI - Coexistence of optic pit and coloboma of iris, lens, and choroid: a case report. AB - A 42-year-old woman was admitted to our clinic with a complaint of glare in both eyes. Biomicroscopic examination of both the eyes revealed iris and lens colobomas in the inferior quadrant. Fundus examination of the right eye revealed an oval and gray inferotemporal optic pit and two choroid colobomas in the inferior quadrant. In the left eye, two choroid colobomas were detected that were inferior to the optic nerve head. Furthermore, a 21-year-old man presented to our clinic for a routine ophthalmologic examination. Bilateral biomicroscopic examination was normal. Fundus examination of the left eye revealed an oval and gray inferotemporal optic pit and a choroid coloboma that was inferior to the optic nerve head. Here we describe optic pits co-occurring with iris, lens, and choroidal colobomas. On the basis of these cases, a defect in the closure of the embryonic fissure is the most plausible etiology of the optic pit. PMID- 27982215 TI - Toxic anterior segment syndrome following deep anterior lamellar keratoplasty. AB - We present the case of a 31-year-old patient with toxic anterior segment syndrome (TASS) that developed after undergoing deep anterior lamellar keratoplasty (DALK). She had keratoconus, and despite wearing hard contact lenses for many years in the left eye, her vision had deteriorated; therefore, DALK was performed on this eye. The preoperative visual acuity (VA) was finger counting at 3 m. Routine DALK was performed using the "big-bubble" technique. The corneal entry incision was hydrated at the end of the surgery, which was terminated by air injection into the anterior chamber. On postoperative day 1, VA was at the level of hand movements, and the cornea was edematous. Topical high-dose dexamethasone and oral steroids were initiated considering the diagnosis of TASS. Subsequently, the patient's VA increased, and the corneal edema decreased. We believe that the use of re-sterilized cannulas may have been the likely cause of TASS. Although DALK can be performed without interfering with the anterior chamber, one should keep in mind that TASS may occur in response to the solution used to hydrate the incision site and the air injected into the anterior chamber. PMID- 27982216 TI - Adenoid cystic carcinoma of the lacrimal sac: case report. AB - Lacrimal sac tumors are rare with a clinical presentation that typically includes obstruction of the lacrimal drainage system and epiphora as the most frequent symptom. Cribriform adenoid cystic carcinoma (ACC) is the most common malignant epithelial tumor of the lacrimal gland and minor salivary glands; however, its occurrence in the lacrimal drainage apparatus is extremely rare. Given the rarity of ACC, definitive diagnosis is almost invariably late conferring a poor prognosis. Herein we report the case of a 41-year-old woman with primary ACC of the lacrimal sac and describe the ophthalmological examination, diagnosis, and multidisciplinary treatment of this rare type of tumor. PMID- 27982217 TI - Bilateral acute angle-closure glaucoma as a first presentation of granulomatosis with polyangiitis (Wegener's). AB - We report a case of bilateral acute angle-closure glaucoma in a patient with undiagnosed granulomatosis with polyangiitis (Wegener's). A 59-year-old man presented with a severe headache, ocular pain, blurred vision, shortness of breath, and mild fever. Clinical examination revealed conjunctival chemosis, corneal edema, and shallow anterior chambers. Closed angles were observed bilaterally on gonioscopy. The patient was treated with intravenous mannitol, oral acetazolamide, and anti-glaucomatous eye drops. Over the following two days, his vision improved and intraocular pressures decreased. Subsequently, laser iridotomies were performed bilaterally and the patient attended consultations with our departments of respiratory medicine, nephrology, and rheumatology and was subsequently diagnosed with granulomatosis with polyangiitis. Bilateral acute angle-closure glaucoma is a very rare ocular manifestation of granulomatosis with polyangiitis. The association of this clinical entity with Wegener's granulomatosis remains unknown. PMID- 27982218 TI - Management of necrotizing scleritis after pterygium surgery with rituximab. AB - The authors present a case of necrotizing scleritis after pterygium excision successfully treated with rituximab after attempts with high doses of corticosteroids and immunosuppressive drugs. A literature review revealed case reports and a phase I/II dose-ranging randomized clinical trial using rituximab for necrotizing scleritis with or without association with autoimmune disease. This is the only case report on rituximab treatment for necrotizing scleritis after pterygium surgery. In cases with refractoriness to immunosuppressive drugs, a CD20 antibody can be used. PMID- 27982219 TI - Nonarteritic anterior ischemic optic neuropathy following pars plana vitrectomy for macular hole treatment: case report. AB - Herein, we report a case of nonarteritic anterior ischemic optic neuropathy (NAION) following uneventful pars plana vitrectomy for macular hole treatment. A 56-year-old previously healthy woman presented with a full-thickness macular hole in right eye (OD) and small cup-to-disc ratios in both eyes. Five days after surgery, she noticed sudden painless loss of vision in OD and was found to have an afferent pupillary defect and intraocular pressure of 29 mmHg. Fundus examination showed right optic disc edema and the resolution of a macular hole with an inferior altitudinal visual field defect. Erythrocyte sedimentation rate, C-reactive protein levels, and general physical examination findings were normal. She was treated with hypotensive eyedrops and oral prednisone, resulting in mild visual improvement and a pale optic disc. A combination of face-down position and increased intraocular pressure due to a small optic disc cup were considered as potential mechanisms underlying NAION in the present case. Vitreoretinal surgeons should be aware of NAION as a potentially serious complication and be able to recognize associated risk factors and clinical findings. PMID- 27982220 TI - Amblyopia: neural basis and therapeutic approaches. AB - Abnormalities in visual processing caused by visual deprivation or abnormal binocular interaction may induce amblyopia, which is characterized by reduced visual acuity. Occlusion therapy, the conventional treatment, requires special attention as occlusion of the fellow normal eye may reduce its visual acuity and impair binocular vision. Besides recovering visual acuity, some researchers have recommended restoration of stereoacuity and motor fusion and reverse suppression in order to prevent diplopia. Recent studies have documented that the amblyopic visual cortex has a normal complement of cells but reduced spatial resolution and a disordered topographical map. Changes occurring in the late sensitive period selectively impact the parvocellular pathway. Distinct morphophysiologic and psychophysical deficits may demand individualization of therapy, which might provide greater and longer-lasting residual plasticity in some children. PMID- 27982221 TI - Retinal nerve fiber layer, ganglion cell complex, and choroidal thicknesses in migraine. PMID- 27982222 TI - Functional Differences In Gingival Fibroblasts Obtained from Young and Elderly Individuals. AB - Fibroblasts participate in the wound repair process through proliferation and migration as well as the synthesis of factors growth and extracellular matrix molecules. However, cell aging and the individual himself can lead to reduction of cell functions and consequently, the ability of tissue repair. This study evaluated the activity of gingival fibroblasts from young (Y) and elderly (Y) patients and their responsiveness to tumor necrosis factor alpha (TNF-a). Gingival fibroblasts were isolated from six patients (3Y; and 3E) and seeded in complete culture medium (DMEM). For cell viability analysis, total protein production and collagen synthesis, fibroblasts were cultured in 96-well plates for 24, 48 or 72 h (n=36). Cell responses to TNF-a, was evaluated by application of this cytokine to cultured cells (100 ng/mL) for 24 h, followed by evaluation of reactive oxygen species (ROS), nitric oxide (NO) and CCL5 production (n=36). Data were analyzed by Kruskal-Wallis and the Mann-Whitney U tests (a = 0.05). Viability of E fibroblasts was higher than Y fibroblasts for 24 and 48 h, but these cells showed gradual reduction of viability over the course of time. For Y cells, reduced collagen synthesis was observed at 48 h. No difference was observed in ROS production for both cells after TNF-a exposure. However, both cultures showed increased production of NO and CCL5 in the presence of TNF-a. Functional differences and distinct responsiveness to TNF-a were observed according to patient's age. PMID- 27982224 TI - Dentifrice Containing Extract of Rosmarinus officinalis Linn.: An Antimicrobial Evaluation. AB - This study aimed to evaluate the antimicrobial activity of a dentifrice containing an alcoholic extract of rosemary on oral bacteria, compared to a commercially available herbal dentifrice. Standard strains of Streptococcus mutans (ATCC 25175), Streptococcus oralis (ATCC 9811) and Lactobacillus rhamnosus (ATCC 7469) were used, as well as different toothpastes based on rosemary (TR), on propolis (TH), triclosan (positive control) (TPC) and non-fluoridated dentifrice (negative control) (TNC). Bacteria were seeded in Petri dishes and paper discs soaked with dilutions of dentifrice placed on the plates. The inhibition halos were analyzed. It was observed that TR did not show statistical difference in relation to the TH to inhibit S. mutans and S. oralis, while TH was more active against L. rhamnosus. The toothpaste containing rosemary extract had the ability to inhibit the growth of S. mutans, S. oralis and L. rhamnosus, revealing an antimicrobial activity similar to commercially available toothpastes for inhibition of S. mutans and S. oralis. PMID- 27982223 TI - Cytotoxicity Evaluation of Two Bis-Acryl Composite Resins Using Human Gingival Fibroblasts. AB - Bis-acryl resins are used for temporary dental restorations and have shown advantages over other materials. The aim of this work was to evaluate the in vitro cytotoxicity of two bis-acryl composite resins (Protemp 4 and Luxatemp Star), obtained at 1, 7 and 40 days after mixing the resin components, using a standardized assay employing human primary cells closely related to oral tissues. Human gingival fibroblast cell cultures were exposed for 24 h to either bis-acryl composite resins, polystyrene beads (negative control) and latex (positive control) extracts obtained after incubation by the different periods, at 37 degrees C under 5% CO2. Cell viability was evaluated using a multiparametric procedure involving sequential assessment (using the same cells) of mitochondrial activity (XTT assay), membrane integrity (neutral red test) and total cell density (crystal violet dye exclusion test). The cells exposed to the resin extracts showed cell viability indexes exceeding 75% after 24 h. Even when cells were exposed to extracts prepared with longer conditioning times, the bis-acryl composite resins showed no significant cytotoxic effects (p>0.05), compared to the control group or in relation to the first 24 h of contact with the products. There were no differences among the results obtained for the bis-acryl composite resins evaluated 24 h, 7 days and 40 days after mixing. It may be concluded that the bis-acryl resins Protemp 4 and Luxatemp Star were cytocompatible with human gingival fibroblasts, suggesting that both materials are suitable for use in contact with human tissues. PMID- 27982225 TI - Strontium Ranelate Effect on the Repair of Bone Defects and Molecular Components of the Cortical Bone of Rats. AB - This study was conducted to evaluate the effects of treatment with strontium ranelate (SR) on the repair of bone defects and molecular components of bones in femurs. Adult female rats (n=27) were subjected to ovariectomy (OVX) or Sham surgery. Thirty days after surgery, a defect was made in the femur and the animals were then divided into three groups: OVX, SHAM and OVX+SR. Euthanasia was performed four weeks after the bone defect surgery. Repair in bone defect was assessed by computed microtomography (MUCT) and chemical composition of cortical bone was analyzed by Fourier transform infrared (FTIR) spectroscopy and energy dispersive X-ray spectroscopy (EDS). The trabecular thickness (Tb.Th) of the newly formed bone in the OVX+SR group was significantly higher than that for the OVX group. The collagen maturity in the OVX+SR group was smaller than in the other two groups. In this group, a significant increase in the amount of strontium (Sr) and a decrease in the amount of calcium (Ca) embedded to bone tissue were also observed. Systemic treatment with SR improved microarchitecture of the newly formed bone inside the defect, but decreased cross-linking of mature collagen in cortical bone. PMID- 27982226 TI - Effect of Silver Nanoparticles on Physicochemical and Antibacterial Properties of Calcium Silicate Cements. AB - Mineral trioxide aggregate (MTA) and Portland cement (PC) are calcium silicate cements. They have similar physicochemical, mechanical and biological properties. The addition of zirconium oxide (ZrO2) to PC provides radiopacity. Silver nanoparticles (AgNPs) may improve some properties of cements. The aim of this study was to evaluate the effect of AgNPs on physicochemical/mechanical properties and antibacterial activity of white MTA (WMTA) and PC associated with ZrO2. The following materials were evaluated: WMTA; PC 70% + ZrO2 30%; WMTA+ AgNPs; and PC 70% + ZrO2 30% + AgNPs. The study evaluated radiopacity, setting time, pH, compressive strength and solubility. For radiopacity analysis, radiographs were made alongside an aluminum (Al) step wedge. To evaluate the antibacterial activity, direct contact test was performed on planktonic cells and Enterococcus faecalis biofilm induced on bovine root dentin for 14 days. The experimental periods were 5 and 15 h. Data were obtained as CFU mL-1. The obtained data were submitted to ANOVA and Tukey tests (p<0.05). The addition of AgNPs to WMTA increased the pH, lowered the solubility and the initial and final setting times. The addition of AgNPs to PC/ZrO2 maintained the pH, lowered the solubility, and increased the setting time and compressive strength. The radiopacity of all materials was higher than 4 mmAl. The addition of AgNPs promoted an increase in antibacterial activity for calcium silicate cements and favored the physicochemical and mechanical properties of the materials. PMID- 27982227 TI - Effects of Zoledronic Acid on Orthodontic Tooth Movement in Rats. AB - The purpose of this study was to assess the effects of the administration of zoledronic acid (ZA) during orthodontic movement in rats. A hundred and twenty male Wistar rats were applied force of 30 cN with spring closed nickel-titanium to move the upper right first molar to mesial. In the Control Movement group (CM), only tooth movement was performed; the Control Acid Zoledronic group (CAZ) received a single dose (0.1 mg/kg) of ZA; the Experimental Acid Zoledronic group (EAZ) received a single dose (0.1 mg/kg) one week prior to the start of tooth movement; and the Control Without movement group (CWM) that received no drug and without application of tooth movement. The animals were euthanized after 3, 7 and 14 days. Tooth movement was measured using a caliper, the number of osteoclasts using TRAP staining, the expression of mature and immature collagen using picrosirius staining, and the presence of hyaline areas and root resorption using HE. The data were compared using two-way ANOVA, Tukey HSD, Games-Howell and chi squared test, at the 5% significance level. It was observed a smaller number of osteoclasts and greater percentage of hyaline area in the EAZ group. There was no difference among the groups regarding bone remodeling, root resorption and tooth movement for all observed times. PMID- 27982228 TI - Effect of Glaze Cooling Rate on Mechanical Properties of Conventional and Pressed Porcelain on Zirconia. AB - The aim of this study was to characterize a conventional and a pressed porcelain for zirconia core as to biaxial flexural strength (BFS), apparent fracture toughness (FT) and microstructure composition, and to investigate the effect of glaze cooling rate on the BFS of the zirconia/porcelain bilayers. Monolayers of conventional porcelain Vita VM9 and pressed porcelain Vita PM9 (n=15) (12 mm diameter x 1.2 mm thick) were prepared for the BFS test (MPa). Apparent fracture toughness (MPa.m1/2) was measured by indentation technique (n=15). t-Student test was performed for statistical analysis. Scanning electron microscopy and x-ray diffraction were used to analyze the porcelain's microstructure. For the BFS of bilayers, zirconia discs (12 mm diameter x 1 mm thick) (Vita In-Ceram YZ) were veneered with the two porcelains (1 mm thick). After the glaze firing simulation, the specimens were submitted to fast or slow cooling (n=15). Apparent fracture toughness (MPa.m1/2) was measured on the porcelain surface of bilayers (n=15) and residual stress was calculated. Two-way ANOVA (porcelain and cooling method) was used for the bilayer analysis (a=0.05). Vita PM9 monolayer exhibited significantly higher BFS (p<0.01), but there was no significant difference (p=0.41) in the FT between the porcelains. For bilayer specimens, the two-way ANOVA for BFS was significant for the porcelain variable only (p<0.01) better for Vita PM9/zirconia. Two-way ANOVA for the FT for the bilayers was not significant for any variable. All groups showed compressive residual stresses. The pressed porcelain seems to be mechanically more effective for zirconia veneering. PMID- 27982229 TI - Effect of Two Antioxidants Agents on Microtensile Bond Strength to Bleached Enamel. AB - This in vitro study evaluated the effect of sodium bicarbonate and sodium ascorbate on the microtensile bond strength of an etch-and-rinse system to bleached bovine enamel. Sixty bovine enamel blocks (4x4 mm) were flattened and randomly allocated into 5 groups: G1 (negative control): without treatment; G2 (positive control): bleached with 35% hydrogen peroxide (HP); G3: bleached and stored for 7 days in artificial saliva before restorative procedures; G4: bleached and treated with 10% sodium bicarbonate solution for 5 min; G5: bleached and treated with 10% sodium ascorbate hydrogel for 15 min. HP gel was applied twice (20 min each, except in G1) and the adhesive restorations were performed. After 24 h, the specimens were sectioned into sticks and submitted to microtensile bond strength testing with a crosshead speed of 0.5 mm/min (n=12). As a complementary visual observation, the enamel surfaces of the G1 and G2 specimens were evaluated with scanning electron microscopy. Data were analyzed by one-way ANOVA (p<0.05). The means (standard deviation) were: G1: 24.22+/-7.74; G2: 18.29+/-5.88; G3: 40.88+/-7.95; G4: 19.95+/-5.67 and G5: 24.43+/-6.43. Adhesive failures were predominant in all groups. The comparison between the treatments indicates that waiting 7 days after bleaching is still the most effective approach. When this waiting period is not possible, application of sodium ascorbate or sodium bicarbonate seems to be a good alternative. Therefore, the practicality of obtaining sodium bicarbonate in the bleaching kits and its higher stability enables its clinical use. PMID- 27982230 TI - Effect of Enamel and Dentin Surface Treatment on the Self-Adhesive Resin Cement Bond Strength. AB - The aim of this study was to evaluate the effect of enamel and dentin surface treatment on the micro-shear bond strength of self-adhesive cement. Seventy-two extracted third molars had their crowns embedded in acrylic resin and worn to obtain a flat enamel or dentin surface. The enamel and dentin specimens were randomly assigned to 8 groups (n=12) that were based on surface treatment (11.5% polyacrylic acid solution or no treatment), substrate condition (wet or dry) and storage period (1 day or 90 days), and treated accordingly. Cylinders (1 * 1 mm) were fabricated using self-adhesive resin cement (RelyX U200) following the manufacturer's instructions. The specimens were stored in distilled water at 37 degrees C for either 1 day or 90 days and subjected to micro-shear bond strength test (EMIC DL 2000 at 0.5 mm/min). After this, the failure type of the specimens was determined. Data were subjected to statistical analysis (a=0.05). According to the results, the 11.5% polyacrylic acid application decreased the bond strength in both enamel and dentin samples. The moist groups showed higher bond strength than the dry ones, regardless of the substrate and surface treatment. Storage period did not influence bond strength. In conclusion, surface treatment with 11.5% polyacrylic acid and absence of moisture decreased the bond strength of the resin-cement (RelyU200), regardless of the storage period. PMID- 27982231 TI - Low-Fusing Porcelain Glaze Application on 3Y-TZP Surfaces can Enhance Zirconia Porcelain Adhesion. AB - The aim of this study was to assess whether surface treatment improves zirconia porcelain adhesion. The 3Y-TZP blocks were cut into squares, then polished and sintered. The zirconia surface treatments were performed as follows: no treatment (C); tribochemical silica coating (TBS); glaze application + hydrofluoric acid etching (GA); glaze application + hydrofluoric acid etching + silanization (GAS); deposition of silica nanofilm (NF). After treatments, veneering porcelain cylinders (3.3 x 3.3 mm) were built up on all specimens and fired. Then the specimens were subjected to thermal cycling (6000 cycles), and subjected to shear test. Fractures were analyzed by stereomicroscopy and SEM. Data were statistically analyzed by 1-way ANOVA and Tukey's test (5%). Zirconia-porcelain bond strength was affected by the ceramic surface treatments (p=0.0001). GA (19.5+/-3 MPa) and GAS (16.2+/-4 MPa) recorded the highest bond strength values, while control group had the lowest bond value (10.1+/-4 MPa). Adhesive failure of the samples predominated. Therefore, glaze application as 3Y-TZP treatment before veneering porcelain stratification may enhance zirconia-porcelain adhesion. PMID- 27982232 TI - Influence of Erosive and Abrasive Cycling on Bonding of Different Adhesive Systems to Enamel: An In situ Study. AB - This study evaluated the impact of orange juice on the bond strength (BS) of dentin bonding systems (DBSs) to enamel surface after simulation with an in situ/ ex vivo erosive cycling. One hundred and ninety two bovine enamel fragments (4x4x2mm) were obtained and randomized regarding superficial microhardness and distributed to palatal devices for 8 volunteers, in three phases (one for each DBS), containing 8 blocks, which were, allocated in 4 pairs. Daily, these pairs were subjected extraorally to the following conditions: CONT- neither erosive nor abrasive challenge; ERO- erosive challenge only; ABR- abrasive challenge only and ERO + ABR- with erosive and abrasive challenges. Erosive cycles (immersion in orange juice, 3 times/day/5 min/5 days) or/and abrasive challenges (electric toothbrush, 3 times/day/1 min/5 days) were performed. After these cycles, all specimens were restored with the adhesive systems Adper Scotchbond Multi Purpose (MP), Adper Single Bond 2 (SB) or Clearfil SE Bond (SE), and the composite resin Filtek Z250. After 7 days, sticks (area ?1 mm2) were obtained and subjected to the microtensile bond strength test (MUTBS) at 0.5 mm/min. Data was statistically analyzed by ANOVA and Tukey tests (a=0.05). Failure modes were determined using a digital microscope (40'). DBS was the only statistical significant factor. SE was the unique DBS not affected in any challenge, whereas MP and SB performed according to the scenario. The adhesive and mixed failures were predominant in all groups. Overall performance suggested that BS to enamel after erosive /abrasive challenged by orange juice was not affected and it was material dependent. PMID- 27982234 TI - Morphological Study and Analysis of Microhardness and Permeability of the Furcation of Maxillary Premolars. AB - The morphology, microhardness and dentin permeability of the furcation region of maxillary premolars were evaluated. Ten premolars were cut lengthwise and the furcation region was delimited. In one group (n=10) microhardness was measured in the buccal, central and palatal regions, in the outer middle and inner layers of the furcation, and in the buccal and palatal regions adjacent to the furcation. Knoop hardness was tested with 10 g load for 15 s. Data were analyzed statistically by ANOVA and Tukey-Kramer test (a=0.05). In the other group (n=10) confocal microscopy was used to study dentin morphology. Other 10 specimens were instrumented with ProTaper and immersed in 10% copper sulfate for analysis of permeability under light microscopy. About microhardness, there was no significant difference (p>0.05) among the buccal (39.9+/-3.1), central (39.5+/ 4.4) and palatal (39.7+/-5.0) regions of the furcation, or between these regions and the adjacent buccal (39.1+/-5.8) and palatal (39.7+/-5.8) regions (p>0.05). The inner layer (42.3+/-3.7) had significantly higher microhardness (p<0.05) than the outer layer (37.1+/-3.9). There was a tendency of calcification of the dentinal tubules from the outer towards the inner layer. The percentage of stained area was 12.45+/-2.0%, restricted to the outer layer. The buccal, central and palatal regions of the furcation as well as the buccal and palatal adjacent regions had similar microhardness values. In conclusion, the inner dentin layer is harder than the outer dentin layer. The dentinal tubules are sinuous and intertwine towards the middle layer. Dye penetration is restricted to the outer layer. PMID- 27982233 TI - Fracture Strength of Weakened Anterior Teeth Associated to Different Reconstructive Techniques. AB - This study evaluated the fracture strength of endodontically treated teeth submitted to reconstructive techniques through dynamic and static tests. Forty human anterior teeth were divided into 4 groups (n=10): GNW (non-weakened) - root restored with glass fiber post (GFP), GW - weakened root restored with GFP, GDA - weakened root restored with direct anatomic GFP, and GIA - weakened root restored with indirect anatomic GFP. The teeth were endodontically treated considering that experimental groups (GW, GDA and GIA) simulated weakened roots for restoration with GFP using different techniques. The GFP was luted with resin cement and the coronal portion was restored with composite resin and metallic crowns. All samples were submitted to chewing simulation at 60 cycles/min in a total of 300,000 cycles. The survival samples were further exposed to compressive loading at a crosshead speed of 1.0 mm/min in a universal testing machine. The load was applied at 135 degrees to the long axis of the tooth until failure. Data were analyzed by ANOVA (a=0.05). After chewing simulation were observed: GNW: 100% of survival roots; GW: 70% of survival roots, and GDA and GIA: 80% of survival roots. The mean fracture strength values (N) were 280.6 (GNW), 239.0 (GW), 221.3 (GDA), and 234.1 (GIA) without significant difference among the groups (p=0.7476). The results suggested similar fracture strength in both weakened and non-weakened teeth regardless the reconstructive technique of root internal wall. Higher incidence of catastrophic fracture was observed in weakened teeth without restoration of the root internal wall. PMID- 27982235 TI - Evaluation of Different Passive Ultrasonic Irrigation Protocols on the Removal of Dentinal Debris from Artificial Grooves. AB - The aim of this study was to evaluate the influence of different passive ultrasonic irrigation protocols on the removal of debris in artificially created grooves in the cervical, middle and apical root thirds. Forty extracted bovine incisor roots were instrumented to 1 mm of the root apex with a R50 Reciproc instrument and irrigated with 2.5% sodium hypochlorite. The roots were then inserted in a muffle and cleaved into two hemisections. Grooves (3-mm long) were done at 2, 7 and 12 mm from the root apex in one hemisection and filled with dentinal debris. The hemisections were regrouped into the muffle and divided into 4 groups (n=10) according to the final irrigation protocol: Control group: 3x20 s using a #30 gauge needle without agitation of the irrigating solution; Group PUI s (static passive ultrasonic irrigation): 3x20 s of passive ultrasonic irrigation with the tip of the insert maintained static on the apical third; Group PUI-t (passive ultrasonic irrigation per third): 20 s of PUI in each third; Group PUI-d (passive dynamic ultrasonic irrigation): 3x20 s of PUI dynamically moving the insert in the whole extent of the root canal. In all groups, was used a total of 6 mL of 2.5% sodium hypochlorite as irrigant. After these procedures, the grooves were analyzed with a stereomicroscope and assigned scores as regards removal of the debris. The data were analyzed statistically (a=0.05). The results showed a better cleaning in all the groups where the irrigating solution was agitated with ultrasonic device than in the control group (p<0.05). In the apical third, the PUI-d and PUI-s showed similar performance (p>0.05) and a better cleanness than PUI-t (p<0.05). The dynamic and static methods of agitation of the irrigating solution provided more effective cleaning. PUI-d provided the most completely clean grooves suggesting that its use is the most adequate in cases of teeth with complex canal anatomy. PMID- 27982236 TI - Limewater and Polymyxin B Associated with NaOCl for Endotoxin Detoxification in Root Canal with Necrotic Pulp. AB - This clinical study investigated the effects of endodontic treatment by using different irrigants (limewater + NaOCl and polymyxin B + NaOCl) and intracanal medication on endotoxins in teeth with primary endodontic infection and radiographically visible apical periodontitis. Thirty-three teeth with necrotic pulp and periapical lesions from different patients were selected for this study. Samples were collected after the coronal opening (S1) and after instrumentation (S2). Root canals were divided in 3 groups (n = 11) according to the irrigant combination used: NaOCl + LW: 2.5% NaOCl + calcium hydroxide solution (0.14%, limewater); NaOCl + PmB: 2.5% NaOCl + 10.000 UI/mL polymyxin B; 2.5% NaOCl (control). The third sampling (S3) was performed after ethylenediaminetetraacetic acid and the fourth (S4) after samples got 14 days with intracanal medication with 2% chlorhexidine gel + calcium hydroxide. Endotoxins (lipopolysaccharide) were quantified by chromogenic Limulus amebocyte lysate (LAL). Endotoxins were detected in all root canals after the coronal opening (S1). NaOCl + PmB group presented the greatest endotoxin reduction after instrumentation (76.17%), similar to NaOCl + LW group (67.64%, p<0.05) and different from NaOCl group (42.17%, p<0.05). After intracanal medication period (S4), there was significant increase of endotoxins neutralization. It was concluded that NaOCl + PmB promoted the greatest reduction of endotoxin levels, followed by NaOCl + LW. Intracanal medications had no significant complementary role in the reduction of endotoxins at the end of the treatment. PMID- 27982237 TI - Murine Experimental Root Canal Infection: Cytokine Expression in Response to F. nucleatum and E. faecalis. AB - The aim of this study was to evaluate the gene expression of proinflammatory (RANKL, TNF-a and IFN-g) and regulatory (TGF-b and IL-10) cytokines as reaction to experimental infection by mono or bi-association of Fusobacterium nucleatum (ATCC 10953) and Enterococcus faecalis (ATCC 19433). F. nucleatum and E. faecalis, either in mono- or bi-association were inoculated into the root canal system (RCS) of Balb/c mice. Animals were sacrificed at 10 and 20 days after infection and periapical tissues surrounding the root were collected. The mRNA expression of the cytokines RANKL, TNF-a, IFN- g, TGF-b and IL-10 was assessed using real-time PCR. The Kruskal-Wallis test was used for statistical analysis. F. nucleatum mono-infection induced high expression of RANKL and TNF-a, while its modulation was due to IL-10. High expression of IFN-g at day 20 was up-regulated by E. faecalis and RANKL; TNF-a was up-regulated by an independent mechanism via IL-10 and TGF-b. Bi-association (F. nucleatum and E. faecalis) stimulated high expression of RANKL, TNF-a and IFN-g, which seemed to be modulated by TGF-b 20 days later. The gene expression of proinflammatory cytokines was more prominent in the earlier periods of the experimental periapical infection, which concomitantly decreased in the later period. This expression may be regulated by IL-10 and TGF-b in an infection-specific condition. PMID- 27982238 TI - Antimicrobial Effect and Surface Tension of Some Chelating Solutions with Added Surfactants. AB - This study assessed the antimicrobial efficacy and surface tension of established irrigating solutions with a new experimental chelating solution in infected dentin tubes. Twenty-five specimens were randomly assigned to each of the irrigating solutions. Twenty specimens were used as negative and positive controls. After 21 days of contamination with E. faecalis, the irrigating solutions MTAD, QMiX and Tetraclean NA were delivered into each infected root canal. The solutions were removed and dentin samples were withdrawn from the root canals with sterile low-speed round burs with increasing ISO diameters. The dentin powder samples obtained with each bur were immediately collected in separate test tubes containing 3 mL of BHI broth. After that, 100 MUL from each test tube was cultured on blood agar. The grown colonies were counted and recorded as colony-forming units (CFU). The surface tension of the irrigants was measured using a Cahn DCA-322 Dynamic Contact Angle Analyzer. A Kruskal Wallis nonparametric ANOVA and a Friedman test were used (p<0.05). Tetraclean NA showed lower surface tension and CFU values than MTAD and QMiX. Better antibacterial action and low surface tension were observed for Tetraclean NA, probably due to the improved penetration into the root canal and dentinal tubes. PMID- 27982239 TI - Unusual Deviation of the Main Foramen from the Root Apex. AB - The relationship of the main foramen to the anatomic root apex has been the subject of several studies. Although they are anatomically close, they rarely coincide, and their distance can vary according to age or tooth type, ranging from 0.2 to 3.0 mm. The aim of this short communication was to evaluate the distance between the main foramen of independent middle mesial canals (MMCs) and the anatomical mesial root apex of mandibular first molars using the micro computed tomography. Twenty-five mandibular first molars with MMCs were scanned (resolution of 9.9 um), and the distance from its main foramen to the anatomical apex was evaluated. Overall, the distance ranged from 0.2 to 2.4 mm; however, in 3 specimens the distance was greater than 3 mm. This report demonstrates that the exit of the main foramen of the MMC varies considerably and could approach a substantial distance from the anatomical apex greater than previously reported in the literature. PMID- 27982240 TI - Influence of the Resin Cement Thickness on the Push-Out Bond Strength of Glass Fiber Posts. AB - The objective of the present study was to evaluate the influence of resin cement thickness on the bond strength of prefabricated and customized glass fiber posts after storage in distilled water. Thirty human uniradicular roots were treated endodontically. The roots were divided into 3 groups: THIN (thin cement layer) - post space preparation with #0.5 drill and cementation of #0.5 post; THICK (thick cement layer) - post space preparation with #1 drill and cementation of #0.5 post; and CUSTOM (customized cement layer) - post space preparation with #1 drill and cementation of a customized post (#0.5 glass fiber posts customized with resin composite). All posts were luted with self-adhesive resin cement. The push out test was carried out after storage for 24 h and 90 days in distilled water at 37 degrees C. The data were analyzed with three-way ANOVA and Tukey's test (a=0.05). Bond strengths were significantly higher for CUSTOM (9.37 MPa), than for THIN (7.85 MPa) and THICK (7.07 MPa), which were statistically similar. Considering the thirds, the bond strength varied in the sequence: apical (7.13 MPa) < middle (8.22 MPa) = coronal (8.94 MPa). Bond strength for 24 h storage was significantly higher (8.80 MPa) than for 90-day storage (7.40 MPa). It may be concluded that the thickness of resin cement influenced the bond strength of glass fiber posts. The customized posts presented higher bond strength. Storage in water for 90 days affected negatively the values of bond strength, especially for thick cement layers in the apical third. PMID- 27982241 TI - Self-Reported Periodontitis and Complications in Type 1 Diabetes Patients: A Brazilian Nationwide Survey. AB - This study aimed to evaluate the possible association between periodontitis and systemic complications in a Brazilian type 1 diabetes population. A multicentre, sectional study was carried out in 28 public clinics located in 20 Brazilian cities. Data from 3,591 patients were obtained (56.0% females, 57.2% Caucasians), with an average age of 21.2 +/- 11.7 years and whose mean duration of type 1 diabetes was 9.6 +/- 8.1 years. Periodontitis was evaluated through self-report. Odds ratios (OR) and 95% confidence intervals were calculated to evaluate the association between periodontitis and systemic diabetes complications (chronic micro and macrovascular complications and hospitalizations by hyperglycemia and diabetic ketoacidosis). The prevalence of periodontitis was 4.7% (n=170). Periodontitis patients had mean age of 27.4 +/- 12.9. This group was older (p<0.001), exhibited longer diabetes duration (p<0.0001) and had elevated total cholesterol (p<0.05), triglycerides (p<0.001) and lower HDL (p<0.05) values than patients without periodontitis. Systolic and diastolic blood pressures were significantly increased in periodontitis patients (p<0.01). Periodontitis patients had increased odds of microvascular complications (2.43 [1.74-3.40]) and of hospitalizations related to hyperglycemia (2.76 [1.72-4.42]) and ketoacidosis (2.72 [1.53-4.80]). In conclusion, periodontitis was associated to systemic complications in Brazilian type 1 diabetes patients. PMID- 27982242 TI - Effect of Head Position on Maxillofacial Transverse Measurements Made on the Skull and Cone Beam Computed Tomography Scans. AB - Article Incorrect patient positioning and the resultant image distortion occur in many radiographic examinations. This study aimed to assess the effect of tilting, rotation and tipping of the head on the accuracy of maxillofacial transverse measurements made on cone beam computed tomography (CBCT) scans. The CBCT scans were obtained in central position of 10 dry human skulls. Using three-dimensional (3D) Dolphin software, six positions namely 10 degrees and 20 degrees tilts, rotations and tips were reconstructed of central position. Transverse distances between landmarks were measured on 3D scans and the skulls. The intraclass correlation coefficient (ICC) and the Bland-Altman plot were used to compare the mean values measured by the two observers. For most landmarks, no significant differences were noted between the mean transverse distances measured in the six positions and those measured in central position on 3D scans (p>0.005). In conclusion, all measurements of transverse distances made on 3D scans in different positions were underestimated compared to the actual values measured on the skull. PMID- 27982243 TI - Association between Facial Type and Mandibular Canal Morphology - Analysis in Digital Panoramic Radiographs. AB - In this study we investigate the association between facial type and mandibular canal course morphology analysing this in digital panoramic radiographs images. We used 603 digital images from panoramic radiographs. We selected only panoramic radiographs of fully dentate individuals, who had all lower molars bilaterally and with complete root formation. The sample distribution was determined by facial type and sex. The course of the mandibular canal, as seen in the panoramic radiographs, was classified into 3 types, bilaterally. The classification used was: type 1 if the mandibular canal is in contact or is positioned at most 2 mm from the root apex of the three permanent molars; type 2 if the mandibular canal is located halfway between the root apex of the three permanent molars and a half away from the mandibular basis; and type 3 if the mandibular canal is in contact with or approaches, a maximum of 2 mm from the cortical bone of the mandibular basis. For results, the data were analyzed by Chi-square test (p<0.05). Data analysis (Chi-square) showed there were more canals type 2 (p=0.0012) and fewer canals type 1 (p=0.0336) in females than in males, without association with the facial types. In conclusion, the facial type does not associated with the mandibular canal course analyzed. PMID- 27982244 TI - Comparison of Face-To-Face Interview and Telephone Methods of Administration on the Ecohis Scores. AB - The aim of this study was to compare the administration of the Brazilian version of Early Childhood Oral Health Impact Scale (ECOHIS) questionnaire, applied by face-to-face and telephone format. A randomized sample of 76 parents/guardians of children up to 6 years old was selected in a Pediatric Dentistry Clinic of the Federal University of Santa Maria, Brazil. Patients were randomly selected for 2 different groups, according to administration sequence: F-T (Face-to-face Telephone) and T-F (Telephone-Face-to-face). Two interviewers administered the ECOHIS questionnaire with 2 week interval between the methods. The reliability between sections of the different methods of administration was assessed by Cronbach's alpha and Intraclass Correlation Coefficient (ICC). There were differences in means of the ECOHIS between face-to-face and telephone methods. However, the value Cronbach's alpha were between 0.94-0.96, and value ICC ranged from 0.91-0.93, proving to be acceptable values. The Bland-Altman plots confirmed the results of reliability tests, supporting the accuracy of the methods. Although there is a slight difference in the scores, the use of both mode of administration of the ECOHIS yields reliable data when single method is used from the beginning to the end of the study. The results provided evidence to use either Face-to-face or Telephone method of administration of the ECOHIS. PMID- 27982245 TI - Craniofacial Morphology Affects Bite Force in Patients with Painful Temporomandibular Disorders. AB - Craniofacial morphology affects masticatory performance in healthy dentate subjects, but little is known about its effects in patients with painful temporomandibular disorders (TMDs). Forty-eight female patients (mean age of 28+/ 5.8 years) with painful TMDs underwent lateral cephalometric radiography. Using Ricketts' cephalometric analysis and the Vert method, subjects were assigned to three groups according to their craniofacial morphology: brachyfacial (n=22), mesofacial (n=13), and dolichofacial (n=13). Research diagnostic criteria for TMD were used to confirm the TMD diagnosis for each patient. Pain intensity was reported by each patient based on a visual analog scale (VAS). Maximum bite force (MBF) was measured with pressure sensors placed on the first molar site. Masticatory performance (MP) was assessed by chewing a silicone-based artificial material and determining the resulting particle size by the sieve method. Chewing ability (CA) was evaluated for seven food types and analyzed by a VAS questionnaire. Data were analyzed by one-way ANOVA followed by a Tukey-Kramer test (p<0.05). MBF differed in each group, with brachyfacial patients having the highest MBF values. There was no difference in MP among the groups. The groups differed only in their ability to chew one of the seven evaluated food types. In summary, craniofacial morphology affects the MBF without impairing MP or CA in patients with painful TMDs. PMID- 27982246 TI - Furuncular Myiasis Affecting the Lower Lip of a Young Patient. AB - Furuncular myiasis is a parasitic infection caused by the larvae of Dipteran insects after penetrating healthy skin, causing an erythematous nodule with a central pore. Additionally, the patient may feel a sensation of movement and intermittent pain. Furuncular myiasis affecting the oral and perioral region is rare, usually leading to misdiagnosis. This paper describes a rare case of furuncular myiasis in a 20-year-old healthy male patient who presented an erythematous nodule in the lower lip. An exploratory surgery was indicated for both diagnostic and curative purposes, with successful healing observed in the following appointment. After 3 years of follow-up, the patient is recovered, with no clinical signs or symptoms of the disease. PMID- 27982248 TI - Reduced versions of dysphonia coping protocols. AB - The purpose of the study is to explore two reduced versions of the PEED-27 (Brazilian VDCQ) and compare them to the original version. It was performed a retrospective analysis of PEED-27 questionnaires of 100 individuals with vocal disorder, 37 men and 63 women, mean age of 43.7 in order to compare reduced versions of the instrument. The analysis showed that the three instruments have high level of correlation, thus their results are comparable (PEED 27 x 15, r=+0.910, p< 0.001; PEED 27 x 10, r=+0.873, p<0.001 and PEED 15 x 10, r=+0.924, p< 0.001). The PEED-10 and PEED-15 are reduced and adapted versions to the Brazilian Portuguese language. They evaluate strategies used by dysphonic individuals to cope with their voice problem. The clinician must decide which version to use based on the available time and on the need of more detailed information. PMID- 27982247 TI - Cardiorespiratory parameters and their relation with gestational age and level of oral feeding skills in preterm infants. AB - Purpose: To correlate cardiorespiratory parameters with gestational age and level of oral feeding skills in the first oral feeding in preterm infants. Methods: Study participants were 37 clinically stable preterm infants. Cardiorespiratory rate was assessed before and after introduction of oral feeding. The newborns were divided into three strata according to gestational age at birth. Oral skill was classified into four levels: I - low oral skill and low resistance to feeding; II - low oral skill and high resistance to feeding; III - high oral skill and low resistance to feeding; IV - high oral skill and high resistance to feeding. Results: No difference was observed in heart and respiratory rate between the strata of gestational age at birth and between the levels of oral skill. Comparison between pre- and post-cardiorespiratory rates within each level of oral skill and stratum of gestational age showed difference between heart rate in the strata of gestational ages of 30 to 33 weeks and of 34 to 36 weeks, as well as between oral skill of levels I, II, and IV. With regard to the comparison between pre- and post- respiratory rates, difference was found in the oral skill of level I. Conclusion: Differences were observed between pre- and post-prandial cardiorespiratory rates regarding the first oral feeding, as well as between strata of gestational age at birth and levels of oral feeding skills. PMID- 27982249 TI - Factors associated with speech-language disorders in motorcycle accident victims. AB - Purpose: To investigate factors associated with speech-language disorders in victims of motorcycle accidents. Methods: This is a cross-sectional study. Victims of motorcycle accidents studied were treated at Hospital da Restauracao between June and July 2014. The data were collected by consulting the records and direct interviews with these, at admission and after discharge. For analysis were raised single frequencies, average and chi-square test or Fisher's exact test. The margin of error used in the statistical tests was 5%, and the intervals were obtained with 95% reliability. Results: 99 individuals were studied, 90.9% male, the mean age of 32.7 years. It found a high percentage of 42.3% of drunk drivers and 51.5% were not enabled. The Head Injuries were present in 30.3% of cases. The most affected body area were the lower limbs (71.7%), followed by the head and face region (56.6%). It was also found that 30.3% had complaints of speech pathology after hospital discharge and a statistically significant association between speech therapy complaint and not enabled (p=0.012) and collisions between bikes (p=0.004). Conclusion: There was a high percentage of lesions in the head and face resulting from accidents, associated mainly not eligible to drive bike and collisions between motorcycles, suggesting that these factors can aggravate injuries speech therapy. PMID- 27982250 TI - Preparation and applicability of a test of speech perception with pictures. AB - Purpose: To prepare and apply support material for responses to the Speech Recognition Percentage Index (SRPI) test in children. Methods: This is a descriptive, exploratory study conducted in two phases: in the first phase, 31 speech-language pathologists (referees) prepared material composed of regular, frequently used monosyllabic and disyllabic words belonging to the vocabulary of children and figures that could represent these words; the second phase consisted in the application of this material to 30 normal-hearing children aged 2 to 4 years and 11 months. Results: The material consisted of 25 words and six boards with six figures each. The word selection criterion adopted by the referees included the initial phoneme and real, colorful figures familiar to the children. The mean scores of the children in the SRPI test were 93% (SD +/- 8%) with the support of figures and 64% (SD +/- 25%) without figure support. Comparison between the results obtained with and without the support of figures showed significant difference for 15 of the 25 test words, with higher scores with the use of supporting figures. Comparison between correct and incorrect responses using the support of figures showed significant difference only for the word "dog" ("cao") (p=0.0079). Conclusion: There was agreement among the referees with respect to the words and figures. The SRPI test can be rapidly and easily applied, allowing evaluation and systematic monitoring of speech perception ability regardless of child verbalization capacity. PMID- 27982251 TI - Hearing loss classification by degree, configuration and relationship with amplified Speech Intelligibility Index (SII). AB - Purpose: To establish the relationship between speech intelligibility index (SII) values generated at the verification of hearing aids programmed according to DSLm [i/o] v5 prescription rule and a proposed individual classification that considers the combination of hearing loss degree and configuration. Methods: Forty-one children aged between 4 and 80 months were selected, totaling 78 ears for analysis. We considered hearing thresholds at the frequencies of 250, 500, 1000, 2000 and 4000 Hz; and analyzed values of the Speech Intelligibility Index (SII) for the input signal of 65 dB SPL obtained during the verification of hearing aids using the equipment Verifit(r)Audioscan. Results: Hearing losses were classified into five homogeneous groups regarding audiometric degree and configuration. The groups were heterogeneous when compared to each other. From the groups, three ranges of SII values were determined. Equations were developed for classification of hearing loss according to groups and for determination of the adjusted SII values. Conclusion: The SII value is a useful indicator of audibility for speech sounds in different characteristics of hearing losses, and can guide observations of auditory skills. The SII has stronger relationship with the association of the audiometric degree and configuration when compared with degree of hearing loss alone. PMID- 27982252 TI - Standard operating procedure: implementation, critical analysis, and validation in the Audiology Department at CESTEH/Fiocruz. AB - Purpose: Evaluate three standard operational procedures (SOPs), regarding the application of the brainstem auditory evoked potential (BAEP) test, implemented by the Audiology Department of the Center for Studies in Occupational Health and Human Ecology (CESTEH) through the application of a questionnaire and to verify whether the SOPs are effective and assess the necessity for improvement. Methods: The study was conducted in three phases: in the first phase, eight speech language pathologists and seven physicians, with no experience in BAEP, were instructed to read and perform each SOP, eventually all individuals evaluated the SOPs by responding to a questionnaire; in the second phase, the questionnaires were analyzed and the three SOP texts were reviewed; in the third phase, nine speech-language pathologists and six physicians, also with no experience in BAEP, read and re-evaluated the reviewed SOPs through a questionnaire. Results: In the first phase, difficulties in understanding the texts were found, raising doubts about the procedures; however, every participant was able to perform the procedure as a whole. In the third phase, after the review, all individuals were able to perform the procedures appropriately and continuously without any doubts. Conclusion: The assessment of the SOPs by questionnaires showed the need for adaptation in the texts. After the texts were reviewed according to the suggestions of the health professionals, it was possible to observe that the SOPs assisted in the execution of the task, which was conducted without any difficulties or doubts, being regarded effective and ensuring quality to the service offered. PMID- 27982253 TI - Comprehension of ambiguity for children with Specific Language Impairment and Autism Spectrum Disorder. AB - Purpose: To verify and compare the performance of children and adolescents with Specific Language Impairment (SLI) and Autism Spectrum Disorder (ASD) using a formal, standardized test that assesses language competence, more specifically comprehension of ambiguity. Methods: The sample comprised 19 individuals aged 6 to 14 years, of both genders, divided into two groups: ASD Group (9) and SLI Group (10). Participants were assessed using the Test of Language Competence - TLC; Ambiguous Sentences subtest (Wiig, Secord, 1989). Analysis included the comparison of the total scores in both groups. Results: We found significant difference between the groups, with better performance of the SLI Group compared with that of the ASD Group. Conclusion: It was possible to analyze and compare the performance of both groups in a metalinguistic activity. We observed better performance of the SLI group compared with that of the ASD Group in the interpretation of ambiguous information. PMID- 27982254 TI - Electrophysiological characterization of hearing in individuals with Down syndrome. AB - Introduction: Few studies have performed Brainstem (BAEP) and P300 Auditory Evoked Potentials simultaneously to assess central auditory pathways in normal hearing individuals with Down syndrome (DS), mainly because of the difficulty in applying these procedures to this population. Previous studies have suggested that individuals with DS might present different patterns of response compared with those of individuals with typical development; nevertheless, the identification of these potentials would be crucial for the establishment of an accurate audiological diagnosis. Purpose: To characterize BAEP and P300 in normal hearing individuals with DS. Methods: BAEP and P300 were analyzed in 17 individuals with DS and in 21 individuals with typical development aged 7 to 15 years. The results were quantitatively and qualitatively analyzed using descriptive measures and hypothesis tests. Results: In the quantitative analysis, latency values were lower in the BAEP for the DS group, with statistically significant difference for wave V and interpeaks III-V and I-V; there were no significant differences in the P300 latency values. In the qualitative analysis, there were a larger number of individuals with early values for BAEP latencies and late latencies for P300 in the DS group; both comparisons showed statistically significant differences. Conclusion: Children and adolescents with DS can present early responses to the components of BAEP, suggesting that their auditory pathway requires less time for the neural transmission of acoustic stimuli to the brainstem. Concerning P300, individuals with DS may present increased latencies, suggesting impairment in the central auditory pathway for the cortical processing of auditory information. PMID- 27982255 TI - E-READING II: words database for reading by students from Basic Education II. AB - Purpose: To develop a database of words of high, medium and low frequency in reading for Basic Education II. Methods: The words were taken from the teaching material for Portuguese Language, used by the teaching network of the State of Sao Paulo in the 6th to the 9th year of Basic Education. Only nouns were selected. The frequency with which each word occurred was recorded and a single database was created. In order to classify the words as of high, medium and low frequency, the decision was taken to work with the distribution terciles, mean frequency and the cutoff point of the terciles. In order to ascertain whether the words of high, medium and low frequency corresponded to this classification, 224 students were assessed: G1 (6th year, n= 61); G2 (7th year, n= 44); G3 (8th year, n= 65); and G4 (9th year, n= 54). The lists of words were presented to the students for reading out loud, in two sessions: 1st) words of high and medium frequency and 2nd) words of low-frequency. Results: Words which encompassed the exclusion criteria, or which caused discomfort or joking on the part of the students, were excluded. The word database was made up of 1659 words and was titled 'E - LEITURA II' ('E-READING II', in English). Conclusion: The E-LEITURA II database is a useful resource for the professionals, as it provides a database which can be used for research, educational and clinical purposes among students of Basic Education II. The professional can choose the words according to her objectives and criteria for elaborating evaluation or intervention procedures involving reading. PMID- 27982256 TI - Effect of curcumin on visfatin and zinc-alpha2-glycoprotein in a rat model of non alcoholic fatty liver disease. AB - PURPOSE:: To investigate the effect of curcumin on visfatin and zinc-alpha2 glycoprotein (ZAG) expression levels in rats with non-alcoholic fatty liver disease (NAFLD). METHODS:: Fifty-six male rats were randomly divided into a control group (n=16) and model group (n=40) and were fed on a normal diet or a high-fat diet, respectively. Equal volumes of sodium carboxymethyl cellulose (CMC) were intragastrically administered to the control group for 4 weeks. At the end of the 12th week, visfatin and ZAG protein expression levels were examined by immunohistochemistry. Visfatin mRNA levels were measured by semi-quantitative reverse transcription polymerase chain reaction. RESULTS:: Compared with the control group, the model group showed significantly increased expression of visfatin in liver tissue (P < 0.01) and significantly decreased expression of ZAG (P < 0.01). These effects were ameliorated by curcumin treatment. CONCLUSIONS:: Visfatin and zinc-alpha2-glycoprotein may be involved in the pathogenesis of NAFLD. Treatment of NAFLD in rats by curcumin may be mediated by the decrease of visfatin and the increase of non-alcoholic fatty liver disease. PMID- 27982257 TI - The effects of passive tobacco smoking on the microcirculation of the abdominal wall in rats. AB - PURPOSE:: To analysis the effects of passive smoking on the microstructure of tissues of the abdominal wall regarding microcirculation, using histopathological study of the tobacco exposed rats. METHODS:: Twenty four male Wistar rats were divided in Control Group (CG = 8 animals) and Exposition Groups (EG = 16 animals). EG was exposed to cigarette smoke 4x/day for 120 days, while CG was preserved from exposure. Food, water and housing were similar for both groups. After 120 days, urine samples were collected before necropsy to analyze cotinine levels (ng/mL) in urine and blinded histopathological analysis of the abdominal wall performed to count arteries and veins in dermal and muscular fascia layer. RESULTS:: No difference in weight was observed between both groups (P>0.05). Cotinine concentration was significantly higher in EG (P<0.05). In dermal layer, the average of vessels per animal was 8.72 (IC95%: 8.31-9.13) for CG and 11,23 (IC95%: 10.09-12.38) for EG. In muscular fascia layer the average of vessels per animal was 17.97 (IC95%: 15.79-20.15) for CG, whereas the average for EG was of 14,85 (IC95%: 12.71-17.01) (P<0.05). CONCLUSION:: Exposition to passive smoking may cause increase in the number of vessels in dermal layer, with the opposite effects at the muscular fascia layer. PMID- 27982258 TI - The positive effect of Botulinum toxin type A on the viability of random flap in tobacco exposed in rats. AB - PURPOSE:: To evaluate the effect of Botulinum Toxin A in different time of tobacco exposure. METHODS:: 60 male, Wistar rats were divided into two tobacco exposure groups: a 2- month or a 4-month regimen. After this period, these two groups were subdivided as two: saline solution(SS) or botulinum toxin A(Bonta), at the time of the surgery. Seven days before the SS or Bonta injection, the animals were submitted to a random flap (3x10cm). On the seventh postoperative day, all animals were assessed for total flap area, viable area, and the viable/ total area ratio. RESULTS:: This study showed a difference between groups 2-month saline vs. BontA injection (p=0.04); groups 4-month saline vs. BontA injection (p=0.001); groups 2-month saline vs. 4-month BontA (p=0.003), and, between groups 2- month BontA vs. 4-month saline(p=0.03). CONCLUSIONS:: Botulinum Toxin A increased random flap viability in tobacco-exposed rats. Two months of tobacco exposure had the same effect as exposure for four months. PMID- 27982259 TI - Hepatotoxicity and nephrotoxicity of 3-bromopyruvate in mice. AB - PURPOSE:: To investigate the hepatotoxicity and nephrotoxicity of 3-Bromopyruvate (3BP) in mice. METHODS:: Fifteen nude mice were grafted subcutaneously in the left flank with MDA-MB-231 cells, then all mice were divided into control group (PBS), 3BP group (8 mg/kg), positive group (DNR: 0.8 mg/kg) when tumor volume reached approximately 100 mm3. 28 days later, tumors, livers and kidneys were stored in 4 % formalin solution and stained with hematoxylin and eosin staining. The Kunming mice experiment included control group (PBS), 3BP group (4mg/kg; 8mg/kg; 16mg/kg), positive group (DNR: 0.8 mg/kg). 24 hours later, the blood were used for the determination of hepatic damage serum biomarkers. Livers were stored in 4 % formalin solution for the later detection. RESULTS:: 3BP at the dose of 8mg/kg had a good effect on inhibiting tumor growth in nude mice and did not damage liver and kidney tissues. Kunming mice experiment showed 3BP at the dose of 16mg/kg did damage to liver tissues. CONCLUSION:: 3-Bromopyruvate at the dose of suppressing tumor growth did not exhibit hepatotoxicity and nephrotoxicity in nude mice, and the effect on liver was confirmed in Kunming mice. PMID- 27982260 TI - Effect of ozone and methylprednisolone treatment following crush type sciatic nerve injury. AB - PURPOSE:: To assess and compare the histopathological effects of ozone therapy and/or methylprednisolone (MPS) treatment on regeneration after crush type sciatic nerve injury. METHODS:: Forty Sprague-Dawley male rats were randomly allocated into four groups. Four groups received the following regimens intraperitoneally every day for 14 days after formation of crush type injury on sciatic nerve: Group I: ozone (20mcg/ml); Group II: methylprednisolone (2mg/kg); Group III: ozone (20 mcg/ml) and methylprednisolone (2mg/kg); Group IV: isotonic saline (0.9%). The histomorphological evaluation was made after biopsies were obtained from the sites of injury. RESULTS:: Significant differences were noted between groups in terms of degeneration (p=0.019), nerve sheath cell atrophy (p=0.012), intraneural inflammatory cellular infiltration (p=0.002), perineural granulation tissue formation (p=0.019), perineural vascular proliferation (p=0.004), perineural inflammatory cellular infiltration (p<0.001) and inflammation in peripheral tissue (p=0.006). Degeneration was remarkably low in Group III, while no change in nerve sheath cell was noted in Group II. CONCLUSION:: The combined use of methylprednisolone and ozone treatment can have beneficial effects for regeneration after crush type nerve injury. PMID- 27982261 TI - The effects of enoxaparin on the liver in experimental pneumoperitoneum model. AB - PURPOSE:: To investigate the potential protective effects of enoxaparin against the adverse events of carbon dioxide (CO2) pneumoperitoneum. METHODS:: Thirty four rats were divided into three groups: Group 1 (sham) underwent insertion of Veress needle into the abdomen and 90 min of anesthesia with no gas insufflation. The animals in control and enoxaparin groups were subjected to 90 min of 14 mmHg CO2 pneumoperitoneum. Enoxaparin (100 u/kg) was administered subcutaneously to the rats in enoxaparin group one hour before the operation. After 90 min of pneumoperitoneum, the rats were allowed for reperfusion through 60 min. Blood and liver samples were obtained for biochemical and histopathological examination. RESULTS:: Treatment with enoxaparin decreased the histopathological abnormalities when compared with the control group. The highest levels of oxidative stress parameters were found in control group. The use of enoxaparin decreased the levels of all oxidative stress parameters, but the difference between the control and enoxaparin groups was not statistically significant. CONCLUSION:: Enoxaparin ameliorated the harmful effects of high pressure CO2 pneumoperitoneum on the liver. PMID- 27982263 TI - Glomerular loss after arteriovenous and arterial clamping for renal warm ischemia in a swine model. AB - PURPOSE:: To evaluate the glomerular loss after arteriovenous or arterial warm ischemia in a swine model. METHODS:: Twenty four pigs were divided into Group Sham (submitted to all surgical steps except the renal ischemia), Group AV (submitted to 30 minutes of warm ischemia by arteriovenous clamping of left kidney vessels), and Group A (submitted to 30 minutes of ischemia by arterial clamping). Right kidneys were used as controls. Weigh, volume, cortical volume, glomerular volumetric density (Vv[Glom]), volume-weighted glomerular volume (VWGV), and the total number of glomeruli were measured for each organ. RESULTS:: Group AV showed a 24.5% reduction in its left kidney Vv[Glom] and a 25.4% reduction in the VWGV, when compared to the right kidney. Reductions were also observed when compared to kidneys of sham group. There was a reduction of 19.2% in the total number of glomeruli in AV kidneys. No difference was observed in any parameters analyzed on the left kidneys from group A. CONCLUSIONS:: Renal warm ischemia of 30 minutes by arterial clamping did not caused significant glomerular damage, but arteriovenous clamping caused significant glomerular loss in a swine model. Clamping only the renal artery should be considered to minimize renal injury after partial nephrectomies. PMID- 27982262 TI - Characterization of an experimental model of progressive renal disease in rats. AB - PURPOSE:: To characterize an experimental model of progressive renal disease induced by different degrees of nephrectomy in rats. METHODS:: Eighty male Wistar rats were divided into four experimental groups (n=20/group): sham surgery (control group), progressive degrees of nephrectomy leading to mild uremia (group 1), moderate uremia (group 2) and severe uremia (group 3). Ten animals of each group were followed for two or four weeks. At the end, blood and 24-hour urine samples were collected to determine renal function parameters. Urine output and water and food intake were daily monitored. RESULTS:: In rats of group 1, serum levels of creatinine and urea and microalbuminuria were increased, while reduced creatinine clearance (p<0.05, compared with control group), without changing blood pressure. Animals of group 2 had more accentuated alterations: increases in urinary output, blood pressure, serum concentrations of urea, creatinine, sodium, potassium, and in microalbuminuria, and reduction of creatinine clearance (p<0.05). Group 3 exhibited even more increased serum concentrations of urea, creatinine, sodium and potassium, blood pressure and microalbuminuria, and decreased creatinine clearance (p<0.05) in comparison with control group and unilateral nephrectomy. CONCLUSION:: Progressive nephrectomy in rats seems to be useful to study the physiopathology of chronic kidney disease and its mechanisms of progression. PMID- 27982264 TI - Influence of chlorpromazine on renal histology of rats submitted to ischemia and reperfusion injury. AB - PURPOSE:: To analyze the influence of chlorpromazine on renal histology of rats submitted to ischemia and reperfusion injury. METHODS:: Sixteen Wistar rats - split in two groups - have been used: control group, receiving 3 mg/kg isotonic saline solution through caudal vein, and, the chlorpromazine group, receiving 3 mg/kg-IV of such medication. The nephrectomy of the left kidney lower third was carried out; immediately, the test-drug was administrated. After 15 minutes of test-drug administration, the renal pedicle was clamped; in 60 minutes of ischemia it was released. After 24 hours of the renal reperfusion, the rats were, once more, anesthetized and submitted to total left nephrectomy, and, afterwards, to euthanasia. Histological findings regarding ischemia have been evaluated and compared between the groups. RESULTS:: There was no statistical difference related to inferior renal pole histological analysis. Regarding 60-minute renal ischemia, chlorpromazine has statistically reduced the accrual of leucocytes within the vasa recta renis (p=0.036) and the congestion of peritubular capillaries (p=0.041). When conducting joint analysis of histological patterns, the control group showed a median score of 11 and chlorpromazine group of 5.5 (p=0.036). CONCLUSION:: Chlorpromazine significantly reduced the occurrence of secondary damage to ischemia and reperfusion process in the overall histological analysis. PMID- 27982265 TI - Osteoarthritis model induced by intra-articular monosodium iodoacetate in rats knee. AB - PURPOSE:: To evaluate the usefulness of a knee osteoarthritis model through functional, radiological and microscopic changes of the synovial membrane. METHODS:: Forty eight rats were divided randomly into two groups. The first received 0.9% saline in the joint and corresponded to the control group. The second was submitted to experimental osteoarthritis of the right knee induced by monosodium iodoacetate and corresponded to the osteoarthritis group. All animals were subjected to comparative tests of forced ambulation and joint movements, inability to articulate and tactile allodynia on day 1 post-experiment by forced ambulation (Roto-rod test), joint assessment of disability (weight bearing test) and assessment of tactile allodynia (Von Frey test). After inflammatory induction they were divided into four sub-groups corresponding to the scheduled death in 7, 14, 21 and 28 days when they were submitted to radiographic examination of the knee, arthrotomy and collection of the synovial membrane. RESULTS:: The osteoarthritis group showed significant differences compared to control group on days 7 and 14 in Roto-rod, in weight bearing and Von Frey tests in all days, and in radiological evaluation. Microscopic examination of the synovial membrane showed abnormalities of inflammatory character at all stages. CONCLUSION:: The osteoarthritis induced by intra-articular monosodium iodoacetate in rats knee is a good model to be used in related research, because it provides mensurable changes on joint movements, tactile allodynia, progressive radiological degeneration and microscopic inflammation of the synovial membrane, that represent markers for osteoarthritis evaluation. PMID- 27982266 TI - III SBC Guidelines on the Analysis and Issuance of Electrocardiographic Reports - Executive Summary. AB - The third version of the guidelines covers recently described topics, such as ion channel diseases, acute ischemic changes, the electrocardiogram in athletes, and analysis of ventricular repolarization. It sought to revise the criteria for overloads, conduction disorders, and analysis of data for internet transmission. Resumo A terceira versao das diretrizes aborda topicos recentemente descritos, como as doencas dos canais ionicos, alteracoes isquemicas agudas, o eletrocardiograma dos atletas e analise da repolarizacao ventricular. Ela buscou rever criterios de sobrecargas, disturbios de conducao e analise de dados transmitidos via internet. PMID- 27982267 TI - In-Lab Upfront Use of Tirofiban May Reduce the Occurrence of No-Reflow During Primary Percutaneous Coronary Intervention. A Pilot Randomized Study. AB - Background:: Despite successful opening of culprit coronary artery, myocardial reperfusion does not always follows primary percutaneous coronary intervention (PPCI). Glycoprotein IIb/IIIa inhibitors are used in the treatment of no-reflow (NR), but their role to prevent it is unproven. Objective:: To evaluate the effect of in-lab administration of tirofiban on the incidence of NR in ST elevation myocardial infarction (STEMI) treated with PPCI. Methods:: STEMI patients treated with PPCI were randomized (24 tirofiban and 34 placebo) in this double-blinded study to assess the impact of intravenous tirofiban on the incidence of NR after PPCI according to angiographic and electrocardiographic methods. End-points of the study were: TIMI-epicardial flow grade; myocardial blush grade (MBG); resolution of ST-elevation < 70% (RST < 70%) at 90min and 24h after PPCI. Results:: Baseline anthropometric, clinical and angiographic characteristics were balanced between the groups. The occurrence of TIMI flow < 3 was not significantly different between the tirofiban (25%) and placebo (35.3%) groups. MBG <= 2 did not occur in the tirofiban group, and was seen in 11.7% of patients in the placebo group (p=0.13). RST < 70% occurred in 41.6% x 55.8% (p=0.42) at 90min and in 29% x 55.9% (p=0.06) at 24h in tirofiban and placebo groups, respectively. Severe NR (RST <= 30%) was detected in 0% x 26.5% (p=0.01) at 90 min, and in 4.2% x 23.5% (p=0.06) at 24h in tirofiban and placebo groups, respectively. Conclusion:: This pilot study showed a trend toward reduction of NR associated with in-lab upfront use of tirofiban in STEMI patients treated with PPCI and paves the way for a full-scale study testing this hypothesis. Fundamento:: Mesmo com abertura da arteria coronaria culpada bem sucedida, a reperfusao miocardica nem sempre sucede a intervencao coronariana percutanea primaria (ICPP). Inibidores da glicoproteina IIb/IIIa sao usados no tratamento do fenomeno de nao reperfusao (NR), mas seu papel para preveni-lo nao esta comprovado. Objetivo:: Avaliar o efeito da administracao, em laboratorio, de tirofibana sobre a incidencia de NR em infarto agudo do miocardio com supra do segmento ST (IAMCSST) tratado com ICPP. Metodos:: Pacientes com IAMCSST tratados com ICPP foram randomizados (24 tirofibana e 34 placebo) neste estudo duplo-cego para avaliar o impacto de tirofibana intravenosa sobre a incidencia de NR apos ICPP de acordo com metodos angiograficos e eletrocardiografico. Os desfechos do estudo foram: fluxo epicardico TIMI (grau), grau de fluxo miocardico (MBG), resolucao da elevacao do segmento ST < 70% (RST < 70%) aos 90 minutos e 24 horas apos ICPP. Resultados:: Caracteristicas antropometricas, clinicas e angiograficas basais eram equilibradas entre os grupos. A ocorrencia de fluxo TIMI < 3 nao foi significativamente diferente entre os grupos tirofibana (25%) e placebo (35,3%). MBG <= 2 nao ocorreu no grupo tirofibana, e foi detectado em 11,7% dos pacientes do grupo placebo (p=0,13). RST < 70% ocorreu em 41,6% x 55,8% (p=0.42) aos 90 minutos, e em 29% x 55,9% (p=0,06) em 24 horas nos grupos tirofibana e placebo, respectivamente. NR grave (RST <= 30%) ocorreu em 0% x 26,5% (p=0,01) aos 90 minutos, e em 4,2% x 23,5% (p=0,06) em 24 horas nos grupos tirofibana e placebo, respectivamente. Conclusao:: Este estudo piloto mostrou uma tendencia de reducao de NR associada ao uso, em laboratorio, de tirofibana em pacientes com IAMCSST tratados com ICPP, e abre caminho para um estudo em escala real que teste essa hipotese. PMID- 27982268 TI - Utility of Ultraportable Echocardiography in the Preoperative Evaluation of Noncardiac Surgery. AB - Background:: The ultraportable echocardiogram machine, with relevant portability and easiness in performing diagnoses, when in experienced hands, may contribute to the reliability of preoperative evaluation in noncardiac surgeries. Objectives:: To assess cardiac function parameters in patients aged older than 60 years, candidates of elective noncardiac surgeries, classified as ASA1 or ASA 2 according to surgical risk. Methods:: A total of 211 patients referred for elective surgeries, without suspicion of previous heart diseases, were included in the study. Assessment of patients was conducted by conventional echocardiogram using the ultraportable V Scan (GE) device right after the pre-anesthetic clinical evaluation. We assessed the clinical impact of echocardiography results by using a questionnaire addressed to the anesthetist. Results:: Mean age of patients was 68.9 +/- 7.0 years, 154 were women. The most frequent surgeries were: a) facectomy - cataract - 18; b) inguinal hernia surgery - 18; c) Cholecystectomy - 16. We found 58 normal tests (27.5%), 70 (33.2%) with mild valve reflux, and 83 (39.3%) with relevant abnormality, such as increase in heart chamber size, global and/or segmental contractile dysfunction, significant valve dysfunction or other unspecified. Test results caused delay of surgical procedure for a more detailed cardiac evaluation in 20 (9.5%) patients, and change in anesthetic management in 7 (3.3%). Conclusion:: There was a considerable clinical impact with the use of the ultraportable echocardiography, since one out of every ten patients evaluated had their clinical management changed due to the detection of previously unsuspected, significant heart diseases, with the potential for severe complications. Fundamento:: O ecocardiografo ultraportatil, com importante mobilidade e facilidade diagnostica em maos experientes pode contribuir para a seguranca na avaliacao pre-operatoria em cirurgias nao cardiacas. Objetivo:: Avaliar os parametros de funcao cardiaca nos pacientes com mais de 60 anos de idade, candidatos a cirurgias nao-cardiacas eletivas, classificados como ASA 1 ou ASA 2 na classificacao de risco cirurgico. Metodos:: Foram incluidos 211 pacientes direcionados para cirurgias eletivas diversas e sem suspeita previa de cardiopatia. Os pacientes foram avaliados por tecnica ecocardiografica convencional, usando o aparelho ultraportatil V Scan (GE) logo apos a avaliacao clinica pre-anestesica. Avaliamos o impacto clinico dos resultados da ecocardiografia por um questionario dirigido ao anestesista. Resultados:: A idade media dos pacientes foi 68,9 +/- 7,0 anos, 154 do sexo feminino. As cirurgias mais frequentes foram: a) Facectomia-catarata - 18; b) Herniorrafia inguinal - 18; c) Colecistectomia - 16. No total, foram observados 58 exames normais (27,5%), 70 (33,2%) exames que apresentavam leves refluxos valvares e 83 (39,3%) exames com alguma anormalidade relevante, como aumento de camara cardiaca, disfuncao contratil global e/ou segmentar, disfuncao valvar mais significativa ou outra nao especificada. Os resultados determinaram que 20 (9,5%) pacientes tivessem seus procedimentos cirurgicos adiados ate avaliacao cardiologica mais detalhada e em 7 (3,3%) houve mudanca na conduta anestesica. Conclusao:: Houve um impacto clinico consideravel com o uso da ecocardiografia ultraportatil, pois um em cada dez pacientes avaliados sofreu modificacao na conduta clinica, em funcao da deteccao de cardiopatias significativas, nao suspeitadas previamente, e com potencial para complicacoes graves. PMID- 27982269 TI - Blood Pressure Treatment Adherence and Control after Participation in the ReHOT. AB - Background:: Lack of adherence to pharmacological treatment is one of the main causes of low control rates in hypertension. Objective:: To verify treatment adherence and associated factors, as well as blood pressure (BP) control in participants of the Resistant Hypertension Optimal Treatment (ReHOT) clinical trial. Method:: Cross-sectional study including all 109 patients who had completed the ReHOT for at least 6 months. We excluded those participants who failed to respond to the new recruitment after three phone contact attempts. We evaluated the BP control by ambulatory BP monitoring (ABPM; controlled levels: 24 hour systolic and diastolic BP < 130 x 80 mmHg) and analyzed the patients' treatment adherence using the Morisky Medication Adherence Scale (MMAS) questionnaire validated by Bloch, Melo, and Nogueira (2008). The statistical analysis was performed with the software IBM SPSS statistics 21.0. We tested the normality of the data distribution with kurtosis and skewness. The variables tested in the study are presented with descriptive statistics. Comparisons between treatment adherence and other variables were performed with Student's t test for independent variables and Pearson's chi-square or Fisher's exact test. To conduct analyses among patients considering adherence to treatment and BP control, we created four groups: G0, G1, G2, and G3. We considered a 5% significance level in all tests. Results:: During the ReHOT, 80% of the patients had good BP control and treatment adherence. Of 96 patients reevaluated in the present study, only 52.1% had controlled hypertension when assessed by ABPM, while 31.3% were considered adherent by the MMAS. Regarding other ABPM measures, we observed an absence of a nocturnal dip in 64.6% of the patients and a white coat effect and false BP control in 23% and 12.5%, respectively. Patients' education level showed a trend towards being a determinant factor associated with lack of adherence (p = 0.05). Resistant hypertension and number of medications were significantly associated with BP control assessed by ABPM (p = 0.009 and p = 0.001, respectively). Resistant hypertension was also significantly associated with group G0 (patients with no control or adherence, p = 0.012). Conclusion:: There was a decrease in BP control and adherence measured by the MMAS after participation of at least 6 months in the ReHOT clinical trial. Fundamento:: A falta de adesao ao tratamento medicamentoso da hipertensao arterial sistemica (HAS) e uma das principais causas das baixas taxas de controle da doenca. Objetivo:: Verificar a adesao e fatores relacionados a ela, alem do controle pressorico de pacientes que participaram do ensaio clinico Resistant Hypertension Optimal Treatment (ReHOT). Metodo:: Estudo transversal que incluiu todos os 109 pacientes que concluiram o ReHOT ha pelo menos 6 meses. Foram excluidos aqueles que nao responderam ao novo recrutamento apos tres tentativas de contato telefonico. Foi realizada avaliacao do controle pressorico atraves de monitorizacao ambulatorial da pressao arterial (MAPA; PA controlada: pressao arterial [PA] sistolica e diastolica de 24 horas < 130 x 80 mmHg) e avaliacao da adesao atraves de respostas ao questionario Morisky Medication Adherence Scale (MMAS) validado por Bloch, Melo e Nogueira (2008). A analise estatistica foi realizada com o programa IBM SPSS statistics 21.0. Para verificar a normalidade da distribuicao dos dados, utilizamos testes de curtose e assimetria. As variaveis relacionadas ao objeto de estudo sao apresentadas por meio de estatistica descritiva. Comparacoes entre a adesao ao tratamento e demais variaveis foi realizada com o teste t de Student para variaveis independentes e teste do qui-quadrado de Pearson ou exato de Fisher. Para a analise entre pacientes considerando a adesao ao tratamento e controle da PA, foram criados quatro grupos: G0, G1, G2 e G3. Em todos os testes estatisticos consideramos um nivel de significancia de 5%. Resultados:: Durante o ReHOT, 80% dos pacientes apresentaram controle pressorico e adesao ao tratamento. Do total de 96 pacientes reavaliados, apenas 52,1% foram identificados como tendo HAS controlada atraves da avaliacao da MAPA e 31,3% apresentaram adesao pelo MMAS. Quando consideradas outras medidas da MAPA, verificou-se que 64,6% dos pacientes nao apresentavam descenso noturno e 23% e 12,5% apresentavam efeito do avental branco e falso controle da PA, respectivamente. A escolaridade apresentou tendencia a ser um fator determinante de falta de adesao (p = 0,05). O numero de medicamentos e a HAS resistente (HAR) tiveram uma relacao significativa com o controle da PA medida por MAPA (p = 0,009 e p = 0,001, respectivamente). A HAR teve relacao significativa com o grupo G0 (sem controle e sem adesao, p = 0,012). Conclusao:: Houve reducao do controle da PA e da adesao pelo MMAS apos pelo menos 6 meses de participacao no ensaio clinico ReHOT. PMID- 27982270 TI - Elevated Heart Rate is Associated with Cardiac Denervation in Patients with Heart Failure: A 123-Iodine-MIBG Myocardial Scintigraphy Study. AB - Background:: In the Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial (SHIFT), heart rate (HR) reduction with ivabradine was associated with improved survival and reduced hospitalizations in patients with heart failure (HF). The mechanisms by which elevated HR increases mortality are not fully understood. Objective:: To assess the relationship of baseline HR with clinical, neurohormonal and cardiac sympathetic activity in patients with chronic HF and elevated HR. Method:: Patients with chronic HF who were in sinus rhythm and had resting HR>70 bpm despite optimal medical treatment were included in a randomized, double-blind study comparing ivabradine versus pyridostigmine. This report refers to the baseline data of 16 initial patients. Baseline HR (before randomization to one of the drugs) was assessed, and patients were classified into two groups, with HR below or above mean values. Cardiac sympathetic activity was assessed by 123-iodine-metaiodobenzylguanidine myocardial scintigraphy. Results:: Mean HR was 83.5+/-11.5 bpm (range 72 to 104), and seven (43.7%) patients had HR above the mean. These patients had lower 6-min walk distance (292.3+/-93 vs 465.2+/-97.1 m, p=0.0029), higher values of N-Terminal-proBNP (median 708.4 vs 76.1, p=0.035) and lower late heart/mediastinum rate, indicating cardiac denervation (1.48+/-0.12 vs 1.74+/-0.09, p<0.001). Conclusion:: Elevated resting HR in patients with HF under optimal medical treatment was associated with cardiac denervation, worse functional capacity, and neurohormonal activation. Fundamento:: No SHIFT (Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial, ou Estudo do Tratamento da Insuficiencia Cardiaca Sistolica com o Inibidor de If Ivabradina), a reducao da frequencia cardiaca (FC) com ivabradina associou-se com melhor sobrevida e reducao das hospitalizacoes em pacientes com insuficiencia cardiaca (IC). Os mecanismos pelos quais a FC elevada aumenta a mortalidade nao sao totalmente compreendidos. Objetivo:: Avaliar a relacao da FC basal com atividade clinica, neuro-hormonal e simpatica cardiaca em pacientes com IC cronica e FC elevada. Metodo:: Pacientes com IC cronica em ritmo sinusal e FC>=70 apesar de tratamento adequado foram incluidos em um estudo duplo cego, randomizado, que comparou ivabradina com piridostigmina. Este artigo refere se a dados basais dos primeiros 16 pacientes. A FC basal (antes da randomizacao para um dos medicamentos) foi avaliada, e os pacientes classificados em dois grupos, com FC abaixo ou acima dos valores medios. A atividade simpatica cardiaca foi avaliada por cintilografia com metaiodobenzilguanidina marcada com iodo 123. Resultados:: A FC media foi 83,5+/-11,5 bpm (intervalo 72 a 104), e sete pacientes (43.7%) tinham FC acima da media. Esses pacientes apresentaram menor distancia percorrida no teste de caminhada de 6 minutos (292,3+/-93 vs 465,2+/ 97,1 m, p=0,0029), valores mais altos de N-terminal do pro-BNP (mediana 708,4 vs 76,1, p=0,035) e menor relacao coracao/mediastino tardia, indicando desnervacao cardiaca (1,48+/-0,12 vs 1,74+/-0,09, p<0,001). Conclusao:: A FC de repouso elevada em pacientes com IC em tratamento medico adequado associou-se com desnervacao cardiaca, pior capacidade funcional e ativacao neuro-hormonal. PMID- 27982271 TI - Cardiac Magnetic Resonance-Verified Myocardial Fibrosis in Chagas Disease: Clinical Correlates and Risk Stratification. AB - Background:: Chagas disease (CD) is an important cause of heart failure and mortality, mainly in Latin America. This study evaluated the morphological and functional characteristics of the heart as well the extent of myocardial fibrosis (MF) in patients with CD by cardiac magnetic resonance (CMR). The prognostic value of MF evaluated by myocardial-delayed enhancement (MDE) was compared with that via Rassi score. Methods:: This study assessed 39 patients divided into 2 groups: 28 asymptomatic patients as indeterminate form group (IND); and symptomatic patients as Chagas Heart Disease (CHD) group. All patients underwent CMR using the techniques of cine-MRI and MDE, and the amount of MF was compared with the Rassi score. Results:: Regarding the morphological and functional analysis, significant differences were observed between both groups (p < 0.001). Furthermore, there was a strong correlation between the extent of MF and the Rassi score (r = 0.76). Conclusions:: CMR is an important technique for evaluating patients with CD, stressing morphological and functional differences in all clinical presentations. The strong correlation with the Rassi score and the extent of MF detected by CMR emphasizes its role in the prognostic stratification of patients with CD. Fundamento:: A doenca de Chagas (DC) e importante causa de insuficiencia cardiaca e mortalidade, principalmente na America Latina. Este estudo avaliou as caracteristicas morfologicas e funcionais do coracao, assim como a extensao da fibrose miocardica (FM) em pacientes com DC atraves de ressonancia magnetica cardiaca (RMC). O valor prognostico da FM avaliada por realce tardio miocardico (RTM) foi comparado aquele do escore de Rassi. Metodos:: Avaliacao de 39 pacientes divididos em 2 grupos: grupo 'forma indeterminada' (IND), 28 pacientes assintomaticos; e grupo 'cardiopatia chagasica' (CC), pacientes sintomaticos. Todos os pacientes foram submetidos a RMC com as tecnicas de cine-RM e RTM, sendo a quantidade de FM evidenciada ao exame comparada ao escore de Rassi. Resultados:: As analises morfologica e funcional mostraram significativas diferencas entre os 2 grupos (p < 0,001). Houve ainda uma forte correlacao entre a extensao da FM e o escore de Rassi (r = 0,76). Conclusoes:: A RMC e uma importante tecnica para avaliar pacientes com DC, ressaltando as diferencas morfologicas e funcionais em todas as apresentacoes clinicas. A forte correlacao entre o escore de Rassi e a extensao da FM detectada por RMC enfatiza seu papel na estratificacao prognostica de pacientes com DC. PMID- 27982273 TI - Rheumatic Fever: a neglected and underdiagnosed disease. New perspective on diagnosis and prevention. PMID- 27982274 TI - Case 5/2016 - A 56-Year-old Man Hospitalized for Unstable Angina, who Presented Recurrence of Precordial Pain and Cardiac Arrest with Pulseless Electrical Activity. PMID- 27982272 TI - Cardiopulmonary Exercise Test: Background, Applicability and Interpretation. AB - Cardiopulmonary exercise test (CPET) has been gaining importance as a method of functional assessment in Brazil and worldwide. In its most frequent applications, CPET consists in applying a gradually increasing intensity exercise until exhaustion or until the appearance of limiting symptoms and/or signs. The following parameters are measured: ventilation; oxygen consumption (VO2); carbon dioxide production (VCO2); and the other variables of conventional exercise testing. In addition, in specific situations, pulse oximetry and flow-volume loops during and after exertion are measured. The CPET provides joint data analysis that allows complete assessment of the cardiovascular, respiratory, muscular and metabolic systems during exertion, being considered gold standard for cardiorespiratory functional assessment.1-6 The CPET allows defining mechanisms related to low functional capacity that can cause symptoms, such as dyspnea, and correlate them with changes in the cardiovascular, pulmonary and skeletal muscle systems. Furthermore, it can be used to provide the prognostic assessment of patients with heart or lung diseases, and in the preoperative period, in addition to aiding in a more careful exercise prescription to healthy subjects, athletes and patients with heart or lung diseases. Similarly to CPET clinical use, its research also increases, with the publication of several scientific contributions from Brazilian researchers in high-impact journals. Therefore, this study aimed at providing a comprehensive review on the applicability of CPET to different clinical situations, in addition to serving as a practical guide for the interpretation of that test. Resumo O teste cardiopulmonar de exercicio (TCPE) vem ganhando importancia crescente como metodo de avaliacao funcional tanto no Brasil quanto no Mundo. Nas suas aplicacoes mais frequentes, o teste consiste em submeter o individuo a um exercicio de intensidade gradativamente crescente ate a exaustao ou o surgimento de sintomas e/ou sinais limitantes. Neste exame se mensura a ventilacao (VE), o consumo de oxigenio (VO2), a producao de gas carbonico (VCO2) e as demais variaveis de um teste de exercicio convencional. Adicionalmente, podem ser verificadas, em situacoes especificas, a oximetria de pulso e as alcas fluxo-volume antes, durante e apos o esforco. A analise integrada dos dados permite a completa avaliacao dos sistemas cardiovascular, respiratorio, muscular e metabolico no esforco, sendo considerado padrao-ouro na avaliacao funcional cardiorrespiratoria.1-6 O TCPE permite definir mecanismos relacionados a baixa capacidade funcional, os quais podem ser causadores de sintomas como a dispneia, correlacionando-os com alteracoes dos sistemas cardiovascular, pulmonar e musculoesqueletico. Tambem pode ser de grande aplicabilidade na avaliacao prognostica em cardiopatas, pneumopatas e em pre-operatorio, alem de auxiliar na prescricao mais criteriosa do exercicio em sujeitos normais, em atletas, em cardiopatas e em pneumopatas. Assim como ocorre com o uso clinico, a pesquisa nesse campo tambem cresce e varias contribuicoes cientificas de pesquisadores nacionais sao publicadas em periodicos de alto fator de impacto. Sendo assim, o objetivo deste documento e fornecer uma revisao ampla da aplicabilidade do TCPE nas diferentes situacoes clinicas, bem como servir como guia pratico na interpretacao desse teste propedeutico. PMID- 27982275 TI - Spontaneous Coronary Artery Dissection in Acute Coronary Syndrome: Report of a Series of Cases with 17 Patients. PMID- 27982276 TI - Focal Arterialization and Neoatherosclerosis of a Saphenous Vein Graft. Improving our Understanding of Late Graft Failures. PMID- 27982277 TI - Measurement of Epicardial Fat Thickness by Echocardiography Presents Challenges PMID- 27982278 TI - Colonial scientific-medical documentary films and the legitimization of an ideal state in post-war Spain. AB - This paper explores the role of film and medical-health practices and discourses in the building and legitimating strategies of Franco's fascist regime in Spain. The analysis of five medical-colonial documentary films produced during the 1940s explores the relationship between mass media communication practices and techno scientific knowledge production, circulation and management processes. These films portray a non-problematic colonial space where social order is articulated through scientific-medical practices and discourses that match the regime's need to consolidate and legitimize itself while asserting the inclusion-exclusion dynamics involved in the definition of social prototypes through processes of medicalization. PMID- 27982279 TI - The discontinuity between humans and animals in Buffon's Natural history. AB - According to Buffon, the difference between man's cognitive abilities and those of other animals could not be attributed to natural causes. Noting these differences necessarily meant accepting that the Creator had endowed man with an immaterial soul that was unparalleled among animals. This article seeks to show that Buffon's abandonment of naturalism was not the result of a theological premise but of the impossibility of reconciling the presumed heterogeneity between animal and human cognitive faculties with the materialist explanation of the origin of species that Buffon outlined in the course of his writings. If man is assumed to be an exceptional being, the origin of the human race must also be seen as miraculous. PMID- 27982280 TI - Mannose-binding lectin 2 (Mbl2) gene polymorphisms are related to protein plasma levels, but not to heart disease and infection by Chlamydia. AB - The presence of the single nucleotide polymorphisms in exon 1 of the mannose binding lectin 2 (MBL2) gene was evaluated in a sample of 159 patients undergoing coronary artery bypass surgery (71 patients undergoing valve replacement surgery and 300 control subjects) to investigate a possible association between polymorphisms and heart disease with Chlamydia infection. The identification of the alleles B and D was performed using real time polymerase chain reaction (PCR) and of the allele C was accomplished through PCR assays followed by digestion with the restriction enzyme. The comparative analysis of allelic and genotypic frequencies between the three groups did not reveal any significant difference, even when related to previous Chlamydia infection. Variations in the MBL plasma levels were influenced by the presence of polymorphisms, being significantly higher in the group of cardiac patients, but without representing a risk for the disease. The results showed that despite MBL2 gene polymorphisms being associated with the protein plasma levels, the polymorphisms were not enough to predict the development of heart disease, regardless of infection with both species of Chlamydia. PMID- 27982281 TI - Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies. AB - The process of drug development involves non-clinical and clinical studies. Non clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose. PMID- 27982282 TI - Effects of perinatal exposure to nonylphenol on delivery outcomes of pregnant rats and inflammatory hepatic injury in newborn rats. AB - The current study aimed to investigate the effects of perinatal exposure to nonylphenol (NP) on delivery outcome of pregnant rats and subsequent inflammatory hepatic injury in newborn rats. The pregnant rats were divided into 2 groups: control group (corn oil) and NP exposure group. Thirty-four pregnant rats were administered NP or corn oil by gavage from the sixth day of pregnancy to 21 days postpartum, with blood samples collected at 12 and 21 days of pregnancy and 60 days after delivery. The NP concentration was measured by HPLC, with chemiluminescence used for detection of estrogen and progesterone levels. Maternal delivery parameters were also observed. Liver and blood of the newborn rats were collected and subjected to automatic biochemical detection of liver function and blood lipid analyzer (immunoturbidimetry), and ultrastructural observation of the hepatic microstructure, with the TNF-alpha and IL-1beta hepatic tissue levels evaluated by immunohistochemistry. Compared with the control group, the pregnant and postpartum serum NP and estradiol levels of the mother rats in the NP group were significantly increased, together with lowered progesterone level, increased number of threatened abortion and dystocia, and fewer newborn rats and lower litter weight. Serum and hepatic NP levels of the newborn rats measured 60 days after birth were significantly higher than those of the control group, as well as lower testosterone levels and increased estradiol levels. When observed under electron microscope, the hepatocyte nuclei of the control group were large and round, with evenly distributed chromatin. The chromatin of hepatocytes in the NP group presented deep staining of the nuclei, significant lipid decrease in the cytoplasm, and the majority of cells bonded with lysate. The results of immunohistochemistry showed that there was almost no TNF-alpha or IL-1beta expression in the hepatocytes of the control group, while the number of TNF-alpha-, PCNA-, and IL-1beta-positive cells in the NP group was increased, with higher integral optical density than the control group. Compared to the control group, the serum levels of alanine aminotransferase, aspartate aminotransferase, triglyceride and low-density lipoprotein in the newborn rats of the NP group were significantly increased. There was no significant difference in the serum level of high-density lipoprotein or cholesterol between the groups. Perinatal exposure to NP can interfere with the in vivo estrogen and progesterone levels of pregnant rats, resulting in threatened abortion, dystocia and other adverse delivery outcomes. High liver and serum NP levels of the newborn rats led to alteration of liver tissue structure and function. The NP-induced hepatotoxicity is probably mediated by inflammatory cytokines TNF-alpha and IL 1alpha. PMID- 27982284 TI - [RhD alloimmunization in pregnant women in Rio de Janeiro State, Brazil: perspectives and challenges]. AB - This study shows research results on the persistence of RhD alloimmunization in pregnant women seen in the public healthcare network in Rio de Janeiro State, Brazil, through patient file analysis and interviews with administrators, health professionals, and patients. We analyzed 289 patient files of RhD-negative pregnant women seen from 2004 to 2012 at the State Reference Center. Individual interviews were held with 15 individuals. The interviews revealed factors contributing to persistence of the problem, such as: loss of restructuring of the Program for the Prevention of RhD Alloimmunization (PPARhD); lack of a system for monitoring the Program; low linkage between the referral and counter-referral network during prenatal care; insufficient training of the health professionals treating pregnant women at risk; and insufficient visibility of the program for RhD alloimmunization prevention. These critical points highlight the need for the State Health Department to reinforce prioritization of the program for alloimmunization prevention and invest in referral and counter-referral in the healthcare network. The study showed that the problem has multiple causes and requires interdisciplinary and complex measures related to comprehensive prenatal care. PMID- 27982283 TI - Propofol inhibits invasion and growth of ovarian cancer cells via regulating miR 9/NF-kappaB signal. AB - Propofol is one of the most commonly used intravenous anesthetic agents during cancer resection surgery. A previous study has found that propofol can inhibit invasion and induce apoptosis of ovarian cancer cells. However, the underlying mechanisms are not known. miR-9 has been reported to be little expressed in ovarian cancer cells, which has been related to a poor prognosis in patients with ovarian cancer. Studies have also demonstrated that propofol could induce microRNAs expression and suppress NF-kappaB activation in some situations. In the present study, we assessed whether propofol inhibits invasion and induces apoptosis of ovarian cancer cells by miR-9/NF-kappaB signaling. Ovarian cancer ES 2 cells were transfected with anti-miR-9 or p65 cDNA or p65 siRNA for 24 h, after which the cells were treated with different concentrations of propofol (1, 5, and 10 MUg/mL) for 24 h. Cell growth and apoptosis were detected using MTT assay and flow cytometry analysis. Cell migration and invasion were detected using Transwell and Wound-healing assay. Western blot and electrophoretic mobility shift assay were used to detect different protein expression and NF-kappaB activity. Propofol inhibited cell growth and invasion, and induced cell apoptosis in a dose-dependent manner, which was accompanied by miR-9 activation and NF kappaB inactivation. Knockdown of miR-9 abrogated propofol-induced NF-kappaB activation and MMP-9 expression, reversed propofol-induced cell death and invasion of ES-2 cells. Knockdown of p65 inhibited NF-kappaB activation rescued the miR-9-induced down-regulation of MMP-9. In addition, overexpression of p65 by p65 cDNA transfection increased propofol-induced NF-kappaB activation and reversed propofol-induced down-regulation of MMP-9. Propofol upregulates miR-9 expression and inhibits NF-kappaB activation and its downstream MMP-9 expression, leading to the inhibition of cell growth and invasion of ES-2 cells. PMID- 27982285 TI - [AmostraBrasil: an R package for household sampling in Brazilian municipalities]. AB - Given the relevance of epidemiological surveys and the difficulties in establishing an adequate sampling plan to conduct them, this article present the AmostraBrasil package, part of the open-access R software, which automatizes the taking of random samples - simple, systematic, and stratified - from households in any Brazilian municipalities (counties). The package also allows automatically obtaining the sampled households' geographic coordinates, was well as shapefiles of the municipality's perimeter and the sample's spatial distribution. The article describes the steps for installing and using the package in the Windows OS. Examples are provided of the package's applications: sampling and spatial distribution of 2,500 residential households in the city of Rio de Janeiro and generation of controls in estimating risk spatial distribution. PMID- 27982286 TI - [Healthcare and maternal morbidity and mortality: a hospital-based case-control study in two regions of Colombia (Bogota and Antioquia), 2009-2011]. AB - The study aimed to identify whether payment forms and insurance schemes are associated with severe obstetric complications and maternal mortality. A hospital based case-control study was conducted in two regions of Colombia, 2009-2011. Data were obtained from each woman's clinical history. Unconditional logistic regression was used. The sample included 1,011 patients: 337 cases and 674 controls. No quality component was statistically significant in either region. In Bogota, the risk of obstetric complications was significantly higher in the contributive insurance scheme than in subsidized coverage or uninsured; Antioquia showed similar associations, but not statistically significant. Differences in maternal morbidity according to payment scheme were not statistically significant in either Antioquia or Bogota. Factors associated with maternal morbidity and mortality differed according to the study population, suggesting the need for local studies to identify determinants and make appropriate decisions. PMID- 27982287 TI - [Personal development of youth in Medellin, Colombia: beyond risk behaviors and resilience]. AB - Research on young people has increasingly focused on dynamic and comprehensive approaches rather than merely behavior and psychopathology. Such studies help shed light on personal development in adolescents and the role of resilience for them from their own perspective, that is, young people facing a complex world of risks, opportunities, and omnipresent violence. A qualitative study was performed with a hermeneutic focus; 48 in-depth interviews were performed, analyzed with tools from the three-stage framework (descriptive, analytic, and interpretative). The results show that all-or-nothing classification of youth as resilient versus non-resilient (or "with" versus "without" behavior problems) fails to reflect how they experience their development, which is dynamic and changes according to their characteristics, potentialities, needs, and interests, as well as the opportunities they find in their contexts. PMID- 27982288 TI - Congenital Zika virus syndrome. PMID- 27982289 TI - [Maternal factors associated with birth weight in term infants, Colombia, 2002 2011]. AB - The study aimed to identify maternal factors associated with birth weight in Colombia from 2002 to 2011. This was a descriptive study based on data from the Live Birth Registry of Colombia, Administrative Department of Vital Statistics. Birth weight was classified as low birth weight < 2,500g, insufficient birth weight 2,500-2,999g, normal birth weight 3,000-3,999g, and high birth weight >= 4,000g. Data analysis used Mann-Whitney U test, Kruskal-Wallis test, and multinomial logistic regression. Women with increased likelihood of low birth weight newborns were 35 years or older (OR = 1.4; 95%CI: 1.39-1.4), had little schooling (OR = 1.1; 95%CI: 1.1-1.1), were single (OR = 1.1; 95%CI: 1.1-1.2), without prenatal care (OR = 1.9; 95%CI: 1.9-2.0), and lived in rural areas (OR = 1.2; 95%CI: 1.1-1.2). Women with higher prevalence of high birth weight newborns were 35 years or older (OR = 1.1; 95%CI: 1.1-1.1) and had four or more children (OR = 2.1; 95%CI 2.0-2.1). Insufficient birth weight showed a similar pattern to low birth weight. In conclusion, social, demographic, and maternal factors influence the birth weight of newborns in Colombia. PMID- 27982290 TI - Hepatitis A seroprevalence in public school children in Campos dos Goytacazes, Rio de Janeiro State, Brazil, prior to the introduction of the hepatitis A universal childhood vaccination. AB - This cross-sectional study was carried out between August 2011 and July 2012 in the city of Campos dos Goytacazes in Rio de Janeiro State, Brazil. Dried blood spot samples were collected on filter paper from 919 individuals between the ages of 1 and 19 and were tested for antibodies against the hepatitis A virus (anti HAV). The total prevalence was 20.7%, while 94.7% of children under the age of 5 were found to be susceptible to HAV infection. The prevalence of anti-HAV increased with age, reaching 33.3% among individuals aged between 15 and 19, thereby indicating that this municipality has a low level of endemicity for hepatitis A. Age, non-white skin color, accustomed to swimming in the river and more than five people living at home were the factors that were associated with an increase in the chance of a positive anti-HAV result. Mother's education level (secondary or tertiary) was considered a protective factor for HAV infection. The data obtained showed that a large proportion of the children from Campos dos Goytacazes were at risk of HAV infection, which should be minimized with the introduction of the vaccination program against hepatitis A that was launched in the municipality in 2011. PMID- 27982291 TI - Towards control of Chagas disease: the contribution of the new brazilian consensus. PMID- 27982292 TI - 2 nd Brazilian Consensus on Chagas Disease, 2015. AB - Chagas disease is a neglected chronic condition with a high burden of morbidity and mortality. It has considerable psychological, social, and economic impacts. The disease represents a significant public health issue in Brazil, with different regional patterns. This document presents the evidence that resulted in the Brazilian Consensus on Chagas Disease. The objective was to review and standardize strategies for diagnosis, treatment, prevention, and control of Chagas disease in the country, based on the available scientific evidence. The consensus is based on the articulation and strategic contribution of renowned Brazilian experts with knowledge and experience on various aspects of the disease. It is the result of a close collaboration between the Brazilian Society of Tropical Medicine and the Ministry of Health. It is hoped that this document will strengthen the development of integrated actions against Chagas disease in the country, focusing on epidemiology, management, comprehensive care (including families and communities), communication, information, education, and research . PMID- 27982293 TI - Postpartum depression: bipolar or unipolar? Analysis of 434 Polish postpartum women. AB - Objective: To assess the prevalence of soft bipolar features in a sample of women with postpartum depressive symptoms, as well as to compare the sociodemographic and obstetric characteristics of subjects with bipolar or unipolar postpartum depressive symptomatology. Methods: Four hundred and thirty-four participants were enrolled in this cross-sectional study. Postpartum depression (PPD) symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS), while the Mood Disorder Questionnaire (MDQ) was used to screen for bipolarity features. Results: Of the 434 participants, 66 (15.2%) scored >= 13 points on the EPDS, thus fulfilling the screening criteria, and 103 scored >= 7 points on the MDQ. In comparison with non-depressed subjects, the women who scored positively on the EPDS were significantly more likely to exhibit symptoms of bipolar spectrum disorders (38 vs. 21%; chi-square test, p = 0.015). Women with bipolar PPD symptomatology were significantly younger than those exhibiting unipolar PPD symptoms (31.0+/-4.8 years vs. 28.5+/-4.1 years; t-test, p = 0.03). The groups did not differ in terms of obstetric characteristics. Conclusion: Our findings suggest that patients with PPD symptomatology may be more likely to exhibit soft bipolarity features as compared with non-depressed women. PMID- 27982294 TI - Boerhaave syndrome - case report. AB - CONTEXT:: Boerhaave syndrome consists of spontaneous longitudinal transmural rupture of the esophagus, usually in its distal part. It generally develops during or after persistent vomiting as a consequence of a sudden increase in intraluminal pressure in the esophagus. It is extremely rare in clinical practice. In 50% of the cases, it is manifested by Mackler's triad: vomiting, lower thoracic pain and subcutaneous emphysema. Hematemesis is an uncommon yet challenging presentation of Boerhaave's syndrome. Compared with ruptures of other parts of the digestive tract, spontaneous rupture is characterized by a higher mortality rate. CASE REPORT:: This paper presents a 64-year-old female patient whose vomit was black four days before examination and became bloody on the day of the examination. Her symptoms included epigastric pain and suffocation. Physical examination showed hypotension, tachycardia, dyspnea and a swollen and painful abdomen. Auscultation showed lateral crackling sounds on inspiration. Ultrasound examination showed a distended stomach filled with fluid. Over 1000 ml of fresh blood was extracted by means of nasogastric suction. Esophagogastroduodenoscopy was discontinued immediately upon entering the proximal esophagus, where a large amount of fresh blood was observed. The patient was sent for emergency abdominal surgery, during which she died. An autopsy established a diagnosis of Boerhaave syndrome and ulceration in the duodenal bulb. CONCLUSION:: Boerhaave syndrome should be considered in all cases with a combination of gastrointestinal symptoms (especially epigastric pain and vomiting) and pulmonary signs and symptoms (especially suffocation). PMID- 27982296 TI - Ectoparasites of the black-chinned siskin Spinus barbatus (Passeriformes: Fringillidae) in Chile. AB - Despite being a bird with a broad and extensive distribution in Chile, the black chinned siskin, Spinus barbatus Molina, 1782 is not well studied in relation to its parasites. This paper aims to describe the ectoparasite fauna of S. barbatus in central and southern Chile. A total of 125 individuals caught with mist nets were examined alive; a total of 22 parasites were found dead and were exposed to parasit autopsy. The extracted parasites were preserved in 70% alcohol for subsequent mounting and identification. Ectoparasites were found in 56 black chinned siskins (38%); 48 of them (33%) had 870 mites - 680 feather mites (Astigmata: Analgoidea) were identified as Proctophyllodes spini, 167 as Knemidokoptes jamaicensis, 19 as Strelkoviacarus critesi, and one as Analges passerinus. Moreover, three mites were chiggers belonging to the tribe Schoengastiini (Prostigmata: Trombiculidae). In 21 birds (14%), 54 lice were found, 21 of which were identified as Philopterus roehreri, 18 as Myrsidea serini, and 15 as Ricinus carolynae. Endoparasites were not found in the necropsied individuals. All of the parasites that were found represent new records for Chile, and they also serve as new records of host-parasite associations for S. barbatus. PMID- 27982295 TI - Infection with Toxoplasma gondii in a red kangaroo (Macropus rufus) and a Patagonian mara (Dolichotis patagonum) in captivity. AB - Toxoplasmosis is an infectious, zoonotic and parasitic disease, caused by Toxoplasma gondii. In this manucript, two cases of infection with T. gondii in captive animals from a zoological park in the central region of Chile are described. One case was a red kangaroo (Macropus rufus), which is highly susceptible to the infection, and the other was a Patagonian mara (Dolichotis patagonum), a rodent in which there is no previous report of the infection. Both animals had myocarditis, with the presence of intralesional tachizoites and cysts suggestive of infection with T. gondii. This infection was confirmed by immunohistochemistry in both animals. The origin of the infection is unknown, but it is likely that free ranging domestic felines were associated with the dissemination of the parasites. This highlights the importance of controlling the domestic animal populations in zoological parks. To the best of our knowledge, this is the first time that T. gondii infection is described in a Patagonian mara, adding a new host for this infectious agent. PMID- 27982297 TI - Ticks parasitizing bats (Mammalia: Chiroptera) in the Caatinga Biome, Brazil. AB - In this paper, the authors report ticks parasitizing bats from the Serra das Almas Natural Reserve (RPPN) located in the municipality of Crateus, state of Ceara, in the semiarid Caatinga biome of northeastern Brazil. The study was carried out during nine nights in the dry season (July 2012) and 10 nights in the rainy season (February 2013). Only bats of the Phyllostomidae and Mormoopidae families were parasitized by ticks. The species Artibeus planirostris and Carolia perspicillata were the most parasitized. A total of 409 larvae were collected and classified into three genera: Antricola (n = 1), Nothoaspis (n = 1) and Ornithodoros (n = 407). Four species were morphologically identified as Nothoaspis amazoniensis, Ornithodoros cavernicolous, Ornithodoros fonsecai, Ornithodoros hasei, and Ornithodoros marinkellei. Ornithodoros hasei was the most common tick associated with bats in the current study. The present study expand the distributional ranges of at least three soft ticks into the Caatinga biome, and highlight an unexpected richness of argasid ticks inhabiting this arid ecosystem. PMID- 27982298 TI - High occurrence of Mycoplasma suis infection in swine herds from non-technified farms in Mossoro, state of Rio Grande do Norte, Northeastern Brazil. AB - Mycoplasma suis, the etiological agent of swine hemoplasmosis, has been neglected in swine herds around the world. Swine hemoplasmosis is frequently associated with hemolytic anemia, disgalacty, infertility and immunosuppression, and it results in significant economic losses. This study investigates the occurrence of M. suis in non-technified swine herds in the northeastern region of Brazil using quantitative PCR (qPCR) based on the 16S rRNA gene. Between March and August 2013, blood samples from 147 swine were collected during slaughter in the city of Mossoro, state of Rio Grande do Norte, northeastern Brazil. One hundred and twelve samples (76.19%) were positive for M. suis by qPCR assays. The range of Cqs and quantification (copies of a M. suis-16S rRNA gene fragment/uL) was 20.86 37.89 and 1.64*101-6.64*107, respectively. One can conclude that M. suis infection have high occurrence (76,19%) in non-technified swine-rearing systems in Mossoro in the state of Rio Grande do Norte, Brazil. PMID- 27982300 TI - Hematological changes associated with hemoplasma infection in cats in Rio de Janeiro, Brazil. AB - This study aimed to detect Mycoplasma spp. in naturally infected cats from Rio de Janeiro and to evaluate hematological abnormalities and factors associated with this infection. Out of the 197 cats sampled, 11.2% presented structures compatible with hemoplasma organisms on blood smears. In contrast, 22.8% were positive for Mycoplasma spp. by means of 16S rRNA gene real-time polymerase chain reaction, which reflects the weak concordance between techniques. The infection rates, by means of 16S rRNA gene conventional polymerase chain reaction, was 4.6%, 4.6% and 11.7% for Mycoplasma haemofelis (Mhf), 'Candidatus Mycoplasma turicensis' (CMt) and 'Candidatus Mycoplasma haemominutum' (CMhm), respectively. Mhf and CMhm infections are more frequent in the summer (p>0.05). Presence of anemia (p < 0.02), lymphocytosis (p < 0.03), thrombocytopenia (p < 0.04) and activated monocytes (p < 0.04) was associated with Mhf infection. No hematological abnormality was associated with CMt or CMhm infection. Male cats were more prone to be infected by Mhf or CMhm (p < 0.01). Adult cats had more chance to be infected by CMhm. Three hemoplasma species occur in the metropolitan region of Rio de Janeiro and Mhf seems to be the most pathogenic of them. Anemia is the most important hematological abnormality. PMID- 27982299 TI - Serosurvey of Borrelia in dogs, horses, and humans exposed to ticks in a rural settlement of southern Brazil. AB - The aims of the present study were to serosurvey dogs, horses, and humans highly exposed to tick bites for anti-Borrelia burgdorferi s.l. antibodies, identify tick species present, and determine risk factors associated with seropositivity in a rural settlement of Parana State, southern Brazil. Eighty-seven residents were sampled, along with their 83 dogs and 18 horses, and individual questionnaires were administered. Immunofluorescence antibody test (IFAT) was performed on serum samples and positive samples were subjected to western blot (WB) analysis. Anti-B. burgdorferi antibodies were found in 4/87 (4.6%) humans, 26/83 (31.3%) dogs, and 7/18 (38.9%) horses by IFAT, with 4/4 humans also positive by WB. Ticks identified were mostly from dogs and included 45/67 Rhipicephalus sanguineus, 21/67 Amblyomma ovale, and 1/67 A. cajennense sensu lato. All (34/34) horse ticks were identified as A. cajennense s.l.. No significant association was found when age, gender, or presence of ticks was correlated to seropositivity to Borrelia sp. In conclusion, although anti Borrelia antibodies have been found in dogs, horses and their owners from the rural settlement, the lack of isolation, molecular characterization, absence of competent vectors and the low specificity of the commercial WB kit used herein may have impaired risk factor analysis. PMID- 27982301 TI - Assessment of different Lippia sidoides genotypes regarding their acaricidal activity against Rhipicephalus (Boophilus) microplus. AB - The aim of this study was to select different genotypes of Lippia sidoides with the highest activity against larvae and engorged females of the tick Rhipicephalus (Boophilus) microplus. The germplasms studied were LSID006, LSID102, LSID103 and LSID104. The LSID104 genotype, that presented carvacrol as a major constituent, was the germplasm with the worst larvicide effect (LC50 2.99 mg/mL). The LSID006 genotype was the least effective against engorged females (LC50 12.46 mg/mL), and it was chemically similar to the LSID102 genotype, which presented the highest acaricide activity (LC50 2.81 mg/mL). We conclude that chemical similarity of the germplasms was not correlated with acaricide activity against R. (B.) microplus. The essential oil of L. sidoides is a potent natural agent. However, the findings of this work provide a better understanding for product development based on this natural product, which must consider synergic effects or the action of minor compounds. PMID- 27982302 TI - Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets. AB - The main challenge in the control of malaria has been the emergence of drug resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC) were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol). The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2) and a human cell line (WI 26VA4). Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 uM) and inactive against WI-26VA4 (IC50 > 200 uM). Further ligand optimisation cycles generated new prospects for docking and biological assays. PMID- 27982303 TI - Genetic diversity of Leptospira in northwestern Colombia: first report of Leptospira santarosai as a recognised leptospirosis agent. AB - The region of Antioquia in northeastern Colombia has the highest number of reported leptospirosis cases in the country. It also shows high seroprevalence indexes in the general population and socio-environmental conditions favourable for the transmission of the disease between humans and animals. In this study, 25 Leptospira isolates from Colombia's Antioquia department were identified to the species level as L. santarosai (12), L. interrogans (9) and L. meyeri (4) using phylogenetic analysis of the Amidohydrolase gene. Typing at the serovar level was performed using multilocus sequence typing (MLST) and monoclonal antibodies. The serovars Canalzonae, Babudieri, Alice, Beye, and Copenhageni have been identified as causing human or animal infections in Antioquia, Colombia. The four environmental isolates were not identified to the serovar level. L. santarosai serovar Canalzonae and Alice were identified as new etiologic agents of human leptospirosis in Antioquia, Colombia. This paper reports species and serovars that were previously unknown in the region. PMID- 27982305 TI - A glance at the non-technical skills of nurses: simulation contributions. PMID- 27982304 TI - Anopheles fauna of coastal Cayenne, French Guiana: modelling and mapping of species presence using remotely sensed land cover data. AB - Little is known about the Anopheles species of the coastal areas of French Guiana, or their spatiotemporal distribution or environmental determinants. The present study aimed to (1) document the distribution of Anopheles fauna in the coastal area around Cayenne, and (2) investigate the use of remotely sensed land cover data as proxies of Anopheles presence. To characterise the Anopheles fauna, we combined the findings of two entomological surveys that were conducted during the period 2007-2009 and in 2014 at 37 sites. Satellite imagery data were processed to extract land cover variables potentially related to Anopheles ecology. Based on these data, a methodology was formed to estimate a statistical predictive model of the spatial-seasonal variations in the presence of Anopheles in the Cayenne region. Two Anopheles species, known as main malaria vectors in South America, were identified, including the more dominant An. aquasalis near town and rural sites, and An. darlingi only found in inland sites. Furthermore, a cross-validated model of An. aquasalis presence that integrated marsh and forest surface area was extrapolated to generate predictive maps. The present study supports the use of satellite imagery by health authorities for the surveillance of malaria vectors and planning of control strategies. PMID- 27982308 TI - Challenges for sustainability of the open access model: Brazilian health journals. PMID- 27982307 TI - Validation of an instrument for evaluating health care services to ostomized people. AB - Objectives: to develop and validate an array of analysis and judgment for the evaluation of Health Care Services of people with stomas. Methods: cross sectional study in 28 health facilities in the state of Minas Gerais. A descriptive analysis of the instrument and a study of its psychometric properties were performed. We used the Delphi technique for the validation of content and appearance. A psychometric analysis was carried out through the study of the reliability and validity of the measures obtained with the instrument. Results: it was possible to construct an array analysis and judgment with 16 components (with scores from zero to five) grouped according to size and structure and process considered essential to evaluate the service. The results achieved in the reliability for structure and process, through the Cronbach alpha coefficient (alpha = 0.771 and alpha = 0.809, respectively), and the validity of content and construct demonstrated good internal consistency and satisfactory validity. An exploratory factor analysis indicated the item "main activity performed in the unit" as a limitation of the scale. Conclusion: the study provides a new tool for the evaluation of structure and process of Health Care Services of a Person with a stoma. PMID- 27982306 TI - Epinephrine in cardiac arrest: systematic review and meta-analysis. AB - Objective: evaluate the effectiveness of epinephrine used during cardiac arrest and its effect on the survival rates and neurological condition. Method: systematic review of scientific literature with meta-analysis, using a random effects model. The following databases were used to research clinical trials and observational studies: Medline, Embase and Cochrane, from 2005 to 2015. Results: when the Return of Spontaneous Circulation (ROSC) with administration of epinephrine was compared with ROSC without administration, increased rates were found with administration (OR 2.02. 95% CI 1.49 to 2.75; I2 = 95%). Meta-analysis showed an increase in survival to discharge or 30 days after administration of epinephrine (OR 1.23; 95% IC 1.05-1.44; I2=83%). Stratification by shockable and non-shockable rhythms showed an increase in survival for non-shockable rhythm (OR 1.52; 95% IC 1.29-1.78; I2=42%). When compared with delayed administration, the administration of epinephrine within 10 minutes showed an increased survival rate (OR 2.03; 95% IC 1.77-2.32; I2=0%). Conclusion: administration of epinephrine appears to increase the rate of ROSC, but when compared with other therapies, no positive effect was found on survival rates of patients with favorable neurological status. PMID- 27982309 TI - Experiences and coping with the altered body image in digestive stoma patients. AB - Objective: to describe the coping of stoma patients with the news about the ostomy, as well as to analyze the meaning and the experience of their new bodily reality. Method: qualitative phenomenological study undertaken through semistructured interviews with 21 stoma patients. The analysis was based on the constant comparison of the data, the progressive incorporation of subjects and triangulation among researchers and stomal therapy nurses. The software Atlas.ti was used. Results: two main categories emerge: "Coping with the news about receiving a stoma" and "Meaning and experience of the new bodily reality". The informants' answer varies, showing situations that range from the natural acceptance of the process to resignation and rejection. The previous experiences of other family members, the possible reconstruction of the stoma or the type of illness act as conditioning factors. Conclusions: the coping with the news about the stoma is conditioned by the type of illness, although the normalization of the process is the trend observed in most informants. Nursing plays a fundamental role in the implementation of cognitive-behavioral interventions and other resources to promote the patients' autonomy in everything related to care for the stoma. PMID- 27982310 TI - Correlation between classification in risk categories and clinical aspects and outcomes. AB - Objective: to correlate classification in risk categories with the clinical profiles, outcomes and origins of patients. Method: analytical cross-sectional study conducted with 697 medical forms of adult patients. The variables included: age, sex, origin, signs and symptoms, exams, personal antecedents, classification in risk categories, medical specialties, and outcome. The Chi-square and likelihood ratio tests were used to associate classifications in risk categories with origin, signs and symptoms, exams, personal antecedents, medical specialty, and outcome. Results: most patients were women with an average age of 44.5 years. Pain and dyspnea were the symptoms most frequently reported while hypertension and diabetes mellitus were the most common comorbidities. Classifications in the green and yellow categories were the most frequent and hospital discharge the most common outcome. Patients classified in the red category presented the highest percentage of ambulance origin due to surgical reasons. Those classified in the orange and red categories also presented the highest percentage of hospitalization and death. Conclusion: correlation between clinical aspects and outcomes indicate there is a relationship between the complexity of components in the categories with greater severity, evidenced by the highest percentage of hospitalization and death. PMID- 27982311 TI - Nursing interventions in monitoring the adolescent with Cystic Fibrosis: a literature review. AB - Objectives: to search for nursing interventions focused on the improvement of quality of life and promotion of self-care of adolescents suffering from the Cystic Fibrosis. Method: literature review. The inclusion criteria were: primary studies and studies with interventions developed by nurses in the adolescent population with Cystic Fibrosis, using Portuguese, Spanish, French and English with no time limit, and supported by the databases Scopus, Web of Science and CINAHL. The search expressions were: nursing AND care AND adolescent AND "Cystic Fibrosis" AND ("quality of life" OR "self-care"). Results: a total of 59 articles was retrieved; 8 matched the criteria chosen. Nursing interventions targeted at adolescents with Cystic Fibrosis and their family members were identified. These interventions were organized according to the nurses' role, namely caregiver, coordinator, counsellor, researcher, trainer and care partner. Conclusions: nursing interventions targeted at following up the adolescent during the entire therapeutic process, involving the presence of parents/significant others, since both the adolescent and family have to be responsible for self-care. Healthcare professionals should be capable of identifying the specific needs of patients with chronic disease and their family, permitting a better understanding and adaptation to the health-disease transition process. PMID- 27982312 TI - Repercussions of imprisonment for conjugal violence: discourses of men. AB - Objective: to know the consequences that men experience related to incarceration by conjugal violence. Methods: qualitative study on 20 men in jail and indicted in criminal processes related to conjugal violence in a Court specialized in Family and Domestic Violence against women. The interviews were classified based on Collective Subject Discourse method, using NVIVO(r) software. Results: the collective discourse shows that the experience of preventive imprisonment starts a process of family dismantling, social stigma, financial hardship and psycho emotional symptoms such as phobia, depression, hypertension, and headaches. Conclusion: due to the physical, mental and social consequences of the conjugal violence-related imprisonment experience, it is urgent to look carefully into the somatization process as well as to the prevention strategies regarding this process. PMID- 27982313 TI - Hodgkin's Lymphoma - evaluation of patients submitted to Autologous transplantation of hematopoietic cells in the Hematology Service of the Hospital Walter Cantidio - Fortaleza, Brazil. AB - The Autologous HSCT is an important alternative for refractory or recurrent HL patients in terms of survival and improved quality of life. This study analyzes the results of autologous BMT performed in HL patients in the Transplant Unit of the HUWC/ HEMOCE (Fortaleza - CE, Brazil). Fifty-two transplanted patients were studied from January 2009 to October 2015, among them, 30 men and 22 women, mean age of 28.2 years. All of them received GCS-F during the mobilization, in some cases associated with Vinorelbine or Plerixafor, with CD34 collection averaging 4.8 CD34/kg. The conditioning was performed with BEAC, NEAM or BEAM and the grafting with an average of 10 days. The evaluation on D + 100 showed: CR - 42 (82.7%), PR - 08 (13.5%) and 02 (3.8%) deaths, three and six days after cell infusion. After the D+100, 08 patients in CR showed HL recurrence from 06 to 36 months; 03 died and 05 are being treated with brentuximab; among the 08 patients in PR, 01 died due to HL activity, 04 months after BMT and 07 patients are undergoing treatment. The final evaluation of HL transplant patients showed an OS of 88.5% and a DFS of 61.5% in 6 years, with OS of the chemosensitive patients of 81% and of the chemoresistant ones, of 72.6%. It is possible to conclude that the Autologous HSCT has shown to be an excellent rescue therapy regarding tolerance, as well as the overall survival. PMID- 27982314 TI - Immunotherapy with natural killer cells: a possible approach for the treatment of Acute Myeloid Leukemia also in Brazil. AB - The allogeneic hematopoietic stem cell transplantation (HSCT) can cure intermediate and high-risk acute myeloid leukemia. Even with the development of strategies to reduce HSCT toxicity, this is still a complex treatment with high morbidity and mortality. Knowledge of the graft versus leukemia effect of HSCT has prepared the way for the development of Adoptive Immunotherapy or in vitro expansion of activated lymphocytes without alloreactivity, with subsequent intravenous infusion. The infusion of genetically modified T lymphocytes and haploidentical natural killer cells has been tested as an alternative to HSCT with very interesting results worldwide and in Brazil, as we not only have the technology of in vitro expansion of clinical grade lymphocytes available, but also do it according to the Good Manufacturing Practices that have been determined internationally. PMID- 27982315 TI - Haploidentical transplantation of hematopoietic stem cells. AB - OBJECTIVE: To review and discuss the literature on hematopoietic stem cell transplantation (HSCT) with haploidentical donors in Brazil. METHOD: Literature review. RESULTS: The haploidentical hematopoietic stem cell transplantations have become a safe option in hematology since the 80s, with the possibility of ex-vivo T-cell depletion. However, its broad use worldwide occurred with the advent of haploidentical nonmyeloablative transplants using in vivo T-cell depletion with the administration of post-transplant cyclophosphamide. The results were encouraging, despite the increased risk of infection and post-transplantation recurrence. Recent publications on acute myeloid leukemia, myelodysplastic syndrome and Hodgkin's lymphoma have shown similar results among haploidentical, unrelated and related full-match transplants. Obviously, these findings of retrospective studies should be confirmed by clinical trials. CONCLUSIONS: Transplantation with haploidentical donor has shown to be feasible in Brazil and the first publications and results are showing encouraging results. PMID- 27982316 TI - Mobilization of hematopoietic progenitor cells for autologous transportation: consensus recommendations. AB - Selected patients with certain hematological malignancies and solid tumors have the potential to achieve long-term survival with autologous hematopoietic progenitor cell transplant. The collection of these cells in peripheral blood avoids multiple bone marrow aspirations, results in faster engraftment and allows treatment of patients with infection, fibrosis, or bone marrow hypocellularity. However, for the procedure to be successful, it is essential to mobilize a sufficient number of progenitor cells from the bone marrow into the blood circulation. Therefore, a group of Brazilian experts met in order to develop recommendations for mobilization strategies adapted to the reality of the Brazilian national health system, which could help minimize the risk of failure, reduce toxicity and improve the allocation of financial resources. PMID- 27982317 TI - Relevance of prognostic factors in the decision-making of stem cell transplantation in Myelodysplastic Syndromes. AB - The hematopoietic stem cell transplantation (HSCT) is the only curative alternative for Myelodysplastic Syndrome (MDS), but many patients are not eligible for this treatment, as there are several limiting factors, especially in the case of patients with low-risk MDS. The aim of this study is to discuss the factors that can guide the decision-making on referring or not a patient to HSCT. Three cases of MDS, two of which were submitted to HSCT are presented. We intend to report the difficulties in referring patients with MDS to transplant and the prognostic factors that contribute to define eligibility. PMID- 27982318 TI - Association of oxidative stress and DNA damage with grafting time in patients with multiple myeloma and lymphoma submitted to autologous hematopoietic stem cell transplantation. AB - The aim of the study was to investigate the association between oxidative stress and DNA damage with grafting time in patients submitted to autologous hematopoietic stem-cell transplantation (HSCT). The study included 37 patients submitted to autologous HSCT diagnosed with Multiple Myeloma (MM) and lymphoma (Hodgkin's and non-Hodgkin's). Biomarkers of oxidative stress and DNA damage index (DI) were performed at baseline (pre-CR) of the disease and during the conditioning regimen (CR), one day after the HSCT, ten days after HSCT and twenty days after HSCT, as well as in the control group consisting of 30 healthy individuals. The outcomes showed that both groups of patients had an hyperoxidative state with high DI when compared to baseline and to the control group and that the CR exacerbated this condition. However, after the follow-up period of the study, this picture was re-established to the baseline levels of each pathology. The study patients with MM showed a mean grafting time of 10.75 days (8 to 13 days), with 10.15 days (8 to 15 days) for the lymphoma patients. In patients with MM, there was a negative correlation between the grafting time and the basal levels of GPx (r = -0.54; p = 0.034), indicating that lower levels of this important enzyme are associated with a longer grafting time. For the DI, the correlation was a positive one (r = 0.529; p = 0.030). In the group with lymphoma, it was observed that the basal levels of NOx were positively correlated with grafting time (r = 0.4664, p = 0.032). The data indicate the potential of these biomarkers as predictors of toxicity and grafting time in patients with MM and Lymphomas submitted to autologous HSCT. PMID- 27982319 TI - Acute and chronic Graft-versus-host disease after hematopoietic stem cell transplantation. AB - graft-versus-host disease (GVHD) is one of the main complications of hematopoietic stem cell transplantation, affecting about 50% to 80% of the patients. Acute GVHD and its clinical manifestations are discussed in this article, as well as the new NIH criteria for the diagnosis and classification of chronic GVHD. Therapy for both chronic and acute GVHD is an important field of discussion, as there is no proven superiority for the majority of therapies used after primary treatment has failed. Hence, this review is meant to be a useful consultation tool for hematologists dealing with this complex transplantation procedure complication. PMID- 27982320 TI - Allogenic bone narrow transplantation in sickle-cell diseases. AB - Sickle-cell diseases are the most common inherited hemoglobinopathies worldwide. Improvement in survival has been seen in the last decades with the introduction of careful screening and prevention of complications and the introduction of hydroxyurea. Stem-cell transplantation is currently the only curative option for these patients and has been indicated for patients with neurological events, repeated vaso-occlusive crisis, any organ damage or presence of red blood cell antibodies. Related bone-marrow or cord-blood transplant has shown an overall survival of more than 90% with a disease-free survival of 90% in 1,000 patients transplanted in the last decades. The use of unrelated donors unfortunately has not shown the same good results, but better typing methods and improved support may improve the outcome with this source of stem cells in the future. In Brazil, only recently stem cell transplant from related donors has been included in the procedures performed in the public health system. The use of related bone marrow or cord blood and a myeloablative conditioning regimen are considered standard of care for patients with sickle-cell diseases. Transplants with non-myeloablative regimens, unrelated donors or haploidentical donors should be performed only in controlled clinical trials. PMID- 27982321 TI - Visceral artery aneurysms. PMID- 27982322 TI - Reflections on the open abdomen. PMID- 27982323 TI - Burnout Syndrome prevalence of on-call surgeons in a trauma reference hospital and its correlation with weekly workload: cross-sectional study. AB - Objective:: to determine the prevalence of Burnout Syndrome (BS) for surgeons working in referral hospital for trauma in Maceio and to evaluate the possible correlation between BS and weekly workload. Methods:: cross-sectional study with 43 on-call surgeons at Professor Osvaldo Brandao Vilela General State Hospital, Maceio, between July and December, 2015. A self-administered form was used to evaluate BS through the Maslach Burnout Inventory (MBI) and socio-demographic characteristics among participants. Spearman's S test was used to compare BS and weekly workload. Significant level was 5%. Results:: among the surgeons studied, 95.35% were male and the mean age was 43.9 +/- 8.95 years. The mean weekly workload on call in trauma was 33.90 +/- 16.82 hours. The frequency of high scores in at least one of the three dimensions of MBI was 46.5%. Professional achievement was correlated with weekly workload (P = 0.020). Conclusion:: the prevalence of Burnout Syndrome among on-call surgeons in referral hospital for trauma was 46.5%. In this sample there was correlation between weekly workload and the Burnout Syndrome. Objetivo:: determinar a prevalencia da Sindrome de Burnout (SB) em medicos cirurgioes que trabalham em hospital de referencia para o trauma em Maceio e avaliar a possivel correlacao entre SB e a carga horaria semanal de trabalho. Metodos:: estudo transversal com 43 cirurgioes de plantao do Hospital Geral do Estado Professor Osvaldo Brandao Vilela, Maceio, entre julho e dezembro de 2015. Um formulario autoadministrado foi utilizado para avaliar SB por meio do Maslach Burnout Inventory (MBI) e as caracteristicas sociodemograficas entre os participantes. Foi utilizado o teste de Spearman S para comparar SB e carga horaria semanal. O nivel de significancia foi 5%. Resultados:: entre os cirurgioes estudados, 95,35% eram do sexo masculino e a media de idade foi 43,9+/-8,95 anos. A media da carga horaria semanal de plantao no trauma foi 33,90+/-16,82 horas. A frequencia de pontuacoes elevadas em pelo menos uma das tres dimensoes do MBI foi 46,5%. Realizacao profissional foi correlacionada com a carga de trabalho semanal (P=0,020). Conclusao:: a prevalencia da Sindrome de Burnout entre cirurgioes plantonistas em hospital de referencia para o trauma foi 46,5%. Nesta amostra houve correlacao entre a carga horaria semanal de trabalho e a Sindrome de Burnout. PMID- 27982324 TI - Pediatric vascular trauma in Manaus, Amazon - Brazil. AB - Objective:: to assess the incidence of pediatric vascular injuries in patients treated at the Emergency Room of the Eastern Children's Hospital, in Manaus. Methods:: we conducted a retrospective study of pediatric patients who suffered vascular injuries treated between February 2001 to February 2012. Results:: we studied 71 patients, predominantly male (78.87%), with a mean age of 7.63 years. The predominant mechanism of injury was stab wound in 27 patients (38.03%). The average hospital stay was 10.18 days; 16 patients required care in intensive care unit, with average stay of 8.81 days. The main injuries occurred in the extremities, the upper limb being the most affected, with lesions of the ulnar artery in 13 (15.66%) and radial in 10 (12.04%). The mostly applied procedure was vascular exploration 35 (32.4%). Complications occurred in nine patients (12.68%). Mortality was 1.4%, in one patient with a lesion of the common iliac vein and the inferior vena cava due fall from height. Conclusion:: pediatric vascular injury occurred predominantly in the extremities. The dimensions of the injured vessels made surgical correction more complex and increased complication rates, particularly amputations. Objetivo:: avaliar a incidencia de traumatismos vasculares pediatricos em doentes atendidos no Hospital Pronto Socorro da Crianca Zona Leste, na cidade de Manaus. Metodos:: estudo retrospectivo de doentes pediatricos vitimas de traumatismos vasculares atendidos no periodo de fevereiro de 2001 a fevereiro de 2012. Resultados:: foram estudados 71 doentes com predominancia do sexo masculino (78,87%) com media de idade de 7,63 anos. O mecanismo de trauma predominante foi o ferimento por arma branca em 27 pacientes (38,03%). A media de internacao foi 10,18 dias, com 16 doentes necessitando de cuidados em unidade de tratamento intensivo com permanencia media de 8,81 dias. As principais lesoes ocorreram em extremidades, com predominio do membro superior, com lesoes das arterias ulnar em 13 (15,66%) e radial em dez (12,04%). O procedimento mais utilizado foi a exploracao vascular 35 (32,4%). Em nove doentes (12,68%) ocorreram complicacoes. A mortalidade foi 1,4%, em um paciente com lesao da veia iliaca comum e da veia cava inferior, devido a queda de altura. Conclusao:: o traumatismo vascular pediatrico ocorreu predominantemente em extremidades. As dimensoes dos vasos lesionados tornaram a correcao cirurgica mais complexa e aumentaram os indices de complicacoes, particularmente, de amputacoes. PMID- 27982326 TI - Analysis of the Revised Trauma Score (RTS) in 200 victims of different trauma mechanisms. AB - Objective:: to analyze the epidemiological profile and mortality associated with the Revised Trauma Score (RTS) in trauma victims treated at a university hospital. Methods:: we conducted a descriptive, cross-sectional study of trauma protocols (prospectively collected) from December 2013 to February 2014, including trauma victims admitted in the emergency room of the Cajuru University Hospital. We set up three groups: (G1) penetrating trauma to the abdomen and chest, (G2) blunt trauma to the abdomen and chest, and (G3) traumatic brain injury. The variables we analyzed were: gender, age, day of week, mechanism of injury, type of transportation, RTS, hospitalization time and mortality. Results:: we analyzed 200 patients, with a mean age of 36.42 +/- 17.63 years, and 73.5% were male. The mean age was significantly lower in G1 than in the other groups (p <0.001). Most (40%) of the visits occurred on weekends and the most common pre-hospital transport service (58%) was the SIATE (Emergency Trauma Care Integrated Service). The hospital stay was significantly higher in G1 compared with the other groups (p <0.01). Regarding mortality, there were 12%, 1.35% and 3.95% of deaths in G1, G2 and G3, respectively. The median RTS among the deaths was 5.49, 7.84 and 1.16, respectively, for the three groups. Conclusion:: the majority of patients were young men. RTS was effective in predicting mortality in traumatic brain injury, however failing to predict it in patients suffering from blunt and penetrating trauma. Objetivo: : analisar o perfil epidemiologico e a mortalidade associada ao escore de trauma revisado (RTS) em vitimas de trauma atendidas em um hospital universitario. Metodos: : estudo transversal descritivo de protocolos de trauma (coletados prospectivamente) de dezembro de 2013 a fevereiro de 2014, incluindo vitimas de trauma admitidas na sala de emergencia do Hospital Universitario Cajuru. Tres grupos foram criados: (G1) trauma penetrante em abdome e torax, (G2) trauma contuso em abdome e torax, e (G3) trauma cranioencefalico. As variaveis analisadas foram: sexo, idade, dia da semana, mecanismo de trauma, tipo de transporte, RTS, tempo de internamento e mortalidade. Resultados: : analisou-se 200 pacientes, com media de idade de 36,42 +/- 17,63 anos, sendo 73,5% do sexo masculino. A media de idade no G1 foi significativamente menor do que nos demais grupos (p <0,001). A maioria (40%) dos atendimentos ocorreu nos finais de semana e o servico de transporte pre hospitalar mais frequente (58%) foi o SIATE (Servico Integrado de Atendimento ao Trauma em Emergencia). O tempo de internamento foi significativamente maior no G1, em comparacao aos demais grupos (p <0,01). Quanto a mortalidade, houve 12%, 1,35% e 3,95% de obitos nos grupos G1, G2 e G3, respectivamente. A mediana do RTS entre os obitos foi 5,49, 7,84 e 1,16, respectivamente, para os tres grupos. Conclusao:: a maioria dos pacientes eram homens jovens. O RTS mostrou-se efetivo na predicao de mortalidade no trauma cranioencefalico, entretanto falhou ao analisar pacientes vitimas de trauma contuso e penetrante. PMID- 27982327 TI - Profile of renal trauma victims treated at a university hospital in Curitiba. AB - Objective:: to study the profile of victims of kidney trauma who underwent surgical and medical treatment in a hospital in Curitiba. Methods:: we conducted a retrospective, analytical, quantitative, cross-sectional study of patients with renal trauma admitted to the Evangelical Hospital of Curitiba between February 2011 and January 2014. Results:: participated in the study 38 patients, four women and 34, men with a mean age of 28.4 years. Most injuries (60.5%) was due to closed mechanisms, especially motorcycle accidents. Injuries were treated conservatively in most cases. Patients who required surgical treatment had severe kidney damage or some other associated lesion, usually intra-abdominal. Hospital stay was lower in the conservative treatment group (10.8 days) compared with the surgical treatment one (18.8 days); mortality was also lower in the conservative treatment group (8.3%) compared with the surgical (14.3%). There were no deaths associated to kidney damage itself. Conclusion:: patients with renal trauma in this study were young men, victims of motorcycle accidents, taking place during the night and early morning. Most injuries were treated conservatively. Objetivo:: estudar o perfil das vitimas de traumas renais submetidos a tratamento cirurgico e clinico em um hospital de Curitiba. Metodos:: estudo transversal quantitativo analitico retrospectivo de pacientes com trauma renal admitidos no Hospital Universitario Evangelico de Curitiba entre fevereiro de 2011 e janeiro de 2014. Resultados:: fizeram parte do estudo 38 pacientes, sendo quatro mulheres e 34 homens, com media de idade de 28,4 anos. A maior parte dos traumas (60,5%) foi decorrente de mecanismo fechado, em especial acidentes automobilisticos envolvendo motos, tratados de maneira conservadora na maior parte dos casos. Os pacientes que necessitaram de tratamento cirurgico possuiam lesoes renais graves ou alguma outra lesao associada, geralmente intra-abdominal. O tempo de internamento foi menor no grupo de tratamento conservador (10,8 dias) em relacao ao grupo de tratamento cirurgico (18,8 dias), assim como a mortalidade tambem foi menor no grupo de tratamento conservador (8,3%) comparada ao cirurgico (14,3%). Nenhuma morte foi relacionada a lesao renal em si. Conclusao:: os pacientes com traumatismo renal neste estudo foram homens jovens, vitimas de acidentes automobilisticos com motos, ocorrendo durante a noite e madrugada. A maioria das lesoes foi tratada de modo conservador. PMID- 27982325 TI - The deceptive concept of hypoparathyroidism and recurrence after parathyroidectomy in dialysis patients: are we offering a Procrustean bed to some patients? AB - Objective:: to analyze the frequency of hypoparathyroidism and of its recurrence after parathyroidectomy in dialysis patients according to different existing classifications. Methods:: we conducted a retrospective study of 107 consecutive dialysis patients undergoing total parathyroidectomy with immediate autograft in a tertiary hospital from 2006 to 2010. We studied the changes in PTH levels in the postoperative period over time. Were grouped patients according to different PTH levels targets recommended according to the dosage method and by the American and Japanese Nephrology Societies, and by an International Experts Consortium. Results:: after parathyroidectomy, there was sustained reduction in serum calcium and phosphatemia. The median value of PTH decreased from 1904pg/ml to 55pg/ml in 12 months. Depending on the considered target level, the proportion of patients below the target ranged between 17% and 87%. On the other hand, the proportion of patients with levels above the target ranged from 3% to 37%. Conclusion:: the application of different recommendations for PTH levels after parathyroidectomy in dialysis patients may lead to incorrect classifications of hypoparathyroidism or recurrent hyperparathyroidism and resultin discordant therapeutic conducts. Objetivo:: analisar as frequencias de hipoparatireoidismo e de recidiva do hiperparatireoidismo apos paratireoidectomia em pacientes dialiticos de acordo com diferentes classificacoes existentes. Metodos:: estudo retrospectivo de 107 pacientes dialiticos consecutivamente submetidos a paratireoidectomia total com autoenxerto imediato em um hospital terciario no periodo de 2006 a 2010. A variacao dos niveis de PTH no pos-operatorio foi estudada ao longo do tempo. Os pacientes foram agrupados de acordo com diferentes metas de niveis de PTH recomendados de acordo com o metodo de dosagem e pelas sociedades de nefrologia americana, japonesa e de um consorcio internacional de especialistas. Resultados:: apos a paratireoidectomia, houve reducao sustentada da calcemia e fosfatemia. O valor mediano do PTH reduziu-se de 1904pg/ml para 55pg/ml, em 12 meses. Dependendo do nivel alvo considerado, a proporcao de pacientes abaixo da meta variou entre 17% e 87%. Ao contrario, a proporcao de pacientes com niveis acima da meta variou de 3% a 37%. Conclusao:: O emprego de diferentes recomendacoes de niveis de PTH em pacientes dialiticos apos paratireoidectomia pode levar a classificacoes incorretas de hipoparatireoidismo ou hiperparatireoidismo recidivado e implicar em condutas terapeuticas discordantes. PMID- 27982329 TI - Relationship between anxiety, depression and quality of life with the intensity of reflex sweating after thoracoscopic sympathectomy for treatment of primary hyperhidrosis. AB - Objective:: to compare the intensity of reflex sweating with the degree of anxiety and its interference in the quality of life of patients undergoing Thoracoscopic (VATS) sympathectomy in the pre- and postoperative period. Methods:: we evaluated 54 patients with a mean age of 26 years (16-49 years) undergoing sympathectomy in the R3-R4 level. We applied two questionnaires at three different times: "Quality of life in patients with primary hyperhidrosis" and "Scale for anxiety and depression". Results:: of the patients studied, 93% showed significant improvement in quality of life 30 days after surgery, the effects remaining after six months. There were no postoperative complications. The patient's level of anxiety is highly correlated with the intensity of reflex sweating after 30 and 180 days. Conclusion:: Thoracoscopic sympathectomy improves quality of life of patients with primary hyperhidrosis, even with the emergence of reflex sweating. Anxiety directly relates to the intensity of reflex sweating, without compromising the degree of patient satisfaction. Objetivo:: avaliar a intensidade de sudorese reflexa com o grau de ansiedade e sua interferencia na qualidade de vida de individuos submetidos a simpatectomia por videotoracoscopia nos periodos pre e pos-operatorio. Metodos:: foram avaliados 54 pacientes com media de idade de 26 anos (16 a 49 anos), submetidos a simpatectomia em nivel R3 R4. Dois questionarios foram aplicados em tres momentos diferentes: "Qualidade de vida em pacientes com hiperidrose primaria e "Escala para ansiedade e depressao". Resultados:: dos pacientes estudados, 93% mostrou melhora significativa na qualidade de vida apos 30 dias da cirurgia, com os efeitos remanescentes apos seis meses. Nao houve complicacoes pos-operatorias. A analise mostrou que o nivel de ansiedade do paciente e altamente correlacionado com a intensidade da sudorese reflexa apos 30 e 180 dias. Conclusao:: a simpatectomia toracica por videotoracoscopia melhora a qualidade de vida de pacientes com hiperidrose primaria, mesmo com o surgimento de sudorese reflexa. A ansiedade esta diretamente relacionada com a intensidade da sudorese reflexa, sem comprometer o grau de satisfacao do paciente. PMID- 27982328 TI - Kidney ischemia and reperfunsion syndrome: effect of lidocaine and local postconditioning. AB - Objective:: to evaluate the effects of blocking the regulation of vascular tone on the ischemia and reperfusion syndrome in rats through the use of lidocaine in the postconditioning technique. Methods:: we randomized 35 rats into seven groups of five animals: Group 1- Control; Group 2- Ischemia and Reperfusion; Group 3- Ischemia, Reperfusion and Saline; Group 4- Ischemic Postconditioning; Group 5- Ischemic Postconditioning and Saline; Group 6- Lidocaine; Group 7- Ischemic Postconditioning and Lidocaine. Except for the control group, all the others were submitted to renal ischemia for 30 minutes. In postconditioning groups, we performed ischemia and reperfusion cycles of five minutes each, applied right after the main ischemia. In saline and lidocaine groups, we instilled the substances at a rate of two drops per minute. To compare the groups, we measured serum levels of urea and creatinine and also held renal histopathology. Results:: The postconditioning and postconditioning + lidocaine groups showed a decrease in urea and creatinine values. The lidocaine group showed only a reduction in creatinine values. In histopathology, only the groups submitted to ischemic postconditioning had decreased degree of tubular necrosis. Conclusion:: Lidocaine did not block the effects of postconditioning on renal ischemia reperfusion syndrome, and conferred better glomerular protection when applied in conjunction with ischemic postconditioning. Objetivo:: avaliar os efeitos do bloqueio da regulacao do tonus vascular por meio do uso da lidocaina na tecnica de pos condicionamento isquemico na sindrome de isquemia e reperfusao renal em ratos. Metodos:: trinta e cinco ratos foram randomizados em sete grupos de cinco animais: Grupo 1- Controle; Grupo 2- Isquemia e Reperfusao; Grupo 3- Isquemia, Reperfusao e Solucao Salina; Grupo 4- Pos-condicionamento Isquemico; Grupo 5- Pos condicionamento Isquemico e Solucao Salina; Grupo 6- Lidocaina; Grupo 7- Pos condicionamento Isquemico e lidocaina. Com excecao do grupo controle, todos os demais foram submetidos a isquemia renal de 30 minutos. Nos grupos de pos condicionamento, foi realizado o ciclo de isquemia e reperfusao de cinco minutos cada, aplicado logo apos a isquemia principal. Nos grupos salina e lidocaina foram instiladas as substancias numa taxa de duas gotas por minuto. Para comparar os grupos, foram dosados os niveis sericos de ureia e creatinina e analise histopatologica renal. Resultados:: os grupos pos-condicionamento e pos condicionamento + lidocaina apresentaram uma reducao nos valores de ureia e creatinina. O grupo lidocaina apresentou apenas uma reducao nos valores de creatinina. Na analise histopatologica, apenas os grupos submetidos ao pos condicionamento isquemico apresentaram reducao do grau de necrose tubular. Conclusao:: a lidocaina nao bloqueou os efeitos do pos-condicionamento na sindrome de isquemia e reperfusao renal, mas conferiu melhor na protecao glomerular quando aplicada em conjunto com o pos-condicionamento isquemico. PMID- 27982330 TI - Bariatric surgery: is it reasonable before the age of 16? AB - Objective:: to assess the severity of obesity in children and adolescents through the presence of comorbidities and the potential indication of bariatric surgery. Methods:: we conducted a cross-sectional study with clinical and laboratory data of the first consultation of patients at the childhood obesity clinic at a tertiary hospital from 2005 to 2013. We divided the patients into groups with or without potential indication for surgery, and recorded age, gender, birth weight, age of obesity onset, BMI Z score, presence of acanthosis nigricans, blood pressure, total cholesterol and fractions, triglycerides, blood glucose and fasting insulin, HOMA1-IR, CRP and ESR. The group with potential indication for surgery included: BMI > 40 or between 35-40 with comorbidities (Triglycerides >130mg/dl, glucose levels >100mg/dl, HOMA1-IR >3.16, Total Cholesterol >200mg/dl, LDL >130mg/dl and HDL <45mg/dl), regardless of age, epiphysis consolidation and previous treatment. Results:: of the 296 patients included in the study, 282 (95.3%) were younger than 16 years. The most frequent change was the HDL (63.2%), followed by HOMA1-IR (37.5%). Of the group of 66 patients with potential indication for surgery (22.3%), only ten (15.1%) had more than 16 years. Acanthosis nigricans, the average HOMA1-IR, insulin, CRP, ESR, age, BMI Z score and systolic and diastolic blood pressure were significant in the group with potential surgical indication. Conclusion:: bariatric surgery might be indicated by BMI and comorbidities in children and adolescents under 16 years. Objetivo: : avaliar a gravidade da obesidade em criancas e adolescentes pela presenca de comorbidades e pela potencial indicacao de cirurgia bariatrica. Metodos: : estudo transversal com dados clinicos e laboratoriais da primeira consulta de pacientes do ambulatorio de obesidade infantil em um hospital terciario no periodo de 2005 a 2013. Os pacientes foram divididos em grupos com ou sem potencial indicacao cirurgica, e associados com idade, sexo, peso de nascimento, idade de inicio da obesidade, escore z de IMC, presenca de acantose nigricans, pressao arterial, colesterol total e fracoes, triglicerides, glicemia e insulina de jejum, HOMA1 IR, PCR e VHS. O grupo com potencial indicacao cirurgica incluiu: IMC >40 ou IMC entre 35-40 com comorbidades (Triglicerides >130mg/dl, Glicemia >100mg/dl, HOMA1 IR >3,16, Colesterol total >200mg/dl, LDL >130mg/dl e HDL <45mg/dl), independente da idade, consolidacao das epifises e tratamento previo. Resultados:: de 296 pacientes incluidos no estudo, 282 (95,3%) tinham menos de 16 anos. A alteracao mais frequente foi a do HDL (63,2%), seguido do HOMA1-IR (37,5%). Do grupo de 66 pacientes com potencial indicacao cirurgica (22,3%), apenas dez (15,1%) tinham mais de 16 anos. Acantose nigricans, as medias de HOMA1-IR, insulina, PCR, VHS, idade, escore z de IMC e pressoes sistolica e diastolica foram significantes no grupo com potencial indicacao cirurgica. Conclusao: : os resultados sugerem que a cirurgia bariatrica, poderia estar indicada pelo IMC e presenca de comorbidades, em criancas e adolescentes com menos de 16 anos. PMID- 27982332 TI - Thoracic damage control surgery. AB - The damage control surgery came up with the philosophy of applying essential maneuvers to control bleeding and abdominal contamination in trauma patients who are within the limits of their physiological reserves. This concept was extended to thoracic injuries, where relatively simple maneuvers can shorten operative time of in extremis patients. This article aims to revise the various damage control techniques in thoracic organs that must be known to the surgeon engaged in emergency care. RESUMO A cirurgia de controle de danos surgiu com a filosofia de se aplicar manobras essenciais para controle de sangramento e contaminacao abdominal, em doentes traumatizados, nos limites de suas reservas fisiologicas. Este conceito se estendeu para as lesoes toracicas, onde manobras relativamente simples, podem abreviar o tempo operatorio de doentes in extremis. Este artigo tem como objetivo, revisar as diversas tecnicas de controle de dano em orgaos toracicos, que devem ser de conhecimento do cirurgiao que atua na emergencia. PMID- 27982331 TI - Comparative study of abdominal cavity temporary closure techniques for damage control. AB - The damage control surgery, with emphasis on laparostomy, usually results in shrinkage of the aponeurosis and loss of the ability to close the abdominal wall, leading to the formation of ventral incisional hernias. Currently, various techniques offer greater chances of closing the abdominal cavity with less tension. Thus, this study aims to evaluate three temporary closure techniques of the abdominal cavity: the Vacuum-Assisted Closure Therapy - VAC, the Bogota Bag and the Vacuum-pack. We conducted a systematic review of the literature, selecting 28 articles published in the last 20 years. The techniques of the bag Bogota and Vacuum-pack had the advantage of easy access to the material in most centers and low cost, contrary to VAC, which, besides presenting high cost, is not available in most hospitals. On the other hand, the VAC technique was more effective in reducing stress at the edges of lesions, removing stagnant fluids and waste, in addition to acting at the cellular level by increasing proliferation and cell division rates, and showed the highest rates of primary closure of the abdominal cavity. RESUMO A cirurgia de controle de danos, com enfase em peritoneostomia, geralmente resulta em retracao da aponeurose e perda da capacidade de fechar a parede abdominal, levando a formacao de hernias ventrais incisionais. Atualmente, varias tecnicas oferecem maiores chances de fechamento da cavidade abdominal, com menor tensao. Deste modo, este estudo tem por objetivo avaliar tres tecnicas de fechamento temporario da cavidade abdominal: fechamento a vacuo (Vacuum-Assisted Closure Therapy - VAC), Bolsa de Bogota e Vacuum-pack. Realizou-se uma revisao sistematica da literatura com selecao de 28 artigos publicados nos ultimos 20 anos. As tecnicas de Bolsa de Bogota e Vacuum-pack tiveram como vantagem o acesso facil ao material, na maioria dos centros, e baixo custo, ao contrario do que se observa na terapia a vacuo, VAC, que alem de apresentar alto custo, nao esta disponivel em grande parte dos hospitais. A tecnica VAC, por outro lado, foi mais eficaz na reducao da tensao nas bordas das lesoes, ao remover fluidos estagnados e detritos, alem de exercer acao a nivel celular, aumentando as taxas de proliferacao e divisao celular, e apresentou as maiores taxas de fechamento primario da cavidade abdominal. PMID- 27982333 TI - Systematic training model for teaching, development and training of instructors in inguinal hernia treatment using the Lichtenstein technique. Hernia campaign 2014 & 2015. AB - Objective:: to evaluate the method of training and continuing education of 18 surgeons in 2014, and 28 surgeons in 2015, in the Holy Homes of Ribeirao Preto, Araraquara, Franca and San Carlos of Sao Paulo, in the performance of Lichtenstein inguinal herniorrhaphy, tutored by the Faculty of Medical Sciences of the Sao Paulo Holy Home and the organization HERNIA HELP - "Hernia Repair for the Underserved". Methods:: the training was tutored and systematized through an active methodology of teaching and learning, aiming to offer competence, skills and attitudes, measured by a previously validated Qualification Form, qualifying leaders in trainees' improvement. Results:: in 2014 the outcomes were: the difficulty of the case, direction, incision, dissection, mesh preparation, mesh cutting, mesh setting, closing, instruments, respect to tissues, flow, time and motion, and performance, all presented change in the general rating (p=0.000002); there was greater confidence in the execution of the procedure in 80% of trainees, considered "very valuable" in 93.3% of the interventions. In 2015, 28 surgeons were trained by ten surgeons previously qualified in 2014. The nerve identification rate, a relevant time the Lichtenstein technique, was 95.5% for the Iliohypogastric, 98.5% for the ilioinguinal and 89.4% for the genital branch of the genitofemoral nerve. Conclusion:: the applied teaching method is possible, reproducible, reliable and valid. The joint efforts offer enormous opportunity of directed education, reaching underserved populations, revealing the great teacher student social responsibility. Objetivo:: avaliar resultados do metodo de treinamento e educacao continuada de 18 cirurgioes, em 2014, e 28 cirurgioes, em 2015, nas Santas Casas de Ribeirao Preto, Araraquara, Franca e Sao Carlos do Estado de Sao Paulo, na realizacao da Herniorrafia Inguinal a Lichtenstein, tutorados pela Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo e pela organizacao HERNIA HELP - "Hernia Repair for the Underserved". Metodos: : treinamento tutorado e sistematizado, atraves de metodologia ativa de ensino e aprendizagem, visando a oferecer competencia, habilidade e atitudes, auferidas por um Formulario de Qualificacao previamente validado, qualificando lideres no aperfeicoamento de treinandos. Resultados:: em 2014, os desfechos foram: dificuldade do caso, direcao, incisao, disseccao, preparo da tela, corte da tela, fixacao da tela, fechamento, instrumentos, respeito aos tecidos, fluxo, tempo e movimento e desempenho, apresentaram mudanca na Classificacao Geral (p=0,000002); houve maior confianca na execucao do procedimento em 80% dos treinandos, sendo considerado "Muito Valioso" em 93,3% das participacoes. Em 2015, os 28 cirurgioes foram treinados por dez cirurgioes previamente qualificados em 2014. A taxa de identificacao dos nervos, tempo relevante da tecnica de Lichtenstein, foi 95,5 % para o ilio-hipogastrico, 98,5% para o ilioinguinal e 89,4% para o ramo genital do nervo genitofemoral. Conclusao: : o metodo de ensino aplicado e possivel, reprodutivel, confiavel e valido. Os mutiroes oferecem a enorme oportunidade do ensino, dirigido, atingindo populacoes carentes, revelando a grande responsabilidade social docente-discente. PMID- 27982334 TI - Modified technique for preparation of venous circulation resin casts in the cirrhotic liver. AB - This study describes two major adaptations for the preparation of resin casts in human cirrhotic liver, harvested at the time of transplantation. The first is the way of fixing the catheter in the ostia of the hepatic and portal veins through a cerclage, so as to prevent displacement of the catheter and / or leakage of the resin during its injection. The second is the extension of corrosion time in the NaOH solution, averaging 6.8 days, with daily replacement the solution until complete removal of parenchymal tissue. We applied the method in 14 cirrhotic livers, with good filling and coloring of the portal and hepatic vein territories, using different colors. This allows an anatomical study of these vessels, able to complement the knowledge of the histopathology in research work, and the planning of therapeutic procedures, such as the Trans-Jugular Intrahepatic Port-Systemic Shunt (TIPS). RESUMO Este estudo descreve duas importantes adaptacoes para o preparo de moldes de resina em figado humano cirrotico, captado no momento do transplante: a primeira, e a maneira de fixacao dos cateteres nos "ostios" das veias hepaticas e porta, atraves de uma "cerclagem" dos mesmos, de modo a evitar o deslocamento do cateter e/ou extravasamento da resina durante sua injecao, e a segunda, e o prolongamento do tempo de corrosao na solucao de NaOH, atingindo a media de 6,8 dias, com a substituicao diaria da solucao, ate a remocao completa do tecido parenquimatoso. O metodo foi empregado em 14 figados cirroticos com bom preenchimento e coloracao dos territorios das veias porta e hepaticas, utilizando cores distintas. Isto permite um estudo anatomico desses vasos, capaz de complementar os conhecimentos da histopatologia em trabalhos de pesquisa, e planejar procedimentos terapeuticos como a derivacao porto-sistemica intra-hepatica transjugular (TIPS - Transjugular Intrahepatic Postosystemic Shunt). PMID- 27982335 TI - Considerations about gastric cancer proteomics. AB - The frequency of molecular studies aimed to analyze promoter methylation of tumor suppressor genes and global proteomics in gastric carcinogenesis is increasing. Nonetheless, only a few considered the different types of stomach cells, the tumor location and the influence of Helicobacter pylori and Epstein Barr virus infection (EBV). Molecular differences relating to anatomical and histological tumor areas were also recently described. The authors propose a molecular classification of gastric cancer, dividing it into four subtypes: tumors positive for EBV; microsatellite unstable tumors; genomically stable tumors and tumors with chromosomal instability. RESUMO A frequencia de estudos moleculares visando a analisar os promotores de metilacao de genes supressores de tumor e proteomica globais na carcinogenese gastrica esta aumentando. No entanto, apenas alguns consideraram os diferentes tipos de celulas do estomago, a localizacao do tumor e a influencia da infeccao por Helicobacter pylori e pelo virus Epstein-Barr (EBV). Diferencas moleculares relacionadas com areas tumorais anatomicas e histologicas tambem foram recentemente descritas. Os autores propoem uma classificacao molecular de cancer gastrico, dividindo-o em quatro subtipos: tumores positivos para o EBV; tumores microssatelite instaveis; tumores genomicamente estaveis e tumores com instabilidade cromossomica. PMID- 27982336 TI - Splenic artery aneurysm. AB - Splenic artery aneurysms - the most common visceral artery aneurysms - are found most often in multiparous women and in patients with portal hypertension. Indications for treatment of splenic artery aneurysm or pseudoaneurysm include specific symptoms, female gender and childbearing age, presence of portal hypertension, planned liver transplantation, a pseudoaneurysm of any size, and an aneurysm with a diameter of more than 2.5cm. Historically, the treatment of splenic artery aneurysm has been surgical ligation of the splenic artery, ligation of the aneurysm, or aneurysmectomy with or without splenectomy, depending on the aneurysm location. There are other percutaneous interventional techniques. The authors present a case of a splenic artery aneurysm in a 51-year old woman, detected incidentally. RESUMO Aneurismas da arteria esplenica - os aneurismas arteriais viscerais mais comuns - sao encontrados mais frequentemente em mulheres multiparas e em pacientes com hipertensao portal. As indicacoes para o seu tratamento incluem sintomas especificos, sexo feminino e idade fertil, presenca de hipertensao portal, paciente em fila de transplante hepatico, um pseudoaneurisma de qualquer tamanho, e um aneurisma com um diametro superior a 2,5cm. Historicamente, o tratamento do aneurisma da arteria esplenica tem sido a ligadura cirurgica da arteria esplenica, a ligadura do aneurisma ou a aneurismectomia, com ou sem esplenectomia, dependendo do local do aneurisma. Existem outras tecnicas intervencionistas percutaneas. Os autores apresentam o caso de um aneurisma de arteria esplenica em uma mulher de 51 anos de idade, diagnosticado incidentalmente. PMID- 27982337 TI - Right hepatic artery aneurysm. AB - We report a case of an aneurysm of the right hepatic artery and its multidisciplinary management by general surgery, endoscopy and radiology services. Being a case of extremely low incidence, it is important to show its diagnostic and therapeutic approach. RESUMO Relatamos um caso de aneurisma da arteria hepatica direita conduzido de forma multidisciplinar pelos Servicos de Cirurgia Geral, Endoscopia e Radiologia. Em se tratando de caso de incidencia baixissima, e importante mostrar o enfoque diagnostico e terapeutico usado em seu manejo. PMID- 27982338 TI - Rupture of celiac trunk aneurysm in patient with Behcet Disease. AB - We report a case of a ruptured aneurysm of the celiac trunk in a 32-year-old, male patient with Behcet Disease (BD). Aneurysm resection was performed and the patient is well during a follow up of 32 months. To our knowledge, this is the first reported case of a ruptured celiac trunk aneurysm successfully treated in a patient with BD. RESUMO Relatamos o caso de um aneurisma roto do tronco celiaco em um paciente de 32 anos, do sexo masculino, portador de Doenca de Behcet (DB). A resseccao do aneurisma foi realizada e o paciente esta bem, com acompanhamento de 32 meses. Ate onde sabemos, este e o primeiro caso relatado de um aneurisma do tronco celiaco roto tratado com sucesso em um paciente com DB. PMID- 27982339 TI - New Performance of the BJCVS. PMID- 27982340 TI - Cardiopulmonary Bypass: a Forgotten Area of Searching for New Knowledge in Brazil and the Importance of Translational Research. PMID- 27982341 TI - Should a Cardiac Surgeon Blame Himself for Replacing a Mitral Valve? PMID- 27982342 TI - In-Vitro Evaluation of Two Types of Neonatal Oxygenators in Handling Gaseous Microemboli and Maintaining Optimal Hemodynamic Stability During Cardiopulmonary Bypass. AB - Objective: Usually only FDA-approved oxygenators are subject of studies by the international scientific community. The objective of this study is to evaluate two types of neonatal membrane oxygenators in terms of transmembrane pressure gradient, hemodynamic energy transmission and gaseous microemboli capture in simulated cardiopulmonary bypass systems. Methods: We investigated the Braile Infant 1500 (Braile Biomedica, Sao Jose do Rio Preto, Brazil), an oxygenator commonly used in Brazilian operating rooms, and compared it to the Dideco Kids D100 (Sorin Group, Arvada, CO, USA), that is an FDA-approved and widely used model in the USA. Cardiopulmonary bypass circuits were primed with lactated Ringer's solution and packed red blood cells (Hematocrit 40%). Trials were conducted at flow rates of 500 ml/min and 700 ml/min at 35oC and 25oC. Real-time pressure and flow data were recorded using a custom-based data acquisition system. For gaseous microemboli testing, 5cc of air were manually injected into the venous line. Gaseous microemboli were recorded using the Emboli Detection and Classification Quantifier. Results: Braile Infant 1500 had a lower pressure drop (P<0.01) and a higher total hemodynamic energy delivered to the pseudopatient (P<0.01). However, there was a higher raw number of gaseous microemboli seen prior to oxygenator at lower temperatures with the Braile oxygenator compared to the Kids D100 (P<0.01). Conclusion: Braile Infant 1500 oxygenator had a better hemodynamic performance compared to the Dideco Kids D100 oxygenator. Braile had more gaseous microemboli detected at the pre-oxygenator site under hypothermia, but delivered a smaller percentage of air emboli to the pseudopatient than the Dideco oxygenator. PMID- 27982343 TI - Intraoperative Analysis of Flow Dynamics in Arteriovenous Composite Y Grafts. AB - Objective: Composite graft of left internal thoracic artery and great saphenous vein in revascularization of the left coronary system is a technique well described in literature. The aim of this study is to analyze blood flow dynamics in this configuration of composite graft especially in what concerns left internal thoracic artery's adaptability and influence of great saphenous vein segment on left internal thoracic artery's flow. Methods: Revascularization of left coronary system with composite graft, with left internal thoracic artery revascularizing the anterior interventricular artery and a great saphenous vein segment, anastomosed to the left internal thoracic artery, revascularizing another branch of the left coronary system, was performed in 23 patients. Blood flow was evaluated by transit time flowmetry in all segments of the composite graft (left internal thoracic artery proximal segment, left internal thoracic artery distal segment and great saphenous vein segment). Measures were performed in baseline condition and after dobutamine-induced stress, without and with non traumatic temporary clamping of the distal segments of the composite graft. Results: Pharmacological stress resulted in increase of blood flow values in the analyzed segments (P<0.05). Non-traumatic temporary clamping of great saphenous vein segment did not result in statistically significant changes in the flow of left internal thoracic artery distal segment, both in baseline condition and under pharmacological stress. Similarly, non-traumatic temporary clamping of left internal thoracic artery distal segment did not result in statistically significant changes in great saphenous vein segment flow. Conclusion: Composite grafts with left internal thoracic artery and great saphenous vein for revascularization of left coronary system, resulted in blood flow dynamics with physiological adaptability, both at rest and after pharmacological stress, according to demand. Presence of great saphenous vein segment did not alter physiological blood flow dynamics in distal segment of left internal thoracic artery. PMID- 27982344 TI - Early Open-Lung Ventilation Improves Clinical Outcomes in Patients with Left Cardiac Dysfunction Undergoing Off-Pump Coronary Artery Bypass: a Randomized Controlled Trial. AB - Objective: To compare pulmonary function, functional capacity and clinical outcomes amongst three groups of patients with left ventricular dysfunction following off-pump coronary artery bypass, namely: 1) conventional mechanical ventilation (CMV); 2) late open lung strategy (L-OLS); and 3) early open lung strategy (E-OLS). Methods: Sixty-one patients were randomized into 3 groups: 1) CMV (n=21); 2) L-OLS (n=20) initiated after intensive care unit arrival; and 3) E OLS (n=20) initiated after intubation. Spirometry was performed at bedside on preoperative and postoperative days (PODs) 1, 3, and 5. Partial pressure of arterial oxygen (PaO2) and pulmonary shunt fraction were evaluated preoperatively and on POD1. The 6-minute walk test was applied on the day before the operation and on POD5. Results: Both the open lung groups demonstrated higher forced vital capacity and forced expiratory volume in 1 second on PODs 1, 3 and 5 when compared to the CMV group (P<0.05). The 6-minute walk test distance was more preserved, shunt fraction was lower, and PaO2 was higher in both open-lung groups (P<0.05). Open-lung groups had shorter intubation time and hospital stay and also fewer respiratory events (P<0.05). Key measures were significantly more favorable in the E-OLS group compared to the L-OLS group. Conclusion: Both OLSs (L-OLS and E-OLS) were able to promote higher preservation of pulmonary function, greater recovery of functional capacity and better clinical outcomes following off-pump coronary artery bypass when compared to conventional mechanical ventilation. However, in this group of patients with reduced left ventricular function, initiation of the OLS intra-operatively was found to be more beneficial and optimal when compared to OLS initiation after intensive care unit arrival. PMID- 27982345 TI - Comparison of Early Outcomes with Three Approaches for Combined Coronary Revascularization and Carotid Endarterectomy. AB - Objective: This study aims to compare three different surgical approaches for combined coronary and carotid artery stenosis as a single stage procedure and to assess effect of operative strategy on mortality and neurological complications. Methods: This retrospective study involves 136 patients who had synchronous coronary artery revascularization and carotid endarterectomy in our institution, between January 2002 and December 2012. Patients were divided into 3 groups according to the surgical technique used. Group I included 70 patients who had carotid endarterectomy, followed by coronary revascularization with on-pump technique, group II included 29 patients who had carotid endarterectomy, followed by coronary revascularization with off-pump technique, group III included 37 patients who had coronary revascularization with on-pump technique followed by carotid endarterectomy under aortic cross-clamp and systemic hypothermia (22 27oC). Postoperative outcomes were evaluated. Results: Overall early mortality and stroke rate was 5.1% for both. There were 3 (4.3%) deaths in group I, 2 (6.9%) deaths in group II and 2 (5.4%) deaths in group III. Stroke was observed in 5 (7.1%) patients in group I and 2 (6.9%) in group II. Stroke was not observed in group III. No statistically significant difference was observed for mortality and stroke rates among the groups. Conclusion: We identified no significant difference in mortality or neurologic complications among three approaches for synchronous surgery for coronary and carotid disease. Therefore it is impossible to conclude that a single principle might be adapted into standard practice. Patient specific risk factors and clinical conditions might be important in determining the surgical tecnnique. PMID- 27982346 TI - Preoperative Nutritional Status and Clinical Complications in the Postoperative Period of Cardiac Surgeries. AB - Objective: This study aims to assess the preoperative nutritional status of patients and the role it plays in the occurrence of clinical complications in the postoperative period of major elective cardiac surgeries. Methods: Cross sectional study comprising 72 patients aged 20 years or older, who underwent elective cardiac surgery. The preoperative nutritional assessment consisted of nutritional screening, anthropometry (including the measurement of the adductor pollicis muscle thickness) and biochemical tests. The patients were monitored for up to 10 days after the surgery in order to control the occurrence of postoperative complications. The R software, version 3.0.2, was used to statistically analyze the data. Results: Clinical complications were found in 62.5% (n=42) of the studied samples and complications of non-infectious nature were most often found. Serum albumin appeared to be associated with renal complications (P=0.026) in the nutritional status indicators analyzed herein. The adductor pollicis muscle thickness was associated with infectious complications and presented mean of 9.39+/-2.32 mm in the non-dominant hand (P=0.030). No significant correlation was found between the other indicators and the clinical complications. Conclusion: The adductor pollicis muscle thickness and the serum albumin seemed be associated with clinical complications in the postoperative period of cardiac surgeries. PMID- 27982347 TI - Reference Values for the Six-Minute Walk Test in Healthy Children and Adolescents: a Systematic Review. AB - Objective: The aim of the study is to compare the available reference values and the six-minute walk test equations in healthy children/adolescents. Our systematic review was planned and performed in accordance with the PRISMA guidelines. We included all studies that established reference values for the six minute walk test in healthy children/adolescents. Methods: To perform this review, a research was performed in PubMed, EMBASE (via SCOPUS) and Cochrane (LILACS), Bibliographic Index Spanish in Health Sciences, Organization Collection Pan-American Health Organization, Publications of the World Health Organization and Scientific Electronic Library Online (SciELO) via Virtual Health Library until June 2015 without language restriction. Results: The initial research identified 276 abstracts. Twelve studies met the inclusion criteria and were fully reviewed and approved by both reviewers. None of the selected studies presented sample size calculation. Most of the studies recruited children and adolescents from school. Six studies reported the use of random samples. Most studies used a corridor of 30 meters. All studies followed the American Thoracic Society guidelines to perform the six-minute walk test. The walked distance ranged 159 meters among the studies. Of the 12 included studies, 7 (58%) reported descriptive data and 6 (50%) established reference equation for the walked distance in the six-minute walk test. Conclusion: The reference value for the six minute walk test in children and adolescents ranged substantially from studies in different countries. A reference equation was not provided in all studies, but the ones available took into account well established variables in the context of exercise performance, such as height, heart rate, age and weight. Countries that did not established reference values for the six-minute walk test should be encouraged to do because it would help their clinicians and researchers have a more precise interpretation of the test. PMID- 27982349 TI - Mortality Risk After Cardiac Surgery: Application of Inscor in a University Hospital in Brazil's Northeast. AB - Objective: To apply the InsCor in patients undergoing cardiac surgery in a university hospital in Brazil's northeast. Methods: It is a retrospective, quantitative and analytical study, carried out at the University Hospital of the Federal University of Maranhao. InsCor is a remodeling of two risk score models. It evaluates the prediction of mortality through variables such as gender, age, type of surgery or reoperation, exams, and preoperative events. Data from January to December 2015 were collected, using a Physical Therapy Evaluation Form and medical records. Quantitative variables were expressed as mean and standard deviation and qualitative variables as absolute and relative frequencies. Fisher's exact and Kruskal-Wallis tests were applied, considering significant differences when P value was < 0.05. Calibration was performed by Hosmer-Lemeshow test. Results: One hundred and forty-eight patients were included. Thirty-six percent were female, with mean age of 54.7+/-15.8 years and mean body mass index (BMI) equal to 25.6 kg/m(2). The most frequent surgery was coronary artery bypass grafting (51.3%). According to InsCor, 73.6% of the patients had low risk, 20.3% medium risk, and only 6.1% high risk. In this sample, 11 (7.4%) patients died. The percentage of death in patients classified as low, medium and high risk was 6.3, 7.1% and 11.1%, respectively. Conclusion: InsCor presented easy applicability due to the reduced number of variables analyzed and it showed satisfactory prediction of mortality in this sample of cardiac surgery patients. PMID- 27982348 TI - A Cycle Ergometer Exercise Program Improves Exercise Capacity and Inspiratory Muscle Function in Hospitalized Patients Awaiting Heart Transplantation: a Pilot Study. AB - Objective: The purpose of this study was to evaluate the effect of a cycle ergometer exercise program on exercise capacity and inspiratory muscle function in hospitalized patients with heart failure awaiting heart transplantation with intravenous inotropic support. Methods: Patients awaiting heart transplantation were randomized and allocated prospectively into two groups: 1) Control Group (n=11) - conventional protocol; and 2) Intervention Group (n=7) - stationary cycle ergometer exercise training. Functional capacity was measured by the six minute walk test and inspiratory muscle strength assessed by manovacuometry before and after the exercise protocols. Results: Both groups demonstrated an increase in six-minute walk test distance after the experimental procedure compared to baseline; however, only the intervention group had a significant increase (P =0.08 and P =0.001 for the control and intervention groups, respectively). Intergroup comparison revealed a greater increase in the intervention group compared to the control (P <0.001). Regarding the inspiratory muscle strength evaluation, the intragroup analysis demonstrated increased strength after the protocols compared to baseline for both groups; statistical significance was only demonstrated for the intervention group, though (P =0.22 and P <0.01, respectively). Intergroup comparison showed a significant increase in the intervention group compared to the control (P <0.01). Conclusion: Stationary cycle ergometer exercise training shows positive results on exercise capacity and inspiratory muscle strength in patients with heart failure awaiting cardiac transplantation while on intravenous inotropic support. PMID- 27982350 TI - Valvular Disorders in Carcinoid Heart Disease. AB - Carcinoid heart disease is a rare but important cause of intrinsic right heart valve disorders leading to right heart failure. Occasionally, left-sided heart valves may also be involved. The characteristic cardiac pathological findings of carcinoid heart disease are endocardial thickening as a result of fibrous deposits on the endocardium. Echocardiographic examination and right heart catheterization are very useful for the diagnosis of the lesion. If more cardiac valves are affected, multiple valve replacement should be considered. The management of the pulmonary valve lesion depends on the extent of the diseased valve, either by valvulotomy, valvectomy, or valve replacement. Percutaneous valve implantations in the pulmonary and in the inferior vena cava positions have been advocated for high-risk patients. PMID- 27982351 TI - Surgical Treatment for Thrombus Straddling a Patent Foramen Ovale. AB - We present a case of a 41-year-old female with deep vein thrombosis after abdominal surgery. The patient quickly developed severe pulmonary embolism and stroke representative of paradoxical embolism. Echocardiography showed a thrombus straddling a patent foramen ovale, which was confirmed intraoperatively. An accurate diagnosis and rapid treatment decisions are crucial for preventing patient deterioration in the form of new pulmonary embolisms or stroke. PMID- 27982352 TI - RISK FACTORS ASSOCIATED WITH AMERICAN CUTANEOUS LEISHMANIASIS IN AN ENDEMIC AREA OF BRAZIL. AB - Brazil is among the top five countries worldwide regarding the number of cases of leishmaniasis, which are present in all of the regions of the country. The northeastern region continues to have higher numbers of cases every year and in the state of Pernambuco, 34% of the municipalities are endemic for this disease. The diversity of vectors, reservoirs and etiological agents, in association with socioeconomic and environmental conditions, gives rise to factors that can modify the behavior of American cutaneous leishmaniasis. Consequently, the aim of the present study was to determine the risk factors associated with American cutaneous leishmaniasis in the municipality of Timbauba, Brazil. A case-control study was conducted. A validated questionnaire was used for data collection. The study included 58 cases and 174 controls, and they were serologically diagnosed at the Oswaldo Cruz Foundation (FIOCRUZ). Our results showed that some factors were associated with American cutaneous leishmaniasis: biological (gender), economic (work activity, hours spent away from home and water supply) and peridomestic (presence of animals). In our study, the associations of these variables with leishmaniasis were linked to precarious housing conditions and poverty, which are parameters that can be managed in order to prevent the disease in this region. PMID- 27982354 TI - GENETIC MUTATIONS AFFECTING THE FIRST LINE ERADICATION THERAPY OF Helicobacter pylori-INFECTED EGYPTIAN PATIENTS. AB - Introduction: : Several genetic mutations affect the first-line triple therapy for Helicobacter pylori. We aimed to study the most common genetic mutations affecting the metronidazole and clarithromycin therapy for H. pylori-infected Egyptian patients. Patients and Methods: : In our study, we included 100 successive dyspeptic patients scheduled for diagnosis through upper gastroscopy at Cairo's University Hospital, Egypt. Gastric biopsies were tested for the presence of H. pylori by detection of the 16S rRNA gene. Positive biopsies were further studied for the presence of the rdxA gene deletion by Polymerase Chain Reaction (PCR), while clarithromycin resistance was investigated by the presence of nucleotide substitutions within H. pylori 23S rRNA V domain using MboII and BsaI to carry out a Restricted Fragment Length Polymorphism (RFLP) assay. Results: : Among 70 H. pylori positive biopsies, the rdxA gene deletion was detected in 44/70 (62.9%) samples, while predominance of the A2142G mutations within the H. pylori 23S rRNA V domain was evidenced in 39/70 (55.7%) of the positive H. pylori cases. No statistically significant difference was found between the presence of gene mutations and different factors such as patients 'age, gender, geographic distribution, symptoms and endoscopic findings. Conclusion: : Infection with mutated H. pylori strains is considerably high, a finding that imposes care in the use of the triple therapy to treat H. pylori in Egypt, since the guidelines recommend to abandon the standard triple therapy when the primary clarithromycin resistance rate is over 20%1. PMID- 27982353 TI - SAND FLIES (DIPTERA: PSYCHODIDAE) IN AN ENDEMIC AREA OF LEISHMANIASIS IN AQUIDAUANA MUNICIPALITY, PANTANAL OF MATO GROSSO DO SUL , BRAZIL. AB - The Aquidauana municipality is considered an endemic area of leishmaniasis and an important tourist site in Mato Grosso do Sul State. The aim of this study was to investigate the sand fly fauna in the city of Aquidauana. Captures were carried out twice a month, from April 2012 to March 2014 with automatic light traps and active aspiration, in the peridomicile and domicile of six residences. A total of 9,338 specimens were collected, 3,179 and 6,159 using light traps and active aspiration, respectively. The fauna consisted of: Brumptomyia brumpti, Evandromyia aldafalcaoae, Ev. evandroi, Ev. lenti, Ev. orcyi, Ev. sallesi, Ev. termitophila, Ev. walkeri, Lutzomyia longipalpis and Psathyromyia bigeniculata. The most abundant species captured was Lutzomyia longipalpis, present in all the ecotopes, predominantly in peridomicile areas, and mainly males. Leishmania DNA was not detected in the insects. It was observed the abundance of the sand fly fauna in the region, as well as the high frequency of Lu. longipalpis, the main vector of L. infantum. The results of this study show the need to increase the monitoring and more effective control measures. It is noteworthy that the studied region presents several activities related to tourism and recreation, increasing the risk of transmission of leishmaniasis to this particular human population. PMID- 27982355 TI - DETECTION OF HUMAN ANTI-ZIKA VIRUS IgG BY ELISA USING AN ANTIGEN FROM in vitro INFECTED VERO CELLS: PRELIMINARY RESULTS. AB - Zika virus (ZKV) infection is a huge public health problem in Brazil because of the increased incidence of microcephaly in neonates from infected mothers. Detection of specific IgG antibodies in maternal serum samples constitutes an important approach for diagnosing ZKV infection and evaluating its relationship with neonatal microcephaly. However, as there is no serological test produced in Brazil to detect IgM and IgG antibodies against ZKV, we sought to examine specific IgG in serum samples from patients or suspected mothers to detect previous infection and to test for specificity with regard to flaviviral infections occurring in the same area. Brazilian Zika virus native antigens were obtained from infected Vero cell layers or free virions in the culture medium and then used in ELISA. We tested sera from eight ZKV RNA-diagnosed infected patients (ZKVR), seven neonates with microcephaly and their mothers after delivery (MM), 140 dengue virus IgM-positive (DM) and IgG (DG)-positive patients, and 100 yellow fever (YF)-vaccinated patients. According to the ELISA, ZKVR samples were mostly positive (7/8), and all the MM serum samples were positive for ZKV IgG (7/7). In contrast, cross-reactions for dengue or yellow fever-vaccinated patients were observed, including DM (48/95), DG (10/45) or YF (3/100) serum samples; however, these cross-reactions exhibited low antigen avidity so that 6 M urea largely removed this cross-reactivity, with only a few cross-reacting samples remaining (8/140). ELISA based on extracted virions was much more specific, with all ZKVR (8/8) and MM sera being positive for ZKV IgG (7/7) and only borderline cross reactivity found for DM (6/95), DG (3/45) or YF (4/100)-vaccinated serum samples. This technique (ELISA) can identify specific IgG in ZKV-infected patients and may be helpful in diagnosing congenital infetions after maternal RNA virus clearance or in epidemiological studies. PMID- 27982356 TI - VERTICAL TRANSMISSION OF DENGUE INFECTION: THE FIRST PUTATIVE CASE REPORTED IN CHINA. AB - Dengue is a systemic viral infection that is commonly transmitted between humans via mosquitoes. Other modes of transmission such as the vertical one are rare and have been infrequently reported in the literature. This report investigates one case of vertical transmission of dengue in Guangzhou, China. A G1P1 lady at 39 weeks of gestation was referred to the Huzhong Hospital presenting a fever for two days. She subsequently developed a skin rash on the back and lower limb and at that time she had already experienced five days of fever. She subsequently went into labor and delivered a female neonate weighting 3,500 g at birth. The neonate developed fever on the third day of life which was associated with a systemic erythematous skin rash. There was no report or evidence of mosquito bites after birth. A complete blood count showed leucopenia, thrombocytopenia and anemia and the liver function test showed elevated AST, GGT and bilirubin. Dengue was diagnosed in the mother and the neonate by the ELISA dengue virus NS1 antigen test (Wantai, Beijing, China) and dengue virus fluorogenic quantitative PCR test (Liferiver, Shanghai, China).The case report illustrates the possibility of the vertical transmission of dengue. Clinicians should be alert to this possibility and institute early treatment. Further direct evidence and research are required. PMID- 27982357 TI - REPORTING DELAY DURING THE YELLOW FEVER OUTBREAK, ANGOLA, 2016. PMID- 27982358 TI - ALTERNATIVE METHODS FOR SEQUENCING FULL TSPyV GENOMES USING SANGER OR NGS. PMID- 27982359 TI - Prevention of childhood obesity through trilateral cooperation. PMID- 27982360 TI - United to Reduce Childhood Obesity in North America. PMID- 27982361 TI - Canada-United States-Mexico Trilateral Cooperation on Childhood Obesity Initiative. AB - Childhood obesity is an important public health problem that affects countries in the Americas. In 2014, Pan American Health Organization (PAHO) Member States agreed on a Plan of Action for the Prevention of Obesity in Children and Adolescents in an effort to address the impact of this disorder in the Americas region. The interventions laid out in this regional plan are multi-faceted and require multi-sectoral partnerships. Building on a strong history of successful trilateral collaboration, Canada, Mexico, and the United States formed a partnership to address the growing epidemic of childhood obesity in the North American region. This collaborative effort, known as the Trilateral Cooperation on Childhood Obesity Initiative, is the first initiative in the region to address chronic noncommunicable diseases by bringing together technical and policy experts, with strong leadership and support from the secretaries and ministers of health. The Initiative's goals include increasing levels of physical activity and reducing sedentary behavior through 1) increased social mobilization and citizen engagement, 2) community- based outreach, and 3) changes to the built (man-made) environment. This article describes the background and development process of the Initiative; specific goals, activities, and actions achieved to date; and opportunities and next steps. This information may be useful for those forming other partnerships designed to address childhood obesity or other complex public health challenges in the region. PMID- 27982362 TI - Role of PAHO/WHO in eHealth Capacity Building in the Americas: Analysis of the 2011-2015 period. AB - Political will and adoption of measures toward the use of eHealth have been steadily increasing, facilitating mobilization of resources necessary to adopt and implement digital services that will make it possible to improve access, expand coverage, and increase financial efficiency of health care systems. Adoption of the Strategy and Plan of Action on eHealth of the Pan American Health Organization (PAHO) in 2011 by all Member States in the Region of the Americas has led the Region to major progress in this regard, including the following: creation of knowledge networks and development of information sources, establishment of eHealth sustainability models, support for development of electronic health records, promotion of standards on health data and related technologies that ensure exchange of information, use of mobile devices to improve health, and improvement in quality of care through telemedicine. This article details the main actions carried out by PAHO with regard to eHealth, specifically by the office of Knowledge Management, Bioethics, and Research in the 2011-2015 period (first period of implementation of the PAHO eHealth strategy and plan of action), which include research and capacity-building activities, development of technical guidelines, and formation of knowledge networks. PMID- 27982363 TI - [Efficiency indicators to assess the organ donation and transplantation process: systematic review of the literature]. AB - Objective: To search the literature and identify indicators used to monitor and control the organ donation and transplantation process and to group these indicators into categories. Method: In November 2014, a systematic review of the literature was carried out in the following databases: Biblioteca Virtual em Saude (BVS), EBSCO, Emerald, Proquest, Science Direct, and Web of Science. The following search terms (and the corresponding terms in Brazilian Portuguese) were employed: "efficiency," "indicators," "organ donation," "tissue and organ procurement," and "organ transplantation." Of the 344 articles retrieved, 23 original articles published between 1992 and 2013 were selected and reviewed for analysis of efficiency indicators. Results: The review revealed 117 efficiency indicators, which were grouped according to similarity of content and divided into three categories: 1) 71 indicators related to organ donation, covering mortality statistics, communication of brain death, clinical status of donors and exclusion of donors for medical reasons, attitude of families, confirmation of donations, and extraction of organs and tissues; 2) 22 indicators related to organ transplantation, covering the surgical procedure per se and post transplantation follow-up; and 3) 24 indicators related to the demand for organs and the resources of hospitals involved in the process. Conclusions: Even if organ transplantation is a recent phenomenon, the high number of efficiency indicators described in the literature suggests that scholars interested in this field have been searching for ways to measure performance. However, there is little standardization of the indicators used. Also, most indicators focus on the donation step, suggesting gaps in the measurement of efficiency at others points in the process. Additional indicators are needed to monitor important stages, such as organ distribution (for example, organ loss indicators) and post transplantation aspects (for example, survival and quality of life). PMID- 27982364 TI - ? PMID- 27982365 TI - ? PMID- 27982366 TI - ? PMID- 27982367 TI - Malnutrition in the Americas: challenges and opportunities. PMID- 27982368 TI - Nutrition situation in Latin America and the Caribbean: current scenario, past trends, and data gaps. AB - Objective: To determine the current nutritional status in Latin America and the Caribbean (LAC) and identify data gaps and trends in nutrition surveillance. Methods: A systematic Internet search was conducted to identify official sources that allowed for monitoring of LAC countries' nutritional status, including progress toward World Health Organization Global Nutrition Targets 2025. Reports from national nutrition surveillance systems and reports on nationally representative surveys were collected and collated to 1) analyze nutritional status, based on life-course anthropometric indicators and biomarkers, and 2) identify gaps in data availability and trends in nutritional deficiencies. Information on iron, vitamin A, iodine, folate, and vitamin B12 deficiency was also collected and collated. Results: Twenty-two of the 46 LAC countries/territories (48%) had information on undernutrition (stunting, underweight, and wasting) in children under 5 years old and women of reproductive age (WRA). Seventeen countries (38%) had information on anemia in children under 5 years old and WRA, and 12 (27%) had information on anemia in pregnant women. Although overall nutritional status has improved in the past few decades in all countries in the region, some LAC countries still had a high prevalence of stunting and anemia in children and WRA. Overweight affected at least 50% of WRA in nine countries with available data, and was increasing in children. Data for school-age children, adolescents, adult males, and older adults were scarce in the region. Conclusions: Overall nutritional status has improved in the LAC countries with available information, but more efforts are needed to scale up nutrition-sensitive and nutrition-specific interventions to tackle malnutrition in all its forms, as stunting, anemia, and vitamin A deficiency are still a public health problem in many countries, and overweight is an epidemic. Nutrition information systems are weak in the region, and countries need to strengthen their capacity to monitor nutritional status indicators. PMID- 27982369 TI - Mapping of nutrition and sectoral policies addressing malnutrition in Latin America. AB - Objective: To map existing policies addressing malnutrition in all its forms in Latin America and identify gaps in enabling environments supporting the five priority lines of action outlined in the World Health Organization Comprehensive Implementation Plan on Maternal, Infant and Young Child Nutrition (CIP) approved in 2014. Methods: This descriptive study consisted of a systematic Internet search for and mapping of publicly available nutrition-related and sectoral policies already in place to address malnutrition in all its forms in 18 Latin American countries (Argentina, Belize, Bolivia, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, and Uruguay). The policies were described in documents retrieved from the websites of ministries of health, education, agriculture, labor, and development; the national congress; and other government agencies. Results: All 18 countries had relevant policies to address malnutrition, especially undernutrition and micronutrient deficiencies, but only a few had policies to address overweight and obesity. Nutrition actions were incorporated in food and nutrition security and social protection policies in all 18 countries, and were part of education, environment, agricultural, development, and/or employment policies in some countries. Information on human and financial resources assigned to nutrition was not available through the search strategies used in the study. Conclusions: All 18 countries included in this review had established enabling environments to support CIP implementation. However, each of the 18 countries needs to develop integrated policies for the promotion of nutrition and prevention of noncommunicable diseases through cross-sector involvement and multi-stakeholder collaboration. PMID- 27982370 TI - Conditional cash transfer programs and the health and nutrition of Latin American children. AB - Objective: To 1) describe the benefits, conditions, coverage, funding, goals, governance, and structure of well-established conditional cash transfer programs (CCTs) in Latin America and 2) identify their health and nutritional impacts among children under 5 years old. Methods: A realist review was conducted. CCTs were included if they met the following inclusion criteria: 1) current national level program; 2) coverage of at least 50% of the target population; 3) continuous operation at scale for 10+ years; 4) clear description of structure, funding sources, and governance; 5) both health/nutrition- and education-related conditions for participation; and 6) available impact evaluation studies with health, development, and/or nutrition indicators among children under 5 years old. Three CCTs (one each in Brazil, Colombia, and Mexico) met the criteria. Results: There was consistent evidence that the three CCTs selected for review had positive impacts on child health and nutrition outcomes in their respective countries. In all three countries, the programs were scaled up and positive impacts were documented relatively quickly. All three programs had strong political support and clear and transparent governance structures, including accountability and social participation mechanisms, which might explain their success and sustainability. Conclusions: CCTs in Latin America have had a positive impact on child health and nutrition outcomes among the poorest families. A key challenge for the future is to reform these programs to help families move out of not only extreme poverty but all poverty in order to lead healthy and productive lives, as called for in the post-2105 Sustainable Development Goals. PMID- 27982371 TI - Tackling malnutrition in Latin America and the Caribbean: challenges and opportunities. AB - Undernutrition and micronutrient deficiencies are still a public health problem in Latin America and the Caribbean (LAC), and overweight and obesity have reached epidemic proportions. To assess the nutrition landscape in LAC countries and guide future nutrition efforts and investments, the Pan American Health Organization and the Micronutrient Initiative joined efforts to 1) identify information gaps and describe the current nutritional situation in the region; 2) map existing policies to address malnutrition in Latin America; 3) describe the impact of conditional cash transfer programs (CCTs) on nutrition and health outcomes; and 4) identify the challenges and opportunities to address malnutrition in the region. This article summarizes the methods and key findings from that research and describes the current challenges and opportunities in addressing malnutrition in the LAC region. LAC countries have advanced in reducing undernutrition and micronutrient deficiencies, but important gaps in information are a major concern. These countries have policies to address undernutrition and micronutrient deficiencies, but comprehensive and intersectoral policies to tackle obesity are lacking. CCTs in Brazil, Colombia, and Mexico have been reported to have a positive impact on child nutrition and health outcomes, providing an opportunity to integrate nutrition actions in intersectoral platforms. The current epidemiological situation and policy options offer an opportunity for countries, technical agencies, donors, and other stakeholders to jointly scale up nutrition actions. This can support the development of comprehensive and intersectoral policies to tackle the double burden of malnutrition, strengthen national nutrition surveillance systems, incorporate monitoring and evaluation as systematic components of policies and programs, document and increase investments in nutrition, and assess the effectiveness of such policies to support political commitment and guarantee sustainability. PMID- 27982372 TI - Use of medicines and other products for therapeutic purposes among children in Brazil. AB - OBJECTIVE: To assess the prevalence of the use of medicines and other products for therapeutic purposes in the Brazilian pediatric population and test whether demographic, socioeconomic and health factors are associated with use. METHODS: A cross-sectional population-based study (National Survey on Access, Use and Promotion of Rational Use of Medicines - PNAUM), including 7,528 children aged 12 or younger, living in urban areas in Brazil. Medicine use to treat chronic or acute diseases was reported by the primary caregiver present at the household interview. Associations between independent variables and medicine use were investigated by Poisson regression. RESULTS: The overall prevalence of medicine use was 30.7% (95%CI 28.3-33.1). The prevalence of medicine use for chronic diseases was 5.6% (95%CI 4.7-6.7) and for acute conditions, 27.1% (95%CI 24.8 29.4). The factors significantly associated with overall use were five years old or under, living in the Northeast region, having health insurance and using health services in the last 12 months (emergency visits and hospitalizations). The following were associated with drug use for chronic diseases: age >= 2 years, Southeast and South regions, and use of health services. For drug use in treating acute conditions, the following associated factors were identified: <= 5 years, North, Northeast or Midwest regions, health insurance, and one or more emergency visits. The most commonly used drugs among children under two years of age were paracetamol, ascorbic acid, and dipyrone; for children aged two years or over they were dipyrone, paracetamol, and amoxicillin. CONCLUSIONS: The use of medicine by children is considerable, especially in treating acute medical conditions. Children using drugs for chronic diseases have a different demographic profile from those using drugs for acute conditions in relation to gender, age, and geographic region. OBJETIVO: Estimar a prevalencia de uso de medicamentos e outros produtos com finalidade terapeutica na populacao pediatrica brasileira e testar se fatores demograficos, socioeconomicos e medicos estao associados ao uso. METODOS: Estudo transversal de base populacional (Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - PNAUM), incluindo 7.528 criancas com 12 anos ou menos de idade, residentes na zona urbana do territorio brasileiro. O uso de medicamentos para tratar doencas cronicas ou agudas foi referido pelo principal cuidador da crianca presente na entrevista domiciliar. Associacoes entre as variaveis independentes e o uso de medicamentos foram investigadas por meio de regressao de Poisson. RESULTADOS: A prevalencia de uso global de medicamentos foi de 30,7% (IC95% 28,3-33,1). A prevalencia de uso de medicamentos para doencas cronicas foi de 5,6% (IC95% 4,7 6,7) e para condicoes agudas, 27,1% (IC95% 24,8-29,4). Os fatores significativamente associados com o uso global foram ter no maximo cinco anos de idade, residir na regiao Nordeste, ter plano de saude e utilizar servicos de saude nos ultimos 12 meses (consultas de emergencia e internacoes). Associaram-se ao uso de medicamentos para doencas cronicas: idade >= 2 anos, regioes Sudeste e Sul e utilizacao de servicos de saude. Para o uso de medicamentos em condicoes agudas, foram identificados os seguintes fatores associados: <= 5 anos, Norte, Nordeste ou Centro-Oeste, plano de saude e uma ou mais consultas de emergencia. Os medicamentos com maior prevalencia de uso pelas criancas menores de dois anos foram paracetamol, acido ascorbico e dipirona; nas criancas com 2 ou mais anos, foram dipirona, paracetamol e amoxicilina. CONCLUSOES: O uso de medicamentos na populacao infantil e substancial, principalmente no tratamento de condicoes medicas agudas. As criancas usuarias de medicamentos para doencas cronicas apresentam perfil demografico diferente das usuarias de medicamentos para condicoes agudas, em relacao ao sexo, a idade e a regiao geografica. PMID- 27982373 TI - Prevalence of self-medication in Brazil and associated factors. AB - OBJECTIVE: To analyze the prevalence and associated factors regarding the use of medicines by self-medication in Brazil. METHODS: This cross-sectional population based study was conducted using data from the PNAUM (National Survey on Access, Use and Promotion of Rational Use of Medicines), collected between September 2013 and February 2014 by interviews at the homes of the respondents. All people who reported using any medicines not prescribed by a doctor or dentist were classified as self-medication practitioners. Crude and adjusted prevalence ratios (Poisson regression) and their respective 95% confidence intervals were calculated in order to investigate the factors associated with the use of self medication by medicines. The independent variables were: sociodemographic characteristics, health conditions and access to and use of health services. In addition, the most commonly consumed medicines by self-medication were individually identified. RESULTS: The self-medication prevalence in Brazil was 16.1% (95%CI 15.0-17.5), with it being highest in the Northeast region (23.8%; 95%CI 21.6-26.2). Following the adjusted analysis, self-medication was observed to be associated with females, inhabitants from the North, Northeast and Midwest regions and individuals that have had one, or two or more chronic diseases. Analgesics and muscle relaxants were the therapeutic groups most used for self medication, with dipyrone being the most consumed medicines. In general, most of the medicines used for self-medication were classified as non-prescriptive (65.5%). CONCLUSIONS: Self-medication is common practice in Brazil and mainly involves the use of non-prescription medicines; therefore, the users of such should be made aware of the possible risks. OBJETIVO: Analisar a prevalencia e os fatores associados a utilizacao de medicamentos por automedicacao no Brasil. METODOS: Este estudo transversal de base populacional foi realizado com dados da Pesquisa Nacional de Acesso, Utilizacao e Promocao do Uso Racional de medicamentos (PNAUM), coletados de setembro de 2013 a fevereiro de 2014, por meio de entrevistas em domicilio. Todas as pessoas que referiram usar qualquer medicamento sem prescricao por medico ou dentista foram classificadas como praticantes de automedicacao. Foram calculadas razoes de prevalencia bruta e ajustada (regressao de Poisson) e seus respectivos intervalos de confianca de 95% na investigacao dos fatores associados ao consumo de medicamentos por automedicacao. As variaveis independentes foram: aspectos sociodemograficos, de condicoes de saude e de acesso e utilizacao de servicos de saude. Adicionalmente, foram identificados os medicamentos mais consumidos por automedicacao. RESULTADOS: A prevalencia da automedicacao no Brasil foi de 16,1% (IC95% 15,0 17,5), sendo maior na regiao Nordeste (23,8%; IC95% 21,6-26,2). Apos analise ajustada, automedicacao mostrou-se associada a ser do sexo feminino, pertencer as faixas etarias 10-19 anos, 20-29 anos, 40-59 anos e 60 anos ou mais, residir na regiao Norte, Nordeste ou Centro-Oeste, e ter uma ou duas ou mais doencas cronicas. Os analgesicos e os relaxantes musculares foram os grupos terapeuticos mais utilizados por automedicacao, sendo a dipirona o farmaco mais consumido. No geral, a maioria dos medicamentos usados por automedicacao foram classificados como isentos de prescricao (65,5%). CONCLUSOES: A automedicacao e pratica corrente no Brasil e envolve, principalmente, o uso de medicamentos isentos de prescricao, devendo os usuarios ficarem atentos aos seus possiveis riscos. PMID- 27982374 TI - Free access to medicines for the treatment of chronic diseases in Brazil. AB - OBJECTIVE: To analyze the free access to medicines for the treatment of chronic diseases in the Brazilian population, according to demographic and socioeconomic factors. We also analyzed the most used pharmacological groups, according to funding source: free-of-charge or out-of-pocket paid. METHODS: Analysis of data from the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines), a population-based household survey, of cross-sectional design, based on probabilistic sample of the Brazilian population. We analyzed as outcome the prevalence of free access (free-of-charge) to all medicines for treatment of the reported chronic diseases, in the last 30 days. We studied the following independent variables: sex, age group, education in complete years of school, economic class, health plan, and geographical region of residence. We estimated the prevalences and 95% confidence intervals (95%CI) and applied the Pearson's Chi-squared test to assess the differences between the groups, considering a 5% significance level. RESULTS: About half of adults and older adults who have had full access to the treatment of chronic diseases in Brazil obtained all needed medicines for free (47.5%; 95%CI 45.1-50.0). The prevalences of free access were higher among men (51.4%; 95%CI 48.1-54.8), age group of 40-59 years (51.1%; 95%CI 48.1-54.2), and in the poorest social classes (53.9%; 95%CI 50.2-57.7). The majority of medicines that act on the cardiovascular system, such as diuretics (C03) (78.0%; 95%CI 75.2-80.5), beta-blockers (C07) (62.7%; 95%CI 59.4-65.8), and the agents that work in the renin-angiotensin system (C09) (73.4%; 95%CI 70.8-75.8), were obtained for free. Medicines that act on the respiratory system, such as agents against obstructive airway diseases (R03) (60.0%; 95%CI 52.7-66.9) were mostly paid with own resources. CONCLUSIONS: Free access to medicines for treatment of chronic diseases occurs to a considerable portion of the Brazilian population, especially for the poorest ones, indicating decreased socioeconomic inequalities, but with differences between regions and between some classes of medicines. OBJETIVO: Analisar o acesso gratuito ao tratamento medicamentoso para doencas cronicas na populacao brasileira, segundo fatores socioeconomicos e demograficos. Analisaram-se tambem os grupos farmacologicos mais utilizados, segundo fonte de financiamento: gratuito ou pago do proprio bolso. METODOS: Analise de dados oriundos da Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM), inquerito domiciliar de base populacional, de delineamento transversal, baseado em amostra probabilistica da populacao brasileira. O desfecho analisado foi a prevalencia de acesso gratuito (sem pagamento) a todos os medicamentos para tratamento das doencas cronicas referidas, nos ultimos 30 dias. As variaveis independentes investigadas foram: sexo, faixa etaria, escolaridade em anos completos de estudo, classe economica, plano de saude e regiao geografica de residencia. Foram estimadas as prevalencias e calculados intervalos de 95% de confianca (IC95%) e aplicado o teste Qui-quadrado de Pearson para avaliacao das diferencas entre os grupos, considerando nivel de significancia de 5%. RESULTADOS: Cerca de metade dos adultos e idosos que tiveram acesso total ao tratamento de doencas cronicas no Brasil obtiveram todos os medicamentos que necessitavam gratuitamente (47,5%; IC95% 45,1-50,0). As prevalencias de acesso gratuito foram maiores entre os homens (51,4%; IC95% 48,1-54,8), na faixa etaria de 40-59 anos (51,1%; IC95% 48,1 54,2) e nas classes sociais mais pobres (53,9%; IC95% 50,2-57,7). Grande parte dos medicamentos que atuam no sistema cardiovascular, como os diureticos (C03) (78,0%; IC95% 75,2-80,5), betabloqueadores (C07) (62,7%; IC95% 59,4-65,8) e os agentes que atuam no sistema renina-angiotensina (C09) (73,4%; IC95% 70,8-75,8) foram obtidos de forma gratuita. Os medicamentos que atuam no sistema respiratorio como os agentes contra doencas obstrutivas das vias aereas (R03) (60,0%; IC95% 52,7-66,9) foram na sua maioria pagos do proprio bolso. CONCLUSOES: O acesso gratuito aos medicamentos para tratamento das doencas cronicas ocorre para uma consideravel parcela da populacao brasileira, principalmente para os mais pobres, indicando diminuicao das desigualdades socioeconomicas, mas com diferencas regionais e entre algumas classes de medicamentos. PMID- 27982375 TI - Sociodemographic profile of medicines users in Brazil: results from the 2014 PNAUM survey. AB - OBJECTIVE: To analyze the prevalence of medicine use by the Brazilian population and its distribution according to sociodemographic factors. METHODS: Study using data from the Pesquisa Nacional de Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines), a nationwide household survey of a representative sample of the Brazilian urban population. The data were collected between September 2013 and February 2014. The overall use of medicines, defined as the use of any medicine, use of medicines for treating chronic medical conditions and for acute health conditions, was evaluated. The independent variables included gender, age group, socioeconomic position, and region of Brazil. Analyzes included prevalence calculations, 95% confidence intervals (95%CI) and Pearson Chi-square tests to evaluate the differences between groups, considering a 5% level of significance. RESULTS: The prevalence of medicines use was 50.7% (95%CI 49.3-52.2), with 39.3% (95%CI 37.5-41.1) accounting for men and 61.0% (95%CI 59.3-62.6) for women. Medicines use was observed to increase with increasing age, except among children within the zero to four years age group. The lowest prevalence for medicines use was found among those with a low socioeconomic position and those who reside in the North region of Brazil. The prevalence of medicine use to treat chronic diseases was 24.3% (95%CI 23.3-25.4), whereas it was 33.7% (95%CI 32.1-35.4) for treating acute diseases. CONCLUSIONS: We found extensive variability in the prevalence of medicines use across regions of Brazil. The poorest regions (North, Northeast, and Midwest) have a lower prevalence of medicines use to treat chronic diseases, indicating the need to minimize inequalities in access to medicines within the country. OBJETIVO: Analisar a prevalencia do uso de medicamentos pela populacao brasileira e sua distribuicao segundo aspectos sociodemograficos. METODOS: Estudo com dados da Pesquisa Nacional de Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM), pesquisa nacional de base populacional, realizada entre setembro de 2013 e fevereiro de 2014 em residencias de municipios urbanos. Avaliou-se o uso de todos os medicamentos (global), uso de medicamentos para doencas cronicas e uso de medicamentos para doencas agudas. As variaveis independentes utilizadas foram sexo, idade, classificacao economica e regiao do Pais. Foram calculados prevalencias e intervalos de confianca de 95% (IC95%) e aplicado teste Qui-quadrado de Pearson para avaliacao das diferencas entre os grupos, considerando o nivel de significancia de 5%. RESULTADOS: A prevalencia global de uso de medicamentos foi de 50,7% (IC95% 49,3-52,2), sendo 39,3% (IC95% 37,5-41,1) no sexo masculino e 61,0% (IC95% 59,3-62,6) no sexo feminino. Observou se aumento nas prevalencias de uso com a idade (exceto de zero a quatro anos). As menores prevalencias de uso ocorreram no grupo mais pobre e na regiao Norte do Pais. A prevalencia de uso de medicamentos para doencas cronicas foi de 24,3% (IC95% 23,3-25,4) e para doencas agudas foi de 33,7% (IC95% 32,1-35,4). CONCLUSOES: Existe grande variabilidade nas prevalencias globais de uso de medicamentos por regioes brasileiras. As regioes consideradas mais pobres (Norte, Nordeste e Centro-Oeste) apresentam menores prevalencias de uso de medicamentos para doencas cronicas, o que indica a necessidade de minimizar as desigualdades no acesso aos medicamentos dentro do Pais. PMID- 27982376 TI - Use of generic medicines by the Brazilian population: an evaluation of PNAUM 2014. AB - OBJECTIVE: To analyze the existence of differences in the use of generic medicines in Brazil according to demographic and socioeconomic variables and acquisition sources of the medicines. METHODS: Population-based cross-sectional study, conducted with data from the Pesquisa Nacional de Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines). Data collection took place between September, 2013 and February, 2014 in homes of Brazilian cities (urban area). The use of medicines has been investigated in relation to the treatment of chronic diseases and, in the case of acute events, regarding use over the previous 15 days. Generics were identified by visualization of packaging presented by the users of the medicines. The independent variables used were sex, age, education level, economic class, and region of the Country. The statistical significance of differences between the groups was evaluated by Pearson's Chi-squared test, considering a 5% significance level. RESULTS: The prevalence of generic medicines use was 45.5% (95%CI 43.7-47.3). There was no difference considering education level. The prevalence was higher in females (47.0%; 95%CI 44.9-49.0) than in males (43.1%; 95%CI 40.5-45.8), and were higher with increasing age. Generic medicines were more used in the economic class C (47.0%; 95%CI 44.9-49.1) and in the South (50.6%; 95%CI 46.6-54.6) and Southeast (49.9%; 95%CI 46.8-53.0) regions. Generics accounted for 37.3% of the medicines provided by the Brazilian Unified Health System. CONCLUSIONS: Currently, there is a choice of purchase or free provision by the Brazilian Unified Health System, characterized by quality assurance and reduced price regarding branded medicines considered as reference. In the private market, a considerable part of the population is choosing generic medicines thanks to the availability of this option for virtually all medicines most used by the population. OBJETIVO: Analisar se ha diferenca no uso de medicamentos genericos no Brasil segundo variaveis demograficas, socioeconomicas e fontes de obtencao dos medicamentos. METODOS: Estudo transversal de base populacional, conduzido com dados da Pesquisa Nacional de Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM), com coleta de dados entre setembro de 2013 e fevereiro de 2014 em residencias de municipios brasileiros urbanos. O uso dos medicamentos foi investigado em relacao ao tratamento de doencas cronicas e, no caso de eventos agudos, quanto ao uso nos ultimos 15 dias. Os genericos foram identificados por visualizacao das embalagens apresentadas pelos usuarios dos medicamentos. As variaveis independentes utilizadas foram sexo, idade, escolaridade, classe economica e regiao do Pais. A avaliacao da significancia estatistica das diferencas entre os grupos foi analisada pelo teste Qui-quadrado de Pearson, considerando nivel de significancia de 5%. RESULTADOS: A prevalencia de uso de genericos foi de 45,5% (IC95% 43,7-47,3). Nao houve diferenca por escolaridade, as prevalencias foram maiores no sexo feminino (47,0%; IC95% 44,9-49,0) em relacao ao masculino (43,1%; IC95% 40,5-45,8) e foram crescentes com o aumento da idade. Maiores usos de genericos foram encontrados na classe economica C (47,0%; IC95% 44,9-49,1) e nas regioes Sul (50,6%; IC95% 46,6 54,6) e Sudeste (49,9%; IC95% 46,8-53,0). Observou-se ainda que os genericos representaram 37,3% dos medicamentos disponibilizados pelo Sistema Unico de Saude . CONCLUSOES: Pode-se concluir que hoje existe uma alternativa de compra ou fornecimento gratuito pelo Sistema Unico de Saude, caracterizada por garantia de qualidade e preco reduzido em relacao aos medicamentos de marca comercial considerados como referencia. No mercado privado, boa parte da populacao esta optando pelo uso de medicamentos genericos, gracas a disponibilidade dessa opcao para praticamente todos os medicamentos mais utilizados pela populacao. PMID- 27982378 TI - Factors associated with low adherence to medicine treatment for chronic diseases in Brazil. AB - OBJECTIVE: To analyze factors associated with low adherence to drug treatment for chronic diseases in Brazil. METHODS: Analysis of data from Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM - Brazilian Survey on Access, Use and Promotion of Rational Use of Medicines), a population-based cross-sectional household survey, based on a probabilistic sample of the Brazilian population. We analyzed the association between low adherence to drug treatment measured by the Brief Medication Questionnaire and demographic, socioeconomic, health, care and prescription factors. We used Poisson regression model to estimate crude and adjusted prevalence ratios, their respective 95% confidence interval (95%CI) and p-value (Wald test). RESULTS: The prevalence of low adherence to drug treatment for chronic diseases was 30.8% (95%CI 28.8-33.0). The highest prevalence of low adherence was associated with individuals: young adults; no education; resident in the Northeast and Midwest Regions of Brazil; paying part of the treatment; poor self-perceived health; three or more diseases; reported limitations caused by a chronic disease; using five drugs or more. CONCLUSIONS: Low adherence to drug treatment for chronic diseases in Brazil is relevant, and regional and demographic differences and those related to patients' health care and therapy regime require coordinated action between health professionals, researchers, managers and policy makers. OBJETIVO: Analisar fatores associados a baixa adesao ao tratamento farmacologico de doencas cronicas no Brasil. METODOS: Analise de dados oriundos da Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM), inquerito domiciliar de base populacional, de delineamento transversal, baseado em amostra probabilistica da populacao brasileira. Analisou-se a associacao entre baixa adesao ao tratamento medicamentoso mensurado pelo Brief Medication Questionnaire e fatores demograficos, socioeconomicos, de saude, assistencia e prescricao. Foi utilizado modelo de regressao de Poisson para estimar as razoes de prevalencia brutas e ajustadas, os respectivos intervalos de 95% de confianca (IC95%) e p-valor (teste de Wald). RESULTADOS: A prevalencia de baixa adesao ao tratamento farmacologico de doencas cronicas foi de 30,8% (IC95% 28,8-33,0). As maiores prevalencias de baixa adesao estiveram associadas a individuos: adultos jovens; que nunca estudaram; residentes na regiao Nordeste e Centro-Oeste do Pais; que tiveram que pagar parte do tratamento; com pior autopercepcao da saude; com tres ou mais doencas; que referiam limitacao causada por uma das doencas cronicas; e que faziam uso de cinco medicamentos ou mais. CONCLUSOES: A baixa adesao ao tratamento medicamentoso para doencas cronicas no Brasil e relevante e as diferencas regionais, demograficas e aquelas relacionadas a atencao a saude do paciente e ao regime terapeutico requerem acoes coordenadas entre profissionais de saude, pesquisadores, gestores e formuladores de politicas para o seu enfrentamento. PMID- 27982377 TI - Polypharmacy and Polymorbidity in Older Adults in Brazil: a public health challenge. AB - OBJECTIVE: To analyze variations in the prevalence of chronic use of medicines by older adults in Brazil according to its possible association with the most prevalent chronic diseases and demographic and health factors, and to identify risk factors for polypharmacy. METHODS: A study based on data from the National Survey on Access, Use and Promotion of Rational Use of Medicines (PNAUM), a cross sectional, population-based survey with probability sampling in Brazilian urban areas. The independent variable was the number of chronic-use medicines taken by older adults, linked to eight chronic diseases investigated. The intervening variables were gender, age group, marital status, level of education, socioeconomic status, Brazilian region, body mass index, smoking, self-perceived health, hospitalization in the previous year and having health insurance, besides the investigated chronic diseases. A multivariable analysis identified risk factors for polypharmacy. RESULTS: Prevalence of at least one chronic-use medicines among older adults was 93.0%. Of the total number of older adults, 18.0% used at least five medications (polypharmacy). Polypharmacy was higher among the oldest individuals (20.0%), in the South region (25.0%), in those with poor self-perceived health (35.0%), in obese individuals (26.0%), in those with reported health insurance (23.0%) or hospitalization in the previous year (31.0%), and among those who reported any of the investigated diseases, particularly diabetes (36.0%) and heart diseases (43.0%). The variables remaining in the final risk model for polypharmacy were age, region, perceived health, health insurance, hospitalization in the previous year and all investigated diseases except stroke. CONCLUSIONS: Older adults with specific diseases have risk factors for polypharmacy modifiable by actions aimed at the rational use of medicines. With the current population aging and successful drug access policy, the trend is an increase in drug use by older adults, which should feature as a priority in the planning agenda of the Brazilian Unified Health System (SUS). OBJETIVO: Analisar as variacoes da prevalencia do uso cronico de medicamentos por idosos no Brasil segundo sua possivel associacao com as doencas cronicas mais prevalentes, fatores sociodemograficos e de saude, e identificar fatores de risco para polifarmacia. METODOS: Estudo com dados da Pesquisa Nacional de Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos, de carater transversal e amostra probabilistica populacional em municipios brasileiros urbanos. A variavel independente foi o numero de medicamentos de uso cronico por idosos, vinculados as oito doencas cronicas investigadas. As variaveis intervenientes foram sexo, faixa etaria, situacao conjugal, escolaridade, nivel socioeconomico, regiao do Pais, indice de massa corporal, habito de fumar, percepcao da propria saude, internacao no ultimo ano e posse de plano de saude privado, alem das doencas cronicas referidas. Uma analise multivariavel identificou os fatores de risco para polifarmacia. RESULTADOS: A prevalencia de pelo menos um medicamento de uso cronico entre idosos foi de 93,0%. Do total de idosos, 18,0% utilizavam pelo menos cinco medicamentos (polifarmacia). A polifarmacia foi maior entre os mais idosos (20,0%), na regiao Sul (25,0%), nos que avaliaram a propria saude como ruim (35,0%), nos obesos (26,0%), nos que referiram ter plano de saude (23,0%) ou internacao no ultimo ano (31,0%) e entre os que referiram qualquer uma das doencas investigadas, particularmente diabetes (36,0%) e doencas cardiacas (43,0%). No modelo final de risco para polifarmacia permaneceram idade, regiao, percepcao de saude, posse de plano de saude, internacao no ultimo ano e todas as doencas investigadas exceto acidente vascular cerebral. CONCLUSOES: Idosos com doencas especificas tem fatores de risco para polifarmacia modificaveis por acoes que visem o uso racional de medicamentos. Com o envelhecimento populacional em curso e a politica exitosa de acesso a medicamentos, a tendencia e aumentar a utilizacao de medicamentos por idosos, que deve ser prioridade na agenda de planejamento do Sistema Unico de Saude. PMID- 27982379 TI - PNAUM: integrated approach to Pharmaceutical Services, Science, Technology and Innovation. AB - This paper describes the development process of the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines) based on an integrated approach to pharmaceutical services, science, technology and innovation. It starts by contextualizing health and development in Brazil and features elements of the National Policy for Science, Technology and Innovation in Health in Brazil and the National Policy for Pharmaceutical Services. On presenting pharmaceutical policy guidelines, it stresses the lack of nationwide data. This survey, commissioned by the Brazilian Ministry of Health, has two components: household survey and evaluation of pharmaceutical services in primary care. The findings point to perspectives that represent, besides the enhancement of public policy for pharmaceutical services and public health, results of government action aimed at developing the economic and industrial health care complex to improve the health conditions of the Brazilian population. RESUMO O artigo apresenta o processo de construcao da Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamento a partir de uma concepcao integradora da Assistencia Farmaceutica, Ciencia, Tecnologia e Inovacao. Inicia se contextualizando a saude e o desenvolvimento no Pais e apresenta elementos da Politica Nacional de Ciencia Tecnologia e Inovacao em Saude no Brasil e da Politica Nacional de Assistencia Farmaceutica. Ao apresentar as diretrizes das Politicas Farmaceuticas, destaca-se a carencia de dados de abrangencia nacional. A presente pesquisa, encomendada pelo Ministerio da Saude, foi estruturada em dois componentes: inquerito domiciliar e avaliacao dos servicos de assistencia farmaceutica na atencao basica. As perspectivas dos resultados representam, alem do incremento das politicas publicas farmaceuticas e de saude publica, resultados de acoes governamentais voltadas ao desenvolvimento do complexo economico industrial da saude, visando a melhoria das condicoes de saude da populacao brasileira. PMID- 27982380 TI - Access to and use of high blood pressure medications in Brazil. AB - OBJECTIVE: To analyze the access to and use of medicines for high blood pressure among the Brazilian population according to social and demographic conditions. METHODS: Analysis of data from Pesquisa Nacional Sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines), a nationwide cross-sectional, population-based study, with probability sampling, carried out between September 2013 and February 2014 in urban households in the five Brazilian regions. The study evaluated the access and use of medicines to treat people with high blood pressure. The independent variables were gender, age, socioeconomic status and Brazilian region. The study also described the most commonly used drugs and the percentage of people treated with one, two, three or more drugs. Point estimations and confidence intervals were calculated considering the sample weights and sample complex plan. RESULTS: Prevalence of high blood pressure was 23.7% (95%CI 22.8-24.6). Regarding people with this condition, 93.8% (95%CI 92.8 94.8) had indication for drug therapy and, of those, 94.6% (95%CI 93.5-95.5) were using the medication at the time of interview. Full access to medicines was 97.9% (95%CI 97.3-98.4); partial access, 1.9% (95%CI 1.4-2.4); and no access, 0.2% (95%CI 0.1-0.4). The medication used to treat high blood pressure, 56.0% (95%CI 52.6-59.2) were obtained from SUS (Brazilian Unified Health System), 16.0% (95%CI 14.3-17.9) from Popular Pharmacy Program, 25.7% (95%CI 23.4-28.2) were paid for by the patients themselves and 2.3% (95%CI 1.8-2.9) were obtained from other locations. The five most commonly used drugs were, in descending order, hydrochlorothiazide, losartan, captopril, enalapril and atenolol. Of the total number of patients on treatment, 36.1% (95%CI 34.1-37.1) were using two medicines and 13.5% (95%CI 12.3-14.9) used three or more. CONCLUSIONS: Access to medicines for the treatment of high blood pressure may be considered high and many of them are available free of charge. The most commonly used drugs are among those recommended as first-line treatment for high blood pressure control. The percentage of people using more than one drug seems to follow the behavior observed in other countries. OBJETIVO: Analisar o acesso e a utilizacao de medicamentos para a hipertensao na populacao brasileira segundo condicoes sociais e demograficas. Analise dos dados da Pesquisa Nacional Sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos, estudo nacional de delineamento transversal de base populacional, com amostra probabilistica, realizado entre setembro de 2013 e fevereiro de 2014 em domicilios urbanos nas cinco regioes do Brasil. Avaliou-se o uso e acesso aos medicamentos para os cuidados com pessoas que apresentam hipertensao arterial. As variaveis independentes utilizadas foram sexo, idade, nivel socioeconomico e regiao do Pais. Tambem foram descritos os farmacos mais utilizados e a proporcao de pessoas tratadas com um, dois, tres ou mais farmacos. As estimativas de ponto e os intervalos de confianca foram calculados considerando os pesos amostrais e o plano complexo da amostra. A prevalencia de hipertensao arterial foi de 23,7% (IC95% 22,8-24,6). Das pessoas com a condicao, 93,8% (IC95% 92,8-94,8) tinham indicacao de tratamento com medicamentos e, destes, 94,6% (IC95% 93,5-95,5) estavam usando os medicamentos no momento da entrevista. O acesso total aos medicamentos foi de 97,9% (IC95% 97,3 98,4); o acesso parcial, de 1,9% (IC95% 1,4-2,4); e o acesso nulo, de 0,2% (IC95% 0,1-0,4). Dos medicamentos utilizados para tratar a hipertensao, 56,0% (IC95% 52,6-59,2) foram obtidos no SUS, 16,0% (IC95% 14,3-17,9), no Programa Farmacia Popular, 25,7% (IC95% 23,4-28,2) pago do proprio bolso e 2,3% (IC95% 1,8-2,9) em outros locais. Os cinco farmacos mais utilizados foram, em ordem descrente, hidroclorotiazida, losartana, captopril, enalapril e atenolol. Do total de tratados, 36,1% (IC95% 34,1-37,1) estavam usando dois farmacos e 13,5% (IC95% 12,3-14,9) utilizavam tres ou mais farmacos. CONCLUSOES: : O acesso aos medicamentos para tratamento da hipertensao pode ser considerado elevado e grande parte desses medicamentos e obtida gratuitamente. Os farmacos mais utilizados estao entre os preconizados como de primeira linha para o controle de hipertensao arterial. A proporcao de pessoas utilizando mais de um farmaco parece seguir o comportamento observado em outros paises. PMID- 27982381 TI - National Survey on Access, Use and Promotion of Rational Use of Medicines (PNAUM): household survey component methods. AB - OBJECTIVE: To describe methodological aspects of the household survey National Survey on Access, Use and Promotion of Rational Use of Medicines (PNAUM) related to sampling design and implementation, the actual obtained sample, instruments and fieldwork. METHODS: A cross-sectional, population-based study with probability sampling in three stages of the population living in households located in Brazilian urban areas. Fieldwork was carried out between September 2013 and February 2014. The data collection instrument included questions related to: information about households, residents and respondents; chronic diseases and medicines used; use of health services; acute diseases and events treated with drugs; use of contraceptives; use of pharmacy services; behaviors that may affect drug use; package inserts and packaging; lifestyle and health insurance. RESULTS: In total, 41,433 interviews were carried out in 20,404 households and 576 urban clusters corresponding to 586 census tracts distributed in the five Brazilian regions, according to eight domains defined by age and gender. CONCLUSIONS: The results of the survey may be used as a baseline for future studies aiming to assess the impact of government action on drug access and use. For local studies using a compatible method, PNAUM may serve as a reference point to evaluate variations in space and population. With a comprehensive evaluation of drug related aspects, PNAUM is a major source of data for a variety of analyses to be carried out both at academic and government level. OBJETIVO: Descrever aspectos metodologicos do inquerito domiciliar da Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM) quanto ao desenho e implementacao da amostragem e da amostra efetivamente obtida, seus instrumentos e implementacao do campo. METODOS: Estudo transversal de base populacional com amostra probabilistica em tres estagios da populacao residente nos domicilios localizados na zona urbana do Brasil. O trabalho de campo foi desenvolvido entre setembro de 2013 e fevereiro de 2014. O instrumento de coleta de dados incluiu questoes relativas a: informacoes do domicilio, dos moradores e dos entrevistados; doencas cronicas e medicamentos utilizados; uso de servicos de saude; doencas e eventos agudos tratados com medicamentos; uso de contraceptivos; uso de servicos de farmacia; comportamentos que podem afetar o uso de medicamentos; bulas e embalagens; estilo de vida e planos de saude. RESULTADOS: Foram realizadas 41.433 entrevistas em 20.404 domicilios e 576 conglomerados que correspondem a 586 setores censitarios distribuidos nas cinco regioes do Brasil, segundo oito dominios definidos por grupos de idade e sexo. CONCLUSOES: Os resultados obtidos no inquerito podem ser utilizados como uma linha de base para futuros estudos que pretendam avaliar o impacto de acoes governamentais nas areas de acesso e de utilizacao de medicamentos. Para estudos locais que venham a usar um metodo compativel, a PNAUM pode servir como ponto de referencia para avaliacao de variacoes do espaco e da populacao. Com ampla avaliacao dos aspectos relacionados aos medicamentos, a PNAUM e uma grande fonte de dados para as mais variadas analises, que podem ser conduzidas tanto no meio academico como no ambito governamental. PMID- 27982382 TI - Access to medicines for chronic diseases in Brazil: a multidimensional approach. AB - OBJECTIVE: To analyze the access to medicines to treat non-communicable diseases in Brazil according to socioeconomic, demographic, and health-related factors, from a multidimensional perspective. METHODS: Analysis of data from the National Survey on Access, Use and Promotion of Rational Use of Medicines (PNAUM), household survey, sampling plan by conglomerates with representativeness of the Brazilian population and large areas of the country, according to sex and age domains. Data collected in 2013-2014 with sample of adults (>= 20 years) who reported having non-communicable diseases and medical indication for use of medicines (n = 12,725). We assessed the prevalence of access to medicines for self-reported non-communicable diseases, considering four dimensions: availability, geographic accessibility, acceptability, and affordability. We applied Pearson's Chi-square test to assess the statistical significance of the differences between strata, considering the level of significance of 5%. We found prevalence of 94.3%, 5.2%, and 0.5% for full, partial, and null access, respectively. Higher prevalence was observed among seniors in the South compared to the Northeast; for those who reported having one non-communicable disease compared to those who reported having two or more; for those who needed one medicine compared to those who needed three or more; and for those who self assessed their health as good or very good. Geographic accessibility was similar in the Unified Health System and in the private pharmacies (72.0%). Total availability of medicines was 45.2% in the Unified Health System, 67.4% in the Popular Pharmacy Program, and 88.5% in private pharmacies. Acceptability was 92.5% in the Unified Health System, 97.8% in the Popular Pharmacy Program, and 98.7% in private pharmacies. As to affordability, 2.6% of the individuals failed to take the medicines they should in the 30-day period prior to the interview due to financial difficulty. Prevalence of full access to medicines for non communicable diseases in Brazil is high and presents significant differences for age group, region of the country, number of non-communicable diseases, and for medicines prescribed and self-assessment of health. The major barriers to access to medicines were identified in the dimensions analyzed. OBJETIVO: Analisar o acesso a medicamentos para tratar doencas cronicas nao transmissiveis no Brasil segundo fatores socioeconomicos, demograficos e de saude, sob perspectiva multidimensional. METODOS: Analise de dados da Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM), inquerito domiciliar, plano amostral por conglomerados com representatividade da populacao brasileira e grandes regioes do Pais, segundo dominios de sexo e idade. Dados coletados em 2013-2014 com amostra constituida por adultos (>= 20 anos) que referiram ter doencas cronicas nao transmissiveis e indicacao medica para usar medicamentos (n = 12.725). Avaliou-se a prevalencia de acesso aos medicamentos para doencas cronicas nao transmissiveis autorreferidas, considerando quatro dimensoes: disponibilidade, acessibilidade geografica, aceitabilidade e capacidade aquisitiva. Aplicou-se teste Qui-quadrado de Pearson para avaliar a significancia estatistica das diferencas entre os estratos, considerando o nivel de significancia de 5%. RESULTADOS: Foram encontradas prevalencias de 94,3%, 5,2% e 0,5% para acesso total, parcial e nulo, respectivamente. Maiores prevalencias ocorreram entre os idosos, na regiao Sul comparada a regiao Nordeste; naqueles que referiram ter uma doenca cronica nao transmissivel comparados aos que referiram ter duas ou mais; naqueles que precisavam de um medicamento comparados aos que precisavam de tres ou mais; e naqueles que autoavaliaram sua saude como boa ou muito boa. A acessibilidade geografica foi semelhante no Sistema Unico de Saude e nas farmacias privadas (72,0%). A disponibilidade total de medicamentos foi de 45,2% no Sistema Unico de Saude, 67,4% no Programa Farmacia Popular e 88,5% nas farmacias privadas. A aceitabilidade foi de 92,5% no Sistema Unico de Saude, 97,8% no Programa Farmacia Popular e 98,7% nas farmacias privadas. Quanto a capacidade aquisitiva, 2,6% dos individuos nao tomou os medicamentos que deveria nos 30 dias anteriores a entrevista devido a dificuldade financeira. CONCLUSOES: A prevalencia do acesso total aos medicamentos para doencas cronicas nao transmissiveis no Brasil e alta e apresenta diferencas significativas por faixa etaria, regiao do Pais, numero de doencas cronicas nao transmissiveis e de medicamentos prescritos e autoavaliacao da saude. Foram identificadas as principais barreiras ao acesso a medicamentos nas dimensoes analisadas. PMID- 27982383 TI - Catastrophic expenditure on medicines in Brazil. AB - OBJECTIVE: To describe the magnitude of the expenditure on medicines in Brazil according to region, household size and composition in terms of residents in a situation of dependency. METHODS: Population-based data from the national household survey were used, with probabilistic sample, applied between September 2013 and February 2014 in urban households. The expenditure on medicines was the main outcome of interest. The prevalence and confidence intervals (95%CI) of the outcomes were stratified according to socioeconomic classification and calculated according to the region, the number of residents dependent on income, the presence of children under five years and residents in a situation of dependency by age. RESULTS: In about one of every 17 households (5.3%) catastrophic health expenditure was reported and, in 3.2%, the medicines were reported as one of the items responsible for this situation. The presence of three or more residents (3.6%) and resident in a situation of dependency (3.6%) were the ones that most reported expenditure on medicines. Southeast was the region with the lowest prevalence of expenditure on medicines. The prevalence of households with catastrophic health expenditure and on medicines in relation to the total of households showed a regressive tendency for economic classes. CONCLUSIONS: Catastrophic health expenditure was present in 5.3%, and catastrophic expenditure on medicines in 3.2% of the households. Multi-person households, presence of residents in a situation of economic dependency and belonging to the class D or E had the highest proportion of catastrophic expenditure on medicines. Although the problem is important, permeated by aspects of iniquity, Brazilian policies seem to be protecting families from catastrophic expenditure on health and on medicine. OBJETIVO: Descrever a magnitude do gasto catastrofico em medicamentos no Brasil segundo regiao, tamanho das familias e composicao familiar em termos de moradores em situacao de dependencia. METODOS: Utilizados dados de inquerito domiciliar nacional, de base populacional, com amostra probabilistica, aplicado entre setembro de 2013 e fevereiro de 2014 em domicilios urbanos. O gasto catastrofico em medicamentos foi o principal desfecho de interesse. As prevalencias e intervalos de confianca de 95% (IC95%) desses desfechos foram estratificados segundo classificacao socioeconomica e calculadas de acordo com a regiao, o numero de moradores dependentes da renda, a presenca de criancas menores de cinco anos e de moradores em situacao de dependencia, por idade. RESULTADOS: Em cerca de um de cada 17 domicilios (5,3%) foi relatado gasto catastrofico em saude e, em 3,2%, os medicamentos foram reportados como um dos itens responsaveis por esta situacao. Presenca de tres ou mais moradores (3,6%) e morador em situacao de dependencia jovem (3,6%) foram as situacoes com maior relato de gasto catastrofico em medicamentos. O Sudeste foi a regiao com menor prevalencia de gasto catastrofico em medicamentos. As prevalencias de domicilios com gasto catastrofico em saude e medicamentos em relacao ao total de domicilios apresentaram tendencia regressiva para as classes economicas. CONCLUSOES: O gasto catastrofico em saude esteve presente em 5,3% e o gasto catastrofico em medicamentos, em 3,2% dos domicilios. Domicilios pluripessoais, presenca de moradores em situacao de dependencia economica e pertencimento a classe D ou E tiveram a maior proporcao de gasto catastrofico em medicamentos. Ainda que o problema se mostre importante, permeado por aspectos de iniquidade, as politicas brasileiras parecem estar protegendo as familias do gasto catastrofico em saude e em medicamentos. PMID- 27982385 TI - Profile of access and use of medicines in the Brazilian population - contributions and challenges of PNAUM - Household Survey. PMID- 27982386 TI - National health surveys are too important to depend on the mood of politics. PMID- 27982384 TI - Use of and access to oral and injectable contraceptives in Brazil. AB - OBJECTIVE: To analyze the prevalence of current use of oral and injectable contraceptives by Brazilian women, according to demographic and socioeconomic variables and issues related to access to those medicines. METHODS: A cross sectional, population-based analytical study with probability sampling based on data from the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines), carried out between September 2013 and February 2014 in 20,404 Brazilian urban households. Prevalence was calculated based on reports from non-pregnant women aged 15-49 on the use of oral or injectable contraceptives. The independent variables were gender, age, level of education, socioeconomic class, Brazilian region and marital status. Also analyzed were access, means of payment, sources, and reported medicines. Statistical analyses considered 95% confidence intervals (95%CI) and Pearson Chi-square test to evaluate the statistical significance of differences between groups, considering a 5% significance level. RESULTS: Prevalence of use was 28.2% for oral contraceptives (OC) and 4.5% for injectable contraceptives (IC). The highest prevalence of oral contraceptives was in the South region (37.5%) and the lowest in the North region (15.7%). For injectable contraceptives there was no difference between regions. Access was higher for oral contraceptive users (90.7%) than injectable contraceptives users (81.2%), as was direct payment (OC 78.1%, IC 58.0%). Users who paid for contraceptives acquired them at retail pharmacies (OC 95.0% and IC 86.6%) and at Farmacia Popular (Popular Pharmacy Program) (OC 4.8% and IC 12.7%). Free of charge contraceptives were mostly obtained from the Brazilian Unified Health System - SUS (OC 86.7%; IC 96.0%). Free samples were reported by 10.4% of users who did not pay for oral contraceptives. Most of paying users did not try to obtain contraceptives from SUS. Monophasic combined oral contraceptives were the most frequently reported (71.6%) and low-level levonorgestrel + ethinylestradiol combination accounted for 38.7% of them. The most frequently reported medicines are included in the Relacao Nacional de Medicamentos Essenciais (RENAME - National List of Essential Medicines. CONCLUSIONS: Most women aged 15 to 49 who reported using contraceptives had access to the medicine and use monophasic combined oral contraceptives of appropriate efficiency and safety purchased by direct payment, mainly from retail pharmacies. OBJETIVO: Analisar a prevalencia do uso atual de contraceptivos orais e injetaveis por mulheres brasileiras, segundo variaveis demograficas, socioeconomicas e aspectos relacionados ao acesso a esses medicamentos. METODOS: Estudo transversal, analitico, baseado nos dados da Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM), de base populacional e amostra probabilistica, realizada entre setembro/2013 e fevereiro/2014, em 20.404 domicilios urbanos brasileiros. A prevalencia foi calculada a partir do relato das mulheres de 15 a 49 anos, nao gravidas, sobre o uso de contraceptivos orais ou contraceptivos injetaveis. As variaveis independentes foram sexo, idade, escolaridade, nivel socioeconomico, regiao geografica e situacao conjugal. Tambem foram analisados acesso, fontes de financiamento, fontes de obtencao e medicamentos citados. As analises estatisticas consideraram intervalos de confianca de 95% (IC95%) e teste Qui quadrado de Pearson para avaliacao da significancia estatistica das diferencas entre os grupos, considerando o nivel de significancia de 5%. RESULTADOS: A prevalencia de uso de contraceptivos orais (CO) foi 28,2% e de contraceptivos injetaveis (CI), 4,5%. A prevalencia de contraceptivos orais foi maior no Sul (37,5%) e menor no Norte (15,7%). Para contraceptivos injetaveis nao houve diferenca entre as regioes. O acesso foi maior para as usuarias de contraceptivos orais (90,7%) do que de contraceptivos injetaveis (81,2%), assim como o pagamento por desembolso direto (CO 78,1%; CI 58,0%). As usuarias que pagaram pelo contraceptivo compraram na farmacia comercial (CO 95,0% e CI 86,6%) e na Farmacia Popular (CO 4,8% e CI 12,7%). A principal fonte de obtencao gratuita foi o SUS (CO 86,7%; CI 96,0%). Amostra gratis foi citada por 10,4% das usuarias que nao pagaram pelos contraceptivos orais. A maioria das usuarias que pagaram, nao tentou obter no SUS. Contraceptivos orais combinados monofasico foram os mais citados (71,6%) e a combinacao levonorgestrel+etinilestradiol de baixa concentracao representou 38,7% destes. Os medicamentos mais citados constam na Relacao Nacional de medicamentos Essenciais. CONCLUSOES: A maioria das mulheres entre 15 e 49 anos que referiram usar contraceptivos obteve acesso ao medicamento, usa contraceptivos orais combinados monofasico, de eficacia e seguranca adequada, obtido com pagamento do proprio bolso, principalmente, nas farmacias comerciais. PMID- 27982387 TI - Roseni Rosangela de Sena: a life dedicated to Nursing sciences, arts and ideals. PMID- 27982388 TI - The Impact Factor: its popularity and impacts, and the need to preserve the scientific knowledge generation process. PMID- 27982389 TI - Effects of auriculotherapy on labour pain: a randomized clinical trial. AB - OBJECTIVE: Assessing the effects of auriculotherapy in pain control and its outcomes on the duration of labour. METHOD: This is a randomized, controlled, double-blind trial with preliminary data. Thirty pregnant women with gestational age >= 37 weeks, cervical dilatation >= 4 cm and two or more contractions in 10 minutes were selected and randomly divided into three groups: auriculotherapy, placebo and control. Auriculotherapy was applied using crystal beads on four strategic points. RESULTS: No statistical significance was found between the groups with regard to pain; however, the women from the auriculotherapy group had lower intensity and less perception of pain at 30, 60 and 120 minutes of treatment. The average duration of labour was shorter in the auriculotherapy group (248.7 versus placebo 414.8 versus control 296.3 minutes); caesarean section rates were higher in the placebo group (50%) and the same in the other groups (10%). CONCLUSION: Mothers who received auriculotherapy presented a tendency for greater pain control and shorter labour duration; however, caesarean section rates in this group were similar to the control group. This trial precedes a larger study in progress. Registration of Brazilian Clinical Trials: RBR-47hhbj. OBJETIVO: Avaliar os efeitos da auriculoterapia no controle da dor e seus desfechos na duracao do trabalho de parto. METODO: Trata-se de um ensaio controlado, randomizado e duplo-cego, com dados preliminares. Foram selecionadas 30 parturientes com idade gestacional >= 37 semanas, dilatacao cervical >= 4 cm e duas ou mais contracoes em 10 minutos, divididas aleatoriamente em tres grupos: auriculoterapia, placebo ou controle. A auriculoterapia foi aplicada com microesferas de cristais em quatro pontos estrategicos. RESULTADOS: Nao houve significancia estatistica entre os grupos com relacao a dor; no entanto, as mulheres do grupo de auriculoterapia, apresentaram menor intensidade e menor percepcao da dor aos 30, 60 e 120 minutos do tratamento. A media de duracao do trabalho de parto foi menor no grupo de auriculoterapia (248,7 versus placebo 414,8 versus controle 296,3 minutos); a taxa de cesarea foi maior no grupo placebo (50%) e igual nos outros (10%). CONCLUSAO: As parturientes que receberam auriculoterapia apresentaram tendencia a um maior controle da dor e menor duracao do trabalho de parto, porem a taxa de cesarea neste grupo foi semelhante a do grupo controle. Este ensaio precede um estudo maior, em andamento. Registro Brasileiro de Ensaio Clinico: RBR-47hhbj. PMID- 27982390 TI - Factors associated to Caesarean delivery in public and private health care systems. AB - OBJECTIVE: Identifying factors associated to Caesarean sections among the residents of Maringa-PR, according to the financing source for delivery. METHODS: A cross-sectional study with data from 920 postpartum women interviewed between October 2013 and February 2014. Association analysis was performed by logistic regression. RESULTS: Caesarean section rates were 55.5% in the Unified Healthcare System (SUS) and 93.8% in the private system. Factors associated with Caesarean section in the SUS were: previous Caesarean section (OR=8.9; CI=4.6-16.9), desire for Caesarean section early in pregnancy (OR=2.0; CI=1.1-3.6), pregestational overweight/obesity (OR=1.8; CI=1.1-2.8), and per capita family income higher than one minimum wage (OR=2.1; CI=1.3-3.4). In the private system, desire for Caesarean section early in pregnancy (OR=25.3) and a previous Caesarean section (OR=11.3) were strongly associated to its performance. CONCLUSION: It is necessary to properly orientate all pregnant women who desire a Caesarean delivery, from both the SUS and the private system, about the inherent risks of the surgical procedure without indication. In the public health sector, guidelines should be focused on pregnant women with previous Caesarean delivery, with a per capita income higher than one minimum wage and those who are overweight or obese, as these women are more likely to have a Caesarean section. OBJETIVO: Identificar fatores associados a cesarea entre residentes de Maringa PR, segundo a fonte de financiamento do parto. METODO: Estudo transversal com dados de 920 puerperas entrevistadas entre outubro de 2013 e fevereiro de 2014. A analise de associacao foi feita por regressao logistica. RESULTADOS: A taxa de cesariana foi de 55,5% e 93,8% no Sistema Unico de Saude (SUS) e no sistema privado, respectivamente. Associou-se a cesarea no SUS: realizacao de cesarea anterior (OR=8,9; IC=4,6-16,9), desejo pela cesarea no inicio da gestacao (OR=2,0; IC=1,1-3,6), sobrepeso/obesidade pre-gestacional (OR=1,8; IC=1,1-2,8), e renda familiar per capita maior que um salario minimo (OR=2,1; IC=1,3-3,4). No sistema privado, o desejo pela cesarea no inicio da gestacao (OR=25,3) e uma cesarea anterior (OR=11,3) estiveram fortemente associados a sua realizacao. CONCLUSAO: E necessario orientar adequadamente todas as gestantes que desejam o parto cesarea, no SUS e no sistema privado, sobre os riscos inerentes ao procedimento cirurgico sem indicacao. No setor publico de saude, devem ser foco das orientacoes as gestantes com parto cesarea anterior, as com renda familiar per capita maior que um salario minimo e com sobrepeso ou obesidade, as quais tem mais chances de realizar cesarea. PMID- 27982391 TI - Using the Bologna Score to assess normal delivery healthcare. AB - OBJECTIVE: Describing the obstetric care provided in public maternity hospitals during normal labour using the Bologna Score in the city of Natal, Northeastern Brazil. METHOD: A quantitative cross-sectional study conducted with 314 puerperal women. Data collection was carried out consecutively during the months of March to July 2014. RESULTS: Prenatal care was provided to 95.9% of the mothers, beginning around the 1st trimester of pregnancy (72.3%) and having seven or more consultations (51%). Spontaneous vaginal delivery was planned for 88.2% women. All laboring women were assisted by a health professional, mostly by a physician (80.6%), and none of them obtained 5 points on the Bologna Score due to the small percentage of births in non-supine position (0.3%) and absence of a partogram (2.2%). A higher number of episiotomies were observed among primiparous women (75.5%). CONCLUSION: The score obtained using the Bologna Index was low. Thus, it is necessary to improve and readjust the existing obstetrical model. OBJETIVO: Descrever a assistencia obstetrica prestada em maternidades publicas municipais durante o parto normal na cidade de Natal, Nordeste do Brasil, com uso do Indice de Bologna. METODO: Estudo transversal com abordagem quantitativa, desenvolvido com 314 puerperas. A coleta de dados processou-se de forma consecutiva durante os meses de marco a julho de 2014. RESULTADOS: A assistencia pre-natal foi prestada a 95,9% das puerperas, com inicio em torno do 1o trimestre de gestacao (72,3%) e realizacao de sete ou mais consultas (51%). O parto vaginal espontaneo foi planejado para 88,2% mulheres. Todas as parturientes foram assistidas por um profissional de saude, especialmente pelo medico (80,6%) e nenhuma obteve 5 pontos no Indice de Bologna em virtude dos baixos percentuais de partos em posicao nao supina (0,3%) e ausencia do partograma (2,2%). Houve maior numero de episiotomias em primiparas (75,5%). CONCLUSAO: A pontuacao obtida por meio do Indice de Bologna foi baixa. Desse modo, e preciso melhorar e readequar o modelo obstetrico vigente. PMID- 27982392 TI - Understanding of the life experience of homeless women. AB - OBJECTIVE: To understand the life experience of homeless women. METHOD: A social phenomenological study was conducted with 10 women assisted by a shelter. The analysis of the interviews was based on the theoretical framework of social phenomenology of Alfred Schutz and thematic literature. RESULTS: The participants face adversities in the street context, with emphasis on the risk of physical and sexual abuse, and seek shelters as a possibility for minimizing difficulties experienced. They hope to leave the streets; however, they see themselves trapped in this social reality, due to the addiction to alcohol and other drugs. CONCLUSION: The understanding of the life experience of homeless women shows daily confrontations and reveals the conflict between the desire for leaving and remaining on the streets, given the complexity of the reality that keeps them in this condition. OBJETIVO: Compreender a vivencia de mulheres em situacao de rua. METODO: Pesquisa fenomenologica social realizada com 10 mulheres assistidas por um albergue. A analise das entrevistas ancorou-se no referencial teorico da fenomenologia social de Alfred Schutz e literatura tematica. RESULTADOS: As participantes enfrentam adversidades no contexto da rua, com destaque para o risco de violencia fisica e sexual, e buscam o albergue como possibilidade de minimizar as dificuldades vivenciadas. Elas tem como expectativa sair da rua, porem se veem presas a esta realidade social em virtude do vicio em alcool e outras drogas. CONCLUSAO: A compreensao da vivencia de mulheres em situacao de rua aponta enfrentamentos cotidianos e revela o conflito entre o desejo de sair e permanecer na rua, dada a complexidade da realidade que as mantem nesta condicao. PMID- 27982393 TI - The culture of patient safety from the perspective of the pediatric emergency nursing team. AB - OBJECTIVE: To identify the patient safety culture in pediatric emergencies from the perspective of the nursing team. METHOD: A quantitative, cross-sectional survey research study with a sample composed of 75 professionals of the nursing team. Data was collected between September and November 2014 in three Pediatric Emergency units by applying the Hospital Survey on Patient Safety Culture instrument. Data were submitted to descriptive analysis. RESULTS: Strong areas for patient safety were not found, with areas identified having potential being: Expectations and actions from supervisors/management to promote patient safety and teamwork. Areas identified as critical were: Non-punitive response to error and support from hospital management for patient safety. The study found a gap between the safety culture and pediatric emergencies, but it found possibilities of transformation that will contribute to the safety of pediatric patients. CONCLUSION: Nursing professionals need to become protagonists in the process of replacing the current paradigm for a culture focused on safety. The replication of this study in other institutions is suggested in order to improve the current health care scenario. OBJETIVO: Identificar a cultura de seguranca do paciente em emergencias pediatricas, na perspectiva da equipe de enfermagem. METODO: Pesquisa quantitativa, tipo survey transversal. Amostra composta por 75 profissionais da equipe de enfermagem. Dados coletados entre setembro e novembro de 2014, em tres Emergencias Pediatricas, aplicando o instrumento Hospital Survey on Patient Safety Culture. Dados submetidos a analise descritiva. RESULTADOS: Nao foram encontradas areas de forca para a seguranca do paciente, sendo identificadas areas com potencial de assim se tornarem: Expectativas e acoes do supervisor/chefia para promocao da seguranca do paciente e Trabalho em equipe. Como area critica identificaram-se: Resposta nao punitiva ao erro e Apoio da gestao hospitalar para seguranca do paciente. O estudo apontou distanciamento entre a cultura de seguranca e as emergencias pediatricas, porem vislumbrou possibilidades de transformacao, que contribuirao para seguranca do paciente pediatrico. CONCLUSAO: Os profissionais de enfermagem precisam se tornar protagonistas no processo de substituicao do atual paradigma para uma cultura focada na seguranca. Sugere-se replicacao deste estudo em outras instituicoes a fim de aprimorar o atual cenario de assistencia a saude. PMID- 27982394 TI - Chronic and asymptomatic diseases influence the control of hypertension treatment in primary care. AB - OBJECTIVE: To identify the association between blood pressure control and the following variables: a) bio-social and lifestyle characteristics of hypertensive patients; and b) factors related to the antihypertensive treatment. METHODS: This is an exploratory study with 290 people with hypertension from primary care. We used a specific instrument, self-administered, with 21 questions on factors that can hinder treatment, divided into four dimensions: medication, socioeconomic, institutional and personal beliefs. We adopted a significance level of p <0.05. RESULTS: The control of blood pressure was associated (p <0.05) with female gender, Caucasian ethnicity, primary/secondary education, not drinking alcohol, higher income and regular physical activity. Regarding the factors that can hinder treatment, there was association of hypertension control with only two questions: "feel nothing" and "have to do treatment for life". CONCLUSION: Sociodemographic variables and beliefs concerning the absence of symptoms and chronicity of the disease influenced the control of hypertension and should be considered in the adherence process to the treatment. OBJETIVO: Identificar a associacao entre o controle da pressao arterial e as seguintes variaveis: a) caracteristicas biossociais e habitos de vida dos hipertensos; e b) fatores relacionados ao tratamento anti-hipertensivo. METODOS: Realizou-se estudo exploratorio com 290 hipertensos da atencao primaria. Utilizou-se de instrumento especifico, autoaplicavel, com 21 questoes sobre fatores que podem dificultar o tratamento, divididas em quatro dominios: medicamentos, socioeconomico, institucional e crencas pessoais. Adotou-se nivel de significancia de p < 0,05. RESULTADOS: O controle da pressao arterial se associou (p < 0,05) com sexo feminino, etnia branca, ensino fundamental/medio, nao ingerir bebida alcoolica, maior renda e atividade fisica regular. Quanto aos fatores que podem dificultar o tratamento, houve associacao do controle com apenas duas questoes: "nao sentir nada" e "ter que fazer tratamento para vida toda". CONCLUSAO: Variaveis sociodemograficas e crencas relativas a ausencia de sintomatologia e cronicidade da doenca influenciaram o controle dos hipertensos e devem ser consideradas no processo de adesao ao tratamento. PMID- 27982395 TI - Maternal perception of their child's nutritional status at less than three years old. AB - OBJECTIVE: Assessing maternal perception of their children's nutritional status and identifying associated factors. METHODS: A cross-sectional study conducted in a small municipality with 342 children less than 3 years of age treated in Basic Health Units of Sao Paulo. Nutritional status was classified in percentiles of body mass index for age and maternal perception was assessed using the scale of verbal descriptors (very thin, thin, healthy weight, fat, very fat). Logistic regression was used to identify the associatedfactors. RESULTS: 44.7% of maternal perception was found to beinadequate. Mothers of overweight (OR = 11.8, 95% CI: 6.4-21.7) and underweight (OR = 5.5; 95% CI: 1.9-16.2) children had a higher chance of having inadequate perception, similar to mothers of children over 24 months of age (OR = 2.9; 95% CI: 1.4-6.0). CONCLUSION: For effective child care in primary care, healthcare professionals should consider maternal perception and helpmothers to identify the nutritional status of children in childcare consultations and growth monitoring. OBJETIVO: Avaliar a percepcao materna do estado nutricional do filho e identificar os fatores associados. METODO: Estudo transversal realizado em municipio de pequeno porte com 342 criancas menores de 3anos atendidas em Unidades Basicas de Saude do Estado de Sao Paulo. O estado nutricional foi classificado em percentis do Indice de Massa Corporalpara Idade e a percepcao materna foi avaliada com escala de descritores verbais (muito magro, magro, peso adequado, gordo, muito gordo). Utilizou-se de regressao logistica para identificar os fatores associados. RESULTADOS: Constatou-se 44,7% de percepcao materna inadequada. Maes de criancas com excesso de peso (OR=11,8; IC95%:6,4-21,7) e com baixo peso (OR=5,5; IC95%:1,9-16,2) apresentaram mais chance de percepcao inadequada, da mesma forma que maes de criancas com mais de 24 meses de idade (OR=2,9; IC95%:1,4-6,0). CONCLUSAO: Para uma efetiva assistencia a crianca na atencao basica, profissionais de saude devem considerar a percepcao materna e auxiliar as maes na identificacao do estado nutricional do filho nas consultas de puericultura e acompanhamento do crescimento. PMID- 27982397 TI - Use of alcohol and other drugs among male university students and its meanings. AB - OBJECTIVE: To understand the meanings that male university students assign to the condition of users of alcohol and other drugs. METHOD: An exploratory study using a qualitative approach, with inductive analysis of the content of semi-structured interviews applied to 20 male university students from a public university in the southeast region of Brazil, grounded on the theoretical-methodological referential of interpretive anthropology and ethnographic method. RESULTS: Data were construed using content inductive analysis for two topics: use of alcohol and/or drugs as an outlet; and use of alcohol and/or other drugs: an alternative for belonging and identity. CONCLUSION: Male university students share the rules of their sociocultural environment that values the use of alcohol and/or other drugs as a way of dealing with the demands and stress ensuing from the everyday university life, and to build identity and belong to this social context, reinforcing the influence of culture. OBJETIVO: Compreender os significados atribuidos pelos universitarios do sexo masculino a condicao de usuarios de alcool e outras drogas. METODO: Estudo exploratorio de abordagem qualitativa, com analise de conteudo indutiva de entrevistas semiestruturadas de 20 universitarios do sexo masculino, matriculados em uma universidade publica da regiao sudeste do Brasil, fundamentado no referencial teorico-metodologico da Antropologia Interpretativa e do metodo etnografico. RESULTADOS: Os dados foram interpretados com a analise de conteudo indutiva em dois temas: O uso do alcool e/ou drogas como valvula de escape; O uso do alcool e/ou outras drogas: alternativa para o pertencimento e para a identidade. CONCLUSAO: Os universitarios do sexo masculino compartilham normas de seu meio sociocultural, que valorizam o uso de alcool e/ou outras drogas, como uma forma de lidar com as exigencias e o estresse da vida universitaria, criar uma identidade e ter pertencimento neste contexto social, reforcando a influencia da cultura. PMID- 27982396 TI - Professionals and interfamily violence against children and adolescents: in between legal and conceptual precepts. AB - OBJECTIVE: To identify the conceptions of professionals regarding interfamily violence against children and adolescents. METHOD: A qualitative study conducted with 15 professionals who had taken children and adolescents under their care as a result of interfamily violence. Data were collected between November, 2013, and March, 2015, through semi-structured interviews. Data were organized and analyzed using the Textual Discourse Analysis technique. RESULTS: The professional discourse highlighted that some legal aspects regarding the handling of interfamily violence against children and adolescents are neglected; an omission supported by the justification of professionals to preserve the family. We highlight the confrontation between the concept of family as a caregiver and the family that commits violence against children, in addition to the positioning of professionals, which does not include the family or the aggressor in the intervention process in facing situations of interfamily violence attended to by the services. CONCLUSION: Acting against interfamily violence requires professionals to do away with some pre-established concepts in ordee to put the actual needs of victims and families into evidence. OBJETIVO: Identificar, com base no discurso dos profissionais, suas concepcoes a respeito da violencia intrafamiliar contra criancas e adolescentes. METODO: Estudo qualitativo, realizado com 15 profissionais, que tiveram sob seus cuidados criancas e adolescentes atendidas em decorrencia da violencia intrafamiliar. Os dados foram coletados entre novembro de 2013 e marco de 2015, por meio de entrevistas semiestruturadas. Os dados foram organizados e analisados utilizando a tecnica de Analise Textual Discursiva. RESULTADOS: O discurso dos profissionais colocou em evidencia que alguns aspectos legais em relacao ao manejo da violencia intrafamiliar contra criancas e adolescentes sao negligenciados, omissao respaldada pela justificativa dos profissionais de preservar a familia. Destaca se o confronto entre a concepcao de familia como cuidadora e a familia que violenta os filhos, alem do posicionamento dos profissionais, os quais nao incluem a familia e o agressor nos processos de intervencao frente as situacoes de violencia intrafamiliar atendidas nos servicos. CONCLUSAO: Atuar frente a violencia intrafamiliar requer do profissional romper com algumas concepcoes preestabelecidas para colocar em evidencia as reais necessidades de vitimas e familias. PMID- 27982398 TI - Nursing workload for cancer patients under palliative care. AB - OBJECTIVE: To verify the nursing workload required by cancer patients undergoing palliative care and possible associations between the demographic and clinical characteristics of the patients and the nursing workload. METHOD: This is a quantitative, cross-sectional, prospective study developed in the Connective Bone Tissue (TOC) clinics of Unit II of the Brazilian National Cancer Institute Jose Alencar Gomes da Silva with patients undergoing palliative care. RESULTS: Analysis of 197 measures of the Nursing Activities Score (NAS) revealed a mean score of 43.09% and an association between the performance status of patients undergoing palliative care and the mean NAS scores. The results of the study point to the need to resize the team of the unit. CONCLUSION: The NAS has proven to be a useful tool in oncologic clinical units for patients undergoing palliative care. OBJETIVO: Verificar a carga de trabalho de enfermagem requerida por pacientes com cancer sob cuidados paliativos e possiveis associacoes entre as caracteristicas demograficas e clinicas dos pacientes e a carga de trabalho de enfermagem. METODO: Trata-se de um estudo de abordagem quantitativa, transversal, prospectivo, desenvolvido na clinica de Tecido Osseo Conectivo (TOC) da Unidade II do Instituto Nacional de Cancer Jose Alencar Gomes da Silva, com pacientes em cuidados paliativos. RESULTADOS: A analise de 197 medidas do Nursing Activities Score (NAS) revelou um escore medio de 43,09% e uma associacao entre a performance status de pacientes em cuidados paliativos com os valores medios do NAS. Os resultados do estudo apontam para a necessidade de redimensionamento da equipe da Unidade. CONCLUSAO: O NAS mostrou-se um instrumento passivel de utilizacao em unidades clinicas oncologicas, com pacientes em cuidados paliativos. PMID- 27982399 TI - Anxiety symptoms and quality of interaction among oncology nurses: a correlational, cross-sectional study. AB - OBJECTIVE: To explore the severity of Anxiety Symptoms (AS) among Greek oncology nursing personnel, the degree of satisfaction from professional relationships, and potential association between them. METHOD: A descriptive cross-sectional correlational study was performed in 2 Greek Oncology Hospitals, in 72 members of nursing personnel. Hamilton Anxiety Scale was used for the assessment of AS severity and the Index of Work Satisfaction subscale "Satisfaction from Interaction" for the degree of satisfaction from professional relationships among nursing personnel (NN) and between nursing personnel and physicians (NP). RESULTS: 11% of the sample reported clinical AS [>=26, scale range (SR): 0-52]. Satisfaction from NN [5.10 (SD: 1.04), SR: 1-7], and NP [4.21 (SD: 0.77), SR: 1 7] professional interaction were both moderate. Statistically significantly associations were observed between clinical AS and satisfaction from NN (p=0.014) and NP (p=0.013) professional interaction. CONCLUSIONS: Anxiety reduction interventions and improvement of professional relationships are essentials in order to reduce oncology nurses' psychological distress. PMID- 27982400 TI - Experience of health professionals in care of the homeless population with tuberculosis. AB - OBJECTIVE: Analyzing statements of health professionals from a Street Clinic regarding care of a homeless population with tuberculosis. METHOD: This is a qualitative research, conducted in the central region of Sao Paulo at three basic health units in the period of November to December 2014. A semi-structured interview guideline was implemented for data collection and all interviews were recorded using a digital recorder. RESULTS: Six health professionals were interviewed. According to the Discourse Analysis perspective, three discursive segments emerged: experiences on care in the streets; weaknesses inherent to the treatment process; and incentives as a means of maintaining sick people in treatment. CONCLUSION: Caring for a the homeless population with tuberculosis constitutes a new and challenging experience. It involves difficulties in dealing with the reality of a miserable social context, a lack and inadequacy of services, as well as care limitations for treatment and treatment dropout, which reinforces multiresistance. However, the investigated Street Clinic teams seek to expand access to health and social care services to this population. OBJETIVO: Analisar os discursos dos profissionais de saude do Consultorio na Rua em relacao ao cuidado a pessoa em situacao de rua com tuberculose. METODO: Trata-se de uma pesquisa qualitativa, realizada na regiao central do municipio de Sao Paulo, em tres Unidades Basicas de Saude, no periodo de novembro a dezembro de 2014. Utilizou-se de um roteiro de entrevista semiestruturada para a coleta de dados e todas as entrevistas foram gravadas com recurso a um gravador digital. RESULTADOS: Foram entrevistados seis profissionais de saude. Segundo a perspectiva da Analise de Discurso, emergiram tres blocos discursivos: experiencia sobre o cuidar na rua; fragilidades inerentes ao processo de tratamento e incentivos como meio para a permanencia do sujeito doente no tratamento. CONCLUSAO: Cuidar da pessoa com tuberculose e em situacao de rua constitui uma experiencia nova e desafiadora, implica dificuldades em lidar com a realidade de um contexto social miseravel, falta e inadequacao de servicos, bem como limitacoes do cuidado para a cura e abandono do tratamento, podendo reforcar a multirresistencia. Contudo, as equipes de Consultorio na Rua investigadas buscam ampliar o acesso aos servicos de saude e assistencia social a essa populacao. PMID- 27982401 TI - Comprehensiveness and humanization of nursing care management in the Intensive Care Unit. AB - OBJECTIVE: Identifying the elements that promote comprehensiveness and humanization of nursing care management in the Intensive Care Unit, with an ecosystemic approach. METHOD: A documentary qualitative study. The method of documentary analysis was used for data analysis. RESULTS: Four pre-established categories were identified - Technical; Organizational; Technological; and Humanizing Dimensions. Data resulted in forming two sub-categories that integrate the humanizing dimension category, namely 'Comprehensiveness in healthcare actions' and 'Integrating processes and promoters of humanization,' bringing forth implications and challenges in forms of managing health work processes, enabling organizational, structural and managerial changes to the provided healthcare. CONCLUSION: It was considered that all structural elements in managing nursing care with a focus on the needs of users should be in line with public policies and the principles of comprehensiveness and humanization, thus possessing strong potential for transforming health practices. OBJETIVO: Identificar os elementos capazes de promover a integralidade e a humanizacao na gestao do cuidado de enfermagem na Unidade de Terapia Intensiva, com enfoque ecossistemico. METODO: Pesquisa documental, de natureza qualitativa. Para a analise dos dados utilizou-se do metodo da analise documental. RESULTADO: SForam identificadas quatro categorias preestabelecidas - Dimensoes: Tecnica; Organizacional; Tecnologica e Humanizadora. Os dados resultantes das duas subcategorias que integraram a categoria Dimensao Humanizadora, Integralidade nas acoes do cuidado e Processos integradores e promotores de humanizacao, trazem implicacoes e desafios nos modos de gerir os processos de trabalho em saude, o que possibilita transformacoes organizacionais, estruturais e gerenciais na producao do cuidado. CONCLUSAO: Considera-se que na gestao do cuidado de enfermagem todos os elementos estruturantes, com enfoque nas necessidades dos usuarios, devem estar em consonancia com as politicas publicas e os principios da integralidade e da humanizacao e possuir forte potencial para a transformacao das praticas em saude. PMID- 27982402 TI - Physical methods for the treatment of fever in critically ill patients: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effects of physical methods of reducing body temperature (ice pack and warm compression) in critically ill patients with fever. METHOD: A randomized clinical trial involving 102 adult patients with tympanic temperature >= 38.3 degrees C of an infectious focus, and randomized into three groups: Intervention I - ice pack associated with antipyretic; Intervention II - warm compress associated with antipyretic; and Control - antipyretic. Tympanic temperature was measured at 15 minute intervals for 3 hours. The effect of the interventions was evaluated through the Mann-Whitney test and Survival Analysis. "Effect size" calculation was carried out. RESULTS: Patients in the intervention groups I and II presented greater reduction in body temperature. The group of patients receiving intervention I presented tympanic temperature below 38.3 degrees C at 45 minutes of monitoring, while the value for control group was lower than 38.3 degrees C starting at 60 minutes, and those who received intervention II had values lower than 38.3 degrees C at 75 minutes of monitoring. CONCLUSION: No statistically significant difference was found between the interventions, but with the intervention group I patients showed greater reduction in tympanic temperature compared to the other groups. Brazilian Registry of Clinical Trials: RBR-2k3kbq. OBJETIVO: Avaliar o efeito de metodos fisicos (bolsa de gelo e compressa morna) na reducao da temperatura corporal de pacientes criticos com febre. METODO: Ensaio clinico randomizado com 102 pacientes adultos e temperatura timpanica >= 38,3 degrees C de foco infeccioso, aleatorizados em tres grupos: Intervencao I - bolsa de gelo associada a antitermico; Intervencao II - compressa morna associada a antitermico; e Controle - antitermico. A temperatura timpanica foi mensurada em intervalos de 15 minutos durante 3 horas. O efeito das intervencoes foi avaliado pelo teste Mann-Whitney e Analise de Sobrevivencia. Calculo do "Effect size" foi procedido. RESULTADOS: Os pacientes dos grupos Intervencao I e II apresentaram maior reducao na temperatura corporal. A partir de 45 minutos de acompanhamento o grupo de pacientes que recebeu a Intervencao I apresentou valor da temperatura timpanica inferior a 38,3 degrees C, os do grupo controle valor menor que 38,3 degrees C a partir de 60 minutos e os que receberam a Intervencao II, valor menor que 38,3 degrees C com 75 minutos de acompanhamento. CONCLUSAO: Nao foi encontrada diferenca estatistica significativa entre as intervencoes, porem os pacientes do grupo Intervencao I apresentaram maior reducao da temperatura timpanica em relacao aos demais grupos. Registro Brasileiro de Ensaios Clinicos: RBR-2k3kbq. PMID- 27982404 TI - Risk management in providing specialized care for people living with AIDS. AB - OBJECTIVE: Analyzing the provision of actions related to managing clinical risk in managing specialized care for people living with AIDS. METHOD: A cross sectional study carried out in a reference outpatient clinic in Paraiba, with a sample of 150 adults with AIDS. Data were collected through primary and secondary sources using a structured questionnaire, analyzed using descriptive statistics, multiple correspondence analysis and logistic regression model to determine the association between "providing care" and "clinical risk." RESULTS: Actions with satisfactory provision express a biological care focus; the dimensions that most contributed to a satisfactory assessment of care provision were "clinical and laboratory evaluations" and "prevention and self-care incentivization"; 45.3% of participants were categorized into high clinical risk, 34% into average clinical risk, and 20.7% into low clinical risk; a positive association between providing care and clinical risk was found. CONCLUSION: The need to use risk classification technologies to direct the planning of local care provision became evident considering its requirements, and thus qualifying the care provided in these areas. OBJETIVO: Analisar a oferta de acoes relacionadas ao manejo de risco clinico na gestao do cuidado especializado a pessoas vivendo com aids. METODO: Estudo transversal realizado em ambulatorio de referencia na Paraiba, com amostra de 150 adultos com aids. Os dados foram coletados por meio de fontes primarias e secundarias utilizando-se de formulario estruturado, e analisados atraves de estatistica descritiva, analise de correspondencia multipla e modelo de regressao logistica para averiguar a associacao entre "oferta" e "risco clinico". RESULTADOS: As acoes de oferta satisfatoria expressam foco biologicista do cuidado; as dimensoes que mais contribuiram para o julgamento satisfatorio da oferta foram "avaliacao clinica e laboratorial" e "prevencao e estimulo ao autocuidado"; 45,3% dos participantes foram categorizados em risco clinico alto, 34% em risco clinico medio, e 20,7% em risco clinico baixo; e verificou-se associacao positiva entre oferta e risco clinico. CONCLUSAO: Ficou evidente a necessidade da utilizacao de tecnologias de classificacao de risco para direcionar o planejamento da oferta local, considerando-se as necessidades, e assim qualificar o cuidado produzido nestes espacos. PMID- 27982405 TI - Analysis of suffering at work in Family Health Support Centers. AB - OBJECTIVE: Analyzing the work process in the Family Health Support Center. METHOD: An exploratory, descriptive case study using a qualitative approach. Focus groups were conducted with 20 workers of a Family Health Support Center, and the empirical material was subjected to content analysis technique and analyzed in light of Work Psychodynamics. RESULTS: The category of suffering is presented herein as arising from the dialectical contradiction between actual work and prescribed work, from resistance to the Family Health Support Center's proposal and a lack of understanding of their role; due to an immediatist and curative culture of the users and the Family Health Strategy; of the profile, overload and identification with work. CONCLUSION: The dialectical contradiction between expectations from Family Health Strategy teams and the work in the Family Health Support Center compromises its execution and creates suffering for workers. OBJETIVO: Analisar o processo de trabalho no Nucleo de Apoio a Saude da Familia. METODO: Estudo de caso exploratorio, descritivo e de abordagem qualitativa. Grupos focais foram realizados com 20 trabalhadores do Nucleo de Apoio a Saude da Familia, o material empirico foi submetido a tecnica de analise de conteudo e analisado a luz da Psicodinamica do Trabalho. RESULTADOS: Apresenta se aqui a categoria sofrimento que neste estudo decorre da contradicao dialetica entre o trabalho real e o trabalho prescrito, da resistencia a proposta do Nucleo de Apoio a Saude da Familia e da falta de compreensao de seu papel; da cultura imediatista e curativa do usuario e da Estrategia Saude da Familia; do perfil, sobrecarga e identificacao com o trabalho. CONCLUSAO: A contradicao dialetica entre expectativas das equipes da Estrategia Saude da Familia e o trabalho no Nucleo de Apoio a Saude da Familia compromete sua efetivacao e gera sofrimento aos trabalhadores. PMID- 27982403 TI - Urinary retention: implications of low-fidelity simulation training on the self confidence of nurses. AB - METHOD: This was a quasi-experimental study carried out among nurses stationed in municipal care units in the interior of Sao Paulo State. Data were collected during the course of a pedagogical workshop that used low-fidelity simulation training. RESULTS: The study included 42 nurses, mostly female with over 15 years of experience. After low-fidelity simulation training, nurses showed a significant increase (p<0.05) in confidence related to nursing care in urinary retention. The lowest self-attributed scores during the activity were related to the objective assessment of urinary retention. CONCLUSION: Low-fidelity simulated training is an effective resource for the development of nurses with respect to nursing care in urinary retention. OBJETIVO: Avaliar o nivel de autoconfianca de enfermeiros na assistencia de enfermagem na retencao urinaria antes e apos atividade simulada de baixa fidelidade. METODO: Estudo quase-experimental realizado junto aos enfermeiros lotados nas unidades de atendimento de municipio do interior do estado de Sao Paulo. Os dados foram coletados durante a realizacao de uma oficina pedagogica que contou com atividade simulada de baixa fidelidade. RESULTADOS: Participaram do estudo 42 enfermeiros, a maioria do sexo feminino e com mais de 15 anos de atuacao. Apos o treino simulado de baixa fidelidade os enfermeiros demonstraram aumento significativo (p < 0,05) na autoconfianca relacionada a assistencia de enfermagem na retencao urinaria. Os menores escores autoatribuidos durante a atividade foram relacionados a avaliacao objetiva da retencao urinaria. CONCLUSAO: A simulacao de baixa fidelidade e um recurso efetivo no aprimoramento de enfermeiros no que diz respeito a assistencia de enfermagem na retencao urinaria. PMID- 27982406 TI - Chinese phytotherapy to reduce stress, anxiety and improve quality of life: randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of Chinese phytotherapyto reduce stress levels, anxiety and improve quality of life. METHOD: double-blind randomized controlled trial with 89 volunteers divided into three groups: control (no intervention), Placebo and Phytotherapy. The study was conducted in 2015 with healthy adults treated at the Integrated and Eastern Therapy Institute,in Sao Paulo, Brazil. Participants were evaluated at baseline and after three weeks with the Stress Symptoms List (SSL), Anxiety Inventory-Trait and State and SF12v2 for quality of life. Intervention groups received a placebo or Gan May Zao formula (GMDZ)flaskwith 50 ml. RESULTS: According to ANOVA, there were significant differences (p = 0.025) after treatment of stress (SSL2). And the difference was between control and Phytotherapy groups, according to the Tukey post hoc (p = 0.022). There were no differences in the levels of state-anxiety and physical and mental domains in the SF12v2. CONCLUSION: The GMDZ formula reduced stress levels, but more studies are needed with greater sample, with reassessment of dosage and a longer period of treatment to confirm and extend the results. Brazilian Registry of Clinical Trials: RBR-28s4hz. OBJETIVO: Avaliar o efeito da fitoterapia chinesa na reducao de niveis de estresse, ansiedade e melhoria de qualidade de vida. METODO: Ensaio clinico randomizado duplo-cego, com 89 voluntarios divididos em tres grupos: Controle (sem intervencao), Placebo e Fitoterapia. Foi realizado em 2015, com adultos saudaveis atendidos no Instituto de Terapia Integrada e Oriental, Sao Paulo. Foram avaliados no baseline e, apos 3 semanas,pela Lista de Sintomas de Stress (LSS), Inventario de Ansiedade-Traco e Estado e o SF12v2 de qualidade de vida. Os grupos de intervencao receberam um frasco de 50 ml de placebo ou da formula Gan Mai Da Zao (GMDZ). RESULTADOS: Segundo ANOVA, houve diferenca (p=0,025) no pos-tratamento de estresse (LSS2). E a diferenca foi entre os grupos Controle e Fitoterapia, de acordo com o post hocde Tukey (p=0,022). Nao houve diferencas nos niveis de ansiedade-estado e dominio fisico e mental do SF12v2. CONCLUSAO: A formula GMDZ reduziu os niveis de estresse, mas sao necessarios mais estudos com amostra significativa, com reavaliacao da posologia e um periodo maior de tratamento para confirmar e ampliar os resultados. Registro Brasileiro de Ensaios Clinicos: RBR-28s4hz. PMID- 27982407 TI - A study of cases reported as incidents in a public hospital from 2011 to 2014. AB - OBJECTIVE: Analyzing incidents reported in a public hospital in the Federal District, Brasilia, according to the characteristics and outcomes involving patients. METHOD: A descriptive and retrospective study of incidents reported between January 2011 and September 2014. RESULTS: 209 reported incidents were categorized as reportable occurrences (n = 22, 10.5%), near misses (n = 16, 7.7%); incident without injury (n = 4, 1.9%) and incident with injury (adverse events) (n = 167, 79.9%). The average age of patients was 44 years and the hospitalization time until the moment of the incident was on average 38.5 days. Nurses were the healthcare professionals who most reported the incidents (n = 55, 67%). No outcomes resulted in death. CONCLUSION: Incidents related to blood/hemoderivatives, medical devices/equipment, patient injuries and intravenous medication/fluids were the most frequent. Standardizing the reporting processes and enhancing participation by professionals in managing incidents is recommended. OBJETIVO: Analisar os incidentes notificados em um hospital publico do Distrito Federal, segundo as caracteristicas e os desfechos quando envolveram pacientes. METODO: Estudo descritivo e retrospectivo dos incidentes notificados entre janeiro de 2011 e setembro de 2014. RESULTADOS: Notificados 209 incidentes categorizados em ocorrencia comunicavel (n = 22, 10,5%), quase evento (n = 16, 7,7%), incidente sem dano (n = 4, 1,9%) e incidente com dano (eventos adversos) (n = 167, 79,9%). A idade media dos pacientes foi de 44 anos e o tempo da internacao ate o momento do incidente teve media de 38,5 dias. Os enfermeiros foram os que mais notificaram (n = 55, 67%). Nenhum desfecho resultou em morte. CONCLUSAO: Os incidentes relacionados a sangue/hemoderivados, dispositivos/equipamento medico, acidentes do doente e medicacao/fluidos endovenosos foram os mais frequentes. Recomenda-se padronizar os processos de notificacao e potencializar a participacao dos profissionais no manejo dos incidentes. PMID- 27982409 TI - The "Batman Effect": Improving Perseverance in Young Children. AB - This study investigated the benefits of self-distancing (i.e., taking an outsider's view of one's own situation) on young children's perseverance. Four- and 6-year-old children (N = 180) were asked to complete a repetitive task for 10 min while having the option to take breaks by playing an extremely attractive video game. Six-year-olds persevered longer than 4-year-olds. Nonetheless, across both ages, children who impersonated an exemplar other-in this case a character, such as Batman-spent the most time working, followed by children who took a third person perspective on the self, or finally, a first-person perspective. Alternative explanations, implications, and future research directions are discussed. PMID- 27982408 TI - Glycemic control strategies and the occurrence of surgical site infection: a systematic review. AB - OBJECTIVE: To analyze the evidence available in the scientific literature regarding the relationship between the glycemic control strategies used and the occurrence of surgical site infection in adult patients undergoing surgery. METHOD: This is a systematic review performed through search on the databases of CINAHL, MEDLINE, LILACS, Cochrane Database of Systematic Reviews and EMBASE. RESULTS: Eight randomized controlled trials were selected. Despite the diversity of tested interventions, studies agree that glycemic control is essential to reduce rates of surgical site infection, and should be maintained between 80 and 120 mg/dL during the perioperative period. Compared to other strategies, insulin continuous infusion during surgery was the most tested and seems to get better results in reducing rates of surgical site infection and achieving success in glycemic control. CONCLUSION: Tight glycemic control during the perioperative period benefits the recovery of surgical patients, and the role of the nursing team is key for the successful implementation of the measure. OBJETIVO: Analisar as evidencias disponiveis na literatura cientifica sobre a relacao entre as estrategias de controle glicemico efetuadas e a ocorrencia de infeccao do sitio cirurgico em pacientes adultos submetidos a cirurgia. METODO: Trata-se de revisao sistematica, por meio das bases de dados CINAHL, MEDLINE, LILACS, Cochrane Database of Systematic Reviews e EMBASE. RESULTADOS: Foram selecionados oito ensaios clinicos randomizados. Apesar da diversidade de intervencoes testadas, os estudos concordam que o controle glicemico e essencial para a reducao das taxas de infeccao do sitio cirurgico e deve ser mantido entre 80 e 120 mg/dL durante o perioperatorio. A infusao continua de insulina no transoperatorio foi a mais testada e parece obter melhores resultados na reducao das taxas de infeccao do sitio cirurgico e sucesso no controle glicemico comparada as demais estrategias. CONCLUSAO: O controle glicemico rigoroso durante o perioperatorio beneficia a recuperacao do paciente cirurgico, destacando-se a atuacao da equipe de enfermagem para a implantacao bem-sucedida da medida. PMID- 27982410 TI - Two novel missense mutations in EPOR gene causes erythrocytosis in two unrelated patients. PMID- 27982411 TI - Migration, Family Arrangement, and Children's Health in China. AB - With unprecedented migration taking place in China, millions of children are profoundly affected. Using a sample of 916 children (aged 5-18) of migrants and the life course perspective, this article examines the impact of parental migration on children's health. Results show that migration has a complex impact on children's health. Although migrating to cities itself does not benefit children, poor housing conditions in cities have a negative impact on their health. The timing of parental migration is important, as preschoolers migrating with parents and teenagers left behind by parents have significantly worse health than others. Migration also has a gendered effect, as teenage boys benefit from migrating to cities but suffer from being left behind when compared to teenage girls. PMID- 27982412 TI - The future of academic haematology. AB - Recent advances in the basic medical sciences, particularly cell biology and genomics, have great promise for the future development of all aspects of haematological practice. They will also impinge on the hitherto neglected fields of haematology, including haematology involving the care of the rapidly increasing number of elderly patients and the complex problems of haematological practice in the developing countries. To obtain the maximum benefit from these new developments it will be necessary to review the patterns of training of haematologists of the future at every level. In short, it will be important to try to design and develop various career pathways for training haematologists including those who wish to work full time in basic research, combine research with clinical practice, or commit all their time to clinical work and teaching. PMID- 27982413 TI - How do we approach thrombocytopenia in critically ill patients? AB - A low platelet count is a frequently encountered haematological abnormality in patients treated in intensive treatment units (ITUs). Although severe thrombocytopenia (platelet count <20 * 109 /l) can be associated with bleeding, even moderate-degree thrombocytopenia is associated with organ failure and adverse prognosis. The aetiology for thrombocytopenia in ITU is often multifactorial and correcting one aetiology may not normalise the low platelet count. The classical view for thrombocytopenia in this setting is consumption associated with thrombin-mediated platelet activation, but other concepts, including platelet adhesion to endothelial cells and leucocytes, platelet aggregation by increased von Willebrand factor release, red cell damage and histone release, and platelet destruction by the complement system, have recently been described. The management of severe thrombocytopenia is platelet transfusion in the presence of active bleeding or invasive procedure, but the risk-benefit of prophylactic platelet transfusions in this setting is uncertain. In this review, the incidence and mechanisms of thrombocytopenia in patients with ITU, its prognostic significance and the impact on organ function is discussed. A practical approach based on the authors' experience is described to guide management of a critically ill patient who develops thrombocytopenia. PMID- 27982415 TI - Evaluations of Conflicts Between Latino Values and Autonomy Desires Among Puerto Rican Adolescents. AB - Puerto Rican adolescents (N = 105; Mage = 15.97 years, SD = 1.40) evaluated hypothetical situations describing conflicts between Latino values (family obligations and respeto) and autonomy desires regarding personal, friendship, and dating activities. Adolescents judged that peers should prioritize Latino values over autonomy, which led to greater feelings of pride than happiness. However, they believed that teens would prioritize autonomy over Latino values, which led to greater feelings of happiness than pride. Adolescents reasoned about autonomy desires as personal issues, whereas reasoning about Latino values was multifaceted, including references to conventions and concerns for others. Furthermore, judgments and reasoning depended on the type of autonomy desire and Latino value and sometimes, by participants' age and sex. PMID- 27982414 TI - "These Pretzels Are Making Me Thirsty": Older Children and Adults Struggle With Induced-State Episodic Foresight. AB - We explored children's and adults' ability to disengage from current physiological states when forecasting future desires. In Study 1, 8- to 13-year olds and adults (N = 104) ate pretzels (to induce thirst) and then predicted and explained what they would want tomorrow, pretzels or water. Demonstrating life span continuity, approximately 70% of participants, regardless of age, chose water and referenced current thirst as their rationale. Individual differences in working memory and undergraduate grade point average were positively related to performance on the pretzel task. In Study 2, we obtained baseline preferences from adults (N = 35) and confirmed that, prior to consuming pretzels, people do not anticipate wanting water more than pretzels the next day. Together, these findings indicate that both children and adults are tethered to the present when forecasting their future desires. PMID- 27982416 TI - How I manage peripheral T-cell lymphoma, not otherwise specified and angioimmunoblastic T-cell lymphoma: current practice and a glimpse into the future. AB - Peripheral T-cell lymphoma (PTCL), not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL) are the most frequent of more than 20 mature PTCL entities featuring a broad spectrum of morphological, immunophenotypic, molecular and clinical characteristics. Unfortunately, recent progress in understanding the (epi)genetic background of PTCL has not been met with similar advances in treatment. Thus, CHO(E)P [cyclophosphamide, doxorubicin, vincristine, and prednisone (plus etoposide)] remains standard first-line therapy. Patients without comorbidities achieving complete or partial remission proceed to autologous stem cell transplantation. With this approach about 50% of patients survive long-term. Patients relapsing after or progressing during first line therapy have a dismal prognosis. They receive salvage gemcitabine-therapy followed by allogeneic transplantation whenever possible. After allografting, approximately half of the patients survive long-term; any other treatment is palliative. New drugs investigated in phase II studies achieved response rates between 10% and 30%; long-term remissions are the exception to the rule. While most new drugs are not licensed and not readily available, a plethora of other innovative drugs targeting (epi-)genetic abnormalities are in early development. These, together with combinations of new and old drugs, will hopefully increase response to first-line therapy, bridge more patients to transplantation, and finally improve prognosis for all patients with PTCL. PMID- 27982417 TI - BCR-ABL1-negative acute myeloid leukaemia relapsing as BCR-ABL1-positive disease. PMID- 27982418 TI - A Developmental Neuroscience Study of Moral Decision Making Regarding Resource Allocation. AB - Distinguishing between equity and equality is essential when making social and moral decisions, yet the related neurodevelopmental processes are unknown. Evaluations of contextually based third-party distributions incorporating recipient need and resource importance were examined in children and adolescents (N = 82; 8-16 years). Spatiotemporal neurodynamic responses show distinct developmental profiles to viewing such distributions. Event-related potentials (ERPs) differentially predicted real-life behaviors based on age, where older children's (8-10 years) evaluations were related to a fairly rapid, automatic ERP component (early posterior negativity), whereas adolescent and preadolescent (11 16 years) evaluations, first-person allocations, and prosocial behaviors were predicted by later, cognitively controlled ERP components (P3 and late positive potential). Together, these results reveal age-related changes regarding the neural responses that correspond to distributive justice decisions. PMID- 27982419 TI - Relations Among Cultural Learning Beliefs, Self-Regulated Learning, and Academic Achievement for Low-Income Chinese American Adolescents. AB - This mixed-methods study of urban low-income, English-proficient Chinese American, second-generation 15-year-olds (conducted in 2004; N = 32) examined the relation among the virtue model of learning communicated by parents and adolescents' learning beliefs, self-regulated learning (SRL) behaviors, and academic achievement. Analysis of in-depth individual interviews revealed that for these adolescents, perceptions of family educational socialization predicted students' endorsement of their culture's virtue-oriented learning beliefs and that adolescents' endorsement of these learning beliefs predicted their academic achievement. Importantly, adolescents' reported that use of SRL strategies mediated the relationship between their endorsement of virtue-oriented learning beliefs and their academic achievement. Findings are discussed in the context of further research linking cultural learning beliefs, SRL, and children's academic achievement. PMID- 27982420 TI - Human monopoiesis is characterized by distinct and stage-specific gene expression profiles. PMID- 27982421 TI - The impact of fertility preservation on treatment delay and progression-free survival in women with lymphoma: a single-centre experience. PMID- 27982422 TI - Update review of the acute porphyrias. AB - Acute porphyrias are rare inherited disorders due to deficiencies of haem synthesis enzymes. To date, all UK cases have been one of the three autosomal dominant forms, although penetrance is low and most gene carriers remain asymptomatic. Clinical presentation is typically with acute neurovisceral attacks characterised by severe abdominal pain, vomiting, tachycardia and hypertension. Severe attacks may be complicated by hyponatraemia, peripheral neuropathy sometimes causing paralysis, seizures and psychiatric features. Attacks are triggered by prescribed drugs, alcohol, hormonal changes, fasting or stress. The diagnosis is made by finding increased porphobilinogen excretion in a light protected random urine sample. Management includes administration of intravenous human haemin and supportive treatment with non-porphyrinogenic drugs. A few patients develop recurrent attacks, a chronic illness requiring specialist management. Late complications include chronic pain, hepatocellular carcinoma, chronic renal failure and hypertension. In the UK, the National Acute Porphyria Service provides clinical advice and supplies haemin when indicated. PMID- 27982423 TI - Outcomes of primary refractory diffuse large B-cell lymphoma (DLBCL) treated with salvage chemotherapy and intention to transplant in the rituximab era. AB - Rituximab-containing salvage chemotherapy followed by high-dose therapy and autologous stem cell transplant (ASCT) in chemosensitive patients remains the standard of care for patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL). However, its role in those patients achieving less than a complete response to first-line therapy (primary refractory disease) in the rituximab era is not well defined. We reviewed the outcomes of 82 transplant eligible patients with primary refractory DLBCL who underwent salvage therapy with the intent of administering high-dose therapy and ASCT to patients achieving chemosensitive remission. The estimated 3-year overall and progression-free survival for all patients was 38% and 29%, respectively, and 65% and 60% respectively for patients proceeding to stem cell transplant. Long-term remission was achieved in 45% of patients achieving a partial response (PR) to initial induction therapy and <20% of patients with stable or progression of disease following initial therapy. These results suggest that salvage chemotherapy with the intent of subsequent high-dose therapy and ASCT remains a feasible strategy in certain patients with primary refractory DLBCL, particularly for those achieving a PR to frontline therapy. The primary barrier to curative therapy in patients with primary refractory disease is resistance to salvage therapy, and future studies should be aimed towards increasing the response rate in this population. PMID- 27982426 TI - Cholecystitis as the initial presentation of acute myeloid leukaemia. PMID- 27982427 TI - Death Due to Decapitation in Two Motorcyclists: A Description of a Unique Case and a Brief Review of the Literature. AB - Deaths due to decapitation, especially related to traffic accidents, are rarely found in forensic practice. The present case involves a man and a woman who died from decapitation due to an unusual mechanism while they were riding on a motorbike down a mountain road. The autopsy, which was completed as a physics study, allowed the accident to be reconstructed as follows: A plastic cable that had detached from a timber-transporting machine whipped the road and hit the two motorcyclists. The impact resulted in the complete severing of both riders' heads. Involving different scientists in this accident investigation was crucial to understanding the dynamics of the accident. In fact, in addition to scene inspection and autopsy, a physics study was carried out on the cable and the clamp involved, which led to an explanation for the abrupt movement of the cable and, thus, to a thorough reconstruction of the accident. PMID- 27982424 TI - Knowledge insufficient: the management of haemoglobin SC disease. AB - Although haemoglobin SC (HbSC) accounts for 30% of sickle cell disease (SCD) in the United States and United Kingdom, evidence-based guidelines for genotype specific management are lacking. The unique pathology of HbSC disease is complex, characterized by erythrocyte dehydration, intracellular sickling and increased blood viscosity. The evaluation and treatment of patients with HbSC is largely inferred from studies of SCD consisting mostly of haemoglobin SS (HbSS) patients. These studies are underpowered to allow definitive conclusions about HbSC. We review the pathophysiology of HbSC disease, including known and potential differences between HbSS and HbSC, and highlight knowledge gaps in HbSC disease management. Clinical and translational research is needed to develop targeted treatments and to validate management recommendations for efficacy, safety and impact on quality of life for people with HbSC. PMID- 27982425 TI - Ublituximab (TG-1101), a novel glycoengineered anti-CD20 antibody, in combination with ibrutinib is safe and highly active in patients with relapsed and/or refractory chronic lymphocytic leukaemia: results of a phase 2 trial. AB - Ibrutinib is effective in patients with chronic lymphocytic leukaemia (CLL); however, treatment resistance remains a problem. Ublituximab is a novel, glycoengineered anti-CD20 monoclonal antibody with single-agent activity in relapsed CLL. We report the results of a phase 2 study evaluating combination therapy with ibrutinib and ublituximab in patients with relapsed or refractory CLL. Patients received ibrutinib 420 mg once daily. Ublituximab was administered on days 1, 8 and 15 of cycle 1 followed by day 1 of cycles 2-6. Response assessments were completed at cycles 3 and 6; patients then continued on ibrutinib monotherapy per standard of care. Forty-one of 45 enrolled patients were evaluable for efficacy. Safety was consistent with prior experience for each drug, with infusion reactions the most prevalent adverse event. Combination therapy resulted in an overall response rate (ORR) of 88% at 6 months. In the 20 patients with high-risk features (17p or 11q deletions or TP53 mutation) and evaluable for efficacy, the ORR was 95%, with three patients (15%) achieving negative minimal residual disease. Median time to response was 8 weeks. Ublituximab in combination with ibrutinib resulted in rapid and high response rates. The long-term clinical benefit of ublituximab will be defined by an ongoing phase 3 trial (NCT 02301156). PMID- 27982428 TI - The Etiology of Basal Vacuolizations in Renal Tubular Epithelial Cells Evaluated in an Isolated Perfused Kidney Model. AB - To determine whether basal lipid vacuolization characteristic of ketoacidosis could be induced with short-term hypertriglyceridemia, adult Sprague Dawley rat kidneys were perfused in an isolated perfused kidney model with, and without, 11.3 mM (10 g/L) of triglycerides in Krebs-Henseleit buffer, for 1 and 2 h (n = 5/group). Additional treatments included perfusion with triglycerides with 20 mM of beta-hydroxybutyrate and 2 mM of acetoacetate (n = 5) and perfusion with triglycerides with 70 mM of glucose (n = 1). Basal vacuolization was produced in all groups, but differed in morphology to that reported in postmortem studies. There was no further increase in vacuolization after 2 h of perfusion compared to 1 h (p = 0.24), and the addition of ketones did not alter the morphology or extent of vacuolization. This study using an ex vivo model has confirmed that isolated hypertriglyceridemia is sufficient to cause basal lipid vacuolization in renal tubular epithelial cells, but with different morphology to vacuoles observed in lethal ketoacidosis at autopsy. PMID- 27982429 TI - MicroRNA-125a-5p Is a Downstream Effector of Sorafenib in Its Antiproliferative Activity Toward Human Hepatocellular Carcinoma Cells. AB - Sorafenib is an antitumor drug for treatment of advanced hepatocellular carcinoma (HCC). It acts as a multikinase inhibitor suppressing cell proliferation and angiogenesis. Human microRNA-125a-5p (miR-125a) is endowed with similar activities and is frequently downregulated in HCC. Looking for a potential microRNA-based mechanism of action of the drug, we found that sorafenib increases cellular expression of miR-125a in cultured HuH-7 and HepG2 HCC cells. Upregulation of the microRNA inhibited cell proliferation by suppression of sirtuin-7, a NAD(+)-dependent deacetylase, and p21/p27-dependent cell cycle arrest in G1. Later, recruitment of miR-125a in the antiproliferative activity of sorafenib was inquired by modulating its expression in combination with the drug treatment. This analysis showed that intracellular delivery of miR-125a had no additive effect on the antiproliferative activity of sorafenib, whereas a miR 125a inhibitor could counteract it. Finally, evaluation of other oncogenic targets of miR-125a revealed its ability to interfere with the expression of matrix metalloproteinase-11, Zbtb7a proto-oncogene, and c-Raf, possibly contributing to the antiproliferative activity of the drug. J. Cell. Physiol. 232: 1907-1913, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27982430 TI - Severe Retinal Hemorrhages with Retinoschisis in Infants are Not Pathognomonic for Abusive Head Trauma. AB - The combination of subdural hemorrhage (SDH), retinal hemorrhage (RH), and encephalopathy, or the presence of severe retinal hemorrhages alone in infants, is often attributed to and has been stated to be pathognomonic for abusive head trauma (AHT) or shaken baby syndrome. These beliefs have been challenged, because the same constellation of findings has been identified in accidental head injuries and natural diseases, and most if not all of the studies that support the concept of diagnostic specificity have serious flaws in their methodology. Presented here are two cases of severe retinal hemorrhages with retinoschisis associated with subdural hemorrhage in a natural disease and with severe cerebral edema in an accidental head injury. These cases challenge the dogma that severe retinal hemorrhages with retinoschisis are pathognomonic for AHT. PMID- 27982431 TI - Validation of Toolmark Comparisons Made At Different Vertical and Horizontal Angles. AB - Numerous studies have focused on determining whether objective statistical methods can be used to discriminate between known matches and nonmatches when comparing laboratory prepared toolmarks. This study involved an analysis of striated toolmarks made as a function of varying vertical and horizontal angles of attack. Comparisons based on experimental data show that replicate toolmarks from the same tool show high correlation values at identical vertical and horizontal angles, with the correlation decreasing as the angular difference increases, especially for horizontal angular changes. Comparisons between nonmatching samples produce low correlation values that remain unchanged as horizontal angular differences increase. While complete statistical separation was not achieved between matching and nonmatching samples, there is evidence demonstrating that toolmarks can be identified if the variation in horizontal angle is within 10 degrees . The experiment shows that computer-aided comparison techniques could be viable for identification with the proper statistical algorithm. PMID- 27982433 TI - Changes in Attenuated Total Reflection Fourier Transform Infrared Spectra as Blood Dries Out. AB - The time since deposition (TSD) of a bloodstain is a valuable piece of evidence for forensic scientists to determine the time at which a crime took place. The objective of this study was to determine whether attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy could be used to estimate the TSD of a bloodstain in a relatively early period (from 0 min to the time required for the bloodstain to dry out). For this purpose, we used ATR-FTIR to study the variation in absorbance at certain wavelengths as rat and human blood sample dried out. The absorbance at 3308/cm (A3308) was found to have a close correlation with the TSD during this time period, and the changes in A3308 during the drying of rat and human blood drops under the same controlled conditions showed similar results. The current study indicates that ATR-FTIR spectroscopy has potential as a tool for estimating TSD at early time periods of blood deposition. PMID- 27982434 TI - Examining Interobserver Reliability of Metric and Morphoscopic Characteristics of the Mandible. AB - Mandibular metric and morphological characteristics have long been used for sex and ancestry estimation. Currently, there are no large-scale studies examining interobserver agreement, particularly examining the role of observer experience. This study examines the interobserver agreement of six morphoscopic and eleven metric mandibular variables. Four observers with varied levels of experience scored 183 mandibles from the William M. Bass Donated Skeletal Collection. Absolute agreement and consistency were evaluated with the intraclass correlation coefficient (ICC). Additionally, technical error of measurement (TEM) and relative TEM (%TEM) were calculated for each metric variable. All analyses were conducted twice-once with all observers and again with only experienced observers. Results show mean morphoscopic agreement of 0.543 among all observers and 0.615 for experienced observers, and mean metric agreement of 0.886 among all observers and 0.911 for experienced observers. Further, no TEM exceeded 2 mm. All results were significant (p < 0.001). PMID- 27982435 TI - Erratum. PMID- 27982432 TI - Spectrum of ATP7B mutations and genotype-phenotype correlation in large-scale Chinese patients with Wilson Disease. AB - Wilson disease (WD), an inherited disorder associated with ATP7B gene, has a wide spectrum of genotypes and phenotypes. In this study, we developed a rapid multiplex PCR-MassArray method for detecting 110 mutant alleles of interest, and used it to examine genomic DNA from 1222 patients and 110 healthy controls. In patients not found to have any mutation in the 110 selected alleles, PCR-Sanger sequencing was used to examine the ATP7B gene. We identified 88 mutations, including 9 novel mutations. Our analyses revealed p.Arg778Leu, p.Arg919Gly and p.Thr935Met showed some correlations to phenotype. The p.Arg778Leu was related to younger onset age and lower levels of ceruloplasmin (Cp) and serum copper, while p.Arg919Gly and p.Thr935Met both indicated higher Cp levels. Besides, the p.Arg919Gly was related to neurological subtype, and p.Thr935Met showed significant difference in the percentage of combined neurological and visceral subtype. Moreover, for ATP7B mutations, the more severe impact on ATP7B protein was, the younger onset age and lower Cp level presented. The feasibility of presymptomatic DNA diagnosis and predicting clinical manifestation or severity of WD would be facilitated with identified mutations and genotype-phenotype correlation precisely revealed in the study. PMID- 27982436 TI - Editorial: Science unskewed - acknowledging and reducing 'risk of bias' in parenting research. AB - There is a growing awareness that 'risk of bias' distorts the process of generating and interpreting evidence and threatens the validity of psychological and psychiatric research at a number of different levels (Rutter & Pickles, ). Such threats are likely to be greatest in fields of study focused on socially/politically contentious issues where beliefs and values are strongly held - especially where there is a lack of methodological rigour. PMID- 27982437 TI - Commentary: 'Unhealthy diet,' nutrient status, and ADHD symptoms: a confounding role for environmental nitrous oxide exposure - reflections on Rijlaarsdam et al. (2016). AB - Rijlaarsdam et al. (2016) recently published their findings utilizing a longitudinal design showing that prenatal 'unhealthy diet' was positively associated with IGF2 DNA methylation at birth across both youth cohorts. However, only in the EOP youth was prenatal 'unhealthy diet' positively associated with ADHD symptoms presumably through IGF2 DNA hypermethylation. Rijlaarsdam et al.'s () choice to assess high fat and sugar diet with the Food Frequency Questionnaire (FFQ) may offer some indication as to prenatal nutrient status, as the foods identified by the FFQ in their study are relatively low in free choline. It has been shown that gestational choline deficiency in rats leads to hypermethylation of IGF2. Consistent with the literature describing an association between air pollution and cognitive neurodevelopmental impairment, the author of this commentary has previously proposed through empirical investigation that chronic environmental exposure to the trace levels of the pervasive air pollutant, nitrous oxide (N2 O), may facilitate core features of neurodevelopmental disorders, like ADHD. Impaired acetylcholine synthesis in rats exposed to N2 O has been shown, with a 53% reduction in [1-2H2,2-2H2] choline. Low-dose N2 O exposure is also thought to stimulate central release of opioid peptides, like dynorphin, which play a role in significantly increasing food intake behavior and/or modulating sucrose intake. Taken altogether, these studies present a strong confounder to the interpretation made by Rijlaarsdam et al. () that prenatal 'unhealthy diet' may play a role in the onset of ADHD symptoms in youth with EOP conduct problems through induction of IGF2 DNA hypermethylation. While the 'unhealthy diet' may represent possible maternal nutrient deficiencies during gestation, it is also possible that exposure to air pollutants, particularly N2 O, may not only directly reduce fetal cholinergic status thereby enhancing IGF2 DNA hypermethylation but may also significantly modulate maternal food intake behaviors (i.e. sucrose). PMID- 27982438 TI - An outbreak of Shewanella putrefaciens group in wild eels Anguilla anguilla L. favoured by hypoxic aquatic environments. AB - Microbiological analyses were conducted on wild eels from the L'Albufera Lake (Spain). A total of 174 individuals were collected in two surveys (i.e. year 2008 and autumn-winter 2014) among those caught by local fishermen into the lagoon. The prevalence of Shewanella putrefaciens group was 1.7% in 2008 and rose above 32% in 2014. It was due to an outbreak of shewanellosis that presented a morbidity rate of 64%. S. putrefaciens group strains were isolated as pure cultures from the sick eels that showed white ulcers surrounded by a reddish inflammation, damage of the mouth, extensive skin discoloration, exophthalmia, ascites and bad odour. The S. putrefaciens group was recovered from freshwater samples taken at the L'Albufera system, along autumn-winter 2015. Its counts significantly increased in freshwater parallel to hypoxia and temperature rising. Shewanellae strains were identified as S. putrefaciens and S. xiamenensis by 16S rRNA gene sequencing. These isolates recovered from sick eels or freshwater were virulent for European eel by IP challenge (LD50 106 CFU g-1 body weight). They also caused 30-38% cumulative mortality, in European eels challenged by a 2-h bath (107 CFU mL-1 ). These results suggest that shewanellosis could be transmitted through water highlighting the fact that hypoxic conditions increase this bacterium levels in water. PMID- 27982439 TI - Molecularly imprinted probe for solid-phase extraction of hippuric and 4 methylhippuric acids directly from human urine samples followed by MEKC analysis. AB - Hippuric acid (HA) and 4-methylhippuric acid (4-MHA) are metabolites as well as biological indicators for toluene and xylenes, respectively, and their determination in urine samples is very important, in order to monitor the occupational exposition to these solvents, ensuring a safe working environment. Thus, this paper describes the synthesis and characterization of a probe impregnated with molecularly imprinted polymers (MIPs) for the solid-phase extraction of HA and 4-MHA directly from untreated urine samples followed by micellar electrokinetic chromatography (MEKC) analyses. The MIP probe selectivity was compared to the non-imprinted polymer probe. The MEKC separations were carried out in 50 mmol/L sodium tetraborate pH 10.0/0.5 mmol/L cetyltrimethylammonium bromide aqueous solution, with a constant voltage of -15 kV. The system variables were optimized to provide ideal conditions for the extraction and desorption of the analytes, as well as for the MEKC analyses. The method was linear from 0.5 to 5.0 g/L for both analytes, with correlation coefficients > 0.994. Precisions and accuracies, expressed as relative standard deviation and relative error, were < 20.0 and within -15.4 to 16.6%, respectively, in accordance with the United States Food and Drug Administration recommendation. The MIP probe has proven to be simple, cheap, resistant, and synthetically reproducible, being successfully used to analyze both HA and 4-MHA from real samples. PMID- 27982440 TI - Disseminated infection due to Exophiala pisciphila in Cardinal tetra, Paracheirodon axelrodi. AB - Cardinal tetra, Paracheirodon axelrodi (Schultz, 1956), kept in an ornamental tank, was found to be affected by severe invasive mycosis. Externally, the disease manifested as abdominal swelling, and internally, the anterior part of the intestine was extremely bloated with abundant dematiaceous septate hyphae and an accumulation of fluid. Histopathologically, a granulomatous inflammatory response was observed in the intestine wall, kidney and spleen. We assume that the mycotic agent was primarily deposited in the intestine and was then gradually disseminated to the other organs. DNA sequencing of ITS and LSU rDNA regions and phenotypic characterization were used for identification of the isolated fungus. The obtained data confirmed that the infection was caused by Exophiala pisciphila. The disease was subsequently reproduced in the carp fingerling using intramuscular and intraperitoneal injection of a spore suspension. The 13th day after intramuscular infection, a marked elevation of neutrophils was recorded in the peripheral blood; this involved a proliferation of band forms and segmented forms. As far as we know, this is the first report of infection due to E. pisciphila in Cardinal tetra. PMID- 27982441 TI - Optimized reverse primer for 16S-RFLP analysis and genomovar assignment of Flavobacterium columnare. PMID- 27982444 TI - Solvent-mediated nonelectrostatic ion-ion interactions predicting anomalies in electrophoresis. AB - We study the effects of solvent-mediated nonelectrostatic ion-ion interactions on electrophoretic mobility of a charged spherical particle. To this end, we consider the case of low surface electrostatic potential resulting in the linearization of the governing equations, which enables us to deduce a closed form analytical solution to the electrophoretic mobility. We subsequently compare our results to the standard model using Henry's approach and report the changes brought about by the nonelectrostatic potential. The classical approach to determine the electrophoretic mobility underpredicts the particle velocity when compared with experiments. We show that this issue can be resolved by taking into account nonelectrostatic interactions. Our analysis further reveals the phenomenon of electrophoretic mobility reversal that has been experimentally observed in numerous previous studies. PMID- 27982443 TI - The use of NH4+ rather than NO3- affects cell stoichiometry, C allocation, photosynthesis and growth in the cyanobacterium Synechococcus sp. UTEX LB 2380, only when energy is limiting. AB - The assimilation of N-NO3- requires more energy than that of N-NH4+ . This becomes relevant when energy is limiting and may impinge differently on cell energy budget depending on depth, time of the day and season. We hypothesize that N-limited and energy-limited cells of the oceanic cyanobacterium Synechococcus sp. differ in their response to the N source with respect to growth, elemental stoichiometry and carbon allocation. Under N limitation, cells retained almost absolute homeostasis of elemental and organic composition, and the use of NH4+ did not stimulate growth. When energy was limiting, however, Synechococcus grew faster in NH4+ than in NO3- and had higher C (20%), N (38%) and S (30%) cell quotas. Furthermore, more C was allocated to protein, whereas the carbohydrate and lipid pool size did not change appreciably. Energy limitation also led to a higher photosynthetic rate relative to N limitation. We interpret these results as an indication that, under energy limitation, the use of the least expensive N source allowed a spillover of the energy saved from N assimilation to the assimilation of other nutrients. The change in elemental stoichiometry influenced C allocation, inducing an increase in cell protein, which resulted in a stimulation of photosynthesis and growth. PMID- 27982442 TI - Assessment of disulfide and hinge modifications in monoclonal antibodies. AB - During the last years there was a substantial increase in the use of antibodies and related proteins as therapeutics. The emphasis of the pharmaceutical industry is on IgG1, IgG2, and IgG4 antibodies, which are therefore in the focus of this article. In order to ensure appropriate quality control of such biopharmaceuticals, deep understanding of their chemical degradation pathways and the resulting impact on potency, pharmacokinetics, and safety is required. Criticality of modifications may be specific for individual antibodies and has to be assessed for each molecule. However, some modifications of conserved structure elements occur in all or at least most IgGs. In these cases, criticality assessment may be applicable to related molecules or molecule formats. The relatively low dissociation energy of disulfide bonds and the high flexibility of the hinge region frequently lead to modifications and cleavages. Therefore, the hinge region and disulfide bonds require specific consideration during quality assessment of mAbs. In this review, available literature knowledge on underlying chemical reaction pathways of modifications, analytical methods for quantification and criticality are discussed. The hinge region is prone to cleavage and is involved in pathways that lead to thioether bond formation, cysteine racemization, and iso-Asp (Asp, aspartic acid) formation. Disulfide or sulfhydryl groups were found to be prone to reductive cleavage, trisulfide formation, cysteinylation, glutathionylation, disulfide bridging to further light chains, and disulfide scrambling. With regard to potency, disulfide cleavage, hinge cleavage, disulfide bridging to further light chains, and cysteinylation were found to influence antigen binding and fragment crystallizable (Fc) effector functionalities. Renal clearance of small fragments may be faster, whereas clearance of larger fragments appears to depend on their neonatal Fc receptor (FcRn) functionality, which in turn may be impeded by disulfide bond cleavage. Certain modifications such as disulfide induced aggregation and heterodimers from different antibodies are generally regarded critical with respect to safety. However, the detection of some modifications in endogenous antibodies isolated from human blood and the possibility of in vivo repair mechanisms may reduce some safety concerns. PMID- 27982445 TI - Search and analysis of genes involved in antibiotic resistance in Chilean strains of Piscirickettsia salmonis. AB - Piscirickettsia salmonis is the pathogen causing Piscirickettsiosis. For treatment, the industry mainly uses oxytetracycline and florfenicol, so it is essential to understand the degree of susceptibility of this pathogen to these drugs. But this is still unknown for a large number of P. salmonis strains, as are the molecular mechanisms responsible for greater or lesser susceptibility. However, genes that confer resistance to these antimicrobials have been reported and characterized for this and other bacterial species, among which are membrane proteins that take out the drug. Our results identified differences in the degree of susceptibility to both antibiotics among different Chilean isolated of these bacteria. We analysed 10 available genomes in our laboratory and identified ~140 genes likely to be involved in antibiotic resistance. We analysed six specific genes, which suggests that some of them would eventually be relevant in conferring resistance to both antibiotics, as they encode for specific transporter proteins, which increase the number of transcripts when grown in media with these antibiotics. Our results were corroborated with EtBr permeability analysis, which revealed that the LF-89 strain accumulates this compound and has a reduced capacity to expulse it compared with the field strains. PMID- 27982446 TI - Armanni-Ebstein Lesions in Terminal Hyperglycemia. AB - Armanni-Ebstein lesions (AEL) occur in deaths related to uncontrolled diabetes mellitus. To investigate the relationship between AEL and terminal hyperglycemia, we retrospectively reviewed 71 cases with vitreous glucose levels >=11.1 mmol/L; 27 (38%) cases had AEL (vitreous glucose 14.0-77.3 mmol/L); and 44 cases (62%) did not (vitreous glucose 11.1-91.9 mmol/L). There was no significant difference (p = 0.271) in vitreous glucose levels between the cases with AEL (mean 39.2, SD 16.7 mmol/L) and those without (mean 34.2, SD 19.8 mmol/L). Similarly, there was no difference in the degree of dehydration, renal failure, or osmolality. However, there was a significantly higher level of beta-hydroxybutyrate among the cases with AEL compared to those without (p = 0.007), suggesting that ketoacidosis may facilitate the development of AEL. Given the possible synergistic role of beta-hydroxybutyrate, the correlation between AEL and terminal hyperglycemia in animal studies may not be applicable to humans. AEL may also possibly occur with sublethal elevations in glucose. PMID- 27982448 TI - beta-cyclodextrin-ionic liquid polymer based dynamically coating for simultaneous determination of tetracyclines by capillary electrophoresis. AB - Tetracyclines are a group of broad spectrum antibiotics widely used in animal husbandry to prevent and treat diseases. However, the improper use of tetracyclines may result in the presence of their residues in animal tissues or waste. Recently, great attention has been drawn towards the green solvents ionic liquids. Ionic liquids have been employed as a coating material to modify the electroosmotic flow in capillary electrophoresis. In this study, a functionalized ionic liquid, mono-6-deoxy-6-(3-methylimidazolium)-beta-cyclodextrin tosylate, was synthesized and used for the simultaneous separation and quantification of tetracyclines by capillary electrophoresis. Good separation efficiency could be achieved due to the multiple functions of beta-cyclodextrin derived ionic liquid, including the electrostatic interaction, the hydrogen bonding, and the cavity structure in beta-cyclodextrin ionic liquid which can entrap the tetracyclines to form inclusion complex. After optimization, baseline separation achieved in 25 min with the running buffer consisted of 10 mmol/L, pH 7.2 phosphate buffer and 20 mmol/L beta-cyclodextrin ionic liquid. The satisfied result demonstrated that the beta-cyclodextrin ionic liquid is an ideal background electrolyte modifier in the separation of tetracyclines with high stability and good reproducibility. And it is an effective strategy to design and synthesize specific ILs as additive applied in separation. PMID- 27982447 TI - Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review. AB - WHAT IS KNOWN AND OBJECTIVE: Posaconazole is an extended-spectrum triazole antifungal with activity against a variety of clinically significant yeasts and moulds. Posaconazole is not currently approved by the U.S. Food and Drug Administration for use in children younger than 13 years of age. Our primary objective was to describe the dosing and observed trough concentrations with posaconazole oral suspension in paediatric patients at the National Institutes of Health Clinical Center (Bethesda, MD). METHODS: This retrospective single-centre study reviewed paediatric patients younger than 13 years of age initiated on posaconazole oral suspension. Patients were included if they were initiated on posaconazole for prophylaxis or treatment for fungal infections from September 2006 through March 2013 with at least one trough concentration collected after at least 7 days of therapy. RESULTS AND DISCUSSION: A total of 20 male patients were included, of whom 15 (75%) had chronic granulomatous disease. The median age of patients was 6.5 years (range: 2.8-10.7). A total of 79 posaconazole trough concentrations were measured in patients receiving posaconazole as prophylaxis (n = 8) or treatment (n = 12). Posaconazole dose referenced to total body weight ranged from 10.0 to 49.2 mg/kg/day. Posaconazole trough concentrations ranged from undetectable (<50 ng/mL) up to 3620 ng/mL and were >=500, >=700 and >=1250 ng/mL in 95%, 60% and 25% of patients, respectively. WHAT IS NEW AND CONCLUSIONS: Patients younger than 13 years of age had highly variable trough concentrations, and recommendations for the appropriate dosing of posaconazole oral suspension remain challenging. Until studies are conducted to determine the appropriate dosing of posaconazole in this patient population, therapeutic drug monitoring should be considered to ensure adequate posaconazole exposure. PMID- 27982449 TI - An Economic Evaluation of the Garrett Lee Smith Memorial Suicide Prevention Program. AB - For more than a decade, the Garrett Lee Smith Youth Suicide Prevention Program has provided funding for community-based suicide prevention programs to states, tribes, and colleges across the United States. Recent studies provided evidence of the program's effectiveness in reducing suicide mortality and suicide attempts among youth. This study compares the cost of implementing the program with the estimated savings resulting from avoided hospitalization and emergency department visits associated with the averted suicide attempts. The findings suggest that the cost of implementing multifaceted community-based suicide prevention strategies may be more than outweighed by savings in the health sector. PMID- 27982450 TI - Self-Embedding Behavior in Adults: A Report of Two Cases and a Systematic Review. AB - Self-embedding behavior (SEB) is the repeated insertion of sharp objects, such as needles or pins, into the soft tissues of abdomen, limbs, and other body parts. In this study, two cases of SEB were reported and the scientific worldwide literature reviewed. Thirty-two cases of SEB were identified through systematic searches in the main bibliographic databases. Mean age was 35 years (SD = 8.97). Just over two-thirds of the patients were female. Although the number of embedded objects could be as high as 200, major clinical and surgical complications were uncommon and mortality was null. Patients with SEB presented three major diagnoses: psychotic (25%), personality (21.9%), and factitious (28.1%) disorders. The practice of SEB largely went undetected as the patients themselves did not bring it to the attention of family members or physicians and usually denied they have engaged in SEB. A high level of suspicion is required to avoid a missed diagnosis. PMID- 27982451 TI - CuGaO2 : A Promising Inorganic Hole-Transporting Material for Highly Efficient and Stable Perovskite Solar Cells. AB - The p-type inorganic semiconductor CuGaO2 as a hole-transporting layer (HTL) in perovskite solar cells (PSCs) provides higher carrier mobility, better-energy level matching, and superior stability, as well as low-temperature processing technique. Compared to organic HTL, a very competitive PCE of 18.51% with long term stability is achieved. This indicates that CuGaO2 is a promising HTL for efficient and stable PSCs. PMID- 27982452 TI - Variation in the use of up-front chemotherapy for indolent B-cell lymphomas and chronic lymphocytic leukemia. PMID- 27982454 TI - Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy. AB - Venetoclax is indicated at a dosage of 400 mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression-free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL). A total of 323 patients from 3 clinical studies of venetoclax, with and without rituximab coadministration, were pooled for the analyses. A time-variant relative risk survival model was used to relate plasma venetoclax concentrations and rituximab administration to PFS. Demographics and baseline disease characteristics were evaluated for their effect on PFS. A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified. The 17p deletion chromosomal aberration was not identified to affect the PFS of patients treated with venetoclax. A venetoclax dose of 400 mg daily QD was estimated to result in a substantial median PFS of 1.8 years (95% confidence interval [CI], 1.7-2.1), whereas the addition of 6 cycles of rituximab was estimated to increase the median PFS to 3.9 years (95% CI, 2.8-5.6). The analysis demonstrates a concentration-dependent effect of venetoclax on PFS and also a synergistic effect with rituximab. Combining venetoclax with the CD20 targeting monoclonal antibody rituximab in R/R CLL/SLL patients provides substantial synergistic benefit compared with increasing the venetoclax monotherapy dose. PMID- 27982453 TI - Trends in celecoxib and etoricoxib prescribing following removal of prior authorization requirement in Spain. AB - WHAT IS KNOWN AND OBJECTIVE: Previous studies indicate that the implementation of a prior authorization requirement for coxibs was followed by a sharp decline in their use. There are no studies showing what happens if coxib prior authorization is removed. The objective of this study is to assess the trend in the use of coxibs marketed in Spain, following removal of their respective prior authorization requirements in November 2006 for celecoxib and February 2007 for etoricoxib. METHODS: We calculated the monthly number of defined daily doses per thousand inhabitants per day (DDD/TID) of coxibs dispensed in a health area of Spain from mid-2005 to December 2007. Data were analysed both graphically and by means of a segmented regression model. RESULTS AND DISCUSSION: At the start of the study period, use of coxibs showed no growth. At the date when prior authorization of celecoxib was removed (November 2006), however, DDD/TID of the coxib whose prior authorization had not been removed - namely etoricoxib - remained unchanged, whereas consumption of celecoxib increased significantly (by the end of the study period, celecoxib use displayed a relative increase of 615% in terms of the DDD/TID prescribed before the removal of its prior authorization requirement). Similarly, etoricoxib use remained unchanged until its prior authorization was removed (February 2007), from which time DDD/TID of etoricoxib also underwent a considerable increase (by the end of the study period, etoricoxib use displayed a relative increase of 793% in terms of the DDD/TID prescribed before the removal of its prior authorization). Segmented regression analysis showed a sharp, statistically significant rise and change in slope in both celecoxib and etoricoxib use immediately after removal of their respective prior authorizations. WHAT IS NEW AND CONCLUSION: Use of celecoxib and etoricoxib rose sharply after removal of their respective prior authorizations. PMID- 27982455 TI - Comparisons of the Interpersonal-Psychological Theory of Suicide Constructs Among Individuals Without Suicidality, Ideators, Planners, and Attempters. AB - The Interpersonal-Psychological Theory of Suicide (IPTS) proposes that combinations of thwarted belongingness, perceived burdensomeness, and acquired capability lead to suicide ideation, planning, and attempting. We compared individuals with and without suicidality on thwarted belongingness and perceived burdensomeness, and compared a combined group of planners and attempters to ideators on fearlessness about death (one component of acquired capability). Individuals with suicidality had higher thwarted belongingness and perceived burdensomeness than individuals without suicidality. Planners and attempters did not have higher fearlessness about death than ideators. These findings partially support IPTS hypotheses. Assessing thwarted belongingness and perceived burdensomeness may improve suicide risk determination. PMID- 27982457 TI - Speed or deliberation: a comparison of post-disaster recovery in Japan, Turkey, and Chile. AB - This paper compares recovery in the wake of three recent earthquakes: the Great East Japan Earthquake in March 2011; the Van earthquake in Turkey in October 2011; and the Maule earthquake in Chile in February 2010. The authors visited all three locations approximately 12-18 months after the incidents and interviewed earthquake specialists, disaster managers, urban planners, and local authorities. A key challenge to post-disaster recovery planning is balancing speed and deliberation. While affected communities must rebuild as quickly as possible, they must also seek to maximise the opportunities for improvement that disasters provide. The three case studies bring this dilemma into stark relief, as recovery was respectively slow, fast, and just right in the aftermath of the events: the Government of Japan adopted a deliberate approach to recovery and reconstruction; speed was of the essence in Turkey; and an effective balance between speed and deliberation was achieved in Chile. PMID- 27982458 TI - Risk factors for long-term post-traumatic stress disorder among medical rescue workers appointed to the 2008 Wenchuan earthquake response in China. AB - This study aims to determine the risk factors for clinically-significant post traumatic stress disorder (PTSD) among Chinese medical rescue workers one year after the response to the Wenchuan earthquake on 12 May 2008. A sample of 337 medical workers who performed response work within the first three months of the event completed an online questionnaire, which included information on demographics, social support, the management and organisation of the disaster response, and an assessment of PTSD. Symptoms consistent with PTSD were prevalent in 17 per cent of the rescue workers. Those who developed PTSD symptoms were more likely to have been injured, experienced a water shortage, been disconnected from family and friends during the response, and have passive coping styles and neurotic personalities. Factors that cannot be changed easily, such as personality traits, should be evaluated prior to deployment to ensure that rescue workers at higher risk of PTSD are provided with adequate support before and during deployment. PMID- 27982460 TI - Vulnerability assessments as a political creation: tsunami management in Portugal. AB - Vulnerability assessments are a cornerstone of contemporary disaster research. This paper shows how research procedures and the presentation of results of vulnerability assessments are politically filtered. Using data from a study of tsunami risk assessment in Portugal, the paper demonstrates that approaches, measurement instruments, and research procedures for evaluating vulnerability are influenced by institutional preferences, lines of communication, or lack thereof, between stakeholder groups, and available technical expertise. The institutional setting and the pattern of stakeholder interactions form a filter, resulting in a particular conceptualisation of vulnerability, affecting its operationalisation via existing methods and technologies and its institutional embedding. The Portuguese case reveals a conceptualisation that is aligned with perceptions prevalent in national government bureaucracies and the exclusion of local stakeholders owing to selected methodologies and assessment procedures. The decisions taken by actors involved in these areas affect how vulnerability is assessed, and ultimately which vulnerability reduction policies will be recommended in the appraisal. PMID- 27982456 TI - The quantal catecholamine release from mouse chromaffin cells challenged with repeated ACh pulses is regulated by the mitochondrial Na+ /Ca2+ exchanger. AB - KEY POINTS: Upon repeated application of short ACh pulses to C57BL6J mouse chromaffin cells, the amperometrically monitored secretory responses promptly decayed to a steady-state level of around 25% of the initial response. A subsequent K+ pulse, however, overcame such decay. These data suggest that mouse chromaffin cells have a ready release-vesicle pool that is selectively recruited by the physiological neurotransmitter ACh. The ACh-sensitive vesicle pool is refilled and maintained by the rate of Ca2+ delivery from mitochondria to the cytosol, through the mitochondrial Na+ /Ca2+ exchanger (mNCX). ITH12662, a novel blocker of the mNCX, prevented the decay of secretion elicited by ACh pulses and delayed the rate of [Ca2+ ]c clearance. This regulatory pathway may be physiologically relevant in situations of prolonged stressful conflicts where a sustained catecholamine release is regulated by mitochondrial Ca2+ circulation through the mNCX, which couples respiration and ATP synthesis to long-term stimulation of chromaffin cells by endogenously released ACh. ABSTRACT: Using caged-Ca2+ photorelease or paired depolarising pulses in voltage-clamped chromaffin cells (CCs), various pools of secretory vesicles with different readiness to undergo exocytosis have been identified. Whether these pools are present in unclamped CCs challenged with ACh, the physiological neurotransmitter at the splanchnic nerve-CC synapse, is unknown. We have explored here whether an ACh-sensitive ready-release vesicle pool (ASP) is present in C57BL6J mouse chromaffin cells (MCCs). Single cells were fast perfused with a Tyrode solution at 37 degrees C, and challenged with 12 sequential ACh pulses (100 MUm, 2 s, every 30 s) plus a K+ pulse given at the end (75 mm K+ ). After the first 2-3 ACh pulses the amperometrically monitored secretory responses promptly decayed to a steady-state level of around 25% of the initial response. The last K+ pulse, however, overcame such decay. Repeated ACh pulses to voltage-clamped cells elicited non-desensitising nicotinic currents. Also, the [Ca2+ ]c transients elicited by repeated ACh pulses that were superimposed on a stable baseline elevation did not undergo decay. The novel blocker of the mitochondrial Na+ /Ca2+ exchanger (mNCX) ITH12662 prevented the decay of secretion elicited by ACh pulses and delayed the rate of [Ca2+ ]c clearance. The experiments are compatible with the idea that C57BL6J MCCs have an ASP vesicle pool that is selectively recruited by the physiological neurotransmitter ACh and is regulated by the rate of Ca2+ delivery from mitochondria to the cytosol, through the mNCX. PMID- 27982459 TI - Posttraumatic Stress Disorder Symptom Clusters and the Interpersonal Theory of Suicide in a Large Military Sample. AB - Prior studies examining posttraumatic stress disorder (PTSD) symptom clusters and the components of the interpersonal theory of suicide (ITS) have yielded mixed results, likely stemming in part from the use of divergent samples and measurement techniques. This study aimed to expand on these findings by utilizing a large military sample, gold standard ITS measures, and multiple PTSD factor structures. Utilizing a sample of 935 military personnel, hierarchical multiple regression analyses were used to test the association between PTSD symptom clusters and the ITS variables. Additionally, we tested for indirect effects of PTSD symptom clusters on suicidal ideation through thwarted belongingness, conditional on levels of perceived burdensomeness. Results indicated that numbing symptoms are positively associated with both perceived burdensomeness and thwarted belongingness and hyperarousal symptoms (dysphoric arousal in the 5 factor model) are positively associated with thwarted belongingness. Results also indicated that hyperarousal symptoms (anxious arousal in the 5-factor model) were positively associated with fearlessness about death. The positive association between PTSD symptom clusters and suicidal ideation was inconsistent and modest, with mixed support for the ITS model. Overall, these results provide further clarity regarding the association between specific PTSD symptom clusters and suicide risk factors. PMID- 27982461 TI - Investigating the strategic antecedents of agility in humanitarian logistics. AB - This study investigates the strategic antecedents of operational agility in humanitarian logistics. It began by identifying the particular actions to be taken at the strategic level of a humanitarian organisation to support field level agility. Next, quantitative data (n=59) were collected on four strategic level capabilities (being purposeful, action-focused, collaborative, and learning oriented) and on operational agility (field responsiveness and flexibility). Using a quantitative analysis, the study tested the relationship between organisational capacity building and operational agility and found that the four strategic-level capabilities are fundamental building blocks of agility. Collectively they account for 52 per cent of the ability of humanitarian logisticians to deal with ongoing changes and disruptions in the field. This study emphasises the need for researchers and practitioners to embrace a broader perspective of agility in humanitarian logistics. In addition, it highlights the inherently strategic nature of agility, the development of which involves focusing simultaneously on multiple drivers. PMID- 27982462 TI - Exploring the Solvatochromism of Betaine 30 with Ab Initio Tools: From Accurate Gas-Phase Calculations to Implicit and Explicit Solvation Models. AB - Betaine 30 is known for the extraordinary solvatochromism of its visible absorption band that goes from lambda=882 nm in tetrachloromethane to lambda=453 nm in water (Deltalambda=-429 nm). This large blueshift partly originates from a dramatic decrease of the dipole moment upon excitation. Despite several decades of research, experimental works still disagree on the exact value of the excess dipole moment, the orientation of the dipole moment of the excited-state, the role and amplitude of the change of the polarisability upon excitation as well as on the gas-phase excitation energy. In this work, we present an in-depth theoretical investigation. First, we carefully tested several levels of theory on the model system and next calculated the electric properties of betaine 30 at the CC2 level. Our best estimates are DeltaMU=-7 D for the excess dipole moment, that is, a significant decrease but no change of direction, a Deltaalpha value of -120 a.u. and a gas-phase vertical excitation energy of 1.127 eV. The implicit solvation models are able to reproduce the experimental trends, with large correlation coefficients for non-hydrogen-bond-donating solvents, the smallest root-mean-square deviation error being reached with the vertical excitation model (VEM). The explicit effective fragment potential method combined with time dependent density functional theory (TD-DFT) in a QM/MM framework provides accurate estimates for hydrogen-bond-donating solvents, whereas the addition of a dispersion correction is needed to restore the correct solvatochromic direction in tetrachloromethane. PMID- 27982463 TI - Are Suicide Note Writers Representative of All Suicides? Analysis of the National Violent Death Reporting System. AB - While suicide notes can offer insights into the causes of suicide and clues for prevention, there is disagreement regarding the degree to which note leavers are representative of the general population of suicides. Previous relevant research on the United States is marked by a series of limitations: small local samples, an over focus on demographic constructs, and lack of multivariable analysis. This study uses a large national sample, a wide range of predictor variables, and multivariable statistical techniques to estimate more reliable similarities and differences between note leavers and other suicides. All data are taken from the National Violent Death Reporting System, which covers 17 states. A total of 9,048 note writers were compared to 21,522 other suicides in terms of 39 variables. In both bivariable (32/39 variables) and multivariable analyses (30/39 variables), note leavers differed from other suicides in most demographic variables, stressful life events, psychiatric issues, and methods of suicide. The national evidence suggests that caution be exercised in generalizing patterns found among writers of suicide notes to suicides in general. This is the first analysis of suicide notes using US data on the issue. PMID- 27982464 TI - A Generalizable Strategy for the 3D Bioprinting of Hydrogels from Nonviscous Photo-crosslinkable Inks. AB - An in situ crosslinking strategy is used for 3D bioprinting of nonviscous photo crosslinkable hydrogels. This method can be generalized to various photo crosslinkable formulations, maintaining high embedded cell viability and tunable cell behavior. Heterogeneous and hollow filaments can be printed using this strategy, allowing fabrication of complex engineered cell-laden constructs. PMID- 27982465 TI - In Situ Polymer Graphenization Ingrained with Nanoporosity in a Nitrogenous Electrocatalyst Boosting the Performance of Polymer-Electrolyte-Membrane Fuel Cells. AB - Rich, porous graphene frameworks decorated with uniformly dispersed active sites are prepared by using polyaniline as a graphene precursor and introducing phenanthroline as a pore-forming agent. The unprecedented fuel-cell performance of this electrocatalyst is linked to the graphene frameworks with vast distribution of pore sizes, which maximizes the active-sites accessibility, facilitates mass-transport properties, and improves the carbon corrosion resistance. PMID- 27982466 TI - Expansion of the genotypic and phenotypic spectrum of xeroderma pigmentosum in Chinese population. AB - BACKGROUND: Xeroderma pigmentosum (XP) is a rare genodermatosis characterized by exaggerated sunburn reactions, freckle-like pigmentation, and a high possibility of developing cutaneous tumors. XP comprised seven complementation groups (from XP-A to XP-G) and a variant form XP-V. METHODS: This study was based on five unrelated Chinese families with six patients clinically suspected to be XP. Mutation screening was performed by direct sequencing of the entire coding region of eight XP genes. RESULTS: All of the pathogenic mutations were identified by mutational analysis, including four novel mutations. CONCLUSIONS: Our study successfully identified the pathogenic mutations in six XP patients (three XP-A, one XP-G, one XP-V, and a rare XP-D group in Chinese population). We reviewed the reported XP cases with mutations in the Chinese population and concluded that four complementation groups (XP-A, XP-C, XP-G, and XP-V) that occupy the major proportion should be considered as a first step in genetic detection (especially, XPA is the most common group, and unlike in other populations, XP-G is not rare in the Chinese population). Moreover, XP-D and XP-F, two rare subgroups, should also be added for further mutational analysis. Further, we provide some information for Chinese dermatologists that, when an early diagnosis is made, XP C and XP-V patients can have relatively good prognoses. PMID- 27982467 TI - The Acculturation of Community Psychology: Is There a Best Way? AB - In this paper I describe a community psychology perspective on acculturation and adjustment of immigrants and refugees and suggest that this field of acculturation research has in turn something to offer heuristically as we consider our identity and training for future generations of community psychologists over the next 50 years. I suggest that honoring our heritage, maintaining our disciplinary identity as community psychologists, and sustaining doctoral programs that offer training specific to community psychology are crucial for our survival as a field and is not antithetical to, and is indeed necessary for, interdisciplinary collaborations. PMID- 27982468 TI - Lamp Lighters and Sidewalk Smoothers: How Individual Residents Contribute to the Maintenance of the Urban Commons. AB - Research on collective efficacy in urban neighborhoods has focused predominantly on whether a community can regulate local behavior and spaces and less on how they do so. This study pursues the latter question by examining the social regularities that create collective efficacy, measured as the behavioral composition of a neighborhood (i.e., the extent to which each individual contributes to a social regularity). This perspective is applied to the database of requests for non-emergency government services received by Boston, MA's 311 system in 2011 (>160,000 requests). The analysis categorized custodians who have used the system to combat physical disorder in the public space (e.g., requesting graffiti removal) into two groups-"typical custodians" who have made one or two requests in a year, and "exemplars" who have made three or more. A neighborhood's collective efficacy in reporting public issues was identified through audits of sidewalk quality and streetlight outages. Analyses revealed a collaborative model of maintenance in which typical and exemplar custodians were each necessary and non-substitutable. A second analysis found that the two types of custodian were associated with different contextual factors, articulating two different pathways from demographic and social characteristics to collective efficacy, suggesting implications for theory and practice. PMID- 27982469 TI - Reflections on the Future of Community Psychology from the Generations after Swampscott: A Commentary and Introduction to the Special Issue. AB - This special issue commemorates the 50th anniversary of the founding of U.S. community psychology in Swampscott, Massachusetts in 1965. The issue includes commentaries from a cross-section of community psychologists educated in community psychology training programs established after Swampscott, in the 1970s or later. The contributors, who vary in their involvement in community-engaged research, training, and practice, offer a diverse set of perspectives on the field. Each was asked to reflect on the future of community psychology based on their own training and experiences. After providing some background to the Swampscott Conference and the era in which it took place, I offer a few of my own reflections on community psychology's future growth and development. I then introduce the 15 commentaries that follow. PMID- 27982470 TI - Action Civics for Promoting Civic Development: Main Effects of Program Participation and Differences by Project Characteristics. AB - Using both quantitative and qualitative data, this study examined the effect of participating in an action civics intervention, Generation Citizen (GC), on civic commitment, civic self-efficacy, and two forms of civic knowledge. The sample consisted of 617 middle and high schools students in 55 classrooms who participated, or were soon to participate, in Generation Citizen. Hierarchical linear models revealed that participating in Generation Citizen was associated with positive gains in action civics knowledge and civic self-efficacy. Qualitative coding identified three types of project characteristics that captured variability in the action projects student chose to complete: context, content, and contact with decision makers. Interactions between project characteristics and participation in GC revealed differences in civic outcomes depending on project characteristics. PMID- 27982473 TI - Csp3 -H Activation without Chelation Assistance in an Iridium Pincer Complex Forming Cyclometallated Products. AB - Cyclometallation of 8-methylquinoline and 2-(dimethylamino)-pyridine in an iridium-based pincer complex is described. The C-H activation of 2 (dimethylamino)pyridine is not chelation assisted, which has not been described before for Csp3 -H bonds in cyclometallation reactions. The mechanism of the cyclometallation of 2-(dimethylamino)pyridine was studied by DFT calculations and kinetic measurements. PMID- 27982472 TI - A Switchable Cross-Species Liquid Repellent Surface. AB - A switchable cross-species liquid-repellent surface is developed that can rapidly switch between two distinct liquid-repellent modes: i) the superhydrophobic mode, modeled after lotus leaves, and ii) the slippery mode, modeled after the pitcher plant peristome. Adaptive liquid repellency and programmable fog harvesting are demonstrated as application examples for the new switchable surface. PMID- 27982474 TI - Silver-Catalyzed [2+1] Cyclopropenation of Alkynes with Unstable Diazoalkanes: N Nosylhydrazones as Room-Temperature Decomposable Diazo Surrogates. AB - The [2+1] cycloaddition of alkynes with diazo compounds represents one of the most powerful and reliable methods for the construction of cyclopropenes. However, it remains a formidable challenge to accomplish the cyclopropenation of alkynes with non-stabilized diazoalkanes, owing to the fact that such compounds are unstable and prone to detonation. Herein, we report a general silver catalyzed cyclopropenation reaction of alkynes with unstable diazoalkanes, by for the first time the discovery and application of N-nosylhydrazones as room temperature decomposiable diazo surrogates. This method allows for the efficient assembly a wide variety of cyclopropene derivatives that are otherwise difficult to access by conventional methods. PMID- 27982475 TI - Progress in 3D Printing of Carbon Materials for Energy-Related Applications. AB - The additive-manufacturing (AM) technique, known as three-dimensional (3D) printing, has attracted much attention in industry and academia in recent years. 3D printing has been developed for a variety of applications. Printable inks are the most important component for 3D printing, and are related to the materials, the printing method, and the structures of the final 3D-printed products. Carbon materials, due to their good chemical stability and versatile nanostructure, have been widely used in 3D printing for different applications. Good inks are mainly based on volatile solutions having carbon materials as fillers such as graphene oxide (GO), carbon nanotubes (CNT), carbon blacks, and solvent, as well as polymers and other additives. Studies of carbon materials in 3D printing, especially GO-based materials, have been extensively reported for energy-related applications. In these circumstances, understanding the very recent developments of 3D-printed carbon materials and their extended applications to address energy related challenges and bring new concepts for material designs are becoming urgent and important. Here, recent developments in 3D printing of emerging devices for energy-related applications are reviewed, including energy-storage applications, electronic circuits, and thermal-energy applications at high temperature. To close, a conclusion and outlook are provided, pointing out future designs and developments of 3D-printing technology based on carbon materials for energy-related applications and beyond. PMID- 27982476 TI - Structural Transformation from Dimerization to Tetramerization of Serine Decorated Rare-Earth-Incorporated Arsenotungstates Induced by the Usage of Rare Earth Salts. AB - Three types of serine-decorated rare- earth-containing arsenotungstate [H2 N(CH3 )2 ]6 NaH[RE2 W4 O10 (H2 O)8 (Ser)2 (B-alpha-AsW9 O33 )2 ]?30 H2 O (RE3+ =Eu3+ , Gd3+ , Tb3+ , Dy3+ , Ho3+ , Er3+ , Tm3+ , Yb3+ , and Y3+ ; 1), [H2 N(CH3 )2 ]6 Na6-x REx H4-2 x [RE4 W8 O19 (H2 O)10+y (OH)2 (Ser)2 (B-alpha-AsW9 O33 )4 ]?n H2 O (RE3+ =Tb3+ , x=1, y=2, n=36; RE3+ =Dy3+ , Ho3+ , Er3+ , Yb3+ , Y3+ , x=0, y=0, n=38; RE3+ = Tm3+ , x=1, y=0, n=38; Ser=serine; 2), and [H2 N(CH3 )2 ]6-2 x Na2+3 x REx H10-6 x+y [RE4 W8 O19 (H2 O)8 (OH)2 (Ser)4 (B-alpha-AsW9 O33 )4 ]?Cly ?n H2 O (RE3+ =Ce3+ , Pr3+ , x=1, y=0, n=65; RE3+ =Nd3+ , Sm3+ , x=0, y=0, n=65; RE3+ =Eu3+ , Gd3+ , x=1, y=2, n=45; 3) were synthesized with the participation of the organic solubilizers dimethylamine hydrochloride and l-serine and were structurally characterized. The use of different amounts of rare-earth salts results in the structural transformation from dimerization to tetramerization of types 1-3. Type 1 is a dimeric sandwich-type assembly of a dual-Ser-participating [RE2 W4 O10 (H2 O)8 (Ser)2 ]10+ entity sandwiched by two [B-alpha-AsW9 O33 ]9- moieties, whereas types 2 and 3 have a tetrameric square structure formed by four [B-alpha-AsW9 O33 ]9- moieties that anchor a dual/tetra- Ser-participating [RE4 W8 O19 (H2 O)10+y (OH)2 (Ser)2 ]20+ or [RE4 W8 O19 (H2 O)8 (OH)2 (Ser)4 ]20+ core. The solid-state luminescence properties and lifetime-decay behaviors of these compounds were investigated. The chromaticity coordinates, dominant wavelengths, color purities, and correlated color temperatures were also calculated. PMID- 27982478 TI - A Mendelian Randomization Study of the Effect of Type-2 Diabetes and Glycemic Traits on Bone Mineral Density. AB - Type-2 diabetes (T2D) is associated in observational studies with both higher bone mineral density (BMD) and higher fracture risk for given BMD. These relationships may however be confounded by factors such as body mass index (BMI). Here we used Mendelian randomization (MR) to obtain non-confounded estimates of the effect of T2D and glycemic traits on BMD. We identified genetic variants strongly associated with T2D risk (34,840 T2D cases and 114,981 controls) and fasting glucose (133,010 nondiabetic individuals), but not associated with BMI, and determined the effects of these variants on BMD (up to 83,894 individuals). Using these variants as instrumental variables, we found that a genetically increased risk of T2D increased femoral neck BMD (+0.034 SD in BMD per unit increase in log-odds of T2D [95% CI, 0.001 to 0.067; p = 0.044]). Genetically increased fasting glucose also increased femoral neck BMD (+0.13 SD in BMD per mmol/L increase in fasting glucose [95% CI, 0.01 to 0.25; p = 0.034]). Similar nonsignificant trends were observed for the effects of T2D and fasting glucose on lumbar spine BMD. Our results indicate that both genetically-increased T2D risk and genetically-increased fasting glucose have weak positive effects on BMD. (c) 2016 American Society for Bone and Mineral Research. PMID- 27982480 TI - Chemoselective Suzuki-Miyaura Cross-Coupling via Kinetic Transmetallation. AB - Chemoselective Suzuki-Miyaura cross-coupling generally requires a designed deactivation of one nucleophile towards transmetallation. Here we show that boronic acids can be chemoselectively reacted in the presence of ostensibly equivalently reactive boronic acid pinacol (BPin) esters by kinetic discrimination during transmetallation. Simultaneous electrophile control allows sequential chemoselective cross-couplings in a single operation in the absence of protecting groups. PMID- 27982479 TI - Hypermethylation: Causes and Consequences in Skeletal Muscle Myopathy. AB - A detrimental consequence of hypermethylation is hyperhomocysteinemia (HHcy), that causes oxidative stress, inflammation, and matrix degradation, which leads to multi-pathology in different organs. Although, it is well known that hypermethylation leads to overall gene silencing and hypomethylation leads to overall gene activation, the role of such process in skeletal muscle dysfunction during HHcy condition is unclear. In this study, we emphasized the multiple mechanisms including epigenetic alteration by which HHcy causes skeletal muscle myopathy. This review also highlights possible role of methylation, histone modification, and RNA interference in skeletal muscle dysfunction during HHcy condition and potential therapeutic molecules, putative challenges, and methodologies to deal with HHcy mediated skeletal muscle dysfunction. We also highlighted that B vitamins (mainly B12 and B6), with folic acid supplementation, could be useful as an adjuvant therapy to reverse these consequences associated with this HHcy conditions in skeletal muscle. However, we would recommend to further study involving long-term trials could help to assess efficacy of the use of these therapeutic agents. J. Cell. Biochem. 118: 2108-2117, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 27982477 TI - Crosstalk Between T Lymphocytes and Lung Fibroblasts: Generation of a Hyaluronan Enriched Extracellular Matrix Adhesive for Monocytes. AB - In immunity and inflammation, T cells are often associated with stromal mesenchymal cells such as fibroblasts. Hyaluronan and proteins that associate with hyaluronan such as versican and tumor necrosis factor-inducible gene-6 (TSG 6) are extracellular matrix (ECM) components that promote leukocyte adhesion, accumulation, and activation. However, the factors responsible for producing this specialized ECM and its impact on inflammatory events are not well understood. In this study, we explored the role of T cells in stimulating lung fibroblasts to produce an ECM that impacts monocyte adhesion. We found that CD3/CD28-activated human CD4+ T cells when co-cultured with human lung fibroblasts stimulated the expression of mRNA for hyaluronan synthase 2 (HAS2) and decreased the expression of hyaluronidase 2 (HYAL2). This led to an increase in the deposition of hyaluronan that formed cable-like structures within the ECM. Co-culturing activated T cells with fibroblasts also led to increased expression and accumulation of TSG-6. Surprisingly, addition of activated CD4+ T cells to the fibroblasts reduced the expression of mRNA for versican, and increased the expression of enzymes that degrade versican, such as ADAMTS4 and ADAMTS9 (a disintegrin and metalloproteinase with a thrombospondin type-1 motif) leading to a decrease in versican in the ECM of the co-cultures. Furthermore, addition of human monocytes to these co-cultures resulted in elevated monocyte adhesion to the cable-like structures in the ECM when compared to controls. These results illustrate the importance of crosstalk between T cells and fibroblasts in promoting the generation of a matrix that is adhesive for monocytes. J. Cell. Biochem. 118: 2118-2130, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27982481 TI - Consistency of effects of tropical-forest disturbance on species composition and richness relative to use of indicator taxa. AB - Lawton et al. (1998) found, in a highly cited study, that the species richness of 8 taxa each responds differently to anthropogenic disturbance in Cameroon forests. Recent developments in conservation science suggest that net number of species is an insensitive measure of change and that understanding which species are affected by disturbance is more important. It is also recognized that all disturbance types are not equal in their effect on species and that grouping species according to function rather than taxonomy is more informative of responses of biodiversity to change. In a reanalysis of most of the original Cameroon data set (canopy and ground ants, termites, canopy beetles, nematodes, and butterflies), we focused on changes in species and functional composition rather than richness and used a more inclusive measure of forest disturbance based on 4 component drivers of change: years since disturbance, tree cover, soil compaction, and degree of tree removal. Effects of disturbance on compositional change were largely concordant between taxa. Contrary to Lawton et al.'s findings, species richness for most groups did not decline with disturbance level, providing support for the view that trends in species richness at local scales do not reflect the resilience of ecosystems to disturbance. Disturbance affected species composition more strongly than species richness for butterflies, canopy beetles, and litter ants. For these groups, disturbance caused species replacements rather than just species loss. Only termites showed effects of disturbance on species richness but not composition, indicating species loss without replacement. Although disturbance generally caused changes in composition, the strength of this relationship depended on the disturbance driver. Butterflies, litter ants, and nematodes were correlated with amount of tree cover, canopy beetles were most strongly correlated with time since disturbance, and termites were most strongly correlated with degree of soil disturbance. There were moderately divergent responses to disturbance between functional feeding groups. Disturbance was most strongly correlated with compositional differences of herbivores within beetles and nematodes and humus feeders within termites. Our results suggest that consideration of the impact of different forms of disturbance on species and functional composition, rather than on net numbers of species, is important when assessing the impacts of disturbance on biodiversity. PMID- 27982482 TI - Evaluation of a formal care worker educational intervention on pressure ulceration in the community. AB - AIMS AND OBJECTIVES: To develop and evaluate an educational intervention for formal care workers on pressure ulceration in the community. BACKGROUND: Pressure ulcers are a major burden to health care and with an ageing population likely to increase. Formal care workers are ideally placed to identify high risk but lack standardised educational provision. DESIGN: An insider approach to action research in one provider organisation, November 2014-May 2015. METHODS: Number and categorisation of pressure ulcers, within three community nursing teams before and four months after intervention was delivered to a purposive sample (n = 250) of formal care workers, were assessed and the taught element evaluated using a questionnaire and verbal feedback. RESULTS: Total number of pressure ulcers reduced from 28-20, category II, 19-11, III unchanged at 6 and IV from 2-0 following the educational intervention. Key risk factors included impaired mobility (71%), urinary incontinence (61%) and previous pressure damage (25%), and 71% had formal care worker input. The intervention was highly rated 4.95/5 by 215 (86%) formal care workers in the evaluation questionnaire. CONCLUSIONS: Formal care workers receive little, if any, education on pressure ulceration. An educational intervention can have a positive effect within community care, with the potential to reduce direct costs of care. However, a standardised approach to education is required; an urgent review of the education provision to formal care workers, in the UK and around the world, is therefore essential if the potential that formal care workers offer is to be realised. RELEVANCE TO CLINICAL PRACTICE: Formal care workers are ideally placed to help identify and alert healthcare professionals about patients at high risk of developing pressure ulcers. If this potential is to be realised, a standardised approach to education is required. PMID- 27982483 TI - c-Myc-Dependent Cell Competition in Human Cancer Cells. AB - Cell Competition is an interaction between cells for existence in heterogeneous cell populations of multicellular organisms. This phenomenon is involved in initiation and progression of cancer where heterogeneous cell populations compete directly or indirectly for the survival of the fittest based on differential gene expression. In Drosophila, cells having lower dMyc expression are eliminated by cell competition through apoptosis when present in the milieu of cells having higher dMyc expression. Thus, we designed a study to develop c-Myc (human homolog) dependent in vitro cell competition model of human cancer cells. Cells with higher c-Myc were transfected with c-myc shRNA to prepare cells with lower c Myc and then co-cultured with the same type of cells having a higher c-Myc in equal ratio. Cells with lower c-Myc showed a significant decrease in numbers when compared with higher c-Myc cells, suggesting "loser" and "winner" status of cells, respectively. During microscopy, engulfment of loser cells by winner cells was observed with higher expression of JNK in loser cells. Furthermore, elimination of loser cells was prevented significantly, when co-cultured cells were treated with the JNK (apoptosis) inhibitor. Above results indicate elimination of loser cells in the presence of winner cells by c-Myc-dependent mechanisms of cell competition in human cancer cells. This could be an important mechanism in human tumors where normal cells are eliminated by c-Myc overexpressed tumor cells. J. Cell. Biochem. 118: 1782-1791, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27982484 TI - How and why are subcutaneous fluids administered in an advanced illness population: a systematic review. AB - AIMS AND OBJECTIVES: To identify the mechanisms of subcutaneous fluid administration in advanced illness. BACKGROUND: Hydration at end of life is a fundamental issue in quality care internationally. Decision-making regarding the provision of artificial hydration in advanced illness is complicated by a paucity of evidence-based guidance. Despite considerable attention given to the topic including two recent Cochrane reviews, there has been no focus in systematically identifying papers that report the mechanisms for delivering hydration subcutaneously. Consequently, there is a need to produce guidance on the site, mode, volume and rate of infusion, based on empirical evidence. DESIGN: Systematic review of papers reporting empirical research data. METHODS: Key databases (CENTRAL, Medline, EMBASE, Web of Science, CINAHL) were searched in September 2015, with no date limitations. Inclusion criteria focused on hypodermoclysis in adults within an advanced illness population. Selected studies were reviewed for quality and a risk-of-bias assessment was conducted for the included studies. RESULTS: Fourteen papers were included in the analysis; most (n = 8) were conducted in hospices with others (n = 6) in long-stay units with a population affected by chronic conditions associated with ageing. Studies were of moderate or high quality. The site and mode of infusion were not well described in these papers, and rates of infusion varied widely allowing for little clear consensus to guide clinical practice in the administration of subcutaneous fluids. CONCLUSIONS: Studies under-report the mechanisms by which artificial hydration is provided, creating a paucity of evidence-based guidance by which to practice. There is a need for evidence generated from nonmalignant populations to ensure applicability to the large number of people with other advanced illness. RELEVANCE TO CLINICAL PRACTICE: In the absence of sufficiently powered robust evidence, the mode of delivery of artificial hydration at end of life remains in the gloaming between evidence and unfounded habit. PMID- 27982485 TI - Urinary incontinence and its management in patients aged 65 and older in orthopaedic care - what nursing and rehabilitation staff know and do. AB - AIMS AND OBJECTIVES: To describe what nursing and rehabilitation staff know and do with regard to urinary incontinence and risk of urinary incontinence in patients 65 years or older undergoing hip surgery. BACKGROUND: Urinary incontinence is a common but often neglected issue for older people. Despite the existence of evidence-based guidelines on how to assess, manage and prevent urinary incontinence, there are indications that these guidelines are not applied in hospital care. DESIGN: A qualitative study with descriptive design was conducted in two orthopaedic units. METHODS: Forty-six interviews and 36 observations of care were conducted from January-October 2014 and analysed with qualitative content analysis. RESULTS: Enrolled nurses performed most of the care related to bladder function, with focus on urinary catheterisation and preventing urinary tract infection and urinary retention. Registered nurses' role in urinary matters mainly comprised documentation, while the rehabilitation staff focused on making it possible for the patient to be independent in toileting. The nursing staff considered urinary incontinence a common condition for older people and that it was convenient for the patients to have an indwelling catheter or incontinence pad/pant, although they acknowledged some of the risks associated with these procedures. CONCLUSIONS: Urinary incontinence is not a priority in orthopaedic care, and urinary incontinence guidelines are not applied. Further, attitudes and actions are mainly characterised by a lack of urinary incontinence knowledge and the nursing and rehabilitation staff do not take a team approach to preventing and managing urinary incontinence. RELEVANCE TO CLINICAL PRACTICE: An increased focus on knowledge on urinary incontinence and evidence-based guidelines is needed. To secure evidence-based practice, the team of nursing and rehabilitation staff and managers must be aligned and work actively together, also including the patient in the team. PMID- 27982486 TI - The effect of laughter therapy on the quality of life of nursing home residents. AB - AIMS AND OBJECTIVES: To evaluate the effect of Laughter therapy on the quality of life of nursing home residents. BACKGROUND: By improving the quality of life of residents living in nursing homes and allowing them to have a healthier existence, their lives can be extended. Therefore, interventions impacting the quality of life of older adults are of critical importance. DESIGN: Quasi experimental design. METHOD: The study was conducted between 2 March - 25 May 2015. The experimental group was composed of 32 nursing home residents from one nursing home, while the control group consisted of 33 nursing home residents from another nursing home in the capital city of Turkey. Laughter therapy was applied with nursing home residents of the experimental group two days per week (21 sessions in total). A socio-demographic form and the Short-Form Health Survey (SF 36) were used for data collection. RESULTS: After the laughter therapy intervention, general and subscales (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and spiritual health) quality-of-life scores of residents in the experimental group significantly increased in comparison with the pretest. CONCLUSION: Laughter therapy improved the quality of life of nursing home residents. Therefore, nursing home management should integrate laughter therapy into health care and laughter therapy should be provided as a routine nursing intervention. RELEVANCE TO CLINICAL PRACTICE: The results indicated that the laughter therapy programme had a positive effect on the quality of life of nursing home residents. Nurses can use laughter therapy as an intervention to improve quality of life of nursing home residents. PMID- 27982487 TI - Magnetization transfer SWIFT MRI consistently detects histologically verified myelin loss in the thalamocortical pathway after a traumatic brain injury in rat. AB - Traumatic brain injury (TBI) is associated with various neurocognitive deficits, and rapid assessment of the damage is potentially important for the prevention and treatment of these deficits. Imaging assessment of mild or moderate damage outside the primary lesion area after TBI, however, remains challenging. Magnetization transfer (MT) has clearly been underutilized in imaging the damage caused by TBI. Here, we applied the MT ratio (MTR) using sweep imaging with Fourier transformation (SWIFT) to study microstructural tissue damage in the thalamocortical pathway outside the primary lesion in a lateral fluid percussion injury rat model of TBI, 5 months after injury. MTR was decreased in layers VIb IV of the barrel cortex and related subcortical areas, mainly indicating demyelination, which was verified by histology. The largest MTR change in the cortex was in layer VIb (-8.2%, pFDR = 0.01), and the largest MTR change in the subcortical areas was in the caudal-most portion of the internal capsule (-11.0%, pFDR < 0.005). These areas exhibited the greatest demyelination and substantial cellularity attributed to gliosis. Correlation analysis of group-averaged results from the subcortical areas revealed an excellent correlation of MTR with myelin (r2 = 0.94, p < 0.001), but no correlation with increased cellularity as detected by Nissl staining. Thus, MTR using SWIFT can be a valuable tool for the assessment of subtle changes after TBI in both cortical and subcortical areas. PMID- 27982488 TI - Effects of a surgical ward care protocol following open colon surgery as part of an enhanced recovery after surgery programme. AB - AIMS AND OBJECTIVES: To investigate the effects of a standardised care protocol as part of an enhanced recovery after surgery programme on the management of patients who underwent open colon surgery at the University Hospital, South Korea. BACKGROUND: Patients who undergo open colon surgery often have concerns about their care as they prepare for hospitalisation. By shortening hospital stay lengths, enhanced recovery after surgery programmes could reduce the number of opportunities for patient education and communication with nurses. Therefore, our surgical team developed an enhanced recovery after surgery programme, applied using a care protocol for patients with colorectal cancer, that spans the entire recovery process. DESIGN: A retrospective, comparative study was conducted using a care protocol as part of an enhanced recovery after surgery programme. Comparisons were made before and after the implementation of an enhanced recovery after surgery programme with a care protocol. METHODS: Records of 219 patients who underwent open colon surgery were retrospectively audited. The records were grouped according to the care protocol used (enhanced recovery after surgery programme with a care protocol or traditional care programme). The outcomes, including postoperative bowel function recovery, postoperative pain control, recovery time and postoperative complications, were compared between two categories. RESULTS: Patients who were managed using the programme with a care protocol had shorter hospital stays, fewer complications, such as postoperative ileus wound infections, and emergency room visits than those who were managed using the traditional care programme. CONCLUSION: The findings can be used to facilitate the implementation of an enhanced recovery after surgery programme with a care protocol following open colon surgery. RELEVANCE TO CLINICAL PRACTICE: We present a care protocol that enables effective management using consistent and standardised education providing bedside care for patients who undergo open colon surgery. This care protocol empowers long-term patient self care capacity, which contributes to increasing the effectiveness of clinical nursing care. PMID- 27982489 TI - What does mental health nursing contribute to improving the physical health of service users with severe mental illness? A thematic analysis. AB - Authors have generally reported that mental health nurses (MHNs) have positive attitudes to providing physical health care to service users with severe mental illness. In the present study, we aimed to explore if this positive attitude translates to enhanced clinical practice by interviewing MHNs and the service users they work with. Semistructured interviews were completed with 15 service users and 18 MHNs from acute, rehabilitation, and community services. These were then transcribed and analysed using thematic analysis. Six themes emerged: (i) not the work of MHNs; (ii) the physical effects of psychiatric drugs are ignored; (iii) the need to upskill; (iv) keeping busy; (v) horrible hospital food/living on takeaways; and (vi) motivation to change. Our overarching meta-theme was of unmet physical health need among service users. PMID- 27982490 TI - RT-PCR quantification of periodontal pathogens in crack users and non-users. AB - OBJECTIVE: To compare counts of Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Porphyromonas gingivalis and Fusobacterium nucleatum between crack users and non-users. MATERIALS AND METHODS: A cross-sectional study was conducted involving seventy-four crack cocaine users and eighty-one non-users matched for age, gender and tobacco use. Demographic and clinical variables were analysed. Subgingival bacterial samples were collected from four sites with the greatest probing depths and were analysed using real-time polymerase chain reaction. RESULTS: No significant difference was found in the prevalence of total counts for each bacterial species analysed between groups. However, crack users had a 1.85 (95% CI: 1.03-3.31), 2.19 (95% CI 1.24-3.88), 2.53 (95% CI 1.27-5.04) and 2.40 (95% CI 1.22-4.75) greater probability of having the higher counts (>=75th percentile) for Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia and Fusobacterium nucleatum, respectively. CONCLUSION: Although some crack users had higher (>75th percentile) bacterial counts for Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia and Fusobacterium nucleatum, total counts did not differ between crack users and non-users, leading to the hypothesis that the higher occurrence of periodontitis on crack users may be related to other non-bacterial factors. PMID- 27982491 TI - Family caregiver's experiences of providing care to patients with End-Stage Renal Disease in South-West Nigeria. AB - AIMS AND OBJECTIVES: To describe the experiences of family caregivers providing care for patients living with End-Stage Renal Disease in Nigeria BACKGROUND: Family caregiving is where an unpaid volunteer, usually a close family member, attends to the needs of a loved one with a chronic, disabling illness within the home. Much research has been conducted in the area of family caregiving in high income countries. However, the same cannot be said for many of the low-resource, multicultural African countries. DESIGN: Qualitative descriptive study. METHOD: This qualitative descriptive study used manifest content analysis to analyse data from semi-structured, individual interviews, with 15 purposively selected family caregivers. Two tertiary institutions providing renal care in South-Western Nigeria: the research setting for this study. RESULT: Five categories were identified, and these included disconnectedness with self and others, never ending burden, 'a fool being tossed around', obligation to care and promoting a closer relationship. CONCLUSION: Experiences associated with the caregiving of patients diagnosed with End-Stage Renal Disease evoked a number of emotions from the family caregivers, and the study revealed that caregiving imposed some burdens that are specific to low-resource countries on participants. RELEVANCE TO CLINICAL PRACTICE: Nurses need to engage family caregivers on disease-specific teachings that might promote understanding of the disease process and role expectation. Family caregivers may benefit from social support services. PMID- 27982492 TI - Possibilities and challenges of a large international benchmarking in pediatric diabetology-The SWEET experience. AB - AIM: Despite the existence of evidence-based guidelines for the care of children with diabetes, widespread gaps in knowledge, attitude, and practice remain. The purpose of this paper is to present a review of benchmarking practices and results of this process within SWEET, moreover focusing on current challenges and future directions. METHODS: Biannually, members electronically transfer de identified clinic data for 37 parameters to the SWEET database. Each center receives benchmarking and data validation reports. RESULTS: In 2015, 48 centers have contributed data for 20 165 unique patients (51.6% male). After exclusion for missing data 19 131 patients remain for further analysis. The median age is 14.2 years, with a median diabetes duration 4.8 years; 96.0% of patients have type 1, 1.1% type 2, and 2.9% other diabetes types. Data completeness has increased over time. In 2015, median HbA1c of all patients' (diabetes type 1) medians was 7.8% (61.7 mmol/mol) with 39.1%, 41.4%, and 19.4% of patients having HbA1c < 7.5% (58 mmol/mol), 7.5%-9% (58-75 mmol/mol) and >9% (75 mmol/mol), respectively. Although HbA1c has been stable over time [7.7%-7.8% (60.7-61.7 mmol/mol)], there remains wide variation between centers. Fourteen centers achieve a median HbA1c <7.5% (58 mmol/mol). CONCLUSIONS: Our vision is that the participation in SWEET is encouraging members to deliver increasingly accurate and complete data. Dissemination of results and prospective projects serve as further motivation to improve data reporting. Comparing processes and outcomes will help members identify weaknesses and introduce innovative solutions, resulting in improved and more uniform care for patients with diabetes. PMID- 27982493 TI - Control of invasive rats on islands and priorities for future action. AB - Invasive rats are one of the world's most successful animal groups that cause native species extinctions and ecosystem change, particularly on islands. On large islands, rat eradication is often impossible and population control, defined as the local limitation of rat abundance, is now routinely performed on many of the world's islands as an alternative management tool. However, a synthesis of the motivations, techniques, costs, and outcomes of such rat-control projects is lacking. We reviewed the literature, searched relevant websites, and conducted a survey via a questionnaire to synthesize the available information on rat-control projects in island natural areas worldwide to improve rat management and native species conservation. Data were collected from 136 projects conducted over the last 40 years; most were located in Australasia (46%) and the tropical Pacific (25%) in forest ecosystems (65%) and coastal strands (22%). Most of the projects targeted Rattus rattus and most (82%) were aimed at protecting birds and endangered ecosystems. Poisoning (35%) and a combination of trapping and poisoning (42%) were the most common methods. Poisoning allows for treatment of larger areas, and poison projects generally last longer than trapping projects. Second-generation anticoagulants (mainly brodifacoum and bromadiolone) were used most often. The median annual cost for rat-control projects was US$17,262 or US$227/ha. Median project duration was 4 years. For 58% of the projects, rat population reduction was reported, and 51% of projects showed evidence of positive effects on biodiversity. Our data were from few countries, revealing the need to expand rat-control distribution especially in some biodiversity hotspots. Improvement in control methods is needed as is regular monitoring to assess short and long-term effectiveness of rat-control. PMID- 27982494 TI - Polar Hinges as Functionalized Conformational Constraints in (Bi)cyclic Peptides. AB - Two polar hinges for cyclization of peptides have been developed, leading to bicyclic peptides and cyclized peptides with improved solubility and biological activity. Increasingly, we note that a good aqueous solubility of peptides is an absolute prerequisite, not only to allow handling and purification of our target peptides but also being crucial for biological activity characteristics. Compared to earlier hinges, the 1,1',1"-(1,3,5-triazinane-1,3,5-triyl)tris(2 bromoethanone) (TATB) and 2,4,6-tris(bromomethyl)-s-triazine (TBMT), each containing three nitrogen atoms are structurally similar but chemically very different. Both were accessible in a one-step fashion from bromoacetonitrile. TATB and TBMT are very suitable for the preparation of more soluble bicyclic peptides. Azide-modified TATB and TBMT derivatives provide hinges for the preparation of cyclized peptides for incorporation on scaffolds to afford protein mimics. PMID- 27982495 TI - Variation in malathion sensitivity among populations of Blanchard's cricket frogs (Acris blanchardi) and implications for risk assessment. AB - Intraspecific variability in contaminant sensitivity could undermine risk assessments for nontarget organisms such as amphibians. To test how amphibian populations vary in tolerance to anticipated lethal and sublethal exposures to a pesticide, we exposed Blanchard's cricket frogs (Acris blanchardi) from 3 populations across a broad portion of their range to the insecticide malathion. Exposure in mesocosms to a nominal concentration of 1 mg/L (measured concentrations at 1 h and 24 h postaddition of 0.160 mg/L and 0.062 mg/L, respectively), a realistic direct-overspray scenario, reduced survival to metamorphosis by 43% relative to controls and revealed variation in tolerance among populations. Survival ranged from 74% for the most tolerant population to 18% for the least tolerant population, a 4.1-fold difference. Mass at metamorphosis and time to metamorphosis were unaffected. Although malathion reduced zooplankton abundance, it did not alter food resources (periphyton or phytoplankton relative abundance), or a suite of water-quality variables (pH, temperature, and dissolved oxygen). A 96-h time-to-death assay designed to isolate direct, lethal effects also revealed variation in tolerance among populations. Time to death (mean +/- standard error) ranged from 2.4 +/- 0.18 h for the least tolerant population to 17.8 +/- 4.72 h for the most tolerant population, a 7.4-fold difference. However, relative sensitivities of populations differed in the mesocosm and laboratory studies, which differed in exposure concentrations, suggesting that populations tolerant of high concentrations can be more sensitive to lower concentrations. We suggest that direct overspray could reduce larval survival in the field for this species. Studies assessing the role of contaminants in declines or extrapolating to untested populations, especially across large geographical regions, should quantify the range of intraspecific variation. Risk assessors could address intraspecific variability directly by using an intraspecific uncertainty factor. Environ Toxicol Chem 2017;36:1917 1923. (c) 2016 SETAC. PMID- 27982496 TI - Forensic mental health clinician's experiences with and assessment of alliance regarding the patient's readiness to be released from mechanical restraint. AB - One of the main reasons for prolonged duration of mechanical restraint is patient behaviour in relation to the clinician-patient alliance. This article reports on the forensic mental health clinicians experiences of the clinician-patient alliance during mechanical restraint, and their assessment of parameters of alliance regarding the patient's readiness to be released from restraint. We used a qualitative, descriptive approach and conducted focus group interviews with nurses, nurse assistants and social and healthcare assistants. The results show that a pre-established personal clinician-patient alliance formed the basis for entering into, and weighing the quality of, the alliance during mechanical restraint. In consideration of the patient's psychiatric condition, the clinicians observed and assessed two quality parameters for the alliance: 'the patient's insight into or understanding of present situation' (e.g. the reasons for mechanical restraint and the behaviour required of the patient to discontinue restraint) and 'the patient's ability to have good and stable contact and cooperation with and across clinicians. These assessments were included, as a total picture of the quality of the alliance with the patient', in the overall team assessment of the patient's readiness to be released from mechanical restraint. The results contribute to inform the development of a short-term risk assessment instrument, with the aim of reducing the duration of mechanical restraint. PMID- 27982497 TI - Lived experience of working with female patients in a high-secure mental health setting. AB - Women's secure hospitals are often considered to be stressful and demanding places to work, with these environments characterized as challenging and violent. However, the staff experience of working in this environment is not well represented in the literature. The present study is the first to examine the 'lived experience' of seven nurses working in the National High Secure Healthcare Service for Women. Interview transcripts were analysed with the use of interpretative phenomenological analysis, and the findings presented within four superordinate themes 'horror', 'balancing acts', 'emotional hard labour', and 'the ward as a community'. These themes all depict the challenges that participants experience in their work, the ways in which they cope with these challenges, and how they make sense of these experiences. A meta-theme of 'making sense by understanding why' is also presented, which represents the importance for participants to attempt to make sense of the tensions and challenges by formulating a fuller meaning. The findings suggest the importance of workforce development in terms of allowing sufficient protected time for reflection and formulation (e.g. within the format of group supervision or reflective practice), and for staff-support mechanisms (e.g. clinical supervision, counselling, debriefs) to be inbuilt into the ethos of a service, so as to provide proactive support for staff 'on the frontline'. PMID- 27982498 TI - Anticoagulation in patients at high risk of stroke without documented atrial fibrillation. Time for a paradigm shift? AB - Atrial fibrillation (AF) is currently considered a risk factor for stroke. Depending on the severity of clinical factors (risk scores) a recommendation for full anticoagulation is made. Although AF is most certainly a risk factor for ischemic stroke, it is not necessarily the direct cause of it. The causality of association between AF and ischemic stroke is questioned by the reported lack of temporal relation between stroke events and AF paroxysms (or atrial high-rate episodes detected by devices). In different studies, only 2% of patients had subclinical AF > 6 minutes in duration at the time of stroke or systemic embolism. Is it time to consider AF only one more factor of endothelial disarray rather than the main contributor to stroke? In this "opinion paper" we propose to consider not only clinical variables predicting AF/stroke but also electrocardiographic markers of atrial fibrosis, as we postulate this as a strong indicator of risk of AF/stroke. We ask if it is time to change the paradigm and to consider, in some special situations, to protect patients (preventing stroke) who have no evidence of AF. PMID- 27982499 TI - Hereditary gelsolin amyloidosis (HGA): a neglected cause of bilateral progressive or recurrent facial palsy. AB - We report the first Italian family affected by hereditary gelsolin amyloidosis (HGA), a rare autosomal dominant disease characterized by adult-onset slowly progressive cranial neuropathy, lattice corneal dystrophy, and cutis laxa. The index case was a 39-year-old male with a 9-year history of progressive bilateral facial nerve palsy. His mother had two episodes of acute facial palsy, and his maternal aunt and grandfather were also affected. Electrophysiological studies confirmed bilateral facial nerve involvement, without signs of peripheral polyneuropathy, and ophthalmological examination showed bilateral lattice corneal dystrophy, in both the index case and his mother. Gelsolin-gene sequencing revealed the heterozygous c.640G>A mutation (p.Asp187Asn) in the proband, his mother and aunt and also in three apparently asymptomatic relatives. The majority of HGA patients come from Finland, although several cases have been reported from other countries. HGA should be considered in the differential diagnosis of progressive or recurrent bilateral facial neuropathy. PMID- 27982500 TI - Growth hormone/IGF-1 axis longitudinal evaluation in clinically isolated syndrome patients on interferon beta-1b therapy: stimulation tests and correlations with clinical and radiological conversion to multiple sclerosis. AB - BACKGROUND AND PURPOSE: Growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis abnormalities in multiple sclerosis (MS) suggest their role in its pathogenesis. Interferon beta (IFN-beta) efficacy could be mediated also by an increase of IGF-1 levels. A 2-year longitudinal study was performed to estimate the prevalence of GH and/or IGF-1 deficiency in clinically isolated syndrome (CIS) patients and their correlation with conversion to MS in IFN treated patients. METHODS: Clinical and demographic features of CIS patients were collected before the start of IFN-beta-1b. IGF-1 levels and GH response after arginine and GH releasing hormone + arginine stimulation tests were assessed. Clinical and magnetic resonance imaging evaluations were performed at baseline, 1 year and 2 years. RESULTS: Thirty CIS patients (24 female) were enrolled. At baseline, four patients (13%) showed a hypothalamic GH deficiency (GHD), whilst no one had a pituitary GHD. Baseline demographic, clinical and radiological data were not related to GHD, whilst IGF-1 levels were inversely related to age (P < 0.001) and GH levels (P = 0.03). GH and IGF-1 serum mean levels were not significantly modified after 1 and 2 years of treatment in the whole group, although 3/4 GHD patients experienced a normalization of GH levels, whilst one dropped out. After 2 years of treatment 13/28 (46%) patients converted to MS. The presence of GHD and GH and IGF-1 levels were not predictive of relapses, new T2 lesions or conversion occurrence. CONCLUSIONS: Growth hormone/IGF-1 axis function was found to be frequently altered in CIS patients, but this was not related to MS conversion. Patients experienced an improvement of GHD during IFN therapy. Longer follow-up is necessary to assess its impact on disease progression. PMID- 27982501 TI - Motor associations of iron accumulation in deep grey matter nuclei in Parkinson's disease: a cross-sectional study of iron-related magnetic resonance imaging susceptibility. AB - BACKGROUND AND PURPOSE: To determine whether iron deposition in deep brain nuclei assessed using high-pass filtered phase imaging plays a role in motor disease severity in Parkinson's disease (PD). METHODS: Seventy patients with mild to moderate PD and 20 age- and gender-matched healthy volunteers (HVs) underwent susceptibility-weighted imaging on a 3 T magnetic resonance imaging scanner. Phase shifts (radians) in deep brain nuclei were derived from high-pass filtered phase images and compared between groups. Analysis of clinical laterality and correlations with motor severity (Unified Parkinson's Disease Rating Scale, Part III, UPDRS-III) were performed. Phase shifts (in radians) were compared between HVs and three PD subgroups divided according to UPDRS-III scores using analysis of covariance, adjusting for age and regional area. RESULTS: Parkinson's disease patients had significantly (P < 0.001) higher radians than HVs bilaterally in the putamen, globus pallidus and substantia nigra (SN). The SN contralateral to the most affected side showed higher radians (P < 0.001) compared to the less affected side. SN radians positively correlated with UPDRS-III and bradykinesia rigidity subscores, but not with tremor subscores. ancova followed by post hoc Bonferroni-adjusted pairwise comparisons revealed that SN radians were significantly greater in the PD subgroup with higher UPDRS-III scores compared to both lowest UPDRS-III PD and HV groups (P < 0.001). CONCLUSIONS: Increased nigral iron accumulation in PD appears to be stratified according to disease motor severity and correlates with symptoms related to dopaminergic neurodegeneration. This semi-quantitative in vivo iron assessment could prove useful for objectively monitoring PD progression, especially in clinical trials concerning iron chelation therapies. PMID- 27982502 TI - The emotion of compassion and the likelihood of its expression in nursing practice. AB - Philosophical and empirical work on the nature of the emotions is extensive, and there are many theories of emotions. However, all agree that emotions are not knee jerk reactions to stimuli and are open to rational assessment or warrant. This paper's focus is on the condition or conditions for compassion as an emotion and the likelihood that it or they can be met in nursing practice. Thus, it is attempting to keep, as far as possible, compassion as an emotion separate from both moral norms and professional norms. This is because empirical or causal conditions that can make experiencing and acting out of compassion difficult seem especially relevant in nursing practice. I consider how theories of emotion in general and of compassion in particular are somewhat contested, but all recent accounts agree that emotions are not totally immune to reason. Then, using accounts of constitutive conditions of the emotion of compassion, I will show how they are often likely to be quite fragile or unstable in practice and particularly so within much nursing practice. In addition, some of the conditions for compassion will be shown to be problematic for nursing practice. It is difficult to keep ideas of compassion separate from morality, and this connection is noticeable in the claims made of compassion for nursing and so I will briefly highlight one such connection that of the need for normative theory to give an account of the value that emotions such as compassion presume and that compassionate motivation is separate from moral motivation and may conflict with it. The fragility or instability of the emotion of compassion in practice has implications for both what can be expected and what should be expected of compassion; at least if what is wanted is a realist rather than idealist account of "should." PMID- 27982504 TI - Climate change and nesting behaviour in vertebrates: a review of the ecological threats and potential for adaptive responses. AB - Nest building is a taxonomically widespread and diverse trait that allows animals to alter local environments to create optimal conditions for offspring development. However, there is growing evidence that climate change is adversely affecting nest-building in animals directly, for example via sea-level rises that flood nests, reduced availability of building materials, and suboptimal sex allocation in species exhibiting temperature-dependent sex determination. Climate change is also affecting nesting species indirectly, via range shifts into suboptimal nesting areas, reduced quality of nest-building environments, and changes in interactions with nest predators and parasites. The ability of animals to adapt to sustained and rapid environmental change is crucial for the long-term persistence of many species. Many animals are known to be capable of adjusting nesting behaviour adaptively across environmental gradients and in line with seasonal changes, and this existing plasticity potentially facilitates adaptation to anthropogenic climate change. However, whilst alterations in nesting phenology, site selection and design may facilitate short-term adaptations, the ability of nest-building animals to adapt over longer timescales is likely to be influenced by the heritable basis of such behaviour. We urgently need to understand how the behaviour and ecology of nest-building in animals is affected by climate change, and particularly how altered patterns of nesting behaviour affect individual fitness and population persistence. We begin our review by summarising how predictable variation in environmental conditions influences nest building animals, before highlighting the ecological threats facing nest-building animals experiencing anthropogenic climate change and examining the potential for changes in nest location and/or design to provide adaptive short- and long-term responses to changing environmental conditions. We end by identifying areas that we believe warrant the most urgent attention for further research. PMID- 27982505 TI - Secular trends in blood pressure in children: A systematic review. AB - Blood pressure (BP) is expected to have increased over time in children in most countries due to the increasing prevalence of childhood obesity worldwide. The authors conducted a systematic review of studies assessing secular trends in BP in children and adolescents. Of 1739 citations screened, the authors identified 18 studies including 2 042 470 participants examined between 1963 and 2012. Thirteen studies were conducted in high-income countries, five in middle-income countries, and none in low-income countries. The prevalence of overweight or obesity increased in 17 studies and decreased in one study. BP decreased over time in 13 studies, increased in four, and did not change in one. These findings suggest that secular trends in BP do not mirror secular trends in overweight. This implies that other factors mitigate the effect of overweight on BP in children and adolescents. PMID- 27982506 TI - Pseudoangiomatous Spindle Cell Lipoma: a distinct subtype of spindle cell lipoma. PMID- 27982507 TI - Cognitive processing in the aftermath of relationship dissolution: Associations with concurrent and prospective distress and posttraumatic growth. AB - Non-marital romantic relationship dissolution is amongst the most stressful life events experienced by young adults. Yet, some individuals experience posttraumatic growth following relationship dissolution. Little is known about the specific and differential contribution of trait-like and event-specific cognitive processing styles to each of these outcomes. A longitudinal design was employed in which trait-like (brooding and reflection) and dissolution-specific (intrusive and deliberate) cognitive processing was examined as predictors of growth (Posttraumatic Growth Inventory) and distress (Breakup Distress Scale) following a recent relationship dissolution. Initially, 148 participants completed measures of trait-like and dissolution-specific cognitive processing, growth, and distress (T1). A subsample completed a seven-month follow-up (T2). Higher frequency of relationship-dissolution intrusive thoughts predicted concurrent distress after accounting for brooding and relationship characteristics. Further, higher brooding and lower reflection predicted higher distress prospectively. Concurrent growth was predicted by both higher brooding and more deliberate relationship-dissolution thoughts. Prospectively, T1 dissolution intrusive thoughts predicted higher T2 deliberate thoughts, and the interaction between these two constructs predicted higher T2 growth. Therefore, deliberately thinking of the dissolution was related to positive psychological outcomes. In contrast, intrusive dissolution cognitions and a tendency for brooding had a mixed (paradoxical) association with psychological adjustment. PMID- 27982508 TI - Regional Differences in Communication Process and Outcomes of Requests for Solid Organ Donation. AB - Although federal mandate prohibits the allocation of solid organs for transplantation based on "accidents of geography," geographic variation of transplantable organs is well documented. This study explores regional differences in communication in requests for organ donation. Administrative data from nine partnering organ procurement organizations and interview data from 1339 family decision makers (FDMs) were compared across eight geographically distinct US donor service areas (DSAs). Authorization for organ donation ranged from 60.4% to 98.1% across DSAs. FDMs from the three regions with the lowest authorization rates reported the lowest levels of satisfaction with the time spent discussing donation and with the request process, discussion of the least donation-related topics, the highest levels of pressure to donate, and the least comfort with the donation decision. Organ procurement organization region predicted authorization (odds ratios ranged from 8.14 to 0.24), as did time spent discussing donation (OR = 2.11), the number of donation-related topics discussed (OR = 1.14), and requesters' communication skill (OR = 1.14). Standardized training for organ donation request staff is needed to ensure the highest quality communication during requests, optimize rates of family authorization to donation in all regions, and increase the supply of organs available for transplantation. PMID- 27982509 TI - Kidney volume and ambulatory blood pressure in children. AB - Low nephron number has been shown to be a risk factor for hypertension (HTN) in adulthood. Kidney volume may serve as a surrogate marker for nephron mass. The relationship between kidney volume and ambulatory blood pressure (BP) in the pediatric population is not known. A retrospective chart review of children younger than 21 years who were evaluated for HTN was performed. Twenty-four-hour BP and ultrasonography data were obtained. Multiple regression was used to examine associations between BP and kidney volume. Of 84 children (mean age 13.87 years, 72.6% males), 54 had HTN. Systolic BP index during the awake, sleep, and 24-hour periods (all P<=.05) was found to be positively correlated with total kidney volume. Greater total kidney volume was found to be a positive predictor of 24-hour and sleep systolic index (P<=.05). It failed to serve as a predictor of HTN, pre-HTN, or white-coat HTN. Contrary to expectation, total kidney volume was positively associated with systolic BP indices. PMID- 27982510 TI - Stress system dysregulation in pediatric generalized anxiety disorder associated with comorbid depression. AB - Because chronic stress is an important risk factor for anxiety states and depressive disorders, we studied hypothalamus-pituitary-adrenal (HPA) axis and sympathetic system activity via changes in cortisol and alpha amylase activity levels in pediatric generalized anxiety disorder (GAD) patients (n = 26) with comorbid depression and a healthy comparison group (n = 26). Morning plasma cortisol and diurnal profiles of salivary cortisol and salivary alpha amylase (sAA) activity were assessed, also reactivity of HPA-axis, sAA activity, and heart rate following a psychosocial stressor (Trier Social Stress Test for children). GAD patients with comorbid depression showed increased morning plasma and salivary cortisol levels, ameliorating throughout in-patient treatment, and higher sAA activity in their diurnal profile. Both HPA and sympathetic activity positively correlated with the severity of anxiety and depression. We also demonstrated a blunted HPA and sympathetic response to acute stress in patients. This pattern of neuroendocrine and sympathetic changes seems to be distinct from the one previously reported in pediatric patients with only social anxiety or depressive disorders. We propose morning plasma and saliva cortisol levels as potential physiological indicators for supporting the evaluation of symptoms' severity and treatment progress in children with GAD and comorbid depressive disorder. PMID- 27982503 TI - T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction. AB - Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-beta. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-beta-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD. PMID- 27982512 TI - Iodine status of pregnant women in South Australia after mandatory iodine fortification of bread and the recommendation for iodine supplementation. AB - Mandatory iodine fortification of bread was introduced in 2009 in Australia in response to the reemergence of iodine deficiency. The aim of this study was to assess iodine intake, urinary iodine concentration (UIC) and their correlation in pregnant women (n = 783) recruited from South Australia 2 years following mandatory iodine fortification. Total iodine intake (food and supplements) and UIC were assessed at study entry (<20 weeks') and at 28 weeks' gestation. Mean (+/-SD) total iodine intake at study entry and 28 weeks' gestation was 307 +/- 128 MUg/day and 300 +/- 127 MUg/day, respectively. Overall, 85.9% of women met the estimated average intake (>=160 MUg/day) for iodine in pregnancy, but only 44.5% met the estimated average intake from food alone. The main food sources of iodine were dairy foods and iodine-fortified bread. Median (interquartile range) UIC at study entry and 28 weeks' gestation was 189 MUg/L and 172 MUg/L, respectively. At study entry, median UIC was higher in women taking supplements containing iodine >=150 MUg/day compared with those containing iodine <150 MUg/day (221 MUg/L vs. 163 MUg/L, p = .003) and those not taking supplements containing iodine (221 MUg/L vs. 159 MUg/L, p < .001). At 28 weeks' gestation, the median UIC for the groups was 187, 152 and 141 MUg/L, respectively (each of the two comparisons yielded p < .001). Total iodine intake (food and supplements) from all women was positively, though weakly, correlated with UIC (r = .23, p < .001). In conclusion, pregnant women in South Australia are iodine sufficient postmandatory iodine fortification of bread. However, without iodine supplementation, it may be difficult to achieve a UIC >150 MUg/L. PMID- 27982513 TI - A New Iridoid Dimer and Other Constituents from the Traditional Kurdish Plant Pterocephalus nestorianus Nabelek. AB - Accompanied by other rare compounds, a new iridoid dimer, named kurdnestorianoside (1), showing an unprecedented secologanol configuration, has been isolated for the first time from the Kurdish medicinal plant Pterocephalus nestorianus, which is used in Kurdistan for treating oral diseases and inflammation. The structure of 1 was established from 1D- and 2D-NMR spectroscopic data. Kaempferol 3-O-[3,6-di-O-(E)-p-coumaroyl]-beta-d glucopyranoside (7) showed a remarkable antiproliferative activity against several human tumor cell lines. PMID- 27982514 TI - Stretchable Substrates for the Assembly of Polymeric Microstructures. AB - The directed assembly of micro-/nanoscale objects relies on physical or chemical processes to generate structures that are not possible via self-assembly alone. A relatively unexplored strategy in directed assembly is the "active" manipulation of building blocks through deformations of elastomeric substrates. This manuscript reports a method which uses macroscopic mechanical deformations of chemically modified silicone films to realize the rational assembly of microscopic polymer structures. Specifically, polystyrene microparticles are deposited onto polydimethylsiloxane substrates using microcontact-printing where, through a process that involved stretching/relaxing the substrates and bonding of the particles, they are elaborated into microstructures of various sizes, shapes, symmetries, periodicities, and functionalities. The resulting polymeric microstructures can be released and redeposited onto planar/nonplanar surfaces. When building blocks with different properties (e.g., those with fluorescent and catalytic properties) are used, it is possible to fabricate structures with heterogeneous functionality. This method can be extended to the assembly of numerous micro-/nanoscale building blocks (e.g., colloidal organic/inorganic materials) with rational control over the size, shape, and functionality of the product. As a strategy, the use of substrate deformations to enable the micromanipulation and fabrication of a potentially diverse set of assemblies represents a powerful tool useful to, for example, nanotechnology and micromanufacturing. PMID- 27982511 TI - Biochemical Changes in the Niche Following Tumor Cell Invasion. AB - Metastatic cancer is the leading cause of all cancer related deaths. Prostate cancer (PCa) metastasizes preferentially to the bone marrow, specifically within the endosteal niche. Endosteal cells secrete homing molecules that may recruit PCa cells to the bone marrow. Once there, the biochemical signature of this niche regulates PCa fate including cellular dormancy or cell cycle arrest, reactivation and resistance to chemotherapeutics. Growth factors, interleukins, adhesion molecules, as well as extra-cellular matrix proteins can collectively change the phenotype of PCa cells. Understanding the biochemical signature of endosteal niche parasitism by PCa is imperative for the establishment of new and innovative therapeutic strategies. This review seeks to summarize these important niche signatures and the potential therapeutic approaches to target metastatic PCa within the bone marrow hematopoietic stem cell (HSC) niche. J. Cell. Biochem. 118: 1956-1964, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27982515 TI - Printing Functional 3D Microdevices by Laser-Induced Forward Transfer. AB - Slender, out-of-plane metal microdevices are made in a new spatial domain, by using laser-induced forward transfer (LIFT) of metals. Here, a thermocouple with a thickness of 10 um and a height of 250 um, consisting of platinum and gold pillars is demonstrated. Multimaterial LIFT enables manufacturing in the micrometer to millimeter range, i.e., between lithography and other 3D printing technologies. PMID- 27982516 TI - Poly(N-phenylglycine)-Based Nanoparticles as Highly Effective and Targeted Near Infrared Photothermal Therapy/Photodynamic Therapeutic Agents for Malignant Melanoma. AB - Malignant melanoma is a highly aggressive tumor resistant to chemotherapy. Therefore, the development of new highly effective therapeutic agents for the treatment of malignant melanoma is highly desirable. In this study, a new class of polymeric photothermal agents based on poly(N-phenylglycine) (PNPG) suitable for use in near-infrared (NIR) phototherapy of malignant melanoma is designed and developed. PNPG is obtained via polymerization of N-phenylglycine (NPG). Carboxylate functionality of NPG allows building multifunctional systems using covalent bonding. This approach avoids complicated issues typically associated with preparation of polymeric photothermal agents. Moreover, PNPG skeleton exhibits pH-responsive NIR absorption and an ability to generate reactive oxygen species, which makes its derivatives attractive photothermal therapy (PTT)/photodynamic therapy (PDT) dual-modal agents with pH-responsive features. PNPG is modified using hyaluronic acid (HA) and polyethylene glycol diamine (PEG diamine) acting as the coupling agent. The resultant HA-modified PNPG (PNPG-PEG HA) shows negligible cytotoxicity and effectively targets CD44-overexpressing cancer cells. Furthermore, the results of in vitro and in vivo experiments reveal that PNPG-PEG-HA selectively kills B16 cells and suppresses malignant melanoma tumor growth upon exposure to NIR light (808 nm), indicating that PNPG-PEG-HA can serve as a very promising nanoplatform for targeted dual-modality PTT/PDT of melanoma. PMID- 27982517 TI - All-Carbon Electrode Molecular Electronic Devices Based on Langmuir-Blodgett Monolayers. AB - Nascent molecular electronic devices, based on monolayer Langmuir-Blodgett films sandwiched between two carbonaceous electrodes, have been prepared. Tightly packed monolayers of 4-((4-((4-ethynylphenyl)ethynyl)phenyl)ethynyl)benzoic acid are deposited onto a highly oriented pyrolytic graphite electrode. An amorphous carbon top contact electrode is formed on top of the monolayer from a naphthalene precursor using the focused electron beam induced deposition technique. This allows the deposition of a carbon top-contact electrode with well-defined shape, thickness, and precise positioning on the film with nm resolution. These results represent a substantial step toward the realization of integrated molecular electronic devices based on monolayers and carbon electrodes. PMID- 27982518 TI - Electron Transfer Mediated by Surface-Tethered Redox Groups in Nanofluidic Devices. AB - Electrochemistry provides a powerful sensor transduction and amplification mechanism that is highly suited for use in integrated, massively parallelized assays. Here, the cyclic voltammetric detection of flexible, linear poly(ethylene glycol) polymers is demonstrated, which have been functionalized with redox active ferrocene (Fc) moieties and surface-tethered inside a nanofluidic device consisting of two microscale electrodes separated by a gap of <100 nm. Diffusion of the surface-bound polymer chains in the aqueous electrolyte allows the redox groups to repeatedly shuttle electrons from one electrode to the other, resulting in a greatly amplified steady-state electrical current. Variation of the polymer length provides control over the current, as the activity per Fc moiety appears to depend on the extent to which the polymer layers of the opposing electrodes can interpenetrate each other and thus exchange electrons. These results outline the design rules for sensing devices that are based on changing the polymer length, flexibility, and/or diffusivity by binding an analyte to the polymer chain. Such a nanofluidic enabled configuration provides an amplified and highly sensitive alternative to other electrochemical detection mechanisms. PMID- 27982520 TI - Efficient Hydrogenation of Biomass Oxoacids to Lactones by Using NHC-Iridium Coordination Polymers as Solid Molecular Catalysts. AB - A series of NHC-iridium coordination polymers have proven to be robust, efficient and recyclable solid molecular catalysts toward the hydrogenation of biomass levulinic acid (LA) to gamma-valerolactone. Along with quantitative yields attained at 0.01 mol % catalyst loading under 50 atm of H2 , the solid molecular catalyst was readily recovered and reused for 12 runs without obvious loss of the selectivity and activity. Remarkably, up to 1.2*105 TON, an unprecedented value could be achieved in this important transformation. In addition, a number of LA homologues, analogues and derivatives were well tolerated to deliver various intriguing and functional lactones in good to excellent yields, which further confirmed the feasibility of the solid molecular catalysts. PMID- 27982521 TI - Structure and Magnetic Property Control of Copper Hydroxide Acetate by Non Classical Crystallization. AB - Copper hydroxide acetate (CHA), one layered hydroxide compound with tunable magnetism, attracts great interest because of its potential applications in memory devices. However, ferromagnetism for CHA is only demonstrated by means of GPa pressure. Herein, a new method is reported, involving the combination of different crystallization pathways to control crystallization of amorphous CHA toward the formation of CHA/polymer composites with tunable magnetic properties and even a tunability that can be tested at room temperature. By using poly[(ethylene glycol)6 methyl ether methacrylate]-block-poly[2-(acetoacetoxy) ethyl methacrylate] (PEGMA-b-PAEMA) diblock copolymers as additives in combination with a post-treatment process by ultracentrifugation, it is demonstrated that CHA and PEGMA-b-PAEMA form composites exhibiting different magnetic properties, depending on CHA in-plane nanostructures. Analytical characterization reveals that crystallization of CHA is induced by ultracentrifugation, during which CHA nanostructures can be well controlled by changing the degrees of polymerization of the PEGMA and PAEMA blocks and their block length ratios. These findings not only present the first example of using crystallization from polymer stabilized amorphous precursors toward the generation of magnetic nanomaterials with tunable magnetism but also pave the way for the future design of functional composite materials. PMID- 27982519 TI - Microbiome precision editing: Using PEG as a selective fermentation initiator against methicillin-resistant Staphylococcus aureus. AB - Recent creation of a Unified Microbiome Initiative (UMI) has the aim of understanding how microbes interact with each other and with us. When pathogenic Staphylococcus aureus infects the skin, the interplay between S. aureus and skin commensal bacteria occurs. Our previous data revealed that skin commensal bacteria can mediate fermentation against the growth of USA300, a community acquired methicillin-resistant S. aureus MRSA. By using a fermentation process with solid media on a small scale, we define poly(ethylene glycol) dimethacrylate (PEG-DMA) as a selective fermentation initiator which can specifically intensify the probiotic ability of skin commensal Staphylococcus epidermidis bacteria. At least five short-chain fatty acids including acetic, butyric and propionic acids with anti-USA300 activities are produced by PEG-DMA fermentation of S. epidermidis. Furthermore, the S. epidermidis-laden PEG-DMA hydrogels effectively decolonized USA300 in skin wounds in mice. The PEG-DMA and its derivatives may become novel biomaterials to specifically tailor the human skin microbiome against invading pathogens. PMID- 27982522 TI - High-Throughput Synthetic Chemistry Enabled by Organic Solvent Disintegrating Tablet. AB - Synthetic chemistry remains a time- and labor-intensive process of inherent hazardous nature. Our organic solvent disintegrating tablet (O-Tab) technology has shown potential to make industrial/synthetic chemistry more efficient. As is the case with pharmaceutical tablets, our reagent-containing O-Tabs are mechanically strong, but disintegrate rapidly when in contact with reaction media (organic solvents). For O-Tabs containing sensitive chemicals, they can be further coated to insulate them from air and moisture. PMID- 27982523 TI - Two New Ergosterol Derivatives from the Basidiomycete Cortinarius glaucopus. AB - Two new sterols 1 and 2 and five known ones 3 - 7 were isolated for the first time from the fruiting bodies of Cortinarius glaucopus. Their structures were established by 1- and 2D-NMR spectra and HR-FABS-MS. The relative configuration of 1 was firmly determined by comparison of the observed 1 H-1 H couplings and NOESY correlations, with those predicted for the computed geometries of the conformers. Calculations were performed by means of DFT with the B3LYP functional at 6-31 + G(d,p) level of theory, in CHCl3 as the solvent. The structures of the new ergosterol derivatives, called glaucoposterol A (1) and B (2), were thus established as (3S,5R,7R,10R,13R,17R,20S,22R,23R,24R)-5,6-epoxy-3,7,23 trihydroxystrophast-8-en-14-one and (22E,3S,5S,9S,10R,13R,17R,20R,24R)-3,5 dihydroxyergosta-6,8(14),22-trien-15-one, respectively. Moreover, the configuration of known strophasterol C (3) was determined as (3S,5R,6S,7R,10R,13R,17R,20S,22S,24R). Glaucoposterol A (1) and strophasterol C (3) represent the second finding in nature of steroids with the rare strophastane skeleton. PMID- 27982524 TI - A novel NDRG1 mutation in a non-Romani patient with CMT4D/HMSN-Lom. AB - Charcot-Marie-Tooth disease type 4D (CMT4D), also known as hereditary motor and sensory neuropathy Lom type (HMSNL), is an autosomal recessive, early onset, severe demyelinating neuropathy with hearing loss, caused by N-Myc downstream regulated gene 1 (NDRG1) mutations. CMT4D is rare with only three known mutations, one of which (p.Arg148Ter) is found in patients of Romani ancestry and accounts for the vast majority of cases. We report a 38-year-old Italian female with motor development delay, progressive neuropathy, and sensorineural deafness. Magnetic resonance imaging showed slight atrophy of cerebellum, medulla oblongata, and upper cervical spinal cord. She had a novel homozygous NDRG1 frameshift mutation (c.739delC; p.His247ThrfsTer74). The identification of this NDRG1 mutation confirms that CMT4D is not a private Romani disease and should be considered in the differential diagnosis of recessive demyelinating CMT. PMID- 27982525 TI - Two-component collagen nerve guides support axonal regeneration in the rat peripheral nerve injury model. AB - Progress in material development has enabled the production of nerve guides that increasingly resemble the characteristics of an autologous nerve graft. In the present study, 20 mm adult rat sciatic nerve defects were bridged with the collagen-based, two-component nerve guide 'Neuromaix', the commercially available NeuraGen(r) nerve tube or an autologous nerve graft. Neuromaix was able to support structural as well as functional regeneration across this gap. The majority of the axons grew across the scaffold into the distal nerve segment and retrograde tracing confirmed that these axons were of somatosensory and motor origin. Histomorphology revealed that axons regenerating through Neuromaix exhibited reduced myelin sheath thickness, whereas axon diameter and axon density were comparable to those of the autograft. Neuromaix implantation resulted in reinnervation of the gastrocnemius muscle to a level that was not significantly different from that supported by the autograft, as demonstrated by electrophysiology. Our findings show that the use of the Neuromaix scaffold not only allowed axonal regeneration across large nerve gaps, but that the regenerating axons were also able to functionally reinnervate the muscles. These data provide a promising perspective for the first in human application of the materials. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27982526 TI - Self-Supporting GaN Nanowires/Graphite Paper: Novel High-Performance Flexible Supercapacitor Electrodes. AB - Flexible supercapacitors have attracted great interest as energy storage devices because of their promise in applications such as wearable and smart electronic devices. Herein, a novel flexible supercapacitor electrode based on gallium nitride nanowire (GaN NW)/graphite paper (GP) nanocomposites is reported. The outstanding electrical conductivities of the GaN NW (6.36 * 102 S m-1 ) and GP (7.5 * 104 S m-1 ) deliver a synergistically enhanced electrochemical performance that cannot be achieved by either of the components alone. The composite electrode exhibits excellent specific capacitance (237 mF cm-2 at 0.1 mA cm-2 ) and outstanding cycling performance (98% capacitance retention after 10 000 cycles). The flexible symmetric supercapacitor also manifests high energy and power densities (0.30 mW h cm-3 and 1000 mW cm-3 ). These findings demonstrate that the GaN/GP composite electrode has significant potential as a candidate for the flexible energy storage devices. PMID- 27982527 TI - Can the ratio galaxolide-lactone: Galaxolide be a good tracer of wastewater in freshwaters? PMID- 27982528 TI - Environmental policy recommendations for the new US President. PMID- 27982529 TI - Reducing the number of fish in regulatory bioconcentration testing: Identifying and overcoming the barriers to using the 1-concentration approach. PMID- 27982530 TI - Authors' response to Turner et al. PMID- 27982531 TI - Response to Panko et al. (2016): Chemical hazard assessment tool comparisons. PMID- 27982534 TI - Learned discourses: Timely scientific opinions. PMID- 27982532 TI - Is nitrate an endocrine disruptor? PMID- 27982533 TI - Age-related differences in sensitivity to metals can matter for Daphnia magna neonates. PMID- 27982535 TI - In memoriam: Edward R Long. PMID- 27982536 TI - Scanning the horizon with IEAM. PMID- 27982537 TI - Effects of the Thai Health Improvement Profile intervention on the physical health and health behaviours of people with schizophrenia: A quasi-experimental study. AB - Physical health problems and unhealthy lifestyle behaviours are common in people with severe mental illness (SMI), leading to high levels of mortality.There is some evidence that nurse-led interventions involving comprehensive health checks may be effective in improving physical health in people with SMI. This quasi experimental before-and-after study investigated the impacts of the Thai Health Improvement Profile (HIP-T) on the physical health and health behaviours of people with schizophrenia over 1-year. All 105 service-users who volunteered to participate completed the study. There were significant reductions in mean BMI ( 0.78 kg/m2 , P < .001) and bodyweight (-1.13 kg, P < .001) at post-test. There was also a significant decrease in the total number of "red-flagged" HIP-T items, suggesting lowered potential health risks (P < .001). Overall, 23 patients (22%) were found to have moved to a healthier BMI classification after 1-year. The findings suggest that the HIP-T intervention has potential for improving the physical health of people with SMI when integrated into routine community mental health care. PMID- 27982538 TI - Recent Advances in Synthesis and Biomedical Applications of Two-Dimensional Transition Metal Dichalcogenide Nanosheets. AB - During recent decades, a giant leap in the development of nanotechnology has been witnessed. Numerous nanomaterials with different dimensions and unprecedented features have been developed and provided unimaginably wide scope to solve the challenging problems in biomedicine, such as cancer diagnosis and therapy. Recently, two-dimensional (2D) transition metal dichalcogenide (TMDC) nanosheets (NSs), including MoS2 , WS2 , and etc., have emerged as novel inorganic graphene analogues and attracted tremendous attention due to their unique structures and distinctive properties, and opened up great opportunities for biomedical applications, including ultrasensitive biosensing, biological imaging, drug delivery, cancer therapy, and antibacterial treatment. A comprehensive overview of different synthetic methods of ultrathin 2D TMDC NSs and their state-of-the art biomedical applications, especially those that have appeared in the past few years, is presented. At the end of this review, the future opportunities and challenges for 2D TMDC NSs in biomedicine are also discussed. PMID- 27982540 TI - Improving Hydrogen Evolution Activity of Earth-Abundant Cobalt-Doped Iron Pyrite Catalysts by Surface Modification with Phosphide. AB - Hydrogen is considered as sustainable and environmentally friendly energy for global energy demands in the future. Here a Co-FeS2 catalyst with surface phosphide doping (P/Co-FeS2 ) for hydrogen evolution reaction (HER) in acidic solutions is developed. The P/Co-FeS2 exhibits superior HER electrochemical performance with overpotential of -90 mV at 100 mA cm-2 and Tafel slope of 41 mV/decade and excellent durability. PMID- 27982541 TI - Patient and researcher perspectives on facilitating patient and public involvement in rheumatology research. PMID- 27982542 TI - Emerging ~800 nm Excited Lanthanide-Doped Upconversion Nanoparticles. AB - Lanthanide-doped upconversion nanoparticles can tune near-infrared light to visible or even ultra-violet light in emissions. Due to their unique photophysical and photochemical properties, as well as their promising bioapplications, there has been a great deal of enthusiastic research performed to study the properties of lanthanide-doped upconversion nanoparticles in the past few years. Despite the considerable progress in this area, numerous challenges associated with the nanoparticles, such as a low upconversion efficiency, limited host materials, and a confined excitation wavelength, still remain, thus hindering further development with respect to their applications and in fundamental science. Recently, innovative strategies that utilize alternative sensitizers have been designed in order to engineer the excitation wavelengths of upconversion nanoparticles. Here, focusing on the excitation wavelength at ~800 nm, recent advances in the design, property tuning, and applications of ~800 nm excited upconversion nanoparticles are summarized. Benefiting from the unique features of ~800 nm light, including deep tissue penetration depth and low photothermal effect, the ~800 nm excited upconversion nanoparticles exhibit superior potential for biosensing, bioimaging, drug delivery, therapy, and three dimensional displays. The critical aspects of such emerging nanoparticles with regards to meeting the ever-changing needs of future development are also discussed. PMID- 27982543 TI - In vivo bioluminescence imaging using orthotopic xenografts towards patient's derived-xenograft Medulloblastoma models. AB - BACKGROUND: Medulloblastoma is a cerebellar neoplasia of the central nervous system. Four molecular subgrups have been identified (MBWNT, MBSHH, MBgroup3 and MBgroup4) with distinct genetics and clinical outcome. Among these, MBgroup3-4 are highly metastatic with the worst prognosis. The current standard therapy includes surgery, radiation and chemotherapy. Thus, specific treatments adapted to cure those different molecular subgroups are needed. The use of orthotopic xenograft models, together with the non-invasive in vivo biolumiscence imaging (BLI) technology, is emerging during preclinical studies to test novel therapeutics for medulloblastoma treatment. METHODS: Orthotopic MB xenografts were performed by injection of Daoy-luc cells, that had been previously infected with lentiviral particles to stably express luciferase gene, into the fourth right ventricle of the cerebellum of ten nude mice. For the implantation, specific stereotactic coordinates were used. Seven days after the implantation the mice were imaged by acquisitions of bioluminescence imaging (BLI) using IVIS 3D Illumina Imaging System (Xenogen). Tumor growth was evaluated by quantifying the bioluminescence signals using the integrated fluxes of photons within each area of interest using the Living Images Software Package 3.2 (Xenogen-Perkin Elmer). Finally, histological analysis using hematoxylin-eosin staining was performed to confirm the presence of tumorigenic cells into the cerebellum of the mice. RESULTS: We describe a method to use the in vivo bioluminescent imaging (BLI) showing the potential to be used to investigate the potential antitumorigenic effects of a drug for in vivo medulloblastoma treatment. We also discuss other studies in which this technology has been applied to obtain a more comprehensive knowledge of medulloblastoma using orthotopic xenograft mouse models. CONCLUSIONS: There is a need to develop patient's derived-xenograft (PDX) model systems to test novel drugs for medulloblastoma treatment within each molecular sub-groups with a higher predictive value. Here we show how this technology should be applied with hopes on generations of new treatments to be applied then in human. PMID- 27982544 TI - Cardiovascular preclinical imaging. AB - Non-invasive imaging in the form of single-photon emission-computed tomography (SPECT), positron-emission tomography (PET), computed tomography (CT), echocardiography or magnetic resonance imaging (MRI) is a very useful tool for cardiovascular research as it allows assessment of biological processes in vivo. Nuclear imaging with SPECT and PET offers the advantage of high sensitivity, the potential for serial imaging, and reliable quantification. Currently a wide range of established as well as innovative agents is available and can be imaged with dedicated preclinical and clinical SPECT and PET imaging systems. These scanners can be equipped with CT and MRI components to form hybrid imaging systems. This review provides an outline on SPECT and PET as capable tools for translational research in cardiology as part of a workflow similar to the one used in clinical imaging illustrating the concept "from bench to bedside". PMID- 27982545 TI - Oral lichen planus: therapy and phenotype. AB - BACKGROUND: Lichen planus (LP) is a mucocutaneous disease of chronic inflammatory nature. Although many therapeutic options are available, none are curative. The aim of this article was to describe a therapeutic algorithm that take into consideration the clinical futures of oral LP (OLP). METHODS: Patients affected by symptomatic OLP were enrolled into three groups to receive cyclosporine mouthwash, retinoic acid lotion 0.05%, and autologous platelet-rich plasma (PRP) gel in the treatment of reticular, plaque-like, and erosive-type respectively. The products were applied as follows: retinoic acid BID for 8 weeks, cyclosporine mouthwash OD for 8 weeks, PRP once a week for 8 weeks. Patients were assessed at 2, 4, 8, and 12 weeks. Improvement was evaluated as complete response, partial response and no response. RESULTS: A total of 20 Caucasian patients, 8 male and 12 female, mean age 56 years (range 40-74) concluded the study. Seven patients showed a complete response, 7 patients a partial response, and 6 patients no response. CONCLUSIONS: We propose a therapeutic algorithm that take into consideration the clinical features and symptoms of OLP. Long-term experience on larger series of cases are necessary to confirm our data. PMID- 27982546 TI - A new treatment regimen with permethrin in scabies. AB - BACKGROUND: Topical permethrin, applied once daily, is considered as the most effective treatment in scabies. METHODS: Eighty-nine adult immunocompetent patients with scabies were treated with 5% permethrin cream: 42 patients were treated with a single application/day (group 1); 47 patients were treated with one application/day for two consecutive days (group 2). Clinical diagnosis of scabies was confirmed by microscopical examinations. The cream was stored in refrigerator and applied cold on the entire skin surface. The cream was left on the skin for 24 hours. No other topical or systemic drugs were allowed, except for a cleanser with chlorhexidine. The treatment was repeated in all patients 7 10 days later. The follow-up was 2 months after the end of the treatment. RESULTS: Twenty-one patients (61.8%) in the group 1 and 34 patients (87.2%) in the group 2 were considered recovered both clinically and microscopically. Three patients (7.1%) in the group 1 and 4 patients (10.2%) in the group 2 developed a mild irritant contact dermatitis. During follow-up, three patients (7.1%) in the group 1 and two patients (4.2%) in the group 2 developed a recurrence or a re infestation. CONCLUSIONS: Five per cent permethrin, when applied as cold cream, on the entire skin surface, once daily for two consecutive days, is more effective than the single application in adult immunocompetent patients with scabies. PMID- 27982548 TI - Syphilitic aortitis and its complications in the modern era. AB - INTRODUCTION: Aortitis is a well-recognized manifestation of the tertiary stage of syphilis. EVIDENCE ACQUISITION: Although often regarded as an unexpected diagnosis, actually new cases of cardiovascular syphilis continue to be reported. Presumably, Treponema pallidum invades the aortic wall and the inflammatory response progresses towards obliterative endarteritis and necrosis of the muscular and elastic fibers in the aortic media. The consequent weakening of the aortic wall can lead to severe complications, represented by aortic aneurysm, aortic valvular insufficiency, aortic root dilation and coronary ostial stenosis. We perused the literature of the last 6 years to assess the prevalence and possible changes over time of syphilis cardiovascular manifestations. EVIDENCE SYNTHESIS: Forty four articles were collected, reporting on 66 patients. Many patients presented more than one complication. Aortic aneurysm was the most frequent involvement, detected in 71% of patients. Fusiform or saccular aneurysms often interested the thoracic aorta, primarily located on the ascending segment. The second most common complication was the aortic valvular insufficiency, found in 47% of patients. Coronary ostial stenosis and dilation of the aortic root were less frequent. CONCLUSIONS: Comparing our study with the previous ones, the cardiovascular involvement appeared roughly constant over time. Although many articles fail to provide useful information, such as a detailed history and the presence of risk factors, we must note that most patients had no predisposing factors and denied a primary infection. Cardiovascular syphilis is still present nowadays and it is important not to forget the "great imitator" in the event of its characteristic symptoms. PMID- 27982547 TI - Back to the future: a new topical approach for mild-to-moderate psoriasis. AB - Psoriasis is a chronic-relapsing skin disorder which requires long-term treatments. Therapeutic options for psoriasis include topical treatments, phototherapy and systemic therapy. However, those treatments, and particularly the topical drug therapies, may present some limitations, including poor efficacy/tolerability ratio and lack of adherence. Recently, the supersaturated aerosol foam formulation of the fixed combination calcipotriene plus betamethasone dipropionate (Cal/BD) has gained major attention because it overcomes some of the limitations associated with other topical treatments. This fixed-combination has increased efficacy compared with its individual components. Moreover, the alcohol-free aerosol foam formulation allows a higher penetration of the active ingredients into the skin, resulting in enhanced bioavailability and, consequently, in better clinical outcomes than other products with the same components. Given the short duration of therapy course and the fast onset of action, a reduced amount of Cal/BD foam formulation would be required for the treatment of psoriasis patients, resulting also in cost saving. Therefore this novel formulation could represent an alternative to other topical agents and a first-line therapy in the treatment of mild and mild-to-moderate psoriasis. PMID- 27982549 TI - Latest insights into pathogenesis of mycosis fungoides and cutaneous T-cell lymphoma. AB - Cutaneous T-cell lymphoma (CTCL) is a rare but increasing malignancy whose protean manifestations necessarily present in the integument, but can also spread to involve blood, lymph nodes and internal organs. We have developed efficacious and varied therapies to treat early and advanced stage disease, but there are still many who suffer tremendously from this illness. Although the pathogenesis of this cancer remains frustratingly elusive, over the last 200 years we have generated a robust body of evidence that points toward possible singular as well as multifactorial etiologies. Combining the historical hypotheses which have focused upon the concept of infectious causes, including carcinogenic genomic viral integration and bacterial superantigenic chronic stimulation as well as industrial/occupational exposure, along with the more recent revelations of both genetic and epigenetic alteration and immune dysregulation, we are closer than ever to understanding the etiology of CTCL. It is through this knowledge and continued research efforts that we will be able to better diagnose, treat, and potentially prevent or cure CTCL. PMID- 27982550 TI - Desmosomes and corneodesmosomes and their relevance to genetic skin diseases. AB - Desmosomes are critical intercellular junctions between keratinocytes in the living cell layers of the epidermis. When the cells are differentiated and become cornified cells, desmosomes are transformed into corneodesmosomes. Distribution patterns of corneodesmosomes change with cell development. Namely, in the lower stratum corneum, corneodesmosomes are seen all around the cell membrane, but in the upper layers, they are only found at the edges of the flattened cells. Recently, it has been proposed that tight junction-derived structures are involved in this unique distribution of corneodesmosomes by protecting corneodesmosome degradation from proteases. Various types of skin diseases can be caused by abnormalities in the genes encoding components of desmosomes and corneodesmosomes or regulators of the proteolytic processing of these structures. Their clinical symptoms vary greatly: palmoplantar keratoderma on the pressure points, syndromic ichthyosis associated with atopic manifestations, diffuse keratoderma with cardiomyopathy, lethal epidermolysis bullosa, hair abnormalities, or a combination of these symptoms. Polymorphisms in some of the genes are risk factors for atopic dermatitis. Genetic diseases of desmosomes and corneodesmosomes are rare, but by studying them we will be enlightened about pathological mechanisms of more common multifactorial skin diseases such as atopic dermatitis. PMID- 27982551 TI - Use of biological treatments in patients with hidradenitis suppurativa. AB - Pilosebaceous unit occlusion and secondary inflammatory perifollicular lympho histiocytic infiltration seem to be the underlying etiopathogenic mechanisms giving rise to hidradenitis suppurativa (HS). Increased levels of tumor necrosis factor (TNF)-alpha and other cytokines such as interleukins 12 and 23 (IL12/23) and interleukins 10 and 17 have been observed in HS lesional skin. Biological drugs have been reported to be effective for HS, but the level and duration of the response are quite variable. Among anti-TNF drugs, adalimumab and infliximab seem to obtain better results in HS. Adalimumab is the only registered systemic agent for HS and results from multicenter clinical trials demonstrate that 58.9% of patients may achieve clinical response without significant adverse events. Continuous treatment seems to maintain the therapeutic response, but discontinuation of the treatment usually results in a rapid relapse of the disease. Infliximab may also obtain a good response profile with 50% improvement of HS lesions. Treatment with ustekinumab for HS resulted in variable results showing a moderate-to-marked improvement in 82% of patients. Anakinra, a recombinant IL-1 receptor antagonist, has been also been postulated as a potential systemic treatment for HS. A reduction in the disease activity in 67% of patients has been reported. Biological drugs seem to represent an effective therapeutic option for HS, but complete and persistent resolution of the disease is rarely achieved. Flares of the disease usually develop regardless the prescribed treatment. Combined treatments including antibiotics and retinoids seem to be a potential additional therapeutic approach. In chronic and severe cases, a surgical approach is mandatory in order to remove persistent scarring tissue. New drugs are currently being evaluated as new insights in the pathogenesis of the disease are elucidated. Several clinical trials with apremilast, anti-IL17 drugs and anti-interleukin-1 alpha are currently ongoing. PMID- 27982552 TI - Profile of skin barrier proteins and cytokines in adults with atopic dermatitis. AB - Atopic dermatitis (AD), an inflammatory skin disorder with chronic course and characterized by intense pruritus, is a dermatosis of high prevalence of childhood. However, persistence of the disease in adolescents and adults may occur, and more studies regarding the interactions of the complex triggering factors, especially between the adaptive and innate immune alterations and skin barrier defects are needed. In this review the authors summarize the major novel findings of a dysfunctional skin barrier in AD, with emphasis on tight junction components, such as claudins and on proteins of the keratinocyte differentiation, such as filaggrin. This review also provides an update on the characterization of immune response in adults with atopic dermatitis. The adaptive immune dysfunction in AD, classically known as a Th2/Th1 model, has changed its profile, with recent reported cytokines such as interleukins 17, 22, and 31; as for the innate immune system scenario in AD, the characterization of skin microbiome opens new frontiers for the understanding of such a complex inflammatory disease. PMID- 27982553 TI - Anterior cerebral artery revascularization: superficial temporal artery callosomarginal artery bypass using a contralateral superficial temporal artery interposition graft. PMID- 27982554 TI - Regional anaesthesia and antithrombotic agents: instructions for use. AB - BACKGROUND: The use of anticoagulant agents represents a serious limitation of regional anesthesia, due to the risk of spinal hematoma. Examining all the principles currently available, it has been possible to notice that published guidelines are very often incomplete or also differ significantly on the rules to be followed relating to a specific drug. METHODS: We have carried out a comparison between the guidelines of major scientific societies in order to take a practical and simple user guide which operators can consult. We took into consideration the more and more frequent occurrence of patients who undergo dual antiplatelet and need to be subjected to surgery, considering the possibility of regional anesthesia as an alternative to general anesthesia in conditions of election and not deferrable urgency. RESULTS: We have described the main anticoagulant drugs used in therapy. Regarding the low molecular weight heparins (LMWH), we have reported the most important properties, highlighting the substantial differences of their use detectable by comparison between American and European Guidelines. A similar comparison has been made for the main antiplatelet drugs, including aspirin, and thrombin inhibitors. A particular chapter was dedicated to new oral anticoagulant drugs (NOACs), especially for the low possibility of allowing regional anesthesia. CONCLUSIONS: The comparison between the main guidelines often highlights substantial disparities and weak evidences, so operators must carry out a careful risk / benefit analysis prior to regional anesthesia. PMID- 27982555 TI - How to manage blood pressure after brain injury? AB - Manipulation of blood pressure (BP) is a mainstay of therapy in patients with acute brain injury (ABI). In the early emergent phase (first hours from injury), depending on intracranial pathology, BP manipulation aims to: 1) limit the progression of parenchymal hematomas or hemorrhagic transformation (in patients with ischemic/hemorrhagic stroke and aneurysmal subarachnoid hemorrhage [SAH]), and 2) attenuate hypoperfusion and secondary cerebral ischemic insults (in patients with traumatic brain injury [TBI]). During the intensive care unit (ICU) phase, BP management is primarily focused at identifying the so-called "optimal" BP/cerebral perfusion pressure (CPP), i.e. the threshold of mean arterial pressure (MAP)/CPP to prevent secondary cerebral ischemia. BP augmentation is also an essential component of the medical management of delayed cerebral ischemia following SAH. Increasing clinical data support the use of surrogate monitoring modalities of cerebral perfusion (including trans-cranial Doppler and brain tissue oximetry) to indentify BP/CPP targets in ABI patients. We reviewed herein the actual evidence regarding BP control in the early phase after ABI and recent clinical investigations using multimodal monitoring to optimize CPP and BP in severe ABI patients. The main purpose of this review is to provide a pragmatic approach of BP management, taking into account the timing of injury and differences in brain pathologies. PMID- 27982556 TI - To ICU or not to ICU: tailoring postoperative care in the face of reduced resources and increased morbidity. PMID- 27982557 TI - Incorrect position of the bite block leads to serious gastrointestinal flatulence during gynecological laparoscopic surgery. PMID- 27982558 TI - Optimal duration of anticoagulation in patients with unprovoked venous thromboembolism: the impact of novel anticoagulants. AB - Once anticoagulation is stopped, the risk of recurrent venous thromboembolism (VTE) over years approaches 50% of all patients with a first episode of unprovoked VTE. The persistence of residual vein thrombosis at ultrasound assessment has consistently been shown to increase the risk, as do persistently high values of D-dimer. Although the latest international guidelines suggest indefinite anticoagulation for most patients with the first episode of unprovoked VTE, strategies that incorporate the assessment of residual vein thrombosis and D dimer have the potential to identify a substantial proportion of subjects in whom anticoagulation can be safely discontinued. For those patients in whom anticoagulation cannot be discontinued, new opportunities are offered by the availability of low-dose anti-Xa compounds, which have been found to possess an extremely favourable benefit/risk profile. PMID- 27982559 TI - Li2CO3-Coated Ni Particles for the Inner Electrodes of Multilayer Ceramic Capacitors: Evaluation of Lifetime. AB - In previous work, it was demonstrated that using Li2CO3-coated Ni particles in the manufacturing of multilayer ceramic capacitor (MLCC) devices could improve both the permittivity and dissipation factors. However, adding Li+ ions to the system gave rise to the concern that ions could migrate under sustained electrical fields and thereby increase the degradation rates of the insulation resistance in MLCCs. In this paper, thermally stimulated depolarization current and highly accelerated lifetime testing were both utilized to evaluate the oxygen vacancy space-charge regions and migration in MLCCs. The results suggested that three parameters (the sintering schedule, Li2CO3 coatings, and oxygen flow during sintering) determine the overall resilience to the degradation. The Li+ ions did not migrate during degradation, as verified by time-of-flight secondary-ion mass spectrometry mapping; however, the Li ions enter the perovskite structure as an acceptor and, if ionically compensated for, could introduce more oxygen vacancies to the system and decrease the lifetime of the MLCCs. Nevertheless, it was demonstrated that the relative lifetimes of the newly designed MLCCs significantly improve relative to the conventional samples. PMID- 27982560 TI - High Visible Photoelectrochemical Activity of Ag Nanoparticle-Sandwiched CdS/Ag/ZnO Nanorods. AB - We report on the sensitizing of CdS-coated ZnO (CdS/ZnO) nanorods (NRs) by Ag nanoparticles (NPs) embedded between the CdS coating and the ZnO nanorod and the improved optical and photoelectrochemical properties of the Ag NP-sandwiched nanostructure CdS/Ag/ZnO NRs. The CdS/Ag/ZnO NRs were fabricated by growing Ag NPs on hydrothermally grown ZnO NRs and subsequently depositing CdS coatings followed by subsequent N2 annealing. The structure of the fabricated CdS/Ag/ZnO NRs was characterized by field-emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and Raman backscattering, revealing that the ZnO NRs and the CdS coatings are both structured with hexagonal wurtzite and the Ag NPs contact well with ZnO and CdS. Optical properties were evaluated by measuring optical absorption and photoluminescence, showing that the Ag NPs behave well as sensitizers for optical property improvement and the CdS/Ag/ZnO NRs exhibit better photoresponse in a wide spectral region than CdS/ZnO because of plasmon-enhanced absorption due to the embedment of Ag NPs. The Ag NPs also serve as electron relays from CdS to ZnO, facilitating electron transfer from the CdS coatings to the ZnO NRs. The excellent photoresponse and efficient electron transfer make the CdS/Ag/ZnO NRs highly photoelectrochemically active. The CdS/Ag/ZnO NRs fabricated on indium-tin oxide present much better photoelectrochemical performance as photoanodes working in the visible region than CdS/ZnO NRs without Ag NPs. Under visible illumination, a maximum optical-to-chemical conversion efficiency of 3.13% is obtained for CdS/Ag/ZnO NR photoanodes against 1.35% for CdS/ZnO NR photoanodes. PMID- 27982561 TI - One-Dimensional Yolk-Shell Sb@Ti-O-P Nanostructures as a High-Capacity and High Rate Anode Material for Sodium Ion Batteries. AB - Development of high energy/power density and long cycle life of anode materials is highly desirable for sodium ion batteries, because graphite anode cannot be used directly. Sb stands out from the potential candidates, due to high capacity, good electronic conductivity, and moderate sodiation voltage. Here, one dimensional yolk-shell Sb@Ti-O-P nanostructures are synthesized by reducing core shell Sb2O3@TiO2 nanorods with NaH2PO2. This structure has Sb nanorod as the core to increase the capacity and Ti-O-P as the shell to stabilize the interface between electrolyte and electrode material. The gap between the core and the shell accommodates the volume change during sodiation/desodiation. These features endow the structure outstanding performances. It could deliver a capacity of about 760 mA h g-1 after 200 cycles at 500 mA g-1, with a capacity retention of about 94%. Even at 10 A g-1, the reversible capacity is still at 360 mA h g-1. The full battery of Sb@Ti-O-P//Na3V2(PO4)3-C presents a high output voltage (~2.7 V) and a capacity of 392 mA h g-1anode after 150 cycles at 1 A g-1anode. PMID- 27982562 TI - Low-Temperature Solution-Processed SnO2 Nanoparticles as a Cathode Buffer Layer for Inverted Organic Solar Cells. AB - SnO2 recently has attracted particular attention as a powerful buffer layer for organic optoelectronic devices due to its outstanding properties such as high electron mobility, suitable band alignment, and high optical transparency. Here, we report on facile low-temperature solution-processed SnO2 nanoparticles (NPs) in applications for a cathode buffer layer (CBL) of inverted organic solar cells (iOSCs). The conduction band energy of SnO2 NPs estimated by ultraviolet photoelectron spectroscopy was 4.01 eV, a salient feature that is necessary for an appropriate CBL. Using SnO2 NPs as CBL derived from a 0.1 M precursor concentration, P3HT:PC60BM-based iOSCs showed the best power conversion efficiency (PCE) of 2.9%. The iOSC devices using SnO2 NPs as CBL revealed excellent long-term device stabilities, and the PCE was retained at ~95% of its initial value after 10 weeks in ambient air. These solution-processed SnO2 NPs are considered to be suitable for the low-cost, high throughput roll-to-roll process on a flexible substrate for optoelectronic devices. PMID- 27982564 TI - Pump- and Valve-Free Flow Injection Capillary Liquid Electrode Discharge Optical Emission Spectrometry Coupled to a Droplet Array Platform. AB - A miniature (2.5 cm length * 2.0 cm width * 1.0 cm height), low power (<10 W), and capillary liquid electrode microplasma optical emission spectrometer was developed for rapid determination of metallic species in aqueous solutions. The sample solution can be automatically introduced into the source without a pump owing to the inherent capillary attraction and the force arising from the solution vaporization induced by microplasma. A droplet array was used as a sampling platform to realize flow injection without using any valve and pump, significantly increasing throughput to 90 samples h-1. Sample volume is controlled through the sampling time and reduced to the nanoliter level. With a sampling time of 10 s (equal to 600 nL), detection limits of 30 MUg L-1 (18 pg) and 75 MUg L-1 (45 pg) were obtained for Cd and Hg, respectively, comparable to those reported for liquid electrode microplasma optical emission spectrometry. However, sample consumption is reduced more than 100-fold, making the proposed technique more suitable for the analysis of elements such as Cd, Hg, Li, Na, and K when sample volumes may be limited. The utility of this system was demonstrated by the determination of Cd and Hg in blood, real water samples, and Certified Reference Materials (rice powder, GBW07601a, and lobster hepatopancreas, TORT-3). PMID- 27982563 TI - Tailoring Nanoscale Morphology of Polymer:Fullerene Blends Using Electrostatic Field. AB - To tailor the nanomorphology in polymer/fullerene blends, we study the effect of electrostatic field (E-field) on the solidification of poly(3-hexylthiophene-2, 5 diyl) (P3HT):[6,6]-phenyl-C61-butyric acid methyl ester (PC60BM) bulk heterojunction (BHJ). In addition to control; wet P3HT:PC60BM thin films were exposed to E-field of Van de Graaff (VDG) generator at three different directions horizontal (H), tilted (T), and vertical (V)-relative to the plane of the substrate. Surface and bulk characterizations of the field-treated BHJs affirmed that fullerene molecules can easily penetrate the spaghetti-like P3HT and move up and down following the E-field. Using E-field treatment, we achieved favorable morphologies with efficient charge separation, transport, and collection. We improve; (1) the hole mobility values up to 19.4 * 10-4 +/- 1.6 * 10-4 cm2 V-1 s 1 and (2) the power conversion efficiency (PCE) of conventional and inverted OPVs up to 2.58 +/- 0.02% and 4.1 +/- 0.40%, respectively. This E-field approach can serve as a new morphology-tuning technique, which is generally applicable to other polymer-fullerene systems. PMID- 27982565 TI - Ultrasensitive Detection of Volatile Organic Compounds by a Pore Tuning Approach Using Anisotropically Shaped SnO2 Nanocrystals. AB - Gas sensing with oxide nanostructures is increasingly important to detect gaseous compounds for safety monitoring, process controls, and medical diagnostics. For such applications, sensor sensitivity is one major criterion. In this study, to sensitively detect volatile organic compounds (VOCs) at very low concentrations, we fabricated porous films using SnO2 nanocubes (13 nm) and nanorods with different rod lengths (50-500 nm) that were synthesized by a hydrothermal method. The sensor response to H2 increased with decreasing crystal size; the film made of the smallest nanocubes showed the best sensitivity, which suggested that the H2 sensing is controlled by crystal size. In contrast, the responses to ethanol and acetone increased with increasing crystal size and resultant pore size; the highest sensitivity was observed for a porous film using the longest nanorods. Using the Knudsen diffusion-surface reaction equation, the gas sensor responses to ethanol and acetone were simulated and compared with experimental data. The simulation results proved that the detection of ethanol and acetone was controlled by pore size. Finally, we achieved ultrahigh sensitivity to ethanol; the sensor response (S) exceeded S = 100 000, which corresponds to an electrical resistance change of 5 orders of magnitude in response to 100 ppm of ethanol at 250 degrees C. The present approach based on pore size control provides a basis for designing highly sensitive films to meet the criterion for practical sensors that can detect a wide variety of VOCs at ppb concentrations. PMID- 27982567 TI - Poly(aryleneethynylene) Tongue That Identifies Nonsteroidal Anti-Inflammatory Drugs in Water: A Test Case for Combating Counterfeit Drugs. AB - We report a sensor array composed of a highly fluorescent positively charged poly(para-phenyleneethynylene) P1 and its complex C with a negatively charged pyridine-containing poly(para-aryleneethynylene) P2 (quencher) at pH 10 and pH 13; a sensor field composed of four elements, P1 (pH 10), P1 (pH 13), C (pH 10), and C (pH 13), results. The elements of this small sensor field experience either fluorescence turn on or fluorescence quenching upon exposure toward nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, diclofenac, or naproxen. The combined responses of the sensor field are analyzed by linear discriminant analysis (LDA). All of the NSAIDs were identified and discriminated, and the sensing mechanism, hydrophobic versus electrostatic, was discussed. PMID- 27982568 TI - Roll-to-Roll Continuous Manufacturing Multifunctional Nanocomposites by Electric Field-Assisted "Z" Direction Alignment of Graphite Flakes in Poly(dimethylsiloxane). AB - A roll-to-roll continuous process was developed to manufacture large-scale multifunctional poly(dimethylsiloxane) (PDMS) films embedded with thickness direction ("Z" direction) aligned graphite nanoparticles by application of electric field. The kinetics of particle "Z" alignment and chain formation was studied by tracking the real-time change of optical light transmission through film thickness direction. Benefiting from the anisotropic structure of aligned particle chains, the electrical and thermal properties of the nanocomposites were dramatically enhanced through the thickness direction as compared to those of the nanocomposites containing the same particle loading without electrical field alignment. With 5 vol % graphite loading, 250 times higher electrical conductivity, 43 times higher dielectric permittivity, and 1.5 times higher thermal conductivity was achieved in the film thickness direction after the particles were aligned under electrical field. Moreover, the aligned nanocomposites with merely 2 vol % graphite particles exhibit even higher electric conductivity and dielectric permittivity than those of the nonaligned nanocomposites at random percolation threshold (10 vol % particles), as the "electric-field-directed" percolation threshold concentration is substantially decreased using this process. As the graphite loading increases to 20 vol %, the aligned nanocomposites exhibit thermal conductivity as high as 6.05 W/m.K, which is 35 times the thermal conductivity of pure matrix. This roll-to-roll electric field continuous process provides a simple, low-cost, and commercially viable method to manufacture multifunctional nanocomposites for applications as embedded capacitor, electromagnetic (EM) shielding, and thermal interface materials. PMID- 27982569 TI - Low-Cost, Robust, and Field Portable Smartphone Platform Photometric Sensor for Fluoride Level Detection in Drinking Water. AB - Groundwater is the major source of drinking water for people living in rural areas of India. Pollutants such as fluoride in groundwater may be present in much higher concentration than the permissible limit. Fluoride does not give any visible coloration to water, and hence, no effort is made to remove or reduce the concentration of this chemical present in drinking water. This may lead to a serious health hazard for those people taking groundwater as their primary source of drinking water. Sophisticated laboratory grade tools such as ion selective electrodes (ISE) and portable spectrophotometers are commercially available for in-field detection of fluoride level in drinking water. However, such tools are generally expensive and require expertise to handle. In this paper, we demonstrate the working of a low cost, robust, and field portable smartphone platform fluoride sensor that can detect and analyze fluoride concentration level in drinking water. For development of the proposed sensor, we utilize the ambient light sensor (ALS) of the smartphone as light intensity detector and its LED flash light as an optical source. An android application "FSense" has been developed which can detect and analyze the fluoride concentration level in water samples. The custom developed application can be used for sharing of in-field sensing data from any remote location to the central water quality monitoring station. We envision that the proposed sensing technique could be useful for initiating a fluoride removal program undertaken by governmental and nongovernmental organizations here in India. PMID- 27982570 TI - Phase-Constrained Spectrum Deconvolution for Fourier Transform Mass Spectrometry. AB - This Article introduces a new computationally efficient noise-tolerant signal processing method, referred to as phased spectrum deconvolution method (PhiSDM), designed for Fourier transform mass spectrometry (FT MS). PhiSDM produces interference-free mass spectra with resolution beyond the Fourier transform (FT) uncertainty limit. With a presumption that the oscillation phases are preserved, the method deconvolves an observed FT spectrum into a distribution of harmonic components bound to a fixed frequency grid, which is several times finer than that of FT. The approach shows stability under noisy conditions, and the noise levels in the resulting spectra are lower than those of the original FT spectra. Although requiring more computational power than standard FT algorithms, PhiSDM runs in a quasilinear time. The method was tested on both synthetic and experimental data, and consistently demonstrated performance superior to the FT based methodologies, be it across the entire mass range or on a selected mass window of interest. PhiSDM promises substantial improvements in the spectral quality and the speed of FT MS instruments. It might also be beneficial for other spectroscopy approaches which require harmonic analysis for data processing. PMID- 27982566 TI - Reactions of Ferrous Coproheme Decarboxylase (HemQ) with O2 and H2O2 Yield Ferric Heme b. AB - A recently discovered pathway for the biosynthesis of heme b ends in an unusual reaction catalyzed by coproheme decarboxylase (HemQ), where the Fe(II)-containing coproheme acts as both substrate and cofactor. Because both O2 and H2O2 are available as cellular oxidants, pathways for the reaction involving either can be proposed. Analysis of reaction kinetics and products showed that, under aerobic conditions, the ferrous coproheme-decarboxylase complex is rapidly and selectively oxidized by O2 to the ferric state. The subsequent second-order reaction between the ferric complex and H2O2 is slow, pH-dependent, and further decelerated by D2O2 (average kinetic isotope effect of 2.2). The observation of rapid reactivity with peracetic acid suggested the possible involvement of Compound I (ferryl porphyrin cation radical), consistent with coproheme and harderoheme reduction potentials in the range of heme proteins that heterolytically cleave H2O2. Resonance Raman spectroscopy nonetheless indicated a remarkably weak Fe-His interaction; how the active site structure may support heterolytic H2O2 cleavage is therefore unclear. From a cellular perspective, the use of H2O2 as an oxidant in a catalase-positive organism is intriguing, as is the unusual generation of heme b in the Fe(III) rather than Fe(II) state as the end product of heme synthesis. PMID- 27982571 TI - Transformation of Iodide by Carbon Nanotube Activated Peroxydisulfate and Formation of Iodoorganic Compounds in the Presence of Natural Organic Matter. AB - In this study, we interestingly found that peroxydisulfate (PDS) could be activated by a commercial multiwalled carbon nanotube (CNT) material via a nonradical pathway. Iodide (I-) was quickly and almost completely oxidized to hypoiodous acid (HOI) in the PDS/CNT system over the pH range of 5-9, but the further transformation to iodate (IO3-) was negligible. A kinetic model was proposed, which involved the formation of reactive PDS-CNT complexes, and then their decomposition into sulfate anion (SO42-) via inner electron transfer within the complexes or by competitively reacting with I-. Several influencing factors (e.g., PDS and CNT dosages, and solution pH) on I- oxidation kinetics by this system were evaluated. Humic acid (HA) decreased the oxidation kinetics of I-, probably resulting from its inhibitory effect on the interaction between PDS and CNT to form the reactive complexes. Moreover, adsordable organic iodine compounds (AOI) as well as specific iodoform and iodoacetic acid were appreciably produced in the PDS/CNT/I- system with HA. These results demonstrate the potential risk of producing toxic iodinated organic compounds in the novel PDS/CNT oxidation process developed very recently, which should be taken into consideration before its practical application in water treatment. PMID- 27982573 TI - Hydroxycamptothecin Nanorods Prepared by Fluorescently Labeled Oligoethylene Glycols (OEG) Codendrimer: Antitumor Efficacy in Vitro and in Vivo. AB - Nanorods based on dendrimers were explored as excellent candidates for nanoscale drug delivery system. In this study, fluorescently labeled PAMAM-b-oligoethylene glycols codendrimer (POC) was utilized as carrier to prepare 10 hydroxycamptothecin (HCPT) loaded nanorods (HCPT NRs) via antisolvent precipitation method augmented by ultrasonication with the optimized drug-loading content (~90.6%) and positive charged surface. The nanorods presented high stability, and the release of HCPT nanorods showed a sustained release manner and was completed within 48 h. The nanorods presented higher cytotoxicity against HepG2 and 4T1 cells than HCPT injections, and the cellular uptake mechanism was proved to involve clathrin-mediated endocytosis and macropincytosis-dependent endobytosis. Importantly, the HCPT nanorods resulted in strong antitumor efficacy on the H22 liver tumor model, and no significant adverse effects was observed. Besides, in vivo studies also showed that HCPT NRs possessed better tumor accumulation over HCPT injection at the equivalent concentration. According to the high drug-loading content, enhanced antitumor efficacy, and appropriate particle size, HCPT NRs as the safe and efficient drug delivery systems could have potential application for cancer chemotherapy in clinic. PMID- 27982572 TI - Amorphous Mixed-Metal Oxide Thin Films from Aqueous Solution Precursors with Near Atomic Smoothness. AB - Thin films with tunable and homogeneous composition are required for many applications. We report the synthesis and characterization of a new class of compositionally homogeneous thin films that are amorphous solid solutions of Al2O3 and transition metal oxides (TMOx) including VOx, CrOx, MnOx, Fe2O3, CoOx, NiO, CuOx, and ZnO. The synthesis is enabled by the rapid decomposition of molecular transition-metal nitrates TM(NO3)x at low temperature along with precondensed oligomeric Al(OH)x(NO3)3-x cluster species, both of which can be processed from aq solution. The films are dense, ultrasmooth (Rrms < 1 nm, near 0.1 nm in many cases), and atomically mixed amorphous metal-oxide alloys over a large composition range. We assess the chemical principles that favor the formation of amorphous homogeneous films over rougher phase-segregated nanocrystalline films. The synthesis is easily extended to other compositions of transition and main-group metal oxides. To demonstrate versatility, we synthesized amorphous V0.1Cr0.1Mn0.1Fe0.1Zn0.1Al0.5Ox and V0.2Cr0.2Fe0.2Al0.4Ox with Rrms ~ 0.1 nm and uniform composition. The combination of ideal physical properties (dense, smooth, uniform) and broad composition tunability provides a platform for film synthesis that can be used to study fundamental phenomena when the effects of transition metal cation identity, solid-state concentration of d electrons or d-states, and/or crystallinity need to be controlled. The new platform has broad potential use in controlling interfacial phenomena such as electron transfer in solar-cell contacts or surface reactivity in heterogeneous catalysis. PMID- 27982574 TI - An Environmentally Benign Antimicrobial Coating Based on a Protein Supramolecular Assembly. AB - The use of antimicrobial materials, for example, silver nanoparticles, has been a cause for concern because they often exert an adverse effect on environmental and safety during their preparation and use. In this study, we report a class of green antimicrobial coating based on a supramolecular assembly of a protein extracted from daily food, without the addition of any other hazardous agents. It is found that a self-assembled nanofilm by mere hen egg white lysozyme has durable in vitro and in vivo broad-spectrum antimicrobial efficacy against Gram positive/negative and fungi. Such enhanced antimicrobial capability over native lysozyme is attributed to a synergistic combination of positive charge and hydrophobic amino acid residues enriched on polymeric aggregates in the lysozyme nanofilm. Accompanied with high antimicrobial activity, this protein-based PTL material simultaneously exhibits the integration of multiple functions including antifouling, antibiofilm, blood compatibility, and low cytotoxicity due to the existence of surface hydration effect. Moreover, the bioinspired adhesion mediated by the amyloid structure contained in the nanofilm induces robust transfer and self-adhesion of the material onto virtually arbitrary substrates by a simple one-step aqueous coating or solvent-free printing in 1 min, thereby allowing an ultrafast route into practical implications for surface functionalized commodity and biomedical devices. Our results demonstrate that the application of pure proteinaceous substance may afford a cost-effective green biomaterial that has high antimicrobial activity and low environmental impact. PMID- 27982575 TI - A Model to Stabilize CO2 Uptake Capacity during Carbonation-Calcination Cycles and its Case of CaO-MgO. AB - Nowadays, capturing anthropogenic CO2 in a highly efficient and cost-effective way is one of the most challenging issues. Herein, the key parameters to stabilize CO2 uptake capacity have been studied based on four kinds of pure calcium oxides (CaO) prepared by a simple calcination method with four different calcium precursors. A simple ideal particle model was proposed to illustrate the uniform distribution of pure CaO, in which the CO2 uptake capacity is positively related with surface area of CaO particles and the stability is opposite to the distance between two CaO particles after carbonation. The adsorption capacity of the best sample with a distance of 398 nm between two CaO particles after carbonation only lost 0.344% per cycle, which is originated from the low possibility of the agglomeration between neighboring particles. On the basis of the proposed model, the composite with magnesium oxide (MgO) distributed uniformly in CaO was fabricated by a simple ball milling method, which possessed an excellent stability with a decay rate of only 3.9% over 100 carbonation calcination cycles. In this case, MgO played as inert to increase the distance between CaO particles for agglomeration prevention. PMID- 27982576 TI - Phosphate Changes Effect of Humic Acids on TiO2 Photocatalysis: From Inhibition to Mitigation of Electron-Hole Recombination. AB - A major challenge for photocatalytic water purification with TiO2 is the strong inhibitory effect of natural organic matter (NOM), which can scavenge photogenerated holes and radicals and occlude ROS generation sites upon adsorption. This study shows that phosphate counteracts the inhibitory effect of humic acids (HA) by decreasing HA adsorption and mitigating electron-hole recombination. As a measure of the inhibitory effect of HA, the ratios of first order reaction rate constants between photocatalytic phenol degradation in the absence versus presence of HA were calculated. This ratio was very high, up to 5.72 at 30 mg/L HA and pH 4.8 without phosphate, but was decreased to 0.76 (5 mg/L HA, pH 8.4) with 2 mM phosphate. The latter ratio indicates a surprising favorable effect of HA on TiO2 photocatalysis. FTIR analyses suggest that this favorable effect is likely due to a change in the conformation of adsorbed HA, from a multiligand exchange arrangement to a complexation predominantly between COOH groups in HA and the TiO2 surface in the presence of phosphate. This configuration can reduce hole consumption and facilitate electron transfer to O2 by the adsorbed HA (indicated by linear sweep voltammetry), which mitigates electron-hole recombination and enhances contaminant degradation. A decrease in HA surface adsorption and hole scavenging (the predominant inhibitory mechanisms of HA) by phosphate (2 mM) was indicated by a 50% decrease in the photocatalytic degradation rate of HA and 80% decrease in the decay rate coefficient of interfacial-related photooxidation in photocurrent transients. These results, which were validated with other compounds (FFA and cimetidine), indicate that anchoring phosphate - or anions that exert similar effects on the TiO2 surface - might be a feasible strategy to counteract the inhibitory effect of NOM during photocatalytic water treatment. PMID- 27982577 TI - Sulfur Transformation during Microwave and Conventional Pyrolysis of Sewage Sludge. AB - The sulfur distributions and evolution of sulfur-containing compounds in the char, tar and gas fractions were investigated during the microwave and conventional pyrolysis of sewage sludge. Increased accumulation of sulfur in the char and less production of H2S were obtained from microwave pyrolysis at higher temperatures (500-800 degrees C). Three similar conversion pathways were identified for the formation of H2S during microwave and conventional pyrolysis. The cracking of unstable mercaptan structure in the sludge contributed to the release of H2S below 300 degrees C. The decomposition of aliphatic-S compounds in the tars led to the formation of H2S (300-500 degrees C). The thermal decomposition of aromatic-S compounds in the tars generated H2S from 500 to 800 degrees C. However, the secondary decomposition of thiophene-S compounds took place only in conventional pyrolysis above 700 degrees C. Comparing the H2S contributions from microwave and conventional pyrolysis, the significant increase of H2S yields in conventional pyrolysis was mainly attributed to the decomposition of aromatic-S (increasing by 10.4%) and thiophene-S compounds (11.3%). Further investigation on the inhibition mechanism of H2S formation during microwave pyrolysis confirmed that, with the special heating characteristics and relative shorter residence time, microwave pyrolysis promoted the retention of H2S on CaO and inhibited the secondary cracking of thiophene-S compounds at higher temperatures. PMID- 27982578 TI - Recent Advances in Inorganic Nanoparticle-Based NIR Luminescence Imaging: Semiconductor Nanoparticles and Lanthanide Nanoparticles. AB - Several types of nanoparticle-based imaging probes have been developed to replace conventional luminescent probes. For luminescence imaging, near-infrared (NIR) probes are useful in that they allow deep tissue penetration and high spatial resolution as a result of reduced light absorption/scattering and negligible autofluorescence in biological media. They rely on either an anti-Stokes or a Stokes shift process to generate luminescence. For example, transition metal doped semiconductor nanoparticles and lanthanide-doped inorganic nanoparticles have been demonstrated as anti-Stokes shift-based agents that absorb NIR light through two- or three-photon absorption process and upconversion process, respectively. On the other hand, quantum dots (QDs) and lanthanide-doped nanoparticles that emit in NIR-II range (~1000 to ~1350 nm) were suggested as promising Stokes shift-based imaging agents. In this topical review, we summarize and discuss the recent progress in the development of inorganic nanoparticle based luminescence imaging probes working in NIR range. PMID- 27982580 TI - Constant Ion Loss Method for the Untargeted Detection of Bis-sulfate Metabolites. AB - The untargeted detection of phase II metabolites is a key issue for the study of drug metabolism in biological systems. Sensitive and selective mass spectrometric (MS) techniques coupled to ultrahigh performance liquid chromatographic (UHPLC) systems are the most effective for this purpose. In this study, we evaluate different MS approaches with a triple quadrupole instrument for the untargeted detection of bis-sulfate metabolites. Bis-sulfates of 23 steroid metabolites were synthesized and their MS behavior was comprehensively studied. Bis-sulfates ionized preferentially as the dianion ([M - 2H]2-) with a small contribution of the monoanion ([M - H]-). Product ion spectra generated from the [M - 2H]2- precursor ions were dominated by the loss of HSO4- to generate two product ions, that is, the ion at m/z 97 (HSO4-) and the ion corresponding to the remaining monosulfate fragment. Other product ions were found to be specific for some structures. As an example, the loss of [CH3 + SO3]- was found to be important for several compounds with unsaturation adjacent to the sulfate. On the basis of the common behavior of the bis-sulfate metabolites two alternatives were evaluated for the untargeted detection of bis-sulfate metabolites (i) a precursor ion scan method using the ion at m/z 97 and (ii) a constant ion loss (CIL) method using the loss of HSO4-. Both methods allowed for the untargeted detection of the model compounds. Eight steroid bis-sulfates were synthesized in high purity in order to quantitatively evaluate the developed strategies. Lower limits of detection (2-20 ng/mL) were obtained using the CIL method. Additionally, the CIL method was found to be more specific in the detection of urinary bis-sulfates. The applicability of the CIL approach was demonstrated by determining progestogens altered during pregnancy and by detecting the bis-sulfate metabolites of tibolone. PMID- 27982579 TI - Lipidomics Characterization of Biosynthetic and Remodeling Pathways of Cardiolipins in Genetically and Nutritionally Manipulated Yeast Cells. AB - Cardioipins (CLs) are unique tetra-acylated phospholipids of mitochondria and define the bioenergetics and regulatory functions of these organelles. An unresolved paradox is the high uniformity of CL molecular species (tetra linoleoyl-CL) in the heart, liver, and skeletal muscles-in contrast to their high diversification in the brain. Here, we combined liquid chromatography-mass spectrometry-based phospholipidomics with genetic and nutritional manipulations to explore CLs' biosynthetic vs postsynthetic remodeling processes in S. cerevisiae yeast cells. By applying the differential phospholipidomics analysis, we evaluated the contribution of Cld1 (CL-specific phospholipase A) and Taz1 (acyl-transferase) as the major regulatory mechanisms of the remodeling process. We further established that nutritional "pressure" by high levels of free fatty acids triggered a massive synthesis of homoacylated molecular species in all classes of phospholipids, resulting in the preponderance of the respective homoacylated CLs. We found that changes in molecular speciation of CLs induced by exogenous C18-fatty acids (C18:1 and C18:2) in wild-type (wt) cells did not occur in any of the remodeling mutant cells, including cld1Delta, taz1Delta, and cld1Deltataz1Delta. Interestingly, molecular speciation of CLs in wt and double mutant cells cld1Deltataz1Delta was markedly different. Given that the bioenergetics functions are preserved in the double mutant, this suggests that the accumulated MLCL-rather than the changed CL speciation-are the likely major contributors to the mitochondrial dysfunction in taz1Delta mutant cells (also characteristic of Barth syndrome). Biochemical studies of Cld1 specificity and computer modeling confirmed the hydrolytic selectivity of the enzyme toward C16 CL substrates and the preservation of C18:1-containing CL species. PMID- 27982581 TI - Comprehensive Landscape of Nrf2 and p53 Pathway Activation Dynamics by Oxidative Stress and DNA Damage. AB - A quantitative dynamics pathway map of the Nrf2-mediated oxidative stress response and p53-related DNA damage response pathways as well as the cross-talk between these pathways has not systematically been defined. To allow the dynamic single cell evaluation of these pathways, we have used BAC-GFP recombineering to tag for each pathway's three key components: for the oxidative stress response, Keap1-GFP, Nrf2-GFP, and Srxn1-GFP; for the DNA damage response, 53bp1-GFP, p53 GFP, and p21-GFP. The dynamic activation of these individual components was assessed using quantitative high throughput confocal microscopy after treatment with a broad concentration range of diethyl maleate (DEM; to induce oxidative stress) and etoposide (to induce DNA damage). DEM caused a rapid activation of Nrf2, which returned to baseline levels at low concentrations but remained sustained at high concentrations. Srxn1-GFP induction and Keap1-GFP translocation to autophagosomes followed later, with upper boundaries reached at high concentrations, close to the onset of cell death. Etoposide caused rapid accumulation of 53bp1-GFP in DNA damage foci, which was later followed by the concentration dependent nuclear accumulation of p53-GFP and subsequent induction of p21-GFP. While etoposide caused activation of Srxn1-GFP, a modest activation of DNA damage reporters was observed for DEM at high concentrations. Interestingly, Nrf2 knockdown caused an inhibition of the DNA damage response at high concentrations of etoposide, while Keap1 knockdown caused an enhancement of the DNA damage response already at low concentrations of etoposide. Knockdown of p53 did not affect the oxidative stress response. Altogether, the current stress response landscapes provide insight in the time course responses of and cross talk between oxidative stress and DNA-damage and defines the tipping points where cell injury may switch from adaptation to injury. PMID- 27982582 TI - Quantitative Analysis and Discovery of Lysine and Arginine Modifications. AB - Post-translational modifications (PTMs) affect protein function, localization, and stability, yet very little is known about the ratios of these modifications. Here, we describe a novel method to quantitate and assess the relative stoichiometry of Lys and Arg modifications (QuARKMod) in complex biological settings. We demonstrate the versatility of this platform in monitoring recombinant protein modification of peptide substrates, PTMs of individual histones, and the relative abundance of these PTMs as a function of subcellular location. Lastly, we describe a product ion scanning technique that offers the potential to discover unexpected and possibly novel Lys and Arg modifications. In summary, this approach yields accurate quantitation and discovery of protein PTMs in complex biological systems without the requirement of high mass accuracy instrumentation. PMID- 27982583 TI - Standard Cellular Testing Conditions Generate an Exaggerated Nanoparticle Cytotoxicity Profile. AB - Cellular internalization of nanoparticles (NPs) is key to many biomedical applications and serves as a model to investigate the potential toxicity of NPs on entire organisms. Large discrepancies between in vitro and in vivo nanotoxicity data however exist, suggesting that cellular systems may not be optimal for predictive in vivo toxicology. Here, we use validated multiparametric high-content imaging protocols to evaluate the impact of common cell culture conditions on NP cytotoxicity studies. The data show that high NP to cell ratios, typical for cellular studies, stress the cells by high endocytosis levels that overstimulate mitochondria, resulting in oxidative stress-mediated mitochondrial damage, which induces autophagy. Using proliferation-restricted models, we show that lowering endocytosis levels overcomes most toxicity while resulting in higher final cellular NP numbers. The data suggest that many common NP cytotoxicity mechanisms may partially be an artifact caused by overstimulated endocytosis. PMID- 27982584 TI - Transition from Molecular Vibrations to Phonons in Atomically Precise Cadmium Selenide Quantum Dots. AB - We use micro-Raman spectroscopy to measure the vibrational structure of the atomically precise cadmium selenide quantum dots Cd35Se20X30L30, Cd56Se35X42L42, and Cd84Se56X56L56. These quantum dots have benzoate (X) and n-butylamine (L) ligands and tetrahedral (Td) shape with edges that range from 1.7 to 2.6 nm in length. Investigating this previously unexplored size regime allows us to identify the transition from molecular vibrations to bulk phonons in cadmium selenide quantum dots for the first time. Room-temperature Raman spectra have broad CdSe peaks at 175 and 200 cm-1. Density functional theory calculations assign these peaks to molecular surface and interior vibrational modes, respectively, and show that the interior, surface, and ligand atom motion is strongly coupled. The interior peak intensity increases relative to the surface peak as the cluster size increases due to the relative increase in the polarizability of interior modes with quantum dot size. The Raman spectra do not change with temperature for molecular Cd35Se20X30L30, while the interior peak narrows and shifts to higher energy as temperature decreases for Cd84Se56X56L56, a spectral evolution typical of a phonon. This result shows that the single bulk unit cell contained within Cd84Se56X56L56 is sufficient to apply a phonon confinement model, and that Cd56Se35X42L42, with its 2.1 nm edge length, marks the boundary between molecular vibrations and phonons. PMID- 27982585 TI - A Novel Polyaniline-Coated Bagasse Fiber Composite with Core-Shell Heterostructure Provides Effective Electromagnetic Shielding Performance. AB - A facile route was proposed to synthesize polyaniline (PANI) uniformly deposited on bagasse fiber (BF) via a one-step in situ polymerization of aniline in the dispersed system of BF. Correlations between the structural, electrical, and electromagnetic properties were extensively investigated. Scanning electron microscopy images confirm that the PANI was coated dominantly on the BF surface, indicating that the as-prepared BF/PANI composite adopted the natural and inexpensive BF as its core and the PANI as the shell. Fourier transform infrared spectra suggest significant interactions between the BF and PANI shell, and a high degree of doping in the PANI shell was achieved. X-ray diffraction results reveal that the crystallization of the PANI shell was improved. The dielectric behaviors are analyzed with respect to dielectric constant, loss tangent, and Cole-Cole plots. The BF/PANI composite exhibits superior electrical conductivity (2.01 +/- 0.29 S.cm-1), which is higher than that of the pristine PANI with 1.35 +/- 0.15 S.cm-1. The complex permittivity, electromagnetic interference (EMI), shielding effectiveness (SE) values, and attenuation constants of the BF/PANI composite were larger than those of the pristine PANI. The EMI shielding mechanisms of the composite were experimentally and theoretically analyzed. The absorption-dominated total EMI SE of 28.8 dB at a thickness of 0.4 mm indicates the usefulness of the composite for electromagnetic shielding. Moreover, detailed comparison of electrical and EMI shielding properties with respect to the BF/PANI, dedoped BF/PANI composite, and the pristine PANI indicate that the enhancement of electromagnetic properties for the BF/PANI composite was due to the improved conductivity and the core-shell architecture. Thus, the composite has potential commercial applications for high-performance electromagnetic shielding materials and also could be used as a conductive filler to endow polymers with electromagnetic shielding ability. PMID- 27982586 TI - Toward Allosterically Increased Catalytic Activity of Insulin-Degrading Enzyme against Amyloid Peptides. AB - The physiological role of insulin-degrading enzyme (IDE) in the intracytosolic clearance of amyloid beta (Abeta) and other amyloid-like peptides supports a hypothesis that human IDE hyperactivation could be therapeutically beneficial for the treatment of late-onset Alzheimer's disease (AD). The major challenge standing in the way of this goal is increasing the specific catalytic activity of IDE against the Abeta substrate. There were previous indications that the allosteric mode of IDE activity regulation could potentially provide a highly specific path toward degradation of amyloid-like peptides, while not dramatically affecting activity against other substrates. Recently developed theoretical concepts are used here to explore potential allosteric modulation of the IDE activity as a result of single-residue mutations. Five candidates are selected for experimental follow-up and allosteric free energy calculations: Ser137Ala, Lys396Ala, Asp426Ala, Phe807Ala, and Lys898Ala. Our experiments show that three mutations (Ser137Ala, Phe807Ala, and Lys898Ala) decrease the Km of the Abeta substrate. Mutation Lys898Ala results in increased catalytic activity of IDE; on the other hand, Lys364Ala does not change the activity and Asp426Ala diminishes it. Quantifying effects of mutations in terms of allosteric free energy, we show that favorable mutations lead to stabilization of the catalytic sites and other function-relevant distal sites as well as increased dynamics of the IDE-N and IDE C halves that allow efficient substrate entrance and cleavage. A possibility for intramolecular upregulation of IDE activity against amyloid peptides via allosteric mutations calls for further investigations in this direction. Ultimately, we are hopeful it will lead to the development of IDE-based drugs for the treatment of the late-onset form of AD characterized by an overall impairment of Abeta clearance. PMID- 27982587 TI - Polymer Coating Materials and Their Fouling Release Activity: A Cheminformatics Approach to Predict Properties. AB - A novel cheminformatics-based approach has been employed to investigate a set of polymer coating materials designed to mitigate the accumulation of marine biofouling on surfaces immersed in the sea. Specifically, a set of 27 nontoxic, amphiphilic polysiloxane-based polymer coatings was synthesized using a combinatorial, high-throughput approach and characterized for fouling-release (FR) activity toward a number of relevant marine fouling organisms, including bacteria, microalgae, and adult barnacles. In order to model these complex systems adequately, a new computational technique was used in which all investigated polymer-based coating materials were considered as mixture systems comprising several compositional variables at a range of concentrations. By applying a combination of methodologies for mixture systems and a quantitative structure-activity relationship approach (QSAR), seven unique QSAR models were developed that were able to successfully predict the desired FR properties. Furthermore, the developed models identified several significant descriptors responsible for FR activity of investigated polymer-based coating materials, with correlation coefficients ranging from rtest2 = 0.63 to 0.94. The computational models derived from this study may serve as a powerful set of tools to predict optimal combinations of source components to produce amphiphilic polysiloxane based coating systems with effective, broad-spectrum FR properties. PMID- 27982589 TI - Synthesis of 1,2-Bis(2-aryl-1H-indol-3-yl)ethynes via 5-exo-Digonal Double Cyclization Reactions of 1,4-Bis(2-isocyanophenyl)buta-1,3-diyne with Aryl Grignard Reagents. AB - New pi-conjugated 1,2-bis(2-aryl-1H-indol-3-yl)ethynes 1a-j having various substituents on the two aryl groups were efficiently synthesized via unusual 5 exo-digonal double isocyanide-acetylene cyclization reactions of 1,4-bis(2 isocyanophenyl)buta-1,3-diyne 3 and aryl Grignard reagents (R-MgBr, R = C6H5 (1a), 4-H3CC6H4 (1b), 2-H3CC6H4 (1c), 3-MeOC6H4 (1d), 3-(CH3)2NC6H4 (1e), 4 F3CC6H4 (1f), 4-FC6H4 (1g), 3-FC6H4 (1h), 4-PhOC6H4 (1i), and 2-Naph (1j)) in 19 85% yields. The UV-vis spectra were rationalized in detail using time-dependent DFT and single point calculations. The fluorescence emission peaks for 1a-j were observed at around 450 nm. Especially for 1f and 1j, those spectra displayed broad emission bands and relatively large Stokes shifts (3977-4503 cm-1), indicating the contribution of an intramolecular charge transfer. The absolute quantum yields (0.50-0.62) of 1a-j were higher than those of parent 8 (0.19) and 2-phenyl-1H-indole (0.11). The electrochemical features for 1a-j were investigated by cyclic voltammetry. The frontier molecular orbital levels for 1a j were estimated based on the combination of oxidation potentials, UV-vis, and DFT calculated data. The structural property of 1,2-bis(2-phenyl-1H-indol-3 yl)ethyne 1a was characterized by several spectroscopic methods and finally determined by X-ray analysis of a single crystal of 1a recrystallized from ethyl acetate. The structural features of 1a-j were also supported by DFT calculations. PMID- 27982590 TI - Thermolysis of Geminal Diazides: Reagent-Free Synthesis of 3-Hydroxypyridines. AB - An operationally simple protocol for the rapid and efficient construction of highly substituted 3-hydroxypyridines is presented. The thermally induced cyclization of easily constructed geminal diazides derived from beta-ketoesters having an additional olefin moiety affords the title compounds in yields up to 97% under reagent-free conditions. The new method allows for the synthesis of preparative quantities of material. Additionally, the synthetic utility of the pyridine products for the synthesis of valuable heterocycles is described. PMID- 27982588 TI - Structure-Activity Relationships of Small Molecule Autotaxin Inhibitors with a Discrete Binding Mode. AB - Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, among others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and by using a crystal structure with ATX we confirm the discrete binding mode. PMID- 27982591 TI - Association of Methotrexate with Native and PEGylated PAMAM-G4 Dendrimers: Effect of the PEGylation Degree on the Drug-Loading Capacity and Preferential Binding Sites. AB - PEGylated PAMAM dendrimers (PEG-PAMAM) have been extensively studied as versatile vehicles for drug delivery. Nevertheless, little information has been reported regarding the effect of the PEGylation degree on the drug-loading properties of these systems, aimed at maximizing their performance as drug carrier nanocarrriers. In this work, fully atomistic molecular dynamics (MD) simulations were employed to examine the association of methotrexate (MTX) with native and diversely PEGylated PAMAM-G4 dendrimers, using 2 kDa PEG chains with substitution degrees from 25 to 100% and 100:1 drug:dendrimer ratios to mimic experimental conditions of drug excess in saturated solution. MD results regarding complex stoichiometries and preferential binding sites were compared to experimental data retrieved from aqueous solubility profiles and 2D-NOESY experiments showing an outstanding level of agreement. The maximum theoretical drug loading capacity was achieved by the system with 34% PEGylation (42:1) through the simultaneous complexation of MTX within internal PAMAM-G4 branches and external PEG chains. On the other hand, higher PEGylation degrees were found to be detrimental for drug complexation due to PEG chains crowding on the dendrimer surface. These results provide valuable information to design more efficient PAMAM-based drug nanocarriers and explain the positive effect that partial PEGylation exerts on the drug-loading capacity of PAMAM-G4 over native and fully PEGylated systems. PMID- 27982592 TI - Time-Domain ab Initio Modeling of Electron-Phonon Relaxation in High-Temperature Cuprate Superconductors. AB - Superconducting pairing due to electron-phonon coupling is investigated in recent pump-probe experiments. Combining time-dependent density functional theory and nonadiabatic molecular dynamics, we report the first direct modeling of such experiments and show how the electron-phonon relaxation depends on chemical bonding, electron-phonon coupling, and electronic state density. The relaxation rate is determined primarily by the nonadiabatic charge-phonon coupling strength, which in turn depends on the strength of chemical interactions between the key atoms, reflected in the wave function delocalization. The differences in the electronic density of states constitute the secondary factor. Having obtained good agreement with the experimental data on YBa2Cu3O6.5, we predict that the relaxation slows if Y is replaced with Sc or Ba with Sr, while the relaxation accelerates if O is replaced with S, indicating that YBa2Cu3S6.5 can exhibit improved superconducting performance. PMID- 27982593 TI - Correction to Accurate Ionization Potentials and Electron Affinities of Acceptor Molecules IV: Electron-Propagator Methods. PMID- 27982594 TI - Capillary Drop Penetration Method to Characterize the Liquid Wetting of Powders. AB - We present a method to characterize the wettability of powders, based on the penetration dynamics of a sessile drop deposited on a slightly compressed powder bed. First, we show that a direct comparison of the wetting properties of different liquids is possible without having to solve the three-dimensional liquid penetration problem, by considering the appropriate dimensionless variables. We show that the contact area between the sessile drop and the powder bed remains constant during most of the penetration process and demonstrate that as a result, the evolution of the dimensionless penetration volume is given by a universal function of the dimensionless time, with no dimensionless parameters. Then, using a reference liquid that completely wets the powder, it is possible to obtain an effective contact angle for a test liquid of interest, independent of other properties of the powder bed, such as permeability and a characteristic pore size. We apply the proposed method to estimate the contact angle of water with different powder blends, by using silicone oil as the reference liquid. Finally, to highlight the potential of the proposed method to characterize pharmaceutical powders, we consider a blend of lactose, acetaminophen, and a small amount of lubricant (magnesium stearate). The proposed method adequately captures a significant decrease in hydrophilicity that results from exposing the blend to excessive mixing, a well-known effect in the pharmaceutical industry. PMID- 27982595 TI - When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode? AB - Traditional hit-to-lead optimization assumes that upon elaboration of chemical structure, the ligand retains its binding mode relative to the receptor. Here, we build a large-scale collection of related ligand pairs solved in complex with the same protein partner: we find that for 41 of 297 pairs (14%), the binding mode changes upon elaboration of the smaller ligand. While certain ligand physiochemical properties predispose changes in binding mode, particularly those properties that define fragments, simple structure-based modeling proves far more effective for identifying substitutions that alter the binding mode. Some ligand pairs change binding mode because the added substituent would irreconcilably conflict with the receptor in the original pose, whereas others change because the added substituent enables new, stronger interactions that are available only in a different pose. Scaffolds that can engage their target using alternate poses may enable productive structure-based optimization along multiple divergent pathways. PMID- 27982597 TI - Fluid Flow Programming in Paper-Derived Silica-Polymer Hybrids. AB - In paper-based devices, capillary fluid flow is based on length-scale selective functional control within a hierarchical porous system. The fluid flow can be tuned by altering the paper preparation process, which controls parameters such as the paper grammage. Interestingly, the fiber morphology and nanoporosity are often neglected. In this work, porous voids are incorporated into paper by the combination of dense or mesoporous ceramic silica coatings with hierarchically porous cotton linter paper. Varying the silica coating leads to significant changes in the fluid flow characteristics, up to the complete water exclusion without any further fiber surface hydrophobization, providing new approaches to control fluid flow. Additionally, functionalization with redox-responsive polymers leads to reversible, dynamic gating of fluid flow in these hybrid paper materials, demonstrating the potential of length scale specific, dynamic, and external transport control. PMID- 27982596 TI - Fullerene as Photocatalyst: Visible-Light Induced Reaction of Perfluorinated alpha,omega-Diiodoalkanes with C60. AB - Solution phase photochemical reaction of fullerene with perfluorinated alkyldiiodides I-RF-I can be efficiently initiated by visible range irradiation that targets solely the fullerene component. Photoinduced electron transfer from fullerene onto the diiodide component effects dissociative formation of alkyl radicals RFI* subsequently consumed by C60 to give the principal detectable radical intermediate C60RFI*. Experimentally established second-order kinetics with respect to the fullerene concentration evidence that fullerene plays its two roles of photocatalyst and reactant in a decoupled fashion, which suggests its catalytic ability to be of potential use in more complex photochemical systems. The main final product of the photochemical transformation observed is the singly linked dimer of the intermediates, I-RF-C60-C60-RF-I. Side reactions of C60RFI* with the environment lead to quenching of the unpaired electron density by ortho- or para- attachment of hydrogen or iodine. The outlined kinetic findings are discussed in detail. PMID- 27982598 TI - Ultrafast Photodissociation Dynamics of Highly Excited Iodobenzene on the C Band. AB - The photodissociation dynamics of highly excited iodobenzene from the C band absorption has been studied by femtosecond time-resolved ion yields techniques. Detailed photodissociation routes are discussed with the aid of high-level, spin orbit resolved ab initio calculations of 1D potential energy curves. Upon 200 nm excitation within the C band, iodobenzene molecules on 7B2 and 7B1 states decay to 7A1 and 8B2 states through internal conversion in 75 fs, with electronic energy converted into high vibrational energy of 7A1 and 8B2 states. Subsequently, 7A1 and 8B2 states decay through internal vibrational energy redistribution in 540 fs, accompanied by the excited C-I mode and the resulting cleavage of the C-I bond. The overall time for the reaction starting from the phenyl-type modes and ending in final C-I fragmentation for I(2P3/2) production is 1.2 ps. PMID- 27982599 TI - Computational and Experimental Investigation of the Structure of Peptide Monolayers on Gold Nanoparticles. AB - The self-assembly and self-organization of small molecules on the surface of nanoparticles constitute a potential route toward the preparation of advanced proteinlike nanosystems. However, their structural characterization, critical to the design of bionanomaterials with well-defined biophysical and biochemical properties, remains highly challenging. Here, a computational model for peptide capped gold nanoparticles (GNPs) is developed using experimentally characterized Cys-Ala-Leu-Asn-Asn (CALNN)- and Cys-Phe-Gly-Ala-Ile-Leu-Ser-Ser (CFGAILSS) capped GNPs as a benchmark. The structure of CALNN and CFGAILSS monolayers is investigated using both structural biology techniques and molecular dynamics simulations. The calculations reproduce the experimentally observed dependence of the monolayer secondary structure on the peptide capping density and on the nanoparticle size, thus giving us confidence in the model. Furthermore, the computational results reveal a number of new features of peptide-capped monolayers, including the importance of sulfur movement for the formation of secondary structure motifs, the presence of water close to the gold surface even in tightly packed peptide monolayers, and the existence of extended 2D parallel beta-sheet domains in CFGAILSS monolayers. The model developed here provides a predictive tool that may assist in the design of further bionanomaterials. PMID- 27982600 TI - Optimization of Spectral and Spatial Conditions to Improve Super-Resolution Imaging of Plasmonic Nanoparticles. AB - Interactions between fluorophores and plasmonic nanoparticles modify the fluorescence intensity, shape, and position of the observed emission pattern, thus inhibiting efforts to optically super-resolve plasmonic nanoparticles. Herein, we investigate the accuracy of localizing dye fluorescence as a function of the spectral and spatial separations between fluorophores (Alexa 647) and gold nanorods (NRs). The distance at which Alexa 647 interacts with NRs is varied by layer-by-layer polyelectrolyte deposition while the spectral separation is tuned by using NRs with varying localized surface plasmon resonance (LSPR) maxima. For resonantly coupled Alexa 647 and NRs, emission to the far field through the NR plasmon is highly prominent, resulting in underestimation of NR sizes. However, we demonstrate that it is possible to improve the accuracy of the emission localization when both the spectral and spatial separations between Alexa 647 and the LSPR are optimized. PMID- 27982601 TI - Two-Dimensional Spectroscopy of Chlorophyll a Excited-State Equilibration in Light-Harvesting Complex II. AB - Excited-state relaxation dynamics and energy-transfer processes in the chlorophyll a (Chl a) manifold of the light-harvesting complex II (LHCII) were examined at physiological temperature using femtosecond two-dimensional electronic spectroscopy (2DES). The experiments were done under conditions free from singlet-singlet annihilation and anisotropic decay. Energy transfer between the different domains of the Chl a manifold was found to proceed on time scales from hundreds of femtoseconds to five picoseconds, before reaching equilibration. No component slower than 10 ps was observed in the spectral equilibration dynamics. We clearly observe the bidirectional (uphill and downhill) energy transfer of the equilibration process between excited states. This bidirectional energy flow, although implicit in the modeling and simulation of the EET processes, has not been observed in any prior transient absorption studies. Furthermore, we identified the spectral forms associated with the different energy transfer lifetimes in the equilibration process. PMID- 27982602 TI - Targeted Biomimetic Nanoparticles for Synergistic Combination Chemotherapy of Paclitaxel and Doxorubicin. AB - Codelivery of multiple chemotherapeutics has become a versatile strategy in recent cancer treatment, but the antagonistic behavior of combined drugs limited their application. We developed a recombinant high-density lipoprotein (rHDL) nanoparticle for the precise coencapsulation and codelivery of two established drugs and hypothesized that they could act synergistically to improve anticancer efficacy. The coloaded rHDL was formulated by passively incorporating hydrophobic paclitaxel (PTX), and subsequently remotely loading hydrophilic doxorubicin (Dox) into the same nanoparticles. The resultant rHDL system restored targeted delivery function toward cancer cells via scavenger receptor class B (SR-BI), as confirmed by in vitro confocal imaging and flow cytometry. These coloaded rHDL nanoparticles were remarkably effective in increasing the ratiometric accumulation of drugs in cancer cells and enhancing antitumor response at synergistic drug ratios. In particular, they exhibited more efficacious anticancer effects in an in vitro cytotoxicity evaluation and in a xenograft tumor model of hepatoma compared with free drug cocktail solutions. These results confirm that the coloaded rHDL nanoparticles are promising candidates for the synergistic delivery of drugs with diverse physicochemical properties in cancer treatment integrating efficiency and safety considerations. PMID- 27982603 TI - Osmotic Second Virial Coefficients of Aqueous Solutions from Two-Component Equations of State. AB - Osmotic second virial coefficients in dilute aqueous solutions of small nonpolar solutes are calculated from three different two-component equations of state. The solutes are five noble gases, four diatomics, and six hydrocarbons in the range C1-C4. The equations of state are modified versions of the van der Waals, Redlich Kwong, and Peng-Robinson equations, with an added hydrogen-bonding term for the solvent water. The parameters in the resulting equations of state are assigned so as to reproduce the experimental values and temperature dependence of the density, vapor pressure, and compressibility of the solvent, the gas-phase second virial coefficient of the pure solute, the solubility and partial molecular volume of the solute, and earlier estimates of the solutes' molecular radii. For all 15 solutes, the calculations are done for 298.15 K, whereas for CH4, C2H6, and C3H8 in particular, they are also done as functions of temperature over the full range 278.15-348.15 K. The calculated osmotic virial coefficients are compared with earlier calculations of these coefficients for these solutes and also with the results derived from earlier computer simulations of model aqueous solutions of methane. They are also compared with the experimental gas-phase second virial coefficients of the pure gaseous solutes to determine the effect the mediation of the solvent has on the resulting solute-solute interactions in the solution. PMID- 27982604 TI - Piezochromic Porous Metal-Organic Framework. AB - Pressure changes the color of a new type of metal-organic porous hybrid material CoBbcDabcoH2O. It is built of Co2+ cations linked by 1,4-benzenedicabroxylate (Bdc) anions and 1,4-diazabicyclo[2.2.2]octane (Dabco) molecules into 2-D grid like sheets, interconnected through OH...O bonds of water molecules to carboxylate H-acceptors. This first piezochromic MOF, stable in air and in many solvents, is an ideal ultraprecise sensor for pressure calibration. The color changes are due to strains generated by pressure in the highly asymmetric crystal field of Co2+ octahedral coordination, involving four different ligand types: a Dabco amine (twice), a monodentate carboxylate, a chelating carboxylate, and a water molecule. At 0.33 GPa/296 K and below 225 K/0.1 MPa a phase transition reduces the crystal symmetry from monoclinic to triclinic system and changes the conformation and orientation of linkers. PMID- 27982605 TI - Organocatalytic, Asymmetric Synthesis of Aza-Quaternary Center of Izidine Alkaloids: Synthesis of (-)-Tricyclic Skeleton of Cylindricine. AB - We report a highly efficient, enantioselective, organocatalytic method for the synthesis of izidinone alkaloids containing a bridgehead aza-quaternary center using ketone-derived N,O-hemiaminal with a tethered acetal. Alkyl-, aryl-, and alkenyl-substituted substrates cyclize to the respective products with excellent enantioselectivities. Five- and seven-membered ring formation has also been established. Furthermore, synthesis of the tricyclic skeleton of cylindricine alkaloids has been achieved in high yield. PMID- 27982606 TI - Candidate Elastic Quantum Critical Point in LaCu_{6-x}Au_{x}. AB - The structural properties of LaCu_{6-x}Au_{x} are studied using neutron diffraction, x-ray diffraction, and heat capacity measurements. The continuous orthorhombic-monoclinic structural phase transition in LaCu_{6} is suppressed linearly with Au substitution until a complete suppression of the structural phase transition occurs at the critical composition x_{c}=0.3. Heat capacity measurements at low temperatures indicate residual structural instability at x_{c}. The instability is ferroelastic in nature, with density functional theory calculations showing negligible coupling to electronic states near the Fermi level. The data and calculations presented here are consistent with the zero temperature termination of a continuous structural phase transition suggesting that the LaCu_{6-x}Au_{x} series hosts an elastic quantum critical point. PMID- 27982607 TI - Tognolini et al. Reply. PMID- 27982608 TI - Puddle-Induced Resistance Oscillations in the Breakdown of the Graphene Quantum Hall Effect. AB - We report on the stability of the quantum Hall plateau in wide Hall bars made from a chemically gated graphene film grown on SiC. The nu=2 quantized plateau appears from fields B?5 T and persists up to B?80 T. At high current density, in the breakdown regime, the longitudinal resistance oscillates with a 1/B periodicity and an anomalous phase, which we relate to the presence of additional electron reservoirs. The high field experimental data suggest that these reservoirs induce a continuous increase of the carrier density up to the highest available magnetic field, thus enlarging the quantum plateaus. These in-plane inhomogeneities, in the form of high carrier density graphene pockets, modulate the quantum Hall effect breakdown and decrease the breakdown current. PMID- 27982609 TI - Barrier-Free Nucleation at Grain-Boundary Triple Junctions During Solid-State Phase Transformations. AB - Molecular dynamics simulations are used to provide strong evidence for barrier free nucleation events in a heterogeneous solid-solid system. The barrier-free events are characterized by an absence of an incubation time and a growth rate of the emerging phase that is independent of the system size. Furthermore, an analysis of the size and shape of the critical nucleus using the Winterbottom construction indicates that no solution exists for these barrier-free cases. We propose that barrier-free nucleation, which will have a profound effect on phase transformation kinetics, may be a general phenomenon for any polycrystalline material. PMID- 27982611 TI - Scaling Theory of a Compressibility-Driven Metal-Insulator Transition in a Two Dimensional Electron Fluid. AB - We present a scaling description of a metal-insulator transition in two dimensional electron systems that is driven by a vanishing compressibility rather than a vanishing diffusion coefficient. A small set of basic assumptions leads to a consistent theoretical framework that is compatible with existing transport and compressibility measurements, and allows us to make predictions for other observables. We also discuss connections between these ideas and other theories of transitions to an incompressible quantum fluid. PMID- 27982612 TI - Nonlinear Waves in the Terrestrial Quasiparallel Foreshock. AB - We provide strongly conclusive evidence that the cubic nonlinearity plays an important part in the evolution of the large amplitude magnetic structures in the terrestrial foreshock. Large amplitude nonlinear wave trains at frequencies above the proton cyclotron frequency are identified after nonharmonic slow variations are filtered out by applying the empirical mode decomposition. Numerical solutions of the derivative nonlinear Schrodinger equation, predicted analytically by the use of a pseudopotential approach, are found to be consistent with the observed wave forms. The approximate phase speed of these nonlinear waves, indicated by the parameters of numerical solutions, is of the order of the local Alfven speed. We suggest that the feedback of the large amplitude fluctuations on background plasma is reflected in the evolution of the pseudopotential. PMID- 27982613 TI - Coherent Cherenkov-Cyclotron Radiation Excited by an Electron Beam in a Metamaterial Waveguide. AB - An electron beam passing through a metamaterial structure is predicted to generate reversed Cherenkov radiation, an unusual and potentially very useful property. We present an experimental test of this phenomenon using an intense electron beam passing through a metamaterial loaded waveguide. Power levels of up to 5 MW are observed in backward wave modes at a frequency of 2.40 GHz using a one microsecond pulsed electron beam of 490 keV, 84 A in a 400 G magnetic field. Contrary to expectations, the output power is not generated in the Cherenkov mode. Instead, the presence of the magnetic field, which is required to transport the electron beam, induces a Cherenkov-cyclotron (or anomalous Doppler) instability at a frequency equal to the Cherenkov frequency minus the cyclotron frequency. Nonlinear simulations indicate that the Cherenkov-cyclotron mode should dominate over the Cherenkov instability at a lower magnetic field where the highest output power is obtained. PMID- 27982614 TI - Erratum: Cluster Glass Transition of Ultrasoft-Potential Fluids at High Density [Phys. Rev. Lett. 117, 165701 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.117.165701. PMID- 27982615 TI - Sharp Transition in the Lift Force of a Fluid Flowing Past Nonsymmetrical Obstacles: Evidence for a Lift Crisis in the Drag Crisis Regime. AB - Bluff bodies moving in a fluid experience a drag force which usually increases with velocity. However in a particular velocity range a drag crisis is observed, i.e., a sharp and strong decrease of the drag force. This counterintuitive result is well characterized for a sphere or a cylinder. Here we show that, for an object breaking the up-down symmetry, a lift crisis is observed simultaneously to the drag crisis. The term lift crisis refers to the fact that at constant incidence the time-averaged transverse force, which remains small or even negative at low velocity, transitions abruptly to large positive values above a critical flow velocity. This transition is characterized from direct force measurements as well as from change in the velocity field around the obstacle. PMID- 27982616 TI - Experimental Demonstration of Higher Precision Weak-Value-Based Metrology Using Power Recycling. AB - The weak-value-based metrology is very promising and has attracted a lot of attention in recent years because of its remarkable ability in signal amplification. However, it is suggested that the upper limit of the precision of this metrology cannot exceed that of classical metrology because of the low sample size caused by the probe loss during postselection. Nevertheless, a recent proposal shows that this probe loss can be reduced by the power-recycling technique, and thus enhance the precision of weak-value-based metrology. Here we experimentally realize the power-recycled interferometric weak-value-based beam deflection measurement and obtain the amplitude of the detected signal and white noise by discrete Fourier transform. Our results show that the detected signal can be strengthened by power recycling, and the power-recycled weak-value-based signal-to-noise ratio can surpass the upper limit of the classical scheme, corresponding to the shot-noise limit. This work sheds light on higher precision metrology and explores the real advantage of the weak-value-based metrology over classical metrology. PMID- 27982617 TI - Ultrafast Coherent Dynamics of a Photonic Crystal All-Optical Switch. AB - We present pump-probe measurements of an all-optical photonic crystal switch based on a nanocavity, resolving fast coherent temporal dynamics. The measurements demonstrate the importance of coherent effects typically neglected when considering nanocavity dynamics. In particular, we report the observation of an idler pulse and more than 10 dB parametric gain. The measurements are in good agreement with a theoretical model that ascribes the observation to oscillations of the free-carrier population in the nanocavity. The effect opens perspectives for the realization of new all-optical photonic crystal switches with unprecedented switching contrast. PMID- 27982619 TI - First On-Sky Fringes with an Up-Conversion Interferometer Tested on a Telescope Array. AB - The Astronomical Light Optical Hybrid Analysis project investigates the combined use of a telescope array interferometer and nonlinear optics to propose a new generation of instruments dedicated to high-resolution imaging for infrared astronomy. The nonlinear process of optical frequency conversion transfers the astronomical light to a shorter wavelength domain. Here, we report on the first fringes obtained on the sky with the prototype operated at 1.55 MUm in the astronomical H band and implemented on the Center for High Angular Resolution Astronomy telescope array. This seminal result allows us to foresee a future extension to the challenging midinfrared spectral domain. PMID- 27982620 TI - One-Loop One-Point Functions in Gauge-Gravity Dualities with Defects. AB - We initiate the calculation of loop corrections to correlation functions in 4D defect conformal field theories (dCFTs). More precisely, we consider N=4 SYM theory with a codimension-one defect separating two regions of space, x_{3}>0 and x_{3}<0, where the gauge group is SU(N) and SU(N-k), respectively. This setup is made possible by some of the real scalar fields acquiring a nonvanishing and x_{3}-dependent vacuum expectation value for x_{3}>0. The holographic dual is the D3-D5 probe brane system where the D5-brane geometry is AdS_{4}*S^{2} and a background gauge field has k units of flux through the S^{2}. We diagonalize the mass matrix of the dCFT making use of fuzzy-sphere coordinates and we handle the x_{3} dependence of the mass terms in the 4D Minkowski space propagators by reformulating these as standard massive AdS_{4} propagators. Furthermore, we show that only two Feynman diagrams contribute to the one-loop correction to the one point function of any single-trace operator and we explicitly calculate this correction in the planar limit for the simplest chiral primary. The result of this calculation is compared to an earlier string-theory computation in a certain double scaling limit and perfect agreement is found. Finally, we discuss how to generalize our calculation to any single-trace operator, to finite N, and to other types of observables such as Wilson loops. PMID- 27982622 TI - Remnant Geometric Hall Response in a Quantum Quench. AB - Out-of-equilibrium systems can host phenomena that transcend the usual restrictions of equilibrium systems. Here, we unveil how out-of-equilibrium states, prepared via a quantum quench in a two-band system, can exhibit a nonzero Hall-type current-a remnant Hall response-even when the instantaneous Hamiltonian is time reversal symmetric (in contrast to equilibrium Hall currents). Interestingly, the remnant Hall response arises from the coherent dynamics of the wave function that retain a remnant of its quantum geometry postquench, and can be traced to processes beyond linear response. Quenches in two-band Dirac systems are natural venues for realizing remnant Hall currents, which exist when either mirror or time-reversal symmetry are broken (before or after the quench). Its long time persistence, sensitivity to symmetry breaking, and decoherence-type relaxation processes allow it to be used as a sensitive diagnostic of the complex out-of-equilibrium dynamics readily controlled and probed in cold-atomic optical lattice experiments. PMID- 27982621 TI - Template-Directed Copolymerization, Random Walks along Disordered Tracks, and Fractals. AB - In biology, template-directed copolymerization is the fundamental mechanism responsible for the synthesis of DNA, RNA, and proteins. More than 50 years have passed since the discovery of DNA structure and its role in coding genetic information. Yet, the kinetics and thermodynamics of information processing in DNA replication, transcription, and translation remain poorly understood. Challenging issues are the facts that DNA or RNA sequences constitute disordered media for the motion of polymerases or ribosomes while errors occur in copying the template. Here, it is shown that these issues can be addressed and sequence heterogeneity effects can be quantitatively understood within a framework revealing universal aspects of information processing at the molecular scale. In steady growth regimes, the local velocities of polymerases or ribosomes along the template are distributed as the continuous or fractal invariant set of a so called iterated function system, which determines the copying error probabilities. The growth may become sublinear in time with a scaling exponent that can also be deduced from the iterated function system. PMID- 27982623 TI - Generalized Master Equations Leading to Completely Positive Dynamics. AB - We provide a general construction of quantum generalized master equations with a memory kernel leading to well-defined, that is, completely positive and trace preserving, time evolutions. The approach builds on an operator generalization of memory kernels appearing in the description of non-Markovian classical processes and puts into evidence the nonuniqueness of the relationship arising due to the typical quantum issue of operator ordering. The approach provides a physical interpretation of the structure of the kernels, and its connection with the classical viewpoint allows for a trajectory description of the dynamics. Previous apparently unrelated results are now connected in a unified framework, which further allows us to phenomenologically construct a large class of non-Markovian evolutions taking as the starting point collections of time-dependent maps and instantaneous transformations describing the microscopic interaction dynamics. PMID- 27982625 TI - Mutation at Expanding Front of Self-Replicating Colloidal Clusters. AB - We construct a scheme for self-replicating square clusters of particles in two spatial dimensions, and validate it with computer simulations in a finite temperature heat bath. We find that the self-replication reactions propagate through the bath in the form of Fisher waves. Our model reflects existing colloidal systems, but is simple enough to allow simulation of many generations and thereby the first study of evolutionary dynamics in an artificial system. By introducing spatially localized mutations in the replication rules, we show that the mutated cluster population can survive and spread with the expanding front in circular sectors of the colony. PMID- 27982624 TI - Interevent Correlations from Avalanches Hiding Below the Detection Threshold. AB - Numerous systems ranging from deformation of materials to earthquakes exhibit bursty dynamics, which consist of a sequence of events with a broad event size distribution. Very often these events are observed to be temporally correlated or clustered, evidenced by power-law-distributed waiting times separating two consecutive activity bursts. We show how such interevent correlations arise simply because of a finite detection threshold, created by the limited sensitivity of the measurement apparatus, or used to subtract background activity or noise from the activity signal. Data from crack-propagation experiments and numerical simulations of a nonequilibrium crack-line model demonstrate how thresholding leads to correlated bursts of activity by separating the avalanche events into subavalanches. The resulting temporal subavalanche correlations are well described by our general scaling description of thresholding-induced correlations in crackling noise. PMID- 27982626 TI - Experimental Investigation of the Collective Raman Scattering of Multiple Laser Beams in Inhomogeneous Plasmas. AB - Experiments have been performed evidencing significant stimulated Raman sidescattering (SRS) at large angles from the density gradient. This was achieved in long scale-length high-temperature plasmas in which two beams couple to the same scattered electromagnetic wave further demonstrating for the first time this multiple-beam collective SRS interaction. The collective nature of the coupling and the amplification at large angles from the density gradient increase the global SRS losses and produce light scattered in novel directions out of the planes of incidence of the beams. These findings obtained in plasmas conditions relevant of inertial confinement fusion experiments similarly apply to the more complex geometry of these experiments where anomalously large levels of SRS were measured. PMID- 27982627 TI - Ballistic Graphene Josephson Junctions from the Short to the Long Junction Regimes. AB - We investigate the critical current I_{C} of ballistic Josephson junctions made of encapsulated graphene-boron-nitride heterostructures. We observe a crossover from the short to the long junction regimes as the length of the device increases. In long ballistic junctions, I_{C} is found to scale as ?exp( k_{B}T/deltaE). The extracted energies deltaE are independent of the carrier density and proportional to the level spacing of the ballistic cavity. As T->0 the critical current of a long (or short) junction saturates at a level determined by the product of deltaE (or Delta) and the number of the junction's transversal modes. PMID- 27982629 TI - Mechanical Actuation of Magnetic Domain-Wall Motion. AB - We theoretically study the motion of a magnetic domain wall induced by transverse elastic waves in a one-dimensional magnetic wire, which respects both rotational and translational symmetries. By invoking the conservation of the associated total angular and linear momenta, we are able to derive the torque and the force on the domain wall exerted by the waves. We then show how ferromagnetic and antiferromagnetic domain walls can be driven by circularly and linearly polarized waves, respectively. We envision that elastic waves may provide effective means to drive the dynamics of magnetic solitons in insulators. PMID- 27982628 TI - Comment on "Rashba Spin-Orbit Coupling in Image Potential States". PMID- 27982630 TI - Top Quark Mass Calibration for Monte Carlo Event Generators. AB - The most precise top quark mass measurements use kinematic reconstruction methods, determining the top mass parameter of a Monte Carlo event generator m_{t}^{MC}. Because of hadronization and parton-shower dynamics, relating m_{t}^{MC} to a field theory mass is difficult. We present a calibration procedure to determine this relation using hadron level QCD predictions for observables with kinematic mass sensitivity. Fitting e^{+}e^{-} 2-jettiness calculations at next-to-leading-logarithmic and next-to-next-to-leading logarithmic order to pythia 8.205, m_{t}^{MC} differs from the pole mass by 900 and 600 MeV, respectively, and agrees with the MSR mass within uncertainties, m_{t}^{MC}?m_{t,1 GeV}^{MSR}. PMID- 27982631 TI - Quantum Critical Scaling in the Disordered Itinerant Ferromagnet UCo_{1 x}Fe_{x}Ge. AB - The Belitz-Kirkpatrick-Vojta (BKV) theory shows in excellent agreement with experiment that ferromagnetic quantum phase transitions (QPTs) in clean metals are generally first order due to the coupling of the magnetization to electronic soft modes, in contrast to the classical analogue that is an archetypical second order phase transition. For disordered metals the BKV theory predicts that the second-order nature of the QPT is restored because the electronic soft modes change their nature from ballistic to diffusive. Our low-temperature magnetization study identifies the ferromagnetic QPT in the disordered metal UCo_{1-x}Fe_{x}Ge as the first clear example that exhibits the associated critical exponents predicted by the BKV theory. PMID- 27982632 TI - Direct Approach to Quantum Tunneling. AB - The decay rates of quasistable states in quantum field theories are usually calculated using instanton methods. Standard derivations of these methods rely in a crucial way upon deformations and analytic continuations of the physical potential and on the saddle-point approximation. While the resulting procedure can be checked against other semiclassical approaches in some one-dimensional cases, it is challenging to trace the role of the relevant physical scales, and any intuitive handle on the precision of the approximations involved is at best obscure. In this Letter, we use a physical definition of the tunneling probability to derive a formula for the decay rate in both quantum mechanics and quantum field theory directly from the Minkowski path integral, without reference to unphysical deformations of the potential. There are numerous benefits to this approach, from nonperturbative applications to precision calculations and aesthetic simplicity. PMID- 27982633 TI - Forces on Rigid Inclusions in Elastic Media and Resulting Matrix-Mediated Interactions. AB - To describe many-particle systems suspended in incompressible low-Reynolds-number fluids, effective hydrodynamic interactions can be introduced. Here, we consider particles embedded in elastic media. The effective elastic interactions between spherical particles are calculated analytically, inspired by the approach in the fluid case. Our experiments on interacting magnetic particles confirm the theory. In view of the huge success of the method in hydrodynamics, we similarly expect many future applications in the elastic case, e.g., for elastic composite materials. PMID- 27982634 TI - Mendoza-Coto, Stariolo, and Nicolao Reply. PMID- 27982635 TI - Clean Quantum and Classical Communication Protocols. AB - By how much must the communication complexity of a function increase if we demand that the parties not only correctly compute the function but also return all registers (other than the one containing the answer) to their initial states at the end of the communication protocol? Protocols that achieve this are referred to as clean and the associated cost as the clean communication complexity. Here we present clean protocols for calculating the inner product of two n-bit strings, showing that (in the absence of preshared entanglement) at most n+3 qubits or n+O(sqrt[n]) bits of communication are required. The quantum protocol provides inspiration for obtaining the optimal method to implement distributed cnot gates in parallel while minimizing the amount of quantum communication. For more general functions, we show that nearly all Boolean functions require close to 2n bits of classical communication to compute and close to n qubits if the parties have access to preshared entanglement. Both of these values are maximal for their respective paradigms. PMID- 27982636 TI - Evolution of a Vortex in a Strain Flow. AB - Experiments and vortex-in-cell simulations are used to study an initially axisymmetric, spatially distributed vortex subject to an externally imposed strain flow. The experiments use a magnetized pure electron plasma to model an inviscid two-dimensional fluid. The results are compared to a theory assuming an elliptical region of constant vorticity. For relatively flat vorticity profiles, the dynamics and stability threshold are in close quantitative agreement with the theory. Physics beyond the constant-vorticity model, such as vortex stripping, is investigated by studying the behavior of nonflat vorticity profiles. PMID- 27982618 TI - Precision Measurement of the Boron to Carbon Flux Ratio in Cosmic Rays from 1.9 GV to 2.6 TV with the Alpha Magnetic Spectrometer on the International Space Station. AB - Knowledge of the rigidity dependence of the boron to carbon flux ratio (B/C) is important in understanding the propagation of cosmic rays. The precise measurement of the B/C ratio from 1.9 GV to 2.6 TV, based on 2.3 million boron and 8.3 million carbon nuclei collected by AMS during the first 5 years of operation, is presented. The detailed variation with rigidity of the B/C spectral index is reported for the first time. The B/C ratio does not show any significant structures in contrast to many cosmic ray models that require such structures at high rigidities. Remarkably, above 65 GV, the B/C ratio is well described by a single power law R^{Delta} with index Delta=-0.333+/-0.014(fit)+/-0.005(syst), in good agreement with the Kolmogorov theory of turbulence which predicts Delta=-1/3 asymptotically. PMID- 27982637 TI - Magnetorotational Turbulence and Dynamo in a Collisionless Plasma. AB - We present results from the first 3D kinetic numerical simulation of magnetorotational turbulence and dynamo, using the local shearing-box model of a collisionless accretion disk. The kinetic magnetorotational instability grows from a subthermal magnetic field having zero net flux over the computational domain to generate self-sustained turbulence and outward angular-momentum transport. Significant Maxwell and Reynolds stresses are accompanied by comparable viscous stresses produced by field-aligned ion pressure anisotropy, which is regulated primarily by the mirror and ion-cyclotron instabilities through particle trapping and pitch-angle scattering. The latter endow the plasma with an effective viscosity that is biased with respect to the magnetic-field direction and spatiotemporally variable. Energy spectra suggest an Alfven-wave cascade at large scales and a kinetic-Alfven-wave cascade at small scales, with strong small-scale density fluctuations and weak nonaxisymmetric density waves. Ions undergo nonthermal particle acceleration, their distribution accurately described by a kappa distribution. These results have implications for the properties of low-collisionality accretion flows, such as that near the black hole at the Galactic center. PMID- 27982638 TI - Experimental Observation of a Topological Band Gap Opening in Ultracold Fermi Gases with Two-Dimensional Spin-Orbit Coupling. AB - The recent experimental realization of synthetic spin-orbit coupling (SOC) opens a new avenue for exploring novel quantum states with ultracold atoms. However, in experiments for generating two-dimensional SOC (e.g., Rashba type), a perpendicular Zeeman field, which opens a band gap at the Dirac point and induces many topological phenomena, is still lacking. Here, we theoretically propose and experimentally realize a simple scheme for generating two-dimensional SOC and a perpendicular Zeeman field simultaneously in ultracold Fermi gases by tuning the polarization of three Raman lasers that couple three hyperfine ground states of atoms. The resulting band gap opening at the Dirac point is probed using spin injection radio-frequency spectroscopy. Our observation may pave the way for exploring topological transport and topological superfluids with exotic Majorana and Weyl fermion excitations in ultracold atoms. PMID- 27982639 TI - Polarization Shaping for Control of Nonlinear Propagation. AB - We study the nonlinear optical propagation of two different classes of light beams with space-varying polarization-radially symmetric vector beams and Poincare beams with lemon and star topologies-in a rubidium vapor cell. Unlike Laguerre-Gauss and other types of beams that quickly experience instabilities, we observe that their propagation is not marked by beam breakup while still exhibiting traits such as nonlinear confinement and self-focusing. Our results suggest that, by tailoring the spatial structure of the polarization, the effects of nonlinear propagation can be effectively controlled. These findings provide a novel approach to transport high-power light beams in nonlinear media with controllable distortions to their spatial structure and polarization properties. PMID- 27982640 TI - Momentum-Resolved Observation of Thermal and Quantum Depletion in a Bose Gas. AB - We report on the single-atom-resolved measurement of the distribution of momenta hk in a weakly interacting Bose gas after a 330 ms time of flight. We investigate it for various temperatures and clearly separate two contributions to the depletion of the condensate by their k dependence. The first one is the thermal depletion. The second contribution falls off as k^{-4}, and its magnitude increases with the in-trap condensate density as predicted by the Bogoliubov theory at zero temperature. These observations suggest associating it with the quantum depletion. How this contribution can survive the expansion of the released interacting condensate is an intriguing open question. PMID- 27982610 TI - Measurement of Singly Cabibbo Suppressed Decays Lambda_{c}^{+}->ppi^{+}pi^{-} and Lambda_{c}^{+}->pK^{+}K^{-}. AB - Using 567 pb^{-1} of data collected with the BESIII detector at a center-of-mass energy of sqrt[s]=4.599 GeV, near the Lambda_{c}^{+}Lambda[over -]_{c}^{-} threshold, we study the singly Cabibbo-suppressed decays Lambda_{c}^{+} >ppi^{+}pi^{-} and Lambda_{c}^{+}->pK^{+}K^{-}. By normalizing with respect to the Cabibbo-favored decay Lambda_{c}^{+}->pK^{-}pi^{+}, we obtain ratios of branching fractions: [B(Lambda_{c}^{+}->ppi^{+}pi^{-})/B(Lambda_{c}^{+}->pK^{ }pi^{+})]=(6.70+/-0.48+/-0.25)%, [B(Lambda_{c}^{+}->pphi)/B(Lambda_{c}^{+}->pK^{ }pi^{+})]=(1.81+/-0.33+/-0.13)%, and [B(Lambda_{c}^{+}->pK^{+}K_{non-phi}^{ })/B(Lambda_{c}^{+}->pK^{-}pi^{+})]=(9.36+/-2.22+/-0.71)*10^{-3}, where the uncertainties are statistical and systematic, respectively. The absolute branching fractions are also presented. Among these measurements, the decay Lambda_{c}^{+}->ppi^{+}pi^{-} is observed for the first time, and the precision of the branching fraction for Lambda_{c}^{+}->pK^{+}K_{non-phi}^{-} and Lambda_{c}^{+}->pphi is significantly improved. PMID- 27982641 TI - Erratum: Induced Magnetoelectric Response in Pnma Perovskites [Phys. Rev. Lett. 107, 197603 (2011)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.107.197603. PMID- 27982642 TI - Single-Shot Ternary Readout of Two-Electron Spin States in a Quantum Dot Using Spin Filtering by Quantum Hall Edge States. AB - We report on the single-shot readout of three two-electron spin states-a singlet and two triplet substates-whose z components of spin angular momentum are 0 and +1, in a gate-defined GaAs single quantum dot. The three spin states are distinguished by detecting spin-dependent tunnel rates that arise from two mechanisms: spin filtering by spin-resolved edge states and spin-orbital correlation with orbital-dependent tunneling. The three states form one ground state and two excited states, and we observe the spin relaxation dynamics among the three spin states. PMID- 27982644 TI - Neutrino Oscillations as a Probe of Light Scalar Dark Matter. AB - We consider a class of models involving interactions between ultralight scalar dark matter and standard model neutrinos. Such couplings modify the neutrino mass splittings and mixing angles to include additional components that vary in time periodically with a frequency and amplitude set by the mass and energy density of the dark matter. Null results from recent searches for anomalous periodicities in the solar neutrino flux strongly constrain the dark matter-neutrino coupling to be orders of magnitude below current and projected limits derived from observations of the cosmic microwave background. PMID- 27982646 TI - 1D to 3D Crossover of a Spin-Imbalanced Fermi Gas. AB - We have characterized the one-dimensional (1D) to three-dimensional (3D) crossover of a two-component spin-imbalanced Fermi gas of ^{6}Li atoms in a 2D optical lattice by varying the lattice tunneling and the interactions. The gas phase separates, and we detect the phase boundaries using in situ imaging of the inhomogeneous density profiles. The locations of the phases are inverted in 1D as compared to 3D, thus providing a clear signature of the crossover. By scaling the tunneling rate t with respect to the pair binding energy epsilon_{B}, we observe a collapse of the data to a universal crossover point at a scaled tunneling value of t[over ~]_{c}=0.025(7). PMID- 27982643 TI - Nanoscale "Dark State" Optical Potentials for Cold Atoms. AB - We discuss the generation of subwavelength optical barriers on the scale of tens of nanometers, as conservative optical potentials for cold atoms. These arise from nonadiabatic corrections to Born-Oppenheimer potentials from dressed "dark states" in atomic Lambda configurations. We illustrate the concepts with a double layer potential for atoms obtained from inserting an optical subwavelength barrier into a well generated by an off-resonant optical lattice, and discuss bound states of pairs of atoms interacting via magnetic dipolar interactions. The subwavelength optical barriers represent an optical "Kronig-Penney" potential. We present a detailed study of the band structure in optical Kronig-Penney potentials, including decoherence from spontaneous emission and atom loss to open "bright" channels. PMID- 27982647 TI - Physical Mechanism of the Transverse Instability in Radiation Pressure Ion Acceleration. AB - The transverse stability of the target is crucial for obtaining high quality ion beams using the laser radiation pressure acceleration (RPA) mechanism. In this Letter, a theoretical model and supporting two-dimensional (2D) particle-in-cell (PIC) simulations are presented to clarify the physical mechanism of the transverse instability observed in the RPA process. It is shown that the density ripples of the target foil are mainly induced by the coupling between the transverse oscillating electrons and the quasistatic ions, a mechanism similar to the oscillating two stream instability in the inertial confinement fusion research. The predictions of the mode structure and the growth rates from the theory agree well with the results obtained from the PIC simulations in various regimes, indicating the model contains the essence of the underlying physics of the transverse breakup of the target. PMID- 27982645 TI - Evidence for a Strong Topological Insulator Phase in ZrTe_{5}. AB - The complex electronic properties of ZrTe_{5} have recently stimulated in-depth investigations that assigned this material to either a topological insulator or a 3D Dirac semimetal phase. Here we report a comprehensive experimental and theoretical study of both electronic and structural properties of ZrTe_{5}, revealing that the bulk material is a strong topological insulator (STI). By means of angle-resolved photoelectron spectroscopy, we identify at the top of the valence band both a surface and a bulk state. The dispersion of these bands is well captured by ab initio calculations for the STI case, for the specific interlayer distance measured in our x-ray diffraction study. Furthermore, these findings are supported by scanning tunneling spectroscopy revealing the metallic character of the sample surface, thus confirming the strong topological nature of ZrTe_{5}. PMID- 27982648 TI - Versatile Method for Renormalized Stress-Energy Computation in Black-Hole Spacetimes. AB - We report here on a new method for calculating the renormalized stress-energy tensor (RSET) in black-hole (BH) spacetimes, which should also be applicable to dynamical BHs and to spinning BHs. This new method only requires the spacetime to admit a single symmetry. Thus far, we have developed three variants of the method, aimed for stationary, spherically symmetric, or axially symmetric BHs. We used this method to calculate the RSET of a minimally coupled massless scalar field in Schwarzschild and Reissner-Nordstrom backgrounds for several quantum states. We present here the results for the RSET in the Schwarzschild case in the Unruh state (the state describing BH evaporation). The RSET is type I at weak field, and becomes type IV at r?2.78M. Then we use the RSET results to explore violation of the weak and null energy conditions. We find that both conditions are violated all the way from r?4.9M to the horizon. We also find that the averaged weak energy condition is violated by a class of (unstable) circular timelike geodesics. Most remarkably, the circular null geodesic at r=3M violates the averaged null energy condition. PMID- 27982649 TI - Unexpectedly Enhanced Solubility of Aromatic Amino Acids and Peptides in an Aqueous Solution of Divalent Transition-Metal Cations. AB - We experimentally observed considerable solubility of tryptophan (Trp) in a CuCl_{2} aqueous solution, which could reach 2-5 times the solubility of Trp in pure water. Theoretical studies show that the strong cation-pi interaction between Cu^{2+} and the aromatic ring in Trp modifies the electronic distribution of the aromatic ring to enhance significantly the water affinity of Trp. Similar solubility enhancement has also been observed for other divalent transition-metal cations (e.g., Zn^{2+} and Ni^{2+}), another aromatic amino acid (phenylalanine), and three aromatic peptides (Trp-Phe, Phe-Phe, and Trp-Ala-Phe). PMID- 27982651 TI - Role of Frequency Chirp and Energy Flow Directionality in the Strong Coupling Regime of Brillouin-Based Plasma Amplification. AB - A detailed analysis is presented of the various stages of strong coupling Brillouin plasma amplification, emphasizing the importance of the chirp which can be of threefold origin: the intrinsic one driven by the amplification process, the one originating from the chirped-pulse-generated laser pulses, and the one associated with the plasma profile. Control of the overall chirp can optimize or quench the energy transfer. The time-dependent phase relation explains the energy flow direction during amplification and is characteristic for this strong coupling process. The study is also of potential importance to understand and maybe control cross-beam-energy transfer in inertial confinement fusion. PMID- 27982650 TI - Proving Nontrivial Topology of Pure Bismuth by Quantum Confinement. AB - The topology of pure Bi is controversial because of its very small (~10 meV) band gap. Here we perform high-resolution angle-resolved photoelectron spectroscopy measurements systematically on 14-202 bilayer Bi films. Using high quality films, we succeed in observing quantized bulk bands with energy separations down to ~10 meV. Detailed analyses on the phase shift of the confined wave functions precisely determine the surface and bulk electronic structures, which unambiguously show nontrivial topology. The present results not only prove the fundamental property of Bi but also introduce a capability of the quantum-confinement approach. PMID- 27982652 TI - Pressure Induced Stripe-Order Antiferromagnetism and First-Order Phase Transition in FeSe. AB - To elucidate the magnetic structure and the origin of the nematicity in FeSe, we perform a high-pressure ^{77}Se NMR study on FeSe single crystals. We find a suppression of the structural transition temperature with pressure up to about 2 GPa from the anisotropy of the Knight shift. Above 2 GPa, a stripe-order antiferromagnetism that breaks the spatial fourfold rotational symmetry is determined by the NMR spectra under different field orientations and with temperatures down to 50 mK. The magnetic phase transition is revealed to be first order type, implying the existence of a concomitant structural transition via a spin-lattice coupling. Stripe-type spin fluctuations are observed at high temperatures, and remain strong with pressure. These results provide clear evidence for strong coupling between nematicity and magnetism in FeSe, and therefore support a universal scenario of magnetic driven nematicity in iron based superconductors. PMID- 27982653 TI - Comment on "Nature of Long-Range Order in Stripe-Forming Systems with Long-Range Repulsive Interactions". PMID- 27982654 TI - Magnetic Excitations and Electronic Interactions in Sr_{2}CuTeO_{6}: A Spin-1/2 Square Lattice Heisenberg Antiferromagnet. AB - Sr_{2}CuTeO_{6} presents an opportunity for exploring low-dimensional magnetism on a square lattice of S=1/2 Cu^{2+} ions. We employ ab initio multireference configuration interaction calculations to unravel the Cu^{2+} electronic structure and to evaluate exchange interactions in Sr_{2}CuTeO_{6}. The latter results are validated by inelastic neutron scattering using linear spin-wave theory and series-expansion corrections for quantum effects to extract true coupling parameters. Using this methodology, which is quite general, we demonstrate that Sr_{2}CuTeO_{6} is an almost ideal realization of a nearest neighbor Heisenberg antiferromagnet but with relatively weak coupling of 7.18(5) meV. PMID- 27982655 TI - Induced-Charge Capacitive Deionization: The Electrokinetic Response of a Porous Particle to an External Electric Field. AB - We demonstrate the phenomenon of induced-charge capacitive deionization that occurs around a porous and conducting particle immersed in an electrolyte, under the action of an external electric field. The external electric field induces an electric dipole in the porous particle, leading to its capacitive charging by both cations and anions at opposite poles. This regime is characterized by a long charging time, which results in significant changes in salt concentration in the electrically neutral bulk, on the scale of the particle. We qualitatively demonstrate the effect of advection on the spatiotemporal concentration field, which, through diffusiophoresis, may introduce corrections to the electrophoretic mobility of such particles. PMID- 27982656 TI - Pattern Formation in Polymerizing Actin Flocks: Spirals, Spots, and Waves without Nonlinear Chemistry. AB - We propose a model solely based on actin treadmilling and polymerization which describes many characteristic states of actin-wave formation: spots, spirals, and traveling waves. In our model, as in experiments on cells recovering motility following actin depolymerization, we choose an isotropic low-density initial condition; polymerization of actin filaments then raises the density towards the Onsager threshold where they align. We show that this alignment, in turn, destabilizes the isotropic phase and generically induces transient actin spots or spirals as part of the dynamical pathway towards a polarized phase which can either be uniform or consist of a series of actin-wave trains (flocks). Our results uncover a universal route to actin-wave formation in the absence of any system-specific nonlinear biochemistry, and it may help to understand the mechanism underlying the observation of actin spots and waves in vivo. They also suggest a minimal setup to design similar patterns in vitro. PMID- 27982657 TI - Chaos in Chiral Condensates in Gauge Theories. AB - Assigning a chaos index for dynamics of generic quantum field theories is a challenging problem because the notion of a Lyapunov exponent, which is useful for singling out chaotic behavior, works only in classical systems. We address the issue by using the AdS/CFT correspondence, as the large N_{c} limit provides a classicalization (other than the standard h->0) while keeping nontrivial quantum condensation. We demonstrate the chaos in the dynamics of quantum gauge theories: The time evolution of homogeneous quark condensates ?q[over -]q? and ?q[over -]gamma_{5}q? in an N=2 supersymmetric QCD with the SU(N_{c}) gauge group at large N_{c} and at a large 't Hooft coupling lambda=N_{c}g_{YM}^{2} exhibits a positive Lyapunov exponent. The chaos dominates the phase space for energy density E?(6*10^{2})*m_{q}^{4}(N_{c}/lambda^{2}), where m_{q} is the quark mass. We evaluate the largest Lyapunov exponent as a function of (N_{c},lambda,E) and find that the N=2 supersymmetric QCD is more chaotic for smaller N_{c}. PMID- 27982658 TI - Erratum: Hanbury Brown-Twiss Interferometry at a Free-Electron Laser [Phys. Rev. Lett. 111, 034802 (2013)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.111.034802. PMID- 27982659 TI - Vortex Pinning and Dynamics in the Neutron Star Crust. AB - The nature of the interaction between superfluid vortices and the neutron star crust, conjectured by Anderson and Itoh in 1975 to be at the heart vortex creep and the cause of glitches, has been a long-standing question in astrophysics. Using a qualitatively new approach, we follow the dynamics as superfluid vortices move in response to the presence of "nuclei" (nuclear defects in the crust). The resulting motion is perpendicular to the force, similar to the motion of a spinning top when pushed. We show that nuclei repel vortices in the neutron star crust, and characterize the force per unit length of the vortex line as a function of the vortex element to the nucleus separation. PMID- 27982660 TI - Randomness Amplification under Minimal Fundamental Assumptions on the Devices. AB - Recently, the physically realistic protocol amplifying the randomness of Santha Vazirani sources producing cryptographically secure random bits was proposed; however, for reasons of practical relevance, the crucial question remained open regarding whether this can be accomplished under the minimal conditions necessary for the task. Namely, is it possible to achieve randomness amplification using only two no-signaling components and in a situation where the violation of a Bell inequality only guarantees that some outcomes of the device for specific inputs exhibit randomness? Here, we solve this question and present a device-independent protocol for randomness amplification of Santha-Vazirani sources using a device consisting of two nonsignaling components. We show that the protocol can amplify any such source that is not fully deterministic into a fully random source while tolerating a constant noise rate and prove the composable security of the protocol against general no-signaling adversaries. Our main innovation is the proof that even the partial randomness certified by the two-party Bell test [a single input-output pair (u^{*}, x^{*}) for which the conditional probability P(x^{*}|u^{*}) is bounded away from 1 for all no-signaling strategies that optimally violate the Bell inequality] can be used for amplification. We introduce the methodology of a partial tomographic procedure on the empirical statistics obtained in the Bell test that ensures that the outputs constitute a linear min-entropy source of randomness. As a technical novelty that may be of independent interest, we prove that the Santha-Vazirani source satisfies an exponential concentration property given by a recently discovered generalized Chernoff bound. PMID- 27982661 TI - Control of Spin Helix Symmetry in Semiconductor Quantum Wells by Crystal Orientation. AB - We investigate the possibility of spin-preserving symmetries due to the interplay of Rashba and Dresselhaus spin-orbit coupling in n-doped zinc-blende semiconductor quantum wells of general crystal orientation. It is shown that a conserved spin operator can be realized if and only if at least two growth direction Miller indices agree in modulus. The according spin-orbit field has in general both in-plane and out-of-plane components and is always perpendicular to the shift vector of the corresponding persistent spin helix. We also analyze higher-order effects arising from the Dresselhaus term, and the impact of our results on weak (anti)localization corrections. PMID- 27982662 TI - Time-Reversal-Breaking Weyl Fermions in Magnetic Heusler Alloys. AB - Weyl fermions have recently been observed in several time-reversal-invariant semimetals and photonics materials with broken inversion symmetry. These systems are expected to have exotic transport properties such as the chiral anomaly. However, most discovered Weyl materials possess a substantial number of Weyl nodes close to the Fermi level that give rise to complicated transport properties. Here we predict, for the first time, a new family of Weyl systems defined by broken time-reversal symmetry, namely, Co-based magnetic Heusler materials XCo_{2}Z (X=IVB or VB; Z=IVA or IIIA). To search for Weyl fermions in the centrosymmetric magnetic systems, we recall an easy and practical inversion invariant, which has been calculated to be -1, guaranteeing the existence of an odd number of pairs of Weyl fermions. These materials exhibit, when alloyed, only two Weyl nodes at the Fermi level-the minimum number possible in a condensed matter system. The Weyl nodes are protected by the rotational symmetry along the magnetic axis and separated by a large distance (of order 2pi) in the Brillouin zone. The corresponding Fermi arcs have been calculated as well. This discovery provides a realistic and promising platform for manipulating and studying the magnetic Weyl physics in experiments. PMID- 27982664 TI - The Health Information Technology Special Issue: current trends and future directions. PMID- 27982663 TI - How health plans promote health IT to improve behavioral health care. AB - OBJECTIVES: Given the large numbers of providers and enrollees with which they interact, health plans can encourage the use of health information technology (IT) to advance behavioral health care. The manner and extent to which commercial health plans promote health IT to improve behavioral health care is unknown. This study aims to address that gap. STUDY DESIGN: Cross-sectional study. METHODS: Data are from a nationally representative survey of commercial health plans regarding administrative and clinical dimensions of behavioral health services in 2010. Data are weighted to be representative of commercial managed care products in the United States (n = 8427; 88% response rate). Approaches within the domains of provider support, access to care, and assessment and treatment were investigated as examples of how health plans can promote health IT to improve behavioral health care delivery. RESULTS: Health plans were using health IT approaches in each domain. About a quarter of products offered financial support for electronic health records, but technical assistance was rare. Primary care providers could bill for e-mail contact with patients for behavioral health in about a quarter of products. Few products offered member-provider e-mail, and none offered online appointment scheduling. However, online referral systems and online provider directories were common, and nearly all offered an online self assessment tool; most offered online counseling and online personalized responses to questions or problems. CONCLUSIONS: In 2010, commercial health plans encouraged the use of health IT strategies for behavioral health care. Health plans have an important role to play for increasing health IT as a tool for behavioral health care. PMID- 27982665 TI - Building health IT capacity to improve HIV infection health outcomes. AB - Eighty-six percent of those engaged in HIV medical care in Massachusetts achieved viral suppression, making Massachusetts's long-term goal of eliminating new infections of HIV a real possibility. In order to achieve this goal, Massachusetts is working to engage all individuals living with HIV/AIDS in HIV medical care, keep them retained in care, and render their viral load non detectable. Currently, in Massachusetts, the data elements necessary to monitor the HIV care continuum are documented in siloed health information systems that do not communicate with each other. Massachusetts has engaged in a pilot project to enhance their health information technology (IT) capacity to monitor the HIV care continuum and identify gaps in care. Massachusetts Virtual Epidemiologic Network (MAVEN) will be enhanced to perform as a consolidated electronic system to document and triage clinic-, laboratory-, and patient-level surveillance, field epidemiology and HIV care continuum data. The consolidation will enhance identification of patients infected with HIV and provide timely, actionable data for engagement and retention in HIV medical care. PMID- 27982666 TI - Getting from here to there: health IT needs for population health. AB - The United States' decade-long transition from a paper- to technology-based information infrastructure has always been recognized as an initial step-a laying of the foundation-for future changes to the delivery of care. An increasingly important focal area for improvement is population health. Numerous policies and programs now require healthcare organizations to manage the risks, outcomes, utilization, and health of entire groups of individuals. Nonetheless, current health information technology (IT) systems are not ready to support population health improvements effectively and efficiently. Existing health IT systems were designed for organizations that are structurally, operationally, and culturally focused on individual care delivery, rather than improving health for a population. Opportunities exist to align health IT resources and population health management strategies to fill the gaps among technological capabilities, use and the emerging demands of population health. To realize this alignment, healthcare leaders must think differently about the types of data their organizations need, the types of partners with whom they share information, and how they can leverage new information and partnerships for evidence-based action. PMID- 27982667 TI - Accountable care organization hospitals differ in health IT capabilities. AB - OBJECTIVES: The aim of this study was to evaluate health information technology (IT) adoption in hospitals participating in accountable care organizations (ACOs) and compare this adoption to non-ACO hospitals. STUDY DESIGN: A cross-sectional sample of US nonfederal, acute care hospitals with data from 3 matched sources: the 2013 American Hospital Association (AHA) Annual Survey, the 2013 AHA Survey of Care Systems and Payments (CSP), and the 2014 AHA Information Technology Supplement. METHODS: To compare health IT adoption in ACO- and non-ACO hospitals, we created measures of Meaningful Use (MU) Stage 1 and Stage 2 core and menu criteria, patient engagement-oriented health IT, and health information exchange (HIE) participation. Adoption was compared using both naive and multivariate logit models. RESULTS: Of the 393 ACO hospitals and 810 non-ACO hospitals, a greater percentage of ACO hospitals were capable of meeting MU Stage 1 (50.9% vs 41.6%; P < .01) and Stage 2 (7.6% vs 4.8%; P < .05), having patient engagement health IT (39.8% vs 15.2%; P < .001), and participating in HIE (49.0% vs 30.1%; P < .001). In adjusted models, no difference was found between ACO and non-ACO hospital ability to meet MU Stage 1 or Stage 2, but ACO hospitals were more likely to have patient engagement health IT (odds ratio (OR), 2.20; 95% CI, 1.59 3.04) and be HIE participants (OR, 1.41; 95% CI, 1.03-1.92). CONCLUSIONS: ACO participating hospitals appear to be focused more on adopting health IT that aligns with broader strategic goals rather than those that achieve MU. Aligning adoption with quality and payment reform may be a productive path forward to encourage hospital health IT adoption behavior. PMID- 27982669 TI - Assessing electronic health record implementation challenges using item response theory. AB - OBJECTIVES: To assess the importance of commonly identified issues in electronic health record (EHR) implementation using item response theory (IRT). STUDY DESIGN: Secondary data from the 2012 American Hospital Association's Annual Survey Information Technology Supplement were used in the analyses. Results were compared and contrasted with the standard descriptive statistic frequencies that have been used to guide most recommendations made using the same data. METHODS: IRT was used to measure the magnitude of difficulty that particular challenges pose in implementing EHRs that meet federal guidelines for Meaningful Use. RESULTS: The IRT analyses yielded significantly different results from descriptive statistics in estimating the magnitude of specific EHR implementation challenges. In particular, IRT revealed that "obtaining physician cooperation" and "ongoing costs of maintaining and upgrading systems" were the most challenging implementation features. However, the frequency counts identified "upfront capital costs" and "complexity of meeting Meaningful Use criteria within implementation timeline" as the most challenging implementation features. CONCLUSIONS: For managers and policy makers, having an accurate assessment of EHR implementation challenges is essential to designing effective programs. IRT provides a statistical approach that allows prior studies to be assessed more accurately and future studies to retain the easier-to-use, check-all-that-apply survey structure while gaining valuable information. PMID- 27982668 TI - Data-driven clinical and cost pathways for chronic care delivery. AB - OBJECTIVES: This study illustrates a systematic methodology to embed medical costs into the exact flow of clinical events associated with chronic care delivery. We summarized and visualized the results using clinical and cost data, with the goal of empowering patients and care providers with actionable information as they navigate through a multitude of clinical events and medical expenses. STUDY DESIGN: We analyzed the electronic health records (EHRs) and medication cost data of 288 patients from 2009 to 2011, whose initial diagnoses included chronic kidney disease stage 3, hypertension, and diabetes. METHODS: We developed chronological pathways of care and costs for each patient from EHR and medication cost data. Using a data-driven method called clinical pathway (CP) learning, which leverages statistical machine-learning algorithms, we categorized patients into clinically similar subgroups based on progressing clinical complexity and associated care needs. The CP-based subgroups were compared against cost-based subgroups stratified by quartiles of total medication costs, and visualized via pathways that are color-coded by costs. RESULTS: Our methods identified 3 CP-based, and 4 cost-based, patient subgroups. Two sets of subgroups from each approach indicated some clinical similarity in terms of average statistics, such as number of diagnoses and medication needs. However, the CP based subgroups displayed significant variation in costs; conversely, large differences in clinical needs were observed among cost-based subgroups. CONCLUSIONS: This study demonstrates that CPs extracted from EHRs can be enhanced with appropriate cost information to potentially provide detailed visibility into the variability and inconsistencies in current best practices for chronic care delivery. PMID- 27982670 TI - Telemedicine and the sharing economy: the "Uber" for healthcare. AB - Telehealth platforms, which include both competitors and complements to traditional care delivery, will offer many benefits for both consumers and clinicians, and may promote increased specialization and competition in service delivery. Traditional medical services providers face a challenge similar to that faced by traditional taxicabs after Uber entered the marketplace: how to compete with a connection services platform that threatens to disrupt existing, regulated, and licensed service providers. PMID- 27982671 TI - Payer-provider patient registry utilized in a behavioral health home. AB - OBJECTIVES: As defined by the Affordable Care Act, health homes seek to improve healthcare coordination through data exchange and health information technologies; however, few examples of how to use such technology are available. The present effort describes a payer-provider patient registry for behavioral health home service. STUDY DESIGN: An observational study design was used to describe characteristics of individuals identified by the payer-provider patient registry. METHODS: In Pennsylvania, behavioral health agencies serve as health homes, with support by a behavioral health managed care organization (BHMCO) in the absence of a state waiver for health homes. The BHMCO initiates a priority patient registry monthly based on diagnoses for serious mental illness (SMI) and at least 1 chronic physical health condition. Providers contribute health data through a secure Web-based portal that become part of the registry and identify new participants. RESULTS: We identified 3759 individuals in the priority patient registry; 91% were identified by the payer. Most commonly, individuals with SMI were identified with hypertension (39%), asthma/chronic obstructive pulmonary disease (27%), hyperlipidemia (20%), and diabetes (18%). Annual behavioral health Medicaid expenditures for individuals in the 12 months prior to appearing on the registry averaged $14,685 per individual. Twelve percent of registry participants had annual behavioral health care expenditures over $25,000. CONCLUSIONS: The use of claims data and health assessment information can identify individuals presenting with complex healthcare needs that may benefit from behavioral health home service. PMID- 27982673 TI - US hospital engagement in core domains of interoperability. AB - OBJECTIVES: To assess US hospital engagement in the 4 core domains of interoperability (find, send, receive, integrate) and whether engaging in these domains is associated with electronic availability of clinical data from outside providers. STUDY DESIGN: Retrospective analysis of survey data. METHODS: Analysis of the American Hospital Association (AHA) Annual Survey of Hospitals and the American Hospital Association (AHA) Annual Survey of Hospitals - IT Supplement datasets for 2014. Respondents included 3307 US hospitals to the AHA Annual Survey - IT Supplement. We created measures of hospital engagement in 4 core domains of interoperability, as well as access to electronic clinical data from outside providers. Regression analysis was to identify hospital characteristics associated with each measure. RESULTS: Twenty-one percent of US hospitals engaged in all 4 interoperability domains, and 25% engaged in none. Hospitals engaged in all 4 domains were more likely to have a "basic" (odds ratio [OR], 3.53; P < .01) or "comprehensive" (OR, 5.04; P < .01) electronic health record (EHR) in comparison to a less than "basic" EHR, participate in a Regional Health Information Organization (OR, 4.29; P < .01), use a single EHR vendor (OR, 2.15; P < .01), and have a third-party health information exchange vendor (OR, 2.32; P < .01). They also differed by non-IT characteristics, such as medical home participation (OR, 1.77; P < .01). Hospitals that find (OR, 5.51; P < .01), receive (OR, 2.56; P < .01), or integrate (OR, 2.53; P < .01) information were more likely to report routine clinical information availability from outside providers. CONCLUSIONS: The one-fifth of US hospitals engaged in key domains of interoperability were more likely to have certain information technology infrastructure and participate in delivery reform. Encouragingly, interoperability engagement was associated with routine clinical information availability. Our results point to the need for ongoing efforts to expand interoperability, with the potential benefit of better information availability for clinicians and better care. PMID- 27982674 TI - Blood pressure and hemodynamics: Mayer waves in different phases of ovarian and menstrual cycle in women. AB - The goal of the research is to investigate the special effect of ovarian menstrual cycle phases on the level of women's blood pressure and characteristics of Mayer waves. 77 women aged 18-19 were tested under condition close to the state of basal metabolism in follicular phase (I), ovulation (II) and luteal phase (III) of ovarian-menstrual cycle. In phases II and III, the increase of mean and diastolic blood pressure level, in comparison with phase I in the prone position at rest and with psycho-emotional loading, were observed. The distinctions between variation parameters of R-R interval duration, stroke volume and its synchronization in phases II and III, in comparison with phase I, were observed in the prone position at rest, during tilt-test and with psycho emotional loading. The substantial level of relationship between the power of Mayer waves and mean and diastolic blood pressure, mainly in phase I under conditions of all types, is observed. The maximum peak amplitude of stroke volume spectrogram is associated with pressure levels in the range of 0.04-0.15 Hz (rho from -0.33 to -0.64). The obtained results indicate the possible participation of spontaneous baroreflex sensitivity characteristics in keeping blood pressure level in women. PMID- 27982672 TI - The effect of EHR-integrated patient-reported outcomes on satisfaction with chronic pain care. AB - OBJECTIVES: Given its complexity, chronic noncancer pain presents an opportunity to use health information technology (IT) to improve care experiences. The objective of this study was to assess whether integrating patient-reported outcomes (PROs) data in an electronic health record (EHR) affects provider and patient satisfaction with chronic noncancer pain care. STUDY DESIGN: We conducted a pragmatic cluster randomized trial involving 4 family medicine clinics. METHODS: We enrolled primary care providers (PCPs) and their patients with chronic noncancer pain. In the first 7 months (education phase), PCPs in intervention practices received education on how to use PROs for pain care. In the second 7 months (PRO phase), patients in intervention practices reported pain related outcomes on arrival at their visits. PROs were immediately reported to PCPs through the EHR. Control group PCPs provided usual care. We compared intervention and control practices in terms of provider and patient satisfaction with care. RESULTS: During the education phase, patients' mean ratings of their visits did not differ between control and intervention (9.33 vs 9.08; P = .20). During the PRO phase, patients' mean ratings did not differ between control and intervention (9.28 vs 9.01; P = .20). Similarly, there were no differences between the intervention and control groups in terms of provider satisfaction. CONCLUSIONS: Delivering EHR-integrated PROs did not consistently improve patient or provider satisfaction. Positively, we found no evidence that the PRO tools negatively affected satisfaction. Future studies and technological innovations are needed to translate point-of-care health IT tools into improvements in patient and provider experiences. PMID- 27982675 TI - Differential responsiveness in VEGF receptor subtypes to hypoxic stress in various tissues of plateau animals. AB - With hypoxic stress, hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) are elevated and their responses are altered in skeletal muscles of plateau animals [China Qinghai-Tibetan plateau pikas (Ochotona curzoniae)] as compared with control animals [normal lowland Sprague Dawley (SD) rats]. The results indicate that HIF-1alpha and VEGF are engaged in physiological functions under hypoxic environment. The purpose of the current study was to examine the protein levels of VEGF receptor subtypes (VEGFRs: VEGFR 1, VEGFR-2 and VEGFR-3) in the end organs, namely skeletal muscle, heart and lung in response to hypoxic stress. ELISA and Western blot analysis were employed to determine HIF-1alpha and the protein expression of VEGFRs in control animals and plateau pikas. We further blocked HIF-1alpha signal to determine if HIF-1alpha regulates alternations in VEGFRs in those tissues. We hypothesized that responsiveness of VEGFRs in the major end organs of plateau animals is differential with insult of hypoxic stress and is modulated by low oxygen sensitive HIF-1alpha. Our results show that hypoxic stress induced by exposure of lower O(2) for 6 h significantly increased the levels of VEGFR-2 in skeletal muscle, heart and lung and the increases were amplified in plateau pikas. Our results also demonstrate that hypoxic stress enhanced VEGFR-3 in lungs of plateau animals. Nonetheless, no significant alternations in VEGFR-1 were observed in those tissues with hypoxic stress. Moreover, we observed decreases of VEGFR-2 in skeletal muscle, heart and lung; and decreases of VEGFR-3 in lung following HIF 1alpha inhibition. Overall, our findings suggest that in plateau animals 1) responsiveness of VEGFRs is different under hypoxic environment; 2) amplified VEGFR-2 response appears in skeletal muscle, heart and lung, and enhanced VEGFR-3 response is mainly observed in lung; 3) HIF-1alpha plays a regulatory role in the levels of VEGFRs. Our results provide the underlying cellular and molecular mechanisms responsible for hypoxic environment in plateau animals, having an impact on research of physiological and ecological adaptive responses to acute or chronic hypoxic stress in humans who living at high attitude and who live at a normal sea level but suffer from hypoxic disorders. PMID- 27982677 TI - Pathophysiological mechanisms of calcineurin inhibitor-induced nephrotoxicity and arterial hypertension. AB - Solid organ transplantation is an established treatment modality in patients with end-stage organ damage in cases where other therapeutic options fail. The long term outcomes of solid organ transplant recipients have improved considerably since the introduction of the first calcineurin inhibitor (CNI) - cyclosporine. In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered. The immunosuppressive effects of CNIs result from the inhibition of interleukin-2 synthesis and reduced proliferation of T cells due to calcineurin blockade. The considerable side effects that are associated with CNIs therapy include arterial hypertension and nephrotoxicity. The focus of this article was to review the available literature on the pathophysiological mechanisms of CNIs that induce chronic nephrotoxicity and arterial hypertension. CNIs lead to activation of the major vasoconstriction systems, such as the renin-angiotensin and endothelin systems, and increase sympathetic nerve activity. On the other hand, CNIs are known to inhibit NO synthesis and NO-mediated vasodilation and to increase free radical formation. Altogether, these processes cause endothelial dysfunction and contribute to the impairment of organ function. A better insight into the mechanisms underlying CNI nephrotoxicity could assist in developing more targeted therapies of arterial hypertension or preventing CNI nephrotoxicity in organ transplant recipients, including heart transplantation. PMID- 27982676 TI - Lipasin/betatrophin is differentially expressed in liver and white adipose tissue without association with insulin resistance in Wistar and Goto-Kakizaki rats. AB - Lipasin is a recently identified lipokine expressed predominantly in liver and in adipose tissue. It was linked to insulin resistance in mice and to type 1 and type 2 diabetes (T1D, T2D) in humans. No metabolic studies concerning lipasin were performed yet in rats. Therefore, we used rat model of T2D and insulin resistance, Goto-Kakizaki (GK) rats, to determine changes of lipasin expression in liver and in white adipose tissue (WAT) over 52 weeks in the relation to glucose tolerance, peripheral tissue insulin sensitivity and adiposity. GK rats were grossly glucose intolerant since the age of 6 weeks and developed peripheral insulin resistance at the age of 20 weeks. Expression of lipasin in the liver did not differ between GK and Wistar rats, declining with age, and it was not related to hepatic triacylglycerol content. In WAT, the lipasin expression was significantly higher in Wistar rats where it correlated positively with adiposity. No such correlation was found in GK rats. In conclusion, lipasin expression was associated neither with a mild age-related insulin resistance (Wistar), nor with severe genetically-based insulin resistance (GK). PMID- 27982678 TI - Disparity between two-dimensional echocardiographic and electroanatomic left and right atrial volumes in patients undergoing catheter ablation for long-standing persistent atrial fibrillation. AB - Left atrial (LA) volume (LAV) is used for the selection of patients with atrial fibrillation (AF) to rhythm control strategies. Calculation of LAV from the LA diameters and areas by two-dimensional (2D) echocardiography may result in significant error. Accuracy of atrial volume assessment has never been studied in patients with long-standing persistent AF (LSPAF) and significant atrial remodeling. This study investigated correlation and agreement between 2D echocardiographic (Simpson method) and electroanatomic (CARTO, Biosense Webster) left and right atrial (RA) volumes (LAV(ECHO) vs. LAV(CARTO) and RAV(ECHO) vs. RAV(CARTO)) in patients undergoing catheter ablation for LSPAF. The study enrolled 173 consecutive subjects (females: 21 %, age: 59+/-9 years). There was only modest correlation between LAV(ECHO) (92+/-31 ml) and LAV(CARTO) (178+/-37 ml) (R=0.57), and RAV(ECHO) (71+/-29 ml) and RAV(CARTO) (173+/-34 ml) (R=0.42), respectively. LAV(ECHO) and RAV(ECHO) underestimated LAV(CARTO) and RAV(CARTO) with the absolute bias (+/-1.96 standard deviation) of -85 (-148; -22) ml and 102 (-169; -35) ml, respectively, and with the relative bias of -48 (-75; -21) % and -59 (-88; -30) %, respectively (all P<0.000001 for their mutual difference). Significant confounders of this difference were not identified. In patients with LSPAF, 2D echocardiography significantly underestimated both LA and RA volumes as compared with electroanatomic reference. This disagreement was independent of clinical, echocardiographic and mapping characteristics. PMID- 27982679 TI - Postnatal alteration of monocarboxylate transporter 1 expression in the rat corpus callosum. AB - In the central nervous system (CNS), monocarboxylate transporter 1 (MCT1) is expressed in astrocytes and endothelial cells but also in oligodendroglia. Oligodendroglia support neurons and axons through lactate transportation by MCT1. Limited information is available on the MCT1 expression changes in candidate cells in the developing rat brain, especially in corpus callosum which is the most vulnerable area in demyelinating diseases. In the present study, we investigated the expression pattern of MCT1 during postnatal development in the rat corpus callosum using immunofluorescene staining, Western blotting analysis and RT-PCR. We reported that MCT1 gene and protein were consistently expressed in the rat corpus callosum from birth to adult. MCT1/CNPase and MCT1/GFAP immunofluorescence staining demonstrated that most of MCT1 positive cells were co labeled with cyclic nucleotide 3' phosphodiesterase (CNPase) in rat corpus callosum from P7 to adult, whereas MCT1(+)/GFAP(+) cells preserve the dominate position before P7. Moreover, there were significant associations between the expression of MCT1 protein and the expression of myelin basic protein (MBP) (correlation coefficient: r=0.962, P=0.009) from P7 to adult. Similarly, the MCT1 mRNA expression was also significantly associated with MBP mRNA expression (r=0.976, P=0.005). Our results are proposing that in the developing brain white matter, MCT1 is predominately expressed in oligodendrocyte though it mainly expressed in astrocyte in early postnatal, which indicate that MCT1 may involve in the oligodendrocyte development and myelination. PMID- 27982680 TI - Distinct response of fat and gastrointestinal tissue to glucose in gestational diabetes mellitus and polycystic ovary syndrome. AB - Gestational diabetes mellitus (GDM) and polycystic ovary syndrome (PCOS) are distinct pathologies with impaired insulin sensitivity as a common feature. The aim of this study was to evaluate the response of fat tissue adipokines and gastrointestinal incretins to glucose load in patients diagnosed with one of the two disorders and to compare it with healthy controls. Oral glucose tolerance test (oGTT) was performed in 77 lean young women: 22 had positive history of GDM, 19 were PCOS patients, and 36 were healthy controls. Hormones were evaluated in fasting and in 60 min intervals during the 3 h oGTT using Bio-Plex ProHuman Diabetes 10-Plex Assay for C-peptide, ghrelin, GIP, GLP1, glucagon, insulin, leptin, total PAI1, resistin, visfatin and Bio-Plex ProHuman Diabetes Adipsin and Adiponectin Assays (Bio-Rad). Despite lean body composition, both PCOS and GDM women were more insulin resistant than controls. Significant postchallenge differences between the GDM and PCOS groups were observed in secretion of adipsin, leptin, glucagon, visfatin, ghrelin, GIP, and also GLP1 with higher levels in GDM. Conversely, PCOS was associated with the highest resistin, C peptide, and PAI1 levels. Our data suggest that decreased insulin sensitivity observed in lean women with GDM and PCOS is associated with distinct hormonal response of fat and gastrointestinal tissue to glucose load. PMID- 27982681 TI - Background levels of neomorphic 2-hydroxyglutarate facilitate proliferation of primary fibroblasts. AB - Each cell types or tissues contain certain "physiological" levels of R-2 hydroxyglutarate (2HG), as well as enzymes for its synthesis and degradation. 2HG accumulates in certain tumors, possessing heterozygous point mutations of isocitrate dehydrogenases IDH1 (cytosolic) or IDH2 (mitochondrial) and contributes to strengthening their malignancy by inhibiting 2-oxoglutarate dependent dioxygenases. By blocking histone de-methylation and 5-methyl-cytosine hydroxylation, 2HG maintains cancer cells de-differentiated and promotes their proliferation. However, physiological 2HG formation and formation by non-mutant IDH1/2 in cancer cells were neglected. Consequently, low levels of 2HG might play certain physiological roles. We aimed to elucidate this issue and found that compared to highest 2HG levels in hepatocellular carcinoma HepG2 cells and moderate levels in neuroblastoma SH-SY5Y cells, rat primary fibroblast contained low basal 2HG levels at early passages. These levels increased at late passage and likewise 2HG/2OG ratios dropped without growth factors and enormously increased at hypoxia, reaching levels compared to cancer HepG2 cells. Responses in SH-SY5Y cells were opposite. Moreover, external 2HG supplementation enhanced fibroblast growth. Hence, we conclude that low 2HG levels facilitate cell proliferation in primary fibroblasts, acting via hypoxia-induced factor regulations and epigenetic changes. PMID- 27982682 TI - Acrylamide: a common food toxin related to physiological functions and health. AB - Acrylamide (AA) is a highly reactive organic compound capable of polymerization to form polyacrylamide, which is commonly used throughout a variety of industries. Given its toxic effect on humans and animals, the last 20 years have seen an increased interest in research devoted to the AA. One of the main sources of AA is food. AA appears in heated food following the reaction between amino acids and reduced sugars. Large concentrations of AA can be found in popular staples such as coffee, bread or potato products. An average daily consumption of AA is between 0.3-2.0 microg/kg b.w. Inhalation of acrylamide is related with occupational exposure. AA delivered with food is metabolized in the liver by cytochrome P450. AA biotransformation and elimination result in formation of toxic glycidamide (GA). Both, AA and GA can be involved in the coupling reaction with the reduced glutathione (GSH) forming glutathione conjugates which are excreted with urine. Biotransformation of AA leads to the disturbance in the redox balance. Numerous research proved that AA and GA have significant influence on physiological functions including signal propagation in peripheral nerves, enzymatic and hormonal regulation, functions of muscles, reproduction etc. In addition AA and GA show neurotoxic, genotoxic and cancerogenic properties. In 1994, International Agency for Research on Cancer (IARC) classified acrylamide as a potentially carcinogenic substance to human. PMID- 27982683 TI - The in vivo effects of adenine-induced chronic kidney disease on some renal and hepatic function and CYP450 metabolizing enzymes. AB - Adenine-induced model of chronic kidney disease (CKD) is a widely used model especially in studies testing novel nephroprotective agents. We investigated the effects of adenine-induced CKD in rats on the activities of some xenobiotic metabolizing enzymes in liver and kidneys, and on some in vivo indicators of drug metabolism (viz pentobarbitone sleeping time, and plasma concentration of theophylline 90 min post administration). CKD was induced by orally feeding adenine (0.25 % w/w) for 35 days. Adenine induced all the characteristics of CKD, which was confirmed by biochemical and histological findings. Glutathione concentration and activities of some enzymes involved in its metabolism were reduced in kidneys and livers of rats with CKD. Renal CYP450 1A1 activity was significantly inhibited by adenine, but other measured isoenzymes (1A2, 3A4 and 2E1) were not significantly affected. Adenine significantly prolonged pentobarbitone-sleeping time and increased plasma theophylline concentration 90 min post administration. Adenine also induced a moderate degree of hepatic damages as indicated histologically and by significant elevations in some plasma enzymes. The results suggest that adenine-induced CKD is associated with significant in vivo inhibitory activities on some drug-metabolizing enzymes, with most of the effect on the kidneys rather than the liver. PMID- 27982684 TI - Nesfatin-1 influences the excitability of gastric distension-responsive neurons in the ventromedial hypothalamic nucleus of rats. AB - The present study investigated the effects of nesfatin-1 on gastric distension (GD)-responsive neurons via an interaction with corticotropin-releasing factor (CRF) receptor signaling in the ventromedial hypothalamic nucleus (VMH), and the potential regulation of these effects by hippocampal projections to VMH. Extracellular single-unit discharges were recorded in VHM following administration of nesfatin-1. The projection of nerve fibers and expression of nesfatin-1 were assessed by retrograde tracing and fluoro-immunohistochemical staining, respectively. Results showed that there were GD-responsive neurons in VMH; Nesfatin-1 administration and electrical stimulation of hippocampal CA1 sub region altered the firing rate of these neurons. These changes could be partially blocked by pretreatment with the non-selective CRF antagonist astressin-B or an antibody to NUCB2/nesfatin-1. Electrolytic lesion of CA1 hippocampus reduced the effects of nesfatin-1 on VMH GD-responsive neuronal activity. These studies suggest that nesfatin-1 plays an important role in GD-responsive neuronal activity through interactions with CRF signaling pathways in VMH. The hippocampus may participate in the modulation of nesfatin-1-mediated effects in VMH. PMID- 27982685 TI - Responses of skeletal muscle hypertrophy in Wistar rats to different resistance exercise models. AB - This study aimed to compare the effects of three different resistance exercise models on the quadriceps muscle cross-sectional area, as well as on mTOR phosphorylation and other pivotal molecules involved in the upstream regulation of mTOR. Twenty-four male Wistar rats were divided into untrained (control), endurance resistance training, strength resistance training, and hypertrophy resistance training (HRT) groups (n=6). After 12 weeks of training, the red portion of the quadriceps was removed for histological and Western blot analyses. The results showed that the quadriceps weight and cross-sectional areas in the exercised groups were higher than those of the untrained rats. However, the HRT group presented better results than the other two experimental groups. This same pattern was observed for mTOR phosphorylation and for the most pivotal molecules involved in the upstream control of mTOR (increase of PKB, 14-3-3, ERK, p38 MAPK, and 4E-BP1 phosphorylation, and reduction of tuberin, sestrin 2, REDD1, and phospho AMPK). In summary, our study showed that HRT leads to high levels of mTOR phosphorylation as well as of other proteins involved in the upstream regulation of mTOR. PMID- 27982686 TI - The expression levels of Notch-related signaling molecules in pulmonary microvascular endothelial cells in bleomycin-induced rat pulmonary fibrosis. AB - Previous studies have suggested that the Notch signaling pathway plays a very important role in the proliferation and differentiation of pulmonary microvascular endothelial cells (PMVECs). Therefore, we aimed to investigate the expression level of Notch-related signaling molecules in PMVECs in bleomycin (BLM)-induced rat pulmonary fibrosis. Immunohistochemistry, immunofluorescence, Western blotting, and real-time PCR were used to analyze the differences in protein and mRNA expression levels of Notch-related signaling molecules, i.e. Notch1, Jagged1, Delta-like ligand 4 (Dll4), and hairy and enhancer of split homolog 1 (Hes1), between a control group treated with intratracheal instillation of saline and a study group treated with intratracheal instillation of BLM solution. Expression levels of the receptor Notch1 and one of its ligands, Jagged1, were upregulated, while the expression levels of the ligand Dll4 and the target molecule of the Notch signaling pathway, Hes1, were downregulated. The differences in protein and mRNA expression levels between the control and study groups were significant (p<0.001). The Jagged1/Notch1 signaling pathway is activated in the pathogenesis of BLM-induced rat pulmonary fibrosis, while the Dll4/Notch1 signaling pathway is inhibited, which inhibits the suppressive effect of Dll4/Notch1 signaling on PMVEC overproliferation, further causing PMVEC dysfunction in cell sprouting and maturation as well as abnormal differentiation of the cell phenotype. Conversely, the down-expression of Hes1 indicates that the Jagged1/Notch1 signaling pathway could be a non-canonical Notch signaling pathway independent of Hes1 activation, which differs from the canonical Dll4/Notch1 signaling pathway. PMID- 27982687 TI - Angiotensinogen and interleukin-18 as markers of chronic kidney damage in children with a history of hemolytic uremic syndrome. AB - Hemolytic uremic syndrome (HUS) is a type of thrombotic microangiopathy, in the course of which some patients may develop chronic kidney disease (CKD). It is clinically important to investigate the markers of a poor prognosis. The levels of angiotensinogen (AGT) and interleukin-18 (IL-18) in serum and urine were evaluated. Study was conducted in 29 children with a history of HUS. Serum and urine AGT concentration was significantly higher in children after HUS as compared to the control group. No differences depending on the type of HUS and gender were noted. The serum concentration of IL-18 in children after HUS was significantly lower, whereas in urine did not differ significantly between the sick and healthy children. A negative correlation between the concentration of AGT in serum and albuminuria in patients after HUS was detected. The results indicate that the concentration of AGT in serum and urine in children after HUS increases, which may indicate the activation of the intrarenal renin-angiotensin aldosterone system. The statement, that AGT may be a good biomarker of CKD after acute kidney injury due to HUS requires prospective studies with follow-up from the acute phase of the disease on a larger group of patients. Reduced IL-18 serum concentration in children after HUS with no difference in its urine concentration may indicate a loss of the protective effects of this cytokine on renal function due to previously occurred HUS. PMID- 27982688 TI - Aerobic exercise of low to moderate intensity corrects unequal changes in BK(Ca) subunit expression in the mesenteric arteries of spontaneously hypertensive rats. AB - Accumulating evidence indicates that hypertension is associated with "ion channel remodeling" of vascular smooth muscle cells (VSMCs). The objective of this study was to determine the effects of exercise intensity/volume on hypertension associated changes in large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels in mesenteric arteries (MAs) from spontaneously hypertensive rats (SHR). Male SHRs were randomly assigned to three groups: a low-intensity aerobic exercise group (SHR-L: 14 m/min), a moderate-intensity aerobic exercise group (SHR-M: 20 m/min), and a sedentary group (SHR). Age-matched Wistar-Kyoto rats (WKYs) were used as normotensive controls. Exercise groups completed an 8-week exercise program. Elevation of the alpha and beta1 proteins was unequal in MA myocytes from SHRs, with the beta1 subunit increasing more than the alpha subunit. BK(Ca) contribution to vascular tone regulation was higher in the myocytes and arteries of SHRs compared to WKYs. SHR BK(Ca) channel subunit protein expression, beta1/alpha ratio, whole cell current density and single-channel open probability was also increased compared with WKYs. Aerobic exercise lowered systemic blood pressure and normalized hypertension-associated BK(Ca) alterations to normotensive control levels in the SHRs. These effects were more pronounced in the moderate-intensity group than in the low-intensity group. There is a dose effect for aerobic exercise training in the range of low to moderate-intensity and accompanying volume for the correction of the pathological adaptation of BK(Ca) channels in myocytes of MAs from SHR. PMID- 27982689 TI - The effect of Laurus nobilis on the blood and lenses antioxidant activity in rabbit under fat-enriched diet. AB - Fat-enriched diet is strongly associated with cataract development. Laurus nobilis shows antioxidant activity. Herein we evaluated the effect of Laurus nobilis oral administration on the blood and lenses antioxidant activity in rabbits under fat-enriched diet. Sixty rabbits divided into 4 groups were used. One group represented the control (N-CTR). The second group (P-CTR) fed a diet supplemented with 2.5 % of pig fat; the third group (EXP1) received a diet supplemented with 2.5 % of pig fat and 1 g/kg of dried-bay leaves; the fourth group (EXP2) was treated with dried-bay leaves at the rate of 1 g/kg of feed. At baseline and at the end of the study (56 days) the following blood parameters were determined: thiobarbituric acid reactive substances (TBARS), reactive oxygen metabolites (ROMs), total phenols, superoxide dismutase (SOD), oxygen radical absorbance capacity (ORAC(pca)), ferric ion reducing antioxidant power (FRAP), retinol and alfa-tocopherol. At the end of the follow-up, the eyes were enucleated and the antioxidant profile, such as total antioxidant activity (TAC), TBARS, retinol and alfa-tocopherol of lenses was evaluated. Plasma ROMs and TBARS levels were statistically lower in the groups receiving bay leaves integration. A significant increase of plasma retinol, FRAP and ORAC(pca) levels was found in EXP1 and EXP2 groups, whereas plasma alfa-tocopherol resulted statistically higher only in EXP2 group. Bay leaves supplementation enhanced TAC, retinol and alfa-tocopherol in rabbit lens, particularly in EXP2 group; whereas lenses TBARS levels significantly decreased in both treated groups. These findings demonstrate that Laurus nobilis oral administration exerts a protective effect on the risk of cataract development in rabbits under fat-enriched diet. PMID- 27982690 TI - Mitochondrial adaptations in aged skeletal muscle: effect of exercise training. AB - The aging process is associated with a decline in mitochondrial functions. Mitochondria dysfunction is involved in initiation and progression of many health problems including neuromuscular, metabolic and cardiovascular diseases. It is well known that endurance exercise improves mitochondrial function, especially in the elderly. However, recent studies have demonstrated that resistance training lead also to substantial increases in mitochondrial function in skeletal muscle. A comprehensive understanding of the cellular mechanisms involved in the skeletal muscle mitochondrial adaptations to exercise training in healthy elderly subjects, can help practitioners to design and prescribe more effective exercise trainings. PMID- 27982691 TI - No Evidence for Long-Term Causal Associations Between Symptoms of Premature Ejaculation and Symptoms of Anxiety, Depression, and Sexual Distress in a Large, Population-Based Longitudinal Sample. AB - Premature ejaculation (PE) is one of the most common male sexual complaints, but its etiology is unclear. Psychological problems, such as symptoms of anxiety and depression, have traditionally been seen as causal or maintaining etiological components of PE, and previous cross-sectional studies have found weak positive associations between them. The aim of the present study was to test possible causal pathways over time between PE and symptoms of the psychological problems anxiety, depression, and sexual distress. A sample of 985 male Finnish twins and brothers of twins completed a questionnaire in 2006 and 2012. Significant bivariate correlations were found both within and across time between PE and the psychological problems. When fitting structural equation models to test hypothesized causal pathways, symptoms of anxiety and sexual distress at the first measurement time point did not predict future PE. Likewise, PE symptoms at the first measurement did not predict increments or decrements in anxiety, sexual distress, or depression later on. These null findings regarding hypothesized associations may partly be explained by the relatively long time between measurements, or that the measures possibly did not capture the aspects of anxiety that are related to PE. PMID- 27982692 TI - Genetic evaluation of weekly body weight in Japanese quail using random regression models. AB - 1. A total of 11 826 records from 2489 quails, hatched between 2012 and 2013, were used to estimate genetic parameters for BW (body weight) of Japanese quail using random regression models. Weekly BW was measured from hatch until 49 d of age. WOMBAT software (University of New England, Australia) was used for estimating genetic and phenotypic parameters. 2. Nineteen models were evaluated to identify the best orders of Legendre polynomials. A model with Legendre polynomial of order 3 for additive genetic effect, order 3 for permanent environmental effects and order 1 for maternal permanent environmental effects was chosen as the best model. 3. According to the best model, phenotypic and genetic variances were higher at the end of the rearing period. Although direct heritability for BW reduced from 0.18 at hatch to 0.12 at 7 d of age, it gradually increased to 0.42 at 49 d of age. It indicates that BW at older ages is more controlled by genetic components in Japanese quail. 4. Phenotypic and genetic correlations between adjacent periods except hatching weight were more closely correlated than remote periods. The present results suggested that BW at earlier ages, especially at hatch, are different traits compared to BW at older ages. Therefore, BW at earlier ages could not be used as a selection criterion for improving BW at slaughter age. PMID- 27982693 TI - Long Noncoding RNA DANCR Is a Positive Regulator of Proliferation and Chondrogenic Differentiation in Human Synovium-Derived Stem Cells. AB - Cartilage tissues have limited capacity for repair after damage and then cause osteoarthritis, so finding alternative treatment is ongoing. Mesenchymal stem cells (MSCs) have become a promising therapy for cartilage damage and diseases due to the advantages of easy separation, high proliferative potentiality, and genetic stability. Synovium-derived MSCs (SMSCs) have been recognized as an ideal source for cartilage repair. In our previous study, we found that Sox4 promoted proliferation and chondrogenesis of SMSCs through upregulation of long noncoding RNA (lncRNA) DANCR. However, the exact molecular mechanism by which DANCR promotes proliferation and chondrogenesis of SMSCs remains unknown. In the present study, we investigated the effect of lncRNA DANCR on the proliferation and chondrogenesis of SMSCs. We found that overexpression of DANCR could promote proliferation and chondrogenesis of SMSCs, while knockdown of DANCR had the opposite effect. Moreover, our data demonstrated that DANCR directly interacted with myc, Smad3, and STAT3 mRNA to regulate their stability. Finally, we found that the promotion of SMSC proliferation induced by DANCR depended on myc. Also, DANCR activated chondrogenesis of SMSCs via upregulation of Smad3 and STAT3 expression. Our growing knowledge of the role of DANCR is pointing toward its potential use as a novel therapeutic approach for cartilage damage and diseases. PMID- 27982694 TI - Cigarette smoke and decreased oxygen tension inhibit pulmonary claudin-6 expression. AB - PURPOSE: Chronic obstructive pulmonary disease is a condition involving perturbed barrier integrity coincident with both emphysema and inflammation of the airways, and smoking is considered a major risk factor. Claudins (Cldns) stabilize barriers and contribute to tight junctions by preventing paracellular transport of extracellular fluid constituents. METHODS: To determine Cldn6 was differentially influenced by tobacco smoke, Cldn6 was evaluated in cells and tissues by q-PCR, immunoblotting, and immunohistochemistry following exposure. Cldn6 transcriptional regulation was also assessed using luciferase reporter constructs. RESULTS: Q-PCR and immunoblotting revealed that Cldn6 was decreased in alveolar type II-like epithelial cells (A549) and primary small airway epithelial cells when exposed to cigarette smoke extract (CSE). Cldn6 was also markedly decreased in the lungs of mice exposed to acute tobacco smoke delivered by a nose-only automated smoke machine compared to controls. Luciferase reporter assays incorporating 0.5-kb, 1.0-kb, or 2.0-kb of the Cldn6 promoter revealed decreased transcription of Cldn6 following exposure to CSE. Cldn6 transcriptional regulation was also assessed in hypoxic conditions due to low oxygen tension observed during smoking. Hypoxia and hypoxia inducible factor-1 alpha caused decreased transcription of the Cldn6 gene via interactions with putative response elements in the proximal promoter sequence. CONCLUSIONS: These data reveal that tight junctional proteins such as Cldn6 are differentially regulated by tobacco smoke exposure and that Cldns are potentially targeted when epithelial cells respond to tobacco smoke. Further research may show that Cldns expressed in tight junctions between parenchymal cells contribute to impaired structural integrity of the lung coincident with smoking. PMID- 27982695 TI - 17-DMAG Protects Against Hypoxia-/Reoxygenation-Induced Cell Injury in HT22 Cells Through Akt/Nrf2/HO-1 Pathway. AB - Oxidative stress is well known to play a pivotal role in hypoxia/reoxygenation (H/R)-induced neuron injury. On the basis of this fact, antioxidative agents have been demonstrated to be neuroprotective. 17-DMAG (HSP90 inhibitor) is reported to have neuroprotective effects in vitro, which may interfere with oxidative stress through reduction in pro-oxidative factors. However, little is known about its effects on H/R-induced neuron injury and the underlying mechanisms. In this study, the effects of 17-DMAG on H/R-treated HT22 cells were investigated. MTT and lactate dehydrogenase (LDH) assays indicated that 17-DMAG led to a dose dependent recovery of cell viability in H/R-treated HT22 cells. Flow cytometry demonstrated that 17-DMAG inhibited the cell apoptosis induced by H/R in HT22 cells. In addition, Western blot and real-time reverse transcription-polymerase chain reaction indicated that 17-DMAG inhibited the H/R-induced upregulation of Bax/Bcl-2 ratio and cleaved caspase-3 expression. Moreover, our results demonstrated that 17-DMAG promoted the expression of antioxidant enzymes, including manganese superoxide dismutase, catalase, and glutathione peroxidase. As a result, 17-DMAG might resist to H/R-induced oxidative stress. Furthermore, 17-DMAG increased the expression of phosphorylation of Akt (p-Akt) and the heme oxygenase-1 (HO-1), as well as the translocation of nuclear factor erythroid 2 related factor 2 (Nrf2) in H/R-treated HT22 cells. However, the Akt inhibitor, LY294002, partially hampered the effects of 17-DMAG on the expression of p-Akt, nuclear Nrf2, and HO-1 and cell viability, as well as cell apoptosis induced by H/R in HT22 cells. In conclusion, the findings of our study thus demonstrate that 17-DMAG protects against H/R-induced HT22 cell injury through Akt/Nrf2/HO-1 pathway, which may be associated with its antiapoptotic and antioxidative stress effects. PMID- 27982696 TI - Theoretical and Empirical Analysis of a Spatial EA Parallel Boosting Algorithm. AB - Many real-world problems involve massive amounts of data. Under these circumstances learning algorithms often become prohibitively expensive, making scalability a pressing issue to be addressed. A common approach is to perform sampling to reduce the size of the dataset and enable efficient learning. Alternatively, one customizes learning algorithms to achieve scalability. In either case, the key challenge is to obtain algorithmic efficiency without compromising the quality of the results. In this article we discuss a meta learning algorithm (PSBML) that combines concepts from spatially structured evolutionary algorithms (SSEAs) with concepts from ensemble and boosting methodologies to achieve the desired scalability property. We present both theoretical and empirical analyses which show that PSBML preserves a critical property of boosting, specifically, convergence to a distribution centered around the margin. We then present additional empirical analyses showing that this meta level algorithm provides a general and effective framework that can be used in combination with a variety of learning classifiers. We perform extensive experiments to investigate the trade-off achieved between scalability and accuracy, and robustness to noise, on both synthetic and real-world data. These empirical results corroborate our theoretical analysis, and demonstrate the potential of PSBML in achieving scalability without sacrificing accuracy. PMID- 27982697 TI - On the Effectiveness of Sampling for Evolutionary Optimization in Noisy Environments. AB - In real-world optimization tasks, the objective (i.e., fitness) function evaluation is often disturbed by noise due to a wide range of uncertainties. Evolutionary algorithms are often employed in noisy optimization, where reducing the negative effect of noise is a crucial issue. Sampling is a popular strategy for dealing with noise: to estimate the fitness of a solution, it evaluates the fitness multiple ([Formula: see text]) times independently and then uses the sample average to approximate the true fitness. Obviously, sampling can make the fitness estimation closer to the true value, but also increases the estimation cost. Previous studies mainly focused on empirical analysis and design of efficient sampling strategies, while the impact of sampling is unclear from a theoretical viewpoint. In this article, we show that sampling can speed up noisy evolutionary optimization exponentially via rigorous running time analysis. For the (1[Formula: see text]1)-EA solving the OneMax and the LeadingOnes problems under prior (e.g., one-bit) or posterior (e.g., additive Gaussian) noise, we prove that, under a high noise level, the running time can be reduced from exponential to polynomial by sampling. The analysis also shows that a gap of one on the value of [Formula: see text] for sampling can lead to an exponential difference on the expected running time, cautioning for a careful selection of [Formula: see text]. We further prove by using two illustrative examples that sampling can be more effective for noise handling than parent populations and threshold selection, two strategies that have shown to be robust to noise. Finally, we also show that sampling can be ineffective when noise does not bring a negative impact. PMID- 27982698 TI - Salmonella enterica Serotype Napoli is the First Cause of Invasive Nontyphoidal Salmonellosis in Lombardy, Italy (2010-2014), and Belongs to Typhi Subclade. AB - Salmonella enterica serotype Napoli (S. Napoli) is currently emerging in Europe and particularly in Italy, where in 2014 it caused a large outbreak associated with elevated rates of bacteremia. However, no study has yet investigated its invasive ability and phylogenetic classification. Here, we show that between 2010 and 2014, S. Napoli was the first cause of invasive salmonellosis affecting 40 cases out of 687 (invasive index: 5.8%), which is significantly higher than the invasive index of all the other nontyphoidal serotypes (2.0%, p < 0.05). Genomic and phylogenetic analyses of an invasive isolate revealed that S. Napoli belongs to Typhi subclade in clade A, Paratyphi A being the most related serotype and carrying almost identical pattern of typhoid-associated genes. This work presents evidence of invasive capacity of S. Napoli and argues for reconsideration of its nontyphoidal category. PMID- 27982700 TI - (Re)evaluating the Implications of the Autoregressive Latent Trajectory Model Through Likelihood Ratio Tests of Its Initial Conditions. AB - The autoregressive latent trajectory (ALT) model synthesizes the autoregressive model and the latent growth curve model. The ALT model is flexible enough to produce a variety of discrepant model-implied change trajectories. While some researchers consider this a virtue, others have cautioned that this may confound interpretations of the model's parameters. In this article, we show that some-but not all-of these interpretational difficulties may be clarified mathematically and tested explicitly via likelihood ratio tests (LRTs) imposed on the initial conditions of the model. We show analytically the nested relations among three variants of the ALT model and the constraints needed to establish equivalences. A Monte Carlo simulation study indicated that LRTs, particularly when used in combination with information criterion measures, can allow researchers to test targeted hypotheses about the functional forms of the change process under study. We further demonstrate when and how such tests may justifiably be used to facilitate our understanding of the underlying process of change using a subsample (N = 3,995) of longitudinal family income data from the National Longitudinal Survey of Youth. PMID- 27982699 TI - "It's Not JUST Skin Cancer": Understanding Their Cancer Experience From Melanoma Survivor Narratives Shared Online. AB - Cancer survivors narrate their experiences in unique ways, articulating different aspects of the cancer journey. The purpose of this study was to analyze the content of cancer narratives that melanoma survivors share online in order to present the ways that survivors narrate their cancer experience, to identify survivors' motivations for sharing, and to better understand the ways in which survivors are impacted by and cope with the diagnosis and treatment of cancer. The sample consisted of 95 unique melanoma survivor narratives, accessed from the Melanoma Research Foundation in November 2015, that were inductively and deductively coded for key themes and subthemes. Emergent themes described different aspects of the melanoma experience during prediagnosis (identification of self-phenotype, searching for causes, suspicious findings, delay in diagnosis), diagnosis (communication of diagnosis, emotional responses), transition from diagnosis to beginning treatment (second opinion), treatment (positive reframing of attitude, proactive cancer management, side effects), and posttreatment phases (social support, vigilance behaviors posttreatment). Two themes that cut across all phases of the cancer journey included recognizing and dealing with uncertainty and survivors' motive for sharing narrative. These findings have implications for understanding how melanoma survivors may benefit personally from sharing their cancer experience online and for the potential for survivor narratives to motivate behavior change and facilitate coping among readers. PMID- 27982701 TI - Dutch Adolescents' Motives, Perceptions, and Reflections Toward Sex-Related Internet Use: Results of a Web-Based Focus-Group Study. AB - The Internet offers adolescents unique opportunities to actively shape their own sexual media environment. The aim of this study was to gain in-depth insight into Dutch adolescents' motives, perceptions, and reflections toward Internet use for (a) finding information or advice related to romance and sexuality; (b) searching for and viewing pornographic or erotic material; and (c) romantic and sexual communication (i.e., cybersex/sexting). Data were collected through 12 Web-based focus groups (36 adolescents aged 16 to 19 years, 72.2% girls) and analyzed through three stages of open, axial, and selective coding. The themes that emerged from the focus-group discussions suggest that sex-related Internet use is a complex and ambivalent experience for adolescents. Sex-related Internet use seems an increasingly normalized and common phenomenon. Participants perceived the Internet as a useful source of sexual information, stimulation, inspiration, and communication. Yet they discussed a range of negative consequences and risks related to sex-related online behaviors, particularly concerning pornography's potential to create unrealistic expectations about sex and sexual attractiveness. Participants generally believed they had the necessary skills to navigate through the online sexual landscape in a responsible way, although they believed other young people could be influenced inadvertently and adversely by sex-related online content. PMID- 27982702 TI - Assessing U.S. Health Journalists' Beliefs About Medical Overtreatment and the Impact of Related News Coverage. AB - The United States spends more on health care than any other country in the world, but often experiences poorer health outcomes and lower patient satisfaction than other developed countries. One possible explanation for this paradox is overtreatment, the use of medical tests and treatment for which harms outweigh benefits. Because journalists play a key role in informing people about the health care system, including issues such as overtreatment, it is important to understand how they define the issue and its importance. This qualitative study of health news journalists offers an analysis of journalists' perspectives on overtreatment coverage. The interviews produced four major themes in regard to journalists' beliefs about overtreatment and its coverage: journalists' roles and responsibilities, the medical context, causes of overtreatment, and economics/costs. Journalists view overtreatment as an important but complex issue driven by Americans' faith in medicine and cultural norms that make uncertainty unacceptable. The medical contexts most associated with overtreatment are cancer testing and treatment and overprescribing. Journalists see themselves as providing information to help consumers make personal treatment decisions, rather than helping audiences understand health policy. For decades, the American public has expressed dissatisfaction with the U.S. health system; in one recent assessment, two-thirds of Americans graded the overall quality of health care in the country at a "C" or worse (Blendon, Benson, SteelFisher, & Weldon, 2011; Blendon, Brodie, Benson, Altman, & Buhr, 2006). A study of patient satisfaction in 11 Western countries showed greater dissatisfaction with the U.S. system than with those in any of the comparison countries, with more than one-quarter of Americans saying the U.S. health system needs to be completely rebuilt (Papanicolas, Cylus, & Smith, 2013). PMID- 27982703 TI - Revisiting Repurposing. AB - Drug repurposing can be a cost-effective strategy to identify new small molecule based therapies. Thus, drug repurposing significantly influences the discovery of therapeutics, particularly for rare and neglected diseases, which are often constrained by limited research and development funds. The push for translational science and access to drug discovery-associated resources such as high throughput screening instrumentation, assay development expertise, and Food and Drug Administration-approved drug libraries have intensified interest in drug repurposing. However, successful drug repurposing is highly challenging and subject to particular limitations. Despite these challenges, drug repurposing is a critical component to any comprehensive drug discovery strategy and has the capacity to benefit a wide variety of therapeutically underserved diseases. PMID- 27982704 TI - Tramadol, an Opioid Receptor Agonist: An Inhibitor of Growth, Morphogenesis, and Biofilm Formation in the Human Pathogen, Candida albicans. AB - Tramadol is a synthetic, centrally acting low-affinity agonist of MU-opioid receptors in humans. It is used as an analgesic and is shown to have local anesthetic action. In this study, we have tried to explore its anti-Candida potential. Minimum inhibitory concentration (MIC50) and minimum fungicidal concentration (MFC) values were established. MIC50 ranged from 2 to 4 mg/mL, whereas MFC was recorded at 8 mg/mL. Also, the effect of tramadol on germ tube formation, adhesion, and biofilms in Candida albicans was studied. Tramadol impaired in vitro growth of C. albicans. A time-dependent killing assay showed that it kills C. albicans within 24 h of exposure. Tramadol has strong activity against Candida virulence factors such as yeast-to-hyphal form switching and adhesion. C. albicans biofilms, which are notoriously resistant to many antifungals, were sensitive to tramadol. At 8 mg/mL of tramadol, 82% of early stage biofilms and 52.88% of matured biofilms were inhibited. Although our results show that the antifungal effect of tramadol requires concentrations that can be achieved only locally, they may provide potential candidates for development of novel antifungal drugs. PMID- 27982705 TI - Drug Repurposing Patent Applications July-September 2016. PMID- 27982706 TI - Drug Repurposing Patent Applications April-June 2016. PMID- 27982708 TI - Kenyan Religious Leaders' Views on Same-Sex Sexuality and Gender Nonconformity: Religious Freedom versus Constitutional Rights. AB - Religion plays an important role in framing the public discourse on sexuality, especially in countries where religion fully permeates social life. We explored the perspectives of Kenyan religious leaders on sexual and gender diversity in their country's specific context. A total of 212 Catholic, Islamic, and Protestant leaders from urban centers and rural townships completed a self administered questionnaire specifically developed for this study. The leaders' perspectives were predominantly negative. Limited acceptance was conditional on sexual minorities not engaging in same-sex practices or seeing such practices as sinful. A substantial minority (37%) endorsed the use of violence for maintaining social values, especially regarding homosexuality and gender nonconformity. The majority of religious leaders agreed on the difference between civil law and religious doctrine. Human rights principles enshrined in Kenya's Constitution were considered to be applicable to sexual and gender minorities. Decriminalization of same-sex sexuality was seen as against one's religion. Perspectives were less negative if leaders were familiar with lesbian, gay, bisexual, and transgender (LGBT) persons. Interventions that promote intergroup contact could be effective in changing religious leaders' mind-sets and advancing human rights and health for sexual and gender minorities. PMID- 27982707 TI - Feasibility of Long-Term Closed-Loop Control: A Multicenter 6-Month Trial of 24/7 Automated Insulin Delivery. AB - BACKGROUND: In the past few years, the artificial pancreas-the commonly accepted term for closed-loop control (CLC) of blood glucose in diabetes-has become a hot topic in research and technology development. In the summer of 2014, we initiated a 6-month trial evaluating the safety of 24/7 CLC during free-living conditions. RESEARCH DESIGN AND METHODS: Following an initial 1-month Phase 1, 14 individuals (10 males/4 females) with type 1 diabetes at three clinical centers in the United States and one in Italy continued with a 5-month Phase 2, which included 24/7 CLC using the wireless portable Diabetes Assistant (DiAs) developed at the University of Virginia Center for Diabetes Technology. Median subject characteristics were age 45 years, duration of diabetes 27 years, total daily insulin 0.53 U/kg/day, and baseline HbA1c 7.2% (55 mmol/mol). RESULTS: Compared with the baseline observation period, the frequency of hypoglycemia below 3.9 mmol/L during the last 3 months of CLC was lower: 4.1% versus 1.3%, P < 0.001. This was accompanied by a downward trend in HbA1c from 7.2% (55 mmol/mol) to 7.0% (53 mmol/mol) at 6 months. HbA1c improvement was correlated with system use (Spearman r = 0.55). The user experience was favorable with identified benefit particularly at night and overall trust in the system. There were no serious adverse events, severe hypoglycemia, or diabetic ketoacidosis. CONCLUSION: We conclude that CLC technology has matured and is safe for prolonged use in patients' natural environment. Based on these promising results, a large randomized trial is warranted to assess long-term CLC efficacy and safety. PMID- 27982709 TI - Assessing Youth-Appealing Content in Alcohol Advertisements: Application of a Content Appealing to Youth (CAY) Index. AB - Underage drinking is a serious public health problem in the United States, and youth exposure to alcohol advertising has been indicated as a possible contributing factor. Although a number of studies have identified advertising content features that youth find appealing, a key limitation of this research is the absence of a broader tool to examine those features, especially those used by alcohol brands that are popular with underage drinkers. We created an index of content elements found in the research literature to be appealing to youth, and then used this index in a content analysis to identify the degree to which youth appealing content appeared in a sample of alcohol ads that aired on television shows popular among youth. Finally, using bivariate analysis, we tested the relationship between alcohol brands' use of this content and the popularity of those brands among youth. We found that many of the ads featured youth-appealing content, and that the ads for the alcohol brands most popular among youth had more youth-appealing content than the less popular brands. PMID- 27982710 TI - A Latent Class Analysis of Behavioral and Psychosocial Dimensions of Adolescent Sexuality: Exploring Race Differences. AB - Adolescent sexuality is a multidimensional concept involving sexual behavior as well as aspects of youth's sexual self-concept and sexual socialization. The current study used latent class analysis (LCA) to examine patterns of adolescent sexuality, with data from a nationally representative sample of youth (Add Health; n = 13,447), incorporating information on behavioral and psychosocial dimensions of adolescent sexual experiences. LCA results highlighted that youth may exhibit similar sexual behaviors but vary on psychosocial dimensions, including sexual self-efficacy, knowledge, and views about sex. Sociodemographic characteristics, family factors, mental health, and substance use emerged as predictors of membership into different latent classes of sexuality. Given persistent racial differences in sexual outcomes and sexually transmitted infection (STI) rates, the current study also examined how adolescent patterns of sexuality may help mediate racial differences in sexual outcomes by young adulthood. Results suggested that racial differences in adolescent patterns of sexuality help mediate racial differences in the number of sexual partners by young adulthood but not differences in STI diagnosis. Findings highlight the need for research on multiple aspects of adolescent sexuality to understand linkages with later outcomes and group differences. PMID- 27982711 TI - Production of Bacterial Ghosts from Gram-Positive Pathogen Listeria monocytogenes. AB - INTRODUCTION: The Gram-positive bacterium Listeria monocytogenes is a ubiquitous intracellular pathogen, which has been implicated within the past decade as the causative organism in several outbreaks of foodborne disease. Bacterial ghosts (BGs) are nonliving and vacant cell envelopes of bacteria generated by releasing the bacterial cytoplasm through a channel in the cell envelope. This study attempted to produce Gram-positive pathogenic L. monocytogenes ghosts (LMGs) with simple chemicals. MATERIALS AND METHODS: The generation of LMGs was based on minimum inhibition concentrations of 1.10 mg/mL NaOH, 0.0675 mg/mL SDS, and 0.035% (v/v) H2O2. The potential efficacy of LMGs as vaccines and their ability to induce protective immune responses against virulent L. monocytogenes challenge through multipoint subcutaneous injection were also evaluated. RESULTS: The detected activity and viability of LMGs showed that nonliving LMGs could be induced. The detected LMG DNA and protein, as well as its morphological features, indicated that the produced LMGs were empty cells with the correct morphological structure. The subcutaneous vaccination of LMGs through multipoint injection conferred effective protection, with an antibody titer that reached 104 U. CONCLUSIONS: These findings strongly suggested that this chemical method can be used to produce LMGs and could be useful in future vaccine development against this foodborne pathogen. PMID- 27982712 TI - Evaluation of the efficacy of an autogenous Escherichia coli vaccine in broiler breeders. AB - In poultry production Escherichia coli autogenous vaccines are often used. However, the efficacy of autogenous E. coli vaccinations has not been evaluated experimentally in chickens after start of lay. The aim of the present study was to evaluate the protective effect of an autogenous E. coli vaccine in broiler breeders. Three groups of 28-week-old broiler breeders (unvaccinated, vaccinated once and twice, respectively) were challenged with a homologous E. coli strain (same strain as included in the vaccine) or a heterologous challenge strain in an experimental ascending model. The clinical outcome was most pronounced in the unvaccinated group; however, the vast majority of chickens in the vaccinated groups had severe pathological manifestations similar to findings in the unvaccinated group after challenge with a homologous as well as a heterologous E. coli strain. Although significant titre rises in IgY antibodies were observed in the twice vaccinated group, antibodies did not confer significant protection in terms of pathological impact. Neither could transfer of maternal-derived antibodies to offspring be demonstrated. In conclusion, with the use of the present model for ascending infection, significant protection of an autogenous E. coli vaccine against neither a homologous nor a heterologous E. coli challenge could not be documented. PMID- 27982713 TI - Not re-inventing the wheel: the adaptive implementation of the meeting centres support programme in four European countries. AB - OBJECTIVES: The implementation of new health services is a complex process. This study investigated the first phase of the adaptive implementation of the Dutch Meeting Centres Support Programme (MCSP) for people with dementia and their carers in three European countries (Italy, Poland, the UK) within the JPND MEETINGDEM project. Anticipated and experienced factors influencing the implementation, and the efficacy of the implementation process, were investigated. Findings were compared with previous research in the Netherlands. METHOD: A qualitative multiple case study design was applied. Checklist on anticipated facilitators and barriers to the implementation and semi-structured interview were completed by stakeholders, respectively at the end and at the beginning of the preparation phase. RESULTS: Overall, few differences between countries were founded. Facilitators for all countries were: added value of MCSP matching needs of the target group, evidence of effectiveness of MCSP, enthusiasm of stakeholders. General barriers were: competition with existing care and welfare organizations and scarce funding. Some countries experienced improved collaborations, others had difficulties finding a socially integrated location for MCSP. The step-by-step implementation method proved efficacious. CONCLUSION: These insights into factors influencing the implementation of MCSP in three European countries and the efficacy of the step-by-step preparation may aid further implementation of MCSP in Europe. PMID- 27982715 TI - The effect of footwear adapted with a multi-curved rocker sole in conjunction with knee-ankle-foot orthoses on walking in poliomyelitis subjects: a pilot study. AB - BACKGROUND: Knee-ankle-foot orthoses (KAFOs) are used by people with poliomyelitis to ambulate. Whist advances in orthotic knee joint designs for use in KAFOs such the provision of stance control capability have proven efficacy, little attention has been paid to shoe adaptations which may also improve gait. AIM: The aim of this study was to evaluate the alteration to the kinematics and temporal-spatial parameters of gait caused by the use of heel-to-toe rocker-soled footwear when ambulating with KAFOs. METHOD: Nine adults with a history of poliomyelitis who routinely wore KAFOs participated in the study. A heel-to-toe rocker sole was added to footwear and worn on the affected side. A three dimensional motion capture system was used to quantify the resulting alteration to specific gait parameters. RESULTS: Maximum hip joint extension was significantly increased (p = 0.011), and hip abduction and adduction were both significantly reduced (p = 0.011 and p = 0.007, respectively) when walking with the rocker sole. A significant increase in stride length (p = 0.035) was demonstrated but there were no significant increases in either walking speed or cadence. CONCLUSIONS: A heel-to-toe rocker sole adaptation may be useful for walking in patients with poliomyelitis who use KAFOs. Implications for Rehabilitation The poor functionality and difficulty in walking when using an orthotic device such as a KAFO which keeps the knee locked during ambulation, plus the significant energy required to walk, are complications of orthoses using. Little evidence exists regarding the biomechanical effect of walking with a KAFO incorporating fixed knee joints, in conjunction with rocker-soled footwear. The main aim of walking with a heel-to-toe rocker sole is to facilitate forward progression of the tibia when used with an AFO or KAFO or to provide easier walking for patients who have undergone an ankle arthrodesis. In this study, a rocker sole profile adaptation produced no significant alteration to hip joint flexion, but hip joint maximum extension was significantly increased in subjects suffering from poliomyelitis, and maximum hip adduction and abduction were both significantly reduced. The most significant alterations were seen in stride length, and although there was a significant increase in this parameter, there was no statistically significant increase in walking velocity or cadence. PMID- 27982716 TI - Apps in therapy: occupational therapists' use and opinions. AB - To gather information on occupational therapy practitioners' use and opinions of apps, an online survey was distributed to occupational therapy practitioners licensed in the state of Ohio. The survey sought information regarding clinical populations and skill areas for which apps are used, potential barriers to use of apps and preferred apps/app features. OTs working in medical and education-based settings and with clients of all ages responded to the survey. Over half (53%) reported not using apps in therapy, with "not having access to the technology at work" being the leading reason endorsed. Of practitioners who did report using apps, the majority used them with <=25% of their case load and primarily used tablets to do so. Clinicians indicated that they use apps for a wide variety of reasons, including to promote skill building and to support the therapeutic process. Preferred features included the ability to grade difficulty up/down, multiple uses and accurate feedback. Recommendations from peers were the most commonly reported way respondents found new apps. The results suggest that occupational therapy practitioners employ clinical reasoning when implementing apps in therapy. Possible ways to improve access to apps for therapists who would like to implement them are discussed. Implications for Rehabilitation Many occupational therapy practitioners are using apps with at least a portion of their caseloads. Therapists select apps based on peer recommendations, most commonly selecting those which promote skill building and support the therapeutic process. More therapists might make use of apps if potential barriers were reduced or eliminated, including availability of technology in the clinical practice setting, therapist training and education, therapist input into app development and an enhanced evidence base. PMID- 27982714 TI - Technology-assisted language intervention for children who are deaf or hard-of hearing; a pilot study of augmentative and alternative communication for enhancing language development. AB - PURPOSE: Pilot study to assess the effect of augmentative and alternative communication technology to enhance language development in children who are deaf or hard-of-hearing. MATERIALS AND METHODS: Five children ages 5-10 years with permanent bilateral hearing loss who were identified with language underperformance participated in an individualized 24-week structured program using the application TouchChat WordPower on iPads(r). Language samples were analyzed for changes in mean length of utterance, vocabulary words and mean turn length. Repeated measures models assessed change over time. RESULTS: The baseline median mean length of utterance was 2.41 (range 1.09-6.63; mean 2.88) and significantly increased over time (p = 0.002) to a median of 3.68 at final visit (range 1.97-6.81; mean 3.62). At baseline, the median total number of words spoken per language sample was 251 (range 101-458), with 100 (range 36-100) different words spoken. Total words and different words significantly increased over time (beta = 26.8 (7.1), p = 0.001 for total words; beta = 8.0 (2.7), p = 0.008 for different words). Mean turn length values also slightly increased over time. CONCLUSIONS: Using augmentative and alternative communication technology on iPads(r) shows promise in supporting rapid language growth among elementary school-age children who are deaf or hard-of-hearing with language underperformance. PMID- 27982717 TI - Intelligent power wheelchair use in long-term care: potential users' experiences and perceptions. AB - PURPOSE: Long-term care (LTC) residents with cognitive impairments frequently experience limited mobility and participation in preferred activities. Although a power wheelchair could mitigate some of these mobility and participation challenges, this technology is often not prescribed for this population due to safety concerns. An intelligent power wheelchair (IPW) system represents a potential intervention that could help to overcome these concerns. The purpose of this study was to explore a) how residents experienced an IPW that used three different modes of control and b) what perceived effect the IPW would have on their daily lives. MATERIALS AND METHODS: We interviewed 10 LTC residents with mild or moderate cognitive impairment twice, once before and once after testing the IPW. Interviews were conducted using a semi-structured interview guide, audio recorded and transcribed verbatim for thematic analyses. RESULTS: Our analyses identified three overarching themes: (1) the difference an IPW would make, (2) the potential impact of the IPW on others and (3) IPW-related concerns. CONCLUSIONS: Findings from this study confirm the need for and potential benefits of IPW use in LTC. Future studies will involve testing IPW improvements based on feedback and insights from this study. Implications for rehabilitation Intelligent power wheelchairs may enhance participation and improve safety and feelings of well-being for long-term care residents with cognitive impairments. Intelligent power wheelchairs could potentially have an equally positive impact on facility staff, other residents, and family and friends by decreasing workload and increasing safety. PMID- 27982723 TI - The antifibrogenic effect of etanercept on development of liver cirrhosis induced by thioacetamide in rats. AB - Liver cirrhosis is an elevating cause of morbidity and mortality worldwide. TNF alpha/TNF-R1 signal is implicated in progression of many liver diseases. This study provides histological and ultrastructural view that clarifies the effect of etanercept, a TNF-alpha inhibitor, on development of thioacetamide (TAA)-induced liver cirrhosis and the accompanied hemosiderosis in rats, highlighting the implication and distribution pattern of hepatic TNF-R1. Sixty male albino rats (Rattus norvegicus) were equally randomized into three groups. Group I served as the control. Liver cirrhosis was triggered in the other two groups by intraperitoneal injection of TAA twice a week for five months. Group II received TAA only, while group III subcutaneously injected with etanercept one hour before TAA, along five months. At the end of the experiment, blood was collected for biochemical analysis and livers were excised for histological, immunohistochemical, and electron microscopical preparations. Rats treated with TAA only developed hepatic cirrhosis accompanied by massive deposition of hemosiderin; strong and widespread expression of hepatic TNF-R1 in sinusoidal endothelial cells (SECs), Kupffer cells (KCs), and many hepatocytes; and frequent appearance of fibrogenic, plasma, and mast cells, at the ultrastructural level. By contrast, administration of etanercept diminished the expression of TNF-R1, attenuated the accumulation of collagen and hemosiderin, and preserved the hepatic histoarchitecture. In conclusion, TNF-alpha signal via TNF-R1 may be implicated in the mechanism of fibrogenesis and the associated hemosiderosis. Etanercept may provide a promising therapeutic approach not only for attenuating the progression of fibrogenesis, but also for hepatic iron overload-associated disorders. PMID- 27982722 TI - TargetLink, a new method for identifying the endogenous target set of a specific microRNA in intact living cells. AB - MicroRNAs are small non-coding RNAs acting as posttranscriptional repressors of gene expression. Identifying mRNA targets of a given miRNA remains an outstanding challenge in the field. We have developed a new experimental approach, TargetLink, that applied locked nucleic acid (LNA) as the affinity probe to enrich target genes of a specific microRNA in intact cells. TargetLink also consists a rigorous and systematic data analysis pipeline to identify target genes by comparing LNA-enriched sequences between experimental and control samples. Using miR-21 as a test microRNA, we identified 12 target genes of miR-21 in a human colorectal cancer cell by this approach. The majority of the identified targets interacted with miR-21 via imperfect seed pairing. Target validation confirmed that miR-21 repressed the expression of the identified targets. The cellular abundance of the identified miR-21 target transcripts varied over a wide range, with some targets expressed at a rather low level, confirming that both abundant and rare transcripts are susceptible to regulation by microRNAs, and that TargetLink is an efficient approach for identifying the target set of a specific microRNA in intact cells. C20orf111, one of the novel targets identified by TargetLink, was found to reside in the nuclear speckle and to be reliably repressed by miR-21 through the interaction at its coding sequence. PMID- 27982724 TI - The Proteasome Inhibitor Bortezomib Inhibits Inflammatory Response of Periodontal Ligament Cells and Ameliorates Experimental Periodontitis in Rats. AB - BACKGROUND: Periodontitis is a chronic inflammatory disease initiated by bacteria and their virulence factors. Bortezomib (BTZ) is the first proteasome inhibitor for clinical treatment of malignancies. Its anticancer activity is accompanied by an anti-inflammatory effect. However, there are few reports about its anti inflammatory effect and underlying mechanism in periodontal disease, especially on human periodontal ligament cells (hPDLCs), which are considered a promising cell-based therapy for treating periodontitis. METHODS: hPDLCs were treated with lipopolysaccharide (LPS) and pretreated with BTZ. mRNA and protein levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 were determined. The anti-inflammatory mechanism of BTZ was studied. Further, experimental rat periodontitis was induced with ligature and LPS injection, and simultaneously and locally treated with BTZ (three injections/week). Four weeks after treatment, microcomputed tomography, immunohistochemical, and histopathologic analyses were performed. RESULTS: Bortezomib administration at safe concentrations (<=1 nM) inhibited production of proinflammatory cytokines in LPS-stimulated hPDLCs via nuclear factor (NF)-kappa B, p38/extracellular signal regulated kinase, and mitogen-activated protein kinase/activator protein-1 pathways. Moreover, in the LPS and ligature-induced periodontitis rat model, BTZ suppressed expression of TNF-alpha, IL-1beta, IL-6, and IL-8, reduced the ratio of receptor activator of NF-kappaB ligand/osteoprotegerin, and prevented alveolar bone absorption. CONCLUSION: These findings demonstrate the anti-inflammatory activity of BTZ against periodontal inflammatory response and present BTZ as a promising therapy for periodontal disease. PMID- 27982725 TI - Differential analysis of genome-wide methylation and gene expression in mesenchymal stem cells of patients with fractures and osteoarthritis. AB - Insufficient activity of the bone-forming osteoblasts leads to low bone mass and predisposes to fragility fractures. The functional capacity of human mesenchymal stem cells (hMSCs), the precursors of osteoblasts, may be compromised in elderly individuals, in relation with the epigenetic changes associated with aging. However, the role of hMSCs in the pathogenesis of osteoporosis is still unclear. Therefore, we aimed to characterize the genome-wide methylation and gene expression signatures and the differentiation capacity of hMSCs from patients with hip fractures. We obtained hMSCs from the femoral heads of women undergoing hip replacement due to hip fractures and controls with hip osteoarthritis. DNA methylation was explored with the Infinium 450K bead array. Transcriptome analysis was done by RNA sequencing. The genomic analyses revealed that most differentially methylated loci were situated in genomic regions with enhancer activity, distant from gene bodies and promoters. These regions were associated with differentially expressed genes enriched in pathways related to hMSC growth and osteoblast differentiation. hMSCs from patients with fractures showed enhanced proliferation and upregulation of the osteogenic drivers RUNX2/OSX. Also, they showed some signs of accelerated methylation aging. When cultured in osteogenic medium, hMSCs from patients with fractures showed an impaired differentiation capacity, with reduced alkaline phosphatase activity and poor accumulation of a mineralized matrix. Our results point to 2 areas of potential interest for discovering new therapeutic targets for low bone mass disorders and bone regeneration: the mechanisms stimulating MSCs proliferation after fracture and those impairing their terminal differentiation. PMID- 27982726 TI - A Bayesian Analysis of a Randomized Clinical Trial Comparing Antimetabolite Therapies for Non-Infectious Uveitis. AB - PURPOSE: To conduct a Bayesian analysis of a randomized clinical trial (RCT) for non-infectious uveitis using expert opinion as a subjective prior belief. METHODS: A RCT was conducted to determine which antimetabolite, methotrexate or mycophenolate mofetil, is more effective as an initial corticosteroid-sparing agent for the treatment of intermediate, posterior, and pan-uveitis. Before the release of trial results, expert opinion on the relative effectiveness of these two medications was collected via online survey. Members of the American Uveitis Society executive committee were invited to provide an estimate for the relative decrease in efficacy with a 95% credible interval (CrI). A prior probability distribution was created from experts' estimates. A Bayesian analysis was performed using the constructed expert prior probability distribution and the trial's primary outcome. RESULTS: A total of 11 of the 12 invited uveitis specialists provided estimates. Eight of 11 experts (73%) believed mycophenolate mofetil is more effective. The group prior belief was that the odds of treatment success for patients taking mycophenolate mofetil were 1.4-fold the odds of those taking methotrexate (95% CrI 0.03-45.0). The odds of treatment success with mycophenolate mofetil compared to methotrexate was 0.4 from the RCT (95% confidence interval 0.1-1.2) and 0.7 (95% CrI 0.2-1.7) from the Bayesian analysis. CONCLUSIONS: A Bayesian analysis combining expert belief with the trial's result did not indicate preference for one drug. However, the wide credible interval leaves open the possibility of a substantial treatment effect. This suggests clinical equipoise necessary to allow a larger, more definitive RCT. PMID- 27982728 TI - A comparison of nanoparticle-antibody conjugation strategies in sandwich immunoassays. AB - Point-of-care (POC) diagnostics such as lateral flow and dipstick immunoassays use gold nanoparticle (NP)-antibody conjugates for visual readout. We investigated the effects of NP conjugation, surface chemistries, and antibody immobilization methods on dipstick performance. We compared orientational, covalent conjugation, electrostatic adsorption, and a commercial conjugation kit for dipstick assays to detect dengue virus NS1 protein. Assay performance depended significantly on their conjugate properties. We also tested arrangements of multiple test lines within strips. Results show that orientational, covalent conjugation with PEG shield could improve NS1 detection. These approaches can be used to optimize immunochromatographic detection for a range of biomarkers. PMID- 27982727 TI - Insights into circular RNA biology. AB - Circular RNAs (circRNAs) are a novel class of non-coding RNA characterized by a covalently closed-loop structure generated through a special type of alternative splicing termed backsplicing. CircRNAs are emerging as a heterogeneous class of molecules involved in modulating gene expression by regulation of transcription, protein and miRNA functions. CircRNA expression is cell type and tissue specific and can be largely independent of the expression level of the linear host gene, indicating that regulation of expression might be an important aspect with regard to control of circRNA function. In this review, a brief introduction to the characteristics that define a circRNA will be given followed by a discussion of putative biogenesis pathways and modulators of circRNA expression as well as of the stage at which circRNA formation takes place. A brief summary of circRNA functions will also be provided and lastly, an outlook with a focus on unanswered questions regarding circRNA biology will be included. PMID- 27982730 TI - Meta-Analysis of the Relationship between TNF-alpha (-308G/A) and IL-10 (-819C/T) Gene Polymorphisms and Susceptibility to Dengue. AB - OBJECTIVE: This study determined whether tumor necrosis factor alpha (TNF-alpha) and Interleukin-10 (IL-10) polymorphisms are associated with susceptibility to dengue. METHODS: a systematic review with meta-analysis was conducted of the associations between the TNF-alpha (-308G/A) and IL-10 (-819C/T) polymorphisms and dengue. RESULTS: A total of eight case-controls studies involving 384 individuals with symptomatic dengue, 571 individuals with dengue hemorrhagic fever, and 995 healthy controls were considered in the meta-analysis. There was no significant association between TNF-alpha (-308G/A) and IL-10 (-819C/T) polymorphism and dengue in overall population. However, stratifying meta-analysis by groups, the meta-analysis revealed association between the TNF-alpha -308 G/G (OR: 1.62, CI: 1.02-2.57, p = 0.04) genotype and allele G (OR: 1.62, CI: 1.04 2.55, p = 0.03) that confers susceptibility to symptomatic dengue, while the TNF alpha -308 G/A genotype (OR: 0.69, CI = 0.39-0.99, p = 0.04) and allele A (OR: 0.64, CI: 0.41-1.00, p = 0.05) confers protection to symptomatic dengue. No difference was observed for the TNF-alpha (-308) and IL-10 (-819C/T) polymorphisms in the comparisons of hemorrhagic dengue versus control and hemorrhagic dengue versus symptomatic dengue. CONCLUSION: This meta-analysis showed that TNF-alpha (-308) polymorphism is associated with dengue symptomatic susceptibility. PMID- 27982731 TI - Letter to the Editor: Postoperative hyponatremia. PMID- 27982729 TI - Differential DNA methylation and PM2.5 species in a 450K epigenome-wide association study. AB - Although there is growing evidence that exposure to ambient particulate matter is associated with global DNA methylation and gene-specific methylation, little is known regarding epigenome-wide changes in DNA methylation in relation to particles and, especially, particle components. Using the Illumina Infinium HumanMethylation450 BeadChip, we examined the relationship between one-year moving averages of PM2.5 species (Al, Ca, Cu, Fe, K, Na, Ni, S, Si, V, and Zn) and DNA methylation at 484,613 CpG probes in a longitudinal cohort that included 646 subjects. Bonferroni correction was applied to adjust for multiple comparisons. Bioinformatics analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was also performed. We observed 20 Bonferroni significant (P-value < 9.4* 10-9) CpGs for Fe, 8 for Ni, and 1 for V. Particularly, methylation at Schlafen Family Member 11 (SLFN11) cg10911913 was positively associated with measured levels of all 3 species. The SLFN11 gene codes for an interferon-induced protein that inhibits retroviruses and sensitizes cancer cells to DNA-damaging agents. Bioinformatics analysis suggests that gene targets may be relevant to pathways including cancers, signal transduction, and cell growth and death. Ours is the first study to examine the epigenome-wide association between ambient particles species and DNA methylation. We found that long-term exposures to specific components of ambient particle pollution, especially particles emitted during oil combustion, were associated with methylation changes in genes relevant to immune responses. Our findings provide insight into potential biologic mechanisms on an epigenetic level. PMID- 27982732 TI - 3D nano- and micro-patterning of biomaterials for controlled drug delivery. AB - Recently, there has been an emerging interest in controlling 3D structures and designing novel 3D shapes for drug carriers at nano- and micro-scales. Certain 3D shapes and structures of drug particles enable transportation of the drugs to desired areas of the body, allow drugs to target specific cells and tissues, and influence release kinetics. Advanced nano- and micro-manufacturing methods including 3D printing, photolithography-based processes, microfluidics and DNA origami have been developed to generate defined 3D shapes and structures for drug carriers. This paper reviews the importance of 3D structures and shapes on controlled drug delivery, and the current state-of-the-art technologies that allow the creation of novel 3D drug carriers at nano- and micro-scales. PMID- 27982733 TI - In vitro and ex vivo approach for anti-urolithiatic potential of bioactive fractions of gokhru with simultaneous HPLC analysis of six major metabolites and their exploration in rat plasma. AB - CONTEXT: Tribulus terrestris L. (Zygophyllaceae) fruits have long been used in traditional systems of medicine for the treatment of various urinary diseases including urolithiasis. OBJECTIVE: To explore the anti-urolithiatic potential of gokhru and to develop an analytical method for quantitative estimation of metabolites for its quality control. MATERIALS AND METHODS: Aqueous extract of gokhru fruit was prepared through maceration followed by decoction to produce a mother extract, which was further used for polarity-based fractionations. In vitro and ex vivo anti-urolithiatic activity of mother extract and fractions at different concentration (100-1000 MUg/mL) were carried out using aggregation assay in synthetic urine and in rat plasma, however, nucleation assay for 30 min was done using confocal microscopy. A simultaneous HPLC method has been developed for quantification of diosgenin, catechin, rutin, gallic acid, tannic acid and quercetin in mother extract and in fractions. RESULTS: The extraction resulted in 14.5% of w/w mother extract, however, polarity-based fractionation yielded 2.1, 2.6, 1.5, 1.3 and 6.1% w/w of hexane, toluene, dichloromethane (DCM), n-butanol and water fractions, respectively. In vitro and ex vivo studies showed a significant anti-urolithiatic potential of n-butanol fraction. Further, HPLC analysis revealed significantly (p < 0.01) higher content of quercetin (1.95 +/- 0.41% w/w), diosgenin (12.75 +/- 0.18% w/w) and tannic acid (9.81 +/- 0.47% w/w) in n-butanol fraction as compared to others fractions. DISCUSSION AND CONCLUSION: In vitro and ex vivo studies demonstrated potent anti-urolithiatic activity of n butanol fraction which can be developed as new phytopharmaceuticals for urolithiasis. HPLC method can be used for quality control and pharmacokinetic studies of gokhru. PMID- 27982734 TI - Increased complexity of circRNA expression during species evolution. AB - Circular RNAs (circRNAs) are broadly identified from precursor mRNA (pre-mRNA) back-splicing across various species. Recent studies have suggested a cell /tissue- specific manner of circRNA expression. However, the distinct expression pattern of circRNAs among species and its underlying mechanism still remain to be explored. Here, we systematically compared circRNA expression from human and mouse, and found that only a small portion of human circRNAs could be determined in parallel mouse samples. The conserved circRNA expression between human and mouse is correlated with the existence of orientation-opposite complementary sequences in introns that flank back-spliced exons in both species, but not the circRNA sequences themselves. Quantification of RNA pairing capacity of orientation-opposite complementary sequences across circRNA-flanking introns by Complementary Sequence Index (CSI) identifies that among all types of complementary sequences, SINEs, especially Alu elements in human, contribute the most for circRNA formation and that their diverse distribution across species leads to the increased complexity of circRNA expression during species evolution. Together, our integrated and comparative reference catalog of circRNAs in different species reveals a species-specific pattern of circRNA expression and suggests a previously under-appreciated impact of fast-evolved SINEs on the regulation of (circRNA) gene expression. PMID- 27982736 TI - Design of novel chemotherapeutic delivery systems for colon cancer therapy based on oral polymeric nanoparticles. AB - Oral delivery of cancer chemotherapeutic drugs (CCDs) is subject matter in the 21st century, which changes the dosage regimens of oncotherapy with enhancement in patient's life and deducts the cost of therapy. The present report explored on the nano-oncology such as polymeric nanoparticles (PNPs) as an oral CCDs delivery vehicle, showing great potential for colon cancer treatment. Proof-of-concept in vitro and in vivo results for delivery of CCDs using various oral PNPs are included in this review from the literatures. Subsequently, the gastrointestinal barriers for oral chemotherapy have been highlighted. Furthermore, PNPs achieving better accumulation in the cancer region by desirable quality of their passive- and active-targeting phenomena have also been highlighted. PMID- 27982735 TI - Differential scanning calorimetric study of antibiotic distamycin A binding with chromatin within isolated rat liver nuclei. AB - CONTEXT: Natural oligopeptide antibiotic distamycin A (Dst) biosynthesized by Streptomyces distallicus is traditionally used in medical practice as an anti inflammatory and antitumour drug. OBJECTIVE: Dst was investigated for its effect on the structural components of native chromatin directly within isolated rat liver nuclei in the presence of physiologically significant cations (magnesium or spermine and spermidine). MATERIALS AND METHODS: Differential scanning calorimetry (DSC) was used to study the Dst action at molar ratio Dst/DNA = 0.1 and 0.15 mM Dst on the melting profile of nuclei suspension in different conditions. RESULTS: Results showed that the thermodynamic parameters of control nuclei in the presence of polyamines or Mg2+ were different. The incubation of nuclei with Dst raised transition temperatures of relaxed (peak II) and topologically constrained DNA (peak III) by 6-8 degrees C and decreased by 2-4 degrees C that of core-histones (peak I). The total excess transition enthalpy (DeltaHexc) in buffer with polyamines (24.7 kJ/mol DNA nucleotides) increased by1.5 times versus control but in buffer with Mg2+, the value of DeltaHexc (35.8 kJ/mol DNA nucleotides) remained unchanged. CONCLUSIONS: The association of Dst with chromatin in the nucleus weakens histone-DNA contacts and causes additional strengthening of interaction between two complementary DNA chains. Our results contribute towards validation of DSC to test drug ability to modulate chromatin structure in the physiological environment and to clarify the mechanism of these modulations. PMID- 27982737 TI - IL-37 a New IL-1 Family Member Emerges as a Key Suppressor of Asthma Mediated by Mast Cells. AB - : In 1986, we reported a multiple biological effect of IL-1 including immunological, inflammatory, and tumor killing activity. Since then other IL-1 family cytokines have been discovered, some with inflammatory and other with anti inflammatory activity. In this review article, we speculate on the possible inhibitory effect of IL-37 in the light of new findings. IL-37, formerly termed IL-1 family member 7 (IL-1F7), binding IL-18 receptor alpha chain, acts as a cytokine with intracellular as well as extracellular functionality and as a natural inhibitor of immune responses and inflammation. IL-37 inhibits many pro inflammatory cytokine and increases anti-inflammatory cytokines such as IL-10. Asthma pathogenesis involves multiple cell types including mast cells, which are important cellular constituents of the human innate and adaptive immunity. IL-37 has an impact on inflammatory cytokines generated by mast cells and is beneficial for and protective in asthma. However, the precise mechanism(s), safety, and tolerability of IL-37 are unclear and still remain a mystery. ABBREVIATIONS: GBP (Guanylate Binding Proteins); HMGB1 (High Mobility Group Box protein 1); NLRP (Nucleotide-like Receptor Pyrin domain 1); ASC (Apoptosis-associated Speck-like protein containing CARD, Caspase Recruitment Domain); FGF2 (Fibroblast Growth Factor 2). PMID- 27982738 TI - Urinary trans-trans muconic acid (exposure biomarker to benzene) and hippuric acid (exposure biomarker to toluene) concentrations in Mexican women living in high-risk scenarios of air pollution. AB - This study aimed to determine t,t-muconic acid (t,t-MA; exposure biomarker for benzene) and hippuric acid (HA; exposure biomarker for toluene) concentrations in the urine of women living in Mexico. In a cross-sectional study, apparently healthy women (n = 104) were voluntarily recruited from localities with a high risk of air pollution; t,t-MA and HA in urine were quantified using a high performance liquid chromatography (HPLC) technique. Mean urinary levels of t,t-MA ranged from 680 to 1,310 MUg/g creatinine. Mean values of HA ranged from 0.38 to 0.87 g/g creatinine. In conclusion, compared to data recently reported in literature, we found high urinary levels of t,t-MA and HA in assessed women participating in this study. We therefore deem the implementation of a strategy aimed at the reduction of exposure as a necessary measure for the evaluated communities. PMID- 27982739 TI - Karl Heinrich Ulrichs: First Theorist of Erotic Age Orientation. AB - The nomination of Karl Heinrich Ulrichs (1825-1895) as the first theorist of homosexuality may be placed in the oblique light of his eligibility for the nomination as the first theorist of erotic age orientation. In Ulrichs's pamphlets, "man-manly" homosexuality emerged as a particular age orientation, with a subsequent typological breakdown that, importantly, blended gender orientation and age orientation. Into the early 20th century, erotic age orientation remained bound up with the classification and emancipation of what here was demarcated as Urningsliebe. Ulrichs's pioneering and shifting comments on age eventually fed into his legal model of consenting adults in private. They also provide a starting point for the historical understanding of the trope of "grooming pedophile" as it, arguably, crossfaded with that of the "seducing homosexual" after the latter's depsychiatricization across the Western world. PMID- 27982740 TI - Identifying the Career-Interest Profiles of Junior-High-School Students Through Latent Profile Analysis. AB - Exploring the career-interest profiles of students has both practical and theoretical significance; however, a minimal amount of research has been conducted to address this issue. The present study combined latent profile analysis and differentiation values to investigate the career-interest profiles of 13,853 junior-high-school students. The results indicate that while the students' interests could be stratified into 25 profiles, 44.6% of students could be classified the as having low-differentiation profiles (such as like or dislike all types of vocational activities) and 24.9% of students could be classified the as having the artistic-social (like both artistic and social types of activities) profile. In addition, the proportions of females and males differed significantly among the profiles, but different grades did not. The proportion of males was higher for all three low-differentiation groups than of female proportions. Implications for career practices and future research are proposed. PMID- 27982741 TI - Quality of life and burden in family caregivers of patients with advanced cancer in active treatment settings and hospice care: A comparative study. AB - The aim of this study was to evaluate caregiver burden and quality of life (QoL) in active treatment settings and hospice care for 76 family caregivers of advanced cancer patients, using the Medical Outcomes Study Short Form and the Caregiver Burden Inventory. Compared to the active group, the hospice group reported significantly lower QoL scores in mental component summary score and higher scores in general health subscale and in physical component summary score. Future research needs to further investigate the complexities of caregivers' needs, especially in the emotional and mental domains, and offer effective, clinically proven interventions. PMID- 27982742 TI - The trend in suicide methods in South Korea in 1997-2015. AB - South Korea exhibited the highest crude suicide rate in the world. To better understand this phenomenon, the author analyzed all suicides in South Korea from 1997 to 2015 and charted the trend in suicide methods by gender. Over time, both genders rapidly chose hanging for suicide at the expense of drug/pesticide poisoning. Gassing was hardly used in the beginning, but its recent gain in use is noteworthy. Including undetermined deaths did not change the main results. The author regressed hanging on demographics and found that hanging was particularly chosen by ever-married men of prime working age with a respectable level of education. PMID- 27982743 TI - Stereotypes, Emotions, and Behaviors Toward Lesbians, Gay Men, Bisexual Women, and Bisexual Men. AB - The utility of the Stereotype Content Model (Fiske, Cuddy, Glick, & Xu, 2002) and the Behaviors from Intergroup Affect and Stereotypes map (Cuddy, Fiske, & Glick, 2007) were examined in the context of heterosexuals' attitudes toward sexual minorities. Heterosexual adults completed a survey measuring stereotypes, emotions, and behavioral tendencies toward lesbians, gay men, bisexual women, and bisexual men. Stereotype content differed across groups and showed "gendered" and "valenced" effects on emotions and behavioral tendencies. Competence predicted behaviors for men, whereas warmth and competence predicted behaviors for women, and, for the most part, more was better. Admiration and contempt mediated most of these relationships across most subgroups, but pity and envy played smaller roles for some subgroups. Across all groups, competence played a more predictive role than warmth. PMID- 27982744 TI - Factors that Influence Physical Activity among Residents in Assisted Living. AB - The purpose of this study was to examine factors that influence physical activity among residents in assisted living. This was a secondary data analysis using baseline data from a function-focused care intervention study including 171 residents from 4 assisted living facilities. Using structural equation modeling, we found that mood, satisfaction with staff and activities, and social support for exercise were directly associated with time spent in physical activity. Gender, cognition, depression, and comorbidities were indirectly associated with physical activity and accounted for 13% of the total variance in physical activity. Implications for future research and social work practice are presented. PMID- 27982745 TI - The Potential Role of Science, Technology, Engineering, and Math Programs in Reducing Teen Dating Violence and Intimate Partner Violence. AB - Science, technology, engineering, and math (STEM) are growing fields that provide job stability, financial security, and health prosperity for professionals in these fields. Unfortunately, females are underrepresented in STEM, which is potentially both a consequence and precipitant of gender inequity in the United States. In addition to the financial and health benefits, increasing the number of girls and women in STEM fields may also indirectly prevent and/or reduce teen dating violence and intimate partner violence by: (1) increasing women's financial independence, thereby reducing dependence on potentially abusive partners; (2) decreasing household poverty and financial stress, which may lead to reductions in relationship discord; and (3) increasing attitudes and beliefs about women as equals, thereby increasing gender equity. In this commentary, we discuss the potential role of primary and secondary school STEM programs in reducing violence against women. We review the literature on existing evaluations of STEM programs for educational outcomes, discuss the limitations of these evaluations, and offer suggestions for future research. PMID- 27982746 TI - Body Mass Index As a Measure of Obesity: Racial Differences in Predictive Value for Health Parameters During Pregnancy. PMID- 27982747 TI - Women's perception of adolescent marijuana use in a hispanic seasonal farm worker community: A qualitative study. AB - We examined the perception of adolescent children's marijuana use and its consequences in the Hispanic seasonal farmworking community of South Florida via three focus groups with Hispanic adult female seasonal workers (n = 29). The women described how adolescents' marijuana use increased over the past five years. Social networks for marijuana use were reported near schools and bus stations. Although participants expressed concern over adolescent marijuana use and involvement in selling marijuana, they reported that their job demands preclude their ability to supervise their children. Participants do not report unlawful marijuana use due to fear of deportation. PMID- 27982748 TI - Self-Reported Reasons for Smoking: Predicting Abstinence and Implications for Smoking Cessation Treatments Among Those With a Psychotic Disorder. AB - OBJECTIVES: People living with a psychotic illness have higher rates of cigarette smoking and face unique barriers to quitting compared to the general population. We examined whether self-reported reasons for smoking are useful predictors of successful quit attempts among people with psychosis. METHODS: As part of a randomized controlled trial addressing smoking and cardiovascular disease risk behaviors among people with psychosis, self-reported reasons for smoking were assessed at baseline (n = 235), 15 weeks (n = 151), and 12 months (n = 139). Three factors from the Reasons for Smoking Questionnaire (Coping, Physiological, and Stimulation/Activation) were entered into a model to predict short- and long term abstinence. The relationship between these factors and mental health symptoms were also assessed. RESULTS: Participants scoring higher on the Stimulation/Activation factor (control of weight, enjoyment, concentration, and "peps me up") at baseline were just less than half as likely to be abstinent at 15 weeks. Female participants were five times more likely to abstinent at 15 weeks, and those with a higher global functioning at baseline were 5% more likely to be abstinent. There was a positive correlation between changes over time in the Stimulation/Activation factor from baseline to 12-month follow-up and the Brief Psychiatric Rating Scale total score at 12-month follow-up. This indicates that increasingly higher endorsement of the factor was associated with more psychological symptoms. There was also a negative correlation between the change over time in the Stimulation/Activation factor and global functioning at 12 months, indicating that increasingly higher endorsement of the factor led to lower global assessment of functioning. CONCLUSIONS: The Stimulation/Activation factor may be particularly important to assess and address among smokers with psychosis. It is recommended that further research use the Reasons for Smoking Questionnaire among smokers with psychosis as a clinical tool to identify specific quit barriers. Further research into why females have higher smoking cessation rates in the short term and relapse prevention interventions seem worthy of further investigation. PMID- 27982749 TI - Energy-triggered drug release from polymer nanoparticles for orthopedic applications. AB - Sequestra, present in many cancers and orthopedic infections, provide a safe harbor for the development of drug resistance. In the face of burgeoning drug resistance, the importance of nanoscale, microenvironment-triggered drug delivery cannot be overestimated. Such strategies may preserve pharmaceutical efficacy and significantly alter the etiology of many orthopedic diseases. Although temperature-, pH- and redox-responsive nanoparticle-based systems have been extensively studied, local drug delivery from polymeric nanoparticles can be triggered by a variety of energy forms. This review offers an overview of the state of the field as well as a perspective on the safety and efficacy of ultrasound, hyperthermia and radio frequency-triggered internal delivery systems in a variety of applications. PMID- 27982750 TI - Impact of Evidence Type and Judicial Warning on Juror Perceptions of Global and Specific Witness Evidence. AB - The Court of Appeal in England and Wales held (R. v. Sardar, 2012) there had been no exceptional circumstances that justified a jury retiring with a transcript of the complainant's interview. This paper reports an investigation into the impact multiple evidence forms and use of a judicial warning has on juror evaluations of a witness. The warning focuses juror attention on placing disproportionate weight on the evidence as opposed to their general impression of it. Sixty jury-eligible participants were presented with witness evidence in transcript, video, or transcript plus video format. Half the participants in each condition received the warning. All mock jurors completed a questionnaire which assessed perceptions of witness and task. Outcomes showed that transcript plus video evidence, when accompanied by a warning, did impact on mock jurors' global assessments of the witness. The warning made the task less clear for jurors and, in the video condition, led to higher ratings of how satisfactory and reliable the witness was. Findings support the provision of a judicial warning to jurors and show some initial support for judiciary opposition to the provision of an additional transcript only when jurors are asked to make the more usual global witness assessments. PMID- 27982751 TI - An expert's opinion on what lies ahead in the field of alternative drug delivery. AB - Tarun Goswami speaks to Hannah Makin, Commissioning Editor: Tarun Goswami obtained his BS (Pharmacy) in 2003 from Delhi University (India) and his PhD in Pharmaceutical Sciences in 2008 from the University of the Pacific (CA, USA). He currently works at Amneal Pharmaceuticals as a Formulation Scientist in the Transdermal Drug Delivery Group. Having published multiple abstracts and articles in the area of transdermal and oral mucosal drug delivery, his current interests include the development of drug products that are administered via alternate routes such as through the skin and oral mucosa. PMID- 27982752 TI - Krill Oil Supplementation Improves Dyslipidemia and Lowers Body Weight in Mice Fed a High-Fat Diet Through Activation of AMP-Activated Protein Kinase. AB - Krill oil is a novel, commercially available marine oil rich in long-chain polyunsaturated omega-3 fatty acids, particularly eicosapentaenoic acid and docosahexaenoic acid. Compared with fish oil, the effects of krill oil supplementation on human health and its underlying action mechanisms are currently poorly understood. In the present study, we examined the effect of krill oil supplementation on metabolic parameters of mice fed a high-fat diet (HFD). Krill oil supplementation in mice fed a HFD for 10 weeks resulted in an ~15% lower body weight gain and a dramatic suppression of hepatic steatosis. These effects were associated with significantly lower serum triglyceride and low density lipoprotein-cholesterol levels. We further uncovered a novel underlying mechanism, showing that AMP-activated protein kinase, a master regulator of glucose and lipid metabolism, mediates the beneficial effects of krill oil. PMID- 27982754 TI - Apium graveolens Extract Inhibits Cell Proliferation and Expression of Vascular Endothelial Growth Factor and Induces Apoptosis in the Human Prostatic Carcinoma Cell Line LNCaP. AB - Apium graveolens has been shown to inhibit the growth of a variety of cancer tissues. In this study, we investigated the anticancer effect of A. graveolens on the human prostatic carcinoma cell line LNCaP. LNCaP cells were treated with increasing concentrations of an ethanolic extract of A. graveolens ranging from 1000 to 3000 MUg/mL, and viability was determined after 24 and 48 h using the XTT cell proliferation assay. The levels of cleaved poly (ADP-ribose) polymerase (PARP), one of the best biomarkers of apoptosis, were analyzed. Finally, quantitative gene expression analysis of vascular endothelial growth factor (VEGF), a critical mediator of angiogenesis, was performed using real-time reverse transcription-polymerase chain reaction. A. graveolens extract inhibited cell viability in both a time- and dose-dependent manner. Data from cleaved PARP assays suggested that A. graveolens caused induction of apoptosis in these cells. Treatment of cells with A. graveolens also resulted in downregulation of VEGF expression. This study showed that the antiproliferative effect exerted by an ethanolic extract of A. graveolens is triggered by induction of apoptosis. We also demonstrated that VEGF expression was downregulated by treatment with A. graveolens extract. PMID- 27982755 TI - Cytotoxicity and Proteasome Inhibition by Alkaloid Extract from Murraya koenigii Leaves in Breast Cancer Cells-Molecular Docking Studies. AB - Murraya koenigii (curry tree) leaves are rich in bioactive compounds such as flavonoids, alkaloids, and coumarins. Alkaloids from M. koenigii leaves have antianalgesic, antiulcerogenic, antiobesity, and antitumor activities. In this study, we tested the cytotoxic and proteasome-inhibitory potential of a total alkaloid extract (TAE) from M. koenigii leaves in the breast cancer cell line MDA MB-231. The TAE decreased cell viability with an IC50 of 14.4 MUg/mL and altered growth kinetics of breast cancer cells. TAE (32 MUg/mL) arrested cells (35%) in the "S" phase of the cell cycle and induced apoptosis. The 26S proteasome, a multicatalytic protease complex, promotes tumor cell proliferation and protects tumor cells from apoptosis. The TAE and mahanine, a carbazole alkaloid present in M. koenigii leaves, preferentially inhibited the trypsin-like, but not the chymotrypsin-like proteolytic activity of the proteasome with an IC50 of 162 MUg/mL and 287 MUM, respectively. In silico analysis of 26 compounds from M. koenigii leaves revealed significant docking scores for mahanine and two other carbazole alkaloids with the beta2 and beta5 subunits of the catalytic 20S proteasome. Taken together, this study demonstrates that inhibition of the proteasome is an important biological activity of M. koenigii alkaloids, which may lead to cancer cell death. PMID- 27982753 TI - FlexPro MD, a Mixture of Krill Oil, Astaxanthin, and Hyaluronic Acid, Suppresses Lipopolysaccharide-Induced Inflammatory Cytokine Production Through Inhibition of NF-kappaB. AB - FlexPro MD(r) (FP-MD), a novel multi-ingredient dietary supplement formulation, has been demonstrated to relieve knee joint pain in humans. However, the mechanisms of action responsible for the activity of FP-MD have not been elucidated. In this study, we show the anti-inflammatory effects of FP-MD in RAW264.7 macrophage cells and mice challenged with lipopolysaccharide (LPS). FP MD significantly inhibited the mRNA levels of pro-inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and IL 1beta. In contrast, it elevated the mRNA levels of anti-inflammatory cytokine IL 10 in LPS-stimulated RAW264.7 cells. FP-MD markedly reduced LPS-induced phosphorylation levels of nuclear factor-kappaB (NF-kappaB) p65 and inhibitor of kappaB-alpha (IkappaB-alpha). Importantly, the anti-inflammatory effects of FP-MD were demonstrated in mice with LPS-induced inflammatory arthritis in which FP-MD significantly reduced the expression levels of pro-inflammatory cytokines and inflammatory markers. Thus, this study suggests that FP-MD has anti-inflammatory effects by inhibiting NF-kappaB that may offer a molecular basis for its pain relief property. PMID- 27982756 TI - Absorption of Orally Administered Hyaluronan. AB - Hyaluronan (HA) has been utilized as a supplement. However, the absorption of orally administrated HA remains controversial. The degradation and absorption of HA in the intestine were investigated in this study. HA excretion into the feces, degradation in the intestinal tract, absorption through the large intestine, and translocation to the blood and skin were examined. HA administered orally was not detected in rat feces. HA was degraded by cecal content, but not by artificial gastric juice and intestinal juice. Oligosaccharide HA passed through excised large intestine sacs. Furthermore, disaccharides, tetrasaccharides, and polysaccharides HA were distributed to the skin of rats following oral administration of high molecular weight HA (300 kDa). The results of the study suggest that orally administered HA is degraded to oligosaccharides by intestinal bacteria, and oligosaccharide HA is absorbed in the large intestine and is subsequently distributed throughout the tissues, including the skin. PMID- 27982757 TI - Relationship Between Plant Food (Fruits, Vegetables, and Kimchi) Consumption and the Prevalence of Rhinitis Among Korean Adults: Based on the 2011 and 2012 Korea National Health and Nutrition Examination Survey Data. AB - The aim of the current study was to analyze the relationship between plant food (fruits, vegetables, and kimchi) and the prevalence of rhinitis among Korean adults using data from the 2011 and 2012 Korea National Health and Nutrition Examination Survey. A total of 7494 subjects aged from 19 to 64 years participated in a rhinitis morbidity survey, health behavior interview, and 24-h dietary recall test. Individuals with energy intakes less than 500 kcal or more than 5000 kcal were excluded. The results showed that kimchi intake was inversely associated with the prevalence of rhinitis. The prevalence of rhinitis decreased with increasing kimchi consumption. The quintile 4 (range of kimchi intake: 108.0 180.0 g) groups, compared with the reference of quintile 1 (0-23.7 g), showed a decrease of 18.9% (odds ratio [OR] = 0.811, 95% confidence interval [CI] = 0.672 0.979) in Model 4. In conclusion, consumption of kimchi lowers the risk of rhinitis, suggesting that its use should be encouraged among the Korean population. PMID- 27982758 TI - Burst Suppression in Hypothermia After Cardiac Arrest Because of Drowning Treated with Targeted Temperature Management: A Case Report. AB - Outcomes of cardiac arrest (CA) because of drowning in children are generally poor, but some reports show that cases with post-CA hypothermia because of drowning exhibit good recovery when treated with targeted temperature management (TTM). However, because electroencephalogram (EEG) findings are not reported in those cases, a complete examination of brain damage has not been performed during TTM. Here we report a case of a 15-month-old boy with post-CA hypothermia recovery after treating with TTM, along with EEG findings. The initial clinical and laboratory data and resuscitation history in the current case strongly indicated an unfavorable outcome. However, the return of normal EEG findings after 36 hours postadmission may indicate favorable neurological outcomes. Although reliable evidence has not been established, we recommend maintained mild therapeutic hypothermia using TTM, followed by slow rewarming in patients with post-CA hypothermia because of drowning, based on the observations in the current case and in other studies. PMID- 27982759 TI - MR Imaging-derived Oxygen Metabolism and Neovascularization Characterization for Grading and IDH Gene Mutation Detection of Gliomas. AB - Purpose To explore the diagnostic performance of physiological magnetic resonance (MR) imaging of oxygen metabolism and neovascularization activity for grading and characterization of isocitrate dehydrogenase (IDH) gene mutation status of gliomas. Materials and Methods This retrospective study had institutional review board approval; written informed consent was obtained from all patients. Eighty three patients with histopathologically proven glioma (World Health Organization [WHO] grade II-IV) were examined with quantitative blood oxygen level-dependent imaging and vascular architecture mapping. Biomarker maps of neovascularization activity (microvessel radius, microvessel density, and microvessel type indicator [MTI]) and oxygen metabolism (oxygen extraction fraction [OEF] and cerebral metabolic rate of oxygen [CMRO2]) were calculated. Receiver operating characteristic analysis was used to determine diagnostic performance for grading and detection of IDH gene mutation status. Results Low-grade (WHO grade II) glioma showed areas with increased OEF (+18%, P < .001, n = 20), whereas anaplastic glioma (WHO grade III) and glioblastoma (WHO grade IV) showed decreased OEF when compared with normal brain tissue (-54% [P < .001, n = 21] and -49% [P < .001, n = 41], respectively). This allowed clear differentiation between low- and high-grade glioma (area under the receiver operating characteristic curve [AUC], 1) for the patient cohort. MTI had the highest diagnostic performance (AUC, 0.782) for differentiation between gliomas of grades III and IV among all biomarkers. CMRO2 was decreased (P = .037) in low-grade glioma with a mutated IDH gene, and MTI was significantly increased in glioma grade III with IDH mutation (P = .013) when compared with the IDH wild-type counterparts. CMRO2 showed the highest diagnostic performance for IDH gene mutation detection in low-grade glioma (AUC, 0.818) and MTI in high-grade glioma (AUC, 0.854) and for all WHO grades (AUC, 0.899) among all biomarkers. Conclusion MR imaging-derived oxygen metabolism and neovascularization characterization may be useful for grading and IDH mutation detection of gliomas and requires only 7 minutes of extra imaging time. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27982760 TI - Two-dimensional Shear-Wave Elastography Performance in the Noninvasive Evaluation of Liver Fibrosis in Patients with Chronic Hepatitis B: Comparison with Serum Fibrosis Indexes. AB - Purpose To investigate the value of two-dimensional (2D) shear-wave elastography (SWE) in the assessment of hepatic fibrosis in patients with chronic hepatitis B (CHB) and to compare the diagnostic performance of this modality with that of liver fibrosis indexes. Materials and Methods The ethics committee approved this study, and informed consent was obtained. From July 2015 to May 2016, 539 subjects who underwent partial hepatectomy were divided into groups according to the Scheuer system by using a resected liver specimen. All patients were examined with 2D SWE and underwent preoperative serologic testing to measure liver stiffness and values of serum fibrosis models, which were compared with histologic findings. Performance of noninvasive methods was determined for index (304 patients) and validation (155 patients) cohorts by using areas under the receiver operating characteristic curve (AUCs). Results For association with substantial fibrosis (>=S2), severe fibrosis (>=S3), and cirrhosis (S4) in the index cohort, the optimal cutoff values of liver stiffness were 7.6, 9.2, and 10.4 kPa, respectively, and AUC values were 0.97, 0.96, and 0.98, respectively. The 2D SWE findings, aspartate transaminase-to-platelet ratio index (APRI), fibrosis index based on the four factors (FIB-4), King's score, and Forns index significantly correlated with hepatic fibrosis stages (rho = 0.88, rho = 0.41, rho = 0.40, rho = 0.43 and rho = 0.45, respectively; P < .05). The AUCs for APRI, FIB-4, King's score, and Forns index were 0.77, 0.73, 0.79, and 0.77, respectively, in the diagnosis of substantial fibrosis and 0.70, 0.71, 0.72, and 0.74, respectively, in the diagnosis of cirrhosis. In the validation cohort, AUCs of noninvasive methods used to assess different fibrosis stages did not significantly differ from those for the index cohort. AUCs of 2D SWE in the diagnosis of substantial fibrosis, severe fibrosis, and cirrhosis were 0.97, 0.97, and 0.98, respectively, which were significantly higher than those in serum models (P < .05). Conclusion The 2D SWE protocol could be used to predict substantial fibrosis, severe fibrosis, and cirrhosis in patients with CHB with notably higher diagnostic accuracy than that attained with serum fibrosis models. (c) RSNA, 2016. PMID- 27982761 TI - Liver Stiffness in Pediatric Patients with Fatty Liver Disease: Diagnostic Accuracy and Reproducibility of Shear-Wave Elastography. AB - Purpose To evaluate the diagnostic accuracy of shear-wave elastography (SWE) in identifying different degrees of fibrosis in a cohort of consecutive children and adolescents with nonalcoholic steatohepatitis (NASH). Materials and Methods Consecutive pediatric patients scheduled to undergo liver biopsy were studied with an ultrasonography-based SWE system. Elastography was performed in 68 of 69 patients with biopsy-proved NASH (37 boys and 31 girls; mean age, 12.6 years +/- 2.48; age range, 8-17 years). The correlations among laboratory findings, liver stiffness, and fibrosis score were analyzed, and the area under the receiver operating characteristic curve (AUC) was used to assess the presence of any fibrosis (score >=F1) or significant fibrosis (score >=F2). Findings from histologic examination were used as the standard of reference. Results SWE showed a very high correlation with liver fibrosis (P < .001) at univariate and multivariate analyses. The AUCs for the association of any and significant fibrosis were 0.92 (95% confidence interval [CI]: 0.86, 0.98) and 0.97 (95% CI: 0.95, 0.99), respectively. The intraclass correlation coefficient for absolute agreement was 0.95 (95% CI: 0.90, 0.97). Conclusion SWE is an accurate and reproducible noninvasive technique that efficiently depicts the presence of significant liver fibrosis and, less accurately, mild liver fibrosis in pediatric patients with nonalcoholic fatty liver disease. Larger clinical prospective studies are warranted to confirm SWE accuracy and establish threshold values for fibrosis grading in comparison or in combination with other noninvasive methods. (c) RSNA, 2016. PMID- 27982762 TI - The response of spinal cord ependymomas to bevacizumab in patients with neurofibromatosis Type 2. AB - OBJECTIVE People with neurofibromatosis Type 2 (NF2) have a genetic predisposition to nervous system tumors. NF2-associated schwannomas stabilize or decrease in size in over half of the patients while they are receiving bevacizumab. NF2 patients treated with bevacizumab for rapidly growing schwannoma were retrospectively reviewed with regard to ependymoma prevalence and response to treatment. METHODS The records of 95 NF2 patients receiving bevacizumab were retrospectively reviewed with regard to spinal ependymoma prevalence and behavior. The maximum longitudinal extent (MLE) of the ependymoma and associated intratumoral or juxtatumoral cysts were measured on serial images. Neurological changes and patient function were reviewed and correlated with radiological changes. RESULTS Forty-one of 95 patients were found to have ependymomas (median age 26 years; range 11-53 years). Thirty-two patients with a total of 71 ependymomas had scans appropriate for serial assessment with a mean follow-up of 24 months (range 3-57 months). Ependymomas without cystic components showed minimal change in MLE. Twelve patients had ependymomas with cystic components or syringes. In these patients, reductions in MLE were observed, particularly due to decreases in the cystic components of the ependymoma. Clinical improvement was seen in 7 patients, who all had cystic ependymomas. CONCLUSIONS Bevacizumab treatment in NF2 patients with spinal cord ependymomas results in a decrease in the size of intratumoral and juxtatumoral cysts as well as adjacent-cord syringes and a decrease in cord edema. This may provide clinical benefit in some patients, although the changes do not meet the current criteria for radiological tumor response. PMID- 27982763 TI - Effects of intradiscal vacuum phenomenon on surgical outcome of lateral interbody fusion for degenerative lumbar disease. AB - OBJECTIVE The authors investigated whether the presence of intradiscal vacuum phenomenon (IVP) results in greater correction of disc height and restoration of segmental lordosis (SL). METHODS A retrospective chart review was performed on every patient at the University of South Florida's Department of Neurosurgery treated with lateral lumbar interbody fusion between 2011 and 2015. From these charts, preoperative plain radiographs and CT images were reviewed for the presence of IVP. Preoperative and postoperative posterior disc height (PDH), anterior disc height (ADH), and SL were measured at disc levels with IVP and compared with those at disc levels without IVP using the t-test. Linear regression was used to evaluate the factors that predict changes in PDH, ADH, and SL. RESULTS One hundred forty patients with 247 disc levels between L-1 and L-5 were treated with lateral lumbar interbody fusion. Among all disc levels treated, the mean PDH increased from 3.69 to 6.66 mm (p = 0.011), the mean ADH increased from 5.45 to 11.53 mm (p < 0.001), and the mean SL increased from 9.59 degrees to 14.55 degrees (p < 0.001). Significantly increased PDH was associated with the presence of IVP, addition of pedicle screws, and lack of cage subsidence; significantly increased ADH was associated with the presence of IVP, anterior longitudinal ligament (ALL) release, addition of pedicle screws, and lack of subsidence; and significantly increased SL was associated with the presence of IVP and ALL release. CONCLUSIONS IVP in patients with degenerative spinal disease remains grossly underreported. The data from the present study suggest that the presence of IVP results in increased restoration of disc height and SL. PMID- 27982764 TI - Spinal cord hemangioblastomas: significance of intraoperative neurophysiological monitoring for resection and long-term outcome. AB - OBJECTIVE Spinal cord hemangioblastomas are rare benign tumors developing either sporadically or as part of von Hippel-Lindau (VHL) disease. Generally, resection is the treatment of choice. However, the significance of intraoperative neurophysiological monitoring (IONM) for resection and postoperative outcome is still controversial. The authors analyzed the surgical and clinical courses of patients who had undergone resection of spinal cord hemangioblastoma, with special attention to preoperative imaging, the use of IONM, and short- and long term outcomes. METHODS A series of 24 patients (male/female 1:1, lesion sporadic/associated with VHL 2.4:1) who had undergone 26 operations for the resection of 27 spinal cord hemangioblastomas was analyzed. All patients had undergone pre- and postoperative contrast-enhanced MRI. In all cases, microsurgical tumor removal had been performed under continuous IONM of both somatosensory and transcranial motor evoked potentials as well as electromyographic recording. Clinical characteristics, imaging findings, and operative records were retrospectively analyzed. Outcome parameters included short- and long-term status as regards sensorimotor deficits and a questionnaire on general performance, patient satisfaction, and Oswestry Disability Index (ODI) at the end of the follow-up period. The impact of IONM findings on postoperative deficits and outcome parameters as well as risk factors affecting functional prognosis was statistically assessed. RESULTS Preoperative symptoms (mean duration 16.2 +/- 22.0 months) included sensory changes (100.0%), pain (66.7%), spinal ataxia (66.7%), motor deficit (41.7%), and bladder/bowel dysfunction (12.5%). Average age at the first operation was 36.8 +/- 12.8 years. Most tumors (21 intramedullary, 6 intra- and/or extramedullary) were located dorsally (92.6%) and cervically (77.8%) and were accompanied by peritumoral edema and/or syringomyelia (81.5%). Tumor resection was achieved via laminectomy for 15 tumors, hemilaminectomy for 5, laminoplasty for 6, and interlaminar approach for 1. Gross-total resection was accomplished for 26 tumors (96.3%) with no local tumor recurrence during follow-up. Intraoperative neurophysiological monitoring was nonpathological in 11 operations (42.3%) and pathological in 15 (57.7%). Patients with nonpathological IONM had significantly fewer new sensorimotor deficits (p = 0.005). Long-term follow-up evaluation (mean 7.9 +/- 4.0 years postoperatively, 7 patients lost to follow-up) revealed a stable or improved McCormick myelopathy grade in 88.2% of the patients, and 88.2% reported a stable or improved overall outcome according to Odom's criteria. Long-term general performance was excellent with 88.2% having a WHO/Eastern Cooperative Oncology Group (ECOG) Performance Status grade <= 1, 76.5% a Karnofsky Performance Scale score >= 80, and 70.6% a Barthel Index (BI) of 100. The mean ODI (11.4% +/- 12.5%) indicated only minimal disability. There was a significant correlation between pathological IONM findings and a worse long-term status according to the BI and ODI (p = 0.011 and 0.024, respectively). Additionally, VHL disease was a risk factor affecting functional prognosis (p = 0.044). CONCLUSIONS Microsurgical removal of spinal cord hemangioblastomas with IONM facilitates a satisfying long term outcome for patients. Nonpathological IONM findings are associated with a lower risk of new sensorimotor deficits and correlate with a better overall long term outcome. von Hippel-Lindau disease is a risk factor for a worse long-term prognosis. PMID- 27982765 TI - The epidemiology of spinal tuberculosis in the United States: an analysis of 2002 2011 data. AB - OBJECTIVE The aim of this study was to investigate the incidence of spinal tuberculosis (TB) in the US between 2002 and 2011. METHODS The Nationwide Inpatient Sample database from 2002 to 2011 was used to identify patients with a discharge diagnosis of TB and spinal TB. Demographic and hospital data were obtained for all admissions, and included age, sex, race, comorbid conditions, insurance status, hospital location, hospital teaching status, and hospital region. The incidence rate of spinal TB adjusted for population growth was calculated after application of discharge weights. RESULTS A total of 75,858 patients with a diagnosis of TB were identified, of whom 2789 had a diagnosis of spinal TB (3.7%); this represents an average of 278.9 cases per year between 2002 and 2011. The incidence of spinal TB decreased significantly-from 0.07 cases per 100,000 persons in 2002 to 0.05 cases per 100,000 in 2011 (p < 0.001), corresponding to 1 case per 2 million persons in the latter year. The median age for patients with spinal TB was 51 years, and 61% were male; 11.6% were patients with diabetes, 11.4% reported recent weight loss, and 8.1% presented with paralysis. There were 619 patients who underwent spinal surgery for TB, with the most common location being the thoracolumbar spine (61.9% of cases); 50% of patients had instrumentation of 3 or more spinal segments. CONCLUSIONS During the examined 10-year period, the incidence of spinal TB was found to significantly decrease over time in the US, reaching a rate of 1 case per 2 million persons in 2011. However, the absolute reduction was relatively small, suggesting that although it is uncommon, spinal TB remains a public health concern and most commonly affects male patients approximately 50 years of age. Approximately 20% of patients with spinal TB underwent surgery, most commonly in the thoracolumbar spine. PMID- 27982766 TI - Gender orientation and alcohol-related weight control behavior among male and female college students. AB - OBJECTIVE: We examine weight control behavior used to (a) compensate for caloric content of heavy alcohol use; and (b) enhance the psychoactive effects of alcohol among college students. We evaluate the role of gender orientation and sex. PARTICIPANTS: Participants completed an online survey (N = 651; 59.9% women; 40.1% men). METHOD: Weight control behavior was assessed via the Compensatory Eating-and-Behaviors-in Response-to-Alcohol-Consumption-Scale. Control variables included sex, race/ethnicity, age, and depressive symptoms. Gender orientation was measured by the Bem Sex Role Inventory. The prevalence and probability of alcohol-related weight control behavior using ordinal logistic regression are reported. RESULTS: Men and women do not significantly differ in compensatory weight-control-behavior. However, regression models suggest that recent binge drinking, other substance use, and masculine orientation are positively associated with alcohol-related weight control behavior. CONCLUSIONS: Sex was not a robust predictor of weight control behavior. Masculine orientation should be considered a possible risk factor for these behaviors and considered when designing prevention and intervention strategies. PMID- 27982767 TI - Octreotide therapy in meningiomas: in vitro study, clinical correlation, and literature review. AB - OBJECTIVE Meningiomas express somatostatin receptor subtype 2 (SST2), which is targeted by the somatostatin analog octreotide. However, to date, using somatostatin analog therapy for the treatment of these tumors in clinical practice has been debated. This study aims to clarify the in vitro effects of octreotide on meningiomas for precise clinical applications. METHODS The effects of octreotide were analyzed in a large series of 80 meningiomas, including 31 World Health Organization (WHO) Grade II and 4 WHO Grade III tumors, using fresh primary cell cultures to study the impact on cell viability, apoptosis, and signal transduction pathways. RESULTS SST2 mRNA was detected in 100% of the tested meningiomas at levels similar to those observed in other SST2-expressing tumors, neuroendocrine tumors, or pituitary adenomas. Octreotide significantly decreased cell proliferation in 88% of meningiomas but did not induce cell death. On average, cell proliferation was more inhibited in the meningioma group expressing a high level of SST2 than in the low-SST2 group. Moreover, octreotide response was positively correlated to the level of merlin protein and inversely correlated to the level of phosphorylated p70-S6 kinase, a downstream effector of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway. Octreotide inhibited Akt phosphorylation and activated tyrosine phosphatase without impacting the extracellular regulated kinase (ERK) pathway. CONCLUSIONS Octreotide acts exclusively as an antiproliferative agent and does not promote apoptosis in meningioma in vitro. Therefore, in vivo, octreotide is likely to limit tumor growth rather than induce tumor shrinkage. A meta-analysis of the literature reveals an interest in octreotide for the treatment of WHO Grade I tumors, particularly those in the skull base for which the 6-month progression-free survival level reached 92%. Moreover, somatostatin analogs, which are well tolerated drugs, could be of interest for use as co-targeting therapies for aggressive meningiomas. PMID- 27982768 TI - Predictive factors for recurrence and clinical outcomes in patients with chronic subdural hematoma. AB - OBJECTIVE Chronic subdural hematoma (CSDH) is a common type of intracranial hemorrhage in elderly patients. Many studies have suggested various factors that may be associated with the recurrence of CSDH. However, the results are inconsistent. The purpose of this study was to determine the associations among patient factors, recurrence, and clinical outcomes of CSDH after bur hole surgery performed during an 11-year period at twin hospitals. METHODS Kaplan-Meier analysis was performed to evaluate the risk factors for CSDH recurrence. Univariate and multivariate Cox proportional hazards regression analyses were used to calculate hazard ratios with 95% CIs for CSDH recurrence based on many variables. One-way repeated-measures ANOVA was used to assess the differences in the mean modified Rankin Scale score between categories for each risk factor during each admission and at the last follow-up. RESULTS This study was a retrospective analysis of 756 consecutive patients with CSDH who underwent bur hole surgery at the Hanyang University Medical Center (Seoul and Guri) between January 1, 2004, and December 31, 2014. During the 6-month follow-up, 104 patients (13.8%) with recurrence after surgery for CSDH were identified. Independent risk factors for recurrence were as follows: age > 75 years (HR 1.72, 95% CI 1.03-2.88; p = 0.039), obesity (body mass index >= 25.0 kg/m2), and a bilateral operation. CONCLUSIONS This study determined the risk factors for recurrence of CSDH and their effects on outcomes. Further studies are needed to account for these observations and to determine their underlying mechanisms. PMID- 27982769 TI - A novel assistive method for rigidity evaluation during deep brain stimulation surgery using acceleration sensors. AB - OBJECTIVE Despite the widespread use of deep brain stimulation (DBS) for movement disorders such as Parkinson's disease (PD), the exact anatomical target responsible for the therapeutic effect is still a subject of research. Intraoperative stimulation tests by experts consist of performing passive movements of the patient's arm or wrist while the amplitude of the stimulation current is increased. At each position, the amplitude that best alleviates rigidity is identified. Intrarater and interrater variations due to the subjective and semiquantitative nature of such evaluations have been reported. The aim of the present study was to evaluate the use of an acceleration sensor attached to the evaluator's wrist to assess the change in rigidity, hypothesizing that such a change will alter the speed of the passive movements. Furthermore, the combined analysis of such quantitative results with anatomy would generate a more reproducible description of the most effective stimulation sites. METHODS To test the reliability of the method, it was applied during postoperative follow-up examinations of 3 patients. To study the feasibility of intraoperative use, it was used during 9 bilateral DBS operations in patients suffering from PD. Changes in rigidity were calculated by extracting relevant outcome measures from the accelerometer data. These values were used to identify rigidity-suppressing stimulation current amplitudes, which were statistically compared with the amplitudes identified by the neurologist. Positions for the chronic DBS lead implantation that would have been chosen based on the acceleration data were compared with clinical choices. The data were also analyzed with respect to the anatomical location of the stimulating electrode. RESULTS Outcome measures extracted from the accelerometer data were reproducible for the same evaluator, thus providing a reliable assessment of rigidity changes during intraoperative stimulation tests. Of the 188 stimulation sites analyzed, the number of sites where rigidity-suppressing amplitudes were found increased from 144 to 170 when the accelerometer evaluations were considered. In general, rigidity release could be observed at significantly lower amplitudes with accelerometer evaluation (mean 0.9 +/- 0.6 mA) than with subjective evaluation (mean 1.4 +/- 0.6 mA) (p < 0.001). Of 14 choices for the implant location of the DBS lead, only 2 were the same for acceleration-based and subjective evaluations. The comparison across anatomical locations showed that stimulation in the fields of Forel ameliorates rigidity at similar amplitudes as stimulation in the subthalamic nucleus, but with fewer side effects. CONCLUSIONS This article describes and validates a new assistive method for assessing rigidity with acceleration sensors during intraoperative stimulation tests in DBS procedures. The initial results indicate that the proposed method may be a clinically useful aid for optimal DBS lead placement as well as a new tool in the ongoing scientific search for the optimal DBS target for PD. PMID- 27982770 TI - The semisitting position: analysis of the risks and surgical outcomes in a contemporary series of 425 adult patients undergoing cranial surgery. AB - OBJECTIVE The objective of this study was to analyze the incidence of the primary complications related to positioning or surgery and their impact on neurological outcome in a consecutive series of patients undergoing elective surgery in the semisitting position. METHODS The authors prospectively collected and retrospectively analyzed data from adult patients undergoing elective surgery in the semisitting position for a cranial disease. Patients were managed perioperatively according to a standard institutional protocol, a standardized stepwise positioning, and surgical maneuvers to decrease the risk of venous air embolism (VAE) and other complications. Intraoperative and postoperative complications were recorded. Neurointensive care unit (NICU) length of stay (LOS) and hospital LOS were the intermediate endpoints. Neurological outcome was the primary endpoint as determined by the modified Rankin scale (mRS) score at 6 months after surgery. RESULTS Four hundred twenty-five patients were included in the analysis. VAE occurred in 90 cases (21%) and it made no significant statistical difference in NICU LOS, hospital LOS, and neurological outcome. No complication was directly related to the semisitting position, although 46 patients (11%) experienced at least 1 surgery-related complication and NICU LOS and hospital LOS were significantly prolonged in this group. Neurological outcome was significantly worse for patients with complications (p < 0.0001). CONCLUSIONS Even in the presence of intraoperative VAE, the semisitting position was not related to an increased risk of postoperative deficits and can represent a safe additional option for the benefit of specific surgical and patient needs. PMID- 27982771 TI - Comparison of probabilistic and deterministic fiber tracking of cranial nerves. AB - OBJECTIVE The depiction of cranial nerves (CNs) using diffusion tensor imaging (DTI) is of great interest in skull base tumor surgery and DTI used with deterministic tracking methods has been reported previously. However, there are still no good methods usable for the elimination of noise from the resulting depictions. The authors have hypothesized that probabilistic tracking could lead to more accurate results, because it more efficiently extracts information from the underlying data. Moreover, the authors have adapted a previously described technique for noise elimination using gradual threshold increases to probabilistic tracking. To evaluate the utility of this new approach, a comparison is provided with this work between the gradual threshold increase method in probabilistic and deterministic tracking of CNs. METHODS Both tracking methods were used to depict CNs II, III, V, and the VII+VIII bundle. Depiction of 240 CNs was attempted with each of the above methods in 30 healthy subjects, which were obtained from 2 public databases: the Kirby repository (KR) and Human Connectome Project (HCP). Elimination of erroneous fibers was attempted by gradually increasing the respective thresholds (fractional anisotropy [FA] and probabilistic index of connectivity [PICo]). The results were compared with predefined ground truth images based on corresponding anatomical scans. Two label overlap measures (false-positive error and Dice similarity coefficient) were used to evaluate the success of both methods in depicting the CN. Moreover, the differences between these parameters obtained from the KR and HCP (with higher angular resolution) databases were evaluated. Additionally, visualization of 10 CNs in 5 clinical cases was attempted with both methods and evaluated by comparing the depictions with intraoperative findings. RESULTS Maximum Dice similarity coefficients were significantly higher with probabilistic tracking (p < 0.001; Wilcoxon signed-rank test). The false-positive error of the last obtained depiction was also significantly lower in probabilistic than in deterministic tracking (p < 0.001). The HCP data yielded significantly better results in terms of the Dice coefficient in probabilistic tracking (p < 0.001, Mann-Whitney U-test) and in deterministic tracking (p = 0.02). The false-positive errors were smaller in HCP data in deterministic tracking (p < 0.001) and showed a strong trend toward significance in probabilistic tracking (p = 0.06). In the clinical cases, the probabilistic method visualized 7 of 10 attempted CNs accurately, compared with 3 correct depictions with deterministic tracking. CONCLUSIONS High angular resolution DTI scans are preferable for the DTI-based depiction of the cranial nerves. Probabilistic tracking with a gradual PICo threshold increase is more effective for this task than the previously described deterministic tracking with a gradual FA threshold increase and might represent a method that is useful for depicting cranial nerves with DTI since it eliminates the erroneous fibers without manual intervention. PMID- 27982772 TI - Deliberate employment of postoperative hypotension for brain arteriovenous malformation surgery and the incidence of delayed postoperative hemorrhage: a prospective cohort study. AB - OBJECTIVE The aim of this study was to examine the impact of deliberate employment of postoperative hypotension on delayed postoperative hemorrhage (DPH) for all Spetzler-Ponce Class (SPC) C brain arteriovenous malformations (bAVMs) and SPC B bAVMs >= 3.5 cm in diameter (SPC B 3.5+). METHODS A protocol of deliberate employment of postoperative hypotension was introduced in June 1997 for all SPC C and SPC B 3.5+ bAVMs. The aim was to achieve a maximum mean arterial blood pressure (BP) <= 70 mm Hg (with cerebral perfusion pressure > 50 mm Hg) for a minimum of 7 days after resection of bAVMs (BP protocol). The authors compared patients who experienced DPH (defined as brain hemorrhage into the resection bed that resulted in a new neurological deficit or that resulted in reoperation during the hospitalization for microsurgical bAVM resection) between 2 periods (prior to adopting the BP protocol and after introduction of the BP protocol) and 4 bAVM categories (SPC A, SPC B 3.5- [that is, SPC B < 3.5 cm maximum diameter], SPC B 3.5+, and SPC C). Patients excluded from treatment by the BP protocol were managed in the intensive care unit to avoid moderate hypertensive episodes. The pooled cases of all bAVM treated by surgery were analyzed to identify characteristics associated with the risk of DPH. These identified characteristics were then examined by multiple logistic regression analysis in both SPC B 3.5+ and SPC C cases. RESULTS From a cohort of 641 bAVMs treated by microsurgery, 32 patients with DPH were identified. Of those, 66% (95% CI 48-80) had a permanent new neurological deficit with a modified Rankin Scale score of 2-6. This included a mortality rate of 13% (95% CI 4.4-29). The BP protocol was used to treat 162 patients with either SPC B 3.5+ or SPC C. For SPC B 3.5+, there was no significant reduction in DPH with the introduction of the BP protocol (p = 0.77). For SPC C, there was a significant (p = 0.035) reduction of DPH from 29% (95% CI 13%-53%) to 8.2% (95% CI 3.2%-18%) associated with the introduction of the BP protocol. Multiple logistic regression analysis found that the absence of the BP protocol (p = 0.011, odds ratio 7.5, 95% CI 1.6-36) remained significant for the development of DPH in patients with SPC C bAVMs. CONCLUSIONS Treating patients with SPC C bAVMs with a protocol that lowers BP immediately after resection seems to reduce the risk of DPH. For SPC A and SPC B 3.5- bAVMs, there is unlikely to be a need to do more than avoid postoperative hypertension. For SPC B 3.5+ bAVMs, a larger number of patients would be required to test the absence of benefit of the BP protocol. PMID- 27982774 TI - Using hypnosis with children: Creating and delivering effective interventions by Lyons, Lynn. PMID- 27982773 TI - Effect of combined VEGF165/ SDF-1 gene therapy on vascular remodeling and blood perfusion in cerebral ischemia. AB - OBJECTIVE Therapeutic neovascularization is a promising strategy for treating patients after an ischemic stroke; however, single-factor therapy has limitations. Stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) proteins synergistically promote angiogenesis. In this study, the authors assessed the effect of combined gene therapy with VEGF165 and SDF-1 in a rat model of cerebral infarction. METHODS An adenoviral vector expressing VEGF165 and SDF-1 connected via an internal ribosome entry site was constructed (Ad- VEGF165-SDF-1). A rat model of middle cerebral artery occlusion (MCAO) was established; either Ad- VEGF165-SDF-1 or control adenovirus Ad- LacZ was stereotactically microinjected into the lateral ventricle of 80 rats 24 hours after MCAO. Coexpression and distribution of VEGF165 and SDF-1 were examined by reverse-transcription polymerase chain reaction, Western blotting, and immunofluorescence. The neurological severity score of each rat was measured on Days 3, 7, 14, 21, and 28 after MCAO. Angiogenesis and vascular remodeling were evaluated via bromodeoxyuridine and CD34 immunofluorescence labeling. Relative cerebral infarction volumes were determined by T2-weighted MRI and triphenyltetrazolium chloride staining. Cerebral blood flow, relative cerebral blood volume, and relative mean transmit time were assessed using perfusion weighted MRI. RESULTS The Ad- VEGF165-SDF-1 vector mediated coexpression of VEGF165 and SDF-1 in multiple sites around the ischemic core, including the cortex, corpus striatum, and hippocampal granular layer. Coexpression of VEGF165 and SDF-1 improved neural function, reduced cerebral infarction volume, increased microvascular density and promoted angiogenesis in the ischemic penumbra, and improved cerebral blood flow and perfusion. CONCLUSIONS Combined VEGF165 and SDF 1 gene therapy represents a potential strategy for improving vascular remodeling and recovery of neural function after cerebral infarction. PMID- 27982775 TI - Review of the International Literature. PMID- 27982776 TI - Training in Therapy-Induction Without Scripts. AB - Hypnotic induction for the purposes of psychotherapy is more than a collection of techniques. Instead, the induction process should be individualized to each client as Erickson (1958) explained years ago. Training professionals in hypnosis and induction then must avoid reading written scripts and healthcare professionals must understand that attention and personal contact are required in order to successfully participate in improvisational communication and the nuances of interpersonal entrainment of psychotherapy. And this all begins with the induction. PMID- 27982777 TI - Exploring, Evolving, and Refining Hypnosis Education. PMID- 27982779 TI - Yearning for the Vastness of the Sea: Reflections and Commentary on Professional Training in Hypnosis. AB - Educational programs are a major focus of most professional hypnosis societies. Many of these programs rely on traditional curricula and teaching strategies with variable success. The articles in this special issue examine and critique these training models and suggest innovative approaches to professional education with an emphasis on more uniform course content and goals and more dynamic and effective educational processes. A convergence of themes is noted and examined including the need to continue to expand the acceptance and utilization of clinical hypnosis, the importance of attending to broader clinical competence beyond hypnosis skills, the need for faculty development and evaluation, and the imperative that course content reflects academic rigor and contemporary science as well as providing for demonstration and supervised clinical practice. These themes are explicated for the development of new training paradigms and for continued programs in the field of clinical hypnosis. PMID- 27982778 TI - State-of-the-Art Pediatric Hypnosis Training: Remodeling Curriculum and Refining Faculty Development. AB - Training in pediatric hypnosis has been part of clinical hypnosis education in the United States since 1976. Workshops expanded over time and are now taught by highly experienced pediatric clinicians across the globe. In 1987, a small vanguard of North American faculty, academic pediatricians, and pediatric psychologists taught a 3-day pediatric hypnosis workshop at the national meeting of the Society for Developmental and Behavioral Pediatrics (SDBP). This model of annual tri-level concurrent workshops (introductory, intermediate, and advanced) was sponsored by the SDBP for 24 years. In 2009, the National Pediatric Hypnosis Training Institute (NPHTI) assembled, and in 2010, offered its first annual workshops. This article documents this history of pediatric hypnosis education and describes NPHTI's remodeling and ongoing refinement toward a state-of-the-art curriculum with innovative methodology based upon (1) current research about adult experiential and small group learning; (2) design principles for presentations that maximize adult learning and memory; and (3) evaluations by participants and faculty. These underpinnings-including clinical training videos, individualized learning choices, emphasis on personalized, goal-oriented sessions, and advances in faculty selection, and ongoing development-are applicable to adult training models. Integration of developmental and self regulation strategies may be more unique to pediatric hypnosis skills training programs. The conclusion proposes expansion of pediatric hypnosis education and elimination of related barriers toward goals that all children learn self hypnosis (SH) for mind-body health. PMID- 27982780 TI - Hypnosis Training and Education: Experiences with a Norwegian One-Year Education Course in Clinical Hypnosis for Children and Adolescents. AB - Although the efficacy of clinical hypnosis is well documented, its implementation in clinical practice is far from completed and there are few reports of systematic, professional training. This article gives a historical overview and description of a 1-year training program in clinical hypnosis which started in Norway in 2008 and has been held yearly since then. We describe the present education course with respect to aims, conceptual framework, structure, target groups, teaching themes, and experiences. The following factors have been considered of importance for the success of this program: The extent and duration of the course, the focus on demonstrations, experiential skill-building and exercises, and that the education is rooted in acknowledged clinical, academic, and educational environments. The participants' evaluations tell stories of mastery and positive experiences with hypnosis as a therapeutic tool in their clinical practice. However, many struggle to understand the various concepts of hypnosis, trance, and suggestions. Some find it hard to get started and challenging to integrate hypnosis in their clinical practice. Finally, some report scarce opportunities to apply their newly acquired skills at their work places and limited support by their leaders. The development of systematic, professional training programs as described in this article may be of importance for further implementation. However, this will also require that clinicians and leaders in universities and professional environments, and policymakers at higher levels, recognize clinical hypnosis as a valid and efficient choice of treatment. This must be reflected in dedicated efforts to ensure successful implementation in practice. PMID- 27982781 TI - Good shrink bad shrink by Kluft, Richard P. PMID- 27982783 TI - American Society of Clinical Hypnosis 2016 Annual Scientific Meeting and Workshops Plenary Sessions. PMID- 27982782 TI - Charles B. Mutter, M.D., ABMH. PMID- 27982784 TI - Hypnosis Training and Education: Distinctive Features of Training Hypnosis Educators. AB - Much of the field of hypnosis education focuses on what to teach (content) and who to teach (professional identities). A deserving area of focus, and less often addressed, is how to teach basic hypnosis concepts. Worldwide models for teaching hypnosis have mostly included lecture, demonstration, and practice, with little attention paid to the meta-level of educational principles (i.e., what makes an expert trainer). Trainers in hypnosis have been compared to parents: They teach the way they were taught (adults parent the way they were parented). There is a human tendency to repeat what we have experienced. This propensity can be seen while watching the new student use the same induction, in the same way, as his or her first "operator" did when s/he was a subject of his/her first hypnotic experience. Mirroring is a part of all learning, and this article asks what else is needed in faculty education for the trainer to take students beyond mere mimicry to scientifically informed, skilled, and clinically creative uses of hypnosis. This article addresses the unique requirements for teaching hypnosis, reviews a teaching program for clinical hypnosis educators developed by the authors, and looks to future innovations in clinical hypnosis training. PMID- 27982785 TI - Clinical hypnosis in pain therapy and palliative care: A handbook of techniques for improving the patient's physical and psychological well-being by Brugnoli, Maria Paola. PMID- 27982786 TI - Reorienting Hypnosis Education. AB - The legacy model of professional clinical hypnosis training presents a restrictive frame increasingly incompatible with our evolving understanding of psychobiology, health, and care. Emerging science recognizes human experience not as disease and diagnosis, but as manifestations of individual, uniquely-endowed, adaptively self-regulating systems. Hypnosis is a particularly well-suited discipline for effecting beneficial change in this paradigm. Training in clinical hypnosis must progress from the current linearly-structured, diagnosis-based, reductionist model toward a more responsive, naturalistic, and client-centered curriculum in order to remain relevant and accessible to clinicians beginning to integrate it into their practices. To that end, this article extends Hope and Sugarman's (2015) thesis of hypnosis as a skill set for systemic perturbation and reorientation to consider what those skills may be, the principles on which they are based, and how they may be taught. Parsing a clinical vignette reveals how incorporation of novelty and uncertainty results in less restrictive and more naturalistic hypnotic encounters that, in response to client-generated cues, elicit psychophysiological plasticity. This disruptive hypnosis education and training framework extends the utility and benefit of applied clinical hypnosis. PMID- 27983463 TI - Long-term effects of the Entre-os-Rios tragedy on grief and traumatic stress symptoms. AB - In 2001, in Entre-os-Rios, Portugal, a bridge fell on Douro River; all 59 passengers from 1 bus and 3 cars died and 36 bodies have never been recovered. The objective is to reveal the cumulative risk from multiple losses and unrecovered bodies, 10 years after, compared with grievers from road accidents. There are 2 groups of relatives of victims: from this tragedy (n = 20), with at least 1 unrecovered body; and from road traffic accidents (n = 20), with the same time after loss. The prevalence of prolonged grief was 95% and for traumatic stress was 70%. The associated factors of multiple losses and unrecovered bodies increase the long-term risk (relative risk = 1.6 to 2.8; R2 = .20 to .28) for prolonged and traumatic grief, providing evidence that the absence of body is an important long-term factor. PMID- 27983464 TI - Le role joue par les fibres afferentes metabosensibles dans les mecanismes adaptatifs neuromusculaires. PMID- 27983468 TI - Humibacter aquilariae sp. nov., an actinobacterium isolated from an agarwood chip. AB - A polyphasic taxonomic approach was used to characterize a presumably novel bacterium, designated strain CC-YTH161T, isolated from an agarwood sample. Cells of strain CC-YTH161T were Gram-stain-positive aerobic rods, which grew at 20-40 degrees C, at pH 5.0-9.0 and with 0-5 % (w/v) NaCl. On the basis of 16S rRNA gene sequence analysis, strain CC-YTH161T appeared to belong to the genus Humibacter, and was closely related to Humibacter antri D7-27T (96.6 % similarity) and Humibacter ginsengiterrae DCY60T (96.2 %). The DNA G+C content was 67.0 mol% and the predominant quinone system was menaquinones (MK) 11 and 12. The major cellular fatty acids of the isolate were C15 : 0, iso-C16 : 0, anteiso-C17 : 0 and C18 : 1omega7c/C18 : 1omega6c. The polar lipid profile comprised predominant amounts of diphosphatidylglycerol followed by two unidentified co-migrating glycolipids and phosphatidylglycerol in significant amounts. The diagnostic diamino acid was 2,4-diaminobutyric acid. All these features confirmed the placement of strain CC-YTH161T within the genus Humibacter. On the basis of evidence from this study, strain CC-YTH161T is considered to represent a novel species of the genus Humibacter, for which the name Humibacter aquilariae sp. nov. is proposed. The type strain is CC-YTH161T (=BCRC 80936T=JCM 31199T). PMID- 27983469 TI - Bacillus terrae sp. nov. isolated from Cistus ladanifer rhizosphere soil. AB - A bacterial strain designated RA9T was isolated from a root of Cistus ladanifer in Spain. Phylogenetic analyses based on 16S rRNA gene sequences placed the isolate into the genus Bacillus with its closest relatives being Bacillus fortis R-6514T and Bacillus fordii R-7190T with 98.2 % similarity in both cases. DNA-DNA hybridization studies showed mean relatedness values of 29 and 30 %, respectively, between strain RA9T and the type strains of B. fortis and B. fordii. Cells of the isolate were Gram-stain-positive, motile, sporulating rods. Catalase and oxidase were positive. Gelatin, starch and casein were not hydrolysed. Menaquinone MK-7 was the only menaquinone detected and iso-C15 : 0 and anteiso-C15 : 0 were the major fatty acids. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unidentified aminophospholipid, one unidentified phospholipid, one unidentifed glycolipid and one unidentified lipid. meso-Diaminopimelic acid was detected in the peptidoglycan. The DNA G+C content was 43.1 mol%. Phylogenetic, chemotaxonomic and phenotypic analyses showed that strain RA9T should be considered as representing a novel species of the genus Bacillus, for which the name Bacillus terrae sp. nov. is proposed. The type strain is RA9T (=LMG 29736T=CECT 9170T). PMID- 27983471 TI - Endothiovibrio diazotrophicus gen. nov., sp. nov., a novel nitrogen-fixing, sulfur-oxidizing gammaproteobacterium isolated from a salt marsh. AB - A novel non-phototrophic, marine, sulfur-oxidizing bacterium, strain S-1T, was isolated from a coastal salt marsh in Massachusetts, USA. Cells are Gram-stain negative vibrios motile by means of a single polar unsheathed flagellum. S-1T is an obligate microaerophile with limited metabolic capacity. It grows chemolithoautotrophically utilizing sulfide and thiosulfate as electron donors, converting these compounds to sulfate, and the Calvin-Benson-Bassham cycle for carbon fixation. Cells of S-1T did not grow on any of a large number of organic carbon sources and there was no evidence for chemoorganoheterotrophic growth. Cells produced internal sulfur globules during growth on sulfide and thiosulfate. S-1T is strongly diazotrophic, as demonstrated by 15N2 fixation and acetylene reduction activity by cells when a fixed nitrogen source is absent from the growth medium. The marine nature of this organism is evident from its ability to grow in 10 to 100 % artificial seawater but not at lower concentrations and NaCl alone cannot substitute for sea salts. The major cellular fatty acids are C16 : 1omega7c, C16 : 0, and C18 : 1omega7c. Phosphatidylethanolamine and phosphatidylglycerol are the major polar lipids. Q8 is the only respiratory quinone. S-1T genomic DNA has a G+C content of 67.6 mol%. Based on its 16S rRNA gene sequence, S-1T shows the closest phylogenetic relationship to non phototrophic species within the family Thioalkalispiraceae of the class Gammaproteobacteria. The name Endothiovibrio diazotrophicus is proposed for this organism, with S-1T as the type strain (ATCC BAA-1439T=JCM 17961T). PMID- 27983470 TI - Single-cell studies of IFN-beta promoter activation by wild-type and NS1 defective influenza A viruses. AB - Deletion or truncation of NS1, the principal IFN antagonist of influenza viruses, leads to increased IFN induction during influenza virus infection. We have studied activation of the IFN induction cascade by both wild-type and NS1 defective viruses at the single-cell level using a cell line expressing GFP under the control of the IFN-beta promoter and by examining MxA expression. The IFN beta promoter was not activated in all infected cells even during NS1-defective virus infections. Loss of NS1 expression is therefore insufficient per se to induce IFN in an infected cell, and factors besides NS1 expression status must dictate whether the IFN response is activated. The IFN response was efficiently stimulated in these cells following infection with other viruses; the differential IFN response we observe with influenza viruses is therefore not cell specific but is likely due to differences in the nature of the infecting virus particles and their subsequent replication. PMID- 27983473 TI - Multiple cag genotypes of Helicobacter pylori isolates colonize the oesophagus in individual hosts in a Venezuelan population. AB - PURPOSE: Multiple Helicobacter pylori strains colonize and coexist in the stomach of one single patient, carrying heterogeneous distributions of cag genotypes. The oesophagus provides a niche for H. pylori colonization; however, little is known about its adaptive role. METHODOLOGY: Using PCR for cagA, cagE and virB11 genes from cag-pathogenicity island (PAI) and Etest for antimicrobial susceptibility test, we determined cag-PAI genotypes associated with H. pylori virulence, when positive cultures were matching in both the stomach and the oesophagus (96 isolates; 8 out of 80 dyspeptic patients). RESULTS: The stomach showed complete cag-PAI islands in 77 % of the isolates, whereas the oesophagus showed complete cag-PAI islands only in 44 % of the isolates. Expression of CagA and interleukin 8 correlated with inflammatory processes and histopathological changes in the stomach, but not in the oesophagus. Different cag-PAI profiles were found in both mucosae of an individual host, and at least one oesophagus profile corresponded to one profile identified in stomach. The antibiotic resistance profiles showed variability in the colonization by single or mixed H. pylori isolates in the gastric and oesophageal mucosa both intra- and inter-individuals. CONCLUSION: These results demonstrate colonization with multiple H. pylori isolates in the oesophageal mucosa, like those found in the stomach of individual hosts. H. pylori was characterized by a dominant partial island, low interleukin 8 induction with lower histopathological damage and lower antibiotic resistance, suggesting that the microenvironmental changes in individual hosts select less virulent isolates in the oesophagus than in the stomach. New approaches to ensure effective eradication therapy in multi-resistant H. pylori strains must be developed. PMID- 27983475 TI - Calorithrix insularis gen. nov., sp. nov., a novel representative of the phylum Calditrichaeota. AB - A moderately thermophilic, anaerobic bacterium designated as strain KRT was isolated from a shallow-water submarine hydrothermal vent (Kunashir Island, Southern Kurils, Russia). Cells of strain KRT were thin (0.2-0.3 um), flexible, motile, Gram-stain-negative rods of variable length. Optimal growth conditions were pH 6.6, 55 degrees C and 1-3 % (w/v) NaCl. Strain KRT was able to ferment a wide range of proteinaceous substrates, pyruvate, and mono-, di- and polysaccharides. The best growth occurred with proteinaceous compounds. Nitrate significantly stimulated the growth on proteinaceous substrates decreasing H2 formation, ammonium being the main product of nitrate reduction. Strain KRT did not need the presence of a reducing agent in the medium and tolerated the presence of oxygen in the gas phase up to 3 % (v/v). In the presence of nitrate, aerotolerance of isolate KRT was enhanced up to 6-8 % O2 (v/v). Strain KRT was able to grow chemolithoheterotrophically, oxidizing H2 and reducing nitrate to ammonium. Yeast extract (0.05 g l-1) was required for growth. The G+C content of the genomic DNA of strain KRT was 47.3 mol%. 16S rRNA gene sequence analysis placed isolate KRT in the phylum Calditrichaeota where it represented a novel species of a new genus, for which the name Calorithrix insularis gen. nov., sp. nov. is proposed. The type strain of Calorithrix insularis is KRT (=DSM 101605T=VKM B-3022T). PMID- 27983474 TI - Induction of protective immunity against influenza A/Jiangxi-Donghu/346/2013 (H10N8) in mice. AB - Human infections with A/Jiangxi-Donghu/346/2013 (H10N8) virus have raised concerns about its pandemic potential. In order to develop a vaccine against this virus, the immunogenicity of its haemagglutinin protein was evaluated in mice. Using both whole-virion and recombinant subunit protein vaccines, we showed that two doses of either vaccine elicited neutralizing antibody responses. The protective efficacy of the vaccine-induced responses was assessed using a reverse genetics-derived H10 reassortant virus on the A/Puerto Rico/8/34 (H1N1) backbone. The reassortant virus replicated efficiently in the respiratory tract of unvaccinated mice whereas vaccinated mice were completely protected from challenge, with no detectable viral load in the lower respiratory tract. Finally, the serum neutralizing antibody responses elicited by the H10 vaccines also exhibited cross-neutralizing activity against three heterologous wild-type H10 viruses. Collectively, these findings demonstrate that different vaccine platforms presenting the H10 haemagglutinin protein induce protective immunity. PMID- 27983478 TI - Jeotgalibaca porci sp. nov. and Jeotgalibaca arthritidis sp. nov., isolated from pigs, and emended description of the genus Jeotgalibaca. AB - Biochemical and molecular genetic studies were performed on two novel Gram-stain positive, catalase-negative, coccus-shaped organisms isolated from liquid joint samples of two pigs. The micro-organisms were not identified as members of a recognized species based on results of cellular, morphological and biochemical tests. 16S rRNA gene sequence comparison studies allowed their identification as members of the genus Jeotgalibaca, but the organisms were different to Jeotgalibaca dankookensis, the single species of the genus. The two micro organisms shared 96.3 and 96.9 % 16S rRNA gene sequence similarity values with their nearest phylogenetic relative, J. dankookensis. The novel bacterial isolates were distinguished from J. dankookensis using biochemical tests. Based on both phenotypic and phylogenetic findings, it is proposed that the unknown bacteria be classified as representatives of two novel species of the genus Jeotgalibaca, Jeotgalibaca porci sp. nov. and Jeotgalibaca arthritidis sp. nov. The type strain of Jeotgalibaca porcisp. nov. is 1804-02T (=CECT 9156T=CCUG 69148T) and that of Jeotgalibaca arthritidissp. nov. is 1805-02T (=CECT 9157T=CCUG 69147T). PMID- 27983476 TI - TNF superfamily members promote hepatitis C virus entry via an NF-kappaB and myosin light chain kinase dependent pathway. AB - Preventing virally induced liver disease begins with an understanding of the host factors that define susceptibility to infection. Hepatitis C virus (HCV) is a global health issue, with an estimated 170 million infected individuals at risk of developing liver disease including fibrosis and hepatocellular carcinoma. The liver is the major reservoir supporting HCV replication and this hepatocellular tropism is defined by HCV engagement of cellular entry receptors. Hepatocytes are polarized in vivo and this barrier function limits HCV entry. We previously reported that activated macrophages promote HCV entry into polarized hepatocytes via a TNF-alpha-dependent process; however, the underlying mechanism was not defined. In this study, we show that several TNF superfamily members, including TNF-alpha, TNF-beta, TWEAK and LIGHT, promote HCV entry via NF-kappaB-mediated activation of myosin light chain kinase (MLCK) and disruption of tight junctions. These observations support a model where HCV hijacks an inflammatory immune response to stimulate infection and uncovers a role for NF-kappaB-MLCK signalling in maintaining hepatocellular tight junctions. PMID- 27983479 TI - Roseomonas nepalensis sp. nov., isolated from oil-contaminated soil. AB - A wine-red-coloured, Gram-stain-negative, aerobic, non-motile and coccus-shaped bacterium, designated strain G-3-5T, was isolated from oil-contaminated soil of Biratnagar, Morang, Nepal, during a study of oil-utilizing bacteria. This strain was catalase-negative and oxidase-positive. It was able to grow at 10-37 degrees C, at pH 6.0-10.0 and with 0.02-1.02 % (w/v) NaCl. This strain was taxonomically characterized by a polyphasic approach. Based on 16S rRNA gene sequence analysis, strain G-3-5T belongs to the genus Roseomonas and is closely related to Roseomonas vinacea CPCC 100056T (97.81 % sequence similarity), Roseomonas aerilata 5420S-30T (96.68 %), Roseomonas pecuniae N75T (96.15 %), 'Roseomonas aceris' R-1 (95.75 %) and Roseomonas rosea 173/96T (95.30 %). The only respiratory quinone was ubiquinone-10. The polar lipid profile revealed the presence of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylcholine. The major fatty acids of strain G-3-5T were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0, C18 : 0 and C18 : 1 2 OH. The genomic DNA G+C content of this novel strain was 68.3 mol%. The DNA-DNA relatedness between strain G-3-5T and Roseomonas. vinacea KACC 13934T was 26.3 %. The morphological, physiological, chemotaxonomic and phylogenetic analyses clearly distinguished this strain from its closest phylogenetic neighbours. Thus, strain G-3-5T represents a novel species of the genus Roseomonas, for which the name Roseomonas nepalensis sp. nov. is proposed. The type strain is G-3-5T (=KEMB 9005-416T=KACC 18908T=JCM 31470T). PMID- 27983483 TI - Cross-regulation between two common ancestral response regulators, HprR and CusR, in Escherichia coli. AB - The uncharacterized two-component system YedVW of Escherichia coli is involved in stress response to hydrogen peroxide. To identify the H2O2-sensing role of YedV, a set of single Cys-to-Ala substitution mutants were constructed. One particular mutant with C165A substitution in the membrane domain rendered YedV inactive in H2O2-dependent transcription of its regulatory target hiuH. We then proposed to rename YedVW to HprSR (hydrogen peroxide response sensor/regulator). One unique characteristic of HprR is the overlapping of its recognition sequence with that of the Cu(II)-response two-component system regulator CusR. Towards understanding this unique regulation system, in this study we analysed the interplay between HprR and CusR with respect to transcription of hiuH, a regulatory target of HprR, and cusC, a target of CusR. Under low protein concentrations in vitro and in vivo, two regulators recognize and transcribe both hiuH and cusC promoters, albeit at different efficiency, apparently in a collaborative fashion. This is a new type of transcription regulation of the common target genes in response to different external signals. Upon increase in protein concentrations, however, HprR and CusR compete with each other in transcription of the common targets, thereby exhibiting a competitive interplay. PMID- 27983480 TI - Characterization of a triple-recombinant, reassortant rotavirus strain from the Dominican Republic. AB - We report the genome of a novel human triple-recombinant G4P[6-8_R] mono reassortant strain identified in a stool sample from the Dominican Republic during routine facility-based rotavirus strain surveillance. The strain was designated as RVA/Human-wt/DOM/2013840364/2013/G4P[6-8_R], with a genomic constellation of G4-P[6-8_R]-I1-R1-C1-M1-(A1-A8_R)-N1-(T1-T7_R)-E1-H1. Recombinant gene segments NSP1 and NSP3 were generated as a result of recombination between genogroup 1 rotavirus A1 human strain and a genotype A8 porcine strain and between genogroup 1 rotavirus T1 human strain and a genotype T7 bovine strain, respectively. Analyses of the RNA secondary structures of gene segment VP4, NSP1 and NSP3 showed that all the recombinant regions appear to start in a loop (single-stranded) region and terminate in a stem (double stranded) structure. Also, the VP7 gene occupied lineage VII within the G4 genotypes consisting of mostly porcine or porcine-like G4 strains, suggesting the occurrence of reassortment. The remaining gene segments clustered phylogenetically with genogroup 1 strains. This exchange of whole or partial genetic materials between rotaviruses by recombination and reassortment contributes directly to their diversification, adaptation and evolution. PMID- 27983482 TI - Lack of formylated methionyl-tRNA has pleiotropic effects on Bacillus subtilis. AB - Bacteria initiate translation using a modified amino acid, N-formylmethionine (fMet), adapted specifically for this function. Most proteins are processed co translationally by peptide deformylase (PDF) to remove this modification. Although PDF activity is essential in WT cells and is the target of the antibiotic actinonin, bypass mutations in the fmt gene that eliminate the formylation of Met-tRNAMet render PDF dispensable. The extent to which the emergence of fmt bypass mutations might compromise the therapeutic utility of actinonin is determined, in part, by the effects of these bypass mutations on fitness. Here, we characterize the phenotypic consequences of an fmt null mutation in the model organism Bacillus subtilis. An fmt null mutant is defective for several post-exponential phase adaptive programmes including antibiotic resistance, biofilm formation, swarming and swimming motility and sporulation. In addition, a survey of well-characterized stress responses reveals an increased sensitivity to metal ion excess and oxidative stress. These diverse phenotypes presumably reflect altered synthesis or stability of key proteins involved in these processes. PMID- 27983485 TI - Hepatitis E Virus Infection after Platelet Transfusion in an Immunocompetent Trauma Patient. AB - Hepatitis E virus (HEV) infection causes acute liver disease, but severe infections are rare in immunocompetent patients. We describe a case of HEV infection in a previously healthy male trauma patient in France who received massive transfusions. Genotyping confirmed HEV in a transfused platelet pool and the donor. PMID- 27983484 TI - Group B Streptococcal Toxic Shock Syndrome and covR/S Mutations Revisited. AB - Gene mutations in the virulence regulator CovR/S of group A Streptococcus play a substantial role in the pathogenesis of streptococcal toxic shock syndrome. We screened 25 group B Streptococcus (GBS) isolates obtained from patients with streptococcal toxic shock syndrome and found only 1 GBS clone harboring this kind of mutation. PMID- 27983486 TI - Haemophilus influenzae Type b Invasive Disease in Amish Children, Missouri, USA, 2014. AB - During 5 months in 2014, three Amish children in Missouri, USA, were diagnosed with invasive Haemophilus influenzae type b infection. Two were rural neighbors infected with a genetically similar rare strain, sequence type 45. One child had recently traveled, raising the possibility of maintenance of this strain among unvaccinated carriers in Amish communities. PMID- 27983487 TI - Frequent Transmission of Gonorrhea in Men Who Have Sex with Men. AB - The rate of gonorrhea is much higher in men who have sex with men than in heterosexuals. Because of unique behavioral characteristics, asymptomatic sites of infection, mainly the pharynx, are principal drivers of gonorrhea prevalence in men who have sex with men. On the basis of this observation, we call for interventions. PMID- 27983488 TI - Hepatitis E Virus in Wild Boars and Spillover Infection in Red and Roe Deer, Germany, 2013-2015. AB - To determine animal hepatitis E virus (HEV) reservoirs, we analyzed serologic and molecular markers of HEV infection among wild animals in Germany. We detected HEV genotype 3 strains in inner organs and muscle tissues of a high percentage of wild boars and a lower percentage of deer, indicating a risk for foodborne infection of humans. PMID- 27983489 TI - Epidemiology of Human Anthrax in China, 1955-2014. AB - Using national surveillance data for 120,111 human anthrax cases recorded during 1955-2014, we analyzed the temporal, seasonal, geographic, and demographic distribution of this disease in China. After 1978, incidence decreased until 2013, when it reached a low of 0.014 cases/100,000 population. The case-fatality rate, cumulatively 3.6% during the study period, has also decreased since 1990. Cases occurred throughout the year, peaking in August. Geographic distribution decreased overall from west to east, but the cumulative number of affected counties increased during 2005-2014. The disease has shifted from industrial to agricultural workers; 86.7% of cases occurred in farmers and herdsmen. Most (97.7%) reported cases were the cutaneous form. Although progress has been made in reducing incidence, this study highlights areas that need improvement. Adequate laboratory diagnosis is lacking; only 7.6% of cases received laboratory confirmation. Geographic expansion of the disease indicates that livestock control programs will be essential in eradicating anthrax. PMID- 27983490 TI - Increased Invasive Pneumococcal Disease, North East England, UK. AB - Since April 2014, invasive pneumococcal disease incidence has increased substantially across North East England, United Kingdom, reversing the decline that followed the 2006 introduction of pneumococcal conjugate vaccines. Significant increases occurred in 23-valent polysaccharide vaccine serotypes and nonvaccine serotypes. Trends in other regions and long-term effects of multivalent vaccines require further investigation. PMID- 27983491 TI - Streptococcal Toxic Shock Syndrome Caused by Group G Streptococcus, United Kingdom. AB - We describe successful management of 3 patients with streptococcal toxic shock syndrome (STSS) attributable to group G Streptococcus infection. This small series supports recognition of group G Streptococcus in the etiology of STSS. We propose intravenous immunoglobulin be used in treatment as it is for STSS caused by group A Streptococcus. PMID- 27983492 TI - Meningitis Associated with Simultaneous Infection by Multiple Dengue Virus Serotypes in Children, Brazil. AB - To determine the causes of viral meningitis, we analyzed 22 cerebrospinal fluid samples collected during the 2014-2015 dengue epidemics in Brazil. We identified 3 serotypes of dengue virus (DENV-1, -2, and -3), as well as co-infection with 2 or 3 serotypes. We also detected the Asian II genotype of DENV-2. PMID- 27983494 TI - Sequence Analysis of Toxin Gene-Bearing Corynebacterium diphtheriae Strains, Australia. AB - By conducting a molecular characterization of Corynebacterium diphtheriae strains in Australia, we identified novel sequences, nonfunctional toxin genes, and 5 recent cases of toxigenic cutaneous diphtheria. These findings highlight the importance of extrapharyngeal infections for toxin gene-bearing (functional or not) and non-toxin gene-bearing C. diphtheriae strains. Continued surveillance is recommended. PMID- 27983495 TI - Media Messages and Perception of Risk for Ebola Virus Infection, United States. AB - News media have been blamed for sensationalizing Ebola in the United States, causing unnecessary alarm. To investigate this issue, we analyzed US-focused news stories about Ebola virus disease during July 1-November 30, 2014. We found frequent use of risk-elevating messages, which may have contributed to increased public concern. PMID- 27983493 TI - Dolphin Morbillivirus Associated with a Mass Stranding of Sperm Whales, Italy. AB - In September 2014, seven sperm whales were stranded along Italy's Adriatic coastline. Postmortem investigations on 3 female adult whales and 1 male fetus carried by the largest female revealed molecular and immunohistochemical evidence of dolphin morbillivirus infection. A possible role of the virus in the stranding event was considered. PMID- 27983496 TI - Avian Pox in Native Captive Psittacines, Brazil, 2015. AB - To investigate an outbreak of avian pox in psittacines in a conservation facility, we examined 94 birds of 10 psittacine species, including sick and healthy birds. We found psittacine pox virus in 23 of 27 sick birds and 4 of 67 healthy birds. Further characterization is needed for these isolates. PMID- 27983497 TI - Epidemiology of Hospitalizations Associated with Invasive Candidiasis, United States, 2002-20121. AB - Invasive candidiasis is a major nosocomial fungal disease in the United States associated with high rates of illness and death. We analyzed inpatient hospitalization records from the Healthcare Cost and Utilization Project to estimate incidence of invasive candidiasis-associated hospitalizations in the United States. We extracted data for 33 states for 2002-2012 by using codes from the International Classification of Diseases, 9th Revision, Clinical Modification, for invasive candidiasis; we excluded neonatal cases. The overall age-adjusted average annual rate was 5.3 hospitalizations/100,000 population. Highest risk was for adults >65 years of age, particularly men. Median length of hospitalization was 21 days; 22% of patients died during hospitalization. Median unadjusted associated cost for inpatient care was $46,684. Age-adjusted annual rates decreased during 2005-2012 for men (annual change -3.9%) and women (annual change -4.5%) and across nearly all age groups. We report a high mortality rate and decreasing incidence of hospitalizations for this disease. PMID- 27983498 TI - Norovirus Infection in Harbor Porpoises. AB - A norovirus was detected in harbor porpoises, a previously unknown host for norovirus. This norovirus had low similarity to any known norovirus. Viral RNA was detected primarily in intestinal tissue, and specific serum antibodies were detected in 8 (24%) of 34 harbor porpoises from the North Sea. PMID- 27983499 TI - Host-Associated Absence of Human Puumala Virus Infections in Northern and Eastern Germany. AB - Human hantavirus disease cases, caused by Puumala virus (PUUV), are mainly recorded in western and southern areas of Germany. This bank vole reservoir survey confirmed PUUV presence in these regions but its absence in northern and eastern regions. PUUV occurrence is associated with the presence of the Western bank vole phylogroup. PMID- 27983500 TI - Mathematical Modeling of Programmatic Requirements for Yaws Eradication. AB - Yaws is targeted for eradication by 2020. The mainstay of the eradication strategy is mass treatment followed by case finding. Modeling has been used to inform programmatic requirements for other neglected tropical diseases and could provide insights into yaws eradication. We developed a model of yaws transmission varying the coverage and number of rounds of treatment. The estimated number of cases arising from an index case (basic reproduction number [R0]) ranged from 1.08 to 3.32. To have 80% probability of achieving eradication, 8 rounds of treatment with 80% coverage were required at low estimates of R0 (1.45). This requirement increased to 95% at high estimates of R0 (2.47). Extending the treatment interval to 12 months increased requirements at all estimates of R0. At high estimates of R0 with 12 monthly rounds of treatment, no combination of variables achieved eradication. Models should be used to guide the scale-up of yaws eradication. PMID- 27983501 TI - A Framework for Modeling Emerging Diseases to Inform Management. AB - The rapid emergence and reemergence of zoonotic diseases requires the ability to rapidly evaluate and implement optimal management decisions. Actions to control or mitigate the effects of emerging pathogens are commonly delayed because of uncertainty in the estimates and the predicted outcomes of the control tactics. The development of models that describe the best-known information regarding the disease system at the early stages of disease emergence is an essential step for optimal decision-making. Models can predict the potential effects of the pathogen, provide guidance for assessing the likelihood of success of different proposed management actions, quantify the uncertainty surrounding the choice of the optimal decision, and highlight critical areas for immediate research. We demonstrate how to develop models that can be used as a part of a decision-making framework to determine the likelihood of success of different management actions given current knowledge. PMID- 27983502 TI - Oral Cholera Vaccine Coverage during an Outbreak and Humanitarian Crisis, Iraq, 2015. AB - During November-December 2015, as part of the 2015 cholera outbreak response in Iraq, the Iraqi Ministry of Health targeted ~255,000 displaced persons >1 year of age with 2 doses of oral cholera vaccine (OCV). All persons who received vaccines were living in selected refugee camps, internally displaced persons camps, and collective centers. We conducted a multistage cluster survey to obtain OCV coverage estimates in 10 governorates that were targeted during the campaign. In total, 1,226 household and 5,007 individual interviews were conducted. Overall, 2 dose OCV coverage in the targeted camps was 87% (95% CI 85%-89%). Two-dose OCV coverage in the 3 northern governorates (91%; 95% CI 87%-94%) was higher than that in the 7 southern and central governorates (80%; 95% CI 77%-82%). The experience in Iraq demonstrates that OCV campaigns can be successfully implemented as part of a comprehensive response to cholera outbreaks among high risk populations in conflict settings. PMID- 27983503 TI - Sequelae and Other Conditions in Ebola Virus Disease Survivors, Sierra Leone, 2015. AB - We rapidly assessed the health of Ebola virus disease (EVD) survivors in Kenema, Sierra Leone, by reviewing medical charts of all patients attending the Survivor Clinic of Kenema Government Hospital. Data were abstracted on signs and symptoms at every attendance. As of November 2015, a total of 621 attendances by 115 survivors with laboratory-confirmed EVD were made to the Survivor Clinic. Most (60.9%) survivors were women. Survivors' median age was 28 years (range 0.25-70 years). Survivors attended the clinic a median of 5 times (range 1-21 times) each, and the median time from EVD discharge to attendance was 261 days (range 4 504 days). The most commonly reported signs and symptoms among the 621 attendances were headache (63.1%), fever (61.7%), and myalgia (43.3%). Because health needs of EVD survivors are complex, rapid chart reviews at survivor clinics should be repeated regularly to assess the extent of illness and prioritize service delivery. PMID- 27983504 TI - Analysis of Anthrax Immune Globulin Intravenous with Antimicrobial Treatment in Injection Drug Users, Scotland, 2009-2010. AB - We studied anthrax immune globulin intravenous (AIG-IV) use from a 2009-2010 outbreak of Bacillus anthracis soft tissue infection in injection drug users in Scotland, UK, and we compared findings from 15 AIG-IV recipients with findings from 28 nonrecipients. Death rates did not differ significantly between recipients and nonrecipients (33% vs. 21%). However, whereas only 8 (27%) of 30 patients at low risk for death (admission sequential organ failure assessment score of 0-5) received AIG-IV, 7 (54%) of the 13 patients at high risk for death (sequential organ failure assessment score of 6-11) received treatment. AIG-IV recipients had surgery more often and, among survivors, had longer hospital stays than did nonrecipients. AIG-IV recipients were sicker than nonrecipients. This difference and the small number of higher risk patients confound assessment of AIG-IV effectiveness in this outbreak. PMID- 27983505 TI - Modeling Tool for Decision Support during Early Days of an Anthrax Event. AB - Health officials lack field-implementable tools for forecasting the effects that a large-scale release of Bacillus anthracis spores would have on public health and hospitals. We created a modeling tool (combining inhalational anthrax caseload projections based on initial case reports, effects of variable postexposure prophylaxis campaigns, and healthcare facility surge capacity requirements) to project hospitalizations and casualties from a newly detected inhalation anthrax event, and we examined the consequences of intervention choices. With only 3 days of case counts, the model can predict final attack sizes for simulated Sverdlovsk-like events (1979 USSR) with sufficient accuracy for decision making and confirms the value of early postexposure prophylaxis initiation. According to a baseline scenario, hospital treatment volume peaks 15 days after exposure, deaths peak earlier (day 5), and recovery peaks later (day 23). This tool gives public health, hospital, and emergency planners scenario specific information for developing quantitative response plans for this threat. PMID- 27983506 TI - Estimated Incidence of Antimicrobial Drug-Resistant Nontyphoidal Salmonella Infections, United States, 2004-2012. AB - Salmonella infections are a major cause of illness in the United States. The antimicrobial agents used to treat severe infections include ceftriaxone, ciprofloxacin, and ampicillin. Antimicrobial drug resistance has been associated with adverse clinical outcomes. To estimate the incidence of resistant culture confirmed nontyphoidal Salmonella infections, we used Bayesian hierarchical models of 2004-2012 data from the Centers for Disease Control and Prevention National Antimicrobial Resistance Monitoring System and Laboratory-based Enteric Disease Surveillance. We based 3 mutually exclusive resistance categories on susceptibility testing: ceftriaxone and ampicillin resistant, ciprofloxacin nonsusceptible but ceftriaxone susceptible, and ampicillin resistant but ceftriaxone and ciprofloxacin susceptible. We estimated the overall incidence of resistant infections as 1.07/100,000 person-years for ampicillin-only resistance, 0.51/100,000 person-years for ceftriaxone and ampicillin resistance, and 0.35/100,000 person-years for ciprofloxacin nonsusceptibility, or ~6,200 resistant culture-confirmed infections annually. These national estimates help define the magnitude of the resistance problem so that control measures can be appropriately targeted. PMID- 27983508 TI - New version of the Epidemic Intelligence Information System for food- and waterborne diseases and zoonoses (EPIS-FWD) launched. PMID- 27983507 TI - Whole-Genome Characterization of a Novel Human Influenza A(H1N2) Virus Variant, Brazil. AB - We report the characterization of a novel reassortant influenza A(H1N2) virus not previously reported in humans. Recovered from a a pig farm worker in southeast Brazil who had influenza-like illness, this virus is a triple reassortant containing gene segments from subtypes H1N2 (hemagglutinin), H3N2 (neuraminidase), and pandemic H1N1 (remaining genes). PMID- 27983509 TI - Community-wide outbreaks of haemolytic uraemic syndrome associated with Shiga toxin-producing Escherichia coli O26 in Italy and Romania: a new challenge for the European Union. PMID- 27983511 TI - Erratum for Euro Surveill. 2016;21(48). PMID- 27983510 TI - Comparison of Leishmania typing results obtained from 16 European clinical laboratories in 2014. AB - Leishmaniasis is endemic in southern Europe, and in other European countries cases are diagnosed in travellers who have visited affected areas both within the continent and beyond. Prompt and accurate diagnosis poses a challenge in clinical practice in Europe. Different methods exist for identification of the infecting Leishmania species. Sixteen clinical laboratories in 10 European countries, plus Israel and Turkey, conducted a study to assess their genotyping performance. DNA from 21 promastigote cultures of 13 species was analysed blindly by the routinely used typing method. Five different molecular targets were used, which were analysed with PCR-based methods. Different levels of identification were achieved, and either the Leishmania subgenus, species complex, or actual species were reported. The overall error rate of strains placed in the wrong complex or species was 8.5%. Various reasons for incorrect typing were identified. The study shows there is considerable room for improvement and standardisation of Leishmania typing. The use of well validated standard operating procedures is recommended, covering testing, interpretation, and reporting guidelines. Application of the internal transcribed spacer 1 of the rDNA array should be restricted to Old World samples, while the heat-shock protein 70 gene and the mini-exon can be applied globally. PMID- 27983513 TI - [A new chapter[Editorial]]. PMID- 27983514 TI - [Medical education in Iceland, 140th anniversary[Editorial]]. PMID- 27983512 TI - Highly pathogenic avian influenza A(H5N8) outbreaks: protection and management of exposed people in Europe, 2014/15 and 2016. AB - Introduction of highly pathogenic avian influenza (HPAI) virus A(H5N8) into Europe prompted animal and human health experts to implement protective measures to prevent transmission to humans. We describe the situation in 2016 and list public health measures and recommendations in place. We summarise critical interfaces identified during the A(H5N1) and A(H5N8) outbreaks in 2014/15. Rapid exchange of information between the animal and human health sectors is critical for a timely, effective and efficient response. PMID- 27983515 TI - [Gallstone disease during pregnancy at Landspitali University Hospital 1990 2010]. AB - INTRODUCTION: Gallstone disease in pregnant patients and their management in Iceland has not been studied. Management of these patients changed after the introduction of laparoscopic cholecystectomy. The aim of this study was to investigate the incidence, symptoms, diagnostic methods and management of gallstone disease during pregnancy at the National University Hospital of Iceland during the years 1990-2010. MATERIAL AND METHODS: This was a retrospective study and included all pregnant women admitted with gallstone diseases to the National University Hospital of Iceland which is the only tertiary hospital in Iceland. Information regarding age, symptoms and diagnostic methods for all women with gallstone disease along with BMI, ASA scores, pathology results and pregnancy related outcomes for women who underwent cholecystectomy were gathered. RESULTS: During the twenty year time period 77 women were admitted with gallstone disease in 139 admissions which makes incidence 0,1% amongst pregnant women. Diagnoses incuded biliary colic (n=59), common bile duct stones (n=10), acute cholecystitis (n=7) and gallstone pancreatitis (n=1). The most common symptom was RUQ pain (n=63). Two preterm births were a direct consequence of gallstone disease. Fifteen women underwent cholecystectomy during pregnancy and 17 during the six week period after birth. Mean BMI was 31,1 and median ASA score was 1. Pathology reports showed chronic inflammation (n=24) and acute inflammation (n=5), one case included gallstones without inflammation Adverse outcomes of surgeries were two cases of gallstones left in the common bile duct. No stillbirths or preterm births resulted from cholecystectomies during pregnancy. CONCLUSION: Gallstone disease during pregnancy is rare and readmissions are frequent. Pregnancy related complications are rare. Laparoscopic cholecystectomy is safe during pregnancy. Key words: gallstones, pregnancy, laparoscopic cholecystectomy. Correspondence: Pall Helgi Moller pallm@landspitali.is. PMID- 27983516 TI - [Results of operations for ascending aortic aneurysm in Iceland 2000-2014]. AB - INTRODUCTION: Thoracic aortic aneurysm (TAA) is an uncommon disease where treatment is complex and associated with significant comorbidity. The main aim of this study was to evaluate the outcomes of operations for TAA in Iceland with emphasis on postoperative complications, 30 day mortality and survival. MATERIALS AND METHODS: A retrospective study on 105 patients (mean age 60.7 yrs., 69.5% males) that underwent operations for TAA between 2000 and 2014 in Iceland. Patients with aortic injury or acute aortic dissection were excluded. Clinical information was collected from hospital charts and long-term survival estimated by Kaplan-Meier method. Mean follow-up was 5.7 yrs. RESULTS: Bicuspid aortic valve was present in 52 patients (51.0%) and family history was positive in 10 of the cases (9.5%). Every other patient (50.5%) was asymptomatic and diagnosed incidentally. The most common procedure was aortic root replacement using biological prosthesis. Two out of three patients had complications, that were regarded as major in 31.4% of cases, however, stroke was only detected in 2 (1.9%) patients. Two patients died within 30 days postoperatively (1.9%). The overall survival at one year was 95.1%; more favorable for males compared to females (97.2 vs. 90.4%, p=0.0012, log rank test) and at 5 years 90.3%. CONCLUSIONS: Outcome following surgery for TAA in Iceland is comparable to studies in neighbouring countries. The complications rate is high, however, the stroke rate was low, as was 30 day mortality. Longterm survival is favorable, and is more favorable for males than females. Key words: Thoracic aortic aneurysm, ascending aorta, open heart surgery, complications, operative mortality, survival. Correspondance: Arnar Geirsson, arnarge@landspitali.is. PMID- 27983518 TI - Impacts of curatorial and research practices on the preservation of fossil hominid remains. AB - Fossil remains are the only physical evidence of past forms of life which researchers can use to study the evolutionary biology of a species, especially regarding the human lineage. We review and consider the way in which the conditions surrounding a fossil's discovery and its use for scientific research impacts its long-term preservation. The deterioration of the body starts soon after death, continues in the sediments and only a subsample of the anatomical elements will persist and may finally be unearthed by archeologists. From their recovery onwards, fossil remains are exposed to many sources of further damage: from handling, restoration, measuring to invasive sampling. On the one hand, curators are faced with the inherent challenge of balancing their responsibility to protect fossil specimens with allowing researchers to perform specific analyses or invasive sampling detrimental to the preservation of the fossil. On the other hand, scientists may find their analyses complicated by multiple factors including taphonomy, or restoration techniques (e.g., consolidants, cleaning chemicals). We provide several historical examples illustrating the complex nature of the factors acting on fossil preservation. We discuss concerns about producing and sharing (digital) data from fossils. Finally, we also suggest and support some curatorial practices which maximize the traceability of treatments underwent by a fossil. PMID- 27983517 TI - [Dizziness in the emergency department - do we lack clinical judgment?] AB - OBJECTIVES: The aim of this study was to evaluate the extent and quality of work up of dizzy patients at the Landspitali Emergency department. PATIENTS AND METHODS: All cases presenting to the emergency department with the main complaint of dizziness over a period of four months were analyzed retrospectively. Demographics, duration of symptoms, diagnosis and results from investigations and consultations were recorded from medical records. Investigations were categorized to blood tests, brain imaging and consultations to simplify interpretation of the results. RESULTS: One hundred sixty three cases were identified. 28% were diagnosed with inner ear problem and 32% were discharged without diagnosis. A serious central nervous system cause was found in 4% of cases. About one-third underwent investigations from all of the three investigation categories. An acute CT scan of the brain was obtained in 40% and MRI in 17% of all cases. Consultation was obtained from a neurologist for 28%, ENT for 26% and a cardiologist for 2% of cases. 11.6% (n=19) of the patients were admitted to the hospital, 53% to neurology, 42% to internal medicine and 5% to ENT. CONCLUSIONS: Dizziness is a common complaint in the emergency department and the cause is most often benign. Nevertheless, patients with dizziness routinely undergo extensive workup which often includes acute CT scan of the brain. Key words: vertigo, dizziness, CT, computed tomography, acute, emergency department. Correspondence: Arni Ornolfsson, arni.ornolfsson@skane.se. PMID- 27983519 TI - Two Acheuleans, two humankinds: From 1.5 to 0.85 Ma at Melka Kunture (Upper Awash, Ethiopian highlands). AB - The Acheulean is the longest-lasting human cultural record, spanning approximately 1.5 Ma and three continents. The most comprehensive sequences are found in East Africa, where, in largescale syntheses, the Lower Pleistocene Acheulean (LPA) has often been considered a uniform cultural entity. Furthermore, the emergence and development of Acheulean technology are seen as linked to the emergence and evolution of Homo ergaster/erectus. The criterion for grouping together different lithic assemblages scattered over space and time is the presence of large cutting tools (LCTs), more than of any other component. Their degree of refinement has been used, in turn, as a parameter for evaluating Acheulean development and variability. But was the East African LPA really uniform as regards all components involved in lithic productions? The aim of this paper is to evaluate the techno-economic similarities and differences among LPA productions in a specific micro-regional and environmental context, i.e. at Melka Kunture, in the Ethiopian highlands, and in a specific period of time: between ~1.5 Ma, when some of the earliest Acheulean complexes appeared, and 1.0-0.85 Ma, when LCTs productions became intensive and widespread. Our detailed comparative analyses investigate all aspects and phases of the chaines operatoires. Since hominin fossil remains were discovered at some of the analyzed sites, we also discuss differences among lithic productions in relation to the changing paleoanthropological record. Our studies show that at Melka Kunture the LPA techno-complexes cannot be grouped into a single uniform entity. The assembled evidence points instead to "two Acheuleans" well-defined by a strong discontinuity in various aspects of techno-economic behaviors. This discontinuity is related to a major step in human evolution: the transition from Homo ergaster/ erectus to Homo heidelbergensis. PMID- 27983520 TI - Dosimetric and workflow evaluation of first commercial synthetic CT software for clinical use in pelvis. AB - To evaluate a commercial synthetic CT (syn-CT) software for use in prostate radiotherapy. Twenty-five prostate patients underwent CT and MR simulation scans in treatment position on a 3T MR scanner. A commercially available MR protocol was used that included a T2w turbo spin-echo sequence for soft-tissue contrast and a dual echo 3D mDIXON fast field echo (FFE) sequence for generating syn-CT. A dual-echo 3D FFE B 0 map was used for patient-induced susceptibility distortion analysis and a new 3D balanced-FFE sequence was evaluated for identification of implanted gold fiducial markers and subsequent image-guidance during radiotherapy delivery. Tissues were classified as air, adipose, water, trabecular/spongy bone and compact/cortical bone and assigned bulk HU values. The accuracy of syn-CT for treatment planning was analyzed by transferring the structures and plan from planning CT to syn-CT and recalculating the dose. Accuracy of localization at the treatment machine was evaluated by comparing registration of kV radiographs to either digitally reconstructed radiographs (DRRs) generated from syn-CT or traditional DRRs generated from the planning CT. Similarly, accuracy of setup using CBCT and syn-CT was compared to that using the planning CT. Finally, a MR only simulation workflow was established and end-to-end testing was completed on five patients undergoing MR-only simulation. Dosimetric comparison between the original CT and syn-CT plans was within 0.5% on average for all structures. The de-novo optimized plans on the syn-CT met institutional clinical objectives for target and normal structures. Patient-induced susceptibility distortion based on B 0 maps was within 1 mm and 0.5 mm in the body and prostate respectively. DRR and CBCT localization based on MR-localized fiducials showed a standard deviation of <1 mm. End-to-end testing and MR simulation workflow was successfully validated. MRI derived synthetic CT can be successfully used for a MR-only planning and treatment for prostate radiotherapy. PMID- 27983521 TI - Expression of TTF-1 in breast cancer independently of ER expression: A case report and pathogenic implications. AB - Thyroid Transcription Factor 1 (TTF-1) is often used for the immunohistochemical evaluation of lung cancers, as a significant proportion of these cancers are positive while other adenocarcinomas are usually negative. Breast cancers are known to express TTF-1 only in a small minority of cases but this may be problematic when this staining is used for its differential diagnosis from lung cancer. We present a case of ER-positive breast cancer in 30% of tumor cells that was also TTF-1 positive in some areas of the primary tumor but lost ER expression completely in the metastatic recurrence site while retaining TTF-1 positivity. Additionally, a PTEN mutation was present on genomic evaluation of the primary tumor. Diagnostic, pathogenic and therapeutic implications of these findings are discussed. PMID- 27983522 TI - Different expression patterns of histone H3K27 demethylases in renal cell carcinoma and bladder cancer. AB - OBJECTIVE: UTX and JMJD3 are recently identified histone H3 lysine 27 (H3K27) demethylases. Many studies have shown aberrant H3K27 trimethylation (H3K27me3) levels widely exist in multiple cancers, and that altered H3K27me3 levels are correlated with tumorigenesis and tumor progression. To investigate expression patterns of UTX and JMJD3 genes in renal cell carcinoma (RCC) and bladder cancer and the relationship between gene expression and tumor development. MATERIAL AND METHODS: Samples were collected from 35 patients with RCC and 21 patients with bladder cancer and qRT-PCR was performed. RESULTS: By comparing with adjacent normal tissues, the expression of JMJD3 (10/21 = 47.62%) and UTX (10/21 = 47.62%) were significantly upregulated in bladder cancer tissues and the expression of JMJD3 (15/35 = 42.86%) was significantly downregulated in RCC tissues. Stratified analyses revealed that upregulated expression of JMJD3 was significantly associated with poorly differentiated tumor nuclear grade (p= 0.005) and advanced clinical stage (p= 0.043) in the bladder cancer group, while downregulated expression of JMJD3 was significantly associated with advanced clinical stage (p= 0.045) and poorly differentiated tumor nuclear grade (p= 0.011) in the RCC group. CONCLUSIONS: These results suggest JMJD3 could be a hallmark and is involved in the development of RCC and bladder cancers. The potential role of H3K27 demethylases as biomarkers needs further investigations. PMID- 27983523 TI - CpG methylation of APC promoter 1A in sporadic and familial breast cancer patients. AB - Tumour suppressor gene (TSG) silencing through promoter hypermethylation plays an important role in cancer initiation. The aim of this study was to assess the extent of methylation of APC gene promoter in 91 sporadic and 44 familial cases of Tunisian patients with breast cancer (BC) in. The frequency of APC promoter methylation is somewhat similar for sporadic and familial breast cancer cases, (52.1%, and 54.5% respectively). For sporadic breast cancer patients, there was a significant correlation of APC promoter hypermethylation with TNM stage (p = 0.024) and 3-year survival (p = 0.025). Regarding the hormonal status (HR), we found significant association between negativity to PR and unmethylated APC (p= 0.005) while ER and Her2/neu are not correlated. Moreover, unmethylated APC promoter is more frequent in tumours expressing at least one out the 3 proteins compared to triple negative cases (p= 0.053). On the other hand, aberrant methylation of APC was associated with tumour size (p = 0.036), lymph node (p = 0.028), distant metastasis (p = 0.031), and 3-year survival (p = 0.046) in the group of patients with familial breast cancer. Moreover, patients with sporadic breast cancer displaying the unmethylated profile have a significant prolonged overall survival compared to those with the methylated pattern of APC promoter (p log rank = 0.008). Epigenetic change at the CpG islands in the APC promoter was associated with the silence of its transcript and the loss of protein expression suggesting that this event is the main mechanism regulating the APC expression in breast cancer. In conclusion, our data showed that the loss of APC through aberrant methylation is associated with the aggressive behavior of both sporadic and familial breast cancer in Tunisian patients. PMID- 27983525 TI - PIM1 gene silencing inhibits proliferation and promotes apoptosis of human esophageal cancer cell line Eca-109. AB - We aimed to study the effect of PIM1 gene silencing on the proliferation and apoptosis of human esophageal cancer cell line Eca109. Cultured Eca109 cells were transfected with the recombinant plasmids in mediation of Lipofectamine TM 2000 Reagent. The Eca109 cells in logarithmic growth phase were collected and assigned into three groups: the PIM1 siRNA group (stably transfected with PIM1-shRNA plasmids), the negative control (NC) group (transfected with vacant plasmids), and the blank group (Eca109 cells without any transfection). The PIM1 mRNA expression was determined by real-time quantitative polymerase chain reaction (RT qPCR). Cell cycle was analyzed by flow cytometry. Cell proliferation was evaluated using the Cell Counting Kit-8 (CCK-8). Cell apoptosis was assessed by Annexin V-FITC/PI double-staining and TUNEL assays. The PIM1 mRNA expression of Eca109 cells in the PIM1 siRNA group was significantly lower than that in the NC and blank groups. Compared with the NC and blank groups, the viability and proliferation of the Eca109 cells in the PIM1 siRNA group were significantly decreased at 48 h, 72 h and 96 h after transfection. The cell growth inhibition rate of the PIM1 siRNA group was higher than that of the NC and blank groups after transfection. Furthermore, the apoptotic rate of the PIM1 siRNA group was also higher than that of the NC and blank groups. In conclusion, our preliminary findings suggest that PIM1 gene silencing could inhibit proliferation and promote apoptosis of esophageal cancer cells. PMID- 27983524 TI - Combined detection of plasma miR-127-3p and HE4 improves the diagnostic efficacy of breast cancer. AB - OBJECTIVE: To explore the diagnostic value of combined detection of plasma miR 127-3p and HE4 for breast cancer (BC). METHODS: Included in this study were 102 patients with pathologically confirmed BC who received treatment in the affiliated hospital of Nantong University between March 2015 and April 2016, 87 patients with benign breast tumors, and 90 healthy volunteers as control. Plasma miR-127-3p was detected by SYBR Green RT-qPCR, and plasma HE4 was detected by chemiluminescent immunoassay. The diagnostic efficacy of miR-127-3p alone, HE4 alone and combined detection of miR-127-3p and HE4 in BC women patients was evaluated by ROC curve analysis. RESULTS: The relative expression quantity (RQ) of plasma miR-127-3p and HE4 in BC patients was 13.561 (3.345~18.281) pmol/L and 105.42 (40.28~156.31) pmol/L. The RQ of plasma miR-127-3p in BC patients was significantly higher than that in benign breast tumor patients and healthy individuals (both P< 0.001), and there was no significant difference between benign breast tumor patients and healthy individuals (P> 0.05). There was no significant correlation between plasma miR-127-3p and HE4 levels (r2= 0.086, P= 0.471). ROC curve analysis on the diagnostic efficacy of plasma miR-127-3p and HE4 in BC diagnosis showed that the cut-off value of miR-127-3p and HE4 in BC diagnosis was 3.471 and 63.21 pmol/L; AUC was 0.767 and 0.670; sensitivity was 78.2% and 64.6%; specificity was 79.1% and 69.3%; accuracy was 73.2% and 65.1%, respectively. Prediction probability (P) obtained from the miR-127-3p and HE4 model established by logistic regression was P= 1/ [1 + exp (-0.142miR-127-3p 0.024HE4 + 2.875)]. AUC calculated from ROC was 0.825 and the sensitivity was increased to 87.4%. CONCLUSION: Combined detection of plasma miR-127-3p and HE4 greatly improved the sensitivity of BC diagnosis and may prove to be a candidate biomarker for early detection and diagnosis of BC. PMID- 27983526 TI - Pri-miR-34b/c rs4938723 polymorphism increased the risk of prostate cancer. AB - The association studies between miR-34b/c rs4938723 polymorphism and cancer risk showed conflicting results. This study aimed to assess the impact of rs4938723 polymorphism on prostate cancer risk. This case-control study was done on 151 prostate cancer (PCa) patients and 152 benign prostate hyperplasia to examine whether rs4938723 polymorphism in the promoter of pri-miR-34b/c was linked to the carcinogenesis of PCa in a sample of Iranian population. Genotyping of Pri-miR-34 b/c rs4938723 polymorphism was performed by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. The results showed that rs4938723 variant significantly increased the risk of PCa in codominant (OR = 1.92, 95% CI = 1.15 - 3.18, p= 0.012, TC vs TT), dominant (OR = 1.99, 95% CI = 1.23 - 3.24, p= 0.005, TC + CC vs TT), and allelic (OR = 1.79, 95% CI = 1.20 - 2.68, p= 0.005, C vs T) inheritance model. Our findings propose that Pri-miR-34 b/c rs4938723 variant may be a risk factor for the development of PCa in a sample of Iranian population. Larger sample sizes with different ethnicities are required to validate our findings. PMID- 27983528 TI - Prognostic value of candidate microRNAs in gastric cancer: A validation study. AB - BACKGROUND: Studies have reported the prognostic value of dysregulated microRNAs (miRNAs) in gastric cancer (GC). However, the results demonstrated so far are inconsistent. OBJECTIVE: To better understand the miRNAs with prognostic relevance. METHODS: Evaluable miRNAs were selected based on our selection criteria and further analyzed in formalin-fixed paraffin-embedded (FFPE) tissue samples of 169 GC patients using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: A total of 19 miRNAs were selected as candidate miRNAs. Among those miRNAs identified, high expression of miR-21-5p was related to poor overall survival (OS) and disease free survival (DFS) and was identified as an independent prognostic factor. Cases with high level of miR-200c-3p showed poor DFS. Subgroup analysis revealed that high expression of miR-21-5p and miR-222-3p was associated with poor OS and DFS in GC patients not received adjuvant chemotherapy. In male patients, high expression level of miR-21-5p was related to poor OS and DFS. CONCLUSIONS: The present study confirmed that elevated level of miR-21-5p could serve as an independent predictor for poor OS and DFS of GC patients. Moreover, miR-200c-3p, miR-222-3p might also play important roles in the prognosis of GC patients. Further studies are warranted to validate our findings and identify the functions and mechanisms of these miRNAs. PMID- 27983527 TI - Clinical significance of circulating tumor cells in squamous cell lung cancer patients. AB - BACKGROUND: Squamous cell carcinoma (SCC) of the lung represents 20-30% of non small cell lung cancers (NSCLC) and is associated with a poor prognosis. OBJECTIVE: This study aims to investigate the presence of circulating tumor cells (CTCs) in squamous cell lung cancer patients and what its role might be in providing prognostic information. METHODS: Serial blood samples from 100 patients both before and after initiation of one cycle of standard chemotherapy were analyzed using CellSearch system. RESULTS: Of 105 patients enrolled, 100 were evaluable. >= 2 CTCs per 7.5 mL of blood were present in 29% of patients at baseline before chemotherapy, and 9% patients have more than 5 CTCs. Based on the current literature, the CTC measurements were dichotomized as 2-4 versus >= 5 CTCs. In the univariate analysis, CTC count >= 5 at baseline and CTC count >= 5 at both time points (before and after one cycle of chemotherapy) were significantly associated with a poor PFS and OS outcome. Both factors remained independent poor prognostic markers in the stepwise multivariate analysis. CONCLUSION: Our study indicate that the CTC count is a prognostic factor for PFS and OS outcomes in Chinese patients with locally advanced SCC of the lung. PMID- 27983529 TI - Autoantibodies against heat shock proteins as biomarkers for the diagnosis and prognosis of cancer. AB - Thanks to their specificity and stability in the sera, autoantibodies (AAbs) against tumor-associated antigens (TAAs) are very attractive biomarkers for the development of less invasive serological tests for the diagnosis and prognosis of cancer. Heat shock proteins (HSP) belong to TAAs and they are over-expressed in various human cancers. Elevated HSP can stimulate the immune system to produce anti-HSP antibodies. So far, AAbs against HSP have been identified in the circulation of various cancer patients. Here we will review current literature on the use of anti-HSP antibodies for cancer diagnosis and prognosis. The challenges as well as future directions of AAbs identification in oncology are also discussed. PMID- 27983530 TI - Role of GSK3beta in breast cancer susceptibility. AB - BACKGROUND: Breast cancer is one of the principal causes of death among Brazilian women, so it is a challenge to find new and specific early diagnostic markers, using simple and fast procedures. GSK3beta gene is an important Wnt signaling regulator involved in beta-Catenin degradation. Wnt signaling is associated with initiation and progression process in many tumor types, and alterations in beta Catenin explain only a small proportion of aberrant signaling found in breast cancer, indicating that other Wnt signaling components and/or regulators as GSK3beta may be involved. OBJECTIVE: The aim of this study was to evaluate the genetic, epigenetic and transcriptional alterations of GSK3beta in breast cancer. METHODS: Peripheral blood samples from 204 breast cancer and healthy women were collected. Assessment of rs334558 polymorphism was performed by PCR-RFLP, promoter methylation profiles analysis by MS-PCR and qPCR was used to determine GSK3beta expression levels. RESULTS: The rs334558 polymorphism showed a strong association with aggressive cancer. A significant increase was observed in GSK3beta expression level respect to hormone receptors status and tumor size. CONCLUSION: The results indicated an inverse relationship between GSK3beta performance and tumor progression. This is the first study to relate GSK3beta gene with breast cancer in Brazilian population. PMID- 27983531 TI - PFKFB3 was overexpressed in gastric cancer patients and promoted the proliferation and migration of gastric cancer cells. AB - OBJECTIVE: Gastric cancer is one of the most common cancers worldwide, and the prognosis is still very poor due to the lack of specific and sensitive biomarkers. Aerobic glycolysis is one of the critical hallmarks of gastric cancer cells, and several glycolytic enzymes are highly expressed in gastric cancer patients. However, the expression and clinical significances of phosphofructokinase-2/fructose-2,6-bisphosphatase3 (PFKFB3, one of the glycolytic enzymes) in a large sample of gastric cancer patients remain unclear. METHODS: The expression of PFKFB3 was detected in 134 gastric cancer patients by qRT-PCR, immunohistochemistry, and western blot analyses. The correlation between PFKFB3 expression and clinicopathological factors was analyzed by chi 2 test. In addition, we also analyzed whether the knockdown of PFKFB3 by siRNAs could inhibit the ability of gastric cancer cells (MGC-803 and AGS) to proliferate and migrate by MTT analysis and transwell analyses. RESULTS: PFKFB3 was highly expressed in 81.3% (109/134) of gastric cancer patients. The overexpression of PFKFB3 was associated with lymph node metastasis (P = 0.045) and TNM stage (P = 0.033). Knockdown of PFKFB3 by siRNAs significantly inhibited the proliferation and migration abilities of gastric cancer cells. CONCLUSION: Our data suggest that PFKFB3 might be a potential biomarker for gastric cancer and anti-neoplastic targeting gene. PMID- 27983532 TI - MN1 and PTEN gene expression in acute myeloid leukemia. AB - OBJECTIVE: Multiple genetic alterations with prognostic significance have been discovered in acute myeloid leukemia (AML). We studied the expression level of two genes, Meningioma1 (MN1) and Phosphatase and Tensin homolog (PTEN) to determine their expression in AML patients and their role as prognostic markers. METHODS: The study included 50 cytogenetic normal de novo AML cases and 10 controls, Their level was detected by Real time Reverse Transcription-Polymerase Chain Reaction. RESULT: Relative mRNA expression of MN1 was significantly higher (p value < 0.001) and PTEN expression was significantly lower (p value = 0.002). No correlation was found between neither MN1 nor PTEN mRNA expression and overall survival (p value = 0.212 and 0.310) respectively. CONCLUSION: Although our study suggests a role for MN1 gene and PTEN genes in AML, we could not recommend their use as routine diagnostic and prognostic markers for AML in Egyptian population. PMID- 27983533 TI - Mechanism of Bushen Jianpi decoction in preventing and treating osteoporosis caused by aromatase inhibitors in breast cancer treatment. AB - PURPOSE: Research on the mechanism of Bushen Jianpi decoction (BJD) for preventing and treating osteoporosis caused by aromatase inhibitors (AI) during treatment for breast cancer resection. METHODS: An ovariectomized mouse model was established using random division into 6 groups: a sham ovariectomized group, a blank control group, a control group, an alendronate group, a BJD group, and a drug combination group. Mice breast cancer cell lines (4T1) were cultured and seeded into the armpits of 6 groups of BALB/c mice. The mouse breast cancer postoperative model was built when resecting the tumor after 3 weeks following seeding tumor. After 1 weeks, the 6 groups of mice were given different drugs. Then the following analyses were made: estradiol (E2) levels and alkaline phosphatase (ALP) levels in the serum; detection of in vitro bone density and calcium and bone phosphorus content; tumor pathology and immunohistochemistry detection. RESULTS: The results suggested that BJD decreased levels of ALP in ovariectomized mice, and there was a trend for improved bone loss. BJD strengthened the trend of alendronate to improve bone loss, improved bone density, bone calcium and phosphorous, and reduced ALP. BJD had a certain role on the promotion of the expression of estrogen receptors (ERs) in the relapse of the tumor tissue. CONCLUSIONS: Combined therapy with BJD and alendronate can act synergistically against osteoporosis, which was possibly related to a reduced bone conversion rate through inhibiting bone resorption. BJD may block the MAPK signal pathway in breast cancer cells, increasing the expression of ERs and making cancer cells sensitive to endocrine treatment. PMID- 27983534 TI - Osteoblastic differentiation and cell calcification of adamantinomatous craniopharyngioma induced by bone morphogenetic protein-2. AB - BACKGROUND: The calcification of adamantinomatous craniopharyngioma (ACP) often creates difficulties for surgical therapy. Nevertheless, the mechanism of ACP calcification is unclear. Our previous studies demonstrated that osteoblastic factors might play important roles in ACP calcification. OBJECTIVE: We examined the effects of recombinant human Bmp2 on ACP cell differentiation by testing osteoblastic proteins and calcium deposition. METHODS: The expression of osteoblastic factors including osteopontin (OPN), Runx2, and osterix in Bmp2 treated ACP cells was examined by western blot and/or real time PCR. ALP activity and calcium deposition after Bmp2 induction were also tested. RESULTS: Bmp2 significantly amplified the expression of Runx2, Osterix and OPN, as well as ALP activity. Both of these effects could be repressed by noggin treatment. Bmp2 also significantly induced the calcification of ACP, and noggin inhibited this calcium deposition. CONCLUSION: Our study demonstrated for the first time that ACP cells could differentiate into an osteoblastic lineage via induction by Bmp2. The mechanism of ACP calcification likely involves osteoblastic differentiation modulated by Bmp2. Further studies targeting Bmp2 cascades could result in novel therapeutic interventions for recurrent ACP. PMID- 27983535 TI - E2F transcription factors associated with up-regulated genes in glioblastoma. AB - BACKGROUND: Glioblastoma is considered to the most common and malignant brain tumor in adults. Patients have a median survival of approximately one year from diagnosis due to poor response to therapy. OBJECTIVE: We applied bioinformatics approaches to predict transcription factors (TF) that are deregulated in glioblastoma in an attempt to point out molecular targets for therapy. METHODS: Up-regulated genes in glioblastoma selected from public microarray data were submitted to two TF association analyses. Thereafter, the expression levels of TF obtained in the overlap of analyses were assessed by RT-qPCR carried out in seven glioblastoma cell lines (T98, U251, U138, U87, U343, M059J, and M059K). RESULTS: E2F1 and E2F4 were highlighted in both TF analyses. However, only E2F1 was confirmed as significantly up-regulated in all glioblastoma cell lines in vitro. CONCLUSION: E2F1 is a potential common regulator of differentially expressed genes in glioblastoma, despite the genetic heterogeneity of tumor cells. PMID- 27983536 TI - New variants in the BRCA1 gene in Buryat Mongol breast cancer patients: Report from two families. AB - BACKGROUND: The BRCA1 mutations that are endemic to the Slavic population of Russia have not been identified among indigenous peoples, including the Buryats, Tuvinians and Altaians with hereditary breast cancer. OBJECTIVE: This study was aimed to identify the mutations that are responsible for the occurrence of hereditary breast cancer in the indigenous population of the Republic of Buryatia. METHODS: Mutations in the BRCA1 gene were identified in blood samples by Sanger-based sequencing. RESULTS: We identified 11 polymorphisms (10 SNPs and 1 Indel) and 6 new unclassified sequence variants in the BRCA1 gene. In our study three new sequence variants (c.321T>A, c.366T>A, c.4357+2T>A) were found in position of previously described polymorphisms in dbSNPs: rs80357544 (c.321delT), rs190900046 (c.366T>G), and rs80358152 (c.4357+2T>C), respectively. Other three new sequence variants (c.3605A>G, c.1998A>C, and c.80+13A>C) have not been previously described in dbSNP, BIC and Human Gene Mutation Databases. CONCLUSIONS: We described six new sequence variants that have never been published in the literature or databases. Further studies are required to confirm the impact of new sequence variants on the risk of breast cancer in the Buryat Mongol population. PMID- 27983537 TI - Clinical potential of miRNA-221 as a novel prognostic biomarker for hepatocellular carcinoma. AB - miRNA-221 is one of the over 700 kinds of currently known microRNAs (miRNAs) and is up-regulated in multiple tumors, suggesting that it may be a potential carcinogenic miRNA. Few studies have explored the relationship between miRNA-221 and hepatocellular carcinoma (HCC). We performed real-time quantitative polymerase chain reaction (qPCR) to detect miRNA-221 expression in HCC and para carcinoma tissues and to explore the relationship between abnormal expression of miRNA-221 and clinicopathological features of HCC patients. miRNA-221 expression was significantly higher in HCC tissues than in adjacent tissues (P < 0.001). We analyzed the relationship between miRNA-221 expression level and clinicopathological characteristics of HCC patients. Our results suggested that miRNA-221 expression level was closely related to tumor stage (P = 0.012), number of tumor nodes (P = 0.018), and microvascular invasion (P = 0.010) in HCC patients. The results of survival analysis suggested that HCC patients with up regulated miRNA-221 expression had a shorter survival time. The high miRNA-221 expression indicates the poor prognosis of HCC patients; thus, miRNA-221 can be regarded an important molecular marker for HCC prognosis. PMID- 27983538 TI - Vitamin D deficiency is associated with a poor prognosis in advanced non-small cell lung cancer patients treated with platinum-based first-line chemotherapy. AB - OBJECTIVES: This study aimed to examine the prognostic role of the plasma 25 hydroxyvitamin D (25(OH)D) level in advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based doublet first-line chemotherapy. METHODS: A total of 195 advanced NSCLC patients were consecutively and prospectively hospitalized to receive platinum-based first-line chemotherapy. The baseline 25(OH)D level was measured at the time of diagnosis. Main outcome measures included overall survival (OS) and progression-free survival (PFS). RESULTS: With 10 ng/mL as the cutoff value for the baseline plasma 25(OH)D level, patients with 25(OH)D < 10 ng/mL (n = 54) and those with 25(OH)D >= 10 ng/mL (n = 141) were found to have similar characteristics in terms of age, sex, smoking status, pathological type, Eastern Cooperative Oncology Group (ECOG) performance status, and clinical staging (all P-values > 0.05). The median OS values of patients with 25(OH)D < 10 ng/mL and >= 10 ng/mL were 17.9 months (95% confidence interval [CI], 14.4-21.4 months) and 20.8 months (95%CI, 17.9-23.8 months), respectively; the median PFS values were 9.4 months (95%CI, 8.2-10.5 months) and 9.4 months (95%CI, 8.3-10.5 months), respectively. Both univariate and multivariate analyses showed that having a plasma 25(OH)D level < 10 ng/mL was associated with a significantly shorter OS (P = 0.003; P = 0.009), while the baseline plasma 25(OH)D level was not significantly associated with PFS. CONCLUSION: Deficiency of 25(OH)D is an independent prognostic factor for a poor OS in advanced NSCLC patients treated with platinum-based first-line chemotherapy. PMID- 27983539 TI - LncRNA-ANCR down-regulation suppresses invasion and migration of colorectal cancer cells by regulating EZH2 expression. AB - Our study aimed to explore the effects of long noncoding RNA (lncRNA)-ANCR on the invasion and migration of colorectal cancer (CRC) cells by regulating enhancer of zeste homolog 2 (EZH2) expression. CRC tissues and adjacent normal tissues were collected and CRC SW620 cells line and normal human intestinal epithelial cells (HIECs) were incubated. CRC SW620 cells line was transfected with ANCR-siRNA. The expressions of ANCR and EZH2 mRNA were measured by real-time quantitative polymerase chain reaction (RT-qPCR). EZH2 and trimethylation of H3K27 (H3K27me3) protein expressions were detected using Western blotting. The relationship between ANCR and EZH2 was determined through RNA pull-down and co immunoprecipitation (co-IP) assays. Cell invasion and migration were determined by Trans-well and cell scratch assays. ANCR, EZH2 and H3K27me3 expressions were up-regulated in CRC tissues and SW620 cells (all P < 0.05). After transfected with ANCR-siRNA, SW620 cells showed decreased ANCR expression and EZH2 mRNA and protein expressions (all P < 0.05). According to the results of RNA pull-down and co-IP assays, ANCR could specifically bind to EZH2. The results of Trans-well and cell scratch tests showed that when ANCR expression was decreased, the invasion and migration abilities of SW620 cells significantly declined (both P < 0.05). In conclusion, these results suggest that lncRNA-ANCR could influence the invasion and migration of CRC cells by specifically binding to EZH2. PMID- 27983540 TI - Plasma nitric oxide level is correlated with microvascular functions in the peripheral arterial disease. AB - At present there is no widely accepted biomarker for monitoring of vascular functions. The purpose of this prospective study was to investigate the association of some blood biomarkers with vascular reactivity in patients with peripheral arterial diseases (PAD). A prospective evaluation was made of 3 groups comprising a control group of healthy individuals, and patients with PAD caused by either atherosclerosis or Buerger's disease. Microvascular perfusion was examined using laser Doppler imaging of cutaneous erythrocyte flux after iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). The correlation of microvascular reactivity with endothelium-related biomarkers was assessed. ACh-induced and SNP-induced vasodilations were significantly diminished in the PAD groups. The plasma nitric oxide (NO) levels of PAD patients were significantly higher than those of the control group, but asymmetric dimethylarginine, total antioxidant capacity and hydrogen sulphide levels were similar. Plasma NO level was negatively correlated with ACh and SNP-stimulated microvascular flow increase, whereas a positive correlation was detected with blood glucose and glycated hemoglobin (HbA1c) levels in all groups. These results indicate that a high plasma level of NO in PAD patients is associated with diminished endothelium-dependent and independent flow increase in the microvascular bed. An excessive amount of NO-induced nitrosative stress in an inflammatory condition that might be a reason for vascular dysfunction should be taken into consideration in the diagnostic and therapeutic approaches to PAD. PMID- 27983541 TI - Effect of increasing mean arterial blood pressure on microcirculation in patients with cardiogenic shock supported by extracorporeal membrane oxygenation. AB - BACKGROUND: Little is known about the effect of mean arterial blood pressure (MAP) augmentation on the microcirculation in cardiogenic-shock patients with peripheral veno-arterial extracorporeal membrane oxygenation (ECMO) support. We investigated the effect of increasing MAP on the microcirculation in cardiogenic shock patients with ECMO support. METHODS: A single-center prospective observational study under taken in ICU patients undergoing ECMO support for post cardiotomy cardiogenic shock was carried out. Patients with MAP <60 mmHg treated with ECMO support were the study cohort. Inotropic and vasopressor agents (dopamine, dobutamine, norepinephrine or epinephrine) were administered to maintain the MAP at 60-90 mmHg. Hemodynamic and microcirculatory data were obtained at a baseline MAP of <60 mmHg and 1 h after target MAP was reached. As parameters of microcirculation, we measured thenar eminence tissue oxygenation (StO2) and its change during the vessel obstruction test and cerebral tissue oxygenation (rSO2) with near-infrared spectroscopy. RESULTS: Seventeen patients were enrolled in the study. MAP of all patients increased and reached predefined therapeutic targets (52 [50-54.5] vs.74 [70-78.5] mmHg; p < 0.001). To obtain these targets, doses of inotropic agents were increased (inotrope score increased from 14 [15.5-28] MUg/kg/min; p < 0.001). No obvious changes were observed in thenarmuscleStO2 and cerebral rSO2. Thenar muscle StO2 desaturation slope and resaturation slopes during the vessel obstruction test were also unchanged. CONCLUSIONS: Increasing MAP from <60 mmHg to 60-90 mmHg did not affect microcirculation variables in cardiogenic-shock patients with ECMO support. PMID- 27983543 TI - Deep tissue near infrared second derivative spectrophotometry for the assessment of claudication in peripheral arterial disease. AB - AIM: The purpose of this study was the application of a second derivative near infrared spectrophotometric (NIRS) technique to the human calf muscle in order to see if peripheral arterial disease (PAD) patients can be discriminated from control subjects, before, during and after a standard treadmill exercise test. METHODS: Three groups of human subjects were studied: group A consisted of 10 control subjects and groups B and C were formed by PAD patients classified as Fontaine's stage 2a (5 patients) and 2b (10 patients), respectively. The measurement protocol for all groups was 9.75 minutes of standing up (phase 1), 1 minute of exercise (phase 2) and 1 minute of rest (phase 3). Seven variables were defined at different times from the onset of the measurement protocol. RESULTS: All variables were significantly higher (p < 0.05) in group A in comparison to groups B and C. The level of significance was ten times higher (p < 0.005) at the onset (15 seconds) of the experiment and during phases 2 and 3. However, none of the variables in group B was significantly different from those in group C. CONCLUSIONS: It is shown for the first time that a second derivative NIRS technique can discriminate (p = 0.003) healthy subjects from PAD patients, in just 15 seconds of standing, with no exercise requirement. More experiments are required in order to uncover the full potential of the technique in the diagnosis of the PAD. PMID- 27983542 TI - Pentoxifylline attenuates the local and systemic inflammatory response after infrarenal abdominal aortic ischemia-reperfusion. AB - AIMS: We studied the new anti-inflammatory effects of non-specific phosphodiesterase (PDE) inhibitor pentoxifylline (PTX) on ischaemia-reperfusion injury and postconditioning of the lower extremities. We aimed to examine the oxidative stress parameters (OSP), the inflammatory response and the changes in structure of skeletal muscle after revascularization surgery. METHODS: 50 Wistar rats in five groups underwent a 60 min infrarenal aortic cross clamping. After the ischaemia in IR+PC group ischemic postconditioning was performed, intermittent 15 seconds reperfusion, 15 seconds ischaemic periods were applied four times. The ischemic phase was followed by a 120 min of reperfusion. In IR+PTX group the animals were treated with PTX. In IR+PC+PTX group both ischemic postconditioning and PTX treatment were performed. Blood samples and biopsy from quadriceps muscle were collected. Plasma malondialdehyde, reduced glutathione, SH-groups, TNF-alpha, IL-6 concentrations and superoxide dismutase enzyme activity were measured. RESULTS: The levels of OSP and the inflammatory proteins were significantly higher in the IR group. PTX treatment and PC could significantly decrease the levels of OSP and inflammatory proteins. When the animals were co-treated with PTX and PC the results were even better. CONCLUSIONS: Inhibition of PDE by PTX could markedly decrease the inflammatory response and moderate the ischaemia-reperfusion damages after lower limb ischemia and reperfusion. Administration of PTX could potentiate the beneficial effects of PC. PMID- 27983545 TI - Comparison of the simple red blood cell adhesiveness/aggregation test with the laser-assisted optical rotational cell analyzer: Red blood cell aggregation in patients with coronary artery disease and a healthy control group. AB - BACKGROUND: Red blood cell (RBC) aggregation influences blood flow properties, impacts blood microcirculation and consequently oxygen delivery. Different methods are established to determine RBC aggregation: under static conditions (i.e. the RBC adhesiveness/aggregation test (EAAT)) or under shear conditions (i.e. the laser-assisted optical rotational cell analyzer (LORCA)). OBJECTIVE: Comparison of these two different methods in detecting the RBC aggregation of patients with coronary artery disease (CAD) and of healthy controls. METHODS: RBC aggregation was quantified in peripheral venous blood of patients with CAD and healthy controls using EAAT and LORCA. RESULTS: Both methods detected an increased RBC aggregation in patients with CAD compared to the healthy control group: the ratio of clot-free area to whole area (rCFA) detected with EAAT (15.65 vs. 11.30%), and aggregation index (66.33 vs. 53.90%), shear rate of disaggregation (SDA) (105.59 vs. 69.21 s-1), and upstroke/ttop (0.03 vs. 0.02 au/s) detected with LORCA device were increased, aggregation half time (detected with LORCA) was decreased (2.11 vs. 3.60 s). rCFA (EAAT) correlated with SDA (LORCA). CONCLUSIONS: Both methods determine an increased RBC aggregation in patients with CAD. However, only one measurement parameter of the LORCA seems to reflect the same RBC aggregation properties as the EAAT. PMID- 27983544 TI - First experience of comparisons between two different shear wave speed imaging systems in differentiating malignant from benign thyroid nodules. AB - OBJECTIVE: The purpose of this study was to comparatively evaluate the two different shear wave speed (SWS) imaging systems of Toshiba shear wave elastography (T-SWE) and SuperSonic SWE (S-SWE) in distinguishing malignant from benign thyroid nodules (TNs). MATERIALS AND METHODS: 140 patients with 140 focal TNs were enrolled and underwent T-SWE and S-SWE before fine-needle aspiration (FNA) biopsy or surgery. SWE indices of mean, standard deviation and maximum values (E-mean, E-SD and E-max) of elastic modulus in TNs were measured on a color-coded mapping. The receiver operating characteristic (ROC) curve was performed to assess the diagnostic performance. RESULTS: Of the 140 nodules, 47 were thyroid carcinomas and 93 were benign. Areas under the receiver operating characteristic curve (AUC) were the highest with E-max among the three SWE parameters both for T-SWE and S-SWE (0.816 and 0.799). The most accurate cut-off values, sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were 26.6 kPa versus 42.9 kPa, 83.0% versus 63.8%, 68.8% versus 88.2%, 72.9% versus 80.0%, 56.5% versus 73.2% and 88.7% versus 82.8% with E-max for T-SWE and S-SWE, respectively. Among these comparisons, the sensitivity in T-SWE was statistically higher than S-SWE (83.0% versus 63.8%, p = 0.022), whereas specificity was statistically lower than S-SWE (68.8% versus 88.2%, p < 0.001). CONCLUSION: T-SWE is equal to S-SWE with comparable and promising results for diagnosis of TNs. In clinical using, the selection of E-max should be recommended both for T-SWE and S-SWE. PMID- 27983546 TI - The measurement of cutaneous blood flow in healthy volunteers subjected to physical exercise with ultrasound Doppler imaging and laser Doppler flowmetry. AB - We aimed to evaluate hemodynamic parameters in the cutaneous microcirculation during recovery to graded dynamic exercise performed on a cycloergometer by using two distinctive methods: high-frequency ultrasound Doppler flowmetry (UDF) and laser Doppler fluxmetry (LDF). Regarding UDF, the medium linear blood flow velocity (Vam) was estimated, expressed in absolute units (cm/s) whereas blood flow assessed by LDF was registered in arbitrary perfusion units (PU). We compared the corresponding perfusion values obtained by UDF and LDF, respectively, every 20 s during recovery period to physical exercise. Three types of microvascular blood flow dynamics were recorded: blood flow with an occasional paroxysm, a pulsatile blood flow pattern, and a shunting-type blood flow pattern. In the first type, the reaction time of registration and the direction of changes of UDF and LDF values coincided in 77.7%, exhibiting high correlation (r = 0.77; p<=0.001). In the second type, the direction of changes of UDF and LDF showed 85.0% similarity and a moderate correlation (r = 0.66; p = 0.0015), whereas in the third type, there was also a moderate correlation (r = 0.53, p = 0.0024). Our pilot experiments have shown that UDF could be regarded as a comparable substitutional method to LDF for studying skin microcirculation. PMID- 27983547 TI - Factors associated with initial incomplete ablation for benign thyroid nodules after radiofrequency ablation: First results of CEUS evaluation. AB - OBJECTIVE: To assess the factors associated with initial incomplete ablation (ICA) after radiofrequency ablation for benign thyroid nodules (BTNs). MATERIALS AND METHODS: 69 BTNs (mean volume 6.35+/-5.66 ml, range 1.00-25.04 ml) confirmed by fine-needle aspiration cytology (FNAC) in fifty-four patients were treated with ultrasound-guided percutaneous radiofrequency ablation (RFA) and the local treatment efficacy was immediately assessed by intra-procedural contrast-enhanced ultrasound (CEUS). The RFA was performed with a bipolar electrode (CelonProSurge 150-T20, output power: 20 W). CEUS was performed with a second generation contrast agent under low acoustic power (i.e. coded phase inversion, CPI). Characteristics of clinical factors, findings on conventional gray-scale ultrasound, color-Doppler ultrasound, and CEUS were evaluated preoperatively. Factors associated with initial ICA and initial ICA patterns on CEUS were assessed. Volume reduction ratios (VRRs) of ICA nodules were compared with those with complete ablation (CA). RESULTS: The RFA procedures were accomplished with a mean ablation time and mean total energy deposition of 11.13+/-3.39 min (range, 5.38-22.13 min) and 12612+/-4466 J (range, 6310-26130 J) respectively. CEUS detected initial ICA in 21 of 69 (30.8%) BTNs and 16 (76.2%) of the 21 BTNs with initial ICA achieved CA after additional RFA, leading to a final CA rate of 92.8% (64/69). The factors associated with initial ICA were predominantly solid nodule, nodule close to danger triangle area, nodule close to carotid artery, and peripheral blood flow on color-Doppler ultrasound (all P < 0.05). The mean VRRs of all BTNs were 23.4%, 54.4% and 81.9% at the 1-, 3- and 6-month follow-up, respectively. All BTNs achieved therapeutic success in this series in that all had VRRs of >50% at the 6-month follow-up, among which 7 nodules (10.1%) had VRRs of >90%. There were significant differences in VRRs between ICA nodules and CA nodules at the 3- and 6-month follow-up (all P < 0.05). CONCLUSION: The factors associated with initial ICA after RFA for BTNs were predominantly solid nodules, nodule close to danger triangle area, nodule close to carotid artery, and peripheral blood flow on color-Doppler ultrasound. CEUS assists quick treatment response evaluation and facilitates subsequent additional RFA and final CA of the nodules. Nodules with CA achieve a better outcome in terms of VRR in comparison with those with ICA. PMID- 27983548 TI - Deep Brain Stimulation for Alzheimer's Disease: Ethical Challenges for Clinical Research. AB - Deep brain stimulation (DBS) is an invasive neuromodulation modality that has shown early promise as a novel treatment of Alzheimer's disease (AD). Further clinical research is warranted on the basis of positive results from animal and human studies, as well as the inadequacy of existing treatments in reducing the enormous medical and financial costs of untreated AD. Nevertheless, unique ethical challenges require particular attention to elements of subject enrollment and informed consent. Study protocols should specify robust assessment and regular monitoring of subject decision-making capacity to consent to trial participation. Investigators should also assess for and mitigate therapeutic misconception (the phenomenon whereby a research participant conflates the goals of research with those of clinical treatment) and ensure that all prospective trial participants have adequate post-trial access to treatment and DBS device maintenance. In the following discussion, each issue is summarized and followed by recommendations for proper ethical procedure. We conclude by assimilating relevant ethical considerations into a decision-making algorithm designed to aid future clinical investigators of DBS for AD with the task of ethical subject enrollment. PMID- 27983549 TI - Estradiol and Cognition in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) Cohort Study. AB - Cardiovascular Risk factors, Aging and Dementia (CAIDE) is a Finnish population based study. 731 cognitively normal women had self-reported hormone therapy (HT) data in 1998 as: no use, use <=5 years, and >5 years. Information on type of HT was only available from 1995-1998 (Prescription Register). Cognition was assessed in 1998 and 2005-2008. Long-term (>5 years) HT use, especially use of estradiol alone among women having hysterectomy with bilateral oophorectomy, was associated with better episodic memory in 1998, but not in 2005-2008. Although a strong evidence for protective effect of estradiol on cognition was not observed in our study, improved global cognition among long-term users suggests that long-term postmenopausal HT may be beneficial for some cognitive domains. PMID- 27983550 TI - Decrease of Amyloid-beta Levels by Curcumin Derivative via Modulation of Amyloid beta Protein Precursor Trafficking. AB - The abnormal production and deposition of amyloid-beta (Abeta) peptides is a pathologic hallmark of Alzheimer's disease. Abeta is generated from amyloid-beta protein precursor (AbetaPP) by two sequential proteolytic cleavage steps involving beta- and gamma-secretases in the trans-Golgi network and endosomes. Since direct inhibition of secretase could induce undesirable side-effects due to inadvertent inhibition of unrelated secretase substrates, it is important to establish methods for inhibiting Abeta production that do not affect secretase activity. It has been suggested that curcumin may have potent anti-amyloidogenic effect. In the present study, we evaluate the effect of curcumin derivatives on Abeta production in human neuroblastoma SH-SY5Y cells and in CHO cells which stably express human AbetaPP (CHO-AbetaPP). We found that the curcumin derivative CU6 was more effective than curcumin itself in reducing Abeta secretion. We further found that in SH-SY5Y cells CU6 inhibited neither beta- nor gamma secretase activity, and that increased amounts of immature forms of AbetaPP accumulated in the endoplasmic reticulum (ER). We also found that CU6 induced expression of the ER chaperone glucose-regulated protein 78 (GRP78), and enhanced formation of the AbetaPP/GRP78 complex. These results suggest that CU6 downregulates intracellular AbetaPP trafficking, resulting in suppression of Abeta production independently of secretase activity. PMID- 27983551 TI - Benefits of Occupational Therapy in Dementia Patients: Findings from a Real-World Observational Study. AB - BACKGROUND: There is a growing interest in developing non-pharmacological approaches in dementia. Clinical efficacy of occupational therapy (OT) under routine care conditions has not been investigated yet. OBJECTIVE: To analyze the short-term effects of OT in patients with dementia; and to identify factors related to greater benefit. METHODS: Patients referred to OT were evaluated before starting a 3-month intervention and at 3 and 6 months later. Measures included: Mini-Mental State Examination (MMSE), Disability Assessment in Dementia (DAD), Neuropsychiatric Inventory (NPI) Questionnaire, patients' quality of life (EQ 5D-VAS), caregivers' burden (Zarit scale), and amount of informal care. Linear mixed models were used to analyze trajectories of outcomes. Logistic regressions with stepwise descending selection were used to study factors associated with benefits. RESULTS: 421 dementia patients benefited from OT (mean MMSE = 17.3). Patients remained cognitively stable over time. Functional performances also remained stable at 3 months and significantly decreased at 6 months (crude reduction of 2.8 points, p < 0.01). Behavioral troubles were significantly reduced over the intervention period and remained stable after (p < 0.01). Patients' quality of life increased over the 3-month intervention (p = 0.16) and significantly decreased thereafter. Caregivers' burden and informal care significantly decreased over the 3-month intervention and remained stable thereafter. Patients who benefited from OT with regard to function were less educated and had higher cognitive level. CONCLUSION: OT may be an effective intervention to maintain cognition and functionality and to reduce psychiatric symptoms in dementia patients. Mild stages of dementia could gain more benefits from OT with regard to functional decline. PMID- 27983552 TI - Histopathology and Florbetaben PET in Patients Incorrectly Diagnosed with Alzheimer's Disease. AB - Of 57 individuals diagnosed with Alzheimer's disease (AD) in a phase III study, 13 (23%) had amyloid-beta (Abeta) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Abeta negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Abeta in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Abeta pathology. PMID- 27983554 TI - Validation of the Spanish Version of the LASSI-L for Diagnosing Mild Cognitive Impairment and Alzheimer's Disease. AB - BACKGROUND: The Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L) is a novel cognitive test that measures recovery from proactive semantic interference, which may be an early cognitive marker of Alzheimer's disease (AD). OBJECTIVE: To generate normative data for a Spaniard population and to validate the LASSI-L for the diagnosis of amnestic mild cognitive impairment (aMCI) and mild AD. METHODS: We performed a cross-sectional study in which 97 healthy participants, 34 with aMCI, and 33 with mild AD were studied with LASSI-L and a comprehensive neuropsychological protocol. The overlapping strategy analysis was used to maximize the sample size and to provide age- and education adjusted normative data using a logistic regression analysis. RESULTS: Internal consistency was 0.932. Convergent validity with the Free and Cued Selective Reminding Test was moderate. LASSI-L raw scores were correlated with age and years of education, but not gender. The area under the curve for discriminating between healthy controls and aMCI was 0.909, and between healthy controls and mild AD was 0.986. LASSI-L sub-scores representing maximum storage capacity, recovery from proactive interference, and delayed recall yielded the highest diagnostic accuracy. CONCLUSIONS: The LASSI-L is a reliable and valid test for the diagnosis of aMCI and mild AD. The age and education influences on the performance of the test and normative data are provided. LASSI-L merits further studies to evaluate its ability to detect preclinical AD and predict progression to aMCI and early dementia. PMID- 27983555 TI - The Effects of Meditation on Grey Matter Atrophy and Neurodegeneration: A Systematic Review. AB - The present systematic review is based on the premise that a variety of neurodegenerative diseases are accompanied by grey matter atrophy in the brain and meditation may impact this. Given that age is a major risk factor for many of these progressive and neurodegenerative diseases and that the percentage of the population over the age of 65 is quickly increasing, there is an obvious need for prompt treatment and prevention advances in research. As there is currently no cure for Alzheimer's disease and other neurodegenerative diseases, many are seeking non-pharmacological treatment options in attempts to offset the disease related cognitive and functional declines. On the basis of a growing body of research suggesting that meditation is effective in increasing grey matter volume in healthy participants, this paper systematically reviewed the literature regarding the effects of meditation on restoring grey matter volume in healthy individuals and those affected by neurodegeneration. This review searched PubMed, CINAHL, and APA PsycNET to identify original studies that included MRI imaging to measure grey matter volume in meditators and post-mindfulness-based intervention participants compared to controls. Thirteen studies were considered eligible for review and involved a wide variety of meditation techniques and included participants with and without cognitive impairment. All studies reported significant increases in grey matter volume in the meditators/intervention group, albeit in assorted regions of the brain. Limited research exists on the mechanisms through which meditation affects disease-related neurodegeneration, but preliminary evidence suggests that it may offset grey matter atrophy. PMID- 27983553 TI - Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer's Disease: The Role of APP. AB - Overexpression of the amyloid precursor protein (APP) gene on chromosome 21 in Down syndrome (DS) has been linked to increased brain amyloid levels and early onset Alzheimer's disease (AD). An elderly man with phenotypic DS and partial trisomy of chromosome 21 (PT21) lacked triplication of APP affording an opportunity to study the role of this gene in the pathogenesis of dementia. Multidisciplinary studies between ages 66-72 years comprised neuropsychological testing, independent neurological exams, amyloid PET imaging with 11C-Pittsburgh compound-B (PiB), plasma amyloid-beta (Abeta) measurements, and a brain autopsy examination. The clinical phenotype was typical for DS and his intellectual disability was mild in severity. His serial neuropsychological test scores showed less than a 3% decline as compared to high functioning individuals with DS who developed dementia wherein the scores declined 17-28% per year. No dementia was detected on neurological examinations. On PiB-PET scans, the patient with PT21 had lower PiB standard uptake values than controls with typical DS or sporadic AD. Plasma Abeta42 was lower than values for demented or non-demented adults with DS. Neuropathological findings showed only a single neuritic plaque and neurofibrillary degeneration consistent with normal aging but not AD. Taken together the findings in this rare patient with PT21 confirm the obligatory role of APP in the clinical, biochemical, and neuropathological findings of AD in DS. PMID- 27983556 TI - The level of 24-Hydroxycholesteryl Esters is an Early Marker of Alzheimer's Disease. AB - Cholesterol (C) brain accumulation seems to play a role in the Alzheimer's disease (AD) pathogenesis. 24(S)-hydroxycholesterol (24OH-C) is the predominant metabolite of brain C and its synthesis is believed to represent a way to remove excess C from neurons. Previous studies showed that 24OH-C level is altered in patients with neurodegenerative diseases, including AD. Only one study demonstrated that 24OH-C esterification is altered in neurodegenerative diseases, i.e., amyotrophic lateral sclerosis. Herein we analyzed the level of 24OH-C esters (% 24OH-CE) in i) cerebrospinal fluid (CSF) and homologous serum of AD (n = 13) and controls (n = 8); ii) plasma from AD (n = 30), controls (n = 30), mild cognitive impairment (MCI) converting to AD (n = 34), and stable MCI (n = 40). The % 24OH-CE in CSF positively correlated with that in homologous serum and was lower in both CSF and blood from AD patients as compared to controls; moreover, the plasma value of % 24OH-CE was lower in MCI conv-AD than in non-converters. Kaplan Meier Survival curves revealed a significant anticipation of the disease onset in AD and MCI conv-AD subjects with the lowest % 24OH-CE values. In conclusion, the reduction of % 24OH-CE in AD and MCI conv-AD, as well as the anticipation of the disease in patients with the lowest % 24OH-CE, support a role of the cholesterol/lecithin-cholesterol acyltransferase axis in AD onset/progression. Thus, targeting brain cholesterol metabolism could be a valuable strategy to prevent AD associated cognitive decline. PMID- 27983557 TI - Investigating Simulated Driving Errors in Amnestic Single- and Multiple-Domain Mild Cognitive Impairment. AB - The areas of driving impairment characteristic of mild cognitive impairment (MCI) remain unclear. This study compared the simulated driving performance of 24 individuals with MCI, including amnestic single-domain (sd-MCI, n = 11) and amnestic multiple-domain MCI (md-MCI, n = 13), and 20 age-matched controls. Individuals with MCI committed over twice as many driving errors (20.0 versus 9.9), demonstrated difficulty with lane maintenance, and committed more errors during left turns with traffic compared to healthy controls. Specifically, individuals with md-MCI demonstrated greater driving difficulty compared to healthy controls, relative to those with sd-MCI. Differentiating between different subtypes of MCI may be important when evaluating driving safety. PMID- 27983558 TI - Diabetes and Alzheimer's Disease: Can Elevated Free Copper Predict the Risk of the Disease? AB - BACKGROUND: Defective copper regulation, primarily referred to as chelatable redox active Cu(II), has been involved in the etiology of diabetes, and Alzheimer's disease (AD). OBJECTIVES: However, no study has determined levels of labile copper non-bound to ceruloplasmin (non-Cp Cu, also known as 'free' copper) in the blood of subjects with diabetes compared with that of AD patients. METHODS: To this aim, values of non-Cp Cu were measured in 25 Type 1 (T1D) and 31 Type 2 (T2D) subjects and in28 healthy controls, along with measurements of C reactive protein, glycated hemoglobin A1c, cholesterol, and triglycerides. Non-Cp Cu levels were compared with those of an AD group previously studied. RESULTS: T2D subjects had significantly higher non-Cp Cu levels than Controls and T1D subjects (both p < 0.001 after adjusting for age, sex, and body mass index). A multinomial logistic model revealed that a one unit standard deviation increase of non-Cp Cu increased the relative risk of having T2D by 9.64 with respect to Controls (95% CI: 2.86-32.47). The comparison of non-Cp Cu levels in T2D with those of an AD population previously studied shows rising blood non-Cp Cu copper levels from Controls to T2D and AD. CONCLUSION: These results suggest the involvement of catalytically-active Cu(II) and glucose dysregulation in oxidative stress reactions leading to tissue damage in both diseases. PMID- 27983559 TI - Phenotype Characterization of HD Intermediate Alleles in PREDICT-HD. AB - BACKGROUND: Huntington disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion on chromosome 4. Pathology is associated with CAG repeat length. Prior studies examining people in the intermediate allele (IA) range found subtle differences in motor, cognitive, and behavioral domains compared to controls. OBJECTIVE: The purpose of this study was to examine baseline and longitudinal differences in motor, cognitive, behavioral, functional, and imaging outcomes between persons with CAG repeats in three ranges: normal (<=26), intermediate (27-35), and reduced penetrance (36-39). METHODS: We examined longitudinal data from 389 participants in three allele groups: 280 normal controls (NC), 21 intermediate allele [IA], and 88 reduced penetrance [RP]. We used linear mixed models to identify differences in baseline and longitudinal outcomes between groups. Three models were tested: 1) no baseline or longitudinal differences; 2) baseline differences but no longitudinal differences; and 3) baseline and longitudinal differences. RESULTS: Model 1 was the best fitting model for most outcome variables. Models 2 and 3 were best fitting for some of the variables. We found baseline and longitudinal trends of declining performance across increasing CAG repeat length groups, but no significant differences between the NC and IA groups. CONCLUSION: We did not find evidence to support differences in the IA group compared to the NC group. These findings are limited by a small IA sample size. PMID- 27983561 TI - Risk Factors for Suicidal Ideation in People at Risk for Huntington's Disease. AB - BACKGROUND: Suicidal ideation (SI) and attempts are increased in Huntington's disease (HD), making risk factor assessment a priority. OBJECTIVE: To determine whether, hopelessness, irritability, aggression, anxiety, CAG expansion status, depression, and motor signs/symptoms were associated with Suicidal Ideation (SI) in those at risk for HD. METHODS: Behavioral and neurological data were collected from subjects in an observational study. Subject characteristics were calculated by CAG status and SI. Logistic regression models were adjusted for demographics. Separate logistic regressions were used to compare SI and non-SI subjects. A combined logistic regression model, including 4 pre-specified predictors, (hopelessness, irritability, aggression, anxiety) was used to assess the relationship of SI to these predictors. RESULTS: 801 subjects were assessed, 40 were classified as having SI, 6.3% of CAG mutation expansion carriers had SI, compared with 4.3% of non- CAG mutation expansion carriers (p = 0.2275). SI subjects had significantly increased depression (p < 0.0001), hopelessness (p < 0.0001), irritability (p < 0.0001), aggression (p = 0.0089), and anxiety (p < 0.0001), and an elevated motor score (p = 0.0098). Impulsivity, assessed in a subgroup of subjects, was also associated with SI (p = 0.0267). Hopelessness and anxiety remained significant in combined model (p < 0.001; p < 0.0198, respectively) even when motor score was included. CONCLUSIONS: Behavioral symptoms were significantly higher in those reporting SI. Hopelessness and anxiety showed a particularly strong association with SI. Risk identification could assist in assessment of suicidality in this group. PMID- 27983562 TI - Plasma Cytokine Levels in Relation to Neuropsychiatric Symptoms and Cognitive Dysfunction in Huntington's disease. AB - BACKGROUND: In Huntington's disease (HD) the innate immune system is activated, as reflected by increased plasma levels of different cytokines. OBJECTIVE: To explore whether increased cytokine levels are associated with neuropsychiatric symptoms and cognitive dysfunction in HD mutation carriers. METHOD: Plasma cytokine levels of TNF-alpha, interleukin (IL)-1ra, IL-1beta, IL-5, IL-6, IL-8 and Il-10 were assessed in 124 HD mutation carriers at two time points 2 years apart (totalling 214 observations). Using multilevel regression analysis, cytokines were analysed in relation to neuropsychiatric symptoms and cognitive dysfunction. Depressed mood was assessed with the depression subscale of the Problem Behaviours Assessment (PBA), apathy with the Apathy Scale, and irritability with the Irritability Scale. Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) and a battery of executive cognitive functioning tests, aggregated into an executive cognitive functioning (ExCog) score. RESULTS: Inverse associations were found in adjusted models between IL-6 and ExCog score (beta= -0.114; p = 0.01) and between IL-1ra and ExCog score (beta= -0.110; p = 0.02). No associations between cytokine levels and any of the other neuropsychiatric symptom scores remained statistically significant in adjusted models. CONCLUSION: Higher plasma levels of IL-6 and IL 1ra are weakly associated with cognitive dysfunction in HD, but not with other neuropsychiatric symptoms. PMID- 27983563 TI - Important but not Enough - Information about HD Related Topics and Peer and Professional Support for Young Adults from HD Families. AB - BACKGROUND: The number of people affected by Huntington's disease (HD) is far greater than those with manifest HD because it also includes those at risk, both HD gene mutation carriers and family members not carrying the HD mutation. Many relevant needs of young adults from HD families may not be met at present. This includes advice on important life decisions e.g. family planning and having children, psychological support and treatment of medical conditions. OBJECTIVE: To survey the opinion of young adults from HD families about relevance and availability of information and support regarding several aspects of HD. METHODS: An online anonymous questionnaire translated into ten languages contained questions regarding the importance and availability of information and support about HD related topics, and attitudes towards research. Answers were captured in categories or on Likert scales. RESULTS: Information about HD related topics and the availability of peer and professional support are very important for young adults from HD families. In addition, with the exception of general information about HD, or predictive testing, the vast majority of respondents stated that they did not receive enough information on other important topics, for instance regarding legal advice and they did not feel supported enough by healthcare professionals. HD research was considered to be of high value, though most did not participate in HD research. CONCLUSION: The results of this survey can help devise a strategy to address these unmet needs and also to facilitate research participation of more young adults from HD families. PMID- 27983560 TI - Targeting the Cholinergic System to Develop a Novel Therapy for Huntington's Disease. AB - In this review, we outline the role of the cholinergic system in Huntington's disease, and briefly describe the dysfunction of cholinergic transmission, cholinergic neurons, cholinergic receptors and cholinergic survival factors observed in post-mortem human brains and animal models of Huntington's disease. We postulate how the dysfunctional cholinergic system can be targeted to develop novel therapies for Huntington's disease, and discuss the beneficial effects of cholinergic therapies in pre-clinical and clinical studies. PMID- 27983566 TI - Survey of the Huntington's Disease Patient and Caregiver Community Reveals Most Impactful Symptoms and Treatment Needs. AB - BACKGROUND: In preparation for a meeting with the U.S. Food and Drug Administration (FDA) on Patient-Focused Drug Development in Huntington's disease, the Huntington's Disease Society of America (HDSA) created and distributed two comprehensive surveys on the symptom experience and treatment approaches for Huntington's disease. OBJECTIVE: The objective of these surveys was to identify the specific symptoms that most impact the daily lives of individuals with Huntington's disease/Juvenile Huntington's disease (HD/JHD) and their caregivers and to solicit input on the types of treatments desired by HD affected families. The data were shared with the FDA to offer background and insight in preparation for the patient-focused meeting, as well as to ensure representation by the community in a manner that would complement those who attended in person. METHODS: Two distinct surveys were created using SurveyMonkey to capture patient and caregiver perspectives on HD symptoms and current treatments. HDSA distributed the surveys to the HD community in August and September 2014 and collected responses through January 2015. RESULTS: More than 3,600 responses to the two surveys were received. The data showed that both caregivers and individuals with HD were severely impacted by the cognitive and behavioral symptoms of HD with HD patients reporting problems with executive functioning and cognitive decline as most impactful to them. However, 30 percent of caregivers reported that chorea was the most impactful symptom compared to 17 percent of people with HD. Across all the symptom categories, patients reported a lower occurrence of symptoms than were reported by their caregivers. CONCLUSIONS: With only one drug approved for treatment of a symptom of Huntington's disease and no disease modifying treatments available, there is a critical need for new medicines to treat the cognitive, psychiatric and motor symptoms associated with HD. While the surveys did not capture risk/benefit data, the data collected do provide new insights around the different perspectives of patients and caregivers. We believe that industry development of treatments would be well informed by incorporating the patient community, which is more knowledgeable and engaged than given credit, in consideration of treatment regimens, risk-benefit and priorities for therapeutic development. PMID- 27983569 TI - Diffuse optical tomography for breast cancer imaging guided by computed tomography: A feasibility study. AB - Diffuse optical tomography (DOT) has attracted attentions in the last two decades due to its intrinsic sensitivity in imaging chromophores of tissues such as hemoglobin, water, and lipid. However, DOT has not been clinically accepted yet due to its low spatial resolution caused by strong optical scattering in tissues. Structural guidance provided by an anatomical imaging modality enhances the DOT imaging substantially. Here, we propose a computed tomography (CT) guided multispectral DOT imaging system for breast cancer imaging. To validate its feasibility, we have built a prototype DOT imaging system which consists of a laser at the wavelength of 650 nm and an electron multiplying charge coupled device (EMCCD) camera. We have validated the CT guided DOT reconstruction algorithms with numerical simulations and phantom experiments, in which different imaging setup parameters, such as projection number of measurements and width of measurement patch, have been investigated. Our results indicate that an air cooling EMCCD camera is good enough for the transmission mode DOT imaging. We have also found that measurements at six angular projections are sufficient for DOT to reconstruct the optical targets with 2 and 4 times absorption contrast when the CT guidance is applied. Finally, we have described our future research plan on integration of a multispectral DOT imaging system into a breast CT scanner. PMID- 27983565 TI - LBH589, A Hydroxamic Acid-Derived HDAC Inhibitor, is Neuroprotective in Mouse Models of Huntington's Disease. AB - BACKGROUND: Modulation of gene transcription by HDAC inhibitors has been shown repeatedly to be neuroprotective in cellular, invertebrate, and rodent models of Huntington's disease (HD). It has been difficult to translate these treatments to the clinic, however, because existing compounds have limited potency or brain bioavailability. OBJECTIVE: In the present study, we assessed the therapeutic potential of LBH589, an orally bioavailable hydroxamic acid-derived nonselective HDAC inhibitor in mouse models of HD. METHOD: The efficacy of LBH589 is tested in two HD mouse models using various biochemical, behavioral and neuropathological outcome measures. RESULTS: We show that LBH589 crosses the blood brain barrier; induces histone hyperacetylation and prevents striatal neuronal shrinkage in R6/2 HD mice. In full-length knock-in HD mice LBH589-treatment improves motor performance and reduces neuronal atrophy. CONCLUSIONS: Our efficacious results of LBH589 in fragment and full-length mouse models of HD suggest that LBH589 is a promising candidate for clinical assessment in HD patients and provides confirmation that non-selective HDAC inhibitors can be viable clinical candidates. PMID- 27983570 TI - Anti-Fatigue Effect by Peptide Fraction from Protein Hydrolysate of Croceine Croaker (Pseudosciaena crocea) Swim Bladder through Inhibiting the Oxidative Reactions including DNA Damage. AB - The swim bladder of the croceine croaker (Pseudosciaena crocea) was believed to have good curative effects in various diseases, including amnesia, insomnia, dizziness, anepithymia, and weakness after giving birth, in traditional Chinese medicine. However, there is no research focusing on the antioxidant and anti fatigue peptides from croceine croaker swim bladders at present. Therefore, the purpose of this study was to investigate the bioactivities of peptide fractions from the protein hydrolysate of croceine croaker related to antioxidant and anti fatigue effects. In the study, swim bladder peptide fraction (SBP-III-3) was isolated from the protein hydrolysate of the croceine croaker, and its antioxidant and anti-fatigue activities were measured using in vitro and in vivo methods. The results indicated that SBP-III-3 exhibited good scavenging activities on hydroxyl radicals (HO*) (EC50 (the concentration where a sample caused a 50% decrease of the initial concentration of HO*) = 0.867 mg/mL), 2,2 diphenyl-1-picrylhydrazyl radicals (DPPH*) (EC50 = 0.895 mg/mL), superoxide anion radical ( O 2 - *) (EC50 = 0.871 mg/mL), and 2,2'-azino-bis-3 ethylbenzothiazoline-6-sulfonic acid radical (ABTS+*) (EC50 = 0.346 mg/mL). SBP III-3 also showed protective effects on DNA damage in a concentration-effect manner and prolonged the swimming time to exhaustion of Institute of Cancer Research (ICR) mice by 57.9%-107.5% greater than that of the control. SBP-III-3 could increase the levels of muscle glucose (9.4%-115.2% increase) and liver glycogen (35.7%-157.3%), and decrease the levels of blood urea nitrogen (BUN), lactic acid (LA), and malondialdehyde (MDA) by 16.4%-22.4%, 13.9%-20.1%, and 28.0%-53.6%, respectively. SBP-III-3 also enhanced the activity of lactic dehydrogenase to scavenge excessive LA for slowing the development of fatigue. In addition, SBP-III-3 increased the activities superoxide dismutase, catalase, and glutathione peroxidase to reduce the reactive oxygen species (ROS) damage in mice. In conclusion, SBP-III-3 possessed good anti-fatigue capacities on mice by inhibiting the oxidative reactions and provided an important basis for developing the swim bladder peptide functional food. PMID- 27983571 TI - Anti-Fatigue Effects of Small Molecule Oligopeptides Isolated from Panax ginseng C. A. Meyer in Mice. AB - Panax ginseng C. A. Meyer (ginseng) is an edible and medicinal Chinese herb, which is often used in Asian countries for physical fitness. Ginseng is reported to have a wide range of biological activity and pharmaceutical properties. There were more studies on ginsenosides and polysaccharides, but fewer studies on ginseng oligopeptides (GOP), which are small molecule oligopeptides isolated from ginseng. The present study was designed to evaluate the anti-fatigue effects of GOP in mice and explore the possible underlying mechanism. Mice were randomly divided into four experimental sets for the detection of different indicators. Each set of mice were then divided into four groups. The control group was administered distilled water, and three GOP intervention groups were administered 125, 250, and 500 mg/kg of body weight, respectively, of GOP by gavage each day. After 30 days of GOP treatment, it was observed that GOP could significantly increase the forced swimming time, enhance lactate dehydrogenase (LDH) activity and hepatic glycogen levels, and retard the accumulation of serum urea nitrogen (SUN) and blood lactic acid (BLA) in mice. GOP also markedly ameliorated fatigue induced alterations of inoxidative stress biomarkers and antioxidant enzymes. Notably, GOP increased the mRNA expression of mitochondrial biogenesis factors and mitochondrial DNA content in skeletal muscles of mice. These results suggest that GOP possess anti-fatigue effects, which may be attributed to the inhibition of oxidative stress and the improvement of mitochondrial function in skeletal muscles. GOP could be a novel natural agent for relieving exercise fatigue. PMID- 27983573 TI - Trends in Consumption of Solid Fats, Added Sugars, Sodium, Sugar-Sweetened Beverages, and Fruit from Fast Food Restaurants and by Fast Food Restaurant Type among US Children, 2003-2010. AB - Energy intakes from fast food restaurants (FFRs) have declined among US children. Less is known about the corresponding trends for FFR-sourced solid fats, added sugars, and sodium, and food groups of interest, such as fruit and sugar sweetened beverages (SSBs). Using data from a single 24-h dietary recall among 12,378 children aged 4-19 years from four consecutive cycles of the nationally representative National Health and Nutrition Examination Survey (NHANES), 2003 2010 a custom algorithm segmented FFRs into burger, pizza, sandwich, Mexican cuisine, chicken, Asian cuisine, fish restaurants, and coffee shops. There was a significant population-wide decline in FFR-sourced solid fats (-32 kcal/day, p trend < 0.001), added sugars (-16 kcal/day; p-trend < 0.001), SSBs (-0.12 servings (12 fluid ounces or 355 mL)/day; p-trend < 0.001), and sodium (-166 mg/day; p-trend < 0.001). Declines were observed when restricted to fast food consumers alone. Sharp declines were observed for pizza restaurants; added sugars, solid fats, and SSBs declined significantly from burger restaurants. Fruit did not change for fast food restaurants overall. Temporal analyses of fast food consumption trends by restaurant type allow for more precise monitoring of the quality of children's diets than can be obtained from analyses of menu offerings. Such analyses can inform public health interventions and policy measures. PMID- 27983575 TI - An Extensive Unified Thermo-Electric Module Characterization Method. AB - Thermo-Electric Modules (TEMs) are being increasingly used in power generation as a valid alternative to batteries, providing autonomy to sensor nodes or entire Wireless Sensor Networks, especially for energy harvesting applications. Often, manufacturers provide some essential parameters under determined conditions, like for example, maximum temperature difference between the surfaces of the TEM or for maximum heat absorption, but in many cases, a TEM-based system is operated under the best conditions only for a fraction of the time, thus, when dynamic working conditions occur, the performance estimation of TEMs is crucial to determine their actual efficiency. The focus of this work is on using a novel procedure to estimate the parameters of both the electrical and thermal equivalent model and investigate their relationship with the operating temperature and the temperature gradient. The novelty of the method consists in the use of a simple test configuration to stimulate the modules and simultaneously acquire electrical and thermal data to obtain all parameters in a single test. Two different current profiles are proposed as possible stimuli, which use depends on the available test instrumentation, and relative performance are compared both quantitatively and qualitatively, in terms of standard deviation and estimation uncertainty. Obtained results, besides agreeing with both technical literature and a further estimation method based on module specifications, also provides the designer a detailed description of the module behavior, useful to simulate its performance in different scenarios. PMID- 27983572 TI - The Effect of Selenium Supplementation on Glucose Homeostasis and the Expression of Genes Related to Glucose Metabolism. AB - The aim of the study was to evaluate the effect of selenium supplementation on the expression of genes associated with glucose metabolism in humans, in order to explain the unclear relationship between selenium and the risk of diabetes. For gene expression analysis we used archival samples of cDNA from 76 non-diabetic subjects supplemented with selenium in the previous study. The supplementation period was six weeks and the daily dose of selenium was 200 ug (as selenium yeast). Blood for mRNA isolation was collected at four time points: before supplementation, after two and four weeks of supplementation, and after four weeks of washout. The analysis included 15 genes encoding selected proteins involved in insulin signaling and glucose metabolism. In addition, HbA1c and fasting plasma glucose were measured at three and four time points, respectively. Selenium supplementation was associated with a significantly decreased level of HbA1c but not fasting plasma glucose (FPG) and significant down-regulation of seven genes: INSR, ADIPOR1, LDHA, PDHA, PDHB, MYC, and HIF1AN. These results suggest that selenium may affect glycemic control at different levels of regulation, linked to insulin signaling, glycolysis, and pyruvate metabolism. Further research is needed to investigate mechanisms of such transcriptional regulation and its potential implication in direct metabolic effects. PMID- 27983574 TI - Use of Micropatterned Thin Film Nitinol in Carotid Stents to Augment Embolic Protection. AB - Stenting is an alternative to endarterectomy for the treatment of carotid artery stenosis. However, stenting is associated with a higher risk of procedural stroke secondary to distal thromboembolism. Hybrid stents with a micromesh layer have been proposed to address this complication. We developed a micropatterned thin film nitinol (M-TFN) covered stent designed to prevent thromboembolism during carotid intervention. This innovation may obviate the need or work synergistically with embolic protection devices. The proposed double layered stent is low-profile, thromboresistant, and covered with a M-TFN that can be fabricated with fenestrations of varying geometries and sizes. The M-TFN was created in multiple geometries, dimensions, and porosities by sputter deposition. The efficiency of various M-TFN to capture embolic particles was evaluated in different atherosclerotic carotid stenotic conditions through in vitro tests. The covered stent prevented emboli dislodgement in the range of 70%-96% during 30 min duration tests. In vitro vascular cell growth study results showed that endothelial cell elongation, alignment and growth behaviour silhouettes significantly enhance, specifically on the diamond-shape M-TFN, with the dimensions of 145 um * 20 um and a porosity of 32%. Future studies will require in vivo testing. Our results demonstrate that M-TFN has a promising potential for carotid artery stenting. PMID- 27983576 TI - Greedy Successive Anchorization for Localizing Machine Type Communication Devices. AB - Localization of machine type communication (MTC) devices is essential for various types of location-based applications. In this paper, we investigate a distributed localization problem in noisy networks, where an estimated position of blind MTC machines (BMs) is obtained by using noisy measurements of distance between BM and anchor machines (AMs). We allow positioned BMs also to work as anchors that are referred to as virtual AMs (VAMs) in this paper. VAMs usually have greater position errors than (original) AMs, and, if used as anchors, the error propagates through the whole network. However, VAMs are necessary, especially when many BMs are distributed in a large area with an insufficient number of AMs. To overcome the error propagation, we propose a greedy successive anchorization process (GSAP). A round of GSAP consists of consecutive two steps. In the first step, a greedy selection of anchors among AMs and VAMs is done by which GSAP considers only those three anchors that possibly pertain to the localization accuracy. In the second step, each BM that can select three anchors in its neighbor determines its location with a proposed distributed localization algorithm. Iterative rounds of GSAP terminate when every BM in the network finds its location. To examine the performance of GSAP, a root mean square error (RMSE) metric is used and the corresponding Cramer-Rao lower bound (CRLB) is provided. By numerical investigation, RMSE performance of GSAP is shown to be better than existing localization methods with and without an anchor selection method and mostly close to the CRLB. PMID- 27983577 TI - A Small Leak Detection Method Based on VMD Adaptive De-Noising and Ambiguity Correlation Classification Intended for Natural Gas Pipelines. AB - In this study, a small leak detection method based on variational mode decomposition (VMD) and ambiguity correlation classification (ACC) is proposed. The signals acquired from sensors were decomposed using the VMD, and numerous components were obtained. According to the probability density function (PDF), an adaptive de-noising algorithm based on VMD is proposed for noise component processing and de-noised components reconstruction. Furthermore, the ambiguity function image was employed for analysis of the reconstructed signals. Based on the correlation coefficient, ACC is proposed to detect the small leak of pipeline. The analysis of pipeline leakage signals, using 1 mm and 2 mm leaks, has shown that proposed detection method can detect a small leak accurately and effectively. Moreover, the experimental results have shown that the proposed method achieved better performances than support vector machine (SVM) and back propagation neural network (BP) methods. PMID- 27983564 TI - Dysregulation of Corticostriatal Connectivity in Huntington's Disease: A Role for Dopamine Modulation. AB - Aberrant communication between striatum, the main information processing unit of the basal ganglia, and cerebral cortex plays a critical role in the emergence of Huntington's disease (HD), a fatal monogenetic condition that typically strikes in the prime of life. Although both striatum and cortex undergo substantial cell loss over the course of HD, corticostriatal circuits become dysfunctional long before neurons die. Understanding the dysfunction is key to developing effective strategies for treating a progressively worsening triad of motor, cognitive, and psychiatric symptoms. Cortical output neurons drive striatal activity through the release of glutamate, an excitatory amino acid. Striatal outputs, in turn, release gamma-amino butyric acid (GABA) and exert inhibitory control over downstream basal ganglia targets. Ample evidence from transgenic rodent models points to dysregulation of corticostriatal glutamate transmission along with corresponding changes in striatal GABA release as underlying factors in the HD behavioral phenotype. Another contributor is dysregulation of dopamine (DA), a modulator of both glutamate and GABA transmission. In fact, pharmacological manipulation of DA is the only currently available treatment for HD symptoms. Here, we review data from animal models and human patients to evaluate the role of DA in HD, including DA interactions with glutamate and GABA within the context of dysfunctional corticostriatal circuitry. PMID- 27983578 TI - Process-Oriented Review of Bacterial Quorum Quenching for Membrane Biofouling Mitigation in Membrane Bioreactors (MBRs). AB - Quorum Quenching (QQ) has been developed over the last few years to overcome practical issues related to membrane biofouling, which is currently the major difficulty thwarting the extensive development of membrane bioreactors (MBRs). QQ is the disruption of Quorum Sensing (QS), cell-to-cell communication enabling the bacteria to harmonize their behavior. The production of biofilm, which is recognized as a major part of the biocake formed on a membrane surface, and which leads to biofouling, has been found to be one of the bacterial behaviors controlled by QS. Since the enzymatic disruption of QS was reported to be efficient as a membrane biofouling mitigation technique in MBRs, the application of QQ to lab-scale MBRs has been the subject of much research using different approaches under different operating conditions. This paper gives an overview of the effectiveness of QQ in mitigating membrane biofouling in MBRs. It is based on the results of previous studies, using two microbial strains, Rhodococcus sp. BH4 and Pseudomonas sp. 1A1. The effect of bacterial QQ on the physical phenomena of the MBR process is analyzed, adopting an original multi-scale approach. Finally, the potential influence of the MBR operating conditions on QQ effectiveness is discussed. PMID- 27983579 TI - What Ion Flow along Ion Channels Can Tell us about Their Functional Activity. AB - The functional activity of channel-forming peptides and proteins is most directly verified by monitoring the flow of physiologically relevant inorganic ions, such as Na+, K+ and Cl-, along the ion channels. Electrical current measurements across bilayer lipid membranes (BLMs) interposed between two aqueous solutions have been widely employed to this end and are still extensively used. However, a major drawback of BLMs is their fragility, high sensitivity toward vibrations and mechanical shocks, and low resistance to electric fields. To overcome this problem, metal-supported tethered BLMs (tBLMs) have been devised, where the BLM is anchored to the metal via a hydrophilic spacer that replaces and mimics the water phase on the metal side. However, only mercury-supported tBLMs can measure and regulate the flow of the above inorganic ions, thanks to mercury liquid state and high hydrogen overpotential. This review summarizes the main results achieved by BLMs incorporating voltage-gated channel-forming peptides, interpreting them on the basis of a kinetic mechanism of nucleation and growth. Hg-supported tBLMs are then described, and their potential for the investigation of voltage-gated and ohmic channels is illustrated by the use of different electrochemical techniques. PMID- 27983580 TI - Insomnia Phenotypes Based on Objective Sleep Duration in Adolescents: Depression Risk and Differential Behavioral Profiles. AB - Based on previous studies on the role of objective sleep duration in predicting morbidity in individuals with insomnia, we examined the role of objective sleep duration in differentiating behavioral profiles in adolescents with insomnia symptoms. Adolescents from the Penn State Child Cohort (n = 397, ages 12-23, 54.7% male) underwent a nine-hour polysomnography (PSG), clinical history, physical examination and psychometric testing, including the Child or Adult Behavior Checklist and Pediatric Behavior Scale. Insomnia symptoms were defined as a self-report of difficulty falling and/or staying asleep and objective "short" sleep duration as a PSG total sleep time <=7 h. A significant interaction showed that objective short sleep duration modified the association of insomnia symptoms with internalizing problems. Consistently, adolescents with insomnia symptoms and short sleep duration were characterized by depression, rumination, mood dysregulation and social isolation, while adolescents with insomnia symptoms and normal sleep duration were characterized by rule-breaking and aggressive behaviors and, to a lesser extent, rumination. These findings indicate that objective sleep duration is useful in differentiating behavioral profiles among adolescents with insomnia symptoms. The insomnia with objective short sleep duration phenotype is associated with an increased risk of depression earlier in the lifespan than previously believed. PMID- 27983583 TI - Treated Seawater as a Magnesium Source for Phosphorous Recovery from Wastewater-A Feasibility and Cost Analysis. AB - Conventional resources of phosphorous are at high risk of depletion in the near future due to current practices of its exploitation, thus new and improved exploration methodologies need to be developed to ensure phosphorous security. Today, some treatment plants recover phosphorous from municipal wastewater as struvite (MgNH4PO4.6H2O). Magnesium is often added to the wastewater as MgCl2.6H2O to facilitate the phosphorous recovery. However, the use of magnesium increases the costs of the process and is not aligned with sustainable development, therefore, alternative magnesium sources have to be found. The current study analyzes the feasibility of integrated membrane processes for magnesium recovery from seawater for utilization in the phosphorous recovery process. The integrated membrane systems consist of nanofiltration (NF), membrane distillation (MD), and membrane crystallization (MCr). The lowest associated cost is found for standalone NF treatment. However, the additional treatment with MD and MCr produces fresh water and salts like NaCl or potentially other valuable minerals at the expense of low-grade heat. PMID- 27983582 TI - Technical Developments and Clinical Use of Telemedicine in Sleep Medicine. AB - The use of assistive technology and telemedicine is likely to continue to shape our medical practice in the future, notably in the field of sleep medicine, especially within developed countries. Currently, the number of people suffering from obstructive sleep apnea syndrome (OSAS) is increasing. Telemedicine (TM) can be used in a variety of ways in sleep medicine: telediagnostics, teleconsultation, teletherapy and telemonitoring of patients being treated with positive pressure devices. In this review, we aim to summarize the recent scientific progresses of these techniques and their potential clinical applications and give consideration to the remaining problems related to TM application. PMID- 27983581 TI - Proteomic Analyses of Agkistrodon contortrix contortrix Venom Using 2D Electrophoresis and MS Techniques. AB - Snake venom is a complex mixture of proteins and peptides which in the Viperidae is mainly hemotoxic. The diversity of these components causes the venom to be an extremely interesting object of study. Discovered components can be used in search for new pharmaceuticals used primarily in the treatment of diseases of the cardiovascular system. In order to determine the protein composition of the southern copperhead venom, we have used high resolution two dimensional electrophoresis and MALDI ToF/ToF MS-based identification. We have identified 10 groups of proteins present in the venom, of which phospholipase A2 and metalloprotease and serine proteases constitute the largest groups. For the first time presence of 5'-nucleotidase in venom was found in this group of snakes. Three peptides present in the venom were also identified. Two of them as bradykinin-potentiating agents and one as an inhibitor. PMID- 27983584 TI - DOA and Polarization Estimation Using an Electromagnetic Vector Sensor Uniform Circular Array Based on the ESPRIT Algorithm. AB - In array signal processing systems, the direction of arrival (DOA) and polarization of signals based on uniform linear or rectangular sensor arrays are generally obtained by rotational invariance techniques (ESPRIT). However, since the ESPRIT algorithm relies on the rotational invariant structure of the received data, it cannot be applied to electromagnetic vector sensor arrays (EVSAs) featuring uniform circular patterns. To overcome this limitation, a fourth-order cumulant-based ESPRIT algorithm is proposed in this paper, for joint estimation of DOA and polarization based on a uniform circular EVSA. The proposed algorithm utilizes the fourth-order cumulant to obtain a virtual extended array of a uniform circular EVSA, from which the pairs of rotation invariant sub-arrays are obtained. The ESPRIT algorithm and parameter pair matching are then utilized to estimate the DOA and polarization of the incident signals. The closed-form parameter estimation algorithm can effectively reduce the computational complexity of the joint estimation, which has been demonstrated by numerical simulations. PMID- 27983585 TI - A New Continuous Rotation IMU Alignment Algorithm Based on Stochastic Modeling for Cost Effective North-Finding Applications. AB - Based on stochastic modeling of Coriolis vibration gyros by the Allan variance technique, this paper discusses Angle Random Walk (ARW), Rate Random Walk (RRW) and Markov process gyroscope noises which have significant impacts on the North finding accuracy. A new continuous rotation alignment algorithm for a Coriolis vibration gyroscope Inertial Measurement Unit (IMU) is proposed in this paper, in which the extended observation equations are used for the Kalman filter to enhance the estimation of gyro drift errors, thus improving the north-finding accuracy. Theoretical and numerical comparisons between the proposed algorithm and the traditional ones are presented. The experimental results show that the new continuous rotation alignment algorithm using the extended observation equations in the Kalman filter is more efficient than the traditional two position alignment method. Using Coriolis vibration gyros with bias instability of 0.1 degrees /h, a north-finding accuracy of 0.1 degrees (1sigma) is achieved by the new continuous rotation alignment algorithm, compared with 0.6 degrees (1sigma) north-finding accuracy for the two-position alignment and 1 degrees (1sigma) for the fixed-position alignment. PMID- 27983587 TI - Role of Redox Signaling and Inflammation in Skeletal Muscle Adaptations to Training. AB - The inflammatory response to exercise-induced muscle damage has been extensively described. Exercise has important modulatory effects on immune function. These effects are mediated by diverse factors including pro-inflammatory cytokines, classical stress hormones, and hemodynamic effects leading to cell redistribution. As has been reported regarding oxidative stress, inflammation can have both detrimental and beneficial effects in skeletal muscle. In this review we will address the role of inflammation on protein metabolism in skeletal muscle. Specifically, we will review studies showing that treatment with cyclooxygenase-inhibiting drugs modulate the protein synthesis response to one bout of resistance exercise and to training. Understanding how these drugs work is important for the millions of individuals worldwide that consume them regularly. We will also discuss the importance of reactive oxygen species and inflammatory cytokines in muscle adaptations to exercise and the Janus faced of the use of antioxidant and anti-inflammatory drugs by athletes for optimizing their performance, especially during the periods in which muscle hypertrophy is expected. PMID- 27983588 TI - Harmonized Collaborative Validation of Aflatoxins and Sterigmatocystin in White Rice and Sorghum by Liquid Chromatography Coupled to Tandem Mass Spectrometry. AB - An interlaboratory study was performed in eight laboratories to validate a liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for the simultaneous determination of aflatoxins and sterigmatocystin (STC) in white rice and sorghum (Sorghum bicolor). Fortified samples (at three different levels) of white rice and sorghum were extracted, purified through a solid-phase extraction (SPE) column, and then analyzed by LC/MS/MS. The apparent recoveries (ARs) ranged from 78.8% to 95.0% for aflatoxins and from 85.3% to 96.7% for STC. The relative standard deviations for repeatability (RSDr) and reproducibility (RSDR) of aflatoxins were in the ranges 7.9%-33.8% and 24.4%-81.0%, respectively. For STC, the RSDr ranged from 7.1% to 40.2% and the RSDR ranged from 28.1% to 99.2%. The Horwitz ratio values for the aflatoxins and STC ranged from 0.4 to 1.2 in white rice and from 0.3 to 1.0 in sorghum, respectively. These results validated this method for the simultaneous determination of aflatoxins and STC by LC/MS/MS after SPE column cleanup. The percentages of satisfactory Z-score values (|Z| <= 2) were the following: for white rice, 100% for aflatoxins and STC; for sorghum, 100%, except in data from two laboratories for STC (0.3 MUg/kg). This validated that the LC/MS/MS method was successfully applied for the determination of aflatoxins and STC in 20 white rice and 20 sorghum samples sourced from Korean markets. PMID- 27983586 TI - Algal Cell Factories: Approaches, Applications, and Potentials. AB - With the advent of modern biotechnology, microorganisms from diverse lineages have been used to produce bio-based feedstocks and bioactive compounds. Many of these compounds are currently commodities of interest, in a variety of markets and their utility warrants investigation into improving their production through strain development. In this review, we address the issue of strain improvement in a group of organisms with strong potential to be productive "cell factories": the photosynthetic microalgae. Microalgae are a diverse group of phytoplankton, involving polyphyletic lineage such as green algae and diatoms that are commonly used in the industry. The photosynthetic microalgae have been under intense investigation recently for their ability to produce commercial compounds using only light, CO2, and basic nutrients. However, their strain improvement is still a relatively recent area of work that is under development. Importantly, it is only through appropriate engineering methods that we may see the full biotechnological potential of microalgae come to fruition. Thus, in this review, we address past and present endeavors towards the aim of creating productive algal cell factories and describe possible advantageous future directions for the field. PMID- 27983589 TI - Improvement of Advanced Parkinson's Disease Manifestations with Deep Brain Stimulation of the Subthalamic Nucleus: A Single Institution Experience. AB - We present our experience at the University of Illinois at Chicago (UIC) in deep brain stimulation (DBS) of the subthalamic nucleus (STN), describing our surgical technique, and reporting our clinical results, and morbidities. Twenty patients with advanced Parkinson's disease (PD) who underwent bilateral STN-DBS were studied. Patients were assessed preoperatively and followed up for one year using the Unified Parkinson's Disease Rating Scale (UPDRS) in "on" and "off" medication and "on" and "off" stimulation conditions. At one-year follow-up, we calculated significant improvement in all the motor aspects of PD (UPDRS III) and in activities of daily living (UPDRS II) in the "off" medication state. The "off" medication UPDRS improved by 49.3%, tremors improved by 81.6%, rigidity improved by 50.0%, and bradykinesia improved by 39.3%. The "off" medication UPDRS II scores improved by 73.8%. The Levodopa equivalent daily dose was reduced by 54.1%. The UPDRS IVa score (dyskinesia) was reduced by 65.1%. The UPDRS IVb score (motor fluctuation) was reduced by 48.6%. Deep brain stimulation of the STN improves the cardinal motor manifestations of the idiopathic PD. It also improves activities of daily living, and reduces medication-induced complications. PMID- 27983590 TI - Conformational Response of 30S-bound IF3 to A-Site Binders Streptomycin and Kanamycin. AB - Aminoglycoside antibiotics are widely used to treat infectious diseases. Among them, streptomycin and kanamycin (and derivatives) are of importance to battle multidrug-resistant (MDR) Mycobacterium tuberculosis. Both drugs bind the small ribosomal subunit (30S) and inhibit protein synthesis. Genetic, structural, and biochemical studies indicate that local and long-range conformational rearrangements of the 30S subunit account for this inhibition. Here, we use intramolecular FRET between the C- and N-terminus domains of the flexible IF3 to monitor real-time perturbations of their binding sites on the 30S platform. Steady and pre-steady state binding experiments show that both aminoglycosides bring IF3 domains apart, promoting an elongated state of the factor. Binding of Initiation Factor IF1 triggers closure of IF3 bound to the 30S complex, while both aminoglycosides revert the IF1-dependent conformation. Our results uncover dynamic perturbations across the 30S subunit, from the A-site to the platform, and suggest that both aminoglycosides could interfere with prokaryotic translation initiation by modulating the interaction between IF3 domains with the 30S platform. PMID- 27983591 TI - An Overview of Vaccination Strategies and Antigen Delivery Systems for Streptococcus agalactiae Vaccines in Nile Tilapia (Oreochromis niloticus). AB - Streptococcus agalactiae is an emerging infectious disease adversely affecting Nile tilapia (Niloticus oreochromis) production in aquaculture. Research carried out in the last decade has focused on developing protective vaccines using different strategies, although no review has been carried out to evaluate the efficacy of these strategies. The purpose of this review is to provide a synopsis of vaccination strategies and antigen delivery systems currently used for S. agalactiae vaccines in tilapia. Furthermore, as shown herein, current vaccine designs include the use of replicative antigen delivery systems, such as attenuated virulent strains, heterologous vectors and DNA vaccines, while non replicative vaccines include the inactivated whole cell (IWC) and subunit vaccines encoding different S. agalactiae immunogenic proteins. Intraperitoneal vaccination is the most widely used immunization strategy, although immersion, spray and oral vaccines have also been tried with variable success. Vaccine efficacy is mostly evaluated by use of the intraperitoneal challenge model aimed at evaluating the relative percent survival (RPS) of vaccinated fish. The major limitation with this approach is that it lacks the ability to elucidate the mechanism of vaccine protection at portals of bacterial entry in mucosal organs and prevention of pathology in target organs. Despite this, indications are that the correlates of vaccine protection can be established based on antibody responses and antigen dose, although these parameters require optimization before they can become an integral part of routine vaccine production. Nevertheless, this review shows that different approaches can be used to produce protective vaccines against S. agalactiae in tilapia although there is a need to optimize the measures of vaccine efficacy. PMID- 27983592 TI - Ensuring Quality in Online Palliative Care Resources. AB - Evidence and information is an integral part of the processes enabling clinical and service delivery within health. It is used by health professionals in clinical practice and in developing their professional knowledge, by policy makers in decision making, and is sought by health consumers to help them manage their health needs and assess their options. Increasingly, this evidence and information is being disseminated and sought through online channels. The internet is fundamentally changing how health information is being distributed and accessed. Clinicians, patients, community members, and decision makers have an unprecedented capacity to find online information about palliative care and end-of-life care. However, it is clear that not all individuals have the skills to be able to find and assess the quality of the resources they need. There are also many issues in creating online resources that are current, relevant and authoritative for use by health professionals and by health consumers. This paper explores the processes and structures used in creating a major national palliative care knowledge resource, the CareSearch website, to meet the needs of health professionals and of patients and their families and carers. PMID- 27983593 TI - Polysaccharides from Traditional Chinese Medicines: Extraction, Purification, Modification, and Biological Activity. AB - Traditional Chinese Medicine (TCM) has been used to treat diseases in China for thousands of years. TCM compositions are complex, using as their various sources plants, animals, fungi, and minerals. Polysaccharides are one of the active and important ingredients of TCMs. Polysaccharides from TCMs exhibit a wide range of biological activities in terms of immunity- modifying, antiviral, anti inflammatory, anti-oxidative, and anti-tumor properties. With their widespread biological activities, polysaccharides consistently attract scientist's interests, and the studies often concentrate on the extraction, purification, and biological activity of TCM polysaccharides. Currently, numerous studies have shown that the modification of polysaccharides can heighten or change the biological activities, which is a new angle of polysaccharide research. This review highlights the current knowledge of TCM polysaccharides, including their extraction, purification, modification, and biological activity, which will hopefully provide profound insights facilitating further research and development. PMID- 27983594 TI - Zinc Up-Regulates Insulin Secretion from beta Cell-Like Cells Derived from Stem Cells from Human Exfoliated Deciduous Tooth (SHED). AB - Stem cells from human exfoliated deciduous tooth (SHED) offer several advantages over other stem cell sources. Using SHED, we examined the roles of zinc and the zinc uptake transporter ZIP8 (Zrt- and irt-like protein 8) while inducing SHED into insulin secreting beta cell-like stem cells (i.e., SHED-beta cells). We observed that ZIP8 expression increased as SHED differentiated into SHED-beta cells, and that zinc supplementation at day 10 increased the levels of most pancreatic beta cell markers-particularly Insulin and glucose transporter 2 (GLUT2). We confirmed that SHED-beta cells produce insulin successfully. In addition, we note that zinc supplementation significantly increases insulin secretion with a significant elevation of ZIP8 transporters in SHED-beta cells. We conclude that SHED can be converted into insulin-secreting beta cell-like cells as zinc concentration in the cytosol is elevated. Insulin production by SHED-beta cells can be regulated via modulation of zinc concentration in the media as ZIP8 expression in the SHED-beta cells increases. PMID- 27983595 TI - Genetic Variations Involved in Vitamin E Status. AB - Vitamin E (VE) is the generic term for four tocopherols and four tocotrienols that exhibit the biological activity of alpha-tocopherol. VE status, which is usually estimated by measuring fasting blood VE concentration, is affected by numerous factors, such as dietary VE intake, VE absorption efficiency, and VE catabolism. Several of these factors are in turn modulated by genetic variations in genes encoding proteins involved in these factors. To identify these genetic variations, two strategies have been used: genome-wide association studies and candidate gene association studies. Each of these strategies has its advantages and its drawbacks, nevertheless they have allowed us to identify a list of single nucleotide polymorphisms associated with fasting blood VE concentration and alpha tocopherol bioavailability. However, much work remains to be done to identify, and to replicate in different populations, all the single nucleotide polymorphisms involved, to assess the possible involvement of other kind of genetic variations, e.g., copy number variants and epigenetic modifications, in order to establish a reliable list of genetic variations that will allow us to predict the VE status of an individual by knowing their genotype in these genetic variations. Yet, the potential usefulness of this area of research is exciting with regard to personalized nutrition and for future clinical trials dedicated to assessing the biological effects of the various isoforms of VE. PMID- 27983597 TI - Antibiofilm Activity of Plant Polyphenols. AB - In the history of human medicine, antibiotics represent epochal examples of medical progress. However, with an approaching antibiotic crisis due to the emergence and extensive spread of antimicrobial resistance among bacterial agents, as well as to increasing number of patients with chronic and recalcitrant bacterial biofilm-associated infections, the naturally occurring molecules may become new sources of antibacterial and antibiofilm drugs for clinical usage. Polyphenols represent a class of plant natural products which are important in plant defense against microbial pathogens. The main focus of the review is on the antibiofilm activities of phenolic compounds against bacteria which play an essential role in medical device biofilm-associated infections. The other, not negligible part of the review is devoted to polyphenols' activity against bacterial agents that cause dental caries and periodontal disease. PMID- 27983598 TI - Plasma Processing with Fluorine Chemistry for Modification of Surfaces Wettability. AB - Using plasma in conjunction with fluorinated compounds is widely encountered in material processing. We discuss several plasma techniques for surface fluorination: deposition of fluorocarbon thin films either by magnetron sputtering of polytetrafluoroethylene targets, or by plasma-assisted chemical vapor deposition using tetrafluoroethane as a precursor, and modification of carbon nanowalls by plasma treatment in a sulphur hexafluoride environment. We showed that conformal fluorinated thin films can be obtained and, according to the initial surface properties, superhydrophobic surfaces can be achieved. PMID- 27983599 TI - Using CRISPR/Cas9-Mediated GLA Gene Knockout as an In Vitro Drug Screening Model for Fabry Disease. AB - The CRISPR/Cas9 Genome-editing system has revealed promising potential for generating gene mutation, deletion, and correction in human cells. Application of this powerful tool in Fabry disease (FD), however, still needs to be explored. Enzyme replacement therapy (ERT), a regular administration of recombinant human alpha Gal A (rhalpha-GLA), is a currently available and effective treatment to clear the accumulated Gb3 in FD patients. However, the short half-life of rhalpha GLA in human body limits its application. Moreover, lack of an appropriate in vitro disease model restricted the high-throughput screening of drugs for improving ERT efficacy. Therefore, it is worth establishing a large-expanded in vitro FD model for screening potential candidates, which can enhance and prolong ERT potency. Using CRISPR/Cas9-mediated gene knockout of GLA in HEK-293T cells, we generated GLA-null cells to investigate rhalpha-GLA cellular pharmacokinetics. The half-life of administrated rhalpha-GLA was around 24 h in GLA-null cells; co administration of proteasome inhibitor MG132 and rhalpha-GLA significantly restored the GLA enzyme activity by two-fold compared with rhalpha-GLA alone. Furthermore, co-treatment of rhalpha-GLA/MG132 in patient-derived fibroblasts increased Gb3 clearance by 30%, compared with rhalpha-GLA treatment alone. Collectively, the CRISPR/Cas9-mediated GLA-knockout HEK-293T cells provide an in vitro FD model for evaluating the intracellular pharmacokinetics of the rhalpha GLA as well as for screening candidates to prolong rhalpha-GLA potency. Using this model, we demonstrated that MG132 prolongs rhalpha-GLA half-life and enhanced Gb3 clearance, shedding light on the direction of enhancing ERT efficacy in FD treatment. PMID- 27983602 TI - Synthesis, Antifungal Evaluation and In Silico Study of N-(4-Halobenzyl)amides. AB - A collection of 32 structurally related N-(4-halobenzyl)amides were synthesized from cinnamic and benzoic acids through coupling reactions with 4 halobenzylamines, using (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) as a coupling agent. The compounds were identified by spectroscopic methods such as infrared, 1H- and 13C- Nuclear Magnetic Resonance (NMR) and high-resolution mass spectrometry. The compounds were then submitted to antimicrobial tests by the minimum inhibitory concentration method (MIC) and nystatin was used as a control in the antifungal assays. The purpose of the tests was to evaluate the influence of structural changes in the cinnamic and benzoic acid substructures on the inhibitory activity against strains of Candida albicans, Candida tropicalis, and Candida krusei. A quantitative structure activity relationship (QSAR) study with KNIME v. 3.1.0 and Volsurf v. 1.0.7 softwares were realized, showing that descriptors DRDRDR, DRDRAC, L4LgS, IW4 and DD2 influence the antifungal activity of the haloamides. In general, 10 benzamides revealed fungal sensitivity, especially a vanillic amide which enjoyed the lowest MIC. The results demonstrate that a hydroxyl group in the para position, and a methoxyl at the meta position enhance antifungal activity for the amide skeletal structure. In addition, the double bond as a spacer group appears to be important for the activity of amide structures. PMID- 27983600 TI - Rat Aquaporin-5 Is pH-Gated Induced by Phosphorylation and Is Implicated in Oxidative Stress. AB - Aquaporin-5 (AQP5) is a membrane water channel widely distributed in human tissues that was found up-regulated in different tumors and considered implicated in carcinogenesis in different organs and systems. Despite its wide distribution pattern and physiological importance, AQP5 short-term regulation was not reported and mechanisms underlying its involvement in cancer are not well defined. In this work, we expressed rat AQP5 in yeast and investigated mechanisms of gating, as well as AQP5's ability to facilitate H2O2 plasma membrane diffusion. We found that AQP5 can be gated by extracellular pH in a phosphorylation-dependent manner, with higher activity at physiological pH 7.4. Moreover, similar to other mammalian AQPs, AQP5 is able to increase extracellular H2O2 influx and to affect oxidative cell response with dual effects: whereas in acute oxidative stress conditions AQP5 induces an initial higher sensitivity, in chronic stress AQP5 expressing cells show improved cell survival and resistance. Our findings support the involvement of AQP5 in oxidative stress and suggest AQP5 modulation by phosphorylation as a novel tool for therapeutics. PMID- 27983601 TI - Transcriptome of Cultured Lung Fibroblasts in Idiopathic Pulmonary Fibrosis: Meta Analysis of Publically Available Microarray Datasets Reveals Repression of Inflammation and Immunity Pathways. AB - Heritable profibrotic differentiation of lung fibroblasts is a key mechanism of idiopathic pulmonary fibrosis (IPF). Its mechanisms are yet to be fully understood. In this study, individual data from four independent microarray studies comparing the transcriptome of fibroblasts cultured in vitro from normal (total n = 20) and IPF (total n = 20) human lung were compiled for meta-analysis following normalization to z-scores. One hundred and thirteen transcripts were upregulated and 115 were downregulated in IPF fibroblasts using the Significance Analysis of Microrrays algorithm with a false discovery rate of 5%. Downregulated genes were highly enriched for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional classes related to inflammation and immunity such as Defense response to virus, Influenza A, tumor necrosis factor (TNF) mediated signaling pathway, interferon-inducible absent in melanoma2 (AIM2) inflammasome as well as Apoptosis. Although upregulated genes were not enriched for any functional class, select factors known to play key roles in lung fibrogenesis were overexpressed in IPF fibroblasts, most notably connective tissue growth factor (CTGF) and serum response factor (SRF), supporting their role as drivers of IPF. The full data table is available as a supplement. PMID- 27983596 TI - Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases. AB - During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese. Also we discuss the brain health effects associated from exposure to EEDs including the promotion of neurodegeneration, protection against neurodegeneration, and involvement in various neurological deficits; changes in rearing behavior, locomotion, anxiety, learning difficulties, memory issues, and neuronal abnormalities. The effects of EEDs on the brain are varied during the entire life span and far-reaching with many different mechanisms. To understand endocrine disrupting chemicals mechanisms, we use bioinformatics, molecular, and epidemiologic approaches. Through those approaches, we learn how the effects of EEDs on the brain go beyond known mechanism to disrupt the circulatory and neural estrogen function and estrogen-mediated signaling. Effects on EEDs-modified estrogen and nuclear respiratory factor 1 (NRF1) signaling genes with exposure to natural estrogen, pharmacological estrogen-ethinyl estradiol, PCBs, phthalates, BPA, and metalloestrogens are presented here. Bioinformatics analysis of gene EEDs interactions and brain disease associations identified hundreds of genes that were altered by exposure to estrogen, phthalate, PCBs, BPA or metalloestrogens. Many genes modified by EEDs are common targets of both 17 beta estradiol (E2) and NRF1. Some of these genes are involved with brain diseases, such as Alzheimer's Disease (AD), Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorder, and Brain Neoplasms. For example, the search of enriched pathways showed that top ten E2 interacting genes in AD-APOE, APP, ATP5A1, CALM1, CASP3, GSK3B, IL1B, MAPT, PSEN2 and TNF-underlie the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD pathway. With AD, the six E2-responsive genes are NRF1 target genes: APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1. These genes are also responsive to the following EEDs: ethinyl estradiol (APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1), BPA (APBB2, EIF2S1, ENO1, MAPT, and PAXIP1), dibutyl phthalate (DPYSL2, EIF2S1, and ENO1), diethylhexyl phthalate (DPYSL2 and MAPT). To validate findings from Comparative Toxicogenomics Database (CTD) curated data, we used Bayesian network (BN) analysis on microarray data of AD patients. We observed that both gender and NRF1 were associated with AD. The female NRF1 gene network is completely different from male human AD patients. AD-associated NRF1 target genes-APLP1, APP, GRIN1, GRIN2B, MAPT, PSEN2, PEN2, and IDE-are also regulated by E2. NRF1 regulates targets genes with diverse functions, including cell growth, apoptosis/autophagy, mitochondrial biogenesis, genomic instability, neurogenesis, neuroplasticity, synaptogenesis, and senescence. By activating or repressing the genes involved in cell proliferation, growth suppression, DNA damage/repair, apoptosis/autophagy, angiogenesis, estrogen signaling, neurogenesis, synaptogenesis, and senescence, and inducing a wide range of DNA damage, genomic instability and DNA methylation and transcriptional repression, NRF1 may act as a major regulator of EEDs-induced brain health deficits. In summary, estrogenic endocrine disrupting chemicals-modified genes in brain health deficits are part of both estrogen and NRF1 signaling pathways. Our findings suggest that in addition to estrogen signaling, EEDs influencing NRF1 regulated communities of genes across genomic and epigenomic multiple networks may contribute in the development of complex chronic human brain health disorders. PMID- 27983604 TI - Detecting Target Objects by Natural Language Instructions Using an RGB-D Camera. AB - Controlling robots by natural language (NL) is increasingly attracting attention for its versatility, convenience and no need of extensive training for users. Grounding is a crucial challenge of this problem to enable robots to understand NL instructions from humans. This paper mainly explores the object grounding problem and concretely studies how to detect target objects by the NL instructions using an RGB-D camera in robotic manipulation applications. In particular, a simple yet robust vision algorithm is applied to segment objects of interest. With the metric information of all segmented objects, the object attributes and relations between objects are further extracted. The NL instructions that incorporate multiple cues for object specifications are parsed into domain-specific annotations. The annotations from NL and extracted information from the RGB-D camera are matched in a computational state estimation framework to search all possible object grounding states. The final grounding is accomplished by selecting the states which have the maximum probabilities. An RGB D scene dataset associated with different groups of NL instructions based on different cognition levels of the robot are collected. Quantitative evaluations on the dataset illustrate the advantages of the proposed method. The experiments of NL controlled object manipulation and NL-based task programming using a mobile manipulator show its effectiveness and practicability in robotic applications. PMID- 27983606 TI - Functional Analysis of the Fusarielin Biosynthetic Gene Cluster. AB - Fusarielins are polyketides with a decalin core produced by various species of Aspergillus and Fusarium. Although the responsible gene cluster has been identified, the biosynthetic pathway remains to be elucidated. In the present study, members of the gene cluster were deleted individually in a Fusarium graminearum strain overexpressing the local transcription factor. The results suggest that a trans-acting enoyl reductase (FSL5) assists the polyketide synthase FSL1 in biosynthesis of a polyketide product, which is released by hydrolysis by a trans-acting thioesterase (FSL2). Deletion of the epimerase (FSL3) resulted in accumulation of an unstable compound, which could be the released product. A novel compound, named prefusarielin, accumulated in the deletion mutant of the cytochrome P450 monooxygenase FSL4. Unlike the known fusarielins from Fusarium, this compound does not contain oxygenized decalin rings, suggesting that FSL4 is responsible for the oxygenation. PMID- 27983605 TI - Effect of the CRAC Peptide, VLNYYVW, on mPTP Opening in Rat Brain and Liver Mitochondria. AB - The translocator protein (TSPO; 18 kDa) is a high-affinity cholesterol-binding protein located in the outer membrane of mitochondria. A domain in the C-terminus of TSPO was characterized as the cholesterol recognition/interaction amino acid consensus (CRAC). The ability of the CRAC domain to bind to cholesterol led us to hypothesize that this peptide may participate in the regulation of mitochondrial membrane permeability. Herein, we report the effect of the synthetic CRAC peptide, VLNYYVW, on mitochondrial permeability transition pore (mPTP) opening. It was found that the CRAC peptide alone prevents the mPTP from opening, as well as the release of apoptotic factors (cytochrome c, AIF, and EndoG) in rat brain mitochondria (RBM). Co-incubation of CRAC, together with the TSPO drug ligand, PK 11195, resulted in the acceleration of mPTP opening and in the increase of apoptotic factor release. VLNYYVW did not induce swelling in rat liver mitochondria (RLM). 3,17,19-androsten-5-triol (19-Atriol; an inhibitor of the cholesterol-binding activity of the CRAC peptide) alone and in combination with the peptide was able to stimulate RLM swelling, which was Ca2+- and CsA sensitive. Additionally, a combination of 19-Atriol with 100 nM PK 11195 or with 100 uM PK 11195 displayed the opposite effect: namely, the addition of 19-Atriol with 100 uM PK 11195 in a suspension of RLM suppressed the Ca2+-induced swelling of RLM by 40%, while the presence of 100 nM PK 11195 with 19-Atriol enhanced the swelling of RLM by 60%. Taken together, these data suggest the participation of the TSPO's CRAC domain in the regulation of permeability transition. PMID- 27983608 TI - Refractive Index Sensing with D-Shaped Plastic Optical Fibers for Chemical and Biochemical Applications. AB - We report the optimization of the length of a D-shaped plastic optical fiber (POF) sensor for refractive index (RI) sensing from a numerical and experimental point of view. The sensing principle is based on total internal reflection (TIR). POFs with 1 mm in diameter were embedded in grooves, realized in planar supports with different lengths, and polished to remove the cladding and part of the core. All D-shaped POF sensors were tested using aqueous medium with different refractive indices (from 1.332 to 1.471) through intensity-based configuration. Results showed two different responses. Considering the refractive index (RI) range (1.33-1.39), the sensitivity and the resolution of the sensor were strongly dependent on the sensing region length. The highest sensitivity (resolution of 6.48 * 10-3 refractive index units, RIU) was obtained with 6 cm sensing length. In the RI range (1.41-1.47), the length of the sensing region was not a critical aspect to obtain the best resolution. These results enable the application of this optical platform for chemical and biochemical evanescent field sensing. The sensor production procedure is very simple, fast, and low-cost. PMID- 27983603 TI - Regulation of Ketone Body Metabolism and the Role of PPARalpha. AB - Ketogenesis and ketolysis are central metabolic processes activated during the response to fasting. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator activated receptor alpha (PPARalpha) is one of the key transcription factors taking part in this regulation. PPARalpha is an important element in the metabolic network, where it participates in signaling driven by the main nutrient sensors, such as AMP-activated protein kinase (AMPK), PPARgamma coactivator 1alpha (PGC-1alpha), and mammalian (mechanistic) target of rapamycin (mTOR) and induces hormonal mediators, such as fibroblast growth factor 21 (FGF21). This work describes the regulation of ketogenesis and ketolysis in normal and malignant cells and briefly summarizes the positive effects of ketone bodies in various neuropathologic conditions. PMID- 27983607 TI - Study of the Genetic Etiology of Primary Ovarian Insufficiency: FMR1 Gene. AB - Menopause is a period of women's life characterized by the cessation of menses in a definitive way. The mean age for menopause is approximately 51 years. Primary ovarian insufficiency (POI) refers to ovarian dysfunction defined as irregular menses and elevated gonadotrophin levels before or at the age of 40 years. The etiology of POI is unknown but several genes have been reported as being of significance. The fragile X mental retardation 1 gene (FMR1) is one of the most important genes associated with POI. The FMR1 gene contains a highly polymorphic CGG repeat in the 5' untranslated region of exon 1. Four allelic forms have been defined with respect to CGG repeat length and instability during transmission. Normal (5-44 CGG) alleles are usually transmitted from parent to offspring in a stable manner. The full mutation form consists of over 200 repeats, which induces hypermethylation of the FMR1 gene promoter and the subsequent silencing of the gene, associated with Fragile X Syndrome (FXS). Finally, FMR1 intermediate (45-54 CGG) and premutation (55-200 CGG) alleles have been principally associated with two phenotypes, fragile X tremor ataxia syndrome (FXTAS) and fragile X primary ovarian insufficiency (FXPOI). PMID- 27983609 TI - Visceral Adiposity Index and Lipid Accumulation Product Index: Two Alternate Body Indices to Identify Chronic Kidney Disease among the Rural Population in Northeast China. AB - We aimed to compare the relative strength of the association between anthropometric obesity indices and chronic kidney disease (CKD). Another objective was to examine whether the visceral adiposity index (VAI) and lipid accumulation product index (LAPI) can identify CKD in the rural population of China. There were 5168 males and 6024 females involved in this cross-sectional study, and 237 participants (2.12%) suffered from CKD. Obesity indices included body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), VAI and LAPI. VAI and LAPI were calculated with triglyceride (TG), high-density lipoprotein (HDL), BMI and WC. VAI = [WC/39.68 + (1.88 * BMI)] * (TG /1.03) * (1.31/ HDL) for males; VAI = [WC/36.58 + (1.89 * BMI)] * (TG/0.81) * (1.52/HDL) for females. LAPI = (WC-65) * TG for males, LAPI = (WC-58) * TG for females. CKD was defined as an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m2. The prevalence of CKD increased across quartiles for WHtR, VAI and LAPI. A multivariate logistic regression analysis of the presence of CKD for the highest quartile vs. the lowest quartile of each anthropometric measure showed that the VAI was the best predictor of CKD in females (OR: 4.21, 95% CI: 2.09-8.47, p < 0.001). VAI showed the highest AUC for CKD (AUC: 0.68, 95% CI: 0.65-0.72) and LAPI came second (AUC: 0.66, 95% CI: 0.61-0.70) in females compared with BMI (both p-values < 0.001). However, compared with the traditional index of the BMI, the anthropometric measures VAI, LAPI, WC, and WHtR had no statistically significant capacity to predict CKD in males. Our results showed that both VAI and LAPI were significantly associated with CKD in the rural population of northeast China. Furthermore, VAI and LAPI were superior to BMI, WC and WHtR for predicting CKD only in females. PMID- 27983610 TI - The Association of Hypertriglyceridemic Waist Phenotype with Chronic Kidney Disease and Its Sex Difference: A Cross-Sectional Study in an Urban Chinese Elderly Population. AB - Background: The primary objective of this study was to explore the association of hypertriglyceridemic waist (HTGW) phenotype with chronic kidney disease (CKD) and its sex difference in an urban Chinese elderly population. Methods: In a cross sectional study, a total of 2102 participants aged 60-95 years were recruited and classified into four phenotypes: normal waist-normal triglyceride (NWNT), normal waist-elevated triglycerides (NWET), elevated waist-normal triglycerides (EWNT), and HTGW. Logistic regression analysis was used to estimate the associations of interest. Results: Total prevalence of CKD was 12.6%, and the CKD prevalence in participants with EWNT and HTGW was higher than with NWNT and NWET without regard to sex. Compared to NWNT phenotype, the adjusted OR for CKD was 1.95 (95% CI: 1.32-2.88) in HTGW groups. In contrast with the null findings (OR: 1.66; 95% CI: 0.94-2.94) in women after additional adjustment for diabetes and hypertension, the OR with HTGW remained strong (OR: 1.88; 95% CI: 1.04-3.39) in men. Similar findings appeared with the EWNT phenotype. Conclusions: The HTGW phenotype is positively associated with CKD among Chinese community elderly and may have a greater impact on men. More attention should be paid to the association between triglycerides and waist circumference in clinical practice and to the further identification this uncertain sex-related association. PMID- 27983611 TI - Minimizing Spatial Variability of Healthcare Spatial Accessibility-The Case of a Dengue Fever Outbreak. AB - Outbreaks of infectious diseases or multi-casualty incidents have the potential to generate a large number of patients. It is a challenge for the healthcare system when demand for care suddenly surges. Traditionally, valuation of heath care spatial accessibility was based on static supply and demand information. In this study, we proposed an optimal model with the three-step floating catchment area (3SFCA) to account for the supply to minimize variability in spatial accessibility. We used empirical dengue fever outbreak data in Tainan City, Taiwan in 2015 to demonstrate the dynamic change in spatial accessibility based on the epidemic trend. The x and y coordinates of dengue-infected patients with precision loss were provided publicly by the Tainan City government, and were used as our model's demand. The spatial accessibility of heath care during the dengue outbreak from August to October 2015 was analyzed spatially and temporally by producing accessibility maps, and conducting capacity change analysis. This study also utilized the particle swarm optimization (PSO) model to decrease the spatial variation in accessibility and shortage areas of healthcare resources as the epidemic went on. The proposed method in this study can help decision makers reallocate healthcare resources spatially when the ratios of demand and supply surge too quickly and form clusters in some locations. PMID- 27983612 TI - Health Profile of Construction Workers in Hong Kong. AB - Construction is a manual, heavy, and complex sector concerning the most fatal accidents and high incidence of occupational illnesses and injuries resulting in days away from work. In Hong Kong, "Pilot Medical Examination Scheme for Construction Workers" was launched in 2014 to detect the health problems of their construction workforce. All registered workers under the Construction Workers Registration Board are eligible to join the scheme. The purpose of this paper is to assess the physical condition, physiological status, and musculoskeletal disorders of 942 construction workers in Hong Kong. This study adopted a two phase design, which includes a basic medical examination to measure the workers' physiological parameters, such as blood pressure, resting heart rate, glucose, cholesterol, uric acid, liver function test, and renal function test; as well as a face-to-face interview following the medical examination to collect their demographic information and pain experience. Individual characteristics, including gender, age, obesity, alcohol drinking habit, and sleeping habit influenced the health condition of construction workers. Among the participants, 36.1% and 6.5% of them were overweight and obese, respectively. In addition, 43.0%, 38.4%, 16.2%, and 13.9% of the participants exceeded the thresholds of cholesterol, blood pressure, urea nitrogen, and uric urea, correspondingly. Moreover, 41.0% of the participants suffered musculoskeletal pain, where the most frequent painful parts occur in the lower back, shoulder, knees, leg, and neck. Through these findings, a series of important issues that need to be addressed is pointed out in terms of maintaining the physical well-being and reducing musculoskeletal disorders of construction workers. The finding may have implications for formulating proper intervention strategies for the sustainable development of Hong Kong's construction industry. PMID- 27983613 TI - Association of School District Policies for Radon Testing and Radon-Resistant New Construction Practices with Indoor Radon Zones. AB - Radon is a naturally occurring, colorless, odorless, and tasteless radioactive gas. Without testing, its presence is unknown. Using nationally representative data from the 2012 School Health Policies and Practices Study, we examined whether the prevalence of school district policies for radon testing and for radon-resistant new construction practices varied by district location in relation to the U.S. Environmental Protection Agency Map of Radon Zones. Among school districts located in counties with high predicted average indoor radon, 42.4% had policies for radon testing and 37.5% had policies for radon-resistant new construction practices. These findings suggest a critical need for improved awareness among policy makers regarding potential radon exposure for both students and school staff. PMID- 27983614 TI - Synthesis and Antitumor Activity of New Thiazole Nortopsentin Analogs. AB - New thiazole nortopsentin analogs in which one of the two indole units was replaced by a naphthyl and/or 7-azaindolyl portion, were conveniently synthesized. Among these, three derivatives showed good antiproliferative activity, in particular against MCF7 cell line, with GI50 values in the micromolar range. Their cytotoxic effect on MCF7 cells was further investigated in order to elucidate their mode of action. Results showed that the three compounds act as pro-apoptotic agents inducing a clear shift of viable cells towards early apoptosis, while not exerting necrotic effects. They also caused cell cycle perturbation with significant decrease in the percentage of cells in the G0/G1 and S phases, accompanied by a concomitant percentage increase of cells in the G2/M phase, and appearance of a subG1-cell population. PMID- 27983616 TI - Three-Factor User Authentication and Key Agreement Using Elliptic Curve Cryptosystem in Wireless Sensor Networks. AB - Secure communication is a significant issue in wireless sensor networks. User authentication and key agreement are essential for providing a secure system, especially in user-oriented mobile services. It is also necessary to protect the identity of each individual in wireless environments to avoid personal privacy concerns. Many authentication and key agreement schemes utilize a smart card in addition to a password to support security functionalities. However, these schemes often fail to provide security along with privacy. In 2015, Chang et al. analyzed the security vulnerabilities of previous schemes and presented the two factor authentication scheme that provided user privacy by using dynamic identities. However, when we cryptanalyzed Chang et al.'s scheme, we found that it does not provide sufficient security for wireless sensor networks and fails to provide accurate password updates. This paper proposes a security-enhanced authentication and key agreement scheme to overcome these security weaknesses using biometric information and an elliptic curve cryptosystem. We analyze the security of the proposed scheme against various attacks and check its viability in the mobile environment. PMID- 27983615 TI - Peripheral Inflammatory Markers Contributing to Comorbidities in Autism. AB - This study evaluates the contribution of peripheral biomarkers to comorbidities and clinical findings in autism. Seventeen autistic children and age-matched typically developing (AMTD), between three to nine years old were evaluated. The diagnostic followed the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DMS-IV) and the Childhood Autism Rating Scale (CARS) was applied to classify the severity. Cytokine profile was evaluated in plasma using a sandwich type ELISA. Paraclinical events included electroencephalography (EEG) record. Statistical analysis was done to explore significant differences in cytokine profile between autism and AMTD groups and respect clinical and paraclinical parameters. Significant differences were found to IL-1beta, IL-6, IL-17, IL 12p40, and IL-12p70 cytokines in individuals with autism compared with AMTD (p < 0.05). All autistic patients showed interictalepileptiform activity at EEG, however, only 37.5% suffered epilepsy. There was not a regional focalization of the abnormalities that were detectable with EEG in autistic patients with history of epilepsy. A higher IL-6 level was observed in patients without history of epilepsy with interictalepileptiform activity in the frontal brain region, p < 0.05. In conclusion, peripheral inflammatory markers might be useful as potential biomarkers to predict comorbidities in autism as well as reinforce and aid informed decision-making related to EEG findings in children with Autism spectrum disorders (ASD). PMID- 27983618 TI - Efficient Terahertz Wide-Angle NUFFT-Based Inverse Synthetic Aperture Imaging Considering Spherical Wavefront. AB - An efficient wide-angle inverse synthetic aperture imaging method considering the spherical wavefront effects and suitable for the terahertz band is presented. Firstly, the echo signal model under spherical wave assumption is established, and the detailed wavefront curvature compensation method accelerated by 1D fast Fourier transform (FFT) is discussed. Then, to speed up the reconstruction procedure, the fast Gaussian gridding (FGG)-based nonuniform FFT (NUFFT) is employed to focus the image. Finally, proof-of-principle experiments are carried out and the results are compared with the ones obtained by the convolution back projection (CBP) algorithm. The results demonstrate the effectiveness and the efficiency of the presented method. This imaging method can be directly used in the field of nondestructive detection and can also be used to provide a solution for the calculation of the far-field RCSs (Radar Cross Section) of targets in the terahertz regime. PMID- 27983620 TI - Biological Control Outcomes Using the Generalist Aphid Predator Aphidoletes aphidimyza under Multi-Prey Conditions. AB - The aphidophagous midge Aphidoletes aphidimyza (Diptera: Cecidomyiidae) is used in biological control programs against aphids in many crops. Short-term trials with this natural enemy demonstrated that that females prefer to oviposit among aphids colonizing the new growth of plants, leading to differential attack rates for aphid species that differ in their within-plant distributions. Thus, we hypothesized that biological control efficacy could be compromised when more than one aphid species is present. We further hypothesized that control outcomes may be different at different crop stages if aphid species shift their preferred feeding locations. Here, we used greenhouse trials to determine biological control outcomes using A. aphidimyza under multi-prey conditions and at different crop stages. At all plant stages, aphid species had a significant effect on the number of predator eggs laid. More eggs were found on M. persicae versus A. solani-infested plants, since M. persicae consistently colonized plant meristems across plant growth stages. This translated to higher numbers of predatory larvae on M. periscae-infested plants in two out of our three experiments, and more consistent control of this pest (78%-95% control across all stages of plant growth). In contrast, control of A. solani was inconsistent in the presence of M. persicae, with 36%-80% control achieved. An additional experiment demonstrated control of A. solani by A. aphidimyza was significantly greater in the absence of M. persicae than in its presence. Our study illustrates that suitability of a natural enemy for pest control may change over a crop cycle as the position of prey on the plant changes, and that prey preference based on within-plant prey location can negatively influence biological control programs in systems with pest complexes. Careful monitoring of the less-preferred pest and its relative position on the plant is suggested. PMID- 27983617 TI - Molecular Mechanisms and Translational Therapies for Human Epidermal Receptor 2 Positive Breast Cancer. AB - Breast cancer is the second leading cause of cancer death among women. Human epidermal receptor 2 (HER2) positive breast cancer (HER2+ BC) is the most aggressive subtype of breast cancer, with poor prognosis and a high rate of recurrence. About one third of breast cancer is HER2+ BC with significantly high expression level of HER2 protein compared to other subtypes. Therefore, HER2 is an important biomarker and an ideal target for developing therapeutic strategies for the treatment HER2+ BC. In this review, HER2 structure and physiological and pathological roles in HER2+ BC are discussed. Two diagnostic tests, immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), for evaluating HER2 expression levels are briefly introduced. The current mainstay targeted therapies for HER2+ BC include monoclonal antibodies, small molecule tyrosine kinase inhibitors, antibody-drug conjugates (ADC) and other emerging anti-HER2 agents. In clinical practice, combination therapies are commonly adopted in order to achieve synergistic drug response. This review will help to better understand the molecular mechanism of HER2+ BC and further facilitate the development of more effective therapeutic strategies against HER2+ BC. PMID- 27983619 TI - RNA Interference of the Ecdysone Receptor Genes EcR and USP in Grain Aphid (Sitobion avenae F.) Affects Its Survival and Fecundity upon Feeding on Wheat Plants. AB - RNA interference (RNAi) has been widely used in functional genomics of insects and received intensive attention in the development of RNAi-based plants for insect control. Ecdysone receptor (EcR) and ultraspiracle protein (USP) play important roles in molting, metamorphosis, and reproduction of insects. EcR and USP orthologs and their function in grain aphid (Sitobion avenae F.) have not been documented yet. Here, RT-PCR, qRT-PCR, dsRNA feeding assay and aphid bioassay were employed to isolate EcR and USP orthologs in grain aphid, investigate their expression patterns, and evaluate the effect of RNAi on aphid survival and fecundity, and its persistence. The results indicated that SaEcR and SaUSP exhibited similar expression profiles at different developmental stages. Oral administration of dsRNAs of SaEcR and dsSaUSP significantly decreased the survival of aphids due to the down-regulation of these two genes, respectively. The silencing effect was persistent and transgenerational, as demonstrated by the reduced survival and fecundity due to knock-down of SaEcR and SaUSP in both the surviving aphids and their offspring, even after switching to aphid-susceptible wheat plants. Taken together, our results demonstrate that SaEcR and SaUSP are essential genes in aphid growth and development, and could be used as RNAi targets for wheat aphid control. PMID- 27983621 TI - Random Splicing of Several Exons Caused by a Single Base Change in the Target Exon of CRISPR/Cas9 Mediated Gene Knockout. AB - The clustered regularly interspaced short palindromic repeats (CRISPR)-associated sequence 9 (CRISPR/Cas9) system is widely used for genome editing purposes as it facilitates an efficient knockout of a specific gene in, e.g. cultured cells. Targeted double-strand breaks are introduced to the target sequence of the guide RNAs, which activates the cellular DNA repair mechanism for non-homologous-end joining, resulting in unprecise repair and introduction of small deletions or insertions. Due to this, sequence alterations in the coding region of the target gene frequently cause frame-shift mutations, facilitating degradation of the mRNA. We here show that such CRISPR/Cas9-mediated alterations in the target exon may also result in altered splicing of the respective pre-mRNA, most likely due to mutations of splice-regulatory sequences. Using the human FLOT-1 gene as an example, we demonstrate that such altered splicing products also give rise to aberrant protein products. These may potentially function as dominant-negative proteins and thus interfere with the interpretation of the data generated with these cell lines. Since most researchers only control the consequences of CRISPR knockout at genomic and protein level, our data should encourage to also check the alterations at the mRNA level. PMID- 27983622 TI - Effect of Tea Polyphenol Compounds on Anticancer Drugs in Terms of Anti-Tumor Activity, Toxicology, and Pharmacokinetics. AB - Multidrug resistance and various adverse side effects have long been major problems in cancer chemotherapy. Recently, chemotherapy has gradually transitioned from mono-substance therapy to multidrug therapy. As a result, the drug cocktail strategy has gained more recognition and wider use. It is believed that properly-formulated drug combinations have greater therapeutic efficacy than single drugs. Tea is a popular beverage consumed by cancer patients and the general public for its perceived health benefits. The major bioactive molecules in green tea are catechins, a class of flavanols. The combination of green tea extract or green tea catechins and anticancer compounds has been paid more attention in cancer treatment. Previous studies demonstrated that the combination of chemotherapeutic drugs and green tea extract or tea polyphenols could synergistically enhance treatment efficacy and reduce the adverse side effects of anticancer drugs in cancer patients. In this review, we summarize the experimental evidence regarding the effects of green tea-derived polyphenols in conjunction with chemotherapeutic drugs on anti-tumor activity, toxicology, and pharmacokinetics. We believe that the combination of multidrug cancer treatment with green tea catechins may improve treatment efficacy and diminish negative side effects. PMID- 27983624 TI - Sharing the Load: Amish Healthcare Financing. AB - When settling healthcare bills, the Old Order Amish of Lancaster County, Pennsylvania rely on an ethos of mutual aid, independent of the government. Consonant with this philosophy, many Amish do not participate in or receive benefits from Social Security or Medicare. They are also exempted from the Affordable Care Act of 2010. This study expands the limited documentation of Amish Hospital Aid, an Amish health insurance program that covers major medical costs. Interview data from 11 Amish adults in Lancaster County depict how this aid program supplements traditional congregational alms coverage of medical expenses. The interview data delineate the structure of the program, its operation, and how it encourages cost containment and community interdependence. The manner in which the Amish collaborate to pay for medical expenses provides a thought-provoking paradigm for managing health care costs. PMID- 27983626 TI - Design and Optimization of a Hybrid-Driven Waist Rehabilitation Robot. AB - In this paper a waist rehabilitation robot driven by cables and pneumatic artificial muscles (PAMs) has been conceptualized and designed. In the process of mechanism design, the human body structure, the waist movement characteristics, and the actuators' driving characteristics are the main considerable factors to make the hybrid-driven waist rehabilitation robot (HWRR) cost-effective, safe, flexible, and well-adapted. A variety of sensors are chosen to measure the position and orientation of the recovery patient to ensure patient safety at the same time as the structure design. According to the structure specialty and function, the HWRR is divided into two independent parallel robots: the waist twist device and the lower limb traction device. Then these two devices are analyzed and evaluated, respectively. Considering the characters of the human body in the HWRR, the inverse kinematics and statics are studied when the waist and the lower limb are considered as a spring and link, respectively. Based on the inverse kinematics and statics, the effect of the contraction parameter of the PAM is considered in the optimization of the waist twist device, and the lower limb traction device is optimized using particle swarm optimization (PSO) to minimize the global conditioning number over the feasible workspace. As a result of the optimization, an optimal rehabilitation robot design is obtained and the condition number of the Jacobian matrix over the feasible workspace is also calculated. PMID- 27983627 TI - Vision-Based Corrosion Detection Assisted by a Micro-Aerial Vehicle in a Vessel Inspection Application. AB - Vessel maintenance requires periodic visual inspection of the hull in order to detect typical defective situations of steel structures such as, among others, coating breakdown and corrosion. These inspections are typically performed by well-trained surveyors at great cost because of the need for providing access means (e.g., scaffolding and/or cherry pickers) that allow the inspector to be at arm's reach from the structure under inspection. This paper describes a defect detection approach comprising a micro-aerial vehicle which is used to collect images from the surfaces under inspection, particularly focusing on remote areas where the surveyor has no visual access, and a coating breakdown/corrosion detector based on a three-layer feed-forward artificial neural network. As it is discussed in the paper, the success of the inspection process depends not only on the defect detection software but also on a number of assistance functions provided by the control architecture of the aerial platform, whose aim is to improve picture quality. Both aspects of the work are described along the different sections of the paper, as well as the classification performance attained. PMID- 27983623 TI - Multiple Forms of Glutamate Dehydrogenase in Animals: Structural Determinants and Physiological Implications. AB - Glutamate dehydrogenase (GDH) of animal cells is usually considered to be a mitochondrial enzyme. However, this enzyme has recently been reported to be also present in nucleus, endoplasmic reticulum and lysosomes. These extramitochondrial localizations are associated with moonlighting functions of GDH, which include acting as a serine protease or an ATP-dependent tubulin-binding protein. Here, we review the published data on kinetics and localization of multiple forms of animal GDH taking into account the splice variants, post-translational modifications and GDH isoenzymes, found in humans and apes. The kinetic properties of human GLUD1 and GLUD2 isoenzymes are shown to be similar to those published for GDH1 and GDH2 from bovine brain. Increased functional diversity and specific regulation of GDH isoforms due to alternative splicing and post translational modifications are also considered. In particular, these structural differences may affect the well-known regulation of GDH by nucleotides which is related to recent identification of thiamine derivatives as novel GDH modulators. The thiamine-dependent regulation of GDH is in good agreement with the fact that the non-coenzyme forms of thiamine, i.e., thiamine triphosphate and its adenylated form are generated in response to amino acid and carbon starvation. PMID- 27983629 TI - Influence of Bovine Whey Protein Concentrate and Hydrolysate Preparation Methods on Motility in the Isolated Rat Distal Colon. AB - Whey protein concentrate (WPC) and hydrolysate (WPH) are protein ingredients used in sports, medical and pediatric formulations. Concentration and hydrolysis methods vary for whey sourced from cheese and casein co-products. The purpose of this research was to investigate the influence of whey processing methods on in vitro gastrointestinal (GI) health indicators for colonic motility, epithelial barrier integrity and immune modulation. WPCs from casein or cheese processing and WPH (11% or 19% degree of hydrolysis, DH) were compared for their effects on motility in a 1 cm section of isolated rat distal colon in an oxygenated tissue bath. Results showed that WPC decreased motility irrespective of whether it was a by-product of lactic acid or mineral acid casein production, or from cheese production. This indicated that regardless of the preparation methodology, the whey protein contained components that modulate aspects of motility within the distal colon. WPH (11% DH) increased contractile frequency by 27% in a delayed manner and WPH (19% DH) had an immediate effect on contractile properties, increasing tension by 65% and frequency by 131%. Increased motility was associated with increased hydrolysis that may be attributed to the abundance of bioactive peptides. Increased frequency of contractions by WPH (19% DH) was inhibited (by 44%) by naloxone, implicating a potential involvement of opioid receptors in modulation of motility. Trans-epithelial electrical resistance and cytokine expression assays revealed that the WPC proteins studied did not alter intestinal barrier integrity or elicit any discernible immune response. PMID- 27983628 TI - The Effects of Annatto Tocotrienol on Bone Biomechanical Strength and Bone Calcium Content in an Animal Model of Osteoporosis Due to Testosterone Deficiency. AB - Osteoporosis reduces the skeletal strength and increases the risk for fracture. It is an underdiagnosed disease in men. Annatto tocotrienol has been shown to improve bone structural indices and increase expression of bone formation genes in orchidectomized rats. This study aimed to evaluate the effects of annatto tocotrienol on biomechanical strength and calcium content of the bone in orchidectomized rats. Thirty three-month-old male Sprague-Dawley rats were randomly assigned to five groups. The baseline control (BC) group was sacrificed at the onset of the study. The sham-operated group (SHAM) received olive oil (the vehicle of tocotrienol) orally daily and peanut oil (the vehicle of testosterone) intramuscularly weekly. The remaining rats were orchidectomized and treated with three different regimens, i.e., (1) daily oral olive oil plus weekly intramuscular peanut oil injection; (2) daily oral annatto tocotrienol at 60 mg/kg plus weekly intramuscular peanut oil injection; (3) daily oral olive oil plus weekly intramuscular testosterone enanthate injection at 7 mg/kg. Blood, femur and tibia of the rats were harvested at the end of the two-month treatment period for the evaluation of serum total calcium and inorganic phosphate levels, bone biomechanical strength test and bone calcium content. Annatto-tocotrienol treatment improved serum calcium level and tibial calcium content (p < 0.05) but it did not affect femoral biomechanical strength (p > 0.05). In conclusion, annatto-tocotrienol at 60 mg/kg augments bone calcium level by preventing calcium mobilization into the circulation. A longer treatment period is needed for annatto tocotrienol to exert its effects on bone strength. PMID- 27983630 TI - Application of Semipermeable Membranes in Glucose Biosensing. AB - Glucose biosensors have received significant attention in recent years due to the escalating mortality rate of diabetes mellitus. Although there is currently no cure for diabetes mellitus, individuals living with diabetes can lead a normal life by maintaining tight control of their blood glucose levels using glucose biosensors (e.g., glucometers). Current research in the field is focused on the optimization and improvement in the performance of glucose biosensors by employing a variety of glucose selective enzymes, mediators and semipermeable membranes to improve the electron transfer between the active center of the enzyme and the electrode substrate. Herein, we summarize the different semipermeable membranes used in the fabrication of the glucose biosensor, that result in improved biosensor sensitivity, selectivity, dynamic range, response time and stability. PMID- 27983625 TI - TRP Channels in Skin Biology and Pathophysiology. AB - Ion channels of the Transient Receptor Potential (TRP) family mediate the influx of monovalent and/or divalent cations into cells in response to a host of chemical or physical stimuli. In the skin, TRP channels are expressed in many cell types, including keratinocytes, sensory neurons, melanocytes, and immune/inflammatory cells. Within these diverse cell types, TRP channels participate in physiological processes ranging from sensation to skin homeostasis. In addition, there is a growing body of evidence implicating abnormal TRP channel function, as a product of excessive or deficient channel activity, in pathological skin conditions such as chronic pain and itch, dermatitis, vitiligo, alopecia, wound healing, skin carcinogenesis, and skin barrier compromise. These diverse functions, coupled with the fact that many TRP channels possess pharmacologically accessible sites, make this family of proteins appealing therapeutic targets for skin disorders. PMID- 27983631 TI - Vitamin E Circular Dichroism Studies: Insights into Conformational Changes Induced by the Solvent's Polarity. AB - We used circular dichroism (CD) to study differences in CD spectra between alpha , delta-, and methylated-alpha-tocopherol in solvents with different polarities. CD spectra of the different tocopherol structures differ from each other in intensity and peak locations, which can be attributed to chromanol substitution and the ability to form hydrogen bonds. In addition, each structure was examined in different polarity solvents using the Reichardt index-a measure of the solvent's ionizing ability, and a direct measurement of solvent-solute interactions. Differences across solvents indicate that hydrogen bonding is a key contributor to CD spectra at 200 nm. These results are a first step in examining the hydrogen bonding abilities of vitamin E in a lipid bilayer. PMID- 27983633 TI - Urban Growth Modeling Using Cellular Automata with Multi-Temporal Remote Sensing Images Calibrated by the Artificial Bee Colony Optimization Algorithm. AB - Cellular Automata (CA) is one of the most common techniques used to simulate the urbanization process. CA-based urban models use transition rules to deliver spatial patterns of urban growth and urban dynamics over time. Determining the optimum transition rules of the CA is a critical step because of the heterogeneity and nonlinearities existing among urban growth driving forces. Recently, new CA models integrated with optimization methods based on swarm intelligence algorithms were proposed to overcome this drawback. The Artificial Bee Colony (ABC) algorithm is an advanced meta-heuristic swarm intelligence-based algorithm. Here, we propose a novel CA-based urban change model that uses the ABC algorithm to extract optimum transition rules. We applied the proposed ABC-CA model to simulate future urban growth in Urmia (Iran) with multi-temporal Landsat images from 1997, 2006 and 2015. Validation of the simulation results was made through statistical methods such as overall accuracy, the figure of merit and total operating characteristics (TOC). Additionally, we calibrated the CA model by ant colony optimization (ACO) to assess the performance of our proposed model versus similar swarm intelligence algorithm methods. We showed that the overall accuracy and the figure of merit of the ABC-CA model are 90.1% and 51.7%, which are 2.9% and 8.8% higher than those of the ACO-CA model, respectively. Moreover, the allocation disagreement of the simulation results for the ABC-CA model is 9.9%, which is 2.9% less than that of the ACO-CA model. Finally, the ABC-CA model also outperforms the ACO-CA model with fewer quantity and allocation errors and slightly more hits. PMID- 27983634 TI - Special Issue "Ring-Opening Polymerization". AB - n/a. PMID- 27983632 TI - Antimicrobial and Antitumor Activities of Novel Peptides Derived from the Lipopolysaccharide- and beta-1,3-Glucan Binding Protein of the Pacific Abalone Haliotis discus hannai. AB - Antimicrobial peptides are a pivotal component of the invertebrate innate immune system. In this study, we identified a lipopolysaccharide- and beta-1,3-glucan binding protein (LGBP) gene from the pacific abalone Haliotis discus hannai (HDH), which is involved in the pattern recognition mechanism and plays avital role in the defense mechanism of invertebrates immune system. The HDH-LGBP cDNA consisted of a 1263-bp open reading frame (ORF) encoding a polypeptide of 420 amino acids, with a 20-amino-acid signal sequence. The molecular mass of the protein portion was 45.5 kDa, and the predicted isoelectric point of the mature protein was 4.93. Characteristic potential polysaccharide binding motif, glucanase motif, and beta-glucan recognition motif were identified in the LGBP of HDH. We used its polysaccharide-binding motif sequence to design two novel antimicrobial peptide analogs (HDH-LGBP-A1 and HDH-LGBP-A2). By substituting a positively charged amino acid and amidation at the C-terminus, the pI and net charge of the HDH-LGBP increased, and the proteins formed an alpha-helical structure. The HDH-LGBP analogs exhibited antibacterial and antifungal activity, with minimal effective concentrations ranging from 0.008 to 2.2 MUg/mL. Additionally, both were toxic against human cervix (HeLa), lung (A549), and colon (HCT 116) carcinoma cell lines but not much on human umbilical vein cell (HUVEC). Fluorescence-activated cell sorter (FACS) analysis showed that HDH-LGBP analogs disturb the cancer cell membrane and cause apoptotic cell death. These results suggest the use of HDH-LGBP analogs as multifunctional drugs. PMID- 27983635 TI - New Cross-Talk Layer between Ultraconserved Non-Coding RNAs, MicroRNAs and Polycomb Protein YY1 in Bladder Cancer. AB - MicroRNAs (miRNAs) are highly conserved elements in mammals, and exert key regulatory functions. Growing evidence shows that miRNAs can interact with another class of non-coding RNAs, so-called transcribed ultraconserved regions (T UCRs), which take part in transcriptional, post-transcriptional and epigenetic regulation processes. We report here the interaction of miRNAs and T-UCRs as a network modulating the availability of these non-coding RNAs in bladder cancer cells. In our cell system, antagomiR-596 increased the expression of T-UCR 201+. Moreover, T-UCR 8+ silencing increased miR-596 expression, which in turn reduced total T-UCR 283+, showing that the perturbation of one element in this network changes the expression of other interactors. In addition, we identify the polycomb protein Yin Yang 1 (YY1) as mediator of binding between miR-596 and T UCR 8+. These new findings describe for the first time a network between T-UCRs, miRNAs and YY1 protein, highlighting the existence of an additional layer of gene expression regulation. PMID- 27983636 TI - Scoparone Inhibits LPS-Simulated Inflammatory Response by Suppressing IRF3 and ERK in BV-2 Microglial Cells. AB - Microglia activation and the release of various inflammatory cytokines are largely related to neurological diseases, including Parkinson's, Alzheimer's, and other brain diseases. The suppression of microglial cells using natural bioactive compounds has become increasingly important for brain therapy owing to the expected beneficial effect of lower toxicity. Scoparone (6,7-dimethoxycoumarin), a major bioactive compound found in various plant parts, including the inner shell of chestnut (Castanea crenata), was evaluated on lipopolysaccharide (LPS) activated BV-2 microglia cells. The results indicated that scoparone suppresses the LPS-stimulated increase of neuroinflammatory responses and inhibited the pro inflammatory cytokine production in the BV-2 microglial cells. A mechanistic study showed that scoparone specifically inhibited the LPS-stimulated activation via a major regulation of IRF-3 and a regulation of ERK, whereby the phosphorylation in the BV-2 microglial cells is blocked. These data suggest that scoparone has anti-neuroinflammatory effects in LPS-activated BV-2 microglial cells, and could possibly be used in the development of novel drugs for the prevention and treatment of neuroinflammatory diseases. PMID- 27983638 TI - Looking inside the Ocean: Toward an Autonomous Imaging System for Monitoring Gelatinous Zooplankton. AB - Marine plankton abundance and dynamics in the open and interior ocean is still an unknown field. The knowledge of gelatinous zooplankton distribution is especially challenging, because this type of plankton has a very fragile structure and cannot be directly sampled using traditional net based techniques. To overcome this shortcoming, Computer Vision techniques can be successfully used for the automatic monitoring of this group.This paper presents the GUARD1 imaging system, a low-cost stand-alone instrument for underwater image acquisition and recognition of gelatinous zooplankton, and discusses the performance of three different methodologies, Tikhonov Regularization, Support Vector Machines and Genetic Programming, that have been compared in order to select the one to be run onboard the system for the automatic recognition of gelatinous zooplankton. The performance comparison results highlight the high accuracy of the three methods in gelatinous zooplankton identification, showing their good capability in robustly selecting relevant features. In particular, Genetic Programming technique achieves the same performances of the other two methods by using a smaller set of features, thus being the most efficient in avoiding computationally consuming preprocessing stages, that is a crucial requirement for running on an autonomous imaging system designed for long lasting deployments, like the GUARD1. The Genetic Programming algorithm has been installed onboard the system, that has been operationally tested in a two-months survey in the Ligurian Sea, providing satisfactory results in terms of monitoring and recognition performances. PMID- 27983639 TI - High-Frequency Fiber-Optic Ultrasonic Sensor Using Air Micro-Bubble for Imaging of Seismic Physical Models. AB - A micro-fiber-optic Fabry-Perot interferometer (FPI) is proposed and demonstrated experimentally for ultrasonic imaging of seismic physical models. The device consists of a micro-bubble followed by the end of a single-mode fiber (SMF). The micro-structure is formed by the discharging operation on a short segment of hollow-core fiber (HCF) that is spliced to the SMF. This micro FPI is sensitive to ultrasonic waves (UWs), especially to the high-frequency (up to 10 MHz) UW, thanks to its ultra-thin cavity wall and micro-diameter. A side-band filter technology is employed for the UW interrogation, and then the high signal-to noise ratio (SNR) UW signal is achieved. Eventually the sensor is used for lateral imaging of the physical model by scanning UW detection and two dimensional signal reconstruction. PMID- 27983640 TI - Long-Term Stability of New Co-Amorphous Drug Binary Systems: Study of Glass Transitions as a Function of Composition and Shelf Time. AB - The amorphous state is of particular interest in the pharmaceutical industry due to the higher solubility that amorphous active pharmaceutical ingredients show compared to their respective crystalline forms. Due to their thermodynamic instability, drugs in the amorphous state tend to recrystallize; in order to avoid crystallization, it has been a common strategy to add a second component to hinder the crystalline state and form a thermally stable co-amorphous system, that is to say, an amorphous binary system which retains its amorphous structure. The second component can be a small molecule excipient (such as a sugar or an aminoacid) or a second drug, with the advantage that a second active pharmaceutical ingredient could be used for complementary or combined therapeutic purposes. In most cases, the compositions studied are limited to 1:1, 2:1 and 1:2 molar ratios, leaving a gap of information about phase transitions and stability on the amorphous state in a wider range of compositions. In the present work, a study of novel co-amorphous formulations in which the selection of the active pharmaceutical ingredients was made according to the therapeutic effect is presented. Resistance against crystallization and behavior of glass transition temperature ( T g were studied through calorimetric measurements as a function of composition and shelf time. It was found that binary formulations with T g temperatures higher than those of pure components presented long-term thermal stability. In addition, significant increments of T g values, of as much as 15 ? C, were detected as a result of glass relaxation at room temperature during storage time; this behavior of glass transition has not been previously reported for co-amorphous drugs. Based on these results, it can be concluded that monitoring behavior of T g and relaxation processes during the first weeks of storage leads to a more objective evaluation of the thermomechanical stability of an amorphous formulation. PMID- 27983637 TI - Limited Link between Oxidative Stress and Ochratoxin A-Induced Renal Injury in an Acute Toxicity Rat Model. AB - Ochratoxin A (OTA) displays nephrotoxicity and hepatotoxicity. However, in the acute toxicity rat model, there is no evidence on the relationship between OTA and nephrotoxicity and hepatotoxicity. Based on this, the integrated analysis of physiological status, damage biomarkers, oxidative stress, and DNA damage were performed. After OTA treatment, the body weight decreased and AST, ALP, TP, and BUN levels in serum increased. Hydropic degeneration, swelling, vacuolization, and partial drop occurred in proximal tubule epithelial cells. PCNA and Kim-1 were dose-dependently increased in the kidney, but Cox-2 expression and proliferation were not found in the liver. In OTA-treated kidneys, the mRNA expressions of Kim-1, Cox-2, Lcn2, and Clu were dose-dependently increased. The mRNA expressions of Vim and Cox-2 were decreased in OTA-treated livers. Some oxidative stress indicators were altered in the kidneys (ROS and SOD) and livers (SOD and GSH). DNA damage and oxidative DNA damage were not found. In conclusion, there is a limited link between oxidative stress and OTA-induced renal injury in an acute toxicity rat model. PMID- 27983641 TI - Electroporation of DNA into Physarum polycephalum Mitochondria: Effects on Transcription and RNA Editing in Isolated Organelles. AB - Mitochondrial RNAs in the acellular slime mold Physarum polycephalum contain nucleotides that are not encoded in the mitochondrial genes from which they are transcribed. These site-specific changes are quite extensive, comprising ~4% of the residues within mRNAs and ~2% of rRNAs and tRNAs. These "extra" nucleotides are added co-transcriptionally, but the means by which this is accomplished have not been elucidated. The cox1 mRNA also contains four sites of C to U changes, which occur post-transcriptionally, most likely via targeted deamination. The currently available in vitro systems for studying P. polycephalum editing are limited in that the template is the entire ~63,000 bp mitochondrial genome. This presents a significant challenge when trying to define the signals that specify editing sites. In an attempt to overcome this issue, a method for introducing DNA into isolated P. polycephalum mitochondria via electroporation has been developed. Exogenous DNA is expressed, but the transcripts synthesized from these templates are not edited under the conditions tested. However, transcripts derived from the mitochondrial genome are accurately edited after electroporation, indicating that the editing machinery is still functional. These findings suggest that this method may ultimately provide a feasible approach to elucidating editing signals. PMID- 27983644 TI - A Novel Synthesis of Fused Uracils: Indenopyrimidopyridazines, Pyrimidopyridazines, and Pyrazolopyrimidines for Antimicrobial and Antitumor Evalution. AB - A variety of different compounds of fused uracils were prepared simply by the heating of 6-hydrazinyl-1-methyl-, 6-hydrazinyl-1-propyl-, or 6-hydrazinyl-1,3 dipropyluracil under reflux with ninhydrin, isatin, benzylidene malononitrile, benzylylidene ethyl cyanoacetate, benzil, and phenacyl bromide derivatives. The newly synthesized compounds were completely screened for antimicrobial and antitumor activity. PMID- 27983642 TI - Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer. AB - Peripheral nerve injury can lead to great morbidity in those afflicted, ranging from sensory loss, motor loss, chronic pain, or a combination of deficits. Over time, research has investigated neuronal molecular mechanisms implicated in nerve damage, classified nerve injury, and developed surgical techniques for treatment. Despite these advancements, full functional recovery remains less than ideal. In this review, we discuss historical aspects of peripheral nerve injury and introduce nerve transfer as a therapeutic option, as well as an adjunct therapy to transplantation of Schwann cells and their stem cell derivatives for repair of the damaged nerve. This review furthermore, will provide an elaborated discussion on the sources of Schwann cells, including sites to harvest their progenitor and stem cell lines. This reflects the accessibility to an additional, concurrent treatment approach with nerve transfers that, predicated on related research, may increase the efficacy of the current approach. We then discuss the experimental and clinical investigations of both Schwann cells and nerve transfer that are underway. Lastly, we provide the necessary consideration that these two lines of therapeutic approaches should not be exclusive, but conversely, should be pursued as a combined modality given their mutual role in peripheral nerve regeneration. PMID- 27983643 TI - Genetic Marker Discovery in Complex Traits: A Field Example on Fat Content and Composition in Pigs. AB - Among the large number of attributes that define pork quality, fat content and composition have attracted the attention of breeders in the recent years due to their interaction with human health and technological and sensorial properties of meat. In livestock species, fat accumulates in different depots following a temporal pattern that is also recognized in humans. Intramuscular fat deposition rate and fatty acid composition change with life. Despite indication that it might be possible to select for intramuscular fat without affecting other fat depots, to date only one depot-specific genetic marker (PCK1 c.2456C>A) has been reported. In contrast, identification of polymorphisms related to fat composition has been more successful. For instance, our group has described a variant in the stearoyl-coA desaturase (SCD) gene that improves the desaturation index of fat without affecting overall fatness or growth. Identification of mutations in candidate genes can be a tedious and costly process. Genome-wide association studies can help in narrowing down the number of candidate genes by highlighting those which contribute most to the genetic variation of the trait. Results from our group and others indicate that fat content and composition are highly polygenic and that very few genes explain more than 5% of the variance of the trait. Moreover, as the complexity of the genome emerges, the role of non-coding genes and regulatory elements cannot be disregarded. Prediction of breeding values from genomic data is discussed in comparison with conventional best linear predictors of breeding values. An example based on real data is given, and the implications in phenotype prediction are discussed in detail. The benefits and limitations of using large SNP sets versus a few very informative markers as predictors of genetic merit of breeding candidates are evaluated using field data as an example. PMID- 27983646 TI - Data Analysis in Chemistry and Bio-Medical Sciences. AB - n/a. PMID- 27983645 TI - Decrease in Circulating Fatty Acids Is Associated with Islet Dysfunction in Chronically Sleep-Restricted Rats. AB - Previous studies have shown that sleep restriction-induced environmental stress is associated with abnormal metabolism, but the underlying mechanism is poorly understood. In the current study, we investigated the possible lipid and glucose metabolism patterns in chronically sleep-restricted rat. Without changes in food intake, body weight was decreased and energy expenditure was increased in sleep restricted rats. The effects of chronic sleep disturbance on metabolites in serum were examined using 1H NMR metabolomics and GC-FID/MS analysis. Six metabolites (lipoproteins, triglycerides, isoleucine, valine, choline, and phosphorylcholine) exhibited significant alteration, and all the fatty acid components were decreased, which suggested fatty acid metabolism was impaired after sleep loss. Moreover, increased blood glucose, reduced serum insulin, decreased glucose tolerance, and impaired glucose-stimulated insulin secretion of islets were also observed in sleep-restricted rats. The islet function of insulin secretion could be partially restored by increasing dietary fat to sleep-disturbed rats suggested that a reduction in circulating fatty acids was related to islet dysfunction under sleep deficiency-induced environmental stress. This study provides a new perspective on the relationship between insufficient sleep and lipid/glucose metabolism, which offers insights into the role of stressful challenges in a healthy lifestyle. PMID- 27983647 TI - Critical Function of PRDM2 in the Neoplastic Growth of Testicular Germ Cell Tumors. AB - Testicular germ cell tumors (TGCTs) derive from primordial germ cells. Their maturation is blocked at different stages, reflecting histological tumor subtypes. A common genetic alteration in TGCT is a deletion of the chromosome 1 short arm, where the PRDM2 gene, belonging to the Positive Regulatory domain gene (PRDM) family, is located. Expression of PRDM2 gene is shifted in different human tumors, where the expression of the two principal protein forms coded by PRDM2 gene, RIZ1 and RIZ2, is frequently unbalanced. Therefore, PRDM2 is actually considered a candidate tumor suppressor gene in different types of cancer. Although recent studies have demonstrated that PRDM gene family members have a pivotal role during the early stages of testicular development, no information are actually available on the involvement of these genes in TGCTs. In this article we show by qRT-PCR analysis that PRDM2 expression level is modulated by proliferation and differentiation agents such as estradiol, whose exposure during fetal life is probably an important risk factor for TGCTs development in adulthood. Furthermore in normal and cancer germ cell lines, PRDM2 binds estradiol receptor alpha (ERalpha) and influences proliferation, survival and apoptosis, as previously reported using MCF-7 breast cancer cell line, suggesting a potential tumor-suppressor role in TGCT formation. PMID- 27983648 TI - Cre Fused with RVG Peptide Mediates Targeted Genome Editing in Mouse Brain Cells In Vivo. AB - Cell penetrating peptides (CPPs) are short peptides that can pass through cell membranes. CPPs can facilitate the cellular entry of proteins, macromolecules, nanoparticles and drugs. RVG peptide (RVG hereinafter) is a 29-amino-acid CPP derived from a rabies virus glycoprotein that can cross the blood-brain barrier (BBB) and enter brain cells. However, whether RVG can be used for genome editing in the brain has not been reported. In this work, we combined RVG with Cre recombinase for bacterial expression. The purified RVG-Cre protein cut plasmids in vitro and traversed cell membranes in cultured Neuro2a cells. By tail vein injecting RVG-Cre into Cre reporter mouse lines mTmG and Rosa26lacZ, we demonstrated that RVG-Cre could target brain cells and achieve targeted somatic genome editing in adult mice. This direct delivery of the gene-editing enzyme protein into mouse brains with RVG is much safer than plasmid- or viral-based methods, holding promise for further applications in the treatment of various brain diseases. PMID- 27983649 TI - Design and Synthesis of Vandetanib Derivatives Containing Nitroimidazole Groups as Tyrosine Kinase Inhibitors in Normoxia and Hypoxia. AB - Sixteen novel epidermal growth factor receptor (EGFR)/vascular endothelial growth factor (VEGF)-2 inhibitors (nitroimidazole-substituted 4-anilinoquinazoline derivatives (16a-p)) were designed and prepared via the introduction of a nitroimidazole group in the piperidine side chain and modification on the aniline moiety of vandetanib. Preliminary biological tests showed that comparing with vandetanib, some target compounds exhibited excellent EGFR inhibitory activities and anti-proliferative over A549/H446 cells in hypoxia. Meanwhile, several of the above compounds demonstrated better bioactivity than vandetanib in VEGF gene expression inhibition. Owing to the excellent IC50 value (1.64 MUmol/L), the inhibition ratios of 16f over A549 and H446 cells were 62.01% and 59.86% at the concentration of 0.5 MUM in hypoxia, respectively. All of these results indicated that 16f was a potential cancer therapeutic agent in hypoxia and was worthy of further development. PMID- 27983650 TI - Discovery of Anti-Hypertensive Oligopeptides from Adlay Based on In Silico Proteolysis and Virtual Screening. AB - Adlay (Coix larchryma-jobi L.) was the commonly used Traditional Chinese Medicine (TCM) with high content of seed storage protein. The hydrolyzed bioactive oligopeptides of adlay have been proven to be anti-hypertensive effective components. However, the structures and anti-hypertensive mechanism of bioactive oligopeptides from adlay were not clear. To discover the definite anti hypertensive oligopeptides from adlay, in silico proteolysis and virtual screening were implemented to obtain potential oligopeptides, which were further identified by biochemistry assay and molecular dynamics simulation. In this paper, ten sequences of adlay prolamins were collected and in silico hydrolyzed to construct the oligopeptide library with 134 oligopeptides. This library was reverse screened by anti-hypertensive pharmacophore database, which was constructed by our research team and contained ten anti-hypertensive targets. Angiotensin-I converting enzyme (ACE) was identified as the main potential target for the anti-hypertensive activity of adlay oligopeptides. Three crystal structures of ACE were utilized for docking studies and 19 oligopeptides were finally identified with potential ACE inhibitory activity. According to mapping features and evaluation indexes of pharmacophore and docking, three oligopeptides were selected for biochemistry assay. An oligopeptide sequence, NPATY (IC50 = 61.88 +/- 2.77 uM), was identified as the ACE inhibitor by reverse-phase high performance liquid chromatography (RP-HPLC) assay. Molecular dynamics simulation of NPATY was further utilized to analyze interactive bonds and key residues. ALA354 was identified as a key residue of ACE inhibitors. Hydrophobic effect of VAL518 and electrostatic effects of HIS383, HIS387, HIS513 and Zn2+ were also regarded as playing a key role in inhibiting ACE activities. This study provides a research strategy to explore the pharmacological mechanism of Traditional Chinese Medicine (TCM) proteins based on in silico proteolysis and virtual screening, which could be beneficial to reveal the pharmacological action of TCM proteins and provide new lead compounds for peptides-based drug design. PMID- 27983652 TI - Novel Resistance Measurement Method: Analysis of Accuracy and Thermal Dependence with Applications in Fiber Materials. AB - Material resistance is important since different physicochemical properties can be extracted from it. This work describes a novel resistance measurement method valid for a wide range of resistance values up to 100 GOmega at a low powered, small sized, digitally controlled and wireless communicated device. The analog and digital circuits of the design are described, analysing the main error sources affecting the accuracy. Accuracy and extended uncertainty are obtained for a pattern decade box, showing a maximum of 1 % accuracy for temperatures below 30 ? C in the range from 1 MOmega to 100 GOmega. Thermal analysis showed stability up to 50 ? C for values below 10 GOmega and systematic deviations for higher values. Power supply V i applied to the measurement probes is also analysed, showing no differences in case of the pattern decade box, except for resistance values above 10 GOmega and temperatures above 35 ? C. To evaluate the circuit behaviour under fiber materials, an 11-day drying process in timber from four species (Oregon pine-Pseudotsuga menziesii, cedar-Cedrus atlantica, ash Fraxinus excelsior, chestnut-Castanea sativa) was monitored. Results show that the circuit, as expected, provides different resistance values (they need individual conversion curves) for different species and the same ambient conditions. Additionally, it was found that, contrary to the decade box analysis, V i affects the resistance value due to material properties. In summary, the proposed circuit is able to accurately measure material resistance that can be further related to material properties. PMID- 27983651 TI - Skin Involvement and Pulmonary Hypertension Are Associated with Vitamin D Insufficiency in Scleroderma. AB - Vitamin D status has been linked to immune system and autoimmune disorders; in fact, low levels of vitamin D are common in many autoimmune disorders. The aims of our study were to assess the prevalence of vitamin D insufficiency and the possible correlation with clinical parameters in systemic sclerosis (SSc). We recruited 40 patients (38 female and two male) with scleroderma and 40 healthy controls matched for age and gender. Demographic and clinical parameters were recorded and the 25-hydroxivitamin D3 serum levels were measured. Serum 25 hydroxivitamin D3 levels were significantly lower in patients with systemic sclerosis than in the control group. The prevalence of 25-hydroxivitamin D3 insufficiency was 50% in the patients and 22.5% in the control group. A statistically significant association was observed between the insufficiency of 25-hydroxivitamin D3 and skin involvement (p = 0.02) and echocardiography systolic pulmonary artery pressure >35 mmHg (p = 0.02). Our data show that the systemic sclerosis group has significantly lower serum 25-hydroxivitamin D3 concentrations compared to the control group; skin involvement and pulmonary hypertension are associated with vitamin D3 insufficiency. PMID- 27983654 TI - Performance Prediction of a MongoDB-Based Traceability System in Smart Factory Supply Chains. AB - In the future, with the advent of the smart factory era, manufacturing and logistics processes will become more complex, and the complexity and criticality of traceability will further increase. This research aims at developing a performance assessment method to verify scalability when implementing traceability systems based on key technologies for smart factories, such as Internet of Things (IoT) and BigData. To this end, based on existing research, we analyzed traceability requirements and an event schema for storing traceability data in MongoDB, a document-based Not Only SQL (NoSQL) database. Next, we analyzed the algorithm of the most representative traceability query and defined a query-level performance model, which is composed of response times for the components of the traceability query algorithm. Next, this performance model was solidified as a linear regression model because the response times increase linearly by a benchmark test. Finally, for a case analysis, we applied the performance model to a virtual automobile parts logistics. As a result of the case study, we verified the scalability of a MongoDB-based traceability system and predicted the point when data node servers should be expanded in this case. The traceability system performance assessment method proposed in this research can be used as a decision-making tool for hardware capacity planning during the initial stage of construction of traceability systems and during their operational phase. PMID- 27983655 TI - Fabrication of a Horizontal and a Vertical Large Surface Area Nanogap Electrochemical Sensor. AB - Nanogap sensors have a wide range of applications as they can provide accurate direct detection of biomolecules through impedimetric or amperometric signals. Signal response from nanogap sensors is dependent on both the electrode spacing and surface area. However, creating large surface area nanogap sensors presents several challenges during fabrication. We show two different approaches to achieve both horizontal and vertical coplanar nanogap geometries. In the first method we use electron-beam lithography (EBL) to pattern an 11 mm long serpentine nanogap (215 nm) between two electrodes. For the second method we use inductively coupled plasma (ICP) reactive ion etching (RIE) to create a channel in a silicon substrate, optically pattern a buried 1.0 mm * 1.5 mm electrode before anodically bonding a second identical electrode, patterned on glass, directly above. The devices have a wide range of applicability in different sensing techniques with the large area nanogaps presenting advantages over other devices of the same family. As a case study we explore the detection of peptide nucleic acid (PNA) DNA binding events using dielectric spectroscopy with the horizontal coplanar device. PMID- 27983656 TI - Flexible Pressure Sensor with Ag Wrinkled Electrodes Based on PDMS Substrate. AB - Flexible pressure sensors are essential components of electronic skins for future attractive applications ranging from human healthcare monitoring to biomedical diagnostics, robotic skins, and prosthetic limbs. Here we report a new kind of flexible pressure sensor. The sensors are capacitive, and composed of two Ag wrinkled electrodes separated by a carbon nanotubes (CNTs)/polydimethylsiloxane (PDMS) composite deformable dielectric layer. Ag wrinkled electrodes were formed by vacuum deposition on top of pre-strained and relaxed PDMS substrates which were treated using an O2 plasma, a surface functionalization process, and a magnetron sputtering process. Ultimately, the developed sensor exhibits a maximum sensitivity of 19.80% kPa-1 to capacitance, great durability over 500 cycles, and rapid mechanical responses (<200 ms). We also demonstrate that our sensor can be used to effectively detect the location and distribution of finger pressure. PMID- 27983653 TI - Differential Impacts of Alternative Splicing Networks on Apoptosis. AB - Apoptosis functions as a common mechanism to eliminate unnecessary or damaged cells during cell renewal and tissue development in multicellular organisms. More than 200 proteins constitute complex networks involved in apoptotic regulation. Imbalanced expressions of apoptosis-related factors frequently lead to malignant diseases. The biological functions of several apoptotic factors are manipulated through alternative splicing mechanisms which expand gene diversity by generating discrete variants from one messenger RNA precursor. It is widely observed that alternatively-spliced variants encoded from apoptosis-related genes exhibit differential effects on apoptotic regulation. Alternative splicing events are meticulously regulated by the interplay between trans-splicing factors and cis responsive elements surrounding the regulated exons. The major focus of this review is to highlight recent studies that illustrate the influences of alternative splicing networks on apoptotic regulation which participates in diverse cellular processes and diseases. PMID- 27983657 TI - Fingolimod Associated Bilateral Cystoid Macular Edema-Wait and See? AB - Fingolimod 0.5-mg once-daily is an approved therapy for patients with relapsing remitting multiple sclerosis (MS). Several pivotal and real-world studies have demonstrated that fingolimod is associated with the development of macular edema (ME). Herein, we present a case of a diabetic MS patient who developed severe bilateral ME during fingolimod treatment. By means of this case study we provide a detailed review about fingolimod associated macular edema (FAME), its current incidence with or without diabetes mellitus, and previous therapy attempts and outcomes in MS patients. Intravitreal administration of antibodies raised against vascular endothelial growth factor A (VEGF-A) has not yet been used in the management of FAME, however, the excellent therapeutic response in our patient may justify the use of anti-VEGF-A agents in combination with cessation of fingolimod to achieve fast resolution of FAME and to prevent visual deficits, particularly in bilateral FAME. PMID- 27983659 TI - Contactless Measurement of Magnetic Nanoparticles on Lateral Flow Strips Using Tunneling Magnetoresistance (TMR) Sensors in Differential Configuration. AB - Magnetic nanoparticles (MNPs) are commonly used in biomedical detection due to their capability to bind with some specific antibodies. Quantification of biological entities could be realized by measuring the magnetic response of MNPs after the binding process. This paper presents a contactless scanning prototype based on tunneling magnetoresistance (TMR) sensors for quantification of MNPs present in lateral flow strips (LFSs). The sensing unit of the prototype composes of two active TMR elements, which are parallel and closely arranged to form a differential sensing configuration in a perpendicular magnetic field. Geometrical parameters of the configuration are optimized according to theoretical analysis of the stray magnetic field produced by the test line (T-line) while strips being scanned. A brief description of our prototype and the sample preparation is presented. Experimental results show that the prototype exhibits the performance of high sensitivity and strong anti-interference ability. Meanwhile, the detection speed has been improved compared with existing similar techniques. The proposed prototype demonstrates a good sensitivity for detecting samples containing human chorionic gonadotropin (hCG) at a concentration of 25 mIU/mL. The T-line produced by the sample with low concentration is almost beyond the visual limit and produces a maximum stray magnetic field some 0.247 mOe at the sensor in the x direction. PMID- 27983658 TI - Regulation of Pseudomonas aeruginosa Virulence by Distinct Iron Sources. AB - Pseudomonas aeruginosa is a ubiquitous environmental bacterium and versatile opportunistic pathogen. Like most other organisms, P. aeruginosa requires iron for survival, yet iron rapidly reacts with oxygen and water to form stable ferric (FeIII) oxides and hydroxides, limiting its availability to living organisms. During infection, iron is also sequestered by the host innate immune system, further limiting its availability. P. aeruginosa's capacity to cause disease in diverse host environments is due to its ability to scavenge iron from a variety of host iron sources. Work over the past two decades has further shown that different iron sources can affect the expression of distinct virulence traits. This review discusses how the individual components of P. aeruginosa's iron regulatory network allow this opportunist to adapt to a multitude of host environments during infection. PMID- 27983660 TI - Investigating Effects of Proteasome Inhibitor on Multiple Myeloma Cells Using Confocal Raman Microscopy. AB - Due to its label-free and non-destructive nature, applications of Raman spectroscopic imaging in monitoring therapeutic responses at the cellular level are growing. We have recently developed a high-speed confocal Raman microscopy system to image living biological specimens with high spatial resolution and sensitivity. In the present study, we have applied this system to monitor the effects of Bortezomib, a proteasome inhibitor drug, on multiple myeloma cells. Cluster imaging followed by spectral profiling suggest major differences in the nuclear and cytoplasmic contents of cells due to drug treatment that can be monitored with Raman spectroscopy. Spectra were also acquired from group of cells and feasibility of discrimination among treated and untreated cells using principal component analysis (PCA) was accessed. Findings support the feasibility of Raman technologies as an alternate, novel method for monitoring live cell dynamics with minimal external perturbation. PMID- 27983661 TI - microRNA Expression in Sentinel Nodes from Progressing Melanoma Patients Identifies Networks Associated with Dysfunctional Immune Response. AB - Sentinel node biopsy (SNB) is a main staging biomarker in melanoma and is the first lymph node to drain the tumor, thus representing the immunological site where anti-tumor immune dysfunction is established and where potential prognostic immune markers can be identified. Here we analyzed microRNA (miR) profiles in archival tumor-positive SNBs derived from melanoma patients with different outcomes and performed an integrated analysis of transcriptional data to identify deregulated immune signaling networks. Twenty-six miRs were differentially expressed in melanoma-positive SNB samples between patients with disease progression and non-progressing patients, the majority being previously reported in the regulation of immune responses. A significant variation in miR expression levels was confirmed in an independent set of SNB samples. Integrated information from genome-wide transcriptional profiles and in vitro assessment in immune cells led to the identification of miRs associated with the regulation of the TNF receptor superfamily member 8 (TNFRSF8) gene encoding the CD30 receptor, a marker increased in lymphocytes of melanoma patients with progressive disease. These findings indicate that miRs are involved in the regulation of pathways leading to immune dysfunction in the sentinel node and may provide valuable markers for developing prognostic molecular signatures for the identification of stage III melanoma patients at risk of recurrence. PMID- 27983662 TI - Effect of Attitudinal, Situational and Demographic Factors on Annoyance Due to Environmental Vibration and Noise from Construction of a Light Rapid Transit System. AB - The aim of this paper is to determine what non-exposure factors influence the relationship between vibration and noise exposure from the construction of a Light Rapid Transit (LRT) system and the annoyance of nearby residents. Noise and vibration from construction sites are known to annoy residents, with annoyance increasing as a function of the magnitude of the vibration and noise. There is not a strong correlation between exposure and levels of annoyance suggesting that factors not directly related to the exposure may have an influence. A range of attitudinal, situational and demographic factors are investigated with the aim of understanding the wide variation in annoyance for a given vibration exposure. A face-to-face survey of residents (n = 350) near three sites of LRT construction was conducted, and responses were compared to semi-empirical estimates of the internal vibration within the buildings. It was found that annoyance responses due to vibration were strongly influenced by two attitudinal variables, concern about property damage and sensitivity to vibration. Age, ownership of the property and the visibility of the construction site were also important factors. Gender, time at home and expectation of future levels of vibration had much less influence. Due to the measurement methods used, it was not possible to separate out the effects of noise and vibration on annoyance; as such, this paper focusses on annoyance due to vibration exposure. This work concludes that for the most cost-effective reduction of the impact of construction vibration and noise on the annoyance felt by a community, policies should consider attitudinal factors. PMID- 27983663 TI - Removal and Biodegradation of Nonylphenol by Four Freshwater Microalgae. AB - The removal and biodegradation of nonylphenol (NP) by four freshwater microalgae, including three green algae (Scendesmus quadriauda, Chlorella vulgaris, and Ankistrodesmus acicularis) and one cyanobacterium (Chroococcus minutus) were studied in bacteria-free cultures exposed to different concentrations of NP for 5 days. All four algal species showed a rapid and high ability to remove NP (including bioaccumulation and biodegradation). Among these species, A. acicularis (Ankistrodesmus acicularis) had the highest NP removal rate (83.77%) at 120 h when exposed to different NP treatments (0.5-2.5 mg.L-1), followed by C. vulgaris (Chlorella vulgaris) (80.80%), S. quadriauda (Scendesmus quadriauda) (70.96%) and C. minutus (Chroococcus minutus) (64.26%). C. vulgaris had the highest NP biodegradation percentage (68.80%) at 120 h, followed by A. acicularis (65.63%), S. quadriauda (63.10%); and C. minutus (34.91%). The extracellular NP contents were lower than the intracellular NP contents in all tested algae. The ratio of the extracellular NP content and the intracellular NP content ranged from 0.04 to 0.85. Therefore, the removal of NP from the medium was mainly due to the algal degradation. These results indicate that A. acicularis and C. vulgaris are more tolerant to NP and could be used for treatment of NP contaminated aqueous systems effectively by bioremoval and biodegradation. PMID- 27983664 TI - A Review of Wearable Sensor Systems for Monitoring Body Movements of Neonates. AB - Characteristics of physical movements are indicative of infants' neuro-motor development and brain dysfunction. For instance, infant seizure, a clinical signal of brain dysfunction, could be identified and predicted by monitoring its physical movements. With the advance of wearable sensor technology, including the miniaturization of sensors, and the increasing broad application of micro- and nanotechnology, and smart fabrics in wearable sensor systems, it is now possible to collect, store, and process multimodal signal data of infant movements in a more efficient, more comfortable, and non-intrusive way. This review aims to depict the state-of-the-art of wearable sensor systems for infant movement monitoring. We also discuss its clinical significance and the aspect of system design. PMID- 27983665 TI - Overview of Cotinine Cutoff Values for Smoking Status Classification. AB - While cotinine is commonly used as a biomarker to validate self-reported smoking status, the selection of an optimal cotinine cutoff value for distinguishing true smokers from true nonsmokers shows a lack of standardization among studies. This review describes how the cutoff values have been derived, and explains the issues involved in the generalization of a cutoff value. In this study, we conducted an English-language literature search in PubMed using the keywords "cotinine" and "cutoff" or "self-reported" and "smoking status" and "validation" for the years 1985-2014. We obtained 104 articles, 32 of which provided (1) sensitivity and specificity of a cutoff value and (2) determination methods for the given cutoff value. We found that the saliva cotinine cutoff value range of 10-25 ng/mL, serum and urine cotinine cutoff of 10-20 ng/mL and 50-200 ng/mL, respectively, have been commonly used to validate self-reported smoking status using a 2 * 2 table or a receiver operating characteristics (ROC) curve. We also found that recent large population-based studies in the U.S. and UK reported lower cutoff values for cotinine in serum (3 ng/mL) and saliva (12 ng/mL), compared to the traditionally accepted ones (15 and 14 ng/mg, respectively). PMID- 27983666 TI - Synergising Public Health Concepts with the Sendai Framework for Disaster Risk Reduction: A Conceptual Glossary. AB - The Sendai Framework for Disaster Risk Reduction (2015) is a global strategy for addressing disaster risk and resilience that has been ratified by member countries of the United Nations. Its guiding principles emphasise building resilience through inter-sectoral collaboration, as well as partnerships that facilitate community empowerment and address underlying risk factors. Both public health and the emergency management sector face similar challenges related to developing and implementing strategies that involve structural change, facilitating community resilience and addressing individual risk factors. Familiarity with public health principles enables an understanding of the holistic approach to risk reduction that is outlined within the Sendai Framework. We present seven concepts that resonate with contemporary public health practice, namely: the social determinants of health; inequality and inequity; the inverse care law; community-based and community development approaches; hard to reach communities and services; the prevention paradox; and the inverse prevention law. These ideas from public health provide a useful conceptual base for the "new" agenda in disaster risk management that underpins the 2015 Sendai Framework. The relevance of these ideas to disaster risk management and research is illustrated through drawing on the Sendai Framework, disaster literature and exemplars from the 2010-2011 earthquakes in Canterbury, New Zealand. PMID- 27983667 TI - Evaluation of Indoor Air Quality Screening Strategies: A Step-Wise Approach for IAQ Screening. AB - Conducting a full indoor air quality (IAQ) assessment in air-conditioned offices requires large-scale material and manpower resources. However, an IAQ index can be adopted as a handy screening tool to identify any premises (with poor IAQ) that need more comprehensive IAQ assessments to prioritize IAQ improvements. This study proposes a step-wise IAQ screening protocol to facilitate its cost effective management among building owners and managers. The effectiveness of three IAQ indices, namely theta1 (with one parameter: CO2), theta2 (with two parameters: CO2 and respirable suspended particulates, RSP) and theta3 (with three parameters: CO2, RSP, and total volatile organic compounds, TVOC) are evaluated. Compared in a pairwise manner with respect to the minimum satisfaction levels as stated in the IAQ Certification Scheme by the Hong Kong Environmental Protection Department, the results show that a screening test with more surrogate IAQ parameters is good at identifying both lower and higher risk groups for unsatisfactory IAQ, and thus offers higher resolution. Through the sensitivity and specificity for identifying IAQ problems, the effectiveness of alternative IAQ screening methods with different monitoring parameters is also reported. PMID- 27983669 TI - Towards Automated Large-Scale 3D Phenotyping of Vineyards under Field Conditions. AB - In viticulture, phenotypic data are traditionally collected directly in the field via visual and manual means by an experienced person. This approach is time consuming, subjective and prone to human errors. In recent years, research therefore has focused strongly on developing automated and non-invasive sensor based methods to increase data acquisition speed, enhance measurement accuracy and objectivity and to reduce labor costs. While many 2D methods based on image processing have been proposed for field phenotyping, only a few 3D solutions are found in the literature. A track-driven vehicle consisting of a camera system, a real-time-kinematic GPS system for positioning, as well as hardware for vehicle control, image storage and acquisition is used to visually capture a whole vine row canopy with georeferenced RGB images. In the first post-processing step, these images were used within a multi-view-stereo software to reconstruct a textured 3D point cloud of the whole grapevine row. A classification algorithm is then used in the second step to automatically classify the raw point cloud data into the semantic plant components, grape bunches and canopy. In the third step, phenotypic data for the semantic objects is gathered using the classification results obtaining the quantity of grape bunches, berries and the berry diameter. PMID- 27983668 TI - Hispanic and Immigrant Paradoxes in U.S. Breast Cancer Mortality: Impact of Neighborhood Poverty and Hispanic Density. AB - To test the Hispanic and Immigrant Paradoxes-i.e., survival advantages despite a worse risk factor profile-and the modifying role of neighborhood context, we examined associations between patient ethnicity, birthplace, neighborhood Hispanic density and neighborhood poverty among 166,254 female breast cancer patients diagnosed 1995-2009 in Texas, U.S. Of all, 79.9% were non-Hispanic White, 15.8% Hispanic U.S.-born, and 4.2% Hispanic foreign-born. We imputed birthplace for the 60.7% of Hispanics missing birthplace data using multiple imputation. Shared frailty Cox proportional hazard models (patients nested within census tracts) adjusted for age, diagnosis year, stage, grade, histology, urban/rural residence, and local mammography capacity. Whites (vs. U.S.-born Hispanics) had increased all-cause and breast cancer mortality. Foreign-born (vs. U.S.-born) Hispanics had increased all-cause and breast cancer mortality. Living in higher Hispanic density neighborhoods was generally associated with increased mortality, although associations differed slightly in magnitude and significance by ethnicity, birthplace, and neighborhood poverty. We found no evidence of an Immigrant Paradox and some evidence of a Hispanic Paradox where protective effects were limited to U.S.-born Hispanics. Contrary to prior studies, foreign birthplace and residence in higher Hispanic density neighborhoods were associated with increased mortality. More research on intersections between ethnicity, birthplace and neighborhood context are needed. PMID- 27983670 TI - An Indoor Positioning Method for Smartphones Using Landmarks and PDR. AB - Recently location based services (LBS) have become increasingly popular in indoor environments. Among these indoor positioning techniques providing LBS, a fusion approach combining WiFi-based and pedestrian dead reckoning (PDR) techniques is drawing more and more attention of researchers. Although this fusion method performs well in some cases, it still has some limitations, such as heavy computation and inconvenience for real-time use. In this work, we study map information of a given indoor environment, analyze variations of WiFi received signal strength (RSS), define several kinds of indoor landmarks, and then utilize these landmarks to correct accumulated errors derived from PDR. This fusion scheme, called Landmark-aided PDR (LaP), is proved to be light-weight and suitable for real-time implementation by running an Android application designed for the experiment. We compared LaP with other PDR-based fusion approaches. Experimental results show that the proposed scheme can achieve a significant improvement with an average accuracy of 2.17 m. PMID- 27983673 TI - Using miRNA-Analyzer for the Analysis of miRNA Data. AB - MicroRNAs (miRNAs) are small biological molecules that play an important role during the mechanisms of protein formation. Recent findings have demonstrated that they act as both positive and negative regulators of protein formation. Thus, the investigation of miRNAs, i.e., the determination of their level of expression, has developed a huge interest in the scientific community. One of the leading technologies for extracting miRNA data from biological samples is the miRNA Affymetrix platform. It provides the quantification of the level of expression of the miRNA in a sample, thus enabling the accumulation of data and allowing the determination of relationships among miRNA, genes, and diseases. Unfortunately, there is a lack of a comprehensive platform able to provide all the functions needed for the extraction of information from miRNA data. We here present miRNA-Analyzer, a complete software tool providing primary functionalities for miRNA data analysis. The current version of miRNA-Analyzer wraps the Affymetrix QCTool for the preprocessing of binary data files, and then provides feature selection (the filtering by species and by the associated p value of preprocessed files). Finally, preprocessed and filtered data are analyzed by the Multiple Experiment Viewer (T-MEV) and Short Time Series Expression Miner (STEM) tools, which are also wrapped into miRNA-Analyzer, thus providing a unique environment for miRNA data analysis. The tool offers a plug-in interface so it is easily extensible by adding other algorithms as plug-ins. Users may download the tool freely for academic use at https://sites.google.com/site/mirnaanalyserproject/d. PMID- 27983672 TI - Abdominal Obesity and Lung Cancer Risk: Systematic Review and Meta-Analysis of Prospective Studies. AB - Several meta-analyses of observational studies have been performed to examine the association between general obesity, as measured by body mass index (BMI), and lung cancer. These meta-analyses suggest an inverse relation between high BMI and this cancer. In contrast to general obesity, abdominal obesity appears to play a role in the development of lung cancer. However, the association between abdominal obesity (as measured by waist circumference (WC) (BMI adjusted) and waist to hip ratio (WHR)) and lung cancer is not fully understood due to sparse available evidence regarding this association. PubMed and Web of Science databases were searched for studies assessing the association between abdominal obesity and lung cancer up to October 2016. The summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with a random-effects model. Six prospective cohort studies with 5827 lung cancer cases among 831,535 participants were included in our meta-analysis. Each 10 cm increase in WC and 0.1 unit increase in WHR were associated with 10% (RR 1.10; 95% CI 1.04, 1.17; I2 = 27.7%, p-heterogeneity = 0.198) and 5% (RR 1.05; 95% CI 1.00, 1.11; I2 = 25.2%, p heterogeneity = 0.211) greater risks of lung cancer, respectively. According to smoking status, greater WHR was only positively associated with lung cancer among former smokers (RR 1.11; 95% CI 1.00, 1.23). In contrast, greater WC was associated with increased lung cancer risk among never smokers (RR 1.11; 95% CI 1.00, 1.23), former smokers (RR 1.12; 95% CI 1.03, 1.22) and current smokers (RR 1.16; 95% CI 1.08, 1.25). The summary RRs for highest versus lowest categories of WC and WHR were 1.32 (95% CI 1.13, 1.54; I2 = 18.2%, p-heterogeneity = 0.281) and 1.10 (95% CI 1.00, 1.23; I2 = 24.2%, p-heterogeneity = 0.211), respectively. In summary, abdominal obesity may play an important role in the development of lung cancer. PMID- 27983676 TI - Estimation of Full-Body Poses Using Only Five Inertial Sensors: An Eager or Lazy Learning Approach? AB - Human movement analysis has become easier with the wide availability of motion capture systems. Inertial sensing has made it possible to capture human motion without external infrastructure, therefore allowing measurements in any environment. As high-quality motion capture data is available in large quantities, this creates possibilities to further simplify hardware setups, by use of data-driven methods to decrease the number of body-worn sensors. In this work, we contribute to this field by analyzing the capabilities of using either artificial neural networks (eager learning) or nearest neighbor search (lazy learning) for such a problem. Sparse orientation features, resulting from sensor fusion of only five inertial measurement units with magnetometers, are mapped to full-body poses. Both eager and lazy learning algorithms are shown to be capable of constructing this mapping. The full-body output poses are visually plausible with an average joint position error of approximately 7 cm, and average joint angle error of 7 ? . Additionally, the effects of magnetic disturbances typical in orientation tracking on the estimation of full-body poses was also investigated, where nearest neighbor search showed better performance for such disturbances. PMID- 27983671 TI - Enzymatic Metabolism of Vitamin A in Developing Vertebrate Embryos. AB - Embryonic development is orchestrated by a small number of signaling pathways, one of which is the retinoic acid (RA) signaling pathway. Vitamin A is essential for vertebrate embryonic development because it is the molecular precursor of the essential signaling molecule RA. The level and distribution of RA signaling within a developing embryo must be tightly regulated; too much, or too little, or abnormal distribution, all disrupt embryonic development. Precise regulation of RA signaling during embryogenesis is achieved by proteins involved in vitamin A metabolism, retinoid transport, nuclear signaling, and RA catabolism. The reversible first step in conversion of the precursor vitamin A to the active retinoid RA is mediated by retinol dehydrogenase 10 (RDH10) and dehydrogenase/reductase (SDR family) member 3 (DHRS3), two related membrane-bound proteins that functionally activate each other to mediate the interconversion of retinol and retinal. Alcohol dehydrogenase (ADH) enzymes do not contribute to RA production under normal conditions during embryogenesis. Genes involved in vitamin A metabolism and RA catabolism are expressed in tissue-specific patterns and are subject to feedback regulation. Mutations in genes encoding these proteins disrupt morphogenesis of many systems in a developing embryo. Together these observations demonstrate the importance of vitamin A metabolism in regulating RA signaling during embryonic development in vertebrates. PMID- 27983675 TI - Assessing Motor Fluctuations in Parkinson's Disease Patients Based on a Single Inertial Sensor. AB - Altered movement control is typically the first noticeable symptom manifested by Parkinson's disease (PD) patients. Once under treatment, the effect of the medication is very patent and patients often recover correct movement control over several hours. Nonetheless, as the disease advances, patients present motor complications. Obtaining precise information on the long-term evolution of these motor complications and their short-term fluctuations is crucial to provide optimal therapy to PD patients and to properly measure the outcome of clinical trials. This paper presents an algorithm based on the accelerometer signals provided by a waist sensor that has been validated in the automatic assessment of patient's motor fluctuations (ON and OFF motor states) during their activities of daily living. A total of 15 patients have participated in the experiments in ambulatory conditions during 1 to 3 days. The state recognised by the algorithm and the motor state annotated by patients in standard diaries are contrasted. Results show that the average specificity and sensitivity are higher than 90%, while their values are higher than 80% of all patients, thereby showing that PD motor status is able to be monitored through a single sensor during daily life of patients in a precise and objective way. PMID- 27983674 TI - Current and Future Perspectives on the Structural Identification of Small Molecules in Biological Systems. AB - Although significant advances have been made in recent years, the structural elucidation of small molecules continues to remain a challenging issue for metabolite profiling. Many metabolomic studies feature unknown compounds; sometimes even in the list of features identified as "statistically significant" in the study. Such metabolic "dark matter" means that much of the potential information collected by metabolomics studies is lost. Accurate structure elucidation allows researchers to identify these compounds. This in turn, facilitates downstream metabolite pathway analysis, and a better understanding of the underlying biology of the system under investigation. This review covers a range of methods for the structural elucidation of individual compounds, including those based on gas and liquid chromatography hyphenated to mass spectrometry, single and multi-dimensional nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry and includes discussion of data standardization. Future perspectives in structure elucidation are also discussed; with a focus on the potential development of instruments and techniques, in both nuclear magnetic resonance spectroscopy and mass spectrometry that, may help solve some of the current issues that are hampering the complete identification of metabolite structure and function. PMID- 27983677 TI - Erratum: Roche, J. et al. Global Decrease of Histone H3K27 Acetylation in ZEB1 Induced Epithelial to Mesenchymal Transition in Lung Cancer Cells. Cancers, 2013, 5, 334-356. AB - n/a. PMID- 27983678 TI - Quorum Sensing and the Use of Quorum Quenchers as Natural Biocides to Inhibit Sulfate-Reducing Bacteria. AB - Sulfate-reducing bacteria (SRB) are one of the main protagonist groups of biocorrosion in the seawater environment. Given their principal role in biocorrosion, it remains a crucial task to develop strategies to reduce the abundance of SRBs. Conventional approaches include the use of biocides and antibiotics, which can impose health, safety, and environmental concerns. This review examines an alternative approach to this problem. This is achieved by reviewing the role of quorum sensing (QS) in SRB populations and its impact on the biofilm formation process. Genome databases of SRBs are mined to look for putative QS systems and homologous protein sequences representative of autoinducer receptors or synthases. Subsequently, this review puts forward the potential use of quorum quenchers as natural biocides against SRBs and outlines the potential strategies for the implementation of this approach. PMID- 27983680 TI - Node Immunization with Time-Sensitive Restrictions. AB - When we encounter a malicious rumor or an infectious disease outbreak, immunizing k nodes of the relevant network with limited resources is always treated as an extremely effective method. The key challenge is how we can insulate limited nodes to minimize the propagation of those contagious things. In previous works, the best k immunised nodes are selected by learning the initial status of nodes and their strategies even if there is no feedback in the propagation process, which eventually leads to ineffective performance of their solutions. In this paper, we design a novel vaccines placement strategy for protecting much more healthy nodes from being infected by infectious nodes. The main idea of our solution is that we are not only utilizing the status of changing nodes as auxiliary knowledge to adjust our scheme, but also comparing the performance of vaccines in various transmission slots. Thus, our solution has a better chance to get more benefit from these limited vaccines. Extensive experiments have been conducted on several real-world data sets and the results have shown that our algorithm has a better performance than previous works. PMID- 27983679 TI - Kunitz-Type Peptide HCRG21 from the Sea Anemone Heteractis crispa Is a Full Antagonist of the TRPV1 Receptor. AB - Sea anemone venoms comprise multifarious peptides modulating biological targets such as ion channels or receptors. The sequence of a new Kunitz-type peptide, HCRG21, belonging to the Heteractis crispa RG (HCRG) peptide subfamily was deduced on the basis of the gene sequence obtained from the Heteractis crispa cDNA. HCRG21 shares high structural homology with Kunitz-type peptides APHC1 APHC3 from H. crispa, and clusters with the peptides from so named "analgesic cluster" of the HCGS peptide subfamily but forms a separate branch on the NJ phylogenetic tree. Three unique point substitutions at the N-terminus of the molecule, Arg1, Gly2, and Ser5, distinguish HCRG21 from other peptides of this cluster. The trypsin inhibitory activity of recombinant HCRG21 (rHCRG21) was comparable with the activity of peptides from the same cluster. Inhibition constants for trypsin and alpha-chymotrypsin were 1.0 * 10-7 and 7.0 * 10-7 M, respectively. Electrophysiological experiments revealed that rHCRG21 inhibits 95% of the capsaicin-induced current through transient receptor potential family member vanilloid 1 (TRPV1) and has a half-maximal inhibitory concentration of 6.9 +/- 0.4 MUM. Moreover, rHCRG21 is the first full peptide TRPV1 inhibitor, although displaying lower affinity for its receptor in comparison with other known ligands. Macromolecular docking and full atom Molecular Dynamics (MD) simulations of the rHCRG21-TRPV1 complex allow hypothesizing the existence of two feasible, intra- and extracellular, molecular mechanisms of blocking. These data provide valuable insights in the structural and functional relationships and pharmacological potential of bifunctional Kunitz-type peptides. PMID- 27983681 TI - First Total Synthesis and Biological Screening of a Proline-Rich Cyclopeptide from a Caribbean Marine Sponge. AB - A natural heptacyclopeptide, stylissamide G (7), previously isolated from the Bahamian marine sponge Stylissa caribica from the Caribbean Sea, was synthesized via coupling of the tetrapeptide l-phenylalanyl-l-prolyl-l-phenylalanyl-l-proline methyl ester with the tripeptide Boc-l-leucyl-l-isoleucyl-l-proline, followed by cyclization of the linear heptapeptide fragment. The structure of the synthesized cyclooligopeptide was confirmed using quantitative elemental analysis, FT-IR, 1H NMR, 13C NMR and mass spectrometry. Results of pharmacological activity studies indicated that the newly synthesized cycloheptapeptide displayed good anthelmintic potential against Megascoplex konkanensis, Pontoscotex corethruses and Eudrilus eugeniea at 2 mg/mL and in addition, potent antifungal activity against pathogenic Candida albicans and dermatophytes Trichophyton mentagrophytes and Microsporum audouinii at a concentration of 6 MUg/mL. PMID- 27983683 TI - Lunasin Attenuates Obesity-Associated Metastasis of 4T1 Breast Cancer Cell through Anti-Inflammatory Property. AB - Obesity prevalence is increasing worldwide and is accompanied by low-grade inflammation with macrophage infiltration, which is linked with a poorer breast cancer prognosis. Lunasin is a natural seed peptide with chemopreventive properties and multiple bioactivities. This is the first study to explore the chemopreventive effects of lunasin in the obesity-related breast cancer condition using 4T1 breast cancer cells, 3T3-L1 adipocytes, and conditioned media. An obesity-related environment, such as leptin-treatment or adipocyte-conditioned medium (Ad-CM), promoted 4T1 cell proliferation and metastasis. Lunasin treatment inhibited metastasis of breast cancer cells, partially through modestly inhibiting production of the angiogenesis-mediator vascular endothelial growth factor (VEGF) and significantly by inhibiting secretion in the Ad-CM condition. Subsequently, two adipocytes inflammation models, 3T3-L1 adipocytes were stimulated by tumor necrosis factor (TNF)-alpha, and RAW 264.7 cell-conditioned medium (RAW-CM) was used to mimic the obese microenvironment. Lunasin significantly inhibited interleukin (IL)-6 and macrophage chemoattractant protein (MCP)-1 secretion by TNF-alpha stimulation, and MCP-1 secretion in the RAW-CM model. This study highlights that lunasin suppressed 3T3-L1 adipocyte inflammation and inhibited 4T1 breast cancer cell migration. Interestingly, lunasin exerted more effective anti-metastasis activity in the obesity-related condition models, indicating that it possesses anti-inflammatory properties and blocks adipocyte-cancer cell cross-talk. PMID- 27983685 TI - Phase- and Workload-Dependent Changes in Corticospinal Excitability to the Biceps and Triceps Brachii during Arm Cycling. AB - This is the first study to examine corticospinal excitability (CSE) to antagonistic muscle groups during arm cycling. Transcranial magnetic stimulation (TMS) of the motor cortex and transmastoid electrical stimulation (TMES) of the corticospinal tract were used to assess changes in supraspinal and spinal excitability, respectively. TMS induced motor evoked potentials (MEPs) and TMES induced cervicomedullary evoked potentials (CMEPs) were recorded from the biceps and triceps brachii at two positions, mid-elbow flexion and extension, while cycling at 5% and 15% of peak power output. While phase-dependent modulation of MEP and CMEP amplitudes occurred in the biceps brachii, there was no difference between flexion and extension for MEP amplitudes in the triceps brachii and CMEP amplitudes were higher during flexion than extension. Furthermore, MEP amplitudes in both biceps and triceps brachii increased with increased workload. CMEP amplitudes increased with higher workloads in the triceps brachii, but not biceps brachii, though the pattern of change in CMEPs was similar to MEPs. Differences between changes in CSE between the biceps and triceps brachii suggest that these antagonistic muscles may be under different neural control during arm cycling. Putative mechanisms are discussed. PMID- 27983684 TI - Lung Involvement in Children with Hereditary Autoinflammatory Disorders. AB - Short-lived systemic inflammatory reactions arising from disrupted rules in the innate immune system are the operating platforms of hereditary autoinflammatory disorders (HAIDs). Multiple organs may be involved and aseptic inflammation leading to disease-specific phenotypes defines most HAIDs. Lungs are infrequently involved in children with HAIDs: the most common pulmonary manifestation is pleuritis in familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), respectively caused by mutations in the MEFV and TNFRSF1A genes, while interstitial lung disease can be observed in STING-associated vasculopathy with onset in infancy (SAVI), caused by mutations in the TMEM173 gene. The specific pleuropulmonary diseases may range from sub-clinical abnormalities during inflammatory flares of FMF and TRAPS to a severe life-threatening disorder in children with SAVI. PMID- 27983686 TI - Impact of Proteins on the Uptake, Distribution, and Excretion of Phenolics in the Human Body. AB - Polyphenols, a complex group of secondary plant metabolites, including flavonoids and phenolic acids, have been studied in depth for their health-related benefits. The activity of polyphenols may, however, be hampered when consumed together with protein-rich food products, due to the interaction between polyphenols and proteins. To that end we have tested the bioavailability of representatives of a range of polyphenol classes when consumed for five days in different beverage matrices. In a placebo-controlled, randomized, cross-over study, 35 healthy males received either six placebo gelatine capsules consumed with 200 mL of water, six capsules with 800 mg polyphenols derived from red wine and grape extracts, or the same dose of polyphenols incorporated into 200 mL of either pasteurized dairy drink, soy drink (both containing 3.4% proteins) or fruit-flavoured protein-free drink . At the end of the intervention urine and blood was collected and analysed for a broad range of phenolic compounds using Gas Chromatography-Mass Spectrometry (GC-MS), Liquid Chromatography-Multiple Reaction Monitoring-Mass Spectrometry (LC-MRM-MS), and Nuclear Magnetic Resonance (NMR) spectroscopy techniques. The plasma and urine concentrations of the polyphenols identified increased with all formats, including the protein-rich beverages. Compared to capsule ingestion, consumption of polyphenol-rich beverages containing either dairy, soy or no proteins had minor to no effect on the bioavailability and excretion of phenolic compounds in plasma (118% +/- 9%) and urine (98% +/- 2%). We conclude that intake of polyphenols incorporated in protein-rich drinks does not have a major impact on the bioavailability of a range of different polyphenols and phenolic metabolites. PMID- 27983682 TI - Zebrafish as an In Vivo Model to Assess Epigenetic Effects of Ionizing Radiation. AB - Exposure to ionizing radiations (IRs) is ubiquitous in our environment and can be categorized into "targeted" effects and "non-targeted" effects. In addition to inducing deoxyribonucleic acid (DNA) damage, IR exposure leads to epigenetic alterations that do not alter DNA sequence. Using an appropriate model to study the biological effects of radiation is crucial to better understand IR responses as well as to develop new strategies to alleviate exposure to IR. Zebrafish, Danio rerio, is a scientific model organism that has yielded scientific advances in several fields and recent studies show the usefulness of this vertebrate model in radiation biology. This review briefly describes both "targeted" and "non targeted" effects, describes the findings in radiation biology using zebrafish as a model and highlights the potential of zebrafish to assess the epigenetic effects of IR, including DNA methylation, histone modifications and miRNA expression. Other in vivo models are included to compare observations made with zebrafish, or to illustrate the feasibility of in vivo models when the use of zebrafish was unavailable. Finally, tools to study epigenetic modifications in zebrafish, including changes in genome-wide DNA methylation, histone modifications and miRNA expression, are also described in this review. PMID- 27983687 TI - Phytochemical Pharmacokinetics and Bioactivity of Oat and Barley Flour: A Randomized Crossover Trial. AB - While dietary fiber plays an important role in the health benefits associated with whole grain consumption, other ingredients concentrated in the outer bran layer, including alkylresorcinols, lignans, phenolic acids, phytosterols, and tocols, may also contribute to these outcomes. To determine the acute bioavailability and pharmacokinetics of the major phytochemicals found in barley and oats, we conducted a randomized, three-way crossover trial in 13 healthy subjects, aged 40-70 years with a body mass index (BMI) of 27-35.9 kg/m2. After a two-day run-in period following a diet low in phytochemicals, subjects were randomized to receive muffins made with either 48 g whole oat flour, whole barley flour, or refined wheat flour plus cellulose (control), with a one-week washout period between each intervention. At the same time, an oral glucose tolerance test was administered. In addition to plasma phytochemical concentrations, glucose and insulin responses, biomarkers of antioxidant activity, lipid peroxidation, inflammation, and vascular remodeling were determined over a 24-h period. There was no significant effect on acute bioavailability or pharmacokinetics of major phytochemicals. Administered concurrently with a glucose bolus, the source of whole grains did not attenuate the post-prandial response of markers of glucoregulation and insulin sensitivity, inflammation, nor vascular remodeling compared to the refined grain control. No significant differences were observed in the bioavailability or postprandial effects between whole-oat and whole-barley compared to a refined wheat control when administered with a glucose challenge. These null results may be due, in part, to the inclusion criteria for the subjects, dose of the whole grains, and concurrent acute administration of the whole grains with the glucose bolus. PMID- 27983688 TI - Maternal Food Restriction during Pregnancy and Lactation Adversely Affect Hepatic Growth and Lipid Metabolism in Three-Week-Old Rat Offspring. AB - Maternal malnutrition influences the early development of foetal adaptive changes for survival. We explored the effects of maternal undernutrition during gestation and lactation on hepatic growth and function. Sprague-Dawley rats were fed a normal or a food-restricted (FR) diet during gestation and/or lactation. We performed analyses of covariance (adjusting for the liver weight/body weight ratio) to compare hepatic growth and lipid metabolism among the offspring. Maternal FR during gestation triggered the development of wide spaces between hepatic cells and increased the expression of mammalian target of rapamycin (mTOR) in three-week-old male offspring compared with controls (both p < 0.05). Offspring nursed by FR dams exhibited wider spaces between hepatic cells and a lower liver weight/body weight ratio than control offspring, and increased mTOR expression (p < 0.05). Interestingly, the significant decrease in expression of lipogenic-related genes was dependent on carbohydrate-responsive element-binding protein, despite the increased expression of sterol regulatory element-binding protein 1 (SREBP1) (p < 0.05). This study demonstrated increased expression of key metabolic regulators (mTOR and SREBP1), alterations in lipid metabolism, and deficits in hepatic growth in the offspring of FR-treated dams. PMID- 27983690 TI - A Review of the Tawny Crazy Ant, Nylanderia fulva, an Emergent Ant Invader in the Southern United States: Is Biological Control a Feasible Management Option? AB - The tawny crazy ant, Nylanderia fulva (Mayr) (Hymenoptera: Formicidae), has invaded states of the U.S. including Texas, Louisiana, Mississippi, Alabama, Florida, and Georgia. Native to South America, N. fulva is considered a pest in the U.S. capable of annoying homeowners and farmers, as well as displacing native ant species. As it continues to expand its range, there is a growing need to develop novel management techniques to control the pest and prevent further spread. Current management efforts rely heavily on chemical control, but these methods have not been successful. A review of the biology, taxonomy, ecology, and distribution of N. fulva, including discussion of ecological and economic consequences of this invasive species, is presented. Options for future management are suggested focusing on biological control, including parasitoid flies in the genus Pseudacteon, the microsporidian parasite Myrmecomorba nylanderiae, and a novel polynucleotide virus as potential biological control agents. We suggest further investigation of natural enemies present in the adventive range, as well as foreign exploration undertaken in the native range including Paraguay, Brazil, and Argentina. We conclude that N. fulva may be a suitable candidate for biological control. PMID- 27983689 TI - Abobotulinum Toxin A in the Treatment of Chronic Low Back Pain. AB - Chronic low back pain is a debilitating condition with a complex and multifactorial pathophysiology. Botulinum neurotoxins (BoNTs) have strong analgesic effects, as shown in both animal models of pain and in human beings. A randomized, double-blind, placebo-controlled, parallel format study to investigate the efficacy of abobotulinum toxin A (aboA) in chronic low back pain was conducted. The study cohort consisted of 18 patients who received 100 units of aboA into each of the five lumbar extensor spinae muscles unilaterally or bilaterally (total dose 500 to 1000 units), and 19 who received normal saline of the same volume. The level of pain and quality of life were assessed using the visual analogue scale (VAS) and three questionnaires including the Oswestry Low Back Pain Disability Questionnaire (OLBPDQ). Patients' perception of improvement was recorded via patient global impression of change (PGIC). The primary outcome measure, the proportion of responders with VAS of <4 at 6 weeks, was not met, but the data was significantly in favor of aboA at 4 weeks (p = 0.008). The total Oswestry score representing quality of life improved in the aboA group compared to the placebo group (p = 0.0448). Moreover, significantly more patients reported their low back pain as "much improved" in the abobotulinum toxin A group (0.0293). PMID- 27983692 TI - GridiLoc: A Backtracking Grid Filter for Fusing the Grid Model with PDR Using Smartphone Sensors. AB - Although map filtering-aided Pedestrian Dead Reckoning (PDR) is capable of largely improving indoor localization accuracy, it becomes less efficient when coping with highly complex indoor spaces. For instance, indoor spaces with a few close corners or neighboring passages can lead to particles entering erroneous passages, which can further cause the failure of subsequent tracking. To address this problem, we propose GridiLoc, a reliable and accurate pedestrian indoor localization method through the fusion of smartphone sensors and a grid model. The key novelty of GridiLoc is the utilization of a backtracking grid filter for improving localization accuracy and for handling dead ending issues. In order to reduce the time consumption of backtracking, a topological graph is introduced for representing candidate backtracking points, which are the expected locations at the starting time of the dead ending. Furthermore, when the dead ending is caused by the erroneous step length model of PDR, our solution can automatically calibrate the model by using the historical tracking data. Our experimental results show that GridiLoc achieves a higher localization accuracy and reliability compared with the commonly-used map filtering approach. Meanwhile, it maintains an acceptable computational complexity. PMID- 27983691 TI - Evaluation of Google Glass Technical Limitations on Their Integration in Medical Systems. AB - Google Glass is a wearable sensor presented to facilitate access to information and assist while performing complex tasks. Despite the withdrawal of Google in supporting the product, today there are multiple applications and much research analyzing the potential impact of this technology in different fields of medicine. Google Glass satisfies the need of managing and having rapid access to real-time information in different health care scenarios. Among the most common applications are access to electronic medical records, display monitorizations, decision support and remote consultation in specialties ranging from ophthalmology to surgery and teaching. The device enables a user-friendly hands free interaction with remote health information systems and broadcasting medical interventions and consultations from a first-person point of view. However, scientific evidence highlights important technical limitations in its use and integration, such as failure in connectivity, poor reception of images and automatic restart of the device. This article presents a technical study on the aforementioned limitations (specifically on the latency, reliability and performance) on two standard communication schemes in order to categorize and identify the sources of the problems. Results have allowed us to obtain a basis to define requirements for medical applications to prevent network, computational and processing failures associated with the use of Google Glass. PMID- 27983694 TI - The Influence of Different Partial Pressure on the Fabrication of InGaO Ultraviolet Photodetectors. AB - A metal-semiconductor-metal ultraviolet photodetector has been fabricated with a radiofrequency (RF)-sputtered InGaO thin film. Results for the devices fabricated under different oxygen partial pressure are here in discussed. Under low oxygen partial pressure, the devices work in the photoconductive mode because of the large number of subgap states. Therefore, the devices exhibit internal gain. These defects in the films result in slow switching times and lower photo/dark current ratios. A higher flow ratio of oxygen during the sputtering process can effectively restrain the oxygen vacancies in the film. The responsivity of the photodetector fabricated under an oxygen flow ratio of 20% can reach 0.31 A/W. The rise time and decay time can reach 21 s and 27 s, respectively. PMID- 27983693 TI - QuEChERS Purification Combined with Ultrahigh-Performance Liquid Chromatography Tandem Mass Spectrometry for Simultaneous Quantification of 25 Mycotoxins in Cereals. AB - A method based on the QuEChERS (quick, easy, cheap, effective, rugged, and safe) purification combined with ultrahigh performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), was optimized for the simultaneous quantification of 25 mycotoxins in cereals. Samples were extracted with a solution containing 80% acetonitrile and 0.1% formic acid, and purified with QuEChERS before being separated by a C18 column. The mass spectrometry was conducted by using positive electrospray ionization (ESI+) and multiple reaction monitoring (MRM) models. The method gave good linear relations with regression coefficients ranging from 0.9950 to 0.9999. The detection limits ranged from 0.03 to 15.0 ug.kg-1, and the average recovery at three different concentrations ranged from 60.2% to 115.8%, with relative standard deviations (RSD%) varying from 0.7% to 19.6% for the 25 mycotoxins. The method is simple, rapid, accurate, and an improvement compared with the existing methods published so far. PMID- 27983696 TI - Polyamines and alpha-Carbonic Anhydrases. AB - Natural products represent a straightforward source for molecular structures bearing a vast array of chemical features and potentially useful for biomedical purposes. Recent examples of this type include the discovery of the coumarins and the polyamine natural products as atypical chemotypes for the inhibition of the metalloenzymes carbonic anhydrases (CAs; EC 4.2.2.1). CA enzymes are established pharmacological targets for important pathologies, which, among others, include glaucoma, hypoxic tumors, and central nervous system (CNS)-affecting diseases. Moreover, they are expressed in many bacteria, fungi and helminths which are the etiological agents of the majority of infectious diseases. In this context, natural products represent the ideal source of new and selective druggable CA modulators for biomedical purposes. Herein we report the state of the art on polyamines of natural origin as well as of synthetic derivatives as inhibitors of human CAs. PMID- 27983695 TI - Validating Intravascular Imaging with Serial Optical Coherence Tomography and Confocal Fluorescence Microscopy. AB - Atherosclerotic cardiovascular diseases are characterized by the formation of a plaque in the arterial wall. Intravascular ultrasound (IVUS) provides high resolution images allowing delineation of atherosclerotic plaques. When combined with near infrared fluorescence (NIRF), the plaque can also be studied at a molecular level with a large variety of biomarkers. In this work, we present a system enabling automated volumetric histology imaging of excised aortas that can spatially correlate results with combined IVUS/NIRF imaging of lipid-rich atheroma in cholesterol-fed rabbits. Pullbacks in the rabbit aortas were performed with a dual modality IVUS/NIRF catheter developed by our group. Ex vivo three-dimensional (3D) histology was performed combining optical coherence tomography (OCT) and confocal fluorescence microscopy, providing high-resolution anatomical and molecular information, respectively, to validate in vivo findings. The microscope was combined with a serial slicer allowing for the imaging of the whole vessel automatically. Colocalization of in vivo and ex vivo results is demonstrated. Slices can then be recovered to be tested in conventional histology. PMID- 27983699 TI - Redox Signaling Regulated by Cysteine Persulfide and Protein Polysulfidation. AB - For decades, reactive persulfide species including cysteine persulfide (CysSSH) have been known to exist endogenously in organisms. However, the physiological significance of endogenous persulfides remains poorly understood. That cystathionine beta-synthase and cystathionine gamma-lyase produced CysSSH from cystine was recently demonstrated. An endogenous sulfur transfer system involving CysSSH evidently generates glutathione persulfide (GSSH) that exists at concentrations greater than 100 MUM in vivo. Because reactive persulfide species such as CysSSH and GSSH have higher nucleophilicity than parental cysteine (Cys) and glutathione do, these reactive species exhibit strong scavenging activities against oxidants, e.g., hydrogen peroxide, and electrophiles, which contributes to redox signaling regulation. Also, several papers indicated that various proteins and enzymes have Cys polysulfides including CysSSH at their specific Cys residues, which is called protein polysulfidation. Apart from the redox signaling regulatory mechanism, another plausible function of protein polysulfidation is providing protection for protein thiol residues against irreversible chemical modification caused by oxidants and electrophiles. Elucidation of the redox signaling regulatory mechanism of reactive persulfide species including small thiol molecules and thiol-containing proteins should lead to the development of new therapeutic strategies and drug discoveries for oxidative and electrophilic stress-related diseases. PMID- 27983698 TI - Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment. AB - Epithelial ovarian cancer is a highly heterogeneous disease characterized by multiple histological subtypes. Molecular diversity has been shown to occur within specific histological subtypes of epithelial ovarian cancer, between different tumors of an individual patient, as well as within individual tumors. Recent advances in the molecular characterization of epithelial ovarian cancer tumors have provided the basis for a simplified classification scheme in which these cancers are classified as either type I or type II tumors, and these two categories have implications regarding disease pathogenesis and prognosis. Molecular analyses, primarily based on next-generation sequencing, otherwise known as high-throughput sequencing, are allowing for further refinement of ovarian cancer classification, facilitating the elucidation of the site(s) of precursor lesions of high-grade serous ovarian cancer, and providing insight into the processes of clonal selection and evolution that may be associated with development of chemoresistance. Potential therapeutic targets have been identified from recent molecular profiling studies of these tumors, and the effectiveness and safety of a number of specific targeted therapies have been evaluated or are currently being studied for the treatment of women with this disease. PMID- 27983702 TI - Improving Free Radical Scavenging Activity of Soy Isoflavone Glycosides Daidzin and Genistin by 3'-Hydroxylation Using Recombinant Escherichia coli. AB - The present study describes the biotransformation of a commercially available crude extract of soy isoflavones, which contained significant amounts of the soy isoflavone glycosides daidzin and genistin, by recombinant Escherichia coli expressing tyrosinase from Bacillus megaterium. Two major products were isolated from the biotransformation and identified as 3'-hydroxydaidzin and 3' hydroxygenistin, respectively, based on their mass and nuclear magnetic resonance spectral data. The two 3'-hydroxyisoflavone glycosides showed potent 2,2-diphenyl 1-picrylhydrazyl free radical scavenging activity with IC50 values of 7.4 and 9.8 MUM for 3'-hydroxydaidzin and 3'-hydroxygenistin, respectively. The free radical scavenging activities of the two 3'-hydroxyisoflavone glycosides were, respectively, 120 and 72 times higher than the activity of their precursors, daidzin and genistin, and were also stronger than the activity of ascorbic acid, which showed an IC50 value of 15.1 MUM. This is the first report of the bio production and potential antioxidant applications of both 3'-hydroxydaidzin and 3'-hydroxygenistin. PMID- 27983700 TI - Characterization of Starch Degradation Related Genes in Postharvest Kiwifruit. AB - Starch is one of the most important storage carbohydrates in plants. Kiwifruit typically accumulate large amounts of starch during development. The fruit retain starch until commercial maturity, and its postharvest degradation is essential for consumer acceptance. The activity of genes related to starch degradation has, however, rarely been investigated. Based on the kiwifruit genome sequence and previously reported starch degradation-related genes, 17 novel genes were isolated and the relationship between their expression and starch degradation was examined using two sets of materials: ethylene-treated (100 uL/L, 20 degrees C; ETH) vs. control (20 degrees C; CK) and controlled atmosphere stored (CA, 5% CO2 + 2% O2, 0 degrees C) vs. normal atmosphere in cold storage (NA, 0 degrees C). Physiological analysis indicated that ETH accelerated starch degradation and increased soluble solids content (SSC) and soluble sugars (glucose, fructose and sucrose), while CA inhibited starch reduction compared with NA. Using these materials, expression patterns of 24 genes that may contribute to starch degradation (seven previously reported and 17 newly isolated) were analyzed. Among the 24 genes, AdAMY1, AdAGL3 and AdBAM3.1/3L/9 were significantly induced by ETH and positively correlated with starch degradation. Furthermore, these five genes were also inhibited by CA, conforming the likely involvement of these genes in starch degradation. Thus, the present study has identified the genes with potential for involvement in starch degradation in postharvest kiwifruit, which will be useful for understanding the regulation of kiwifruit starch content and metabolism. PMID- 27983703 TI - Half-Sandwich Ru(II) Halogenido, Valproato and 4-Phenylbutyrato Complexes Containing 2,2'-Dipyridylamine: Synthesis, Characterization, Solution Chemistry and In Vitro Cytotoxicity. AB - Halogenido and carboxylato Ru(II) half-sandwich complexes of the general composition [Ru(eta6-p-cym)(dpa)X]PF6 (1-5) were prepared and thoroughly characterized with various techniques (e.g., mass spectrometry, NMR spectroscopy and X-ray analysis); dpa = 2,2'-dipyridylamine; p-cym = p-cymene; X = Cl- (for 1), Br- (for 2), I- (for 3), valproate(1-) (for 4) or 4-phenylbutyrate(1-) (for 5). A single-crystal X-ray analysis showed a pseudo-octahedral piano-stool geometry of [Ru(eta6-p-cym)(dpa)I]PF6 (3), with a eta6-coordinated p-cymene, bidentate N-donor dpa ligand and iodido ligand coordinated to the Ru(II) atom. The results of the 1H-NMR solution behaviour studies proved that the complexes 1 5 hydrolyse were in the mixture of solvents used (10% MeOD-d4/90% D2O). Complexes 1-5 were in vitro inactive against the A2780 human ovarian carcinoma cell line, up to the highest tested concentration (IC50 > 100 MUM). PMID- 27983704 TI - Thermal Property Analysis of Axle Load Sensors for Weighing Vehicles in Weigh-in Motion System. AB - Systems which permit the weighing of vehicles in motion are called dynamic Weigh in-Motion scales. In such systems, axle load sensors are embedded in the pavement. Among the influencing factors that negatively affect weighing accuracy is the pavement temperature. This paper presents a detailed analysis of this phenomenon and describes the properties of polymer, quartz and bending plate load sensors. The studies were conducted in two ways: at roadside Weigh-in-Motion sites and at a laboratory using a climate chamber. For accuracy assessment of roadside systems, the reference vehicle method was used. The pavement temperature influence on the weighing error was experimentally investigated as well as a non uniform temperature distribution along and across the Weigh-in-Motion site. Tests carried out in the climatic chamber allowed the influence of temperature on the sensor intrinsic error to be determined. The results presented clearly show that all kinds of sensors are temperature sensitive. This is a new finding, as up to now the quartz and bending plate sensors were considered insensitive to this factor. PMID- 27983701 TI - Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting. AB - Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases. PMID- 27983705 TI - Riboflavin Reduces Pro-Inflammatory Activation of Adipocyte-Macrophage Co culture. Potential Application of Vitamin B2 Enrichment for Attenuation of Insulin Resistance and Metabolic Syndrome Development. AB - Due to the progressive increase in the incidence of obese and overweight individuals, cardiometabolic syndrome has become a worldwide pandemic in recent years. Given the immunomodulatory properties of riboflavin, the current study was performed to investigate the potency of riboflavin in reducing obesity-related inflammation, which is the main cause of insulin resistance, diabetes mellitus 2 or arteriosclerosis. We determined whether pretreatment with a low dose of riboflavin (10.4-1000 nM) affected the pro-inflammatory activity of adipocyte macrophage co-culture (3T3 L1-RAW 264.7) following lipopolysaccharide stimulation (LPS; 100 ng/mL) which mimics obesity-related inflammation. The apoptosis of adipocytes and macrophages as well as tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), interleukin 1beta (IL-1beta), monocyte chemotactic protein 1 (MCP-1), high-mobility group box 1 (HMGB1), transforming growth factor-beta 1 (TGFbeta), interleukin 10 (IL-10), inducible nitric oxide synthase (iNOS), nitric oxide (NO), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1) expression and release, macrophage migration and adipokines (adiponectin and leptin) were determined. Our results indicated an efficient reduction in pro-inflammatory factors (TNFalpha, IL-6, MCP-1, HMGB1) upon culture with riboflavin supplementation (500-1000 nM), accompanied by elevation in anti-inflammatory adiponectin and IL-10. Moreover, macrophage migration was reduced by the attenuation of chemotactic MCP-1 release and degradation of the extracellular matrix by MMP-9. In conclusion, riboflavin effectively inhibits the pro-inflammatory activity of adipocyte and macrophage co cultures, and therefore we can assume that its supplementation may reduce the likelihood of conditions associated with the mild inflammation linked to obesity. PMID- 27983707 TI - Low-Cost GNSS Receivers for Local Monitoring: Experimental Simulation, and Analysis of Displacements. AB - The geodetic monitoring of local displacements and deformations is often needed for civil engineering structures and natural phenomena like, for example, landslides. A local permanent GNSS (Global Navigation Satellite Systems) network can be installed: receiver positions in the interest area are estimated and monitored with respect to reference stations. Usually, GNSS geodetic receivers are adopted and provide results with accuracies at the millimeter level: however, they are very expensive and the initial cost and the risk of damage and loss can discourage this approach. In this paper the accuracy and the reliability of low cost u-blox GNSS receivers are experimentally investigated for local monitoring. Two experiments are analyzed. In the first, a baseline (65 m long) between one geodetic reference receiver and one u-blox is continuously observed for one week: the data are processed by hourly sessions and the results provide comparisons between two processing packages and a preliminary accuracy assessment. Then, a network composed of one geodetic and two u-blox receivers is set up. One u-blox is installed on a device (slide) that allows to apply controlled displacements. The geodetic and the other u-blox (at about 130 m) act as references. The experiment lasts about two weeks. The data are again processed by hourly sessions. The estimated displacements of the u-blox on the slide are analyzed and compared with the imposed displacements. All of the results are encouraging: in the first experiment the standard deviations of the residuals are smaller than 5 mm both in the horizontal and vertical; in the second, they are slightly worse but still satisfactory (5 mm in the horizontal and 13 mm in vertical) and the imposed displacements are almost correctly identified. PMID- 27983706 TI - Latino and Non-Latino Perceptions of the Air Quality in California's San Joaquin Valley. AB - The San Joaquin Valley (SJV) of California has poor air quality, high rates of asthma, and high rates of obesity. Informational campaigns aimed at increasing awareness of the health impacts of poor air quality and promoting behavior change need to be tailored to the specific target audiences. The study examined perceptions of air quality, perceived health impacts, and methods of accessing information about air quality between Latinos and other groups in the SJV. Residents of the SJV (n = 744) where surveyed via one of three methods: community organizations (256), public locations (251), and an internet panel (237). The results suggest that people perceive the air quality in their region to be generally unhealthy, particularly for sensitive groups. The air quality is more likely to be reported as being unhealthy by people with health problems and less unhealthy by Latinos and people who report regularly exercising. Latinos are more likely to report working outdoors regularly, but also more likely to report being able to reduce their exposure if the air quality is unhealthy. The results report differences in informational sources about air quality, suggesting that informational campaigns should target high risk groups using a variety of media. PMID- 27983697 TI - alpha-Tocopherol and Hippocampal Neural Plasticity in Physiological and Pathological Conditions. AB - Neuroplasticity is an "umbrella term" referring to the complex, multifaceted physiological processes that mediate the ongoing structural and functional modifications occurring, at various time- and size-scales, in the ever-changing immature and adult brain, and that represent the basis for fundamental neurocognitive behavioral functions; in addition, maladaptive neuroplasticity plays a role in the pathophysiology of neuropsychiatric dysfunctions. Experiential cues and several endogenous and exogenous factors can regulate neuroplasticity; among these, vitamin E, and in particular alpha-tocopherol (alpha-T), the isoform with highest bioactivity, exerts potent effects on many plasticity-related events in both the physiological and pathological brain. In this review, the role of vitamin E/alpha-T in regulating diverse aspects of neuroplasticity is analyzed and discussed, focusing on the hippocampus, a brain structure that remains highly plastic throughout the lifespan and is involved in cognitive functions. Vitamin E-mediated influences on hippocampal synaptic plasticity and related cognitive behavior, on post-natal development and adult hippocampal neurogenesis, as well as on cellular and molecular disruptions in kainate-induced temporal seizures are described. Besides underscoring the relevance of its antioxidant properties, non-antioxidant functions of vitamin E/alpha-T, mainly involving regulation of cell signaling molecules and their target proteins, have been highlighted to help interpret the possible mechanisms underlying the effects on neuroplasticity. PMID- 27983708 TI - The HK2 Dependent "Warburg Effect" and Mitochondrial Oxidative Phosphorylation in Cancer: Targets for Effective Therapy with 3-Bromopyruvate. AB - This review summarizes the current state of knowledge about the metabolism of cancer cells, especially with respect to the "Warburg" and "Crabtree" effects. This work also summarizes two key discoveries, one of which relates to hexokinase 2 (HK2), a major player in both the "Warburg effect" and cancer cell immortalization. The second discovery relates to the finding that cancer cells, unlike normal cells, derive as much as 60% of their ATP from glycolysis via the "Warburg effect", and the remaining 40% is derived from mitochondrial oxidative phosphorylation. Also described are selected anticancer agents which generally act as strong energy blockers inside cancer cells. Among them, much attention has focused on 3-bromopyruvate (3BP). This small alkylating compound targets both the "Warburg effect", i.e., elevated glycolysis even in the presence oxygen, as well as mitochondrial oxidative phosphorylation in cancer cells. Normal cells remain unharmed. 3BP rapidly kills cancer cells growing in tissue culture, eradicates tumors in animals, and prevents metastasis. In addition, properly formulated 3BP shows promise also as an effective anti-liver cancer agent in humans and is effective also toward cancers known as "multiple myeloma". Finally, 3BP has been shown to significantly extend the life of a human patient for which no other options were available. Thus, it can be stated that 3BP is a very promising new anti-cancer agent in the process of undergoing clinical development. PMID- 27983709 TI - No Ifs, No Butts: Compliance with Smoking Cessation in Secondary Care Guidance (NICE PH48) by Providers of Cancer Therapies (Radiotherapy and Chemotherapy) in the UK. AB - Background: Legislation preventing smoking in public places was introduced in England in July 2007. Since then, smoke-free policies have been extended to the majority of hospitals including those providing cancer therapies. Whilst studies have been conducted on the impact and effectiveness of hospital smoke-free policy in the UK and other countries, there have not been any studies with a focus on cancer care providers. Cancer patients are a priority group for smoking cessation and support and this study aimed to examine implementation of the National Institute Clinical Excellence (NICE) guidance (PH48) in acute cancer care trusts in the UK. Methods: Participants were recruited from UK radiotherapy and chemotherapy departments (total 80 sites, 65 organisations) and asked to complete a 15 min online questionnaire exploring the implementation of NICE guidance at their hospital site. Results: Considerable variability in implementation of the NICE guidance was observed. A total of 79.1% trusts were smoke-free in theory; however, only 18.6% were described as smoke-free in practice. Areas of improvement were identified in information and support for patients and staff including in Nicotine Replacement Therapy (NRT) provision, staff training and clarity on e-cigarette policies. Conclusions: While some trusts have effective smoke-free policies and provide valuable cessation support services for patients, improvements are required to ensure that all sites fully adopt the NICE guidance. PMID- 27983711 TI - High Contributions of Secondary Inorganic Aerosols to PM2.5 under Polluted Levels at a Regional Station in Northern China. AB - Daily PM2.5 samples were collected at Shangdianzi (SDZ) regional site in Beijing Tianjin-Hebei (BTH) region in 2015. Samples were subject to chemical analysis for organic carbon (OC), elemental carbon (EC), and major water-soluble inorganic ions. The annual average PM2.5 mass concentration was 53 +/- 36 MUg.m-3 with the highest seasonal average concentration in spring and the lowest in summer. Water soluble inorganic ions and carbonaceous aerosols accounted for 34% +/- 15% and 33% +/- 9%, respectively, of PM2.5 mass on annual average. The excellent, good, lightly polluted, moderately polluted, and heavily polluted days based on the Air Quality Index (AQI) of PM2.5 accounted for 40%, 42%, 11%, 4%, and 3%, respectively, of the year. The sum of the average concentration of sulfate, nitrate, and ammonium (SNA) increased from 4.2 +/- 2.9 MUg.m-3 during excellent days to 85.9 +/- 22.4 MUg.m-3 during heavily polluted days, and their contributions to PM2.5 increased from 15% +/- 8% to 49% +/- 10% accordingly. In contrast, the average concentration of carbonaceous aerosols increased from 9.2 +/- 2.8 MUg.m-3 to 51.2 +/- 14.1 MUg.m-3, and their contributions to PM2.5 decreased from 34% +/- 6% to 29% +/- 7%. Potential source contribution function (PSCF) analysis revealed that the major sources for high PM2.5 and its dominant chemical components were within the area mainly covering Shandong, Henan, and Hebei provinces. Regional pollutant transport from Shanxi province and Inner Mongolia autonomous region located in the west direction of SDZ was also important during the heating season. PMID- 27983710 TI - Additive Interaction of MTHFR C677T and MTRR A66G Polymorphisms with Being Overweight/Obesity on the Risk of Type 2 Diabetes. AB - Although both methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms have been associated with type 2 diabetes (T2D), their interactions with being overweight/obesity on T2D risk remain unclear. To evaluate the associations of the two polymorphisms with T2D and their interactions with being overweight/obesity on T2D risk, a case-control study of 180 T2D patients and 350 healthy controls was conducted in northern China. Additive interaction was estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (S). After adjustments for age and gender, borderline significant associations of the MTHFR C677T and MTRR A66G polymorphisms with T2D were observed under recessive (OR = 1.43, 95% CI: 0.98-2.10) and dominant (OR = 1.43, 95% CI: 1.00-2.06) models, respectively. There was a significant interaction between the MTHFR 677TT genotype and being overweight/obesity on T2D risk (AP = 0.404, 95% CI: 0.047-0.761), in addition to the MTRR 66AG/GG genotypes (RERI = 1.703, 95% CI: 0.401-3.004; AP = 0.528, 95% CI: 0.223-0.834). Our findings suggest that individuals with the MTHFR 677TT or MTRR 66AG/GG genotypes are more susceptible to the detrimental effect of being overweight/obesity on T2D. Further large-scale studies are still needed to confirm our findings. PMID- 27983713 TI - Problem Formulation in Knowledge Discovery via Data Analytics (KDDA) for Environmental Risk Management. AB - With the growing popularity of data analytics and data science in the field of environmental risk management, a formalized Knowledge Discovery via Data Analytics (KDDA) process that incorporates all applicable analytical techniques for a specific environmental risk management problem is essential. In this emerging field, there is limited research dealing with the use of decision support to elicit environmental risk management (ERM) objectives and identify analytical goals from ERM decision makers. In this paper, we address problem formulation in the ERM understanding phase of the KDDA process. We build a DM3 ontology to capture ERM objectives and to inference analytical goals and associated analytical techniques. A framework to assist decision making in the problem formulation process is developed. It is shown how the ontology-based knowledge system can provide structured guidance to retrieve relevant knowledge during problem formulation. The importance of not only operationalizing the KDDA approach in a real-world environment but also evaluating the effectiveness of the proposed procedure is emphasized. We demonstrate how ontology inferencing may be used to discover analytical goals and techniques by conceptualizing Hazardous Air Pollutants (HAPs) exposure shifts based on a multilevel analysis of the level of urbanization (and related economic activity) and the degree of Socio-Economic Deprivation (SED) at the local neighborhood level. The HAPs case highlights not only the role of complexity in problem formulation but also the need for integrating data from multiple sources and the importance of employing appropriate KDDA modeling techniques. Challenges and opportunities for KDDA are summarized with an emphasis on environmental risk management and HAPs. PMID- 27983714 TI - A Real-Time Marker-Based Visual Sensor Based on a FPGA and a Soft Core Processor. AB - This paper introduces a real-time marker-based visual sensor architecture for mobile robot localization and navigation. A hardware acceleration architecture for post video processing system was implemented on a field-programmable gate array (FPGA). The pose calculation algorithm was implemented in a System on Chip (SoC) with an Altera Nios II soft-core processor. For every frame, single pass image segmentation and Feature Accelerated Segment Test (FAST) corner detection were used for extracting the predefined markers with known geometries in FPGA. Coplanar PosIT algorithm was implemented on the Nios II soft-core processor supplied with floating point hardware for accelerating floating point operations. Trigonometric functions have been approximated using Taylor series and cubic approximation using Lagrange polynomials. Inverse square root method has been implemented for approximating square root computations. Real time results have been achieved and pixel streams have been processed on the fly without any need to buffer the input frame for further implementation. PMID- 27983712 TI - Increased Urinary Phthalate Levels in Women with Uterine Leiomyoma: A Case Control Study. AB - We assessed the urinary concentration of 16 phthalate metabolites in 57 women with and without uterine leiomyoma (n = 30 and 27; respectively) to determine the association between phthalate exposure and uterine leiomyoma. To evaluate exposure to di-(2-ethylhexyl) phthalate (DEHP); we calculated the molar sum of DEHP metabolites; ?3-DEHP (combining mono-(2-ethylhexyl) phthalate (MEHP); mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP); and mono-(2-ethyl-5-oxohexyl) phthalate); ?4-DEHP (?3-DEHP plus mono-(2-ethyl-5-carboxypentyl) phthalate); and ?5-DEHP (?4-DEHP plus mono (2-(carboxylmethyl)hexyl) phthalate (2cx-MMHP)). The log transformed urinary levels of MEHP; MEHHP; 2cx-MMHP; ?3-DEHP; ?4-DEHP; and ?5 DEHP in the leiomyoma group were significantly higher than those of controls. When we adjusted for age; waist circumference; and parity using multiple logistic regression analyses; we found log ?3-DEHP (OR = 10.82; 95% CI = 1.25; 93.46) and ?4-DEHP (OR = 8.78; 95% CI = 1.03; 75.29) were significantly associated with uterine leiomyoma. Our findings suggest an association between phthalate exposure and uterine leiomyoma. However; larger studies are needed to investigate potential interactions between phthalate exposure and uterine leiomyoma. PMID- 27983715 TI - Fine Particulate Matter in Urban Environments: A Trigger of Respiratory Symptoms in Sensitive Children. AB - The overall objective of this research was to study children's respiratory illness levels in Targoviste (Romania) in relationship to the outdoor concentrations of airborne particulate matter with an aerodynamic diameter below 2.5 um (PM2.5). We monitored and analysed the PM2.5 concentrations according to a complex experimental protocol. The health trial was conducted over three months (October-December 2015) and required the active cooperation of the children's parents to monitor carefully the respiratory symptoms of the child, i.e., coughing, rhinorrhoea, wheezing, and fever, as well as their outdoor program. We selected the most sensitive children (n = 25; age: 2-10 years) with perturbed respiratory health, i.e., wheezing, asthma, and associated symptoms. The estimated average PM2.5 doses were 0.8-14.5 ug.day-1 for weekdays, and 0.4-6.6 ug.day-1 for the weekend. The frequency and duration of the symptoms decreased with increasing age. The 4- to 5-year old children recorded the longest duration of symptoms, except for rhinorrhoea, which suggested that this age interval is the most vulnerable to exogenous trigger agents (p < 0.01) compared to the other age groups. PM2.5 air pollution was found to have a direct positive correlation with the number of wheezing episodes (r = 0.87; p < 0.01) in November 2015. Monitoring of wheezing occurrences in the absence of fever can provide a reliable assessment of the air pollution effect on the exacerbation of asthma and respiratory disorders in sensitive children. PMID- 27983716 TI - The Optimisation of Pseudotyped Viruses for the Characterisation of Immune Responses to Equine Influenza Virus. AB - Pseudotyped viruses (PVs) produced by co-transfecting cells with plasmids expressing lentiviral core proteins and viral envelope proteins are potentially powerful tools for studying various aspects of equine influenza virus (EIV) biology. The aim of this study was to optimise production of equine influenza PVs. Co-transfection of the HAT protease to activate the haemagglutinin (HA) yielded a higher titre PV than TMPRSS2 with the HA from A/equine/Richmond/1/2007 (H3N8), whereas for A/equine/Newmarket/79 (H3N8), both proteases resulted in equivalent titres. TMPRSS4 was ineffective with the HA of either strain. There was also an inverse relationship between the amount of protease-expression plasmids and the PV titre obtained. Interestingly, the PV titre obtained by co transfection of a plasmid encoding the cognate N8 NA was not as high as that generated by the addition of exogenous neuraminidase (NA) from Clostridium perfringens to allow the release of nascent PV particles. Finally, initial characterisation of the reliability of PV neutralisation tests (PVNTs) demonstrated good intra-laboratory repeatability. In conclusion, we have demonstrated that equine influenza PV production can be readily optimised to provide a flexible tool for studying EIV. PMID- 27983717 TI - Evaluation of Methylation Biomarkers for Detection of Circulating Tumor DNA and Application to Colorectal Cancer. AB - Solid tumors shed DNA into circulation, and there is growing evidence that the detection of circulating tumor DNA (ctDNA) has broad clinical utility, including monitoring of disease, prognosis, response to chemotherapy and tracking tumor heterogeneity. The appearance of ctDNA in the circulating cell-free DNA (ccfDNA) isolated from plasma or serum is commonly detected by identifying tumor-specific features such as insertions, deletions, mutations and/or aberrant methylation. Methylation is a normal cell regulatory event, and since the majority of ccfDNA is derived from white blood cells (WBC), it is important that tumour-specific DNA methylation markers show rare to no methylation events in WBC DNA. We have used a novel approach for assessment of low levels of DNA methylation in WBC DNA. DNA methylation in 29 previously identified regions (residing in 17 genes) was analyzed in WBC DNA and eight differentially-methylated regions (DMRs) were taken through to testing in clinical samples using methylation specific PCR assays. DMRs residing in four genes, BCAT1, GRASP, IKZF1 and IRF4, exhibited low positivity, 3.5% to 7%, in the plasma of colonoscopy-confirmed healthy subjects, with the sensitivity for detection of ctDNA in colonoscopy-confirmed patients with colorectal cancer being 65%, 54.5%, 67.6% and 59% respectively. PMID- 27983718 TI - Adeno-associated virus-mediated expression of myostatin propeptide improves the growth of skeletal muscle and attenuates hyperglycemia in db/db mice. AB - Inhibition of myostatin, a negative growth modulator for muscle, can functionally enhance muscle mass and improve glucose and fat metabolism in myostatin propeptide (MPRO) transgenic mice. This study was to investigate whether myostatin inhibition by adeno-associated virus (AAV)-mediated gene delivery of MPRO could improve muscle mass and achieve therapeutic effects on glucose regulation and lipid metabolism in the db/db mice and the mechanisms involved in that process. Eight-week-old male db/db mice were administered saline, AAV-GFP and AAV-MPRO/Fc vectors and monitored random blood glucose levels and body weight for 36 weeks. Body weight gain was not different during follow-up among the groups, but AAV-MPRO/Fc vectors resulted high level of MPRO in the blood companied by an increase in skeletal muscle mass and muscle hypertrophy. In addition, AAV-MPRO/Fc-treated db/db mice showed significantly lower blood glucose and insulin levels and significantly increased glucose tolerance and insulin sensitivity compared with the control groups (P<0.05). Moreover, these mice exhibited lower triglyceride (TG) and free fatty acid (FFA) content in the skeletal muscle, although no difference was observed in fat pad weights and serum TG and FFA levels. Finally, AAV-MPRO/Fc-treated mice had enhanced insulin signaling in the skeletal muscle. These data suggest that AAV-mediated MPRO therapy may provide an important clue for potential clinical applications to prevent type II diabetes, and these studies confirm that MPRO is a therapeutic target for type II diabetes. PMID- 27983720 TI - Microbiota network and mathematic microbe mutualism in colostrum and mature milk collected in two different geographic areas: Italy versus Burundi. AB - Human milk is essential for the initial development of newborns, as it provides all nutrients and vitamins, such as vitamin D, and represents a great source of commensal bacteria. Here we explore the microbiota network of colostrum and mature milk of Italian and Burundian mothers using the auto contractive map (AutoCM), a new methodology based on artificial neural network (ANN) architecture. We were able to demonstrate the microbiota of human milk to be a dynamic, and complex, ecosystem with different bacterial networks among different populations containing diverse microbial hubs and central nodes, which change during the transition from colostrum to mature milk. Furthermore, a greater abundance of anaerobic intestinal bacteria in mature milk compared with colostrum samples has been observed. The association of complex mathematic systems such as ANN and AutoCM adopted to metagenomics analysis represents an innovative approach to investigate in detail specific bacterial interactions in biological samples. PMID- 27983719 TI - Convergent patterns in the evolution of mealybug symbioses involving different intrabacterial symbionts. AB - Mealybugs (Insecta: Hemiptera: Pseudococcidae) maintain obligatory relationships with bacterial symbionts, which provide essential nutrients to their insect hosts. Most pseudococcinae mealybugs harbor a unique symbiosis setup with enlarged betaproteobacterial symbionts ('Candidatus Tremblaya princeps'), which themselves contain gammaproteobacterial symbionts. Here we investigated the symbiosis of the manna mealybug, Trabutina mannipara, using a metagenomic approach. Phylogenetic analyses revealed that the intrabacterial symbiont of T. mannipara represents a novel lineage within the Gammaproteobacteria, for which we propose the tentative name 'Candidatus Trabutinella endobia'. Combining our results with previous data available for the nested symbiosis of the citrus mealybug Planococcus citri, we show that synthesis of essential amino acids and vitamins and translation-related functions partition between the symbiotic partners in a highly similar manner in the two systems, despite the distinct evolutionary origin of the intrabacterial symbionts. Bacterial genes found in both mealybug genomes and complementing missing functions in both symbioses were likely integrated in ancestral mealybugs before T. mannipara and P. citri diversified. The high level of correspondence between the two mealybug systems and their highly intertwined metabolic pathways are unprecedented. Our work contributes to a better understanding of the only known intracellular symbiosis between two bacteria and suggests that the evolution of this unique symbiosis included the replacement of intrabacterial symbionts in ancestral mealybugs. PMID- 27983721 TI - Fungal-bacterial dynamics and their contribution to terrigenous carbon turnover in relation to organic matter quality. AB - Ecological functions of fungal and bacterial decomposers vary with environmental conditions. However, the response of these decomposers to particulate organic matter (POM) quality, which varies widely in aquatic ecosystems, remains poorly understood. Here we investigated how POM pools of substrates of different qualities determine the relative contributions of aquatic fungi and bacteria to terrigenous carbon (C) turnover. To this end, surface sediments were incubated with different POM pools of algae and/or leaf litter. 13C stable-isotope measurements of C mineralization were combined with phospholipid analysis to link the metabolic activities and substrate preferences of fungal and bacterial heterotrophs to dynamics in their abundance. We found that the presence of labile POM greatly affected the dominance of bacteria over fungi within the degrader communities and stimulated the decomposition of beech litter primarily through an increase in metabolic activity. Our data indicated that fungi primarily contribute to terrigenous C turnover by providing litter C for the microbial loop, whereas bacteria determine whether the supplied C substrate is assimilated into biomass or recycled back into the atmosphere in relation to phosphate availability. Thus, this study provides a better understanding of the role of fungi and bacteria in terrestrial-aquatic C cycling in relation to environmental conditions. PMID- 27983722 TI - Photosynthetic temperature adaptation during niche diversification of the thermophilic cyanobacterium Synechococcus A/B clade. AB - We take an in vivo fluorescence approach to investigate photosynthetic adaptation by ecologically divergent members of the A/B clade of the hot spring cyanobacterium Synechococcus, the most thermotolerant of which defines the upper thermal limit for photosynthesis. During Synechococcus diversification, both photosystem II and the light-harvesting phycobilisome have evolved greater thermostability as the group has invaded higher temperature habitats, particularly for the most thermotolerant lineage. This enhanced function at higher temperatures has come at the cost of reduced performance at lower temperatures, and these trade-offs contribute to niche specialization in the clade. Molecular evolutionary analyses revealed specific adaptive protein changes in the most thermotolerant lineage. Our study advances our understanding of the origins of Synechococcus diversity. PMID- 27983723 TI - Viruses and the origin of microbiome selection and immunity. AB - The last common metazoan ancestor (LCMA) emerged over half a billion years ago. These complex metazoans provided newly available niche space for viruses and microbes. Modern day contemporaries, such as cnidarians, suggest that the LCMA consisted of two cell layers: a basal endoderm and a mucus-secreting ectoderm, which formed a surface mucus layer (SML). Here we propose a model for the origin of metazoan immunity based on external and internal microbial selection mechanisms. In this model, the SML concentrated bacteria and their associated viruses (phage) through physical dynamics (that is, the slower flow fields near a diffusive boundary layer), which selected for mucin-binding capabilities. The concentration of phage within the SML provided the LCMA with an external microbial selective described by the bacteriophage adherence to mucus (BAM) model. In the BAM model, phage adhere to mucus protecting the metazoan host against invading, potentially pathogenic bacteria. The same fluid dynamics that concentrated phage and bacteria in the SML also concentrated eukaryotic viruses. As eukaryotic viruses competed for host intracellular niche space, those viruses that provided the LCMA with immune protection were maintained. If a resident virus became pathogenic or if a non-beneficial infection occurred, we propose that tumor necrosis factor (TNF)-mediated programmed cell death, as well as other apoptosis mechanisms, were utilized to remove virally infected cells. The ubiquity of the mucosal environment across metazoan phyla suggest that both BAM and TNF-induced apoptosis emerged during the Precambrian era and continue to drive the evolution of metazoan immunity. PMID- 27983724 TI - Helminth burden and ecological factors associated with alterations in wild host gastrointestinal microbiota. AB - Infection by gastrointestinal helminths of humans, livestock and wild animals is common, but the impact of such endoparasites on wild hosts and their gut microbiota represents an important overlooked component of population dynamics. Wild host gut microbiota and endoparasites occupy the same physical niche spaces with both affecting host nutrition and health. However, associations between the two are poorly understood. Here we used the commonly parasitized European shag (Phalacrocorax aristotelis) as a model wild host. Forty live adults from the same colony were sampled. Endoscopy was employed to quantify helminth infection in situ. Microbiota from the significantly distinct proventriculus (site of infection), cloacal and faecal gastrointestinal tract microbiomes were characterised using 16S rRNA gene-targeted high-throughput sequencing. We found increasingly strong associations between helminth infection and microbiota composition progressing away from the site of infection, observing a pronounced dysbiosis in microbiota when samples were partitioned into high- and low-burden groups. We posit this dysbiosis is predominately explained by helminths inducing an anti-inflammatory environment in the proventriculus, diverting host immune responses away from themselves. This study, within live wild animals, provides a vital foundation to better understand the mechanisms that underpin the three-way relationship between helminths, microbiota and hosts. PMID- 27983725 TI - A gene expression inflammatory signature specifically predicts multiple myeloma evolution and patients survival. AB - Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory/immunosuppressive bone marrow milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune-impairment. We investigated the relevance of inflammatory genes in predicting disease evolution and patient survival. A bioinformatics study by Ingenuity Pathway Analysis on gene expression profiling dataset of monoclonal gammopathy of undetermined significance, smoldering and symptomatic-MM, identified inflammatory and cytokine/chemokine pathways as the most progressively affected during disease evolution. We then selected 20 candidate genes involved in B-cell inflammation and we investigated their role in predicting clinical outcome, through univariate and multivariate analyses (log rank test, logistic regression and Cox-regression model). We defined an 8-genes signature (IL8, IL10, IL17A, CCL3, CCL5, VEGFA, EBI3 and NOS2) identifying each condition (MGUS/smoldering/symptomatic-MM) with 84% accuracy. Moreover, six genes (IFNG, IL2, LTA, CCL2, VEGFA, CCL3) were found independently correlated with patients' survival. Patients whose MM cells expressed high levels of Th1 cytokines (IFNG/LTA/IL2/CCL2) and low levels of CCL3 and VEGFA, experienced the longest survival. On these six genes, we built a prognostic risk score that was validated in three additional independent datasets. In this study, we provide proof-of-concept that inflammation has a critical role in MM patient progression and survival. The inflammatory-gene prognostic signature validated in different datasets clearly indicates novel opportunities for personalized anti-MM treatment. PMID- 27983726 TI - Risk stratification in myeloma by detection of circulating plasma cells prior to autologous stem cell transplantation in the novel agent era. AB - The impact of circulating plasma cells (CPCs) prior to autologous stem cell transplantation (ASCT) for multiple myeloma has not been defined in the novel agent era. We evaluated the impact of pre-transplant CPCs, detected by six-color flow cytometry in patients undergoing early ASCT on post-transplant response, progression-free survival (PFS) and overall survival (OS). CPCs were detected in 162 out of 840 (19.3%) patients, with the median number of CPCs being 58 per 150 000 events. Ninety-nine percent of patients had received proteasome inhibitor and/or immunomodulator-based induction. The incidence of post-transplant stringent complete response (sCR) in the subgroups with and without CPCs was 15% and 38%, respectively, (P<0.001). The median PFS in the subgroups with and without CPCs was 15.1 (95% confidence interval (CI), 12.5-17.8) and 29.6 months (95% CI, 26.2-32.8), respectively, and the median OS was 41.0 months (95% CI, 32.6-58.2) and not reached (NR) (95% CI, 99.1-NR), respectively, (P<0.001 for both). On multivariate analysis for OS, factors independently predictive of mortality were the presence of CPCs (hazard ratio (HR) 2.5; 95% CI, 1.8-3.6; P<0.001) and sCR post transplant (HR 0.4; 95% CI, 0.2-0.6; P<0.001). Presence of CPCs prior to transplant has a high prognostic impact and should be prospectively validated in clinical trials. PMID- 27983727 TI - The complexity of interpreting genomic data in patients with acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the accumulation of complex genetic alterations responsible for the initiation and progression of the disease. Translating genomic information into clinical practice remained challenging with conflicting results regarding the impact of certain mutations on disease phenotype and overall survival (OS) especially when clinical variables are controlled for when interpreting the result. We sequenced the coding region for 62 genes in 468 patients with secondary AML (sAML) and primary AML (pAML). Overall, mutations in FLT3, DNMT3A, NPM1 and IDH2 were more specific for pAML whereas UTAF1, STAG2, BCORL1, BCOR, EZH2, JAK2, CBL, PRPF8, SF3B1, ASXL1 and DHX29 were more specific for sAML. However, in multivariate analysis that included clinical variables, only FLT3 and DNMT3A remained specific for pAML and EZH2, BCOR, SF3B1 and ASXL1 for sAML. When the impact of mutations on OS was evaluated in the entire cohort, mutations in DNMT3A, PRPF8, ASXL1, CBL EZH2 and TP53 had a negative impact on OS; no mutation impacted OS favorably; however, in a cox multivariate analysis that included clinical data, mutations in DNMT3A, ASXL1, CBL, EZH2 and TP53 became significant. Thus, controlling for clinical variables is important when interpreting genomic data in AML. PMID- 27983728 TI - Safety and acceptability of an organic light-emitting diode sleep mask as a potential therapy for retinal disease. AB - PurposeThe purpose of the study was to study the effect of an organic light emitting diode sleep mask on daytime alertness, wellbeing, and retinal structure/function in healthy volunteers and in diabetic macular oedema (DMO).Patients and methodsHealthy volunteers in two groups, 18-30 yrs (A), 50-70 yrs (B) and people with DMO (C) wore masks (504 nm wavelength; 80 cd/m2 luminance; <=8 h) nightly for 3 months followed by a 1-month recovery period. Changes from baseline were measured for (means): psychomotor vigilance task (PVT) (number of lapses (NL), response time (RT)), sleep, depression, psychological wellbeing (PW), visual acuity, contrast sensitivity, colour, electrophysiology, microperimetry, and retinal thickness on OCT.ResultsOf 60 participants, 16 (27%) withdrew, 8 (13%) before month 1, due to sleep disturbances and mask intolerance. About 36/55 (65%) who continued beyond month 1 reported >=1 adverse event. At month 3 mean PVT worsened in Group A (RT (7.65%, P<0.001), NL (43.3%, P=0.005)) and mean PW worsened in all groups (A 28.0%, P=0.01, B 21.2%, P=0.03, C 12.8%, P<0.05). No other clinically significant safety signal was detected. Cysts reduced/resolved in the OCT subfield of maximal pathology in 67% Group C eyes. Thinning was greater at 3 and 4 months for greater baseline thickness (central subfield P<0.001, maximal P<0.05).ConclusionSleep masks showed no major safety signal apart from a small impairment of daytime alertness and a moderate effect on wellbeing. Masks were acceptable apart from in some healthy participants. Preliminary data suggest a beneficial effect on retinal thickness in DMO. This novel therapeutic approach is ready for large clinical trials. PMID- 27983730 TI - Comment on: 'Effect of smoking on retrobulbar blood flow in thyroid eye disease'. PMID- 27983729 TI - Genetic screening in Iranian patients with retinoblastoma. AB - PurposeThe most common intraocular tumor in childhood, retinoblastoma, is largely associated with mutations in the RB1 gene. In the most comprehensive RB1 screening in Iran, we evaluated the RB1 mutations in 106 patients with retinoblastoma, including 73 bilateral (heritable) and 33 unilateral (sporadic) cases.Patients and methodsMutations were identified using amplification refractory mutation system (ARMS) PCR and direct sequencing of the 27 coding exons of RB1 and multiplex ligation-dependent probe amplification (MLPA).Results and ConclusionWe found 33 (31%) and 64 (60%) patients with sporadic unilateral and bilateral retinoblastoma, respectively as well as 9 (8.5%) cases with hereditary bilateral retinoblastoma. In total, we identified 52 causative RB1 mutations in 106 patients (global mutation rate of 49%). Of the 52 patients, 48 (92%) had sporadic and familial bilateral and 4 (8%) had sporadic unilateral RB. Therefore, the detection rate of RB1 mutations was 66% (48/73) and 12% (4/33) in bilateral and unilateral cases, respectively. Mutations were classified as nonsense in 31 (60%), missense in 1 (2%), large deletion in 11 (21%), small deletion in the 7 novel (15%) and splice site mutation in 2 (4%) patients with RB. Of 31 nonsense mutations, 23 (74%) occurred in the 11 Arginine codons of the RB1. Seven mutations (13%) were novel, and 45 (87%) had been previously reported. Thirty-three mutations were single-base substitutions leading to 31 nonsense amino acid changes and 2 splice site mutations in introns 12 and 16 of RB1. The altered 3D model structures of the RB1 novel mutant proteins are also predicted in this study. PMID- 27983731 TI - Whole-eye transplantation: a look into the past and vision for the future. AB - Blindness afflicts ~39 million people worldwide. Retinal ganglion cells are unable to regenerate, making this condition irreversible in many cases. Whole-eye transplantation (WET) provides the opportunity to replace diseased retinal ganglion cells, as well as the entire optical system and surrounding facial tissue, if necessary. Recent success in face transplantation demonstrates that this may be a promising treatment for what has been to this time an incurable condition. An animal model for WET must be established to further enhance our knowledge of nerve regeneration, immunosuppression, and technical aspects of surgery. A systematic review of the literature was performed to evaluate studies describing animal models for WET. Only articles in which the eye was completely enucleated and reimplanted were included. Study methods and results were compared. In the majority of published literature, WET can result in recovery of vision in cold-blooded vertebrates. There are a few instances in which mammalian WET models demonstrate survival of the transplanted tissue following neurovascular anastomosis and the ability to maintain brief electroretinogram activity in the new host. In this study we review in cold-blooded vertebrates and mammalian animal models for WET and discuss prospects for future research for translation to human eye transplantation. PMID- 27983732 TI - Why autophagy is good for retinal ganglion cells? AB - Autophagy is a catabolic pathway that promotes the degradation and recycling of cellular components. Proteins, lipids, and even whole organelles are engulfed in autophagosomes and delivered to the lysosome for elimination. In response to stress, autophagy mediates the degradation of cell components, which are recycled to generate the nutrients and building blocks required to sustain cellular homeostasis. Moreover, it has an important role in cellular quality control, particularly in neurons, in which the total burden of altered proteins and damaged organelles cannot be reduced by redistribution to daughter cells through cell division. Autophagy occurs in all cells and tissues, and it is regulated by the Atg genes. The importance of this pathway has been recently recognized by the Nobel Prize in Physiology and Medicine award to Professor Yoshinori Ohsumi who was the discoverer of the first Atg genes in yeast in the 1990s. Research has only begun to examine the role of autophagy in the visual system. Both the retina and the eye are exposed to a variety of environmental insults and stressors, including genetic mutations and age-associated alterations that impair their function. Here, we review studies that have sought to explain autophagy's importance for retinal ganglion cells, and their implications for diseases like glaucoma and optic neuropathies. PMID- 27983733 TI - Caffeine intake is associated with pupil dilation and enhanced accommodation. AB - PurposeIt is purported that caffeine, an autonomic stimulant, affects visual performance. This study sought to assess whether caffeine intake was associated with changes in pupil size and/or amplitude of accommodation.Patients and methodsA double-masked, crossover study was conducted in 50 healthy subjects of age range 19 to 25 years. Subjects were randomized to treatments such that subjects consumed either 250 mg caffeine drink or vehicle on separate days. Amplitude of accommodation was measured by the push-up technique, and pupil size using a millimeter ruler fixed to a slit lamp biomicroscope in dim illumination (5 lux). Amplitude of accommodation and pupil size were taken at baseline, and at 30, 60 and 90 min time points post treatment. Repeated measures one-way ANOVA and paired t-test were used in analyzing data.ResultsAmplitude of accommodation and pupil size after caffeine intake were significantly greater than vehicle (P<0.001) at each time point. Consumption of the caffeine beverage was associated with significant increases in amplitude of accommodation and pupil size with time (P<0.001). Amplitude of accommodation rose from 12.4 (+/-2.2 D) at baseline to 15.8(+/-2.6 D) at 90 min. Similarly, pupil size increased from 3.4 (+/-0.4 mm) at baseline to 4.5 (+/-0.72 mm) at 90 min. Consumption of vehicle was not associated with increase in amplitude of accommodation or pupil size with time.ConclusionPupil size and accommodation are affected after ingestion of caffeine. This study suggests caffeine may have some influence on visual functions. PMID- 27983735 TI - Dyslipidaemia: Predicting the benefits and risks of PCSK9 inhibition. PMID- 27983734 TI - Clinical outcomes of Ahmed glaucoma valve in anterior chamber versus ciliary sulcus. AB - PurposeTo evaluate the outcomes of Ahmed glaucoma valve (AGV) tube insertion through the anterior chamber angle (ACA) or through the ciliary sulcus (CS).Patients and methodsIn this case-control study, we retrospectively reviewed the charts of consecutive glaucoma patients who had undergone AGV implantation either through the ACA or the CS between March 2009 and December 2014. The main outcome measures were intraocular pressure (IOP), number of glaucoma medications prescribed, best corrected visual acuity (BCVA), glaucoma type, success rate, complications, and survival ratios. Statistical analysis was carried out using SPSS.ResultsThere were 68 eyes in the ACA group and 35 eyes in the CS group. There were no significant differences between the groups for age, sex, laterality, IOP, preoperative glaucoma medication number, BCVA or glaucoma type (P>0.05). The postoperative follow-up period was 27.2+/-16.5 months and 30.2+/ 17.7 months for the ACA and the CS groups (P=0.28); IOP values were significantly reduced at the last visit to 16.4+/-7.2 mm Hg and 14.4+/-6.8 mm Hg. The difference in the last-visit IOP between the groups was not significant (P=0.06), but the IOP reduction ratio was higher in the CS group (P=0.03). There was no significant difference in the number of postoperative medications (P=0.18). Postoperative complications were similar, but the incidence of flat anterior chamber was higher in the ACA group (P=0.05).ConclusionsThe use of an AGV can control IOP in the majority of cases whether placed in the ACA or the CS. The IOP reduction ratio seemed to be higher in the CS group. PMID- 27983737 TI - Obesity: Obesity alters fatty acid sensing. PMID- 27983736 TI - FGF21 and metabolic disease in 2016: A new frontier in FGF21 biology. PMID- 27983738 TI - To each his own: isonitriles for all flavors. Functionalized isocyanides as valuable tools in organic synthesis. AB - The term functionalized isocyanides refers to all those isocyanides in which a neighbouring functional group can finely tune the reactivity of the isocyano group or can be exploited in post-functionalization processes. In this manuscript, we have reviewed all the isocyanides in which the pendant functional group causes either deviation from or reinforces the normal reactivity of the isocyano group and categorized them to highlight their common features and differences. An analysis of their synthetic potential and the possible unexplored directions for future research studies is also addressed. PMID- 27983739 TI - Effiectiveness and safety of transcranial direct current stimulation in fibromyalgia: A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the effectiveness and safety of transcranial direct current stimulation for fibro-myalgia. METHODS: Databases, conference records and registered trials were searched for articles published from the date of establishment of the database through to October 2015. Six randomized controlled trials (n=192) of transcranial direct current stimulation for fibromyalgia were included in the current study. DATA EXTRACTION: Two researchers independently screened the literature, assessed methodological quality using the Cochrane Collaboration's tool, and extracted data. DATA SYNTHESIS: Studies were divided into 3 groups for meta-analysis according to stimulation site and polarity. Significant improvement in pain and general fibromyalgia-related function was seen with anodal transcranial direct current stimulation over the primary motor cortex (p<0.05). However, the pressure pain threshold did not improve (p>0.05). Anodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex did not significantly reduce pain or improve general fibromyalgia-related function compared with sham stimulation (p>0.05). Cathodal transcranial direct current stimulation over the primary motor cortex did not improve the pressure pain threshold compared with sham stimulation (p>0.05). No significant adverse effects were seen. CONCLUSION: Anodal transcranial direct current stimulation over the primary motor cortex is more likely than sham transcranial direct current stimulation to relieve pain and improve general fibromyalgia-related function. PMID- 27983740 TI - Efficacy of Body Lotion Containing N-palmitoylethanolamine in Subjects with Chronic Pruritus due to Dry Skin: A Dermatocosmetic Study. PMID- 27983741 TI - Psoriatic Arthritis, but not Psoriasis, is Associated with Primary Adrenal Insufficiency. PMID- 27983742 TI - Double-ended Pseudocomedones in Hidradenitis Suppurativa: Clinical, Dermoscopic, and Histopatho-logical Correlation. PMID- 27983743 TI - Expression of Antimicrobial Peptides in Nail Psoriasis and Normal Nails. PMID- 27983744 TI - ItchApp(c): An App-based eDiary for Assessment of Chronic Pruritus in Clinical Trials. AB - Performing a reliable assessment of chronic pruritus remains a challenge. Electronic diaries are often used, but many of the scales have not been validated. ItchApp(c) was developed for Android smartphones in order to address this lack. A total of 40 subjects with chronic pruritus completed questionnaires both on paper and with ItchApp(c) (verbal rating scale, numerical rating scale, dynamic pruritus score) in order to validate the software application. Strong correlations were found for test-retest reliability (intraclass correlation coefficient: 0.865-0.977) and convergent validity (Spearman's r: 0.442-0.924). A feasibility questionnaire for ItchApp(c) revealed a high level of user friendliness and compliance. This was confirmed in a randomized controlled trial with 68 subjects, for which the clinically important difference in the numerical rating scale values for ItchApp(c) was calculated (2.61 points). In summary, ItchApp(c) is a recently developed eDiary that can provide experts with a reliable evaluation of patients with chronic pruritus. It will be made available for future clinical trials. PMID- 27983745 TI - Health-related Quality of Life in Children and Adolescents with Psoriasis: A Systematic Review and Meta-analysis. AB - Studies demonstrating the negative impact of paediatric psoriasis on health related quality of life (HRQOL) are accumulating, but little is known about moderators of HRQOL. The objectives of this review were to summarize studies on HRQOL in paediatric psoriasis and to explore the potential moderating influences of demographic and clinical variables. Searches were conducted by 2 independent researchers in PubMed, Embase, CINAHL, PsycINFO, and Scopus for papers published between 1995 (the date the first dermatology-specific HRQOL-instrument for children was introduced) and 2016. Eligible studies were required to report HRQOL data for children and/or adolescents with psoriasis (4-18 years) using validated HRQOL questionnaires. Seven-teen eligible studies (number of patients=1,185) were identified. Moderation analyses revealed that study samples with a higher percentage of girls were associated with better HRQOL (beta = 0.19), while a higher mean age of onset (beta = 0.83) and study quality (beta = 0.28) were associated with lower HRQOL (all p<0.05). Several papers did not provide the information necessary for exploring between-study differences, thus the moderation analysis results should be interpreted with caution. In conclusion, children and adolescents with psoriasis experience moderate impairment of HRQOL. Certain demographic characteristics (e.g. sex) and clinical characteristics (e.g. age at onset) appear to moderate this impact. PMID- 27983746 TI - Increased Serum Levels of Th2-type Cytokines and Eotaxin in Fibrillar-type Dermatitis Herpetiformis. PMID- 27983747 TI - Laboratory and Clinical Monitoring of Direct Acting Oral Anticoagulants: What Clinicians Need to Know. AB - The direct acting oral anticoagulants (DOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, have favorable pharmacokinetic and pharmacodynamic properties and equal or superior efficacy and an improved safety profile compared with warfarin. Noted shortcomings with DOACs are shorter half-lives requiring stricter adherence, lack of standardized laboratory monitoring, lack of anticoagulation reversal agents, and loss of routine coagulation monitoring leading to fewer patient-clinician interactions. This review addresses many of these limitations including monitoring of DOACs for efficacy and toxicity, an assessment of selected qualitative and quantitative tests, and development of monitoring strategies for special populations. Coagulation monitoring is generally recommended only in overdose situations, but once standardized assays are readily available, they could be helpful to ensure efficacy, assess bleeding, and aid in drug selection in a number of other patient scenarios. Coagulation tests that may provide qualitative assessment include activated partial thromboplastin time, prothrombin time, and thrombin time. Methods with potential utility for quantitative assessment of DOACs include plasma drug concentrations, ecarin clotting time, dilute thrombin time, and anti-factor Xa concentrations. Noncoagulation laboratory monitoring should include serum creatinine, liver function tests, and complete blood counts. Clinical monitoring of the DOAC treated patient should include routine assessment of adherence, bleeding risks, and drug interactions. Frequency of monitoring should be 1-3 months after initiation and then at least every 6 months, with more frequent follow-up (i.e., 3 months) based on patient specific characteristics such as age, renal impairment, hepatic impairment, and concomitant drug therapy. The authors provide a practical tool to assist in DOAC monitoring and recommend that pharmacists collaborate with physicians in selecting appropriate patients and tailoring patient-specific monitoring plans. PMID- 27983748 TI - "For Me It Was a Key Moment of Therapy": Corrective Experience From the Client's Perspective. AB - Despite recent attempts to develop a consensus definition, questions still remain as to what constitutes corrective experiences (CEs) in psychotherapy and how clients perceive them. This qualitative study assessed clients' first person accounts of CEs associated with their own treatment-related changes. Participants were 8 clients in private psychotherapy in Buenos Aires. Treatment, by therapists from diverse theoretical backgrounds, varied from 4 to 24 months. The Patients' Perceptions of Corrective Experiences in Individual Therapy interview protocol was used to assess clients' perceptions of CEs at posttreatment. All interviews were audiorecorded and transcribed and submitted to a 2-stage thematic analysis to assess CEs and the contextual factors that contributed to them. Of the 8 participants, 5 narrated stories about CEs that changed the way they thought about themselves and their behavior. Additionally, clients highlighted disconfirmation of therapist role expectations and surprise regarding therapists' actions and behaviors as mechanisms of these corrective moments. PMID- 27983749 TI - Social and emotional loneliness and self-reported difficulty initiating and maintaining sleep (DIMS) in a sample of Norwegian university students. AB - Social and emotional loneliness negatively impact several areas of health, including sleep. However, few comprehensive population-based studies have evaluated this relationship. Over 12,000 students aged 21-35 years who participated in the student survey for higher education in Norway (the SHoT study) were assessed. Loneliness was assessed using the Social and Emotional Loneliness Scale. Difficulty initiating and maintaining sleep (DIMS) was assessed by a single-item subjective response on the depression scale of the Hopkins Symptoms Checklist (HSCL-25). Social loneliness was associated with more serious DIMS (unadjusted proportional odds-ratio [OR] = 2.69, 95% CI = 2.46-2.95). This association was attenuated following adjustment for anxiety (adjusted OR = 1.92, 95% CI = 1.75-2.10) and depression (adjusted OR = 1.48, 95% CI = 1.34-1.63), however was not substantially altered when all demographics and psychological distress were accounted for (fully adjusted OR = 1.46, 95% CI = 1.30-1.63). Emotional loneliness was also associated with more serious DIMS (unadjusted proportional OR = 2.33, 95% CI = 2.12-2.57). Adjustment for anxiety (adjusted OR = 1.96, 95% CI = 1.78-2.15) and depression (adjusted OR = 1.64, 95% CI = 1.48 1.80) attenuated, but did not extinguish this relationship in the fully adjusted model (adjusted OR = 1.22, 95% CI = 1.09-1.31). Mediation analyses revealed that the social loneliness-DIMS association was fully attributed to psychological distress, while the emotional loneliness-DIMS association was only partially mediated, and a direct association was still observed. Associations between social and emotional loneliness and subjective DIMS were embedded in a larger pattern of psychological distress. Mitigating underlying feelings of loneliness may reduce potentially deleterious effects on sleep health and psychological wellbeing in young adults. PMID- 27983750 TI - Cognitive Coping as a Mechanism of Change in Cognitive-Behavioral Therapy for Fear of Flying: A Longitudinal Study With 3-Year Follow-Up. AB - OBJECTIVE: To examine the predictive value of cognitive coping strategies at pretreatment and the value of changes in these strategies during cognitive behavioral treatment for aviophobia for long-term therapy results. METHOD: Data from baseline, after therapy at 2 months, short-term follow-up at 5 months, and long-term follow-up at 41 months were analyzed (N = 59). RESULTS: Participants were in a long-term process of change, which continued positively after therapy for maladaptive cognitive coping strategies. The use of cognitive coping strategies at baseline was not predictive of long-term outcome. However, a greater increase in the use of adaptive coping strategies, and more importantly, a greater decrease in the use of maladaptive coping strategies were predictive of improvements indicated in self-report of flight anxiety and actual flight behavior at long-term follow-up. CONCLUSION: Improvement of maladaptive cognitive coping strategies is possibly a key mechanism of change in cognitive-behavioral therapy for aviophobia. PMID- 27983751 TI - Muscle glycogen: where did you come from, where did you go? PMID- 27983753 TI - Effectiveness and Safety of Tigecycline Compared with Other Broad-Spectrum Antimicrobials in Abdominal Solid Organ Transplant Recipients with Polymicrobial Intraabdominal Infections. AB - STUDY OBJECTIVE: Because patients with abdominal solid organ transplants (SOTs) are at increased risk of polymicrobial intraabdominal infections (IAIs) following transplantation, the objective of this study was to compare the effectiveness and adverse event profile of tigecycline with those of other broad-spectrum therapies for polymicrobial IAIs in this population. DESIGN: Retrospective cohort study. SETTING: Large academic medical center with multiple outpatient clinics. PATIENTS: A total of 81 adult SOT recipients were included who were treated for confirmed or suspected polymicrobial IAIs from 2007-2012. Of these patients, 27 received tigecycline and 54 received comparator therapy with a broad-spectrum beta-lactam (e.g., piperacillin-tazobactam, cefepime, or meropenem) with or without glycopeptide or lipopeptide gram-positive therapy (vancomycin or daptomycin) (comparator group). Patients in the comparator group were matched to tigecycline-treated patients based on transplant type (kidney, combined kidney pancreas, combined kidney-liver, or solitary pancreas) in a 1:2 ratio (tigecycline-to-other broad-spectrum antibiotics). MEASUREMENTS AND MAIN RESULTS: Data on patient demographics, comorbidities, and clinical variables were collected and compared by using bivariate analyses. Clinical outcomes-clinical cure, improvement or failure, and disease recurrence-as well as death within 1 year were analyzed by bivariate analyses and logistic regression. Clinical cure was lower in the tigecycline group versus the comparator group (40.7% vs 72.2%, p=0.008), but cure combined with improvement was similar between the two groups (85.2% vs 88.9%, p=0.724). Multiple logistic regression analysis showed that treatment with comparator antibiotics increased the odds of cure (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.15-12.27) and reduced the odds of treatment failure (OR 0.59, 95% CI 0.07-4.55) and death within 1 year (OR 0.79, 95% CI 0.22 2.86); however, patients receiving comparator antibiotics were more likely to have disease recurrence (OR 1.45, 95% CI 0.33-6.36). Patients receiving tigecycline experienced a higher rate of adverse events than those receiving comparator antibiotics (29.6% vs 9.3%, p=0.026). CONCLUSION: Patients receiving tigecycline were less likely to achieve optimal clinical outcomes and had more adverse events. Alternative regimens should be selected over tigecycline for the treatment of polymicrobial IAIs in abdominal SOT recipients until additional studies are completed to examine its role in this population. PMID- 27983755 TI - The known unknown. PMID- 27983754 TI - Estimating the prevalence of atrial fibrillation from a three-class mixture model for repeated diagnoses. AB - Atrial fibrillation (AF) is an abnormal heart rhythm characterized by rapid and irregular heartbeat, with or without perceivable symptoms. In clinical practice, the electrocardiogram (ECG) is often used for diagnosis of AF. Since the AF often arrives as recurrent episodes of varying frequency and duration and only the episodes that occur at the time of ECG can be detected, the AF is often underdiagnosed when a limited number of repeated ECGs are used. In studies evaluating the efficacy of AF ablation surgery, each patient undergoes multiple ECGs and the AF status at the time of ECG is recorded. The objective of this paper is to estimate the marginal proportions of patients with or without AF in a population, which are important measures of the efficacy of the treatment. The underdiagnosis problem is addressed by a three-class mixture regression model in which a patient's probability of having no AF, paroxysmal AF, and permanent AF is modeled by auxiliary baseline covariates in a nested logistic regression. A binomial regression model is specified conditional on a subject being in the paroxysmal AF group. The model parameters are estimated by the Expectation Maximization (EM) algorithm. These parameters are themselves nuisance parameters for the purpose of this research, but the estimators of the marginal proportions of interest can be expressed as functions of the data and these nuisance parameters and their variances can be estimated by the sandwich method. We examine the performance of the proposed methodology in simulations and two real data applications. PMID- 27983752 TI - High-fat diet induces protein kinase A and G-protein receptor kinase phosphorylation of beta2 -adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts. AB - KEY POINTS: Patients with diabetes show a blunted cardiac inotropic response to beta-adrenergic stimulation despite normal cardiac contractile reserve. Acute insulin stimulation impairs beta-adrenergically induced contractile function in isolated cardiomyocytes and Langendorff-perfused hearts. In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high-fat diet (HFD) feeding on the cardiac beta2 -adrenergic receptor signalling and the impacts on cardiac contractile function. We showed that 8 weeks of HFD feeding leads to reductions in cardiac functional reserve in response to beta-adrenergic stimulation without significant alteration of cardiac structure and function, which is associated with significant changes in beta2 -adrenergic receptor phosphorylation at protein kinase A and G-protein receptor kinase sites in the myocardium. The results suggest that clinical intervention might be applied to subjects in early diabetes without cardiac symptoms to prevent further cardiac complications. ABSTRACT: Patients with diabetes display reduced exercise capability and impaired cardiac contractile reserve in response to adrenergic stimulation. We have recently uncovered an insulin receptor and adrenergic receptor signal network in the heart. The aim of this study was to understand the impacts of high-fat diet (HFD) on the insulin-adrenergic receptor signal network in hearts. After 8 weeks of HFD feeding, mice exhibited diabetes, with elevated insulin and glucose concentrations associated with body weight gain. Mice fed an HFD had normal cardiac structure and function. However, the HFD-fed mice displayed a significant elevation of phosphorylation of the beta2 -adrenergic receptor (beta2 AR) at both the protein kinase A site serine 261/262 and the G protein-coupled receptor kinase site serine 355/356 and impaired adrenergic reserve when compared with mice fed on normal chow. Isolated myocytes from HFD fed mice also displayed a reduced contractile response to adrenergic stimulation when compared with those of control mice fed normal chow. Genetic deletion of the beta2 AR led to a normalized adrenergic response and preserved cardiac contractile reserve in HFD-fed mice. Together, these data indicate that HFD promotes phosphorylation of the beta2 AR, contributing to impairment of cardiac contractile reserve before cardiac structural and functional remodelling, suggesting that early intervention in the insulin-adrenergic signalling network might be effective in prevention of cardiac complications in diabetes. PMID- 27983756 TI - First person: Margaret Spitz, MD, MPH. PMID- 27983757 TI - Cancer mortality rates vary among specific Asian American ethnic groups. PMID- 27983758 TI - Device rapidly measures cell growth and can help determine drug resistance in cancer. PMID- 27983759 TI - Relative Impact of Risk Factors, Thwarted Belongingness, and Perceived Burdensomeness on Suicidal Ideation in Veteran Service Members. AB - OBJECTIVE: We tested the associations between individualized risk factors, empirically validated constructs specific to suicide risk (i.e., thwarted belongingness and perceived burdensomeness, and two methods for conceptualizing suicidal ideation based on Suicide Index Score (SIS) and overall severity score of the Beck Scale for Suicide Ideation [BSS]). METHOD: The current study included a sample of 134 suicidal Veterans who were recruited from an inpatient psychiatry unit of a Veterans Affairs Medical Center. Participants completed the BSS, Interpersonal Needs Questionnaire, Outcome Questionnaire-45.2, Alcohol Use Disorder Identification Test, Drug Abuse Screening Test, and abbreviated versions of the Posttraumatic Stress Disorder Checklist-Military version (PCL-M) and Insomnia Severity Index. We used ordinary least squares regression with bootstrapping to conduct analyses due to the skewed distributions observed in the suicidal ideation outcomes. RESULTS: Thwarted belongingness was the only statistically significant correlate of the SIS, indicating a stronger desire to be dead than alive as Veterans perceived themselves as being increasingly disconnected and isolated from others (B = 0.36, standard error [SE] = 0.01, p = 0.005). In contrast, greater overall severity scores on the BSS were associated with higher ratings on the PCL-M (B = 0.21, SE = 0.07, p = 0.02) and for thwarted belongingness (B = 0.27, SE = 0.09, p = 0.04). Problematic alcohol use was significantly associated with lower overall severity scores (B = -.27, SE = 1.17, p < 0.001). CONCLUSION: Findings may inform clinical strategies for conceptualizing and targeting factors associated with suicidal risk. PMID- 27983761 TI - Analysis of terpenes and turpentines using gas chromatography with vacuum ultraviolet detection. AB - The separation and identification of natural mixtures of terpenes is challenging and laborious. A gas chromatographic method based on vacuum ultraviolet spectroscopic detection, which is characterized by full-scan absorption in the range of 125-240 nm, was developed and applied to analyze terpenes. In this study, the vacuum ultraviolet absorption spectra of 41 different standard terpenes were investigated and compared. The spectra were found to be highly featured and easily differentiated. Several commercial turpentine samples were analyzed and the vacuum ultraviolet detector demonstrated good specificity for qualitative identification of constituent terpenes. A total of 31 terpenes were detected in the four turpentine samples. alpha-Pinene was the predominant terpene ranging from 744.2 +/- 9.7 to 917 +/- 21 mg/mL. The other major constituents in the turpentines included beta-pinene, delta-3-carene, camphene, and p isopropyltoluene. Deconvolution of co-eluting signals of terpenes was achieved utilizing the data analysis software. The technique has been demonstrated to be a powerful tool for reliable and accurate qualitative and quantitative analysis of terpenes from complex natural mixtures. PMID- 27983760 TI - The survival outcome of patients with relapsed/refractory peripheral T-cell lymphoma-not otherwise specified and angioimmunoblastic T-cell lymphoma. AB - Survival outcome of patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) who experience disease progression/relapse remains very poor. A total of 321 patients, newly diagnosed with PTCL-NOS (n = 180) or AITL (n = 141) between 1999 and 2015, were analysed. Failure-free survival (FFS) and overall survival (OS) were calculated from the time of first disease progression (FFS1, OS1), from second disease progression (FFS2, OS2) and from third progression (FFS3, OS3). With a median follow-up duration of 52 months, 240 patients (135 PTCL-NOS, 105 AITL) experienced progression/relapse. In patients with PTCL-NOS, the median durations of FFS1, FFS2 and FFS3 were 3.1, 2.5 and 2.1 months, respectively. In patients with AITL, they were 5.5, 2.9 and 2.3 months, respectively. There was no improvement in FFS1 and OS1 by the time of recurrence during this period (1999 2004, 2005-2009 and 2010-2015). The median FFS after pralatrexate and romidepsin was only 3.0 and 2.5 months, respectively. The 5-year OS rates after salvage autologous and allogeneic transplant were 32% and 52%, respectively; while the 5 year OS rates for patients who did not undergo transplant was 10%. Further research for novel therapeutic approaches with higher efficacy and better safety profile are needed. PMID- 27983762 TI - Differences in background characteristics of patients with chronic hepatitis C who achieved sustained virologic response with interferon-free versus interferon based therapy and the risk of developing hepatocellular carcinoma after eradication of hepatitis C virus in Japan. AB - We compared the background characteristics of patients with chronic hepatitis C who achieved eradication of hepatitis C virus (HCV), that is sustained virologic response (SVR), with interferon (IFN)-based versus IFN-free antiviral therapy in Japan. In addition, we used a previously reported risk assessment model to compare the incidence of hepatocellular carcinoma (HCC) after SVR by treatment type. Pretreatment characteristics of 1533 patients who achieved SVR with IFN based therapy and 1086 patients with IFN-free therapy from five institutions across Japan were compared. The risk of HCC after SVR was assessed based on pretreatment characteristics, and the incidence of HCC after SVR was estimated in both groups. Age and serum alpha-fetoprotein levels were higher, platelet count was lower, and liver fibrosis was more advanced in patients who achieved SVR with IFN-free therapy compared with IFN-based therapy. The incidence of HCC after SVR in the IFN-free group was estimated to be more than twofold higher than in the IFN-based therapy group (7.29% vs. 3.09%, and 6.23% vs. 3.01% when excluding patients who have underwent curative treatment for HCC). There are large differences in pretreatment characteristics between patients who achieved SVR with IFN-based and IFN-free therapies in Japan, which are associated with differential risk of HCC after SVR. These differences can influence the incidence of HCC after SVR and should be taken into consideration when comparing IFN-based and IFN-free therapies in terms of hepatocarcinogenesis suppression with HCV eradication. PMID- 27983763 TI - The common dietary flavonoid myricetin attenuates liver fibrosis in carbon tetrachloride treated mice. AB - SCOPE: Myricetin is found in most berries, vegetables, and various medicinal herbs, which has been reported to possess various bio-activities. However, the role of myricetin on liver fibrosis remains to be elucidated. METHODS AND RESULTS: Hepatic stellate cell (HSC) line CFSC-8B was stimulated by transforming growth factor beta1 (TGF-beta1) or platelet-derived growth factor BB (PDGF-BB) to induce liver fibrosis in vitro. The results showed that myricetin significantly ameliorated TGF-beta1- or PDGF-BB-induced HSCs activation, cell migration, and extracellular matrix production; blocked TGF-beta1-induced phosphorylation of Smad2, P38, extracellular signal-regulated kinase (ERK), and protein kinase B (Akt); and downregulated PDGF-BB stimulated phosphorylation of extracellular signal-regulated kinase and Akt in HSCs in a dose-dependent manner. Meanwhile, the carbon tetrachloride (CCl4 ) induced mouse model has been used to study antifibrosis role of myricetin in vivo. Our data demonstrated that myricetin suppressed alpha-smooth muscle actin and collagen type I deposition and blocked phosphorylation of Smad2, mitogen-activated protein kinases, and Akt in CCl4 treated mice. CONCLUSION: Myricetin inhibits the activation of HSCs and ameliorates CCl4 -induced liver fibrosis in mice and may serve as a potential therapeutic agent in the treatment of liver fibrosis. PMID- 27983765 TI - Selected ion flow tube study of the reactions of H3 O+ and NO+ with a series of primary alcohols in the presence of water vapour in support of selected ion flow tube mass spectrometry. AB - RATIONALE: Alcohols are often present in foods and other biological media, including exhaled breath, urine and cell culture headspace. For their analysis by selected ion flow tube mass spectrometry (SIFT-MS), the ion chemistry initiated by the reactions of the reagent ions H3 O+ and NO+ with alcohol molecules in the presence of water molecules needs to be understood and quantitatively described. METHODS: The reactions of H3 O+ and NO+ ions have been studied with the primary alcohols, methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol and 1-hexanol, under the conditions used for SIFT-MS analyses (1 Torr He; 0.1 Torr air sample; 300 K) and over a range of sample gas humidity from 1% to 5.5%. RESULTS: The H3 O+ reactions led to the formation of protonated alcohol molecules MH+ and their hydrates MH+ (H2 O)1,2,3 and (MH+ -H2 O) fragment ions. The NO+ reactions were observed to proceed mainly via hydride ion transfer, resulting in the formation of [M-H]+ product ions. Formation of the NO+ M adduct ions was also observed due to ligand switching between the NO+ (H2 O)1,2 hydrated reagent ions and M, and via direct NO+ /M association in the case of ethanol. The variation in the percentages of the hydrated product ions with the air sample humidity is reported. CONCLUSIONS: This detailed study has provided the kinetics data, including the secondary hydrated ion product distributions, for the reactions of a number of volatile primary alcohols with the SIFT-MS reagent ions H3 O+ and NO+ , which allows their analyses by SIFT-MS in humid air and also helps in the interpretation of proton transfer reaction (PTR)-MS data. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27983766 TI - Polydopamine-assisted immobilization of zeolitic imidazolate framework-8 for open tubular capillary electrochromatography. AB - In this work, we developed a capillary column modified with zeolitic imidazolate framework-8 as a novel stationary phase for open-tubular capillary electrochromatography. To immobilize zeolitic imidazolate framework-8 onto the inner surface of silica capillary, a bio-inspired polydopamine functionalization was used to functionalize the capillary surface with polydopamine. First, a polydopamine layer was assembled inside the capillary. Second, due to noncovalent adsorption and covalent reaction ability, polydopamine could attract and anchor zeolitic imidazolate framework-8 onto the inner surface of capillary. It has been demonstrated that zeolitic imidazolate framework-8 was successfully grafted on the inner wall of the capillary by scanning electron microscopy, and Fourier transform infrared spectroscopy. The electro-osmotic flow characteristics of capillaries were also investigated by varying the pH value and acetonitrile content of mobile phase. The zeolitic imidazolate framework-8 coating not only increased the phase ratio of open-tubular column, but also improved the interactions between tested analytes and the stationary phase. Three groups of isomers including acidic, basic, and neutral compounds were well separated on the zeolitic imidazolate framework-8 bonded column, with theoretic plate numbers up to 1.9 * 105 N for catechol. The repeatability of the prepared columns was also studied, and the relative standard deviations for intra- and interday runs were less than 5%. PMID- 27983764 TI - Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2nd -line therapy for relapsed and refractory multiple myeloma - a phase II trial. AB - The combination of lenalidomide (Revlimid(r) , R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small fraction of patients will achieve high quality responses [>= very good partial response (VGPR)]. The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose-limiting haematotoxicity restricted its use in extensively pre-treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BRd in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68.5 years [range 46 83]) and were treated with B 75 mg/m2 days 1, 2; R 25 mg days 1-21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28-day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol-defined criteria. The study aimed to demonstrate a complete response (CR)/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR/VGPR. Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BRd is a safe and efficacious regimen as a second line treatment for rrMM, leading to high quality responses in a considerable proportion of patients. PMID- 27983767 TI - Sulphoraphane Improves Neuronal Mitochondrial Function in Brain Tissue in Acute Carbon Monoxide Poisoning Rats. AB - Carbon monoxide (CO) poisoning is one of the leading causes of toxicity-related mortality and morbidity worldwide, primarily manifested by acute and delayed central nervous system (CNS) injuries and other organ damages. However, its definite pathogenesis is poorly understood. The aim of this study was to explore the pathogenesis of the ultrastructural and functional impairment of mitochondria and the protection of sulphoraphane (SFP) at different dosages on hippocampus neurons in rats after exposure to CO. We found that CO poisoning could induce advanced cognitive dysfunction, while the mitochondrial ultrastructure of neurons in rats of the CO poisoning group was seriously damaged and mitochondrial membrane potential (DeltaPsim) was accordingly reduced by transmission electron microscopy (TEM) and JC-1 fluorescent probe assay. CO poisoning could also increase the expressions of both nuclear factor erythroid 2-related factor 2 (Nrf 2) and thioredoxin-1 (Trx-1) proteins and their mRNA in brain tissue with immunohistochemistry and quantitative PCR (qPCR) techniques. Early administration of either middle-dose or high-dose SFP could efficiently improve mitochondrial structure and function and enhance the antioxidative stress ability, thus exerting a positive effect against brain damage induced by acute CO poisoning. PMID- 27983770 TI - Highly Enantioselective Ferrocenyl Palladacycle-Acetate Catalysed Arylation of Aldimines and Ketimines with Arylboroxines. AB - Benzylic N-substituted stereocenters constitute a frequent structural motif in drugs. Their highly enantioselective generation is hence of technical importance. An attractive strategy is the arylation of imines with organoboron reagents. Chiral Rh complexes have reached a high level of productivity for this reaction type. In this article we describe that an electron rich PdII catalyst also performs well in the arylation of aldimines, comparable to the best Rh catalysts. The ferrocenyl palladacycle-acetate catalyst allows for a broad substrate scope and very high enantioselectivities. Commonly observed side reactions like aryl aryl homocouplings and imine hydrolysis could be blocked. Mechanistic studies implicate that a) the acetate ligand is crucial for transmetallation, b) the active catalyst is most likely a palladacycle-OAc monomer, c) the rate limiting step is probably the product release. By added KOAc the arylation could also be applied to ketimines. PMID- 27983768 TI - Association of maternal and infant variants in PNOC and COMT genes with neonatal abstinence syndrome severity. AB - BACKGROUND AND OBJECTIVES: There is significant variability in severity of neonatal abstinence syndrome (NAS) due to in utero opioid exposure. Our previous study identified single nucleotide polymorphisms (SNPs) in the prepronociceptin (PNOC) and catechol-O-methyltransferase (COMT) genes that were associated with differences in NAS outcomes. This study looks at the same SNPs in PNOC and COMT in an independent cohort in an attempt to replicate previous findings. METHODS: For the replication cohort, full-term opioid-exposed newborns and their mothers (n = 113 pairs) were studied. A DNA sample was obtained and genotyped for five SNPs in the PNOC and COMT genes. The association of each SNP with NAS outcomes (length of hospitalization, need for pharmacologic treatment, and total opioid days) was evaluated, with an experiment-wise significance level set at alpha < .003 and point-wise level of alpha < .05. SNP associations in a combined cohort of n = 199 pairs (replication cohort plus 86 pairs previously reported), were also examined. RESULTS: In the replication cohort, mothers with the COMT rs4680 G allele had infants with a reduced risk for treatment with two medications for NAS (adjusted OR = .5, p = .04), meeting point-wise significance. In the combined cohort, infants with the PNOC rs4732636 A allele had a reduced need for medication treatment (adjusted OR 2.0, p = .04); mothers with the PNOC rs351776 A allele had infants who were treated more often with two medications (adjusted OR 2.3, p = .004) with longer hospitalization by 3.3 days (p = .01). Mothers with the COMT rs740603 A allele had infants who were less often treated with any medication (adjusted OR .5, p = .02). Though all SNP associations all met point wise and clinical significance, they did not meet the experiment-wise significance threshold. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: We found differences in NAS outcomes depending on PNOC and COMT SNP genotype. This has important implications for identifying infants at risk for severe NAS who could benefit from tailored treatment regimens. Further testing in a larger sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants with NAS. (Am J Addict 2017;26:42 49). PMID- 27983771 TI - Host lifespan and the evolution of resistance to multiple parasites. AB - Hosts are typically challenged by multiple parasites, but to date theory on the evolution of resistance has mainly focused on single infections. We develop a series of models that examine the impact of multiple parasites on the evolution of resistance under the assumption that parasites coexist at the host population scale as a consequence of superinfection. In this way, we are able to explicitly examine the impact of ecological dynamics on the evolutionary outcome. We use our models to address a key question of how host lifespan affects investment in resistance to multiple parasites. We show that investment in costly resistance depends on the specificity of the immune response and on whether or not the focal parasite leads to more acute infection than the co-circulating parasite. A key finding is that investment in resistance always increases as the immune response becomes more general independently of whether it is the focal or the co circulating parasite that exploits the host most aggressively. Long-lived hosts always invest more than short-lived hosts in both general resistance and resistance that is specific to relatively acute focal parasites. However, for specific resistance to parasites that are less acute than co-circulating parasites it is the short-lived hosts that are predicted to invest most. We show that these results apply whatever the mode of defence, that is whether it is through avoidance or through increased recovery, with or without acquired immunity, or through acquired immunity itself. As a whole, our results emphasize the importance of considering multiple parasites in determining optimal immune investment in eco-evolutionary systems. PMID- 27983769 TI - How do women at increased breast cancer risk perceive and decide between risks of cancer and risk-reducing treatments? A synthesis of qualitative research. AB - OBJECTIVE: Risk-reducing procedures can be offered to people at increased cancer risk, but many procedures can have iatrogenic effects. People therefore need to weigh risks associated with both cancer and the risk-reduction procedure in their decisions. By reviewing relevant literature on breast cancer (BC) risk reduction, we aimed to understand how women at relatively high risk of BC perceive their risk and how their risk perceptions influence their decisions about risk reduction. METHODS: Synthesis of 15 qualitative studies obtained from systematic searches of SCOPUS, Web of Knowledge, PsychINFO, and Medline electronic databases (inception-June 2015). RESULTS: Women did not think about risk probabilistically. Instead, they allocated themselves to broad risk categories, typically influenced by their own or familial experiences of BC. In deciding about risk-reduction procedures, some women reported weighing the risks and benefits, but papers did not describe how they did so. For many women, however, an overriding wish to reduce intense worry about BC led them to choose aggressive risk-reducing procedures without such deliberation. CONCLUSIONS: Reasoning that categorisation is a fundamental aspect of risk perception, we argue that patients can be encouraged to develop more nuanced and accurate categorisations of their own risk through their interactions with clinicians. Empirically-based ethical reflection is required to determine whether and when it is appropriate to provide risk reduction procedures to alleviate worry. PMID- 27983772 TI - Metabolic Response to Olanzapine in Healthy Chinese Subjects with rs7093146 Polymorphism in Transcription Factor 7-like 2 Gene (TCF7L2): A Prospective Study. AB - Olanzapine is a widely used atypical antipsychotic with significant weight gain and other metabolic side effects. The locus of the transcription factor 7-like 2 (TCF7L2) gene is strongly associated with type 2 diabetes (T2D). The goal of this study was to determine whether polymorphic TCF7L2 is involved in the susceptibility to the metabolic changes associated with the atypical antipsychotic agents (AAPs). In this study, a parallel clinical study with 3-day consecutive administration of olanzapine (10 mg/day) was conducted in 17 healthy subjects with a genotype of TCF7L2 rs7903146 CC (N = 10) or CT (N = 7). Olanzapine caused rapid metabolic changes including body-weight gain, increased triglycerides level and reduced HDL-cholesterol level in the healthy subjects. rs7093146 T carriers (CT) were found to have greater AUC0-2 hr of insulin during OGTT compared to those (CC) bearing only reference alleles before and after olanzapine treatment. However, the triglyceride level in the subjects with the CT genotype was found to be significantly lower than that in the subjects with CC genotype. Moreover, a significant interaction between the effect by genotype and that by olanzapine treatment on triglyceride level was identified. Acute olanzapine treatment also significantly caused total protein, albumin and haemoglobin decrease and uric acid increase in the healthy subjects. In conclusion, even acute olanzapine treatment induces significant and rapid metabolic changes, and TCF7L2 polymorphism is a genetic risk factor of olanzapine associated metabolic side effects. PMID- 27983773 TI - Exploiting interspecific olfactory communication to monitor predators. AB - Olfaction is the primary sense of many mammals and subordinate predators use this sense to detect dominant species, thereby reducing the risk of an encounter and facilitating coexistence. Chemical signals can act as repellents or attractants and may therefore have applications for wildlife management. We devised a field experiment to investigate whether dominant predator (ferret Mustela furo) body odor would alter the behavior of three common mesopredators: stoats (Mustela erminea), hedgehogs (Erinaceus europaeus), and ship rats (Rattus rattus). We predicted that apex predator odor would lead to increased detections, and our results support this hypothesis as predator kairomones (interspecific olfactory messages that benefit the receiver) provoked "eavesdropping" behavior by mesopredators. Stoats exhibited the most pronounced responses, with kairomones significantly increasing the number of observations and the time spent at a site, so that their occupancy estimates changed from rare to widespread. Behavioral responses to predator odors can therefore be exploited for conservation and this avenue of research has not yet been extensively explored. A long-life lure derived from apex predator kairomones could have practical value, especially when there are plentiful resources that reduce the efficiency of food-based lures. Our results have application for pest management in New Zealand and the technique of using kairomones to monitor predators could have applications for conservation efforts worldwide. PMID- 27983774 TI - Cost-effectiveness of indwelling pleural catheter compared with talc in malignant pleural effusion. AB - BACKGROUND AND OBJECTIVE: Malignant pleural effusion is associated with morbidity and mortality. A randomized controlled trial previously compared clinical outcomes and resource use with indwelling pleural catheter (IPC) and talc pleurodesis in this population. Using unpublished quality of life data, we estimate the cost-effectiveness of IPC compared with talc pleurodesis. METHODS: Healthcare utilization and costs were captured during the trial. Utility weights produced by the EuroQol Group five-dimensional three-level questionnaire and survival were used to determine quality-adjusted life-years (QALYs) gained. The incremental cost-effectiveness ratio (ICER) was calculated over the 1-year trial period. Sensitivity analysis used patient survival data and modelled additional nursing time required per week for catheter drainage. RESULTS: Utility scores, cost and QALYs gained did not differ significantly between groups. The ICER for IPC compared with talc was favorable at $US10 870 per QALY gained. IPC was less costly with a probability exceeding 95% of being cost-effective when survival was <14 weeks, and was more costly when 2-h nursing time per week was assumed for catheter drainage. CONCLUSION: IPC is cost-effective when compared with talc, although substantial uncertainty exists around this estimate. IPC appears most cost-effective in patients with limited survival. If significant nursing time is required for catheter drainage, IPC becomes less likely to be cost-effective. Either therapy may be considered as a first-line option in treating malignant pleural effusion in patients without history of prior pleurodesis, with consideration for patient survival, support and preferences. PMID- 27983776 TI - Ab Initio Crystal Field for Lanthanides. AB - An ab initio methodology for the first-principle derivation of crystal-field (CF) parameters for lanthanides is described. The methodology is applied to the analysis of CF parameters in [Tb(Pc)2 ]- (Pc=phthalocyanine) and Dy4 K2 ([Dy4 K2 O(OtBu)12 ]) complexes, and compared with often used approximate and model descriptions. It is found that the application of geometry symmetrization, and the use of electrostatic point-charge and phenomenological CF models, lead to unacceptably large deviations from predictions based on ab initio calculations for experimental geometry. It is shown how the predictions of standard CASSCF (Complete Active Space Self-Consistent Field) calculations (with 4f orbitals in the active space) can be systematically improved by including effects of dynamical electronic correlation (CASPT2 step) and by admixing electronic configurations of the 5d shell. This is exemplified for the well-studied Er trensal complex (H3 trensal=2,2',2"-tris(salicylideneimido)trimethylamine). The electrostatic contributions to CF parameters in this complex, calculated with true charge distributions in the ligands, yield less than half of the total CF splitting, thus pointing to the dominant role of covalent effects. This analysis allows the conclusion that ab initio crystal field is an essential tool for the decent description of lanthanides. PMID- 27983775 TI - Carnitine and gamma-Butyrobetaine Stimulate Elimination of Meldonium due to Competition for OCTN2-mediated Transport. AB - Meldonium (3-(2,2,2-trimethylhydrazinium)propionate) is the most potent clinically used inhibitor of organic cation transporter 2 (OCTN2). Inhibition of OCTN2 leads to a decrease in carnitine and acylcarnitine contents in tissues and energy metabolism optimization-related cardioprotective effects. The recent inclusion of meldonium in the World Anti-Doping Agency List of Prohibited Substances and Methods has raised questions about the pharmacokinetics of meldonium and its unusually long elimination time. Therefore, in this study, the rate of meldonium washout after the end of the treatment was tested with and without administration of carnitine, gamma-butyrobetaine (GBB) and furosemide to evaluate the importance of competition for OCTN2 transport in mice. Here, we show that carnitine and GBB administration during the washout period effectively stimulated the elimination of meldonium. GBB induced a more pronounced effect on meldonium elimination than carnitine due to the higher affinity of GBB for OCTN2. The diuretic effect of furosemide did not significantly affect the elimination of meldonium, carnitine and GBB. In conclusion, the competition of meldonium, carnitine and GBB for OCTN2-mediated transport determines the pharmacokinetic properties of meldonium. Thus, due to their affinity for OCTN2, GBB and carnitine but not furosemide stimulated meldonium elimination. During long-term treatment, OCTN2-mediated transport ensures a high muscle content of meldonium, while tissue clearance depends on relatively slow diffusion, thus resulting in the unusually long complete elimination period of meldonium. PMID- 27983777 TI - Aging of Silicon Nanocrystals on Elastomer Substrates: Photoluminescence Effects. AB - Nanocrystalline silicon is widely known as an efficient and tunable optical emitter and is attracting great interest for applications such as light-emitting devices (LEDs), electronic displays, sensors, and solar-photovoltaics. To date, however, luminescent silicon nanocrystals have been used exclusively in traditional rigid devices, leaving a gap in knowledge regarding how they behave on elastomeric substrates. The present study shows how the optical and structural/morphological properties of plasma-synthesized silicon nanocrystals (SiNCs) change when they are deposited on stretchable substrates made from polydimethylsiloxane (PDMS). Our results indicate that SiNCs deposited directly from the gas phase onto PDMS exhibit morphological changes, as well as modified aging characteristics due to enhanced oxidation. These results begin to fill the knowledge gap and point to the potential of using luminescent SiNC layers for flexible and stretchable electronics such as LEDs, displays, and sensors. PMID- 27983778 TI - Facile Synthesis of Mesocrystalline SnO2 Nanorods on Reduced Graphene Oxide Sheets: An Appealing Multifunctional Affinity Probe for Sequential Enrichment of Endogenous Peptides and Phosphopeptides. AB - A novel multifunctional composite comprising mesocrystalline SnO2 nanorods (NRs) vertically aligned on reduced graphene oxide (rGO) sheets was synthesized and developed for sequential capture of endogenous peptides and phosphopeptides. With the hydrophobicity of rGO and high affinity of SnO2 nanorods, sequential enrichment of endogenous peptides and phosphopeptides could be easily achieved through a modulation of elution buffer. With this multifunctional nanomaterial, 36 peptides were observed from diluted bovine serum albumin (BSA) tryptic digest and 4 phosphopeptides could be selectively captured from beta-casein digest. The detection limit of tryptic digest of beta-casein was low to 4 * 10-10 M, and the selectivity was up to 1:500 (molar ratio of beta-casein and BSA digest). The effectiveness and robustness of rGO-SnO2 NRs in a complex biological system was also confirmed by using human serum as a real sample. Our work is promising for small peptide enrichment and identification especially in complicated biological sample preparation, which also opens a new perspective in the design of multifunctional affinity probes for proteome or peptidome. PMID- 27983779 TI - On-Surface Synthesis and Characterization of Honeycombene Oligophenylene Macrocycles. AB - We report the on-surface formation and characterization of [30]-honeycombene, a cyclotriacontaphenylene, which consists of 30 phenyl rings (C180H120) and has a diameter of 4.0 nm. This shape-persistent, conjugated, and unsubstituted hexagonal hydrocarbon macrocycle was obtained by solvent-free synthesis on a silver (111) single-crystal surface, making solubility-enhancing alkyl side groups unnecessary. Side products include strained macrocycles with square, pentagonal, and heptagonal shape. The molecules were characterized by scanning tunneling microscopy and density functional theory (DFT) calculations. On the Ag(111) surface, the macrocycles act as molecular quantum corrals and lead to the confinement of surface-state electrons inside the central cavity. The energy of the confined surface state correlates with the size of the macrocycle and is well described by a particle-in-the-box model. Tunneling spectroscopy suggests conjugation within the planar rings and reveals influences of self-assembly on the electronic structure. While the adsorbed molecules appear to be approximately planar, the free molecules have nonplanar conformation, according to DFT. PMID- 27983780 TI - Zr-Doped Mesoporous Ta3N5 Microspheres for Efficient Photocatalytic Water Oxidation. AB - Tantalum nitride (Ta3N5) has been considered as a promising candidate for photocatalytic water splitting because of its strong visible-light absorbance as far as 600 nm. However, its catalytic activity is often hampered by various intrinsic/extrinsic defects. Here, we prepared a series of Zr-doped mesoporous tantalum nitride (Ta3N5) via a template-free method and carried out a detailed investigation of the role of Zr doping upon the photocatalytic performance. Various physicochemical properties including crystal structure, optical absorption, and so on were systematically explored. Our results show that doping Zr into Ta3N5 induces an enhancement of oxygen content and a suppression of absorption band around 720 nm, indicating an increase of ON* defects and a decrease of VN*** defects in the structure. Introduction of Zr significantly boosts the photocatalytic oxygen production of Ta3N5. The optimized photocatalytic oxygen production rate approaches 105 MUmol h-1 under visible light illumination (lambda >= 420 nm), corresponding to an apparent quantum efficiency as high as 3.2%. Photoelectrochemical analysis and DFT calculation reveal that the superior photocatalytic activity of Zr-doped Ta3N5 originates from a high level of ON* defects' concentration, which contributes to a high electron mobility, and a low level of VN*** defects' concentration, which often act as charge recombination centers. PMID- 27983781 TI - One-Shot In Vitro Evolution Generated an Antibody Fragment for Testing Urinary Cotinine with More Than 40-Fold Enhanced Affinity. AB - Immunoassays for cotinine, a major nicotine metabolite, in the urine are useful for monitoring the degree of tobacco smoke exposure. However, hybridoma-based anti-cotinine antibodies lack sufficient binding affinity to perform practically sensitive measurements, and thus most cotinine assays still rely on polyclonal antibodies. Here, we describe the generation of a mutant single-chain Fv fragment (scFv) that was used in an enzyme-linked immunosorbent assay (ELISA) to determine urinary cotinine levels in passive smokers. A "wild-type" scFv (scFv-wt) with a Ka value of 2.7 * 107 M-1 (at 4 degrees C) was prepared by linking the VH and VL domains in a mouse anti-cotinine antibody. "One-shot" random mutagenesis on the scFv-wt gene by error-prone PCR generated mutant scFv genes, which were expressed on phage particles. Repeated panning directed toward mutants with slower off rates selected scFv clones that showed improved sensitivity in an ELISA system. One of these mutants (scFv#m1-54) with five amino acid substitutions showed more than a 40-fold enhanced Ka (1.2 * 109 M-1 at 4 degrees C) and, thus, was used to monitor human urinary cotinine. A limited amount of soluble scFv was reacted with urine specimens (or cotinine standards) at 4 degrees C for 120 min in microwells on which cotinine residues had been immobilized. The midpoint of the dose response curves under optimized conditions (0.27 ng/assay) was more than 100-fold lower than the ELISA results obtained using scFv-wt. The limit of detection (8.4 pg/assay) corresponded to 0.17 ng/mL urinary cotinine, which was satisfactorily low for testing the threshold levels for passive smoke exposure. The assay values for volunteers correlated with the values determined using a commercial assay kit. This study evidently showed the potential of a molecular breeding approach, in which simple in vitro evolution might generate superior antibody reagents as cloned proteins, overcoming the limited molecular diversity inherent to conventional immunization-based antibodies. PMID- 27983782 TI - Anchoring Sb6O13 Nanocrystals on Graphene Sheets for Enhanced Lithium Storage. AB - Sb6O13/reduced graphene oxide (Sb6O13/rGO) nanocomposite was synthesized by the solvothermal method using Sb2O3 and graphene oxide as raw material. On the basis of the physical and electrochemical characterizations, Sb6O13 nanocrystals of 10 20 nm size were uniformly anchored on rGO sheets, and the nanocomposite displayed a large reversible specific capacity of 1271 mA h g-1 and an excellent cyclability of 1090 mA h g-1 after 140 cycles at 100 mA g-1 when proposed as a potential anode material for lithium ion batteries, emphasizing the advantages of anchoring of Sb6O13 nanocrystals on rGO sheets for the maximum utilization of electrochemically active Sb6O13 and rGO for lithium storage. PMID- 27983783 TI - Metabolic Pathway Extension Approach for Metabolomic Biomarker Identification. AB - Discovery of metabolomic biomarkers represents an important task in disease diagnosis and therapy. Although the development of various analytical tools and online libraries facilitates the identification of biomarkers, the fast and reliable identification of new biomarkers that are not included in databases still represents a major bottleneck in the field of metabolomics. Here, we developed a metabolic pathway extension (MPE) approach to the fast characterization of metabolomic biomarkers. This approach was proposed based on a core concept that the whole metabolome is built from a limited number of initial metabolites via various kinds and multiple steps of metabolic reactions, and thus, theoretically, the whole metabolome might be mapped from the initial metabolites and metabolic reactions. Carnitine was used as an example of initial metabolites to validate this concept and the usefulness of MPE approach. The intragastric dosing of carnitine to mice induced a significant alternation of a total of 97 metabolites. Mass differences between each pair of metabolites were calculated and then matched with those of typical metabolic pathways automatically by an in-house developed program. Diagnostic ions and neutral losses were used for validating the matches. With this approach, 93 out of a total of 97 metabolites were putatively identified, while only half of them could be traced from the currently available online database. The MPE approach was further validated by applying to the identification of carnitine-associated biomarkers in a typical mice model of fasting, and extended to the development of bile acids submetabolome. Our study indicates that the MPE approach is highly useful for rapid and reliable identification of metabolically and structurally associated biomarkers. PMID- 27983784 TI - Bridging Redox Species-Coated Graphene Oxide Sheets to Electrode for Extending Battery Life Using Nanocomposite Electrolyte. AB - Substituting conventional electrolyte for redox electrolyte has provided a new intriguing method for extending battery life. The efficiency of utilizing the contained redox species (RS) in the redox electrolyte can benefit from increasing the specific surface area of battery electrodes from the electrode side of the electrode-electrolyte interface, but is not limited to that. Herein, a new strategy using nanocomposite electrolyte is proposed to enlarge the interface with the aid of nanoinclusions from the electrolyte side. To do this, graphene oxide (GO) sheets are first dispersed in the electrolyte solution of tungstosilicic salt/lithium sulfate/poly(vinyl alcohol) (SiWLi/Li2SO4/PVA), and then the sheets are bridged to electrode, after casting and evaporating the solution on the electrode surface. By applying in situ conductive atomic force microscopy and Raman spectra, it is confirmed that the GO sheets doped with RS of SiWLi/Li2SO4 can be bridged and electrically reduced as an extended electrode electrolyte interface. As a result, the RS-coated GO sheets bridged to LiTi2(PO4)3//LiMn2O4 battery electrodes are found to deliver extra energy capacity (~30 mAh/g) with excellent electrochemical cycling stability, which successfully extends the battery life by over 50%. PMID- 27983785 TI - S, N Dual-Doped Graphene-like Carbon Nanosheets as Efficient Oxygen Reduction Reaction Electrocatalysts. AB - Replacement of rare and precious metal catalysts with low-cost and earth-abundant ones is currently among the major goals of sustainable chemistry. Herein, we report the synthesis of S, N dual-doped graphene-like carbon nanosheets via a simple pyrolysis of a mixture of melamine and dibenzyl sulfide as efficient metal free electrocatalysts for oxygen reduction reaction (ORR). The S, N dual-doped graphene-like carbon nanosheets show enhanced activity toward ORR as compared with mono-doped counterparts, and excellent durability in contrast to the conventional Pt/C electrocatalyst in both alkaline and acidic media. A high content of graphitic-N and pyridinic-N is necessary for ORR electrocatalysis in the graphene-like carbon nanosheets, but an appropriate amount of S atoms further contributes to the improvement of ORR activity. Superior ORR performance from the as-prepared S, N dual-doped graphene-like carbon nanosheets implies great promises in practical applications in energy devices. PMID- 27983788 TI - Data Streaming for Metabolomics: Accelerating Data Processing and Analysis from Days to Minutes. AB - The speed and throughput of analytical platforms has been a driving force in recent years in the "omics" technologies and while great strides have been accomplished in both chromatography and mass spectrometry, data analysis times have not benefited at the same pace. Even though personal computers have become more powerful, data transfer times still represent a bottleneck in data processing because of the increasingly complex data files and studies with a greater number of samples. To meet the demand of analyzing hundreds to thousands of samples within a given experiment, we have developed a data streaming platform, XCMS Stream, which capitalizes on the acquisition time to compress and stream recently acquired data files to data processing servers, mimicking just-in time production strategies from the manufacturing industry. The utility of this XCMS Online-based technology is demonstrated here in the analysis of T cell metabolism and other large-scale metabolomic studies. A large scale example on a 1000 sample data set demonstrated a 10 000-fold time savings, reducing data analysis time from days to minutes. Further, XCMS Stream has the capability to increase the efficiency of downstream biochemical dependent data acquisition (BDDA) analysis by initiating data conversion and data processing on subsets of data acquired, expanding its application beyond data transfer to smart preliminary data decision-making prior to full acquisition. PMID- 27983787 TI - Separation, Sizing, and Quantitation of Engineered Nanoparticles in an Organism Model Using Inductively Coupled Plasma Mass Spectrometry and Image Analysis. AB - For environmental studies assessing uptake of orally ingested engineered nanoparticles (ENPs), a key step in ensuring accurate quantification of ingested ENPs is efficient separation of the organism from ENPs that are either nonspecifically adsorbed to the organism and/or suspended in the dispersion following exposure. Here, we measure the uptake of 30 and 60 nm gold nanoparticles (AuNPs) by the nematode, Caenorhabditis elegans, using a sucrose density gradient centrifugation protocol to remove noningested AuNPs. Both conventional inductively coupled plasma mass spectrometry (ICP-MS) and single particle (sp)ICP-MS are utilized to measure the total mass and size distribution, respectively, of ingested AuNPs. Scanning electron microscopy/energy-dispersive X ray spectroscopy (SEM/EDS) imaging confirmed that traditional nematode washing procedures were ineffective at removing excess suspended and/or adsorbed AuNPs after exposure. Water rinsing procedures had AuNP removal efficiencies ranging from 57 to 97% and 22 to 83%, while the sucrose density gradient procedure had removal efficiencies of 100 and 93 to 98%, respectively, for the 30 and 60 nm AuNP exposure conditions. Quantification of total Au uptake was performed following acidic digestion of nonexposed and Au-exposed nematodes, whereas an alkaline digestion procedure was optimized for the liberation of ingested AuNPs for spICP-MS characterization. Size distributions and particle number concentrations were determined for AuNPs ingested by nematodes with corresponding confirmation of nematode uptake via high-pressure freezing/freeze substitution resin preparation and large-area SEM imaging. Methods for the separation and in vivo quantification of ENPs in multicellular organisms will facilitate robust studies of ENP uptake, biotransformation, and hazard assessment in the environment. PMID- 27983786 TI - Internal Structure and Preferential Protein Binding of Colloidal Aggregates. AB - Colloidal aggregates of small molecules are the most common artifact in early drug discovery, sequestering and inhibiting target proteins without specificity. Understanding their structure and mechanism has been crucial to developing tools to control for, and occasionally even exploit, these particles. Unfortunately, their polydispersity and transient stability have prevented exploration of certain elementary properties, such as how they pack. Dye-stabilized colloidal aggregates exhibit enhanced homogeneity and stability when compared to conventional colloidal aggregates, enabling investigation of some of these properties. By small-angle X-ray scattering and multiangle light scattering, pair distance distribution functions suggest that the dye-stabilized colloids are filled, not hollow, spheres. Stability of the coformulated colloids enabled investigation of their preference for binding DNA, peptides, or folded proteins, and their ability to purify one from the other. The coformulated colloids showed little ability to bind DNA. Correspondingly, the colloids preferentially sequestered protein from even a 1600-fold excess of peptides that are themselves the result of a digest of the same protein. This may reflect the avidity advantage that a protein has in a surface-to-surface interaction with the colloids. For the first time, colloids could be shown to have preferences of up to 90-fold for particular proteins over others. Loaded onto the colloids, bound enzyme could be spun down, resuspended, and released back into buffer, regaining most of its activity. Implications of these observations for colloid mechanisms and utility will be considered. PMID- 27983789 TI - Feasibility of Spatially Offset Raman Spectroscopy for in Vitro and in Vivo Monitoring Mineralization of Bone Tissue Engineering Scaffolds. AB - We investigated the feasibility of using spatially offset Raman spectroscopy (SORS) for nondestructive characterization of bone tissue engineering scaffolds. The deep regions of these scaffolds, or scaffolds implanted subcutaneously in live animals, are typically difficult to measure by confocal Raman spectroscopy techniques because of the limited depth penetration of light caused by the high level of light scattering. Layered samples consisting of bioactive glass foams (IEIC16), three-dimensional (3D)-printed biodegradable poly(lactic-co-glycolic acid) scaffolds (PLGA), and hydroxyapatite powder (HA) were used to mimic nondestructive detection of biomineralization for intact real-size 3D tissue engineering constructs. SORS spectra were measured with a new SORS instrument using a digital micromirror device (DMD) to allow software selection of the spatial offsets. The results show that HA can be reliably detected at depths of 0 2.3 mm, which corresponds to the maximum accessible spatial offset of the current instrument. The intensity ratio of Raman bands associated with the scaffolds and HA with the spatial offset depended on the depth at which HA was located. Furthermore, we show the feasibility for in vivo monitoring mineralization of scaffold implanted subcutaneously by demonstrating the ability to measure transcutaneously Raman signals of the scaffolds and HA (fresh chicken skin used as a top layer). The ability to measure spectral depth profiles at high speed (5 s acquisition time) and the ease of implementation make SORS a promising approach for noninvasive characterization of cell/tissue development in vitro, and for long-term in vivo monitoring the mineralization in 3D scaffolds subcutaneously implanted in small animals. PMID- 27983790 TI - Multifunctional Polymer Ligand Interface CdZnSeS/ZnS Quantum Dot/Cy3-Labeled Protein Pairs as Sensitive FRET Sensors. AB - High-quality CdZnSeS/ZnS alloyed core/thick-shell quantum dots (QDs) as energy donors were first exploited in Forster resonance energy transfer (FRET) applications. A highly efficient ligand-exchange method was used to prepare low toxicity, high quantum yield, stabile, and biocompatible CdZnSeS/ZnS QDs densely capped with multifunctional polymer ligands containing dihydrolipoic acid (DHLA). The resulting QDs can be applied to construct QDs-based Forster resonance energy transfer (FRET) systems by their high affinity interaction with dye cyanine 3 (Cy3)-labeled human serum albumin (HSA). This QD-based FRET protein complex can serve as a sensitive sensor for probing the interaction of clofazimine with proteins using fluorescence spectroscopic techniques. The ability of FRET imaging both in vitro and in vivo not only reveals that the current FRET system can remain intact for 2 h but also confirms the potential of the FRET system to act as a nanocarrier for intracellular protein delivery or to serve as an imaging probe for cancer diagnosis. PMID- 27983791 TI - Quantitative Profiling of Nanoscale Liposome Deformation by a Localized Surface Plasmon Resonance Sensor. AB - Characterizing the shape of sub-100 nm, biological soft-matter particulates (e.g., liposomes and exosomes) adsorbed at a solid-liquid interface remains a challenging task. Here, we introduce a localized surface plasmon resonance (LSPR) sensing approach to quantitatively profile the deformation of nanoscale, fluid phase 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes contacting a titanium dioxide substrate. Experimental and theoretical results validate that, due to its high sensitivity to the spatial proximity of phospholipid molecules near the sensor surface, the LSPR sensor can discriminate fine differences in the extent of ionic strength-modulated liposome deformation at both low and high surface coverages. By contrast, quartz crystal microbalance-dissipation (QCM-D) measurements performed with equivalent samples were qualitatively sensitive to liposome deformation only at saturation coverage. Control experiments with stiffer, gel-phase 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes verified that the LSPR measurement discrimination arises from the extent of liposome deformation, while the QCM-D measurements yield a more complex response that is also sensitive to the motion of adsorbed liposomes and coupled solvent along with lateral interactions between liposomes. Collectively, our findings demonstrate the unique measurement capabilities of LSPR sensors in the area of biological surface science, including competitive advantages for probing the shape properties of adsorbed, nanoscale biological particulates. PMID- 27983792 TI - Mechanisms of Contact, Adhesion, and Failure of Metallic Nanoasperities in the Presence of Adsorbates: Toward Conductive Contact Design. AB - The properties of contacting interfaces are strongly affected not only by the bulk and surface properties of contacting materials but also by the ubiquitous presence of adsorbed contaminants. Here, we focus on the properties of single asperity contacts in the presence of adsorbates within a molecular dynamics description of metallic asperity normal contact and a parametric description of adsorbate properties. A platinum-platinum asperity contact is modeled with adsorbed oligomers with variable properties. This system is particularly tailored to the context of nanoelectromechanical system (NEMS) contact switches, but the results are generally relevant to metal-metal asperity contacts in nonpristine conditions. Even though mechanical forces can displace adsorbate out of the contact region, increasing the adsorbate layer thickness and/or adsorbate/metal adhesion makes it more difficult for metal asperity/metal surface contact to occur, thereby lowering the electrical contact conductance. Contact separation is a competition between plastic necking in the asperity or decohesion at the asperity/substrate interface. The mechanism which operates at a lower tensile stress dominates. Necking dominates when the adsorbate/metal adhesion is strong and/or the adsorbate layer thickness is small. In broad terms, necking implies larger asperity deformation and mechanical work, as compared with decohesion. Optimal NEMS switch performance requires substantial contact conductance and minimal asperity deformation; these results indicate that these goals can be achieved by balancing the quantity of adsorbates and their adhesion to the metal surface. PMID- 27983793 TI - Enhanced Brain Delivery of Dimethyl Fumarate Employing Tocopherol-Acetate-Based Nanolipidic Carriers: Evidence from Pharmacokinetic, Biodistribution, and Cellular Uptake Studies. AB - Dimethyl fumarate (DMF) is an approved drug for the management of relapsing multiple sclerosis. Despite efficacy, DMF is also reported to be a challenging drug owing to concerns like gastrointestinal tract flushing, multiple dosing, lower brain permeability, less patient compliance, and economic hurdles. The present study aims to develop DMF-tocopherol acetate nanolipidic carrier (NLCs) to enhance brain permeability and improve the gastric tolerance. The developed DMF-tocopherol acetate NLCs offered an average size of 69.70 nm, PDI of 0.317, and a zeta potential of -9.71 mV. Higher drug entrapment (90.12%) and drug loading (20.13%) assured controlled drug release behavior both in gastric and intestinal pH. Cellular uptake studies on Caco-2 and SH-SY5Y monolayers confirmed better intestinal absorption and neuronal uptake of the developed system, which was further corroborated by the pharmacokinetic and biodistribution studies. The oral bioavailability was enhanced by 4.09 times and brain availability was substantially improved vis-a-vis plain drug. The findings are promising and offer preclinical evidence for better brain availability of DMF, which can be exploited in the better management of diseases like multiple sclerosis. PMID- 27983794 TI - Enhanced Corrosion Resistance and Biocompatibility of Magnesium Alloy by Mg-Al Layered Double Hydroxide. AB - Magnesium (Mg) and its alloys have been suggested as revolutionary biodegradable materials. However, fast degradation hinders its clinic application. To improve the corrosion resistance and biocompatibility of Mg-Nd-Zn-Zr alloy (JDBM), magnesium-aluminum-layered double hydroxide (Mg-Al LDH) was successfully introduced into Mg(OH)2 coating by hydrothermal treatment. The anions in the interlayer of Mg-Al LDH can be replaced by chloride ions, resulting in a relatively low chloride ion concentration near the surface of the coating. The favorable corrosion resistance of the coating was proved by polarization curves and hydrogen collection test. The Mg-Al LDH significantly promoted cell adhesion, migration and proliferation in vitro. In addition, the coating almost fulfilled the request of the clinical application in the hemolysis ratio test. Finally, in vivo results indicated that the coating offered the greatest long-lasting protection from corrosion and triggered the mildest inflammation comparing to the pure Mg(OH)2 coatings and untreated magnesium alloy. Mg(OH)2 coating containing Mg-Al LDH in the present study shows a promising application in improving anticorrosion and biocompatibility of Mg alloys, and might act as a platform for a further modification of Mg alloys ascribed to its special layer structure. PMID- 27983795 TI - Using Similarity Metrics to Quantify Differences in High-Throughput Data Sets: Application to X-ray Diffraction Patterns. AB - The objective of this research is to demonstrate how similarity metrics can be used to quantify differences between sets of diffraction patterns. A set of 49 similarity metrics is implemented to analyze and quantify similarities between different Gaussian-based peak responses, as a surrogate for different characteristics in X-ray diffraction (XRD) patterns. A methodological approach was used to identify and demonstrate how sensitive these metrics are to expected peak features. By performing hierarchical clustering analysis, it is shown that most behaviors lead to unrelated metric responses. For instance, the results show that the Clark metric is consistently one of the most sensitive metrics to synthetic single peak changes. Furthermore, as an example of its utility, a framework is outlined for analyzing structural changes because of size convergence and isotropic straining, as calculated through the virtual XRD patterns. PMID- 27983796 TI - Revealing Nanostructures through Plasmon Polarimetry. AB - Polarized optical dark-field spectroscopy is shown to be a versatile noninvasive probe of plasmonic structures that trap light to the nanoscale. Clear spectral polarization splittings are found to be directly related to the asymmetric morphology of nanocavities formed between faceted gold nanoparticles and an underlying gold substrate. Both experiment and simulation show the influence of geometry on the coupled system, with spectral shifts Deltalambda = 3 nm from single atoms. Analytical models allow us to identify the split resonances as transverse cavity modes, tightly confined to the nanogap. The direct correlation of resonance splitting with atomistic morphology allows mapping of subnanometre structures, which is crucial for progress in extreme nano-optics involving chemistry, nanophotonics, and quantum devices. PMID- 27983797 TI - High-Performance Ratiometric Electrochemical Method Based on the Combination of Signal Probe and Inner Reference Probe in One Hairpin-Structured DNA. AB - In this work, the dual signal-tagged hairpin structured DNA (dhDNA)-based ratiometric probe was developed by the combination of ferrocene-labeled signal probe (Fc-sP) and methylene blue-modified inner reference probe (MB-rP) in one hairpin-structured DNA. On the basis of this, a high-performance ratiometric electrochemical method was proposed for biomarker detection. In contrast to the conventional ratiometric electrochemical probe, this dhDNA ratiometric probe integrated sP and rP into one structure, which ensured the completely same modification condition and the interdependence of sP and rP on one sensing interface. As a result, the dhDNA ratiometric probe possesses a stronger ability to eliminate the disturbance of environmental change, which was proven by the fact that the changes of the surface roughness and pH value had no significant effects on the reproducibility and stability of the sensor. Moreover, in the proposed strategy, the initial ratio responses of Fc-sP to MB-rP ((IFc-sP/IMB rP)0) are controllable and can be kept constant at 1:1, which is favorable for the increase in signal-to-noise ratio and sensitivity. When the sequence of Fc-sP is designed as the aptamer of mucin 1 (MUC1), the dhDNA ratiometric sensor with signal amplification of Au nanoparticles becomes feasible for the sensitive detection of MUC1 by one-step incubation procedure. Compared with the conventional ratiometric sensor, the proposed dhDNA sensor has higher reproducibility, accuracy, stability, sensitivity, and simplicity, which are significant for the development of the sensor in various fields for practical applications. PMID- 27983798 TI - Nanostructures Significantly Enhance Thermal Transport across Solid Interfaces. AB - The efficiency of thermal transport across solid interfaces presents large challenges for modern technologies such as thermal management of electronics. In this paper, we report the first demonstration of significant enhancement of thermal transport across solid interfaces by introducing interfacial nanostructures. Analogous to fins that have been used for macroscopic heat transfer enhancement in heat exchangers, the nanopillar arrays patterned at the interface help interfacial thermal transport by the enlarged effective contact area. Such a benefit depends on the geometry of nanopillar arrays (e.g., pillar height and spacing), and a thermal boundary conductance enhancement by as much as ~88% has been measured using the time-domain thermoreflectance technique. Theoretical analysis combined with low-temperature experiments further indicates that phonons with low frequency are less influenced by the interfacial nanostructures due to their large transmissivity, but the benefit of the nanostructure is fully developed at room temperature where higher frequency phonons dominate interfacial thermal transport. The findings from this work can potentially be generalized to benefit real applications such as the thermal management of electronics. PMID- 27983799 TI - On-Chip Peptide Mass Spectrometry Imaging for Protein Kinase Inhibitor Screening. AB - Protein kinases are enzymes that are important targets for drug discovery because of their involvement in regulating the essential cellular processes. For this reason, the changes in protein kinase activity induced by each drug candidate (the inhibitor in this case) need to be accurately determined. Here, an on-chip secondary ion mass spectrometry (SIMS) imaging technique of the peptides was developed for determining protein kinase activity and inhibitor screening without a matrix. In our method, cysteine-tethered peptides adsorbed onto a gold surface produced changes in the relative peak intensities of the phosphorylated and unphosphorylated substrate peptides, which were quantitatively dependent on protein kinase activity. Using mass spectrometry imaging of multiple compartments on the gold surface in the presence of a peptide substrate, we screened 13,727 inhibitors, of which seven were initially found to have inhibitor efficiencies that surpassed 50%. Of these, we were able to identify a new breakpoint cluster region-abelson (BCR-ABL)T315I kinase inhibitor, henceforth referred to as KR135861. KR135861 showed no cytotoxicity and was subsequently confirmed to be superior to imatinib, a commercial drug marketed as Gleevec. Moreover, KR135861 exhibited a greater inhibitory effect on the BCR-ABLT315I tyrosine kinase, with an IC50 value as low as 1.3 MUM. In in vitro experiments, KR135861 reduced the viability of both Ba/F3 cells expressing wild-type BCR-ABL and BCR-ABLT315I, in contrast to imatinib's inhibitory effects only on Ba/F3 cells expressing wild type BCR-ABL. Due to the surface sensitivity and selectivity of SIMS imaging, it is anticipated that our approach will make it easier to validate the small modifications of a substrate in relation to enzyme activity as well as for drug discovery. This mass spectrometry imaging analysis enables efficient screening for protein kinase inhibitors, thus permitting high-throughput drug screening with high accuracy, sensitivity, and specificity. PMID- 27983800 TI - Dual-Metal Centered Zirconium-Organic Framework: A Metal-Affinity Probe for Highly Specific Interaction with Phosphopeptides. AB - The highly specific affinity between probes and phosphopeptides is the fundamental interaction for selective identification of phosphoproteomes that uncover the mechanisms of signal transduction, cell cycle, enzymatic regulation, and gene expression in biological systems. In this study, a metal-affinity probe possessing both interactions of metal oxide affinity chromatography (MOAC) and immobilized metal ion affinity chromatography (IMAC) was facilely prepared by immobilizing zirconium(IV) on a zirconium-organic framework of UiO-66-NH2, which holds dual-metal centers of not only the inherent Zr-O cluster but also the immobilized Zr(IV) center. This dual-metal centered zirconium-organic framework (DZMOF) demonstrates as a highly specific metal-affinity probe toward the extraction of phosphopeptides due to the metal-affinity interactions of MOAC and IMAC toward either mono-phosphorylated or multi-phosphorylated peptides. The binding energies of zirconium 3d5/2 and 3d3/2 in this DZMOF are 183.07 and 185.47 eV, respectively, which are higher than those of the intact UiO-66-NH2 (182.84 and 185.17 eV, respectively), confirming the higher metal-affinity interaction between the DZMOF and phosphopeptides. This high metal-affinity probe presents an unprecedented strong performance in anti-nonspecific interference during the capturing of phosphopeptides of beta-casein with the molar ratio of beta-casein vs bovine serum albumin up to ca. 1:5000. The enrichment of phosphopeptides from a human saliva sample by DZMOF further confirms the great potential of DZMOF in the extraction of low-abundance phosphopeptides for real complex biological samples. PMID- 27983801 TI - Resonance Energy Transfer in Upconversion Nanoplatforms for Selective Biodetection. AB - Resonance energy transfer (RET) describes the process that energy is transferred from an excited donor to an acceptor molecule, leading to a reduction in the fluorescence emission intensity of the donor and an increase in that of the acceptor. By this technique, measurements with the good sensitivity can be made about distance within 1 to 10 nm under physiological conditions. For this reason, the RET technique has been widely used in polymer science, biochemistry, and structural biology. Recently, a number of RET systems incorporated with nanoparticles, such as quantum dots, gold nanoparticles, and upconversion nanoparticles, have been developed. These nanocrystals retain their optical superiority and can act as either a donor or a quencher, thereby enhancing the performance of RET systems and providing more opportunities in excitation wavelength selection. Notably, lanthanide-doped upconversion nanophosphors (UCNPs) have attracted considerable attention due to their inherent advantages of large anti-Stoke shifts, long luminescence lifetimes, and absence of autofluorescence under low energy near-infrared (NIR) light excitation. These nanoparticles are promising for the biodetection of various types of analytes. Undoubtedly, the developments of those applications usually rely on resonance energy transfer, which could be regarded as a flexible technology to mediate energy transfer from upconversion phosphor to acceptor for the design of luminescent functional nanoplatforms. Currently, researchers have developed many RET-based upconversion nanosystems (RET-UCNP) that respond to specific changes in the biological environments. Specifically, small organic molecules, biological molecules, metal-organic complexes, or inorganic nanoparticles were carefully selected and bound to the surface of upconversion nanoparticles for the preparation of RET-UCNP nanosystems. Benefiting from the advantage and versatility offered by this technology, the research of RET-based upconversion nanomaterials should have significant implications for advanced biomedical applications. It should be noted that energy transfer in a UCNP based nanosystem is most often related to resonance energy transfer but that reabsorption (and maybe other energy transfer processes) may also play an important role and that more studies regarding the fundamental aspects for energy transfer with UCNPs is necessary. In this Account, we present an overview of recent advances in RET based upconversion nanocomposites for biodetection with a particular focus on our own work. We have designed a series of upconversion nanoplatforms with remarkably high versatility for different applications. The experience gained from our strategic design and experimental investigations will allow for the construction of next-generation luminescent nanoplatform with marked improvements in their performance. The key aspects of this Account include fundamental principles, design and preparation strategies, biodetection in vitro and in vivo, future opportunities, and challenges of RET-UCNP nanosystems. PMID- 27983802 TI - Photoelectrochemical DNA Biosensor Based on Dual-Signal Amplification Strategy Integrating Inorganic-Organic Nanocomposites Sensitization with lambda Exonuclease-Assisted Target Recycling. AB - Sensitive and accurate analysis of DNA is crucial to better understanding of DNA functions and early diagnosis of fatal disease. Herein, an enhanced photoelectrochemical (PEC) DNA biosensor was proposed based on dual-signal amplification via coupling inorganic-organic nanocomposites sensitization with lambda-exonuclease (lambda-Exo)-assisted target recycling. The short DNA sequence about chronic myelogenous leukemia (CML, type b3a2) was selected as target DNA (tDNA). ZnO nanoplates were deposited with CdS nanocrystals to form ZnO/CdS hetero-nanostructure, and it was used as PEC substrate for immobilizing hairpin DNA (hDNA). CdTe quantum dots (QDs) covalently linked with meso-tetra(4 carboxyphenyl)porphine (TCPP) to form CdTe/TCPP inorganic-organic nanocomposites, which were utilized as sensitization agents labeling at the terminal of probe DNA (pDNA). When the hDNA-modified sensing electrode was incubated with tDNA and lambda-Exo, hDNA hybridized with tDNA, and meanwhile it could be recognized and cleaved by lambda-Exo, resulting in the release of tDNA. The rest of nonhybridized hDNA would continuously hybridize with the released tDNA, cleave by lambda-Exo, and set free the tDNA again. After lambda-Exo-assisted tDNA recycling, more amounts of short DNA (sDNA) fragments coming from digestion of hDNA produced on the electrode and hybridized with CdTe/TCPP-labeled pDNA (pDNA CdTe/TCPP conjugates). In this case, the sensitization of CdTe/TCPP inorganic organic nanocomposites occurred, which evidently extend the absorption range and strengthened the absorption intensity of light energy, and accordingly the photocurrent signal significantly promoted. Through introducing the dual-signal amplification tactics, the developed PEC assay allowed a low calculated detection limit of 25.6 aM with a wide detection scope from 0.1 fM to 5 pM for sensitive and selective determination of tDNA. PMID- 27983804 TI - Quantitative Chemical Imaging of Nonplanar Microfluidics. AB - Confocal and multiphoton optical imaging techniques have been powerful tools for evaluating the performance of and monitoring experiments within microfluidic devices, but this application suffers from two pitfalls. The first is that obtaining the necessary imaging contrast often requires the introduction of an optical label which can potentially change the behavior of the system. The emerging analytical technique stimulated Raman scattering (SRS) microscopy promises a solution, as it can rapidly measure 3D concentration maps based on vibrational spectra, label-free; however, when using any optical imaging technique, including SRS, there is an additional problem of optical aberration due to refractive index mismatch between the fluid and the device walls. New approaches such as 3D printing are extending the range of materials from which microfluidic devices can be fabricated; thus, the problem of aberration can be obviated simply by selecting a chip material that matches the refractive index of the desired fluid. To demonstrate complete chemical imaging of a geometrically complex device, we first use sacrificial molding of a freeform 3D printed template to create a round-channel, 3D helical micromixer in a low-refractive index polymer. We then use SRS to image the mixing of aqueous glucose and salt solutions throughout the entire helix volume. This fabrication approach enables truly nonperturbative 3D chemical imaging with low aberration, and the concentration profiles measured within the device agree closely with numerical simulations. PMID- 27983803 TI - Peroxidase-Like Activity of Ethylene Diamine Tetraacetic Acid and Its Application for Ultrasensitive Detection of Tumor Biomarkers and Circular Tumor Cells. AB - Ethylene diamine tetraacetic acid (EDTA) is such a powerful chelating agent that it may form stable complexes with most metal ions, which has wide applications in industry, agriculture, environment, and pharmaceutical technology. Recently, EDTA was found to enhance the photocatalytic property of some materials. Inspired by this fact of EDTA in the photocatalytic role, we further investigated the photocatalytic property of EDTA and found much the same as that of natural horseradish peroxidase (HRP). This significant discovery of peroxidase-like property may extend the applications of conventional EDTA in life science. A novel and colorimetric sensor based on the peroxidase-like EDTA and unique gold nanorods (GNRs) was designed. Under light irradiation, EDTA may catalyze decomposition of hydrogen peroxide and in situ regulate the longitudinal plasmon wavelength (LPW) of GNRs, displaying various color solution as a read-out means. This colorimetric nanosensor has a great potential to develop into a platform to quantitatively determine analytes as long as the specific antibodies against them were available. Biomarkers of different diseases, such as breast cancer and prostate cancer, were detected with high accuracy. Moreover, combined with immunomagnetic separation of circulating tumor cells (CTCs) from blood, a visual read-out for detection of CTCs was established, which has promising applications in clinical diagnosis, environmental monitoring, and food quality control only using naked eyes. PMID- 27983805 TI - The Life of Pi Star: Exploring the Exciting and Forbidden Worlds of the Benzophenone Photophore. AB - The widespread applications of benzophenone (BP) photochemistry in biological chemistry, bioorganic chemistry, and material science have been prominent in both academic and industrial research. BP photophores have unique photochemical properties: upon n-pi* excitation at 365 nm, a biradicaloid triplet state is formed reversibly, which can abstract a hydrogen atom from accessible C-H bonds; the radicals subsequently recombine, creating a stable covalent C-C bond. This light-directed covalent attachment process is exploited in many different ways: (i) binding/contact site mapping of ligand (or protein)-protein interactions; (ii) identification of molecular targets and interactome mapping; (iii) proteome profiling; (iv) bioconjugation and site-directed modification of biopolymers; (v) surface grafting and immobilization. BP photochemistry also has many practical advantages, including low reactivity toward water, stability in ambient light, and the convenient excitation at 365 nm. In addition, several BP-containing building blocks and reagents are commercially available. In this review, we explore the "forbidden" (transitions) and excitation-activated world of photoinduced covalent attachment of BP photophores by touring a colorful palette of recent examples. In this exploration, we will see the pros and cons of using BP photophores, and we hope that both novice and expert photolabelers will enjoy and be inspired by the breadth and depth of possibilities. PMID- 27983806 TI - Key Phytochemicals Contributing to the Bitter Off-Taste of Oat (Avena sativa L.). AB - Sensory-directed fractionation of extracts prepared from oat flour (Avena sativa L.) followed by LC-TOF-MS, LC-MS/MS, and 1D/2D-NMR experiments revealed avenanthramides and saponins as the key phytochemicals contributing to the typical astringent and bitter off-taste of oat. Besides avenacosides A and B, two previously unreported bitter-tasting bidesmosidic saponins were identified, namely, 3-(O-alpha-l-rhamnopyranosyl(1->2)-[beta-d-glucopyranosyl(1->3)-beta-d glucopyranosyl(1->4)]-beta-d-glucopyranosid)-26-O-beta-d-glucopyranosyl-(25R) furost-5-ene-3beta,22,26-triol, and 3-(O-alpha-l-rhamnopyranosyl(1->2)-[beta-d glucopyranosyl(1->4)]-beta-d-glucopyranosid)-26-O-beta-d-glucopyranosyl-(25R) furost-5-ene-3beta,22,26-triol. Depending on the chemical structure of the saponins and avenanthramides, sensory studies revealed human orosensory recognition thresholds of these phytochemicals to range between 3 and 170 MUmol/L. PMID- 27983807 TI - Three-in-One: Sensing, Self-Assembly, and Cascade Catalysis of Cyclodextrin Modified Gold Nanoparticles. AB - We herein present a three-in-one nanoplatform for sensing, self-assembly, and cascade catalysis, enabled by cyclodextrin modified gold nanoparticles (CD@AuNPs). Monodisperse AuNPs 15-20 nm in diameter are fabricated in an eco friendly way by the proposed one-step colloidal synthesis method using CD as both reducing agents and stabilizers. First, the as-prepared AuNPs are employed as not only scaffolds but energy acceptors for turn-on fluorescent sensing based on guest replacement reaction. Then, the macrocyclic supramolecule functionalized AuNPs can be controllably assembled and form well-defined one- and two dimensional architectures using tetrakis(4-carboxyphenyl)porphyrin as mediator. Finally, in addition to conventional host-guest interaction based properties, the CD@AuNPs possess unpredictable catalytic activity and exhibit mimicking properties of both glucose oxidase and horseradish peroxidase simultaneously. Especially, the cascade reaction (glucose is first catalytically oxidized and generates gluconic acid and H2O2; then the enzymatic H2O2 and preadded TMB (3,3',5,5'-tetramethylbenzidine) are further catalyzed into H2O and oxTMB, respectively) is well-achieved using the AuNPs as the sole catalyst. By employing a joint experimental-theoretical study, we reveal that the unique catalytic properties of the CD@AuNPs probably derive from the special topological structures of CD molecules and the resulting electron transfer effect from the AuNP surface to the appended CD molecules. PMID- 27983808 TI - Shear Alignment of Bola-Amphiphilic Arginine-Coated Peptide Nanotubes. AB - The bola-amphiphilic arginine-capped peptide RFL4RF self-assembles into nanotubes in aqueous solution. The nanostructure and rheology are probed by in situ simultaneous rheology/small-angle scattering experiments including rheo-SAXS, rheo-SANS, and rheo-GISANS (SAXS: small-angle X-ray scattering, SANS: small-angle neutron scattering, GISANS: grazing incidence small-angle neutron scattering). Nematic alignment of peptide nanotubes under shear is observed at sufficiently high shear rates under steady shear in either Couette or cone-and-plate geometry. The extent of alignment increases with shear rate. A shear plateau is observed in a flow curve measured in the Couette geometry, indicating the presence of shear banding above the shear rate at which significant orientation is observed (0.1-1 s-1). The orientation under shear is transient and is lost as soon as shear is stopped. GISANS shows that alignment at the surface of a cone-and-plate cell develops at sufficiently high shear rates, very similar to that observed in the bulk using the Couette geometry. A small isotope effect (comparing H2O/D2O solvents) is noted in the CD spectra indicating increased interpeptide hydrogen bonding in D2O, although this does not influence nanotube self-assembly. These results provide new insights into the controlled alignment of peptide nanotubes for future applications. PMID- 27983809 TI - A Collaborative Study: Determination of Mycotoxins in Corn, Peanut Butter, and Wheat Flour Using Stable Isotope Dilution Assay (SIDA) and Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). AB - A collaborative study was conducted to evaluate stable isotope dilution assay (SIDA) and LC-MS/MS for the simultaneous determination of aflatoxins B1, B2, G1, and G2; deoxynivalenol; fumonisins B1, B2, and B3; ochratoxin A; HT-2 toxin; T-2 toxin; and zearalenone in foods. Samples were fortified with 12 13C uniformly labeled mycotoxins (13C-IS) corresponding to the native mycotoxins and extracted with acetonitrile/water (50:50 v/v), followed by centrifugation, filtration, and LC-MS/MS analysis. In addition to certified reference materials, the six participating laboratories analyzed corn, peanut butter, and wheat flour fortified with the 12 mycotoxins at concentrations ranging from 1.0 to 1000 ng/g. Using their available LC-MS/MS platform, each laboratory developed in-house instrumental conditions for analysis. The majority of recoveries ranged from 80 to 120% with relative standard derivations (RSDs) <20%. Greater than 90% of the average recoveries of the participating laboratories were in the range of 90 110%, with repeatability RSDr (within laboratory) < 10% and reproducibility RSDR (among laboratory) < 15%. All Z scores of the results of certified reference materials were between -2 and 2. Using 13C-IS eliminated the need for matrix matched calibration standards for quantitation, simplified sample preparation, and achieved simultaneous identification and quantitation of multiple mycotoxins in a simple LC-MS/MS procedure. PMID- 27983810 TI - Aquatic Global Passive Sampling (AQUA-GAPS) Revisited: First Steps toward a Network of Networks for Monitoring Organic Contaminants in the Aquatic Environment. AB - Organic contaminants, in particular persistent organic pollutants (POPs), adversely affect water quality and aquatic food webs across the globe. As of now, there is no globally consistent information available on concentrations of dissolved POPs in water bodies. The advance of passive sampling techniques has made it possible to establish a global monitoring program for these compounds in the waters of the world, which we call the Aquatic Global Passive Sampling (AQUA GAPS) network. A recent expert meeting discussed the background, motivations, and strategic approaches of AQUA-GAPS, and its implementation as a network of networks for monitoring organic contaminants (e.g., POPs and others contaminants of concern). Initially, AQUA-GAPS will demonstrate its operating principle via two proof-of-concept studies focused on the detection of legacy and emerging POPs in freshwater and coastal marine sites using both polyethylene and silicone passive samplers. AQUA-GAPS is set up as a decentralized network, which is open to other participants from around the world to participate in deployments and to initiate new studies. In particular, participants are sought to initiate deployments and studies investigating the presence of legacy and emerging POPs in Africa, Central, and South America. PMID- 27983811 TI - Real-Time Investigation of Chemical Compositions and Hygroscopic Properties of Aerosols Generated from NaCl and Malonic Acid Mixture Solutions Using in Situ Raman Microspectrometry. AB - Recently, ambient sea spray aerosols (SSAs) have been reported to undergo reactions with dicarboxylic acids (DCAs). Several studies have examined the hygroscopic behavior and chemical reactivity of aerosols generated from NaCl-DCA mixture solutions, but the results have varied, especially for the NaCl-malonic acid (NaCl-MA) mixture system. In this work, in situ Raman microspectrometry (RMS) was used to simultaneously monitor the change in chemical composition, size, and phase as a function of the relative humidity, for individual aerosols generated from NaCl-MA solutions, during two hygroscopic measurement cycles, which were performed first through the dehydration process, followed by a humidification process, in each cycle. In situ RMS analysis for the aerosols showed that the chemical reaction between NaCl and MA occurred rapidly in the time scale of 1 h and considerably in the aqueous phase, mostly during the first dehydration process, and the chemical reaction occurs more rapidly when MA is more enriched in the aerosols. For example, the reaction between NaCl and MA for aerosols generated from solutions of NaCl:MA = 2:1 and 1:2 occurred by 81% and 100% at RH = 42% and 45%, respectively, during the first dehydration process. The aerosols generated from the solution of NaCl:MA = 2:1 revealed single efflorescence and deliquescence transitions repeatedly during two hygroscopic cycles. The aerosols from NaCl:MA = 1:1 and 1:2 solutions showed just an efflorescence transition during the first dehydration process and no efflorescence and deliquescence transition during the hygroscopic cycles, respectively. The observed different hygroscopic behavior was due to the different contents of NaCl, MA, and monosodium malonate in the aerosols, which were monitored real-time by in situ RMS. PMID- 27983812 TI - Bisulfite Sequencing with Daphnia Highlights a Role for Epigenetics in Regulating Stress Response to Microcystis through Preferential Differential Methylation of Serine and Threonine Amino Acids. AB - Little is known about the influence that environmental stressors may have on genome-wide methylation patterns, and to what extent epigenetics may be involved in environmental stress response. Yet, studies of methylation patterns under stress could provide crucial insights on stress response and toxicity pathways. Here, we focus on genome-wide methylation patterns in the microcrustacean Daphnia magna, a model organism in ecotoxicology and risk assessment, exposed to the toxic cyanobacterium Microcystis aeruginosa. Bisulfite sequencing of exposed and control animals highlighted differential methylation patterns in Daphnia upon exposure to Microcystis primarily in exonic regions. These patterns are enriched for serine/threonine amino acid codons and genes related to protein synthesis, transport and degradation. Furthermore, we observed that genes with differential methylation corresponded well with genes susceptible to alternative splicing in response to Microcystis stress. Overall, our results suggest a complex mechanistic response in Daphnia characterized by interactions between DNA methylation and gene regulation mechanisms. These results underscore that DNA methylation is modulated by environmental stress and can also be an integral part of the toxicity response in our study species. PMID- 27983813 TI - Stereoselective Analysis and Dissipation of Propiconazole in Wheat, Grapes, and Soil by Supercritical Fluid Chromatography-Tandem Mass Spectrometry. AB - An efficient and sensitive chiral analytical method was established for the determination of propiconazole stereoisomers by supercritical fluid chromatography-tandem mass spectrometry (SFC-MS/MS). Stereoisomeric separation was performed on a Chiralpak AD-3 column with CO2/ethanol (93:7) as the mobile phase. The four propiconazole stereoisomers were well separated in 4.7 min with resolutions above 2.0. The specificity, linearity, matrix effects, accuracy, precision, and stability of the developed method were evaluated. The stereoselective dissipation of propiconazole in wheat straw, grape, and soil samples was investigated according to the proposed method. The results indicated that significant stereoselective degradation occurred in wheat straw and grapes, with preferential degradation of (-)-propiconazole A and (+)-propiconazole B in wheat straw and the opposite case in grapes. No enantioselectivity was observed in soil, although diastereoisomer A degraded more rapidly than diastereoisomer B. These results could contribute to a more accurate assessment of the environmental risk and food safety of propiconazole. PMID- 27983814 TI - Structure and Electronic Properties of the Quasi-One-Dimensional Ba2Co1-xZnxS3 Series. AB - This work focuses on the structure and physical properties of the solid solution Ba2Co1-xZnxS3 (0 <= x <= 1), a family of quasi-one-dimensional sulfides with end members Ba2CoS3 and Ba2ZnS3. The structure of selected compounds with increasing Zn2+ content has been analyzed using neutron diffraction, transmission electron microscopy, and extended X-ray absorption fine structure, and the physical properties have been analyzed via magnetic susceptibility and resistivity measurements. The progressive substitution of the nonmagnetic Zn2+ cation for Co2+ rapidly destroys the antiferromagnetic transition present at 46 K in the quasi-one-dimensional Ba2CoS3, leading to paramagnetic behavior down to the lowest investigated temperature (5 K) for compounds with x > 0.25. For compounds with x >= 0.4, a pure Curie-Weiss regime is recovered around 300 K, yielding effective moments consistent with the g factor of the tetrahedrally coordinated Co2+ previously determined for Ba2CoS3. The substitution of Zn2+ for Co2+ also removes the metallic-like behavior of Ba2CoS3, causing an increase in the value of the resistivity with all the Ba2Co1-xZnxS3 compounds showing semiconducting behavior. The negative magnetoresistance of Ba2CoS3 is improved by the substitution of Zn2+ for Co2+, with values of -6% for Ba2Co0.75Zn0.25S3, -9% for Ba2Co0.5Zn0.5S3, and -8% for Ba2Co0.25Zn0.75S3. However, there does not seem to be a correlation between the values of resistivity and magnetoresistance and the content of Zn2+, leading to the hypothesis that transport properties may be linked more closely to extrinsic properties. PMID- 27983815 TI - Imaging Organophosphate and Pyrophosphate Sequestration on Brucite by in Situ Atomic Force Microscopy. AB - In order to evaluate the organic phosphorus (OP) and pyrophosphate (PyroP) cycle and their fate in the environment, it is critical to understand the effects of mineral interfaces on the reactivity of adsorption and precipitation of OP and PyroP. Here, in situ atomic force microscopy (AFM) is used to directly observe the kinetics of coupled dissolution-precipitation on cleaved (001) surfaces of brucite [Mg(OH)2] in the presence of phytate, glucose-6-phosphate (G6P) and pyrophosphate, respectively. AFM results show that the relative order of contribution to mineral surface adsorption and precipitation is phytate > pyrophosphate > G6P under the same solution conditions and can be quantified by the induction time of OP/PyroP-Mg nucleation in a boundary layer at the brucite water interface. Calculations of solution speciation during brucite dissolution in the presence of phytate or pyrophosphate at acidic pH conditions show that the solutions may reach supersaturation with respect to Mg5H2Phytate.6H2O as a Mg phytate phase or Mg2P2O7 as a Mg-pyrophosphate phase that becomes thermodynamically stable before equilibrium with brucite is reached. This is consistent with AFM dynamic observations for the new phase formations on brucite. Direct nanoscale observations of the transformation of adsorption/complexation surface precipitation, combined with spectroscopic characterizations and species simulations may improve the mechanistic understanding of organophosphate and pyrophosphate sequestration by mineral replacement reactions through a mechanism of coupled dissolution-precipitation occurring at mineral-solution interfaces in the environment. PMID- 27983816 TI - Complete Nitrogen Removal from Synthetic Anaerobic Sludge Digestion Liquor through Integrating Anammox and Denitrifying Anaerobic Methane Oxidation in a Membrane Biofilm Reactor. AB - Partial nitritation and Anammox processes are increasingly used for nitrogen removal from anaerobic sludge digestion liquor. However, their nitrogen removal efficiency is often limited due to the production of nitrate by the Anammox reaction and the sensitivity to the nitrite to ammonium ratio. This work develops and demonstrates an innovative process that achieves complete nitrogen removal from partially nitrified anaerobic sludge digestion liquor through the use of a membrane biofilm reactor (MBfR), with methane supplied through hollow fiber membranes. When steady state with a hydraulic retention time (HRT) of 1 day was reached, the process achieved complete nitrite and ammonium removal at rates of 560 mg N/L/d and 470 mg N/L/d, respectively, without any nitrate accumulation. The process is relatively insensitive to the nitrite to ammonium ratio, achieving complete nitrogen removal when their ratio in influent varied in the range of 1.125-1.32. Pyrosequencing and fluorescence in situ hybridization analysis revealed that denitrifying anaerobic methane oxidation (DAMO) archaea, Anammox bacteria and DAMO bacteria jointly dominated the microbial community. Mass balance analysis showed that nitrate produced by Anammox (122.2 mg N/L/d) was entirely converted to nitrite by DAMO archaea, while nitrite in the feed and produced by DAMO archaea was jointly removed by Anammox (90%) and DAMO bacteria (10%). The nitrogen removal rate of over 1 kg N/m3/d is comparable to the practical rates reported for side-stream nitrogen removal processes. PMID- 27983817 TI - Effect of Hydration Forces on Protein Fouling of Ultrafiltration Membranes: The Role of Protein Charge, Hydrated Ion Species, and Membrane Hydrophilicity. AB - To investigate the influence of hydration forces on the protein fouling of membranes and the major influence factors of hydration forces during the ultrafiltration process, bovine serum albumin (BSA) was chosen as model foulant. For various pH levels and hydrated ion and membrane species, the membrane-BSA and BSA-BSA interaction forces, and fouling experiments with BSA, as a function of ionic strength, were measured. Results showed that hydration forces were a universal phenomenon during the membrane filtration process, when the levels of pH, ion species, and membrane performances were appropriate. First, for the BSA negatively charged or neutral, hydration forces caused a decrease in the membrane fouling. Conversely, for the BSA positively charged, the hydration forces were absent because the counterions were not hydrated, and membrane fouling was enhanced. For different hydrated ions, the smaller the radii of the ions were, the stronger the hydration forces that were produced, and the membrane fouling observed was less, indicating that hydration forces are closely correlated with the size of the hydrated ions. Moreover, in comparison with a hydrophobic membrane, it is more difficult to observe hydrophilic membrane-BSA hydration forces because the hydrophilic membrane surface adsorbs water molecules, which weakens its binding efficiency to hydrated ions. PMID- 27983818 TI - Structural and Functional Effects of Cardiomyopathy-Causing Mutations in the Troponin T-Binding Region of Cardiac Tropomyosin. AB - Hypertrophic cardiomyopathy (HCM) is a severe heart disease caused by missense mutations in genes encoding sarcomeric proteins of cardiac muscle. Many of these mutations are identified in the gene encoding the cardiac isoform of tropomyosin (Tpm), an alpha-helical coiled-coil actin-binding protein that plays a key role in Ca2+-regulated contraction of cardiac muscle. We employed various methods to characterize structural and functional features of recombinant human Tpm species carrying HCM mutations that lie either within the troponin T-binding region in the C-terminal part of Tpm (E180G, E180V, and L185R) or near this region (I172T). The results of our structural studies show that all these mutations affect, although differently, the thermal stability of the C-terminal part of the Tpm molecule: mutations E180G and I172T destabilize this part of the molecule, whereas mutation E180V strongly stabilizes it. Moreover, various HCM-causing mutations have different and even opposite effects on the stability of the Tpm actin complexes. Studies of reconstituted thin filaments in the in vitro motility assay have shown that those HCM-associated mutations that lie within the troponin T-binding region of Tpm similarly increase the Ca2+ sensitivity of the sliding velocity of the filaments and impair their relaxation properties, causing a marked increase in the sliding velocity in the absence of Ca2+, while mutation I172T decreases the Ca2+ sensitivity and has no influence on the sliding velocity under relaxing conditions. Finally, our data demonstrate that various HCM mutations can differently affect the structural and functional properties of Tpm and cause HCM by different molecular mechanisms. PMID- 27983819 TI - A General Method for Selective Recognition of Monosaccharides and Oligosaccharides in Water. AB - Molecular recognition of carbohydrates plays vital roles in biology but has been difficult to achieve with synthetic receptors. Through covalent imprinting of carbohydrates in boroxole-functionalized cross-linked micelles, we prepared nanoparticle receptors for a wide variety of mono- and oligosaccharides. The boroxole functional monomer bound the sugar templates through cis-1,2-diol, cis 3,4-diol, and trans-4,6-diol. The protein-sized nanoparticles showed excellent selectivity for d-aldohexoses in water with submillimolar binding affinities and completely distinguished the three biologically important hexoses (glucose, mannose, and galactose). Glycosides with nonpolar aglycon showed stronger binding due to enhanced hydrophobic interactions. Oligosaccharides were distinguished on the basis of their monosaccharide building blocks, glycosidic linkages, chain length, as well as additional functional groups that could interact with the nanoparticles. PMID- 27983820 TI - Zn Speciation and Stable Isotope Fractionation in a Contaminated Urban Wetland Soil-Typha latifolia System. AB - Wetlands play a key role in the immobilization of metallic contaminants. In this context the mechanisms of Zn sequestration and Zn transfer and storage in Typha latifolia L. colonizing a frequently flooded contaminated soil were studied. A combination of EXAFS spectroscopy, micro X-ray fluorescence (MUXRF) and Zn isotope measurements was applied to soil, plant organs and decaying biomass. Zn was present in the soil as Zn-layered double hydroxide, as tetrahedral and octahedral sorbed Zn species, and as ZnS. Octahedral and tetrahedral Zn (attributed to symplastic Zn-organic acid and apoplasmic Zn-cell wall complexes, respectively) and Zn-thiol species were observed in the roots, rhizomes and stems. Iron plaque was present on the rhizomes and roots. Enrichment in light isotopes for Zn sorbed on the plaque relative to the soil (Delta66Znplaque-soil = -0.3 to -0.10/00) suggested the dissolution of ZnS (enriched in light isotopes) in the rhizosphere with subsequent Zn2+ sorption on the root plaque. Furthermore, enrichment in light isotopes of stems relative to leaves (Delta66Znstem-leaves = 0.20/00) suggested the remobilization of Zn via the phloem, from leaves back to the stems. Overall these data highlight the role of thiols in controlling Zn speciation during its transfer and storage in T. latifolia. PMID- 27983821 TI - Dehydrogenation of Formic Acid Catalyzed by a Ruthenium Complex with an N,N' Diimine Ligand. AB - We report a ruthenium complex containing an N,N'-diimine ligand for the selective decomposition of formic acid to H2 and CO2 in water in the absence of any organic additives. A turnover frequency of 12 000 h-1 and a turnover number of 350 000 at 90 degrees C were achieved in the HCOOH/HCOONa aqueous solution. Efficient production of high-pressure H2 and CO2 (24.0 MPa (3480 psi)) was achieved through the decomposition of formic acid with no formation of CO. Mechanistic studies by NMR and DFT calculations indicate that there may be two competitive pathways for the key hydride transfer rate-determining step in the catalytic process. PMID- 27983822 TI - Measuring Biotic Ligand Model (BLM) Parameters in Vitro: Copper and Silver Binding to Rainbow Trout Gill Cells as Cultured Epithelia or in Suspension. AB - Biotic ligand models (BLMs) for metals are useful for risk assessment. The modeling of metal complexation by the biotic ligand has received little attention relative to the modeling of organic and inorganic complexation of metals in solution. We used ion selective electrodes (ISEs) to directly characterize copper and silver binding to rainbow trout gill cells, either as cultured reconstructed epithelia, or dispersed in suspension. Preparations were composed of pavement cells (PVCs) alone or mixtures of PVCs (~85%) and mitochondria-rich cells (MRCs, ~15%). Mixed cells showed up to an order of magnitude greater binding for both metals, indicating that MRCs were much more important than PVCs. Also, cell orientation had a dramatic effect; cells cultured as epithelia exhibited much greater binding than cells in suspension. Silver and copper demonstrated generally similar binding behavior, with stronger (logK ~ 10 or greater) and weaker binding sites (logK ~ 8). Comparisons to existing BLM calibrations show good agreement, but reveal that selection of analytical window can impact which binding sites are titrated. We conclude that cultured gill epithelia in vitro provide a powerful approach to studying metal complexation directly at the biotic ligand. PMID- 27983823 TI - Ferrimagnetic Cage Framework in Ca12Fe10Si4O32Cl6. AB - The positively charged cage framework of the natural mineral mayenite, which enables various species with negative charge to be stabilized, is one of the key structures to provide the new functionalities exploited in applications. Here we report the structural and magnetic properties of recently found eltyubyuite, Ca12Fe10Si4O32Cl6, which is the first compound bearing a transition metal oxide as a main constituent in the mayenite-type structure. From neutron powder diffraction measurements at T = 20 K and the low temperature Mossbauer measurement, we determined the magnetic structure of eltyubyuite to be a ferrimagnet with oppositely aligned magnetic moments of +3.17(3) and -3.05(8) MUB in two tetrahedral Fe sites with different oxygen ligands, all bridging oxygens or mixed bridging and nonbridging oxygens. As far as is known, this result is likely to be a first example showing ferrimagnetism stemming from only tetrahedral Fe3+ ions. The reduced magnetic moment per Fe3+ and the resultant small net moment per unit cell of 22 MUB at MU0H = 5 T and T = 15 K are attributed to strong covalency in much shorter Fe-O bonds in the FeO4 tetrahedra. PMID- 27983824 TI - Equilibria and Speciation of Chloramines, Bromamines, and Bromochloramines in Water. AB - The stabilities and speciation of the halamines in water are difficult to characterize experimentally. We provide theoretical estimates of aqueous standard free energies of formation for inorganic chloramines, bromamines, and bromochloramines, based on high-accuracy theoretical standard free energies of formation in gas phase combined with quantum chemical estimates of Henry's law constant. Based on comparisons between several theoretical and experimental datasets, we assign an error of 1.1-1.2 log unit for equilibrium constants of several reactions leading to halamines in water. The reactions of ammonia with HOCl or HOBr that lead to dichloramine, trichloramine, and tribromamine are found to be thermodynamically more favorable than was previously believed. The newly reported equilibrium data also allow us to propose rate constant values for some hydrolysis and disproportionation reactions of dichloramine, monobromamine, and bromochloramine. Finally, theoretical results indicate aqueous acid dissociation constant (pKa) values of 1.5 +/- 1 for NH3Cl+, 0.8 +/- 1 for NH3Br+, 11.8 +/- 1 for NHCl2, and 12.5 +/- 1 for NHBrCl. The present report provides a comprehensive data set describing the free energies of the neutral inorganic halamines, the anionic conjugate base species, and the cationic conjugate acid species, with approximately uniform uncertainty bounds assigned throughout. PMID- 27983825 TI - Frustrated Lewis Acid/Bronsted Base Catalysts for Direct Enantioselective alpha Amination of Carbonyl Compounds. AB - A method for enantioselective direct alpha-amination reaction catalyzed by a sterically "frustrated" Lewis acid/Bronsted base complex is disclosed. Cooperative functioning of the Lewis acid and Bronsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen-bond activated dialkyl azodicarboxylates delivers alpha aminocarbonyl compounds in high enantiomeric purity. PMID- 27983827 TI - Chemical Formation of Methanol and Hydrocarbon ("Organic") Derivatives from CO2 and H2-Carbon Sources for Subsequent Biological Cell Evolution and Life's Origin. AB - Formation of methanol and hydrocarbon derivatives from CO2 and H2, their simplest molecular building blocks, under biocompatible conditions is proposed. Alternate panspermia of similar extraterrestrially formed and observed hydrocarbons to earth is also discussed. The simple molecular building blocks derived from CO2 and H2 are carbon sources in the initial stage of biological evolution of cells leading to life's origin. PMID- 27983826 TI - Ozone-Activated Halogenation of Mono- and Dimethylbipyrrole in Seawater. AB - Polyhalogenated N-methylbipyrroles of two different structure classes have been detected worldwide in over 100 environmental samples including seawater, bird eggs, fish, dolphin blubber, and in the breast milk of humans that consume seafood. These molecules are concentrated in the fatty tissues in comparable abundance to some of the most important anthropogenic contaminants, such as the halogenated flame-retardants and pesticides. Although the origin of these compounds is still unknown, we present evidence that the production of these materials can involve the direct ozone activated seawater halogenation of N methylbipyrrole precursors. This observation shows that environmental polyhalogenated bipyrroles can be produced via an abiotic process, and implies that the ozone activated halogenation of a variety of natural and anthropogenic seawater organics may be a significant process occurring in surface ocean waters. PMID- 27983828 TI - Determination of Krypton Diffusion Coefficients in Uranium Dioxide Using Atomic Scale Calculations. AB - We present a study of the diffusion of krypton in UO2 using atomic scale calculations combined with diffusion models adapted to the system studied. The migration barriers of the elementary mechanisms for interstitial or vacancy assisted migration are calculated in the DFT+U framework using the nudged elastic band method. The attempt frequencies are obtained from the phonon modes of the defect at the initial and saddle points using empirical potential methods. The diffusion coefficients of Kr in UO2 are then calculated by combining this data with diffusion models accounting for the concentration of vacancies and the interaction of vacancies with Kr atoms. We determined the preferred mechanism for Kr migration and the corresponding diffusion coefficient as a function of the oxygen chemical potential MUO or nonstoichiometry. For very hypostoichiometric (or U-rich) conditions, the most favorable mechanism is interstitial migration. For hypostoichiometric UO2, migration is assisted by the bound Schottky defect and the charged uranium vacancy, VU4-. Around stoichiometry, migration assisted by the charged uranium-oxygen divacancy (VUO2-) and VU4- is the favored mechanism. Finally, for hyperstoichiometric or O-rich conditions, the migration assisted by two VU4- dominates. Kr migration is enhanced at higher MUO, and in this regime, the activation energy will be between 4.09 and 0.73 eV depending on nonstoichiometry. The experimental values available are in the latter interval. Since it is very probable that these values were obtained for at least slightly hyperstoichiometric samples, our activation energies are consistent with the experimental data, even if further experiments with precisely controlled stoichiometry are needed to confirm these results. The mechanisms and trends with nonstoichiometry established for Kr are similar to those found in previous studies of Xe. PMID- 27983829 TI - Integrated Multivariate Analysis with Nondetects for the Development of Human Sewage Source-Tracking Tools Using Bacteriophages of Enterococcus faecalis. AB - We developed sewage-specific microbial source tracking (MST) tools using enterococci bacteriophages and evaluated their performance with univariate and multivariate analyses involving data below detection limits. Newly isolated Enterococci faecalis bacterial strains AIM06 (DSM100702) and SR14 (DSM100701) demonstrated 100% specificity and 90% sensitivity to human sewage without detecting 68 animal manure pooled samples of cats, chickens, cows, dogs, ducks, pigs, and pigeons. AIM06 and SR14 bacteriophages were present in human sewage at 2-4 orders of magnitude. A principal component analysis confirmed the importance of both phages as main water quality parameters. The phages presented only in the polluted water, as classified by a cluster analysis, and at median concentrations of 1.71 * 102 and 4.27 * 102 PFU/100 mL, respectively, higher than nonhost specific RYC2056 phages and sewage-specific KS148 phages (p < 0.05). Interestingly, AIM06 and SR14 phages exhibited significant correlations with each other and with total coliforms, E. coli, enterococci, and biochemical oxygen demand (Kendall's tau = 0.348 to 0.605, p < 0.05), a result supporting their roles as water quality indicators. This research demonstrates the multiregional applicability of enterococci hosts in MST application and highlights the significance of multivariate analysis with nondetects in evaluating the performance of new MST host strains. PMID- 27983830 TI - Peptides Derived from Soy and Lupin Protein as Dipeptidyl-Peptidase IV Inhibitors: In Vitro Biochemical Screening and in Silico Molecular Modeling Study. AB - Dipeptidyl peptidase IV (DPP-IV) is a new molecular target correlated with the development of type 2 diabetes. Literature describes the identification of some inhibitory peptides from the hydrolysis of different food proteins. This article reports a study on six peptides from soybean and lupin proteins, i.e., Soy 1 (IAVPTGVA), Soy 2 (YVVNPDNDEN), Soy 3 (YVVNPDNNEN), Lup 1 (LTFPGSAED), Lup 2 (LILPKHSDAD), and Lup 3 (GQEQSHQDEGVIVR), which were screened for their capacity to inhibit the activity of DPP-IV, using an in vitro bioassay against human recombinant DPP-IV. Two peptides Soy 1 and Lup 1 resulted to be efficient inhibitors with IC50 values equal to 106 and 228 MUM, respectively. A molecular docking analysis predicted the key molecular interactions, stabilizing the active peptides within DPP-IV enzyme. Soy and lupin proteins may be sources of DPP-IV inhibitory peptides potentially useful for the prevention of type 2 diabetes. PMID- 27983831 TI - Phase Transition and Second Harmonic Generation in Thiophosphates Ag2Cd(P2S6) and AgCd3(PS4)S2 Containing Two Second-Order Jahn-Teller Distorted Cations. AB - Two new phases in the Ag-Cd-P-S system containing two second-order Jahn-Teller (SOJT) distorted d10 cations (Cd2+ and Ag+), namely, Ag2Cd(P2S6) (1) and AgCd3(PS4)S2 (2), are obtained via medium-temperature solid-state synthesis. Compound 1 exhibits a two-dimensional layered structure and undergoes a first order structural phase transition at approximately 280 degrees C. This outcome can be ascribed to the significant mismatch in the expansion coefficients between Cd-S (Ag-S) and P-P (P-S) bonds evaluated through bond valence theory. The three dimensional non-centrosymmetric (NCS) framework of 2 is constructed by two types of tetrahedral layers consisting of corner-shared CdS4, AgS4, and PS4 tetrahedra. Compound 2 exhibits second harmonic generation (SHG) intensity of 0.45 times that of commercial AgGaS2 (AGS) at a laser irradiation of 1.85 MUm and an optical band gap of 2.56 eV, and no intrinsic vibrational absorption of chemical bonds is observed in the range of 2.5-18.2 MUm. Both phase transition in 1 and SHG properties in 2 are closely related to the SOJT distorted d10 cations and diverse phosphorus-sulfur polyanions (PaSb)n-, which together can easily result in NCS distorted structures and interesting properties. PMID- 27983832 TI - Polaron Effects on Charge Transport through Molecular Wires: A Multiscale Approach. AB - Modeling charge transport along molecular wires immersed in polarizable environments poses a grand challenge due to the high dimensionality of the problem and the various time scales involved. A previous multiscale nonequilibrium Green's function simulation scheme (Popescu, B.; Woiczikowski, P. B.; Elstner, M.; Kleinekathofer, U. Phys. Rev. Lett. (2012), 109, 176802) has been extended significantly so that the present approach provides a much more complete physical description of the process. While the previous scheme involved the environmental fluctuations and their influence of the electronic structure of the wire, several previously neglected effects were added to the formalism: the electric field between the leads, the polarization of the dielectric environment in response to the charge present on the wire, and the relaxation of the electronic structure of the wire. Still, the underlying Hamiltonian of the wire is evaluated with electronic structure calculations, and the dynamics of the molecular system are described using molecular dynamics simulation so that (i) the formalism remains free of any model parameters and (ii) no assumptions on the underlying transport mechanism are being made. All the newly introduced details prove to affect the charge transfer along the wire markedly, while interestingly, their effects compensate each other partially. The new method is suitable for application to charge transport in junctions composed of well-defined molecular fragments, which is the case, e.g., in typical organic electronics materials. In this work, the method has been applied to hole transport through a double stranded DNA, which nicely displays the influence of all of the newly introduced effects. PMID- 27983833 TI - Identification of the Male-Produced Aggregation Pheromone of the Four-Spotted Coconut Weevil, Diocalandra frumenti. AB - The four-spotted coconut weevil, Diocalandra frumenti Fabricius (Coleoptera: Dryophthoridae), is a small weevil found attacking economically important palm species, such as coconut, date, oil, and Canary palms. Given the scarcity of detection and management tools for this pest, the availability of a pheromone to be included in trapping protocols would be a crucial advantage. Previous laboratory experiments showed evidence for aggregation behavior; thus, our main goal was to identify the aggregation pheromone in this species. The volatile profile of D. frumenti individuals was studied by aeration and collection of effluvia in Porapak-Q and also by solid phase microextraction (SPME) techniques. Moreover, solvent extraction of previously frozen crushed individuals was also performed. All resulting extracts and SPME fibers were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). The comparison of male and female samples provided the candidate compound, 5-ethyl-2,4-dimethyl-6,8 dioxabicyclo[3.2.1]octane (multistriatin), whose biological activity was evaluated in olfactometer and field assays. PMID- 27983834 TI - Cycloaddition of Fluorenone N-Aryl Nitrones with Methylenecyclopropanes and Sequential 1,3-Rearrangement: An Entry to Synthesis of Spirofluorenylpiperidin-4 ones. AB - A facile synthesis of various spirofluorenylpiperidin-4-ones has been achieved in good yields from fluorenone N-aryl nitrones and methylenecyclopropanes. This method involved an initial cycloaddition to form a 5-spirocyclopropane isoxazoline, which underwent a highly selective 1,3-rearrangement to give the desired product. The stereochemistry of the spirofluorenylpiperidin-4-one could be controlled by the cycloaddition and sequential rearrangement strategy. Furthermore, the spirofluorenylpiperidin-4-ones could be not only prepared in one pot procedure but also converted to useful scaffolds by reduction or oxidation conditions. PMID- 27983836 TI - Ammoniated Complexes of Uracil and Transition Metal Ions: Structures of [M(Ura H)(Ura)(NH3)]+ by IRMPD Spectroscopy and Computational Methods (M = Fe, Co, Ni, Cu, Zn, Cd). AB - The structures of deprotonated d-block metal dication bound uracil dimers, solvated by a single ammonia molecule, were explored in the gas phase using infrared multiple photon dissociation (IRMPD) spectroscopy in a Fourier transform ion cyclotron resonance-mass spectrometer. The IRMPD spectra were then compared with computed IR spectra for various isomers. Calculations were performed using B3LYP with the 6-31+G(d,p) basis set for all atoms, with the exception of Cd, for which the LANL2DZ basis set with relativistic core potentials was used. The calculations were then repeated using the def2-TZVPP basis set on all atoms and were compared to the first set of calculations. The lowest-energy structures are those in which one uracil is deprotonated at the N3 position and, aside from the Cu complex, the intact uracil is a tautomer in which the N3 hydrogen is at the O4 carbonyl oxygen. The metal displays a tetradentate interaction to the uracil moieties, with the exception of Cu, which is tridentate, and the ammonia molecule is bound directly to the metal center. In the Cu complex, a square planar geometry is observed about the metal center, consistent with Jahn-Teller distortions commonly observed in Cu(II) complexes, and the intact uracil assumes its canonical tautomer. All other metal cation complexes are five-coordinate, square pyramidal complexes, with the intact uracil adopting a tautomer in which the N3 hydrogen is on O4. The IRMPD spectroscopic data are consistent with the computed infrared spectra for the lowest-energy structures in all cases. PMID- 27983837 TI - Prediction of Protein Kinase-Ligand Interactions through 2.5D Kinochemometrics. AB - So far, 518 protein kinases have been identified in the human genome. They share a common mechanism of protein phosphorylation and are involved in many critical biological processes of eukaryotic cells. Deregulation of the kinase phosphorylation function induces severe illnesses such as cancer, diabetes, or inflammatory diseases. Many actors in the pharmaceutical domain have made significant efforts to design potent and selective protein kinase inhibitors as new potential drugs. Because the ATP binding site is highly conserved in the protein kinase family, the design of selective inhibitors remains a challenge and has negatively impacted the progression of drug candidates to late-stage clinical development. The work presented here adopts a 2.5D kinochemometrics (KCM) approach, derived from proteochemometrics (PCM), in which protein kinases are depicted by a novel 3D descriptor and the ligands by 2D fingerprints. We demonstrate in two examples that the protein descriptor successfully classified protein kinases based on their group membership and their Asp-Phe-Gly (DFG) conformation. We also compared the performance of our models with those obtained from a full 2D KCM model and QSAR models. In both cases, the internal validation of the models demonstrated good capabilities to distinguish "active" from "inactive" protein kinase-ligand pairs. However, the external validation performed on two independent data sets showed that the two statistical models tended to overestimate the number of "inactive" pairs. PMID- 27983838 TI - Long Chain Saturated and Unsaturated Carboxylic Acids: Filling a Large Gap of Knowledge in Their Enthalpies of Formation. AB - Despite their abundance in nature and their importance in biology, medicine, nutrition, and in industry, gas phase enthalpies of formation of many long chain saturated and unsaturated fatty acids and of dicarboxylic acids are either unavailable or have been estimated with large uncertainties. Available experimental values for stearic acid show a spread of 68 kJ mol-1. This work fills the knowledge gap by obtaining reliable values by quantum theoretical calculations using G4 model chemistry. Compounds with up to 20 carbon atoms are treated. The theoretical results are in excellent agreement with well established experimental values when such values exist, and they provide a large number of previously unavailable values. PMID- 27983835 TI - Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF 06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin. AB - By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies. PMID- 27983839 TI - Palladium-Mediated Catalysis Leads to Intramolecular Narcissistic Self-Sorting on a Cavitand Platform. AB - Palladium-catalyzed aminocarbonylation reactions have been used to directly convert a tetraiodocavitand intermediate into the corresponding carboxamides and 2-ketocarboxamides. When complex mixtures of the amine reactants are employed in competition experiments using polar solvents, such as DMF, no "mixed" products possessing structurally different amide fragments are detected either by 1H or 13C NMR. Only highly symmetrical cavitands are sorted out of a large number of potentially feasible products, which represents a rare example of intramolecular, narcissistic self-sorting. Our experimental results along with thermodynamic energy analysis suggest that the observed self-sorting is a symmetry-driven, kinetically controlled process. PMID- 27983840 TI - Hypervalency in Organic Crystals: A Case Study of the Oxicam Sulfonamide Group. AB - The theoretical charge density of the active pharmaceutical ingredient piroxicam (PXM) was evaluated through density functional theory with a localized basis set. To understand the electronic nature of the sulfur atom within the sulfonamide group, a highly ubiquitous functional group in pharmaceutical molecules, a theoretical charge density study was performed on PXM within the framework of Bader theory. Focus is on developing a topological description of the sulfur atom and its bonds within the sulfonamide group. It was found that sulfur d-orbitals do not participate in bonding. Instead, the existence of a strongly polarized ("ionic") bonding structure is found through a combined topological and natural bonding orbital analysis. This finding is in stark contrast to long-held theories of the bonding structure of organic sulfonamide and has important implications for the parametrization of calculations using classical approaches. PMID- 27983841 TI - Synthesis of Branched Tryptamines via the Domino Cloke-Stevens/Grandberg Rearrangement. AB - The rearrangement of cyclopropylketone arylhydrazones generated in situ from arylhydrazine hydrochlorides and ketones leads to formation of tryptamine derivatives. The use of (2-arylcyclopropyl)ethanones in the reactions with model 4-bromophenylhydrazine hydrochloride gives branched tryptamines with aryl groups in the alpha-position to the amino group, while (2-methylcyclopropyl)ethanone gives a mixture of alpha- and beta-substituted products in a ratio of 1:3. The method was found effective in the synthesis of enantiomerically pure tryptamine. Thus, (R,R)-(2-phenylcyclopropyl)ethanone gives the (S)-alpha-phenyltryptamine derivative with an enantiomeric excess over 99%. PMID- 27983842 TI - Cardiac Glycoside Constituents of Streblus asper with Potential Antineoplastic Activity. AB - Three new (1-3) and two known (4 and 5) cytotoxic cardiac glycosides were isolated and characterized from a medicinal plant, Streblus asper Lour. (Moraceae), collected in Vietnam, with six new analogues and one known derivative (5a-g) synthesized from (+)-strebloside (5). A preliminary structure-activity relationship study indicated that the C-10 formyl and C-5 and C-14 hydroxy groups and C-3 sugar unit play important roles in the mediation of the cytotoxicity of (+)-strebloside (5) against HT-29 human colon cancer cells. When evaluated in NCr nu/nu mice implanted intraperitoneally with hollow fibers facilitated with either MDA-MB-231 human breast or OVCAR3 human ovarian cancer cells, (+)-strebloside (5) showed significant cell growth inhibitory activity in both cases, in the dose range 5-30 mg/kg. PMID- 27983844 TI - Water-Induced Organization of Palmitic Acid at the Surface of a Model Sea Salt Particle: A Molecular Dynamics Study. AB - Marine aerosols represent the most important aerosol fraction in the Earth atmosphere. Field studies have revealed that fatty acids form an organic film at the surface of sea salt particles, altering the properties of the aerosol. By means of classical molecular dynamics simulation, the surface organization of palmitic acid (PA) on a salt surface, NaCl, has been investigated at two different temperatures, 235 and 300 K, and with relative humidity varying from 0 to 40%. Calculations show that water promotes the formation of well-ordered close packed PA islands. As a result, some area of the salt may be covered by water only or by PA molecules supported by water. Depending on the relative humidity, the hydrophilic/hydrophobic character of the sea salt surface varies. This heterogeneous coating gives rise locally to very different surface properties and hence may affect the transfer of gas phase species to the salt and their reactivity. PMID- 27983843 TI - Computational Assessment of Potassium and Magnesium Ion Binding to a Buried Pocket in GTPase-Associating Center RNA. AB - An experimentally well-studied model of RNA tertiary structures is a 58mer rRNA fragment, known as GTPase-associating center (GAC) RNA, in which a highly negative pocket walled by phosphate oxygen atoms is stabilized by a chelated cation. Although such deep pockets with more than one direct phosphate to ion chelation site normally include magnesium, as shown in one GAC crystal structure, another GAC crystal structure and solution experiments suggest potassium at this site. Both crystal structures also depict two magnesium ions directly bound to the phosphate groups comprising this controversial pocket. Here, we used classical molecular dynamics simulations as well as umbrella sampling to investigate the possibility of binding of potassium versus magnesium inside the pocket and to better characterize the chelation of one of the binding magnesium ions outside the pocket. The results support the preference of the pocket to accommodate potassium rather than magnesium and suggest that one of the closely binding magnesium ions can only bind at high magnesium concentrations, such as might be present during crystallization. This work illustrates the complementary utility of molecular modeling approaches with atomic-level detail in resolving discrepancies between conflicting experimental results. PMID- 27983847 TI - Charge Transfer at the Qo-Site of the Cytochrome bc1 Complex Leads to Superoxide Production. AB - The cytochrome bc1 complex is the third protein complex in the electron transport chain of mitochondria or photosynthetic bacteria, and it serves to create an electrochemical gradient across a cellular membrane, which is used to drive ATP synthesis. The purpose of this study is to investigate interactions involving an occasionally trapped oxygen molecule (O2) at the so-called Qo site of the bc1 complex, which is one of the central active sites of the protein complex, where redox reactions are expected to occur. The investigation focuses on revealing the possibility of the oxygen molecule to influence the normal operation of the bc1 complex and acquire an extra electron, thus becoming superoxide, a biologically toxic free radical. The process is modeled by applying quantum chemical calculations to previously performed classical molecular dynamics simulations. Investigations reveal several spontaneous charge transfer modes from amino acid residues and cofactors at the Qo-site to the trapped O2 molecule. PMID- 27983846 TI - Highly Potent and Isoform Selective Dual Site Binding Tankyrase/Wnt Signaling Inhibitors That Increase Cellular Glucose Uptake and Have Antiproliferative Activity. AB - Compounds 13 and 14 were evaluated against 11 PARP isoforms to reveal that both 13 and 14 were more potent and isoform selective toward inhibiting tankyrases (TNKSs) than the "standard" inhibitor 1 (XAV939)5, i.e., IC50 = 100 pM vs TNKS2 and IC50 = 6.5 MUM vs PARP1 for 14. In cellular assays, 13 and 14 inhibited Wnt signaling, enhanced insulin-stimulated glucose uptake, and inhibited the proliferation of DLD-1 colorectal adenocarcinoma cells to a greater extent than 1. PMID- 27983848 TI - Binding Interactions between a Ferrocenylguanidinium Guest and Cucurbit[n]uril Hosts. AB - The binding interactions between a novel ferrocenylguanidinium derivative (FcG+) and the macrocyclic hosts cucurbit[7]uril (CB7) and cucurbit[8]uril (CB8) were investigated in aqueous solution. 1H NMR spectroscopic experiments indicated that both hosts form stable 1:1 inclusion complexes with FcG+, in which the ferrocenyl group is engulfed by the host cavity. The stoichiometry of the CB7.FcG+ complex was also confirmed by electrospray mass spectrometric (ESI MS) experiments. The association equilibrium constants (K) were determined from NMR competition experiments. The measured K values were 3.5 * 109 and 2.5 * 108 M-1 for CB7 and CB8, respectively, in 50 mM sodium acetate-d3 D2O solution (pD 4.7). DFT computational studies confirmed the 1:1 stoichiometry and the inclusion character of both complexes. Voltammetric experiments were carried out to measure the complexation-induced shifts on the half-wave potentials for the one-electron oxidation of the ferrocenyl moiety. Complexation by CB7 led to a 12 mV anodic shift, while CB8 caused a larger 32 mV shift also in the positive direction. These potential shifts suggest that the delocalization of the positive charge on the side arm over the three nitrogens in the guanidinium unit results in electrochemical behavior similar to that observed with neutral ferrocene derivatives. PMID- 27983845 TI - Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor. AB - Both dopamine D3 receptor (D3R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (R)-enantiomers are antagonists/weak partial agonists, whereas the (S)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond scale molecular dynamics simulations starting from the inactive state of D3R in complex with these enantiomers. Analysis of the simulation results reveals common structural rearrangements near the ligand binding site induced by the bound (S) enantiomers, but not by the (R)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agonists may be useful for structure-based design of compounds with tailored efficacy profiles. PMID- 27983849 TI - On-the-Fly QM/MM Docking with Attracting Cavities. AB - We developed a hybrid quantum mechanical/molecular mechanical (QM/MM) on-the-fly docking algorithm to address the challenges of treating polarization and selected metal interactions in docking. The algorithm is based on our classical docking algorithm Attracting Cavities and relies on the semiempirical self-consistent charge density functional tight-binding (SCC-DFTB) method and the CHARMM force field. We benchmarked the performance of this approach on three very diverse data sets: (1) the Astex Diverse set of 85 common noncovalent drug/target complexes formed both by hydrophobic and electrostatic interactions; (2) a zinc metalloprotein data set of 281 complexes, where polarization is strong and ligand/protein interactions are dominated by electrostatic interactions; and (3) a heme protein data set of 72 complexes, where ligand/protein interactions are dominated by covalent ligand/iron binding. Redocking performance of the on-the fly QM/MM docking algorithm was compared to the performance of classical Attracting Cavities, AutoDock, AutoDock Vina, and GOLD. The results demonstrate that the QM/MM code preserves the high accuracy of most classical scores on the Astex Diverse set, while it yields significant improvements on both sets of metalloproteins at moderate computational cost. PMID- 27983850 TI - Computational Modeling of the Catalytic Cycle of Glutathione Peroxidase Nanomimic. AB - To elucidate the role of a derivative of ebselen as a mimic of the antioxidant selenoenzyme glutathione peroxidase, density functional theory and solvent assisted proton exchange (SAPE) were applied to model the reaction mechanism in a catalytic cycle. This mimic plays the role of glutathione peroxidase through a four-step catalytic cycle. The first step is described as the oxidation of 1 in the presence of hydrogen peroxide, while selenoxide is reduced by methanthiol at the second step. In the third step of the reaction, the reduction of selenenylsulfide occurs by methanthiol, and the selenenic acid is dehydrated at the final step. Based on the kinetic parameters, step 4 is the rate-determining step (RDS) of the reaction. The bond strength of the atoms involved in the RDS is discussed with the quantum theory of atoms in molecules (QTAIM). Low value of electron density, rho(r), and positive Laplacian values are the evidence for the covalent nature of the hydrogen bonds rupture (O30-H31, O33-H34). A change in the sign of the Laplacian, L(r), from the positive value in the reactant to a negative character at the transition state indicates the depletion of the charge density, confirming the N5-H10 and O11-Se1 bond breaking. The analysis of electron location function (ELF) and localized orbital locator (LOL) of the Se1 N5 and Se1-O11 bonds have been done by multi-WFN program. High values of ELF and LOL at the transition state regions between the Se, N, and O atoms display the bond formation. Finally, the main donor-acceptor interaction energies were analyzed using the natural bond orbital analysis for investigation of their stabilization effects on the critical bonds at the RDS. PMID- 27983851 TI - Quantitative Infrared Absorption Spectra and Vibrational Assignments of Crotonaldehyde and Methyl Vinyl Ketone Using Gas-Phase Mid-Infrared, Far Infrared, and Liquid Raman Spectra: s-cis vs s-trans Composition Confirmed via Temperature Studies and ab Initio Methods. AB - Methyl vinyl ketone (MVK) and crotonaldehyde are chemical isomers; both are also important species in tropospheric chemistry. We report quantitative vapor-phase infrared spectra of crotonaldehyde and MVK vapors over the 540-6500 cm-1 range. Vibrational assignments of all fundamental modes are made for both molecules on the basis of far- and mid-infrared vapor-phase spectra, liquid Raman spectra, along with density functional theory and ab initio MP2 and high energy-accuracy compound theoretical models (W1BD). Theoretical results indicate that at room temperature the crotonaldehyde equilibrium mixture is approximately 97% s-trans and only 3% s-cis conformer. Nearly all observed bands are thus associated with the s-trans conformer, but a few appear to be uniquely associated with the s-cis conformer, notably nu16c at 730.90 cm-1, which displays a substantial intensity increase with temperature (70% upon going from 5 to 50 o C). The intensity of the corresponding mode of the s-trans conformer decreases with temperature. Under the same conditions, the MVK equilibrium mixture is approximately 69% s-trans conformer and 31% s-cis. W1BD calculations indicate that for MVK this is one of those (rare) cases where there are comparable populations of both conformers, approximately doubling the number of observed bands and exacerbating the vibrational assignments. We uniquely assign the bands associated with both the MVK s-cis conformer as well as those of the s-trans, thus completing the vibrational analyses of both conformers from the same set of experimental spectra. Integrated band intensities are reported for both molecules along with global warming potential values. Using the quantitative IR data, potential bands for atmospheric monitoring are also discussed. PMID- 27983852 TI - Validation of Density Functionals for Adsorption Energies on Transition Metal Surfaces. AB - The quantitative prediction of adsorption energies of radicals and molecules on surfaces is essential for the design and understanding of heterogeneous catalytic processes. A recent paper by Wellendorff et al. collected an experimental database of 39 reaction energies involving adsorption energies on transition metal surfaces that can be used as benchmarks for testing quantum mechanical electronic structure methods, and we compared the experimental data to Kohn-Sham density functional calculations with six exchange-correlation functionals. In this paper, we rearranged the data into two categories: open-shell radical adsorption reactions and closed-shell molecular adsorption reactions. We recalculated the adsorption energies with PBE, and we also calculated them with three functionals, M06-L, GAM, and MN15-L, that were not studied in the Wellendorff et al. paper; then we compared our results to the benchmark data. Of the nine functionals that have been compared to the databases, we find that BEEF vdW, GAM, and RPBE perform best for the open-shell radical adsorption reactions, and MN15-L performs best for the closed-shell molecular adsorption, followed by BEEF-vdW and M06-L. PMID- 27983853 TI - Quantifying the Heat Dissipation from a Molecular Motor's Transport Properties in Nonequilibrium Steady States. AB - Theoretical analysis, which maps single-molecule time trajectories of a molecular motor onto unicyclic Markov processes, allows us to evaluate the heat dissipated from the motor and to elucidate its dependence on the mean velocity and diffusivity. Unlike passive Brownian particles in equilibrium, the velocity and diffusion constant of molecular motors are closely inter-related. In particular, our study makes it clear that the increase of diffusivity with the heat production is a natural outcome of active particles, which is reminiscent of the recent experimental premise that the diffusion of an exothermic enzyme is enhanced by the heat released from its own catalytic turnover. Compared with freely diffusing exothermic enzymes, kinesin-1, whose dynamics is confined on one dimensional tracks, is highly efficient in transforming conformational fluctuations into a locally directed motion, thus displaying a significantly higher enhancement in diffusivity with its turnover rate. Putting molecular motors and freely diffusing enzymes on an equal footing, our study offers a thermodynamic basis to understand the heat-enhanced self-diffusion of exothermic enzymes. PMID- 27983854 TI - Ab Initio Thermodynamics and the Relationship between Octahedral Distortion, Lattice Structure, and Proton Substitution Defects in Malachite/Rosasite Group Endmember Pokrovskite Mg2CO3(OH)2. AB - Divalent metal hydroxycarbonates with M2CO3(OH)2 stoichiometry are widely used in industry and are abundant in nature as the malachite/rosasite group of minerals. Essential to their performance as catalytic precursors and in nanoelectronics, these materials and minerals exhibit a high degree of cation ordering in mixed metal systems due to differences in distortion of the octahedral metal sites. Density-functional theory (DFT) calculations on pokrovskite Mg2CO3(OH)2 in the rosasite structure and Mg analogues of monoclinic and orthorhombic forms of malachite determine that the octahedral sites are innately distorted, and that d9 Cu(II) Jahn-Teller distortion accommodates this distortion rather than causes it, leading to the significant preference of Cu for the type I octahedral sites. This distortion also leads to a high propensity for formation of cation vacancies charge balanced by proton substitution. Ab initio thermodynamics is used to determine that there are conditions under which proton substitution defects are slightly more stable than the stoichiometric structure, consistent with the widespread observation of such defects in pokrovskite in nature. Pokrovskite itself is most likely to form under CO2-rich/low water conditions, particularly those utilizing supercritical CO2 for carbon sequestration and is sufficiently thermodynamically stable to trap CO2 under geological conditions. Low temperature and high water concentration promotes the formation of proton substitution defects, which has implications for synthesis of any material where octahedral strain may be relieved by proton substitution defects. PMID- 27983855 TI - NIR Light-Activated Drug Release for Synergetic Chemo-Photothermal Therapy. AB - Nanocarriers like PEGylated liposomes have achieved enhanced drug accumulation in tumors and reduced systemic side effects, but failed to actively release the carried drug into cancer cells. To obtain improved therapeutic efficacy, we designed a novel liposome that was inserted by the amphiphilic agent PEG-IR780 C13 (PIC-Lipo) and encapsulated therapeutic agent doxorubicin (DOX), termed as DOX@PIC-Lipo. Upon NIR laser irradiation, the novel liposomes could generate hyperthermia and facilitate the release of encapsulated DOX from PIC-Lipo, which were confirmed by photothermal curves and the DOX release assay in vitro, respectively. In addition, the enhanced DOX release and sufficient hyperthermia have performed synergetic therapeutic efficacy both in vitro and in vivo. Therefore, DOX@PIC-Lipo might provide an active strategy to release the loaded drug for synergetic chemo-photothermal combined therapy. PMID- 27983856 TI - Sodium Oleate-Based Nanoemulsion Enhances Oral Absorption of Chrysin through Inhibition of UGT-Mediated Metabolism. AB - Oral bioavailability of flavonoids (and many phenolic drugs) is severely limited by extensive first-pass glucuronidation. Here we aimed to determine the modulatory effects of commonly used pharmaceutical excipients (PEs) on UDP glucuronosyltransferase (UGT) activities and to evaluate the potential of nanoemulsions containing a UGT-inhibitory PE for oral absorption enhancement of chrysin, a model flavonoid. The effects of PEs on glucuronidation were determined using tissue (liver and intestine) microsomes, expressed UGT1A1 enzyme, and UGT1A1-overexpressing HeLa cells. Nanoemulsions were prepared using a modified emulsification technique and subsequently characterized by particle size, zeta potential, morphology, and in vitro drug release. Pharmacokinetic studies were performed with rats to assess the effects of nanoemulsions on the metabolism and pharmacokinetics of chrysin. Of 21 PEs, five (i.e., Brij 35, Brij 58, labrasol, sodium oleate, and Tween 20) significantly inhibited chrysin glucuronidation. Of note, sodium oleate was the most potent inhibitor of glucuronidation. Eight PEs including Tween 80 had no effects on glucuronidation of chrysin. The chrysin nanoemulsions prepared with sodium oleate (named SO-NE) were spherical or near spherical (particle size, 83.2 nm; zeta-potential, -43.7 mV; entrapment efficiency, 89.5%). The reference nanoemulsions prepared with Tween 80 (T80-NE) were highly similar to SO-NE in terms of particle size, zeta-potential, and drug release. It was demonstrated in pharmacokinetic studies that SO-NE led to a 4.3 fold increase in systemic exposure of chrysin and a 3.5-fold increase in Cmax value, whereas T80-NE did not cause any changes in chrysin pharmacokinetics. In conclusion, sodium oleate-based nanoemulsions greatly enhanced oral absorption of chrysin. Oral absorption enhancement of chrysin was attained through targeted inhibition of first-pass glucuronidation by sodium oleate. PMID- 27983857 TI - Tuning Carrier Tunneling in van der Waals Heterostructures for Ultrahigh Detectivity. AB - Semiconducting transition metal dichalcogenides (TMDs) are promising materials for photodetection over a wide range of visible wavelengths. Photodetection is generally realized via a phototransistor, photoconductor, p-n junction photovoltaic device, and thermoelectric device. The photodetectivity, which is a primary parameter in photodetector design, is often limited by either low photoresponsivity or a high dark current in TMDs materials. Here, we demonstrated a highly sensitive photodetector with a MoS2/h-BN/graphene heterostructure, by inserting a h-BN insulating layer between graphene electrode and MoS2 photoabsorber, the dark-carriers were highly suppressed by the large electron barrier (2.7 eV) at the graphene/h-BN junction while the photocarriers were effectively tunneled through small hole barrier (1.2 eV) at the MoS2/h-BN junction. With both high photocurrent/dark current ratio (>105) and high photoresponsivity (180 AW-1), ultrahigh photodetectivity of 2.6 * 1013 Jones was obtained at 7 nm thick h-BN, about 100-1000 times higher than that of previously reported MoS2-based devices. PMID- 27983858 TI - Interaction of Charged Patchy Protein Models with Like-Charged Polyelectrolyte Brushes. AB - We study the adsorption of charged patchy particle models (CPPMs) on a thin film of a like-charged and dense polyelectrolyte (PE) brush (of 50 monomers per chain) by means of implicit-solvent, explicit-salt Langevin dynamics computer simulations. Our previously introduced set of CPPMs embraces well-defined one- and two-patched spherical globules, each of the same net charge and (nanometer) size, with mono- and multipole moments comparable to those of small globular proteins. We focus on electrostatic effects on the adsorption far away from the isoelectric point of typical proteins, i.e., where charge regulation plays no role. Despite the same net charge of the brush and globule, we observe large binding affinities up to tens of the thermal energy, kBT, which are enhanced by decreasing salt concentration and increasing charge of the patch(es). Our analysis of the distance-resolved potentials of mean force together with a phenomenological description of all leading interaction contributions shows that the attraction is strongest at the brush surface, driven by multipolar, Born (self-energy), and counterion-release contributions, dominating locally over the monopolar and steric repulsions. PMID- 27983859 TI - Reply to "Comment on 'In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models'". AB - This is a reply to the comment on "In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models" by Turner and other Simcyp associates. In the reply we address the major concerns raised by Turner et al. regarding the methodology to compare the predictive performance of the different absorption models and at the same time ensure that the systemic pharmacokinetic input was exactly the same for the different models; the selection of the human effective permeability value of fexofenadine; the adoption of model default values and settings; and how supersaturation/precipitation was handled. In addition, we also further discuss aspects related to differences in in silico models and the potential implications of such differences. Our original report should be viewed as the starting point in a thorough and transparent review of absorption prediction models with the overall aim of improving their application as validated tools for bridging studies of active pharmaceutical ingredients from various sources and origins in a regulatory context. With this reply we encourage other independent investigators to perform further model evaluations of commercial as well as other existing or recently implemented models. This will boost the overall progression of physiologically based biopharmaceutical models for predicting and simulating intestinal drug absorption both in research and development and in a regulatory context. PMID- 27983860 TI - Gold Nanotriangle Formation through Strong-Field Laser Processing of Aqueous KAuCl4 and Postirradiation Reduction by Hydrogen Peroxide. AB - Femtosecond laser irradiation of aqueous KAuCl4 followed by postirradiation reduction with hydrogen peroxide (H2O2) is investigated as a new approach for the synthesis of gold nanotriangles (AuNTs) without any added surfactant molecules. Laser irradiation was applied for times ranging from 5 to 240 s, and postirradiation reduction of the solutions was monitored by UV-vis spectroscopy. Laser processing of aqueous KAuCl4 for 240 s, where the full reduction of Au(III) occurred during irradiation, produced spherical gold nanoparticles (AuNPs) with an average size of 11.4 +/- 3.4 nm. Irradiation for shorter times (i.e., 15 s) resulted in the formation of laser-generated AuNP seeds (5.7 +/- 1.8 nm) in equilibrium with unreacted KAuCl4 after termination of laser irradiation. The postirradiation reduction of these solutions by H2O2 produced a mixture of spherical and triangular AuNPs. Decreasing the laser irradiation time from 45 to 5 s significantly reduced the number of laser-generated Au seeds, the amount of H2O2 produced, and the rate of postirradiation reduction, resulting in the formation of a large number of AuNTs with sizes increasing from 29.5 +/- 10.2 to 125 +/- 43.2 nm. Postirradiation reduction is kinetically inhibited in the absence of laser-generated AuNP seeds. PMID- 27983861 TI - Understanding the Seed-Mediated Growth of Gold Nanorods through a Fractional Factorial Design of Experiments. AB - Since the development of simple, aqueous protocols for the synthesis of anisotropic metal nanoparticles, research into many promising, valuable applications of gold nanorods has grown considerably, but a number of challenges remain, including gold-particle yield, robustness to minor impurities, and precise control of gold nanorod surface chemistry. Herein we present the results of a composite fractional factorial series of experiments designed to screen seven additional potential avenues of control and to understand the seed-mediated silver-assisted synthesis of gold nanorods. These synthesis variables are the amount of sodium borohydride used and the rate of stirring when producing seed nanoparticles, the age of and the amount of seeds added, the reaction temperature, the amounts of silver nitrate and ascorbic acid added, and the age of the reduced growth solution before seed nanoparticles are added to initiate rod formation. This statistical experimental design and analysis method, besides determining which experimental variables are important and which are not when synthesizing gold nanorods (and quantifying their effects), gives further insight into the mechanism of growth by measuring the degree to which variables interact with each other by mapping out their mechanistic connections. This work demonstrates that when forming gold nanorods by the reduction of auric ions by ascorbic acid onto seed nanoparticles, ascorbic acid determines how much gold is reduced, and the amount of seeds determine how it is divided, yet both influence the intrinsic growth rates, in both width and length, of the forming nanorods. Furthermore, this work shows that the reduction of gold proceeds via direct reduction on the surface of seeds and not through a disproportionation reaction. Further control over the length of gold nanorods can be achieved by tuning the amount of silver nitrate or the reaction temperature. This work shows that silver does not directly influence rod length or width, and a new primary role for silver is proposed as a catalyst promoting the reduction of gold on the ends of forming nanorods. Furthermore, this silver catalyst is removed from the reaction by adsorption onto the surface of the growing nanorod. This work also demonstrates the importance of freshly prepared silver nitrate and ascorbic acid solutions, free from even a few hours of photodegradation, in preparing gold nanorods with high shape purity and gold yield. PMID- 27983862 TI - Hybrid-Mode-Assisted Long-Distance Excitation of Short-Range Surface Plasmons in a Nanotip-Enhanced Step-Index Fiber. AB - We propose and experimentally demonstrate a monolithic nanowire-enhanced fiber based nanoprobe for the broadband delivery of light (550-730 nm) to a deep subwavelength scale using short-range surface plasmons. The geometry is formed by a step index fiber with an integrated gold nanowire in its core and a protruding gold nanotip with sub-10 nm apex radius. We present a novel coupling scheme to excite short-range surface plasmons, whereby the radially polarized hybrid mode propagating inside the nanowire section excites the plasmonic mode close to the fiber endface, which is in turn superfocused down to nanoscale dimensions at the tip apex. We show that in this all-integrated fiber-plasmonic coupling scheme the wire length can be orders of magnitude longer than the attenuation length of short-range plasmon polaritons, yielding a broadband plasmon excitation and reducing demands in fabrication. We observe that the scattered light in the far field from the nanotip is axially polarized and preferentially excited by a radially polarized input, unambiguously revealing that it originates from a short range plasmon propagating on the nanotip, in agreement with simulations. This novel excitation scheme will have important applications in near-field microscopy and nanophotonics and potentially offers significantly improved resolution compared to current delivery near-field probes. PMID- 27983863 TI - Synthesis of Tricyclic Benzazocines by Aza-Prins Reaction. AB - The aza-Prins reaction of 3-vinyltetrahydroquinolines with aldehydes proceeded smoothly in the presence of hydrogen halides, and the tricyclic benzazocine derivatives were isolated in good to high yields. The reaction would proceed through the formation and cyclization of the iminium ion intermediate. PMID- 27983864 TI - Subsurface Oxygen in Oxide-Derived Copper Electrocatalysts for Carbon Dioxide Reduction. AB - Copper electrocatalysts derived from an oxide have shown extraordinary electrochemical properties for the carbon dioxide reduction reaction (CO2RR). Using in situ ambient pressure X-ray photoelectron spectroscopy and quasi in situ electron energy-loss spectroscopy in a transmission electron microscope, we show that there is a substantial amount of residual oxygen in nanostructured, oxide derived copper electrocatalysts but no residual copper oxide. On the basis of these findings in combination with density functional theory simulations, we propose that residual subsurface oxygen changes the electronic structure of the catalyst and creates sites with higher carbon monoxide binding energy. If such sites are stable under the strongly reducing conditions found in CO2RR, these findings would explain the high efficiencies of oxide-derived copper in reducing carbon dioxide to multicarbon compounds such as ethylene. PMID- 27983865 TI - Suicide Risk Management Protocol in Post-Cardiac Arrest Survivors: Development, Feasibility, and Outcomes. AB - RATIONALE: Suicidal ideation is an important part of the spectrum of depression, but studies of outcomes after cardiac events often avoid asking about suicide as part of their assessment due to perceived resource constraints and the complexity of managing this finding. OBJECTIVES: To describe the development, feasibility, and outcomes of a suicide risk management protocol implemented by research assistants administering the Patient Health Questionnaire Depression Scale (PHQ 9). METHODS: Patients surviving in-hospital cardiac arrest at any Veterans Affairs hospital during 2014 to 2015 received PHQ-9 screening as a part of longitudinal telephone or mail interviews administered at 3, 6, 9, and 12 months after hospital discharge. Those who screened positive for suicidal ideation were administered a telephone risk assessment protocol. MEASUREMENTS AND MAIN RESULTS: Fifty-five of 366 (15%) interviewed Veterans endorsed suicidal ideation according to the PHQ-9 on 82 of their completed interviews. Of those who endorsed suicidal ideation during their interview, 81% of interviews included passive suicidal ideation without intent or plan. Five (9%) patients were recommended to receive expedited follow-up with a mental health provider or suicide prevention coordinator located within their Veterans Affairs healthcare facility. In 50 (63%) interviews, the patient already had reliable resources, such as a mental health provider or the number to the Veterans Crisis Line. CONCLUSIONS: Suicidal ideation is common after in-hospital cardiac arrest, although most patients are at low risk. Addressing suicidal ideation in an observational research study is feasible, with a detailed protocol and research staff who can respond to incidents of high-risk suicidal ideation in collaboration with study clinicians. PMID- 27983866 TI - Therapeutic Implications of Epigenetic Signaling in Breast Cancer. AB - Breast cancer is a heterogeneous disease and its complexity has hindered the development of efficacious treatments targeting all breast cancer subtypes. Many studies have linked the diversity of breast carcinogenesis and metastasis to aberrant epigenetic signaling and control. Here, we focus on the current state of the discipline and review the major epigenetic enzymes controlling chromatin structure and function in the context of breast cancer, including (1) DNA methyltransferases, (2) lysine methyltransferases and demethylases, (3) protein arginine methyltransferases, and (4) histone acetyltransferases and deacetylases. Moreover, therapeutic drugs targeting these epigenetic enzymes are rapidly emerging and/or undergoing clinical trials. Therefore, we discuss the pharmacological manipulation of epigenetic enzymes for breast cancer treatment and present new clinical and survival outcome analysis on epigenetic factors that have evaded analysis to date. Understanding and pharmacologically exploiting epigenetic regulation in breast cancer promises to be an essential aspect of next generation drug development and adjuvant therapies targeting advanced disease and treatment-resistant tumors. PMID- 27983867 TI - Roles of RFRP-3 in the Daily and Seasonal Regulation of Reproductive Activity in Female Syrian Hamsters. AB - In females, reproductive activity relies on proper integration of daily and environmental changes as well as cyclic sex-steroid feedback. This study sought to investigate the role of the hypothalamic Arg-Phe amide-related peptide (RFRP) 3 in the daily and seasonal control of reproductive activity in female Syrian hamsters by analyzing the RFRP system and investigating the effects of central administration of RFRP-3 at different reproductive stages. In long day-adapted sexually active female hamsters, the number of c-Fos-activated RFRP immunoreactive neurons was reduced in the afternoon of diestrus and proestrus; the latter was correlated with increased kisspeptin activity and the luteinizing hormone (LH) surge. Moreover, acute RFRP-3 administration decreased LH secretion when given midafternoon, before the LH surge, and had no effect at other time points of proestrus or diestrus. These data indicate that RFRP-3 exerts a tonic inhibition on LH secretion, which is lifted at the time of the preovulatory surge on the afternoon of proestrus. In short day-adapted sexually inactive female hamsters, Rfrp expression is strongly inhibited in a sex steroid-independent manner, and prolonged central infusion of RFRP-3 completely reactivated the reproductive axis through increased kisspeptin expression, gonadotropin and estradiol secretion, and gonadal weight. These findings reveal a critical role of RFRP-3 in the control of reproductive activity in female rodents and suggest that RFRP neurons, acting alongside kisspeptin neurons, are essential for proper synchronization of reproductive activity with the time of the day, the stage of the estrous cycle, and the seasonal changes in photoperiod. PMID- 27983868 TI - One Step Forward, One Step Back: Changes in News Coverage of Medical Interventions. AB - During 2005-2013, the award-winning website HealthNewsReview.org offered reviews of major media outlets' news stories related to health interventions, including tests, treatments, dietary changes, and prescription drugs. The reviews offered a measure by which the public and journalists themselves could assess the completeness and usefulness of health coverage across 10 criteria for quality reporting. This study produced an analysis of those reviews from 2005 to 2013, indicating significant changes in key areas. Analysis of 1,889 health news story reviews published by HealthNewsReview.org (HNR) between 2005 and 2013 showed that, on average, the stories reviewed during 2005-2010 successfully met just less than half of the criteria, but by 2010-2013, that average had improved to almost 70%. There were significant improvements over time in news organizations' success in meeting six of HNR's 10 criteria for a successful health news story related to drugs, devices, surgery and other medical procedures, and diet; however, when data for television stories were excluded, only the improvement in avoiding disease-mongering remained significant. In addition, there was a statistically significant decline in the percentage of stories rated satisfactory on establishing the true novelty of the intervention discussed in the story. There was no improvement in quantification of possible harms from medical interventions. Changes over time in meeting the criteria were related to outlet type and story topic. PMID- 27983869 TI - Pharmacological Rescue of Conditionally Reprogrammed Cystic Fibrosis Bronchial Epithelial Cells. AB - Well-differentiated primary human bronchial epithelial (HBE) cell cultures are vital for cystic fibrosis (CF) research, particularly for the development of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs. Culturing of epithelial cells with irradiated 3T3 fibroblast feeder cells plus the RhoA kinase inhibitor Y-27632 (Y), termed conditionally reprogrammed cell (CRC) technology, enhances cell growth and lifespan while preserving cell-of origin functionality. We initially determined the electrophysiological and morphological characteristics of conventional versus CRC-expanded non-CF HBE cells. On the basis of these findings, we then created six CF cell CRC populations, three from sequentially obtained CF lungs and three from F508 del homozygous donors previously obtained and cryopreserved using conventional culture methods. Growth curves were plotted, and cells were subcultured, without irradiated feeders plus Y, into air-liquid interface conditions in nonproprietary and proprietary Ultroser G-containing media and were allowed to differentiate. Ussing chamber studies were performed after treatment of F508 del homozygous CF cells with the CFTR modulator VX-809. Bronchial epithelial cells grew exponentially in feeders plus Y, dramatically surpassing the numbers of conventionally grown cells. Passage 5 and 10 CRC HBE cells formed confluent mucociliary air-liquid interface cultures. There were differences in cell morphology and current magnitude as a function of extended passage, but the effect of VX-809 in increasing CFTR function was significant in CRC-expanded F508 del HBE cells. Thus, CRC technology expands the supply of functional primary CF HBE cells for testing CFTR modulators in Ussing chambers. PMID- 27983870 TI - Kisspeptin in the Hypothalamus of 2 Rat Models of Polycystic Ovary Syndrome. AB - Hyperandrogenism, disturbance of the hypothalamus-pituitary-ovary axis followed by elevated serum luteinizing hormone (LH) levels, and insulin resistance are involved in the complicated pathophysiology of polycystic ovary syndrome (PCOS). Kisspeptin is coexpressed with neurokinin B (NKB) in the arcuate nucleus (ARC), the center of the gonadotropin-releasing hormone pulse generator that is responsible for pulsatile LH secretion. We compared 2 androgenized rat models of PCOS to evaluate the estrous cycle, hormonal profiles, and expression of kisspeptin and NKB in the ARC. Rats in our postnatal dihydrotestosterone (DHT) treatment model exhibited weight gain and persistent diestrus with normal LH levels. In contrast, irregular cycles, with elevated LH serum levels and normal body weight, were found in the prenatally DHT-treated rats. We also found increased signals of kisspeptin and NKB in the ARC of the prenatally DHT-treated rats, and not in the postnatally DHT-treated rats. Our results suggest that prenatal exposure to androgens may result in higher kisspeptin and NKB levels in the ARC, which could be associated with 1 phenotype of PCOS that is characterized by normal body weight and higher LH secretion, whereas in postnatally DHT-treated rats, characteristics such as weight gain and normal LH levels are seen in the obese PCOS phenotype. PMID- 27983871 TI - Difficult Airway Characteristics Associated with First-Attempt Failure at Intubation Using Video Laryngoscopy in the Intensive Care Unit. AB - RATIONALE: Video laryngoscopy has overcome the need to align the anatomic axes to obtain a view of the glottic opening to place a tracheal tube. However, despite this advantage, a large number of attempts are unsuccessful. There are no existing data on anatomic characteristics in critically ill patients associated with a failed first attempt at laryngoscopy when using video laryngoscopy. OBJECTIVES: To identify characteristics associated with first-attempt failure at intubation when using video laryngoscopy in the intensive care unit (ICU). METHODS: This is an observational study of 906 consecutive patients intubated in the ICU with a video laryngoscope between January 2012 and January 2016 in a single-center academic medical ICU. After each intubation, the operator completed a data collection form, which included information on difficult airway characteristics, device used, and outcome of each attempt. Multivariable regression models were constructed to determine the difficult airway characteristics associated with a failed first attempt at intubation. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in sex, age, reason for intubation, or device used between first-attempt failures and first attempt successes. First-attempt successes more commonly reported no difficult airway characteristics were present (23.9%; 95% confidence interval [CI], 20.7 27.0% vs. 13.3%; 95% CI, 8.0-18.8%). In logistic regression analysis of the entire 906-patient database, blood in the airway (odds ratio [OR], 2.63; 95% CI, 1.64-4.20), airway edema (OR, 2.85; 95% CI, 1.48-5.45), and obesity (OR, 1.59; 95% CI, 1.08-2.32) were significantly associated with first-attempt failure. Data collection on limited mouth opening and secretions began after the first 133 intubations, and we fit a second logistic model to examine cases in which these additional difficult airway characteristics were collected. In this subset (n = 773), the presence of blood (OR, 2.73; 95% CI, 1.60-4.64), cervical immobility (OR, 3.34; 95% CI, 1.28-8.72), and airway edema (OR, 3.10; 95% CI, 1.42-6.70) were associated with first-attempt failure. CONCLUSIONS: In this single-center study, presence of blood in the airway, airway edema, cervical immobility, and obesity are associated with higher odds of first-attempt failure, when intubation was performed with video laryngoscopy in an ICU. PMID- 27983874 TI - A More Practical Algorithm for the Rooted Triplet Distance. AB - The rooted triplet distance is a measure of the dissimilarity of two phylogenetic trees with identical leaf label sets. An algorithm by Brodal et al. that computes it in [Formula: see text] time and [Formula: see text] space, where n is the number of leaf labels, has recently been implemented in the software package tqDist. In this article, we show that replacing the hierarchical decomposition tree used in Brodal et al.'s algorithm by a centroid paths-based data structure yields an [Formula: see text]-time and [Formula: see text]-space algorithm that, although slower in theory, is faster in practice as well as less memory consuming. Simulations for values of n up to 4,000,000 support our claims experimentally. PMID- 27983873 TI - Leptin and leptin-receptor polymorphisms in fertile and infertile men. AB - : The association of leptin (LEP) -2548G/A and/or leptin receptor (LEPR) Gln223Arg polymorphisms with male infertility and plasma FSH, LH, and testosterone (T) levels was examined. The genotypes and allele frequency distributions of LEP -2548G/A and LEPR Gln223Arg polymorphisms were investigated in 150 fertile and 150 infertile men by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Also, plasma levels of FSH, LH, and T were measured using commercial ELISA kits. Frequencies of AA, AG and GG genotypes of LEP-2548G/A polymorphism were statistically different in fertile and infertile men (p=0.012). The AG genotype showed a protective effect which could decrease risk of male infertility about 3 fold (p = 0.004). We did not observe any differences in frequencies of LEPR Gln223Arg alleles and genotypes between groups (p > 0.05). Sperm counts from infertile men with the AG and GG genotypes of the LEP polymorphism were significantly higher than AA genotype (p<0.05). Moreover, infertile men who carried the RR genotype of LEPR showed a statistically higher percentage of sperm with progressive motility than individuals with other genotypes (p = 0.004). There was no correlation between different combinations of LEP and LEPR genotypes and LH, FSH, and T levels (p > 0.05). Our study suggests that the LEP -2548G/A polymorphism may play a role in male fertility and the AG genotype may have a protective effect through increasing sperm counts. The distribution of genotypes of LEP -2548G/A polymorphism are different in fertile and infertile males and may be a useful tool in evaluation of male infertility. ABBREVIATIONS: LEP: leptin; LEPR: leptin receptor; T: testosterone; FSH: follicle stimulating hormone; LH: luteinizing hormone. PMID- 27983872 TI - Recovery from Dysphagia Symptoms after Oral Endotracheal Intubation in Acute Respiratory Distress Syndrome Survivors. A 5-Year Longitudinal Study. AB - RATIONALE: Nearly 60% of patients who are intubated in intensive care units (ICUs) experience dysphagia after extubation, and approximately 50% of them aspirate. Little is known about dysphagia recovery time after patients are discharged from the hospital. OBJECTIVES: To determine factors associated with recovery from dysphagia symptoms after hospital discharge for acute respiratory distress syndrome (ARDS) survivors who received oral intubation with mechanical ventilation. METHODS: This is a prospective, 5-year longitudinal cohort study involving 13 ICUs at four teaching hospitals in Baltimore, Maryland. The Sydney Swallowing Questionnaire (SSQ), a 17-item visual analog scale (range, 0-1,700), was used to quantify patient-perceived dysphagia symptoms at hospital discharge, and at 3, 6, 12, 24, 36, 48, and 60 months after ARDS. An SSQ score greater than or equal to 200 was used to indicate clinically important dysphagia symptoms at the time of hospital discharge. Recovery was defined as an SSQ score less than 200, with a decrease from hospital discharge greater than or equal to 119, the reliable change index for SSQ score. Fine and Gray proportional subdistribution hazards regression analysis was used to evaluate patient and ICU variables associated with time to recovery accounting for the competing risk of death. MEASUREMENTS AND MAIN RESULTS: Thirty-seven (32%) of 115 patients had an SSQ score greater than or equal to 200 at hospital discharge; 3 died before recovery. All 34 remaining survivors recovered from dysphagia symptoms by 5-year follow-up, 7 (23%) after 6 months. ICU length of stay was independently associated with time to recovery, with a hazard ratio (95% confidence interval) of 0.96 (0.93-1.00) per day. CONCLUSIONS: One-third of orally intubated ARDS survivors have dysphagia symptoms that persist beyond hospital discharge. Patients with a longer ICU length of stay have slower recovery from dysphagia symptoms and should be carefully considered for swallowing assessment to help prevent complications related to dysphagia. PMID- 27983875 TI - Orbital Cellulitis, Cavernous Sinus Thrombosis, Internal Jugular Vein Thrombus, and Clival Osteomyelitis Secondary to Acute Sinusitis. PMID- 27983876 TI - Risk Factors of Poor Outcomes after Admission for a COPD Exacerbation: Multivariate Logistic Predictive Models. AB - The aim of this study was to identify a multivariate model to predict poor outcomes after admission for exacerbation of chronic obstructive pulmonary disease (COPD). We performed a multicenter, observational, prospective study. Patients admitted to hospital for COPD were followed up for 3 months. Relevant clinical variables at admission were selected. For each variable, the best cut offs for the risk of poor outcome were identified using receiver operating characteristic (ROC) curves. Finally, a stepwise logistic regression model was performed. A total of 106 patients with a mean age of 71.1 (9.8) years were included. The mean maximum expiratory volume in the first second (FEV1)(%) was 45.2%, and the mean COPD assessment test (CAT) score at admission was 24.8 (7.1). At 3 months, 39 (36.8%) patients demonstrated poor outcomes: death (2.8%), readmission (20.8%) or new exacerbation (13.2%). Variables included in the logistic model were: previous hospital admission, FEV1 < 45%, Charlson >= 3, hemoglobin (Hb)<13 g/L, PCO2 >= 46 mmHg, fibrinogen >= 554 g/L, C-reactive protein (CRP)>=45 mg/L, leukocyte count < 9810 * 109/L, purulent sputum, long term oxygen therapy (LTOT) and CAT >= 31 at admission. The final model showed that Hb < 13 g/L (OR = 2.46, 95%CI 1.09-6.36), CRP >= 45 mg/L (OR = 2.91, 95%CI: 1.11-7.49) and LTOT (3.07, 95%CI: 1.07-8.82) increased the probability of poor outcome up to 82.4%. Adding a CAT >= 31 at admission increased the probability to 91.6% (AUC = 0.75; p = 0.001). Up to 36.8% of COPD patients had a poor outcome within 3 months after hospital discharge, with low hemoglobin and high CRP levels being the risk factors for poor outcome. A high CAT at admission increased the predictive value of the model. PMID- 27983877 TI - New insights into the anti-diabetic actions of metformin: from the liver to the gut. AB - INTRODUCTION: Metformin is established as the first-line therapy for type 2 diabetes (T2DM), but its mode of action remains elusive. Elucidation of the mechanisms underlying the anti-diabetic action of metformin may have the potential to optimise its glucose-lowering efficacy and lead to the development of agents acting on novel targets for the management of type 2 diabetes. Areas covered: This review highlights key pharmacokinetic features of metformin, summarises recent insights into its hepatic and gastrointestinal actions relevant to blood glucose homeostasis, and discusses the common gastrointestinal side effects of metformin. Literature concerning these areas was reviewed on PubMed. Expert commentary: The mechanisms by which metformin improves glycaemic control in type 2 diabetes are complex. Although novel hepatic pathways continue to be reported in preclinical studies, there is a lack of human evidence for most of these. Considering the fundamental role of the gastrointestinal tract in the regulation of blood glucose homeostasis and pleiotropic actions of metformin on several gastrointestinal targets relevant to glycaemic control, the gut is likely to represent at least as important a site of metformin action as the liver in the management of type 2 diabetes. PMID- 27983878 TI - Foodborne enterotoxigenic Escherichia coli: from gut pathogenesis to new preventive strategies involving probiotics. AB - Enterotoxigenic Escherichia coli (ETEC) are a major cause of traveler's diarrhea and infant mortality in developing countries. Given the rise of antibiotic resistance worldwide, there is an urgent need for the development of new preventive strategies. Among them, a promising approach is the use of probiotics. Although many studies, mostly performed under piglet digestive conditions, have shown the beneficial effects of probiotics on ETEC by interfering with their survival, virulence or adhesion to mucosa, underlying mechanisms remain unclear. This review describes ETEC pathogenesis, its modulation by human gastrointestinal cues as well as novel preventive strategies with a particular emphasis on probiotics. The potential of in vitro models simulating human digestion in elucidating probiotic mode of action will be discussed. PMID- 27983879 TI - Effects of Simulated Mobile Phone Electromagnetic Radiation on Fertilization and Embryo Development. AB - This study investigated the effects of 935-MHz electromagnetic radiation (ER) on fertilization and subsequent embryonic development in mice. Ovulating mice were irradiated at three ER intensities for 4 h/day (d) or 2 h/d for three consecutive days; the ova were then harvested for in vitro fertilization to observe the 6-h fertilization rate (6-FR), 72-h morula rate (72-MR), and 110-h blastula rate (110 BR). Compared with the control group, the 6-FR, 72-MR, and 110-BR were decreased in the low ER intensity group, but the differences were not significant; in the mid- and high-intensity ER groups, 72-MR and 110-BR in the 4 h/d and 2 h/d subgroups were decreased, showing significant differences compared with the control group. Moreover, the comparison between 4 h/d and 2 h/d subgroups showed significant differences. Mid- and high-intensity ER at 935 MHz can reduce the fertilization rate in mice, and reduce the blastulation rate, thus reducing the possibility of embryo implantation. PMID- 27983880 TI - How ruxolitinib modified the outcome in myelofibrosis: focus on overall survival, allele burden reduction and fibrosis changes. AB - INTRODUCTION: Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor that has shown superiority as compared to available conventional chemotherapies, in terms of reduction in splenomegaly and improvement of symptoms and quality of life. Areas covered: Data published about overall survival in the major randomized sponsored trials and in independent series of patients were detailed. Indeed, data regarding action of ruxolitinib on allele burden reduction and potential activity of the drug on pathogenetic mechanisms involved in increased fibrosis has been reviewed. Expert commentary: Data extrapolated from clinical trials demonstrated an advantage of survival when the drug was compared to placebo or to best available therapy. Moreover, in the long-term, JAK2 allele burden was reduced during treatment and about 50% of patients achieved improvement or stabilization of fibrosis. For this latter activity, several pathways have been involved. In conclusion, ruxolitinib is able to modify the natural outcome of patients affected by myelofibrosis, independently from its nature, both in primary and secondary diseases. PMID- 27983881 TI - Hysingla(r) ER, a once-daily, single-entity hydrocodone with abuse-deterrent properties in treating chronic nonmalignant and nonneuropathic pain in patients with osteoarthritis. AB - OBJECTIVES: Osteoarthritis (OA)-related chronic pain is associated with physical and psychosocial impairment as well as poorer quality of life. There is limited literature on long-term opioid therapy in OA patients. This post hoc analysis of OA patients assessed the long-term safety and effectiveness of a once-daily, single-entity, extended-release formulation of hydrocodone (HYD) with abuse deterrent properties for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which other treatment options are inadequate. METHODS: This is a post hoc analysis of the 307 patients with OA pain from a primary open-label study. Following screening and dose titration, patients who achieved a stable HYD dose continued into a 52-week maintenance period. Supplemental non-opioid or short-acting opioid analgesics were allowed throughout the study. Safety was monitored. Effectiveness evaluations included "average pain over the last 24 hours" scores, "pain right now" scores, Brief Pain Inventory-Short Form and treatment satisfaction questionnaire. RESULTS: No new or unexpected safety concerns emerged during treatment with HYD. HYD demonstrated a safety profile consistent with other u opioid agonists with 22% discontinuations of treatment due to adverse events, a majority of which were related to the study drug. Clinically meaningful analgesia was achieved as mean "average pain over the last 24 hours"; scores decreased by 2.9 points from baseline to the end of maintenance. During the maintenance period, pain severity declined 2.7 points and interference by 2.5 points from baseline. Mean "pain right now" scores were similar at dosing and 12 hours later. A majority of patients reported satisfaction with HYD. CONCLUSION: In OA patients, long-term HYD treatment was generally well tolerated and provided clinically important analgesia. PMID- 27983882 TI - Building a National Framework for Adolescent and Young Adult Hematology and Oncology and Transition from Pediatric to Adult Care: Report of the Inaugural Meeting of the "AjET" Working Group of the German Society for Pediatric Oncology and Hematology. AB - Adolescents and young adults (AYAs) with hemato-oncological problems constitute a heterogenous group with characteristic particularities, specific needs, and age related clinical and unique psychosocial features. Strong collaboration between pediatric and adult hemato-oncology settings is essential to address their needs appropriately. This is not only true for patients who first become ill during adolescence or young adulthood, but equally so for people who contract hemato oncological diseases congenitally or as younger children and who are now becoming old enough to leave the pediatric setting and have to transit into "adult" medical care. Efforts to create environments that meet the specific needs of the AYA population affected by hemato-oncological diseases have been initiated in many countries. Due to international variations between societies in general and healthcare infrastructures in particular, the challenges posed to creating such environments vary considerably from country to country. Aiming at addressing these on a national basis for Germany, a dedicated Working Group on Adolescents, Young Adults, and Transition (Arbeitsgemeinschaft Adoleszenten, junge Erwachsene, Transition, AjET) was established. This meeting report depicts the content and discussions of the first interdisciplinary conference on treatment, transition, and long-term follow-up in AYAs with cancer or chronic/inborn hematological diseases. The AjET group of the German Society for Pediatric Oncology and Hematology (GPOH) intends to increase the national awareness for AYAs; strengthen the collaboration of pediatric and adult care givers; and initiate, promote, and coordinate collaborative activities in the fields of basic and translational research, clinical care, and long-term follow-up aimed at improving the current situation. PMID- 27983883 TI - Intra-arterial therapies for liver cancer: assessing tumor response. AB - INTRODUCTION: Intra-arterial therapies (IATs) play an integral role in the management of unresectable hepatocellular carcinoma and liver metastases. The ability to accurately assess tumor response to intra-arterial therapies is crucial for clinical management. Several one- and two-dimensional manual imaging based response assessment techniques, based both on tumor size or enhancement, have shown to be highly subjective and merely surrogate for the actual tumor as a whole. Areas covered: Given the currently existing literature, we will discuss all available tumor assessment techniques and criteria for liver cancer with a strong emphasis on 3D quantitative imaging biomarkers of tumor response in this review. Expert commentary: The growing role of information technology in medicine has brought about the advent of software-assisted, segmentation-based assessment techniques that address the outstanding issues of a subjective reader and provide for more accurate assessment techniques for the locally treated lesions. Three dimensional quantitative tumor assessment techniques are superior to one- and two dimensional measurements. This allows for treatment alterations and more precise targeting, potentially resulting in improved patient outcome. PMID- 27983884 TI - Extra-motor abnormalities in amyotrophic lateral sclerosis: another layer of heterogeneity. AB - INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease defined by the presence of muscle weakness. The motor features of disease are heterogeneous in site of onset and progression. There are also extra-motor features in some patients. The genetic basis for extra-motor features is uncertain. The heterogeneity of ALS is an issue for clinical trials. Areas covered: This paper reviews the range and prevalence of extra-motor features associated with ALS, and highlights the current information about genetic associations with extra-motor features. Expert commentary: There are extra-motor features of ALS, but these are not found in all patients. The most common is cognitive abnormality. More data is required to ascertain whether extra-motor features arise with progression of disease. Extra-motor features are reported in patients with a range of causative genetic mutations, but are not found in all patients with these mutations. Further studies are required of the heterogeneity of ALS, and genotype/phenotype correlations are required, taking note of extra motor features. PMID- 27983885 TI - Multifocal Kaposiform Hemangioendothelioma Causing Massive Fetal Chylous Ascites. AB - Kaposiform hemangioendothelioma (KHE) is a locally aggressive vascular tumor that usually occurs in soft tissues of the extremity and rarely in the retroperitoneum. We report a unique case of isolated massive fetal ascites attributed to KHE, involving the retroperitoneum and multiple visceral organs, along with the Kasabach-Merritt phenomenon. We suspect that retroperitoneal KHE might have caused massive fetal ascites because of its high potential to invade the lymphatic vessels aggressively in the retroperitoneal space, which possibly permits intestinal lymph leakage into the peritoneal cavities. PMID- 27983887 TI - Does the evidence really suggest that we should completely revascularise bystander disease in patients with ST elevation myocardial infarction undergoing primary angioplasty? Why we still need more definitive trial data to change routine practice. AB - INTRODUCTION: There remains considerable heterogeneity in the management of significant lesions in non culprit coronary arteries in STEMI patients undergoing primary percutaneous coronary intervention (PPCI). Three recent randomised trials have shown clinical outcome benefit in a complete revascularisation approach when compared to PPCI of the culprit artery alone. By contrast, observational data suggest that an aggressive complete revascularisation may not confer clinical benefit and may, in some cases, be harmful. Areas covered: In this review we discuss the three recent randomised trials that have advocated a complete revasculariation approach in addition to data available from registries. Expert commentary: An adequately powered, randomised controlled trial is required to answer the question of whether complete revascularisation in STEMI patients is beneficial and, if so, whether it should be ischaemia directed and whether it should be at the index procedure or staged. PMID- 27983886 TI - Graft-Versus-Host Disease in Adolescents and Young Adults (15-24 Years Old) After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Leukemia in First Complete Remission. AB - PURPOSE: Adolescents and young adults (AYAs) with cancer are a unique group of patients in terms of disease incidence and biology, outcome, and psychosocial needs. This study aims to correlate the risk of graft-versus-host disease (GvHD) and age in a population of children and young adults with acute leukemia undergoing hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). METHODS: We analyzed the outcome of 153 consecutive children (<15 years), AYAs (15-24 years), and adults (25-35 years) with lymphoblastic or myeloid acute leukemia in first CR who underwent HSCT with matched donors after myeloablative conditioning. GvHD prophylaxis was methotrexate and cyclosporine A (CsA) in all patients. RESULTS: The cumulative incidence of grade II-IV acute GvHD (aGvHD) was significantly higher in AYA patients than in children (subdistribution hazard ratio (SHR), 2.04, p = 0.005) or adults (SHR 1.59, p = 0.048). Both gut and skin aGvHD occurred more frequently in AYA patients. Increasing CsA blood levels with age could not fully account for this difference. No difference in terms of grade III-IV aGvHD was observed. Chronic GvHD was more frequent in AYAs (SHR 2.81, p = 0.007) and adults (SHR 2.31, p = 0.033) than in children. No difference in terms of nonrelated mortality and overall survival was observed among the age subgroups. CONCLUSION: Since GvHD occurrence is strongly correlated to quality of life, specific attention should be paid to AYAs undergoing HSCT. Further studies should investigate the reasons for the excess of GvHD observed in this population. PMID- 27983888 TI - Eosinophilic and Neutrophilic Airway Inflammation in the Phenotyping of Mild-to Moderate Asthma and Chronic Obstructive Pulmonary Disease. AB - Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases with different inflammatory phenotypes. Various inflammatory mediators play a role in these diseases. The aim of this study was to analyze the neutrophilic and eosinophilic airway and systemic inflammation as the phenotypic characterization of patients with asthma and COPD. Twenty-four patients with asthma and 33 patients with COPD were enrolled in the study. All the patients were in mild-to-moderate stage of disease, and none of them were treated with inhaled corticosteroids. Concentrations of IL-6, neutrophil elastase (NE), matrix metalloproteinase 9 (MMP-9), eosinophil cationic protein (ECP), and IL-33 and IL 17 in serum and induced sputum (IS) were measured by enzyme-linked immunosorbent assay (ELISA). The cellular composition of blood and IS was evaluated. Hierarchical clustering of patients was performed for the combination of selected clinical features and mediators. Asthma and COPD can be differentiated based on eosinophilic/neutrophilic systemic or airway inflammation with unsatisfactory efficiency. Hierarchical clustering of patients based on blood eosinophil percentage and clinical data revealed two asthma clusters differing in the number of positive skin prick tests and one COPD cluster with two subclusters characterized by low and high blood eosinophil concentrations. Clustering of patients according to IS measurements and clinical data showed two main clusters: pure asthma characterized by high eosinophil/atopy status and mixed asthma and COPD cluster with low eosinophil/atopy status. The neutrophilic phenotype of COPD was associated with more severe airway obstruction and hyperinflation. PMID- 27983889 TI - Interview with Katherine A. High, MD. PMID- 27983890 TI - Gene Therapy Briefs. PMID- 27983891 TI - User-Friendly Technology the Key to Gene-Editing's Bloom: Market for Gene-Editing Tools Estimated at $608m and Growing as New Applications Are Found. PMID- 27983892 TI - Investor Outlook: Solving Gene Therapy Pricing...with a Cures Voucher? AB - Gene therapy reimbursement continues to be an intense topic of discussion in the field given the unique and durable benefits from a single administration and generally small patient populations against a reimbursement framework that is not optimized for such "cures" or long-lived benefits. As more gene therapy programs enter the market and late-stage development, it is increasingly important for the field to define a reimbursement model that works for all stakeholders in order to encourage the next wave of innovation. To add to the discussion around new payment models and potential solutions, we propose a flexible voucher system that takes advantage of existing infrastructure, precedent, and regulatory frameworks. PMID- 27983893 TI - Suitability of blood-pressure-to-height ratio as the criterion for high blood pressure in children in an environmental study. AB - BACKGROUND: Blood-pressure-to-height ratio is considered a simple, accurate, inexpensive and non-age-dependent index for screening high blood pressure in a clinical setting, but its suitability in epidemiological surveys was not taken into consideration. The aim of this study was to test the suitability of blood pressure-to-height ratio against blood pressure for age percentiles for the identification of high blood pressure in an environmental study. METHODS: The sample consisted of 2195 children, aged 3 to 15 years, whose blood pressure was measured as part of an environmental study in Belgrade, Serbia. High blood pressure was estimated using percentiles (gold standard) and blood-pressure-to height ratios for systolic and diastolic pressures separately (proposed criterion). The optimal cut-offs of the blood-pressure-to-height ratio (BPHR) were selected based on Youden's index (sensitivity + specificity - 1) calculated from the receiver operator characteristic curve analysis. RESULTS: The proposed criterion identified five times more cases of high blood pressure in the investigated children of all age groups in comparison to the gold standard. The optimal cut-off values were selected based on the sensitivity and specificity values by age groups and gender. CONCLUSION: Blood-pressure-to-height ratio can be a reliable criterion for the estimation of high blood pressure in epidemiological studies. This is the first study on the applicability of blood pressure-to-height ratio in Serbian children, but it may not be easily generalized to other populations due to small sample size across the examined age groups and potential diversities in risk factors for high blood pressure. Applied in epidemiological studies, BPHR would help researchers estimate the role of certain environmental factors on blood pressure in children. PMID- 27983895 TI - Statement of withdrawal. PMID- 27983894 TI - Health System Advance Care Planning Culture Change for High-Risk Patients: The Promise and Challenges of Engaging Providers, Patients, and Families in Systematic Advance Care Planning. AB - BACKGROUND: The success of a facilitator-based model for advance care planning (ACP) in LaCrosse, Wisconsin, has inspired health systems to aim for widespread documentation of advance directives, but limited resources impair efforts to replicate this model. One promising strategy is the development of interactive, Internet-based tools that might increase access to individualized ACP at minimal cost. However, widespread adoption and implementation of Internet-based ACP efforts has yet to be described. OBJECTIVE: We describe our early experiences in building a systematic, population-based ACP initiative focused on health system wide deployment of an Internet-based tool as an adjunct to a facilitator-based model. METHODS: With the sponsorship of our healthcare system's population health leadership, we engaged a diverse group of clinical stakeholders as champions to design an Internet-based ACP tool and facilitate local practice change. We describe how we simultaneously began to train clinicians in ACP conversations, engage patients and health system employees in thinking about ACP, redesign clinic workflows to accommodate ACP discussions, and integrate the Internet-based tool into the electronic medical record (EMR). RESULTS: Over 18 months, our project engaged two subspecialty clinics in a systematic ACP process and began work with a large primary care practice with a large Medicare Accountable Care Organization at-risk population. Overall, 807 people registered at the Internet site and 85% completed ACPs. CONCLUSION: We learned that changing culture and systems to promote ACP requires a comprehensive vision with simultaneous, interconnected strategies targeting patient education, clinician training, EMR documentation, and community awareness. PMID- 27983898 TI - I Lost a Patient Today. PMID- 27983897 TI - A Comparison of Trans Women, Trans Men, Genderqueer Individuals, and Cisgender Brothers and Sisters on the Bem Sex-Role Inventory: Ratings by Self and Siblings. AB - A U.S. national sample of 295 transgender adults (trans women, trans men, and genderqueer individuals) and their cisgender siblings completed the Bem Sex-Role Inventory about their siblings as well as themselves, which enabled a comparison between self-perceptions and sibling's perceptions of personality characteristics. Self-reported personality characteristics scored as feminine of trans women were not statistically different from those of their cisgender sisters, but they were significantly higher than self-reported femininity scores of trans men, genderqueer individuals, and cisgender brothers. Self-reported personality characteristics scored as masculine of trans men did not differ significantly from those of their cisgender brothers, but they were higher than those of trans women. Trans men and cisgender brothers were viewed by their siblings in a more sex-typed way than they rated themselves, whereas trans women and cisgender sisters were rated by their siblings in a less sex-typed way than they viewed themselves. PMID- 27983896 TI - How often people google for vaccination: Qualitative and quantitative insights from a systematic search of the web-based activities using Google Trends. AB - Nowadays, more and more people surf the Internet seeking health-related information. Information and communication technologies (ICTs) can represent an important opportunities in the field of Public Health and vaccinology. The aim of our current research was to investigate a) how often people search the Internet for vaccination-related information, b) if this search is spontaneous or induced by media, and c) which kind of information is in particular searched. We used Google Trends (GT) for monitoring the interest for preventable infections and related vaccines. When looking for vaccine preventable infectious diseases, vaccine was not a popular topic, with some valuable exceptions, including the vaccine against Human Papillomavirus (HPV). Vaccines-related queries represented approximately one third of the volumes regarding preventable infections, greatly differing among the vaccines. However, the interest for vaccines is increasing throughout time: in particular, users seek information about possible vaccine related side-effects. The five most searched vaccines are those against 1) influenza; 2) meningitis; 3) diphtheria, pertussis (whooping cough), and tetanus; 4) yellow fever; and 5) chickenpox. ICTs can have a positive influence on parental vaccine-related knowledge, attitudes, beliefs and vaccination willingness. GT can be used for monitoring the interest for vaccinations and the main information searched. PMID- 27983899 TI - [The use of microvascular free flaps in head and neck reconstruction performed by the otorhinolaryngologists: a series of 65 flaps]. AB - OBJECTIVES: This study aims to assess the success rate of surgery and postoperative morbidity in patients who underwent major head and neck surgery with reconstruction by microvascular free flaps performed by otolaryngologists. PATIENTS AND METHODS: We retrospectively analyzed the medical records of 63 patients (31 males, 32 females; mean age 47.9+/-12.5 years; range 20-71 years) operated in our clinic between September 2012 - August 2016. The indications of reconstruction by free flap, success rates, need for revision and re-exploration, reasons of flap failure, morbidity and mortality were evaluated. RESULTS: Thirty seven (56.9%) of the 65 microvascular free flaps were radial forearm; 23 flaps (35.4%) were fibula and five flaps (7.7%) were rectus abdominis. Three of the total 65 flaps ended up in failure; accordingly the success rate was 95.4%. Except for these three failure cases, an urgent re-exploration was performed on 13 patients in the first postoperative 48 hours (n=16, %24.6). No permanent major sequel was observed in any of the patients. CONCLUSION: From the otolaryngologists' point of view, we observed that performing microvascular surgery and the successful surgical results not only gives the flexibility in reconstruction but also provides safer resection during ablative surgery. PMID- 27983900 TI - Comparison of the effects of radiofrequency ablation and microdebrider reduction on nasal physiology in lower turbinate surgery. AB - OBJECTIVES: This study aims to compare the effects of radiofrequency ablation and microdebrider reduction in lower turbinate surgery on nasal physiology. PATIENTS AND METHODS: Between January 2009 and March 2010, 40 patients with the complaint of nasal obstruction, who were diagnosed with lower turbinate hypertrophy, were randomly assigned into two groups to undergo either radiofrequency (group 1, n=20) or microdebrider (group 2, n=20) treatments. Nasal obstruction, the grade of turbinate hypertrophy and other symptoms were evaluated with subjective nasal obstruction scale and anterior rhinoscopy before the operation, and three days, seven days, four weeks, and eight weeks after the surgical intervention. RESULTS: The patients in group 2 had a significantly greater symptomatic improvement based on subjective nasal obstruction scale (SNOS) scores than the patients in group 1 (p<0.01). Acoustic rhinometry (ARM) measurements without decongestant application showed significant increase in postoperative MCA2 (Minimum Cross-sectional Area/cm2 2) and Vol 2 (Volume/cm3 2) (p<0.01), while there was no significant change in MCA1 (Minimum Cross-sectional Area/cm2 1) and Vol 1 (Volume/cm3 1). There was no statistically significant difference between the two groups with respect to ARM and anterior rhinoscopy (AnR) parameters (p>0.05). CONCLUSION: Based on these results, both radiofrequency ablation and microdebrider reduction may be considered as minimally invasive, straightforward, and reliable methods that provide sufficient airway passage without disruption of the nasal physiology. PMID- 27983901 TI - The importance of the first three days and other diagnostic indicators in sudden hearing loss. AB - OBJECTIVES: This study aims to compare different therapy methods used for sudden sensorineural hearing losses, to determine the prognostic factors and particularly to investigate the importance of starting the therapy within the first three days of the prognosis. PATIENTS AND METHODS: Between January 1995 and December 2008, the files of 213 patients who were treated in our clinic were reviewed. A total of 155 patients who met the inclusion criteria were included in the study. The study groups were classified according to the prognostic and audiometric factors. RESULTS: With regard to the effectiveness of treatment options, post-treatment audiometric improvement was significantly better in the patients treated with carbogen in addition to the medical therapy compared to the other groups (p=0.018). In terms of the patient characteristics at the time of admission, having vertigo, presence of a descending type audiogram curve and severe hearing loss affected the success of treatment negatively, while mild hearing loss and presence of an ascending type audiogram curve had a positive effect. The recovery rate was higher in patients who were admitted within the first three days (p=0.005). CONCLUSION: It was found that starting the therapy within the first three days and adding the carbogen to the conventional medical treatment may improve the outcome of the treatment. PMID- 27983902 TI - [Treatment approaches to temporal bone osteomas]. AB - OBJECTIVES: This study aims to evaluate treatment approaches in relation to the localization, size and symptoms of temporal bone osteoma according to the complaints of the patient. PATIENTS AND METHODS: We retrospectively reviewed the records of 23 patients (16 males, 7 females; mean age 28.6 years; range 14-69 years) followed up with the diagnosis of temporal bone osteoma at our clinic between January 2005 and April 2016. We obtained the demographic features, clinical presentations (symptoms, location and size of the tumors), treatment approaches and postoperative outcomes of the patients from patients file. Treatment approaches were analyzed according to the characteristics of patients and of the tumor. RESULTS: The most common localization of osteomas was external auditory canal (66%), followed by mastoid bone (21%) and middle ear cavity (13%). The osteoma was detected incidentally in five patients out of 23. Treatment approaches were determined according to the presence of symptoms, size and localization of tumors. CONCLUSION: Physical examination and periodic follow-up is recommended in asymptomatic patients. In symptomatic patients, surgical resection is needed with an appropriate surgical approach based on the location and size of the tumor. PMID- 27983903 TI - Analyses and classification of complexities in rhinoplasties based on factors increasing the difficulty and their appropriate reconstruction. AB - OBJECTIVES: This study aims to classify the factors that make rhinoplasty difficult and appropriate reconstruction of it. PATIENTS AND METHODS: We retrospectively evaluated the records of 103 patients who underwent rhinoplasty at our private clinic between April 2002 and December 2014. The most important reagent affecting the degree of difficulty in our study was the adhesion of the bone and cartilaginous structures to the skin and mucosa, as an outcome of on previous operations. Structural deficiencies in various parts of bone and cartilaginous structures, presence of septum deviation at a very advanced level, asymmetries in the lower and upper lateral cartilages, fracture deformities or trauma-related bone compressions, skin quality and thickness and the age of the patient were other criteria that affected the degree of difficulty of rhinoplasty. Taking these compelling factors into consideration, a difficulty coefficient table was set up with a new classification that determines complexity and suggests appropriate reconstructions. RESULTS: The total of difficulty coefficients of rhinoplasties between 1-3 were considered to be less complex, those between 4-6 as intermediate complex and those being >7 as very complex rhinoplasty. CONCLUSION: Calculation of the difficulty coefficient provides objective determination of the degree of difficulty of the operation. Reconstruction plans, probable duration of surgery, preoperative preparations, all grafts and materials considered for use may be predicted according to the difficulty coefficient. The surgeon can test whether his or her experience is sufficient or not according to the difficulty coefficient. Surgical risks can be assessed in the light of the difficulty coefficient and shared with the patient. PMID- 27983904 TI - Transient bilateral vocal fold paralysis after total thyroidectomy. AB - Vocal fold paralysis is a serious complication of thyroidectomy that is worrisome for health providers and potentially disastrous for the patient and family. A 56 year-old woman presented with bilateral vocal fold paralysis immediately after routine thyroidectomy and neck dissection for a large goiter with compressive symptoms. She was extubated the next day with full recovery of vocal fold motion. We discuss possible causes of vocal fold paralysis, including surgical, metabolic and anesthetic factors. PMID- 27983905 TI - [Cochlear implantation in far advanced otosclerosis: series of four cases]. AB - In this article, we present four patients who underwent cochlear implantation due to far advanced otosclerosis. Preoperative evaluations, intraoperative findings, complications, and postoperative benefits were analyzed. Cochlear implantation is a treatment option providing excellent audiological results for rehabilitation of patients with far advanced otosclerosis. However, facial nerve stimulation after cochlear implantation is observed more frequently in patients with otosclerosis. Also, caution should be paid in patients with otosclerosis in terms of cochlear ossification and inconsistent results. PMID- 27983906 TI - [B-cell non-Hodgkin's lymphoma with the involvement of inferior turbinate: a case report]. AB - The non-Hodgkin's lymphoma is a significant malignant disease that can involve in the extranodal region of the head and neck. It does not show any specific symptoms when it resides in this region. Swelling, pain and ulceration are important clinical findings. In this article, we report a 57-year-old male patient diagnosed with B cell non-Hodgkin's lymphoma by histopathologic examination, who had nasal blockage, snoring and headache complaints for one year, whose endoscopic nasal examination revealed a mass arising from the right inferior turbinate and the mass was removed surgically by endoscopic approach. PMID- 27983907 TI - [Variable prevalence of allergic rhinitis and risk factors affecting the prevalence]. AB - Allergic rhinitis is described as a chronic inflammation of the nasal mucosa causing rhinorrhea, sneezing, nasal congestion and itching, often characterized with conjunctival injection and ocular itching. The prevalence of pediatric allergic rhinitis has recently shown a sharp increase throughout the world. However, there are significant differences among the regions, thus indicating to the influence of varying genetic and environmental factors upon the development of allergic rhinitis. This regional difference is mainly related to the 'western diet' and 'western lifestyle', with its swift changes in environmental and behavioral factors, besides a genetic predisposition. Some main and potential risk factors contributing to the development of allergic rhinitis are still unclear. In this review, we discuss mostly well known and some emerging new risk factors in the light of recent literature. PMID- 27983908 TI - Calcium Concentration in Culture Medium as a Nondestructive and Rapid Marker of Osteogenesis. AB - Artificial bones made of beta-tricalcium phosphate (beta-TCP) combined with bone marrow-derived mesenchymal stromal cells (BM-MSCs) are used for effective reconstruction of bone defects caused by genetic defects, traumatic injury, or surgical resection of bone tumors. However, the selection of constructs with high osteogenic potential before implantation is challenging. The purpose of this study was to determine whether the calcium concentration in BM-MSC culture medium can be used as a nondestructive and simple osteogenic marker for selecting tissue engineered grafts constructed using beta-TCP and BM-MSCs. We prepared three cell passages of BM-MSCs derived from three 7-week-old, male Fischer 344 rats; the cells were cultured in osteoinductive medium in the presence of beta-TCP for 15 days. The medium was replaced with fresh medium on day 1 in culture and subsequently changed every 48 h; it was collected for measurement of osteocalcin secretion and calcium concentration by enzyme-linked immunosorbent assay and X ray fluorescence spectrometry, respectively. After cultivation, the constructs were implanted subcutaneously into the backs of recipient rats. Four weeks after implantation, the alkaline phosphatase (ALP) activity and osteocalcin content of the constructs were measured. A strong inverse correlation was observed between the calcium concentration in the medium and the ALP activity and osteocalcin content of the constructs, with Pearson's correlation coefficients of 0.92 and 0.90, respectively. These results indicate that tissue-engineered bone with high osteogenic ability can be selected before implantation based on low calcium content of the culture medium, resulting in successful bone formation after implantation. This nondestructive, simple method shows great promise for assessing the osteogenic ability of tissue-engineered bone. PMID- 27983909 TI - Tumor Protein D52 (TPD52) Inhibits Growth and Metastasis in Renal Cell Carcinoma Cells Through the PI3K/Akt Signaling Pathway. AB - Tumor protein D52 (TPD52) is a member of the TPD52-like protein family and plays different roles in various types of malignancies. However, its role in renal cell carcinoma (RCC) is still unclear. In this study, we investigated the role of TPD52 in RCC. The mechanism of TPD52 in RCC was also investigated. Our data demonstrated that the expression levels of TPD52 in both mRNA and protein were significantly decreased in RCC cells. Overexpression of TPD52 inhibited proliferation, migration, and invasion with decreased epithelial-mesenchymal transition (EMT) phenotype in RCC cells, as well as attenuated tumor growth in renal cancer xenografts. Mechanistically, overexpression of TPD52 significantly inhibited downregulated phosphorylation levels of PI3K and Akt in RCC cells. In conclusion, the present study demonstrated that TPD52 inhibited growth and metastasis of RCC, at least in part, by suppressing the PI3K/Akt signaling pathway. Therefore, these findings suggest that TPD52 may be a promising therapeutic target for the treatment of human RCC. PMID- 27983911 TI - Validity of Osteoprotegerin and Receptor Activator of NF-kappaB Ligand for the Detection of Bone Metastasis in Breast Cancer. AB - Osteoprotegerin (OPG) is a robust antiresorptive molecule that acts as a decoy receptor for the receptor activator of nuclear factor kappaB ligand (RANKL), the mediator of osteoclastogenesis. This study was designed to explore the possible role of serum OPG and RANKL in detecting bone metastasis in breast cancer and its interaction with clinicopathologic parameters. Serum levels of RANKL and OPG were estimated in 44 metastatic and 36 nonmetastatic breast cancer patients using ELISA kits. Serum OPG levels were significantly reduced in patients with bone metastasis and correlated negatively with the number of bone lesions and CA 15-3 levels. At concentrations <=82 pg/ml, OPG showed a high specificity in identifying the presence of bone metastasis (92%), albeit with low sensitivity (59%), which improved after the exclusion of diabetics and patients treated with aromatase inhibitors (AI). Serum RANKL levels were significantly higher in the presence of bone metastasis and hypercalcemia. At concentrations >12.5 pg/ml, RANKL had an associated sensitivity of 86%, albeit with low specificity (53%), in detecting bone metastasis. The RANKL/OPG ratio significantly increased in the presence of bone metastasis with appropriate sensitivity and specificity (73% and 72%, respectively) at a cutoff of >=0.14 for the detection of bone metastasis. Serum OPG and RANKL/OPG ratios are promising biomarkers for detecting bone metastasis in breast cancer patients. PMID- 27983910 TI - Active Subjects With Autoimmune Type 1 Diabetes Have Better Metabolic Profiles Than Sedentary Controls. AB - Previous studies in humans with type 1 diabetes mellitus (T1D) and in nonobese diabetic mice have investigated the beneficial immunomodulatory potential of aerobic physical activity. Performing high volume of aerobic exercise may favorably regulate autoimmunity in diabetes. We tested whether increased physical activity is a self-sufficient positive factor in T1D subjects. During a 3-month observational period, active (six males; 40.5 +/- 6.1 years; BMI: 24.5 +/- 2.1) and sedentary (four males, three females; 35.9 +/- 8.9 years; BMI: 25.7 +/- 3.8) T1D individuals on insulin pump therapy were studied for metabolic, inflammatory, and autoimmune parameters. At baseline and at the end of a 3-month period, glycosylated hemoglobin (HbA1c), autoantibodies (anti-GAD, anti-ZnT8, anti-IA2, and ICA) and proinflammatory cytokines (IL-6 and TNF-alpha) were evaluated. During the third month of the period, physically active T1D patients showed a significant reduction in the average glucose levels (-9%, p = 0.025, by CGM) compared to the first month values, and even their hyperglycemic episodes (>180 mg/dl) diminished significantly (-24.2%, p = 0.032 vs. first month). Moreover, active T1D subjects exhibited an improved body composition with respect to sedentary controls. No significant changes were detected as to the autoimmune and inflammatory profiles. This study confirms the beneficial role of physical exercise associated with insulin pump therapy in order to improve metabolic control in individuals with T1D. These preliminary positive observations need to be challenged in a prolonged interventional follow-up. PMID- 27983914 TI - Protease Serine S1 Family Member 8 (PRSS8) Inhibits Tumor Growth In Vitro and In Vivo in Human Non-Small Cell Lung Cancer. AB - Protease serine S1 family member 8 (PRSS8), a membrane-anchored serine protease, has been reported to be involved in the development of several human cancers. However, the role of PRSS8 in non-small cell lung cancer (NSCLC) pathogenesis remains unclear. The objective of this study was to investigate PRSS8 expression, biological function, and its related molecular mechanism in NSCLC. Our results showed that PRSS8 was expressed in a low amount in NSCLC cell lines. Ectopic expression of PRSS8 inhibited tumor growth in vitro and in vivo. Furthermore, ectopic expression of PRSS8 inhibited the migration and invasion of NSCLC cells. It also suppressed the EMT process in A549 cells. Mechanistically, we found that the ectopic expression of PRSS8 downregulated the protein expression levels of p JAK1, p-JAK2, and p-STAT3 in A549 cells. Taken together, our study showed that PRSS8 plays an important role in the growth and metastasis of NSCLC. Thus, PRSS8 may be a novel therapeutic target for NSCLC. PMID- 27983913 TI - Precise Regulation of miR-210 Is Critical for the Cellular Homeostasis Maintenance and Transplantation Efficacy Enhancement of Mesenchymal Stem Cells in Acute Liver Failure Therapy. AB - Stem cell transplantation is a promising clinical strategy to cure acute liver failure. However, a low cell survival ratio after transplantation significantly impairs its therapeutic efficacy. This is partly due to insufficient resistance of transplanted stem cells to severe oxidative and inflammatory stress at the injury sites. In the current study, we demonstrated that a small molecule zeaxanthin dipalmitate (ZD) could enhance the defensive abilities against adverse stresses of human adipose-derived mesenchymal stem cells (hADMSCs) in vitro and increase their therapeutic outcomes of acute liver failure after transplantation in vivo. Treatment with ZD dramatically improved cell survival and suppressed apoptosis, inflammation, and reactive oxygen species (ROS) production of hADMSCs through the PKC/Raf-1/MAPK/NF-kappaB pathway to maintain a reasonably high expression level of microRNA-210 (miR-210). The regulation loop between miR-210 and cellular/mitochondrial ROS production was found to be linked by the ROS inhibitor iron-sulfur cluster assembly proteins (ISCU). Pretreatment with ZD and stable knockdown of miR-210 significantly improved and impaired the stem cell transplantation efficacy through the alteration of hepatic cell expansion and injury amelioration, respectively. Vehicle treatment with ZD did not pose any adverse effect on cell homeostasis or healthy animal. In conclusion, elevating endogenous antioxidant level of hADMSCs with ZD significantly enhances their hepatic tissue-repairing capabilities. Maintenance of a physiological level of miR-210 is critical for hADMSC homeostasis. PMID- 27983915 TI - Kallistatin Suppresses Cell Proliferation and Invasion and Promotes Apoptosis in Cervical Cancer Through Blocking NF-kappaB Signaling. AB - Kallistatin has been recognized as an endogenous angiogenesis inhibitor and exerts pleiotropic effects in inhibiting tumor growth, migration, apoptosis, and inflammation. The purpose of the present study was to investigate the potential role and mechanisms of kallistatin in cervical cancer. We demonstrated that kallistatin effectively inhibited cell proliferation and enhanced apoptosis in a dose-dependent manner. Additionally, kallistatin suppressed migration and invasion activities and markedly reduced the expression of matrix-degrading metalloproteinases, progelatinase (MMP-2), MMP-9, and urokinase-type PA (uPA). Kallistatin reversed the epithelial-mesenchymal transition (EMT) and caused the upregulation of epithelial markers such as E-cadherin and inhibited mesenchymal markers such as N-cadherin and vimentin. Moreover, kallistatin led to a marked decrease in the expression of vascular endothelial growth factor (VEGF) and HIF 1alpha. In a xenograft mouse model, kallistatin treatment reduced tumor growth. Importantly, kallistatin strikingly impeded NF-kappaB activation by suppressing IkappaBalpha degradation and the level of phosphorylation of p65. Interestingly, similar to kallistatin, treatment with PDTC (an inhibitor of NF-kappaB) also attenuated cell invasion and migration. Taken together, these findings suggest that kallistatin suppresses cervical cancer cell proliferation, migration, and EMT and promotes cell apoptosis by blocking the NF-kappaB signaling pathway, suggesting that kallistatin may be a novel therapeutic target for cervical cancer treatment. PMID- 27983916 TI - Silencing of A-Kinase Anchor Protein 4 (AKAP4) Inhibits Proliferation and Progression of Thyroid Cancer. AB - A-kinase anchor protein 4 (AKAP4), a member of the A-kinase anchor family of proteins, plays a role in tumor development and progression. However, its expression pattern and function in human thyroid cancer remain obscure. Here we examined AKAP4 expression in thyroid cancer cell lines as well as the effects of AKAP4 on the proliferation and metastasis of thyroid cancer cells. We also explored the molecular mechanism by which AKAP4 mediates the metastatic potential of thyroid cancer cells. Our results revealed that the transcript and protein levels of AKAP4 were significantly upregulated in thyroid cancer cell lines. In vitro experiments showed that knockdown of AKAP4 significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in thyroid cancer cells. Additionally, knockdown of AKAP4 greatly decreased the protein expression of Shh as well as Smo, Ptc, and Gli-1 in ACT-1 cells. Finally, the in vivo nude mice model confirmed that knockdown of AKAP4 attenuated tumor growth. In conclusion, our findings demonstrated that knockdown of AKAP4 inhibited proliferation and metastasis, likely through suppressing the Shh signaling pathway, in thyroid cancer cells. Thus, AKAP4 may act as a potential therapeutic target for human thyroid cancer. PMID- 27983917 TI - CLIC1 Induces Drug Resistance in Human Choriocarcinoma Through Positive Regulation of MRP1. AB - Chemotherapy is typically used to treat choriocarcinoma. However, a small proportion of this malignancy develops resistance to common chemotherapeutic drugs such as methotrexate (MTX) and floxuridine (FUDR). This study aimed to investigate the role and potential mechanisms of chloride intracellular channel protein 1 (CLIC1) in the development of chemoresistance in choriocarcinoma JeG3 cells. Two chemoresistant sublines were induced from their parental cell line JeG3 through intermittent exposure to MTX (named JeG3/MTX) or FUDR (named JeG3/FUDR). It was found that expression of CLIC1 was significantly higher in the chemoresistant sublines JeG3/MTX and JeG3/FUDR than in their parental cell line JeG3. Knockdown of CLIC1 by specific siRNA significantly increased cell sensitivity to MTX and FUDR in vitro and in vivo. Moreover, the high expression of CLIC1 in chemoresistant sublines was associated with upregulation of multidrug resistance-associated protein 1 (MRP1). Knockdown of CLIC1 decreased the expression of MRP1 accordingly. While reexpression of CLIC1 in the parental cell JeG3 increased its resistance to MTX and FUDR, depletion of MRP1 significantly blunted CLIC1 reexpression-mediated acquirement of chemoresistance in JeG3 cells. In conclusion, our results suggest that CLIC1 may serve as a critical mediator of chemoresistance in human choriocarcinoma JeG3 cells. The CLIC1-mediated chemoresistance is achieved through positive regulation of MRP1. Depletion of either CLIC1 or its downstream MRP1 may be a promising therapeutic strategy concerning reversing the chemoresistance in human choriocarcinoma JeG3 cells. PMID- 27983918 TI - Downregulation of MicroRNA-449 Promotes Migration and Invasion of Breast Cancer Cells by Targeting Tumor Protein D52 (TPD52). AB - Our study aimed to investigate whether microRNA-449 (miR-449) plays a key role in regulating the migration and invasion of breast cancer cells via targeting tumor protein D52 (TPD52). The results of the qRT-PCR and Western blotting showed that, in comparison with normal breast tissues and cells, miR-449 was significantly downregulated in breast cancer tissues and cells, while TPD52 was markedly upregulated. After transfection with an miR-449 inhibitor, suppression of miR-449 significantly promoted cell migration and invasion. Also, when miR-449 was overexpressed by transfection with miR-449 mimics, E-cadherin expression significantly increased, and the expression of N-cadherin and vimentin were markedly decreased, whereas the opposite effects were obtained when miR-449 was suppressed by transfection with an miR-449 inhibitor. TPD52 was also confirmed as the direct target of miR-449 via luciferase reporter analysis. Knockdown of TPD52 significantly alleviated the effects of miR-449 overexpression on cell migration and invasion, as well as the expression of E-cadherin, N-cadherin, and vimentin. Our results indicate that downregulation of miR-449 may promote the migration and invasion of breast cancer cells by targeting TPD52. miR-449 may serve as a potential target in the therapy of breast cancer. PMID- 27983919 TI - Overexpression of PER3 Inhibits Self-Renewal Capability and Chemoresistance of Colorectal Cancer Stem-Like Cells via Inhibition of Notch and beta-Catenin Signaling. AB - PER3, a circadian clock gene, plays an important role in colorectal cancer, but its action and underlying mechanism in colorectal cancer stem-like cells (CSCs) remain unclear. In this study, the colorectal CSCs were enriched in colorectal HCT-116 sphere-forming cells, expressing lower levels of stem cell markers CD133, CD44, LGR5, and SOX2 compared with HCT-116 cells. A drug-resistant strain from HCT-116 was established. Western blot and qRT-PCR analysis showed that PER3 was downregulated in colorectal CSCs and drug-resistant HCT-116. Overexpression of PER3 could strengthen 5-FU-induced inhibitory effects on colorectal CSCs, but knockdown of PER3 decreased its inhibition of colorectal CSCs. In addition, overexpression of PER3 in colorectal CSCs resulted in reduced colony formation efficiency in a soft agar medium and self-renewal efficiency. Inversely, knockdown of PER3 enhanced self-renewal of colorectal CSCs. Overexpression of PER3 decreased stemness markers and Notch1, Jagged1, beta-catenin, c-Myc, and LGR5 in colorectal CSCs. When Notch or beta-catenin signaling was inhibited, the chemoresistance and self-renewal capability of colorectal CSCs were decreased. It was confirmed that PER3 can reduce chemoresistance and self-renewal capability of colorectal CSCs via inhibition of Notch and beta-catenin signaling. Our results reveal that PER3 plays a critical role in maintaining the stemness of colorectal CSCs and may be a promising target for elimination of CSCs. PMID- 27983920 TI - CDGSH Iron Sulfur Domain 2 Activates Proliferation and EMT of Pancreatic Cancer Cells via Wnt/beta-Catenin Pathway and Has Prognostic Value in Human Pancreatic Cancer. AB - Recently, increasing evidence has shown that CDGSH iron sulfur domain 2 (CISD2) is involved in the initiation and metastasis of several cancers. However, the evidence of its potential role in pancreatic cancer is still lacking. In our present study, CISD2 was found to be increased in pancreatic cancer samples and multiple cell lines. Moreover, statistical analysis revealed that a high level of CISD2 was related to advanced clinical stage, advanced T-stage, positive vascular invasion, positive distant metastasis, and larger tumor size. In addition, multivariate analysis suggests that CISD2 was an independent prognostic factor in pancreatic cancer. Importantly, downregulation of CISD2 was capable of inhibiting the survival and growth of pancreatic cancer cells. Mechanistic study showed that inactivation of the Wnt/beta-catenin pathway contributed to the CISD2 deficit induced death of pancreatic cancer cells. Furthermore, we showed that CISD2 silencing significantly inhibited EMT via the Wnt/beta-catenin pathway. Finally, in nude mice, the CISD2 deficit suppressed the tumorigenesis of pancreatic cancer cells. Collectively, our study demonstrated that CISD2 could be an independent prognostic factor for pancreatic cancer and suggested that the CISD2/Wnt/beta catenin pathway contributes to the proliferation of pancreatic cancer cells and EMT, hinting at a novel promising molecular target in the therapeutic strategy for pancreatic cancer. PMID- 27983921 TI - Long Noncoding RNA Taurine-Upregulated Gene 1 Promotes Cell Proliferation and Invasion in Gastric Cancer via Negatively Modulating miRNA-145-5p. AB - Long noncoding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) is involved in the development and carcinogenesis of various tumors, suggesting the diagnostic potential of TUG1 in these cancers. However, the exact role of TUG1 and its underlying mechanism in gastric cancer (GC) remain unknown. In this study, the expression of TUG1 and miR-145-5p in GC cell lines and nonmalignant gastric epithelial cell lines was detected by qRT-PCR. BGC-823 and SGC-7901 cells were transfected with si-TUG1, pcDNA 3.1-TUG1, miR-145-5p mimics, or matched controls. The biological function of TUG1 and miR-145-5p in GC cell proliferation and invasion in vitro and tumor growth in vivo was investigated by MTT assay, Transwell invasion assay, and tumor xenograft experiments. The regulating relationship between TUG1 and miR-145-5 was confirmed by luciferase reporter assay. The results showed that TUG1 was significantly overexpressed and miR-145 5p was dramatically downregulated in GC cell lines. TUG1 knockdown strikingly inhibited cell proliferation and invasion in vitro and markedly suppressed tumor growth in vivo. Furthermore, TUG1 could directly bind to miR-145-5p and repress miR-145-5p expression. TUG1 overexpression significantly relieved the inhibition on GC cell proliferation and invasion in vitro and tumor growth in vivo, mediated by miR-145-5p overexpression. In conclusion, TUG1 promotes cell proliferation and invasion in GC via negatively modulating miRNA-145-5p, which undoubtedly contributes to understanding the mechanism of GC occurrence and development. PMID- 27983922 TI - Overexpression of Protease Serine 8 Inhibits Glioma Cell Proliferation, Migration, and Invasion via Suppressing the Akt/mTOR Signaling Pathway. AB - Protease serine 8 (PRSS8), a serine peptidase, has a widespread expression in normal epidermal cells. Recently, many researchers demonstrated downregulation of PRSS8 in cancer tissues as well as its tumor suppressor role in cancer development. However, the biological functions of PRSS8 in glioma remain unclear. In the current study, we demonstrated a decreased expression of PRSS8 in glioma tissues and cell lines. PRSS8 upregulation inhibited glioma cell proliferation, migration, and invasion. In addition, xenograft experiments showed that PRSS8 overexpression suppressed glioma cell growth in vivo. We also found that upregulated PRSS8 reduced the protein expression levels of p-Akt and p-mTOR in glioma cells. Taken together, our study demonstrated that overexpression of PRSS8 inhibited glioma cell proliferation, migration, and invasion via suppressing the Akt/mTOR signaling pathway. Therefore, PRSS8 may act as a novel therapeutic target for glioma. PMID- 27983923 TI - Downregulation of Homeobox B7 Inhibits the Tumorigenesis and Progression of Osteosarcoma. AB - Homeobox B7 (HOXB7), a member of the HOX gene family, plays a role in tumorigenesis. However, until now the expression status and role of HOXB7 in osteosarcoma remain unclear. Therefore, the present study aimed to investigate the functional role and mechanism of HOXB7 in osteosarcoma. Our results demonstrated that HOXB7 was overexpressed in osteosarcoma cell lines. Downregulation of HOXB7 significantly inhibited osteosarcoma cell proliferation in vitro, as well as attenuated xenograft tumor growth in vivo. Downregulation of HOXB7 also inhibited the migration and invasion of osteosarcoma cells. Furthermore, downregulation of HOXB7 significantly suppressed the protein expression levels of p-PI3K and p-Akt in U2OS cells. In summary, our data demonstrated that downregulation of HOXB7 inhibited proliferation, invasion, and tumorigenesis, partly through suppressing the PI3K/Akt signaling pathway in osteosarcoma cells. Our findings provide new insights into the role of HOXB7 in osteosarcoma and new therapeutic targets for the treatment of osteosarcoma. PMID- 27983924 TI - Knockdown of SALL4 Inhibits Proliferation, Migration, and Invasion in Osteosarcoma Cells. AB - Sal-like protein 4 (SALL4) is a zinc finger transcription factor that has been reported to be aberrantly expressed in several human malignancies and identified as an oncogene. However, the potential role of SALL4 in osteosarcoma remains to be elucidated. In this study, we explored the biological functions of SALL4 in osteosarcoma. We found that SALL4 was overexpressed in osteosarcoma tissues and cell lines. Knockdown of SALL4 inhibited osteosarcoma cell proliferation, migration, and invasion in vitro. In addition, SALL4 knockdown suppressed osteosarcoma growth and metastasis in vivo. We also showed that SALL4 knockdown decreased the protein expression of Wnt3a and beta-catenin in osteosarcoma cells. Taken together, our study showed that SALL4 plays an important role in regulating the proliferation, migration, and invasion of osteosarcoma cells. Thus, SALL4 may represent a potential therapeutic target in the treatment of osteosarcoma. PMID- 27983925 TI - Forkhead Box A2 (FOXA2) Inhibits Invasion and Tumorigenesis in Glioma Cells. AB - The forkhead box A2 (FOXA2) is the key transcriptional factor that plays an important role in tumorigenesis. However, until now the expression pattern and role of FOXA2 in glioma have yet to be elucidated. Therefore, the aim of this study was to evaluate the expression of FOXA2 in glioma and investigate its role in glioma cells. Our data showed that FOXA2 was significantly downregulated in human glioma cell lines. Forced expression of FOXA2 suppressed the ability of glioma cells to proliferate, migrate, and invade and influenced the expression level of EMT-associated proteins. In addition, forced expression of FOXA2 attenuated tumor growth of glioma in a nude mouse xenograft model. Mechanistically, we disclosed that forced expression of FOXA2 greatly downregulated the expression of beta-catenin, cyclin D1, and c-Myc in glioma cells. Taken together, these results show that FOXA2 may play an important role in proliferation, invasion, and tumorigenesis in glioma cells. Thus, FOXA2 may be a potential therapeutic target for the treatment of glioma. PMID- 27983927 TI - Oxysterol-Binding Protein-Related Protein 8 Inhibits Gastric Cancer Growth Through Induction of ER Stress, Inhibition of Wnt Signaling, and Activation of Apoptosis. AB - Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide. Oxysterol-binding protein-related protein 8 (ORP8) functions as a sterol sensor that regulates a number of cellular functions. We showed that ORP8 expression was significantly lower in GC tissues and cells. Overexpression of ORP8 significantly inhibited GC cell proliferation in several GC cells. The formation of colonies in AGS cells was inhibited by the overexpression of ORP8. Moreover, overexpression of ORP8 significantly decreased implanted tumor growth in nude mice. Overexpression of ORP8 resulted in a significant increase in CHOP and GRP78 expression and the phosphorylation of PERK, indicating the occurrence of ER stress. Inhibition of ER stress by 4-PBA notably suppressed overexpression of ORP8-induced decrease of GC cell proliferation, formation of colonies, and implanted tumor growth. Overexpression of ORP8 resulted in a significant decrease in Wnt3a and beta-catenin expression, and activation of Wnt signaling by HLY78 markedly blocked overexpression of ORP8-induced decrease in GC cell proliferation, formation of colonies, and implanted tumor growth. 4-PBA inhibited overexpression of ORP8-induced decrease in Wnt signaling. Furthermore, overexpression of ORP8 resulted in significant activation of mitochondrial apoptotic events and increase in apoptosis, which was inhibited by 4-PBA and HLY78. Induction of ER stress, inhibition of Wnt signaling, and apoptotic cell death were involved in ORP8-induced inhibition of GC cell proliferation. These findings indicate that downregulation of ORP8 plays a pivotal role in the progression of GC, and it may be a novel therapeutic target in the treatment of GC. PMID- 27983928 TI - Knockdown of Serine Threonine Tyrosine Kinase 1 (STYK1) Inhibits the Migration and Tumorigenesis in Glioma Cells. AB - Pediatric glioma is a devastating brain tumor. Serine threonine tyrosine kinase 1 (STYK1) is a member of the protein tyrosine kinase family and plays a significant role in the formation of several malignant tumors. However, the expression pattern and role of STYK1 in glioma are not yet clear. The aim of this study was to investigate the role and molecular mechanism of STYK1 in glioma. The results showed that STYK1 was highly expressed in glioma cell lines. We also found that knockdown of STYK1 inhibited cell proliferation, migration, and invasion in vitro as well as tumorigenesis in vivo. Furthermore, knockdown of STYK1 significantly decreased the expression levels of phosphorylation of PI3K and Akt in glioma cells. Taken together, our data suggest that STYK1 plays an important role in the development and progression of glioma. Therefore, STYK1 may represent a novel therapeutic target for the treatment of glioma. PMID- 27983929 TI - Long Noncoding RNA LINC00261 Suppresses Cell Proliferation and Invasion and Promotes Cell Apoptosis in Human Choriocarcinoma. AB - Choriocarcinoma is one of the gestational trophoblastic neoplasias (GTNs) that originate in the chorionic villi and the extravillous trophoblast. Long noncoding RNAs (lncRNAs) are a type of non-protein-coding RNAs that have recently been implicated in human tumorigenesis. The present study investigated the role of the lncRNA LINC00261 in cell proliferation, metastasis, and apoptosis in choriocarcinoma cell lines. The transcription level of LINC00261 was significantly lower in choriocarcinoma tissues and in choriocarcinoma cell lines. Overexpression of LINC00261 caused a decrease in cell proliferation and arrested the cell cycle at the G0/G1 phase. Furthermore, overexpression of LINC00261 inhibited cell migration and invasion. Meanwhile, it promoted cell apoptosis and the relative activities of caspase 3 and caspase 9 in choriocarcinoma JEG-3 and JAR cells. These data suggested that LINC00261 promotes cell proliferation and metastasis in choriocarcinoma. Our data might provide novel insight into the early diagnosis and treatment of choriocarcinoma in clinics. PMID- 27983926 TI - The Regulatory Effects of Transforming Growth Factor-beta on Nerve Regeneration. AB - Transforming growth factor-beta (TGF-beta) belongs to a group of pleiotropic cytokines that are involved in a variety of biological processes, such as inflammation and immune reactions, cellular phenotype transition, extracellular matrix (ECM) deposition, and epithelial-mesenchymal transition. TGF-beta is widely distributed throughout the body, including the nervous system. Following injury to the nervous system, TGF-beta regulates the behavior of neurons and glial cells and thus mediates the regenerative process. In the current article, we reviewed the production, activation, as well as the signaling pathway of TGF beta. We also described altered expression patterns of TGF-beta in the nervous system after nerve injury and the regulatory effects of TGF-beta on nerve repair and regeneration in many aspects, including inflammation and immune response, phenotypic modulation of neural cells, neurite outgrowth, scar formation, and modulation of neurotrophic factors. The diverse biological actions of TGF-beta suggest that it may become a potential therapeutic target for the treatment of nerve injury and regeneration. PMID- 27983930 TI - Downregulation of Ubiquitin-Specific Protease 22 Inhibits Proliferation, Invasion, and Epithelial-Mesenchymal Transition in Osteosarcoma Cells. AB - Ubiquitin-specific protease 22 (USP22), a novel deubiquitinating enzyme, belongs to an extended family of proteins that have ubiquitin hydrolase activity. Recently, USP22 has attracted widespread attention because of its implication in carcinogenesis. However, there have been no studies, to our knowledge, investigating the expression of USP22 in osteosarcoma (OS) and its association with OS progression. In this study, we explored the role of USP22 in OS. We demonstrated that USP22 was highly expressed in OS tissue and cell lines. Downregulation of USP22 inhibited OS cell proliferation, invasion, and epithelial mesenchymal transition (EMT) in vitro. In addition, downregulation of USP22 suppressed OS tumor growth and metastasis in vivo. We also found that the PI3K/Akt signaling pathway was involved in the tumor-promoting effect of USP22 on OS progression. Taken together, we suggest USP22 as a novel therapeutic target for OS. PMID- 27983931 TI - Fibroblast Activation Protein-alpha-Positive Fibroblasts Promote Gastric Cancer Progression and Resistance to Immune Checkpoint Blockade. AB - Gastric cancer (GC) is one of the main causes of cancer death. The tumor microenvironment has a profound effect on inducing tumor growth, metastasis, and immunosuppression. Fibroblast activation protein-alpha (FAP) is a protein that is usually expressed in fibroblasts, such as cancer-associated fibroblasts, which are major components of the tumor microenvironment. However, the role of FAP in GC progression and treatment is still unknown. In this study, we explored these problems based on GC patient samples and experimental models. We found that high FAP expression was an independent prognosticator of poor survival in GC patients. FAP+ cancer-associated fibroblasts (CAFs) promoted the survival, proliferation, and migration of GC cell lines in vitro. Moreover, they also induced drug resistance of the GC cell lines and inhibited the antitumor functions of T cells in the GC tumor microenvironment. More importantly, we found that targeting FAP+ CAFs substantially enhanced the antitumor effects of immune checkpoint blockades in GC xenograft models. This evidence highly suggested that FAP is a potential prognosticator of GC patients and a target for synergizing with other treatments, especially immune checkpoint blockades in GC. PMID- 27983932 TI - Overexpression of RAS-Association Domain Family 6 (RASSF6) Inhibits Proliferation and Tumorigenesis in Hepatocellular Carcinoma Cells. AB - Ras-association domain family 6 (RASSF6), a member of the RASSF family, is frequently downregulated in various types of cancer. However, the roles of RASSF6 in human hepatocellular carcinoma (HCC) are still unclear. In this study, we investigated the biological functions and related molecular mechanisms in HCC. Our results found that RASSF6 is expressed in low amounts in HCC tissues and cell lines. Overexpression of RASSF6 obviously inhibited the proliferation, invasion, and EMT process in HCC cells. Furthermore, overexpression of RASFF6 greatly downregulated the protein levels of phosphorylated focal adhesion kinase (FAK), MMP-2, and MMP-9 in HepG2 cells. Last, overexpression of RASFF6 significantly attenuated tumor growth in Balb/c nude mice. In conclusion, the present study revealed that RASFF6 can inhibit the proliferation, invasion, and migration of HCC cells both in vivo and in vitro. These inhibitory effects are through suppressing FAK phosphorylation, leading to decreased MMP-2/9 expression. RASFF6 is therefore a potential therapeutic target for treating HCC. PMID- 27983933 TI - Knockdown of Cyclin-Dependent Kinase Inhibitor 3 Inhibits Proliferation and Invasion in Human Gastric Cancer Cells. AB - Cyclin-dependent kinase inhibitor 3 (CDKN3) has been reported to promote tumorigenesis. Since it is unclear whether CDKN3 participates in the development of human gastric cancer, this study assessed the association between CDKN3 expression and cell biological function and demonstrated the clinical significance and prognosis of CDKN3 in human gastric cancer. In this study, we found that CDKN3 showed a high expression in 35 paired human gastric cancer tissues and was correlated with poor patient survival, AJCC clinical staging, and recurrence. Silencing of CDKN3 in human gastric cancer cells can significantly reduce proliferation, migration, invasion, and adhesion abilities. Also, silencing of CDKN3 in human gastric cancer cells can induce G0-G1 cell cycle arrest and apoptosis. Detection of cell cycle marker expression showed that CDKN3 knockdown promotes cell cycle arrest by decreasing the expression of CDK2, CDC25A, CCNB1, and CCNB2 in human gastric cancer cells. The results of this study will help elucidate the oncogene function of CDKN3 in human gastric cancer. PMID- 27983934 TI - MicroRNA-219-5p Represses the Proliferation, Migration, and Invasion of Gastric Cancer Cells by Targeting the LRH-1/Wnt/beta-Catenin Signaling Pathway. AB - MicroRNAs (miRNAs) are reportedly involved in gastric cancer development and progression. In particular, miR-219-5p has been reported to be a tumor-associated miRNA in human cancer. However, the role of miR-219-5p in gastric cancer remains unclear. In this study, we investigated for the first time the potential role and underlying mechanism of miR-219-5p in the proliferation, migration, and invasion of human gastric cancer cells. miR-219-5p was found to be markedly decreased in gastric cancer tissues and cell lines compared with adjacent tissues and normal gastric epithelial cells. miR-219-5p mimics or anti-miR-219-5p was transfected into gastric cancer cell lines to overexpress or suppress miR-219-5p expression, respectively. Results showed that miR-219-5p overexpression significantly decreased the proliferation, migration, and invasion of gastric cancer cells. Conversely, miR-219-5p suppression demonstrated a completely opposite effect. Bioinformatics and luciferase reporter assays indicated that miR-219-5p targeted the 3'-untranslated region of the liver receptor homolog-1 (LRH-1), a well characterized oncogene. Furthermore, miR-219-5p inhibited the mRNA and protein levels of LRH-1. LRH-1 mRNA expression was inversely correlated with miR-219-5p expression in gastric cancer tissues. miR-219-5p overexpression significantly decreased the Wnt/beta-catenin signaling pathway in gastric cancer cells. Additionally, LRH-1 restoration can markedly reverse miR-219-5p-mediated tumor suppressive effects. Our study suggests that miR-219-5p regulated the proliferation, migration, and invasion of human gastric cancer cells by suppressing LRH-1. miR-219-5p may be a potential target for gastric cancer therapy. PMID- 27983935 TI - miR-644a Inhibits Cellular Proliferation and Invasion via Suppression of CtBP1 in Gastric Cancer Cells. AB - Epithelial-mesenchymal transition (EMT) is one of the most important mechanisms in the metastasis of various cancers, including gastric cancer (GC). In this study, we explored the putative significance of miR-644a and its role in EMT mediated metastasis of GC. We first detected the expression of miR-644a in a cohort of 107 GC tissues using quantitative RT-PCR. The expression of miR-644a was suppressed in GC tissues and was associated with a later clinical stage and tumor metastasis. Restoring the expression of miR-644a could significantly suppress the migration and invasion of HGC-27 and SGC-7901 cells, which might be correlated to its suppressive effect on the EMT process. We also found that carboxyl-terminal-binding protein 1 (CtBP1) was a putative target gene of miR 644a in GC and might be involved in the suppressive effect. Collectively, through targeting CtBP1-mediated suppression of the EMT process, miR-644a might suppress the tumor metastasis of GC cells. PMID- 27983936 TI - Silencing of Btbd7 Inhibited Epithelial-Mesenchymal Transition and Chemoresistance in CD133+ Lung Carcinoma A549 Cells. AB - Cancer stem cells (CSCs) are responsible for tumorigenesis and recurrence, so targeting CSCs is an effective method to potentially cure cancer. BTB/POZ domain containing protein 7 (Btbd7) has been found in various cancers, including lung cancer and liver cancer, but the role of Btbd7 in non-small cell lung cancer (NSCLC), CSC self-renewal, and chemoresistance is still unknown. Therefore, in this study we found that the ratio of tumor sphere formation and stem cell transcription factors in CD133+ cells was dramatically enhanced compared to parental cells, which indicated successful sorting of CD133+ cells from A549. Meanwhile, Btbd7 and the markers of the epithelial-mesenchymal transition (EMT) process were more highly expressed in CD133+ cells than in parental cells. Silencing of Btbd7 significantly inhibited the self-renewal and EMT process in CD133+ cells. Furthermore, we found that downregulation of Btbd7 promoted cell apoptosis and increased the sensitivity to paclitaxel in CD133+ and parental cells. In conclusion, our results suggest that Btbd7 is a promising agent for the inhibition of survival and chemoresistance of cancer stem-like cells of NSCLC, which may act as an important therapeutic target in NSCLC. PMID- 27983937 TI - Knockdown of Long Noncoding RNA FTX Inhibits Proliferation, Migration, and Invasion in Renal Cell Carcinoma Cells. AB - Renal cell carcinoma (RCC) is one of the most common kidney cancers worldwide. Although great progressions have been made in the past decades, its morbidity and lethality remain increasing. Long noncoding RNAs (lncRNAs) are demonstrated to play significant roles in the tumorigenesis. This study aimed to investigate the detailed roles of lncRNA FTX in RCC cell proliferation and metastasis. Our results showed that the transcript levels of FTX in both clinical RCC tissues and the cultured RCC cells were significantly upregulated and associated with multiple clinical parameters of RCC patients, including familial status, tumor sizes, lymphatic metastasis, and TNM stages. With cell proliferation assays, colony formation assays, and cell cycle assays, we testified that knockdown of FTX in A498 and ACHIN cells with specific shRNAs inhibited cell proliferation rate, colony formation ability, and arrested cell cycle in the G0/G1 phase. FTX depletion also suppressed cell migration and invasion with Transwell assays and wound-healing assays. These data indicated the pro-oncogenic potential of FTX in RCC, which makes it a latent therapeutic target of RCC diagnosis and treatment in the clinic. PMID- 27983938 TI - Chikungunya Fever in Traveler from Angola to Japan, 2016. AB - Simultaneous circulation of multiple arboviruses presents diagnostic challenges. In May 2016, chikungunya fever was diagnosed in a traveler from Angola to Japan. Travel history, incubation period, and phylogenetic analysis indicated probable infection acquisition in Angola, where a yellow fever outbreak is ongoing. Thus, local transmission of chikungunya virus probably also occurs in Angola. PMID- 27983939 TI - Puumala Virus in Bank Voles, Lithuania. AB - Little is known about the presence of human pathogenic Puumala virus (PUUV) in Lithuania. We detected this virus in bank voles (Myodes glareolus) in a region of this country in which previously PUUV-seropositive humans were identified. Our results are consistent with heterogeneous distributions of PUUV in other countries in Europe. PMID- 27983940 TI - Loiasis in US Traveler Returning from Bioko Island, Equatorial Guinea, 2016. AB - The filarial parasite Loa loa overlaps geographically with Onchocera volvulus and Wuchereria bancrofti filariae in central Africa. Accurate information regarding this overlap is critical to elimination programs targeting O. volvulus and W. bancrofti. We describe a case of loiasis in a traveler returning from Bioko Island, Equatorial Guinea, a location heretofore unknown for L. loa transmission. PMID- 27983941 TI - Invasive Infections with Multidrug-Resistant Yeast Candida auris, Colombia. AB - Candida auris is an emerging multidrug-resistant fungus that causes a wide range of symptoms. We report finding 17 cases of C. auris infection that were originally misclassified but correctly identified 27.5 days later on average. Patients with a delayed diagnosis of C. auris had a 30-day mortality rate of 35.2%. PMID- 27983942 TI - Flight motor modulation with speed in the hawkmoth Manduca sexta. AB - The theoretical underpinnings for flight, including animal flight with flapping wings, predict a curvilinear U-shaped or J-shaped relationship between flight speed and the power required to maintain that speed. Experimental data have confirmed this relationship for a variety of bird and bat species but not insects, possibly due to differences in aerodynamics and physiology or experimental difficulties. Here we quantify modulation of the main flight motor muscles (the dorsolongitudinal and dorsoventral) via electromyography in hawkmoths (Manduca sexta) flying freely over a range of speeds in a wind tunnel and show that these insects exhibit a U-shaped speed-power relationship, with a minimum power speed of 2ms-1, indicating that at least large flying insects achieve sufficiently high flight speeds that drag and power become limiting factors. PMID- 27983943 TI - The process of lipid storage in insect oocytes: The involvement of beta-chain of ATP synthase in lipophorin-mediated lipid transfer in the chagas' disease vector Panstrongylus megistus (Hemiptera: Reduviidae). AB - Lipophorin is the main lipoprotein in the hemolymph of insects. During vitellogenesis, lipophorin delivers its hydrophobic cargo to developing oocytes by its binding to non-endocytic receptors at the plasma membrane of the cells. In some species however, lipophorin may also be internalized to some extent, thus maximizing the storage of lipid resources in growing oocytes. The ectopic beta chain of ATP synthase (beta-ATPase) was recently described as a putative non endocytic lipophorin receptor in the anterior midgut of the hematophagous insect Panstrongylus megistus. In the present work, females of this species at the vitellogenic stage of the reproductive cycle were employed to investigate the role of beta-ATPase in the transfer of lipids to the ovarian tissue. Subcellular fractionation and western blot revealed the presence of beta-ATPase in the microsomal membranes of the ovarian tissue, suggesting its localization in the plasma membrane. Immunofluorescence assays showed partial co-localization of beta ATPase and lipophorin in the membrane of oocytes as well as in the basal domain of the follicular epithelial cells. Ligand blotting and co-immunoprecipitation approaches confirmed the interaction between lipophorin and beta-ATPase. In vivo experiments with an anti-beta-ATPase antibody injected to block such an interaction demonstrated that the antibody significantly impaired the transfer of fatty acids from lipophorin to the oocyte. However, the endocytic pathway of lipophorin was not affected. On the other hand, partial inhibition of ATP synthase activity did not modify the transfer of lipids from lipophorin to oocytes. When the assays were performed at 4 degrees C to diminish endocytosis, the results showed that the antibody interfered with lipophorin binding to the oocyte plasma membrane as well as with the transfer of fatty acids from the lipoprotein to the oocyte. The findings strongly support that beta-ATPase plays a role as a docking lipophorin receptor at the ovary of P. megistus, similarly to its function in the midgut of such a vector. In addition, the role of beta-ATPase as a docking receptor seems to be independent of the enzymatic ATP synthase activity. PMID- 27983944 TI - Discovery of a novel insecticidal protein from Chromobacterium piscinae, with activity against Western Corn Rootworm, Diabrotica virgifera virgifera. AB - Western corn rootworm (WCR), Diabrotica virgifera virgifera, is one of the most significant pests of corn in the United States. Although transgenic solutions exist, increasing resistance concerns make the discovery of novel solutions essential. In order to find a novel protein with high activity and a new mode of action, a large microbial collection was surveyed for toxicity to WCR using in vitro bioassays. Cultures of strain ATX2024, identified as Chromobacterium piscinae, had very high activity against WCR larvae. The biological activity from the strain was purified using chromatographic techniques and fractions were tested against WCR larvae. Proteins in the final active fraction were identified by mass spectrometry and N-terminal sequencing and matched to the genome of ATX2024. A novel 58.9kDa protein, identified by this approach, was expressed in a recombinant expression system and found to have specific activity against WCR. Transgenic corn events containing this gene showed good protection against root damage by WCR, with average scores ranging between 0.01 and 0.04 on the Iowa State node injury scale. Sequence analysis did not reveal homology to any known insecticidal toxin, suggesting that this protein may act in a novel way to control WCR. The new WCR active protein is named GNIP1Aa, for Gram Negative Insecticidal Protein. PMID- 27983945 TI - The effect of memantine on trinitrobenzene sulfonic acid-induced ulcerative colitis in mice. AB - Previous reports suggest a significant role for N-Methyl-D-aspartate (NMDA) activation in inflammatory processes. So, this study was conducted to investigate the effect of memantine, a commonly used NMDA receptor antagonist, on inflammatory changes in mice model of colitis. Colitis was induced by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS) (40mg/kg). Animals received memantine (12.5, 25 and 50mg/kg, i.p.), glutamate (2g/kg, p.o.) or dexamethasone (1mg/kg, i.p.) 24h before TNBS instillation and daily thereafter for 4 days. The colonic injury was measured by clinical, macroscopic, microscopic and biochemical analysis. Memantine significantly attenuated the body weight loss, colon weight, the plasma levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and colon level of tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO); as well as macroscopic and microscopic signs of colitis. Oral administration of glutamate had no significant effect on investigated parameters. Memantine as a NMDA antagonist may provide a novel venue for the development of strategies for the treatment of ulcerative colitis. PMID- 27983947 TI - L-Carnitine in rooster semen cryopreservation: Flow cytometric, biochemical and motion findings for frozen-thawed sperm. AB - Rooster semen cryopreservation is not efficient for artificial insemination in breeder flocks. L-Carnitine (LC) has been evaluated for effectiveness in cryopreservation media on the characteristics of rooster sperm after freeze thawing. Motility characteristics, membrane functionality, abnormal morphology, apoptotic like changes, mitochondria activity and lipid peroxidation of rooster sperms were assessed after freeze-thawing with different concentrations of LC in Beltsville medium. Semen samples were collected from 12 roosters, twice a week, and diluted in the extenders that contained different concentrations of LC. Supplementation of Beltsevile with 1 and 2 mM LC was found to result in higher total motility (68.2+/- 1.7% and 69.1+/- 1.7%, respectively), progressive motility (28.4+/- 1.6%, 29.8+/- 1.6%), membrane functionality (76.2+/- 1.9% and 75.9+/- 1.9%), viability (58.2 +/- 1.1%, 59.1 +/- 1.1%) and lower significant of lipid peroxidation (2.53 +/- 0.08 nmol/ml, 2.49 +/- 0.08 nmol/ml) compared to control group containing no LC. Lower motility, progressive motility, and viability were observed in frozen-thawed sperm in extender containing 8 mM LC (35.8+/- 1.7%, 9.6+/- 1.2% and 27.1 +/- 1.2%, respectively) compared to control. Morphology and mitochondrial activity were not affected by different concentrations of LC. Our results showed that supplementation of Beltsville extender with 1 and 2 mM LC significantly improved the quality of rooster sperm quality after freeze-thawing. PMID- 27983950 TI - Elucidating the Role of the Interleukin-10 Receptor in Mucosal Inflammation Uncovers a Potential Treatment for Infantile Inflammatory Bowel Disease. PMID- 27983948 TI - Probing the orientation of inhibitor and epoxy-eicosatrienoic acid binding in the active site of soluble epoxide hydrolase. AB - Soluble epoxide hydrolase (sEH) is an important therapeutic target of many diseases, such as chronic obstructive pulmonary disease (COPD) and diabetic neuropathic pain. It acts by hydrolyzing and thus regulating specific bioactive long chain polyunsaturated fatty acid epoxides (lcPUFA), like epoxyeicosatrienoic acids (EETs). To better predict which epoxides could be hydrolyzed by sEH, one needs to dissect the important factors and structural requirements that govern the binding of the substrates to sEH. This knowledge allows further exploration of the physiological role played by sEH. Unfortunately, a crystal structure of sEH with a substrate bound has not yet been reported. In this report, new photoaffinity mimics of a sEH inhibitor and EET regioisomers were prepared and used in combination with peptide sequencing and computational modeling, to identify the binding orientation of different regioisomers and enantiomers of EETs into the catalytic cavity of sEH. Results indicate that the stereochemistry of the epoxide plays a crucial role in dictating the binding orientation of the substrate. PMID- 27983951 TI - Transarterial Radioembolization for Hepatocellular Carcinoma: Who, When... and Y(90)? PMID- 27983949 TI - Reciprocal regulation of acetyl-CoA carboxylase 1 and senescence in human fibroblasts involves oxidant mediated p38 MAPK activation. AB - We sought to explore the fate of the fatty acid synthesis pathway in human fibroblasts exposed to DNA damaging agents capable of inducing senescence, a state of irreversible growth arrest. Induction of premature senescence by doxorubicin or hydrogen peroxide led to a decrease in protein and mRNA levels of acetyl-CoA carboxylase 1 (ACC1), the enzyme that catalyzes the rate-limiting step in fatty-acid biosynthesis. ACC1 decay accompanied the activation of the DNA damage response (DDR), and resulted in decreased lipid synthesis. A reduction in protein and mRNA levels of ACC1 and in lipid synthesis was also observed in human primary fibroblasts that underwent replicative senescence. We also explored the consequences of inhibiting fatty acid synthesis in proliferating non-transformed cells. Using shRNA technology, we knocked down ACC1 in human fibroblasts. Interestingly, this metabolic perturbation was sufficient to arrest proliferation and trigger the appearance of several markers of the DDR and increase senescence associated beta-galactosidase activity. Reactive oxygen species and p38 mitogen activated protein kinase phosphorylation participated in the induction of senescence. Similar results were obtained upon silencing of fatty acid synthase (FAS) expression. Together our results point towards a tight coordination of fatty acid synthesis and cell proliferation in human fibroblasts. PMID- 27983952 TI - Subcapsular Hepatic Dendritic Cells: Hiding in Plain Sight. PMID- 27983953 TI - Interleukin-22 Connects Smoking and Pancreatic Fibrosis During Chronic Pancreatitis. PMID- 27983954 TI - A lateral flow assay (LFA) for the rapid detection of extraparenchymal neurocysticercosis using cerebrospinal fluid. AB - A lateral flow assay (LFA) for the diagnosis and monitoring of extraparenchymal neurocysticercosis, has been developed. The assay is based on the use of the monoclonal antibody HP10, and when applied to cerebrospinal fluid, correctly identified 34 cases of active extraparenchymal neurocysticercosis, but was negative with 26 samples from treated and cured neurocysticercosis patients and with 20 samples from unrelated neurological diseases. There was complete agreement between the HP10 Ag-ELISA results and the HP10-LFA. The HP10-LFA thus has utility for diagnosis and treatment of extraparenchymal neurocysticercosis, frequently a more dangerous form of the infection. PMID- 27983955 TI - Reconstruction of Anterior Tracheal Defects Using a Bioengineered Graft in a Porcine Model. AB - BACKGROUND: Reconstruction of long-segment tracheal defects can be challenging and a suitable tracheal substitute remains lacking. We sought to create a bioengineered tracheal graft to repair such lesions using acellullar bovine dermis extracellular matrix (ECM) and male human mesenchymal stem cells (hMSCs) and implant it in a porcine model. METHODS: hMSCs were seeded on the ECM and incubated for 1 week with chondrogenic factors. An anterior 4 cm * 3 cm defect was surgically created in the trachea of 4-week-old female Yorkshire pigs. The defect was reconstructed using the bioengineered graft (n = 7) or control (n = 3, ECM only). The study duration was 3 months. RESULTS: Survival ranged from 7 days (n = 3) to 3 months (n = 7). Early death was due to graft malacia (n = 1, control), graft infection (n = 1, bioengineered), and pneumonia (n = 1, bioengineered). There was substantial animal growth at 3 months (>200% weight). Surveillance bronchoscopy showed patent airway, mild stenosis, and integration of the graft with the native trachea. On histology, luminal epithelialization and neovascularization with scant submucosa were observed in both the bioengineered graft and control groups. Chondrogenesis was seen only in the bioengineered graft. The neocartilage was less mature and organized compared to native cartilage. SRY immunostain was positive in the neocartilage but not control or native trachea. CONCLUSIONS: We demonstrate the feasibility of the bioengineered graft for reconstruction of long anterior tracheal defects with favorable short term outcomes. Furthermore, we show its ability to facilitate chondrogenesis, neovascularization, and epithelialization. Importantly, it supported rapid animal growth offering potential solutions for both pediatric and adult applications. PMID- 27983957 TI - IN VITRO RELEASE KINETICS MODEL FITTING OF LIPOSOMES: AN INSIGHT. AB - Liposomes are emerging cargoes for bioactive delivery owing to their widely accepted biocompatible and biodegradable nature. It is always a challenge to control the release of payload for effective delivery to the site of interest. Over the couple of decennia, mathematical modeling of release process is a need of time whether the drug remains in the circulation or reaches at the target site. For establishing a better in vitro - in vivo correlation, release kinetics models viz. Peppas, Higuchi, Weibull, Zero Order and First order including mechanistic models like All-or-None, Toroidal, and Biomembrane models etc. are continuously exploited to predict drug release profile. Most of these models rely on the diffusion equations based on the composition of liposomes and conditions of release. Here, we summarized the crucial reports exploring these models and associated interventions to know the underlying physicochemical release phenomenon. Such mathematical model fitting can be a promising approach to deduce release/delivery process to help in designing the safe and efficacious ("Smart") liposomes. PMID- 27983956 TI - Increasing the accuracy and scalability of the Immunofluorescence Assay for Epstein Barr Virus by inferring continuous titers from a single sample dilution. AB - High Epstein Barr Virus (EBV) titers detected by the indirect Immunofluorescence Assay (IFA) are a reliable predictor of Nasopharyngeal Carcinoma (NPC). Despite being the gold standard for serological detection of NPC, the IFA is limited by scaling bottlenecks. Specifically, 5 serial dilutions of each patient sample must be prepared and visually matched by an evaluator to one of 5 discrete titers. Here, we describe a simple method for inferring continuous EBV titers from IFA images acquired from NPC-positive patient sera using only a single sample dilution. In the first part of our study, 2 blinded evaluators used a set of reference titer standards to perform independent re-evaluations of historical samples with known titers. Besides exhibiting high inter-evaluator agreement, both evaluators were also in high concordance with historical titers, thus validating the accuracy of the reference titer standards. In the second part of the study, the reference titer standards were IFA-processed and assigned an 'EBV Score' using image analysis. A log-linear relationship between titers and EBV Score was observed. This relationship was preserved even when images were acquired and analyzed 3days post-IFA. We conclude that image analysis of IFA processed samples can be used to infer a continuous EBV titer with just a single dilution of NPC-positive patient sera. This work opens new possibilities for improving the accuracy and scalability of IFA in the context of clinical screening. PMID- 27983958 TI - Rebuttal From Dr Freedman. PMID- 27983959 TI - COUNTERPOINT: Is It Time for Pulmonary Concierge Practices? Not Yet. PMID- 27983960 TI - Rebuttal From Drs Foreman, Lopez, and Flenaugh. PMID- 27983961 TI - POINT: Is It Time for Pulmonary Concierge Practices? Yes. PMID- 27983962 TI - Organoids: A new in vitro model system for biomedical science and disease modelling and promising source for cell-based transplantation. PMID- 27983964 TI - Functional consequences of I56ii Dlx enhancer deletion in the developing mouse forebrain. AB - Dlx homeobox genes encode a group of transcription factors that play an essential role during developmental processes including maintaining the differentiation, proliferation and migration of GABAergic interneurons. The Dlx1/2 and Dlx5/6 genes are expressed in the forebrain and are arranged in convergently transcribed bigene clusters, with I12a/I12b and I56i/I56ii cis-regulatory elements (CREs) located in the intergenic region of each cluster respectively. We have characterized the phenotypic consequences of deleting I56ii on forebrain development and spatial patterning of corridor cells that are involved in guiding thalamocortical projections. Here we report that deletion of I56ii impairs expression of Dlx genes and that of potential targets including Gad2 as well as striatal markers Islet1, Meis2, and Ebf1. In addition, I56ii deletion reduces both the binding of DLX2 in the Dlx5/Dlx6 intergenic region and the presence of H3K9Ac at the Dlx5/Dlx6 locus, consistent with the reduced expression of these genes. Deletion of I56ii reduces the expression of the ISLET1 and CTIP2 in the striatum and disrupts the number of parvalbumin and calretinin expressing cells in the adult somatosensory cortex of the DeltaI56ii mice. These data suggest an important regulatory role for I56ii in the developing forebrain by means of a potential regulatory mechanism which may regulate the expression of Dlx genes, notably Dlx6 as well as the spatial patterning of the ventral telencephalon, including possibly corridor cells. PMID- 27983965 TI - Cyanidin-3-glucoside attenuates angiotensin II-induced oxidative stress and inflammation in vascular endothelial cells. AB - Angiotensin II (Ang II) causes oxidative stress and vascular inflammation, leading to vascular endothelial cell dysfunction, and is associated with the development of inflammatory cardiovascular diseases such as atherosclerosis. Therefore, interventions of oxidative stress and inflammation may contribute to the reduction of cardiovascular diseases. Cyanidin-3-glucoside (C3G) plays a role in the prevention of oxidative damage in several diseases. Here, we investigated the effect of C3G on Ang II-induced oxidative stress and vascular inflammation in human endothelial cells (EA.hy926). C3G dose-dependently suppressed the free radicals and inhibited the nuclear factor-kappa B (NF-kappaB) signaling pathway by protecting the degradation of inhibitor of kappa B-alpha (IkappaB-alpha), inhibiting the expression and translocation of NF-kappaB into the nucleus through the down-regulation of NF-kappaB p65 and reducing the expression of inducible nitric oxide synthase (iNOS). Pretreatment with C3G not only prohibited the NF kappaB signaling pathway but also promoted the activity of the nuclear erythroid related factor 2 (Nrf2) signaling pathway through the upregulation of endogenous antioxidant enzymes. Particularly, we observed that C3G significantly enhanced the production of superoxide dismutase (SOD) and induced the expression of heme oxygenase (HO-1). Our findings confirm that C3G can protect against vascular endothelial cell inflammation induced by AngII. C3G may represent a promising dietary supplement for the prevention of inflammation, thereby decreasing the risk for the development of atherosclerosis. PMID- 27983963 TI - Simultaneous paralogue knockout using a CRISPR-concatemer in mouse small intestinal organoids. AB - Approaches based on genetic modification have been invaluable for investigating a wide array of biological processes, with gain- and loss-of-function approaches frequently used to investigate gene function. However, the presence of paralogues, and hence possible genetic compensation, for many genes necessitates the knockout (KO) of all paralogous genes in order to observe clear phenotypic change. CRISPR technology, the most recently described tool for gene editing, can generate KOs with unprecedented ease and speed and has been used in adult stem cell-derived organoids for single gene knockout, gene knock-in and gene correction. However, the simultaneous targeting of multiple genes in organoids by CRISPR technology has not previously been described. Here we describe a rapid, scalable and cost effective method for generating double knockouts in organoids. By concatemerizing multiple gRNA expression cassettes, we generated a 'gRNA concatemer vector'. Our method allows the rapid assembly of annealed synthetic DNA oligos into the final vector in a single step. This approach facilitates simultaneous delivery of multiple gRNAs to allow up to 4 gene KO in one step, or potentially to increase the efficiency of gene knockout by providing multiple gRNAs targeting one gene. As a proof of concept, we knocked out negative regulators of the Wnt pathway in small intestinal organoids, thereby removing their growth dependence on the exogenous Wnt enhancer, R-spondin1. PMID- 27983966 TI - Gastroprotective effects of Kangfuxin-against ethanol-induced gastric ulcer via attenuating oxidative stress and ER stress in mice. AB - Oxidative stress and ER stress play a role in the pathogenesis of gastric ulcer. Kangfuxin (KFX) has been used to treat gastric ulcer in patients. However, the underlying mechanisms of KFX action remain unclear. The current study was undertaken to evaluate the gastroprotective effects of KFX and to determine its potential mechanisms. Ethanol-induced gastric ulcer mouse model was employed. Ethanol pretreated mice were treated with low (0.02 g/kg) and high (0.05 g/kg) dose of KFX for 14 days. Cimetidine (0.8 g/kg) was used as positive control. Histological evaluation of the gastric mucosa revealed that mice treated with ethanol exhibited severe gastric mucosal damage. Ethanol treatment increased plasma and gastric MDA level, decreased plasma and gastric SOD activity, and reduced gastric HO-1 and GCL-c mRNA levels. ER stress markers (CHOP, GRP78, and caspase 12) were up-regulated upon ethanol administration. Moreover, increased cell apoptosis and pro-apoptotic protein Bax and caspase 3 were observed in ethanol treated mice, while the anti-apoptotic protein Bcl 2 was inhibited. Finally, KFX treatment reversed ethanol-induced phenotypes and ameliorated gastric ulcer. Our results demonstrated that the gastroprotective effects of KFX against ethanol-induced gastric ulcer could be attributed to its anti-oxidative stress, anti-ER stress and anti-apoptotic effects. PMID- 27983967 TI - MiR-200a acts as an oncogene in colorectal carcinoma by targeting PTEN. AB - The expression pattern of miR-200a in different types of cancer is diverse, and its mechanism in tumorigenesis has yet to be elucidated. In this study, miR-200a was significantly upregulated in the cancer tumor tissues of colorectal cancer (CRC) patients, and its expression was positively correlated with the degree of tumor differentiation. Overexpression of miR-200a enhanced cell proliferation, migration, and invasion. To understand the potential mechanism of miR-200a in tumorigenesis, we showed that miR-200a directly targeted phosphatase and tensin homolog (PTEN). To test the clinical relevance of these results, we used 107 pairs of CRC and adjacent normal tissues, analyzed miR-200a levels and PTEN expression in these tissues, and found that miR-200a levels were significantly inversely correlated with PTEN levels in the cancer tissues. These results suggest that miR-200a plays an oncogene role by regulating PTEN signaling in CRC. Our findings present important implications for further understanding the signaling mechanisms involved in modulating CRC tumorigenesis. PMID- 27983968 TI - Cardiac fibroblast cytokine profiles induced by proinflammatory or profibrotic stimuli promote monocyte recruitment and modulate macrophage M1/M2 balance in vitro. AB - Macrophage polarization plays an essential role in cardiac remodeling after injury, evolving from an initial accumulation of proinflammatory M1 macrophages to a greater balance of anti-inflammatory M2 macrophages. Whether cardiac fibroblasts themselves influence this process remains an intriguing question. In this work, we present evidence for a role of cardiac fibroblasts (CF) as regulators of macrophage recruitment and skewing. Adult rat CF, were treated with lipopolysaccharide (LPS) or TGF-beta1, to evaluate ICAM-1 and VCAM-1 expression using Western blot and proinflammatory/profibrotic cytokine secretion using LUMINEX. We performed in vitro migration and adhesion assays of rat spleen monocytes to layers of TGF-beta1- or LPS-pretreated CF. Finally, TGF-beta1- or LPS-pretreated CF were co-cultured with monocyte, to evaluate their effects on macrophage polarization, using flow cytometry and cytokine secretion. There was a significant increase in monocyte adhesion to LPS- or TGF-beta1-stimulated CF, associated with increased CF expression of ICAM-1 and VCAM-1. siRNA silencing of either ICAM-1 or VCAM-1 inhibited monocyte adhesion to LPS-pretreated CF; however, monocyte adhesion to TGF-beta1-treated CF was dependent on only VCAM-1 expression. Pretreatment of CF with LPS or TGF-beta1 increased monocyte migration to CF, and this effect was completely abolished with an MCP-1 antibody blockade. LPS-treated CF secreted elevated levels of TNF-alpha and MCP-1, and when co cultured with monocyte, LPS-treated CF stimulated increased macrophage M1 polarization and secretion of proinflammatory cytokines (TNF-alpha, IL-12 and MCP 1). On the other hand, CF stimulated with TGF-beta1 produced an anti-inflammatory cytokine profile (high IL-10 and IL-5, low TNF-alpha). When co-cultured with monocytes, the TGF-beta1 stimulated fibroblasts skewed monocyte differentiation towards M2 macrophages accompanied by increased IL-10 and decreased IL-12 levels. Taken together, our results show for the first time that CF can recruit monocytes (via MCP-1-mediated chemotaxis and adhesion to ICAM-1/VCAM-1) and induce their differentiation to M1 or M2 macrophages (through the CF cytokine profile induced by proinflammatory or profibrotic stimuli). PMID- 27983969 TI - Clinical and laboratory characteristics, epidemiology, and outcomes of murine typhus: A systematic review. AB - Murine or endemic typhus, a febrile disease caused by Rickettsia typhi, is often misdiagnosed due to its non-specific presentation. We sought to evaluate all available evidence in the literature regarding the clinical and laboratory manifestations, epidemiological characteristics, and outcomes of murine typhus. Pubmed was searched for all articles providing available data. In an effort to incorporate contemporary data, only studies from 1980 were included. Thirty-three case series including 2074 patients were included in final analysis. Available evidence suggests that the classic triad of fever, headache and rash is encountered in only one-third of patients. Other frequent symptoms were chills, malaise, myalgia, and anorexia. A tetrad of reported laboratory abnormalities consisting of elevated liver enzymes, lactate dehydrogenase, erythrocyte sedimentation rate and hypoalbuminemia was detected. Complications were observed in one-fourth of patients, reported mortality was extremely low, but untreated patients had notably longer duration of fever. Among epidemiological characteristics, a seasonal distribution with most cases reported during warmer months, was the most prominent finding. Murine typhus in children exhibits several different characteristics, with abdominal pain, diarrhea, and sore throat reported more commonly, higher frequency of anemia, lower frequency of hypoalbuminemia, hematuria and proteinuria and a much lower rate of complications. This systematic review of published evidence provides a thorough description of the clinical and laboratory features of murine typhus and highlights important differences in children. PMID- 27983970 TI - The new situation of cutaneous leishmaniasis after Syrian civil war in Gaziantep city, Southeastern region of Turkey. AB - Cutaneous leishmaniasis (CL) is an important public health problem with around 2.000 autochthonous reported cases each year in Turkey. Due to the civil war in Syria, Turkey received around three million refugees and they are mainly located at either camps or homes in south/southeastern part of Turkey. In the present study, we aimed to collect samples from CL suspected patients admitting to State Hospital in Gaziantep City and perform parasitological and DNA-based techniques for diagnosis as well as species identification of the parasite for better understanding the prevalence of each species among Turkish and Syrian patients in the region. The collection of samples was carried out between January 2009 and July 2015. The lesion aspiration samples were taken and stained with Giemsa stain followed by microscopical examination for parasitological diagnosis. After the DNA extraction from Giemsa stained slides, real time and semi-nested PCRs both targeting ITS1 region were performed for molecular diagnosis and species identification. A total of 567 people were admitted to the hospital with the suspicion of CL and 263 (46.4%) of them were found to be positive by parasitological examination. One hundred seventy-four (66.15%), 88 (33.46%) and 1 (0.38%) of them were Turkish, Syrians and Afghan, respectively. Slide samples obtained from 34 CL suspected patients were analyzed by PCR and 20 of them were found positive. Eighteen (13 Turkish and 13 Syrians) of the positive samples were identified as L. tropica, while two (1 Turkish and 1 Syrian) of them were L. infantum. In conclusion, the effects of Syrian civil war on the epidemiology of CL in Gaziantep city is demonstrated in the present study. The use of molecular tool in the diagnosis of leishmaniasis is effective, sensitive and time saving which will enable the species typing. Species typing of the causative agent in endemic areas will bring valuable data to epidemiological knowledge. PMID- 27983971 TI - Immune-protective effect of echinococcosis on colitis experimental model is dependent of down regulation of TNF-alpha and NO production. AB - Hydatid disease (echinococcosis) is a chronic, endemic helminthic disease caused by the larval stage of the tapeworm, Echinococcus granulosus. This disease is endemic in many parts of the world, such as the Mediterranean area, and in particular in Algeria. Helminth parasites have developed complex strategies to modulate the immune responses of their hosts through versatile immune-regulatory mechanisms. These mechanisms may regulate immune responses associated with inflammatory diseases such as inflammatory bowel diseases (IBD). the goal of this study was to investigate the effect of Echinococcus granulosus infection on the development of dextran sulfate sodium (DSS)-induced colitis. Our results demonstrated that E. granulosus infection significantly improved the clinical symptoms and histological scores observed during DSS-induced colitis, and also maintained mucus production by goblet cells. Interestingly, this infection reduced Nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) production and attenuated inducible nitric oxide synthase (iNOS) and nuclear factor-kappaB (NF-kappaB) expression in colonic tissues. Collectively, our data support the hygiene hypothesis and indicate that prior infection with E. granulosus can effectively protect mice from DSS-induced colitis by enhancing immune-regulatory mechanisms. PMID- 27983972 TI - Early detection of Trichinella spiralis DNA in the feces of experimentally infected mice by using PCR. AB - The aim of this study was to detect Trichinella spiralis DNA in mouse feces during the early stages of infection using PCR. The target gene fragment, a 1.6kb repetitive sequence of T. spiralis genome, was amplified by PCR from feces of mice infected with 100 or 300 larvae at 3-24h post infection (hpi) and 2-28dpi. The sensitivity of PCR was 0.016 larvae in feces. The primers used were highly specific for T. spiralis. No cross-reactivity was observed with the DNA of other intestinal helminths. T. spiralis DNA was detected in 100% (12/12) of feces of mice infected with 100 or 300 larvae as early as 3hpi, with the peak detection lasting to 12-24hpi, and then fluctuating before declining gradually. By 28dpi, the detection rate of T. spiralis DNA in feces of the two groups of infected mice decreased to 8.33% and 25%, respectively. PCR detection of T. spiralis DNA in feces is simple and specific; it might be useful for the early diagnosis of Trichinella infection. PMID- 27983973 TI - Agroecology and healthy food systems in semi-humid tropical Africa: Participatory research with vulnerable farming households in Malawi. AB - This paper assesses the relationship between agroecology, food security, and human health. Specifically, we ask if agroecology can lead to improved food security and human health among vulnerable smallholder farmers in semi-humid tropical Africa. The empirical evidence comes from a cross-sectional household survey (n=1000) in two districts in Malawi, a small country in semi-humid, tropical Africa. The survey consisted of 571 agroecology-adoption and 429 non agroecology-adoption households. Ordered logistics regression and average treatment effects models were used to determine the effect of agroecology adoption on self-reported health. Our results show that agroecology-adoption households (OR=1.37, p=0.05) were more likely to report optimal health status, and the average treatment effect shows that adopters were 12% more likely to be in optimal health. Furthermore, being moderately food insecure (OR=0.59, p=0.05) and severely food insecure (OR=0.89, p=0.10) were associated with less likelihood of reporting optimal health status. The paper concludes that with the adoption of agroecology in the semi-humid tropics, it is possible for households to diversify their crops and diets, a condition that has strong implications for improved food security, good nutrition and human health. PMID- 27983974 TI - Glycoprotein quality control-related proteins effectively inhibit fibrillation of amyloid beta 1-42. AB - Formation of amyloid beta (Abeta) aggregates is a risk factor for Alzheimer's disease. Accumulation of Abeta aggregates on the cell surface causes oxidative stress, and ultimately results in cell death. Consequently, inhibition of aggregate formation is predicted to be beneficial. Recently, translocation of glycoprotein quality control-related (GPQC) proteins such as chaperones and protein disulfide-isomerase (PDI) family members was reported under oxidative stress conditions. Therefore, it is possible that GPQC proteins contact Abeta peptides on the cell membrane during stress conditions. Here, we examined the effect of ER resident proteins on Abeta aggregation. Our results show that minimal expression of GPQC proteins enables Abeta to effectively avoid aggregation. Moreover, further analyses show that Abeta structure remains in the monomer state in the presence of ER proteins. Thus, our findings show that GPQC proteins have strong affinity for Abeta monomers, and suggests that the interaction between them repeatedly associates and dissociates in a short period of time. PMID- 27983976 TI - Saturated fatty acid in the phospholipid monolayer contributes to the formation of large lipid droplets. AB - The degree of saturation of fatty acid chains in the bilayer membrane structure is known to control membrane fluidity and packing density. However, the significance of fatty acid composition in the monolayers of lipid droplets (LDs) has not been elucidated. In this study, we noted a relationship between the size of LDs and the fatty acid composition of the monolayer. To obtain large LDs, we generated NIH3T3 cells overexpressing fat-specific protein 27 (FSP27). This induced the fusion of LDs, resulting in larger LDs in FSP27-overexpressing cells compared with LDs in control cells. Moreover, the lipid extracts of LDs from FSP27-overexpressing cells reconstituted large-droplet emulsions in vitro, implying that the lipid properties of LDs might affect the size of LDs. FSP27 overexpressing cells had more saturated fatty acids in the phospholipid monolayer of the LDs compared with control cells. To further investigate the effects of the degree of phospholipid unsaturation on the size of LDs, we synthesized artificial emulsions of a lipid mixed with distearoylphosphatidylcholine (DSPC, diC18:0-PC) and with dioleoylphosphatidylcholine (DOPC, diC18:1n-9-PC) and compared the sizes of the resulting LDs. The emulsions prepared from saturated PC had larger droplets than those prepared from unsaturated PC. Our results suggest that saturated fatty acid chains in phospholipid monolayers might establish the form and/or stability of large LDs. PMID- 27983977 TI - Inhibition of tyrosinase activity and melanin production by the chalcone derivative 1-(2-cyclohexylmethoxy-6-hydroxy-phenyl)-3-(4-hydroxymethyl-phenyl) propenone. AB - Abnormal accumulation of melanin pigments in the skin can be lead to hyperpigmentation disorders and melanoma. Melanin biosynthesis is ultimately regulated by the rate-limiting enzyme tyrosinase. In the present study, we synthesized chalcone derivatives and identified 1-(2-cyclohexylmethoxy-6-hydroxy phenyl)-3-(4-hydroxymethyl-phenyl)-propenone (chalcone-21) as an anti-melanogenic substance in B16F10 melanoma cells. Chalcone-21 strongly inhibited cellular melanin production and tyrosinase activity in B16F10 melanoma cells stimulated with alpha-melanocyte stimulating hormone (alpha-MSH) or protoporphyrin IX. In addition, the compound suppressed not only the expression of tyrosinase, tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor (MITF), but also the transcriptional activity of tyrosinase and MITF. Our results demonstrated chalcone-21 to be an effective depigmenting agent. PMID- 27983978 TI - O-GlcNAc is required for the survival of primed pluripotent stem cells and their reversion to the naive state. AB - "Naive" mouse embryonic stem cells (ESCs) are derived from pre-implantation embryos and possess pluripotency, the ability to differentiate into any cell type of the body. "Primed" mouse epiblast stem cells (EpiSCs) are also pluripotent but are derived from post-implantation embryos. ESC-derived EpiSCs (ESD-EpiSCs) are "primed" pluripotent stem cells and can revert to naive reverted ESCs (rESCs). O linked beta-N-acetylglucosaminylation (O-GlcNAcylation) is a posttranslational modification in the cytoplasm and nucleus. O-GlcNAc is transferred to serine and threonine residues of proteins by O-GlcNAc transferase (Ogt) and removed from them by O-GlcNAcase (Oga). In naive ESCs, O-GlcNAc contributes to maintain the undifferentiated state. In the transition from naive state to primed state, Ogt maintains cell survival, whereas Oga has no function. However, the function of O GlcNAc in primed ESD-EpiSCs and during the reversion from the primed state to naive rESCs remains unclear. Here, we show that Ogt is required for the survival of primed ESD-EpiSCs. The expression of cytosolic Oga was significantly increased during induction from naive ESCs to primed ESD-EpiSCs. Furthermore, both Ogt and Oga were required for the reversion from primed ESD-EpiSCs to naive rESCs. These findings indicate that O-GlcNAcylation plays an important role in the survival of primed ESD-EpiSCs and in their reversion to naive rESCs. PMID- 27983979 TI - Ibandronate concomitantly blocks immobilization-induced bone and muscle atrophy. AB - Both bone and muscle volume is concomitantly reduced under immobilization conditions; however, no single drug is currently available to block these outcomes simultaneously. Bisphosphonates are utilized clinically to inhibit osteoclast-dependent bone resorption, but their effects on muscle are largely unknown. Here we show that skeletal muscle is a direct target of the bisphosphonate ibandronate (IBN) and that reduced muscle volume and induction of Atrogin-1 and MuRF1, both atrogenes, are significantly inhibited by IBN administration in vivo using a mouse model of muscle atrophy. IBN treatment also significantly blocked immobilization-induced bone loss in vivo. We also report that expression of Atrogin-1 and MuRF1 and accumulation of Smad2/3 proteins, which are upstream of atrogines, occurred following serum starvation of myogenic C2C12 cells in vitro, effects significantly inhibited by IBN treatment. Interestingly, IBN effects on C2C12 cells were abrogated by MG132, an ubiquitin/proteasome inhibitor, suggesting that IBN functions via the ubiquitin proteasome system. Our findings lend new insight into the role of IBN in preventing muscle atrophy. PMID- 27983980 TI - Muscle fiber-type conversion in the transgenic pigs with overexpression of PGC1alpha gene in muscle. AB - The peroxisome proliferator-activated receptor gamma, co-activator 1 alpha(PGC1alpha) effectively induced the biosynthesis of the mitochondria and the energy metabolism, and also regulated the muscle fiber-type shift. Overexpression of PGC1alpha gene in mice led to higher oxidative muscle fiber composition in muscle. However, no researches about the significant differences of muscle fiber phenotype in pigs after PGC1alpha overexpression had been reported. The composition of muscle fiber-types which were distinguished by four myosin heavy chain(MYHC) isoforms, can significantly affect the muscle functions. In our study, we generated the transgenic pigs to investigate the effect of overexpression of PGC1alpha gene on muscle fiber-type conversion. The results showed that the number of oxidative muscle fiber(type1 muscle fiber) was increased and the number of glycolytic muscle fiber(type2b muscle fiber) was decreased in the transgenic pigs. Furthermore, we found that PGC1alpha overexpression up-regulated the expression of MYHC1 and MYHC2a and down-regulated the expression of MYHC2b.The analysis of genes expression demonstrated the main differentially expressed genes were MSTN, Myog and FOXO1. In conclusion, the overexpression of PGC1alpha gene can promote the glycolytic muscle fiber transform to the oxidative muscle fiber in pigs. PMID- 27983981 TI - CUL4A functions as an oncogene in ovarian cancer and is directly regulated by miR 494. AB - Cullin 4A (CUL4A), as a well-defined oncogene, has been reported to be upregulated in ovarian cancer clinically. However, the biological functions of CUL4A and the molecular mechanism underlying its upregulation in ovarian cancer remains unknown throughly. Here, we show that expression of CUL4A is significantly higher in ovarian cancer tissues compared to corresponding non cancerous tissues. Moreover, silencing of CUL4A by siRNA markedly inhibits cell proliferation, invasion and epithelial-mesenchymal transition (EMT). We identified CUL4A as a novel target gene of miR-494. Further investigations showed that miR-494 was remarkably downregulated and correlated with poor prognosis in ovarian cancer. Overexpression of miR-494 inhibited proliferation, migration, invasion and EMT of ovarian cancer cells by directly suppressing CUL4A expression. Therefore, our findings indicate that miR-494/CUL4A axis is important in the control of ovarian cancer tumorigenesis. PMID- 27983982 TI - miR-24 suppression of POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) protects endothelial cell from diabetic damage. AB - The regulatory transcriptional factor PATZ1 is abnormally up-regulated in diabetic endothelial cells (ECs) where it acts as an anti-angiogenic factor via modulation of fatty acid-binding protein 4 (FABP4) signaling. The aim of the present work was to elucidate the upstream molecular events regulating PATZ1 expression in diabetic angiogenesis. The bioinformatics search for microRNAs (miRNAs) able to potentially target PATZ1 led to the identification of several miRNAs. Among them we focused on the miR-24 since the multiple targets of miR-24, which have so far been identified in beta cells, cardiomyocytes and macrophages, are all involved in diabetic complications. miR-24 expression was significantly impaired in the ECs isolated from diabetic hearts. Functionally, endothelial migration was profoundly inhibited by miR-24 suppression in Ctrl ECs, whereas miR 24 overexpression by mimics treatment effectively restored the migration rate in diabetic ECs. Mechanistically, miR-24 directly targeted the 3'untranslated region (3'UTR) of PATZ1, and miR-24 accumulation potentiated endothelial migration by reducing the mRNA stability of PATZ1. Together, these results suggest a novel mechanism regulating endothelial PATZ1 expression based on the down-regulation of miR-24 expression caused by hyperglycemia. Interfering with PATZ1 expression via miRNAs or miRNA mimics could potentially represent a new way to target endothelial PATZ1-dependent signaling of vascular dysfunction in diabetes. PMID- 27983983 TI - Clusterin in the protein corona plays a key role in the stealth effect of nanoparticles against phagocytes. AB - In biological fluids, nanoparticles interact with biological components such as proteins, and a layer called the "protein corona" forms around the nanoparticles. It is believed that the composition of the protein corona affects the cellular uptake and in vivo biodistribution of nanoparticles; however, the key proteins of the protein corona that control the biological fate of nanoparticles remain unclear. Recently, it was reported that clusterin binding to pegylated nanoparticles is important for the stealth effect of pegylated nanoparticles in phagocytes. However, the effect of clusterin on non-pegylated nanoparticles is unknown, although it is known that clusterin is present in the protein corona of non-pegylated nanoparticles. Here, we assessed the stealth effect of clusterin in the corona of non-pegylated silver nanoparticles and silica nanoparticles. We found that serum- and plasma-protein corona inhibited the cellular uptake of silver nanoparticles and silica nanoparticles in phagocytes and that the plasma protein corona showed a greater stealth effect compared with the serum-protein corona. Clusterin was present in both the serum- and plasma-protein corona, but was present at a higher level in the plasma-protein corona than in the serum protein corona. Clusterin binding to silver nanoparticles and silica nanoparticles suppressed the cellular uptake of nanoparticles in human macrophage like cells (THP-1 cells). Although further studies are required to determine how clusterin suppresses non-specific cellular uptake in phagocytes, our data suggest that clusterin plays a key role in the stealth effect of not only pegylated nanoparticles but also non-pegylated nanoparticles. PMID- 27983984 TI - Angiotensin II induces the differentiation of mouse epicardial progenitor cells into vascular smooth muscle-like cells. AB - Epicardial progenitor cells (EpiCs) have a crucial role in cardiac development and vasculature formation. Here we detected the expression of Angiotensin II (Ang II) receptors AT1 and AT2 on EpiCs and demonstrated that AngII could increase the expression of smooth muscle specific markers, including alpha-smooth muscle actin (alpha-SMA) and myosin heavy chain 11 (Myh11) in EpiCs. Moreover, the expression of alpha-SMA and Myh11 induced by Ang II was blocked by pretreatment of EpiCs with the AT1 receptor antagonist losartan, but not the AT2 receptor antagonist PD123319. We further showed that the AngII-induced cells showed significant contractile responses to carbachol. These results implied that AngII could effectively induce EpiCs to differentiate into vascular smooth muscle-like cells through the AT1 receptor. PMID- 27983985 TI - Functional characterization and efficient detection of Nucleophosmin/NPM1 oligomers. AB - NPM1/nucleophosmin is a multifunctional and oligomeric phosphoprotein. A number of observations have suggested that changes in the oligomer formation of NPM1 could influence its biological functions, especially its oncogenic functions. To understand the functional meaning of oligomerization of NPM1/nucleophosmin, we have established a novel method to monitor protein oligomerization in cells. We utilized the split synthetic Renilla luciferase protein fragment-assisted complementation (SRL-PFAC) bioluminescence activity and observed the change of NPM1 oligomer levels under various cell culture conditions. Our study provides a method for systematic characterization of NPM1 oligomer formation changes and for screening inhibitors of NPM1 oligomerization. PMID- 27983986 TI - Ectoderm mesenchymal stem cells promote differentiation and maturation of oligodendrocyte precursor cells. AB - Many neurological diseases are closely associated with demyelination caused by pathological changes of oligodendrocytes. Although intrinsic remyelination occurs after injury, the regeneration efficiency of myelinating oligodendrocytes remains to be improved. Herein, we reported an initiative finding of employing a valuable cell source, namely neural crest-derived ectoderm mesenchymal stem cells (EMSCs), for promoting oligodendrocyte differentiation and maturation by co-culturing oligodendrocyte precursor cells (OPCs) with the EMSCs. The results demonstrated that the OPCs/EMSCs co-culture could remarkably increase the number and length of oligodendrocyte processes in comparison with the mono-cultured OPCs and non contact OPCs/EMSCs transwell culture. Furthermore, the inhibition experiments revealed that the EMSCs-produced soluble factor Sonic hedgehog, gap junction protein connexin 43 and extracellular matrix molecule laminin accounted for the promoted OPC differentiation since inhibiting the function of anyone of the three proteins led to substantial retraction of processes and detachment of oligodendrocytes. Altogether, OPCs/EMSCs co-culture system could be a paradigmatic approach for promoting differentiation and maturation of oligodendrocytes, and EMSCs will be a promising cell source for the treatment of neurological diseases caused by oligodendrocyte death and demyelination. PMID- 27983987 TI - Differentially expressed genes in iron-induced prion protein conversion. AB - The conversion of the cellular prion protein (PrPC) to the protease-resistant isoform is the key event in chronic neurodegenerative diseases, including transmissible spongiform encephalopathies (TSEs). Increased iron in prion-related disease has been observed due to the prion protein-ferritin complex. Additionally, the accumulation and conversion of recombinant PrP (rPrP) is specifically derived from Fe(III) but not Fe(II). Fe(III)-mediated PK-resistant PrP (PrPres) conversion occurs within a complex cellular environment rather than via direct contact between rPrP and Fe(III). In this study, differentially expressed genes correlated with prion degeneration by Fe(III) were identified using Affymetrix microarrays. Following Fe(III) treatment, 97 genes were differentially expressed, including 85 upregulated genes and 12 downregulated genes (>=1.5-fold change in expression). However, Fe(II) treatment produced moderate alterations in gene expression without inducing dramatic alterations in gene expression profiles. Moreover, functional grouping of identified genes indicated that the differentially regulated genes were highly associated with cell growth, cell maintenance, and intra- and extracellular transport. These findings showed that Fe(III) may influence the expression of genes involved in PrP folding by redox mechanisms. The identification of genes with altered expression patterns in neural cells may provide insights into PrP conversion mechanisms during the development and progression of prion-related diseases. PMID- 27983988 TI - Protein folding is a convergent problem! AB - Protein folding, tagged as a grand challenge/NP hard problem, has been an open area of research in diverse fields. Exploring folding from the configurational volume perspective in terms of phi (phi), psi(psi) backbone dihedral angles, we asked ourselves a fundamental question as to when do the neighborhood effects on the allowed phi, psi values of each residue take over to assure convergence of proteins to their observed unique tertiary structures. A mapping of the higher order steric correlations beyond Ramachandran plots from ~43612 protein structures comprising ~26.5 million amino acid residues reveals that conformational restrictions on allowed phi, psi values of each amino acid residue due to the N and C terminal neighbors - essentially a consideration of the sterically allowed regions of a tripeptide - ensure convergence of the configurational volume. PMID- 27983990 TI - Selective disulfide reduction for labeling and enhancement of Fab antibody fragments. AB - Many methods have been developed for chemical labeling and enhancement of the properties of antibodies and their common fragments, including the Fab and F(ab')2 fragments. Somewhat selective reduction of some antibody disulfide bonds has been previously achieved, yielding antibodies and antibody fragments that can be labeled at defined sites, enhancing their utility and properties. Selective reduction of the two hinge disulfide bonds present in F(ab')2 fragments using mild reduction has been useful. However, such reduction is often not quantitative and results in the reduction of multiple disulfide bonds, and therefore subsequent multiple labeling or conjugation sites are neither homogenous nor stoichiometric. Here, a simple and efficient selective reduction of the single disulfide bond linking the partial heavy chain and the intact light chain which compose the Fab fragment is accomplished utilizing tris(2-carboxyethyl)phosphine (TCEP) immobilized on agarose beads. The resultant reduced cysteine residues were labeled with several cysteine-selective fluorescent reagents, as well as by cysteine-directed PEGylation. These two cysteine residues can also be re-ligated by means of a bifunctional cysteine cross-linking agent, dibromobimane, thereby both restoring a covalent linkage between the heavy and light chains at this site, far removed from the antigen binding site, and also introducing a fluorescent probe. There are many other research and clinical uses for these selectively partially reduced Fab fragments, including biotinylation, toxin and drug conjugation, and incorporation of radioisotopes, and this technique enables simple generation of very useful Fab fragment derivatives with many potential applications. PMID- 27983991 TI - Estrogen modulates exercise endurance along with mitochondrial uncoupling protein 3 downregulation in skeletal muscle of female mice. AB - Estrogen is a hormone that regulates physiological processes and its dysregulation may relate to muscle disorders particularly in female, although the mechanism remains to be elucidated. We here show that estrogen deficiency repressed exercise endurance in female mice whereas the administration of estrogen to ovariectomized mice recovered it. Microarray analysis of mouse muscles showed that mitochondrial uncoupling protein 3 (UCP3) is upregulated by ovariectomy and downregulated by estrogen administration. Intriguingly, ectopic expression of constitutively active estrogen receptor alpha decreased UCP3 level and increased cellular ATP content in differentiated myoblastic C2C12 cells. Overall, the present study suggests that estrogen plays a critical role in the regulation of energy expenditure and exercise endurance in female. PMID- 27983992 TI - Single injection of a novel nerve growth factor coacervate improves structural and functional regeneration after sciatic nerve injury in adult rats. AB - The prototypical neurotrophin, nerve growth factor (NGF), plays an important role in the development and maintenance of many neurons in both the central and peripheral nervous systems, and can promote functional recovery after peripheral nerve injury in adulthood. However, repair of peripheral nerve defects is hampered by the short half-life of NGF in vivo, and treatment with either NGF alone or NGF contained in synthetic nerve conduits is inferior to the use of nerve autografts, the current gold standard. We tested the reparative ability of a single local injection of a polyvalent coacervate containing polycation poly(ethylene argininylaspartate diglyceride; PEAD), heparin, and NGF, in adult rats following sciatic nerve crush injury, using molecular, histological and behavioral approaches. In vitro assays demonstrated that NGF was loaded into the coacervate at nearly 100% efficiency, and was protected from proteolytic degradation. In vivo, the coacervate enhanced NGF bioavailability, leading to a notable improvement in motor function (track walking analysis) after 30days. The NGF coacervate treatment was also associated with better weight gain and reduction in atrophy of the gastrocnemius muscle. Furthermore, light and electron microscopy showed that the number of myelinated axons and axon-to-fiber ratio (G ratio) were significantly higher in NGF coacervate-treated rats compared with control groups. Expression of markers of neural tissue regeneration (MAP-2, S 100beta, MBP and GAP-43), as well as proliferating Schwann cells and myelin-axon relationships (GFAP and NF200), were also increased. These observations suggest that even a single administration of NGF coacervate could have therapeutic value for peripheral nerve regeneration and functional recovery. PMID- 27983993 TI - Lentiviral vector-driven inhibition of 5-HT synthesis in B3 bulbo-spinal serotonergic projections - Consequences on nociception, inflammatory and neuropathic pain in rats. AB - Although it is well established that bulbo-spinal serotonergic projections contribute to pain control mechanisms, whether they exert anti- or pro nociceptive modulations is still a matter of debate. In order to reappraise the role of 5-HT in descending controls, we used RNA interference to selectively inhibit 5-HT synthesis in B3 neurons and assess resulting changes in nociception. Rats were injected into the bulbar B3 group with a recombinant lentiviral vector, LV-shTPH2, encoding RNA interfering with tryptophan hydroxylase 2 expression. Together with the long term disappearance of this enzyme in the whole rostro caudal extent of B3 group, 5-HT was markedly depleted selectively in the dorsal horn at all levels of the spinal cord. In contrast, immunolabeling of the 5-HT transporter was unaffected by LV-shTPH2 injection, indicating the preservation of serotonergic fibers integrity. Whereas mechanical and thermal nociceptive thresholds were unchanged by 5-HT depletion, marked reductions in intraplantar formalin (but not carrageenin)-evoked nocifensive responses, and, in contrast, significant increases in mechanical and thermal hyperalgesia evoked by sciatic nerve ligation were noted in LV-shTPH2-injected rats versus controls. Parallel changes in c-Fos immunolabeling within the dorsal horn confirmed that bulbo spinal serotonergic projections modulate pain signaling under these various conditions. These results suggest that serotonergic neurons of the B3 group are only moderately concerned, if any, by acute nociception but exert modulatory influences under pain sensitizing conditions. The opposite changes in formalin injected- versus sciatic nerve ligated rats might be related to the implication of different receptors in 5-HT-mediated modulation of inflammatory versus neuropathic pain. PMID- 27983995 TI - N-terminal pro B-type natriuretic peptide and angiogenic biomarkers in the prognosis of adverse outcomes in women with suspected preeclampsia. AB - BACKGROUND: This study compares the performance of the soluble fms-like tyrosine kinase 1 to placental growth factor (sFlt-1/PlGF) ratio and the cardiac biomarker N-terminal pro-B type natriuretic peptide (NT-proBNP) in the prediction of adverse outcomes in women with suspicion of PE. METHODS: A retrospective cohort study was conducted on women admitted at triage with signs and/or symptoms of PE (n=340). Serum levels of sFlt-1, PlGF and NT-proBNP were determined by an electrochemiluminescence immunoassay (Roche Diagnostics). The main outcomes were early- or late-onset PE and development of adverse outcome, defined as delivery within the first week since clinical presentation or fetal/early neonatal death. RESULTS: NT-proBNP concentrations (ng/L) were significantly increased in PE versus non-PE women, both at <34 (169 versus 34) and >=34weeks of gestation (101 versus 49) (p<0.001). A cut-point of 70 showed sensitivities/specificities of 78/74% for early-, and 70/62% for late-onset PE; slightly lower than those offered by the sFlt-1/PlGF ratio or uric acid. The respective cut-points of 178 and 219 for sFlt-1/PlGF ratio and NT-proBNP, demonstrated similar performance in the prediction of adverse outcome, with sensitivity/specificity of 95/84% and 94/76%, respectively. CONCLUSION: NT-proBNP and sFlt-1/PlGF ratio can be used to predict the development of an adverse outcome. PMID- 27983996 TI - Diagnostic and prognostic accuracy of galectin-3 and soluble ST2 for acute heart failure. AB - BACKGROUND: We aimed to compare head-to-head the diagnostic and prognostic capabilities of galectin-3, soluble ST2 (sST2) and B-type natriuretic peptide (BNP) for heart failure (HF) in an emergency setting. METHODS: We studied 251 consecutive patients with dyspnoea as a chief compliant presenting to an emergency department. The diagnosis of HF was based on the Framingham score for HF plus echocardiographic evidence of systolic or diastolic dysfunction. All cause mortality was assessed at one year. Plasma concentrations of galectin-3 and BNP were measured with two commercially available assays from Abbott Diagnostics, plasma concentrations of sST2 were quantified with the Presage ST2 assay. The diagnostic and prognostic accuracies of galectin-3, sST2 and BNP were assessed by receiver operating characteristic (ROC) curve analysis. RESULTS: Of the 251 patients, 137 had dyspnoea attributable to acute HF and 114 had dyspnoea attributable to other reasons. BNP had a higher area under the curve (AUC) for the diagnosis of HF (0.92; 95% CI, 0.87-0.95) than galectin-3 (0.57; 95% CI, 0.51 0.64) and sST2 (0.63; 95% CI, 0.56-0.69). Of the 137 patients with acute HF, 41 died and 96 survived during follow up. The AUC of BNP for the prediction of one year all-cause mortality in HF patients (0.72; 95% CI, 0.63-0.79) was not different from the AUCs of galectin-3 (0.70; 95% CI, 0.62-0.78) and sST2 (0.75; 95% CI, 0.67-0.82). CONCLUSIONS: In this study, galectin-3, sST2 and BNP were equally useful for the prediction of one-year all-cause mortality in patients with acute HF. However, in contrast to BNP, galectin-3 and sST2 were not useful as an aid in the diagnosis of acute HF in short of breath patients presenting to an emergency department. PMID- 27983997 TI - Association between serum triglyceride to high-density lipoprotein cholesterol ratio and sarcopenia in elderly Korean males: The Korean National Health and Nutrition Examination Survey. AB - BACKGROUND: We investigated the association between the triglycerides to high density lipoprotein cholesterol (TG/HDL) ratio and sarcopenia in elderly Korean males. METHODS: We examined the relationship between the TG/HDL ratio and sarcopenia in 879 elderly males >=60years who participated in the 2010-2011 KNHANES. Sarcopenia was defined as an appendicular skeletal muscle mass (ASM) divided by the weight (%), which is >1 SD below the mean for young adults. The odds ratios (ORs) for sarcopenia were calculated using multiple logistic regression across the TG/HDL ratio quartiles (Q1: <=1.4, Q2: 1.5-2.4, Q3: 2.5-3.8 and Q4: >=3.9) after adjusting for confounding variables. RESULTS: The prevalence of sarcopenia significantly increased in accordance with TG/HDL ratio quartiles. Compared with the lowest quartile of the TG/HDL ratio, the corresponding OR (95% CI) of the highest quartile of the TG/HDL ratio for sarcopenia was 2.10 (1.12 3.91) after adjusting for age, body mass index (BMI), cigarette smoking, alcohol intake and physical activity. CONCLUSION: TG/HDL ratio was positively related with a higher risk of sarcopenia in elderly Korean males. PMID- 27983998 TI - Plasma levels of soluble intercellular adhesion molecule-1 as a biomarker for disease severity of patients with community-acquired pneumonia. AB - BACKGROUND: Community-acquired pneumonia (CAP) is characterized as an acute inflammation of the lung associated with the activation of macrophages and neutrophils. Intercellular adhesion molecule-1 (ICAM-1) is an essential adhesion molecule involved in immune cell recruitment in lung inflammation. We investigated whether ICAM-1 is a useful biomarker for assessing the disease severity of hospitalized adult patients with CAP. METHODS: Plasma soluble ICAM-1 (sICAM-1) levels were measured in 78 patients with CAP and 69 healthy controls by using a commercial enzyme-linked immunosorbent assay. The pneumonia severity index scores were used to determine CAP severity in patients upon initial hospitalization. RESULTS: The sICAM-1 and C-reactive protein (CRP) levels decreased significantly in patients with CAP after antibiotic treatment. The plasma concentration of sICAM-1 alone, but not CRP, was correlated with CAP severity according to the pneumonia severity index scores (r=0.431, p<0.001). The sICAM-1 levels in patients with CAP with high mortality risk were significantly higher than those in patients with CAP with medium or low mortality risk. Moreover, the sICAM-1 level showed a significant correlation with the length of hospital stay (r=0.488, p<0.001). Mechanistic investigations found that bacterial lipopolysaccharide induced upregulation of ICAM-1 expression through the c-Jun N terminal kinase pathway in RAW264.7 macrophages. CONCLUSIONS: Plasma sICAM-1 levels may play a role in the diagnosis and clinical assessment of CAP severity. PMID- 27983999 TI - WDR73 missense mutation causes infantile onset intellectual disability and cerebellar hypoplasia in a consanguineous family. AB - Galloway-Mowat syndrome (GMS) is a very rare autosomal-recessive disorder characterized by nephrotic syndrome associated with microcephaly, and various central nervous system abnormalities, mostly cerebral hypoplasia or cerebellar atrophy, intellectual disability and neural-migration defects. WDR73 is the only gene known to cause GMS, and has never been implicated in other disease. Here we present a Chinese consanguineous family with infantile onset intellectual disability and cerebellar hypoplasia but no microcephaly. Whole exome sequencing identified a WDR73 p.W371G missense mutation. The mutation is confirmed to be segregated in this family by Sanger sequencing according to a recessive inheritance pattern. It is predicted to be deleterious by multiple algorithms and affect highly conserved site. Structural modeling revealed conformational differences between the wild type protein and the p.W371G protein. Real-time PCR and Western blotting revealed altered mRNA and protein levels in mutated samples. Our study indicates the novel WDR73 p.W371G missense mutation causes infantile onset intellectual disability and cerebellar hypoplasia in recessive mode of inheritance. Our findings imply that microcephaly is a variable phenotype in WDR73-related disease, suggest WDR73 to be a candidate gene of severe intellectual disability and cerebellar hypoplasia, and expand the molecular spectrum of WDR73-related disease. PMID- 27984000 TI - Flavonoid dimers are highly potent killers of multidrug resistant cancer cells overexpressing MRP1. AB - MRP1 overexpression in multidrug-resistant cancer cells has been shown to be responsible for collateral sensitivity to some flavonoids that stimulate a huge MRP1-mediated GSH efflux. This massive GSH depletion triggers the death of these cancer cells. We describe here that bivalent flavonoid dimers strikingly stimulate such MRP1-mediated GSH efflux and trigger a 50-100 fold more potent cell death than their corresponding monomers. This selective and massive cell death of MRP1-overexpressing cells (both transfected and drug-selected cell lines) is no longer observed either upon catalytic inactivation of MRP1 or its knockdown by siRNA. The best flavonoid dimer, 4e, kills MRP1-overexpressing cells with a selective ratio higher than 1000 compared to control cells and an EC50 value of 0.1 MUM, so far unequaled as a collateral sensitivity agent targeting ABC transporters. This result portends the flavonoid dimer 4e as a very promising compound to appraise in vivo the therapeutic potential of collateral sensitivity for eradication of MRP1-overexpressing chemoresistant cancer cells in tumors. PMID- 27984001 TI - Psoriatic inflammation enhances allergic airway inflammation through IL-23/STAT3 signaling in a murine model. AB - Psoriasis is an autoimmune inflammatory skin disease characterized by activated IL-23/STAT3/Th17 axis. Recently psoriatic inflammation has been shown to be associated with asthma. However, no study has previously explored how psoriatic inflammation affects airway inflammation. Therefore, this study investigated the effect of imiquimod (IMQ)-induced psoriatic inflammation on cockroach extract (CE)-induced airway inflammation in murine models. Mice were subjected to topical and intranasal administration of IMQ and CE to develop psoriatic and airway inflammation respectively. Various analyses in lung/spleen related to inflammation, Th17/Th2/Th1 cell immune responses, and their signature cytokines/transcription factors were carried out. Psoriatic inflammation in allergic mice was associated with increased airway inflammation with concurrent increase in Th2/Th17 cells/signature cytokines/transcription factors. Splenic CD4+ T and CD11c+ dendritic cells in psoriatic mice had increased STAT3/RORC and IL-23 mRNA expression respectively. This led us to explore the effect of systemic IL-23/STAT3 signaling on airway inflammation. Topical application of STA-21, a small molecule STAT3 inhibitor significantly reduced airway inflammation in allergic mice having psoriatic inflammation. On the other hand, adoptive transfer of IL-23-treated splenic CD4+ T cells from allergic mice into naive recipient mice produced mixed neutrophilic/eosinophilic airway inflammation similar to allergic mice with psoriatic inflammation. Our data suggest that systemic IL 23/STAT3 axis is responsible for enhanced airway inflammation during psoriasis. The current study also suggests that only anti-asthma therapy may not be sufficient to alleviate airway inflammatory burden in asthmatics with psoriasis. PMID- 27984002 TI - Endophytes as sources of antibiotics. AB - Until a viable alternative can be accessible, the emergence of resistance to antimicrobials requires the constant development of new antibiotics. Recent scientific efforts have been aimed at the bioprospecting of microorganisms' secondary metabolites, with special emphasis on the search for antimicrobial natural products derived from endophytes. Endophytes are microorganisms that inhabit the internal tissues of plants without causing apparent harm to the plant. The present review article compiles recent (2006-2016) literature to provide an update on endophyte research aimed at finding metabolites with antibiotic activities. We have included exclusively information on endophytes that produce metabolites capable of inhibiting the growth of bacterial, fungal and protozoan pathogens of humans, animals and plants. Where available, the identified metabolites have been listed. In this review, we have also compiled a list of the bacterial and fungal phyla that have been isolated as endophytes as well as the plant families from which the endophytes were isolated. The majority of endophytes that produce antibiotic metabolites belong to either phylum Ascomycota (kingdom Fungi) or to phylum Actinobacteria (superkingdom Bacteria). Endophytes that produce antibiotic metabolites were predominant, but certainly not exclusively, from the plant families Fabaceae, Lamiaceae, Asteraceae and Araceae, suggesting that endophytes that produce antimicrobial metabolites are not restricted to a reduced number of plant families. The locations where plants (and inhabiting endophytes) were collected from, according to the literature, have been mapped, showing that endophytes that produce bioactive compounds have been collected globally. PMID- 27984003 TI - A Systematic Analysis of Treatment and Outcomes of NOD2-Associated Autoinflammatory Disease. AB - OBJECTIVES: Yao syndrome, formerly named NOD2-associated autoinflammatory disease, is a periodic disease characterized by fever, dermatitis, polyarthritis/leg swelling, and gastrointestinal and sicca-like symptoms associated with specific NOD2 sequence variants. Our aim was to evaluate the treatment and outcomes of the disease. METHODS: A total of 52 adult patients with autoinflammatory disease phenotype were diagnosed with Yao syndrome and enrolled at the Cleveland Clinic between November 2009 and May 2015. All patients were genotyped for the NOD2 variants, and systematically studied for treatment outcomes. RESULTS: Among the 52 Yao syndrome patients, all were white, and 72% were women. The mean age at diagnosis was 38.0 +/- 12.0 years, and the disease duration was 8.8 +/- 5.8 years. In the multi-organ disease, more common and typical manifestations were recurrent dermatitis and inflammatory arthritis with or without distal leg swelling besides recurrent fever. It was genotypically associated with the NOD2 IVS8+158 or R702W. Therapeutically, glucocorticoids markedly decreased the disease severity and duration of flares in 19 patients (36.6%), sulfasalazine treatment achieved a significant symptomatic improvement in 22 (42%) patients, and 3 patients received canakinumab or tocilizumab with benefits. Prognostically, 13% of the 52 patients had somewhat physical impairment, and there was no mortality during the follow-up. Associated comorbidities were fibromyalgia, asthma, renal stones, and ventricular hypertrophy. CONCLUSIONS: As a systemic disease, Yao syndrome uncommonly affects the solid internal organs, but it can be complicated with chronic pain syndrome and even disability. Glucocorticoids or sulfasalazine may be considered as the first-line treatment option, and interleukin (IL)-1/IL-6 inhibitors may be tried for refractory cases. The potential associations between certain comorbidities and Yao syndrome deserve further study. PMID- 27984004 TI - High Positive End-Expiratory Pressure Is Associated with Improved Survival in Obese Patients with Acute Respiratory Distress Syndrome. AB - BACKGROUND: In acute respiratory distress syndrome, minimizing lung injury from repeated collapse and reopening of alveoli by applying a high positive end expiratory pressure improves oxygenation without influencing mortality. Obesity causes alveolar atelectasis, thus suggesting that a higher positive end expiratory pressure might be more protective among the obese. We hypothesized that the effect of applying a high positive end-expiratory pressure on mortality from acute respiratory distress syndrome would differ by obesity status. METHODS: This was a retrospective analysis of 505 patients from the Assessment of Low tidal Volume and elevated End-expiratory volume to Obviate Lung Injury Trial, a multicenter randomized trial that compared a higher vs a lower positive end expiratory pressure ventilatory strategy in acute respiratory distress syndrome. We examined the relationship between positive end-expiratory pressure strategy and 60-day mortality stratified by obesity status. RESULTS: Among obese patients with acute respiratory distress syndrome, those assigned to a high positive end expiratory pressure strategy experienced lower mortality compared with those assigned to a low strategy (18% vs 32%; P = .04). Among the nonobese, those assigned to high positive end-expiratory pressure strategy experienced similar mortality with those assigned to low strategy (34% vs 23%; P = .13). Multivariate analysis demonstrated an interaction between obesity status and the effect of positive end-expiratory pressure strategy on mortality (P <.01). CONCLUSIONS: Ventilation with higher levels of positive end-expiratory pressure was associated with improved survival among the subgroup of patients with acute respiratory distress syndrome who are obese. PMID- 27984005 TI - Treatment-Resistant Hypertension and Outcomes Based on Randomized Treatment Group in ALLHAT. AB - BACKGROUND: Although hypertension guidelines define treatment-resistant hypertension as blood pressure uncontrolled by >=3 antihypertensive medications, including a diuretic, it is unknown whether patient prognosis differs when a diuretic is included. METHODS: Participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) were randomly assigned to first-step therapy with chlorthalidone, amlodipine, or lisinopril. At a Year 2 follow-up visit, those with average blood pressure >=140 mm Hg systolic or >=90 mm Hg diastolic on >=3 antihypertensive medications, or blood pressure <140/90 mm Hg on >=4 antihypertensive medications were identified as having apparent treatment-resistant hypertension. The prevalence of treatment-resistant hypertension and its association with ALLHAT primary (combined fatal coronary heart disease or nonfatal myocardial infarction) and secondary (all-cause mortality, stroke, heart failure, combined coronary heart disease, and combined cardiovascular disease) outcomes were identified for each treatment group. RESULTS: Of participants assigned to chlorthalidone, amlodipine, or lisinopril, 9.6%, 11.4%, and 19.7%, respectively, had treatment-resistant hypertension. During mean follow-up of 2.9 years, primary outcome incidence was similar for those assigned to chlorthalidone compared with amlodipine or lisinopril (amlodipine- vs chlorthalidone-adjusted hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.53-1.39; P = .53; lisinopril- vs chlorthalidone-adjusted HR = 1.06; 95% CI, 0.70-1.60; P = .78). Secondary outcome risks were similar for most comparisons except coronary revascularization, which was higher with amlodipine than with chlorthalidone (HR 1.86; 95% CI, 1.11-3.11; P = .02). An as-treated analysis based on diuretic use produced similar results. CONCLUSIONS: In this study, which titrated medications to a goal, participants assigned to chlorthalidone were less likely to develop treatment-resistant hypertension. However, prognoses in those with treatment-resistant hypertension were similar across treatment groups. PMID- 27984006 TI - Improving Warfarin Management Within the Medical Home: A Health-System Approach. AB - BACKGROUND: Anticoagulation clinics have been considered the optimal strategy for warfarin management with demonstrated improved patient outcomes through increased time in therapeutic international normalized ratio (INR) range, decreased critical INR values, and decreased anticoagulation-related adverse events. However, not all health systems are able to support a specialized anticoagulation clinic or may see patient volume exceed available anticoagulation clinic resources. The purpose of this study was to utilize an anticoagulation clinic model to standardize warfarin management in a primary care clinic setting. METHODS: A warfarin management program was developed that included standardized patient assessment, protocolized warfarin-dosing algorithm, and electronic documentation and reporting tools. Primary care clinics were targeted for training and implementation of this program. RESULTS: The warfarin management program was applied to over 2000 patients and implemented at 39 clinic sites. A total of 160 nurses and 15 pharmacists were trained on the program. Documentation of warfarin dose and date of the next INR increased from 70% to 90% (P <.0001), documentation occurring within 24 hours of the INR result increased from 75% to 87% (P <.0001), and monitoring the INR at least every 4 weeks increased from 71% to 83% (P <.0001) per patient encounter. Time in therapeutic INR range improved from 65% to 75%. CONCLUSION: Incorporating a standardized approach to warfarin management in the primary care setting significantly improves warfarin-related documentation and time in therapeutic INR range. PMID- 27984007 TI - Inferior Vena Cava Filters in Elderly Patients with Stable Acute Pulmonary Embolism. AB - BACKGROUND: Patients aged >60 years with pulmonary embolism who were stable and did not require thrombolytic therapy were shown to have a somewhat lower in hospital all-cause mortality with vena cava filters. In this investigation we further assess mortality with filters in stable elderly patients. METHODS: In hospital all-cause mortality according to use of inferior vena cava filters was assessed from the National (Nationwide) Inpatient Sample, 2003-2012, in: 1) All patients with pulmonary embolism; 2) All with pulmonary embolism who had none of the comorbid conditions listed in the Charlson Comorbidity Index; 3) Patients with a primary (first-listed) diagnosis of pulmonary embolism, and 4) Patients with a primary diagnosis of pulmonary embolism and none of the comorbid conditions listed in the Charlson Comorbidity Index. RESULTS: From 2003-2012, 2,621,575 stable patients with pulmonary embolism were hospitalized in the US. Patients aged >80 years showed lower mortality with vena cava filters (all pulmonary embolism, 6.1% vs 10.5%; all pulmonary embolism with no comorbid conditions, 3.3% vs 6.3%; primary pulmonary embolism, 4.1% vs 5.7%; primary pulmonary embolism with no comorbid conditions, 2.1% vs 3.7%; all P <.0001). In the all-patient category, patients aged 71-80 years showed somewhat lower mortality with filters, 6.3% vs 7.4% (P <.0001), and those without comorbid conditions, 2.5% vs 2.8% (P = .04). Those aged 71-80 years with primary pulmonary embolism, irrespective of comorbid conditions, did not show lower mortality with filters. CONCLUSION: At present, in the absence of a randomized controlled trial, it seems prudent to consider a vena cava filter in very elderly (aged >80 years) stable patients with acute pulmonary embolism. PMID- 27984009 TI - Personalized Activity Intelligence (PAI) for Prevention of Cardiovascular Disease and Promotion of Physical Activity. AB - PURPOSE: To derive and validate a single metric of activity tracking that associates with lower risk of cardiovascular disease mortality. METHODS: We derived an algorithm, Personalized Activity Intelligence (PAI), using the HUNT Fitness Study (n = 4631), and validated it in the general HUNT population (n = 39,298) aged 20-74 years. The PAI was divided into three sex-specific groups (<=50, 51-99, and >=100), and the inactive group (0 PAI) was used as the referent. Hazard ratios for all-cause and cardiovascular disease mortality were estimated using Cox proportional hazard regressions. RESULTS: After >1 million person-years of observations during a mean follow-up time of 26.2 (SD 5.9) years, there were 10,062 deaths, including 3867 deaths (2207 men and 1660 women) from cardiovascular disease. Men and women with a PAI level >=100 had 17% (95% confidence interval [CI], 7%-27%) and 23% (95% CI, 4%-38%) reduced risk of cardiovascular disease mortality, respectively, compared with the inactive groups. Obtaining >=100 PAI was associated with significantly lower risk for cardiovascular disease mortality in all prespecified age groups, and in participants with known cardiovascular disease risk factors (all P-trends <.01). Participants who did not obtain >=100 PAI had increased risk of dying regardless of meeting the physical activity recommendations. CONCLUSION: PAI may have a huge potential to motivate people to become and stay physically active, as it is an easily understandable and scientifically proven metric that could inform potential users of how much physical activity is needed to reduce the risk of premature cardiovascular disease death. PMID- 27984008 TI - Treatment of Alcohol Use Disorder in Patients with Alcoholic Liver Disease. AB - Alcohol is a leading cause of liver disease worldwide. Although alcohol abstinence is the crucial therapeutic goal for patients with alcoholic liver disease, these patients have less access to psychosocial, behavioral, and/or pharmacologic treatments for alcohol use disorder. Psychosocial and behavioral therapies include 12-step facilitation, brief interventions, cognitive behavioral therapy, and motivational enhancement therapy. In addition to medications approved by the US Food and Drug Administration for alcohol use disorder (disulfiram, naltrexone, and acamprosate), recent efforts to identify potential new treatments have yielded promising candidate pharmacotherapies. Finally, more efforts are needed to integrate treatments across disciplines toward patient centered approaches in the management of patients with alcohol use disorder and alcoholic liver disease. PMID- 27984010 TI - Nothing to (S)cough at: Pulmonary Mycobacterium avium Complex Infection. PMID- 27984011 TI - Balancing Service and Education: An AAIM Consensus Statement. PMID- 27984012 TI - Isolation of detergent-resistant membranes (DRMs) from Escherichia coli. AB - Lipid rafts or membrane microdomains have been proposed to compartmentalize cellular processes by spatially organizing diverse molecules/proteins in eukaryotic cells. Such membrane microdomains were recently reported to also exist in a few bacterial species. In this work, we report the development of a procedure for membrane microdomain isolation from Escherichia coli plasma membranes as well as a method to purify the latter. The method here reported could easily be adapted to other gram-negative bacteria, wherein the isolation of this kind of sub-membrane preparation imposes special difficulties. The analysis of isolated membrane microdomains might provide important information on the nature and function of these bacterial structures and permit their comparison with the ones of eukaryotic cells. PMID- 27984013 TI - Label-free colorimetric assay for T4 polynucleotide kinase/phosphatase activity and its inhibitors based on G-quadruplex/hemin DNAzyme. AB - Here we report a new approach for label-free colorimetric assay of T4 polynucleotide kinase/phosphatase (PNKP) activity based on G-quadruplex/hemin DNAzyme. In the presence of T4 PNKP, the DNA primer with a 3'-phosphate can be dephosphorylated into a 3'-hydroxyl and initiate a primer elongation reaction to open the hairpin probe, and leading to releasing the G-quartets. Under optimal conditions, the proposed method exhibited a considerable performance with a detection limit of 0.01 U/mL. Furthermore, the present assay can be used to study the potential T4 PNKP inhibitor screening, making it promise to be applied in the fields of drug discovery. PMID- 27984014 TI - Thermodynamic and kinetic approaches for evaluation of monoclonal antibody - Lipoprotein interactions. AB - Two complementary instrumental techniques were used, and the data generated was processed with advanced numerical tools to investigate the interactions between anti-human apoB-100 monoclonal antibody (anti-apoB-100 Mab) and apoB-100 containing lipoproteins. Partial Filling Affinity Capillary Electrophoresis (PF ACE) combined with Adsorption Energy Distribution (AED) calculations provided information on the heterogeneity of the interactions without any a priori model assumptions. The AED calculations evidenced a homogenous binding site distribution for the interactions. Quartz Crystal Microbalance (QCM) studies were used to evaluate thermodynamics and kinetics of the Low-Density Lipoprotein (LDL) and anti-apoB-100 Mab interactions. High affinity and selectivity were observed, and the emerging data sets were analysed with so called Interaction Maps. In thermodynamic studies, the interaction between LDL and anti-apoB-100 Mab was found to be predominantly enthalpy driven. Both techniques were also used to study antibody interactions with Intermediate-Density (IDL) and Very Low-Density (VLDL) Lipoproteins. By screening affinity constants for IDL-VLDL sample in a single injection we were able to distinguish affinity constants for both subpopulations using the numerical Interaction Map tool. PMID- 27984015 TI - Adaptation of CRISPR nucleases for eukaryotic applications. PMID- 27984016 TI - Trace elements and diabetes: Assessment of levels in tears and serum. AB - Tear film is critical for the well-being and homeostasis of the ocular surface. Although the composition of the tear film is well known, the composition of metallic elements have yet to be analysed. Despite trace elements metabolism has been reported to play a role in the pathogenesis of diabetes mellitus, a metabolic disease that affects several aspects of homeostasis, little is known in the literature regarding concentration and possible variation of metallic elements in tear film. We studied the concentrations of several essential and non essential metallic elements in the tear fluid and serum of patients with type II diabetes mellitus and a group of non-diabetic controls. Serum and tear fluid were collected from 97 patients: 47 type II diabetic patients and 50 non-diabetic controls. Regarding tear film, there were statistically significant differences in Zinc, Chrome, Cobalt, Manganese, Barium, and Lead between groups; the values of all metallic elements were found to be statistically significant higher in patients with mellitus type II diabetes. Regarding serum values there was a statistically significant difference in Chrome, Cobalt, and Selenium values; the concentrations of Chrome and Cobalt were higher in the control group, while Selenium concentration was higher in diabetic patients. In patients with type II diabetes, metal elements with higher concentrations in tears compared to serum were: Lead, Barium, Manganese, Cobalt, and Chrome. In the control group, the metal elements with the highest concentration in tear film compared to serum were Chrome, Manganese, Barium, and Lead. In this study, we attempted to evaluate the possible effect of a disease, such as diabetes, on the metabolism of metallic elements. Although our evidence was very interesting, it is probably limited in its accuracy due to the fact that individuals in the control group harboured ocular pathologies. This work lays the foundation for future studies. PMID- 27984018 TI - Sphingolipids modulate the function of human serotonin1A receptors: Insights from sphingolipid-deficient cells. AB - Sphingolipids are essential components of eukaryotic cell membranes and are known to modulate a variety of cellular functions. It is becoming increasingly clear that membrane lipids play a crucial role in modulating the function of integral membrane proteins such as G protein-coupled receptors (GPCRs). In this work, we utilized LY-B cells, that are sphingolipid-auxotrophic mutants defective in sphingolipid biosynthesis, to monitor the role of cellular sphingolipids in the function of an important neurotransmitter receptor, the serotonin1A receptor. Serotonin1A receptors belong to the family of GPCRs and are implicated in behavior, development and cognition. Our results show that specific ligand binding and G-protein coupling of the serotonin1A receptor exhibit significant enhancement under sphingolipid-depleted conditions, which reversed to control levels upon replenishment of cellular sphingolipids. In view of the reported role of sphingolipids in neuronal metabolism and pathogenesis of several neuropsychiatric disorders, exploring the role of serotonin1A receptors under conditions of defective sphingolipid metabolism assumes relevance, and could contribute to our overall understanding of such neuropsychiatric disorders. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid control of protein activity edited by Dirk Schneider. PMID- 27984017 TI - Magic angle spinning 31P NMR spectroscopy reveals two essentially identical ionization states for the cardiolipin phosphates in phospholipid liposomes. AB - Specific membrane lipid composition is crucial for optimized structural and functional organization of biological membranes. Cardiolipin is a unique phospholipid and important component of the inner mitochondrial membrane. It is involved in energy metabolism, inner mitochondrial membrane transport, regulation of multiple metabolic reactions and apoptotic cell death. The physico-chemical properties of cardiolipin have been studied extensively but despite all these efforts there is still lingering controversy regarding the ionization of the two phosphate groups of cardiolipin. Results obtained in the 1990s and early 2000s suggested that cardiolipin has two disparate pKa values where one of the protons was proposed to be stabilized by an intramolecular hydrogen bond. This has led to extensive speculations on the roles of these two putative ionization states of cardiolipin in mitochondria. More recently the notion of two pKa values has been challenged and rejected by several groups. These studies relied on external measurements of proton adsorption or electrophoretic mobility of membranes but did not take into account the low pH phase behavior and chemical stability of cardiolipin. Here we used 31P NMR to show that in the physiologically relevant membrane phospholipid environment, cardiolipin carries two negative charges at physiological pH. We additionally demonstrate the pH dependent phase behavior and chemical stability of cardiolipin containing membranes. PMID- 27984019 TI - Biopores/membrane proteins in synthetic polymer membranes. AB - BACKGROUND: Mimicking cell membranes by simple models based on the reconstitution of membrane proteins in lipid bilayers represents a straightforward approach to understand biological function of these proteins. This biomimetic strategy has been extended to synthetic membranes that have advantages in terms of chemical and mechanical stability, thus providing more robust hybrid membranes. SCOPE OF THE REVIEW: We present here how membrane proteins and biopores have been inserted both in the membrane of nanosized and microsized compartments, and in planar membranes under various conditions. Such bio-hybrid membranes have new properties (as for example, permeability to ions/molecules), and functionality depending on the specificity of the inserted biomolecules. Interestingly, membrane proteins can be functionally inserted in synthetic membranes provided these have appropriate properties to overcome the high hydrophobic mismatch between the size of the biomolecule and the membrane thickness. MAJOR CONCLUSION: Functional insertion of membrane proteins and biopores in synthetic membranes of compartments or in planar membranes is possible by an appropriate selection of the amphiphilic copolymers, and conditions of the self-assembly process. These hybrid membranes have new properties and functionality based on the specificity of the biomolecules and the nature of the synthetic membranes. GENERAL SIGNIFICANCE: Bio-hybrid membranes represent new solutions for the development of nanoreactors, artificial organelles or active surfaces/membranes that, by further gaining in complexity and functionality, will promote translational applications. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider. PMID- 27984020 TI - Physical exercise reverses spatial memory deficit and induces hippocampal astrocyte plasticity in diabetic rats. AB - Physical exercise can induce brain plasticity and reduce the cognitive decline observed in type 1 diabetes mellitus (T1DM). We investigated the effects of physical exercise to prevent or reverse spatial memory deficits produced by diabetes and some biochemical and immunohistochemical changes in hippocampal astrocytes of T1DM model. In this study, 56 male Wistar rats were divided in four groups: trained control (TC), non-trained control (NTC), trained diabetic (TD) and non-trained diabetic (NTD). 27 days after streptozotocin-induced (STZ) diabetes, the exercise groups were submitted to 5 weeks of aerobic exercise. All groups were assessed in place recognition (PR) test before and after training. The glial fibrillary acidic protein (GFAP) positive astrocytes were evaluated using planar morphology, optical densitometry and Sholl's concentric circles method. Glucose and glutamate uptake, reduced glutathione (GSH) and glutamine synthetase (GS) levels were measured using biochemical assays. Our main results are: 1-Exercise reverses spatial memory impairments generated by T1DM; 2-Exercise increases GSH and GS in TC but not in TD rats; 3-Exercise increases density of GFAP positive astrocytes in the TC and TD groups and increases astrocytic ramification in TD animals. Our findings indicate that physical exercise reverses the cognitive deficits present in T1DM and induces important biochemical and immunohistochemical astrocytic changes. PMID- 27984021 TI - Neuropeptide Y Y5 receptor localization in mouse central nervous system. AB - Neuropeptide Y (NPY) and its receptors affect blood pressure, feeding behavior, and neurogenesis. In this study, the distribution of neurons expressing NPY Y5 receptor (Y5) was examined in adult mouse central nervous system by immunohistochemistry. Y5 protein localization was investigated using polyclonal anti-Y5 antibody, which was successfully preabsorbed with Y5 knockout brain tissues. The preabsorbed anti-Y5 antibody did not react with Y5 knockout brain tissues, thus meeting the "hard specificity criterion," which is the absence of staining in tissues genetically deficient for the antigen (Pradidarcheep et al., 2008). Y5-positive neurons were found in most brain areas. Most Y5 immunoreactivities were observed as dot-like structures adjacent to the plasma membrane, as expected for a cell membrane receptor. In situ hybridization showed that the Y5 mRNA expression was correlated with the Y5 protein level in each case and that it was probably controlled by the transcriptional regulation of the Y5 gene. In the nuclei where Y5 was expressed, Y5 immunoreactivities were found mainly in the somatic and dendritic areas. The distribution patterns of the Y5 positive cells that were broader than previously expected suggest important biological activities of the Y5 in many brain areas. PMID- 27984022 TI - Effects of subthalamic deep brain stimulation with duloxetine on mechanical and thermal thresholds in 6OHDA lesioned rats. AB - Chronic pain is the most common non-motor symptom of Parkinson's disease (PD) and is often overlooked. Unilateral 6-hydroxydopamine (6-OHDA) medial forebrain bundle lesioned rats used as models for PD exhibit decreased sensory thresholds in the left hindpaw. Subthalamic deep brain stimulation (STN DBS) increases mechanical thresholds and offers improvements with chronic pain in PD patients. However, individual responses to STN high frequency stimulation (HFS) in parkinsonian rats vary with 58% showing over 100% improvement, 25% showing 30-55% improvement, and 17% showing no improvement. Here we augment STN DBS by supplementing with a serotonin-norepinephrine reuptake inhibitor commonly prescribed for pain, duloxetine. Duloxetine was administered intraperitoneally (30mg/kg) in 15 parkinsonian rats unilaterally implanted with STN stimulating electrodes in the lesioned right hemisphere. Sensory thresholds were tested using von Frey, Randall-Selitto and hot-plate tests with or without duloxetine, and stimulation to the STN at HFS (150Hz), low frequency (LFS, 50Hz), or off stimulation. With HFS or LFS alone (left paw; p=0.016; p=0.024, respectively), animals exhibited a higher mechanical thresholds stable in the three days of testing, but not with duloxetine alone (left paw; p=0.183). Interestingly, the combination of duloxetine and HFS produced significantly higher mechanical thresholds than duloxetine alone (left paw, p=0.002), HFS alone (left paw, p=0.028), or baseline levels (left paw; p<0.001). These findings show that duloxetine paired with STN HFS increases mechanical thresholds in 6-OHDA-lesioned animals more than either treatment alone. It is possible that duloxetine augments STN DBS with a central and peripheral additive effect, though a synergistic mechanism has not been excluded. PMID- 27984023 TI - Cytomegalovirus Retinitis in Patients With Acquired Immunodeficiency Syndrome After Initiating Antiretroviral Therapy. AB - PURPOSE: To evaluate the rates of new-onset cytomegalovirus (CMV) retinitis and worsening existing CMV retinitis in patients with AIDS after initiating combination antiretroviral therapy (cART) and the role of an immune recovery inflammatory syndrome (IRIS). DESIGN: Cohort study. METHODS: Immune recovery was defined as an increase in CD4+ T cells to >=100 cells/MUL; rates of new-onset CMV retinitis and of worsening of CMV retinitis (either increasing border activity or retinitis progression) were compared between those with and without immune recovery. RESULTS: Among patients without CMV retinitis, 1 of 75 patients with immune recovery developed CMV retinitis in the first 6 months after initiating cART vs 1 of 31 without immune recovery (P = .14). Among patients with CMV retinitis, the rates of retinitis progression and increasing retinitis border activity among patients during the first 6 months after initiating cART in those with immune recovery were 0.11 per person-year (PY; 95% confidence interval [CI] 0-0.62) and 0.11 per PY (95% CI 0-0.62), respectively, vs 0.67 per PY (95% CI 0.22-1.56) and 0.40 per PY (95% CI 0.08-1.17), respectively, for those without immune recovery (P = .11 and .47). CONCLUSIONS: Among persons with AIDS who experience immune recovery, there was neither an increased rate of new-onset CMV retinitis nor worsening of existing CMV retinitis in the first 6 months after initiating cART vs those without immune recovery. These data are consistent with the known 3- to 6-month lag in recovery of specific immunity to CMV after initiating cART and suggest that "immune recovery retinitis," a proposed immune recovery inflammatory syndrome phenomenon, is rare. PMID- 27984025 TI - Post-Cataract Surgery Optic Neuropathy: Prevalence, Incidence, Temporal Relationship, and Fellow Eye Involvement. AB - PURPOSE: To reassess the prevalence and incidence of post-cataract surgery optic neuropathy (PCSON) in the modern era. DESIGN: Retrospective cohort study. METHODS: Setting: Single-center tertiary care practice. STUDY POPULATION: All patients with a diagnosis of nonarteritic anterior ischemic optic neuropathy (NAION) seen in the Wilmer Eye Network system between January 1, 2010 and December 31, 2014 were included. Inclusion was based on the following: (1) a history of an acute unilateral decrease in vision, (2) a visual field defect consistent with NAION, (3) a relative afferent pupillary defect, (4) observed optic disc swelling, and (5) no other etiology being found. MAIN OUTCOME MEASURES: The prevalence and incidence of PCSON and the temporal association between surgery and onset of PCSON. The secondary outcome was the risk of PCSON in the fellow eye of patients with prior unilateral spontaneous NAION. RESULTS: One hundred eighty-eight patients had developed NAION during the study period. Of these, 18 (9.6%) had undergone cataract surgery (CS) during the year prior to developing NAION. There was no significant temporal pattern associated with the distribution of NAION cases (P = .28). The incidence of PCSON in patients who had noncomplex CS was 10.9 cases per 100 000 (95% CI, 1.3, 39.4). CONCLUSIONS: Our data indicate that both the prevalence and incidence of NAION after modern CS are comparable to those of the general population and that there is no significant temporal relationship between modern CS and the subsequent development of NAION in the operated eye. Thus, although this study has inherent biases owing to its retrospective nature, concern regarding an increased risk of PCSON in the fellow eye in patients who have experienced it or spontaneous NAION in 1 eye may be unwarranted. PMID- 27984026 TI - Allosteric Inhibition of a Semaphorin 4D Receptor Plexin B1 by a High-Affinity Macrocyclic Peptide. AB - Semaphorin axonal guidance factors are multifunctional proteins that play important roles in immune response, cancer cell proliferation, and organogenesis, making semaphorins and their signaling receptor plexins important drug targets for various diseases. However, the large and flat binding surface of the semaphorin-plexin interaction interface is difficult to target by traditional small-molecule drugs. Here, we report the discovery of a high-affinity plexin B1 (PlxnB1)-binding macrocyclic peptide, PB1m6 (KD = 3.5 nM). PB1m6 specifically inhibited the binding of physiological ligand semaphorin 4D (Sema4D) in vitro and completely suppressed Sema4D-induced cell collapse. Structural studies revealed that PB1m6 binds at a groove between the fifth and sixth blades of the sema domain in PlxnB1 distant from the Sema4D-binding site, indicating the non competitive and allosteric nature of the inhibitory activity. The discovery of this novel allosteric site can potentially be used to target plexin family proteins for the development of drugs that modulate semaphorin and plexin signaling. PMID- 27984024 TI - Prospective, Randomized Clinical Trial of Povidone-Iodine 1.25% Solution Versus Topical Antibiotics for Treatment of Bacterial Keratitis. AB - PURPOSE: To compare povidone-iodine 1.25% ophthalmic solution with topical antibiotics for treatment of bacterial keratitis in areas of the world where use of effective topical antibiotics may not be an option. STUDY DESIGN: Randomized, controlled, investigator-masked clinical trial. METHODS: We randomized 172 individuals with bacterial keratitis to topical treatment with povidone-iodine or antibiotics (neomycin-polymyxin B-gramicidin in the Philippines; ciprofloxacin 0.3% in India). Using survival analysis, we compared intervals from start of treatment to "presumed cure" (primary outcome measure, defined as a closed epithelial defect without associated inflammatory signs) and to "recovering" (residual epithelial defect <1 mm2 with only minimal inflammation). RESULTS: Median interval to presumed cure in the Philippines was 7 days for povidone iodine and 7 days for neomycin-polymyxin B-gramicidin (95% confidence interval [CI] for difference in median interval, -9.5 to 0.7 days) and in India was 12 days for povidone-iodine and 17 days for ciprofloxacin (95% CI, -35.2 to 3.2 days). Hazard ratio (HR) for presumed cure among those treated with povidone iodine (vs antibiotics) was 1.46 in the Philippines (95% CI, 0.90-2.36; P = .13) and 1.70 in India (95% CI, 0.73-3.94; P = .22). Comparisons of intervals to recovering and HR for recovering also revealed no significant differences between treatment groups in either country. CONCLUSIONS: There is no significant difference between the effect of topical povidone-iodine 1.25% and topical antibiotics commonly available in the developing world for treatment of bacterial keratitis. Povidone-iodine 1.25%, which is widely available and inexpensive, can be considered for treatment of bacterial keratitis when antibiotic treatment is not practical. PMID- 27984027 TI - Generating Functional Recombinant NRPS Enzymes in the Laboratory Setting via Peptidyl Carrier Protein Engineering. AB - Non-ribosomal peptide synthetases (NRPSs) are modular enzymatic assembly lines where substrates and intermediates undergo rounds of transformation catalyzed by adenylation (A), condensation (C), and thioesterase (TE) domains. Central to the NRPS biosynthesis are peptidyl carrier protein (PCP) domains, small, catalytically inactive domains that shuttle substrates and intermediates between the catalytic modules and govern product release from TE domains. There is strong interest in recombination of NRPS systems to generate new chemical entities. However, the intrinsic complexity of these systems has been a major challenge. Here, we employ domain substitution and random mutagenesis to recapitulate NRPS evolution, focusing on PCP domains. Using NRPS model systems that produce two different pigmented molecules, pyoverdine and indigoidine, we found that only evolutionarily specialized recombinant PCP domains could interact effectively with the native TE domain for product release. Overall, we highlight that substituted PCP domains require very minor changes to result in functional NRPSs, and infer that positive selection pressure may improve recombinant NRPS outcomes. PMID- 27984028 TI - Large-Scale Gene Expression Profiling Platform for Identification of Context Dependent Drug Responses in Multicellular Tumor Spheroids. AB - Cancer cell lines grown as two-dimensional (2D) cultures have been an essential model for studying cancer biology and anticancer drug discovery. However, 2D cancer cell cultures have major limitations, as they do not closely mimic the heterogeneity and tissue context of in vivo tumors. Developing three-dimensional (3D) cell cultures, such as multicellular tumor spheroids, has the potential to address some of these limitations. Here, we combined a high-throughput gene expression profiling method with a tumor spheroid-based drug-screening assay to identify context-dependent treatment responses. As a proof of concept, we examined drug responses of quiescent cancer cells to oxidative phosphorylation (OXPHOS) inhibitors. Use of multicellular tumor spheroids led to discovery that the mevalonate pathway is upregulated in quiescent cells during OXPHOS inhibition, and that OXPHOS inhibitors and mevalonate pathway inhibitors were synergistically toxic to quiescent spheroids. This work illustrates how 3D cellular models yield functional and mechanistic insights not accessible via 2D cultures. PMID- 27984029 TI - Geographic Variation in Outpatient Health Care Service Utilization After Spinal Cord Injury. AB - OBJECTIVE: To assess whether travel distances between patients and providers predict the frequency in which outpatient health care services are accessed after spinal cord injury (SCI). DESIGN: A retrospective cohort study was carried out in South Carolina among employee health plan and Medicaid insurance recipients. SETTING: Research center. PARTICIPANTS: Two years of outpatient claimant data were evaluated from patients (N=243) aged >=18 years who were hospitalized between 2010 and 2012. INTERVENTIONS: Travel distances were estimated by geocoding provider and patient address information onto street network files. MAIN OUTCOME MEASURES: Variation in service utilization use was assessed using negative binomial regression. Outpatient visits for physical medicine and rehabilitation, physician and specialty clinic, radiology, internal medicine, behavioral mental health, and "other" were evaluated. RESULTS: Longer travel distances were statistically significant predictors of decreased physician/specialty clinic (relative risk [RR]=.87; 95% confidence interval [CI], .79-.96) and physiotherapy (RR=.57; 95% CI, .46-.71) utilization, with mixed findings for other providers. Secondary analyses in which differences in service use were analyzed using census-defined classifications of urban and rural status did not demonstrate any geographic pattern. CONCLUSIONS: There are significant geographic variations in the use of select outpatient services among SCI populations across the state that are related to longer travel distances. That these patterns were only visible when using travel distance models as opposed to census-based classifications of urban and rural status adds support to augmenting routine data collection and surveillance with spatial analytical models. PMID- 27984030 TI - To What Degree Does Active Cervical Range of Motion Differ Between Patients With Neck Pain, Patients With Whiplash, and Those Without Neck Pain? A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To quantify differences in active cervical range of motion (aCROM) between patients with neck pain and those without neck pain, in patients with whiplash-associated disorders (WADs) and nontraumatic neck pain, and in patients with acute complaints versus those with chronic complaints. DATA SOURCES: Seven bibliographic databases were searched from inception to April 2015. In addition, a manual search was performed. STUDY SELECTION: Full articles on a numerical comparison of aCROM in patients with neck pain and asymptomatic control persons of similar ages were included. Two reviewers independently selected studies and assessed risk of bias. DATA EXTRACTION: Two reviewers extracted the data. Pooled mean differences of aCROM were calculated using a random-effects model. DATA SYNTHESIS: The search yielded 6261 hits; 27 articles (2366 participants, 13 low risk of bias) met the inclusion criteria. The neck pain group showed less aCROM in all movement directions compared with persons without neck pain. Mean differences ranged from -7.04 degrees (95% CI, -9.70 degrees to -4.38 degrees ) for right lateral bending (11 studies) to -89.59 degrees (95% CI, -131.67 degrees to -47.51 degrees ) for total aCROM (4 studies). Patients with WADs had less aCROM than patients with nontraumatic neck pain. No conclusive differences in aCROM were found between patients with acute and patients with chronic complaints. CONCLUSIONS: Patients with neck pain have a significantly decreased aCROM compared with persons without neck pain, and patients with WADs have less aCROM than those with nontraumatic neck pain. PMID- 27984032 TI - Sex and estrous cycle differences in immediate early gene activation in the hippocampus and the dorsal striatum after the cue competition task. AB - The hippocampus and dorsal striatum are important structures involved in place and response learning strategies respectively. Both sex and estrous cycle phase differences in learning strategy preference exist following cue competition paradigms. Furthermore, significant effects of sex and learning strategy on hippocampal neural plasticity have been reported. However, associations between learning strategy and immediate early gene (IEG) expression in the hippocampus and dorsal striatum are not completely understood. In the current study we investigated the effects of sex and estrous cycle phase on strategy choice and IEG expression in the hippocampus and dorsal striatum of rats following cue competition training in the Morris water maze. We found that proestrous rats were more likely to choose a place strategy than non-proestrous or male rats. Although male cue strategy users travelled greater distances than the other groups on the first day of training, there were no other sex or strategy differences in the ability to reach a hidden or a visible platform. Female place strategy users exhibited greater zif268 expression and male place strategy users exhibited greater cFos expression compared to all other groups in CA3. Furthermore, cue strategy users had greater expression of cFos in the dorsal striatum than place strategy users. Shorter distances to reach a visible platform were associated with less activation of cFos in CA3 and CA1 of male place strategy users. Our findings indicate multiple differences in brain activation with sex and strategy use, despite limited behavioral differences between the sexes on this cue competition paradigm. PMID- 27984033 TI - Cross-talk among immune and neuroendocrine systems in molluscs and other invertebrate models. AB - The comparison between immune and neuroendocrine systems in vertebrates and invertebrates suggest an ancient origin and a high degree of conservation for the mechanisms underlying the integration between immune and stress responses. This suggests that in both vertebrates and invertebrates the stress response involves the integrated network of soluble mediators (e.g., neurotransmitters, hormones and cytokines) and cell functions (e.g., chemotaxis and phagocytosis), that interact with a common objective, i.e., the maintenance of body homeostasis. During evolution, several changes observed in the stress response of more complex taxa could be the result of new roles of ancestral molecules, such as ancient immune mediators may have been recruited as neurotransmitters and hormones, or vice versa. We review older and recent evidence suggesting that immune and neuro endocrine functions during the stress response were deeply intertwined already at the dawn of multicellular organisms. These observations found relevant reflections in the demonstration that immune cells can transdifferentiate in olfactory neurons in crayfish and the recently re-proposed neural transdifferentiation in humans. PMID- 27984031 TI - Polestriding Intervention Improves Gait and Axial Symptoms in Mild to Moderate Parkinson Disease. AB - OBJECTIVE: To evaluate the effects of 12-week polestriding intervention on gait and disease severity in people with mild to moderate Parkinson disease (PD). DESIGN: A-B-A withdrawal study design. SETTING: Outpatient movement disorder center and community facility. PARTICIPANTS: Individuals (N=17; 9 women [53%] and 8 men [47%]; mean age, 63.7+/-4.9y; range, 53-72y) with mild to moderate PD according to United Kingdom brain bank criteria with Hoehn & Yahr score ranging from 2.5 to 3.0 with a stable medication regimen and ability to tolerate "off" medication state. INTERVENTIONS: Twelve-week polestriding intervention with 12 week follow-up. MAIN OUTCOME MEASURES: Gait was evaluated using several quantitative temporal, spatial, and variability measures. In addition, disease severity was assessed using clinical scales such as Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn & Yahr scale, and Parkinson's Disease Questionnaire 39. RESULTS: Step and stride lengths, gait speed, and step-time variability were improved significantly (P<.05) because of 12-week polestriding intervention. Also, the UPDRS motor score, the UPDRS axial score, and the scores of UPDRS subscales on walking and balance improved significantly after the intervention. CONCLUSIONS: Because increased step-time variability and decreased step and stride lengths are associated with PD severity and an increased risk of falls in PD, the observed improvements suggest that regular practice of polestriding may reduce the risk of falls and improve mobility in people with PD. PMID- 27984034 TI - Tolerance of infection: A role for animal behavior, potential immune mechanisms, and consequences for parasite transmission. AB - Infected organisms can resist or tolerate infection, with tolerance of infection defined as minimizing per-parasite reductions in fitness. Although tolerance is well studied in plants, researchers have only begun to probe the mechanisms and transmission consequences of tolerance in animals. Here we suggest that research on tolerance in animals would benefit from explicitly incorporating behavior as a component of tolerance, given the importance of behavior for host fitness and parasite transmission. We propose two distinct manifestations of tolerance in animals: tissue-specific tolerance, which minimizes fitness losses due to tissue damage during infection, and behavioral tolerance, which minimizes fitness losses by maintaining normal, fitness-enhancing behaviors during infection. Here we briefly review one set of potential immune mechanisms underlying both responses in vertebrate animals: inflammation and its associated signaling molecules. Inflammatory responses, including broadly effective resistance mechanisms like the production of reactive oxygen species, can incur severe costs in terms of damage to a host's own tissues, thereby reducing tissue-specific tolerance. In addition, signaling molecules involved in these responses facilitate stereotypical behavioral changes during infection, which include lethargy and anorexia, reducing normal behaviors and behavioral tolerance. We consider how tissue-specific and behavioral tolerance may vary independently or in conjunction and outline potential consequences of such covariation for the transmission of infectious diseases. We put forward the distinction between tissue-specific and behavioral tolerance not as a definitive framework, but to help stimulate and broaden future research by considering animal behavior as intimately linked to the mechanisms and consequences of tolerance in animals. PMID- 27984035 TI - Trends in gestational age at time of surgical abortion for fetal aneuploidy and structural abnormalities. AB - BACKGROUND: Screening for fetal aneuploidy has evolved over the past 2 decades. Whether these advances impact gestational age at abortion has received little study. OBJECTIVE: We sought to describe trends in the gestational age at the time of abortion by fetal diagnosis over an 11-year study period. We hypothesized that gestational age at time of abortion would decrease for fetal aneuploidy but remain unchanged for structural abnormalities. STUDY DESIGN: We conducted a retrospective case series of all women undergoing surgical abortion for fetal aneuploidy or structural abnormalities up to 24 weeks' gestation from 2004 through 2014 in a hospital operating room setting at a single, urban medical center. We excluded labor induction abortions (<1% of abortions at our medical center) and suction aspirations performed in the office practice. We performed suction aspiration up to 14 weeks and dilation and evacuation after that gestational age. We describe the median gestational age at abortion by fetal indication and year. RESULTS: For women undergoing abortion for fetal aneuploidy (n = 392), the median gestational age at time of abortion decreased from 19.0 weeks (interquartile range 18.0-21.0) in 2004 to 14.0 weeks (interquartile range 13.0-17.0) in 2014 (Kruskal-Wallis P < .0001). For women undergoing abortion for fetal structural abnormalities (n = 586), the median gestational age was >=20 weeks for each year during the study interval (P = .1). As gestational age decreased in the fetal aneuploidy group, fewer women underwent dilation and evacuation and more became eligible for suction aspiration (<14 weeks). In 2004, >90% of women underwent dilation and evacuation for either indication. By 2014, 31% of women with fetal aneuploidy were eligible for suction aspiration compared to 11% of those with structural anomalies. CONCLUSION: Gestational age at the time of abortion for fetal aneuploidy decreased substantially from 2004 through 2014; earlier abortion is safer for women. In contrast, women seeking abortion for fetal structural abnormalities did not experience a change in timing. Legislation restricting gestational age at the time of abortion could disproportionately affect women with fetal structural abnormalities. PMID- 27984036 TI - Minimizing blood loss at cesarean-hysterectomy for placenta previa percreta. AB - Preventing blood loss at the time of a cesarean delivery during a scheduled, nonemergent cesarean hysterectomy for placenta percreta may reduce the need for crystalloid and blood product transfusion. Commonly a classical hysterotomy is created and this can result in as much as a 500-800 mL blood loss before the hysterotomy is closed. Our technique involves placement of 4 full-thickness interrupted sutures in a box pattern to create an unperfused area of upper uterine segment. Diathermy is used to open the uterus to the membranes in the center of the "box" without blood loss. A finger is then inserted between the membranes and uterus to create a space into which 1 side of an 80-mm linear cutting stapler is introduced. The other side of the stapler is then attached and clamped closed, and the stapler is activated. Forward motion of the lever lays down 2 rows of staples, and backward movement of the lever divides the uterine muscle between the 2 staple lines. The stapler is removed and reloaded and reintroduced 1 or 2 times as needed to create an avascular hysterotomy large enough to atraumatically deliver the baby. The membranes are then opened and the baby is delivered. Following this the umbilical cord is clamped and cut without any attempt to remove the placenta, replaced in the uterine cavity, and the hysterotomy is closed with a running locked suture that incorporates the membrane edges. The hysterectomy then proceeds. In most cases there is minimal blood loss (usually <20 mL) from the cesarean delivery. PMID- 27984039 TI - Glycolipids and Lectins in Endocytic Uptake Processes. AB - A host of endocytic processes has been described at the plasma membrane of eukaryotic cells. Their categorization has most commonly referenced cytosolic machinery, of which the clathrin coat has occupied a preponderant position. In what concerns intra-membrane constituents, the focus of interest has been on phosphatidylinositol lipids and their capacity to orchestrate endocytic events on the cytosolic leaflet of the membrane. The contribution of extracellular determinants to the construction of endocytic pits has received much less attention, depite the fact that (glyco)sphingolipids are exoplasmic leaflet fabric of membrane domains, termed rafts, whose contributions to predominantly clathrin-independent internalization processes is well recognized. Furthermore, sugar modifications on extracellular domains of proteins, and sugar-binding proteins, termed lectins, have also been linked to the uptake of endocytic cargoes at the plasma membrane. In this review, we first summarize these contributions by extracellular determinants to the endocytic process. We thus propose a molecular hypothesis - termed the GL-Lect hypothesis - on how GlycoLipids and Lectins drive the formation of compositional nanoenvrionments from which the endocytic uptake of glycosylated cargo proteins is operated via clathrin-independent carriers. Finally, we position this hypothesis within the global context of endocytic pathway proposals that have emerged in recent years. PMID- 27984038 TI - Increased Expression of PLS3 Correlates with Better Outcome in Sezary Syndrome. PMID- 27984040 TI - Phospholipids in Autophagosome Formation and Fusion. AB - Autophagosomes are double membrane organelles that are formed during a process referred to as macroautophagy. They serve to deliver cytoplasmic material into the lysosome for degradation. Autophagosomes are formed in a de novo manner and are the result of substantial membrane remodeling processes involving numerous protein-lipid interactions. While most studies focus on the proteins involved in autophagosome formation it is obvious that lipids including phospholipids, sphingolipids and sterols play an equally important role. Here we summarize the current knowledge about the role of lipids, especially focusing on phospholipids and their interplay with the autophagic protein machinery during autophagosome formation and fusion. PMID- 27984037 TI - Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice. AB - IL-6 inhibition has been unsuccessful in treating psoriasis, despite high levels of tissue and serum IL-6 in patients. In addition, de novo psoriasis onset has been reported after IL-6 blockade in patients with rheumatoid arthritis. To explore mechanisms underlying these clinical observations, we backcrossed an established psoriasiform mouse model (IL-17C+ mice) with IL-6-deficient mice (IL 17C+KO) and examined the cutaneous phenotype. IL-17C+KO mice initially exhibited decreased skin inflammation; however, this decrease was transient and reversed rapidly, concomitant with increases in skin Tnf, Il36alpha/beta/gamma, Il24, Epgn, and S100a8/a9 to levels higher than those found in IL-17C+ mice. A comparison of IL-17C+ and IL-17C+KO mouse skin transcriptomes with that of human psoriasis skin revealed significant correlation among transcripts of skin of patients with psoriasis and IL-17C+KO mouse skin, and confirmed an exacerbation of the inflammatory signature in IL-17C+KO mice that aligns closely with human psoriasis. Transcriptional analyses of IL-17C+ and IL-17C+KO primary keratinocytes confirmed increased expression of proinflammatory molecules, suggesting that in the absence of IL-6, keratinocytes increase production of numerous additional proinflammatory cytokines. These preclinical findings may provide insight into why patients with arthritis being treated with IL-6 inhibitors develop new onset psoriasis and why IL-6 blockade for the treatment of psoriasis has not been clinically effective. PMID- 27984041 TI - Structural and Functional Characterization of Plasmodium falciparum Nicotinic Acid Mononucleotide Adenylyltransferase. AB - Nicotinic acid mononucleotide adenylyltransferase (NaMNAT) is an indispensable enzyme for the synthesis of NAD and NAD phosphate. It catalyzes the adenylylation of nicotinic acid mononucleotide (NaMN) to yield nicotinic acid adenine dinucleotide (NaAD). Since NAD(H) and NAD phosphate(H) are essentially involved in metabolic and redox regulatory reactions, NaMNAT is an attractive drug target in the fight against bacterial and parasitic infections. Notably, NaMNAT of the malaria parasite Plasmodium falciparum possesses only 20% sequence identity with the homologous human enzyme. Here, we present for the first time the two X-ray structures of P. falciparum NaMNAT (PfNaMNAT)-in the product-bound state with NaAD and complexed with an alpha,beta-non-hydrolizable ATP analog-the structures were determined to a resolution of 2.2A and 2.5A, respectively. The overall architecture of PfNaMNAT was found to be more similar to its bacterial homologs than its human counterparts although the PPHK motif conserved in bacteria is missing. Furthermore, PfNaMNAT possesses two cysteine residues within the active site that have not been described for any other NaMNATase so far and are likely to be involved in redox regulation of PfNaMNAT activity. Enzymatic studies and surface plasmon resonance data reveal that PfNaMNAT is capable of utilizing NaMN and nicotinamide mononucleotide with a slight preference for NaMN. Surprisingly, a comparison with the active site of Escherichia coli NaMNAT showed very similar architectures, despite different substrate preferences. PMID- 27984042 TI - A Structural Investigation into Oct4 Regulation by Orphan Nuclear Receptors, Germ Cell Nuclear Factor (GCNF), and Liver Receptor Homolog-1 (LRH-1). AB - Oct4 is a transcription factor required for maintaining pluripotency and self renewal in stem cells. Prior to differentiation, Oct4 must be silenced to allow for the development of the three germ layers in the developing embryo. This fine tuning is controlled by the nuclear receptors (NRs), liver receptor homolog-1 (LRH-1) and germ cell nuclear factor (GCNF). Liver receptor homolog-1 is responsible for driving the expression of Oct4 where GCNF represses its expression upon differentiation. Both receptors bind to a DR0 motif located within the Oct4 promoter. Here, we present the first structure of mouse GCNF DNA binding domain in complex with the Oct4 DR0. The overall structure revealed two molecules bound in a head-to-tail fashion on opposite sides of the DNA. Additionally, we solved the structure of the human LRH-1 DNA-binding domain bound to the same element. We explore the structural elements that govern Oct4 recognition by these two NRs. PMID- 27984043 TI - Myeloid Leukemia Factor Acts in a Chaperone Complex to Regulate Transcription Factor Stability and Gene Expression. AB - Mutations that affect myelodysplasia/myeloid leukemia factor (MLF) proteins are associated with leukemia and several other cancers. However, with no strong homology to other proteins of known function, the role of MLF proteins in the cell has remained elusive. Here, we describe a proteomics approach that identifies MLF as a member of a nuclear chaperone complex containing a DnaJ protein, BCL2-associated anthanogene 2, and Hsc70. This complex associates with chromatin and regulates the expression of target genes. The MLF complex is bound to sites of nucleosome depletion and sites containing active chromatin marks (e.g., H3K4me3 and H3K4me1). Hence, MLF binding is enriched at promoters and enhancers. Additionally, the MLF-chaperone complex functions to regulate transcription factor stability, including the RUNX transcription factor involved in hematopoiesis. Although Hsc70 and other co-chaperones have been shown to play a role in nuclear translocation of a variety of proteins including transcription factors, our findings suggest that MLF and the associated co-chaperones play a direct role in modulating gene transcription. PMID- 27984045 TI - Age-specific trends in antibiotic resistance in Escherichia coli infections in Oxford, United Kingdom 2013-2014. PMID- 27984044 TI - BFDCA: A Comprehensive Tool of Using Bayes Factor for Differential Co-Expression Analysis. AB - Comparing the gene-expression profiles between biological conditions is useful for understanding gene regulation underlying complex phenotypes. Along this line, analysis of differential co-expression (DC) has gained attention in the recent years, where genes under one condition have different co-expression patterns compared with another. We developed an R package Bayes Factor approach for Differential Co-expression Analysis (BFDCA) for DC analysis. BFDCA is unique in integrating various aspects of DC patterns (including Shift, Cross, and Re wiring) into one uniform Bayes factor. We tested BFDCA using simulation data and experimental data. Simulation results indicate that BFDCA outperforms existing methods in accuracy and robustness of detecting DC pairs and DC modules. Results of using experimental data suggest that BFDCA can cluster disease-related genes into functional DC subunits and estimate the regulatory impact of disease-related genes well. BFDCA also achieves high accuracy in predicting case-control phenotypes by using significant DC gene pairs as markers. BFDCA is publicly available at http://dx.doi.org/10.17632/jdz4vtvnm3.1. PMID- 27984046 TI - Psychophysiological relationships between a multi-component self-report measure of mood, stress and behavioural signs and symptoms, and physiological stress responses during a simulated firefighting deployment. AB - Physical work and sleep loss are wildland firefighting demands that elicit psychological and physiological stress responses. Research shows that these responses are statistically related which presents an opportunity to use subjective psychological questionnaires to monitor physiological changes among firefighters; an approach used extensively in sport settings. The aim of the present study was to investigate if changes in self-reported psychological factors on the multi-component training distress scale (MTDS), relate to cytokines and cortisol levels among firefighters completing three days of simulated physical firefighting work separated by an 8-h or restricted 4-h sleep each night. Each day firefighters completed the MTDS in the morning and salivary cortisol and inflammatory cytokines were measured throughout the day. When sleep restricted, firefighters demonstrated increases in MTDS factors of general fatigue, perceived stress and depressed mood that were related to elevated cytokines (TNF-alpha, IL-8, IL-10). Conversely, firefighters who had an 8-h sleep demonstrated a positive relationship between physical signs and symptoms and elevated IL-6, while depressed mood was inversely related to decreasing cortisol and cytokines (IL-6, TNF-alpha, IL-10). Findings highlight the utility of the MTDS to detect psychological changes that reflect physiological responses among firefighters. Future research that establishes thresholds for specific factors which predict health-related physiological changes, will allow fire agencies implement multi-component measures to monitor and manage the health of personnel on the fire-ground. PMID- 27984048 TI - Hypothalamic expression of inflammatory mediators in an animal model of binge eating. AB - Binge eating episodes are characterized by uncontrollable, distressing eating of a large amount of highly palatable food and represent a central feature of bingeing related eating disorders. Research suggests that inflammation plays a role in the onset and maintenance of eating-related maladaptive behavior. Markers of inflammation can be selectively altered in discrete brain regions where they can directly or indirectly regulate food intake. In the present study, we measured expression levels of different components of cytokine systems (IL-1, IL 6, IL-18, TNF-alpha and IFN-gamma) and related molecules (iNOS and COX2) in the preoptic and anterior-tuberal parts of the hypothalamus of a validated animal model of binge eating. In this animal model, based on the exposure to both food restriction and frustration stress, binge-like eating behavior for highly palatable food is not shown when animals are exposed to the frustration stress during the estrus phase. We found a characteristic down-regulation of the IL 18/IL-18 receptor system (with increased expression of the inhibitor of the pro inflammatory cytokine IL-18, IL-18BP, together with a decreased expression of the binding chain of the IL-18 receptor) and a three-fold increase in the expression of iNOS specifically in the anterior-tuberal region of the hypothalamus of animals that develop a binge-like eating behavior. Differently, when food restricted animals were stressed during the estrus phase, IL-18 expression increased, while iNOS expression was not significantly affected. Considering the role of this region of the hypothalamus in controlling feeding related behavior, this can be relevant in eating disorders and obesity. Our data suggest that by targeting centrally selected inflammatory markers, we may prevent that disordered eating turns into a full blown eating disorder. PMID- 27984049 TI - Disruptions in effort-based decision-making and consummatory behavior following antagonism of the dopamine D2 receptor. AB - Dopamine is known to influence motivational processes, however the precise role of this neurotransmitter remains a contentious issue. In the current study we sought to further characterize dopamine signaling in reward-based decision-making and consummatory behavior in mice, via lateral ventricle infusion of the dopamine D2 receptor antagonist eticlopride. In Experiment 1, we examined effort-based decision-making, in which mice had a choice between one lever, where a single response led to the delivery of a low value reward (2% sucrose); and a second lever, which led to a higher value reward (20% sucrose) that gradually required more effort to obtain. As the response schedule for the high value reward became more strict, low dose (4MUg in 0.5MUl) central infusions of eticlopride biased preference away from the high value reward, and toward the lever that led to the low value reward. Similarly, a higher dose of eticlopride (8MUg in 0.5MUl) also disrupted choice responding for the high value reward, however it did so by increasing omissions. In Experiment 2, we assessed the effects of eticlopride on consumption of 20% sucrose. The antagonist led to a dose-dependent reduction in intake, and through an analysis of licking microstructure, it was revealed that this in part reflected a reduction in the motivation to engage in consummatory behavior, rather than alterations in the evaluation of the reward. These results suggest that disruptions in D2 receptor signaling reduce the willingness to engage in effortful operant responding and consumption of a desirable outcome. PMID- 27984051 TI - Brain endothelial dysfunction following pyrithiamine induced thiamine deficiency in the rat. AB - Prolonged vitamin B1 (thiamine) deficiency can lead to neurological disorders such as Wernicke's encephalopathy and Wernicke-Korsakoff Syndrome (WKS) in humans. These thiamine deficiency disorders have been attributed to vascular leakage, blood-brain barrier breakdown and neuronal loss in the diencephalon and brain stem. However, endothelial dysfunction following thiamine deficiency and its relationship to the phenomenon of neurodegeneration has not been clearly elucidated. The present study sought to begin to address this issue by evaluating vascular morphology and integrity in a pyrithiamine (PT)-induced rat model of thiamine deficiency. Adjacent brain sections were used to either assess vascular integrity through immunohistochemical localization of rat endothelial cell antigen (RECA-1) and endothelial brain barrier antigen (EBA-1) or neurodegeneration using the de Olmos cupric silver method. GFAP and CD11b immunolabeling was used to evaluate astrocytic and microglial/macrophagic changes. Extensive neurodegeneration occurred concomitant with both vascular damage (thinning and breakage) and microglial activation in the inferior olive, medial thalamic area, and medial geniculate nuclei of pyrithiamine treated rats. Likewise, glucose transporter-1 (Glut-1), which is mostly expressed in endothelial cells, was also severely decreased in this pyrithiamine induced thiamine deficient rat model. MRI scans of these animals prior to sacrifice show that the pyrithiamine induced thiamine deficient animals have abnormal T2 relaxation values, which are commensurate with, and possibly predictive of, the neurodegeneration and/or endothelial dysfunction subsequently observed histologically in these same animals. PMID- 27984052 TI - Beta-Adrenergic Receptor Blockers in Hypertension: Alive and Well. AB - Beta-adrenergic receptor blockers (beta-blockers) are an appropriate treatment for patients having systemic hypertension (HTN) who have concomitant ischemic heart disease (IHD), heart failure, obstructive cardiomyopathy, aortic dissection or certain cardiac arrhythmias. beta-Blockers can be used in combination with other antiHTN drugs to achieve maximal blood pressure control. Labetalol can be used in HTN emergencies and urgencies. beta-Blockers may be useful in HTN patients having a hyperkinetic circulation (palpitations, tachycardia, HTN, and anxiety), migraine headache, and essential tremor. beta-Blockers are highly heterogeneous with respect to various pharmacologic properties: degree of intrinsic sympathomimetic activity, membrane stabilizing activity, beta1 selectivity, alpha1-adrenergic blocking effects, tissue solubility, routes of systemic elimination, potencies and duration of action, and specific properties may be important in the selection of a drug for clinical use. beta-Blocker usage to reduce perioperative myocardial ischemia and cardiovascular (CV) complications may not benefit as many patients as was once hoped, and may actually cause harm in some individuals. Currently the best evidence supports perioperative beta blocker use in two patient groups: patients undergoing vascular surgery with known IHD or multiple risk factors for it, and for those patients already receiving beta-blockers for known CV conditions. PMID- 27984050 TI - Influence of tetramethylenedisulfotetramine on synchronous calcium oscillations at distinct developmental stages of hippocampal neuronal cultures. AB - The spatial and temporal patterns of spontaneous synchronous Ca2+ oscillations (SCOs) regulate physiological pathways that influence neuronal development, excitability, and health. Hippocampal neuronal cultures (HN) and neuron/glia co cultures (HNG) produced from neonatal mice were loaded with Fluo-4/AM and SCOs recorded in real-time using a Fluorescence Imaging Plate Reader at different developmental stages in vitro. HNG showed an earlier onset of SCOs, with low amplitude and low frequency SCOs at 4days in vitro (DIV), whereas HN were quiescent at this point. SCO amplitude peaked at 9 DIV for both cultures. SCO network frequency peaked at 12 DIV in HN, whereas in HNG the frequency peaked at 6 DIV. SCO patterns were associated with the temporal development of neuronal networks and their ratio of glutamatergic to GABAergic markers of excitatory/inhibitory balance. HN and HNG exhibited differential responses to the convulsant tetramethylenedisulfotetramine (TETS) and were highly dependent on DIV. In HN, TETS triggered an acute rise of intracellular Ca2+ (Phase I response) only in 14 DIV and a sustained decrease of SCO frequency with increased amplitude (Phase II response) at all developmental stages. In HNG, TETS decreased the SCO frequency and increased the amplitude at 6 and 14 but not 9 DIV. There was no acute Ca2+ rise (Phase I response) in any age of HNG tested with TETS. These data demonstrated the importance of glia and developmental stage in modulating neuronal responses to TETS. Our results illustrate the applicability of the model for investigating how caged convulsants elicit abnormal network activity during the development of HN and HNG cultures in vitro. PMID- 27984054 TI - Reply by the Authors. PMID- 27984053 TI - Aggressive Angiomyxoma of the Vulva Mimicking Clitoromegaly in a Young Child. AB - Aggressive angiomyxoma (AAM) is a rare soft tissue tumor of mesenchymal origin that chiefly involves the vulvar and perineal region. In 90% of cases, AAM presents in women of reproductive age with a peak incidence in the fourth decade of life. To date, AAM of the vulva in young children and infancy has never been reported. We present a case of AAM of the vulva that was initially interpreted as clitoromegaly in a 3-year-old girl. PMID- 27984055 TI - A few words on differentiating magno- and parvocellular contributions to vision on the basis of temporal frequency. AB - A number of authors have proposed that changes in temporal frequency within the range of 0-30Hz may be used to differentiate contributions from the magno- and parvocellular systems. The present analyses estimate the percentage of active magnocellular cells as a function of frequency based on published cut-off values for magno- and parvocellular cells. These analyses indicate that varying the temporal frequency over the range of 0-30Hz has little effect upon the percentage of active magnocellular cells. The analyses were also carried out for a series of hypothetical cut-off frequencies and standard deviations of these frequencies for magnocellular cells. The results of these simulations indicate that even large alterations in these values do not alter the above conclusion to a noteworthy extent. PMID- 27984056 TI - Reciprocal effects between dominance and anger: A systematic review. AB - Dominance and high status are directly associated with perception of angry expressions. However, studies that have sought to empirically assess the causal mechanisms between these construct are still relatively scarce. Moreover, several variables can influence and be influenced by both anger and dominance, increasing the complexity of synthesizing the findings related to the association between these agonistic behaviors. We conducted a systematic review in five electronic databases. A total of 207 potentially relevant publications were identified and screened. Of those, 20 articles were found eligible for detailed review, with 26 empirical studies. All reviewed studies reported an association between dominance and anger. Social status and dominance have a direct effect on the perception of anger. In turn, the perception of anger has a consistent effect on attributions of dominance for those who express this emotion. There are mutual effects between dominance and anger, which, if recurring and positively feedback-regulated, at least in perceptual terms, can lead to the establishment and maintenance of dominance hierarchies in social groups. PMID- 27984057 TI - Optimizing of a protein extraction method for Mycobacterium tuberculosis proteome analysis using mass spectrometry. AB - A critical step in proteomic analyses comprises the implementation of a reliable cell lysis method with high yields of qualitative proteins. In Mycobacteria, the protein extraction step is often hampered by the thick waxy cell wall which is rich in mycolic acids. Harsh disruption techniques to release proteins from the cells are thus required. Here, we demonstrate an optimized protein extraction procedure for Mycobacterium tuberculosis (Mbt) that results in protein extracts that are useful for all currently used proteomics platforms, including gel and LC MS based strategies. We compared the effectiveness of using both thiourea and urea and/or SDS and DTT in the solubilization buffer, in combination or not with sonication and/or bead beating. After some preliminary optimization steps on fast growing Mbt-like organisms, namely Mycobacterium smegmatis and Mycobacterium fortuitum, the final protein extraction protocol was tested on M. tuberculosis. Based on the concentrations of the proteins recovered from each of the tested methods and on the quality of the extracted proteins as evaluated by SDS PAGE, we propose a lysis buffer that contains both thiourea and urea, in combination with two mechanical cell disruption methods: sonication and bead beating. The optimized protocol results in protein extracts that are useful in M. tuberculosis proteomics studies based on any proteomics strategy or platform. PMID- 27984058 TI - Enhancing melting curve analysis for the discrimination of loop-mediated isothermal amplification products from four pathogenic molds: Use of inorganic pyrophosphatase and its effect in reducing the variance in melting temperature values. AB - Loop-mediated isothermal amplification (LAMP) is widely used for differentiating causative agents in infectious diseases. Melting curve analysis (MCA) in conjunction with the LAMP method reduces both the labor required to conduct an assay and contamination of the products. However, two factors influence the melting temperature (Tm) of LAMP products: an inconsistent concentration of Mg2+ ion due to the precipitation of Mg2P2O7, and the guanine-cytosine (GC) content of the starting dumbbell-like structure. In this study, we investigated the influence of inorganic pyrophosphatase (PPase), an enzyme that inhibits the production of Mg2P2O7, on the Tm of LAMP products, and examined the correlation between the above factors and the Tm value using MCA. A set of LAMP primers that amplify the ribosomal DNA of the large subunit of Aspergillus fumigatus, Penicillium expansum, Penicillium marneffei, and Histoplasma capsulatum was designed, and the LAMP reaction was performed using serial concentrations of these fungal genomic DNAs as templates in the presence and absence of PPase. We compared the Tm values obtained from the PPase-free group and the PPase containing group, and the relationship between the GC content of the theoretical starting dumbbell-like structure and the Tm values of the LAMP product from each fungus was analyzed. The range of Tm values obtained for several fungi overlapped in the PPase-free group. In contrast, in the PPase-containing group, the variance in Tm values was smaller and there was no overlap in the Tm values obtained for all fungi tested: the LAMP product of each fungus had a specific Tm value, and the average Tm value increased as the GC% of the starting dumbbell-like structure increased. The use of PPase therefore reduced the variance in the Tm value and allowed the differentiation of these pathogenic fungi using the MCA method. PMID- 27984061 TI - Harmful algae: Effects of cyanobacterial cyclic peptides on aquatic invertebrates a short review. AB - Cyanotoxins are secondary metabolites produced by cyanobacteria. Cyclic peptides, microcystins and nodularin commonly detected in water reservoirs of different parts of the world may induce various detrimental effects in a wide range of organisms from bacteria to humans. This paper presents the current state of knowledge on the effects of microcystins and nodularin on aquatic invertebrates: zooplankton, decapods and mollusks. Accumulation of microcystins and nodularin in these organisms and possible transfer of the cyanotoxins through the food web and possible threat to humans as consumers are also discussed. PMID- 27984060 TI - Identification of drug resistance and immune-driven variations in hepatitis C virus (HCV) NS3/4A, NS5A and NS5B regions reveals a new approach toward personalized medicine. AB - Cellular immune responses (T cell responses) during hepatitis C virus (HCV) infection are significant factors for determining the outcome of infection. HCV adapts to host immune responses by inducing mutations in its genome at specific sites that are important for HLA processing/presentation. Moreover, HCV also adapts to resist potential drugs that are used to restrict its replication, such as direct-acting antivirals (DAAs). Although DAAs have significantly reduced disease burden, resistance to these drugs is still a challenge for the treatment of HCV infection. Recently, drug resistance mutations (DRMs) observed in HCV proteins (NS3/4A, NS5A and NS5B) have heightened concern that the emergence of drug resistance may compromise the effectiveness of DAAs. Therefore, the NS3/4A, NS5A and NS5B drug resistance variations were investigated in this study, and their prevalence was examined in a large number of protein sequences from all HCV genotypes. Furthermore, potential CD4+ and CD8+ T cell epitopes were predicted and their overlap with genetic variations was explored. The findings revealed that many reported DRMs within NS3/4A, NS5A and NS5B are not drug-induced; rather, they are already present in HCV strains, as they were also detected in HCV-naive patients. This study highlights several hot spots in which HLA and drug selective pressure overlap. Interestingly, these overlapping mutations were frequently observed among many HCV genotypes. This study implicates that knowledge of the host HLA type and HCV subtype/genotype can provide important information in defining personalized therapy. PMID- 27984065 TI - Isolation and characterization of a novel human scFv inhibiting EGFR vIII expressing cancers. AB - EGFRvIII, a mutant form of epidermal growth factor receptor is highly expressed in glioblastoma, carcinoma of the breast, ovary, and lung but not in normal cells. This tumor specific antigen has emerged as a promising candidate for antibody based therapy of several cancers. The aim of the present study was isolation and characterization of a human single chain antibody against EGFRvIII as a promising target for cancer therapy. For this, a synthetic peptide corresponding to EGFRvIII protein was used for screening the naive human scFv phage library. Selection was performed using a novel screening strategy for enrichment of rare specific clones. After five rounds of screening, six positive scFv clones against EGFRvIII were selected using monoclonal phage ELISA, among them, a clone with an amber mutation in VH CDR2 coding sequence showed higher reactivity. The mutation was corrected through site directed mutagenesis and then scFv fragment was expressed after subcloning into the bacterial expression vector. Expression in BL21 pLysS resulted in a highly soluble scFv appeared in soluble fraction of E. coli lysate. Bioinformatic in silico analysis between scFv and EGFRvIII sequences confirmed specific binding of desired scFv to EGFRvIII in CDR regions. The specific reactivity of the purified scFv with native EGFRvIII was confirmed by cell based ELISA and western blot. In conclusion, human anti- EGFRvIII scFv isolated from a scFv phage library displayed high reactivity with EGFRvIII. The scFv isolated in this study can be the groundwork for developing more effective diagnostic and therapeutic agents against EGFRvIII expressing cancers. PMID- 27984066 TI - A position for tumor necrosis factor inhibitors in the management of colchicine resistant familial Mediterranean fever? PMID- 27984067 TI - Co-speech hand movements during narrations: What is the impact of right vs. left hemisphere brain damage? AB - Persons with brain damage show deviant patterns of co-speech hand movement behaviour in comparison to healthy speakers. It has been claimed by several authors that gesture and speech rely on a single production mechanism that depends on the same neurological substrate while others claim that both modalities are closely related but separate production channels. Thus, findings so far are contradictory and there is a lack of studies that systematically analyse the full range of hand movements that accompany speech in the condition of brain damage. In the present study, we aimed to fill this gap by comparing hand movement behaviour in persons with unilateral brain damage to the left and the right hemisphere and a matched control group of healthy persons. For hand movement coding, we applied Module I of NEUROGES, an objective and reliable analysis system that enables to analyse the full repertoire of hand movements independent of speech, which makes it specifically suited for the examination of persons with aphasia. The main results of our study show a decreased use of communicative conceptual gestures in persons with damage to the right hemisphere and an increased use of these gestures in persons with left brain damage and aphasia. These results not only suggest that the production of gesture and speech do not rely on the same neurological substrate but also underline the important role of right hemisphere functioning for gesture production. PMID- 27984069 TI - Corticosteroids or biopsy for idiopathic orbital inflammation. PMID- 27984070 TI - Reply re: Dr. Kubota's Letter to the Editor, Corticosteroids or biopsy for idiopathic orbital inflammation. PMID- 27984068 TI - Age-related differences in resolving semantic and phonological competition during receptive language tasks. AB - Receptive language (e.g., reading) is largely preserved in the aging brain, and semantic processes in particular may continue to develop throughout the lifespan. We investigated the neural underpinnings of phonological and semantic retrieval in older and younger adults during receptive language tasks (rhyme and semantic similarity judgments). In particular, we were interested in the role of competition on language retrieval and varied the similarities between a cue, target, and distractor that were hypothesized to affect the mental process of competition. Behaviorally, all participants responded faster and more accurately during the rhyme task compared to the semantic task. Moreover, older adults demonstrated higher response accuracy than younger adults during the semantic task. Although there were no overall age-related differences in the neuroimaging results, an Age*Task interaction was found in left inferior frontal gyrus (IFG), with older adults producing greater activation than younger adults during the semantic condition. These results suggest that at lower levels of task difficulty, older and younger adults engaged similar neural networks that benefited behavioral performance. As task difficulty increased during the semantic task, older adults relied more heavily on largely left hemisphere language regions, as well as regions involved in perception and internal monitoring. Our results are consistent with the stability of language comprehension across the adult lifespan and illustrate how the preservation of semantic representations with aging may influence performance under conditions of increased task difficulty. PMID- 27984059 TI - Cruising the cellular highways: How human papillomavirus travels from the surface to the nucleus. AB - The non-enveloped human papillomaviruses (HPVs) specifically target epithelial cells of the skin and mucosa. Successful infection requires a lesion in the stratified tissue for access to the basal cells. Herein, we discuss our recent progress in understanding binding, internalization, uncoating, and intracellular trafficking of HPV particles. Our focus will be on HPV type 16, which is the most common HPV type associated with various anogenital and oropharyngeal carcinomas. The study of HPV entry has revealed a number of novel cellular pathways utilized during infection. These include but are not restricted to the following: a previously uncharacterized form of endocytosis, membrane penetration by a capsid protein, the use of retromer complexes for trafficking to the trans-Golgi network, the requirement for nuclear envelope breakdown and microtubule-mediated transport during mitosis for nuclear entry, the existence of membrane-bound intranuclear vesicles harboring HPV genome, and the requirement of PML protein for efficient transcription of incoming viral genome. The continued study of these pathways may reveal new roles in basic biological cellular processes. PMID- 27984071 TI - Reply re: Dr. Kubota's Letter to the Editor, "Corticosteroids or biopsy for idiopathic orbital inflammation". PMID- 27984072 TI - Gene silencing of Dim-1, a member of the disorganized muscle family, in Haemonchus contortus. AB - RNA interference has been widely used in parasites. In Haemonchus contortus, reproducible silencing has been reported; however, in this species an altered phenotype has been observed for only a few genes silenced by RNA interference. The aim of this work was to evaluate the effect of silencing Dim-1, a member of the disorganized muscle family on third stage larvae (L3) of H. contortus. Effective silencing of Dim-1 in L3 led to reduced L3 migration and slowed larval development from L3 to early L4. To our knowledge, this is the first report to demonstrate Dim-1 silencing affecting phenotypic characteristics of this parasite. PMID- 27984074 TI - Alterations in ventral and dorsal striatal allosteric A2AR-D2R receptor-receptor interactions after amphetamine challenge: Relevance for schizophrenia. AB - Striatal dopamine D2R homodimerization is increased in the dorsal striatum after acute amphetamine challenge and in the amphetamine-induced sensitized state, a well-known animal model of schizophrenia. Therefore, it was tested if the increase in D2R homoreceptor complexes found after acute amphetamine challenge in the saline or the amphetamine sensitized state leads to changes in the antagonistic adenosine A2AR-D2R interactions in the striatum. [3H]-raclopride binding was performed in membrane preparations from the ventral and dorsal striatum involving competition with the D2R like agonist quinpirole. In the ventral striatum CGS 21680 produced a significant increase of the KiH values (p<0.05) in the amphetamine sensitized group when expressed in percent versus the corresponding values in saline sensitized rats after amphetamine challenge. However, in the dorsal striatum a significant change did not develop in the KiH values when expressed in percent of the corresponding values in saline sensitized rats after amphetamine challenge. In fact, the non-significant change was in the opposite direction towards a reduction of the KiH values. Taken together, a reduced affinity of the high affinity D2 agonist binding site (KiH value) developed in the ventral but not in the dorsal striatum as a result of increased antagonistic allosteric A2AR-D2R interactions in the amphetamine-induced sensitized state versus the saline sensitized state after an acute amphetamine challenge. The selective reappearance of antagonistic A2AR-D2R receptor-receptor interactions in the ventral striatum after amphetamine challenge in the amphetamine sensitized rat may give one possible mechanism for the atypical antipsychotic-like actions of A2AR receptor agonists. PMID- 27984076 TI - Sustained oscillations in the MAP kinase cascade. AB - The MAP kinase cascade is a network of enzymatic reactions arranged in layers. In each layer occurs a multiple futile cycle of phosphorylations. The fully phosphorylated substrate then serves as an enzyme for the layer below. This paper focusses on the existence of parameters for which Hopf bifurcations occur and generate periodic orbits. Furthermore it is explained how geometric singular perturbation theory allows to generalize results from simple models to more complex ones. PMID- 27984075 TI - Moderate aerobic exercise on the recovery phase of gentamicin-induced acute kidney injury in rats. AB - INTRODUCTION: Acute kidney injury is a serious public health problem, especially in intensive care units, where patients may require dialysis support, resulting in 50% mortality. AIM: To evaluate the effects of moderate aerobic exercise on the recovery phase of acute kidney injury induced by gentamicin in rats. MAIN METHODS: Male adult Wistar rats were allocated into 4 groups: W10+R30, G10+R30, W10+EX30 and G10+EX30; W10 received water (gentamicin vehicle) and G10 received gentamicin for 10days; R30 remained resting and EX30 made exercise for 30days after gentamicin suspension. Training was performed on treadmill. Blood, 24h urine and kidneys were collected for renal function and oxidative stress, antioxidant, TGF-beta and histological analysis. KEY FINDINGS: Gentamicin treatment caused decreased renal function significant oxidative stress, reduced urinary nitric oxide and increased TGF-beta. G10+R30 presented partial recovery of metabolic data, renal function and lipoperoxidation levels, although they were still altered compared to W10+R30. Besides, we observed the presence of lymphomononuclear infiltrate in the kidneys of G10+R30. G10+EX30 vs G10+R30 showed additional improvement of all the mentioned parameters, showing at histology, regeneration of the tubule epithelium. SIGNIFICANCE: Our data suggest that moderate exercises could help in the recovery of metabolic parameters, renal function and structure on gentamicin-induced AKI, perhaps due to restoration of redox balance. This could protect the kidneys from further insults like challenges with nephrotoxic drugs or the aging per se. PMID- 27984073 TI - Host Epac1 is required for cAMP-mediated invasion by Trypanosoma cruzi. AB - Mechanistic details of the modulation by cAMP of Trypanosoma cruzi host cell invasion remain ill-defined. Here we report that activation of host's Epac1 stimulated invasion, whereas specific pharmacological inhibition or maneuvers that alter Epac1 subcellular localization significantly reduced invasion. Furthermore, while specific activation of host cell PKA showed no effect, its inhibition resulted in an increased invasion, revealing a crosstalk between the PKA and Epac signaling pathways during the process of invasion. Therefore, our data suggests that subcellular localization of Epac might be playing an important role during invasion and that specific activation of the host cell cAMP/Epac1 pathway is required for cAMP-mediated invasion. PMID- 27984077 TI - Solvability of implicit final size equations for SIR epidemic models. AB - Final epidemic size relations play a central role in mathematical epidemiology. These can be written in the form of an implicit equation which is not analytically solvable in most of the cases. While final size relations were derived for several complex models, including multiple infective stages and models in which the durations of stages are arbitrarily distributed, the solvability of those implicit equations have been less studied. In this paper the SIR homogeneous mean-field and pairwise models and the heterogeneous mean-field model are studied. It is proved that the implicit equation for the final epidemic size has a unique solution, and that through writing the implicit equation as a fixed point equation in a suitable form, the iteration of the fixed point equation converges to the unique solution. The Markovian SIR epidemic model on finite networks is also studied by using the generation-based approach. Explicit analytic formulas are derived for the final size distribution for line and star graphs of arbitrary size. Iterative formulas for the final size distribution enable us to study the accuracy of mean-field approximations for the complete graph. PMID- 27984078 TI - Anti-inflammatory and protective effects of MT-031, a novel multitarget MAO-A and AChE/BuChE inhibitor in scopolamine mouse model and inflammatory cells. AB - Previous study demonstrated that the novel multitarget compound, MT-031 preserved in one molecule entity the beneficial properties of its parent drugs, rasagiline and rivastigmine, and exerted high dual potencies of monoamine oxidase-A (MAO-A) and cholinesterase (ChE) inhibition in acute-treated mice and neuroprotective effects against H2O2-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. The present study aimed to further investigate the anti-inflammatory and protective effects of MT-031 in scopolamine mouse model and inflammatory cell cultures. Our findings demonstrated that once daily chronic administration of MT 031 (5-10 mg/kg) to mice antagonized scopolamine-induced memory and cognitive impairments, displayed brain selective MAO-A and AChE/BuChE inhibition, increased the levels of striatal dopamine (DA), serotonin (5-HT) and norepinephrine and prevented the metabolism of DA and 5-HT. In addition, MT-031 upregulated mRNA expression levels of Bcl-2, the neurotrophic factors, (e.g., brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF)), the antioxidant enzyme catalase and the anti inflammatory cytokine, neurotrophic tyrosine kinase receptor (Ntrk), and down regulated the mRNA expression levels of the pro-inflammatory interleukin (IL)-6 in scopolamine-induced mice. In accordance, MT-031 was shown to reduce reactive oxygen species accumulation, increase the levels of anti-inflammatory cytokines, IL-10 and decrease the levels of the pro-inflammatory cytokines, IL-1beta, IL-6, IL-17 and interferon-gamma (IFN-gamma) in activated mouse splenocytes and microglial cells. Taken together, these pharmacological properties of MT-031 can be of clinical importance for developing this novel multitarget compound as a novel drug candidate for the treatment of Alzheimer's disease. PMID- 27984080 TI - Punctuated equilibrium as an emergent process and its modified thermodynamic characterization. AB - We address evolutionary dynamics and consider under which conditions the ecosystem interaction network allows punctuated equilibrium (i.e., alternation between hectic and quasi-stable phases). We focus on the links connecting various species and on the strength and sign of those links. For this study we consider the Tangled Nature model, which allows considerable flexibility and plasticity in the analysis of interspecies interactions. We find that it is necessary to have a proper balance of connectivity and interaction intensities so as to establish the kind of mutual cooperation and competition found in nature. It suggests evolutionary punctuated equilibrium as an emergent process, thus displaying features of complex systems. To explicitly demonstrate this fact we consider an extended form of thermodynamics, defining (for the present context) relevant out of-equilibrium "collective" functions. We then show how to characterize the punctuated equilibrium through entropy-like and free energy-like quantities. Finally, from a close analogy to thermodynamic systems, we propose a protocol similar to simulated annealing. It is based on controlling the species' rate of mutation during the hectic periods, in this way enhancing the exploration of the genome space (similar to the known behavior of bacteria in stressful environments). This allows the system to more rapidly converge to long-duration quasi-stable phases. PMID- 27984081 TI - Anti-predator behavioral variation among Physa acuta in response to temporally fluctuating predation risk by Procambarus. AB - Research in behavioral ecology routinely quantifies individual variation in behavior using transitions between discrete environments, for example prey moving from a no predator to predator treatment. This research often ignores behavioral variation in response to temporal fluctuations in environmental conditions around an unchanging mean environment. In this study we evaluate the effects of temporal fluctuations in predation risk (predator cue concentration of Procambarus spp.), without the confounding effects of a changing mean, on among-individual variation in anti-predator behavior in freshwater snails (Physa acuta). We also evaluate how the interaction between environmental and individual variation affects snail survival and reproduction by exposing snails to lethal predators following the behavioral assays. Our analyses revealed a trend towards higher among-individual variation in mean behavior when snails were exposed to intermediate levels of environmental variation compared to highly variable or constant environments. However, because of large uncertainty in estimates of among-individual variation, differences among treatments were indistinguishable from noise for most, but not all behaviors. In the lethal predator trials, snail survival and time to mortality was the lowest in the high variation environment. Also, as environmental variation increased snail egg production decreased and snails laid more of their eggs underneath a provided shelter. PMID- 27984079 TI - Combining sequence and Gene Ontology for protein module detection in the Weighted Network. AB - Studies of protein modules in a Protein-Protein Interaction (PPI) network contribute greatly to the understanding of biological mechanisms. With the development of computing science, computational approaches have played an important role in locating protein modules. In this paper, a new approach combining Gene Ontology and amino acid background frequency is introduced to detect the protein modules in the weighted PPI networks. The proposed approach mainly consists of three parts: the feature extraction, the weighted graph construction and the protein complex detection. Firstly, the topology-sequence information is utilized to present the feature of protein complex. Secondly, six types of the weighed graph are constructed by combining PPI network and Gene Ontology information. Lastly, protein complex algorithm is applied to the weighted graph, which locates the clusters based on three conditions, including density, network diameter and the included angle cosine. Experiments have been conducted on two protein complex benchmark sets for yeast and the results show that the approach is more effective compared to five typical algorithms with the performance of f-measure and precision. The combination of protein interaction network with sequence and gene ontology data is helpful to improve the performance and provide a optional method for protein module detection. PMID- 27984082 TI - Effect of an anti-malaria drug on behavioural performance on a problem-solving task: an experiment in wild great tits. AB - Malaria parasites have been shown to decrease host fitness in several species in the wild and their detrimental effects on host cognitive ability are well established in humans. However, experimental demonstrations of detrimental effects on non-human host behaviour are currently limited. In this study, we experimentally tested whether injections of an anti-malaria drug affected short term behavioural responses to a problem-solving task during breeding in a wild population of great tits (Parus major) naturally infected with malaria. Adult females treated against malaria were more active than control females, even though they were not more likely to solve the task or learn how to do so, suggesting that energetic constraints could shape differences in some behaviours while changes in cognitive performances might require more time for the neural system to recover or may depend mainly on infection at the developmental stage. Alternatively, parasite load might be a consequence, rather than a cause, of inter-individual variation in cognitive performance. These results also suggest that inter-individual as well as inter-population differences in some behavioural traits may be linked to blood parasite load. PMID- 27984083 TI - Dihydromyricetin delays the onset of hyperglycemia and ameliorates insulin resistance without excessive weight gain in Zucker diabetic fatty rats. AB - Many flavonoids are reported to be partial agonists of PPARgamma and exert antidiabetic effects with fewer side effects compared with full agonists. Here, we assessed the effects of flavonoid dihydromyricetin (DHM) on glucose homeostasis in male Zucker diabetic fatty rats. Animals were treated with DHM (50 200 mg kg-1) or rosiglitazone (4 mg kg-1) once a day for 8 weeks. We found that DHM reduced fasting blood glucose and delayed the onset of hyperglycemia by 4 weeks. Furthermore, DHM preserved pancreatic beta-cell mass, elevated adiponectin and improved lipid profile more vigorously than rosiglitazone. Notably, DHM decreased body weight gain and fat accumulation in both liver and adipose tissue, while rosiglitazone caused a significant increase of body weight and fat accumulation. DHM inhibited phosphorylation of PPARgamma at serine 273 more efficiently than rosiglitazone. These results suggest that DHM exerts antidiabetic effects without causing excessive body weight gain via inhibition of PPARgamma phosphorylation. PMID- 27984084 TI - Eicosapentaenoic acid abolishes inhibition of insulin-induced mTOR phosphorylation by LPS via PTP1B downregulation in skeletal muscle. AB - Dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) increase insulin signaling in skeletal muscle. In the current study, we investigated the effect of eicosapentaenoic acid (EPA) on insulin-induced mammalian target of rapamycin (mTOR) phosphorylation in myotubes. We showed that EPA did not affect basal and insulin-induced mTOR phosphorylation in myotubes. However, EPA abolished lipopolysaccharide (LPS) -induced deficiency in insulin signaling (P < 0.05). Pre incubation of nuclear factor kappaB (NF-kappaBeta) and c-Jun N-terminal kinases (JNK) inhibitors prevented the decreased insulin-induced mTOR phosphorylation elicited by LPS (P < 0.05). In addition, in protein tyrosine phosphatase-1B (PTP1B) knockdown myotubes, LPS failed to decrease insulin-induced mammalian target of rapamycin (mTOR) phosphorylation in myotubes (P > 0.05). In myotubes, LPS stimulated PTP1B expression via NF-kappaB and activation protein-1 (AP1). Pre incubation of 50 MUM EPA prevented the LPS-induced activation of AP1 and NF kappaBeta as well as PTP1B expression (P < 0.05). Interestingly, incubation of peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist (GW9662) prior to EPA treatment, the effect of EPA on insulin-induced mTOR phosphorylation was blocked. Accordingly, EPA did not inhibit the LPS-induced activation of AP1 or NF-kappaBeta as well as PTP1B expression when incubation of GW9662 prior to EPA treatment. The in vivo study showed that EPA prevented LPS-induced PTPT1B expression and a decrease in insulin-induced mTOR phosphorylation in muscle of mice. In summary, EPA abolished LPS inhibition of insulin-induced mTOR phosphorylation in myotubes, and one of the key mechanisms was to inhibit AP1 and NF-kappaB activation and PTP1B transcription. PMID- 27984085 TI - Go for broke: The role of somatic states when asked to lose in the Iowa Gambling Task. AB - The Somatic Marker Hypothesis (SMH) posits that somatic states develop and guide advantageous decision making by "marking" disadvantageous options (i.e., arousal increases when poor options are considered). This assumption was tested using the standard Iowa Gambling Task (IGT) in which participants win/lose money by selecting among four decks of cards, and an alternative version, identical in both structure and payoffs, but with the aim changed to lose as much money as possible. This "lose" version of the IGT reverses which decks are advantageous/disadvantageous; and so reverses which decks should be marked by somatic responses - which we assessed via skin conductance (SC). Participants learned to pick advantageously in the original (Win) IGT and in the (new) Lose IGT. Using multilevel regression, some variability in anticipatory SC across blocks was found but no consistent effect of anticipatory SC on disadvantageous deck selections. Thus, while we successfully developed a new way to test the central claims of the SMH, we did not find consistent support for the SMH. PMID- 27984086 TI - Fetal heart rate variability mediates prenatal depression effects on neonatal neurobehavioral maturity. AB - This study analyzed the mediating role of fetal heart rate variability (FHR) on prenatal depression and neonatal neurobehavioral maturity. A sample of 104 pregnant women was recruited and divided into two groups according to their Edinburgh Postnatal Depression Scale (EPDS) scores (depressed/non-depressed). FHR variability in response to speech stimuli was assessed at term (between 37 and 39 weeks gestation). The neonates were then assessed on the Neonatal Behavioral Assessment Scale (NBAS) during the first 5days after birth. The fetuses of non depressed pregnant women showed higher HR variability than the fetuses of depressed pregnant women in response to speech stimuli, and later as neonates they performed more optimally on the NBAS (on autonomic stability and total scores). FHR variability mediated the relationship between the mother's prenatal depression and the neonates NBAS performance. Prenatal depression effects on neonatal behavior may be partially explained by its adverse effects on fetal neurobehavioral maturity. PMID- 27984087 TI - Genomic and genetic studies of systemic sclerosis: A systematic review. AB - Systemic sclerosis is an autoimmune rheumatic disease characterised by fibrosis, vasculopathy and inflammation. The exact aetiology of SSc remains unknown but evidences show that various genetic factors may be involved. This review aimed to assess HLA alleles/non-HLA polymorphisms, microsatellites and chromosomal abnormalities that have thus far been associated with SSc. PubMed, Embase and Scopus databases were searched up to July 29, 2015 using a combination of search terms. Articles retrieved were evaluated based on set exclusion and inclusion criteria. A total of 150 publications passed the filters. HLA and non-HLA studies showed that particular alleles in the HLA-DRB1, HLA-DQB1, HLA-DQA1, HLA-DPB1 genes and variants in STAT4, IRF5 and CD247 are frequently associated with SSc. Non-HLA genes analysis was performed using the PANTHER and STRING10 databases. PANTHER classification revealed that inflammation mediated by chemokine and cytokine, interleukin and integrin signalling pathways are among the common extracted pathways associated with SSc. STRING10 analysis showed that NFKB1, CSF3R, STAT4, IFNG, PRL and ILs are the main "hubs" of interaction network of the non-HLA genes associated with SSc. This study gathers data of valid genetic factors associated with SSc and discusses the possible interactions of implicated molecules. PMID- 27984088 TI - Ten-year survival and complication rates of lithium-disilicate (Empress 2) tooth supported crowns, implant-supported crowns, and fixed dental prostheses. AB - OBJECTIVES: To prospectively evaluate the clinical long-term outcome of tooth supported crowns (SCs), implant-supported crowns (ISCs), and fixed dental prostheses (FDPs) made of a lithium-disilicate glass-ceramic framework material (IPS Empress 2). MATERIALS AND METHODS: Between 1997 and 1999, a total of 184 restorations (106 SCs, 32 ISCs, 33 FDPs, and 13 diverse restorations) were placed in 73 patients. Kaplan-Meier estimation was applied for survival and chipping free rates. Inter-group comparison of both rates was realized by a log rank test and a 2*2 contingency table. Also, SCs and FDPs were compared regarding adhesive vs. conventional cementation, and anterior vs. posterior positioning, for impact on survival. RESULTS: Due to 14 dropouts (34 restorations) and reasonable exclusion of 19 other restorations, the final dataset included: i) 87 SCs [37 patients, mean observation time 11.4 (+/-3.8)years]; ii) 17 ISCs [12 patients, mean observation time 13.3 (+/-2.3)years; and iii) 27 FDPs [19 patients, mean observation time 8.9 (+/-5.4)years]. The 10-year survival rate/chipping-free rate for SCs were 86.1%/83.4%, for ISCs 93.8%/94.1%, and for FDPs were 51.9%/90.8%. Both ISCs and SCs had a significantly higher survival than FDPs (ISCs vs. FDPs: both tests p=0.001; SCs vs. FDPs: p=0.001 and p=0.005). Differences in the chipping-free rates did not reach significance. Also, neither the cementation mode nor positioning of the restoration had an impact on survival. CONCLUSIONS: SCs had a slightly lower outcome than can generally be expected from single crowns. In contrast, ICSs had a favorable outcome and the FDPs predominantly failed. CLINICAL SIGNIFICANCE: The practitioner's choice of dental materials is based (at best) on long-term experience. The present 10-year results are based on comprehensive data analyses and show the high potential of lithium-disilicate as a reliable material, especially for single-unit restoration. PMID- 27984089 TI - Cost-effectiveness of root caries preventive treatments. AB - INTRODUCTION: With a growing number of individuals retaining their teeth lifelong, often with periodontitis-induced root surface exposure, there is the need for cost-effective management strategies for root caries lesions. The present study aimed to assess the cost-effectiveness of root caries preventive treatments. METHODS: Patients were simulated over 10 years using a Markov model. Four treatments were compared: No treatment, daily 225-800ppm fluoride rinses, chlorhexidine (CHX) varnish (2*/year), silver diamine fluoride (SDF) varnish (2*/year). Data from a systematic review were submitted to network meta-analysis for inferring relative efficacies of treatments. The health outcome was years of teeth being free of root caries. A mixed public-private payer perspective within 2016 German healthcare was taken, with costs being estimated from fee item catalogues or based on market prices. Populations with different numbers of teeth and tooth-level risks were modelled. Monte-Carlo microsimulations, univariate- and probabilistic sensitivity analyses were performed. RESULTS: In populations with 16 teeth at risk and low tooth-level risk for root caries, providing no preventive treatment was least costly, but also least effective (130 Euro, 144 years). SDF ranked next, being more costly (180 Euro), but also more effective (151 years). Payers willing to invest 8.30 Euro per root caries-free tooth-year found SDF most cost-effective. CHX varnish and fluoride rinse were not cost effective. In populations with more teeth and high tooth-level risk, SDF was the most effective and least costly option. CONCLUSIONS: Root caries preventive treatments (like SDF) are effective and might even be cost-saving in high risk populations. CLINICAL SIGNIFICANCE: Application of SDF can be recommended as a cost-saving treatment for prevention of root caries in patients with high risk of root caries. PMID- 27984090 TI - RIP3 antagonizes a TSC2-mediated pro-survival pathway in glioblastoma cell death. AB - Glioblastomas are the deadliest type of brain cancer and are frequently associated with poor prognosis and a high degree of recurrence despite removal by surgical resection and treatment by chemo- and radio-therapy. Photodynamic therapy (PDT) is a treatment well known to induce mainly necrotic and apoptotic cell death in solid tumors. 5-Aminolevulinic acid (5-ALA)-based PDT was recently shown to sensitize human glioblastoma cells (LN-18) to a RIP3 (Receptor Interacting Protein 3)-dependent cell death which is counter-acted by activation of autophagy. These promising results led us to investigate the pathways involved in cell death and survival mechanisms occurring in glioblastoma following PDT. In the present study, we describe a new TSC2 (Tuberous Sclerosis 2)-dependent survival pathway implicating MK2 (MAPKAPK2) kinase and 14-3-3 proteins which conducts to the activation of a pro-survival autophagy. Moreover, we characterized a new RIP3/TSC2 complex where RIP3 is suggested to promote cell death by targeting TSC2-dependent survival pathway. These results highlight (i) a new role of TSC2 to protect glioblastoma against PDT-induced cell death and (ii) TSC2 and 14-3-3 as new RIP3 partners. PMID- 27984091 TI - The Bacillus subtilis TatAdCd system exhibits an extreme level of substrate selectivity. AB - The Tat system preferentially transports correctly folded proteins across the bacterial membrane although little is known of the proofreading mechanism. Most research has focused on TatABC systems from Gram-negative bacteria, especially Escherichia coli, and much less is known of the TatAC-type systems from Gram positive organisms. We have previously shown that the Bacillus subtilis TatAdCd system is functional in an E. coli tat null background and able to transport TorA GFP and native TorA (TMAO reductase); here, we examined its ability to transport other proteins bearing a TorA signal sequence. We show that whereas E. coli TatABC transports a wide range of biotherapeutics including human growth hormone, interferon alpha2b, a VH domain protein and 2 different scFvs, TatAdCd transports the scFvs but completely rejects the other proteins. The system also rejects two native E. coli substrates, NrfC and FhuD. Moreover, we have shown that TatABC will transport a wide range of folded scFv variants with the surface altered to incorporate multiple salt bridges, charged residues (5 glutamate, lysine or arginine), or hydrophobic residues (up to 6 leucines). In contrast, TatAdCd completely rejects many of these variants including those with 5 or 6 added Leu residues. The combined data show that the TatABC and TatAdCd systems have very different substrate selectivities, with the TatAdCd system displaying an extreme level of selectivity when compared to the E. coli system. The data also provide a preliminary suggestion that TatAdCd may not tolerate substrates that contain surface domains with a level of hydrophobicity above a certain threshold. PMID- 27984092 TI - The budding yeast orthologue of Parkinson's disease-associated DJ-1 is a multi stress response protein protecting cells against toxic glycolytic products. AB - Saccharomyces cerevisiae Hsp31p is a DJ-1/ThiJ/PfpI family protein that was previously shown to be important for survival in the stationary phase of growth and under oxidative stress. Recently, it was identified as a chaperone or as glutathione-independent glyoxalase. To elucidate the role played by this protein in budding yeast cells, we investigated its involvement in the protection against diverse environmental stresses. Our study revealed that HSP31 gene expression is controlled by multiple transcription factors, including Yap1p, Cad1p, Msn2p, Msn4p, Haa1p and Hsf1p. These transcription factors mediate the HSP31 promoter responses to oxidative, osmotic and thermal stresses, to potentially toxic products of glycolysis, such as methylglyoxal and acetic acid, and to the diauxic shift. We also demonstrated that the absence of the HSP31 gene sensitizes cells to these stressors. Overproduction of Hsp31p and its homologue Hsp32p rescued the sensitivity of glo1Delta cells to methylglyoxal. Hsp31p also reversed the increased sensitivity of the ald6Delta strain to acetic acid. Since Hsp31p glyoxalase III coexists in S. cerevisiae cells with thousand-fold more potent glyoxalase I/II system, its biological purpose requires substantiation. We postulate that S. cerevisiae Hsp31p may have broader substrate specificity than previously proposed and is able to eliminate various toxic products of glycolysis. Alternatively, Hsp31p might be effective under high concentration of exogenous methylglyoxal present in some natural environmental niches populated by budding yeast, when glyoxalase I/II system capacity is saturated. PMID- 27984093 TI - Annexin A6 in the liver: From the endocytic compartment to cellular physiology. AB - Annexin A6 (AnxA6) belongs to the conserved annexin family - a group of Ca2+ dependent membrane binding proteins. AnxA6 is the largest of all annexins and highly expressed in smooth muscle, hepatocytes, endothelial cells and cardiomyocytes. Upon activation, AnxA6 binds to negatively charged phospholipids in a wide range of intracellular localizations, in particular the plasma membrane, late endosomes/pre-lysosomes, but also synaptic vesicles and sarcolemma. In these cellular sites, AnxA6 is believed to contribute to the organization of membrane microdomains, such as cholesterol-rich lipid rafts and confer multiple regulatory functions, ranging from vesicle fusion, endocytosis and exocytosis to programmed cell death and muscle contraction. Growing evidence supports that Ca2+ and Ca2+-binding proteins control endocytosis and autophagy. Their regulatory role seems to operate at the level of the signalling pathways that initiate autophagy or at later stages, when autophagosomes fuse with endolysosomal compartments. The convergence of the autophagic and endocytic vesicles to lysosomes shares several features that depend on Ca2+ originating from lysosomes/late endosomes and seems to depend on proteins that are subsequently activated by this cation. However, the involvement of Ca2+ and its effector proteins in these autophagic and endocytic stages still remains poorly understood. Although AnxA6 makes up almost 0.25% of total protein in the liver, little is known about its function in hepatocytes. Within the endocytic route, we identified AnxA6 in endosomes and autophagosomes of hepatocytes. Hence, AnxA6 and possibly other annexins might represent new Ca2+ effectors that regulate converging steps of autophagy and endocytic trafficking in hepatocytes. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. PMID- 27984094 TI - Selegiline induces a wake promoting effect in rats which is related to formation of its active metabolites. AB - The goal of the present work was to characterise the effects of selegiline on the rat sleep pattern. Furthermore, for comparative purposes, the pharmacokinetics of selegiline and its metabolites in brain and plasma were investigated, and microdialysis experiments were performed to examine the resulting effect on dopamine, noradrenaline and serotonin levels. Selegiline (1, 5, 10 and 30mg/kg) was found to dose-dependently increase the time spent awake following acute dosing. The pharmacokinetic assessment of selegiline showed that, following an oral dose of 5mg/kg, low circulating levels of the parent compound were found relative to those of biotransformed l-methamphetamine and l-amphetamine. The time course of selegiline-induced wakefulness was shown to follow the time course of l methamphetamine and l-amphetamine in brain, suggesting that these metabolites are responsible for the modulation of sleep architecture. Furthermore, selegiline (5mg/kg) caused a significant increase of extracellular levels of DA (250%) and NA (200%), but not of 5-HT, in the rat prefrontal cortex. In summary, an integrated experimental approach was undertaken here to evaluate selegiline's effect on sleep architecture in rats in relation to its pharmacokinetics and changes in monoaminergic neurotransmitter levels in the brain. The effect of selegiline on sleep was likely mediated by an increase of dopamine and noradrenaline levels in the brain caused by the formed metabolites. PMID- 27984095 TI - Acute oral 18-methoxycoronaridine (18-MC) decreases both alcohol intake and IV nicotine self-administration in rats. AB - The ibogaine derivative 18-methoxycoronaridine (18-MC) has been found to decrease self-administration of morphine, nicotine and alcohol in rats after systemic injection. However oral dosing is the preferred route clinically. The current study evaluated the effect of oral 18-MC dosing in rats on alcohol and nicotine self-administration. For the nicotine study, young adult female Sprague-Dawley rats were fitted with IV jugular infusion catheters and trained for nicotine self administration in 45min. sessions. At weekly intervals they were administered by oral gavage doses of 18-MC (0, 10, 20 and 40mg/kg) following a repeated measures counterbalanced design twice. Acute oral 18-MC, at the 40mg/kg dosage, significantly reduced nicotine self-administration. There was a differential effect of 18-MC with rats above or below the median level of nicotine self administration during the pretreatment baseline performance. Rats with lower baseline performance showed a significant reduction in nicotine self administration with the 40mg/kg dosage, while those in the higher baseline group did not show a significant effect of 18-MC. In alcohol studies, the effects of the same doses of 18-MC were tested in both male and female alcohol preferring (P) rats that had free access to water and alcohol (10% v/v) 6h/day. The results show that 18-MC dose-dependently reduced alcohol intake in both male and female rats. All doses caused significant reductions in alcohol self-administration. These data reinforce previous findings that 18-MC is significantly effective in reducing alcohol intake and nicotine self-administration. The finding that 18-MC is also effective orally makes it advantageous for further development as a possible new therapy for treating alcoholism as well as smoking addiction. PMID- 27984096 TI - Protective effects of salicylate on PKA inhibitor (H-89)-induced spatial memory deficit via lessening autophagy and apoptosis in rats. AB - In this study, the effects of salicylate on spatial learning and memory, through its effects on autophagy and apoptosis, were evaluated in the presence of the PKA inhibitor H-89. Adult male Wistar rats were divided into experimental groups as follows: salicylate (30, 50, 100MUg/0.5MUl/side, intra-hippocampal; 400mg/kg, intra-peritoneal), donepezil (1mg/kg as a positive control for behavioral effects of salicylate), H-89 (1MUl/side of 5 or 20MUM), H-89 plus salicylate and H-89 plus donepezil. The Morris water maze test was used for evaluation of spatial learning and memory. The levels of different apoptotic and autophagic biomarkers were evaluated using the western blot technique. Salicylate (100MUg/0.5MUl/side) significantly reduced the escape latency on training days, increased the percentage of time spent in the target quadrant during the probe trial and reversed the inhibitory effects of H-89 during the process of spatial learning and memory. The behavioral efficacy of salicylate was comparable to that of donepezil. In addition, salicylate significantly decreased the levels of apoptotic proteins, Bax and caspase 3, and increased the Bcl2 levels in all groups. Furthermore, the levels of LC3II and Atg7 were decreased by salicylate. Our study revealed that both systemic and direct intra-hippocampal administration of salicylate can facilitate the spatial learning and memory. Additionally, intra hippocampal administration of salicylate can reduce apoptotic and autophagic proteins. The antioxidant activity of salicylate might lead to increased pCREB via stimulation of signaling pathways, resulting in reduction of H-89-induced apoptosis and autophagy. PMID- 27984098 TI - Dynamic Cross-Entropy. AB - BACKGROUND: Complexity measures for time series have been used in many applications to quantify the regularity of one dimensional time series, however many dynamical systems are spatially distributed multidimensional systems. NEW METHOD: We introduced Dynamic Cross-Entropy (DCE) a novel multidimensional complexity measure that quantifies the degree of regularity of EEG signals in selected frequency bands. Time series generated by discrete logistic equations with varying control parameter r are used to test DCE measures. RESULTS: Sliding window DCE analyses are able to reveal specific period doubling bifurcations that lead to chaos. A similar behavior can be observed in seizures triggered by electroconvulsive therapy (ECT). Sample entropy data show the level of signal complexity in different phases of the ictal ECT. The transition to irregular activity is preceded by the occurrence of cyclic regular behavior. A significant increase of DCE values in successive order from high frequencies in gamma to low frequencies in delta band reveals several phase transitions into less ordered states, possible chaos in the human brain. COMPARISON WITH EXISTING METHOD: To our knowledge there are no reliable techniques able to reveal the transition to chaos in case of multidimensional times series. In addition, DCE based on sample entropy appears to be robust to EEG artifacts compared to DCE based on Shannon entropy. CONCLUSIONS: The applied technique may offer new approaches to better understand nonlinear brain activity. PMID- 27984097 TI - Anti-allodynic effect of mangiferin in neuropathic rats: Involvement of nitric oxide-cyclic GMP-ATP sensitive K+ channels pathway and serotoninergic system. AB - The neurobiology of neuropathic pain is caused by injury in the central or peripheral nervous system. Recent evidence points out that mangiferin shows anti nociceptive effect in inflammatory pain. However, its role in inflammatory and neuropathic pain and the possible mechanisms of action are not yet established. The purpose of this study was to determine the possible anti-allodynic effect of mangiferin in rats with spinal nerve ligation (SNL). Furthermore, we sought to investigate the possible mechanisms of action that contribute to these effects. Mechanical allodynia to stimulation with the von Frey filaments was measured by the up and down method. Intrathecal administration of mangiferin prevented, in a dose-dependent fashion, SNL-induced mechanical allodynia. Mangiferin-induced anti allodynia was prevented by the intrathecal administration of L-NAME (100MUg/rat, non-selective nitric oxide synthase inhibitor), ODQ (10MUg/rat, inhibitor of guanylate-cyclase) and glibenclamide (50MUg/rat, channel blocker of ATP-sensitive K+ channels). Moreover, methiothepin (30MUg/rat, non-selective 5-HT receptor antagonist), WAY-100635 (6MUg/rat, selective 5-HT1A receptor antagonist), SB 224289 (5MUg/rat, selective 5-HT1B receptor antagonist), BRL-15572 (4MUg/rat, selective 5-HT1D receptor antagonist) and SB-659551 (6MUg/rat, selective 5-HT5A receptor antagonist), but not naloxone (50MUg/rat, non-selective opioid receptor antagonist), were able to prevent mangiferin-induced anti-allodynic effect. These data suggest that the anti-allodynic effect induced by mangiferin is mediated at least in part by the serotoninergic system, involving the activation of 5 HT1A/1B/1D/5A receptors, as well as the nitric oxide-cyclic GMP-ATP-sensitive K+ channels pathway, but not by the opioidergic system, in the SNL model of neuropathic pain in rats. PMID- 27984099 TI - Recovery of sensorimotor function following sciatic nerve injury across multiple rat strains. AB - BACKGROUND: Peripheral nerve injury (PNI) can result in neurodegenerative changes leading to motor, sensory and autonomic dysfunction. Injury to the rat sciatic nerve is used to model pathophysiologic processes following PNI and assess the efficacy of therapeutic interventions. Frequently, temporal changes in the sciatic functional index (SFI), a measure of sensorimotor integration are measured in rats to assess functional recovery following sciatic nerve injury. However, multiple rat strains and behavioral endpoints have been employed to investigate pathophysiology of PNI and impact of therapeutic intervention on recovery, raising the possibility that rat strain may influence the outcome of such studies. NEW METHOD: The temporal course of recovery from sham, sciatic nerve crush or transection injury was assessed using SFI determined by two methods (footprint and DigiGait), and proprioceptive hind limb placement (a measure of proprioceptive integrity) of the sciatic nerve innervation, in male Sprague Dawley, Lewis, Fischer, Wistar and Long Evans rats. RESULTS: The SFI profile, as assessed by both inked footprint analysis and DigiGait, following sciatic nerve injury was remarkably conserved across strains. Dramatic strain related differences were observed in the latency to place the crush- or transection-injured hind limb following proprioceptive hind limb stimulation. COMPARISON WITH EXISTING METHOD: The novelty of this study is the parallel comparison of multiple strains using existing and novel tests. CONCLUSION: These results suggest that some sensorimotor function tests may be sensitive to the choice of strain, as evidenced by the differences between SFI and proprioceptive function outcomes. PMID- 27984100 TI - Air-puff induced vocalizations: A novel approach to detecting negative affective state following concussion in rats. AB - BACKGROUND: Negative emotional states resulting from concussion are of increasing concern. In the current study, we developed a model to investigate negative affect following concussion in the projectile concussive impact (PCI) model. High frequency ultrasonic vocalizations (22kHz USVs) are associated with negative affective stimuli in rats. Changes in negative affective state were examined following PCI using a mild air-puff stimulus to elicit 22kHz USVs. NEW METHOD: Forty-eight hours post-injury, animals were placed into a clean acrylic box lined with bedding. A 5min baseline recording was followed by 15 air puffs (55psi) spaced 15s apart aimed at the upper back and neck. RESULTS: Injured animals produced on average 153.5+/-55.13 more vocalizations than shams, vocalizing on average 4min longer than shams. Additionally, concussed animals vocalized to fewer air-puffs, exhibiting a 1.5 fold lower threshold for the expression of negative affect. COMPARISON WITH EXISTING METHODS: Studies currently used to test negative affective states following concussion in animals, such as the elevated plus maze and forced swim task have, as of yet, been unsuccessful in demonstrating injury effects in the PCI model. While the air-puff test has been applied in other fields, to our knowledge it has not been utilized to study traumatic brain injury. CONCLUSION: The current study demonstrates that the air puff vocalization test may be a valuable tool in assessing negative mood states following concussion in rat models and may be used to evaluate novel therapies following brain injury for the treatment of mood dysfunction. PMID- 27984101 TI - Imaging flow cytometry and GST pulldown assays provide new insights into channel catfish leukocyte immune-type receptor-mediated phagocytic pathways. AB - Channel catfish (Ictalurus punctatus) leukocyte immune-type receptors (IpLITRs) control various innate immune cell effector responses including the phagocytic process. This large immunoregulatory receptor family also consists of multiple receptor-types with variable signaling abilities that is dependent on their inherent or acquired tyrosine-containing cytoplasmic tail (CYT) regions. For example, IpLITR 2.6b associates with the immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor molecule IpFcRgamma-L, and when expressed in mammalian cells it activates phagocytosis using a similar profile of intracellular signaling mediators that also regulate the prototypical mammalian Fc receptor (FcR) phagocytic pathway. Alternatively, IpLITR 1.1b contains a long tyrosine-containing CYT with multifunctional capabilities including both inhibitory and stimulatory actions. Recently, we demonstrated that IpLITR 1.1b activates a unique phagocytic pathway involving the generation of multiple plasma membrane extensions that rapidly capture extracellular targets and secure them on the cell surface in phagocytic cup-like structures. Occasionally, these captured targets are completely engulfed albeit at a significantly lower rate than what was observed for IpLITR 2.6b. While this novel IpLITR 1.1b phagocytic activity is insensitive to classical blockers of phagocytosis, its distinct target capture and engulfment actions depend on the engagement of the actin polymerization machinery. However, it is not known how this protein translates target recognition into intracellular signaling events during this atypical mode of phagocytosis. Using imaging flow cytometry and GST pulldown assays, the aims of this study were to specifically examine what regions of the IpLITR 1.1b CYT trigger phagocytosis and to establish what profile of intracellular signaling molecules likely participate in its actions. Our results show that in stably transfected AD293 cells, the membrane proximal and distal CYT segments of IpLITR 1.1b independently regulate its phagocytic activities. These CYT regions were also shown to differentially recruit various SH2 domain-containing intracellular mediators, which provides new information about the dynamic immunoregulatory abilities of IpLITR 1.1b. Overall, this work further advances our understanding of how certain immunoregulatory receptor-types link extracellular target binding events to the actin polymerization machinery during a non-classical mode of phagocytosis. PMID- 27984102 TI - Comparative analysis of two thioredoxin-like genes in black rockfish Sebastes schlegelii and their possible involvement in redox homeostasis and innate immune responses. AB - Elevated levels of ROS can cause serious intracellular damages by reacting readily with nucleic acids, proteins and lipids, thus triggering tissue damage and cell death. Thioredoxin system is one of the principal factors that maintain the intracellular redox balance via its antioxidant property. In this study, we characterized two new thioredoxin isoforms (SsTXN-like 1 and SsMtTXN-like) from black rockfish, Sebastes schlegelii. The molecular and structural characteristics, as well as the evolutionary relationships of SsTXN-like 1 and SsMtTXN-like confirmed that they belong to the thioredoxin superfamily. A classical thioredoxin domain was found in both proteins with a conserved redox active site CXYC, however, only the precursor of SsMtTXN-like protein possessed a mitochondrial targeting signal. The results from insulin disulfide reduction activity assay demonstrated that their recombinant proteins are capable of reducing the disulfide bonds of oxidatively damaged proteins via their oxidoreductase activities. The free radical scavenging activity assay revealed the prominent hydroxyl and DPPH scavenging activities of rSsTXN-like 1 and rSsMtTXN-like in a dose-dependent manner. Transcriptional studies showed a broad distribution of SsTXN-like 1 and SsMtTXN-like transcripts in all the examined tissues. Significant (p < 0.05) up-regulations of both genes in immune-related tissues after LPS, poly I:C and Streptococcus iniae challenges reflect their critical role in redox homeostasis in black rockfish. Taken together, SsTXN-like 1 and SsMtTXN-like, as two active members of thioredoxin superfamily, have significant antioxidant properties to housekeep the redox potential during various stress conditions and innate immune response of Sebastes schlegelii. PMID- 27984103 TI - Generation and characterization of new monoclonal antibodies against swine origin 2009 influenza A (H1N1) virus and evaluation of their prophylactic and therapeutic efficacy in a mouse model. AB - In 2009, a swine-origin influenza A virus - A(H1N1)pdm09 - emerged and has became a pandemic strain circulating worldwide. The hemagglutinin (HA) of influenza virus is a potential target for the development of anti-viral therapeutic agents. Here, we generated mAbs by immunization of baculovirus-insect expressing trimeric recombinant HA of the A(H1N1)pdm09 strain. Results indicated that the mAbs recognized two novel neutralizing and protective epitopes-"STAS" and "FRSK" which located near Cb and Ca1 antigenic regions respectively and were conserved in almost 2009-2016 influenza H1N1 stains. The mAb 12E11 demonstrated higher protective efficacy than mAb 8B10 in mice challenge assay. Both mAb pretreatments significantly reduced virus titers and pro-inflammatory cytokines in mice lung postinfection (p < 0.01), and showed prophylactic and therapeutic efficacies even 48 h postinfection (p < 0.05). Combination therapy using the mAbs with oseltamivir pre- and post-treatment showed synergistic therapeutic effect in mice model (p < 0.01). Further investigation for clinical application in humans is warranted. PMID- 27984104 TI - Hyperthermia-triggered drug delivery from iRGD-modified temperature-sensitive liposomes enhances the anti-tumor efficacy using high intensity focused ultrasound. AB - An important limitation to successful cancer treatment with chemotherapeutics is the inability to achieve therapeutically effective drug concentrations while avoiding healthy tissue damage. In this work, a new tumor-targeting peptide iRGD (CCRGDKGPDC) was used to modify drug-loaded low temperature-sensitive liposomes (iRGD-LTSL-DOX) to explore the anti-tumor effects in combination with high intensity focused ultrasound (HIFU) in vitro and in vivo. iRGD-LTSL-DOX can specifically target to alphanubeta3-positive cells and locally release the encapsulated doxorubicin (DOX) in a hyperthermia-triggered manner. In vivo results showed that DOX from iRGD-LTSL-DOX was intravascularly released and rapidly penetrated into tumor interstitial space after HIFU-triggered heat treatment, thereby overcoming the limited tumor penetration of anticancer drugs. Significantly stronger anti-tumor efficacy further supported the effective combination of iRGD-LTSL-DOX with HIFU-induced hyperthermia. Our study provided a novel tumor-targeting LTSL-DOX and demonstrated its usefulness in HIFU-induced hyperthermia-triggered drug delivery. PMID- 27984105 TI - Photothermally triggered on-demand insulin release from reduced graphene oxide modified hydrogels. AB - On-demand delivery of therapeutics plays an essential role in simplifying and improving patient care. The high loading capacity of reduced graphene oxide (rGO) for drugs has made this matrix of particular interest for its hybridization with therapeutics. In this work, we describe the formulation of rGO impregnated poly(ethylene glycol) dimethacrylate based hydrogels (PEGDMA-rGO) and their efficient loading with insulin. Near-infrared (NIR) light induced heating of the PEGDMA-rGO hydrogels allows for highly efficient insulin release. Most importantly, we validate that the NIR irradiation of the hydrogel has no effect on the biological and metabolic activities of the released insulin. The ease of insulin loading/reloading makes this photothermally triggered release strategy of interest for diabetic patients. Additionally, the rGO-based protein releasing platform fabricated here can be expanded towards 'on demand' release of various other therapeutically relevant biomolecules. PMID- 27984106 TI - Andrographolide-loaded polymerized phenylboronic acid nanoconstruct for stimuli responsive chemotherapy. AB - Along with the successful discovery of paclitaxel as an anticancer drug, natural products have drawn great attention in drug discovery. Recently, andrographolide (AND) from Andrographis paniculata was reported to provide several benefits, including an anticancer effect. However, the extremely low solubility of the compound in an aqueous medium was an obstacle to overcome for the systemic administration and clinical application of AND. Based on our previous report, we formulated a water-soluble nanoconstruct by forming a boronic ester between the cis-1,3-diol of AND with hydrophilically polymerized phenylboronic acid (pPBA). The release of loaded AND was controlled by intracellular conditions, specifically, by low pH and high ATP concentrations, due to the pH- and diol dependent affinity of the boronic ester. Because of the intrinsic property of the PBA moiety, the pPBA-AND nanoconstruct exhibited an excellent tumor targeting ability both in vitro and in vivo. Finally, a significant inhibition of tumor growth was observed in vivo. Taken together, our strategy, which is based on the formulation of a soluble nanoconstruct using hydrophilically polymerized PBA and a cis-diol, is plausible and provides a delivery system for a wide variety of chemotherapeutics. This strategy has applications not only in cancer therapy but also broader fields such as anti-inflammation or immunotherapy. PMID- 27984107 TI - Evaluating Region of Interest Measurement Strategies to Characterize Upper Urinary Tract Stones on Computerized Tomography. AB - PURPOSE: Computerized tomography imaging is regularly used to assess stone HU values as a surrogate for stone composition and fragility. Techniques for measuring HU values are unstandardized, leading to high variability. We investigated several region of interest measurement strategies to quantify this variability. MATERIALS AND METHODS: Patients from an institutional database who underwent preoperative computerized tomography, surgical stone extraction and stone composition analysis were identified. HU measurements were made of each patient stone using transverse/coronal slices in the abdominal/bone windows with 4 region of interest techniques, including 1) the maximum diameter region of interest, 2) the maximum diameter region of interest at all stone inclusive slices, 3) 2 equal-sized, nonoverlapping circular regions of interest and 4) 3 to 5 smaller nonoverlapping regions of interest randomly placed on the stone. Stones that were 80% or greater pure by composition were separately analyzed. RESULTS: A total of 172 patients were included in study. Mean +/- SD stone size was 19.3 +/- 15.6 mm. On subtype analysis 51 stones were calcium oxalate monohydrate, 9 were calcium oxalate dihydrate, 7 were calcium phosphate hydroxyapatite/brushite and 16 were uric acid. Mean HU values in the abdominal window for all stones identified by region of interest techniques 1 to 4 were 457 +/- 253, 351 +/- 210, 581 +/- 363 and 587 +/- 329, respectively. The distribution of means significantly differed across region of interest techniques, planes and windows when considering all stones together (p <0.0001), stones with greater than 80% calcium oxalate dihydrate (p = 0.0113) and greater than 80% calcium oxalate monohydrate (p <0.0001), and uric acid stones (p <0.0001). CONCLUSIONS: HU values obtained to assess stone density vary depending on window, plane and region of interest technique. We recommend that clinicians select a single region of interest measurement technique and use it consistently to minimize interinstitutional variability. PMID- 27984108 TI - The Effect of Metformin Use during Docetaxel Chemotherapy on Prostate Cancer Specific and Overall Survival of Diabetic Patients with Castration Resistant Prostate Cancer. AB - PURPOSE: Docetaxel is the first line chemotherapy currently used to treat patients with symptomatic metastatic castration resistant prostate cancer. Although it provides survival benefits, it is associated with significant side effects. Novel therapeutic options are needed for patients with metastatic castration resistant prostate cancer and an approach is combining docetaxel with chemosensitizing agents. Metformin has been shown to improve the survival of patients with breast, lung and endometrial cancer receiving chemotherapy, and enhance chemotherapeutic efficacy in breast cancer and colon cancer cells. However, to our knowledge the chemosensitizing effect of metformin in prostate cancer has not been explored. Therefore, the hypothesis for our study was that diabetic patients with metastatic castration resistant prostate cancer who were administered metformin during docetaxel chemotherapy would have improved prostate cancer specific and overall survival. MATERIALS AND METHODS: This retrospective cohort study used data from several Ontario administrative health care databases. Men older than 65 years diagnosed with metastatic castration resistant prostate cancer and treated with docetaxel were stratified into groups based on diabetes status and use of antidiabetic medications. We evaluated the effect of metformin use with docetaxel on prostate cancer specific survival and overall survival using Kaplan-Meier survival curves, the log rank test and multivariate Cox proportional HRs. RESULTS: Survival curves showed that metformin use with docetaxel did not improve prostate cancer specific survival (p = 0.9562) or overall survival (p = 0.9927). HRs showed no significant effect of metformin use with docetaxel on prostate cancer specific survival (HR = 0.96, p = 0.66) or overall survival (HR = 0.94, p = 0.39). CONCLUSIONS: Metformin use during docetaxel chemotherapy did not significantly improve prostate cancer specific or overall survival in diabetic patients with metastatic castration resistant prostate cancer. This study indicates that metformin may not be an effective chemosensitizer for metastatic castration resistant prostate cancer. PMID- 27984109 TI - A Comparison of Secondary Polycythemia in Hypogonadal Men Treated with Clomiphene Citrate versus Testosterone Replacement: A Multi-Institutional Study. AB - PURPOSE: We evaluated the relative prevalence of secondary polycythemia in hypogonadal men treated with clomiphene citrate or testosterone replacement therapy. MATERIALS AND METHODS: In this retrospective, multi-institutional study, we included 188 men who received clomiphene citrate and 175 who received testosterone replacement therapy with symptomatic hypogonadism. The overall prevalence and ORs of secondary polycythemia for clomiphene citrate treatment vs testosterone replacement were primarily measured, as were baseline characteristics. Subset analysis included polycythemia rates for different types of testosterone replacement therapy. RESULTS: Overall, men on testosterone replacement therapy were older than clomiphene citrate treated men (age 51.5 vs 38 years). Men on testosterone replacement had longer treatment duration than clomiphene citrate treated men (19.6 vs 9.2 months). For testosterone replacement therapy and clomiphene citrate the mean change in hematocrit was 3.0% and 0.6%, and the mean change in serum testosterone was 333.1 and 367.6 ng/dl, respectively. The prevalence of polycythemia in men on testosterone replacement was 11.2% vs 1.7% in men on clomiphene citrate (p = 0.0003). This significance remained on logistic regression after correcting for age, site, smoking history and pretreatment hematocrit. CONCLUSIONS: The prevalence of polycythemia in men treated with clomiphene citrate was markedly lower than that in men on testosterone replacement therapy. The improvement in absolute serum testosterone levels was similar to that in men on testosterone replacement. There is no significant risk of polycythemia in men treated with clomiphene citrate for hypogonadism. PMID- 27984110 TI - More Judicious Use of Expectant Management for Localized Prostate Cancer during the Last 2 Decades. AB - PURPOSE: Urologists have been criticized for overtreating men with low risk prostate cancer and for passively observing older men with higher risk disease. Proponents of active surveillance for low risk disease and critics of watchful waiting for higher risk disease have advocated for more judicious use of observation. Thus, we compared 2 population based cohorts to determine how expectant management has evolved during the last 2 decades. MATERIALS AND METHODS: A total of 5,871 men with localized prostate cancer were enrolled in the PCOS (Prostate Cancer Outcomes Study) or the CEASAR (Comparative Effectiveness Analysis of Surgery and Radiation) study. We compared the use of definitive treatment vs expectant management (watchful waiting or active surveillance) across cohorts, focusing on the influence of disease risk, age and comorbidities. RESULTS: Use of watchful waiting or active surveillance was similar in PCOS and CEASAR (14% in each). Compared to the PCOS, more men in the CEASAR study with low risk disease selected watchful waiting or active surveillance (25% vs 15%, respectively), whereas fewer men with intermediate (7% vs 14%) and high risk (3% vs 10%) disease chose watchful waiting or active surveillance (p <0.001 for each). The association of disease risk with watchful waiting or active surveillance was significantly larger in CEASAR than in PCOS (OR 7.3, 95% CI 3.4 to 15.7). Older age was associated with watchful waiting or active surveillance in both cohorts but there was no association between comorbidity and watchful waiting or active surveillance in the CEASAR study. CONCLUSIONS: Use of watchful waiting or active surveillance was more aligned with disease risk in CEASAR compared to PCOS, suggesting there has been a pivot from watchful waiting to active surveillance. While older men were more likely to be observed, comorbidity had little, if any, influence. PMID- 27984114 TI - Glutathionylation of chikungunya nsP2 protein affects protease activity. AB - BACKGROUND: Chikungunya fever is an emerging disease caused by the chikungunya virus and is now being spread worldwide by the mosquito Aedes albopictus. The infection can cause a persistent severe joint pain and recent reports link high levels of viremia to neuropathologies and fatalities. The viral protein nsP2 is a multifunctional enzyme that plays several critical roles in virus replication. Virus infection induces oxidative stress in host cells which the virus utilizes to aid viral propagation. Cellular oxidative stress also triggers glutathionylation which is a post-translational protein modification that can modulate physiological roles of affected proteins. METHODS: The nsP2 protease is necessary for processing of the virus nonstructural polyprotein generated during replication. We use the recombinant nsP2 protein to measure protease activity before and after glutathionylation. Mass spectrometry allowed the identification of the glutathione-modified cysteines. Using immunoblots, we show that the glutathionylation of nsP2 occurs in virus-infected cells. RESULTS: We show that in virus-infected cells, the chikungunya nsP2 can be glutathionylated and we show this modification can impact on the protease activity. We also identify 6 cysteine residues that are glutathionylated of the 20 cysteines in the protein. CONCLUSIONS: The virus-induced oxidative stress causes modification of viral proteins which appears to modulate virus protein function. GENERAL SIGNIFICANCE: Viruses generate oxidative stress to regulate and hijack host cell systems and this environment also appears to modulate virus protein function. This may be a general target for intervention in viral pathogenesis. PMID- 27984115 TI - Epigenetic disruption of miR-130a promotes prostate cancer by targeting SEC23B and DEPDC1. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that mediate post-transcriptional gene silencing, fine tuning gene expression. In an initial screen, miRNAs were found to be globally down-regulated in prostate cancer (PCa) cell lines and primary tumours. Exposure of PCa cell lines to a demethylating agent, 5-Aza-CdR resulted in an increase in the expression levels of miRNAs in general. Using stringent filtering criteria miR-130a was identified as the most promising candidate and selected for validation analyses in our patient series. Down regulation of miR-130a was associated with promoter hypermethylation. MiR-130a methylation levels discriminated PCa from non-malignant tissues (AUC = 0.956), and urine samples revealed high specificity for non-invasive detection of patients with PCa (AUC = 0.89). Additionally, repressive histone marks were also found in the promoter of miR-130a. Over-expression of miR-130a in PCa cells reduced cell viability and invasion capability, and increased apoptosis. Putative targets of miR-130a were assessed by microarray expression profiling and DEPD1C and SEC23B were selected for validation. Silencing of both genes resembled the effect of over-expressing miR-130a in PCa cells. Our data indicate that miR-130a is an epigenetically regulated miRNA involved in regulation of key molecular and phenotypic features of prostate carcinogenesis, acting as a tumour suppressor miRNA. PMID- 27984117 TI - Lipid production with Trichosporon oleaginosus in a membrane bioreactor using microalgae hydrolysate. AB - Lipid production by Trichosporon oleaginosus was first studied in fed-batch operated stirred-tank bioreactors on a milliliter- and liter-scale making use of typical sugar monomers and a sugar mixture that may be derived from microalgae biomass hydrolysis after the extraction of lipids. 20.3gL-1 lipids (58% of dry cell mass) were produced with T. oleaginosus in a defined medium at nitrogen starvation in the fed-batch process with a typical microalgae derived carbohydrate mixture (60% glucose, 20% mannose, 20% galactose). Real microalgae hydrolysate resulted in superior growth of T. oleaginosus but no enhanced lipid formation was possible due to nitrogen and phosphorus excess in the hydrolysate. Phosphate precipitation and the application of a continuously operated membrane bioreactor with total cell retention due to the low sugar concentrations (~40gL 1) in the microalgae hydrolysate resulted in the production of 30gL-1 lipids (53% of dry cell mass) with T. oleaginosus at high space-time-yields of 0.33g lipids L 1h-1. A high apparent lipid yield of 0.43g lipids g-1 sugars consumed (130% of the theoretical maximum) was achieved with the microalgae hydrolysate most likely due to the additional conversion of other carbon sources (e.g. uronic acids, peptides) in the hydrolysate. PMID- 27984118 TI - Processing recommendations for using low-solids digestate as nutrient solution for poly-beta-hydroxybutyrate production with Synechocystis salina. AB - Within the last decades, environmental pollution with persistent plastics steadily increased; therefore the production of biodegradable materials like poly beta-hydroxybutyrate (PHB) is essential. Currently, PHB is produced with heterotrophic bacteria from crops. This leads to competition with food and feed production, which can be avoided by using photoautotrophic cyanobacteria, as Synechocystis salina, synthesizing PHB from CO2 at nutrient limitation. This study aims to increase the economic efficiency of PHB production with cyanobacteria by using nutrients from anaerobic digestate. First, growth and PHB production of S. salina in digestate fractions (supernatant and permeate, with/without precipitating agents) and dilutions thereof and then the scale-up (photobioreactor, 200 L working volume) were evaluated. With precipitated and centrifuged digestate diluted 1/3 the highest biomass (1.55gL-1) and PHB concentrations (95.4mgL-1), being 78% of those in mineral media, were achieved. In the photobioreactor-experiments biomass (1.63gL-1) and PHB concentrations (88.7mgL-1), being 79% and 72% of those in mineral medium, were reached, but in a cultivation time 10days longer than in mineral medium. The possibility to use digestate as sustainable and low cost nutrient solution for microalgae cultivation and photoautotrophic PHB production, instead of applying it on fields or processing it to achieve discharge limits, makes this application a highly valid option. PMID- 27984119 TI - Comparative study on toxicity of extracellularly biosynthesized and laboratory synthesized CdTe quantum dots. AB - Nanobiosynthesis belongs to the most recent methods for synthesis of nanoparticles. This type of synthesis provides many advantages including the uniformity in particle shape and size. The biosynthesis has also a significant advantage regarding chemical properties of the obtained particles. In this study, we characterized the basic properties and composition of quantum dots (QDs), obtained by the extracellular biosynthesis by Escherichia coli. Furthermore, the toxicity of the biosynthesized QDs was compared to QDs prepared by microwave synthesis. The obtained results revealed the presence of cyan CdTe QDs after removal of substantial amounts of organic compounds, which stabilized the nanoparticle surface. QDs toxicity was evaluated using three cell lines Human Foreskin Fibroblast (HFF), Human Prostate Cancer cells (PC-3) and Breast Cancer cells (MCF-7) and the MTT assay. The test revealed differences in the toxicity between variants of QDs, varying about 10% in the HFF and 30% in the MCF-7 cell lines. The toxicity of the biosynthesized QDs to the PC-3 cell lines was about 35% lower in comparison with the QDs prepared by microwave synthesis. PMID- 27984120 TI - A simple statistical test of taxonomic or functional homogeneity using replicated microbiome sequencing samples. AB - One important question in microbiome analysis is how to assess the homogeneity of the microbial composition in a given environment, with respect to a given analysis method. Do different microbial samples taken from the same environment follow the same taxonomic distribution of organisms, or the same distribution of functions? Here we provide a non-parametric statistical "triangulation test" to address this type of question. The test requires that multiple replicates are available for each of the biological samples, and it is based on three-way computational comparisons of samples. To illustrate the application of the test, we collected three biological samples taken from different locations in one piece of human stool, each represented by three replicates, and analyzed them using MEGAN. (Despite its name, the triangulation test does not require that the number of biological samples or replicates be three.) The triangulation test rejects the null hypothesis that the three biological samples exhibit the same distribution of taxa or function (error probability <=0.05), indicating that the microbial composition of the investigated human stool is not homogenous on a macroscopic scale, suggesting that pooling material from multiple locations is a reasonable practice. We provide an implementation of the test in our open source program MEGAN Community Edition. PMID- 27984121 TI - An S100P-positive biliary epithelial field is a preinvasive intraepithelial neoplasm in nodular-sclerosing cholangiocarcinoma. AB - Nodular-sclerosing cholangiocarcinoma (NS-CCA) is a common CCA of the intrahepatic large, perihilar, and distal bile ducts. Intraepithelial biliary neoplasms, such as the mucosal extension of carcinoma and preinvasive neoplastic lesions (ie, biliary intraepithelial neoplasia) reportedly occur in the bile ducts around CCA. In the present study, we collectively refer to these intraepithelial lesions as "intraepithelial neoplasms of the bile duct (IENBs)". We examined the IENBs in 57 surgically resected cases of NS-CCA. S100P immunostaining was used to help detect IENBs. The IENBs formed field(s) of continuous neoplastic biliary epithelial cells and showed a flat, micropapillary, or papillotubular configuration. IENBs could be classified into 3 categories based on their atypia: group A (neoplastic but not enough for malignancy), B (neoplastic and sufficiently well differentiated for high-grade dysplasia), and C (overtly malignant and variably differentiated). IENB was found in 31 of 57 cases, with group C the most common (26 cases) followed by group B (22 cases) and group A (16 cases). The expression of cancer-related molecules and MIB-1 index of groups A and B differed from those of invasive CCA, whereas these features of group C were relatively similar to those of invasive CCA. In conclusion, IENB was not infrequently found in NS-CCA and could be classified into 3 grades. Preinvasive lesions (biliary intraepithelial neoplasias) are likely to be found in groups A and B, whereas cancerization would be included in group C. The classification of IENB may be useful for future studies of the preinvasive intraepithelial neoplastic lesions of NS-CCAs. PMID- 27984116 TI - MicroRNA and gene co-expression networks characterize biological and clinical behavior of rhabdomyosarcomas. AB - Rhabdomyosarcomas (RMS) in children and adolescents are heterogeneous sarcomas broadly defined by skeletal muscle features and the presence/absence of PAX3/7 FOXO1 fusion genes. MicroRNAs are small non-coding RNAs that regulate gene expression in a cell context specific manner. Sequencing analyses of microRNAs in 64 RMS revealed expression patterns separating skeletal muscle, fusion gene positive and negative RMS. Integration with parallel gene expression data assigned biological functions to 12 co-expression networks/modules that reassuringly included myogenic roles strongly correlated with microRNAs known in myogenesis and RMS development. Modules also correlated with clinical outcome and fusion status. Regulation of microRNAs by the fusion protein was demonstrated after PAX3-FOXO1 reduction, exemplified by miR-9-5p. MiR-9-5p levels correlated with poor outcome, even within fusion gene positive RMS, and were higher in metastatic versus non-metastatic disease. MiR-9-5p reduction inhibited RMS cell migration. Our findings reveal microRNAs in a regulatory framework of biological and clinical significance in RMS. PMID- 27984122 TI - Diagnostic utility of cyclin D1 in the diagnosis of small round blue cell tumors in children and adolescents. AB - Small round blue cell tumors (SRBCTs) of children and adolescents are often diagnostically challenging lesions. With the increasing diagnostic approach based on small biopsies, there is the need of specific immunomarkers that can help in the differential diagnosis among the different tumor histotypes to assure the patient a correct diagnosis for proper treatment. Based on our recent studies showing cyclin D1 overexpression in both Ewing sarcoma/primitive peripheral neuroectodermal tumor (EWS/pPNET) and peripheral neuroblastic tumors (neuroblastoma and ganglioneuroblastoma), we immunohistochemically assessed cyclin D1 immunoreactivity in 128 cases of SRBCTs in children and adolescents to establish its potential utility in the differential diagnosis. All cases of EWS/pPNET and the undifferentiated/poorly differentiated neuroblastomatous component of all peripheral neuroblastic tumors exhibited strong and diffuse nuclear staining (>50% of neoplastic cells) for cyclin D1. In contrast, this marker was absent from rhabdomyosarcoma (regardless of subtype) and lymphoblastic lymphoma (either B- or T-cell precursors), whereas it was only focally detected (<5% of neoplastic cells) in some cases of Wilms tumor (blastemal component) and desmoplastic small round cell tumor. Our findings suggest that cyclin D1 can be exploitable as a diagnostic adjunct to conventional markers in confirming the diagnosis of EWS/pPNET or neuroblastoma/ganglioneuroblastoma. Its use in routine practice may also be helpful for those cases of SRBCT with undifferentiated morphology that are difficult to diagnose after application of the conventional markers. PMID- 27984123 TI - Clinicopathological features of a kindred with SCG5-GREM1-associated hereditary mixed polyposis syndrome. AB - Since first characterized in 1997, patients with hereditary mixed polyposis syndrome (HMPS) have been difficult to identify because of lack of well established diagnostic criteria. Recently, HMPS was found to be caused by a duplication on chromosome 15 spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. Clinical testing for the duplication is available; however, the clinical characteristics of hereditary mixed polyposis to support testing are ill defined. The clinicopathological findings of 10 HMPS patients with confirmed germline SCG5-GREM1 duplication were reviewed. Mean age at presentation was 33.3 years. Fifty-one colonoscopies yielded 207 polyp specimens, all of which were reexamined. Adenomas (n = 80) and a fairly unique polyp composed of a mixture of hyperplastic polyp and inflammatory polyp-type changes (n = 74) were the most common findings; however, other polyps, including hyperplastic (n = 28), mixed inflammatory polyp/adenoma (n = 8), inflammatory polyp (n = 7), prolapse-type polyp (n = 6), and lymphoid aggregates (n = 4), were encountered. None of the patients developed colorectal malignancy during surveillance, demonstrated extracolonic manifestations, or underwent colectomy on follow-up (mean, 26.2 years). SCG5-GREM1 duplication-associated polyposis is characterized by a few polyps per endoscopy with a mixture of phenotypes, most commonly adenoma and nondysplastic mixed hyperplastic/inflammatory polyps. Nine of 10 patients had at least 1 mixed hyperplastic-inflammatory polyp, which is the characteristic lesion of SCG5-GREM1 duplication-associated HMPS. PMID- 27984124 TI - Loss of BRCA1-associated protein 1 (BAP1) expression is rare in non-small cell lung cancer. AB - BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene involved in regulation of the cell cycle, cellular differentiation, repair of DNA damage, and apoptosis. In the distinction of malignant mesothelioma from benign mesothelial proliferations, immunohistochemical loss of BAP1, the protein expressed by the BAP1 gene, has proven highly specific for malignant mesothelioma. However, few studies have investigated the rate of BAP1 loss in tumors that commonly metastasize to the pleura. Our objective is to determine the rate of BAP1 loss in non-small cell lung cancer (NSCLC). Immunohistochemistry for BAP1 was performed using tissue microarrays containing 133 confirmed cases of NSCLC (80 of lung adenocarcinoma and 53 of squamous cell carcinoma). Cases were interpreted as showing BAP1 loss if nuclear staining was completely absent in all tumor cells and present in stromal and inflammatory cells that served as internal controls. Cases showing no BAP1 staining in the internal controls were excluded. After exclusion of 32 cases for technical reasons, only 1 case of pulmonary adenocarcinoma of 101 cases of NSCLC (69 adenocarcinoma and 32 squamous cell carcinoma; 1.0% of cases) showed BAP1 loss. We conclude that loss of BAP1 expression is a rare event in NSCLC. Therefore, BAP1 is a potentially useful addition to the immunohistochemical markers used to distinguish mesothelioma from pleural metastasis of NSCLC. PMID- 27984125 TI - Predictors of renal survival in antineutrophil cytoplasmic antibody-associated vasculitis-reply. PMID- 27984126 TI - Malignant transformation of a beta-catenin inflammatory adenoma due to an S45 beta-catenin-activating mutation present 12 years before. AB - In 1984, a 24-year-old woman underwent a right hepatectomy after a 17-cm nodule, diagnosed as a hepatocellular adenoma with some atypia. The resection was incomplete. Follow-up was interrupted. In 1996, a computed tomographic scan revealed a large multifocal hepatocellular carcinoma confirmed on biopsies. The patient died the same year. We reviewed these nodules using immunohistochemistry and gene sequencing. C-reactive protein was overexpressed in the tumor resected in 1984. Glutamine synthetase was heterogeneous in the tumor, with a few tumor nuclei expressing beta-catenin. Glypican and heat shock protein 70 were negative. In this beta-catenin-activated inflammatory hepatocellular adenoma, S45 beta catenin-activating mutation was detected on fixed tissue, embedded in paraffin without TERT promoter mutation. An identical CTNNB1 mutation was identified in the 1996 liver tumor together with a TERT promoter mutation showing that this hepatocellular carcinoma results from the malignant transformation of the initial beta-catenin inflammatory adenoma. PMID- 27984127 TI - Predictors of renal survival in antineutrophil cytoplasmic antibody-associated vasculitis. PMID- 27984129 TI - Aluminum exposure for one hour decreases vascular reactivity in conductance and resistance arteries in rats. AB - AIMS: Aluminum (Al) is an important environmental contaminant; however, there are not enough evidences of Al-induced cardiovascular dysfunction. We investigated the effects of acute exposure to aluminum chloride (AlCl3) on blood pressure, vascular reactivity and oxidative stress. METHODS AND RESULTS: Male Wistar rats were divided into two groups: Untreated: vehicle (ultrapure water, ip) and AlCl3: single dose of AlCl3 (100mg/kg,ip). Concentration-response curves to phenylephrine in the absence and presence of endothelium, the nitric oxide synthase inhibitor l-NAME, the potassium channel blocker tetraethylammonium, and the NADPH oxidase inhibitor apocynin were performed in segments from aortic and mesenteric resistance arteries. NO released was assessed in aorta and reactive oxygen species (ROS), malondialdehyde, non-protein thiol levels, antioxidant capacity and enzymatic antioxidant activities were investigated in plasma, aorta and/or mesenteric arteries. After one hour of AlCl3 exposure serum Al levels attained 147.7+/-25.0MUg/L. Al treatment: 1) did not affect blood pressure, heart rate and vasodilator responses induced by acetylcholine or sodium nitroprusside; 2) decreased phenylephrine-induced vasoconstrictor responses; 3) increased endothelial modulation of contractile responses, NO release and vascular ROS production from NADPH oxidase; 4) increased plasmatic, aortic and mesenteric malondialdehyde and ROS production, and 5) decreased antioxidant capacity and affected the antioxidant biomarkers non-protein thiol levels, glutathione peroxidase, glutathione-S-transferase, superoxide dismutase and catalase enzymatic activities. CONCLUSION: AlCl3-acute exposure reduces vascular reactivity. This effect is associated with increased NO production, probably acting on K+ channels, which seems to occur as a compensatory mechanism against Al-induced oxidative stress. Our results suggest that Al exerts toxic effects to the vascular system. PMID- 27984130 TI - Dual effect of insulin resistance and cadmium on human granulosa cells - In vitro study. AB - Combined exposure of cadmium (Cd) and insulin resistance (IR) might be responsible for subfertility. In the present study, we investigated the effects of Cd in vitro in IR human granulosa cells. Isolated human granulosa cells from control and polycystic ovary syndrome (PCOS) follicular fluid samples were confirmed for IR by decrease in protein expression of insulin receptor-beta. Control and IR human granulosa cells were then incubated with or without 32MUM Cd. The combined effect of IR with 32MUM Cd in granulosa cells demonstrated significant decrease in expression of StAR, CYP11A1, CYP19A1, 17beta-HSD, 3beta HSD, FSH-R and LH-R. Decrease was also observed in progesterone and estradiol concentrations as compared to control. Additionally, increase in protein expression of cleaved PARP-F2, active caspase-3 and a positive staining for Annexin V and PI indicated apoptosis as the mode of increased cell death ultimately leading to decreased steroidogenesis, as observed through the combined exposure. Taken together the results suggest decrease in steroidogenesis ultimately leading to abnormal development of the follicle thus compromising fertility at the level of preconception. PMID- 27984128 TI - DNA damage response in nephrotoxic and ischemic kidney injury. AB - DNA damage activates specific cell signaling cascades for DNA repair, cell cycle arrest, senescence, and/or cell death. Recent studies have demonstrated DNA damage response (DDR) in experimental models of acute kidney injury (AKI). In cisplatin-induced AKI or nephrotoxicity, the DDR pathway of ATR/Chk2/p53 is activated and contributes to renal tubular cell apoptosis. In ischemic AKI, DDR seems more complex and involves at least the ataxia telangiectasia mutated (ATM), a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, and p53; however, while ATM may promote DNA repair, p53 may trigger cell death. Targeting DDR for kidney protection in AKI therefore relies on a thorough elucidation of the DDR pathways in various forms of AKI. PMID- 27984131 TI - Enhanced photo(geno)toxicity of demethylated chlorpromazine metabolites. AB - Chlorpromazine (CPZ) is an anti-psychotic drug widely used to treat disorders such as schizophrenia or manic-depression. Unfortunately, CPZ exhibits undesirable side effects such as phototoxic and photoallergic reactions in humans. In general, the influence of drug metabolism on this type of reactions has not been previously considered in photosafety testing. Thus, the present work aims to investigate the possible photo(geno)toxic potential of drug metabolites, using CPZ as an established reference compound. In this case, the metabolites selected for the study are demethylchlorpromazine (DMCPZ), didemethylchlorpromazine (DDMCPZ) and chlorpromazine sulfoxide (CPZSO). The demethylated CPZ metabolites DMCPZ and DDMCPZ maintain identical chromophore to the parent drug. In this work, it has been found that the nature of the aminoalkyl side chain modulates the hydrophobicity and the photochemical properties (for instance, the excited state lifetimes), but it does not change the photoreactivity pattern, which is characterized by reductive photodehalogenation, triggered by homolytic carbon-chlorine bond cleavage with formation of highly reactive aryl radical intermediates. Accordingly, these metabolites are phototoxic to cells, as revealed by the 3T3 NRU assay; their photo-irritation factors are even higher than that of CPZ. The same trend is observed in photogenotoxicity studies, both with isolated and with cellular DNA, where DMCPZ and DDMCPZ are more active than CPZ itself. In summary, side-chain demethylation of CPZ, as a consequence of Phase I biotransformation, does not result a photodetoxification. Instead, it leads to metabolites that exhibit in an even enhanced photo(geno)toxicity. PMID- 27984132 TI - Enterolactone: A novel radiosensitizer for human breast cancer cell lines through impaired DNA repair and increased apoptosis. AB - INTRODUCTION: Radiotherapy is a potent treatment against breast cancer, which is the most commonly diagnosed cancer among women. However, the emergence of radioresistance due to increased DNA repair leads to radiotherapeutic failure. Applying polyphenols combined with radiation is a more promising method leading to better survival. Enterolactone, a phytoestrogenic polyphenol, has been reported to inhibit an important radioresistance signaling pathway, therefore we conjectured that enterolactone could enhance radiosensitivity in breast cancer. To assess this hypothesis, radiation response of enterolactone treated MDA-MB-231 and T47D cell lines and corresponding cellular mechanisms were investigated. METHODS: Cytotoxicity of enterolactone was measured via MTT assay. Cells were treated with enterolactone before X-irradiation, and clonogenic assay was used to evaluate radiosensitivity. Cell cycle distribution and apoptosis were measured by flow cytometric analysis. In addition, DNA damages and corresponding repair, chromosomal damages, and aberrations were assessed by comet, micronucleus, and cytogenetic assays, respectively. RESULTS: Enterolactone decreased the viability of cells in a concentration- and time dependent manner. Enterolactone significantly enhanced radiosensitivity of cells by abrogating G2/M arrest, impairing DNA repair, and increasing radiation-induced apoptosis. Furthermore, increased chromosomal damages and aberrations were detected in cells treated with enterolactone combined with X-rays than X-ray alone. These effects were more prominent in T47D than MDA-MB-231 cells. DISCUSSION: To our knowledge, this is the first report that enterolactone is a novel radiosensitizer for breast cancer irrespective of estrogen receptor status. Authors propose enterolactone as a candidate for combined therapy to decrease the radiation dose delivered to patients and subsequent side effects. PMID- 27984136 TI - Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. AB - Inhalation of diacetyl vapors by workers has been associated with obliterative bronchiolitis (OB), a poorly understood fibroproliferative disease of the small airways. Significant insights into the pathogenesis of OB have been obtained through the use of a rat model. Inhalation exposure of rats to diacetyl or 2,3 pentanedione, a related flavoring agent, can cause severe injury to the airway epithelium and underlying basement membrane. Repeated exposure to diacetyl or 2,3 pentanedione leads to aberrant repair, fibroproliferation and partial to complete occlusion of the airway lumen. Fibroproliferative lesions in rat airways were found to include both intraluminal polyps and circumferential intramural lesions. Intraluminal polyps have been observed to form secondary attachments spanning the airway lumen causing increasing obstruction. These airway lesions in rats are accompanied by inflammation in the form of peribronchial and perivascular infiltrates of lymphocytes, eosinophils and neutrophils. Diacetyl-induced OB lesions in the rat are similar to OB lesions in humans and provide a good model for studying the pathogenesis of this disease. PMID- 27984137 TI - Novel eugenol derivatives: Potent acetylcholinesterase and carbonic anhydrase inhibitors. AB - Eugenol was used as starting material to obtain some phenolic compounds. The synthesis of these phenolic compounds was performed in a two-step procedure. The structures of the formed products (novel eugenol derivatives 1-6) have been determined on the basis of NMR spectroscopy and other spectroscopic methods. The compounds were tested in terms of carbonic anhydrase (CA) inhibition potency. Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes, which catalyse the reaction between carbon dioxide (CO2) and water (H2O), to generate bicarbonate (HCO3-) and protons (H+). CO2, HCO3- and H+ are essential molecules and ions for many important physiologic processes occurring in all living organisms. Acetylcholinesterase (AChE, E.C.3.1.1.7) is found in high concentrations in the red blood cells and brain. Novel eugenol derivatives (1-6) were tested for the inhibition of two cytosolic CA isoforms I, and II (hCA I, and II) and AChE. These compounds demonstrated effective inhibitory profiles with Ki values in ranging of 113.48-738.69nM against hCA I, 92.35-530.81nM against hCA II, and 90.10-379.57nM against AChE, respectively. On the other hand, acetazolamide clinically used as CA inhibitor, shoed Ki value of 594.11nM against hCA I, and 120.68nM against hCA II, respectively. Also, AChE was inhibited by tacrine as an AChE inhibitor at the 71.18nM level. PMID- 27984138 TI - Physico-chemical, structural, pasting and thermal properties of starches of fourteen Himalayan rice cultivars. AB - Starch of fourteen rice cultivars grown in Himalayan region were evaluated for physico-chemical, structural, pasting and thermal properties. The rice cultivars selected showed a wide variation in apparent amylose content (AAC), ranging between 10.76%-26.87%, highest in CH-1039 and lowest in SKAU-292 starch. There were ten low, three intermediate and one high AAC rice. Resistant starch content varied significantly among the rice cultivars, ranging from 6.00% to 19.60%. Generally, high ACC starches presented high contents of resistant starch. Water absorption capacity (80.10-130.32%), swelling (5.73-9.61g/g) and solubility (0.037-0.090g/g) indices varied significantly among the rice cultivars. The rice starch granule morphology showed polyhedral or irregular shapes and granular sizes in the range of 1.8-6.7MUm in different rice starches. Pasting profile of starch varied significantly among the rice cultivars, probably due to variations in their AAC. Thermal properties of the starches ranged considerably among different rice cultivars: onset temperature of gelatinization, To (58.25-72.49 degrees C), peak temperature of gelatinization, Tp (69.93-93.26 degrees C), conclusion temperature of gelatinization, Tc (97.28+/-8.28-112.16 degrees C) and gelatinization enthalpy DeltaHG (14.29-29.63J/g). The ATR-FTIR spectroscopy of rice starches identified most of the alpha-1->4 glucosidic linkages within the absorption bands of 1149-1023cm-1. PMID- 27984139 TI - Fc fragments of immunoglobulin G are an inductor of regulatory rheumatoid factor and a promising therapeutic agent for rheumatic diseases. AB - We recently identified rheumatoid factor, the production of which neither predicts nor exacerbates experimental autoimmune disease, but the opposite, namely it is associated with autoimmune disease resistance and remission. We have named it regulatory rheumatoid factor (regRF). The aim of this study was to determine whether rat Fc fragments and human Fc fragments are an antigen for regRF, and to determine the conditions for obtaining them. The presence of an antigenic determinant for regRF on IgG fragments was inferred from the fragments' ability to inhibit the agglutination caused by regRF and to induce regRF production in vivo. It was found that antigenic determinants for both human regRF and rat regRF are absent from native IgG and can be induced in the hinge region of Fc fragments of homologous IgG by papain digestion. The rat Fc fragments are susceptible to spontaneous reconfiguration, which results in loss of the antigenic determinants for regRF. Reconfiguration can be observed by SDS-PAGE. Immunization of arthritic rats with Fc fragments of rat IgG that carry antigenic determinants for rat regRF reduces the symptoms of collagen-induced arthritis. The Fc fragments can be viewed as the basis for a therapeutic vaccine to suppress autoimmune responses. PMID- 27984140 TI - Preparation and properties of cellulose nanocomposite films with in situ generated copper nanoparticles using Terminalia catappa leaf extract. AB - In the present work, copper nanoparticles (CuNPs) were in situ generated inside cellulose matrix using Terminalia catappa leaf extract as a reducing agent. During this process, some CuNPs were also formed outside the matrix. The CuNPs formed outside the matrix were observed with transmission electron microscope (TEM) and scanning electron microscope (SEM). Majority of the CuNPs formed outside the matrix were in the size range of 21-30nm. The cellulose/CuNP composite films were characterized by Fourier transform infrared spectroscopic, X Ray diffraction and thermogravimetric techniques. The crystallinity of the cellulose/CuNP composite films was found to be lower than that of the matrix indicating rearrangement of cellulose molecules by in situ generated CuNPs. Further, the expanded diffractogram of the composite films indicated the presence of a mixture of Cu, CuO and Cu2O nanoparticles. The thermal stability of the composites was found to be lower than that of the composites upto 350 degrees C beyond which a reverse trend was observed. This was attributed to the catalytic behaviour of CuNPs for early degradation of the composites. The composite films possessed sufficient tensile strength which can replace polymer packaging films like polyethylene. Further, the cellulose/CuNP composite films exhibited good antibacterial activity against E.coli bacteria. PMID- 27984141 TI - Improvement of activity, thermo-stability and fruit juice clarification characteristics of fungal exo-polygalacturonase. AB - An extracellular exo-polygalacturonase (exo-PG) from Penicillium notatum was immobilized in sodium-alginate matrix through two different protocols, viz. covalent bonding and adsorption to enhance its catalytic activity, thermal stability and life-time properties for industrial applications. Covalent immobilization was more efficient in terms of high relative activity (45.89%) and immobilization yield (71.6%) as compared to adsorption. Immobilized exo-PG derivatives displayed maximum activities at pH 5.5 and 55 degrees C as compared to free enzyme which showed its optimum activity at pH 6.0 and 50 degrees C. The affinity of enzyme towards its substrate (Km(app)) was reduced after immobilization and Vmax of covalently immobilized exo-PG decreased to 66.7% while the Vmax value of adsorbed enzyme increased up to 150% as compared to free counterpart. Both immobilization techniques greatly enhanced the thermal stability profile of the enzyme. At 60 degrees C, immobilized exo-PGs retained more than 90% of their residual activities after 60min of heating, while free enzyme did not show any activity at the same temperature. Thermodynamic properties (i.e., Ea, DeltaH*, DeltaS*and DeltaG*) of the free and immobilized enzymes were also investigated. Sodium-alginate covalently immobilized and adsorbed enzymes showed excellent recycling efficiencies and retained 50.0% and 41.0% of original activities, respectively after seven consecutive batch reactions. Moreover, the immobilized enzymes treatment achieved promising results in turbidity and viscosity reduction as well as clarity amelioration in various fruit juices. Altogether catalytic, thermo-stability and fruit juices clarification characteristics of the immobilized ex-PGs suggest a high potential for biotechnological exploitability. PMID- 27984142 TI - Broad substrate affinity and catalytic diversity of fibrinolytic enzyme from Pheretima posthumous-Purification and molecular characterization study. AB - In this research, a serine protease was isolated and purified from Indian earthworm Pheretima posthumous by fractionation with ammonium sulfate followed by ion exchange and size exclusion chromatography. The molecular weight of purified protease was determined 29.5kDa by Maldi-TOF/MS. The enzyme exhibited a maximum proteolytic activity of 1.2U/ml with specific activity of 17.65U/mg at pH 8 and temperature 40 degrees C. 2D electrophoresis study illustrated purity of enzyme, purified as a single peptide and isoelectric point (pI) 4.5. The enzyme has shown tremendous stability and proteolytic activity in the wide range of pH range (4 12) and temperatures (20-60 degrees C). The kinetic constant Km and Vmax of purified protease were reported 0.09mg/ml and 23.25mg/ml/min. The enzyme also possesses excellent catalytic capacity with Kcat (341.9min-1) and catalytic efficiency (3798.88). The N-terminal sequence of purified protease Arg-Lys-Lys Gly-Ala-Ser-Try-Phe-Try-Pro-Trp-Ser-Val-Lys-Lys-Arg, PMF and MS/MS studies had shown a partial homology with Lumbrokinase-P2 (2) from Lumbricus rubellus. The CD spectroscopy result provided an evidence for broad substrate affinity and stability of enzyme. The different forms of secondary structures determined in EFE result broad substrate affinity of enzyme. PMID- 27984143 TI - Delineating residues for haemolytic activities of snake venom cardiotoxin 1 from Naja naja as probed by molecular dynamics simulations and in vitro validations. AB - Cardiotoxins (CTXs) are single polypeptide chain consisting of 59-62 amino acids with four disulfide bridges and globular proteins of simple beta-sheet folds. The CTXs are one of principal toxic components causing haemolysis and damaging various cells and belong to three-finger toxin (TFT) superfamily of snake venoms. However, there is no natural or synthetic small molecular inhibitor to the protein toxins to date. In the present study, modes of interaction of cardiotoxin 1 (CTX1) from Indian cobra (Naja naja) with heterogeneous erythrocyte membrane (EM) model system have been extensively examined by using all-atom molecular dynamics (MD) simulations in near physiological conditions and comprehensive analyses of the MD data revealed two distinct principal regions ('head groove' and 'loop groove') of the protein toxin for establishing structural interactions with the EM system. Moreover, combined analyses of data from high-throughput virtual screening of NCI small molecular database, in vitro haemolytic assays for top-hits of the chemical compounds against crude venom of Naja naja and as well CTXs purified from the venom and pharmacokinetic examinations on the chemical compounds retarding haemolytic activities of CTXs suggested that Etidronic acid and Zoledronic acid are promising prototypic chemical inhibitors to CTXs of snake venoms. PMID- 27984144 TI - Lectin from seeds of a Brazilian lima bean variety (Phaseolus lunatus L. var. cascavel) presents antioxidant, antitumour and gastroprotective activities. AB - Lectins are proteins able to interact specifically and reversibly with carbohydrates. They are present in all living beings, particularly in legume seeds, which have many biological functions. The aim of this study was to isolate, characterize and verify antioxidant, anti-hemolytic, antitumor and gastroprotective activities in a lectin present in seeds of Phaseolus lunatus L. var. cascavel (PLUN). The isolation of lectin was performed by size exclusion chromatography on Sephadex G-100, which was isolated from a protein capable of agglutinating only human erythrocytes type A, being this the only inhibited haemagglutination n-acetyl-d-galactosamine. Its weight was estimated by PAGE is 128kDa. The lectin is thermostable up to 80 degrees C and is active between pH 2 11. As 8M urea was able to denature the lectin. PLUN is a glycoprotein consisting of 2% carbohydrate and has antioxidant action with ascorbic acid equivalent antioxidant capacity (MUMAA/g) of 418.20, 326 and 82.9 for total antioxidant activity, ABTS radical capture and capture of DPPH radical, respectively. The lectin has antitumor activity against melanoma derived cells at doses of 100 and 50mg/ml, reducing up to 83% tumor cells, and gastroprotective action, reducing up to 63% damaged area of the stomach induced by ethanol. PMID- 27984145 TI - Characteristics of surface layer proteins from two new and native strains of Lactobacillus brevis. AB - In this work, some important characteristics of surface layer (S-layer) proteins extracted from two new and native Lactobacillus strains, L.brevis KM3 and L.brevis KM7, were investigated. The presence of S-layer on the external surface of L.brevis KM3 was displayed by thin sectioning and negative staining. SDS-PAGE analysis were shown same dominant protein bands approximately around 48kDa for both S-layer proteins. Moreover, the S-layer reappeared when LiCl treated cells were allowed to grow again. Protein secondary structure and thermal behavior were evaluated by using circular dichroism (CD) and differential scanning calorimetry (DSC), respectively. Both S-layer proteins had high content of beta-sheet and low amount of alpha-helix. The thermograms of lyophilized S-layer proteins of L.brevis KM3 and L.brevis KM7 showed one transition peak at 67.9 degrees C and 59.14 degrees C, respectively. To determine monodispersity of extracted S-layer proteins, dynamic light scattering (DLS) was used. The results indicated that the main population of S-layer molecules in two tested lactobacillus strains were composed of monomer with an expected diameter close to 10nm. Furthermore, Zeta potential measurements were showed positive potential for both S-layer proteins, as expected. Our results could be used as the basis for biotechnological applications of these two new S-layer proteins. PMID- 27984147 TI - Characteristics of bovine lactoferrin powders produced through spray and freeze drying processes. AB - Bovine lactoferrin (LFb) powders were produced using spray drying and freeze drying. Industrially obtained fresh liquid-LFb was used as starting material. The antioxidant capacity, solubility in water, moisture sorption behaviour, the extent of denaturation and changes in the secondary structural features of spray dried (SDLFb) and freeze-dried bovine lactoferrin (FDLFb) powders were determined. The residual moisture content, water activity, particle size and amorphous/crystalline nature of the SDLFb and FDLFb were also measured. Results showed that both SDLFb and FDLFb powders had negligible denaturation and conformation changes compared to the liquid-LFb. Both SDLFb and FDLFb showed type II sorption behaviour with almost identical monolayer moisture content. The SDLFb powders were amorphous in nature with >98% solubility in water. The antioxidant activity of SDLFb was similar to that of the liquid-LFb while it was ~6% less in FDLFb. Based on the residual moisture content, water activity, solubility and preservation of secondary structure of LFb in resultant powders, a spray drying process with 180 degrees C inlet and 95 degrees C outlet temperature was found to produce similar or better quality LFb powders compared to the ones produced through a freeze drying process. PMID- 27984146 TI - Deciphering the interaction of bovine heart cystatin with ZnO nanoparticles: Spectroscopic and thermodynamic approach. AB - ZnO-NPs have been widely used in biomedical fields such as therapeutics, cellular imaging, and drug delivery. However, the risk of exposure of nanoparticles to the biological system is not well understood. Nanoparticle-protein interaction is pivotal to understand their biological behavior and predict nanoparticle toxicity that is crucial for its safer applications. In the present study zinc oxide nanoparticles (ZnO-NPs) were synthesized and subjected to interact with buffalo heart cystatin (BHC), purified from buffalo heart, to assess the effect(s) of ZnO NPs on the structure and function of BHC. In vitro toxicity assessments revealed that BHC, upon interaction with ZnO-NPs, led to the altered protein conformation and perturbed function. A decrease in the anti-papain activity of BHC was observed. Spectroscopic studies demonstrated that formation of BHC-ZnO-NPs complex accompanied by structural changes in BHC along with a significant decrease in its alpha-helical content. ITC determined the thermodynamic parameters of binding between ZnO-NPs and BHC quantitatively. Increased surface hydrophobicity (change in the tertiary structure) was observed by ANS fluorescence that demonstrated the formation of molten globular intermediates that were found to be stable without any signs of aggregation as depicted by ThT fluorescence. TEM images gave the physical evidence of the formation of ZnO-NPs BHC corona. PMID- 27984148 TI - Evaluation of alginate hydrogel cytotoxicity on three-dimensional culture of type A spermatogonial stem cells. AB - The culture of spermatogonial cells for future transplantation, based on the specific biology of these cells is important and necessary. Recently, the use of scaffolds especially alginate for culturing stem cells has been the focus of many researchers. The aim of this study was to evaluate the cytotoxicity of alginate hydrogels to cultures of type A spermatogonial stem cells. Spermatogonial stem cells of 6day-old immature mice were isolated by surgery; thereafter, the cells were purified by MACS using antibodies against thy-1 and C-kit and cultured on a layer of laminin. After purification, spermatogonial stem cells were encapsulated in alginate hydrogels. After one month of encapsulation and culture in DMEM culture medium containing 10ng/ml GDNF, cells were removed from hydrogel and were examined for viability, cell morphology and structure, cytotoxicity and expression of apoptosis genes Fas, P53, Bax, Bcl2, Caspase3 by staining with trypan blue, scanning electron microscopy, LDH test, and Real time PCR, respectively. The encapsulation did not change the morphology and viability of spermatogonial stem cells. Investigations showed that spermatogonial stem cells preserve by the high viability (74.08%) and cytotoxicity of alginate hydrogel was estimated to be 5%. Expression of Fas gene increased in main group compared with the control group, and expression of Bax and P53 was reduced in main group compared with the control group. Expression of Bcl2 and Caspase3 genes did not show any significant difference between the main group and the control group. Considering the lack of cytotoxicity and antioxidant properties of alginate hydrogel scaffold and high viability of cells, this three-dimensional scaffold is applicable for culturing and encapsulation of spermatogonial stem cells. PMID- 27984149 TI - Improved biodegradation of synthetic azo dye by horseradish peroxidase cross linked on nano-composite support. AB - A ZnO nanowires/macroporous SiO2 composite was used as support to immobilize horseradish peroxidase (HRP) by in-situ cross-linking method. Using diethylene glycol diglycidyl ether (DDE) as a long-chained cross-linker, it was adsorbed on the surface of ZnO nanowires before reaction with HRPs, the resulted composite was quite different from the traditional cross-linking enzyme aggregates (CLEAs) on both structure and catalytic performance. The immobilized HRP showed high activity in the decolorization of azo dyes. The effect of various conditions such as the loading amount of HRP, solution pH, temperature, contact time and concentration of dye were optimized on the decolorization. The decolorization percentage of Acid Blue 113 and Acid black 10 BX reached as high as 95.4% and 90.3%, respectively. The immobilized HRP gave the highest decolorization rate under dye concentration as 50mg/L and reaction time of 35min. The immobilized HRP exhibited much better resistance to temperature and pH inactivation than free HRP. The storage stability and reusability were greatly improved through the immobilization, from the decolorization of Acid blue 113 it was found that 80.4% of initial efficiency retained after incubation at 4 degrees C for 60 days, and that 79.4% of decolorization efficiency retained after 12 cycles reuse. PMID- 27984150 TI - Enantiomeric separation of pharmaceutically important drug intermediates using a Metagenomic lipase and optimization of its large scale production. AB - In the present study, efficient enzymatic methods were developed using a recombinant metagenomic lipase (LipR1) for the synthesis of corresponding esters by the transesterification of five different pharmaceutically important secondary alcohols. The recombinant lipase (specific activity=87m6U/mg) showed maximum conversion in presence of ionic liquid with Naphthyl-ethanol (eeP=99%), Indanol and Methyl-4 pyridine methanol (eeS of 98% and 99%) respectively in 1h. Vinyl acetate was found as suitable acyl donor in transesterification reactions. It was interesting to observe that maximum eeP of 85% was observed in just 15min with 1 indanol. As this enzyme demonstrated pharmaceutical applications, attempts were made to scale up the enzyme production on a pilot scale in a 5litre bioreactor. Different physical parameters affecting enzyme production and biomass concentration such as agitation rate, aeration rate and inoculum concentration were evaluated. Maximum lipase activity of 8463U/ml was obtained at 7h of cultivation at 1 lpm, 300rpm and 1.5% inoculum. PMID- 27984151 TI - Copper incorporated microporous chitosan-polyethylene glycol hydrogels loaded with naproxen for effective drug release and anti-infection wound dressing. AB - Copper ion (Cu2+) incorporated microporous chitosan-polyethylene glycol films were developed as a multipotent wound dressing material. The mechanical properties, swelling behavior and moisture permeability of hydrogel films with varying Cu2+ concentration and the release of Cu2+ from films were evaluated. The results revealed the enhanced mechanical stability of films with increasing Cu2+ concentration without compromising moisture permeability and absorption capability of wound exudates. Microporous surface and swollen micropores in hydrated conditions were confirmed from morphological analysis. Degradation studies in lysozyme and H2O2 demonstrated increasing stability of films with increasing Cu2+ concentration up to 30days. Antibacterial tests revealed superiority in inhibiting biofilm formation in comparison to chitosan films. In vitro drug release, MTT assays and cell adhesion tests demonstrated the efficiency of Cu2+ incorporated hydrogels in sustained drug release and antibacterial activity with excellent keratinocyte cell response. PMID- 27984152 TI - Association of brain metabolites with blood lactate and glucose levels with respect to neurological outcomes after out-of-hospital cardiac arrest: A preliminary microdialysis study. AB - AIM: Out-of-hospital cardiac arrest (OHCA) is associated with poor prognosis. Cerebral microdialysis (CMD) is an efficient sampling technique to detect neurochemical changes in brain interstitial tissue. In this retrospective study, we hypothesised that there are different CMD levels between patients with favourable and unfavourable neurological outcomes. METHODS: Data of patients with OHCA admitted to Kagawa University Hospital and administered therapeutic hypothermia (TH) were collected. Using a CMD probe, extracellular glucose, lactate and pyruvate levels were measured hourly along with intracranial perfusion pressure (ICP) and cerebral perfusion pressure (CPP) for the initial 72h during TH. The lactate/pyruvate (LP) ratio was calculated. Patients were divided into favourable [Glasgow-Pittsburgh cerebral performance category 1-2 at 30days after cardiac arrest] or unfavourable neurological outcome groups. CMD biochemical markers and blood lactate and glucose levels were compared between two groups. RESULTS: Ten patients were included. ICP was significantly higher in the unfavourable than in the favourable neurological outcome group; there were no significant differences with respect to CPP. The CMD LP ratio in the unfavourable outcome group progressively increased; significant differences were observed on days 2, 3 and 4 (p<0.01). Significant differences in blood lactate levels were observed between the groups only on day 3.5. CMD and blood glucose levels were higher in the unfavourable than in the favourable outcome group during TH. CONCLUSION: The association of CMD levels with long-term outcomes would be better defined in a large randomised prospective study. PMID- 27984153 TI - Incidence, characteristics, and survival following cardiopulmonary resuscitation in the quaternary neonatal intensive care unit. AB - BACKGROUND: The contemporary characteristics and outcomes of cardiopulmonary resuscitation (CPR) in the neonatal intensive care unit (NICU) are poorly described. The objectives of this study were to determine the incidence, interventions, and outcomes of CPR in a quaternary referral NICU. METHODS: Retrospective observational study of infants who received chest compressions for resuscitation in the Children's Hospital of Philadelphia NICU between April 1, 2011 and June 30, 2015. Patient, event, and survival characteristics were abstracted from the medical record and the hospital-wide resuscitation database. The primary outcome was survival to hospital discharge. Univariable and multivariable analyses were performed to identify patient and event factors associated with survival to discharge. RESULTS: There were 1.2 CPR events per 1000 patient days. CPR was performed in 113 of 5046 (2.2%) infants admitted to the NICU during the study period. The median duration of chest compressions was 2min (interquartile range 1, 6min). Adrenaline was administered in 34 (30%) CPR events. Of 113 infants with at least one CPR event, 69 (61%) survived to hospital discharge. Factors independently associated with decreased survival to hospital discharge were inotrope treatment prior to CPR (adjusted Odds Ratio [aOR] 0.14, 95% Confidence Interval [CI] 0.04, 0.54), and adrenaline administration during CPR (aOR 0.14, 95% CI 0.04, 0.50). CONCLUSIONS: Although it was not uncommon, the incidence of CPR was low (<3%) among infants hospitalized in a quaternary referral NICU. Infants receiving inotropic therapy prior to CPR and adrenaline administration during CPR were less likely to survive to hospital discharge. PMID- 27984154 TI - Cardiac arrest in schools: Nationwide incidence, risk, and outcome. AB - AIM: Schools are an important location for improving OHCA outcome. But there are few data on out of hospital cardiac arrest (OHCA) in schools. This study aimed to show incidence and outcome of OHCA in schools, specifying location and activities. METHODS: We used the Korean nationwide OHCA registry from 2008 to 2014. OHCA victims were categorized regarding level of school. The average annual incidence of OHCA was calculated based on per 1000 schools. The epidemiological characteristics are analysed and location and activity at the time of arrest is further described. The outcome of OHCA victims were analysed. RESULTS: 511 OHCA occurred in school while 374 cases were cardiac origin, 125 cases were non cardiac, and 12 cases were missing in information. Annual incidence was 5.72 per 1000 school while highest incidence was shown in university (11.02 per 1000 school). The majority of victims were male (84.1%), aged 19-64 (62.2%, median 44.75), either students (35.0%) or visitors (35.2%). Most victims had none shockable rhythms, did not received EMS defibrillation and were not witnessed arrests, while most received bystander CPR. A large proportion of arrests occurred at an outdoor campus (29.7%) or sports facility (28.8%), and the most frequent activity was exercise (30.7%). 100 patients (19.6%) survived to discharge, and 66 patients (12.9%) were discharged with good neurological outcome. CONCLUSION: Incidence of OHCA in school is low. Most of victims were adult visitors. About one third of OHCA occurred during sports activity or at the sports facility. PMID- 27984155 TI - How fast is too fast? Chest compression rate revisited from a new perspective. PMID- 27984157 TI - Achieved glucose level and mortality risk in randomized clinical trials. PMID- 27984158 TI - Association of norepinephrine transporter gene polymorphisms in attention deficit/hyperactivity disorder in Korean population. AB - We investigated the association of three single nucleotide polymorphisms(SNP) of the norepinephrine transporter (NET) gene SLC6A2, T-182C (rs2242446), A-3081T (rs28386840), and G-1287A (rs5569) with the prevalence of attention deficit/hyperactivity disorder (ADHD), its clinical severity, and other disease related characteristics in a Korean population. The genotype, allele frequency and haplotype of 103 ADHD patients and 173 controls were analyzed for these three SNPs. All participants completed the Korean version of the ADHD Rating Scale (K ARS). The ADHD group also completed the Korean Educational Development Institute Wechsler Intelligence Scale for Children (KEDI-WISC) and the Continuous Performance Test (CPT) in a drug-naive state. The chi2 test and logistic regression analysis revealed no significant differences in the genotype distribution or allele frequencies of each SNP between the ADHD group and the control. In the haplotype analysis, the most common T-A-G haplotype was related to an increased risk of ADHD in females (P=0.002). There was no statistical significance between clinical features of ADHD and any specific allele of each SNP after multiple test correction except lower omission error in non-A girl carriers (GG type) of G-1287A (carrier 76.75+/-18.74, non-carrier 55.00+/-9.26, t=3.026, P=0.007, Bonferroni-corrected P=0.042). Some values related A-3081 and G 1287A showed a trend approaching the significance level when analyzed separately by gender. Even though it was not statistically meaningful after multiple test correction, G allele might have some protective effect against development of ADHD symptoms and this finding was consistent with previous studies. PMID- 27984156 TI - Resuscitating leadership research. PMID- 27984159 TI - Spectroscopy markers of suicidal risk and mental pain in depressed patients. AB - OBJECTIVE: Suicidal behavior has been associated with structural and functional impairments in neuroimaging studies, mainly localized in the prefrontal cortex. However, little is known of the in vivo biochemical alterations that could be markers of suicidal risk. METHODS: Proton magnetic resonance spectroscopy was used to measure at-rest levels of 9 metabolites (glutamate, glutamine, glutathione, GABA, N-acetylaspartate (NAA), N-acetylaspartylglutamate, myo inositol, aspartate, total choline), in the right dorsal prefrontal cortex of 25 unmedicated depressed patients, including 15 with a history of suicidal behavior, and 33 healthy controls. We compared metabolite levels between groups, and run correlations with 9 clinical variables relevant for suicide risk. RESULTS: We found very significant associations between NAA levels and psychological pain measured by a simple analog scale (r=-0.47, p<10-3), and between choline levels and current suicidal ideas (r=0.53, p<10-3). These associations were independent from group, gender, age or depression level. While psychological pain and suicidal ideas were highly inter-correlated (r=0.61, p<10-3), the above-mentioned associations with compounds were independent. Mental pain was also correlated with Stroop interference, verbal fluency and (indirectly) decision-making, all cognitive measures previously associated with suicidal risk. Lower NAA levels, and higher glutamine levels were found in suicide attempters and in all patients relative to healthy controls, but these differences did not survive co-variation with age or Bonferroni's correction. CONCLUSION: This preliminary study suggests that markers of impaired neuronal and glial functioning in right dorsal prefrontal cortex underlie cardinal symptoms of the suicidal crisis. Targeting this region may be relevant for the short-term suicidal prevention. This study also supports a dimensional perspective in research on suicidal behavior. PMID- 27984160 TI - To which chemical mixtures is the French population exposed? Mixture identification from the second French Total Diet Study. AB - Through their diet, humans are exposed to a wide range of substances with possible adverse effects. Total diet studies (TDS) assess exposure and risk for many single substances or mixtures from the same chemical family. This research aims to identify from 440 substances in the second French TDS, the major mixtures to which the French population is exposed and their associated diet. Firstly, substances with a contamination value over the detection limit were selected. Secondly, consumption systems comprising major consumed foods were identified using non-negative matrix factorisation and combined with concentration levels to form the main mixture. Thirdly, individuals were clustered to identify "diet clusters" with similar consumption patterns and co-exposure profiles. Six main consumption systems and their associated mixtures were identified. For example, a mixture of ten pesticides, six trace elements and bisphenol A was identified. Exposure to this mixture is related to fruit and vegetables consumed by a diet cluster comprising 62% of women with a mean age of 51 years. Six other clusters are described with their associated diets and mixtures. Cluster co-exposures were compared to the whole population. This work helps prioritise mixtures for which it is crucial to investigate possible toxicological effects. PMID- 27984161 TI - Modulatory effects of Cassia fistula fruits against free radicals and genotoxicity of mutagens. AB - Cassia fistula L. (Fabaceae) fruits are highly recommended in folklore medicine for curing various ailments. In the current study, methanol (CaFM), hexane (CaFH), chloroform (CaFCl), ethyl acetate (CaFE), butanol (CaFB) and aqueous (CaFA) fractions of C. fistula fruits were investigated for their potential to inhibit the genotoxicity of mutagens and free radicals. The antimutagenicity of fractions was evaluated against the reactive carcinogenic ester generating mutagen, 2-aminofluorene (2-AF) and frame-shift mutation inducing mutagen, 4 nitro-o-phenylenediamine (NPD) in Ames Salmonella typhimurium TA98 tester strain. Among the fractions, CaFE showed strongest protective effect against the mutagenicity of both S9-dependent and direct-acting mutagen with an inhibitory percentage of 81% and 64% at the concentration of 1 * 103 and 2.5 * 103 respectively. All the fractions were analyzed for free radical scavenging activity using DPPH, nitric oxide, lipid peroxidation and superoxide anion assays. CaFE fraction showed maximum antioxidant activity in comparison to other fractions with an IC50 of 97.01, 172.36, 144 and 264.79 MUg/ml respectively. High performance liquid chromatography showed the presence of catechin, epicatechin and umbelliferone in appreciable amount which may account for its efficacy in combating free radicals and also showed protective effect against the mutagenicity of S9-dependent mutagen, 2-AF. PMID- 27984162 TI - Glycidamide inhibits progesterone production through reactive oxygen species induced apoptosis in R2C Rat Leydig Cells. AB - The food contaminant acrylamide (AA) is usually recognized as a probable human carcinogen. In addition, AA has also been found able to induce male infertility in animals. Interestingly, resent research work revealed that the toxic effect of AA on the ability of male reproduction in vivo may due to glycidamide (GA) which is the metabolite of AA. In this study, R2C Leydig cells was used to investigate the toxic effects of GA on progesterone production. GA caused dose-dependent inhibition on the cell growth, with IC25, IC50, and IC75 values found at 0.635, 0.872, and 1.198 mM, respectively. The results of single cell gel/Comet assay showed that GA significantly induced early-phase cell apoptosis, reduced progesterone production, as well as decreasing the protein expression of steroidogenic acute regulatory (StAR) in R2C cells. Furthermore, GA induced overproduction of intracellular reactive oxygen species (ROS), upregulated Bax expression, decreased mitochondrial membrane potential, and triggered mitochondria-mediated cell apoptosis. Consequently, the downstream effector caspase-3 was activated, resulting in Leydig cells apoptosis. Overall, our results showed that GA could damage R2C Leydig cells by the lesion of the ability of progesterone genesis and inducing cells apoptosis. PMID- 27984163 TI - Risk assessment of methylmercury in five European countries considering the national seafood consumption patterns. AB - Although seafood is a nutritious protein source, due to marine environmental pollution, seafood may also be a source of contaminants. The results obtained within the FP7-ECsafeSEAFOOD-project show that among the range of studied environmental contaminants certainly methylmercury (MeHg) requires deeper investigation. This paper presents the results of a probabilistic risk assessment for MeHg based on: (1) primary concentration data, as well as secondary data from published papers, and (2) primary species-specific consumption data collected in five European countries (Belgium, Ireland, Italy, Portugal and Spain). The results indicated that in the southern European countries, larger subgroups of the population (up to 11% in Portugal) are potentially at risk for a MeHg exposure above the Tolerable Weekly Intake (TWI) value, while this risk is much lower in Ireland and Belgium. This research confirms the substantial contribution of tuna to MeHg exposure in each of the countries. Also hake, cod, sea bream, sea bass and octopus are identified as important contributors. From this study, it is concluded that a country-specific seafood consumption advice is needed. Policy makers may adopt the results of this study in order to develop consumer advices that optimise health benefits versus potential health risks by providing species specific information. PMID- 27984164 TI - Timeline and bibliography of early isolations of plant metabolites (1770-1820) and their impact to pharmacy: A critical study. AB - Plant metabolites became objects of chemical research for pharmaceutical and medicinal reasons. The period of pure plant substances in chemistry started 1770 with isolation of tartaric acid from wine (wine in pharmacy is a plant-derived preparation). Carl Scheele isolated 7 plant acids: tartaric, benzoic, citric, oxalic, malic, glucuronic and gallic. The era of alkaloids started 1803 when narcotine was discovered and published. Since that time, pharmacists and toxicologists began to recognize alkaloids (or substances regarded as such) as highly active principles responsible for their powerful, thus easily-observed actions to humans and test animals. By 1820 when solanine was isolated, pharmaceutical chemistry has dealt with increasing number of natural plant derived substances as organic medicines or reagents. The following historical facts have been unknown: Scheele's tartaric acid was introduced officially as a medicinal substance as early as in 1775, benzoic, citric and oxalic acids became official by the end of the 18th century. Morphine was effectively published in 1806 (not 1804), hence the first alkaloid known in isolated state is narcotine (published 1803, official since 1827). Morphine became official in French pharmacy in 1818. And, 1814 is the year when 2 first toxicological accounts on plant-derived acids (oxalic and tartaric) appeared. Practical use in therapy, sometimes soon after discovery, inspired practical pharmacy and stimulated the progress of toxicology. We studied the earliest 50years of plant metabolites isolations era. A revised bibliography and a timeline chart for 24 plant substances from this period is provided. Plants from original publications are taxonomically identified. PMID- 27984165 TI - Bioactive constituents from the rhizomes of Dioscorea septemloba Thunb. AB - Eight new compounds, dioscorosides G (1), H1 (2), H2 (3), dioscorol B (4), dioscorosides I (5), J (6), K1 (7), and K2 (8), together with twelve known ones (9-20) were obtained from the rhizomes of Dioscorea septemloba. Their structures were elucidated by chemical and spectroscopic methods. Among the known isolates, 12-14, 18, and 20 were isolated from the Dioscoreae genus for the first time. While, 9-11, 15, and 16 were firstly obtained from the plant. Moreover, all the isolates were evaluated for in vitro anti-inflammatory potential using LPS stimulated RAW 264.7 murine macrophages, and compounds 7, 11, 15, and 16 were found to display significant inhibition of nitrite production. PMID- 27984167 TI - Sesquiterpenes from the whole plants of Parasenecio roborowskii. AB - Six eremophilane-type (parasenolide A-F) and an eudesmane-type (parasenin) sesquiterpenoids, along with eight known sesquiterpenes, were isolated from the whole plants of Parasenecio roborowskii. The structures and absolute configurations of new compounds were elucidated using extensive spectroscopic analysis, including HRESIMS, 1D and 2D NMR experiments, the CD exciton chirality methods, and single-crystal X-ray crystallography. All isolated compounds were evaluated for cytotoxicity against five human cancer (HeLa, HepG2, K562, MDA231, and NCI-H460) cell lines and a murine melanoma B16 F10 cell line by MTT assay. Compounds 1-15 showed cytotoxic activities, especially compounds 3, 4, 8, 10, and 12. These five compounds showed broad spectrum activities against all the tested cancer cell lines with IC50 ranging from 9.2 to 35.5MUM. The study supports that eremophilenolides and eudesmane-type sesquiterpenes occur mainly in the genus Parasenecio and can be used as a chemosystematic marker of the genus. PMID- 27984168 TI - The protective mechanism of docosahexaenoic acid in mouse model of Parkinson: The role of hemeoxygenase. AB - Parkinson's disease (PD) is characterized by degeneration of the dopaminergic neurons in substantia nigra (SN). Its major clinical symptoms are tremor, rigidity, bradykinesia and postural instability. Docosahexaenoic acid (DHA) is an essential fatty acid for neural functions that resides within the neural membrane. A decline in fatty acid concentration is observed in case of neurodegenerative diseases such as PD. The present study aimed to explore the role of the heme oxygenase (HO) enzyme in protective effects of DHA administration in an experimental model of PD by using the neurotoxin 1-Methly-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP). Three-month old male C57BL/6 mice were randomly divided into 4 groups as Control, DHA-treated (DHA), MPTP-injected (MPTP) and DHA-treated + MPTP injected (DHA + MPTP). DHA was administered daily (36 mg kg-1 day-1) by gavage to DHA and DHA + MPTP groups for 30 days. On the 23rd day of DHA administration, MPTP was intraperitoneally injected at a dose of 4 * 20 mg kg-1 with 2-hr. intervals. Motor activities of mice were evaluated by pole test, locomotor activity and rotarod tests on the 7th day of the utilization of experimental Parkinson's model. Total brain tissues were used in immunohistochemical analysis of the tyrosine hydroxylase (TH) and Nuclear factor E2 related factor2 (Nrf2). SN tissues were extracted for biochemical analysis. HO 1 and HO-2 protein levels were detected by western blotting. Further, HO activity was measured by spectrophotometric assay. As an indicator of motor coordination and balance, the rotarod test at 40 rpm showed that MPTP-treated animals exhibited shorter time on the rotating rod mill, which was significantly increased by DHA treatment in DHA + MPTP group. The total locomotor activity, ambulatory movement and total distance were decreased in MPTP group, whereas they were improved upon DHA treatment. The results of the pole test indicating the intensity of the bradykinesia showed that the T-turn and T-total were increased in MPTP group, while DHA treatment significantly shortened both parameters. The number of TH-positive cells in SN was significantly reduced in MPTP group compared to the Control and DHA + MPTP groups. Also, immunoreactive Nrf2 levels were clearly increased in MPTP group compared to DHA + MPTP group. HO-1 expression level decreased in the DHA + MPTP group compared to MPTP group. The results of the present study indicated that DHA has protective effects on dopaminergic neurons in MPTP-induced experimental model of PD. In addition, the pathways of HO-1 and HO-2 might participate in this protective mechanism. PMID- 27984169 TI - A novel splice variant of the Excitatory Amino Acid Transporter 5: Cloning, immunolocalization and functional characterization of hEAAT5v in human retina. AB - Excitatory Amino Acid Transporter 5 (EAAT5) is abundantly expressed by retinal photoreceptors and bipolar cells, where it acts as a slow glutamate transporter and a glutamate-gated chloride channel. The chloride conductance is large enough for EAAT5 to serve as an "inhibitory" glutamate receptor. Our recent work in rodents has shown that EAAT5 is differentially spliced and exists in many variant forms. The chief aim of the present study was to examine whether EAAT5 is also alternately spliced in human retina and, if so, what significance this might have for retinal function in health and disease. Retinal tissues from human donor eyes were used in RT-PCR to amplify the entire coding region of EAAT5. Amplicons of differing sizes were sub-cloned and analysis of sequenced data revealed the identification of wild-type human EAAT5 (hEAAT5) and an abundant alternately spliced form, referred to as hEAAT5v, where the open reading frame is expanded by insertion of an additional exon. hEAAT5v encodes a protein of 619 amino acids and when expressed in COS7 cells, the protein functioned as a glutamate transporter. We raised antibodies that selectively recognized the hEAAT5v protein and have performed immunocytochemistry to demonstrate expression in photoreceptors in human retina. We noted that in retinas afflicted by dry aged-related macular degeneration (AMD), there was a loss of hEAAT5v from the lesioned area and from photoreceptors adjacent to the lesion. We conclude that hEAAT5v protein expression may be perturbed in peri-lesional areas of AMD-afflicted retinas that do not otherwise exhibit evidence of damage. The loss of hEAAT5v could, therefore, represent an early pathological change in the development of AMD and might be involved in its aetiology. PMID- 27984170 TI - Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products. AB - The increasing incidence of autism suggests a major environmental influence. Epidemiology has implicated many candidates and genetics many susceptibility genes. Gene/environment interactions in autism were analysed using 206 autism susceptibility genes (ASG's) from the Autworks database to interrogate ~1 million chemical/gene interactions in the comparative toxicogenomics database. Any bias towards ASG's was statistically determined for each chemical. Many suspect compounds identified in epidemiology, including tetrachlorodibenzodioxin, pesticides, particulate matter, benzo(a)pyrene, heavy metals, valproate, acetaminophen, SSRI's, cocaine, bisphenol A, phthalates, polyhalogenated biphenyls, flame retardants, diesel constituents, terbutaline and oxytocin, inter alia showed a significant degree of bias towards ASG's, as did relevant endogenous agents (retinoids, sex steroids, thyroxine, melatonin, folate, dopamine, serotonin). Numerous other suspected endocrine disruptors (over 100) selectively targeted ASG's including paraquat, atrazine and other pesticides not yet studied in autism and many compounds used in food, cosmetics or household products, including tretinoin, soy phytoestrogens, aspartame, titanium dioxide and sodium fluoride. Autism polymorphisms influence the sensitivity to some of these chemicals and these same genes play an important role in barrier function and control of respiratory cilia sweeping particulate matter from the airways. Pesticides, heavy metals and pollutants also disrupt barrier and/or ciliary function, which is regulated by sex steroids and by bitter/sweet taste receptors. Further epidemiological studies and neurodevelopmental and behavioural research is warranted to determine the relevance of large number of suspect candidates whose addition to the environment, household, food and cosmetics might be fuelling the autism epidemic in a gene-dependent manner. PMID- 27984172 TI - Reply to: "Multiparametric magnetic resonance imaging to predict clinical outcomes in patients with chronic liver disease: A cautionary note on a promising technique". PMID- 27984173 TI - Multiparametric magnetic resonance imaging to predict clinical outcomes in patients with chronic liver disease: A cautionary note on a promising technique. PMID- 27984174 TI - Emergency TIPS in a Child-Pugh B patient: When does the window of opportunity open and close? AB - Transjugular intrahepatic portosystemic shunt (TIPS) is used to treat complications of cirrhosis such as variceal bleeding and refractory ascites, but it also bears the risk of liver failure, overt hepatic encephalopathy (HE) and cardiac decompensation. Variceal bleeding may be controlled using endoscopic and medical treatment in patients with compensated cirrhosis; in decompensated patients, however, TIPS improves survival. Therefore, an early TIPS (within 72h or if later, still early after bleeding) might improve the survival of patients by preventing an inflammatory response and bacterial translocation. Both these processes mediate an impaired immunological and hemodynamic response, thereby facilitating the development of acute-on-chronic liver failure (ACLF) and/or death. Similarly, in patients with refractory ascites, TIPS should be used early in treatment to prevent acute kidney injury (AKI) and hepatorenal syndrome (HRS) after precipitating events induced by complications of portal hypertension. Whether TIPS and/or embolization should be used to treat portal vein thrombosis and spontaneous shunts is still a matter of debate and should be further investigated. In summary, the careful selection of patients for TIPS is crucial. New biomarkers, especially those evaluating systemic inflammation and bacterial translocation, might improve the predictive value of established clinical parameters such as bilirubin and overt HE. However, a significant amount of further research must be carried out. PMID- 27984175 TI - New diagnostic criteria and management of acute kidney injury. PMID- 27984177 TI - Hydrogen sulfide inhibits giant depolarizing potentials and abolishes epileptiform activity of neonatal rat hippocampal slices. AB - Hydrogen sulfide (H2S) is an endogenous gasotransmitter with neuroprotective properties that participates in the regulation of transmitter release and neuronal excitability in various brain structures. The role of H2S in the growth and maturation of neural networks however remains unclear. The aim of the present study is to reveal the effects of H2S on neuronal spontaneous activity relevant to neuronal maturation in hippocampal slices of neonatal rats. Sodium hydrosulfide (NaHS) (100MUM), a classical donor of H2S produced a biphasic effect with initial activation and subsequent concentration-dependent suppression of network-driven giant depolarizing potentials (GDPs) and neuronal spiking activity. Likewise, the substrate of H2S synthesis l-cysteine (1mM) induced an initial increase followed by an inhibition of GDPs and spiking activity. Our experiments indicate that the increase in initial discharge activity by NaHS is evoked by neuronal depolarization which is partially mediated by a reduction of outward K+ currents. The subsequent decrease in the neuronal activity by H2S appears to be due to the rightward shift of activation and inactivation of voltage-gated Na+ currents, thus preventing network activity. NaHS also reduced N methyl-d-aspartate (NMDA)-mediated currents, without essential effect on AMPA/kainate or GABAA-mediated currents. Finally, H2S abolished the interictal like events induced by bicuculline. In summary, our results suggest that through the inhibitory action on voltage-gated Na+ channels and NMDA receptors, H2S prevents the enhanced neuronal excitability typical to early hippocampal networks. PMID- 27984176 TI - PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis. AB - BACKGROUND & AIMS: Mitochondrial dysfunction, oxidative stress, inflammation, and metabolic reprograming are crucial contributors to hepatic injury and subsequent liver fibrosis. Poly(ADP-ribose) polymerases (PARP) and their interactions with sirtuins play an important role in regulating intermediary metabolism in this process. However, there is little research into whether PARP inhibition affects alcoholic and non-alcoholic steatohepatitis (ASH/NASH). METHODS: We investigated the effects of genetic deletion of PARP1 and pharmacological inhibition of PARP in models of early alcoholic steatohepatitis, as well as on Kupffer cell activation in vitro using biochemical assays, real-time PCR, and histological analyses. The effects of PARP inhibition were also evaluated in high fat or methionine and choline deficient diet-induced steatohepatitis models in mice. RESULTS: PARP activity was increased in livers due to excessive alcohol intake, which was associated with decreased NAD+ content and SIRT1 activity. Pharmacological inhibition of PARP restored the hepatic NAD+ content, attenuated the decrease in SIRT1 activation and beneficially affected the metabolic-, inflammatory-, and oxidative stress-related alterations due to alcohol feeding in the liver. PARP1-/- animals were protected against alcoholic steatohepatitis and pharmacological inhibition of PARP or genetic deletion of PARP1 also attenuated Kupffer cell activation in vitro. Furthermore, PARP inhibition decreased hepatic triglyceride accumulation, metabolic dysregulation, or inflammation and/or fibrosis in models of NASH. CONCLUSION: Our results suggests that PARP inhibition is a promising therapeutic strategy in steatohepatitis with high translational potential, considering the availability of PARP inhibitors for clinical treatment of cancer. LAY SUMMARY: Poly(ADP-ribose) polymerases (PARP) are the most abundant nuclear enzymes. The PARP inhibitor olaparib (Lynparza) is a recently FDA approved therapy for cancer. This study shows that PARP is overactivated in livers of subjects with alcoholic liver disease and that pharmacological inhibition of this enzyme with 3 different PARP inhibitors, including olaparib, attenuates high fat or alcohol induced liver injury, abnormal metabolic alteration, fat accumulation, inflammation and/or fibrosis in preclinical models of liver disease. These results suggest that PARP inhibition is a promising therapeutic strategy in the treatment of alcoholic and non-alcoholic liver diseases. PMID- 27984178 TI - Endogenous modulation of TrkB signaling by treadmill exercise after peripheral nerve injury. AB - After peripheral nerve injury, transected fibers distal to the lesion are disconnected from the neuronal body. This results in target denervation but also massive stripping of the central synapses of axotomized motoneurons, disrupting spinal circuits. Even when axonal regeneration is successful, the non-specific target reinnervation and the limited rebuilding of spinal circuits impair functional recovery. Therefore, strategies aimed to preserve spinal circuits after nerve lesions may improve the functional outcome. Activity-dependent therapy in the form of early treadmill running reduces synaptic stripping, mainly of excitatory synapses, and the disorganization of perineuronal nets (PNNs) on axotomized motoneurons. The mechanism underlying these effects remains unknown, although the benefits of exercise are often attributed to an increase in the neurotrophin brain-derived neurotrophic factor (BDNF). In this study, tropomyosin related kinase (TrkB) agonist and antagonist were administered to rats subjected to sciatic nerve injury in order to shed light on the role of BDNF. The maintenance of synapses on axotomized motoneurons induced by treadmill running was partially dependent on TrkB activation. Treatment with the TrkB agonist at a low dose, but not at a high dose, prevented the decrease of excitatory glutamatergic synapses, and both doses increased the density of inhibitory synapses. TrkB inactivation counteracted only some of the positive effects exerted by exercise after nerve injury, such as maintenance of excitatory synapses surrounding motoneurons. Therefore, specific regimes of physical exercise are a better strategy to attenuate the alterations that motoneurons suffer after axotomy than pharmacological modulation of the TrkB pathway. PMID- 27984179 TI - Immunohistochemical analysis of huntingtin-associated protein 1 in adult rat spinal cord and its regional relationship with androgen receptor. AB - Huntingtin-associated protein 1 (HAP1) is a neuronal interactor with causatively polyglutamine (polyQ)-expanded huntingtin in Huntington's disease and also associated with pathologically polyQ-expanded androgen receptor (AR) in spinobulbar muscular atrophy (SBMA), being considered as a protective factor against neurodegenerative apoptosis. In normal brains, it is abundantly expressed particularly in the limbic-hypothalamic regions that tend to be spared from neurodegeneration, whereas the areas with little HAP1 expression, including the striatum, thalamus, cerebral neocortex and cerebellum, are targets in several neurodegenerative diseases. While the spinal cord is another major neurodegenerative target, HAP1-immunoreactive (ir) structures have yet to be determined there. In the current study, HAP1 expression was immunohistochemically evaluated in light and electron microscopy through the cervical, thoracic, lumbar, and sacral spinal cords of the adult male rat. Our results showed that HAP1 is specifically expressed in neurons through the spinal segments and that more than 90% of neurons expressed HAP1 in lamina I-II, lamina X, and autonomic preganglionic regions. Double-immunostaining for HAP1 and AR demonstrated that more than 80% of neurons expressed both in laminae I-II and X. In contrast, HAP1 was specifically lacking in the lamina IX motoneurons with or without AR expression. The present study first demonstrated that HAP1 is abundantly expressed in spinal neurons of the somatosensory, viscerosensory, and autonomic regions but absent in somatomotor neurons, suggesting that the spinal motoneurons are, due to lack of putative HAP1 protectivity, more vulnerable to stresses in neurodegenerative diseases than other HAP1-expressing neurons probably involved in spinal sensory and autonomic functions. PMID- 27984180 TI - Somatostatin receptor 5 is a prominent regulator of signaling pathways in cells with coexpression of Cannabinoid receptors 1. AB - Endocannabinoids and somatostatin (SST) play critical roles in several pathophysiological conditions via binding to different receptor subtypes. Cannabinoid receptor 1 (CB1R) and somatostatin receptors (SSTRs) are expressed in several brain regions and share overlapping functions. Whether these two prominent members of G-protein-coupled receptor (GPCR) family interact with each other and constitute a functional receptor complex is not known. In the present study, we investigated the colocalization of CB1R and SSTR5 in rat brain, and studied receptor internalization, interaction and signal transduction pathways in HEK-293 cells cotransfected with human cannabinoid receptor 1 (hCB1R) and hSSTR5. Our results showed that CB1R and SSTR5 colocalized in rat brain cortex, striatum, and hippocampus. CB1R was expressed in SSTR5 immunoprecipitate prepared from the brain tissue lysate, indicating their association in a system where these receptors are endogenously expressed. In cotransfected HEK-293 cells, SSTR5 and CB1R existed in a constitutive heteromeric complex under basal condition, which was disrupted upon agonist treatments. Furthermore, concurrent receptor activation led to preferential formation of SSTR5 homodimer and dissociation of CB1R homodimer. We also discovered that second messenger cyclic adenosine monophosphate and downstream signaling pathways were modulated in a SSTR5 dominant and concentration-dependent manner in the presence of receptor-specific agonist. In conclusion, with predominant role of SSTR5, the functional consequences of crosstalk between SSTR5 and CB1R resulting in the regulation of receptor trafficking and signal transduction pathways open new therapeutic avenue in cancer biology and excitotoxicity. PMID- 27984181 TI - AP-2alpha and AP-2beta regulate dorsal interneuron specification in the spinal cord. AB - To date, five AP-2 genes that encode AP-2alpha, beta, gamma, delta and epsilon have been identified in vertebrates and they have been reported to be key regulators of embryonic development. However, the role of AP-2 family members in the development of central nervous system (CNS) has not been characterized. In the present study, we systematically examined the spatiotemporal expression pattern of AP-2 genes in the developing spinal cord of mouse and chick embryos and found that AP-2alpha and AP-2beta are specifically expressed in post-mitotic dorsal interneurons. Loss-of-function analysis using in ovo electroporation in embryonic chick spinal cord preliminarily demonstrated that cAP-2alpha and cAP 2beta regulates dorsal Class A and Class B interneuron specification, respectively. Gain-of-function experiments further revealed that misexpression of cAP-2alpha, but not cAP-2beta, was able to induce the ectopic generation of Class A interneurons. Together, our studies indicated that AP-2 family members, AP 2alpha and AP-2beta, have distinct functions in the regulation of dorsal interneuron development. PMID- 27984182 TI - Contribution of Nav1.8 sodium channels to retinal function. AB - We examined the contribution of the sodium channel isoform Nav1.8 to retinal function using the specific blocker A803467. We found that A803467 has little influence on the electroretinogram (ERG) a- and b-waves, but significantly reduces the oscillatory potentials (OPs) to 40-60% of their original amplitude, with significant changes in implicit time in the rod-driven range. To date, only two cell types were found in mouse to express Nav1.8; the starburst amacrine cells (SBACs), and a subtype of retinal ganglion cells (RGCs). When we recorded light responses from ganglion cells using a multielectrode array we found significant and opposing changes in two physiological groups of RGCs. ON sustained cells showed significant decreases while transient ON-OFF cells showed significant increases. The effects on ON-OFF transient cells but not ON-sustained cells disappeared in the presence of an inhibitory cocktail. We have previously shown that RGCs have only a minor contribution to the OPs (Smith et al., 2014), therefore suggesting that SBACs might be a significant contributor to this ERG component. Targeting SBACs with the cholinergic neurotoxin ethylcholine mustard aziridinium (AF64A) caused a reduction in the amplitude of the OPs similar to A803467. Our results, both using the ERG and MEA recordings from RGCs, suggest that Nav1.8 plays a role in modulating specific aspects of the retinal physiology and that SBACs are a fundamental cellular contributor to the OPs in mice, a clear demonstration of the dichotomy between ERG b-wave and OPs. PMID- 27984183 TI - Repeated prenatal exposure to valproic acid results in cerebellar hypoplasia and ataxia. AB - Autism spectrum disorder (ASD) is a developmental brain disorder characterized by restricted and repetitive patterns of behavior, social and communication defects, and is commonly associated with difficulties with motor coordination. The etiology of ASD, while mostly idiopathic, has been linked to hereditary factors and teratogens, such as valproic acid (VPA). VPA is used clinically to treat epilepsy, mood disorders, and in the prevention of migraines. The use of VPA during pregnancy significantly increases the risk of ASD in the offspring. Neuropathological studies show decreased cerebellar function in patients with ASD, resulting in gait, balance and coordination impairments. Herein, we have exposed pregnant rats to a repeated oral dose of VPA on embryonic days 10 and 12 and performed a detailed investigation of the structure and function of the cerebellar vermis. We found that throughout all ten lobules of the cerebellar vermis, Purkinje cells were significantly smaller and expression of the calcium binding protein calbindin (CB) was significantly reduced. We also found that dendritic arbors of Purkinje cells were shorter and less complex. Additionally, animals exposed to a repeated dose of VPA performed significantly worse in a number of motor tasks, including beam walking and the rotarod. These results suggest that repeated embryonic exposure to VPA induces significant cerebellar dysfunction and is an effective animal model to study the cerebellar alterations in ASD. PMID- 27984184 TI - Electrophysiological characterization of the M-current in rat hypoglossal motoneurons. AB - The M-current (IM) is a voltage-dependent, persistent K+ current so termed because it is strongly inhibited by the cholinergic agonist muscarine. The IM main function is to limit neuronal excitability by contrasting action potential firing. Although motoneurons are sensitive to acetylcholine, the role of IM in modulating their excitability is still controversial. The aim of the present report was to examine the presence of IM in hypoglossal motoneurons (HMs) and its role in the modulation of firing properties using an in vitro model of rat brainstem slice. For this purpose, we employed the whole-cell patch-clamp technique to record HM responses upon stimulation with either a standard IM deactivation voltage protocol or depolarizing current steps. Voltage commands from depolarized potential induced inward relaxations with the common characteristics of IM, comprising inhibition by either muscarine (10MUM) or the selective IM inhibitor linopirdine (30MUM). IM was pharmacologically distinguished from the hyperpolarization-activated inward-rectifying current and, within the -20 to -50mV range, deactivated with >100-ms time constant. Current clamp experiments demonstrated that IM strongly regulated HM action potential firing, since both muscarine and linopirdine increased spike frequency whereas the M-channel opener retigabine (20MUM) reduced it. Conversely, IM seemed uninvolved in the generation of the medium afterhyperpolarizing potential. Our results suggest that HMs possess IM, whose pharmacological modulation is an important tool to up- or down-regulate excitability, to be explored in experimental models of neurodegeneration. PMID- 27984185 TI - Structural organization of the dendritic reticulum linked by gap junctions in layer 4 of the visual cortex. AB - Neuronal gap junctions are ubiquitous in the brain, but their precise positions in actual neuronal circuits have been uncertain, and their functional roles remain unclear. In this study, I visualized connexin36-immunoreactive gap junctions and examined the structural features of the interconnected dendrites arising from parvalbumin (PV)-positive interneurons in layer 4 of the feline visual cortex. I observed evidence for net-like dense linkages of dendrites among virtually all PV neurons (56/58 cells, 96.6%) in the tissue. This dendritic reticulum established connections among clustered cells and further among remote cells. The latter connectivity exhibited a preference for vertical direction, including translaminar linkages, but was also characterized by lateral continuity. Measurement of the distances from each dendritic gap junction back to the two connected somata revealed that at least one of two somata was within 50MUm from the junction in 77.5% of the cases and within 75MUm in 91.2% of the cases. Thus, distal gap junctions mediated morphologically asymmetrical connection where one soma was close to, but the other soma was far from the connecting junction. This connectivity was typically observed between neurons located apart in the same columnar space, where a long vertical dendrite bridged two neurons through an asymmetrically positioned gap junction. In contrast, gap junctions formed between nearby cells were close to both somata. Thalamocortical afferents established synapses densely on somata of layer 4 PV neurons, indicating the possible involvement of proximal gap junctions in visual stimulus driven feedforward regulation. These findings provide a new structural basis for cortical investigations. PMID- 27984186 TI - Immunolocalization of glutaryl-CoA dehydrogenase (GCDH) in adult and embryonic rat brain and peripheral tissues. AB - Glutaryl-CoA dehydrogenase (GCDH) is a mitochondrial enzyme that is involved in the degradation of tryptophan, lysine and hydroxylysine. Deficient enzyme activity leads to glutaric aciduria type-I (GA-I). This neurometabolic disease usually manifests with acute encephalopathic crises and striatal neuronal death in early childhood leading to an irreversible dystonic-dyskinetic movement disorder. Fronto-temporal atrophy and white matter changes are already present in the pre-symptomatic period. No detailed information on GCDH expression during embryonic development and in adulthood was available so far. Using immunofluorescence microscopy and cell-type-specific markers to localize GCDH in different tissues, we describe the differential cellular localization of GCDH in adult rat brain and peripheral organs as well as its spatiotemporal expression pattern. During embryonic development GCDH was predominantly expressed in neurons of the central and peripheral nervous system. Significant expression levels were found in epithelial cells (skin, intestinal and nasal mucosa) of rat embryos at different developmental stages. Besides the expected strong expression in liver, GCDH was found to be significantly expressed in neurons of different brain regions, renal proximal tubules, intestinal mucosa and peripheral nerves of adult rats. GCDH was found widely expressed in embryonic and adult rat tissues. In rat embryos GCDH is predominantly expressed in brain implying an important role for brain development. Interestingly, GCDH was found to be significantly expressed in different other organs (e.g. kidney, gut) in adult rats probably explaining the evolving phenotype in GA-I patients. PMID- 27984187 TI - A qualitative study of Southern U.S. consumers' top of the mind beliefs about the safety of local beef. AB - Following the Reasoned Action Approach, the aim of this study was to explore consumers' top-of-mind food safety beliefs about local beef. Beef consumers recruited from farmers' markets (N = 101) and grocery stores (N = 174) across the state of Alabama participated in face-to-face intercept surveys. The survey included closed- and open-ended questions designed to elicit consumers' food safety beliefs about local beef. Results indicate that beef safety was not a top of-mind concern for a majority of participants, however of the total number of participants familiar with the term "local beef" (n = 168, 61%), a majority (n = 105, 63%) associated local beef with improved food safety. Content analysis of verbatim text revealed that consumers believed local beef was safer because they possess greater knowledge about the product and less shipping was involved. Respondents also believe that locally processed meat is derived from small-scale operations which provided the assurance that local beef is more likely to meet U.S. regulatory standards and therefore be safer. Consumers believe they have more oversight of local beef due to both their relationships with supply chain actors and proximity which also provided food safety assurances. PMID- 27984188 TI - Postprandial suppression of appetite is more reproducible at a group than an individual level: Implications for assessing inter-individual variability. AB - Individual differences in appetite are increasingly appreciated. However, the individual day-to-day reliability of appetite measurement is currently uncharacterised. This study aimed to assess the reliability of appetite following ingestion of mixed-macronutrient liquid meals at a group and individual level. Two experiments were conducted with identical protocols other than meal energy content. During each experiment, 10 non-obese males completed four experimental trials constituting high- and low-energy trials, each performed twice. Experiment one employed 579 kJ (138 kcal) and 1776 kJ (424 kcal) liquid meals. Experiment two employed 828 (198 kcal) and 4188 kJ (1001 kcal) liquid meals. Visual analogue scales were administered to assess appetite for 60 min post-ingestion. The typical error (standard error of measurement) of appetite area under the curve was 6.2 mm?60 min-1 (95%CI 4.3-11.3 mm?60 min-1), 6.5 mm (95%CI 4.5-11.9 mm?60 min-1), 7.1 mm?60 min-1 (95%CI 4.9-12.9 mm?60 min-1) and 6.5 mm?60 min-1 (95%CI 4.5-11.8 mm?60 min-1) with the 579, 828, 1776 and 4188 kJ meals, respectively. A systematic bias between first and second exposure was detected for all but the 4188 kJ meal. The change in appetite with high-vs. low-energy meals did not differ at a group level between first and second exposure (mean difference: -0.97 mm?60 min-1; 95%CI -6.48-4.53 mm?60 min-1), however, ~50% of individuals differed in their response with first vs second exposure by more than the typical error. Appetite responses are more reliable when liquid meals contain a higher-vs lower energy content. Appetite suppression with high-vs low-energy meals is reproducible at the group- but not individual level, suggesting that multiple exposures to an intervention are required to understand true individual differences in appetite. PMID- 27984189 TI - A commentary on the "eating addiction" versus "food addiction" perspectives on addictive-like food consumption. AB - The food addiction construct posits that vulnerable individuals may experience an addictive-like response to certain foods, such as those high in fat and refined carbohydrates. Recently, an alternative model to food addiction was proposed, suggesting that the act of eating may be a behavioral addiction that can trigger an addictive-like response in susceptible individuals. One major rationale for the eating addiction framework is that the assessment of food addiction is based on behavioral indicators, such as consuming greater quantities of food than intended and eating certain foods despite negative consequences. It is also suggested that the lack of investigation into which foods and food attributes (e.g., sugar) may have an addictive potential is evidence that food addiction does not parallel a substance-based addiction and more closely resembles a behavioral addiction. The present paper provides a commentary suggesting that the substance-based, food-addiction framework is more appropriate than the behavioral addiction, eating-addiction perspective to conceptualize addictive-like food consumption. In order to illustrate this point, this manuscript will discuss behavioral components characteristic of all substance-use disorders, preliminary evidence to suggest that all foods are not equally associated with addictive-like eating, and key differences between the hypothesized eating addiction phenotype and the only existing behavioral addiction in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), gambling disorder. Further, this paper will consider implications of applying an addiction label to food versus eating and suggest future research directions to evaluate whether food addiction is a valid and clinically useful construct. PMID- 27984190 TI - Mutation screening of PDGFB gene in Chinese population with primary familial brain calcification. AB - BACKGROUND: Until recently, primary familial brain calcification (PFBC) has been determined by four genes, SLC20A2, PDGFRB, PDGFB and XPR1. No studies have been carried out to analyze the gene mutation of PDGFB in Chinese population. OBJECTIVE: To screen mutations of PDGFB gene in a large cohort of Chinese PFBC patients with no SLC20A2 mutations. METHODS: We recruited 192 PFBC patients, including 21 index cases and 171 sporadic cases, in our study. Peripheral venous blood samples of all included participants were collected for genomic DNA extraction. The coding sequence of PDGFB was amplified by polymerase chain reaction (PCR) followed by direct sequencing. The potential effects of the identified variants on protein function were assessed by bioinformatics analysis. RESULTS: Three missense variants (c.35G>T, c.232C>T, and c.610C>A) and one nonsense variant (c.220G>T) of PDGFB were identified in five sporadic PFBC patients. The variant c.35G>T was found in 2 healthy controls from the same ethnic background, whereas c.220G>T, c.232C>T and c.610C>A were absent from 500 controls. c.220G>T (p.E74*) produced a stop codon in the place of the glutamicacid residue number 74. c.232C>T (p.R78C) occurred at highly conserved regions and were predicted as damaging by at least two computational predictive programs, suggesting that this variant were likely to have a causal role in PFBC. Although variant c.610C>A (p.P204T) also occurred at a highly conserved region, it was predicted to be most likely benign by two computational predictive programs, suggesting an uncertain role of this variant on PFBC. CONCLUSIONS: The present study identified one likely pathogenic variant (p.E74*) and two variants of uncertain significance (p.R78C and p.P204T) in PDGFB. Further studies of PDGF B functional expression for these variants are still required to confirm the pathogenic effect. PMID- 27984191 TI - Association of a Vascular Endothelial Growth Factor genetic variant with Serum VEGF level in subjects with Metabolic Syndrome. AB - BACKGROUND: The metabolic syndrome (MetS) is a clustering of metabolic disorders that is associated with an increased risk of developing cardiovascular-disease, diabetes, and related diseases. Against this background, Vascular Endothelial Growth Factor (VEGF) plays an essential role in angiogenesis, vascular permeability, and hematopoiesis and its increased level is reported to be associated with increasing the risk of developing cardiovascular-disease, stroke and diabetes. Therefore the aim of present study was to explore the association of serum VEGF level and its associated genetic-polymorphism, rs10738760 (A>G) at 9p24.2, in 850 subjects with/without MetS. METHODS: MetS was defined according to the International-Diabetes-Federation criteria. Genotyping was carried out using Polymerase chain reaction-amplification refractory mutation system. Anthropometric/biochemical parameters, including FBG, Triglyceride, HDL, TC, etc., were determined followed by univariate and multivariate analyses. RESULTS: MetS patients had significantly higher levels of BMI, waist-circumference, cholesterol, triglyceride, Hs-CRP and SBP/DBP, while the HDL-C levels was lower in patients group, compared to control group (P<0.05). Moreover, our analysis showed that MetS patients with GA or AA genotypes had a significantly (P=0.03) higher serum level of VEGF. CONCLUSIONS: we demonstrate an association between a VEGF genetic variant with MetS, suggesting its role as a risk stratification factor for MetS. PMID- 27984194 TI - The human tRNA-modifying protein, TRIT1, forms amyloid fibers in vitro. AB - TRIT1 is a highly conserved tRNA isopentenyl transferase that modifies a subset of tRNAs in human cells and is a candidate tumor suppressor in lung cancer in certain ethnic populations. The yeast homologue, Mod5, has similar tRNA-modifying functions in the cytoplasm and is required for the transcriptional silencing activity of RNA polymerase II promoters near tRNA genes in the nucleus, a phenomenon termed tRNA gene mediated (tgm) silencing. Furthermore, Mod5 can fold into amyloid fibers in vitro and in vivo, which confers resistance to certain fungicides in yeast. Since TRIT1 complements both tRNA modifying and tgm silencing activities in yeast where the Mod5 gene has been deleted, it seemed possible that TRIT1 might also have amyloid-forming capabilities. Here we show that TRIT1, like Mod5, directly binds to tRNAs that are both substrate and non substrates for modification with similar affinity, and to an unstructured, non tRNA. Binding appears to involve distinct protein-RNA multimers which decrease in electrophoretic mobility as the protein to RNA ratio increases. Furthermore, we characterize TRIT1 as a novel human amyloid fiber forming protein. We discuss these data in light of TRIT1's functional roles and possible implications for disease. PMID- 27984193 TI - Structural characterization of the alpha-mating factor prepro-peptide for secretion of recombinant proteins in Pichia pastoris. AB - The methylotrophic yeast Pichia pastoris has been used extensively for expressing recombinant proteins because it combines the ease of genetic manipulation, the ability to provide complex posttranslational modifications and the capacity for efficient protein secretion. The most successful and commonly used secretion signal leader in Pichia pastoris has been the alpha mating factor (MATalpha) prepro secretion signal. However, limitations exist as some proteins cannot be secreted efficiently, leading to strategies to enhance secretion efficiency by modifying the secretion signal leader. Based on a Jpred secondary structure prediction and knob-socket modeling of tertiary structure, numerous deletions and duplications of the MATalpha prepro leader were engineered to evaluate the correlation between predicted secondary structure and the secretion level of the reporters horseradish peroxidase (HRP) and Candida antarctica lipase B. In addition, circular dichroism analyses were completed for the wild type and several mutant pro-peptides to evaluate actual differences in secondary structure. The results lead to a new model of MATalpha pro-peptide signal leader, which suggests that the N and C-termini of MATalpha pro-peptide need to be presented in a specific orientation for proper interaction with the cellular secretion machinery and for efficient protein secretion. PMID- 27984192 TI - The mitochondrial genome of the lepidopteran host cadaver (Thitarodes sp.) of Ophiocordyceps sinensis and related phylogenetic analysis. AB - To understand the phylogeny of the host insect (Thitarodes sp.) of the fungus Ophiocordyceps sinensis, we sequenced, annotated and characterized the complete mitochondrial (mt) genome of the host cadaver of a natural O. sinensis. Further, we compared the Thitarodes sp. mt genome with those of the other 7 sequenced Hepialidae and examined the phylogenetic relationships using a constructed Maximum Likelihood (ML) phylogenetic tree and mt genomic features (genetic distances and intergenic spacers). The mt genome is a circular molecule of 16,280bp in length with a high A+T content (81.20%) and contains 13 protein coding genes (PCGs), 2 rRNA genes, 22 tRNA genes and an AT-rich region. The gene arrangement is identical to the ancestral arrangement but differs from those of other lepidopteran mt genomes because of the arrangement of tRNA genes. The tRNA region, which is located between the AT-rich region and nad2, is trnI/trnQ/trnM (IQM) in Thitarodes sp., rather than the trnM/trnI/trnQ (MIQ) of the Lepidoptera specific rearrangement. All PCGs begin with the canonical start codons ATN or NTG, except for cox1, which starts with CGA. Most PCGs terminate with the typical stop codon TAA, although some have an incomplete stop codon (T). The 1473bp AT rich region is located between the rrnS (12S rRNA) and trnI, which is the longest sequenced in a Thitarodes mt genome to date, containing nine 112bp copies and one partial copy of a 55bp sequence. The results derived from the phylogenetic tree, the genetic distances and the intergenic spacers of the mt genome show that the host insect of O. sinensis belongs to the Thitarodes, while Endoclita signifer and Napialus hunanensis form a relatively distinct lineage from Thitarodes. The sequence and full annotation of this moth mt genome will provide more molecular information about the Exoporia within the Lepidoptera, and the clarification of its phylogeny will improve the management of this insect resource and the conservation and sustainable use of this endangered medicinal species in China. PMID- 27984195 TI - Abnormal mitochondrial dynamics and impaired mitochondrial biogenesis in trigeminal ganglion neurons in a rat model of migraine. AB - Accumulating evidence has demonstrated a possible role of mitochondrial dysfunction in migraine pathophysiology. Migraine sufferers exhibit impaired metabolic capacity, with an increased formation of reactive oxygen species (ROS). Mitochondrial dynamics and mitochondrial biogenesis are key processes regulating mitochondrial homeostasis. The aim of this study was to explore the alterations of mitochondrial regulatory networks in a rat model of migraine induced by repeated dural stimulation with inflammatory soup (IS). Ultrastructural, protein, gene and mitochondrial DNA analysis were applied to assess mitochondrial dynamics and biogenesis in trigeminal ganglion (TG) neurons. Mitochondria in TG neurons exhibited small and fragmented morphology after repeated dural stimulation. Further investigations showed that mitochondrial fission protein dynamin-related protein 1 (Drp1) was increased while mitochondrial fusion protein Mitofusin1 (Mfn1) was reduced in TG neurons. In addition, our results also presented that mitochondrial DNA copy number in TG neurons was reduced significantly, accompanied by alterations in mRNA and protein levels of regulatory factors related to mitochondrial biogenesis including peroxisome proliferator-activated receptor-gamma coactivator-1a (PGC-1alpha) and its downstream regulators in TG neurons in the IS-induced migraine model. These findings suggest that the mitochondrial dynamic regulatory networks are maladjusted in TG neurons in a rat model of migraine. Regulation of mitochondrial dynamics and biogenesis signaling may indicate a new mitochondria-targeted therapeutic strategy for migraine. PMID- 27984196 TI - Cutaneous afferent feedback from the posterior ankle contributes to proprioception. AB - Cutaneous mechanoreceptors in skin surrounding joints can respond to the skin strain generated by movement, and thus provide proprioceptive cues. The objective of this experiment was to determine the contribution of skin feedback from the posterior ankle to position sense during passive movements. In 28 healthy adults (12 male), a topical anesthetized (n=14) or placebo cream (n=14) was applied to an area of skin on the posterior ankle that undergoes stretch and compression during ankle dorsi- and plantar-flexion. Position sense was assessed before and after anesthetization using a passive joint matching task (target angles: 6 degrees , 12 degrees , and 18 degrees dorsiflexion and plantar flexion). Results showed that reducing skin feedback caused the perception that the ankles were aligned when the anesthetized ankle was relatively more dorsiflexed, suggesting that posterior ankle skin primarily signals the magnitude of skin stretch. Larger movement into dorsiflexion was likely necessary to provide enough stretch of muscle and surrounding intact skin to compensate for reduced signals from the anesthetized skin region. Reducing skin feedback also increased matching variability during larger movements. These findings suggest that skin feedback from the posterior ankle has a significant contribution to position sense during passive movement. Therefore, the sensitivity of skin surrounding the ankle could be important to consider in populations with reduced peripheral skin sensitivity as a result of ageing or neurological disorders. PMID- 27984197 TI - Chronic nicotine treatment decreases LPS signaling through NF-kappaB and TLR-4 modulation in the hippocampus. AB - The hippocampus is a brain region that is rich in nicotinic acetylcholine receptors (nAChRs), especially the alpha7 subtype. The hippocampus is severely affected in disorders that have a neuroinflammatory component, such as Alzheimer's disease, Parkinson's disease, and schizophrenia. Previous studies demonstrated both in vivo and in vitro that nicotine inhibits immunological responses, including those that are triggered by the inflammatory agent lipopolysaccharide (LPS), the endotoxin of Gram-negative bacteria. The present study investigated whether chronically administered nicotine interferes with the nuclear binding of nuclear factor-kappaB (NF-kappaB) and the expression of LPS induced inflammatory response genes. The results indicated that chronic nicotine administration (0.1mg/kg, s.c., 14days) inhibited the LPS-induced nuclear binding of NF-kappaB and mRNA expression levels of Tnf, Il1b, Nos2, and Tlr4. The presence of both the selective alpha7 nAChR antagonist methyllycaconitine (MLA; 5.0mg/kg i.p., 14days) and the nonselective nAChR antagonist mecamylamine (Meca; 1.0mg/kg, s.c., 14days) reversed the inhibitory effects of nicotine. These results suggest that the chronic activation of alpha7- and alphaxbetay-containing nAChRs reduces acute inflammatory responses in the brain. PMID- 27984198 TI - Effects of pregabalin on spinal d-serine content and NMDA receptor-mediated synaptic transmission in mice with neuropathic pain. AB - Pregabalin (PGB) is a chemical derivative of the inhibitory neurotransmitter gamma-aminobutyric acid, and is successfully used for the treatment of neuropathic pain. Substantial evidence suggests that d-serine, an endogenous co agonist at the strychnine-insensitive glycine site of the NMDA receptor, counteracts the antinociceptive actions of PGB at the level of the spinal cord. In the present study, we examined the impact of PGB treatment on spinal d-serine content and NMDA receptor-mediated synaptic transmission in the superficial dorsal horn of peripheral nerve-ligated neuropathic mice. Mechanical allodynia was assessed using von Frey filaments. On post-surgical day 9 (after 5days of treatment with PGB [50mg/kg] or saline vehicle), the lumbar spinal cord was removed, homogenized, and ultrafiltrated. Supernatant samples were treated with Marfey's reagent and analyzed with liquid chromatography-mass spectrometry to measure d-serine content. In the electrophysiological experiments, tight-seal whole-cell recording was performed on neurons in the superficial dorsal horn of spinal cord slices. Partial sciatic nerve ligation increased spinal d-serine content, increased the NMDA/non-NMDA ratio of EPSC amplitudes, and slowed the decay phase of the NMDA component of EPSCs (NMDA-EPSCs). PGB treatment attenuated mechanical allodynia and reduced spinal d-serine content, decreased the NMDA/non NMDA ratio, and shortened the decay time of NMDA-EPSCs. Furthermore, bath-applied d-serine attenuated the effects of PGB treatment. Although the precise mechanism for the effect of PGB on d-serine metabolism and abundance is unknown, the antinociceptive action of PGB likely involves the reduction of spinal d-serine content and subsequent attenuation of NMDA receptor-mediated synaptic transmission in the superficial dorsal horn. PMID- 27984199 TI - Midazolam impairs the retrieval of conditioned taste aversion via opioidergic transmission in mice. AB - Midazolam is a benzodiazepine agonist that affects the acquisition, retention, and retrieval of malaise-induced conditioned taste aversion (CTA) in rats. Our previous study suggested that the palatability-enhancing rather than amnesic effects of midazolam were responsible for impaired retrieval of conditioned aversion to palatable conditioned stimuli (CSs). However, it remains unclear whether this effect is opioid-dependent. In the present study, we examined the involvement of opioid signaling with the ability of peripheral midazolam administration to transiently impair CTA retrieval in mice. CTA was established by pairing 5mM saccharin ingestion (conditioned stimulus, CS) with an intraperitoneal (i.p.) injection of 0.15M lithium chloride (LiCl, 2% body weight) (unconditioned stimulus) for two consecutive days. Conditioned mice that received midazolam (1.5mg/kg, i.p.) before the first retention test consumed significantly more saccharin (CS) than conditioned mice that received vehicle (phosphate buffered physiological saline, PBS; i.p.). On the next day, both conditioned groups showed strong aversions to the CS. Next, naloxone, an opioid receptor antagonist, was peripherally administered prior to the midazolam injection before the retention test. Pre-administration of naloxone but not PBS attenuated midazolam-induced increases in CS intake. Finally, we examined aversive orofacial taste reactions (TRs) to an oral infusion of the CS with pre-administration of naloxone or PBS prior to midazolam using a taste reactivity test. Conditioned mice that received midazolam showed significantly longer latencies to express aversive orofacial TRs than those that received PBS. Pre-administration of naloxone eliminated the effect of midazolam on latency to express aversive TRs. Taken together, these data suggest that midazolam activates opioidergic transmission and opioid-dependent palatability enhancement of the CS to eliminate conditioned aversion to a sweet taste. PMID- 27984200 TI - Multi-system state shifts and cognitive deficits induced by chronic morphine during abstinence. AB - Chronic morphine administration induces neural plasticity followed by withdraw. And clinic observation indicates that obvious cognitive deficits are found during withdrawal. However, current neural substrates that regulate dysfunction in withdrawal are unknown. In our studies, chronic morphine administration was used to induce the spontaneous withdrawal model in rats. A series of cognitive abilities was tested to explore brain function. To further evaluate the neural substrates of dysfunction, Manganese-enhanced MRI(MEMRI) was used to map the dysfunctional regions in vivo.We observed that chronic morphine administration could induce obvious withdrawal behaviors in abstinence followed by cognitive impairments, such as impairments in working memory, reward, interaction and enhancement of anxiety. Our in-vivo MEMRI data using the voxel-wise comparisons showed that the manganese-enhanced signal intensity (VMI) within morphine withdrawal groups was increased in cingulate cortex (Cg), secondary motor cortex (M2), CA3 subfield of hippocampus, dorsal striatum (D-striatum), retrosplenial cortex (RS), shell subregion of NAc (AcbSh), core subregion of NAc (AcbC), central nucleus of amygdala (CeC), basolateral amygdaloid nucleus (BLA), central amygdaloid nucleus (CeM), anterior hypothalamic area, central (AHC), ventral tegmental area (VTA) and scaphoid thalamic nucleus (SC).However, decreasing of VMI was found in the ventrolateral striatum (V-striatum) and lateral posterior thalamic nucleus (LP) compared to the control group. These brain regions were beleived to be components of the memory, executive, limbic and regulatory systems. Therefore, our present studies indicate that withdrawal induced by chronic morphine adiministration could disturb brain function leading to multi systems state shifts and cognitive deficits in abstinence. PMID- 27984201 TI - Characterization of a new alpha-l-fucosidase isolated from Fusarium proliferatum LE1 that is regioselective to alpha-(1 -> 4)-l-fucosidic linkage in the hydrolysis of alpha-l-fucobiosides. AB - Here, we report the biochemical characterization of a novel alpha-l-fucosidase with broad substrate specificity (FpFucA) isolated from the mycelial fungus Fusarium proliferatum LE1. Highly purified alpha-l-fucosidase was obtained from several chromatographic steps after growth in the presence of l-fucose. The purified alpha-l-fucosidase appeared to be a monomeric protein of 67 +/- 1 kDa that was able to hydrolyze the synthetic substrate p-nitrophenyl alpha-l fucopyranoside (pNPFuc), with Km = 1.1 +/- 0.1 mM and kcat = 39.8 +/- 1.8 s-1. l fucose, 1-deoxyfuconojirimycin and tris(hydroxymethyl)aminomethane inhibited pNPFuc hydrolysis, with inhibition constants of 0.2 +/- 0.05 mM, 7.1 +/- 0.05 nM, and 12.2 +/- 0.1 mM, respectively. We assumed that the enzyme belongs to subfamily A of the GH29 family (CAZy database) based on its ability to hydrolyze practically all fucose-containing oligosaccharides used in the study and the phylogenetic analysis. We found that this enzyme was a unique alpha-l-fucosidase that preferentially hydrolyzes the alpha-(1 -> 4)-L-fucosidic linkage present in alpha-L-fucobiosides with different types of linkages. As a retaining glycosidase, FpFucA is capable of catalyzing the transglycosylation reaction with alcohols (methanol, ethanol, and 1-propanol) and pNP-containing monosaccharides as acceptors. These features make the enzyme an important tool that can be used in the various modifications of valuable fucose-containing compounds. PMID- 27984202 TI - Ribosome profiling reveals an adaptation strategy of reduced bacterium to acute stress. AB - Bacteria of class Mollicutes (mycoplasmas) feature significant genome reduction which makes them good model organisms for systems biology studies. Previously we demonstrated, that drastic transcriptional response of mycoplasmas to stress results in a very limited response on the level of protein. In this study we used heat stress model of M. gallisepticum and ribosome profiling to elucidate the process of genetic information transfer under stress. We found that under heat stress ribosomes demonstrate selectivity towards mRNA binding. We identified that heat stress response may be divided into two groups on the basis of absolute transcript abundance and fold-change in the translatome. One represents a noise like response and another is likely an adaptive one. The latter include ClpB chaperone, cell division cluster, homologs of immunoblocking proteins and short ORFs with unknown function. We found that previously identified read-through of terminators contributes to the upregulation of transcripts in the translatome as well. In addition we identified that ribosomes of M. gallisepticum undergo reorganization under the heat stress. The most notable event is decrease of the amount of associated HU protein. In conclusion, only changes of few adaptive transcripts significantly impact translatome, while widespread noise-like transcription plays insignificant role in translation during stress. PMID- 27984203 TI - UCP1: A transporter for H+ and fatty acid anions. AB - Adaptive thermogenesis regulates core body temperature, controls fat deposition, and contributes strongly to the overall energy balance. This process occurs in brown fat and requires uncoupling protein 1 (UCP1), an integral protein of the inner mitochondrial membrane. Classic biochemical studies revealed the general principle of adaptive thermogenesis: in the presence of long-chain fatty acids (FA), UCP1 increases the permeability of the inner mitochondrial membrane for H+, which makes brown fat mitochondria produce heat rather than ATP. However, the exact mechanism by which UCP1 increases the membrane H+ conductance in a FA dependent manner has remained a fundamental unresolved question. Recently, the patch-clamp technique was successfully applied to the inner mitochondrial membrane of brown fat to directly characterize the H+ currents carried by UCP1. Based on the patch-clamp data, a new model of UCP1 operation was proposed. In brief, FA anions are transport substrates of UCP1, and UCP1 operates as an unusual FA anion/H+ symporter. Interestingly, in contrast to short-chain FA anions, long-chain FA anions cannot easily dissociate from UCP1 due to strong hydrophobic interactions established by their carbon tails, and a single long chain FA participates in many H+ transport cycles. Therefore, in the presence of long-chain FA, endogenous activators of brown fat thermogenesis, UCP1 effectively operates as an H+ uniport. In addition to their transport function, long-chain FA competitively remove tonic inhibition of UCP1 by cytosolic purine nucleotides, thus enabling activation of the thermogenic H+ leak through UCP1 under physiological conditions. PMID- 27984205 TI - Definition of insulin resistance affects prevalence rate in pediatric patients: a systematic review and call for consensus. AB - BACKGROUND: As a result of the rising prevalence of childhood obesity, there is an increasing interest in the type 2 diabetes mellitus precursor insulin resistance (IR). The aim of this study is to review definitions (methods and cutoff values) to define IR in children and to apply these definitions to a previously described obese pediatric population. METHODS: A systematic literature review on prevalence and/or incidence rates in children was performed. The extracted definitions were applied to an obese pediatric population. RESULTS: In the 103 identified articles, 146 IR definitions were reported based on 14 different methods. Fasted definitions were used 137 times, whereas oral/intravenous glucose tolerance test-derived methods were used nine times. The homeostasis model for the assessment of insulin resistance (HOMA-IR) and fasted plasma insulin (FPI) were the most frequently used fasted methods (83 and 37 times, respectively). A wide range in cutoff values to define IR was observed, resulting in prevalence rates in the predefined obese pediatric population between 5.5% (FPI>30 mU/L) and 72.3% (insulin sensitivity indexMatsuda<=7.2). CONCLUSIONS: To compare IR incidence and prevalence rates in pediatric populations, a uniform definition of IR should be defined. PMID- 27984206 TI - Correction: Polarized cell migration induces cancer type-specific CD133/integrin/Src/Akt/GSK3beta/beta-catenin signaling required for maintenance of cancer stem cell properties. PMID- 27984204 TI - Noninvasive diagnosis of chronic kidney diseases using urinary proteome analysis. AB - Background: In spite of its invasive nature and risks, kidney biopsy is currently required for precise diagnosis of many chronic kidney diseases (CKDs). Here, we explored the hypothesis that analysis of the urinary proteome can discriminate different types of CKD irrespective of the underlying mechanism of disease. Methods: We used data from the proteome analyses of 1180 urine samples from patients with different types of CKD, generated by capillary electrophoresis coupled to mass spectrometry. A set of 706 samples served as the discovery cohort, and 474 samples were used for independent validation. For each CKD type, peptide biomarkers were defined using statistical analysis adjusted for multiple testing. Potential biomarkers of statistical significance were combined in support vector machine (SVM)-based classifiers. Results: For seven different types of CKD, several potential urinary biomarker peptides (ranging from 116 to 619 peptides) were defined and combined into SVM-based classifiers specific for each CKD. These classifiers were validated in an independent cohort and showed good to excellent accuracy for discrimination of one CKD type from the others (area under the receiver operating characteristic curve ranged from 0.77 to 0.95). Sequence analysis of the biomarkers provided further information that may clarify the underlying pathophysiology. Conclusions: Our data indicate that urinary proteome analysis has the potential to identify various types of CKD defined by pathological assessment of renal biopsies and current clinical practice in general. Moreover, these approaches may provide information to model molecular changes per CKD. PMID- 27984207 TI - Acquired Exchange Protein Directly Activated by Cyclic Adenosine Monophosphate Activity Induced by p38 Mitogen-activated Protein Kinase in Primary Afferent Neurons Contributes to Sustaining Postincisional Nociception. AB - BACKGROUND: The molecular mechanisms responsible for sustained pain after tissue injury are largely unknown. The aim of this study was to clarify the role of exchange protein directly activated by cyclic adenosine monophosphate (EPAC) in sustained postincisional nociception, using tissue injury-induced nociceptor priming, and involvement of p38 mitogen-activated protein kinase (p38MAPK) in EPAC-mediated nociceptor priming. METHODS: Plantar incisions were made in the hind paws of Sprague-Dawley rats (n = 144). Nociceptor priming was confirmed by behavior testing followed by prostaglandin E2 injection 14 to 21 days after the incision. ESI-09, a selective EPAC inhibitor, was administered to assess its effects on nociceptor priming. Expression of two isoforms of EPAC (EPAC1/EPAC2) in dorsal root ganglions from naive rats and those 14 days after the incision was detected by immunohistochemistry and Western blotting. Separately, FR167653, a selective p38MAPK inhibitor, was administered to assess its effect on EPAC1/EPAC2 expression and the development of nociceptor priming. RESULTS: Prostaglandin E2 injection 14 to 21 days after the plantar incision induced persistent mechanical hyperalgesia for 7 days. EPAC1/EPAC2 expression in dorsal root ganglion neurons was trivial in naive rats (7.7 +/- 4.8% for EPAC1; 6.3 +/- 4.1% for EPAC2) but markedly increased 14 days after the incision (21.0 +/- 9.4% and 20.1 +/- 3.8%, respectively). ESI-09 treatment inhibited prostaglandin E2-induced persistent mechanical hypersensitivity but had no effect on incision-induced acute nociceptive hypersensitivity. Treatment with FR167653 before the incision inhibited the development of nociceptor priming and incision-induced EPAC1/EPAC2 expression (8.5 +/- 5.4% and 7.6 +/- 3.3%, respectively). CONCLUSIONS: Transient inflammatory stimulation causes long-lasting nociceptive hypersensitivity via nociceptor priming during the subacute period after incision. Acquired EPAC activity by p38MAPK in the dorsal root ganglion neurons is a key for this event. PMID- 27984208 TI - Oral administration of grape seed polyphenol extract restores memory deficits in chronic cerebral hypoperfusion rats. AB - Chronic cerebral hypoperfusion (CCH) has been recognized as an important cause of both vascular dementia and Alzheimer's disease (AD), the two most prominent neurodegenerative diseases causing memory impairment in the elderly. However, an effective therapy for CCH-induced memory impairment has not yet been established. Grape seed polyphenol extract (GSPE) has powerful antioxidant properties and protects neurons and glia during ischemic injury, but its potential use in the prevention of CCH-induced memory impairment has not yet been investigated. Here, CCH-related memory impairment was modeled in rats using permanent bilateral occlusion of the common carotid artery. A Morris water maze task was used to evaluate memory, the levels of acetylcholinesterase, choline acetyltransferase, acetylcholine were used to evaluate cholinergic function, and oxidative stress was assessed by measuring the enzyme activity of superoxide dismutase, glutathione peroxidase, malonic dialdehyde, and catalase. We found that oral administration of GSPE for 1 month can rescue memory deficits. We also found that GSPE restores cholinergic neuronal function and represses oxidative damage in the hippocampus of CCH rats. We propose that GSPE protects memory in CCH rats by reducing ischemia-induced oxidative stress and cholinergic dysfunction. These findings provide a novel application of GSPE in CCH-related memory impairments. PMID- 27984211 TI - Perihilar Glissonian Approach for Anatomical Parenchymal Sparing Liver Resections: Technical Aspects: The Taping Game. AB - OBJECTIVE: To present technical details for central hepatectomy and right anterior and posterior sectionectomies using perihilar Glissonian approach for anatomical delineation and selective inflow occlusion. BACKGROUND: Central tumors and those deeply located in the right liver may require extensive resections because of their proximity to major vascular structures. In such cases, anatomical more limited resections such as central hepatectomy or sectionectomies may provide an alternative to extensive surgery by assuring both parenchymal sparing and suitable oncologic resection. METHODS: We present the global concept for performing a perihilar Glissonian approach and its application to each individual anatomical procedure. This includes detailed descriptions, illustrations, and videos demonstrating the technique. RESULTS: This technique was applied since 1991 for anatomical parenchymal resections including central hepatectomy (resection of segments 4, 5, and 8), right anterior sectionectomy (resection of segments 5 and 8), and right posterior sectionectomy (resection of segments 6 and 7). The feasibility rate of the Glissonian approach was 88%. CONCLUSIONS: Perihilar Glissonian approach is a safe and reproducible technique that enables anatomical parenchymal preserving liver resections for selected central and right-sided deeply located tumors. PMID- 27984209 TI - Inhibition of glycogen synthase kinase-3 by SB 216763 affects acquisition at lower doses than expression of amphetamine-conditioned place preference in rats. AB - Dopamine (DA) drives incentive learning, whereby neutral stimuli acquire the ability to elicit responses. DA influences the signaling molecule glycogen synthase kinase-3 (GSK3). Inhibition of GSK3 attenuates the development of behavioral sensitization to stimulant drugs and conditioned place preference (CPP), a measure of incentive learning. We examined the role of GSK3 in the nucleus accumbens (NAc) of rats in CPP produced by amphetamine (1.5 mg/kg, i.p. or 20.0 MUg/0.5 MUl/side intra-NAc) by administering the inhibitor SB 216763 (1.0, 2.0, and 2.5 mg/kg, i.p. or 0.03, 0.30, 3.00, and 5.00 MUg/0.5 MUl/side intra-NAc) during acquisition or expression. We hypothesized a dose-dependent effect of SB 216763 and that acquisition would be affected by smaller doses than expression. For the systemic groups, 1.0 mg/kg of SB 216763 did not block CPP; 2.0 mg/kg administered in acquisition but not expression blocked CPP; and 2.5 mg/kg administered in either phase blocked CPP. For the central groups, 0.03 MUg/0.5 MUl/side of SB 216763 prevented acquisition but not expression, whereas larger doses administered in either phase blocked CPP. Thus, systemic or NAc inhibition of GSK3 by SB 216763 during acquisition or expression blocks amphetamine-produced CPP and acquisition is sensitive to lower doses than expression. PMID- 27984212 TI - A Highly Predictive Model for Diagnosis of Colorectal Neoplasms Using Plasma MicroRNA: Improving Specificity and Sensitivity. PMID- 27984210 TI - Hypertensive Crisis From the Aquamantys Bipolar Sealing System. AB - Hypertension is a common occurrence during general anesthesia. Apart from pathological causes of hypertension, it is rarely extreme enough to be classified as a hypertensive crisis (systolic blood pressure >180 mm Hg or diastolic blood pressure >120 mm Hg). There is literature concerning the unintentional electrocauterization of the adrenal gland leading to hypertensive crisis, but to date, no reports have been made of adrenal stimulation from the use of an Aquamantys for hemostasis. Here, we report such a case when a hypertensive crisis (systolic blood pressure >300 mm Hg) occurred while using an Aquamantys during a liver transplant after unintentional stimulation of the adrenal glands. PMID- 27984213 TI - Critical View of the Myopectineal Orifice. PMID- 27984214 TI - Comparison of Preoperative Inflammation-based Prognostic Scores in Patients With Colorectal Cancer. AB - OBJECTIVE: To evaluate the prognostic impact of the systemic inflammation score (SIS) in colorectal cancer (CRC) patients in comparison with a conventional inflammation-based score, the modified Glasgow Prognostic Score (mGPS). SUMMARY BACKGROUND DATA: The SIS, which is calculated based on the preoperative serum albumin level and lymphocyte-to-monocyte ratio, is a reported prognostic marker in clear-cell renal cell carcinoma. However, the utility of the SIS in CRC remains unclear. METHODS: The study involved 727 CRC patients who underwent curative resection between September 2005 and December 2011. The prognostic impact of SIS and mGPS was evaluated using survival analyses. The prognostic impact of each score was compared visually by means of time-dependent receiver operating characteristics analysis. RESULTS: The median age of the patients was 67 (interquartile range: 58-75) years. The TNM stage distribution was stage I, 29.8%; stage II, 33.6%; stage III, 30.3%; and stage IV, 6.3%. The median follow up period was 5.61 years (interquartile range: 4.24-7.06). Multivariate analysis revealed that an increased SIS and mGPS were independent prognostic factors (SIS: P = 0.018; mGPS: P = 0.005, respectively). The time-dependent receiver operating characteristics curve of the SIS was superior to that of the mGPS throughout the observation period. The estimated area under the curve (AUC) of the SIS was significantly higher than that of the mGPS (7-yr survival: SIS 0.673, mGPS 0.605, P = 0.030). CONCLUSIONS: The SIS is a novel prognostic factor in CRC patients. Additionally, the SIS is an alternative inflammation-based biomarker, which may improve the prediction of clinical outcomes. PMID- 27984215 TI - Psychosocial Evaluation for First Hand Allotransplantation in Taiwan. AB - Hand transplantation has raised ethical and psychological concerns. Few studies have focused on reasons for not selecting candidates on waiting lists. To describe the psychosocial evaluation of referred prospective hand transplant candidates, we investigated candidate suitability by using 22-month follow-up data regarding the first hand transplant recipient in Taiwan. Pretransplant psychosocial assessments comprised an interview with 2 psychiatrists, a social worker, and a psychologist, followed by intelligence quotient scoring with the Wechsler Adult Intelligence Scale and Taiwanese Depression Questionnaire. After team member consensus, of the 20 patients referred to our team to confirm their hand transplantation suitability during April 26, 2013, to March 19, 2015, 7 potential recipients were placed on the waiting list after completing all prehand transplant evaluations. On September 3, 2014, the left distal forearm and hand of a brain-dead man was transplanted to a 45-year-old man who had undergone traumatic amputation of the distal third of his right forearm 30 years previously. During a 22-month follow-up, he complied with scheduled visits, including routine posttransplant laboratory tests, skin biopsies, and intensive physical therapy. Moreover, he overcame repeated graft rejections, bacterial and viral infections, immunosuppressant side effects, considerable economic stress, and the difficulties associated with the adhesion of hand tendons. Finally, he regained some satisfactory function of the transplanted hand. Considering posttransplantation difficulties, suitable candidates for hand transplantation should have persistent motivation, appropriate expectations, patience, immediate availability, fair intelligence, fair social functioning, and adequate economic and familial support. PMID- 27984216 TI - Fingertip Replantation With Palmar Venous Anastomoses in Children. AB - BACKGROUND: Fingertip amputation in children is difficult to manage using microsurgical replantation techniques and many salvage procedures have failed owing to the nonavailability of suitable veins for anastomosis in the fingertip. This study reviewed our experience of pediatric fingertip replantation involving palmar venous anastomoses and evaluated the clinical outcomes. METHODS: From October 2008 to May 2013, 21 pediatric fingertips that had been completely amputated at or distal to the distal interphalangeal joint of the finger, or at or distal to the interphalangeal joint of the thumb were managed using complete replantation. One artery was anastomosed for revascularization with or without nerve repair, and a palmar venous anastomosis was performed to reestablish the outflow system. RESULTS: Twenty (95.2%) of the 21 fingertips survived. One replant involving an avulsion amputation of the left little finger failed, and the patient underwent stump cap-plasty. Excellent restoration of finger motion, pinch strength, and appearance was observed during the mean 39.9-month (range, 18 65 months) follow-up. The mean regained static 2-point discrimination sensation was 3.8 mm (range, 3.2-4.2 mm). All of the children and their families were satisfied with the surgical outcomes. CONCLUSIONS: Successful palmar venous anastomosis appears to promote the survival of replanted fingertips in children. Given that the procedure may simplify postoperative care, minimize complications, and achieve a high survival rate, it should be attempted if the technical expertise is available. PMID- 27984217 TI - Using Levator Aponeurosis to Create Physiologically Natural Double Eyelid: A New Reconstruction Technique Based on Three Key Factors in Double Eyelid Formation. AB - BACKGROUND: Double eyelidplasty has 3 key factors: motor power, connecting tissue, and skin adhesion. OBJECTIVE: To create natural double eyelid, new anatomy structure should be rebuilt according to physiological double eyelid in these 3 aspects. METHODS: Levator aponeurosis is used as "connecting tissue" to transmit dynamic "motor power" of levator muscle to upper eyelid, and "skin adhesion" is induced between levator aponeurosis and skin in a plane manner. Postoperation evaluation includes stability of double eyelid, asymmetry, double fold curve, and scar formation. RESULTS: A total of 119 patients were operated on in this study. Two hundred fourteen eyes (89.9%) showed good fold curve and 13 eyes (5.5%) showed fair results. No scar on the upper eyelid was encountered, 24 patients (20.2%) had fair scar formation and 89 patients (74.8%) had no prominent scar. CONCLUSIONS: This novel surgical technique utilized pretarsal levator aponeurosis as the connecting material to bridge levator muscle and upper eyelid skin; by establishing a direct force transmission mechanism, palpebral crease is created in a more natural way in terms of anatomy and physiology. Furthermore, skin adhesion is formed between levator aponeurosis and dermis in a planar manner, allowing for more stable palpebral crease and more preserved orbicularis oculi in situ, thereby minimizing eyelid scar formation. PMID- 27984219 TI - One Stage Aesthetic and Functional Reconstruction of Major Lower Lip Defects. AB - INTRODUCTION: Multiple techniques have been used for reconstruction of large defects of the lower lip. However, some complications, such as microstomia, distortion of oral commissure, lip functional problems, and sensory loss might occur with these techniques. The aim of this work is to evaluate a new method of reconstruction of large lower lip defects after excision of squamous cell carcinoma. PATIENTS AND METHODS: Eighteen patients with lower lip squamous cell carcinomas were managed with this new technique of reconstruction using dermal fat flap, mucobuccal flap, and muscle transfer after excision of the tumor with 1 cm safety margin on both sides. The functional and aesthetic assessments were performed at least 6 months after surgery, and the results were compared statistically with a control group. RESULTS: Of the 18 patients, sensibility was normal in 16 (89%) and complete competence was determined in all cases (100%). In 17 patients (94%), complete and symmetric pouting and mouth-opening movements were ensured. Interlabial measurements would be better in all patients. Nasolabial asymmetry was detected in 1 patient (6%) and apparent mentolabial scar tissue was detected in 2 patients (11%). The new vermilion was of equal width to the upper lip vermilion in 15 patients (83%). CONCLUSIONS: Based on our results, this technique could be considered a good choice for repair of major lip defects. In addition, using this technique will give good aesthetic and functional results. PMID- 27984218 TI - Treatment of Head and Neck Melanoma In Situ With Staged Contoured Marginal Excisions. AB - Staged marginal evaluation of melanoma in situ (MIS) is performed to avoid reconstruction on positive margins. Contoured marginal excision (CME) is an excision of a 2-mm wide strip of normal-appearing skin taken approximately 5 mm from the visible tumor periphery. If positive, a new CME is excised; the tumor is resected once negative margins are confirmed. The purpose of this study is to report our experience using this technique for the treatment of head/neck MIS. Clinicopathological data were abstracted for all patients who underwent staged CME followed by central tumor resection for head/neck MIS; patients with invasive melanoma were excluded. Statistical analyses included chi test and t test. Overall, 127 patients with MIS were identified. Fifty-six percent were men; the average age was 68 years. The median number of CME procedures per patient was 1 (range, 1-4). Twenty-three percent of patients required more than 1 CME procedure to achieve negative margins. Local recurrence occurred in 3 of 127 patients after a median follow-up of 5 months. Patients requiring multiple CME procedures were more likely to experience local recurrence (P < 0.001). In conclusion, this technique is an effective method to avoid reconstruction on positive MIS margins with high local disease control rates. PMID- 27984220 TI - Molecular Mechanism of the "Babysitter" Procedure for Nerve Regeneration and Muscle Preservation in Peripheral Nerve Repair in a Rat Model. AB - OBJECTIVE: To investigate the molecular mechanism of nerve "babysitter" for nerve regeneration and muscle preservation in peripheral nerve repair. METHODS: Eighty rats were equalized into 4 groups: peroneal nerve transected, group A received no treatment; group B underwent end-to-end repair; group C underwent end-to-side "babysitter" with donor epineurial window; group D underwent end-to-side "babysitter" with 40% donor neurectomy. During second-stage procedure, end-to-end neurorrhaphies were executed in groups A, C, and D. Expression of Insulin-like growth factor (IGF)-1 in spinal cord and IGF-1, TNF-like weak inducer of apoptosis (TWEAK), and Fn14 in anterior tibial muscles were evaluated by histopathology at 4-, 8-, 12-, and 24-week timepoints postoperatively. RESULTS: At 4 weeks, group D expressed comparable IGF-1 with group B, and greater value than groups A and C in spinal cord. By 24 weeks, groups B and D showed higher values than groups A and C. Insulin-like growth factor 1 in muscles were greater in groups C and D than in groups A and B at 4 weeks, and comparable in all groups at 24 weeks. At 4 weeks, immunoreactive scores of TWEAK were 9.00 +/- 0, 3.00 +/- 0, 6.75 +/- 0.75, and 6.75 +/- 0.75, respectively. No differences were noticed in all groups by 24 weeks. At 4 weeks, Fn14 were similar in groups A, C, and D, but lower in group B. Group D showed comparable Fn14 with groups B and C, but lower value than group A at 24 weeks. CONCLUSIONS: End-to-side nerve "babysitter" in peripheral nerve could promote fiber regeneration and muscle preservation by regulating expression of IGF-1 and TWEAK-Fn14. End-to-side "babysitter" with partial donor neurectomy could achieve comparable effects with end-to-end repair. PMID- 27984221 TI - Strengthening Rehabilitation in Health Systems Worldwide by Integrating Information on Functioning in National Health Information Systems. AB - A complete understanding of the experience of health requires information relevant not merely to the health indicators of mortality and morbidity but also to functioning-that is, information about what it means to live in a health state, "the lived experience of health." Not only is functioning information relevant to healthcare and the overall objectives of person-centered healthcare but to the successful operation of all components of health systems.In light of population aging and major epidemiological trends, the health strategy of rehabilitation, whose aim has always been to optimize functioning and minimize disability, will become a key health strategy. The increasing prominence of the rehabilitative strategy within the health system drives the argument for the integration of functioning information as an essential component in national health information systems.Rehabilitation professionals and researchers have long recognized in WHO's International Classification of Functioning, Disability and Health the best prospect for an internationally recognized, sufficiently complete and powerful information reference for the documentation of functioning information. This paper opens the discussion of the promise of integrating the ICF as an essential component in national health systems to secure access to functioning information for rehabilitation, across health systems and countries. PMID- 27984222 TI - Succinylcholine for Emergency Airway Rescue in Class B Ambulatory Facilities: The Society for Ambulatory Anesthesia Position Statement. AB - Procedures in class B ambulatory facilities are performed exclusively with oral or IV sedative-hypnotics and/or analgesics. These facilities typically do not stock dantrolene because no known triggers of malignant hyperthermia (ie, inhaled anesthetics and succinylcholine) are available. This article argues that, in the absence of succinylcholine, the morbidity and mortality from laryngospasm can be significant, indeed, higher than the unlikely scenario of succinylcholine triggered malignant hyperthermia. The Society for Ambulatory Anesthesia (SAMBA) position statement for the use of succinylcholine for emergency airway management is presented. PMID- 27984224 TI - Meeting Report: 38th Annual Scientific Meeting and Workshops of the Society of Cardiovascular Anesthesiologists. PMID- 27984223 TI - Multimodal Analgesic Therapy With Gabapentin and Its Association With Postoperative Respiratory Depression. AB - BACKGROUND: Gabapentinoids are widely used in perioperative multimodal analgesic regimens. The primary aim of this study was to determine whether gabapentin was associated with respiratory depression during phase-I postanesthesia recovery after major laparoscopic procedures. METHODS: We retrospectively reviewed the electronic health records of 8567 patients who underwent major laparoscopic procedures (lasting >=90 minutes) from January 1, 2010, to July 31, 2014. We assessed potential associations among patient and perioperative variables and episodes of respiratory depression during phase-I recovery. Multivariable and propensity score-matched analyses were performed to assess potential associations between preoperative gabapentin use and postoperative respiratory depression. RESULTS: The incidence of respiratory depression was 153 (95% confidence interval [CI], 146-161) episodes per 1000 cases. Multivariable analysis showed that gabapentin was associated with respiratory depression (odds ratio [OR], 1.47 [95% CI, 1.22-1.76]; P < .001). These results were confirmed by propensity score matched analysis among a subset of patients who did not have analgesia supplemented by intrathecal opioids (OR, 1.26 [95% CI, 1.02-1.58]; P = .04). Older patients and those who received more intraoperative opioids had increased risk of respiratory depression. Those who had an episode of respiratory depression had a longer phase-I recovery (P < .001) and an increased rate of admission to a higher level of care (P = .03). CONCLUSIONS: The use of gabapentin is associated with increased rates of respiratory depression among patients undergoing laparoscopic surgery. When gabapentinoids are included in multimodal analgesic regimens, intraoperative opioids must be reduced, and increased vigilance for respiratory depression may be warranted, especially in elderly patients. PMID- 27984225 TI - Anesthetic Management of Patients With Inborn Errors of Metabolism. AB - Inborn errors of metabolism (IEM) are characterized by the body's inability to convert food into energy. The pathogenetic mechanism is based on defects in a variety of cellular enzymes. In addition to impairment of energy generation, accumulation of substrates may occur, which can deposit in tissue and lead to organ dysfunction. IEM can have profound implications for perioperative management, including difficult airway management, cardiac dysfunction, aspiration risk, seizures, and metabolic dysregulation. For the anesthesiologist, comprehensive knowledge is difficult to attain because of the heterogeneity of this group and the low prevalence of specific diseases. The first part of this article reviews intermediary metabolism, whereas the second part aims to highlight important aspects in perioperative management of patients with IEM. Instead of reviewing each single disorder within the vast group of IEM, we provide a conceptual framework that will facilitate the understanding of main problems encountered in each of the disease subgroups. PMID- 27984227 TI - Physical Compatibility of Propofol-Sufentanil Mixtures. AB - BACKGROUND: Combined infusions of propofol and sufentanil preparations are frequently used in clinical practice to induce anesthesia and analgesia. However, the stability of propofol emulsions can be affected by dilution with another preparation, sometimes leading to particle coalescence and enlargement. Such unwanted effects can lead to fat embolism syndrome after intravenous application. This study describes the physical stability of 5 commercially available propofol preparations mixed with sufentanil citrate solutions. METHODS: Two common markers of emulsion stability were used in this study; namely, the zeta potential and size distribution of the emulsion droplets. Both were measured using dynamic light scattering. The data for the pure propofol preparations and their mixtures with sufentanil citrate solution were compared. RESULTS: The absolute value of zeta potential decreased in 4 of the 5 propofol preparations after they had been mixed with sufentanil citrate. This effect indicates a lowering of repulsive interactions between the emulsion droplets. Although this phenomenon tends to cause agglomeration, none of the studied mixtures displayed a substantial increase in droplet size within 24 hours of blending. However, our long-term stability study revealed the instability of some of the propofol-sufentanil samples. Two of the 5 studied mixtures displayed a continual increase in particle size. The same 2 preparations showed the greatest reductions in the absolute value of zeta potential, thereby confirming the correlation of both measurement methods. The increase in particle size was more distinct in the samples stored at higher temperatures and with higher sufentanil concentrations. CONCLUSIONS: To ensure the microbial stability of an emulsion infusion preparation, clinical regulations require that such preparations should be applied to patients within 12 hours of opening. In this respect, we can confirm that during this period, none of the studied propofol-sufentanil mixtures displayed any physical instability that could lead to particle enlargement; thus, fat embolism should not be a risk after their intravenous application. However, our long-term stability study revealed differences between commercially available preparations containing the same active ingredient; some of the mixtures showed an increase in particle size and polydispersity over a longer period. Although our results should not be generalized beyond the particular propofol-sufentanil preparations and concentrations studied here, they do suggest that, as a general principle, a compatibility study should be performed for any preparation before the first intravenous application to exclude the risk of droplet aggregation. PMID- 27984228 TI - New Innovations in Circulatory Support With Ventricular Assist Device and Extracorporeal Membrane Oxygenation Therapy. AB - The past decade has seen an exponential increase in the application and development of durable long-term as well as nondurable short-term mechanical circulatory support for cardiogenic shock and acute or chronic heart failure. Support has evolved from bridge-to-transplant to destination therapy, bridge to rescue, bridge to decision making, and bridge to a bridge. Notable trends include device miniaturization, minimally invasive and/or percutaneous insertion, and efforts to superimpose pulsatility on continuous flow. We can certainly anticipate that innovation will accelerate in the months and years to come. However, despite-or perhaps because of-the enhanced equipment now available, mechanical circulatory support is an expensive, complex, resource-intensive modality. It requires considerable expertise that should preferably be centralized to highly specialized centers. Formidable challenges remain: systemic inflammatory response syndromes and vasoplegia after device insertion; postoperative sepsis; optimal anticoagulation regimens to prevent device-induced thrombosis and cerebral thromboembolism; wound site, intracranial, and gastrointestinal bleeding; multisystem injury and failure; patient dissatisfaction (even when providers consider the procedure a "success"); and ethical decision making in conditions of futility. PMID- 27984226 TI - Intraperitoneal Instillation of Lidocaine Improves Postoperative Analgesia at Cesarean Delivery: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Cesarean delivery is a commonly performed procedure worldwide. Despite improvements in balanced multimodal analgesia, there remains a proportion of women for whom postoperative pain relief and patient satisfaction are still inadequate. Intraperitoneal instillation of local anesthetic has been shown to be effective in reducing postoperative pain after abdominal surgery. We sought to investigate the effect of intraperitoneal instillation of lidocaine on postcesarean delivery pain as part of a multimodal analgesia regimen. METHODS: We studied women scheduled for elective cesarean delivery under spinal anesthesia. Spinal anesthesia was performed with 0.75% hyperbaric bupivacaine, fentanyl, and morphine. At the end of the cesarean delivery, immediately before parietal peritoneum or fascia closure, patients were randomized to receive either lidocaine (20 mL 2% lidocaine with epinephrine) or placebo (20 mL normal saline) instilled into the peritoneal cavity. The primary outcome was pain score on movement at 24 hours. Secondary outcomes were pain score at rest and on movement at 2, 24, and 48 hours; maternal satisfaction score; analgesic consumption; incidence of nausea, vomiting, and itching; and return of bowel function. RESULTS: Two hundred four women were recruited. Baseline characteristics were similar between the lidocaine and placebo groups. Pain scores at 24 hours postcesarean delivery on movement (parameter estimate 0.02 [95% confidence interval {CI} -0.14 to 0.18]; P = .823) and at rest (parameter estimate 0.00 [95% CI -0.32 to 0.33]; P = .986) were similar in both groups. Pain scores at 2 hours postcesarean delivery on movement (parameter estimate -0.58 [95% CI -0.90 to 0.26]; P = .001) and at rest (parameter estimate -1.00 [95% CI -1.57 to -0.43]; P = .001) were lower in the lidocaine group. Subgroup analysis of patients with peritoneum closure revealed significantly lower pain scores at 24 hours on movement (parameter estimate -0.33 [95% CI -0.64 to -0.03]; P = .032) in the lidocaine group. The number of women requesting postoperative opioids for breakthrough pain was significantly lower in the lidocaine group compared with that of the placebo (40 [40%] vs 61 [65%], respectively, relative risk 0.59 [95% CI 0.43-0.81]; P = 0.001). CONCLUSIONS: The use of intraperitoneal instillation of lidocaine improves early postoperative pain management after cesarean delivery. Furthermore, it reduces the number of women requesting systemic opioids in the immediate postpartum period. Women undergoing peritoneal closure may particularly benefit from this intervention. PMID- 27984229 TI - Sedation After Cardiac Surgery: Is One Drug Better Than Another? AB - The classic high-dose narcotic-based cardiac anesthetic has been modified to facilitate a fast-track, rapid recovery in the intensive care unit (ICU). Postoperative sedation is consequently now an essential component in recovery of the patient undergoing cardiac surgery. It must facilitate the patient's unawareness of the environment as well as reduce the discomfort and anxiety caused by surgery, intubation, mechanical ventilation, suction, and physiotherapy. Benzodiazepines seem well suited for this role, but propofol, opioids, and dexmedetomidine are among other agents commonly used for sedation in the ICU. However, what is an ideal sedative for this application? When compared with benzodiazepine-based sedation regimens, nonbenzodiazepines have been associated with shorter duration of mechanical ventilation and ICU length of stay. Current sedation guidelines recommend avoiding benzodiazepine use in the ICU. However, there are no recommendations on which alternatives should be used. In postcardiac surgery patients, inotropes and vasoactive medications are often required because of the poor cardiac function. This makes sedation after cardiac surgery unique in comparison with the requirements for most other ICU patient populations. We reviewed the current literature to try to determine if 1 sedative regimen might be better than others; in particular, we compare outcomes of propofol and dexmedetomidine in postoperative sedation in the cardiac surgical ICU. PMID- 27984230 TI - Transversus Abdominis Plane Block Versus Wound Infiltration for Analgesia After Cesarean Delivery: A Randomized Controlled Trial. AB - BACKGROUND: Transversus abdominis plane (TAP) block and local anesthetic wound infiltration provide analgesia after cesarean delivery. Studies comparing the 2 techniques are scarce, with conflicting results. This double-blind, randomized controlled trial aimed to compare bilateral ultrasound-guided TAP block with single-shot local anesthetic wound infiltration for analgesia after cesarean delivery performed under spinal anesthesia. We hypothesized that the TAP block would decrease postoperative cumulative fentanyl consumption at 24 hours. METHODS: Eligible subjects were American Society of Anesthesiologists physical status II parturients with full-term singleton pregnancies undergoing elective cesarean delivery under spinal anesthesia. Exclusion criteria were: <19 years of age or >40 years of age; height <150 cm, weight <60 kg, body mass index >=40 kg/m; contraindications to spinal anesthesia; history of recent opioid exposure; hypersensitivity to any of the drugs used in the study; significant cardiovascular, renal, or hepatic disease; and known fetal abnormalities. Eighty subjects were randomly allocated to 2 equal groups. In the infiltration group, participants received 15 mL of bupivacaine 0.25% in each side of the surgical wound (total 30 mL); and in the TAP group, participants received 20 mL of bupivacaine 0.25% bilaterally in the TAP block (total 40 mL). The TAP block and wound infiltration were performed by the primary investigator and the operating obstetrician, respectively. All participants received postoperative standard analgesia (ketorolac and paracetamol) and intravenous fentanyl via patient controlled analgesia. Patients and outcome assessors were blinded to the study group. The primary outcome was the cumulative fentanyl consumption at 24 hours. Secondary outcomes were the time to the first postoperative fentanyl dose, cumulative fentanyl consumption at 2, 4, 6, and 12 hours, pain scores at rest and on movement at 2, 4, 6, 12, and 24 hours, the deepest level of sedation, the incidence of side effects (nausea and vomiting and pruritis), and patient satisfaction. RESULTS: Data from 78 patients (39 patients in each group) were analyzed. The mean +/- SD of cumulative fentanyl consumption at 24 hours was 157.4 +/- 63.4 MUg in the infiltration group and 153.3 +/- 68.3 MUg in the TAP group (difference in means [95% confidence interval] is 4.1 [-25.6 to 33.8] MUg; P = .8). There were no significant differences between the 2 groups in the time to the first postoperative fentanyl dose, cumulative fentanyl consumption at 2, 4, 6, and 12 hours, pain scores at rest and on movement at 2, 4, 6, 12, and 24 hours, the deepest level of sedation, and patient satisfaction. The incidence of side effects (nausea and vomiting and pruritis) was low in the 2 groups. CONCLUSIONS: TAP block and wound infiltration did not significantly differ regarding postoperative fentanyl consumption, pain scores, and patient satisfaction in parturients undergoing cesarean delivery under spinal anesthesia. PMID- 27984232 TI - Balloon Cell Melanoma and Its Metastasis, a Rare Entity. AB - Balloon cell melanoma (BCM) with metastasis is a rarely occurring neoplasia. The incidence of BCM is low, and hence, the frequency of these lesions presenting metastasis is even less frequent. This review exposes the balloon cell metastasis cases that have been published and a new case. These cases share the histopathological features but the location of initial melanoma, age and sex vary. It is relevant for the dermatologist and dermatopathologist to keep in mind the diagnosis of BCM and consider the possibility of it metastasizing as nonpigmented skin lesions. PMID- 27984231 TI - Effects of Cycled Lighting Versus Continuous Near Darkness on Physiological Stability and Motor Activity Level in Preterm Infants. AB - BACKGROUND: Preterm infants generally spend weeks in the neonatal intensive care unit where light intensity can fluctuate as well as be high, leading to physiological instability and increased motor activity in these infants. To date, 2 lighting control methods have been studied: cycled lighting and continuous near darkness. The most appropriate method of lighting is still unknown due to ambivalent results from the studies that have assessed these 2 interventions. OBJECTIVE: To compare the effects of cycled lighting versus continuous near darkness on physiological stability and motor activity level in preterm infants born between 28 and 32 weeks of gestation. METHODS: A randomized clinical trial was conducted to compare physiological stability and motor activity level in preterm infants assigned to cycled lighting or continuous near darkness. Thirty eight participants were recruited and randomly assigned to one of the lighting conditions for 24 hours. Physiological stability was measured using the Stability of the Cardiorespiratory System in Premature Infants (SCRIP) score, the means, and the coefficient of variation of each physiological parameter measured. The level of motor activity was measured with an accelerometer. RESULTS: There were no significant differences between the 2 groups with regard to physiological stability measured by the SCRIP score, means, and coefficient of variation as well as motor activity level. Participants in both groups were physiologically stable and their motor activity level was comparable. IMPLICATIONS FOR PRACTICE AND RESEARCH: Neither cycled lighting nor continuous near darkness negatively impacted infant's physiologic stability and motor activity level. Further research is required to identify the most appropriate lighting control method for preterm infants born between 28 and 32 weeks of gestation. PMID- 27984234 TI - Fine-tuning inflammation-resolution programs: focus on atherosclerosis. AB - PURPOSE OF REVIEW: Nonresolving inflammation is now considered the underpinning of several prevalent human diseases, including atherosclerosis. The resolution of inflammation is a highly coordinated program to counterbalance proinflammatory signals for a swift return to tissue homeostasis. This process is controlled in part by endogenous specialized proresolving lipid mediators (SPMs). Emerging evidence has revealed that the balance of SPMs and proinflammatory mediators during acute inflammation regulates the duration of the inflammatory response and the timing of tissue resolution. Moreover, an imbalance between SPMs and proinflammatory mediators has been linked to several prevalent chronic inflammatory diseases in humans, including atherosclerosis. RECENT FINDINGS: Lipid mediator imbalances have recently been linked to atherosclerotic plaque instability. Administration of key SPMs restored this imbalance and led to plaque stability. SPMs have also recently been shown to be protective in other cardiovascular disease models including myocardial infarction, stroke and neointimal hyperplasia. SUMMARY: The current review highlights recent work that supports the concept of dysregulated inflammation-resolution in atherosclerosis with a particular focus on mechanisms and therapeutic opportunities associated with SPM receptors and lipid mediator imbalances. This article is based on experimental studies. PMID- 27984233 TI - Dermatofibrosarcoma Protuberans-Like Tumor With COL1A1 Copy Number Gain in the Absence of t(17;22). AB - A 57-year-old woman presented with a 3-year history of a progressive firm plaque on the right cheek. Skin biopsies revealed a bland, storiform, spindle-cell proliferation involving the deep dermis and subcutaneous fat. By immunohistochemistry, the tumor cells were diffusely positive for CD34 and caldesmon with multifocal reactivity for epithelial membrane antigen and focal, weak staining for smooth muscle actin. Retinoblastoma protein expression was not detectable in tumor cells by immunohistochemistry. An interphase fluorescence in situ hybridization analysis for platelet-derived growth factor B (PDGFB) gene rearrangement was negative. A single-nucleotide polymorphism array study detected 1) a gain of chromosome segment 17q21.33-q25.3 which overlapped the entire COL1A1 gene with a breakpoint at 17q21.33, approximately 250 Kb centromeric to the 3' end of COL1A1 gene, 2) several segmental gains on chromosome 11, and 3) an RB1 gene locus with normal copy number and allele frequency. Although the current case resembles dermatofibrosarcoma protuberans, it is unique in that it demonstrates a copy number gain of chromosome 17q in the absence of fusion of COL1A1 and PDGFB genes and an unusual immunohistochemical staining profile. The morphologic and molecular findings suggest a novel molecular variant of dermatofibrosarcoma protuberans not detectable with standard fluorescence in situ hybridization for PDGFB rearrangement. This variant appears to respond to imatinib after 9 months of follow-up. PMID- 27984236 TI - Duodenal Neoplasms of Gastric Phenotype: An Immunohistochemical and Genetic Study With a Practical Approach to the Classification. AB - Duodenal neoplasm of gastric phenotype (DNGP) is very rare, and details of its histopathologic, genetic, and biological features are still unclear. Frequent gene mutations in GNAS, KRAS, and APC have been reported in pyloric gland adenomas and fundic gland-type neoplasms (initially reported as low-grade adenocarcinomas) of the stomach. Here we retrospectively analyzed 16 cases of extra-ampullary DNGP (benign to malignant), and we examined the mucin immunoprofile and oncogene mutations (GNAS, KRAS, APC, BRAF, and CTNNB1). The 16 DNGPs were histologically classified into adenomas (5 pyloric gland adenomas and 2 foveolar-type adenomas), neoplasms of uncertain malignant potential (NUMPs, n=6), and invasive adenocarcinomas (n=3). NUMPs consisted of slightly atypical epithelial cells with pale, eosinophilic, or basophilic cytoplasm growing in an anastomosing or branching glandular pattern, often with expansive submucosal extension. In contrast to invasive adenocarcinomas, NUMPs lacked significant nuclear irregularity, desmoplastic stromal reaction, lymphovascular invasion, and metastasis; their features were reminiscent of fundic gland-type neoplasms of the stomach. Immunophenotypically, most of NUMPs were predominantly positive for MUC6 with variable expressions of pepsinogen-I, HKATPase, human gastric mucin, and MUC5AC. Molecular analyses revealed the gene mutations of GNAS in 6 (38%) of 16 DNGPs (4 [57%] adenomas, 1 [16%] NUMP, and 1 [33%] invasive adenocarcinoma) and APC in 4 of 15 (27%) DNGPs: no adenomas, 2 (33%) NUMPs, and 2 (67%) invasive adenocarcinomas. BRAF mutation was present in only 1 (16%) NUMP, and KRAS and CTNNB1 mutations were absent. In conclusion, gastric-phenotype adenomas and NUMPs of the duodenum are similar to their counterparts of the stomach, in terms of histologic, genetic, and clinicopathologic features. We propose the term "NUMP" as an intermediate category between adenoma and definitely invasive adenocarcinoma. Our findings may provide novel insights into the classification of undescribed but distinctive duodenal tumors showing similarity to gastric phenotype neoplasms of the stomach. PMID- 27984237 TI - Rhabdoid and Undifferentiated Phenotype in Renal Cell Carcinoma: Analysis of 32 Cases Indicating a Distinctive Common Pathway of Dedifferentiation Frequently Associated With SWI/SNF Complex Deficiency. AB - Undifferentiated (anaplastic) and rhabdoid cell features are increasingly recognized as adverse prognostic findings in renal cell carcinoma (RCC), but their molecular pathogenesis has not been studied sufficiently. Recent studies identified alterations in the Switch Sucrose nonfermentable (SWI/SNF) chromatin remodeling complex as molecular mechanisms underlying dedifferentiation and rhabdoid features in carcinomas of different organs. We herein have analyzed 32 undifferentiated RCCs having in common an undifferentiated (anaplastic) phenotype, prominent rhabdoid features, or both, irrespective of the presence or absence of conventional RCC component. Cases were stained with 6 SWI/SNF pathway members (SMARCB1, SMARCA2, SMARCA4, ARID1A, SMARCC1, and SMARCC2) in addition to conventional RCC markers. Patients were 20 males and 12 females aged 32 to 85 years (mean, 59). A total of 22/27 patients with known stage presented with >=pT3. A differentiated component varying from microscopic to major component was detected in 20/32 cases (16 clear cell and 2 cases each chromophobe and papillary RCC). The undifferentiated component varied from rhabdoid dyscohesive cells to large epithelioid to small monotonous anaplastic cells. Variable loss of at least 1 SWI/SNF complex subunit was noted in the undifferentiated/rhabdoid component of 21/32 cases (65%) compared with intact or reduced expression in the differentiated component. A total of 15/17 patients (88%) with follow-up died of metastatic disease (mostly within 1 y). Only 2 patients were disease free at last follow-up (1 and 6 y). No difference in survival, age distribution, or sex was observed between the SWI/SNF-deficient and the SWI/SNF-intact group. This is the first study exploring the role of SWI/SNF deficiency as a potential mechanism underlying undifferentiated and rhabdoid phenotype in RCC. Our results highlight the association between the aggressive rhabdoid phenotype and the SWI/SNF complex deficiency, consistent with studies on similar neoplasms in other organs. Thorough sampling of such tumors that are usually huge and locally advanced is necessary for recognizing the clone of origin and hence for proper subtyping and also for differentiating them from undifferentiated urothelial carcinoma. PMID- 27984235 TI - Intraductal Tubulopapillary Neoplasm of the Pancreas: A Clinicopathologic and Immunohistochemical Analysis of 33 Cases. AB - Intraductal tubulopapillary neoplasm (ITPN) is a relatively recently described member of the pancreatic intraductal neoplasm family. Thus, the literature on its histologic and immunohistochemical features, clinical behavior, and its similarities and differences from other pancreatic neoplasms is limited. Thirty three cases of ITPN, the largest series to date, were identified. Immunohistochemical labeling for cytokeratins, glycoproteins, pancreatic enzymes, markers for intestinal and neuroendocrine differentiation, and antibodies associated with genetic alterations previously described in pancreatic neoplasms was performed. Clinicopathologic features and survival was assessed. Seventeen patients were female and 14 were male. Mean age was 55 years (range, 25 to 79 y). Median overall tumor size was 4.5 cm (range, 0.5 to 15 cm). Forty-five percent of the tumors occurred in the head, 32% in the body/tail, and 23% showed diffuse involvement. Microscopically, the tumors were characterized by intraductal nodules composed of tightly packed small tubular glands lined by cuboidal cells lacking apparent mucin. Although it was often challenging to determine its extent, invasion was present in 71%. Almost all tumors labeled for CAM5.2, CK7, and CK19; most expressed CA19.9, MUC1, and MUC6. CDX2, MUC2, trypsin, chymotrypsin, chromogranin, and synaptophysin were not expressed. SMAD4 expression was retained in 100%; p16 expression and p53 overexpression was seen in 33% and 27%, respectively. Follow-up information was available for 22 patients (median follow-up, 45 mo; range, 11 to 173 mo). Two patients with invasive carcinoma died of disease at 23 and 41 months, respectively. One patient died of unrelated causes at 49 months. Twelve patients were alive with disease. Seven patients were alive with no evidence of disease. The overall 1-, 3-, and 5-year survival rates were 100% in patients without an invasive component and 100%, 91%, and 71%, respectively, in patients with an invasive component (P=0.7). ITPN is a distinct clinicopathologic entity in the pancreas. Despite the difficulties of determining the extent of invasive carcinoma in many cases, the overall outcome seems to be relatively favorable and substantially better than that of conventional pancreatic ductal adenocarcinoma, even when only the cases with invasive carcinoma are considered. PMID- 27984239 TI - Synovial Sarcomas Do Not Show H3K27 Trimethylation Loss Using Immunohistochemistry. PMID- 27984238 TI - PD-L1 Expression in Mismatch Repair-deficient Endometrial Carcinomas, Including Lynch Syndrome-associated and MLH1 Promoter Hypermethylated Tumors. AB - Mismatch repair (MMR)-deficient endometrial carcinomas (ECs) bearing Lynch syndrome (LS)-associated germline mutations or sporadic MLH1 promoter hypermethylation (MLH1hm) are highly immunogenic and may represent excellent candidates for therapies targeting the programmed cell death (PD)/programmed cell death ligand-1 (PD-L1) immune checkpoint pathway. This study evaluates PD-L1 expression in MMR-deficient ECs including LS-associated and MLH1hm cases, in comparison with MMR-intact tumors. Immunohistochemistry for PD-L1/CD274 was performed on 38 MMR-deficient and 29 MMR-intact ECs. Staining was scored in the tumor and the peritumoral immune compartment. The majority of MMR-deficient tumors were PD-L1 positive (53%) in at least a subset of tumor cells. LS associated tumors were more likely to be PD-L1 positive relative to MLH1hm tumors (70% vs. 33%, P=0.05). Only 10% of MMR-intact ECs demonstrated any tumoral PD-L1 expression; this was significantly lower than was observed in MMR-deficient tumors (P=0.0005). When reviewed by histologic grade, PD-L1 expression remained highest in LS-associated ECs followed by MLH1hm and MMR-intact carcinomas, respectively. The MMR immunohistochemical pattern most uniformly associated with PD-L1 expression was MSH6 loss. Immune PD-L1 expression was seen in 100% of MMR deficient and 66% of MMR-intact cases. This study represents the first to characterize differences in PD-L1 expression between LS-associated and MLH1hm endometrial cancers. It demonstrates that tumoral PD-L1 expression is more common in LS-associated endometrial cancers relative to MLH1hm and MMR-intact tumors, although sporadic cancers often show PD-L1 positive immune staining. These data suggest that MMR deficiency may be a better predictor of response to PD-1/PD-L1 inhibitor therapy than tumor grade in EC, and that potential benefit may vary based on the molecular mechanism of MMR defects. PMID- 27984240 TI - Interstitial Mycosis Fungoides: Setting the Record Straight. PMID- 27984242 TI - Impact of Abuse on Adjustment and Chronic Pain Disability: A Structural Equation Model. AB - INTRODUCTION/AIM: Sexual abuse, state and trait psychosocial factors, pain intensity, and pain-related disability have been shown to be correlated among individuals with chronic pain. However, the interacting relationships among these factors are poorly understood. The current study aims to test model which examines the effect of abuse, state and trait psychosocial factors, and pain intensity on pain-related disability among individuals with chronic pain. METHODS: In total, 229 participants diagnosed with chronic pain were recruited from a specialist chronic pain hospital in London, Ontario. Participants completed self-report measures related to sexual abuse history, pain intensity, personality (anxiety sensitivity, experiential avoidance, perfectionism), and adjustment (depression, anxiety, disability, maladaptive worrying). A path analysis was used to test the relationship among these variables. RESULTS: The model provided a close fit to the data (chi21=17.02; P=0.71; root-mean-square error of approximation=0.00; normal fit index=0.97; comparative fit index=1.0). The model demonstrates the direct and indirect effects of childhood sexual abuse on state and trait psychosocial factors among individuals with chronic pain. Pain anxiety, maladaptive worrying, and pain intensity were the main determinants of pain-related disability. DISCUSSION/CONCLUSIONS: The current model has important implications in understanding the interplay of factors involved in adjustment of individuals with chronic pain. Sexual abuse did not have a direct effect on pain related disability. However, indirect effects through other psychosocial factors were demonstrated. PMID- 27984243 TI - Chronic obstructive pulmonary disease and sleep related disorders. AB - PURPOSE OF REVIEW: Sleep related disorders are common and under-recognized in the chronic obstructive pulmonary disease (COPD) population. COPD symptoms can disrupt sleep. Similarly, sleep disorders can affect COPD. This review highlights the common sleep disorders seen in COPD patients, their impact, and potential management. RECENT FINDINGS: Treatment of sleep disorders may improve quality of life in COPD patients. Optimizing inhaler therapy improves sleep quality. Increased inflammatory markers are noted in patients with the overlap syndrome of COPD and obstructive sleep apnea versus COPD alone. There are potential benefits of noninvasive positive pressure ventilation therapy for overlap syndrome patients with hypercapnia. Nocturnal supplemental oxygen may be beneficial in certain COPD subtypes. Nonbenzodiazepine hypnotic therapy for insomnia has shown benefit without associated respiratory failure or worsening respiratory symptoms. Melatonin may provide mild hypnotic and antioxidant benefits. SUMMARY: This article discusses the impact of sleep disorders on COPD patients and the potential benefits of managing sleep disorders on respiratory disease control and quality of life. PMID- 27984241 TI - The Resilience in Illness Model Part 2: Confirmatory Evaluation in Adolescents and Young Adults With Cancer. AB - BACKGROUND: Empirically derived and tested models are necessary to develop effective, holistic interventions to improve positive health outcomes in adolescents and young adults (AYA) with cancer, yet few exist. This article is the second of 2 articles reporting on evaluation of the Resilience in Illness Model (RIM) as a predictive model to guide positive health research and practice. OBJECTIVE: The aim of this study was to report the confirmatory model evaluation of the RIM. METHODS: A confirmatory evaluation of RIM was done using baseline data from a sample of 113 AYA aged 11 to 24 years who were undergoing hematopoietic stem cell transplant and enrolled in a randomized controlled trial of a behavioral intervention to enhance resilience. Data were analyzed using latent variable structural equation modeling. RESULTS: Goodness-of-fit indices supported RIM as a confirmed model that accounted for large amounts of variance in the outcomes of self-transcendence (62%) and resilience (72%), and in 3 of 5 mediators, specifically social integration (74%), courageous coping (80%), and hope-derived meaning (87%), as well as small to moderate amounts of variance in the remaining mediators of defensive coping (1%) and family environment (35%). CONCLUSIONS: Findings establish the RIM as a plausible predictive framework for explaining ways AYA with cancer transcend their illness and achieve resilience resolution and for guiding intervention studies in this population. Additional research is needed to explore RIM's transferability based on stage of illness, other chronic diseases, and cultural diversity. IMPLICATIONS FOR PRACTICE: Results support the RIM as an appropriate guide for developing and evaluating interventions to foster positive adjustment in AYA with cancer. PMID- 27984244 TI - Identification of Severe Mitral Stenosis Using Real-Time Three-Dimensional Transesophageal Echocardiography During an Left Ventricular Assist Device Insertion. PMID- 27984245 TI - Bacterial pneumonia as an influenza complication. AB - PURPOSE OF REVIEW: The pathogenesis and impact of coinfection, in particular bacterial coinfection, in influenza are incompletely understood. This review summarizes results from studies on bacterial coinfection in the recent pandemic influenza outbreak. RECENT FINDINGS: Systemic immune mechanisms play a key role in the development of coinfection based on the complexity of the interaction of the host and the viral and bacterial pathogens. Several studies were performed to determine the point prevalence of bacterial coinfection in influenza. Coinfection in influenza is frequent in critically ill patients with Streptococcus pneumoniae being the most frequent bacterial pathogen and higher rates of potentially resistant pathogens over the years. SUMMARY: Bacterial pneumonia is certainly an influenza complication. The recent epidemiology findings have helped to partially resolve the contribution of different pathogens. Immunosuppression is a risk factor for bacterial coinfection in influenza, and the epidemiology of coinfection has changed over the years during the last influenza pandemic, and these recent findings should be taken into account during present outbreaks. PMID- 27984246 TI - The Hypothalamic-Pituitary-Adrenal Axis and Anesthetics: A Review. AB - The hypothalamic-pituitary-adrenal (HPA) axis is essential for human adaptation to stress. However, many anesthetic agents may interfere with the activity of this axis. Although etomidate is known for its suppressive effect on HPA axis function, in vitro evidence suggests that many other drugs used in anesthesia care may also interfere with HPA activity. In this review, we discuss the mechanisms by which all HPA axis activity may be altered during anesthesia and critical care and focus on the impact of hypnotic and analgesic drugs. PMID- 27984247 TI - Dynamic Ultrasound-Guided Short-Axis Needle Tip Navigation Technique for Facilitating Cannulation of Peripheral Veins in Obese Patients. AB - This preliminary observational study evaluated a specific ultrasound technique for venous access. Ultrasound was utilized for navigating a needle and catheter within the vessel lumen after venopuncture. One hundred adult obese surgical patients without visible vessels on their upper extremities were enrolled. Forty five different operators ranging from medical students to attending anesthesia faculty performed venous cannulation with the specific ultrasound technique. Veins in 95 patients were cannulated successfully on the first attempt. This ultrasound-guided protocol facilitates navigation of both the catheter and needle within a vessel, increasing the first-attempt success rate of peripheral venous cannulation in adult obese patients. PMID- 27984248 TI - The Geographic Distribution of Pediatric Anesthesiologists Relative to the US Pediatric Population. AB - BACKGROUND: The geographic relationship between pediatric anesthesiologists and the pediatric population has potentially important clinical and policy implications. In the current study, we describe the geographic distribution of pediatric anesthesiologists relative to the US pediatric population (0-17 years) and a subset of the pediatric population (0-4 years). METHODS: The percentage of the US pediatric population that lives within different driving distances to the nearest pediatric anesthesiologist (0 to 25 miles, >25 to 50 miles, >50 to 100 miles, >100 to 250 miles, and >250 miles) was determined by creating concentric driving distance service areas surrounding pediatric anesthesiologist practice locations. US Census block groups were used to determine the sum pediatric population in each anesthesiologist driving distance service area. The pediatric anesthesiologist-to-pediatric population ratio was then determined for each of the 306 hospital referral regions (HRRs) in the United States and compared with ratios of other physician groups to the pediatric population. All geographic mapping and analysis was performed using ArcGIS Desktop 10.2.2 mapping software (Redlands, CA). RESULTS: A majority of the pediatric population (71.4%) lives within a 25-mile drive of a pediatric anesthesiologist; however, 10.2 million US children (0-17 years) live greater than 50 miles from the nearest pediatric anesthesiologist. More than 2.7 million children ages 0 to 4 years live greater than 50 miles from the nearest identified pediatric anesthesiologist. The median ratio of pediatric anesthesiologists to 100,000 pediatric population at the HRR level was 2.25 (interquartile range, 0-5.46). Pediatric anesthesiologist geographic distribution relative to the pediatric population by HRR is lower and less uniform than for all anesthesiologists, neonatologists, and pediatricians. CONCLUSIONS: A substantial proportion of the US pediatric population lives greater than 50 miles from the nearest pediatric anesthesiologist, and pediatric anesthesiologist-to-pediatric population ratios by HRR vary widely across the United States. These findings are important given that the new guidelines from the American College of Surgeons Children's Surgery VerificationTM Quality Improvement Program state that pediatric anesthesiologists must care for a subset of pediatric patients. Because of the geographic distribution of pediatric anesthesiologists relative to the pediatric population, access to care by a pediatric anesthesiologist may not be feasible for all children, particularly for those with limited resources or in emergent situations. PMID- 27984249 TI - Predicting Fluid Responsiveness in Acute Liver Failure: A Prospective Study. AB - BACKGROUND: The profound hemodynamic changes seen in acute liver failure (ALF) resemble the hyperdynamic state found in the later stages of septic shock. Vasopressor support frequently is required after initial volume therapy. Markers of preload dependency have not been studied in this patient group. Dynamic maneuvers such as passive leg raising or end-expiratory hold, which have shown good predictive accuracy in a general intensive care unit population, cannot be considered safe in this cohort because of the concerns of intracranial hypertension. METHODS: Mechanically ventilated patients with ALF admitted to a tertiary specialist intensive care unit in shock and multiorgan failure were enrolled. Markers of fluid responsiveness derived from transpulmonary thermodilution, pulse contour analysis, and echocardiography were compared between responders (cardiac index >=15%) and nonresponders to a colloid fluid challenge (5 mL/kg predicted body weight). The ability to predict fluid responsiveness of stroke volume variation, pulse pressure variation (PPV), and respiratory change in peak (delta V peak) left ventricular outflow tract velocity for preload dependency were analyzed. RESULTS: Thirty-five patients (mean +/- SD age, 38 [14] years, 13 male, 22 female]) were assessed after a single fluid challenge. Ten patients (29%) were fluid responders. Changes in cardiac index and stroke volume index in the cohort of 35 patients were correlated (R = 0.726 [99% confidence interval, 0.401-0.910]; P < .001). PPV predicted fluid responsiveness (area under the receiver operating characteristic curve [AUROC], 0.752 [95% confidence interval, 0.565-0.889]; P = .005; cutoff >9%). The AUROC for stroke volume variation was 0.678 ([95% confidence interval, 0.499-0.825]; P = .084; cutoff >11%). The AUROC for [delta] V peak before fluid bolus was 0.637 (95% confidence interval, 0.413-0.825; P = .322). CONCLUSIONS: PPV based on pulse contour analysis predicted fluid responsiveness in ALF. PMID- 27984250 TI - A Randomized Controlled Trial of Music Use During Epidural Catheter Placement on Laboring Parturient Anxiety, Pain, and Satisfaction. AB - BACKGROUND: Although music is frequently used to promote a relaxing environment during labor and delivery, the effect of its use during the placement of neuraxial techniques is unknown. Our study sought to determine the effects of music use on laboring parturients during epidural catheter placement, with the hypothesis that music use would result in lower anxiety, lower pain, and greater patient satisfaction. METHODS: We conducted a prospective, randomized, controlled trial of laboring parturients undergoing epidural catheter placement with or without music. The music group listened to the patient's preferred music on a Pandora(r) station broadcast through an external amplified speaker; the control group listened to no music. All women received a standardized epidural technique and local anesthetic dose. The primary outcomes were 3 measures of anxiety. Secondary outcomes included pain, patient satisfaction, hemodynamic parameters, obstetric parameters, neonatal outcomes, and anesthesia provider anxiety. Intention-to-treat analysis with Bonferroni correction was used for the primary outcomes. For secondary outcomes, a P value of <.001 was considered statistically significant. RESULTS: A total of 100 parturients were randomly assigned, with 99 included in the intention-to-treat analysis. Patient characteristics were similar in both groups; in the music group, the duration of music use was 31.1 +/- 7.7 minutes (mean +/- SD). The music group experienced higher anxiety as measured by Numeric Rating Scale scores immediately after epidural catheter placement (2.9 +/ 3.3 vs 1.4 +/- 1.7, mean difference 1.5 [95% confidence interval {CI} 0.2-2.7], P = .02), and as measured by fewer parturients being "very much relaxed" 1 hour after epidural catheter placement (51% vs 78%, odds ratio {OR} 0.3 [95% CI 0.1 0.9], P = .02). No differences in mean pain scores immediately after placement or patient satisfaction with the overall epidural placement experience were observed; however, the desire for music use with future epidural catheter placements was higher in the music group (84% vs 45%, OR 6.4 [95% CI 2.5-16.5], P < .0001). No differences in the difficulty with the epidural catheter placement or in the rate of cesarean delivery were observed. CONCLUSIONS: Music use during epidural catheter placement in laboring parturients is associated with higher postprocedure anxiety and no improvement in pain or satisfaction; however, a stronger desire for music with future epidural catheter placements was observed. Further investigation is needed to determine the effect of music use in parturients requesting and using epidural labor analgesia. PMID- 27984251 TI - Imbalanced: The Confusing Circular Nature of Falls Research...and a Possible Antidote. PMID- 27984252 TI - Perioperative Complications of Spinal Metastases Surgery. AB - The incidence of symptomatic spinal metastasis has increased due to treatment improvements and longer patient survival. More patients with spinal tumors are choosing operative treatment with an associated increased rate of perioperative complications. Operative metastatic disease treatment complication rates have also increased with overall rates ranging from 5.3% to 76.20%. The common surgical-related complications are iatrogenic dural injury and wound complications. The most common postoperative medical complications are delirium, pneumonia, and deep vein thrombosis. Risk factors for perioperative complications after spinal metastatic surgery include older age, multilevel of spinal metastases, preoperative irradiation, low preoperative Karnofsky Performance Score (10-40) and multiple comorbidities. Charlson Comorbidity Index and New England Spinal Metastasis Score were significant predictor of 30-day complications. The reoperation rate is 10.7%, and the reoperation is most commonly performed in the same admission. In addition, the 30-day mortality rate in this patient population is ~7% (0.9%-13%) and is influenced by the type of cancer, disease burden, and patient comorbidities. We reviewed the prevalence and risk factors of common perioperative complications that occur with surgical treatment of metastatic spine disease, in an effort to guide the spine surgeon in anticipating and potentially avoiding these complications. PMID- 27984253 TI - Does heart rate really matter to patients with heart failure? AB - PURPOSE OF REVIEW: Measurement of heart rate (HR) and rhythm is used to identify patients at increased risk of disease progression, guide selection of treatments and gauge response to therapy. RECENT FINDINGS: Lowering HR with a pure HR lowering agent (ivabradine) in heart failure with reduced ejection fraction (HFrEF) and sinus rate more than 70 beats/min despite beta blockade has been shown to improve outcomes. Additionally, coadministration of ivabradine and beta blockade may enhance symptoms and HR control. In the case of patients with heart failure and preserved ejection fraction (HFpEF), or with paced rhythm, optimal HR control is not known. Also, in atrial fibrillation the relationship between HR and outcomes is not clear and minimal evidence for HR reduction to less than 100 beats/min exists. Reasons for this disconnect between atrial fibrillation and sinus rhythm are not known. SUMMARY: HR continues to be a critical vital sign in assessment and forms the basis for a treatment target in patients with HFrEF at rates more than 70 beats/min. The target for HR patients with HFpEF and those who are paced continuously or in atrial fibrillation is less clear and at present is recommended to be in the 60-100 beats/min range at rest. Further study is needed to refine treatment strategies in these latter patients. PMID- 27984254 TI - Considerations in Writing About Single-Case Experimental Design Studies. AB - Single-case experimental design (SCED) studies are particularly useful for examining the processes and outcomes of psychological and behavioral studies. Accurate reporting of SCED studies is critical in explaining the study to the reader and allowing replication. This paper outlines important elements that authors should cover when reporting the results of a SCED study. Authors should provide details on the participant, independent and dependent variables under examination, materials and procedures, and data analysis. Particular emphasis should be placed on justifying the assumptions made and explaining how violations of these assumptions may alter the results of the SCED study. PMID- 27984255 TI - Knowns and Unknowns About Delirium in Stroke: A Review. AB - Delirium is a transient condition characterized by sudden and fluctuating disturbances in cognitive function. The condition can be considered a sign of the brain's vulnerability and diminished resilience to insult. Among the many clinical manifestations are cognitive, psychomotor, and sleep disturbances. Delirium is associated with longer hospital stays, worse functional outcomes, and higher mortality. Although up to 48% of patients who have had a stroke develop delirium, the condition has been studied much less in these patients than in general medicine, surgical, and intensive care patients. Coexisting neurologic deficits in patients with stroke limit the use of screening tools that are widely accepted in other populations. The variability of reported assessment methods highlights the need for delirium screening guidelines in stroke. Further, risk factors that are specific to stroke may play an important role in the etiology of delirium, along with such well-known factors as older age and infections. The delirium literature lacks data on differences in clinical manifestations and course in the various types of stroke. Here we review predisposing factors, diagnostic methods, and biomarkers of delirium in stroke and discuss aspects that need further research. PMID- 27984256 TI - Cognition in Patients With a Clinical Diagnosis of Parkinson Disease and Scans Without Evidence of Dopaminergic Deficit (SWEDD): 2-Year Follow-Up. AB - OBJECTIVE AND BACKGROUND: More than 10% of patients clinically diagnosed with Parkinson disease demonstrate normal dopamine uptake on dopamine transporter single-photon emission computed tomography (DaTscan), but little is known about how cognitive function differs between patients with dopamine deficiency on DaTscan and patients with scans without evidence of dopaminergic deficit (SWEDD). We compared the cognitive function of these two groups of patients over 2 years. METHODS: We retrospectively analyzed data obtained from the Parkinson's Progression Markers Initiative on 309 participants clinically diagnosed with idiopathic Parkinson disease who had scored in the normal range on the Montreal Cognitive Assessment at baseline and had completed 1- and 2-year follow-up visits. We compared the Montreal Cognitive Assessment scores at 1 and 2 years between the 42 participants with SWEDD and the 267 with dopamine deficiency. RESULTS: Mean cognitive scores did not differ significantly between groups at 1 year, but at 2 years the participants with SWEDD performed more poorly. At 2 years, 31% of the participants with SWEDD versus 15% of those with dopamine deficiency had statistically reliable cognitive impairment. CONCLUSIONS: This study provides evidence that some individuals clinically diagnosed with idiopathic Parkinson disease but with SWEDD demonstrate early cognitive decline. The results also suggest that recently diagnosed patients with SWEDD may be at even greater risk for cognitive decline than patients with DaTscan-confirmed early-stage Parkinson disease. While patients with SWEDD likely represent a heterogeneous group of etiologies, our results highlight the need to monitor these patients' cognitive function over time. PMID- 27984257 TI - Preliminary Predictors of Initial Attendance, Symptom Burden, and Motor Subtype in a US Functional Neurological Disorders Clinic Population. AB - BACKGROUND AND OBJECTIVE: Although many patients present with functional neurological symptoms (FNS), few US clinics offer specialized FNS care, and data on clinic attendees remain limited. We determined predictors of initial attendance, symptom burden, and FNS subtype in the first patients referred to our Functional Neurological Disorders Clinic for suspected FNS. METHODS: We reviewed the charts of 62 consecutive patients (46 women, 16 men). Regression analyses investigated predictors of keeping the first scheduled clinic appointment. For the 49 patients who did keep that appointment, regression analyses examined neuropsychiatric factors associated with symptom burden and motor FNS subtypes. RESULTS: The odds of not keeping the first appointment were 10.4 times greater for patients referred from the emergency department than from other sources. The patients who kept their appointment reported a symptom burden that was significantly associated with a past FNS-related emergency department visit and a diagnosis of another medically unexplained somatic syndrome. The number of FNS findings on neurological examination also correlated with a history of an FNS related emergency department visit. Patients with psychogenic non-epileptic seizures reported cognitive complaints and prior psychiatric hospitalizations significantly more often than did patients with other FNS. One fourth of all patients had two or more motor FNS. CONCLUSIONS: In our FNS cohort, patients were less likely to keep an initial clinic appointment if they were referred from the emergency department than from other sources. Patients with psychogenic non epileptic seizures were more likely to report cognitive symptoms and past psychiatric hospitalizations than patients with other FNS. PMID- 27984258 TI - Incidental Learning: A Brief, Valid Measure of Memory Based on the WAIS-IV Vocabulary and Similarities Subtests. AB - OBJECTIVE: We assessed the validity of a brief incidental learning measure based on the Similarities and Vocabulary subtests of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV). BACKGROUND: Most neuropsychological assessments for memory require intentional learning, but incidental learning occurs without explicit instruction. Incidental memory tests such as the WAIS-III Symbol Digit Coding subtest have existed for many years, but few memory studies have used a semantically processed incidental learning model. METHODS: We conducted a retrospective analysis of 37 veterans with traumatic brain injury, referred for outpatient neuropsychological testing at a Veterans Affairs hospital. As part of their evaluation, the participants completed the incidental learning tasks. We compared their incidental learning performance to their performance on traditional memory measures. RESULTS: Incidental learning scores correlated strongly with scores on the California Verbal Learning Test-Second Edition (CVLT II) and Brief Visuospatial Memory Test-Revised (BVMT-R). After we conducted a partial correlation that controlled for the effects of age, incidental learning correlated significantly with the CVLT-II Immediate Free Recall, CVLT-II Short Delay Recall, CVLT-II Long-Delay Recall, and CVLT-II Yes/No Recognition Hits, and with the BVMT-R Delayed Recall and BVMT-R Recognition Discrimination Index. CONCLUSIONS: Our incidental learning procedures derived from subtests of the WAIS IV Edition are an efficient and valid way of measuring memory. These tasks add minimally to testing time and capitalize on the semantic encoding that is inherent in completing the Similarities and Vocabulary subtests. PMID- 27984259 TI - Musicogenic Epilepsy and Treatment of Affective Disorders: Case Report and Review of Pathogenesis. AB - Musicogenic epilepsy is a rare syndrome in which music triggers seizures. Affective network processing appears to play a key role in epileptogenesis. Many people with epilepsy suffer from comorbid affective disorders, the shared basis of which involves similar pathophysiologies, including deficiencies of serotonergic and noradrenergic function. Seizures and mood disorders may thus have reciprocal effects on one another, particularly in emotionally precipitated syndromes such as musicogenic epilepsy. I report a man with long-standing depression and anxiety who developed focal epilepsy that evolved into musicogenic seizures. His case suggests a pathophysiologic basis for this shared phenomenon. PMID- 27984260 TI - Persistent Interictal Musical Hallucination in a Patient With Mesial Temporal Sclerosis-Related Epilepsy: First Case Report and Etiopathological Hypothesis. AB - Musical hallucination is a disorder of complex sound processing of instrumental music, songs, choirs, chants, etc. The underlying pathologies include moderate to severe acquired hearing loss (the auditory equivalent of Charles Bonnet syndrome), psychiatric illnesses (depression, schizophrenia), drug intoxication (benzodiazepines, salicylate, pentoxifylline, propranolol), traumatic lesions along the acoustic pathways, and epilepsy. The hallucinations are most likely to begin late in life; 70% of patients are women. Musical hallucination has no known specific therapy. Treating the underlying cause is the most effective approach; neuroleptic and antidepressant medications have only rarely succeeded.Musical hallucination in epilepsy typically presents as simple partial seizures originating in the lateral temporal cortex. To our knowledge, no formal report of musical hallucination in the interictal state has been published before. In contrast, other interictal psychotic features are a relatively common complication, especially in patients with long-standing drug-resistant epilepsy.We describe a 62-year-old woman with a long history of mesial temporal lobe epilepsy whose musical hallucination was solely interictal. We speculate on the possible link between temporal epilepsy and her hallucination. We hypothesize that, as a result of her epileptic activity-induced damage, an imbalance developed between the excitatory and inhibitory projections connecting the mesial temporal cortex to the other auditory structures. These structures may have generated hyperactivity in the lateral temporal cortex through a "release" mechanism that eventually resulted in musical hallucination. PMID- 27984261 TI - Isolated Forearm Test: Replicated, Relevant, and Unexplained. PMID- 27984262 TI - Incidence of Connected Consciousness after Tracheal Intubation: A Prospective, International, Multicenter Cohort Study of the Isolated Forearm Technique. AB - BACKGROUND: The isolated forearm technique allows assessment of consciousness of the external world (connected consciousness) through a verbal command to move the hand (of a tourniquet-isolated arm) during intended general anesthesia. Previous isolated forearm technique data suggest that the incidence of connected consciousness may approach 37% after a noxious stimulus. The authors conducted an international, multicenter, pragmatic study to establish the incidence of isolated forearm technique responsiveness after intubation in routine practice. METHODS: Two hundred sixty adult patients were recruited at six sites into a prospective cohort study of the isolated forearm technique after intubation. Demographic, anesthetic, and intubation data, plus postoperative questionnaires, were collected. Univariate statistics, followed by bivariate logistic regression models for age plus variable, were conducted. RESULTS: The incidence of isolated forearm technique responsiveness after intubation was 4.6% (12/260); 5 of 12 responders reported pain through a second hand squeeze. Responders were younger than nonresponders (39 +/- 17 vs. 51 +/- 16 yr old; P = 0.01) with more frequent signs of sympathetic activation (50% vs. 2.4%; P = 0.03). No participant had explicit recall of intraoperative events when questioned after surgery (n = 253). Across groups, depth of anesthesia monitoring values showed a wide range; however, values were higher for responders before (54 +/- 20 vs. 42 +/- 14; P = 0.02) and after (52 +/- 16 vs. 43 +/- 16; P = 0.02) intubation. In patients not receiving total intravenous anesthesia, exposure to volatile anesthetics before intubation reduced the odds of responding (odds ratio, 0.2 [0.1 to 0.8]; P = 0.02) after adjustment for age. CONCLUSIONS: Intraoperative connected consciousness occurred frequently, although the rate is up to 10-times lower than anticipated. This should be considered a conservative estimate of intraoperative connected consciousness. PMID- 27984263 TI - Ketamine Increases the Function of gamma-Aminobutyric Acid Type A Receptors in Hippocampal and Cortical Neurons. AB - BACKGROUND: The "dissociative " general anesthetic ketamine is a well-known N methyl-D-aspartate receptor antagonist. However, whether ketamine, at clinically relevant concentrations, increases the activity of inhibitory gamma-aminobutyric acid (GABA) receptor type A (GABAA) receptors in different brain regions remains controversial. Here, the authors studied the effects of ketamine on synaptic and extrasynaptic GABAA receptors in hippocampal neurons. Ketamine modulation of extrasynaptic GABAA receptors in cortical neurons was also examined. METHODS: Whole cell currents were recorded from cultured murine neurons. Current evoked by exogenous GABA, miniature inhibitory postsynaptic currents, and currents directly activated by ketamine were studied. RESULTS: Ketamine did not alter the amplitude, frequency, or kinetics of postsynaptic currents but increased a tonic inhibitory current generated by extrasynaptic GABAA receptors in hippocampal neurons. For example, ketamine (100 uM) increased the tonic current by 33.6 +/- 6.5% (mean +/- SEM; 95% CI, 18.2 to 48.9; n = 8, P < 0.001). Ketamine shifted the GABA concentration-response curve to the left, but only when GABAA receptors were activated by low concentrations of GABA (n = 6). The selective increase in tonic current was attributed to ketamine increasing the apparent potency of GABA at high-affinity extrasynaptic GABAA receptors. Ketamine also increased a tonic current in cortical neurons (n = 11). Ketamine directly gated the opening of GABAA receptors, but only at high concentrations that are unlikely to occur during clinical use. CONCLUSIONS: Clinically relevant concentrations of ketamine increased the activity of high-affinity extrasynaptic GABAA receptors in the hippocampus and cortex, an effect that likely contributes to ketamine's neurodepressive properties. PMID- 27984265 TI - Sulfasalazine for Inflammatory Arthritis Induced by Hyaluronic Acid. PMID- 27984266 TI - Unintentional Epinephrine Auto-injector Injuries: A National Poison Center Observational Study. AB - BACKGROUND: Epinephrine is the only first-line therapeutic agent used to treat life-threatening anaphylaxis. Epinephrine auto-injectors are commonly carried by patients at risk for anaphylaxis, and reported cases of unintentional auto injector injury have increased over the last decade. Modifications of existing designs and release of a new style of auto-injector are intended to reduce epinephrine auto-injector misuse. STUDY QUESTION: The aim of the study was to characterize reported cases of unintentional epinephrine auto-injector exposures from 2013 to 2014 and compare demographics, auto-injector model, and anatomical site of such exposures. METHODS: The American Association of Poison Control Center's National Poison Data System was searched from January 1, 2013, to December 31, 2014, for cases of unintentional epinephrine auto-injector exposures. Anatomical site data were obtained from all cases reported to the Virginia Poison Center and participating regional poison center for Auvi-Q cases. RESULTS: A total of 6806 cases of unintentional epinephrine auto-injector exposures were reported to US Poison Centers in 2013 and 2014. Of these cases, 3933 occurred with EpiPen, 2829 with EpiPen Jr, 44 with Auvi-Q, and no case reported of Adrenaclick. The most common site of unintentional injection for traditional epinephrine auto-injectors was the digit or thumb, with 58% of cases for EpiPen and 39% of cases with EpiPen Jr. With Auvi-Q, the most common site was the leg (78% of cases). CONCLUSIONS: The number of unintentional epinephrine auto injector cases reported to American Poison Centers in 2013-2014 has increased compared with previous data. Most EpiPen exposures were in the digits, whereas Auvi-Q was most frequently in the leg. Because of the limitations of Poison Center data, more research is needed to identify incidence of unintentional exposures and the effectiveness of epinephrine auto-injector redesign. PMID- 27984267 TI - Falls or Skin Tears: Which Came First? PMID- 27984264 TI - Reducing Restraint With Clozapine in Involuntarily Admitted Patients With Schizophrenia. AB - BACKGROUND: In the entire world, restraint and seclusion are common interventions in psychiatric inpatient settings because of aggressive behavior. STUDY QUESTION: Our objective was to test for the immediate antiaggressive property of clozapine compared with other antipsychotic treatments in an enriched cohort with high rates of restraint during early hospitalization. METHODS: We present a retrospective chart review in all involuntary admissions with schizophrenia during 2011-2014 in Psychiatry and Neurology Hospital, Brasov, Romania. Timing and number of restraints in addition to clinical, demographic, and treatment characteristics were extracted. Based on our earlier observation of clinical efficacy of early, fast titration of clozapine, we tested the hypothesis that clozapine treatment was associated with reduced use of restraint and with longer restraint-free periods. RESULTS: In 115 consecutive patients with schizophrenia (age = 39.7 +/- 11.1 years; male = 59%) involuntarily admitted because of externalized (74.7%) or self-directed violence (25.2%), restraint was used in 89.6%; with a median duration of 3 hours until restraint past admission. Antipsychotics used immediately after hospitalization included haloperidol (70.4%), clozapine (11.3%), olanzapine (10.4%), and other second-generation antipsychotics (7.9%). Comparison of restraint characteristics favored immediate clozapine use with highly reduced rates of restraint (23% vs. 95.6%; P < 0.001) and significantly extended hours until restraint [(118, 24, 426 hours) vs. (3, 0.25, 48 hours); median; 25th, 75th percentile; P < 0.001] relative to the remaining cohort. These effects remained highly significant after controlling for potential moderators of restraint use in multivariate models. CONCLUSIONS: These retrospective data suggest an early antiaggressive effect of clozapine during the immediate use of clozapine in highly problematic patients. PMID- 27984268 TI - Addressing the Educational Needs of Wound Care Professionals. PMID- 27984269 TI - The 2017 Office of Inspector General Work Plan Pertains to You! PMID- 27984270 TI - Bitter Melon Extract Promotes Granulation Tissue Growth and Angiogenesis in the Diabetic Wound. AB - OBJECTIVE: Bitter melon is a plant fruit that has been shown to exert a hypoglycemic effect when used systemically in patients with diabetes. This study was designed to investigate the topical effect of bitter melon on diabetic wounds using the wound chamber model in rats. DESIGN: Two bilateral wound chambers were implanted subcutaneously in the thoracic-lumbar region of male Sprague-Dawley rats. Diabetes was induced with streptozotocin 7 days after implantation of wound chambers. After 24 hours of induction of diabetes, aqueous extract of bitter melon was injected into 1 wound chamber, and saline (0.9% sodium chloride solution) was injected into the contralateral chamber once daily for 3 days. Wound fluid was collected on day 4 for analysis, following which rats were euthanized. The granulation tissue encapsulating the wound chamber was removed and processed for histology. Controls included diabetic rats with wound chambers injected with saline (instead of bitter melon) and nondiabetic rats with wound chambers injected with bitter melon. RESULTS: In rats with diabetes, wound granulation tissue treated with bitter melon was well formed, with distinct cellular layers, whereas the saline-treated granulation tissue showed a severe loss of tissue organization and blood vessels. Moreover, the bitter melon treatment increased angiogenesis in the diabetic granulation tissue, marked by abundant microvessels and large blood vessels. In nondiabetic rats, no differences in wound granulation tissues were observed between saline- and bitter melon-treated groups. Bitter melon treatment had no effect on systemic blood glucose levels or insulin receptor substrate 1, suggesting that its stimulatory effect on diabetic granulation tissue was not due to alteration of systemic blood glucose levels. CONCLUSIONS: When applied locally to diabetic wounds, bitter melon extract prevents regression of granulation tissue and blood vessels, thus accelerating and improving wound healing. PMID- 27984271 TI - Effects of Colloidal Oatmeal Lotion on Symptoms of Dermatologic Toxicities Induced by Epidermal Growth Factor Receptor Inhibitors. AB - OBJECTIVE: The common adverse effects associated with targeted therapy for cancer, such as epidermal growth factor receptor inhibitors (EGFRIs), are dermatologic toxicities that cause the patient physical discomfort and affect treatment. Colloidal oatmeal lotion (COL) has been proven to help prevent dermatitis and xerosis. Evidence of its effect on EGFRI-induced dermatologic toxicities, however, is limited. The purpose of this study was to explore the effect of COL on EGFRI-induced dermatologic toxicities. DESIGN AND SETTING: This study used a 1-group pretest-posttest design with a convenience sample of 30 patients with cancer who developed EGFRI-induced dermatologic toxicities from a medical center in southern Taiwan. All participants applied topical COL 3 to 5 times a day for 4 consecutive weeks and received a pretest and 4 posttests. OUTCOME MEASURES: A generalized estimating equation was used to assess the impact of demographics, disease characteristics, and weeks of COL use on dermatologic toxicity severity, body surface area affected, and level of pruritus. MAIN RESULTS: Significant differences were found between the pretest and all posttests after using COL with regard to the severity, body surface area affected, and level of pruritus in participants who developed EGFRI-induced dermatologic toxicities (P < .05). There were no significant differences in demographics or disease characteristics on EGFRI-induced dermatologic toxicities. CONCLUSIONS: Based on the study results, COL could improve the symptoms of dermatologic toxicities in those receiving EGFRIs with no adverse effects. Therefore, the authors suggest the use of COL in clinical settings. PMID- 27984272 TI - Association of Sociodemographic Factors with Spirituality and Hope in Patients with Diabetic Foot Ulcers. AB - OBJECTIVE: To evaluate levels of spirituality and hope in patients with diabetic foot ulcers (DFUs) according to sociodemographic factors. DESIGN: This was a primary, prospective, descriptive, analytical, and clinical study. Questionnaires assessing sociodemographic and clinical characteristics of the patients, the Spirituality Self-rating Scale (SSRS), and the Herth Hope Index (HHI) were administered to all participants. SETTING: University-affiliated skilled nursing center and outpatient wound care clinic in Pouso Alegre, Brazil. PATIENTS: Fifty adult patients with DFUs participated in the study. Patients with ischemic diabetic foot and mixed ulcers were excluded from the study. MAIN RESULTS: On average, patients with DFUs had low levels of spirituality (mean SSRS score, 12.6) and low hope for cure (mean HHI, 16.5). Patients younger than 60 years reported significantly lower levels of spirituality (mean SSRS scores, 11.0), and those older than 70 years had significantly lower hope for cure (mean HHI, 12.5) than other age groups (P = .040). Level of spirituality was significantly lower among women (P = .015) and those living with an ulcer for more than 2 years, who also reported significantly lower hope for cure (P = .029) compared with patients having an ulcer for less than 2 years. CONCLUSION: On average, patients with DFUs, especially women and older adults, had a low sense of hope and spirituality. Except for gender, age, and ulcer duration, other sociodemographic and ulcer characteristics had no significant effect on the study population's spirituality and hope. PMID- 27984273 TI - Older Adults, Falls, and Skin Integrity. AB - GENERAL PURPOSE: To provide an overview of the assessment and management of risk factors for falls in older adults. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant should be better able to:1. Outline the components of an evidence-based falls assessment and identify risk factors for falls.2. Specify strategies to reduce falls in older adults, especially as related to maintaining skin integrity. ABSTRACT: Older adult patients may present to skin and wound care clinicians with skin injuries as a result of falls. In addition, chronic wounds associated with the patient's conditions may also increase his/her falls risk. Hence, appropriate assessment and management of the risk of falls in older adult patients are key elements of patient-centered care. PMID- 27984274 TI - Medicare Access and CHIP Reauthorization Act: Focus on the Merit-Based Incentive Payment System CY2017: Part 1. PMID- 27984275 TI - Older Adults, Falls, and Skin Integrity. PMID- 27984276 TI - Mechanisms of liver-induced tolerance. AB - PURPOSE OF REVIEW: To highlight the results of the ongoing research on the mechanisms of liver-induced tolerance focusing on results from the last year. RECENT FINDINGS: The liver is exposed to a massive antigenic burden of dietary and commensal products from the gastrointestinal tract via portal vein, most of which are necessary for survival. To prevent the immune system from destroying these foreign yet beneficial elements, the liver has developed unique mechanisms to suppress immune responses. It is thought that these mechanisms of acquired tolerance may also underlie the spontaneous acceptance of liver allografts observed after transplantation in many species. The fact that isolated hepatocyte transplants are acutely rejected, suggests that nonparenchymal liver cells play a critical role in spontaneous liver allograft acceptance. IFN-gamma, a key inflammatory cytokine produced by T effector (Tef) cells, is paradoxically compulsory for spontaneous liver allograft acceptance. Analysis of IFN-gamma signaling points to liver mesenchymal nonparenchymal liver cell that eliminate infiltrating Tef cells via expression of B7-H1, IL-10, and tumor growth factor beta, as well as the enhancement of Tregs and MDSCs. Thus, liver mesenchymal cells are thought to promote tolerance by eliminating alloreactive Tef cells and enhancing suppressor cells (T and B). SUMMARY: The research during last year offered some key insights into the mechanisms of liver-induced tolerance. Through interactions with activated T cells and B cells via IFN-gamma/B7-H1 pathways, liver mesenchymal cells have been shown to be critical components of liver specific tolerance induction. PMID- 27984279 TI - Sepsis Diagnostics: From Discovery to Application. PMID- 27984281 TI - Is It HIT? PMID- 27984280 TI - Source Control in Sepsis Urgent or Not So Fast? PMID- 27984278 TI - Guidelines for Family-Centered Care in the Neonatal, Pediatric, and Adult ICU. AB - OBJECTIVE: To provide clinicians with evidence-based strategies to optimize the support of the family of critically ill patients in the ICU. METHODS: We used the Council of Medical Specialty Societies principles for the development of clinical guidelines as the framework for guideline development. We assembled an international multidisciplinary team of 29 members with expertise in guideline development, evidence analysis, and family-centered care to revise the 2007 Clinical Practice Guidelines for support of the family in the patient-centered ICU. We conducted a scoping review of qualitative research that explored family centered care in the ICU. Thematic analyses were conducted to support Population, Intervention, Comparison, Outcome question development. Patients and families validated the importance of interventions and outcomes. We then conducted a systematic review using the Grading of Recommendations, Assessment, Development and Evaluations methodology to make recommendations for practice. Recommendations were subjected to electronic voting with pre-established voting thresholds. No industry funding was associated with the guideline development. RESULTS: The scoping review yielded 683 qualitative studies; 228 were used for thematic analysis and Population, Intervention, Comparison, Outcome question development. The systematic review search yielded 4,158 reports after deduplication and 76 additional studies were added from alerts and hand searches; 238 studies met inclusion criteria. We made 23 recommendations from moderate, low, and very low level of evidence on the topics of: communication with family members, family presence, family support, consultations and ICU team members, and operational and environmental issues. We provide recommendations for future research and work tools to support translation of the recommendations into practice. CONCLUSIONS: These guidelines identify the evidence base for best practices for family centered care in the ICU. All recommendations were weak, highlighting the relative nascency of this field of research and the importance of future research to identify the most effective interventions to improve this important aspect of ICU care. PMID- 27984282 TI - Not "Out of Sight, Out of Mind": Interventions to Relieve Suffering for Bereaved Families After an ICU Death. PMID- 27984283 TI - What Are the Long-Term Outcomes After Acute, Severe Kidney Injury and What Should We Be Doing About Them? PMID- 27984284 TI - Rural Sepsis Mortality: Patient Emergency Care Preference Impacts Resuscitation Outcome Value. PMID- 27984277 TI - Impact of hyperlipidemia on alloimmunity. AB - PURPOSE OF REVIEW: Hyperlipidemia is a comorbidity affecting a significant number of transplant patients despite treatment with cholesterol lowering drugs. Recently, it has been shown that hyperlipidemia can significantly alter T-cell responses to cardiac allografts in mice, and graft rejection is accelerated in dyslipidemic mice. Here, we review recent advances in our understanding of hyperlipidemia in graft rejection. RECENT FINDINGS: Hyperlipidemic mice have significant increases in serum levels of proinflammatory cytokines, and neutralization of interleukin 17 (IL-17) slows graft rejection, suggesting that IL-17 production by Th17 cells was necessary but not sufficient for rejection. Hyperlipidemia also causes an increase in alloreactive T-cell responses prior to antigen exposure. Analysis of peripheral tolerance mechanisms indicated that this was at least in part due to alterations in FoxP3 T cells that led to reduced Treg function and the expansion of FoxP3 CD4 T cells expressing low levels of CD25. Functionally, alterations in Treg function prevented the ability to induce operational tolerance to fully allogeneic heart transplants through costimulatory molecule blockade, a strategy that requires Tregs. SUMMARY: These findings highlight the importance of considering the contribution of inflammatory comorbidities to cardiac allograft rejection, and point to the potential importance of managing hyperlipidemia in the transplant population. PMID- 27984285 TI - Standardization of Ventilator Weaning Benefits Both Researchers and Clinicians. PMID- 27984286 TI - Knowing Risk Factors for Iatrogenic Withdrawal Syndrome in Children May Still Leave Us Empty-Handed. PMID- 27984287 TI - Can We Use "Pretty Big" Data to Settle the Score in Pediatric Extracorporeal Membrane Oxygenation? PMID- 27984289 TI - Editorial Board Acknowledgment. PMID- 27984288 TI - Desperate Times Call for Desperate Measures: Self-Cannibalism Is Protective During Sepsis. PMID- 27984290 TI - The Potential to Increase Organ Donation After Death by Circulatory Criteria. PMID- 27984291 TI - The authors reply. PMID- 27984292 TI - Functional Limitations Do Not Mean Poor Quality of Life. PMID- 27984293 TI - The authors reply. PMID- 27984295 TI - The authors reply. PMID- 27984294 TI - Potential Confounders of the Accuracy and Reliability of Delirium Assessment Tools. PMID- 27984296 TI - Mortality Prediction in Acute Respiratory Distress Syndrome. PMID- 27984297 TI - The authors reply. PMID- 27984298 TI - Knowledge, Skills, and Attitudes Concerning Intraosseous Access Among Hospital Physicians. PMID- 27984299 TI - The authors reply. PMID- 27984301 TI - Problem Shared Is a Problem Acknowledged. PMID- 27984300 TI - Return of Voice for Tracheostomized Patients in ICU, Not Only Psychologic Advantages. PMID- 27984302 TI - ABCDEF: Not So Simple. PMID- 27984304 TI - Artificial vision: principles and prospects. AB - PURPOSE OF REVIEW: The aim of this article is to give an overview of the strategies and technologies currently under development to return vision to blind patients and will answer the question: What options exist for artificial vision in patients blind from retinal disease; how close are these to clinical practice? RECENT FINDINGS: Retinal approaches will be the focus of this review as they are most advanced in terms not only of development, but entry into the imagination of the general public; they are technologies patients ask about, but may be less familiar to practicing neurologists.The prerequisites for retinal survivor cell stimulation are discussed, followed by consideration of the state of the art of four promising methods making use of this principle: electronic prostheses, stem cells, gene therapy and the developing field of ophthalmic optogenetics. SUMMARY: Human applications of artificial vision by survivor cell stimulation are certainly with us in the research clinic and very close to commercialization and general use. This, together with their place in the public consciousness, makes the overview provided by this review particularly helpful to practicing neurologists. PMID- 27984305 TI - From Contact to Contactless Pulse Oximetry: Can You Measure Me Now? PMID- 27984306 TI - Peripheral Nerve Catheters: Ready for a Central Role? PMID- 27984303 TI - The complexity of atrial fibrillation newly diagnosed after ischemic stroke and transient ischemic attack: advances and uncertainties. AB - PURPOSE OF REVIEW: Atrial fibrillation is being increasingly diagnosed after ischemic stroke and transient ischemic attack (TIA). Patient characteristics, frequency and duration of paroxysms, and the risk of recurrent ischemic stroke associated with atrial fibrillation detected after stroke and TIA (AFDAS) may differ from atrial fibrillation already known before stroke occurrence. We aim to summarize major recent advances in the field, in the context of prior evidence, and to identify areas of uncertainty to be addressed in future research. RECENT FINDINGS: Half of all atrial fibrillations in ischemic stroke and TIA patients are AFDAS, and most of them are asymptomatic. Over 50% of AFDAS paroxysms last less than 30 s. The rapid initiation of cardiac monitoring and its duration are crucial for its timely and effective detection. AFDAS comprises a heterogeneous mix of atrial fibrillation, possibly including cardiogenic and neurogenic types, and a mix of both. Over 25 single markers and at least 10 scores have been proposed as predictors of AFDAS. However, there are considerable inconsistencies across studies. The role of AFDAS burden and its associated risk of stroke recurrence have not yet been investigated. SUMMARY: AFDAS may differ from atrial fibrillation known before stroke in several clinical dimensions, which are important for optimal patient care strategies. Many questions remain unanswered. Neurogenic and cardiogenic AFDAS need to be characterized, as it may be possible to avoid some neurogenic cases by initiating timely preventive treatments. AFDAS burden may differ in ischemic stroke and TIA patients, with distinctive diagnostic and treatment implications. The prognosis of AFDAS and its risk of recurrent stroke are still unknown; therefore, it is uncertain whether AFDAS patients should be treated with oral anticoagulants. PMID- 27984307 TI - Maybe the Wand Does Matter? PMID- 27984308 TI - Implementation of Massive Transfusion Protocols in the United States: The Relationship Between Evidence and Practice. PMID- 27984309 TI - Summative Assessments Using Simulation Requires Safeguards. PMID- 27984310 TI - In Response. PMID- 27984311 TI - The Global Burden of Pain and Disability. PMID- 27984312 TI - "Wave" of the Future in Neuroanesthesiology Too! PMID- 27984315 TI - Effect of Pulsatility on Microcirculation in Patients Treated with Extracorporeal Cardiopulmonary Resuscitation: A Pilot Study. AB - The effect of pulsatile blood flow on microcirculation during extracorporeal cardiopulmonary resuscitation (ECPR) is not elucidated; therefore, we designed an observational study comparing sublingual microcirculation in patients with refractory cardiac arrest (CA) with spontaneously pulsatile or low/nonpulsatile blood flow after treatment with ECPR. Microcirculation was assessed with Sidestream Dark Field technology in 12 patients with CA who were treated with ECPR and 12 healthy control subjects. Microcirculatory images were analyzed offline in a blinded fashion, and consensual parameters were determined for the vessels <=20 MUm. The patients' data, including actual hemodynamic parameters, were documented. Pulsatile blood flow was defined by a pulse pressure (PP) >= 15 mm Hg. Compared with the healthy volunteers, the patients who were treated with ECPR exhibited a significantly lower proportion of perfused capillaries (PPC); other microcirculatory parameters did not differ. The groups of patients with pulsatile (n = 7) versus low/nonpulsatile (n = 5) blood flow did not differ in regards to the collected data and hemodynamic variables (except for the PP and ejection fraction of the left ventricle) as well as microcirculatory parameters. In conclusion, microcirculation appeared to be effectively supported by ECPR in our group of patients with CA with the exception of the PPC. We found only nonsignificant contribution of spontaneous pulsatility to extracorporeal membrane oxygenation-generated microcirculatory blood flow. PMID- 27984314 TI - Medical Management of Pump-Related Thrombosis in Patients with Continuous-Flow Left Ventricular Assist Devices: A Systematic Review and Meta-Analysis. AB - Pump thrombosis is a dreaded complication of left ventricular assist devices (LVADs). We completed a systematic review to evaluate the efficacy and complications associated with medical management of LVAD thrombosis. Databases were searched using the terms "vad*" or "ventricular assist device" or "heart assist device" and "thrombus" or "thrombosis" or "thromboembolism." Of 2,383 manuscripts, 49 articles met the inclusion criteria. The risk of partial or no resolution of LVAD thrombosis did not significantly differ between thrombolytic and nonthrombolytic regimens (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.20-1.16). When response to therapy was evaluated based on pump type, there were no significant differences in how patients with a HeartMate II or HeartWare ventricular assist device responded to thrombolytic or nonthrombolytic treatment. Pooled risk of major bleeding in the thrombolytic group was 29% (95% CI, 0.17-0.44) and 12% (95% CI, 0.01-0.57) in the nonthrombolytic group. Odds of death did not differ between thrombolytic and nonthrombolytic regimens (OR, 1.28; 95% CI, 0.42-3.89). Although thrombolytic and nonthrombolytic treatment similarly resolved LVAD thrombosis, major hemorrhage may be increased with the use of thrombolysis. Randomized clinical trials comparing thrombolytic and nonthrombolytic treatment of LVAD thrombosis are needed to establish the most effective and safe option for patients who are not surgical candidates. PMID- 27984316 TI - Venoarterial Extracorporeal Life Support for Neonatal Respiratory Failure: Indications and Impact on Mortality. AB - Venoarterial (VA) extracorporeal life support (ECLS) for neonatal respiratory failure is associated with increased mortality compared with venovenous (VV) ECLS. It is unclear whether this is a causal relationship or reflects differences in baseline disease severity between infants managed with these two strategies. Our objective was to identify clinical variables associated with the preferential selection of VA over VV ECLS, as these may confound the association between VA ECLS and increased mortality. We identified documented indications for preferential VA selection through chart review. We then assessed how the presence of common indications impacted mortality. Thirty-nine cases met eligibility. Severity of hypotension/degree of inotropic support and ventricular dysfunction on echocardiogram before cannulation were the most common specific indications for preferential VA ECLS. Mortality was 12.5% when neither high inotropic support nor ventricular dysfunction was present. Mortality rose to 20% with high inotropic support and 25% with ventricular dysfunction present alone and to 50% when both were present. We conclude that severe hypotension and ventricular dysfunction before ECLS cannulation are common indications for VA ECLS that likely influence survival. Research assessing the impact of ECLS cannulation mode on survival should adjust for baseline differences between groups for these important variables. PMID- 27984318 TI - Systemic Inflammatory Response Syndrome Is Not an Indicator of Bacteremia in Hemodialysis Patients With Native Accesses: A Multicenter Study. AB - Bloodstream infection (BSI) in hemodialysis (HD) patients is often difficult to diagnose. Systemic inflammatory response syndrome (SIRS) is a sensitive predictor of BSI in the general population. We aimed to assess the usefulness of SIRS in predicting BSI in HD patients. We designed a multicenter retrospective observational study of adult (age > 18 years) HD patients who underwent two sets of blood cultures for suspected BSI at first hospital visit from August 2011 to July 2012. Clinical, biological, and microbial data were evaluated to evaluate SIRS as a predictor of BSI upon initial presentation to the hospital. Data were obtained from 279 HD patients. Vascular access other than arteriovenous fistula and subcutaneously fixed superficial artery, and those administered antimicrobial drugs before visit were excluded; thus, a total of 202 patients were finally enrolled. Mean patient age was 71 years, 67.3% were male, 49.3% had diabetes, 28.2% had indwelling hardware, and 18.3% patients had BSI. Endocarditis and vertebral osteomyelitis were common infection sites, and Staphylococcus aureus was the most common pathogen. Of those with SIRS, 25.3% had BSI and 74.7% did not (odds ratio for SIRS, 2.10; 95% confidence interval, 0.90-4.91; p = 0.11). Thus, SIRS had a low sensitivity for predicting BSI in HD patients (sensitivity, 71.9%; specificity, 45.2%; positive likelihood ratio, 1.31; negative likelihood ratio, 0.62). Systemic inflammatory response syndrome has low sensitivity in identifying BSI in HD patients. A low threshold for drawing blood cultures and initiating antibiotic treatment should be considered for HD patients. PMID- 27984317 TI - Efficacy of Subcutaneous Electrocardiogram Leads for Synchronous Timing During Chronic Counterpulsation Therapy. AB - Counterpulsation devices (CPDs) require an accurate, reliable electrocardiogram (ECG) waveform for triggering inflation and deflation. Surface electrodes are for short-term use, and transvenous/epicardial leads require invasive implant procedure. A subcutaneous ECG lead configuration was developed as an alternative approach for long-term use with timing mechanical circulatory support (MCS) devices. In this study, efficacy testing was completed by simultaneously recording ECG waveforms from clinical-grade epicardial (control) and subcutaneous (test) leads in chronic ischemic heart failure calves implanted with CPD for up to 30 days. Sensitivity and specificity of CPD triggering by R-wave detection was quantified for each lead configuration. The subcutaneous leads provided 98.9% positive predictive value and 98.9% sensitivity compared to the epicardial ECG leads. Lead migration (n = 1) and fracture (n = 1) were observed in only 2 of 40 implanted leads, without adversely impacting triggering efficacy due to lead redundancy. These findings demonstrate the efficacy of subcutaneous ECG leads for long-term CPD timing and potential use as an alternative method for MCS device timing. PMID- 27984319 TI - Optimization of Positive End-Expiratory Pressure Targeting the Best Arterial Oxygen Transport in the Acute Respiratory Distress Syndrome: The OPTIPEP Study. AB - The optimal setting for positive end-expiratory pressure (PEEP) in mechanical ventilation remains controversial in the treatment of acute respiratory distress syndrome (ARDS). The aim of this study was to determine the optimum PEEP level in ARDS, which we defined as the level that allowed the best arterial oxygen delivery (DO2). We conducted a physiologic multicenter prospective study on patients who suffering from ARDS according to standard definition and persistent after 6 hours of ventilation. The PEEP was set to 6 cm H2O at the beginning of the test and then was increased by 2 cm H2O after at least 15 minutes of being stabilized until the plateau pressure achieved 30 cm H2O. At each step, the cardiac output was measured by transesophageal echocardiography and gas blood was sampled. We were able to determine the optimal PEEP for 12 patients. The ratio of PaO2/FiO2 at inclusion was 131 +/- 40 with a mean FiO2 of 71 +/- 3%. The optimal PEEP level was lower than the higher PEEP despite a constant increase in SaO2. The optimal PEEP levels varied between 8 and 18 cm H2O. Our results show that in patients with ARDS the optimal PEEP differs between each patient and require being determined with monitoring. PMID- 27984320 TI - Low Accuracy of the HeartMate Risk Score for Predicting Mortality Using the INTERMACS Registry Data. AB - Selection is a key determinant of clinical outcomes after left ventricular assist device (LVAD) placement in patients with end-stage heart failure. The HeartMate II risk score (HMRS) has been proposed to facilitate risk stratification and patient selection for continuous flow pumps. This study retrospectively assessed the performance of HMRS in predicting 90 day and 1 year mortality in patients within the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). A total of 11,523 INTERMACS patients who received a continuous flow LVAD between 2010 and 2015 were retrospectively categorized per their calculated HMRS to predict their 90 day and 1 year risk of mortality. The performance of the score was evaluated by the area under curve (AUC) of the receiver operator characteristic. We also performed multiple regression analysis using variables from the HMRS calculation on the INTERMACS data. The HMRS model showed moderate discrimination for both 90 day and 1 year mortality prediction with AUCs of 61% and 59%, respectively. The predictions had similar accuracy irrespective of whether the pump was axial or centrifugal flow. Multivariable analysis using independent variables used in the original HMRS analysis revealed different set of variables to be predictive of 90 day mortality than those used to calculate HMRS. HMRS predicts both 90 day and 1 year mortality with poor discrimination when applied to a large cohort of LVAD patients. Newer risk prediction models are therefore needed to optimize the therapeutic application of LVAD therapy. Patient selection for appropriate use of LVADs is critical. Currently available risk stratification tools (HMRS) continue to be limited in their ability to accurately predict mortality after LVAD. This study highlights these limitations when applied to a large, comprehensive, multicenter database. HMRS predicts mortality with only modest discrimination when applied to a large cohort of LVAD patients. Better risk stratification tools are needed to optimize outcomes. PMID- 27984321 TI - Extracorporeal Life Support Organization Registry International Report 2016. AB - Data on extracorporeal life support (ECLS) use and survival submitted to the Extracorporeal Life Support Organization's data registry from the inception of the registry in 1989 through July 1, 2016, are summarized in this report. The registry contained information on 78,397 ECLS patients with 58% survival to hospital discharge. Extracorporeal life support use and centers providing ECLS have increased worldwide. Extracorporeal life support use in the support of adults with respiratory and cardiac failure represented the largest growth in the recent time period. Extracorporeal life support indications are expanding, and it is increasingly being used to support cardiopulmonary resuscitation in children and adults. Adverse events during the course of ECLS are common and underscore the need for skilled ECLS management and appropriately trained ECLS personnel and teams. PMID- 27984322 TI - C-reactive protein-to-albumin ratio is a predictor of hepatitis B virus related decompensated cirrhosis: time-dependent receiver operating characteristics and decision curve analysis. AB - BACKGROUND AND AIMS: Hepatitis B virus (HBV) infection remains a major health problem and HBV-related-decompensated cirrhosis (HBV-DC) usually leads to a poor prognosis. Our aim was to determine the utility of inflammatory biomarkers in predicting mortality of HBV-DC. MATERIALS AND METHODS: A total of 329 HBV-DC patients were enrolled. Survival estimates for the entire study population were generated using the Kaplan-Meier method. The prognostic values for model for end stage liver disease (MELD) score, Child-Pugh score, and inflammatory biomarkers neutrophil/lymphocyte ratio, C-reactive protein-to-albumin ratio (CAR), and lymphocyte-to-monocyte ratio (LMR) for HBV-DC were compared using time-dependent receiver operating characteristic curves and time-dependent decision curves. RESULTS: The survival time was 23.1+/-15.8 months. Multivariate analysis identified age, CAR, LMR, and platelet count as prognostic independent risk factors. Kaplan-Meier analysis indicated that CAR of at least 1.0 (hazard ratio, 7.19; 95% confidence interval, 4.69-11.03), and LMR less than 1.9 (hazard ratio, 2.40; 95% confidence interval, 1.69-3.41) were independently associated with mortality of HBV-DC. The time-dependent receiver operating characteristic indicated that CAR showed the best performance in predicting mortality of HBV-DC compared with LMR, MELD score, and Child-Pugh score. The results were also confirmed by time-dependent decision curves. CONCLUSION: CAR and LMR were associated with the prognosis of HBV-DC. CAR was superior to LMR, MELD score, and Child-Pugh score in HBV-DC mortality prediction. PMID- 27984323 TI - Use of large healthcare databases for rheumatology clinical research. AB - PURPOSE OF REVIEW: Large healthcare databases, which contain data collected during routinely delivered healthcare to patients, can serve as a valuable resource for generating actionable evidence to assist medical and healthcare policy decision-making. In this review, we summarize use of large healthcare databases in rheumatology clinical research. RECENT FINDINGS: Large healthcare data are critical to evaluate medication safety and effectiveness in patients with rheumatologic conditions. Three major sources of large healthcare data are: first, electronic medical records, second, health insurance claims, and third, patient registries. Each of these sources offers unique advantages, but also has some inherent limitations. To address some of these limitations and maximize the utility of these data sources for evidence generation, recent efforts have focused on linking different data sources. Innovations such as randomized registry trials, which aim to facilitate design of low-cost randomized controlled trials built on existing infrastructure provided by large healthcare databases, are likely to make clinical research more efficient in coming years. SUMMARY: Harnessing the power of information contained in large healthcare databases, while paying close attention to their inherent limitations, is critical to generate a rigorous evidence-base for medical decision-making and ultimately enhancing patient care. PMID- 27984324 TI - Reconstruction of a Lateral Upper Lip Defect. PMID- 27984325 TI - Pseudocarcinomatous Epithelial Hyperplasia Induced by Imiquimod: A Mimic of Cutaneous Squamous Cell Carcinoma. PMID- 27984326 TI - Complications With New Oral Anticoagulants Dabigatran and Rivaroxaban in Cutaneous Surgery. PMID- 27984327 TI - Implantable Body Jewelry and Methods for Their Removal. PMID- 27984328 TI - Sex Differences in the Effect of Atomoxetine on the QT Interval in Adult Patients With Attention-Deficit Hyperactivity Disorder. AB - BACKGROUND: The effects of atomoxetine on QT in adults remain unclear. In this study, we examined whether the use of atomoxetine to treat attention-deficit hyperactivity disorder in adults is associated with QT prolongation. METHODS: Forty-one subjects with attention-deficit hyperactivity disorder were enrolled in this study. Participants were administered 40, 80, or 120 mg atomoxetine daily and were maintained on their respective dose for at least 2 weeks. We conducted electrocardiographic measurements and blood tests, measuring plasma atomoxetine concentrations after treatment. Electrocardiograms of 24 of the patients were also obtained before atomoxetine treatment. The QT interval was corrected using Bazett (QTcB) and Fridericia (QTcF) correction formulas. RESULTS: In these 24 patients, only the female patients had prolonged QTcB (P = 0.039) after atomoxetine treatment. There was no correlation between plasma atomoxetine concentrations and the corrected QT interval (QTc), or between atomoxetine dosage and the QTc. However, in female patients, there was a significant positive correlation between atomoxetine dosage and the QTcB (r = 0.631, P = 0.012), and there was a marginally significant positive correlation between atomoxetine dosage and the QTcF (r = 0.504, P = 0.055). In male patients, there was no correlation between atomoxetine dosage and the QTcB or QTcF intervals. There was no correlation between plasma atomoxetine concentrations and the QTc in either female or male patients. IMPLICATIONS: Clinicians should exhibit caution when prescribing atomoxetine, particularly for female patients. PMID- 27984329 TI - Perception of Gait Asymmetry During Split-Belt Walking. AB - Optimization of gait rehabilitation using split-belt treadmills critically depends on our understanding of the roles of somatosensory perception and sensorimotor recalibration in perceiving gait asymmetry and adapting to split belt walking. Recent evidence justifies the hypothesis that perception of gait asymmetry is based mainly on detection of temporal mismatches between afferent inputs at the spinal level. PMID- 27984330 TI - Palliative care in pulmonary arterial hypertension. AB - PURPOSE OF REVIEW: Developments in the management of pulmonary arterial hypertension have significantly improved prognosis changing this from an acute to a chronic disease. Despite optimal treatment many patients still have a high symptom burden both because of the disease and the side-effects of therapy, consequently there is an increasing need for a palliative care approach to improve the quality of life for this patient group. This review article will outline the need for palliative care support for patients with pulmonary arterial hypertension, discuss the barriers that currently exist and suggest how this may be improved. RECENT FINDINGS: Studies have been conducted which explore the role of palliative care in pulmonary arterial hypertension including physicians attitudes and the current barriers that exist to prevent its implementation. SUMMARY: Specialist palliative support is utilized in the minority of patients with pulmonary arterial hypertension despite a need for symptom control. Patients may benefit from the introduction of a palliative care approach as part of their standard care, but to achieve this there needs to be a greater understanding of the role of palliative care by both clinicians and patients and more research into the benefits for patients with pulmonary arterial hypertension. PMID- 27984332 TI - External validation of predictive models for acute kidney injury following cardiac surgery: A prospective multicentre cohort study. AB - BACKGROUND: Four predictive models for acute kidney injury associated with cardiac surgery were developed by Demirjian in the United States in 2012. However, the usefulness of these models in clinical practice needs to be established in different populations independent of that used to develop the models. OBJECTIVES: Our aim was to evaluate the predictive performance of these models in a Spanish population. DESIGN: A multicentre, prospective observational study. DATA SOURCES: Twenty-three Spanish hospitals in 2012 and 2013. ELIGIBILITY CRITERIA: Of 1067 consecutive cardiac patients recruited for the study, 1014 patients remained suitable for the final analysis. MAIN OUTCOME MEASURES: Dialysis therapy, and a composite outcome of either a doubling of the serum creatinine level or dialysis therapy, in the 2 weeks (or until discharge, if sooner) after cardiac surgery. RESULTS: Of the 1014 patients analysed, 34 (3.4%) required dialysis and 95 (9.4%) had either dialysis or doubled their serum creatinine level. The areas under the receiver operating characteristic curves of the two predictive models for dialysis therapy, which include either presurgical variables only, or combined presurgical and intrasurgical variables, were 0.79 and 0.80, respectively. The model for the composite endpoint that combined presurgical and intrasurgical variables showed better discriminatory ability than the model that included only presurgical variables: the areas under the receiver operating characteristic curves were 0.76 and 0.70, respectively. All four models lacked calibration for their respective outcomes in our Spanish population. CONCLUSION: Overall, the lack of calibration of these models and the difficulty in using the models clinically because of the large number of variables limit their applicability. PMID- 27984334 TI - Optimizing healthcare quality: teamwork in education, research, and practice. PMID- 27984335 TI - Influence of Manual Screwdriver Design in Combination With and Without Predrilling on Insertion Torque of Orthodontic Mini-Implants. AB - PURPOSE: The study focused on the influence of screwdriver design in combination with and without predrilling a pilot hole of inner implant diameter on insertion torque of orthodontic mini-implants, controlling for cortical thickness and vertical insertion force as cofactors. METHODS: One hundred twenty mini-implants (Forestadent) of 1.7 mm in diameter and 6 and 8 mm in length were manually inserted into 120 swine rib bone samples. Maximal insertion torque as a measure of primary stability and vertical force were measured. The study included procedures with and without pilot hole and different screwdriver handles and shaft length and 2 implant lengths. RESULTS: Design of manual screwdriver does not modify insertion torque to a significant extent. In multiple linear regression model, significant predictors of insertion torque are thicker cortical bone (explaining 16.6% of variability), higher vertical force at maximal torque (13.5%), 6-mm implant length (2.5%), and the presence of pilot hole (2.3%). CONCLUSIONS: Handle type and shaft length of manual screwdriver do not significantly influence insertion torque, whereas predrilling a pilot hole has low impact on torque values of manually inserted self-drilling orthodontic mini implants. PMID- 27984333 TI - Vitamin C Deficiency, High-Sensitivity C-Reactive Protein, and Cardiac Event-Free Survival in Patients With Heart Failure. AB - BACKGROUND: Vitamin C is related to lower levels of high-sensitivity C-reactive protein (hsCRP), an inflammatory biomarker that predicts cardiovascular disease. Whether vitamin C deficiency is associated with hsCRP and cardiac events in heart failure (HF) patients has not been examined. PURPOSE: The aim of this study is to determine the relationships among vitamin C intake, serum levels of hsCRP, and cardiac events. METHODS: A total of 200 HF patients completed a 3-day food diary to determine vitamin C deficiency and provided blood to measure serum levels of hsCRP. Patients were followed for 2 years to obtain data on cardiac event-free survival. Moderation analyses with hierarchical logistic and Cox regressions were used for the data analysis. RESULTS: Seventy-eight patients (39%) had vitamin C deficiency and 100 (50%) had an hsCRP level higher than 3 mg/L. Vitamin C deficiency was associated with an hsCRP level higher than 3 mg/L in the hierarchical logistic regression (odds ratio, 2.40; 95% confidence interval, [1.13-5.10]; P = .023). Vitamin C deficiency (hazard ratio, 1.68; 95% CI, 1.05 2.69, P = .029) and hsCRP level higher than 3 mg/L (hazard ratio, 1.79; 95% CI, 1.07-3.01; P = .027) predicted shorter cardiac event-free survival in hierarchical Cox regression. The interaction of hsCRP level higher than 3 mg/L and vitamin C deficiency produced a 2.3-fold higher risk for cardiac events (P = .002) in moderation analysis. Higher level of hsCRP predicted shorter cardiac event-free survival only in patients with vitamin C deficiency (P = .027), but not in those with vitamin C adequacy. CONCLUSION: Vitamin C deficiency moderated the relationship between inflammation and cardiac events in patients with HF. Future study is required to determine whether adequate intake of vitamin C could play a protective role against the impact of inflammation on cardiac events in HF patients. PMID- 27984336 TI - Demineralized Xenogenic Dentin and Autogenous Bone as Onlay Grafts to Rabbit Tibia. AB - PURPOSE: The present study was undertaken to evaluate the healing pattern of xenogenic demineralized dentin onlay grafts in comparison with autogenous bone grafts to the rabbit tibia. MATERIAL AND METHODS: Eight 6-month-old New Zealand male rabbits were used in the experiments. Standardized sized dentin blocks from human premolars and similar autogenous bone blocks harvested from tibia were grafted as onlay blocks on each tibia (n = 8 * 2). All animals were killed after a healing period of 12 weeks. RESULTS: Healing was uneventful for all animals. In general, both the dentin and bone block grafts were fused to the bone, resorbed, and replaced by bone and connective tissue to a varying degree. Both types of grafts were still present after 12 weeks, on an average to approximately one third of the original sizes. Resorption cavities could be seen in the dentin with bone formation. Zones of osseous replacement resorption of the dentin could be noted. In both graft types, higher rate of bone formation was seen at the interface between graft and recipient site. CONCLUSION: Demineralized xenogenic dentin onlay grafts showed similar resorption characteristics as autogenous bone onlay grafts, being resorbed in a similar rate during 12 weeks. New bone formation occurred mainly in terms of replacement resorption in the interface between dentin/bone graft and native bone. PMID- 27984337 TI - Inhibition of osteo/chondrogenic transformation of vascular smooth muscle cells by MgCl2 via calcium-sensing receptor. AB - OBJECTIVES: The progression of vascular calcification, an active process promoted by osteo/chondrogenic transformation of vascular smooth muscle cells (VSMCs) is attenuated by activation of the calcium-sensing receptor (CASR). Recent in-vitro studies revealed that vascular calcification could be blunted by Mg, but the underlying mechanisms remained elusive. The present study explored whether the effects of MgCl2 on vascular calcification involve the CASR. METHODS: Experiments were performed in primary human aortic smooth muscle cells (HAoSMCs) and in the mouse vascular calcification model of vitamin D3 overload. RESULTS: Phosphate induced calcium deposition and mRNA expression of the osteogenic markers msh homeobox 2 (MSX2), CBFA1 (core-binding factor alpha 1), and ALPL (tissue nonspecific alkaline phosphatase) in HAoSMCs were blunted by additional treatment with MgCl2. MgCl2 upregulated CASR mRNA expression in HAoSMCs in a dose-dependent manner. Furthermore, the inhibitory effects of MgCl2 on phosphate-induced calcium deposition and osteogenic markers mRNA expression were mimicked by the CASR agonist GdCl3 and reversed by additional treatment with the CASR antagonist NPS 2143 or by silencing of the CASR gene in HAoSMCs. MgCl2 also blunted the osteogenic transformation of VSMCs induced by hydroxyapatite particles. High dosed cholecalciferol treatment induced vascular calcification and upregulated aortic osteogenic markers Msx2, Cbfa1 and Alpl and collagen type I (Col1a1), collagen type III (Col3a1) and fibronectin (Fbn) mRNA expression in mice, effects reduced by additional treatment with MgCl2. These effects were paralleled by increased aortic Casr mRNA expression in cholecalciferol-treated mice, which was further augmented by MgCl2. CONCLUSION: The protective effects of MgCl2 on osteo/chondrogenic transformation of VSMCs and vascular calcification involve regulation of CASR and CASR-dependent signaling. PMID- 27984338 TI - Hypertension prevalence, awareness, treatment, control, and associated factors in Southwest China: an update. AB - OBJECTIVES: The study was conducted to investigate the prevalence, awareness, treatment, control, and risk factors of hypertension in Chongqing Province in Southwest China. METHODS: Multistage, stratified, random cluster sampling scheme was adopted to recruit representative samples. All of the selected study participants completed a questionnaire and physical examinations. Multivariable logistic regression models were used to identify the associated factors. RESULTS: Overall, 14 420 study participants (men = 7186) above 18 years were enrolled. The overall hypertension prevalence was 23.9%, with rural residents having a higher prevalence than urban residents (26.0 vs. 21.6%, P < 0.001). The awareness, treatment, control, and control among treated patients were 44.1, 36.6, 8.5, and 23.3%, respectively. Elderly women inhabiting urban areas had better awareness and treatment. The urban and rural areas differed in control (12.9 vs. 5.1%, P < 0.001). Age, sex, alcohol consumption, family history of hypertension, overweight/obesity, visceral adipose index, and body fat percentage were identified as risk factors for hypertension in both areas. Education levels, smoking, and daily salt intake were correlated with hypertension only among rural residents, and central obesity was correlated with hypertension only among urban residents. Sex, rurality, age, education level, alcohol consumption, overweight/obesity, central obesity, visceral adipose index, and body fat percentage were identified as associated factors of awareness, treatment, and control. CONCLUSION: During the past decade, there is an increasing prevalence of hypertension in the general population in Chongqing Province. The levels of awareness, treatment, and control have improved, but remain extremely low. More aggressive strategies should thus be adopted. PMID- 27984339 TI - Diagnostic Evaluation of Children with Autism Spectrum Disorders: Clinician Compliance with Published Guidelines. AB - OBJECTIVE: To assess to what extent child neurologists (CNs) and developmental behavioral pediatricians (DBPs) order diagnostic tests that are not recommended/indicated and/or fail to order tests that are recommended/indicated when evaluating children with an autism spectrum disorder (ASD). METHOD: CNs and DBPs in the United States were asked which laboratory tests they would "routinely order" for a preschool child with ASD and IQ = 58 (ASD + Intellectual Disability (ID)), and a preschool child with ASD and IQ = 85 (ASD-ID). Chi-square tests were performed to identify differences (CNs vs DBPs) in laboratory testing. RESULTS: The sample consisted of 267 respondents (127 CN's; 140 DBPs). When evaluating ASD + ID or ASD - ID, inappropriate tests (>=1) were ordered by 76.8% and 76.4% of MDs, respectively. There was no significant difference between specialties in compliance with evaluation guidelines for ASD + ID (CN = 20.5% vs DBP = 16.4%; chi = 0.73). No significant differences were noted (DBP vs CN) regarding the percent ordering inappropriate tests for either clinical case or within each specialty when comparing testing for ASD + ID versus ASD - ID. Relative to DBPs, CNs were more likely to order EEGs and MRIs when evaluating children with ASD + ID or ASD - ID. 10% and 40% of respondents did not order any recommended genetic tests when evaluating ASD + ID and ASD - ID, respectively. CONCLUSION: When evaluating children with ASD, many CNs and DBPs fail to order tests that should be routinely performed and often order tests that are not routinely indicated yet are neither benign nor inexpensive. Recommended molecular genetic tests are often not ordered. Clinical guidelines must be updated and better promulgated. PMID- 27984341 TI - Orthopaedic Infection: Prevention and Diagnosis. AB - Host optimization, reduction of bacteria, and establishing proper wound environment in the preoperative, intraoperative, and postoperative periods are the traditional cornerstones of infection prevention. Most institutions have standardized a systems approach to reduce the incidence of surgical site infections. Typically, these systems-based approaches promote protocols for hand and environmental hygiene, patients risk assessment and screening, surgical delays for identifiable and modifiable risk factors, infection surveillance, antibiotic stewardship programs, communication/coordination of care, physician 360 degrees reporting, and unit-based safety programs. Despite the institution of these prevention efforts, there remains controversy about the efficacy and cost-effectiveness of a number of these approaches. PMID- 27984340 TI - Predictors of Long-Term Victimization After Early Pediatric Traumatic Brain Injury. AB - OBJECTIVE: Pediatric traumatic brain injuries (TBIs) adversely affect long-term functional and social outcomes. Limited research suggests children with TBI are more likely to be victimized by peers than noninjured children. Deficits in social information processing (SIP), cognitive ability, and executive functioning (EF) may contribute to increased victimization risk. This study examined rates of peer victimization/bullying in children with early TBI compared with children with orthopedic injuries (OIs) and the role of processing speed, executive function (EF), and SIP as mediators of the association of TBI and peer victimization. METHOD: Children ages 10 to 14 years who sustained a complicated mild/moderate or severe TBI (N = 58) or OI (N = 72) during early childhood (ages 3-7 yr) and their parents participated in a longitudinal prospective follow-up 6.8 years postinjury. SIP, EF and processing speed, and peer victimization were assessed. RESULTS: Parents of children with severe TBI reported greater rates of peer victimization than parents of children with OIs. Children with severe TBI demonstrated greater EF deficits than children with complicated mild/moderate TBI or OI and poorer processing speed than children with OI. No significant indirect relationships were found between groups and any outcome variables to indicate mediation. CONCLUSION: Based on parent report, children with severe TBI have higher risk of peer victimization than those with less severe injuries. In addition, children with severe TBI have more impaired EF and cognitive ability than counterparts with less severe TBI. Further research is needed to explore predictors of long-term victimization after early TBI to create interventions aimed at providing social, emotional, and behavioral skill building for victimized youth. PMID- 27984342 TI - Strategies to Prevent Periprosthetic Joint Infection After Total Knee Arthroplasty and Lessen the Risk of Readmission for the Patient. AB - There is yet to be a standardized total knee arthroplasty (TKA) surgical protocol that has been studied to a sufficient degree to offer evidence-based practices regarding infection and readmission prevention. Although high-level evidence is often sought to provide guidance concerning protocol- and process-level decisions, the literature is often confusing and nondefinitive in its conclusions and recommendations regarding periprosthetic joint infection and readmission prevention. Areas of study that require further investigation include the following: the role of patient optimization and preoperative mitigation of risk; perioperative antibiotics; operating room environment; blood management; operative techniques, implants, and infection prevention measures; wound care management; and post acute care. Patient-associated modifiable risk must be optimized to decrease poly joint infection rates after TKA. Protocol measures for TKA need to be standardized, and evidence-based practice measures need to be validated. PMID- 27984343 TI - Value-based Purchasing for Osteoarthritis and Total Knee Arthroplasty: What Role for Patient-reported Outcomes? AB - Prompted by the aims to improve the patient experience of care (including quality and satisfaction), improve the health of populations, and reduce the per capita cost of health care, the US healthcare system is embarking upon a new era in care delivery that seeks to optimize healthcare value. Value, the consideration of quality relative to cost, can be increased by improving quality, reducing cost, or doing both. Given that patient-reported outcomes related to pain, function, and quality of life underlay both the reason patients seek care for and the benchmarks by which treatment success is measured for osteoarthritis, measures of these patient-reported outcomes figure prominently in understanding the quality and hence value. Directed attention to patient-reported outcomes has the potential to drive quality and efficiency improvements, but only if the quality measures that are developed from them are clinically important, scientifically acceptable, usable, and feasible. PMID- 27984344 TI - Genomic profiling of gynecologic cancers and implications for clinical practice. AB - PURPOSE OF REVIEW: This article summarizes advances in the application of next generation sequencing (NGS) to the personalized treatment of gynecologic malignancies. RECENT FINDINGS: Many recurrent genomic alterations (GA) in gynecologic malignancies have been identified by studies applying NGS to tumor tissue, which can provide insights into tumor biology, diagnostic or prognostic information, and potential targeted therapy options. NGS can be used to assay single genes, portions of multiple genes ("hot-spot" panels), or the complete coding sequence of a broad range of cancer-associated genes [i.e. comprehensive genomic profiling (CGP)]. CGP of a patient's tumor reveals to practitioners clinically relevant GA (CRGA) and associated biomarker-matched treatments, with a goal of improving therapeutic response while limiting cumulative chemotherapeutic toxicities. Although the use of precision medicine for gynecologic cancers holds much promise, the data detailing impact on survival and quality of life is still accumulating, lagging behind other areas of oncology. Enrolling gynecologic oncology patients in genotype-matched trials remains challenging and highlights the need for more molecular-based basket trials for reproductive tract malignancies. SUMMARY: Identification of molecular subsets with distinct clinical attributes, prognostic significance, and targeted therapy directed options is now feasible in clinical gynecologic oncology practice. PMID- 27984345 TI - Vulvodynia: What We Know and Where We Should Be Going. AB - OBJECTIVE: The aim of the study was to review the current nomenclature and literature examining microbiome cytokine, genomic, proteomic, and glycomic molecular biomarkers in identifying markers related to the understanding of the pathophysiology and diagnosis of vulvodynia (VVD). MATERIALS AND METHODS: Computerized searches of MEDLINE and PubMed were conducted focused on terminology, classification, and "omics" variations of VVD. Specific MESH terms used were VVD, vestibulodynia, metagenomics, vaginal fungi, cytokines, gene, protein, inflammation, glycomic, proteomic, secretomic, and genomic from 2001 to 2016. Using combined VVD and vestibulodynia MESH terms, 7 references were identified related to vaginal fungi, 15 to cytokines, 18 to gene, 43 to protein, 38 to inflammation, and 2 to genomic. References from identified publications were manually searched and cross-referenced to identify additional relevant articles. A narrative synthesis of the articles was conducted; however, meta analysis was not conducted because of substantial heterogeneity in the studies and limited numbers of control-matched studies. RESULTS: Varying definitions of VVD complicate a meta-analysis, and standard definitions will better allow for comparisons of studies and enhance the applicability of evidence to patient populations. Although data are still limited, genomic and molecular diagnostic testings continue to be investigated as potential tools for the diagnosis of VVD. CONCLUSIONS: Standardized nomenclature will allow for comparability of studies and progress in research related to the pathophysiology of VVD and to facilitate clinical decision making and treatment choices. Although the current understanding of the pathogenesis of VVD is limited, there are new opportunities to explore potential diagnostic markers differences in women with VVD, which may lead to targeted therapy. PMID- 27984347 TI - Hepatic Issues and Complications Associated With Inflammatory Bowel Disease: A Clinical Report From the NASPGHAN Inflammatory Bowel Disease and Hepatology Committees. AB - Hepatobiliary disorders are common in patients with inflammatory bowel disease (IBD), and persistent abnormal liver function tests are found in approximately 20% to 30% of individuals with IBD. In most cases, the cause of these elevations will fall into 1 of 3 main categories. They can be as a result of extraintestinal manifestations of the disease process, related to medication toxicity, or the result of an underlying primary hepatic disorder unrelated to IBD. This latter possibility is beyond the scope of this review article, but does need to be considered in anyone with elevated liver function tests. This review is provided as a clinical summary of some of the major hepatic issues that may occur in patients with IBD. PMID- 27984346 TI - An Examination of Claims-based Predictors of Overdose from a Large Medicaid Program. AB - BACKGROUND: Health systems may play an important role in identification of patients at-risk of opioid medication overdose. However, standard measures for identifying overdose risk in administrative data do not exist. OBJECTIVE: Examine the association between opioid medication overdose and 2 validated measures of nonmedical use of prescription opioids within claims data. RESEARCH DESIGN: A longitudinal retrospective cohort study that estimated associations between overdose and nonmedical use. SUBJECTS: Adult Pennsylvania Medicaid program 2007 2012 patients initiating opioid treatment who were: nondual eligible, without cancer diagnosis, and not in long-term care facilities or receiving hospice. MEASURES: Overdose (International Classification of Disease, ninth edition, prescription opioid poisonings codes), opioid abuse (opioid use disorder diagnosis while possessing an opioid prescription), opioid misuse (a composite indicator of number of opioid prescribers, number of pharmacies, and days supplied), and dose exposure during opioid treatment episodes. RESULTS: A total of 372,347 Medicaid enrollees with 583,013 new opioid treatment episodes were included in the cohort. Opioid overdose was higher among those with abuse (1.5%) compared with those without (0.2%, P<0.001). Overdose was higher among those with probable (1.8%) and possible (0.9%) misuse compared with those without (0.2%, P<0.001). Abuse [adjusted rate ratio (ARR), 1.52; 95% confidence interval (CI), 1.10-2.10), probable misuse (ARR, 1.98; 95% CI, 1.46-2.67), and possible misuse (ARR, 1.76; 95% CI, 1.48-2.09) were associated with significantly more events of opioid medication overdose compared with those without. CONCLUSIONS: Claims-based measures can be used by health systems to identify individuals at-risk of overdose who can be targeted for restrictions on opioid prescribing, dispensing, or referral to treatment. PMID- 27984348 TI - Low-impedance Baseline Values Predict Severe Esophagitis. AB - OBJECTIVES: The aim of the study was to determine whether esophageal baseline impedance (BI) values in children could be predictive of esophagitis. MATERIALS AND METHODS: Multichannel intraluminal impedance (MII) tracings of children 3 to 17 years of age suspected of having gastroesophageal reflux and esophagitis, who had also undergone upper endoscopy with multiple esophageal biopsies, were reviewed. Patients with eosinophilic esophagitis were excluded. Esophagitis was assessed by macroscopic and microscopic parameters. Esophageal histology was reported by 2 blinded independent pathologists unaware of the MII results. Mean BI was automatically calculated in the different MII channels (ch) by the specific software without removing any episode of increased/decreased BI. BI results were plotted against macroscopic and histological scores for each channel. RESULTS: Tracings of 87 children, 53 boys, were evaluated. Mean age was 7.4 years: 45 had histologic esophagitis, 8 macroscopic. Histologic mild esophagitis (grade 1) was observed in 30, and 15 had moderate to severe esophagitis (grade 2-3). Ten had grade 3 esophagitis. Eight had macroscopic esophagitis as well. RESULTS: in channel 6 of the MII, all 10 patients with grade 3 esophagitis and the 8 with macroscopic esophagitis had a BI <900 Omega/s (positive predictive value 100% and negative predictive value 100%), whereas none of those having a biopsy score of 0 to 2 or no endoscopic evidence of esophagitis had a mean BI below 2000 Omega/s. CONCLUSIONS: The evaluation of the BI measured in channel 6 gave us 100% prediction of grade 3 and macroscopic esophagitis. BI on channel 6 may be useful to predict severe esophageal mucosa inflammation and could potentially be used for follow-up evaluation, rather than repeating an upper endoscopy. In addition, it would seem that grade 3 esophagitis even in the absence of macroscopic esophagitis affects the integrity of the esophageal epithelium. PMID- 27984349 TI - Creatively Improving Care Delivery. AB - The medical community has been challenged to improve upon deficiencies in the delivery of patient care. Quality improvement methods are therefore increasingly used in everyday clinical practice. As demonstrated in this review, creative and impactful improvement projects within pediatric gastroenterology can be successfully achieved as either multicenter projects or single-center efforts. Through our willingness to accept the challenge to improve, practitioners within the pediatric gastroenterology community have become leaders in using quality improvement to change practice and improve clinical outcomes. PMID- 27984350 TI - Nonarteritic Anterior Ischemic Optic Neuropathy and Erectile Dysfunction Drugs: Is There an Elephant in the Bedroom? PMID- 27984351 TI - Structural and Functional Analyses in Nonarteritic Anterior Ischemic Optic Neuropathy: Optical Coherence Tomography Angiography Study. AB - BACKGROUND: Retinal and optic disc perfusion in nonarteritic anterior ischemic optic neuropathy (NAION) is incompletely understood. Our aim was to investigate the characteristics of the microvascular structures at the peripapillary area and optic disc, and their associations with retinal structure and function in patients with NAION. METHODS: We conducted a prospective, observational case series study. Thirty-four eyes, consisting of 15 NAION eyes and 19 normal eyes, were included. Optical coherence tomography (OCT) angiography was used to measure the vessel densities in the peripapillary superficial retina and whole-depth mode inside the optic disc. Measurement of circumpapillary retinal nerve fiber layer (cpRNFL) thickness was performed using OCT. Sectorial division analysis of cpRNFL was performed by eliminating the influences of the difference in disc rotation between OCT images and OCT angiography images. RESULTS: The vessel densities of peripapillary retina and inside the optic disc were significantly reduced in the NAION compared to the normal (both P < 0.001). Both the severity of visual field defect and cpRNFL thinning were significantly associated with the peripapillary vessel density (P = 0.006, P = 0.046), but not with the optic disc vessel density (P = 0.981, P = 0.856). cpRNFL and peripapillary vessel density showed reduction predominantly in the superior sectors, corresponding to the visual field defect. However, the correlations showed discrepancy of the sectors. CONCLUSIONS: The microvascular structures in the peripapillary retina and optic disc were reduced, but the cpRNFL thinning was associated with vessel density only in the peripapillary retina, indicating that the vessel densities in the peripapillary retina and optic disc may be differently affected in the pathological process of NAION. PMID- 27984352 TI - Short Follow-up Bias Confounds Estimates of the "Typical" Clinical Course of Susac Syndrome. AB - BACKGROUND: To evaluate the validity of the prevailing concept that Susac syndrome (SS), a rare microvasculopathy of the brain, retina, and inner ear, is a self-limiting disease. METHODS: We performed a literature search to identify all cases of SS reported between 1973 and October 2015. If available, we determined their demographics, duration of follow-up, and the clinical course that was labeled as monocyclic or polycyclic. We attempted to determine the number of relapses and the relapse rate in patients with polycyclic disease. RESULTS: Our literature search yielded 185 relevant publications reporting 405 cases of SS. The duration of follow-up could be determined in 247/405 cases, with a range 0.5 312 months. The mean was 41 months but the distribution was skewed, with a median of 24 months. Defining the clinical course as monocyclic or polycyclic was possible in 102 patients who were followed for greater than 24 months; 53 were identified as having a polycyclic course. Patients labeled polycyclic were followed longer than those labeled monocyclic (median 62 vs 42 months, P < 0.001). The number or frequency of attacks per patient could not be determined. CONCLUSIONS: The follow-up of published cases of SS is short, creating an inherent bias toward the impression that the disease is self-limiting. Our findings suggest that stratification of SS into monocyclic, polycyclic, and chronic continuous courses may oversimplify the phenotype of SS; instead, the possibility of a relapsing-remitting course must be considered in all patients with this disorder. PMID- 27984353 TI - Reversible Charles Bonnet Syndrome After Oculoplastic Procedures. AB - Individuals with Charles Bonnet syndrome (CBS) typically have severe visual loss and experience visual hallucinations yet have no psychiatric disease. Visual impairment often is due to end-stage glaucoma or macular degeneration. We report 3 cases of CBS in patients who underwent an oculoplastic surgical procedure. One patient experienced binocular visual distortion due to excessive topical ophthalmic ointment, and 2 patients experienced monocular visual impairment from patching. Visual hallucinations resolved once vision returned to baseline. We highlight the possibility of transient CBS in postoperative patients who have temporary iatrogenic vision impairment in one or both eyes. PMID- 27984354 TI - Predictors of Suboptimal Follow-up in Pediatric Cancer Survivors. AB - Attendance to follow-up care after completion of cancer treatment is an understudied area. We examined demographic, clinical, and socioeconomic predictors of follow-up by pediatric cancer patients at a large center in 442 newly diagnosed patients using multivariable logistic regression analyses. Patients who did not return to clinic for at least 1000 days were considered lost to follow-up. Two hundred forty-two (54.8%) patients were lost. In multivariable analyses, the following variables were independent predictors of being lost to follow-up: treatment with surgery alone (odds ratio [OR]=6.7; 95% confidence interval [CI], 3.1-14.9), older age at diagnosis (reference, 0 to 4; ages, 5 to 9: OR=1.8, 95% CI, 1.1-3; ages, 10 to 14: OR=3.3; CI, 1.8-6.1; and ages, 15 and above: OR=4.8; CI, 2.1-11.7), lack of history of stem cell transplantation (OR=2, 95% CI, 1.04-3.7) and lack of insurance (OR=3.4; CI, 1.2-9.2). Hispanic patients had the best follow-up rates (53.7%) compared to whites and blacks (P=0.03). Attendance to long-term follow-up care is suboptimal in childhood cancer survivors. Predictors that were associated with nonattendance can be used to design targeted interventions to improve follow-up care for survivors of pediatric cancer. PMID- 27984356 TI - STRUCTURAL AND FUNCTIONAL MONITORING OF EXTRAMACULAR CYSTOID SPACES IN A CASE OF X-LINKED RETINOSCHISIS TREATED WITH ACETAZOLAMIDE. AB - BACKGROUND: Carbonic anhydrase inhibitors (CAIs) have been shown to have a beneficial effect on cystoid macular edema in X-linked retinoschisis (XLRS) and other inherited retinal conditions. The effect of CAIs outside the macula has been less well studied. METHODS: Snellen visual acuity, spectral-domain optical coherence tomography (SD-OCT), kinetic visual field, and dark-adapted single flash full-field electroretinogram (ERG) testing were all done at baseline and at least one follow-up visit. A 55-year-old male diagnosed with XLRS exhibited extensive macular and extramacular cystoid splitting in the right eye and was treated with oral extended-release acetazolamide 500 mg/day. RESULTS: By 6 months of follow-up on acetazolamide treatment, SD-OCT demonstrated resolution of cystoid spaces both within the macula and out to the midperiphery. Visual acuity improved from 20/70 to 20/30. The full-field ERG was distinctly electronegative at both baseline and at a follow-up visit, with oscillatory potentials becoming more apparent at the follow-up visit. Peripheral visual field boundaries did not change significantly. CONCLUSION: This report demonstrates structural resolution of cystoid spaces throughout much of the retina in a patient with XLRS, adding to a published case report in which we first noted that extramacular cystoid spaces observed in XLRS may respond to CAI treatment. To our knowledge, this is the first reported study of follow-up functional studies (ERG and perimetry) in a CAI treatment responder with XLRS. PMID- 27984357 TI - Perceptions of Teamwork in the Interprofessional Bedside Rounding Process. AB - Patient perceptions of teamwork have been a relatively undiscovered domain. Our study investigated the use of the Patients' Insights and Views of Teamwork (PIVOT) survey on an acute cardiology unit in an academic teaching hospital with patients receiving Rounding with Heart, an interprofessional bedside rounding initiative, and others receiving traditional rounding processes. Sixty-three subjects were surveyed during their hospital stay. We found a significant difference (p = .006) in PIVOT scores between those receiving interprofessional rounding and those not receiving this rounding structure. In an item-by-item analysis, four specific items were found to be significant which were supported by analysis of qualitative data. Observations of the structured interprofessional rounding process by our research team reveal themes that emerged from observations: (1) openness/inclusivity, (2) patient-centeredness, (3) attending role/shared leadership, (4) nonconfrontational learning, (5) efficacy, and (6) team at bedside. Our results indicate that patients may be able to recognize the teamwork in the structured bedside rounding process and that interfacing with the team may be an important component to patients. We conclude that patient perceptions of teamwork are a valuable informant to modeling collaborative practices, and there are key observable components to the structured rounding model that may foster collaboration among different disciplines. PMID- 27984358 TI - Quality Improvement: Changing Patterns of Antibiotic Prophylaxis for Surgical Abortion. AB - OBJECTIVE: Postprocedure infection complicates nearly 5% of abortions. Multiple organizations endorse prophylactic antibiotics to reduce infection risk with surgical abortion, but the adherence rate remains unknown for women who obtain antibiotics at a pharmacy and take them at home before their procedure. Our objective was to evaluate the effect of quality improvement interventions on antibiotic utilization and preoperative documentation for women undergoing surgical abortion at our academic institution. METHODS: An initial quality evaluation of antibiotic utilization by women who had abortions in our operating room between April 2012 and June 2013 revealed suboptimal antibiotic adherence and poor physician documentation. To address these issues, we recommended patients to fill prescriptions at the pharmacy located in the same building as our clinic and created a standard preoperative template for the medical record. We reexamined outcomes for women having abortions from April 2014 to June 2015. RESULTS: Antibiotic adherence increased from 81% to 90% (p < .001). The proportion of patients not receiving antibiotics decreased from 2.4% to 0.5% (p = .01). Adherence documentation rates improved from 69% to 99% (p < .001). CONCLUSIONS: Using an easily accessible pharmacy and a standard preoperative template improves utilization of prophylactic antibiotics for patients undergoing abortions in the operating room. PMID- 27984359 TI - Analysis of Factors Affecting the Outcomes of In-hospitalized Vestibular Rehabilitation in Patients With Intractable Dizziness. AB - OBJECTIVE: To analyze somatic and psychological factors affecting the outcomes of in-hospital vestibular rehabilitation in patients with intractable dizziness. MATERIALS AND METHODS: The study involved 138 patients with persistent dizziness caused by peripheral vestibular dysfunction. They were hospitalized and taught to conduct a vestibular rehabilitation program for 30 minutes by themselves three times a day over 5 days. They were then instructed to continue performing the program every day after discharge. Several questionnaires were conducted immediately before, and 1 month after, the treatment. For example, the dizziness handicap inventory (DHI), the somatosensory catastrophizing scale (SSCS), and indexes of depression and anxiety. Posturography was also performed. The main outcome was the difference between the DHI scores before and after rehabilitation. Body sway was objectively evaluated using static posturography. RESULTS: The vestibular rehabilitation significantly improved the DHI score, the SSCS score, depression, and anxiety. Multivariate analysis indicated that the improvement in the DHI score was poorer in patients who showed high SSCS score before intervention. A higher prevalue of the DHI was associated with greater improvements in this perceived handicap after the rehabilitation. Small body sway pre-rehabilitation was related to positive effects on the DHI score in patients with a high prevalue of the DHI. CONCLUSION: The vestibular rehabilitation contributed to the improvement of perceived handicap due to dizziness, catastrophization of bodily sensation, and emotional distress. Patients who catastrophized their bodily sensations before vestibular rehabilitation saw smaller improvements in perceived handicap due to dizziness. PMID- 27984360 TI - Upper Eyelid Response to Topical 0.5% Apraclonidine. AB - PURPOSE: To describe the change in upper eyelid position in a self-reportedly normal population after the administration of topical 0.5% apraclonidine in each eye. METHODS: One hundred self-reportedly normal subjects received a 1-time administration of topical 0.5% apraclonidine in each eye. Digital photographs were taken at baseline and then 30 and 45 minutes following apraclonidine instillation. Marginal reflex distance 1 was determined via image analysis of acquired digital photographs (image-derived measurements are given the prefix "i" in this study). The horizontal corneal diameter was used as a constant measurement scale in each photograph. RESULTS: The mean increase in i-marginal reflex distance 1 post-administration of 0.5% apraclonidine was +0.70 +/- 0.60 mm (range, -0.94 to +2.66 mm) after 30 minutes and +0.68 +/- 0.59 mm (range, -0.69 to +2.54 mm) after 45 minutes. Of the 200 total eyelids in 100 subjects, 181 (90.5%) had an increase in i-marginal reflex distance 1 at 30 minutes. Of the 100 subjects, 85 (85%) had a bilateral increase in i-marginal reflex distance 1, 4 (4%) had a bilateral decrease, and 11 (11%) had a unilateral increase with a contralateral decrease. CONCLUSIONS: Given its predominant small-amplitude upper eyelid elevating effect, topical apraclonidine may be a useful off-label alternative treatment for mild upper eyelid ptosis and in eyelid asymmetry due to eyelid retraction through use in the contralateral eye. PMID- 27984361 TI - Dorsal Distraction Plating and Lunate Decortication for Stage III Kienbock Disease: A Novel Technique. AB - Kienbock disease (KD) is a progressive condition and difficult to manage. A number of treatment algorithms exist but there is no clear consensus as to which method produces the best outcome, particularly for Lichtman stage III disease. The majority of the current treatment options for KD emphasize lunate unloading and restoration of biology with bone graft. However, less attention has been given to the protection of the lunate during revascularization process. We report a novel technique of lunate decompression and bone grafting, combined with wrist distraction with or without radial shortening osteotomy via dorsal wrist bridge plating for the treatment of stage II-IIIa/b KD. This technique provides the advantages of distraction of the carpus unloading the lunate after bone grafting and during revascularization without the issues inherent to external fixation. In addition, this technique allows compression through a radial osteotomy site when performed. Our approach to the treatment of KD has incorporated this technique for patients with stage II or IIIa/b disease. PMID- 27984364 TI - Age-Stratified Analysis of Diabetes and Pseudophakia Effects on Corneal Endothelial Cell Density: A Retrospective Eye Bank Study. AB - PURPOSE: To perform an age-stratified analysis of the effect of diabetes and pseudophakia on corneal endothelial cell density (ECD). METHODS: This is a comparative analysis of donor characteristics from data supplied by the Lions Eye Institute for Transplant and Research on tissue harvested from July 1, 2007, through May 23, 2014. The mixed-effects model was used to compare age-adjusted mean corneal ECD between donors with and without diabetes. RESULTS: A total of 20,026 nondiabetic donor eyes and 13,617 diabetic donor eyes were included in this study. ECD was 2604 cells per square millimeter in nondiabetic corneas and 2576 cells per square millimeter in diabetic corneas (P < 0.001). Among phakic patients, diabetic ECD was significantly less in the middle-age subgroups: -33 cells per square millimeter in the 21-to-40-year-old subgroup (P = 0.048) and -25 cells per square millimeter in the 41-to-60-year-old subgroup (P = 0.009). Among pseudophakic patients, diabetic ECD was significantly less only in the subgroup 61 years or older: -56 cells per square millimeter (P = 0.026). The magnitude of difference in ECD between phakic and pseudophakic donors was greater in patients with diabetes in the subgroup 61 years or older (P < 0.001). CONCLUSIONS: Donor eyes with a history of diabetes had a slightly lower ECD (-29 cells/mm) than eyes without a history of diabetes. Although this statistical relationship is consistent with our pathophysiologic understanding of diabetes and the corneal endothelium, such a minor difference in ECD would be expected to have minimal clinical impact on overall corneal endothelial function. PMID- 27984365 TI - Mid-Term Results of a Single Intrastromal Corneal Ring Segment for Mild to Moderate Progressive Keratoconus. AB - PURPOSE: To study the mid-term effects of implanting a single intracorneal ring segment (ICRS) for treatment of mild to moderate progressive keratoconus. METHODS: This retrospective study was conducted on patients with progressive keratoconus treated with ICRS. The mean follow-up time was 15.2 +/- 8.8 (range, 7 26) months before and 27.8 +/- 7.5 (range, 18-35) months after surgery. Patients received no other treatment during this time. Of the cases studied, 59.1% had inferior keratoconus. RESULTS: Thirty eyes of 30 patients with a mean age of 27.5 +/- 4.6 years were included in the study. Corrected distance visual acuity decreased by 1 line during the preoperative follow-up and improved by 2 lines after surgery (P < 0.05). Maximum keratometry (Kmax) of the anterior (2.39 +/- 0.75 D) and posterior (0.33 +/- 0.32 D) corneas at 3 mm and anterior Kmax at 8 mm (2.39 +/- 0.95 D) decreased after treatment (all P < 0.05). The posterior Q value shifted toward a more oblate curvature (0.50 +/- 0.52, P = 0.023). Decreases in anterior elevation at the thinnest point (5.22 +/- 7.21 MUm) and posterior corneal central elevation (8.89 +/- 11.26 MUm) were significant (both P < 0.05). Corneal thickness at the center (11.11 +/- 12.38 MUm) and thinnest point (15.89 +/- 12.75 MUm) increased after treatment (all P < 0.001). Other significant changes included postoperative decreases in the keratoconus index (0.12 +/- 0.06), index of height decentration (0.06 +/- 0.05), index of surface variance (27.32 +/- 13.08), index of vertical asymmetry (0.42 +/- 0.21), index of height asymmetry (8.42 +/- 20.57), and an increase in the center keratoconus index (0.01 +/- 0.02) (P < 0.001). CONCLUSIONS: This study demonstrates that ICRS implantation provides favorable mid-term outcomes in treatment of mild and moderate progressive keratoconus and can improve corneal indices compared with their preoperative states. PMID- 27984366 TI - Human Ex Vivo Artificial Anterior Chamber Model for Practice DMEK Surgery. AB - PURPOSE: To describe a wet lab model using human corneas for practicing all steps of Descemet membrane endothelial keratoplasty (DMEK). METHODS: Twelve human research corneas were used for training purposes. Each DMEK surgery required 2 corneas; one for donor graft preparation and one to practice graft insertion and unfolding in a novel artificial anterior chamber model. RESULTS: Six complete DMEK procedures were successfully performed. Apart from donor graft preparation and graft insertion into the anterior chamber, it was feasible to practice different and combinations of graft unfolding techniques in conditions similar to real human procedures. CONCLUSIONS: This wet lab model allows practicing steps of DMEK and learning significant surgical skills. Reusable instruments can be used in regular operating facilities resulting in reasonable costs. PMID- 27984368 TI - Outcomes in emergency care research. PMID- 27984369 TI - Factors influencing intensive care admission: a mixed methods study of EM and ICU. AB - OBJECTIVES: Twenty-six percent of ICU patients in the UK are referred directly from the Emergency Department (ED). There is limited literature examining the attitudes or practice of ED/ICU physicians towards referrals from the ED to the ICU. We examined these attitudes through a mixed methods study, designing a model incorporating these attitudes to promote a shared mental model between ED and ICU specialities. METHODS: Individual semistructured interviews were conducted with 11 ED consultants and 11 ICU consultants at two hospitals in the west of Scotland. Interviews were based on 10 'case-based vignettes' representing patients for whom referral from the ED to the ICU is borderline or challenging. Participants were asked to note whether they would refer/accept the patient from the ED to the ICU. The proportions of participants from each speciality choosing to refer or accept patients were compared using a t-test comparing proportions. The reasons behind these decisions were explored during the semistructured interviews. RESULTS: Twelve factors emerged as influencing the decisions made by the participants. These belonged three core themes: patient factors, clinician factors and resource factors, which were incorporated into a shared mental model. Two cases demonstrated statistically significant differences in referral rates between specialities. There were also clinically significant differences among other cases. CONCLUSION: We have described the attitudes of physicians towards ED to ICU referrals in two west of Scotland hospitals, and we have demonstrated that there is a difference in the aspects of the decision-making process. We have developed a model encompassing all factors considered by participants when assessing these difficult referrals. It is hoped that this model will promote shared and more efficient decision-making in the future. PMID- 27984370 TI - Has the die been cast? Discharge of body stuffers from the Emergency Department. PMID- 27984372 TI - Intubation success rates of prehospital rapid sequence induction. PMID- 27984371 TI - Intubation success rates of prehospital rapid sequence induction of anaesthesia by physicians versus paramedics. PMID- 27984373 TI - HNRNPA1, a Splicing Regulator, Is an Effective Target Protein for Cervical Cancer Detection: Comparison With Conventional Tumor Markers. AB - OBJECTIVE: Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), serine/arginine rich splicing factor 1 (SRSF1), and SRSF3 are splicing regulators associated with oncogenesis. However, the alterations of SF proteins and their diagnostic values in cervical cancer are unclear. To apply SFs clinically, effective marker selection and characterization of the target organ properties are essential. MATERIALS AND METHODS: We concurrently analyzed HNRNPA1, SRSF1, SRSF3, and the conventional tumor markers squamous cell carcinoma antigen (SCCA) and carcinoembryonic antigen (CEA) in cervical tissue samples (n = 127) using semiquantitative immunoblotting. In addition, we compared them with p16 (cyclin dependent kinase inhibitor 2A [CDKN2A]), which has shown high diagnostic efficacy in immunohistochemical staining studies and has been proposed as a candidate protein for point-of-care screening biochemical tests of cervical neoplasia. RESULTS: HNRNPA1, higher molecular weight forms of SRSF1 (SRSF1-HMws), SRSF3, CEA, and p16 levels were higher (P < 0.05) in cervical carcinoma tissue samples than in nontumoral cervical tissue samples. However, the levels of SRSF1-Total (sum of SRSF1-HMws and a lower molecular weight form of SRSF1) and SCCA, a commonly used cervical tumor marker, were not different between carcinoma and nontumoral tissue samples. In paired sample comparisons, HNRNPA1 (94%) showed the highest incidence of up-regulation (carcinoma/nontumor, >1.5) in cervical carcinoma, followed by p16 (84%), SRSF1-HMws (69%), SRSF3 (66%), CEA (66 %), SCCA (32%), and SRSF1-Total (31%). HNRNPA1 (92%) and p16 (91%) presented the two highest diagnostic accuracies for cervical carcinoma, which were superior to those of SRSF3 (75%), SRSF1-HMws (72%), CEA (72%), SCCA (59%), and SRSF1-Total (55%). CONCLUSIONS: Our results identified that HNRNPA1 is the best diagnostic marker among the SFs and conventional markers given its excellent diagnostic efficacy for cervical carcinoma, and it has a p16-comparable diagnostic value. We suggest that HNRNPA1 is an additional effective target protein for developing cervical cancer detection tools. PMID- 27984374 TI - CD56 (Neural Cell Adhesion Molecule) Expression in Ovarian Carcinomas: Association With High-Grade and Advanced Stage But Not With Neuroendocrine Differentiation. AB - OBJECTIVE: Neural cell adhesion molecule (CD56) has been proposed as a potential marker for neuroendocrine differentiation in carcinomas, together with synaptophysin and chromogranin A. However, CD56 immunoreactivity by itself can be found in a broad variety of tumors, including ovarian neoplasms. CD56 has recently been suggested as a potential target for antibody-based therapy. However, for ovarian carcinoma, there is only limited data available regarding the pattern of CD56 immunoreactivity, coexpression of neuroendocrine markers, and correlation with histological types and clinical parameters. METHODS: In our study, we therefore evaluated CD56 staining by immunohistochemistry on a tissue micrroarray with 206 ovarian carcinomas, including 151 high-grade serous, 7 low grade serous, 32 endometrioid, 11 clear cell, 5 mucinous, as well as 33 atypically proliferating serous tumors/serous borderline tumors. RESULTS: At least focal CD56 immunoreactivity was observed in 65% of carcinomas of all histological types. Moderate staining with at least 10% positive cells was found in 44 (28%) high-grade serous carcinomas (HGSOCs), 2 (29%) low-grade serous and 3(9%) endometrioid carcinomas. Strong immunoreactivity was limited to 10 (7%) HGSOCs. There was no correlation with the expression of chromogranin or synaptophysin. Serous borderline tumors showed only weak and focal staining in 11 (33%). Expression of CD56 overall was significantly associated with high-grade and advanced stage. In the subgroup of HGSOCs, CD56 expression was associated with reduced overall survival (median 30 vs. 47 months, P = 0.039, log rank, univariate analysis). CONCLUSIONS: CD56 (neural cell adhesion molecule) is frequently expressed in ovarian carcinomas and is significantly associated with HGSOC and advanced tumor stage. Due to its lack of correlation with neuroendocrine differentiation, CD56 expression is of limited diagnostic value, but may rather serve as a marker for tumor progression or as a potential therapeutic target. PMID- 27984375 TI - Survival After Pelvic Exenteration for Cervical Cancer: A National Cancer Database Study. AB - OBJECTIVE: To determine overall survival (OS) and factors associated with OS after pelvic exenteration for cervical cancer. METHODS: Women with cervical cancer who underwent exenteration (n = 517) were identified from the 1998 to 2011 National Cancer Database. Kaplan-Meier and multivariate Cox proportional-hazards survival analyses were performed to test for associations of potential explanatory variables with OS. Analyzed confounders included age, insurance status, income, distance from home to treatment center, stage, exenteration type, surgical margin status, and treatment with adjuvant radiation and/or chemotherapy. RESULTS: Among the entire cohort with clinical follow-up (n = 313), median OS was 24 months. Stage (P = 2.5 * 10), lymph node status (P = 1.3 * 10), insurance status (P = 1.5 * 10), and histologic type (P = 0.04) were significantly associated with OS by the log-rank test. Unadjusted median OS was 24.2 and 61.8 months for women with squamous and adenocarcinoma histologies, respectively. By multivariate Cox regression, age, insurance status, stage, margin status, and adjuvant radiation were associated with OS. Histology was not independently associated with OS on multivariate regression. Among women with node-negative disease, median OS was 73.2 months. CONCLUSIONS: Exenteration may be curative for more than half of women with node-negative cervical cancer. Stage, insurance status, lymph node status, and surgical margin are independently associated with differential OS after exenteration. PMID- 27984376 TI - Long-Term Morbidity and Quality of Life in Cervical Cancer Survivors: A Multicenter Comparison Between Surgery and Radiotherapy as Primary Treatment. AB - OBJECTIVE: To compare long-term morbidity and quality of life after primary surgery or primary radiotherapy for stage IB/II cervical cancer. METHODS: A cross sectional study was performed. Patients treated for stage IB/II cervical cancer between 2000 and 2010 were approached to participate. Primary treatment consisted of radical hysterectomy with pelvic lymphadenectomy (RHL), for selected cases followed by adjuvant (chemo-)radiotherapy, or primary (chemo)radiotherapy (PRT). European Organization for Research and Treatment of Cancer-C30 and European Organization for Research and Treatment of Cancer-CX24 questionnaires were administered. A multivariable analysis was performed to identify factors associated with morbidity/quality of life. In a subgroup analysis, we compared patients with RHL + adjuvant radiotherapy with those after PRT. RESULTS: Three hundred twenty-three cervical cancer survivors were included (263 RHL/60 PRT). In the PRT group, International Federation of Gynecology and Obstetrics stage was higher and women were older. In the RHL group, more women had a partner. Women treated with PRT reported lower physical (beta, -6.01) and social functioning (beta, -15.2), more financial problems (beta, 10.9), diarrhea (beta, 9.98), symptom experience (beta, 6.13), sexual worry (beta, 11.3), and worse sexual/vaginal functioning (beta, 11.4). Women treated with RHL reported significantly more lymphedema (beta, -16.1). No differences in global health were found. In the subgroup analysis, women after PRT (n = 60) reported poorer social functioning, less sexual enjoyment, and higher symptoms experience than women after RHL and adjuvant radiotherapy (n = 60). The latter reported more lymphedema. CONCLUSIONS: Although global health scores are not significantly different, women after PRT report more physical, social, and sexual symptoms. These results can be well used by physicians to inform their patients about treatment-related morbidity. PMID- 27984377 TI - Weekly Versus Triweekly Cisplatin-Based Chemotherapy Concurrent With Radiotherapy in the Treatment of Cervical Cancer: A Meta-Analysis. AB - BACKGROUND: The aim of this study was to evaluate toxicity, compliance, recurrence and the survival of weekly and triweekly cisplatin-based concomitant chemoradiation in treatment of cervical cancer. MATERIALS AND METHODS: The databases were searched from 1995 until 2015 to identify eligible studies on weekly versus triweekly cisplatin chemoradiotherapy. The data were analyzed by RevMan 5.3 software. RESULTS: A total of 5 randomized controlled trials were included in this review. Weekly cisplatin regimen significantly reduced the incidence of Hematologic toxicity. However, there was no significantly different between the 2 arms in compliance, recurrence and the survival rate (all P >0.05). CONCLUSIONS: Weekly cisplatin regimen had the similar therapeutic effect as the triweekly cisplatin regimen but with less hematologic toxicity. Therefore, we recommend the weekly cisplatin 30 to 40 mg/m chemoradiotherapy as the strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer. PMID- 27984378 TI - Analysis of Conservative Surgical Treatment and Prognosis of Microinvasive Squamous Cell Carcinoma of the Cervix Stage IA1: Results of Follow-Up to 20 Years. AB - OBJECTIVE: The aim of this study was to evaluate the prognosis and recurrence of microinvasive squamous cervical (MIC) cancer stage IA1 in women treated conservatively or by hysterectomy, and followed-up to 20 years. METHODS: It was studied in a cohort of 139 women with MIC, 41 definitively managed by conization and 98 by hysterectomy from January 1994 to December 2003 and followed-up until 2013. The definitive treatment, age, conization technique (loop electrosurgical excision procedure or cold knife conization), cone margin, residual disease in hysterectomy specimen, and the association with recurrence (intraepithelial cervical neoplasia grade 3/intraepithelial vaginal neoplasia grade 3 or worse, and microinvasive or worse) were analyzed. RESULTS: There were 2.5 times more conservative treatment in younger women than older (>40 years), and high proportion of residual disease in hysterectomy specimens (67% of intraepithelial cervical neoplasia grade 3 or worse), more common if positive cone margin (74% vs 35%, P < 0.002). There were 2.3% (3/133) recurrences detected as microinvasive or worse, and 6% (8/133) recurrences detected as intraepithelial cervical neoplasia grade 3/intraepithelial vaginal neoplasia grade 3 or worse: 7.3% (3/41) in the conization group and 5.4% (5/92) in the hysterectomy group (P = 0.701). Almost all recurrences (88%, 7/8) were diagnosed until 36 months after treatment, and they were not associated with conization technique. There were no differences in risk of recurrence and overall disease-free survival time related to type of treatment. CONCLUSIONS: This study demonstrates the good prognosis of MIC, regardless the treatment. When fertility is not a concern, hysterectomy should be considered as definitive treatment to avoid the risk of residual disease. Regular follow-up for a long period should be maintained. PMID- 27984380 TI - "Noninterventional Pulmonology": Birth of a New Subspecialty With Emergence of Interventional Pulmonology. PMID- 27984379 TI - Is Neurosurgery With Adjuvant Radiotherapy an Effective Treatment Modality in Isolated Brain Involvement From Endometrial Cancer?: From Case Report to Analysis. AB - AIM: The aim of this study was to evaluate the treatment options and post-brain involvement survival (PBIS) of patients with isolated brain involvement from endometrial cancer (EC). MATERIALS AND METHODS: The literature electronic search was conducted from 1972 to May 2016 to identify articles about isolated (without extracranial metastases) brain involvement from EC at recurrence and the initial diagnosis. Forty-eight articles were found. After comprehensive evaluation of case series and case reports, the study included 49 cases. RESULTS: The median age of the patients at initial diagnosis was 57 years (range, 40-77 years). Poor differentiation was determined in 36 (73.5%) patients. Thirty-five (71.4%) patients had a single brain lesion. Lesion was found in the supratentorial part of the brain in 33 (67.3%) patients. Median PBIS for all cohorts was 13 months (range, 0.25-118 months) with 2-year PBIS of 52% and 5-year PBIS of 37%. Age, tumor type, grade, disease-free interval, diagnosis time of brain lesion, localization, and number of brain lesion were not predictive of PBIS. Two-year PBIS was 77% in patients who underwent surgical resection and radiotherapy, whereas it was 19% in the surgical resection-only group, and 20% in the primary radiotherapy-only group (Ps = 0.003 and 0.001, respectively). Chemotherapy was not associated with improved PBIS. CONCLUSIONS: Although neuroinvasion from EC appears mostly with a disseminated disease, there is a considerable amount of patients with isolated brain involvement who would have a higher chance of curability. Surgery with radiotherapy is the rational current management option, and this improves the survival for isolated brain involvement from EC. PMID- 27984381 TI - Bronchoscopist-guided Sedation in EBUS-TBNA: Can the Pitcher Also be a Hitter? PMID- 27984382 TI - Diagnostic Yield and Complications of EBUS-TBNA Performed Under Bronchoscopist directed Conscious Sedation: Single Center Experience of 1004 Subjects. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) can be performed under either conscious sedation or general anesthesia. Herein, we describe the diagnostic yield and complications of EBUS TBNA performed under bronchoscopist-directed conscious sedation. METHODS: This is a retrospective analysis of data collected in the bronchoscopy suite of this center on EBUS-TBNA or endoscopic ultrasound with a bronchoscope-guided fine needle aspiration (EUS-B-FNA) procedures performed between July 2011 and January 2016. All procedures were performed under bronchoscopist-directed conscious sedation with midazolam and pentazocine. The diagnostic yield, sample adequacy rate, complications, and doses of sedative agents are presented. RESULTS: Of the total 1005 EBUS-TBNA/EUS-B-FNA procedures performed during the study period, 1004 were performed under conscious sedation in spontaneously breathing subjects [mean (SD) age, 45.9 (15.8) years; 378 (37.6%) women]. The mean (SD) doses of midazolam and pentazocine used were 2.53 (1.8) mg and 30.9 (6.9) mg, respectively. The diagnostic yield of the procedure (972 subjects) was 61.2%. Complications related to EBUS were observed in 60 (5.9%) subjects. Majority of them were minor and self limiting; major complications occurred in 11 (1.1%) subjects and included respiratory failure requiring assisted ventilation (n=6), arrhythmia (n=3), and hypotension (n=2). Escalation of the level of care was needed in only 8 (0.8%) subjects. CONCLUSION: EBUS-TBNA/EUS-B-FNA performed under bronchoscopist-guided conscious sedation was found to be safe and is associated with a reasonable diagnostic yield. PMID- 27984383 TI - Hippocrates Quoted "If an Empyema Does Not Rupture, Death Will Occur": Is Medical Thoracoscopy Able to Make It Rupture Safely? AB - BACKGROUND: The aim of this study was to evaluate the safety and efficacy of medical thoracoscopy through a single port [single-port medical thoracoscopy (S MT)] for the treatment of empyema thoracis in its early stages. METHODS: We performed a retrospective analysis reviewing the medical records of 84 patients referred for empyema and treated by medical thoracoscopy at our Thoracic Departments from January 2001 until November 2014. S-MT was performed under local anesthesia with neuroleptoanalgesia and spontaneous breathing using a single 1-cm incision for debridement and lavage of the pleural cavity. RESULTS: A total of 84 patients underwent S-MT for pleural empyema stage I (9 patients, 10.7%) or II (75 patients, 89.3%). Median age was 61.8 years (range, 18 to 84 y). Male to female ratio was 3.76. Surgery was performed 5 to 26 days after the onset of symptoms. Macroscopically complete debridement of the pleural cavity was achieved in 71 patients (84.5% of cases). The rest 15.5% of cases required video-assisted thoracoscopic surgery or open decortication due to trapped-lung syndrome. Median operation time was 45 minutes (range, 30 to 94 min). No intraoperative complications occurred. In-hospital mortality was zero, whereas in-hospital morbidity rate was 16.7%. Median hospital stay was 7.8 days (range, 3 to 18 days). Recurrence rate was 4.8% as 4 patients experienced a relapse of empyema. CONCLUSION: It seems that S-MT is a minimally invasive, safe and effective procedure for the treatment of pleural empyema with very good results in early stages of the disease and reduced time of hospital stay. PMID- 27984384 TI - Mixing It Up: Coadministration of tPA/DNase in Complicated Parapneumonic Pleural Effusions and Empyema. AB - BACKGROUND: A recent randomized controlled trial showed 12 serial doses of tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) is safe and effective in managing complicated parapneumonic pleural effusions and empyema (CPEE). However, this regimen is laborious, requiring trained personnel to open/close the chest tube 8 times daily for 3 days. We present our observational data using a simplified regimen of coadministered tPA/DNase. MATERIALS AND METHODS: This is a retrospective observational study of patients who received coadministered tPA/DNase for CPEE from January 2012 to April 2015 at the University of Texas Medical Branch. Patient demographics, pleural fluid, radiologic and treatment characteristics, and outcomes were collected. Data are presented as proportions and percentages. Our primary outcome was successful treatment without need of surgery and discharge home alive. Secondary outcomes were dose and length of treatment and hospital stay, treatment complications, and 90-day mortality. RESULTS: The study included 39 patients. All pleural effusions were loculated, 59% macroscopically purulent, 50% had a positive organism in Gram stain, and 40% were culture positive. A median of 6 (interquartile range, 3.5 to 6) doses were coadministered mainly via small bore chest tube (<=14 Fr in 79%) with a median of 14.5 (interquartile range, 9.5 to 21.5) hospital days. Overall, 85% were successfully treated without need for surgery. Treatment failures occurred in 15%: 3/39 (7%) received surgery; 3/39 (7%) died. Only 1 (2.5%) complication of hemorrhagic pleural effusion resolved after discontinuation of intrapleural treatment. CONCLUSIONS: Our study shows intrapleural coadministration of tPA/DNase was effective and safe in management of CPEE. PMID- 27984385 TI - Conventional Transbronchial Needle Aspiration Versus Endobronchial Ultrasound guided Transbronchial Needle Aspiration, With or Without Rapid On-Site Evaluation, for the Diagnosis of Sarcoidosis: A Randomized Controlled Trial. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as a standalone modality is superior to conventional TBNA (c-TBNA) for the diagnosis of sarcoidosis. However, the overall yield is not different if combined with endobronchial biopsy (EBB) and transbronchial lung biopsy (TBLB). The utility of rapid on-site evaluation (ROSE) in a comparative evaluation of EBUS-TBNA versus c-TBNA for the diagnosis of sarcoidosis has not been previously evaluated. METHODS: Eighty patients with suspected sarcoidosis were randomized 1:1:1:1 into 4 groups: c-TBNA without ROSE (TBNA-NR), c-TBNA with ROSE (TBNA-R), EBUS-TBNA without ROSE (EBUS-NR), and EBUS-TBNA with ROSE (EBUS-R). EBB and TBLB were performed in all patients. Primary objective was detection of granulomas for combined procedure. Secondary objectives were individual procedure yields, sedation dose, and procedure duration. Patients without a diagnosis following c TBNA subsequently underwent EBUS-TBNA. RESULTS: A total of 74 patients were finally diagnosed with sarcoidosis. Overall, granuloma detection was not significantly different between the 4 groups (68% in TBNA-NR, 89% in TBNA-R, 84% in EBUS-NR, and 83% in EBUS-R groups, P=0.49). The yield of c-TBNA in the TBNA-NR group was lower compared with that in TBNA-R group and EBUS-TBNA in EBUS groups (32%, 72%, 68%, and 67% for TBNA-NR, TBNA-R, EBUS-NR, and EBUS-R groups, respectively, P=0.04). Additional 20% patients were diagnosed when EBUS-TBNA was performed following a nondiagnostic bronchoscopy procedure in the TBNA-NR group. Sedation requirement and procedure duration were significantly lower with c-TBNA as compared with EBUS-TBNA (P<0.001). CONCLUSION: When performing TBNA in the setting of suspected sarcoidosis, we found c-TBNA with ROSE and EBUS-TBNA (with or without ROSE) to be superior to c-TBNA alone. Whether c-TBNA with ROSE is equivalent to EBUS-TBNA cannot be determined from our study due to small sample size/low power. PMID- 27984386 TI - Fatal Progressive Membranous Obliterative Bronchitis: A Sequela of Influenza? AB - Occlusion of the bronchial orifices by tissue-like structures is an uncommonly reported finding: it has been referred to as bronchial webs, bronchial synechiae, vanishing bronchus syndrome, or membranous obliterative bronchitis. It differs from bronchiolitis obliterans, a well-described clinical entity that involves smaller airways not visualized on bronchoscopy. Although initially only recognized as a congenital condition, later reports have described it in situations where chronic inflammation results in the irritation of the airways. Here we report a case of a woman with postinfectious bronchiectasis who developed membranous occlusion of multiple subsegmental bronchi, resulting in progressive airflow obstruction and postobstructive collapse of involved lung parenchyma. This process eventually caused her demise. It the first report of membranous occlusion of the bronchi in an adult who does not have cystic fibrosis or a history of lung transplantation. Clinicians should be aware of this entity, and further research could help illuminate its pathogenesis and management. PMID- 27984387 TI - Interventional Pulmonologist and Thoracic Surgeon: A Difficult but Necessary Relationship. PMID- 27984388 TI - Endobronchial Prostate Metastasis. PMID- 27984389 TI - Catch of the Day. PMID- 27984390 TI - A Case of Birt-Hogg-Dube, Presenting With Recurrent Pneumothorax, Managed With Intrabronchial Valve Placement. PMID- 27984391 TI - A Pulmonary Artery Sling and In Vitro Fertilization. PMID- 27984392 TI - "Jaws of Steel" After Very Low Dose of Fentanyl During Prebronchoscopy Sedation. PMID- 27984393 TI - Etiology of Malignant Pleural Effusion and Utilization of Diagnostic and Therapeutic Procedures: A Nationwide Analysis. PMID- 27984394 TI - The Use of Extracorporeal Membrane Oxygenation in the Bronchoscopic Management of Critical Upper Airway Obstruction. PMID- 27984395 TI - Endoscopic Laser Management of a Leiomyoma of the Left Main Stem Bronchus. PMID- 27984397 TI - Donor Screening Experience for Fecal Microbiota Transplantation in Patients With Recurrent C. difficile Infection. AB - GOALS: To evaluate our experience with stool donor recruitment, screening, retention, and donor perception for fecal microbiota transplantation (FMT). BACKGROUND: Multiply recurrent Clostridium difficile infection is being increasingly managed with FMT from donor stools. However, donor selection and recruitment is challenging due to lack of standard evidence-based guidelines, donor exclusion criteria, frequency of screening and donor commitment. METHODS: Data on donors screened using institutional guidelines with history, blood and stool testing and their perspectives on donation were analyzed. RESULTS: Overall 42 potential donors (21 known and 21 standard) were prescreened. Of known donors (median age 34 y, 66.6% female), none failed prescreening, blood or stool tests. Twelve standard donors (57%) failed prescreening based on history (depression, diarrhea, autoimmune disease, recent antibiotic exposure, colon polyps, pregnancy). Nine (median age 35 y, 44.4% female) passed blood and stool testing. On repeat screening, 3 were excluded (2-positive stool shiga toxin (asymptomatic), 1-pregnancy). One donor opted out and 5 became long-term donors; 3 have donated >50 times and 2 have donated >25 times. On the basis of donor perception questionnaire, most standard donors were aware of FMT for C. difficile infection as a treatment option and would not consider 3-monthly blood and stool testing inconvenient. CONCLUSIONS: A significant proportion of healthy individuals who volunteered to become a standard donor failed prescreening and were not subjected to blood and stool testing. Repeat testing for asymptomatic donors may be a barrier to donor retention. Universal guidelines are needed to develop strategies to facilitate donor screening. PMID- 27984398 TI - Optical Diagnosis of Sessile Serrated Adenomas/Polyps: A Blind Spot for Endoscopists? PMID- 27984399 TI - Accuracy of Consecutive Fecal Calprotectin Measurements to Predict Relapse in Inflammatory Bowel Disease Patients Under Maintenance With Anti-TNF Therapy: A Prospective Longitudinal Cohort Study. AB - BACKGROUND AND GOAL: Predicting relapse in inflammatory bowel disease (IBD) patients could allow early changes in therapy. We aimed at evaluating the accuracy of consecutive fecal calprotectin (FC) measurements to predict flares in IBD patients under maintenance treatment with anti-tumor necrosis factor (TNF) drugs. STUDY: A prospective longitudinal cohort study with 16-month follow-up period was designed. IBD patients in clinical remission for at least 6 months under anti-TNF therapy were included. FC was quantified at 4-month intervals for 1 year, and patients were clinically evaluated for relapse at 2-month intervals. Diagnostic accuracy of FC for predicting relapse was evaluated by receiver operating characteristic curve analysis. RESULTS: In total, 95 of 106 included patients finalized the study and were analyzed (median age 44 y, 50.5% female, 75% with Crohn's disease). A total of 30 patients (31.6%) had a relapse over follow-up. FC concentration was significantly higher in patients who relapsed (477 MUg/g) than in patients who maintained in remission (65 MUg/g) (P<0.005). The optimal cutoff to predict remission was 130 MUg/g (negative predictive value of 100%), and 300 MUg/g to predict relapse (positive predictive value of 78.3%). CONCLUSIONS: FC is a good predictor of clinical relapse and a particularly good predictor of remission over the following 4 months in patients with IBD on maintenance therapy with anti-TNF drugs. FC levels <130 MUg/g is consistently associated with maintained disease remission, whereas concentrations >300 MUg/g allow predicting relapse with a high probability at any time over the following 4 months. PMID- 27984400 TI - National Trends in Use of Opioid Drugs Among Cirrhosis-related Hospitalizations in the United States, 2004 to 2012. PMID- 27984401 TI - Who Orders a Head CT?: Perceptions of the Cirrhotic Bleeding Risk in an International, Multispecialty Survey Study. AB - OBJECTIVE: Traditional coagulopathic indices, including elevated international normalized ratio, do not correlate with bleeding risk in patients with cirrhosis. For this reason, head computed tomography (CT) has a low yield in cirrhotic patients with altered mental status and no trauma history. The initial diagnostic evaluation, however, is often made by nongastroenterologists influenced by the so called "coagulopathy of cirrhosis." We sought to examine the prevalence, impact, and malleability of this perception in an international, multispecialty cohort. DESIGN: An electronic survey was distributed to internal medicine, surgery, emergency medicine, and gastroenterology physicians. Respondents were presented with a cirrhotic patient with hepatic encephalopathy, no history of trauma, and a nonfocal neurological examination. Respondents rated likelihood to order head CT at presentation, after obtaining labs [international normalized ratio (INR) 2.4 and platelets 59*10/MUL], and finally after reading the results of a study demonstrating the low yield of head CT in this setting. RESULTS: In total, 1286 physicians from 6 countries, 84% from the United States. Of these, 62% were from internal medicine, 25% from emergency medicine, 8% from gastroenterology, and 5% from surgery. Totally, 47% of respondents were attending physicians. At each timepoint, emergency physicians were more likely, and gastroenterologists less likely, to scan than all other specialties (P<0.0001). Evidence on the low yield of head CT reduced likelihood to scan for all specialties. Qualitative analysis of open-ended comments confirmed that concern for "coagulopathy of cirrhosis" motivated CT orders. CONCLUSIONS: Perceptions regarding the coagulopathy of cirrhosis, which vary across specialties, impact clinical decision-making. Exposure to clinical evidence has the potential to change practice patterns. PMID- 27984402 TI - Adherence to Surveillance Guidelines in Nondysplastic Barrett's Esophagus. AB - INTRODUCTION: Surveillance patterns in Barrett's esophagus (BE) are not well characterized. Guidelines published between 2002 and 2008 recommended surveillance esophagogastroduodenoscopy (sEGD) at 3-year intervals for nondysplastic BE (NDBE). We assessed guideline adherence in incident NDBE in a Veterans Affairs (VA)-based study. METHODS: At a single VA center, we identified incident cases of biopsy-confirmed NDBE between January, 2006 and December, 2008. We excluded patients aged 76 years and above and those who developed BE associated dysplasia or cancer during follow-up. All sEGDs through October, 2014 were documented. Our primary criteria classified cases as guideline adherent if a sEGD was performed within 6 months of each expected 3-year surveillance interval; in cases with >=2 sEGDs, 1 sEGD >6 months, and <=1 year outside an interval was allowed if the average interval was between 2.5 and 3.5 years. Comorbidity, primary care encounters, presence of long-segment BE (LSBE), endoscopist recommendations, and Charlson comorbidity index (CCI) were assessed. RESULTS: We identified 110 patients (96.4% male, 93.6% white) with mean age 58.9+/-8.5 years at index EGD. Median follow-up was 6.7 years (range, 3.7 to 8.6). Thirty-three (30.0%) cases were guideline adherent; 77 (70.0%) cases were nonadherent, including 52 (47.3%) with irregular surveillance and 25 (22.7%) with no surveillance. Forty cases (14 adherent) had 1 sEGD, 36 (18 adherent) had 2, 8 (1 adherent) had 3, and 1 nonadherent case had 4. Adherent cases were significantly older (61.5 vs. 57.9 y, P=0.04), and tended to have more LSBE (33.3% vs. 20.8%, P=0.16). There were no differences between adherent and nonadherent cases in annual primary care encounters (72.7% vs. 66.2%, P=0.66), CCI>=4 (15.2% vs. 15.6%, P=0.95), biopsy-positive sEGDs (75.8% vs. 76.6%, P=0.92), and any recommendation for subsequent surveillance (81.8% vs. 77.9%, P=0.65). A logistic regression model using age, CCI, and LSBE showed an independent association between adherence and older age (P=0.03). CONCLUSIONS: In a single-center VA cohort, sEGD of NDBE was mostly nonadherent to guidelines. Adherent cases were older at baseline with a trend toward more LSBE. A larger study is needed to identify medical and social factors associated with adherence or nonadherence to surveillance. PMID- 27984403 TI - The Glasgow Prognostic Score at the Time of Palliative Esophageal Stent Insertion is a Predictive Factor of 30-Day Mortality and Overall Survival. AB - BACKGROUND: Optimizing the timing of esophageal stent insertion is a challenge, partly due to difficulty predicting survival in advanced malignancy. The Glasgow prognostic score (GPS) is a validated tool for predicting survival in a number of cancers. GOALS: To assess the utility of the GPS in predicting 30-day mortality and overall survival postesophageal stent insertion. STUDY: Patients at a tertiary referral center who had received an esophageal stent for palliation of dysphagia were included if they had a measurement of albumin and C-reactive protein (CRP) in the week preceding the procedure (n=209). Patients with both an elevated CRP (>10 mg/L) and hypoalbuminemia (<35 g/L) were given a GPS score of 2 (GPS2). Patients with only one of these abnormalities were assigned as GPS1 and those with normal CRP and albumin were assigned as GPS0. Clinical and pathologic parameters were also collected to assess for potential confounding factors in the survival analysis. RESULTS: Increasing GPS was associated with 30-day mortality; for patients with GPS0, 30-day mortality was 5% (2/43), for GPS1 it was 23% (26/114), and for GPS2 it was 33% (17/52). The adjusted hazard ratio for overall poststent mortality was 1.6 (95% confidence interval, 1.1-2.4; P=0.02) for GPS1 and 2.4 (95% confidence interval, 1.5-3.8; P<0.001) for GPS2 patients compared with GPS0. CONCLUSIONS: GPS is an independent prognostic factor of 30-day mortality and overall survival after esophageal stent insertion. It is a potential adjunct to clinical assessment in identifying those patients at high risk of short-term mortality poststent. PMID- 27984404 TI - Determinants of knowledge-sharing networks in primary care. AB - BACKGROUND: Around the world, health reforms are increasingly fostering collaboration and integration among primary care physicians with the aim of facilitating knowledge sharing and evidence-informed decision-making. Although extant research on this topic is abundant, the evidence and results regarding social and organizational factors affecting the formation of knowledge-sharing networks in this setting are inconclusive. PURPOSE: The aim of this article is to explore multiple theoretical mechanisms explaining the formation of knowledge sharing networks among primary care physicians across relevant clinical areas. METHODOLOGY/APPROACH: The data are collected from two local health authorities in the Italian National Health Service that are responsible for delivering primary care in two Italian regions. Exponential random graph models are used to test the hypotheses. FINDINGS: Our findings indicate that knowledge-sharing networks are highly correlated across clinical areas. In addition, knowledge-sharing networks are highly reciprocal and clustered. We also observe that formal models adopted to foster collaboration have remarkably different effects on the formation of knowledge networks, depending upon the diverse knowledge management approaches adopted in the surveyed local health authorities. PRACTICE IMPLICATIONS: Primary care organizations need to develop and implement knowledge management practices in order to help physicians in identifying knowledge domain experts as well as to support connections through formal groupings and incentives. PMID- 27984406 TI - Correlates of interorganizational relationship strategies among critical access hospitals. AB - BACKGROUND: Interorganizational relationships (IORs) between hospitals and other health care providers have many potential benefits for critical access hospitals (CAHs) that operate in resource-constrained environments. Given the potential benefits of IORs, especially for CAHs, it is important to identify the conditions that support or hinder IOR development. However, most research examining IORs isolates individual types of relationships while ignoring the practical reality that many hospitals participate in a portfolio of relationships simultaneously. PURPOSE: The aim of the study was to examine the IOR strategies of CAHs as a function of market and organizational characteristics. METHODOLOGY: The sample consisted of CAHs operating in the United States between the years 2002 and 2012. For each year, hospitals were assigned to one of four mutually exclusive IOR categories: (a) no IOR, (b) vertical IOR only, (c) horizontal IOR only, and (d) both vertical and horizontal IOR. Organizational characteristics were categorized as structural, operational, and financial. Environmental characteristics were categorized as sociodemographic, physical, and health delivery system-related. A multinomial logistic regression model was used to assess the relationship between IOR strategies and organizational and environmental characteristics, with results reported as average marginal effects. RESULTS: Approximately 41% of the CAHs were pursuing a combined vertical and horizontal IOR strategy, 20% were pursuing a vertical IOR-only strategy, 18% were pursuing a horizontal IOR-only strategy, and 21% were not engaged in an IOR strategy. Among the organizational characteristics, the type of IOR strategy used by a hospital varied as a function of ownership, total margin, days cash on hand, number of community orientation activities, and census. In contrast, among the environmental characteristics, only the number of community health centers in the community was associated with the type of IOR strategy pursued. CONCLUSION: CAHs' construction of IOR portfolios may be more dependent on organizational attributes than by environmental conditions. PMID- 27984405 TI - The quality perception gap between employees and patients in hospitals. AB - BACKGROUND: To assess hospital performance, quality perceptions of various stakeholders are increasingly taken into account. However, because of substantial background differences, various stakeholder groups might have different and even contrasting quality perceptions. PURPOSE: We test the hypothesis that an overall perception gap exists between employees and patients with respect to perceived hospital quality. We additionally elaborate on how various employee groups differ from each other and from patients. METHODOLOGY: We use primary survey data on perceived hospital quality from 9,979 patients and 4,306 employees from 11 German hospitals. With a multilevel regression and variance analysis, we test the impact of respondent type (employee or patient) on quality perception scores and test the interaction with hospital size. We additionally contrast different employee groups and test differences for various quality dimensions. RESULTS AND CONCLUSION: Hospital employees score hospital quality consistently lower than patients and are also more heterogeneous in their assessments. This makes it from a managerial point of view relevant to subdivide employees in more homogeneous subgroups. Hospital size has no clear effect on the perception gap. Doctors compared to patients and other employee groups have substantially different perceptions on hospital quality. PRACTICE IMPLICATIONS: Our findings fuel the practical and ethical debate on the extent that perception gaps could and should be allowed in the context of high-quality and transparent hospital performance. Furthermore, we recommend that the quality perception gap is a substantial part of the overall hospital evaluation for ethical reasons but also to enable managers to better understand the (mis)match between employees' priorities and patients' preferences. However, we do warn practitioners that perceptions are only to a limited extent related to the organizational level (in contrast to the individual level), and only minimal improvements can thus be reached by differentiating from other hospitals. PMID- 27984407 TI - Organizational characteristics associated with the provision of cultural competency training in home and hospice care agencies. AB - BACKGROUND: Despite the increasing interest in community-based health care, little information exists on cultural competency training (CCT) and its predictors in this setting. PURPOSE: We examined the associations between six organizational characteristics and the provision of CCT in home health care and hospice agencies. METHODOLOGY: We used cross-sectional data from the agency component of the 2007 National Home and Hospice Care Survey. The CCT provision composite was composed of three items: whether the agency provides mandatory cultural training to understand cultural differences/beliefs that may affect delivery of services to (a) all administrators, clerical, and management staff; (b) all direct service providers; and (c) all volunteers. Organizational characteristics were volume, ownership status, chain membership, teaching status, Joint Commission accreditation status, and formal contracts. PRINCIPAL FINDINGS: The weighted sample (n = 14,469) had a mean CCT provision score of 1.75 (range = 0-3). Our ordinal logistic regression model showed that Joint Commission accreditation increased CCT provision odds in the home health (odds ratio [OR] = 2.07, 95% confidence interval [CI] [1.01, 4.24]) and hospice (OR = 4.40, 95% CI [2.07, 9.38]) settings. Teaching status increased CCT provision odds (OR = 2.71, 95% CI [1.19, 6.17]) in the home health setting. Formal contracts increased CCT provision odds (OR = 4.03, 95% CI [1.80, 9.00]), whereas not-for-profit ownership decreased CCT provision odds (OR = 0.19; 95% CI [0.07, 0.50]) in the hospice setting. PRACTICE IMPLICATIONS: Home health care and hospice agencies need to increase their CCT practices to overcome health disparities in an increasingly diverse and aging population. PMID- 27984408 TI - Assessing Primary Care Trainee Comfort in the Diagnosis and Management of Thermal Injuries. AB - Thermal injuries are common and the majority will initially present to primary care physicians. Despite being a part of the objectives of training in family medicine (FM) and emergency medicine (EM), previous study has shown that in practice, gaps exist in the delivery of care. An electronic survey was sent to all FM/EM trainees at our university for the 2014 to 2015 academic year. Plastic Surgery trainees were included as a control group. Demographics and educational/clinical experience were assessed. Trainee comfort was measured on a five-point Likert scale across 15 domains related to thermal injuries. Preferences for educational interventions were also ranked. Descriptive statistics and the Kruskal-Wallis test were used (P < .05 considered significant). The survey response rate was 27.4% (117/427). FM and EM (CCFP and Royal College) trainees estimated a median 0, 1, and 2 hours of total didactic instruction, respectively. During that academic year, FM and EM (CCFP and Royal College) trainees cared for a median 1, 4, and 5 patients, respectively. Significant differences were noted in comfort levels across all 15 domains when compared with plastic surgery trainees. Preferences for educational interventions were ranked, with clinical rotations and traditional lecture scoring the highest. Primary care trainees are not comfortable in the diagnosis and management of thermal injuries. This may be attributed to limited clinical exposure and teaching during their postgraduate training. There exists an opportunity for specialists in burn care to collaborate with primary care training programs and deliver an educational intervention with the aim of long-lasting quality improvement. PMID- 27984409 TI - Sickle Cell Disease, Severe Acidosis, and Inhalation Injury: Case Report of Neurologically Intact Survival After Cardiac Arrest From Smoke Inhalation. AB - Smoke inhalation and carbon monoxide poisoning are a significant cause of mortality and neurologic morbidity. We present the unusual case of complete neurologic survival after prolonged hypoxia, severe acidosis, out of hospital cardiac arrest, and exposure to high levels of carbon monoxide poisoning in a patient with sickle cell disease. The hypothesis that there might be a potential protective effect from the type of hemoglobin seen in patients with sickle cell disease in carbon monoxide poisoning is discussed. PMID- 27984410 TI - Revisiting Escharotomy in Patients With Burns in Extremities. AB - Escharotomy incisions must be made in the inelastic skin eschar that is typical of circumferential third-degree burns. Later, the necrotic tissue must be debrided and substituted with a skin graft. Many reports on this topic have revealed that concepts and techniques vary widely. This study aims to present a critical review of the literature about escharotomy in burns and to highlight a different strategy to perform escharotomy in patients with burned extremities. We conducted a critical review in Pubmed/MEDLINE using the keywords "escharotomy" and "burns." In the present study, we included 22 articles published from 1955 to 2015 (60 years) that contain the aforementioned keywords. With respect to the extremities, most of the publications recommend that medial and lateral longitudinal incisions be performed and that care must be taken to avoid deep structures, particularly nerves. Moreover, the publications mention that escharotomy might result in thick, hypertrophic, retracting, and painful scars. We advocate that incisions performed only on the lateral and medial borders of the extremities are usually unnecessary, and that they contribute to the creation of misconceptions about burns. In addition, these incisions can somehow trigger complications that can be avoided by using the concept of escharotomy in multiple directions, as highlighted in this review. PMID- 27984412 TI - Impact of home blood pressure monitoring on blood pressure control in older individuals: a French randomized study. AB - OBJECTIVE: Home blood pressure (BP) monitoring is one of the tools recommended in hypertension management. However, its influence in older adults is seldom investigated. We aimed to assess whether regular home BP monitoring leads to a reduction of BP and an improvement in hypertension control in older adults. METHODS: In a 24-month trial, individuals aged 73-97 years were randomized in a control (office and home BP measured at 0, 12, and 24 months) or an intervention (office measured at 0, 12, and 24 months; home BP measured every 3 months) group. The primary outcome was the difference in means office BP over 24 months in hypertensive patients. Secondary outcomes included differences in mean home BP over follow-up in hypertensive patients, and frequency of hypertension and of drug use at 24 months in the total sample. Intention-to-treat analyses comprised 1733 persons, among which 1043 were hypertensive. RESULTS: Hypertensive patients in the intervention group experienced a significantly greater fall in office systolic BP (SBP) [mean between-group difference -2.1 mmHg, 95% confidence interval (CI) -4.1; -0.2, P = 0.03], home SBP (mean between-group difference 3.4, 95% CI -4.8; -2.1, P < 0.0001), and home diastolic BP (mean between-group difference -1.1, 95% CI -1.8; -0.4, P = 0.002) than those in the control group, in the main model. No overall differences were observed for office diastolic BP (P = 0.74), frequency of hypertension (P = 0.92), or drug use (P = 0.51) over time. Similar results were observed after adjustment for known predictors of BP though attenuated for office SBP (P = 0.07). CONCLUSION: Regular home BP monitoring every 3 months without co-intervention results in small but greater reductions of BP over time. Further research in large trials focused on older adults is needed to confirm the effectiveness of this intervention in a variety of settings. PMID- 27984411 TI - Multiple-Drug Resistance in Burn Patients: A Retrospective Study on the Impact of Antibiotic Resistance on Survival and Length of Stay. AB - Despite improvements in early treatment, survival following burn injury remains challenged by sepsis and multiple organ dysfunction syndrome (MODS). Additionally, susceptibility to infections and growing antibiotic resistance places burn patients at increased risk for infections with multiple-drug resistant organisms (MDROs). We therefore aimed to evaluate the impact of MDRO infections on survival and hospital length of stay, as well as examine the role of these organisms in the development of complications, such as acute kidney injury, sepsis, and MODS. To study this, we included all burn patients with infections, admitted between January 1, 2012, and December 31, 2013. Patients were divided into two groups: patients with infections caused by MDROs and patients with infections caused by susceptible organisms. Data were collected on all available cultures, as well as demographic, injury, and treatment-related variables from the medical record. The number of operative procedures (median: 2 vs 1, P < .0001), ventilator days (21 vs 0 days, P < .0001), total antibiotic days (21 vs 7days, P < .0001), and length of hospitalization (39 vs 14 days, P < .0001) were significantly different in the MDRO group vs the nonresistant group. While MDRO infection was not associated with patient mortality, univariable logistic regression analyses demonstrated >20% TBSA (odds ratio [OR] = 4.30, 95% confidence interval [CI]: 1.14-16.29, P = .03), acute kidney injury (OR = 10.93, 95% CI: 2.74-43.57, P = .001), sepsis (OR = 19.20, 95% CI: 3.79-97.27, P < .001), and MODS (OR = 85.49, 95% CI: 12.97-563.28, P < .0001) significantly increased the odds of patient mortality. These findings suggest that infections with MDROs are associated with a greater number of surgical procedures, longer duration of mechanical ventilation, more antibiotic days, and longer hospitalization. PMID- 27984413 TI - Gamma-glutamyltransferase, fatty liver index and hepatic insulin resistance are associated with incident hypertension in two longitudinal studies. AB - OBJECTIVE: We hypothesized that liver markers and the fatty liver index (FLI) are predictive of incident hypertension and that hepatic insulin resistance plays a role. METHODS: The association between liver markers and incident hypertension was analysed in two longitudinal studies of normotensive individuals, 2565 from the 9-year data from an epidemiological study on the insulin resistance cohort and the 321 from the 3-year 'Relationship between Insulin Sensitivity and Cardiovascular disease' cohort who had a measure of endogenous glucose production. The FLI is calculated from BMI, waist circumference, triglycerides and gamma-glutamyltransferase (GGT) and the hepatic insulin resistance index from endogenous glucose production and fasting insulin. RESULTS: The incidence of hypertension increased across the quartiles groups of both baseline GGT and alanine aminotransferase. After adjustment for sex, age, waist circumference, fasting glucose, smoking and alcohol intake, only GGT was significantly related with incident hypertension [standardized odds ratio: 1.21; 95% confidence interval (1.10-1.34); P = 0.0001]. The change in GGT levels over the follow-up was also related with an increased risk of hypertension, independently of changes in body weight. FLI analysed as a continuous value, or FLI at least 60 at baseline were predictive of incident hypertension in the multivariable model. In the RISC cohort, the hepatic insulin resistance index was positively related with the risk of 3-year incident hypertension [standardized odds ratio: 1.54 (1.07 2.22); P = 0.02]. CONCLUSION: Baseline GGT and FLI, as well as an increase in GGT over time, were associated with the risk of incident hypertension. Enhanced hepatic insulin resistance predicted the onset of hypertension and may be a link between liver markers and hypertension. PMID- 27984414 TI - Noninvasive assessment of haemodynamics in resistant hypertension: the role of the renal resistive index. AB - OBJECTIVE: The association of resistant hypertension (RHTN) with renal haemodynamics is unclear. Our aim was to evaluate differences in haemodynamic characteristics of patients with RHTN compared with patients with controlled hypertension (HTN) at the level of the heart, kidney and aorta. METHODS: We studied 50 patients with RHTN confirmed by ambulatory blood pressure monitoring and 50 controlled hypertensive patients matched for age and sex. All participants underwent renal Doppler ultrasound to determine the renal resistive index (RRI), a complete echocardiographic study including measurements of diastolic function and evaluation of augmentation index. RESULTS: Hypertensive patients with RHTN compared with those without RHTN had a significantly decreased E/A ratio (by 0.12, P = 0.043), an increased E/e' ratio (by 3.1, P < 0.001), increased albumin to-creatinine ratio levels (by 49 mg/g, P = 0.023) and a significantly higher RRI (by 0.078, P < 0.001) but similar augmentation index values (P = 0.79). Logistic regression revealed that presence of RHTN was the strongest predictor of an RRI more than 0.7 after controlling for other haemodynamic variables including blood pressure levels. Receiver-operator characteristic analysis revealed an area under the curve for prediction of RHTN by the RRI alone of 80.3% (95% confidence interval: 0.72-0.89, P < 0.001). An RRI cut-point of 0.648 has a sensitivity of 78% and a specificity of 72% for prediction of RHTN. CONCLUSION: In a well treated hypertensive population, patients with RHTN show more pronounced renal and cardiac haemodynamic dysfunction compared with patients with controlled HTN. A greater RRI seems to be associated with RHTN and may help identify such patients. PMID- 27984416 TI - Family Functioning and Mood and Anxiety Symptoms in Adolescents Born Extremely Preterm. AB - OBJECTIVE: To (1) compare adolescent- and parent-perceived family functioning between extremely preterm/extremely low birth weight (<28 wk/<1000 g, EP/ELBW) and normal birth weight (>2499 g, NBW) adolescents and (2) determine whether adolescents' or parents' ratings of family functioning were related to concurrent depression and anxiety symptoms in the adolescent and whether these relationships varied by birth group. METHODS: One hundred ninety-three EP/ELBW and 151 NBW adolescents (aged 15-20 yr) and their parents rated aspects of family functioning on the Family Environment Scale. Adolescents rated current depression and anxiety symptoms on the Center for Epidemiologic Studies Depression Scale-Revised and Beck Anxiety Inventory. Family functioning was compared across the groups using linear regression, and logistic regression was used to assess relationships between family functioning domains and elevated depression and anxiety scores. RESULTS: Compared with NBW controls, EP/ELBW adolescents reported similar levels of family Cohesiveness and Expressiveness, but less Conflict, and more Organization and Control. Parent ratings of family functioning were similar between groups except for higher Control scores in EP/ELBW group parents. Poorer family functioning as rated by adolescents, but not parents, was associated with increased depression/anxiety symptoms. These findings were generally consistent across both the EP/ELBW and control groups. CONCLUSION: EP/ELBW adolescents report generally positive family functioning. While adolescents' perceptions of family functioning are associated with concurrent adolescent mental health, parental perceptions of family functioning may not be indicative of adolescents' mental health. Importantly, EP/ELBW adolescents do not appear to be more vulnerable to anxiety/depression in the context of poorly perceived family functioning than their NBW peers. PMID- 27984418 TI - Congenital Zika Virus Infection: A Developmental-Behavioral Perspective. PMID- 27984417 TI - Association Between Age of Beginning Primary School and Attention Deficit Hyperactivity Disorder. AB - OBJECTIVE: In April 2012, the Turkish national education system was modified, and the compulsory school age of entry (first grade) was redefined as a minimum of 60 months and a maximum of 66 months (replacing the former minimum criterion of 72 months). In this study, we hypothesized that students starting school before 72 months (the previous age standard for the first grade) may experience (1) a greater number of symptoms of attention deficit hyperactivity disorder (ADHD) and (2) lower functioning in social, behavioral, and academic domains. METHOD: We performed a cross-sectional community-based study in the first and second grades of all primary schools (4356 students) located in the Kadikoy county of Istanbul, Turkey. Teachers completed Swanson, Nolan, and Pelham version IV and Conners' Teacher's report forms for symptoms of ADHD, the Perceived Competence Scale for functioning, and a sociodemographic questionnaire. RESULTS: Among first graders, the group that began primary school before the age of 72 months had a higher ADHD prevalence than both of the groups that began primary school between the ages of 72 to 77 months and 78 to 83 months (p < .001 for both groups). ADHD symptoms diminished and academic, social, and behavioral functioning improved with age for the first and second grade students. CONCLUSION: The probability of displaying ADHD symptoms (and caseness) is greater among the "earlier" beginners, whereas the "conventional" classmates exhibited better academic, social, and behavioral functioning. PMID- 27984419 TI - Family Functioning Predicts Body Mass Index and Biochemical Levels of Youths with Nonalcoholic Fatty Liver Disease. AB - : : Family functioning is associated with obesity-related chronic illnesses and impedes effective treatment of weight-related conditions, such as nonalcoholic fatty liver disease (NAFLD). OBJECTIVES: Evaluate the utility of a brief screening measure of family functioning among youth aged 8 to 18 years being treated in a specialty care clinic for NAFLD. METHODS: Thirty-nine youths and their caregivers participated. Relations between family functioning and anthropometric and biochemical variables assessed 3 to 6 months later were evaluated using regression analyses, controlling for child age, gender, and ethnicity. RESULTS: Family functioning was related to significantly higher body mass index (BMI) and levels of cholesterol, HbA1c, and glucose, but not serum alanine aminotransferase (ALT)-a marker of NAFLD-controlling for baseline levels. The magnitudes of effects were medium for models of BMI (Cohen's f = 0.29), cholesterol (0.32), and blood glucose (0.30) and small to medium for HbA1c (0.23) and ALT (0.10). CONCLUSION: This is the first study to examine the role of family functioning in youth with NALFD. Treatment programs might consider screening for family functioning to identify families that could benefit from a family-centered behavioral intervention. PMID- 27984420 TI - Parametric Mediational g-Formula Approach to Mediation Analysis with Time-varying Exposures, Mediators, and Confounders. AB - The assessment of direct and indirect effects with time-varying mediators and confounders is a common but challenging problem, and standard mediation analysis approaches are generally not applicable in this context. The mediational g formula was recently proposed to address this problem, paired with a semiparametric estimation approach to evaluate longitudinal mediation effects empirically. In this article, we develop a parametric estimation approach to the mediational g-formula, including a feasible algorithm implemented in a freely available SAS macro. In the Framingham Heart Study data, we apply this method to estimate the interventional analogues of natural direct and indirect effects of smoking behaviors sustained over a 10-year period on blood pressure when considering weight change as a time-varying mediator. Compared with not smoking, smoking 20 cigarettes per day for 10 years was estimated to increase blood pressure by 1.2 mm Hg (95% CI: -0.7, 2.7). The direct effect was estimated to increase blood pressure by 1.5 mm Hg (95% CI: -0.3, 2.9), and the indirect effect was -0.3 mm Hg (95% CI: -0.5, -0.1), which is negative because smoking which is associated with lower weight is associated in turn with lower blood pressure. These results provide evidence that weight change in fact partially conceals the detrimental effects of cigarette smoking on blood pressure. Our study represents, to our knowledge, the first application of the parametric mediational g-formula in an epidemiologic cohort study (see video abstract at, http://links.lww.com/EDE/B159.). PMID- 27984421 TI - Cancer Incidence in Workers Exposed to Styrene in the Danish-reinforced Plastics Industry, 1968-2012. AB - BACKGROUND: Occupational exposure to styrene is widespread and has been suggested to be carcinogenic. The aim of this study was to investigate whether occupational exposure to styrene increases the risk of cancer, in particular lymphohematopoietic cancers. METHODS: We established a study population of 72,292 workers employed in 443 small and medium-sized companies producing reinforced plastics 1964-2007 by utilizing several national registries, expert assessment, and worker survey data. We identified incident cancer cases from 1968 to 2012 in the national Danish cancer registry and computed standardized incidence rate ratios (SIRs) with 95% confidence intervals (95% CI) based on national rates. RESULTS: Increasing SIRs of Hodgkin lymphoma, myeloid leukemia, and cancer of nasal cavities and sinuses were inconsistently associated with increasing duration of employment, early year of first employment, or styrene exposure probability. No such trends were observed for cancer of the esophagus, pancreas, lung, kidney, or urinary bladder, which have previously been associated with styrene exposure. Lung cancer showed an overall increased risk that decreased by duration of employment. CONCLUSION: Occupational styrene exposure may be associated with Hodgkin lymphoma, myeloid leukemia, and cancer of nasal cavities and sinuses. Further studies are needed to evaluate if the observed associations are likely to be causal. PMID- 27984422 TI - The Epidemiologic Silver Lining of Climate Change. PMID- 27984423 TI - Evaluation of Medication-mediated Effects in Pharmacoepidemiology. AB - Medical conditions such as epilepsy or infection with human immunodeficiency virus (HIV) are known to be associated with a spectrum of adverse health outcomes if not appropriately managed by efficacious treatment and care. Medications for such conditions can be potent, and their use might sometimes have unintended health consequences. Prominent examples have emerged in HIV perinatal research in which use of antiretroviral treatment during pregnancy to treat maternal HIV infection and prevent transmission of the virus to the fetus have been shown to be associated with adverse birth outcomes. Likewise, use of antiepileptic drugs during pregnancy to treat maternal epilepsy has been shown to increase the risk of birth defects. Pharmacoepidemiology studies routinely aim to quantify the extent to which, in such settings, an observed association between an underlying medical condition and certain health outcomes can be attributed to the natural progression of the disease, and the extent to which it might be mediated by medication used to slow disease progression. We describe a simple yet principled methodology to quantify medication-mediated effects to address these types of queries. While methods for causal mediation analysis abound, there also has been much criticism of these methods as relying on untestable and sometimes unrealistic assumptions. In contrast, here we show that when the disease-free control group is also medication-free, mediated effects of the type described above are nonparametrically identified under standard no-unobserved confounding conditions, thus establishing that such effects are in a sense immune to recent criticism leveled at causal mediation methodology. PMID- 27984426 TI - Stem Cell Divisions Per Se Do Not Cause Cancer. PMID- 27984424 TI - Estimating Acute Cardiorespiratory Effects of Ambient Volatile Organic Compounds. AB - BACKGROUND: The health effects of ambient volatile organic compounds (VOCs) have received less attention in epidemiologic studies than other commonly measured ambient pollutants. In this study, we estimated acute cardiorespiratory effects of ambient VOCs in an urban population. METHODS: Daily concentrations of 89 VOCs were measured at a centrally-located ambient monitoring site in Atlanta and daily counts of emergency department visits for cardiovascular diseases and asthma in the five-county Atlanta area were obtained for the 1998-2008 period. To understand the health effects of the large number of species, we grouped these VOCs a priori by chemical structure and estimated the associations between VOC groups and daily counts of emergency department visits in a time-series framework using Poisson regression. We applied three analytic approaches to estimate the VOC group effects: an indicator pollutant approach, a joint effect analysis, and a random effect meta-analysis, each with different assumptions. We performed sensitivity analyses to evaluate copollutant confounding. RESULTS: Hydrocarbon groups, particularly alkenes and alkynes, were associated with emergency department visits for cardiovascular diseases, while the ketone group was associated with emergency department visits for asthma. CONCLUSIONS: The associations observed between emergency department visits for cardiovascular diseases and alkenes and alkynes may reflect the role of traffic exhaust, while the association between asthma visits and ketones may reflect the role of secondary organic compounds. The different patterns of associations we observed for cardiovascular diseases and asthma suggest different modes of action of these pollutants or the mixtures they represent. PMID- 27984425 TI - Effects of Sample Handling and Analytical Procedures on Thyroid Hormone Concentrations in Pregnant Women's Plasma. AB - BACKGROUND: Maternal thyroid function is a critical mediator of fetal brain development. Pregnancy-related physiologic changes and handling conditions of blood samples may influence thyroid hormone biomarkers. We investigated the reliability of thyroid hormone biomarkers in plasma of pregnant women under various handling conditions. METHODS: We enrolled 17 pregnant women; collected serum and plasma were immediately frozen. Additional plasma aliquots were subjected to different handling conditions before the analysis of thyroid biomarkers: storage at room temperature for 24 or 48 hours before freezing and an extra freeze-thaw cycle. We estimated free thyroid hormone indices in plasma based on T3 uptake. RESULTS: High correlations between plasma and serum (>0.94) and intraclass correlation coefficients for plasma handling conditions (0.96 to 1.00) indicated excellent reliability for all thyroid hormone biomarkers. CONCLUSION: Delayed freezing and freeze-thaw cycles did not affect reliability of biomarkers of thyroid function in plasma during pregnancy. See video abstract at, http://links.lww.com/EDE/B180. PMID- 27984427 TI - The Authors Respond. PMID- 27984428 TI - beta-Adrenergic Responsiveness in the Type 2 Diabetic Heart: Effects on Cardiac Reserve. AB - : Type 2 diabetes (T2D) is associated with reduced cardiac reserve and aerobic capacity. Altered myocardial autonomic nervous regulation has been demonstrated in humans with diabetes (indirectly) and animal models (directly). PURPOSE: This study aimed to determine the chronotopic and inotropic response of the type 2 diabetic heart to beta-adrenergic stimulation. METHODS: Eight people with uncomplicated T2D and seven matched controls performed a dual-energy x-ray absorptiometry scan and VO2peak test. Plasma catecholamines were determined at rest and during peak exercise. On a second visit, HR and left ventricular contractility were assessed using echocardiography during supine rest, parasympathetic blockade (atropine), and during incremental beta-adrenergic stimulation (dobutamine). RESULTS: VO2peak and HR reserve were lower in T2D (P < 0.05) as expected. Both groups increased norepinephrine comparably (P = 0.23) during peak exercise; however, epinephrine increased less in the T2D group (P < 0.05). The dobutamine dose required to achieve 85% of age-predicted maximal HR was 36% higher in CON (P < 0.05). Resting HR was higher (P < 0.01) and stroke volume indexed to fat free mass was smaller (P < 0.05) in T2D. During dobutamine infusion the response (% change) in HR, end-diastolic volumeFFM, stroke volume, ejection fraction, and cardiac output were not different between the groups. However, HR was higher (P < 0.01) and end-diastolic volume indexed to fat free mass (P < 0.01), stroke volumeFFM (P < 0.01), ejection fraction (P < 0.05), and stroke work (P < 0.01) were lower in T2D. CONCLUSIONS: Although the type 2 diabetic heart worked at smaller volumes, the HR and contractile response to beta adrenergic stimulation were unaffected by diabetes. The reduced cardiac reserve observed in uncomplicated T2D was not explained by impaired myocardial sympathetic responsiveness but may reflect changes in the loading conditions or function of the diabetic left ventricle. PMID- 27984429 TI - Exercise-Induced Hypoalgesia Is Not Influenced by Physical Activity Type and Amount. AB - : Physical activity (PA), especially vigorous-intensity PA, has been shown to be related to pain sensitivity. The relationship among PA levels and PA types on endogenous pain inhibition after exercise, termed exercise-induced hypoalgesia (EIH), remains unclear. PURPOSE: This studied examined the EIH response to pressure stimuli among college-age women of differing activity levels. METHODS: Fifty women were tested. Pressure pain threshold (PPT) values were assessed before and immediately after isometric handgrip exercise to exhaustion in the right and left forearms. Participant's PA levels were assessed by wearing an accelerometer for seven consecutive days during waking hours, excluding water activities. Participants were classified into four PA groups: met the American College of Sports Medicine aerobic recommendations (AERO), met aerobic and resistance training recommendations (AERO + RT), insufficiently aerobically active but resistance trained (RT), and insufficiently active (IA) based on their measured and self-reported PA level and type. RESULTS: AERO and AERO + RT had greater vigorous (P < 0.001) and total PA (P < 0.001) compared with RT and IA. EIH was observed for PPT in both right and left arms (P < 0.001), with PPT increasing 7.7% (529 +/- 236 vs 569 +/- 235 kPa) and 7.0% (529 +/- 299 vs 571 +/- 250 kPa) in the right and left forearms, respectively. EIH did not differ among activity groups (P = 0.82). PPT values were found to be inversely related to vigorous-intensity PA (r = -0.29). CONCLUSIONS: PA levels and types had no effect on endogenous pain inhibition after exercise in college-age women. PMID- 27984430 TI - Cone Beam Computed Tomography Heralding New Vistas in Appropriate Diagnosis and Efficient Management of Incidentally Found Impacted Mesiodens. AB - As dentistry continues to go "digital," the field has seen a phenomenal increase in the use of digital imaging in dental practice. Complex impacted mesiodens present potential treatment complications and sometimes possible patient morbidity. Objectives of diagnostic imaging are to aid in diagnosis, decision making, and enhance treatment outcomes. As cases become more complex, sophisticated multiplane imaging methods allowing for a three-dimensional view are more likely to meet these objectives as opposed to traditional two dimensional radiography. The clinical report elucidates with the help of an illustrative patient how cone beam computed tomography imaging can assist the surgeon during surgical treatment planning, risk assessment, and treatment outcomes of impacted mesiodens. PMID- 27984431 TI - Assessment of the Factors That Affect the Anatomic and Functional Success of Cartilage Tympanoplasty in Children. AB - OBJECTIVES: Many factors may influence the surgical outcome of tympanoplasty in children, including age, the size and location of perforation, otorrhea, status of contralateral ear, surgical technique, and adenoid hypertrophy. This study aims to evaluate the outcomes of pediatric cartilage tympanoplasty and to assess the factors that affect the success of tympanoplasty in children. METHODS: Children with chronic otitis media who underwent tympanoplasty using cartilage as graft material were evaluated retrospectively. Patient age, gender, size and site of the perforation, status of the contralateral ear, preoperative and postoperative hearing levels, surgical technique, and postoperative complications were noted. RESULTS: Of the 72 patients included in the study, 27 were male and 35 were female. The average age was 13.22 +/- 2.64 and mean follow-up time was 18.4 +/- 8.62 months. Anatomic and functional success rates were 88.8% and 80.6%, respectively. Age, gender, and the status of the contralateral ear had no effect on surgical success rate. The mean preoperative and postoperative pure-tone averages were 33.2 6+/- 10.37 and 21.00 +/- 13.25 dB, respectively. CONCLUSION: Anatomic and functional outcomes of cartilage tympanoplasty are quite satisfactory in pediatric patients. Chronic otitis media should be treated surgically as early as when patient cooperation is possible. PMID- 27984432 TI - Incidence of a Bifid Mandibular Condyle in Dry Mandibles. AB - BACKGROUND: A bifid mandibular condyle (BMC) is a rare anatomical variation with an etiology not fully understood. Although there are numerous case reports regarding it, purposeful epidemiological investigations on the BMC frequency among different groups are scarce. This study aims to investigate the incidence and laterality of BMC among series of adult males from Bulgaria and perform a morphometric analysis of it. MATERIALS AND METHODS: A series of 500 dry intact mandibles from adult males was investigated. The condyles were macroscopically observed and when skulls were available, the corresponding mandibular fossae were also inspected. In the cases when bifid condyles were found, 27 measurements were taken. RESULTS: Bifid mandibular condyle was observed in 4 (0.8%) mandibles. All of the cases were unilateral, 2 on the right side (0.4%) and 2 on the left (0.4%). The condyles were divided into medial and lateral heads by a sagittal fissure or a notch. CONCLUSION: The established frequency of BMC was comparable with those reported in Turkish and Korean populations. The lack of injury marks and traces implies a developmental etiology of this condition. PMID- 27984433 TI - Cone Beam Computed Tomography Findings of Desmoplastic Ameloblastoma of Maxilla. AB - Desmoplastic ameloblastoma (DA) is one of 6 subtypes and also a rare variant of ameloblastoma. It is not recognized perfectly up to now. Although most of the conventional ameloblastomas can be diagnosed in posterior of the mandible, DA more transpires in anterior of the jaws. Our patient was a 57-year-old man with swelling in the right side of the anterior maxilla. In the medical examination bone expansion was detected with a normal covering mucosa and no discoloration. This paper provides more information about cone beam computed tomography image features of DA. PMID- 27984434 TI - Effects of Surface Treatment Modification and Implant Design in Implants Placed Crestal and Subcrestally Applying Delayed Loading Protocol. AB - OBJECTIVES: The aim of this study is to evaluate the effect of the surface modification and cervical implant design on the bone remodeling in implants installed at the crestal and subcrestal bone level. METHODS: Ten American Fox Hound of approximately 1 year of age, each weighing approximately 14 to 15 kg, were used for this study. Two different dental implant macrodesign were used: cylindric-conical with 3.5 mm of diameter and 9 in length (implant A) and conical with 2.9 mm of diameter and 9 mm in length (implant B). Two surfaces were used: sandblasting and acid etching (surface 1) and sandblasting and acid etching, then maintained in an isotonic solution of 0.9% sodium chloride (surface 2). Four groups were performed (n = 20 implants): Group A1 (implant A with the surface 1), Group A2 (implant A with surface 2), Group B1 (implant B with surface 1), and Group B2 (implant B with surface 2). The mandibular premolars and molars (P1, P2, P3, M1) were removed and, after 2 months of healing, implants were inserted at the crestal and 2 mm subcrestal position related to the buccal bone level. Analysis was performed at 4 and 8 weeks. Histomorphometry with longitudinal measurements and bone implant contact, bone remodeling and implant stability quotient analysis were realized. RESULTS: The surface 2 showed to get more close contact between implant and new bone formed after implant placement and more stability surrounding platform both at 4 and 8 weeks. Surface 2 groups and subrestally placed showed to have better results in terms of linear measurements, with less bone loss and soft tissue distance to the IS. The data showed significant differences among the groups (P < 0.001). CONCLUSIONS: Surface modification (surface 2) has shown to be an effective alternative to conventional surface with better results in situations placed subcrestally and combined with implant design. PMID- 27984435 TI - Tissue Fluorescence Imaging (VELscope) for Quick Non-Invasive Diagnosis in Oral Pathology. AB - Oral squamous cell carcinoma is the most common form of malignancy of the oral cavity; its incidence is increasing and late-stage presentation is common. It is usually predated by oral premalignant disorders. For this reason, early diagnosis is fundamental to reduce the malignant transformation of oral premalignant disorders and for increase the survival rate for oral cancer. Scraping the surface of the lesion is useful for having cytological features of the investigated tissue. The features of smears of oral premalignant lesions are the keratinization growth (red, orange, brown), the increased nuclear area and so the nuclear hyperchromatism, the nuclear pleomorphism, and the chromatin clumping. All those features are essential for doing the right diagnosis. However, the oral disease should be recognized at the first view by the clinical investigation without touching the lesions avoiding possible alteration in the cells of the tissue. The current standard of incisional biopsy with histology is painful for patients and involves a delay, although histology is completed. The aim of this article is to evaluate the effectiveness of other available tests that are unobtrusive and provide immediate results like the tissue fluorescence imaging. PMID- 27984436 TI - The Effects of Short- and Long-Term Exposure to Hyperbaric Oxygen on Nasal Mucociliary Clearance. AB - The aim of this study is to assess the effects of short- and long-term exposure to hyperbaric oxygen (HBO) on nasal mucociliary clearance (MCC). This study included 47 consecutive nondiabetic patients treated with hyperbaric oxygen therapy (HBOT). Participants were divided into 2 groups according to the taken number of HBOT sessions. Nineteen patients who received <11 HBOT sessions comprised short-term HBOT group, 28 patients who received more than 15 sessions comprised the long-term HBOT group. Mucociliary clearance was measured using a saccharin clearance test, which was performed 3 times on patients: prior to, at completion of, and 6 months after HBOT. The average number of HBOT sessions was 8 +/- 1.9 in short-term HBOT group and 20 +/- 4.8 in long-term group. Both short- and long-term exposure to HBO led to significant influence on MCC upon treatment completion (both P < 0.001). In addition, only long-term exposure to HBO caused significant elongation of MCC at long-term evaluation (6 months after HBOT). From these objective measurements, the authors can conclude that long-term exposure to HBO can cause irreversible damage to MCC compared with short-term exposure and HBOT appears to affect MCC in a dose-dependent manner. The clinical significance of this effect is of concern for patients undergoing HBOT for middle ear, sinonasal, or respiratory tract infections. Patients who undergo chronic HBOT should be monitored closely and informed about the possible negative effects. PMID- 27984438 TI - Assessing the Effectiveness of the Functional Movement Screen in Predicting Noncontact Injury Rates in Soccer Players. AB - Smith, PD, and Hanlon, D. Assessing the effectiveness of the functional movement screen in predicting noncontact injury rates in soccer players. J Strength Cond Res 31(12): 3327-3332, 2017-This study assessed if the Functional Movement Screen (FMS) can accurately predict noncontact injury in adult soccer players when normalizing noncontact injury occurrence against match exposure levels. Senior male players (n = 89) from 5 League of Ireland semiprofessional clubs participated in the study (mean age = 23.2 +/- 4.4 years; mean height = 179.5 +/- 6.6 cm; mean body mass = 77.5 +/- 7.8 kg). Participants performed the FMS during preseason, and their injury occurrence rates and match minutes were tracked throughout 1 season. In total, 66 noncontact injuries were recorded. No significant difference was found in FMS composite scores between players receiving noncontact injuries and players not suffering a noncontact injury (p = 0.96). There was no significant difference in exposure-normalized noncontact injury incidence between those scoring 14 or below and those scoring above 14 on the FMS (0.36 vs. 0.29 non-contact injuries per player per 1,000 match minutes). Players scoring 14 or below on the FMS had an odds ratio of 0.63 (p = 0.45; 95% CI = 0.19-2.07) of receiving a noncontact injury. Despite previous research showing links between low FMS composite scores and subsequent injury, these results suggest that the FMS cannot accurately predict a male soccer player's likelihood of receiving a noncontact injury and that a lower FMS composite score does not significantly increase their noncontact injury incidence rate per 1,000 match minutes. Caution should therefore be used when using the FMS as a predictor of noncontact injury, and pain prevalence during the FMS, previous injuries, and training/match exposure levels should also be taken into account. PMID- 27984437 TI - Descriptive Epidemiology of Orofacial Clefts in Ethiopia. AB - BACKGROUND: The prevalence of birth defects including orofacial clefts (OFC) in Ethiopia is not known and there is no established birth defects registration system. OBJECTIVES: To investigate the prevalence and incidence of OFC in Ethiopia. DESIGN: Retrospective hospital-based descriptive study. METHODS: The authors obtained data from the Smile Train database on Ethiopian patients with OFC who underwent surgical treatment from June 2007 to December 2013 at 31 hospitals distributed throughout the country. Data related to live births in Ethiopia during the mentioned period were obtained from the Federal Ministry of Health database for estimates of the incidence and prevalence rates. RESULTS: The total number of life births during the study period was 18,811,316. During this same period, 18,073 cleft patients approximately ranging from 1 to 75 years old were examined and treated at the hospitals mentioned earlier. The incidence rate estimated from the total number of affected children during the study period (N = 8232) is 0.44/1000 live births. The prevalence rate is 0.20/1000 and this was estimated using the number of total population in 2013 (N = 88,703,914). There is a significant difference in frequency between bilateral clefts of the lip and/or palate (CLP) (26.9%) versus unilateral CLP (73.1%) (P < 0.0001). There is also a significant difference in frequency between bilateral cleft lips only (15.4%) versus unilateral cleft lip only (84.6%), P < 0001. CONCLUSION: It is obvious that the findings in this study cannot be representative of the true picture but provides a previously unavailable national estimate of incidence and prevalence of OFC in Ethiopia. It can also be used as comparison for future community-based studies. PMID- 27984440 TI - Evaluation of a Program for Improving Advanced Imaging Interpretation. AB - OBJECTIVES: Self-referred imaging has grown rapidly, raising concerns about increased costs and compromised quality of care. A quality improvement program using imaging interpretation criteria was designed by a national payer to ensure that noninvasive diagnostic images are interpreted by appropriately trained physicians. The objective of this program evaluation was to compare self-referral rates before and after institution of the imaging interpretation criteria program. METHODS: The imaging interpretation criteria program allocated privileges to bill for advanced imaging interpretation according to physician specialty. Nonradiologist physicians could obtain exemptions by appeal. Some physicians were not restricted in their billing because of successful appeals of the restrictions or the timing of their contract renewals. Self-referral rates were compared between the period 12 months before and 25 months after the program was initiated using t tests. The preprogram and postprogram self-referral rate for computed tomography and magnetic resonance imaging in aggregate was calculated both for the physicians that came into contact with the program and nationally, and then was stratified based on physician appeal status and reimbursement restrictions. RESULTS: The program was associated with significantly less frequent self-referrals by physicians whose appeals were denied (17.4%-8.2%; P = 0.0011) and by physicians notified of the program but not subject to it (24.8%-18.5%; P = 0.026). Self-referrals in the program states declined from 19.9% to 13.7% (P < 0.01). CONCLUSIONS: A significant reduction in image interpretations billed by physicians working outside of the scope of their training occurred after the implementation of the imaging interpretation criteria program.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 27984439 TI - Skeletal Muscle Fatigability and Myosin Heavy Chain Fiber Type in Resistance Trained Men. AB - Bagley, JR, McLeland, KA, Arevalo, JA, Brown, LE, Coburn, JW, and Galpin, AJ. Skeletal muscle fatigability and myosin heavy chain fiber type in resistance trained men. J Strength Cond Res 31(3): 602-607, 2017-Forty years ago, Thorstensson and Karlsson in 1976 described the link between muscle fatigability and fiber type, finding that more fast-twitch fibers were associated with a quicker onset of quadriceps fatigue. This provided the foundation for the Classic Thorstensson Test of fatigability and subsequent noninvasive fiber type prediction equation. This equation was developed with data from recreationally active (REC) men but has been implemented in participants with heterogeneous physical activity/exercise backgrounds. The accuracy of this approach in resistance trained (RET) men has not been established. Moreover, muscle fiber typing techniques have evolved considerably since this seminal work. Therefore, we reexamined this relationship using RET men and a more sensitive fiber typing method (single fiber myosin heavy chain [MHC] isoform classification). Fifteen RET men (age = 24.8 +/- 1.3 years) performed maximal knee extensions (via isokinetic dynamometry) to determine peak torque (PT) and quadriceps fatigue percentage (FP) after 30 and 50 repetitions. Vastus lateralis (VL) single fiber MHC type was determined and fibers were grouped as %Fast (expressing MHC IIa, IIa/IIX, or IIx; no MHC I containing fibers). Resistance trained men exhibited 46% greater PT (RET = 207 +/- 28 N.m vs. REC = 130 +/- 8 N.m) and 28% more %Fast (RET = 61 +/- 4% vs. REC = 44 +/- 4%) than REC men. Additionally, RET men had a relatively homogeneous FP (64 +/- 1%) ranging from 53 to 72%. No relationship was found between FP and MHC fiber type (R = 0.01, p > 0.05). The Classic Thorstensson Test may not accurately estimate VL fiber type composition in RET men, highlighting the (a) unique phenotypical/functional adaptations induced by chronic RET and (b) the need for more sensitive cellular/molecular analyses in RET muscle. PMID- 27984441 TI - Outcome After Tibial Plateau Fracture: How Important Is Restoration of Articular Congruity? AB - OBJECTIVES: Does restoration of articular congruity have any effect on long-term outcome following tibial plateau fracture? DESIGN: Cohort study. SETTING: A secondary hospital in New Zealand, which services a population of 150,000. PATIENTS: All patients with a depressed tibial plateau fracture seen over a 6 year period were invited to participate in the study. There were 41 patients (average age 54 years) recruited from an eligible population of 97. Average follow-up was 3.9 years after injury. INTERVENTION: Patients had either been treated operatively or nonoperatively after depressed tibial plateau fracture. MAIN OUTCOME MEASUREMENTS: The primary outcome analyzed was residual articular depression (as measured on coronal plane tomogram) and its effect on clinical outcome [Oxford Knee Score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, Knee injury and Osteoarthritis Outcome Score (KOOS), Iowa knee score, and a visual analogue satisfaction score] and functional outcome (knee range of motion) at a minimum of 12 months after fracture. Patients were divided into 3 groups based on the amount of articular depression: <2.5, 2.5 5.0, and >=5.0 mm. The secondary outcome analyzed was mechanical axis (as measured on weightbearing long leg alignment radiographs) and its effect on clinical and functional outcomes. RESULTS: Statistical analysis found that patients with <2.5 mm of articular depression had significantly smaller losses in knee range of motion (P = 0.000), better Oxford (P = 0.006), Iowa (P = 0.003), and KOOS symptom (P = 0.011) and pain (P = 0.001) scores. We found that there was no significant relationship between restoration of mechanical axis and loss in range of motion (P = 0.126), Oxford (P = 0.584), WOMAC (P = 0.101), IOWA (P = 0.418), Visual Analogue Score (VAS) (P = 0.466) or any subgroup within the KOOS survey other than activities of daily living (P = 0.029). CONCLUSIONS: This study found that patients with smaller amounts of residual articular depression at a minimum of 12 months after tibial plateau fracture had significantly smaller losses in knee range of motion and better functional outcomes than those with greater amounts of articular depression. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27984442 TI - Symptomatic Implant Removal Following Dual Mini-Fragment Plating for Clavicular Shaft Fractures. AB - OBJECTIVES: To determine the proportion of patients requiring secondary surgery for symptomatic implant removal after open reduction, internal fixation using dual mini-fragment plating technique for clavicular shaft fractures. DESIGN: Retrospective observational study. SETTING: Single university Level 1 trauma center. PATIENTS: Eighty-one patients treated with open reduction, internal fixation using dual mini-fragment plating technique for clavicular shaft fractures (OTA/AO 15-B1, B2, and B3) with minimum 12-month follow-up (median 477 days; range 371-1549 days). INTERVENTION: Open reduction, internal fixation using dual mini-fragment plating technique for clavicular shaft fractures. MAIN OUTCOME MEASUREMENTS: Incidence of secondary surgery, QuickDASH (Disabilities of the Arm, Shoulder, and Hand) scores. RESULTS: Six of 81 patients (7.4%) underwent secondary surgery for implant removal for any reason. Of these, 3 (3.7%) underwent symptomatic implant (soft-tissue irritation) removal, 2 (2.5%) required implant removal in the setting of infection, and 1 patient (1.2%) required revision open reduction internal fixation for early implant failure. The mean QuickDASH score in this series was 8.44 (+/-6.94, range 0-77.27). The associated implant cost of the typical construct utilized in this series was $1511.38. The mean surgical time was 97 minutes (range 71-143 minutes). CONCLUSIONS: The utilization of a dual mini-fragment plating technique in the treatment of clavicular shaft fractures results in a low rates of secondary surgery for symptomatic implant removal (3.7%) and similar QuickDASH scores when compared with historical controls treated with 3.5-mm plates placed on the superior clavicle. Potential disadvantages in using this technique include a higher surgical implant cost and length of surgery. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27984443 TI - The Role of Computed Tomography in Surgical Planning for Trimalleolar Fracture. A Survey of OTA Members. AB - OBJECTIVE: Does the additional information provided by computed tomography (CT) alter surgeons' treatment plans for trimalleolar ankle fracture? DESIGN: Prospective. SETTING: Electronic survey. PATIENTS/PARTICIPANTS: Members of the OTA. INTERVENTION: Compare management of trimalleolar ankle fracture before and after CT. MAIN OUTCOME MEASUREMENTS: Compare types of fixation used, indication for fixation, and approach need for fixation before and after CT. RESULTS: Overall, OTA members' operative technique changed in 430 of the 1710 (25.1%) cases after review of the CT images. Of the 430 observations in which the operative technique was altered, the surgeon had initially stated that they would not have requested a CT in 51.2% incidences. When analyzing if CT affected whether or not operative fixation was indicated, a total of 16.3% responses changed. Surgeons were significantly more likely to change from no fixation to fixation (11.5%) than vice versa (4.8%) after reviewing CT imaging. A total of 17.8% of responses changed operative approach after reviewing the CT; 11.7% changed to open reduction internal fixation, whereas 6.1% changed away from open reduction internal fixation. CONCLUSION: A consensus on the ideal treatment of trimalleolar fractures remains elusive, evidenced by a high variation in treatment preference, both before and after CT review. Our results demonstrate with the additional information delineated on CT, a surgeons' operative plan, technique, and approach often change. With greater than 25% of respondents changing their treatment strategy after seeing CT imaging, radiographs alone limited surgeon understanding of fracture pattern. Because of difficulty understanding the posterior fracture fragment, we recommend preoperative CT on all trimalleolar fractures. LEVEL OF EVIDENCE: Diagnostic Level V. See Instructions for Authors for a complete description of levels of evidence. PMID- 27984444 TI - Advanced Imaging Lacks Clinical Utility in Treating Geriatric Pelvic Ring Injuries Caused by Low-Energy Trauma. AB - OBJECTIVES: Is advanced imaging necessary in the evaluation of pelvic fractures caused by low-energy trauma in elderly patients? DESIGN: Retrospective review. SETTING: Single institution, Level 1 Trauma Center. PATIENTS: Age >=60 years old treated for low-energy traumatic pelvic ring injuries. INTERVENTION: None. MAIN OUTCOMES: Posterior pelvic ring injuries diagnosed on advanced imaging, radiographic displacement, admission status, hospital length of stay, change in weight-bearing status recommendations, and whether operative treatment was pursued. RESULTS: Eighty-seven patients met the inclusion criteria, of which 42 had advanced imaging to evaluate the posterior pelvic ring (10 magnetic resonance imaging, 32 computed tomography). More posterior pelvic ring injuries were identified with advanced imaging compared with radiographs alone (P < 0.001). There was no statistically significant difference in rate of admission (P = 0.5) or hospital length of stay (P = 0.31) between patients with radiographs alone compared with patients evaluated with radiographs plus advanced imaging. The rate of displacement >1 cm at presentation and 6-week follow-up was unaffected by the presence of a posterior injury diagnosed on advanced imaging. Treatment for all 87 patients remained weight-bearing as tolerated with assist device irrespective of advanced imaging findings, and no patient underwent surgical intervention by 12-week follow-up. CONCLUSIONS: Despite frequent identification of posterior pelvic ring injuries in patients evaluated with advanced imaging, admission status, length of hospital stay, radiographic displacement, and treatment recommendations were unaffected by these findings. The use of advanced imaging in elderly patients with low-energy traumatic pelvic ring fractures may not be necessary. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27984446 TI - Primary Wound Closure After Open Fracture: A Prospective Cohort Study Examining Nonunion and Deep Infection. AB - OBJECTIVES: Determine the proportion of subjects developing deep infection or nonunion after primary wound closure of open fractures (humerus, radius/ulna, femur, and tibia/fibula). Secondarily, a matched-series analysis compared outcomes with subjects who underwent delayed wound closure. DESIGN: Prospective cohort between 2009 and 2013 of subjects undergoing primary closure. SETTING: Trauma center. PARTICIPANTS: Eighty-three (84 fractures) subjects were enrolled. Eighty-two (99%) subjects (83 fractures) provided follow-up data. Matching (age, sec, fracture location, and grade) was performed using study data of delayed wound closure undertaken at the same center between 2001 and 2009 (n = 68 matched subjects). INTERVENTION: Primary wound closure occurred when the fracture grade was Gustilo grade 3A or lower and the wound deemed clean at initial surgery. Standardized evaluations occurred until the fracture(s) healed; phone interviews and chart reviews were also undertaken at 1 year. MAIN OUTCOME MEASUREMENTS: Deep infection is defined as infection requiring unplanned surgical debridement and/or sustained antibiotic therapy after wound closure; nonunion is defined as unplanned surgical intervention after definitive wound closure or incomplete radiographic healing 1-year after fracture. RESULTS: Three (4%) subjects had deep infections, whereas 10 (12%) subjects developed nonunion in the primary closure cohort. In the matched analyses [n = 68 pairs; (136 subjects)], the primary closure cohort had fewer deep infections [n = 3 (4%) vs. n = 6 (9%)] and nonunions [n = 9 (13%) vs. n = 19 (29%)] than the delayed closure cohort (P < 0.001). CONCLUSIONS: Primary wound closure after an open fracture appears acceptable in appropriately selected patients and may reduce the risk of deep infection and nonunion compared with delayed closure; a definitive randomized trial is needed. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 27984447 TI - Local Zinc Chloride Release From a Calcium Sulfate Carrier Enhances Fracture Healing. AB - BACKGROUND: This study examined the efficacy of calcium sulfate (CaSO4) as a carrier for intramedullary delivery of zinc chloride (ZnCl2) to treat fracture healing in a BB Wistar rat model. A non-carrier-mediated injection of 3.0 mg/kg of ZnCl2 has previously been shown to enhance fracture healing. METHODS: A heterogeneous mixture of ZnCl2 and CaSO4 was administered into the intramedullary femoral canal and a mid-diaphyseal femur fracture was created unilaterally. Early and late parameters of fracture healing were assessed using biomechanical testing, radiographic scoring, quantitative histomorphometry (for percentage of new cartilage and bone within the fracture callus), and long-term histologic evaluation. RESULTS: Fractures treated with 1.0 mg/kg of ZnCl2/CaSO4 demonstrated a significantly higher maximum torque to failure compared with both CaSO4 (P = 0.048) and saline (P = 0.005) controls at 4 weeks postfracture (396.4 versus 251.3 versus 178.7 N mm, respectively). Statistically significant increases in torsional rigidity, effective shear modulus, and effective shear stress were also found, as well as a 3.5 times increase in radiographic score (based on bone union). Histologic examination of the fracture callus indicated enhanced chondrogenesis at day 14 postfracture, with increased percent cartilage for the ZnCl2/CaSO4 group compared with saline (P = 0.0004) and CaSO4 (P = 0.0453) controls. Long-term radiographic and histologic evaluation revealed no abnormal bone formation or infection up to 12 weeks postoperatively. CONCLUSIONS: The effective dose of ZnCl2 augmentation for the enhancement of fracture healing in rats was reduced 3-fold in this study compared with previous findings. Furthermore, CaSO4 acted synergistically with ZnCl2 to increase the mechanical strength and stability at the fracture site. PMID- 27984448 TI - Novel Spiked-Washer Repair Is Biomechanically Superior to Suture and Bone Tunnels for Arcuate Fracture Repair. AB - OBJECTIVES: Injuries to the posterolateral corner of the knee can lead to chronic degenerative changes, external rotation instability, and varus instability if not repaired adequately. A proximal fibula avulsion fracture, referred to as an arcuate fracture, has been described in the literature, but a definitive repair technique has yet to be described. The objective of this study was to present a novel arcuate fracture repair technique, using a spiked-washer with an intramedullary screw, and to compare its biomechanical integrity to a previously described suture and bone tunnel method. METHODS: Ten fresh-frozen cadaveric knees underwent a proximal fibula osteotomy to simulate a proximal fibula avulsion fracture. The lateral knee capsule and posterior cruciate ligament were also sectioned to create maximal varus instability. Five fibulas were repaired using a novel spiked-washer technique and the other 5 were repaired using the suture and bone tunnel method. The repaired knees were subjected to a monotonic varus load using a mechanical testing system instrument until failure of the repair or associated posterolateral corner structures. RESULTS: Compared with the suture repair group, the spiked-washer repair group demonstrated a 100% increase in stiffness, 100% increase in yield, 110% increase in failure force, and 108% increase in energy to failure. CONCLUSIONS: The spiked-washer technique offers superior quasi-static biomechanical performance compared with suture repair with bone tunnels for arcuate fractures of the proximal fibula. Further clinical investigation of this technique is warranted and the results of this testing may lead to improved outcomes and patient satisfaction for proximal fibula avulsion fractures. PMID- 27984450 TI - Invited Commentary Related to: "Gartland Type-3 Supracondylar Humeral Fractures in Children. Which Open Reduction Approach Should Be Used After Failed Closed Reduction?" PMID- 27984449 TI - Operative Treatment of Rib Fractures in Flail Chest Injuries: A Meta-analysis and Cost-Effectiveness Analysis. AB - OBJECTIVES: Flail chest is a common injury sustained by patients who experience high-energy blunt chest trauma and results in severe respiratory compromise because of altered mechanics of respiration. There has been increased interest in operative fixation of these injuries with the intention of restoring the mechanical integrity of the chest wall, and several studies have shown that ventilation requirements and pulmonary complications may be decreased with operative intervention. The purpose of this study was to evaluate fixation of rib fractures in flail chest injuries using cost-effectiveness analysis, supported by systematic review and meta-analysis. METHODS: This was a 2-part study in which we initially conducted a systematic literature review and meta-analysis on outcomes after operative fixation of flail chest injuries, evaluating intensive care unit (ICU) stay, hospital length of stay (LOS), mortality, pneumonia, and need for tracheostomy. The results were then applied to a decision-analysis model comparing the costs and outcomes of operative fixation versus nonoperative treatment. The validity of the results was tested using probabilistic sensitivity analysis. RESULTS: Operative treatment decreased mortality, pneumonia, and tracheotomy (risk ratios of 0.44, 0.59, and 0.52, respectively), as well as time in ICU and total LOS (3.3 and 4.8 days, respectively). Operative fixation was associated with higher costs than nonoperative treatment ($23,682 vs. $8629 per case, respectively) and superior outcomes (32.60 quality-adjusted life year (QALY) vs. 30.84 QALY), giving it an incremental cost-effectiveness ratio of $8577/QALY. CONCLUSIONS: Surgical fixation of rib fractures sustained from flail chest injuries decreased ICU time, mortality, pulmonary complications, and hospital LOS and resulted in improved health care-related outcomes and was a cost effective intervention. These results were sensitive to overall complication rates, and operations should be conducted by surgeons or combined surgical teams comfortable with both thoracic anatomy and exposures as well as with the principles and techniques of internal fixation. LEVEL OF EVIDENCE: Economic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27984451 TI - Clavicular Refracture at the Site of Angular Malunion in Young Athletes. AB - OBJECTIVE: The treatment of midshaft clavicle fractures has, in the last 2 decades, shifted markedly towards operative management. Prospective trials have defined accepted clinical and radiographic indications for the surgical management of clavicle fractures. This report documents 3 cases of clinically united angular malunion of the midshaft clavicle in young athletes that subsequently refractured to highlight angular deformity in the absence of displacement as a potential indication for surgical fixation. DESIGN: Case series. SETTING: A level 1 trauma centre. PATIENTS/PARTICIPANTS: Three young athletic patients with angular malunion of the midshaft clavicle who experienced refracture, requiring surgical fixation. INTERVENTION: Surgical fixation of midshaft clavicle fracture, as treatment for refracture after angular malunion. RESULTS: All 3 patients required subsequent surgical fixation of their midshaft clavicle fracture, correcting the angular malunion and restoring shoulder function. CONCLUSIONS: Midshaft clavicular fractures that malunite with significant angulation in the absence of displacement represent a risk for subsequent refracture. For this reason, angular deformity should be considered as a potential indication for surgical fixation in acute clavicular fractures. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27984452 TI - Comparison of 3 Methods for Maintaining Inter-Fragmentary Compression After Fracture Reduction and Fixation. AB - OBJECTIVES: It is recommended that the intra-articular component of a supracondylar distal femoral fracture be stabilized by a lag screw to create interfragmental compression. Generally, it is thought that lag screw fixation should precede any positional screw or locking screw application. This study compared 3 methods of maintaining interfragmentary compression after fracture reduction with a reduction clamp. METHODS: Intra-articular vertical split fractures were created in synthetic femora. A force transducer was interposed between the medial and lateral condyles and 20 lbs of compression was applied to the fracture with a reduction clamp. 3.5-mm cortical lag screws (group 1), 3.5-mm cortical position screws (group 2), and 5.4-mm distal locking screws through a distal femur locking plate (group 3) were placed across the fracture (n = 4/group). After screw placement, the clamp was removed and the amount of residual interfragmentary compression was recorded. After 2 minutes, a final steady-state force was measured and compared across groups. RESULTS: Locking screws placed through the plate (group 3) maintained 27% of the initial force applied by the clamp (P = 0.043), whereas positional screws (group 2) maintained 90% of the initial force applied by the clamp (P = 0.431). The steady-state compression force measured with lag screws (group 1) increased by 240% (P = 0.030) relative to the initial clamp force. The steady-state force in the lag screw group was significantly greater than groups 1 and 2 (P = 0.012). CONCLUSIONS: When reducing intra-articular fractures and applying interfragmentary compression with reduction clamps, additional lag screws increase the amount of compression across the fracture interface. Compressing a fracture with reduction clamps and relying on locking screws to maintain the compression result in a loss of interfragmentary compression and should be avoided. This study lends biomechanical support that lag screws placed outside of the plate before locking screws for fracture fixation help maintain optimal interfragmentary compression. PMID- 27984453 TI - Management of Closed Diaphyseal Humerus Fractures in Patients With Injury Severity Score >=17. AB - OBJECTIVES: The management of closed diaphyseal humerus fractures in the polytrauma patient varies widely. The aim of this study was to compare outcomes of operative and nonoperative management in this patient population. DESIGN: Single-center, retrospective cohort analysis. SETTING: Urban, Level 1 trauma center. PATIENTS: Seventy-one patients with closed diaphyseal humerus fractures, and Injury Severity Score (ISS) of >=17, treated between 2006 and 2011 were identified. INTERVENTION: Patients were treated operatively versus nonoperatively with a functional brace by surgeon preference. MAIN OUTCOMES: Primary outcome was union. Secondary outcomes included time to union, time to release to weightbearing, and complications other than nonunion. RESULTS: There was no statistical difference between age, Injury Severity Score, or fracture type between the 2 cohorts. There was a statistically higher incidence of associated orthopaedic injury, and more specifically, lower extremity injury in the group treated with operative intervention. There was no difference in union rates (95% operative, 94% nonoperative), time to union (17 weeks operative, 15 weeks nonoperative), or complication rates between the 2 groups. Time to release to weightbearing was 3 weeks shorter in the operative group (9.3 weeks operative, 12.8 weeks nonoperative). CONCLUSIONS: Polytrauma patients with closed diaphyseal humerus fractures can be treated successfully with equivalent union rates, time to union, and complication rates when selected for conservative management techniques. The decision to undertake operative management of closed diaphyseal humerus fractures in the polytraumatized patient is multifaceted and should consider patient expectations, demographics, injury profile, and ambulatory status. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27984455 TI - Change and Continuity. PMID- 27984454 TI - Nonunion After Clavicle Osteosynthesis: High Incidence of Propionibacterium acnes. AB - OBJECTIVE: The objective of this study was to review the etiology of clavicle nonunions after osteosynthesis and investigate the outcomes of a treatment with a single-stage revision. DESIGN: Retrospective case series. SETTING: Orthopaedic specialty hospital. PATIENTS: Twenty cases of nonunion after osteosynthesis of the clavicle were identified. The average age was 44 years (+/-13 years). In 9 cases, there was catastrophic implant failure that prompted the revision surgery. In the 18 cases in which cultures were taken, 15 of the 18 (83%) were treated as infections with a course of antibiotics. In 14 cases, the cultures were positive for Propionibacterium acnes. RESULTS: Fifteen patients were treated with a prolonged course of antibiotics. Eighteen patients had follow-up, and the average time to radiographic union was 22 weeks. There were no cases of nonunion after revision surgery. CONCLUSIONS: There is a high rate of positive cultures in cases of nonunion after osteosynthesis of the clavicle. This suggests the etiology of midshaft clavicle nonunions may result from a combination of suboptimal mechanical fixation and latent infection. Our treatment protocol of superior and anterior plating, interfragmentary fixation, bone grafting, and appropriate antimicrobial treatment of latent infections has resulted in 100% union rate. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27984456 TI - Developing a Clinical Protocol for Habitual Physical Activity Monitoring in Youth With Cerebral Palsy. AB - PURPOSE: The StepWatch (SW) has been used to monitor physical activity (PA) in youth with cerebral palsy; however, there is no standard collection protocol. The goal was to develop such a protocol. METHODS: Data were examined from patients who wore the SW for 8 to 14 days. The Spearman-Brown prediction formula determined the minimum number of days for reliable PA. Weekdays were compared to weekends and 10- and 60-second collection intervals were examined. RESULTS: The PA data were collected from 98 youth with cerebral palsy. Results showed 3 days would provide reliable representation of PA, participants took significantly more steps during school days compared with weekends, and there were no differences between collection intervals. CONCLUSIONS: We recommend setting the SW for 7 days at 10-second collection rate. Data should be analyzed if at least 3 days of data are present. Weekdays and weekend days should be noted, and both included when possible. PMID- 27984457 TI - Commentary on "Developing a Clinical Protocol for Habitual Physical Activity Monitoring in Youth With Cerebral Palsy". PMID- 27984458 TI - Habitual Physical Activity in Children With Cerebral Palsy Aged 4 to 5 Years Across All Functional Abilities. AB - PURPOSE: To compare ambulatory status in children with cerebral palsy aged 4 to 5 years with their habitual physical activity and time spent sedentary, and to compare their activity with physical activity guidelines. METHODS: Sixty-seven participants-independently ambulant, marginally ambulant, and nonambulant-wore accelerometers for 3 days. Time spent sedentary as a percentage of wear time and activity counts were compared between groups. RESULTS: There were significant differences in time spent sedentary and activity counts between groups. Children who were independently ambulant were more likely to meet physical activity guidelines. CONCLUSION: Children with cerebral palsy spent more than half of their waking hours in sedentary time. Interventions to reduce sedentary behavior and increase habitual physical activity are needed in children with cerebral palsy at age 4 to 5 years. PMID- 27984459 TI - Commentary on "Habitual Physical Activity in Children With Cerebral Palsy Age 4 to 5 Years Across All Functional Abilities". PMID- 27984460 TI - Leisure Participation Patterns of Children With Movement Impairments in New Zealand. AB - PURPOSE: To investigate the leisure participation patterns of children with movement impairments in New Zealand. METHODS: A cross-sectional survey was conducted with children with movement impairments aged 6 to 12 years using the Children's Assessment of Participation and Enjoyment questionnaire. Descriptive statistics were used to analyze the data. RESULTS: Children participated in an average of 57.3% of activities, with a greater number and frequency of recreational, social, and self-improvement activities as compared with skill based and physical activities. Children performed nearly 50% of activities with family and 13% of activities with friends. Approximately 50% of activities were performed at home and 50% of activities were performed outside the home. CONCLUSIONS: Children with movement impairments participated in diverse leisure activities. However, reduced involvement in physical activities needs further investigation to identify the actual level of physical exertion, barriers faced, and how increased opportunities for regular physical activity could be instigated. PMID- 27984461 TI - Commentary on: "Leisure Participation Patterns of Children With Movement Impairments in New Zealand". PMID- 27984462 TI - The Relationships Between Capacity and Performance in Youths With Cerebral Palsy Differ for GMFCS Levels. AB - PURPOSE: To examine change in, and longitudinal relationships between motor capacity and activity performance across the Gross Motor Function Classification System (GMFCS). METHODS: Ninety-two youths with cerebral palsy were examined at 2 time points, 1 year apart, using the Gross Motor Function Measure-66 (GMFM-66) for motor capacity, and the Chinese version of the Activities Scale for Kids Performance Version (ASKp-C) for activity performance. The score changes and capacity-to-performance/performance-to-capacity pathways were explored across GMFCS levels. RESULTS: The GMFM-66 scores declined over time in GMFCS levels IV-V while ASKp-C scores increased in GMFCS level I. The correlations for both pathways in GMFCS levels I, III, and IV-V were significant with a higher correlation for performance-to-capacity pathway in GMFCS levels IV-V. CONCLUSIONS: Longitudinal changes in and relationships between capacity and performance differ between GMFCS levels. The opportunities to perform activities need to be emphasized in GMFCS levels IV-V. PMID- 27984463 TI - Commentary on "The Relationships Between Capacity and Performance in Youths With Cerebral Palsy Differ for GMFCS Levels". PMID- 27984464 TI - Power-Up: Exploration and Play in a Novel Modified Ride-On Car for Standing. AB - PURPOSE: The purpose of this study was to compare the physical activity and play behaviors of preschoolers without disabilities and 1 preschooler with physical disability. METHODS: Participants were 42 preschoolers without disabilities and 1 preschooler with physical disability (Child A). Child A used either crutches or a modified ride-on car while in the gymnasium and playground. RESULTS: In the gymnasium, Child A engaged in less solitary play and more parallel play while using the modified ride-on car compared with crutches. On the playground, Child A engaged in more sitting and less running while using crutches compared with preschoolers without disabilities. On the playground, Child A engaged in more peer interaction and less teacher interaction when using the modified ride-on car compared with crutches. CONCLUSIONS: For children with disabilities who may use assistive devices, clinicians, families, and teachers are encouraged to embrace a "right device, right time, right place" approach. PMID- 27984465 TI - Commentary on "Power-Up: Exploration and Play in a Novel Modified Ride-On Car for Standing". PMID- 27984466 TI - Effects of Combined Exercise Training on Functional Performance in Children With Cerebral Palsy: A Randomized-Controlled Study. AB - PURPOSE: The purpose of this study was to investigate the effects of combined exercise training on functional performance in participants with cerebral palsy. METHODS: Fifteen participants with spastic cerebral palsy were randomly allocated into either exercise or control groups. Participants in the exercise group participated in a combined strength and endurance training program for 70 minutes per day, 3 days per week, for 8 weeks, whereas those in the control group did not participate in an exercise program. Study participants in both groups continued with their regular physical therapy during the study. RESULTS: After the 8-week training, a 6-minute walk, 30-second sit-to-stand, 10-m walk, and Functional Reach Tests, participants in the exercise group had significant improvement over their baseline values and were significantly higher than those in the control group. CONCLUSIONS: Combined exercise training improved walking ability, functional lower limb strength, and balance in participants with cerebral palsy. PMID- 27984467 TI - Commentary on "Effects of Combined Exercise Training on Functional Performance in Children With Cerebral Palsy: A Randomized-Controlled Study". PMID- 27984468 TI - Physical Therapy Dosing: Frequency and Type of Intervention in Pediatric Postacute Hospital Care. AB - PURPOSE: To examine differences in physical therapy dosing frequency recommendations based on children's characteristics and to describe types of intervention recommended at postacute hospital admission. METHODS: Demographic and clinical information, recommended physical therapy intervention frequency, and intervention types were collected for all admissions from April 1, 2015, to March 1, 2016. Differences across 2 groups, children with recommendations for "less" (<=3x/wk) or "more" (>=4x/wk) frequent therapy, were examined. Types of interventions recommended were described and the measure of association between frequency and type was determined. RESULTS: Older children, those with higher admission functional scores, and children with less dependence on medical technology were recommended for "more." Therapeutic exercise was the most common intervention recommended. Greater physical therapy frequency was associated with Functional Training and Motor Function Training. CONCLUSION: Children's age, functional level, and technology dependence influence dosing recommendations. Interventions focused on function are associated with greater physical therapy frequency. PMID- 27984469 TI - Commentary on "Physical Therapy Dosing: Frequency and Type of Intervention in Pediatric Postacute Hospital Care". PMID- 27984471 TI - Commentary on "Constraint-Induced Movement Therapy for Children With Brain Tumors". PMID- 27984470 TI - Constraint-Induced Movement Therapy for Children With Brain Tumors. AB - PURPOSE: The purpose of this pilot study was to investigate the feasibility of a 3-week constraint-induced movement therapy program in children with brain tumors and upper extremity hemiplegia and to describe resultant change in extremity use. METHODS: Affected arm use, health-related quality of life, and parent-reported feasibility of program participation were measured before and after the intervention and at a 3-month follow-up visit. RESULTS: All 9 participants completed the entire study. The quality and amount of affected arm use improved significantly; gains were maintained at the 3-month follow-up evaluation. Some parents (44%) reported that program participation was difficult; however, all reported satisfaction with the program. Participants did not experience negative changes in health-related quality of life during the intervention, indicating that they tolerated the program well. CONCLUSIONS: Findings suggest that a child with hemiplegia as a result of a brain tumor can adhere to and benefit from a constraint-induced movement therapy program. PMID- 27984472 TI - Six-Month Follow-up of Supervised Spinal Stabilization Exercises for Low Back Pain in Adolescent Idiopathic Scoliosis. AB - PURPOSE: To evaluate the effectiveness of 8 weeks of weekly spinal stabilization exercises compared with 1-time treatment in participants with adolescent idiopathic scoliosis and low back pain at a 6-month follow-up. METHODS: Thirty two participants were evaluated at a 6-month follow-up. The supervised group received weekly spinal stabilization exercises. The unsupervised group received a 1-time treatment and home exercise program. RESULTS: Both groups improved in all outcome measures. The supervised group had significantly reduced Numeric Pain Rating Scale and Improved Global Rating of Change scores, but had no differences in the revised Oswestry Back Pain Disability Questionnaire, or Patient-Specific Functional Scale scores in comparison with the unsupervised group. PMID- 27984473 TI - Commentary on "Six-Month Follow-up of Supervised Spinal Stabilization Exercises for Low Back Pain in Adolescent Idiopathic Scoliosis". PMID- 27984474 TI - Importance of Initiating a "Tummy Time" Intervention Early in Infants With Down Syndrome. AB - PURPOSE: This study compared differences in motor development in infants with Down syndrome beginning a tummy time intervention before 11 weeks of age and after 11 weeks of age. METHODS: Nineteen infants with Down syndrome participated in tummy time until they could independently transition in and out of sitting. Motor development was assessed monthly using the Bayley III Motor Scales and compared between the groups. RESULTS: A difference in motor development between early and late groups is apparent 1, 2, and 3 months following intervention initiation. CONCLUSION: Early implemented tummy time was effective in reducing motor delay in young infants with Down syndrome and is a prudent first step in intervention. PMID- 27984475 TI - Commentary on "Importance of Initiating a 'Tummy Time' Intervention Early in Infants With Down Syndrome". PMID- 27984476 TI - Minimal Detectable Change for TUG and TUDS Tests for Children With Down Syndrome. AB - PURPOSE: To determine test-retest reliability and minimal detectable change of the Timed Up and Go (TUG) and Timed Up and Down Stairs (TUDS) for Down syndrome. SUBJECTS: Twelve children with Down syndrome (DS) aged 3 to 17 years. METHODS: Two sessions, 1 week apart, with 3 trials of the TUG and 2 trials of the TUDS. Test-retest reliability was estimated using intraclass correlation coefficients and the standard error of measurement. The minimal detectable changes (MDCs) for both tests were calculated. RESULTS: The TUG and TUDS tests both had high test retest reliability. The MDC was 1.26 seconds for the TUG and 12.52 seconds for the TUDS test. CONCLUSIONS: Both tests were reliable in this population, but the MDC results suggest only the TUG is clinically useful. PMID- 27984477 TI - Commentary on "Minimal Detectable Change for TUG and TUDS Tests for Children With Down Syndrome". PMID- 27984478 TI - Reliability of the Arch Height Index as a Measure of Foot Structure in Children. AB - PURPOSE: To determine the intrarater and interrater reliability of the arch height index (AHI) in children developing typically. The AHI is tested with a device that measures foot structure. METHODS: Thirty children, ages 6 to 12 years, participated for a total of n = 60 feet. The AHI measurements were taken by 2 investigators in sitting and standing and repeated twice by each investigator in a single visit. Intrarater and interrater reliabilities were determined using intraclass correlation coefficient (ICC) (2,1) statistical analysis. RESULTS: The mean age was 9.61 +/- 1.96 years. The intrarater and interrater reliability had an ICC 0.76 or more in both sitting and standing. The average AHI value was 0.36 +/- 0.02 in sitting and 0.32 +/- 0.02 in standing. CONCLUSIONS: Pediatric therapists, physicians, and orthotists should consider using the AHI as an objective measure to be used for research, to assess foot structure, monitor change over time, and assist with treatment planning in children. PMID- 27984479 TI - Commentary on "Reliability of the Arch Height Index as a Measure of Foot Structure in Children". PMID- 27984480 TI - A Child With a Burn-Related Foot and Ankle Contracture Treated With Multiple Modalities. AB - PURPOSE: The presence of hypertrophic scars, which cross lower extremity joints, can often result in decreased range of motion, limitations in functional mobility, and gait deviations. This article reviews a case and describes a multimodal treatment approach. SUMMARY OF KEY POINTS: A 6-year-old girl developed aggressive hypertrophic scars following a burn injury. A multimodal treatment approach, including splinting, elastomers, and physical therapy, was developed. CONCLUSIONS: Rapid improvements were demonstrated in measured objective outcomes. RECOMMENDATIONS FOR CLINICAL PRACTICE: Early multimodal intervention, in addition to range of motion, stretching, massage, and compression garments, is recommended when treating hypertrophic scars. This case suggests that further study into a multimodal treatment approach may be beneficial to develop a standardized protocol for more efficient scar management. PMID- 27984481 TI - Gamification in Physical Therapy: More Than Using Games. AB - The implementation of computer games in physical therapy is motivated by characteristics such as attractiveness, motivation, and engagement, but these do not guarantee the intended therapeutic effect of the interventions. Yet, these characteristics are important variables in physical therapy interventions because they involve reward-related dopaminergic systems in the brain that are known to facilitate learning through long-term potentiation of neural connections. In this perspective we propose a way to apply game design approaches to therapy development by "designing" therapy sessions in such a way as to trigger physical and cognitive behavioral patterns required for treatment and neurological recovery. We also advocate that improving game knowledge among therapists and improving communication between therapists and game designers may lead to a novel avenue in designing applied games with specific therapeutic input, thereby making gamification in therapy a realistic and promising future that may optimize clinical practice. PMID- 27984482 TI - Time to Update the Gross Motor Function Classification System (GMFCS) for Early Age Bands by Incorporation of Assisted Mobility? PMID- 27984483 TI - Response Letter to the Editor. PMID- 27984484 TI - Authors' Response to Commentary by Drs Sueki and Achhnani on the Article, "Does Exercise Decrease Pain via Conditioned Pain Modulation in Adolescents?" PMID- 27984485 TI - Platelet * CRP Multiplier Value as an Indicator of Poor Prognosis in Patients With Resectable Pancreatic Cancer. AB - OBJECTIVE: Thrombocytosis in patients with various cancers has been considered a parameter for poor prognosis; however, its contribution to pancreatic cancer remains controversial. METHODS: Potential preoperative prognostic parameters (platelets, neutrophils, lymphocytes, the platelet-lymphocyte ratio, the neutrophil-lymphocyte ratio, the serum C-reactive protein [CRP], and carbohydrate antigen 19-9) were retrospectively analyzed in 95 patients with pancreatic cancer. Cutoff values were defined according to receiver operating characteristic curve analysis, and median survival times (MSTs) were compared. RESULTS: Median survival times (days) significantly differed according to platelet count (high [552] vs low [735], P = 0.017), CRP (high [471] vs low [750], P = 0.001), and carbohydrate antigen 19-9 level (high [639] vs low [765], P = 0.021), whereas there was no difference in the platelet-lymphocyte ratio and the neutrophil lymphocyte ratio. Multivariate analysis identified thrombocytosis (hazard ratio, 2.015) and CRP level (hazard ratio, 1.771) as independent prognostic factors. The combinatory effects of platelets and the inflammatory response using a platelet * CRP multiplier value could effectively distinguished the MSTs (days) of patients with pancreatic cancer (high [482] vs low [812], P < 0.001). CONCLUSIONS: Thrombocytosis and CRP influenced pancreatic cancer patient prognosis. Platelet * CRP multiplier is assumed as a useful parameter that reflects the contribution of activated platelets to cancer progression. PMID- 27984486 TI - A Clinicopathological Study of Malignant Insulinoma in a Contemporary Series. AB - OBJECTIVE: The aim of the study was to address the origin and natural history of malignant insulinoma. METHODS: Retrospective review of medical records of patients diagnosed with insulinoma at Cedars-Sinai Medical Center between 2000 and 2015 was conducted. Hormonal expression in tumor specimens was examined by immunostaining. RESULTS: All the 9 patients with malignant insulinoma (35% of 26 patients with insulinoma) already had liver metastasis at hypoglycemia presentation with bulky cumulative tumor burden. Six patients had de novo diagnosis, 2 had known metastatic nonfunctioning pancreatic neuroendocrine tumor, and 1 had a known pancreatic mass. Tumor grade at presentation was G1 in 4 patients, G2 in 4, and unknown in 1. Four patients died 2 to 32 months after presentation, all with extensive liver tumor involvement. Tumor expression of proinsulin and insulin was heterogeneous and overall infrequent. The proinsulin levels and proinsulin/insulin molar ratio in patients with malignant versus benign insulinoma were 334 versus 44 pmol/L and 2.1 versus 0.9, respectively. CONCLUSIONS: Malignant insulinoma seems to arise from and behave like nonfunctioning pancreatic neuroendocrine tumor oncologically but with metachronous hyperinsulinemic hypoglycemia. High proinsulin levels and proinsulin/insulin molar ratio may suggest malignant insulinoma. PMID- 27984487 TI - Genetic Susceptibility in Acute Pancreatitis: Genotyping of GSTM1, GSTT1, GSTP1, CASP7, CASP8, CASP9, CASP10, LTA, TNFRSF1B, and TP53 Gene Variants. AB - OBJECTIVES: Genetic testing could play a critical role in diagnosis and prognosis of acute pancreatitis (AP) and guide effective therapeutic interventions. We hypothesized that genetic polymorphisms in apoptosis and oxidative stress genes could determine incidence or severity in AP. METHODS: We conducted a hospital based case-control study in a white Portuguese population (133 AP patients and 232 age- and sex-matched healthy controls) to evaluate the role of 15 gene polymorphisms (2 deletions and 13 single nucleotide polymorphisms [SNPs]) in oxidative stress (GSTM1, GSTT1, GSTP1) and apoptosis genes (CASP7, CASP8, CASP9, CASP10, LTA, TNFRSF1B, TP53) in AP. Criteria for AP were abdominal pain, hyperamylasemia, and contrast-enhanced computed tomography. RESULTS: The presence of GSTM1 is associated with increased susceptibility for AP, and the GSTP1 Val105Ile SNP is associated with an increased risk for AP in men. CASP9 Phe136Leu/Phe136Phe SNPs (heterozygotes) increases the risk for mild AP (odds ratio, 3.616; 95% confidence interval, 1.151-11.364; P < 0.05), whereas the homozygotic genotype of CASP9 Ala28Val decreases risk for mild AP (odds ratio, 0.296; 95% confidence interval, 0.091-0.963; P < 0.05). CONCLUSIONS: Our results suggest that variations in GSTM1, GSTP1, and CASP9 may influence risk for AP. PMID- 27984488 TI - Chronic Pancreatitis-Like Changes Detected by Endoscopic Ultrasound in Type 1 Diabetics Are Not Associated With Gastrointestinal Symptoms or Nutritional Deficiencies. AB - OBJECTIVES: Previous studies have shown changes in the pancreas of type 1 diabetic (T1-DM) patients, similar to those present in patients with chronic pancreatitis. Our aim was to analyze the prevalence of endoscopic ultrasound (EUS) criteria for chronic pancreatitis in T1-DM, to determine the association with factors related to the diabetes and to define its clinical significance. METHODS: Eighty-six T1-DM patients were prospectively included. All of them underwent EUS. Standard criteria were used. Patients were divided into 3 groups according to the number of EUS criteria they met: group A, 0 to 2 criteria; group B, 3 to 4; and group C, more than 4. Association between EUS findings and demographic or clinical factors was studied as well as the relationship between EUS abnormalities and the presence of gastrointestinal symptoms or nutritional deficiencies. RESULTS: Fifty-three patients (61.6%) showed at least 1 morphologic abnormality. Fifty-eight patients were included in group A, 21 in group B, and 7 in Group C. No significant differences were found when comparing the 3 groups. CONCLUSIONS: Chronic pancreatitis-like changes are frequent in the pancreas of T1 DM patients. These changes are not associated with demographic or clinical data. Therefore, the clinical relevance seems to be scarce. PMID- 27984490 TI - Examination of an Internet-Delivered Cognitive Behavioural Pain Management Course for Adults with Fibromyalgia: A Randomized Controlled Trial. AB - Fibromyalgia (FM) is a common and often debilitating chronic pain condition. Research shows that symptoms of depression and anxiety are present in up to three quarters of individuals with FM. Of concern, most adults with FM cannot access traditional face-to-face cognitive behavioural pain management programs, which are known to be beneficial. Given known difficulties with treatment access, the present study sought to explore the efficacy and acceptability of a previously developed Internet-delivered cognitive behavioural pain management course, the Pain Course, for adults with FM. The five-lesson course was delivered over eight weeks and was provided with brief weekly contact, via telephone and secure email, with a guide throughout the course. Participants were randomized either to the Pain Course (n = 30) or to a waiting-list control group (n = 30). Symptoms were assessed at pre-treatment, post-treatment and 4-week follow-up. Completion rates (87%) and satisfaction ratings (86%) were high. Improvements were significantly greater in treatment group participants compared to waiting-list group participants on measures of FM (Cohen's d =.70; 18% reduction), depression (Cohen's d =.63-.72; 20-28% reduction), pain (Cohen's d =.87; 11% improvement) and fear of pain (Cohen's d =1.61; 12% improvement). Smaller effects were also observed on measures of generalized anxiety and physical health. The changes were maintained at four-week follow-up. The current findings add to existing literature and highlight the specific potential of Internet-delivered cognitive behavioural pain management programs for adults with FM, especially as a part of stepped-care models of care. Future research directions are described. PMID- 27984489 TI - Intraobserver and Interobserver Measurement Variability of the Rib-Vertebral Angle Difference. AB - BACKGROUND: The rib-vertebral angle (RVAD) differentiates between progressive and resolving infantile idiopathic scoliosis (IIS) curves. Those with a RVAD<20 degrees often resolve without treatment, whereas those >20 degrees often progress and require treatment. The mathematical magnitude of RVAD measurement variability has not been described, and was thus the purpose of this study. It is important to know the reliability of RVAD measurements so as to understand changes that can be attributed to observer error alone. PURPOSE: The purpose of the study was to mathematically determine the intraobserver and interobserver measurement variability of the RVAD difference in IIS. METHODS: A convenience sample of 50 patients with IIS was selected. The RVAD was measured twice by 7 different observers separated by a minimum of 3 weeks. The 7 different readers chosen to measure the RVAD were 2 orthopaedic residents, 1 pediatric radiologist, and 4 attending pediatric orthopaedic surgeons. The same goniometer was used for all measurements. Intraobserver and interobserver measurement variability was determined using 3 well known used statistical methods. RESULTS: The 3 different methods used to determine intraobserver and interobserver variability using 95% prediction/confidence limits gave very similar results. Intraobserver variability was ~24 degrees and the interobserver variability was ~23 degrees. DISCUSSION: The utility of the RVAD in medical decision-making and counseling of patients with IIS should be approached with caution when used in isolation due to the large measurement variability. LEVEL OF EVIDENCE: Level 3. PMID- 27984495 TI - Are We Really Ready for Telehealth Cognitive Behavioral Therapy for Pain? PMID- 27984491 TI - Sex differences in the efficacy of psychological therapies for the management of chronic and recurrent pain in children and adolescents: A systematic review and meta-analysis. AB - Sex differences in chronic pain are reported to emerge during adolescence, although it is unclear if this includes responses to treatment. We conducted a meta-analysis to examine whether sex differences were present on outcome variables at pre-treatment, and whether the efficacy of psychological therapies for pediatric chronic pain differs between boys and girls at post-treatment and follow-up time points. Searches were conducted, extending two existing Cochrane reviews of randomized-controlled trials examining the efficacy of psychological therapies for chronic and recurrent pain in children and adolescents. Forty-six articles were eligible for inclusion, and data were extracted regarding pain, disability, anxiety, and depression in boys and girls at pre-treatment, post treatment, and follow-up time points. No published study reported outcome data separately by sex, so authors of all studies were contacted and 17 studies provided data. Twice as many girls (n =1760) were enrolled into clinical trials of psychological therapies for pediatric chronic pain than boys (n = 828). Girls reported higher depression and anxiety at pre-treatment than boys. Girls with headache also reported significantly greater pre-treatment pain severity. Treatment gains were consistent across the sexes. One exception was for post treatment disability in children with non-headache pain conditions; girls exhibited a significant effect of treatment relative to control condition (SMD= 0.50[-0.80,-0.20], p < .01), but no such effect was observed for boys (SMD= 0.08[-0.44,0.28], p = .66). Future research should examine whether mechanisms of treatment efficacy differ between boys and girls, and consider the impact of pre treatment sex differences on response to treatment. PMID- 27984496 TI - Influence of Clothing on Thermoregulation and Comfort During Exercise in the Heat. AB - Davis, JK, Laurent, CM, Allen, KE, Zhang, Y, Stolworthy, NI, Welch, TR, and Nevett, ME. Influence of clothing on thermoregulation and comfort during exercise in the heat. J Strength Cond Res 31(12): 3435-3443, 2017-Sport textiles of synthetic fiber have been proposed to have superior properties for keeping wearers cooler, drier, and more comfortable compared with natural fibers. The impact of various fiber content and fabric construction on thermoregulation and perceptual responses are not well understood. Eight male collegiate athletes performed 3 counterbalanced trials of 45-minute treadmill run at 60% of maximal oxygen uptake in an environmental chamber (32 degrees C). Three different fibers, consisting of 100% cotton, a blend of natural fibers (50/50% cotton/soybean), and a synthetic fiber (100% polyester) with mesh loops to facilitate ventilation through the clothing, were tested. Heat strain indices, microenvironment temperature, ratings of perceived exertion (RPE), and clothing comfort were measured. Session RPE (S-RPE) and session thermal sensation (S-TS) were recorded 20 minutes after each trial. There was no effect of clothing on rectal, skin, and body temperatures, heart rate, RPE, or comfort measures (p >= 0.05). A significant effect was observed for synthetic fiber compared with cotton on S-RPE (p = 0.03), S-TS (p = 0.04), and the microenvironment temperature at the chest (p = 0.02). No significant difference was shown for any other fibers on S RPE, S-TS, or other microenvironment areas (p >= 0.05). These results show that clothing fiber content and fabric construction had no effect on thermoregulation, RPE, or clothing comfort during moderate-intensity exercise in the heat; whereas synthetic fabric construction indeed effectively reduced regional microenvironment temperature and attenuated global exertion and TS, which may have important implications for exercise tolerance in the heat. PMID- 27984497 TI - Acute Effects of the Different Intensity of Static Stretching on Flexibility and Isometric Muscle Force. AB - Kataura, S, Suzuki, S, Matsuo, S, Hatano, G, Iwata, M, Yokoi, K, Tsuchida, W, Banno, Y, and Asai, Y. Acute effects of the different intensity of static stretching on flexibility and isometric muscle force. J Strength Cond Res 31(12): 3403-3410, 2017-In various fields, static stretching is commonly performed to improve flexibility, whereas the acute effects of different stretch intensities are unclear. Therefore, we investigated the acute effects of different stretch intensities on flexibility and muscle force. Eighteen healthy participants (9 men and 9 women) performed 180-second static stretches of the right hamstrings at 80, 100, and 120% of maximum tolerable intensity without stretching pain, in random order. The following outcomes were assessed as markers of lower limb function and flexibility: static passive torque (SPT), range of motion (ROM), passive joint (muscle-tendon) stiffness, passive torque (PT) at onset of pain, and isometric muscle force. Static passive torque was significantly decreased after all stretching intensities (p <= 0.05). Compared with before stretching at 100 and 120% intensities, ROM and PT were significantly increased after stretching (p <= 0.05), and passive stiffness (p = 0.05) and isometric muscle force (p <= 0.05) were significantly decreased. In addition, ROM was significantly greater after stretching at 100 and 120% than at 80%, and passive stiffness was significantly lower after 120% than after 80% (p <= 0.05). However, all measurements except SPT were unchanged after 80% intensity. There was a weak positive correlation between the intensities of stretching and the relative change for SPT (p <= 0.05), a moderate positive correlation with ROM (p <= 0.05), and a moderate positive correlation with passive stiffness (p <= 0.05). These results indicate that static stretching at greater intensity is more effective for increasing ROM and decreasing passive muscle-tendon stiffness. PMID- 27984498 TI - The Biomechanical Demands on the Hip During Progressive Stepping Tasks. AB - Hatfield, GL, Charlton, JM, Cochrane, CK, Hammond, CA, Napier, C, Takacs, J, Krowchuk, NM, and Hunt, MA. The biomechanical demands on the hip during progressive stepping tasks. J Strength Cond Res 31(12): 3444-3453, 2017 Functional hip strengthening exercises are important components of lower extremity (LE) rehabilitation and include single-leg squats (SLS), step-downs (SD), and step-ups (SU). The biomechanical demand of these tasks is unclear. This repeated-measures study determined hip biomechanical demands in a healthy population. Twenty individuals (10 men, 26.6 +/- 5.1 years, 22.1 +/- 2.3 kg.m) participated. Three-dimensional motion, ground reaction force data, and surface electromyograms (EMG) were recorded during 4 randomly ordered tasks. Outcomes included frontal and sagittal plane hip moment impulses and muscle activity for each task. Repeated measures analysis of variance models (alpha = 0.05) determined between-task differences. Step-down and SLS were most biomechanically demanding, with significantly higher hip flexion and adduction moment impulses, and gluteus medius (GM) and quadriceps activity compared with half step-down (HSD) and SU. No significant difference was found between SD and SLS, indicating minimal difference in demand between the 2 tasks, likely due to kinematic similarities in performance; there were no significant differences in knee or hip sagittal plane angle excursion, or peak pelvic obliquity angle between the 2 tasks. Step-up was least demanding, with the lowest hip flexion and adduction moment impulses and GM, quadriceps, and hamstrings activity. Step-up was least demanding on the hip and would be a good starting task for hip strengthening protocols. Step-down and SLS were most demanding, requiring higher hip moments and muscle activity. These results provide evidence, which may be used in planning of progressive rehabilitation programs for patients with LE pathologies. PMID- 27984499 TI - Effects of Pre-exhaustion on the Patterns of Muscular Activity in the Flat Bench Press. AB - Golas, A, Maszczyk, A, Pietraszewski, P, Stastny, P, Tufano, JJ, and Zajac, A. Effects of pre-exhaustion on the patterns of muscular activity in the flat bench press. J Strength Cond Res 31(7): 1919-1924, 2017-Pre-exhaustion (PE) has been applied in resistance training (RT) to manipulate the order of performing 2 resistance exercises, a single-joint exercise to momentary exhaustion, followed by a multi-joint movement that includes the same muscle group. This method ensures greater recruitment of muscles or muscle groups in the multi-joint exercise to further increase muscle strength and overcome strength plateaus. The purpose of the present study was to investigate muscle activity by electromyography during high-intensity (95% of 1 repetition maximum [RM]) bench press (BP), before and after PE of the pectoralis major (PM), anterior deltoid (AD), and triceps brachii (TB) muscles to determine the effects of PE of the prime movers. Eight healthy athletes, experienced in RT, participated in the study. There were 4 sessions in the experiment. Session 1 was aimed at determination of 1RM during a flat BP. Sessions 2, 3, and 4 consisted of performing a BP after PE of the muscles studied by the incline dumbbell fly, front deltoid raise, and lying triceps extension exercise. Peak concentric TB activation after TB PE (mean +/- SD, 147.76 +/- 18.6%) was significantly greater by analysis of variance (eta = 0.82, F = 5.45, p = 0.004) compared with peak TB activation (114.77 +/- 19.4%) before TB PE. The statistical analysis for PM and AD did not show any significant differences. Coaches should not expect the usefulness of PE protocol to elicit higher PM or AD activity or fatigue, but they can use it to increase TB activity before high-intensity BP exercise. PMID- 27984500 TI - Seasonal Changes in Soccer Players' Body Composition and Dietary Intake Practices. AB - Devlin, BL, Kingsley, M, Leveritt, MD, and Belski, R. Seasonal changes in soccer players' body composition and dietary intake practices. J Strength Cond Res 31(12): 3319-3326, 2017-The aims of this study were 2-fold: to determine seasonal changes in dietary intake and body composition in elite soccer players and to evaluate the influence of self-determined individual body composition goals on dietary intake and body composition. This longitudinal, observational study assessed body composition (total mass, fat-free soft tissue mass, and fat mass) using dual-energy x-ray absorptiometry and dietary intake (energy and macronutrients) via multiple-pass 24-hour recalls, at 4 time points over a competitive season in elite soccer players from one professional club in the Australian A-League competition. Self-reported body composition goals were also recorded. Eighteen elite male soccer players took part (25 +/- 5 years, 180.5 +/- 7.4 cm, 75.6 +/- 6.5 kg). Majority (>=67%) reported the goal to maintain weight. Fat-free soft tissue mass increased from the start of preseason (55,278 +/- 5,475 g) to the start of competitive season (56,784 +/- 5,168 g; p < 0.001), and these gains were maintained until the end of the season. Fat mass decreased over the preseason period (10,072 +/- 2,493 g to 8,712 +/- 1,432 g; p < 0.001), but increased during the latter part of the competitive season. Dietary intake practices on training days were consistent over time and low compared with sport nutrition recommendations. The self-reported body composition goals did not strongly influence dietary intake practices or changes in body composition. This study has demonstrated that body composition changes over the course of a soccer season are subtle in elite soccer players despite relatively low self-reported intake of energy and carbohydrate. PMID- 27984503 TI - Does Intervening In Childcare Settings Impact Fundamental Movement Skills Development? PMID- 27984504 TI - Response. PMID- 27984505 TI - Relationship between Corneal Thickness and Radius to Body Height. AB - PURPOSE: To investigate the possible association between body stature (height) and corneal thickness and radius in younger-adult Caucasians, especially within the context of previously published literature. METHODS: Body height and weight were measured in 109 healthy subjects, with an average age of 24 +/- 6 years (mean +/- SD). Subjects underwent an ophthalmic assessment including anterior segment imaging by Scheimpflug topography and specular microscopy. Central and peripheral corneal thickness and corneal radius were analyzed. The relationship between body stature and corneal parameters was assessed using simple and multiple regression analysis. Effect size was determined by generating regression and correlation coefficients. RESULTS: Body height ranged from 1.54 to 1.86 m (mean +/- SD 1.67 +/- 0.08 m), central corneal thickness from 465 to 629 MUm (554 +/- 33 MUm), whereas corneal radius measured between 7.16 and 8.49 mm (7.75 +/- 0.24 mm). Body height was weakly associated with central corneal thickness and peripheral corneal thickness (r >= -0.180), and moderately with corneal radius (r = 0.351). Based on the regression equations, central corneal thickness decreases by 8 MUm, whereas corneal radius increases by 0.11 mm for each 0.1-m difference in body height. No significant correlations were found for similar assessments using body weight or body mass index. CONCLUSIONS: Differences in corneal radius and corneal thickness can be linked to body stature. However, effect sizes were consistently small and no more than 13% of the variability in corneal curvature could be explained by variations in body stature. PMID- 27984506 TI - SD-OCT and Adaptive Optics Imaging of Outer Retinal Tubulation. AB - PURPOSE: To investigate outer retinal tubulation (ORT) using spectral domain optical coherence tomography (SD-OCT) and an adaptive optics scanning laser ophthalmoscope (AOSLO). To document the frequency of ORT in atrophic retinal conditions and quantify ORT dimensions versus adjacent retinal layers. METHODS: SD-OCT images were reviewed for the presence of retinal atrophy, scarring, and/or exudation. The greatest width of each ORT was quantified. Inner and outer retinal thicknesses adjacent to and within the area of ORT were measured for 18 patients. AOSLO imaged ORTs in five subjects with direct and scattered light imaging. RESULTS: ORT was identified in 47 of 76 subjects (61.8%) and in 65 eyes via SD OCT in a wide range of conditions and ages, and in peripapillary atrophy. ORTs appeared as finger-like projections in atrophy, seen in the en face images. AOSLO showed some ORTs with bright cones that guide light within atrophic areas. Multiply scattered light mode AOSLO visualized variegated lines (18-35 MUm) radiating from ORTs. The ORTs' width on OCT b-scan images varied from 70 to 509 MUm. The inner retina at the ORT was significantly thinner than the adjacent retina, 135 vs.170 MUm (P = .004), whereas the outer retina was significantly thicker, 115 vs. 80 MUm (P = .03). CONCLUSIONS: ORTs are quite common in eyes with retinal atrophy in various disorders. ORTs demonstrate surviving photoreceptors in tubular structures found within otherwise nonsupportive atrophic areas that lack retinal pigment epithelium and choriocapillaris. PMID- 27984507 TI - Perceived Stress After Acute Myocardial Infarction: A Comparison Between Young and Middle-Aged Women Versus Men. AB - OBJECTIVE: The aim of the study was to examine how psychological stress changes over time in young and middle-aged patients after experiencing an acute myocardial infarction (AMI) and whether these changes differ between men and women. METHODS: We analyzed data obtained from 2358 women and 1151 men aged 18 to 55 years hospitalized for AMI. Psychological stress was measured using the 14 item Perceived Stress Scale (PSS-14) at initial hospitalization and at 1 month and 12 months after AMI. We used linear mixed-effects models to examine changes in PSS-14 scores over time and sex differences in these changes, while adjusting for patient characteristics and accounting for correlation among repeated observations within patients. RESULTS: Overall, patients' perceived stress decreased over time, especially during the first month after AMI. Women had higher levels of perceived stress than men throughout the 12-month period (difference in PSS-14 score = 3.63, 95% confidence interval = 3.08 to 4.18, p < .001), but they did not differ in how stress changed over time. Adjustment for patient characteristics did not alter the overall pattern of sex difference in changes of perceived stress over time other than attenuating the magnitude of sex difference in PSS-14 score (difference between women and men = 1.74, 95% confidence interval = 1.32 to 2.16, p < .001). The magnitude of sex differences in perceived stress was similar in patients with versus without post-AMI angina, even though patients with angina experienced less improvement in PSS-14 score than those without angina. CONCLUSIONS: In young and middle-aged patients with AMI, women reported higher levels of perceived stress than men throughout the first 12 months of recovery. However, women and men had a similar pattern in how perceived stress changed over time. PMID- 27984508 TI - Characterization of ADME gene variation in 21 populations by exome sequencing. AB - OBJECTIVE: Proteins involving absorption, distribution, metabolism, and excretion (ADME) play a critical role in drug pharmacokinetics. The type and frequency of genetic variation in the ADME genes differ among populations. The aim of this study was to systematically investigate common and rare ADME coding variation in diverse ethnic populations by exome sequencing. MATERIALS AND METHODS: Data derived from commercial exome capture arrays and next-generation sequencing were used to characterize coding variation in 298 ADME genes in 251 Northeast Asians and 1181 individuals from the 1000 Genomes Project. RESULTS: Approximately 75% of the ADME coding sequence was captured at high quality across the joint samples harboring more than 8000 variants, with 49% of individuals carrying at least one 'knockout' allele. ADME genes carried 50% more nonsynonymous variation than non ADME genes (P=8.2*10) and showed significantly greater levels of population differentiation (P=7.6*10). Out of the 2135 variants identified that were predicted to be deleterious, 633 were not on commercially available ADME or general-purpose genotyping arrays. Forty deleterious variants within important ADME genes, with frequencies of at least 2% in at least one population, were identified as candidates for future pharmacogenetic studies. CONCLUSION: Exome sequencing was effective in accurately genotyping most ADME variants important for pharmacogenetic research, in addition to identifying rare or potentially de novo coding variants that may be clinically meaningful. Furthermore, as a class, ADME genes are more variable and less sensitive to purifying selection than non ADME genes. PMID- 27984509 TI - ASSOCIATION BETWEEN PARAFOVEAL CAPILLARY NONPERFUSION AND MACULAR FUNCTION IN EYES WITH BRANCH RETINAL VEIN OCCLUSION. AB - PURPOSE: To investigate the parafoveal perfusion status of the superficial and deep capillary layer in eyes with resolved branch retinal vein occlusion, and to study its effects on retinal sensitivity. METHODS: In 27 enrolled eyes (27 patients) with resolved branch retinal vein occlusion, superficial and deep capillaries in the macular area (3- * 3-mm, centered on the fovea) were examined with optical coherence tomography angiography. Retinal sensitivity was examined with fundus-monitored microperimetry. RESULTS: Optical coherence tomography angiography clearly showed the parafoveal superficial and deep capillaries individually. On the affected side of retina, 25 eyes (92.6%) showed capillary nonperfusion; 23 (85.2%) in the superficial layer and 22 (81.5%) in the deep layer. Capillary nonperfusions of both layers frequently overlapped and appeared to be connected with each other. Mean (+/-SD) retinal sensitivity at the superficial capillary nonperfusion was 19.2 +/- 6.3 dB, significantly lower than that at the superficial capillary perfusion (24.4 +/- 2.8 dB, P < 0.001). Similarly, mean retinal sensitivity at the deep capillary nonperfusion was 20.8 +/- 5.0 dB, significantly lower than that at deep capillary perfusion (24.3 +/- 2.8 dB, P = 0.0016). Mean retinal sensitivity with superficial capillary nonperfusion was significantly lower than that with deep capillary nonperfusion (P = 0.0226). CONCLUSION: Optical coherence tomography angiography visualized parafoveal capillary nonperfusion in superficial and deep layers individually in eyes with resolved branch retinal vein occlusion. Retinal sensitivity was significantly reduced at these capillary nonperfusions. PMID- 27984513 TI - Cancer Measurement at Ultrasound: State of the Art. AB - Reliable and reproducible tumor measurement is fundamental in the oncologic decision making. In this article, we first highlight the importance of a precise tumor measurement, reviewing the correct modality of measuring tumor lesions at ultrasound. Then we analyze the measurement discrepancies between ultrasound and pathology as well as the discrepancies reported between ultrasound and other imaging modalities. Thereafter, basing on the existent literature and on our experience, we discuss the factors influencing the tumor size measurements at ultrasound. Finally, we illustrate the current strategies to improve the effectiveness of cancer lesions measurement. PMID- 27984514 TI - Hepatic Kaposi Sarcoma Revisited: An Important but Less Commonly Seen Neoplasm in Patients With Acquired Immunodeficiency Syndrome. AB - Hepatic Kaposi sarcoma (KS) is the most commonly seen hepatic neoplasm in patients with acquired immunodeficiency syndrome (AIDS), found in 34% of patients in an autopsy series. However, the incidence of hepatic KS has significantly declined since the advent of highly active antiretroviral therapy and is not as commonly seen on imaging. We present a case of hepatic KS in a patient with AIDS, which was initially mistaken for hepatic abscesses on computed tomography. We discuss the computed tomography, grayscale ultrasound, and contrast-enhanced ultrasound appearance of hepatic KS and how to distinguish this hepatic neoplasm from other common hepatic lesions seen in patients with AIDS. PMID- 27984516 TI - Ultrasound-Guided Needle Biopsy of Neck Lymph Nodes in Patients With Suspected Lung Cancer: Are the Specimens Sufficient for Complete Pathologic Evaluation to Guide Patient Management? AB - BACKGROUND: The purpose of this study is to determine the ability of ultrasound guided needle biopsy of a neck lymph node to provide adequate tissue for complete pathologic evaluation of suspected metastatic lung cancer, including molecular testing for epidermal growth factor receptor gene mutations by pyrosequencing and anaplastic lymphoma kinase gene rearrangement by fluorescence in situ hybridization. METHODS: Institutional review board approval was obtained and the requirement for informed consent was waived. All ultrasound guided neck biopsies performed July 1, 2011, to June 30, 2015, were retrospectively reviewed, and all biopsies performed for suspected lung cancer metastatic to supraclavicular and cervical lymph nodes were included. RESULTS: Forty patients with suspected lung cancer underwent ultrasound-guided needle biopsy of an abnormal appearing neck lymph node identified on preprocedure computed tomography or positron emission tomography/computed tomography. Thirty-seven patients were subsequently diagnosed with lung cancer and 3 were diagnosed with lymphoma. A definitive pathologic diagnosis was rendered in 95% of neck node biopsies (38/40; 95% confidence interval, 84%-99%). Of the 36 specimens diagnostic for lung cancer, 16 were considered for further molecular testing and the specimen was adequate for molecular testing in 15 (94%; 73%-100%) cases. Therefore, the neck node biopsy specimens were adequate for complete pathologic workup in 93% (37/40; 81%-98%). No complications related to the biopsies were observed. CONCLUSIONS: In patients presenting with suspected lung cancer and suspicious neck lymph nodes, ultrasound guided needle biopsy frequently provides adequate tissue for complete pathologic evaluation and eliminates the need for more invasive procedures. PMID- 27984517 TI - Transplant Surgery Training in Europe: Board Examinations in Transplant Surgery and the Accreditation of Transplant Centers. PMID- 27984518 TI - Stroma Cells in Transplantation. PMID- 27984510 TI - Factors That Influence the Quality of RNA From the Pancreas of Organ Donors. AB - OBJECTIVES: Attaining high-quality RNA from the tissues or organs of deceased donors used for research can be challenging due to physiological and logistical considerations. In this investigation, METHODS: RNA Integrity Number (RIN) was determined in pancreatic samples from 236 organ donors and used to define high (>=6.5) and low (<=4.5) quality RNAs. Logistic regression was used to evaluate the potential effects of novel or established organ and donor factors on RIN. RESULTS: Univariate analysis revealed donor cause of death (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.15-0.77; P = 0.01), prolonged tissue storage before RNA extraction (OR, 0.65; 95% CI, 0.52-0.79; P < 0.01), pancreas region sampled (multiple comparisons, P < 0.01), and sample type (OR, 0.32; 95% CI, 0.15-0.67; P < 0.01) negatively influenced outcome. Conversely, duration of final hospitalization (OR, 3.95; 95% CI, 1.59-10.37; P < 0.01) and sample collection protocol (OR, 8.48; 95% CI, 3.96-19.30; P < 0.01) positively impacted outcome. Islet RNA obtained via laser capture microdissection improved RIN when compared with total pancreatic RNA from the same donor (DeltaRIN = 1.3; 95% CI, 0.6-2.0; P < 0.01). CONCLUSIONS: A multivariable model demonstrates that autopsy free and biopsy-free human pancreata received, processed, and preserved at a single center, using optimized procedures, from organ donors dying of anoxia with normal lipase levels increase the odds of obtaining high-quality RNA. PMID- 27984519 TI - The Importance and Utility of Hemoglobin A1c Levels in the Assessment of Donor Pancreas Allografts. AB - BACKGROUND: Hemoglobin A1C (HbA1c) levels are often obtained in potential pancreas graft donors to assess the overall long-term functional glycemic control or the possibility of unrecognized diabetes. Although routinely measured, the impact of donor HbA1c levels on pancreas graft outcomes has not been reported. Here, we researched the relationship between donor HbA1c levels and postoperative pancreas graft survival. METHODS: Data from 266 pancreas transplant patients including 182 simultaneous kidney-pancreas and 84 pancreas alone transplants were reviewed for the study. The patients were separated into groups according to their HbA1c levels (5 groups: HbA1c < 5.0, 5.0-5.4, 5.5-5.9, >=6.0 % and not available, or 2 groups: HbA1c <5.7, >=5.7%). Overall, death-censored and technically successful pancreas graft survival and rejection rates of each group were compared. In the case of technically successful graft survival, graft losses due to technical problems in the first 60 days were excluded. RESULTS: All groups were similar with regard to donor variables including age, sex, ABO blood type, ethnicity, donor type and recipient variables including recipient age, sex, induction agents and maintenance treatment. Mean follow-up time was 4.2 +/- 1.97 years. The overall graft survivals and death censored graft survivals among groups were not statistically different from one other (P > 0.05). Additionally, excluding early technical losses in 18 patients did not reveal any differences in graft survivals. Patient survival and biopsy-proven acute rejections were statistically similar among HbA1c strata. CONCLUSIONS: This univariate retrospective analysis of a single center/organ procurement organization use of HbA1c shows that donor HbA1c levels between 3.5 and 6.2 in otherwise transplantable pancreata are not associated with different short-term outcomes. PMID- 27984520 TI - Vascularized Composite Allotransplantation at a Crossroad: Adopting Lessons From Technology Innovation to Novel Clinical Applications. PMID- 27984521 TI - Buprenorphine Analgesia Leads to Coagulopathy and Increased Plasma Fibrinogen in Healthy Rats: Implications For Small Animal Research. AB - INTRODUCTION: Buprenorphine is the recommended analgesic for post-surgical pain and associated stress in small animal research. Our aim was to examine the effect of isoflurane anesthesia and buprenorphine analgesia on blood coagulation in the rat using rotational thromboelastometry. METHODS: Adult male Sprague Dawley rats were randomly assigned to one of four groups (n = 6): baseline (Thiobarb anesthesia), 5% isoflurane anesthesia, isoflurane-buprenorphine (0.05-mg/kg s.c.), and buprenorphine alone. After 1 h, animals were anesthetized and blood was sampled. RESULTS: We report that isoflurane or buprenorphine had little or no effects on clotting times, clot formation, or clot lysis in EXTEM or INTEM. However, buprenorphine significantly increased FIBTEM alpha-angle, clot formation rates, and maximum clot formation velocities. Buprenorphine also increased EXTEM, FIBTEM, and INTEM A10 (clot strength), maximum clot firmness (clot quality), and maximum clot elasticity ( (clot elasticity). The combination of isoflurane and buprenorphine significantly increased clot amplitude but not to the same extent. The fibrinogen contribution to clot strength was 1.9-fold higher than baseline in the buprenorphine group, and 1.4-fold higher in the isoflurane-buprenorphine group. Plasma fibrinogen levels were 2.5-fold higher in both groups compared with the baseline value or isoflurane group (6.1 g/L vs. 2.4 g/L, P < 0.05). CONCLUSIONS: We conclude buprenorphine analgesia significantly increased clot strength without affecting fibrinolysis, and increased plasma fibrinogen, implying that the drug increased liver fibrinogen synthesis and release. Possible implications for small animal research are discussed. PMID- 27984523 TI - Etiology of Shock in the Emergency Department; A 12 Year Population Based Cohort Study. AB - INTRODUCTION: The knowledge of the etiology and associated mortality of undifferentiated shock in the emergency department (ED) is limited. We aimed to describe the etiology based proportions and incidence rates (IR) of shock, as well as the associated mortality in the ED. METHODS: Population-based cohort study at an University Hospital ED in Denmark from January 1, 2000, to December 31, 2011. Patients aged >=18 years living in the ED-catchment area (N = 225,000) with a first time ED presentation with shock (n = 1,646) defined as hypotension (systolic blood pressure <=100 mmHg)) and >=1 organ failures were included. Discharge diagnoses defined the etiology and were grouped as; distributive septic shock (SS), distributive non-septic shock (NS)), cardiogenic shock (CS), hypovolemic shock (HS), obstructive shock (OS) and other conditions (OC). Outcomes were etiology-based characteristics, annual IR per 100,000 person-years at risk (95% CIs), mortality at 0-7-, and 0-90 days (95% CIs) and hazard rates (HR) at 0-7, 8-90 days (95% CIs). Poisson and Cox regression models were used for analyses. RESULTS: Among 1,646 shock patients: 434 (26.4%) had SS, 384 (23.3%) NS, 237 (14.4%) CS, 515 (31.3%) HS, 15 (0.9%) OS and 61 (3.7%) OC. The corresponding IR's were: 16.7/100,000 (11.7-23.6), 14.7/100,000 (12.7-17.1), 9.1/100,000 (6.5-12.8), 19.8/100,000 (15.0-26.0), 0.6/100,000 (0.3-10.5) and 2.3/100,000 (1.8-3.0). SS IR increased from 8.9-28.5/100,000 during the period 2000-2011. Accordingly, the 7-, and 90-day mortalities of SS, NS, CS, and HS were: 28.9% (95% CI: 24.3-34.1) and 53.4% (95% CI: 48.0-58.8), 12.1% (95% CI: 8.8 16.4) and 23.3% (95% CI: 18.8-28.6), 32.0% (95% CI: 25.5-39.2) and 50.2% (95% CI: 42.8-57.6), 20.4% (95% CI: 16.6-24.7) and 37.6% (95% CI: 32.8-42.5). SS (HR = 1.56 (95% CI, 1.11-2.20)), and CS (HR = 2.03 (95% CI, 1.40-2.93)) were independent predictors of death within 0-7 days, whereas SS was a predictor within 8-90 days (HR = 1.71 (95% CI: 1.19-2.46)). CONCLUSION: HS and SS are frequent etiological characteristics followed by NS and CS, whereas OS is a rare condition. We confirm the increasing trend of SS, as previously reported. 7-day mortality ranged from 12% to 32% while 90-day mortality ranged from 23% to 54%. The underlying etiology was an independent predictor of mortality. PMID- 27984522 TI - Validation of the Sepsis Severity Score Compared with Updated Severity Scores in Predicting Hospital Mortality in Sepsis Patients. AB - INTRODUCTION: Recently, the Sepsis Severity Score (SSS) was constructed to predict mortality in sepsis patients. The aim of this study was to compare performance of the SSS with the Acute Physiology and Chronic Health Evaluation (APACHE) II-IV, Simplified Acute Physiology Score (SAPS) II, and SAPS 3 scores in predicting hospital outcome in sepsis patients. METHODS: A retroprospective analysis was conducted in the medical intensive care unit of a tertiary university hospital. RESULTS: A total of 913 patients were enrolled; 476 of these patients (52.1%) had septic shock. The median SSS was 80 (range 20-137). The SSS presented good discrimination with an area under the receiver operating characteristic curve (AUC) of 0.892. However, the AUC of the SSS did not differ significantly from that of APACHE II (P = 0.07), SAPS II (P = 0.06), and SAPS 3 (P = 0.11). The APACHE IV score showed the best discrimination with an AUC of 0.948 and the overall performance by a Brier score of 0.096. The AUC of the APACHE IV score was statistically greater than the SSS, APACHE II, SAPS II, and SAPS 3 (P <0.0001 for all) and APACHE III (P = 0.0002). The calibration of all scores was poor with the Hosmer-Lemeshow goodness-of-fit H test <0.05. CONCLUSIONS: The SSS provided as good discrimination as the APACHE II, SAPS II, and SAPS 3 scores. However, the APACHE IV score had the best discrimination and overall performance in our sepsis patients. The SSS needs to be adapted and modified with new parameters to improve its performance. PMID- 27984524 TI - Investigating generalizability of results from a randomized controlled trial of the management of chronic widespread pain: the MUSICIAN study. AB - The generalisability of randomised controlled trials will be compromised if markers of treatment outcome also affect trial recruitment. In a large trial of chronic widespread pain, we aimed to determine the extent to which randomised participants represented eligible patients, and whether factors predicting randomisation also influenced trial outcome. Adults from 8 UK general practices were surveyed to determine eligibility for a trial of 2 interventions (exercise and cognitive behavioural therapy [CBT]). Amongst those eligible, logistic regression identified factors associated with reaching the randomisation step in the recruitment process. The main trial analysis was recomputed, weighting for the inverse of the likelihood of reaching the randomisation stage, and the numbers needed to treat were calculated for each treatment. Eight hundred eighty four persons were identified as eligible for the trial, of whom 442 (50%) were randomised. Several factors were associated with the likelihood of reaching the randomisation stage: higher body mass index (odds ratio: 1.99; 0.85-4.61); more severe/disabling pain (1.90; 1.21-2.97); having a treatment preference (2.11; 1.48-3.00); and expressing positivity about interventions offered (exercise: 2.66; 1.95-3.62; CBT: 3.20; 2.15-4.76). Adjusting for this selection bias decreased the treatment effect associated with exercise and CBT but increased that observed for combined therapy. All were associated with changes in numbers needed to treat. This has important implications for the design and interpretation of pain trials generally. PMID- 27984525 TI - Temporal change in headache and its contribution to the risk of developing first onset temporomandibular disorder in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. AB - While cross-sectional studies have demonstrated an association between headache and temporomandibular disorder (TMD), whether headache can predict the onset of TMD is unknown. The aims of this study were to evaluate the contribution of headache to the risk of developing TMD and describe patterns of change in headache types over time. An initially TMD-free cohort of 2410 persons with low frequency of headache completed quarterly questionnaires assessing TMD and headache symptoms over a median 3.0-year follow-up period. First-onset TMD was confirmed by clinical examination in 199 participants. Baseline reports of migraine (hazard ratio [HR] = 1.67, 95% confidence interval [CI]: 1.06-2.62) or mixed headache types (HR = 4.11, 95% CI: 1.47-11.46), or headache frequency (HR = 2.13, 95% CI: 1.31-3.48) predicted increased risk of developing TMD. In addition, headache dynamics across the follow-up period before the TMD onset were evaluated in a nested case-control study where 248 incident TMD cases were matched to 191 TMD-free controls. Both headache prevalence and frequency increased across the observation period among those who developed TMD but not among controls. Patients with TMD were more likely to experience worsening in the headache type compared with that by controls, eg, prevalence of definite migraine among TMD cases increased 10-fold. Among all headache types experienced by patients with TMD before the TMD onset, migraine had the highest odds of progression relative to remission (odds ratio = 2.8, 95% CI: 1.6-4.8), whereas for controls this ratio was significant only for the tension-type headache (odds ratio = 2.1, 95% CI: 1.2 3.9). The important clinical implication of these findings is that adequate treatment of migraine may reduce the risk for developing TMD. PMID- 27984528 TI - We do not need a third mechanistic descriptor for chronic pain states! Not yet. PMID- 27984527 TI - Agomelatine: a new opportunity to reduce neuropathic pain-preclinical evidence. AB - Antidepressants are first-line treatments of neuropathic pain but not all these drugs are really effective. Agomelatine is an antidepressant with a novel mode of action, acting as an MT1/MT2 melatonergic receptor agonist and a 5-HT2C receptor antagonist that involves indirect norepinephrine release. Melatonin, serotonin, and norepinephrine have been involved in the pathophysiology of neuropathic pain. Yet, no study has been conducted to determine agomelatine effects on neuropathic pain in animal models. Using 3 rat models of neuropathic pain of toxic (oxaliplatin/OXA), metabolic (streptozocin/STZ), and traumatic (sciatic nerve ligation/CCI [chronic constriction nerve injury]) etiologies, we investigated the antihypersensitivity effect of acute and repeated agomelatine administration. We then determined the influence of melatonergic, 5-HT2C, alpha-2 and beta-1/2 adrenergic receptor antagonists in the antihypersensitivity effect of agomelatine. The effect of the combination of agomelatine + gabapentin was evaluated using an isobolographic approach. In STZ and CCI models, single doses of agomelatine significantly and dose dependently reduced mechanical hypersensitivity. After daily administrations for 2 weeks, this effect was confirmed in the CCI model and agomelatine also displayed a marked antihypersensitivity effect in the OXA model. The antihypersensitivity effect of agomelatine involved melatonergic, 5-HT2C, and alpha-2 adrenergic receptors but not beta adrenoceptors. The isobolographic analysis demonstrated that the combination of agomelatine + gabapentin had additive effects. Agomelatine exerts a clear-cut antihypersensitivity effect in 3 different neuropathic pain models. Its effect is mediated by melatonergic and 5-HT2C receptors and, although agomelatine has no affinity, also by alpha-2 adrenergic receptors. Finally, agomelatine combined with gabapentin produces an additive antihypersensitivity effect. PMID- 27984526 TI - Incident and long-term opioid therapy among patients with psychiatric conditions and medications: a national study of commercial health care claims. AB - There is growing evidence that opioid prescribing in the United States follows a pattern in which patients who are at the highest risk of adverse outcomes from opioids are more likely to receive long-term opioid therapy. These patients include, in particular, those with substance use disorders (SUDs) and other psychiatric conditions. This study examined health insurance claims among 10,311,961 patients who filled prescriptions for opioids. Specifically, we evaluated how opioid receipt differed among patients with and without a wide range of preexisting psychiatric and behavioral conditions (ie, opioid and nonopioid SUDs, suicide attempts or other self-injury, motor vehicle crashes, and depressive, anxiety, and sleep disorders) and psychoactive medications (ie, antidepressants, benzodiazepines, hypnotics, mood stabilizers, antipsychotics, and medications used for SUD, tobacco cessation, and attention deficit/hyperactivity disorder). Relative to those without, patients with all assessed psychiatric conditions and medications had modestly greater odds of subsequently filling prescriptions for opioids and, in particular, substantially greater risk of long-term opioid receipt. Increases in risk for long-term opioid receipt in adjusted Cox regressions ranged from approximately 1.5-fold for prior attention-deficit/hyperactivity disorder medication prescriptions (hazard ratio [HR] = 1.53; 95% confidence interval [CI], 1.48-1.58) to approximately 3-fold for prior nonopioid SUD diagnoses (HR = 3.15; 95% CI, 3.06-3.24) and nearly 9-fold for prior opioid use disorder diagnoses (HR = 8.70; 95% CI, 8.20-9.24). In sum, we found evidence of greater opioid receipt among commercially insured patients with a breadth of psychiatric conditions. Future studies assessing behavioral outcomes associated with opioid prescribing should consider preexisting psychiatric conditions. PMID- 27984529 TI - Reply. PMID- 27984530 TI - Clinical assessment of new antineuropathic strategies for chemotherapy-induced peripheral neuropathy: pain should not be the principal endpoint. PMID- 27984531 TI - Reply. PMID- 27984532 TI - What's New in Shock, January 2017? PMID- 27984534 TI - Prognostic Value of Relative Adrenal Insufficiency During Cardiogenic Shock: A Prospective Cohort Study With Long-Term Follow-Up. AB - BACKGROUND: Relative adrenal insufficiency (RAI) is common in intensive care unit patients, particularly during septic shock (SS). Cardiogenic shock (CS) may share some pathophysiological features with SS. The aim of this study was to evaluate the prevalence and long-term prognosis of RAI during CS. PATIENTS AND METHODS: Prospective observational study conducted in the intensive care and cardiology units in one university hospital in France. Patients meeting the criteria for CS without prior corticosteroid therapy were included. Total blood cortisol levels were assessed immediately before (T0) a short corticotropin stimulation test (0.25 mg i.v. of tetracosactrin) and 30 and 60 min afterward. Deltamax was defined as the difference between the maximal value after the test and T0. RESULTS: Of the 92 patients enrolled, 42 (46%) (95% confidence interval [CI] [36% 56%]) died in hospital and 7 more died during a median follow-up of 616 [57 2,498] days, for an overall mortality rate of 53% (95% CI [43%-63%]). Three groups were identified based on the corticotropin test: group 1 (T0 <=798 nmol/L and Deltamax >473 nmol/L), group 2 ([T0 >798 nmol/L and Deltamax >473 nmol/L] or [T0 <=798 nmol/L and Deltamax <=473 nmol/L]), and group 3 (T0 >798 nmol/L and Deltamax <=473 nmol/L) with an overall survival of 76%, 43%, and 15%, respectively (log rank P = 0.003). In the multivariable analysis, adrenal nonresponse (group 3) was an independent predictor of mortality (P = 0.04), along with left ventricular ejection fraction, Simplified Acute Physiology Score II, and cardiac arrest. CONCLUSIONS: These data suggest that a short corticotropin test has a good prognostic value in CS and allows identifying patients at higher risk of death. PMID- 27984533 TI - Prevention or Treatment of Ards With Aspirin: A Review of Preclinical Models and Meta-Analysis of Clinical Studies. AB - BACKGROUND: The acute respiratory distress syndrome (ARDS) is a life-threating disorder that contributes significantly to critical illness. No specific pharmacological interventions directed at lung injury itself have proven effective in improving outcome of patients with ARDS. Platelet activation was identified as a key component in ARDS pathophysiology and may provide an opportunity for preventive and therapeutic strategies. We hypothesize that use of acetyl salicylic acid (ASA) may prevent and/or attenuate lung injury. METHODS: We conducted a systematic review of preclinical studies and meta-analysis of clinical studies investigating the efficacy of ASA in the setting of lung injury. Medline, embase, and cochrane databases were searched. RESULTS: The literature search yielded 1,314 unique articles. Fifteen preclinical studies and eight clinical studies fulfilled the in- and exclusion criteria. In the animal studies, the overall effect of ASA was positive, e.g., ASA improved survival and attenuated inflammation and pulmonary edema. Mechanisms of actions involved, among others, are interference with the neutrophil-platelets interaction, reduction of leukotrienes, neutrophil extracellular traps, and prostaglandins. High-dose ASA may be the drug of choice. A meta-analysis of three clinical studies showed an association between ASA use and a reduced incidence of ARDS (OR 0.59, 95% CI 0.36-0.98), albeit with substantial between-study heterogeneity. All studies had their own shortcomings in methodological quality. CONCLUSION: This systematic review of preclinical studies and meta-analysis of clinical studies suggests a beneficial role for ASA in ARDS prevention and treatment. However, the currently available data is insufficient to justify an indication for ASA in ARDS. The body of literature does support further studies in humans. We suggest clinical trials in which the mechanisms of action of ASA in lung injury models are being evaluated to guide optimal timing and dose, before prospective randomized trials. PMID- 27984535 TI - Modulation by Polymyxin-B Hemoperfusion of Inflammatory Response Related to Severe Peritonitis. AB - Conflicting results have been reported on the influence of Polymyxin-B hemoperfusion treatment on systemic inflammation markers. The aim of the study was to assess in a randomized control trial the influence on plasma cytokine concentrations of Polymyxin-B hemoperfusion in septic shock due to peritonitis. A panel of 10 pro- or anti-inflammatory cytokines was measured in 213 patients with peritonitis-induced septic shock enrolled in the randomized trial ABDOMIX testing the impact of 2 Polymyxin-B hemoperfusion sessions with standard treatment. Gram negative bacteria were identified in 69% of patients. In the overall population, baseline plasma cytokine concentrations were not different between the two groups. Circulating tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-10, IL-6, and IL-1RA decreased significantly over time in both groups (P <0.0001 for all in controls, and P = 0.0002, 0.003, and <0.0001 in patients treated with Polymyxin-B hemoperfusion). IL-17A decreased significantly in patients treated with Polymyxin B hemoperfusion (P = 0.045) but not in controls. At the end of the second Polymyxin-B hemoperfusion session or at corresponding time in controls, plasma levels of cytokines did not differ between the two groups. Similar results were found in the subgroup of patients with gram-negative peritonitis who completed two Polymyxin-B hemoperfusion sessions. These results do not support a significant influence of Polymyxin-B hemoperfusion on circulating cytokines assessed except for IL-17A which clinical significance remains to be elucidated. PMID- 27984536 TI - Interleukin-1 Receptor 2: A New Biomarker for Sepsis Diagnosis and Gram Negative/Gram-Positive Bacterial Differentiation. AB - This study was undertaken to explore the value of interleukin-1 receptor 2 (IL1R2) as a novel potential biomarker for diagnosis of sepsis and discrimination of gram-negative (G)/gram-positive (G) bacterial sepsis. The study was performed in Kunming mice and septic patients. Inactive Escherichia coli or Staphylococcus aureus were used to stimulate Kunming mice (10 CFU/kg). In clinical study, septic patients with different pathogen infection were studied, and healthy volunteers and patients with systemic inflammatory response syndrome without definite infection were enrolled as control. IL1R2 transcriptions of human subjects' peripheral leukocytes were measured by real-time quantitative polymerase chain reaction assay. IL1R2 serum concentrations of mice and human subjects were measured by enzyme-linked immunosorbent assay. The value of IL1R2 as a biomarker was compared with procalcitonin (PCT), C-reactive protein (CRP), and Acute Physiology and Chronic Health Evaluation II (APACHE II). The results showed that IL1R2 expression was upregulated in mice treated with inactive Escherichia coli and septic patients. The elevation of serum IL1R2 was more significant in septic patients infected by Escherichia coli or G bacteria than in those infected by Staphylococcus aureus or G bacteria. For sepsis diagnosis and G/G bacterial sepsis discrimination, serum IL1R2 was more sensitive and specific than the traditional biomarkers such as PCT, CRP, and APACHE II as shown by the receiver operating characteristic curves. It was suggested that IL1R2 was a potential biomarker for diagnosis and G/G bacterial differentiation in sepsis. PMID- 27984537 TI - 18F-FCho PET and MRI for the prediction of response in glioblastoma patients according to the RANO criteria. AB - PURPOSE: In this study, we investigated fluorine-18 fluoromethylcholine (F-FCho) PET and contrast-enhanced MRI for predicting therapy response in glioblastoma (GB) patients according to the Response Assessment in Neuro-Oncology criteria. Our second aim was to investigate which imaging modality enabled prediction of treatment response first. MATERIALS AND METHODS: Eleven GB patients who underwent no surgery or debulking only and received concomitant radiation therapy (RT) and temozolomide were included. The gold standard Response Assessment in Neuro Oncology criteria were applied 6 months after RT to define responders and nonresponders. F-FCho PET and MRI were performed before RT, during RT (week 2, 4, and 6), and 1 month after RT. The contrast-enhancing tumor volume on T1-weighted MRI (GdTV) and the metabolic tumor volume (MTV) were calculated. GdTV, standardized uptake value (SUV)mean, SUVmax, MTV, MTV*SUVmean, and percentage change of these variables between all time-points were assessed to differentiate responders from nonresponders. RESULTS: Absolute SUV values did not predict response. MTV must be taken into account. F-FCho PET could predict response with a 100% sensitivity and specificity using MTV*SUVmean 1 month after RT. A decrease in GdTV between week 2 and 6, week 4 and 6 during RT and week 2 during RT, and 1 month after RT of at least 31%, at least 18%, and at least 53% predicted response with a sensitivity and specificity of 100%. As such, the parameter that predicts therapy response first is MR derived, namely, GdTV. CONCLUSION: Our data indicate that both F-FCho PET and contrast-enhanced T1-weighted MRI can predict response early in GB patients treated with RT and temozolomide. PMID- 27984538 TI - Clinical outcomes of low-dose and high-dose postoperative radioiodine therapy in patients with intermediate-risk differentiated thyroid cancer. AB - PURPOSE: Recent studies have suggested that a low dose (LD) of radioiodine (RAI) is sufficient to treat differentiated thyroid cancer (DTC) even in patients with intermediate risk. However, these studies evaluated the efficacy of RAI therapy, irrespective of the results of the whole-body scan (WBS). The aim of the present study was to evaluate the response to LD and high-dose (HD) RAI therapy using two different criteria (with and without WBS results) and the reclassification system according to the revised 2015 guidelines of the American Thyroid Association in Korean intermediate-risk DTC patients. In addition, we evaluated the long-term clinical outcomes of treatment with LD and HD RAI. MATERIALS AND METHODS: In total, 204 intermediate-risk DTC patients who underwent postoperative RAI therapy at two tertiary referral hospitals from 2003 to 2004 were enrolled in the present retrospective study. One hundred and twenty-four patients were treated with 3.7 and 5.55 GBq (HD) of RAI in one center and 80 patients were treated with 1.11 GBq (LD) in the other center. The success rate of RAI therapy was assessed with or without the inclusion of WBS results in the analysis. In addition, the response to therapy during the first 2 years of follow-up after the initial RAI therapy was categorized according to the reclassification system of 2015 American Thyroid Association guidelines as excellent response, indeterminate response, biochemical incomplete response, or structural incomplete response. Recurrence was defined as a newly detected cytologically or pathologically confirmed lesion. RESULTS: There were no significant differences between the success rates of the HD and LD groups irrespective of the inclusion of WBS results in the analysis (with WBS: 54.84 vs. 45.0%, P=0.23; without WBS: 60.48 vs. 62.5%, P=0.77). The response to HD and LD RAI therapy was excellent in 54.84 and 45.0% of the patients, respectively; indeterminate in 34.68 and 30.0% of the patients, respectively; biochemical incomplete in 4.03 and 13.75% of the patients, respectively; and structural incomplete in 6.45% and in 11.25% of the patients, respectively (P=0.04). In particular, the biochemical or structural incomplete response rate was lower in patients treated with HD than in patients treated with LD (HD, 10.48%; LD, 25.0%, P=0.01). At the last follow-up (HD, median 11 years; LD, median 10 years), patients who achieved an excellent response showed no evidence of disease. After the initial RAI therapy, eight patients in the HD group and 18 patients in the LD group who achieved either indeterminate response or biochemical incomplete response received additional RAI therapy. Seven patients (indeterminate response in five patients; biochemical incomplete response in two patients) in the HD group and seven patients (indeterminate response in five patients; biochemical incomplete response in two patients) in the LD group showed recurrences. CONCLUSION: LD RAI therapy after thyroidectomy appears to be insufficient in Korean DTC patients with intermediate risk. The patients in the LD group predominantly showed biochemical or structural incomplete response to initial RAI therapy and additional RAI therapy was required. PMID- 27984539 TI - Validation of an electronic image reader training programme for interpretation of [18F]flutemetamol beta-amyloid PET brain images. AB - OBJECTIVES: An electronic training programme (ETP) was developed for interpretation of images during routine clinical use of the PET amyloid imaging agent [F]flutemetamol injection (VIZAMYL). This study was carried out to validate the ETP. MATERIALS AND METHODS: Five nuclear medicine technologists (NMTs) and five readers previously inexperienced in amyloid image interpretation were required to self-train using the ETP and pass a test to participate. A total of 305 [F]flutemetamol PET images were then tested as the validation set, following preassessment and reorientation (where required) by one of five NMTs. Next, a new set of readers blinded to clinical information independently assessed all 305 images. Images had been acquired in previous studies from patients representing the full spectrum of cognitive capacity. When available, a standard of truth determined by histopathology or clinical history was used to derive sensitivity and specificity for image interpretation from this validation set. Randomly selected images (n=29) were read in duplicate to measure intrareader reproducibility. Images were read first without, and subsequently with anatomic images, if available. RESULTS: All NMTs and all readers scored 100% on the qualifying test. The interpretation of 135 cases without anatomic image support resulted in sensitivity ranging from 84% to 94% (majority 94%, median 92%) and specificity ranging from 77% to 96% (majority 92%, median 81%). Inter-reader agreement was very high, with most kappa scores more than 0.8. Intrareader reproducibility ranged from 93 to 100%. CONCLUSION: The self-guided ETP effectively trained new amyloid PET image readers to accurately and reproducibly interpret [F]flutemetamol PET images. PMID- 27984540 TI - Electrophysiological dynamic brain connectivity during symbolic magnitude comparison in children with different mathematics achievement levels. AB - Children with mathematical difficulties usually have an impaired ability to process symbolic representations. Functional MRI methods have suggested that early frontoparietal connectivity can predict mathematic achievements; however, the study of brain connectivity during numerical processing remains unexplored. With the aim of evaluating this in children with different math proficiencies, we selected a sample of 40 children divided into two groups [high achievement (HA) and low achievement (LA)] according to their arithmetic scores in the Wide Range Achievement Test, 4th ed.. Participants performed a symbolic magnitude comparison task (i.e. determining which of two numbers is numerically larger), with simultaneous electrophysiological recording. Partial directed coherence and graph theory methods were used to estimate and depict frontoparietal connectivity in both groups. The behavioral measures showed that children with LA performed significantly slower and less accurately than their peers in the HA group. Significantly higher frontocentral connectivity was found in LA compared with HA; however, when the connectivity analysis was restricted to parietal locations, no relevant group differences were observed. These findings seem to support the notion that LA children require greater memory and attentional efforts to meet task demands, probably affecting early stages of symbolic comparison. PMID- 27984541 TI - Crosstalk between Notch and Sonic hedgehog signaling in a mouse model of amyotrophic lateral sclerosis. AB - The developmental morphogen Sonic hedgehog (Shh) may continue to play a sustaining role in adult motor neurons, of potential relevance to motor neuron diseases including amyotrophic lateral sclerosis. The Shh signaling pathway is incompletely understood and interactions with other signaling pathways are possible. We focus here on Notch, and first show that there is an almost linear reduction in light output from a Gli reporter in Shh Light II cells in the presence of increasing concentrations of the Notch inhibitor DAPT (r=0.982). Second, in the spinal cord of mutant superoxide dismutase mice, but not control mice, a key marker of Notch signaling changes with age. Before the onset of clinical signs, the Notch intracellular domain is expressed predominantly in motor neurons, but by 125 days of age, Notch intracellular domain expression is markedly reduced in motor neurons and increased in neighboring astroglia. Third, there is a parallel reduction in Gli protein expression in mutant superoxide dismutase mouse spinal motor neurons, consistent with the observed reduction in Notch signaling and also a redistribution of Gli away from the nucleus. Thus, there is a reduction in motor neuronal Notch signaling and associated changes in Shh signaling, occurring coincidentally with disease expression, that may contribute toward the dysfunction and death of motor neurons in amyotrophic lateral sclerosis. PMID- 27984542 TI - Transcranial direct current stimulation over the opercular somatosensory region does not influence experimentally induced pain: a triple blind, sham-controlled study. AB - Transcranial magnetic stimulation (TMS) over the opercular somatosensory region (OP), which includes the secondary somatosensory cortex and the insular cortex, suppresses pain sensation. However, whether transcranial direct current stimulation (tDCS) over the OP has a similar effect on pain sensation remains unknown. We examined whether pain sensation would be suppressed by tDCS over the OP. Our experiment with a triple-blind, sham-controlled, crossover design involved 12 healthy participants. Participants were asked to rate their subjective pain intensity during and after three types of bihemispheric tDCS: right anodal/left cathodal OP tDCS, left anodal/right cathodal OP tDCS (2 mA, 12 min), and sham tDCS (15 s). Pain stimuli were alternately applied to the dorsum of each index finger using intraepidermal electrical stimulation. We observed no significant effect of tDCS over the OP on the perception of experimentally induced pain. Subjective pain intensity did not differ significantly between the three tDCS conditions. The present null results have crucial implications for the selection of optimal stimulation regions and parameters for clinical pain treatment. PMID- 27984543 TI - Altered electroencephalogram complexity in autistic children shown by the multiscale entropy approach. AB - Autism spectrum disorder (ASD) is a severe neurodevelopment disorder. This study tests the hypothesis that children with ASD show atypical intrinsic complexity of brain activity. Electroencephalogram data were collected from boys with ASD and matching normal typically developing children while performing an observation and an imitation task. The multiscale entropy was estimated within the 0.5-30 Hz frequency band over 30 time scales using a coarse-grained procedure. A decreased electroencephalogram complexity was observed in the ASD children both during the observation and during the imitation tasks. On comparing the two tasks, significant differences were observed between groups in the right hemisphere, and also the central cortex for the observation task. Multiscale entropy could provide further evidence of the relationship between ASD and cerebral dysfunction. PMID- 27984544 TI - BILATERAL SEROUS MACULAR DETACHMENT IN A PATIENT WITH NEPHROTIC SYNDROME. AB - PURPOSE: The purpose of this study was to report a case of a woman with nephrotic syndrome who presented with blurred vision because of bilateral serous macular detachment. METHODS: Case report and literature review. RESULTS: A 55-year-old woman with a history of essential hypertension, diabetes, and nephrotic syndrome was presented with blurred vision in both eyes. Her fluorescein angiography revealed dye leakage in the early and subretinal pooling in the late phases, and optical coherence tomography scans confirmed the presence of subretinal fluid in the subfovel area. CONCLUSION: In nephrotic syndrome cases especially with accompaniment of high blood pressure, fluid accumulation in the retina layer may occur. Serous macular detachment must be kept in mind when treating these patients. PMID- 27984545 TI - EFFICACY OF DEXAMETHASONE INTRAVITREAL IMPLANT FOR REFRACTORY MACULAR EDEMA CAUSED BY RETINAL VEIN OCCLUSION. AB - PURPOSE: To investigate efficacy of dexamethasone intravitreal (DEX) implant in treating refractory macular edema caused by retinal vein occlusion. METHODS: Retrospective chart review. RESULTS: Twenty-two eyes with refractory macular edema caused by retinal vein occlusion were treated with a mean of 2.2 DEX over 12 months. Patient had previously received a mean of 7 treatments (laser, bevacizumab, and/or triamcinolone) for macular edema present for at least 4 months duration (mean 20.8 +/- 17.6 months, range 4-72 months) before starting DEX. Mean baseline visual acuity was 20/91, and mean central subfield thickness was 506 MUm. DEX improved mean best-corrected visual acuity to 20/75 and 20/66 at 7 weeks and 6 months follow-up, although it worsened to 20/132 at 12 months. Mean central subfield thickness improved to 292, 352, and 356 MUm at 7 weeks, 6 months, and 12 months follow-up, respectively. There was a statistically significant association between number of DEX treatments and central subfield thickness (P = 3.28 * 10). There was a statistically significant association between number of days followed and best-corrected visual acuity (P = 0.006). Six of 12 (50%) phakic patients developed visually significant cataract requiring surgery. Five of 22 (23%) patients developed ocular hypertension (intraocular pressure > 30) and consequently did not undergo further treatment with DEX. CONCLUSION: DEX resulted in sustained anatomical reduction of retinal vein occlusion-associated refractory macular edema, although this did not translate into long-term best-corrected visual acuity improvement in either phakic or pseudophakic patients, possibly related to chronic structural alterations in the retina despite reduction of edema. PMID- 27984546 TI - SCLERAL SUTURE FIXATION TECHNIQUE FOR ONE-PIECE ACRYLIC INTRAOCULAR LENS. AB - PURPOSE: To apply a previously published scleral fixation technique to secure one piece acrylic intraocular lenses (IOLs) to the sclera. METHODS: Retrospective, consecutive, noncomparative case series. RESULTS: All patients (16 eyes of 15 patients) who underwent scleral fixation of 1-piece acrylic IOLs using the loop method from 2014 to 2016 were included. The mean follow-up was 8.1 months. Repositioning of dislocated 1-piece acrylic IOLs was performed in 8 eyes, a primary implantation in 5 eyes, and IOL exchange in 3 eyes. All IOLs remained well-centered postoperatively. The vision improved from an initial best-corrected visual acuity of 0.97 +/- 0.74 logMAR (Snellen equivalent ~20/190) to 0.47 +/- 0.49 logMAR (~20/60, P = 0.031) at the last follow-up. The postoperative complications were self-limited. CONCLUSION: The previously reported scleral suture fixation technique can be readily applied to one-piece acrylic IOLs. PMID- 27984547 TI - EN-FACE OPTICAL COHERENCE TOMOGRAPHY IMAGING IN A CASE OF CHOROIDAL RUPTURE. AB - PURPOSE: To report a case of choroidal rupture resulting due to blunt trauma using en-face optical coherence tomography (OCT) imaging. METHODS: Case report. RESULTS: A 22-year-old man sustained a blunt trauma to his right eye. At the initial examination, four lesions with a subretinal hemorrhage were observed during a fundus examination of the macular area including the fovea, but the findings under the lesions were unclear. The authors observed the extent of the minute findings noninvasively by en-face OCT imaging from the initial examination. Six months after the trauma, the fine crescent-shaped lines seen by angiography and OCT B-scan images were consistent with findings observed on the en-face OCT images. CONCLUSION: The en-face OCT imaging would be useful to examine the pathological changes in a choroidal rupture noninvasively during frequent follow-up examinations in a case of choroidal rupture. PMID- 27984548 TI - CAPILLARY NONPERFUSION AND PHOTORECEPTOR LOSS IN BRANCH RETINAL VEIN OCCLUSION: Spatial Correlation and Morphologic Characteristics. AB - PURPOSE: To evaluate the photoreceptor layer in eyes with branch retinal vein occlusion associated with macular ischemia, using a method of en face optical coherence tomography (OCT) representation of the ellipsoid zone. METHODS: Customized macular OCT scans of 9 patients (10 eyes) with branch retinal vein occlusion and macular ischemia were exported and subsequently postprocessed (removal of vascular and cystic spaces' shadows, segmentation, and alignment to the retinal pigment epithelium). The ellipsoid band was then isolated, aligned, and used to produce an en face OCT image. Areas with photoreceptor loss (hyporeflective ellipsoid) were compared with ischemic areas as identified in an early-phase fluorescein angiography. RESULTS: The areas of capillary nonperfusion (as detected in fluorescein angiography) were closely associated with disruption of the ellipsoid zone (depicted as areas of low reflectance in the en face reconstruction of the OCT images). The ellipsoid zone disruption had a patchy appearance and either sharp or fuzzy borders, depending on the grade of the loss of reflectance. CONCLUSION: En face OCT reconstruction and subsequent representation of ellipsoid zone revealed a close association between capillary nonperfusion and photoreceptor disruption in eyes with branch retinal vein occlusion. It seems that the deep capillary plexus plays an important role on the metabolic demands of outer retina and, consequently, an ischemia at the level of deep capillary plexus has significant impact on the integrity of the photoreceptors. PMID- 27984549 TI - GORE-TEX VASCULAR GRAFT FOR MACULAR BUCKLING IN HIGH MYOPIA EYES. AB - PURPOSE: To evaluate a new application of an expanded polytetrafluoroethylene (Gore-Tex) vascular graft for use in macular buckling surgery for treatment of highly myopic eyes. METHODS: The Gore-Tex vascular graft was used as a macular buckling material in eight consecutive cases of myopic macular diseases which included fovea detachment, foveoschisis, or macular hole retinal detachment. RESULTS: Retinal reattachment was achieved in all cases except one which had partial resolution (88%). The postoperative best-corrected visual acuity ranged from 20/2000 to 20/100 depending on the degree preexisting macular degeneration, and significant better than the preoperative best-corrected visual acuity (P = 0.048, paired t-test). During the follow-up period, which ranged from 8 months to 3 years, no eye developed buckle-related complications such as infection or dislocation. CONCLUSION: The initial pilot results from this series using a Gore Tex graft for macular buckling is promising. Throughout the follow-up period, the Gore-Tex was well tolerated in the highly myopic eyes. Large scale and long-term follow-up is warranted. PMID- 27984550 TI - LONG-TERM ANATOMICAL AND FUNCTIONAL OUTCOMES FOLLOWING VITRECTOMY FOR ADVANCED COATS DISEASE. AB - PURPOSE: To assess the long-term anatomical and functional results of vitreoretinal surgery in patients with advanced Coats disease. METHODS: Retrospective analysis of 23 patients who underwent 23-gauge pars plana vitrectomy combined with transscleral cryotherapy, laser photocoagulation, and intraocular tamponade between 2005 and 2014 and had a follow-up of at least 1 year. The primary outcomes were mean visual acuity and anatomical success. RESULTS: The average age at the time of surgery was 8.7 +/- 1.3 years (range, 2 18 years). The mean follow-up period was 55.2 +/- 31 months (range, 12-120 months). In 16 eyes (70%), further treatment was not necessary. In the remaining 7 patients (30%), revision surgery with silicone oil tamponade was required. In 20 eyes (87%), the retina was reattached. At the final visit, 8 eyes (35%) had improved mean Snellen visual acuity from 20/1,000 at initial presentation to 20/160, 3 eyes (13%) showed stabilization, and 6 eyes (26%) had decline in visual acuity. No enucleation was necessary, and no progression to neovascular glaucoma was observed. CONCLUSION: Pars plana vitrectomy combined with cryotherapy, laser photocoagulation, and intraocular tamponade could be an effective treatment option for advanced Coats disease. Despite surgery, disease-related complications remained high, but the main aim of management in these young patients is functional and anatomical stability. PMID- 27984551 TI - Use of the APTIMA Combo 2 Assay and a Secondary Algorithm to Detect and Confirm Chlamydia trachomatis in Rectal-Only Infections. AB - We sought to confirm the results of 81 rectal specimens positive for Chlamydia trachomatis by the APTIMA Combo 2 assay among patients with concurrently collected negative genitourinary specimens. A total of 79 (97.5%) samples were confirmed by the APTIMA single target assay and/or sequencing of the C. trachomatis ompA gene. PMID- 27984552 TI - Increased Detection of Pharyngeal and Rectal Gonorrhea in Men Who Have Sex With Men After Transition From Culture To Nucleic Acid Amplification Testing. AB - BACKGROUND: This before-and-after study measured the impact of a change in testing methods from culture to nucleic acid amplification testing (NAAT) on the detection of pharyngeal and rectal gonorrhea in men who have sex with men (MSM) on a sexual health service level, including the effect on subgroups anticipated to have higher rates of gonorrhea. METHODS: In March 2015, Melbourne Sexual Health Centre changed its laboratory method for gonococcal testing from culture to NAAT using the Aptima Combo 2 and Aptima GC tests. We compared the proportion of tests positive for rectal and pharyngeal gonorrhea in MSM using culture in 2014 with those using NAAT in 2015. RESULTS: The proportion of tests positive for rectal gonorrhea by NAAT was double that obtained by culture (8% vs 3.9%; prevalence ratio [PR], 2.0; 95% confidence interval [CI], 1.8-2.4) and 5-fold for pharyngeal gonorrhea (8.3% vs 1.6%; PR, 5.2; 95% CI, 4.2-6.4). Similar increases in test positivity were observed in human immunodeficiency virus (HIV)-positive and HIV-negative men. By NAAT, test positivity for rectal gonorrhea was higher in HIV-positive compared with HIV-negative men (15.4% vs 7.3%; PR, 2.1; 95% CI, 1.7 2.6). Culture and NAAT had similar test positivity for rectal gonorrhea among men who reported contact with gonorrhea (24.9% vs 25.3%, PR 1.0, 95% CI 0.8-1.4) and men who presented with symptoms of proctitis (22.2% vs 27.9%, PR 1.3, 95% CI 0.8 2.0). CONCLUSIONS: A switch from culture to Aptima Combo 2 testing for extragenital gonorrhea in MSM increased detection and was most marked for pharyngeal infections. PMID- 27984553 TI - Prevalence and Predictors of Human Immunodeficiency Virus and Selected Sexually Transmitted Infections Among People Who Inject Drugs in Dar es Salaam, Tanzania: A New Focus to Get to Zero. AB - BACKGROUND: Previous studies in Tanzania indicated that human immunodeficiency virus (HIV) prevalence among people who inject drugs (PWIDs) could be as high as 40%. We aim to provide data on the prevalence of HIV and sexually transmitted infection among PWIDs to inform national plans to get to zero. MATERIALS AND METHODS: Respondent-driven sampling was used to collect drug use, and sexual practices data among PWIDs aged 15 years and older. Blood samples were examined for HIV, herpes simplex virus type 2, syphilis, and hepatitis B. RESULTS: A total of 620 PWIDs with a median age of 32 (interquartile range, 17-52) participated in the study. Their use of drugs had typically started during adolescence. The prevalence of HIV was found to be 15.5%, whereas that of herpes simplex type 2 was 43.3%. Associated with an increased likelihood of HIV infection was being a female (adjusted odds ratio [aOR], 2.3; 95% confidence interval [CI], 1.0-3.6), sharing of syringes (aOR, 2.4; 95% CI, 1.1-6.1), used syringes hidden in public places (aOR, 5.1; 95% CI, 1.3-10.2), and having had a genital ulcer during the last 12 months before this survey. On the other hand, being educated, use of noninjectable drugs, access (aOR, 0.5; 95% CI, 0.2-0.8), and use of clean syringes (aOR, 0.3; 95% CI, 0.1-0.6) were associated with decreased likelihood of HIV infection. CONCLUSIONS: The prevalence of HIV infection among PWIDs in Dar es Salaam is 3 times higher than that in the general population. Behavioral and biological risk factors contribute to HIV transmission and needs to be addressed to be able to get to zero. PMID- 27984554 TI - Trichomonas vaginalis Treated With Boric Acid in a Metronidazole Allergic Female. PMID- 27984556 TI - A Population-Based Study of Care at the End of Life Among People With HIV in Ontario From 2010 to 2013. AB - BACKGROUND: Aging and increasing comorbidity is changing the end-of-life experience of people living with HIV (PLHIV) in the developed world. We quantified, at a population level, the receipt of health care services and associated costs across a comprehensive set of sectors among decedents with and without HIV. METHODS: We conducted a retrospective population-level observational study of all decedents in Ontario and their receipt of health care services, captured through linked health administrative databases, between April 1, 2010 and March 31, 2013. We identified PLHIV using a validated algorithm. We described the characteristics of PLHIV and their receipt of health care services and associated costs by health care sector in the last year of life. RESULTS: We observed 264,754 eligible deaths, 570 of whom had HIV. PLHIV were significantly younger than those without HIV (mean age of death 56.1 years vs. 76.6 years, [P < 0.01]). PLHIV spent a mean of 20.0 days in an acute care hospital in the last 90 days of life compared with 12.1 days for decedents without HIV (P < 0.01); after adjustment, HIV was associated with 4.5 more acute care days (P < 0.01). Mean cost of care in the last year was significantly higher among PLHIV ($80,885.62 vs. $53,869.77), mostly attributable to acute care costs. INTERPRETATION: PLHIV in Ontario are dying younger, spending more time and dying more often in hospital, and incur significantly increased costs before death. Greater involvement of community-based palliative care may improve the dying experience for this complex population. PMID- 27984557 TI - Brief Report: The Relationship Between Injection Drug Use Risk Behaviors and Markers of Immune Activation. AB - High levels of immune activation are reported for people who inject drugs. Studies of the relationship between injection behaviors and immune activation have yielded mixed results, in part due to lack of control for hepatitis C virus in analyses. This study, of 48 HIV-seronegative people who inject drugs, examines this relationship controlling for hepatitis C virus viremia. Frequency of injection was positively related to markers of immune activation (soluble CD14, %CD8CD38HLADR T cells), as was duration of injection (high-specificity C-reactive protein and D-dimer). Sharing injection equipment was not related to markers studied. Findings suggest that efforts to encourage injection cessation or reduction in frequency can have positive health benefits through reducing immune activation. PMID- 27984558 TI - Brief Report: The Impact of Ledipasvir/Sofosbuvir on HIV-Positive and HIV Negative Japanese Hemophilia Patients With 1, 4, and Mixed-Genotype HCV. AB - INTRODUCTION: Approximately 80% of patients with hemophilia who received nonheated coagulation factor concentrates in the early 1980s were infected with hepatitis C virus (HCV), and approximately 40% of them were infected with HIV. AIM: We evaluated the efficacy and safety of administering ledipasvir (LDV)/sofosbuvir (SOF) to Japanese patients with hemophilia. METHODS: Forty-three patients with hemophilia with genotype 1 or 4 HCV were treated with LDV/SOF for 12 weeks. The efficacy, safety, and results of the laboratory tests were evaluated. RESULTS: Twenty patients were coinfected with HIV and HCV. The sustained virological response (SVR) at 12 weeks after therapy was 90% in HIV positive patients and 100% in HIV-negative patients. The efficacy of LDV/SOF was not significantly different between HIV-positive and HIV-negative patients (P = 0.12). However, the rate of SVR at 12 weeks after therapy in the patients with cirrhosis was significantly lower than that in patients without cirrhosis (P = 0.005). Overall, 20 patients (46%) had adverse events, and while the severity of most was mild to moderate, 3 were serious, including 1 death in the HIV-positive group. All patients completed treatment with no alterations in the antiretroviral regimen. No significant abnormalities in the renal function were detected in patients taking an antiretroviral regimen of tenofovir disoproxil fumarate. CONCLUSIONS: In this cohort study, LDV/SOF was effective and safe, but the SVR in patients with cirrhosis was lower than that in the noncirrhosis group. Thus, patients with hemophilia with genotype 1/4 HCV should be treated as early as possible before the onset of cirrhosis. PMID- 27984555 TI - Implementation of Antiretroviral Therapy for Life in Pregnant/Breastfeeding HIV+ Women (Option B+) Alongside Rollout and Changing Guidelines for ART Initiation in Rural Zimbabwe: The Lablite Project Experience. AB - BACKGROUND: Lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women (Option B+) was rolled out in Zimbabwe from 2014, with simultaneous raising of the CD4 treatment threshold to 500 cells per cubic millimeter in nonpregnant/breastfeeding adults and children 5 years and over. METHODS: Lablite is an implementation project in Zimbabwe, Malawi, and Uganda evaluating ART rollout. Routine patient-level data were collected for 6 months before and 12 months after Option B+ rollout at a district hospital and 3 primary care facilities in Zimbabwe (2 with outreach ART and 1 with no ART provision before Option B+). RESULTS: Between September 2013 and February 2015, there were 1686 ART initiations in the 4 facilities: 91% adults and 9% children younger than 15 years. In the 3 facilities with established ART, initiations rose from 300 during 6 months before Option B+ to 869 (2.9-fold) and 463 (1.5-fold), respectively, 0-6 months and 6-12 months after Option B+. Post-Option B+, an estimated 43% of pregnant/breastfeeding women needed ART for their own health, based on World Health Organization stage 3/4 or CD4 <=350 per cubic millimeter (64% for CD4 <=500). Seventy-four men (22%) and 123 nonpregnant/breastfeeding women (34%) initiated ART with CD4 >350 after the CD4 threshold increase. Estimated 12-month retention on ART was 79% (69%-87%) in Option B+ women (significantly lower in younger women, P = 0.01) versus 93% (91%-95%) in other adults (difference P < 0.001). CONCLUSIONS: There were increased ART initiations in all patient groups after implementation of World Health Organization 2013 guidelines. Retention of Option B+ women was poorer than retention of other adults; younger women require attention because they are more likely to disengage from care. PMID- 27984559 TI - Psychiatric Symptoms in Patients Receiving Dolutegravir. AB - INTRODUCTION: Psychiatric symptoms (PSs) are reported to occur frequently in people living with HIV and may be associated with specific antiretrovirals. We analyzed PSs observed with dolutegravir (DTG) and other frequently prescribed anchor drugs. METHODS: Selected PSs (insomnia, anxiety, depression, and suicidality) occurring in HIV-positive patients during DTG treatment across 5 randomized clinical trials (3 double-blind), in the Observational Pharmaco Epidemiology Research & Analysis (OPERA) cohort, and among cases spontaneously reported to ViiV Healthcare were analyzed. RESULTS: In clinical trials, PSs were reported at low and similar rates in patients receiving DTG or comparators [atazanavir, darunavir, efavirenz, or raltegravir (RAL)]. Insomnia was most commonly reported. The highest rates were observed in SINGLE (DTG 17%, efavirenz 12%), with consistently lower rates in the other trials (DTG: 3%-8% versus comparator: 3%-7%). More efavirenz-treated patients withdrew because of PSs than patients treated with other anchor drugs. In OPERA, history of PSs at baseline was lowest in efavirenz-treated patients compared with patients treated with DTG, RAL, or darunavir. Despite baseline differences, prevalence and incidence during treatment were similar across the 4 anchor drugs. Withdrawal rates for PSs were lowest for DTG (0%-0.6%) and highest for RAL (0%-2.5%). Spontaneously reported events were similar in nature to clinical trial data. CONCLUSIONS: Analysis of 3 different data sources shows that, similar to other frequently prescribed anchor drugs to treat HIV infection, PSs are also reported in DTG-treated patients. These events are reported with low frequency and rarely necessitate DTG discontinuation. PMID- 27984561 TI - TSLP in bacterial skin infection. PMID- 27984562 TI - Apoptosis footprint. PMID- 27984560 TI - Relationship Between Carotid Stenosis and Infarct Volume in Ischemic Stroke Patients. AB - BACKGROUND Stroke is a serious health problem all over the world. Ischemia causes 85% of strokes and 75% of these ischemic strokes occur within the area supplied by the internal carotid artery (ICA). MATERIAL AND METHODS This study included 47 acute stroke patients who were in the large-artery atherosclerosis group according to Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification and who had an infarct in the area supplied by the internal carotid artery. We sought to determine whether there was a significant correlation between the infarct volume of the patients as measured by diffusion-weighted magnetic resonance imaging (DW MRI), their National Institutes of Health Stroke Scale (NIHSS), and degree of carotid stenosis as identified by carotid computed tomography angiography (CTA). RESULTS A significant correlation was observed between the percentage of carotid artery stenosis and infarct volume (p<0.001). In addition, there was a significant positive correlation between the NIHSS and infarct volume; the correlation was of moderate strength (r=0.366, p=0.001). CONCLUSIONS Our findings indicate that the percentage of carotid artery stenosis could be useful in predicting the infarct volume of the stroke. PMID- 27984563 TI - Clearing liver metastases. PMID- 27984564 TI - Finding the 'ubiquitous' threads in infection and autoimmune neuroinflammation. PMID- 27984566 TI - Linking air pollution to atopic dermatitis. PMID- 27984567 TI - Counting HSCs. PMID- 27984565 TI - 1st International Conference on Human &Translational Immunology. AB - The 1st International Conference on Human &Translational Immunology convened in Rhodes, Greece, and provided a venue for stimulating scientific discussions on the human immune system. PMID- 27984569 TI - Motile recognition. PMID- 27984568 TI - How lymphocytes add up. PMID- 27984571 TI - CD148 function in B-1 cells. PMID- 27984570 TI - iNKT cells do a fat lot of good. PMID- 27984573 TI - Protein folding: Minimizing frustration. PMID- 27984572 TI - Old dog, new tricks: IL-6 cluster signaling promotes pathogenic TH17 cell differentiation. PMID- 27984574 TI - Biocatalysis: Custom carbon cycling. PMID- 27984575 TI - RNA structure: Widening the probe. PMID- 27984576 TI - Neurodegeneration: Untangling tau. PMID- 27984577 TI - RAS signaling: Divide and conquer. PMID- 27984578 TI - Natural products: Mapping an amazing thicket. PMID- 27984580 TI - The C. elegans Discoidin Domain Receptor DDR-2 Modulates the Met-like RTK-JNK Signaling Pathway in Axon Regeneration. AB - The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. However, the signaling pathways that orchestrate axon regeneration are not well understood. In Caenorhabditis elegans, initiation of axon regeneration is positively regulated by SVH-2 Met like growth factor receptor tyrosine kinase (RTK) signaling through the JNK MAPK pathway. Here we show that SVH-4/DDR-2, an RTK containing a discoidin domain that is activated by collagen, and EMB-9 collagen type IV regulate the regeneration of neurons following axon injury. The scaffold protein SHC-1 interacts with both DDR 2 and SVH-2. Furthermore, we demonstrate that overexpression of svh-2 and shc-1 suppresses the delay in axon regeneration observed in ddr-2 mutants, suggesting that DDR-2 functions upstream of SVH-2 and SHC-1. These results suggest that DDR 2 modulates the SVH-2-JNK pathway via SHC-1. We thus identify two different RTK signaling networks that play coordinated roles in the regulation of axonal regeneration. PMID- 27984579 TI - Modeling Contact Inhibition of Locomotion of Colliding Cells Migrating on Micropatterned Substrates. AB - In cancer metastasis, embryonic development, and wound healing, cells can coordinate their motion, leading to collective motility. To characterize these cell-cell interactions, which include contact inhibition of locomotion (CIL), micropatterned substrates are often used to restrict cell migration to linear, quasi-one-dimensional paths. In these assays, collisions between polarized cells occur frequently with only a few possible outcomes, such as cells reversing direction, sticking to one another, or walking past one another. Using a computational phase field model of collective cell motility that includes the mechanics of cell shape and a minimal chemical model for CIL, we are able to reproduce all cases seen in two-cell collisions. A subtle balance between the internal cell polarization, CIL and cell-cell adhesion governs the collision outcome. We identify the parameters that control transitions between the different cases, including cell-cell adhesion, propulsion strength, and the rates of CIL. These parameters suggest hypotheses for why different cell types have different collision behavior and the effect of interventions that modulate collision outcomes. To reproduce the heterogeneity in cell-cell collision outcomes observed experimentally in neural crest cells, we must either carefully tune our parameters or assume that there is significant cell-to-cell variation in key parameters like cell-cell adhesion. PMID- 27984581 TI - CystiSim - An Agent-Based Model for Taenia solium Transmission and Control. AB - Taenia solium taeniosis/cysticercosis was declared eradicable by the International Task Force for Disease Eradication in 1993, but remains a neglected zoonosis. To assist in the attempt to regionally eliminate this parasite, we developed cystiSim, an agent-based model for T. solium transmission and control. The model was developed in R and available as an R package (http://cran.r project.org/package=cystiSim). cystiSim was adapted to an observed setting using field data from Tanzania, but adaptable to other settings if necessary. The model description adheres to the Overview, Design concepts, and Details (ODD) protocol and consists of two entities-pigs and humans. Pigs acquire cysticercosis through the environment or by direct contact with a tapeworm carrier's faeces. Humans acquire taeniosis from slaughtered pigs proportional to their infection intensity. The model allows for evaluation of three interventions measures or combinations hereof: treatment of humans, treatment of pigs, and pig vaccination, and allows for customary coverage and efficacy settings. cystiSim is the first agent-based transmission model for T. solium and suggests that control using a strategy consisting of an intervention only targeting the porcine host is possible, but that coverage and efficacy must be high if elimination is the ultimate goal. Good coverage of the intervention is important, but can be compensated for by including an additional intervention targeting the human host. cystiSim shows that the scenarios combining interventions in both hosts, mass drug administration to humans, and vaccination and treatment of pigs, have a high probability of success if coverage of 75% can be maintained over at least a four year period. In comparison with an existing mathematical model for T. solium transmission, cystiSim also includes parasite maturation, host immunity, and environmental contamination. Adding these biological parameters to the model resulted in new insights in the potential effect of intervention measures. PMID- 27984582 TI - Improved Prediction of Non-methylated Islands in Vertebrates Highlights Different Characteristic Sequence Patterns. AB - Non-methylated islands (NMIs) of DNA are genomic regions that are important for gene regulation and development. A recent study of genome-wide non-methylation data in vertebrates by Long et al. (eLife 2013;2:e00348) has shown that many experimentally identified non-methylated regions do not overlap with classically defined CpG islands which are computationally predicted using simple DNA sequence features. This is especially true in cold-blooded vertebrates such as Danio rerio (zebrafish). In order to investigate how predictive DNA sequence is of a region's methylation status, we applied a supervised learning approach using a spectrum kernel support vector machine, to see if a more complex model and supervised learning can be used to improve non-methylated island prediction and to understand the sequence properties of these regions. We demonstrate that DNA sequence is highly predictive of methylation status, and that in contrast to existing CpG island prediction methods our method is able to provide more useful predictions of NMIs genome-wide in all vertebrate organisms that were studied. Our results also show that in cold-blooded vertebrates (Anolis carolinensis, Xenopus tropicalis and Danio rerio) where genome-wide classical CpG island predictions consist primarily of false positives, longer primarily AT-rich DNA sequence features are able to identify these regions much more accurately. PMID- 27984583 TI - Diagnostic Accuracy of the Enhanced Liver Fibrosis (ELF(r)) Score Using HCV Infected Serum Samples Cryopreserved for up to 25 Years. AB - INTRODUCTION & AIMS: Cryopreservation of serum samples is a standard procedure for biomedical research in tertiary centers. However, studies evaluating the long term biological stability of direct liver fibrosis markers using cryopreserved samples are scarce. METHODS: We compared the stability of hyaluronic acid (HA), tissue inhibitor of metalloproteinases (TIMP-1) and amino-terminal propeptide of type III procollagen (PIIINP) in 225 frozen serum samples of HCV-infected patients with a paired liver biopsy for up to 25 years (1990-2014). Moreover, we assessed the diagnostic accuracy (AUROC) of the Enhanced Liver Fibrosis (ELF(r)) score to identify significant fibrosis (F2-4) and its predictive capacity to identify clinical events during follow-up. RESULTS: Seventy-six patients (39,8%) had mild fibrosis (F0-1) and 115 (60,2%) significant fibrosis (F2-4). HA, PIIINP and TIMP-1 values remained stable during the period from 1995 to 2014 while those of 1990-94 were slightly higher. We did not find significant differences in the median ELF(r) values during the 20-year period from 1995-2014 in patients with mild (from 8,4 to 8,7) and significant fibrosis (from 9,9 to 10,9) (p = ns between periods and fibrosis stages). The AUROCs of ELF(r) to identify significant fibrosis were high in all the periods (from 0,85 to 0,91). The ELF(r) score showed a good predictive capability to identify clinical events during follow-up. CONCLUSIONS: The biological stability of direct serum markers (HA, PIIINP and TIMP-1) using HCV-infected samples cryopreserved for 20 years is good. Therefore, the diagnostic accuracy of the ELF(r) score to identify significant fibrosis and clinical events during follow-up is very high. PMID- 27984584 TI - Inhibition of Adhesion Molecule Gene Expression and Cell Adhesion by the Metabolic Regulator PGC-1alpha. AB - Cell adhesion plays an important role in determining cell shape and function in a variety of physiological and pathophysiological conditions. While links between metabolism and cell adhesion were previously suggested, the exact context and molecular details of such a cross-talk remain incompletely understood. Here we show that PGC-1alpha, a pivotal transcriptional co-activator of metabolic gene expression, acts to inhibit expression of cell adhesion genes. Using cell lines, primary cells and mice, we show that both endogenous and exogenous PGC-1alpha down-regulate expression of a variety of cell adhesion molecules. Furthermore, results obtained using mRNA stability measurements as well as intronic RNA expression are consistent with a transcriptional effect of PGC-1alpha on cell adhesion gene expression. Interestingly, the L2/L3 motifs of PGC-1alpha, necessary for nuclear hormone receptor activation, are only partly required for inhibition of several cell adhesion genes by PGC-1alpha. Finally, PGC-1alpha is able to modulate adhesion of primary fibroblasts and hepatic stellate cells to extracellular matrix proteins. Our results delineate a cross talk between a central pathway controlling metabolic regulation and cell adhesion, and identify PGC-1alpha as a molecular link between these two major cellular networks. PMID- 27984585 TI - Atrial Heterogeneity Generates Re-entrant Substrate during Atrial Fibrillation and Anti-arrhythmic Drug Action: Mechanistic Insights from Canine Atrial Models. AB - Anti-arrhythmic drug therapy is a frontline treatment for atrial fibrillation (AF), but its success rates are highly variable. This is due to incomplete understanding of the mechanisms of action of specific drugs on the atrial substrate at different stages of AF progression. We aimed to elucidate the role of cellular, tissue and organ level atrial heterogeneities in the generation of a re-entrant substrate during AF progression, and their modulation by the acute action of selected anti-arrhythmic drugs. To explore the complex cell-to-organ mechanisms, a detailed biophysical models of the entire 3D canine atria was developed. The model incorporated atrial geometry and fibre orientation from high resolution micro-computed tomography, region-specific atrial cell electrophysiology and the effects of progressive AF-induced remodelling. The actions of multi-channel class III anti-arrhythmic agents vernakalant and amiodarone were introduced in the model by inhibiting appropriate ionic channel currents according to experimentally reported concentration-response relationships. AF was initiated by applied ectopic pacing in the pulmonary veins, which led to the generation of localized sustained re-entrant waves (rotors), followed by progressive wave breakdown and rotor multiplication in both atria. The simulated AF scenarios were in agreement with observations in canine models and patients. The 3D atrial simulations revealed that a re-entrant substrate was typically provided by tissue regions of high heterogeneity of action potential duration (APD). Amiodarone increased atrial APD and reduced APD heterogeneity and was more effective in terminating AF than vernakalant, which increased both APD and APD dispersion. In summary, the initiation and sustenance of rotors in AF is linked to atrial APD heterogeneity and APD reduction due to progressive remodelling. Our results suggest that anti-arrhythmic strategies that increase atrial APD without increasing its dispersion are effective in terminating AF. PMID- 27984586 TI - Plasma Metabolites Predict Severity of Depression and Suicidal Ideation in Psychiatric Patients-A Multicenter Pilot Analysis. AB - Evaluating the severity of depression (SOD), especially suicidal ideation (SI), is crucial in the treatment of not only patients with mood disorders but also psychiatric patients in general. SOD has been assessed on interviews such as the Hamilton Rating Scale for Depression (HAMD)-17, and/or self-administered questionnaires such as the Patient Health Questionnaire (PHQ)-9. However, these evaluation systems have relied on a person's subjective information, which sometimes lead to difficulties in clinical settings. To resolve this limitation, a more objective SOD evaluation system is needed. Herein, we collected clinical data including HAMD-17/PHQ-9 and blood plasma of psychiatric patients from three independent clinical centers. We performed metabolome analysis of blood plasma using liquid chromatography mass spectrometry (LC-MS), and 123 metabolites were detected. Interestingly, five plasma metabolites (3-hydroxybutyrate (3HB), betaine, citrate, creatinine, and gamma-aminobutyric acid (GABA)) are commonly associated with SOD in all three independent cohort sets regardless of the presence or absence of medication and diagnostic difference. In addition, we have shown several metabolites are independently associated with sub-symptoms of depression including SI. We successfully created a classification model to discriminate depressive patients with or without SI by machine learning technique. Finally, we produced a pilot algorithm to predict a grade of SI with citrate and kynurenine. The above metabolites may have strongly been associated with the underlying novel biological pathophysiology of SOD. We should explore the biological impact of these metabolites on depressive symptoms by utilizing a cross species study model with human and rodents. The present multicenter pilot study offers a potential utility for measuring blood metabolites as a novel objective tool for not only assessing SOD but also evaluating therapeutic efficacy in clinical practice. In addition, modification of these metabolites by diet and/or medications may be a novel therapeutic target for depression. To clarify these aspects, clinical trials measuring metabolites before/after interventions should be conducted. Larger cohort studies including non-clinical subjects are also warranted to clarify our pilot findings. PMID- 27984587 TI - Identification of a Novel L-rhamnose Uptake Transporter in the Filamentous Fungus Aspergillus niger. AB - The study of plant biomass utilization by fungi is a research field of great interest due to its many implications in ecology, agriculture and biotechnology. Most of the efforts done to increase the understanding of the use of plant cell walls by fungi have been focused on the degradation of cellulose and hemicellulose, and transport and metabolism of their constituent monosaccharides. Pectin is another important constituent of plant cell walls, but has received less attention. In relation to the uptake of pectic building blocks, fungal transporters for the uptake of galacturonic acid recently have been reported in Aspergillus niger and Neurospora crassa. However, not a single L-rhamnose (6 deoxy-L-mannose) transporter has been identified yet in fungi or in other eukaryotic organisms. L-rhamnose is a deoxy-sugar present in plant cell wall pectic polysaccharides (mainly rhamnogalacturonan I and rhamnogalacturonan II), but is also found in diverse plant secondary metabolites (e.g. anthocyanins, flavonoids and triterpenoids), in the green seaweed sulfated polysaccharide ulvan, and in glycan structures from viruses and bacteria. Here, a comparative plasmalemma proteomic analysis was used to identify candidate L-rhamnose transporters in A. niger. Further analysis was focused on protein ID 1119135 (RhtA) (JGI A. niger ATCC 1015 genome database). RhtA was classified as a Family 7 Fucose: H+ Symporter (FHS) within the Major Facilitator Superfamily. Family 7 currently includes exclusively bacterial transporters able to use different sugars. Strong indications for its role in L-rhamnose transport were obtained by functional complementation of the Saccharomyces cerevisiae EBY.VW.4000 strain in growth studies with a range of potential substrates. Biochemical analysis using L [3H(G)]-rhamnose confirmed that RhtA is a L-rhamnose transporter. The RhtA gene is located in tandem with a hypothetical alpha-L-rhamnosidase gene (rhaB). Transcriptional analysis of rhtA and rhaB confirmed that both genes have a coordinated expression, being strongly and specifically induced by L-rhamnose, and controlled by RhaR, a transcriptional regulator involved in the release and catabolism of the methyl-pentose. RhtA is the first eukaryotic L-rhamnose transporter identified and functionally validated to date. PMID- 27984588 TI - A Data Fusion Approach to Enhance Association Study in Epilepsy. AB - Among the scientific challenges posed by complex diseases with a strong genetic component, two stand out. One is unveiling the role of rare and common genetic variants; the other is the design of classification models to improve clinical diagnosis and predictive models for prognosis and personalized therapies. In this paper, we present a data fusion framework merging gene, domain, pathway and protein-protein interaction data related to a next generation sequencing epilepsy gene panel. Our method allows integrating association information from multiple genomic sources and aims at highlighting the set of common and rare variants that are capable to trigger the occurrence of a complex disease. When compared to other approaches, our method shows better performances in classifying patients affected by epilepsy. PMID- 27984589 TI - Replication Protein A Presents Canonical Functions and Is Also Involved in the Differentiation Capacity of Trypanosoma cruzi. AB - Replication Protein A (RPA), the major single stranded DNA binding protein in eukaryotes, is composed of three subunits and is a fundamental player in DNA metabolism, participating in replication, transcription, repair, and the DNA damage response. In human pathogenic trypanosomatids, only limited studies have been performed on RPA-1 from Leishmania. Here, we performed in silico, in vitro and in vivo analysis of Trypanosoma cruzi RPA-1 and RPA-2 subunits. Although computational analysis suggests similarities in DNA binding and Ob-fold structures of RPA from T. cruzi compared with mammalian and fungi RPA, the predicted tridimensional structures of T. cruzi RPA-1 and RPA-2 indicated that these molecules present a more flexible tertiary structure, suggesting that T. cruzi RPA could be involved in additional responses. Here, we demonstrate experimentally that the T. cruzi RPA complex interacts with DNA via RPA-1 and is directly related to canonical functions, such as DNA replication and DNA damage response. Accordingly, a reduction of TcRPA-2 expression by generating heterozygous knockout cells impaired cell growth, slowing down S-phase progression. Moreover, heterozygous knockout cells presented a better efficiency in differentiation from epimastigote to metacyclic trypomastigote forms and metacyclic trypomastigote infection. Taken together, these findings indicate the involvement of TcRPA in the metacyclogenesis process and suggest that a delay in cell cycle progression could be linked with differentiation in T. cruzi. PMID- 27984593 TI - CAPD Is Classified in ICD-10 as H93.25 and Hearing Evaluation-Not Screening Should Be Implemented in Children With Verified Communication and/or Listening Deficits. AB - Purpose: The article "It Is Time to Rethink Central Auditory Processing Disorder Protocols for School-Aged Children" (DeBonis, 2015) appeared in the American Journal of Audiology as a tutorial. The author used the argument made by Cowan, Rosen, and Moore (2009), referring to central auditory processing disorder (CAPD), that "such impairments have not been shown to uniquely contribute to a clearly defined condition that would warrant its inclusion in any of the major disease classification systems" (emphasis added; p. 129). However, CAPD is included in the U.S. version of the International Statistical Classification of Diseases and Related Health Problems-10th Revision (ICD-10) under the code H93.25; this was not mentioned in the article by DeBonis. We would like to point out some additional omissions of this tutorial that may bias its conclusions. PMID- 27984592 TI - Inferring Aggregated Functional Traits from Metagenomic Data Using Constrained Non-negative Matrix Factorization: Application to Fiber Degradation in the Human Gut Microbiota. AB - Whole Genome Shotgun (WGS) metagenomics is increasingly used to study the structure and functions of complex microbial ecosystems, both from the taxonomic and functional point of view. Gene inventories of otherwise uncultured microbial communities make the direct functional profiling of microbial communities possible. The concept of community aggregated trait has been adapted from environmental and plant functional ecology to the framework of microbial ecology. Community aggregated traits are quantified from WGS data by computing the abundance of relevant marker genes. They can be used to study key processes at the ecosystem level and correlate environmental factors and ecosystem functions. In this paper we propose a novel model based approach to infer combinations of aggregated traits characterizing specific ecosystemic metabolic processes. We formulate a model of these Combined Aggregated Functional Traits (CAFTs) accounting for a hierarchical structure of genes, which are associated on microbial genomes, further linked at the ecosystem level by complex co occurrences or interactions. The model is completed with constraints specifically designed to exploit available genomic information, in order to favor biologically relevant CAFTs. The CAFTs structure, as well as their intensity in the ecosystem, is obtained by solving a constrained Non-negative Matrix Factorization (NMF) problem. We developed a multicriteria selection procedure for the number of CAFTs. We illustrated our method on the modelling of ecosystemic functional traits of fiber degradation by the human gut microbiota. We used 1408 samples of gene abundances from several high-throughput sequencing projects and found that four CAFTs only were needed to represent the fiber degradation potential. This data reduction highlighted biologically consistent functional patterns while providing a high quality preservation of the original data. Our method is generic and can be applied to other metabolic processes in the gut or in other ecosystems. PMID- 27984590 TI - Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments. AB - Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. A precondition for improved strategies to disrupt and/or reverse the damage is a credible explanatory mechanism for how toxicity phenomena emerge and converge to cause hepatic necrosis. The Target Phenomenon in mice is that necrosis begins adjacent to the lobule's central vein (CV) and progresses outward. An explanatory mechanism remains elusive. Evidence supports that location dependent differences in NAPQI (the reactive metabolite) formation within hepatic lobules (NAPQI zonation) are necessary and sufficient prerequisites to account for that phenomenon. We call that the NZ-mechanism hypothesis. Challenging that hypothesis in mice is infeasible because 1) influential variables cannot be controlled, and 2) it would require sequential intracellular measurements at different lobular locations within the same mouse. Virtual hepatocytes use independently configured periportal-to-CV gradients to exhibit lobule-location dependent behaviors. Employing NZ-mechanism achieved quantitative validation targets for acetaminophen clearance and metabolism but failed to achieve the Target Phenomenon. We posited that, in order to do so, at least one additional feature must exhibit zonation by decreasing in the CV direction. We instantiated and explored two alternatives: 1) a glutathione depletion threshold diminishes in the CV direction; and 2) ability to repair mitochondrial damage diminishes in the CV direction. Inclusion of one or the other feature into NZ-mechanism failed to achieve the Target Phenomenon. However, inclusion of both features enabled successfully achieving the Target Phenomenon. The merged mechanism provides a multilevel, multiscale causal explanation of key temporal features of acetaminophen hepatotoxicity in mice. We discovered that variants of the merged mechanism provide plausible quantitative explanations for the considerable variation in 24-hour necrosis scores among 37 genetically diverse mouse strains following a single toxic acetaminophen dose. PMID- 27984594 TI - Response to the Letter to the Editor From Iliadou, Sirimanna, and Bamiou Regarding DeBonis (2015). AB - Purpose: The purpose of this letter is to respond to "Central Auditory Processing Disorder Is Classified in ICD-10 and H93.25 and Hearing Evaluation-Not Screening Should Be Implemented in Children With Verified Communication and/or Listening Deficits" by Iliadou, Sirimanna, and Bamiou (2016). The methodology used involved a close reading of the concerns expressed by Iliadou et al. in view of the central auditory processing disorder (CAPD) literature and the stated purpose of my original article (DeBonis, 2015). The literature used included clinical practice guidelines, respected journals, and recognized authorities on the topic. Many of the objections stated by Iliadou et al. are not well founded (e.g., ICD 10, use of ASHA definition, effect of auditory intervention, lack of research for the model, bias of the article), but their statement that a complete hearing assessment is necessary for students with listening difficulties is an important one that I endorse completely. In conclusion, my original article remains an effective vehicle for discussion about the value of current tests of auditory processing and how to better help students who have listening difficulties. PMID- 27984591 TI - The Multilayer Connectome of Caenorhabditis elegans. AB - Connectomics has focused primarily on the mapping of synaptic links in the brain; yet it is well established that extrasynaptic volume transmission, especially via monoamines and neuropeptides, is also critical to brain function and occurs primarily outside the synaptic connectome. We have mapped the putative monoamine connections, as well as a subset of neuropeptide connections, in C. elegans based on new and published gene expression data. The monoamine and neuropeptide networks exhibit distinct topological properties, with the monoamine network displaying a highly disassortative star-like structure with a rich-club of interconnected broadcasting hubs, and the neuropeptide network showing a more recurrent, highly clustered topology. Despite the low degree of overlap between the extrasynaptic (or wireless) and synaptic (or wired) connectomes, we find highly significant multilink motifs of interaction, pinpointing locations in the network where aminergic and neuropeptide signalling modulate synaptic activity. Thus, the C. elegans connectome can be mapped as a multiplex network with synaptic, gap junction, and neuromodulator layers representing alternative modes of interaction between neurons. This provides a new topological plan for understanding how aminergic and peptidergic modulation of behaviour is achieved by specific motifs and loci of integration between hard-wired synaptic or junctional circuits and extrasynaptic signals wirelessly broadcast from a small number of modulatory neurons. PMID- 27984595 TI - Transient risk factors of acute occupational injuries: a case-crossover study in two Danish emergency departments. AB - Objectives The objectives of this study were to (i) identify transient risk factors of occupational injuries and (ii) determine if the risk varies with age, injury severity, job task, and industry risk level. Method A case-crossover design was used to examine the effect of seven specific transient risk factors (time pressure, disagreement with someone, feeling sick, being distracted by someone, non-routine task, altered surroundings, and broken machinery and materials) for occupational injuries. In the study, 1693 patients with occupational injuries were recruited from a total of 4002 occupational injuries seen in 2013 at two emergency departments in Denmark. Effect estimates were calculated using the matched-pair interval approach. Results Increased risk for an occupational injury was found for time pressure [odds ratio (OR) 1.6, 95% confidence interval (95% CI) 1.3-2.0], feeling sick (OR 2.7, 95% CI 1.9-3.9), being distracted by someone (OR 3.1, 95% CI 2.3-4.1), non-routine task (OR 8.2, 95% CI 5.3-12.5), altered surroundings (OR 20.9, 95% CI 12.2-35.8), and broken machinery or materials (OR 20.6, 95% CI 13.5-31.7). The risk of occupational injury did not vary substantially in relation to sex, age, job task, industry risk level, or injury severity. Conclusion Use of a case-crossover design identified several worker-related transient risk factors (time pressure, feeling sick, being distracted by someone) that led to significantly increased risks for occupational injuries. In particular, equipment (broken machinery or materials) and work-practice-related factors (non-routine task and altered surroundings) increased the risk of an occupational injury. Elaboration of results in relation to hazard period and information bias is warranted. PMID- 27984596 TI - Potential Future Applications for Negative Pressure Wound Therapy and Installation Devices. AB - Negative-pressure wound therapy (NPWT) applies vacuum pressure to a wound bed sealed by an adhesive dressing to improve wound healing. A cleansing solution, often antibiotics or saline, may be instilled into the wound bed concurrently and removed via suction, thus enhancing the therapeutic effect. The therapeutic effect results from improved blood flow and removal of inflammatory factors. Since 1995, the FDA has approved NPWT for medical use. Since then, this technology has been applied to different types of wounds, including diabetic and decubitus ulcers and postsurgical incisional wounds. There are many applications for NPWT that remain to be explored. In this article, we postulate on novel and future uses for NPWT, including application in targeted drug delivery, stem cell therapy, and the prospect of combination with filtration devices, adaptable smart dressings, and remote monitoring. PMID- 27984597 TI - Neurofibroma of the Gallbladder Not Associated with Neurofibromatosis. AB - An 82-year-old woman had visited her local clinic with a history of abdominal discomfort and dyspepsia related to meals over a period of several months. Esophagogastroduodenoscopy revealed a superficial spreading tumor that, on biopsy, was proven to be an adenocarcinoma, and colonoscopy revealed an ascending mass that was found to be an adenocarcinoma on biopsy, so the patient was referred to our hospital. Abdominal computed tomography revealed a mass in the ascending colon with regional lymph node swelling and a gallbladder stone measuring 1.5 cm in diameter. The patient underwent laparoscopy-assisted distal gastrectomy with cholecystectomy and right colectomy with regional lymph node dissection, resulting in a diagnosis of poorly differentiated adenocarcinoma invading the gastric submucosal layer and moderately differentiated tubular adenocarcinoma invading the colonic serosa with lymph node metastasis. Macroscopic examination of the gallbladder revealed a well-circumscribed, solid tumor measuring 0.3 x 0.3 cm with a firm consistency in the neck portion associated with lithiasis. Microscopic examination of the gallbladder tumor revealed infiltration of spindle-shaped neoplastic cells that were arranged in a fasciculated and woven pattern in abundant intersecting bundles. Immunohistochemical analyses were positive for S-100 protein and neurofilament. Although neurofibromas commonly occur in the superficial skin or subcutaneous region, isolated neurofibroma of the gallbladder is quite rare. To the best of our knowledge, this is only the 11th case of a neurofibroma of the gallbladder to be reported in English literature. In the present case, as in most previously reported cases, the tumor was found incidentally in the resected gallbladder following cholecystectomy for cholecystolithiasis. PMID- 27984598 TI - [The role of MT-ND1 m.3635G>A mutation in Leber's hereditary optic neuropathy]. AB - OBJECTIVE: To investigate the role of MT-ND1 m.3635G>A mutation in the pathogenesis of Leber's hereditary optic neuropathy (LHON). METHODS: Biochemical characteristics including the activity of complex I, ATP production and oxygen consumption rate among lymphoblastoid cell lines derived from 3 carriers, 3 affected matrilineal relatives of the families and 3 controls were compared. RESULTS: Comparison of mitochondrial functions in lymphoblastoid cell lines of the carriers, patients and controls showed a 51.0% decrease in the activity of complex I in patients compared with controls (P<0.05). The m.3635G>A mutation has resulted in decreased efficiency of ATP synthesis (P<0.05). Comparison of oxygen consumption rate showed that the basal OCR (P<0.05), ATP-linked OCR (P<0.05) and the maximum OCR (P<0.05) have all reduced to some extent compared with the controls. CONCLUSION: These results showed that m.3635G>A, as a LHON-associated mutation, can lead to mitochondrial dysfunction. PMID- 27984599 TI - [Application of chromosome microarray analysis for fetuses with multicystic dysplastic kidney]. AB - OBJECTIVE: To explore the genetic etiology of fetuses with multicystic dysplastic kidney (MCDK) by chromosome microarray analysis (CMA). METHODS: Seventy-two fetuses with MCDK were analyzed with conventional cytogenetic technique, among which 30 fetuses with a normal karyotype were subjected to CMA analysis with Affymetrix CytoScan HD arrays by following the manufacturer's protocol. The data was analyzed with ChAS software. RESULTS: Conventional cytogenetic technique has revealed three fetuses (4.2%) with identifiable chromosomal aberrations. CMA analysis has detected pathogenic CNVs in 5 fetuses (16.7%), which included two well-known microdeletion or microduplication syndromes, i.e., 17q12 microdeletion syndrome and Williams-Beuren syndrome (WBS) and three submicroscopic imbalances at 4q35.2, 22q13.33, and 1p33. PEX26, FKBP6, TUBGCP6, ALG12, and CYP4A11 are likely the causative genes. CONCLUSION: CMA can identify the submicroscopic imbalances unidentifiable by conventional cytogenetic technique, and therefore has a significant role in prenatal diagnosis and genetic counseling. The detection rate of pathogenic CNVs in fetuses with MCDK was 16.7% by CMA. 17q12 microdeletion syndrome and WBS are associated with MCDK. Mutations of PEX26, FKBP6, TUBGCP6, ALG12, and CYP4A11 genes may be the causes for MCDK. PMID- 27984600 TI - [Identification of novel common mutations among patients with non-syndromic hearing loss with high-throughput gene capture technology]. AB - OBJECTIVE: To identify novel common mutations among patients with non-syndromic hearing loss (NSHL). METHODS: High-throughput gene capture technology was used to analyze 18 patients with NSHL in whom common mutations of deafness genes including GJB2, SLC26A4, GJB3, and mtDNA were excluded. Suspected mutation was verified with Sanger sequencing. RESULTS: Next generation sequencing has identified 62 mutations in 29 genes associated with hearing loss, which included 54 missense mutations, 4 splicing mutations, 3 deletional mutations, and 1 nonsense mutation. Mutations occurring more than twice in the 18 patients were verified by Sanger sequencing. This has confirmed 15 mutations in 8 genes, including 3 missense mutations (p.C2184G, p.L2825P, p.H1888Y) which have not been reported previously. Meanwhile, p.L445W, p.D866N, and IVS919-2A>G were common causative mutations. CONCLUSION: A number of common causative mutations, e.g., p.L445W, p.D866N, IVS919-2A>G, have been identified by high-throughput capture technology, which may facilitate the research and genetic diagnosis for hearing loss. PMID- 27984601 TI - [Mutation analysis of 81 cases with Duchenne/Becker muscular dystrophy]. AB - OBJECTIVE: To perform mutation analysis for 81 unrelated patients with Duchenne/Becker muscular dystrophy (DMD/BMD) from Henan Province. METHODS: Multiplex ligation-dependent probe amplification (MLPA) was used to detect potential deletion/duplications of the DMD gene. Those with single exon deletions were validated with PCR amplification and Sanger sequencing to rule out false positive results. Patients with negative MLPA results were further analyzed with next-generation sequencing (NGS), and the result was validated by Sanger sequencing. RESULTS: DMD gene deletion/duplications were detected in 67 cases by MLPA, and exons 45-54 was the most frequently deleted. The phenotypes of 79.1% patients with a deletion or duplication has conformed to the reading frame rule. In addition, 13 mutations were detected by NGS and Sanger sequencing, which included 6 novel mutations including one frameshift mutation c.4708-4709insTG and 5 nonsense mutations (c.8812G>T, c.2131A>T, c.6035T>A, c.3426C>A, and c.3055C>T). CONCLUSION: This results have enriched the DMD gene mutation database. Combined MLPA, NGS and Sanger sequencing can greatly enhance the sensibility and specificity of genetic testing for the DMD/BMD. PMID- 27984602 TI - [Analysis of clinical phenotypes and genetic variations in a Chinese family affected with craniofacial and skeletal deformities]. AB - OBJECTIVE: To identify pathogenic mutation in a pedigree affected with craniofacial and skeletal abnormalities featuring an autosomal dominant inheritance. METHODS: Clinical data and peripheral venous blood samples of the pedigree were collected. A total of 326 exons of skeletal disease-related genes were screened using Roche NimbleGen probes, and the results were confirmed by Sanger sequencing. Suspected variants were analyzed by bioinformatic software. RESULTS: A novel heterozygous mutation c.480C>A (p.160K>N) of HDAC4, the pathogenic gene for brachydactyly mental retardation syndrome, was found in the affected proband, his father and uncle. The proband and his father also carried a novel heterozygous c.880-882delAAG (p.294delK) mutation of TRPS1, the pathogenic gene for tricho-rhino-phalangeal syndrome. Bioinformatic analysis suggested that both mutations are pathogenic. In addition, three novel genetic variants, namely c.4817G>A (p.1606S>L) of MLL2, c.83A>G (p.28H>R) of TP63, and c.1712G>C (p.571T>S) of ERCC2, were also identified in this family. CONCLUSION: The HDAC4 c.480C>A (p.160K>N) mutation probably underlies the disease in this pedigree, while the TRPS1 c.880-882delAAG (p.294delK) mutation may be related with certain features of the affected family members. Genetic analysis has facilitated the diagnosis of this complex disease. PMID- 27984603 TI - [A strategy to clarify ambiguities during genotyping of functional KIR framework genes by sequencing-based typing among ethnic Hans from southern China]. AB - OBJECTIVE: To categorize ambiguous allelic combinations encountered in genotyping of functional KIR genes by sequencing-based typing of the entire coding sequence and develop an efficient approach to identify such ambiguities. METHODS: Fourteen KIR functional framework genes from 306 ethnic Chinese individuals were genotyped for the entire encoding sequence. The number of ambiguities was directly counted. Based on the differences within each ambiguous allelic combination, group specific PCR primers and sequencing primers for amplifying the target allelic sequence were designed. The PCR products were then subjected to sequencing in order to identify the ambiguities. RESULTS: The 14 functional KIR genes were subjected to sequencing-based typing (SBT) for the entire encoding sequence. Six ambiguous allelic combinations were identified. The most common ambiguity 3DL2*(002, 007/010, 015) has accounted for 12.09% of the 306 tested samples. The remaining 5 ambiguities were (2DL5A*001, 2DL5B*006/2DL5A*012, 2DL5B*008), 3DL3*(001, 010/009, 048), 3DL2*(007, 008/016, 027), 3DL3*(00801, 048/01001, 026) and 3DL3*(00802, 048/01002, 026) have accounted for 5.88% (18/306), 3.59% (11/306), 2.29% (7/306), 1.31% (4/306) and 1.31% (4/306) of all samples, respectively. For two ambiguities (2DL5A*001, 2DL5B*006/2DL5A*012, 2DL5B*008) and 3DL2*(007, 008/016, 027) subjected to group-specific PCR and re-sequencing, only one demonstrable genotype was identified, While for in each of other four ambiguities subjected to group-specific PCR and re-sequencing, two different genotypes were identified. CONCLUSION: An efficient approach by group-specific PCR and sequencing retest has been established to clarify the ambiguities during SBT testing for functional KIR framework genes, which may have a broad application in KIR sequencing-based typing. PMID- 27984604 TI - [Identification of a novel splicing mutation of PKD1 gene in a pedigree affected with autosomal dominant polycystic kidney disease]. AB - OBJECTIVE: To identify potential mutations of PKD1 gene in a family affected with autosomal dominant polycystic kidney disease (ADPKD). METHODS: The coding regions of the PKD1 gene were subjected to PCR and Sanger sequencing. Reverse transcription-PCR (RT-PCR) was used to determine the relative mRNA expression in the patient. RESULTS: A splicing site mutation, c.8791+1_8791+5delGTGCG (IVS23+1_+5delGTGCG), was detected in the PKD1 gene in all 5 patients from the pedigree but not in 6 phenotypically normal relatives and 40 healthy controls. Sequencing of RNA has confirmed that there were 8 bases inserted in the 3' end of exon 23 of the PKD1 gene. CONCLUSION: The novel c.8791+1_8791+5delGTGCG mutation has created a new splice site and led to a frameshift, which probably underlies the ADPKD in the family. Above finding has enriched the mutation spectrum of the PKD1 gene. PMID- 27984605 TI - [Genetic analysis for a family affected with hemophilia type A due to a large deletion of F8 gene]. AB - OBJECTIVE: To detect potential mutation of F8 gene in a family affected with hemophilia type A. METHODS: Inverse-shifting PCR (IS-PCR), next-generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA), and short tandem repeat (STR) assays were used. RESULTS: IS-PCR showed that no inversion of F8 gene has occurred in the family. NGS detected no point mutation or small InDel in the proband, but suggested that the exon 2 of the F8 gene may be deleted. MLPA also showed that exon 2 of the F8 gene was absent in the proband, while the carriers were heterozygous for the deletion, though STR analysis yielded a paradoxical result. CONCLUSION: NGS analysis has identified a large deletion of exon 2 of the F8 gene in a family affected with hemophilia A. Discretion is required when STR analysis was used for carrier screening and antenatal diagnosis. Combination of multiple methods can improve the accuracy for the detection of F8 gene mutations. PMID- 27984606 TI - [Analysis of CYP21A2 gene mutations among patients with classical steroid 21 hydroxylase deficiency]. AB - OBJECTIVE: To assess the frequencies of CYP21A2 gene mutations among patients from Fujian area with classical 21-hydroxylase deficiency. METHODS: For 19 probands from different families affected with classical steroid 21-hydroxylase deficiency and 74 family members, mutations of the CYP21A2 gene were analyzed with combined nested polymerase chain reaction, Sanger sequencing and multiplex ligation-dependent probe amplification. Time resolved fluorescence immunoassay was performed to determine the level of 17-hydroxyprogesterone (17-OHP) in all family members. Clinical data and laboratory results of the probands and their family members were analyzed. RESULTS: Eleven mutations were identified among the 38 alleles from the 19 probands. 92.1% (35/38) of the mutant CYP21A2 alleles were due to recombination between CYP21A2 and CYP21A1P. Gene conversion and deletions were identified in 84.2% (32/38) and 7.9% (3/38) of the alleles, respectively. IVS2-13A/C>G and chimeras were the most common mutations, which respectively accounted for 34.2% (13/38) and 18.4% (7/38) of all mutant alleles. Among these, IVS2+1G>A and Q318X+356W were first reported in China. 74.3% (55/74) of the family members were carriers of heterozygous mutations. However, no significant difference was found in the 17-OHP levels between carriers and non-carriers (P>0.05). CONCLUSION: There seems to be a specific spectrum of CYP21A2 gene mutations in Fujian area, where IVS2-13A/C>G and chimeras are the most common mutations. PMID- 27984607 TI - [Phenotypic and genetic analysis of a family affected with microvillus inclusion disease]. AB - OBJECTIVE: To explore the clinical features and mutations of MYO5B gene in a family affected with microvillus inclusion disease. METHODS: Clinical data of an infant affected with microvillus inclusion disease was collected. Genomic DNA was extracted from peripheral blood samples from the patient and her parents. PCR amplification and Sanger sequencing were performed to analyze all the exons and their flanking sequences of the MYO5B gene. RESULTS: The patient presented with complicated manifestations including respiratory distress syndrome, dehydration, acidosis, bowel dilatation, liver and kidney dysfunction, and severe and intractable diarrhea. A compound mutation of the MYO5B gene, i.e., IVS37 1G>C/c.2729_2731delC (p.R911Afs916X), was discovered in the patient. The former was a splice-site mutation inherited from the mother, while the latter was a frameshift mutation inherited from the father. Both were not reported previously. CONCLUSION: Based on the clinical and molecular evidence, the patient was diagnosed with microvillus inclusion disease. Above finding has expanded the mutation spectrum of the MYO5B gene, which can provide valuable information for genetic counseling for the family. PMID- 27984608 TI - [Application of combined chromosome karyotype analysis and multiplex ligation probe amplification technique for the prenatal diagnosis of fetal abnormalities]. AB - OBJECTIVE: To assess the value of combined chromosome karyotype analysis and multiplex ligation probe amplification (MLPA) assay for the prenatal diagnosis of fetuses with abnormalities detected by ultrasonography. METHODS: With informed consent obtained, 72 pregnant women with ultrasound detected fetal structural abnormalities underwent percutaneous umbilical cord blood sampling. Routine karyotype analysis and MLPA assay were used to detect potential chromosomal deletions and duplications. RESULTS: Five cases were found with an abnormal karyotype. In addition, the MLPA has detected 2 chromosomal microdeletions and 1 microduplication. Together the two methods have yielded a detection rate of 11.11%. CONCLUSION: For fetal abnormalities revealed by ultrasonography, combined karyotype analysis and MLPA assay can provide a better option for its efficiency and simplicity. PMID- 27984609 TI - [Study of polymorphisms of genes related to folic acid metabolism among women of child-bearing age from Shanxi]. AB - OBJECTIVE: To analyze polymorphisms of genes related to folic acid metabolism among women of child-bearing age from Shanxi. METHODS: Buccal smears were collected from 1070 women of child bearing age with cotton swabs. Sequences of MTHFR C667T and A1298C, MTRR A66G, and SLC19A1 A80G were determined by DNA sequencing. The results were compared with data from other regions of China. RESULTS: For MTHFR C667T, the wild type homozygote, heterozygous mutants, and homozygous mutants have respectively accounted for 20.5%, 50.3%, and 29.2% of the study group, with the frequency of the mutant T allele being 54.4%. For MTHFR A1298C, these were 68.7%, 29.3%, and 2.0%, with the frequency of mutant C allele being 16.6%. For MTRR A66G, the above frequencies were 51.5%, 41.8%, and 6.7%, with the frequency of the mutant G allele being 27.6%. For SLC19A1 A80G, these were 29.2%, 48.0%, 22.8%, with the frequency of mutation G allele being 46.8%. Compared with other regions of China, women of child-bearing age from Shanxi has shown a significant difference in allelic distribution of MTRR A66G and SLC19A1 A80G (P<0.05). CONCLUSION: The polymorphisms of genes related to folic acid metabolism showed significant regional difference. Over half of women from Shanxi have carried high-risk alleles for folic acid insufficiency and should have individualized folic acid supplement. PMID- 27984610 TI - [Association of LMP gene polymorphisms with chronic HCV infection among ethnic Han population from Yunnan]. AB - OBJECTIVE: To assess the association of single nucleotide polymorphisms (SNPs) of the low molecular weight polypeptide (LMP) gene with chronic hepatitis C virus (HCV) infection among ethnic Han population from Yunnan. METHODS: A total of 427 patients with chronic HCV infection and 412 healthy controls were recruited. SNPs rs1351383, rs17587 and rs2127675 from the promoter region of the LMP2 gene and rs2071543 from the promoter region of the LPM7 gene were genotyped using a TaqMan probe. The haplotypes were constructed. Frequencies of various alleles, genotypes and haplotypes of the selected SNPs were calculated, and their association with chronic HCV infection was analyzed. RESULTS: The frequencies of rs1351383 and rs2127675 alleles of the LMP2 gene, as well as the A-G-A and C-G-G haplotypes of the rs1351383/rs17587/rs2127675 loci, had differed significantly between the two groups (P<0.05). CONCLUSION: The C allele of the rs1351383 locus and G allele of the rs2217675 locus of the LMP2 gene may be susceptible factors for chronic HCV infection among ethnic Han people from Yunnan. The A-G-A haplotype of the rs1351383/rs17587/rs2127675 loci may confer a protective effect, while the C-G-G haplotype may be a susceptible factor for chronic HCV infection in this population. PMID- 27984611 TI - [Analysis of single nucleotide polymorphisms and haplotypes of FCGR2A gene among patients with ulcerative colitis]. AB - OBJECTIVE: To assess the association of several single nucleotide polymorphisms and haplotypes of the FCGR2A gene with ulcerative colitis (UC) among Chinese patients. METHODS: For 198 UC patients and 356 healthy controls, the alleles and genotypes of the FCGR2A gene (rs1801274, rs10800309 and rs6696854) were detected with a multiplex SNaPshot technique. All subjects were also subjected to linkage disequilibrium and haplotype analyses. RESULTS: The mutant homozygote (CC) of the FCGR2A gene rs1801274 polymorphism was less frequent among UC patients compared with the controls (5.56% vs. 11.80%, P=0.017, OR=0.440, 95%CI: 0.221-0.875). However, the allelic and genotypic distributions of other two SNPs did not differ significantly between the two groups (all P>0.05). Furthermore, no association of the three SNPs (rs1801274, rs10800309 and rs6696854) of the FCGR2A gene with the severity and location of the UC was found (all P>0.05). The three SNPs were shown to be in a strong linkage [rs1801274-rs10800309 (D'=0.863, r2=0.634); rs1801274 rs6696854 (D'=0.753, r2=0.546); rs10800309-rs6696854(D'=0.990, r2=0.802)]. Moreover, the frequency of T-A-T haplotype was higher among the UC patients compared with the controls (67.40% vs. 60.93%, P=0.032, OR=1.326, 95%CI: 1.024 1.717). CONCLUSION: Our findings suggested that the mutant homozygote (CC) of the FCGR2A gene (rs1801274) may have a protective role among Chinese patients with UC. Moreover, the T-A-T haplotype formed by rs1801274, rs10800309 and rs6696854 may confer a higher risk for UC. PMID- 27984612 TI - [Molecular cytogenetic analysis of a case with ring chromosome 3 syndrome]. AB - OBJECTIVE: To investigate the genetic cause for a child with developmental delay and congenital heart disease through molecular cytogenetic analysis. METHODS: G banded karyotyping and chromosomal microarray analysis (CMA) were performed for the patient and his parents. RESULTS: The proband's karyotype was detected as ring chromosome 3, and a 3q26.3-25.3 deletion encompassing 45 genes has been found with CMA. Testing of both parents was normal. CONCLUSION: Clinical phenotype of the patient with ring chromosome 3 mainly depends on the involved genes. It is necessary to combine CMA and karyotyping for the diagnosis of ring chromosome, as CMA can provide more accurate information for variations of the genome. PMID- 27984613 TI - [Detection of a fetus with paternally derived 2q37.3 microdeletion and 20p13p12.2 microduplication using whole genome microarray technology]. AB - OBJECTIVE: To perform prenatal diagnosis for a fetus with multiple malformations. METHODS: The fetus was subjected to routine karyotyping and whole genome microarray analysis. The parents were subjected to high-resolution chromosome analysis. RESULTS: Fetal ultrasound at 28+4 weeks has indicated intrauterine growth restriction, left kidney agenesis, right kidney dysplasia, ventricular septal defect, and polyhydramnios. Chromosomal analysis showed that the fetus has a karyotype of 46,XY,der(2),der(20), t(2;20)(q37.3;p12.2), t(5;15) (q12.2;q25) pat. SNP array analysis confirmed that the fetus has a 5.283 Mb deletion at 2q37.3 and a 11.641 Mb duplication at 20p13p12.2. High-resolution chromosome analysis suggested that the father has a karyotype of 46,XY,t(2;20)(q37.3;p12.2),t(5;15)(q12.2;q25), while the mother has a normal karyotype. CONCLUSION: The abnormal phenotype of the fetus may be attributed to a 2q37.3 microdeletion and a 20p13p12.2 microduplication. The father has carried a complex translocation involving four chromosomes. To increase the chance for successful pregnancy, genetic diagnosis and/or assisted reproductive technology are warranted. PMID- 27984614 TI - [Accurate detection of a case with Angelman syndrome (type 1) using SNP array]. AB - OBJECTIVE: To analyze a case with Angelman syndrome (AS) using single nucleotide polymorphism array (SNP array) and explore its genotype-phenotype correlation. METHODS: G-banded karyotyping and SNP array were performed on a child featuring congenital malformations, intellectual disability and developmental delay. Mendelian error checking based on the SNP information was used to delineate the parental origin of detected abnormality. Result of the SNP array was validated with fluorescence in situ hybridization (FISH). RESULTS: The SNP array has detected a 6.053 Mb deletion at 15q11.2q13.1 (22,770,421- 28,823,722) which overlapped with the critical region of AS (type 1). The parents of the child showed no abnormal results for G-banded karyotyping, SNP array and FISH analysis, indicating a de novo origin of the deletion. Mendelian error checking based on the SNP information suggested that the 15q11.2q13.1 deletion was of maternal origin. CONCLUSION: SNP array can accurately define the size, location and parental origin of chromosomal microdeletions, which may facilitate the diagnosis of AS due to 15q11q13 deletion and better understanding of its genotype-phenotype correlation. PMID- 27984615 TI - [Improved identification for trisomy 9p and partial trisomy 6q presented in a patient by array-based comparative genomic hybridization]. AB - OBJECTIVE: To analyze the genetic cause for a child with growth retardation and mental retardation and discuss the application of array-based comparative genomic hybridization (aCGH) in its molecular genetic diagnosis. METHODS: Conventional karyotyping of peripheral blood for the family was carried out. aCGH was performed to further ascertain the size and origin of the additional chromosome fragments. RESULTS: In the trio family here, the karyotype of the father was normal, the karyotype of the mother was 46,XX, t(6;9)(q26;q21)and the proband child's was 47,XX,+der(9)?t(6;9)(q26;q21). aCGH showed that the extra chromosomal fragments originated from chromosome 9p24.3-q21.13 and the size was 78.26 Mb, and the repeat region included the 9p trisomy's clinical area. At the same time, it was confirmed that 6q26-q27 was trisomic and the fragment that related to development delay was 6.6 Mb. We determined that the proband's karyotype was 47,XX,+der(9)t(6;9)(q26;q21.13)mat finally. CONCLUSION: The patient's abnormal chromosome has originated from her mother with balance translocation. The duplications of 9p24.3-q21.13 and 6q26-q27 may lead to growth retardation and mental retardation. Accompanied with the cytogenetic methods, aCGH can accurately identify the origin and size of the abnormal chromosomes, contributing to the genetic analysis. PMID- 27984616 TI - [Study of the molecular basis of an individual with Aw43 subtype of the ABO blood group]. AB - OBJECTIVE: To explore the molecular basis of an individual with A subtype of the ABO blood group. METHODS: The ABO antigen and serum antibody of the proband and his parents and sister were detected by a serological method. The whole coding regions of the ABO gene were amplified by PCR and subjected to bidirectional sequencing. RESULTS: Red blood cells of the proband showed mixed field agglutination with anti-A but did not agglutinate with anti-B, and his serum did not agglutinate with A and O cells but with B cells. The proband was identified as an Aw phenotype. Heterozygous status of 1A/G, 106G/T, 188A/G, 189C/T, 220C/T, 261G/del, 297A/G, 467C/T, 646A/T, and 681A/G of the coding region of the ABO gene were identified by directly sequencing of the proband. The serological characteristics and nucleotide sequences of the mother were similar to those of the proband. However, the ABO genotypes of his father and sister were B101/O02 and O02/O02. The proband therefore has carried an O02 allele and a novel allele. Compared with A102, the novel allele contains 1A>G, which resulted in translation initiator code change and was nominated as Aw43 by dbRBC of NCBI. CONCLUSION: An Aw43 subtype has been identified for the first time, which may be attributed to the 1A>G and 467C>T variants on the alpha1,3-N-acetyl-galactosaminyltransferase gene. PMID- 27984617 TI - [Molecular genetic analysis of four cases with weak D variant of Rh blood type]. AB - OBJECTIVE: To explore the molecular basis of 4 cases with weak D variant of Rh blood type. METHODS: Routine serological testing was applied to determine the D, C, c, E and e antigens of the Rh blood group. The D antigen was further detected with an indirect antiglobulin test. RHD zygosity was detected by sequence specific primer PCR method. All exons and flanking intron regions of the RHD gene were sequenced. RESULTS: The samples were determined as weak D phenotype by serological testing. DNA sequencing showed that the 4 cases were heterozygous for 17C>T mutation in exon 1, 29G>C mutation in exon 1, 1212C>A mutation in exon 9, and IVS4+5G>A mutation in intron 4 of the RHD gene, respectively. According to the rule of Rhesus Base Nomenclature, the 4 samples were respectively named as weak D type 31, weak D type 71, weak D type 72, and weak D type 82. CONCLUSION: Serological and molecular testing for the weak D can facilitate in-depth understanding of its immunology and genetics, and provide guidance for clinical blood transfusion and prevention of hemolytic disease in newborns. PMID- 27984618 TI - [Identification of a novel HLA allele A*29:49 using sequence based typing]. AB - OBJECTIVE: To report on a novel HLA-A allele, A*29:49, identified in a Chinese Han population by sequence based typing (SBT). METHODS: A donor from China Marrow Donor Programme (CMDP) was typed with a bi-allelic PCR-SBT kit, and no full matched result was obtained for the HLA-A locus. The novel HLA allele was verified with an allele-specific amplification SBT kit. RESULTS: A novel HLA-A allele was identified, which has differed by one nucleotide from the closest matched allele, HLA-A*29:01:01:01, at position 368(A->T), codon 99 (TAT->TTT), resulting in an amino acid substitution (Y->F). Another allele was verified as A*02:06:01. CONCLUSION: A novel HLA-A allele was identified and officially named as HLA-A*29:49 by the WHO Nomenclature Committee for Factors of the HLA System. PMID- 27984619 TI - [Tri-primer-florescence PCR-Sanger sequencing method for screening of full and pre-mutations of FMR1 gene]. AB - OBJECTIVE: To screen for CGG repeats in the FMR1 gene among patients with fragile X syndrome and carriers of pre-mutations. METHODS: Potential full and pre mutations of the FMR1 gene were detected with a Tri-primer-florescence PCR-Sanger sequencing method. The results were validated with positive and negative controls. RESULTS: All positive and negative controls were confirmed. A male patient was found to have > 200 CGG repeats (full mutation). For a pregnant women who was heterozygous for 35/115 CGG repeats, > 200 CGG repeats were also found with amniotic fluid sample from her fetus who was a male. The result was confirmed by following selective abortion with informed consent. CONCLUSION: Tri primer-florescence PCR-Sanger sequencing is a simple, effective and reliable method for routine screening of patients/carriers with full/pre-mutations of the FMR1 gene in the population. PMID- 27984620 TI - [Influence of chromosomal polymorphisms on the clinical outcome of patients undergoing in vitro fertilization embryo transfer]. AB - OBJECTIVE: To explore the influence of chromosome polymorphisms on the outcome of in vitro fertilization embryo transfer (IVF-ET). METHODS: Patients who completed the first cycle of in vitro fertilization fresh embryo transfer were retrospective studied. Patients with the chromosome polymorphisms were classified as to the study group (200 treatment cycles), all patients with normal chromosomes at the same period were classified as the control group (4777 treatment cycles). RESULTS: No significant difference was found between the chromosome polymorphisms and the control groups in terms of clinical pregnancy rate (44.50% vs. 39.85%, P=0.750), early abortion rate (15.73% vs. 10.79%, P=0.163) and live birth rate per cycle (34.5% vs. 30.73%, P=0.437) except for fertilization rate (60.94% vs. 64.08%, P=0.001), cleavage rate (95.01% vs. 97.09%, P=0.000) and good quality embryo rate (53.8% vs. 58.2%, P=0.001). CONCLUSION: Chromosomal polymorphisms appeared to have no adverse influence on the outcome of IVF-ET treatment. PMID- 27984621 TI - [Identification of a rare D13S317-5 allele in an ethnic Han Chinese from Hainan]. AB - OBJECTIVE: To report on a rare D13S317-off-ladder (OL) allele identified in an ethnic Han Chinese from Hainan. METHODS: The rare allele D13S317-OL was detected with a short tandem repeat (STR)-PCR method and DNA sequencing. RESULTS: The core repeat sequence of the rare allele was found to be [TATC]5. CONCLUSION: The rare D13S317-5 allele also exists among ethnic Hans from Hainan, which may have a significant value for personal identification and paternity testing. PMID- 27984622 TI - [Applications of ZFN, TALEN and CRISPR/Cas9 techniques in disease modeling and gene therapy]. AB - Precise and effective modification of complex genomes at the predicted loci has long been an important goal for scientists. However, conventional techniques for manipulating genomes in diverse organisms and cells have lagged behind the rapid advance in genomic studies. Such genome engineering tools have featured low efficiency and off-targeting. The newly developed custom-designed nucleases, zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated (Cas) system have conferred genome modification with ease of customization, flexibility and high efficiency, which may impact biological research and studies on pathogenesis of human diseases. These novel techniques can edit the genomic DNA with high efficiency and specificity in a rich variety of organisms and cell types including the induced pluripotent stem cells (iPSCs), which has conferred them with the potential for revealing the pathogenesis and treatment of many human diseases. This review has briefly introduced the mechanisms of ZFN, TALENs and CRISPR/Cas9 system, and compared the efficiency and specificity of such approaches. In addition, the application of ZFN, TALENs and CRISPR/Cas9 mediated genome modification for human disease modeling and gene therapy was also discussed. PMID- 27984623 TI - [Advances of research on the mechanism of Down syndrome birth at advanced maternal age]. AB - Down syndrome is caused by partial or complete triplication of genes located on chromosome 21. Its incidence increases dramatically with the age of women. Hypotheses proposed for this have included abnormal homologous recombination, defective spindle assembly, biological aging, reduction of cohesion complexes, endocrine disorders, oocyte selection model, and single nucleotide polymorphisms of genes that maintain chromosome stability, etc. A literature review is provided here. PMID- 27984625 TI - [Progress of research on the pathogenesis of obesity in Bardet-Biedl syndrome]. AB - Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disease characterized by retinopathy, obesity, and polydactyly. So far 21 candidate genes have been discovered, and mutations of such genes can all cause the BBS phenotype. As one of the main features of the disease, the obesity in BBS has been associated with leptin resistance and abnormal adipogenesis. However, its molecular etiology is not yet completely clear. Here the molecular mechanism of BBS-associated obesity is reviewed. PMID- 27984626 TI - [Regulatory roles of non-coding RNAs in cardiomyocyte differentiation]. AB - Heart is the first organ to function during mammalian embryogenesis. The differentiation of embryonic stem cells (ESCs) into cardiomyocyte is complex and dynamic, which involves 4 differentiation stages including ESCs, mesoderm, cardiac precursor, and terminal cardiomyocytes. Abnormal expression of certain genes can lead to congenital heart diseases during cardiomyocyte differentiation. Epigenetic regulation plays a crucial role on the switch of gene activation and deactivation during cardiomyocyte differentiation. Non-coding RNA, particularly microRNA and long non-coding RNA, may significantly influence gene expression. Exploring the regulatory roles of non-coding RNA in cardiomyocyte differentiation may contribute to the understanding of the functions of myocardial cells and mechanism of congenital heart diseases. PMID- 27984624 TI - [Progress in research on genetic polymorphisms and sequence-based typing of KIR genes]. AB - Killer cell immunoglobulin-like receptors (KIRs) are members of the immunoglobulin superfamily expressed on natural killer (NK) cells and a subset of T cells. Given the receptor-ligand relationship between certain KIR and human leukocyte antigen (HLA) classImolecules, the KIRs are involved in the regulation of NK cell activation through conveying activating or inhibitory signals, which plays an important role in immunities involved in transplantation, tumor, infection as well as autoimmune diseases. This paper has provided a review for the research on KIR gene polymorphisms and summarized the characteristics of the sequence-based typing method for KIR genes. PMID- 27984627 TI - [Advance in research on congenital hemidysplasia with ichthyosiform nevus and limb defects syndrome]. AB - Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare X-linked dominant and male-lethal multi-system disorder characterized by congenital hemidysplasia, strictly lateralized ichthyosiform nevus and ipsilateral limb defects. CHILD syndrome is caused by mutations of nicotinamide adenine dinucleotide phosphate steroid dehydrogenase-like protein (NSDHL) gene mapped to chromosome Xq28. The gene encodes 3beta-hydroxylsterol dehydrogenase, which catalyses a step in the cholesterol biosynthetic pathway. This paper has provided a review for recent progress in research on CHILD syndrome including its clinical aspects, pathology, etiology, pathogenesis, differential diagnosis, and treatment, with a particular emphasis on its treatment.. PMID- 27984628 TI - [Report of a pedigree affected with spinocerebellar ataxia type 1]. PMID- 27984629 TI - [Analysis of a pedigree affected with brachydactyly]. PMID- 27984630 TI - [Report of a pedigree affected with congenital heart disease]. PMID- 27984632 TI - Local epiphyte establishment and future metapopulation dynamics in landscapes with different spatiotemporal properties. AB - Understanding the relative importance of different ecological processes on the metapopulation dynamics of species is the basis for accurately forecasting metapopulation size in fragmented landscapes. Successful local colonization depends on both species dispersal range and how local habitat conditions affect establishment success. Moreover, there is limited understanding of the effects of different spatiotemporal landscape properties on future metapopulation size. We investigate which factors drive the future metapopulation size of the epiphytic model lichen species Lobaria pulmonaria in a managed forest landscape. First, we test the importance of dispersal and local conditions on the colonization extinction dynamics of the species using Bayesian state-space modelling of a large-scale data set collected over a 10-yr period. Second, we test the importance of dispersal and establishment limitation in explaining establishment probability and subsequent local population growth, based on a 10-yr propagule sowing experiment. Third, we test how future metapopulation size is affected by different metapopulation and spatiotemporal landscape dynamics, using simulations with the metapopulation models fitted to the empirical data. The colonization probability increased with tree inclination and connectivity, with a mean dispersal distance of 97 m (95% credible intervals, 5-530 m). Local extinctions were mainly deterministic set by tree mortality, but also by tree cutting by forestry. No experimental establishments took place on clearcuts, and in closed forest the establishment probability was higher on trees growing on moist than on dry-mesic soils. The subsequent local population growth rate increased with increasing bark roughness. The simulations showed that the restricted dispersal range estimated (compared to non-restricted dispersal range), and short tree rotation length (65 yr instead of 120) had approximately the same negative effects on future metapopulation size, while regeneration of trees creating a random tree pattern instead of an aggregated one had only some negative effect. However, using the colonization rate obtained with the experimentally added diaspores led to a considerable increase in metapopulation size, making the dispersal limitation of the species clear. The future metapopulation size is thus set by the number of host trees located in shady conditions, not isolated from occupied trees, and by the rotation length of these host trees. PMID- 27984631 TI - Interim assessment of liver damage in patients with sickle cell disease using new non-invasive techniques. AB - We explored transient elastography (TE) and enhanced liver fibrosis (ELFTM ) score with standard markers of liver function to assess liver damage in 193 well patients with sickle cell disease (SCD). Patients with HbSS or HbSbeta0 thalassaemia (sickle cell anaemia, SCA; N = 134), had significantly higher TE results and ELF scores than those with HbSC (N = 49) disease (TE, 6.8 vs. 5.3, P < 0.0001 and ELF, 9.2 vs. 8.6 P < 0.0001). In SCA patients, TE and ELF correlated significantly with age and all serum liver function tests (LFTs). Additionally, (weak) positive correlation was found with lactate dehydrogenase (TE: r = 0.24, P = 0.004; ELF: r = 0.26 P = 0.002), and (weak) negative correlation with haemoglobin (TE: r = -0.25, P = 0.002; ELF: r = -0.25 P = 0.004). In HbSC patients, correlations were weaker or not significant between TE or ELF, and serum LFTs. All markers of iron loading correlated with TE values when corrected for sickle genotype (serum ferritin, beta = 0.25, P < 0.0001, total blood transfusion units, beta = 0.25, P < 0.0001 and LIC beta = 0.32, P = 0.046). The exploratory study suggests that, while TE could have a role, the utility of ELF score in monitoring liver damage in SCD, needs further longitudinal studies. PMID- 27984633 TI - Early response does not predict outcome in children and adolescents with chronic myeloid leukaemia treated with high-dose imatinib. PMID- 27984634 TI - Approach to patients with essential thrombocythaemia and very high platelet counts: what is the evidence for treatment? AB - Treatment of essential thrombocythaemia (ET) is directed at decreasing the risk of complications of the disease, including arterial and venous thrombosis and bleeding episodes. Established risk factors for vascular events in patients with ET include advanced age (>60 years) and prior history of thrombosis or haemorrhage. The role, if any, of other potential risk factors, including cardiovascular risk factors, leucocytosis, high haematocrit, and JAK2 V617F has been analysed in multiple studies. The impact of thrombocytosis on the risk of vascular events has also been investigated. Many clinicians consider an elevated platelet count to be a risk factor for thrombosis or, when extreme, bleeding and utilize this as a criterion to start cytoreductive therapy. However, the relationship between thrombocytosis and vascular events is controversial and solid evidence to support the use of cytoreductive therapy in ET patients who have no other risk factors is lacking. In this review, we discuss current treatment recommendations for patients with ET, the biology underlying vascular events and risk factors thereof. We then review the evidence on the management of patients with ET and extreme thrombocytosis. PMID- 27984635 TI - Sources of variation in foliar secondary chemistry in a tropical forest tree community. AB - Specialist herbivores and pathogens could induce negative conspecific density dependence among their hosts and thereby contribute to the diversity of plant communities. A small number of hyperdiverse genera comprise a large portion of tree diversity in tropical forests. These closely related congeners are likely to share natural enemies. Diverse defenses could still allow congeners to partition niche space defined by natural enemies, but interspecific differences in defenses would have to exceed intraspecific variation in defenses. We ask whether interspecific variation in secondary chemistry exceeds intraspecific variation for species from four hyperdiverse tropical tree genera. We used novel methods to quantify chemical structural similarity for all compounds present in methanol extracts of leaf tissue. We sought to maximize intraspecific variation by selecting conspecific leaves from different ontogenetic stages (expanding immature vs. fully hardened mature), different light environments (deep understory shade vs. large forest gaps), and different seasons (dry vs. wet). Chemical structural similarity differed with ontogeny, light environment, and season, but interspecific differences including those among congeneric species were much larger. Our results suggest that species differences in secondary chemistry are large relative to within-species variation, perhaps sufficiently large to permit niche segregation among congeneric tree species based on chemical defenses. PMID- 27984636 TI - Rationale for combinatory chronic lymphocytic leukaemia treatment paradigms in the era of the B-cell receptor pathway and anti-apoptotic inhibitors: how do we mix, match, and move forward? PMID- 27984638 TI - Dawning of the age of genomics for platelet granule disorders: improving insight, diagnosis and management. AB - Inherited disorders of platelet granules are clinically heterogeneous and their prevalence is underestimated because most patients do not undergo a complete diagnostic work-up. The lack of a genetic diagnosis limits the ability to tailor management, screen family members, aid with family planning, predict clinical progression and detect serious consequences, such as myelofibrosis, lung fibrosis and malignancy, in a timely manner. This is set to change with the introduction of high throughput sequencing (HTS) as a routine clinical diagnostic test. HTS diagnostic tests are now available, affordable and allow parallel screening of DNA samples for variants in all of the 80 known bleeding, thrombotic and platelet genes. Increased genetic diagnosis and curation of variants is, in turn, improving our understanding of the pathobiology and clinical course of inherited platelet disorders. Our understanding of the genetic causes of platelet granule disorders and the regulation of granule biogenesis is a work in progress and has been significantly enhanced by recent genomic discoveries from high-powered genome-wide association studies and genome sequencing projects. In the era of whole genome and epigenome sequencing, new strategies are required to integrate multiple sources of big data in the search for elusive, novel genes underlying granule disorders. PMID- 27984637 TI - Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics. AB - Major advances in genetic and epigenetic profiling of acute lymphoblastic leukaemia (ALL) have enhanced the understanding of key biological subsets of de novo and relapsed ALL, which has led to improved risk stratification of patients. These achievements have further defined critical leukaemia-associated pathways and somatic alterations that may be preferentially sensitive to treatment with kinase inhibitors, epigenetic therapy or other novel agents. Therapeutic success in childhood ALL currently relies upon refined risk stratification of patients based on (i) underlying biological and clinical characteristics, and (ii) depth of initial treatment response with appropriate modulation of chemotherapy intensity. This review describes the current mutational landscape of childhood ALL and discusses opportunities for substantial improvements in survival with implementation of molecularly targeted therapies. PMID- 27984639 TI - Exacerbation of oxidative stress during sickle vaso-occlusive crisis is associated with decreased anti-band 3 autoantibodies rate and increased red blood cell-derived microparticle level: a prospective study. AB - Painful vaso-occlusive crisis, a hallmark of sickle cell anaemia, results from complex, incompletely understood mechanisms. Red blood cell (RBC) damage caused by continuous endogenous and exogenous oxidative stress may precipitate the occurrence of vaso-occlusive crises. In order to gain insight into the relevance of oxidative stress in vaso-occlusive crisis occurrence, we prospectively compared the expression levels of various oxidative markers in 32 adults with sickle cell anaemia during vaso-occlusive crisis and steady-state conditions. Compared to steady-state condition, plasma levels of free haem, advanced oxidation protein products and myeloperoxidase, RBC caspase-3 activity, as well as the concentrations of total, neutrophil- and RBC-derived microparticles were increased during vaso-occlusive crises, whereas the reduced glutathione content was decreased in RBCs. In addition, natural anti-band 3 autoantibodies levels decreased during crisis and were negatively correlated with the rise in plasma advanced oxidation protein products and RBC caspase-3 activity. These data showed an exacerbation of the oxidative stress during vaso-occlusive crises in sickle cell anaemia patients and strongly suggest that the higher concentration of harmful circulating RBC-derived microparticles and the reduced anti-band 3 autoantibodies levels may be both related to the recruitment of oxidized band 3 into membrane aggregates. PMID- 27984641 TI - CSF3R T618I, ASXL1 G942 fs and STAT5B N642H trimutation co-contribute to a rare chronic neutrophilic leukaemia manifested by rapidly progressive leucocytosis, severe infections, persistent fever and deep venous thrombosis. PMID- 27984640 TI - Changes in flowering functional group affect responses of community phenological sequences to temperature change. AB - Our ability to predict how temperature modifies phenology at the community scale is limited by our lack of understanding of responses by functional groups of flowering plants. These responses differ among species with different life histories. We performed a reciprocal transplant experiment along four elevation gradients (e.g., 3,200, 3,400, 3,600 and 3,800 m) to investigate the effects of warming (transferred downward) and cooling (transferred upward) on plant flowering functional groups (FFGs) and community phenological sequences (i.e., seven phenological events). Warming significantly decreased early-spring flowering (ESF) plant coverage and increased mid-summer-flowering plant (MSF) coverage, while cooling had the opposite effect. All community phenological events were advanced by warming and delayed by cooling except for the date of complete leaf-coloring, which showed the opposite response. Warming and cooling could cause greater advance or delay in early-season phenological events of the community through increased coverage of MSF species, and warming could delay late season phenological events of the community by increased coverage of ESF species. These results suggested that coverage change of FFGs in the community induced by temperature change could mediate the responses of the community phenological events to temperature change in the future. The response of phenological events to temperature change at the species level may not be sufficient to predict phenological responses at the community-level due to phenological compensation between species in the community. PMID- 27984642 TI - TP53 mutations predict decitabine-induced complete responses in patients with myelodysplastic syndromes. AB - To identify the molecular signatures that predict responses to decitabine (DAC), we examined baseline gene mutations (28 target genes) in 109 myelodysplastic syndrome (MDS) patients at diagnosis. We determined that TP53 mutations predicted complete response (CR), as 10 of 15 patients (66.7%) who possessed TP53 mutations achieved a CR. Univariate and multivariate analyses showed that TP53 mutations are the only molecular signatures predictive of a CR to DAC in MDS. Among the ten patients with TP53 mutations who achieved a CR, nine presented with complex karyotypes due to abnormalities involving chromosome 5 and/or chromosome 7, and eight possessed monosomies. Although TP53 mutations were associated with a higher frequency of CRs, they were not associated with improved survival. Poor outcomes were attributed to early relapses and transformation to acute myeloid leukaemia after CR. Post-DAC therapy patient gene mutation profiles showed that most CR patients exhibited fewer gene mutations after achieving a CR. It seems that suppression of these gene mutations was facilitated by DAC, resulting in a CR. In summary, TP53 mutations might predict decitabine-induced complete responses in patients with MDS. DAC-induced responses may result from partial suppression of malignant clones containing mutated TP53 genes. PMID- 27984643 TI - Brentuximab vedotin and bendamustine produce high complete response rates in patients with chemotherapy refractory Hodgkin lymphoma. PMID- 27984644 TI - Li-Fraumeni syndrome: a paradigm for the understanding of hereditary cancer predisposition. AB - Li-Fraumeni syndrome (LFS) is a rare cancer predisposing condition caused by germline mutations in TP53, the gene encoding the TP53 transcription factor. LFS is typified by the development of a wide spectrum of childhood and adult-onset malignancies, which includes, among others, the lymphoid and myeloid leukaemias, myelodysplastic syndrome and, to a lesser extent, lymphoma. Accordingly, it is important that haematologists/oncologists be familiar with this pleiotropic hereditary cancer syndrome. The high cancer risk and variability in type and age of cancer onset have raised questions about the underlying biology and optimal treatment approaches for individuals with LFS. Since its description almost 50 years ago, many clinical and basic research investigations have provided insights into the pathogenesis, manifestations, genetic testing and management strategies for individuals with LFS. Here we provide an update on the current state of knowledge regarding LFS with an emphasis, where possible, on information relevant to practicing haematologists. PMID- 27984645 TI - Detrending phenological time series improves climate-phenology analyses and reveals evidence of plasticity. AB - Time series have played a critical role in documenting how phenology responds to climate change. However, regressing phenological responses against climatic predictors involves the risk of finding potentially spurious climate-phenology relationships simply because both variables also change across years. Detrending by year is a way to address this issue. Additionally, detrending isolates interannual variation in phenology and climate, so that detrended climate phenology relationships can represent statistical evidence of phenotypic plasticity. Using two flowering phenology time series from Colorado, USA and Greenland, we detrend flowering date and two climate predictors known to be important in these ecosystems: temperature and snowmelt date. In Colorado, all climate-phenology relationships persist after detrending. In Greenland, 75% of the temperature-phenology relationships disappear after detrending (three of four species). At both sites, the relationships that persist after detrending suggest that plasticity is a major component of sensitivity of flowering phenology to climate. Finally, simulations that created different strengths of correlations among year, climate, and phenology provide broader support for our two empirical case studies. This study highlights the utility of detrending to determine whether phenology is related to a climate variable in observational data sets. Applying this as a best practice will increase our understanding of phenological responses to climatic variation and change. PMID- 27984647 TI - Pathology findings in patients with cutaneous T-cell lymphomas treated with allogeneic haematopoietic stem cell transplantation. PMID- 27984646 TI - Arbuscular mycorrhizal fungal diversity and natural enemies promote coexistence of tropical tree species. AB - Negative population feedbacks mediated by natural enemies can promote species coexistence at the community scale through disproportionate mortality of numerically dominant (common) tree species. Simultaneously, associations with arbuscular mycorrhizal fungi (AMF) can result in positive effects on tree populations. Coupling data on seedling foliar damage from herbivores and pathogens and DNA sequencing of soil AMF diversity, we assessed the effects of these factors on tree seedling mortality at local (1 m2 ) and community (16 ha plot) scales in a tropical rainforest in Puerto Rico. At the local scale, AMF diversity in soil counteracted negative effects from foliar damage on seedling mortality. At the community scale, mortality of seedlings of common tree species increased with foliar damage while rare tree species benefited from soil AMF diversity. Together, the effects of foliar damage and soil AMF diversity on seedling mortality might foster tree species coexistence in this forest. PMID- 27984648 TI - Seasonal changes in the assembly mechanisms structuring tropical fish communities. AB - Despite growing interest in trait-based approaches to community assembly, little attention has been given to seasonal variation in trait distribution patterns. Mobile animals can rapidly mediate influences of environmental factors and species interactions through dispersal, suggesting that the relative importance of different assembly mechanisms can vary over short time scales. This study analyzes seasonal changes in functional trait distributions of tropical fishes in the Xingu River, a major tributary of the Amazon with large predictable temporal variation in hydrologic conditions and species density. Comparison of observed functional diversity revealed that species within wet-season assemblages were more functionally similar than those in dry-season assemblages. Further, species within wet-season assemblages were more similar than random expectations based on null model predictions. Higher functional richness within dry season communities is consistent with increased niche complementarity during the period when fish densities are highest and biotic interactions should be stronger; however, null model tests suggest that stochastic factors or a combination of assembly mechanisms influence dry-season assemblages. These results demonstrate that the relative influence of community assembly mechanisms can vary seasonally in response to changing abiotic conditions, and suggest that studies attempting to infer a single dominant mechanism from functional patterns may overlook important aspects of the assembly process. During the prolonged flood pulse of the wet season, expanded habitat and lower densities of aquatic organisms likely reduce the influence of competition and predation. This temporal shift in the influence of different assembly mechanisms, rather than any single mechanism, may play a large role in maintaining the structure and diversity of tropical rivers and perhaps other dynamic and biodiverse systems. PMID- 27984649 TI - A life cycle database for parasitic acanthocephalans, cestodes, and nematodes. AB - Parasitologists have worked out many complex life cycles over the last ~150 yr, yet there have been few efforts to synthesize this information to facilitate comparisons among taxa. Most existing host-parasite databases focus on particular host taxa, do not distinguish final from intermediate hosts, and lack parasite life-history information. We summarized the known life cycles of trophically transmitted parasitic acanthocephalans, cestodes, and nematodes. For 973 parasite species, we gathered information from the literature on the hosts infected at each stage of the parasite life cycle (8,510 host-parasite species associations), what parasite stage is in each host, and whether parasites need to infect certain hosts to complete the life cycle. We also collected life-history data for these parasites at each life cycle stage, including 2,313 development time measurements and 7,660 body size measurements. The result is the most comprehensive data summary available for these parasite taxa. In addition to identifying gaps in our knowledge of parasite life cycles, these data can be used to test hypotheses about life cycle evolution, host specificity, parasite life-history strategies, and the roles of parasites in food webs. PMID- 27984650 TI - Learning Health Systems as Facilitators of Precision Medicine. PMID- 27984651 TI - Neoadjuvant long-course chemoradiation remains strongly favored over short-course radiotherapy by radiation oncologists in the United States. AB - BACKGROUND: Short-course radiotherapy (SC-RT) and long-course chemoradiotherapy (LC-CRT) are accepted neoadjuvant treatments of rectal cancer. In the current study, the authors surveyed US radiation oncologists to assess practice patterns and attitudes regarding SC-RT and LC-CRT for patients with rectal cancer. METHODS: The authors distributed a survey to 1701 radiation oncologists regarding treatment of neoadjuvant rectal cancer. Respondents were asked questions regarding the number of patients with rectal cancer treated, preference for SC-RT versus LC-CRT, and factors influencing regimen choice. RESULTS: Of 1659 contactable physicians, 182 responses (11%) were received. Approximately 83% treated at least 5 patients with rectal cancer annually. The majority of responding radiation oncologists (96%) preferred neoadjuvant LC-CRT for the treatment of patients with locally advanced rectal cancer and 44% never used SC RT. Among radiation oncologists using SC-RT, respondents indicated they would not recommend this regimen for patients with low (74%) or bulky tumors (70%) and/or concern for a positive circumferential surgical resection margin (69%). The most frequent reasons for not offering SC-RT were insufficient downstaging for sphincter preservation (53%) and a desire for longer follow-up (45%). Many radiation oncologists indicated they would prescribe SC-RT for patients not receiving chemotherapy (62%) or patients with a geographic barrier to receiving LC-CRT (82%). Patient comorbidities appeared to influence regimen preferences for 79% of respondents. Approximately 20% of respondents indicated that altered oncology care reimbursement using capitated payment by diagnosis would impact their consideration of SC-RT. CONCLUSIONS: US radiation oncologists rarely use neoadjuvant SC-RT despite 3 randomized controlled trials demonstrating no significant differences in outcome compared with LC-CRT. Further research is necessary to determine whether longer follow-up coupled with the benefits of lower cost, increased patient convenience, and lower acute toxicity will increase the adoption of SC-RT by radiation oncologists in the United States. Cancer 2017;123:1434-1441. (c) 2016 American Cancer Society. PMID- 27984653 TI - Scalpels not hammers: The way forward for precision drug prescription. PMID- 27984654 TI - Extended Clearance Classification System (ECCS) informed approach for evaluating investigational drugs as substrates of drug transporters. PMID- 27984652 TI - A multi-institutional analysis of peritransplantation radiotherapy in patients with relapsed/refractory Hodgkin lymphoma undergoing autologous stem cell transplantation. AB - BACKGROUND: No consensus exists regarding the use of radiotherapy (RT) in conjunction with high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) for patients with relapsed/refractory classical Hodgkin lymphoma (HL). The objectives of the current study were to characterize practice patterns and assess the efficacy and toxicity of RT at 2 major transplantation centers. METHODS: Eligible patients underwent HDC/ASCT from 2006 through 2015 using the combination of either carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) or cyclophosphamide, BCNU, and etoposide (CBV). RESULTS: For the cohort of 189 patients, the 4-year overall survival rate was 80%, the progression-free survival rate was 67%, and the local control (LC) rate was 68%. RT was used within 4 months of ASCT for 22 patients (12%) and was given more often for disease that was early stage, primary refractory, or [18 F]fluorodeoxyglucose (FDG)-avid at the time of HDC/ASCT. Disease recurrence occurring after HDC/ASCT was associated with primary refractory disease and FDG-avidity at the time of HDC/ASCT. RT was not found to be associated with LC, progression-free survival, or overall survival on univariate analysis. In a model incorporating primary refractory HL and FDG-avid disease at the time of HDC/ASCT, RT was found to be associated with a decreased risk of local disease recurrence (hazard ratio, 0.3; P = .02). In patients with primary refractory HL and/or FDG-avid disease at the time of HDC/ASCT, the 4-year LC rate was 81% with RT versus 49% without RT (P = .03). There was one case of Common Terminology Criteria for Adverse Events grade >= 3 RT-related toxicity (acute grade 3 pancytopenia). CONCLUSIONS: In patients undergoing ASCT for relapsed/refractory HL, peritransplantation RT was used more often for disease that was early stage, primary refractory, or FDG-avid after salvage conventional-dose chemotherapy. RT was associated with improved LC of high-risk localized disease and was well tolerated with modern techniques. Cancer 2017;123:1363-1371. (c) 2016 American Cancer Society. PMID- 27984655 TI - Local therapy reduces the risk of liver failure and improves survival in patients with intrahepatic cholangiocarcinoma: A comprehensive analysis of 362 consecutive patients. AB - BACKGROUND: Treatment methods for intrahepatic cholangiocarcinoma (ICC) have improved, but their impact on outcome remains unclear. We evaluated the outcomes of patients definitively treated with resection, radiation, and chemotherapy for ICC, stratified by era. METHODS: Clinico-pathologic characteristics, cause of death, disease-specific survival (DSS), and intrahepatic progression-free survival (IPFS) were compared among patients who underwent resection, radiation, or chemotherapy as definitive treatment strategies for ICC (without distant organ metastasis) between 1997 and 2015. Variables were also analyzed by era (1997-2006 [early] or 2007-2015 [late]) within each group. RESULTS: Among 362 patients in our cohort, 122 underwent resection (early, 38; late, 84), 85 underwent radiation (early, 17; late, 68), and 148 underwent systemic chemotherapy alone (early, 51; late, 97) as definitive treatment strategies, and 7 patients received best supportive care. In the resection group, the 3-year DSS rate was 58% for the early era and 67% for the late era (P = .036), and the 1-year IPFS was 50% for the early era and 75% for the late era (P = .048). In the radiation group, the 3 year DSS was 12% for the early era and 37% for the late era (P = .048), and the 1 year IPFS was 48% for the early era and 64% for the late era (P = .030). In the chemotherapy group, DSS and IPFS did not differ by era. Patients treated with chemotherapy developed liver failure at the time of death significantly more frequently than patients treated with resection (P < .001) or radiation (P < .001). Multivariable analysis identified local therapy (resection or radiation) as a sole predictor of death without liver failure. CONCLUSION: Survival outcomes have improved for local therapy-based definitive treatment strategies for ICC, which may be attributable to maintaining control of intrahepatic disease, thereby reducing the occurrence of death due to liver failure. Cancer 2017;123:1354-1362. (c) 2016 American Cancer Society. PMID- 27984657 TI - Individual isotopic specializations predict subsequent inter-individual variation in movement in a freshwater fish. AB - Despite many similarities and intuitive links between individual dietary specialization and behavioral inter-individual variation, these phenomena have been studied in isolation, and empirical data confirming relationships between these intraspecific variance sources are lacking. Here we use stable isotope analysis and acoustic telemetry to test the hypothesis that individual specialization in trophic (delta15 N) and littoral/pelagic prey reliance (delta13 C) covary with inter-individual variation in movement in a group of 34 free swimming burbot (Lota lota). By performing stable isotope analysis on tissues with differing isotopic turnover rates (anal fin and dorsal muscle), in 24 lethally sampled burbot, we demonstrate that individual specialization in trophic niche (delta15 N) and littoral/pelagic prey reliance (delta13 C) occurred within the population. By performing stable isotope analysis on anal fins of a group of telemetry tagged burbot, we were able to show that interactions between trophic niche and littoral/pelagic prey reliance, explained a significant proportion of the subsequent between-individual variance in mean movement rates. These findings demonstrate an empirical connection between behavioral inter-individual variation and dietary specialization, thus providing a substantial expansion of our understanding of the wider ecological consequences of these interesting phenomena. PMID- 27984659 TI - Clinical Pharmacology: a Discipline at the Nexus Between Translational Science and Precision Medicine: Commentary on "Enhancing Value of Clinical Pharmacodynamics in Oncology Drug Development: An Alliance Between Quantitative Pharmacology and Translational Science". PMID- 27984656 TI - The toxicity and efficacy of concomitant chemoradiotherapy in patients aged 70 years and older with oropharyngeal carcinoma in the intensity-modulated radiotherapy era. AB - BACKGROUND: Despite controversy surrounding its benefit, the use of concomitant chemoradiotherapy (CCRT) in patients with oropharyngeal squamous cell carcinoma (OPSCC) who are aged > 70 years is increasing. However, to the authors' knowledge, few studies to date have compared the outcomes of different systemic treatments in this population. METHODS: Records from 74 patients aged >= 70 years with stage III to stage IVB OPSCC who were undergoing CCRT from 2002 to 2013 at a single institution were reviewed. Patients were stratified according to the systemic therapy received, including cisplatin, carboplatin with either 5 fluorouracil or paclitaxel (CARB), or cetuximab to compare oncologic outcome and toxicity. RESULTS: The median follow-up was 36 months. The median age of the patients was 75.3 years (range, 70-91 years), with significantly older patients receiving cetuximab (P = .03). A total of 28, 20, and 26 patients, respectively, received CCRT with cisplatin, CARB, and cetuximab. RT interruptions of > 1 day were needed in 4% of patients receiving cisplatin, 20% of patients receiving CARB, and 15% of patients receiving cetuximab (P = .19). Unplanned hospitalizations during CCRT occurred in 25%, 55%, and 58%, respectively, of patients receiving cisplatin, CARB, and cetuximab (P = .03). There were 2 treatment-related deaths, both of which occurred among the patients who were treated with cetuximab. At 5 years, locoregional control was achieved in 100%, 88%, and 60% (P<.001), respectively, and the overall survival rate was 87%, 61%, and 47% (P = .03), respectively, among patients treated with cisplatin, CARB, and cetuximab. CONCLUSIONS: Toxicity from CCRT remains a challenge for older adults with OPSCC. Herein, the authors found no evidence that this toxicity was mitigated by treatment with cetuximab. Nevertheless, a subset of patients aged >=70 years appear to tolerate cisplatin-based treatment with acceptable toxicity and excellent outcomes. Further identification of this patient subgroup is crucial to optimize therapy for older patients with OPSCC. Cancer 2017;123:1345 1353. (c) 2016 American Cancer Society. PMID- 27984658 TI - No impact of breast magnetic resonance imaging on 15-year outcomes in patients with ductal carcinoma in situ or early-stage invasive breast cancer managed with breast conservation therapy. AB - BACKGROUND: For women undergoing breast conservation therapy (BCT), the added value of breast magnetic resonance imaging (MRI) at the time of initial diagnosis remains controversial. The current study was performed to determine long-term outcomes after BCT for women with and without pretreatment breast MRI. METHODS: Between 1992 and 2001, a total of 755 women with ductal carcinoma in situ or early-stage invasive breast cancer underwent breast-conserving surgery (with axillary lymph node staging for invasive carcinoma) followed by definitive breast radiotherapy. Evaluation at the time of the initial diagnosis included conventional mammography in all subjects and breast MRI in 215 women (28%). Clinical, pathologic, and treatment characteristics were comparable for patients with and without breast MRI. Outcomes were determined using the Kaplan-Meier method and compared using the log-rank method. RESULTS: At a median follow-up of 13.8 years, there were 49 local failures (15 women with and 34 women without breast MRI, respectively). The 15-year local failure rates were 8% for women with and 8% for women without MRI (P = .59). There also were no differences noted between women with and without breast MRI with regard to 15-year rates of overall survival (77% vs 71%; P = .24), freedom from distant metastases (86% vs 90%; P = .08), and contralateral breast cancer (10% vs 8%; P = .10). Multivariate analysis demonstrated no significant impact of breast MRI on local failure (P = .96). CONCLUSIONS: Breast MRI during the initial evaluation for BCT appears to have no significant impact on 15-year rates for local control, overall survival, freedom from distant metastases, or contralateral breast cancer. The routine use of pretreatment breast MRI is not indicated for patients undergoing BCT. Cancer 2017;123:1324-1332. (c) 2016 American Cancer Society. PMID- 27984660 TI - Recommendations for the standardization of bone marrow disease assessment and reporting in children with neuroblastoma on behalf of the International Neuroblastoma Response Criteria Bone Marrow Working Group. AB - BACKGROUND: The current study was conducted to expedite international standardized reporting of bone marrow disease in children with neuroblastoma and to improve equivalence of care. METHODS: A multidisciplinary International Neuroblastoma Response Criteria Bone Marrow Working Group was convened by the US National Cancer Institute in January 2012 with representation from Europe, North America, and Australia. Practical transferable recommendations to standardize the reporting of bone marrow disease were developed. RESULTS: To the authors' knowledge, the current study is the first to comprehensively present consensus criteria for the collection, analysis, and reporting of the percentage area of bone marrow parenchyma occupied by tumor cells in trephine-biopsies. The quantitative analysis of neuroblastoma content in bone marrow aspirates by immunocytology and reverse transcriptase-quantitative polymerase chain reaction are revised. The inclusion of paired-like homeobox 2b (PHOX2B) for immunohistochemistry and reverse transcriptase-quantitative polymerase chain reaction is recommended. Recommendations for recording bone marrow response are provided. The authors endorse the quantitative assessment of neuroblastoma cell content in bilateral core needle biopsies-trephines and aspirates in all children with neuroblastoma, with the exception of infants, in whom the evaluation of aspirates alone is advised. It is interesting to note that 5% disease is accepted as an internationally achievable level for disease assessment. CONCLUSIONS: The quantitative assessment of neuroblastoma cells is recommended to provide data from which evidence-based numerical criteria for the reporting of bone marrow response can be realized. This is particularly important in the minimal disease setting and when neuroblastoma detection in bone marrow is intermittent, where clinical impact has yet to be validated. The wide adoption of these harmonized criteria will enhance the ability to compare outcomes from different trials and facilitate collaborative trial design. Cancer 2017;123:1095-1105. (c) 2016 American Cancer Society. PMID- 27984662 TI - Long-term structural and biomass dynamics of virgin Tsuga canadensis-Pinus strobus forests after hurricane disturbance. AB - The development of old-growth forests in northeastern North America has largely been within the context of gap-scale disturbances given the rarity of stand replacing disturbances. Using the 10-ha old-growth Harvard Tract and its associated 90-year history of measurements, including detailed surveys in 1989 and 2009, we document the long-term structural and biomass development of an old growth Tsuga canadensis-Pinus strobus forest in southern New Hampshire, USA following a stand-replacing hurricane in 1938. Measurements of aboveground biomass pools were integrated with data from second- and old-growth T. canadensis forests to evaluate long-term patterns in biomass development following this disturbance. Ecosystem structure across the Tract prior to the hurricane exhibited a high degree of spatial heterogeneity with the greatest levels of live tree basal area (70-129 m2 /ha) on upper west-facing slopes where P. strobus was dominant and intermixed with T. canadensis. Live-tree biomass estimates for these stratified mixtures ranged from 159 to 503 Mg/ha at the localized, plot scale (100 m2 ) and averaged 367 Mg/ha across these portions of the landscape approaching the upper bounds for eastern forests. Live-tree biomass 71 years after the hurricane is more uniform and lower in magnitude, with T. canadensis currently the dominant overstory tree species throughout much of the landscape. Despite only one living P. strobus stem in the 2009 plots (and fewer than five stems known across the entire 10-ha area), the detrital legacy of this species is pronounced with localized accumulations of coarse woody debris exceeding 237.7 404.2 m3 /ha where this species once dominated the canopy. These patterns underscore the great sizes P. strobus attained in pre-European landscapes and its great decay resistance relative to its forest associates. Total aboveground biomass pools in this 71-year-old forest (255 Mg/ha) are comparable to those in modern old-growth ecosystems in the region that also lack abundant white pine. Results highlight the importance of disturbance legacies in affecting forest structural conditions over extended periods following stand-replacing events and underscore that post-disturbance salvage logging can alter ecosystem development for decades. Moreover, the dominant role of old-growth P. strobus in live and detrital biomass pools before and after the hurricane, respectively, demonstrate the disproportionate influence this species likely had on carbon storage at localized scales prior to the widespread, selective harvesting of large P. strobus across the region in the 18th and 19th centuries. PMID- 27984664 TI - Sonofragmentation of Ionic Crystals. AB - Mechanochemistry deals with the interface between the chemical and the mechanical worlds and explores the physical and chemical changes in materials caused by an input of mechanical energy. As such, the chemical and physical effects of ultrasound, i.e., sonochemistry, are forms of mechanochemistry. In this paper, the fragmentation of ionic crystals during ultrasonic irradiation of slurries has been quantitatively investigated: the rate of fragmentation depends strongly on the strength of the materials (as measured by Vickers hardness or by Young's modulus). This is a mechanochemical extension of the Bell-Evans-Polanyi Principle or Hammond's Postulate: activation energies for solid fracture correlate with binding energies of solids. Sonofragmentation is unaffected by slurry loading or liquid vapor pressure, but is suppressed by increasing liquid viscosity. The mechanism of the particle breakage is consistent with a direct interaction between the shockwaves created by the ultrasound (through acoustic cavitation) and the solid particles in the slurry. Fragmentation is proposed to occur from defects in the solids induced by compression-expansion, bending, or torsional distortions of the crystals. PMID- 27984663 TI - Community assembly and the functioning of ecosystems: how metacommunity processes alter ecosystems attributes. AB - Recent work linking community structure and ecosystem function has primarily focused on the effects of local species richness but has neglected the dispersal dependent processes of community assembly that are ultimately involved in determining community structure and its relation to ecosystems. Here we combine simple consumer-resource competition models and metacommunity theory with discussion of case studies to outline how spatial processes within metacommunities can alter community assembly and modify expectations about how species diversity and composition influence ecosystem attributes at local scales. We argue that when community assembly is strongly limited by dispersal, this can constrain ecosystem functioning by reducing positive selection effects (reducing the probability of the most productive species becoming dominant) even though it may often also enhance complementarity (favoring combinations of species that enhance production even though they may not individually be most productive). Conversely, excess dispersal with strong source-sink relations among heterogeneous habitats can reduce ecosystem functioning by swamping local filters that would normally favor better-suited species. Ecosystem function is thus most likely maximized at intermediate levels of dispersal where both of these effects are minimized. In this scenario, we find that the selection effect is maximized, while complementarity is often reduced and local diversity may often be relatively low. Our synthesis emphasizes that it is the entire set of community assembly processes that affect the functioning of ecosystems, not just the part that determines local species richness. PMID- 27984666 TI - Functionalization of Hydrogenated Chemical Vapour Deposition-Grown Graphene by On Surface Chemical Reactions. AB - The reactivity of hydrogenated graphene when treated with oxidising agents, KMnO4 and KIO4 , as well as alkylated with benzyl bromide (BnBr) was studied. The probed reactions are strictly limited to the partly hydrogenated form of graphene in which most of the hydrogen atoms are located in activated benzylic/allylic positions. This, in turn, clearly demonstrates the presence of hydrogen attached to the graphene lattice. Attachment of the benzyl group was also unequivocally demonstrated by characteristic vibrations recorded in the surface-enhanced Raman spectra, and all reactions were shown to proceed solely on hydrogenated graphene as evidenced by the comparison with pristine chemical vapour deposition-grown graphene. PMID- 27984665 TI - Coastal regime shifts: rapid responses of coastal wetlands to changes in mangrove cover. AB - Global changes are causing broad-scale shifts in vegetation communities worldwide, including coastal habitats where the borders between mangroves and salt marsh are in flux. Coastal habitats provide numerous ecosystem services of high economic value, but the consequences of variation in mangrove cover are poorly known. We experimentally manipulated mangrove cover in large plots to test a set of linked hypotheses regarding the effects of changes in mangrove cover. We found that changes in mangrove cover had strong effects on microclimate, plant community, sediment accretion, soil organic content, and bird abundance within 2 yr. At higher mangrove cover, wind speed declined and light interception by vegetation increased. Air and soil temperatures had hump-shaped relationships with mangrove cover. The cover of salt marsh plants decreased at higher mangrove cover. Wrack cover, the distance that wrack was distributed from the water's edge, and sediment accretion decreased at higher mangrove cover. Soil organic content increased with mangrove cover. Wading bird abundance decreased at higher mangrove cover. Many of these relationships were non-linear, with the greatest effects when mangrove cover varied from zero to intermediate values, and lesser effects when mangrove cover varied from intermediate to high values. Temporal and spatial variation in measured variables often peaked at intermediate mangrove cover, with ecological consequences that are largely unexplored. Because different processes varied in different ways with mangrove cover, the "optimum" cover of mangroves from a societal point of view will depend on which ecosystem services are most desired. PMID- 27984661 TI - A global database of ant species abundances. AB - What forces structure ecological assemblages? A key limitation to general insights about assemblage structure is the availability of data that are collected at a small spatial grain (local assemblages) and a large spatial extent (global coverage). Here, we present published and unpublished data from 51 ,388 ant abundance and occurrence records of more than 2,693 species and 7,953 morphospecies from local assemblages collected at 4,212 locations around the world. Ants were selected because they are diverse and abundant globally, comprise a large fraction of animal biomass in most terrestrial communities, and are key contributors to a range of ecosystem functions. Data were collected between 1949 and 2014, and include, for each geo-referenced sampling site, both the identity of the ants collected and details of sampling design, habitat type, and degree of disturbance. The aim of compiling this data set was to provide comprehensive species abundance data in order to test relationships between assemblage structure and environmental and biogeographic factors. Data were collected using a variety of standardized methods, such as pitfall and Winkler traps, and will be valuable for studies investigating large-scale forces structuring local assemblages. Understanding such relationships is particularly critical under current rates of global change. We encourage authors holding additional data on systematically collected ant assemblages, especially those in dry and cold, and remote areas, to contact us and contribute their data to this growing data set. PMID- 27984667 TI - Optimization of on-line hydrogen stable isotope ratio measurements of halogen- and sulfur-bearing organic compounds using elemental analyzer-chromium/high temperature conversion isotope ratio mass spectrometry (EA-Cr/HTC-IRMS). AB - RATIONALE: Accurate hydrogen isotopic analysis of halogen- and sulfur-bearing organics has not been possible with traditional high-temperature conversion (HTC) because the formation of hydrogen-bearing reaction products other than molecular hydrogen (H2 ) is responsible for non-quantitative H2 yields and possible hydrogen isotopic fractionation. Our previously introduced, new chromium-based EA Cr/HTC-IRMS (Elemental Analyzer-Chromium/High-Temperature Conversion Isotope Ratio Mass Spectrometry) technique focused primarily on nitrogen-bearing compounds. Several technical and analytical issues concerning halogen- and sulfur bearing samples, however, remained unresolved and required further refinement of the reactor systems. METHODS: The EA-Cr/HTC reactor was substantially modified for the conversion of halogen- and sulfur-bearing samples. The performance of the novel conversion setup for solid and liquid samples was monitored and optimized using a simultaneously operating dual-detection system of IRMS and ion trap MS. The method with several variants in the reactor, including the addition of manganese metal chips, was evaluated in three laboratories using EA-Cr/HTC-IRMS (on-line method) and compared with traditional uranium-reduction-based conversion combined with manual dual-inlet IRMS analysis (off-line method) in one laboratory. RESULTS: The modified EA-Cr/HTC reactor setup showed an overall H2 recovery of more than 96% for all halogen- and sulfur-bearing organic compounds. All results were successfully normalized via two-point calibration with VSMOW SLAP reference waters. Precise and accurate hydrogen isotopic analysis was achieved for a variety of organics containing F-, Cl-, Br-, I-, and S-bearing heteroelements. The robust nature of the on-line EA-Cr/HTC technique was demonstrated by a series of 196 consecutive measurements with a single reactor filling. CONCLUSIONS: The optimized EA-Cr/HTC reactor design can be implemented in existing analytical equipment using commercially available material and is universally applicable for both heteroelement-bearing and heteroelement-free organic-compound classes. The sensitivity and simplicity of the on-line EA-Cr/HTC IRMS technique provide a much needed tool for routine hydrogen-isotope source tracing of organic contaminants in the environment. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27984668 TI - Survival and Growth of Probiotic Lactic Acid Bacteria in Refrigerated Pickle Products. AB - We examined 10 lactic acid bacteria that have been previously characterized for commercial use as probiotic cultures, mostly for dairy products, including 1 Pediococcus and 9 Lactobacilli. Our objectives were to develop a rapid procedure for determining the long-term survivability of these cultures in acidified vegetable products and to identify suitable cultures for probiotic brined vegetable products. We therefore developed assays to measure acid resistance of these cultures to lactic and acetic acids, which are present in pickled vegetable products. We used relatively high acid concentrations (compared to commercial products) of 360 mM lactic acid and 420 mM acetic acid to determine acid resistance with a 1 h treatment. Growth rates were measured in a cucumber juice medium at pH 5.3, 4.2, and 3.8, at 30 degrees C and 0% to 2% NaCl. Significant differences in acid resistance and growth rates were found among the 10 cultures. In general, the acid resistant strains had slower growth rates than the acid sensitive strains. Based on the acid resistance data, selected cultures were tested for long-term survival in a simulated acidified refrigerated cucumber product. We found that one of the most acid resistant strains (Lactobacillus casei) could survive for up to 63 d at 4 degrees C without significant loss of viability at 108 CFU/mL. These data may aid in the development of commercial probiotic refrigerated pickle products. PMID- 27984669 TI - The influence of Ringer's lactate or HES 130/0.4 administration on the integrity of the small intestinal mucosa in a pig hemorrhagic shock model under general anesthesia. AB - OBJECTIVE: To determine the effect of fluid resuscitation with 2 different physiological solutions, Ringer's lactate (RL) and hydroxyethyl starch (HES) 130/0.4, on histological lesions of the small intestinal mucosa in anesthetized pigs subjected to severe acute bleeding. DESIGN: Prospective experimental study. SETTING: University teaching hospital. ANIMALS: Twenty-eight healthy Large White pigs, 3 months of age. INTERVENTIONS: Pigs were subjected to severe acute bleeding (30 mL/kg) under total intravenous anesthesia with propofol and remifentanil. Pigs were randomly allocated to 3 groups: Group 1 (n = 11) received RL solution (25 mL/kg) after bleeding; Group 2 (n = 11) received HES 130/0.4 solution (20 mL/kg) after bleeding; and Group 3 (n = 6) volume replacement nor induced bleeding. Pigs were euthanized and the small intestine was harvested for histopathological analysis. MEASUREMENTS AND MAIN RESULTS: The small intestine was histologically evaluated and the presence of the following lesions were characterized: edema, congestion, hyperemia, hemorrhage, inflammatory infiltration, cellular degeneration, necrosis, and epithelial detachment. Mucosal loss percentage (%ML) and crypt:interstitium ratio (C:I) were also assessed. In the duodenum, jejunum, and ileum, and the entire small intestine, the %ML was significantly higher in Group 1, than in Groups 2 and 3. Hyperemia in the small intestine was significantly higher in pigs resuscitated with HES 130/0.4 compared to pigs resuscitated with RL. CONCLUSIONS AND CLINICAL RELEVANCE: In a setting of controlled hemorrhage, resuscitation with HES 130/0.4 was associated with a lower percentage of mucosal loss on the small intestine, compared with resuscitation with RL solution. Our study also suggests that the duodenum may be more sensitive to hypovolemia induced by severe hemorrhage. PMID- 27984670 TI - Overexpression of the triose phosphate translocator (TPT) complements the abnormal metabolism and development of plastidial glycolytic glyceraldehyde-3 phosphate dehydrogenase mutants. AB - The presence of two glycolytic pathways working in parallel in plastids and cytosol has complicated the understanding of this essential process in plant cells, especially the integration of the plastidial pathway into the metabolism of heterotrophic and autotrophic organs. It is assumed that this integration is achieved by transport systems, which exchange glycolytic intermediates across plastidial membranes. However, it is unknown whether plastidial and cytosolic pools of 3-phosphoglycerate (3-PGA) can equilibrate in non-photosynthetic tissues. To resolve this question, we employed Arabidopsis mutants of the plastidial glycolytic isoforms of glyceraldehyde-3-phosphate dehydrogenase (GAPCp) that express the triose phosphate translocator (TPT) under the control of the 35S (35S:TPT) or the native GAPCp1 (GAPCp1:TPT) promoters. TPT expression under the control of both promoters complemented the vegetative developmental defects and metabolic disorders of the GAPCp double mutants (gapcp1gapcp2). However, as the 35S is poorly expressed in the tapetum, full vegetative and reproductive complementation of gapcp1gapcp2 was achieved only by transforming this mutant with the GAPCp1:TPT construct. Our results indicate that the main function of GAPCp is to supply 3-PGA for anabolic pathways in plastids of heterotrophic cells and suggest that the plastidial glycolysis may contribute to fatty acid biosynthesis in seeds. They also suggest a 3-PGA deficiency in the plastids of gapcp1gapcp2, and that 3-PGA pools between cytosol and plastid do not equilibrate in heterotrophic cells. PMID- 27984672 TI - Effectiveness of Interactive Self-Management Interventions in Individuals With Poorly Controlled Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials. AB - AIMS: To identify, assess, and summarize available scientific evidence on the effectiveness of interactive self-management interventions on glycemic control and patient-centered outcomes in individuals with poorly controlled type 2 diabetes. METHODS: Major English and Chinese electronic databases including Medline, EMBASE, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, and WanFang Data were searched to identify randomized controlled trials that reported the effectiveness of interactive self-management interventions in individuals with poorly controlled type 2 diabetes (glycated hemoglobin [HbA1c] >= 7.5% or 58 mmol/mol), from inception to June 2015. Data extraction and risk-of-bias assessment were performed by two reviewers independently. Meta-analysis was performed using Review Manager 5.3. RESULTS: A total of 16 trials with 3,545 participants were included in the meta-analysis. Interactive self-management interventions could have a beneficial effect in individuals with poorly controlled type 2 diabetes in reducing HbA1c (mean difference: -0.43%, 95% CI: -0.67% to -0.18%), improving diabetes knowledge (standardized mean difference [SMD]: 0.30, 95% CI: 0.03 to 0.58), enhancing self efficacy (SMD: 0.29, 95% CI: 0.14 to 0.44), and reducing diabetes-related distress (SMD: -0.21, 95% CI: -0.39 to -0.04). Self-management interventions supported with theory and structured curriculum showed desirable results in glycemic control. The behavioral change techniques, including providing feedback on performance, problem-solving, and action planning, were associated with a significant reduction in HbA1c. LINKING EVIDENCE TO ACTION: Individuals with poorly controlled type 2 diabetes could benefit from interactive self-management interventions. Interventions targeting patients with poorly controlled diabetes, those who are at the greatest risk of developing complications, should be prioritized. Our findings indicate that providing feedback on performance, problem-solving, and action planning are promising behavioral change techniques specifically for individuals with poor glycemic control. PMID- 27984671 TI - Towards Versatile and Sustainable Hydrogen Production through Electrocatalytic Water Splitting: Electrolyte Engineering. AB - Recent advances in power generation from renewable resources necessitate conversion of electricity to chemicals and fuels in an efficient manner. Electrocatalytic water splitting is one of the most powerful and widespread technologies. The development of highly efficient, inexpensive, flexible, and versatile water electrolysis devices is desired. This review discusses the significance and impact of the electrolyte on electrocatalytic performance. Depending on the circumstances under which the water splitting reaction is conducted, the required solution conditions, such as the identity and molarity of ions, may significantly differ. Quantitative understanding of such electrolyte properties on electrolysis performance is effective to facilitate the development of efficient electrocatalytic systems. The electrolyte can directly participate in reaction schemes (kinetics), affect electrode stability, and/or indirectly impact the performance by influencing the concentration overpotential (mass transport). This review aims to guide fine-tuning of the electrolyte properties, or electrolyte engineering, for (photo)electrochemical water splitting reactions. PMID- 27984673 TI - Co-occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma. AB - Ganglioglioma (GG) is a grade I tumor characterized by alterations in the MAPK pathway, including BRAF V600E mutation. Recently, diffuse midline glioma with an H3 K27M mutation was added to the WHO 2016 classification as a new grade IV entity. As co-occurrence of H3 K27M and BRAF V600E mutations has been reported in midline tumors and anaplastic GG, we searched for BRAF V600E and H3 K27M mutations in a series of 54 paediatric midline grade I GG (midline GG) to determine the frequency of double mutations and its relevance for prognosis. Twenty-seven patients (50%) possessed the BRAF V600E mutation. The frequency of the co-occurrence of H3F3A/BRAF mutations at diagnosis was 9.3%. No H3 K27M mutation was detected in the absence of the BRAF V600E mutation. Double immunostaining revealed that BRAF V600E and H3 K27M mutant proteins were present in both the glial and neuronal components. Immunopositivity for the BRAF V600E mutant protein correlated with BRAF mutation status as detected by massARRAY or digital droplet PCR. The median follow-up of patients with double mutation was 4 years. One patient died of progressive disease 8 years after diagnosis, whereas the four other patients were all alive with stable disease at the last clinical follow-up (at 9 months, 1 year and 7 years) without adjuvant therapy. We demonstrate in this first series of midline GGs that the H3 K27M mutation can occur in association with the BRAF V600E mutation in grade I glioneuronal tumors. Despite the presence of H3 K27M mutations, these cases should not be graded and treated as grade IV tumors because they have a better spontaneous outcome than classic diffuse midline H3 K27M-mutant glioma. These data suggest that H3 K27M cannot be considered a specific hallmark of grade IV diffuse gliomas and highlight the importance of integrated histomolecular diagnosis in paediatric brain tumors. PMID- 27984675 TI - Exercise Interventions for Preventing Falls Among Older People in Care Facilities: A Meta-Analysis. AB - BACKGROUND: Falls in older people are a common problem, often leading to considerable morbidity. However, the overall effect of exercise interventions on fall prevention in care facilities remains controversial. AIMS: To evaluate the effectiveness of exercise interventions on the rate of falls and number of fallers in care facilities. METHODS: A meta-analysis was conducted of randomized controlled trials published up to December 2014. Eight databases were searched including Ovid-Medline, Embase, CINAHL, Cochrane Library, KoreaMed, KMbase, KISS, and KisTi. Two investigators independently extracted data and assessed study quality. RESULTS: Twenty-one studies were selected, that included 5,540 participants. Fifteen studies included exercise as a single intervention, whereas the remaining six included exercise combined with two or more fall interventions tailored to each resident's fall risk (i.e., medication review, environmental modification or staff education). Meta-analysis showed that exercise had a preventive effect on the rate of falls (risk ratio [RR] 0.81, 95% CI 0.68-0.97). This effect was stronger when exercise combined with other fall interventions on the rate of falls (RR 0.61, 95% CI 0.52-0.72) and on the number of fallers (RR 0.85, 95% CI 0.77-0.95). Exercise interventions including balance training (i.e., gait, balance, and functional training; or balance and strength) resulted in reduced the rate of falls. Sensitivity analyses indicated that exercise interventions resulted in reduced numbers of recurrent fallers (RR 0.71, 95% CI 0.53-0.97). LINKING EVIDENCE TO ACTION: This review provides an important basis for developing evidence-based exercise intervention protocols for older people living in care facilities. Exercise programs, which are combined with tailored other fall interventions and challenge balance training to improve balance skills, should be applied to frail older people with functional limitations in institutional settings. PMID- 27984674 TI - Abortion Stigma Among Low-Income Women Obtaining Abortions in Western Pennsylvania: A Qualitative Assessment. AB - CONTEXT: Abortion stigma may cause psychological distress in women who are considering having an abortion or have had one. This phenomenon has been relatively underexplored in low-income women, who may already be at an increased risk for poor abortion-related outcomes because of difficulties accessing timely and safe abortion services. METHODS: A qualitative study conducted between 2010 and 2013 used semistructured interviews to explore pregnancy intentions among low income women recruited from six reproductive health clinics in Western Pennsylvania. Transcripts from interviews with 19 participants who were planning to terminate a pregnancy or had had an abortion in the last two weeks were examined through content analysis to identify the range of attitudes they encountered that could contribute to or reflect abortion stigma, the sources of these attitudes and women's responses to them. RESULTS: Women commonly reported that partners, family members and they themselves held antiabortion attitudes. Such attitudes communicated that abortion is morally reprehensible, a rejection of motherhood, rare and thus potentially deviant, detrimental to future fertility and an irresponsible choice. Women reacted to external and internal negative attitudes by distinguishing themselves from other women who obtain abortions, experiencing negative emotions, and concealing or delaying their abortions. CONCLUSIONS: Women's reactions to antiabortion attitudes may perpetuate abortion stigma. Further research is needed to inform interventions to address abortion stigma and improve women's abortion experiences. PMID- 27984676 TI - Quantitative Prediction of Drug-Drug Interactions Involving Inhibitory Metabolites by Physiologically Based Pharmacokinetic Models: Is it Worth It? PMID- 27984678 TI - Assessing the ecosystem-level consequences of a small-scale artisanal kelp fishery within the context of climate-change. AB - Coastal communities worldwide rely on small-scale artisanal fisheries as a means of increasing food security and alleviating poverty. Even small-scale fishing activities, however, are prone to resource depletion and environmental degradation, which can erode livelihoods in the long run. Thus, there is a pressing need to identify viable and resilient artisanal fisheries, and generate knowledge to support management within the context of a rapidly changing climate. We examined the ecosystem-level consequences of an artisanal kelp fishery (Macrocystis pyrifera), finding small-scale harvest of this highly productive species poses minimal impacts on kelp recovery rates, survival, and biomass dynamics, and abundances of associated commercial and culturally important fish species. These results suggest that small-scale harvest poses minimal trade-offs for the other economic benefits provided by these ecosystems, and their inherent, spiritual, and cultural value to humans. However, we detected a negative impact of warmer seawater temperatures on kelp recovery rates following harvest, indicating that the viability of harvest, even at small scales, may be threatened by future increases in global ocean temperature. This suggests that negative impacts of artisanal fisheries may be more likely to arise in the context of a warming climate, further highlighting the widespread effects of global climate change on coastal fisheries and livelihoods. PMID- 27984677 TI - Brassinosteroid signaling converges with SUPPRESSOR OF PHYTOCHROME B4-#3 to influence the expression of SMALL AUXIN UP RNA genes and hypocotyl growth. AB - Interactions between signaling pathways help guide plant development. In this study, we found that brassinosteroid (BR) signaling converges with SUPPRESSOR OF PHYTOCHROME B4-#3 (SOB3) to influence both the transcription of genes involved in cell elongation and hypocotyl growth. Specifically, SOB3 mutant hypocotyl phenotypes, which are readily apparent when the seedlings are grown in dim white light, were attenuated by treatment with either brassinolide (BL) or the BR biosynthesis inhibitor brassinazole (BRZ). Hypocotyls of SOB3 mutant seedlings grown in white light with a higher fluence rate also exhibited altered sensitivities to BL, further suggesting a connection to BR signaling. However, the impact of BL treatment on SOB3 mutants grown in moderate-intensity white light was reduced when polar auxin transport was inhibited. BL treatment enhanced transcript accumulation for all six members of the SMALL AUXIN UP RNA19 (SAUR19) subfamily, which promote cell expansion, are repressed by SOB3 and light, and are induced by auxin. Conversely, BRZ inhibited the expression of SAUR19 and its homologs. Expression of these SAURs was also enhanced in lines expressing a constitutively active form of the BR signaling component BZR1, further indicating that the transcription of SAUR19 subfamily members are influenced by this hormone signaling pathway. Taken together, these results indicate that SOB3 and BR signaling converge to influence the transcription of hypocotyl growth-promoting SAUR19 subfamily members. PMID- 27984679 TI - Making the cut: Innovative methods for optimizing perfusion-based migration assays. AB - Application of fluid shear stress to adherent cells dramatically influences their cytoskeletal makeup and differentially regulates their migratory phenotype. Because cytoskeletal rearrangements are necessary for cell motility and migration, preserving these adaptations under in vitro conditions and in the presence of fluid flow are physiologically essential. With this in mind, parallel plate flow chambers and microchannels are often used to conduct in vitro perfusion experiments. However, both of these systems currently lack capacity to accurately study cell migration in the same location where cells were perfused. The most common perfusion/migration assays involve cell perfusion followed by trypsinization which can compromise adaptive cytoskeletal geometry and lead to misleading phenotypic conclusions. The purpose of this study was to quantitatively highlight some limitations commonly found with currently used cell migration approaches and to introduce two new advances which use additive manufacturing (3D printing) or laser capture microdissection (LCM) technology. The residue-free 3D printed insert allows accurate cell seeding within defined areas, increases cell yield for downstream analyses, and more closely resembles the reported levels of fluid shear stress calculated with computational fluid dynamics as compared to other residue-free cell seeding techniques. The LCM approach uses an ultraviolet laser for "touchless technology" to rapidly and accurately introduce a custom-sized wound area in otherwise inaccessible perfusion microchannels. The wound area introduced by LCM elicits comparable migration characteristics compared to traditional pipette tip-induced injuries. When used in perfusion experiments, both of these newly characterized tools were effective in yielding similar results yet without the limitations of the traditional modalities. These innovative methods provide valuable tools for exploring mechanisms of clinically important aspects of cell migration fundamental to the pathogenesis of many flow-mediated disorders and are applicable to other perfusion-based models where migration is of central importance. (c) 2016 International Society for Advancement of Cytometry. PMID- 27984680 TI - Mitochondrial activity in the frontal cortex area 8 and angular gyrus in Parkinson's disease and Parkinson's disease with dementia. AB - Altered mitochondrial function is characteristic in the substantia nigra in Parkinson's disease (PD). Information about mitochondria in other brain regions such as the cerebral cortex is conflicting mainly because most studies have not contemplated the possibility of variable involvement depending on the region, stage of disease progression and clinical symptoms such as the presence or absence of dementia. RT-qPCR of 18 nuclear mRNAs encoding subunits of mitochondrial complexes and 12 mRNAs encoding energy metabolism-related enzymes; western blotting of mitochondrial proteins; and analysis of enzymatic activities of complexes I, II, II, IV and V of the respiratory chain were assessed in frontal cortex area 8 and the angular gyrus of middle-aged individuals (MA), and those with incidental PD (iPD), long-lasting PD with parkinsonism without dementia (PD) and long-lasting PD with dementia (PDD). Up-regulation of several genes was found in frontal cortex area 8 in PD when compared with MA and in the angular gyrus in iPD when compared with MA. Marked down-regulation of genes encoding mitochondrial subunits and energy metabolism-related enzymes occurs in frontal cortex but only of genes coding for energy metabolism-related enzymes in the angular gyrus in PDD. Significant decrease in the protein expression levels of several mitochondrial subunits encoded by these genes occurs in frontal cortex area 8 and angular gyrus in PDD. Moreover, expression of MT-ND1 which is encoded by mitochondrial DNA is also reduced in PDD. Reduced enzymatic activity of complex III in frontal cortex area 8 and angular gyrus is observed in PD, but dramatic reduction in the activity of complexes I, II, II and IV in both regions characterizes PDD. Dementia in the context of PD is linked to region-specific deregulation of genomic genes encoding subunits of mitochondrial complexes and to marked reduction in the activity of mitochondrial complexes I, II, III and IV. PMID- 27984681 TI - Movements of a deep-water fish: establishing marine fisheries management boundaries in coastal Arctic waters. AB - Management boundaries that define populations or stocks of fish form the basis of fisheries planning. In the Arctic, decreasing sea ice extent is driving increasing fisheries development, highlighting the need for ecological data to inform management. In Cumberland Sound, southwest Baffin Island, an indigenous community fishery was established in 1987 targeting Greenland halibut (Reinhardtius hippoglossoides) through the ice. Following its development, the Cumberland Sound Management Boundary (CSMB) was designated and a total allowable catch (TAC) assigned to the fishery. The CSMB was based on a sink population of Greenland halibut resident in the northern section of the Sound. Recent fishing activities south of the CSMB, however, raised concerns over fish residency, the effectiveness of the CSMB and the sustainability of the community-based winter fishery. Through acoustic telemetry monitoring at depths between 400 and 1200 m, and environmental and fisheries data, this study examined the movement patterns of Greenland halibut relative to the CSMB, the biotic and abiotic factors driving fish movement and the dynamics of the winter fishery. Greenland halibut undertook clear seasonal movements between the southern and northern regions of the Sound driven by temperature, dissolved oxygen, and sea ice cover with most fish crossing the CSMB on an annual basis. Over the lifespan of the fishery, landfast ice cover initially declined and then became variable, limiting accessibility to favored fisher locations. Concomitantly, catch per unit effort declined, reflecting the effect of changing ice conditions on the location and effort of the fishery. Ultimately, these telemetry data revealed that fishers now target less productive sites outside of their favored areas and, with continued decreases in ice, the winter fishery might cease to exist. In addition, these novel telemetry data revealed that the CSMB is ineffective and led to its relocation to the entrance of the Sound in 2014. The community fishery can now develop an open-water fishery in addition to the winter fishery to exploit the TAC, which will ensure the longevity of the fishery under projected climate change scenarios. Telemetry shows great promise as a tool for understanding deep water species and for directly informing fisheries management of these ecosystems that are inherently complex to study. PMID- 27984683 TI - [Etiological agents more common in primary hip and knee joint replacement infections in older adults]. AB - BACKGROUND: The most common etiological agents in periprosthetic infections are Escherichia coli and Staphylococcus aureus. The frequency of these infections are found in knee replacement with 0.68 to 1.60% compared to the hip with 0.67 to 2.4%. OBJECTIVE: To identify what are the most common etiologic agents in periprosthetic infections in elderly patients with primary hip and knee surgery. MATERIAL AND METHODS: An observational study, transverse and retrospective case series was performed in a period from June 2011 to December 2014, patients over 60 years with a diagnosis of periprosthetic infection by two positive cultures with antibiograma. RESULTS: 62 patients were evaluated 59.7% were infections of knee and hip 40.3%, 59% were infections by Escherichia coli and Staphylococcus aureus 22%. The best sensitivity reported antibiotic trimethoprim sulfamethoxazole was 40.3%. The largest penicillin G resistance 32.2%. CONCLUSION: The most common causative agents were Escherichia coli and Staphylococcus aureus. PMID- 27984684 TI - [Anterior knee pain in knee arthroplasty with or without a patellar component]. AB - INTRODUCTION: The appearance of patellofemoral pain after a knee arthroplasty, particularly in rheumatic diseases, resulted in the incorporation of the substitution of the patellar component in all designs. The replacement of the patella became a standard part of knee arthroplasty, but the controversy over whether to restore it or not continues among orthopedists that perform knee arthroplasties. OBJECTIVE: To analyze the incidence of anterior knee pain in patients who underwent primary knee arthroplasty with or without replacement of the patellar component. MATERIAL AND METHODS: Observational, retrospective, descriptive and transversal study from January 2011 to December 2013. RESULTS: A total of 54 patients were included, 12 men (with an average age of 63 years) and 42 women (with an average age of 71 years), totaling 64 knees that were surgically intervened. CONCLUSION: This study found no significant difference in anterior knee pain and in the function of the patellofemoral joint and the knee in the groups of patients who were tested with the different scales. PMID- 27984685 TI - [Prevalence and frequency of factors associated with infection in patients older than 18 years with closed fractures]. AB - INTRODUCTION: Surgical site infection (ISO) is the most common nosocomial infection and is a process associated with multiple factors, which together generate a condition that directly affects the welfare of the patient. MATERIAL AND METHODS: Cross-sectional study, conducted over 1 year period, the sample size was established for all patients who met the inclusion criteria. An instrument takes the variables; double tabulation of patients is performed in Excel 2013 and data are analyzed in Stata version 11. RESULTS: The average age was 44.3 +/- 18.8 years and the male: female ratio is 1.7:1. Clinical features, lower limbs are the most affected and 21.9 % of cases affect the femur. A prevalence of 6.6 % was found, being the most common deep infection classification. Staphylococcus aureus was cultured in 38.5% of which 40% were methicillin sensible. CONCLUSION: ISO prevalence in patients with closed fractures in HUS is 6.6% higher compared with literature data. The findings of this study it was established that hemoglobin below 10 g/dl, transfusion, reoperation and surgical risk ASA were associated statistically with ISO. PMID- 27984686 TI - [Surgical treatment of malignant primary tumors of the pelvis on Ennekings zone II]. AB - INTRODUCTION: Surgical treatment of malignant bone tumors of the pelvis with periacetabular involvement is constantly evolving. Even though acetabular reconstructions improve quality of life without impairing cancer control, they are not complication free. Our purpose is to describe the functional outcomes and surgical complications of different reconstructive techniques for Enneking zone II tumors. MATERIAL AND METHODS: Fifteen patients underwent surgery for malignant pelvic bone tumors between 2002 and 2012. Seven patients were retrospectively evaluated according to the Enneking and Dunham classification and were found to have periacetabular involvement, as follows: 3 were type II; 1 types I + II; 2 types II + III, and one types I + II + III. Five patients had a standard chondrosarcoma and 2 osteosarcoma. Patients included 4 males and 3 females; mean age was 43 years. The minimum follow-up period was 12 months (mean 6.14 years). All of them underwent cancer resection with periacetabular reconstruction: massive osteochondral allograft in 3 patients, structural allograft and hip arthroplasty in 2 patients, and prosthesis with iliac anchoring in 2. They were clinically, radiologically and functionally evaluated with the MSTS scale (1993). RESULTS: The mean MSTS score 6 months after surgery was 20.71 (69%). Five patients (71.4%) had surgical complications: 2 dislocations of the native femoral head on the allograft; one aseptic prosthetic dislodgement, and 2 deep infections. All patients had free intraoperative borders. CONCLUSIONS: Acetabular reconstructions after oncologic resection for malignant bone tumors seem to provide good functional outcomes. However, only selected cases should undergo surgeries associated with a high complication rate. PMID- 27984687 TI - [Three successive fractures of different hip femoral stems on the same patient]. AB - The clinical case of an 80-year-old female who suffered three fractures in uncemented stems implanted in her right hip in a period of three years is presented. A fracture occurred in the prosthetic neck and the other two at the juncture of the conical and cylindrical stem portion, coinciding with the metaphyseal-diaphyseal junction of the femur. The main causes of the failure were an increasing concentration of forces at the level of the implant as a consequence of the increased length of the neck and lateralization of the femur (offset). Other causes that have contributed to this prosthetic failure are analyzed. PMID- 27984688 TI - [Ankle fracture in adolescents: triplanar injury associated to fracture of leg]. AB - INTRODUCTION: the vast mayority of epiphyseal children fractures could be classified according to Salter Harris. There are other types of patterns such as triplanar and Tillaux fractures. The former is a complex type with fracture lines in sagital, axial and frontal planes. These fractures have main complications such as early epiphyseal closure, mechanical axis malalignment and gait disturbances. A clinical case is pictured which had a tibial shaft and ipsilateral triplanar fracture, this complex scenario of rare ocurrence was treated with reduction and osteosynthesis of both fractures. This clinical case is shown to help in the management of these injuries that with the early sport practice initiation, could appear more frequently. PMID- 27984689 TI - [Congenital knee dislocation: case report]. AB - Congenital knee dislocation is an infrequent condition with unknown etiology. In some cases it occurs as an isolated condition, while in others it coexists with associated conditions or syndromes. The treatment of congenital knee dislocation is driven by the severity and flexibility of the deformity. The literature includes from serial casting or the Pavlik harness to quadriceps tendon plasty or femoral osteotomies. We report herein the case of a congenital dislocation treated with serial casting with a good outcome. PMID- 27984690 TI - [Pretibial pseudocyst after anterior cruciate ligament reconstruction with a biocomposite screw]. AB - We report the case of a patient who presented a pretibial extra-articular cyst two years after an arthroscopically assisted ACL reconstruction using an autologous bone-patellar tendon-bone graft. The tibial fixation was achieved with a bioabsorbable screw made of poly-L, D-lactic and -tricalcium phosphate (-TCP). A subcutaneous pseudocystic lesion was excised. It consisted of a capsular fibrous tissue with minimal milky fluid (1 ml) centrally. It penetrated into the tibial tunnel but did not communicate with the knee joint space. The histopathological analysis demonstrated fibrous tissue with multinucleated giant cells and refractile particles which suggested a foreign body reaction. After the surgery, the patient recovered perfectly well and he returned to his pre-injury level of physical activity in two months. To the best of our knowledge, this is the first report of this complication in a patient with a biocomposite screw made of poly-L, D-lactic and -tricalcium phosphate (-TCP). PMID- 27984691 TI - [Iliacus muscle injury caused by inadequate exercise]. AB - BACKGROUND: Traumatic iliacus muscle injury is rare; it is usually caused by trauma or intense exercise involving the pelvic girdle; it can produce a hematoma with femoral nerve neuropathy. Spontaneous muscle hematomas occur in patients with coagulation disorders. CLINICAL CASE: A 45-year-old male with 18 days of evolution, with an intense pain in the right buttock, groin and iliac fossa, with an inability for hip flexion and ambulation caused by inadequate exercise (supine double leg lifts). On the physical examination: intense pain with bending and/or internal rotation of the right hip, positive Thomas maneuver, quadriceps rated 3/5; area of paresthesia in the right femoral nerve territory. Pelvic magnetic resonance imaging showed: right iliacus muscle tear with blood between its fibers. Initial treatment was rest and analgesics for eight days and gradual extension of the hip, axillary crutches with partial weight bearing and diathermy on the right abdominal lower quadrant, active hip exercises, bicycle and right quadriceps strengthening. The evolution was satisfactory, with full recovery in six weeks. PMID- 27984692 TI - Probing Deep Brain Circuitry: New Advances in in Vivo Calcium Measurement Strategies. AB - The study of neuronal ensembles in awake and behaving animals is a critical question in contemporary neuroscience research. Through the examination of calcium fluctuations, which are correlated with neuronal activity, we are able to better understand complex neural circuits. Recently, the development of technologies including two-photon microscopy, miniature microscopes, and fiber photometry has allowed us to examine calcium activity in behaving subjects over time. Visualizing changes in intracellular calcium in vivo has been accomplished utilizing GCaMP, a genetically encoded calcium indicator. GCaMP allows researchers to tag cell-type specific neurons with engineered fluorescent proteins that alter their levels of fluorescence in response to changes in intracellular calcium concentration. Even with the evolution of GCaMP, in vivo calcium imaging had yet to overcome the limitation of light scattering, which occurs when imaging from neural tissue in deep brain regions. Currently, researchers have created in vivo methods to bypass this problem; this Review will delve into three of these state of the art techniques: (1) two-photon calcium imaging, (2) single photon calcium imaging, and (3) fiber photometry. Here we discuss the advantages and disadvantages of the three techniques. Continued advances in these imaging techniques will provide researchers with unparalleled access to the inner workings of the brain. PMID- 27984693 TI - Global N-Glycan Site Occupancy of HIV-1 gp120 by Metabolic Engineering and High Resolution Intact Mass Spectrometry. AB - A vital step in HIV vaccine development strategies has been the observation that some infected individuals generate broadly neutralizing antibodies that target the glycans on the surface of HIV-1 gp120. These antibodies target glycan epitopes on viral envelope spikes, and yet the positions and degree of occupancy of glycosylation sites is diverse. Therefore, there is a need to understand glycosylation occupancy on recombinant immunogens. The sheer number of potential glycosylation sites and degree of chemical heterogeneity impedes assessing the global sequon occupancy of gp120 glycoforms. Here, we trap the glycan processing of recombinant gp120 to generate homogeneous glycoforms, facilitating occupancy assessment by intact mass spectrometry. We show that gp120 monomers of the BG505 strain contain either fully occupied sequons or missing the equivalent of one and sometimes two glycans across the molecule. This biosynthetic engineering approach enables the analysis of therapeutically important glycoproteins otherwise recalcitrant to analysis by native mass spectrometry. PMID- 27984694 TI - Aggregation Reverses the Carrier Effects of TiO2 Nanoparticles on Cadmium Accumulation in the Waterflea Daphnia magna. AB - Our previous study reported that the Ca-dependent aggregation of polyacrylate coated TiO2 nanoparticles (PAA-TiO2-NPs) determines their routes of uptake by the waterflea Daphnia magna. Besides the effects of aggregation on NP bioaccumulation, how this process may influence the bioavailability of NP adsorbed pollutants remains obscure. In the present study, the aggregation of PAA TiO2-NPs was also adjusted through Ca. Then the accumulation and toxicity of Cd in D. magna were investigated in the presence and absence of the NPs. Although PAA-TiO2-NPs ameliorated Cd toxicity at both low and high Ca concentrations, the underlying mechanisms differed completely. At low Ca, the metal-NP complexes were accumulated by endocytosis and passive drinking, with both pollutants distributed throughout the daphnid. Nevertheless, Cd accumulation was reduced due to its rapid dissociation from the NPs during the endocytosis of the metal-NP complexes. At high Ca, the metal-NP complexes were actively ingested, Cd accumulation was induced, and both pollutants were concentrated in the daphnid gut. The aggregation-dependent effects of PAA-TiO2-NPs on Cd bioaccumulation were further evidenced by the distinct patterns of metal efflux from D. magna at different Ca concentrations. Overall, Cd adsorption by PAA-TiO2-NPs may either increase or reduce its bioaccumulation, as determined by the aggregation of the NPs. PMID- 27984696 TI - Trapping Reactions of the Sulfenyl and Sulfinyl Tautomers of Sulfenic Acids. AB - Sulfenic acids react as both nucleophiles and electrophiles, which may be attributable to interconversion between sulfenyl and sulfinyl tautomers. We demonstrate one-pot trapping of both tautomeric forms of glutathione sulfenic acid by LCMS. The sulfinyl tautomers are characterized by reaction with nucleophilic reagents such as dimedone and cyanide, giving unique products that are analogous to corresponding adducts of aldehydes. Likewise, we show that aldehyde reactive reagents such as silyl enol ethers also react with glutathione sulfenic acid to give products characteristic of both sulfenyl and sulfinyl tautomers. PMID- 27984695 TI - Mass Spectrometric Characterization of an Acid-Labile Adduct Formed with 2-Amino 1-methyl-6-phenylimidazo[4,5-b]pyridine and Albumin in Humans. AB - 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a carcinogenic heterocyclic aromatic amine formed during the high-temperature cooking of meats. The cytochrome P450-mediated N-hydroxylation of the exocyclic amine group of PhIP produces 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine, an electrophilic metabolite that forms adducts with DNA and proteins. Previous studies conducted by our laboratory showed that the reaction of N-oxidized PhIP metabolites with human albumin in vitro primarily occurs at the Cys34 residue, to produce an acid labile linked sulfinamide adduct. On the basis of these findings, we developed a sensitive ultraperformance liquid chromatography-mass spectrometry method to measure acid-labile albumin-PhIP adducts in human volunteers administered a dietary-relevant dose of 14C-labeled PhIP [Dingley, K. H., et al. (1999) Cancer Epidemiol., Biomarkers Prev. 8, 507-512]. Mild acid treatment of albumin (0.1 N HCl, 37 degrees C for 1 h) or proteolytic digestion with Pronase [50 mM ammonium bicarbonate buffer (pH 8.5) at 37 degrees C for 18 h] released similar amounts of covalently bound PhIP, which was characterized by multistage scanning and quantified by Orbitrap mass spectrometry. The amount of [14C]PhIP recovered by acid treatment of albumin 24 h following dosing accounted for 7.2-21.3% of the [14C]PhIP bound to albumin based on accelerator mass spectrometry measurements. 2 Amino-1-methyl-6-(5-hydroxy)phenylimidazo[4,5-b]pyridine, a hydrolysis product of the Cys34 S-N linked sulfenamide adduct of PhIP, was not detected in either acid treated or protease-treated samples. These findings suggest that a portion of the PhIP bound to albumin in vivo probably occurs as an acid-labile sulfinamide adduct formed at the Cys34 residue. PMID- 27984697 TI - Delineating Amyloid Plaque Associated Neuronal Sphingolipids in Transgenic Alzheimer's Disease Mice (tgArcSwe) Using MALDI Imaging Mass Spectrometry. AB - The major pathological hallmarks of Alzheimer's disease (AD) are the progressive aggregation and accumulation of beta-amyloid (Abeta) and hyperphosphorylated tau protein into neurotoxic deposits. Abeta aggregation has been suggested as the critical early inducer, driving the disease progression. However, the factors that promote neurotoxic Abeta aggregation remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides, and proteins in biological tissue sections. In the present study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS)-based imaging was used on transgenic Alzheimer's disease mouse (tgArcSwe) brain tissue to investigate the sphingolipid microenvironment of individual Abeta plaques and elucidate plaque associated sphingolipid alterations. Multivariate data analysis was used to interrogate the IMS data for identifying pathologically relevant, anatomical features based on their lipid chemical profile. This approach revealed sphingolipid species that distinctly located to cortical and hippocampal deposits, whose Abeta identity was further verified using fluorescent amyloid staining and immunohistochemistry. Subsequent multivariate statistical analysis of the spectral data revealed significant localization of gangliosides and ceramides species to Abeta positive plaques, which was accompanied by distinct local reduction of sulfatides. These plaque-associated changes in sphingolipid levels implicate a functional role of sphingolipid metabolism in Abeta plaque pathology and AD pathogenesis. Taken together, the presented data highlight the potential of imaging mass spectrometry as a powerful approach for probing Abeta plaque-associated lipid changes underlying AD pathology. PMID- 27984700 TI - Beef assessments using functional magnetic resonance imaging and sensory evaluation. AB - Functional magnetic resonance imaging (fMRI) has been used to unveil how some foods and basic rewards are processed in the human brain. This study evaluated how resting state functional connectivity in regions of the human brain changed after differing qualities of beef steaks were consumed. Functional images of participants (n=8) were collected after eating high or low quality beef steaks on separate days, after consumption a sensory ballot was administered to evaluate consumers' perceptions of tenderness, juiciness, flavor, and overall liking. Imaging data showed that high quality steak samples resulted in greater functional connectivity to the striatum, medial orbitofrontal cortex, and insular cortex at various stages after consumption (P<=0.05). Furthermore, high quality steaks elicited higher sensory ballot scores for each palatability trait (P<=0.01). Together, these results suggest that resting state fMRI may be a useful tool for evaluating the neural process that follows positive sensory experiences such as the enjoyment of high quality beef steaks. PMID- 27984701 TI - Watch the language! Language and linguistic-cognitive abilities in children with nocturnal epileptiform activity. AB - We studied the language and linguistic-cognitive abilities of a group of children with nocturnal epileptiform activity (NEA; N=33) who were hospitalized at a tertiary epilepsy hospital. The children were compared with two groups: one age- and gender-matched group (N=33) and one group matched on language ability (vocabulary) and gender (N=66). We also examined how NEA-related variables affected language abilities. Overall, the children with NEA showed delayed language abilities and a trend for specific difficulties with phonology and naming speed. We did not find firm evidence that the amount of NEA, the use of antiepileptic drugs (AEDs), and the lateralization and localization of NEA had an effect on language. However, we found that children with right-lateralized epileptiform activity seemed to have specific difficulties with naming speed. Additionally, our results indicated that NEA located in the centrotemporal areas particularly affected phonology and orthographic skills. PMID- 27984698 TI - Simultaneous Voltammetric Measurements of Glucose and Dopamine Demonstrate the Coupling of Glucose Availability with Increased Metabolic Demand in the Rat Striatum. AB - Cerebral blood flow ensures delivery of nutrients, such as glucose, to brain sites with increased metabolic demand. However, little is known about rapid glucose dynamics at discrete locations during neuronal activation in vivo. Acute exposure to many substances of abuse elicits dopamine release and neuronal activation in the striatum; however, the concomitant changes in striatal glucose remain largely unknown. Recent developments have combined fast-scan cyclic voltammetry with glucose oxidase enzyme modified carbon-fiber microelectrodes to enable the measurement of glucose dynamics with subsecond temporal resolution in the mammalian brain. This work evaluates several waveforms to enable the first simultaneous detection of endogenous glucose and dopamine at single recording sites. These molecules, one electroactive and one nonelectroactive, were found to fluctuate in the dorsal striatum in response to electrical stimulation of the midbrain and systemic infusion of cocaine/raclopride. The data reveal the second by-second dynamics of these species in a striatal microenvironment, and directly demonstrate the coupling of glucose availability with increased metabolic demand. This work provides a foundation that will enable detailed investigation of local mechanisms that regulate the coupling of cerebral blood flow with metabolic demand under normal conditions, and in animal studies of drug abuse and addiction. PMID- 27984699 TI - Gene Expression Correlated with Severe Asthma Characteristics Reveals Heterogeneous Mechanisms of Severe Disease. AB - RATIONALE: Severe asthma (SA) is a heterogeneous disease with multiple molecular mechanisms. Gene expression studies of bronchial epithelial cells in individuals with asthma have provided biological insight and underscored possible mechanistic differences between individuals. OBJECTIVES: Identify networks of genes reflective of underlying biological processes that define SA. METHODS: Airway epithelial cell gene expression from 155 subjects with asthma and healthy control subjects in the Severe Asthma Research Program was analyzed by weighted gene coexpression network analysis to identify gene networks and profiles associated with SA and its specific characteristics (i.e., pulmonary function tests, quality of life scores, urgent healthcare use, and steroid use), which potentially identified underlying biological processes. A linear model analysis confirmed these findings while adjusting for potential confounders. MEASUREMENTS AND MAIN RESULTS: Weighted gene coexpression network analysis constructed 64 gene network modules, including modules corresponding to T1 and T2 inflammation, neuronal function, cilia, epithelial growth, and repair mechanisms. Although no network selectively identified SA, genes in modules linked to epithelial growth and repair and neuronal function were markedly decreased in SA. Several hub genes of the epithelial growth and repair module were found located at the 17q12-21 locus, near a well-known asthma susceptibility locus. T2 genes increased with severity in those treated with corticosteroids but were also elevated in untreated, mild to-moderate disease compared with healthy control subjects. T1 inflammation, especially when associated with increased T2 gene expression, was elevated in a subgroup of younger patients with SA. CONCLUSIONS: In this hypothesis-generating analysis, gene expression networks in relation to asthma severity provided potentially new insight into biological mechanisms associated with the development of SA and its phenotypes. PMID- 27984702 TI - Co-occurring aggression and suicide attempt among veterans entering residential treatment for PTSD: The role of PTSD symptom clusters and alcohol misuse. AB - Aggression and suicidality are two serious public health concerns among U.S. veterans that can co-occur and share many overlapping risk factors. The current study aims to elucidate the contribution of posttraumatic stress disorder (PTSD) symptom clusters defined by a five-factor model and alcohol misuse in predicting aggression and suicide attempts among veterans entering residential treatment for PTSD. Participants were 2570 U.S. veterans across 35 Veterans Health Administration sites. Multinomial logistic regression models were used to identify correlates of aggression only (n = 1471; 57.2%), suicide attempts only (n = 41; 1.6%), co-occurring aggression and suicide attempts (n = 202; 7.9%), and neither behavior (n = 856; 33.3%) over the past four months. When compared to veterans endorsing neither behavior, greater PTSD re-experiencing symptoms were related to suicide attempts (odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.09-2.30), aggression (OR = 1.13, 95% CI = 1.02-1.26), and co-occurring aggression and suicide (OR = 1.38, 95% CI = 1.13-1.68), and higher PTSD dysphoric arousal symptoms and alcohol misuse symptoms were related to aggression (OR = 1.54, 95% CI = 1.38-1.71; OR = 1.30, 95% CI = 1.18-1.44, respectively) and co occurring aggression and suicide (OR = 1.66, 95% CI = 1.35-2.04; OR = 1.50, 95% CI = 1.28-1.75, respectively). Our findings suggest that assessment of PTSD symptom clusters and alcohol misuse can potentially help to identify veterans who endorse suicide attempts, aggression, or both concurrently. These results have important implications for risk assessment and treatment planning with U.S. veterans seeking care for PTSD. PMID- 27984703 TI - Dissociating models of visual working memory by reaction-time distribution analysis. AB - There have been heated debates on whether visual working memory (VWM) represents information in discrete-slots or a reservoir of flexible-resources. However, one key aspect of the models has gone unnoticed, the speed of processing when stored information in memory is assessed for accuracy. The present study evaluated contrasting predictions from the two models regarding the change detection decision times spent on the assessment of stored information by estimating the ex Gaussian parameters from change detection RT distributions across different set sizes (2, 4, 6, or 8). The estimation showed that the Gaussian components MU and sigma became larger as the set size increased from 2 to 4, but stayed constant as it reached 6 and 8, with an exponential component tau increasing at above capacity set sizes. Moreover, we found that an individual's capacity limit correlates with the memory set size where the Gaussian MU reaches a plateau. These results indicate that the decision time for assessing in-memory items is constant regardless of memory set sizes whereas the time for the remaining not-in memory items increases as the set size exceeds VWM storage capacity. The findings suggest that the discrete-slot model explains the observed RT distributions better than the flexible-resource model. PMID- 27984704 TI - Synthesis of aza-crown analogues and macrocyclic bis-lactams with sucrose scaffold. AB - 2,3,3',4,4'-Penta-O-benzylsucrose was converted into the corresponding diaminoalcohol which was used as a key building block in the synthesis of the analogues of aza-crown ethers and bis-lactams. PMID- 27984705 TI - Detection of heart failure-related biomarker in whole blood with graphene field effect transistor biosensor. AB - Since brain natriuretic peptide (BNP) has become internationally recognized biomarkers in the diagnosis and prognosis of heart failure (HF), it is highly desirable to search for a novel sensing tool for detecting the patient's BNP level at the early stage. Here we report a platinum nanoparticles (PtNPs) decorated reduced graphene oxide (rGO) field effect transistor (FET) biosensor coupled with a microfilter system for label-free and highly sensitive detection of BNP in whole blood. The PtNPs-decorated rGO FET sensor was obtained by drop casting rGO onto the pre-fabricated FET chip and subsequently assembling PtNPs on the graphene surface. After anti-BNP was bound to the PtNPs surface, BNP was successfully detected by the anti-BNP immobilized FET biosensor. It was found that the developed FET biosensor was able to achieve a low detection limitation of 100fM. Moreover, BNP was successfully detected in human whole blood sample treated by a custom-made microfilter, suggesting the sensor's capability of working in a complex sample matrix. The developed FET biosensor provides a new sensing platform for protein detection, showing its potential applications in clinic sample. PMID- 27984706 TI - Recent advances in biosensor development for the detection of cancer biomarkers. AB - Cancer is the second largest disease throughout the world with an increasing mortality rate over the past few years. The patient's survival rate is uncertain due to the limitations of cancer diagnosis and therapy. Early diagnosis of cancer is decisive for its successful treatment. A biomarker-based cancer diagnosis may significantly improve the early diagnosis and subsequent treatment. Biosensors play a crucial role in the detection of biomarkers as they are easy to use, portable, and can do analysis in real time. This review describes various biosensors designed for detecting nucleic acid and protein-based cancer biomarkers for cancer diagnosis. It mainly lays emphasis on different approaches to use electrochemical, optical, and mass-based transduction systems in cancer biomarker detection. It also highlights the analytical performances of various biosensor designs concerning cancer biomarkers in detail. PMID- 27984708 TI - A primary standard source of radon-222 based on the HPGe detector. AB - The present paper describes the prototype of a calibration standard system for radon concentrations to be used in establishing the traceability of radon concentration measurements in dwellings. Radon gas was generated with a radium 226 solid source in a certified volume as a closed system. The activity of the radon that was released in the closed system was determined from the difference between the absolute activity of the standard radium solid source and the residual radon decay products (214Bi or 214Pb). A high-purity germanium (HPGe) detector, which was calibrated using gamma reference standard sources, was used to measure the activity of a radium solid source and radon decay products (214Bi or 214Pb). The emanation factor of the 226Ra source was controlled online with the HPGe detector. Radon activity was achieved at ~1500+/-45Bq from the radium source at 3.95+/-0.2kBq under equilibrium conditions. After this activity, the radon gas was transferred into the closed system producing radon activity concentrations of 31.1+/-0.3kBq/m3. Systematic errors were found of less than 4% with a random error around 0.5%. The random error is generally associated with the estimation of the count rate of the measured radon progenies (214Po and 214Po for alpha measurements or 214Pb and 214Bi for gamma measurements), but systematic errors are associated with the errors introduced by the instrumentation and measurement technique. The system that was developed has a high degree of accuracy and can be recommended as a national or regional prototype standard of radon activity concentration to calibrate different working radon measurement devices. PMID- 27984707 TI - Detection of aberrant protein phosphorylation in cancer using direct gold-protein affinity interactions. AB - Protein phosphorylation is one of the most prominent post-translational mechanisms for protein regulation, which is frequently impaired in cancer. Through the covalent addition of phosphate groups to certain amino-acids, the interactions of former residues with nearby amino-acids are drastically altered, resulting in major changes of protein conformation that impacts its biological function. Herein, we report that these conformational changes can also disturb the protein's ability to interact with and adsorb onto bare gold surfaces. We exploited this feature to develop a simple electrochemical method for detecting the aberrant phosphorylation of EGFR protein in several lung cancer cell lines. This method, which required as low as 10ng/uL (i.e., 50ng) of purified EGFR protein, also enabled monitoring cell sensitivity to tyrosine kinase inhibitors (TKI) - a common drug used for restoring the function of aberrantly phosphorylated proteins in lung cancer. The reported strategy based on direct gold-protein affinity interactions avoids the conventional paradigm of requiring a phospho-specific antibody for detection and could be a potential alternative of widely used mass spectrometry. PMID- 27984709 TI - Laboratory simulation of recent NAPL spills to investigate radon partition among NAPL vapours and soil air. AB - Soil radon is employed to trace residual NAPL (Non-Aqueous Phase Liquid) contamination because it is very soluble in these substances and is strongly depleted over polluted volumes of the subsoil. The solubility of radon into NAPL vapors, generally poorly considered, is investigated here, either as growth of radon exhalation from a material contaminated with increasing volumes of kerosene, or as radon partition between liquid kerosene, water and total air, considered ad the sum of kerosene vapors plus air. PMID- 27984710 TI - Research and development of a high-performance differential-hybrid charge sensitive preamplifier. AB - A differential-hybrid charge sensitive preamplifier (CSP) was designed by taking a monolithic dual N-Channel Junction Field-effect Transistor (JFET) and a high speed, low-noise, operational amplifier as the core parts. Input-stage of the circuit employs low-noise differential dual JFET, which ensures high input impedance and low noise. The differential dual transistor makes the quiescent point of the first-stage differential output stable, which is convenient for connecting with the post stage high-speed operational amplifier. Broadband could be amplified by connecting to the double differential dual transistors through the folded cascode-bootstrap. The amplifying circuit which replaces the interstage and post stage discrete components of a traditional CSP with integrated operational amplifier is simpler and more reliable. It simplifies the design of the quiescent point, gives full play to advantages of releasing large open-loop gain, and improves charge-voltage conversion gain stability. Particularly, the charge-voltage conversion gain is larger under a smaller feedback capacitor, thus enabling to gain better signal-noise ratio. The designed CSP was tested, reporting 3.3*1013 V/C charge sensitivity, about 90ns rise time of signals, 35:1 signal-noise ratio to gamma-rays of 137Cs (662keV) and a 0.023 fC/pF noise slope. Gamma-rays of 241Am (59.5keV) were measured by the BPX66 detector and the designed CSP under room temperature, providing 1.97% energy resolution. PMID- 27984711 TI - Evaluation of anaphylactoid constituents in vitro and in vivo. AB - Natural medicine injections have been widely used in clinics, while adverse reaction reports also have increased rapidly in recent years. To examine the anaphylactoid constituents of natural medicine injections, RBL-2H3 cell degranulation and human serum complement activation models were used to screen the anaphylactoid constituents, and the BN rat model was used to explore the anaphylactoid mechanism of these constituents. The result of an in vitro study showed that the individual compounds of natural medicine injections (chlorogenic acid, hyodeoxycholic acid, cholalic acid, ginkgolic acid, phillyrin, schisandrin B, schisandrin A, puerarin, and tanshinone IIA) and polysaccharide could not induce RBL-2H3 to release histamine and beta-hexosaminidase, while proteins Tween 80 and tannic acid were the main anaphylactoid constituents in the natural medicine injections. The in vivo study also indicated that >10kDa molecules (proteins) activated classical complement pathways through direct stimulation to cause an anaphylactoid reaction. Tween-80 activated direct stimulation and coagulation pathways through classical and alternative pathways; tannic acid induced anaphylactoid reaction through co-activation of the kallikrein-kinin system, coagulation, integrated, classical and alternative complement pathways. This is the first study to evaluate the anaphylactoid constituents systematically through in vitro and in vivo study. And tannic acid, >10kDa molecules (proteins), and injection additives such as Tween-80 are the main anaphylactoid constituents of natural medicine injections. PMID- 27984713 TI - Harvesting Benefits from Cannabinoids. PMID- 27984712 TI - Mangiferin inhibits mastitis induced by LPS via suppressing NF-KB and NLRP3 signaling pathways. AB - During the past era, small molecules derived from various plants have attracted extensive attention for their versatile medicinal benefits. Among these, one organic molecule called mangiferin from certain plant species including mangoes and honey bush tea is widely used in treating inflammation. In this study, a LPS induced mastitis model in mouse is established to investigate the anti inflammatory effects and mechanism of mangiferin. The result shows that mangiferin significantly alleviates LPS-induced histopathology, meanwhile, also decreases LPS-induced MPO activity. Furthermore, mangiferin treatment remarkably impeded the expression of pro-inflammatory cytokines TNF-alpha, IL-1beta, and IL 6. In addition, mangiferin was found to inhibit LPS-induced NF-KB and NLRP3 inflammasome activation. In conclusion, these results suggested that LPS-induced mastitis can be abated by mangiferin through inhibiting NF-KB and NLRP3 signaling pathways. PMID- 27984714 TI - IL-17 Blockade in Psoriasis. AB - IL-17A both directly induces and synergizes with other cytokines to promote autoimmune tissue inflammation. Secukinumab and ixekizumab are monoclonal antibodies (mAb) that inhibit interleukin-17A. These two agents were recently approved for treatment of psoriasis, and secukinumab is also approved for treatment of two spondyloarthropathies, psoriatic arthritis and ankylosing spondylitis. PMID- 27984715 TI - Metformin: Restraining Nucleocytoplasmic Shuttling to Fight Cancer and Aging. AB - In this issue of Cell, Wu et al. employed C. elegans and human cell experiments to identify a pathway through which metformin increases lifespan and inhibits growth. A key transcriptional target, ACAD10, is activated when metformin induces nuclear exclusion of the GTPase RagC, thereby inhibiting mTORC1 through an unexpected mechanism. PMID- 27984716 TI - Bursts of Reprogramming: A Path to Extend Lifespan? AB - In a thought-provoking study, Ocampo et al. show that the cyclic expression of stem cell reprogramming factors in vivo increases the lifespan of a mouse model of premature aging and provides health benefits to chronologically old, normal mice. PMID- 27984717 TI - A Breakdown in Cooperativity Leads to Cardiac Identity Crisis. AB - Using induced pluripotent stem cells, Ang et al. elucidate how a mutation in the transcription factor GATA4 causes congenital heart disease. They find that, although the recruitment of GATA4 to cardiac super-enhancers is retained, it no longer functions in partnership with another key transcription factor, leading to misexpression of non-cardiomyocyte genes. PMID- 27984718 TI - A Zygotic Checkpoint for Unrepaired Lesions. AB - DNA demethylation, a process involving DNA repair, is critical for reprogramming of the paternal genome during the oocyte-to-zygote transition. A new study by Ladstatter and Tachibana-Konwalski shows that a Chk1-mediated zygotic checkpoint monitors the cohesin-dependent repair of DNA lesions arising from DNA demethylation, which prevents zygotes carrying unrepaired lesions from entering mitosis. PMID- 27984719 TI - Easy Stress Relief by EZH2. AB - While we are beginning to appreciate the cellular roles played by long noncoding RNAs, the function of transcripts emerging from repetitive genomic regions remains enigmatic. In this issue, Zovoilis et al. report that the polycomb protein EZH2, upon heat shock, facilitates transcription of stress-responsive genes by inducing the degradation of the transcriptional repressor B2 repeat RNA. PMID- 27984720 TI - Beyond the Triplet Code: Context Cues Transform Translation. AB - The elucidation of the genetic code remains among the most influential discoveries in biology. While innumerable studies have validated the general universality of the code and its value in predicting and analyzing protein coding sequences, established and emerging work has also suggested that full genome decryption may benefit from a greater consideration of a codon's neighborhood within an mRNA than has been broadly applied. This Review examines the evidence for context cues in translation, with a focus on several recent studies that reveal broad roles for mRNA context in programming translation start sites, the rate of translation elongation, and stop codon identity. PMID- 27984721 TI - Roles of Caspases in Necrotic Cell Death. AB - Caspases were originally identified as important mediators of inflammatory response and apoptosis. Recent discoveries, however, have unveiled their roles in mediating and suppressing two regulated forms of necrotic cell death, termed pyroptosis and necroptosis, respectively. These recent advances have significantly expanded our understanding of the roles of caspases in regulating development, adult homeostasis, and host defense response. PMID- 27984722 TI - An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer. AB - Metformin has utility in cancer prevention and treatment, though the mechanisms for these effects remain elusive. Through genetic screening in C. elegans, we uncover two metformin response elements: the nuclear pore complex (NPC) and acyl CoA dehydrogenase family member-10 (ACAD10). We demonstrate that biguanides inhibit growth by inhibiting mitochondrial respiratory capacity, which restrains transit of the RagA-RagC GTPase heterodimer through the NPC. Nuclear exclusion renders RagC incapable of gaining the GDP-bound state necessary to stimulate mTORC1. Biguanide-induced inactivation of mTORC1 subsequently inhibits growth through transcriptional induction of ACAD10. This ancient metformin response pathway is conserved from worms to humans. Both restricted nuclear pore transit and upregulation of ACAD10 are required for biguanides to reduce viability in melanoma and pancreatic cancer cells, and to extend C. elegans lifespan. This pathway provides a unified mechanism by which metformin kills cancer cells and extends lifespan, and illuminates potential cancer targets. PAPERCLIP. PMID- 27984723 TI - In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. AB - Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process through reprogramming has not been directly demonstrated in vivo. Here, we report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging. PMID- 27984725 TI - CDK Substrate Phosphorylation and Ordering the Cell Cycle. AB - S phase and mitotic onset are brought about by the action of multiple different cyclin-CDK complexes. However, it has been suggested that changes in the total level of CDK kinase activity, rather than substrate specificity, drive the temporal ordering of S phase and mitosis. Here, we present a phosphoproteomics based systems analysis of CDK substrates in fission yeast and demonstrate that the phosphorylation of different CDK substrates can be temporally ordered during the cell cycle by a single cyclin-CDK. This is achieved by rising CDK activity and the differential sensitivity of substrates to CDK activity over a wide dynamic range. This is combined with rapid phosphorylation turnover to generate clearly resolved substrate-specific activity thresholds, which in turn ensures the appropriate ordering of downstream cell-cycle events. Comparative analysis with wild-type cells expressing multiple cyclin-CDK complexes reveals how cyclin substrate specificity works alongside activity thresholds to fine-tune the patterns of substrate phosphorylation. PMID- 27984726 TI - Functional Segregation of Overlapping Genes in HIV. AB - Overlapping genes pose an evolutionary dilemma as one DNA sequence evolves under the selection pressures of multiple proteins. Here, we perform systematic statistical and mutational analyses of the overlapping HIV-1 genes tat and rev and engineer exhaustive libraries of non-overlapped viruses to perform deep mutational scanning of each gene independently. We find a "segregated" organization in which overlapped sites encode functional residues of one gene or the other, but never both. Furthermore, this organization eliminates unfit genotypes, providing a fitness advantage to the population. Our comprehensive analysis reveals the extraordinary manner in which HIV minimizes the constraint of overlapping genes and repurposes that constraint to its own advantage. Thus, overlaps are not just consequences of evolutionary constraints, but rather can provide population fitness advantages. PMID- 27984727 TI - Destabilization of B2 RNA by EZH2 Activates the Stress Response. AB - More than 98% of the mammalian genome is noncoding, and interspersed transposable elements account for ~50% of noncoding space. Here, we demonstrate that a specific interaction between the polycomb protein EZH2 and RNA made from B2 SINE retrotransposons controls stress-responsive genes in mouse cells. In the heat shock model, B2 RNA binds stress genes and suppresses their transcription. Upon stress, EZH2 is recruited and triggers cleavage of B2 RNA. B2 degradation in turn upregulates stress genes. Evidence indicates that B2 RNA operates as a "speed bump" against advancement of RNA polymerase II, and temperature stress releases the brakes on transcriptional elongation. These data attribute a new function to EZH2 that is independent of its histone methyltransferase activity and reconcile how EZH2 can be associated with both gene repression and activation. Our study reveals that EZH2 and B2 together control activation of a large network of genes involved in thermal stress. PMID- 27984724 TI - Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis. AB - Mutation of highly conserved residues in transcription factors may affect protein protein or protein-DNA interactions, leading to gene network dysregulation and human disease. Human mutations in GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy. Here, iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling, and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment, particularly to cardiac super-enhancers, concomitant with dysregulation of genes related to the phenotypic abnormalities, including cardiac septation. Conversely, the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease causing missense mutations can disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects. PMID- 27984728 TI - Mutant KRAS Enhances Tumor Cell Fitness by Upregulating Stress Granules. AB - There is growing evidence that stress-coping mechanisms represent tumor cell vulnerabilities that may function as therapeutically beneficial targets. Recent work has delineated an integrated stress adaptation mechanism that is characterized by the formation of cytoplasmic mRNA and protein foci, termed stress granules (SGs). Here, we demonstrate that SGs are markedly elevated in mutant KRAS cells following exposure to stress-inducing stimuli. The upregulation of SGs by mutant KRAS is dependent on the production of the signaling lipid molecule 15-deoxy-delta 12,14 prostaglandin J2 (15-d-PGJ2) and confers cytoprotection against stress stimuli and chemotherapeutic agents. The secretion of 15-d-PGJ2 by mutant KRAS cells is sufficient to enhance SG formation and stress resistance in cancer cells that are wild-type for KRAS. Our findings identify a mutant KRAS-dependent cell non-autonomous mechanism that may afford the establishment of a stress-resistant niche that encompasses different tumor subclones. These results should inform the design of strategies to eradicate tumor cell communities. PMID- 27984729 TI - PAM-Dependent Target DNA Recognition and Cleavage by C2c1 CRISPR-Cas Endonuclease. AB - C2c1 is a newly identified guide RNA-mediated type V-B CRISPR-Cas endonuclease that site-specifically targets and cleaves both strands of target DNA. We have determined crystal structures of Alicyclobacillus acidoterrestris C2c1 (AacC2c1) bound to sgRNA as a binary complex and to target DNAs as ternary complexes, thereby capturing catalytically competent conformations of AacC2c1 with both target and non-target DNA strands independently positioned within a single RuvC catalytic pocket. Moreover, C2c1-mediated cleavage results in a staggered seven nucleotide break of target DNA. crRNA adopts a pre-ordered five-nucleotide A-form seed sequence in the binary complex, with release of an inserted tryptophan, facilitating zippering up of 20-bp guide RNA:target DNA heteroduplex on ternary complex formation. Notably, the PAM-interacting cleft adopts a "locked" conformation on ternary complex formation. Structural comparison of C2c1 ternary complexes with their Cas9 and Cpf1 counterparts highlights the diverse mechanisms adopted by these distinct CRISPR-Cas systems, thereby broadening and enhancing their applicability as genome editing tools. PMID- 27984730 TI - Naturally Occurring Off-Switches for CRISPR-Cas9. AB - CRISPR-Cas9 technology would be enhanced by the ability to inhibit Cas9 function spatially, temporally, or conditionally. Previously, we discovered small proteins encoded by bacteriophages that inhibit the CRISPR-Cas systems of their host bacteria. These "anti-CRISPRs" were specific to type I CRISPR-Cas systems that do not employ the Cas9 protein. We posited that nature would also yield Cas9 inhibitors in response to the evolutionary arms race between bacteriophages and their hosts. Here, we report the discovery of three distinct families of anti CRISPRs that specifically inhibit the CRISPR-Cas9 system of Neisseria meningitidis. We show that these proteins bind directly to N. meningitidis Cas9 (NmeCas9) and can be used as potent inhibitors of genome editing by this system in human cells. These anti-CRISPR proteins now enable "off-switches" for CRISPR Cas9 activity and provide a genetically encodable means to inhibit CRISPR-Cas9 genome editing in eukaryotes. VIDEO ABSTRACT. PMID- 27984731 TI - Single-Molecule Real-Time 3D Imaging of the Transcription Cycle by Modulation Interferometry. AB - Many essential cellular processes, such as gene control, employ elaborate mechanisms involving the coordination of large, multi-component molecular assemblies. Few structural biology tools presently have the combined spatial temporal resolution and molecular specificity required to capture the movement, conformational changes, and subunit association-dissociation kinetics, three fundamental elements of how such intricate molecular machines work. Here, we report a 3D single-molecule super-resolution imaging study using modulation interferometry and phase-sensitive detection that achieves <2 nm axial localization precision, well below the few-nanometer-sized individual protein components. To illustrate the capability of this technique in probing the dynamics of complex macromolecular machines, we visualize the movement of individual multi-subunit E. coli RNA polymerases through the complete transcription cycle, dissect the kinetics of the initiation-elongation transition, and determine the fate of sigma70 initiation factors during promoter escape. Modulation interferometry sets the stage for single-molecule studies of several hitherto difficult-to-investigate multi-molecular transactions that underlie genome regulation. PMID- 27984734 TI - Dissecting Immune Circuits by Linking CRISPR-Pooled Screens with Single-Cell RNA Seq. AB - In multicellular organisms, dedicated regulatory circuits control cell type diversity and responses. The crosstalk and redundancies within these circuits and substantial cellular heterogeneity pose a major research challenge. Here, we present CRISP-seq, an integrated method for massively parallel single-cell RNA sequencing (RNA-seq) and clustered regularly interspaced short palindromic repeats (CRISPR)-pooled screens. We show that profiling the genomic perturbation and transcriptome in the same cell enables us to simultaneously elucidate the function of multiple factors and their interactions. We applied CRISP-seq to probe regulatory circuits of innate immunity. By sampling tens of thousands of perturbed cells in vitro and in mice, we identified interactions and redundancies between developmental and signaling-dependent factors. These include opposing effects of Cebpb and Irf8 in regulating the monocyte/macrophage versus dendritic cell lineages and differential functions for Rela and Stat1/2 in monocyte versus dendritic cell responses to pathogens. This study establishes CRISP-seq as a broadly applicable, comprehensive, and unbiased approach for elucidating mammalian regulatory circuits. PMID- 27984735 TI - ALKBH1-Mediated tRNA Demethylation Regulates Translation. PMID- 27984732 TI - Perturb-Seq: Dissecting Molecular Circuits with Scalable Single-Cell RNA Profiling of Pooled Genetic Screens. AB - Genetic screens help infer gene function in mammalian cells, but it has remained difficult to assay complex phenotypes-such as transcriptional profiles-at scale. Here, we develop Perturb-seq, combining single-cell RNA sequencing (RNA-seq) and clustered regularly interspaced short palindromic repeats (CRISPR)-based perturbations to perform many such assays in a pool. We demonstrate Perturb-seq by analyzing 200,000 cells in immune cells and cell lines, focusing on transcription factors regulating the response of dendritic cells to lipopolysaccharide (LPS). Perturb-seq accurately identifies individual gene targets, gene signatures, and cell states affected by individual perturbations and their genetic interactions. We posit new functions for regulators of differentiation, the anti-viral response, and mitochondrial function during immune activation. By decomposing many high content measurements into the effects of perturbations, their interactions, and diverse cell metadata, Perturb-seq dramatically increases the scope of pooled genomic assays. PMID- 27984736 TI - Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity. PMID- 27984737 TI - The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery. PMID- 27984738 TI - SnapShot: Cartography of Intramembrane Proteolysis. AB - Intramembrane proteases hydrolyze peptide bonds within the cell membrane as the decision-making step of various signaling pathways or during general proteostasis. Although initially thought to be rare, fourteen proteases from four superfamilies are now known to be distributed among nearly every membrane compartment of a human cell. Each protease is endowed with specific enzymatic properties that determine both substrate choice and outcome. PMID- 27984733 TI - A Multiplexed Single-Cell CRISPR Screening Platform Enables Systematic Dissection of the Unfolded Protein Response. AB - Functional genomics efforts face tradeoffs between number of perturbations examined and complexity of phenotypes measured. We bridge this gap with Perturb seq, which combines droplet-based single-cell RNA-seq with a strategy for barcoding CRISPR-mediated perturbations, allowing many perturbations to be profiled in pooled format. We applied Perturb-seq to dissect the mammalian unfolded protein response (UPR) using single and combinatorial CRISPR perturbations. Two genome-scale CRISPR interference (CRISPRi) screens identified genes whose repression perturbs ER homeostasis. Subjecting ~100 hits to Perturb seq enabled high-precision functional clustering of genes. Single-cell analyses decoupled the three UPR branches, revealed bifurcated UPR branch activation among cells subject to the same perturbation, and uncovered differential activation of the branches across hits, including an isolated feedback loop between the translocon and IRE1alpha. These studies provide insight into how the three sensors of ER homeostasis monitor distinct types of stress and highlight the ability of Perturb-seq to dissect complex cellular responses. PMID- 27984739 TI - Come Together: CRISPR-Cas Immunity Senses the Quorum. AB - In this issue of Molecular Cell, Patterson et al. (2016) reveal a functional link between the CRISPR-Cas and quorum sensing systems, which could allow bacteria to activate the potentially lethal adaptive immunity when they need it most: in high density cultures, when bacteriophage infections can be most detrimental. PMID- 27984740 TI - pRB Takes an EZ Path to a Repetitive Task. AB - Repetitive DNA elements are essential for genome function; in this issue of Molecular Cell, Ishak et al. (2016) describe a novel mechanism of epigenetic repression at these elements that requires pRB-dependent recruitment of EZH2. PMID- 27984741 TI - Stressing Out About RAD52. AB - The role of mammalian RAD52 has been mysterious due to the lack of a strong DNA repair phenotype of RAD52-deficient cells. In this issue of Molecular Cell, studies by Bhowmick et al. (2016) and Sotiriou et al. (2016) reveal an unexpected role for RAD52 in promoting DNA synthesis following replication stress. PMID- 27984742 TI - Back to the Roots: Deep View into the Evolutionary History of ADP-Ribosylation Opened by the DNA-Targeting Toxin-Antitoxin Module DarTG. AB - In this issue of Molecular Cell, Jankevicius et al. (2016) characterize the DarTG toxin-antitoxin module in which the DarT toxin ADP-ribosylates single-stranded DNA and the DarG antitoxin counteracts DarT by direct binding and by enzymatic removal of the ADP-ribosylation. PMID- 27984743 TI - Misregulation of an Activity-Dependent Splicing Network as a Common Mechanism Underlying Autism Spectrum Disorders. AB - A key challenge in understanding and ultimately treating autism is to identify common molecular mechanisms underlying this genetically heterogeneous disorder. Transcriptomic profiling of autistic brains has revealed correlated misregulation of the neuronal splicing regulator nSR100/SRRM4 and its target microexon splicing program in more than one-third of analyzed individuals. To investigate whether nSR100 misregulation is causally linked to autism, we generated mutant mice with reduced levels of this protein and its target splicing program. Remarkably, these mice display multiple autistic-like features, including altered social behaviors, synaptic density, and signaling. Moreover, increased neuronal activity, which is often associated with autism, results in a rapid decrease in nSR100 and splicing of microexons that significantly overlap those misregulated in autistic brains. Collectively, our results provide evidence that misregulation of an nSR100 dependent splicing network controlled by changes in neuronal activity is causally linked to a substantial fraction of autism cases. PMID- 27984745 TI - RAD52 Facilitates Mitotic DNA Synthesis Following Replication Stress. AB - Homologous recombination (HR) is necessary to counteract DNA replication stress. Common fragile site (CFS) loci are particularly sensitive to replication stress and undergo pathological rearrangements in tumors. At these loci, replication stress frequently activates DNA repair synthesis in mitosis. This mitotic DNA synthesis, termed MiDAS, requires the MUS81-EME1 endonuclease and a non-catalytic subunit of the Pol-delta complex, POLD3. Here, we examine the contribution of HR factors in promoting MiDAS in human cells. We report that RAD51 and BRCA2 are dispensable for MiDAS but are required to counteract replication stress at CFS loci during S-phase. In contrast, MiDAS is RAD52 dependent, and RAD52 is required for the timely recruitment of MUS81 and POLD3 to CFSs in early mitosis. Our results provide further mechanistic insight into MiDAS and define a specific function for human RAD52. Furthermore, selective inhibition of MiDAS may comprise a potential therapeutic strategy to sensitize cancer cells undergoing replicative stress. PMID- 27984744 TI - Survival in Quiescence Requires the Euchromatic Deployment of Clr4/SUV39H by Argonaute-Associated Small RNAs. AB - Quiescence (G0) is a ubiquitous stress response through which cells enter reversible dormancy, acquiring distinct properties including reduced metabolism, resistance to stress, and long life. G0 entry involves dramatic changes to chromatin and transcription of cells, but the mechanisms coordinating these processes remain poorly understood. Using the fission yeast, here, we track G0 associated chromatin and transcriptional changes temporally and show that as cells enter G0, their survival and global gene expression programs become increasingly dependent on Clr4/SUV39H, the sole histone H3 lysine 9 (H3K9) methyltransferase, and RNAi proteins. Notably, G0 entry results in RNAi-dependent H3K9 methylation of several euchromatic pockets, prior to which Argonaute1 associated small RNAs from these regions emerge. Overall, our data reveal another function for constitutive heterochromatin proteins (the establishment of the global G0 transcriptional program) and suggest that stress-induced alterations in Argonaute-associated sRNAs can target the deployment of transcriptional regulatory proteins to specific sequences. PMID- 27984747 TI - Imaging diagnostics in ovarian cancer: magnetic resonance imaging and a scoring system guiding choice of primary treatment. AB - OBJECTIVE: To analyze the ability of magnetic resonance imaging (MRI) and systematic evaluation at surgery to predict optimal cytoreduction in primary advanced ovarian cancer and to develop a preoperative scoring system for cancer staging. STUDY DESIGN: Preoperative MRI and standard laparotomy were performed in 99 women with either ovarian or primary peritoneal cancer. Using univariate and multivariate logistic regression analysis of a systematic description of the tumor in nine abdominal compartments obtained by MRI and during surgery plus clinical parameters, a scoring system was designed that predicted non-optimal cytoreduction. RESULTS: Non-optimal cytoreduction at operation was predicted by the following: (A) presence of comorbidities group 3 or 4 (ASA); (B) tumor presence in multiple numbers of different compartments, and (C) numbers of specified sites of organ involvement. The score includes: number of compartments involved (1-9 points), >1 subdiaphragmal location with presence of tumor (1 point); deep organ involvement of liver (1 point), porta hepatis (1 point), spleen (1 point), mesentery/vessel (1 point), cecum/ileocecal (1 point), rectum/vessels (1 point): ASA groups 3 and 4 (2 points). Use of the scoring system based on operative findings gave an area under the curve (AUC) of 91% (85 98%) for patients in whom optimal cytoreduction could not be achieved. The score AUC obtained by MRI was 84% (76-92%), and 43% of non-optimal cytoreduction patients were identified, with only 8% of potentially operable patients being falsely evaluated as suitable for non-optimal cytoreduction at the most optimal cut-off value. Tumor in individual locations did not predict operability. CONCLUSION: This systematic scoring system based on operative findings and MRI may predict non-optimal cytoreduction. MRI is able to assess ovarian cancer with peritoneal carcinomatosis with satisfactory concordance with laparotomic findings. This scoring system could be useful as a clinical guideline and should be evaluated and developed further in larger studies. PMID- 27984748 TI - Interleukin-16 rs11556218 is associated with a risk of osteoporosis in Chinese postmenopausal women. AB - BACKGROUND: Interleukins (ILs), a multifunctional cytokine, play a fundamental role in inflammatory diseases, as well as in the development of osteoporosis. However, there are no data about the role of IL-16 polymorphism in development of osteoporosis. PATIENTS AND METHODS: In this study, we investigated the association between the IL-16 rs11556218 T/G and rs4072122 C/T polymorphisms respectively, and the risk of osteoporosis among 230 patients with osteoporosis and 230 healthy controls. Serum IL-16 level and its correlation with the IL-16 rs11556218 T/G genotypes were analyzed. RESULTS: Significant differences of genotype distribution were observed between osteoporosis cases and controls at the IL-16 rs11556218 T/G genotypes. Compared with the IL-16 rs11556218 T/G homozygote TT, the heterozygous TG genotype was associated with significantly increased risk for osteoporosis (OR=2.29, 95% CI=(1.15-3.82), p=0.026); the GG genotype was associated with increased risk for osteoporosis (OR=1.84, 95% CI=1.48-3.97, p=0.015). TG and GG combined variants that were associated with increased risk for osteoporosis compared with the TT genotype (OR=1.92, 95% CI=1.43-4.86, p=0.023). Moreover, in patients with osteoporosis, there was a correlation between the serum IL-16 and rs11556218 T/G genotype. However, the genotype and allele frequencies of IL-16 rs4072122 C/T polymorphisms in osteoporosis patients were not significantly different from controls. CONCLUSION: IL-16 rs11556218 T/G genotype was associated with increased risk for development of osteoporosis in Chinese postmenopausal women. PMID- 27984749 TI - Laparoscopic management of ureteral endometriosis: A systematic review. AB - The optimal management of ureteral endometriosis (UE) is not yet well defined. The choice on surgical approach and type of procedure has been based both on surgeons' experience and the location and depth of the lesion. The aim of this study was to review evidence about laparoscopic management of ureteral endometriosis, including preoperative evaluation, surgical details and postoperative follow-up. PubMed Central and SCOPUS databases were searched to identify studies reporting cases of laparoscopically managed ureteral endometriosis and including data regarding preoperative findings, surgical interventions and postoperative follow-up. Two sets of MeSH terms were used: 1) "laparoscopy", "endometriosis" and "ureter"; 2) "laparoscopy", "endometriosis" and "urinary tract". Databases were searched for articles published since 1996, in English, French, Spanish and Portuguese, without restrictions regarding study design. Studies reporting surgical approaches other than conventional laparoscopy were excluded, as were case reports and case studies including fewer than 5 cases. From 327 studies obtained through database searching, 18 articles were finally included in this review, including a total of 700 patients with ureteral endometriosis. 57% of patients had at least one previous surgery for endometriosis. Preoperative evidence of significant hydroureter/hydronephrosis was found in 324 of 671 (48.3%) patients. Dysmenorrhea (81.4%), pelvic pain (70.2%) and dyspareunia (66.4%) were the presenting symptoms more commonly reported by the patients. Most patients presented no symptoms specific to the urinary tract. Ureteral endometriosis was more frequent in the left ureter (53.6%) and it was bilateral in 10.6% of cases. Ureterolysis alone was considered a sufficient procedure in 579 of 668 patients (86.7%), and in the remaining 89 patients ureteral resection was necessary. Rectovaginal and uterosacral involvement was present in 58.8% and 47.9% of patients, respectively. Concomitant ureteral and bladder endometriosis was described in 19.8% of patients. Only 6 studies reported cases of accidental ureteral injuries, in 1-24% of patients. Cases of conversion to laparotomy are reported in only 6 studies, in 3-6,7% of patients. Major postoperative complications occurred in 21 out of 682 patients (3.2%). The need for reoperation during follow-up period because of ureteral endometriosis persistence or recurrence was 3.9%. When performed in specialized centers, laparoscopic ureterolysis showed to be a feasible and safe procedure, with a low risk of complications and with satisfactory long-term results. This conservative approach may be used as the initial treatment option in most patients with ureteral endometriosis. PMID- 27984746 TI - Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks. AB - Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, a gene dispensable for normal development in mice, was among the top hits. In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells. PMID- 27984750 TI - Comparison of HeNe laser and sinusoidal non-uniform magnetic field seed pre sowing treatment effect on Glycine max (Var 90-I) germination, growth and yield. AB - Recently, laser and magnetic field pre-sowing seed treatments attracted the attention of the scientific community in response to their positive effect on plant characteristics and the present study was exemplified for Glycine max Var 90-I. Seeds were exposed to laser (HeNe-wave length 632nm and density power of 1mW/cm2) and magnetic field (sinusoidal non-uniform-50, 75 and 100mT for 3, 5min with exposure) and seed germination, seedling growth and yield attributes were compared. The germination (mean germination, germination percentage, emergence index, germination speed, relative germination coefficient, emergence coefficient of uniformity) growth (root dry weight, root length, shoot fresh weight and shoot dry weight, leaf dry & fresh weight, root fresh weight, leaf area, shoot length, plant total dry weight at different stages, stem diameter, number of leaves, vigor index I & II), biochemical (essential oil) and yield attributes (seed weight, count) were enhanced significantly in response to both laser and magnetic field treatments. However, magnetic field treatment furnished slightly higher response versus laser except relative water contents, whole plant weight and shoot length. Results revealed that both laser and magnetic field pre-sowing seed treatments affect the germination, seedling growth, and yield characteristics positively and could possibly be used to enhance Glycine max productivity. PMID- 27984751 TI - Benzophenone based fluorophore for selective detection of Sn2+ ion: Experimental and theoretical study. AB - Synthesis of novel benzophenone-based chemosensor is presented for the selective sensing of Sn2+ ion. Screening of competitive metal ions was performed by competitive experiments. The specific cation recognition ability of chemosensor towards Sn2+ was investigated by experimental (UV-visible, fluorescence spectroscopy, 1H NMR, 13C NMR, FTIR and HRMS) methods and further supported by Density Functional Theory study. The stoichiometric binding ratio and binding constant (Ka) for complex is found to be 1:1 and 1.50*104, respectively. The detection limit of Sn2+ towards chemosensor was found to be 0.3898ppb. Specific selectivity and superiority of chemosensor over another recently reported chemosensor is presented. PMID- 27984752 TI - Analyses of polycyclic aromatic hydrocarbon (PAH) and chiral-PAH analogues-methyl beta-cyclodextrin guest-host inclusion complexes by fluorescence spectrophotometry and multivariate regression analysis. AB - The negative health impact of polycyclic aromatic hydrocarbons (PAHs) and differences in pharmacological activity of enantiomers of chiral molecules in humans highlights the need for analysis of PAHs and their chiral analogue molecules in humans. Herein, the first use of cyclodextrin guest-host inclusion complexation, fluorescence spectrophotometry, and chemometric approach to PAH (anthracene) and chiral-PAH analogue derivatives (1-(9-anthryl)-2,2,2 triflouroethanol (TFE)) analyses are reported. The binding constants (Kb), stoichiometry (n), and thermodynamic properties (Gibbs free energy (DeltaG), enthalpy (DeltaH), and entropy (DeltaS)) of anthracene and enantiomers of TFE methyl-beta-cyclodextrin (Me-beta-CD) guest-host complexes were also determined. Chemometric partial-least-square (PLS) regression analysis of emission spectra data of Me-beta-CD-guest-host inclusion complexes was used for the determination of anthracene and TFE enantiomer concentrations in Me-beta-CD-guest-host inclusion complex samples. The values of calculated Kb and negative DeltaG suggest the thermodynamic favorability of anthracene-Me-beta-CD and enantiomeric of TFE-Me-beta-CD inclusion complexation reactions. However, anthracene-Me-beta CD and enantiomer TFE-Me-beta-CD inclusion complexations showed notable differences in the binding affinity behaviors and thermodynamic properties. The PLS regression analysis resulted in square-correlation-coefficients of 0.997530 or better and a low LOD of 3.81*10-7M for anthracene and 3.48*10-8M for TFE enantiomers at physiological conditions. Most importantly, PLS regression accurately determined the anthracene and TFE enantiomer concentrations with an average low error of 2.31% for anthracene, 4.44% for R-TFE and 3.60% for S-TFE. The results of the study are highly significant because of its high sensitivity and accuracy for analysis of PAH and chiral PAH analogue derivatives without the need of an expensive chiral column, enantiomeric resolution, or use of a polarized light. PMID- 27984754 TI - Laser-induced optical breakdown spectroscopy of polymer materials based on evaluation of molecular emission bands. AB - Laser-induced breakdown spectroscopy (LIBS) for composition analysis of polymer materials results in optical spectra containing atomic and ionic emission lines as well as molecular emission bands. In the present work, the molecular bands are analyzed to obtain spectroscopic information about the plasma state in an effort to quantify the content of different elements in the polymers. Polyethylene (PE) and a rubber material from tire production are investigated employing 157nmF2 laser and 532nm Nd:YAG laser ablation in nitrogen and argon gas background or in air. The optical detection reaches from ultraviolet (UV) over the visible (VIS) to the near infrared (NIR) spectral range. In the UV/VIS range, intense molecular emissions, C2 Swan and CN violet bands, are measured with an Echelle spectrometer equipped with an intensified CCD camera. The measured molecular emission spectra can be fitted by vibrational-rotational transitions by open access programs and data sets with good agreement between measured and fitted spectra. The fits allow determining vibrational-rotational temperatures. A comparison to electronic temperatures Te derived earlier from atomic carbon vacuum-UV (VUV) emission lines show differences, which can be related to different locations of the atomic and molecular species in the expanding plasma plume. In the NIR spectral region, we also observe the CN red bands with a conventional CDD Czerny Turner spectrometer. The emission of the three strong atomic sulfur lines between 920 and 925nm is overlapped by these bands. Fitting of the CN red bands allows a separation of both spectral contributions. This makes a quantitative evaluation of sulfur contents in the start material in the order of 1wt% feasible. PMID- 27984753 TI - Validated spectrofluorimetric methods for the determination of apixaban and tirofiban hydrochloride in pharmaceutical formulations. AB - Apixaban and Tirofiban Hydrochloride are low molecular weight anticoagulants. The two drugs exhibit native fluorescence that allow the development of simple and valid spectrofluorimetric methods for the determination of Apixaban at lambda ex/lambda em=284/450nm and tirofiban HCl at lambda ex/lambda em=227/300nm in aqueous media. Different experimental parameters affecting fluorescence intensities were carefully studied and optimized. The fluorescence intensity concentration plots were linear over the ranges of 0.2-6MUgml-1 for apixaban and 0.2-5MUgml-1 for tirofiban HCl. The limits of detection were 0.017 and 0.019MUgml 1 and quantification limits were 0.057 and 0.066MUgml-1 for apixaban and tirofiban HCl, respectively. The fluorescence quantum yield of apixaban and tirofiban were calculated with values of 0.43 and 0.49. Method validation was evaluated for linearity, specificity, accuracy, precision and robustness as per ICH guidelines. The proposed spectrofluorimetric methods were successfully applied for the determination of apixaban in Eliquis tablets and tirofiban HCl in Aggrastat intravenous infusion. Tolerance ratio was tested to study the effect of foreign interferences from dosage forms excipients. Using Student's t and F tests, revealed no statistically difference between the developed spectrofluorimetric methods and the comparison methods regarding the accuracy and precision, so can be contributed to the analysis of apixaban and tirofiban HCl in QC laboratories as an alternative method. PMID- 27984755 TI - Graphene quantum dots coordinated to mercaptopyridine-substituted phthalocyanines: Characterization and application as fluorescence "turn ON" nanoprobes. AB - This study reports on the design of novel nanoconjugates of graphene quantum dots (GQDs) and tetra or octa-mercaptopyridine-substituted zinc and aluminium phthalocyanines (Pcs) deployed as fluorescence "turn ON" nanoprobes. The phthalocyanines were separately adsorbed onto the planar structure of graphene quantum dots (GQDs) via pi-pi stacking interaction to form GQDs-mercaptopyridine Pcs nanoconjugates. The quaternized Pc complexes could also interact with the GQDs through electrostatic attraction due to the positive charges on the Pcs ring substituents and the negative charges on the surface of GQDs. The fluorescence emission of the GQDs was quenched upon coordination to the respective Pcs. However, the fluorescence emission was "turned ON" in the presence of Hg2+ employed as a test analyte. The mechanism of the "turn ON" of the GQDs emission in the nanoconjugates is ascribed to the strong affinity of Hg2+ to bind with the bridging sulfur on the Pcs periphery thereby disrupting the pi-pi stacking interaction between the GQDs and the Pcs with a consequent "turn ON" of the coordinated GQDs' fluorescence. PMID- 27984756 TI - Non-reconstructable peripheral vascular disease of the lower extremity in ten patients treated with adipose-derived stromal vascular fraction cells. AB - We present a series of ten patients with non-reconstructable peripheral vascular disease (PVD), secondary to arteriosclerosis (AS) and/or diabetes mellitus (DM), treated with local injection of non-expanded autologous, adipose-derived stromal vascular fraction (SVF) cells for the purposes of enhancing neovascularization and chronic wound healing. Adipose tissue was surgically harvested and processed to yield the heterogeneous SVF cells for immediate point-of-care injection. The gastrocnemius muscles and ulcers or wounds where present were locally injected with the resulting SVF. Response to treatment was evaluated both clinically based on pain-free ambulation, wound healing capacity over time and ankle/brachial index (ABI) measurements, and by imaging using MRI-based angiography. All patients exhibited clinical improvement (reduction in rest pain and claudication and improvements in ABI), with imaging signs of neovascularization in the majority (5 of 6) of patients in whom the evaluation was feasible. Similarly, 5 of 6 chronic wounds healed without further surgical intervention. This series highlights the utility of non-expanded adipose-derived heterogeneous SVF cell population processed at the point-of-care, to treat patients with end-stage PVD as an alternative to palliation or amputation. PMID- 27984758 TI - Determination of cortisol in lake sturgeon (Acipenser fulvescens) eggs by liquid chromatography tandem mass spectrometry. AB - Quantifying cortisol concentrations in fish eggs is important to understand the effects of environmental conditions on maternal physiological condition and on egg provisioning and quality. Data are particularly relevant to studies of the ecology of threatened species such as lake sturgeon (Aciperser fulvescens) as well as assessments of larval physical and behavioral phenotypes, fish health and caviar quality in sturgeon aquaculture. This study focuses on development of bioanalytical methods for high sensitivity and robust determination of cortisol in sturgeon eggs. Sample preparation was optimized after investigating protein precipitation and liquid-liquid extraction techniques. Ethyl acetate was found to be the most efficient solvent (recovery parameter) and also provided the best sample clean up (matrix effect parameter). The method was determined to be linear for cortisol concentrations between 0.025 and 100ng/mL. The limits of detection and quantification were 0.025 and 0.1ng/mL respectively. Intra- and inter-day performances of the method were validated at three concentrations (0.25; 10 and 100ng/mL). The method was applied to field-collected samples for the determination of endogenous cortisol in lake sturgeon eggs. Cortisol was detected in all egg samples and statistical analysis showed significant differences between fertilized and non-fertilized eggs. PMID- 27984757 TI - Therapeutic effect of ursolic acid in experimental visceral leishmaniasis. AB - Leishmaniasis is an important neglected tropical disease, affecting more than 12 million people worldwide. The available treatments are not well tolerated and present diverse side effects in patients, justifying the search for new therapeutic compounds. In the present study, the therapeutic potential and toxicity of ursolic acid (UA), isolated from the leaves of Baccharis uncinella C. DC. (Asteraceae), were evaluated in experimental visceral leishmaniasis. To evaluate the therapeutic potential of UA, hamsters infected with L. (L.) infantum were treated daily during 15 days with 1.0 or 2.0 mg UA/kg body weight, or with 5.0 mg amphotericin B/kg body weight by intraperitoneal route. Fifteen days after the last dose, the parasitism of the spleen and liver was stimated and the main histopathological alterations were recorded. The proliferation of splenic mononuclear cells was evaluated and IFN-gamma, IL-4, and IL-10 gene expressions were analyzed in spleen fragments. The toxicity of UA and amphotericin B were evaluated in healthy golden hamsters by histological analysis and biochemical parameters. Animals treated with UA had less parasites in the spleen and liver when compared with the infected control group, and they also showed preservation of white and red pulps, which correlate with a high rate of proliferation of splenic mononuclear cells, IFN-gamma mRNA and iNOS production. Moreover, animals treated with UA did not present alterations in the levels of AST, ALT, creatinine and urea. Taken together, these findings indicate that UA is an interesting natural compound that should be considered for the development of prototype drugs against visceral leishmaniasis. PMID- 27984760 TI - Spatial and temporal variation in endotoxin and PM10 concentrations in ambient air in a livestock dense area. AB - Several studies have reported associations between farming and respiratory health in neighboring residents. Health effects are possibly linked to fine dust and endotoxin emissions from livestock farms. Little is known about levels of these air pollutants in ambient air in livestock dense areas. We aimed to explore temporal and spatial variation of PM10 and endotoxin concentrations, and the association with livestock-related spatial and meteorological temporal determinants. From March till September 2011, one week average PM10 samples were collected using Harvard Impactors at eight sites (residential gardens) representing a variety of nearby livestock-related characteristics. A background site was included in the study area, situated at least 500m away from the nearest farm. PM10 mass was determined by gravimetric analysis and endotoxin level by means of Limulus-Amebocyte-Lysate assay. Data were analyzed using mixed models. The range between sites of geometric mean concentrations was for PM10 19.8 22.3ug/m3 and for endotoxin 0.46-0.66EU/m3. PM10 concentrations and spatial variation were very similar for all sites, while endotoxin concentrations displayed a more variable pattern over time with larger differences between sites. Nonetheless, the temporal pattern at the background location was highly comparable to the sites mean temporal pattern both for PM10 and endotoxin (Pearson correlation: 0.92, 0.62). Spatial variation was larger for endotoxin than for PM10 (within/between site variance ratio: 0.63, 2.03). Spatial livestock related characteristics of the surroundings were more strongly related to endotoxin concentrations, while temporal determinants were more strongly related to PM10 concentrations. The effect of local livestock-related sources on PM10 concentration was limited in this study carried out in a livestock dense area. The effect on endotoxin concentrations was more profound. To gain more insight in the effect of livestock-related sources on ambient levels of PM10 and endotoxin, measurements should be based on a broader set of locations. PMID- 27984759 TI - Systematic review of the association between particulate matter exposure and autism spectrum disorders. AB - Particulate matter (PM) as an environmental pollutant is suspected to be associated with autism spectrum disorders. The aim of the present study was to review the epidemiological literature currently available on the relation between PM exposure and diagnosis of ASD. The PubMed database was searched from November 2015 up to January 2016 by one of the authors. We included observational studies (cohort and case-control studies) published in English carried out in children within the last 10 years, measuring PM exposure and health outcomes related to ASD. 13 studies met the inclusion criteria. Four of the studies found no association between PM exposure and ASD. The other 8 studies show positive associations restricted to specific exposure windows which however do not reach statistical significance at times. To conclude, the evidence from the studies allows us to conclude that there is an association between PM exposure and ASD whose strength varies according to the particle size studied with the association with PM2.5 and diesel PM being stronger. Given the potential importance for public health, cohort studies with proper adjustment for confounding variables and identification of critical windows of exposure are urgently needed to further improve knowledge about potential causal links between PM exposure and the development of ASD. PMID- 27984761 TI - Metal residues, histopathology and presence of parasites in the liver and gills of fourhorn sculpin (Myoxocephalus quadricornis) and shorthorn sculpin (Myoxocephalus scorpius) near a former lead-zinc mine in East Greenland. AB - Fourhorn sculpins (Myoxocephalus quadricornis) and shorthorn sculpins (Myoxocephalus scorpius) have been considered suitable local bioindicators for environmental monitoring studies in the Arctic. Because these species share many characteristics, data from the two species have previously been pooled when assessing marine metal contamination. A chemical and histological study was conducted on fourhorn and shorthorn sculpins collected around a contaminated lead zinc mine at East Greenland to investigate whether there were any differences in the residues of metals, histopathology and parasites in liver and gills between the two sculpin species. The results demonstrated that concentrations of copper (Cu), zinc (Zn), mercury (Hg) and lead (Pb) were significantly higher in the fourhorn sculpins (p<0.001) while there were no significant differences for arsenic (As) or cadmium (Cd). Furthermore, density of blood vessel fibrosis (p=0.028), prevalence and density of chondroplasia (p=0.002 and p=0.005, respectively), number of mucin-containing mucous cells (p<0.001) and chloride cells (p<0.001) and mean intensity of colonial Peritricha (p<0.001) were significantly higher in fourhorn sculpin. Based on these results we suggest that pooling the two species when conducting environmental assessments is not recommended as it can lead to incorrect conclusions. We propose that a larger study investigating the biological effects of zinc-lead mining in Greenland is needed. PMID- 27984762 TI - HCV prevalence and risk behaviours among injectors of new psychoactive substances in a risk environment in Hungary-An expanding public health burden. AB - BACKGROUND: In Hungary a large increase in injecting new psychoactive substances (NPS) coincided with decreasing harm reduction efforts and rising HCV infection. We describe these, and assess changes in HCV prevalence and risk behaviours, 2011 2014, among NPS injectors, using 2011-2015 syringe exchange programme (SEP) data as a key contextual ('risk environment') variable. METHODS: We conducted repeated national sero-behavioural surveys in people who inject drugs (PWID) injecting in the last month and attending SEPs or drug treatment centres (n=399, 2011; 384, 2014), using face-to-face interviews and dried blood-spot samples. Prevalence of injected drugs and SEP coverage (2011-2015) were assessed through our national SEP monitoring system and using population size estimates. RESULTS: NPS injecting tripled among PWID attending SEPs in Hungary (2011: 26%; 2015: 80%). Among NPS injectors, HCV prevalence, sharing syringes and sharing any injecting equipment (last month), doubled (2011-2014: 37%-74%, 20%-48%, 42%-71%, respectively), significantly exceeding prevalence in other PWID groups. Among young NPS injectors (aged<25), HCV prevalence increased 7-fold (12%-76%), among new injectors (injecting<2years) 4-fold (13%-42%), coupled with high levels of equipment sharing (79% and 72% respectively). Not using a condom at last intercourse (79%), ever-imprisonment (65%) and last-year homelessness (57%) were highly prevalent among NPS injectors (2014). The number of syringes distributed per estimated PWID nationally fell from 114 to 81 (2011-2014) and dropped to 28 in 2015. CONCLUSION: NPS injectors in Hungary are at severe risk of blood-borne infections due to high levels of injecting and sexual risk behaviours within a high-risk environment, including continuously low SEP provision, imprisonment and homelessness. An HIV outbreak cannot be excluded. Stronger investment in evidence based prevention measures, with special focus on young and new injectors, and expansion of hepatitis C treatment are urgently needed. PMID- 27984763 TI - Soluble HLA-G concentrations in obese women during pregnancy and in cord blood. AB - CONTEXT: Little is known about soluble HLA-G (sHLA-G) concentrations in obese pregnant women with uncomplicated pregnancies. OBJECTIVE: To investigate the role of sHLA-G in obese pregnancies. DESIGN: Case-control study, from 2013 to 2015. SETTING: A tertiary care centre. PATIENTS: 168 healthy normal weight women and 59 overweight/obese women; to avoid the effect of preeclampsia on sHLA-G concentrations, cases were further divided in two groups: 42 with normotensive pregnancy and 17 who developed preeclampsia. INTERVENTIONS: all the women enrolled received standard antenatal care and plasma sample collections were performed. MAIN OUTCOME MEASURES: sHLA-G concentrations during pregnancy, before delivery and in cord blood. RESULTS: Maternal sHLA-G concentrations in overweight/obese with normotensive pregnancies increased by 14.7% (IQR=-26.4 to +89.6) in the 2nd trimester and by 19.6% (IQR=-33 to +104) before delivery and were significantly higher than in controls (p=0.024). Median cord blood sHLA-G concentrations were 53.5ng/ml (IQR=36-62.7) in the overweight/obese women with uncomplicated pregnancies (p<0.001 compared to controls) and 19.7ng/ml (IQR=7.5 36.3) in controls. Maternal concentrations of sHLA-G in the two trimesters and before delivery were significantly lower among subjects who developed preeclampsia than in controls (p<0.001) or in obese subjects with normotensive pregnancies (p<0.001). CONCLUSIONS: sHLA-G concentratons are higher in normotensive overweight/obese women and their babies while lower in preeclamptic overweight/obese women and their cords. Obesity influences maternal and fetal sHLA-G concentrations during pregnancy, to optimize the reproductive success, while preeclampsia impairs the mother-offspring antinflammatory response. PMID- 27984764 TI - Timing temporal transitions during brain development. AB - During development a limited number of progenitors generate diverse cell types that comprise the nervous system. Neuronal diversity, which arises largely at the level of neural stem cells, is critical for brain function. Often these cells exhibit temporal patterning: they sequentially produce neurons of distinct cell fates as a consequence of intrinsic and/or extrinsic cues. Here, we review recent advances in temporal patterning during neuronal specification, focusing on conserved players and mechanisms in invertebrate and vertebrate models. These studies underscore temporal patterning as an evolutionarily conserved strategy to generate neuronal diversity. Understanding the general principles governing temporal patterning and the molecular players involved will improve our ability to direct neural progenitors towards specific neuronal fates for brain repair. PMID- 27984765 TI - HPV prevalence in women attending cervical screening in rural Malawi using the cartridge-based Xpert(r) HPV assay. AB - BACKGROUND AND OBJECTIVES: Early experience with Cepheid Xpert(r) HPV assay (Xpert(r) HPV) suggests that its quick turnaround time and ease of application might make it a relevant contender for routine use in low and middle income countries (LMICs). In the context of a cervical screening service in rural Malawi, we aimed to assess practicalities of local laboratory testing with Xpert(r) HPV and provide preliminary high-risk HPV (HR-HPV) prevalence data. STUDY DESIGN: Liquid-based cytology (LBC) specimens were collected from women attending cervical screening clinics in Nkhoma, Malawi. Xpert(r) HPV testing was carried out according to manufacturer's instructions. Partial genotyping results were obtained immediately (HPV 16, 18/45 and HR-HPV 'other'). Review of individual channel data provided further breakdown of other HR-HPV types into HPV 31 and related; HPV 51/59 and HPV 39 and related. RESULTS: Valid HR-HPV results were obtained from 750/763 samples. Most samples were from previously unscreened women, with 92.3% aged between 20 and 60 years. Overall HR-HPV positivity was 19.9%, with HR-HPV 'other' being more than twice as frequent as HPV 16 or HPV 18/45 and HPV 31-related (HPV 31, 33, 35, 52 or 58) most prevalent. Known HIV status was low (7.3%), but HR-HPV positivity in this group was much higher (43.4%). CONCLUSIONS: HR-HPV testing using Xpert(r) HPV was practical in a small rural laboratory. The rapid turnaround (within 2h) could facilitate a 'see and treat' programme. Partial genotyping allows assessment of risk beyond HPV 16/18. The high prevalence of HPV 31 and related types warrants further investigation. PMID- 27984766 TI - Diagnostic usefulness of dynamic changes of CMV-specific T-cell responses in predicting CMV infections in HCT recipients. AB - BACKGROUND: CMV-specific cell mediated immune responses before and after hematopoietic stem cell transplantation (HCT) can categorize patients as at high or low risk of CMV development. OBJECTIVES: We evaluated the usefulness of the CMV-specific T-cell ELISPOT assay for predicting the development of CMV infections after HCT in recipients with donor-positive and recipient-positive CMV serology (D+/R+ ). STUDY DESIGN: CMV pp65 and IE1-specific ELISPOT assays were performed before HCT (D0), and at 30 (D30) and 90 (D90) days after HCT. RESULTS: Of the 84 HCT recipients with D+/R+, 42 (50%) developed>=1 episode of CMV infection. Thirty-nine (64%) of 61 patients with Delta(D30-D0) pp65<42 developed CMV infections compared with 3 (14%) of 21 patients with Delta(D30-D0) pp65>=42 (P<0.001). Twenty-three (74%) of 31 patients with Delta(D30-D0) IE1<-4 developed CMV infections compared with 19 (37%) of 51 patients with Delta(D30-D0) IE1>=-4 (P=0.001). pp65 Delta(D30-D0) >=42 had 93% sensitivity for ruling out subsequent CMV infection, and pp65 Delta(D30-D0)<42 followed by Delta(D30-D0) IE1<-4 had 100% specificity for ruling in the subsequent CMV infection. In addition, 10 (53%) of 19 patients with Delta(D90-D30) pp65<23 had relapsing CMV infections, compared with 3 (15%) of 20 patients with Delta(D90-D30) pp65>=23 (P=0.02). The sensitivity and specificity of Delta(D90-D30) pp65 were 77% (95% CI 50-92) and 65% (95% CI, 46-81). CONCLUSION: Dynamic change in the CMV-specific ELISPOT assay before versus after HCT appears to predict the subsequent development of CMV infection and relapsing CMV infection. PMID- 27984767 TI - Understanding the local food environment: A participatory photovoice project in a low-income area in Madrid, Spain. AB - There is a need to partner between researchers, practitioners and residents to increase our understanding of environmental influences on dietary behaviors. We used the participatory method of Photovoice to understand key determinants of the local food environment influencing residents' diets. This project was conducted in Villaverde, a low-income area located in Madrid, Spain. From February to May 2015, 24 residents working in four Photovoice groups, took photographs related to their local food environment. Each group analyzed and critically discussed their photographs in small group sessions. Through a consensus-building process, participants identified 30 emerging categories, which followed five conceptual themes related to their food environment: 1) eating in moderation, 2) cultural diversity, 3) food stores, 4) social relationships and 5) economic crisis and poverty. Participants, researchers and practitioners successfully collaborated in analyzing, writing, disseminating the project results, and directly informing local policy-makers, media, and other residents. The project results may guide community-generated interventions for promoting a healthier food environment. PMID- 27984768 TI - Merkel cell carcinoma: Epidemiology, prognosis, therapy and unmet medical needs. AB - Merkel cell carcinoma (MCC) is a rare skin cancer that is associated with Merkel cell polyomavirus infection in most cases. Incidence rates of MCC have increased in past decades. Risk factors for MCC include ultraviolet light exposure, immunosuppression and advanced age. MCC is an aggressive malignancy with frequent recurrences and a high mortality rate, although patient outcomes are generally more favourable if the patient is referred for treatment at an early stage. Although advances have been made recently in the MCC field, large gaps remain with regard to definitive biomarkers and prognostic indicators. Although MCC is chemosensitive, responses in advanced stages are mostly of short duration, and the associated clinical benefit on overall survival is unclear. Recent nonrandomised phase 2 clinical trials with anti-PD-L1/PD-1 antibodies have demonstrated safety and efficacy; however, there are still no approved treatments for patients with metastatic MCC. Patients with advanced disease are encouraged to participate in clinical trials for treatment, indicating the largely unmet need for durable, safe treatment within this population. PMID- 27984769 TI - Use of complementary and alternative medicine: A multicenter cross-sectional study in 1089 melanoma patients. AB - BACKGROUND: About half of patients with cancer use complementary and alternative medicine (CAM). So far, data on melanoma patients are missing. OBJECTIVE: The aim of our study was to evaluate the prevalence and predictors for the use of CAM in this patient group. METHODS: All patients with melanoma being attended at one of 7 skin cancer centres in Germany between March 2012 and March 2013 were invited to take part in a survey using a structured questionnaire on CAM. The physicians filled in a second part on the diagnosis, state and former and current therapy. RESULTS: Nearly half of the 1089 participants (41.0%) used CAM and half of those using CAM (56.8%) marked that this made them feel better. Biological-based CAMs which consists of substances taken were used by 25.9% of all patients (63.1% of those using CAM). Predictors of CAM use were education, psychological support, interest in CAM and previous CAM use. CAM users show higher physical activity, more often use psychosocial help and have contact with a self-help group. Family and friends (41.0%) as well as print media (41.7%) are the main sources of information. Most important reasons to use CAM are to strengthen one's own forces (57.7%) or the immune system (63.4%) and to be able to do something for oneself (53.7%). CONCLUSION: Communication on CAM should become a regular topic in counselling melanoma patients. To increase safety, patients and physicians must have access to evidence-based information on these methods and their interactions with modern cancer treatments. PMID- 27984770 TI - Improving quality of life in patients with advanced cancer: Targeting metastatic bone pain. AB - Metastatic bone disease in patients with advanced cancer is frequently associated with skeletal complications. These can be debilitating, causing pain, impaired functioning and decreased quality of life, as well as reduced survival. This review considers how the management of metastatic bone pain might be optimised, to limit the considerable burden it can impose on affected patients. Cancer related pain is notoriously under-reported and under-treated, despite the availability of many therapeutic options. Non-opioid and opioid analgesics can be used; the latter are typically administered with radiotherapy, which forms the current standard of care for patients with metastatic bone pain. Surgery is appropriate for certain complicated cases of metastatic bone disease, and other options such as radiopharmaceuticals may provide additional relief. Treatments collectively referred to as bone-targeted agents (BTAs; bisphosphonates and denosumab) can offer further pain reduction. Initiation of therapy with BTAs is recommended for all patients with metastatic bone disease because these agents delay not only the onset of skeletal-related events but also the onset of bone pain. With evidence also emerging for pain control properties of new anticancer agents, the potential to individualise care for these patients is increased further. Optimisation of care depends on physicians' thorough appreciation of the complementary benefits that might be achieved with the various agents, as well as their limitations. Appropriate anti-tumour treatment combined with early initiation of BTAs and adequate analgesia plays a key role in the holistic approach to cancer pain management and may minimise the debilitating effects of metastatic bone pain. PMID- 27984771 TI - The perils of climate change: In utero exposure to temperature variability and birth outcomes in the Andean region. AB - The discussion on the effects of climate change on human activity has primarily focused on how increasing temperature levels can impair human health. However, less attention has been paid to the effect of increased climate variability on health. We investigate how in utero exposure to temperature variability, measured as the fluctuations relative to the historical local temperature mean, affects birth outcomes in the Andean region. Our results suggest that exposure to a temperate one standard deviation relative to the municipality's long-term temperature mean during pregnancy reduces birth weight by 20g. and increases the probability a child is born with low birth weight by a 0.7 percentage point. We also explore potential channels driving our results and find some evidence that increased temperature variability can lead to a decrease in health care and increased food insecurity during pregnancy. PMID- 27984772 TI - Strategies for fostering basic psychological needs support in high quality youth leadership programs. AB - Youth leadership programming has become an increasingly common context to foster basic psychological needs and promote youth development. The purpose of this qualitative study was to explore strategies involved in fostering youth needs support within six leadership programs. Two leaders and 30 youth participated in semi-structured interviews to better understand the strategies used to foster needs support. Findings revealed that leaders were able to foster a sense of relatedness among youth through building trusting adult-youth relationships and nurturing an inclusive environment. Maximizing choice and negotiating youth voice helped to foster youth's autonomy. Finally, creating a task-oriented climate and providing intentional opportunities for skill-building helped to foster youth's competence. Findings suggest that training for leaders is critical in understanding what, and how strategies should be employed to help foster youth needs support in leadership programming. Limitations and future directions are outlined. PMID- 27984773 TI - The economic costs of intrapartum care in Tower Hamlets: A comparison between the cost of birth in a freestanding midwifery unit and hospital for women at low risk of obstetric complications. AB - OBJECTIVE: to compare the economic costs of intrapartum maternity care in an inner city area for 'low risk' women opting to give birth in a freestanding midwifery unit compared with those who chose birth in hospital. DESIGN: micro costing of health service resources used in the intrapartum care of mothers and their babies during the period between admission and discharge, data extracted from clinical notes. SETTING: the Barkantine Birth Centre, a freestanding midwifery unit and the Royal London Hospital's consultant-led obstetric unit, both run by the former Barts and the London NHS Trust in Tower Hamlets, a deprived inner city borough in east London, England, 2007-2010. PARTICIPANTS: maternity records of 333 women who were resident in Tower Hamlets and who satisfied the Trust's eligibility criteria for using the Birth Centre. Of these, 167 women started their intrapartum care at the Birth Centre and 166 started care at the Royal London Hospital. MEASUREMENTS AND FINDINGS: women who planned their birth at the Birth Centre experienced continuous intrapartum midwifery care, higher rates of spontaneous vaginal delivery, greater use of a birth pool, lower rates of epidural use, higher rates of established breastfeeding and a longer post-natal stay, compared with those who planned for care in the hospital. The total average cost per mother-baby dyad for care where mothers started their intrapartum care at the Birth Centre was L1296.23, approximately L850 per patient less than the average cost per mother and baby who received all their care at the Royal London Hospital. These costs reflect intrapartum throughput using bottom up costing per patient, from admission to discharge, including transfer, but excluding occupancy rates and the related running costs of the units. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: the study showed that intrapartum throughput in the Birth Centre could be considered cost-minimising when compared to hospital. Modelling the financial viability of midwifery units at a local level is important because it can inform the appropriate provision of these services. This finding from this study contribute a local perspective and thus further weight to the evidence from the Birthplace Programme in support of freestanding midwifery unit care for women without obstetric complications. PMID- 27984774 TI - Changes in aquatic toxicity of potassium dichromate as a function of water quality parameters. AB - Potassium dichromate (K2Cr2O7) is used as a general reference toxicant in aquatic toxicity testing, but relatively little is known regarding the effects of water quality parameters on K2Cr2O7 toxicity to Daphnia magna. The acute toxicity of K2Cr2O7 to D. magna was comparatively examined in one very hard (M4 medium for D. magna assay), four hard, one moderately hard and one soft dilution water samples. The 48-h EC50 (50% effective concentration) of K2Cr2O7 to D. magna was reproducible (coefficient of variation [CV]: 13%) in tests using the same dilution water sample, but reproducibility was poor (CV: 62%) in tests using seven different dilution water samples. The observed 48-h EC50 value increased with increasing water hardness (28-250 mg CaCO3/L) and Na+ concentration (4.3 19.7 mg Na/L). The effect of Ca2+ and Mg2+ on K2Cr2O7 toxicity was equivalent in terms of molar concentration. The 48-h EC50 for K2Cr2O7 was determined according to OECD TG 202 by six contract laboratories using M4 medium and were shown to be reproducible (CV: 15%), indicating that the toxicity level can be determined with high accuracy if holding and dilution water samples are standardized. Multiple regression analysis revealed that the 48-h EC50 was strongly correlated (r2 = 0.927) with the Ca2+, Mg2+, Na+ concentration, and alkalinity of the dilution water samples. Detailed monitoring of water quality characteristics thus facilitates intra- and inter-laboratory comparisons of toxicity data and enables predictions of changes in the susceptibility of test animals. PMID- 27984775 TI - Cetylpyridinium chloride at sublethal levels increases the susceptibility of rat thymic lymphocytes to oxidative stress. AB - Cetylpyridinium chloride (CPC) is an antimicrobial agent used in many personal care products, with subsequent release into the environment. Since CPC is found at low concentrations in river and municipal wastewater, its influence on wildlife is of concern. Therefore, in this study, we used flow cytometry to examine the effects of sublethal concentrations of CPC on rat thymic lymphocytes in order to characterize the cellular actions of CPC at low concentrations in the presence and absence of H2O2-induced oxidative stress. CPC treatment increased the population of living cells with phosphatidylserine exposed on the outer surface of their plasma membranes (a marker of early stage apoptosis), elevated intracellular Zn2+ levels, and decreased the cellular content of nonprotein thiols. CPC also potentiated the cytotoxicity of H2O2. Our results suggest that, even at environmentally relevant sublethal concentrations, CPC exerts cytotoxic effects under oxidative stress conditions by increasing intracellular Zn2+ concentration and decreasing the cellular content of nonprotein thiols. These findings indicate that, under some in vitro conditions, CPC is bioactive at environmentally relevant concentrations. Therefore, CPC release from personal care products into the environment may need to be regulated to avoid its adverse effects on wildlife. PMID- 27984776 TI - Mercury levels in largemouth bass (Micropterus salmoides) from regulated and unregulated rivers. AB - Within areas of comparable atmospheric mercury deposition rates methylmercury burden in largemouth bass populations vary significantly between regulated and unregulated rivers. To investigate if trophic dynamics strongly influenced pollutant body load, we sampled largemouth bass from two adjacent rivers, one regulated and one unregulated, and applied a suite of biochemical and stable isotope assays to compare their trophic dynamics. Total mercury burden in the bass from the unregulated Sipsey River (Elrod, AL, USA) and the regulated Black Warrior River (Demopolis, AL, USA) averaged 0.87 mg kg-1 and 0.19 mg kg-1 wet weight, respectively. For both populations, age, weight, and length were positively correlated with muscle mercury concentration. Compound specific stable isotope analysis of amino acids showed the trophic position of both populations was just under four. Quantitative and isotopic analysis of neutral lipid fatty acid of Sipsey River bass indicated a greater reliance upon the detrital component of the food web compared to Demopolis Reservoir bass which fed within the autochthonous, pelagic component of the food web. Since the close proximity of the rivers makes differences in atmospheric deposition unlikely and both populations had similar trophic position, our findings indicate that food web dynamics should be included among the factors that can strongly influence mercury concentration in fish. PMID- 27984777 TI - Concurrent administration of diethylhexyl phthalate reduces the threshold dose at which bisphenol A disrupts blastocyst implantation and cadherins in mice. AB - Many people are repeatedly exposed to both bisphenol A (BPA) and diethylhexyl phthalate (DEHP), but there has been little research concerning their effects in combination. Both can disrupt blastocyst implantation in inseminated females, albeit at high doses. We exposed mice on gestation days (GD) 1-4 to combinations of BPA and DEHP in doses below the threshold necessary to disrupt implantation on their own. On GD 6, there were fewer normally-developed implantation sites and more underdeveloped implantation sites in females given the combined subthreshold doses. Uterine epithelial cadherin (e-cadherin), a protein that assists in blastocyst adhesion to the uterine epithelium, was significantly reduced by these combined doses, but not by the individual doses. A similar trend was seen in integrin alphavbeta3, another uterine adhesion molecule. Cadherin-11 was disrupted by BPA but not DEHP. These data are consistent with competition of BPA and DEHP for conjugating enzymes. PMID- 27984778 TI - Oral administration of nano-titanium dioxide particle disrupts hepatic metabolic functions in a mouse model. AB - TiO2 nano-particle (TiO2 NP) is widely used in industrial, household necessities, as well as medicinal products. However, the effect of TiO2 NP on liver metabolic function has not been reported. In this study, after mice were orally administered TiO2 NP (21nm) for 14days, the serum and liver tissues were assayed by biochemical analysis, real time quantitative polymerase chain reaction, western blot and transmission electron microscopy. The serum bilirubin was increased in a dose dependent manner. Deposition of TiO2 NP in hepatocytes and the abnormality of microstructures was observed. Expression of metabolic genes involved in the endogenous and exogenous metabolism was modified, supporting the toxic phenotype. Collectively, oral administration of TiO2 NP (21nm) led to deposition of particles in hepatocytes, mitochondrial edema, and the disturbance of liver metabolism function. These data suggested oral administration disrupts liver metabolic functions, which was more sensitive than regular approaches to detect material hepatotoxicity. This study provided useful information for risk analysis and regulation of TiO2 NPs by administration agencies. PMID- 27984779 TI - Oxidative stress, endocrine disruption, and malformation of Bufo gargarizans embryo exposed to sub-lethal cadmium concentrations. AB - Thyroid hormone (TH) is critical for vertebrate postembryonic development as well as embryonic development. Chinese toad (Bufo gargarizans) embryos were exposed to different concentrations of cadmium (5, 50, 100, 200 and 500MUg Cd L-1) for 7days. Malformations were monitored daily, and growth and development of embryos were measured at day 4 and 7, and type 2 and 3 iodothyronine deiodinase (Dio2 and Dio3), thyroid hormone receptors (TRalpha and TRbeta) mRNA levels were also measured to assess disruption of TH synthesis. In addition, superoxide dismutase (SOD), glutathione peroxidase (GPx) and heat shock proteins (HSPs) mRNA expression were examined to evaluate the ability of scavenging ROS. Our results demonstrated a bimodal inhibitory effect of Cd on the embryo growth and development of Bufo gargarizans. Reduced mean stage, total length and weight were observed at 5, 50, 200 and 500, but not at 100MUg Cd L-1. Embryos malformation occurred in all cadmium treatments. Morphological abnormalities of embryos are characterized by axial flexures, abdominal edema, stunted growth and fin flexure. Real-time PCR results show that exposure to cadmium down-regulated TRalpha and Dio3 mRNA expression and up-regulated Dio2 mRNA level. SOD and GPx mRNA expression was significantly up-regulated after cadmium exposure. We concluded that cadmium could change mRNA expression of TRalpha, Dio2 and Dio3 leading the inhibition of growth and development of B. gargarizans embryo, which suggests that cadmium might have the endocrine-disrupting effect in embryos. Moreover, the reduced ability of scavenging ROS induced by cadmium might be responsible for the teratogenic effects of cadmium. PMID- 27984780 TI - High rates of CTX-M-15-producing Escherichia coli and Klebsiella pneumoniae in wild boars and Barbary macaques in Algeria. AB - OBJECTIVES: The present study aimed to screen for the presence of extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in wild boars and Barbary macaques in Bejaia and Jijel, Algeria. METHODS: A total of 216 faecal samples collected between September 2014 and August 2015 were cultured on MacConkey agar supplemented with 1MUg/mL ceftazidime. Isolates were identified by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF/MS). Antimicrobial susceptibility testing was performed by the disk diffusion method, and ESBLs were characterised by PCR and sequencing. Clonal relatedness was studied by multilocus sequence typing (MLST). RESULTS: A total of 47 ESBL-producing isolates were recovered from faecal samples from 40 (44%) of 90 wild boars and 7 (6%) of 126 from Barbary macaques, including 30 Escherichia coli and 17 Klebsiella pneumoniae. Results of PCR and sequencing analysis showed that all of the isolates produced CTX-M-15, and 25 isolates co-produced TEM-1. MLST demonstrated the presence of eight sequence types (STs) among the E. coli isolates (ST617, ST131, ST648, ST405, ST1431, ST1421, ST69 and ST226), whereas only one clone (ST584) was identified for all isolates of K. pneumoniae recovered from wild boars (n=10) and Barbary macaques (n=7). CONCLUSIONS: This is the first report of CTX-M-15-producing E. coli and K. pneumoniae in wild animals from Algeria. The results show that African wildlife can act as a reservoir of the epidemic E. coli clone ST131 producing CTX-M-15, suggesting that this lineage can survive in different ecological niches and adapt to different hosts. PMID- 27984781 TI - Simvastatin augments revascularization and reperfusion in a murine model of hind limb ischemia - Multimodal imaging assessment. AB - INTRODUCTION: Peripheral artery disease can lead to severe disability and limb loss. Therapeutic strategies focussing on macrovascular repair have shown benefit but have not significantly reduced amputation rates in progressive PAD. Proangiogenic small molecule therapies may substantially improve vascularisation in limb ischemia. The purpose of the current study was to assess the proangiogenic effects of simvastatin in a murine model of hind limb ischemia using longitudinal multimodal imaging. METHODS: Mice underwent surgical intervention to induce hind limb ischemia, and were treated with simvastatin orally for 28days. Neovascularisation was assessed using 99mTc-RGD SPECT imaging, and macrovascular volume was assessed by quantitative time of flight MRI. At each imaging time point, VEGF expression and capillary vessel density were quantified using immunohistochemical analysis. RESULTS: Simvastatin significantly increased 99mTc-RGD retention in the ischemic hind limb by day 3 post-surgery, with maximal retention at day 8. Vascular volume was significantly increased in the ischemic hind limb of simvastatin treated animals, but only by day 22. Immunohistochemical analysis shows that simvastatin significantly augmented tissue VEGF expression from day 8 with increase in capillary density (CD31+) from day 14. CONCLUSIONS: Early assessment of proangiogenic therapy efficacy can be identified using 99mTc RGD SPECT, which displays significant increases in retention before macrovascular volume changes are measureable with MRI. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Simvastatin offers an effective proangiogenic therapy as an adjunct for management of limb ischemia. Simvastatin induces integrin expression and vascular remodeling leading to neovascularisation and improved perfusion. PMID- 27984783 TI - Autophagic targeting and avoidance in intracellular bacterial infections. AB - Eukaryotic cells use autophagy to break down and recycle components such as aggregated proteins and damaged organelles. Research in the past decade, particularly using Salmonella enterica serovar Typhimurium as a model pathogen, has revealed that autophagy can also target invading intracellular bacterial pathogens for degradation. However, many bacterial pathogens have evolved mechanisms that allow for evasion of the autophagic pathway, such as motility or direct and irreversible cleavage of proteins that comprise the autophagic machinery. As a complete and detailed understanding of the autophagic pathway and its derivatives continues to develop, it is likely that other mechanisms of inhibition by bacterial pathogens will be discovered. PMID- 27984784 TI - Porcine deltacoronavirus nsp5 inhibits interferon-beta production through the cleavage of NEMO. AB - Porcine deltacoronavirus (PDCoV) causes acute enteric disease and mortality in seronegative neonatal piglets. Previously we have demonstrated that PDCoV infection suppresses the production of interferon-beta (IFN-beta), while the detailed mechanisms are poorly understood. Here, we demonstrate that nonstructural protein 5 (nsp5) of PDCoV, the 3C-like protease, significantly inhibits Sendai virus (SEV)-induced IFN-beta production by targeting the NF kappaB essential modulator (NEMO), confirmed by the diminished function of NEMO cleaved by PDCoV. The PDCoV nsp5 cleavage site in the NEMO protein was identified as glutamine 231, and was identical to the porcine epidemic diarrhea virus nsp5 cleavage site, revealing the likelihood of a common target in NEMO for coronaviruses. Furthermore, this cleavage impaired the ability of NEMO to activate the IFN response and downstream signaling. Taken together, our findings reveal PDCoV nsp5 to be a newly identified IFN antagonist and enhance the understanding of immune evasion by deltacoronaviruses. PMID- 27984782 TI - NK cells in host responses to viral infections. AB - Natural killer (NK) cells are cytotoxic innate lymphocytes that play an important role in viral clearance. NK cell responses to viral infections were originally believed to be non-specific and lacked immune memory recall responses. It is now appreciated that NK cell responses to viral infections can be specific and in some cases memory recall responses are established. Increasing evidence also illuminates the complexity of NK cell interactions with both innate and adaptive immune cells. Here, we summarize the evidence for NK cell-specific memory responses to viral infections and the intricate reciprocal interactions between NK cells and other immune cells that dictate their activation and effector functions. PMID- 27984785 TI - Comparison of N- and O-linked glycosylation patterns of ebolavirus glycoproteins. AB - Ebolaviruses are emerging pathogens that cause severe and often fatal viral hemorrhagic fevers. Four distinct ebolaviruses are known to cause Ebola virus disease in humans. The ebolavirus envelope glycoprotein (GP1,2) is heavily glycosylated, but the precise glycosylation patterns of ebolaviruses are largely unknown. Here we demonstrate that approximately 50 different N-glycan structures are present in GP1,2 derived from the four pathogenic ebolaviruses, including high mannose, hybrid, and bi-, tri-, and tetra-antennary complex glycans with and without fucose and sialic acid. The overall N-glycan composition is similar between the different ebolavirus GP1,2s. In contrast, the amount and type of O glycan structures varies widely between ebolavirus GP1,2s. Notably, this O-glycan dissimilarity is also present between two variants of Ebola virus, the original Yambuku variant and the Makona variant responsible for the most recent Western African epidemic. The data presented here should serve as the foundation for future ebolaviral entry and immunogenicity studies. PMID- 27984786 TI - Enhancement of antibiotic-activity through complexation with metal ions - Combined ITC, NMR, enzymatic and biological studies. AB - Alternative solutions need to be developed to overcome the growing problem of multi-drug resistant bacteria. This study explored the possibility of creating complexes of antibiotics with metal ions, thereby increasing their activity. Analytical techniques such as isothermal titration calorimetry and nuclear magnetic resonance were used to examine the structure and interactions between Cu(II), Ag(I) or Zn(II) and beta-lactam antibiotics. The metal-beta-lactam complexes were also tested for antimicrobial activity, by micro-broth dilution and disk diffusion methods, showing a synergistic increase in the activity of the drugs, and enzymatic inhibition assays confirming inhibition of beta-lactamases responsible for resistance. The metal-antibiotic complex concept was proven to be successful with the activity of the drugs enhanced against beta-lactamase producing bacteria. The highest synergistic effects were observed for complexes formed with Ag(I). PMID- 27984787 TI - Pathways from uncertainty to anxiety: An evaluation of a hierarchical model of trait and disorder-specific intolerance of uncertainty on anxiety disorder symptoms. AB - Uncertainty is central to anxiety-related pathology and intolerance of uncertainty (IU) appears to be a transdiagnostic risk and maintaining factor. The aim of the present study was to evaluate a hierarchical model to identify the unique contributions of trait and disorder-specific IU (i.e., uncertainty specific to generalised anxiety disorder, social anxiety, obsessive compulsive disorder, and panic disorder) to disorder-specific symptoms, beyond other disorder-specific cognitive vulnerabilities (i.e., negative metacognitive beliefs, fear of negative evaluation, inflated responsibility, and agoraphobic cognitions, respectively). Participants (N=506) completed a battery of online questionnaires. Structural equation modelling was used to evaluate model fit, as well as direct and indirect pathways. Trait and disorder-specific IU were significantly associated with multiple cognitive vulnerability factors and disorder symptoms. Indirect effects between trait IU and symptoms were observed through disorder-specific IU and cognitive vulnerabilities. The relative contribution of trait IU and disorder-specific IU to symptoms varied and theoretical and clinical implications are highlighted. Limitations include the cross-sectional design and reliance on self-report. Avenues for further research include a need for replication and extension of the model in different samples and using experimental and multi-method research methods. PMID- 27984788 TI - Disentangling meaning in the brain: Left temporal involvement in agreement processing. AB - Sentence comprehension is successfully accomplished by means of a form-to-meaning mapping procedure that relies on the extraction of morphosyntactic information from the input and its mapping to higher-level semantic-discourse representations. In this study, we sought to determine whether neuroanatomically distinct brain regions are involved in the processing of different types of information contained in the propositional meaning of a sentence, namely person and number. While person information indexes the role that an individual has in discourse (i.e., the speaker, the addressee or the entity being talked about by speaker and addressee), number indicates its cardinality (i.e., a single entity vs a multitude of entities). An event-related functional magnetic resonance imaging (fMRI) experiment was run using agreement-Correct and Person- and Number violated sentences in Spanish, to disentangle the processing mechanisms and neural substrates associated with the building of discourse and cardinality representations. The contrast between Person and Number Violations showed qualitative and quantitative differences. A greater response for person compared to number was found in the left middle temporal gyrus (LMTG). However, critically, a posterior-to-anterior functional gradient emerged within this region. While the posterior portion of the LMTG was sensitive to both Person and Number Violations, the anterior portion of this region showed selective response for Person Violations. These results confirm that the comprehension of the propositional meaning of a sentence results from a composite, feature-sensitive mechanism of form-to-meaning mapping in which the nodes of the language network are differentially involved. PMID- 27984789 TI - Concussion reporting, sex, and conformity to traditional gender norms in young adults. AB - This study assessed whether between-sex differences in concussion reporting intention and behavior among young adults are explained by the extent to which the individual conforms to traditional masculine norms that often characterize contemporary sport culture. A survey of college athletes in the United States (n = 328) found greater symptom reporting intention among females as compared to males, but no difference in their likelihood continued play while experiencing symptoms of a possible concussion. Greater conformity to the norms of risk-taking was associated with greater likelihood of continued play while symptomatic among female athletes but not among male athletes. These findings suggest that gendered behavior, rather than biologically determined sex, is an important consideration for concussion safety in this age group. Addressing elements of the contemporary sport ethos that reinforce risk taking in service of athletic achievement may be a relevant direction for interventions aimed at improving injury reporting among all athletes. PMID- 27984791 TI - Does economic, financial and institutional developments matter for environmental quality? A comparative analysis of EU and MEA countries. AB - The aim of this study is to test the hypothesis of the Environmental Kuznets Curve (EKC) with a sample of 58 MEA (Middle East & African) and 41 EU (European Union) countries for the period 1990 to 2011. The empirical analysis is carried out using the GMM-system method to solve the problem of endogenous variables. We focused on direct and indirect effects of institutional quality (through the efficiency of public expenditure, financial development, trade openness and foreign direct investment) and the income-emission relationship. We found a monotonically increasing relationship between CO2 emissions and GDP in both MEA and EU regions. The policy implication is clear: in order to have sustainable positive economic performance and to reduce carbon dioxide emission in the country at the same time, policy makers should regulate and enhance the role and efficiency of domestic institutions. PMID- 27984793 TI - Sludge from paper mill effluent treatment as raw material to produce carbon adsorbents: An alternative waste management strategy. AB - Pulp and paper industry produces massive amounts of sludge from wastewater treatment, which constitute an enormous environmental challenge. A possible management option is the conversion of sludge into carbon-based adsorbents to be applied in water remediation. For such utilization it is important to investigate if sludge is a consistent raw material originating reproducible final materials (either over time or from different manufacturing processes), which is the main goal of this work. For that purpose, different primary (PS) and biological sludge (BS) batches from two factories with different operation modes were sampled and subjected to pyrolysis (P materials) and to pyrolysis followed by acid washing (PW materials). All the materials were characterized by proximate analysis, total organic carbon (TOC) and inorganic carbon (IC), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and N2 adsorption isotherms (specific surface area (SBET)and porosity determination). Sludge from the two factories proved to have distinct physicochemical properties, mainly in what concerns IC. After pyrolysis, the washing step was essential to reduce IC and to considerably increase SBET, yet with high impact in the final production yield. Among the materials here produced, PW materials from PS were those having the highest SBET values (387-488 m2 g-1). Overall, it was found that precursors from different factories might originate final materials with distinct characteristics, being essential to take into account this source of variability when considering paper mill sludge as a raw material. Nevertheless, for PS, low variability was found between batches, which points out to the reliability of such residues to be used as precursors of carbon adsorbents. PMID- 27984792 TI - Collating science-based evidence to inform public opinion on the environmental effects of marine drilling platforms in the Mediterranean Sea. AB - The use of rigorous methodologies to assess environmental, social and health impacts of specific interventions is crucial to disentangle the various components of environmental questions and to inform public opinion. The power of systematic maps relies on the capacity to summarise and organise the areas or relationships most studied, and to highlight key gaps in the evidence base. The recent Italian technical referendum (2016) - a public consultation inviting people to express their opinion by voting to change the rules on the length of licence duration and the decommissioning of offshore oil and gas platform drilling licences - inspired the creation of a systematic map of evidence to scope and quantify the effects of off-shore extraction platforms on Mediterranean marine ecosystems. The map was aimed as a useful model to standardise a "minimal informational threshold", which can inform public opinion at the beginning of any public consultation. Produced by synthesising scientific information, the map represents a reliable layer for any future sustainable strategy in the Mediterranean basin by: (i) providing a summary of the effects of marine gas and oil platforms on the Mediterranean marine ecosystem, (ii) describing the best known affected components on which the biggest monitoring efforts have been focused, and (iii) strengthening the science-policy nexus by offering a credible, salient and legitimate knowledge baseline to both public opinion and decision makers. The map exercise highlights the knowledge gaps that need filling and taking into due consideration before future transnational and cross-border monitoring and management plans and activities can be addressed. PMID- 27984794 TI - Can stream and riparian restoration offset climate change impacts to salmon populations? AB - Understanding how stream temperature responds to restoration of riparian vegetation and channel morphology in context of future climate change is critical for prioritizing restoration actions and recovering imperiled salmon populations. We used a deterministic water temperature model to investigate potential thermal benefits of riparian reforestation and channel narrowing to Chinook Salmon populations in the Upper Grande Ronde River and Catherine Creek basins in Northeast Oregon, USA. A legacy of intensive land use practices in these basins has significantly reduced streamside vegetation and increased channel width across most of the stream network, resulting in water temperatures that far exceed the optimal range for salmon growth and survival. By combining restoration scenarios with climate change projections, we were able to evaluate whether future climate impacts could be offset by restoration actions. A combination of riparian restoration and channel narrowing was predicted to reduce peak summer water temperatures by 6.5 degrees C on average in the Upper Grande Ronde River and 3.0 degrees C in Catherine Creek in the absence of other perturbations. These results translated to increases in Chinook Salmon parr abundance of 590% and 67% respectively. Although projected climate change impacts on water temperature for the 2080s time period were substantial (i.e., median increase of 2.7 degrees C in the Upper Grande Ronde and 1.5 degrees C in Catherine Creek), we predicted that basin-wide restoration of riparian vegetation and channel width could offset these impacts, reducing peak summer water temperatures by about 3.5 degrees C in the Upper Grande Ronde and 1.8 degrees C in Catherine Creek. These results underscore the potential for riparian and stream channel restoration to mitigate climate change impacts to threatened salmon populations in the Pacific Northwest. PMID- 27984795 TI - Phenolic sensor development based on chromium oxide-decorated carbon nanotubes for environmental safety. AB - A nanocomposite (NC) composed of chromium(III)oxide nanomaterials decorated carbon nanotubes (Cr2O3-CNT NC) was prepared via a simple solution method with reducing agents in an alkaline medium. The Cr2O3-CNT NC was characterized using ultraviolet-visible (UV/Vs.) spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, energy-dispersive X-ray spectroscopy (XEDS), X-ray powder diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and field-emission scanning electron microscopy (FESEM). The Cr2O3-CNT composite was deposited on a flat glassy carbon electrode (GCE) with conducting nafion (5%) binders to produce a sensor that exhibited fast response and high selectivity toward 4-methoxyphenol (4MP) in phosphate buffer phase at pH 7. Furthermore, the sensor performance parameters, including the sensitivity, lower detection range, reliability, and reproducibility, ease of integration, long-term stability, and selectivity were investigated in detail. The calibration plot was found to be linear in the concentration range of 0.01 nM-0.1 MUM. The sensitivity and detection limit were calculated as 1.4768 MUA cm-2 MUM-1 and 0.06428 +/- 0.0002 nM (at a signal-to noise ratio of 3), respectively. Thus, it was concluded that the proposed selective and efficient sensor represents a promising approach to effectively detect toxic phenolic compounds in the environment with acceptable and reliable results. PMID- 27984796 TI - Power dynamics in the student-teacher relationship in clinical settings. AB - BACKGROUND: Among many factors that influence clinical learning, the teacher student relationship has been found to be crucial. The imbalance of power in that relationship tends to be regarded as negative, but how students actually perceive the power within the relationship is unknown. AIM: This study explored nurse students' perceptions of the power dynamics in the teacher-student relationship during their clinical placement. DESIGN: A descriptive qualitative study. METHODS: A total of 51 students were recruited from a nursing school in Hong Kong. Seven focus group interviews consisted of three groups of Year 3 students (n=26) and four groups of final year students (n=25). A semi-structured interview guideline was designed. Content analysis was employed to analyse the research data. RESULTS: The three core themes that emerged from the qualitative data were: (1) meanings of power - avoiding doing harm to patients; (2) the desired power dynamics - master vs apprentice; and (3) enhancing the clinical learning experience. CONCLUSIONS: The dominant theme in the participants' discourse was that teachers should possess more power than students in order to prevent students from causing harm to patients. The consensus was that the teacher's power in supervising students' clinical practice is accepted and necessary for the benefit of patient safety. The cultural relevance of the power dynamics in the teacher-student relationship should be embraced in order to understand the student's perspective. PMID- 27984790 TI - A review of redox signaling and the control of MAP kinase pathway in plants. AB - Mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved modules among eukaryotic species that range from yeast, plants, flies to mammals. In eukaryotic cells, reactive oxygen species (ROS) has both physiological and toxic effects. Both MAPK cascades and ROS signaling are involved in plant response to various biotic and abiotic stresses. It has been observed that not only can ROS induce MAPK activation, but also that disturbing MAPK cascades can modulate ROS production and responses. This review will discuss the potential mechanisms by which ROS may activate and/or regulate MAPK cascades in plants. The role of MAPK cascades and ROS signaling in regulating gene expression, stomatal function, and programmed cell death (PCD) is also discussed. In addition, the relationship between Rboh-dependent ROS production and MAPK activation in PAMP triggered immunity will be reviewed. PMID- 27984797 TI - On the mechanism of substrate/non-substrate recognition by P-glycoprotein. AB - P-Glycoprotein (P-gp, multi-drug resistance protein, MDR1) plays a gatekeeper role, interfering delivery of multiple pharmaceuticals to the target tissues and cells. We performed Molecular Dynamics (MD) simulations to generate fifty side chain variants for P-gp (PDB ID: 4Q9H-L) followed by docking of 31 drugs (0.6<=ER<=22.7) to the whole surface except the ATPase domains and the extracellular part. A selection of the most negative energy complex for each ligand followed. All compounds docked to the two areas - the main binding cavity at the top of P-gp (12.5% of compounds with ER<1; 44.4% of 1<=ER<=2; and 100% of ER>2), and the binding sites in the middle of P-gp (87.5% of ER<1; 55.6% of 1<=ER<=2; and 0% of ER>2). Our results show that anti-substrates (ER<1), intermediate compounds (1<=ER<=2) and strong substrates (ER>2) might behave differently in relation to the P-gp. According to our calculations, the anti substrates almost do not bind the main binding cavity (MBC) of P-gp and rather approach the other binding sites on the protein; the substrates preferably bind the MBC; the intermediate compounds with 1<=ER<=2 bind both MBC and other binding sites almost equally. The modelling results are in line with the known hypothesis that binding the MBC is prerequisite for the pumping the compound off the P-gp. PMID- 27984798 TI - Alchemical determination of drug-receptor binding free energy: Where we stand and where we could move to. AB - Alchemical molecular dynamics simulations for evaluating the binding free energy in ligand-receptor systems are emerging a new powerful tool for in silico drug discovery projects. Nonetheless, theoretical and technical challenges for these methodologies remain high and their use in industrial applications is still limited. In this contribution, the many variants of the alchemical approach are critically revised, discussing their strengths as well as their pitfalls and entanglements and placing existing computational theories into the broader context of nonequilibrium thermodynamics. PMID- 27984799 TI - Antidiabetic activity of Embelia ribes, embelin and its derivatives: A systematic review and meta-analysis. AB - Embelia ribes (ER) has been documented in Ayurveda for treating various diseases, including diabetes mellitus (DM). The present systematic review and meta-analysis evaluated the efficacy and safety of ER and its active bio-marker, embelin and its derivatives in the treatment of DM. Literature search was performed in PubMed/MEDLINE, EMBASE, Scopus, ScienceDirect, Scifinder, and Google Scholar. Using Review Manager, meta-analysis of ER/embelin/derivatives of embelin versus diabetic control was performed with inverse-variance model, providing mean differences (MDs) and 95% confidence intervals (CIs). Heterogeneity was determined by I2 statistic. A total of 13 studies were included in the systematic review and meta-analysis, and were conducted in experimental rats. ER and embelin significantly (P<=0.01) resorted blood glucose (MD, -231.30; CI, -256.79, 205.82; and MD, -154.70; CI, -168.65, -140.74) and glycosylated haemoglobin (MD, 6.36; CI, -8.33, -4.39; and MD,-4.68; CI, -7.76, -1.60), respectively. Meta analysis findings also reported considerable restoration of insulin, lipid profile, haemodynamic parameters, serum and oxidative stress markers. The derivatives of embelin, 6-bromoembelin and vilangin, also improved diabetic condition. In addition, treatments also ameliorated body weight changes due to diabetes. The present systematic review and meta-analysis supports scientific evidence for the antidiabetic activity of ER/embelin/derivatives of embelin. However, further research is warranted in clinical trials to validate the present findings. PMID- 27984800 TI - Saponins from the roots of Platycodon grandiflorum ameliorate high fat diet induced non-alcoholic steatohepatitis. AB - Platycodon grandiflorum has been healthy effects due to its various nutritious compounds and is considered as a functional food. Platycodon grandiflorum root derived saponins (CKS) have been reported to show a variety of effects including anti-inflammatory and anti-oxidative activity. Although CKS have been studied on various bioactivities, the inhibitory effect of CKS on non-alcoholic steatohepatitis (NASH) is not examined. In this study, the inhibitory effects on HFD-induced NASH by CKS were determined. CKS suppressed HFD-induced hepatic lipid peroxidation level, collagen deposition, pro-fibrogenic and pro-inflammatory cytokines expression. CKS treatment suppressed HFD-induced COX-2 expression via inhibition of NF-kappaB p65 nuclear translocation and IkappaBalpha degradation. CKS treatment restored HFD-reduced Nrf2-mediated antioxidant enzymes expression. Furthermore, CKS treatment reinstated HFD-reduced peroxisomal proliferator activated receptor alpha (PPARalpha)-regulated acyl-coA oxidase and carnitine palmitoyl-coA transferase-1 expression. These findings suggest that CKS reduces HFD-induced NASH by up-regulation of Nrf2-mediated anti-oxidant enzymes and PPARalpha-regulated fatty acid oxidation. PMID- 27984801 TI - Isolation of PCR ready-human DNA using copper nanoparticles from skeletal remains. AB - Present study represents a novel approach of PCR ready-human DNA extraction method from skeletal remains using copper nanoparticles (CuNPs) for personnel identification. To achieve rapid, cost effective, sensitive and non-hazardous method for DNA extraction we utilized CuNPs synthesized using microwave. The applicability of this approach was first tested in blood samples and afterwards, this system was extended to skeletal remains' samples also. This method yields good quality DNA that are ready for PCR reactions from small quantities of blood and skeletal remains. Consequently, even small quantities of nanoparticles could be potentially utilized for a highly efficient isolation of DNA from skeletal remains as well as from ancient archaeological samples. The present method has the advantages that it is quick with high yield, inexpensive, robust, environment friendly and does not require use of hazardous organic solvents. PMID- 27984802 TI - Microbial soil community analyses for forensic science: Application to a blind test. AB - Soil complexity, heterogeneity and transferability make it valuable in forensic investigations to help obtain clues as to the origin of an unknown sample, or to compare samples from a suspect or object with samples collected at a crime scene. In a few countries, soil analysis is used in matters from site verification to estimates of time after death. However, up to date the application or use of soil information in criminal investigations has been limited. In particular, comparing bacterial communities in soil samples could be a useful tool for forensic science. To evaluate the relevance of this approach, a blind test was performed to determine the origin of two questioned samples (one from the mock crime scene and the other from a 50:50 mixture of the crime scene and the alibi site) compared to three control samples (soil samples from the crime scene, from a context site 25m away from the crime scene and from the alibi site which was the suspect's home). Two biological methods were used, Ribosomal Intergenic Spacer Analysis (RISA), and 16S rRNA gene sequencing with Illumina Miseq, to evaluate the discriminating power of soil bacterial communities. Both techniques discriminated well between soils from a single source, but a combination of both techniques was necessary to show that the origin was a mixture of soils. This study illustrates the potential of applying microbial ecology methodologies in soil as an evaluative forensic tool. PMID- 27984803 TI - Identification of new bacteria harboring qnrS and aac(6')-Ib/cr and mutations possibly involved in fluoroquinolone resistance in raw sewage and activated sludge samples from a full-scale WWTP. AB - Wastewater treatment plants (WWTPs) harbor bacteria and antimicrobial resistance genes, favoring gene exchange events and resistance dissemination. Here, a culture-based and metagenomic survey of qnrA, qnrB, qnrS, and aac(6')-Ib genes from raw sewage (RS) and activated sludge (AS) of a full-scale municipal WWTP was performed. A total of 96 bacterial isolates were recovered from nalidixic acid enrichment cultures. Bacteria harboring the aac(6')-Ib gene predominated in RS, whereas qnrS-positive isolates were specific to AS. Novel qnrS- and aac(6')-Ib-cr positive species were identified: Morganella morganii, Providencia rettgeri, and Pseudomonas guangdongensis (qnrS), and Alcaligenes faecalis and P. rettgeri (aac(6')-Ib-cr). Analysis of qnrS and aac(6')-Ib sequences from isolates and clone libraries suggested that the diversity of qnrS is wider than that of aac(6')-Ib. A large number of amino acid mutations were observed in the QnrS and AAC(6')-Ib proteins at previously undetected positions, whose structural implications are not clear. An accumulation of mutations at the C72, Q73, L74, A75 and M76 positions of QnrS, and D181 of AAC(6')-Ib might be important for resistance. These findings add significant information on bacteria harboring qnrS and aac(6')-Ib genes, and the presence of novel mutations that may eventually emerge in clinical isolates. PMID- 27984804 TI - On constitutive functions for hindered settling velocity in 1-D settler models: Selection of appropriate model structure. AB - Advanced 1-D models for Secondary Settling Tanks (SSTs) explicitly account for several phenomena that influence the settling process (such as hindered settling and compression settling). For each of these phenomena a valid mathematical expression needs to be selected and its parameters calibrated to obtain a model that can be used for operation and control. This is, however, a challenging task as these phenomena may occur simultaneously. Therefore, the presented work evaluates several available expressions for hindered settling based on long-term batch settling data. Specific attention is paid to the behaviour of these hindered settling functions in the compression region in order to evaluate how the modelling of sludge compression is influenced by the choice of a certain hindered settling function. The analysis shows that the exponential hindered settling forms, which are most commonly used in traditional SST models, not only account for hindered settling but partly lump other phenomena (compression) as well. This makes them unsuitable for advanced 1-D models that explicitly include each phenomenon in a modular way. A power-law function is shown to be more appropriate to describe the hindered settling velocity in advanced 1-D SST models. PMID- 27984805 TI - Formation of 2,6-dichloro-1,4-benzoquinone from aromatic compounds after chlorination. AB - Halobenzoquinones are a group of disinfection byproducts formed by chlorination of certain substances in water. However, to date, the identities of halobenzoquinone precursors remain unknown. In this study, the formation of 2,6 dichloro-1,4-benzoquinone (DCBQ), a typical halobenzoquinone, from 31 aromatic compounds was investigated after 60 min of chlorination. DCBQ was formed from 21 compounds at molar formation yields ranging from 0.0008% to 4.9%. Phenol and chlorinated phenols served as DCBQ precursors, as reported previously. Notably, DCBQ was also formed from para-substituted phenolic compounds. Compounds with alkyl and carboxyl groups as para-substituents led to relatively higher molar formation yields of DCBQ. Moreover, p-quinone-4-chloroimide, 2,6-dichloroquinone 4-chloroimide (2,6-DCQC), and para-substituted aromatic amines (e.g., aniline and N-methyl aniline) served as DCBQ precursors upon chlorination. It was deduced that DCBQ was formed from the para-substituted aromatic amines via 3,5 dichloroquinone-4-chloroimide, a structural isomer of 2,6-DCQC. These results suggested that DCBQ was formed by chlorination of natural organic matter containing para-substituted phenolic species and para-substituted aromatic amines, despite the absence of phenol in water. PMID- 27984806 TI - The intoxicated EEG. PMID- 27984807 TI - BRAF V600E mutation in epilepsy-associated glioneuronal tumors: Prevalence and correlation with clinical features in a Chinese population. AB - PURPOSE: Glioneuronal tumors (GNTs) are the most common histological type of brain tumors in patients who received epilepsy surgery, and part of them presented with BRAF V600E mutation. We aimed to verify the presence of the BRAF V600E mutation in epilepsy-associated GNTs from Chinese population and evaluate the association with clinical features. METHODS: Data from 35 patients diagnosed with GNTs, including 24 gangliogliomas and 11 dysembryoplastic neuroepithelial tumors, were retrospectively collected. DNA was extracted from GNTs tissues and BRAF V600E mutation was examined by DNA sequencing. The correlations between BRAF V600E mutation and clinical features were analyzed. RESULTS: Totally, BRAF V600E mutations were detected in 11 patients with GNTs, the rate of mutation were 33.3% and 27.3% in GGs (8/24) and DNTs (3/11), respectively. The probability of BRAF V600E mutation in females (7/12, 58.3%) was significantly higher than that in males (4/23, 17.4%) (P=0.022). Moreover, patients with BRAF-mutated GNTs had a significantly wider variety of seizure types compared to GNTs with BRAF wild-type status (P=0.027). However, no significant correlation between the BRAF status and certain clinical features, such as age of seizure onset, duration of epilepsy, age at surgery, location of the tumor and postoperative seizure free, were observed. CONCLUSION: We demonstrated the presence of BRAF V600E mutation in Chinese epileptic patients with GNTs, which was significantly correlated with gender and multiple seizure types. Large sample studies and long-term follow-up are required for further confirmation. PMID- 27984808 TI - Screening of anxiety and quality of life in people with epilepsy. AB - PURPOSE: Up to 60% of people with epilepsy (PwE) have psychiatric comorbidity including anxiety. Anxiety remains under recognized in PwE. This study investigates if screening tools validated for depression could be used to detect anxiety disorders in PWE. Additionally it analyses the effect of anxiety on QoL. METHOD: 261 participants with a confirmed diagnosis of epilepsy were included. Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Emotional Thermometers (ET), both validated to screen for depression were used. Hospital Anxiety and Depression Scale-Anxiety (HADS-A) with a cut off for moderate and severe anxiety was used as the reference standard. QoL was measured with EQ5-D. Sensitivity, specificity, positive and negative predictive value and ROC analysis as well as multivariate regression analysis were performed. RESULTS: Patients with depression (n=46) were excluded as multivariate regression analysis showed that depression was the only significant determinant of having anxiety in the group. Against HADS-A, NDDI-E and ET-7 showed highest level of accuracy in recognizing anxiety with ET7 being the most effective tool. QoL was significantly reduced in PwE and anxiety. CONCLUSION: Our study showed that reliable screening for moderate to severe anxiety in PwE without co-morbid depression is feasible with screening tools for depression. The cut off values for anxiety are different from those for depression in ET7 but very similar in NDDI-E. ET7 can be applied to screen simultaneously for depression and "pure" anxiety. Anxiety reduces significantly QoL. We recommend screening as an initial first step to rule out patients who are unlikely to have anxiety. PMID- 27984809 TI - Clinical outcomes in patients with generalized periodic discharges. AB - PURPOSE: Generalized periodic discharges (GPDs) are frequently identified in the EEGs of hospitalized patients but their prognostic significance remains unclear. We retrospectively reviewed clinical data in patients with GPDs to elucidate factors associated with in-hospital mortality. METHOD: We reviewed data from inpatients at three different hospitals affiliated with our institution in whom GPDs were reported on routine EEGs by fellowship-trained electroencephalographers during the years 2010-2012. Cox regression was used to determine statistical association between in-hospital death and demographics, medical comorbidities, neurological and neuroimaging abnormalities and antiepileptic drug use. RESULTS: We identified 113 patients with GPDs. The mean age was 70.4 years and 70 (61.9%) were women. There were 60 inpatient deaths (53.1%). The variables significantly associated with in-hospital mortality were dementia, poor mental status at the time of the EEG, chronic focal abnormalities on neuroimaging, cardiac arrest and chronic obstructive pulmonary disease (COPD). CONCLUSION: Dementia, poor mental status during EEG, chronic focal abnormalities on neuroimaging, cardiac arrest and COPD are independently associated with increased in-hospital mortality in patients with GPDs (P<0.05). PMID- 27984810 TI - Decreasing prevalence of social drinkers in Australia. AB - INTRODUCTION: There has been a recent decrease in population level alcohol consumption in Australia, particularly in young people. Whether this is due to increasing abstinence or a shift in the way people think about alcohol is not known. The aim of this study is to investigate trends in self-identification of drinker types in Australia from 2001 to 2013 in light of shifting patterns of alcohol consumption in Australia. METHODS: Five waves of the National Drug Strategy Household Survey from 2001 to 2013 (N=118,416) were used to assess trends in self-identification as a drinker type (non-, ex-, occasional, light, social, heavy and binge drinker). Consumption patterns and demographics of the self-identified groups were also examined. RESULTS: The pattern of self identification has mostly remained steady over time. The two exceptions to this are a decrease in identification as a social drinker (28% to 22%) and a corresponding increase in identification as a non-drinker (from 19% to 27%). There are few changes over time in the demographic make-up of, or consumption patterns in, the social drinker category with the exception of those over 50, who continue to identify as social drinkers at the same rate. CONCLUSION: The recent increase in abstinence in Australia seems to be matched by a corresponding decrease in self-identified social drinkers, particularly among those under 50. This indicates that the decrease in consumption is not occurring in those most likely to experience harms. PMID- 27984811 TI - Path-sampling strategies for simulating rare events in biomolecular systems. AB - Despite more than three decades of effort with molecular dynamics simulations, long-timescale (ms and beyond) biologically relevant phenomena remain out of reach in most systems of interest. This is largely because important transitions, such as conformational changes and (un)binding events, tend to be rare for conventional simulations (<10MUs). That is, conventional simulations will predominantly dwell in metastable states instead of making large transitions in complex biomolecular energy landscapes. In contrast, path sampling approaches focus computing effort specifically on transitions of interest. Such approaches have been in use for nearly 20 years in biomolecular systems and enabled the generation of pathways and calculation of rate constants for ms processes, including large protein conformational changes, protein folding, and protein (un)binding. PMID- 27984813 TI - The role of personality traits and driving experience in self-reported risky driving behaviors and accident risk among Chinese drivers. AB - The purpose of this study was to explore the role of personality traits and driving experience in the prediction of risky driving behaviors and accident risk among Chinese population. A convenience sample of drivers (n=511; mean (SD) age=34.2 (8.8) years) completed a self-report questionnaire that was designed based on validated scales for measuring personality traits, risky driving behaviors and self-reported accident risk. Results from structural equation modeling analysis demonstrated that the data fit well with our theoretical model. While showing no direct effects on accident risk, personality traits had direct effects on risky driving behaviors, and yielded indirect effects on accident risk mediated by risky driving behaviors. Both driving experience and risky driving behaviors directly predicted accident risk and accounted for 15% of its variance. There was little gender difference in personality traits, risky driving behaviors and accident risk. The findings emphasized the importance of personality traits and driving experience in the understanding of risky driving behaviors and accident risk among Chinese drivers and provided new insight into the design of evidence-based driving education and accident prevention interventions. PMID- 27984814 TI - Prevalence and trends of drugged driving in Canada. AB - OBJECTIVES: This study evaluates prevalence and trends in drugged driving in Canada based on multiple indicators collected from the Road Safety Monitor (RSM) and Canada's National Fatality Database maintained by the Traffic Injury Research Foundation (TIRF). The objective of this paper is to identify the state of drug positive driving in Canada, as well as to make comparisons with data from previous years to determine whether changes have occurred. METHODS: Available data from the RSM on self-reported drugged driving behaviours were collected and analyzed using multivariate techniques in various years spanning from 2002 to 2015. Data from TIRF's National Fatality Database from 2000 to 2012 were also analyzed to evaluate trends and prevalence of drugs in fatally injured drivers across Canada. Additionally, differences among drugged drivers with respect to gender and age were studied. RESULTS: Analyses of the RSM data and of the National Fatality Database showed that, as a whole, the prevalence of drugged driving has remained relatively stable over the past decade, with some changes noticed in specific years for some drug types. Specifically from the RSM, there was a 62.5% increase from the 1.6% of drivers reporting driving within two hours of using marijuana in 2013 to 2.6% in 2015. The analyses of the fatality data revealed a 16.9% increase in the percentage of fatally injured drivers testing positive for drugs between 2000 and 2012 (from 33.56% to 39.24%). Cocaine positive fatally injured drivers increased from 3.6% in 2000 to 6.2% in 2012. Similarly, marijuana-positive fatally injured drivers increased from 12.8% in 2000 to 19.7% in 2012. Results showed varying characteristics with respect to gender and age among self-reported and fatally injured drugged drivers. CONCLUSIONS: Drugged driving behaviours remain prevalent among Canadian drivers and drugs continue to be found in over one-third of tested fatally injured drivers. Although self-reported behaviours have neither decreased nor increased overall in the past decade according to RSM data, with the exception of driving within two hours of using marijuana, data from fatally injured drivers reveal that small, but significant increases in some behaviours have occurred. PMID- 27984815 TI - How do user experiences with different transport modes affect the risk of traffic accidents? From the viewpoint of licence possession status. AB - Road accidents between different modes of transport-such as between automobiles and pedestrians, automobiles and bicycles, or automobiles and motorcycles-are frequent. In such cases, it is important to consider the other side's perspective. This involves the ability to correctly judge, for every given situation, how other people on the road perceive their surroundings and what they intend to do next. In this paper, we conduct two types of studies assuming that this kind of ability to consider perspectives is higher when the person is licenced to drive the mode of transport used by the other party. For Study 1, we analysed accidents involving senior citizens between the ages of 65 and 74 years, who collided with automobiles as pedestrians or cyclists (1656 and 3192 cases respectively), in terms of the accident category and type of road at the accident spot. The results indicate that possession or non-possession of a licence was irrelevant for accidents involving cyclists, but for accidents with pedestrians, senior citizens who did not possess a licence are likely to be involved in a greater number of accidents in places that require interaction with automobiles, such as while crossing at crosswalks or at intersections. For Study 2, we reviewed 875 ordinary first-class licence practical test examinees, categorised them according to their licence possession status (motorcycle licence, moped licence, or no licence), and made a category-wise comparison of the test instructor's assessment of their ability to make a left turn. The results showed that those who had a motorcycle or moped licence tended to make a left turn more safely. Thus, the results indicate that experience with different modes of transport is likely to reduce the risk of accidents. These findings may be used to popularise educational interventions encouraging users of various transport modes to consider the perspective of others (i.e. via perspective-taking). PMID- 27984812 TI - Sex-specific associations of testosterone with prefrontal-hippocampal development and executive function. AB - Testosterone is thought to play a crucial role in mediating sexual differentiation of brain structures. Examinations of the cognitive effects of testosterone have also shown beneficial and potentially sex-specific effects on executive function and mnemonic processes. Yet these findings remain limited by an incomplete understanding of the critical timing and brain regions most affected by testosterone, the lack of documented links between testosterone related structural brain changes and cognition, and the difficulty in distinguishing the effects of testosterone from those of related sex steroids such as of estradiol and dehydroepiandrosterone (DHEA). Here we examined associations between testosterone, cortico-hippocampal structural covariance, executive function (Behavior Rating Inventory of Executive Function) and verbal memory (California Verbal Learning Test-Children's Version), in a longitudinal sample of typically developing children and adolescents 6-22 yo, controlling for the effects of estradiol, DHEA, pubertal stage, collection time, age, handedness, and total brain volume. We found prefrontal-hippocampal covariance to vary as a function of testosterone levels, but only in boys. Boys also showed a specific association between positive prefrontal-hippocampal covariance (as seen at higher testosterone levels) and lower performance on specific components of executive function (monitoring the action process and flexibly shifting between actions). We also found the association between testosterone and a specific aspect of executive function (monitoring) to be significantly mediated by prefrontal hippocampal structural covariance. There were no significant associations between testosterone-related cortico-hippocampal covariance and verbal memory. Taken together, these findings highlight the developmental importance of testosterone in supporting sexual differentiation of the brain and sex-specific executive function. PMID- 27984816 TI - Truck crash severity in New York city: An investigation of the spatial and the time of day effects. AB - This paper investigates the differences between single-vehicle and multi-vehicle truck crashes in New York City. The random parameter models take into account the time of day effect, the heterogeneous truck weight effect and other influencing factors such as crash characteristics, driver and vehicle characteristics, built environment factors and traffic volume attributes. Based on the results from the co-location quotient analysis, a spatial generalized ordered probit model is further developed to investigate the potential spatial dependency among single vehicle truck crashes. The sample is drawn from the state maintained incident data, the publicly available Smart Location Data, and the BEST Practices Model (BPM) data from 2008 to 2012. The result shows that there exists a substantial difference between factors influencing single-vehicle and multi-vehicle truck crash severity. It also suggests that heterogeneity does exist in the truck weight, and it behaves differently in single-vehicle and multi-vehicle truck crashes. Furthermore, individual truck crashes are proved to be spatially dependent events for both single and multi-vehicle crashes. Last but not least, significant time of day effects were found for PM and night time slots, crashes that occurred in the afternoons and at nights were less severe in single-vehicle crashes, but more severe in multi-vehicle crashes. PMID- 27984817 TI - Learning potential and cognitive abilities in preschool boys with fragile X and Down syndrome. AB - BACKGROUND: Enhancing cognitive abilities is relevant when devising treatment plans. AIMS: This study examined the performance of preschool boys with Down syndrome and fragile X syndrome in cognitive tasks (e.g., nonverbal reasoning and short-term memory), as well as in improving cognitive functions by means of a learning potential methodology. METHODS AND PROCEDURES: The basic scales corresponding to the Skills and Learning Potential Preschool Scale were administered to children with Down syndrome and others with fragile X syndrome, matched for chronological age and nonverbal cognitive development level. RESULTS: The fragile X syndrome group showed stronger performance on short-term memory tasks than the Down syndrome group prior to intervention, with no differences recorded in nonverbal reasoning tasks. In addition, both groups' cognitive performance improved significantly between pre- and post-intervention. However, learning potential relative to auditory memory was limited in both groups, and for rule-based categorization in Down syndrome children. CONCLUSION: The scale offered the opportunity to assess young children's abilities and identify the degree of cognitive modifiability. Furthermore, factors that may potentially affect the children's performance before and during learning potential assessment are discussed. PMID- 27984818 TI - The effect of an integrated perceived competence and motor intervention in children with developmental coordination disorder. AB - BACKGROUND AND AIMS: Children with DCD have lower self-perceptions and are less physically active than typically developing children. The aim of this quasi experimental study was to investigate whether an integrated perceived competence and motor intervention affects DCD children's motor performance, self perceptions, and physical activity compared with a motor intervention only. METHODS AND PROCEDURES: The intervention group consisted of 20 children and the care-as-usual group consisted of 11 children, all aged 7-10 years. The perceived competence component of the intervention focused primarily on providing positive, specific, and progress feedback to enhance self-perceptions. We assessed children at baseline, after 12 treatment sessions (trial end-point), and at 3-month follow up. OUTCOMES AND RESULTS: Mixed linear models revealed no differences between the intervention and the care-as-usual group on any of the outcome measures. Children improved their motor performance and increased their perceived athletic competence, global self-esteem, and perceived motor competence after 12 treatment sessions. This improvement was maintained at 3-month follow-up. Motor task values and physical activity remained unchanged for all children. CONCLUSIONS AND IMPLICATIONS: A perceived competence and motor intervention is as effective as care-as-usual in children with DCD. Future research should focus on improving physical activity in children with DCD. WHAT THIS PAPER ADDS: This is the first study that has investigated the effect of an integrated perceived competence and motor intervention (intervention group) on motor performance, self-perceptions, and physical activity compared with a motor intervention (care-as-usual group) in children with DCD. We made the perceived competence component explicit by providing positive, specific, and progress feedback to enhance children's self perceptions. Also, this is one of the first studies that has investigated the effect after both 12 treatment sessions (trial end-point) and after 3 months of no intervention (3-month follow-up). We found no differences between the intervention and the care-as-usual group, but children improved their motor performance and increased (most) of their self-perceptions after 12 treatment sessions, while physical activity remained the same. The improvement was still present at the 3-month follow-up. We also benchmarked our results about self perceptions and physical activity to a group of typically developing children. Self-perceptions in children with DCD had improved to the level of typically developing children after 12 treatment sessions, but their physical activity levels remained significantly lower. This result was the same at the 3-month follow-up, except for perceived athletic competence, which was lower in children with DCD at the 3-month follow-up. In accordance with previous intervention studies that have investigated children with DCD, we found large intra-group variability in the change in motor performance and self-perceptions in children with DCD. We argue that we need to better understand why some children with DCD improve and others do not after a motor intervention. PMID- 27984819 TI - Characterization and quantitation of the polyphenolic compounds detected in methanol extracts of Pistacia atlantica Desf. fruits from the Guelmim region of Morocco. AB - High performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC-ESI-MS) was used for the identification of the major phenolic compounds in mature P. atlantica fruits from the Guelmim region (southeast of Morocco). In this study twenty seven polyphenolic compounds are identified and quantitated. To date, this is the most comprehensive report on the polyphenolic content of Pistacia fruits. The profiles comprise, three major polyphenolic classes, namely gallates (18.76g/kg; 63.92%), flavonoids (10.12g/kg; 34.48%) and ellagic acid derivatives (0.47g/kg; 1.60%) with a total of 29.35g/kg detected. The major gallate was pentagalloyl glucoside (5.0g/kg; 17.04% of total polyphenolics), the major flavonoid luteolin (3.18g/kg; 10.83% of total polyphenolics) and the major ellagic acid derivative ellagic acid (0.25g/kg; 0.85% of total polyphenolics). Identification of galloyl quinate, digalloyl quinates (x 2), galloyl glucoside, digalloyl glucosides (x 2), trigalloyl glucoside, tetragalloyl glucosides (x 2), pentagalloyl glucoside, 2"-O-galloyl quercetin-3-O-galactoside, quercetin-3-O-rhamnogalactoside, quercetin-3-O galactoside, ellagic acid diglucoside, luteolin-4'-O-glucoside, 2"-O-galloyl luteolin-4'-O-glucoside, quercetin-3-O-glucuronide, kaempferol-3-O-glucoside, eriodictyol, apigenin, ellagic acid diglucoside, ellagic acid glucoside, methyl ellagic acid glucoside, and ellagic acid are described as phytochemical components of Pistacia fruits for the first time. PMID- 27984820 TI - Comparative proteomics reveal the mechanism of Tween80 enhanced phenanthrene biodegradation by Sphingomonas sp. GY2B. AB - Previous study concerning the effects of surfactants on phenanthrene biodegradation focused on observing the changes of cell characteristics of Sphingomonas sp. GY2B. However, the impact of surfactants on the expression of bacterial proteins, controlling phenanthrene transport and catabolism, remains obscure. To overcome the knowledge gap, comparative proteomic approaches were used to investigate protein expressions of Sphingomonas sp. GY2B during phenanthrene biodegradation in the presence and absence of a nonionic surfactant, Tween80. A total of 23 up-regulated and 19 down-regulated proteins were detected upon Tween80 treatment. Tween80 could regulate ion transport (e.g. H+) in cell membrane to provide driving force (ATP) for the transmembrane transport of phenanthrene thus increasing its uptake and biodegradation by GY2B. Moreover, Tween80 probably increased GY2B vitality and growth by inducing the expression of peptidylprolyl isomerase to stabilize cell membrane, increasing the abundances of proteins involved in intracellular metabolic pathways (e.g. TCA cycle), as well as decreasing the abundances of translation/transcription-related proteins and cysteine desulfurase, thereby facilitating phenanthrene biodegradation. This study may facilitate a better understanding of the mechanisms that regulate surfactants-enhanced biodegradation of PAHs at the proteomic level. PMID- 27984821 TI - Accumulation and distribution of metallic elements and metalloids in edible Amanita fulva mushrooms. AB - Baseline concentrations of Ag, Al, As, Ba, Ca, Cd, Co, Cu, Cr, Fe, K, Mg, Mn, Na, Ni, P, Pb, Rb, Sr, Tl, V, U and Zn were presented in Amanita fulva collected from unpolluted areas in Poland. There is no previous data published on the bio element constituents of A. fulva. A very narrow range of values was determined by ICP-DRC-MS and ICP-AES for the trace elements Ag, Co, Cu, Cr, Ni, Rb, Sr, Tl and Zn in caps and of Ag, Co, Cu, Mn, Ni, Sr, U and Zn in stipes and also for the macro elements K, P, Na and Mg. The fruitbodies of A. fulva from the northern (Baltic Sea coastal forests) and southwestern (Lower Silesia forests) sites differed substantially in cadmium, lead and uranium, and those from the Lower Silesia region showed them in greater concentrations. This observation may imply that A. fulva under typical geochemical site conditions is able to regulate the accumulation of many of the elements mentioned in fruiting bodies. PMID- 27984822 TI - Utility of risk-status for predicting psychosis and related outcomes: evaluation of a 10-year cohort of presenters to a specialised early psychosis community mental health service. AB - Psychosis transition rates by those at clinical high risk have been highly variable and few studies have compared service presenters across the full psychosis risk spectrum with respect to medium-term outcomes. A 10-year service cohort was examined (N=1997), comprising all presentations to an early psychosis service for young people experiencing a recent psychotic episode or at increased risk ('Psychological Assistance Service', Newcastle, Australia). Baseline and longitudinal service data (median follow-up =7.3 years) were used in a series of logistic regressions to examine relationships between psychosis risk-status and subsequent illness episodes, hospital admissions, and community contacts. Six baseline groups were identified: existing (14.5%) and recent psychosis (19.8%); ultra-high risk (UHR, 9.6%); non-psychotic disorders without (35.4%, the reference group) and with psychiatric admissions (8.3%); and incomplete assessments (12.5%). High comorbidity levels were reported by the cohort (psychosocial problems, 61.1%; depression, 54.1%; substance misuse, 40.7%). UHR clients experienced similar psychosis transition rates to the reference group (17.3% vs. 14.6%; 8.9% vs. 9.1% within 2-years) and comparable rates of subsequent non-psychosis outcomes. A 25.9% conversion rate from early psychosis to schizophrenia was detected. However, among transitioning individuals, UHR clients faired relatively better, particularly with respect to changes in comorbidity and mental health contacts. Interventions tailored to current problems, recovery and psychological strengthening may be more appropriate than those based on estimated psychosis risk, which currently lacks clinical utility. PMID- 27984823 TI - Hydrochlorothiazide in intensive care unit-acquired hypernatremia: A randomized controlled trial. AB - PURPOSE: Thiazides are suggested as a treatment for intensive care unit (ICU) acquired hypernatremia (IAH). The primary aim of the study was reducing serum sodium concentration (sNa) in patients with IAH with hydrochlorothiazide (HCT) in comparison to placebo. Secondary end points were a difference in urine sodium concentration (uNa) and duration of severe IAH. MATERIALS: A monocentric, double blind, placebo-controlled trial was conducted in 50 patients with IAH and urine potassium + uNa less than sNa in a spot urine sample. Patients were randomized to HCT 25 mg or placebo 1 qd for maximal 7 days. Patients on renal replacement therapy, on medication inducing diabetes insipidus, or with recent use of diuretics were excluded. IAH was defined as sNa of at least 143 mmol/L. RESULTS: At baseline, sNa and uNa were comparable between groups. During the study period, sNa decreased significantly with median 4 mmol/L in both groups, with no significant difference between groups (P=.32). Median uNa increased significantly in both groups (46 [16-86] mmol/L in the HCT-group; 20 [10-66]mmol/L in the placebo group), with no difference between groups (P=.34). Median duration of sNa of at least 145 mmol/L was 3 days in both groups (P=.91). CONCLUSION: HCT 25 mg 1 qd did not significantly affect sNa or uNa in patients with IAH. PMID- 27984826 TI - Decoding the role of regulatory element polymorphisms in complex disease. AB - Genetic variation in gene regulatory elements contributes to diverse human diseases, ranging from rare and severe developmental defects to common and complex diseases such as obesity and diabetes. Early examples of regulatory mechanisms of human diseases involve large chromosomal rearrangements that change the regulatory connections within the genome. Single nucleotide variants in regulatory elements can also contribute to disease, potentially via demonstrated associations with changes in transcription factor binding, enhancer activity, post-translational histone modifications, long-range enhancer-promoter interactions, or RNA polymerase recruitment. Establishing causality between non coding genetic variants, gene regulation, and disease has recently become more feasible with advances in genome-editing and epigenome-editing technologies. As establishing causal regulatory mechanisms of diseases becomes routine, functional annotation of target genes is likely to emerge as a major bottleneck for translation into patient benefits. In this review, we discuss the history and recent advances in understanding the regulatory mechanisms of human disease, and new challenges likely to be encountered once establishing those mechanisms becomes rote. PMID- 27984824 TI - ARCPHdb: A comprehensive protein database for SF1 and SF2 helicase from archaea. AB - PURPOSE: Superfamily 1 and Superfamily 2 helicases, two of the largest helicase protein families, play vital roles in many biological processes including replication, transcription and translation. Study of helicase proteins in the model microorganisms of archaea have largely contributed to the understanding of their function, architecture and assembly. Based on a large phylogenomics approach, we have identified and classified all SF1 and SF2 protein families in ninety five sequenced archaea genomes. Here we developed an online webserver linked to a specialized protein database named ARCPHdb to provide access for SF1 and SF2 helicase families from archaea. METHODS: ARCPHdb was implemented using MySQL relational database. Web interfaces were developed using Netbeans. Data were stored according to UniProt accession numbers, NCBI Ref Seq ID, PDB IDs and Entrez Databases. RESULTS: A user-friendly interactive web interface has been developed to browse, search and download archaeal helicase protein sequences, their available 3D structure models, and related documentation available in the literature provided by ARCPHdb. The database provides direct links to matching external databases. CONCLUSIONS: The ARCPHdb is the first online database to compile all protein information on SF1 and SF2 helicase from archaea in one platform. This database provides essential resource information for all researchers interested in the field. PMID- 27984825 TI - Colloid, adhesive and release properties of nanoparticular ternary complexes between cationic and anionic polysaccharides and basic proteins like bone morphogenetic protein BMP-2. AB - Herein we describe an interfacial local drug delivery system for bone morphogenetic protein 2 (BMP-2) based on coatings of polyelectrolyte complex (PEC) nanoparticles (NP). The application horizon is the functionalization of bone substituting materials (BSM) used for the therapy of systemic bone diseases. Nanoparticular ternary complexes of cationic and anionic polysaccharides and BMP 2 or two further model proteins, respectively, were prepared in dependence of the molar mixing ratio, pH value and of the cationic polysaccharide. As further proteins chymotrypsin (CHY) and papain (PAP) were selected, which served as model proteins for BMP-2 due to similar isoelectric points and molecular weights. As charged polysaccharides ethylenediamine modified cellulose (EDAC) and trimethylammonium modified cellulose (PQ10) were combined with cellulose sulphatesulfate (CS). Mixing diluted cationic and anionic polysaccharide and protein solutions according to a slight either anionic or cationic excess charge colloidal ternary dispersions formed, which were cast onto germanium model substrates by water evaporation. Dynamic light scattering (DLS) demonstrated, that these dispersions were colloidally stable for at least one week. Fourier Transform Infrared (FTIR) showed, that the cast protein loaded PEC NP coatings were irreversibly adhesive at the model substrate in contact to HEPES buffer and solely CHY, PAP and BMP-2 were released within long-term time scale. Advantageously, out of the three proteins BMP-2 showed the smallest initial burst and the slowest release kinetics and around 25% of the initial BMP-2 content were released within 14days. Released BMP-2 showed significant activity in the myoblast cells indicating the ability to regulate the formation of new bone. Therefore, BMP-2 loaded PEC NP are suggested as novel promising tool for the functionalization of BSM used for the therapy of systemic bone diseases. PMID- 27984827 TI - pH-switchable bacteria detection using zwitterionic fluorescent polymer. AB - A zwitterionic fluorescent polymer with high sensitivity to pH changes was constructed for the detection and imaging of both gram-positive and gram-negative pathogenic bacteria. A detection probe using the zwitterionic fluorescent polymer was synthesized with single boron dipyrromethane (BODIPY) as a hydrophobic dye and bromoethane as a cationic group for bacteria binding with conjugated poly(sulfobetaine methacrylate) (BOD/BE-PSM). The zwitterionic fluorescent polymer bound to bacteria through ionic complexes between anionic groups on the bacterial surface and cationic BOD/BE-PSM groups after 1h incubation. This finding demonstrated that the fluorescence on/off system operated via changes in the hydrophilic and hydrophobic nature of the zwitterionic fluorescent polymer, depending on the pH (6.0, 7.4, or 9.0), at a fixed 1mg/mL polymer concentration. The system showed good stability with a limit of detection of 1mg/mL. Quenching caused by interactions with the hydrophobic BODIPY dye was also observed, enabling bacteria detection, as shown by fluorescence spectroscopy and confocal microscopy images. Our results indicated that the zwitterionic fluorescent polymer could be used to detect bacteria over a wide range of pH values. PMID- 27984829 TI - ? PMID- 27984828 TI - Imaging appearance of benign multicystic peritoneal mesothelioma: a case report and review of the literature. AB - Benign multicystic peritoneal mesothelioma (BMPM) is a rare entity with fewer than 150 reported cases in the literature. Here we discuss a case of BMPM in a 22 year old female as presented to our urban community hospital, review epidemiology and clinical presentations of this entity, and perform a comprehensive literature review of various CT, US, and MR imaging features of BMPM. PMID- 27984830 TI - ? PMID- 27984831 TI - [Total Joint Replacement and Return to Sports]. AB - Background: An increasing number of physically active patients not only need to know if they will basically be able to engage in sports after undergoing arthroplasty. They also would like to know whether or not they will be able to resume their preoperative activity levels. This article aims to provide an overview of recent data regarding the following questions on hip, knee and shoulder arthroplasty: (1) What is the impact of physical activity on an endoprosthesis? (2) What level of sports can be achieved after an arthroplasty procedure? (3) What types of sport are recommended for patients with an endoprosthesis? Methods: PubMed-based review of the literature. Narrative review focusing on current data from the years 2010 to 2016. Results: The commonly known recommendation to exercise low-impact sports such as hiking, swimming, cycling or golf at a moderate intensity remains valid for all types of prostheses in all joints. There is broad consensus that the benefits of these sports outweigh the negative effects. Having undergone total hip or knee arthroplasty, most patients with a high preoperative activity level return to sports after 3-6 months, albeit with a clear tendency to lower intensity and a shift from high-impact to low impact sports. Some key questions have to be answered regarding the effects of low-impact sports that are exercised with high intensity, the effects resulting from high-impact sports, effects specific to different types of sport, and possibilities provided by different prosthesis types. In this context, a lot remains to be done to investigate the limits between positive and negative effects resulting from physical activity of varying intensity. New data suggests that generally a higher physical performance level may be achieved than has been traditionally recommended. Early results of unicondylar knee prostheses are far better than those achieved with bicondylar prostheses. In contrast to expert recommendations, shoulder endoprostheses show the highest postoperative activity levels after inverted arthroplasty, followed by anatomic arthroplasty, and the lowest activity level after the implantation of a hemiprosthesis. Conclusion: There is a significant discrepancy between previous expert recommendations and the actual activity levels that may be achieved after the implantation of a joint prosthesis. Future studies have to define the sports level, the type of sports and the type of prosthesis that provide a positive benefit-risk ratio using state of-the-art low-abrasion bearing surfaces and prosthesis designs. PMID- 27984832 TI - [Injuries in Karate Sports: A Survey Performed During the World Championship 2014]. AB - Background: In literature, the competitive sport of modern karate is almost always characterised as a combat sport involving injuries caused by impact effects and physical contact with opponents. There is a lack of data regarding the outcome after karate injuries, specifically with a view to the contact-free Kata karate. Methods: Performing a random test using a questionnaire, we collected data concerning regular medical treatment, prior surgeries of the locomotor system, and medical care. This study included 300 athletes from 65 countries (average age: 24.1 years; 176 male, 124 female) participating in the Karate World Cup 2014. Seven participants competed in both disciplines, 87 only in the Kata discipline, and 206 only in Kumite (the discipline involving physical contact with opponents). The statistical analysis was performed using a two-sided Chi-square test and the Fisher's exact test. Results: Recurrent medical treatment was most commonly required for the knee region (Kata 28.7 %, Kumite 26.7 %). In Kata the shoulder region came second (22.9 %), in Kumite the ankle region (21.8 %), followed by hand and foot in both groups. Medical treatment of the elbow area was more frequent in the Kata Group (p = 0.033), while in Kumite athletes' hand (p = 0.002) and foot injuries (p = 0.007) prevailed. Prior surgeries of athletes of both disciplines most commonly concerned the knee, followed by the ankle region in the Kata group and by the hand and head region in the Kumite group. Statistically significant differences between the two disciplines were found in head injuries (p = 0.004), which commonly do not occur in the Kata discipline. During the World Cup, 56.0 % of the athletes had no individual medical care and 24.6 % received no sports-related medical care in their home countries. Conclusion: Although the risk of injuries in Kumite Karate has been reduced by the introduction of gumshields, hand and foot protectors as well as a reform of the scoring system, the potential for chronic physical damage should not be underestimated. Since in athletes competing in the Kata discipline the rate of surgeries and injuries is only slightly lower than in the Kumite group, Kumite Karate may be regarded as a martial arts competitive sport with a relatively low risk of injuries. In contrast, the risk of chronic musculoskeletal damage in Kata athletes seems to be underestimated thus far. Suggested improvements concern the training techniques and conditions (i. e. the tatami material), and there is a need for regular medical care, including preventative care, to be provided for these athletes. PMID- 27984833 TI - [Injuries during Equestrian Vaulting]. AB - Background: Vaulting is the least studied equestrian sports regarding the occurrence of injuries. As its sequences of motion do not compare to riding, vaulting must be assessed separately. Material and Methods: This retrospective, questionnaire-aided survey was aimed to gain insight into the overall frequency of injuries among equestrian vaulters. The second part of the study looked into the knee injuries that occurred. Survey forms were sent to 60 vaulting and equestrian clubs all over Germany, making for a response rate of 63 %. Results: 95 % of 624 responding athletes were female. The pool of participants consisted of both amateur and professional level vaulters with a mean age of 15 years. The survey showed a mean number of 4.1 injuries sustained during the observation period, i. e. the entire time an athlete had been active in the sport up to the data collection. The lower extremities were the most commonly injured area with a total proportion of 45 %, followed by injuries to the spine and the head with 30 %, and the upper extremities with 25 %. Contusions accounted for the highest number of reported injuries. Other frequently reported injuries included muscle strain to the head and spine, fractures to the upper extremity and ligament damage to the lower extremity. 14 % of the participants experienced at least one knee injury. The medial collateral ligament (27 %) was found to be most prone to lesions, followed by the anterior cruciate ligament (23 %) and the medial meniscus (22 %). Half of all knee injuries occurred during dismounts, especially when swing-offs or flanks led to faulty landings. Conclusions: The results show that the lower extremity is the most commonly affected area. The ligamentous injuries affecting the lower extremity mainly result from dismounts. A specific training aimed at improving landing techniques might therefore prove beneficial in preventing injuries. The frequency of contusions and fractures to the upper extremity suggests that these injuries are related to falls. PMID- 27984834 TI - [Ophthalmological Monitoring of Diabetic Neuropathy in a Mouse Model]. AB - Patients with diabetes mellitus suffer from late damage, including microvascular and macrovascular complications and diabetic polyneuropathy, even though blood glucose is well controlled and the HbA1c value normalised. Peripheral nerves are affected, and when these are damaged, this can result in disturbed sensation and pain. Such nerves are mainly Adelta und C fibres, which are present in the skin, but also in the subbasal nerve plexus of the cornea. Imaging of the subbasal nerve plexus using microscopic techniques allows a very early and objective view of neuropathy, which is only possible invasively by skin biopsy. We have used a thy1-YFP mouse strain in which the peripheral nerves are detectable by fluorescence excitation. Using two photon microscopy, we produced high resolution three dimensional images of the corneal subbasal nerve plexus of these mice. We induced diabetes mellitus in thy1-YFP mice by injection of streptocotocin. We showed that the increase in blood glucose was accompanied by a loss of subbasal nerve fibres, mainly in the centre of the cornea. Subsequent treatment of the animals with insulin normalised blood glucose and was accompanied by an increase in subbasal nerve fibres. Thus, this model is highly suited to investigate the pathogenesis of diabetic polyneuropathy, with the aim of developing new causal strategies to treat the disease. PMID- 27984835 TI - [Phenomenology and Clinical Relevance of the Flammer Syndrome]. AB - The Flammer syndrome (FS) describes the phenotype of people with a predisposition for an altered reaction of the blood vessels to stimuli like coldness, emotional stress or high altitude. Frequent symptoms are: cold hands and/or feet, low blood pressure, prolonged sleep onset time, reduced feeling of thirst, increased sensitivity to odour, pain, vibration and certain drugs. SF subjects are often ambitious and successful but also perfectionistic and sometimes brooding. Frequent signs are: altered gene expression, prolonged blood flow cessation in nailfold capillaroscopy after cold provocation, reduced autoregulation of ocular blood flow, and reduced vasodilation after stimulation with flickering light. Retinal venous pressure is on the average higher and retinal astrocytes are more often activated. FS occurs more often in females than in males, in thin than in obese subjects, in young than in old people, in graduates than in blue collar workers, in subjects with indoor than outdoor jobs. Associated diseases are: normal tension glaucoma, occlusion of ocular vessels, retinitis pigmentosa, multiple sclerosis, tinnitus or even sudden hearing loss. PMID- 27984836 TI - [Do We Still Need Electrophysiology in Ophthalmology?] AB - Electrophysiological methods in clinical ophthalmology include the full-field electroretinogram (ERG) for assessment of outer and middle retinal layers, pattern ERG (PERG) for assessment of ganglion cell function, the electrooculogram (EOG) for assessment of retinal pigment epithelium function, as well as visual evoked potentials (VEP) for assessment of the visual pathway, including the optic nerve and visual cortex. Multifocal recording techniques for ERG and VEP are used for tests within selected areas of the visual field. Technical progress in ocular imaging, especially optical coherence tomography (OCT) and fundus autofluorescence (FAF), allows high-resolution imaging of subtle morphological changes of the retina and posterior fundus. Typical retinal diseases may then be diagnosed at an early stage, without conventional electrophysiological investigations (e.g. x-linked retinoschisis, Stargardt disease, vitelliform macular dystrophy). OCT outclasses electrophysiological methods in the quantification of optic atrophies. With newly developed optic techniques, peripheral retinal structures (wide angle optics) and subtle structures up to the photoreceptor level (adaptive optics) can be imaged with increasing quality. However, differentiation of central retinal disorders (e.g. macular dystrophy) from generalised retinal diseases requires electrophysiological diagnostic testing. The same applies to discrimination between different functional disorders in generalised retinal diseases (e.g. enhanced S-cone syndrome, congenital stationary night blindness, achromatopsia). PMID- 27984837 TI - [Magnetic Resonance Microscopy of the Accommodative Apparatus]. AB - Magnetic resonance microscopy (MRM) at ultra-high magnetic fields allows acquisition of high resolution MR images in the micrometre range. The use of ultra-high magnetic fields opens the possibility of user-independent and artefact free detailed characterisation of the anatomical tissue of the human eye, which is not achievable with classical imaging techniques. This article correlates MRM of the anterior eye segment and the accommodative apparatus at 9.4 Tesla with conventional histology. PMID- 27984838 TI - [Imaging Blood Flow and Pulsation of Retinal Vessels with Full-Field Swept-Source OCT]. AB - Optical coherence tomography (OCT) uses interference to image the retina with high axial resolution. In the last 25 years, new technologies have permitted a steady increase in imaging speed, which made it possible to enlarge the imaged field and to avoid motion artefacts. The speed and precision of retinal imaging is now limited by photodamage of the retina caused by the focused OCT beam and by the speed of the scanning mechanics. Full-field swept-source (FF-SS)-OCT decreases irradiance on the retina and dispenses moving parts by using a camera to acquire the full volume of the retina in parallel. Here we show that FF-SS-OCT is rapid and precise enough to image pulsation in the retina induced by the heart beat. Series of OCT volumes 1.8 * 0.7 mm wide and 1.8 mm deep were recorded in young volunteers over a few cycles of the heart beat. Morphology of the retinal vessels, blood flow and tissue motion as caused by vessel pulsation were calculated from the OCT data. FF-SS-OCT was able to visualise the main structures of the neuronal retina, including vessels and small capillaries and without any motion artefacts. Information on three different dynamic processes was obtained from only one recorded series of OCT volumes: pulsation of blood flow and blood pressure in retinal vessels as well as pulsation of the choroid. Delays between arterial and venous pulse and delay between pulsation in retinal and choroidal vessels were calculated. With a time resolution of 0.5 ms, FF-SS-OCT is able to visualise previously unmeasurably fast changes in the retina, including the propagation of pulse waves. PMID- 27984839 TI - [Influence of Macular Hole Width on Visual Acuity, Endotamponade and Closure Rate]. AB - Background: The influence of the width of a full-thickness macular hole on preoperative visual acuity and its role for the intraoperative approach and closure rate were analysed in a prospective study. Methods: For 47 patients with a full thickness macular hole, a precise analysis of the central retina was performed with SD-OCT. An SF6-gas-air mixture was used, with a lower concentration (15 %) for smaller holes <= 400 um (group 1, n = 17) and a higher concentration (30 %) for larger holes > 400 um (group 2, n = 30). Besides preoperative visual acuity, postoperative IOP fluctuations and closure rate were reviewed. Results: The mean hole width with SD-OCT was 419 +/- 155 um, with a significant negative correlation with preoperative visual acuity (r = - 0.56, p = 0.002). In the first group, mean early postoperative IOP was 23 mmHg and in the second group 33 mmHg (p < 0.001). Thus, for small macular holes, early postoperative IOP decompensation from gas expansion in the eye could be minimised. The closure rate was 90 %, with no significant difference between the two groups (p > 0.05). Conclusion: Determining the width of a macular hole with SD-OCT is an important indicator for the necessary endotamponade. Using a lower gas concentration (15 %) for smaller holes (<= 400 um) to prevent postoperative IOP fluctuations does not negatively influence closure rates. PMID- 27984840 TI - Glycemic Control and Pregnancy Outcomes in Women with Type 2 Diabetes Treated with Oral Hypoglycemic Agents. AB - Objective There is limited data regarding the use of oral hypoglycemic agents (OHAs) in pregnant women with type 2 diabetes mellitus (T2DM). Study Design This was a retrospective cohort study of women with T2DM who were treated with OHA or insulin from the first trimester onward. Bivariate and multivariate logistic regression analyses were used to compare pregnancy outcomes in women treated with OHA to those treated with insulin. Results One-third (67/198) of women were treated with OHA. Women treated with OHA had a shorter disease duration (4.4 vs. 6.8 years; p = 0.001), were more likely to have a normal prepregnancy body mass index, and had less gestational weight gain (GWG; 22.4 vs. 30.4 lbs; p = 0.005). A lower GWG was noted in obese women treated with OHA (19.9 +/- 18.6 vs. 28.3 +/- 17.7 pounds; p = 0.008). First-trimester hemoglobin A1c values were lower with OHAs, but second- and third-trimester values were similar. Among women who started pregnancy using OHA, 37/67 (55.2%) remained on OHA at delivery. Pregnancy outcomes did not differ between women who received OHA and those treated with insulin. Conclusion OHA treatment is more likely in women with T2DM who begin pregnancy with less severe disease, and use of OHA may be associated with decreased GWG. PMID- 27984841 TI - Does Circadian Variation of Mothers Affect Macronutrients of Breast Milk? AB - Objective To determine the within-day variation of fat, protein, and carbohydrate content of breast milk. Methods The study was conducted at Zekai Tahir Burak Maternity Teaching Hospital between April 2013 and January 2014. We obtained milk samples from lactating mothers of hospitalized infants through hand expression after breast-feeding or pumping three times a day. A mid-infrared human milk analyzer was used for measuring the macronutrient contents of breast milk samples. Results Lactating mothers of 52 infants (30 preterm, 22 term) were recruited to the study. No significant difference was found in protein, fat, and carbohydrate content of milk samples throughout the day. We compared within-day variation of macronutrients of transitional and mature milk, milk samples from the mothers of preterm and term infants, and samples collected by either hand expression or pumping. We did not find a significant difference between the groups. Conclusion Absence of circadian variations in lipid, carbohydrate, and protein content of breast milk in our study may be related to ethnic differences, maternal nutritional status, different milk content measurement technique, and population characteristics. PMID- 27984842 TI - Asymmetry of Inter-joint Coordination during Single Leg Jump after Anterior Cruciate Ligament Reconstruction. AB - Little is known about the contralateral asymmetry in inter-joint coordination after anterior cruciate ligament reconstruction (ACL-R) during multi-segmental movements. This study aimed to evaluate inter-joint coordination asymmetry between the injured (IL) and non-injured leg (NIL) in patients after ACL-R during single-leg jumping. 12 male patients having undergone ACL-R (7.3 months post surgery) and 12 healthy males performed maximal vertical single-leg jumps with the right and left leg. The kinematics of each jump were recorded. The inter joint coordination between the ankle, knee and hip joints was assessed by computing the continuous relative phase (CRP) and its variability. The effect of the group and leg was tested with a mixed linear model. The CRP and its variability were similar between the dominant and non-dominant leg of the healthy group. By contrast the CRP of the coupling ankle/knee and ankle/hip was smaller (p<0.01) for IL in comparison to NIL in the ACL-R group (-30% and -22% respectively). The CRP variability of the couplings ankle/knee and knee/hip was greater (p<0.05) for IL compared to NIL (+23% and +40% respectively). In conclusion, the jumping strategy assessed through the analysis of inter-joint coordination was still affected in ACL-R patients, which may be a cause of re injury. PMID- 27984843 TI - Acute and Long-term Responses to Different Rest Intervals in Low-load Resistance Training. AB - We investigated the effects of low-load resistance training to failure performed with different rest intervals on acute hormonal responses and long-term muscle and strength gains. In the acute study, 14 participants were assigned to either a short rest (S, 30 s) or long rest (L, 150 s) protocol at 40% one-repetition maximum. Blood samples were taken before and after the workout. Both groups showed significant (p<0.05) increases in growth hormone and insulin-like growth factor 1 immediately post-workout. In the longitudinal study, the same protocol as in the acute study was performed 2 times per week for 8 weeks by 21 volunteers. Both groups showed significant increases in triceps (S: 9.8+/-8.8%, L: 10.6+/-9.6%, p<0.05) and thigh (S: 5.7+/-4.7%, L: 8.3+/-6.4%, p<0.05) cross sectional area. One-repetition maximum also significantly increased for the bench press (S: 9.9+/-6.9%, L: 6.5+/-5.8%, p<0.05) and squat (S: 5.2+/-6.7%, L: 5.4+/ 3.5%, p<0.05). In conclusion, our results suggest that acute hormonal responses, as well as chronic changes in muscle hypertrophy and strength in low-load training to failure are independent of the rest interval length. PMID- 27984846 TI - Who is SMIO? PMID- 27984844 TI - Beneficial Effects of Cooling during Constant Power Non-steady State Cycling. AB - This study compared the effects of cooling on the energetic and associated physiological and perceptual responses to constant power, non-steady state cycling. Twelve males cycled at their lactate threshold power for 60 min or until exhaustion under 3 conditions: wearing a cooling vest and sleeves (COOL), a synthetic shirt embedded with an active particle technology claimed to facilitate evaporative heat loss (EVAP), and a standard synthetic shirt (CON). When adjusted for time, the increase in gastrointestinal temperature from baseline was reduced during COOL and EVAP compared to CON (1.44+/-0.45 and 1.52+/-0.43 vs. 1.66+/-0.45 degrees C, p<0.05). Sweat rate was reduced during COOL compared to EVAP and CON (1 312+/-331 vs. 1 525+/-393 and 1 550+/-548 mL.h-1, p<0.01). Gross efficiency decreased over time across conditions (p<0.01), but COOL attenuated this decrease by 22% compared to CON (p<0.05). The rating of perceived exertion was reduced during COOL and EVAP compared to CON (p<0.01). In conclusion, cooling using a vest and sleeves or wearing an active particle technology shirt reduced the rise in gastrointestinal temperature and rating of perceived exertion compared to a standard synthetic shirt. Cooling using a vest and sleeves also reduced the decrease in gross efficiency and sweat rate compared to wearing the standard synthetic shirt. PMID- 27984847 TI - Intraarticular Administration of Tranexamic Acid is Safe and Effective in Total Knee Arthroplasty Patients at High-Risk for Thromboembolism. AB - INTRODUCTION: Tranexamic acid (TXA) is an antifibrinolytic agent that can be used to reduce blood loss in total knee arthroplasty (TKA) patients. Due to its thrombogenic properties, intravenous (IV) TXA is contraindicated in patients who have an increased risk of arterial or venous thrombosis. For such patients, intraarticular (IA) TXA may be a safe alternative. In this study, we compare: 1) complication rates; 2) intraoperative blood loss; and 3) need for transfusion in TKA patients who received IA TXA versus patients who used IV TXA. MATERIALS AND METHODS: A retrospective chart review of a single surgeon was performed for patients who received a TKA and had either IV TXA or IA TXA (due to increased risk of thrombosis). This yielded 60 patients who had a mean age of 65 years (range, 36 to 84 years). Twenty-six patients received IA TXA as a consequence of being ineligible for IV TXA, because of increased risk for arterial or venous thromboembolism. Thirty-four patients received IV TXA. Complication rates and need for transfusion were evaluated as categorical variables. Amount of blood loss was evaluated as a continuous variable. All categorical variables and continuous variables were analyzed using chi-square test and student's t-test respectively. RESULTS: Overall, four patients (7 %) developed complications after the procedure, three of which were in the IA cohort and one in the IV cohort (p= 0.444). In the IA cohort, two patients developed arthrofibrosis and subsequently underwent manipulation under anesthesia. Additionally, one patient in this group developed a hematoma one week after TKA. This patient was managed conservatively until the condition resolved, and no further issues have been reported. One patient in the IV cohort developed a deep vein thrombosis, which was appropriately treated with no further issues. There was no significant difference in mean blood loss or number of transfusions between patients who received IA TXA or IV TXA (289 mL vs. 268 mL, p= 0.503; 3 vs. 4, p= 0.651, respectively). CONCLUSION: High-risk patients who have contraindications against intravenous TXA may be good candidates for intraarticular TXA. Our study demonstrated no significant differences in complication rates, blood loss, and transfusion rates in patients who received intravenous TXA as compared to those who received intraarticular TXA during total knee arthroplasty. We conclude that the intraarticular administration of TXA may be a safe and effective alternative for patients who have contraindications against intravenous TXA. PMID- 27984848 TI - Long-Term Outcome After Laparoscopic Repair of Primary, Unilateral Inguinal Hernia Using a Self-Adhering Mesh. AB - Following our previous study about a lightweight self-adhering mesh (Adhesix(r), Cousin Biotech, Wervicq-Sud, France; distributed by Davol Inc., subsidiary of C.R. Bard, Inc.), we report the long-term results with the use of this mesh in patients treated for a primary, unilateral inguinal hernia without any other hernias. Prospectively collected data of 100 patients between February 2011 and February 2014 were analyzed. The mean follow-up time was 2.7 years (range 1-4), and mean length of hospital stay was 0.6 days (range 0.5-1). At the time of the last follow-up visit, two patients (2%) had a recurrent inguinal hernia. Compared to preoperative values, patients reported a significant reduction in their pain sensation (visual analogue scale, VAS) after one month (4.61 vs. 1.32; P<0.001). A difference in VAS scores remained significant at the last follow-up visit (1.31 vs. 0.28; P<0.001). Patients reported high quality of life scores. Only one patient (1%) developed a clinically significant seroma that required an evacuating puncture. Two patients (2%) had superficial wound infections. Neither mesh infections nor mortalities occurred. This study, with a long follow-up, confirms our previous results: use of the Adhesix(r) mesh is safe, feasible, and efficient in laparoscopic hernia repair. PMID- 27984849 TI - Composition of Unrecorded Distilled Alcohol (bai jiu) Produced in Small Rural Factories in Central China. AB - BACKGROUND: Unrecorded traditional distilled spirits (bai jiu, ) are made and used throughout rural China for everyday use and special occasions. Nearly every town or village has a distiller to supply the demand. In rural China, distilling bai jiu is legal and regulated lightly or not at all. The World Health Organization estimates that as much as 25% of all alcohol consumed in China is unrecorded alcohol, of which an unknown portion is unrecorded bai jiu. Little is known about the composition of unrecorded Chinese spirits from rural parts of the country. This study focused on white spirits because the high ethanol (EtOH) concentration makes them more likely to contribute to health risks compared to other types of lower alcohol by volume (ABV) Chinese unrecorded alcohol. METHODS: Researchers purchased samples of Chinese white spirits from small-factory distillers in central China. An independent laboratory conducted the analysis. Alcohol strength (ABV) was determined by hydrometer. Gas chromatography was used to determine the concentration of volatile organic compounds: EtOH, methanol, acetaldehyde, ethyl acetate, and higher alcohols. Samples were tested for 3 heavy metals-arsenic, cadmium, and lead. We used the guidelines developed by the Alcohol Measures for Public Health Research Alliance (AMPHORA) of the European Commission to assess risk. RESULTS: ABV ranged from 35.7 to 61.4%, and 58 of the 61 samples exceeded 40% ABV. The concentration of methanol, ethyl acetate, lead, arsenic, and cadmium was below AMPHORA guideline. The sum of higher alcohols exceeded the AMPHORA maximum in just 1 sample. Forty of the 61 samples had acetaldehyde levels beyond the AMPHORA guideline. CONCLUSIONS: The unrecorded Chinese alcohols we analyzed had a high EtOH concentration-a public health concern that is also presented by recorded alcohols. The high percentage of samples (65.5%) that had elevated acetaldehyde suggests the need to investigate the causes for this result and the need for steps to reduce acetaldehyde levels. The cumulative long-term risks of using high EtOH and high acetaldehyde Chinese spirits are heightened by the percentage of people in China who have a genetic trait for impaired acetaldehyde metabolism. PMID- 27984850 TI - Development of endometrioid adenocarcinoma despite Levonorgestrel-releasing intrauterine system: a case report with discussion and review of the RCOG/BSGE Guideline on the Management of Endometrial Hyperplasia. AB - Obesity is a significant risk factor for the development of endometrial hyperplasia and cancer. More conservative prevention and management strategies are attractive due to the increased surgical risk and complication rates associated with obesity. The Levonorgestrel-releasing intrauterine system (LNG IUS, Mirena) has been shown to reduce the risk of developing endometrial cancer. The recent joint Green Top Guideline on the Management of Endometrial Hyperplasia published by the Royal College of Obstetricians and Gynaecologists (RCOG) with the British Society for Gynaecological Endoscopy (BSGE) recommends the LNG-IUS for the medical management of endometrial hyperplasia without atypia. This case study reports on the development of endometrioid adenocarcinoma despite the presence of an LNG-IUS following a negative hysteroscopy in a 56-year-old woman with morbid obesity. This report highlights the need for patients and clinicians to remain vigilant to the early warning signs of developing endometrial cancer, especially in those at an increased risk secondary to obesity. PMID- 27984851 TI - Who wants weight loss? What do they need? Time to re-think non-surgical approaches in obesity management. PMID- 27984853 TI - Butia spp. (Arecaceae) LC-MS-Based Metabolomics for Species and Geographical Origin Discrimination. AB - The metabolic variability of fruit from Butia spp. (Arecaceae) genotypes from different geographical locations was characterized using untargeted metabolomics by liquid chromatography-mass spectrometry (LC-MS) followed by multivariate data analyses. Principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) from LC-MS data sets showed a clear distinction among Butia catarinensis, Butia odorata, Butia paraguayensis, and Butia yatay. The major metabolites that contributed to species discrimination were primary metabolites including sugars and organic acids and specialized metabolites such as tetrahydroxy-trans-stilbene and rutin. B. odorata fruit from Tapes, RS, Brazil, showed a high content of organic acids and flavonoids, whereas B. odorata fruits from Capao do Leao, RS, Brazil, showed a high sugar content. The results demonstrate that LC-ESI-qToF-MS-based metabolic profiling coupled with chemometric analysis can be used to discriminate among Butia species and between geographical origins of B. odorata and to identify primary and specialized metabolites responsible for the discrimination. PMID- 27984854 TI - Use of Polycrystalline Ice for Assembly of Large Area Au Nanoparticle Superstructures as SERS Substrates. AB - It is still a great challenge to develop simple and low-cost methods for preparation of surface-enhanced Raman scattering (SERS) substrates with high sensitivity and reproducibility. Taking advantage of the microstructure of polycrystalline ice, we developed a new method to assemble large area gold nanoparticle (AuNP) superstructures as SERS substrates without external templating and aggregating agent. The assembly was conducted by freezing AuNP colloid at -20 degrees C, which concentrated AuNPs in the ice veins and produced an AuNP superstructure upon thawing the ice. The AuNP superstructures exhibited high SERS activity with enhancement factors on the order of 7.63 * 107 owing to the high-density hot spots throughout the superstructures. The SERS activity was found to increase with particle size and aggregate size of AuNP superstructures. Besides, the substrates showed good uniformity and reproducibility with relative standard deviations of 11.9% and 12.4%, respectively. The substrates showed long term stability, maintaining SERS activity over a period of five months without noticeable change in morphology of the superstructures. The substrates was further used for label-free detection of trace Thiram on apple fruit with high sensitivity down to the concentration of 0.28 ng/cm2, offering great potential to monitor Thiram levels in foodstuffs and environmental samples. PMID- 27984852 TI - Biochemical Analysis of the Lipoprotein Lipase Truncation Variant, LPLS447X, Reveals Increased Lipoprotein Uptake. AB - Lipoprotein lipase (LPL) is responsible for the hydrolysis of triglycerides from circulating lipoproteins. Whereas most identified mutations in the LPL gene are deleterious, one mutation, LPLS447X, causes a gain of function. This mutation truncates two amino acids from LPL's C-terminus. Carriers of LPLS447X have decreased VLDL levels and increased HDL levels, a cardioprotective phenotype. LPLS447X is used in Alipogene tiparvovec, the gene therapy product for individuals with familial LPL deficiency. It is unclear why LPLS447X results in a serum lipid profile more favorable than that of LPL. In vitro reports vary as to whether LPLS447X is more active than LPL. We report a comprehensive, biochemical comparison of purified LPLS447X and LPL dimers. We found no difference in specific activity on synthetic and natural substrates. We also did not observe a difference in the Ki for ANGPTL4 inhibition of LPLS447X relative to that of LPL. Finally, we analyzed LPL-mediated uptake of fluorescently labeled lipoprotein particles and found that LPLS447X enhanced lipoprotein uptake to a greater degree than LPL did. An LPL structural model suggests that the LPLS447X truncation exposes residues implicated in LPL binding to uptake receptors. PMID- 27984856 TI - Characterization of silver nanoparticles-alginate complexes by combined size separation and size measurement techniques. AB - The detection and quantification of nanoparticles is a complex issue due to the need to combine "classical" identification and quantification of the constituent material, with the accurate determination of the size of submicrometer objects, usually well below the optical diffraction limit. In this work, the authors show that one of the most used analytical methods for silver nanoparticles, asymmetric flow field-flow fractionation, can be strongly influenced by the presence of dissolved organic matter (such as alginate) and lead to potentially misleading results. The authors explain the anomalies in the separation process and show a very general way forward based on the combination of size separation and size measurement techniques. This combination of techniques results in more robust AF4 based methods for the sizing of silver nanoparticles in environmental conditions and could be generally applied to the sizing of nanoparticles in complex matrices. PMID- 27984855 TI - Anion Recognition as a Supramolecular Switch of Cell Internalization. AB - The cell internalization of designed oligoarginine peptides equipped with six glutamic acid residues and an anionic pyranine at the N-terminus is triggered upon addition of a supramolecular host. This host binds specifically to the pyranine moiety, enabling the complex to traverse the cell membrane. Interestingly, none of the components, neither the host nor the guest, are able to cross the cell membrane on their own. PMID- 27984857 TI - Effects of sublethal concentrations of silver nanoparticles on Escherichia coli and Bacillus subtilis under aerobic and anaerobic conditions. AB - The present work is aimed at comparing the effects of sublethal concentrations of silver nanoparticles (AgNPs) on the growth kinetic, adhesion ability, oxidative stress, and phenotypic changes of model bacteria (Escherichia coli and Bacillus subtilis) under both aerobic and anaerobic conditions. Growth kinetic tests conducted in 96-well microtiter plates revealed that sublethal concentrations of AgNPs do not affect E. coli growth, whereas 1 MUg/ml AgNPs increased B. subtilis growth rate under aerobic conditions. At the same concentration, AgNPs promoted B. subtilis adhesion, while it discouraged E. coli attachment to the surface in the presence of oxygen. As determined by 2,7-dichlorofluorescein-diacetate assays, AgNPs increased the formation of intracellular reactive oxygen species, but not at the highest concentrations, suggesting the activation of scavenging systems. Finally, motility assays revealed that 0.01 and 1 MUg/ml AgNPs, respectively, promoted surface movement in E. coli and B. subtilis under aerobic and anaerobic conditions. The results demonstrate that E. coli and B. subtilis react differently from AgNPs over a wide range of sublethal concentrations examined under both aerobic and anaerobic conditions. These findings will help elucidate the behavior and impact of engineered nanoparticles on microbial ecosystems. PMID- 27984859 TI - The behavior of a magnetic filament in flow under the influence of an external magnetic field. AB - We present an extensive numerical study of the behaviour of a filament made of ferromagnetic colloidal particles subjected to the simultaneous action of a fluid flow and a stationary external magnetic field perpendicular to the flow lines. We found that in the presence of a shear flow, the tumbling motion observed at zero field is strongly inhibited when the external magnetic field is applied. The field is able to stabilise the filament with a well defined degree of alignment that depends on the balance between hydrodynamic and magnetic torques. In addition, for a Poiseuille flow, it has been found that the initial position has a long lasting influence on the behaviour of the magnetic filament when the external field is applied. PMID- 27984860 TI - Carrier mobility in double-helix DNA and RNA: A quantum chemistry study with Marcus-Hush theory. AB - Charge mobilities of six DNAs and RNAs have been computed using quantum chemistry calculation combined with the Marcus-Hush theory. Based on this simulation model, we obtained quite reasonable results when compared with the experiment, and the obtained charge mobility strongly depends on the molecular reorganization and electronic coupling. Besides, we find that hole mobilities are larger than electron mobilities no matter in DNAs or in RNAs, and the hole mobility of 2L8I can reach 1.09 * 10-1 cm2 V-1 s-1 which can be applied in the molecular wire. The findings also show that our theoretical model can be regarded as a promising candidate for screening DNA- and RNA-based molecular electronic devices. PMID- 27984861 TI - Erratum: "Quantum and quasi-classical collisional dynamics of O2-Ar at high temperatures" [J. Chem. Phys. 144, 234311 (2016)]. PMID- 27984858 TI - Gold nanoparticles increases UV and thermal stability of human serum albumin. AB - Ultraviolet (UV) radiation, temperature, and time can degrade proteins. Here, the authors show that gold nanoparticles significantly protect human serum albumin from denaturation when exposed to "stressing" conditions such as UV irradiation and sustained exposure in suboptimal conditions. In particular, the authors show that gold nanoparticles significantly reduce the decrease in secondary structure induced by UV irradiation or extended exposure to ambient temperature. PMID- 27984862 TI - Adaptive resolution simulation of oligonucleotides. AB - Nucleic acids are characterized by a complex hierarchical structure and a variety of interaction mechanisms with other molecules. These features suggest the need of multiscale simulation methods in order to grasp the relevant physical properties of deoxyribonucleic acid (DNA) and RNA using in silico experiments. Here we report an implementation of a dual-resolution modeling of a DNA oligonucleotide in physiological conditions; in the presented setup only the nucleotide molecule and the solvent and ions in its proximity are described at the atomistic level; in contrast, the water molecules and ions far from the DNA are represented as computationally less expensive coarse-grained particles. Through the analysis of several structural and dynamical parameters, we show that this setup reliably reproduces the physical properties of the DNA molecule as observed in reference atomistic simulations. These results represent a first step towards a realistic multiscale modeling of nucleic acids and provide a quantitatively solid ground for their simulation using dual-resolution methods. PMID- 27984863 TI - Optical properties of azobenzene-functionalized self-assembled monolayers: Intermolecular coupling and many-body interactions. AB - In a joint theoretical and experimental work, the optical properties of azobenzene-functionalized self-assembled monolayers (SAMs) are studied at different molecular packing densities. Our results, based on density-functional and many-body perturbation theory, as well as on differential reflectance (DR) spectroscopy, shed light on the microscopic mechanisms ruling photo-absorption in these systems. While the optical excitations are intrinsically excitonic in nature, regardless of the molecular concentration, in densely packed SAMs intermolecular coupling and local-field effects are responsible for a sizable weakening of the exciton binding strength. Through a detailed analysis of the character of the electron-hole pairs, we show that distinct excitations involved in the photo-isomerization at low molecular concentrations are dramatically broadened by intermolecular interactions. Spectral shifts in the calculated DR spectra are in good agreement with the experimental results. Our findings represent an important step forward to rationalize the excited-state properties of these complex materials. PMID- 27984864 TI - Electric potential invariants and ions-in-molecules effective potentials for molecular Rydberg states. AB - The dependence of multipole moments and polarizabilities on external fields appears in many applications including biomolecular molecular mechanics, optical non-linearity, nanomaterial calculations, and the perturbation of spectroscopic signatures in atomic clocks. Over a wide range of distances, distributed multipole and polarizability potentials can be applied to obtain the variation of atom-centered atoms-in-molecules electric properties like bonding-quenched polarizability. For cylindrically symmetric charge distributions, we examine single-center and atom-centered effective polarization potentials in a non relativistic approximation for Rydberg states. For ions, the multipole expansion is strongly origin-dependent, but we note that origin-independent invariants can be defined. The several families of invariants correspond to optimized representations differing by origin and number of terms. Among them, a representation at the center of dipole polarizability optimizes the accuracy of the potential with terms through 1/r4. We formulate the single-center expansion in terms of polarization-modified effective multipole moments, defining a form related to the source-multipole expansion of Brink and Satchler. Atom-centered potentials are an origin independent alternative but are limited both by the properties allowed at each center and by the neglected effects like bond polarizability and charge flow. To enable comparisons between single-center effective potentials in Cartesian or spherical form and two-center effective potentials with differing levels of mutual induction between atomic centers, we give analytical expressions for the bond-length and origin-dependence of multipole and polarizability terms projected in the multipole and polarizability expansion of Buckingham. The atom-centered potentials can then be used with experimental data and ab initio calculations to estimate atoms-in-molecules properties. Some results are given for BaF+ and HF showing the utility and limitations of the approach. More detailed results on X 1Sigma+ CaF+ are published separately. PMID- 27984865 TI - Thermodynamic scaling of vibrational dynamics and relaxation. AB - We investigate by thorough molecular dynamics simulations the thermodynamic scaling (TS) of a polymer melt. Two distinct models, with strong and weak virial energy correlations, are considered. Both evidence the joint TS with the same characteristic exponent gammats of the fast mobility-the mean square amplitude of the picosecond rattling motion inside the cage-and the much slower structural relaxation and chain reorientation. If the cage effect is appreciable, the TS master curves of the fast mobility are nearly linear, grouping in a bundle of approximately concurrent lines for different fragilities. An expression of the TS master curve of the structural relaxation with one adjustable parameter less than the available three-parameter alternatives is derived. The novel expression fits well with the experimental TS master curves of thirty-four glassformers and, in particular, their slope at the glass transition, i.e., the isochoric fragility. For the glassformer OTP, the isochoric fragility allows to satisfactorily predict the TS master curve of the fast mobility with no adjustments. PMID- 27984866 TI - Poisson-Boltzmann model of electrolytes containing uniformly charged spherical nanoparticles. AB - Like-charged macromolecules typically repel each other in aqueous solutions that contain small mobile ions. The interaction tends to turn attractive if mobile ions with spatially extended charge distributions are added. Such systems can be modeled within the mean-field Poisson-Boltzmann formalism by explicitly accounting for charge-charge correlations within the spatially extended ions. We consider an aqueous solution that contains a mixture of spherical nanoparticles with uniform surface charge density and small mobile salt ions, sandwiched between two like-charged planar surfaces. We perform the minimization of an appropriate free energy functional, which leads to a non-linear integral differential equation for the electrostatic potential that we solve numerically and compare with predictions from Monte Carlo simulations. Nanoparticles with uniform surface charge density are contrasted with nanoparticles that have all their charges relocated at the center. Our mean-field model predicts that only the former (especially when large and highly charged particles) but not the latter are able to mediate attractive interactions between like-charged planar surfaces. We also demonstrate that at high salt concentration attractive interactions between like-charged planar surfaces turn into repulsion. PMID- 27984867 TI - Dynamics of water confined in mesoporous magnesium carbonate. AB - We have measured the dynamics of water confined in a porous magnesium carbonate material, Upsalite(r), using the high-resolution neutron backscattering spectrometer SPHERES. We found quasielastic scattering that does not flatten out up to 360 K, which means that the dynamics of water are much slower than in other matrix materials. Specifically, a single Lorentzian line could be fitted to the quasielastic part of the acquired spectra between 220 and 360 K. This, accompanied by an elastic line from dynamically frozen water present at all experimental temperatures, even above the melting point, signaled a significant amount of bound or slow water. PMID- 27984868 TI - Mixed brush made of 4-arm stars and linear chains: MD simulations. AB - We investigate the structural properties of binary polymer brushes, composed of functional 4-armed star polymers and chemically identical linear polymers of different molecular weights. The molecular dynamics simulations confirm recent self-consistent field studies, in which a considerable potential of these systems for the design of switchable surfaces has been claimed. The length of the linear chains serves as a control parameter, which, while passing over a critical value, induces a sharp transition of the molecular conformation. We investigate these transitions at different grafting densities and summarize our findings in a phase diagram. The temperature dependence of the brush structure is investigated in a non-selective solvent, and non-trivial variations of the surface composition are observed. The quantity of these latter effects would be insufficient to build switchable systems, and we argue that a minor quantity of solvent selectivity would suffice to enable the desired feature of an environment-responsive coating. PMID- 27984869 TI - Structure in sheared supercooled liquids: Dynamical rearrangements of an effective system of icosahedra. AB - We consider a binary Lennard-Jones glassformer whose super-Arrhenius dynamics are correlated with the formation of particles organized into icosahedra under simple steady state shear. We recast this glassformer as an effective system of icosahedra [Pinney et al., J. Chem. Phys. 143, 244507 (2015)]. From the observed population of icosahedra in each steady state, we obtain an effective temperature which is linearly dependent on the shear rate in the range considered. Upon shear banding, the system separates into a region of high shear rate and a region of low shear rate. The effective temperatures obtained in each case show that the low shear regions correspond to a significantly lower temperature than the high shear regions. Taking a weighted average of the effective temperature of these regions (weight determined by region size) yields an estimate of the effective temperature which compares well with an effective temperature based on the global mesocluster population of the whole system. PMID- 27984870 TI - Erratum: "On the vapor-liquid equilibrium of attractive chain fluids with variable degree of molecular flexibility" [J. Chem. Phys. 142, 224504 (2015)]. PMID- 27984871 TI - Coupled jump rotational dynamics in aqueous nitrate solutions. AB - A nitrate ion (NO3-) with its trigonal planar geometry and charges distributed among nitrogen and oxygen atoms can couple to the extensive hydrogen bond network of water to give rise to unique dynamical characteristics. We carry out detailed atomistic simulations and theoretical analyses to investigate these aspects and report certain interesting findings. We find that the nitrate ions in aqueous potassium nitrate solution exhibit large amplitude rotational jump motions that are coupled to the hydrogen bond rearrangement dynamics of the surrounding water molecules. The jump motion of nitrate ions bears certain similarities to the Laage-Hynes mechanism of rotational jump motions of tagged water molecules in neat liquid water. We perform a detailed atomic-level investigation of hydrogen bond rearrangement dynamics of water in aqueous KNO3 solution to unearth two distinct mechanisms of hydrogen bond exchange that are instrumental to promote these jump motions of nitrate ions. As observed in an earlier study by Xie et al., in the first mechanism, after breaking a hydrogen bond with nitrate ion, water forms a new hydrogen bond with a water molecule, whereas the second mechanism involves just a switching of hydrogen bond between the two oxygen atoms of the same nitrate ion (W. J. Xie et al., J. Chem. Phys. 143, 224504 (2015)). The magnitude as well as nature of the reorientational jump of nitrate ion for the two mechanisms is different. In the first mechanism, nitrate ion predominantly undergoes out-of-plane rotation, while in the second mechanism, in plane reorientation of NO3- is favourable. These have been deduced by computing the torque on the nitrate ion during the hydrogen bond switching event. We have defined and computed the time correlation function for coupled reorientational jump of nitrate and water and obtained the associated relaxation time which is also different for the two mechanisms. These results provide insight into the relation between the coupled reorientational jump dynamics of solute and solvent molecules. PMID- 27984872 TI - Dynamics of single semiflexible polymers in dilute solution. AB - We study the dynamics of a single semiflexible chain in solution using computer simulations, where we systematically investigate the effect of excluded volume, chain stiffness, and hydrodynamic interactions. We achieve excellent agreement with previous theoretical considerations, but find that the crossover from the time taub, up to which free ballistic motion of the monomers describes the chain dynamics, to the times W-1 or tau0, where anomalous monomer diffusion described by Rouse-type and Zimm-type models sets in, requires two decades of time. While in the limit of fully flexible chains the visibility of the anomalous diffusion behavior is thus rather restricted, the t3/4 power law predicted for stiff chains without hydrodynamic interactions is verified. Including hydrodynamics, evidence for the predicted [tln(t)]3/4 behavior is obtained. Similar good agreement with previous theoretical predictions is found for the decay of the bond autocorrelation functions and the end-to-end vector correlation. Finally, several predictions on the variation of characteristic relaxation times with persistence length describing the chain stiffness are tested. PMID- 27984873 TI - Hydrogen bonding in the protic ionic liquid triethylammonium nitrate explored by density functional tight binding simulations. AB - The applicability of the density functional based tight binding (DFTB) method to the description of hydrogen bond dynamics and infrared (IR) spectroscopy is addressed for the exemplary protic ionic liquid triethylammonium nitrate. Potential energy curves for proton transfer in gas and liquid phases are shown to be comparable to the high level coupled cluster theory in the thermally accessible range of bond lengths. Geometric correlations in the hydrogen bond dynamics are analyzed for a cluster of six ion pairs. Comparing DFTB and DFT data lends further support for the reliability of the DFTB method. Therefore, DFTB bulk simulations are performed to quantify the extent of geometric correlations in terms of Pauling's bond order model. Further, IR absorption spectra are obtained using DFTB and analyzed putting emphasis on the signatures of hydrogen bonding in the NH-stretching and far IR hydrogen bond range. PMID- 27984874 TI - Free energy calculations along entropic pathways. II. Droplet nucleation in binary mixtures. AB - Using molecular simulation, we study the nucleation of liquid droplets from binary mixtures and determine the free energy of nucleation along entropic pathways. To this aim, we develop the MU1MU2VT-S method, based on the grand canonical ensemble modeling the binary mixture, and use the entropy of the system S as the reaction coordinate to drive the formation of the liquid droplet. This approach builds on the advantages of the grand-canonical ensemble, which allows for the direct calculation of the entropy of the system and lets the composition of the system free to vary throughout the nucleation process. Starting from a metastable supersaturated vapor, we are able to form a liquid droplet by gradually decreasing the value of S, through a series of umbrella sampling simulations, until a liquid droplet of a critical size has formed. The MU1MU2VT-S method also allows us to calculate the free energy barrier associated with the nucleation process, to shed light on the relation between supersaturation and free energy of nucleation, and to analyze the interplay between the size of the droplet and its composition during the nucleation process. PMID- 27984875 TI - Methyl rotor quantum states and the effect of chemical environment in organic crystals: gamma-picoline and toluene. AB - Using a set of first-principles calculations, we have studied the methyl tunnel splitting for molecular crystals of gamma-picoline and toluene. The effective rotational potential energy surface of the probe methyl rotor along the tunneling path is evaluated using first-principles electronic structure calculations combined with the nudged elastic band method. The tunnel splitting is calculated by an explicit diagonalization of the one-dimensional time-independent Hamiltonian matrix. The effects of chemical environment and rotor-rotor coupling on the rotational energy barriers were investigated. It is found that more dense packing of the molecules in toluene compared to that in gamma-picoline gives rise to a larger rotational barrier which in turn yields a considerably smaller tunnel splitting. Moreover, it turned out that coupled motion of the face-to-face methyl groups in gamma-picoline has a significant effect on the reduction of the rotational barrier. Our results are in good agreement with the experimentally observed tunnel splitting. PMID- 27984876 TI - Time-dependent quantum wave packet dynamics to study charge transfer in heavy particle collisions. AB - The method of time-dependent quantum wave packet dynamics has been successfully extended to study the charge transfer/exchange process in low energy two-body heavy particle collisions. The collision process is described by coupled-channel equations with diabatic potentials and (radial and rotational) couplings. The time-dependent coupled equations are propagated with the multiconfiguration time dependent Hartree method and the modulo squares of S-matrix is extracted from the wave packet by the flux operator with complex absorbing potential (FCAP) method. The calculations of the charge transfer process 12Sigma+ H-(1s2)+Li(1s22s) >22Sigma+/32Sigma+/12Pi H(1s)+Li-(1s22s2l)(l=s,p) at the incident energy of about [0.3, 1.3] eV are illustrated as an example. It shows that the calculated reaction probabilities by the present FCAP reproduce that of quantum-mechanical molecular-orbital close-coupling very well, including the peak structures contributed by the resonances. Since time-dependent external interactions can be directly included in the present FCAP calculations, the successful implementation of FCAP provides us a powerful potential tool to study the quantum control of heavy particle collisions by lasers in the near future. PMID- 27984877 TI - Semi-empirical estimation of ion-specific cross sections in electron ionization of molecules. AB - Partial ionization cross sections are the absolute yields of specific ions from an electron-molecule collision. They are necessary for modeling plasmas and determining the sensitivity of mass spectrometers, among other applications. They can be predicted semi-empirically when experimental data are available for channel-specific oscillator strengths. However, such data are seldom available because they are obtained using specialized apparatus. Here, an alternative semi empirical method is proposed that exploits experimental data obtained using ordinary mass spectrometers, as corrected for mass discrimination. Data are presented for an incident electron energy of 70 eV. PMID- 27984878 TI - Uncertainty quantification for generalized Langevin dynamics. AB - We present efficient finite difference estimators for goal-oriented sensitivity indices with applications to the generalized Langevin equation (GLE). In particular, we apply these estimators to analyze an extended variable formulation of the GLE where other well known sensitivity analysis techniques such as the likelihood ratio method are not applicable to key parameters of interest. These easily implemented estimators are formed by coupling the nominal and perturbed dynamics appearing in the finite difference through a common driving noise or common random path. After developing a general framework for variance reduction via coupling, we demonstrate the optimality of the common random path coupling in the sense that it produces a minimal variance surrogate for the difference estimator relative to sampling dynamics driven by independent paths. In order to build intuition for the common random path coupling, we evaluate the efficiency of the proposed estimators for a comprehensive set of examples of interest in particle dynamics. These reduced variance difference estimators are also a useful tool for performing global sensitivity analysis and for investigating non-local perturbations of parameters, such as increasing the number of Prony modes active in an extended variable GLE. PMID- 27984879 TI - Single-chain-in-mean-field simulations of weak polyelectrolyte brushes. AB - Structural properties of brushes which are composed of weak acidic and basic polyelectrolytes are studied in the framework of a particle-based approach that implicitly accounts for the solvent quality. Using a semi-grandcanonical partition function in the framework of the Single-Chain-in-Mean-Field (SCMF) algorithm, the weak polyelectrolyte is conceived as a supramolecular mixture of polymers in different dissociation states, which are explicitly treated in the partition function and sampled by the SCMF procedure. One obtains a local expression for the equilibrium acid-base reaction responsible for the regulation of the charged groups that is also incorporated to the SCMF sampling. Coupled to a simultaneous treatment of the electrostatics, the approach is shown to capture the main features of weak polyelectrolyte brushes as a function of the bulk pH in the solution, the salt concentration, and the grafting density. Results are compared to experimental and theoretical works from the literature using coarse grained representations of poly(acrylic acid) (PAA) and poly(2-vinyl pyridine) (P2VP) polymer-based brushes. As the Born self-energy of ions can be straightforwardly included in the numerical approach, we also study its effect on the local charge regulation mechanism of the brush. We find that its effect becomes significant when the brush is dense and exposed to high salt concentrations. The numerical methodology is then applied (1) to the study of the kinetics of collapse/swelling of a P2VP brush and (2) to the ability of an applied voltage to induce collapse/swelling of a PAA brush in a pH range close to the pKa value of the polymer. PMID- 27984880 TI - Potential energy landscape of the apparent first-order phase transition between low-density and high-density amorphous ice. AB - The potential energy landscape (PEL) formalism is a valuable approach within statistical mechanics to describe supercooled liquids and glasses. Here we use the PEL formalism and computer simulations to study the pressure-induced transformations between low-density amorphous ice (LDA) and high-density amorphous ice (HDA) at different temperatures. We employ the ST2 water model for which the LDA-HDA transformations are remarkably sharp, similar to what is observed in experiments, and reminiscent of a first-order phase transition. Our results are consistent with the view that LDA and HDA configurations are associated with two distinct regions (megabasins) of the PEL that are separated by a potential energy barrier. At higher temperature, we find that low-density liquid (LDL) configurations are located in the same megabasin as LDA, and that high-density liquid (HDL) configurations are located in the same megabasin as HDA. We show that the pressure-induced LDL-HDL and LDA-HDA transformations occur along paths that interconnect these two megabasins, but that the path followed by the liquid is different from the path followed by the amorphous solid. At higher pressure, we also study the liquid-to-ice-VII first-order phase transition, and find that the behavior of the PEL properties across this transition is qualitatively similar to the changes found during the LDA-HDA transformation. This similarity supports the interpretation that the LDA-HDA transformation is a first-order phase transition between out-of-equilibrium states. Finally, we compare the PEL properties explored during the LDA-HDA transformations in ST2 water with those reported previously for SPC/E water, for which the LDA-HDA transformations are rather smooth. This comparison illuminates the previous work showing that, at accessible computer times scales, a liquid-liquid phase transition occurs in the case of ST2 water, but not for SPC/E water. PMID- 27984881 TI - Communication: Length-dependent thermopower of single-molecule junctions. AB - In the present work, we theoretically study the length dependence of thermopower of a single-molecule junction with a chain-like molecular bridge of an arbitrary length using a tight-binding model. We analyze conditions bringing a nonlinear growth of the thermopower accompanying the extension of the bridge length. Also, we show that the thermopower may decrease with increasing molecular length provided that the molecular bridge is sufficiently long. PMID- 27984882 TI - Simultaneous observations of electromagnetically induced transparency (EIT) and absorption (EIA) in a multi-level V-type system of 87Rb and theoretical simulation of the observed spectra using a multi-mode approach. AB - We report here simultaneous experimental observation of Electromagnetically Induced Transparency (EIT) and Electromagnetically Induced Absorption (EIA) in a multi-level V-type system in D2 transition of Rb87, i.e., F=2->F' with a strong pump and a weak probe beam. We studied the probe spectrum by locking the probe beam to the transition F=2->F'=2 while the pump is scanned from F=2->F'. EIA is observed for the open transition (F=2->F'=2) whereas EIT is observed in the closed transition (F=2->F'=3). Sub natural line-width is observed for the EIA. To simulate the observed spectra theoretically, Liouville equation for the three level V-type system is solved analytically with a multi-mode approach for the density matrix elements. We assumed both the pump and the probe beams can couple the excited states. A multi-mode approach for the coherence terms facilitates the study of all the frequency contributions due to the pump and the probe fields. Since the terms contain higher harmonics of the pump and the probe frequencies, we expressed them in Fourier transformed forms. To simulate the probe spectrum, we have solved inhomogeneous difference equations for the coherence terms using the Green's function technique and continued fraction theory. The experimental line-widths of the EIT and the EIA are compared with our theoretical model. Our system can be useful in optical switching applications as it can be precisely tuned to render the medium opaque and transparent simultaneously. PMID- 27984883 TI - Ab initio ro-vibronic spectroscopy of the Pi2 PCS radical and Sigma+1PCS- anion. AB - Near-equilibrium potential energy surfaces have been calculated for both the PCS radical and its anion using a composite coupled cluster approach based on explicitly correlated F12 methods in order to provide accurate structures and spectroscopic properties. These transient species are still unknown and the present study provides theoretical predictions of the radical and its anion for the first time. Since these species are strongly suggested to play an important role as intermediates in the interstellar medium, the rotational and vibrational spectroscopic parameters are presented to help aid in the identification and assignment of these spectra. The rotational constants produced will aid in ground based observation. Both the PCS radical and the PCS- anion are linear. In the PCS anion, which has a predicted adiabatic electron binding energy (adiabatic electron affinity of PCS) of 65.6 kcal/mol, the P-C bond is stronger than the corresponding neutral radical showing almost triple bond character, while the C-S bond is weaker, showing almost single bond character in the anion. The PCS anion shows a smaller rotational constant than that of the neutral. The omega3 stretching vibrational frequencies of PCS- are red-shifted from the radical, while the omega1 and omega2 vibrations are blue-shifted with omega1 demonstrating the largest blue shift. The ro-vibronic spectrum of the PCS radical has been accurately calculated in variational nuclear motion calculations including both Renner-Teller (RT) and spin-orbit (SO) coupling effects using the composite potential energy near-equilibrium potential energy and coupled cluster dipole moment surfaces. The spectrum is predicted to be very complicated even at low energies due to the presence of a strong Fermi resonance between the bending mode and symmetric stretch, but also due to similar values of the bending frequency, RT, and SO splittings. PMID- 27984884 TI - Analytic second derivatives from auxiliary density perturbation theory. AB - The working equations for the calculation of analytic second energy derivatives in the framework of auxiliary density functional theory (ADFT) are presented. The needed perturbations are calculated with auxiliary density perturbation theory (ADPT) which is extended to perturbation dependent basis and auxiliary functions sets. The obtained ADPT equation systems are solved with the Eirola-Nevanlinna algorithm. The newly developed analytic second ADFT energy derivative approach was implemented in deMon2k and validated with respect to the corresponding finite difference approach by calculating the harmonic frequencies of small molecules. Good agreement between these two methodologies is found. To analyze the scaling of the new analytic second ADFT energy derivatives with respect to the number of processors in parallel runs, the harmonic frequencies of the carbon fullerene C240 are calculated with varying numbers of processors. Fair scaling up to 720 processors was found. As showcase applications, symmetry unrestricted optimization and frequency analyses of icosahedral carbon fullerenes with up to 960 atoms are presented. PMID- 27984885 TI - A DFT+U study of the structural, electronic, magnetic, and mechanical properties of cubic and orthorhombic SmCoO3. AB - SmCoO3 is a perovskite material that has gained attention as a potential substitute for La1-xSrxMnO3-d as a solid oxide fuel cell cathode. However, a number of properties have remained unknown due to the complexity of the material. For example, we know from experimental evidence that this perovskite exists in two different crystal structures, cubic and orthorhombic, and that the cobalt ion changes its spin state at high temperatures, leading to a semiconductor-to-metal transition. However, little is known about the precise magnetic structure that causes the metallic behavior or the spin state of the Co centers at high temperature. Here, we therefore present a systematic DFT+U study of the magnetic properties of SmCoO3 in order to determine what magnetic ordering is the one exhibited by the metallic phase at different temperatures. Similarly, mechanical properties are difficult to measure experimentally, which is why there is a lack of data for the two different phases of SmCoO3. Taking advantage of our DFT calculations, we have determined the mechanical properties from our calculated elastic constants, finding that both polymorphs exhibit similar ductility and brittleness, but that the cubic structure is harder than the orthorhombic phase. PMID- 27984886 TI - Full-dimensional quantum dynamics of rovibrationally inelastic scattering between CN and H2. AB - We report six-dimensional (6D) potential energy surface (PES) and rovibrational scattering calculations for the CN-H2 collision system. The PES was computed using the high-level ab initio spin-restricted coupled-cluster with single, double, and perturbative triple excitations-F12B method and fitted to an analytic function using an invariant polynomial method in 6D. Quantum close-coupling calculations are reported for rotational transitions in CN by H2 and D2 collisions in 6D as well as four-dimensional (4D) within a rigid rotor model for collision energies of 1.0-1500 cm-1. Comparisons with experimental data and previous 4D calculations are presented for CN rotational levels j1 = 4 and 11. For the first time, rovibrational quenching cross sections and rate coefficients of CN (v1 = 1,j1 = 0) in collisions with para- and ortho-H2 are also reported in full-dimension. Agreement for pure rotational transitions is found to be good, but no experimental data on rovibrational collisional quenching for CN-H2 are available. Applications of the current rotational and rovibrational rate coefficients in astrophysical modeling are briefly discussed. PMID- 27984887 TI - Perspective: Methods for large-scale density functional calculations on metallic systems. AB - Current research challenges in areas such as energy and bioscience have created a strong need for Density Functional Theory (DFT) calculations on metallic nanostructures of hundreds to thousands of atoms to provide understanding at the atomic level in technologically important processes such as catalysis and magnetic materials. Linear-scaling DFT methods for calculations with thousands of atoms on insulators are now reaching a level of maturity. However such methods are not applicable to metals, where the continuum of states through the chemical potential and their partial occupancies provide significant hurdles which have yet to be fully overcome. Within this perspective we outline the theory of DFT calculations on metallic systems with a focus on methods for large-scale calculations, as required for the study of metallic nanoparticles. We present early approaches for electronic energy minimization in metallic systems as well as approaches which can impose partial state occupancies from a thermal distribution without access to the electronic Hamiltonian eigenvalues, such as the classes of Fermi operator expansions and integral expansions. We then focus on the significant progress which has been made in the last decade with developments which promise to better tackle the length-scale problem in metals. We discuss the challenges presented by each method, the likely future directions that could be followed and whether an accurate linear-scaling DFT method for metals is in sight. PMID- 27984888 TI - Orbit-orbit relativistic correction calculated with all-electron molecular explicitly correlated Gaussians. AB - An algorithm for calculating the first-order electronic orbit-orbit magnetic interaction correction for an electronic wave function expanded in terms of all electron explicitly correlated molecular Gaussian (ECG) functions with shifted centers is derived and implemented. The algorithm is tested in calculations concerning the H2 molecule. It is also applied in calculations for LiH and H3+ molecular systems. The implementation completes our work on the leading relativistic correction for ECGs and paves the way for very accurate ECG calculations of ground and excited potential energy surfaces (PESs) of small molecules with two and more nuclei and two and more electrons, such as HeH-, H3+, HeH2+, and LiH2+. The PESs will be used to determine rovibrational spectra of the systems. PMID- 27984889 TI - Chirality-sensitive effects induced by nuclear relaxation in an electric field. AB - Two effects induced by the interaction between an electric field E and a permanent electric dipole moment ???? of a chiral molecule placed in a magnetic field B are discussed as follows: (i) a spin-1/2 nucleus relaxes faster and the increase in the relaxation rate is the same for both enantiomers and (ii) in a two-spin system a cross correlation between the dipole-dipole relaxation mechanism and the interaction between nuclear magnetic shielding and the dipole moment ???? enables the direct discrimination between the enantiomers. The former effect is too small in magnitude to be observed experimentally. For detection of the latter, an experimental procedure based on the application of an electric field oscillating at a frequency equal to the difference between the spin precession frequencies of two heteronuclear spins is proposed. PMID- 27984890 TI - Comparison of flow-controlled calcium and barium carbonate precipitation patterns. AB - Various precipitation patterns can be obtained in flow conditions when injecting a solution of sodium carbonate in a confined geometry initially filled with a solution of either barium or calcium chloride. We compare here the barium and calcium carbonate precipitate structures as a function of initial concentrations and injection flow rate. We show that, in some part of the parameter space, the patterns are similar and feature comparable properties indicating that barium and calcium behave similarly in the related flow-controlled precipitation conditions. For other values of parameters though, the precipitate structures are different indicating that the cohesive and microscopic properties of barium versus calcium carbonate are then important in shaping the pattern in flow conditions. PMID- 27984891 TI - High order harmonic generation from SF6: Deconvolution of macroscopic effects. AB - We measure high order harmonics from the molecule SF6 over a large range of phase matching conditions and observe several features in the harmonics that are largely independent of such macroscopic conditions. The experimental data are then compared to the quantitative rescattering theory for the generation of harmonics from three orbitals. With this comparison, we are able to assign spectroscopic features in the harmonics to contributions from 1t1g (HOMO) and 5t1u (HOMO-1) orbitals. PMID- 27984892 TI - Convergence of coupled cluster perturbation theory. AB - The convergence of a recently proposed coupled cluster (CC) family of perturbation series [J. J. Eriksen et al., J. Chem. Phys. 140, 064108 (2014)], in which the energetic difference between two CC models-a low-level parent and a high-level target model-is expanded in orders of the Moller-Plesset (MP) fluctuation potential, is investigated for four prototypical closed-shell systems (Ne, singlet CH2, distorted HF, and F-) in standard and augmented basis sets. In these investigations, energy corrections of the various series have been calculated to high orders and their convergence radii have been determined by probing for possible front- and back-door intruder states, the existence of which would make the series divergent. In summary, we conclude how it is primarily the choice of the target state, and not the choice of the parent state, which ultimately governs the convergence behavior of a given series. For example, restricting the target state to, say, triple or quadruple excitations might remove intruders present in series which target the full configuration interaction limit, such as the standard MP series. Furthermore, we find that whereas a CC perturbation series might converge within standard correlation consistent basis sets, it may start to diverge whenever these become augmented by diffuse functions, similar to the MP case. However, unlike for the MP case, such potential divergences are not found to invalidate the practical use of the low order corrections of the CC perturbation series. PMID- 27984894 TI - Editorial: The Future of Chemical Physics Conference 2016. PMID- 27984893 TI - Phase behavior of decorated soft disks in two dimensions. AB - Molecular dynamics simulations are used to investigate the phase behavior of disks decorated with small ligands in two-dimensional films. We consider disks with four ligands, which are fixed at vertices of a square or slide over the circle delimiting the core. For selected model systems, phase diagrams are evaluated and discussed. We show that ligand mobility can change the topology of phase diagrams. In particular, it can affect fluid-solid transitions, changing the solid phase symmetry. Moreover, the mobility of ligands can either hamper or facilitate crystallization. PMID- 27984895 TI - On the structure of an aqueous propylene glycol solution. AB - Using a combination of neutron diffraction and empirical potential structure refinement computational modelling, the interactions in a 30 mol. % aqueous solution of propylene glycol (PG), which govern both the hydration and association of this molecule in solution, have been assessed. From this work it appears that PG is readily hydrated, where the most prevalent hydration interactions were found to be through both the PG hydroxyl groups but also alkyl groups typically considered hydrophobic. Hydration interactions of PG dominate the solution over PG self-self interactions and there is no evidence of more extensive association. This hydration behavior for PG in solutions suggests that the preference of PG to be hydrated rather than to be self-associated may translate into a preference for PG to bind to lipids rather than itself, providing a potential explanation for how PG is able to enhance the apparent solubility of drug molecules in vivo. PMID- 27984896 TI - The angularly resolved O 1s ion-yield spectrum of O2 revisited. AB - The high-resolution photoabsorption spectrum of O2 below the O 1ssigma-1 ionization threshold has been reanalyzed by using a sophisticated fit approach. For the vibrational substates of the O 1ssigmau-1(4?u-)3ssigmag(3?u-) Rydberg state Fano lineshapes are observed indicating an interaction with the O 1ssigmag 1(4?g-)3sigmau*(3?u-) core-to-valence excited state. In the angularly resolved ion-yield spectrum recorded at 90 degrees relative to the polarization direction of the synchrotron radiation clear evidence for the O 1ssigmag-1(2?g )3sigmau*(3?u-) and the O 1ssigmau-1(2?u-)3ssigmag(3?u-) state was found. This observation clearly suggests thatLambda, the projection of total orbital angular momentum on the molecular axis, is not well separated in the angularly resolved ion-yield spectrum due to a partial breakdown of the axial-recoil approximation for these transitions. PMID- 27984897 TI - A hydrated ion model of [UO2]2+ in water: Structure, dynamics, and spectroscopy from classical molecular dynamics. AB - A new ab initio interaction potential based on the hydrated ion concept has been developed to obtain the structure, energetics, and dynamics of the hydration of uranyl in aqueous solution. It is the first force field that explicitly parameterizes the interaction of the uranyl hydrate with bulk water molecules to accurately define the second-shell behavior. The [UO2(H2O)5]2+ presents a first hydration shell U-O average distance of 2.46 A and a second hydration shell peak at 4.61 A corresponding to 22 molecules using a coordination number definition based on a multisite solute cavity. The second shell solvent molecules have longer mean residence times than those corresponding to the divalent monatomic cations. The axial regions are relatively de-populated, lacking direct hydrogen bonding to apical oxygens. Angle-solved radial distribution functions as well as the spatial distribution functions show a strong anisotropy in the ion hydration. The [UO2(H2O)5]2+ solvent structure may be regarded as a combination of a conventional second hydration shell in the equatorial and bridge regions, and a clathrate-like low density region in the axial region. Translational diffusion coefficient, hydration enthalpy, power spectra of the main vibrational modes, and the EXAFS spectrum simulated from molecular dynamics trajectories agree fairly well with the experiment. PMID- 27984898 TI - Using an internal coordinate Gaussian basis and a space-fixed Cartesian coordinate kinetic energy operator to compute a vibrational spectrum with rectangular collocation. AB - We demonstrate that it is possible to use basis functions that depend on curvilinear internal coordinates to compute vibrational energy levels without deriving a kinetic energy operator (KEO) and without numerically computing coefficients of a KEO. This is done by using a space-fixed KEO and computing KEO matrix elements numerically. Whenever one has an excellent basis, more accurate solutions to the Schrodinger equation can be obtained by computing the KEO, potential, and overlap matrix elements numerically. Using a Gaussian basis and bond coordinates, we compute vibrational energy levels of formaldehyde. We show, for the first time, that it is possible with a Gaussian basis to solve a six dimensional vibrational Schrodinger equation. For the zero-point energy (ZPE) and the lowest 50 vibrational transitions of H2CO, we obtain a mean absolute error of less than 1 cm-1; with 200 000 collocation points and 40 000 basis functions, most errors are less than 0.4 cm-1. PMID- 27984899 TI - Quantum electron-vibrational dynamics at finite temperature: Thermo field dynamics approach. AB - Quantum electron-vibrational dynamics in molecular systems at finite temperature is described using an approach based on the thermo field dynamics theory. This formulation treats temperature effects in the Hilbert space without introducing the Liouville space. A comparison with the theoretically equivalent density matrix formulation shows the key numerical advantages of the present approach. The solution of thermo field dynamics equations with a novel technique for the propagation of tensor trains (matrix product states) is discussed. Numerical applications to model spin-boson systems show that the present approach is a promising tool for the description of quantum dynamics of complex molecular systems at finite temperature. PMID- 27984900 TI - Rotation mechanism of methylammonium molecules in organometal halide perovskite in cubic phase: An ab initio molecular dynamics study. AB - Rotation of methylammonium (CH3NH3 or MA) molecules is believed to govern the excellent transport properties of photocarriers in the MA lead iodide (MAPbI3) perovskite. Of particular interest is its cubic phase, which exists in industrially important films at room temperature. In order to investigate the rotational behaviors of the MA molecules, we have performed ab initio molecular dynamics simulations of cubic-MAPbI3 at room temperature. There are two types of rotational motions of MA molecules in a crystalline PbI3 cage: reorientation of a whole molecule and intramolecular rotation around the C-N bond within MA molecules. Using a cubic symmetry-assisted analysis (CSAA), we found that the prominent orientation of the C-N bond is the crystalline ?110? directions, rather than the ?100? and ?111? directions. Rapid rotation around the C-N bond is also observed, which easily occurs when the rotational axis is parallel to the ?110? directions according to the CSAA. To explain the atomistic mechanisms underlying these CSAA results, we have focused on the relation between H-I hydrogen bonds and the orientation of an MA molecule. Here, the hydrogen bonds were defined by population analysis, and it has been found that, while H atoms in the CH3 group (HC) hardly interacts with I atoms, those in the NH3 group (HN) form at least one hydrogen bond with I atoms and their interatomic distances are in a wide range, 2.2-3.7 A. Based on these findings, we have given a possible explanation to why the ?110? directions are preferred. Namely, the atomic arrangement and interatomic distance between MA and surrounding I atoms are most suitable for the formation of hydrogen bonds. In addition to films, these results are potentially applicable to the rotational behaviors in bulk MAPbI3 as well, considering that the atomistic structure and time constants regarding the rotation of MA molecules statistically agree with bulk experiments. PMID- 27984901 TI - Point charge embedding for ONIOM excited states calculations. AB - Hybrid quantum mechanical methods can assist in the interpretation and prediction of the electronic spectra of large molecular structures. In this work, we study the performance of the ONIOM (Our own N-layered Integrated molecular Orbital molecular Mechanics) hybrid method for the calculation of transition energies and oscillator strengths by embedding the core region in a field of fixed point charges. These charges introduce polarization effects from the substituent groups to the core region. We test various charge definitions, with particular attention to the issue of overpolarization near the boundary between layers. To minimize this issue, we fit the charges on the electrostatic potential of the entire structure in the presence of the link atoms used to cap dangling bonds. We propose two constrained fitting strategies: one that produces an average set of charges common to both model system calculations, EE(L1), and one that produces two separate sets of embedding charges, EE(L2). The results from our tests show that indeed electronic embedding with constrained-fitted charges tends to improve the performance of ONIOM compared to non-embedded calculations. However, the EE(L2) charges work best for transition energies, and the EE(L1) charges work best for oscillator strengths. This may be an indication that fixed point charges do not have enough flexibility to adapt to each system, and other effects (e.g., polarization of the embedding field) may be necessary. PMID- 27984902 TI - Ab initio study of nitrogen and position-specific oxygen kinetic isotope effects in the NO + O3 reaction. AB - Ab initio calculations have been carried out to investigate nitrogen (k15/k14) and position-specific oxygen (k17/k16O & k18/k16) kinetic isotope effects (KIEs) for the reaction between NO and O3 using CCSD(T)/6-31G(d) and CCSD(T)/6-311G(d) derived frequencies in the complete Bigeleisen equations. Isotopic enrichment factors are calculated to be -6.70/00, -1.30/00, -44.70/00, -14.10/00, and 0.30/00 at 298 K for the reactions involving the 15N16O, 14N18O, 18O16O16O, 16O18O16O, and 16O16O18O isotopologues relative to the 14N16O and 16O3 isotopologues, respectively (CCSD(T)/6-311G(d)). Using our oxygen position specific KIEs, a kinetic model was constructed using Kintecus, which estimates the overall isotopic enrichment factors associated with unreacted O3 and the oxygen transferred to NO2 to be -19.60/00 and -22.80/00, respectively, (CCSD(T)/6-311G(d)) which tends to be in agreement with previously reported experimental data. While this result may be fortuitous, this agreement suggests that our model is capturing the most important features of the underlying physics of the KIE associated with this reaction (i.e., shifts in zero-point energies). The calculated KIEs will useful in future NOx isotopic modeling studies aimed at understanding the processes responsible for the observed tropospheric isotopic variations of NOx as well as for tropospheric nitrate. PMID- 27984903 TI - Steady state equivalence among autocatalytic peroxidase-oxidase reactions. AB - Peroxidase-oxidase is an enzymatic reaction that can exhibit dynamical scenarios such as bistability, sustained oscillations, and Shilnikov chaos. In this work, we apply the chemical reaction network theory approach to find kinetic constants such that the associated mass action kinetics ordinary differential equations induced by three four dimensional structurally different enzymatic reaction systems can support the same steady states for several chemical species despite differences in their chemical nature. PMID- 27984904 TI - Competition between inter- and intra-molecular hydrogen bonding: An infrared spectroscopic study of jet-cooled amino-ethanol and its dimer. AB - The Fourier transform IR vibrational spectra of amino-ethanol (AE) and its dimer have been recorded at room temperature and under jet-cooled conditions over the far and mid infrared ranges (50-4000 cm-1) using the White-type cell and the supersonic jet of the Jet-AILES apparatus at the synchrotron facility SOLEIL. Assignment of the monomer experimental frequencies has been derived from anharmonic frequencies calculated at a hybrid CCSD(T)-F12/MP2 level. Various thermodynamical effects in the supersonic expansion conditions including molar dilution of AE and nature of carrier gas have been used to promote or not the formation of dimers. Four vibrational modes of the observed dimer have been unambiguously assigned using mode-specific scaling factors deduced from the ratio between experimental and computed frequencies for the monomer. The most stable g'Gg' monomer undergoes strong deformation upon dimerization, leading to a homochiral head to head dimer involving two strong hydrogen bonds. PMID- 27984905 TI - Outstanding performance of configuration interaction singles and doubles using exact exchange Kohn-Sham orbitals in real-space numerical grid method. AB - To assess the performance of multi-configuration methods using exact exchange Kohn-Sham (KS) orbitals, we implemented configuration interaction singles and doubles (CISD) in a real-space numerical grid code. We obtained KS orbitals with the exchange-only optimized effective potential under the Krieger-Li-Iafrate (KLI) approximation. Thanks to the distinctive features of KLI orbitals against Hartree-Fock (HF), such as bound virtual orbitals with compact shapes and orbital energy gaps similar to excitation energies; KLI-CISD for small molecules shows much faster convergence as a function of simulation box size and active space (i.e., the number of virtual orbitals) than HF-CISD. The former also gives more accurate excitation energies with a few dominant configurations than the latter, even with many more configurations. The systematic control of basis set errors is straightforward in grid bases. Therefore, grid-based multi-configuration methods using exact exchange KS orbitals provide a promising new way to make accurate electronic structure calculations. PMID- 27984906 TI - Thermopower of molecular junctions: Tunneling to hopping crossover in DNA. AB - We study the electrical conductance G and the thermopower S of single-molecule junctions and reveal signatures of different transport mechanisms: off-resonant tunneling, on-resonant coherent (ballistic) motion, and multi-step hopping. These mechanisms are identified by studying the behavior of G and S while varying molecular length and temperature. Based on a simple one-dimensional model for molecular junctions, we derive approximate expressions for the thermopower in these different regimes. Analytical results are compared to numerical simulations, performed using a variant of Buttiker's probe technique, the so called voltage-temperature probe, which allows us to phenomenologically introduce environmentally induced elastic and inelastic electron scattering effects, while applying both voltage and temperature biases across the junction. We further simulate the thermopower of GC-rich DNA sequences with mediating A:T blocks and manifest the tunneling-to-hopping crossover in both the electrical conductance and the thermopower, in accord with measurements by Li et al. [Nat. Commun. 7, 11294 (2016)]. PMID- 27984907 TI - Conformational analysis of ethyl-substituted Criegee intermediate by FTMW spectroscopy. AB - Ethyl-substituted Criegee intermediate, C2H5CHOO, has been generated in the discharged plasma of a 1,1-diiodopropane/O2 gas mixture and spectroscopically characterized by Fourier transform microwave spectroscopy in a pulsed supersonic jet. The comparison between the experimental rotational constants and those calculated ab initio unambiguously confirms the identification of three conformers, providing the definitive probe for their molecular structures. Some of the observed pure rotational transitions show small splittings corresponding to the A/E components due to the threefold methyl internal rotation, which made it possible to determine the barrier heights of the hindered methyl rotation. The conformational abundances as well as the non observation of a plausible fourth conformer have been rationalized in terms of interconversion processes between conformers and interactions between the terminal oxygen and the protons of the ethyl moiety. PMID- 27984908 TI - Infrared laser spectroscopy of the n-propyl and i-propyl radicals: Stretch-bend Fermi coupling in the alkyl CH stretch region. AB - The n-propyl and i-propyl radicals were generated in the gas phase via pyrolysis of n-butyl nitrite [CH3(CH2)3ONO] and i-butyl nitrite [(CH3)2CHCH2ONO], respectively. Nascent radicals were promptly solvated by a beam of He nanodroplets, and the infrared spectra of the radicals were recorded in the CH stretching region. Several previously unreported bands are observed between 2800 and 3150 cm-1. The CH stretching modes observed above 3000 cm-1 are in excellent agreement with CCSD(T) anharmonic frequencies computed using second-order vibrational perturbation theory. However, between 2800 and 3000 cm-1, the spectra of n- and i-propyl radicals become congested and difficult to assign due to the presence of multiple anharmonic resonance polyads. To model the spectrally congested region, Fermi and Darling-Dennison resonances are treated explicitly using "dressed" Hamiltonians and CCSD(T) quartic force fields in the normal mode representation, and the agreement with experiment is less than satisfactory. Computations employing local mode effective Hamiltonians reveal the origin of the spectral congestion to be strong coupling between the high frequency CH stretching modes and the lower frequency CHn bending/scissoring motions. The most significant coupling is between stretches and bends localized on the same CH2/CH3 group. Spectral simulations using the local mode approach are in excellent agreement with experiment. PMID- 27984909 TI - The d 3Pi state of LiRb. AB - We report our spectroscopic studies of the d 3Pi state of ultra-cold 7Li85Rb using resonantly enhanced multi-photon ionization and depletion spectroscopy with bound-to-bound transitions originating from the metastable a 3Sigma+ state. We evaluate the potential of this state for use as the intermediate state in a stimulated-Raman-adiabatic-passage transfer scheme from triplet Feshbach LiRb molecules to the X 1Sigma+ ground state and find that the lowest several vibrational levels possess the requisite overlap with initial and final states, as well as convenient energies. Using depletion measurements, we measured the well depth and spin-orbit splitting. We suggest possible pathways for short-range photoassociation using deeply bound vibrational levels of this electronic state. PMID- 27984910 TI - Dynamic force matching: Construction of dynamic coarse-grained models with realistic short time dynamics and accurate long time dynamics. AB - We recently developed a dynamic force matching technique for converting a coarse grained (CG) model of a molecular system, with a CG potential energy function, into a dynamic CG model with realistic dynamics [A. Davtyan et al., J. Chem. Phys. 142, 154104 (2015)]. This is done by supplementing the model with additional degrees of freedom, called "fictitious particles." In that paper, we tested the method on CG models in which each molecule is coarse-grained into one CG point particle, with very satisfactory results. When the method was applied to a CG model of methanol that has two CG point particles per molecule, the results were encouraging but clearly required improvement. In this paper, we introduce a new type (called type-3) of fictitious particle that exerts forces on the center of mass of two CG sites. A CG model constructed using type-3 fictitious particles (as well as type-2 particles previously used) gives a much more satisfactory dynamic model for liquid methanol. In particular, we were able to construct a CG model that has the same self-diffusion coefficient and the same rotational relaxation time as an all-atom model of liquid methanol. Type-3 particles and generalizations of it are likely to be useful in converting more complicated CG models into dynamic CG models. PMID- 27984911 TI - Water dynamics in rigid ionomer networks. AB - The dynamics of water within ionic polymer networks formed by sulfonated poly(phenylene) (SPP), as revealed by quasi-elastic neutron scattering (QENS), is presented. These polymers are distinguished from other ionic macromolecules by their rigidity and therefore in their network structure. QENS measurements as a function of temperature as the fraction of ionic groups and humidity were varied have shown that the polymer molecules are immobile while absorbed water molecules remain dynamic. The water molecules occupy multiple sites, either bound or loosely constrained, and bounce between the two. With increasing temperature and hydration levels, the system becomes more dynamic. Water molecules remain mobile even at subzero temperatures, illustrating the applicability of the SPP membrane for selective transport over a broad temperature range. PMID- 27984912 TI - Quantum effects in graphene monolayers: Path-integral simulations. AB - Path-integral molecular dynamics (PIMD) simulations have been carried out to study the influence of quantum dynamics of carbon atoms on the properties of a single graphene layer. Finite-temperature properties were analyzed in the range from 12 to 2000 K, by using the LCBOPII effective potential. To assess the magnitude of quantum effects in structural and thermodynamic properties of graphene, classical molecular dynamics simulations have been also performed. Particular emphasis has been laid on the atomic vibrations along the out-of-plane direction. Even though quantum effects are present in these vibrational modes, we show that at any finite temperature classical-like motion dominates over quantum delocalization, provided that the system size is large enough. Vibrational modes display an appreciable anharmonicity, as derived from a comparison between kinetic and potential energies of the carbon atoms. Nuclear quantum effects are found to be appreciable in the interatomic distance and layer area at finite temperatures. The thermal expansion coefficient resulting from PIMD simulations vanishes in the zero-temperature limit, in agreement with the third law of thermodynamics. PMID- 27984913 TI - Calculating potential energy curves with fixed-node diffusion Monte Carlo: CO and N2. AB - This study reports on the prospect for the routine use of Quantum Monte Carlo (QMC) for the electronic structure problem, applying fixed-node Diffusion Monte Carlo (DMC) to generate highly accurate Born-Oppenheimer potential energy curves (PECs) for small molecular systems. The singlet ground electronic states of CO and N2 were used as test cases. The PECs obtained by DMC employing multiconfigurational trial wavefunctions were compared with those obtained by conventional high-accuracy electronic structure methods such as multireference configuration interaction and/or the best available empirical spectroscopic curves. The goal was to test whether a straightforward procedure using available QMC codes could be applied robustly and reliably. Results obtained with DMC codes were found to be in close agreement with the benchmark PECs, and the n3 scaling with the number of electrons (compared with n7 or worse for conventional high accuracy quantum chemistry) could be advantageous depending on the system size. Due to a large pre-factor in the scaling, for the small systems tested here, it is currently still much more computationally intensive to compute PECs with QMC. Nevertheless, QMC algorithms are particularly well-suited to large-scale parallelization and are therefore likely to become more relevant for future massively parallel hardware architectures. PMID- 27984914 TI - Tetrel bond of pseudohalide anions with XH3F (X = C, Si, Ge, and Sn) and its role in SN2 reaction. AB - The complexes of XH3F?N3-/OCN-/SCN- (X = C, Si, Ge, and Sn) have been investigated at the MP2/aug-cc-pVTZ(PP) level. The sigma-hole of X atom in XH3F acts as a Lewis acid forming a tetrel bond with pseudohalide anions. Interaction energies of these complexes vary from -8 to -50 kcal/mol, mainly depending on the nature of X and pseudohalide anions. Charge transfer from N/O/S lone pair to X-F and X-H sigma* orbitals results in the stabilization of these complexes, and the former orbital interaction is responsible for the large elongation of X-F bond length and the remarkable red shift of its stretch vibration. The tetrel bond in the complexes of XH3F (X = Si, Ge, and Sn) exhibits a significant degree of covalency with XH3F distorted significantly in these complexes. A breakdown of the individual forces involved attributes the stability of the interaction to mainly electrostatic energy, with a relatively large contribution from polarization. The transition state structures that connect the two minima for CH3Br?N3- complex have been localized and characterized. The energetic, geometrical, and topological parameters of the complexes were analyzed in the different stages of the SN2 reaction N3- + CH3Br -> Br- + CH3N3. PMID- 27984915 TI - Quantum heat current under non-perturbative and non-Markovian conditions: Applications to heat machines. AB - We consider a quantum system strongly coupled to multiple heat baths at different temperatures. Quantum heat transport phenomena in this system are investigated using two definitions of the heat current: one in terms of the system energy and the other in terms of the bath energy. When we consider correlations among system bath interactions (CASBIs)-which have a purely quantum mechanical origin-the definition in terms of the bath energy becomes different. We found that CASBIs are necessary to maintain the consistency of the heat current with thermodynamic laws in the case of strong system-bath coupling. However, within the context of the quantum master equation approach, both of these definitions are identical. Through a numerical investigation, we demonstrate this point for a non equilibrium spin-boson model and a three-level heat engine model using the reduced hierarchal equations of motion approach under the strongly coupled and non-Markovian conditions. We observe the cyclic behavior of the heat currents and the work performed by the heat engine, and we find that their phases depend on the system-bath coupling strength. Through consideration of the bath heat current, we show that the efficiency of the heat engine decreases as the strength of the system-bath coupling increases, due to the CASBI contribution. In the case of a large system-bath coupling, the efficiency decreases further if the bath temperature is increased, even if the ratio of the bath temperatures is fixed, due to the discretized nature of energy eigenstates. This is also considered to be a unique feature of quantum heat engines. PMID- 27984916 TI - Random phase approximation with second-order screened exchange for current carrying atomic states. AB - The direct random phase approximation (RPA) and RPA with second-order screened exchange (SOSEX) have been implemented with complex orbitals as a basis for treating open-shell atoms. Both RPA and RPA+SOSEX are natural implicit current density functionals because the paramagnetic current density implicitly is included through the use of complex orbitals. We confirm that inclusion of the SOSEX correction improves the total energy accuracy substantially compared to RPA, especially for smaller-Z atoms. Computational complexity makes post self consistent-field (post-SCF) evaluation of RPA-type expressions commonplace, so orbital basis origins and properties become important. Sizable differences are found in correlation energies, total atomic energies, and ionization energies for RPA-type functionals evaluated in the post-SCF fashion with orbital sets obtained from different schemes. Reference orbitals from Kohn-Sham calculations with semi local functionals are more suitable for RPA+SOSEX to generate accurate total energies, but reference orbitals from exact exchange (non-local) yield essentially energetically degenerate open-shell atom ground states. RPA+SOSEX correlation combined with exact exchange calculated from a hybrid reference orbital set (half the exchange calculated from exact-exchange orbitals, the other half of the exchange from orbitals optimized for the Perdew-Burke-Ernzerhof (PBE) exchange functional) gives the best overall performance. Numerical results show that the RPA-like functional with SOSEX correction can be used as a practical implicit current density functional when current effects should be included. PMID- 27984917 TI - The South Carolina rural-urban HIV continuum of care. AB - The HIV continuum of care model is widely used by various agencies to describe the HIV epidemic in stages from diagnosis through to virologic suppression. It identifies the various points at which persons living with HIV (PLWHIV) within a population fail to reach their next step in HIV care. The rural population in the Southern United States is disproportionally affected by the HIV epidemic. The purpose of this study was to examine these rural-urban disparities using the HIV care continuum model and determine at what stages these differences become apparent. PLWHIV aged 13 years and older in South Carolina (SC) were identified using data from the enhanced HIV/AIDS Reporting System. The percentages of PLWHIV linked to care, retained in care, and virologically suppressed were determined. Rural versus urban residence was determined using the Office of Management and Budget classification. There were 14,523 PLWHIV in SC at the end of 2012; 11,193 (77%) of whom were categorized as urban and 3305 (22%) as rural. There was no difference between urban and rural for those who had received any care: 64% versus 64% (p = .61); retention in care 53% versus 53% (p = .71); and virologic suppression 49% versus 48% (p = .35), respectively. The SC rural-urban HIV cascade represents the first published cascade of care model using rural versus urban residence. Although significant health care disparities exist between rural and urban residents, there were no major differences between rural and urban residents at the various stages of engagement in HIV care using the HIV continuum of care model. PMID- 27984918 TI - Phone-based safety monitoring of the first year of baclofen treatment for alcohol use disorder: the BACLOPHONE cohort study protocol. AB - BACKGROUND: In France, baclofen is frequently used off-label for alcohol use disorder (AUD). Baclofen has been associated with diverse adverse events (AEs), but the causality of these AEs has never been properly assessed. METHODS/DESIGN: BACLOPHONE is a prospective multicenter cohort study conducted in the Hauts-de France and Normandie French regions. BACLOPHONE consists of the phone-based monitoring of 792 patients during their first year of baclofen treatment for AUD. Two initial phone interviews assess the medical history, current medications, and substance use as well as complete the alcohol use identification test (AUDIT) and severity of alcohol dependence questionnaire (SADQ). Daily alcohol use and baclofen doses are noted throughout the follow-up. For every reported AE, additional phone interviews determine the seriousness of the AE, the causality of baclofen using validated causality algorithms, and the final outcome. The main objective of the study is to determine the rate of patients who stop baclofen due to an AE during the first year of treatment. DISCUSSION: BACLOPHONE will provide important safety data on baclofen as a complement to the forthcoming efficacy data of randomized clinical trials. PMID- 27984919 TI - From chemotherapy to target therapies associated with radiation in the treatment of NSCLC: a durable marriage? AB - INTRODUCTION: The integration between radiotherapy and drugs, from chemotherapy to recently available target therapies, continues to have a relevant role in the treatment of locally advanced and metastatic Non-small cell lung cancer (NSCLC). Aim of the present review is to evaluate the promising and emerging application of the best interaction between new drugs and new modalities of radiotherapy. Areas covered: We searched Medline, Google Scholar, PubMed, ProQuest Dissertation, and Theses databases for reports published in English. A study was included when it reported on cancer-related radiotherapy and included patients with NSCLC treated with chemo and/or target therapies. Review articles were excluded from the analysis. Expert commentary: Chemo-radiotherapy still represents the standard of choice in locally advanced NSCLC, while to date the addition of target therapies to chemo-radiotherapy did not demonstrate any robust advantage in this stage of disease. Considering the absence of randomized controlled trials, the role of target therapies in early stage adjuvant NSCLC is not yet recommended in clinical practice. On the contrary, in the setting of oligometastatic and oligoprogressive disease, new molecules demonstrated to be safe and effective, opening to a promising and emerging application of the best interaction between new drugs and new modalities of radiotherapy. PMID- 27984920 TI - Alkaloids from aerial parts of Annona senegalensis against Streptococcus mutans. AB - Antimicrobial potential of medicinal plants have been explored extensively these days. This study was carried out to evaluate the antibacterial potential from aerial parts of plant, called 'Annona senegalensis' and its constituents. Bioassay guided fractionation led to the isolation of four metabolites, (+) catechin (1), (-)-anonaine (2), (-)-asimilobine (3) and (+)-nornantenine (4). This is the first report on the isolation of compounds 1, 3 and 4 from this plant. Compounds 2 and 4 showed good activity, whereas 1 and 3 displayed weak inhibition against Streptococcus mutans (ATCC 25175). The results showed that compound 2 and 3 showed significant activity with a minimum inhibition concentration (MIC) of 0.12 and 0.25 mg/mL, respectively. The present study reports for the first time the antibacterial activity of the extract of A. senegalensis and its constituents. As S. mutans is a rather resistant bacteria, the MIC obtained during the present study is significant. PMID- 27984921 TI - Deprescribing: a new goal focused on the patient. AB - It is estimated that one-fifth of adult patients are treated with polypharmacy (five or more drugs) and the prevalence of this phenomenon in the elderly is even higher, ranging from 30% to 70%, even reaching 90% in residents of residential aged care facilities. Polypharmacy in the elderly increases the risk of adverse reactions, inappropriate prescriptions, drug interactions, number of hospitalizations, costs, and even death. In a recent systematic review, the authors proposed defining deprescribing as 'the process of withdrawal of inappropriate medication supervised by a health care professional with the goal of managing polypharmacy and improving outcomes'. PMID- 27985284 TI - Drug poisoning in the community among children: a nine years' experience from a tertiary care center in south India. AB - OBJECTIVES: This study was performed to determine the incidence, demographic distribution, types and outcomes across various drug poisonings among children from south India. METHODS: This retrospective study included children less than 16 years who presented to the Pediatric Emergency Department with drug poisoning from the 1st of October 2004 to the 30th of September 2013. RESULTS: Out of the total 997 poisoning cases, 366 (36.71%) were contributed by drugs; mainly antiepileptics, central nervous system depressants, psychotropics, analgesic antipyretics and natural drugs. Males and children of < 5 years were mostly affected. Although many children developed complications and required intensive care unit admissions, the total mortality rate was less than 1%. The incidence of drug poisoning showed a decreasing trend over the last 4 years. CONCLUSION: This study for the first time gives an elaborative insight into pediatric drug poisoning over a nine-year period from a Pediatric Emergency Department tertiary care center in south India. PMID- 27985968 TI - Career planning for the non-clinical workforce - an opportunity to develop a sustainable workforce in primary care. AB - Many health and social care systems worldwide have been developing a variety of navigator and signposting roles to help patients negotiate care through increasingly complex systems and multiple provider agencies. This UK project aims to explore, through a combination of job description review and workshops of stakeholders, the common competencies and features of non-clinical roles. The information is collated to develop common job descriptions at four key levels. These form the basis for a career pathway supported by portfolio-based educational programmes, embracing Apprenticeship Training Programmes. The programmes have the potential to support recruitment and retention of an increasingly skilled workforce to move between traditional health and social care provider boundaries. This offers the opportunity to release clinicians from significant administrative workload and support patients in an integrated care system. PMID- 27986075 TI - Knockdown of ST6Gal-I increases cisplatin sensitivity in cervical cancer cells. AB - BACKGROUND: Sialyltransferase I (ST6Gal-I) is an enzyme involved in tumor metastasis that processes sialic acid precursors into their mature form, enabling them to regulate gene expression. However, the effect of ST6Gal-I on the biological behavior of cancer cells remain unclear. This study was the first to demonstrate the influence of ST6Gal-I on cisplatin sensitivity in cervical cancer cells. METHODS: Knockdown of ST6Gal-I was performed by shRNA and HeLa cells combination with cisplatin were tested. RESULTS: We showed that down-regulation of ST6Gal-I promoted cell apoptosis and inhibited proliferation and invasion in cervical cancer cells. Knockdown of ST6Gal-I by RNA interference increased the sensitivity of HeLa cells to cisplatin in vitro, and reduced tumor volume and suppressed subcutaneous tumor growth in response to cisplatin treatment in a xenograft mouse model in vivo. CONCLUSIONS: The results provide new information that ST6Gal-I plays an important role in several biological or pathological processes including drug resistance in cervical cancer and may be a potential therapeutic target to improve the response to chemotherapy in cervical cancer patients. PMID- 27986076 TI - Transcriptome analysis in switchgrass discloses ecotype difference in photosynthetic efficiency. AB - BACKGROUND: Switchgrass, a warm-season perennial grass studied as a potential dedicated biofuel feedstock, is classified into two main taxa - lowland and upland ecotypes - that differ in morphology and habitat of adaptation. But there is limited information on their inherent molecular variations. RESULTS: Transcriptome analysis by RNA-sequencing (RNA-Seq) was conducted for lowland and upland ecotypes to document their gene expression variations. Mapping of transcriptome to the reference genome (Panicum virgatum v1.1) revealed that the lowland and upland ecotypes differ substantially in sets of genes transcribed as well as levels of expression. Differential gene expression analysis exhibited that transcripts related to photosynthesis efficiency and development and photosystem reaction center subunits were upregulated in lowlands compared to upland genotype. On the other hand, catalase isozymes, helix-loop-helix, late embryogenesis abundant group I, photosulfokinases, and S-adenosyl methionine synthase gene transcripts were upregulated in the upland compared to the lowlands. At >=100x coverage and >=5% minor allele frequency, a total of 25,894 and 16,979 single nucleotide polymorphism (SNP) markers were discovered for VS16 (upland ecotype) and K5 (lowland ecotype) against the reference genome. The allele combination of the SNPs revealed that the transition mutations are more prevalent than the transversion mutations. CONCLUSIONS: The gene ontology (GO) analysis of the transcriptome indicated lowland ecotype had significantly higher representation for cellular components associated with photosynthesis machinery controlling carbon fixation. In addition, using the transcriptome data, SNP markers were detected, which were distributed throughout the genome. The differentially expressed genes and SNP markers detected in this study would be useful resources for traits mapping and gene transfer across ecotypes in switchgrass breeding for increased biomass yield for biofuel conversion. PMID- 27986078 TI - Monoplacophoran mitochondrial genomes: convergent gene arrangements and little phylogenetic signal. AB - BACKGROUND: Although recent studies have greatly advanced understanding of deep molluscan phylogeny, placement of some taxa remains uncertain as different datasets support competing class-relationships. Traditionally, morphologists have placed Monoplacophora, a group of morphologically simple, limpet-like molluscs as sister group to all other conchiferans (shelled molluscs other than Polyplacophora), a grouping that is supported by the latest large-scale phylogenomic study that includes Laevipilina. However, molecular datasets dominated by nuclear ribosomal genes support Monoplacophora + Polyplacophora (Serialia). Here, we evaluate the potential of mitochondrial genome data for resolving placement of Monoplacophora. RESULTS: Two complete (Laevipilina antarctica and Vema ewingi) and one partial (Laevipilina hyalina) mitochondrial genomes were sequenced, assembled, and compared. All three genomes show a highly similar architecture including an unusually high number of non-coding regions. Comparison of monoplacophoran gene order shows a gene arrangement pattern not previously reported; there is an inversion of one large gene cluster. Our reanalyses of recently published polyplacophoran mitogenomes show, however, that this feature is also present in some chiton species. Maximum Likelihood and Bayesian Inference analyses of 13 mitochondrial protein-coding genes failed to robustly place Monoplacophora and hypothesis testing could not reject any of the evaluated placements of Monoplacophora. CONCLUSIONS: Under both serialian or aculiferan-conchiferan scenarios, the observed gene cluster inversion appears to be a convergent evolution of gene arrangements in molluscs. Our phylogenetic results are inconclusive and sensitive to taxon sampling. Aculifera (Polyplacophora + Aplacophora) and Conchifera were never recovered. However, some analyses recovered Serialia (Monoplacophora + Polyplacophora), Diasoma (Bivalvia + Scaphopoda) or Pleistomollusca (Bivalvia + Gastropoda). Although we could not shed light on deep evolutionary traits of Mollusca we found unique patterns of gene arrangements that are common to monoplacophoran and chitonine polyplacophoran species but not to acanthochitonine Polyplacophora. Complete mitochondrial genome of Laevipilina antarctica. PMID- 27986080 TI - Erratum to: Prevalence, sensitivity and specificity of antibodies against carbamylated proteins in a monocentric cohort of patients with rheumatoid arthritis and other autoimmune rheumatic diseases. AB - RESULTS: Anti-CarP antibodies were detected in 117 patients with RA (37.9%), ACPA in 190 patients (61.4%) and RF in 202 patients (65.3%). Two (2.04%) of the NHS were positive for anti-CarP, one NHS (1.02%) was positive for ACPA and three NHS were positive for RF (3.06%). Among disease controls, anti-CarP antibodies were detected in 33 patients (16.5%), ACPA in 29 patients (14.5%) and RF in 64 patients (32%). In particular, 16.8% of patients with systemic lupus erythematosus and 31.1% of patients with Sjogren syndrome were positive for anti CarP. The sensitivity of anti-CarP, ACPA and RF was 46.8, 61.8 and 64.4%, respectively and specificity was 91.95, 89.93 and 76.51%, respectively. PMID- 27986079 TI - Pre-discharge factors predicting readmissions of psychiatric patients: a systematic review of the literature. AB - BACKGROUND: Readmission rate is considered an indicator of the mental health care quality. Previous studies have examined a number of factors that are likely to influence readmission. The main objective of this systematic review is to identify the studied pre-discharge variables and describe their relevance to readmission among psychiatric patients. METHODS: Studies on the association between pre-discharge variables and readmission after discharge with a main psychiatric diagnosis were searched in the bibliographic databases Ovid Medline, PsycINFO, ProQuest Health Management and OpenGrey. Relevant publications published between January 1990 and June 2014 were included. For each variable, the number of papers that considered it as a predictor of readmission and that found a significant association was recorded, together with the association direction and whether it was found respectively in bivariate and in multivariate analyses. RESULTS: Of the 734 articles identified in the search, 58 papers were included in this review, mainly from the USA and concerning patients with severe mental disorders. Analysed variables were classified according to the following categories: patients' demographic, social and economic characteristics; patients' clinical characteristics; patients' clinical history; patients' attitude and perception; environmental, social and hospital characteristics; and admission and discharge characteristics. The most consistently significant predictor of readmission was previous hospitalisations. Many socio-demographic variables resulted as influencing readmission, but the results were not always homogeneous. Among other patients' clinical characteristics, diagnosis and measures of functional status were the most often used variables. Among admission characteristics, length of stay was the main factor studied; however, the results were not very consistent. Other relevant aspects resulted associated with readmission, including the presence of social support, but they have been considered only in few papers. Results of quality assessment are also reported in the review. The majority of papers were not representative of the general psychiatric population discharged from an inpatient service. Almost all studies used multivariate analytical methods, i.e., confounders were controlled for, but only around 60% adjusted for previous hospitalisation, the variable most consistently considered associated to readmission in the literature. CONCLUSIONS: The results contribute to increase knowledge on pre-discharge factors that could be considered by researchers as well as by clinicians to predict and prevent readmissions of psychiatric patients. Associations are not always straightforward and interactions between factors have to be considered. PMID- 27986077 TI - Impact of peer support on virologic failure in HIV-infected patients on antiretroviral therapy - a cluster randomized controlled trial in Vietnam. AB - BACKGROUND: The effect of peer support on virologic and immunologic treatment outcomes among HIVinfected patients receiving antiretroviral therapy (ART) was assessed in a cluster randomized controlled trial in Vietnam. METHODS: Seventy one clusters (communes) were randomized in intervention or control, and a total of 640 patients initiating ART were enrolled. The intervention group received peer support with weekly home-visits. Both groups received first-line ART regimens according to the National Treatment Guidelines. Viral load (VL) (ExaVirTM Load) and CD4 counts were analyzed every 6 months. The primary endpoint was virologic failure (VL >1000 copies/ml). Patients were followed up for 24 months. Intention-to-treat analysis was used. Cluster longitudinal and survival analyses were used to study time to virologic failure and CD4 trends. RESULTS: Of 640 patients, 71% were males, mean age 32 years, 83% started with stavudine/lamivudine/nevirapine regimen. After a mean of 20.8 months, 78% completed the study, and the median CD4 increase was 286 cells/MUl. Cumulative virologic failure risk was 7.2%. There was no significant difference between intervention and control groups in risk for and time to virologic failure and in CD4 trends. Risk factors for virologic failure were ART-non-naive status [aHR 6.9;(95% CI 3.2-14.6); p < 0.01]; baseline VL >=100,000 copies/ml [aHR 2.3;(95% CI 1.2-4.3); p < 0.05] and incomplete adherence (self-reported missing more than one dose during 24 months) [aHR 3.1;(95% CI 1.1-8.9); p < 0.05]. Risk factors associated with slower increase of CD4 counts were: baseline VL >=100,000 copies/ml [adj.sq.Coeff (95% CI): -0.9 (-1.5;-0.3); p < 0.01] and baseline CD4 count <100 cells/MUl [adj.sq.Coeff (95% CI): -5.7 (-6.3;-5.4); p < 0.01]. Having an HIV-infected family member was also significantly associated with gain in CD4 counts [adj.sq.Coeff (95% CI): 1.3 (0.8;1.9); p < 0.01]. CONCLUSION: There was a low virologic failure risk during the first 2 years of ART follow-up in a rural low-income setting in Vietnam. Peer support did not show any impact on virologic and immunologic outcomes after 2 years of follow up. TRIAL REGISTRATION: NCT01433601 . PMID- 27986081 TI - Comparison of the lifetime host-to-tick transmission between two strains of the Lyme disease pathogen Borrelia afzelii. AB - BACKGROUND: Transmission from the vertebrate host to the arthropod vector is a critical step in the life-cycle of any vector-borne pathogen. How the probability of host-to-vector transmission changes over the duration of the infection is an important predictor of pathogen fitness. The Lyme disease pathogen Borrelia afzelii is transmitted by Ixodes ricinus ticks and establishes a chronic infection inside rodent reservoir hosts. The present study compares the temporal pattern of host-to-tick transmission between two strains of B. afzelii. METHODS: Laboratory mice were experimentally infected via tick bite with one of two strains of B. afzelii: A3 and A10. Mice were repeatedly infested with pathogen free larval Ixodes ricinus ticks over a period of 4 months. Engorged larval ticks moulted into nymphal ticks that were tested for infection with B. afzelii using qPCR. The proportion of infected nymphs was used to characterize the pattern of host-to-tick transmission over time. RESULTS: Both strains of B. afzelii followed a similar pattern of host-to-tick transmission. Transmission decreased from the acute to the chronic phase of the infection by 16.1 and 29.3% for strains A3 and A10, respectively. Comparison between strains found no evidence of a trade-off in transmission between the acute and chronic phase of infection. Strain A10 had higher lifetime fitness and established a consistently higher spirochete load in nymphal ticks than strain A3. CONCLUSION: Quantifying the relationship between host-to-vector transmission and the age of infection in the host is critical for estimating the lifetime fitness of vector-borne pathogens. PMID- 27986082 TI - Mesenchymal stem cells as therapeutic target of biophysical stimulation for the treatment of musculoskeletal disorders. AB - BACKGROUND: Musculoskeletal disorders are regarded as a major cause of worldwide morbidity and disability, and they result in huge costs for national health care systems. Traditional therapies frequently turned out to be poorly effective in treating bone, cartilage, and tendon disorders or joint degeneration. As a consequence, the development of novel biological therapies that can treat more effectively these conditions should be the highest priority in regenerative medicine. Mesenchymal stem cells (MSCs) represent one of the most promising tools in musculoskeletal tissue regenerative medicine, thanks to their proliferation and differentiation potential and their immunomodulatory and trophic ability. Indeed, MSC-based approaches have been proposed for the treatment of almost all orthopedic conditions, starting from different cell sources, alone or in combination with scaffolds and growth factors, and in one-step or two-step procedures. While all these approaches would require cell harvesting and transplantation, the possibility to stimulate the endogenous MSCs to enhance their tissue homeostasis activity represents a less-invasive and cost-effective therapeutic strategy. Nowadays, the role of tissue-specific resident stem cells as possible therapeutic target in degenerative pathologies is underinvestigated. Biophysical stimulations, and in particular extracorporeal shock waves treatment and pulsed electromagnetic fields, are able to induce proliferation and support differentiation of MSCs from different origins and affect their paracrine production of growth factors and cytokines. SHORT CONCLUSIONS: The present review reports the attempts to exploit the resident stem cell potential in musculoskeletal pathologies, highlighting the role of MSCs as therapeutic target of currently applied biophysical treatments. PMID- 27986084 TI - Harmonisation and standardisation of health sector and programme reviews and evaluations - how can they better inform health policy dialogue? AB - BACKGROUND: Health sector and programme performance assessments provide a rich source of contextual data directly linked to implementation of programmes and can inform health policy dialogue, planning and resource allocation. In seeking to maximise this opportunity, there are challenges to overcome. A meeting convened by the World Health Organization African Region discussed the strengths, weaknesses and challenges to harmonising and standardising health sector and programme performance assessments, as well as use of evidence from such processes in decision making. This article synthesises the deliberations which emerged from the meeting. Discussing these in light of other literature we propose practical options to standardising health sector and programme performance assessment and improve realisation of using evidence in decision making. DISCUSSION: Use of evidence generated from health sector and programme performance assessments into regular country processes of sectoral monitoring, dialogue and policy modification is crucial. However, this process faces several challenges. Identified challenges were categorised under several themes, namely the weak institutional capacities for monitoring and evaluation in reference to weak health information systems, a lack of tools and skills, and weak accountability mechanisms; desynchronised planning timeframes between programme and overall health sector strategies; inadequate time to undertake comprehensive and good quality performance assessment; weak mechanisms for following up on implementation of recommendations; lack of effective stakeholder participation; and divergent political aspirations. CONCLUSION: The question of what performance assessment is for in a country must be asked and answered clearly if the utility of these processes is to be realised. Standardising programme and sector reviews offers numerable opportunities that need to be maximised. Identified challenges need to be overcome through strengthened Ministry of Health leadership, effective stakeholder engagement and institutionalising follow-up mechanisms for agreed recommendations. In addition, health sector performance assessments need to be institutionalised as part of the accountability mechanism, and they must be planned for and funding secured within annual budget and medium term expenditure frameworks. PMID- 27986083 TI - IMP: a pipeline for reproducible reference-independent integrated metagenomic and metatranscriptomic analyses. AB - Existing workflows for the analysis of multi-omic microbiome datasets are lab specific and often result in sub-optimal data usage. Here we present IMP, a reproducible and modular pipeline for the integrated and reference-independent analysis of coupled metagenomic and metatranscriptomic data. IMP incorporates robust read preprocessing, iterative co-assembly, analyses of microbial community structure and function, automated binning, as well as genomic signature-based visualizations. The IMP-based data integration strategy enhances data usage, output volume, and output quality as demonstrated using relevant use-cases. Finally, IMP is encapsulated within a user-friendly implementation using Python and Docker. IMP is available at http://r3lab.uni.lu/web/imp/ (MIT license). PMID- 27986086 TI - Pelvic and breast examination skills curricula in United States medical schools: a survey of obstetrics and gynecology clerkship directors. AB - BACKGROUND: Learning to perform pelvic and breast examinations produces anxiety for many medical students. Clerkship directors have long sought strategies to help students become comfortable with the sensitive nature of these examinations. Incorporating standardized patients, simulation and gynecologic teaching associates (GTAs) are approaches gaining widespread use. However, there is a paucity of literature guiding optimal approach and timing. Our primary objective was to survey obstetrics and gynecology (Ob/Gyn) clerkship directors regarding timing and methods for teaching and assessment of pelvic and breast examination skills in United States medical school curricula, and to assess clerkship director satisfaction with current educational strategies at their institutions. METHODS: Ob/Gyn clerkship directors from all 135 Liaison Committee on Medical Education accredited allopathic United States medical schools were invited to complete an anonymous 15-item web-based questionnaire. RESULTS: The response rate was 70%. Pelvic and breast examinations are most commonly taught during the second and third years of medical school. Pelvic examinations are primarily taught during the Ob/Gyn and Family Medicine (FM) clerkships, while breast examinations are taught during the Ob/Gyn, Surgery and FM clerkships. GTAs teach pelvic and breast examinations at 72 and 65% of schools, respectively. Over 60% of schools use some type of simulation to teach examination skills. Direct observation by Ob/Gyn faculty is used to evaluate pelvic exam skills at 87% of schools and breast exam skills at 80% of schools. Only 40% of Ob/Gyn clerkship directors rated pelvic examination training as excellent, while 18% rated breast examination training as excellent. CONCLUSIONS: Pelvic and breast examinations are most commonly taught during the Ob/Gyn clerkship using GTAs, simulation trainers and clinical patients, and are assessed by direct faculty observation during the Ob/Gyn clerkship. While the majority of Ob/Gyn clerkship directors were not highly satisfied with either pelvic or breast examination training programs, they were less likely to describe their breast examination training programs as excellent as compared to pelvic examination training-overall suggesting an opportunity for improvement. The survey results will be useful in identifying future challenges in teaching such skills in a cost-effective manner. PMID- 27986085 TI - Evidence for harm reduction in COPD smokers who switch to electronic cigarettes. AB - BACKGROUND: Electronic cigarettes (ECs) are battery-operated devices designed to vaporise nicotine, which may help smokers quitting or reducing their tobacco consumption. There is a lack of data on the health effects of EC use among smokers with COPD and whether regular use results in improvement in subjective and objective COPD outcomes. We investigated long-term changes in objective and subjective respiratory outcomes in smokers with a diagnosis of COPD who quit or reduced substantially their tobacco consumption by supplementing with or converting only to ECs use. METHODS: We conducted a retrospective chart review of patients with COPD to identify those reporting regular daily use of ECs on at least two follow-up visits at 12- (F/up1) and 24-months (F/up2). Regularly smoking COPD patients were included as a reference group. RESULTS: A marked reduction in cigarette consumption was observed in ECs users. A significant reduction in COPD exacerbations was reported in the COPD EC user group, their mean (+/-SD) decreasing from 2.3 (+/-1) at baseline to 1.8 (+/-1; p = 0.002) and 1.4 (+/-0.9; p < 0.001) at F/up1 and F/up2 respectively. A significant reduction in COPD exacerbations was also observed in ECs users who also smoked conventional cigarettes (i.e. 'dual users'). COPD symptoms and ability to perform physical activities improved statistically in the EC group at both visits, with no change in the control group. CONCLUSIONS: These findings suggest that ECs use may aid smokers with COPD reduce their cigarette consumption or remain abstinent, which results in marked improvements in annual exacerbation rate as well as subjective and objective COPD outcomes. PMID- 27986087 TI - A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains most co-occurrence. AB - In cancer, mutually exclusive or co-occurring somatic alterations across genes can suggest functional interactions. Existing tests for such patterns make the unrealistic assumption of identical gene alteration probabilities across tumors. We present Discrete Independence Statistic Controlling for Observations with Varying Event Rates (DISCOVER), a novel test that is more sensitive than other methods and controls its false positive rate. A pan-cancer analysis using DISCOVER finds no evidence for widespread co-occurrence, and most co-occurrences previously detected do not exceed expectation by chance. Many mutual exclusivities are identified involving well-known genes related to cell cycle and growth factor signaling, as well as lesser known regulators of Hedgehog signaling. PMID- 27986088 TI - Designing and screening of universal drug from neem (Azadirachta indica) and standard drug chemicals against influenza virus nucleoprotein. AB - BACKGROUND: Different strains of influenza virus are affecting a large number of people worldwide. Many synthetic antiviral medicines are available for influenza virus in the market. But still there is a need for the development of universal drugs against these strains of influenza virus. METHODS: For this purpose conserved residues within the influenza virus nucleoprotein have been retrieved. The drugs, previously known to have antiviral properties, were screened to identify the best candidate universal drug against Influenza virus strains. Compounds from leaf extracts of neem, were also screened to identify the natural drugs without side effects. RESULT: Molecular docking identified three potential compounds (Nimbaflavone, Rutin, and Hyperoside) having perfect binding with reported conserved residues (ASP302, SER50) of influenza virus nucleoprotein that is involved in the binding of drugs. Further analysis showed Hyperoside as a universal drug against various influenza strains. Some chemical drugs were also evaluated through screening against nucleoprotein. The results showed six drugs (OMS, CBX, LGH, Naproxen, BMS-883559, and BMS-885838) which were interacting with same conserved residues (ASP302, TYR52, SER50, GLY288, SER376, and ARG99) as were found in the case of neem phytochemicals. Hyperoside from neem leaf extract along with drugs LGH, Naproxen, BMS-885838, and BMS-883559 showed best interactions with conserved residues of nucleoprotein. CONCLUSION: The compound Hyperoside from neem leaf extract along with drugs LGH, Naproxen, BMS-885838, and BMS-883559 showed best interactions with conserved residues of nucleoprotein. So these compounds have been identified for their potential against influenza strains to be utilized as a universal drug. PMID- 27986090 TI - First report of L1014F-kdr mutation in Culex pipiens complex from Morocco. AB - BACKGROUND: Mosquitoes of the Culex pipiens complex, competent vectors for West Nile virus (WNV) and Rift Valley fever virus (RVFV) are widely targeted by insecticide treatments. The intensive application of chemical insecticides led to the development of resistance in many insects including Culex pipiens mosquitoes. The absence of data on resistance mechanisms in Morocco allow us to assess the levels of lambda-cyhalothrin resistance and the frequency of the mutated gene L1014F kdr in different forms of Cx. pipiens complex from three regions of Morocco. METHODS: Mosquito adults were reared from immature stages collected in three different regions in Morocco (Tangier, Casablanca and Marrakech). Standard WHO insecticide susceptibility tests were conducted on adults emerged from collected larvae. Specimens were identified as belonging to the Culex pipiens complex using a multiplex PCR assay with diagnostic primers designed from the flanking region of microsatellite CQ11. Identified mosquitoes were then tested for the presence of the L1014F kdr mutation using PCR assay. RESULTS: Our results showed that 21% of the tested population has a resistance to lambda-cyhalothrin. The molecular identification of survivors shows that 43% belonged to the Cx. pipiens pipiens and only 9.5% to the Cx. pipiens molestus form. On the other hand, 416 specimens were screened for the L1014F kdr mutation. L1014F mutation was detected in different forms of Cx. pipiens in different sites. The frequency of L1014F mutation was similar between the Cx. pipiens pipiens form and hybrid form, while it was lower in the Cx. pipiens molestus form. The presence of the L1014F kdr allele was significantly associated with resistance to lambda cyhalothrin in Cx. pipiens pipiens (P < 0.0001) and hybrid form (P < 0.0001). CONCLUSION: Resistance to lambda-cyhalothrin of Cx. pipiens populations appears to be largely due to the L1014F kdr mutation. To our knowledge, the frequencies of L1014F kdr mutation are examined for the first time in natural populations of the Culex pipiens complex in Morocco. These findings will provide important information to propose more adapted vector control measures towards this mosquito species, potential vector of arboviruses. PMID- 27986089 TI - The anti-inflammatory role of extranuclear apurinic/apyrimidinic endonuclease 1/redox effector factor-1 in reactive astrocytes. AB - Apurinic/apyrimidinic endonuclease 1 (APE1), a ubiquitous multipurpose protein, is also known as redox effector factor-1 (Ref-1). It is involved in DNA repair and redox signaling and, in turn, oxidative stress-induced neurodegeneration. Although previous studies have demonstrated that APE1/Ref-1 functions as a negative regulator of inflammatory response via several mechanisms in neuronal cells, little is known about the roles of APE1/Ref-1 in glial cells. In this study, we found that cytoplasmic APE1/Ref-1 expression was upregulated in reactive astrocytes of the kainic acid- or lipopolysaccharide (LPS)-injected hippocampus. Analysis of the inflammatory response induced by extranuclear APE1/Ref-1 (DeltaNLS-Ref-1) in cultured primary astrocytes revealed that it markedly suppressed inducible nitric oxide synthase (iNOS) expression and tumor necrosis factor-alpha (TNF-alpha) secretion induced by LPS to a similar extent as did wild type APE1/Ref-1 (WT-Ref-1), supporting the concept an anti-inflammatory role of extranuclear APE1/Ref-1 in astrocytes. Additionally, overexpression of WT and DeltaNLS-Ref-1 suppressed the transcriptional activity of nuclear factor kappaB (NF-kappaB), although it effectively enhanced activator protein 1 (AP-1) activity. The blunting effect of APE1/Ref-1 on LPS-induced NF-kappaB activation was not mediated by IkappaB kinase (IKK) activity. Instead, APE1/Ref-1 inhibited p300-mediated acetylation of p65 by suppressing intracellular reactive oxygen species (ROS) levels following LPS treatment. Taken together, our results showed that altered expression and/or subcellular distribution of APE1/Ref-1 in activated astrocytes regulated the neuroinflammatory response to excitotoxin and endotoxin insults used in model of neurodegenerative brain diseases. PMID- 27986091 TI - From early detection to rehabilitation in the community: reading beyond the blog testimonies of survivors' quality of life and prostate cancer representation. AB - BACKGROUND: Survivors' testimonies can reveal much about men's experiences of prostate cancer and impacts on their quality of life (QOL) during the clinical trajectory of the disease. These survivors' shared thoughts and views were hypothesized to reflect salient features of their lived social representation of prostate cancer. CONTEXT: We explored the content of testimonies posted by men to a public blog hosted by a French national prostate cancer patients' association. The study question, "What do French bloggers' testimonies reveal about their lived experiences with prostate cancer, especially regarding their quality of life in community settings, that underpin their social representation of prostate cancer?" guided the exploration and analysis of the textual data. The aims were to better understand men's experiences and predominant thoughts and views, to elucidate patients' behaviours, and to enlighten medical policy and practice. PURPOSE: Explore issues of QOL as reported by French prostate cancer survivors in a public blog by: (a) identifying the salient aspects and issues of the experience of living with prostate cancer from the perspective of survivors; and (b) analyzing the content in the posted testimonies regarding perceived and lived impacts of prostate cancer on QOL. METHODS: A critical ethnographic study guided the selection of textual data from 196 male bloggers' testimonies about prostate cancer posted in the period from 2008 to 2013. Media content analysis method was undertaken on blog testimonies, framed by a multidimensional conceptual framework of QOL. RESULTS: Testimonies focused mainly on medical care and rehabilitation, recovery, health education and self-care, as well as on a global vision of prostate cancer and its impacts on personal views of manhood and masculinity. The language used indicated that political, educative and compassionate discourses were intertwined to create a complex representation of the experience and effects of prostate cancer; this multi-faceted representation can inform the public and professional debate about men's capacity to provide emotional support and problem solve within a community of interest. CONCLUSION: Findings, while based on data limited to mostly one-time entries to a French blog, contribute to understanding a unique, collective expression of men's lived experiences of prostate cancer. These anonymous survivors shared their varied reactions, ways of coping, and thoughts on needed change. PMID- 27986092 TI - Urogenital schistosomiasis transmission on Unguja Island, Zanzibar: characterisation of persistent hot-spots. AB - BACKGROUND: Elimination of urogenital schistosomiasis transmission is a priority for the Zanzibar Ministry of Health. Preventative chemotherapy together with additional control interventions have successfully alleviated much of the disease burden. However, a persistently high Schistosoma haematobium prevalence is found in certain areas. Our aim was to characterise and evaluate these persistent "hot spots" of transmission and reinfection in comparison with low-prevalence areas, to support the intervention planning for schistosomiasis elimination in Zanzibar. METHODS: Prevalences of S. haematobium were annually determined by a single urine filtration in schoolchildren from 45 administrative areas (shehias) in Unguja in 2012, 2013 and 2014. Coverage data for biannual treatment with praziquantel were available from ministerial databases and internal surveys. Among the 45 shehias, five hot-spot (>= 15 % prevalence) and two low-prevalence (<= 5 %) shehias were identified and surveyed in mid-2014. Human-water contact sites (HWCSs) and the presence of S. haematobium-infected and uninfected Bulinus globosus, as well as safe water sources (SWSs) and their reliability in terms of water availability were determined and mapped. RESULTS: We found no major difference in the treatment coverage between persistent hot-spot and low-prevalence shehias. On average, there were considerably more HWCSs containing B. globosus in hot-spot than in low-prevalence shehias (n = 8 vs n = 2) and also more HWCSs containing infected B. globosus (n = 2 vs n = 0). There was no striking difference in the average abundance of SWSs in hot-spot and low-prevalence shehias (n = 45 vs n = 38) and also no difference when considering SWSs with a constant water supply (average: 62 % vs 62 %). The average number of taps with a constant water supply, however, was lower in hot-spot shehias (n = 7 vs n = 14). Average distances from schools to the nearest HWCS were considerably shorter in hot-spot shehias (n = 229 m vs n = 722 m). CONCLUSION: The number of HWCSs, their infestation with B. globosus and their distance to schools seem to play a major role for a persistently high S. haematobium prevalence in children. In addition to treatment, increasing access to reliably working taps, targeted snail control at HWCSs near schools and enhanced behaviour change measures are needed to reduce prevalences in hot-spot areas and to finally reach elimination. TRIAL REGISTRATION: ISRCTN48837681 . PMID- 27986095 TI - Deep Work: A Productivity Superpower. PMID- 27986093 TI - The societal costs of dementia in Sweden 2012 - relevance and methodological challenges in valuing informal care. AB - BACKGROUND: In this study, we sought to estimate the societal cost of illness in dementia in Sweden in 2012 using different costing approaches to highlight methodological issues. METHODS: We conducted a prevalence-based cost-of-illness study with a societal perspective. RESULTS: The societal costs of dementia in Sweden in 2012 were SEK 62.9 billion (approximately ?7.2 billion, approximately US$9.0 billion) or SEK 398,000 per person with dementia (approximately ?45,000, approximately US$57,000). By far the most important cost item is the cost of institutional care: about 60% of the costs. In the sensitivity analysis, different quantification and costing approaches for informal care resulted in a great variation in the total societal cost, ranging from SEK 60 billion (?6.8 billion, US$8.6 billion) to SEK 124 billion (?14.1 billion, US$17.8 billion). CONCLUSIONS: The societal costs of dementia are very high. The cost per person with dementia has decreased somewhat, mainly because of de-institutionalisation. The majority of the costs occur in the social care sector, but the costing of informal care is crucial for the cost estimates. PMID- 27986094 TI - Using an intervention mapping approach for planning, implementing and assessing a community-led project towards malaria elimination in the Eastern Province of Rwanda. AB - BACKGROUND: Active community participation in malaria control is key to achieving malaria pre-elimination in Rwanda. This paper describes development, implementation and evaluation of a community-based malaria elimination project in Ruhuha sector, Bugesera district, Eastern province of Rwanda. METHODS: Guided by an intervention mapping approach, a needs assessment was conducted using household and entomological surveys and focus group interviews. Data related to behavioural, epidemiological, entomological and economical aspects were collected. Desired behavioural and environmental outcomes were identified concurrently with behavioural and environmental determinants. Theoretical methods and their practical applications were enumerated to guide programme development and implementation. An operational plan including the scope and sequence as well as programme materials was developed. Two project components were subsequently implemented following community trainings: (1) community malaria action teams (CMATs) were initiated in mid-2014 as platforms to deliver malaria preventive messages at village level, and (2) a mosquito larval source control programme using biological substances was deployed for a duration of 6 months, implemented from January to July 2015. Process and outcome evaluation has been conducted for both programme components to inform future scale up. RESULTS: The project highlighted malaria patterns in the area and underpinned behavioural and environmental factors contributing to malaria transmission. Active involvement of the community in collaboration with CMATs contributed to health literacy, particularly increasing ability to make knowledgeable decisions in regards to malaria prevention and control. A follow up survey conducted six months following the establishment of CMATs reported a reduction of presumed malaria cases at the end of 2014. The changes were related to an increase in the acceptance and use of available preventive measures, such as indoor residual spraying and increase in community-based health insurance membership, also considered as a predictor of prompt and adequate care. The innovative larval source control intervention contributed to reduction in mosquito density and nuisance bites, increased knowledge and skills for malaria control as well as programme ownership. CONCLUSION: This community-based programme demonstrated the feasibility and effectiveness of active community participation in malaria control activities, which largely contributed to community empowerment and reduction of presumed malaria in the area. Further studies should explore how gains may be sustained to achieve the goal of malaria pre-elimination. PMID- 27986096 TI - Comparison of Mineral Trioxide Aggregate and iRoot BP Plus Root Repair Material as Root-end Filling Materials in Endodontic Microsurgery: A Prospective Randomized Controlled Study. AB - INTRODUCTION: This prospective randomized controlled study evaluated the clinical and radiographic outcome of endodontic microsurgery when using iRoot BP Plus Root Repair Material (BP-RRM; Innovative BioCeramix Inc, Vancouver, BC, Canada) or mineral trioxide aggregate (MTA) as the retrograde filling material and analyzed the relationship between some potential prognostic factors and the outcome of the surgery. METHODS: By using strict inclusion and exclusion criteria, 240 teeth were successfully enrolled and randomly and equally allocated to either the MTA or BP-RRM treatment group. A standardized surgical procedure was performed by a single operator. The patients were followed up at 1 week, 3 months, 6 months, and 12 months; follow-up included clinical and radiographic examination. Clinical and radiographic evaluations acquired at the 12-month follow-up were taken as the primary outcome. For the identification of prognostic factors, the dichotomous outcome (success vs failure) was taken as the dependent variable. RESULTS: A total of 158 teeth were analyzed at the 12-month follow-up, including 87 teeth in the MTA group and 71 teeth in the BP-RRM group. The success rate in the MTA and BP-RRM groups was 93.1% (81/87 teeth) and 94.4% (67/71 teeth), respectively (P > .05). Three significant outcome predictors were identified: quality of root filling (P < .05), tooth type (P < .05), and size of the lesion (P < .05) CONCLUSIONS: These results suggest that BP-RRM is comparable with MTA in clinical outcome when used as root-end filling materials in endodontic microsurgery. PMID- 27986097 TI - Endodontic Working Length Measurement Using Cone-beam Computed Tomographic Images Obtained at Different Voxel Sizes and Field of Views, Periapical Radiography, and Apex Locator: A Comparative Ex Vivo Study. AB - INTRODUCTION: The aim of this study was to evaluate the accuracy of working length determination by using an electronic apex locator, periapical radiography, and cone-beam computed tomographic (CBCT) imaging obtained at different voxel sizes and field of views (FOVs) in extracted human teeth. METHODS: Thirty extracted human mandibular premolar teeth were used. The electronic working length measurements were performed by using an electronic apex locator (Root ZX; J Morita Corp, Kyoto, Japan). Five different image sets were obtained as follows: (1) CBCT imaging: 40 * 40 mm FOV, 0.080 mm3 (FOV40); (2) CBCT imaging: 60 * 60 mm FOV, 0.125 mm3 (FOV60); (3) CBCT imaging: 80 * 80 mm FOV, 0.160 mm3 (FOV80); (4) CBCT imaging: 100 * 100 mm FOV, 0.250 mm3 (FOV100); and (5) periapical digital radiography. Direct measurements performed with an electronic digital caliper were considered as the gold standard and compared with the electronic apex locator, CBCT, and periapical image measurements. Data were analyzed using a 2 way analysis of variance test. Significance level was set at P < .05. RESULTS: There was no significant difference between or within operators in intraoral radiographs (P > .05 and the Gage R&R value was <30%). There were significant differences between and within operators for CBCT images (P < .05 and Gage R&R value was >30%). There were significant differences in the methods in terms of mean differences from the gold standard (P < .05). CONCLUSIONS: This study showed that available CBCT scans with different FOVs can be used for working length measurement. PMID- 27986098 TI - The Effects of Torsional Preloading on the Torsional Resistance of Nickel titanium Instruments. AB - INTRODUCTION: This study evaluated the effect of torsional preloading on the torsional resistance of nickel-titanium (NiTi) endodontic instruments. METHODS: WaveOne Primary (Dentsply Maillefer, Ballaigues, Switzerland) and ProTaper Universal F2 (Dentsply Maillefer) files were used. The ultimate torsional strength until fracture was determined for each instrument. In the phase 1 experiment, the ProTaper and WaveOne files were loaded to have a maximum load from 2.0 up to 2.7 or 2.8 Ncm, respectively. In the phase 2 experiment, the number of repetitions of preloading for each file was increased from 50 to 200, whereas the preloading torque was fixed at 2.4 Ncm. Using torsionally preloaded specimens from phase 1 and 2, the torsional resistances were calculated to determine the ultimate strength, distortion angle, and toughness. The results were analyzed using 1-way analysis of variance and Duncan post hoc comparison. The fracture surfaces and longitudinal aspect of 5 specimens per group were examined under a scanning electron microscope. RESULTS: All preloaded groups showed significantly higher ultimate strength than the unpreloaded groups (P < .05). There was no significant difference among all groups for distortion angle and toughness. Although WaveOne had no significant difference between the repetition groups for ultimate strength, fracture angle, and toughness, ProTaper had a higher distortion angle and toughness in the 50-repetition group compared with the other repetition groups (P < .05). Scanning electron microscopic examinations of the fractured surface showed typical features of torsional fracture. CONCLUSIONS: Torsional preloading within the ultimate values could enhance the torsional strength of NiTi instruments. The total energy until fracture was maintained constantly, regardless of the alloy type. PMID- 27986099 TI - Sodium Hypochlorite Accident: A Systematic Review. AB - INTRODUCTION: Sodium hypochlorite (NaOCl) extrusion beyond the apex, also known as "a hypochlorite accident," is a well-known complication that seldom occurs during root canal therapy. These "accidents" have been the subject of several case reports published over the years. Until now, no publication has addressed the global synthesis of the general and clinical data related to NaOCl extrusion. The main purpose of this article was to conduct a systematic review of previously published case reports to identify, synthesize, and present a critical analysis of the available data. A second purpose was to propose a standardized presentation of reporting data concerning NaOCl extrusions to refine and develop guidelines that should be used in further case report series. METHODS: A review of clinical cases reporting NaOCl accidents was conducted in June 2016 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist; it combined an electronic search of the PubMed database and an extensive manual search. RESULTS: Forty full-text articles corresponding to 52 case reports published between 1974 and 2015 were selected. Four main categories of data were highlighted: general and clinical information, clinical signs and symptoms of NaOCl extrusions, management of NaOCl extrusions, and healing and prognosis. Overall, up to now, clinical cases were reported in a very unsystematic manner, and some relevant information was missing. CONCLUSIONS: A better understanding of the potential causes, management, and prognosis of NaOCl accidents requires a standardization of reported data; this study proposes a template that can fulfill this objective. PMID- 27986100 TI - Examining the Sensitivity and Specificity of 2 Screening Instruments: Odontogenic or Temporomandibular Disorder Pain? AB - INTRODUCTION: Two groups of patients with orofacial pains that are clinically important to distinguish from each other are patients with odontogenic pain and temporomandibular disorder (TMD) pain. The aim of this study was to determine the sensitivity and specificity of 2 screening instruments in distinguishing between patients with these types of pain. METHODS: A convenience sample of patients seeking care at an endodontic clinic and an orofacial pain clinic were recruited. The 14-item dental pain questionnaire (DePaQ) was used to screen for odontogenic pain and the 6-item TMD screener was used to screen for TMD pain. Sensitivity and specificity calculations with 95% confidence intervals (CIs) were performed for both instruments, and thresholds/acceptability/performance was assessed using published guidelines. RESULTS: Thirty-four patients with odontogenic pain and 37 patients with TMD pain were included in this study. The sensitivity of the DePaQ was 0.85 (95% CI, 0.69-0.95), and specificity was 0.11 (95% CI, 0.03-0.25). The sensitivity of the TMD screener was 0.92 (95% CI, 0.78-0.98), and specificity was 0.59 (95% CI, 0.41-0.75). The point estimates, a single value used to estimate the population parameter, for both the DePaQ and TMD screener were "acceptable" in identifying patients who had the pain condition in question (ie, sensitivity), whereas the point estimate for appropriately identifying patients who did not have the pain condition when they did not have it (ie, specificity) was "nonacceptable" for both. CONCLUSIONS: The DePaQ and the TMD screener lack diagnostic accuracy for differentiating TMD from odontogenic tooth pain without adjunctive (clinical) investigation(s) or examination. However, the TMD screener has high sensitivity for identifying true positives (ie, TMD pain) and would therefore be useful as a screening instrument when one can definitively exclude odontogenic etiology for pain on clinical and radiographic grounds, for instance in endodontic practices. In this study, the negative predictive value was also high in the TMD screener, and, therefore, we can trust a negative result (ie, when the TMD screener is negative, we can be fairly certain the pain diagnosis is not TMD and rule out TMD). PMID- 27986101 TI - Endodontic Outcomes in Mandibular Second Premolars with Complex Apical Branching. AB - INTRODUCTION: Mandibular premolars that have rare and complex anatomies may have the highest failure rate in nonsurgical endodontic treatment. Awareness of rare and complex anatomies of mandibular second premolars would aid in better outcomes of the treatment. This study aimed to evaluate the success of nonsurgical root canal treatment of mandibular second premolar teeth with complex apical branching. METHODS: Twenty-six mandibular second premolar teeth with complex apical branching treated with multiple-visit nonsurgical root canal treatment or nonsurgical retreatment were retrospectively evaluated. RESULTS: For the clinical outcomes, 9 subjects had complete healing, 1 subject had functional healing, and no subject had no healing scores out of 10 root canal treatment subjects. Six subjects had complete healing, 8 subjects had functional healing, and 2 subjects had no healing scores out of 16 retreatment subjects. For the radiographic outcomes, 7 subjects had complete healing, 3 subjects had incomplete healing, and no subject had no healing scores out of 10 root canal treatment subjects. Six subjects had complete healing, 8 subjects had incomplete healing, and 2 subjects had no healing scores out of 16 retreatment subjects. The clinical outcome of root canal treatment subjects was significantly different than retreatment subjects (P < .05). Similarly, the radiographic outcome of root canal treatment subjects was also significantly different than retreatment cases (P < .05). CONCLUSIONS: The outcome of endodontic treatment of mandibular second premolars may be influenced by treatment type. PMID- 27986102 TI - Regenerative Endodontic Procedures: A Perspective from Stem Cell Niche Biology. AB - INTRODUCTION: Endodontics uses cell therapy strategies to treat pulpal and periapical diseases. During these therapies, surgeons aim to reconstruct the natural microenvironments that regulate the activity of dental stem cells. METHODS: We searched for more than 400 articles in PubMed using key words from regenerative endodontics and dental stem cell biology. In 268 articles, we reviewed what factors may influence histologic results after preclinical dental treatments that use regenerative endodontic procedures after pulpectomy. RESULTS: Several factors, such as the origin of stem cells, the biomimicry of scaffolds used, and the size of lesions, are considered to influence the histologic appearance of the regenerated pulp-dentin complex after treatments. Information is accumulating on transcription factors that generate the pulp-dentin complex and survival/trophic factors that would benefit niche recovery and histologic results. CONCLUSIONS: In this article, we discuss the noninterchangeability of stem cells, the influence of dentin-entrapped molecule release on pulp regeneration and survival of stem cells, and the need of positional markers to assess treatments histologically. The ex vivo amplification of appropriate dental stem cells, the search for scaffolds storing the molecular diversity entrapped in the dentin, and the use of positional transcription factors as histologic markers are necessary to improve future preclinical experiments. PMID- 27986103 TI - Lipid sensing G protein-coupled receptors in the CNS. PMID- 27986104 TI - The endoscopist, the anesthesiologists, and safety in GI endoscopy. PMID- 27986105 TI - Provocative endoscopy: Let sleeping dogs lie or grab the tiger by the tail? PMID- 27986106 TI - POEMs for gastroparesis. PMID- 27986107 TI - Expanding submucosal endoscopy with applied knowledge. PMID- 27986108 TI - Are randomized control studies needed to evaluate the efficacy of treatment techniques that are clearly minimally invasive and already widely used? PMID- 27986109 TI - EUS-guided pancreatic duct drainage: a rare indication in need of prospective evidence. PMID- 27986110 TI - Preparation for video capsule endoscopy: A clear choice? PMID- 27986111 TI - Is it a prime time for small-bowel colon video capsule endoscopy to cover both sides of the ileocecal valve in Crohn's disease? PMID- 27986113 TI - Ten-year intervals between screening colonoscopies: it's not too long. PMID- 27986112 TI - Water-aided insertion and CO2-assisted withdrawal: Do we still need routine sedation for colonoscopy? PMID- 27986114 TI - Endoscopic detection of large and advanced colonic lesions: Are we missing the forest for the trees? PMID- 27986115 TI - EUS-guided intrahepatic portosystemic shunt: A real alternative to transjugular intrahepatic portalsystemic shunt? PMID- 27986116 TI - Response. PMID- 27986117 TI - Immediate diagnosis of ERCP-related perforation: by air, contrast medium, or eyes. PMID- 27986118 TI - New era in acute cholecystitis treatment: encouraging results for interventional endoscopists. PMID- 27986119 TI - Enhancing bowel preparation instructions: Is the bang worth the buck, or are we stuck with the muck? PMID- 27986120 TI - COPB2 Is Upregulated in Prostate Cancer and Regulates PC-3 Cell Proliferation, Cell Cycle, and Apoptosis. AB - BACKGROUND AND AIMS: Transport of membranes and proteins in eukaryotic cells is mediated by vesicular carriers. Coatomer complex I (COPI)-coated vesicles are involved in the transport between endoplasmic reticulum (ER) and Golgi complex. Several studies indicated that some subunits of COPI were correlated with the cell proliferation of malignant tumors. The present study focused on the function of coatomer protein complex subunit beta 2 (COPB2), one of seven proteins in COPI, in prostate cancer (PCa). METHODS: COPB2 gene expression was first analyzed by immunohistochemistry (IHC) in 15 paired PCa and carcinoma adjacent normal tissue from patients. To investigate the role of COPB2 in PCa, we used lentivirus mediated small interfering RNA (siRNA) to knockdown COPB2 expression in human PCa cell line PC-3 and assessed it by RT-qPCR. Cellomics ArrayScan VTI imaging and colony formation were conducted to evaluate cell proliferation. Cell cycle phase arrest and apoptosis were assayed by flow cytometry. RESULTS: COPB2 gene was upregulated in the PCa tissue. Cell proliferation was significantly inhibited in COPB2-silenced PC-3 cells using both Cellomics ArrayScan VTI imaging and colony formation assays. S-phase cell counts were significantly decreased; G1- and G2 phase cell counts were significantly increased in COPB2-siRNA group than the control group. Apoptosis was significantly increased in COPB2-siRNA cells. CONCLUSIONS: COPB2 significantly promoted PC-3 cell proliferation and colony formation through the cell cycle and apoptosis pathway. Moreover, COPB2 showed a clinical correlation and may serve as a biomarker for the detection for PCa. PMID- 27986121 TI - Intracellular Progesterone Receptor Mediates the Increase in Glioblastoma Growth Induced by Progesterone in the Rat Brain. AB - BACKGROUND AND AIMS: Progesterone (P) is a steroid hormone involved in the development of several types of cancer including astrocytomas, the most common and malignant brain tumors. We undertook this study to investigate the effects of P on the growth and infiltration of a tumor caused by the xenotransplant of U87 cells derived from a human astrocytoma grade IV (glioblastoma) in the cerebral cortex of male rats and the participation of intracellular progesterone receptor (PR) on these effects. METHODS: Eight weeks after the implantation of U87 cells in the cerebral cortex, we administered phosphorothioated antisense oligodeoxynucleotides (ODNs) to silence the expression of PR. This treatment lasted 15 days and was administered at the site of glioblastoma cells implantation using Alzet osmotic pumps. Vehicle (propylene glycol) or P4 (400 MUg/100 g) was subcutaneously injected for 14 days starting 1 day after the beginning of ODN administration. RESULTS: We observed that P significantly increased glioblastoma tumor area and infiltration length as compared with vehicle, whereas PR antisense ODNs blocked these effects. CONCLUSION: P, through the interaction with PR, increases the area and infiltration of a brain tumor formed from the xenotransplant of human glioblastoma-derived U87 cells in the cerebral cortex of the rat. PMID- 27986122 TI - Vitamin B12 Deficiency Across Three Generations Adversely Influences Long-chain Polyunsaturated Fatty Acid Status and Cardiometabolic Markers in Rats. AB - BACKGROUND AND AIMS: Vitamin B12 and omega-3 fatty acid deficiency is prevalent in the vegetarian population and is associated with adverse pregnancy outcomes and cardiometabolic risk. The present study investigates the long-term effects of vitamin B12 deficiency/supplementation in the presence of omega-3 fatty acids on cardiometabolic profile and long-chain polyunsaturated fatty acid levels (LCPUFA) in the F3 generation offspring. METHODS: Three generations of rats were fed the following diets: control; vitamin B12 deficient; vitamin B12 supplemented; vitamin B12 deficient + omega-3 fatty acid supplemented; vitamin B12 + omega-3 fatty acid supplemented. Animals were sacrificed at 3 months of age. RESULTS: Vitamin B12 deficiency lowered (p <0.01 for both) plasma eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), liver DHA (p <0.05), plasma/liver omega-3 fatty acids (p <0.05 for both), increased triglycerides (p <0.05) and systolic BP (p <0.01) and lowered cholesterol levels (p <0.05) as compared to control. Vitamin B12 deficiency in the presence of omega-3 fatty acids improved plasma/liver EPA, DHA and omega-3 fatty acid profile and maintained cholesterol, triglyceride and BP levels. Vitamin B12 supplementation lowered liver DHA (p <0.05) and cholesterol (p <0.01), whereas BP was similar to control. Combined supplementation of vitamin B12 and omega-3 fatty acids improved omega-3 fatty acid profile, lowered cholesterol/triglyceride levels and maintained the BP similar to that of control. CONCLUSION: Vitamin B12 deficiency across three generations adversely affects LCPUFA and cardiometabolic profile in the adult offspring. This study provides clues for a combined supplementation of vitamin B12 and omega-3 fatty acids to reduce the risk for noncommunicable diseases. PMID- 27986123 TI - Effects of Castanospermine on Inflammatory Response in a Rat Model of Experimental Severe Acute Pancreatitis. AB - BACKGROUND AND AIMS: Acute pancreatitis (AP) is an acute inflammatory disorder characterized by autodigestion of pancreatic tissue resulting in local pancreatic injury or systemic inflammatory response. Castanospermine (CAST) is an alkaloid from the Castanospermum australe, known as an anti-inflammatory agent and immunosuppressant in animal experiments. However, whether CAST can attenuate AP remains unclear. This study investigated the effects of CAST on sodium taurocholate (STC)-induced severe acute pancreatitis (SAP) in rats and the pertinent mechanism. METHODS: SAP was induced in rats by a retrograde infusion of 5% STC (1 mL/kg) into the biliopancreatic duct. CAST (10, 50, 100, 200 and 500 mg/kg body weight) was then administered via intraperitoneal injection. Measurement of serum amylase, lipase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen and pancreas pathological grading was used to estimate the severity of pancreatitis. Serum levels of interleukin (IL) -1beta, IL-6 and IL-10 were studied by enzyme-linked immunosorbent assay (ELISA). Nuclear factor (NF) -kappaB, tumor necrosis factor (TNF)-alpha, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression in pancreas was evaluated by immunohistochemistry. RESULTS: Administration of CAST following SAP was found to ameliorate the acute pancreatic tissue injury and exhibit a more appropriately protective effect at the dose of 200 mg/kg body weight. In addition, it decreased the interleukin production in serum and NF-kappaB activation, TNF-alpha, ICAM-1 and VCAM-1 up regulation in pancreatic tissue. CONCLUSIONS: Our study demonstrated that CAST exerts a protective effect on SAP in rats. PMID- 27986124 TI - Long Noncoding RNA Highly Up-regulated in Liver Cancer Predicts Unfavorable Outcome and Regulates Metastasis by MMPs in Triple-negative Breast Cancer. AB - BACKGROUND AND AIMS: Long noncoding RNA (lncRNA) highly up-regulated in liver cancer (HULC) is the first identified lncRNA highly expressed in hepatocellular carcinoma and acts as an oncogenic lncRNA. However, the significance of HULC in triple-negative breast cancer (TNBC) is still unclear. Our purpose is to explore the clinical significance and biological function of HULC in TNBC. METHODS: Expression of HULC in TNBC tissues and cell lines was measured and the association between HULC expression and clinicopathological factors was analyzed. Cell proliferation, migration, and invasion assays were executed by using TNBC cell lines transfected with si-HULC or si-NC. The potential mechanism of HULC was explored by Western blot. RESULTS: HULC expression was increased in TNBC tissues and cell lines and associated with malignant status and poor prognosis of TNBC patients. Furthermore, silencing TNBC expression effectively suppressed TNBC cells metastasis through MMP-2 and MMP-9. CONCLUSION: HULC acts as an oncogene lncRNA in TNBC and as an independent poor prognostic factor in TNBC patients. PMID- 27986125 TI - Evaluation of Circulating Tumor Cells in Predicting Therapeutic Response in Small Cell Lung Cancer Patients. AB - BACKGROUND AND AIMS: Circulating tumor cells (CTCs) have prognostic significance in patients with metastatic cancer, but their utility in predicting the response to tumor therapy is unknown. This study examined the correlation of CTCs with the therapeutic response in small cell lung cancer (SCLC). METHODS: Clinical and pathological data from 96 SCLC patients were evaluated in this study. CellSearch kits were used to detect CTCs in peripheral blood samples. Statistical analysis was performed using Fisher exact test and Mann-Whitney U test. RESULTS: At baseline, 47 (50.0%) SCLC patients had detectable CTC counts. Serum neuron specific enolase (NSE) was found to be associated with CTC thresholds. However, no significant differences were observed for an association of any threshold CTC count with the treatment response, with gender, age (<=60 or >60 years), smoking status, syndrome of inappropriate antidiuretic hormone (SIADH), or Ki67 expression. CONCLUSION: Detection of CTCs in SCLC patients was associated with serum NSE but not with response to cancer therapy. PMID- 27986126 TI - Aberrant CpG Island Shore Region Methylation of CAV1 Is Associated with Tumor Progression and Poor Prognosis in Gastric Cardia Adenocarcinoma. AB - BACKGROUND AND AIMS: Caveolin-1 (CAV1) is a multifunctional scaffolding protein and plays an important role in tumorigenesis. However, the epigenetic changes of CAV1 in gastric cardia adenocarcinoma (GCA) have not been investigated so far. The purpose of this study was to clarify the contribution of critical CpG sites in CAV1 to progression/prognosis of GCA and to further elucidate the effect of critical CpG sites on the ectopic expression of beta-catenin in GCA. METHODS: Methylation-specific polymerase chain reaction (MSP) and bisulfite genomic sequencing (BGS) methods were, respectively, applied to examine the methylation status of CAV1. RT-PCR and immunohistochemistry methods were used to determine the mRNA and protein expression of CAV1 and beta-catenin. RESULTS: Decreased mRNA and protein expression of CAV1 were observed in GCA tumor tissues and were associated with hypermethylation of CpG island shore and transcription start site (TSS) regions in CAV1. Hypermethylation of the other two regions within CpG islands in CAV1 was observed both in tumor and corresponding adjacent tissues but was not related to the transcriptional inhibition of CAV1. The methylation status of CpG island shore region in CAV1 was associated with the ectopic expression of beta-catenin and was independently associated with survival in GCA patients. CONCLUSIONS: Hypermethylation of CpG island shore and TSS regions is cancer specific and is closely associated with reduced expression of CAV1. The CpG island shore methylation of CAV1 may play an important role in progression of GCA and may serve as a prognostic methylation biomarker for GCA patients. PMID- 27986127 TI - Irisin and Myostatin Levels in Patients with Graves' Disease. AB - BACKGROUND AND AIMS: Skeletal muscle system, which is one of the primary targets for thyroid hormones, has an important role in energy metabolism. Some myokines such as irisin and myostatin have considerable effects on energy metabolism in addition to the musculoskeletal system. Our aim was to investigate circulating irisin and myostatin levels in patients with Graves' Disease (GD). METHODS: This study included 41 patients with GD who were in overt hyperthyroid status and 44 healthy subjects. RESULTS: Serum irisin levels were higher in patients with hyperthyroidism than in control group (p = 0.003). However, there was no statistical difference in myostatin levels between groups (p = 0.21). Irisin levels were positively correlated with free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin receptor antibody (TRAb) (p = 0.03, p = 0.02, p = 0.02, respectively) and negatively correlated with thyroid-stimulating hormone (TSH) (p = 0.006) in both groups. In multiple regression analysis, the presence of GD was the only significant factor associated with serum irisin levels (beta = 0.29, p = 0.01). Myostatin levels were positively correlated with age, body mass index (BMI), FT4, HOMA-IR (p = 0.001, p = 0.04, p = 0.003, p = 0.03, respectively) and negatively correlated with TSH (p = 0.01). Multiple regression analysis also revealed that age and FT4 were the significant factors associated with circulating myostatin levels (beta = 0.27, p = 0.02; beta = 0.22, p = 0.04, respectively). CONCLUSION: Our results suggest that increased irisin levels might contribute to altered energy metabolism in hyperthyroidism. Further studies to determine whether myostatin is affected due to hyperthyroidism are needed. PMID- 27986128 TI - High Thyroid-stimulating Hormone Levels Increase Proinflammatory and Cardiovascular Markers in Patients with Extreme Obesity. AB - BACKGROUND AND AIMS: Obesity is an important health problem worldwide and many studies have suggested a relationship between obesity and thyroid function, with controversial results. Interestingly, high TSH levels have been involved with the presence of inflammatory state and risk for developing cardiovascular diseases in hypothyroid and obese patients. The aim in this work was to determine the prevalence of hypothyroidism in patients with extreme obesity and to determine whether their TSH levels were related to increased serum levels of inflammatory and cardiovascular markers. METHODS: A cross-sectional study in 101 patients with extreme obesity (BMI >=40) was performed. Anthropometric (weight, height and waist circumference) and biochemical (fasting glucose, glycosylated hemoglobin, triglycerides, total cholesterol, LDL-C, HDL-C and insulin) parameters were measured. TSH and FT4 levels as well as clinical exploration for diagnosis of hypothyroidism were carried out. Serum concentration of IL-10, IL-6, adiponectin, resistin, leptin, ICAM-1, VCAM-1 and E-selectin were determined. RESULTS: A high prevalence for diabetes (37.6%), prediabetes (50.5%), dyslipidemia (74.3%), hypertension (61.4%) and hypothyroidism (48.5%) was observed in patients with extreme obesity. The presence of hypothyroidism increased serum concentration of proinflammatory cytokines IL-6 and leptin and decreased the antiinflammatory cytokine adiponectin. In addition, serum TSH levels showed a correlation for waist circumference, weight, BMI, A1c, insulin, IL-6, leptin, ICAM-1 and E selectin. CONCLUSION: There is a high prevalence for hypothyroidism in patients with extreme obesity. High levels of TSH contribute to elevate proinflammatory and cardiovascular risk markers, increasing the risk for development of cardiovascular diseases. PMID- 27986129 TI - Ischemic Postconditioning Before Percutaneous Coronary Intervention for Acute ST Segment Elevation Myocardial Infarction Reduces Contrast-induced Nephropathy and Improves Long-term Prognosis. AB - BACKGROUND AND AIMS: Contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) is one of the major adverse outcomes affecting the prognosis of patients with acute ST-segment elevation myocardial infarction (STEMI). Ischemic postconditioning prior to PCI (pre-PCI) in patients with STEMI is hypothesized to be protective against CIN after PCI. METHODS: A total of 251 patients with STEMI were randomized into two groups: ischemic postconditioning group (n = 123, age, 61.1 +/- 12.5 years) who underwent ischemic postconditioning prior to PCI; control group (n = 128; age, 64.1 +/- 12.1 years) who underwent only PCI. Ischemic postconditioning was administered by three cycles of deflation and inflation of the balloon (1-min ischemia and 1-min reperfusion) starting 1 min after infarct-related artery (IRA) opening. Diagnostic criterion for CIN was: increase in serum creatinine level by >=0.5 mg/dL or by >=25% increase from preoperative level within 48 h of surgery. All patients were followed for 1 year for incidence of major cardiovascular events (MACE). RESULTS: The incidence of postoperative CIN in the ischemic postconditioning group was 5.69% as compared to 14.06% in the control group (p <0.05). At one year, the MACE incidence in the ischemic postconditioning group was 7.32% as compared to 15.63% in the control group (p <0.05). CONCLUSIONS: Pre-PCI ischemic postconditioning in STEMI patients significantly reduces the post-PCI incidence of CIN and improves long-term prognosis. PMID- 27986130 TI - Influenza and Immune Profile. PMID- 27986131 TI - Response: Differential Immune Profiles in Two Pandemic Influenza A(H1N1)pdm09 Virus Waves at Pandemic Epicenter. PMID- 27986132 TI - Prevention and management of glucocorticoid-induced side effects: A comprehensive review: A review of glucocorticoid pharmacology and bone health. AB - Systemic glucocorticoids are an essential therapy for a range of conditions, but their multiple side effects can produce significant morbidity for patients. The objective of this review is to discuss these side effects while addressing 3 questions: 1) What dose and duration of glucocorticoid therapy should prompt concern for individual side effects?; 2) How should clinicians counsel patients about these complications?; and 3) How can these problems be prevented or managed? To accomplish these objectives, we have created a series of tables and algorithms based on a review of relevant data to guide counseling, prophylaxis, and management of 11 glucocorticoid side effects. The first article in this 4 part continuing medical education series begins with a review of glucocorticoid pharmacology followed by a discussion of bone health (ie, osteoporosis and osteonecrosis). PMID- 27986133 TI - Prevention and management of glucocorticoid-induced side effects: A comprehensive review: Gastrointestinal and endocrinologic side effects. AB - Part 2 of this 4-part continuing medical education series continues with a discussion of the prevention and management of gastrointestinal side effects associated with corticosteroid use, including peptic ulcer disease, gastrointestinal bleeding, and pancreatitis, followed by a review of corticosteroid-related endocrinologic side effects, such as diabetes, adrenal suppression, and Cushing syndrome. PMID- 27986134 TI - Minimal improvements in the global burden of skin disease from 1990 to 2013. PMID- 27986135 TI - A double-blind, placebo-controlled, phase-II clinical trial to evaluate oral simvastatin as a treatment for vitiligo. PMID- 27986136 TI - Increased blood levels of NKG2D+CD4+ T cells in patients with alopecia areata. PMID- 27986137 TI - Classic and HIV-related Kaposi sarcoma treated with 0.1% topical timolol gel. PMID- 27986138 TI - Menses and pregnancy affect symptoms in hidradenitis suppurativa: A cross sectional study. PMID- 27986139 TI - Interleukin 6 and high-sensitivity C-reactive protein are potential predictive markers of response to infliximab in hidradenitis suppurativa. PMID- 27986140 TI - Intradermal injection of autologous platelet-rich plasma for the treatment of vulvar lichen sclerosus. PMID- 27986141 TI - Localized hypohidrosis is an unrecognized sequela of herpes zoster. PMID- 27986142 TI - The natural history of actinic keratoses in organ transplant recipients. PMID- 27986143 TI - A cross-sectional study of indoor tanning use among patients seeking skin cancer screening. PMID- 27986144 TI - A population-based cohort study of the influence of socioeconomic factors and race on survival in Merkel cell carcinoma. PMID- 27986145 TI - Valuable or vain: An ethical analysis of free skin cancer screening. PMID- 27986146 TI - Commentary: American Academy of Dermatology free skin cancer screening: 30 years of value. PMID- 27986147 TI - Total body skin exams (TBSEs): Saving lives or wasting time? PMID- 27986148 TI - Beyond JAAD January 2017: Articles of interest from the nondermatologic literature. PMID- 27986150 TI - Use of a cotton-tipped applicator for superior clinical diagnosis and biopsy of suspected basal cell carcinoma of the nasal ala. PMID- 27986152 TI - Percutaneous ligature of the superficial temporal artery: A simple technique to reduce bleeding. PMID- 27986151 TI - Leishmania tropica: Combined debulking and imiquimod for the treatment of nonresponsive cutaneous leishmaniasis. PMID- 27986153 TI - A painless, minimally invasive technique for debulking onychomycotic nails. PMID- 27986154 TI - Star closure of circular defects. PMID- 27986155 TI - Cell adhesion phenotyping by quantitative polymerase chain reaction in melanoma: Clarifying misconceptions. PMID- 27986156 TI - Wisely choosing thin melanomas for sentinel lymph node biopsy. PMID- 27986157 TI - Revisiting vertical growth phase and regression for thin melanoma. PMID- 27986158 TI - Melanoma during pregnancy: Level of evidence and principles of precaution. PMID- 27986160 TI - On the utility of soak and smear. PMID- 27986161 TI - Reply to: "On the utility of soak and smear". PMID- 27986162 TI - A proactive approach to ending the use of university debit cards for indoor tanning. PMID- 27986163 TI - Is treatment of acne as simple as encouraging primary care physicians to prescribe more retinoids? PMID- 27986164 TI - Reply to: "Is treatment of acne as simple as encouraging primary care physicians to prescribe more retinoids?" PMID- 27986168 TI - Letter from the Editor. PMID- 27986169 TI - Hepatic Steatosis: Etiology, Patterns, and Quantification. AB - Hepatic steatosis can occur because of nonalcoholic fatty liver disease (NAFLD), alcoholism, chemotherapy, and metabolic, toxic, and infectious causes. Pediatric hepatic steatosis is also becoming more frequent and can have distinctive features. The most common pattern is diffuse form; however, it can present in heterogenous, focal, multinodular, perilesional, perivascular, subcapsular, and lobar forms. Focal steatosis and fat sparing can occur because of the presence of veins of Sappey, pancreaticoduodenal vein, and aberrant right and left gastric veins, which drain into the liver as third inflow. Hypersteatosis and multinodular forms can mimic metastasis in patients with cancer. Perilesional fat can be seen in insulinoma. Recent introduction of proton-density fat fraction enabled easy and reproducible quantification of hepatic fat. Follow up of patients with NAFLD can be performed for the assessment of treatment response using proton-density fat fraction as biomarker. Multiecho gradient-echo techniques also simultaneously calculate T2* maps, which is important to rule out coexisting hepatic iron overload. NAFLD can progress to steatohepatitis (nonalcoholic steatohepatitis), which can result in cirrhosis. Magnetic resonance (MR) elastography and functional evaluation with Gd-EOB-DTPA are becoming important for monitoring this process. Hepatocellular carcinoma can develop in patients with NAFLD, which is usually a large tumor with necrotic center. In the future, fatty acid maps obtained by MR imaging may allow more detailed analysis of steatosis. MR imaging is superior to ultrasonography and computed tomography for comprehensive evaluation of steatosis. PMID- 27986170 TI - Imaging of Hepatic Focal Nodular Hyperplasia: Pictorial Review and Diagnostic Strategy. AB - Focal nodular hyperplasia (FNH) is the second most common benign solid liver lesion after hemangioma, occurring more frequently in young women. The prime differential diagnoses include hepatocellular adenoma, hepatocellular carcinoma, and hypervascular metastasis. As the management of FNH is typically conservative, imaging plays a key role in diagnostic pathway, and misdiagnosis may have a major clinical effect. In this article, we describe the ultrasound, computed tomography, and magnetic resonance imaging features of FNH, underlining the importance of typical radiological features that allow a specific noninvasive diagnosis. We present a large spectrum of a typical imaging findings that FNH may present and discuss the up-to-date diagnostic strategy. PMID- 27986171 TI - Hepatic Sinusoidal Dilatation: A Review of Causes With Imaging-Pathologic Correlation. AB - Hepatic sinusoids are vascular conduits connecting the portal triad with the central vein. Multiple conditions can lead to sinusoidal dilatation and congestion with resultant stasis of blood within the lumen. The altered hemodynamics associated with hepatic sinusoidal dilatation generally result in heterogeneous enhancement of the hepatic parenchyma on contrast-enhanced computed tomography and magnetic resonance imaging, a pattern often described as "mosaic" enhancement. In this article, we review the causes of hepatic sinusoidal dilatation and the imaging manifestations on contrast-enhanced computed tomography and magnetic resonance. PMID- 27986172 TI - Magnetic Resonance Imaging of Liver Metastasis. AB - Liver magnetic resonance imaging (MRI) is becoming the gold standard in liver metastasis detection and treatment response assessment. The most sensitive magnetic resonance sequences are diffusion-weighted images and hepatobiliary phase images after Gd-EOB-DTPA. Peripheral ring enhancement, diffusion restriction, and hypointensity on hepatobiliary phase images are hallmarks of liver metastases. In patients with normal ultrasonography, computed tomography (CT), and positron emission tomography (PET)-CT findings and high clinical suspicion of metastasis, MRI should be performed for diagnosis of unseen metastasis. In melanoma, colon cancer, and neuroendocrine tumor metastases, MRI allows confident diagnosis of treatment-related changes in liver and enables differential diagnosis from primary liver tumors. Focal nodular hyperplasia-like nodules in patients who received platinum-based chemotherapy, hypersteatosis, and focal fat can mimic metastasis. In cancer patients with fatty liver, MRI should be preferred to CT. Although the first-line imaging for metastases is CT, MRI can be used as a problem-solving method. MRI may be used as the first-line method in patients who would undergo curative surgery or metastatectomy. Current limitation of MRI is low sensitivity for metastasis smaller than 3mm. MRI fingerprinting, glucoCEST MRI, and PET-MRI may allow simpler and more sensitive diagnosis of liver metastasis. PMID- 27986173 TI - Liver Function Assessment by Magnetic Resonance Imaging. AB - Liver function assessment by hepatocyte-specific contrast-enhanced magnetic resonance imaging is becoming a new biomarker. Liver function can be assessed by T1 mapping (reduction rate) and signal intensity measurement (relative enhancement ratio) before and after GD-EOB-DTPA (gadoxetic acid) administration, as alternative to Tc-99m galactosyl serum albumin scintigraphy, 99m Tc-labeled mebrofenin scintigraphy, and indocyanine green clearance test. Magnetic resonance imaging assessment of liver function can enable diagnosis of cirrhosis, nonalcoholic fatty liver disease associated fibrosis and steatohepatitis, primary sclerosing cholangitis, toxic hepatitis, and chemotherapy and radiotherapy related changes, which may be only visible on hepatobiliary phase images. Simple visual assessment of signal intensity at hepatobiliary phase images is important for the diagnosis of different patterns of liver dysfunction including diffuse, lobar, segmental, and subsegmental forms. Furthermore, preoperative assessment of liver function is feasible before oncologic hepatic surgery, which may be important to prevent posthepatectomy liver failure and to estimate future remnant volume. Functional magnetic resonance cholangiography obtained by T1-weighted images at hepatobiliary phase can allow diagnosis of acalculous cholecystitis, biliary leakage, bile reflux to the stomach, sphincter of oddi dysfunction, and lesions with communication to biliary tree. Functional information can be easily obtained when Gd-EOB-DTPA is used for liver magnetic resonance imaging. PMID- 27986174 TI - Avoiding Pitfalls in the Interpretation of Gadoxetic Acid-Enhanced Magnetic Resonance Imaging. AB - Gadoxetic acid is extensively used in the following 3 main clinical situations: characterization of small nodules in patients with cirrhosis, preoperative staging of liver metastases, and characterization of incidentally discovered focal liver lesions. Owing to the rapid entry of gadoxetic acid into hepatocytes, the traditional features of liver tumors are modified on magnetic resonance (MR) imaging, especially during delayed phase sequences. Thus, although the added value of gadoxetic acid for the detection and characterization of focal liver lesions is now clear, its unique pharmacokinetics as well as the presence of mimicking and atypical lesions may lead to misdiagnoses. The goal of this article is to illustrate common and uncommon pitfalls associated with the use of gadoxetic acid-enhanced MR imaging. Moreover, additional MR imaging features that can help establish a correct diagnosis are described. PMID- 27986175 TI - Contrast-Enhanced Ultrasound in Focal Liver Lesions: Where Do We Stand? AB - Contrast-enhanced ultrasound (CEUS) represents a significant breakthrough in sonography, and it is being increasingly used for the evaluation of focal liver lesions (FLLs). Currently, CEUS is included as a part of the suggested diagnostic workup of FLLs, resulting in a better patient management and delivering cost effective therapy. After a brief technical note, contrast-enhancement patterns of different types of benign and malignant FLLs, along with hepatic pseudolesions, are described and discussed based on our experience and literature data. At the same time, the most recent concepts and the use of CEUS in different clinical settings are presented. PMID- 27986177 TI - Fibrome uterin pedicule : maitre du deguisement. PMID- 27986176 TI - A Pedunculated Fibroid: The Master of Disguise. PMID- 27986178 TI - Thank You, and Good Night. PMID- 27986179 TI - Merci, bonsoir. PMID- 27986180 TI - A Systematic Review of the Association Between Psychiatric Disturbances and Endometriosis. PMID- 27986181 TI - Atonic Postpartum Hemorrhage: Blood Loss, Risk Factors, and Third Stage Management. AB - OBJECTIVE: Atonic postpartum hemorrhage rates have increased in many industrialized countries in recent years. We examined the blood loss, risk factors, and management of the third stage of labour associated with atonic postpartum hemorrhage. METHODS: We carried out a case-control study of patients in eight tertiary care hospitals in Canada between January 2011 and December 2013. Cases were defined as women with a diagnosis of atonic postpartum hemorrhage, and controls (without postpartum hemorrhage) were matched with cases by hospital and date of delivery. Estimated blood loss, risk factors, and management of the third stage labour were compared between cases and controls. Conditional logistic regression was used to adjust for confounding. RESULTS: The study included 383 cases and 383 controls. Cases had significantly higher mean estimated blood loss than controls. However, 16.7% of cases who delivered vaginally and 34.1% of cases who delivered by Caesarean section (CS) had a blood loss of < 500 mL and < 1000 mL, respectively; 8.2% of controls who delivered vaginally and 6.7% of controls who delivered by CS had blood loss consistent with a diagnosis of postpartum hemorrhage. Factors associated with atonic postpartum hemorrhage included known protective factors (e.g., delivery by CS) and risk factors (e.g., nulliparity, vaginal birth after CS). Uterotonic use was more common in cases than in controls (97.6% vs. 92.9%, P < 0.001). Delayed cord clamping was only used among those who delivered vaginally (7.7% cases vs. 14.6% controls, P = 0.06). CONCLUSION: There is substantial misclassification in the diagnosis of atonic postpartum hemorrhage, and this could potentially explain the observed temporal increase in postpartum hemorrhage rates. PMID- 27986182 TI - Episiotomy Technique and Management of Anal Sphincter Tears-A Survey of Clinical Practice and Education. AB - OBJECTIVE: To ascertain current techniques of episiotomy used by obstetrics and gynaecology faculty members and residents in an academic department and to determine the current management strategies for third and fourth degree tears. METHOD: A 14-question anonymous online survey was circulated to all faculty members and residents in the University of Toronto Department of Obstetrics and Gynaecology between October 2015 and March 2016. Results were analyzed descriptively or with Fisher exact test. RESULTS: The survey response rate was 65.5% (169/258) among 108 faculty members and 61 residents. A history of clinical teaching regarding episiotomy was reported by 87% of faculty members and 75.4% of residents. Right mediolateral episiotomy was the most frequently used method among faculty members (88.0%) and residents (95.1%). The majority of respondents indicated that they would use an end-to-end technique for repair in the labour and delivery room under regional anaesthesia. Prophylactic antibiotics were never prescribed by 18.5% of faculty members and 13.1% of residents for third or fourth degree tears. In analysis by type of training, respondents who had taken a workshop or formal class were significantly more likely to prescribe physiotherapy postpartum (P = 0.001). CONCLUSION: The most common reported method of learning episiotomy was clinical experience. A substantial number of responses differed from current SOGC guidelines for episiotomy technique and repair and management of anal sphincter injury. We propose developing a workshop and/or simulation-based method of instruction for episiotomy technique and repair. PMID- 27986183 TI - Effect of Maternal Retroplacental Leiomyomas on Fetal Growth. AB - OBJECTIVE: To evaluate the association between retroplacental leiomyoma identified on second trimester ultrasound and fetal growth. METHODS: We performed a retrospective study comparing the presence or absence of one or more retroplacental leiomyomas on birth weight in a cohort of women with singleton pregnancies undergoing second trimester fetal anatomic ultrasound at our institution between 2007 and 2012. The incidence of small for gestational age (SGA) infants was recorded. Secondary analysis evaluated the effect of number and size of retroplacental leiomyomas. RESULTS: Birth weight in women with at least one retroplacental leiomyoma was 177 grams less than in women without leiomyomas (95% CI -295 to -95, P = 0.003). There was a non-significant trend towards a higher incidence of SGA in infants born to women with retroplacental leiomyoma compared with women without leiomyoma (OR 2.84; 95% CI 0.97 to 6.84, P = 0.057). Women with a retroplacental leiomyoma > 4 cm in mean diameter were more likely to deliver an SGA infant than women without leiomyomas (OR 2.84, 95% CI 1.01 to 8.01; P = 0.048). Multiple retroplacental leiomyomas did not have a greater effect on pregnancy outcomes than single leiomyomas. CONCLUSION: Infants born to women with one or more retroplacental leiomyomas had a lower mean birth weight than infants born to women without leiomyomas. In addition, retroplacental leiomyomas > 4 cm in mean diameter were associated with an increased risk of delivering an SGA infant. PMID- 27986184 TI - The Canadian Gynaecologic Oncology Perioperative Management Survey: Baseline Practice Prior to Implementation of Enhanced Recovery After Surgery (ERAS) Society Guidelines. AB - OBJECTIVE: To survey the current practice of Society of Gynecologic Oncology of Canada (GOC) members about preoperative, intraoperative, and postoperative phases of care. The survey was carried out prior to publication of the Enhanced Recovery After Surgery (ERAS) Society gynaecologic/oncology guidelines. METHODS: A survey was developed by the GOC and distributed to all surgical members between September and December 2015. RESULTS: The survey was completed by 77 of 92 practising gynaecologic oncologists (84%), representing 19 centres in 16 cities across Canada. Only 14.3% of respondents counselled their patients to stop smoking and drinking four weeks before surgery, while 41.6% routinely counselled patients to stop taking oral contraceptive pills. Approximately half of respondents (44.7%) prescribed preoperative mechanical bowel preparation. Over two thirds (67.5%) asked their patients not to eat solid foods after midnight on the day of surgery, and 19.5% recommended carbohydrate loading. Venous thromboembolism prophylaxis was given prior to laparotomy by 85.7% of participants overall, and by 67.6% prior to laparoscopy. The majority of respondents did not routinely use nasogastric tubes or intra-abdominal drains. The preferred modality for postoperative pain control after laparotomy was patient-controlled analgesia with narcotics (66.2%); only 29.9% chose epidural analgesia. Over half of respondents (56.6%) prescribed a progressive diet after surgery, while 42.1% recommended starting on an immediate standard diet postoperatively. CONCLUSION: The responses to this survey show wide variations in practice in the perioperative phases of surgical care. Implementation of the ERAS Society gynaecologic/oncology guidelines should help integrate evidence-based knowledge into practice, align perioperative care, and minimize practice variations, resulting in improved outcomes for patients. PMID- 27986185 TI - Postoperative Infection in the Setting of Massive Intraoperative Blood Loss. AB - OBJECTIVE: To determine the local rates of massive intraoperative blood loss and subsequent infectious morbidity for patients undergoing gynaecologic laparotomy. METHODS: We performed a retrospective chart review of all patients undergoing gynaecologic laparotomy between January 1, 2013 and December 31, 2013 to identify cases of massive intraoperative blood loss (defined as >=1 L estimated intraoperative blood loss, a postoperative reduction in hemoglobin concentration of >=40 g/L, or a perioperative blood transfusion). For cases meeting these criteria, we abstracted further data to assess the rate of postoperative infectious morbidity (defined as a positive wound swab culture, positive urine culture, or satisfying the 1991 criteria for systemic inflammatory response syndrome). RESULTS: The rate of massive intraoperative blood loss was 13.5% (n = 69). The average age in this cohort was 50.4 years (range 18-84 years) and the average BMI was 27.9 kg/m2. Perioperative transfusion was required in 31.9% (n = 22). Notably, 26.1% of patients (n = 18) met one of our primary endpoints for postoperative infectious morbidity. A further 10.1% (n = 7) had morbidities including hyponatremia, wound dehiscence, intra-abdominal abscess, positive blood cultures, acute respiratory distress syndrome, myocardial infarction, intensive care unit admission, or death. CONCLUSION: Our rate of massive intraoperative blood loss during gynaecologic laparotomy was found to be 13.5%, and our rate of postoperative infectious morbidity subsequent to massive intraoperative blood loss was 26.1%. PMID- 27986186 TI - Saline Hysteroscopy for Removal of Retained Intrauterine Contraceptive Devices in Early Pregnancy. AB - OBJECTIVE: Pregnancies complicated by a retained intrauterine device (IUD) are at increased risk for adverse outcomes such as miscarriage and preterm labour. There is limited evidence to guide the management of retained IUDs in pregnancy when the strings are not visible at the external cervical os. We describe a method for IUD retrieval in such cases. METHODS: Twenty-six patients underwent saline hysteroscopy with or without concurrent ultrasound guidance for retrieval of a retained IUD in early pregnancy between 2002 and 2015. We retrospectively evaluated procedural and pregnancy-related outcomes in this case series. RESULTS: The average gestational age at the time of the procedure was 11+0 weeks. Successful IUD retrieval occurred in 22 of 26 cases (84.6%). There were 23 live births, including 20 full term and three preterm deliveries. The average gestational age at delivery was 38+4 weeks. There was one miscarriage and one elective termination of pregnancy following the procedure. There were no complications directly related to the procedure. CONCLUSION: Saline hysteroscopy is a safe and effective method for retrieval of a retained IUD in early pregnancy. It appears that concurrent ultrasound guidance can facilitate IUD localization, but more cases are needed to confirm this. Pregnancy outcomes after IUD retrieval were favourable, with a low rate of miscarriage and preterm labour. PMID- 27986187 TI - Bias Against the Null Hypothesis in Retrospective Registries of Gestational Drug Exposure. AB - OBJECTIVE: The findings in retrospective pregnancy registries related to prenatal drug exposure (collected after pregnancy outcome is known) are commonly reported in regulatory documents and in the medical literature. However, there is little information about the accuracy of the estimates of risk from such registries. We therefore sought to compare the rates of major congenital malformations reported in retrospective and prospective registries for the same drug to quantify the potential bias of retrospective reports. METHODS: We searched for all fetal safety reports related to medications for which information from both prospective and retrospective registries was available. These were published either in the peer-reviewed literature or as pharmaceutical company documents between 1984 and 2011. RESULTS: For all drugs registries studied, estimates of major congenital malformations from retrospective registries tended to be higher than the rates in prospective registries; median estimates of risk were higher by a factor of 4.18 +/- 1.23 (range 2.13-5.97). CONCLUSIONS: The present study confirms a major and consistent bias against the null hypothesis in studies of teratogenic risk using retrospective registries, and this must be considered when interpreting such data. Spontaneous reporting of outcomes after exposure to a drug is highly selective towards adverse events, which families with normal pregnancy outcomes are less likely to report. PMID- 27986188 TI - Balancing the Needs of Patients and Learners in Surgery. AB - In this commentary, we explore the need for academic physicians to balance the needs of their patients and of learners during surgery. We approach this discussion from the perspective of the duty of care to the patient and reflect on methods to respect this duty of care but still maximize the educational experience of the learner without jeopardizing the patient's health. We also identify pedagogical methods to facilitate this balance, both in routine situations and during unforeseen events. PMID- 27986189 TI - The Management of Nausea and Vomiting of Pregnancy. AB - OBJECTIVES: To review the evidence-based management of nausea and vomiting of pregnancy and hyperemesis gravidarum. EVIDENCE: MEDLINE and Cochrane database searches were performed using the medical subject headings of treatment, nausea, vomiting, pregnancy, and hyperemesis gravidarum. The quality of evidence reported in these guidelines has been described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on Preventative Health Care. BENEFITS: Nausea and vomiting of pregnancy has a profound effect on women's health and quality of life during pregnancy as well as a financial impact on the health care system, and its early recognition and management is recommended. COST: Costs, including hospitalizations, additional office visits, and time lost from work, may be reduced if nausea and vomiting in pregnancy is treated early. RECOMMENDATIONS: PMID- 27986190 TI - Prise en charge des nausees et vomissements de la grossesse. PMID- 27986191 TI - Addendum to the Canadian Consensus on Contraception - Emergency Contraception: 1) Excluding pre-existing pregnancy when inserting copper IUD and 2) Initiation of hormonal contraception after emergency contraception. PMID- 27986192 TI - Addenda au Consensus canadien sur la contraception - Contraception d'urgence : 1) Exclure la presence d'une grossesse avant l'insertion d'un DIU de cuivre et 2) Amorcer une contraception hormonale apres la prise d'une contraception d'urgence. PMID- 27986193 TI - Cost-Effectiveness of a Care Program for HIV/AIDS Patients Affiliated with a Health Insurer in Colombia, Comparing Three Health Care Providers Nationwide. AB - BACKGROUND: In Colombia, HIV and AIDS constitute one of the major diseases of high cost to the health system, making necessary health risk management of patients with this disease through comprehensive health care programs with their respective evaluation of results. OBJECTIVE: To evaluate the relative cost effectiveness of a care program for patients with HIV/AIDS affiliated to a health insurer in Colombia, comparing their results in three Health care provider (HCP). METHODS: The study population corresponded to a cohort of patients older than 18 years with HIV/AIDS and affiliated to a health insurer in Colombia during 2011 and 2012. A cost-effectiveness and cost-utility analysis of a health care program for this population was performed on the basis of a Markov model, in which quality-adjusted life-years (QALYs) and life-years gained were assessed. This analysis was conducted from the insurer perspective. The time horizon was life expectancy. A discount rate of 3% was applied. RESULTS: Drugs accounted for 80.54% of care costs. The average annual cost of patients in health state 5 was 3 times higher than that of patients in state 1. HCP A compared with HCP B generated an additional 1.53 QALYs, with a rate of incremental cost-effectiveness of $2400 per QALY gained. HCP C showed a dominated behavior. The variables that most influence the uncertainty were the cost of HCP A in health state 5 (55.52%) and the cost of HCP B in state 3 (27.51%). CONCLUSIONS: HCP A is a very cost effective option considering a threshold of 1 time the per-capita gross domestic product. PMID- 27986194 TI - Cost-Effectiveness Study of HPV Vaccination as a Primary Prevention Strategy for Anal Cancer in HIV-Positive Men in Chile. AB - BACKGROUND: Most anal cancers are caused by the human papilloma virus (HPV) infection. The incidence is increasing, especially in high-risk individuals such as HIV-positive men. Evidence shows that the new quadrivalent HPV vaccine reduces the rates of anal intraepithelial neoplasia among men who have sex with men. OBJECTIVE: To determine whether vaccinating against HPV-related anal cancer is cost-effective in HIV-positive men in Chile. METHODS: A cost-effectiveness analysis was conducted by constructing a cohort multistate life-table-based Markov model in MS Excel in which the prevention of HPV infection was expected to influence the incidence of anal cancer in HIV-positive men. The comparator was the current practice of no systematic HPV prevention. Estimates of the efficacy of the vaccine were obtained from a substudy of a larger randomized controlled trial, incidence rates from the Chilean Population Cancer Registries, mortality rates from the National Institute of Statistics, and disease costs from a cost effectiveness report. A public health care sector perspective was applied. The outcome was measured in averted disability-adjusted life-years. The incremental cost-effectiveness ratio was calculated considering a lifetime horizon for costs and health outcomes. RESULTS: The estimated incremental cost-effectiveness ratio was US $138,269/ disability-adjusted life-year (95% confidence interval $95,936 $221,862). Assuming a threshold of 3 times the gross domestic product per capita, the intervention was not cost-effective. The outcome was sensitive to the vaccine price and vaccine efficacy. CONCLUSIONS: HPV vaccination in HIV-positive men from a Chilean public health care sector perspective is not cost-effective. PMID- 27986195 TI - Interchangeability between Pneumococcal Conjugate Vaccines: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To assess the efficacy, cost-effectiveness, immunogenicity, and safety related to the interchangeability between pneumococcal conjugate vaccines (PCVs) and vaccination schedules in pediatric population. METHODS: Systematic searches were conducted in December 2010 and April 2015 for economic evaluations in MEDLINE, EMBASE, LILACS, and Cochrane Central Register of Controlled Trials. Web sites and databases from medical societies, experts, and associations related to the topic, proceedings or congressional annals, and doctoral theses were also searched. No language or temporal restriction was applied. We included randomized controlled trials, economic evaluations, and systematic reviews evaluating antibody response, cost-effectiveness, and effectiveness of PCVs' interchangeability. A Strengthening the Reporting of Observational Studies in Epidemiology-based checklist was used to assess the risk of bias in observational studies and a Cochrane approach for experimental/quasi-experimental studies. Pairs of reviewers independently selected (through the Web-based Early Reviewer Organizer Software), assessed the quality, and extracted the data of the studies. Discrepancies were resolved by consensus. We planned to perform meta-analysis whenever appropriate. RESULTS: Forty-six of 202 studies were included. There was no direct information available on the interchangeability between PCVs. The immunogenicity and safety between the 10-valent PCV (PCV10) and the 7-valent PCV were similar when both vaccines were coadministered with other routine pediatric vaccines. PCV10 and 13-valent PCV (PCV13) were consistently more cost-effective than 7-valent PCV. CONCLUSIONS: There was no direct comparative information available on the interchangeability among PCVs, but they have pretty similar immunogenicity and safety. PCV10 versus PCV13 cost-effectiveness varied according to price, indirect effects, and indirect costs. PCV10 gains more quality-adjusted life-years because of the prevention of more frequent yet less severe events such as otitis media, and PCV13 prevents less frequent but more costly events such as invasive diseases. PMID- 27986196 TI - Cardiovascular Disease and Health Care System Impact on Functionality and Productivity in Argentina: A Secondary Analysis. AB - OBJECTIVES: To examine the impact of cardiovascular disease (CVD) events on patient functionality and productivity on the basis of patient use of public or social/private institution health care. METHODS: A secondary analysis was conducted of data drawn from records of Argentinian patients, 3 to 15 months posthospitalization after a CVD event, who had originally participated in a multicountry, cross-sectional study assessing the microeconomic impact of a CVD event. Respondents were stratified according to their use of health care institution (public or social/private). Among these groups, pre- and post-CVD event changes in functionality and productivity were compared. RESULTS: Participants' (N = 431) mean age was 56.5 years, and 73.5% were men. Public sector patients reported significantly higher rates of decline in ability to perform moderate activities (P < 0.05), a greater decrease in time spent at work (P < 0.01), a greater limit in the type of work-related activities (P < 0.01), and a higher rate of emotional problems (P < 0.01). Having health insurance (private or social) (odds ratio [OR] = 0.55; 95% confidence interval [CI] 0.35 0.85; P < 0.01) and a higher income (OR = 0.99; 95% CI 0.99-0.99; P < 0.01) were inversely and significantly associated with loss of productivity. Cerebrovascular disease (OR = 2.55; 95% CI 1.42-4.60; P < 0.01) was also significantly associated with productivity loss. CONCLUSIONS: In Argentina, patients receiving care in the public sector experienced a greater impact on functionality and productivity after their hospitalization for a CVD event. Lack of insurance, low income, and cerebrovascular disease event were the major determinants of productivity loss. Further investigation is needed to better understand contributors to these differences. PMID- 27986197 TI - Cost-Effectiveness of the Quantification of Enzymatic Activity in Leukocytes in Comparison to Its Nonrealization for a Rare Disease in Latin America: The Case of Mucopolysaccharidosis Type II in Colombia. AB - BACKGROUND: Mucopolysaccharidosis (MPS) type II is produced by a deficiency of iduronate-2-sulfatase (I2S). The quantification of the enzyme activity in leukocytes is used as diagnostic confirmation of MPS. OBJECTIVE: To determinate the cost-effectiveness of the measurement of I2S enzyme activity in leukocytes compared with not carrying out the enzyme activity measurement for diagnostic confirmation of MPS II from the perspective of the Colombian health system. METHODS: A cost-effectiveness analysis was conducted on the basis of a decision tree model. The measure of effectiveness was the correct diagnosis of cases of MPS II. The costs of I2S enzymatic quantification in leukocytes, consultation with a geneticist and with other specialists, and costs of diagnostic procedures were included. The time horizon was less than 1 year. A probabilistic sensitivity analysis was performed using Monte-Carlo simulation with 10,000 iterations. RESULTS: The incremental cost was -US $43,145 with an incremental effectiveness of 42 cases. The probabilistic sensitivity analysis confirms the results of basal data, in which the quantification of I2S enzyme activity was less costly and more effective than the alternative. CONCLUSIONS: The quantification of I2S enzymatic activity is a dominant technology for the diagnostic confirmation of MPS II, compared with not making the quantification, from the perspective of the Colombian health system. PMID- 27986198 TI - [Cost-Effectiveness of using Picture Archiving and Communication System (PACS) in digital mammography]. PMID- 27986199 TI - Direct Medical Costs of Chronic Urticaria in a Private Health Organization of Buenos Aires, Argentina. AB - BACKGROUND: Scarce studies address the issue of resource consumption and direct health care costs of patients diagnosed with adult-onset chronic urticaria (CU). OBJECTIVES: To estimate medical resource consumption and direct health care costs of affected patients in a private health maintenance organization in Buenos Aires, Argentina. METHODS: Patients diagnosed with adult-onset CU (International Classification of Diseases, Ninth Revision, Clinical Modification code 708.1, 708.8, or 708.9) and who were members of the Italian Hospital Medical Care Program were included in the study. All data on hospitalizations, drug prescription, outpatient episodes, consultations, and investigations/tests in the 12 months before inclusion in the study were considered for the estimation of medical resource consumption and direct health care costs. Third-quarter 2014 costs were obtained from the Italian Hospital Medical Care Program and converted into US dollars (using the November 2014 exchange rate). RESULTS: A total of 232 patients were included in the study. The mean age at diagnosis was 54.2 +/- 20.0 years, and the mean disease duration was 5.4 +/- 2.6 years (range, 2-22 years). Of the total number of patients, 75% had allergists as their usual source of care, 23% had dermatologists, 18% had internists, and 3% had rheumatologists. Only 7.8% of the patients had an emergency room admission to manage CU symptoms. To manage the disease, 57.8% of patients used antihistamines and 11.6% used oral corticosteroids. The most relevant source of cost was the medical treatment received, followed by physician visits. The average yearly direct cost per patient was US $1015 +/- $752 (95% confidence interval 803-2003). CONCLUSIONS: This is the first Argentine study that evaluated the costs of CU considering the direct medical costs of the disease. The study provides information on resource utilization and the disease-related economic burden, which is valuable to better understand CU in the local setting. Future research that takes into consideration the direct and indirect costs of the disease will expand knowledge and improve management of the disease. PMID- 27986200 TI - Toward Explicit Prioritization for the Caribbean: An EQ-5D Value Set for Trinidad and Tobago. AB - BACKGROUND: Resource allocation decision making in the Caribbean can be greatly enhanced by the introduction of cost per quality-adjusted life-year (QALY) analysis on the basis of local preferences. In the valuation literature there have been recommendations for the elicitation methods of the EuroQol five dimensional questionnaire (EQ-5D) that combine discrete-choice experiment (DCE) for bulk valuation with a time trade-off component for rescaling. OBJECTIVES: To create a three-level EQ-5D value set for Trinidad and Tobago using an elicitation method that takes into account the local constraints, and that can be easily deployed in other Caribbean islands. METHODS: A D-efficient DCE was completed by a representative sample of 307 adults. A time trade-off procedure was used to obtain values for rescaling the DCE model on a scale anchored at 0 (dead) and 1 (full health). RESULTS: A mixed logit analysis of the DCE data produced an internally valid model that is similar to the results obtained in earlier pilot studies. CONCLUSIONS: This EQ-5D value set allows cost per QALY analyses to be carried out on the basis of preferences from Trinidad and Tobago, and the approach to the DCE design can be taken for similar value sets to be created in the small, resource-constrained health systems of the Caribbean. Some guidelines for the initial application and introduction of cost per QALY analysis into the Trinidad and Tobago health system are also presented. PMID- 27986202 TI - Pharmacoeconomics, Outcomes Research, Health Technology Assessment, Comparative Effectiveness, Patient Centered Outcomes Research in Latin America 2016: brief update. PMID- 27986201 TI - Health-Related Quality of Life of Patients with HIV/AIDS in Bogota, Colombia. AB - BACKGROUND: There has rarely been any reporting on health-related quality of life (HRQOL) of patients with HIV/AIDS in developing countries. OBJECTIVES: To estimate the health utilities of people with HIV/AIDS in Bogota, Columbia. METHODS: A cross-sectional survey was conducted for 181 patients receiving antiretroviral therapy from an outpatient HIV/AIDS clinic in Bogota. The five level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L) and the EuroQol visual analogue scale (EQ-VAS) were used to estimate HRQOL scores. To derive utilities on the basis of the EQ-5D-5L, the Spanish value set was used. Subgroup analyses were performed according to sex, age, the Centers for Disease Control and Prevention classification, and CD4 cell count. RESULTS: The mean utility of the EQ-5D-5L was estimated at 0.85 +/- 0.21 and the EQ-VAS score was estimated at 84 +/- 14. Pain/discomfort and anxiety/depression were the two EQ-5D 5L dimensions associated with the poorer outcomes. Subgroup analyses revealed significantly higher utilities (using the EQ-5D-5L) for men than for women (0.88 vs. 0.76; P = 0.002) and lower utilities for patients with severe HIV (0.83 for CD4 < 200 vs. 0.87 for CD4 >= 500; P = 0.024). CONCLUSIONS: The HRQOL scores of patients with HIV/AIDS receiving antiretroviral therapy were relatively high in Bogota, Colombia, using the EuroQol questionnaire. The utility data could be useful, in combination with cost data, for future economic evaluations. PMID- 27986204 TI - Erratum. PMID- 27986203 TI - Estimacion de la Relacion Costo-Efectividad de las Vacunas Neumococicas Conjugadas Prevenar-13 y Synflorix(r), Utilizadas en Los Programas de Vacunacion de Poblacion Infantil Mexicana. AB - OBJECTIVE: To estimate the cost effectiveness associated with the use of pneumococcal conjugated vaccines, Prevenar-13 and Synflorix(r), in the Mexican pediatric population. METHODS: The cost-effectiveness ratio of instrumenting vaccination programs based upon the use of Prevenar-13 and Synflorix(r) in the Mexican pediatric population was estimated by using a Markov's simulation model. The robustness of the conclusions reached on cost-effectiveness for both vaccines was assayed through an univariate and probabilistic sensitivity analysis that included all of the parameters considered by the model. RESULTS: Synflorix(r) was dominant over Prevenar-13 in the cost-utility analysis; the former generated more quality-adjusted life years at a lower cost and with a lower incremental cost utility ratio. Based on the cost-effective analysis, Prevenar-13 generated more life years gained but at a higher cost. The use of Prevenar-13 originated a higher incremental cost-effectiveness ratio and, therefore, it was not cost effective as compared with Synflorix(r). CONCLUSIONS: Even though the simulations for Prevenar-13 and Synflorix(r) revealed both of them to be cost-effective when used to instrument pediatric vaccination campaigns in Mexico, Synflorix(r) had a better cost-utility/effectiveness profile. In addition, although Prevenar-13 and Synflorix(r) produced equivalent health outcomes, the overall analysis predicted that Synflorix(r) would save 360 million Mexican pesos, as compared with Prevenar 13. PMID- 27986206 TI - Introduction. PMID- 27986205 TI - Costo- Efectividad Del Uso Profilactico Del Factor Estimulante De Colonias De Granulocitos En Adultos Con Leucemia Linfoblastica Aguda en Colombia. AB - OBJECTIVE: To assess the cost-effectiveness of prophylactic administration of Granulocyte Colony-Stimulating Factor (G-CSF) compared with no use of it, during the induction phase of chemotherapy in Adults with Acute Lymphoblastic Leukemia (ALL) in Colombia. METHODS: A decision tree with a time horizon of 30 days was built under colombian health system perspective including only direct costs. The costs of procedures and medications were taken from official sources and an institution of national reference of oncology services. The safety and effectiveness data were taken from the literature and two Colombian cohorts with patients older than 15 years. The unit of outcome was the proportion of deaths avoided. RESULTS: Base-case results on a clinical trial indicate that using factor is a dominant strategy. The variable that most impacted the outcome was the incidence of febrile neutropenia. Considering a threshold of $22.228 USD in 80% of cases using factor was cost effective. However, the use of factor is not cost-effective for the country for incidences of febrile neutropenia > 48%. It was not possible to establish cost-effectiveness of pegfilgrastim because no information was found. CONCLUSION: As per Colombian data, the use of prophylactic factor under chemotherapeutic induction in adults with ALL, turns out to be not cost effective. The difference in the results suggests the need of a careful extrapolation of information from clinical trials (ideal world) for developing economic evaluations in Colombia. PMID- 27986207 TI - Biomarkers of Outcome in Patients With Localized Prostate Cancer Treated With Radiotherapy. AB - Prostate cancer represents one of the most prevalent malignancies in the world. Although subsets of prostate cancer are aggressive and can metastasize, it is also evident that most patients harbor indolent disease. Although current risk stratification approaches use both clinical and pathologic factors, it is clear that biomarkers can be used to improve on these approaches. In this article, we review the currently published literature on prostate cancer molecular biomarkers, primarily in the context of radiation therapy, focusing on those found in serum, plasma, urine, and within the tumor biopsy itself. We highlight the potential use and limitations of these biomarkers and present possible future directions for biomarker investigation. PMID- 27986210 TI - Emerging Technologies and Techniques in Radiation Therapy. AB - The past decade has brought an improved ability to precisely target and deliver radiation as well as other focal prostate-directed therapy. Stereotactic body radiotherapy (SBRT), proton beam radiation, high-dose-rate (HDR) brachytherapy, as well as nonradiotherapy treatments such as cryoablation and high-intensity focused ultrasound are several therapeutic modalities that have been investigated for the treatment of prostate cancer in an attempt to reduce toxicity while improving cancer control. However, high-risk prostate cancer requires a comprehensive treatment of the prostate as well as areas at risk for cancer spread. Therefore, most new radiation treatment (SBRT, HDR, and proton beam radiation) modalities have been largely investigated in combination with regional radiation therapy. Though the evidence is evolving, the use of SBRT, HDR, and proton beam radiation is promising. Nonradiation focal therapy has been proposed mainly for partial gland treatment in men with low-risk disease, and its use in high-risk prostate cancer patients remains experimental. PMID- 27986208 TI - Advances in Prostate Cancer Magnetic Resonance Imaging and Positron Emission Tomography-Computed Tomography for Staging and Radiotherapy Treatment Planning. AB - Conventional prostate cancer staging strategies have limited accuracy to define the location, grade, and burden of disease. Evaluations have historically relied upon prostate-specific antigen levels, digital rectal examinations, random systematic biopsies, computed tomography, pelvic lymphadenectomy, or 99mtechnetium methylene diphosphonate bone scans. Today, risk-stratification tools incorporate these data in a weighted format to guide management. However, the limitations and potential consequences of their uncertainties are well known. Inaccurate information may contribute to understaging and undertreatment, or overstaging and overtreatment. Meanwhile, advances in multiparametric magnetic resonance imaging (MRI), whole-body MRI, lymphotropic nanoparticle-enhanced MRI, and positron emission tomography are now available to improve the accuracy of risk stratification to facilitate more informed medical decisions. They also guide radiation oncologists to develop more accurate treatment plans. This review provides a primer to incorporate these advances into routine clinical workflow. PMID- 27986209 TI - Prostate Cancer Genetics: Variation by Race, Ethnicity, and Geography. AB - Prostate cancer rates vary substantially by race, ethnicity, and geography. These disparities can be explained by variation in access to screening and treatment, variation in exposure to prostate cancer risk factors, and variation in the underlying biology of prostate carcinogenesis (including genomic propensity of some groups to develop biologically aggressive disease). It is clear that access to screening and access to treatment are critical influencing factors of prostate cancer rates; yet, even among geographically diverse populations with similar access to care (eg, low- and medium-income countries), African descent men have higher prostate cancer rates and poorer prognosis. To date, the proportion of prostate cancer that can be explained by environmental exposures is small, and the effect of these factors across different racial, ethnic, or geographical populations is poorly understood. In contrast, prostate cancer has one of the highest heritabilities of all major cancers. Numerous genetic susceptibility markers have been identified from family-based studies, candidate gene association studies, and genome-wide association studies. Some prostate cancer loci, including the risk loci found at chromosome 8q24, have consistent effects in all groups studied to date. However, replication of many susceptibility loci across race, ethnicity, and geography remains limited, and additional studies in certain populations (particularly in men of African descent) are needed to better understand the underlying genetic basis of prostate cancer. PMID- 27986212 TI - Postoperative Radiation After Radical Prostatectomy. AB - A total of 3 randomized clinical trials have demonstrated a significant clinical benefit with adjuvant radiation in patients with high-risk prostate cancer after radical prostatectomy, with each showing improved biochemical control outcomes, and one trial (SWOG 8794) also demonstrating increased overall survival. How broadly these results have informed clinical practice has evolved over time, given the widespread availability of ultrasensitive prostate-specific antigen level testing and increased awareness that the high-risk patients are not a uniform cohort. In this review, we discuss the evidence from published and ongoing trials as well as current controversies, focusing on unanswered questions such as when postoperative radiation should be offered and whether the inclusion of androgen-deprivation therapy improves clinical outcomes. The emerging interest in genomic prediction tools and the enhanced sensitivity of novel imaging modalities should offer strategies to improve patient selection, which would help to identify men who may benefit from postoperative radiation while avoiding unnecessary treatment and toxicities in other men. PMID- 27986211 TI - Optimization of the Radiation Management of High-Risk Prostate Cancer. AB - Radiation and androgen-deprivation therapy (ADT) are mainstays of treatment for men with high-risk prostate cancer. High-risk disease is heterogeneous and subcategories of "favorable" high risk and very high risk can identify subgroups with particularly good or poor prognosis to help personalize treatment. Overall, randomized trials show that the combination of radiation and ADT improves survival when compared with either by itself. The optimum duration of ADT remains controversial, but for most healthy men with aggressive disease, approximately 2 3 years of ADT is well supported by the literature. The role of prophylactic pelvic nodal irradiation remains controversial, and there is an ongoing trial testing whether it improves overall survival. The use of brachytherapy boost appears to improve recurrence-free survival without yet improving survival, and may come at the cost of slightly higher toxicity. The addition of docetaxel to radiation and ADT may also improve failure-free survival, but a meta-analysis did not find that it improved overall survival. Retrospective data about the relative value of surgery vs radiation for high-risk disease have yielded varied conclusions and are ultimately hampered by the major issue of selection bias in retrospective series. PMID- 27986213 TI - Options for Salvage of Radiation Failures for Prostate Cancer. AB - Biochemical failure after primary external beam radiotherapy for prostate cancer is common, and a significant proportion of these failures are due to local residual or recurrent disease. Early or delayed palliation using androgen deprivation therapy is the most common approach. Although a conservative approach is appropriate for many individuals, selected patients would benefit from retreatment with curative intent. We review the pertinent literature on salvage of locally recurrent prostate cancer after primary radiotherapy, including the modalities of surgery, cryotherapy, high-intensity focused ultrasound, or reirradiation with brachytherapy or stereotactic body radiotherapy. We discuss patient selection, outcomes, and toxicities. Patients with local recurrence and sufficient life expectancy, in the absence of metastatic disease, could be considered for local salvage. Although highly dependent on patient selection, the efficacy of the various salvage options seems comparable, with biochemical recurrence-free survivals ranging approximately 50% at 5 years. The toxicity profiles differ, but all salvage treatments are more toxic than primary treatment. Management of isolated local failure after radiotherapy remains challenging. However, with the recent progress in salvage techniques, and more sensitive functional imaging for tumor localization and staging, salvage treatments are likely to play an increasingly important role. PMID- 27986214 TI - Management of Node-Positive and Oligometastatic Prostate Cancer. AB - Historically, stage IV prostate cancer was considered incurable. Although node positive and oligometastatic prostate cancers are both classified as stage IV, these likely represent distinct clinical groups, and some patients may be curable with aggressive multimodality treatments. There is a lack of randomized evidence, but retrospective studies suggest that radical prostatectomy or radiotherapy may improve survival in these patients. This is an area of great current research interest and prospective randomized trials are needed to help define the optimal treatments for these patients. PMID- 27986215 TI - Beyond Just Androgen Deprivation Therapy: Novel Therapies Combined With Radiation. AB - External beam radiation therapy (EBRT) combined with androgen deprivation are standard of care for selected patients with prostate cancer. In recent years, multiple therapies have been experimentally combined with EBRT either concomitantly or adjuvantly. These therapies include chemotherapies, immunotherapies, and novel hormones. In addition to EBRT, clinical trials with radiopharmaceuticals are planned or have been performed with concomitant chemotherapy, immunotherapies, novel hormones, and inhibitors of DNA damage repair. Herein we cover the therapeutic landscape of radiation, both EBRT and radiopharmaceuticals, and various novel therapies. Today, these therapies have yet to change the standard of care, but in the future, these combinations may improve upon currently available therapies. Clinical trials with radiation and novel forms of therapy are the key to progress, and newer adaptive clinical trial designs may allow such progress to occur faster. PMID- 27986216 TI - Editorial overview: Parasitic and fungal diseases. PMID- 27986217 TI - BBB crossing assessment and BBB crossing technologies in CNS Drug Discovery. PMID- 27986218 TI - Intracerebral microdialysis in blood-brain barrier drug research with focus on nanodelivery. AB - Microdialysis has contributed significantly to advance the understanding of BBB transport of drugs and to reveal key aspects of BBB transport, including quantifying active efflux and active uptake. Microdialysis studies on pharmacokinetic-pharmacodynamic relationships have given in-depth understanding of the processes involved. Recently, nanodelivery to the brain has been investigated with microdialysis, contributing to nanodelivery science by giving quantitative information on the possible success of different delivery vehicles and how they are involved in BBB transport. PMID- 27986219 TI - Cerebral open flow microperfusion (cOFM) an innovative interface to brain tissue. AB - Cerebral open flow microperfusion (cOFM) is a new in-vivo technique for continuous sampling of the interstitial fluid in brain tissue. cOFM can be used to monitor substance transport across the blood-brain barrier (pharmacokinetics) and to investigate metabolic changes in brain tissue after drug application (pharmacodynamics). The possibility of long-term implantation into the brain makes cOFM an outstanding tool in the development of brain relevant pharmaceutics. PMID- 27986220 TI - Measuring blood-brain barrier penetration using the NeuroCart, a CNS test battery. AB - To systematically study the pharmacodynamics of a CNS drug early in the development process, we developed and validated a battery of drug-sensitive CNS tests, which we call NeuroCart. Using this test battery, data-intensive phase 1 studies in healthy subjects can be performed to demonstrate the specific, time- and dose-dependent, neurophysiological and/or neuropsychological effects of a compound, thereby confirming whether the test compound reaches its intended target in the CNS - or does not reach its intended target. We use this test battery to demonstrate that a compound passes the blood-brain barrier. PMID- 27986221 TI - Modulating the paracellular pathway at the blood-brain barrier: current and future approaches for drug delivery to the CNS. AB - The blood-brain barrier (BBB) is the tightly regulated point of entry by which any neuro-targeting therapy must pass through. BBB modulation is a means to loosen the size exclusion properties of the barrier by temporarily interfering with the formation of intercellular tight junction (TJ) or adheren junction (AJ) complexes, allowing for diffusion of small molecule therapeutics from blood to brain. Several technologies, such as RNAi, peptidomimetics, high frequency ultrasound and nanoparticles, have been developed and refined over the years, paving the way for barrier modulation to become an effective part of conventional central nervous system therapies. Here, we review the current and future approaches aimed at facilitating enhanced drug delivery to the central nervous system (CNS). PMID- 27986223 TI - Exploiting transferrin receptor for delivering drugs across the blood-brain barrier. AB - Delivery of large molecule drugs across the blood brain barrier is increasingly being seen as an achievable goal. Several technologies have been described where following peripheral administration the molecules can be detected in the brain. Foremost amongst these technologies are antibodies against the transferrin receptor. Following a burst of publications in the very early twenty first century, excitement seemed to wane as contrary data started to emerge. Over the last few years antibodies against transferrin receptor have again started to raise hopes of successful drug delivery to the central nervous system, as protein engineering techniques have allowed a more detailed understanding of the antibody properties necessary for successful transport across the blood brain barrier. PMID- 27986224 TI - Altered blood-brain barrier transport in neuro-inflammatory disorders. AB - During neurodegenerative and neuroinflammatory disorders of the central nervous system (CNS), such as Alzheimer's disease (AD) and multiple sclerosis (MS), the protective function of the blood-brain barrier (BBB) may be severely impaired. The general neuro-inflammatory response, ranging from activation of glial cells to immune cell infiltration that is frequently associated with such brain diseases may underlie the loss of the integrity and function of the BBB. Consequentially, the delivery and disposition of drugs to the brain will be altered and may influence the treatment efficiency of such diseases. Altered BBB transport of drugs into the CNS during diseases may be the result of changes in both specific transport and non-specific transport pathways. Potential alterations in transport routes like adsorptive mediated endocytosis and receptor mediated endocytosis may affect drug delivery to the brain. As such, drugs that normally are unable to traverse the BBB may reach their target in the diseased brain due to increased permeability. In contrast, the delivery of (targeted) drugs could be hampered during inflammatory conditions due to disturbed transport mechanisms. Therefore, the inventory of the neuro-inflammatory status of the neurovasculature (or recovery thereof) is of utmost importance in choosing and designing an adequate drug targeting strategy under disease conditions. Within this review we will briefly discuss how the function of the BBB can be affected during disease and how this may influence the delivery of drugs into the diseased CNS. PMID- 27986222 TI - Ultrasound-mediated drug delivery to the brain: principles, progress and prospects. AB - The blood-brain barrier (BBB) limits drug delivery to the central nervous system. When combined with microbubbles, ultrasound can transiently permeate blood vessels in the brain. This approach, which can be referred to as sonoporation or sonopermeabilization, holds significant promise for shuttling large therapeutic molecules, such as antibodies, growth factors and nanomedicine formulations, across the BBB. We here describe the basic principles of BBB permeation using ultrasound and microbubbles, and we summarize several (pre-) clinical studies showing the potential of BBB opening for improving the treatment of cancer and neurodegenerative disorders. PMID- 27986225 TI - Liposome technologies and drug delivery to the CNS. AB - Brain and nervous system disorders represent a large unmet medical need. Central nervous system drug development is hampered by the restricted transport of drugs across the blood-brain barrier. Different strategies to deliver drugs to the brain have been developed. We discuss the current status of development of liposomal drug delivery to the brain. There is a growing interest in targeted delivery of liposomes to the brain and much progress has been made towards successful development of novel treatments for patients with devastating brain diseases. PMID- 27986226 TI - Glutathione conjugation dose-dependently increases brain-specific liposomal drug delivery in vitro and in vivo. AB - The blood-brain barrier (BBB) represents a major obstacle for the delivery and development of drugs curing brain pathologies. However, this biological barrier presents numerous endogenous specialized transport systems that can be exploited by engineered nanoparticles to enable drug delivery to the brain. In particular, conjugation of glutathione (GSH) onto PEGylated liposomes (G-Technology(r)) showed to safely enhance delivery of encapsulated drugs to the brain. Yet, understanding of the mechanism of action remains limited and full mechanistic understanding will aid in the further optimization of the technology. In order to elucidate the mechanism of brain targeting by GSH-PEG liposomes, we here demonstrate that the in vivo delivery of liposomal ribavirin is increased in brain extracellular fluid according to the extent of GSH conjugation onto the liposomes. In vitro, using the hCMEC/D3 human cerebral microvascular endothelial (CMEC) cell line, as well as primary bovine and porcine CMEC (and in contrast to non-brain derived endothelial and epithelial cells), we show that liposomal uptake occurs through the process of endocytosis and that the brain-specific uptake is also glutathione conjugation-dependent. Interestingly, the uptake mechanism is an active process that is temperature-, time- and dose-dependent. Finally, early endocytosis events rely on cytoskeleton remodeling, as well as dynamin- and clathrin-dependent endocytosis pathways. Overall, our data demonstrate that the glutathione-dependent uptake mechanism of the G-Technology involves a specific endocytosis pathway indicative of a receptor-mediated mechanism, and supports the benefit of this drug delivery technology for the treatment of devastating brain diseases. PMID- 27986227 TI - Global Surgical Ecosystems: A Need for Systems Strengthening. AB - BACKGROUND: As surgery is gaining recognition as a critical component of universal health care worldwide, surgical communities have come together with unprecedented unity to advocate for systems to support surgical care. This community has long believed that much care could be performed in a cost-effective manner even in low resource settings, despite skepticism voiced by many in public health. To do so will require the development of new systems and re-vamping of old systems that are not effective. In the last five years, coalitions, expert panels, commissions, consortia and alliances have emerged to address these issues and there has been landmark success in advocacy with a new resolution at the 2015 World Health Assembly to include surgical care as a component of universal health coverage. It is critical to understand the ecosystem that constitutes the surgical environment. A surgical ecosystem could be described as a network of people, processes, and materials necessary for surgical services in the context of the facilities and environment in which it functions. METHODS: We describe components of a functioning surgical ecosystem in terms of administration, support staff and clinicians, and the necessary sub-systems for providing consumable materials such as anesthetic medication and suture and sterile instruments. Related systems that must be integrated are facilities and utilities such as electricity, lighting, plumbing and waste management and even laundry. But especially in low and middle income countries (LMICs) lack of any one of these may be rate-limiting. The World Health Organization (WHO) has developed situational analyses and checklists for first level district hospitals to identify missing elements. CONCLUSIONS: A siloed approach cannot solve a systems problem. However, to scale up rapidly and to develop and sustain quality standards, a holistic "ecosystem" approach, including local and global professional societies and advocacy organizations will need to become engaged. PMID- 27986228 TI - Challenges to Cancer Program Development in Low- and Middle-Income Countries. PMID- 27986229 TI - Vien Tim Institut du Coeur: Success of a Congenital Heart Disease Center in a Developing Country. AB - OBJECTIVE: The goal of the Vien Tim Institute du Coeur is to provide high quality cardiac surgical care to the Vietnamese population with 25% of care allocated to the indigent. This article discusses the history; functional and financial implementation of creating a long-term fully sustainable adult and pediatric cardiac surgery center in Southeast Asia in a developing country. METHODS: The Institut du Coeur in Ho Chi Minh City, Vietnam is a fully functional and financially solvent cardiac surgery center that was formed 28 years ago. It was borne from the Alain Carpentier Foundation which oversees its activity and the Centre Medical International which is an outpatient clinic in Ho Chi Minh City and continues to financially support and oversee the development and future of the Institute. This article details many of the key components to the development of this sustainable program and its evolution. RESULTS: Since 1996, over 25,000 patients with complicated adult and congenital cardiac disease have been treated at the infirmary with support from the Alain Carpentier Foundation since it was established in 1992. The hospital has also performed surgery and treatment to poor patients across Vietnam with over 6,700 impoverished patients having had free operations with an estimated cost of VND230 billion (US$10.2 million). In addition, 96 surgeons and nearly 500 medical staff have carried out charitable health checks on 12,000 patients in many provinces and cities throughout Vietnam. Through profit sharing with the Centre Medical International and corporate and personal donations, proceeds are given to the Institute to help perform roughly 25% of all cardiac surgery free of charge to indigent patients in need of congenital heart surgery. CONCLUSION: The Vien Tim Institute du Coeur has stayed true to its goal of offering high quality cardiac surgical care including congenital heart surgery to a large patient population with one quarter directed to the medically indigent. It also continues to empower and train the health care professionals locally and throughout the country. Creation and growth through this model may help provide a fully functional and financially self-sustaining institution in a developing nation. PMID- 27986230 TI - Barriers to Global Health Training in Obstetrics and Gynecology. AB - BACKGROUND: The Lancet Commission on Global Surgery includes obstetrics and gynecology as an area needing international strengthening in low- and middle income countries. Despite interest, a majority of participants in US residency programs graduate with little exposure to global health or preparation to work abroad. OBJECTIVE: The aim of this study was to determine the level of interest of obstetrics and gynecology (Ob/Gyn) residents in gaining global health training and to identify perceived barriers to receiving training. METHODS: Residents in accredited Ob/Gyn programs were identified using a national residency database. The survey was online and anonymous. FINDINGS: A total of 278 residents completed the survey. A high level of motivation to participate in a global health elective was associated with interests in preparation for future global work, desire for activism in maternal health and social determinants of health, and becoming better informed on global health policy. Eighty-two percent of respondents stated they would participate in a global health curriculum if it were offered, and 54.8% would use their vacation time. There were associations between personal safety, family, lack of resources, and lack of interest from faculty and motivational level as perceived barriers. Eighty-one percent strongly agreed that scheduling conflicts and time constraints pose barriers; more than 80% either agreed or strongly agreed that funding such endeavors and a lack of mentorship are major deterrents to pursuing global health. CONCLUSIONS: Because resident motivation is clearly high and international need persists, we determined that most barriers to training abroad are related to the structure and budget of residency programs. PMID- 27986231 TI - Building a Sustainable Global Surgical Program in an Academic Department of Surgery. AB - BACKGROUND: Global surgery and volunteerism in surgery has gained significant interest in recent years for general surgery residents across the country. However, there are few well-established long-term surgical programs affiliated with academic institutions. The present report discusses the implementation process and challenges facing an academic institution in building a long-term sustainable global surgery program. METHODS: As one of the pioneer programs in global surgery for residents, the Icahn School of Medicine at Mount Sinai global surgery rotation has been successfully running for the last 10 years in a small public hospital in the Dominican Republic. The present report details many key components of implementing a sustainable global surgery program and the evolution of this program over time. FINDINGS: Since 2005, 80 general surgery residents have rotated through Juan Pablo Pina Hospital in the Dominican Republic. They have performed a total of 1239 major operations and 740 minor operations. They have also participated in 328 emergency cases. More importantly, this rotation helped shape residents' sense of social responsibility and ownership in their surgical training. Residents have also contributed to the training of local residents in laparoscopic skills and through cultural exchange. CONCLUSIONS: As interest in global surgery grows among general surgery residents, it is essential that supporting academic institutions create sustainable and capacity-building rotations for their residents. These programs must address many of the barriers that can hinder maintenance of a sustainable global surgery experience for residents. After 10 years of sending our residents to the Dominican Republic, we have found that it is possible and valuable to incorporate a formal global surgery rotation into a general surgery residency. PMID- 27986232 TI - The Need for Formal Surgical Global Health Programs and Improved Mission Trip Coordination. AB - BACKGROUND: There is a dire need for more surgical services as part of improving global health. Conditions treatable with surgery account for 11% of the global burden of disease, with a disproportionate burden affecting low- and middle income countries (LMICs). Less than 6% of the world's operations are performed in LMICs, with relief organizations performing nearly 250,000 operations annually in LMICs in addition to each country's domestic surgical capacity. Currently, surgical needs are not adequately met by the existing patchwork of federal and nongovernmental organizations' surgical services and surgical mission trips. Improving coordination between mission trips may have synergistic benefits for maximizing the efficacy of the individual trips and improving the overall quality of care. OBJECTIVES: To establish whether cooperation between surgical mission trips can lead to operational efficiency and to identify obstacles to cooperation. METHODS: In order to establish the veracity of cooperation translating into efficiency and to identify obstacles that prevent cooperation, a 50-question survey was created (see Supplement 1). The survey was sent to surgical program directors of the 147 major surgical programs in the United States and Canada with a follow-up telephone survey of 18 randomly selected programs. FINDINGS: The survey response rate was 14%. Although 90% of respondent programs mount at least 1 mission trip per year, only one-third confirmed the existence of global health or surgical global health programs at their institution (33%). There was significant interest in cooperating with programs at other institutions (80%). When asked why they do not communicate with humanitarian aid organizations doing similar work, 53% of respondents reported a "lack of knowledge of how to find similar organizations to mine doing similar work." An additional 21% of respondents were "unaware that coordination is possible." CONCLUSIONS: A minority of respondent surgery programs host formal, organized surgical global health programs with a structured leadership based at academic medical centers. Although most institutions have individuals leading international humanitarian missions to LMICs, these leaders do not function in an integrated fashion with their departments, institutions, or other academic medical programs. The majority of respondents were interested in coordinating their surgical trips with other groups. Respondents suggested the creation of a central database that would allow trip organizers to share information about upcoming trips, site logistics, and personnel or supply needs. PMID- 27986233 TI - Implementing Electronic Surgical Registries in Lower-Middle Income Countries: Experiences in Latin America. PMID- 27986234 TI - Improved Techniques and Future Advances in Plastic Surgery in Global Health. AB - BACKGROUND: Plastic surgery has a long-standing history of being deeply interconnected with global health. This paper reviews the current state of global health as it relates to plastic surgery and makes forecasts for the future. METHODS: This study reviews the most current literature on global plastic surgery, as well as offers insights based on our 2 senior authors' experiences. For our literature search, the MEDLINE database was queried using relevant keywords through both PubMed and OVID user interfaces. FINDINGS: Early exposure to global plastic surgery often leads to a lifelong involvement. Formal integration of global surgery into residencies is becoming more common. Models of care for global plastic surgery range from small to large groups, spanning the full spectrum of reconstructive plastic surgery. The best of these groups have longitudinal relationships with their operative sites to allow for continuous care. Logistics and funding are crucial for successful care. Technological advances will make long-distance care more facile in the future. CONCLUSIONS: Global plastic surgery is rewarding to both patient and physician. Plastic surgery has been and will continue to be committed to providing high-quality global health care. PMID- 27986235 TI - Building a Sustainable Global Surgery Nonprofit Organization at an Academic Institution. AB - BACKGROUND: Surgical Outreach for the Americas is a 501(c)3 nonprofit organization providing surgical care to those in need in developing countries of the Western Hemisphere. Every year since its inception in 2008, teams of surgeons, nurses, and allied health professionals have traveled to areas of need and performed primarily hernia repair surgeries for those without access to affordable health care. METHODS: Surgical Outreach for the Americas (SOfA) began as a general concept based on World Health Organization statistics claiming that 11% of the global burden of disease can be resolved via surgery. Armed with this information, a group of compassionate and selfless health care professionals planned the first trip, to the Dominican Republic, in January 2009. Building on what was first just an ambition to help others, we now also train surgeons, surgery residents, and nurses in the countries we serve. FINDINGS: To date, SOfA has successfully treated 734 patients, with 899 total surgical procedures performed (693 of these under general anesthesia). These procedures include inguinal hernia, umbilical hernia, testicular masses, orchiectomies, and various general surgical procedures. CONCLUSIONS: Through the efforts of a great many talented individuals and robust fundraising efforts, the SOfA message continues to gain momentum. SOfA not only considers the health and well-being of the disadvantaged through capacity-building efforts but strives to educate and improve the skills of health care professionals in the countries we visit. Our goal is to increase the number of missions each year and begin a 2-fold educational program that (a) provides surgical resident education through participation in mission work and (b) provides local surgeon education in the areas served. PMID- 27986236 TI - Surgical Management and Reconstruction Training (SMART) Course for International Orthopedic Surgeons. AB - BACKGROUND: The burden of complex orthopedic trauma in low- and middle-income countries (LMICs) is exacerbated by soft-tissue injuries, which can often lead to amputations. This study's purpose was to create and evaluate the Surgical Management and Reconstruction Training (SMART) course to help orthopedic surgeons from LMICs manage soft-tissue defects and reduce the rate of amputations. METHODS: In this prospective observational study, orthopedic surgeons from LMICs were recruited to attend a 2-day SMART course taught by plastic surgery faculty in San Francisco. Before the course, participants were asked to assess the burden of soft-tissue injury and amputation encountered at their respective sites of practice. A survey was then given immediately and 1-year postcourse to evaluate the quality of instructional materials and the course's effect in reducing the burden of amputation, respectively. RESULTS: Fifty-one practicing orthopedic surgeons from 25 countries attended the course. No participant reported previously attempting a flap reconstruction procedure to treat a soft-tissue defect. Before the course, participants cumulatively reported 580-970 amputations performed annually as a result of soft-tissue defects. Immediately after the course, participants rated the quality and effectiveness of training materials to be a mean of >=4.4 on a Likert scale of 5 (Excellent) in all 14 instructional criteria. Of the 34 (66.7%) orthopedic surgeons who completed the 1-year postcourse survey, 34 (100%, P < 0.01) reported performing flaps learned at the course to treat soft-tissue defects. Flap procedures prevented 116 patients from undergoing amputation; 554 (93.3%) of the cumulative 594 flaps performed by participants 1 year after the course were reported to be successful. Ninety-seven percent of course participants taught flap reconstruction techniques to colleagues or residents, and a self-reported estimate of 28 other surgeons undertook flap reconstruction as a result of information dissemination by 1 year postcourse. CONCLUSION: The SMART Course can give orthopedic surgeons in LMICs the skills and knowledge to successfully perform flaps, reducing the self reported incidence of amputations. Course participants were able to disseminate flap reconstructive techniques to colleagues at their home institution. While this course offers a collaborative, sustainable approach to reduce global surgical disparities in amputation, future investigation into the viability of teaching the SMART course in LMICs is warranted. PMID- 27986238 TI - Malignant Catatonia Versus Delirium. PMID- 27986239 TI - The Reply. PMID- 27986237 TI - Sex Differences in the Relationship between Depressive Symptoms and Risk of Amnestic Mild Cognitive Impairment. AB - OBJECTIVE: The relationship between depressive symptoms and subsequent cognitive impairment in older adults is controversial. Sex differences and the differences in the method of categorizing depressive symptoms may contribute to the inconsistencies. The authors examined the effect of severity of baseline depressive symptoms on risk of incident amnestic mild cognitive impairment (aMCI) separately in men and women. METHODS: Community-dwelling and cognitively healthy older adults (aged >= 70 years) from the Einstein Aging Study completed the 15 item Geriatric Depression Scale (GDS-15) at their baseline visit. Participants were categorized into "no/low symptoms" (GDS-15 score = 0-2), "mild symptoms" (GDS-15 score = 3-5), and "moderate/severe symptoms" (GDS-15 score > 6) groups. Sex-stratified Cox proportional hazards models, adjusted for age, education, and antidepressant medication, estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for incident aMCI as a function of depressive symptoms group. RESULTS: We followed 572 women (mean age: 78) and 345 men (mean age: 77) for 4.2 years on average (range: 1.0-14.6 years). Ninety women and 64 men developed aMCI during follow-up. Cox models revealed that compared with no/low depressive symptoms, mild symptoms were associated with a two times greater risk of developing aMCI in men (HR: 2.22; 95% CI: 1.26-3.89) but not in women (HR: 1.26; 95% CI: 0.77-2.06). Conversely, moderate/severe depressive symptoms were associated with a two times greater risk of developing aMCI in women (HR: 1.99; 95% CI: 1.05-3.77) but not in men (HR: 0.28; 95% CI: 0.04-2.11), possibly because of low statistical power in this subgroup. CONCLUSION: Results indicate that mild depressive symptoms in men and moderate/severe symptoms in women may represent a marker for future cognitive impairment. PMID- 27986241 TI - From the Editor: Volume 100. PMID- 27986240 TI - Dietary Management of Gout: What is the Evidence? PMID- 27986242 TI - Engaging patients in understanding and using evidence to inform shared decision making. PMID- 27986243 TI - North American Spine Society Presidential Address. PMID- 27986245 TI - The optimal treatment for symptomatic neurogenic claudication or radiculopathy in the presence of mild degenerative scoliosis remains unclear. PMID- 27986246 TI - New format for the Journal. PMID- 27986247 TI - The putative mechanism of recurrent valve regurgitation after valve repair in ischemic mitral valve regurgitation. PMID- 27986244 TI - A response to a commentary by Dr. Daniel J. Cher. PMID- 27986248 TI - Predicting recurrent mitral regurgitation after mitral valve repair: A difficult endeavor and a necessity. PMID- 27986249 TI - Cardiac surgery centers are ideal places to treat patients undergoing life threatening deep accidental hypothermia using extracorporeal membrane oxygenation venoarterial therapy. PMID- 27986251 TI - Intravenous acetaminophen: Can the benefit outweigh the cost in selected patients? PMID- 27986250 TI - A call for standardized end point definitions regarding outcomes of extracorporeal membrane oxygenation. PMID- 27986252 TI - Routine intravenous acetaminophen for postcardiac surgery analgesia: High costs and questionable benefits. PMID- 27986253 TI - Less is more. PMID- 27986255 TI - Pectus excavatum: A rare cause of dysphagia. PMID- 27986254 TI - Inhibition of Na-K-Cl cotransporter isoform 1 reduces lung injury induced by ischemia-reperfusion. AB - OBJECTIVES: Ischemia-reperfusion acute lung injury is characterized by increased vascular permeability, lung edema, and neutrophil sequestration. Ischemia reperfusion acute lung injury occurs in lung transplantation and other major surgical procedures. Effective regulation of alveolar fluid balance is critical for pulmonary edema. Sodium-potassium-chloride co-transporter regulates alveolar fluid and is associated with inflammation. We hypothesized that sodium-potassium chloride co-transporter is important in ischemia-reperfusion acute lung injury. Bumetanide, a sodium-potassium-chloride co-transporter inhibitor, is used to treat pulmonary edema clinically. We studied the effect of bumetanide in ischemia reperfusion acute lung injury. METHODS: Isolated perfusion of mouse lungs in situ was performed. The main pulmonary artery and left atrium were catheterized for lung perfusion and effluent collection for recirculation, respectively, with perfusate consisting of 1 mL blood and 9 mL physiologic solution. Ischemia reperfusion was induced by 120 minutes of ischemia (no ventilation or perfusion) and reperfused for 60 minutes. Wild-type, SPAK knockout (SPAK-/-), and WNK4 knockin (WNK4D561A/+) mice were divided into control, ischemia-reperfusion, and ischemia-reperfusion + bumetanide groups (n = 6 per group). Bumetanide was administered via perfusate during reperfusion. Measurements were taken of lung wet/dry weight, microvascular permeability, histopathology, cytokine concentrations, and activity of the nuclear factor-kappaB pathway. RESULTS: In wild-type mice, ischemia-reperfusion caused lung edema (wet/dry weight 6.30 +/- 0.36) and hyperpermeability (microvascular permeability, 0.29 +/- 0.04), neutrophil sequestration (255.0 +/- 55.8 cells/high-power field), increased proinflammatory cytokines, and nuclear factor-kappaB activation (1.33 +/- 0.13). Acute lung injury was more severe in WNK4 mice with more lung edema, permeability, neutrophil sequestration, and nuclear factor-kappaB activation. Severity of acute lung injury was attenuated in SPAK-/-mice. Bumetanide decreased pulmonary edema (wild-type: wet/dry weight 5.05 +/- 0.44, WNK4: wet/dry weight 5.13 +/- 0.70), neutrophil sequestration (wild-type: 151.7 +/- 27.8 cells/high power field, WNK4: 135.3 +/- 19.1 cells/high-power field), permeability (wild type: 0.19 +/- 0.01, WNK4: 0.21 +/- 0.03), cytokines, and nuclear factor-kappaB activation after ischemia-reperfusion. CONCLUSIONS: Functional reduction of sodium-potassium-chloride co-transporter by genetic or pharmacologic treatment to inhibit sodium-potassium-chloride co-transporter resulted in lower severity of acute lung injury induced by ischemia-reperfusion. Sodium-potassium-chloride co transporter may present a promising target for therapeutic interventions in a clinical setting. PMID- 27986256 TI - Physiologic implications of pectus excavatum. PMID- 27986257 TI - The Mitroflow aortic valve: A past, present, and future illuminated. PMID- 27986258 TI - Ascending aortopathy with bicuspid aortic valve: More, but not enough, evidence for the hemodynamic theory. PMID- 27986259 TI - Acute retrograde aortic dissection: "To be [treated] or not to be, that is the question". PMID- 27986260 TI - Utility of MRCP in clinical decision making of suspected choledocholithiasis: An institutional analysis and literature review. AB - BACKGROUND: The ideal treatment algorithm for suspected choledocholithiasis is not yet well defined. Imaging options include magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and intraoperative cholangiogram (IOC). MRCP is diagnostic, while the other two modalities can also be therapeutic. Each of these modalities for diagnosis and treatment carries its own set of risks, benefits, and institutional costs. We hypothesized that there would be a significant difference between the biochemical profiles and characteristics of patients who undergo ERCP vs. MRCP vs. operative intervention as the initial choice of treatment/imaging modality. METHODS: We performed a retrospective review of the electronic medical records for all patients with a coded diagnosis of choledocholithiasis from 2011 to 2014. The initial diagnostic modality was assessed for each hospital encounter. The statistical characteristics of MRCP as compared to fluoroscopic imaging of the biliary tree (ERCP, IOC) were analyzed. RESULTS: Overall, 527 hospital encounters were identified. Initial intervention included ERCP in 63%, MRCP in 12%, and cholecystectomy in 25% of patients. Patients undergoing cholecystectomy first, compared to MRCP or ERCP, tended to have lower values for alkaline phosphatase (P < 0.001) and AST (P = 0.002) as well as be of younger age (P < 0.0001). Of the patients that underwent MRCP as their initial procedure, 82% subsequently underwent either ERCP or laparoscopic cholecystectomy. In patients who underwent an initial MRCP followed by either ERCP or IOC, the predictive performance of MRCP was as follows: sensitivity = 0.90, specificity = 0.86, positive predictive value = 0.97, negative predictive value = 0.60, agreement (Cohen's Kappa) = 0.64. CONCLUSIONS: There is a significant difference in the laboratory evaluation and demographics of patients undergoing ERCP, MRCP, and laparoscopic cholecystectomy. MRCP was followed with a more invasive test a majority of the time. Since MRCP did not change the management of patients with suspected choledocholithiasis, its utility in this patient population should be questioned. Further research is needed to better define the pretest characteristics which would predict which patients do not need further intervention after MRCP as well as defining the most cost-effective strategy. PMID- 27986261 TI - Accuracy and Radiation Dose Reduction Using Low-Voltage Computed Tomography Coronary Artery Calcium Scoring With Tin Filtration. AB - This study prospectively investigated the accuracy and radiation dose reduction of CT coronary artery calcium scoring (CACS) using a 100 kVp acquisition protocol with tin filtration (Sn100 kVp) compared with the standard 120 kVp acquisition protocol; 70 patients (59% men, 62.1 +/- 10.7 years) who underwent a clinically indicated CACS acquisition using the standard 120 kVp protocol on a third generation dual-source CT system were enrolled. An additional Sn100 kVp CACS scan was performed. Agatston scores and categories, percentile-based risk categorization, and radiation dose estimates were derived from 120 and Sn100 kVp studies and compared. Median Agatston scores from the Sn100 and 120 kVp acquisitions were 38.2 and 41.2, respectively (p <0.0001). Excellent correlation of Agatston scores was found between the 2 acquisitions (r = 0.99, p <0.0001). Although the Agatston scores were systematically lower with Sn100 than with 120 kVp, the comparison of Agatston score categories and percentile-based cardiac risk categories showed excellent agreement (kappa = 0.98 and kappa = 0.98). Image noise was 26.3 +/- 5.7 Hounsfield units in Sn100 kVp and 17.6 +/- 4.1 Hounsfield units in 120 kVP scans (p <0.0001). The dose-length product was 14.1 +/- 3.7 mGy.cm with Sn100 kVp and 58.5 +/- 23.5 mGy.cm with 120 kVp scans (p <0.0001), resulting in a significantly lower effective radiation dose (0.19 +/- 0.05 vs 0.82 +/- 0.32 mSv, p <0.0001) for Sn100 kVp scans. CACS using a low-voltage tin filtration protocol shows excellent correlation and agreement with the standard method with regard to the Agatston score and subsequent cardiac risk categorization, while achieving a 75% reduction in radiation dose. PMID- 27986262 TI - Daily Energy Expenditure and Its Relation to Health Care Costs in Patients Undergoing Ambulatory Electrocardiographic Monitoring. AB - Our increasingly sedentary lifestyle is associated with a heightened risk of obesity, diabetes, heart disease, and cardiovascular mortality. Using the recently developed heart rate index formula in 843 patients (mean +/- SD age 62.3 +/- 15.7 years) who underwent 24-hour ambulatory electrocardiographic (ECG) monitoring, we estimated average and peak daily energy expenditure, expressed as metabolic equivalents (METs), and related these data to subsequent hospital encounters and health care costs. In this cohort, estimated daily average and peak METs were 1.7 +/- 0.7 and 5.5 +/- 2.1, respectively. Patients who achieved daily bouts of peak energy expenditure >=5 METs had fewer hospital encounters (p = 0.006) and median health care costs that were nearly 50% lower (p <0.001) than their counterparts who attained <5 METs. In patients whose body mass index was >=30 kg/m2, there were significant differences in health care costs depending on whether they achieved <5 or >=5 METs estimated by ambulatory ECG monitoring (p = 0.005). Interestingly, patients who achieved >=5 METs had lower and no significant difference in their health care costs, regardless of their body mass index (p = 0.46). Patients with previous percutaneous coronary intervention who achieved >=5 METs had lower health care costs (p = 0.044) and fewer hospital encounters (p = 0.004) than those who achieved <5 METs. In conclusion, average and peak daily energy expenditures estimated from ambulatory ECG monitoring may provide useful information regarding health care utilization in patients with and without previous percutaneous coronary intervention, irrespective of body habitus. Our findings are the first to link lower intensities of peak daily energy expenditure, estimated from ambulatory ECG monitoring, with increased health care utilization. PMID- 27986263 TI - Simulation based teaching in interventional radiology training: is it effective? AB - AIM: To establish the educational effectiveness of simulation teaching in interventional radiology training. MATERIALS AND METHODS: Electronic databases (MEDLINE, ERIC, Embase, OvidSP, and Cochrane Library) were searched (January 2000 to May 2015). Studies specifically with educational outcomes conducted on radiologists were eligible. All forms of simulation in interventional training were included. Data were extracted based on the population, intervention, comparison, and outcome (PICO) model. Kirkpatrick's hierarchy was used to establish educational intervention effectiveness. The quality of studies was assessed using the Cochrane risk of bias tool. RESULTS: Search resulted in 377 articles, of which 15 met the inclusion criteria. Thirteen of the 15 studies achieved level 2 of Kirkpatrick's hierarchy with only one reaching level 4. Statistically significant improvements in performance metrics as objective measures, demonstrating trainee competence were seen in 12/15 studies. Subjective improvements in confidence were noted in 13/15. Only one study demonstrated skills transferability and improvements in patient outcomes. CONCLUSION: Results demonstrate the relevance of simulated training to current education models in improving trainee competence; however, this is limited to the simulated environment as there is a lack of literature investigating its predictive validity and the effect on patient outcomes. The requirement for further research in this field is highlighted. Simulation is thus currently only deemed useful as an adjunct to current training models with the potential to play an influential role in the future of the interventional radiology training curriculum. PMID- 27986264 TI - Imaging of palatal lumps. AB - Palatal tumours are relatively rare and of variable aetiology, rendering radiological evaluation a daunting process for many. A systematic approach to the imaging of a palatal lump is therefore essential. The hard and soft palates are oral cavity and oropharyngeal structures, respectively. They have different tissue compositions, and therefore, lesions occur with different frequencies at each site. The hard palate has the highest concentration of minor salivary glands in the upper aerodigestive tract and most tumours here are salivary in origin, whereas most tumours at the soft palate are epithelial in origin, i.e., squamous cell carcinomas, in line with other oropharyngeal subsites. The most common malignant tumours of the palate, after squamous cell carcinoma, are minor salivary gland tumours, predominantly adenoid cystic and mucoepidermoid carcinomas. These tumours have a propensity to spread perineurally; understanding the anatomy and imaging features of perineural spread is vital, as it can have significant implications for patient management and tumour resectability. When confronted with a palatal lump, it is important to consider the following: its location on the hard or soft palate; whether it is mucosal or submucosal; the frequently occurring lesions at that site; the most suitable imaging techniques (ultrasound, computed tomography, magnetic resonance imaging); whether there are typical imaging features for any of the common lesions; and whether there are aggressive features, such as bone erosion or perineural spread. This approach allows the radiologist to narrow the differential diagnosis and assist the clinicians with planning treatment. PMID- 27986265 TI - Imaging techniques used in the diagnostic workup of acute venous thromboembolic disease. AB - Early diagnosis is one of the most important factors affecting the prognosis of pulmonary embolism (PE); however, the clinical presentation of PE is often very unspecific and it can simulate other diseases. For these reasons, imaging tests, especially computed tomography angiography (CTA) of the pulmonary arteries, have become the keystone in the diagnostic workup of PE. The wide availability and high diagnostic performance of pulmonary CTA has led to an increase in the number of examinations done and a consequent increase in the population's exposure to radiation and iodinated contrast material. Thus, other techniques such as scintigraphy and venous ultrasonography of the lower limbs, although less accurate, continue to be used in certain circumstances, and optimized protocols have been developed for CTA to reduce the dose of radiation (by decreasing the kilovoltage) and the dose of contrast agents. We describe the technical characteristics and interpretation of the findings for each imaging technique used to diagnose PE and discuss their advantages and limitations; this knowledge will help the best technique to be chosen for each case. Finally, we comment on some data about the increased use of CTA, its clinical repercussions, its "overuse", and doubts about its cost-effectiveness. PMID- 27986266 TI - General dentists', pediatric dentists', and endodontists' diagnostic assessment and treatment strategies for deep carious lesions: A comparative analysis. AB - BACKGROUND: There is a large variation among clinicians when managing deep carious lesions (DCLs). The purpose of this study was to assess general dentists' (GDs), pediatric dentists' (PDs), and endodontists' (EDs) diagnostic methods, clinical decision-making considerations, treatment strategies, and knowledge, behavior, and attitudes related to the diagnosis and treatment of DCLs. METHODS: A total of 175 GDs, 511 PDs, and 377 EDs responded to a nationwide Web-based survey. RESULTS: Most EDs (68%) and GDs (47%) practiced complete caries removal. PDs (31%) were more likely than GDs (12%) and EDs (4%) to remove carious tissues partially. Dentin hardness was the most important diagnostic criterion used during caries excavation (GDs, 90%; PDs, 72%; EDs, 88%). Only 30% of GDs, 17% of PDs, and 90% of EDs used diagnostic tests (for example, a cold test) when assessing pupal health. A substantial percentage of respondents considered endodontic treatment as a choice for treating DCLs in asymptomatic teeth in young patients (GDs, 40%; PDs, 30%; EDs, 40%). GDs rarely used a rubber dam when treating these lesions. CONCLUSIONS: Most respondents practiced complete caries removal until hard dentin was felt, using hardness as the primary excavation criterion, and did not use pulp diagnostic tests routinely before making decisions about treatment of teeth with DCLs. PRACTICAL IMPLICATIONS: Efforts should be made to translate the growing body of evidence supporting the use of conservative caries removal criteria to preserve pulpal health and tooth structure integrity when managing DCLs. PMID- 27986267 TI - [Evaluation of the immune infiltrate in breast cancer]. AB - Tumour-infiltrating lymphocytes (TIL) are major components of the immune/"inflammatory" infiltrate found in tumour microenvironment. They reflect the intensity and the quality of the immune reaction to cancer. In breast cancer, TIL density and phenotypic profile have been demonstrated to be predictive of response to neoadjuvant treatment and of patient outcome. TIL density, currently the best-developed TIL-related biomarker, is defined as the percentage of tumour stroma surface occupied by TIL. The baseline TIL density of 50% and higher is associated with particularly high rates of pathological complete response to neoadjuvant therapy in triple negative and HER2+ breast cancer, as well as with significantly better recurrence-free and overall survival. Similar predictive and prognostic value has been demonstrated for the ratio between the numbers of CD8+ and FoxP3+ TIL. TIL density and the CD8+/FoxP3+ ratio are promising biomarkers in breast cancer, which could be used in tailoring of neoadjuvant and adjuvant systemic therapy and in selection of patients for different immunotherapy modalities. This article reviews elements of the immune response to cancer, methods of TIL analysis, evidence of TIL' prognostic and predictive value in the current breast cancer management as well as the perspectives for use of TIL' characteristics as biomarkers in breast cancer immunotherapy. PMID- 27986269 TI - Malleolar ulcers due to hidroxyurea treatment. PMID- 27986268 TI - [Incidence and risk factors for ifosfamide-related encephalopathy in sarcoma patients]. AB - CONTEXT: Ifosfamide remains one of the major cytotoxic drugs for sarcoma management. Ifosfamid-related encephalopathy (IRE) is a rare but severe adverse event, without clearly identified risk factors. METHOD: We have carried out a single-center, retrospective study to assess the occurrence and the risk factors for IRE after the two first cycles of chemotherapy. We have collected the data describing patients, biological data, tumors characteristics (histology, leptomeningeal metastasis) and ifosfamide administration modalities. RESULTS: From September 2008 to November 2013, we have identified 8 IRE out of 187 patients (4.2% [CI95%: 1.8-8.2]). The median age was 27 (0-78). Histologies were adult soft tissue sarcomas (78 patients), osteosarcoma (48), ewing sarcoma (41) and rhabdomyosarcoma (26). Most of factors were not associated with IRE. Only 8 patients have received aprepitant, none of them experienced IRE. Under univariate analysis, the risk factors for IRE were: PS>=2 (OR=9.52 [CI95%: 2.38-38.80]), albumin<=36g/L (OR=9.79 [CI95%: 1.19-80.26]), leptomeningeal metastasis (OR=13.20 [CI95%: 2.76-63.19]), 4 or 5 successive days of ifosfamide administration (OR=6.00 [CI95%: 1.40-25.60]). Under multivariate analysis, the risk factors for IE were: PS>=2 (OR=16.00 [IC95%: 2.80-67.00]), leptomeningial metastasis (OR=23.56 [IC95%: 2.01-456.80]) and 4 or 5 days of ifosfamide administration (OR=57.45 [IC95%: 1.66-35.00]). CONCLUSION: Ifosfamide administration must be given with caution in patients with poor performans status. A 4 to 5 days fractioned ifosfamide and leptomeningeal metastasis seems associated with increased risk for IRE, whatever the total administered dose. PMID- 27986270 TI - Is attendance at an ovarian cancer screening clinic a worry-reducing event? Findings from pre- to post-screening. AB - OBJECTIVE: Many studies have examined the relationship between worry and cancer screening. Due to methodological inconsistencies, results of these studies have varied and few conclusions can be made when generalizing across studies. The purpose of the current study was to better understand the worry-cancer screening relationship using a prospective research design. METHOD: 180 women enrolled in an annual ovarian cancer (OC) screening clinic completed surveys at three time points-pre-screening, day of screening, and post-screening-using three measures of cancer-specific worry. RESULTS: OC worry was highest in the weeks prior to screening and mere presentation at a screening clinic was associated with a significant worry decline. Observed elevations in worry following abnormal screening were not universal and varied by the instrument used to measure worry. CONCLUSIONS: In contrast to our hypotheses, it appears that mere presentation at a cancer screening clinic may be a worry-reducing event. Receipt of abnormal results was not necessarily associated with increased worry. PMID- 27986271 TI - Social determinants of health: integral to developmental risk assessment in congenital heart disease. PMID- 27986272 TI - Predictors of amputation in high-energy forefoot and midfoot injuries. AB - INTRODUCTION: High energy injuries to the midfoot and forefoot are highly morbid injury groups that are relatively unstudied in the literature. Patients sustaining injuries of this region are challenging to counsel at the time of injury because so little is known about the short and long term results of these injuries. The purpose of this study was to investigate injury specific factors that were predictive of amputation in patients sustaining high energy midfoot and forefoot injuries. PATIENTS AND METHODS: 137 patients with 146 injured feet [minimum of two fractures located in the forefoot and midfoot, excluding phalanges, talus, calcaneus, with a high energy mechanism]. RESULTS: 121 of 146 feet (83%) were treated operatively; 27 patients sustained 34 total surgical amputation events. 30-day amputation rate was 13.9% and 1-year amputation rate was 18.9%; 27 of 146 feet ultimately sustained amputation with 23 of 27 sustaining a below the knee amputation (BKA) and 17 of 23 (73.9%) received a BKA as their first amputation. Statistically significant predictors of amputation included the number of bones fractured in the foot (p=0.015), open injury to the plantar or dorsal surfaces of the foot, Gustilo grade, vascular injury, and complete loss of sensation to any surface of the foot (all p<0.001). Specific fracture patterns predictive of any amputation were fracture of all five metatarsals (p<0.001) and fracture of the first metatarsal (p=0.003). Presence of a dislocation or fracture of the distal tibia were not predictive of amputation. Midterm patient-reported-outcomes (N=51) demonstrated no difference in physical function for patients with and without amputations. CONCLUSIONS: High-energy forefoot and midfoot injuries are associated with a high degree of morbidity; 1/5th of patients sustaining these injuries proceeded to amputation within 1year. Injury characteristics can be used to counsel patients regarding severity and amputation risk. PMID- 27986274 TI - Discussion. PMID- 27986273 TI - Traumatic pulmonary pseudocyst: An underreported entity. AB - BACKGROUND: Traumatic pulmonary pseudocysts (TPP) are underreported cavitary lesions of the pulmonary parenchyma that can develop following blunt chest trauma. Although the occurrence of traumatic pulmonary pseudocyst is rare, this condition should be considered in the differential diagnosis of any cavitary lesion. Awareness of this injury and its clinical significance is important for successful management in order to avoid medical errors in the course of treatment. METHODS: A literature search was conducted through Medline using the key phrases "traumatic pulmonary pseudocyst" and "traumatic pneumatocele." Relevant articles, especially those with focus on diagnosis and management of traumatic pneumatocele in adults, were selected. Due to the scarcity of literature and lack of Level I evidence on this subject, studies published in any year were considered. RESULTS: A search of "traumatic pulmonary pseudocyst" and "traumatic pneumatocele" yielded 114 studies. Most of these were excluded based on inclusion and exclusion criteria. Thirty-five articles were reviewed. The majority of these were individual case studies; only eight articles were considered large case studies (greater than eight patients). CONCLUSION: Traumatic pulmonary pseudocysts are lesions that occur secondary to blunt chest trauma. Diagnosis is based on a history of trauma and appearance of a cystic lesion on CT. Accurate diagnosis of traumatic pulmonary pseudocyst is imperative to achieve successful outcomes. Failure to do so may lead to unnecessary procedures and complications. PMID- 27986275 TI - Calpain inhibition modulates glycogen synthase kinase 3beta pathways in ischemic myocardium: A proteomic and mechanistic analysis. AB - BACKGROUND: Calpain inhibition has an enhancing effect on myocardial perfusion and improves myocardial density by inhibiting glycogen synthase kinase 3beta (GSK 3beta) and up-regulating downstream signaling pathways, including the insulin/PI3K and WNT/beta-catenin pathways, in a pig model of chronic myocardial ischemia in the setting of metabolic syndrome. METHODS: Pigs were fed a high-fat diet for 4 weeks, then underwent placement of an ameroid constrictor to the left circumflex artery. Three weeks later, the animals received no drug (high cholesterol controls [HCC]), a high-dose calpain inhibitor (HCI), a low-dose calpain inhibitor (LCI), or a GSK-3beta inhibitor (GSK-3betaI). The diets and drug regimens were continued for 5 weeks and the myocardial tissue was harvested. RESULTS: Calpain and GSK-3beta inhibition caused an increase in myocardial perfusion ratios at rest and during pacing compared with controls. Pigs in the LCI and HCI groups had increased vessel density in the ischemic myocardium, and pigs in the GSK-3betaI group had increased vessel density in the ischemic and nonischemic myocardium compared with the HCC group. Calpain inhibition modulates proteins involved in the insulin/PI3K and WNT/beta-catenin pathways. Quantitative proteomics revealed that calpain and GSK-3beta inhibition significantly modulated the expression of proteins enriched in cytoskeletal regulation, metabolism, respiration, and calcium-binding pathways. CONCLUSIONS: In the setting of metabolic syndrome, calpain or GSK-3beta inhibition increases vessel density in both ischemic and nonischemic myocardial tissue. Calpain inhibition may exert these effects through the inhibition of GSK-3beta and up-regulation of downstream signaling pathways, including the insulin/PI3K and WNT/beta-catenin pathways. PMID- 27986276 TI - Assessment of the variability in the dimensions of the intact pelvic canal in South Africans: A pilot study. AB - Cephalopelvic disproportion is common among Africans and is a major cause of maternal and perinatal mortality and morbidity. As the dimensions of the pelvis may vary between populations and according to stature and age, they need to be considered during childbirth and also in the planning and performance of pelvic and perineal procedures. The aim of this study was to assess the possible variations in the dimensions of the intact pelvic canal in South Africans and their implications. Eighty intact cadaver pelves, belonging to 40 white South Africans (20 males and 20 females) and 40 black South Africans (20 males and 20 females) were used for both metric and geometric morphometric analyses. Pelvic inlet shapes did not differ significantly between groups but pelvic inlet and midpelvic dimensions were the greatest in white South Africans and females. The pubic symphyseal length was the greatest in white males and the smallest in black females, resulting in a smaller pelvic cavity anteriorly than for white females. Pelvic outlet shapes varied significantly between sexes in white South Africans and between white and black males. Females presented with the greatest dimensions. Black South African females presented with an elongated anteroposterior outlet diameter. Certain transverse pelvic diameters correlated positively with age in white males and with height in females. In planning childbirth options, the smaller pelvic inlet of black females and stature dependent diameters should be considered. Pelvic and perineal surgery may be technically more challenging because of smaller pelvic dimensions in black South Africans, especially in males. PMID- 27986277 TI - Relationship between foot pain, muscle strength and size: a systematic review. AB - BACKGROUND: Foot pain is common and disabling and thought to be associated with muscle weakness. Understanding the relationship between pain and weakness may help identify effective treatment targets. OBJECTIVES: To conduct a systematic review to evaluate the relationship between foot pain and foot muscle weakness, or muscle size as a proxy for weakness. DATA SOURCES: Electronic databases and reference lists were searched for all years to April 2015. ELIGIBILITY CRITERIA: Full-text articles were retrieved based on the question 'Does the study evaluate an association between foot pain and foot muscle weakness or size?' DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened eligible studies, extracted data and completed a methodological rating. RESULTS: Eight studies were identified evaluating the relationship between foot pain and foot muscle strength (n=6) or size (n=2). Four studies reported a significant relationship between pain and toe flexor force. One study reported a significant relationship between heel pain and reduced forefoot muscle size. One study reported an inconsistent association depending on measurement technique. One study reported no association between pain and hindfoot muscle size. One study reported no association between low to moderate pain and toe flexion force. LIMITATIONS: Due to data heterogeneity, no data were pooled for meta-analysis. CONCLUSION: There is evidence of a significant association between foot pain and muscle weakness when foot pain is of high intensity and primarily measured by toe flexion force. However there is inconsistent evidence that lower intensity foot pain is associated with other measures of foot muscle weakness or size. Systematic Research Registry ID reviewregistry166. PMID- 27986278 TI - Preparation, characterization and biological activity of C8-substituted cytokinins. AB - Naturally occurring cytokinins are adenine-based plant hormones. Although, the effect of various substituents at positions N1, C2, N3, N6, N7, or N9 on the biological activity of cytokinins has been studied, the C8-substituted compounds have received little attention. Here, we report the synthesis and in vitro biological testing of thirty-one cytokinin derivatives substituted at the C8 position of the adenine skeleton and twenty-seven compounds which served as their N9-tetrahydropyranyl protected precursors. The cytokinin activity of all the compounds was determined in classical cytokinin biotests (wheat leaf senescence, Amaranthus and tobacco callus assays). With some exceptions, the compounds with a N9-tetrahydropyranyl group were generally less active than their de-protected analogs. The latter were further tested for their ability to activate the Arabidopsis cytokinin receptors AHK3 and CRE1/AHK4 in bacterial receptor activation assays. Using this approach, we identified derivatives bearing short aliphatic chains and retaining high cytokinin activity. Such compounds are suitable candidates for fluorescence labeling or as protein-affinity ligands. We further found that some C8-substituted cytokinins exhibited no or lower cytotoxicity toward tobacco cells when compared to their parent compound. Therefore, we also present and discuss the cytotoxicity of all the compounds against three normal human cell lines. PMID- 27986279 TI - From CARs to TRUCKs and Beyond: Safely en Route to Adoptive T-cell Therapy for Cancer. PMID- 27986280 TI - Reliability and mode of failure of bonded monolithic and multilayer ceramics. AB - OBJECTIVES: To evaluate the reliability of monolithic and multilayer ceramic structures used in the CAD-on technique (Ivoclar), and the mode of failure produced in ceramic structures bonded to a dentin analog material (NEMA-G10). METHODS: Ceramic specimens were fabricated as follows (n=30): CAD-on- trilayer structure (IPS e.max ZirCAD/IPS e.max Crystall./Connect/IPS e.max CAD); YLD- bilayer structure (IPS e.max ZirCAD/IPS e.max Ceram); LDC- monolithic structure (IPS e.max CAD); and YZW- monolithic structure (Zenostar Zr Translucent). All ceramic specimens were bonded to G10 and subjected to compressive load in 37 degrees C distilled water until the sound of the first crack, monitored acoustically. Failure load (Lf) values were recorded (N) and statistically analyzed using Weibull distribution, Kruskal-Wallis test, and Student-Newman Keuls test (alpha=0.05). RESULTS: Lf values of CAD-on and YZW structures were statistically similar (p=0.917), but higher than YLD and LDC (p<0.01). Weibull modulus (m) values were statistically similar for all experimental groups. Monolithic structures (LDC and YZW) failed from radial cracks. Failures in the CAD-on and YLD groups showed, predominantly, both radial and cone cracks. SIGNIFICANCE: Monolithic zirconia (YZW) and CAD-on structures showed similar failure resistance and reliability, but a different fracture behavior. PMID- 27986282 TI - Letter to the Editor: "Unaltered L-arginine/NO pathway in a MELAS patient: Is mitochondrial NO synthase involved in the MELAS syndrome?" PMID- 27986281 TI - Extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest: A multicentre experience. AB - AIM: To describe the ECPR experience of two Australian ECMO centres, with regards to survival and neurological outcome, their predictors and complications. METHODS: Retrospective observational study of prospectively collected data on all patients who underwent extracorporeal cardiopulmonary resuscitation (ECPR) at two academic ECMO referral centres in Sydney, Australia. MEASUREMENTS AND MAIN RESULTS: Thirty-seven patients underwent ECPR, 25 (68%) were for in-hospital cardiac arrests. Median age was 54 (IQR 47-58), 27 (73%) were male. Initial rhythm was ventricular fibrillation or pulseless ventricular tachycardia in 20 patients (54%), pulseless electrical activity (n=14, 38%), and asystole (n=3, 8%). 27 (73%) arrests were witnessed and 30 (81%) patients received bystander CPR. Median time from arrest to initiation of ECMO flow was 45min (IQR 30-70), and the median time on ECMO was 3days (IQR 1-6). Angiography was performed in 54% of patients, and 27% required subsequent coronary intervention (stenting or balloon angioplasty 24%). A total of 13 patients (35%) survived to hospital discharge (IHCA 33% vs. OHCA 37%). All survivors were discharged with favourable neurological outcome (Cerebral Performance Category 1 or 2). Pre-ECMO lactate level was predictive of mortality OR 1.35 (1.06-1.73, p=0.016). CONCLUSIONS: In selected patients with refractory cardiac arrest, ECPR may provide temporary support as a bridge to intervention or recovery. We report favourable survival and neurological outcomes in one third of patients and pre-ECMO lactate levels predictive of mortality. Further studies are required to determine optimum selection criteria for ECPR. PMID- 27986284 TI - Spontaneous coronary artery dissection and Takotsubo's cardiomyopathy: A random association? PMID- 27986283 TI - Galectin-3 and atrial fibrillation. PMID- 27986285 TI - Methods for monitoring Ca2+ and ion channels in the lysosome. AB - Lysosomes and lysosome-related organelles are emerging as intracellular Ca2+ stores and play important roles in a variety of membrane trafficking processes, including endocytosis, exocytosis, phagocytosis and autophagy. Impairment of lysosomal Ca2+ homeostasis and membrane trafficking has been implicated in many human diseases such as lysosomal storage diseases (LSDs), neurodegeneration, myopathy and cancer. Lysosomal membrane proteins, in particular ion channels, are crucial for lysosomal Ca2+ signaling. Compared with ion channels in the plasma membrane, lysosomal ion channels and their roles in lysosomal Ca2+ signaling are less understood, largely due to their intracellular localization and the lack of feasible functional assays directly applied to the native environment. Recent advances in biomedical methodology have made it possible to directly investigate ion channels in the lysosomal membrane. In this review, we provide a summary of the newly developed methods for monitoring lysosomal Ca2+ and ion channels, as well as the recent discovery of lysosomal ion channels and their significances in intracellular Ca2+ signaling. These new techniques will expand our research scope and our understanding of the nature of lysosomes and lysosome-related diseases. PMID- 27986286 TI - Magnetic porous carbon derived from a bimetallic metal-organic framework for magnetic solid-phase extraction of organochlorine pesticides from drinking and environmental water samples. AB - In this work, magnetic porous carbon material derived from a bimetallic metal organic framework was explored as an adsorbent for magnetic solid-phase extraction of organochlorine pesticides (OCPs). The synthesized porous carbon possessed a high specific surface area and magnetization saturation. The OCPs in the samples were quantified using gas chromatography coupled with a triple quadrupole mass spectrometer. The experimental parameters, including the desorption solvent and conditions, amount of adsorbent, extraction time, extraction temperature, and ionic strength of the solution, were optimized. Under optimal conditions, the developed method displayed good linearity (r>0.99) within the concentration range of 2-500ngL-1. Low limits of detection (0.39-0.70ngL-1, signal-to-noise ratio=3:1) and limits of quantification (1.45-2.0ngL-1, signal-to noise ratio=10:1) as well as good precision (relative standard deviation<10%) were also obtained. The developed method was applied in the analysis of OCPs in drinking and environmental water samples. PMID- 27986287 TI - Membrane-based sample preparation for ion chromatography-Techniques, instrumental configurations and applications. AB - Sample preparation is the bottleneck of many analytical methods, including ion chromatography (IC). Procedures based on the application of membranes are important, yet not well appreciated means for clean-up and analyte preconcentration of liquid samples. Filtration, ultrafiltration, the variety of dialysis techniques, i.e. passive dialysis, Donnan dialysis and electrodialysis, as well as gas-diffusion are being reviewed here with respect to their application in combination with IC. Instrumental aspects including hardware requirements, configuration of membrane separation units and membrane characteristics are presented. Operation in batch and flow-through mode is described with emphasis on the latter to in-line coupling with IC, permitting fully automated operation. Attention is also drawn to dialysis probes and microdialysis both providing options for in-situ measurements with inherent selective sampling of analytes and sample preparation. The respective features of the various techniques are outlined with respect to the possibilities of matrix removal and selectivity enhancement. In this article, we provide examples of application of the diverse membrane separation techniques and discuss the benefits and limitations thereof. PMID- 27986288 TI - A practical approach for predicting retention time shifts due to pressure and temperature gradients in ultra-high-pressure liquid chromatography. AB - Large pressure gradients are generated in ultra-high-pressure liquid chromatography (UHPLC) using sub-2MUm particles causing significant temperature gradients over the column due to viscous heating. These pressure and temperature gradients affect retention and ultimately result in important selectivity shifts. In this study, we developed an approach for predicting the retention time shifts due to these gradients. The approach is presented as a step-by-step procedure and it is based on empirical linear relationships describing how retention varies as a function of temperature and pressure and how the average column temperature increases with the flow rate. It requires only four experiments on standard equipment, is based on straightforward calculations, and is therefore easy to use in method development. The approach was rigorously validated against experimental data obtained with a quality control method for the active pharmaceutical ingredient omeprazole. The accuracy of retention time predictions was very good with relative errors always less than 1% and in many cases around 0.5% (n=32). Selectivity shifts observed between omeprazole and the related impurities when changing the flow rate could also be accurately predicted resulting in good estimates of the resolution between critical peak pairs. The approximations which the presented approach are based on were all justified. The retention factor as a function of pressure and temperature was studied in an experimental design while the temperature distribution in the column was obtained by solving the fundamental heat and mass balance equations for the different experimental conditions. We strongly believe that this approach is sufficiently accurate and experimentally feasible for this separation to be a valuable tool when developing a UHPLC method. After further validation with other separation systems, it could become a useful approach in UHPLC method development, especially in the pharmaceutical industry where demands are high for robustness and regulatory oversight. PMID- 27986289 TI - Characterisation of chemical components for identifying historical Chinese textile dyes by ultra high performance liquid chromatography - photodiode array - electrospray ionisation mass spectrometer. AB - This research makes the first attempt to apply Ultra High Performance Liquid Chromatography (UHPLC) coupled to both Photodiode Array detection (PDA) and Electrospray Ionisation Mass Spectrometer (ESI-MS) to the chemical characterisation of common textile dyes in ancient China. Three different extraction methods, respectively involving dimethyl sulfoxide (DMSO)-oxalic acid, DMSO and hydrochloric acid, are unprecedentedly applied together to achieve an in depth understanding of the chemical composition of these dyes. The first LC-PDA MS database of the chemical composition of common dyes in ancient China has been established. The phenomena of esterification and isomerisation of the dye constituents of gallnut, gardenia and saffron, and the dye composition of acorn cup dyed silk are clarified for the first time. 6-Hydroxyrubiadin and its glycosides are first reported on a dyed sample with Rubia cordifolia from China. UHPLC-PDA-ESI-MS with a C18 BEH shield column shows significant advantages in the separation and identification of similar dye constituents, particularly in the cases of analysing pagoda bud and turmeric dyed sample extracts. PMID- 27986290 TI - Pressurised liquid extraction and liquid chromatography-high resolution mass spectrometry to determine high-intensity sweeteners in fish samples. AB - An analytical method based on pressurised liquid extraction (PLE) followed by liquid chromatography-high resolution mass spectrometry (Orbitrap) was developed for the simultaneous determination of ten high-intensity sweeteners in fish samples. As the method was developed, the different PLE parameters were optimised and different clean-up strategies were evaluated, of which in-cell clean-up using alumina and on-cell clean-up with hexane were the most effective. PLE recoveries were between 43% and 94%. The method quantification limits were between 12.5ngg-1 dry weight (d.w.) and 250ngg-1 (d.w.) and the method detection limits between 2.5ngg-1 (d.w.) and 125ngg-1 (d.w.). Intra-day precision and inter-day precision were below 16% and 25%, respectively. Fish samples from different species were analysed and, saccharin was found below its method quantification limit in the species Scomber scombrus (Atlantic mackerel). PMID- 27986291 TI - Mechanisms for Improved Hygroscopicity of L-Arginine Valproate Revealed by X-Ray Single Crystal Structure Analysis. AB - Valproic acid is widely used as an antiepileptic agent. Valproic acid is in liquid phase while sodium valproate is in solid phase at room temperature. Sodium valproate is hard to manufacture because of its hygroscopic and deliquescent properties. To improve these, cocrystal and salt screening for valproic acid was employed in this study. Two solid salt forms, l-arginine valproate and l-lysine valproate, were obtained and characterized. By using dynamic vapor sorption method, the critical relative humidity of sodium valproate, l-arginine valproate, and l-lysine valproate were measured. Critical relative humidity of sodium valproate was 40%, of l-lysine valproate was 60%, and of l-arginine valproate was 70%. Single-crystal X-ray structure determination of l-arginine valproate was employed. l-Lysine valproate was of low diffraction quality, and l-arginine valproate formed a 1:1 salt. Crystal l-arginine valproate has a disorder in the methylene carbon chain that creates 2 conformations. The carboxylate group of valproic acid is connected to the amino group of l-arginine. Crystalline morphologies were calculated from its crystal structure. Adsorption of water molecules to crystal facets was simulated by Material Studio. When comparing adsorption energy per site of these salts, sodium valproate is more capable of adsorption of water molecule than l-arginine valproate. PMID- 27986292 TI - Molecular Dynamics Simulation of Amorphous Hydroxypropylmethylcellulose and Its Mixtures With Felodipine and Water. AB - Understanding drug-polymer molecular interactions, their miscibility, supersaturation potential, and the effects of water uptake may be invaluable for selecting amorphous polymer dispersions that can maximize the oral bioavailability of poorly water-soluble drugs. Molecular dynamics simulations were performed using a model for hydroxypropylmethylcellulose (HPMC) resembling the substitution patterns found experimentally. HPMC at low and high water contents (0.9%-23.0% wt/wt) and mixtures with a hydrophobic drug, felodipine (FEL), were constructed. Tg values and densities after ~30 ns aging at 298 K were close to published results. Except for hydrogen bonds (HBs) between the 5-O- and a 3-OH group in a neighboring repeat unit, HPMC oxygen atoms have a low HB probability (p < 0.1) perhaps due to shielding by surrounding substituents. Water molecules tend to be isolated at low water content while clusters were prevalent at >=10.7% water. The Flory-Huggins FEL-HPMC interaction parameter (-0.20 +/- 0.07) predicts complete miscibility at all HPMC compositions, in agreement with experiments. However, HBs between the FEL-N-H and HPMC favoring miscibility are disrupted with increasing water. Apparent diffusion coefficients versus water content were generated for water and FEL and a theory for the non-Einsteinian nature of water diffusion is proposed. PMID- 27986293 TI - NeuroLSD1: Splicing-Generated Epigenetic Enhancer of Neuroplasticity. AB - The acquisition and maintenance of the specific neuronal functions underlying learning, memory, and emotion require transduction of environmental stimuli into remodeling of neuronal circuitry. This process occurs via induction of plasticity related transcriptional programs. The epigenetic enzyme lysine-specific demethylase-1 (LSD1), also known as lysine demethylase 1A (KDM1A), and its neurospecific splicing variant neuroLSD1 have been implicated in this process through an antagonistic mechanism. Specifically, LSD1/neuroLSD1 are involved in the negative and positive regulation of activity-evoked transcription of immediate early genes (IEGs) impacting memory formation and emotional behavior. Remarkably, the splicing process generating neuroLSD1 is homeostatically modulated by environmental contingencies, further implicating the LSD1/neuroLSD1 dual system as a modifier of information processing in the brain. PMID- 27986294 TI - Monitoring Demands for Executive Control: Shared Functions between Human and Nonhuman Primates. AB - Fifteen years ago, an influential model proposed that the human dorsal anterior cingulate cortex (dACC) detects conflict and induces adaptive control of behavior. Over the years support for this model has been mixed, in particular due to divergent findings in human versus nonhuman primates. We here review recent findings that suggest greater commonalities across species. These include equivalent behavioral consequences of conflict and similar neuronal signals in the dACC, but also a common failure of dACC lesions to reliably abolish conflict driven behavior. We conclude that conflict might be one among many drivers of adjustments in executive control and that the ACC might be just one component of overlapping distributed systems involved in context-dependent learning and behavioral control. PMID- 27986295 TI - Emission of volatile organic compounds from domestic coal stove with the actual alternation of flaming and smoldering combustion processes. AB - Volatile organic compounds (VOCs) emissions from the chimney of a prevailing domestic stove fuelled with raw bituminous coal were measured under flaming and smoldering combustion processes in a farmer's house. The results indicated that the concentrations of VOCs quickly increased after the coal loading and achieved their peak values in a few minutes. The peak concentrations of the VOCs under the smoldering combustion process were significantly higher than those under the flaming combustion process. Alkanes accounted for the largest proportion (43.05%) under the smoldering combustion, followed by aromatics (28.86%), alkenes (21.91%), carbonyls (5.81%) and acetylene (0.37%). The emission factors of the total VOCs under the smoldering combustion processes (5402.9 +/- 2031.8 mg kg-1) were nearly one order of magnitude greater than those under the flaming combustion processes (559.2 +/- 385.9 mg kg-1). Based on the VOCs emission factors obtained in this study and the regional domestic coal consumption, the total VOCs emissions from domestic coal stoves was roughly estimated to be 1.25 * 108 kg a-1 in the Beijing-Tianjin-Hebei region. PMID- 27986296 TI - Effects of a mixed media education intervention program on increasing knowledge, attitude, and compliance with standard precautions among nursing students: A randomized controlled trial. AB - BACKGROUND: Standard precautions (SPs) are considered fundamental protective measures to manage health care-associated infections and to reduce occupational health hazards. This study intended to assess the effectiveness of a mixed media education intervention to enhance nursing students' knowledge, attitude, and compliance with SPs. METHOD: A randomized controlled trial with 84 nursing students was conducted in a teaching hospital in Hubei, China. The intervention group (n = 42) attended 3 biweekly mixed media education sessions, consisting of lectures, videos, role-play, and feedback with 15-20 minutes of individual online supervision and feedback sessions following each class. The control group learned the same material through self-directed readings. Pre- and posttest assessments of knowledge, attitudes, and compliance were assessed with the Knowledge with Standard Precautions Questionnaire, Attitude with Standard Precautions Scale, and the Compliance with Standard Precautions Scale, respectively. The Standard Bacterial Colony Index was used to assess handwashing effectiveness. RESULTS: At 6-week follow-up, performance on the Knowledge with Standard Precautions Questionnaire, Attitude with Standard Precautions Scale, and Compliance with Standard Precautions Scale were significantly improved in the intervention group compared with the control group (P < .01). The hand hygiene standard in the intervention group (38 passed) outperformed the control group (23 passed) (P < .01). CONCLUSIONS: A mixed media education intervention is effective in improving knowledge, attitude, and compliance with SPs. PMID- 27986297 TI - Triple synchronous gastric tumors: A rare combination diffuse adenocarcinoma, B cell MALT lymphoma and large cell neuroendocrine carcinoma. PMID- 27986298 TI - Long-term monitoring study of beached seabirds shows that chronic oil pollution in the southern North Sea has almost halted. AB - Trends in oil rates of beached seabirds reflect temporal and spatial patterns in chronic oil pollution at sea. We analysed a long-term dataset of systematic beached bird surveys along the Belgian North Sea coast during 1962-2015, where extreme high oil contamination rates and consequently high mortality rates of seabirds during the 1960s used to coincide with intensive ship traffic. In the 1960s, >90% of all swimming seabirds that washed ashore were contaminated with oil and estimated oil-induced mortality of seabirds was probably several times higher than natural mortality. More than 50years later oil rates of seabirds have dropped to historically low levels while shipping is still very intense, indicating that chronic oil pollution has significantly declined. The declining trend is discussed in the light of a series of legislative measures that were enacted in the North Sea region to reduce oil pollution. PMID- 27986299 TI - Assessment of phytoplankton and environmental variables for water quality and trophic state classification in the Gemlik Gulf, Marmara Sea (Turkey). AB - Phytoplankton assemblages related to environmental factors and ecological status of the Gemlik Gulf were investigated between June 2010 and May 2011. A total 155 phytoplankton species were detected and 6 taxa (Amphisolenia laticincta, Archaeperidinium minutum, Cochlodinium sp., Gynogonadinium aequatoriale, Heterocapsa rotundata and Metaphalacroma sp.) were new records for the Turkish Seas. The lowest and highest total phytoplankton abundance among the sampling units (depths) was recorded in April 2011 (7.4*103cellsL-1) and July 2010 (251.8*103cellsL-1). Local small patches of visible red tide events were detected especially in the gulf, although a phytoplankton bloom was not observed. The water column was well stratified in the early autumn and well mixed in the early spring according to stratification index values. Surface nutrient concentrations increased especially at stations located inside of the gulf. The limiting effect of silicate was observed in early, mid-summer and early winter periods while the nitrogen was the limiting nutrient in the gulf during the whole sampling period. In the Gulf, low water quality-high mesotrophic and bad water quality-eutrophic status, high quality and low trophic level were generally detected according to Chl a, dissolved oxygen and trophic index. However, indices developed to determine the trophic level and water quality of the Mediterranean Sea can give unexpected results about the current environmental quality status when it is applied to the Marmara Sea which has limited photic zone by the halocline pycnocline and thermocline. PMID- 27986300 TI - Mercury concentrations in dusky grouper Epinephelus marginatus in littoral and neritic habitats along the Southern Brazilian coast. AB - Our study incorporated a comprehensive suite of parameters (i.e., body size, age, diet and trophic position) to investigate mercury concentration in dusky groupers Epinephelus marginatus. This study was carried out in rocky bottoms in littoral and neritic habitats along the Southern Brazilian coast. We also determined spatial variation in mercury concentrations in individuals inhabiting both zones, which may provide insights into how dietary differences or potential pollution sources affect bioaccumulation. A total of 244 dusky groupers was analyzed to determine total mercury concentrations. Our study revealed that when considering similar body sizes, individuals inhabiting littoral rocky habitats had higher concentrations of mercury probably due to proximity to pollution sources associated with human activities in the estuary and its drainage basin. Furthermore, large individuals (>650mm and >8years old) showed mercury contamination levels that are potentially harmful for this endangered fish species and above the acceptable limits for human consumption. PMID- 27986302 TI - Combined effects of temperature and copper and S-metolachlor on embryo-larval development of the Pacific oyster, Crassostrea gigas. AB - This study evaluates the combined effects of two contaminants (copper and a herbicide S-metolachlor) and temperature on the early life stages of the Pacific oyster Crasssotrea gigas, which is native to Arcachon Bay (southwest France). The responses of D-larvae, obtained from wild and cultivated oysters, were investigated for one year during the oyster breeding period at different sampling sites and compared with the response of D-larvae from a commercial hatchery. Embryotoxicity was measured by considering the percentage of abnormal D-shaped larvae. Normal development of embryos occurred only from 22 degrees C to 26 degrees C. There were synergistic effects of copper at low and high temperatures. Native oysters appear particularly sensitive to an increase in water temperature, suggesting a future increase in the percentage of larval abnormalities as a result of global climate change. Hatchery oysters represent a good alternative model for studying the effects of both pollutants and climate change stressors. PMID- 27986303 TI - Situating Arab-Israeli artisanal fishermen's perceptions of marine litter in a socio-institutional and socio-cultural context. AB - Understanding the mental constructs underlying people's social responses, decisions and behaviors is crucial to defining the governance challenges faced in dealing with marine anthropogenic litter. Using interactive governance theory, this study provides qualitative insights into how a small group of Arab-Israeli artisanal fishermen perceive marine litter and its impact (system to be governed) in the context of the socio-institutional structures (governing system) which manage waste and aim to protect the surrounding environment. It demonstrates that, until the relationships between local people and the various governing institutions are transformed, there is little hope for citizen cooperation in reducing marine litter long-term in the case-study site. More generally, underlying narratives and politics playing out at a local level need to be understood in order to identify which interventions are likely to be effective and which are not. An intervention checklist to assess the potential effectiveness of a marine litter intervention is proposed. PMID- 27986305 TI - In response to the recent original research article: Nose R. Optical coherence tomography analysis of hydrofluoric acid decontamination of human cornea by mannitol solution. Burns In press, Corrected proof, Available online 05 September 2016. PMID- 27986304 TI - Kinetic analysis of changes in T- and B-lymphocytes after anti-CD20 treatment in renal pathology. AB - INTRODUCTION: The main objective of this study is to describe qualitatively and quantitatively the different immune lymphocyte phenotypes of patients with renal disease after treatment with anti-CD20. MATERIAL AND METHODS: Two cohorts of transplanted and autoimmune kidney patients were compared: (1) Those who began treatment with Rituximab, matched (for sex, age and general clinical parameters) with (2) Non-treated control kidney patients. Different analyses were performed: (A) B-lymphocyte subpopulations; (B) T-cell subpopulations; (C) serum levels of BAFF, APRIL, Rituximab and anti-Rituximab; (D) rs396991 polymorphism of CD16a and at different time points for each type of analysis: (i) at baseline, (ii) day 15, (iii) at three and (iv) six months post-antiCD20. RESULTS: (A) A depletion of all B cell subsets analysed was observed preferentially decreasing the CD40+memory B cells, switched memory cells and plasmablasts. (B) A significant decreased percentage of CD4+T-lymphocytes was observed. A significant decrease of the percentage of memory T-cells and an increase in naive T-cells was also observed. (C) A significant increase for APRIL was observed, as well as a positive correlation between the APRIL levels, and the differential of B-cells. (D) The presence of CD16a Valine-variant induced greater changes in the variations of total T-cell and T-naive subpopulations. CONCLUSION: Our results highlight that the treatment of renal disease with Rituximab affects T-cells, particularly naive/memory balance, while APRIL could be also a secondary marker of this treatment. The sequential analysis of phenotypic alterations of B- and T-cells could help patient management, although further studies to identify periods of remission or clinical relapse are warranted. PMID- 27986306 TI - Re: Re: Tattoos: could they be used to advantage as a medical alert in oral and maxillofacial surgery? PMID- 27986307 TI - Diameter of alveolar antral artery in the lateral sinus wall: study of related factors. AB - To identify the variables that influence the diameter of the artery in the lateral sinus wall, we studied 240 sinuses, focusing on sex, pattern of tooth loss, type of residual crest, thickness of the lateral wall, height and width of the ridge, and width of the sinus. PMID- 27986308 TI - Corrigendum to "The vapor-phase multi-stage CMD test for characterizing contaminant mass discharge associated with VOC sources in the vadose zone: Application to three sites in different lifecycle stages of SVE operations" [J. Contam. Hydrol. 179 (2015) 55-64]. PMID- 27986309 TI - Use of the cell salvage for re-infusion of autologous blood retrieved vaginally in a case of major postpartum haemorrhage. PMID- 27986310 TI - Early-life income inequality and adolescent health and well-being. AB - A prevailing hypothesis about the association between income inequality and poor health is that inequality intensifies social hierarchies, increases stress, erodes social and material resources that support health, and subsequently harms health. However, the evidence in support of this hypothesis is limited by cross sectional, ecological studies and a scarcity of developmental studies. To address this limitation, we used pooled, multilevel data from the Health Behaviour in School-aged Children study to examine lagged, cumulative, and trajectory associations between early-life income inequality and adolescent health and well being. Psychosomatic symptoms and life satisfaction were assessed in surveys of 11- to 15-year-olds in 40 countries between 1994 and 2014. We linked these data to national Gini indices of income inequality for every life year from 1979 to 2014. The results showed that exposure to income inequality from 0 to 4 years predicted psychosomatic symptoms and lower life satisfaction in females after controlling lifetime mean income inequality, national per capita income, family affluence, age, and cohort and period effects. The cumulative income inequality exposure in infancy and childhood (i.e., average Gini index from birth to age 10) related to lower life satisfaction in female adolescents but not to symptoms. Finally, individual trajectories in early-life inequality (i.e., linear slopes in Gini indices from birth to 10 years) related to fewer symptoms and higher life satisfaction in females, indicating that earlier exposures mattered more to predicting health and wellbeing. No such associations with early-life income inequality were found in males. These results help to establish the antecedent consequence conditions in the association between income inequality and health and suggest that both the magnitude and timing of income inequality in early life have developmental consequences that manifest in reduced health and well-being in adolescent girls. PMID- 27986311 TI - Lignocellulose-degrading enzymes, free-radical transformations during composting of lignocellulosic waste and biothermal phases in small-scale reactors. AB - Environmentally friendly strategies of waste management are both part of legal solutions currently in place and a focus of interest worldwide. Large-scale composting plants are set up across various regions while home composting is becoming increasingly popular. A variety of microbial groups are successively at work during composting and enzymatic activities detected in the composting mass fluctuate accordingly. Changes in the activities of oxidoreductases and hydrolases, i.e. glucose oxidase, horseradish peroxidase, lignin peroxidase, laccase, xylanase, superoxide dismutase and keratinase, low-molecular weight compounds, i.e. methoxyphenolic and hydroxyphenolic compounds, and the relative level of superoxide radicals and glucose were determined periodically in water extracts of composts to investigate the process of biochemical transformations of ligninocellulose in relation to biothermal phases and to identify a potential priming effect in two composts containing different ratios of lignocellulosic waste and chicken feathers. Composting was conducted for 30weeks. An important aim of the study was to demonstrate that a positive priming effect was induced during composting of a variety of lignocellulosic waste types using native keratin (chicken feathers) as a source of N. The effect was more evident in compost containing grass, which was related to a more rapid depletion of easily available sources of C and energy (glucose) during composting. Ligninolytic enzymes known to biodegrade recalcitrant organic matter were induced in subsequent biothermal phases of composting. Compost I enriched with grass (pine bark, grass, sawdust and chicken feathers) exhibited a higher enzymatic activity than compost II which did not contain any grass but which had a greater number of hardly-degradable components (pine bark, wheat straw, sawdust, chicken feathers). Similar observations were made for the concentrations of low-molecular weight compounds. The enzymes activities and concentration of low-molecular weight compounds listed above can be used to estimate the biodegradation of lignocellulose during composting. PMID- 27986312 TI - Suspended sediment in a high-Arctic river: An appraisal of flux estimation methods. AB - Quantifying fluxes of water, sediment and dissolved compounds through Arctic rivers is important for linking the glacial, terrestrial and marine ecosystems and to quantify the impact of a warming climate. The quantification of fluxes is not trivial. This study uses a 8-years data set (2005-2012) of daily measurements from the high-Artic Zackenberg River in Northeast Greenland to estimate annual suspended sediment fluxes based on four commonly used methods: M1) is the discharge weighted mean and uses direct measurements, while M2-M4) are one uncorrected and two bias corrected rating curves extrapolating a continuous concentration trace from measured values. All methods are tested on complete and reduced datasets. The average annual runoff in the period 2005-2012 was 190+/ 25mio.m3y-1. The different estimation methods gave a range of average annual suspended sediment fluxes between 43,000+/-10,000ty-1 and 61,000+/-16,000ty-1. Extreme events with high discharges had a mean duration of 1day. The average suspended sediment flux during extreme events was 17,000+/-5000ty-1, which constitutes a year-to-year variation of 20-37% of the total annual flux. The most accurate sampling strategy was bi-daily sampling together with a sampling frequency of 2h during extreme events. The most consistent estimation method was an uncorrected rating curve of bi-daily measurements (M2), combined with a linear interpolation of extreme event fluxes. Sampling can be reduced to every fourth day, with both method-agreements and accuracies <+/-10%, using 7year averages. The specific annual method-agreements were <+/-10% for all years and the specific annual accuracies <+/-20% for 6years out of 7. The rating curves were less sensitive to day-to-day variations in the measured suspended sediment concentrations. The discharge weighted mean was not recommended in the high Arctic Zackenberg River, unless sampling was done bi-daily, every day and events sampled high-frequently. PMID- 27986313 TI - Are we preventing flood damage eco-efficiently? An integrated method applied to post-disaster emergency actions. AB - Flood damage results in economic and environmental losses in the society, but flood prevention also entails an initial investment in infrastructure. This study presents an integrated eco-efficiency approach for assessing flood prevention and avoided damage. We focused on ephemeral streams in the Maresme region (Catalonia, Spain), which is an urbanized area affected by damaging torrential events. Our goal was to determine the feasibility of post-disaster emergency actions implemented after a major event through an integrated hydrologic, environmental and economic approach. Life cycle assessment (LCA) and costing (LCC) were used to determine the eco-efficiency of these actions, and their net impact and payback were calculated by integrating avoided flood damage. Results showed that the actions effectively reduced damage generation when compared to the registered water flows and rainfall intensities. The eco-efficiency of the emergency actions resulted in 1.2kgCO2eq. per invested euro. When integrating the avoided damage into the initial investment, negative net impacts were obtained (e.g., -5.2E+05? and -2.9E+04kgCO2eq. per event), which suggests that these interventions contributed with environmental and economic benefits to the society. The economic investment was recovered in two years, whereas the design could be improved to reduce their environmental footprint, which is recovered in 25years. Our method and results highlight the effects of integrating the environmental and economic consequences of decisions at an urban scale and might help the administration and insurance companies in the design of prevention plans and climate change adaptation. PMID- 27986314 TI - Baseline study and risk analysis of landfill leachate - Current state-of-the science of computer aided approaches. AB - For the successful completion of a risk analysis process, its foundation (i.e. a baseline study) has to be well established. For this purpose, a baseline study needs to be more integrated than ever, particularly when environmental legislation is increasingly becoming stringent and integrated. This research investigates and concludes that no clear evidence of computer models for baseline study has been found in a whole-system and integrated format, which risk assessors could readily and effectively use to underpin risk analyses holistically and yet specifically for landfill leachate. This is established on the basis of investigation of software packages that are particularly closely related to landfills. Holistic baseline study is also defined along with its implications and in the context of risk assessment of landfill leachate. The study also indicates a number of factors and features that need to be added to baseline study in order to render it more integrated thereby enhancing risk analyses for landfill leachate. PMID- 27986315 TI - Thinning effect on photosynthesis depends on needle ages in a Chinese fir (Cunninghamia lanceolata) plantation. AB - Canopies in evergreen coniferous plantations often consist of various-aged needles. However, the effect of needle age on the photosynthetic responses to thinning remains ambiguous. Photosynthetic responses of different-aged needles to thinning were investigated in a Chinese fir (Cunninghamia lanceolata) plantation. A dual isotope approach [simultaneous measurements of stable carbon (delta13C) and oxygen (delta18O) isotopes] was employed to distinguish between biochemical and stomatal limitations to photosynthesis. Our results showed that increases in net photosynthesis rates upon thinning only occurred in the current-year and one year-old needles, and not in the two- to four-year-old needles. The increased delta13C and declined delta18O in current year needles of trees from thinned stands indicated that both the photosynthetic capacity and stomatal conductance resulted in increasing photosynthesis. In one-year-old needles of trees from thinned stands, an increased needle delta13C and a constant needle delta18O were observed, indicating the photosynthetic capacity rather than stomatal conductance contributed to the increasing photosynthesis. The higher water-soluble nitrogen content in current-year and one-year-old needles in thinned trees also supported that the photosynthetic capacity plays an important role in the enhancement of photosynthesis. In contrast, the delta13C, delta18O and water-soluble nitrogen in the two- to four-year-old needles were not significantly different between the control and thinned trees. Thus, the thinning effect on photosynthesis depends on needle age in a Chinese fir plantation. Our results highlight that the different responses of different-aged needles to thinning have to be taken into account for understanding and modelling ecosystem responses to management, especially under the expected environmental changes in future. PMID- 27986316 TI - Heavy metals removal using hydrogel-supported nanosized hydrous ferric oxide: Synthesis, characterization, and mechanism. AB - A new polymer-supported hybrid adsorbent (HFO-P(TAA/HEA)) for highly efficient removal of Pb2+, Cu2+, Cd2+ and Ni2+ from wastewater was developed by supporting hydrous ferric oxide (HFO) nanoparticles onto a porous poly(trans-Aconitic acid/2 hydroxyethyl acrylate) hydrogel (P(TAA/HEA)) with in situ precipitation method. Swelling kinetics, scanning electron microscope (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), thermo-gravimetric analysis (TGA), Fourier transform infrared spectra (FTIR) and X-ray photoelectron spectroscopy (XPS) were used for characterization of the prepared HFO-P(TAA/HEA). The characterization data demonstrated that the hybrid hydrogel HFO-P(TAA/HEA) was successfully fabricated, and swelling ability as well as thermal stability was promoted after loading. The results of batch equilibrium experiments indicated that pH and temperature significantly influenced the adsorption process and adsorption of heavy metals was better fitted to Langmuir and pseudo-second-order models. Selectivity of HFO-P(TAA/HEA) towards heavy metals was greatly improved under the calcium ions competition at higher concentration compared to P(TAA/HEA). Competitive adsorption evidenced the priority order in multifold metal species system was Pb2+>Cu2+>Ni2+>Cd2+. What's more, FTIR and XPS analyses manifested that heavy metals might mainly be adsorbed via inner sphere complexation. These findings revealed that hydrogel HFO-P(TAA/HEA) is a potential adsorption material to remove the heavy metals from polluted water. PMID- 27986318 TI - Sensitivity analysis of the STICS-MACRO model to identify cropping practices reducing pesticides losses. AB - STICS-MACRO is a process-based model simulating the fate of pesticides in the soil-plant system as a function of agricultural practices and pedoclimatic conditions. The objective of this work was to evaluate the influence of crop management practices on water and pesticide flows in contrasted environmental conditions. We used the Morris screening sensitivity analysis method to identify the most influential cropping practices. Crop residues management and tillage practices were shown to have strong effects on water percolation and pesticide leaching. In particular, the amount of organic residues added to soil was found to be the most influential input. The presence of a mulch could increase soil water content so water percolation and pesticide leaching. Conventional tillage was also found to decrease pesticide leaching, compared to no-till, which is consistent with many field observations. The effects of the soil, crop and climate conditions tested in this work were less important than those of cropping practices. STICS-MACRO allows an ex ante evaluation of cropping systems and agricultural practices, and of the related pesticides environmental impacts. PMID- 27986317 TI - On the summertime air quality and related photochemical processes in the megacity Shanghai, China. AB - Summertime surface ozone (O3) and related secondary formation of fine particles are the major air quality concerns in the megacity of Shanghai. We performed mobile Cavity Enhanced Differential Optical Absorption Spectroscopy (CE-DOAS) measurements to investigate the spatial distribution of on-road nitrogen dioxide (NO2) concentrations along the Inner Ring Elevated Road (IRER) in Shanghai. The observations show a ratio of 4 between CE-DOAS averaged on-road NO2 and the in situ ambient measurements, illustrating the strong impact of vehicle emissions over the urban area. The air mass transport analysis suggests that the observed episodic ozone events arise from both the abundance of volatile organic compounds (VOCs) precursors in the sampled plume and the regional transport of ozone-rich air masses. Analysis of the sources of PM2.5 shows that the secondary heterogeneous gas-to-particle conversion of sulfate and nitrate from sulfur dioxide (SO2) and nitrogen oxides (NOx) is the largest source of PM2.5 contributing 44.8+/-9.2% of the total PM2.5. Ozone-related photochemical formation of fine particles is estimated to contribute about 22.5+/-11.9% of the total PM2.5, which is strongly facilitated by solar radiation in summer. According to our results, nitrous acid (HONO) is the major precursor of hydroxyl radicals (OH) accounting for 40% to 80% of the total OH production during daytime. A significant correlation is found between the HONO levels in the early morning and the daily O3 and PM2.5 levels. The summertime measurements indicate that the photolytic reaction of HONO after sunrise increased the abundance of daytime OH and oxidative capacity, resulting in an enhancement of ground level ozone and secondary organic aerosol formation. This study provides quantitative information to better understand photochemical formation of ozone and fine particles in Shanghai during summertime, which is useful for designing collaborative strategies to mitigate emissions of precursor pollutants. PMID- 27986319 TI - Species at Risk (SPEAR) index indicates effects of insecticides on stream invertebrate communities in soy production regions of the Argentine Pampas. AB - We investigated relationships among insecticides and aquatic invertebrate communities in 22 streams of two soy production regions of the Argentine Pampas over three growing seasons. Chlorpyrifos, endosulfan, cypermethrin, and lambda cyhalothrin were the insecticides most frequently detected in stream sediments. The Species at Risk (SPEAR) pesticide bioassessment index (SPEARpesticides) was adapted and applied to evaluate relationships between sediment insecticide toxic units (TUs) and invertebrate communities associated with both benthic habitats and emergent vegetation habitats. SPEARpesticides was the only response metric that was significantly correlated with total insecticide TU values for all three averaged data sets, consistently showing a trend of decreasing values with increasing TU values (r2=0.35 to 0.42, p-value=0.001 to 0.03). Although pyrethroids were the insecticides that contributed the highest TU values, toxicity calculated based on all insecticides was better at predicting changes in invertebrate communities than toxicity of pyrethroids alone. Crustaceans, particularly the amphipod Hyalella spp., which are relatively sensitive to pesticides, played a large role in the performance of SPEARpesticides, and the relative abundance of all crustaceans also showed a significant decreasing trend with increasing insecticide TUs for two of three data sets (r2=0.30 to 0.57, p value=0.003 to 0.04) examined. For all data sets, total insecticide TU was the most important variable in explaining variance in the SPEARpesticides index. The present study was the first application of the SPEAR index in South America, and the first one to use it to evaluate effects of pesticides on invertebrate communities associated with aquatic vegetation. Although the SPEAR index was developed in Europe, it performed well in the Argentine Pampas with only minor modifications, and would likely improve in performance as more data are obtained on traits of South American taxa, such as pesticide sensitivity and generation time. PMID- 27986320 TI - Daily estimation of ground-level PM2.5 concentrations at 4km resolution over Beijing-Tianjin-Hebei by fusing MODIS AOD and ground observations. AB - The satellite-borne Moderate Resolution Imaging Spectroradiometer (MODIS) aerosol optical depth (AOD) is widely used to estimate ground-level fine ambient particulate matter (PM2.5) concentrations to evaluate their health effects. The associated estimation accuracy is often reduced by AOD missing values and by insufficiently accounting for the spatio-temporal PM2.5 variations. In this study, we aim to estimate ground-level PM2.5 concentrations at a fine resolution with improved accuracy by fusing fine-scale satellite and ground observations in the populated and polluted Beijing-Tianjin-Hebei (BTH) area of China in 2014. We employed a Bayesian-based statistical downscaler to model the spatio-temporal linear AOD-PM2.5 relationships. We used a 3km MODIS AOD product, which was resampled to a 4km resolution in a Lambert conic conformal projection, to assist comparison and fusion with predictions by atmospheric chemistry models. A two step method was used to fill the missing AOD values to obtain a full AOD dataset with complete spatial coverage. The downscaler has a good performance in the fitting procedure (R2=0.75) and in the cross validation procedure (R2=0.58 by random method and R2=0.47 by city-specific method). The number of missing AOD values was serious and related to elevated PM2.5 concentrations. The gap-filled AOD values corresponded well with our understanding of PM2.5 pollution conditions in BTH. The prediction accuracy of PM2.5 concentrations were improved in terms of their annual and seasonal mean. As a result of its fine spatio-temporal resolution and complete spatial coverage, the daily PM2.5 estimation dataset could provide extensive and insightful benefits to related studies in the BTH area. This may include understanding the formation processes of regional PM2.5 pollution episodes, evaluating daily human exposure, and establishing pollution controlling measures. PMID- 27986321 TI - The impacts of fracking on the environment: A total environmental study paradigm. AB - Fracking has become a hot topic in the media and public discourse not only because of its economic benefit but also its environmental impacts. Recently, scientists have investigated the environmental impacts of fracking, and most studies focus on its air and ground water pollution. A systematic research structure and an overall evaluation of fracking's impacts on the environment are needed, because fracking does not only influence ground water but most environmental elements including but not limited to air, water, soil, rock, vegetation, wildlife, human, and many other ecosystem components. From the standpoint of the total environment, this communication assesses the overall impacts of fracking on the environment and then designs a total environmental study paradigm that effectively examines the complicated relationship among the total environment. Fracking dramatically changes the anthroposphere, which in turn significantly impacts the atmosphere, hydrosphere, lithosphere, and biosphere through the significant input or output of water, air, liquid or solid waste disposals, and the complex chemical components in fracking fluids. The proposed total environment study paradigm of fracking can be applied to other significant human activities that have dramatic impacts on the environment, such as mountain top coal mining or oil sands for environmental studies. PMID- 27986322 TI - Physiochemical characteristics of aerosol particles in the typical microenvironment of hospital in Shanghai, China. AB - Health risk of populations dwelling in the hospital has been a global concern, but has not been adequately examined. PM2.5 and PM1 samples were collected in two indoor locations (outpatient department and inpatient department) and one outdoor location (courtyard) of the hospital in Shanghai. The concentrations of size fractionated trace metals and the morphology of single particles were determined to accurately assess the health risk for populations in the hospital. The results indicated that the mean concentrations of PM2.5 and PM1 were in the order of outpatient department>courtyard>inpatient department. The mean concentrations of PM1 decreased with floors (first floor: 78.0MUg/m3, second floor: 64.1MUg/m3, fourth floor: 48.4MUg/m3). However, the mean PM2.5 concentrations were in the order of first floor (124.0MUg/m3)>fourth floor (91.4MUg/m3)>second floor (90.6MUg/m3), which was likely associated with the number of patients. The PM2.5 and PM1 concentrations have begun to increase rapidly from 9:00am and decreased after 15:00pm in the first floor, whereas they remain relatively stable in the second and fourth floor. The abundance of Mg, Ca, Al and K in the fine particles and coarse particles were both higher than other elements for all floors. The concentrations of trace metals (e.g., Zn, Ba, Fe, Mn, Cr, Ca, Ti, Na, and K) except Mg and Al in the coarse particles (>2.5MUm) decreased with floors, whereas Zn, Ba, Fe, and Cr in the fine particles (<2.5MUm) displayed opposite variation. Trace metals in the first floor were mainly concentrated in the >2.5MUm and 1 2.5MUm, whereas they chiefly peaked at 0.25-0.5MUm and below 0.25MUm in the second and fourth floor. Single particles analysis showed that mineral particles, soot, and Fe-rich particles were mainly concentrated in the first floor, indicating the impacts of walking of patients, traffic emissions, and food cooking, respectively. Sulfate particles were internally mixed with soot, fly ash and Fe-rich particles in the second floor, which suggested that these sulfate particles probably underwent aging processes during the atmospheric long-range transport. In the fourth floor, fly ash, sulfate particles, Zn-rich particles, and biogenic particles were identified under the transmission electron microscopy (TEM). Higher abundance of sulfates and absence of chlorate hinted existence of heterogeneous reactions during long-range transport with the Cl- replaced by SO42 . The index of average daily intake (ADI), hazard quotient (HQ), and carcinogenic risks (CR) indicated that Cr pose carcinogenic risks to the surrounding populations, while non-carcinogenic risks of Mn, Zn, and Cr were not remarkable. PMID- 27986323 TI - Persistent organic pollutants in China's surface water systems. AB - Following recent rapid industrialization, China is now one of the largest producers and consumers of organic chemicals in the world. This is compounded by variable regulatory oversight with respect to storage, use and waste management of these chemicals and their byproducts. This review synthesizes the data on the distribution of selected persistent organic pollutants (POPs) in waters in China. Surface water heavily polluted with POPs is distributed in the Yangtze River Estuary, Pearl River Delta, Minjiang River Estuary, Jiulongjiang Estuary, Daya Bay, Taihu Lake, and the waterways of Zhejiang Province, where concentrations of Polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) frequently exceed both international and Chinese guideline values. These areas are mainly distributed along the southeast coast of China, within or downstream of major manufacturing districts, intensive agricultural basins, and other industrial centers. A comparison of the levels of OCPs in the aquatic environment of China with other indicative regions worldwide shows comparable levels of pollution (overall range from below detection limit (BDL) to 5104.8ng/L and regional means from 2.9-929.6ng/L). PAHs and PCBs pollution appear to be particularly serious in China (PAHs overall ranging from BDL to 474,000ng/L with regional means from 15.1-72,400ng/L; PCBs from BDL to 3161ng/L with regional means ranging from 0.2-985.2ng/L). There is as yet limited evidence of serious perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) pollution. We discuss major sources and processes responsible for high POP occurrence using a range of measures (including diagnostic ratios of different compounds), regulatory oversight and policy gaps in the control of POPs in China, and potential long-term health and ecological effects. We argue that water quality guidelines, pollution control measures and cleanup strategies for POPs in China should be urgently improved. PMID- 27986324 TI - Determination of sediment metal background concentrations and enrichment in marine environments - A critical review. AB - 'Background' is the concentration of metals in pristine sediment, unaltered by human activity and 'enrichment' is the extent present-day sediment metal concentrations exceed pre-anthropogenic levels (the magnitude of human-induced change). Background and enrichment are becoming more frequently used for management measures to bring sediment and the environment back to near-pristine levels. Of the six empirical methods reviewed for determining background (global values, pristine marine and fluvial sediments, catchment soils and rocks), the use of sedimentary cores has the greatest advantage. Most of the eight statistical methods reviewed are adversely affected by the polymodality and an absence of normality or log-normality, however robust regression procedures are most commonly used. Sorption hypothesis techniques require further development. Indices used to determine enrichment incorporate background levels (enrichment indices) or do not (contamination indices). Of the 20 indices reviewed, the New Nemerow Index and the Mean Enrichment Quotient rate highly in performance, based on 5 beneficial attributes assessed: use of background and normalised data, provision of thresholds, a classification scheme, and inclusion of multiple metals. Variance in background metal concentrations determined in the 43 global projects reviewed is surprisingly moderate, however regional variability may be considerable due to local catchment mineralisation. Chemical analysis of sediment should not include metals bound in the mineral matrix and weak acid extractions are advisable. The use of appropriate and effective indicators of environmental condition are critical to the protection and restoration of marine regions and ensuring that human activities are carried out in a sustainable manner to promote safe, healthy and productive ecosystems. PMID- 27986325 TI - Effects of transient receptor potential canonical 1 (TRPC1) on the mechanical stretch-induced expression of airway remodeling-associated factors in human bronchial epithelioid cells. AB - Research has shown that mechanical stress stimulation can cause airway remodeling. We investigate the effects of mechanical stretch on the expression of the airway remodeling-associated factors interleukin-13 (IL-13) and matrix metalloprotein-9 (MMP-9) and signaling pathways in human bronchial epithelioid (16HBE) cells under mechanical stretch. A Flexcell FX-4000 Tension System with a flexible substrate was applied to stretch 16HBE cells at a 15% elongation amplitude and 1Hz frequency, with stretching for 0.5h, 1h, 1.5h and 2h. The experimental group with higher IL-13, MMP-9, and TRPC1 expression and higher Ca2+ levels was selected for performing intervention experiment. These cells were pretreated with the transient receptor potential canonical 1 (TRPC1) channel antagonist SKF96365 and TRPC1-specific siRNA, and then mechanical stretch was applied. Our results provided evidences that mechanical pressure significantly increased IL-13, MMP-9, and TRPC1 protein and mRNA expression levels and intracellular Ca2+ fluorescence intensity at 4 time points compared with the control group. The peak IL-13, MMP-9, and TRPC1 expression levels were observed at 0.5h after exposure to mechanical pressure. IL-13 and MMP-9 expression levels and Ca2+ fluorescence intensity in the stretch+SKF96365 group and in the stretch+TRPC1 siRNA group were significantly lower than those were in the mechanical stretch group. By incubating the cells with the intracellular calcium chelator BAPTA-AM, the expression of IL-13 and MMP9 was significantly decreased, and the expression level of TRPC1 remained unchanged. These observations suggest that mechanical stretch may induce an influx of Ca2+ and up-regulation of IL-13 and MMP-9 expression in 16HBE cells via activation of TRPC1. PMID- 27986326 TI - Kinematic models of the upper limb joints for multibody kinematics optimisation: An overview. AB - Soft tissue artefact (STA), i.e. the motion of the skin, fat and muscles gliding on the underlying bone, may lead to a marker position error reaching up to 8.7cm for the particular case of the scapula. Multibody kinematics optimisation (MKO) is one of the most efficient approaches used to reduce STA. It consists in minimising the distance between the positions of experimental markers on a subject skin and the simulated positions of the same markers embedded on a kinematic model. However, the efficiency of MKO directly relies on the chosen kinematic model. This paper proposes an overview of the different upper limb models available in the literature and a discussion about their applicability to MKO. The advantages of each joint model with respect to its biofidelity to functional anatomy are detailed both for the shoulder and the forearm areas. Models capabilities of personalisation and of adaptation to pathological cases are also discussed. Concerning model efficiency in terms of STA reduction in MKO algorithms, a lack of quantitative assessment in the literature is noted. In priority, future studies should concern the evaluation and quantification of STA reduction depending on upper limb joint constraints. PMID- 27986327 TI - Improved reduced-order modelling of cerebrovascular flow distribution by accounting for arterial bifurcation pressure drops. AB - Reduced-order modelling offers the possibility to study global flow features in cardiovascular networks. In order to validate these models, previous studies have been conducted in which they compared 3D computational fluid dynamics simulations with reduced-order simulations. Discrepancies have been reported between the two methods. The loss of energy at the bifurcations is usually neglected and has been pointed out as a possible explanation for these discrepancies. We present distributed lumped models of cerebrovasculatures created automatically from 70 cerebrovascular networks segmented from 3D angiograms. The outflow rate repartitions predicted with and without modelling the energy loss at the bifurcations are compared against 3D simulations. When neglecting the energy loss at the bifurcations, the flow rates though the anterior cerebral arteries are overestimated by 4.7+/-6.8% (error relative to the inlet flow rate, mean +/- standard deviation), impacting the remaining volume of flow going to the other vessels. When the energy loss is modelled, this error is dropping to 0.1+/-3.2%. Overall, over the total of 337 outlet vessels, when the energy losses at the bifurcations are not modelled the 95% of agreement is in the range of +/-13.5% and is down to +/-6.5% when the energy losses are considered. With minimal input and computational resources, the presented method can estimate the outflow rates reliably. This study constitutes the largest validation of a reduced-order flow model against 3D simulations. The impact of the energy loss at the bifurcations is here demonstrated for cerebrovasculatures but can be applied to other physiological networks. PMID- 27986328 TI - Pathogenesis of NEC: Impact of an altered intestinal microbiome. AB - Necrotizing enterocolitis (NEC), a disease most commonly seen in preterm infants, often presents without warning and is associated with very high mortality and morbidity. Progress in the prevention and treatment of NEC has been slow. In this article, we will discuss some of the reasons as to why this progress has been slow. We will describe some of the factors that appear to be highly associated and important components in the pathophysiology of NEC. We will discuss the intestinal microbial environment of the fetus as well as the preterm infant and how interaction of dysbiosis with an immature gastrointestinal tract combined with dietary factors play a role in the pathogenesis of NEC. Testable hypotheses are discussed as well as how these may lead to not only a better understanding of the pathophysiology of the disease but also the preventative strategies. PMID- 27986329 TI - Preemptive hemodynamic intervention restricting the administration of fluids attenuates lung edema progression in oleic acid-induced lung injury. AB - OBJECTIVE: A study is made of the influence of preemptive hemodynamic intervention restricting fluid administration upon the development of oleic acid induced lung injury. DESIGN: A randomized in vivo study in rabbits was carried out. SETTING: University research laboratory. SUBJECTS: Sixteen anesthetized, mechanically ventilated rabbits. VARIABLES: Hemodynamic measurements obtained by transesophageal Doppler signal. Respiratory mechanics computed by a least square fitting method. Lung edema assessed by the ratio of wet weight to dry weight of the right lung. Histological examination of the left lung. INTERVENTIONS: Animals were randomly assigned to either the early protective lung strategy (EPLS) (n=8) or the early protective hemodynamic strategy (EPHS) (n=8). In both groups, lung injury was induced by the intravenous infusion of oleic acid (OA) (0.133mlkg-1h-1 for 2h). At the same time, the EPLS group received 15mlkg-1h-1 of Ringer lactate solution, while the EPHS group received 30mlkg-1h-1. Measurements were obtained at baseline and 1 and 2h after starting OA infusion. RESULTS: After 2h, the cardiac index decreased in the EPLS group (p<0.05), whereas in the EPHS group it remained unchanged. Lung compliance decreased significantly only in the EPHS group (p<0.05). Lung edema was greater in the EPHS group (p<0.05). Histological damage proved similar in both groups (p=0.4). CONCLUSIONS: In this experimental model of early lung injury, lung edema progression was attenuated by preemptively restricting the administration of fluids. PMID- 27986331 TI - An Unusual Cause of Airway Compromise in the Emergency Department: Mediastinal Bronchogenic Cyst. PMID- 27986330 TI - Making the Quick Diagnosis: A Case of Neonatal Shock. AB - BACKGROUND: The work-up and initial management of a critically ill neonate is challenging and anxiety provoking for the Emergency Physician. While sepsis and critical congenital heart disease represent a large proportion of neonates presenting to the Emergency Department (ED) in shock, there are several additional etiologies to consider. Underlying metabolic, endocrinologic, gastrointestinal, neurologic, and traumatic disorders must be considered in a critically ill infant. Several potential etiologies will present with nonspecific and overlapping signs and symptoms, and the diagnosis often is not evident at the time of ED assessment. CASE REPORT: We present the case of a neonate in shock, with a variety of nonspecific signs and symptoms who was ultimately diagnosed with tachycardia-induced cardiomyopathy secondary to a resolved dysrhythmia. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the diagnostic and therapeutic approach to the critically ill neonate in the ED, and expands the differential diagnosis beyond sepsis and critical congenital heart disease. Knowledge of the potential life-threatening etiologies of shock in this population allows the Emergency Physician to appropriately test for, and empirically treat, several potential etiologies simultaneously. Additionally, we discuss the diagnosis and management of supraventricular tachycardia and Wolff Parkinson-White syndrome in the neonatal and pediatric population, which is essential knowledge for an Emergency Physician. PMID- 27986332 TI - First report of the macrolide efflux genetic assembly (MEGA) element in Haemophilus parainfluenzae. PMID- 27986333 TI - Comments on tocotrienols, health and ageing. PMID- 27986334 TI - Septic shock without hyperlactatemia. PMID- 27986336 TI - Comparison of the Trachway video intubating stylet and Macintosh laryngoscope for endotracheal intubation. Preliminary data. PMID- 27986335 TI - Presenting phenotypes of acute heart failure patients in the ED: Identification and implications. AB - BACKGROUND: There is little known about the baseline hemodynamic (HD) profiles (beyond pulse/blood pressure) of patients presenting to the Emergency department (ED) with acute heart failure (AHF). Assessing these baseline parameters could help differentiate underlying HD phenotypes which could be used to develop specific phenotypic specific approaches to patient care. METHODS: Patients with suspected AHF were enrolled in the PREMIUM (Prognostic Hemodynamic Profiling in the Acutely Ill Emergency Department Patient) multinational registry and continuous HD monitoring was initiated on ED presentation using noninvasive finger cuff technology (Nexfin, BMEYE, Edwards Lifesciences, Irvine, California). Individuals with clinically suspected and later confirmed AHF were included in this analysis and initial 15minute averages for available HD parameters were calculated. K-means clustering was performed to identify out of 23 HD variables a set that provided the greatest level of inter-cluster discrimination and intra cluster cohesions. RESULTS: A total of 127 patients had confirmed AHF. The final model, using mean normalized patient baseline HD values was able to differentiate these individuals into 3 distinct phenotypes. Cluster 1: normal cardiac index (CCI) and systemic vascular resistance index (SVRI); cluster 2: very low CI and markedly increased SVRI: and cluster 3: low CI and an elevated SVRI. These clusters were not differentiated using clinically available ED information. CONCLUSIONS: Three distinct clusters were defined using novel noninvasive presenting HD monitoring technology in this cohort of ED AHF patients. Further studies are needed to determine whether phenotypic specific therapies based on these clusters can improve outcomes. PMID- 27986337 TI - Comparison of cricoid pressure effect between McGRATH(r) MAC and Pentax-AWS Airwayscope(r): A prospective randomized trials. PMID- 27986338 TI - Understanding competition between healthcare providers: Introducing an intermediary inter-organizational perspective. AB - Pro-competitive policy reforms have been introduced in several countries, attempting to contain increasing healthcare costs. Yet, research proves ambiguous when it comes to the effect of competition in healthcare, with a number of studies highlighting unintended and unwanted effects. We argue that current empirical work overlooks the role of inter-organizational relations as well as the interplay between policy at macro level, inter-organizational networks at meso level, and outcomes at micro level. To bridge this gap and stimulate a more detailed understanding of the effect of competition in health care, this article introduces a cross-level conceptual framework which emphasizes the intermediary role of cooperative inter-organizational relations at meso level. We discuss how patient transfers, specialist affiliations, and interlocking directorates constitute three forms of inter-organizational relations in health care which can be used within this framework. The paper concludes by deriving several propositions from the framework which can guide future research. PMID- 27986339 TI - Short-term Care With Long-term Costs: The Unintended Consequences of EMTALA. PMID- 27986340 TI - Infective endocarditis in patients with oncological diseases. AB - INTRODUCTION: Cancer patients may constitute a special risk group for the development of infective endocarditis (IE) because they are often subjected to invasive procedures. The aim of this study is to determine the differential clinical profile and prognosis of patients with IE and cancer. METHODS: A retrospective observational study was conducted on all patients consecutively diagnosed with IE in a single centre between 2005 and 2015. A comparative analysis was performed between patients with cancer and those free of disease, as well as a long-term follow-up. RESULTS: There were 208 IE cases, of which 32 had a cancer diagnosis. There were no significant differences in age (67.5 [59.2-74] vs. 64 [51-74] years). The Charlson comorbidity index was same whether cancer was diagnosed or not (4 [2.2-5] vs. 3.9 [2-5]). IE in cancer patients was mainly associated with health care (59.5% vs 24.4%, P<.001). Staphylococcus aureus was the main causative agent (35%), and the tricuspid location was three times more common (18.8% vs. 6.2%). Surgery was not performed in 18.7% of patients, despite having an indication, compared with 7.4% of patients without cancer. In-hospital mortality for cancer patients was 45.5%, and the probability of survival at one year was 40%. CONCLUSIONS: IE in patients with cancer is predominantly caused by staphylococci, and has high early mortality. Although it is often related to health care, patients are limited from the therapeutic point of view. PMID- 27986341 TI - Incretin-related drugs and cardiovascular events: A comparison of GLP-1 analogue and DPP-4 inhibitor. PMID- 27986342 TI - Trends and outcomes of sepsis hospitalizations complicated by acute kidney injury requiring hemodialysis. PMID- 27986343 TI - Nation-Scale Adoption of Shorter Breast Radiation Therapy Schedules Can Increase Survival in Resource Constrained Economies: Results From a Markov Chain Analysis. AB - PURPOSE: Hypofractionated whole breast irradiation and accelerated partial breast irradiation (APBI) offer women options for shorter courses of breast radiation therapy. The impact of these shorter schedules on the breast cancer populations of emerging economies with limited radiation therapy resources is unknown. We hypothesized that adoption of these schedules would improve throughput in the system and, by allowing more women access to life-saving treatments, improve patient survival within the system. METHODS AND MATERIALS: We designed a Markov chain model to simulate the different health states that a postlumpectomy or postmastectomy patient could enter over the course of a 20-year follow-up period. Transition rates between health states were adapted from published data on recurrence rates. We used primary data from a tertiary care hospital in Lahore, Pakistan, to populate the model with proportional use of mastectomy versus breast conservation and to estimate the proportion of patients suitable for APBI. Sensitivity analyses on the use of APBI and relative efficacy of APBI were conducted to study the impact on the population. RESULTS: The shorter schedule resulted in more women alive and more women remaining without evidence of disease (NED) compared with the conventional schedule, with an absolute difference of about 4% and 7% at 15 years, respectively. Among women who had lumpectomies, the chance of remaining alive and with an intact breast was 62% in the hypofractionation model and 54% in the conventional fractionation model. CONCLUSIONS: Increasing throughput in the system can result in improved survival, improved chances of remaining without evidence of disease, and improved chances of remaining alive with a breast. These findings are significant and suggest that adoption of hypofractionation in emerging economies is not simply a question of efficiency and cost but one of access to care and patient survivorship. PMID- 27986344 TI - Decreased Lung Perfusion After Breast/Chest Wall Irradiation: Quantitative Results From a Prospective Clinical Trial. AB - PURPOSE: To quantify lung perfusion changes after breast/chest wall radiation therapy (RT) using pre- and post-RT single photon emission computed tomography/computed tomography (SPECT/CT) attenuation-corrected perfusion scans; and correlate decreased perfusion with adjuvant RT dose for breast cancer in a prospective clinical trial. METHODS AND MATERIALS: As part of an institutional review board-approved trial studying the impact of RT technique on lung function in node-positive breast cancer, patients received breast/chest wall and regional nodal irradiation including superior internal mammary node RT to 50 to 52.2 Gy with a boost to the tumor bed/mastectomy scar. All patients underwent quantitative SPECT/CT lung perfusion scanning before RT and 1 year after RT. The SPECT/CT scans were co-registered, and the ratio of decreased perfusion after RT relative to the pre-RT perfusion scan was calculated to allow for direct comparison of SPECT/CT perfusion changes with delivered RT dose. The average ratio of decreased perfusion was calculated in 10-Gy dose increments from 0 to 60 Gy. RESULTS: Fifty patients had complete lung SPECT/CT perfusion data available. No patient developed symptoms consistent with pulmonary toxicity. Nearly all patients demonstrated decreased perfusion in the left lung according to voxel based analyses. The average ratio of lung perfusion deficits increased for each 10-Gy increment in radiation dose to the lung, with the largest changes in regions of lung that received 50 to 60 Gy (ratio 0.72 [95% confidence interval 0.64-0.79], P<.001) compared with the 0- to 10-Gy region. For each increase in 10 Gy to the left lung, the lung perfusion ratio decreased by 0.06 (P<.001). CONCLUSIONS: In the assessment of 50 patients with node-positive breast cancer treated with RT in a prospective clinical trial, decreased lung perfusion by SPECT/CT was demonstrated. Our study allowed for quantification of lung perfusion defects in a prospective cohort of breast cancer patients for whom attenuation corrected SPECT/CT scans could be registered directly to RT treatment fields for precise dose estimates. PMID- 27986345 TI - Morphologic Features of Magnetic Resonance Imaging as a Surrogate of Capsular Contracture in Breast Cancer Patients With Implant-based Reconstructions. AB - PURPOSE: Capsular contracture (CC) is a serious complication in patients receiving implant-based reconstruction for breast cancer. Currently, no objective methods are available for assessing CC. The goal of the present study was to identify image-based surrogates of CC using magnetic resonance imaging (MRI). METHODS AND MATERIALS: We analyzed a retrospective data set of 50 patients who had undergone both a diagnostic MRI scan and a plastic surgeon's evaluation of the CC score (Baker's score) within a 6-month period after mastectomy and reconstructive surgery. The MRI scans were assessed for morphologic shape features of the implant and histogram features of the pectoralis muscle. The shape features, such as roundness, eccentricity, solidity, extent, and ratio length for the implant, were compared with the Baker score. For the pectoralis muscle, the muscle width and median, skewness, and kurtosis of the intensity were compared with the Baker score. Univariate analysis (UVA) using a Wilcoxon rank sum test and multivariate analysis with the least absolute shrinkage and selection operator logistic regression was performed to determine significant differences in these features between the patient groups categorized according to their Baker's scores. RESULTS: UVA showed statistically significant differences between grade 1 and grade >=2 for morphologic shape features and histogram features, except for volume and skewness. Only eccentricity, ratio length, and volume were borderline significant in differentiating grade <=2 and grade >=3. Features with P<.1 on UVA were used in the multivariate least absolute shrinkage and selection operator logistic regression analysis. Multivariate analysis showed a good level of predictive power for grade 1 versus grade >=2 CC (area under the receiver operating characteristic curve 0.78, sensitivity 0.78, and specificity 0.82) and for grade <=2 versus grade >=3 CC (area under the receiver operating characteristic curve 0.75, sensitivity 0.75, and specificity 0.79). CONCLUSIONS: The morphologic shape features described on MR images were associated with the severity of CC. MRI has the potential to further improve the diagnostic ability of the Baker score in breast cancer patients who undergo implant reconstruction. PMID- 27986346 TI - Proton Treatment Techniques for Posterior Fossa Tumors: Consequences for Linear Energy Transfer and Dose-Volume Parameters for the Brainstem and Organs at Risk. AB - PURPOSE: In proton therapy of posterior fossa tumors, at least partial inclusion of the brainstem in the target is necessary because of its proximity to the tumor and required margins. Additionally, the preferred beam geometry results in directing the field distal edge toward this critical structure, raising concerns for brainstem toxicity. Some treatment techniques place the beam's distal edge within the brainstem (dose-sparing techniques), and others avoid elevated linear energy transfer (LET) of the proton field by placing the distal edge beyond it (LET-sparing techniques). Hybrid approaches are also being used. We examine the dosimetric efficacy of these techniques, accounting for LET-dependent and dose dependent variable relative biologic effectiveness (RBE) distributions. METHODS: Six techniques were applied in ependymoma cases: (a) 3-field dose-sparing; (b) 3 field LET-sparing; (c) 2-field dose-sparing, wide angles; (d) 2-field LET sparing, wide angles; (e) 2-field LET-sparing, steep angles; and (f) 2-field LET sparing with feathered distal end. Monte Carlo calculated dose, LET, and RBE weighted dose distributions were compared. RESULTS: Decreased LET values in the brainstem by LET-sparing techniques were accompanied by higher, not statistically significant, median dose: 53.6 Gy(RBE), 53.4 Gy(RBE), and 54.3 Gy(RBE) for techniques (b), (d), and (e) versus 52.1 Gy(RBE) for technique (a). Accounting for variable RBE distributions, the brainstem volume receiving at least 55 Gy(RBE) increased from 72.5% for technique (a) to 80.3% for (b) (P<.01) and from 70.7% for technique (c) to 77.6% for (d) (P<.01). Less than 2%, but statistically significant, decrease in maximum variable RBE-weighted brainstem dose was observed for the LET-sparing techniques compared with the corresponding dose sparing (P=.03 and .004). CONCLUSIONS: Extending the proton range beyond the brainstem to reduce LET results in clinically comparable maximum radiobiologic effective dose to this sensitive structure. However this method significantly increasing the brainstem volume receiving RBE-weighted dose higher than 55 Gy(RBE) with possible consequences based on known dose-volume parameters for increased toxicity. PMID- 27986347 TI - Subgroup Analysis According to Human Papillomavirus Status and Tumor Site of a Randomized Phase II Trial Comparing Cetuximab and Cisplatin Combined With Radiation Therapy for Locally Advanced Head and Neck Cancer. AB - PURPOSE: We report a subgroup analysis primarily focused on human papillomavirus (HPV)-related oropharyngeal cancer (OPC) from the Cetuximab Plus Radiotherapy Versus Cisplatin Plus Radiotherapy in Locally Advanced Head and Neck Cancer (CTXMAB+RT; ClinicalTrials.gov identifier NCT01216020) trial comparing radiation therapy with concomitant cisplatin (CDDP) versus concomitant cetuximab (CTX) as first-line treatment of locally advanced head and neck cancer. METHODS AND MATERIALS: The data from all the patients in the CTXMAB+RT trial were reviewed and separately analyzed in 3 groups: p16-positive OPC, p16-negative OPC, and all other cancer sites. The endpoints of interest were locoregional control (LC), metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS). Severe and fatal infectious complications were also reanalyzed to more thoroughly investigate the association between CTX treatment and potentially life threatening reactions. RESULTS: A total of 33 patients had OPC. The HPV status was available for 30 of the 33 patients. Thus, 3 patients treated with CDDP but with unknown HPV status were excluded from the survival analysis. The small number of patients in each group did not allow for significance to be reached for any of the outcomes analyzed. A trend favored the CDDP arm in the p16-positive group for the 2-year LC and OS/CSS rates (100% vs 72.9% and 100% vs 77.8% for CDDP vs CTX). In this group of patients, the hazard ratio for the treatment arm (CTX vs CDDP) was 4.7 (95% confidence interval [CI] 0.5-40.3) for LC, 3.4 (95% CI 0.4-30.5) for OS, and 2.4 for CSS (95% CI 0.2-23.2). A survival benefit favoring the CDDP arm was not evident in the p16-negative OPC group or for patients with cancer located in other sites. Serious or fatal infectious complications occurred only in the CTX arm. CONCLUSIONS: In patients with p16-positive OPC in the CTXMAB+RT trial, CTX had lower efficacy than CDDP, with possible implications for treatment selection in this clinical setting. PMID- 27986348 TI - Updated Outcome and Analysis of Tumor Response in Mobile Spine and Sacral Chordoma Treated With Definitive High-Dose Photon/Proton Radiation Therapy. AB - PURPOSE: Treatment of spine and sacral chordoma generally involves surgical resection, usually in conjunction with radiation therapy. In certain circumstances where resection may result in significant neurologic or organ dysfunction, patients can be treated definitively with radiation therapy alone. Herein, we report the outcome and the assessment of tumor response to definitive radiation therapy. METHODS AND MATERIALS: A retrospective analysis was performed on 40 patients with unresected chordoma treated with photon/proton radiation therapy. Nineteen patients had complete sets of imaging scans. The soft tissue and bone compartments of the tumor were defined separately. Tumor response was evaluated by the modified Response Evaluation Criteria in Solid Tumors (RECIST) and volumetric analysis. RESULTS: With a median follow-up time of 50.3 months, the rates of 5-year local control, overall survival, disease-specific survival, and distant failure were 85.4%, 81.9%, 89.4%, and 20.2%, respectively. Eighty four computed tomographic and magnetic resonance imaging scans were reviewed. Among the 19 patients, only 4 local failures occurred, and the median tumor dose was 77.4 GyRBE. Analysis at a median follow-up time of 18 months showed significant volumetric reduction of the total target volume (TTV) and the soft tissue target volume (STTV) within the first 24 months after treatment initiation, followed by further gradual reduction throughout the rest of the follow-up period. The median maximum percentage volumetric regressions of TTV and STTV were 43.2% and 70.4%, respectively. There was only a small reduction in bone target volume over time. In comparison with the modified RECIST, volumetric analysis was more reliable, more reproducible, and could help in measuring minimal changes in the tumor volume. CONCLUSION: These results continue to support the use of high-dose definitive radiation therapy for selected patients with unresected spine and sacral chordomas. Assessment of tumor response to radiation therapy by volumetric analysis is superior to modified RECIST in chordoma patients. Evaluating the soft tissue target volume is an excellent indicator of tumor response. PMID- 27986349 TI - Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy. AB - PURPOSE: In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops. Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects. METHODS AND MATERIALS: We performed a phase 1 study using a modified 3 + 3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy. After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8 Gy each (total dose, 66.6 Gy). Patients were monitored for both acute (<=90 days) and chronic (>90 days) treatment-related toxicities. RESULTS: Eighteen patients received everolimus at dose levels of 5 mg (n=6), 7.5 mg (n=6), or 10 mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8 months (range, 1.2-46.0 months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%). CONCLUSIONS: Everolimus at a dose of <=10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy. PMID- 27986351 TI - Serum 25-hydroxyvitamin D, non-alcoholic fatty liver disease and type 2 diabetes. PMID- 27986350 TI - Dietary glycemic index, glycemic load and cancer: An overview of the literature. AB - AIMS: The aim of this paper is to provide an overview of the current evidence for associations between dietary glycemic index (GI) and dietary glycemic load (GL), and the risk of various types of cancer, and to summarize mechanisms proposed to explain the associations found. DATA SYNTHESIS: Medline was searched for cohort studies, case-control studies, and meta-analyses, published up to February 2016, that examined associations between dietary GI/GL and cancer. Findings from the main meta-analyses showed a weak-to-moderate association of high dietary GI/GL with increased risk of some cancers. High dietary GI but not GL was significantly and consistently associated with increased colorectal cancer risk in both cohort and case-control studies. Dietary GL was directly associated with breast and endometrial cancer risk in cohort studies. Positive associations between dietary GI or GL and cancer risk were found more frequently in case-control studies than cohort studies. The main mechanism for these associations is thought to be chronic hyperinsulinemia. Insulin is itself a mitogen and also increases the bioactivity of insulin-like growth factors which can promote cancer by inhibiting apoptosis and stimulating cell proliferation. CONCLUSIONS: The review has uncovered consistent evidence that high dietary GI is associated with increased risk of colorectal cancer, and that high dietary GL is associated with increased risk of breast and endometrial cancer. However the risk increases are small or moderate. PMID- 27986353 TI - Detection of Babesia microti parasites by highly sensitive 18S rRNA reverse transcription PCR. AB - Babesia are increasingly appreciated as a cause of transfusion-transmitted infection. Sensitive methods are needed to screen blood products. We report herein that B. microti 18S rRNA is over 1,000-fold more abundant than its coding genes, making reverse transcription PCR (RT-PCR) much more sensitive than PCR. Babesia 18S rRNA may be useful for screening the blood supply. PMID- 27986352 TI - Colorectal Cancer Screening and Chinese Americans: Efficacy of Lay Health Worker Outreach and Print Materials. AB - INTRODUCTION: Chinese Americans have low colorectal cancer (CRC) screening rates. Evidence-based interventions to increase CRC screening in this population are lacking. This study aims to compare the efficacy of two interventions in increasing CRC screening among Chinese Americans. DESIGN: Cluster randomized comparative trial. SETTING/PARTICIPANTS: From 2010 to 2014, a community-academic team conducted this study in San Francisco, CA with Chinese Americans aged 50-75 years who spoke English, Cantonese, or Mandarin. INTERVENTION: Lay health worker (LHW) intervention plus in-language brochure (LHW+Print) versus brochure (Print). LHWs in the LHW+Print arm were trained to teach participants about CRC in two small group sessions and two telephone calls. MAIN OUTCOME MEASURES: Change in self-reports of ever having had CRC screening and being up to date for CRC screening from baseline to 6 months post-intervention. Statistical analysis was performed from 2014 to 2015. RESULTS: This study recruited 58 LHWs, who in turn recruited 725 participants. The average age of the participants was 62.2 years, with 81.1% women and 99.4% foreign born. Knowledge increase was significant (p<0.002) for nine measures in the LHW+Print group and six in the Print group. Both groups had increases in having ever been screened for CRC (LHW+Print, 73.9% 88.3%, p<0.0001; Print, 72.3%-79.5%, p=0.0003) and being up to date for CRC screening (LHW+Print, 60.0%-78.1%, p<0.0001; Print, 58.1%-64.1%, p=0.0003). In multivariable analyses, the intervention OR for LHW+Print versus Print was 1.94 (95% CI=1.34, 2.79) for ever screening and 2.02 (95% CI=1.40, 2.90) for being up to date. CONCLUSIONS: Both in-language print materials and LHW outreach plus print materials increased CRC screening among Chinese Americans. The combination of LHW+Print was more effective than Print alone. These findings can guide clinicians and policymakers in choosing appropriate interventions to increase CRC screening among Chinese American immigrants. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT00947206. PMID- 27986356 TI - The human photosensitivity model for the development of drugs for focal onset seizures: A debate. PMID- 27986355 TI - The prolyl oligopeptidase inhibitor IPR19 ameliorates cognitive deficits in mouse models of schizophrenia. AB - Cognitive deficits are considered a key feature of schizophrenia, and they usually precede the onset of the illness and continue after psychotic symptoms appear. Current antipsychotic drugs have little or no effect on the cognitive deficits of this disorder. Prolyl oligopeptidase (POP) is an 81-kDa monomeric serine protease that is expressed in brain and other tissues. POP inhibitors have shown neuroprotective, anti-amnesic and cognition-enhancing properties. Here we studied the potential of IPR19, a new POP inhibitor, for the treatment of the cognitive symptoms related to schizophrenia. The efficacy of the inhibitor was evaluated in mouse models based on subchronic phencyclidine and acute dizocilpine administration, and in adult offspring from mothers with immune reaction induced by polyinosinic:polycytidylic acid administration during pregnancy. Acute IPR19 administration (5mg/kg, i.p.) reversed the cognitive performance deficits of the three mouse models in the novel object recognition test, T-maze, and eight-arm radial maze. The compound also ameliorates deficits of the prepulse inhibition response. The in vitro inhibitory efficacy and selectivity, brain penetration and exposure time after injection of IPR19 were also addressed. Our results indicate that the inhibition of POP using IPR19 may offer a promising strategy to develop drugs to ameliorate the cognitive deficits of schizophrenia. PMID- 27986354 TI - Lived experiences of routine antenatal dietetic services among women with obesity: A qualitative phenomenological study. AB - OBJECTIVE: to understand the lived experiences and views of being referred to an antenatal dietetic service from the perspective of pregnant women with obesity. DESIGN: a qualitative, interpretive approach using one-to-one in-depth interviews to explore the lived experience of pregnant women with obesity following referral to an antenatal dietetics service. Thematic content analysis was carried out by two researchers independently to develop data-driven themes. SETTING: one NHS Trust maternity and dietetic services, North East England, UK. PARTICIPANTS: fifteen pregnant women with a booking body mass index >=30kg/m2 attending an obesity-specific antenatal dietetic service. All women were White, parity between 0 and 2, and BMI range 30-51kg/m2. FINDINGS: four themes were identified. (1) Women's overall experience of the service: experiences were predominately positive with only two negative cases identified. (2) Process of referral: women placed importance on informative and in-person communication about the service, with health professionals, at the point of referral. (3) Delivery of the service: dietitians were considered to be the experts and women wanted more frequent contact. (4) Content of the service: tailored advice enabled behaviour change, and women desired increased physical activity support and weight monitoring. KEY CONCLUSIONS: women reported an overall positive experience and thought that dietitians were the expert health professionals to support them. Women in this study felt that tailoring advice specific to their personal circumstances helped them implement changes, and had a strong interest in the nutritional benefits for fetal development. Women considered weight monitoring to be a positive element of the service; however, further research is required given the limited and conflicting evidence-base. IMPLICATIONS FOR PRACTICE: it is important to incorporate women's experiences in the development and delivery of antenatal weight management services to facilitate person-centred care. Communication by health professionals at the point of referral is particularly important to provide accurate expectations of services and to reduce anxieties. Dietitians are considered to be appropriate experts to deliver these services, although they may need additional support to address women's physical activity needs in pregnancy. PMID- 27986357 TI - Interaction of Left Ventricular Remodeling and Regional Dyssynchrony on Long-Term Prognosis after Cardiac Resynchronization Therapy. AB - BACKGROUND: Left ventricular (LV) remodeling in heart failure (HF) manifested by chamber dilatation is associated with worse clinical outcomes. However, the impact of LV dilatation on the association of measures of dyssynchrony with long term prognosis and resynchronization potential after cardiac resynchronization therapy (CRT) remains unclear. METHODS: Two hundred sixty CRT patients in New York Heart Association classes II to IV, with ejection fractions <= 35% and QRS intervals >= 120 msec, were prospectively studied. Quantitative echocardiographic assessment of LV volumes and mechanical dyssynchrony by radial strain was conducted at both baseline and 6-month follow-up. Primary outcome events were predefined as death or HF hospitalization, and secondary outcome events were defined as all-cause death over the 4 years after CRT. RESULTS: Patients were divided into two groups using the median of the baseline indexed LV end-diastolic volume (EDVI). Patients with less dilated left ventricles (EDVI < 90 mL/m2) had improved prognosis compared to those with severely dilated left ventricles (EDVI >= 90 mL/m2) for both primary (adjusted hazard ratio [HR], 2.20; 95% CI, 1.44 3.38; P < .01) and secondary (adjusted HR, 1.94; 95% CI, 1.21-3.11; P < .01) events. Similarly, reduction in baseline dyssynchrony was associated with good prognosis for both the primary (HR, 0.39; 95% CI, 0.23-0.68; P = .001) and secondary (HR, 0.41; 95% CI, 0.22-0.75; P = .004) events. A linear association was found between each 10% reduction in dyssynchrony and events (P < .01). Notably, patients with less dilated left ventricles had nearly fourfold more frequent improvement in dyssynchrony compared to those with severely dilated left ventricles (odds ratio, 4.10; 95% CI, 1.81-9.28; P < .01). No other baseline prognostic marker was associated with the resynchronization ability of CRT. CONCLUSIONS: Patients with severe LV remodeling (EDVI >= 90 mL/m2) have a poor prognosis following CRT device implantation. This is most likely due to impaired resynchronization efficacy. PMID- 27986358 TI - Novel Ultrasound Methods to Investigate Carotid Artery Plaque Vulnerability. AB - Features of vulnerable plaque include a high lipid content, an irregular shape, a thin fibrous cap, and neovascularization, but such lesions often fall into the category of nonstenotic, despite being at high risk for rupture, and therefore may be overlooked. In this review, the authors describe state-of-the-art investigative ultrasound methods to assess the activity, quality, and morphology of atherosclerotic plaque to determine vulnerability. Specifically, the authors focus on carotid artery plaque, describing the assessment of plaque activity through the detection of neovascularization using contrast-enhanced ultrasound, the characterization of plaque quality by advanced grayscale and integrated backscatter analysis methods, and the assessment of plaque morphology using three dimensional ultrasound. PMID- 27986359 TI - Commonly Used Echocardiographic Diastolic Function Parameters and Left Atrial Appendage Thrombus. PMID- 27986360 TI - Authors' Reply. PMID- 27986361 TI - Systematic review and meta-analysis of the effectiveness of antiseptic agents for meatal cleaning in the prevention of catheter-associated urinary tract infections. AB - BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) are among the most common healthcare-associated infections. Antiseptic cleaning of the meatal area before and during catheter use may reduce the risk of CAUTIs. AIM: To undertake a systematic review of the literature and meta-analysis of studies investigating the effectiveness of antiseptic cleaning before urinary catheter insertion and during catheter use for prevention of CAUTIs. METHODS: Electronic databases were searched to identify randomized controlled trials. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated and compared across intervention and control groups using DerSimonian-Laird random-effects model. Subgroup analyses were performed. Heterogeneity was estimated using the I2 statistic. FINDINGS: In total, 2665 potential papers were identified; of these, 14 studies were eligible for inclusion. There was no difference in the incidence of CAUTIs when comparing antiseptic and non-antiseptic agents (pooled OR 0.90, 95% CI 0.73-1.10; P=0.31), or when comparing different agents: povidone-iodine vs routine care; povidone-iodine vs soap and water; chlorhexidine vs water; povidone iodine vs saline; povidone-iodine vs water; and green soap and water vs routine care (P>0.05 for all). Comparison of an antibacterial agent with routine care indicated near significance (P=0.06). There was no evidence of heterogeneity (I2=0%; P>0.05). Subgroup analyses showed no difference in the incidence of CAUTIs in terms of country, setting, risk of bias, sex and frequency of administration. CONCLUSIONS: There were no differences in CAUTI rates, although methodological issues hamper generalizability of this finding. Antibacterial agents may prove to be significant in a well-conducted study. The present results provide good evidence to inform infection control guidelines in catheter management. PMID- 27986362 TI - Acute focal bacterial nephritis in a cohort of hospitalized adult patients with acute pyelonephritis. Assessment of risk factors and a predictive model. AB - BACKGROUND: Acute focal bacterial nephritis (AFBN) is a complicated form of acute pyelonephritis (APN) characterized by single or multiple areas of localised infection in the kidney without liquefaction or abscess. Studies investigating AFBN in adults are scarce. AIM: The present study was aimed at evaluating the prevalence, associated factors, and presence of atypical clinical and radiological manifestations in adult AFBN patients. Also, we developed a clinical prediction model to evaluate the probability of AFBN in patients with APN. METHODS: The clinical records of 377 patients (mean age 54years, 74.0% females) admitted to a hospital over a 5-year period with APN were reviewed. RESULTS: A total of 57 cases of AFBN were radiologically identified (prevalence, 15.1%). Patients with AFBN were younger and displayed atypical manifestations more frequently than patients without AFBN; these included both clinical and radiological (pleural effusion, gallbladder wall thickening, fluid around the gallbladder, perirenal fluid, and ascites) manifestations. Patients with AFBN showed lower systolic blood pressure and needed more days of therapy to become afebrile, longer total duration of antibiotic therapy, and longer hospital stay than patients without AFBN. Contraceptive use was more frequent in patients with AFBN. A model based on five clinical variables showed good discrimination performance for the diagnosis of AFBN (Area under the curve, 0.77 (95% CI, 0.69 0.89)). CONCLUSIONS: Patients with AFBN frequently present with atypical clinical and radiological manifestations. Clinical presentation by means of a predictive model may predict the presence of AFBN. Patients with AFBN need more intensive therapy, which is followed by a favourable outcome. PMID- 27986364 TI - The evolving clinical management of cerebral metastases. AB - Concepts in the management of brain metastases are evolving. Until recently, brain metastases have been considered as a homogenous condition, managed with whole brain radiotherapy, surgical resection for large lesions and stereotactic radiosurgery for smaller lesions. Increasingly, specific systemic medical therapies are being used to treat brain metastases based on the primary site of disease. This disease specific management is causing a change in perspective about brain metastases and has led to improved survival for patients with primary disease subtypes amenable to tailored medical therapies. We review the recent literature to present evidence for the use of subtype specific medical therapies, advances in surgical resection techniques and stereotactic radiosurgery as the primary treatment modalities. The decline in use of whole brain radiotherapy as first line treatment is also discussed. Based on the recent literature, we propose a new management algorithm to reflect the progress in available options for tailoring disease specific treatments and support the change in paradigm to consider brain metastases as separate disease states based on the primary site of cancer rather than as a homogenous entity. PMID- 27986363 TI - Efficacy of FOLFOXIRI plus bevacizumab in liver-limited metastatic colorectal cancer: A pooled analysis of clinical studies by Gruppo Oncologico del Nord Ovest. AB - Secondary resection is a chance of cure for a subgroup of metastatic colorectal cancer (mCRC) patients with unresectable liver-limited disease. Medical treatment has a dual goal: to induce tumour shrinkage and to prevent disease relapse. The aims of the present analysis were to assess the efficacy of FOLFOXIRI plus bevacizumab in this setting, and to investigate whether this regimen could revert the poor prognosis of high-risk patients defined by clinical and molecular factors. We performed a pooled analysis of patients with unresectable and liver limited mCRC, treated with first-line FOLFOXIRI plus bevacizumab in three prospective clinical trials by Gruppo Oncologico del Nord Ovest. 205 (37.9%) patients with liver-limited disease were selected, out of 541 treated patients. Liver metastases were synchronous, >=4 and bilobar in 90%, 61%, and 79% of cases, respectively. The largest diameter was >5 cm in 42% of cases, and >=6 segments were involved in 25%. Seventy-four patients (36.1%) underwent R0 or R1 resection of metastases. R2 resections were performed in 17 cases (8.3%). Having <6 involved segments (p < 0.001) and achieving RECIST response (p = 0.019) were associated with higher chances of resection. R0/R1 resected patients had significantly longer median progression-free survival (PFS) (18.1 versus 10.7 months, HR: 0.48 [0.35-0.66], p < 0.001) and overall survival (OS) (44.3 versus 24.4 months, HR: 0.32 [0.22-0.48], p < 0.001) compared with other patients, both in the univariate and multivariate analyses (PFS p = 0.025; OS p < 0.001). The 5 year PFS and OS rate in R0 resected patients were 12% and 43%, respectively. Neither negative baseline characteristics nor high clinical risk scores or RAS/BRAF mutations were associated with poor post-resection outcomes. In conclusion, FOLFOXIRI plus bevacizumab demonstrates efficacy in the conversion setting with considerable long-term outcome results independent of clinical and molecular prognostic factors (NCT00719797, NCT01163396 and NCT02271464). PMID- 27986365 TI - Silicon-dioxide-polyvinylpyrrolidone as a wound dressing for skin defects in a murine model. AB - OBJECTIVE: There is a high demand for temporary wound dressings that improve wound healing and regeneration. Silicon (as SiO2) has been shown to support the growth and collagen formation in biological systems. METHODS: A nanocomposite was made from PVP (polyvinylpyrrolidon), nano-sized silica aggregates and water and served for fabrication of a wet dressing material (SiO2-PVP gel, by cross-linking the gel) and a freeze-dried dressing material (SiO2-PVP fleece). Materials were characterized by SAXS, DSC, EDX and viscosity measurements. A 10 mm circular defect was set on both sides of the back of SKH1-hr mice (n = 40) and both dressing materials were compared with untreated controls. After 3, 6, 9, 12 and 15 days, the defect regions were explanted and evaluated by histomorphometric measurements and CD31-immunohistochemistry. RESULTS: The microstructure of the compound was composed of fiber like structures. SiO2 nano-aggregates inside the composite remained stable and embedded in a rigid amorphous PVP fraction. In animal experiments, all groups showed a non-irritated defect closure after 9 days. EDX of SiO2-PVP gel and fleeces revealed SiO2-PVP diffusion into the wound. Wound contraction was significantly enhanced after treatment with SiO2-PVP gel followed by SiO2-PVP fleece compared to controls. Re-epithelialization was increased in SiO2-PVP treated wounds and the regenerated epidermis showed a well differentiated layer structure compared to untreated controls. CONCLUSIONS: The results indicate that silica diffuses from the dressing into the wound. Both dressings affect the wound healing. The SiO2-based wound dressing may counteract scarring and might be suitable as a temporary wound dressing. PMID- 27986366 TI - End-tidal CO2 relates to seasickness susceptibility: A study in Antarctic voyages. AB - OBJECTIVE: To investigate the relationship between end-tidal CO2 (EtCO2) and seasickness (motion sickness at sea) during an Antarctic voyage. METHODS: In this study, we measured EtCO2 and severity of seasickness using the subjective symptoms of motion sickness (SSMS). We sampled EtCO2 and SSMS every 3-4h for 3 days from the date of sail in 16 healthy subjects. This experiment was performed on an icebreaker (standard displacement: 12,650t). RESULTS: Since 2 subjects dropped out because of severe motion sickness, available data were collected from 14 subjects. On analysis of all data of all subjects grouped together, there seemed to be a significant negative correlation between EtCO2 and SSMS (R=-0.27, P=0.0005). However, in individual subjects, this correlation was not obvious. During the voyage, EtCO2 level in the seasickness susceptible group was lower than that in the non-susceptible group (P=0.018). Both EtCO2 increasing in the non-susceptible group and decreasing in the susceptible group contribute to the difference in EtCO2 levels. We suggest that the cause of this increase in EtCO2 level in the non-susceptible group was unwitting slow and deep breathing to resist seasickness. CONCLUSION: We revealed that for seasickness during an Antarctic voyage, EtCO2 level relates to susceptibility, but not occurrence or severity. Measurement of EtCO2 levels may be useful to identify seasickness susceptible persons and to efficiently prevent seasickness. PMID- 27986367 TI - Translating the 'Sugar Code' into Immune and Vascular Signaling Programs. AB - The vast range and complexity of glycan structures and their dynamic variations in health and disease have presented formidable challenges toward understanding the biological significance of these molecules. Despite these limitations, compelling evidence highlights a major role for galectins, a family of soluble glycan-binding proteins, as endogenous decoders that translate glycan-containing information into a broad spectrum of cellular responses by modulating receptor clustering, reorganization, endocytosis, and signaling. Here, we underscore pioneer findings and recent advances in understanding the biology of galectin glycan interactions in myeloid, lymphoid, and endothelial compartments, highlighting important pathways by which these multivalent complexes control immune and vascular programs. Implementation of novel glycoanalytical approaches, as well as the use of genetically engineered cell and organism models, have allowed glycans and galectins to be explored across a range of cellular processes. PMID- 27986368 TI - Extraprostatic Extension Is Extremely Rare for Contemporary Gleason Score 6 Prostate Cancer. AB - BACKGROUND: A significant proportion of men with Gleason score 6 (GS6) prostate cancer undergo treatment with radiation or surgery. OBJECTIVE: To assess pathologic stage of pure GS6 at radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: In the period 2003-2014, 7817 patients underwent RP at two institutions. Of 2502 patients with GS6 at surgery, 60 were identified as stage pT3a-b on initial pathologic review, 55 with pT3a (extraprostatic extension, EPE), and five with pT3b (seminal vesicle invasion; SVI). All cases of GS6 with pT3 disease underwent contemporary pathologic evaluation for Gleason grade, stage, and extent of EPE. At one institution, all GS>=7 pT3b cases were re reviewed for downgrading. The 2014 International Society of Urological Pathology (ISUP) Gleason grading criteria and 2009 ISUP recommendations on pT3 staging were applied. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Calculated incidence (%) of pT3a, pT3b, pT4, and lymph node-positive disease. RESULTS AND LIMITATIONS: Of the 60 GS6 pT3a-b cases identified in the period 2003-2014, seven (0.28% of entire GS6 cohort) with GS6 and pT3a were identified after re-review, all focal EPE. Among the re-examined cohort, no cases of GS6 with pT3b were observed. None of the 132 GS>=7 pT3b cases were downgraded to GS6. Limitations include partial embedding of specimens and separate pathologic review at each institution. CONCLUSIONS: In a large prostatectomy cohort, GS6 never had seminal vesicle invasion (0%) and was very rarely (0.28%) associated with extraprostatic extension. PATIENT SUMMARY: GS6 prostate cancer rarely spreads outside the prostate. A new finding in this study was that GS6 prostate cancer never spread to the seminal vesicles. PMID- 27986369 TI - Updated European Association of Urology Guidelines Regarding Adjuvant Therapy for Renal Cell Carcinoma. AB - : The European Association of Urology Renal Cell Carcinoma (RCC) guidelines panel updated their recommendation on adjuvant therapy in unfavourable, clinically nonmetastatic RCC following the recently reported results of a second randomised controlled phase 3 trial comparing 1-yr sunitinib to placebo for high-risk RCC after nephrectomy (S-TRAC). On the basis of conflicting results from the two available studies, the panel rated the quality of the evidence, the harm-to benefit ratio, patient preferences, and costs. Finally, the panel, including representatives from a patient advocate group (International Kidney Cancer Coalition) voted and reached a consensus to not recommend adjuvant therapy with sunitinib for patients with high-risk RCC after nephrectomy. PATIENT SUMMARY: In two studies, sunitinib was given for 1 yr and compared to no active treatment (placebo) in patients who had their kidney tumour removed and who had a high risk of cancer coming back after surgery. Although one study demonstrated that 1 yr of sunitinib therapy resulted in a 1.2-yr longer time before the disease recurred, the other study did not show a benefit and it has not been shown that patients live longer. Despite having been diagnosed with high-risk disease, many patients remain without recurrence, and the side effects of sunitinib are high. Therefore, the panel members, including patient representatives, do not recommend sunitinib after tumour removal in these patients. PMID- 27986370 TI - Effects of ethyl chloride spray on early recovery after total knee arthroplasty: A prospective study. AB - BACKGROUND: Ethyl chloride spray as a common cooling modality has been widely used in acute sports injuries and joint injection procedures. Several clinical studies reported that use of ethyl chloride has positive effects on swelling, pain reduction and recovery from sports injuries. The main aim of present study was to analyze whether postoperative use of ethyl chloride spray benefits results after primary total knee arthroplasty (TKA). METHODS: Between April 1, 2014 and October 21, 2015, 306 subjects undergoing primary TKA used ethyl chloride spray for improving recovery from the damage from surgery. After exclusion of 31 subjects due to adverse events including periprosthetic joint infection (PJI), deep venous thrombosis (DVT), acute myocardial infarction, finally 275 subjects' data regarding pain score, knee range of motion (ROM), knee girth, time of being able to reach 90 degrees knee flexion and analgesic consumption were analyzed. RESULTS: Significant differences in pain score, knee ROM at each time point and knee girth at on 21st and 28th postoperatively were detected without increased incidence of adverse events. Besides, time of being able to reach 90 degrees knee flexion and analgesic consumption in the treatment group were significantly decreased in comparison to the control group. CONCLUSION: Use of ethyl chloride spray can help patients recovery from the damage from TKA safely. PMID- 27986372 TI - Introduction to the Addendum Guidelines for the Prevention of Peanut Allergy in the United States. PMID- 27986371 TI - Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway. AB - Monoubiquitination and deubiquitination of FANCD2:FANCI heterodimer is central to DNA repair in a pathway that is defective in the cancer predisposition syndrome Fanconi anemia (FA). The "FA core complex" contains the RING-E3 ligase FANCL and seven other essential proteins that are mutated in various FA subtypes. Here, we purified recombinant FA core complex to reveal the function of these other proteins. The complex contains two spatially separate FANCL molecules that are dimerized by FANCB and FAAP100. FANCC and FANCE act as substrate receptors and restrict monoubiquitination to the FANCD2:FANCI heterodimer in only a DNA-bound form. FANCA and FANCG are dispensable for maximal in vitro ubiquitination. Finally, we show that the reversal of this reaction by the USP1:UAF1 deubiquitinase only occurs when DNA is disengaged. Our work reveals the mechanistic basis for temporal and spatial control of FANCD2:FANCI monoubiquitination that is critical for chemotherapy responses and prevention of Fanconi anemia. PMID- 27986373 TI - School Experiences of Siblings of Children with Chronic Illness: A Systematic Literature Review. AB - PROBLEM: Siblings of children with chronic illness have unique experiences that can affect their school functioning, such that they may miss ongoing periods of school, experience difficulties with schoolwork or experience changes in their peer and teacher interactions. This review provides an overview of these siblings' school experiences. ELIGIBILITY CRITERIA: Six databases (Medline, PsychINFO, CINAHL, ERIC, Embase and The Cochrane Library) were systematically searched for studies examining the school experiences and peer relationships of siblings of children with chronic illness, as well as school-based interventions for these siblings. Studies were included if they were published in or after 2000 and were published in English. SAMPLE: We identified 2137 articles upon initial search. From these, we identified 28 eligible studies examining the school experiences of >1470 siblings of children with chronic illness. RESULTS: Three key themes were identified throughout the reviewed articles. The literature described 1) the psychological impact on siblings at school; 2) decreases in school attendance and academic functioning, and; 3) changes or perceived differences in peer and teacher interactions. Siblings value teacher and peer support, and this support may contribute to better sibling school functioning. CONCLUSIONS: Many siblings are socially resilient, yet overlooked, members of the family who may present with psychological, academic and peer related difficulties at school following diagnosis of a brother or sister with chronic illness. IMPLICATIONS: Future research is needed to further delineate the sibling school experience to better facilitate the development of targeted sibling support interventions within the school environment. PMID- 27986374 TI - Evaluating the effect of time from prostate cancer diagnosis to radical prostatectomy on cancer control: Can surgery be postponed safely? AB - OBJECTIVE: To test the prognostic role of treatment delay in patients affected by prostate cancer (PCa). MATERIALS AND METHODS: The study included 2,653 patients treated with radical prostatectomy (RP) at a single institution between 2006 and 2011. The evaluated outcomes were biochemical recurrence (BCR) and clinical recurrence (CR). Multivariable Cox regression analysis was used to test the association between time from diagnosis to RP and oncological outcomes. Nonparametric curve fitting methods were used to graphically explore the relationship between time from diagnosis to RP and oncological outcomes. Sensitivity analyses were repeated in the subgroups of low-, intermediate-, and high-risk patients. RESULTS: At median follow-up of 56 months (interquartile range: 26, 92), 283 patients experienced BCR, and 84 patients developed CR. Median time from PCa diagnosis to surgery was 2.8 months (interquartile range: 1.6, 4.7). At multivariable Cox regression analysis, time from biopsy to RP was significantly associated with an increased risk of BCR (hazard ratio = 1.02, P = 0.0005) and CR (hazard ratio = 1.03, P = 0.0002). Using Nonparametric curve fitting methods, a significant increased risk of BCR and CR after approximately 18 months was observed. However, when sensitivity analyses were repeated according to risk groups, this effect was maintained in high-risk patients only, and such time interval was reduced to 12 months. CONCLUSIONS: Despite the overall trend on higher rate of cancer relapse after RP, the effect of treatment delay from biopsy to RP was significantly evident in high-risk patients only. Even in high-risk patients surgical treatment can be postponed safely, but not beyond the 12-month landmark. PMID- 27986375 TI - Biological evaluation of a new pulp capping material developed from Portland cement. AB - This study evaluates the biological properties of a new pulp capping material developed from Portland cement. This study was conducted on 48 teeth in 4 dogs (12 teeth/dog). The dogs were classified into two equal groups (n=24 teeth) according to the evaluation period including: group A (3 weeks) and group B (3 months). Each group was further subdivided into three equal subgroups (n=8 teeth) according to the capping material including: subgroup 1: mineral trioxide aggregate (MTA), subgroup2: Portland cement+10% calcium hydroxide+20% bismuth oxide (Port Cal) and subgroup 3: Portland cement+bismuth oxide. After general anesthesia, a class V buccal cavity was prepared coronal to the gingival margin. After pulp exposure and hemostasis,the capping materials and glass ionomer filling were placed on the exposure sites. All histopathological findings, inflammatory cell count and dentin bridge formation were recorded. Data were analyzed statistically. After 3 months, the histopathological picture of the pulp in subgroup 1 showed normal pulp, continuous odontoblastic layer and complete dentin bridge formation while subgroup 2 showed partial and complete dentin bridge over a normal and necrotic pulps. Subgroup 3 showed loss of normal architecture, areas of necrosis, complete, or incomplete dentin bridge formation, attached and detached pulp stones and fatty degeneration in group B. For group A, MTA subgroup showed the least number of inflammatory cell infiltrate followed by Port Cal subgroup. While subgroup 3 showed the highest number of inflammatory cell infiltrate. For group B, the mean inflammatory cell count increased with the three tested materials with no statistical difference. Regarding dentin bridge formation at group A, no significant differences was found between subgroups, while at group B, MTA subgroup exhibited significantly higher scores than other subgroups. In conclusion, addition of calcium hydroxide to Portland cement improves the dentin bridge formation qualitatively and quantitatively. PMID- 27986376 TI - Bilateral upregulation of alpha-synuclein expression in the mouse substantia nigra by intracranial rotenone treatment. AB - The pesticide rotenone has been shown to cause systemic inhibition of mitochondrial complex I activity, with consequent degeneration of dopamine neurons along the nigrostriatal pathway, as observed in Parkinson's disease (PD). Recently, intracranial infusion of rotenone was found to increase the protein levels of the Lewy body constituents, alpha-synuclein and small ubiquitin-related modifier-1(SUMO-1), in the lesioned hemisphere of the mouse brain. These findings are supportive of a mouse model of PD, but information about the dopamine synthesizing enzyme, tyrosine hydroxylase (TH), an essential marker of dopaminergic status, was not reported. Clarification of this issue is important because an intracranial rotenone mouse model of Parkinson's disease has not been established. Towards this end, the present study examined the effects of intracranial rotenone treatment on TH and alpha-synuclein immunohistochemistry in addition to forelimb motor function. Mice were unilaterally infused with either vehicle or rotenone (2MUg/site) in both the medial forebrain bundle and the substantia nigra. The forelimb asymmetry (cylinder) test indicated a significant decrease in use of the contralateral forelimb in lesioned animals as compared to the sham group. Densitometric analysis revealed a significant depletion of TH immunofluorescence within the ipsilateral striatum and substantia nigra of lesioned animals. Moreover, a significant bilateral increase in alpha-synuclein immunofluorescence was found in the substantia nigra of lesioned mice, as compared to control animals. These findings indicate that this intracranial rotenone mouse model will be useful for studies of neurodegenerative disorders such as PD. PMID- 27986377 TI - Vocal Fry Use in Adult Female Speakers Exposed to Two Languages. AB - OBJECTIVE: Several studies have identified the widespread use of vocal fry among American women. Popular explanations for this phenomenon appeal to sociolinguistic purposes that likely take significant time for second language users to learn. The objective of this study was to determine if mere exposure to this vocal register, as opposed to nuanced sociolinguistic motivations, might explain its widespread use. STUDY DESIGN: This study used multigroup within- and between-subjects design. METHODS: Fifty-eight women from one of three language background groups (functionally monolingual in English, functionally monolingual in Spanish, and Spanish-English bilinguals) living in El Paso, Texas, repeated a list of nonwords conforming to the sound rules of English and another list of nonwords conforming to the sound rules of Spanish. Perceptual analysis identified each episode of vocal fry. RESULTS: There were no statistically significant differences between groups in their frequency of vocal fry use despite large differences in their amount of English-language exposure. All groups produced more vocal fry when repeating English than when repeating Spanish nonwords. CONCLUSIONS: Because the human perceptual system encodes for vocal qualities even after minimal language experience, the widespread use of vocal fry among female residents in the United States likely is owing to mere exposure to English rather than nuanced sociolinguistic motivations. PMID- 27986378 TI - Human Papillomavirus Infection Status of Various Laryngeal Diseases in Japan: A Comprehensive Study. AB - OBJECTIVE: The aim of our study was to clarify the human papillomavirus (HPV) infection status of various laryngeal diseases in Tokyo, Japan. STUDY DESIGN: This is a retrospective study. METHODS: A total of 144 patients who underwent surgical resection for various laryngeal lesions were enrolled in this study. These subjects were categorized into four groups based on lesion type: non neoplastic, 44; precancerous, 29; cancer, 35; and papilloma, 36. To determine the rate of HPV infection, laryngeal secretions and resected tissue from our study participants were examined by liquid-phase hybridization (LPH) and consensus primer-directed polymerase chain reaction (PCR). RESULTS: The LPH for low-risk HPV was applied to all 144 patients, and that for high-risk HPV was additionally applied to 121 of the 144 patients. The PCR was applied to 94 of the 144 patients. The LPH detected low-risk HPV-DNA in 23 patients (1 cancer and 22 papillomas) and high-risk HPV-DNA in 3 patients (1 cancer and 2 papillomas). The PCR detected HPV-6 and HPV-11 in the papilloma group, whereas it detected HPV-31 in one patient with laryngeal cancer and one patient with precancerous lesion. Both the LPH and the PCR revealed the HPV infection rate in the non-neoplastic group to be 0%. CONCLUSIONS: Although we found no significant difference in the HPV-DNA positive rates of laryngeal cancer and precancerous lesions in the non neoplastic group, the positive rates were significantly smaller in this group than in the papilloma group. In the Tokyo area, HPV had little or no association with laryngeal cancer, precancerous lesions, and non-neoplastic lesions in the larynx. PMID- 27986379 TI - Lung nodule classification using deep feature fusion in chest radiography. AB - Lung nodules are small, round, or oval-shaped masses of tissue in the lung region. Early diagnosis and treatment of lung nodules can significantly improve the quality of patients' lives. Because of their small size and the interlaced nature of chest anatomy, detection of lung nodules using different medical imaging techniques becomes challenging. Recently, several methods for computer aided diagnosis (CAD) were proposed to improve the detection of lung nodules with good performances. However, the current methods are unable to achieve high sensitivity and high specificity. In this paper, we propose using deep feature fusion from the non-medical training and hand-crafted features to reduce the false positive results. Based on our experimentation of the public dataset, our results show that, the deep fusion feature can achieve promising results in terms of sensitivity and specificity (69.3% and 96.2%) at 1.19 false positive per image, which is better than the single hand-crafted features (62% and 95.4%) at 1.45 false positive per image. As it stands, fusion features that were used to classify our candidate nodules have resulted in a more promising outcome as compared to the single features from deep learning features and the hand-crafted features. This will improve the current CAD method based on the use of deep feature fusion to more effectively diagnose the presence of lung nodules. PMID- 27986380 TI - Evaluation of the magnitude of hip joint deformation in subjects with avascular necrosis of the hip joint during walking with and without Scottish Rite orthosis. AB - The femoral head in subjects with leg calve perthes disease (LCPD) is generally considerably deformed. It is debatable whether this deformation is due to an increase in applied loads, a decrease in bone mineral density or a change in containment of articular surfaces. The aim of this study was to determine the influence of these factors on deformation of the femoral head. Two subjects with LCPD participated in this study. Subject motion and the forces applied on the affected leg were recorded using a motion analysis system (QualsisTM) and a Kistler force plate. OpenSim software was used to determine joint contact force of the hip joint whilst walking with and without a Scottish Rite orthosis. 3D Models of hip joints of both subjects were produced by Mimics software. The deformation of femoral bone was determined by Abaqus. Mean values of the force applied on the leg increased while walking with the orthosis. There was no difference between bone mineral density (BMD) of the femoral bone of normal and LCPD sides (p-value>0.05) and no difference between hip joint contact force of normal and LCPD sides. Hip joint containment appeared to decrease follow the use of the orthosis. It can be concluded that the deformation of femoral head in LCPD may not be due to change in BMD or applied load. Although the Scottish Rite orthosis is used mostly to increase hip joint containment, it appears to reduce hip joint contact area. It is recommended that a similar study is conducted using a higher number of subjects. PMID- 27986381 TI - Metal Oxide Reduction Linked to Anaerobic Methane Oxidation. AB - Microbial methanotrophy is important in mitigating methane emissions to the atmosphere. Geochemical evidence suggests the occurrence of anaerobic methane oxidation with metal oxides in natural environments. A study has now identified, for the first time, novel freshwater archaea of the order Methanosarcinales that can oxidize methane with Fe(III) and Mn(IV) minerals as electron acceptors. PMID- 27986382 TI - Dacryocystorhinostomy for Acquired Nasolacrimal Duct Stenosis in the Elderly (>=80 Years of Age). AB - PURPOSE: The incidence of acquired nasolacrimal duct obstruction (NLDO) increases with age. Dacryocystorhinostomy, the definitive treatment for NLDO, has a high success rate (80%-100%) with a low complication rate (1%-6%), but surgical outcomes have not been reported previously specifically for an elderly population, in which there may be increased risk for intraoperative and postoperative complications. The purpose of this study was to examine surgical outcomes and complication rates of dacryocystorhinostomy in an elderly population. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients 80 years of age or older undergoing external dacryocystorhinostomy at the Mayo Clinic between January 1, 1990, and December 31, 2010, were compared with a matched control group of younger patients (40-79 years of age) undergoing external dacryocystorhinostomy by the same surgeons. METHODS: We reviewed the medical charts for patients as described above. Data abstracted from patient medical records included symptomatic relief and complications such as tube protrusion, infection, persistent bleeding, and return to operating room. Statistical analysis included a 2-sample t test to compare continuous variables, chi-square testing for categorical comparisons, and the generalized estimating equation model to control for nonindependence. MAIN OUTCOME MEASURES: Primary end point was symptomatic improvement at last follow-up. Secondary end points included anatomic patency, adverse event rate, and return to operating room within 1 month of surgery. RESULTS: Forty-two dacryocystorhinostomies (32 patients) were performed in the elderly group. The control group comprised 73 dacryocystorhinostomies in 63 patients. Resolution of symptom rate at last follow up was 64% in the elderly group versus 86% in the younger cohort (P = 0.02). Although there was no difference between groups with respect to common postoperative complications, there was a higher rate of predefined serious complications in the elderly group (5 events vs. 1 event; P = 0.01). There was no difference between groups regarding need for additional eyelid surgery (P = 0.30). CONCLUSIONS: Although most elderly patients experience symptom resolution after dacryocystorhinostomy, the rate of symptom resolution was lower than that of younger patients. The risk of routine complications was similar between the groups. The risk of serious complications was higher in the elderly group. PMID- 27986383 TI - Correlation between Stereopsis and Reverse Stereopsis. PMID- 27986384 TI - Cystoid Macular Edema after Descemet's Stripping Automated Endothelial Keratoplasty. PMID- 27986386 TI - Intraocular Hemorrhages and Retinopathy of Prematurity in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study. AB - PURPOSE: To describe the clinical characteristics of intraocular hemorrhages (IOHs) in infants in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study and to evaluate their potential use for prediction of disease severity. DESIGN: Secondary data analysis from a prospective study. PARTICIPANTS: Preterm infants with birth weight (BW) <=1250 g. METHODS: Infants underwent serial digital retinal imaging in both eyes starting at 32 weeks' postmenstrual age. Nonphysician trained readers (TRs) evaluated all image sets from eyes that ever had IOHs documented on image evaluation or eye examination for the presence, location, type, area, and relation of the IOH to the junction between vascularized and avascular retina. Associations of IOH with demographic and neonatal factors, and with the presence and severity of retinopathy of prematurity (ROP) were investigated by univariate and multivariate analyses. Sensitivity and specificity of the telemedicine system for detecting referral-warranted ROP (RW-ROP) were calculated with and without incorporating hemorrhage into the standardized grading protocol. MAIN OUTCOME MEASURES: Retinal and vitreous hemorrhage. RESULTS: Among 1239 infants (mean [standard deviation] BW = 864 [212] g; gestational age [GA] = 27 [2.2] weeks) who underwent an average of 3.2 imaging sessions, 22% had an IOH in an eye on at least 1 of the e-ROP visits. Classification of IOH was preretinal (57%), blot (57%), dot (38%), flame shaped (16%), and vitreous (8%); most IOHs were unilateral (70%). The IOH resolved in 35% of eyes by the next imaging session and in the majority (76%) of cases by 8 weeks after initial detection. Presence of IOH was inversely associated with BW and GA and significantly associated (P < 0.0001) with the presence and severity of ROP (BW and GA adjusted odds ratios [ORs] of 2.46 for any ROP, 2.88 for stage 3, and 3.19 for RW-ROP). Incorporating IOH into the grading protocol minimally altered the sensitivity of the system (94% vs. 95%). CONCLUSIONS: Approximately 1 in 5 preterm infants examined had IOHs, generally unilateral. The presence of hemorrhage was directly correlated with both presence and severity of ROP and inversely correlated with BW and GA, although including hemorrhage in the grading algorithm only minimally improved the sensitivity of the telemedicine system to detect RW-ROP. PMID- 27986387 TI - An observational cross-sectional study on the corneal endothelium of medium-term rigid gas permeable contact lens wearers. AB - PURPOSE: To assess if polymegethism and pleomorphism were evident in corneal endothelium after medium-term rigid gas permeable (RGP) contact lens wear. METHODS: In a cross-sectional observational study over 12 years, single images of the central region of the corneal endothelium of one eye of 46 subjects were taken with a non-contact specular microscope, along with a measure of central corneal thickness (CCT). The images were printed onto A3-sized paper and 100 cells/image measured by planimetry. RESULTS: Subjects aged between 20 and 32 years, with an average cumulative RGP wear of 6.0+/- 1.6 years (range 3-9 years) were assessed; 26 of the subjects were Caucasian and 20 were Asian. The mean CCT was 0.515+/- 0.027mm. The group cell area value was 401+/- 42 sq micron to give an estimated endothelial cell density (ECD) of 2520+/- 273 cells/sq mm. As compared to a historical database, most endothelia (37/46) showed some changes with the mean coefficient of variation on cell area (COV) being 36.7+/- 8.0% and the percentage of 6-sided (HEX) being 51.8+/- 8.8%. There were modest correlations between years of RGP wear and both COV (p=0.009, r spearman=0.424) and HEX (p=0.025, r spearman=-0.291), but not for ECD or CCT. CONCLUSIONS: Corneal endothelial polymegethism appears to be a commonplace consequence of RGP lens wear with the magnitude of the change being related to the cumulative duration of the lens wear. PMID- 27986385 TI - Natural History of the Central Structural Abnormalities in Choroideremia: A Prospective Cross-Sectional Study. AB - PURPOSE: To describe in detail the central retinal structure of a large group of patients with choroideremia (CHM). DESIGN: A prospective, cross-sectional, descriptive study. PARTICIPANTS: Patients (n = 97, age 6-71 years) with CHM and subjects with normal vision (n = 44; ages 10-50 years) were included. METHODS: Subjects were examined with spectral-domain optical coherence tomography (SD OCT) and near-infrared reflectance imaging. Visual acuity (VA) was measured during their encounter or obtained from recent ophthalmic examinations. Visual thresholds were measured in a subset of patients (n = 24) with automated static perimetry within the central regions (+/-15 degrees ) examined with SD OCT. MAIN OUTCOME MEASURES: Visual acuity and visual thresholds; total nuclear layer, inner nuclear layer (INL), and outer nuclear layer (ONL) thicknesses; and horizontal extent of the ONL and the photoreceptor outer segment (POS) interdigitation zone (IZ). RESULTS: Earliest abnormalities in regions with normally appearing retinal pigment epithelium (RPE) were the loss of the POS and ellipsoid zone associated with rod dysfunction. Transition zones (TZs) from relatively preserved retina to severe ONL thinning and inner retinal thickening moved centripetally with age. Most patients (88%) retained VAs better than 20/40 until their fifth decade of life. The VA decline coincided with migration of the TZ near the foveal center. There were outer retinal tubulations in degenerated, nonatrophic retina in the majority (69%) of patients. In general, RPE abnormalities paralleled photoreceptor degeneration, although there were regions with detectable but abnormally thin ONL co-localizing with severe RPE depigmentation and choroidal thinning. CONCLUSIONS: Abnormalities of the POS and rod dysfunction are the earliest central abnormalities observed in CHM. Foveal function is relatively preserved until the fifth decade of life. Migration of the TZs to the foveal center with foveal thinning and structural disorganization heralded central VA loss. The relationships established may help outline the eligibility criteria and outcome measures for clinical trials for CHM. PMID- 27986389 TI - [Cerebral hydatid cyst: Clinical case and review of the literature]. AB - Hydatid disease is an accidental parasitosis, with brain location being rare. The case is reported of a 33year-old male, with no history of note, who was admitted to hospital with intracranial hypertension syndrome and right hemiparesis. Computed tomography showed a cystic lesion in the left frontal-parietal lobule. Surgery was performed by complete excision of the lesion, with a good outcome. Hydatid disease is a rare condition in the brain. Clinical suspicion is important for an early diagnosis. A review is presented on the pathogenesis, diagnosis and treatment of cerebral hydatid disease. PMID- 27986390 TI - Severe thrombocytopenia induced by iodinated contrast after coronary angiography: The use of gadolinium contrast and intravascular ultrasound as an alternative to guide percutaneous coronary intervention. AB - Acute contrast-induced thrombocytopenia is a rare event with the use of modern low osmolarity iodinated contrast media. The pathophysiological mechanism that causes platelet counts to drop has not been identified, but an immunological mechanism is suspected due to cytotoxicity after previous exposure to contrast. We report the case of a 47-year-old male patient with acute severe thrombocytopenia due to iodinated contrast media exposure. His platelet count after the procedure with the highest amount of contrast was zero, which is the lowest reported platelet count to date. Percutaneous coronary revascularization under both intravascular ultrasound and gadolinium contrast guidance was performed without complications. The most feared complication after the use of gadolinium is nephrogenic systemic fibrosis, especially in patients on hemodialysis. PMID- 27986391 TI - Simultaneous acute closure of the right coronary artery and left anterior descending artery in a young male. PMID- 27986388 TI - [3D anatomy of cerebellar peduncles based on fibre microdissection and a demonstration with tractography]. AB - OBJECTIVE: To perform an anatomical and radiological study, using fibre microdissection and diffusion tensor tractography (DTT), to demonstrate the three dimensionality of the superior, middle and inferior cerebellar peduncles. MATERIAL AND METHODS: A total of 15 brain-stem, 15 cerebellar hemispheres, and 5 brain hemispheres were dissected in the laboratory under the operating microscope with microsurgical instruments between July 2014 and July 2015. Brain magnetic resonance imaging was obtained from 15 healthy subjects between July and December of 2015, using diffusion-weighted images, in order to reproduce the cerebellar peduncles on DTT. RESULTS: The main bundles of the cerebellar peduncles were demonstrated and delineated along most of their trajectory in the cerebellum and brain-stem, noticing their overall anatomical relationship to one another and with other white matter tracts and the grey matter nuclei the surround them, with their corresponding representations on DTT. CONCLUSIONS: The arrangement, architecture, and general topography of the cerebellar peduncles were able to be distinguished using the fibre microdissection technique. This knowledge has given a unique and profound anatomical perspective, supporting the correct representation and interpretation of DTT images. This information should be incorporated in the clinical scenario in order to assist surgeons in the detailed and critical analysis of lesions that may be located near these main bundles in the cerebellum and/or brain-stem, and therefore, improve the surgical planning and achieve a safer and more precise microsurgical technique. PMID- 27986393 TI - Self-perceived provision of patient centered care by healthcare professionals: The role of emotional intelligence and general self-efficacy. AB - OBJECTIVE: This study aimed to investigate whether healthcare professionals' emotional intelligence (EI) is associated with self-perceived provision of patient-centered care (PCC), taking into account the potential mediating effect of general self-efficacy (GSE). METHODS: A sample of 318 healthcare professionals, recruited in 2015 among four hospitals in Italy, completed the Provider-Patient Relationship Questionnaire, the Emotional Intelligence Scale, and the General Self-Efficacy scale. A structural equation model was tested with GSE mediating the relationship between EI and self-perceived provision of PCC. Groups of participants based on gender, profession, and work setting were also compared on the study variables. RESULTS: EI had direct effects on the self perceived provision of PCC dimensions. GSE partially mediated only the relationship between EI and involving the patient in care. Healthcare professionals in rehabilitation units showed higher self-perceived provision of PCC than those in acute care or ambulatory services. CONCLUSION: Self-perceived provision of PCC seems to have the potential to be improved by EI and to be distinguishable from GSE. PRACTICE IMPLICATIONS: Since EI can be developed, findings of this study have potential implications for improving PCC through continuing education interventions for healthcare professionals. PMID- 27986394 TI - Increased risk of avascular necrosis in patients with psoriatic disease: A nationwide population-based matched cohort study. AB - BACKGROUND: Avascular necrosis (AVN) and psoriasis have some pathogenic mechanisms and associated conditions in common. OBJECTIVE: To examine the association between psoriasis and AVN. METHODS: This study used data from the Taiwan National Health Insurance Research Database for the period 2004-2006 and identified 28,268 patients with psoriasis, who were then matched for age and sex with 113,072 controls without psoriasis from the Taiwan Longitudinal Health Insurance Database 2000. Multivariate Cox proportional hazards models were used for the analysis. RESULTS: The unadjusted risk of AVN was significantly higher for patients with psoriasis than for controls (hazard ratio [HR] 2.29) and remained significant after adjustment for other risk factors (adjusted HR 1.96; 95% confidence interval 1.62-2.38). The risk for AVN increased in relation to psoriasis severity and was higher for patients with psoriasis and arthritis than for patients without arthritis. The adjusted HRs were higher for male patients than for female patients and for patients younger than 30 years compared with older patients. LIMITATIONS: We lacked information on daily tobacco use, alcohol consumption, and physical activity. CONCLUSION: The risk for AVN increased with the disease severity of psoriasis. PMID- 27986392 TI - Solving Immunology? AB - Emergent responses of the immune system result from the integration of molecular and cellular networks over time and across multiple organs. High-content and high throughput analysis technologies, concomitantly with data-driven and mechanistic modeling, hold promise for the systematic interrogation of these complex pathways. However, connecting genetic variation and molecular mechanisms to individual phenotypes and health outcomes has proven elusive. Gaps remain in data, and disagreements persist about the value of mechanistic modeling for immunology. Here, we present the perspectives that emerged from the National Institute of Allergy and Infectious Disease (NIAID) workshop 'Complex Systems Science, Modeling and Immunity' and subsequent discussions regarding the potential synergy of high-throughput data acquisition, data-driven modeling, and mechanistic modeling to define new mechanisms of immunological disease and to accelerate the translation of these insights into therapies. PMID- 27986395 TI - A clinical, histologic, and follow-up study of genital melanosis in men and women. AB - BACKGROUND: Genital melanosis may clinically mimic melanoma. Little is known about the potential risk for genital and nongenital melanoma in these patients. OBJECTIVE: In this retrospective cohort study, we analyzed clinical and histologic data from patients with genital melanosis to better characterize these lesions and the risk they confer for genital and nongenital melanoma. METHODS: In all, 41 patients were identified for a retrospective chart review and histologic analysis. RESULTS: Genital melanosis can clinically mimic melanoma but the typical age of onset is younger than for genital melanoma. A majority of lesions were found to stabilize or regress over time. Five patients were found to have a history of melanoma, only 1 of which was in the genital region. Lesions from these patients were more likely to show melanocytes with suprabasal movement (P = .0101) and to have a higher melanocyte count (P < .0462). LIMITATIONS: We present a relatively small cohort of patients with an average follow-up of only 30.5 months. CONCLUSION: Patients with genital melanosis, and in particular those with any level of histologic atypia in the genital melanosis lesion, may require careful total body skin examinations for the possibility of melanoma in any body site. PMID- 27986396 TI - Relative versus absolute risk of comorbidities in patients with psoriasis. AB - BACKGROUND: Psoriasis is associated with numerous comorbidities, often reported in terms of relative risk. Both doctors and the general population tend to overestimate the effects of exposures when presented in relative terms, leading to anxiety and potentially poor treatment decisions. Absolute risks might provide a better basis for risk assessment. OBJECTIVE: To characterize and compare relative and absolute risks of comorbidities in patients with psoriasis. METHODS: A systematic review using Medline identified comorbidities associated with psoriasis, their relative risks, and information for calculating absolute risks. RESULTS: The comorbidities associated with psoriasis with the highest relative risk were nonmelanoma skin cancer, melanoma, and lymphoma, with relative risks of 7.5, 6.12, and 3.61, respectively; the attributable risk for these 3 conditions were 0.64, 0.05, and 0.17 per 1000 person-years, respectively. To attribute 1 event of these conditions to psoriasis would require seeing 1551; 20,135; and 5823 patients, respectively. LIMITATIONS: Database studies might not fully account for confounders, resulting in overestimates of the risk impact of comorbidities. CONCLUSIONS: Presenting attributable risk in the form of the number needed to harm provides a clearer picture of the magnitude of risk and a basis for wiser medical decision making and patient education. PMID- 27986397 TI - Weakness of Eye Closure with Central Facial Paralysis after Unilateral Hemispheric Stroke Predicts a Worse Outcome. AB - BACKGROUND: Upper facial dysfunction is not generally considered a feature of central facial paralysis after unilateral hemispheric stroke; however, weakness of eye closure (WEC) has been observed in some cases. We aimed to investigate the frequency and characteristics of WEC in unilateral stroke and its association with stroke prognosis. METHODS: Patients with unilateral stroke and central facial paralysis were prospectively recruited within 7 days of onset. Facial paralysis was evaluated via the fourth item in the National Institute of Health Stroke Scale (NIHSS-4) and the Japan Facial Score (JFS) on admission, and at days 7, 14, 21, and 30 after stroke. Eye closure strength was measured daily using an ergometer for 30 days after stroke. Primary outcome was assessed using the modified Rankin Scale (mRS) at 90 and 180 days. Univariate and multivariate analyses were performed to investigate risk factors of WEC. RESULTS: WEC was identified in 16 of 242 patients (6.6%). Baseline characteristics, stroke risk factors, and lesion volume were not significantly different between patients with and patients without WEC. Patients with WEC featured higher NIHSS-4 scores and lower JFS between admission and at 21 days after stroke. Severe central facial paralysis (odds ratio [OR] = 8.1, 95% confidence interval [CI] = 2.3-28.6, P = .001) and right hemispheric stroke (OR = 13.7, 95% CI = 3.7-51.2, P < .001) were potential predictors of WEC. At 180 days after stroke, patients with WEC demonstrated a lower rate of functional independence (mRS = 0-2: 37.5% versus 72.1%, P < .001). CONCLUSIONS: WEC, which predicts a worse functional outcome at 180 days after unilateral stroke, demonstrates an association with severe central facial paralysis and right hemispheric stroke. PMID- 27986398 TI - Role of radiation therapy. AB - Because most patients with epithelial ovarian cancer have advanced disease at the time of initial diagnosis, radiation therapy usually does not play a major role in their treatment. Although ovarian carcinomas appear to be no less sensitive to radiation therapy than Mullerian carcinomas arising in other sites, the dose of radiation required to control gross disease, typically at least 60 Gy, cannot be safely delivered to the entire abdomen or even to large partial volumes of the pelvis and abdomen. Moreover, in most cases, localized radiation is ineffective because of the high risk of disseminated recurrence in peritoneal and extraperitoneal sites. There is strong evidence that radiation therapy can be used to achieve prolonged disease-free intervals and even cure selected patients with epithelial ovarian cancer. The challenge is to determine the select few who stand to benefit from radiation therapy. In all cases, the potential benefits of treatment must be carefully weighed against the risks, particularly for patients who are referred after multiple operations and courses of chemotherapy. For patients with incurable ovarian cancer, radiation therapy can also be very effective as a tool for improving symptoms and quality of life. PMID- 27986399 TI - Paranodal lesions in chronic inflammatory demyelinating polyneuropathy associated with anti-Neurofascin 155 antibodies. AB - Antibodies to Contactin-1 and Neurofascin 155 (Nfasc155) have recently been associated with subsets of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Contactin-1 and Nfasc155 are cell adhesion molecules that constitute the septate-like junctions observed by electron microscopy in the paranodes of myelinated axons. Antibodies to Contactin-1 have been shown to affect the localization of paranodal proteins both in patient nerve biopsies and in animal models after passive transfer. However, it is unclear whether these antibodies alter the paranodal ultrastructure. We examined by electron microscopy sural nerve biopsies from two patients presenting with anti-Nfasc155 antibodies, and also four patients lacking antibodies, three normal controls, and five patients with other neuropathies. We found that patients with anti-Nfasc155 antibodies presented a selective loss of the septate-like junctions at all paranodes examined. Further, cellular processes penetrated into the expanded spaces between the paranodal myelin loops and the axolemma in these patients. These patients presented with important nerve conduction slowing and demyelination. Also, the reactivity of anti-Nfasc155 antibodies from these patients was abolished in neurofascin-deficient mice, confirming that the antibodies specifically target paranodal proteins. Our data indicate that anti Nfasc155 destabilizes the paranodal axo-glial junctions and may participate in conduction deterioration. PMID- 27986400 TI - Optimisation of excitation schemes for 14N overtone MAS NMR using numerically exact simulations. AB - Numerically exact simulations of the 14N overtone (14NOT) MAS NMR experiment are used to investigate the effects of the applied magnetic field strength as well as three types of excitation pulse. The results show that both the resolution and sensitivity of 14NOT MAS NMR increase linearly with the applied static magnetic field strength. Standard RF excitation pulses are compared with frequency-swept WURST pulses as well as several composite pulses. WURST pulses are demonstrated to provide the largest bandwidths, while the direction of the frequency sweep is shown to be important when these pulses are used for the direct observation of 14NOT signals. A composite pulse is shown to provide the most efficient excitation overall, but only when applied on resonance. WURST excitation pulses are therefore the best option when studying a sample with unknown 14N NMR parameters. PMID- 27986401 TI - Multinuclear solid-state magnetic resonance study of oxo-bridged diniobium and quadruply-bonded dimolybdenum carboxylate clusters. AB - Carboxylate paddlewheels and their oxo-bridged analogues constitute ideal building blocks for the assembly of two- and three-dimensional framework materials. Here, we present a multinuclear (1H, 13C, 93Nb, 95Mo) magnetic resonance study of solid samples of Nb2OCl6(O2Ph)2 (1), Mo2(O2CMe)4 (2), and Mo2(O2CCHF2)4 (3). High-resolution proton and 13C CP/MAS NMR spectra provide valuable information on structure and crystal symmetry and on cocrystallized solvent. 93Nb solid-state NMR spectra of 1 provide quadrupolar coupling constants and chemical shift tensors which are characteristic of the axially asymmetric Nb O-Nb bridging environment. 95Mo solid-state NMR spectra of 2 and 3 provide quadrupolar coupling constants and chemical shift tensors which are directly characteristic of the molybdenum-molybdenum quadruple bonds in these compounds. The quadruple bonds are characterized by particularly large 95Mo chemical shift tensor spans on the order of 5500ppm. Density functional theoretical computations provide good agreement with the 93Nb and 95Mo experimental data, with some exceptions noted. This work demonstrates possible NMR approaches to characterize more complex framework materials and provides key insight into the Mo-Mo quadruple bond. PMID- 27986402 TI - The domestic pig as a potential model for Borrelia skin infection. AB - The skin lesion erythema migrans is a characteristic early manifestation of Lyme borreliosis in humans. However, the pathomechanisms leading to development of this erythema are not fully understood. Models that mimic human skin would enhance research in this field. Human and porcine skin structures strongly resemble each other. Therefore, we attempted to induce erythema migrans lesions in experimental Borrelia burgdorferi sensu lato infection in the skin of domestic pigs. The formation of erythema migrans-like lesions was observed after intradermal injection of these spirochetes, with the lesions forming very clearly in 2/6 animals when a strain of B. garinii was used. However, no molecular or clinical proof of systemic infection of the pigs with B. afzelii, B. burgdorferi sensu stricto, or B. garinii could be achieved. PMID- 27986403 TI - Temperature dependence of nitrogen removal activity by anammox bacteria enriched at low temperatures. AB - The anaerobic ammonium oxidation (anammox) process, which is applicable at ambient temperature, is necessary to develop more versatile nitrogen removal technologies. In this study, two anammox reactors, Low-R1 and Low-R2 inoculated with activated sludge respectively in Kumamoto and Hokkaido, Japan, achieved nitrogen removal rates (NRRs) of 1.5 kg-N/m3/day at 20 degrees C. The specific anammox activity (SAA) of the Low-R1 and Low-R2 sludge samples had peaks, respectively, of 2.8+/-0.3 mg-N/g-VSS/h at 25 degrees C and 4.2+/-0.3 mg-N/g VSS/h at 30 degrees C and dropped over the optimum temperature. Moreover, the SAA values of the Low-R1 and Low-R2 were higher at 10-25 degrees C and 10-35 degrees C, respectively, than that of an anammox reactor inoculated with activated sludge in Kumamoto operated at 35 degrees C (Mod-R). The apparent activation energy for anammox of Low-R1, Low-R2, and Mod-R were 108 kJ/mol (10-25 degrees C), 73 kJ/mol (10-30 degrees C), and 89 kJ/mol (10-35 degrees C), respectively. Candidatus Kuenenia stuttgartiensis dominated in the Mod-R sludge. The Low-R1 sludge was comprised of Ca. K. stuttgartiensis, Ca. Brocadia caroliniensis and Ca. B. fulgida and uncultured anammox-like or planctomycete-like bacteria. The Low-R2 sludge was comprised of various uncultured anammox-like or planctomycete-like bacteria. As Low-R2 was constructed, enrichment of freshwater anammox bacteria at low temperature with seed sludge collected from cold regions is expected to be an effective strategy for anammox applications under a wide temperature range. PMID- 27986404 TI - Mutations in mitochondrial complex I assembly factor NDUFAF3 cause Leigh syndrome. AB - NDUFAF3 is an assembly factor of mitochondrial respiratory chain complex I. Variants in NDUFAF3 have been identified as a cause of severe multisystem mitochondrial disease. In a patient presenting with Leigh syndrome, which has hitherto not been described as a clinical feature of NDUFAF3 deficiency, we identified a novel homozygous variant and confirmed its pathogenicity in patient fibroblasts studies. Furthermore, we present an analysis of complex I assembly routes representative of each functional module and, thereby, link NDUFAF3 to a specific step in complex I assembly. Therefore, our report expands the phenotype of NDUFAF3 deficiency and further characterizes the role of NDUFAF3 in complex I biogenesis. PMID- 27986405 TI - An elevated 1-h post- load glucose level during the oral glucose tolerance test detects prediabetes. AB - AIM: The objective of the study was to compare the diagnosis of dysglycemic states by conventional oral glucose tolerance test (OGTT) criteria (fasting and 2 h plasma glucose) with the 1-h post-load plasma glucose level. MATERIAL AND METHODS: 34 individuals (mean age: 55+/-13years; BMI: 27.7+/-6.3kg/m2) at risk for prediabetes were administered a 75g OGTT. Individuals with normal glucose tolerance (NGT) or prediabetes were identified according to fasting and/or 2-h plasma glucose (PG) concentrations. Subsequently, subjects were divided in 2 groups: group 1 (n=21) with a 1-h PG<155mg/dl and group 2 (n=13) with a 1-h PG>=155mg/dl. HOMA was performed to assess beta-cell function and insulin sensitivity. RESULTS: NGT or prediabetes based on conventional criteria correlated with the 1-h PG=155mg/dl (p<0.001). Moreover, the 1-h PG>=155mg/dl was associated with higher HbA1c levels (6.1+/-0.5 vs. 5.5+/-0.3%, p<0.001) and significantly impaired insulin secretion and hyperbolic product (BxS) on HOMA test vs. 1-h PG<155mg/dl. CONCLUSION: The 1-h post-load plasma glucose value >=155mg/dl is strongly associated with conventional criteria for (pre)diabetes and alterations of beta-cell function. PMID- 27986406 TI - Addition of once daily prandial lixisenatide to basal insulin therapy in patients with type-2 diabetes results in a reduction of HbA1c as an effect of postprandial glucose lowering. AB - AIMS: Basal insulin has been shown to effectively reduce fasting blood glucose (FBG), but postprandial plasma glucose (PPG) excursions may remain higher than normal. Glucagon-like peptide (GLP)-1 receptor agonists such as the short-acting lixisenatide are able to control such excursions by slowing gastric emptying. However, data regarding its use in a real world clinical setting are scarce. METHODS: 24 week, prospective, multicentre, non-interventional study in 1437 patients with type-2 diabetes receiving 20MUg lixisenatide once daily in combination with basal insulin. The per-protocol set (PPS) comprised 540 patients. RESULTS: HbA1c levels were found to decrease significantly over 24 weeks of treatment in the PPS (0.94+/-0.99% [7.9+/-8.5]; p<=0.001). An HbA1c of <7% (53mmol/mol) was achieved in 26.9% of patients, with 9.8% reaching <6.5% (48mmol/mol) and 30.0% reaching their individual treatment goal. There was a slight decrease in FBG (2.84+/-30.4mg/dl; p<=0.001), and a significant reduction in PPG, with levels decreasing by between 35mg/dl (1.9mmol/l) and 38mg/dl (2.1mmol/l), respectively on average after all main meals in basal optimised patients (PPS; <=140mg/dl). Body weight decreased from 101 to 98kg with a mean difference of 3.10+/-4.10kg (p<=0.001). There were few reports of hypoglycaemia and no reports of serious hypoglycaemia and need for external help. AEs were infrequent, and were in line with previous studies. CONCLUSIONS: Lixisenatide in combination with basal insulin was shown to be an effective treatment strategy for patients with type 2 diabetes, controlling HbA1c levels by reduction of PPG excursions during the whole day. PMID- 27986407 TI - Lung cancer in a patient with lymphangioleiomyomatosis. PMID- 27986408 TI - Lung Cancer in Patients With Combined Pulmonary Fibrosis and Emphysema and Idiopathic Pulmonary Fibrosis. A Descriptive Study in a Spanish Series. AB - INTRODUCTION: Information on the association of lung cancer (LC) and combined pulmonary fibrosis and emphysema (CPFE) is limited and derived almost exclusively from series in Asian populations. The main objective of the study was to assess the impact of LC on survival in CPFE patients and in patients with idiopathic pulmonary fibrosis (IPF). METHODS: A retrospective study was performed with data from patients with CFPE and IPF diagnosed in our hospital over a period of 5 years. RESULTS: Sixty-six patients were included, 29 with CPFE and 37 with IPF. Nine had a diagnosis of LC (6 with CPFE and 3 with IPF). Six patients (67%) received palliative treatment even though 3 of them were diagnosed atstage i-ii. Overall mortality did not differ significantly between groups; however, in patients with LC, survival was significantly lower compared to those without LC (P=.044). The most frequent cause of death was respiratory failure secondary to pulmonary fibrosis exacerbation (44%). In a multivariate analysis, the odds ratio of death among patients with LC compared to patients without LC was 6.20 (P=.037, 95% confidence interval: 1.11 to 34.48). CONCLUSIONS: Lung cancer reduces survival in both entities. The diagnostic and therapeutic management of LC is hampered by the increased risk of complications after any treatment modality, even after palliative treatment. PMID- 27986409 TI - Validity Study of Catalan, Galician and Basque Language Versions of the COPD Assessment Test and Equivalence With the Spanish Version. AB - OBJECTIVES: To assess the linguistic equivalence of the COPD Assessment Test versions in Catalan (CAT-C), Galician (CAT-G) and Basque (CAT-V) with the validated Spanish version (CAT) in COPD patients able to use both official languages. METHODS: Study performed in primary care centers in Catalonia, Galicia and the Basque Country. Half of the patients completed the questionnaire in their local language followed by the CAT in Spanish, while the other half did so in reverse order. RESULTS: 151 COPD patients were included in the study, with a mean age of 69.0 (SD: 9.7) years. Most (79.5%) were men, 11.3% were educated up touniversity level, and 31.8% were current smokers. Mean FEV1 was 61.4% (SD: 16.8) predicted and 83.9% of patients were GOLD grade i or ii. Concordance between CAT-C, CAT-G and CAT-V and CAT was high, with differences between scores from 0.4 to-0.5. Reliability (Cronbach's alpha) ranged from0.72 to0.86. Convergent validity, when correlated with the Medical Research Council Dyspnea scale (P=.003) and Saint George's Respiratory Questionnaire (ICC, r=0.74) scores, was significant. CONCLUSIONS: CAT-C, CAT-G and CAT-V scores were similar to CAT scores, with high correlation and concordance. These results show the equivalence between the validated Spanish CAT and the versionin other languages, so CAT-C, CAT-G and CAT-V can be used in individuals whose main language is Catalan, Galician or Basque. PMID- 27986410 TI - Simplification of intradermal skin testing in Hymenoptera venom allergic children. AB - BACKGROUND: The direct comparison between children and adults with Hymenoptera venom anaphylaxis (HVA) has never been extensively reported. Severe HVA with IgE documented mechanism is the recommendation for venom immunotherapy, regardless of age. OBJECTIVE: To determine the differences in the basic diagnostic profile between children and adults with severe HVA and its practical implications. METHODS: We reviewed the medical records of 91 children and 121 adults. RESULTS: Bee venom allergy was exposure dependent, regardless of age (P < .001). Atopy was more common in children (P = .01), whereas cardiovascular comorbidities were present almost exclusively in adults (P = .001). In the bee venom allergic group, specific IgE levels were significantly higher in children (29.5 kUA/L; interquartile range, 11.30-66.30 kUA/L) compared with adults (5.10 kUA/L; interquartile range, 2.03-8.30 kUA/L) (P < .001). Specific IgE levels for culprit insect venom were higher in bee venom allergic children compared with the wasp venom allergic children (P < .001). In adults, intradermal tests revealed higher sensitivity, accompanied by larger area of skin reactions, regardless of type of venom. At concentrations lower than 0.1 MUg/mL, 16% of wasp venom allergic children and 39% of bee venom allergic children had positive intradermal test results. The median tryptase level was significantly higher in adults than in children for the entire study group (P = .002), as well as in bee (P = .002) and wasp venom allergic groups (P = .049). CONCLUSION: The basic diagnostic profile in severe HVA reactors is age dependent. Lower skin test reactivity to culprit venom in children may have practical application in starting the intradermal test procedure with higher venom concentrations. PMID- 27986411 TI - Interleukin 16 and CCL17/thymus and activation-regulated chemokine in patients with aspirin-exacerbated respiratory disease. AB - BACKGROUND: Interleukin (IL) 16 and thymus and activation-regulated cytokine (TARC) are chemoattractant cytokines for eosinophils and TH2 cells. Differential levels of these components in aspirin-exacerbated respiratory disease (AERD) and allergic rhinitis with asthma (ARwA) may be related to a different inflammatory response in both asthma phenotypes. OBJECTIVE: To assess the nasal lavage immunoreactivity of IL-16 and TARC cytokines. METHODS: We used multienzyme-linked immunosorbent assays to detect IL-5, IL-13, IL-16, IL-33, I-309/CCL1, TARC/CCL17, monocyte-derived chemokine/CCL22, periostin, and eosinophil cationic protein levels in nasal lavages from patients with AERD and patients with ARwA. RESULTS: The IL-13, IL-16, TARC, and periostin levels were significantly higher in patients with AERD compared with those of patients with ARwA. Correlation analysis of mediator levels in AERD revealed a possible role of IL-16 and TARC in eosinophil recruitment and activation. CONCLUSION: IL-16, TARC, and periostin distinguish between patients with AERD and those with ARwA. These mediators, taken together rather than individually, may comprise good specific nasal markers in patients with AERD. The effects of IL-16 and TARC on TH1, TH2, and T regulatory cell functions in AERD cannot be disregarded. PMID- 27986413 TI - Stomatin-like protein 2 is involved in endometrial stromal cell proliferation and differentiation during decidualization in mice and humans. AB - The molecular mechanisms underlying endometrial stromal cell proliferation and differentiation (decidualization) are still not fully understood. This study revealed that increased Slp-2 expression is a significant factor modulating endometrial stromal cell proliferation and decidualization in both mice and humans. Our results showed a significant difference in the mRNA and protein levels between the implantation site and inter-implantation site on day 5 and day 6 of pregnancy in mice (all P < 0.05). Strong Slp-2 immunostaining was mainly localized within the decidual zone of mice through the post-implantation period. Mice with artificially induced deciduoma showed significantly higher expression of Slp-2 compared with uninduced controls (P < 0.005). Human stromal cells in the middle and late-secretory phases demonstrated significantly (all P < 0.05) upregulated SLP-2, compared with cells in the proliferative phase and early secretory phases. Further analyses of the SLP-2 gene knocked down revealed a significant (P < 0.005) repression of both the decidualization marker gene's expression (decidual/trophoblast prolactin-related protein in mice, insulin-like growth factor binding protein and prolactin in human) and the cell proliferation in in vitro-induced decidualized primary endometrial stromal cells in mice and humans. PMID- 27986412 TI - Hippocampal Response to a 24-Month Physical Activity Intervention in Sedentary Older Adults. AB - BACKGROUND: Greater hippocampal volume is observed in healthy older adults after short-term structured exercise. Whether long-term exposure to real-world physical activity (PA) programs has similar effects for sedentary older adults with impaired mobility and comorbid conditions is not known. HYPOTHESIS: A long-term moderate intensity regimen of PA is related to larger volume of the hippocampus in older adults at risk for mobility disability. We further explore whether these associations are modified by factors known to be related to dementia. METHODS: Twenty-six sedentary adults at risk for mobility disability participated in a 24 month randomized intervention program of physical activity (PA, N = 10, age: 74.9 years, 7 women) or health education (HE, N = 16, age: 76.8 years, 14 women). Volumes of total hippocampus, dentate gyrus, and cornu ammonis were measured at baseline and at 24-month follow-up using 7-Tesla magnetic resonance imaging. Between-group volumetric differences at 24 months were adjusted for sessions attended and baseline volumes. The contribution of each dementia-related factor was tested separately for education, APOE, diabetes, cardiovascular diseases, white matter hyperintensities, and brain atrophy. RESULTS: Between-group differences were significant for left hippocampus, left cornu ammonis, and right hippocampus. Adjustment for regional baseline volume attenuated the associations to statistically nonsignificant for right hippocampus and left conru ammonis; associations for left hippocampus were robust for all adjustments. Results were similar after adjustment for dementia-related factors. CONCLUSIONS: In this group of sedentary older adults there was a hippocampal response to a long-term program of moderate-intensity PA. Future studies should examine whether hippocampal response could explain the beneficial effects of PA on cognition for vulnerable older adults. PMID- 27986414 TI - Clinical trials transparency and access to anonymized individual participant data. PMID- 27986415 TI - Esophageal cancer: Risk factors, genetic association, and treatment. AB - The poor prognosis and rising incidence of esophageal cancer highlight the need for improved detection and prediction methods that are essential prior to treatment. Esophageal cancer is one of the most fatal malignancies worldwide, with a dramatic increase in incidence in the Western world occurring over the past few decades. Despite improvements in the management and treatment of esophageal cancer patients, the general outcome remains very poor for overall 5 year survival rates (~10%) and 5-year postesophagectomy survival rates (~15-40%). Esophageal cancer is often diagnosed during its advanced stages, the main reason being the lack of early clinical symptoms. In an attempt to improve the outcome of patients after surgery, such patients are often treated with neoadjuvent concurrent chemoradiotherapy (CCRT) in order to decrease tumor size. However, CCRT may enhance toxicity levels and possibly cause a delay in surgery for patients who respond poorly to CCRT. Thus, precise biomarkers that could predict or identify patients who may or may not respond well to CCRT can assist physicians in choosing the appropriate therapy for patients. Identifying susceptible gene and biomarkers can help in predicting the treatment response of patients while improving their survival rates. PMID- 27986416 TI - Interview with Robert K. Kraft. PMID- 27986417 TI - Does a second resection provide a survival benefit in patients diagnosed with incidental T1b/T2 gallbladder cancer following cholecystectomy? AB - BACKGROUND: Incidental T1b/T2 gallbladder cancers are often managed with a second resection. However it is unclear whether the additional surgical risk is associated with any survival advantage. The aim of this study was to examine the outcomes of patients who underwent a second resection following a diagnosis of incidental T1b/T2 gallbladder cancer. METHODS: A retrospective analysis of patients undergoing surgical management following a diagnosis of incidental T1b/T2 gallbladder cancer between 1994 and 2014. Survival outcomes were analysed using the Kaplan-Meier method. RESULTS: Twenty two patients underwent completion surgery following diagnosis of T1b/T2 gallbladder cancer at initial cholecystectomy, 11 of which were found to have residual disease. The presence of residual disease at second surgery in T1b/T2 disease was associated with worse overall survival (residual disease: median survival 12 months, absence of residual disease: median survival not reached, p = 0.025). CONCLUSION: A significant percentage of patients with T1b/T2 disease have identifiable residual disease following second surgery. Residual disease is associated with poor survival. It is therefore important to inform patients that completion cholecystectomy is primarily performed to inform staging rather than to improve prognosis. PMID- 27986418 TI - Absence epilepsy: Continuum of clinical presentation and epigenetics? AB - PURPOSE: Although absence seizures do predominate in childhood they may occur at all ages and clinical presentation varies widely. Albeit considered a benign seizure type, chronic evolution with therapeutic refractoriness is possible in some patients with absences. The aim of this paper is to summarize the main syndromic presentation of absence seizures and its outcome regarding treatment and prognosis. METHOD: We performed a review of literature with emphasis in historic and classical manuscripts about absence epilepsy. RESULTS: Absence was described in the beginning of last century as a seizure type with good evolution, but it is still difficult to preview a strict prognosis for an individual patient. Some positive early predictors were reported such as response to initial treatment and seizure onset in childhood. Genetic aspects are not yet well understood although some families have been reported with rare mutations in ion channel coding genes. CONCLUSION: Absence seizures are present in different epilepsy syndromes and nosological classification is not always possible. Outcome depends on clinical variables such as age of onset, presence of other seizure types and initial response to treatment. PMID- 27986419 TI - Epilepsy in the tropics: Emerging etiologies. AB - Epilepsy is considered by the World Health Organization a public health priority with more than 50 million human beings affected by the disease. More than 80% of persons with epilepsy live in low and middle income countries and most of them in tropical areas. Several emerging, re-emerging and neglected diseases are symptomatic etiologies that jointly contribute to the enormous global burden of epilepsy. Besides the clinical strengths to reduce diagnostic and treatment gaps, other strategies in social, economic, cultural, educational and health policies are needed to prevent and treat appropriately vulnerable and affected persons with epilepsy. From the public health point of view, several of those strategies could be more effective in reducing the incidence and burden of the disease than the clinical approach of diagnosis and treatment. Special attention has to be given to stigma reduction and promotion of human rights. Several aspects mentioned in this abstract slip away the scope of the article, but it is a remainder to approach epilepsy in an inter- and transdisciplinary manner, an integral and pertinent approach needed and requested in tropical counties. The article focuses only on emergent and re-emergent etiologies of epilepsy in the tropics like malaria, HIV, neurocysticercosis, viral encephalitis and traumatic brain injury. PMID- 27986420 TI - Fumarates and Cancer. AB - Accumulation of intermediate metabolites of the tricarboxylic acid (TCA) cycle in tumor cells can cause epithelial-to-mesenchymal transition (EMT), although the exact mechanisms remain elusive. Recent studies show that the oncometabolite fumarate, which accumulates in fumarate hydratase-deficient renal cancers, confers tumor aggressiveness by causing epigenetic changes in the antimetastatic miRNA cluster mir-200ba429. This may have important implications for the use of fumarates in the clinic. PMID- 27986421 TI - Bacterial Biofilms in Colorectal Cancer Initiation and Progression. AB - Intestinal microbiota have emerged as an important factor in colorectal cancer (CRC) initiation and progression. The currently prominent view on bacterial tumorigenesis is that CRC initiation is triggered by local mucosal colonization with specific pathogens (drivers), and that subsequent changes in the peritumoral environment allow colonization by opportunistic (passenger) microbes, further facilitating disease progression. Screening for CRC 'driver-passenger' microorganisms might thus allow early CRC diagnosis or preventive intervention. Such efforts are now being revolutionized by the notion that CRC initiation and progression require organization of bacterial communities into higher-order structures termed biofilms. We explore here the concept that a polymicrobial biofilm promotes pro-carcinogenic activities that may partially underlie progression along the adenoma-CRC axis. PMID- 27986422 TI - Extrinsic compression of the biliary tract due to idiopathic retroperitoneal fibrosis: MR imaging findings. PMID- 27986425 TI - Two-Year Course of Corneal Densitometry After Descemet Membrane Endothelial Keratoplasty. AB - PURPOSE: To investigate the 2-year course of corneal densitometry following Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial dystrophy (FED). DESIGN: Retrospective, interventional case series. METHODS: Densitometry values (corneal light backscatter in grayscale units) measured by Scheimpflug based imaging and clinical records of 160 eyes of 160 patients undergoing DMEK for FED were reviewed. Outcome measures included densitometry data in 4 corneal layers (anterior layer [AL], central layer [CL], posterior layer [PL], and total layer [TL]) and 2 annuli (central annular zone 0-2 mm and peripheral zone 2-10 mm), central corneal thickness (CCT), best spectacle-corrected visual acuity (BSCVA), and endothelial cell density (ECD) prior to DMEK and at 1, 3, 6, 12, and 24 months postoperatively. RESULTS: Corneal densitometry decreased in all 4 layers over 2 years after DMEK surgery. Regarding TL 0-2 mm, the reduction of corneal light backscatter was statistically significant for all follow-up time points compared with preoperative values (P < .001) and compared in between follow-up periods (P <= .010). Corneal light backscatter reduction was significantly higher in the center (0-2 mm) than in the periphery (2-10 mm) for all layers at 12 and 24 months (P <= .002). ECD and CCT did not correlate with corneal densitometry, whereas BSCVA correlated moderately for TL 0-2 mm (P = .026; r = 0.449) and TL 2-10 mm (P = .001; r = 0.585) at 12 months. CONCLUSIONS: Corneal light backscatter showed a significant reduction after DMEK surgery in Fuchs endothelial dystrophy over a period of 2 years, more pronounced in the corneal center, apparently in association with visual acuity improvement. PMID- 27986423 TI - Learning To Breathe: Developmental Phase Transitions in Oxygen Status. AB - Plants are developmentally disposed to significant changes in oxygen availability, but our understanding of the importance of hypoxia is almost entirely limited to stress biology. Differential patterns of the abundance of oxygen, nitric oxide (*NO), and reactive oxygen species (ROS), as well as of redox potential, occur in organs and meristems, and examples are emerging in the literature of mechanistic relationships of these to development. We describe here the convergence of these cues in meristematic and reproductive tissues, and discuss the evidence for regulated hypoxic niches within which oxygen-, ROS-, *NO , and redox-dependent signalling curate developmental transitions in plants. PMID- 27986424 TI - Retinal Pigment Epithelium Degeneration Associated With Subretinal Drusenoid Deposits in Age-Related Macular Degeneration. AB - PURPOSE: To test whether increased light transmission (hypertransmission) through subretinal drusenoid deposits (SDD) into the choroid in age-related macular degeneration (AMD) represented retinal pigment epithelium (RPE) degeneration. DESIGN: Cross-sectional study. METHODS: Nineteen eyes of 12 patients with early- to intermediate-stage AMD and 18 eyes of 12 normal subjects were evaluated with color fundus photography, optical coherence tomography (OCT), and high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) at baseline and 24 months later. SDD were classified using an OCT-based 3-stage grading system. Hypertransmission beneath SDD into the choroid was examined in OCT. SDD microstructure was assessed with AOSLO. To characterize the hypertransmission associated chorioretinal degeneration, choroidal thickness and photoreceptor length were measured in OCT at 1 mm and 2 mm superior, inferior, temporal, and nasal to the foveal center. RESULTS: OCT disclosed hypertransmission beneath stage 3 SDD in 8 eyes. These lesions showed a distinctive regressing structure in AOSLO, compared with stage 3 lesions without hypertransmission. The phenomenon persisted at follow-up, and new hypertransmission developed as SDD advanced. In eyes with hypertransmission, choroids were thinner than those of normal eyes at all sites (by 44%-56%, P <= .0028) and those of eyes with SDD but without hypertransmission at superior and temporal sites (by 31%-46%, P <= .039). Photoreceptors were significantly shorter than those in normal eyes (by 6%-26%, P <= .0379). CONCLUSIONS: Hypertransmission into the choroid, accompanied with SDD regression and thinning of choroid and photoreceptor layers, indicates RPE degeneration associated with advanced stages in the SDD life cycle. PMID- 27986426 TI - Repeated Loss of Consciousness in a Young Woman: A Suspicious SMAD3 Mutation Underlying Spontaneous Coronary Artery Dissection. AB - Spontaneous coronary artery dissection (SCAD) is an infrequent cause of acute coronary syndrome and is often underdiagnosed. Intramural hematoma is the most frequent angiographic presentation and is a challenging diagnosis that may require intravascular imaging techniques to confirm it and guide treatment. It affects mostly young women without coronary risk factors and is usually associated with fibromuscular dysplasia. SCAD has an underlying disease in 80% of patients. A SMAD3 mutation has been linked to aneurysm-osteoarthritis syndrome and has been identified as a cause of familial thoracic aortic aneurysm and dissection. The first reported case, to our knowledge, of a SMAD3 mutation underlying SCAD is described here. PMID- 27986427 TI - Gait and energy consumption in adolescent idiopathic scoliosis: A literature review. AB - BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a progressive growth disease that affects spinal anatomy, mobility, and left-right trunk symmetry. The disease can modify human gait. OBJECTIVE: We aimed to review articles describing the measurement of gait parameters and energy consumption in AIS during walking without any intervention. STUDY DESIGN: Literature review. METHODS: The search strategy was based on the Population Intervention Comparison Outcome method and included all relevant articles published from 1996 to 2015. Articles were searched in MEDLINE via PubMed, Science Direct, Google Scholar, and ISI Web of Knowledge databases. RESULTS: We selected 33 studies investigating the effect of scoliosis deformity on gait parameters and energy expenditure during walking. Most of the studies concluded no significant differences in walking speed, cadence and step width in scoliosis patients and normal participants. However, patients showed decreased hip and pelvic motion, excessive energy cost of walking, stepping pattern asymmetry and ground reaction force asymmetry. CONCLUSION: We lack consistent evidence of the effect of scoliosis on temporal spatial and kinematic parameters in AIS patients as compared with normal people. However, further research is needed to assess the effect of scoliosis on gait and energy consumption. PMID- 27986428 TI - Rehabilitation of unilateral neglect: Evidence-based medicine. AB - BACKGROUND: In the last decades, several rehabilitation methods have been developed to improve spatial neglect. These can be classified according to their theoretical basis: (i) enhance awareness of neglect behaviour through a top-down mechanism; (ii) low-level bottom-up sensory stimulation; (iii) modulation of inhibitory processes; (iv) increase arousal. OBJECTIVE: The purpose of this study was to provide an overview of the evidence on the effectiveness of rehabilitation procedures for unilateral neglect. METHOD: A systematic search was performed to look for all randomised controlled trials aimed at reducing left spatial neglect that included a functional assessment. In addition, recent review papers and meta analyses were analysed. RESULTS: Thirty-seven randomized controlled trials were found (12 bottom-up; 12 top-down; 1 interhemispheric competition; 12 combination of approaches) that included 1027 patients with neglect. Although there are some encouraging results, overall, the level of evidence remains low. Poor methodological quality and small sample sizes are major limitations in many published trials. CONCLUSION: There is a need for well-conducted, large-scale randomised controlled trials that incorporate blinded assessments, evaluation of the generalization to activities of daily living and long-term follow-up. PMID- 27986429 TI - Practical Considerations in Managing Relapsed Multiple Myeloma. AB - Considerable advances have been made in the treatment of relapsed and relapsed/refractory multiple myeloma, with numerous novel agents and combination strategies receiving regulatory approval worldwide during the past several years. An increasing body of phase III data has clearly demonstrated increased overall response rates, improved depths of response, and more durable responses when a third novel agent is incorporated into lenalidomide-dexamethasone and bortezomib dexamethasone platforms, in most cases with acceptable toxicity. The carfilzomib dexamethasone doublet has also demonstrated promising activity. With this rapid progress has come many new questions. We review the data supporting the use of these novel treatment paradigms for relapsed/refractory multiple myeloma, discuss the place of autologous and allogeneic hematopoietic stem cell transplantation in this rapidly evolving treatment space, and propose strategies to best use these regimens, considering the disease, host, and previous treatment factors. PMID- 27986430 TI - Computational approaches to schizophrenia: A perspective on negative symptoms. AB - Schizophrenia is a heterogeneous spectrum disorder often associated with detrimental negative symptoms. In recent years, computational approaches to psychiatry have attracted growing attention. Negative symptoms have shown some overlap with general cognitive impairments and were also linked to impaired motivational processing in brain circuits implementing reward prediction. In this review, we outline how computational approaches may help to provide a better understanding of negative symptoms in terms of the potentially underlying behavioural and biological mechanisms. First, we describe the idea that negative symptoms could arise from a failure to represent reward expectations to enable flexible behavioural adaptation. It has been proposed that these impairments arise from a failure to use prediction errors to update expectations. Important previous studies focused on processing of so-called model-free prediction errors where learning is determined by past rewards only. However, learning and decision making arise from multiple cognitive mechanisms functioning simultaneously, and dissecting them via well-designed tasks in conjunction with computational modelling is a promising avenue. Second, we move on to a proof-of-concept example on how generative models of functional imaging data from a cognitive task enable the identification of subgroups of patients mapping on different levels of negative symptoms. Combining the latter approach with behavioural studies regarding learning and decision-making may allow the identification of key behavioural and biological parameters distinctive for different dimensions of negative symptoms versus a general cognitive impairment. We conclude with an outlook on how this computational framework could, at some point, enrich future clinical studies. PMID- 27986431 TI - Foreign Body Mimicking a Granuloma in the Ear in an Asymptomatic Child. PMID- 27986432 TI - Essential role of Cdc42 in cardiomyocyte proliferation and cell-cell adhesion during heart development. AB - Cdc42 is a member of the Rho GTPase family and functions as a molecular switch in regulating cell migration, proliferation, differentiation and survival. However, the role of Cdc42 in heart development remains largely unknown. To determine the function of Cdc42 in heart formation, we have generated a Cdc42 cardiomyocyte knockout (CCKO) mouse line by crossing Cdc42 flox mice with myosin light chain (MLC) 2a-Cre mice. The inactivation of Cdc42 in embryonic cardiomyocytes induced lethality after embryonic day 12.5. Histological analysis of CCKO embryos showed cardiac developmental defects that included thin ventricular walls and ventricular septum defects. Microarray and real-time PCR data also revealed that the expression level of p21 was significantly increased and cyclin B1 was dramatically decreased, suggesting that Cdc42 is required for cardiomyocyte proliferation. Phosphorylated Histone H3 staining confirmed that the inactivation of Cdc42 inhibited cardiomyocytes proliferation. In addition, transmission electron microscope studies showed disorganized sarcomere structure and disruption of cell-cell contact among cardiomyocytes in CCKO hearts. Accordingly, we found that the distribution of N-cadherin/beta-Catenin in CCKO cardiomyocytes was impaired. Taken together, our data indicate that Cdc42 is essential for cardiomyocyte proliferation, sarcomere organization and cell-cell adhesion during heart development. PMID- 27986433 TI - Cutaneous lymphomas with a panniculitic presentation. AB - Subcutaneous panniculitis-like T-cell lymphoma and primary cutaneous gamma/delta T-cell lymphoma are the two most common types of cutaneous T-cell lymphoma presenting with panniculitis-like lesions. In this article the characteristic clinical, histological and immunophenotypical features of these conditions are reviewed and criteria to differentiate these tumors from other benign and malignant lymphoproliferations presenting with panniculitis-like lesions are discussed. PMID- 27986434 TI - Cutaneous marginal zone lymphomas. AB - Primary cutaneous marginal zone lymphoma (CMZL) is one of the major primary B cell lymphomas of skin. Two types are recognized: a more common class-chain switched CMZL, and a much less common IgM+ CMZL. The extremely indolent course, together with other features distinct from most other MALT lymphomas, has led some to question whether at least the class-switched cases should be considered an overt lymphoma. PMID- 27986435 TI - Osteosarcoma in tophaceous gout: A case report and literature review. PMID- 27986436 TI - Interaction of plant essential oil terpenoids with the southern cattle tick tyramine receptor: A potential biopesticide target. AB - An outbreak of the southern cattle tick, Rhipicephalus (Boophilus) microplus, (Canestrini), in the United States would have devastating consequences on the cattle industry. Tick populations have developed resistance to current acaricides, highlighting the need to identify new biochemical targets along with new chemistry. Furthermore, acaricide resistance could further hamper control of tick populations during an outbreak. Botanically-based compounds may provide a safe alternative for efficacious control of the southern cattle tick. We have developed a heterologous expression system that stably expresses the cattle tick's tyramine receptor with a G-protein chimera, producing a system that is amenable to high-throughput screening. Screening an in-house terpenoid library, at two screening concentrations (10 MUM and 100 MUM), has identified four terpenoids (piperonyl alcohol, 1,4-cineole, carvacrol and isoeugenol) that we believe are positive modulators of the southern cattle tick's tyramine receptor. PMID- 27986437 TI - Intralesional rituximab in primary conjunctival follicular lymphoma relapsed. AB - CLINICAL CASE: A 49-year-old woman experienced a local relapse of a primary follicular lymphoma (FL) of the conjunctiva. She received 4 weekly intra-lesional injections followed by 6 monthly injections of rituximab (6mg/ml). A clinical response was achieved after first injection. No adverse ocular event or signs of lymphoma relapse were seen after 10 months of follow-up. DISCUSSION: Intralesional administration of rituximab for treating primary FL of the conjunctiva was an effective and safe therapeutic option; therefore it could be an alternative to other conventional treatments, such as radiotherapy or chemotherapy. PMID- 27986438 TI - Frangipane's Penitent's ectropion. PMID- 27986439 TI - Expression Levels of KMT2C and SLC20A1 Identified by Information-theoretical Analysis Are Powerful Prognostic Biomarkers in Estrogen Receptor-positive Breast Cancer. AB - INTRODUCTION: In general, it has been considered that estrogen receptor-positive (ER+) breast cancer has a good prognosis and is responsive to endocrine therapy. However, one third of patients with ER+ breast cancer exhibit endocrine therapy resistance, and many patients develop recurrence and die 5 to 10 years after diagnosis. In ER+ breast cancer, a major problem is to distinguish those patients most likely to develop recurrence or metastatic disease within 10 years after diagnosis from those with a sufficiently good prognosis. MATERIALS AND METHODS: We downloaded the messenger RNA expression data and the clinical information for 401 patients with ER+ breast cancer from the cBioPortal for Cancer Genomics. An information-theoretical approach was used to identify the prognostic factors for survival in patients with ER+ breast cancer and to classify those patients according to the prognostic factors. RESULTS: The information-theoretical approach contributed to the identification of KMT2C and SLC20A1 as prognostic biomarkers in ER+ breast cancer. We found that low KMT2C expression was associated with a poor outcome and high SLC20A1 expression was associated with a poor outcome. Both levels of KMT2C and SLC20A1 expression were significantly and strongly associated with the differentiation of survival. The 10-year survival rate for ER+ patients with low KMT2C and high SLC20A1 expression was 0%. In contrast, for ER+ patients with high KMT2C and low SLC20A1 expression, the 10 year survival rate was 86.78%. CONCLUSION: Our results strongly suggest that clinical examination of the expression of both KMT2C and SLC20A1 in ER+ breast cancer will be very useful for the determination of prognosis and therapy. PMID- 27986440 TI - Sitagliptin May Reduce Breast Cancer Risk in Women With Type 2 Diabetes. AB - BACKGROUND: Whether sitagliptin may affect breast cancer risk remains to be answered. This study evaluated such an association in Taiwanese female patients with type 2 diabetes. METHODS: A retrospective cohort of female patients with newly diagnosed type 2 diabetes at an age >= 25 years between 1999 and 2010 was recruited from the National Health Insurance database. A total of 32,457 ever users and 396,021 never-users of sitagliptin were followed until December 31, 2011. The treatment effect was estimated by Cox regression incorporated with the inverse probability of treatment weighting using propensity score. Sensitivity analyses were conducted in a matched cohort. RESULTS: During follow-up, 78 ever users and 2204 never-users were diagnosed with breast cancer, representing an incidence of 150.44 and 215.87 per 100,000 person-years, respectively. The hazard ratio (95% confidence intervals [CIs]) for ever- versus never-users was 0.718 (95% CI, 0.573-0.901). The hazard ratio for the first, second, and third tertile of cumulative duration < 5.73, 5.73-12.73, and > 12.73 months was 0.783 (95% CI, 0.523-1.171), 1.021 (95% CI, 0.723-1.441), and 0.455 (95% CI, 0.296-0.700), respectively; and was 0.823 (95% CI, 0.554-1.222), 0.918 (95% CI, 0.639-1.317), and 0.499 (95% CI, 0.331-0.753) for cumulative dose < 14,400, 14,400-33,800, and > 33,800 mg, respectively. Findings were supported by analyses in the matched cohort. CONCLUSIONS: Sitagliptin may reduce breast cancer risk in female patients with type 2 diabetes mellitus, especially 1 year after its use. PMID- 27986441 TI - Silent genetic alterations identified by targeted next-generation sequencing in pheochromocytoma/paraganglioma: A clinicopathological correlations. AB - AIMS: The goal of this pilot study was to develop a customized, cost-effective amplicon panel (Ampliseq) for target sequencing in a cohort of patients with sporadic phaeochromocytoma/paraganglioma. METHODS: Phaeochromocytoma/paragangliomas from 25 patients were analysed by targeted next generation sequencing approach using an Ion Torrent PGM instrument. Primers for 15 target genes (NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, MEN1, KIF1Bbeta, EPAS1, CDKN2 & PHD2) were designed using ion ampliseq designer. Ion Reporter software and Ingenuity(r) Variant AnalysisTM software (www.ingenuity.com/variants) from Ingenuity Systems were used to analysis these results. RESULTS: Overall, 713 variants were identified. The variants identified from the Ion Reporter ranged from 64 to 161 per patient. Single nucleotide variants (SNV) were the most common. Further annotation with the help of Ingenuity variant analysis revealed 29 of these 713variants were deletions. Of these, six variants were non-pathogenic and four were likely to be pathogenic. The remaining 19 variants were of uncertain significance. The most frequently altered gene in the cohort was KIF1B followed by NF1. Novel KIF1B pathogenic variant c.3375+1G>A was identified. The mutation was noted in a patient with clinically confirmed neurofibromatosis. Chromosome 1 showed the presence of maximum number of variants. CONCLUSIONS: Use of targeted next-generation sequencing is a sensitive method for the detecting genetic changes in patients with phaeochromocytoma/paraganglioma. The precise detection of these genetic changes helps in understanding the pathogenesis of these tumours. PMID- 27986443 TI - 3D-Printed Simulation Device for Orbital Surgery. AB - OBJECTIVES: Orbital surgery is a challenging procedure because of its complex anatomy. Training could especially benefit from dedicated study models. The currently available devices lack sufficient anatomical representation and realistic soft tissue properties. Hence, we developed a 3D-printed simulation device for orbital surgery with tactual (haptic) correct simulation of all relevant anatomical structures. DESIGN, SETTING, AND PARTICIPANTS: Based on computed tomography scans collected from patients treated in a third referral center, the hard and soft tissue were segmented and virtually processed to generate a 3D-model of the orbit. Hard tissue was then physically realized by 3D printing. The soft tissue was manufactured by a composite silicone model of the nucleus and the surrounding tissue over a negative mold model also generated by 3D-printing. The final model was evaluated by a group of 5 trainees in oral and maxillofacial surgery (1) and a group of 5 consultants (2). All participants were asked to reconstruct an isolated orbital floor defect with a titanium implant. A stereotactic navigation system was available to all participants. Their experience was evaluated for haptic realism, correct representation of surgical approach, general handling of model, insertion of implant into the orbit, placement and fixation of implant, and usability of navigated control. The items were evaluated via nonparametric statistics (1 [poor]-5 [good]). RESULTS: Group 1 gave an average mark of 4.0 (+/-0.9) versus 4.6 (+/-0.6) by group 2. The haptics were rated as 3.6 (+/-1.1) [1] and 4.2 (+/-0.8) [2]. The surgical approach was graded 3.7 (+/-1.2) [1] and 4.0 (+/-1.0) [2]. Handling of the models was rated 3.5 (+/-1.1) [1] and 4 (+/-0.7) [2]. The insertion of the implants was marked as 3.7 (+/-0.8) [1] and 4.2 (+/-0.8) [2]. Fixation of the implants was also perceived to be realistic with 3.6 (+/-0.9) [1] and 4.2 (+/-0.45) [2]. Lastly, surgical navigation was rated 3.8 (+/-0.8) [1] and 4.6 (+/-0.56) [2]. CONCLUSION: In this project, all relevant hard and soft tissue characteristics of orbital anatomy could be realized. Moreover, it was possible to demonstrate that the entire workflow of an orbital procedure may be simulated. Hence, using this model training expenses may be reduced and patient security could be enhanced. PMID- 27986442 TI - World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung. AB - Exposure to World Trade Center (WTC) dust has been linked to respiratory disease in humans. In the present studies we developed a rodent model of WTC dust exposure to analyze lung oxidative stress and inflammation, with the goal of elucidating potential epigenetic mechanisms underlying these responses. Exposure of mice to WTC dust (20MUg, i.t.) was associated with upregulation of heme oxygenase-1 and cyclooxygenase-2 within 3days, a response which persisted for at least 21days. Whereas matrix metalloproteinase was upregulated 7days post-WTC dust exposure, IL-6RA1 was increased at 21days; conversely, expression of mannose receptor, a scavenger receptor important in particle clearance, decreased. After WTC dust exposure, increases in methylation of histone H3 lysine K4 at 3days, lysine K27 at 7days and lysine K36, were observed in the lung, along with hypermethylation of Line-1 element at 21days. Alterations in pulmonary mechanics were also observed following WTC dust exposure. Thus, 3days post-exposure, lung resistance and tissue damping were decreased. In contrast at 21days, lung resistance, central airway resistance, tissue damping and tissue elastance were increased. These data demonstrate that WTC dust-induced inflammation and oxidative stress are associated with epigenetic modifications in the lung and altered pulmonary mechanics. These changes may contribute to the development of WTC dust pathologies. PMID- 27986446 TI - [Peripheral magnetic resonance scan in the diagnosis of acute lymphoblastic leukaemia]. PMID- 27986447 TI - [Massive pulmonary atelectasis: Is it always a foreign body?] PMID- 27986448 TI - [Clinical impact of translocation t(7;15) (p22;q26) on several family members]. PMID- 27986449 TI - Quantification of muscular inflammation by 18F-FDG PET/CT for initial evaluation and treatment response on inflammatory myopathy: A case report. PMID- 27986444 TI - omega3-Polyunsaturated fatty acids for heart failure: Effects of dose on efficacy and novel signaling through free fatty acid receptor 4. AB - Heart failure (HF) affects 5.7 million in the U.S., and despite well-established pharmacologic therapy, the 5-year mortality rate remains near 50%. Furthermore, the mortality rate for HF has not declined in years, highlighting the need for new therapeutic options. Omega-3 polyunsaturated fatty acids (omega3-PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are important regulators of cardiovascular health. However, questions of efficacy and mechanism of action have made the use of omega3-PUFAs in all cardiovascular disease (CVD) controversial. Here, we review recent studies in animal models of HF indicating that omega3-PUFAs, particularly EPA, are cardioprotective, with the results indicating a threshold for efficacy. We also examine clinical studies suggesting that omega3-PUFAs improve outcomes in patients with HF. Due to the relatively small number of clinical studies of omega3-PUFAs in HF, we discuss EPA concentration-dependency on outcomes in clinical trials of CVD to gain insight into the perceived questionable efficacy of omega3-PUFAs clinically, with the results again indicating a threshold for efficacy. Ultimately, we suggest that the main failing of omega3-PUFAs in clinical trials might be a failure to reach a therapeutically effective concentration. We also examine mechanistic studies suggesting that omega3-PUFAs signal through free fatty acid receptor 4 (Ffar4), a G-protein coupled receptor (GPR) for long-chain fatty acids (FA), thereby identifying an entirely novel mechanism of action for omega3-PUFA mediated cardioprotection. Finally, based on mechanistic animal studies suggesting that EPA prevents interstitial fibrosis and diastolic dysfunction, we speculate about a potential benefit for EPA-Ffar4 signaling in heart failure preserved with ejection fraction. PMID- 27986450 TI - [Nanotechnology offers a promising therapeutic approach for hypertension treatment]. AB - Hypertension is a medical condition considered one of the most important public health problems in developed countries, affecting around one billion people. Therefore, the study of its mechanisms, development and treatment is a priority. Of particular interest are the multiple contributing factors, and efforts by experts to fully understand it are also important. However, studies are currently insufficient and consequently, attention is focused on the exploration of new therapeutic approaches. This raises a growing interest in nanotechnology given the ability of certain structures to mimic the behavior of extracellular matrices. This opens a promising field in the treatment of diseases such as hypertension, where it stands to tissue engineering and its potential applications incorporating concepts such as controlled release drug, reduced side effects and receptor activation locally. PMID- 27986445 TI - NADPH oxidase 4 regulates vascular inflammation in aging and atherosclerosis. AB - We recently reported that increased NADPH oxidase 4 (NOX4) expression and activity during aging results in enhanced cellular and mitochondrial oxidative stress, vascular inflammation, dysfunction, and atherosclerosis. The goal of the present study was to elucidate the molecular mechanism(s) for these effects and determine the importance of NOX4 modulation of proinflammatory gene expression in mouse vascular smooth muscle cells (VSMCs). A novel peptide-mediated siRNA transfection approach was used to inhibit Nox4 expression with minimal cellular toxicity. Using melittin-derived peptide p5RHH, we achieved significantly higher transfection efficiency (92% vs. 85% with Lipofectamine) and decreased toxicity (p<0.001 vs. Lipofectamine in MTT and p<0.0001 vs. Lipofectamine in LDH assays) in VSMCs. TGFbeta1 significantly upregulates Nox4 mRNA (p<0.01) and protein (p<0.01) expression in VSMCs. p5RHH-mediated Nox4 siRNA transfection greatly attenuated TGFbeta1-induced upregulation of Nox4 mRNA (p<0.01) and protein (p<0.0001) levels and decreased hydrogen peroxide production (p<0.0001). Expression of pro-inflammatory genes Ccl2, Ccl5, Il6, and Vcam1 was significantly upregulated in VSMCs in several settings cells isolated from aged vs. young wild type mice, in atherosclerotic arteries of Apoe-/- mice, and atherosclerotic human carotid arteries and correlated with NOX4 expression. p5RHH-mediated Nox4 siRNA transfection significantly attenuated the expression of these pro-inflammatory genes in TGFbeta1-treated mouse VSMCs, with the highest degree of inhibition in the expression of Il6. p5RHH peptide-mediated knockdown of TGFbeta-activated kinase 1 (TAK1, also known as Map3k7), Jun, and Rela, but not Nfkb2, downregulated TGFbeta1-induced Nox4 expression in VSMCs. Together, these data demonstrate that increased expression and activation of NOX4, which might result from increased TGFbeta1 levels seen during aging, induces a proinflammatory phenotype in VSMCs, enhancing atherosclerosis. PMID- 27986451 TI - Involvement of an RNA binding protein containing Alba domain in the stage specific regulation of beta-amastin expression in Trypanosoma cruzi. AB - Amastins are surface glycoproteins, first identified in amastigotes of T. cruzi but later found to be expressed in several Leishmania species, as well as in T. cruzi epimastigotes. Amastins are encoded by a diverse gene family that can be grouped into four subfamilies named alpha, beta, gamma, and delta amastins. Differential expression of amastin genes results from regulatory mechanisms involving changes in mRNA stability and/or translational control. Although distinct regulatory elements were identified in the 3' UTR of T. cruzi and Leishmania amastin mRNAs, RNA binding proteins involved with amastin gene regulation have only being characterized in L. infantum where an Alba-domain protein (LiAlba20) able to bind to the 3' UTR of a delta-amastin mRNA was identified. Here we investigated the role of TcAlba30, the LiAlba20 homologue in T. cruzi, in the post transcriptional regulation of amastin genes. TcAlba30 transcripts are present in all stages of the T. cruzi life cycle. RNA immunoprecipitation assays using a transfected cell line expressing a cMyc tagged TcAlba30 revealed that TcAlba30 can interact with beta-amastin mRNA. In addition, over-expression of TcAlba30 in epimastigotes resulted in 50% decreased levels of beta-amastin mRNAs compared to wild type parasites. Since luciferase assays indicated the presence of regulatory elements in the 3' UTR of beta-amastin mRNA and reduced levels of luciferase mRNA were found in parasites over expressing TcAlba30, we conclude that TcAlba30 acts as a T. cruzi RNA binding protein involved in the negative control of beta-amastin expression through interactions with its 3'UTR. PMID- 27986452 TI - Proteomic investigation of human cystic echinococcosis in the liver. AB - Cystic echinococcosis (CE) is a pandemic infectious disease caused by the tapeworm Echinococcus granulosus that forms cysts in different organs such as lungs and liver. Imaging examination and serological tests have some drawbacks such as low sensitivity. In this study, we used an up-to-date workflow of laser microdissection-based microproteomics and matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry in order to depict the proteomic pattern of CE in the liver. This investigation revealed specific markers of a parasitic cyst in liver. This proteomic pattern could facilitate diagnosis of CE in the future. PMID- 27986454 TI - Reconstruction of LPS Transfer Cascade Reveals Structural Determinants within LBP, CD14, and TLR4-MD2 for Efficient LPS Recognition and Transfer. AB - Lipopolysaccharide (LPS), the major component of the outer membrane of Gram negative bacteria, binds Toll-like receptor 4 (TLR4)-MD2 complex and activates innate immune responses. LPS transfer to TLR4-MD2 is catalyzed by both LPS binding protein (LBP) and CD14. To define the sequential molecular interactions underlying this transfer, we reconstituted in vitro the entire LPS transfer process from LPS micelles to TLR4-MD2. Using electron microscopy and single molecule approaches, we characterized the dynamic intermediate complexes for LPS transfer: LBP-LPS micelles, CD14-LBP-LPS micelle, and CD14-LPS-TLR4-MD2 complex. A single LBP molecule bound longitudinally to LPS micelles catalyzed multi-rounds of LPS transfer to CD14s that rapidly dissociated from LPB-LPS complex upon LPS transfer via electrostatic interactions. Subsequently, the single LPS molecule bound to CD14 was transferred to TLR4-MD2 in a TLR4-dependent manner. The definition of the structural determinants of the LPS transfer cascade to TLR4 may enable the development of targeted therapeutics for intervention in LPS-induced sepsis. PMID- 27986453 TI - CD8+ T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections. AB - Differentiation of effector and memory CD8+ T cells is accompanied by extensive changes in the transcriptome and histone modifications at gene promoters; however, the enhancer repertoire and associated gene regulatory networks are poorly defined. Using histone mark chromatin immunoprecipitation coupled with deep sequencing, we mapped the enhancer and super-enhancer landscapes in antigen specific naive, differentiated effector, and central memory CD8+ T cells during LCMV infection. Epigenomics-based annotation revealed a highly dynamic repertoire of enhancers, which were inherited, de novo activated, decommissioned and re activated during CD8+ T cell responses. We employed a computational algorithm to pair enhancers with target gene promoters. On average, each enhancer targeted three promoters and each promoter was regulated by two enhancers. By identifying enriched transcription factor motifs in enhancers, we defined transcriptional regulatory circuitry at each CD8+ T cell response stage. These multi-dimensional datasets provide a blueprint for delineating molecular mechanisms underlying functional differentiation of CD8+ T cells. PMID- 27986455 TI - Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency. AB - Animal models have highlighted the importance of innate lymphoid cells (ILCs) in multiple immune responses. However, technical limitations have hampered adequate characterization of ILCs in humans. Here, we used mass cytometry including a broad range of surface markers and transcription factors to accurately identify and profile ILCs across healthy and inflamed tissue types. High dimensional analysis allowed for clear phenotypic delineation of ILC2 and ILC3 subsets. We were not able to detect ILC1 cells in any of the tissues assessed, however, we identified intra-epithelial (ie)ILC1-like cells that represent a broader category of NK cells in mucosal and non-mucosal pathological tissues. In addition, we have revealed the expression of phenotypic molecules that have not been previously described for ILCs. Our analysis shows that human ILCs are highly heterogeneous cell types between individuals and tissues. It also provides a global, comprehensive, and detailed description of ILC heterogeneity in humans across patients and tissues. PMID- 27986457 TI - Development of an Online Learning Module to Improve Pediatric Residents' Confidence and Knowledge of the Pubertal Examination. AB - PURPOSE: Pediatric residents must know how to perform pubertal examinations. The initial objective of this study was to evaluate pediatric resident knowledge and comfort related to the pubertal examination and to determine whether and why these examinations are avoided. The subsequent objective was to develop and assess a learning module (LM) addressing identified education gaps. METHODS: A learning needs assessment (LNA) was administered to residents in four Canadian pediatric training programs. Identified themes and knowledge gaps were used to develop an online, case-based LM. A randomized assessment of the LM was conducted among residents from nine training programs across Canada. RESULTS: Sixty-four residents completed the LNA. About 52% reported discomfort introducing the pubertal examination, 50% reported a lack of confidence related to the examination, and 56% reported having avoided a warranted examination. Ninety seven residents participated in the LM assessment. The baseline results were similar to those from the LNA in terms of discomfort, lack of confidence, and avoidance related to pubertal examinations. However, the intervention group showed improvement on a knowledge assessment compared with control group (p < .001). Confidence levels also improved in the intervention group LM (p < .01). Most residents (95%) stated they found the LM to be useful. CONCLUSIONS: Residents report being uncomfortable with and avoiding the pubertal examination and have significant knowledge gaps. The online, case-based LM used in this study improved the knowledge and confidence related to this aspect of pediatric care and may be an effective adjunct to pediatric training. PMID- 27986458 TI - Use of Foul Language Among Chinese Adolescents: Developmental Change and Relations With Psychosocial Competences. AB - PURPOSE: The use of foul language becomes increasingly popular among youth, yet scientific research on this topic is grossly missing in the literature. This longitudinal study examined the developmental change of foul language use and its relations to emotional competence, social competence, and moral competence over high school years. METHODS: Data were from a six-year longitudinal study between grade 7 and grade 12 with an annual assessment on 3,328 Hong Kong adolescents (mean age = 12.59 +/- .74 years). Multiple-group latent growth curve modeling based on six waves of longitudinal data were conducted. RESULTS: Results showed that the use of foul language increased, but the increase rate slowed down over time; males showed faster increase rate yet faster deceleration than did females. In addition, changes in emotional competence, social competence, and moral competence negatively predicted the change in use of foul language across males and females, respectively. CONCLUSIONS: Adolescents are vulnerable to increasing their use of foul language. However, promoting emotional competence, social competence, and moral competence could be helpful to minimize the increasing trend of use of foul language. PMID- 27986459 TI - [Oncological results of active surveillance in prostate cancer: A retrospective multicentric cohort]. AB - PURPOSE: To report oncological outcomes of patients with prostate cancer undergoing active surveillance according to SURACAP criteria. METHODS: This multicentric study included patients who were initially treated with active surveillance for localized prostate cancer according to the SURACAP criteria. The duration of active surveillance as well as the causes of discontinuing the protocol and the definitive pathological results of patients who further underwent radical prostatectomy were retrospectively evaluated. The predictors of discontinuing active surveillance were assessed using a univariable Cox Model. In addition, the predictive value of initial MRI was assessed for patients who performed such imagery. RESULTS: Between 2007 and 2013, 80 patients were included, with a median age of 64 years [47-74]. Median follow-up was 52.9 months [24-108]. At 5 years follow-up, 43.4% patients were still under surveillance. Among patients that underwent surgery, 17.8% had an extra-capsular extension. The risk of discontinuing was not significantly greater for patients with tumor size of 2 or 3mm versus 1mm (HR=0.9 [0.46-1.75], P=0.763), 2 positives cores versus 1 (HR=0.98 [0.48-2.02], P=0.967), T2a vs. T1c stage (HR=2.18 [0.77-6.18], P=0.133), increased PSA level (HR=1 [0.96-1.15], P=0.975) or the patient's age (HR=1 [0.93 1.16], P=0.966). Among the 50 patients who performed initial MRI, the results of such imagery was not significantly associated to the risk of discontinuing active surveillance MRI (HR=1.49 [0.63-3.52], P=0.36). CONCLUSION: Although this study reveals a high rate of release from active surveillance at 5 years, the rate of extra-capsular tumors reported in the group of patients that underwent surgery is among the lowest in literature. LEVEL OF EVIDENCE: 4. PMID- 27986456 TI - Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification. AB - The cell fate decision between interferon-producing plasmacytoid DC (pDC) and antigen-presenting classical DC (cDC) is controlled by the E protein transcription factor TCF4 (E2-2). We report that TCF4 comprises two transcriptional isoforms, both of which are required for optimal pDC development in vitro. The long Tcf4 isoform is expressed specifically in pDCs, and its deletion in mice impaired pDCs development and led to the expansion of non canonical CD8+ cDCs. The expression of Tcf4 commenced in progenitors and was further upregulated in pDCs, correlating with stage-specific activity of multiple enhancer elements. A conserved enhancer downstream of Tcf4 was required for its upregulation during pDC differentiation, revealing a positive feedback loop. The expression of Tcf4 and the resulting pDC differentiation were selectively sensitive to the inhibition of enhancer-binding BET protein activity. Thus, lineage-specifying function of E proteins is facilitated by lineage-specific isoform expression and by BET-dependent feedback regulation through distal regulatory elements. PMID- 27986462 TI - Factors Contributing to Unintentional Leak During CPAP Treatment: A Systematic Review. AB - CPAP is the first-line treatment for moderate to severe OSA syndrome. Up to 25% of patients with OSA syndrome discontinue CPAP treatment due to side effects. Unintentional leakage and its associated annoying consequences are the most frequently reported adverse effects of CPAP. Successive technological improvements have not succeeded in addressing this issue. A systematic review was conducted (1) to assess the impact of different technological advances on unintentional leaks and (2) to determine if any patient characteristics have already been identified as determinants of unintentional leakage. No CPAP modality was superior to another in reducing unintentional leaks and, surprisingly, oronasal masks were associated with higher unintentional leaks. Nasal obstruction, older age, higher BMI, central fat distribution, and male sex might be associated with an increased risk of unintentional leakage. Such leaks remain an important problem. Further studies are needed to improve the understanding of underlying clinical factors so that patients at risk of unintentional leaks may be identified and individualized solutions applied. PMID- 27986460 TI - The effect of intrauterine devices on acquisition and clearance of human papillomavirus. AB - BACKGROUND: Previous studies have shown a decrease in cervical cancer associated with intrauterine device use. It has been hypothesized that intrauterine device use may alter the natural history of human papillomavirus infections, preempting development of precancerous lesions of the cervix and cervical cancer, but the effect of intrauterine devices on the natural history of human papillomavirus infection and subsequent development of cervical cancer is poorly understood. OBJECTIVE: The purpose of this study was to evaluate the association between intrauterine device use and cervical high-risk human papillomavirus acquisition and clearance. STUDY DESIGN: This is a prospective cohort study conducted from October 2000 through June 2014 among 676 sexually active young women and girls enrolled from family planning clinics in San Francisco, CA. Data were analyzed using a Cox proportional hazards model, including time-varying indicators of intrauterine device use, and adjusting for fixed and time-dependent predictor variables. RESULTS: A total of 85 women used an intrauterine device at some time during follow-up. Among 14,513 study visits, women reported intrauterine device use at 505 visits. After adjusting for potential behavioral confounders, there was no association between intrauterine device use and human papillomavirus acquisition (hazard ratio, 0.50; 95% confidence interval, 0.20-1.23; P = .13) or clearance of human papillomavirus infection (hazard ratio, 1.44; 95% confidence interval, 0.76-2.72; P = .26). CONCLUSION: Current intrauterine device use is not associated with acquisition or persistence of human papillomavirus infection. Intrauterine device use is safe among women and girls with human papillomavirus infections and at risk for human papillomavirus acquisition. Intrauterine device use may play a role further downstream in the natural history of cervical cancer by inhibiting the development of precancerous lesions of the cervix in human papillomavirus-infected women, or enhancing clearance of established precancerous lesions. PMID- 27986461 TI - Randomized clinical trial between hourly titrated and 2 hourly static oral misoprostol solution for induction of labor. AB - BACKGROUND: Misoprostol is an effective agent for the induction of labor. Existing guidelines recommend oral misoprostol solution 25 MUg every 2 hours. However, more research is required to optimize the use of oral misoprostol solution for the induction of labor. OBJECTIVE: The purpose of this study was to compare efficacy and safety of hourly titrated-dose oral misoprostol solution with static-dose oral misoprostol solution every 2 hours for labor induction. STUDY DESIGN: In this randomized controlled study, oral misoprostol solution was administered as (1) 20 MUg hourly (<=4 doses) that was increased in the absence of regular uterine contractions to 40 MUg hourly (<=4 doses) and then to 60 MUg hourly (<=16 doses) or (2) 25 MUg every 2 hours until active labor began (<=12 doses). A sample size of 146 women was planned with the use of a projected 95% rate for the primary endpoint (vaginal delivery within 24 hours) for hourly titrated-dose misoprostol and 80% rate for static-dose misoprostol every 2 hours. Safety outcomes included maternal morbidity and adverse neonatal outcomes. RESULTS: From December 2013 to July 2015, 146 women were assigned randomly to treatment. Demographic and clinical factors were similar between groups, except for age. Vaginal delivery was achieved within 24 hours in 47 women (64.4%) who received hourly titrated-doses of misoprostol solution and 48 women (65.8%) who received 2-hourly static-dose misoprostol solution (P=1.00). Rates of vaginal delivery within 24 hours did not differ significantly between treatment groups for women who were nulliparous (P=1.00) or who had postterm pregnancies (P=.66), a Bishop score of <=3 (P=.84), or oxytocin augmentation (P=.83). Cesarean deliveries were performed within 24 hours in 9 women who received hourly titrated dose misoprostol solution and 2 women who received 2-hourly static-dose misoprostol solution (P=.056). Pyrexia and meconium-stained liquor occurred more frequently with the hourly titrated-dose regimen. CONCLUSION: The static-dose oral misoprostol solution every 2 hours has similar efficacy as hourly titrated dose misoprostol solution but with fewer side-effects and lower complication rates. PMID- 27986464 TI - Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer. AB - Circular RNAs (circRNAs) comprise a novel class of widespread non-coding RNAs that may regulate gene expression in eukaryotes. However, the characterization and function of circRNAs in human cancer remain elusive. Here we identified at least 5500 distinct circRNA candidates and a series of circRNAs that are differentially expressed in gastric cancer (GC) tissues compared with matched normal tissues. We further characterized one circRNA derived from the PVT1 gene and termed it as circPVT1. The expression of circPVT1 is often upregulated in GC tissues due to the amplification of its genomic locus. circPVT1 may promote cell proliferation by acting as a sponge for members of the miR-125 family. The level of circPVT1 was observed as an independent prognostic marker for overall survival and disease-free survival of patients with GC. Our findings suggest that circPVT1 is a novel proliferative factor and prognostic marker in GC. PMID- 27986465 TI - Exploring vector-borne infection ecology in multi-host communities: A case study of West Nile virus. AB - In this study, we develop a model to investigate how ecological factors might affect the dynamics of a vector-borne pathogen in a population composed by different hosts which interact with each other. Specifically, we consider the case when different host species compete with each other, as they share the same habitat, and the vector might have different feeding preference, which can also be time dependent. As a prototypical example, we apply our model to study the invasion and spread, during a typical season, of West Nile virus in an ecosystem composed of two competent avian host species and possibly of dead-end host species. We found that competition and vector feeding preferences can profoundly influence pathogen invasion, influencing its probability to start an epidemic, and influencing transmission rates. Finally, when considering time-dependent feeding preferences, as observed in the field, we noted that the virus circulation could be amplified and that the timing of epidemic peaks could be changed. Our work highlights that ecological interactions between hosts can have a profound influence on the dynamics of the pathogen and that, when modeling vector-borne infections, vector feeding behavior should, for this reason, be carefully evaluated. PMID- 27986463 TI - Tamoxifen differentially regulates miR-29b-1 and miR-29a expression depending on endocrine-sensitivity in breast cancer cells. AB - Endocrine-resistance develops in ~40% of breast cancer patients after tamoxifen (TAM) therapy. Although microRNAs are dysregulated in breast cancer, their contribution to endocrine-resistance is not yet understood. Previous microarray analysis identified miR-29a and miR-29b-1 as repressed by TAM in MCF-7 endocrine sensitive breast cancer cells but stimulated by TAM in LY2 endocrine-resistant breast cancer cells. Here we examined the mechanism for the differential regulation of these miRs by TAM in MCF-7 versus TAM-resistant LY2 and LCC9 breast cancer cells and the functional role of these microRNAs in these cells. Knockdown studies revealed that ERalpha is responsible for TAM regulation of miR-29b-1/a transcription. We also demonstrated that transient overexpression of miR-29b-1/a decreased MCF-7, LCC9, and LY2 proliferation and inhibited LY2 cell migration and colony formation but did not sensitize LCC9 or LY2 cells to TAM. Furthermore, TAM reduced DICER1 mRNA and protein in LY2 cells, a known target of miR-29. Supporting this observation, anti-miR-29b-1 or anti-miR-29a inhibited the suppression of DICER by 4-OHT. These results suggest miR-29b-1/a has tumor suppressor activity in TAM-resistant cells and does not appear to play a role in mediating TAM resistance. PMID- 27986466 TI - Mitochondrial Adaptation in Nonalcoholic Fatty Liver Disease: Novel Mechanisms and Treatment Strategies. AB - Nonalcoholic fatty liver disease (NAFLD) is prevalent in patients with obesity or type 2 diabetes. Nonalcoholic steatohepatitis (NASH), encompassing steatosis with inflammation, hepatocyte injury, and fibrosis, predisposes to cirrhosis, hepatocellular carcinoma, and even cardiovascular disease. In rodent models and humans with NAFLD/NASH, maladaptation of mitochondrial oxidative flux is a central feature of simple steatosis to NASH transition. Induction of hepatic tricarboxylic acid cycle closely mirrors the severity of oxidative stress and inflammation in NASH. Reactive oxygen species generation and inflammation are driven by upregulated, but inefficient oxidative flux and accumulating lipotoxic intermediates. Successful therapies for NASH (weight loss alone or with incretin therapy, or pioglitazone) likely attenuate mitochondrial oxidative flux and halt hepatocellular injury. Agents targeting mitochondrial dysfunction may provide a novel treatment strategy for NAFLD. PMID- 27986468 TI - Heart rate variability in bipolar disorder: A systematic review and meta analysis. AB - BACKGROUND: Heart rate variability (HRV) has been suggested reduced in bipolar disorder (BD) compared with healthy individuals (HC). This meta-analysis investigated: HRV differences in BD compared with HC, major depressive disorder or schizophrenia; HRV differences between affective states; HRV changes from mania/depression to euthymia; and HRV changes following interventions. METHODS: A systematic review and meta-analysis reported according to the PRISMA guidelines was conducted. MEDLINE, Embase, PsycINFO, The Cochrane Library and Scopus were searched. A total of 15 articles comprising 2534 individuals were included. RESULTS: HRV was reduced in BD compared to HC (g=-1.77, 95% CI: -2.46; -1.09, P<0.001, 10 comparisons, n=1581). More recent publication year, larger study and higher study quality were associated with a smaller difference in HRV. Large between-study heterogeneity, low study quality, and lack of consideration of confounding factors in individual studies were observed. CONCLUSIONS: This first meta-analysis of HRV in BD suggests that HRV is reduced in BD compared to HC. Heterogeneity and methodological issues limit the evidence. Future studies employing strict methodology are warranted. PMID- 27986467 TI - Guidelines of the French Society of Otorhinolaryngology (SFORL) (short version). Specific treatment of epistaxis in Rendu-Osler-Weber disease. AB - OBJECTIVES: The authors present the guidelines of the French Oto-Rhino Laryngology - Head and Neck Surgery Society (Societe Francaise d'Oto-Rhino Laryngologie et de Chirurgie de la Face et du Cou: SFORL) concerning specific treatment of epistaxis in Rendu-Osler-Weber disease. METHODS: A multidisciplinary work-group was entrusted with a review of the scientific literature on the above topic. Guidelines were drawn up, based on the articles retrieved and the group members' individual experience. They were then read over by an editorial group independent of the work group. The final version was established in a coordination meeting. The guidelines were graded as A, B, C or expert opinion, by decreasing level of evidence. RESULTS: Rendu-Osler-Weber disease is diagnosed from the presence of at least three of Curacao's four criteria. In acute epistaxis, bidigital compression is recommended. Embolization is reserved for resistant epistaxis. Non-resorbable nasal packing and cauterization are contraindicated. Patient education is essential. Telangiectasia of the nasal mucosa can be treated by various local means. In the event of insufficient control, systemic administration of tranexamic acid is recommended. PMID- 27986469 TI - A systematic review of the psychobiological burden of informal caregiving for patients with dementia: Focus on cognitive and biological markers of chronic stress. AB - As the physiological impact of chronic stress is difficult to study in humans, naturalistic stressors are invaluable sources of information in this area. This review systematically evaluates the research literature examining biomarkers of chronic stress, including neurocognition, in informal dementia caregivers. We identified 151 papers for inclusion in the final review, including papers examining differences between caregivers and controls as well as interventions aimed at counteracting the biological burden of chronic caregiving stress. Results indicate that cortisol was increased in caregivers in a majority of studies examining this biomarker. There was mixed evidence for differences in epinephrine, norepinephrine and other cardiovascular markers. There was a high level of heterogeneity in immune system measures. Caregivers performed more poorly on attention and executive functioning tests. There was mixed evidence for memory performance. Interventions to reduce stress improved cognition but had mixed effects on cortisol. Risk of bias was generally low to moderate. Given the rising need for family caregivers worldwide, the implications of these findings can no longer be neglected. PMID- 27986470 TI - Anticancer activity and tissue distribution of platinum (II) complex with lignin derived polymer of benzene-poly-carboxylic acids. AB - Platinum-containing antineoplastic agents with physiologically active ligands seem to be a promising direction in anticancer drug design. PDBA is a novel promising antineoplastic agent, containing polymer ligand of natural origin (international patent WO2013/143549 A1). Polymer ligand of PDBA has a highly functionalised polyphenolic backbone, which exerts its own pharmacological effect via immune modulation and regulation of gene expression. PDBA is a cis diammineplatinum(II) complex, containing mono-deprotonated benzene-poly carboxylic acids, derived from lignin, and hydroxyl group as O-donor ligands (approximate bulk formula C83H70N2O27Pt). The agent is being evaluated in Phase II controlled clinical trials in metastatic breast cancer patients. In the present study, tissue distribution and tumour growth inhibition effects of PDBA, cisplatin and carboplatin were compared in SHR female mice, bearing inoculated solid Ehrlich carcinoma. The agents were administered subcutaneously every second day for the period of 10days (5 injections) at 62.5mg/kg, 3.0mg/kg and 18.5mg/kg for PDBA, cisplatin and carboplatin, respectively. Experimental animals were sacrificed on the Days 11, 16 and 23 after the inoculation of the tumour. The doses of all studied drugs were selected to obtain similar antitumour efficacy with ca. 50% growth inhibition of the Ehrlich tumour at the end of the study. The efficacy of a single platinum reactive moiety [cis-diammineplatinum(II)] was shown to be the highest for cisplatin, followed by PDBA and finally carboplatin. However, the toxicity of PDBA was considerably lower than that of carboplatin and especially cisplatin. The drugs were mainly distributed in lungs, kidneys, liver, spleen and tumour tissue. PDBA showed quite high accumulation in the tumour tissue, possibly, owing to the effect of the lignin-derived ligand. PMID- 27986471 TI - Retrospective Clinical Study of Maxillary Sagittal Fractures: Predictors of Postoperative Outcome. AB - PURPOSE: Because of less attention to the sagittal component of maxillary fractures, these fractures are often misdiagnosed or the reduction is missed leading to maxillary transverse discrepancies. Therefore, the purpose of this study was to identify factors associated with good or adverse postoperative outcomes of maxillary sagittal fractures. MATERIALS AND METHODS: This study was a single-center retrospective cohort study. The sample was composed of cases of maxillary sagittal fractures treated at the Department of Oral and Maxillofacial Surgery, Craniomaxillofacial Trauma Unit of Xi'an Jiaotong University (Xi'an, China) from January 2008 through December 2013. The predictor variables were age, gender, occupation, cause of injury, injury severity, treatment timing, treatment method, and quality of fracture reduction. The outcome variable was the postoperative treatment effect index. Descriptive, bivariate, and multivariate statistics were computed. The P value was set to .05. RESULTS: The sample was composed of 40 cases. The male-to-female ratio was 4:1; the most vulnerable age group was 20 to 30 years (30%); laborers (72.5%) were more prone to injury; and the main cause of injury was motor vehicle accident (62.5%). No cases of isolated sagittal fracture were found and most (35%) occurred with other maxillary fractures, including Le Fort fractures. A statistically significant association between treatment timing and quality of fracture reduction and the postoperative treatment effect index (P < .05) was found. CONCLUSION: The results of this study suggest that better results are achieved when fractured bone is treated sooner. Anatomic repositioning of the fractured bone is the important predictor for good postoperative outcomes. PMID- 27986472 TI - Positive association between vocal and facial attractiveness in women but not in men: A cross-cultural study. AB - Various species use multiple sensory modalities in the communication processes. In humans, female facial appearance and vocal display are correlated and it has been suggested that they serve as redundant markers indicating the bearer's reproductive potential and/or residual fertility. In men, evidence for redundancy of facial and vocal attractiveness is ambiguous. We tested the redundancy/multiple signals hypothesis by correlating perceived facial and vocal attractiveness in men and women from two different populations, Brazil and the Czech Republic. We also investigated whether facial and vocal attractiveness are linked to facial morphology. Standardized facial pictures and vocal samples of 86 women (47 from Brazil) and 81 men (41 from Brazil), aged 18-35, were rated for attractiveness by opposite-sex raters. Facial and vocal attractiveness were found to positively correlate in women but not in men. We further applied geometric morphometrics and regressed facial shape coordinates on facial and vocal attractiveness ratings. In women, facial shape was linked to their facial attractiveness but there was no association between facial shape and vocal attractiveness. In men, none of these associations was significant. Having shown that women with more attractive faces possess also more attractive voices, we thus only partly supported the redundant signal hypothesis. PMID- 27986474 TI - Phosphatidyl-hydroxytyrosol and phosphatidyl-tyrosol bilayer properties. AB - Hydroxytyrosol and tyrosol phospholipids were enzymatically synthesized and investigated for their bilayer properties. Dynamic light scattering demonstrated that hand extrusion at 100nm consistently resulted in liposomes of nearly 85nm diameter for both phosphatidyl-hydroxytyrosol (DOPHT) and phosphatidyl-tyrosol (DOPT). Transmission electron microscopy showed DOPT and DOPHT liposomes extruded at 100-nm to be spherical and non-distinctive from one another. Zeta potential measurements resulted in surface charges<-25mV, demonstrating both DOPT and DOPHT form highly stable liposomes. Quartz crystal microbalance with dissipation monitoring measurements demonstrated that liposomal adsorption was dependent on a combination of DOPT (or DOPHT) mole-percent and calcium ions concentration. Fluorescence anisotropy measurements indicated that melting temperatures of DOPT and DOPHT were below 4 degrees C, suggesting that adsorption behavior and liposome formation was limited by electrostatic interactions and not gel-state formation. PMID- 27986475 TI - Polymeric nanoparticles - Influence of the glass transition temperature on drug release. AB - The physico-chemical characterisation of nanoparticles is often lacking the determination of the glass transition temperature, a well-known parameter for the pure polymer carrier. In the present study the influence of water on the glass transition temperature of poly (DL-lactic-co-glycolic acid) nanoparticles was assessed. In addition, flurbiprofen and mTHPP as model drugs were incorporated in poly (DL-lactic-co-glycolic acid), poly (DL-lactic acid), and poly (L-lactic acid) nanoparticles. For flurbiprofen-loaded nanoparticles a decrease in the glass transition temperature was observed while mTHPP exerted no influence on this parameter. Based on this observation, the release behaviour of the drug loaded nanoparticles was investigated at different temperatures. For all preparations an initial burst release was measured that could be attributed to the drug adsorbed to the large nanoparticle surface. At temperatures above the glass transition temperature an instant drug release of the nanoparticles was observed, while at lower temperatures less drug was released. It could be shown that the glass transition temperature of drug loaded nanoparticles in suspension more than the corresponding temperature of the pure polymer is the pivotal parameter when characterising a nanostructured drug delivery system. PMID- 27986476 TI - Micro-feeding and dosing of powders via a small-scale powder pump. AB - Robust and accurate powder micro-feeding (<100mg/s) and micro-dosing (<5 mg) are major challenges, especially with regard to regulatory limitations applicable to pharmaceutical development and production. Since known micro-feeders that yield feed rates below 5mg/s use gravimetric feeding principles, feed rates depend primarily on powder properties. In contrast, volumetric powder feeders do not require regular calibration because their feed rates are primarily determined by the feeder's characteristic volume replacement. In this paper, we present a volumetric micro-feeder based on a cylinder piston system (i.e., a powder pump), which allows accurate micro-feeding and feed rates of a few grams per hours even for very fine powders. Our experimental studies addressed the influence of cylinder geometries, the initial conditions of bulk powder, and the piston speeds. Additional computational studies via Discrete Element Method simulations offered a better understanding of the feeding process, its possible limitations and ways to overcome them. The powder pump is a simple yet valuable tool for accurate powder feeding at feed rates of several orders of magnitude. PMID- 27986477 TI - Sex differences in mortality and morbidity following repair of intact abdominal aortic aneurysms. AB - OBJECTIVE: Medicare studies have shown increased perioperative mortality in women compared with men following endovascular and open abdominal aortic aneurysm (AAA) repair. However, a recent regional study of high-volume centers, adjusting for anatomy but limited in sample size, did not show sex to be predictive of worse outcomes. This study aimed to evaluate sex differences after intact AAA repair in a national clinical registry. METHODS: The targeted vascular module of the National Surgical Quality Improvement Program was queried to identify patients undergoing endovascular aneurysm repair (EVAR) or open repair for intact, infrarenal AAA from 2011 to 2014. Univariate analysis was performed using the Fisher exact test and Mann-Whitney test. Multivariable logistic regression was used to account for differences in comorbidities, aneurysm details, and operative characteristics. RESULTS: We identified 6611 patients (19% women) who underwent intact AAA repair (87% EVAR; 83% women vs 88% men; P < .001). Women were older (median age, 76 vs 73 years; P < .001), had smaller aneurysms (median, 5.4 vs 5.5 cm; P < .001), and had more chronic obstructive pulmonary disease (22% vs 17%; P < .001). Among patients undergoing EVAR, women had longer operative times (median, 138 [interquartile range, 103-170] vs 131 [106-181] minutes; P < .01) and more often underwent renal (6.3% vs 4.1%; P < .01) and lower extremity (6.6% vs 3.8%; P < .01) revascularization. After open repair, women had shorter operative time (215 [177-304] vs 226 [165-264] minutes; P = .02), but women less frequently underwent lower extremity revascularization (3.1% vs 8.2%; P = .03). Thirty-day mortality was higher in women after EVAR (3.2% vs 1.2%; P < .001) and open repair (8.0% vs 4.0%; P = .04). After adjusting for repair type, age, aneurysm diameter, and comorbidities, female sex was independently associated with mortality (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.1-2.6; P = .02) and major complications (OR, 1.4; CI, 1.1-1.7; P < .01) after intact AAA repair. However, after adjusting for aortic size index rather than for aortic diameter, the association between female sex and mortality (OR, 1.5; CI, 0.98 2.4; P = .06) and major complications (OR, 1.1; CI, 0.9-1.4; P = .24) was reduced. CONCLUSIONS: Women were at higher risk for 30-day death and major complications after intact AAA repair. Some of this disparity may be explained by differences in aortic size index, which should be further evaluated to determine the ideal threshold for repair. PMID- 27986478 TI - Sarcopenia is a risk factor for cardiovascular events experienced by patients with critical limb ischemia. AB - BACKGROUND: Prognosis is poor for patients with critical limb ischemia (CLI), and the most frequent cause of death is cardiovascular disease. Low grip strength is a risk factor for cardiovascular events, and sarcopenia may be associated as well. Thus, we hypothesized that sarcopenia is a risk factor for cardiovascular events experienced by patients with CLI. If this is true and appropriate therapy becomes available, the prognosis of patients with CLI will improve with appropriate risk management strategies to prevent cardiovascular events. Therefore, the aim of this study was to verify this hypothesis. METHODS: We studied 114 patients who underwent revascularization and computed tomography between January 2002 and December 2012 in the Department of Surgery and Sciences at Kyushu University in Japan. Sarcopenia was defined as skeletal muscle area measured by L3-level computed tomography scan <114.0 cm2 and <89.8 cm2 for men and women, respectively. Clinical characteristics, cardiovascular event-free survival, <2-year death, causes of death, and effective treatments for sarcopenia were investigated. RESULTS: We identified 53 (46.5%) patients with sarcopenia. Three-year cardiovascular event-free survival rates were 43.1% and 91.2% for patients with and without sarcopenia, respectively (P < .01). During follow-up, cardiovascular disease caused the deaths of 4 and 15 patients without and with sarcopenia (P < .01), respectively, and in particular, ischemic heart disease caused the deaths of 0 and 5 patients without or with sarcopenia (P < .05), respectively. Single antiplatelet therapy (SAPT; hazard ratio, 0.46; 95% confidence interval, 0.24-0.82; P < .01) and statin therapy (hazard ratio, 0.38; 95% confidence interval, 0.16-0.78; P < .01) were independent factors associated with improved cardiovascular event-free survival. Three-year cardiovascular event free survival rates for patients with sarcopenia who received SAPT, dual antiplatelet therapies, and no antiplatelet therapy were 75.3%, 21.1%, and 29.5%, respectively (P < .01). CONCLUSIONS: Sarcopenia is a risk factor for worse cardiovascular event-free survival, and SAPT and statin therapy reduced this risk for patients with CLI. Furthermore, SAPT but not dual antiplatelet therapy increased cardiovascular event-free survival in patients with sarcopenia. PMID- 27986479 TI - Prospective, nonrandomized study to evaluate endovascular repair of pararenal and thoracoabdominal aortic aneurysms using fenestrated-branched endografts based on supraceliac sealing zones. AB - PURPOSE: To investigate outcomes of manufactured fenestrated and branched endovascular aortic repair (F-BEVAR) endografts based on supraceliac sealing zones to treat pararenal aortic aneurysms and thoracoabdominal aortic aneurysms (TAAAs). METHODS: A total of 127 patients (91 male; mean age, 75 +/- 10 years old) were enrolled in a prospective, nonrandomized single-center study using manufactured F-BEVAR (November 2013-March 2015). Stent design was based on supraceliac sealing zone in all patients with >= four vessels in 111 (89%). Follow-up included clinical examination, laboratory studies, duplex ultrasound, and computed tomography imaging at discharge, 1 month, 6 months, and yearly. End points adjudicated by independent clinical event committee included mortality, major adverse events (any mortality, myocardial infarction, stroke, paraplegia, acute kidney injury, respiratory failure, bowel ischemia, blood loss >1 L), freedom from reintervention, and branch-related instability (occlusion, stenosis, endoleak or disconnection requiring reintervention), target vessel patency, sac aneurysm enlargement, and aneurysm rupture. RESULTS: There were 47 pararenal, 42 type IV, and 38 type I-III TAAAs with mean diameter of 59 +/- 17 mm. A total of 496 renal-mesenteric arteries were incorporated by 352 fenestrations, 125 directional branches, and 19 celiac scallops, with a mean of 3.9 +/- 0.5 vessels per patient. Technical success of target vessel incorporation was 99.6% (n = 493/496). There were no 30-day or in-hospital deaths, dialysis, ruptures or conversions to open surgical repair. Major adverse events occurred in 27 patients (21%). Paraplegia occurred in two patients (one type IV, one type II TAAAs). Follow-up was >30 days in all patients, >6 months in 79, and >12 months in 34. No patients were lost to follow-up. After a mean follow-up of 9.2 +/- 7 months, 23 patients (18%) had reinterventions (15 aortic, 8 nonaortic), 4 renal artery stents were occluded, five patients had type Ia or III endoleaks, and none had aneurysm sac enlargement. Primary and secondary target vessel patency was 96% +/- 1% and 98% +/- 0.7% at 1 year. Freedom from any branch instability and any reintervention was 93% +/- 2% and 93% +/- 2% at 1 year, respectively. Patient survival was 96% +/- 2% at 1 year for the entire cohort. CONCLUSIONS: Endovascular repair of pararenal aortic aneurysms and TAAAs, using manufactured F BEVAR with supraceliac sealing zones, is safe and efficacious. Long-term follow up is needed to assess the impact of four-vessel designs on device-related complications and progression of aortic disease. PMID- 27986481 TI - Discussion. PMID- 27986480 TI - Arteriovenous fistula patency in the 3 years following vonapanitase and placebo treatment. AB - OBJECTIVE: This study explored the long-term outcomes of arteriovenous fistulas treated with vonapanitase (recombinant human elastase) at the time of surgical creation. METHODS: This was a randomized, double-blind, placebo-controlled trial of 151 patients undergoing radiocephalic or brachiocephalic arteriovenous fistula creation who were randomized equally to placebo, vonapanitase 10 MUg, or vonapanitase 30 MUg. The results after 1 year of follow-up were previously reported. The current analysis occurred when the last patient treated was observed for 3 years. For the current analysis, the primary end point was primary patency; the secondary end points included secondary patency, use of the fistula for hemodialysis, and rate of procedures to restore or to maintain patency. RESULTS: There was no significant difference in the risk of primary patency loss with vonapanitase 10 MUg or 30 MUg vs placebo. When seven initial patency loss events related to cephalic arch and central vein balloon angioplasty were excluded, the risk of patency loss was reduced with vonapanitase overall (hazard ratio [HR], 0.63; P = .049) and 30 MUg (HR, 0.51; P = .03). In patients with radiocephalic fistulas (n = 67), the risks of primary and secondary patency loss were reduced with 30 MUg (HR, 0.37 [P = .02] and 0.24 [P = .046], respectively). The rate of procedures to restore or to maintain fistula patency was reduced with 30 MUg vs placebo (0.23 vs 0.72 procedure days/patient/year; P = .03) and also reduced in patients with radiocephalic fistulas with 30 MUg vs placebo (0.17 vs 0.85 procedure days/patient/year; P = .048). CONCLUSIONS: In this study, vonapanitase did not significantly improve primary patency in the primary analysis but did significantly improve primary patency in an analysis that excluded patency loss due to cephalic arch and central vein balloon angioplasty. In patients with radiocephalic fistulas, 30 MUg significantly improved primary and secondary patency. Vonapanitase 30 MUg decreased the rate of procedures to restore or to maintain patency in the analysis that included all patients and in the subset with radiocephalic fistulas. PMID- 27986482 TI - High dose-rate brachytherapy for the treatment of lower extremity in-stent restenosis. AB - OBJECTIVE: Historically, edge stenosis and late thrombosis limited the effectiveness of adjunctive endovascular brachytherapy (EVBT) for in-stent restenosis (ISR) after percutaneous transluminal angioplasty (PTA) and stenting. We evaluated an updated protocol of PTA and EVBT for ISR among patients with lower extremity occlusive disease. METHODS: This is a retrospective, single center review of patients treated with PTA and EVBT for ISR in the iliac and femoropopliteal segments between 2004 and 2012. A dose of 20 Gy was given at a depth of 0.5 mm beyond the radius of the largest PTA balloon using iridium 192, with at least 2-cm-long margins of radiation coverage proximal and distal to the injured area. Stents were assessed for patency by duplex ultrasound imaging at 1, 3, 6, 9, 12, and 18 months and then yearly. The primary end point was freedom from >=50% restenosis in the treated segment at 6 months, 1 year, and 2 years. Patency data were estimated using the Kaplan-Meier method. Secondary end points were early and late thrombotic occlusion. RESULTS: Among 42 consecutive cases in 35 patients of EVBT for ISR in common or external iliac (9 [20.8%]) and superficial femoral or popliteal (33 [76.7%]) arteries, or both, 21 patients (50%) had claudication, asymptomatic hemodynamically significant stenoses were identified on duplex ultrasound imaging in 16 (38.1%), and 4 (9.8%) had critical limb ischemia. Mean treated length was 23.5 +/- 12.3 cm over a mean duration of 16.1 +/- 9.6 minutes. There was one technical failure (2.3%). Median post-EVBT follow-up time was 682 days (range, 1-2262 days). There were two (4.9%) and five (11.9%) cases of early and late thrombotic occlusions, respectively. There was one death, believed to be secondary to acute coronary syndrome. Primary, assisted primary, and secondary patency in the entire cohort was 75.2%, 89.1%, and 89.1%, respectively, at 1 year and 63.7%, 80.6%, and 85.6%, respectively, at 2 years. CONCLUSIONS: This contemporary protocol of PTA and adjunctive EVBT for lower extremity ISR, which is updated from those used in prior trials and includes a surveillance strategy that identifies at-risk stents for reintervention before occlusion, may be a promising treatment for lower extremity ISR at institutions where a close collaboration between vascular surgeons and radiation oncologists is feasible. PMID- 27986483 TI - Contemporary open repair of ruptured abdominal aortic aneurysms. AB - OBJECTIVE: Although endovascular repair of ruptured abdominal aortic aneurysms (rAAAs) is increasingly more prevalent and may yield better results, open repair of rAAAs is still commonly performed. Our goal was to assess the contemporary practice patterns and outcomes of open repair of rAAA. METHODS: The 2011-2014 American College of Surgeons National Surgical Quality Improvement Program targeted open AAA database was queried for all rAAAs. Patient characteristics, presentation, aneurysm details, and operative details were analyzed to identify factors that may affect outcome in this population of patients. RESULTS: We identified 404 patients who underwent open repair of rAAA. The average age was 72 +/- 9.4 years, and 76.2% were male. There were 230 (56.9%) patients who presented with hypotension. The operative approach was retroperitoneal in 16.3% of cases. The proximal extents of the aneurysms were infrarenal (52.5%), juxtarenal (24.3%), pararenal (4.2%), and suprarenal (8.2%). The distal extents were aortic (38.6%), common iliac artery (34.2%), and external or internal iliac artery (8.9%). Renal, visceral, and lower extremity revascularization was performed in 6.4%, 2.2%, and 7.9% of patients, respectively. Thirty-day mortality was 35.6%, and postoperative complications included cardiac (18.3%), pulmonary (42.3%), wound complications (6.7%), acute renal failure (17.3%), and ischemic colitis (9.4%). Postoperative length of stay was 13.1 +/- 12.7 days, and 30-day readmission was 4.5%. Predictors of 30-day mortality were transperitoneal approach (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.38-7.89; P < .001), hypotension at presentation (OR, 2.03; 95% CI, 1.2-3.56; P = .007), and age (OR, 1.05; 95% CI, 1.02-1.09; P = .001). Transperitoneal approach also increased the risk of postoperative cardiac complications (OR, 3.25; 95% CI, 1.01 10.4; P = .047). Postoperative pulmonary complications were predicted by chronic obstructive pulmonary disease (OR, 2.06; 95% CI, 1.07-3.94; P = .03) and hypotension at presentation (OR, 1.77; 95% CI, 1.06-2.96; P = .03). CONCLUSIONS: The majority of contemporary open rAAA repairs were performed for infrarenal aneurysms. Transperitoneal approach, hypotension, and chronic obstructive pulmonary disease were associated with higher mortality and postoperative complications. Thirty-day mortality after rAAA was lower compared with historical data. PMID- 27986485 TI - Jean Kunlin: Correspondence and commentary regarding distal fistulas for lower limb ischemia. PMID- 27986484 TI - A comparison of brachial artery-brachial vein arteriovenous fistulas with arteriovenous grafts in patients with poor superficial venous anatomy. AB - OBJECTIVE: The autogenous arteriovenous fistula (AVF) has been shown to be superior to the arteriovenous graft (AVG) with respect to cost, complications, and primary patency. Therefore, the National Kidney Foundation Disease Outcomes Quality Initiative guidelines recommend reserving AVGs for patients who do not have adequate superficial venous anatomy to support AVF placement. The brachial artery-brachial vein arteriovenous fistula (BVAVF) has emerged as an autologous last-effort alternative. However, there are limited data comparing BVAVFs and AVGs in patients who are otherwise not candidates for a traditional AVF. METHODS: Patients who received a BVAVF from July 2009 to July 2014 were compared with those who received an AVG during the same period. At our institution, BVAVF and AVG are only performed in patients with poor superficial venous anatomy. Patient demographic data, operative details, and subsequent follow-up were collected. BVAVFs were performed with a two-stage approach, with initial arteriovenous anastomosis, followed by delayed superficialization or transposition. Our primary outcome measure was primary functional assisted patency at 1 year. Patients lost to follow-up were excluded. A subgroup analysis was also performed for patients in whom the BVAVF or the AVG was their first hemodialysis access surgery. RESULTS: During the study period, 29 patients underwent BVAVF and 32 underwent AVG. There were no differences in age, gender, or presence of diabetes between the two groups. The median days to cannulation from the initial operation were 141 (interquartile range, 94-214) in the BVAVF group and 29 (interquartile range, 14-33) in the AVG group (P < .001). Fewer patients required interventions to maintain or re-establish patency in the BVAVF group than in the AVG group (10% v. 44%; P < .01). The 1-year primary patency was greater for BVAVF (62% vs 25%; P < .01); however, there was no difference in the functional assisted primary patency rates at 1 year (45% vs 25%; P = .1). Subgroup analysis demonstrated greater 1 year primary functional assisted primary patency (52% vs 19%; P < .05) in patients without prior access surgery. CONCLUSIONS: The BVAVF is a viable alternative to the AVG in patients with inadequate superficial venous anatomy, especially in access-naive patients. The decision to perform BVAVF must be weighed against the delay in functional maturation expected compared with AVG. PMID- 27986486 TI - One-year pivotal trial outcomes of the Nellix system for endovascular aneurysm sealing. AB - OBJECTIVE: The Nellix EndoVascular Aneurysm Sealing (EVAS) System (Endologix, Inc, Irvine, Calif) is a novel approach to abdominal aortic aneurysm (AAA) treatment whereby polymer is used to fill the AAA sac. We report 1-year results of the investigational device exemption pivotal trial. METHODS: Eligible patients were treated at 30 sites in the United States and Europe. Inclusion criteria required an asymptomatic infrarenal AAA, with a neck length >=10 mm and <=60 degrees angle, iliac artery blood lumen diameter 9 to 35 mm, access artery diameter >=6 mm, and serum creatinine <=2 mg/dL. Follow-up included computed tomography angiography scans at 30 days, 6 months, and 1 year that were evaluated by a core laboratory. The primary safety end point was 30-day major adverse events (MAEs), which were compared with a performance goal of <56% (the Society for Vascular Surgery open repair control group rate). The primary effectiveness end point was treatment success at 1 year, which was compared with a performance goal of >80%. Treatment success required procedural technical success and absence of AAA rupture during follow-up, conversion to open surgical repair, endoleak (type I or III) at 1 year, migration >10 mm causing complications or requiring secondary intervention, aneurysm enlargement, or secondary procedures through 1 year for resolution of endoleak, device obstruction or occlusion, or device defect. RESULTS: Of 150 treated patients, 149 (99.3%) completed 1-year follow-up. The MAEs rate at 30 days was 2.7% (95% confidence interval, 0.7%-6.7%), satisfying the primary safety end point (<56%). The 1-year treatment success was 94% (95% confidence interval, 88.6%-97.4%), achieving the primary effectiveness end point (>80%). At 1 year, key secondary outcomes included 6.7% MAEs, 4.7% serious device-related events, 1.3% AAA-related mortality, 3.7% secondary interventions, and 0.7% surgical conversions. MAEs through 1 year included death (n = 6), stroke (n = 3), bowel ischemia (n = 2), renal failure (n = 2), respiratory failure (n = 2), and myocardial infarction (n =1). One iatrogenic AAA rupture occurred and one AAA rupture was reported during follow-up. AAA sac enlargement (>5 mm) was 1.5% at 1 year. Endoleaks were present in four patients (3.1%) at 1 year (1 type Ib and 3 type II). Migration >10 mm occurred in three patients (2.3%), but none required secondary intervention. CONCLUSIONS: Outcomes with this novel endovascular therapy for AAA, the Nellix EVAS System, are encouraging. The primary safety and effectiveness end points have been met. Low morbidity, low mortality, and high procedural and treatment success were achieved despite the inevitability of a learning curve and unique risks associated with a new device and technique. Long-term follow-up is in progress. PMID- 27986487 TI - The disproportionate growth of office-based atherectomy. AB - OBJECTIVE: The purpose of this study was to evaluate the trends in procedure volume, clinical sites of care, and Medicare expenditure for peripheral vascular interventions (PVIs) for lower extremity occlusive disease since the Centers for Medicare and Medicaid Services instituted reimbursement policy changes that broadened payment for procedures performed in physician-owned office-based laboratories (OBLs). METHODS: We analyzed fee-for-service Medicare claims data from 2011 to 2014 to obtain the frequency of use of PVI by type, care setting, and physician specialty. We also assessed changes in the total Medicare cost for PVI by setting. RESULTS: There was a 60% increase in atherectomy cases among Medicare beneficiaries between 2011 and 2014. During the same period, OBLs experienced a 298% increase in atherectomy volume vs a 27% increase in hospital outpatient settings and an 11% decrease for inpatient hospital settings. In 2014, OBLs were the most common setting for atherectomy. Nonatherectomy PVIs grew more modestly at just 3% but also experienced site of care shifts. Vascular surgeons and cardiologists accounted for the majority of office-based PVIs in 2014. Total Medicare costs for PVIs increased 18% from 2011 to 2014. Hospital inpatient costs declined 1%, whereas costs for hospital outpatient PVIs increased by 41% and physician office costs increased by 258%. CONCLUSIONS: The migration of revascularization procedures for lower extremity peripheral arterial occlusive disease continues from the inpatient to the outpatient setting and especially to OBLs. Increased use of atherectomy in all segments of the lower extremity arterial system has been observed, particularly in OBLs, without substantial evidence in the literature of increased efficacy compared with standard angioplasty with or without stenting. Generous Medicare reimbursement for in office atherectomy procedures is likely contributing to the volume shifts observed. PMID- 27986488 TI - Predicting the need for vascular surgeons in Canada. AB - OBJECTIVE: With the introduction of direct entry (0+5) residency programs in addition to the traditional (5+2) programs, the number of vascular surgery graduates across Canada is expected to increase significantly during the next 5 to 10 years. Society's need for these newly qualified surgeons is unclear. This study evaluated the predicted requirement for vascular surgeons across Canada to 2021. A program director survey was also performed to evaluate program directors' perceptions of the 0+5 residency program, the expected number of new trainees, and faculty recruitment and retirement. METHODS: The estimated and projected Canadian population numbers for each year between 2013 and 2021 were determined by the Canadian Socio-economic Information and Management System (CANSIM), Statistics Canada's key socioeconomic database. The number of vascular surgery procedures performed from 2008 to 2012 stratified by age, gender, and province was obtained from the Canadian Institute for Health Information Discharge Abstract Database. The future need for vascular surgeons was calculated by two validated methods: (1) population analysis and (2) workload analysis. In addition, a 12-question survey was sent to each vascular surgery program director in Canada. RESULTS: The estimated Canadian population in 2013 was 35.15 million, and there were 212 vascular surgeons performing a total of 98,339 procedures. The projected Canadian population by 2021 is expected to be 38.41 million, a 9.2% increase from 2013; however, the expected growth rate in the age group 60+ years, who are more likely to require vascular procedures, is expected to be 30% vs 3.4% in the age group <60 years. Using population analysis modeling, there will be a surplus of 10 vascular surgeons in Canada by 2021; however, using workload analysis modeling (which accounts for the more rapid growth and larger proportion of procedures performed in the 60+ age group), there will be a deficit of 11 vascular surgeons by 2021. Program directors in Canada have a positive outlook on graduating 0+5 residents' skill, and the majority of programs will be recruiting at least one new vascular surgeon during the next 5 years. CONCLUSIONS: Although population analysis projects a potential surplus of surgeons, workload analysis predicts a deficit of surgeons because it accounts for the rapid growth in the 60+ age group in which the majority of procedures are performed, thus more accurately modeling future need for vascular surgeons. This study suggests that there will be a need for newly graduating vascular surgeons in the next 5 years, which could have an impact on resource allocation across training programs in Canada. PMID- 27986489 TI - High mortality outbreak of carbapenem-resistant Pseudomonas aeruginosa infection in a Brazilian pediatric oncology hospital. PMID- 27986490 TI - Serosurvey for canine visceral leishmaniasis in rural and urban areas of the Brazilian Legal Amazon. PMID- 27986491 TI - Removing the bottleneck in whole genome sequencing of Mycobacterium tuberculosis for rapid drug resistance analysis: a call to action. AB - Whole genome sequencing (WGS) can provide a comprehensive analysis of Mycobacterium tuberculosis mutations that cause resistance to anti-tuberculosis drugs. With the deployment of bench-top sequencers and rapid analytical software, WGS is poised to become a useful tool to guide treatment. However, direct sequencing from clinical specimens to provide a full drug resistance profile remains a serious challenge. This article reviews current practices for extracting M. tuberculosis DNA and possible solutions for sampling sputum. Techniques under consideration include enzymatic digestion, physical disruption, chemical degradation, detergent solubilization, solvent extraction, ligand-coated magnetic beads, silica columns, and oligonucleotide pull-down baits. Selective amplification of genomic bacterial DNA in sputum prior to WGS may provide a solution, and differential lysis to reduce the levels of contaminating human DNA is also being explored. To remove this bottleneck and accelerate access to WGS for patients with suspected drug-resistant tuberculosis, it is suggested that a coordinated and collaborative approach be taken to more rapidly optimize, compare, and validate methodologies for sequencing from patient samples. PMID- 27986492 TI - Effects of Low-Intensity Extracorporeal Shockwave Therapy on Erectile Dysfunction: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Low-intensity extracorporeal shock wave therapy (Li-ESWT) has been proposed as an effective non-invasive treatment option for erectile dysfunction (ED). AIM: To use systematic review and meta-analysis to assess the efficacy of Li-ESWT by comparing change in erectile function as assessed by the erectile function domain of the International Index of Erectile Function (IIEF-EF) in men undergoing Li-ESWT vs sham therapy for the treatment of ED. METHODS: Systematic search was conducted of MEDLINE, EMBASE, and ClinicalTrials.gov for randomized controlled trials that were published in peer-reviewed journals or presented in abstract form of Li-ESWT used for the treatment of ED from January 2010 through March 2016. Randomized controlled trials were eligible for inclusion if they were published in the peer-reviewed literature and assessed erectile function outcomes using the IIEF-EF score. Estimates were pooled using random-effects meta analysis. MAIN OUTCOME MEASURES: Change in IIEF-EF score after treatment with Li ESWT in patients treated with active treatment vs sham Li-ESWT probes. RESULTS: Data were extracted from seven trials involving 602 participants. The average age was 60.7 years and the average follow-up was 19.8 weeks. There was a statistically significant improvement in pooled change in IIEF-EF score from baseline to follow-up in men undergoing Li-ESWT vs those undergoing sham therapy (6.40 points; 95% CI = 1.78-11.02; I2 = 98.7%; P < .0001 vs 1.65 points; 95% CI = 0.92-2.39; I2 = 64.6%; P < .0001; between-group difference, P = .047). Significant between-group differences were found for total treatment shocks received by patients (P < .0001). CONCLUSION: In this meta-analysis of seven randomized controlled trials, treatment of ED with Li-ESWT resulted in a significant increase in IIEF-EF scores. PMID- 27986493 TI - Increased levels of inflammation among infants with disorganized histories of attachment. AB - Early life adversity is associated with adult elevations of inflammatory markers such as circulating levels of C-reactive protein (CRP). Few studies have examined inflammation levels during infancy nor the associations between sources of adversity and concurrent inflammation early in life. Existing evidence suggests that early adversity in the form of compromised caregiving relationships can embed itself into young children's biology with implications for lifelong development. This study examined the association between infants' histories of attachment with their mothers and salivary concentrations of CRP, all of which were assessed when infants were 17 months of age. Results show that infants with disorganized attachments histories and those exhibiting disorganized and avoidant regulatory behaviors when faced with an attachment stressor were all associated with significantly elevated levels of salivary CRP. These results suggest that exposure to significant interpersonal adversity very early in life may engender a proinflamotry phenotype with life-long implications for health. PMID- 27986494 TI - The psychometric properties of the Leicester Cough Questionnaire and Respiratory Symptoms in CF tool in cystic fibrosis: A preliminary study. AB - BACKGROUND: There are few tools to quantify the impact of cough in cystic fibrosis (CF). The psychometric properties of the Leicester Cough Questionnaire (LCQ) and Respiratory Symptoms in CF (ReS-CF) tool were investigated in adults with CF. METHODS: Validity and reliability were assessed in clinically stable participants who completed the questionnaires twice, along with the Cystic Fibrosis Questionnaire - Revised (CFQ-R). Responsiveness was assessed by change in questionnaires following treatment for an acute respiratory exacerbation. RESULTS: Correlations between the LCQ and CFQ-R respiratory domain were moderate (n=59, rs=0.78, p<0.001). Correlations between ReS-CF and CFQ-R respiratory domain were fair (rs=-0.50, p<0.001). The LCQ total score was repeatable (ICC 0.92, 95%CI 0.87-0.96, n=50). In those reporting improvement in symptoms following treatment (n=36), LCQ total score had a mean change of 4.6 (SD 3.7) and effect size of 1.2. CONCLUSIONS: The LCQ and ReS-CF appear to be valid, reliable and responsive in CF. TRIAL REGISTRATION: www.anzctr.org.au: ACTRN12615000262505. PMID- 27986495 TI - Current strategies for the long-term assessment, monitoring, and management of cystic fibrosis patients treated with CFTR modulator therapy. AB - The content for this activity is based on the satellite symposium, "Current Strategies for the Long-term Assessment, Monitoring, and Management for Cystic Fibrosis Patients Treated with CFTR Modulator Therapy" that was presented at the 39th European Cystic Fibrosis Society Conference on June 10, 2016 (Online access: http://courses.elseviercme.com/ecfs2016e/619e). The emergence of novel targeted agents, that directly correct CFTR loss function alleles, has created new treatment opportunities for patients with cystic fibrosis with advanced disease. Knowledge of the role of these agents in the clinical setting is quickly evolving and will require physicians to stay acquainted with the latest data as well as evidence-based treatment guidelines in order to achieve optimized cystic fibrosis patient care. Ideally, after diagnosis, a personalized approach would be adapted and tailored to the patient through genome-informed medicine. However, due to the relative recentness of genomic-based therapeutics, physicians may have a limited knowledge base regarding these new treatment options and how to best incorporate these agents into patient management plans. Although cystic fibrosis is still largely regarded as a pediatric disease, the median survival for patients is 35years of age. Consequently, pediatric-to-adult cystic fibrosis care programs would allow suitable preparation time for this transition and develop a standardized group of self-care and management skills. PMID- 27986497 TI - Regional differences in mu-opioid receptor-dependent modulation of basal dopamine transmission in rat striatum. AB - The nigrostriatal dopamine system is implicated in the regulation of reward and motor activity. Dopamine (DA) release in dorsal striatum (DS) is controlled by the firing rate of DA neurons in substantia nigra pars compacta. However, influences at terminal level, such as those involving activation of mu opioid receptors (MORs), can play a key role in determining DA levels in striatum. Nonetheless, published data also suggest that the effect of opioid drugs on DA levels may differ depending on the DS subregion analyzed. In this study, in vivo microdialysis in rats was used to explore this regional dependence. Changes in basal DA levels induced by local retrodialysis application of DAMGO (selective MORs agonist) in three different subregions of DS along the rostro-caudal axis were studied. Our results indicate that whereas administration of 10MUM DAMGO into the rostral and caudal DS significantly reduced DA levels, in medial DS an increase in DA levels was observed. These data reveal a regional-dependent MOR modulation of DA release in DS, similar to that described in the ventral striatum. Our findings may lead to a better understanding of the nigrostriatal DA system regulation. PMID- 27986496 TI - Medical diagnostics for indoor mold exposure. AB - In April 2016, the German Society of Hygiene, Environmental Medicine and Preventative Medicine (Gesellschaft fur Hygiene, Umweltmedizin und Praventivmedizin (GHUP)) together with other scientific medical societies, German and Austrian medical societies, physician unions and experts has provided an AWMF (Association of the Scientific Medical Societies) guideline 'Medical diagnostics for indoor mold exposure'. This guideline shall help physicians to advise and treat patients exposed indoors to mold. Indoor mold growth is a potential health risk, even without a quantitative and/or causal association between the occurrence of individual mold species and health effects. Apart from the allergic bronchopulmonary aspergillosis (ABPA) and the mycoses caused by mold, there is only sufficient evidence for the following associations between moisture/mold damages and different health effects: Allergic respiratory diseases, asthma (manifestation, progression, exacerbation), allergic rhinitis, exogenous allergic alveolitis and respiratory tract infections/bronchitis. In comparison to other environmental allergens, the sensitizing potential of molds is estimated to be low. Recent studies show a prevalence of sensitization of 3-10% in the total population of Europe. The evidence for associations to mucous membrane irritation and atopic eczema (manifestation, progression, exacerbation) is classified as limited or suspected. Inadequate or insufficient evidence for an association is given for COPD, acute idiopathic pulmonary hemorrhage in children, rheumatism/arthritis, sarcoidosis, and cancer. The risk of infections from indoor molds is low for healthy individuals. Only molds that are capable to form toxins can cause intoxications. The environmental and growth conditions and especially the substrate determine whether toxin formation occurs, but indoor air concentrations are always very low. In the case of indoor moisture/mold damages, everyone can be affected by odor effects and/or impairment of well-being. Predisposing factors for odor effects can be given by genetic and hormonal influences, imprinting, context and adaptation effects. Predisposing factors for impairment of well-being are environmental concerns, anxieties, conditioning and attributions as well as a variety of diseases. Risk groups that must be protected are patients with immunosuppression and with mucoviscidosis (cystic fibrosis) with regard to infections and individuals with mucoviscidosis and asthma with regard to allergies. If an association between mold exposure and health effects is suspected, the medical diagnosis includes medical history, physical examination, conventional allergy diagnosis, and if indicated, provocation tests. For the treatment of mold infections, it is referred to the AWMF guidelines for diagnosis and treatment of invasive Aspergillus infections. Regarding mycotoxins, there are currently no validated test methods that could be used in clinical diagnostics. From the perspective of preventive medicine, it is important that mold damages cannot be tolerated in indoor environments. PMID- 27986498 TI - Comparison of auditory stream segregation in sighted and early blind individuals. AB - An important characteristic of the auditory system is the capacity to analyze complex sounds and make decisions on the source of the constituent parts of these sounds. Blind individuals compensate for the lack of visual information by an increase input from other sensory modalities, including increased auditory information. The purpose of the current study was to compare the fission boundary (FB) threshold of sighted and early blind individuals through spectral aspects using a psychoacoustic auditory stream segregation (ASS) test. This study was conducted on 16 sighted and 16 early blind adult individuals. The applied stimuli were presented sequentially as the pure tones A and B and as a triplet ABA-ABA pattern at the intensity of 40dBSL. The A tone frequency was selected as the basis at values of 500, 1000, and 2000Hz. The B tone was presented with the difference of a 4-100% above the basis tone frequency. Blind individuals had significantly lower FB thresholds than sighted people. FB was independent of the frequency of the tone A when expressed as the difference in the number of equivalent rectangular bandwidths (ERBs). Early blindness may increase perceptual separation of the acoustic stimuli to form accurate representations of the world. PMID- 27986499 TI - Targeting chromatin aging - The epigenetic impact of longevity-associated interventions. AB - A rapidly growing body of evidence has shown that chromatin undergoes radical alterations as an organism ages, but how these changes relate to aging itself is an open question. It is likely that these processes contribute to genomic instability and loss of transcriptional fidelity, which in turn drives deleterious age-related phenotypes. Interventions associated with increased healthspan and longevity such as reduced insulin/IGF signalling (IIS), inhibition of mTOR and energy depletion resulting in SIRT1/AMPK activation, all have beneficial effects which ameliorate multiple facets of age-associated decline. The impact of these interventions on the epigenome is less certain. In this review we highlight the potential of these interventions to act directly upon the epigenome and promote a youthful chromatin landscape, maintaining genetic and transcriptional memory throughout the lifecourse. We propose that this is a fundamental mechanism through which these interventions are able to curtail the incidence of age-related disease. By revisiting these well characterised interventions, we may be able to identify targetable effectors of chromatin function and use this knowledge to enhance healthspan and longevity in human populations through the measured application of dietary and small molecule interventions. PMID- 27986500 TI - Omission of axillary staging in elderly patients with early stage breast cancer impacts regional control but not survival: A systematic review and meta-analysis. AB - INTRODUCTION: Management of early breast cancer in the elderly population is challenging due to different breast cancer biology and limited tolerance to aggressive treatments. The aim of this study is to evaluate whether the omission of axillary staging impacts breast cancer outcomes in elderly patients. PATIENTS AND METHODS: A systematic review and meta-analysis was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The electronic databases were searched in August 2014 using the following inclusion criteria: RESULTS: Two RCTs met the eligibility criteria and were included. A meta-analysis of the included RCTs of 692 patients found that axillary staging reduced the risk of axillary recurrence compared to no axillary staging (RR 0.24, 95% CI: 0.06 to 0.95, I2=0%, p=0.04). There were no differences observed in in-breast recurrence or distant recurrence (RR 1.20, 95% CI: 0.55 to 2.64, I2=62%, p=0.65, RR 1.17, 95% CI: 0.75 to 1.82, I2=0%, p=0.48, respectively). There were no differences observed in overall or breast-cancer specific mortality (RR 0.99, 95% CI: 0.79 to 1.24, I2=0%, p=0.92, RR 1.07, 95% CI: 0.72 to 1.57, I2=0%, p=0.75, respectively). DISCUSSION: Omission of axillary staging in elderly patients with clinically negative axillae results in increased regional recurrence but does not appear to impact survival. PMID- 27986502 TI - Pathophysiology, screening and diagnosis of pulmonary hypertension in infants with bronchopulmonary dysplasia - A review of the literature. AB - Bronchopulmonary dysplasia (BPD) is a common complication of extreme prematurity, which has increased over the last 20 years. BPD is associated with increased morbidities and mortality. It has been increasingly recognized that BPD affects overall lung development including the pulmonary vasculature. More recent studies have demonstrated an increased awareness of pulmonary arterial hypertension (PH) in BPD patients and recent international guidelines have advocated for better screening. This review will describe the current understanding of the pathophysiology of PH in infants with BPD, the in-depth assessment of the available literature linking PH and BPD, and propose an approach of screening and diagnosis of PH in infants with BPD. PMID- 27986503 TI - Sleep is an eye-opener: Behavioral causes and consequences of hypersomnolence in children. AB - The most common behavioral cause of hypersomnia in children is insufficient sleep. Behavioral causes of insufficient sleep for children, ages six months through 12 years, include inadequate sleep hygiene, bedtime struggles, prolonged sleep onset latency, nighttime fears, and nightmares. Behavioral interventions are efficacious and should be individualized to meet the needs of the child and family. Insufficient sleep affects many areas of child development, including academic, cognitive, and psychosocial, as well as parents and caregivers. Behavioral causes of sleepiness in children are best identified through a clinical interview, sleep diary, and actigraphy. PMID- 27986501 TI - Motivation and mortality in older women with early stage breast cancer: A longitudinal study with ten years of follow-up. AB - OBJECTIVES: The Getting Out of Bed Scale (GOB) was validated as a health-related quality of life (HRQoL) variable in older women with early stage breast cancer, suggesting its potential as a concise yet powerful measure of motivation. The aim of our project was to assess the association between GOB and mortality over 10years of follow-up. MATERIALS AND METHODS: We studied 660 women >=65-years old diagnosed with stage I-IIIA primary breast cancer. Data were collected over 10years of follow-up from interviews, medical records, and death indexes. RESULTS: Compared to women with lower GOB scores, women with higher GOB had an unadjusted hazard ratio (HR) of all-cause mortality of 0.78 at 5years, 95% confidence interval (CI) (0.52, 1.19) and 0.77 at 10years, 95%CI (0.59, 1.00). These associations diminished after adjusting for age and stage of breast cancer, and further after adjusting for other HRQoL variables including physical function, mental health, emotional health, psychosocial function, and social support. Unadjusted HRs of breast cancer-specific mortality were 0.92, 95%CI (0.49, 1.74), at 5years, and 0.82, 95%CI (0.52, 1.32), at 10years. These associations also decreased in adjusted models. CONCLUSION: Women with higher GOB scores had a lower hazard of all-cause mortality in unadjusted analysis. This effect diminished after adjusting for confounding clinical and HRQoL variables. GOB is a measure of motivation that may not be independently associated with cancer mortality, but reflects other HRQoL variables making it a potential outcome to monitor in older patients with cancer. PMID- 27986504 TI - The consequences of chronic cannabis smoking in vulnerable adolescents. AB - Cannabis, like the mythic shape-shifter, presents in various guises, morphing with the perspective and context of the observer. Arguments about cannabis are confused by a myriad of debates-medical, social, ethical and political-as if a single conceptual umbrella can capture the variety and granularity of marijuana related issues. This paper responds to marijuana use as it is commonly practised by youth in Australia. It has little to say about synthetic cannabinoids, specific medicinal cannabinoids, or medicinal properties of marijuana. We address those adolescents genetically and environmentally vulnerable to mental illness, with specific emphasis on indigenous and neurodevelopmentally impaired young people who show patterns of usage and response very different to adults and more resilient members of the population. Specifically, the practice of mixing tobacco with marijuana by aboriginal youth, and the resultant coalition of dependencies, will likely presage a rise in pulmonary and central nervous system pathology over the coming decades. Aboriginal youth begin using earlier, persist longer, and take greater quantities of cannabis than non-indigenous youth. This paper recommends practical interventions to reduce the multiple health consequences of chronic cannabis use in young people, especially indigenous young people. PMID- 27986505 TI - Secondary Pulmonary Hypertension: Who to consider, how to confirm and when to follow-up. PMID- 27986506 TI - Proteomic assessment of colorectal cancers and respective resection margins from patients of the Amazon state of Brazil. AB - : Colorectal cancer (CRC) is the third most common type of cancer in the world with a low survival rate and therapeutic efficiency. Tumor surgery implies the removal of an apparently non-tumorous tissue around the tumor in an attempt to reduce recurrence chances; this tissue is referred to as the resection margin. Our analysis employed an 8-plex iTRAQ to label four adenocarcinoma biopsies and their corresponding resection margins at 5cm; our results disclose fifty-six proteins as being differentially abundant. These proteins are mainly involved in energetic metabolism (e.g. S100 calcium binding protein A11), cell migration (e.g. transgelin), formation of the cytoskeleton (e.g. profilin 1) and degradation of extracellular matrix (e.g. carbonic anhydrase 2). A gene ontology enrichment analysis revealed several proteins related to adhesion, invasion, metastasis, death, and recognition cell. Taken together, our results highlight proteins related to invasion, cell proliferation, and linked to the metastasis of colorectal cancer in tumor tissue. Finally, we argue that the expression patterns revealed in our comparison helps shed light on the development of more effective surgical strategies and add to the comprehension of this disease. BIOLOGICAL SIGNIFICANCE: Colorectal cancer (CRC) is the third most common type of cancer in the world with a low survival rate and therapeutic efficiency. Tumor surgery implies the removal of an apparently non-tumorous tissue around the tumor in an attempt to reduce recurrence chances; this tissue is also referred to as the resection margin. In this regard, resection margins pose as a treasure trove for investigating the molecular characteristics of the tumorigenesis process. While most studies focus on comparing cancer versus control tissue, this study contrasts the proteomic profiles of colorectal cancer biopsies with their corresponding resection margin at 5cm apart. Our analysis employed an 8-plex iTRAQ labeling and a 4-step offline MudPIT online with a Velos. A gene ontology enrichment analysis revealed several proteins related to adhesion, invasion, metastasis, death, and recognition cell. PMID- 27986507 TI - Effects of Iterative Reconstruction Algorithms on Computer-assisted Detection (CAD) Software for Lung Nodules in Ultra-low-dose CT for Lung Cancer Screening. AB - RATIONALE AND OBJECTIVES: This study aimed to evaluate the effects of iterative reconstruction (IR) algorithms on computer-assisted detection (CAD) software for lung nodules in ultra-low-dose computed tomography (ULD-CT) for lung cancer screening. MATERIALS AND METHODS: We selected 85 subjects who underwent both a low-dose CT (LD-CT) scan and an additional ULD-CT scan in our lung cancer screening program for high-risk populations. The LD-CT scans were reconstructed with filtered back projection (FBP; LD-FBP). The ULD-CT scans were reconstructed with FBP (ULD-FBP), adaptive iterative dose reduction 3D (AIDR 3D; ULD-AIDR 3D), and forward projected model-based IR solution (FIRST; ULD-FIRST). CAD software for lung nodules was applied to each image dataset, and the performance of the CAD software was compared among the different IR algorithms. RESULTS: The mean volume CT dose indexes were 3.02 mGy (LD-CT) and 0.30 mGy (ULD-CT). For overall nodules, the sensitivities of CAD software at 3.0 false positives per case were 78.7% (LD-FBP), 9.3% (ULD-FBP), 69.4% (ULD-AIDR 3D), and 77.8% (ULD-FIRST). Statistical analysis showed that the sensitivities of ULD-AIDR 3D and ULD-FIRST were significantly higher than that of ULD-FBP (P < .001). CONCLUSIONS: The performance of CAD software in ULD-CT was improved by using IR algorithms. In particular, the performance of CAD in ULD-FIRST was almost equivalent to that in LD-FBP. PMID- 27986509 TI - On the preservation of cooperation in two-strategy games with nonlocal interactions. AB - Nonlocal interactions such as spatial interaction are ubiquitous in nature and may alter the equilibrium in evolutionary dynamics. Models including nonlocal spatial interactions can provide a further understanding on the preservation and emergence of cooperation in evolutionary dynamics. In this paper, we consider a variety of two-strategy evolutionary spatial games with nonlocal interactions based on an integro-differential replicator equation. By defining the invasion speed and minimal traveling wave speed for the derived model, we study the effects of the payoffs, the selection pressure and the spatial parameter on the preservation of cooperation. One of our most interesting findings is that, for the Prisoners Dilemma games in which the defection is the only evolutionary stable strategy for unstructured populations, analyses on its asymptotic speed of propagation suggest that, in contrast with spatially homogeneous games, the cooperators can invade the habitat under proper conditions. Other two-strategy evolutionary spatial games are also explored. Both our theoretical and numerical studies show that the nonlocal spatial interaction favors diversity in strategies in a population and is able to preserve cooperation in a competing environment. A real data application in a virus mutation study echoes our theoretical observations. In addition, we compare the results of our model to the partial differential equation approach to demonstrate the importance of including non local interaction component in evolutionary game models. PMID- 27986508 TI - Screening Breast MRI Outcomes in Routine Clinical Practice: Comparison to BI-RADS Benchmarks. AB - RATIONALE AND OBJECTIVES: The BI-RADS Atlas 5th Edition includes screening breast magnetic resonance imaging (MRI) outcome benchmarks. However, the metrics are from expert practices and clinical trials of women with hereditary breast cancer predispositions, and it is unknown if they are appropriate for routine practice. We evaluated screening breast MRI audit outcomes in routine practice across a spectrum of elevated risk patients. MATERIALS AND METHODS: This Institutional Review Board-approved, Health Insurance Portability and Accountability Act compliant retrospective study included all consecutive screening breast MRI examinations from July 1, 2010 to June 30, 2013. Examination indications were categorized as gene mutation carrier (GMC), personal history (PH) breast cancer, family history (FH) breast cancer, chest radiation, and atypia/lobular carcinoma in situ (LCIS). Outcomes were determined by pathology and/or >=12 months clinical and/or imaging follow-up. We calculated abnormal interpretation rate (AIR), cancer detection rate (CDR), positive predictive value of recommendation for tissue diagnosis (PPV2) and biopsy performed (PPV3), and median size and percentage of node-negative invasive cancers. RESULTS: Eight hundred and sixty examinations were performed in 566 patients with a mean age of 47 years. Indications were 367 of 860 (42.7%) FH, 365 of 860 (42.4%) PH, 106 of 860 (12.3%) GMC, 14 of 860 (1.6%) chest radiation, and 8 of 22 (0.9%) atypia/LCIS. The AIR was 134 of 860 (15.6%). Nineteen cancers were identified (13 invasive, 4 DCIS, two lymph nodes), resulting in CDR of 19 of 860 (22.1 per 1000), PPV2 of 19 of 88 (21.6%), and PPV3 of 19 of 80 (23.8%). Of 13 invasive breast cancers, median size was 10 mm, and 8 of 13 were node negative (61.5%). CONCLUSIONS: Performance outcomes of screening breast MRI in routine clinical practice across a spectrum of elevated risk patients met the American College of Radiology Breast Imaging Reporting and Data System benchmarks, supporting broad application of these metrics. The indication of a personal history of treated breast cancer accounted for a large proportion (42%) of our screening examinations, with breast MRI performance in this population at least comparable to that of other screening indications. PMID- 27986510 TI - Simulation-based training for cardiology procedures: Are we any further forward in evidencing real-world benefits? AB - Simulation-based training as an educational tool for healthcare professionals continues to grow in sophistication, scope, and usage. There have been a number of studies demonstrating the utility of the technique, and it is gaining traction as part of the training curricula for the next generation of cardiologists. In this review, we focus on the recent literature for the efficacy of simulation for practical procedures specific to cardiology, focusing on transesophageal echocardiography, cardiac catheterization, coronary angioplasty, and electrophysiology. A number of studies demonstrated improved performance by those trained using SBT when compared to other methods, although evidence of this leading to an improvement in patient outcomes remains scarce. We discuss this evidence, and the implications for practice for training in cardiology. PMID- 27986511 TI - Anaphylaxis after zoster vaccine: Implicating alpha-gal allergy as a possible mechanism. PMID- 27986512 TI - Influence of periodontal treatment on rheumatoid arthritis: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the influence of periodontal treatment on rheumatoid arthritis activity. METHODS: MEDLINE/PUBMED, The Cochrane Library, Clinical Trials, SciELO and LILACS were searched for studies published until December 2014. Included articles were: prospective studies; including patients older than 18 years, diagnosed with periodontitis and rheumatoid arthritis submitted to non surgical periodontal treatment; with a control group receiving no periodontal treatment; with outcomes including at least one marker of rheumatoid arthritis activity. Methodological quality of the studies was assessed using PEDro scale. Quantitative data were pooled in statistical meta-analysis using Review Manager 5. RESULTS: Four articles were included. Non-surgical periodontal treatment was associated with a significant reduction of DAS28 (OR: -1.18; 95% CI: -1.43, 0.93; p <0.00001). Erythrocyte sedimentation rate, C-reactive protein, patient's assessment of rheumatoid activity using visual analogical scale, tender and swollen joint counts showed a trend towards reduction (not statistically significant). CONCLUSIONS: The reduction of DAS 28 in patients with rheumatoid arthritis after periodontal treatment suggests that the improvement of periodontal condition is beneficial to these patients. Further randomized controlled clinical trials are necessary to confirm this finding. PMID- 27986514 TI - Parenting stress and salivary cortisol in parents of children with autism spectrum disorder: Longitudinal variations in the context of a service dog's presence in the family. AB - A significant portion of parents of children with autism spectrum disorder report high levels of stress related to parenting responsibilities, which have been linked to abnormal cortisol patterns. This study seeks to better understand the parents' adaptation to caregiving demands and use of a service dog, by taking into account longitudinal variations in salivary cortisol and perception of parental stress. Salivary cortisol was collected one day per week for 15 weeks by 98 primary caregivers of children with ASD. Overall, parents perceived high levels of stress at baseline. Mean morning cortisol increase was below expected levels for healthy adults, and perception of stress predicted morning cortisol activity. Hypocorticolism related to chronic stress may be present in parents of children with ASD. Longitudinal analysis revealed that the presence of a service dog in the family had an effect on parenting stress, wakening and morning cortisol levels. PMID- 27986515 TI - An assessment of sex differences in Delta9-tetrahydrocannabinol (THC) taste and place conditioning. PMID- 27986517 TI - Comparison of Nutritional and Clinical Outcomes in Patients with Head and Neck Cancer Undergoing Chemoradiotherapy Utilizing Prophylactic versus Reactive Nutrition Support Approaches. AB - BACKGROUND: The optimal method of tube feeding for patients with head and neck cancer remains unclear. A validated protocol is available that identifies high nutritional-risk patients who would benefit from prophylactic gastrostomy tube placement. Adherence to this protocol is ultimately determined by clinical team discretion or patient decision. OBJECTIVE: The study aim was to compare outcomes after adherence and nonadherence to this validated protocol, thus comparing a prophylactic and reactive approach to nutrition support in this patient population. DESIGN: We conducted a prospective comparative cohort study. Patients were observed during routine clinical practice over 2 years. PARTICIPANTS/SETTING: Patients with head and neck cancer having curative-intent treatment between August 2012 and July 2014 at a tertiary hospital in Queensland, Australia, were included if assessed as high nutrition risk according to the validated protocol (n=130). Patients were grouped according to protocol adherence as to whether they received prophylactic gastrostomy (PEG) per protocol recommendation (prophylactic PEG group, n=69) or not (no PEG group, n=61). MAIN OUTCOME MEASURES: Primary outcome was percentage weight change during treatment. Secondary outcomes were feeding tube use and hospital admissions. STATISTICAL ANALYSIS PERFORMED: Fisher's exact, chi2, and two sample t tests were performed to determine differences between the groups. Linear and logistic regression were used to examine weight loss and unplanned admissions, respectively. RESULTS: Patients were 88% male, median age was 59 years, with predominantly stage IV oropharyngeal cancer receiving definitive chemoradiotherapy. Statistically significantly less weight loss in the prophylactic PEG group (7.0% vs 9.0%; P=0.048) and more unplanned admissions in the no PEG group (82% vs 75%; P=0.029). In the no PEG group, 26 patients (43%) required a feeding tube or had >=10% weight loss. CONCLUSIONS: Prophylactic gastrostomy improved nutrition outcomes and reduced unplanned hospital admissions. Additional investigation of characteristics of patients with minimal weight loss or feeding tube use could help refine and improve the protocol. PMID- 27986516 TI - Effects of withdrawal from repeated phencyclidine administration on behavioural function and brain arginine metabolism in rats. AB - Phencyclidine (PCP) induces behavioural changes in humans and laboratory animals that resemble positive and negative symptoms, and cognitive impairments in schizophrenia. It has been shown repeated treatment of PCP leading to persistent symptoms even after the drug discontinuation, and there is a growing body of evidence implicating altered arginine metabolism in the pathogenesis of schizophrenia. The present study investigated the effects of withdrawal from repeated daily injection of PCP (2mg/kg) for 12 consecutive days on animals'behavioural performance and arginine metabolism in the hippocampus and prefrontal cortex in male young adult rats. Repeated PCP treatment reduced spontaneous alternations in the Y-maze and exploratory and locomotor activities in the open field under the condition of a washout period of 24h, but not 4days. Interestingly, the PCP treated rats also displayed spatial working memory deficits when tested 8-10days after withdrawal from PCP and showed altered levels of arginase activities and eight out of ten l-arginine metabolites in neurochemical- and region-specific manner. Cluster analyses showed altered relationships among l-arginine and its three main metabolites as a function of withdrawal from repeated PCP treatment in a duration-specific manner. Multiple regression analysis revealed significant neurochemical-behavioural correlations. Collectively, the results suggest both the residual and long-term effects of withdrawal from repeated PCP treatment on behavioural function and brain arginine metabolism. These findings demonstrate, for the first time, the influence of the withdrawal duration on animals' behaviour and brain arginine metabolism. PMID- 27986518 TI - Using the Human Gastrointestinal Microbiome to Personalize Nutrition Advice: Are Registered Dietitian Nutritionists Ready for the Opportunities and Challenges? PMID- 27986519 TI - HCV and diabetes: towards a 'Sustained' glycaemic improvement after treatment with DAAs? - Authors' reply. PMID- 27986520 TI - Delayed management of Staphyloccocus aureus infective endocarditis in a Middle East respiratory syndrome coronavirus possible case hospitalized in 2015 in Paris, France. PMID- 27986521 TI - Lower Vitamin D Levels Are Associated With Depression in People With Chronic Spinal Cord Injury. AB - OBJECTIVES: To determine (1) whether the serum concentration of 25-hydroxy vitamin D (25(OH)D3) was associated with depression levels in people with chronic spinal cord injury (SCI) and (2) whether any observed association was independent of potential confounders. DESIGN: Cross-sectional study. SETTING: Rehabilitation institute. PARTICIPANTS: Patients with chronic SCI (N=100) recruited consecutively. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patients underwent clinical and biochemical evaluations, including assessment of 25(OH)D3 levels and the presence and severity of depressive symptoms, by using the interviewer-assisted self-report Beck Depression Inventory-II (BDI-II). RESULTS: Depression (BDI-II score >=14) was observed in 15 of 28 women (53.6%) and 18 of 72 men (25.0%) of the study population. They exhibited significantly lower 25(OH)D3 levels, lower functional independence degree in performing activities of daily living, poorer engagement in leisure time physical activity, and higher body mass index. Lower 25(OH)D3 levels were associated with higher BDI-II scores as well as with the occurrence of depression. These associations persisted after adjustment for all significant predictors of the BDI-II score that were selected, as possible confounders, by univariate analysis. In receiver operating characteristic analysis, a 25(OH)D3 level of <9.99ng/mL had the highest accuracy in discriminating patients with depression. CONCLUSIONS: In people with chronic SCI, an inverse association exists between serum 25(OH)D3 levels and depressive symptoms, widely independent of potential confounders, especially those, peculiar to this population, that can mediate the effects of depression on vitamin D levels. PMID- 27986524 TI - Smoking Cessation: The Urgent Need for Increased Utilization of Varenicline. PMID- 27986522 TI - Longitudinal Patterns of Cardiorespiratory Fitness Predict the Development of Hypertension Among Men and Women. AB - BACKGROUND: Most of the existing literature has linked a baseline cardiorespiratory fitness or change between baseline and one follow-up measurement of cardiorespiratory fitness to hypertension. The purpose of the study is to assess the association between longitudinal patterns of cardiorespiratory fitness changes with time and incident hypertension in adult men and women. METHODS: Participants were aged 20 to 82 years, were free of hypertension during the first 3 examinations, and received at least 4 preventive medical examinations at the Cooper Clinic in Dallas, Texas, from 1971 to 2006. They were classified into 1 of 5 groups based on all of the measured cardiorespiratory fitness values (in metabolic equivalents) during maximal treadmill tests. Logistic regression was used to compute odds ratios and 95% confidence intervals. RESULTS: Among 4932 participants (13% women), 1954 developed hypertension. After controlling for baseline potential confounders, follow-up duration, and number of follow-up visits, odds ratios (95% confidence intervals) for hypertension were 1.00 for the decreasing group (referent), 0.64 (0.52-0.80) for the increasing group, 0.89 (0.70-1.12) for the bell-shape group, 0.78 (0.62-0.98) for the U-shape group, and 0.83 (0.69-1.00) for the inconsistent group. The general pattern of the association was consistent regardless of participants' baseline cardiorespiratory fitness or body mass index levels. CONCLUSIONS: An increasing pattern of cardiorespiratory fitness provides the lowest risk of hypertension in this middle-aged relatively healthy population. Identifying specific pattern(s) of cardiorespiratory fitness change may be important for determining associations with comorbidity, such as hypertension. PMID- 27986526 TI - Nontraumatic "isolated" posterior interosseous nerve palsy: Reinterpretation of electrodiagnostic studies and MRIs. AB - INTRODUCTION: Different hypotheses have been proposed for the pathophysiology of posterior interosseous nerve (PIN) palsy, namely compression, nerve inflammation, and fascicular constriction. We hypothesized that critical reinterpretation of electrodiagnostic (EDX) studies and MRIs of patients with a diagnosis of PIN palsy could provide insight into the pathophysiology and treatment. MATERIALS AND METHODS: We retrospectively reviewed patients with a diagnosis of nontraumatic PIN palsy and an upper extremity EDX and MRI. The original EDX studies and MRIs were reinterpreted by a neuromuscular neurologist and musculoskeletal radiologist, respectively, both blinded to our hypothesis. RESULTS: Fifteen patients met the inclusion criteria, i.e., having an "isolated" PIN palsy. Four patients (27%) had a defined mass compressing the PIN. The remaining 11 patients (73%) presented with at least one finding incompatible with the compression hypothesis: physical examination revealed that weakness in muscles was not innervated by the PIN in 4 patients (36%); EDX abnormalities not related to the PIN were found in 4 patients (36%); and reinterpretation of the MRIs showed muscle atrophy or nerve enlargement beyond the territory of the PIN in 9 patients (82%), without any evidence of compression of the PIN in the proximal forearm. CONCLUSION: The eleven patients in our series with presumed isolated and idiopathic PIN palsy had evidence of a more diffuse nerve-muscle involvement pattern, without any radiologic signs of nerve compression of the PIN itself. These data would favor an inflammatory pathophysiology when a structural lesion compressing the nerve is ruled out with imaging. PMID- 27986525 TI - Trends in Prolonged Hospitalizations in the United States from 2001 to 2012: A Longitudinal Cohort Study. AB - BACKGROUND: Health policy debate commonly focuses on frequently hospitalized patients, but less research has examined trends in long-stay patients, despite their high cost, effect on availability of hospital beds, and physical and financial implications for patients and hospitals. METHODS: Using the National Inpatient Sample, a nationally representative sample of acute care hospitalizations in the US, we examined trends in long-stay hospitalizations from 2001-2012. We defined long stays as those 21 days or longer and evaluated characteristics and outcomes of those hospitalizations, including discharge disposition and length of stay and trends in hospital characteristics. We excluded patients under 18 years of age and those with primary psychiatry, obstetric, or rehabilitation diagnoses, and weighted estimates to the US population. RESULTS: Prolonged hospitalizations represented only 2% of hospitalizations, but approximately 14% of hospital days and incurred estimated charges of over $20 billion dollars annually. Over time, patients with prolonged hospitalizations were increasingly younger, male, and of minority status, and these hospitalizations occurred more frequently in urban, academic hospitals. In hospital mortality for patients with prolonged stays progressively decreased over the 10-year period from 14.5% to 11.6% (P <.001 for trend in grouped years), even accounting for changes in demographics and comorbidity. CONCLUSIONS: The profile of patients with prolonged hospitalizations in the US has changed, although their impact remains large, as they continue to represent 1 of every 7 hospital days. Their large number of hospital days and expense increasingly falls upon urban academic medical centers, which will need to adapt to this vulnerable patient population. PMID- 27986527 TI - Effects of orbicularis oculi flap anchorage to the periosteum of the upper orbital rim on the lower eyelid position after transcutaneous blepharoplasty: Statistical analysis of clinical outcomes. AB - BACKGROUND: The aging process affects the skin, muscle, and fat of the eyes in a different manner. Their individual rejuvenation would require specific surgical treatments according to their particular demands. In the present study, we analyzed the effect of an orbicularis oculi muscle flap fixed to the superior orbital rim to prevent lower eyelid dislocation during transcutaneous blepharoplasty. METHODS: The study was conducted retrospectively comparing pre- and postoperative images of two different groups of patients: group A (20 patients) treated with an orbicularis oculi flap and group B (17 patients) treated without the flap. Pre- and postoperative distances between the center of the pupil and upper border of the lower lid at the midpupillary line were measured in each photo and then compared and statistically analyzed. RESULTS: The mean age of the 37 patients was 57 years. From the estimated linear mixed model, we observed a significant effect of the presence of the flap (p-value < 0.0001). All the patients treated with the orbicularis oculi flap (group A) showed a cranial movement of the lower eyelid, although only minimally. All the patients treated without the muscle flap (Group B) showed a caudal movement of the lower eyelid. In total, 47% of the eyes in group B showed a positive variation of >10%. CONCLUSION: The study suggests that the anchorage of the orbicularis muscle flap to the upper orbital rim reinforces the lower eyelid's anterior lamellae. It efficiently stabilizes lower eyelid position after transcutaneous blepharoplasty, thus confirming clinical results and improving surgical outcomes even in patients with minimal or no eyelid laxity. PMID- 27986528 TI - Chemical basis for the disparate neuroprotective effects of the anthocyanins, callistephin and kuromanin, against nitrosative stress. AB - Oxidative and nitrosative stress are major factors in neuronal cell death underlying neurodegenerative disease. Thus, supplementation of antioxidant defenses may be an effective therapeutic strategy for diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. In this regard, treatment with nutraceutical antioxidants has garnered increasing attention; however, the differential neuroprotective effects of structurally similar nutraceuticals, which may affect their suitability as therapeutic agents, has not been directly examined. In this study we compare the ability of two anthocyanins, callistephin (pelargonidin-3-O-glucoside) and kuromanin (cyanidin-3 O-glucoside) to protect cerebellar granule neurons from damage induced by either oxidative or nitrosative stress. These anthocyanins differ by the presence of a single hydroxyl group on the B-ring of kuromanin, forming a catechol moiety. While both compounds protected neurons from oxidative stress induced by glutamate excitotoxicity, a stark contrast was observed under conditions of nitrosative stress. Only kuromanin displayed the capacity to defend neurons from nitric oxide (NO)-induced apoptosis. This protective effect was blocked by addition of Cu, Zn superoxide dismutase, indicating that the neuroprotective mechanism is superoxide dependent. Based on these observations, we suggest a unique mechanism by which slight structural variances, specifically the absence or presence of a catechol moiety, lend kuromanin the unique ability to generate superoxide, which acts as a scavenger of NO. These findings indicate that kuromanin and compounds that share similar chemical characteristics may be more effective therapeutic agents for treating neurodegenerative diseases than callistephin and related (non-catechol) compounds. PMID- 27986529 TI - Patterns of Performance of Oncologic Surgery by North American Pediatric Urologists: A Report from the Pediatric Urologic Oncology Working Group of the Society for Pediatric Urology. AB - PURPOSE: Objective data on patterns of oncology practice among pediatric urologists are lacking. We reviewed surgical case logs submitted to the American Board of Urology by those self-reporting as pediatric urologists. We hypothesized that logs would reveal a low oncology volume (fewer than 5 cases) and identify orchiectomy as the most common oncology cases, and that less than 25% of logs would show nephrectomy for renal tumor. MATERIALS AND METHODS: Case logs submitted for American Board of Urology certification, recertification or pediatric subspecialty certification were reviewed and standardized to represent 12-month practice. Data were collected on pediatric oncologic surgeries as noted by procedure codes linked with oncologic diagnosis codes for patients up to age 30 years. RESULTS: We identified 281 case logs meeting study criteria. A total of 364 oncology cases were logged and 131 logs (46.6%) listed at least 1 oncology case, while 150 (53.4%) contained no oncology cases. The 75th, 90th and 95th percentiles of oncology volume were represented by reporting 2, 3 and 4 cases, respectively. A total of 13 logs (4.6%) accounted for more than a third of all oncology cases (35.9%). The most frequent oncology case logged was orchiectomy, which was documented in 83 logs (29.5%). On Poisson regression surgeon variables associated with higher oncology volume included male gender (IRR 2.8, 95% CI 2.1 3.9), 2010 log year (IRR 2.4, 95% CI 1.3-4.4), 2015 log year (IRR 3.7, 95% CI 2.1 6.4) and nonpediatric subspecialty certification log (IRR 1.6, 95% CI 1.2-2.3). CONCLUSIONS: Few pediatric urologists perform a high volume of oncologic surgeries based on surgical case logs submitted to the American Board of Urology. A small cohort of pediatric urologists logged the majority of such cases. PMID- 27986530 TI - Basic Laparoscopic Skills Assessment Study: Validation and Standard Setting among Canadian Urology Trainees. AB - PURPOSE: As urology training programs move to a competency based medical education model, iterative assessments with objective standards will be required. To develop a valid set of technical skills standards we initiated a national skills assessment study focusing initially on laparoscopic skills. MATERIALS AND METHODS: Between February 2014 and March 2016 the basic laparoscopic skill of Canadian urology trainees and attending urologists was assessed using 4 standardized tasks from the AUA (American Urological Association) BLUS (Basic Laparoscopic Urological Surgery) curriculum, including peg transfer, pattern cutting, suturing and knot tying, and vascular clip applying. All performances were video recorded and assessed using 3 methods, including time and error based scoring, expert global rating scores and C-SATS (Crowd-Sourced Assessments of Technical Skill Global Rating Scale), a novel, crowd sourced assessment platform. Different methods of standard setting were used to develop pass-fail cut points. RESULTS: Six attending urologists and 99 trainees completed testing. Reported laparoscopic experience and training level correlated with performance (p <0.01). Attending urologists were significantly better than trainees (p <0.05), demonstrating construct validity evidence for the 4 AUA BLUS tasks. The C-SATS method of assessment correlated well with the traditional methods of time and error based scoring, and the global rating scale. We were able to use relative and absolute standard setting methods to define pass-fail cut points for all 4 AUA BLUS tasks. CONCLUSIONS: The 4 AUA BLUS tasks demonstrated good construct validity evidence for use in assessing basic laparoscopic skill. Performance scores using the novel C-SATS platform correlated well with traditional time consuming methods of assessment. Various standard setting methods were used to develop pass-fail cut points for educators to use when making formative and summative assessments of basic laparoscopic skill. PMID- 27986523 TI - Outcome of Patients with Venous Thromboembolism and Factor V Leiden or Prothrombin 20210 Carrier Mutations During the Course of Anticoagulation. AB - BACKGROUND: Individuals with factor V Leiden or prothrombin G20210A mutations are at a higher risk to develop venous thromboembolism. However, the influence of these polymorphisms on patient outcome during anticoagulant therapy has not been consistently explored. METHODS: We used the Registro Informatizado de Enfermedad TromboEmbolica database to compare rates of venous thromboembolism recurrence and bleeding events occurring during the anticoagulation course in factor V Leiden carriers, prothrombin mutation carriers, and noncarriers. RESULTS: Between March 2001 and December 2015, 10,139 patients underwent thrombophilia testing. Of these, 1384 were factor V Leiden carriers, 1115 were prothrombin mutation carriers, and 7640 were noncarriers. During the anticoagulation course, 160 patients developed recurrent deep vein thrombosis and 94 patients developed pulmonary embolism (16 died); 154 patients had major bleeding (10 died), and 291 patients had nonmajor bleeding. On multivariable analysis, factor V Leiden carriers had a similar rate of venous thromboembolism recurrence (adjusted hazard ratio [HR], 1.16; 95% confidence interval [CI], 0.82-1.64), half the rate of major bleeding (adjusted HR, 0.50; 95% CI, 0.25-0.99) and a nonsignificantly lower rate of nonmajor bleeding (adjusted HR, 0.66; 95% CI, 0.43-1.01) than noncarriers. Prothrombin mutation carriers and noncarriers had a comparable rate of venous thromboembolism recurrence (adjusted HR, 1.00; 95% CI, 0.68-1.48), major bleeding (adjusted HR, 0.75; 95% CI, 0.42-1.34), and nonmajor bleeding events (adjusted HR, 1.10; 95% CI, 0.77-1.57). CONCLUSIONS: During the anticoagulation course, factor V Leiden carriers had a similar risk for venous thromboembolism recurrence and half the risk for major bleeding compared with noncarriers. This finding may contribute to decision-making regarding anticoagulation duration in selected factor V Leiden carriers with venous thromboembolism. PMID- 27986531 TI - Patient Function and the Value of Surgical Care for Kidney Cancer. AB - PURPOSE: Frailty and functional status have emerged as significant predictors of morbidity and mortality for patients undergoing cancer surgery. To articulate the impact on value (ie quality per cost), we compared perioperative outcomes and expenditures according to patient function for older adults undergoing kidney cancer surgery. MATERIALS AND METHODS: Using linked SEER (Surveillance, Epidemiology and End Results)-Medicare data, we identified 19,129 elderly patients with kidney cancer treated with nonablative surgery from 2000 to 2009. We quantified patient function using function related indicators (claims indicative of dysfunction and disability) and measured 30-day morbidity, mortality, resource use and cost. Using multivariable, mixed effects models to adjust for patient and hospital characteristics, we estimated the relationship of patient functionality with both treatment outcomes and expenditures. RESULTS: Of 19,129 patients we identified 5,509 (28.8%) and 3,127 (16.4%) with a function related indicator count of 1 and 2 or greater, respectively. While surgical complications did not vary (OR 0.95, 95% CI 0.86-1.05), patients with 2 or more indicators more often experienced a medical event (OR 1.22, 95% CI 1.10-1.36) or a geriatric event (OR 1.55, 95% CI 1.33-1.81), or died within 30 days of surgery (OR 1.43, 95% CI 1.10-1.86) compared with patients with no baseline dysfunction. These patients utilized significantly more medical resources and amassed higher acute care expenditures (p <0.001). CONCLUSIONS: During kidney cancer surgery, patients in poor functional health can face a more eventful medical recovery at elevated cost, indicating lower value care. Greater consideration of frailty and functional status during treatment planning and transitions may represent areas for value enhancement in kidney cancer and urology care. PMID- 27986532 TI - Performance Characteristics of a Multigene Urine Biomarker Test for Monitoring for Recurrent Urothelial Carcinoma in a Multicenter Study. AB - PURPOSE: Urothelial carcinoma is associated with a high rate of recurrence. Guidelines recommend rigorous, regular surveillance programs that are invasive and expensive. This study describes a noninvasive urine test with sufficient sensitivity to rule out recurrent urothelial carcinoma, thereby reducing invasive diagnostic evaluations without compromising patient care. METHODS AND MATERIALS: A total of 1,036 urine samples were prospectively collected from 763 patients undergoing routine surveillance for recurrent urothelial carcinoma of the bladder. The purpose was to develop and validate a test with combined high sensitivity and high negative predictive value. Cxbladder Monitor combines gene expression, clinical and patient data, and it is designed to rule out the presence of recurrent urothelial carcinoma. RESULTS: Cxbladder Monitor showed an internally validated sensitivity of 0.93 with a negative predictive value of 0.97 and a test negative rate of 0.34. Sensitivity was 0.95 for recurrent disease with a high risk of progression (all high grade disease and low grade, stage T1 or greater disease) compared with 0.86 for low grade Ta disease. Subgroup analyses indicated that diagnostic performance was not significantly different in different age groups, or by gender or tumor stage. Sensitivity was not affected by adjuvant bacillus Calmette-Guerin treatment within the last 6 months. False negative findings were reported in fewer than 1.5% of all samples collected. CONCLUSIONS: The Cxbladder Monitor test offers combined high sensitivity and high negative predictive value to rule out urothelial carcinoma. This test has clinical utility as a confirmatory negative adjunct to cystoscopy, potentially justifying the postponement/avoidance of cystoscopic investigations to monitor recurrence in patients. PMID- 27986533 TI - Structure of bovine lactoperoxidase with a partially linked heme moiety at 1.98A resolution. AB - Lactoperoxidase (LPO) is a member of mammalian heme peroxidase superfamily whose other members are myeloperoxidase (MPO), eosinophil peroxidase (EPO) and thyroid peroxidase (TPO). In these enzymes, the heme moiety is linked to protein through two or three covalent bonds. In the mature LPO, the heme moiety is linked to protein through two ester bonds with highly conserved glutamate and aspartate residues. The previously reported structures of LPO have confirmed the formation of two covalent linkages involving Glu258 and Asp108 with 1-methyl and 5-methyl groups of pyrrole rings A and C respectively. We report here a new form of structure of LPO where the covalent bond between Glu258 and 1-methyl group of pyrrole ring A is present only in a fraction of protein molecules. In this case, the side chain of Glu258 occupies two distinct positions, each of which has a 0.5 occupancy. In one position, it forms a normal ester covalent linkage while in the second position, the side chain of Glu258 is located in the middle of the substrate binding site on the distal heme side. In this position, the atom of the side chain of Glu258 forms several contacts with atoms of other residues and heme moiety. Out of the two observed positions of the side chain of Glu258, the former contributes to the stabilization of heme position and improved catalytic action of LPO while the latter is responsible for the reduced stability of the heme position as well as it blocks the substrate binding site. PMID- 27986535 TI - Reduction of quinones and nitroaromatic compounds by Escherichia coli nitroreductase A (NfsA): Characterization of kinetics and substrate specificity. AB - NfsA, a major FMN-associated nitroreductase of E. coli, reduces nitroaromatic compounds via consecutive two-electron transfers. NfsA has potential applications in the biodegradation of nitroaromatic environment pollutants, e.g. explosives, and is also of interest for the anticancer strategy gene-directed enzyme prodrug therapy. However, the catalytic mechanism of NfsA is poorly characterized. Here we examined the NADPH-dependent reduction of quinones (n = 16) and nitroaromatic compounds (n = 12) by NfsA. We confirmed a general "ping-pong" reaction scheme, and preliminary rapid reaction studies of the enzyme reduction by NADPH showed that this step is much faster than the steady-state turnover number, i.e., the enzyme turnover is limited by the oxidative half-reaction. The reactivity of nitroaromatic compounds (log kcat/Km) followed a linear dependence on their single-electron reduction potential (E17), indicating a limited role for compound structure or active site flexibility in their reactivity. The reactivity of quinones was lower than that of nitroaromatics having similar E17 values, except for the significantly enhanced reactivity of 2-OH-1,4-naphthoquinones, consistent with observations previously made for the group B nitroreductase of Enterobacter cloacae. We present evidence that the reduction of quinones by NfsA is most consistent with a single-step (H-) hydride transfer mechanism. PMID- 27986536 TI - Unusual Cystic Mass of Retrovesical Space: A Retrovesical Kidney. AB - Retrovesical cysts are very rare, with more reported cases being hydatid or seminal cyst. To our knowledge, no case of pelvic kidney revealed as cystic mass of the retrovesical space has been reported. We provide images of a direct retrovesical kidney in a 24-year-old patient who presented with lower urinary tract symptoms. PMID- 27986534 TI - Mechanical Communication at the Immunological Synapse. AB - T and B lymphocytes communicate by forming immunological synapses with antigen presenting target cells. These highly dynamic contacts are characterized by continuous cytoskeletal remodeling events, which not only structure the interface but also exert a considerable amount of mechanical force. In recent years, it has become increasingly clear that synaptic forces influence information transfer both into and out of the lymphocyte. Here, we review our current understanding of synapse mechanics, focusing on its role as an avenue for intercellular communication. PMID- 27986537 TI - Meaningful respirometric measurements of UCP1-mediated thermogenesis. AB - Regarding the enormous interest in brown and brite/beige adipose tissue in the context of metabolic disease, reliable quantification of thermogenesis in these adipocytes is a central issue. This requires an assay specific for uncoupling protein 1 (UCP1) mediated thermogenesis in adherent intact cells. In a recent study we identified a major pitfall associated with established procedures generally applied for this purpose. Meaningful respirometry of UCP1-mediated thermogenesis imperatively requires activation of UCP1 and control over free fatty acid levels. By comparison of respiration profiles of wild-type (WT) and UCP1 knock-out (KO) cells we reproducibly quantified the thermogenic capacity enabled by UCP1 in both brown and brite adipocytes. Employing this protocol, we demonstrated that (1) brite adipocytes display a similar thermogenic capacity as classical brown adipocytes, (2) variations in brite adipogenesis known for inbred mouse strains are associated with differential capacities for thermogenesis in these cells, and (3) adipose triglyceride lipase (ATGL) activity is required for UCP1 activation in intact cells. We here further refined our cell-based respirometry assay by implementation of two strategies to inhibit UCP1 in WT cells. First, we employed the purine nucleotide guanosine diphosphate (GDP) to directly quantify the fraction of thermogenesis enabled by UCP1 activity. Second, applying siRNA mediated knockdown of UCP1 and ATGL we demonstrated the feasibility of this technology to study the functional relevance of candidate genes for thermogenesis in brown and brite adipocytes. PMID- 27986538 TI - Women's social eating environment and its associations with dietary behavior and weight management. AB - As an unhealthy social eating environment is considered a risk factor for obesity, this study aimed to examine women's regular eating networks and the extent to which diet-related variables were associated with those of their regular eating companions. In Study Part I (N = 579), an egocentric network approach was used to investigate women's perceptions of their eating networks. In Study Part II (N = 262), the participants' most important eating companions responded to a similar survey, and the corresponding answers were matched. The results showed that women shared their meals most frequently with spouses and other family members. Women who dined more often with healthy eaters reported on average a higher diet quality and a lower body mass index (BMI), which were also significant after controlling for individual factors. Study Part II expanded these results by showing that different diet-related factors such as diet quality, eating styles and BMI were correlated between women and their most important eating companions (r = 0.16-0.30, p < 0.05). Moreover, an actor-partner interdependence model revealed that a higher diet quality of the eating companions was associated with a lower BMI in women, controlled for their own eating behavior (b = -0.45, p < 0.05). This study showed similarities and interdependence between women's dietary behavior and body weight and those of their regular eating companions. This might indicate that regular eating networks have a shared understanding of what constitutes a normal diet, which might be an important factor to consider in the promotion of healthy eating. PMID- 27986539 TI - Antihistamines as promising drugs in cancer therapy. AB - Histamine is a biogenic amine, synthetized and released by mast cells, which acts as a vasodilator in several pathologic processes, namely in allergies and conjunctivitis. Its role on cancer is not fully understood. High levels of histamine have been associated with a bivalent behavior in regulation of several tumors (i.e. cervical, ovarian, vaginal, uterine, vulvar, colorectal cancer, and melanoma), promoting or inhibiting their growth. Histamine receptors (H1, H2, H3 and H4) are present in a vast group of cells, including tumor cells, making them sensitive to histamine variations. In this work, we review the role of mast cells and histamine on cancer development and the possibility of use antihistamines in the clinical management of this disease. PMID- 27986545 TI - First description of a new cryptic species, Simulium vanluni from Peninsular Malaysia: An integrated morpho-taxonomical and genetic approach for naming cryptic species in the family Simuliidae. AB - In recent decades, the numbers of cryptic taxa have increased significantly with current progress in DNA barcoding, yet, most of these cryptic taxa have not been formally named and recognized as valid species. To address this issue, we provide a guide for applying the procedure of describing new cryptic species in the family Simuliidae. Simulium (Simulium) vanluni from Pahang, Peninsular Malaysia, previously treated as S. nobile De Meijere, is described as a new species by using an integrated morpho-taxonomical and genetic approach. This new species is morphologically identical to S. nobile from Java and S. kiuliense Smart & Clifford from Borneo, but their distinctiveness is supported by an expanded multigene phylogeny analysis. PMID- 27986543 TI - Magnitude of viremia, antigenemia and infection of circulating monocytes in children with mild and severe dengue. AB - Dengue is a major public health problem in tropical regions around the world. Viral and immune host factors determine the clinical courses of the infection. We analyzed the dynamics of viremia (by real-time polymerase chain reactions), antigenemia (through detection of the viral non-structural protein [NS]-1 by enzyme-linked immunosorbent assays) and the frequency of virus-infected peripheral blood mononuclear cells (PBMCs) (by multiparametric flow cytometry) in children with primary or secondary dengue virus (DENV) infection in mild to severe cases. Additionally, we evaluated the association of these factors with clinical severity and laboratory parameters. The levels of viremia and antigenemia peaked during the early days of illness and these viral parameters were correlated (rho=0.37, P=0.003). Circulating monocytes were the most naturally infected subset within the PBMCs population, with kinetics similar to those of viremia and antigenemia. The levels of viremia and antigenemia were higher in children with primary infections than in those with secondary infections (P<=0.04). Although there were no associations between the three evaluated factors and clinical severity, the levels of plasma NS1 and the frequency of dengue virus-infected monocytes correlated with prolonged coagulation times. In short, the viremia, antigenemia and infected monocytes were detected early and were not related to clinical severity. The magnitude of antigenemia and infected circulating monocytes was associated with coagulation disorders. PMID- 27986544 TI - "Candidatus Rickettsia asemboensis" in Rhipicephalus sanguineus ticks, Brazil. AB - "Candidatus Rickettsia asemboensis" is an obligate intracellular bacterium of the Rickettsiales order, genetically related to species belonging to the Rickettsia felis group, agents of flea-borne spotted fever. Here we report for the first time the detection of "Ca. R. asemboensis", a flea-associated organism, in Rhipicephalus sanguineus ticks. It is the first occurrence of this emerging bacterium in Brazil, which increases the geographical distribution of this R. felis-like agent. PMID- 27986541 TI - The influence of androgens on hibernation phenology of free-living male arctic ground squirrels. AB - Free-living ground squirrel species are sexually dimorphic in hibernation phenology. The underlying causes of these differences are not yet known. Androgens, testosterone (T) in particular, inhibit hibernation. To determine the influence of endogenous androgens on annual timing of hibernation we first measured circulating levels of T and dehydroepiandrosterone (DHEA), an adrenal androgen implicated in non-mating season aggression in other species, in free living male arctic ground squirrels (Urocitellus parryii, AGS). We also manipulated endogenous androgen levels by surgical castration, and consequently compared body temperature records from intact (n=24) and castrated (n=9) males to elucidate the influence of endogenous androgens on annual body temperature cycles. The highest T levels (0.53+/-0.10ng/mL) were in reproductively mature male AGS in spring; whereas, both immature males in spring and all males in late summer had T levels an order of magnitude lower (0.07+/-0.01 and 0.06+/ 0.00ng/mL, respectively). DHEA levels were higher in males during the late summer compared to reproductively mature males in spring (120.6+/-18.9 and 35.9+/ 2.3pg/mL, respectively). Eliminating gonadal androgens via castration resulted in males delaying euthermy by extending heterothermy significantly in spring (Apr 22 +/-2.9) than reproductive males (Mar 28 +/-3.9) but did not change the timing of hibernation onset (castrate: Oct 12 +/-1.0 vs. intact: Oct 3 +/-3.1). We conclude that while androgens play a significant role in spring hibernation phenology of males, their role in fall hibernation onset is unclear. PMID- 27986540 TI - The physical environment of positive places: Exploring differences between age groups. AB - Features of the physical environment have an impact on the human behaviour. Thus, planners and policymakers around the world should aim at providing environments that are perceived as being of good quality, in which the residents enjoy spending time and moving around in. It is widely acknowledged that urban environmental quality associates with well-being, but there is currently very little research examining which features of urban environments people of different ages perceive as appealing in their living environments. Individuals experience different age-related developmental environments throughout their life course. Thus, the usage and perceptions of different spaces can also differ between various age groups. Public Participation GIS datasets collected in 2009 and 2011 in Helsinki Metropolitan Area were used to study places perceived as being positive by adults (n=3119) and children (n=672). Participants marked points on a map that were overlaid with GIS data to study whether the physical environment of positive places of different age groups differed. The results demonstrated that the physical environment differs significantly in the positive places of different age groups. The places of adult age groups were characterized by green, blue and commercial spaces, whereas sports, residential and commercial spaces characterize children's and adolescents' places. Older adults' places were found to be closest to home, while adolescents' places were the most distant. Providing appealing environments for all age groups in one setting remains problematic but should nevertheless be strived for, especially in the urban context where a constant competition over different usages of space occurs. PMID- 27986546 TI - Molecular epidemiological survey of bacterial and parasitic pathogens in hard ticks from eastern China. AB - Ticks are able to transmit various pathogens-viruses, bacteria, and parasites-to their host during feeding. Several molecular epidemiological surveys have been performed to evaluate the risk of tick-borne pathogens in China, but little is known about pathogens circulating in ticks from eastern China. Therefore, this study aimed to investigate the presence of bacteria and parasites in ticks collected from Xuzhou, a 11258km2 region in eastern China. In the present study, ticks were collected from domestic goats and grasses in urban districts of Xuzhou region from June 2015 to July 2016. After tick species identification, the presence of tick-borne bacterial and parasitic pathogens, including Anaplasma phagocytophilum, Borrelia burgdorferi, Rickettsia sp., Bartonella sp., Babesia sp., and Theileria sp., was established via conventional or nested polymerase chain reaction assays (PCR) and sequence analysis. Finally, a total of 500 questing adult ticks, identified as Haemaphysalis longicornis, were investigated. Among them, 28/500 tick samples (5.6%) were infected with A. phagocytophilum, and 23/500 (4.6%) with Theileria luwenshuni, whereas co-infection with these pathogens was detected in only 1/51 (2%) of all infected ticks. In conclusion, H. longicornis is the dominant tick species in the Xuzhou region and plays an important role in zoonotic pathogen transmission. Both local residents and animals are at a significant risk of exposure to anaplasmosis and theileriosis, due to the high rates of A. phagocytophilum and T. luwenshuni tick infection. PMID- 27986548 TI - A method comparison of total and HMW adiponectin: HMW/total adiponectin ratio varies versus total adiponectin, independent of clinical condition. AB - BACKGROUND: Total and high-molecular-weight (HMW) adiponectin have been associated with endocrine and cardiovascular pathology. As no gold standard is available, the discussion about biological relevance of isoforms is complicated. In our study we perform a method comparison between two commercially available assays measuring HMW and total adiponectin, in various patient groups, thus contributing further to this discussion. METHODS: We determined levels of HMW and total adiponectin using assays by Lumipulse(r) and Millipore(r) respectively, in 126 patients with different clinical characteristics (n=29 healthy volunteers, n=22 dialysis patients, n=25 elderly with body mass index (BMI) <21kg/m2, n=25 elderly with BMI 30-35kg/m2, n=26 children). RESULTS: The Passing & Bablock regression analysis resulted in HMW adiponectinLUMIPULSE*0.5-0.9=total adiponectinMILLIPORE, albeit with significant deviation from linearity (p<0.001). Pearson's correlation was R=0.987 (p=0.000). No significant differences between patient groups were observed (p=0.190). CONCLUSIONS: The HMW/total adiponectin ratio varies with total adiponectin concentration independent of clinical conditions studied. Our results imply that total and HMW adiponectin have similar utility when assessing adiponectin levels in blood, as the ratio is independent of clinical condition. PMID- 27986542 TI - The impact of spin coupling signal loss on fat content characterization in multi echo acquisitions with different echo spacing. AB - PURPOSE: This study aimed to assess the effect of echo spacing in transverse magnetization (T2) signal decay of gel and fat (oil) samples. Additionally, we assess the feasibility of using spin coupling as a determinant of fat content. METHODS: Phantoms of known T2 values, as well as vegetable oil phantoms, were scanned at 1.5T scanner with a multi echo FSE sequence of variable echo spacing above and below the empirical threshold of 20ms for echo train signal modulation (6.7, 13.6, 26.8, and 40ms). T2 values were calculated from monoexponential fitting of the data. Relative signal loss between the four acquisitions of different echo spacing was calculated. RESULTS: Agreement in the T2 values of water gel phantom was observed in all acquisitions as opposed to fat phantom (oil) samples. Relative differences in signal intensity between two successive sequences of different echo spacing on composite fat/water regions of interest was found to be linearly correlated to fat fraction of the ROI. CONCLUSION: The sample specific degree of signal loss that was observed between different fat samples (vegetable oils) can be attributed to the composition of each sample in J coupled fat components. Hence, spin coupling may be used as a determinant of fat content. PMID- 27986549 TI - Evaluation of the biochemical, inflammatory and oxidative profile of obese patients given clinical treatment and bariatric surgery. AB - BACKGROUND: We investigated the biochemical and inflammatory parameters as well as biomarkers of oxidative stress in morbidly obese patients before and after bariatric surgery and clinical treatment. METHODS: This study was conducted using 60 individuals (10 men and 50 women) distributed into 3 groups: the control group, 20 non-diabetic obese patients given clinical treatment, the bariatric group, 20 non-diabetic obese patients given a Roux-en-Y bypass gastroplasty, and the bariatric diabetic group, 20 diabetic obese patients given a Roux-en-Y bypass gastroplasty. Measurements were made before and 1, 3, 6, and 12months after surgery and clinical treatment. RESULTS: We showed a significant decrease in body weight, body mass index (BMI) and waist circumference, accompanied by a decrease in the lipid profile and glucose and glycated hemoglobin concentrations in the groups that received bariatric surgery. The concentrations of lipid peroxidation, carbonyl protein and NPSH, as well as superoxide dismutase (SOD) and catalase (CAT) activity, significantly decreased in both groups after surgery. The concentrations of inteleukin-6, inteleukin-1, TNF-alpha and resistin were also significantly lower, while adiponectin concentrations significantly increased 12months after bariatric surgery. No significant alterations were observed in the biochemical, inflammatory or oxidative parameters of the control group. CONCLUSIONS: Our findings demonstrate a decrease in body mass and a subsequent improvement in biochemical, metabolic and anthropometric parameters in patients given bariatric surgery. This may contribute to the reduction of oxidative damage in these patients and consequently a reduction in the risk of the development and progression of multiple co-morbidities associated with obesity. PMID- 27986547 TI - The Evolutionary Origin of Diversity in Chagas Disease Vectors. AB - Chagas disease is amongst the ten most important neglected tropical diseases but knowledge on the diversification of its vectors, Triatominae (Hemiptera: Reduviidae), is very scarce. Most Triatominae species occur in the Americas, and are all considered potential vectors. Despite its amazing ecological vignette, there are remarkably few evolutionary studies of the whole subfamily, and only one genome sequence has been published. The young age of the subfamily, coupled with the high number of independent lineages, are intriguing, yet the lack of genome-wide data makes it a challenge to infer the phylogenetic relationships within Triatominae. Here we synthesize what is known, and suggest the next steps towards a better understanding of how this important group of disease vectors came to be. PMID- 27986550 TI - Triglyceride content in remnant lipoproteins is significantly increased after food intake and is associated with plasma lipoprotein lipase. AB - BACKGROUND: Previous large population studies reported that non-fasting plasma triglyceride (TG) reflect a higher risk for cardiovascular disease than TG in the fasting plasma. This is suggestive of the presence of higher concentration of remnant lipoproteins (RLP) in postprandial plasma. METHODS: TG and RLP-TG together with other lipids, lipoproteins and lipoprotein lipase (LPL) in both fasting and postprandial plasma were determined in generally healthy volunteers and in patients with coronary artery disease (CAD) after consuming a fat load or a more typical moderate meal. RESULTS: RLP-TG/TG ratio (concentration) and RLP TG/RLP-C ratio (particle size) were significantly increased in the postprandial plasma of both healthy controls and CAD patients compared with those in fasting plasma. LPL/RLP-TG ratio demonstrated the interaction correlation between RLP concentration and LPL activity The increased RLP-TG after fat consumption contributed to approximately 90% of the increased plasma TG, while approximately 60% after a typical meal. Plasma LPL in postprandial plasma was not significantly altered after either type of meal. CONCLUSIONS: Concentrations of RLP-TG found in the TG along with its particle size are significantly increased in postprandial plasma compared with fasting plasma. Therefore, non-fasting TG determination better reflects the presence of higher RLP concentrations in plasma. PMID- 27986551 TI - alphavbeta3 Integrin-targeted reduction-sensitive micellar mertansine prodrug: Superb drug loading, enhanced stability, and effective inhibition of melanoma growth in vivo. AB - Antibody-maytansinoid conjugates (AMCs) have emerged as one of the most promising active targeting cancer therapeutics. Their clinical use is, however, challenged by their low drug content, poor stability, high cost and potential immune response. Here, we designed and developed robust, cRGD-functionalized, reduction sensitive polymeric micellar mertansine (DM1) prodrug (cRGD-MMP) that showed targeted treatment of B16F10 melanoma-bearing C57BL/6 mice. cRGD-MMP was obtained with a superb drug content of ~40wt.% and a small size of ~45nm from poly(ethylene glycol)-b-(poly(trimethylene carbonate)-graft-SSDM1) (PEG-P(TMC-g SSDM1)) and cRGD-functionalized PEG-P(TMC-g-SSDM1) copolymers. cRGD-MMP exhibited excellent stability in 10% fetal bovine serum and cell culture medium while fast swelling and markedly accelerated drug release under a reductive environment. Confocal microscopy, flow cytometry and MTT assays indicated receptor-mediated uptake and high antitumor effect of cRGD-MMP in alphavbeta3 integrin over expressing B16F10 melanoma cells. Notably, cRGD-MMP displayed a long elimination half-life of 5.25h and 4-fold better maximum-tolerated dose than free DM1. The in vivo studies demonstrated that cRGD-MMP effectively inhibited B16F10 melanoma growth and greatly improved mice survival rate as compared to free DM1 and non targeted MMP control. cRGD-MMP with superior stability, drug loading, and alphavbeta3 targetability offers an attractive alternative to AMCs for malignant tumor therapy. PMID- 27986552 TI - Combining different types of multifunctional liposomes loaded with ammonium bicarbonate to fabricate microneedle arrays as a vaginal mucosal vaccine adjuvant dual delivery system (VADDS). AB - To develop effective mucosal vaccines, two types of multifunctional liposomes, the mannosylated lipid A-liposomes (MLLs) with a size of 200nm and the stealth lipid A-liposomes (SLLs) of 50nm, both loaded with a model antigen and NH4HCO3, were fabricated together into microneedles, forming the proSLL/MLL-constituted microneedle array (proSMMA), which upon rehydration dissolved rapidly recovering the initial MLLs and SLLs. Mice vaccinated with proSMMAs by vaginal mucosa patching other than conventional intradermal administration established robust antigen-specific humoral and cellular immunity at both systemic and mucosal levels, especially, in the reproductive and intestinal ducts. Further exploration demonstrated that the MLLs reconstituted from the administered proSMMAs were mostly taken up by vaginal mucosal dendritic cells, whereas the recovered SLLs trafficked directly to draining lymph nodes wherein to be picked up by macrophages. Moreover, the antigens delivered by either liposomes were also cross presented for MHC-I displaying by APCs thanks to lysosome escape and ROS (reactive oxygen species) stimulation, both of which occurred when lysosomal acidifying the liposome-released NH4HCO3 into CO2 and NH4+/NH3 to rupture lysosomes by gas expansion and to cause ROS production by excessive ammonia induction, resulting in a mixed Th1/Th2 type response which was also promoted by liposomal lipid A via activation of TLR4. In addition, vaginal vaccination of the engineered HSV2 antigen gD-loaded proSMMAs successfully protected mice from the virus challenge. Thus, the proSMMAs are in fact a vaccine adjuvant-dual delivery system capable of eliciting robust humoral and cellular immunity against the invading pathogens, especially, the sexually transmitted ones. PMID- 27986553 TI - Molecular characterization of porcine circovirus-like virus P1 in eastern China. AB - A large-scale epidemiological study of porcine circovirus-like virus P1 was carried out from 2007 to 2015 in China, which revealed a high level of P1 infection. Thirty-nine sequences obtained from pigs in eastern China showed remarkable genetic diversity, with the P1 predominant sequences and the mutant P1 with ORF1 or ORF2 containing an additional amino-acid extension at the C terminus. This information may be useful for understanding the evolution of P1 circovirus-like virus. PMID- 27986554 TI - Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt induced hypertension. AB - OBJECTIVE: To determine whether a clinically-utilised IL-1 receptor antagonist, anakinra, reduces renal inflammation, structural damage and blood pressure (BP) in mice with established hypertension. METHODS: Hypertension was induced in male mice by uninephrectomy, deoxycorticosterone acetate (2.4mg/d,s.c.) and replacement of drinking water with saline (1K/DOCA/salt). Control mice received uninephrectomy, a placebo pellet and normal drinking water. 10days post-surgery, mice commenced treatment with anakinra (75mg/kg/d, i.p.) or vehicle (0.9% saline, i.p.) for 11days. Systolic BP was measured by tail cuff while qPCR, immunohistochemistry and flow cytometry were used to measure inflammatory markers, collagen and immune cell infiltration in the kidneys. RESULTS: By 10days post-surgery, 1K/DOCA/salt-treated mice displayed elevated systolic BP (148.3+/ 2.4mmHg) compared to control mice (121.7+/-2.7mmHg; n=18, P<0.0001). The intervention with anakinra reduced BP in 1K/DOCA/salt-treated mice by ~20mmHg (n=16, P<0.05), but had no effect in controls. In 1K/DOCA/salt-treated mice, anakinra modestly reduced (~30%) renal expression of some (CCL5, CCL2; n=7-8; P<0.05) but not all (ICAM-1, IL-6) inflammatory markers, and had no effect on immune cell infiltration (n=7-8, P>0.05). Anakinra reduced renal collagen content (n=6, P<0.01) but paradoxically appeared to exacerbate the renal and glomerular hypertrophy (n=8-9, P<0.001) that accompanied 1K/DOCA/salt-induced hypertension. CONCLUSION: Despite its anti-hypertensive and renal anti-fibrotic actions, anakinra had minimal effects on inflammation and leukocyte infiltration in mice with 1K/DOCA/salt-induced hypertension. Future studies will assess whether the anti-hypertensive actions of anakinra are mediated by protective actions in other BP-regulating or salt-handling organs such as the arteries, skin and brain. PMID- 27986555 TI - Serological approaches for the diagnosis of schistosomiasis - A review. AB - Schistosomiasis is a common disease in endemic areas of Sub-Saharan Africa, South America and Asia. It is rare in Europe, mainly imported from endemic countries due to travelling or human migration. Available methods for the diagnosis of schistosomiasis comprise microscopic, molecular and serological approaches, with the latter detecting antigens or antibodies associated with Schistosoma spp. infection. The serological approach is a valuable screening tool in low endemicity settings and for travel medicine, though the interpretation of any diagnostic results requires knowledge of test characteristics and a patient's history. Specific antibody detection by most currently used assays is only possible in a relatively late stage of infection and does not allow for the differentiation of acute from previous infections for therapeutic control or the discrimination between persisting infection and re-infection. Throughout the last decades, new target antigens have been identified, and assays with improved performance and suitability for use in the field have been developed. For numerous assays, large-scale studies are still required to reliably characterise assay characteristics alone and in association with other available methods for the diagnosis of schistosomiasis. Apart from S. mansoni, S. haematobium and S. japonicum, for which most available tests were developed, other species of Schistosoma that occur less frequently need to be taken into account. This narrative review describes and critically discusses the results of published studies on the evaluation of serological assays that detect antibodies against different Schistosoma species of humans. It provides insights into the diagnostic performance and an overview of available assays and their suitability for large scale use or individual diagnosis, and thus sets the scene for serological diagnosis of schistosomiasis and the interpretation of results. PMID- 27986556 TI - New reference values of heart rate variability during ordinary daily activity. PMID- 27986557 TI - Reference values of heart rate variability. PMID- 27986558 TI - Lethal Fournier gangrene following cardiac surgery with cardiopulmonary bypass. PMID- 27986559 TI - [Left atrial appendage in rheumatic mitral valve disease: The main source of embolism in atrial fibrillation]. AB - OBJECTIVE: To demonstrate that surgical removal of the left atrial appendage in patients with rheumatic mitral valve disease and long standing persistent atrial fibrillation decreases the possibility of stroke. This also removes the need for long-term oral anticoagulation after surgery. METHOD: A descriptive, prospective, observational study was conducted on 27 adult patients with rheumatic mitral valve disease and long standing persistent atrial fibrillation, who had undergone mitral valve surgery and surgical removal of the left atrial appendage. Oral anticoagulation was stopped in the third month after surgery. The end-point was the absence of embolic stroke. An assessment was also made of postoperative embolism formation in the left atrium using transthoracic echocardiography. RESULTS: None of the patients showed embolic stroke after the third post operative month. Only one patient exhibited transient ischaemic attack on warfarin therapy within the three postoperative months. Left atrial thrombi were also found in 11 (40.7%) cases during surgery. Of these, 6 (54.5%) had had embolic stroke, with no statistical significance (P=.703). CONCLUSIONS: This study suggests there might be signs that the left atrial appendage may be the main source of emboli in rheumatic mitral valve disease, and its resection could eliminate the risk of stroke in patients with rheumatic mitral valve disease and long-standing persistent atrial fibrillation. PMID- 27986560 TI - [Design of an atrial fibrillation and embolic risk registry in Mexico: CARMEN AF]. AB - OBJECTIVE: Atrial fibrillation (AF) is one of the most common arrhythmias, and its prevalence increase with age. It is associated with high risk of stroke. The prevention of such thromboembolism is done with oral anticoagulants, which in our country seem to be underused. CARMEN-AF registry aims primarily to determine the current status of thromboprophylaxis of non-valvular AF in Mexico. A secondary objective is to know the morbidity and mortality associated with non-valvular AF in at least one year of follow-up. METHODS: CARMEN-AF registry is an observational, longitudinal, multicenter, and national survey about the use of oral anticoagulants in patients with non-valvular AF. Patients 18years old or older, diagnosed with AF during the last 6months, and with at least one risk factor of thromboembolism based in the CHA2DS2-Vasc score are being selected. Demographic and clinical data will be collected during the visits to their usual clinic with a follow-up of 2years. The recruitment began on September 19, 2014, and the inclusion of the last patient is expected on September 18, 2016. According to the reported incidence of AF globally and taking into account the total Mexican population, the inclusion of 1,200 patients is estimated. CONCLUSIONS: The Atrial Fibrillation and Embolic Risk Registry (CARMEN-AF) will reveal the current status of thromboprophylaxis in patients with non-valvular AF, and will allow to get an overview of the national and international clinical practice guidelines accomplishment in this area. PMID- 27986561 TI - [Portopulmonary hypertension: Updated review]. AB - Portopulmonary hypertension (PPH) is a rare condition worldwide, although epidemiological data are unknown in Mexico. However, chronic liver diseases are very prevalent in Mexico. PPH is the 4th subtype in frequency in the group of pulmonary arterial hypertension. Its diagnosis is made within 2 scenarios: patients with suspected pulmonary hypertension and candidates for orthotopic liver transplantation (OLT). Both echocardiogram and a right cardiac catheterisation are crucial for diagnosis in both cases. PPH is a challenge for OLT, since it can significantly increase perioperative mortality. The use of specific therapy is the cornerstone of this disease, as a measure to improve the outcome of those who become candidates for OLT with moderate to severe PPH. It is important to recognise that PPH can be a contraindication to OLT. The role of lung-liver transplantation or heart-lung-liver transplantation as a measure to heal pulmonary vascular disease in patients with PPH is still uncertain. PMID- 27986562 TI - Free fatty acids or high-concentration glucose enhances hepatitis A virus replication in association with a reduction in glucose-regulated protein 78 expression. AB - Although the interaction between host and hepatitis A virus (HAV) factors could lead to severe hepatitis A, the exact mechanism of acute liver failure caused by HAV infection is not yet fully understood. The effects of metabolic diseases such as dyslipidemia or diabetes mellitus on HAV replication are still unknown. Here, we examined the effects of free fatty acids or high-concentration glucose on HAV replication and the effects on mitogen-activated protein kinase signaling pathway related genes in human hepatocytes. We discovered a novel effect of free fatty acids or high-concentration glucose on HAV replication in association with a reduction in the expression of glucose-regulated protein 78 (GRP78). We also observed that thapsigargin induced GRP78 expression and inhibited HAV replication. These findings may provide a new interpretation of the relationship between metabolic diseases and severity of hepatitis A and suggest a new understanding of the mechanism of severe HAV infection. PMID- 27986563 TI - Role and mechanism of PTEN in adiponectin-induced osteogenesis in human bone marrow mesenchymal stem cells. AB - Human bone marrow-derived stromal cells (hBMSC) are multi-potent stem cells that can differentiate into osteogenic and adipogenic lineages. Adiponectin (APN) is an adipocyte-derived hormone that modulates a series of metabolic processes. Recent studies revealed a relationship between APN and bone regeneration, though the underlying mechanism was not fully examined. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a tumor suppressor and a therapeutic target for the metabolic syndrome. Its deletion mutants increase osteoblast activity and bone mineral density. Both APN and PTEN are involved in osteogenic differentiation. However, whether PTEN is involved in APN-induced bone metabolism remains unclear. This project was designed to study whether PTEN was involved in APN-mediated osteogenesis of hBMSCs. We found that APN downregulated PTEN expression and that both it and an inhibitor of PTEN (SF1670) increased the expression of osteogenic markers such as osteocalcin, alkaline phosphatase, and runt-related transcription factor-2 in APN-treated hBMSCs. Our results suggested that APN enhanced osteogenic differentiation of hBMSCs in vitro partially by inhibiting PTEN expression. APN could be a therapeutic agent in tissue regeneration engineering and bone regeneration by inhibiting PTEN expression and then promoting the osteogenic differentiation of hBMSCs. PMID- 27986564 TI - Inhibition of Japanese encephalitis virus (JEV) replication by specific RNA aptamer against JEV methyltransferase. AB - Japanese encephalitis virus (JEV) is the most common etiological agent of epidemic viral encephalitis. JEV encodes a single methyltransferase (MTase) domain located at the N-terminal region of the viral nonstructural protein NS5. JEV MTase is essential for viral replication and specifically catalyzes methylation of the viral RNA cap, which occurs exclusively in the cytoplasm. Therefore, JEV MTase is a potential target for antiviral therapy. Here, we identified specific and avid RNA aptamer (Kd ~ 12 nM) with modified 2'-O-methyl pyrimidines against JEV MTase. The RNA aptamer efficiently inhibited viral cap methylation activity of MTase and interfered with JEV production in cells. Moreover, we generated a 24-mer truncated aptamer that could specifically bind to JEV MTase with high affinity (Kd ~16 nM). The 24-mer aptamer efficiently inhibited JEV production and replication in cells. Therefore, MTase-specific RNA aptamer might be useful as an anti-JEV agent. PMID- 27986565 TI - Inhibition of protein tyrosine phosphatases unmasks vasoconstriction and potentiates calcium signaling in rat aorta smooth muscle cells in response to an agonist of 5-HT2B receptors BW723C86. AB - In blood vessels, serotonin 5-HT2B receptors mainly mediate relaxation, although their activation by the selective agonist BW723C86 is known to exert contraction of aorta in deoxycorticosterone acetate (DOCA)-salt and N(omega)-nitro-l-arginine (l-NAME) hypertensive rats [Russel et al., 2002; Banes et al., 2003] and in mice with type 2 diabetes [Nelson et al., 2012]. The unmasking effect on vasoconstriction can be caused by a shift in the balance of tyrosine phosphorylation in smooth muscle cells (SMC) due to oxidative stress induced inhibition of protein tyrosine phosphatases (PTP). We have demonstrated that BW723C86 which does not cause contraction of rat aorta and mesenteric artery rings, evoked a vasoconstrictor effect in the presence of PTP inhibitors sodium orthovanadate (Na3VO4) or BVT948. BW723C86 induced a weak rise of [Ca2+]i in the SMC isolated from rat aorta; however, after pre-incubation with Na3VO4 the response to BW723C86 increased more than 5-fold. This effect was diminished by protein tyrosine kinase (PTK) inhibitor genistein, inhibitor of Src-family kinases PP2, inhibitor of NADPH-oxidase VAS2870 and completely suppressed by N acetylcysteine and 5-HT2B receptor antagonist RS127445. Using fluorescent probe DCFH-DA we have shown that Na3VO4 induces oxidative stress in SMC. In the presence of Na3VO4 BW723C86 considerably increased formation of reactive oxygen species while alone had no appreciable effect on DCFH oxidation. We suggest that oxidative stress causes inhibition of PTP and unmasking of 5-HT2B receptors functional activity. PMID- 27986566 TI - A flavanone derivative from the Asian medicinal herb (Perilla frutescens) potently suppresses IgE-mediated immediate hypersensitivity reactions. AB - Perilla frutescens is a dietary leafy herb consumed as a traditional Japanese condiment as well as used for Chinese medicine with anti-inflammatory activity. Here we report a hitherto-unrecognized P. frutescens phytochemical that potently suppresses IgE-mediated type I hypersensitivity reactions. Structural analysis reveals that the purified anti-allergic compound (Perilla-derived methoxyflavanone, PDMF) is identified as 8-hydroxy-5,7-dimethoxyflavanone. PDMF significantly inhibits IgE-mediated histamine release from RBL-2H3 rat basophilic leukemia cells as compared with those seen in known P. frutescens-derived anti inflammatory polyphenols. We also show that oral administration of PDMF not only suppresses passive cutaneous anaphylaxis, but also prevents allergic rhinitis like nasal symptoms in a murine model of Japanese cedar pollinosis. Mechanistically, PDMF negatively regulates Akt phosphorylation and intracellular Ca2+ influx, both of which are essential for mast cell secretory granule translocation and its exocytosis upon high-affinity IgE receptor (FcepsilonRI) cross-linking. These results represent PDMF as a new potent anti-allergic phytochemical useful for prevention of IgE-driven hypersensitivity reactions. PMID- 27986567 TI - Irisin suppresses the migration, proliferation, and invasion of lung cancer cells via inhibition of epithelial-to-mesenchymal transition. AB - Irisin is involved in promoting metabolism, immune regulation, and affects chronic inflammation in many systemic diseases, including gastric cancer. However, the role of irisin in lung cancer is not well characterized. To determine whether irisin has a protective effect against lung cancer, we cultured A549 and NCI-H446 lung cancer cells and treated them with irisin. We detected the proliferation by MTT assay, and assessed the migration and invasion of the cells by scratch wound healing assay and Tran-swell assay. The expression levels of epithelial-to-mesenchymal transition (EMT) markers and the related signaling pathways were detected by western blot analysis. Meanwhile, an inhibitor of PI3K was used to investigate the effect of irsin. Finally, the expression of Snail was detected. We demonstrated that irisin inhibits the proliferation, migration, and invasion of lung cancer cells, and has a novel role in mediating the PI3K/AKT pathway in the cells. Irisin can reverse the activity of EMT and inhibit the expression of Snail via mediating the PI3K/AKT pathway, which is a key regulator of Snail. These results revealed that irisin inhibited EMT and reduced the invasion of lung cancer cells via the PI3K/AKT/Snail pathway. PMID- 27986568 TI - Distinct responses of compartmentalized glutathione redox potentials to pharmacologic quinones targeting NQO1. AB - Deoxynyboquinone (DNQ), a potent novel quinone-based antineoplastic agent, selectively kills solid cancers with overexpressed cytosolic NAD(P)H:quinone oxidoreductase-1 (NQO1) via excessive ROS production. A genetically encoded redox sensitive probe was used to monitor intraorganellar glutathione redox potentials (EGSH) as a direct indicator of cellular oxidative stress following chemotherapeutic administration. Beta-lapachone (beta-lap) and DNQ-induced spatiotemporal redox responses were monitored in human lung A549 and pancreatic MIA-PaCa-2 adenocarcinoma cells incubated with or without dicumarol and ES936, potent NQO1 inhibitors. Immediate oxidation of EGSH in both the cytosol and mitochondrial matrix was observed in response to DNQ and beta-lap. The DNQ induced cytosolic oxidation was fully prevented with NQO1 inhibition, whereas mitochondrial oxidation in A549 was NQO1-independent in contrast to MIA-PaCa-2 cells. However, at pharmacologic concentrations of beta-lap both quinone-based substrates directly oxidized the redox probe, a possible sign of off-target reactivity with cellular thiols. Together, these data provide new evidence that DNQ's direct and discerning NQO1 substrate specificity underlies its pharmacologic potency, while beta-lap elicits off-target responses at its effective doses. PMID- 27986571 TI - The Journey of the Autophagosome through Mammalian Cell Organelles and Membranes. AB - Autophagy is an intracellular degradation process carried out by a double membrane organelle, termed the autophagosome, which sequesters cytoplasmic material destined for lysosomal degradation and recycling. Autophagy and autophagosome biogenesis are highly conserved processes in eukaryotes and are essential for cell survival, stress responses, and homeostasis. Autophagosomes are dynamic and complex organelles that can originate from several different membrane compartments. Autophagosomes traffic through the cell to fuse with lysosomes or other compartments. Despite identification of key proteins necessary for autophagosome assembly and transport, such as those encoded by the autophagy related genes, the relationship and interdependence of the autophagosome with other intracellular endo-membranes, including those of organelles involved in exocytosis and endocytic trafficking pathways, are still poorly understood. Here we discuss formation of autophagosomes, the journey of these organelles through the cell, and their close interplay with other mammalian organelles from points of view of signalization platforms and membrane dynamics. PMID- 27986570 TI - The C-Box Region of MAF1 Regulates Transcriptional Activity and Protein Stability. AB - MAF1 is a conserved negative regulator of RNA polymerase (pol) III and intracellular lipid homeostasis across species. Here, we show that the MAF1 C-box region negatively regulates its activity. Mutations in Caenorhabditis elegans mafr-1 that truncate the C-box retain the ability to inhibit the transcription of RNA pol III targets, reduce lipid biogenesis, and lower reproductive output. In human cells, C-box deletion of MAF1 leads to increased MAF1 nuclear localization and enhanced repression of ACC1 and FASN, but with impaired repression of RNA pol III targets. Surprisingly, C-box mutations render MAF1 insensitive to rapamycin, further defining a regulatory role for this region. Two MAF1 species, MAF1L and MAF1S, are regulated by the C-box YSY motif, which, when mutated, alters species stoichiometry and proteasome-dependent turnover of nuclear MAF1. Our results reveal a role for the C-box region as a critical determinant of MAF1 stability, activity, and response to cellular stress. PMID- 27986569 TI - Backbone Engineering within a Latent beta-Hairpin Structure to Design Inhibitors of Polyglutamine Amyloid Formation. AB - Candidates for the toxic molecular species in the expanded polyglutamine (polyQ) repeat diseases range from various types of aggregates to "misfolded" monomers. One way to vet these candidates is to develop mutants that restrict conformational landscapes. Previously, we inserted two self-complementary beta hairpin enhancing motifs into a short polyQ sequence to generate a mutant, here called "betaHP," that exhibits greatly improved amyloid nucleation without measurably enhancing beta-structure in the monomer ensemble. We extend these studies here by introducing single-backbone H-bond impairing modifications alphaN methyl Gln or l-Pro at key positions within betaHP. Modifications predicted to allow formation of a fully H-bonded beta-hairpin at the fibril edge while interfering with H-bonding to the next incoming monomer exhibit poor amyloid formation and act as potent inhibitors in trans of simple polyQ peptide aggregation. In contrast, a modification that disrupts intra-beta-hairpin H bonding within betaHP, while also aggregating poorly, is ineffective at inhibiting amyloid formation in trans. The inhibitors constitute a dynamic version of the edge-protection negative design strategy used in protein evolution to limit unwanted protein aggregation. Our data support a model in which polyQ peptides containing strong beta-hairpin encouraging motifs only rarely form beta hairpin conformations in the monomer ensemble, but nonetheless take on such conformations at key steps during amyloid formation. The results provide insights into polyQ solution structure and fibril formation while also suggesting an approach to the design of inhibitors of polyQ amyloid growth that focuses on conformational requirements for fibril and nucleus elongation. PMID- 27986572 TI - Downregulation of DNA methyltransferase 3 alpha promotes cell proliferation and invasion of ectopic endometrial stromal cells in adenomyosis. AB - Adenomyosis is a common benign gynecological condition in female reproductive tract and the detailed molecular etiology remains largely elusive. Previous studies implicated that deregulated expression of DNA (cytosine-5) methyltransferase 3A (DNMT3A), a de novo DNA methyltransferase, might be involved in the pathogenesis of adenomyosis. Meanwhile, ectopic endometrial stromal cells (EESCs) were suggested to play crucial roles in adenomyosis. Herein, we evaluated the expression of DNMT3A protein in 36 ectopic endometriums with adenomyosis and 37 eutopic endometriums in controls with Western blotting (WB) or immunohistochemistry (IHC), we found that the expression of DNMT3A was significantly decreased in the ectopic endometriums and EESCs in adenomyosis relative to that of eutopic endometriums and EESCs in control samples, respectively. In addition, our functional assays revealed that overexpression of DNMT3A suppressed cell proliferation and invasion, while knockdown of DNMT3A enhanced cell proliferation and invasion in EESCs. Taken together, our results suggested that DNMT3A expression was decreased in ectopic endometriums and EESCs in adenomyosis, and we provided the first evidence that decreased DNMT3A expression in EESCs facilitated the development of adenomyosis via enhanced cell growth and invasion. PMID- 27986573 TI - Constructing a competency-based bariatric surgery fellowship training curriculum. AB - BACKGROUND: Bariatric fellowship training after general surgery has historically been time based and competence was determined at completion based on a minimum number of cases during the fellowship. Graduate medical education is moving toward competency-based medical education where learners are evaluated during the course of their training and competence assessment occurs throughout. OBJECTIVES: The Executive Council of the American Society of Metabolic and Bariatric Surgery (ASMBS) at the direction of the American Board of Surgery wanted to transition the bariatric surgery fellowship curriculum from its traditional format to a competency-based curriculum using competency-based medical education principles. METHODS: The ASMBS Education and Training Committee established a task force of 9 members to create a new curriculum and all of the necessary evaluation tools to support the curriculum, and initiate a pilot program. RESULTS: A competency-based curriculum consisting of 6 modules with cognitive and technical milestones, and the innovative evaluation tools needed to evaluate the learners, was created. A pilot program consisting of 10 programs and 19 fellows has been undertaken for the 2016-2017 academic year. CONCLUSION: The Education Committee of the ASMBS is leading the charge in curriculum development for competency-based medical education for bariatric fellowship. PMID- 27986574 TI - Mammography before and after bariatric surgery. AB - BACKGROUND: Morbidly obese women are at increased risk for breast cancer, and the majority of surgical weight-loss patients are older than 40 years old. OBJECTIVE: The purpose of the present study was to determine the technical and interpretive changes in mammography following bariatric surgery. SETTING: Accredited Academic Hospital. METHODS: Two breast-imaging radiologists reviewed screening mammograms performed on 10 morbidly obese women undergoing bariatric surgery both pre- and postoperatively. American College of Radiology Breast Imaging Reporting and Data System (ACR BI-RADS) density, imaging quality measurements, compression force, breast thickness, pectoral nipple line (PNL) length, and x-ray beam kilovoltage (kVp) and miliamperes per second (mAs) were recorded. RESULTS: The average patient age was 56 years old, with mean age at menarche of 13 years old; 70% of patients were postmenopausal (average age 49 years at menopause) and 50% had a family history of breast cancer. There was a significant reduction in both BMI ( 13.2 kg/m2, P<.01) and waist circumference (-32.0 cm, P<.01) following bariatric surgery. There was a significant reduction in breast thickness (-23.8 mm), reduction in PNL length (-1.9 cm), reduction in kVp (-1.2), and reduction in mAs (-16.7) even though there was no compression force change in pre- and postoperative mammograms detected. All breast densities were fatty or scattered though there were more scattered and fewer fatty images after surgery (P = .002). CONCLUSION: Morbidly obese women can undergo quality mammograms before and after bariatric surgery; however, weight loss after bariatric surgery leads to only slightly denser mammograms. Furthermore, weight loss reduces mammographic radiation doses. PMID- 27986576 TI - Response to letter to the editor by Scheimann, Miller, and Glaze: Laparoscopic sleeve gastrectomy in children and adolescents with Prader-Willi Syndrome: A matched control study. PMID- 27986575 TI - Conversion of one anastomosis gastric bypass/mini gastric bypass to Roux-en-Y gastric bypass for bile reflux gastritis after failed Braun jejunojejunostomy. PMID- 27986577 TI - Fast track bariatric surgery: safety of discharge on the first postoperative day after bariatric surgery. AB - BACKGROUND: Fast track recovery pathways have resulted in a multidisciplinary approach to enhance postoperative recovery. OBJECTIVES: To assess feasibility and outcome of early discharge after laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB). SETTING: The American College of Surgeons National Surgical Quality Improvement Program database was analyzed to identify patients with body mass index>=35 kg/m2 who underwent LSG or LRYGB in 2012 and 2013. METHODS: Patients were allocated to early discharge (ED) when discharged on postoperative (POD) 1 and late discharge (LD) when discharged on POD 2 or 3. Baseline characteristics and 30-day outcomes were compared between the 2 groups. RESULTS: Records of 15,468 LSG and 16,483 LRYGB patients were analyzed; 5220 patients with LSG (33.7%) and 2960 patients with LRYGB (18%) were discharged on POD 1. The early discharge group had significantly fewer co morbidities and lower rate of complications and readmission. Thirty-day readmission rate in LSG was 2.8% in ED versus 3.6% in LD (P = .008), and in LRGYB, it was 4.3% in ED versus 5.8% in LD (P = .001). Based on multivariate analysis, early discharge was not an independent risk factor for a higher readmission rate after LSG or LRYGB. Predictors of late discharge were age>50 years, body mass index>50 kg/m2, Hispanic or non-Hispanic black race/ethnicity, impaired functional status, diabetes on insulin, chronic steroid/immunosuppressant use, bleeding disorder, being on dialysis, chronic obstructive pulmonary disease, albumin<3.5 mg/dL, longer operative time, and concurrent cholecystectomy. CONCLUSION: Discharge on POD 1 after LSG and LRYGB is feasible in a considerable proportion of patients. In this subgroup, early discharge is well tolerated and may be associated with lower complication and readmission rates. PMID- 27986578 TI - Diabetic lumbosacral radiculoplexus neuropathy after bariatric surgery. PMID- 27986579 TI - Bariatric operative reporting: Quality assessment and perceptions among bariatric surgeons. AB - BACKGROUND: The quality of narrative operative notes is poor. No investigation has previously addressed operative reporting specifically in bariatric surgery. OBJECTIVES: To evaluate surgeons' perceptions of the quality of operative reporting in bariatric surgery and compare this to an audit of Roux-en-Y gastric bypass (RYGB) narrative reports using validated quality indicators. SETTING: University hospital, Canada. METHODS: A Web-based survey was distributed to bariatric surgeons across Canada. Perceptions regarding the quality of reporting were gathered using a Likert scale (modified Structured Assessment Format for Evaluating Operative Reports) and free text fields. Forty RYGB narrative reports were analyzed against established quality indicators and compared to respondent's perceptions based on themes. RESULTS: Twenty-four of 34 bariatric surgeons (71%) completed the survey. The most commonly performed procedures were RYGB and sleeve gastrectomy (96% and 100%, respectively). Currently, 70.8% perform a traditional narrative report. The average Structured Assessment Format for Evaluating Operative Reports score for narrative dictations by bariatric surgeons was neutral (27.9/40). The lowest scoring items were the "description of indications" (2.9/5) and "succinctness" (3.3/5). Opinions reflected a need for an immediately generated, standardized, template-based report to improve the quality and accessibility of operative documentation. The quality audit reinforced respondents' perceptions. Reports included only 62.0%+/-6.6% of quality indicators, with the lowest scoring areas being "patient details," "preoperative events," and "postoperative details" (41.1%, 32.4%, and 31.7%, respectively). CONCLUSION: This survey revealed a perception of mediocre quality of narrative dictations. This was reinforced by an audit of RYGB operative reports. Future investigations should focus on improving this form of operative communication. PMID- 27986580 TI - No effect of different bariatric surgery procedures on LINE-1 DNA methylation in diabetic and nondiabetic morbidly obese patients. AB - BACKGROUND: Bariatric surgery (BS) is proposed as a highly effective therapy for reducing weight and improving obesity-related co-morbidities. The molecular mechanisms involved in the metabolic improvement after BS are not completely resolved. Epigenetic modifications could have an important role. OBJECTIVE: The aim of this study was to evaluate the effect of different BS procedures (Roux-en Y gastric bypass and laparoscopic sleeve gastrectomy) on global DNA methylation (long interspersed nucleotide element 1 [LINE-1]) in a group of nondiabetic and diabetic severely obese patients. SETTING: University hospital, Spain. METHODS: This study included 60 patients (30 nondiabetic and 30 diabetic severely obese patients) undergoing BS: 31 patients underwent Roux-en-Y gastric bypass and 29 underwent laparoscopic sleeve gastrectomy. Before and 6 months post-BS, anthropometric data, blood pressure, and metabolic parameters were determined. LINE-1 DNA methylation was quantified by pyrosequencing. We used the methylation levels of tumor necrosis factor-alpha as a control gene promoter. RESULTS: There were no differences between LINE-1 methylation levels at baseline and at 6 months after surgery (66.3+/-1.6 versus 66.2+/-2.06). Likewise, there was no statistically significant difference on LINE-1 methylation levels when we stratified according to metabolic status (diabetic versus nondiabetic), nor was there regarding the BS procedure. A strong correlation was shown between LINE-1 methylation levels and weight at baseline both in diabetic and nondiabetic obese patients (r = .486; P<.001). Tumor necrosis factor-alpha methylation levels increased significantly after BS in the group of diabetic obese patients. CONCLUSION: After BS, global LINE-1 methylation is not modified in the short term. More studies are required to determine if LINE-1 is a stable epigenetic marker, or, on the contrary, if it is susceptible to modification by external factors such as changes in lifestyle or a surgical intervention. PMID- 27986581 TI - Comment on: Bariatric operative reporting: quality assessment and perceptions amongst bariatric surgeons. PMID- 27986582 TI - Comment on: Sexual functioning of bariatric patients. PMID- 27986583 TI - A matched cohort study of laparoscopic biliopancreatic diversion with duodenal switch and sleeve gastrectomy performed by one surgeon. AB - SETTING: Spectrum Blodgett and Mercy Health St. Mary's hospitals in Grand Rapids, Michigan OBJECTIVE: To compare the 30-day outcomes of laparoscopic biliopancreatic diversion with duodenal switch (BPD/DS) to laparoscopic sleeve gastrectomy (SG). BACKGROUND: Laparoscopic BPD/DS has been shown to be superior to SG in terms of excess weight loss. Despite this superiority, BPD/DS accounts for a small percentage of all metabolic surgeries due partly to the perception that BPD/DS has a higher complication rate than SG. METHODS: Retrospective review of all patients who underwent BPD/DS or SG from January 2008 to August 2014 by 1 surgeon was completed. These patients were used to construct cohorts matched via propensity score matching and compared by surgical type. Data collected included patient demographic characteristics; hospital length of stay (LOS); and 30-day rates of leak, bleed, reoperation, readmission, and mortality. RESULTS: Of the 741 patients who underwent BPD/DS or SG, 2 cohorts of 167 patients each were matched for age, sex, and BMI. LOS was longer in the BPD/DS cohort (2.5+/-.9 days versus 2.1+/-.7 days, P<.001). There were no significant differences between the groups in relation to 30-day postoperative rates of leak (.3% versus .6%, P>.99), bleed (0% versus .3%, P>.99), reoperation (1.2% versus .6%, P>.99), or readmission (3% versus 1.2%, P = .45). There were no mortalities. CONCLUSION: After matching for age, sex, and BMI, BPD/DS found no significant differences from SG with regard to 30-day postoperative rates of leak, bleed, reoperation, readmission, or mortality. PMID- 27986584 TI - Bariatric surgery in morbidly obese patients with inflammatory bowel disease: A systematic review. AB - BACKGROUNDS: With increased prevalence of obesity, the number of inflammatory bowel disease (IBD) patients suffering from morbid obesity has raised. It is not clear yet if bariatric surgery is a safe and effective option in this population. OBJECTIVES: Our systematic review aims to summarize the available literature on the safety and efficacy of bariatric surgery in morbidly obese patients with IBD. SETTING: University hospital, Iran. METHODS: A PubMed/MEDLINE search was performed to identify studies reporting the outcome of morbidly obese IBD patients. Postoperative outcome of IBD patients after bariatric surgery were pooled for early and late complications, change of IBD status, and medication alteration. RESULTS: A total of 7 studies reported post-bariatric surgery outcomes of 43 morbidly obese IBD patients (31 females, 11 males) with an age ranging from 30 to 64 years and a body mass index from 35.7 to 71 kg/m2. Of these, 25 suffered Crohn's disease (CD) (58.2%) and 18 were ulcerative colitis (UC) patients (41.8%). The small bowel was the most common involved gastrointestinal segment in 27.3% of patients. CD patients more commonly underwent sleeve gastrectomy (72%), while UC patients similarly underwent sleeve gastrectomy and Roux-en-Y gastric bypass (44.4%). After a follow-up of 8 to 77 months, IBD patients lost up to 71.4%+/-5.9% of excess weight and 14.3 kg/m2+/ 5.7 kg/m2 of body mass index. There were 9 early (21.4%) and 10 late (23.8%) postoperative complications related to the bariatric procedure. IBD remitted in 20 patients (47.6%), improved in 2 patients (4.8%), but exacerbated in 7 patients (16.7%). CONCLUSIONS: Although available data on morbidly obese patients with IBD is scarce, bariatric surgery seems to be a safe and effective option for these patients with no added morbidity or mortality. Further studies are necessary to confirm this data. PMID- 27986586 TI - Evaluation of carbohydrate restriction as primary treatment for post-gastric bypass hypoglycemia. AB - BACKGROUND: Up to 15% of patients who have undergone Roux-en-Y gastric bypass (RYGB) surgery may eventually develop symptoms of hypoglycemia. OBJECTIVES: To evaluate the daily life efficacy of a carbohydrate (carb)-restricted dietary advice (CRD) of 6 meals per day with a 30 g carb maximum per meal in patients with documented post-RYGB hypoglycemia. SETTING: Teaching hospital, the Netherlands. METHODS: Frequency and severity of hypoglycemic events before and after CRD were assessed retrospectively in 41 patients with documented post-RYGB hypoglycemia, based on medical records and telephone questionnaires. Hypoglycemia was defined as a blood glucose level<3.0 mmol/L. Results are expressed as mean values+/-standard error or median and range. RESULTS: CRD decreased the number of hypoglycemic events per month from 17.1 (1.5-180) to 2.5 (0-180), i.e., a decline of 85% (P<.001). The lowest blood glucose measured during a hypoglycemic event increased from 2.1+/-.4 to 2.6+/-.2 mmol/L (P = .004). The number of patients who had required outside help in the treatment of hypoglycemia, decreased from 23 to 6 (P<.001). In 14 patients (34.1%) the diet-induced reduction of hypoglycemia was insufficient and required the start of insulin suppressive therapy. CONCLUSION: A CRD, consisting of 6 meals per day with up to 30 g carbs each, is an effective treatment of post-RYGB hypoglycemia in the majority of patients. Additional medication is needed in about a third of patients. PMID- 27986585 TI - Sexual functioning of men and women with severe obesity before bariatric surgery. AB - BACKGROUND: Obesity may impair sexual function through multiple mechanisms, but little is known about sexual dysfunction among adults with severe obesity seeking bariatric procedures. OBJECTIVES: To describe sexual function and associated factors before bariatric surgery. SETTING: Ten U.S. clinical facilities. METHODS: Before bariatric surgery, 2225 of 2458 Longitudinal Assessment of Bariatric Surgery-2 study participants (79% female, median age 45 years and median body mass index 46 kg/m2) completed a survey about sexual function over the past month. Mixed effects ordinal logistic regression models were used to identify factors independently related to 4 domains of sexual function. RESULTS: One third of women (34%) and one quarter of men (25%) were not sexually active, alone or with a partner, in the past month. Twenty-six percent of women and 12% of men reported no sexual desire. Physical health limited sexual activity at least moderately in 38% of women and 44% of men. About one half of the women (49%) and the men (54%) were moderately or very dissatisfied with their sexual life. Among women, older age, being Caucasian, urinary incontinence, depressive symptoms, and antidepressant medication use were associated with poorer sexual function in multiple domains. In men, older age, not being married, depressive symptoms, and antidepressant medication use were associated with poorer sexual function in multiple domains. CONCLUSION: Before bariatric surgery, approximately one half of women and men with severe obesity are dissatisfied with their sexual life. Older age, severity of depressive symptoms, and antidepressant medication use are associated with poorer sexual function in both sexes. PMID- 27986587 TI - The utility of weight loss medications after bariatric surgery for weight regain or inadequate weight loss: A multi-center study. AB - BACKGROUND: Patients who undergo bariatric surgery often have inadequate weight loss or weight regain. OBJECTIVES: We sought to discern the utility of weight loss pharmacotherapy as an adjunct to bariatric surgery in patients with inadequate weight loss or weight regain. SETTING: Two academic medical centers. METHODS: We completed a retrospective study to identify patients who had undergone bariatric surgery in the form of a Roux-en-Y gastric bypass (RYGB) or a sleeve gastrectomy from 2000-2014. From this cohort, we identified patients who were placed on weight loss pharmacotherapy postoperatively for inadequate weight loss or weight regain. We extracted key demographic data, medical history, and examined weight loss in response to surgery and after the initiation of weight loss pharmacotherapy. RESULTS: A total of 319 patients (RYGB = 258; sleeve gastrectomy = 61) met inclusion criteria for analysis. More than half (54%; n = 172) of all study patients lost>=5% (7.2 to 195.2 lbs) of their total weight with medications after surgery. There were several high responders with 30.3% of patients (n = 96) and 15% (n = 49) losing>=10% (16.7 to 195.2 lbs) and>=15% (25 to 195.2 lbs) of their total weight, respectively, Topiramate was the only medication that demonstrated a statistically significant response for weight loss with patients being twice as likely to lose at least 10% of their weight when placed on this medication (odds ratio = 1.9; P = .018). Regardless of the postoperative body mass index, patients who underwent RYGB were significantly more likely to lose>=5% of their total weight with the aid of weight loss medications. CONCLUSIONS: Weight loss pharmacotherapy serves as a useful adjunct to bariatric surgery in patients with inadequate weight loss or weight regain. PMID- 27986588 TI - Circulating Apolipoprotein A-IV presurgical levels are associated with improvement in insulin sensitivity after Roux-en-Y gastric bypass surgery. AB - BACKGROUND: Apolipoprotein A-IV (ApoA-IV) has been shown to be involved in obesity and diabetes pathogenesis in animal studies, but its role in humans is uncertain. OBJECTIVES: The objective of this study was to determine the relation of ApoA-IV with changes in glucose metabolism and weight after bariatric surgery. SETTING: University Hospital. METHODS: The patients (n = 49) included lean controls (n = 8) and patients before and after a mean of 7 months after laparoscopic adjustable gastric banding (LAGB, n = 12), laparoscopic Roux-en-Y gastric bypass (RYGB, n = 22), or laparoscopic sleeve gastrectomy (SG, n = 11). ApoA-IV and other hormone assays were performed in the fasting and the postprandial state. Pearson's correlation analyses controlled for baseline BMI and percent excess weight loss (EWL) were used to determine relationships between ApoA-IV levels and insulin resistance (HOMA-IR). RESULTS: With all bariatric procedures combined, the change in ApoA-IV [533 versus 518 microg/L, P = .813] or ApoA-IV area under the curve (AUC - 1072 versus 1042, P = .939) was not significant. None of the surgeries individually affected levels of fasting or ApoA-IV AUC. Bariatric surgery resulted in a decrease in HOMA-IR (5.3 versus 2.0, P<.001). In the RYGB group, higher baseline ApoA-IV levels correlated with decrease in HOMA-IR [r = -.6, P = .008]. This relationship was independent of EWL and was not observed in the LAGB or SG group. There was no association of ApoA-IV levels with EWL, insulin secretion, Peptide-YY, or leptin levels. CONCLUSION: Preoperative ApoA-IV levels, rather than changes in levels, positively correlate with improvements in insulin sensitivity independent of weight loss after RYGB. PMID- 27986589 TI - 3-Acetylpyridine neurotoxicity in mice. AB - 3-acetylpyridine (3-AP) is a metabolic antagonist used in research to decrease levels of nicotinamide (niacinamide) in laboratory animals. The administration of 3-AP followed by nicotinamide to rats leads to the selective destruction of neurons in the medial inferior olive, resulting in a loss of climbing fibers innervating cerebellar Purkinje cells and a consequent ataxia manifest by alterations in both balance and gait. Although 3-AP has also been administered to mice to destroy neurons in the inferior olive, there are limited studies quantifying the consequent effects on balance, and no studies on gait. Further, the relationship between 3-AP-induced lesions of the inferior olive and behavior has not been elucidated. Because 3-AP continues to be used for experiments involving mice, this study characterized the effects of this toxin on both balance and gait, and on the neuronal integrity of several brain regions involved in motor coordination. Results indicate that C57BL/6 mice are less sensitive to the neurotoxic effects of 3-AP than rats, and a dose more than 6.5 times that used for rats produces deficits in both balance and gait comparable to those in rats. This dose led to a significant (p<0.05) loss of NeuN(+) neurons in several subregions of the inferior olive including the rostral medial nucleus, dorsomedial cell column, ventrolateral protrusion, and cap of Kooy. Further, the number of NeuN(+) neurons in these subregions, with the exception of the dorsomedial cell column, was significantly (p<0.05) related to rotorod performance, implicating their involvement in this behavior. PMID- 27986591 TI - Spinal D-Serine Increases PKC-Dependent GluN1 Phosphorylation Contributing to the Sigma-1 Receptor-Induced Development of Mechanical Allodynia in a Mouse Model of Neuropathic Pain. AB - : We have recently shown that spinal sigma-1 receptor (Sig-1R) activation facilitates nociception via an increase in phosphorylation of the N-methyl-D aspartate (NMDA) receptor GluN1 subunit (pGluN1). The present study was designed to examine whether the Sig-1R-induced facilitative effect on NMDA-induced nociception is mediated by D-serine, and whether D-serine modulates spinal pGluN1 expression and the development of neuropathic pain after chronic constriction injury (CCI) of the sciatic nerve. Intrathecal administration of the D-serine degrading enzyme, D-amino acid oxidase attenuated the facilitation of NMDA induced nociception induced by the Sig-1R agonist, 2-(4-morpholinethyl)1 phenylcyclohexane carboxylate. Exogenous D-serine increased protein kinase C (PKC)-dependent (Ser896) pGluN1 expression and facilitated NMDA-induced nociception, which was attenuated by preteatment with the PKC inhibitor, chelerythrine. In CCI mice, administration of the serine racemase inhibitor, L serine O-sulfate potassium salt or D-amino acid oxidase on postoperative days 0 to 3 suppressed CCI-induced mechanical allodynia (MA) and pGluN1 expression on day 3 after CCI surgery. Intrathecal administration of D-serine restored MA as well as the GluN1 phosphorylation on day 3 after surgery that was suppressed by the Sig-1R antagonist, N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2 (dimethylamino)ethylamine dihydrobromide or the astrocyte inhibitor, fluorocitrate. In contrast, D-serine had no effect on CCI-induced thermal hyperalgesia or GluN1 expression. These results indicate that spinal D-serine: 1) mediates the facilitative effect of Sig-1R on NMDA-induced nociception, 2) modulates PKC-dependent pGluN1 expression, and 3) ultimately contributes to the induction of MA after peripheral nerve injury. PERSPECTIVE: This report shows that reducing D-serine suppresses central sensitization and significantly alleviates peripheral nerve injury-induced chronic neuropathic pain and that this process is modulated by spinal Sig-1Rs. This preclinical evidence provides a strong rationale for using D-serine antagonists to treat peripheral nerve injury induced neuropathy. PMID- 27986590 TI - Phytosteroids beyond estrogens: Regulators of reproductive and endocrine function in natural products. AB - Foods and botanical supplements can interfere with the endocrine system through the presence of phytosteroids - chemicals that interact with steroids receptors. Phytoestrogens are well studied, but compounds such as kaempferol, apigenin, genistein, ginsenoside Rf, and glycyrrhetinic acid have been shown to interact with non-estrogen nuclear receptors. These compounds can have agonist, antagonist, or mixed agonist/antagonist activity depending on compound, receptor, cell line or tissue, and concentration. Some phytosteroids have also been shown to inhibit steroid metabolizing enzymes, resulting in biological effects through altered endogenous steroid concentrations. An interesting example, compound A (4 [1-chloro-2-(methylamino)ethyl]phenyl acetate hydrochloride (1:1)) is a promising selective glucocorticoid receptor modulator (SGRM) based on a phytosteroid isolated from Salsola tuberculatiformis Botschantzev. Given that $6.9 billion of herbal supplements are sold each year, is clear that further identification and characterization of phytosteroids is needed to ensure the safe and effective use of botanical supplements. PMID- 27986594 TI - Mechanical model of an arched basilar membrane in the gerbil cochlea. AB - The frequency selectivity of a gerbil cochlea, unlike other mammals, does not depend on varying thickness and width of its basilar membrane from the basal to the apical end. We model the gerbil arched basilar membrane focusing on the radial tension, embedded fiber thickness, and the membrane arch, which replace the functionality of the variation in thickness and width. The model is verified with the previous gerbil cochlea model which estimated the equivalent basilar membrane thickness and is shown to be more accurate than the flat sandwiched basilar membrane model. The simple sinusoidal-shaped bending mode assumption in previous models is found to be valid in the present model with <12% error. Parametric study on the present model shows that fiber thickness contribution to the membrane stiffness is close to the 3rd order, higher than the 1st order estimation of previous models. We found that the effective Young's modulus of the fiber bundle is at least 6 orders higher than the shear modulus of the soft-cells and the membrane radial bending stiffness is more sensitive to the membrane arch and the shear modulus of the soft-cells near the apical end. PMID- 27986592 TI - The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2. AB - Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs. PMID- 27986593 TI - Modeling emissions from CAFO poultry farms in Poland and evaluating potential risk to surrounding populations. AB - The world-wide use of concentrated animal feeding operations (CAFOs) for livestock production demands the need to evaluate the potential impact to public health. We estimated the exposure of various airborne pollutants for populations residing in close proximity to 10 poultry CAFOs located in Central Poland. Ammonia (NH3), carbon dioxide (CO2), carbon monoxide (CO), hydrogen sulfide (H2S), methane (CH4), nitrogen dioxide (NO2), nitrous oxide (N2O), sulfur dioxide (SO2), and organic dust were the pollutants of interest for this study. Because no monitoring data were available, we used the steady-state Gaussian dispersion model AERMOD to estimate pollutant concentrations for the exposed population in order to calculate the hazard index (HI) for a combined mixture of chemicals. Our results indicate that while the levels of certain pollutants are expected to exceed background levels commonly found in the environment they did not result in calculated hazard indexes which exceeded unity suggesting low potential for adverse health effects for the surrounding community for the mixture of chemicals. The study was conducted through a cooperation between the Agency for Toxic Substances and Disease Registry (ATSDR) in the USA and the Nofer Institute of Occupational Medicine (NIOM) in Poland. PMID- 27986595 TI - The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity. AB - Glioblastoma multiforme (GBM) is the high-grade primary glioma in adults. Temozolomide (TMZ), an alkylating agent of the imidazotetrazine series, is a first-line chemotherapeutic drug for clinical therapy. However, the expense of TMZ therapy and increasing drug resistance to TMZ decreases its therapeutic effects. Therefore, our aim was to investigate the detailed molecular mechanisms of TMZ-mediated cytotoxicity to enhance the efficacy of TMZ in clinical GBM therapy. First, TMZ-mediated gene expression profiles and networks in U87-MG cells were identified by transcriptome microarray and bioinformatic analyses. Cation transport regulator-like protein 1 (CHAC1) was the most highly TMZ upregulated gene. Overexpression and knockdown of CHAC1 expression significantly influenced TMZ-mediated cell viability, apoptosis, caspase-3 activation, and poly(ADP ribose) polymerase (PARP) degradation. The c-Jun N-terminal kinase (JNK)1/c-JUN pathway was identified to participate in TMZ-upregulated CHAC1 expression via transcriptional control. Furthermore, CHAC1 levels were significantly decreased in GBM cell lines, TCGA array data, and tumor tissues. Overexpression of CHAC1 enhanced glioma apoptotic death via caspase-3/9 activation, PARP degradation, autophagy formation, reactive oxygen species generation, increased intracellular calcium, and loss of the mitochondria membrane potential. Finally, we also identified that TMZ significantly reduced Notch3 levels, which are upregulated in gliomas. TMZ also induced CHAC1 to bind to the Notch3 protein and inhibit Notch3 activation, resulting in attenuation of Notch3-mediated downstream signaling pathways. These results emphasize that CHAC1 inhibited Notch3 signaling can influence TMZ-mediated cytotoxicity. Our findings may provide novel therapeutic strategies for future glioblastoma therapy. PMID- 27986596 TI - Effects of the synthetic neurosteroid ganaxolone on seizure activity and behavioral deficits in an Angelman syndrome mouse model. AB - Angelman syndrome (AS) is a rare neurogenetic disorder characterized by severe developmental delay, motor impairments, and epilepsy. GABAergic dysfunction is believed to contribute to many of the phenotypic deficits seen in AS. We hypothesized that restoration of inhibitory tone mediated by extrasynaptic GABAA receptors could provide therapeutic benefit. Here, we report that ganaxolone, a synthetic neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, was anxiolytic, anticonvulsant, and improved motor deficits in the Ube3a-deficient mouse model of AS when administered by implanted mini-pump for 3 days or 4 weeks. Treatment for 4 weeks also led to recovery of spatial working memory and hippocampal synaptic plasticity deficits. This study demonstrates that ganaxolone ameliorates many of the behavioral abnormalities in the adult AS mouse, and tolerance did not occur to the therapeutic effects of the drug. The results support clinical studies to investigate ganaxolone as a symptomatic treatment for AS. PMID- 27986597 TI - Literature mining supports a next-generation modeling approach to predict cellular byproduct secretion. AB - The metabolic byproducts secreted by growing cells can be easily measured and provide a window into the state of a cell; they have been essential to the development of microbiology, cancer biology, and biotechnology. Progress in computational modeling of cells has made it possible to predict metabolic byproduct secretion with bottom-up reconstructions of metabolic networks. However, owing to a lack of data, it has not been possible to validate these predictions across a wide range of strains and conditions. Through literature mining, we were able to generate a database of Escherichia coli strains and their experimentally measured byproduct secretions. We simulated these strains in six historical genome-scale models of E. coli, and we report that the predictive power of the models has increased as they have expanded in size and scope. The latest genome-scale model of metabolism correctly predicts byproduct secretion for 35/89 (39%) of designs. The next-generation genome-scale model of metabolism and gene expression (ME-model) correctly predicts byproduct secretion for 40/89 (45%) of designs, and we show that ME-model predictions could be further improved through kinetic parameterization. We analyze the failure modes of these simulations and discuss opportunities to improve prediction of byproduct secretion. PMID- 27986598 TI - Optimizing Oral Bioavailability in Drug Discovery: An Overview of Design and Testing Strategies and Formulation Options. AB - For discovery teams working toward new, orally administered therapeutic agents, one requirement is to attain adequate systemic exposure after oral dosing, which is best accomplished when oral bioavailability is optimized. This report summarizes the bioavailability challenges currently faced in drug discovery, and the design and testing methods and strategies currently utilized to address the challenges. Profiling of discovery compounds usually includes separate assessments of solubility, permeability, and susceptibility to first-pass metabolism, which are the 3 most likely contributors to incomplete oral bioavailability. An initial assessment of absorption potential may be made computationally, and high throughput in vitro assays are typically performed to prioritize compounds for in vivo studies. The initial pharmacokinetic study is a critical decision point in compound evaluation, and the importance of the effect the dosing vehicle or formulation can have on oral bioavailability, especially for poorly water soluble compounds, is emphasized. Dosing vehicles and bioavailability-enabling formulations that can be used for discovery and preclinical studies are described. Optimizing oral bioavailability within a chemical series or for a lead compound requires identification of the barrier limiting bioavailability, and methods used for this purpose are outlined. Finally, a few key guidelines are offered for consideration when facing the challenges of optimizing oral bioavailability in drug discovery. PMID- 27986600 TI - Effect of culture residence time on substrate uptake and storage by a pure culture of Thiothrix (CT3 strain) under continuous or batch feeding. AB - A pure culture of the filamentous bacterium Thiothrix, strain CT3, was aerobically cultured in a chemostat under continuous acetate feeding at three different culture residence times (RT 6, 12 or 22 d) and the same volumetric organic load rate (OLR 0.12gCOD/L/d). Cells cultured at decreasing RT in the chemostat had an increasing transient response to acetate spikes in batch tests. The maximum specific acetate removal rate increased from 25 to 185mgCOD/gCOD/h, corresponding to a 1.8 to 8.1 fold higher respective steady-state rate in the chemostat. The transient response was mainly due to acetate storage in the form of poly(3-hydroxybutyrate) (PHB), whereas no growth response was observed at any RT. Interestingly, even though the storage rate also decreased as the RT increased, the storage yield increased from 0.41 to 0.50 COD/COD. This finding does not support the traditional view that storage plays a more important role as the transient response increases. The transient response of the steady-state cells was much lower than in cells cultured under periodic feeding (at 6 d RT, from 82 to 247mgCOD/gCOD/h), with the latter cells showing both storage and growth responses. On the other hand, even though steady-state cells had no growth response and their storage rate was also less, steady-state cells showed a higher storage yield than cells cultured under dynamic feeding. This suggests that in Thiothrix strain CT3, the growth response is triggered by periodic feeding, whereas the storage response is a constitutive mechanism, independent from previous acclimation to transient conditions. PMID- 27986599 TI - Development of a Novel Formulation That Improves Preclinical Bioavailability of Tenofovir Disoproxil Fumarate. AB - Tenofovir disoproxil fumarate (TDF), the bisphosphonate ester prodrug of tenofovir (TFV), has poor bioavailability due to intestinal degradation and efflux transport. Reformulation using U.S. Food and Drug Administration-approved esterase and efflux inhibitors to increase oral bioavailability could provide lower dose alternatives and reduce costs for patients with HIV in resource limited settings. Inhibition of mucosal and intracellular esterases was studied in human and rat intestinal extracts (S9), where TDF was protected by the carboxylesterase inhibitor bis-para-nitrophenylphosphate, the ester mix EM1, and the generally recognized-as-safe (GRAS) excipient propylparaben. Permeability studies using Madin-Darby canine kidney and Caco-2 cell monolayers demonstrated that TDF was a substrate for the permeability glycoprotein with permeability glycoprotein inhibitors reducing basolateral to apical transport of TDF. These studies also showed that transport was increased by esterase inhibitors. TDF, TFV, and tenofovir monophosphonate ester transport across Caco-2 monolayers with esterase and efflux inhibitors revealed a maximum 38.7-fold increase in apical to basolateral TDF transport with the potent non-GRAS combination of EM1 and GF120918. Transport was increased 22.8-fold by the GRAS excipients, propylparaben, and d-a-tocopheryl polyethylene glycol 1000 succinate (a vitamin E derivative). TFV pharmacokinetics in rats following oral administration of TDF and GRAS esterase and efflux inhibitors confirmed enhanced bioavailability. Area under the curve increased 1.5- to 2.1-fold with various combinations of parabens and d-a-tocopheryl polyethylene glycol 1000 succinate. This significant inhibition of TDF hydrolysis and efflux in vivo exhibits the potential to safely increase TDF bioavailability in humans. PMID- 27986601 TI - Identification and characterization of C1 inhibitor in Nile tilapia (Oreochromis niloticus) in response to pathogenic bacteria. AB - C1 inhibitor (C1INH) is a multi-functional serine protease inhibitor in plasmatic cascades, not only inactivating various proteases, but also regulating both complement and contact system activation. In this study, we described the identification and characterization of a C1INH ortholog from Nile tilapia (Oreochromis niloticus) at molecular, protein and cellular levels. The full length cDNA of Oreochromis niloticus C1INH (OnC1INH) consisted of 1791 bp of nucleotide sequence encoding polypeptides of 596 amino acids. The deduced protein possessed a serpin domain at the C-terminal domain, and two Ig-like domains in the N-terminal domain with significant homology to teleost. Expression analysis revealed that the OnC1INH was extremely highly expressed in the liver; however, much weakly exhibited in other tissues including spleen, kidney, blood and heart. After the in vivo challenges of the lipopolysaccharide (LPS) and Streptococcus agalactiae, the expression of OnC1INH was significantly up-regulated in liver and spleen at the late phase, which was confirmed at the protein level with immunohistochemical analysis. The up-regulation of OnC1INH expression was also demonstrated in head kidney monocytes/macrophages in vitro stimulated with LPS, Aeromonas hydrophila and Streptococcus agalactiae, which was positively correlated with the protein expression pattern in the culture media. Taken together, the results of this study indicated that OnC1INH might be involved in the immune response of Nile tilapia against to bacterial challenge. PMID- 27986602 TI - Long-term influence of cyanobacterial bloom on the immune system of Litopenaeus vannamei. AB - Cyanobacteria are ubiquitously distributed in water on the Earth. It has long been known that the cyanobacterial bloom in aquaculture ponds can cause acute and massive deaths of shrimp. However, the long-term and chronic effects of the cyanobacterial bloom on shrimp are still poorly understood. In this study, the immune state of white pacific shrimp, Litopenaeus vannamei, surviving a naturally occurring cyanobacterial bloom was investigated and tracked for 70 d. Compared with the control, the growth of shrimp suffering high concentrations of cyanobacteria was obviously postponed. In these shrimp, the activities of the NF kappaB, JAK/STAT and P38 MAPK immune signaling pathways and the expression of many antimicrobial peptide genes were down-regulated, whereas the expression of C type lectins was significantly up-regulated. Although the mRNA level of lysozyme was reduced, the expression of the invertebrate-type lysozyme gene was increased. Furthermore, the concentration of hemocytes in hemolymph was greatly decreased, but the phagocytic activity of hemocytes was increased. These suggested that the cyanobacterial bloom has significant and complex influences on the immune system of shrimp, and in turn, alteration of the immune state could be a factor by which few shrimp can survive the cyanobacterial bloom. Thus, the current study could help further understand the interactions between the aquaculture water environment and the immune system of shrimp. PMID- 27986603 TI - New potential strategies for Alzheimer's disease prevention: pegylated biodegradable dexibuprofen nanospheres administration to APPswe/PS1dE9. AB - Dexibuprofen loaded pegylated poly(lactic-co-glycolic) nanospheres prepared by solvent diffusion method were designed to increase Dexibuprofen brain delivery reducing systemic side effects. Nanospheres exhibited a mean particle size around 200 nm (195.4 nm), monomodal population and negative surface charge. Drug loaded nanospheres showed a sustained release profile, allowing to modify the posology in vivo. Nanospheres were non-toxic neither in brain endothelial cells nor astrocytes and do not cause blood-brain barrier disruption. Nanospheres were able to partially cross the cells barrier and release the drug after co-culture in vitro experiments, increasing Dexibuprofen permeation coefficient. Behavioral tests performed in APPswe/PS1dE9 mice (mice model of familial Alzheimer's disease) showed that nanospheres reduce memory impairment more efficiently than the free drug. Developed nanospheres decrease brain inflammation leading to beta amyloid plaques reduction. According to these results, chronical oral Dexibuprofen pegylated poly(lactic-co-glycolic) nanosystems could constitute a suitable strategy for the prevention of neurodegeneration. PMID- 27986606 TI - Imaging the neuroplastic effects of ketamine with VBM and the necessity of placebo control. AB - In the last years a plethora of studies have investigated morphological changes induced by behavioural or pharmacological interventions using structural T1 weighted MRI and voxel-based morphometry (VBM). Ketamine is thought to exert its antidepressant action by restoring neuroplasticity. In order to test for acute impact of a single ketamine infusion on grey matter volume we performed a placebo controlled, double-blind investigation in healthy volunteers using VBM. 28 healthy individuals underwent two MRI sessions within a timeframe of 2 weeks, each consisting of two structural T1-weighted MRIs within a single session, one before and one 45min after infusion of S-ketamine (bolus of 0.11mg/kg, followed by an maintenance infusion of 0.12mg/kg) or placebo (0.9% NaCl infusion) using a crossover design. In the repeated-measures ANOVA with time (post-infusion/pre infusion) and medication (placebo/ketamine) as factors, no significant effect of interaction and no effect of medication was found (FWE-corrected). Importantly, further post-hoc t-tests revealed a strong "decrease" of grey matter both in the placebo and the ketamine condition over time. This effect was evident mainly in frontal and temporal regions bilaterally with t-values ranging from 4.95 to 5.31 (FWE-corrected at p<0.05 voxel level). The vulnerabilities of VBM have been repeatedly demonstrated, with reports of influence of blood flow, tissue water and direct effects of pharmacological compounds on the MRI signal. Here again, we highlight that the relationship between intervention and VBM results is apparently subject to a number of physiological influences, which are partly unknown. Future studies focusing on the effects of ketamine on grey matter should try to integrate known influential factors such as blood flow into analysis. Furthermore, the results of this study highlight the importance of a carefully performed placebo condition in pharmacological fMRI studies. PMID- 27986607 TI - Spatio-temporal reconstruction of brain dynamics from EEG with a Markov prior. AB - Electroencephalography (EEG) can capture brain dynamics in high temporal resolution. By projecting the scalp EEG signal back to its origin in the brain also high spatial resolution can be achieved. Source localized EEG therefore has potential to be a very powerful tool for understanding the functional dynamics of the brain. Solving the inverse problem of EEG is however highly ill-posed as there are many more potential locations of the EEG generators than EEG measurement points. Several well-known properties of brain dynamics can be exploited to alleviate this problem. More short ranging connections exist in the brain than long ranging, arguing for spatially focal sources. Additionally, recent work (Delorme et al., 2012) argues that EEG can be decomposed into components having sparse source distributions. On the temporal side both short and long term stationarity of brain activation are seen. We summarize these insights in an inverse solver, the so-called "Variational Garrote" (Kappen and Gomez, 2013). Using a Markov prior we can incorporate flexible degrees of temporal stationarity. Through spatial basis functions spatially smooth distributions are obtained. Sparsity of these are inherent to the Variational Garrote solver. We name our method the MarkoVG and demonstrate its ability to adapt to the temporal smoothness and spatial sparsity in simulated EEG data. Finally a benchmark EEG dataset is used to demonstrate MarkoVG's ability to recover non-stationary brain dynamics. PMID- 27986605 TI - The role of myelination in measures of white matter integrity: Combination of diffusion tensor imaging and two-photon microscopy of CLARITY intact brains. AB - Diffusion tensor imaging (DTI) is used extensively in neuroscience to noninvasively estimate white matter (WM) microarchitecture. However, the diffusion signal is inherently ambiguous because it infers WM structure from the orientation of water diffusion and cannot identify the biological sources of diffusion changes. To compare inferred WM estimates to directly labeled axonal elements, we performed a novel within-subjects combination of high-resolution ex vivo DTI with two-photon laser microscopy of intact mouse brains rendered optically transparent by Clear Lipid-exchanged, Anatomically Rigid, Imaging/immunostaining compatible, Tissue hYdrogel (CLARITY). We found that myelin basic protein (MBP) immunofluorescence significantly correlated with fractional anisotropy (FA), especially in WM regions with coherent fiber orientations and low fiber dispersion. Our results provide evidence that FA is particularly sensitive to myelination in WM regions with these characteristics. Furthermore, we found that radial diffusivity (RD) was only sensitive to myelination in a subset of WM tracts, suggesting that the association of RD with myelin should be used cautiously. This combined DTI-CLARITY approach illustrates, for the first time, a framework for using brain-wide immunolabeling of WM targets to elucidate the relationship between the diffusion signal and its biological underpinnings. This study also demonstrates the feasibility of a within-subject combination of noninvasive neuroimaging and tissue clearing techniques that has broader implications for neuroscience research. PMID- 27986604 TI - Cell therapy for the degenerating intervertebral disc. AB - Spinal conditions related to intervertebral disc (IVD) degeneration cost billions of dollars in the US annually. Despite the prevalence and soaring cost, there is no specific treatment that restores the physiological function of the diseased IVD. Thus, it is vital to develop new treatment strategies to repair the degenerating IVD. Persons with IVD degeneration without back pain or radicular leg pain often do not require any intervention. Only patients with severe back pain related to the IVD degeneration or biomechanical instability are likely candidates for cell therapy. The IVD progressively degenerates with age in humans, and strategies to repair the IVD depend on the stage of degeneration. Cell therapy and cell-based gene therapy aim to address moderate disc degeneration; advanced stage disease may require surgery. Studies involving autologous, allogeneic, and xenogeneic cells have all shown good survival of these cells in the IVD, confirming that the disc niche is an immunologically privileged site, permitting long-term survival of transplanted cells. All of the animal studies reviewed here reported some improvement in disc structure, and 2 studies showed attenuation of local inflammation. Among the 50 studies reviewed, 25 used some type of scaffold, and cell leakage is a consistently noted problem, though some studies showed reduced cell leakage. Hydrogel scaffolds may prevent cell leakage and provide biomechanical support until cells can become established matrix producers. However, these gels need to be optimized to prevent this leakage. Many animal models have been leveraged in this research space. Rabbit is the most frequently used model (28 of 50), followed by rat, pig, and dog. Sheep and goat IVDs resemble those of humans in size and in the absence of notochordal cells. Despite this advantage, there were only 2 sheep and 1 goat studies of 50 studies in this cohort. It is also unclear if a study in large animals is needed before clinical trials since some of the clinical trials proceeded without a study in large animals. No animal studies or clinical trials completely restored IVD structure. However, results suggest cause for optimism. In light of the fact that patients primarily seek medical care for back pain, attenuating local inflammation should be a priority in benchmarks for success. Clinicians generally agree that short-term back pain should be treated conservatively. When interventions are considered, the ideal therapy should also be minimally invasive and concurrent with other procedures such as discography or discectomy. Restoration of tissue structure and preservation of spinal motion are desirable. PMID- 27986608 TI - Changes in brain iron concentration after exposure to high-altitude hypoxia measured by quantitative susceptibility mapping. AB - Hypoxia can induce physiological changes. This study aims to explore effects of high-altitude (HA) hypoxia on cerebral iron concentration. Twenty-nine healthy sea-level participants were tested shortly before and after approximately 4-week adaptation to the HA environment at fQinghai-Tibet Plateau (4200m), and were re investigated after re-adaptation to the sea-level environment one year later. Iron concentration was quantified with quantitative susceptibility mapping (QSM), and the results were compared with transverse relaxation rate (R*2) measurements. The variations of magnetic susceptibility indicate that the iron concentration in gray matter regions, especially in basal ganglia, including caudate nucleus, putamen, globus pallidus and substantia nigra, increases significantly after HA exposure. This increase appears consistent with the conclusion from R*2 value variations. However, unlike QSM, the R*2 value fails to demonstrate the statistical difference of iron content in red nucleus. The re-investigation results show that most variations are recovered after sea-level re-adaptation for one year. Additionally, hemisphere- and gender-related differences in iron concentration changes were analyzed among cerebral regions. The results show greater possibilities in the right hemisphere and females. Further studies based on diffusion tensor imaging (DTI) suggest that the fractional anisotropy increases and the mean diffusivity decreases after HA exposure in six deep gray matter nuclei, with linear dependence on iron concentration only in putamen. In conclusion, the magnetic susceptibility value can serve as a quantitative marker of brain iron, and variations of regional susceptibility reported herein indicate that HA hypoxia can result in significant iron deposition in most deep gray matter regions. Additionally, the linear dependence of DTI metrics on iron concentration in putamen indicates a potential relationship between ferritin and water diffusion. PMID- 27986609 TI - The neural circuits for arithmetic principles. AB - Arithmetic principles are the regularities underlying arithmetic computation. Little is known about how the brain supports the processing of arithmetic principles. The current fMRI study examined neural activation and functional connectivity during the processing of verbalized arithmetic principles, as compared to numerical computation and general language processing. As expected, arithmetic principles elicited stronger activation in bilateral horizontal intraparietal sulcus and right supramarginal gyrus than did language processing, and stronger activation in left middle temporal lobe and left orbital part of inferior frontal gyrus than did computation. In contrast, computation elicited greater activation in bilateral horizontal intraparietal sulcus (extending to posterior superior parietal lobule) than did either arithmetic principles or language processing. Functional connectivity analysis with the psychophysiological interaction approach (PPI) showed that left temporal-parietal (MTG-HIPS) connectivity was stronger during the processing of arithmetic principle and language than during computation, whereas parietal-occipital connectivities were stronger during computation than during the processing of arithmetic principles and language. Additionally, the left fronto-parietal (orbital IFG-HIPS) connectivity was stronger during the processing of arithmetic principles than during computation. The results suggest that verbalized arithmetic principles engage a neural network that overlaps but is distinct from the networks for computation and language processing. PMID- 27986610 TI - The minimal clinically important difference raised the significance of outcome effects above the statistical level, with methodological implications for future studies. AB - OBJECTIVE: To illustrate and discuss current and proposed new concepts of effect size (ES) quantification and significance, with a focus on statistical and clinical/subjective interpretation and supported by empirical examples. STUDY DESIGN AND SETTINGS: Different methods for determining minimal clinically important differences (MCIDs) are reviewed, applied to practical examples (pain score differences in knee osteoarthritis), and further developed. Their characteristics, advantages, and disadvantages are illustrated and discussed. RESULTS: Empirical score differences between verum and placebo become statistically significant if sample sizes are sufficiently large. MCIDs, by contrast, are defined by patients' perceptions. MCIDs obtained by the most common "mean change method" can be expressed as absolute or relative scores, as different ES parameters, and as the optimal cutoff point on the receiver operating characteristic curve. They can further be modeled by linear and logistic regression, adjusting for potential confounders. CONCLUSION: Absolute and relative MCIDs are easy to interpret and apply to data of investigative studies. MCIDs expressed as effect sizes reduce bias, which mainly results from dependency on the baseline score. Multivariate linear and logistic regression modeling further reduces bias. Anchor-based methods use clinical/subjective perception to define MCIDs and should be clearly differentiated from distribution based methods that provide statistical significance only. PMID- 27986611 TI - Antrodia salmonea induces G2 cell-cycle arrest in human triple-negative breast cancer (MDA-MB-231) cells and suppresses tumor growth in athymic nude mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Antrodia salmonea (AS), is a well-known folk medicinal mushroom in Taiwan, has been reported to exhibit anti-oxidant, anti angiogenic, and anti-inflammatory effects. MATERIALS AND METHODS: In the present study, we examined the effects of AS on cell-cycle arrest in vitro in MDA-MB-231 cells and on tumor regression in vivo using an athymic nude mice model. RESULTS: AS (0-200MUg/mL) treatment significantly induced G2 cell-cycle arrest in MDA-MB 231 cells by reducing the levels of cyclin B1, cyclin A, cyclin E, and CDC2 proteins. In addition, N-acetylcysteine (NAC) pretreatment prevented AS induced G2 cell-cycle arrest, indicating that ROS accumulation and subsequent cell cycle arrest might be a major mechanism of AS-induced cytotoxicity. Further, AS treatment decreased COX-2 expression and induced PARP cleavage was significantly reversed by NAC pretreatment in MDA-MB-231 cells. The in vivo study results revealed that AS treatment was effective in terms of delaying the tumor incidence and reducing the tumor growth in MDA-MB-231-xenografted nude mice. TUNEL assay, immunohistochemical staining and Western blotting confirmed that AS significantly modulated the xenografted tumor progression as demonstrated by induction of apoptosis, autophagy, and cell-cycle arrest. CONCLUSION: Our data strongly suggest that Antrodia salmonea could be an anti-cancer agent for human breast cancer. PMID- 27986612 TI - Standardizing Maternity Care Data to Improve Coordination of Care. AB - The amount of data generated by health information technology systems is staggering, and using those data to make meaningful care decisions that improve patient outcomes is difficult. The purpose of this article is to describe the Maternal Health Information Initiative, a multidisciplinary group of maternity care stakeholders charged with standardizing maternity care data. Complementary strategies that practicing clinicians can use to support this initiative and improve the usability of maternity care data are provided. PMID- 27986613 TI - Oxygen flux reduces Cux1 positive neurons and cortical growth in a gestational rodent model of growth restriction. AB - BACKGROUND: The mammalian cerebral cortex forms in an inside-out manner, establishing deep cortical layers before superficial layers and is regulated by transcription factors which influence cell differentiation. Preterm birth interrupts the trajectory of normal neurodevelopment and adverse perinatal exposures have been implicated in cortical injury. We hypothesise that growth restriction (GR) and fluctuating hyperoxia (DeltaO2) impair cortical laminar development. METHODS: Sprague-Dawley rats received 18% (non-restricted, NR) or 9% (growth restricted, GR) protein diet from E15-P7. Litters were reared in air or fluctuating hyperoxia (circa 10kPa) from P0 to P7. Cortical laminae were stained and measured. Neuronal subtypes were quantified using immunofluorescence for subtype-specific transcription factors (Satb2, Cux1, Ctip2, Tbr1). RESULTS: DeltaO2 did not affect brain weight at P7 but reduced cortical thickness in both NR (p<0.05) and GR groups (p<0.001). DeltaO2 resulted in superficial cortical thinning in both groups and in the deep layers of GR pups (p<0.001). Cell density was preserved. DeltaO2 did not affect proportions of callosal, corticothalamic and corticospinal neurons but resulted in a reduction of neurons expressing Cux1 (p<0.01) implicated in dendritic branching and synapse formation. CONCLUSION: Postnatal DeltaO2, a modifiable factor in neonatal care, impairs cortical development in a rodent model with preferential disadvantage to superficial neurons. PMID- 27986614 TI - Overview of retinal differentiation potential of mesenchymal stem cells: A promising approach for retinal cell therapy. AB - Retinal disease caused by retinal cell apoptosis leads to irreversible vision loss. Stem cell investigation efforts have been made to solve and cure retinal disorders. There are several sources of stem cells which have been used in these experiments. Numerous studies demonstrated that transplanted stem cells can migrate into and integrate in different layers of retina. Among these, mesenchymal stem cells (MSCs) were considered a promising source for cell therapy. Here, we review the literature assessing the potential of MSCs to differentiate into retinal cells in vivo and in vitro as well as their clinical application. However, more investigation is required to define the protocols that optimize stem cell differentiation and their functional integration in the retina. PMID- 27986615 TI - "I just realized that something happened to me today" - An innovative educational approach to support students in dealing with the dissection course, death and dying. AB - BACKGROUND AND AIM: The dissection course is an essential part of preclinical medical education. At the Medical Faculty of Duesseldorf, a required elective course has been developed over three semesters with the aim of encouraging students to reflect on their experiences in the dissection course and offering them support in dealing with aspects of death and dying. The aim of this paper is to present this educational approach and the student evaluations. METHODS AND RESULTS: The educational concept follows a peer group approach and is comprised of several components spanning three semesters: introductory lectures, tours of the dissection hall and clinical wards, an online diary, and reflection groups. Quantitative and qualitative evaluation has shown that students rate the course positively as to its benefits and workload. While all of the components should be retained, students do wish more time to visit sites and engage with professionals in connection with death and dying. DISCUSSION: This strategy could serve as a cornerstone for longitudinal training to promote adequate coverage of topics such as death and dying. The course has a reasonable cost-benefit ratio. When transferring it to another setting, a gratification system should be considered. PMID- 27986617 TI - Accuracy and efficiency of computer-aided anatomical analysis using 3D visualization software based on semi-automated and automated segmentations. AB - OBJECTIVE: We investigated and compared the functionality of two 3D visualization software provided by a CT vendor and a third-party vendor, respectively. Using surgical anatomical measurement as baseline, we evaluated the accuracy of 3D visualization and verified their utility in computer-aided anatomical analysis. METHODS: The study cohort consisted of 50 adult cadavers fixed with the classical formaldehyde method. The computer-aided anatomical analysis was based on CT images (in DICOM format) acquired by helical scan with contrast enhancement, using a CT vendor provided 3D visualization workstation (Syngo) and a third-party 3D visualization software (Mimics) that was installed on a PC. Automated and semi automated segmentations were utilized in the 3D visualization workstation and software, respectively. The functionality and efficiency of automated and semi automated segmentation methods were compared. Using surgical anatomical measurement as a baseline, the accuracy of 3D visualization based on automated and semi-automated segmentations was quantitatively compared. RESULTS: In semi automated segmentation, the Mimics 3D visualization software outperformed the Syngo 3D visualization workstation. No significant difference was observed in anatomical data measurement by the Syngo 3D visualization workstation and the Mimics 3D visualization software (P>0.05). CONCLUSIONS: Both the Syngo 3D visualization workstation provided by a CT vendor and the Mimics 3D visualization software by a third-party vendor possessed the needed functionality, efficiency and accuracy for computer-aided anatomical analysis. PMID- 27986616 TI - Thermogenesis, fatty acid synthesis with oxidation, and inflammation in the brown adipose tissue of ob/ob (-/-) mice. AB - Brown adipose tissue (BAT) is specialized in heat production, but its metabolism in ob/ob mice is still a matter of debate. We aimed to verify ob/ob mice BAT using C57Bl/6 male mice (as the wild-type, WT) and leptin-deficient ob/ob mice (on the C57Bl/6 background strain), at three months of age (n=10/group). At euthanasia, animals had their interscapular BAT weighed, and prepared for analysis (Western blot, and RT-qPCR). In comparison with the WT group, the ob/ob group showed reduced thermogenic signaling markers (gene expression of beta 3 adrenergic receptor, beta3-AR; PPARgamma coactivator 1 alpha, PGC1alpha, and uncoupling protein 1, UCP1). The ob/ob group also showed impaired gene expression for lipid utilization (perilipin was increased, while other markers were diminished: carnitine palmitoyltransferase-1b, CPT-1b; cluster of differentiation 36, CD36; fatty acid binding protein 4, FABP4; fatty acid synthase, FAS, and sterol regulatory element-binding protein 1c, SREBP1c), and altered protein expression of insulin signaling (diminished pAKT, TC10, and GLUT-4). Lastly, the ob/ob group showed increased gene expression of markers of inflammation (interleukin 1 beta, IL-1beta; IL-6, tumor necrosis factor alpha, TNFalpha; and monocyte chemotactic protein-1, MCP-1). In conclusion, the ob/ob mice have decreased thermogenic markers associated with reduced gene expression related to fatty acid synthesis, mobilization, and oxidation. There were also alterations in insulin signaling and protein and gene expressions of inflammation. The findings suggest that the lack of substrate for thermogenesis and the local inflammation negatively regulated thermogenic signaling in the ob/ob mice. PMID- 27986618 TI - Recurrent episodes of life-threatening vasodilatory shock following unintentional intoxication with amlodipine. AB - Calcium channel blockers (CCBs) have a narrow therapeutic index, and their intake in excess is associated with a critical clinical presentation of sustained hypotension and non-cardiogenic pulmonary edema, which are difficult to treat. Unfortunately, the available treatments fail to resuscitate a significant number of patients poisoned by CCBs, rendering them the main cardiovascular drugs involved in death due to overdose. Importantly, in all cases reported until now in the literature, CCB intoxication was known at the time of patients' presentation and the medical challenge solely consisted of the therapeutic approach. In this case report, we describe our experience in treating a 72-year old patient with recurrent episodes of sustained hypotension refractory to crystalloid and vasoconstrictor infusions. Prolonged pharmacologic support and intermittent sessions of hemofiltration induced stabilization and recovery. The results of an extensive diagnostic workup to elucidate the cause were unfruitful. The recurrent and paroxysmal nature of the clinical presentation along with its incidence after the patient left the protected setting of the hospital led the diagnostic approach to search for a possible external factor, which was shown to be, after toxicological investigation, unintentional amlodipine intoxication. PMID- 27986619 TI - Genetic factors contribute more to hip than knee surgery due to osteoarthritis - a population-based twin registry study of joint arthroplasty. AB - OBJECTIVE: To explore and quantify the relative strengths of the genetic contribution vs the contribution of modifiable environmental factors to severe osteoarthritis (OA) having progressed to total joint arthroplasty. DESIGN: Incident data from the Norwegian Arthroplasty Registry were linked with the Norwegian Twin Registry on the National ID-number in 2014 in a population-based prospective cohort study of same-sex twins born 1915-60 (53.4% females). Education level and height/weight were self-reported and Body Mass Index (BMI) calculated. The total follow-up time was 27 years for hip arthroplasty (1987 2014, 424,914 person-years) and 20 years for knee arthroplasty (1994-2014, 306,207 person-years). We estimated concordances and the genetic contribution to arthroplasty due to OA in separate analyses for the hip and knee joint. RESULTS: The population comprised N = 9058 twin pairs (N = 3803 monozygotic (MZ), N = 5226 dizygotic (DZ)). In total, 73% (95% confidence intervals (CI) = 66-78%) and 45% (95% CI = 30-58%) of the respective variation in hip and knee arthroplasty could be explained by genetic factors. Zygosity (as a proxy for genetic factors) was associated with hip arthroplasty concordance over time when adjusted for sex, age, education and BMI (HR = 2.98, 95% CI = 1.90-4.67 for MZ compared to DZ twins). Knee arthroplasty was to a greater extent dependent on BMI when adjusted for zygosity and the other covariates (HR = 1.15, 95% CI = 1.02-1.29). CONCLUSION: Hip arthroplasty was strongly influenced by genetic factors whereas knee arthroplasty to a greater extent depended on a high BMI. The study may imply there is a greater potential for preventing progression of knee OA to arthroplasty in comparison with hip OA. PMID- 27986620 TI - Subchondral bone in osteoarthritis: association between MRI texture analysis and histomorphometry. AB - OBJECTIVE: Magnetic resonance imaging (MRI) texture analysis is a method of analyzing subchondral bone alterations in osteoarthritis (OA). The objective of this study was to evaluate the association between MR texture analysis and ground truth subchondral bone histomorphometry at the tibial plateau. DESIGN: The local research ethics committee approved the study. All subjects provided written, informed consent. This was a cross-sectional study carried out at our institution between February and August 2014. Ten participants aged 57-84 with knee OA scheduled for total knee arthroplasty (TKA) underwent pre-operative MRI of the symptomatic knee at 3T using a high spatial-resolution coronal T1 weighted sequence. Tibial plateau explants obtained at the time of TKA underwent histological preparation to allow calculation of bone volume fraction (BV.TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp) and trabecular number (Tb.N). Texture analysis was performed on the tibial subchondral bone of MRI images matched to the histological sections. Regression models were created to assess the association of texture analysis features with BV.TV, Tb.Th, Tb.Sp and Tb.N. RESULTS: MRI texture features were significantly associated with BV.TV (R2 = 0.76), Tb.Th (R2 = 0.47), Tb.Sp (R2 = 0.75) and Tb.N (R2 = 0.60, all P < 0.001). Simple gray-value histogram based texture features demonstrated the highest standardized regression coefficients for each model. CONCLUSION: MRI texture analysis features were significantly associated with ground-truth subchondral bone histomorphometry at the tibial plateau. PMID- 27986621 TI - The association of pre-operative body pain diagram scores with pain outcomes following total knee arthroplasty. AB - OBJECTIVE: Approximately 20% of total knee arthroplasty (TKA) recipients have suboptimal pain relief. We evaluated the association between pre-surgical widespread body pain and incomplete pain relief following TKA. METHOD: This prospective analysis included 241 patients with knee osteoarthritis (OA) undergoing unilateral TKA who completed questionnaires preoperatively and up to 12 months post-operatively. Questionnaires included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale and a body pain diagram. We derived the number of non-index painful body regions from the diagram. We used Poisson regression to determine the association between painful body regions identified preoperatively and both WOMAC pain at follow-up and improvement in pain as defined by the minimal clinically important difference (MCID). RESULTS: Mean subject age was 66 years (SD 9), and 61% were females. Adjusting for age, sex, co-morbid conditions, baseline pain, pain catastrophizing, and mental health, we found that more widespread body pain was associated with a higher likelihood of reporting 12-month WOMAC pain score >15 (relative risk [RR] per painful body region 1.39, 95% CI 1.18-1.63) and a greater likelihood of failing to achieve the MCID (RR 1.47, 95% CI 1.16-1.86).). Pain catastrophizing was an independent predictor of persistent pain and failure to improve by the MCID (RR 3.57, 95% CI 1.73-7.31). CONCLUSIONS: Pre-operative widespread pain was associated with greater pain at 12-months and failure to reach the MCID. Widespread pain as captured by the pain diagram, along with the pain catastrophizing score, may help identify persons with suboptimal TKA outcome. PMID- 27986622 TI - Unique spatiotemporal and dynamic gait compensations in the rat monoiodoacetate injection and medial meniscus transection models of knee osteoarthritis. AB - OBJECTIVE: In rodent osteoarthritis (OA) models, behavioral changes are often subtle and require highly sensitive methods to detect these changes. Gait analysis is one assay that may provide sensitive, quantitative measurement of these behavioral changes. To increase detection sensitivity of gait assessments relative to spatiotemporal gait collection alone, we combined our spatiotemporal and dynamic gait collection systems. Using this combined system, gait was assessed in the rat medial meniscus transection (MMT) model and monoiodoacetate (MIA) injection model of knee OA. DESIGN: 36 male Lewis rats were separated into MMT (n = 8), medial collateral ligament transection (MCLT) (n = 8), skin incision (n = 4), MIA injection (n = 8), and saline injection (n = 8) groups. After initiation of OA, gait data were collected weekly in each group out to 4 weeks. RESULTS: The MMT and MIA injection models produced unique pathologic gait profiles, with MMT animals developing a shuffling gait and MIA injection animals exhibiting antalgic gait. Spatiotemporal changes were also observed in the MMT model at week 1 (P < 0.01), but were not observed in the MIA injection model until week 3 (P < 0.01). Dynamic gait changes were observed in both models as early as 1 week post-surgery (P < 0.01). CONCLUSION: Combined analysis of spatiotemporal and dynamic gait data increased detection sensitivity for gait modification in two rat OA models. Analyzing the combined gait data provided a robust characterization of the pathologic gait produced by each model. Furthermore, this characterization revealed different patterns of gait compensations in two common rat models of knee OA. PMID- 27986623 TI - One-year incidence of prosthetic joint infection in total hip arthroplasty: a cohort study with linkage of the Danish Hip Arthroplasty Register and Danish Microbiology Databases. AB - OBJECTIVE: To examine the trend of Prosthetic Joint Infections (PJI) following primary total hip arthroplasty (THA) and the antimicrobial resistance of the bacteria causing these infections. MATERIALS AND METHODS: We identified a population-based cohort of patients in the Danish Hip Arthroplasty Register (DHR) who had primary THA and received their surgery in Jutland or Funen between 2005 and 2014. We followed the patients until revision, emigration, death, or up to 1 year of follow-up. Data from the DHR were combined with those from microbiology databases, the National Register of Patients, and the Civil Registration System. We estimated the cumulative 1-year incidence of PJI for two 5-year periods; 2005 2009 and 2010-2014. The hazard ratio of PJI as a measure of relative risk after adjusting for multiple risk factors was calculated. RESULTS: Of 48,867 primary THAs identified, 1120 underwent revision within 1 year. Of these, 271 were due to PJI. The incidence of PJI was 0.53% (95% confidence interval (CI): 0.44; 0.63) during 2005-2009 and 0.57% (95% CI: 0.49; 0.67) during 2010-2014. The adjusted relative risk was 1.05 (95% CI: 0.82; 1.34) for the 2010-2014 period vs the 2005 2009 period. The most common micro-organisms identified in the 271 PJI were Staphylococcus aureus (36%) and coagulase-negative staphylococci (CoNS) (33%); others commonly identified included Enterobacteriaceae, enterococci, and streptococci. Antimicrobial resistance to beta-lactams and gentamicin did not change during the study period. CONCLUSION: The risk of PJI within 1-year after primary THA and the antimicrobial resistance of the most prevalent bacteria remained unchanged during the 2005-2014 study period. PMID- 27986624 TI - Ilexgenin A exerts anti-inflammation and anti-angiogenesis effects through inhibition of STAT3 and PI3K pathways and exhibits synergistic effects with Sorafenib on hepatoma growth. AB - Recently, we reported that Ilexgenin A exhibits anti-cancer activities and induces cell arrest. Here, we investigated the effect of Ilexgenin A on the inflammation, angiogenesis and tumor growth of hepatocellular carcinoma (HCC). Our current study revealed that Ilexgenin A significantly inhibited the inflammatory cytokines TNF-alpha and IL-6 levels and downregulated pro-angiogenic factor VEGF production and transcription in HepG2 cells. The underlying mechanism for Ilexgenin A effects appears to be through inhibiting STAT3 and PI3K pathways. Furthermore, we found that not only Ilexgenin A inhibited STAT3 and PI3K pathways in HepG2 cells but also blocked these signaling pathways in HUVECs. Most importantly, by employing two HCC xenografts models - HepG2 and H22, we showed that Ilexgenin A reduced tumor growth and exhibited synergy effect with Sorafenib. ELISA assay, histological analysis and immunohistochemistry examination revealed that the expression of VEGF and MVD was significantly decreased after the treatment with Ilexgenin A and the combination. Moreover, Ilexgenin A could enhance caspase-3/7 activity in vitro and transmission electron microscope indicated that the combination induced evident apoptosis of tumor cells and caused the structural changes of mitochondria in vivo. Although no apparent adverse effects occurred during the treatment period, Sorafenib monotherapy elicited hepatotoxicity for specific expression in the increased level of AST and the ratio of AST/ALT. However, the combination could remedy this adverse effect. In conclusion, the results described in the present study identifies Ilexgenin A as a promising therapeutic candidate that modulates inflammation, angiogenesis, and HCC growth. PMID- 27986625 TI - GZ-793A inhibits the neurochemical effects of methamphetamine via a selective interaction with the vesicular monoamine transporter-2. AB - Lobeline and lobelane inhibit the behavioral and neurochemical effects of methamphetamine via an interaction with the vesicular monoamine transporter-2 (VMAT2). However, lobeline has high affinity for nicotinic receptors, and tolerance develops to the behavioral effects of lobelane. A water-soluble analog of lobelane, R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), also interacts selectively with VMAT2 to inhibit the effects of methamphetamine, but does not produce behavioral tolerance. The current study further evaluated the mechanism underlying the GZ-793A-mediated inhibition of the neurochemical effects of methamphetamine. In contrast to lobeline, GZ-793A does not interact with the agonist recognition site on alpha4beta2* and alpha7* nicotinic receptors. GZ-793A (0.3-100uM) inhibited methamphetamine (5uM)-evoked fractional dopamine release from rat striatal slices, and did not evoke dopamine release in the absence of methamphetamine. Furthermore, GZ-793A (1-100uM) inhibited neither nicotine (30uM)-evoked nor electrical field-stimulation-evoked (100Hz/1min) fractional dopamine release. Unfortunately, GZ-793A inhibited [3H]dofetilide binding to human-ether-a-go-go related gene channels expressed on human embryonic kidney cells, and further, prolonged action potentials in rabbit cardiac Purkinje fibers, suggesting the potential for GZ-793A to induce ventricular arrhythmias. Thus, GZ-793A selectively inhibits the neurochemical effects of methamphetamine and lacks nicotinic receptor interactions; however, development as a pharmacotherapy for methamphetamine use disorders will not be pursued due to its potential cardiac liabilities. PMID- 27986626 TI - Propofol attenuates pancreatic cancer malignant potential via inhibition of NMDA receptor. AB - Propofol is a commonly used intravenous anesthetic, and could attenuate cancer cells malignant potential via inhibiting hypoxia-inducible factor-1alpha (HIF 1alpha) expression. However, the mechanism is still inclusive. In the present study, we mainly focus on the mechanism by which propofol down-regulated HIF 1alpha expression and malignant potential in pancreatic cancer cells. Human pancreatic cancer cells (Miapaca-2 and Panc-1) in vitro and murine pancreatic cancer cell (Panc02) in vivo were used to assess the effect of propofol on vascular endothelial growth factor (VEGF) expression and migration of pancreatic cancer cells. Propofol inhibited cells migration, expression of VEGF and HIF 1alpha, phosphorylation of extracellular regulated protein kinases (ERK), AKT, Ca2+/calmodulin dependent protein kinases II (CaMK II), and Ca2+ concentration in a concentration-dependent manner (5, 25, 50, 100MUM). Furthermore, MK801, an inhibitor of NMDA receptor, and KN93, an inhibitor of CaMK II, could inhibit the expression of VEGF, HIF-1a, p-AKT, p-ERK, p-CaMK II in vitro, growth of tumor and VEGF expression in vivo, which were similar to the effect of propofol. In addition, the anti-tumor effect of propofol could be counteracted by rapastinel, an activator of NMDA receptor. Our study indicated that propofol suppressed VEGF expression and migration ability of pancreatic cancer cells in vitro and in vivo, probably via inhibiting NMDA receptor. PMID- 27986627 TI - A novel and selective melanin-concentrating hormone receptor 1 antagonist ameliorates obesity and hepatic steatosis in diet-induced obese rodent models. AB - Melanin-concentrating hormone (MCH), a cyclic neuropeptide expressed predominantly in the lateral hypothalamus, plays an important role in the control of feeding behavior and energy homeostasis. Mice lacking MCH or MCH1 receptor are resistant to diet-induced obesity (DIO) and MCH1 receptor antagonists show potent anti-obesity effects in preclinical studies, indicating that MCH1 receptor is a promising target for anti-obesity drugs. Moreover, recent studies have suggested the potential of MCH1 receptor antagonists for treatment of non-alcoholic fatty liver disease (NAFLD). In the present study, we show the anti-obesity and anti hepatosteatosis effect of our novel MCH1 receptor antagonist, Compound A. Repeated oral administration of Compound A resulted in dose-dependent body weight reduction and had an anorectic effect in DIO mice. The body weight lowering effect of Compound A was more potent than that of pair-feeding. Compound A also reduced lipid content and the expression level of lipogenesis-, inflammation-, and fibrosis-related genes in the liver of DIO mice. Conversely, intracerebroventricular infusion of MCH caused induction of hepatic steatosis as well as increase in body weight in high-fat diet-fed wild type mice, but not MCH1 receptor knockout mice. The pair-feeding study revealed the MCH-MCH1 receptor system affects hepatic steatosis through a mechanism that is independent of body weight change. Metabolome analysis demonstrated that Compound A upregulated lipid metabolism-related molecules, such as acylcarnitines and cardiolipins, in the liver. These findings suggest that our novel MCH1 receptor antagonist, Compound A, exerts its beneficial therapeutic effect on NAFLD and obesity through a central MCH-MCH1 receptor pathway. PMID- 27986628 TI - Hysteresis losses and specific absorption rate measurements in magnetic nanoparticles for hyperthermia applications. AB - BACKGROUND: Magnetic hysteresis loops areas and hyperthermia on magnetic nanoparticles have been studied with the aim of providing reliable and reproducible methods of measuring the specific absorption rate (SAR). METHODS: The SAR of Fe3O4 nanoparticles with two different mean sizes, and Ni1-xZnxFe2O4 ferrites with 0 <= x <= 0.8 has been measured with three approaches: static hysteresis loops areas, dynamic hysteresis loops areas and hyperthermia of a water solution. For dynamic loops and thermometric measurements, specific experimental setups have been developed, that operate at comparable frequencies (~ 69kHz and ~ 100kHz respectively) and rf magnetic field peak values (up to 100mT). The hyperthermia setup has been fully modelled to provide a direct measurement of the SAR of the magnetic nanoparticles by taking into account the heat exchange with the surrounding environment in non-adiabatic conditions and the parasitic heating of the water due to ionic currents. RESULTS: Dynamic hysteresis loops are shown to provide an accurate determination of the SAR except for superparamagnetic samples, where the boundary with a blocked regime could be crossed in dynamic conditions. Static hysteresis loops consistently underestimate the specific absorption rate but can be used to select the most promising samples. CONCLUSIONS: A means of reliably measure SAR of magnetic nanoparticles by different approaches for hyperthermia applications is presented and its validity discussed by comparing different methods. GENERAL SIGNIFICANCE: This work fits within the general subject of metrological traceability in medicine with a specific focus on magnetic hyperthermia. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editor: Dr. Marie Louise Saboungi and Dr. Samuel D. Bader. PMID- 27986630 TI - Molecular mechanism of lysozyme adsorption onto chemically modified alginate guar gum matrix. AB - The equilibrium isotherms and adsorption kinetics of lysozyme (LZ) on epichlorohydrin (Epi) cross-linked alginate-guar gum (Alg-GG) matrix were studied. Adsorption kinetics followed a pseudo-first-order model while the equilibrium isotherm could be represented by the Freundlich equation. The maximal amount of LZ adsorbed onto this matrix was around 2.4mg per g of hydrated matrix at pH 7.00. The adsorption mechanism was associated to a simple diffusion process with a weak columbic interaction between LZ and the matrix. The presence of NaCl 0.3M induced a total displacement of the LZ from the matrix. Under this condition, the percentage of desorbed protein was 95%. Successive cycles of adsorption-washing-elution were performed and the results showed the reversibility of the process and the usefulness of the method for enzyme purification and separation. A last successful step was carried out for the purification of LZ from egg white as natural source. The model proved to be useful applied as a platform design in the isolation and purification of proteins. PMID- 27986631 TI - Internalization properties of the anti-tumor alpha-lactalbumin-oleic acid complex. AB - alpha-Lactalbumin (alpha-LA) can bind oleic acid (OA) to form the anti-tumor alpha-LA-OA complex. Previous studies suggested alpha-LA-OA induced apoptosis or autophagy in an independent way. Furthermore, as a large molecule, alpha-LA-OA could enter tumor cells and accumulated in the nucleus, which was speculated as the basis of its anti-tumor activity. In this study, we evaluated the internalization property of alpha-LA-OA with and without endocytosis inhibitors using flow cytometry and laser scanning confocal microscopy. It was shown alpha LA-OA transported from the cell membrane to the cytoplasm, then accumulated around the nucleus, which consequently began to shrink and condense. The alpha-LA component only located in the membrane whereas the OA component entered cytoplasm. When pre-treated cells with these inhibitors, the internalization of OA would all decrease while the interaction of alpha-LA with membrane did not influence. As for the complex, the internalization of alpha-LA-OA was completely blocked at 4 degrees C and significantly decreased in the presence of cytochalasin D, an inhibitor of phagocytosis (p<0.01). In conclusion, the anti tumor activity of alpha-LA-OA was mainly dependent on the OA component whereas the internalization mechanism was related to the alpha-LA component to be temperature-dependent and have a close relationship with the phagocytosis pathway. PMID- 27986632 TI - Structural insight into mode of binding of Meropenem to CTX-M-15 type beta lactamase. AB - Among Enterobacteriaceae, CTX-M type extended spectrum beta lactamase confers potent hydrolytic activity against cephalosporin group of antibiotics. Strains producing CTX-M type beta lactamase enzymes, show high level of resistance against cefotaxime. Therefore carbapenem antibiotics are used against beta lactamase producing strains. Hence, this study was designed to understand an insight of molecular basis of CTX-M-15 interaction with meropenem, and its effect on CTX-M-15 efficiency. Clinical strain of Enterobacter cloacae (EC-15) was used to clone blaCTX-M-15 gene in E.coli BL21cells. The protein was then expressed and purified. Results showed that CTX-M-15 producing strains are susceptible to meropenem. It quenches the fluorescence of CTX-M-15 spontaneously with binding constant of the order of 103M-1. Meropenem binds on the active site of CTX-M-15, hydrogen bonded with four common amino acid residues of cefotaxime binding site, as revealed by molecular docking studies. Conformational change in the structure of CTX-M-15 was observed upon meropenem binding by CD spectroscopy. The catalytic efficiency of CTX-M-15 was decreased up to 4 times upon meropenem binding. Docking study shows that few amino acids of active site of enzyme are also involved in meropenem binding, hence substrate is difficult to bind on active site properly and does not get hydrolysed. Moreover, meropenem binding induces structural changes in CTX-M-15, making the enzyme less efficient. PMID- 27986629 TI - Circulating miRNAs and miRNA shuttles as biomarkers: Perspective trajectories of healthy and unhealthy aging. AB - Human aging is a lifelong process characterized by a continuous trade-off between pro-and anti-inflammatory responses, where the best-adapted and/or remodeled genetic/epigenetic profile may develop a longevity phenotype. Centenarians and their offspring represent such a phenotype and their comparison to patients with age-related diseases (ARDs) is expected to maximize the chance to unravel the genetic makeup that better associates with healthy aging trajectories. Seemingly, such comparison is expected to allow the discovery of new biomarkers of longevity together with risk factor for the most common ARDs. MicroRNAs (miRNAs) and their shuttles (extracellular vesicles in particular) are currently conceived as those endowed with the strongest ability to provide information about the trajectories of healthy and unhealthy aging. We review the available data on miRNAs in aging and underpin the evidence suggesting that circulating miRNAs (and cognate shuttles), especially those involved in the regulation of inflammation (inflamma miRs) may constitute biomarkers capable of reliably depicting healthy and unhealthy aging trajectories. PMID- 27986633 TI - Unraveling the interaction of hemoglobin with a biocompatible and cleavable oxy diester-functionalized gemini surfactant. AB - Surfactant-protein mixtures have attracted considerable research interest in recent years at the interface of chemical biology and medicinal chemistry. Herein, the interaction between a green gemini surfactant (C16-E2O-C16) and a redox protein hemoglobin was examined through a series of in vitro experimental techniques with an attempt to provide a comprehensive knowledge of the surfactant protein binding interactions. Quantitative appraisal of the fluorescence/CV data showed that the binding of C16-E2O-C16 to Hb leads to the formation of thermodynamically favorable non-covalent adduct with 1:1 stoichiometry. UV-vis spectra demonstrated that the effect of C16-E2O-C16 on Hb is highly concentration dependent. Far-UV and near-UV CD spectra together elucidated the formation of molten globule state of Hb upon C16-E2O-C16 addition. Temperature dependent CD explicated the effect of C16-E2O-C16 on the thermal stability of Hb. Furthermore, the structural investigation of Hb via pyrene/synchronous/three-dimensional fluorescence and FT-IR spectroscopy provided the complementary information related to its microenvironmental and conformational changes. Computational studies delineated that C16-E2O-C16 binds in the vicinity of beta-37 Trp at the alpha1beta2 interface of Hb. Overall, this study is expected to clarify the binding mechanism between Hb/other congeners and surfactant at the molecular level that are known to have immense potential in biomedical and industrial areas. PMID- 27986634 TI - Novel interacting proteins identified by tandem affinity purification coupled to nano LC-MS/MS interact with ribosomal S6 protein kinase 4 (RSK4) and its variant protein (RSK4m). AB - Ribosomal S6 protein kinase 4 (RSK4) is an important novel tumor suppressor that inhibits breast cancer cell growth and induces senescence. However, RSK4m, which is a variant of RSK4 resulting from alternative splicing, may play distinct roles in some aspects. Knowledge about the mechanisms of RSK4 or RSK4m activity has been lacking. Analysis of the RSK4 and RSK4m interactome could provide insight into their specific functions and integrative mechanisms. Using tandem affinity purification, we obtained protein complexes that interacted with RSK4 or RSK4m. Mass spectrum analysis was performed to identify the obtained protein complexes, and bioinformatics analysis was performed. In this study, we isolated and identified 82 RSK4-associated proteins and 137 RSK4m-associated proteins using two STREP II and a single Flag tag-based tandem affinity purification (SF-TAP) coupled with nano LC-MS/MS in MDA-MB-231 cells. Gene Ontology and Ingenuity Pathway Analysis analyses provided functional annotations and protein-protein interaction networks of the protein interactome of RSK4 and RSK4m. Functional annotations of these proteins by bioinformatics analyses highlight the essential role of RSK4 and RSK4m in coordination with their interacting partners to mediate multiple biological processes, especially cell senescence. Moreover, after comparing the interactome of RSK4 and RSK4m, we found that RSK4m is involved in more molecular functions than RSK4. PMID- 27986635 TI - Electrophysiological correlates of motion extrapolation: An investigation on the CNV. AB - Motion extrapolation (ME), the ability to estimate the current position of moving objects hidden by an occluder, is critical to interact with a dynamic environment. In a typical paradigm, participants estimate time to contact (TTC) by pressing a button when they estimate the occluded moving target reaches a certain cue. Research using this paradigm has shown that motion adaptation of the occluded area produces a shift in the TTC estimate (Gilden et al., 1995). We examined the effect of motion adaptation on the contingent negative variation (CNV), a frontal electrophysiological component (Tecce, 1972) that could reflect the activity of an accumulator (Buhusi and Meck, 2005) for time processing. We predicted that longer TTC estimates due to previous visual motion adaptation would result in a larger CNV because the accumulator can collect more time units. Results showed that motion adaptation actually modulates the CNV, but the CNV amplitude did not correlate with TTC duration, falsifying the accumulator hypothesis. We suggest that motion adaptation interferes with the remembered speed (stored during the visible part of the trajectory) that may be used as input by higher cognitive function to guide the temporal update of target position, regardless of the TTC estimate. PMID- 27986636 TI - Sleep duration moderates the association between insula activation and risky decisions under stress in adolescents and adults. AB - Insufficient sleep has been associated with increased risk-taking and poor decision-making, enhanced physiological responses to stress, and attenuated anterior insula (AI) activity to risk. The AI has also been linked to risky decision-making under acute stress. However, it is yet unknown how naturalistic sleep habits affect risky decision-making and AI activity when individuals feel stressed. In the current study, a daily diary approach was used to document participants' daily stress. Adolescents and adults reported their recent sleep duration and completed two fMRI visits during which they performed a risky decision-making task: once each when they endorsed a high and low level of stress. Results revealed that, regardless of age, individuals who reported receiving more sleep took fewer non-advantageous risks during high stress relative to those who reported receiving fewer hours of sleep per night while sleep duration was not associated with risky behavior under low stress. Among individuals who reported less sleep, those who exhibited reduced AI activation during risk-taking under high stress also took more disadvantageous risks whereas this effect was attenuated for those who reported longer sleep duration. Moreover, longer sleep duration was associated with greater functional coupling between the AI and dorsolateral prefrontal cortex (DLPFC) under high stress whereas sleep duration was not associated with AI-DLPFC functional coupling under low stress. These findings suggest that naturalistic sleep duration may amplify the effects of daily stress and alter risky decision-making behavior through interactions with the AI. PMID- 27986637 TI - New insights into insight: Neurophysiological correlates of the difference between the intrinsic "aha" and the extrinsic "oh yes" moment. AB - Insight refers to a situation in which a problem solver immediately changes his understanding of a problem situation. This representational change can either be triggered by external stimuli, like a hint or the solution itself, or by internal solution attempts. In the present paper, the differences and similarities between these two phenomena, namely "extrinsic" and "intrinsic" insight, are examined. To this end, electroencephalogram (EEG) is recorded while subjects either recognize or generate solutions to German verbal compound remote associate problems (CRA). Based on previous studies, we compare the alpha power prior to insightful solution recognition with the alpha power prior to insightful solution generation. Results show that intrinsic insights are preceded by an increase in alpha power at right parietal electrodes, while extrinsic insights are preceded by a respective decrease. These results can be interpreted in two ways. In consistency with other studies, the increase in alpha power before intrinsic insights can be interpreted as an increased internal focus of attention. Accordingly, the decrease in alpha power before extrinsic insights may be associated with a more externally oriented focus of attention. Alternatively, the increase in alpha power prior to intrinsic insights can be interpreted as an active inhibition of solution-related information, while the alpha power decrease prior to extrinsic insights may reflect its activation. Regardless of the interpretation, the results provide strong evidence that extrinsic and intrinsic insight differ on the behavioral as well as the neurophysiological level. PMID- 27986638 TI - The immune properties of Manduca sexta transferrin. AB - Transferrins are secreted proteins that bind iron. The well-studied transferrins are mammalian serum transferrin, which is involved in iron transport, and mammalian lactoferrin, which functions as an immune protein. Lactoferrin and lactoferrin-derived peptides have bactericidal activity, and the iron-free form of lactoferrin has bacteriostatic activity due to its ability to sequester iron. Insect transferrin is similar in sequence to both serum transferrin and lactoferrin, and its functions are not well-characterized; however, many studies of insect transferrin indicate that it has some type of immune function. The goal of this study was to determine the specific immune functions of transferrin from Manduca sexta (tobacco hornworm). We verified that transferrin expression is upregulated in response to infection in M. sexta larvae and determined that the concentration of transferrin in hemolymph increases from 2 MUM to 10 MUM following an immune challenge. It is also present in molting fluid and prepupal midgut fluid, two extracellular fluids with immune capabilities. No immune induced proteolytic cleavage of transferrin in hemolymph was observed; therefore, M. sexta transferrin does not appear to be a source of antimicrobial peptides. Unlike iron-saturated lactoferrin, iron-saturated transferrin had no detectable antibacterial activity. In contrast, 1 MUM iron-free transferrin inhibited bacterial growth, and this inhibition was blocked by supplementing the culture medium with 1 MUM iron. Our results suggest that M. sexta transferrin does not have bactericidal activity, but that it does have a bacteriostatic function that depends on its iron sequestering ability. This study supports the hypothesis that insect transferrin participates in an iron withholding strategy to protect insects from infectious bacteria. PMID- 27986639 TI - Identification of the binding domains and key amino acids for the interaction of the transcription factors BmPOUM2 and BmAbd-A in Bombyx mori. AB - The transcription factor BmPOUM2 interacted with another transcription factor BmAbd-A to regulate the expression of the wing cuticle protein gene BmWCP4 in Bombyx mori. In this study, the binding domains and amino acids for the interaction between BmPOUM2 and BmAbd-A were reported. Two isoforms of BmPOUM2 were identified. The short isoform (BmPOUM2-S) lacks a 114-amino acid sequence containing a POU-homeodomain and a nuclear localization signal peptide (NLS), as compared to the full-length isoform (BmPOUM2). Both BmPOUM2 and BmPOUM2-S proteins bound to the BmAbd-A through the POU-specific domain. When the six amino acids (Lys166, Gly173, Gln176, Ser192, Glu200 and Asn208) that are highly conserved in POU family genes were mutated, BmPOUM2 did not bind to BmAbd-A. BmAbd-A interacted with BmPOUM2 by the homeobox domain or the LCR2 (low complexity region) domain. When seven amino acids (Phe156/248, His158/250, Ala175/263, Cys180/265, Glu190/268, Trp196/274 and Val214/289) that are shared in the homeobox and LCR2 domains were mutated, BmAbd-A did not bind to BmPOUM2. Overexpression of either BmPOUM2 or BmAbd-A or both increased the activity of BmWCP4 promoter in CHO cells. ChIP assay and EMSA showed that BmAbd-A protein bound to the Hox cis-regulatory element in the BmWCP4 promoter, while the BmPOUM2 bound to the nearby POU CRE. A model for the interaction and action of BmPOUM2 and BmAbd-A in regulation of the BmWCP4 expression is proposed. PMID- 27986640 TI - Microscopic observations show invasion of inflammatory cells in the limb blastema and epidermis in pre-metamorphic frog tadpoles which destroy the Apical Epidermal CAP and impede regeneration. AB - Some limb regeneration in tadpoles of Rana dalmatina occurs at stages 44-48 when small hind-limbs are present while scarring occurs at stages 51-52 when forelimbs have developed and metamorphosis is approaching. Ultrastructural analysis of cells forming the regenerating blastema detects mesenchymal cells and an Apical Epidermal Cap (AEC) in regenerating limb blastema 5-6 days post-amputation at stages 46-48. In contrast, granulocytes and numerous macrophages and lymphocytes prevail over mesenchymal cells in limb blastema at stages 51-52, which are destined to form scars. An increase in inflammatory cells in limb blastema prior to metamorphosis suggests a negative influence of immune cells on limb regeneration. Inflammatory cells invade the apical wound epidermis where stem keratinocytes are likely destroyed, impeding the formation of an AEC, the microregion which leads to limb regeneration. The invasion of immune cells, however, may also represent a physiological consequence of the death of cell populations in the tadpoles occurring with approaching metamorphosis. The passage from an aquatic to a terrestrial life in this frog elicits the typical amniote scarring reaction after wounding, and the limb cannot regenerate. The present observations sustain the hypothesis that the evolution of the adaptive immunity in tetrapods while efficiently preserving adult self-condition, determined the loss of tissue regeneration since the embryonic antigens evocated in blastema cells are removed by immune cells of the adult. PMID- 27986641 TI - Implementation of clinical references for undergraduates in anatomy. AB - This study evaluates the implementation of clinical references in undergraduate medical education. For this purpose, images of typical diagnostic, intraoperative and clinical findings were integrated into two different teaching formats and adapted to the learning objectives of the Institute of Anatomy in Leipzig. Paper based questionnaires were used to evaluate the status quo (without clinical images) and the optimal time of implementation, as well as the benefit for the students of human medicine. Three test groups were drawn from two preclinical semesters (2014 and 2015). The first group in 2014 represents the control group, which did not have any image-supported clinical references but only defined learning objectives regarding the five exams in special anatomy. Primary implementation took place in the dissection course (second semester) as automatically running Power Point presentations while secondary implementation was during one of the five clinical seminars within the fourth semester. All groups were asked to evaluate the pros and cons through a self-developed paper based questionnaire. The analysis was performed employing Microsoft Excel and SPSS. It has been demonstrated that most of the students welcome and appreciate the implementation of appropriate images as a valuable support in understanding clinical references. On the contrary, the dissection course did not seem to be the right time for this implementation. In keeping with previous studies, the important role of anatomy in medical education was outlined. A close collaboration between preclinical and clinical physicians concerning educational matters was presented. Considering these approaches, high-quality and sustainable education can be provided. Better patient care and education of young academics should be the motivation. PMID- 27986642 TI - Anatomic characteristics of the mitral isthmus region: The left atrial appendage isthmus as a possible ablation target. AB - The mitral isthmus is a part of the postero-inferior area of the lateral left atrial wall located between the mitral annulus and the left inferior pulmonary vein ostium. Linear ablation lesions are created within the mitral isthmus for the invasive treatment of left atrial arrhythmias. However, the anatomy of this region is not fully understood. The aim of this study has been to provide a detailed morphometric description of the mitral isthmus region and to propose another possible isthmus within the investigated heart area that may serve as a potential new ablation target. Two hundred autopsied, non-atrial fibrillation hearts (23.5% deriving from females) whose donors were a mean of 47.6+/-17.6years old were investigated. We macroscopically assessed the anatomy of the postero inferior area of the lateral left atrial wall. The mean mitral isthmus length was 28.8+/-7.0mm and was significantly longer than the left atrial appendage (LAA) isthmus (14.2+/-4.8mm) (p=.00). The distance between the LAA orifice and the left inferior pulmonary vein ostium (18.4+/-4.8mm) was longer than the LAA isthmus (p=.00) and shorter than the mitral isthmus (p=.00). The LAA isthmus was longer in hearts with a common left pulmonary vein (p=.037). In 65.5% of all cases the area between the right and left mitral isthmus lines was completely smooth. In the remaining hearts, crevices and diverticula (18.0%), intertrabecular recesses (7.0%), trabecular bridges (3.5%), or co-existence of these structures (6%) could be observed. The LAA isthmus line was smooth in 95.5% of all cases, with only small crevices in the remaining 4.5%. In conclusion, regardless of the anatomical variants of the left-sided pulmonary veins, the mitral isthmus area is quite uniform in size. The LAA isthmus is considerably shorter than the mitral isthmus. The mitral isthmus line has many unwanted structures that may entrap the catheter, which is not the case for the LAA isthmus. We proposed the LAA isthmus line for potential clinical use. PMID- 27986643 TI - Cigarette smoke extracts induce overexpression of the proto-oncogenic gene interleukin-13 receptor alpha2 through activation of the PKA-CREB signaling pathway to trigger malignant transformation of lung vascular endothelial cells and angiogenesis. AB - Cigarette smoking is a major cause of lung cancer. Tumor-associated endothelial cells (TAECs) play important roles in tumor angiogenesis and metastasis. However, whether cigarette smoking can trigger genesis of lung TAECs has not been reported yet. In the current study, we used lung endothelial cell (EC) lines as a model to study the pathological effect of cigarette smoke extracts (CSEs) on human lung ECs, and found that a lower dose of 4% CSEs obviously caused abnormal morphological changes in ECs, increased the permeability of endothelial monolayer, while a higher concentration of 8% CSEs caused EC apoptosis. Strikingly, CSEs induced a 117-fold overexpression of a pro-tumorigenic interleukin-13 receptor alpha2 gene (IL-13Ralpha2, also named as CT-19) through activation of the protein kinase A (PKA) and cAMP response element-binding protein (CREB) signaling pathway. A PKA specific inhibitor H89 completely abolished CSEs-induced IL-13Ralpha2 overexpression. The overexpression of IL 13Ralpha2 in lung ECs significantly increased the tumorigenic, migratory, and angiogenic capabilities of the cells, suggesting that IL-13Ralpha2 promotes genesis of lung TAECs. Together, our data show that CSEs activate the PKA, CREB, and IL-13Ralpha2 axis in lung ECs, and IL-13Ralpha2 promotes the malignant transformation of lung ECs and genesis of TAECs with robust angiogenic and oncogenic capabilities. Our study provides new insight into the mechanism of CSEs triggered lung cancer angiogenesis and tumorigenesis, suggesting that the PKA CREB-IL-13Ralpha2 axis is a potential target for novel anti-lung tumor angiogenesis and anti-lung cancer drug discovery. PMID- 27986645 TI - Cardiopulmonary Resuscitation Training by Avatars: A Qualitative Study of Medical Students' Experiences Using a Multiplayer Virtual World. AB - BACKGROUND: Emergency medical practices are often team efforts. Training for various tasks and collaborations may be carried out in virtual environments. Although promising results exist from studies of serious games, little is known about the subjective reactions of learners when using multiplayer virtual world (MVW) training in medicine. OBJECTIVE: The objective of this study was to reach a better understanding of the learners' reactions and experiences when using an MVW for team training of cardiopulmonary resuscitation (CPR). METHODS: Twelve Swedish medical students participated in semistructured focus group discussions after CPR training in an MVW with partially preset options. The students' perceptions and feelings related to use of this educational tool were investigated. Using qualitative methodology, discussions were analyzed by a phenomenological data driven approach. Quality measures included negotiations, back-and-forth reading, triangulation, and validation with the informants. RESULTS: Four categories characterizing the students' experiences could be defined: (1) Focused Mental Training, (2) Interface Diverting Focus From Training, (3) Benefits of Practicing in a Group, and (4) Easy Loss of Focus When Passive. We interpreted the results, compared them to findings of others, and propose advantages and risks of using virtual worlds for learning. CONCLUSIONS: Beneficial aspects of learning CPR in a virtual world were confirmed. To achieve high participant engagement and create good conditions for training, well-established procedures should be practiced. Furthermore, students should be kept in an active mode and frequent feedback should be utilized. It cannot be completely ruled out that the use of virtual training may contribute to erroneous self-beliefs that can affect later clinical performance. PMID- 27986644 TI - Guidelines for Developing and Reporting Machine Learning Predictive Models in Biomedical Research: A Multidisciplinary View. AB - BACKGROUND: As more and more researchers are turning to big data for new opportunities of biomedical discoveries, machine learning models, as the backbone of big data analysis, are mentioned more often in biomedical journals. However, owing to the inherent complexity of machine learning methods, they are prone to misuse. Because of the flexibility in specifying machine learning models, the results are often insufficiently reported in research articles, hindering reliable assessment of model validity and consistent interpretation of model outputs. OBJECTIVE: To attain a set of guidelines on the use of machine learning predictive models within clinical settings to make sure the models are correctly applied and sufficiently reported so that true discoveries can be distinguished from random coincidence. METHODS: A multidisciplinary panel of machine learning experts, clinicians, and traditional statisticians were interviewed, using an iterative process in accordance with the Delphi method. RESULTS: The process produced a set of guidelines that consists of (1) a list of reporting items to be included in a research article and (2) a set of practical sequential steps for developing predictive models. CONCLUSIONS: A set of guidelines was generated to enable correct application of machine learning models and consistent reporting of model specifications and results in biomedical research. We believe that such guidelines will accelerate the adoption of big data analysis, particularly with machine learning methods, in the biomedical research community. PMID- 27986646 TI - Investigation of the Association Between Alcohol Outlet Density and Alcohol Related Hospital Admission Rates in England: Study Protocol. AB - BACKGROUND: Availability of alcohol is a major policy issue for governments, and one of the availability factors is the density of alcohol outlets within geographic areas. OBJECTIVE: The aim of this study is to investigate the association between alcohol outlet density and hospital admissions for alcohol related conditions in a national (English) small area level ecological study. METHODS: This project will employ ecological correlation and cross-sectional time series study designs to examine spatial and temporal relationships between alcohol outlet density and hospital admissions. Census units to be used in the analysis will include all Lower and Middle Super-Output Areas (LSOAs and MSOAs) in England (53 million total population; 32,482 LSOAs and 6781 MSOAs). LSOAs (approximately 1500 people per LSOA) will support investigation at a fine spatial resolution. Spatio-temporal associations will be investigated using MSOAs (approximately 7500 people per MSOA). The project will use comprehensive coverage data on alcohol outlets in England (from 2003, 2007, 2010, and 2013) from a commercial source, which has estimated that the database includes 98% of all alcohol outlets in England. Alcohol outlets may be classified into two broad groups: on-trade outlets, comprising outlets from which alcohol can be purchased and consumed on the premises (eg, pubs); and off-trade outlets, in which alcohol can be purchased but not consumed on the premises (eg, off-licenses). In the 2010 dataset, there are 132,989 on-trade and 51,975 off-trade outlets. The longitudinal data series will allow us to examine associations between changes in outlet density and changes in hospital admission rates. The project will use anonymized data on alcohol-related hospital admissions in England from 2003 to 2013 and investigate associations with acute (eg, admissions for injuries) and chronic (eg, admissions for alcoholic liver disease) harms. The investigation will include the examination of conditions that are wholly and partially attributable to alcohol, using internationally standardized alcohol-attributable fractions. RESULTS: The project is currently in progress. Results are expected in 2017. CONCLUSIONS: The results of this study will provide a national evidence base to inform policy decisions regarding the licensing of alcohol sales outlets. PMID- 27986647 TI - IDEAS (Integrate, Design, Assess, and Share): A Framework and Toolkit of Strategies for the Development of More Effective Digital Interventions to Change Health Behavior. AB - Developing effective digital interventions to change health behavior has been a challenging goal for academics and industry players alike. Guiding intervention design using the best combination of approaches available is necessary if effective technologies are to be developed. Behavioral theory, design thinking, user-centered design, rigorous evaluation, and dissemination each have widely acknowledged merits in their application to digital health interventions. This paper introduces IDEAS, a step-by-step process for integrating these approaches to guide the development and evaluation of more effective digital interventions. IDEAS is comprised of 10 phases (empathize, specify, ground, ideate, prototype, gather, build, pilot, evaluate, and share), grouped into 4 overarching stages: Integrate, Design, Assess, and Share (IDEAS). Each of these phases is described and a summary of theory-based behavioral strategies that may inform intervention design is provided. The IDEAS framework strives to provide sufficient detail without being overly prescriptive so that it may be useful and readily applied by both investigators and industry partners in the development of their own mHealth, eHealth, and other digital health behavior change interventions. PMID- 27986648 TI - Associations between maternal characteristics and women's responses to acupuncture during labour: a secondary analysis from a randomised controlled trial. AB - BACKGROUND: Patient characteristics are modulators of pain experience after acupuncture treatment for chronic pain. Whether this also applies to labour pain is unknown. AIM: To examine for associations between maternal characteristics and response to acupuncture in terms of labour pain intensity in close proximity to the treatment (within 60 min) and over a longer time period (up to 240 min), and whether or not epidural analgesia is used, before and after adjustment for obstetric status upon admission to the labour ward. METHODS: Cohort study (n=253) using data collected for a randomised controlled trial. Associations were examined using linear mixed models and logistic regression analyses. Tests of interactions were also applied to investigate whether maternal characteristics were influenced by treatment group allocation. RESULTS: In close proximity to the treatment, advanced age and cervical dilation were associated with lower pain scores (mean difference (MD) -13.2, 95% CI -23.4 to -2.9; and MD -5.0, 95% CI 9.6 to -0.5, respectively). For the longer time period, labour pain was negatively associated with age (MD -11.8, 95% CI -19.6 to -3.9) and positively associated with dysmenorrhoea (MD 5.5, 95% CI 1.6 to 9.5). Previous acupuncture experience and advanced cervical dilatation were associated with higher and lower use of epidural analgesia (OR 2.7, 95% CI 1.3 to 5.9; and OR 0.3, 95% CI 0.1 to 0.5, respectively). No interactions with treatment allocation were found. CONCLUSIONS: This study did not identify any maternal characteristics associated with women's responses to acupuncture during labour. TRIAL REGISTRATION NUMBER: NCT01197950; Post-results. PMID- 27986649 TI - CQC demands improvement at London hospital where mothers "could leave with wrong baby". PMID- 27986650 TI - Editorial authors' reply to Barlow. PMID- 27986652 TI - Authors' reply to Perol and colleagues. PMID- 27986653 TI - Can a reduced-intensity conditioning regimen cure blastic plasmacytoid dendritic cell neoplasm? PMID- 27986651 TI - Effects of PCSK9 Inhibition With Alirocumab on Lipoprotein Metabolism in Healthy Humans. AB - BACKGROUND: Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known whether inhibition of PCSK9 has any effects on very low-density lipoprotein or intermediate-density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma lipoprotein (a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors in the clearance of Lp(a), is poorly defined, and no mechanistic studies of the Lp(a) lowering by alirocumab in humans have been published to date. METHODS: Eighteen (10 F, 8 mol/L) participants completed a placebo-controlled, 2-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCRs) and production rates (PRs) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides and apoB48 levels were measured. RESULTS: Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was caused by an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was due to a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of very low-density lipoproteins-apoB and very low-density lipoproteins triglycerides or on postprandial plasma triglycerides or apoB48 concentrations. CONCLUSIONS: Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs and decreasing LDL-apoB PR. These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition. The increase in apo(a) FCR during alirocumab treatment suggests that increased LDL receptors may also play a role in the reduction of plasma Lp(a). CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01959971. PMID- 27986656 TI - Response to: 'Why CAPS criteria are not diagnostic criteria?' by Landewe and van der Heijde. PMID- 27986654 TI - Association of Weight Change after Colorectal Cancer Diagnosis and Outcomes in the Kaiser Permanente Northern California Population. AB - BACKGROUND: Higher body mass index (BMI) is associated with incident colorectal cancer but not consistently with colorectal cancer survival. Whether weight gain or loss is associated with colorectal cancer survival is largely unknown. METHODS: We identified 2,781 patients from Kaiser Permanente Northern California diagnosed with stages I-III colorectal cancer between 2006 and 2011 with weight and height measurements within 3 months of diagnosis and approximately 18 months after diagnosis. We evaluated associations between weight change and colorectal cancer-specific and overall mortality, adjusted for sociodemographics, disease severity, and treatment. RESULTS: After completion of treatment and recovery from stage I-III colorectal cancer, loss of at least 10% of baseline weight was associated with significantly worse colorectal cancer-specific mortality (HR 3.20; 95% confidence interval [CI], 2.33-4.39; Ptrend < 0.0001) and overall mortality (HR 3.27; 95% CI, 2.56-4.18; Ptrend < 0.0001). For every 5% loss of baseline weight, there was a 41% increased risk of colorectal cancer-specific mortality (95% CI, 29%-56%). Weight gain was not significantly associated with colorectal cancer-specific mortality (Ptrend = 0.54) or overall mortality (Ptrend = 0.27). The associations were largely unchanged after restricting analyses to exclude patients who died within 6 months and 12 months of the second weight measurement. No significant interactions were demonstrated for weight loss or gain by gender, stage, primary tumor location, or baseline BMI. CONCLUSIONS: Weight loss after diagnosis was associated with worse colorectal cancer-specific mortality and overall mortality. Reverse causation does not appear to explain our findings. IMPACT: Understanding mechanistic underpinnings for the association of weight to worse mortality is important to improving patient outcomes. Cancer Epidemiol Biomarkers Prev; 26(1); 30-37. (c)2016 AACR SEE ALL THE ARTICLES IN THIS CEBP FOCUS SECTION, "THE OBESITY PARADOX IN CANCER EVIDENCE AND NEW DIRECTIONS". PMID- 27986655 TI - Association between Body Mass Index and Cancer Survival in a Pooled Analysis of 22 Clinical Trials. AB - BACKGROUND: Data are inconsistent on the association between body mass index (BMI) at time of cancer diagnosis and prognosis. We used data from 22 clinical treatment trials to examine the association between BMI and survival across multiple cancer types and stages. METHODS: Trials with >=5 years of follow-up were selected. Patients with BMI < 18.5 kg/m2 were excluded. Within a disease, analyses were limited to patients on similar treatment regimens. Variable cutpoint analysis identified a BMI cutpoint that maximized differences in survival. Multivariable Cox regression analyses compared survival between patients with BMI above versus below the cutpoint, adjusting for age, race, sex, and important disease-specific clinical prognostic factors. RESULTS: A total of 11,724 patients from 22 trials were identified. Fourteen analyses were performed by disease site and treatment regimen. A cutpoint of BMI = 25 kg/m2 maximized survival differences. No statistically significant trend across all 14 analyses was observed (mean HR = 0.96; P = 0.06). In no cancer/treatment combination was elevated BMI associated with an increased risk of death; for some cancers there was a survival advantage for higher BMI. In sex-stratified analyses, BMI >= 25 kg/m2 was associated with better overall survival among men (HR = 0.82; P = 0.003), but not women (HR = 1.04; P = 0.86). The association persisted when sex specific cancers were excluded, when treatment regimens were restricted to dose based on body surface area, and when early-stage cancers were excluded. CONCLUSION: The association between BMI and survival is not consistent across cancer types and stages. IMPACT: Our findings suggest that disease, stage, and gender-specific body size recommendations for cancer survivors may be warranted. Cancer Epidemiol Biomarkers Prev; 26(1); 21-29. (c)2016 AACR SEE ALL THE ARTICLES IN THIS CEBP FOCUS SECTION, "THE OBESITY PARADOX IN CANCER EVIDENCE AND NEW DIRECTIONS". PMID- 27986657 TI - The interaction of estrogen and CSE/H2S pathway in the development of atherosclerosis. AB - Both estrogen and hydrogen sulfide (H2S) have been shown to inhibit the development of atherosclerosis. We previously reported that cystathionine gamma lyase knockout (CSE-KO) male mice develop atherosclerosis earlier than male wild type (WT) mice. The present study investigated the interaction of CSE/H2S pathway and estrogen on the development of atherosclerosis in female mice. Plasma estrogen levels were significantly lower in female CSE-KO mice than in female WT mice. NaHS treatment had no effect on plasma estrogen levels in both WT and CSE KO female mice. After CSE-KO and WT female mice were fed with atherogenic diet for 12 wk, plasma lipid levels were significantly increased and triglyceride levels decreased compared with those of control diet-fed mice. Atherogenic diet induced more atherosclerotic lesion, oxidative stress, intracellular adhesion molecule-1 (ICAM-1), and NF-kappaB in CSE-KO mice than in WT mice. Estrogen treatment of atherogenic diet-fed WT mice attenuated hypercholesterolemia, oxidative stress, ICAM-1 expression, and NF-kappaB in WT mice but not in atherogenic diet-fed CSE-KO mice. Furthermore, H2S production in both the liver and vascular tissues was enhanced by estrogen in WT mice but not in CSE-KO mice. It is concluded that the antiatherosclerotic effect of estrogen is mediated by CSE-generated H2S. This study provides new insights into the interaction of H2S and estrogen signaling pathways on the regulation of cardiovascular functions.NEW & NOTEWORTHY Female cystathionine gamma-lyase (CSE)-knockout mice have significantly lower plasma estrogen levels and more severe early atherosclerotic lesion than female wild-type mice. H2S production in liver and vascular tissues is enhanced by estrogen via its stimulatory effect on CSE activity. The antiatherosclerotic effect of estrogen is mediated by CSE-generated H2S. PMID- 27986658 TI - Kvbeta1.1 (AKR6A8) senses pyridine nucleotide changes in the mouse heart and modulates cardiac electrical activity. AB - The present study investigates the physiological role of Kvbeta1 subunit for sensing pyridine nucleotide (NADH/NAD+) changes in the heart. We used Kvbeta1.1 knockout (KO) or wild-type (WT) mice and established that Kvbeta1.1 preferentially binds with Kv4.2 and senses the pyridine nucleotide changes in the heart. The cellular action potential duration (APD) obtained from WT cardiomyocytes showed longer APDs with lactate perfusion, which increases intracellular NADH levels, while the APDs remained unaltered in the Kvbeta1.1 KO. Ex vivo monophasic action potentials showed a similar response, in which the APDs were prolonged in WT mouse hearts with lactate perfusion; however, the Kvbeta1.1 KO mouse hearts did not show APD changes upon lactate perfusion. COS-7 cells coexpressing Kv4.2 and Kvbeta1.1 were used for whole cell patch-clamp recordings to evaluate changes caused by NADH (lactate). These data reveal that Kvbeta1.1 is required in the mediated inactivation of Kv4.2 currents, when NADH (lactate) levels are increased. In vivo, isoproterenol infusion led to increased NADH in the heart along with QTc prolongation in wild-type mice; regardless of the approach, our data show that Kvbeta1.1 recognizes NADH changes and modulates Kv4.2 currents affecting AP and QTc durations. Overall, this study uses multiple levels of investigation, including the heterologous overexpression system, cardiomyocyte, ex vivo, and ECG, and clearly depicts that Kvbeta1.1 is an obligatory sensor of NADH/NAD changes in vivo, with a physiological role in the heart.NEW & NOTEWORTHY Cardiac electrical activity is mediated by ion channels, and Kv4.2 plays a significant role, along with its binding partner, the Kvbeta1.1 subunit. In the present study, we identify Kvbeta1.1 as a sensor of pyridine nucleotide changes and as a modulator of Kv4.2 gating, action potential duration, and ECG in the mouse heart. PMID- 27986659 TI - Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice. AB - Angiotensin-(1-7) [ANG-(1-7)] acts at Mas receptors (MasR) to oppose effects of angiotensin II (ANG II). Previous studies demonstrated that protection of female mice from obesity-induced hypertension was associated with increased systemic ANG (1-7), whereas male obese hypertensive mice exhibited increased systemic ANG II. We hypothesized that MasR deficiency (MasR-/- ) augments obesity-induced hypertension in males and abolishes protection of females. Male and female wild type (MasR+/+ ) and MasR-/- mice were fed a low-fat (LF) or high-fat (HF) diet for 16 wk. MasR deficiency had no effect on obesity. At baseline, male and female MasR-/- mice had reduced ejection fraction (EF) and fractional shortening than MasR+/+ mice. Male, but not female, HF-fed MasR+/+ mice had increased systolic and diastolic (DBP) blood pressures compared with LF-fed controls. In HF-fed females, MasR deficiency increased DBP compared with LF-fed controls. In contrast, male HF-fed MasR-/- mice had lower DBP than MasR+/+ mice. We quantified cardiac function after 1 mo of HF feeding in males of each genotype. HF-fed MasR /- mice had higher left ventricular (LV) wall thickness than MasR+/+ mice. Moreover, MasR+/+ , but not MasR-/- , mice displayed reductions in EF from HF feeding that were reversed by ANG-(1-7) infusion. LV fibrosis was reduced in HF fed MasR+/+ but not MasR-/- ANG-(1-7)-infused mice. These results demonstrate that MasR deficiency promotes obesity-induced hypertension in females. In males, HF feeding reduced cardiac function, which was restored by ANG-(1-7) in MasR+/+ but not MasR-/- mice. MasR agonists may be effective therapies for obesity associated cardiovascular conditions.NEW & NOTEWORTHY MasR deficiency abolishes protection of female mice from obesity-induced hypertension. Male MasR-deficient obese mice have reduced blood pressure and declines in cardiac function. ANG-(1 7) infusion restores obesity-induced cardiac dysfunction of wild-type, but not MasR-deficient, male mice. MasR agonists may be cardioprotective in obese males and females. PMID- 27986661 TI - The JCR:LA-cp rat: a novel rodent model of cystic medial necrosis. AB - Although there are multiple rodent models of the metabolic syndrome, very few develop vascular complications. In contrast, the JCR:LA-cp rat develops both metabolic syndrome and early atherosclerosis in predisposed areas. However, the pathology of the normal vessel wall has not been described. We examined JCR:LA control (+/+) or cp/cp rats fed normal chow diet for 6 or 18 mo. JCR:LA-cp rats developed multiple features of advanced cystic medial necrosis including "cysts," increased collagen formation and proteoglycan deposition around cysts, apoptosis of vascular smooth muscle cells, and spotty medial calcification. These appearances began within 6 mo and were extensive by 18 mo. JCR:LA-cp rats had reduced medial cellularity, increased medial thickness, and vessel hypoxia that was most marked in the adventitia. In conclusion, the normal chow-fed JCR:LA-cp rat represents a novel rodent model of cystic medial necrosis, associated with multiple metabolic abnormalities, vascular smooth muscle cell apoptosis, and vessel hypoxia.NEW & NOTEWORTHY Triggers for cystic medial necrosis (CMN) have been difficult to study due to lack of animal models to recapitulate the pathologies seen in humans. Our study is the first description of CMN in the rat. Thus the JCR:LA-cp rat represents a useful model to investigate the underlying molecular changes leading to the development of CMN. PMID- 27986662 TI - A pathogenic role of complement in arterial hypertension and hypertensive end organ damage. AB - The self-amplifying cascade of messenger and effector molecules of the complement system serves as a powerful danger-sensing system that protects the host from a hostile microbial environment, while maintaining proper tissue and organ function through effective clearance of altered or dying cells. As an important effector arm of innate immunity, it also plays important roles in the regulation of adaptive immunity. Innate and adaptive immune responses have been identified as crucial players in the pathogenesis of arterial hypertension and hypertensive end organ damage. In line with this view, complement activation may drive the pathology of hypertension and hypertensive injury through its impact on innate and adaptive immune responses. It is well known that complement activation can cause tissue inflammation and injury and complement-inhibitory drugs are effective treatments for several inflammatory diseases. In addition to these proinflammatory properties, complement cleavage fragments of C3 and C5 can exert anti-inflammatory effects that dampen the inflammatory response to injury. Recent experimental data strongly support a role for complement in arterial hypertension. The remarkably similar clinical and histopathological features of malignant nephrosclerosis and atypical hemolytic uremic syndrome, which is driven by complement activation, suggest a role for complement also in the development of malignant nephrosclerosis. Herein, we will review canonical and noncanonical pathways of complement activation as the framework to understand the multiple roles of complement in arterial hypertension and hypertensive end organ damage. PMID- 27986663 TI - Syria violence is condemned as evacuation begins. PMID- 27986660 TI - Dendritic cells and isolevuglandins in immunity, inflammation, and hypertension. AB - Hypertension is the major risk factor for morbidity and mortality from myocardial infarction, stroke, heart failure, and chronic kidney disease. Despite its importance, the pathogenesis of essential hypertension is poorly understood. During the past several years, it has become evident that T cells contribute to hypertension. Activated T cells accumulate in the perivascular space and the kidney and release cytokines that promote vascular dysfunction and end-organ damage. Although dendritic cells play a pivotal role in initiating adaptive immune responses, T cells have taken center stage in studies implicating the immune system in the genesis of hypertension. The mechanisms by which T cells are activated and the antigens involved are poorly understood. We recently showed that hypertension is associated with increased dendritic cell production of the TH17 polarizing cytokines, IL-6, IL-1beta, and IL-23. This occurs in part by increased superoxide production via NADPH oxidase and protein modification by highly reactive isolevuglandins (IsoLGs). IsoLGs are produced via the isoprostane pathway of free radical-mediated lipid peroxidation and, when adducted to proteins, have the potential to act as neoantigens. In this review, we discuss recent advances in our understanding of the role of antigen-presenting dendritic cells in the pathophysiology of hypertension and highlight potential neoantigens that may contribute to this disease. PMID- 27986664 TI - Clinical and Microbiological Characteristics of Clostridium difficile Infection Among Hospitalized Children in the Netherlands. AB - BACKGROUND: Little is known about pediatric Clostridium difficile infection (CDI) epidemiology. We describe the clinical and microbiological characteristics of CDI among hospitalized children in the Netherlands. METHODS: Between May 2009 and May 2015, 26 hospitals registered characteristics of pediatric (aged 2-18 years) and adult (aged 18 years) CDI in a national sentinel surveillance study. Routine polymerase chain reaction (PCR) ribotyping and multiple-locus variable-number tandem-repeat analysis (MLVA) of selected strains was performed. Pediatric and adult results were compared using proportion and 95% confidence interval (CI). Time trend of pediatric CDI was evaluated using a mixed-effect Poisson model. RESULTS: Pediatric CDIs were reported in 17 of the 26 participating hospitals (n = 135; 3% of all CDIs); the monthly number was constant over time. The median age of pediatric cases was 10 years (interquartile range, 4.7-14.5 years). Fifty-five percent of the children had community onset and 31% had severe CDI. Compared with adults (n = 4,556), complication and mortality rates were lower. Clostridium difficile PCR ribotype 265 (toxin A negative, B positive) was most prevalent in children (15%; 95% CI, 8.8%-24.0%) but rarely found in adults (1%; 95% CI, 0.9% 1.6%). This strain was rarely found in other countries, except for Belgium. MLVA showed genetic relatedness between three-fourths of pediatric and adult ribotype 265 strains, without a clear epidemiological link. CONCLUSIONS: Pediatric CDI in hospitals has remained stable over the last 6 years and resulted in fewer complications than for adult CDI. Further studies are needed to elucidate the source and epidemiology of PCR ribotype 265, primarily found in children. PMID- 27986665 TI - Risk of Active Tuberculosis in Patients with Cancer: A Systematic Review and Meta Analysis. AB - Background: Cancer is a known risk factor for developing active tuberculosis (TB). We determined the incidence and relative risk of active TB in cancer patients compared to the general population. Methods: Electronic databases were searched up to December 2015: Medline, Medline InProcess, EMBASE, PubMed, the Cochrane Database of Systematic Reviews, Cancerlit, and Web of Science. Studies of pathologically confirmed cancer patients were included if active TB was identified concurrently or after the diagnosis. Cumulative incidence rate/100,000 population (CIR) of new cases of TB occurring in cancer patients and comparative incidence rate ratios (IRR) to the general population from the same country of origin were estimated. A random effect meta-analysis was conducted on the CIR and IRR. Results: A total of 23 studies reporting 593 TB cases occurring in 324,041 cancer patients between 1950 and 2011 were identified. In a meta-analysis of 6 studies conducted in the US in 317,243 cancer patients (98% of all patients) the CIR of active TB decreased by 3 fold and 6.5 fold in hematologic and solid cancers respectively before and after 1980. After 1980 the CIR of active TB was highest in hematologic (219/100,000 population, IRR=26), head and neck (143; 16), lung cancers (83; 9) and was lowest in breast and other solid cancers (38; 4). Conclusions: Individuals living in the US with hematologic, head and neck, and lung cancers had a 9-fold higher rate of developing active TB compared to those without cancer and would benefit from targeted latent TB screening and therapy. PMID- 27986667 TI - Reply to Zavascki and Nation. PMID- 27986668 TI - Universal Mask Policy in the Neonatal Unit to Reduce Respiratory Viral Infections. PMID- 27986666 TI - Congenital Cytomegalovirus Infection: Prognostic Value of Maternal DNAemia at Amniocentesis. AB - BACKGROUND: Human Cytomegalovirus (HCMV) is the most common cause of childhood hearing loss and can lead to neurodevelopmental delay. To date, few studies have examined the correlation between maternal viremia and congenital HCMV infection. The aim of our study was to ascertain if HCMV DNA in the peripheral blood of pregnant women with primary HCMV infection at the time of amniocentesis may have a prognostic value in terms of congenital infection and neonatal symptomatic disease. METHODS: We performed a prospective observational study of pregnant women referred to our maternal-fetal medicine division with suspected HCMV infection. Primary infection was diagnosed based on seroconversion for HCMV and/or HCMV immunoglobulin M-positive and low or moderate HCMV immunoglobulin G avidity. At the time of amniocentesis, maternal blood samples were collected and analyzed by means of real-time polymerase chain reaction to determine the presence of viral DNAemia. Fetuses and newborns were evaluated for the presence of congenital infection and symptomatic disease. RESULTS: A total of 239 pregnant women were enrolled; 32 blood samples (13.4%) were positive, and 207 (86.6%) were negative for HCMV DNA. The overall rate of transmission was 23.4%. Fifteen infected patients (26.8%) were symptomatic. Vertical transmission occurred in 14 women (43.8%) with positive and 42 (20.3%) with negative results for HCMV DNAemia (P = .006; odds ratio, 3.06; 95% confidence interval, 1.41-6.64). Symptomatic infection occurred in 6 (42.9%) infected fetuses or newborns from women with and in 9 (21.4%) from women without viral DNAemia (P = .16). CONCLUSION: Maternal viremia at amniocentesis is associated with a 3-fold greater chance of congenital infection, but it is not correlated with symptomatic disease. PMID- 27986670 TI - Emerging Public Health Challenges of Shiga Toxin-Producing Escherichia coli Related to Changes in the Pathogen, the Population, and the Environment. AB - Emerging public health challenges of Shiga toxin (stx)-producing Escherichia coli (STEC) include the occurrence of more frequent or severe disease and risk factors shifts associated with changes, often interconnected, in the pathogen, the population, and the environment. In 3 outbreaks with heightened severity attributed to enhanced pathogen virulence, including the acquisition of an stx2 phage in 1 outbreak, population and environmental factors likely contributed significantly to disease outcomes. Evolving population risk factors that are associated with more severe disease include consumption of fresh produce, contact with STEC-contaminated environments, demographics, socioeconomic status, and immunity. Risks of increasing STEC environmental pollution are related to continued intensification of agriculture and super-shedder cattle. Mitigation strategies include surveillance and research on emerging STEC, development of effective communications and public education strategies, and improved policies and interventions to mitigate risks, including those related to the contamination of produce and the environment, using a "One Health" approach. PMID- 27986671 TI - Definitions of Complicated Urinary Tract Infection and Pyelonephritis. PMID- 27986672 TI - Reply to Burnham and Vazquez Guillamet. PMID- 27986674 TI - What to Do for the Asymptomatic Pulmonary Coccidioidal Nodule or Cavity in Immunosuppressed Patients? A Focus in the Recent Coccidioidomycosis Guidelines. PMID- 27986669 TI - Risk of Acute Kidney Injury in Patients on Concomitant Vancomycin and Piperacillin-Tazobactam Compared to Those on Vancomycin and Cefepime. AB - BACKGROUND: Recent evidence suggests that among patients receiving vancomycin, receipt of concomitant piperacillin-tazobactam increases the risk of nephrotoxicity. Well-controlled, adequately powered studies comparing rates of acute kidney injury (AKI) among patients receiving vancomycin + piperacillin tazobactam (VPT) compared to similar patients receiving vancomycin + cefepime (VC) are lacking. In this study we compared the incidence of AKI among patients receiving combination therapy with VPT to a matched group receiving VC. METHODS: A retrospective, matched, cohort study was performed. Patients were eligible if they received combination therapy for >=48 hours. Patients were excluded if their baseline serum creatinine was >1.2mg/dL or they were receiving renal replacement therapy. Patients receiving VC were matched to patients receiving VPT based on severity of illness, intensive care unit status, duration of combination therapy, vancomycin dose, and number of concomitant nephrotoxins. The primary outcome was the incidence of AKI. Multivariate modeling was performed using Cox proportional hazards. RESULTS: A total of 558 patients were included. AKI rates were significantly higher in the VPT group than the VC group (81/279 [29%] vs 31/279 [11%]). In multivariate analysis, therapy with VPT was an independent predictor for AKI (hazard ratio = 4.27; 95% confidence interval, 2.73-6.68). Among patients who developed AKI, the median onset was more rapid in the VPT group compared to the VC group (3 vs 5 days P =< .0001). CONCLUSION: The VPT combination was associated with both an increased AKI risk and a more rapid onset of AKI compared to the VC combination. PMID- 27986673 TI - Diabetes Mellitus and Latent Tuberculosis Infection: A Systemic Review and Metaanalysis. AB - Background: Despite the well-documented association between diabetes and active tuberculosis, evidence of the association between diabetes and latent tuberculosis infection (LTBI) remains limited and inconsistent. Methods: We included observational studies that applied either the tuberculin skin test or the interferon gamma release assay for diagnosis of LTBI and that provided adjusted effect estimate for the association between diabetes and LTBI. We searched PubMed and EMBASE through 31 January 2016. The risk of bias of included studies was assessed using a quality assessment tool modified from the Newcastle Ottawa scale. Results: Thirteen studies (1 cohort study and 12 cross-sectional studies) were included, involving 38263 participants. The cohort study revealed an increased but nonsignificant risk of LTBI among diabetics (risk ratio, 4.40; 95% confidence interval [CI], 0.50-38.55). For the cross-sectional studies, the pooled odds ratio from the random-effects model was 1.18 (95% CI, 1.06-1.30), with a small statistical heterogeneity across studies (I2, 3.5%). The risk of bias assessment revealed several methodological issues, but the overall direction of biases would reduce the positive causal association between diabetes and LTBI. Conclusions: Diabetes was associated with a small but statistically significant risk for LTBI. Findings from this review could be used to inform future cost effectiveness analysis on the impact of LTBI screening programs among diabetics. PMID- 27986676 TI - Preexposure Prophylaxis in the United States: An Evolving HIV Prevention Opportunity. PMID- 27986675 TI - Prediction of Congenital Cytomegalovirus Infection in High-Risk Pregnant Women. AB - BACKGROUND: This prospective study aimed to determine maternal clinical, laboratory, and ultrasound findings that effectively predict the occurrence of congenital cytomegalovirus (CMV) infection (CCI) in high-risk pregnant women. METHODS: Three hundred CMV immunoglobulin (Ig) M-positive pregnant women were enrolled. The maternal clinical and laboratory findings, including serum CMV IgM and IgG; IgG avidity index (AI); antigenemia assay (C7-HRP); polymerase chain reaction (PCR) for the detection of CMV-DNA in the maternal serum, urine, and uterine cervical secretion; and prenatal ultrasound findings, were evaluated. To determine predictive factors for the occurrence of CCI, logistic regression analyses were performed. RESULTS: In 22 of the 300 women, CCI was confirmed using PCR for CMV-DNA in newborn urine. Univariate analyses demonstrated that the presence of maternal flu-like symptoms, presence of ultrasound fetal abnormalities, serum titers of CMV IgM, positive results for C7-HRP, CMV IgG AI <40%, and positive PCR results in the uterine cervical secretion were statistically associated with the occurrence of CCI. Multivariable analysis revealed that the presence of ultrasound fetal abnormalities (odds ratio [OR], 31.9; 95% confidence interval [CI], 8.5-120.3; P < .001) and positive PCR results in the uterine cervical secretion (OR, 16.4; 95% CI, 5.0-54.1; P < .001) were independent predictive factors of CCI in CMV IgM-positive women. CONCLUSIONS: This is the first prospective cohort study to suggest that the presence of CMV DNA in the maternal uterine cervical secretion and ultrasound fetal abnormalities are predictive of the occurrence of congenital CMV infection in high-risk pregnant women. PMID- 27986678 TI - Is Plasmodium Species Parasitemia Really Associated With Increased Survival in Ebola Virus-Infected Patients? PMID- 27986677 TI - Thymic Function Impacts the Peripheral CD4/CD8 Ratio of HIV-Infected Subjects. AB - BACKGROUND: The persistence of an inverted CD4/CD8 ratio has been extensively associated with the increased morbimortality of chronic human immunodeficiency virus (HIV)-infected subjects. Thymic function is crucial for the maintenance of T cell homeostasis. We explored the impact of thymic function on the CD4/CD8 ratio of HIV-infected subjects. METHODS: In a cohort of 53 antiretroviral-naive HIV-infected subjects, the measure of thymic volume, as a representative marker for thymic function, was available at baseline and at 12, 24, and 48 weeks post antiretroviral treatment. RESULTS: Baseline thymic volume was associated with the CD4/CD8 ratio ( Rho: = 0.413, P = .002), being this association highly dependent on the CD4 T cell levels. In subjects who achieved undetectable viral load after treatment (n = 33), a higher baseline thymic volume was associated with a higher increase in CD4 T cell counts and a decreasing trend in CD8 T cell counts during follow-up. Moreover, the baseline thymic volume was independently associated with the normalization of the CD4/CD8 ratio after 96 weeks of treatment (odds ratio, 95% confidence interval: 1.95 (1.07-3.55); P = .03). CONCLUSIONS: Our data indicate the relevance of the remaining thymic function before the start of treatment to the CD4/CD8 ratio of HIV- infected subjects and, hence, potentially, in their clinical progression. PMID- 27986679 TI - Prevention and Infection Management in Mechanical Circulatory Support Device Recipients. AB - There are currently no guidelines for the management of infection and its prevention in mechanical circulatory support (MCS) device recipients. The International Society of Heart and Lung Transplantation (ISHLT) has initiated a multidisciplinary collaboration for the creation of a consensus document to guide clinicians in infection prevention and management in MCS patients. Most medical centers use local protocols that are based on expert opinion. MCS recipients are debilitated and have some immunological dysfunction. Over the years there have been technical advancements with smaller devices and drivelines with improved durability. The pulsatile devices have been replaced with newer-generation continuous-flow devices. Patient are living longer with MCSs for bridge to transplant (BTT) and destination therapy (DT). MCS centers have improved patient management by introducing standardized driveline protocols, leading to reduced infection rates among MCS recipients. PMID- 27986680 TI - Reply to Colebunders. PMID- 27986681 TI - HIV-Infected Youths: Transition in Spain Compared to the Netherlands. PMID- 27986682 TI - Long-term Impact of a "3 + 0" Schedule for 7- and 13-Valent Pneumococcal Conjugate Vaccines on Invasive Pneumococcal Disease in Australia, 2002-2014. AB - BACKGROUND: Australia introduced universal 7-valent pneumococcal conjugate vaccine (PCV7) from 2005, replaced by 13-valent PCV (PCV13) in 2011, uniquely among high-income countries giving doses at 2, 4, and 6 months (3 + 0 schedule). Data on impact of a timely 3 + 0 PCV schedule with high coverage are sparse, with none for PCV13. METHODS: We used national surveillance of invasive pneumococcal disease (IPD) from 2002 for baseline and appropriate later comparison periods to calculate incidence rate ratios (IRRs) by serotype and age using a Poisson model. PCV coverage was assessed from the Australian Childhood Immunisation Register. RESULTS: After 9 years of timely 3-dose PCV coverage of >92%, all-age IPD in Australia almost halved (IRR, 0.53; 95% confidence interval [CI], .50-.57), but differed by PCV era. Reductions in IPD due to vaccine serotypes from PCV7 (IRR, 0.20; CI, .17-.22) were about 2-fold greater than for IPD due to extra serotypes in PCV13 (13v-non7v) in a similar period (IRR, 0.58; CI, .51-.66). Post-PCV13 declines in serotype 19A IPD in persons aged <2 years (IRR, 0.23; CI, .13-.35) and >=2 years (IRR, 0.35; CI, .28-.44) differed from other 13v-non7v IPD (IRR, 0.73; CI, .35-1.48 for those aged <2 years and IRR, 0.96; CI, .81-1.15 for those >=2 years). Meningitis due to vaccine serotypes nearly disappeared in children eligible for 3 PCV13 doses. IPD due to non-PCV13 serotypes increased by 30% compared with 76% for non-PCV7 serotypes in equivalent period of vaccine use. CONCLUSIONS: Reductions in vaccine-type IPD post-PCV13 were inferior to Australian experience with PCV7 and reports from high-income countries giving a PCV booster dose. Applicability of findings to other settings would depend on age of IPD onset, serotype profile, and timeliness of vaccination. PMID- 27986683 TI - High Rate of Treatment Failures in Nonimmune Travelers Treated With Artemether Lumefantrine for Uncomplicated Plasmodium falciparum Malaria in Sweden: Retrospective Comparative Analysis of Effectiveness and Case Series. AB - BACKGROUND: Artemisinin-based combination therapy (ACT) is the first-line treatment of Plasmodium falciparum malaria. Since the introduction of artemether lumefantrine (AL) for treatment of uncomplicated malaria in Sweden, treatment failures have been reported in adults. METHODS: A retrospective comparative analysis of treatment regimen for P. falciparum malaria in adults in Stockholm during 2000-2015 was performed to evaluate the effectiveness of AL. Parasite genotyping and drug concentrations were investigated in the AL treatment failures. RESULTS: Among the total 397 P. falciparum episodes, 310 were treated with oral regimen only (95 AL, 162 mefloquine, 36 atovaquone-proguanil [AP], and 17 others), and 87 were administered initial intravenous therapy (38 artesunate and 49 quinine) followed by oral treatments. Five late treatment failures were detected after AL and one slow response to AP. The effectiveness of AL alone was 94.7% (95% confidence interval [CI], 88.1%-98.3%), compared with 99.5% for other oral regimens (P = .003). All AL failures occurred in European men and the effectiveness in this group was only 73.7% (95% CI, 48.8%-90.0%). Genotyping confirmed recrudescence of the initial parasite populations and drug resistance markers revealed no clinically significant resistance patterns. Lumefantrine concentrations suggested subtherapeutic concentrations in at least 2 cases. CONCLUSIONS: Our findings indicate a high rate of symptomatic late treatment failures after 6-dose AL regime in nonimmune adults, especially in men. Our report warrants the need to establish optimal dosing of AL in adults and to alert clinicians about the importance of informing patients regarding the risk of parasites reappearing weeks after AL treatment. PMID- 27986686 TI - Reply to Sainz and Navarro. PMID- 27986687 TI - Low doses of colistimethate: Don't rush in! PMID- 27986685 TI - Partner Bereavement and Risk of Herpes Zoster: Results from Two Population-Based Case-Control Studies in Denmark and the United Kingdom. AB - Background: Psychological stress is commonly thought to increase the risk of herpes zoster by causing immunosuppression. However, epidemiological studies on the topic are sparse and inconsistent. We conducted 2 parallel case-control studies of the association between partner bereavement and risk of zoster using electronic healthcare data covering the entire Danish population and general practices in the UK Clinical Practice Research Datalink. Methods: We included patients with a zoster diagnosis from the primary care or hospital-based setting in 1997-2013 in Denmark (n = 190671) and 2000-2013 in the United Kingdom (n = 150207). We matched up to 4 controls to each case patient by age, sex, and general practice (United Kingdom only) using risk-set sampling. The date of diagnosis was the index date for case patients and their controls. We computed adjusted odds ratios with 99% confidence intervals for previous bereavement among case patients versus controls using conditional logistic regression with results from the 2 settings pooled using random-effects meta-analysis. Results: Overall, the adjusted odds ratios for the association between partner bereavement and zoster were 1.05 (99% confidence interval, 1.03-1.07) in Denmark and 1.01 (.98 1.05) in the United Kingdom. The pooled estimates were 0.72, 0.90, 1.10, 1.08, 1.02, 1.04, and 1.03 for bereavement within 0-7, 8-14, 15-30, 31-90, 91-365, 366 1095, and >1095 days before the index date, respectively. Conclusions: We found no consistent evidence of an increased risk of zoster after partner death. Initial fluctuations in estimates may be explained by delayed healthcare contact due to the loss. PMID- 27986684 TI - MTN-017: A Rectal Phase 2 Extended Safety and Acceptability Study of Tenofovir Reduced-Glycerin 1% Gel. AB - Background: Human immunodeficiency virus (HIV) disproportionately affects men who have sex with men (MSM) and transgender women (TGW). Safe and acceptable topical HIV prevention methods that target the rectum are needed. Methods: MTN-017 was a phase 2, 3-period, randomized sequence, open-label, expanded safety and acceptability crossover study comparing rectally applied reduced-glycerin (RG) 1% tenofovir (TFV) and oral emtricitabine/TFV disoproxil fumarate (FTC/TDF). In each 8-week study period participants were randomized to RG-TFV rectal gel daily, or RG-TFV rectal gel before and after receptive anal intercourse (RAI; or at least twice weekly in the event of no RAI), or daily oral FTC/TDF. Results: MSM and TGW (n = 195) were enrolled from 8 sites in the United States, Thailand, Peru, and South Africa with mean age of 31.1 years (range 18-64). There were no differences in >=grade 2 adverse event rates between daily gel (incidence rate ratio [IRR], 1.09; P = .59) or RAI gel (IRR, 0.90; P = .51) compared to FTC/TDF. High adherence (>=80% of prescribed doses assessed by unused product return and Short Message System reports) was less likely in the daily gel regimen (odds ratio [OR], 0.35; P < .001), and participants reported less likelihood of future daily gel use for HIV protection compared to FTC/TDF (OR, 0.38; P < .001). Conclusions: Rectal application of RG TFV gel was safe in MSM and TGW. Adherence and product use likelihood were similar for the intermittent gel and daily oral FTC/TDF regimens, but lower for the daily gel regimen. Clinical Trials Registration: NCT01687218. PMID- 27986688 TI - Male-to-Female Sexual Transmission of Zika Virus-United States, January-April 2016. AB - We report on 9 cases of male-to-female sexual transmission of Zika virus in the United States occurring January-April 2016. This report summarizes new information about both timing of exposure and symptoms of sexually transmitted Zika virus disease, and results of semen testing for Zika virus from 2 male travelers. PMID- 27986690 TI - Minding the Gap: Specimen Referral Systems for Diagnosis of Infectious Diseases. PMID- 27986692 TI - Train all maternity staff to treat postpartum haemorrhage, say guidelines. PMID- 27986691 TI - Uptake of HIV Preexposure Prophylaxis Among Commercially Insured Persons-United States, 2010-2014. AB - BACKGROUND: Daily, oral use of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) for preexposure prophylaxis (PrEP) is an effective strategy to prevent acquisition of human immunodeficiency virus (HIV) infection. It is important to monitor PrEP uptake at the national level to increase our understanding of trends in its utilization, but national HIV surveillance data do not include PrEP uptake. Our objective was to develop feasible methods to estimate PrEP uptake and to estimate uptake each year among commercially insured persons during 2010-2014. METHODS: We conducted a retrospective analysis of the 2010-2014 MarketScan database, a national sample of persons with commercial health insurance in the United States. We developed an algorithm to identify persons aged >=16 years who were prescribed TDF-FTC for PrEP each year. We generated nationally representative estimates of prevalence of persons prescribed PrEP. RESULTS: We found a significantly increasing trend in the proportion of persons prescribed TDF-FTC for PrEP during the study period, with 417 users in 2010 and 9375 in 2014 (P < .001); 97% of PrEP users were male and 98% lived in metropolitan areas in 2014. During the study period, the numbers of women prescribed PrEP were low. CONCLUSIONS: Our analytic method provides the only feasible means to monitor PrEP uptake in the United States. Although a marked increasing trend in uptake was observed for men, the number of women who used PrEP remained very low during the study period. Interventions are needed to increase PrEP use by women at substantial risk of acquiring HIV infection. PMID- 27986689 TI - HLA-B*57 and IFNL4-related polymorphisms are associated with protection against HIV-1 disease progression in controllers. AB - Background: HIV-1-controllers maintain HIV-1 viremia at low levels (normally <2000 HIV-RNA copies/mL) without antiretroviral treatment. However, some HIV-1 controllers have evidence of immunologic progression with marked CD4+T-cell decline. We investigated host genetic factors associated with protection against CD4+T-cell loss in HIV-1-controllers. Methods: We analysed the association of interferon lambda 4 (IFNL4)-related polymorphisms and HLA-B haplotypes within Long Term Non-Progressor HIV-1-controllers ((LTNP-C), defined by maintaining CD4+T-cells counts >500 cells/mm3 for more than 7 years after HIV-1 diagnosis) versus non-LTNP-C, who developed CD4+T-cells counts <500 cells/mm3 Both a Spanish study cohort (n=140) and an international validation cohort (n=914) were examined. Additionally, in a subgroup of individuals HIV-1-specific T-cell responses and soluble cytokines were analysed RESULTS: HLA-B*57 was independently associated with the LTNP-C phenotype (OR=3.056 (1.029-9.069) p=0.044 and OR=1.924 (1.252-2.957) p=0.003) while IFNL4 genotypes represented independent factors for becoming non-LTNP-C (TT/TT, ss469415590, OR=0.401 (0.171-0.942) p=0.036 or A/A, rs12980275, OR=0.637 (0.434-0.934) p=0.021) in the Spanish and validation cohort, respectively, after adjusting for sex, age at HIV-1 diagnosis, IFNL4-related polymorphisms and different HLA-B haplotypes. LTNP-C showed lower plasma IP-10 (p=0.019) and higher IFN-gamma (p=0.02) levels than the HIV-1-controllers with diminished CD4+T-cell numbers. Moreover, LTNP-C exhibited higher quantities of IL2+CD57- and IFN-gamma+CD57- HIV-1-specific CD8+T-cells (p=0.002 and 0.041, respectively) than non-LTNP-C. Conclusions: We have defined genetic markers able to segregate stable HIV-1-controllers from those who experience CD4+T-cell decline. These findings allow for identification of HIV-1-controllers at risk for immunologic progression, and provide avenues for personalized therapeutic interventions and precision medicine for optimizing clinical care of these individuals. PMID- 27986694 TI - Adhesive arachnoiditis in mixed connective tissue disease: a rare neurological manifestation. AB - The overall incidence of neurological manifestations is relatively low among patients with mixed connective tissue disease (MCTD). We recently encountered a case of autoimmune adhesive arachnoiditis in a young woman with 7 years history of MCTD who presented with severe back pain and myeloradiculopathic symptoms of lower limbs. To the best of our knowledge, adhesive arachnoiditis in an MCTD patient has never been previously reported. We report here this rare case, with the clinical picture and supportive ancillary data, including serology, cerebral spinal fluid analysis, electrophysiological evaluation and spinal neuroimaging, that is, MRI and CT (CT scan) of thoracic and lumbar spine. Her neurological deficit improved after augmenting her immunosuppressant therapy. Our case suggests that adhesive arachnoiditis can contribute to significant neurological deficits in MCTD and therefore requires ongoing surveillance. PMID- 27986693 TI - Cautious use and optimal dose of morphine for relieving malignant pain in a complex patient with multiple comorbidities. AB - Oral morphine remains the drug of choice for the management of severe pain due to cancer as per WHO ladder of analgesia. Providing adequate pain relief in palliative care settings for pain due to cancer is challenging. Options become limited in cases of associated systemic comorbidities such as renal dysfunction, hypoproteinaemia, anaemia. Patients with renal dysfunction and other comorbidities may develop drug overdose due to abnormal pharmacokinetics. Renal dysfunction affects the pharmacokinetics of morphine by altering its absorption, metabolism and clearance. Plasma albumin also influences drug availability, its plasma distribution and thus available free morphine for its clinical effect. Morphine should be used cautiously for the treatment of pain in patients with renal failure, hypoproteinaemia, hyperbilirubinaemia and anaemia. In such patients, alternate opiates like fentanyl, hydromorphone, or oxycodone may be used as these drugs are not significantly excreted by the kidneys. PMID- 27986695 TI - Acute oxygenator failure: a new presentation of heparin-induced thrombocytopenia in a patient undergoing venovenous extracorporeal membrane oxygenation support. AB - A 58-year-old man with medical history of thrombocytopenia was admitted to an outside hospital for a 6-day history of worsening dyspnoea requiring mechanical ventilator support. He was transferred to our institution for extracorporeal membrane oxygenation (ECMO) given his refractory hypoxaemia. On arrival, H1N1 influenza virus was confirmed and all measures to improve oxygenation were ineffective. Thus, the decision was made to start venovenous (VV)-ECMO. Although a low baseline platelet count was recognised (60-70*109/L), a sudden further decrease occurred (30*109/L) and platelet transfusion was initiated. A substantial increase in the pressure across the ECMO oxygenator was identified, and the diagnosis of type II heparin-induced thrombocytopenia was suspected and confirmed. Heparin was discontinued, the oxygenator was exchanged and argatroban was used for anticoagulation. After 28 days on VV-ECMO support, the decision was made to withdraw organ support in conjunction with the patient and family wishes. PMID- 27986696 TI - Uncommon cause for anorexia and weight loss. PMID- 27986697 TI - Does increased duration of consultant presence affect length of hospital stay for unplanned admissions in acute paediatrics?: an observational before-and-after analysis using administrative healthcare data. AB - OBJECTIVES: This study aims to review whether implementation of increased duration of consultant presence is associated with reduction in length of hospital stay (LoS) in children with an unplanned admission to hospital. METHOD DESIGN/SETTING/PARTICIPANTS/INTERVENTIONS/OUTCOME MEASURES: An observational before-and-after study of all unplanned general paediatric admissions to a UK hospital between 1 September 2012 and 31 August 2015, comparing LoS and readmission rates before and after implementation of a policy mandating consultant review within 12 hours of unplanned hospital admission. RESULTS: 5367 inpatient admissions were analysed: 3386 prior to implementation of the policy and 1981 afterwards. There was no significant difference in median LoS between the two groups or in readmission rates at 24 hours, 48 hours or 7 days. However, among children who stayed in hospital for under 24 hours, and those who were discharged with a diagnosis of acute gastroenteritis, consultant review within 12 hours of admission was associated with a shorter LoS-respectively, 16 hours 23 min versus 15 hours 45 min (p=0.01) and 28 hours 46 min versus 19 hours 41 m (p<0.01). CONCLUSIONS: Increased duration of consultant presence was not associated with significant impact on LoS, other than in admissions of brief duration and in gastroenteritis, where diagnosis is based on clinical judgement in the absence of objective diagnostic thresholds. Future studies should focus on whether these results are generalisable across other settings, and other measures of cost-effectiveness of early consultant review, given the major implications on resource and workforce planning of such policies. PMID- 27986698 TI - Does measurement technique explain the mismatch between European head size and WHO charts? AB - OBJECTIVE: To test whether different measuring techniques produce systematic differences in head size that could explain the large head circumferences found in Northern European children compared with the WHO standard. DESIGN: Cross sectional observational study. SETTING: Scotland, UK. PATIENTS: Study 1: 68 healthy children aged 0.4-18 months from mother and baby groups and a medical students teaching session. Study 2: 81 children aged 0.4 to 25 months from hospital wards and neonatal follow-up clinics. INTERVENTIONS: Study 1: heads measured with plastic tape using both the WHO tight and UK loose technique. Study 2: heads measured using WHO research technique and a metal measuring tape and compared with routinely acquired measurements. MAIN OUTCOME MEASURES: Mean difference in head z-scores using WHO standard between the two methods. RESULTS: The tight technique resulted in a mean (95% CI) z-score difference of 0.41 (0.27 to 0.54, p<0.001) in study 1 and 0.44 (0.36 to 0.53, p<0.001) in study 2. However, the mean WHO measurements in the healthy infants still produced a mean z score that was two-third of a centile space (0.54 SD (0.28 to 0.79) p<0.001) above the 50th centile. CONCLUSION: The WHO measurement techniques produced significantly lower measures of head size, but average healthy Scottish children still had larger heads than the WHO standard using this method. PMID- 27986700 TI - Hepatitis B: changing epidemiology and interventions. AB - Hepatitis B virus infection is still a major public health problem worldwide, since more than 350 million people have chronic, lifelong infection and nearly 1 million deaths occur each year owing to complications. Most infections are acquired at birth or during early childhood. Nowadays, low- and middle-income countries bear the majority of the burden of hepatitis B-related liver cancer deaths despite the availability of an effective vaccine and antiviral treatments. In this review the epidemiology, strategies of prevention and the recent advances in therapy, genotype diversity and resistance are discussed. PMID- 27986699 TI - Ethnic and socioeconomic variation in incidence of congenital heart defects. AB - INTRODUCTION: Ethnic differences in the birth prevalence of congenital heart defects (CHDs) have been reported; however, studies of the contemporary UK population are lacking. We investigated ethnic variations in incidence of serious CHDs requiring cardiac intervention before 1 year of age. METHODS: All infants who had a cardiac intervention in England and Wales between 1 January 2005 and 31 December 2010 were identified in the national congenital heart disease surgical audit and matched with paediatric intensive care admission records to create linked individual child records. Agreement in reporting of ethnic group by each audit was evaluated. For infants born 1 January 2006 to 31 December 2009, we calculated incidence rate ratios (IRRs) for CHDs by ethnicity and investigated age at intervention, antenatal diagnosis and area deprivation. RESULTS: We identified 5350 infants (2940 (55.0%) boys). Overall CHD incidence was significantly higher in Asian and Black ethnic groups compared with the White reference population (incidence rate ratios (IRR) (95% CIs): Asian 1.5 (1.4 to 1.7); Black 1.4 (1.3 to 1.6)); incidence of specific CHDs varied by ethnicity. No significant differences in age at intervention or antenatal diagnosis rates were identified but affected children from non-White ethnic groups were more likely to be living in deprived areas than White children. CONCLUSIONS: Significant ethnic variations exist in the incidence of CHDs, including for specific defects with high infant mortality. It is essential that healthcare provision mitigates ethnic disparity, including through timely identification of CHDs at screening, supporting parental choice and effective interventions. Future research should explore the factors underlying ethnic variation and impact on longer-term outcomes. PMID- 27986702 TI - A Systems Science Approach to Understanding Polytrauma and Blast-Related Injury: Bayesian Network Model of Data From a Survey of the Florida National Guard. AB - We sought to further define the epidemiology of the complex, multiple injuries collectively known as polytrauma/blast-related injury (PT/BRI). Using a systems science approach, we performed Bayesian network modeling to find the most accurate representation of the complex system of PT/BRI and identify key variables for understanding the subsequent effects of blast exposure in a sample of Florida National Guard members (1,443 deployed to Operation Enduring Freedom/Operation Iraqi Freedom and 1,655 not deployed) who completed an online survey during the period from 2009 to 2010. We found that postdeployment symptoms reported as present at the time of the survey were largely independent of deployment per se. Blast exposure, not mild traumatic brain injury (TBI), acted as the primary military deployment-related driver of PT/BRI symptoms. Blast exposure was indirectly linked to mild TBI via other deployment-related traumas and was a significant risk for a high level of posttraumatic stress disorder (PTSD) arousal symptoms. PTSD arousal symptoms and tinnitus were directly dependent upon blast exposure, with both acting as bridge symptoms to other postdeployment mental health and physical symptoms, respectively. Neurobehavioral or postconcussion-like symptoms had no significant dependence relationship with mild TBI, but they were synergistic with blast exposure in influencing PTSD arousal symptoms. A replication of this analysis using a larger PT/BRI database is warranted. PMID- 27986703 TI - Cesarean Section and Risk of Childhood Acute Lymphoblastic Leukemia in a Population-Based, Record-Linkage Study in California. AB - The relationship of mode of delivery to risk of childhood acute lymphoblastic leukemia (ALL) is uncertain. After linking birth records and cancer registry data from California, we conducted a population-based case-control study to investigate the role of delivery by cesarean section (C-section) in the etiology of childhood ALL. This study included 5,081 cases and 18,927 matched controls born in 1978-2009; more detailed data were available on type of C-section (i.e., elective vs. emergency) for a subset of 1,552 cases and 5,688 controls. No association was observed between C-section overall and childhood ALL risk (<15 years of age), but elective C-section was associated with a significantly elevated risk of ALL (odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.01, 1.36). At the peak ages of ALL incidence (2-4 years), C-section was associated with an 11% higher risk of ALL (OR = 1.11, 95% CI: 1.01, 1.22) compared with vaginal delivery, and the magnitude of the association was larger for elective C section (OR = 1.38, 95% CI: 1.11, 1.70). Emergency C-section was not associated with childhood ALL. Because of design features minimizing nonparticipation and inaccurate recall, this record linkage-based study is less prone to bias. Our results suggest that delivery by elective C-section was associated with a higher risk of childhood ALL, especially at the peak ages of incidence. It is important to evaluate possible mechanisms, because this potential risk factor is modifiable. PMID- 27986704 TI - Comparison of Collection Methods for Fecal Samples in Microbiome Studies. AB - Prospective cohort studies are needed to assess the relationship between the fecal microbiome and human health and disease. To evaluate fecal collection methods, we determined technical reproducibility, stability at ambient temperature, and accuracy of 5 fecal collection methods (no additive, 95% ethanol, RNAlater Stabilization Solution, fecal occult blood test cards, and fecal immunochemical test tubes). Fifty-two healthy volunteers provided fecal samples at the Mayo Clinic in Rochester, Minnesota, in 2014. One set from each sample collection method was frozen immediately, and a second set was incubated at room temperature for 96 hours and then frozen. Intraclass correlation coefficients (ICCs) were calculated for the relative abundance of 3 phyla, 2 alpha diversity metrics, and 4 beta diversity metrics. Technical reproducibility was high, with ICCs for duplicate fecal samples between 0.64 and 1.00. Stability for most methods was generally high, although the ICCs were below 0.60 for 95% ethanol in metrics that were more sensitive to relative abundance. When compared with fecal samples that were frozen immediately, the ICCs were below 0.60 for the metrics that were sensitive to relative abundance; however, the remaining 2 alpha diversity and 3 beta diversity metrics were all relatively accurate, with ICCs above 0.60. In conclusion, all fecal sample collection methods appear relatively reproducible, stable, and accurate. Future studies could use these collection methods for microbiome analyses. PMID- 27986706 TI - Bias in medical literature on health outcomes: bias in commentary? PMID- 27986705 TI - Exposure to Neighborhood Foreclosures and Changes in Cardiometabolic Health: Results From MESA. AB - Home foreclosures can precipitate declines in health among the individuals who lost their homes. Whether home foreclosures can "spillover" to affect the health of other neighborhood residents is largely unknown. Using longitudinal data from the Multi-Ethnic Study of Atherosclerosis that were linked to foreclosure data from 2005 to 2012, we assessed whether greater exposure to neighborhood foreclosures was associated with temporal changes in 3 objectively measured cardiometabolic risk factors: body mass index, systolic blood pressure, and fasting glucose level. We used fixed-effects models to estimate mean changes in cardiometabolic risk factors associated with changes in neighborhood foreclosures over time. In models in which we controlled for time-varying income, working status, medication use, neighborhood poverty, neighborhood unemployment, and interactions of age, sex, race, and state foreclosure laws with time, a standard deviation increase in neighborhood foreclosures (1.9 foreclosures per quarter mile) was associated with increases in fasting glucose (mean = 0.22 mg/dL, 95% confidence interval: -0.05, 0.50) and decreases in blood pressure (mean = -0.27 mm Hg, 95% confidence interval: -0.49, -0.04). Changes in neighborhood foreclosure rates were not associated with changes in body mass index. Overall, greater exposure to neighborhood foreclosures had mixed associations with cardiometabolic risk factors over time. Given the millions of mortgages still in default, further research clarifying the potential health effects of neighborhood foreclosures is needed. PMID- 27986713 TI - Abemaciclib Shows Promise for Early Breast Cancer. AB - Treatment with the CDK4/6 inhibitor abemaciclib, alone or in combination with endocrine therapy, significantly lowered expression of the protein Ki67-a key marker of cell proliferation-in women with hormone receptor-positive, HER2 negative breast cancer. The findings from the phase II neoMONARCH trial suggest that CDK4/6 inhibition may be effective for neoadjuvant treatment of early breast cancer. PMID- 27986707 TI - Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists. AB - Recent studies have identified somatic ESR1 mutations in patients with metastatic breast cancer and found some of them to promote estrogen-independent activation of the receptor. The degree to which all recurrent mutants can drive estrogen independent activities and reduced sensitivity to ER antagonists like fulvestrant is not established. In this report, we characterize the spectrum of ESR1 mutations from more than 900 patients. ESR1 mutations were detected in 10%, with D538G being the most frequent (36%), followed by Y537S (14%). Several novel, activating mutations were also detected (e.g., L469V, V422del, and Y537D). Although many mutations lead to constitutive activity and reduced sensitivity to ER antagonists, only select mutants such as Y537S caused a magnitude of change associated with fulvestrant resistance in vivo Correspondingly, tumors driven by Y537S, but not D5358G, E380Q, or S463P, were less effectively inhibited by fulvestrant than more potent and bioavailable antagonists, including AZD9496. These data point to a need for antagonists with optimal pharmacokinetic properties to realize clinical efficacy against certain ESR1 mutants.Significance: A diversity of activating ESR1 mutations exist, only some of which confer resistance to existing ER antagonists that might be overcome by next-generation inhibitors such as AZD9496. Cancer Discov; 7(3); 277-87. (c)2016 AACR.This article is highlighted in the In This Issue feature, p. 235. PMID- 27986714 TI - Benefit Mixed with Caution for Buparlisib. AB - Data from the BELLE-3 trial suggest that adding the investigational PI3K inhibitor buparlisib to endocrine therapy may improve outcomes for patients with hormone receptor-positive advanced breast cancer whose tumors become resistant to mTOR inhibition. However, experts remain concerned about a high rate of serious adverse events seen during the trial. PMID- 27986708 TI - Blastic Plasmacytoid Dendritic Cell Neoplasm Is Dependent on BCL2 and Sensitive to Venetoclax. AB - : Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with dismal outcomes for which no standard therapy exists. We found that primary BPDCN cells were dependent on the antiapoptotic protein BCL2 and were uniformly sensitive to the BCL2 inhibitor venetoclax, as measured by direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling. Animals bearing BPDCN patient-derived xenografts had disease responses and improved survival after venetoclax treatment in vivo Finally, we report on 2 patients with relapsed/refractory BPDCN who received venetoclax off-label and experienced significant disease responses. We propose that venetoclax or other BCL2 inhibitors undergo expedited clinical evaluation in BPDCN, alone or in combination with other therapies. In addition, these data illustrate an example of precision medicine to predict treatment response using ex vivo functional assessment of primary tumor tissue, without requiring a genetic biomarker. SIGNIFICANCE: Therapy for BPDCN is inadequate, and survival in patients with the disease is poor. We used primary tumor cell functional profiling to predict BCL2 antagonist sensitivity as a common feature of BPDCN, and demonstrated in vivo clinical activity of venetoclax in patient-derived xenografts and in 2 patients with relapsed chemotherapy-refractory disease. Cancer Discov; 7(2); 156-64. (c)2016 AACR.This article is highlighted in the In This Issue feature, p. 115. PMID- 27986716 TI - Routinely collected data may usefully supplement randomised controlled data on treatment effects for mortality. PMID- 27986717 TI - FlrA Represses Transcription of the Biofilm-Associated bpfA Operon in Shewanella putrefaciens. AB - : Manipulation of biofilm formation in Shewanella is beneficial for application to industrial and environmental biotechnology. BpfA is an adhesin largely responsible for biofilm formation in many Shewanella species. However, the mechanism underlying BpfA production and the resulting biofilm remains vaguely understood. We previously described the finding that BpfA expression is enhanced by DosD, an oxygen-stimulated diguanylate cyclase, under aerobic growth. In the present work, we identify FlrA as a critical transcription regulator of the bpfA operon in Shewanella putrefaciens CN32 by transposon mutagenesis. FlrA acted as a repressor of the operon promoter by binding to two boxes overlapping the -10 and 35 sites recognized by sigma70 DosD regulation of the expression of the bpfA operon was mediated by FlrA, and cyclic diguanylic acid (c-di-GMP) abolished FlrA binding to the operon promoter. We also demonstrate that FlhG, an accessory protein for flagellum synthesis, antagonized FlrA repression of the expression of the bpfA operon. Collectively, this work demonstrates that FlrA acts as a central mediator in the signaling pathway from c-di-GMP to BpfA-associated biofilm formation in S. putrefaciens CN32. IMPORTANCE: Motility and biofilm are mutually exclusive lifestyles, shifts between which are under the strict regulation of bacteria attempting to adapt to the fluctuation of diverse environmental conditions. The FlrA protein in many bacteria is known to control motility as a master regulator of flagellum synthesis. This work elucidates its effect on biofilm formation by controlling the expression of the adhesin BpfA in S. putrefaciens CN32 in response to c-di-GMP. Therefore, FlrA plays a dual role in controlling motility and biofilm formation in S. putrefaciens CN32. The cooccurrence of flrA, bpfA, and the FlrA box in the promoter region of the bpfA operon in diverse Shewanella strains suggests that bpfA is a common mechanism that controls biofilm formation in this bacterial species. PMID- 27986718 TI - A Rhizobiales-Specific Unipolar Polysaccharide Adhesin Contributes to Rhodopseudomonas palustris Biofilm Formation across Diverse Photoheterotrophic Conditions. AB - : Bacteria predominantly exist as members of surfaced-attached communities known as biofilms. Many bacterial species initiate biofilms and adhere to each other using cell surface adhesins. This is the case for numerous ecologically diverse Alphaprotebacteria, which use polar exopolysaccharide adhesins for cell-cell adhesion and surface attachment. Here, we show that Rhodopseudomonas palustris, a metabolically versatile member of the alphaproteobacterial order Rhizobiales, contains a functional unipolar polysaccharide (UPP) biosynthesis gene cluster. Deletion of genes predicted to be critical for UPP biosynthesis and export abolished UPP production. We also found that R. palustris uses UPP to mediate biofilm formation across diverse photoheterotrophic growth conditions, wherein light and organic substrates are used to support growth. However, UPP was less important for biofilm formation during photoautotrophy, where light and CO2 support growth, and during aerobic respiration with organic compounds. Expanding our analysis beyond R. palustris, we examined the phylogenetic distribution and genomic organization of UPP gene clusters among Rhizobiales species that inhabit diverse niches. Our analysis suggests that UPP is a conserved ancestral trait of the Rhizobiales but that it has been independently lost multiple times during the evolution of this clade, twice coinciding with adaptation to intracellular lifestyles within animal hosts. IMPORTANCE: Bacteria are ubiquitously found as surface-attached communities and cellular aggregates in nature. Here, we address how bacterial adhesion is coordinated in response to diverse environments using two complementary approaches. First, we examined how Rhodopseudomonas palustris, one of the most metabolically versatile organisms ever described, varies its adhesion to surfaces in response to different environmental conditions. We identified critical genes for the production of a unipolar polysaccharide (UPP) and showed that UPP is important for adhesion when light and organic substrates are used for growth. Looking beyond R. palustris, we performed the most comprehensive survey to date on the conservation of UPP biosynthesis genes among a group of closely related bacteria that occupy diverse niches. Our findings suggest that UPP is important for free-living and plant-associated lifestyles but dispensable for animal pathogens. Additionally, we propose guidelines for classifying the adhesins produced by various Alphaprotebacteria, facilitating future functional and comparative studies. PMID- 27986720 TI - Erg4A and Erg4B Are Required for Conidiation and Azole Resistance via Regulation of Ergosterol Biosynthesis in Aspergillus fumigatus. AB - : Ergosterol, a fungus-specific sterol enriched in cell plasma membranes, is an effective antifungal drug target. However, current knowledge of the ergosterol biosynthesis process in the saprophytic human fungal pathogen Aspergillus fumigatus remains limited. In this study, we found that two endoplasmic reticulum localized sterol C-24 reductases encoded by both erg4A and erg4B homologs are required to catalyze the reaction during the final step of ergosterol biosynthesis. Loss of one homolog of Erg4 induces the overexpression of the other one, accompanied by almost normal ergosterol synthesis and wild-type colony growth. However, double deletions of erg4A and erg4B completely block the last step of ergosterol synthesis, resulting in the accumulation of ergosta 5,7,22,24(28)-tetraenol, a precursor compound of ergosterol. Further studies indicate that erg4A and erg4B are required for conidiation but not for hyphal growth. Importantly, the Deltaerg4A Deltaerg4B mutant still demonstrates wild type virulence in a compromised mouse model but displays remarkable increased susceptibility to antifungal azoles. Our data suggest that inhibitors of Erg4A and Erg4B may serve as effective candidates for adjunct antifungal agents with azoles. IMPORTANCE: Knowledge of the ergosterol biosynthesis pathway in the human opportunistic pathogen A. fumigatus is useful for designing and finding new antifungal drugs. In this study, we demonstrated that the endoplasmic reticulum localized sterol C-24 reductases Erg4A and Erg4B are required for conidiation via regulation of ergosterol biosynthesis. Moreover, inactivation of both Erg4A and Erg4B results in hypersensitivity to the clinical guideline-recommended antifungal drugs itraconazole and voriconazole. Therefore, our finding indicates that inhibition of Erg4A and Erg4B might be an effective approach for alleviating A. fumigatus infection. PMID- 27986721 TI - Unexpected Diversity and High Abundance of Putative Nitric Oxide Dismutase (Nod) Genes in Contaminated Aquifers and Wastewater Treatment Systems. AB - : It has recently been suggested that oxygenic dismutation of NO into N2 and O2 may occur in the anaerobic methanotrophic "Candidatus Methylomirabilis oxyfera" and the alkane-oxidizing gammaproteobacterium HdN1. It may represent a new pathway in microbial nitrogen cycling catalyzed by a putative NO dismutase (Nod). The formed O2 enables microbes to employ aerobic catabolic pathways in anoxic habitats, suggesting an ecophysiological niche space of substantial appeal for bioremediation and water treatment. However, it is still unknown whether this physiology is limited to "Ca Methylomirabilis oxyfera" and HdN1 and whether it can be coupled to the oxidation of electron donors other than alkanes. Here, we report insights into an unexpected diversity and remarkable abundance of nod genes in natural and engineered water systems. Phylogenetically diverse nod genes were recovered from a range of contaminated aquifers and N-removing wastewater treatment systems. Together with nod genes from "Ca Methylomirabilis oxyfera" and HdN1, the novel environmental nod sequences formed no fewer than 6 well-supported phylogenetic clusters, clearly distinct from canonical NO reductase (quinol dependent NO reductase [qNor] and cytochrome c-dependent NO reductase [cNor]) genes. The abundance of nod genes in the investigated samples ranged from 1.6 * 107 to 5.2 * 1010 copies . g-1 (wet weight) of sediment or sludge biomass, accounting for up to 10% of total bacterial 16S rRNA gene counts. In essence, NO dismutation could be a much more widespread physiology than currently perceived. Understanding the controls of this emergent microbial capacity could offer new routes for nitrogen elimination or pollutant remediation in natural and engineered water systems. IMPORTANCE: NO dismutation into N2 and O2 is a novel process catalyzed by putative NO dismutase (Nod). To date, only two bacteria, the anaerobic methane-oxidizing bacterium "Ca Methylomirabilis oxyfera" and the alkane-oxidizing gammaproteobacterium HdN1, are known to harbor nod genes. In this study, we report efficient molecular tools that can detect and quantify a wide diversity of nod genes in environmental samples. A surprisingly high diversity and abundance of nod genes were found in contaminated aquifers as well as wastewater treatment systems. This evidence indicates that NO dismutation may be a much more widespread physiology in natural and man-made environments than currently perceived. The molecular tools presented here will facilitate further studies on these enigmatic microbes in the future. PMID- 27986722 TI - Detection of ESKAPE Bacterial Pathogens at the Point of Care Using Isothermal DNA Based Assays in a Portable Degas-Actuated Microfluidic Diagnostic Assay Platform. AB - : An estimated 1.5 billion microbial infections occur globally each year and result in ~4.6 million deaths. A technology gap associated with commercially available diagnostic tests in remote and underdeveloped regions prevents timely pathogen identification for effective antibiotic chemotherapies for infected patients. The result is a trial-and-error approach that is limited in effectiveness, increases risk for patients while contributing to antimicrobial drug resistance, and reduces the lifetime of antibiotics. This paper addresses this important diagnostic technology gap by describing a low-cost, portable, rapid, and easy-to-use microfluidic cartridge-based system for detecting the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) bacterial pathogens that are most commonly associated with antibiotic resistance. The point of-care molecular diagnostic system consists of a vacuum-degassed microfluidic cartridge preloaded with lyophilized recombinase polymerase amplification (RPA) assays and a small portable battery-powered electronic incubator/reader. The isothermal RPA assays detect the targeted ESKAPE pathogens with high sensitivity (e.g., a limit of detection of ~10 nucleic acid molecules) that is comparable to that of current PCR-based assays, and they offer advantages in power consumption, engineering, and robustness, which are three critical elements required for the point-of-care setting. IMPORTANCE: This paper describes a portable system for rapidly identifying bacteria in resource-limited environments; we highlight the capabilities of the technology by detecting different pathogens within the ESKAPE collection, which cause nosocomial infections. The system is designed around isothermal DNA-based assays housed within an autonomous plastic cartridge that are designed with the end user in mind, who may have limited technological training. Displaying excellent sensitivity and specificity, the assay systems that we demonstrate may enable future diagnoses of bacterial infection to guide the development of effective chemotherapies and may have a role in areas beyond health where rapid detection is valuable, including in industrial processing and manufacturing, food security, agriculture, and water quality testing. PMID- 27986719 TI - Effects of Actinomycete Secondary Metabolites on Sediment Microbial Communities. AB - : Marine sediments harbor complex microbial communities that remain poorly studied relative to other biomes such as seawater. Moreover, bacteria in these communities produce antibiotics and other bioactive secondary metabolites, yet little is known about how these compounds affect microbial community structure. In this study, we used next-generation amplicon sequencing to assess native microbial community composition in shallow tropical marine sediments. The results revealed complex communities comprised of largely uncultured taxa, with considerable spatial heterogeneity and known antibiotic producers comprising only a small fraction of the total diversity. Organic extracts from cultured strains of the sediment-dwelling actinomycete genus Salinispora were then used in mesocosm studies to address how secondary metabolites shape sediment community composition. We identified predatory bacteria and other taxa that were consistently reduced in the extract-treated mesocosms, suggesting that they may be the targets of allelopathic interactions. We tested related taxa for extract sensitivity and found general agreement with the culture-independent results. Conversely, several taxa were enriched in the extract-treated mesocosms, suggesting that some bacteria benefited from the interactions. The results provide evidence that bacterial secondary metabolites can have complex and significant effects on sediment microbial communities. IMPORTANCE: Ocean sediments represent one of Earth's largest and most poorly studied biomes. These habitats are characterized by complex microbial communities where competition for space and nutrients can be intense. This study addressed the hypothesis that secondary metabolites produced by the sediment-inhabiting actinomycete Salinispora arenicola affect community composition and thus mediate interactions among competing microbes. Next-generation amplicon sequencing of mesocosm experiments revealed complex communities that shifted following exposure to S. arenicola extracts. The results reveal that certain predatory bacteria were consistently less abundant following exposure to extracts, suggesting that microbial metabolites mediate competitive interactions. Other taxa increased in relative abundance, suggesting a benefit from the extracts themselves or the resulting changes in the community. This study takes a first step toward assessing the impacts of bacterial metabolites on sediment microbial communities. The results provide insight into how low-abundance organisms may help structure microbial communities in ocean sediments. PMID- 27986723 TI - Whole-Genome Analysis of Antimicrobial-Resistant and Extraintestinal Pathogenic Escherichia coli in River Water. AB - Contamination of surface waters by antimicrobial-resistant bacteria and pathogenic bacteria is a great concern. In this study, 531 Escherichia coli isolates obtained from the Yamato River in Japan were evaluated phenotypically for resistance to 25 antimicrobials. Seventy-six isolates (14.3%) were multidrug resistant (MDR), 66 (12.4%) were nonsusceptible to one or two classes of agents, and 389 (73.3%) were susceptible. We performed whole-genome sequencing of selected strains by using Illumina technology. In total, the genome sequences of 155 strains were analyzed for antibiotic resistance determinants and phylogenetic characteristics. More than 50 different resistance determinants, including acquired resistance genes and chromosomal resistance mutations, were detected. Among the sequenced MDR strains (n = 66), sequence type 155 (ST155) complex (n = 9), ST10 complex (n = 9), and ST69 complex (n = 7) were prevalent. Among extraintestinal pathogenic E. coli (ExPEC) strains (n = 58), clinically important clonal groups, namely, ST95 complex (n = 18), ST127 complex (n = 8), ST12 complex (n = 6), ST14 complex (n = 6), and ST131 complex (n = 6), were prevalent, demonstrating the clonal distribution of environmental ExPEC strains. Typing of the fimH (type 1 fimbrial adhesin) gene revealed that ST131 complex strains carried fimH22 or fimH41, and no strains belonging to the fimH30 subgroup were detected. Fine-scale phylogenetic analysis and virulence gene content analysis of strains belonging to the ST95 complex (one of the major clonal ExPEC groups causing community-onset infections) revealed no significant differences between environmental and clinical strains. The results indicate contamination of surface waters by E. coli strains belonging to clinically important clonal groups.IMPORTANCE The prevalence of antimicrobial-resistant and pathogenic E. coli strains in surface waters is a concern because surface waters are used as sources for drinking water, irrigation, and recreational purposes. In this study, MDR and ExPEC strains in river water were characterized by genomic sequencing and analysis. We detected more than 50 resistance determinants and identified clonal groups specific to MDR and ExPEC strains. This study showed contamination of surface waters by E. coli strains belonging to clinically important clonal groups. Overall, this study advances our understanding of environmental MDR and ExPEC strains. PMID- 27986724 TI - Sybr Green- and TaqMan-Based Quantitative PCR Approaches Allow Assessment of the Abundance and Relative Distribution of Frankia Clusters in Soils. AB - The nodule-forming actinobacterial genus Frankia can generally be divided into 4 taxonomic clusters, with clusters 1, 2, and 3 representing nitrogen-fixing strains of different host infection groups and cluster 4 representing atypical, generally non-nitrogen-fixing strains. Recently, quantitative PCR (qPCR)-based quantification methods have been developed for frankiae of clusters 1 and 3; however, similar approaches for clusters 2 and 4 were missing. We amended a database of partial 23S rRNA gene sequences of Frankia strains belonging to clusters 1 and 3 with sequences of frankiae representing clusters 2 and 4. The alignment allowed us to design primers and probes for the specific detection and quantification of these Frankia clusters by either Sybr Green- or TaqMan-based qPCR. Analyses of frankiae in different soils, all obtained from the same region in Illinois, USA, provided similar results, independent of the qPCR method applied, with abundance estimates of 10 * 105 to 15 * 105 cells (g soil)-1 depending on the soil. Diversity was higher in prairie soils (native, restored, and cultivated), with frankiae of all 4 clusters detected and those of cluster 4 dominating, while diversity in soils under Alnus glutinosa, a host plant for cluster 1 frankiae, or Betula nigra, a related nonhost plant, was restricted to cluster 1 and 3 frankiae and generally members of subgroup 1b were dominating. These results indicate that vegetation affects the basic composition of frankiae in soils, with higher diversity in prairie soils compared to much more restricted diversity under some host and nonhost trees.IMPORTANCE Root nodule formation by the actinobacterium Frankia is host plant specific and largely, but not exclusively, correlates with assignments of strains to specific clusters within the genus. Due to the lack of adequate detection and quantification tools, studies on Frankia have been limited to clusters 1 and 3 and generally excluded clusters 2 and 4. We have developed tools for the detection and quantification of clusters 2 and 4, which can now be used in combination with those developed for clusters 1 and 3 to retrieve information on the ecology of all clusters delineated within the genus Frankia Our initial results indicate that vegetation affects the basic composition of frankiae in soils, with higher diversity in prairie soils compared to much more restricted diversity under some host and nonhost trees. PMID- 27986725 TI - Imaging of Borrelia turicatae Producing the Green Fluorescent Protein Reveals Persistent Colonization of the Ornithodoros turicata Midgut and Salivary Glands from Nymphal Acquisition through Transmission. AB - Relapsing fever (RF) spirochetes colonize and are transmitted to mammals primarily by Ornithodoros ticks, and little is known regarding the pathogen's life cycle in the vector. To further understand vector colonization and transmission of RF spirochetes, Borrelia turicatae expressing a green fluorescent protein (GFP) marker (B. turicatae-gfp) was generated. The transformants were evaluated during the tick-mammal infectious cycle, from the third nymphal instar to adult stage. B. turicatae-gfp remained viable for at least 18 months in starved fourth-stage nymphal ticks, and the studies indicated that spirochete populations persistently colonized the tick midgut and salivary glands. Our generation of B. turicatae-gfp also revealed that within the salivary glands, spirochetes are localized in the ducts and lumen of acini, and after tick feeding, the tissues remained populated with spirochetes. The B. turicatae-gfp generated in this study is an important tool to further understand and define the mechanisms of vector colonization and transmission.IMPORTANCE In order to interrupt the infectious cycle of tick-borne relapsing fever spirochetes, it is important to enhance our understanding of vector colonization and transmission. Toward this, we generated a strain of Borrelia turicatae that constitutively produced the green fluorescent protein, and we evaluated fluorescing spirochetes during the entire infectious cycle. We determined that the midgut and salivary glands of Ornithodoros turicata ticks maintain the pathogens throughout the vector's life cycle and remain colonized with the spirochetes for at least 18 months. We also determined that the tick's salivary glands were not depleted after a transmission blood feeding. These findings set the framework to further understand the mechanisms of midgut and salivary gland colonization. PMID- 27986726 TI - Detection of Salmonella enterica in Meat in Less than 5 Hours by a Low-Cost and Noncomplex Sample Preparation Method. AB - Salmonella is recognized as one of the most important foodborne bacteria and has wide health and socioeconomic impacts worldwide. Fresh pork meat is one of the main sources of Salmonella, and efficient and fast methods for detection are therefore necessary. Current methods for Salmonella detection in fresh meat usually include >16 h of culture enrichment, in a few cases <12 h, thus requiring at least two working shifts. Here, we report a rapid (<5 h) and high-throughput method for screening of Salmonella in samples from fresh pork meat, consisting of a 3-h enrichment in standard buffered peptone water and a real-time PCR compatible sample preparation method based on filtration, centrifugation, and enzymatic digestion, followed by fast-cycling real-time PCR detection. The method was validated in an unpaired comparative study against the Nordic Committee on Food Analysis (NMKL) reference culture method 187. Pork meat samples (n = 140) were either artificially contaminated with Salmonella at 0, 1 to 10, or 10 to 100 CFU/25 g of meat or naturally contaminated. Cohen's kappa for the degree of agreement between the rapid method and the reference was 0.64, and the relative accuracy, sensitivity, and specificity for the rapid method were 81.4, 95.1, and 97.9%, respectively. The 50% limit of detections (LOD50s) were 8.8 CFU/25 g for the rapid method and 7.7 CFU/25 g for the reference method. Implementation of this method will enable faster release of Salmonella low-risk meat, providing savings for meat producers, and it will help contribute to improved food safety.IMPORTANCE While the cost of analysis and hands-on time of the presented rapid method were comparable to those of reference culture methods, the fast product release by this method can provide the meat industry with a competitive advantage. Not only will the abattoirs save costs for work hours and cold storage, but consumers and retailers will also benefit from fresher meat with a longer shelf life. Furthermore, the presented sample preparation might be adjusted for application in the detection of other pathogenic bacteria in different sample types. PMID- 27986728 TI - Alternative Protein Sources in the Diet Modulate Microbiota and Functionality in the Distal Intestine of Atlantic Salmon (Salmo salar). AB - The present study aimed to investigate whether alternative dietary protein sources modulate the microbial communities in the distal intestine (DI) of Atlantic salmon, and whether alterations in microbiota profiles are reflected in modifications in host intestinal function and health status. A 48-day feeding trial was conducted, in which groups of fish received one of five diets: a reference diet in which fishmeal (diet FM) was the only protein source and four experimental diets with commercially relevant compositions containing alternative ingredients as partial replacements of fishmeal, i.e., poultry meal (diet PM), a mix of soybean meal and wheat gluten (diet SBMWG), a mix of soy protein concentrate and poultry meal (diet SPCPM), and guar meal and wheat gluten (diet GMWG). Samples were taken of DI digesta and mucosa for microbial profiling using high-throughput sequencing and from DI whole tissue for immunohistochemistry and expression profiling of marker genes for gut health. Regardless of diet, there were significant differences between the microbial populations in the digesta and the mucosa in the salmon DI. Microbial richness was higher in the digesta than the mucosa. The digesta-associated bacterial communities were more affected by the diet than the mucosa-associated microbiota. Interestingly, both legume-based diets (SBMWG and GMWG) presented high relative abundance of lactic acid bacteria in addition to alteration in the expression of a salmon gene related to cell proliferation (pcna). It was, however, not possible to ascertain the cause-effect relationship between changes in bacterial communities and the host's intestinal responses to the diets.IMPORTANCE The intestine of cultivated Atlantic salmon shows symptoms of compromised function, which are most likely caused by imbalances related to the use of new feed ingredients. Intestinal microbiota profiling may become in the future a valuable endpoint measurement in order to assess fish intestinal health status and effects of diet. The present study aimed to gain information about whether alternative dietary protein sources modulate the microbial communities in the Atlantic salmon intestine and whether alterations in microbiota profiles are reflected in alterations in host intestinal function and health status. We demonstrate here that there are substantial differences between the intestinal digesta and mucosa in the presence and abundance of bacteria. The digesta-associated microbiota showed clear dependence on the diet composition, whereas mucosa-associated microbiota appeared to be less affected by diet composition. Most important, the study identified bacterial groups associated with diet-induced gut dysfunction that may be utilized as microbial markers of gut health status in fish. PMID- 27986727 TI - Burkholderia humptydooensis sp. nov., a New Species Related to Burkholderia thailandensis and the Fifth Member of the Burkholderia pseudomallei Complex. AB - During routine screening for Burkholderia pseudomallei from water wells in northern Australia in areas where it is endemic, Gram-negative bacteria (strains MSMB43T, MSMB121, and MSMB122) with a similar morphology and biochemical pattern to B. pseudomallei and B. thailandensis were coisolated with B. pseudomallei on Ashdown's selective agar. To determine the exact taxonomic position of these strains and to distinguish them from B. pseudomallei and B. thailandensis, they were subjected to a series of phenotypic and molecular analyses. Biochemical and fatty acid methyl ester analysis was unable to distinguish B. humptydooensis sp. nov. from closely related species. With matrix-assisted laser desorption ionization-time of flight analysis, all isolates grouped together in a cluster separate from other Burkholderia spp. 16S rRNA and recA sequence analyses demonstrated phylogenetic placement for B. humptydooensis sp. nov. in a novel clade within the B. pseudomallei group. Multilocus sequence typing (MLST) analysis of the three isolates in comparison with MLST data from 3,340 B. pseudomallei strains and related taxa revealed a new sequence type (ST318). Genome-to-genome distance calculations and the average nucleotide identity of all isolates to both B. thailandensis and B. pseudomallei, based on whole-genome sequences, also confirmed B. humptydooensis sp. nov. as a novel Burkholderia species within the B. pseudomallei complex. Molecular analyses clearly demonstrated that strains MSMB43T, MSMB121, and MSMB122 belong to a novel Burkholderia species for which the name Burkholderia humptydooensis sp. nov. is proposed, with the type strain MSMB43T (American Type Culture Collection BAA 2767; Belgian Co-ordinated Collections of Microorganisms LMG 29471; DDBJ accession numbers CP013380 to CP013382).IMPORTANCEBurkholderia pseudomallei is a soil-dwelling bacterium and the causative agent of melioidosis. The genus Burkholderia consists of a diverse group of species, with the closest relatives of B. pseudomallei referred to as the B. pseudomallei complex. A proposed novel species, B. humptydooensis sp. nov., was isolated from a bore water sample from the Northern Territory in Australia. B. humptydooensis sp. nov. is phylogenetically distinct from B. pseudomallei and other members of the B. pseudomallei complex, making it the fifth member of this important group of bacteria. PMID- 27986730 TI - The Sinorhizobium (Ensifer) fredii HH103 Nodulation Outer Protein NopI Is a Determinant for Efficient Nodulation of Soybean and Cowpea Plants. AB - The type III secretion system (T3SS) is a specialized secretion apparatus that is commonly used by many plant and animal pathogenic bacteria to deliver proteins, termed effectors, to the interior of the host cells. These effectors suppress host defenses and interfere with signal transduction pathways to promote infection. Some rhizobial strains possess a functional T3SS, which is involved in the suppression of host defense responses, host range determination, and symbiotic efficiency. The analysis of the genome of the broad-host-range rhizobial strain Sinorhizobium fredii HH103 identified eight genes that code for putative T3SS effectors. Three of these effectors, NopL, NopP, and NopI, are Rhizobium specific. In this work, we demonstrate that NopI, whose amino acid sequence shows a certain similarity with NopP, is secreted through the S. fredii HH103 T3SS in response to flavonoids. We also determined that NopL can be considered an effector since it is directly secreted to the interior of the host cell as demonstrated by adenylate cyclase assays. Finally, the symbiotic phenotype of single, double, and triple nopI, nopL, and nopP mutants in soybean and cowpea was assayed, showing that NopI plays an important role in determining the number of nodules formed in both legumes and that the absence of both NopL and NopP is highly detrimental for symbiosis.IMPORTANCE The paper is focused on three Rhizobium-specific T3SS effectors of Sinorhizobium fredii HH103, NopL, NopP, and NopI. We demonstrate that S. fredii HH103 is able to secrete through the T3SS in response to flavonoids the nodulation outer protein NopI. Additionally, we determined that NopL can be considered an effector since it is secreted to the interior of the host cell as demonstrated by adenylate cyclase assays. Finally, nodulation assays of soybean and cowpea indicated that NopI is important for the determination of the number of nodules formed and that the absence of both NopL and NopP negatively affected nodulation. PMID- 27986729 TI - Western Bats as a Reservoir of Novel Streptomyces Species with Antifungal Activity. AB - At least two-thirds of commercial antibiotics today are derived from Actinobacteria, more specifically from the genus Streptomyces Antibiotic resistance and new emerging diseases pose great challenges in the field of microbiology. Cave systems, in which actinobacteria are ubiquitous and abundant, represent new opportunities for the discovery of novel bacterial species and the study of their interactions with emergent pathogens. White-nose syndrome is an invasive bat disease caused by the fungus Pseudogymnoascus destructans, which has killed more than six million bats in the last 7 years. In this study, we isolated naturally occurring actinobacteria from white-nose syndrome (WNS)-free bats from five cave systems and surface locations in the vicinity in New Mexico and Arizona, USA. We sequenced the 16S rRNA region and tested 632 isolates from 12 different bat species using a bilayer plate method to evaluate antifungal activity. Thirty-six actinobacteria inhibited or stopped the growth of P. destructans, with 32 (88.9%) actinobacteria belonging to the genus Streptomyces Isolates in the genera Rhodococcus, Streptosporangium, Luteipulveratus, and Nocardiopsis also showed inhibition. Twenty-five of the isolates with antifungal activity against P. destructans represent 15 novel Streptomyces spp. based on multilocus sequence analysis. Our results suggest that bats in western North America caves possess novel bacterial microbiota with the potential to inhibit P. destructansIMPORTANCE This study reports the largest collection of actinobacteria from bats with activity against Pseudogymnoascus destructans, the fungal causative agent of white-nose syndrome. Using multigene analysis, we discovered 15 potential novel species. This research demonstrates that bats and caves may serve as a rich reservoir for novel Streptomyces species with antimicrobial bioactive compounds. PMID- 27986733 TI - Mining routinely collected acute data to reveal non-linear relationships between nurse staffing levels and outcomes. AB - OBJECTIVES: Nursing is a safety critical activity but not easily quantified. This makes the building of predictive staffing models a challenge. The aim of this study was to determine if relationships between registered and non-registered nurse staffing levels and clinical outcomes could be discovered through the mining of routinely collected clinical data. The secondary aim was to examine the feasibility and develop the use of 'big data' techniques commonly used in industry for this area of healthcare and examine future uses. SETTING: The data were obtained from 1 large acute National Health Service hospital trust in England. Routinely collected physiological, signs and symptom data from a clinical database were extracted, imported and mined alongside a bespoke staffing and outcomes database using Mathmatica V.10. The physiological data consisted of 120 million patient entries over 6 years, the bespoke database consisted of 9 years of daily data on staffing levels and safety factors such as falls. PRIMARY AND SECONDARY OUTCOMES: To discover patterns in these data or non-linear relationships that would contribute to modelling. To examine feasibility of this technique in this field. RESULTS: After mining, 40 correlations (p<0.00005) emerged between safety factors, physiological data (such as the presence or absence of nausea) and staffing factors. Several inter-related factors demonstrated step changes where registered nurse availability appeared to relate to physiological parameters or outcomes such as falls and the management of symptoms. Data extraction proved challenging as some commercial databases were not built for extraction of the massive data sets they contain. CONCLUSIONS: The relationship between staffing and outcomes appears to exist. It appears to be non linear but calculable and a data-driven model appears possible. These findings could be used to build an initial mathematical model for acute staffing which could be further tested. PMID- 27986731 TI - Novel Cadmium Resistance Determinant in Listeria monocytogenes. AB - Listeria monocytogenes is a foodborne pathogen that can cause severe disease (listeriosis) in susceptible individuals. It is ubiquitous in the environment and often exhibits resistance to heavy metals. One of the determinants that enables Listeria to tolerate exposure to cadmium is the cadAC efflux system, with CadA being a P-type ATPase. Three different cadA genes (designated cadA1 to cadA3) were previously characterized in L. monocytogenes A novel putative cadmium resistance gene (cadA4) was recently identified through whole-genome sequencing, but experimental confirmation for its involvement in cadmium resistance is lacking. In this study, we characterized cadA4 in L. monocytogenes strain F8027, a cadmium-resistant strain of serotype 4b. By screening a mariner-based transposon library of this strain, we identified a mutant with reduced tolerance to cadmium and that harbored a single transposon insertion in cadA4 The tolerance to cadmium was restored by genetic complementation with the cadmium resistance cassette (cadA4C), and enhanced cadmium tolerance was conferred to two unrelated cadmium-sensitive strains via heterologous complementation with cadA4C Cadmium exposure induced cadA4 expression, even at noninhibitory levels. Virulence assessments in the Galleria mellonella model suggested that a functional cadA4 suppressed virulence, potentially promoting commensal colonization of the insect larvae. Biofilm assays suggested that cadA4 inactivation reduced biofilm formation. These data not only confirm cadA4 as a novel cadmium resistance determinant in L. monocytogenes but also provide evidence for roles in virulence and biofilm formation.IMPORTANCEListeria monocytogenes is an intracellular foodborne pathogen causing the disease listeriosis, which is responsible for numerous hospitalizations and deaths every year. Among the adaptations that enable the survival of Listeria in the environment are the abilities to persist in biofilms, grow in the cold, and tolerate toxic compounds, such as heavy metals. Here, we characterized a novel determinant that was recently identified on a larger mobile genetic island through whole-genome sequencing. This gene (cadA4) was found to be responsible for cadmium detoxification and to be a divergent member of the Cad family of cadmium efflux pumps. Virulence assessments in a Galleria mellonella model suggested that cadA4 may suppress virulence. Additionally, cadA4 may be involved in the ability of Listeria to form biofilms. Beyond the role in cadmium detoxification, the involvement of cadA4 in other cellular functions potentially explains its retention and wide distribution in L. monocytogenes. PMID- 27986732 TI - Insight into the Genome of Brochothrix thermosphacta, a Problematic Meat Spoilage Bacterium. AB - Brochothrix thermosphacta is a dominant but poorly studied meat spoilage organism. It is a close relative of the foodborne pathogen Listeria monocytogenes, and Brochothrix constitutes the second genus in the Listeriaceae family. Here, the genomes of 12 B. thermosphacta strains were sequenced, assembled into draft genomes, characterized, and compared with the genomes of Brochothrix campestris and L. monocytogenes Phenotypic properties including biogenic amine production and antibiotic and heavy metal susceptibilities were tested. Comparative genomic analyses revealed a high degree of similarity among the B. thermosphacta strains, with bacteriophage genes constituting a significant proportion of the accessory genome. Genes for the production of the malodorous compounds acetate, acetoin, butanediol, and fatty acids were found, as were stress response regulatory genes, which likely play important roles in the spoilage process. Amino acid decarboxylases were not identified in the genomes, and phenotypic testing confirmed their absence. Orthologs of Listeria virulence proteins involved in virulence regulation, intracellular survival, and surface protein anchoring were found; however, key virulence genes were absent. Analysis of antibiotic susceptibility showed that strains were sensitive to the four tested antibiotics, except for one tetracycline-resistant isolate with plasmid mediated tetracycline resistance genes. Strains tolerated higher levels of copper and cobalt than of cadmium although not at concentrations high enough to categorize the strains as being resistant. This study provides insight into the Brochothrix genome, links previous phenotypic data and data provided here to the gene inventory, and identifies genes that may contribute to the persistence of this organism in the food chain.IMPORTANCE Despite increasing knowledge and advances in food preservation techniques, microbial spoilage of foods causes substantial losses, with negative social and economic consequences. To better control the contamination and microbial spoilage of foods, fundamental knowledge of the biology of key spoilage bacteria is crucial. As a common meat spoilage organism, B. thermosphacta contributes substantially to spoilage-associated losses. Nonetheless, this organism and particularly its genome remain largely unstudied. This study contributes to improving our knowledge of the Brochothrix genus. Spoilage-relevant pathways and genes that may play a role in the survival of this organism in a food processing environment were identified, linking previous phenotypic data and data provided here to the gene inventory of Brochothrix and establishing parallels to and differences from the closely related foodborne pathogen L. monocytogenes. PMID- 27986735 TI - Assessing the exposure of street sweeping and potential risk factors for developing musculoskeletal disorders and related disabilities: a cross-sectional study. AB - OBJECTIVE: This study aims to assess the exposure of those involved in street sweeping to the development of musculoskeletal disorders (MSDs) and related disabilities and tries to identify the individual risk factors thereof. DESIGN: A cross-sectional survey was conducted among street sweepers together with a comparison group. A modified Standardized Nordic Questionnaire was adopted to measure the prevalence of MSDs and related disabilities. The impact of the occupation of sweeping on the development of MSDs and related disabilities was assessed using the propensity score matching (PSM) method. A multivariate logistic regression model was employed to identify the individual risk factors. PARTICIPANTS: Street sweepers (n=180) and a comparison group (n=180), working for at least a year as formal employees of the Municipal Corporation of Greater Mumbai (MCGM), were randomly selected from 6 municipal wards. RESULTS: The prevalence of the MSDs was significantly higher among the sweepers for shoulders (32%), wrists/hands (29%), elbows (27%) and neck (17%) compared with the comparison group, in which the prevalence was 11%, 19%, 9% and 11%, respectively. The disabilities too were significantly higher among the street sweepers for the lower back (27%), upper back (27%), wrists/hands (26%), shoulders (24%) and elbows (23%) compared with the comparison group, for which the figures were 18%, 19%, 13%, 9% and 6% respectively. The PSM method highlighted that the occupation of sweeping raised the risk of developing MSDs and disabilities particularly for the shoulders (17-16%), wrists/hands (14% each), elbows (13% each) and the upper back (12-13%). After adjusting the age, body mass index and the caste of the street sweepers, the number of years of engagement in street sweeping and the location of work emerged as potential risk factors in the development of MSDs and, thereby, related disabilities. CONCLUSIONS: The study concluded that the occupation of street sweeping raises the risk of MSDs and related disabilities. This study recommends preventive and curative measures to deal with MSDs among street sweepers. PMID- 27986734 TI - How to measure the impacts of antibiotic resistance and antibiotic development on empiric therapy: new composite indices. AB - OBJECTIVES: We aimed to construct widely useable summary measures of the net impact of antibiotic resistance on empiric therapy. Summary measures are needed to communicate the importance of resistance, plan and evaluate interventions, and direct policy and investment. DESIGN, SETTING AND PARTICIPANTS: As an example, we retrospectively summarised the 2011 cumulative antibiogram from a Toronto academic intensive care unit. OUTCOME MEASURES: We developed two complementary indices to summarise the clinical impact of antibiotic resistance and drug availability on empiric therapy. The Empiric Coverage Index (ECI) measures susceptibility of common bacterial infections to available empiric antibiotics as a percentage. The Empiric Options Index (EOI) varies from 0 to 'the number of treatment options available', and measures the empiric value of the current stock of antibiotics as a depletable resource. The indices account for drug availability and the relative clinical importance of pathogens. We demonstrate meaning and use by examining the potential impact of new drugs and threatening bacterial strains. CONCLUSIONS: In our intensive care unit coverage of device associated infections measured by the ECI remains high (98%), but 37-44% of treatment potential measured by the EOI has been lost. Without reserved drugs, the ECI is 86-88%. New cephalosporin/beta-lactamase inhibitor combinations could increase the EOI, but no single drug can compensate for losses. Increasing methicillin-resistant Staphylococcus aureus (MRSA) prevalence would have little overall impact (ECI=98%, EOI=4.8-5.2) because many Gram-positives are already resistant to beta-lactams. Aminoglycoside resistance, however, could have substantial clinical impact because they are among the few drugs that provide coverage of Gram-negative infections (ECI=97%, EOI=3.8-4.5). Our proposed indices summarise the local impact of antibiotic resistance on empiric coverage (ECI) and available empiric treatment options (EOI) using readily available data. Policymakers and drug developers can use the indices to help evaluate and prioritise initiatives in the effort against antimicrobial resistance. PMID- 27986736 TI - Efficacy and safety of Wuling San for treatment of breast-cancer-related upper extremity lymphoedema: study protocol for a pilot trial. AB - INTRODUCTION: Breast-cancer-related upper extremity lymphoedema (BCUL), a common complication of mastectomy, can cause physical discomfort, psychological distress, cosmetic defects, functional disability and chronic recurrent erysipelas in the affected arm(s). It is a challenge to physicians involved in the management of these patients. Wuling San, a classic prescription in Traditional Chinese Medicine used in treating oedema for thousands of years, is reported by many Chinese journals to perform well in BCUL. Therefore, the aim of this study is to verify its efficacy and evaluate its safety using rigorous methodological designs in patients with BCUL. METHODS AND ANALYSIS: To verify the efficacy and assess the safety of Wuling San over a placebo, this double-blind, randomised, placebo-controlled, multicentre trial will be carried out in three hospitals. A total of 200 eligible patients with BCUL will be randomly allocated, in a ratio of 1:1, to either the experimental medicine group or the placebo group. The primary outcome measure will be the proportion of absolute reduced limb volume, as measured by perometry. The second outcome measure will be the number of participants with adverse events. The assessment will be carried out at the following time points: before enrolment (baseline) and 2, 4, 6 and 8 weeks after treatment. ETHICS AND DISSEMINATION: This trial will be conducted in accordance with the Declaration of Helsinki and supervised by the institutional review board of the Fourth Affiliated Hospital of Guangxi Medical University (approval number PJK2016088). All patients will receive information about the trial in verbal and written forms and will give informed consent before enrolment. This trial will help to demonstrate whether Wuling San is effective in the treatment of patients with BCUL. The results will be published in peer reviewed journals or disseminated through conference presentations. TRIAL REGISTRATION NUMBER: NCT02726477; Pre-results. PMID- 27986737 TI - Evaluating factors influencing the delivery and outcomes of an incentive-based behaviour change strategy targeting child obesity: protocol for a qualitative process and impact evaluation. AB - INTRODUCTION: Community-based weight management programmes are important in addressing childhood obesity. However, the mechanisms that lead to behaviour change within the programmes are rarely studied within the context of the programmes themselves once they have been implemented. This means that further potential gains in the effectiveness of the programme are often not made and any potential losses of efficacy are often not noticed. Qualitative research alongside randomised controlled trials (RCTs) can tell us the context in which these programmes are implemented and elucidate potential mediators or modifiers of the programmes' effectiveness. The aim of this evaluation is to determine the barriers and enablers to the delivery and impact of an incentive-based behaviour change strategy targeting child obesity to inform future translation. METHODS AND ANALYSIS: Qualitative analysis, including stakeholder and family interviews, focus groups and a survey, will be used. The research will be conducted in collaboration with policymakers, researchers and community health professionals. Participants will be selected from programme providers, and parents/carers and children participating in an Australian community weight management programme during an RCT examining the effectiveness of incentives for improving behaviour change. A maximum variation sampling method based on participant demographics and group characteristics will be used. Thematic analysis will be carried out inductively based on emergent themes, using NVivo V.9. ETHICS AND DISSEMINATION: This research is approved by the South West Sydney Human Ethics Committee review body (HREC/14/LPOOL/480). The evaluation will provide information about the contextual and influencing factors related to the outcomes of the RCT. The results will assist researchers, community health practitioners and policymakers regarding the development, implementation and translation of behaviour change strategies in community initiatives for obese children. Insights gained may be applicable to a range of chronic conditions where similar preventive intervention approaches are indicated. TRIAL REGISTRATION NUMBER: ACTRN12615000558527, Pre results. PMID- 27986739 TI - Relationship of social and economic factors to mental disorders among population based samples of Jamaicans and Guyanese. AB - BACKGROUND: There have been growing concerns about increasing mental health problems in the Caribbean region. This study explores rates and factors associated with selected mental health disorders within 2 Caribbean countries: Jamaica and Guyana. METHODS: Probability samples of 1218 Jamaicans and 2068 Guyanese participants were used. A modified version of the WHO Composite International Diagnostic Interview (WHO CIDI) defined by the Diagnostic Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) was administered in order to assess lifetime mental disorders. Descriptive statistics, chi2 and hierarchical regression analytic procedures were used to examine rates and factors associated with mental disorders. RESULTS: Rates of mental health conditions were different across contexts and were generally higher for Guyanese compared with Jamaicans for alcohol abuse (3.6% vs 2.2%), drug abuse (1.4% vs 1.3%), substance abuse (4.7% vs 2.7%) and mania (0.4% vs 0.1%). The rate of depression, however, was higher among Jamaicans than Guyanese (7.4% vs 4.1%). There were also noticeable differences in rates in both countries, due to social and economic factors, with social factors playing a larger contributory role in the mental health status of individuals across countries. CONCLUSIONS: The results of this study suggest the need for more indepth analyses of factors contributing to mental health conditions of peoples within the Caribbean region, including the influence of additional sources of stress, quality of care and help seeking behaviours of individuals. PMID- 27986738 TI - African-American patients with cancer Talking About Clinical Trials (TACT) with oncologists during consultations: evaluating the efficacy of tailored health messages in a randomised controlled trial-the TACT study protocol. AB - INTRODUCTION: Low rates of accrual of African-American (AA) patients with cancer to therapeutic clinical trials (CTs) represent a serious and modifiable racial disparity in healthcare that impedes the development of promising cancer therapies. Suboptimal physician-patient consultation communication is a barrier to the accrual of patients with cancer of any race, but communication difficulties are compounded with AA patients. Providing tailored health messages (THM) to AA patients and their physician about CTs has the potential to improve communication, lower barriers to accrual and ameliorate health disparities. OBJECTIVE: (1) Demonstrate the efficacy of THM to increase patient activation as measured by direct observation. (2) Demonstrate the efficacy of THM to improve patient outcomes associated with barriers to AA participation. (3) Explore associations among preconsultation levels of: (A) trust in medical researchers, (B) knowledge and attitudes towards CTs, (C) patient-family member congruence in decision-making, and (D) involvement/information preferences, and group assignment. METHODS AND ANALYSIS: First, using established methods, we will develop THM materials. Second, the efficacy of the intervention is determined in a 2 by 2 factorial randomised controlled trial to test the effectiveness of (1) providing 357 AA patients with cancer with THM with 2 different 'depths' of tailoring and (2) either providing feedback to oncologists about the patients' trial THM or not. The primary analysis compares patient engaged communication in 4 groups preconsultation and postconsultation. ETHICS AND DISSEMINATION: This study was approved by the Virginia Commonwealth University Institutional Review Board. To facilitate use of the THM intervention in diverse settings, we will convene 'user groups' at 3 major US cancer centres. To facilitate dissemination, we will post all materials and the implementation guide in publicly available locations. TRIAL REGISTRATION NUMBER: NCT02356549. PMID- 27986740 TI - Self-reported breast feeding practices and the Baby Friendly Hospital Initiative in Riyadh, Saudi Arabia: prospective cohort study. AB - BACKGROUND: The Baby Friendly Hospital Initiative (BFHI) is a practice guideline for healthcare providers to promote breastfeeding and increase breastfeeding rates. OBJECTIVE: This study aimed to examine reported experiences and views on breastfeeding of women using prenatal and postnatal services, and opinions of staff, in the context of the BFHI programme in Riyadh, Saudi Arabia. DESIGN: Prospective cohort study. SETTING: This prospective, longitudinal study was conducted from December 2013 to September 2015 at two healthcare facilities (BFHI and non-BFHI) in Riyadh Saudi Arabia. METHODS: Women 36-40 weeks gestation receiving antenatal care at the hospitals were enrolled. Questionnaires were administered prenatally, at 1, 3 and 6 months postnatal and to the administrator and maternity staff. RESULTS: We recruited 277 women with an estimated 80% response rate. 156 (BFHI=78/139, non-BFHI=78/138, 56%) participants completed all questionnaires. Most BFHI-hospital participants (77.9%, n=8 for this question) acknowledged seeing the breast feeding policy compared to 23.5% (n=23) at the non BFHI-hospital (p<0.01). Breast feeding education and encouragement was higher at the BFHI-hospital (93.3%) compared to the non-BFHI-hospital (48.2%; p<0.01). At postpartum discharge, 51% (n=53) of mothers in the BFHI-hospital were breast feeding exclusively versus 29.6% (n=29) at the non-BFHI-hospital. Where formula feed was introduced, women in the BFHI-hospital more often practiced mixed feeding rather than exclusive formula feeding with some switching from mixed feeding to exclusive breast feeding between 3 and 6 months postpartum. Exclusive breast feeding rates declined in both hospitals at 3 and 6 months postpartum with lack of community services for lactation being a major reason. Although BFHI hospital staff (n=9) were more conversant with BFHI principles, defects in adherence to the BFHI 10 Steps were identified. CONCLUSIONS: This is the first study assessing the effectiveness of BFHI implementation in Saudi Arabia. Although women reported increased breast feeding rates, we identified important weaknesses that could be improved through strict compliance with BFHI practices. PMID- 27986741 TI - Cognitive bias modification for interpretation with and without prior repetitive negative thinking to reduce worry and rumination in generalised anxiety disorder and depression: protocol for a multisession experimental study with an active control condition. AB - INTRODUCTION: Worry and rumination are two forms of repetitive thinking characterised by their negative content and apparently uncontrollable nature. Although worry and rumination share common features and have been conceptualised as part of a transdiagnostic repetitive negative thinking (RNT) process, it remains unclear whether they share the same underlying cognitive mechanisms. This multisession experimental study investigates the tendency to make negative interpretations regarding ambiguous information as a cognitive mechanism underlying RNT. We compare multisession cognitive bias modification for interpretations (CBM-I) with an active control condition to examine whether repeatedly training positive interpretations reduces worry and rumination in individuals with generalised anxiety disorder or depression, respectively. Further, we examine the potential modulatory effects of engaging in RNT immediately prior to CBM-I. DESIGN, METHODS AND ANALYSIS: A community sample of individuals meeting diagnostic criteria for either generalised anxiety disorder (n=60) or current major depressive episode (n=60) will be randomly allocated to CBM-I with prior RNT, CBM-I without prior RNT (ie, standard CBM-I), or an active control (no resolution of ambiguity) condition. All conditions receive a 3-week internet-based intervention consisting of one initial session at the first study visit and nine home-based sessions of CBM-I training (or active control). We will assess and compare the effects of CBM-I with and without prior RNT on 'near transfer' measures of interpretation bias closely related to the training as well as 'far-transfer' outcomes related to RNT and emotional distress. Impact on questionnaire measures will additionally be assessed at 1-month follow-up. Multigroup analyses will be conducted to assess the impact of CBM-I on near transfer and far-transfer outcome measures. PMID- 27986742 TI - Assessment of the effectiveness and safety of Ethosuximide in the Treatment of non-Diabetic Peripheral Neuropathic Pain: EDONOT-protocol of a randomised, parallel, controlled, double-blinded and multicentre clinical trial. AB - INTRODUCTION: Currently available analgesics are ineffective in 30-50% of patients suffering from neuropathic pain and often induce deleterious side effects. T-type calcium channel blockers (mibefradil, ethosuximide, NNC 55-0396) are of great interest for the development of new symptomatic treatments of neuropathic pain, due to their various effects on pain perception. Interestingly, ethosuximide, which has already been approved for treating epilepsy, is available on the European market for clinical use. Despite numerous preclinical data demonstrating an antinociceptive effect of ethosuximide in various animal models of neuropathic pain, no clinical studies have been published to date on the analgesic efficacy of ethosuximide in patients with neuropathic pain. METHODS AND ANALYSIS: The Ethosuximide in the Treatment of non-Diabetic Peripheral Neuropathic Pain (EDONOT) trial is a randomised, parallel, controlled, double blinded, multicentre clinical study. It is the first clinical trial to evaluate the efficacy and safety of ethosuximide in the treatment of non-diabetic peripheral neuropathic pain. Adult patients exhibiting peripheral neuropathic pain (Numeric Rating Scale (NRS) >=4 and Douleur Neuropathique 4 (DN4)>=4) for at least 3 months and under stable analgesic treatment for at least 1 month will be included. Patients (n=220) will be randomly assigned to receive either ethosuximide or control treatment for 6 weeks following a 1 week run-in period. The primary end point is the intensity of neuropathic pain, assessed by NRS (0 10) before and after 6 weeks of treatment. The secondary end points are safety (adverse events are collected during the study: daily by the patient on the logbook and during planned phone calls by investigators), the intensity and features of neuropathic pain (assessed by Brief Pain Inventory (BPI) and Neuropathic Pain Symptom Inventory (NPSI) questionnaires) and health-related quality of life (assessed by Medical Outcome Study Short Form 12 (MOS SF-12) and Leeds questionnaires). ETHICS AND COMMUNICATION: The study was approved by an independent ethics committee (CPP Sud-Est VI, France, IRB00008526) and registered by the French competent authority (Agence nationale de securite du medicament (ANSM)). TRIAL REGISTRATION NUMBER: NCT02100046, Recruiting. PMID- 27986743 TI - Treatment of febrile geriatric patients with suspected urinary tract infections in a hospital with high rates of ESBL producing bacteria: a cohort study. AB - PURPOSE: To determine the consequences of treating febrile geriatric patients with a suspected urinary tract infection (UTI) with antibiotics that have high resistance rates due primarily to extended-spectrum beta-lactamase (ESBL) producing bacteria. METHODS: In this cohort study, we selected 257 consecutive hospitalised patients aged >=70 years with a chief symptom of fever, possibly due to a UTI and initially treated with antibiotics with rates in our hospital of urinary culture resistance >20%. Patients with severe sepsis were excluded. The main outcomes measures were in vitro bacterial resistance to initial antibiotic therapy (BRIAT), response to therapy, hospitalisation days and mortality. RESULTS: Urine cultures were positive in 64.2% (165 of 257) of the patients and BRIAT occurred in 28.0% (72 of 257). Response rates were 100% (93 of 93) in those with bacteria sensitive to initial antibiotic therapy, 95.7% (88 of 92) in the culture negative patients, and 66.7% (48 of 72) in those with BRIAT (p<0.001). There were no deaths due to deterioration during the initial treatment period because of BRIAT. In the patients with BRIAT, the median length of hospitalisation was 3 days longer than that in the other patients (7 and 4 days, respectively, p<0.001). CONCLUSIONS: We conclude that initial broad spectrum antibiotic treatment could potentially lower the median length of hospitalisation by 3 days in many hospitalised geriatric patients without an extra-urinary tract source for their fever. This benefit needs to be balanced against the risk to the individual patient and to the general public of increasing bacterial resistance rates to broader spectrum antibiotics often held in reserve. PMID- 27986744 TI - Selling falsehoods? A cross-sectional study of Canadian naturopathy, homeopathy, chiropractic and acupuncture clinic website claims relating to allergy and asthma. AB - OBJECTIVE: To identify the frequency and qualitative characteristics of marketing claims made by Canadian chiropractors, naturopaths, homeopaths and acupuncturists relating to the diagnosis and treatment of allergy and asthma. DESIGN: Cross sectional study. SETTING: Canada. DATA SET: 392 chiropractic, naturopathic, homeopathic and acupuncture clinic websites located in 10 of the largest metropolitan areas in Canada, as identified using 400 Google search results. Duplicates were not excluded from data analysis. MAIN OUTCOME MEASURES: Mention of allergy, sensitivity or asthma, claim of ability to diagnose allergy, sensitivity or asthma, claim of ability to treat allergy, sensitivity or asthma, and claim of allergy, sensitivity or asthma treatment efficacy. Tests and treatments promoted were noted as qualitative examples. RESULTS: Naturopath clinic websites have the highest rates of advertising at least one of diagnosis, treatment or efficacy for allergy or sensitivity (85%) and asthma (64%), followed by acupuncturists (68% and 53%, respectively), homeopaths (60% and 54%) and chiropractors (33% and 38%). Search results from Vancouver, British Columbia were most likely to advertise at least one of diagnosis, treatment or efficacy for allergy or sensitivity (72.5%) and asthma (62.5%), and results from London, Ontario were least likely (50% and 40%, respectively). Of the interventions advertised, few are scientifically supported; the majority lack evidence of efficacy, and some are potentially harmful. CONCLUSIONS: The majority of alternative healthcare clinics studied advertised interventions for allergy and asthma. Many offerings are unproven. A policy response may be warranted in order to safeguard the public interest. PMID- 27986746 TI - A Glycomics-Based Test Predicts the Development of Hepatocellular Carcinoma in Cirrhosis. AB - Purpose: Cirrhosis is a major risk factor for the development of hepatocellular carcinoma but remains underdiagnosed in the compensated stage. Fibrosis progression and cirrhosis are associated with changes in blood serum glycomic profiles. Previously, the serum glycomics-based GlycoCirrhoTest was shown to identify 50% to 70% of compensated cirrhosis cases in chronic liver disease cohorts, at >90% specificity. This study assessed GlycoCirrhoTest for the risk of hepatocellular carcinoma development in compensated cirrhosis.Experimental Design: Serum glycomics were analyzed in sera of 133 patients, with compensated cirrhosis collected between 1995 and 2005 in a surveillance protocol for hepatocellular carcinoma using an optimized glycomic technology on a DNA sequencer.Results: Baseline GlycoCirrhoTest values were significantly increased in patients who developed hepatocellular carcinoma after a median follow-up of 6.4 years as compared with patients who did not. For patients with a baseline GlycoCirrhoTest exceeding 0.2, the HR for hepatocellular carcinoma development over the entire study (Cox regression) was 5.1 [95% confidence interval (CI), 2.2 11.7; P < 0.001], and the HR for hepatocellular carcinoma development within 7 years was 12.1 (95% CI, 2.8-51.6; P = 0.01) based on the cut-off value optimized in the same cohort. An absolute increase in GlycoCirrhoTest of 0.2 was associated with an HR of 10.29 (95% CI, 3.37-31.43; P < 0.001) for developing hepatocellular carcinoma. In comparison, the HR for the development of hepatocellular carcinoma within 7 years for AFP levels above the optimal cutoff in this study (5.75 ng/mL) was 4.65 (95% CI, 1.59-13.61).Conclusions: This prognostic study suggests that GlycoCirrhoTest is a serum biomarker that identifies compensated cirrhotic patients at risk for developing hepatocellular carcinoma. Screening strategies could be guided by a positive test on GlycoCirrhoTest. Clin Cancer Res; 23(11); 2750-8. (c)2016 AACR. PMID- 27986747 TI - Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer. AB - Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism.Experimental Design: We used EGFR-mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of osimertinib in vitro and in vivo Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR.Results:EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with osimertinib could regress tumors in EGFR-mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR-T790M mutations.Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139-49. (c)2016 AACR. PMID- 27986745 TI - Dual ALK and CDK4/6 Inhibition Demonstrates Synergy against Neuroblastoma. AB - Purpose: Anaplastic lymphoma kinase (ALK) is the most frequently mutated oncogene in the pediatric cancer neuroblastoma. We performed an in vitro screen for synergistic drug combinations that target neuroblastomas with mutations in ALK to determine whether drug combinations could enhance antitumor efficacy.Experimental Design: We screened combinations of eight molecularly targeted agents against 17 comprehensively characterized human neuroblastoma-derived cell lines. We investigated the combination of ceritinib and ribociclib on in vitro proliferation, cell cycle, viability, caspase activation, and the cyclin D/CDK4/CDK6/RB and pALK signaling networks in cell lines with representative ALK status. We performed in vivo trials in CB17 SCID mice bearing conventional and patient-derived xenograft models comparing ceritinib alone, ribociclib alone, and the combination, with plasma pharmacokinetics to evaluate for drug-drug interactions.Results: The combination of ribociclib, a dual inhibitor of cyclin dependent kinase (CDK) 4 and 6, and the ALK inhibitor ceritinib demonstrated higher cytotoxicity (P = 0.008) and synergy scores (P = 0.006) in cell lines with ALK mutations as compared with cell lines lacking mutations or alterations in ALK Compared with either drug alone, combination therapy enhanced growth inhibition, cell-cycle arrest, and caspase-independent cell death. Combination therapy achieved complete regressions in neuroblastoma xenografts with ALK-F1174L and F1245C de novo resistance mutations and prevented the emergence of resistance. Murine ribociclib and ceritinib plasma concentrations were unaltered by combination therapy.Conclusions: This preclinical combination drug screen with in vivo validation has provided the rationale for a first-in-children trial of combination ceritinib and ribociclib in a molecularly selected pediatric population. Clin Cancer Res; 23(11); 2856-68. (c)2016 AACR. PMID- 27986748 TI - Clinical Use of Programmed Cell Death-1 and Its Ligand Expression as Discriminatory and Predictive Markers in Ovarian Cancer. AB - Purpose: We aimed to establish whether programmed cell death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression, in ovarian cancer tumor tissue and blood, could be used as biomarkers for discrimination of tumor histology and prognosis of ovarian cancer.Experimental Design: Immune cells were separated from blood, ascites, and tumor tissue obtained from women with suspected ovarian cancer and studied for the differential expression of possible immune biomarkers using flow cytometry. PD-L1 expression on tumor-associated inflammatory cells was assessed by immunohistochemistry and tissue microarray. Plasma soluble PD-L1 was measured using sandwich ELISA. The relationships among immune markers were explored using hierarchical cluster analyses.Results: Biomarkers from the discovery cohort that associated with PD-L1+ cells were found. PD-L1+ CD14+ cells and PD-L1+ CD11c+ cells in the monocyte gate showed a distinct expression pattern when comparing benign tumors and epithelial ovarian cancers (EOCs)-confirmed in the validation cohort. Receiver operating characteristic curves showed PD-L1+ and PD-L1+ CD14+ cells in the monocyte gate performed better than the well established tumor marker CA-125 alone. Plasma soluble PD-L1 was elevated in patients with EOC compared with healthy women and patients with benign ovarian tumors. Low total PD-1+ expression on lymphocytes was associated with improved survival.Conclusions: Differential expression of immunological markers relating to the PD-1/PD-L1 pathway in blood can be used as potential diagnostic and prognostic markers in EOC. These data have implications for the development and trial of anti-PD-1/PD-L1 therapy in ovarian cancer. Clin Cancer Res; 23(13); 3453 60. (c)2016 AACR. PMID- 27986749 TI - Heterodimeric IL15 Treatment Enhances Tumor Infiltration, Persistence, and Effector Functions of Adoptively Transferred Tumor-specific T Cells in the Absence of Lymphodepletion. AB - Purpose: Adoptive cell transfer (ACT) is a promising immunotherapeutic approach for cancer. Host lymphodepletion is associated with favorable ACT therapy outcomes, but it may cause detrimental effects in humans. We tested the hypothesis that IL15 administration enhances ACT in the absence of lymphodepletion. We previously showed that bioactive IL15 in vivo comprises a stable complex of the IL15 chain with the IL15 receptor alpha chain (IL15Ralpha), termed heterodimeric IL15 (hetIL15).Experimental Design: We evaluated the effects of the combination regimen ACT + hetIL15 in the absence of lymphodepletion by transferring melanoma-specific Pmel-1 T cells into B16 melanoma-bearing mice.Results: hetIL15 treatment delayed tumor growth by promoting infiltration and persistence of both adoptively transferred Pmel-1 cells and endogenous CD8+ T cells into the tumor. In contrast, persistence of Pmel-1 cells was severely reduced following irradiation in comparison with mice treated with hetIL15. Importantly, we found that hetIL15 treatment led to the preferential enrichment of Pmel-1 cells in B16 tumor sites in an antigen-dependent manner. Upon hetIL15 administration, tumor-infiltrating Pmel-1 cells showed a "nonexhausted" effector phenotype, characterized by increased IFNgamma secretion, proliferation, and cytotoxic potential and low level of PD-1. hetIL15 treatment also resulted in an improved ratio of Pmel-1 to Treg in the tumor.Conclusions: hetIL15 administration improves the outcome of ACT in lymphoreplete hosts, a finding with significant implications for improving cell-based cancer immunotherapy strategies. Clin Cancer Res; 23(11); 2817-30. (c)2016 AACR. PMID- 27986752 TI - Commentary on: Nipple Reconstruction After Autologous or Expander Breast Reconstruction: A Multimodal and 3-Dimensional Analysis. PMID- 27986750 TI - Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients. AB - Purpose: Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of head and neck squamous cell carcinomas (HNSCC), where viral expression of the E6 and E7 oncoproteins is necessary for tumor growth and maintenance. Although patients with HPV+ tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV+ versus HPV- tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide-3-kinase (PI3K) in HPV+ tumors. Therefore, we investigated the role of HPV oncoproteins in regulating HER3-mediated signaling and determined whether HER3 could be a molecular target in HPV+ HNSCC.Experimental Design: HER3 was investigated as a molecular target in HPV+ HNSCC using established cell lines, patient-derived xenografts (PDX), and human tumor specimens. A mechanistic link between HPV and HER3 was examined by augmenting E6 and E7 expression levels in HNSCC cell lines. The dependency of HPV+ and HPV- HNSCC models on HER3 was evaluated with anti-HER3 siRNAs and the clinical stage anti-HER3 monoclonal antibody KTN3379.Results: HER3 was overexpressed in HPV+ HNSCC, where it was associated with worse overall survival in patients with pharyngeal cancer. Further investigation indicated that E6 and E7 regulated HER3 protein expression and downstream PI3K pathway signaling. Targeting HER3 with siRNAs or KTN3379 significantly inhibited the growth of HPV+ cell lines and PDXs.Conclusions: This study uncovers a direct relationship between HPV infection and HER3 in HNSCC and provides a rationale for the clinical evaluation of targeted HER3 therapy for the treatment of HPV+ patients. Clin Cancer Res; 23(12); 3072-83. (c)2016 AACR. PMID- 27986751 TI - A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer. AB - Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22 22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575-83. (c)2016 AACR. PMID- 27986753 TI - Nipple Reconstruction After Autologous or Expander Breast Reconstruction: A Multimodal and 3-Dimensional Analysis. AB - BACKGROUND: Little is known about the influence of the underlying tissue as donor for nipple-areola complex (NAC) reconstruction. Also, there is a complete lack of knowledge about the fate of nipple volume. OBJECTIVES: The goal of this retrospective, single-institution study was to analyze a case series after nipple reconstruction using a multimodal evaluation including 3-dimensional (3D) laser scanner analyses. METHODS: Unilateral mastectomy patients after either expander based or autologous breast reconstruction using the skate flap were included. NAC caliper measurement of nipple and areola size was performed. 3D laser scanner analysis (Minolta Vivid 900) was used to calculate nipple volume, measurement of nipple, and areolar projection and diameter. Sensitivity was evaluated using the Semmes Weinstein test and patient satisfaction by a visual analog scale (VAS 1 10). RESULTS: A total of 10 patients were included in the expander group and 12 patients were included in the flap group. After a median follow-up period of 32 months in the expander group and 34 months in the flap group, non-contact 3D laser surface scanning revealed a difference in projection of 55 to 60% compared to the contralateral side. The contraction in all 3 dimensions led to a dramatic difference in nipple volume with 12 +/- 8% (flap reconstructions) and 12 +/- 7% (expander reconstructions). Sensitivity of the areola showed better values after expander-based reconstruction. Despite the significant discrepancy in nipple volume and projection as well as areolar diameter, overall patient satisfaction was acceptable (VAS 4.1 +/- 3.5). CONCLUSIONS: Volume assessment revealed a massive asymmetry to the intact nipple but not between expander and flap reconstructions. Although asymmetry of the areola and nipple remains, patient satisfaction is acceptable. LEVEL OF EVIDENCE 4. PMID- 27986754 TI - Cannula Versus Sharp Needle for Placement of Soft Tissue Fillers: An Observational Cadaver Study. AB - Background: Soft-tissue fillers have become important products for facial rejuvenation. Deep fat compartments and facial bones lose volume during the natural aging process. For the most natural-looking results, deep volumetric injections at strategic sites are therefore preferred. Supraperiosteal placement is performed with a sharp needle or a non-traumatic cannula. Objectives: The primary objective was to determine whether there is a difference in precision between supraperiosteal placement with a sharp needle compared with a non traumatic cannula in cadaver specimens. A secondary objective was to analyze the safety profiles of both injection techniques. Methods: Cadaver heads were injected with dye material and soft-tissue fillers at multiple aesthetic facial sites on the supraperiosteum and subsequently dissected for observation of dye and filler placement. Results: The non-traumatic cannula technique resulted in product being confined to the deep anatomic layers. In contrast, with the sharp needle technique, material was placed in multiple anatomic layers, from the periosteum to more superficial skin layers. For both techniques results were consistent for all facial sites. Conclusions: Although direct extrapolation from cadavers to the in vivo situation cannot be made, cannulae showed more precision in placement of product. With the sharp needle, the material was injected on the periosteum, and then migrated in a retrograde direction along the trajectory of the needle path, ending up in multiple anatomic layers. The sharp needle technique also showed a higher complication risk with intra-arterial injection occurring, even though the needle tip was positioned on the periosteum and the product was injected with the needle in constant contact with the periosteum. PMID- 27986756 TI - Nonobstructive Versus Obstructive Coronary Artery Disease in Acute Coronary Syndrome: A Meta-Analysis. AB - BACKGROUND: Differences in prognosis and baseline clinical presentation have been documented among patient with acute coronary syndrome and coronary artery disease with obstructive (ObCAD) or nonobstructive arteries (NObCAD), but the rates of events largely varied across single studies. We carried out a meta-analysis to compare the clinical presentation and prognosis of NObCAD versus ObCAD acute coronary syndrome patients, as well as of the subjects with zero versus mild occlusion. METHODS AND RESULTS: Searches were made in MedLine, EMBASE, Cochrane databases, and proceedings of international meetings up to June 30, 2015. We compared the risk of events of NObCAD versus ObCAD patients using random-effect meta-analyses. We also performed meta-analyses to estimate the yearly or monthly outcome rates in each single group. In NObCAD and ObCAD patients, respectively, the combined yearly rates were as follows: 2.4% versus 10.1% (all-cause mortality); 1.2% versus 6.0% (myocardial infarction), 4.0% versus 12.8% (all cause mortality plus myocardial infarction), 1.4% versus 5.9% (cardiac death), and 9.2% versus 16.8% (major cardiovascular events). In the studies directly comparing NObCAD versus ObCAD, all of the above outcomes were significantly less frequent in NObCAD subjects (with risk ratios ranging from 0.33 to 0.66). No differences in any outcome rate were observed between mild occlusion (1-49% stenosis) and zero occlusion patients. CONCLUSIONS: NObCAD in patients with acute coronary syndrome has a significantly lower cardiovascular risk at baseline and a subsequent lower likelihood of death or main cardiovascular events. However, these subjects are still at high risk for cardiovascular mortality and morbidity, suggesting potential undertreatment and calling for specific management. PMID- 27986758 TI - Research authors' reply to Barlow and Barr and Taylor-Robinson. PMID- 27986755 TI - Impact of Incomplete Percutaneous Revascularization in Patients With Multivessel Coronary Artery Disease: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Up to half of patients undergoing percutaneous coronary intervention have multivessel coronary artery disease (MVD) with conflicting data regarding optimal revascularization strategy in such patients. This paper assesses the evidence for complete revascularization (CR) versus incomplete revascularization in patients undergoing percutaneous coronary intervention, and its prognostic impact using meta-analysis. METHODS AND RESULTS: A search of PubMed, EMBASE, MEDLINE, Current Contents Connect, Google Scholar, Cochrane library, Science Direct, and Web of Science was conducted to identify the association of CR in patients with multivessel coronary artery disease undergoing percutaneous coronary intervention with major adverse cardiac events and mortality. Random effects meta-analysis was used to estimate the odds of adverse outcomes. Meta regression analysis was conducted to assess the relationship with continuous variables and outcomes. Thirty-eight publications that included 156 240 patients were identified. Odds of death (OR 0.69, 95% CI 0.61-0.78), repeat revascularization (OR 0.60, 95% CI 0.45-0.80), myocardial infarction (OR 0.64, 95% CI 0.50-0.81), and major adverse cardiac events (OR 0.63, 95% CI 0.50-0.79) were significantly lower in the patients who underwent CR. These outcomes were unchanged on subgroup analysis regardless of the definition of CR. Similar findings were recorded when CR was studied in the chronic total occlusion (CTO) subgroup (OR 0.65, 95% CI 0.53-0.80). A meta-regression analysis revealed a negative relationship between the OR for mortality and the percentage of CR. CONCLUSION: CR is associated with reduced risk of mortality and major adverse cardiac events, irrespective of whether an anatomical or a score-based definition of incomplete revascularization is used, and this magnitude of risk relates to degree of CR. These results have important implications for the interventional management of patients with multivessel coronary artery disease. PMID- 27986757 TI - Cyanate-Impaired Angiogenesis: Association With Poor Coronary Collateral Growth in Patients With Stable Angina and Chronic Total Occlusion. AB - BACKGROUND: Cyanate has recently gained attention for its role in the pathogenesis of vascular injury. Nonetheless, the effect of cyanate on angiogenesis remains unclear. METHODS AND RESULTS: In this study, we demonstrated that oral administration of cyanate impaired blood perfusion recovery in a mouse hind-limb ischemia model. A reduction in blood perfusion recovery at day 21 was observed in the ischemic tissue of cyanate-treated mice. Likewise, there were fewer capillaries in the ischemic hind-limb tissue of cyanate-exposed mice. Our in vitro study showed that cyanate, together with its carbamylated products, inhibited the migration, proliferation, and tube-formation abilities of endothelial cells. Further research revealed that cyanate regulated angiogenesis partly by interrupting the vascular endothelial growth factor receptor 2/phosphatidylinositol 3-kinase/Akt pathway. The serum concentrations of homocitrulline, a marker of cyanate exposure, were determined in 117 patients with stable angina and chronic total occlusion. Consistent with the antiangiogenic role of cyanate, homocitrulline levels were increased in patients with poor coronary collateralization (n=58) compared with those with high collateralization (n=59; 21.09+/-13.08 versus 15.54+/-9.02 ng/mL, P=0.009). In addition, elevated homocitrulline concentration was a strong predictor of poor coronary collateral growth. CONCLUSIONS: Impaired angiogenesis induced by cyanate might contribute to poor coronary collateral growth. PMID- 27986759 TI - Are all sport activities equal? A systematic review of how youth psychosocial experiences vary across differing sport activities. AB - OBJECTIVE: Models of sport development often support the assumption that young athletes' psychosocial experiences differ as a result of seemingly minor variations in how their sport activities are designed (eg, participating in team or individual sport; sampling many sports or specialising at an early age). This review was conducted to systematically search sport literature and explore how the design of sport activities relates to psychosocial outcomes. DESIGN: Systematic search, followed by data extraction and synthesis. The Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines were applied and a coding sheet was used to extract article information and code for risk of bias. DATA SOURCES: Academic databases and manual search of peer-reviewed journals. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Search criteria determined eligibility primarily based on the sample (eg, ages 7 through 17 years) and study design (eg, measured psychosocial constructs). RESULTS: 35 studies were located and were classified within three categories: (1) sport types, (2) sport settings, and (3) individual patterns of sport involvement. These studies represented a wide range of scores when assessed for risk of bias and involved an array of psychosocial constructs, with the most prevalent investigations predicting outcomes such as youth development, self-esteem and depression by comparing (1) team or individual sport participants and (2) youth with varying amounts of sport involvement. SUMMARY/CONCLUSION: As variations in sport activities impact youth sport experiences, it is vital for researchers to carefully describe and study these factors, while practitioners may use the current findings when designing youth sport programmes. PMID- 27986760 TI - Concurrent aerobic plus resistance exercise versus aerobic exercise alone to improve health outcomes in paediatric obesity: a systematic review and meta analysis. AB - OBJECTIVE: To determine if the combination of aerobic and resistance exercise is superior to aerobic exercise alone for the health of obese children and adolescents. DESIGN: Systematic review with meta-analysis. DATA SOURCES: Computerised search of 3 databases (MEDLINE, EMBASE, and Cochrane Controlled Trials Registry). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies that compared the effect of supervised concurrent exercise versus aerobic exercise interventions, with anthropometric and metabolic outcomes in paediatric obesity (6-18 years old). The mean differences (MD) of the parameters from preintervention to postintervention between groups were pooled using a random effects model. RESULTS: 12 trials with 555 youths were included in the meta analysis. Compared with aerobic exercise alone, concurrent exercise resulted in greater reductions in body mass (MD=-2.28 kg), fat mass (MD=-3.49%; and MD=-4.34 kg) and low-density lipoprotein cholesterol (MD=-10.20 mg/dL); as well as greater increases in lean body mass (MD=2.20 kg) and adiponectin level (MD=2.59 MUg/mL). Differences were larger for longer term programmes (>24 weeks). SUMMARY: Concurrent aerobic plus resistance exercise improves body composition, metabolic profiles, and inflammatory state in the obese paediatric population. TRIAL REGISTRATION NUMBER: CRD42016039807. PMID- 27986761 TI - Resistance training interventions across the cancer control continuum: a systematic review of the implementation of resistance training principles. AB - OBJECTIVES: The primary purpose of this systematic review is to examine the extant resistance training (RT) cancer research to evaluate the proportion of RT interventions that: (1) implemented key RT training principles (specificity, progression, overload) and (2) explicitly reported relevant RT prescription components (frequency, intensity, sets, reps). DESIGN: A qualitative systematic review was performed by two reviewers (CMF and PNH) who inspected the titles and abstracts to determine eligibility for this systematic review. Identified papers were obtained in full and further reviewed. Data were extracted to evaluate the application of principles of training, along with specific RT components. DATA SOURCES: Electronic databases (PubMed, EMBASE, CINAHL, Cochrane, PEDro, PsychInfo, Cancer Lit, Sport Discus, AMED, Cochrane Central Register of Controlled Trials) and reference lists of included articles from inception to May 2016. RESULTS: 37 studies were included. The principle of specificity was used appropriately in all of the studies, progression in 65% and overload in 76% of the studies. The most common exercise prescription (~50%) implemented in the studies included in this review were 2-3 days/week, focusing on large muscle groups, 60-70% 1 repetition maximum (RM), 1-3 sets of 8-12 repetitions. CONCLUSIONS: Reporting of RT principles in an oncology setting varies greatly, with often vague or non-existent references to the principles of training and how the RT prescription was designed. PMID- 27986762 TI - Wearable, yes, but able...?: it is time for evidence-based marketing claims! PMID- 27986763 TI - No clinically important benefits of surgery over rehabilitation for lumbar spinal stenosis (PEDro synthesis). PMID- 27986765 TI - Skating to Where the Puck Is Going to Be. PMID- 27986764 TI - Low risk of concussions in top-level karate competition. AB - BACKGROUND: Although it is well known that injuries occur in combat sports, the true incidence of concussions is not clearly defined in the literature for karate competition. AIM: To determine the incidence of concussions in top-level (World Karate Federation World Championships) karate competition. METHODS: Injuries that took place in 4 consecutive World Karate Championships (from 2008 to 2014) were prospectively registered. A total of 4625 fights (2916 in the male category and 1709 in the female category) were scrutinised, and concussions were identified and analysed separately for frequency (rate per fight) and injury risk. RESULTS: A total of 4 concussions were diagnosed by the attending physicians after carrying out athlete examinations. Globally, there was 1 concussion in every 1156 fights, or 0.43/1000 athlete-exposures (AE). In male athletes, the rate of concussion was 1/5832 min of fighting, and in female athletes, it was 1/6836 min. OR for concussion in women is 0.57 (95% CI 0.06 to 5.47; z=0.489; p=0.6249) and risk ratio for concussions in men is RR 1.478 (95% CI 0.271 to 8.072), p=0.528, representing a higher risk of definite concussions in men than in women, but not statistically significant. There is not a significantly higher risk of concussions in team competition (no weight limit) when compared with individual competition (held with strict weight limits for each category). CONCLUSION: The risk of concussions in top-level karate competition is low, with a tendency for an increased risk for men and for competition without weight limits, but not statistically significant with respect to women or individual competition. PMID- 27986766 TI - Editorial Commentary: The Cervicovaginal Microbiota and Infection Risk After Exposure to an Exogenous Pathogen. PMID- 27986770 TI - Commentary on: Subplatysmal Necklift: A Retrospective Analysis of 504 Patients. PMID- 27986771 TI - Commentary on: Auto-Rim Flap Technique for Lateral Crura Caudal Excess Treatment. PMID- 27986773 TI - Commentary on: What Do Our Patients Truly Want? Conjoint Analysis of an Aesthetic Plastic Surgery Practice Using Internet Crowdsourcing. PMID- 27986772 TI - Increased Capacity for Work and Productivity After Breast Reduction. AB - BACKGROUND: Breast hypertrophy is a prevalent condition among women worldwide, which can affect different aspects of their quality of life. The physical and emotional impact of breast hypertrophy may harm daily activities, including work. OBJECTIVES: To assess the impact of reduction mammaplasty on the ability to work and productivity of women with breast hypertrophy. METHODS: A total of 60 patients with breast hypertrophy, already scheduled for breast reduction, aged 18 to 60 years and who had formal or autonomous employment were prospectively enrolled. The Brazilian versions of two validated tools, Work Productivity and Activity Impairment - General Health (WPAI-GH) and Work Limitations Questionnaire (WLQ) were self-administered at the preoperative evaluation and six months following surgery. RESULTS: The median age was 33 years, median body mass index was 24 kg/m2, and the median total weight of resected breast tissue was 617.5 g. According to the Brazilian classification of occupation, most patients (53%) had technical, scientific, artistic and similar occupations. There was a significant improvement in work capacity and productivity six months after the reduction mammaplasty, denoted by a decrease in presenteeism, absenteeism, and WLQ Productivity Loss Score (Wilcoxon analysis of variance: P < .0001 for each of these domains). CONCLUSIONS: Reduction mammaplasty increases the work capacity and productivity of Brazilian women with breast hypertrophy. LEVEL OF EVIDENCE 4. PMID- 27986774 TI - ASAPS and Aesthetic Surgery: The Next 50 Years. PMID- 27986775 TI - ASJ Welcomes New International Affiliate: The Hong Kong Society of Plastic, Reconstructive and Aesthetic Surgeons. PMID- 27986776 TI - Breast Implant Infection After Nipple Piercing. PMID- 27986777 TI - Comments on "Ptosis: An Underestimated Complication after Autologous Fat Injection into the Upper Eyelid". PMID- 27986778 TI - Response to "Comments On 'Ptosis: An Underestimated Complication After Autologous Fat Injection into the Upper Eyelid'". PMID- 27986779 TI - Long-Term Radiographic and Photographic Evaluation of the Pectoralis Muscle Loop in Reduction Mammaplasty. PMID- 27986780 TI - Response to "Long-Term Radiographic and Photographic Evaluation of the Pectoralis Muscle Loop in Reduction Mammaplasty". PMID- 27986783 TI - Double Monoclonal Immunoassay for Quantifying Human Visinin-Like Protein-1 in CSF. PMID- 27986784 TI - Anabasine Is a Poor Marker for Determining Smoking Status of Transplant Patients. PMID- 27986785 TI - Safety of lumen-apposing metal stents (LAMS) for pancreatic fluid collection drainage. PMID- 27986786 TI - Novel lncRNA T-UCR as a potential downstream driver of the Wnt/beta-catenin pathway in hepatobiliary carcinogenesis. PMID- 27986787 TI - Fifteen-minute consultation: problems in the healthy paediatrician-managing the effects of shift work on your health. AB - "You're not healthy unless your sleep is healthy"Professor William Dement, Stanford University, one of the founders of modern sleep medicineSleep is fundamental to good health. Healthcare professionals receive little teaching on the importance of sleep, particularly with respect to their own health when working night shifts. Knowledge of basic sleep physiology, together with simple strategies to improve core sleep and the ability to cope with working nights, can result in significant improvements both for healthcare professionals and for the patients they care for. PMID- 27986788 TI - Integrating teaching into everyday clinical practice. AB - The teaching and training of doctors-in-training in paediatrics has become increasingly challenging in recent times. All too often there is a perception that training must come second to service provision. In this article, the case of a child with community-acquired pneumonia is considered and used to illustrate how a culture of teaching can be embedded in everyday clinical practice. PMID- 27986789 TI - Presentation of acute suppurative parotitis in a newborn with incessant crying. PMID- 27986790 TI - When nuclear-encoded proteins and mitochondrial RNAs do not get along, species split apart. PMID- 27986792 TI - Alternative Oxidase Transcription Factors AOD2 and AOD5 of Neurospora crassa Control the Expression of Genes Involved in Energy Production and Metabolism. AB - In Neurospora crassa, blocking the function of the standard mitochondrial electron transport chain results in the induction of an alternative oxidase (AOX). AOX transfers electrons directly from ubiquinol to molecular oxygen. AOX serves as a model of retrograde regulation since it is encoded by a nuclear gene that is regulated in response to signals from mitochondria. The N. crassa transcription factors AOD2 and AOD5 are necessary for the expression of the AOX gene. To gain insight into the mechanism by which these factors function, and to determine if they have roles in the expression of additional genes in N. crassa, we constructed strains expressing only tagged versions of the proteins. Cell fractionation experiments showed that both proteins are localized to the nucleus under both AOX inducing and noninducing conditions. Furthermore, chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) analysis revealed that the proteins are bound to the promoter region of the AOX gene under both conditions. ChIP-seq also showed that the transcription factors bind to the upstream regions of a number of genes that are involved in energy production and metabolism. Dependence on AOD2 and AOD5 for the expression of several of these genes was verified by quantitative PCR. The majority of ChIP-seq peaks observed were enriched for both AOD2 and AOD5. However, we also observed occasional sites where one factor appeared to bind preferentially. The most striking of these was a conserved sequence that bound large amounts of AOD2 but little AOD5. This sequence was found within a 310 bp repeat unit that occurs at several locations in the genome. PMID- 27986793 TI - A SNP Based Linkage Map of the Arctic Charr (Salvelinus alpinus) Genome Provides Insights into the Diploidization Process After Whole Genome Duplication. AB - Diploidization, which follows whole genome duplication events, does not occur evenly across the genome. In salmonid fishes, certain pairs of homeologous chromosomes preserve tetraploid loci in higher frequencies toward the telomeres due to residual tetrasomic inheritance. Research suggests this occurs only in homeologous pairs where one chromosome arm has undergone a fusion event. We present a linkage map for Arctic charr (Salvelinus alpinus), a salmonid species with relatively fewer chromosome fusions. Genotype by sequencing identified 19,418 SNPs, and a linkage map consisting of 4508 markers was constructed from a subset of high quality SNPs and microsatellite markers that were used to anchor the new map to previous versions. Both male- and female-specific linkage maps contained the expected number of 39 linkage groups. The chromosome type associated with each linkage group was determined, and 10 stable metacentric chromosomes were identified, along with a chromosome polymorphism involving the sex chromosome AC04. Two instances of a weak form of pseudolinkage were detected in the telomeric regions of homeologous chromosome arms in both female and male linkage maps. Chromosome arm homologies within the Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss) genomes were determined. Paralogous sequence variants (PSVs) were identified, and their comparative BLASTn hit locations showed that duplicate markers exist in higher numbers on seven pairs of homeologous arms, previously identified as preserving tetrasomy in salmonid species. Homeologous arm pairs where neither arm has been part of a fusion event in Arctic charr had fewer PSVs, suggesting faster diploidization rates in these regions. PMID- 27986794 TI - Characteristics of Activities for Persons With Dementia at the Mild, Moderate, and Severe Stages. AB - Purpose: To understand activity in dementia care, we examine relationships of disease stage with types and characteristics of meaningful activities (cueing needs, help with initiation, and recommended engagement time) provided in a home based intervention trial designed to reduce behavioral symptoms. Design and Methods: Data involved 158 activity prescriptions or written documents detailing prescribed activities, cueing needs, and engagement goals designed by occupational therapists for 56 families. Activities were categorized as arts and crafts, exercise/physical, cognitive, music/entertainment, manipulation/sensory/sorting, family/social/ reminiscence, and domestic/homemaking. Bivariate correlations examined relationships of activity categories and characteristics with disease stage (mild, moderate, or severe). Kruskal-Wallis H tests examined differences among disease stages and frequency of type of activities prescribed, recommended cues, and engagement time. For significant Kruskal-Wallis tests, pairwise comparisons utilized the Mann-Whitney U test. Results: Activity categories and instructions for set up were significantly related to cognitive and functional levels. Persons with mild dementia were most often prescribed complex arts and crafts and cognitive activities. Persons with moderate dementia were most often prescribed music/entertainment. Persons with severe dementia were most often prescribed simple physical exercises and manipulation/sensory/sorting activities. Average time prescribed for activities was less for those in severe (15min) versus moderate (24min) and mild (28min) stages. The severe group required more assistance with activity initiation and cueing/redirection. Implications: Type of activity, recommended cueing, and engagement time differed by dementia stage. Findings provide guidance as to how to use and set up activities across the dementia trajectory. PMID- 27986795 TI - Defibrillation thresholds with right pectoral implantable cardioverter defibrillators and impact of waveform tuning (the Tilt and Tune trial). AB - Aims: Assess defibrillation thresholds (DFTs) with right active pectoral implantable cardioverter defibrillator (RICDs). Defibrillation thresholds in patients receiving RICDs are regarded as 'high' and potentially improved by waveform optimization (tuning). However, this has not been systematically tested. Methods and results: Patients receiving RICDs [Single chamber (VVI) = 16, DDD = 32, cardiac resynchronization therapy (CRT) = 43] were randomized to either 50/50% fixed tilt (FT) or tuned waveform (3.5 ms time constant based). Defibrillation threshold was tested with a binary search protocol in single coil anodal configuration. Then RICDs were compared with left-sided placements. Baseline patient characteristics in FT (n = 54) and tuned (n = 37) were similar (65 +/- 14 years, 71% male, Left ventricular ejection fraction 31 +/- 13%; and proportions VVI/DDD/Cardiac resynchronization therapy defibrillator). Tuning reduced Phase 1 by 15% and Phase 2 by 45%. For FT vs. tuned: high voltage impedance was 61.9 +/- 13.2 vs. 64.5 +/- 12.7 Omega (P = 0.33) and mean DFT 14.2 +/- 8.8 vs. 14.9 +/- 9.2 J (P = 0.8). When high voltage impedance was >62 Omega (mean 73.6 +/- 8.6 Omega), DFT was identical [FT 13.0 +/- 7.9 J vs. tuned 12.0 +/ 5.9 J (P= 0.7)]. Defibrillation thresholds exceeded 20 J (600 V) in >20% of patients [FT 11/54 (20.4%) vs. tuned 12/37 (32%) patients]. Defibrillation threshold with RICD was greater and exhibited wider dispersion compared with left ICDs (n = 54) under similar conditions. Conclusion: This first randomized trial investigating DFTs with right ICDs confirms relatively higher DFTs with RICDs than reported for left pectoral ICDs. However, DFTs were generally unaffected by 3.5 ms time constant-based waveform tuning compared with a 50% tilt waveform. Implant testing may be preferred with RICDs. Clinical trial number: NCT00873691. PMID- 27986791 TI - The NLR protein SUMM2 senses the disruption of an immune signaling MAP kinase cascade via CRCK3. AB - MAP kinase signaling is an integral part of plant immunity. Disruption of the MEKK1-MKK1/2-MPK4 kinase cascade results in constitutive immune responses mediated by the NLR protein SUMM2, but the molecular mechanism is so far poorly characterized. Here, we report that SUMM2 monitors a substrate protein of MPK4, CALMODULIN-BINDING RECEPTOR-LIKE CYTOPLASMIC KINASE 3 (CRCK3). Similar to SUMM2, CRCK3 was isolated from a suppressor screen of mkk1 mkk2 and is required for the autoimmunity phenotypes in mekk1, mkk1 mkk2, and mpk4 mutants. In wild-type plants, CRCK3 is mostly phosphorylated. MPK4 interacts with CRCK3 and can phosphorylate CRCK3 in vitro In mpk4 mutant plants, phosphorylation of CRCK3 is substantially reduced, suggesting that MPK4 phosphorylates CRCK3 in vivo Further, CRCK3 associates with SUMM2 in planta, suggesting SUMM2 senses the disruption of the MEKK1-MKK1/2-MPK4 kinase cascade through CRCK3. Our study suggests that a MAP kinase substrate is used as a guardee or decoy for monitoring the integrity of MAP kinase signaling. PMID- 27986796 TI - Association of Cardiovascular Risk Factors and Myocardial Fibrosis With Early Cardiac Dysfunction in Type 1 Diabetes: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study. AB - OBJECTIVE: We investigated the association of cardiovascular risk factors and myocardial fibrosis with early cardiac dysfunction in type 1 diabetes. RESEARCH DESIGN AND METHODS: Participants with type 1 diabetes aged 13-39 years without a known history of cardiovascular disease (CVD) (n = 1,441) were recruited into the Diabetes Control and Complications Trial (1983-1993) and subsequently followed in the Epidemiology of Diabetes Interventions and Complications study (1994 to present). Seven hundred fourteen participants underwent cardiac magnetic resonance (CMR) imaging (2007-2009) with late gadolinium enhancement sequences to assess ischemic and nonischemic scars and tagging sequences to evaluate circumferential strain. CMR-derived T1 mapping also was used to assess interstitial fibrosis. The influence of cardiovascular risk factors and myocardial scar on circumferential strain was assessed using linear regression. RESULTS: Circumferential dysfunction was consistently associated with older age, male sex, smoking history, obesity, higher blood pressure, lower HDL cholesterol, and higher mean HbA1c. Participants with nonischemic scars (n = 16) had the worst circumferential function compared with those without scars (beta +/- SE 1.32 +/- 0.60; P = 0.03). In sex-adjusted models, the correlation between T1 times and circumferential strain was not significant. In the fully adjusted models, a trend toward circumferential dysfunction in participants with nonischemic scars was found. Left ventricular ejection fraction was not associated with risk factors but was significantly lower if a myocardial scar was present. CONCLUSIONS: Traditional CVD risk factors and elevated HbA1c levels are major factors related to early cardiac dysfunction in type 1 diabetes. Nonischemic myocardial scar, possibly as a marker of chronic exposure to known risk factors, may predict early cardiac dysfunction mediated by diffuse myocardial fibrosis as seen in diabetic cardiomyopathy. PMID- 27986798 TI - Do workplace interventions reduce disability rates? AB - BACKGROUND: Increasing life expectancy and decreasing fertility have led to a shift in the workforce age structure towards older age groups. Deteriorating health and reduced work capacity are among the challenges to retaining older workers in the labour force. AIMS: To examine whether workplace interventions to facilitate work among employees with health problems or reduced work capacity affect disability rates among employees aged 50 years and older. METHODS: Data from a survey of Norwegian companies (n = 713) were linked with registry data on their employees aged 50-61 years (n = 30771). By means of a difference-in differences approach, we compared change in likelihood of receiving a full disability pension among employees in companies with and without workplace interventions. RESULTS: Employees in companies reporting to have workplace interventions in 2005 had a higher risk of receiving full disability pension during the period 2001-03 compared with employees in companies without such interventions [odds ratio (OR) 1.25, 95% confidence interval (CI) 1.07-1.45]. During the period 2005-07, there was an overall reduction in disability rates (OR 0.83, 95% CI 0.71-0.96) in both the intervention and control group. However, employees in companies reporting to have interventions in 2005 experienced an additional reduction in an employee's likelihood of receiving a full disability pension (OR 0.80, 95% CI 0.64-0.99) compared with employees in companies without interventions. CONCLUSIONS: Interventions to facilitate work among employees with health problems or reduced work capacity have reduced disability rates among employees aged 50-61. This suggests that companies' preventive interventions are an effective means to retain older workers with deteriorating health. PMID- 27986799 TI - Income-based equity weights in healthcare planning and policy. AB - Recent research indicates that there is a gap in life expectancy between the rich and the poor. This raises the question: should we on egalitarian grounds use income-based equity weights when we assess benefits of alternative benevolent interventions, so that health benefits to the poor count for more? This article provides three egalitarian arguments for using income-based equity weights under certain circumstances. If income inequality correlates with inequality in health, we have reason to use income-based equity weights on the ground that health inequality is bad. If income inequality correlates with inequality in opportunity for health, we have reason to use such weights on the ground that inequality in opportunity for health is bad. If income inequality correlates with inequality in well-being, income-based equity weights should be used to mitigate inequality in well-being. Three different ways in which to construe income-based equity weights are introduced and discussed. They can be based on relative income inequality, on income rankings and on capped absolute income. The article does not defend any of these types of weighting schemes, but argues that in order to settle which of these types of weighting scheme to choose, more empirical research is needed. PMID- 27986800 TI - A matter of life and death: controversy at the interface between clinical and legal decision-making in prolonged disorders of consciousness. AB - Best interests decision-making and end-of-life care for patients in permanent vegetative or minimally conscious states (VS/MCS) is a complex area of clinical and legal practice, which is poorly understood by most clinicians, lawyers and members of the public. In recent weeks, the Oxford Shrieval lecture by Mr Justice Baker ('A Matter of Life and Death', 11 October 2016) and its subsequent reporting in the public press has sparked debate on the respective roles of clinicians, the Court of Protection and the Mental Capacity Act 2005 in decisions to withhold or withdraw life-sustaining treatments from patients with disorders of consciousness. The debate became polarised and confused by misquotation and inaccurate terminology, and highlighted a lack of knowledge about how patients in VS/MCS die in the absence of court approval. This article sets out the background and discussion and attempts to give a more accurate representation of the facts. In the spirit of transparency, I present a mortality review of all the patients in VS/MCS who have died under the care of my own unit in the last decade-with or without referral to the court, but always in accordance with the law. These data demonstrate that clinicians regularly undertake best interests decision-making in conjunction with families that may include life and death decisions (sometimes even the withdrawal or withholding of clinically assisted nutrition and hydration); and that these can be made within the current legal framework without necessarily involving the court in all cases. This is the first published case series of its kind. PMID- 27986797 TI - Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. AB - Reduced mitochondrial electron transport chain activity promotes longevity and improves energy homeostasis via cell-autonomous and -non-autonomous factors in multiple model systems. This mitohormetic effect is thought to involve the mitochondrial unfolded protein response (UPRmt), an adaptive stress-response pathway activated by mitochondrial proteotoxic stress. Using mice with skeletal muscle-specific deficiency of Crif1 (muscle-specific knockout [MKO]), an integral protein of the large mitoribosomal subunit (39S), we identified growth differentiation factor 15 (GDF15) as a UPRmt-associated cell-non-autonomous myomitokine that regulates systemic energy homeostasis. MKO mice were protected against obesity and sensitized to insulin, an effect associated with elevated GDF15 secretion after UPRmt activation. In ob/ob mice, administration of recombinant GDF15 decreased body weight and improved insulin sensitivity, which was attributed to elevated oxidative metabolism and lipid mobilization in the liver, muscle, and adipose tissue. Thus, GDF15 is a potent mitohormetic signal that safeguards against the onset of obesity and insulin resistance. PMID- 27986801 TI - Decreased telomere length in children with cartilage-hair hypoplasia. AB - BACKGROUND: Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia caused by RMRP (RNA component of mitochondrial RNA processing endoribonuclease) gene mutations. Manifestations include short stature, variable immunodeficiency, anaemia and increased risk of malignancies, all of which have been described also in telomere biology disorders. RMRP interacts with the telomerase RT (TERT) subunit, but the influence of RMRP mutations on telomere length is unknown. We measured relative telomere length (RTL) in patients with CHH, their first-degree relatives and healthy controls and correlated RTL with clinical and laboratory features. METHODS: The study cohort included 48 patients with CHH with homozygous (n=36) or compound heterozygous RMRP mutations (median age 38.2 years, range 6.0-70.8 years), 86 relatives (74 with a heterozygous RMRP mutation) and 94 unrelated healthy controls. We extracted DNA from peripheral blood, sequenced the RMRP gene and measured RTL by qPCR. RESULTS: Compared with age-matched and sex-matched healthy controls, median RTL was significantly shorter in patients with CHH (n=40 pairs, 1.05 vs 1.21, p=0.017), but not in mutation carriers (n=48 pairs, 1.16 vs 1.10, p=0.224). RTL correlated significantly with age in RMRP mutation carriers (r=-0.482, p<0.001) and non carriers (r=-0.498, p<0.001), but not in patients (r=-0.236, p=0.107). In particular children (<18 years) with CHH had shorter telomeres than controls (median RTL 1.12 vs 1.26, p=0.008). In patients with CHH, RTL showed no correlation with genotype, clinical or laboratory characteristics. CONCLUSIONS: Telomere length was decreased in children with CHH. We found no correlation between RTL and clinical or laboratory parameters. PMID- 27986803 TI - Androgen deprivation therapy for prostate cancer and the risk of hospitalisation for community-acquired pneumonia. AB - BACKGROUND: Androgens have been shown to influence both the immune system and lung tissue, raising the hypothesis that androgen deprivation therapy (ADT) for prostate cancer may increase the risk of pneumonia. Thus, the aim of this study was to determine whether ADT is associated with an increased risk of hospitalisation for community-acquired pneumonia in patients with prostate cancer. METHODS: This was a population-based cohort study using the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics repository. The cohort consisted of 20 310 men newly diagnosed with non-metastatic prostate cancer between 1 April 1998 and 31 March 2015. Time dependent Cox proportional hazards models were used to estimate adjusted HRs and 95% CIs for hospitalisation for community-acquired pneumonia associated with current and past use of ADT compared with non-use. RESULTS: During a mean follow up of 4.3 years, there were 621 incident hospitalisations for community-acquired pneumonia (incidence rate: 7.2/1000 person-years). Current ADT use was associated with an 81% increased risk of hospitalisation for community-acquired pneumonia (12.1 vs 3.8 per 1000 person-years, respectively; HR 1.81, 95% CI 1.47 to 2.23). The association was observed within the first six months of use (HR 1.73, 95% CI 1.23 to 2.42) and remained elevated with increasing durations of use (>=25 months; HR 1.79, 95% CI 1.39 to 2.30). In contrast, past ADT use was not associated with an increased risk (HR 1.23, 95% CI 0.95 to 1.60). CONCLUSIONS: The use of ADT is associated with an increased risk of hospitalisation for community-acquired pneumonia in men with prostate cancer. PMID- 27986804 TI - Dwarfism and Altered Craniofacial Development in Rabbits Is Caused by a 12.1 kb Deletion at the HMGA2 Locus. AB - The dwarf phenotype characterizes the smallest of rabbit breeds and is governed largely by the effects of a single dwarfing allele with an incompletely dominant effect on growth. Dwarf rabbits typically weigh under 1 kg and have altered craniofacial morphology. The dwarf allele is recessive lethal and dwarf homozygotes die within a few days of birth. The dwarf phenotype is expressed in heterozygous individuals and rabbits from dwarf breeds homozygous for the wild type allele are normal, although smaller when compared to other breeds. Here, we show that the dwarf allele constitutes a ~12.1 kb deletion overlapping the promoter region and first three exons of the HMGA2 gene leading to inactivation of this gene. HMGA2 has been frequently associated with variation in body size across species. Homozygotes for null alleles are viable in mice but not in rabbits and probably not in humans. RNA-sequencing analysis of rabbit embryos showed that very few genes (4-29 genes) were differentially expressed among the three HMGA2/dwarf genotypes, suggesting that dwarfism and inviability in rabbits are caused by modest changes in gene expression. Our results show that HMGA2 is critical for normal expression of IGF2BP2, which encodes an RNA-binding protein. Finally, we report a catalog of regions of elevated genetic differentiation between dwarf and normal-size rabbits, including LCORL-NCAPG, STC2, HOXD cluster, and IGF2BP2 Levels and patterns of genetic diversity at the LCORL-NCAPG locus further suggest that small size in dwarf breeds was enhanced by crosses with wild rabbits. Overall, our results imply that small size in dwarf rabbits results from a large effect, loss-of-function (LOF) mutation in HMGA2 combined with polygenic selection. PMID- 27986805 TI - Emergence of a Novel Chimeric Gene Underlying Grain Number in Rice. AB - Grain number is an important factor in determining grain production of rice (Oryza sativa L.). The molecular genetic basis for grain number is complex. Discovering new genes involved in regulating rice grain number increases our knowledge regarding its molecular mechanisms and aids breeding programs. Here, we identified GRAINS NUMBER 2 (GN2), a novel gene that is responsible for rice grain number, from "Yuanjiang" common wild rice (O. rufipogon Griff.). Transgenic plants overexpressing GN2 showed less grain number, reduced plant height, and later heading date than control plants. Interestingly, GN2 arose through the insertion of a 1094-bp sequence from LOC_Os02g45150 into the third exon of LOC_Os02g56630, and the inserted sequence recruited its nearby sequence to generate the chimeric GN2 The gene structure and expression pattern of GN2 were distinct from those of LOC_Os02g45150 and LOC_Os02g56630 Sequence analysis showed that GN2 may be generated in the natural population of Yuanjiang common wild rice. In this study, we identified a novel functional chimeric gene and also provided information regarding the molecular mechanisms regulating rice grain number. PMID- 27986806 TI - Repair of Meiotic DNA Breaks and Homolog Pairing in Mouse Meiosis Requires a Minichromosome Maintenance (MCM) Paralog. AB - The mammalian Mcm-domain containing 2 (Mcmdc2) gene encodes a protein of unknown function that is homologous to the minichromosome maintenance family of DNA replication licensing and helicase factors. Drosophila melanogaster contains two separate genes, the Mei-MCMs, which appear to have arisen from a single ancestral Mcmdc2 gene. The Mei-MCMs are involved in promoting meiotic crossovers by blocking the anticrossover activity of BLM helicase, a function presumably performed by MSH4 and MSH5 in metazoans. Here, we report that MCMDC2-deficient mice of both sexes are viable but sterile. Males fail to produce spermatozoa, and formation of primordial follicles is disrupted in females. Histology and immunocytological analyses of mutant testes revealed that meiosis is arrested in prophase I, and is characterized by persistent meiotic double-stranded DNA breaks (DSBs), failure of homologous chromosome synapsis and XY body formation, and an absence of crossing over. These phenotypes resembled those of MSH4/5-deficient meiocytes. The data indicate that MCMDC2 is essential for invasion of homologous sequences by RAD51- and DMC1-coated single-stranded DNA filaments, or stabilization of recombination intermediates following strand invasion, both of which are needed to drive stable homolog pairing and DSB repair via recombination in mice. PMID- 27986808 TI - Activation of transient receptor potential vanilloid 1 by lipoxygenase metabolites depends on PKC phosphorylation. AB - Peripheral neuronal activation by inflammatory mediators is a multifaceted physiological response that involves a multitude of regulated cellular functions. One key pathway that has been shown to be involved in inflammatory pain is Gq/GPCR, whose activation by inflammatory mediators is followed by the regulated response of the cation channel transient receptor potential vanilloid 1 (TRPV1). However, the mechanism that underlies TRPV1 activation downstream of the Gq/GPCR pathway has yet to be fully defined. In this study, we employ pharmacological and molecular biology tools to dissect this activation mechanism via perforated-patch recordings and calcium imaging of both neurons and a heterologous system. We showed that TRPV1 activity downstream of Gq/GPCR activation only produced a subdued current, which was noticeably different from the robust current that is typical of TRPV1 activation by exogenous stimuli. Moreover, we specifically demonstrated that 2 pathways downstream of Gq/GPCR signaling, namely endovanilloid production by lipoxygenases and channel phosphorylation by PKC, converge on TRPV1 to evoke a tightly regulated response. Of importance, we show that only when both pathways are acting on TRPV1 is the inflammatory-mediated response achieved. We propose that the requirement of multiple signaling events allows subdued TRPV1 activation to evoke regulated neuronal response during inflammation.-Kumar R., Hazan, A., Geron, M., Steinberg, R., Livni, L., Matzner, H., Priel, A. Activation of transient receptor potential vanilloid 1 by lipoxygenase metabolites depends on PKC phosphorylation. PMID- 27986807 TI - Effects of 4 multitargeted receptor tyrosine kinase inhibitors on regional hemodynamics in conscious, freely moving rats. AB - VEGF inhibitors, including receptor tyrosine kinase inhibitors, are used as adjunct therapies in a number of cancer treatments. An emerging issue with these drugs is that most cause hypertension. To gain insight into the physiological mechanisms involved, we evaluated their regional hemodynamic effects in conscious rats. Male Sprague Dawley rats (350-450 g) were chronically implanted with pulsed Doppler flow probes (renal and mesenteric arteries, and the descending abdominal aorta) and catheters (jugular vein, peritoneal cavity, and distal abdominal aorta). Regional hemodynamics were measured over 4 d, before and after daily administration of cediranib (3 and 6 mg/kg, 3 and 6 mg/kg/h for 1 h, i.v.), sorafenib (10 and 20 mg/kg, 10 and 20 mg kg/h for 1 h, i.v.), pazopanib (30 and100 mg/kg, i.p.), or vandetanib (12.5 and 25 mg/kg, i.p.). All drugs evoked significant increases (P < 0.05; n = 7-8) in mean arterial pressure, which were generally accompanied by significant mesenteric and hindquarters, but not renal, vasoconstrictions. The hypertensive effects of cediranib were unaffected by losartan (10 mg/kg/h), bosentan (20 mg/kg/h), or a combination of phentolamine and propranolol (each 1 mg/kg/h), suggesting a need for new strategies to overcome them.-Carter, J. J., Fretwell, L. V., Woolard, J. Effects of 4 multitargeted receptor tyrosine kinase inhibitors on regional hemodynamics in conscious, freely moving rats. PMID- 27986809 TI - Urokinase-type Plasminogen Activator (uPA) Binding to the uPA Receptor (uPAR) Promotes Axonal Regeneration in the Central Nervous System. AB - Axonal injury is a common cause of neurological dysfunction. Unfortunately, in contrast to axons from the peripheral nervous system, the limited capacity of regeneration of central nervous system (CNS) axons is a major obstacle for functional recovery in patients suffering neurological diseases that involve the subcortical white matter. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to the urokinase-type plasminogen activator receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface. uPAR expression increases after an injury, and signaling through uPAR promotes tissue remodeling. However, it is yet unknown whether uPA binding to uPAR has an effect on axonal recovery in the CNS. Here, we used in vitro and in vivo models of CNS axonal injury to test the hypothesis that uPA binding to uPAR promotes axonal regeneration in the CNS. We found that newly formed growth cones from axons re-emerging from an axonal injury express uPAR and that binding of uPA to this uPAR promotes axonal recovery by a mechanism that does not require the generation of plasmin. Our data indicate that the binding of recombinant uPA or endogenous uPA to uPAR induces membrane recruitment and activation of beta1 integrin via the low density lipoprotein receptor-related protein-1 (LRP1), which leads to activation of the Rho family small GTPase Rac1 and Rac1-induced axonal regeneration. Our results show that the uPA/uPAR/LRP1 system is a potential target for the development of therapeutic strategies to promote axonal recovery following a CNS injury. PMID- 27986810 TI - Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function. AB - GPRC6A is a G protein-coupled receptor activated by l-amino acids, which, based on analyses of knock-out mice, has been suggested to have physiological functions in metabolism and testicular function. The human ortholog is, however, mostly retained intracellularly in contrast to the cell surface-expressed murine and goldfish orthologs. The latter orthologs are Gq-coupled and lead to intracellular accumulation of inositol phosphates and calcium release. In the present study we cloned the bonobo chimpanzee GPRC6A receptor, which is 99% identical to the human receptor, and show that it is cell surface-expressed and functional. By analyses of chimeric human/mouse and human/bonobo receptors, bonobo receptor mutants, and the single nucleotide polymorphism database at NCBI, we identify an insertion/deletion variation in the third intracellular loop responsible for the intracellular retention and lack of function of the human ortholog. Genetic analyses of the 1000 genome database and the Inter99 cohort of 6,000 Danes establish the distribution of genotypes among ethnic groups, showing that the cell surface-expressed and functional variant is much more prevalent in the African population than in European and Asian populations and that this variant is partly linked with a stop codon early in the receptor sequence (rs6907580, amino acid position 57). In conclusion, our data solve a more than decade-old question of why the cloned human GPRC6A receptor is not cell surface-expressed and functional and provide a genetic framework to study human phenotypic traits in large genome sequencing projects linked with physiological measurement and biomarkers. PMID- 27986811 TI - EphB3 Stimulates Cell Migration and Metastasis in a Kinase-dependent Manner through Vav2-Rho GTPase Axis in Papillary Thyroid Cancer. AB - Eph receptors, the largest subfamily of transmembrane tyrosine kinase receptors, have been increasingly implicated in various physiologic and pathologic processes, and the roles of the Eph family members during tumorigenesis have recently attracted growing attentions. In the present study, we explored the function of EphB3, one member of Eph family, in papillary thyroid cancer (PTC). We found that the expression of EphB3 was significantly elevated in PTC. Either overexpression of EphB3 or activation of EphB3 by EfnB1-Fc/EfnB2-Fc stimulated in vitro migration of PTC cells. In contrast, siRNA-mediated knockdown of EphB3 or EphB3-Fc treatment, which only blocked EphB3-mediated forward signaling, inhibited migration and metastasis of PTC cells. A mechanism study revealed that EphB3 knockdown led to suppressed activity of Rac1 and enhanced activity of RhoA. Moreover, we found that Vav2, an important regulator of Rho family GTPases, was activated by EphB3 in a kinase-dependent manner. Altogether, our work suggested that EphB3 acted as a tumor promoter in PTC by increasing the in vitro migration as well as the in vivo metastasis of PTC cells through regulating the activities of Vav2 and Rho GTPases in a kinase-dependent manner. PMID- 27986814 TI - Wrong guidelines: why and how often they occur. AB - Evidence-based guidelines are considered an essential tool in assisting physicians, policymakers and patients when choosing among alternative care options and are considered unbiased standards of care. Unfortunately, depending on how their reliability is measured, up to 50% of guidelines can be considered untrustworthy. This carries serious consequences for patients' safety, resource use and health economics burden. Although conflict of interests, panel composition and methodological flaws are traditionally thought to be the main reasons undermining their untrustworthiness, corruption and waste of biomedical research also contribute. We discuss these issues in the hope for a wider awareness of the limits of guidelines. PMID- 27986812 TI - Barbiturates Bind in the GLIC Ion Channel Pore and Cause Inhibition by Stabilizing a Closed State. AB - Barbiturates induce anesthesia by modulating the activity of anionic and cationic pentameric ligand-gated ion channels (pLGICs). Despite more than a century of use in clinical practice, the prototypic binding site for this class of drugs within pLGICs is yet to be described. In this study, we present the first X-ray structures of barbiturates bound to GLIC, a cationic prokaryotic pLGIC with excellent structural homology to other relevant channels sensitive to general anesthetics and, as shown here, to barbiturates, at clinically relevant concentrations. Several derivatives of barbiturates containing anomalous scatterers were synthesized, and these derivatives helped us unambiguously identify a unique barbiturate binding site within the central ion channel pore in a closed conformation. In addition, docking calculations around the observed binding site for all three states of the receptor, including a model of the desensitized state, showed that barbiturates preferentially stabilize the closed state. The identification of this pore binding site sheds light on the mechanism of barbiturate inhibition of cationic pLGICs and allows the rationalization of several structural and functional features previously observed for barbiturates. PMID- 27986815 TI - Informing treatment decisions through meta-analysis: to network or not? AB - Evidence from randomised trials and their meta-analyses is typically formed of head-to-head comparisons of a couple of treatments; multiarm trials are infrequent. However, in real-life healthcare, there are many more than two treatment options for a particular condition. To be relevant for the shop-floor of practice, evidence-based medicine requires the use a comprehensive approach to compile, compare and contrast evidence on all options in one synthesis. Network meta-analysis (NMA) offers exactly such a solution. It generates a rank order of the available treatments for practitioners and policymakers that has the merit of objectivity. However, reviewers should make transparent the limitations of NMA as it uses direct and indirect comparisons, inevitably collating data with a certain degree of heterogeneity. This approach is increasingly being deployed to underpin evidence syntheses for incorporating research into practice. PMID- 27986813 TI - Dopamine Transporter Amino and Carboxyl Termini Synergistically Contribute to Substrate and Inhibitor Affinities. AB - Extracellular dopamine and serotonin concentrations are determined by the presynaptic dopamine (DAT) and serotonin (SERT) transporters, respectively. Numerous studies have investigated the DAT and SERT structural elements contributing to inhibitor and substrate binding. To date, crystallographic studies have focused on conserved transmembrane domains, where multiple substrate binding and translocation features are conserved. However, it is unknown what, if any, role the highly divergent intracellular N and C termini contribute to these processes. Here, we used chimeric proteins to test whether DAT and SERT N and C termini contribute to transporter substrate and inhibitor affinities. Replacing the DAT N terminus with that of SERT had no effect on DA transport Vmax but significantly decreased DAT substrate affinities for DA and amphetamine. Similar losses in uptake inhibition were observed for small DAT inhibitors, whereas substituting the DAT C terminus with that of SERT affected neither substrate nor inhibitor affinities. In contrast, the N-terminal substitution was completely tolerated by the larger DAT inhibitors, which exhibited no loss in apparent affinity. Remarkably, all affinity losses were rescued in DAT chimeras encoding both SERT N and C termini. The sensitivity to amino-terminal substitution was specific for DAT, because replacing the SERT N and/or C termini affected neither substrate nor inhibitor affinities. Taken together, these findings provide compelling experimental evidence that DAT N and C termini synergistically contribute to substrate and inhibitor affinities. PMID- 27986816 TI - Wrong guidelines: how to detect them and what to do in the case of flawed recommendations. AB - Any evidence-based recommendation needs careful assessment of its methodological background as well as of its content trustworthiness, especially given that following it will not necessarily produce the intended clinical outcomes. There are no established instruments to evaluate guidelines for their content, while useful tools assessing the quality of methods followed are well recognised and adopted. We suggest a 'safety bundle' considering methodological aspects and content trustworthiness of guidelines, by adopting the GRADE method in a backward fashion. Sharing the critical analysis of the guidelines with patients, including any eventual uncertainty about them, is of key importance in order to avoid the possible adverse effects derived from following the wrong guidelines. Such critical approach is also helpful and beneficial in producing better care pathways, health policy decisions and more relevant and ethical research. PMID- 27986817 TI - The slow growing embryo and premature progesterone elevation: compounding factors for embryo-endometrial asynchrony. AB - STUDY QUESTION: Is there an association of progesterone (P4) on the day of trigger with live birth in autologous ART transfer cycles on day 5 versus day 6? SUMMARY ANSWER: P4 had a greater negative effect on live birth in day 6 fresh transfers compared to day 5 fresh transfers. WHAT IS KNOWN ALREADY: Premature P4 elevation is associated with lower live birth rates in fresh autologous ART cycles, likely due to worsened endometrial-embryo asynchrony. Few studies have evaluated whether the effect of an elevated P4 on the day of trigger is different on live birth rates with a day 5 compared to a day 6 embryo transfer. STUDY DESIGN SIZE, DURATION: This was a retrospective cohort study with autologous IVF cycles with fresh embryo transfers on day 5 and day 6 from 2011 to 2014. A total of 4120 day 5 and 230 day 6 fresh autologous embryo transfers were included. The primary outcome was live birth, defined as a live born baby at 24 weeks gestation or later. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients from a large private ART practice were included. Analysis was performed with generalized estimating equations (GEE) modeling and receiver operating characteristic (ROC) curves. MAIN RESULTS AND THE ROLE OF CHANCE: Day 6 transfers were less likely to have good quality embryos (73% versus 83%, P < 0.001) but the cohorts had similar rates of blastocyst stage transfer (92% versus 91%, P = 0.92). Live birth was less likely in fresh day 6 versus day 5 embryo transfers (34% versus 46%, P = 0.01) even when controlling for embryo confounders. In adjusted GEE models, the effect of P4 as a continuous variable on live birth was more pronounced on day 6 (P < 0.001). Similarly, the effect of P4 > 1.5 ng/ml on day of trigger was more pronounced on day 6 than day 5 (P < 0.001). Day 6 live birth rates were 8% lower than day 5 when P4 was in the normal range (P = 0.04), but became 17% lower when P4 was > 1.5 ng/ml (P < 0.01). ROC curves for P4 predicting live birth demonstrated a greater AUC in day 6 transfers (AUC 0.59, 95% CI 0.51-0.66) than day 5 (AUC 0.54, 95% CI 0.52-0.55). Interaction testing of P4 * day of embryo transfer was highly significant (P < 0.001), further suggesting that the effect of P4 was more pronounced on day 6 embryo transfer. In fresh oocyte retrieval cycles with elevated P4, a subsequent 760 frozen-thaw transfers did not demonstrate a difference between embryos that were frozen after blastulation on day 5 versus 6. LIMITATIONS REASONS FOR CAUTION: Limitations include the retrospective design and the inability to control for certain confounding variables, such as thaw survival rates between day 5 and day 6 blastocysts. Also, the data set lacks the known ploidy status of the embryos and the progesterone assay is not currently optimized to discriminate between patients with a P4 of 1.5 versus 1.8 ng/ml. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests further endometrial embryo asynchrony when a slow growing embryo is combined with an advanced endometrium, ultimately leading to decreased live births. This suggests that premature elevated P4 may be a factor in the lower live birth rates in day 6 fresh embryo transfers. Further studies are needed to evaluate if a frozen embryo transfer cycle can ameliorate the effect of elevated P4 on the day of trigger among these slower growing embryos that reach blastocyst staging on day 6. STUDY FUNDING/COMPETING INTERESTS: No external funding was received for this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 27986818 TI - mRNA levels of low-density lipoprotein receptors are overexpressed in the foci of deep bowel endometriosis. AB - STUDY QUESTION: Is mRNA expression of LDL receptors altered in deep bowel endometriotic foci? SUMMARY ANSWER: mRNA expression of LDL receptors is up regulated in deep bowel endometriotic foci of patients with endometriosis. WHAT IS KNOWN ALREADY: Several studies have demonstrated the overexpression of low density lipoprotein receptors in various tumour cell lines and endometriosis has similar aspects to cancer, mainly concerning the pathogenesis of both diseases. This is the first study we know of to investigate lipoprotein receptors expression in deep endometriosis with bowel involvement. STUDY DESIGN, SIZE, DURATION: During 2014-2015, an exploratory case-control study was conducted with 39 patients, including 20 women with a histological diagnosis of deep endometriosis compromising the bowel and 19 women without endometriosis who underwent laparoscopic tubal ligation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Peripheral blood samples were collected on the day of surgery for lipid profile analysis, and samples of endometrial tissue and of bowel endometriotic lesions were also collected. The tissue samples were sent for histopathological analysis and for LDL-R and LRP-1 gene expression screening using quantitative real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE: Patients with deep endometriosis had lower LDL-cholesterol than patients without the disease (119 +/- 23 versus 156 +/ 35; P = 0.001). Gene expression analysis of LDL receptors revealed that LDL-R was more highly expressed in endometriotic lesions when compared to the endometrium of the same patient but not more than in the endometrium of women without endometriosis (0.027 +/- 0.022 versus 0.012 +/- 0.009 versus 0.019 +/- 0.01, respectively; P < 0.001). LRP-1 was more highly expressed in endometriotic lesions, both when compared with the endometrium of the same patient and when compared with the endometrium of patients without the disease (0.307 +/- 0.207 versus 0.089 +/- 0.076 and versus 0.126 +/- 0.072, respectively; P < 0.001). The study also showed that LDL-R gene expression in the endometrium of women with endometriosis was higher during the secretory phase of the menstrual cycle (P = 0.001). LRP-1 gene expression was increased during the secretory phase in the endometrium of women without the disease (P = 0.008). LIMITATIONS, REASONS FOR CAUTION: In the endometriotic lesions, the presence of fibrosis is substantial, restricting access to the stromal and glandular components of the lesion. Despite that, we found that LDL receptor mRNA was overexpressed. Future studies may perform laser microdissection to isolate the area of interest in the target tissue, excluding fibrosis contamination. WIDER IMPLICATIONS OF THE FINDINGS: This study supports the feasibility of LDL-R targeted therapy in the treatment of deep endometriosis. STUDY FUNDING/COMPETING INTERESTS: This study was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP #2011/17245-0). The authors have no conflicts of interest to declare. PMID- 27986819 TI - There is no evidence that the time from egg retrieval to embryo transfer affects live birth rates in a freeze-all strategy. AB - STUDY QUESTION: Does the time from ovum pick-up (OPU) to frozen embryo transfer (FET) affect reproductive outcomes in a freeze-all strategy? SUMMARY ANSWER: Our study did not detect statistically significant differences between first and subsequent cycles, clinically relevant differences are not ruled out and further and larger studies are required. WHAT IS KNOWN ALREADY: Following controlled ovarian hyperstimulation (COH) delaying FET until the endometrium has returned to an optimal pre-stimulation state may have a significant emotional impact on patients, which adds to the stress and anxiety accompanying a standard IVF cycle. Currently there is no agreement on the best time to perform a FET after a freeze all cycle in order to maximize reproductive outcomes for the patient. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 512 freeze-all cycles, performed between January 2012 and December 2014. COH was performed by either a GnRH antagonist (n = 397) or a long GnRH agonist protocol (n = 115). Ovulation was triggered using either a GnRH agonist (n = 258) or hCG (n = 254). Endometrial preparation was performed in an artificial cycle by either oral (n = 238) or transdermal (n = 274) oestrogen. Differences were considered significant if P < 0.05. PARTICIPANTS/MATERIALS, SETTING, METHODS: Reproductive outcomes between FETs which took place either within the first menstrual cycle following OPU (Cycle 1; n = 263) or afterwards (Cycle >=2; n = 249) were compared. Student's t test for independent samples, Mann-Whitney U-test and Chi-square analysis were used where appropriate. A multivariable logistic regression analysis was performed adjusting for maternal age, drug used for ovulation trigger, number of retrieved oocytes, number of embryos obtained, day of embryonic development at transfer, number of embryos transferred and type of endometrial preparation. Differences were considered significant if P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth rate (LBR) was significantly higher in FET performed during Cycle 1 vs Cycle >=2 (37.6% vs 27.3%, respectively; P = 0.01) before adjusting for confounding factors. We found no difference for biochemical pregnancy (49.8% vs 43.8%; P = 0.17), clinical pregnancy (44.1% vs 36.1%; P = 0.07) or pregnancy loss (11.8% vs 16.1%; P = 0.16). A multivariable analysis found no impact of timing of elective FET on LBR (odds ratio, OR 0.73; 95% CI 0.49-1.08). The impact remained not significant after adjusting for number of retrieved oocytes, drug used for ovulation trigger (hCG vs GnRH agonist) and reason for cryopreservation. The factors that significantly affected LBR were: maternal age in both age categories (women between 35 and 40 years vs women below 35 years, OR 0.63, 95% CI 0.4-0.95; and women over 40 years vs women below 35 years, OR 0.34, 95% CI 0.2 0.7), day of embryonic development at transfer (day +4 vs +3; OR 1.7, 95% CI 1.1 2.8) and number of transferred embryos (OR 2.2, 95% CI 1.4-3.3) and oestrogen used for endometrial preparation (transdermal vs oral; OR 0.62, 95% CI 0.4-0.9). LIMITATIONS REASONS FOR CAUTION: The main limitation of our study is its retrospective nature. Although we adjusted our statistical analysis for a number of known and suspected confounders, we cannot exclude the possibility of residual confounding factors. WIDER IMPLICATIONS OF THE FINDINGS: According to our results, clinicians might not need to wait more than one menstrual cycle before performing FET. This allows us to reduce unnecessary delays in FET, without compromising reproductive outcomes. STUDY FUNDING/COMPETING INTERESTS: No funding was sought for this study. Authors declare no competing interests. TRIAL REGISTRATION NUMBER: NA. PMID- 27986820 TI - Identification of complex genomic rearrangements in cancers using CouGaR. AB - The genomic alterations associated with cancers are numerous and varied, involving both isolated and large-scale complex genomic rearrangements (CGRs). Although the underlying mechanisms are not well understood, CGRs have been implicated in tumorigenesis. Here, we introduce CouGaR, a novel method for characterizing the genomic structure of amplified CGRs, leveraging both depth of coverage (DOC) and discordant pair-end mapping techniques. We applied our method to whole-genome sequencing (WGS) samples from The Cancer Genome Atlas and identify amplified CGRs in at least 5.2% (10+ copies) to 17.8% (6+ copies) of the samples. Furthermore, ~95% of these amplified CGRs contain genes previously implicated in tumorigenesis, indicating the importance and widespread occurrence of CGRs in cancers. Additionally, CouGaR identified the occurrence of 'chromoplexy' in nearly 63% of all prostate cancer samples and 30% of all bladder cancer samples. To further validate the accuracy of our method, we experimentally tested 17 predicted fusions in two pediatric glioma samples and validated 15 of these (88%) with precise resolution of the breakpoints via qPCR experiments and Sanger sequencing, with nearly perfect copy count concordance. Additionally, to further help display and understand the structure of CGRs, we have implemented CouGaR-viz, a generic stand-alone tool for visualization of the copy count of regions, breakpoints, and relevant genes. PMID- 27986822 TI - The excreted microbiota of bats: evidence of niche specialisation based on multiple body habitats. AB - Animal-associated microbiotas form complex communities, which play crucial functions for their host, including susceptibility to infections. Despite increasing attention to bats as reservoirs of zoonotic pathogens, their microbiota is poorly documented, especially for samples potentially implicated in pathogen transmission such as urine and saliva. Here, using low-biomass individual samples, we examined the composition and structure of bacterial communities excreted by insectivorous bats, focusing on three body habitats (saliva, urine and faeces). We show that niche specialisation occurs as bacterial community composition was distinct across body habitats with the majority of phylotypes being body habitat specific. Our results suggest that urine harbours more diverse bacterial communities than saliva and faeces and reveal potentially zoonotic bacteria such as Leptospira, Rickettsia, Bartonella and Coxiella in all body habitats. Our study emphasised that, in addition to the traditional use of gut-associated samples such as faeces, both urine and saliva are also of interest because of their diverse microbiota and the potential transmission of pathogenic bacteria. Our results represent a critical baseline for future studies investigating the interactions between microbiota and infection dynamics in bats. PMID- 27986821 TI - Using reference-free compressed data structures to analyze sequencing reads from thousands of human genomes. AB - We are rapidly approaching the point where we have sequenced millions of human genomes. There is a pressing need for new data structures to store raw sequencing data and efficient algorithms for population scale analysis. Current reference based data formats do not fully exploit the redundancy in population sequencing nor take advantage of shared genetic variation. In recent years, the Burrows Wheeler transform (BWT) and FM-index have been widely employed as a full-text searchable index for read alignment and de novo assembly. We introduce the concept of a population BWT and use it to store and index the sequencing reads of 2705 samples from the 1000 Genomes Project. A key feature is that, as more genomes are added, identical read sequences are increasingly observed, and compression becomes more efficient. We assess the support in the 1000 Genomes read data for every base position of two human reference assembly versions, identifying that 3.2 Mbp with population support was lost in the transition from GRCh37 with 13.7 Mbp added to GRCh38. We show that the vast majority of variant alleles can be uniquely described by overlapping 31-mers and show how rapid and accurate SNP and indel genotyping can be carried out across the genomes in the population BWT. We use the population BWT to carry out nonreference queries to search for the presence of all known viral genomes and discover human T lymphotropic virus 1 integrations in six samples in a recognized epidemiological distribution. PMID- 27986823 TI - Cag-delta (Cag3) protein from the Helicobacter pylori 26695 cag type IV secretion system forms ring-like supramolecular assemblies. AB - Helicobacter pylori is an important cause of gastric pathologies and persistent infection can lead to stomach cancer. Virulent H. pylori strains encode a type IV secretion system responsible for translocation of the oncogenic CagA protein into cells of the gastric mucosa. Gene HP0522 encodes the essential component Cagdelta (Cag3), and we show by gel filtration and cross-linking that purified Cagdelta forms high molecular mass complexes. In contrast, its interaction partner CagT is mostly monomeric, but co-fractionates after gel filtration. Analysis by transmission electron microscopy revealed that purified Cagdelta complexes can self-assemble ring-like structures. Cagdelta-overexpressing Escherichia coli exhibits membrane-associated circular profiles in regions of the cell envelope with intense immunogold labelling with a Cagdelta-specific antiserum. Our results suggest that Cagdelta has the capacity to form macromolecular structures contributing to the assembly of the type IV secretion system. PMID- 27986824 TI - The intersection of antimicrobial stewardship and microbiology: educating the next generation of health care professionals. AB - With the alarming rise of antibiotic resistance, clinical professionals are called upon to manage antibiotic therapies using the most relevant and recent clinical and laboratory data. To this end, antimicrobial stewardship (AMS) programs aim to reduce unnecessary or suboptimal use of antibiotics while maximizing outcomes for the patient. For AMS programs to succeed, the active participation of clinical professionals at all levels of patient care is required. Although programs exist to train established clinicians in AMS, there is a paucity of literature on how and when to integrate AMS concepts and skills in pre-clinical and clinical coursework. Here, we discuss the crucial microbiology concepts and proficiencies that are necessary for building and supporting an AMS program. We provide recommendations for key points to include in clinical curricula in order to develop the necessary microbiology interpretation skills to participate in AMS. The influence of AMS programs on local organism susceptibility patterns is emphasized. The importance of antibiograms, rapid diagnostic testing and the practical interpretations of microbiology laboratory reporting are discussed in regard to prioritization in clinical curricula. We also review the current literature on instructional strategies for introducing AMS into clinical programs, and propose concepts that should be included in didactic coursework in order to provide a foundation for AMS education. PMID- 27986825 TI - Vitamin C targets (p)ppGpp synthesis leading to stalling of long-term survival and biofilm formation in Mycobacterium smegmatis. AB - Earlier, vitamin C was demonstrated to sterilize Mycobacterium tuberculosis culture via Fenton's reaction at high concentration. It alters the regulatory pathways associated with stress response and dormancy. Since (p)ppGpp is considered to be the master regulator of stress response and is responsible for bacterial survival under stress, we tested the effect of vitamin C on the formation of (p)ppGpp. In vivo estimation of (p)ppGpp showed a decrease in (p)ppGpp levels in vitamin C-treated M. smegmatis cells in comparison to the untreated cells. Furthermore, in vitro (p)ppGpp synthesis using RelMSM enzyme was conducted in order to confirm the specificity of the inhibition in the presence of variable concentrations of vitamin C. We observed that vitamin C at high concentration can inhibit the synthesis of (p)ppGpp. We illustrated binding of vitamin C to RelMSM by isothermal titration calorimetry. Enzyme kinetics was followed where K0.5 was found to be increased with the concomitant reduction of Vmax value suggesting mixed inhibition. Both long-term survival and biofilm formation were inhibited by vitamin C. The experiments suggest that vitamin C has the potential to be developed as the inhibitor of (p)ppGpp synthesis and stress response, at least in the concentration range used here. PMID- 27986826 TI - The contribution of genome mining strategies to the understanding of active principles of PGPR strains. AB - Pathogenic microorganisms and insects affecting plant health are a major and chronic threat to food production and the ecosystem worldwide. As agricultural production has intensified over the years, the use of agrochemicals has in turn increased. However, this extensive usage has had several detrimental effects, with a pervasive environmental impact and the emergence of pathogen resistance. In addition, there is an increasing tendency among consumers to give preference to pesticide-free food products. Biological control, through the employment of plant growth-promoting rhizobacteria (PGPR), is therefore considered a possible route to the reduction, even the elimination, of the use of agrochemicals. PGPR exert their beneficial influence by a multitude of mechanisms, often involving antibiotics and proteins, to defend the host plant against pathogens. To date, these key metabolites have been uncovered only by systematic investigation or by serendipity; their discovery has nevertheless been propelled by the genomic revolution of recent years, as increasing numbers of genomic studies have been integrated into this field, facilitating a holistic view of this topic and the rapid identification of ecologically important metabolites. This review surveys the highlights and advances of genome-driven compound and protein discovery in the field of bacterial PGPR strains, and aims to advocate for the benefits of this strategy. PMID- 27986827 TI - Potential of semiarid soil from Caatinga biome as a novel source for mining lignocellulose-degrading enzymes. AB - The litterfall is the major organic material deposited in soil of Brazilian Caatinga biome, thus providing the ideal conditions for plant biomass-degrading microorganisms to thrive. Herein, the phylogenetic composition and lignocellulose degrading capacity have been explored for the first time from a fosmid library dataset of Caatinga soil by sequence-based screening. A complex bacterial community dominated by Proteobacteria and Actinobacteria was unraveled. SEED subsystems-based annotations revealed a broad range of genes assigned to carbohydrate and aromatic compounds metabolism, indicating microbial ability to utilize plant-derived material. CAZy-based annotation identified 7275 genes encoding 37 glycoside hydrolases (GHs) families related to hydrolysis of cellulose, hemicellulose, oligosaccharides and other lignin-modifying enzymes. Taxonomic affiliation of genes showed high genetic potential of the phylum Acidobacteria for hemicellulose degradation, whereas Actinobacteria members appear to play an important role in celullose hydrolysis. Additionally, comparative analyses revealed greater GHs profile similarity among soils as compared to the digestive tract of animals capable of digesting plant biomass, particularly in the hemicellulases content. Combined results suggest a complex synergistic interaction of community members required for biomass degradation into fermentable sugars. This large repertoire of lignocellulolytic enzymes opens perspectives for mining potential candidates of biochemical catalysts for biofuels production from renewable resources and other environmental applications. PMID- 27986829 TI - Examiner manoeuvres 'sensory tricks' in functional (psychogenic) movement disorders. PMID- 27986828 TI - The specific and exclusive microbiome of the deep-sea bone-eating snail, Rubyspira osteovora. AB - Rubyspira osteovora is an unusual deep-sea snail from Monterey Canyon, California. This group has only been found on decomposing whales and is thought to use bone as a novel source of nutrition. This study characterized the gut microbiome of R. osteovora, compared to the surrounding environment, as well as to other deep-sea snails with more typical diets. Analysis of 16S rRNA gene sequences revealed that R. osteovora digestive tissues host a much lower bacterial diversity (average Shannon index of 1.9; n = 12), compared to environmental samples (average Shannon index of 4.4; n = 2) and are dominated by two bacterial genera: Mycoplasma and Psychromonas (comprising up to 56% and 42% average total recovered sequences, respectively). These two bacteria, along with Psychrilyobacter sp. (~16% average recovered sequences), accounted for between 43% and 92% of the total recovered sequences in individual snail digestive systems, with other OTUs present at much lower proportions. The relative abundance of these three groups remained similar over 6 years of sampling (collection date was not shown to be a significant predictor of community structure), suggesting a long-term association. Furthermore, these bacterial genera were either not present (Mycoplasma and Psychromonas) or at very low abundance (<0.04% for Psychrilyobacter), in environmental samples and other deep sea gastropods, supporting the uniqueness of the R. osteovora gut microbiome. PMID- 27986830 TI - Subtle motor disturbances in PREDICT-PD participants. AB - OBJECTIVE: The PREDICT-PD study aims to identify increased risk of Parkinson''s disease (PD) using online assessments of previously identified risk and early features of PD and an evidence-based scoring algorithm. We sought to determine whether higher risk participants (defined as those above the 15th centile of risk estimates) were more likely to have mild parkinsonian signs compared with lower risk participants. METHODS: Video recordings of neurological examinations, including the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III, of 208 individuals who had previously completed an online risk assessment were scored blindly and independently by two movement-disorders experts. Higher risk and lower risk subjects were compared for MDS-UPDRS part III score (and derivations of this) to identify subclinical parkinsonism, and association of risk estimates with MDS-UPDRS III scores assessed. RESULTS: Higher risk subjects had significantly higher median UPDRS part III scores (3, IQR 1 5.5) than lower risk subjects (1, IQR 0-3.0; p<0.001), and there was a significantly greater proportion of individuals classified as having subclinical parkinsonism. 18% of the higher risk subjects and 6% of the lower risk subjects exceeded the most stringent published cut-off for subtle parkinsonism of three definitions examined (p=0.027). Linear regression analysis demonstrated a continuous relationship of log-transformed risk estimates with UPDRS part III scores (increase in MDS-UPDRS per doubling of odds 0.52, 95% CI 0.31 to 0.72; p<0.001), which remained after adjustment for multiple vascular risk factors and scores on the Montreal Cognitive Assessment (0.58, 95% CI 0.30 to 0.87; p<0.001). CONCLUSIONS: The PREDICT-PD algorithm identifies a population with an increased rate of motor disturbances. PMID- 27986831 TI - Nonsuppressed Glucagon After Glucose Challenge as a Potential Predictor for Glucose Tolerance. AB - Glucagon levels are classically suppressed after glucose challenge. It is still not clear as to whether a lack of suppression contributes to hyperglycemia and thus to the development of diabetes. We investigated the association of postchallenge change in glucagon during oral glucose tolerance tests (OGTTs), hypothesizing that higher postchallenge glucagon levels are observed in subjects with impaired glucose tolerance (IGT). Glucagon levels were measured during OGTT in a total of 4,194 individuals without diabetes in three large European cohorts. Longitudinal changes in glucagon suppression were investigated in 50 participants undergoing a lifestyle intervention. Only 66-79% of participants showed suppression of glucagon at 120 min (fold change glucagon120/0 <1) during OGTT, whereas 21-34% presented with increasing glucagon levels (fold change glucagon120/0 >=1). Participants with nonsuppressed glucagon120 had a lower risk of IGT in all cohorts (odds ratio 0.44-0.53, P < 0.01). They were also leaner and more insulin sensitive and had lower liver fat contents. In the longitudinal study, an increase of fold change glucagon120/0 was associated with an improvement in insulin sensitivity (P = 0.003). We characterize nonsuppressed glucagon120 during the OGTT. Lower glucagon suppression after oral glucose administration is associated with a metabolically healthier phenotype, suggesting that it is not an adverse phenomenon. PMID- 27986832 TI - Placental and Cord Blood Methylation of Genes Involved in Energy Homeostasis: Association With Fetal Growth and Neonatal Body Composition. AB - Low weight at birth is associated with subsequent susceptibility to diabetes. Epigenetic modulation is among the mechanisms potentially mediating this association. We performed a genome-wide DNA methylation analysis in placentas from term infants born appropriate-for-gestational-age (AGA) or small-for gestational-age (SGA) to identify new genes related to fetal growth and neonatal body composition. Candidate genes were validated by bisulfite pyrosequencing (30 AGA, 21 SGA) and also analyzed in cord blood. Gene expression analyses were performed by RT-PCR. Neonatal body composition was assessed by dual X-ray absorptiometry at age 2 weeks. The ATG2B, NKX6.1, and SLC13A5 genes (respectively related to autophagy, beta-cell development and function, and lipid metabolism) were hypermethylated in placenta and cord blood from SGA newborns, whereas GPR120 (related to free fatty acid regulation) was hypomethylated in placenta and hypermethylated in cord blood. Gene expression levels were opposite to methylation status, and both correlated with birth weight, circulating IGF-I, and total and abdominal fat at age 2 weeks. In conclusion, alterations in methylation and expression of genes involved in the regulation of energy homeostasis were found to relate to fetal growth and neonatal body composition and thus may be among the early mechanisms modulating later susceptibility to diabetes. PMID- 27986833 TI - Diverse subcellular localizations of the insect CMP-sialic acid synthetases. AB - The occurrence and biological importance of sialic acid (Sia) and its metabolic enzymes in insects have been studied using Drosophila melanogaster. The most prominent feature of D. melanogaster CMP-Sia synthetase (DmCSS) is its Golgi localization, contrasted with nuclear localization of vertebrate CSSs. However, it remains unclear if the Golgi-localization is common to other insect CSSs and why it happens. To answer these questions, Aedes aegypti (mosquito) CSS (AaCSS) and Tribolium castaneum (beetle) CSS (TcCSS) were cloned and characterized for their activity and subcellular localization. Our new findings show: (1) AaCSS and TcCSS share a common overall structure with DmCSS in terms of evolutionarily conserved motifs and the absence of the C-terminal domain typical to vertebrate CSSs; (2) when expressed in mammalian and insect cells, AaCSS and TcCSS showed in vivo and in vitro CSS activities, similar to DmCSS. In contrast, when expressed in bacteria, they lacked CSS activity because the N-terminal hydrophobic region appeared to induce protein aggregation; (3) when expressed in Drosophila S2 cells, AaCSS and TcCSS were predominantly localized in the ER, but not in the Golgi. Surprisingly, DmCSS was mainly secreted into the culture medium, although partially detected in Golgi. Consistent with these results, the N-terminal hydrophobic regions of AaCSS and TcCSS functioned as a signal peptide to render them soluble in the ER, while the N-terminus of DmCSS functioned as a membrane spanning region of type II transmembrane proteins whose cytosolic KLK sequence functioned as an ER export signal. Accordingly, the differential subcellular localization of insect CSSs are distinctively more diverse than previously recognized. PMID- 27986834 TI - Distribution of the O-acetyl groups and beta-galactofuranose units in galactoxylomannans of the opportunistic fungus Cryptococcus neoformans. AB - Galactoxylomannans (GalXMs) are a mixture of neutral and acidic capsular polysaccharides produced by the opportunistic fungus Cryptococcus neoformans that exhibit potent suppressive effects on the host immune system. Previous studies describing the chemical structure of C. neoformans GalXMs have reported species without O-acetyl substituents. Herein we describe that C. neoformans grown in capsule-inducing medium produces highly O-acetylated GalXMs. The location of the O-acetyl groups was determined by nuclear magnetic resonance (NMR) spectroscopy. In the neutral GalXM (NGalXM), 80% of 3-linked mannose (alpha-Manp) residues present in side chains are acetylated at the O-2 position. In the acidic GalXM also termed glucuronoxylomannogalactan (GXMGal), 85% of the 3-linked alpha-Manp residues are acetylated either in the O-2 (75%) or in the O-6 (25%) position, but O-acetyl groups are not present at both positions simultaneously. In addition, NMR spectroscopy and methylation analysis showed that beta-galactofuranose (beta Galf) units are linked to O-2 and O-3 positions of nonbranched alpha galactopyranose (alpha-Galp) units present in the GalXMs backbone chain. These findings highlight new structural features of C. neoformans GalXMs. Among these features, the high degree of O-acetylation is of particular interest, since O acetyl group-containing polysaccharides are known to possess a range of immunobiological activities. PMID- 27986838 TI - A randomised experiment comparing low-cost ultrasound gel alternative with commercial gel. AB - OBJECTIVE: Point-of-care ultrasound is a portable, relatively low-cost imaging modality with great potential utility in low-resource settings. However, commercially produced ultrasound gel is often cost-prohibitive and unavailable. We investigated whether images obtained using an alternative cornstarch-based gel would be of comparable quality with those using commercial gel. METHODS: This was a blinded, randomised, cross-over study comparing commercially produced ultrasound gel with home-made cornstarch-based gel. Ultrasound-trained faculty obtained three video clips with each gel type from patients at one urban ED. The clips were evaluated by a radiologist and an ultrasound-trained emergency physician. Images were assessed in terms of overall adequacy (dichotomous) and quality, resolution and detail using a rating scale (0-10). All sonographers and physicians reviewing the images were blinded to the type of gel used. RESULTS: Thirty-four patients were enrolled in the study, producing 204 separate images (102 with each gel). The cornstarch gel clips were deemed accurate in 70.6% (95% CI 63.9% to 76.5%) of the scans, as compared with 65.2% (95% CI 58.4% to 71.4%) of those using commercial gel. There was no difference between the two groups with respect to image detail, resolution or quality. CONCLUSIONS: Images produced using the cornstarch-based alternative ultrasound gel were of similar quality to those using commercial gel. The low cost and easy preparation of the cornstarch based gel make it an attractive coupling medium for use in low-resource settings. PMID- 27986835 TI - Tannerella forsythia strains display different cell-surface nonulosonic acids: biosynthetic pathway characterization and first insight into biological implications. AB - Tannerella forsythia is an anaerobic, Gram-negative periodontal pathogen. A unique O-linked oligosaccharide decorates the bacterium's cell surface proteins and was shown to modulate the host immune response. In our study, we investigated the biosynthesis of the nonulosonic acid (NulO) present at the terminal position of this glycan. A bioinformatic analysis of T. forsythia genomes revealed a gene locus for the synthesis of pseudaminic acid (Pse) in the type strain ATCC 43037 while strains FDC 92A2 and UB4 possess a locus for the synthesis of legionaminic acid (Leg) instead. In contrast to the NulO in ATCC 43037, which has been previously identified as a Pse derivative (5-N-acetimidoyl-7-N-glyceroyl-3,5,7,9 tetradeoxy-l-glycero-l-manno-NulO), glycan analysis of strain UB4 performed in this study indicated a 350-Da, possibly N-glycolyl Leg (3,5,7,9-tetradeoxy-d glycero-d-galacto-NulO) derivative with unknown C5,7 N-acyl moieties. We have expressed, purified and characterized enzymes of both NulO pathways to confirm these genes' functions. Using capillary electrophoresis (CE), CE-mass spectrometry and NMR spectroscopy, our studies revealed that Pse biosynthesis in ATCC 43037 essentially follows the UDP-sugar route described in Helicobacter pylori, while the pathway in strain FDC 92A2 corresponds to Leg biosynthesis in Campylobacter jejuni involving GDP-sugar intermediates. To demonstrate that the NulO biosynthesis enzymes are functional in vivo, we created knockout mutants resulting in glycans lacking the respective NulO. Compared to the wild-type strains, the mutants exhibited significantly reduced biofilm formation on mucin coated surfaces, suggestive of their involvement in host-pathogen interactions or host survival. This study contributes to understanding possible biological roles of bacterial NulOs. PMID- 27986836 TI - Diverse mechanisms of metaeffector activity in an intracellular bacterial pathogen, Legionella pneumophila. AB - Pathogens deliver complex arsenals of translocated effector proteins to host cells during infection, but the extent to which these proteins are regulated once inside the eukaryotic cell remains poorly defined. Among all bacterial pathogens, Legionella pneumophila maintains the largest known set of translocated substrates, delivering over 300 proteins to the host cell via its Type IVB, Icm/Dot translocation system. Backed by a few notable examples of effector effector regulation in L. pneumophila, we sought to define the extent of this phenomenon through a systematic analysis of effector-effector functional interaction. We used Saccharomyces cerevisiae, an established proxy for the eukaryotic host, to query > 108,000 pairwise genetic interactions between two compatible expression libraries of ~330 L. pneumophila-translocated substrates. While capturing all known examples of effector-effector suppression, we identify fourteen novel translocated substrates that suppress the activity of other bacterial effectors and one pair with synergistic activities. In at least nine instances, this regulation is direct-a hallmark of an emerging class of proteins called metaeffectors, or "effectors of effectors". Through detailed structural and functional analysis, we show that metaeffector activity derives from a diverse range of mechanisms, shapes evolution, and can be used to reveal important aspects of each cognate effector's function. Metaeffectors, along with other, indirect, forms of effector-effector modulation, may be a common feature of many intracellular pathogens-with unrealized potential to inform our understanding of how pathogens regulate their interactions with the host cell. PMID- 27986839 TI - Optimisation of Intestinal Fibrosis and Survival in the Mouse S. Typhimurium Model for Anti-fibrotic Drug Discovery and Preclinical Applications. AB - Background and Aims: Intestinal fibrosis is a frequent complication in Crohn's disease [CD]. The mouse Salmonella typhimurium model, due to its simplicity, reproducibility, manipulability, and penetrance, is an established fibrosis model for drug discovery and preclinical trials. However, the severity of fibrosis and mortality are host- and bacterial strain-dependent, thus limiting the original model. We re-evaluated the S. typhimurium model to optimise fibrosis and survival, using commercially available mouse strains. Methods: Fibrotic and inflammatory markers were evaluated across S. typhimurium DeltaaroA:C57bl/6 studies performed in our laboratory. A model optimisation study was performed using three commercially available mouse strains [CBA/J, DBA/J, and 129S1/SvImJ] infected with either SL1344 or DeltaaroA S. typhimurium. Fibrotic penetrance was determined by histopathology, gene expression, and alphaSMA protein expression. Fibrosis severity, penetrance, and survival were analysed across subsequent CBA studies. Results: Fibrosis severity and survival are both host- and bacterial strain-dependent. Marked tissue fibrosis and 100% survival occurred in the CBA/J strain infected with SL1344. Subsequent experiments demonstrated that CBA/J mice develop extensive intestinal fibrosis, characterised by transmural tissue fibrosis, a Th1/Th17 cytokine response, and induction of pro-fibrotic genes and extracellular matrix proteins. A meta-analysis of subsequent SL1344:CBA/J studies demonstrated that intestinal fibrosis is consistent and highly penetrant across histological, protein, and gene expression markers. As proof-of-concept, we tested the utility of the SL1344:CBA/J fibrosis model to evaluate efficacy of CCG 203971, a novel anti-fibrotic drug. Conclusion: The S. typhimurium SL1344:CBA/J model is an optimised model for the study of intestinal fibrosis. PMID- 27986837 TI - Greater VO2peak is correlated with greater skeletal muscle deoxygenation amplitude and hemoglobin concentration within individual muscles during ramp incremental cycle exercise. AB - It is axiomatic that greater aerobic fitness (VO2peak) derives from enhanced perfusive and diffusive O2 conductances across active muscles. However, it remains unknown how these conductances might be reflected by regional differences in fractional O2 extraction (i.e., deoxy [Hb+Mb] and tissue O2 saturation [StO2]) and diffusive O2 potential (i.e., total[Hb+Mb]) among muscles spatially heterogeneous in blood flow, fiber type, and recruitment (vastus lateralis, VL; rectus femoris, RF). Using quantitative time-resolved near-infrared spectroscopy during ramp cycling in 24 young participants (VO2peak range: ~37.4-66.4 mL kg-1 min-1), we tested the hypotheses that (1) deoxy[Hb+Mb] and total[Hb+Mb] at VO2peak would be positively correlated with VO2peak in both VL and RF muscles; (2) the pattern of deoxygenation (the deoxy[Hb+Mb] slopes) during submaximal exercise would not differ among subjects differing in VO2peak Peak deoxy [Hb+Mb] and StO2 correlated with VO2peak for both VL (r = 0.44 and -0.51) and RF (r = 0.49 and -0.49), whereas for total[Hb+Mb] this was true only for RF (r = 0.45). Baseline deoxy[Hb+Mb] and StO2 correlated with VO2peak only for RF (r = -0.50 and 0.54). In addition, the deoxy[Hb+Mb] slopes were not affected by aerobic fitness. In conclusion, while the pattern of deoxygenation (the deoxy[Hb+Mb] slopes) did not differ between fitness groups the capacity to deoxygenate [Hb+Mb] (index of maximal fractional O2 extraction) correlated significantly with VO2peak in both RF and VL muscles. However, only in the RF did total[Hb+Mb] (index of diffusive O2 potential) relate to fitness. PMID- 27986840 TI - Dedicated health systems strengthening of the Global Fund to Fight AIDS, Tuberculosis, and Malaria: an analysis of grants. AB - BACKGROUND: This study aims to understand the determinants of the Global Fund to Fight AIDS, Tuberculosis, and Malaria's dedicated channel for health systems strengthening (HSS) funding across countries and to analyze their health system priorities expressed in budgets and performance indicators. METHODS: We obtained publicly available data for disease-specific and HSS grants from the Global Fund over 2004-2013 prior to the new funding model. Regression analysis was employed to assess the determinants of dedicated HSS funding across 111 countries. Documents for 27 dedicated HSS grants including budgets and performance indicators were collected, and activities were analyzed by health system functions. RESULTS: HSS funding per capita is significantly associated with TB and HIV funding per capita, but not per capita income and health worker density. Of 27 dedicated HSS grants, 11 had line-item budgets publicly available, in which health workforce and medical products form the majority (89% or US$132 million of US$148 million) of funds. Yet these areas accounted for 41.7% (215) of total 516 performance indicators. CONCLUSIONS: Health worker densities were not correlated with HSS funding, despite the emphasis on health workforce in budgets and performance indicators. Priorities in health systems in line-item budgets differ from the numbers of indicators used. PMID- 27986842 TI - Effect of occupational exposure to lead on new risk factors for cardiovascular diseases. AB - OBJECTIVE: The cardiovascular effects of lead are caused primarily through an effect on blood pressure but are not just limited to an increased risk of hypertension. The aim of our study was to determine to what extent chronic exposure to lead affects new risk factors for cardiovascular disease (CVD) development, such as biomarkers of inflammation (C reactive protein (CRP) and fibrinogen) and biomarkers of endothelial dysfunction (homocysteine, asymmetric dimethylarginine (ADMA) and L-homoarginine). METHODS: A cross-sectional study was performed on a sample of 231 male volunteers, aged 20-60 years, working for at least 2 years in jobs with exposure to lead during the mining and processing of lead-zinc ores. The association between lead in blood and CVD biomarkers was evaluated using multiple linear regression, and the effects of exposure level were observed in workers divided into subgroups according to their blood lead concentration: <250, 250-400 and >400 ug/L. RESULTS: Lead in the blood correlated with new risk factors for CVD except for ADMA. Multiple regression analysis revealed that predictive properties for lead in the blood increased for particular biomarkers in the following order: L-homoarginine, fibrinogen, CRP and homocysteine. Among the specified groups, significant differences were observed only between the groups with the most and least exposure to lead, which differed in concentrations by 54.3% for CRP, 19.3% for fibrinogen, 10.6% for homocysteine and -25.5% for L-homoarginine. CONCLUSIONS: These findings support the hypothesis that occupational exposure to lead can promote atherosclerosis, particularly in highly exposed individuals. PMID- 27986841 TI - Financial burden of health care for Buruli ulcer patients in Nigeria: the patients' perspective. AB - BACKGROUND: The economic burden of Buruli ulcer for patients has not been well documented. This study assessed the costs of Buruli ulcer care to patients from the onset of illness to diagnosis and to the end of treatment. METHODS: This was a cross-sectional cost of illness study conducted among patients with Buruli ulcer in four States in Nigeria between July and September 2015. A structured questionnaire was used to collect data on the patients' characteristics, household income and out-of-pocket costs of care. RESULTS: Of 92 patients surveyed, 54 (59%) were older than 15years, 49 (53%) were males, and 86 (93%) resided in a rural area. The median (IQR) direct medical and non-medical cost per patient was US$124 (50-282) and US$3 (3-6); corresponding to 149% and 4% of the patients' median monthly household income, respectively. The overall direct costs per patient was US$135 (58-327), which corresponded to 162% of median monthly household income, with pre-diagnosis costs accounting for 94.8% of the total costs. The direct costs of Buruli ulcer care were catastrophic for 50% of all patients/households - the rates of catastrophic costs for Buruli ulcer care was 66% and 19% for patients belonging to the lowest and highest income quartiles, respectively. CONCLUSIONS: Direct costs of Buruli ulcer diagnosis and treatment are catastrophic to a substantial proportion of patients and their families. PMID- 27986846 TI - Hospital transfer associated with increased mortality after endovascular revascularization for acute ischemic stroke. AB - BACKGROUND: Patients with an acute ischemic stroke (AIS) due to large vessel occlusion often require transfer to an endovascular center for treatment. OBJECTIVE: To assess the effect of hospital transfer on outcomes after endovascular revascularization. METHODS: Outcomes of endovascular revascularization were compared between directly admitted and transferred patients using data from a national database and our own institution. RESULTS: 118 institutions within the database reported outcomes of 8533 inpatient admissions for endovascular treatment of AIS. Mortality rate (14.9% vs 18.6%; p=0.049) and mortality index (1.1 vs 1.6; p=0.048) were significantly lower among directly admitted patients than among transferred patients. Within our institutional cohort of 140 patients who underwent endovascular therapy, directly admitted patients had a significantly faster time to revascularization than transferred patients (277.4 vs 420.4 min; p<=0.0001). Among transferred patients, an increasing distance of transferred hospital to our home institution was associated with an increasing risk of mortality (unit OR=1.26, 95% CI 1.07 to 1.54; p=0.0061). CONCLUSIONS: Outcomes of revascularization may improve with methods to identify patients with large vessel occlusion before hospital admission, thus increasing the likelihood of initial triage to a comprehensive stroke center for patients eligible for endovascular intervention. PMID- 27986845 TI - Unique photosynthetic phenotypes in Portulaca (Portulacaceae): C3-C4 intermediates and NAD-ME C4 species with Pilosoid-type Kranz anatomy. AB - Portulacaceae is a family that has considerable diversity in photosynthetic phenotypes. It is one of 19 families of terrestrial plants where species having C4 photosynthesis have been found. Most species in Portulaca are in the alternate leaved (AL) lineage, which includes one clade (Cryptopetala) with taxa lacking C4 photosynthesis and three clades having C4 species (Oleracea, Umbraticola and Pilosa). All three species in the Cryptopetala clade lack Kranz anatomy, the leaves have C3-like carbon isotope composition and they have low levels of C4 cycle enzymes. Anatomical, biochemical and physiological analyses show they are all C3-C4 intermediates. They have intermediate CO2 compensation points, enrichment of organelles in the centripetal position in bundle sheath (BS) cells, with selective localization of glycine decarboxylase in BS mitochondria. In the three C4 clades there are differences in Kranz anatomy types and form of malic enzyme (ME) reported to function in C4 (NAD-ME versus NADP-ME): Oleracea (Atriplicoid, NAD-ME), Umbraticola (Atriplicoid, NADP-ME) and Pilosa (Pilosoid, NADP-ME). Structural and biochemical analyses were performed on Pilosa clade representatives having Pilosoid-type leaf anatomy with Kranz tissue enclosing individual peripheral vascular bundles and water storage in the center of the leaf. In this clade, all species except P. elatior are NADP-ME-type C4 species with grana-deficient BS chloroplasts and grana-enriched M chloroplasts. Surprisingly, P. elatior has BS chloroplasts enriched in grana and NAD-ME-type photosynthesis. The results suggest photosynthetic phenotypes were probably derived from an ancestor with NADP-ME-type C4, with two independent switches to NAD-ME type. PMID- 27986847 TI - MRI audit of complications in intracranial stenosis treated with Wingspan device. AB - OBJECTIVES: To evaluate the safety and efficacy of the Wingspan device for the treatment of symptomatic intracranial atherosclerotic stenosis (ICAS). METHODS: We audited a prospective ongoing database of consecutive patients who received Wingspan stenting between January 2013 and December 2015. All patients underwent MRI to audit any complications during the early follow-up period. We focused on the clinical demographics, lesion characteristics, treatment results, and periprocedural complications. Functional outcomes were measured with the modified Rankin Scale (mRS) at discharge and after 3 months. RESULTS: Intracranial stenting was performed in 50 patients (100%). Mean stenosis pre-stenting was 76.5+/-13.1% and post-stenting residual stenosis was 19.8+/-13.8%. The overall 30 day rate of procedure-related complications was 6.0% (3/50). Two patients (4%) developed in-stent restenosis, one of whom had a dissection at the middle cerebral artery. Interestingly, on the follow-up MRI scan there was a high incidence of asymptomatic diffusion-weighted imaging (DWI) hyperintensities, 46% (23/50) presumed to be due to microembolic causes. At the 90-day, 180-day, and 1 year follow-up, three patients had further strokes resulting in a total complication rate of 12%. 92% had excellent outcomes (mRS 0-1) and only one patient had deterioration of his mRS score. CONCLUSIONS: ICAS treated by Wingspan stenting using pre-placement balloon angioplasty appears safe and effective with a high technical success rate and favorable outcomes. There is a high incidence of asymptomatic DWI hyperintensites post-procedure, but these do not appear to result in long-term sequelae. PMID- 27986848 TI - Continuous aspiration prior to intracranial vascular embolectomy (CAPTIVE): a technique which improves outcomes. AB - BACKGROUND: Modern stent retriever-based embolectomy for patients with emergent large vessel occlusion improves outcomes. Techniques aimed at achieving higher rates of complete recanalization would benefit patients. OBJECTIVE: To evaluate the clinical impact of an embolectomy technique focused on continuous aspiration prior to intracranial vascular embolectomy (CAPTIVE). METHODS: A retrospective review was performed of 95 consecutive patients with intracranial internal carotid artery or M1 segment middle cerebral artery occlusion treated with stent retriever-based thrombectomy over an 11-month period. Patients were divided into a conventional local aspiration group (traditional group) and those treated with a novel continuous aspiration technique (CAPTIVE group). We compared both early neurologic recovery (based on changes in National Institute of Health Stroke Scale (NIHSS) score), independence at 90 days (modified Rankin score 0-2), and angiographic results using the modified Thrombolysis in Cerebral Ischemia (TICI) scale including the TICI 2c category. RESULTS: There were 56 patients in the traditional group and 39 in the CAPTIVE group. Median age and admission NIHSS scores were 78 years and 19 in the traditional group and 77 years and 19 in the CAPTIVE group. Median times from groin puncture to recanalization in the traditional and CAPTIVE groups were 31 min and 14 min, respectively (p<0.0001). While rates of TICI 2b/2c/3 recanalization were similar (81% traditional vs 100% CAPTIVE), CAPTIVE offered higher rates of TICI 2c/3 recanalization (79.5% vs 40%, p<0.001). Median discharge NIHSS score was 10 in the traditional group and 3 in the CAPTIVE group; this difference was significant. There was also an increased independence at 90 days (25% traditional vs 49% CAPTIVE). CONCLUSIONS: The CAPTIVE embolectomy technique may result in higher recanalization rates and better clinical outcomes. PMID- 27986849 TI - What Does Successful Aging Mean? Lay Perception of Successful Aging Among Elderly Singaporeans. AB - Objectives: We explore the culturally specific meaning of successful aging in Singapore, an ethnically diverse city-state in Asia. We aim to investigate lay perceptions of successful aging among the elderly individuals in Singapore and further examine variations of these perceptions. Methods: We applied a mixed method research design. Firstly, we conducted qualitative interviews with 49 elderly respondents, generating 12 main subjective components of successful aging. Next, we did a national survey with a sample of 1,540 local residents aged 50 to 69 years, in which respondents were asked to evaluate the importance of each subjective component of successful aging. We used the regression models and latent class analysis to analyze the correlatives of successful aging and to classify the elderly individuals by perception types. Results: Among 12 components of successful aging, those related to self-sufficiency received the highest acknowledgment among the elderly individuals in Singapore. At least half of them simultaneously highlighted independence from family and dependence on family. Malays and Indians in Singapore valued more of the roles of spouse and children in successful aging, as compared with Chinese. The latent class analysis classified four groups of the elderly individuals according to their lay views on successful aging. Discussion: As compared with the western model of successful aging, the elderly individuals in Singapore perceived successful aging with a strong focus on familism. These lay perceptions also significantly varied among these elderly individuals. PMID- 27986850 TI - Antecedents of Gray Divorce: A Life Course Perspective. AB - Objectives: Increasingly, older adults are experiencing divorce, yet little is known about the risk factors associated with divorce after age 50 (termed "gray divorce"). Guided by a life course perspective, our study examined whether key later life turning points are related to gray divorce. Method: We used data from the 1998-2012 Health and Retirement Study to conduct a prospective, couple-level discrete-time event history analysis of the antecedents of gray divorce. Our models incorporated key turning points (empty nest, retirement, and poor health) as well as demographic characteristics and economic resources. Results: Contrary to our expectations, the onset of an empty nest, the wife's or husband's retirement, and the wife's or husband's chronic conditions were unrelated to the likelihood of gray divorce. Rather, factors traditionally associated with divorce among younger adults were also salient for older adults. Marital duration, marital quality, home ownership, and wealth were negatively related to the risk of gray divorce. Discussion: Gray divorce is especially likely to occur among couples who are socially and economically disadvantaged, raising new questions about the consequences of gray divorce for individual health and well-being. PMID- 27986853 TI - siRNA carrying an (E)-vinylphosphonate moiety at the 5? end of the guide strand augments gene silencing by enhanced binding to human Argonaute-2. PMID- 27986851 TI - Activation mode of the eukaryotic m2G10 tRNA methyltransferase Trm11 by its partner protein Trm112. AB - Post-transcriptional and post-translational modifications of factors involved in translation are very important for the control and accuracy of protein biosynthesis. Among these factors, tRNAs harbor the largest variety of grafted chemical structures, which participate in tRNA stability or mRNA decoding. Here, we focused on Trm112 protein, which associates with four different eukaryotic methyltransferases modifying tRNAs (Trm9 and Trm11) but also 18S-rRNA (Bud23) and translation termination factor eRF1 (Mtq2). In particular, we have investigated the role of Trm112 in the Trm11-Trm112 complex, which forms 2-methylguanosine at position 10 on several tRNAs and thereby is assumed to stabilize tRNA structure. We show that Trm112 is important for Trm11 enzymatic activity by influencing S adenosyl-L-methionine binding and by contributing to tRNA binding. Using hydrogen deuterium eXchange coupled to mass spectrometry, we obtained experimental evidences that the Trm11-Trm112 interaction relies on the same molecular bases as those described for other Trm112-methyltransferases complexes. Hence, all Trm112 dependent methyltransferases compete to interact with this partner. PMID- 27986852 TI - Structure of a 30S pre-initiation complex stalled by GE81112 reveals structural parallels in bacterial and eukaryotic protein synthesis initiation pathways. AB - In bacteria, the start site and the reading frame of the messenger RNA are selected by the small ribosomal subunit (30S) when the start codon, typically an AUG, is decoded in the P-site by the initiator tRNA in a process guided and controlled by three initiation factors. This process can be efficiently inhibited by GE81112, a natural tetrapeptide antibiotic that is highly specific toward bacteria. Here GE81112 was used to stabilize the 30S pre-initiation complex and obtain its structure by cryo-electron microscopy. The results obtained reveal the occurrence of changes in both the ribosome conformation and initiator tRNA position that may play a critical role in controlling translational fidelity. Furthermore, the structure highlights similarities with the early steps of initiation in eukaryotes suggesting that shared structural features guide initiation in all kingdoms of life. PMID- 27986855 TI - miSTAR: miRNA target prediction through modeling quantitative and qualitative miRNA binding site information in a stacked model structure. AB - In microRNA (miRNA) target prediction, typically two levels of information need to be modeled: the number of potential miRNA binding sites present in a target mRNA and the genomic context of each individual site. Single model structures insufficiently cope with this complex training data structure, consisting of feature vectors of unequal length as a consequence of the varying number of miRNA binding sites in different mRNAs. To circumvent this problem, we developed a two layered, stacked model, in which the influence of binding site context is separately modeled. Using logistic regression and random forests, we applied the stacked model approach to a unique data set of 7990 probed miRNA-mRNA interactions, hereby including the largest number of miRNAs in model training to date. Compared to lower-complexity models, a particular stacked model, named miSTAR (miRNA stacked model target prediction; www.mi-star.org), displays a higher general performance and precision on top scoring predictions. More importantly, our model outperforms published and widely used miRNA target prediction algorithms. Finally, we highlight flaws in cross-validation schemes for evaluation of miRNA target prediction models and adopt a more fair and stringent approach. PMID- 27986854 TI - A type III-B CRISPR-Cas effector complex mediating massive target DNA destruction. AB - The CRISPR (clustered regularly interspaced short palindromic repeats) system protects archaea and bacteria by eliminating nucleic acid invaders in a crRNA guided manner. The Sulfolobus islandicus type III-B Cmr-alpha system targets invading nucleic acid at both RNA and DNA levels and DNA targeting relies on the directional transcription of the protospacer in vivo. To gain further insight into the involved mechanism, we purified a native effector complex of III-B Cmr alpha from S. islandicus and characterized it in vitro. Cmr-alpha cleaved RNAs complementary to crRNA present in the complex and its ssDNA destruction activity was activated by target RNA. The ssDNA cleavage required mismatches between the 5?-tag of crRNA and the 3?-flanking region of target RNA. An invader plasmid assay showed that mutation either in the histidine-aspartate acid (HD) domain (a quadruple mutation) or in the GGDD motif of the Cmr-2alpha protein resulted in attenuation of the DNA interference in vivo. However, double mutation of the HD motif only abolished the DNase activity in vitro. Furthermore, the activated Cmr alpha binary complex functioned as a highly active DNase to destroy a large excess DNA substrate, which could provide a powerful means to rapidly degrade replicating viral DNA. PMID- 27986856 TI - Interstrand cross-linking implies contrasting structural consequences for DNA: insights from molecular dynamics. AB - Oxidatively-generated interstrand cross-links rank among the most deleterious DNA lesions. They originate from abasic sites, whose aldehyde group can form a covalent adduct after condensation with the exocyclic amino group of purines, sometimes with remarkably high yields. We use explicit solvent molecular dynamics simulations to unravel the structures and mechanical properties of two DNA sequences containing an interstrand cross-link. Our simulations palliate the absence of experimental structural and stiffness information for such DNA lesions and provide an unprecedented insight into the DNA embedding of lesions that represent a major challenge for DNA replication, transcription and gene regulation by preventing strand separation. Our results based on quantum chemical calculations also suggest that the embedding of the ICL within the duplex can tune the reaction profile, and hence can be responsible for the high difference in yields of formation. PMID- 27986857 TI - Cryo-EM structure of the spinach chloroplast ribosome reveals the location of plastid-specific ribosomal proteins and extensions. AB - Ribosomes are the protein synthesizing machines of the cell. Recent advances in cryo-EM have led to the determination of structures from a variety of species, including bacterial 70S and eukaryotic 80S ribosomes as well as mitoribosomes from eukaryotic mitochondria, however, to date high resolution structures of plastid 70S ribosomes have been lacking. Here we present a cryo-EM structure of the spinach chloroplast 70S ribosome, with an average resolution of 5.4 A for the small 30S subunit and 3.6 A for the large 50S ribosomal subunit. The structure reveals the location of the plastid-specific ribosomal proteins (RPs) PSRP1, PSRP4, PSRP5 and PSRP6 as well as the numerous plastid-specific extensions of the RPs. We discover many features by which the plastid-specific extensions stabilize the ribosome via establishing additional interactions with surrounding ribosomal RNA and RPs. Moreover, we identify a large conglomerate of plastid-specific protein mass adjacent to the tunnel exit site that could facilitate interaction of the chloroplast ribosome with the thylakoid membrane and the protein-targeting machinery. Comparing the Escherichia coli 70S ribosome with that of the spinach chloroplast ribosome provides detailed insight into the co-evolution of RP and rRNA. PMID- 27986858 TI - Evidence for ARGONAUTE4-DNA interactions in RNA-directed DNA methylation in plants. AB - RNA polymerase V (Pol V) long noncoding RNAs (lncRNAs) have been proposed to guide ARGONAUTE4 (AGO4) to chromatin in RNA-directed DNA methylation (RdDM) in plants. Here, we provide evidence, based on laser UV-assisted zero-length cross linking, for functionally relevant AGO4-DNA interaction at RdDM targets. We further demonstrate that Pol V lncRNAs or the act of their transcription are required to lock Pol V holoenzyme into a stable DNA-bound state that allows AGO4 recruitment via redundant glycine-tryptophan/tryptophan-glycine AGO hook motifs present on both Pol V and its associated factor, SPT5L. We propose a model in which AGO4-DNA interaction could be responsible for the unique specificities of RdDM. PMID- 27986859 TI - In-room computed tomography-based brachytherapy for uterine cervical cancer: results of a 5-year retrospective study. AB - Herein, we investigate the long-term clinical outcomes for cervical cancer patients treated with in-room computed tomography-based brachytherapy. Eighty patients with Stage IB1-IVA cervical cancer, who had undergone treatment with combined 3D high-dose rate brachytherapy and conformal radiotherapy between October 2008 and May 2011, were retrospectively analyzed. External beam radiotherapy (50 Gy) with central shielding after 20-40 Gy was performed for each patient. Cisplatin-based chemotherapy was administered concurrently to advanced stage patients aged <=75 years. Brachytherapy was delivered in four fractions of 6 Gy per week. In-room computed tomography imaging with applicator insertion was performed for treatment planning. Information from physical examinations at diagnosis, and brachytherapy and magnetic resonance imaging at diagnosis and just before the first brachytherapy session, were referred to for contouring of the high-risk clinical target volume. The median follow-up duration was 60 months. The 5-year local control, pelvic progression-free survival and overall survival rates were 94%, 90% and 86%, respectively. No significant differences in 5-year local control rates were observed between Stage I, Stage II and Stage III-IVA patients. Conversely, a significant difference in the 5-year overall survival rate was observed between Stage II and III-IVA patients (97% vs 72%; P = 0.006). One patient developed Grade 3 late bladder toxicity. No other Grade 3 or higher late toxicities were reported in the rectum or bladder. In conclusion, excellent local control rates were achieved with minimal late toxicities in the rectum or bladder, irrespective of clinical stage. PMID- 27986860 TI - Quantification of ONO-2952 Occupancy of 18-kDaTranslocator Protein in Conscious Monkey Brains using Positron Emission Tomography. AB - We have previously shown that ONO-2952, a novel 18-kDa translocator protein (TSPO) antagonist, inhibits stress-induced accumulation of neurosteroids and noradrenaline release in the rat brain and alleviates the subsequent symptomatic responses with a brain TSPO occupancy of 50% or more. In this study, we measured ONO-2952 brain TSPO occupancy in conscious rhesus monkeys using positron emission tomography (PET) with 11C-PBR28 as ligand for translational research to clinical application. PET scans were performed after single and repeated oral administration of ONO-2952 at several dose levels for each animal, with sequential arterial blood sampling. In vitro binding studies showed that ONO-2952 potently binds to brain TSPO in monkeys with an affinity equivalent to that in rats. ONO-2952, given orally before PET scans, dose dependently decreased 11C PBR28 uptake without marked brain region specificity. Results of the quantitative analysis using arterial input function revealed that TSPO occupancy after ONO 2952 single and repeated oral administration tended to increase in parallel with its plasma concentration, reaching the highest level of 100%. These findings indicate that ONO-2952 has sufficient brain distribution in primates and that ONO 2952 TSPO occupancy in humans can also be determined using PET. PMID- 27986862 TI - Demographic factors, workplace factors and active transportation use in the USA: a secondary analysis of 2009 NHTS data. AB - BACKGROUND: While active transportation has health, economic and environmental benefits, participation within the USA is low. The purpose of this study is to examine relationships of demographic and workplace factors with health-enhancing active transportation and commuting. METHODS: Participants in the 2009 National Household Travel Survey reported demographics, workplace factors (time/distance to work, flextime availability, option to work from home and work start time) and active transportation (for any purpose) or commuting (to and from work, workers only) as walking or biking (>=10 min bouts only). Multiple logistic regression examined cross-sectional relationships between demographics and workplace factors with active transportation and commuting. RESULTS: Among 152 573 participants, active transportation was reported by 1.11% by biking and 11.74% by walking. Among 111 808 working participants, active commuting was reported by 0.80% by biking and 2.76% by walking. Increased odds (p<0.05) of active commuting and transportation were associated with younger age, lower income, urban dwelling, and the highest and lowest education categories. Males had greater odds of commuting and transporting by bike but decreased odds of walk transporting. Inconsistent patterns were observed by race, but whites had greater odds of any biking (p<0.05). Odds of active commuting were higher with a flexible schedule (p<0.001), the option to work from home (p<0.05), shorter time and distance to work (both p<0.001), and work arrival time between 11:00 and 15:59 (walking only, p=0.001). CONCLUSIONS: Active transportation differed across demographic and workplace factors. These relationships could inform infrastructure policy decisions and workplace wellness programming targeting increased active transportation. PMID- 27986863 TI - Impact of contaminated household environment on stunting in children aged 12-59 months in Burkina Faso. AB - BACKGROUND: Stunting affects 165 million children worldwide, with repercussions on their survival and development. A contaminated environment is likely to contribute to stunting: frequent faecal-oral transmission possibly causes environmental enteropathy, a chronic inflammatory disorder that may contribute to faltering growth in children. This study's objective was to assess the effect of contaminated environment on stunting in Burkina Faso, where stunting prevalence is persistently high. METHODS: Panel study of children aged 1-5 years in Kaya. Household socioeconomic characteristics, food needs and sanitary conditions were measured once, and child growth every year (2011-2014). Using multiple correspondence analysis and 12 questions and observations on water, sanitation, hygiene behaviours, yard cleanliness and animal proximity, we constructed a 'contaminated environment' index as a proxy of faecal-oral transmission exposure. Analysis was performed using a generalised structural equation model (SEM), adjusting for repeat observations and hierarchical data. RESULTS: Stunting (<2 SD height-for-age) prevalence was 29% among 3121 children (median (IQR) age 36 (25 48) months). Environment contamination was widespread, particularly in rural and peri-urban areas, and was associated with stunting (prevalence ratio 1.30; p=0.008), controlling for sex, age, survey year, setting, mother's education, father's occupation, household food security and wealth. This association was significant for children of all ages (1-5 years) and settings. Lower contamination and higher food security had effects of comparable magnitude. CONCLUSIONS: Environment contamination can be at least as influential as nutritional components in the pathway to stunting. There is a rationale for including interventions to reduce environment contamination in stunting prevention programmes. PMID- 27986864 TI - MicroRNA-322 inhibits inflammatory cytokine expression and promotes cell proliferation in LPS-stimulated murine macrophages by targeting NF-kappaB1 (p50). AB - Inflammation is the body's normal self-protection mechanism to eliminate pathogens and resist pathogen invasion. The excessive inflammatory response may lead to inflammatory lesions. The mechanisms accounting for inflammation remain hazy. miRNAs have been proposed to have crucial effects on inflammation. In the present study, we reported that lipopolysaccharide (LPS)-stimulation increased the expression levels of inflammatory cytokines and the cell-cycle progression was suppressed in RAW264.7 cells. Meanwhile, the expression of miR-322 was significantly down-regulated after LPS treatment. Bioinformatics predictions revealed a potential binding site of miR-322 in 3'-UTR of NF-kappaB1 (p50) and it was further confirmed by luciferase assay. Moreover, both the mRNA and protein levels of NF-kappaB1 (p50) were down-regulated by miR-322 in RAW264.7 cells. Subsequently, we demonstrated that miR-322 mimics decrease in the expression levels of inflammatory cytokines and cell-cycle repression can be rescued following LPS treatment in RAW264.7 cells. The anti-inflammatory cytokines expression including IL-4 and IL-10 were significantly up-regulated. Furthermore, miR-322 could also promote RAW264.7 cells proliferation. These results demonstrate that miR-322 is a negative regulator of inflammatory response by targeting NF-kappaB1 (p50). PMID- 27986865 TI - Cross-talks via mTORC2 can explain enhanced activation in response to insulin in diabetic patients. AB - The molecular mechanisms of insulin resistance in Type 2 diabetes have been extensively studied in primary human adipocytes, and mathematical modelling has clarified the central role of attenuation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activity in the diabetic state. Attenuation of mTORC1 in diabetes quells insulin-signalling network-wide, except for the mTOR in complex 2 (mTORC2)-catalysed phosphorylation of protein kinase B (PKB) at Ser473 (PKB S473P), which is increased. This unique increase could potentially be explained by feedback and interbranch cross-talk signals. To examine if such mechanisms operate in adipocytes, we herein analysed data from an unbiased phosphoproteomic screen in 3T3-L1 adipocytes. Using a mathematical modelling approach, we showed that a negative signal from mTORC1-p70 S6 kinase (S6K) to rictor-mTORC2 in combination with a positive signal from PKB to SIN1-mTORC2 are compatible with the experimental data. This combined cross-branch signalling predicted an increased PKB-S473P in response to attenuation of mTORC1 - a distinguishing feature of the insulin resistant state in human adipocytes. This aspect of insulin signalling was then verified for our comprehensive model of insulin signalling in human adipocytes. Introduction of the cross-branch signals was compatible with all data for insulin signalling in human adipocytes, and the resulting model can explain all data network-wide, including the increased PKB S473P in the diabetic state. Our approach was to first identify potential mechanisms in data from a phosphoproteomic screen in a cell line, and then verify such mechanisms in primary human cells, which demonstrates how an unbiased approach can support a direct knowledge-based study. PMID- 27986868 TI - Proprotein convertase subtilisin/Kexin type 9 (PCSK9) single domain antibodies are potent inhibitors of low density lipoprotein receptor degradation. PMID- 27986866 TI - EXTRA-LARGE G PROTEINs Interact with E3 Ligases PUB4 and PUB2 and Function in Cytokinin and Developmental Processes. AB - Heterotrimeric GTP-binding proteins (G proteins) composed of Galpha, Gbeta, and Ggamma subunits are conserved signal transduction molecules in animals and plants. In Arabidopsis (Arabidopsis thaliana), there are three Galpha-like proteins named EXTRA-LARGE G PROTEINs (XLGs) in addition to the canonical Galpha protein GPA1. XLGs have been reported to be implicated in multiple pathways, although the underlying mechanisms of their action remain elusive. Here, we report that all three XLGs interact with two closely related plant U-box (PUB) E3 ligases, PUB2 and PUB4. Three XLGs are predominantly localized at the plasma membrane, whereas XLG2 and XLG3 also show nuclear localization. The interactions between PUB2/4 and XLGs suggest that they might function in the same pathways. Indeed, we found that a newly obtained xlg1/2/3 triple knockout mutant, the pub4 mutant, and the pub2/4 double mutant all exhibited defects in cytokinin responses, stamen development, tapetum development, and male fertility. However, the xlg single mutants and the pub2 mutant did not exhibit an obvious defect in these processes, which suggests functional redundancy among the three XLGs and between PUB2 and PUB4. Overexpressing ARR10 to enhance the cytokinin response in pub4 or in the xlg1/2/3 triple mutant partially restored several phenotypes caused by the pub4 and xlg1/2/3 mutations. Our findings reveal that the XLGs and PUB2/4 are components in the complex cytokinin signaling networks regulating many developmental and physiological processes. PMID- 27986869 TI - Mechanism of 17alpha,20-lyase and new hydroxylation reactions of human cytochrome P450 17A1. 18O LABELING AND OXYGEN SURROGATE EVIDENCE FOR A ROLE OF A PERFERRYL OXYGEN. PMID- 27986870 TI - MEK-ERK-mediated phosphorylation of Mdm2 at Ser-166 in hepatocytes. Mdm2 IS ACTIVATED IN RESPONSE TO INHIBITED Akt SIGNALING. PMID- 27986867 TI - Sucrose Transporter Localization and Function in Phloem Unloading in Developing Stems. AB - How sucrose transporters (SUTs) regulate phloem unloading in monocot stems is poorly understood and particularly so for species storing high Suc concentrations. To this end, Sorghum bicolor SUTs SbSUT1 and SbSUT5 were characterized by determining their transport properties heterologously expressed in yeast or Xenopus laevis oocytes, and their in planta cellular and subcellular localization. The plasma membrane-localized SbSUT1 and SbSUT5 exhibited a strong selectivity for Suc and high Suc affinities in X. laevis oocytes at pH 5-SbSUT1, 6.3 +/- 0.7 mm, and SbSUT5, 2.4 +/- 0.5 mm Suc. The Suc affinity of SbSUT1 was dependent on membrane potential and pH. In contrast, SbSUT5 Suc affinity was independent of membrane potential and pH but supported high transport rates at neutral pH. Suc transport by the tonoplast localized SbSUT4 could not be detected using yeast or X. laevis oocytes. Across internode development, SUTs, other than SbSUT4, were immunolocalized to sieve elements, while for elongating and recently elongated internodes, SUTs also were detected in storage parenchyma cells. We conclude that apoplasmic Suc unloading from de-energized protophloem sieve elements in meristematic zones may be mediated by reversal of SbSUT1 and/or by uniporting SWEETs. Storage parenchyma localized SbSUT1 and SbSUT5 may accumulate Suc from the stem apoplasms of elongating and recently elongated internodes, whereas SbSUT4 may function to release Suc from vacuoles. Transiting from an apoplasmic to symplasmic unloading pathway as the stem matures, SbSUT1 and SbSUT5 increasingly function in Suc retrieval into metaphloem sieve elements to maintain a high turgor to drive symplasmic unloading by bulk flow. PMID- 27986872 TI - New Species and New Records of Mites of the Family Myocoptidae (Acariformes: Sarcoptoidea) From African Rodents. AB - Eleven species of myocoptid mites (Acariformes: Myocoptidae) are recorded from African rodents. Among them, three species are described as new for science: Myocoptes lophuromys sp. nov. from Lophuromys woosnami Thomas, 1906 (Rodentia: Muridae) from Uganda, Trichoecius hylomyscus sp. nov. from Hylomyscus anselli Bishop, 1979 (Rodentia: Muridae) from Tanzania (type host and locality) and Hylomyscus stella (Thomas, 1911) from Gabon, and Trichoecius faini sp. nov. from Hylomyscus arcimontanus Carlton and Stanley, 2005 from Tanzania. Gliricoptes graphiuri Fain, 1970 syn. nov. is synonymized with Gliricoptes vulcanorum Fain, 1970, and the female of Trichoecius angolensis Fain, 1972 is described for the first time. New hosts and localities are provided for four species: Myocoptes grammomys Fain, 1970 from Grammomys dryas (L., 1758) (Rodentia: Muridae) from Burundi and Uganda, Myocoptes spinulatus Fain, 1970 from Dendromus mystacalis (Heuglin, 1863) (Rodentia: Muridae) from Tanzania, Crinicastor congolensis Fain, 1970 from Grammomys macmillani (Wroughton, 1907) (Rodentia: Muridae) from Tanzania, and Trichoecius otomys Fain, 1970 from Otomys typus (Heuglin, 1877) (Rodentia: Muridae) from Uganda. Three species are recorded from new localities: Gliricoptes vulcanorum from Tanzania, Trichoecius angolensis from South Africa, and Trichoecius lootensi Fain, 1970 from Tanzania. PMID- 27986871 TI - Frontline Science: HIV infection of Kupffer cells results in an amplified proinflammatory response to LPS. AB - End-stage liver disease is a common cause of non-AIDS-related mortality in HIV+ patients, despite effective anti-retroviral therapies (ARTs). HIV-1 infection causes gut CD4 depletion and is thought to contribute to increased gut permeability, bacterial translocation, and immune activation. Microbial products drain from the gut into the liver via the portal vein where Kupffer cells (KCs), the resident liver macrophage, clear translocated microbial products. As bacterial translocation is implicated in fibrogenesis in HIV patients through unclear mechanisms, we tested the hypothesis that HIV infection of KCs alters their response to LPS in a TLR4-dependent manner. We showed that HIV-1 productively infected KCs, enhanced cell-surface TLR4 and CD14 expression, and increased IL-6 and TNF-alpha expression, which was blocked by a small molecule TLR4 inhibitor. Our study demonstrated that HIV infection sensitizes KCs to the proinflammatory effects of LPS in a TLR4-dependent manner. These findings suggest that HIV-1-infected KCs and their dysregulated innate immune response to LPS may play a role in hepatic inflammation and fibrosis and represent a novel target for therapy. PMID- 27986873 TI - Long-term cortisol measures predict Alzheimer disease risk. AB - OBJECTIVE: To examine whether long-term measures of cortisol predict Alzheimer disease (AD) risk. METHOD: We used a prospective longitudinal design to examine whether cortisol dysregulation was related to AD risk. Participants were from the Baltimore Longitudinal Study of Aging (BLSA) and submitted multiple 24-hour urine samples over an average interval of 10.56 years. Urinary free cortisol (UFC) and creatinine (Cr) were measured, and a UFC/Cr ratio was calculated to standardize UFC. To measure cortisol regulation, we used within-person UFC/Cr level (i.e., within-person mean), change in UFC/Cr over time (i.e., within-person slope), and UFC/Cr variability (i.e., within-person coefficient of variation). Cox regression was used to assess whether UFC/Cr measures predicted AD risk. RESULTS: UFC/Cr level and UFC/Cr variability, but not UFC/Cr slope, were significant predictors of AD risk an average of 2.9 years before AD onset. Elevated UFC/Cr level and elevated UFC/Cr variability were related to a 1.31- and 1.38-times increase in AD risk, respectively. In a sensitivity analysis, increased UFC/Cr level and increased UFC/Cr variability predicted increased AD risk an average of 6 years before AD onset. CONCLUSIONS: Cortisol dysregulation as manifested by high UFC/Cr level and high UFC/Cr variability may modulate the downstream clinical expression of AD pathology or be a preclinical marker of AD. PMID- 27986876 TI - Changes in insomnia subtypes in early Parkinson disease. AB - OBJECTIVE: To examine the development of factors associated with insomnia in a cohort of originally drug-naive patients with incident Parkinson disease (PD) during the first 5 years after diagnosis. METHODS: One hundred eighty-two drug naive patients with PD derived from a population-based incident cohort and 202 control participants were assessed for insomnia before treatment initiation and were repeatedly examined after 1, 3, and 5 years. Insomnia was diagnosed according to the Stavanger Sleepiness Questionnaire. The Parkinson's Disease Sleep Scale was used to differentiate sleep initiation problems from problems of sleep maintenance. Generalized estimating equation models were applied for statistical measures. RESULTS: The prevalence of insomnia in general was not higher in patients with PD compared to controls at the 5-year follow-up. There were changes in the prevalence of the different insomnia subtypes over the 5-year follow-up. The prevalence of solitary problems in sleep maintenance increased from 31% (n = 18) in the drug-naive patients at baseline to 49% (n = 29) after 1 year and were associated with the use of dopamine agonists and higher Montgomery Asberg Depression Rating Scale scores. The prevalence of solitary sleep initiation problems decreased continuously from 21% (n = 12) at baseline to 7.4% (n = 4) after 5 years; these were associated with less daytime sleepiness. CONCLUSIONS: The prevalence rates of the different insomnia subtypes changed notably in patients with early PD. The frequency of sleep maintenance problems increased, and these problems were associated with dopamine agonist use and depressive symptoms, while the total number of patients with insomnia remained stable. Our findings reflect the need for early individual assessments of insomnia subtypes and raise the possibility of intervention to reduce these symptoms in patients with early PD. PMID- 27986875 TI - Brain MRI atrophy quantification in MS: From methods to clinical application. AB - Patients with the main clinical phenotypes of multiple sclerosis (MS) manifest varying degrees of brain atrophy beyond that of normal aging. Assessment of atrophy helps to distinguish clinically and cognitively deteriorating patients and predicts those who will have a less-favorable clinical outcome over the long term. Atrophy can be measured from brain MRI scans, and many technological improvements have been made over the last few years. Several software tools, with differing requirements on technical ability and levels of operator intervention, are currently available and have already been applied in research or clinical trial settings. Despite this, the measurement of atrophy in routine clinical practice remains an unmet need. After a short summary of the pathologic substrates of brain atrophy in MS, this review attempts to guide the clinician towards a better understanding of the methods currently used for quantifying brain atrophy in this condition. Important physiologic factors that affect brain volume measures are also considered. Finally, the most recent research on brain atrophy in MS is summarized, including whole brain and various compartments thereof (i.e., white matter, gray matter, selected CNS structures). Current methods provide sufficient precision for cohort studies, but are not adequate for confidently assessing changes in individual patients over the scale of months or a few years. PMID- 27986883 TI - What to Do With the Participants/Patients in Phase III Clinical Cancer Trials That Have Been Stopped by the FDA. PMID- 27986882 TI - General Biomarker Recommendations for Lymphoma. AB - Lymphoid malignancies are a heterogeneous group of tumors that have distinctive clinical and biological behaviors. The increasing prevalence of disease reflects both treatment advances and the fact that some of these tumors are indolent. The ability to determine treatment needs at diagnosis remains problematic for some of the tumors, such as in follicular lymphomas. Major clinical advances will likely depend on precision oncology that will enable identification of specific disease entities, prognostic determination at diagnosis, and identification of precise therapeutic targets and essential pathways. However, refinement in diagnostic evaluation is an evolving science. The ability to determine prognosis at diagnosis is variable, and for many of the lymphoid malignancies prognosis can only be made after initial treatment. Clinical trials that aim to evaluate specific features of these diseases are required in order to advance clinical practice that meaningfully addresses this important public health challenge. Herein, we describe the process and general recommendation from the National Cancer Institute (NCI) clinical trials planning meeting in November 2014 to address clinical trial design and biomarker proposals in the context of NCI supported lymphoma clinical trials in the National Clinical Trials Network. PMID- 27986877 TI - Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies. AB - OBJECTIVE: To review population-based studies of the prevalence and incidence of epilepsy worldwide and use meta-analytic techniques to explore factors that may explain heterogeneity between estimates. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards were followed. We searched MEDLINE and EMBASE for articles published on the prevalence or incidence of epilepsy since 1985. Abstract, full-text review, and data abstraction were conducted in duplicate. Meta-analyses and meta-regressions were used to explore the association between prevalence or incidence, age group, sex, country level income, and study quality. RESULTS: A total of 222 studies were included (197 on prevalence, 48 on incidence). The point prevalence of active epilepsy was 6.38 per 1,000 persons (95% confidence interval [95% CI] 5.57-7.30), while the lifetime prevalence was 7.60 per 1,000 persons (95% CI 6.17-9.38). The annual cumulative incidence of epilepsy was 67.77 per 100,000 persons (95% CI 56.69 81.03) while the incidence rate was 61.44 per 100,000 person-years (95% CI 50.75 74.38). The prevalence of epilepsy did not differ by age group, sex, or study quality. The active annual period prevalence, lifetime prevalence, and incidence rate of epilepsy were higher in low to middle income countries. Epilepsies of unknown etiology and those with generalized seizures had the highest prevalence. CONCLUSIONS: This study provides a comprehensive synthesis of the prevalence and incidence of epilepsy from published international studies and offers insight into factors that contribute to heterogeneity between estimates. Significant gaps (e.g., lack of incidence studies, stratification by age groups) were identified. Standardized reporting of future epidemiologic studies of epilepsy is needed. PMID- 27986874 TI - Second monotherapy in childhood absence epilepsy. AB - OBJECTIVE: To determine optimal second monotherapy for children with childhood absence epilepsy (CAE) experiencing initial treatment failure. METHODS: Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16-20 and month 12 visits after randomization. Secondary study outcome was percentage of participants experiencing attentional dysfunction at these visits. RESULTS: A total of 208 children were enrolled, randomized, and received second therapy. At both week 16-20 visit and month 12 visit, ethosuximide's (63%, 57%) and valproic acid's (65%, 49%) freedom from failure proportions were similar to each other and higher than lamotrigine's (45%, 36%, p = 0.051 and p = 0.062). At both time points, ethosuximide and valproic acid had superior seizure control compared to lamotrigine (p < 0.0001). At both the week 16-20 and month 12 visits, attentional dysfunction was numerically more common with valproic acid than with ethosuximide or lamotrigine. For each medication, second monotherapy freedom from failure proportions demonstrated noninferiority to initial monotherapy freedom from failure proportions. CONCLUSIONS: As second monotherapy, ethosuximide and valproic acid, demonstrated higher freedom from failure proportions and greater efficacy than lamotrigine; valproic acid was associated with more attentional dysfunction. Ethosuximide is the optimal second monotherapy for children with CAE not responding to initial therapy with other medications. CLINICALTRIALSGOV IDENTIFIER: NCT00088452. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for children with CAE experiencing initial treatment failure, second monotherapy with ethosuximide or valproic acid is superior to lamotrigine. PMID- 27986885 TI - Response. PMID- 27986886 TI - RE: Long-term Outcome of an Organ Preservation Program After Neoadjuvant Treatment for Rectal Cancer. PMID- 27986884 TI - Beyond RCHOP: A Blueprint for Diffuse Large B Cell Lymphoma Research. AB - Diffuse large B cell lymphoma (DLBCL) comprises multiple molecular and biological subtypes, resulting in a broad range of clinical outcomes. With standard chemoimmunotherapy, there remains an unacceptably high treatment failure rate in certain DLBCL subsets: activated B cell (ABC) DLBCL, double-hit lymphoma defined by the dual translocation of MYC and BCL2, dual protein-expressing lymphomas defined by the overexpression of MYC and BCL2, and older patients and those with central nervous system involvement. The main research challenges for DLBCL are to accurately identify molecular subsets and to determine if specific chemotherapy platforms and targeted agents offer differential benefit. The ultimate goal should be to maximize initial cure rates to improve long-term survival while minimizing toxicity. In particular, a frontline trial should focus on biologically defined risk groups not likely to be cured with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP). An additional challenge is to develop effective and personalized strategies in the relapsed setting, for which there is no current standard other than autologous stem cell transplantation, which benefits a progressively smaller proportion of patients. Relapsed/refractory DLBCL is the ideal setting for testing novel agents and new biomarker tools and will require a national call for biopsies to optimize discovery in this setting. Accordingly, the development of tools with both prognostic and predictive utility and the individualized application of new therapies should be the main priorities. This report identifies clinical research priorities for critical areas of unmet need in this disease. PMID- 27986887 TI - Genomics Studies in Esophageal Cancers Yield New Approaches. PMID- 27986888 TI - Two Federal Agencies Tighten Rules for Clinical Trials. PMID- 27986889 TI - The Cancer Moonshot: Poised To Make Advances. PMID- 27986890 TI - Artificial Turf and Cancer Risk. PMID- 27986895 TI - Mapping discussion of canine obesity between veterinary surgeons and dog owners: a provisional study. AB - This study maps communication between veterinary surgeons and dog owners on obesity management in four first-opinion practices in the UK. A total of 74 dog owners who met the study's inclusion criteria and 24 veterinary surgeons were interviewed using oral questionnaires between November 2013 and May 2014. The dog owner questionnaire was based on potential discussion areas that could influence an owner's intention to act (initiate a weight loss regime) based on Ajzen's Theory of Planned Behaviour. The veterinary surgeons' questionnaires assessed perception of canine obesity, their personal communication strategies and current practice-level interventions. The findings identify opportunities for more proactive approaches to obesity management by veterinary surgeons and their practices. PMID- 27986894 TI - Alternative splicing of the OCC-1 gene generates three splice variants and a novel exonic microRNA, which regulate the Wnt signaling pathway. AB - The Wnt signaling pathway is hyperactivated in most colorectal cancers (CRC). Finding new regulators of this pathway represents the potential for cancer diagnosis or treatment. OCC-1 was initially reported as an up-regulated gene in colon carcinoma, without knowing its mechanism of action. Here, two novel transcript variants and an exonic microRNA that originated from the OCC-1 gene are reported, showing positive effects on Wnt activity. Up-regulation of the known OCC-1 variant (assigned as OCC-1A/B) was limited to CRC, and its overexpression increased survival of CRC-originated SW480 cells (Wnt+), while resulting in apoptosis of Wnt-suppressed SW480 cells or HeLa cells (Wnt-) detected by PI staining. Immunocytochemistry showed that the OCC-1A/B-encoded peptide was localized to the nucleus, where its overexpression resulted in Wnt signaling up-regulation, detected by TOP/FOPflash assay. The noncoding portion of the OCC-1A/B transcript had a suppressive effect on Wnt activity and had a negative correlation with APPL2 neighboring gene expression. Unlike OCC-1A/B, the novel OCC-1C splice variant had no expression alteration in CRC, and it seemed to encode a smaller peptide with cytoplasmic localization. A 60-nucleotide (nt) fragment containing an AUG start codon is spliced out to produce an OCC-1D noncoding RNA variant. The 60-nt RNA was validated as the precursor of a novel microRNA, which we named miR-ex1 Both OCC-1D and miR-ex1 were coordinately up regulated in CRC. MiR-ex1 functional analysis revealed that it is targeting the APC2 tumor suppressor gene and is an activator of the Wnt signaling pathway. Overall, the OCC-1 gene is now introduced as a novel Wnt signaling regulator and as a potential therapeutic target. PMID- 27986897 TI - It Was a Great, Green Year: Identification of a Chlorophyll Dephytylase That Functions in Chlorophyll Turnover. PMID- 27986896 TI - easyGWAS: A Cloud-Based Platform for Comparing the Results of Genome-Wide Association Studies. AB - The ever-growing availability of high-quality genotypes for a multitude of species has enabled researchers to explore the underlying genetic architecture of complex phenotypes at an unprecedented level of detail using genome-wide association studies (GWAS). The systematic comparison of results obtained from GWAS of different traits opens up new possibilities, including the analysis of pleiotropic effects. Other advantages that result from the integration of multiple GWAS are the ability to replicate GWAS signals and to increase statistical power to detect such signals through meta-analyses. In order to facilitate the simple comparison of GWAS results, we present easyGWAS, a powerful, species-independent online resource for computing, storing, sharing, annotating, and comparing GWAS. The easyGWAS tool supports multiple species, the uploading of private genotype data and summary statistics of existing GWAS, as well as advanced methods for comparing GWAS results across different experiments and data sets in an interactive and user-friendly interface. easyGWAS is also a public data repository for GWAS data and summary statistics and already includes published data and results from several major GWAS. We demonstrate the potential of easyGWAS with a case study of the model organism Arabidopsis thaliana, using flowering and growth-related traits. PMID- 27986899 TI - Association between inappropriate empirical antimicrobial therapy and hospital length of stay in Gram-negative bloodstream infections: stratification by prognosis. AB - OBJECTIVES: The potential benefit from appropriate empirical antimicrobial therapy in patients with favourable prognosis at initial presentation with Gram negative bloodstream infection (BSI) remains unclear. This retrospective cohort study examined the impact of inappropriate empirical antimicrobial therapy on hospital length of stay (HLOS) following Gram-negative BSI after stratification by predicted prognosis using the BSI mortality risk score (BSIMRS). METHODS: Hospitalized adults with first episodes of Gram-negative BSI from 1 January 2010 to 31 December 2013 at Palmetto Health Hospitals in Columbia, SC, USA were identified. Multivariate Cox proportional hazards regression was used to examine the association between inappropriate empirical antimicrobial therapy and HLOS overall and within each predefined BSIMRS category (<5 and >=5). RESULTS: Among 830 unique patients with Gram-negative BSI, 469 and 361 had BSIMRS <5 and >=5, respectively. Overall, the median age was 65 years, 448 (54%) were women, Escherichia coli (444; 53%) was the most common bloodstream isolate and 444 (53%) had a urinary source of infection. After adjustments in the multivariate model, BSIMRS (HR = 1.14 per point, 95% CI = 1.11-1.17, P < 0.001) and inappropriate empirical antimicrobial therapy (HR = 1.41, 95% CI = 1.07-1.91, P = 0.01) were independently associated with increased risk of remaining hospitalized following Gram-negative BSI. Median HLOS with appropriate and inappropriate empirical antimicrobial therapy was 7 and 10 days, respectively, in patients with BSIMRS <5 (P = 0.03) and 13 and 17 days, respectively, in those with BSIMRS >=5 (P = 0.02). CONCLUSIONS: Inappropriate empirical antimicrobial therapy is associated with prolonged HLOS following Gram-negative BSI in patients with both good and guarded prognosis. PMID- 27986900 TI - A primer on PDSA: executing plan-do-study-act cycles in practice, not just in name. PMID- 27986898 TI - Antimicrobial activity of antisense peptide-peptide nucleic acid conjugates against non-typeable Haemophilus influenzae in planktonic and biofilm forms. AB - BACKGROUND: Antisense peptide nucleic acids (PNAs) are synthetic polymers that mimic DNA/RNA and inhibit bacterial gene expression in a sequence-specific manner. METHODS: To assess activity against non-typeable Haemophilus influenzae (NTHi), we designed six PNA-peptides that target acpP, encoding an acyl carrier protein. MICs and minimum biofilm eradication concentrations (MBECs) were determined. Resistant strains were selected by serial passages on media with a sub-MIC concentration of acpP-PNA. RESULTS: The MICs of six acpP-PNA-peptides were 2.9-11 mg/L (0.63-2.5 MUmol/L) for 20 clinical isolates, indicating susceptibility of planktonic NTHi. By contrast, MBECs were up to 179 mg/L (40 MUmol/L). Compared with one original PNA-peptide (acpP-PNA1-3'N), an optimized PNA-peptide (acpP-PNA14-5'L) differs in PNA sequence and has a 5' membrane penetrating peptide with a linker between the PNA and peptide. The optimized PNA peptide had an MBEC ranging from 11 to 23 mg/L (2.5-5 MUmol/L), indicating susceptibility. A resistant strain that was selected by the original acpP-PNA1 3'N had an SNP that introduced a stop codon in NTHI0044, which is predicted to encode an ATP-binding protein of a conserved ABC transporter. Deletion of NTHI0044 caused resistance to the original acpP-PNA1-3'N, but showed no effect on susceptibility to the optimized acpP-PNA14-5'L. The WT strain remained susceptible to the optimized PNA-peptide after 30 serial passages on media containing the optimized PNA-peptide. CONCLUSIONS: A PNA-peptide that targets acpP, has a 5' membrane-penetrating peptide and has a linker shows excellent activity against planktonic and biofilm NTHi and is associated with a low risk for induction of resistance. PMID- 27986901 TI - What we know about designing an effective improvement intervention (but too often fail to put into practice). PMID- 27986902 TI - Reducing Voices by Direct Dialogue. PMID- 27986903 TI - Classic Spotlight, 1967 and 1968: Articles of Significant Interest Selected from the Journal of Virology Archives by the Editors. PMID- 27986905 TI - Sweet Solutions to Reduce Procedural Pain in Neonates: A Meta-analysis. AB - CONTEXT: Abundant evidence of sweet taste analgesia in neonates exists, yet placebo-controlled trials continue to be conducted. OBJECTIVE: To review all trials evaluating sweet solutions for analgesia in neonates and to conduct cumulative meta-analyses (CMAs) on behavioral pain outcomes. DATA SOURCES: (1) Data from 2 systematic reviews of sweet solutions for newborns; (2) searches ending 2015 of CINAHL, Medline, Embase, and psychINFO. DATA EXTRACTION AND ANALYSIS: Two authors screened studies for inclusion, conducted risk-of-bias ratings, and extracted behavioral outcome data for CMAs. CMA was performed using random effects meta-analysis. RESULTS: One hundred and sixty-eight studies were included; 148 (88%) included placebo/no-treatment arms. CMA for crying time included 29 trials (1175 infants). From the fifth trial in 2002, there was a statistically significant reduction in mean cry time for sweet solutions compared with placebo (-27 seconds, 95% confidence interval [CI] -51 to -4). By the final trial, CMA was -23 seconds in favor of sweet solutions (95% CI -29 to -18). CMA for pain scores included 50 trials (3341 infants). Results were in favor of sweet solutions from the second trial (0.5, 95% CI -1 to -0.1). Final results showed a standardized mean difference of -0.9 (95% CI -1.1 to -0.7). LIMITATIONS: We were unable to use or obtain data from many studies to include in the CMA. CONCLUSIONS: Evidence of sweet taste analgesia in neonates has existed since the first published trials, yet placebo/no-treatment, controlled trials have continued to be conducted. Future neonatal pain studies need to select more ethically responsible control groups. PMID- 27986906 TI - Shedding New Light on the Process of "Licensing" for Pathogenicity by Th Lymphocytes. AB - Th cells sensitized against autoantigens acquire pathogenicity following two sequential events, namely activation by their target Ag and a process named "licensing." In this study, we analyzed these processes in a transgenic mouse system in which TCR-transgenic Th cells specific to hen egg lysozyme (HEL) are adoptively transferred to recipients and induce inflammation in eyes expressing HEL. Our data show that the notion that the lung is the organ where "licensing" for pathogenicity takes place is based on biased data collected with cells injected i.v., a route in which most transferred cells enter via the lung. Thus, we found that when donor cells were activated in vitro and injected intraperitoneally, or were activated in vivo, they migrated simultaneously to the lung, spleen, and other tested organs. In all, tested organs donor cells undergo "licensing" for pathogenicity, consisting of vigorous increase in number and changes in expression levels of inflammation-related genes, monitored by both flow cytometry and microarray analysis. After reaching peak numbers, around day 3, the "licensed" donor cells migrate to the circulation and initiate inflammation in the HEL-expressing recipient eyes. Importantly, the kinetics of increase in number and of changes in gene expression by the donor cells were similar in lung, spleen, and other tested organs of the recipient mice. Furthermore, the total numbers of donor cells in the spleen at their peaks were 10- to 100-fold larger in the spleen than in the lung, contradicting the notion that the lung is the organ where "licensing" takes place. PMID- 27986907 TI - Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Center T Follicular Helper Cell Differentiation during the Primary Response to Vaccination. AB - Adenosine A2a receptor (A2aR) signaling acts as a barrier to autoimmunity by promoting anergy, inducing regulatory T cells, and inhibiting effector T cells. However, in vivo effects of A2aR signaling on polyclonal CD4 T cells during a primary response to foreign Ag has yet to be determined. To address this problem, we immunized mice with peptide Ag 2W1S coupled to PE in CFA and treated with the selective A2aR agonist CGS-21680 (CGS). 2W1S:I-Ab-specific tetramer-binding CD4 T cells did not become anergic or differentiate into Foxp3+ regulatory T cells. Additionally, CGS treatment did not inhibit Th1 or Th17 differentiation. However, CGS did abrogate germinal center T follicular helper cells, and blunted PE specific germinal center B cell responses. The use of A2aR-deficient CD4 T cells established that this CGS effect was T cell intrinsic. Therefore, this study has identified a unique role for A2aRs in regulating CD4 T cell differentiation during vaccination. PMID- 27986909 TI - SOS1, ARHGEF1, and DOCK2 rho-GEFs Mediate JAK-Dependent LFA-1 Activation by Chemokines. AB - JAK-dependent activation of the rho module of integrin affinity triggering mediates chemokine-induced leukocyte adhesion. However, the signaling events linking JAKs to rho small GTPase activation by chemokines is still incompletely described. In this study, we show that son of sevenless 1 (SOS1), rho guanine nucleotide exchange factor (GEF)1 (ARHGEF1), and dedicator of cytokinesis (DOCK)2 GEFs mediate CXCL12-induced LFA-1 activation in human primary T lymphocytes. Downregulated expression of SOS1, ARHGEF1, and DOCK2 impairs LFA-1-mediated rapid T lymphocyte adhesion as well as underflow arrest on ICAM-1 induced by CXCL12. Moreover, LFA-1 affinity triggering by CXCL12 is impaired by SOS1, ARHGEF1, and DOCK2 downregulation. Notably, the three GEFs are all critically involved in chemokine-induced RhoA and Rac1 activation, thus suggesting the occurrence of a SOS1 specificity shift in the context of chemokine signaling. Accordingly, SOS1, ARHGEF1, and DOCK2 are tyrosine phosphorylated upon chemokine signaling with timing coherent with rapid LFA-1 affinity activation. Importantly, chemokine induced tyrosine phosphorylation of these GEFs is fully mediated by JAK protein tyrosine kinases. Unexpectedly, and differently from VAV1, tyrosine phosphorylation of SOS1, ARHGEF1, and DOCK2 is completely inhibited by pertussis toxin pretreatment, thus suggesting different routes of rho-GEF triggering upon CXCR4 engagement. Taken together, these findings reveal a deeper level of complexity in the rho-signaling module, with at least four different rho-GEFs cooperating in the regulation of chemokine-induced integrin activation, possibly suggesting the emergence of stochastic concurrency in signaling mechanisms controlling leukocyte trafficking. PMID- 27986908 TI - A20 Ameliorates Intracerebral Hemorrhage-Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination. AB - Reducing excessive inflammation is beneficial for the recovery from intracerebral hemorrhage (ICH). Here, the roles and mechanisms of A20 (TNFAIP3), an important endogenous anti-inflammatory factor, are examined in ICH. A20 expression in the PBMCs of ICH patients and an ICH mouse model was detected, and the correlation between A20 expression and neurologic deficits was analyzed. A20 expression was increased in PBMCs and was negatively related to the modified Rankin Scale score. A20 expression was also increased in mouse perihematomal tissues. A20-/- and A20 overexpressing mice were generated to further analyze A20 function. Compared with wild-type (WT) mice, A20-/- and A20-overexpressing mice showed significant increases and decreases, respectively, in hematoma volume, neurologic deficit score, mortality, neuronal degeneration, and proinflammatory factors. Moreover, WT-A20-/- parabiosis was established to explore the role of A20 in peripheral blood in ICH injury. ICH-induced damage, including brain edema, neurologic deficit score, proinflammatory factors, and neuronal apoptosis, was reduced in A20-/- parabionts compared with A20-/- mice. Finally, the interactions between TRAF6 and Ubc13 and UbcH5c were increased in A20-/- mice compared with WT mice; the opposite occurred in A20-overexpressing mice. Enhanced IkappaBalpha degradation and NF-kappaB activation were observed in A20-/- mice, but the results were reversed in A20-overexpressing mice. These results suggested that A20 is involved in regulating ICH-induced inflammatory injury in both the central and peripheral system and that A20 reduces ICH-induced inflammation by regulating TRAF6 polyubiquitination. Targeting A20 may thus be a promising therapeutic strategy for ICH. PMID- 27986910 TI - Establishing High Dimensional Immune Signatures from Peripheral Blood via Mass Cytometry in a Discovery Cohort of Stage IV Melanoma Patients. AB - The identification of blood-borne biomarkers correlating with melanoma patient survival remains elusive. Novel techniques such as mass cytometry could help to identify melanoma biomarkers, allowing simultaneous detection of up to 100 parameters. However, the evaluation of multiparametric data generated via time-of flight mass cytometry requires novel analytical techniques because the application of conventional gating strategies currently used in polychromatic flow cytometry is not feasible. In this study, we have employed 38-channel time of-flight mass cytometry analysis to generate comprehensive immune cell signatures using matrix boolean analysis in a cohort of 28 stage IV melanoma patients and 17 controls. Clusters of parameters were constructed from the abundance of cellular phenotypes significantly different between patients and controls. This approach identified patient-specific combinatorial immune signatures consisting of high-resolution subsets of the T cell, NK cell, B cell, and myeloid compartments. An association with superior survival was characterized by a balanced distribution of myeloid-derived suppressor cell-like and APC-like myeloid phenotypes and differentiated NK cells. The results of this study in a discovery cohort of melanoma patients suggest that multifactorial immune signatures have the potential to allow more accurate prediction of individual patient outcome. Further investigation of the identified immune signatures in a validation cohort is now warranted. PMID- 27986911 TI - Aldehyde Dehydrogenase 2 Polymorphism Is a Predictor of Smoking Cessation. AB - Introduction: Smoking cessation has been known to be associated with drinking behaviors, which are influenced by polymorphisms in genes encoding alcohol metabolizing enzymes. The aim was to evaluate the impact of aldehyde dehydrogenase 2 (ALDH2, rs671) and alcohol dehydrogenase 1B (ADH1B, rs1229984) polymorphisms together with drinking behaviors on smoking cessation. Methods: We conducted a cross-sectional study with 1137 former smokers and 1775 current smokers without any cancer at Aichi Cancer Center Hospital between 2001 and 2005. Unconditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for successful smoking cessation by comparing former smokers (quitters) with current smokers (non-quitters). Results: Older age, lower amount of cumulative smoking exposure, lower number of cigarettes per day, younger age of smoking initiation, shorter smoking duration, longer time to first cigarette in the morning, and lower amount of drinking among ever drinkers were predictors of smoking cessation. After careful adjustment for age, sex, smoking patterns, and drinking status, the ORs for smoking cessation among subjects with ALDH2 Glu/Lys and Lys/Lys were 1.02 (95% CI 0.84-1.23) and 1.78 (95% CI 1.23-2.58) compared with those with ALDH2 Glu/Glu, respectively Mediation analyses confirmed that the effect of ALDH2 Lys/Lys on smoking cessation was independent by dinking behaviors. No statistically significant association between ADH1B polymorphism and smoking cessation was observed. Conclusions: In our Japanese population, ALDH2 polymorphism predicts smoking cessation, independent by drinking behaviors. Interventions for promoting smoking cessation by ALDH2 polymorphism may be useful in Asian populations. Implications: We newly show that subjects with ALDH2 Lys/Lys genotype in a functional polymorphism, rs671, are more likely to quit smoking than those with ALDH2 Glu allele in a Japanese population. Our finding suggests that ALDH2 polymorphism may be useful for promoting smoking cessation in those specific populations as East Asian ones with frequent ALDH2 Lys allele carriers. PMID- 27986912 TI - Nondaily Smokers' Characteristics and Likelihood of Prenatal Cessation and Postpartum Relapse. AB - Introduction: This study aimed to calculate the prevalence of pre-pregnancy nondaily smoking (<1 cigarette/day), risk factors, and report of prenatal provider smoking education; and assess the likelihood of prenatal cessation and postpartum relapse for nondaily smokers. Methods: We analyzed data from 2009 to 2011 among women with live-born infants participating in the Pregnancy Risk Assessment Monitoring System. We compared characteristics of pre-pregnancy daily smokers (>=1 cigarette/day), nondaily smokers, and nonsmokers (chi-square adjusted p < .025). Between nondaily and daily smokers, we compared proportions of prenatal cessation, postpartum relapse (average 4 months postpartum), and reported provider education. Multivariable logistic regression calculated adjusted prevalence ratios (APR) for prenatal cessation among pre-pregnancy smokers (n = 27 360) and postpartum relapse among quitters (n = 13 577). Results: Nondaily smokers (11% of smokers) were more similar to nonsmokers and differed from daily smokers on characteristics examined (p <= .001 for all). Fewer nondaily smokers reported provider education than daily smokers (71.1%, 86.3%; p < .001). A higher proportion of nondaily compared to daily smokers quit during pregnancy (89.7%, 49.0%; p < .001), and a lower proportion relapsed postpartum (22.2%, 48.6%; p < .001). After adjustment, nondaily compared to daily smokers were more likely to quit (APR: 1.65; 95% confidence interval [CI]: 1.58-1.71) and less likely to relapse postpartum (APR: 0.55; 95% CI: 0.48-0.62). Conclusions: Nondaily smokers were more likely to quit smoking during pregnancy, less likely to relapse postpartum, and less likely to report provider education than daily smokers. Providers should educate all women, regardless of frequency of use, about the harms of tobacco during pregnancy, provide effective cessation interventions, and encourage women to be tobacco free postpartum and beyond. Implication: Nondaily smoking (<1 cigarette/day) is increasing among US smokers and carries a significant risk of disease. However, smoking patterns surrounding pregnancy among nondaily smokers are unknown. Using 2009-2011 data from the Pregnancy Risk Assessment Monitoring System, we found pre-pregnancy nondaily smokers compared to daily smokers were 65% more likely to quit smoking during pregnancy and almost half as likely to relapse postpartum. Providers should educate all women, regardless of frequency of use, about the harms of tobacco during pregnancy, provide effective cessation interventions, and encourage women to be tobacco free postpartum and beyond. PMID- 27986913 TI - The Prevalence of Exposure to Workplace Secondhand Smoke in the United States: 2010 to 2015. AB - Objective: To compare changes in exposure to workplace secondhand smoke (SHS) by industry of employment and occupation from 2010 to 2015. Methods: Data were collected from 2010 and 2015 National Health Interview Survey. Weighted estimates of the prevalence of exposure to workplace SHS among currently working nonsmokers in 2010 (n = 12 627) and 2015 (n = 16 399) were compared. Results: The prevalence of exposure to workplace SHS among currently working nonsmokers was 10.0% in 2015 and 9.5% in 2010. Exposure to workplace SHS is disproportionally high among male workers, young workers, non-Hispanic blacks, Hispanics, workers with low education and low income, and workers residing in the Southern United States. Tobacco control policies have effectively reduced exposure to workplace SHS in a few white-collar and service job categories but blue-collar workers remain to have a high prevalence of exposure to workplace SHS. From 2010 to 2015, "transportation and warehousing industries" had the largest increase in SHS exposure (13.3%-21.5%, p value = .004) and "arts, entertainment, and recreation industries" had the largest decline in prevalence of exposure to SHS (20.1% 11.5%, p value = .01). In the multivariate analysis, workers with service (aOR = 1.4, p < .0001) and blue-collar occupations (aOR = 2.5, p < .0001) had a significantly higher prevalence of exposure to workplace SHS than those with white-collar occupations. Conclusions: Disparities of SHS exposure by industry, occupation, and social demographic class continue to exist. Blue-collar workers, especially those working in "transportation and construction industries," along with young workers and workers in high risk social classes are priority groups for future workplace SHS prevention. Implications: An estimated 12.6 million working nonsmokers were regularly exposed to SHS at work in 2015. We compared the changes in prevalence of exposure to workplace SHS from 2010 to 2015 by social demographic class, industry of employment and occupation. Our findings could help inform the policymakers and health practitioners to establish stronger smoke-free air laws and conduct education campaigns to reduce the exposure to workplace SHS, especially among certain industries and occupations with a disproportionally high prevalence of exposure to workplace SHS. PMID- 27986915 TI - Efficient and Heritable Targeted Mutagenesis in Mosses Using the CRISPR/Cas9 System. AB - Targeted genome modification by RNA-guided nucleases derived from the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9 (Cas9) system has seen rapid development in many organisms, including several plant species. In the present study, we succeeded in introducing the CRISPR/Cas9 system into the non-model organism Scopelophila cataractae, a moss that exhibits heavy metal tolerance, and the model organism Physcomitrella patens Utilizing the process by which moss plants regenerate from protoplasts, we conducted targeted mutagenesis by expression of single-chain guide RNA (sgRNA) and Cas9 in protoplasts. Using this method, the acquisition rate of strains exhibiting phenotypic changes associated with the target genes was approximately 45-69%, and strains with phenotypic changes exhibited various insertion and deletion mutations. In addition, we report that our method is capable of multiplex targeted mutagenesis (two independent genes) and also permits the efficient introduction of large deletions (~3 kbp). These results demonstrate that the CRISPR/Cas9 system can be used to accelerate investigations of bryology and land plant evolution. PMID- 27986914 TI - Molecular Characterization of Soybean Pterocarpan 2-Dimethylallyltransferase in Glyceollin Biosynthesis: Local Gene and Whole-Genome Duplications of Prenyltransferase Genes Led to the Structural Diversity of Soybean Prenylated Isoflavonoids. AB - Soybean (Glycine max) accumulates several prenylated isoflavonoid phytoalexins, collectively referred to as glyceollins. Glyceollins (I, II, III, IV and V) possess modified pterocarpan skeletons with C5 moieties from dimethylallyl diphosphate, and they are commonly produced from (6aS, 11aS)-3,9,6a trihydroxypterocarpan [(-)-glycinol]. The metabolic fate of (-)-glycinol is determined by the enzymatic introduction of a dimethylallyl group into C-4 or C 2, which is reportedly catalyzed by regiospecific prenyltransferases (PTs). 4 Dimethylallyl (-)-glycinol and 2-dimethylallyl (-)-glycinol are precursors of glyceollin I and other glyceollins, respectively. Although multiple genes encoding (-)-glycinol biosynthetic enzymes have been identified, those involved in the later steps of glyceollin formation mostly remain unidentified, except for (-)-glycinol 4-dimethylallyltransferase (G4DT), which is involved in glyceollin I biosynthesis. In this study, we identified four genes that encode isoflavonoid PTs, including (-)-glycinol 2-dimethylallyltransferase (G2DT), using homology based in silico screening and biochemical characterization in yeast expression systems. Transcript analyses illustrated that changes in G2DT gene expression were correlated with the induction of glyceollins II, III, IV and V in elicitor treated soybean cells and leaves, suggesting its involvement in glyceollin biosynthesis. Moreover, the genomic signatures of these PT genes revealed that G4DT and G2DT are paralogs derived from whole-genome duplications of the soybean genome, whereas other PT genes [isoflavone dimethylallyltransferase 1 (IDT1) and IDT2] were derived via local gene duplication on soybean chromosome 11. PMID- 27986916 TI - CCX1, a Putative Cation/Ca2+ Exchanger, Participates in Regulation of Reactive Oxygen Species Homeostasis and Leaf Senescence. AB - The major developmental significance of leaf senescence is the massive recycling of nutrients from senescing leaves to nascent organs, including seeds, to meet the requirement of their rapid development, so-called nutrient remobilization. The efficiency of nutrient remobilization is associated with the activity of diverse transporters. A large number of transporters are up-regulated during leaf senescence in Arabidopsis, many of which participate in regulating leaf senescence via different signaling pathways. Here, we report that a member of the cation/Ca2+ exchanger family, CCX1, is highly induced during leaf senescence in Arabidopsis. Although single mutation of CCX1 did not change the senescence phenotype, double mutation of CCX1 and CCX4 resulted in a subtle but significant stay-green phenotype during natural and dark-induced leaf senescence, suggesting that some members of the cation/Ca2+ exchanger family act redundantly in mediating leaf senescence. Consistently, overexpression of CCX1 accelerated leaf senescence. Moreover, the ccx1ccx4 double mutant was more tolerant to H2O2, whereas CCX1-overexpressing lines showed an elevated response to H2O2 treatment, presumably due to an overaccumulation of reactive oxygen species (ROS), indicating that CCX1 may promote leaf senescence via modulating ROS homeostasis. Notably, both ccx1-1 and ccx1ccx4 were sensitive to Ca2+ deprivation, implying that CCX1 may also be involved in modulating Ca2+ signaling and consequently affecting the initiation of leaf senescence. PMID- 27986917 TI - Differential Cellular Control by Cotyledon-Derived Phytohormones Involved in Graft Reunion of Arabidopsis Hypocotyls. AB - When wounding or grafting interrupts the original connection of plant tissue, cell proliferation is induced and the divided tissue is reunited. Previous studies suggested that gibberellin derived from the cotyledon is required for tissue reunion in cucumber and tomato incised hypocotyls, and tissue reunion of Arabidopsis incised flowering stems is controlled by auxin. Differences in the hormone requirements of the tissue reunion process between Arabidopsis and cucumber might be due to differences in organs or species. In this study, we performed morphological and gene expression analyses of graft union in Arabidopsis hypocotyl. We found that removal of the cotyledon and treatment of the cotyledon with the auxin transport inhibitor triiodobenzoic acid (TIBA) suppressed cell proliferation of vascular tissue during graft union formation. These treatments also suppressed expression of IAA5, ANAC071, ANAC096 and CYCB1;1. ANAC071 is involved in the tissue reunion process. The anac071 anac096 double mutant suppressed cell proliferation more so than either of the single mutants. On the other hand, paclobutrazol treatment or deficiency of gibberellin biosynthesis genes suppressed expansion of cortex cells, and exogenous gibberellin treatment or rga/gai mutations that lack the negative regulator of gibberellin reversed this inhibition. The up-regulation of the key gibberellin biosynthesis gene GA20ox1 during graft union formation was prevented by cotyledon removal or TIBA treatment. These data suggest that auxin regulates cell proliferation of vascular tissue and expansion of cortex cells by promoting gibberellin biosynthesis during graft attachment. We hypothesize that the cotyledon-derived phytohormones are essential for graft reunion of the hypocotyl, processed in a cell type-specific manner, in Arabidopsis. PMID- 27986918 TI - Reengineering of the human pyruvate dehydrogenase complex: from disintegration to highly active agglomerates. AB - The pyruvate dehydrogenase complex (PDC) plays a central role in cellular metabolism and regulation. As a metabolite-channeling multi-enzyme complex it acts as a complete nanomachine due to its unique geometry and by coupling a cascade of catalytic reactions using 'swinging arms'. Mammalian and specifically human PDC (hPDC) is assembled from multiple copies of E1 and E3 bound to a large E2/E3BP 60-meric core. A less restrictive and smaller catalytic core, which is still active, is highly desired for both fundamental research on channeling mechanisms and also to create a basis for further modification and engineering of new enzyme cascades. Here, we present the first experimental results of the successful disintegration of the E2/E3BP core while retaining its activity. This was achieved by C-terminal alpha-helixes double truncations (eight residues from E2 and seven residues from E3BP). Disintegration of the hPDC core via double truncations led to the formation of highly active (approximately 70% of wildtype) apparently unordered clusters or agglomerates and inactive non-agglomerated species (hexamer/trimer). After additional deletion of N-terminal 'swinging arms', the aforementioned C-terminal truncations also caused the formation of agglomerates of minimized E2/E3BP complexes. It is likely that these 'swinging arm' regions are not solely responsible for the formation of the large agglomerates. PMID- 27986919 TI - Generation of inhibitory monoclonal antibodies targeting matrix metalloproteinase 14 by motif grafting and CDR optimization. AB - Matrix metalloproteinase-14 (MMP-14) plays important roles in cancer metastasis, and the failures of broad-spectrum MMP compound inhibitors in clinical trials suggested selectivity is critical. By grafting an MMP-14 specific inhibition motif into complementarity determining region (CDR)-H3 of antibody scaffolds and optimizing other CDRs and the sequences that flank CDR-H3, we isolated a Fab 1F8 showing a binding affinity of 8.3 nM with >1000-fold enhancement on inhibition potency compared to the peptide inhibitor. Yeast surface display and fluorescence activated cell sorting results indicated that 1F8 was highly selective to MMP-14 and competed with TIMP-2 on binding to the catalytic domain of MMP-14. Converting a low-affinity peptide inhibitor into a high potency antibody, the described methods can be used to develop other inhibitory antibodies of therapeutic significance. PMID- 27986920 TI - Annexin-directed beta-glucuronidase for the targeted treatment of solid tumors. AB - Enzyme prodrug therapy has the potential to remedy the lack of selectivity associated with the systemic administration of chemotherapy. However, most current systems are immunogenic and constrained to a monotherapeutic approach. We developed a new class of fusion proteins centered about the human enzyme beta glucuronidase (betaG), capable of converting several innocuous prodrugs into chemotherapeutics. We targeted betaG to phosphatidylserine on tumor cells, tumor vasculature and metastases via annexin A1/A5. Phosphatidylserine shows promise as a universal marker for solid tumors and allows for tumor type-independent targeting. To create fusion proteins, human annexin A1/A5 was genetically fused to the activity-enhancing 16a3 mutant of human betaG, expressed in chemically defined, fed-batch suspension culture, and chromatographically purified. All fusion constructs achieved >95% purity with yields up to 740 MUg/l. Fusion proteins displayed cancer selective cell-surface binding with cell line-dependent binding stability. One fusion protein in combination with the prodrug SN-38 glucuronide was as effective as the drug SN-38 on Panc-1 pancreatic cancer cells and HAAE-1 endothelial cells, and demonstrated efficacy against MCF-7 breast cancer cells. betaG fusion proteins effectively enable localized combination therapy that can be tailored to each patient via prodrug selection, with promising clinical potential based on their near fully human design. PMID- 27986921 TI - Development of a cancer-marker activated enzymatic switch from the herpes simplex virus thymidine kinase. AB - Discovery of new cancer biomarkers and advances in targeted gene delivery mechanisms have made gene-directed enzyme prodrug therapy (GDEPT) an attractive method for treating cancer. Recent focus has been placed on increasing target specificity of gene delivery systems and reducing toxicity in non-cancer cells in order to make GDEPT viable. To help address this challenge, we have developed an enzymatic switch that confers higher prodrug toxicity in the presence of a cancer marker. The enzymatic switch was derived from the herpes simplex virus thymidine kinase (HSV-TK) fused to the CH1 domain of the p300 protein. The CH1 domain binds to the C-terminal transactivation domain (C-TAD) of the cancer marker hypoxia inducible factor 1alpha. The switch was developed using a directed evolution approach that evaluated a large library of HSV-TK/CH1 fusions using a negative selection for azidothymidine (AZT) toxicity and a positive selection for dT phosphorylation. The identified switch, dubbed TICKLE (Trigger-Induced Cell Killing Lethal-Enzyme), confers a 4-fold increase in AZT toxicity in the presence of C-TAD. The broad substrate specificity exhibited by HSV-TK makes TICKLE an appealing prospect for testing in medical imaging and cancer therapy, while establishing a foundation for further engineering of nucleoside kinase protein switches. PMID- 27986925 TI - Contributions of the Ventral Striatum to Conscious Perception: An Intracranial EEG Study of the Attentional Blink. AB - : The brain is limited in its capacity to consciously process information, necessitating gating of information. While conscious perception is robustly associated with sustained, recurrent interactions between widespread cortical regions, subcortical regions, including the striatum, influence cortical activity. Here, we examined whether the ventral striatum, given its ability to modulate cortical information flow, contributes to conscious perception. Using intracranial EEG, we recorded ventral striatum activity while 7 patients performed an attentional blink task in which they had to detect two targets (T1 and T2) in a stream of distractors. Typically, when T2 follows T1 within 100-500 ms, it is often not perceived (i.e., the attentional blink). We found that conscious T2 perception was influenced and signaled by ventral striatal activity. Specifically, the failure to perceive T2 was foreshadowed by a T1-induced increase in alpha and low beta oscillatory activity as early as 80 ms after T1, indicating that the attentional blink to T2 may be due to very early T1-driven attentional capture. Moreover, only consciously perceived targets were associated with an increase in theta activity between 200 and 400 ms. These unique findings shed new light on the mechanisms that give rise to the attentional blink by revealing that conscious target perception may be determined by T1 processing at a much earlier processing stage than traditionally believed. More generally, they indicate that ventral striatum activity may contribute to conscious perception, presumably by gating cortical information flow. SIGNIFICANCE STATEMENT: What determines whether we become aware of a piece of information or not? Conscious access has been robustly associated with activity within a distributed network of cortical regions. Using intracranial electrophysiological recordings during an attentional blink task, we tested the idea that the ventral striatum, because of its ability to modulate cortical information flow, may contribute to conscious perception. We find that conscious perception is influenced and signaled by ventral striatal activity. Short-latency (80-140 ms) striatal responses to a first target determined conscious perception of a second target. Moreover, conscious perception of the second target was signaled by longer-latency (200-400 ms) striatal activity. These results suggest that the ventral striatum may be part of a subcortical network that influences conscious experience. PMID- 27986926 TI - Spatial Organization of Chromatic Pathways in the Mouse Dorsal Lateral Geniculate Nucleus. AB - : In both dichromats and trichromats, cone opsin signals are maintained independently in cones and combined at the bipolar and retinal ganglion cell level, creating parallel color opponent pathways to the central visual system. Like other dichromats, the mouse retina expresses a short-wavelength (S) and a medium-wavelength (M) opsin, with the S-opsin shifted to peak sensitivity in the ultraviolet (UV) range. Unlike in primates, nonuniform opsin expression across the retina and coexpression in single cones creates a mostly mixed chromatic signal. Here, we describe the visuotopic and chromatic organization of spiking responses in the dorsal lateral geniculate and of the local field potentials in their recipient zone in primary visual cortex (V1). We used an immersive visual stimulus dome that allowed us to present spatiotemporally modulated UV and green luminance in any region of the visual field of an awake, head-fixed mouse. Consistent with retinal expression of opsins, we observed graded UV-to-green dominated responses from the upper to lower visual fields, with a smaller difference across azimuth. In addition, we identified a subpopulation of cells (<10%) that exhibited spectrally opponent responses along the S-M axis. Luminance signals of each wavelength and color signals project to the middle layers of V1. SIGNIFICANCE STATEMENT: In natural environments, color information is useful for guiding behavior. How small terrestrial mammals such as mice use graded expression of cone opsins to extract visual information from their environments is not clear, even as the use of mice for studying visually guided behavior grows. In this study, we examined the color signals that the retina sends to the visual cortex via the lateral geniculate nucleus of the thalamus. We found that green dominated responses in the lower and nasal visual field and ultraviolet dominated responses in the upper visual field. We describe a subset of cells that exhibit color opponent responses. PMID- 27986924 TI - Pharmacological Rescue of Long-Term Potentiation in Alzheimer Diseased Synapses. AB - : Long-term potentiation (LTP) is an activity-dependent and persistent increase in synaptic transmission. Currently available techniques to measure LTP are time intensive and require highly specialized expertise and equipment, and thus are not well suited for screening of multiple candidate treatments, even in animal models. To expand and facilitate the analysis of LTP, here we use a flow cytometry-based method to track chemically induced LTP by detecting surface AMPA receptors in isolated synaptosomes: fluorescence analysis of single-synapse long term potentiation (FASS-LTP). First, we demonstrate that FASS-LTP is simple, sensitive, and models electrically induced LTP recorded in intact circuitries. Second, we conducted FASS-LTP analysis in two well-characterized Alzheimer's disease (AD) mouse models (3xTg and Tg2576) and, importantly, in cryopreserved human AD brain samples. By profiling hundreds of synaptosomes, our data provide the first direct evidence to support the idea that synapses from AD brain are intrinsically defective in LTP. Third, we used FASS-LTP for drug evaluation in human synaptosomes. Testing a panel of modulators of cAMP and cGMP signaling pathways, FASS-LTP identified vardenafil and Bay-73-6691 (phosphodiesterase-5 and -9 inhibitors, respectively) as potent enhancers of LTP in synaptosomes from AD cases. These results indicate that our approach could provide the basis for protocols to study LTP in both healthy and diseased human brains, a previously unattainable goal. SIGNIFICANCE STATEMENT: Learning and memory depend on the ability of synapses to strengthen in response to activity. Long-term potentiation (LTP) is a rapid and persistent increase in synaptic transmission that is thought to be affected in Alzheimer's disease (AD). However, direct evidence of LTP deficits in human AD brain has been elusive, primarily due to methodological limitations. Here, we analyze LTP in isolated synapses from AD brain using a novel approach that allows testing LTP in cryopreserved brain. Our analysis of hundreds of synapses supports the idea that AD-diseased synapses are intrinsically defective in LTP. Further, we identified pharmacological agents that rescue LTP in AD, thus opening up a new avenue for drug screening and evaluation of strategies for alleviating memory impairments. PMID- 27986927 TI - Histological Underpinnings of Grey Matter Changes in Fibromyalgia Investigated Using Multimodal Brain Imaging. AB - : Chronic pain patients present with cortical gray matter alterations, observed with anatomical magnetic resonance (MR) imaging. Reduced regional gray matter volumes are often interpreted to reflect neurodegeneration, but studies investigating the cellular origin of gray matter changes are lacking. We used multimodal imaging to compare 26 postmenopausal women with fibromyalgia with 25 healthy controls (age range: 50-75 years) to test whether regional gray matter volume decreases in chronic pain are associated with compromised neuronal integrity. Regional gray matter decreases were largely explained by T1 relaxation times in gray matter, a surrogate measure of water content, and not to any substantial degree by GABAA receptor concentration, an indirect marker of neuronal integrity measured with [18F] flumazenil PET. In addition, the MR spectroscopy marker of neuronal viability, N-acetylaspartate, did not differ between patients and controls. These findings suggest that decreased gray matter volumes are not explained by compromised neuronal integrity. Alternatively, a decrease in neuronal matter could be compensated for by an upregulation of GABAA receptors. The relation between regional gray matter and T1 relaxation times suggests decreased tissue water content underlying regional gray matter decreases. In contrast, regional gray matter increases were explained by GABAA receptor concentration in addition to T1 relaxation times, indicating perhaps increased neuronal matter or GABAA receptor upregulation and inflammatory edema. By providing information on the histological origins of cerebral gray matter alterations in fibromyalgia, this study advances the understanding of the neurobiology of chronic widespread pain. SIGNIFICANCE STATEMENT: Regional gray matter alterations in chronic pain, as detected with voxel-based morphometry of anatomical magnetic resonance images, are commonly interpreted to reflect neurodegeneration, but this assumption has not been tested. We found decreased gray matter in fibromyalgia to be associated with T1 relaxation times, a surrogate marker of water content, but not with GABAA receptor concentration, a surrogate of neuronal integrity. In contrast, regional gray matter increases were partly explained by GABAA receptor concentration, indicating some form of neuronal plasticity. The study emphasizes that voxel-based morphometry is an exploratory measure, demonstrating the need to investigate the histological origin of gray matter alterations for every distinct clinical entity, and advances the understanding of the neurobiology of chronic (widespread) pain. PMID- 27986928 TI - Presynaptic Neuronal Pentraxin Receptor Organizes Excitatory and Inhibitory Synapses. AB - : Three neuronal pentraxins are expressed in brain, the membrane-bound "neuronal pentraxin receptor" (NPR) and the secreted proteins NP1 and NARP (i.e., NP2). Neuronal pentraxins bind to AMPARs at excitatory synapses and play important, well-documented roles in the activity-dependent regulation of neural circuits via this binding activity. However, it is unknown whether neuronal pentraxins perform roles in synapses beyond modulating postsynaptic AMPAR-dependent plasticity, and whether they may even act in inhibitory synapses. Here, we show that NPR expressed in non-neuronal cells potently induces formation of both excitatory and inhibitory postsynaptic specializations in cocultured hippocampal neurons. Knockdown of NPR in hippocampal neurons, conversely, dramatically decreased assembly and function of both excitatory and inhibitory postsynaptic specializations. Overexpression of NPR rescued the NPR knockdown phenotype but did not in itself change synapse numbers or properties. However, the NPR knockdown decreased the levels of NARP, whereas NPR overexpression produced a dramatic increase in the levels of NP1 and NARP, suggesting that NPR recruits and stabilizes NP1 and NARP on the presynaptic plasma membrane. Mechanistically, NPR acted in excitatory synapse assembly by binding to the N-terminal domain of AMPARs; antagonists of AMPA and GABA receptors selectively inhibited NPR-induced heterologous excitatory and inhibitory synapse assembly, respectively, but did not affect neurexin-1beta-induced synapse assembly as a control. Our data suggest that neuronal pentraxins act as signaling complexes that function as general trans-synaptic organizers of both excitatory and inhibitory synapses by a mechanism that depends, at least in part, on the activity of the neurotransmitter receptors at these synapses. SIGNIFICANCE STATEMENT: Neuronal pentraxins comprise three neuronal proteins, neuronal pentraxin receptor (NPR) which is a type-II transmembrane protein on the neuronal surface, and secreted neuronal pentraxin-1 and NARP. The general functions of neuronal pentraxins at synapses have not been explored, except for their basic AMPAR binding properties. Here, we examined the functional role of NPR at synapses because it is the only neuronal pentraxin that is anchored to the neuronal cell-surface membrane. We find that NPR is a potent inducer of both excitatory and inhibitory heterologous synapses, and that knockdown of NPR in cultured neurons decreases the density of both excitatory and inhibitory synapses. Our data suggest that NPR performs a general, previously unrecognized function as a universal organizer of synapses. PMID- 27986932 TI - Placental-specific sFLT-1: role in pre-eclamptic pathophysiology and its translational possibilities for clinical prediction and diagnosis. AB - Pre-eclampsia is a common obstetric complication globally responsible for a significant burden of maternal and perinatal morbidity and mortality. Central to its pathophysiology is the anti-angiogenic protein, soluble fms-like tyrosine kinase-1 (sFLT-1). sFLT-1 is released from a range of tissues into the circulation, where it antagonizes the activity of vascular endothelial growth factor and placental growth factor leading to endothelial dysfunction. It is this widespread endothelial dysfunction that produces the clinical features of pre eclampsia including hypertension and proteinuria. There are multiple splice variants of sFLT-1. One, known as sFLT-1 e15a, evolved quite recently and is only present in humans and higher order primates. This sFLT-1 variant is also the main sFLT-1 secreted from the placenta. Recent work has shown that sFLT-1 e15a is significantly elevated in the placenta and circulation of women with pre eclampsia. It is also biologically active, capable of causing endothelial dysfunction and the end-organ dysfunction seen in pre-eclampsia. Indeed, the over expression of sFLT-1 e15a in mice recapitulates the pre-eclamptic phenotype in pregnancy. Therefore, here we propose that sFLT-1 e15a may be the sFLT-1 variant primarily responsible for pre-eclampsia, a uniquely human disease. Furthermore, this placental-specific sFLT-1 variant provides promise for use as an accurate biomarker in the prediction or diagnosis of pre-eclampsia. PMID- 27986931 TI - Bone morphogenetic protein 2 regulates cell-cell communication by down-regulating connexin43 expression in luteinized human granulosa cells. AB - STUDY QUESTION: Does bone morphogenetic protein 2 (BMP2) regulate connexin43 (Cx43) and modulate cell-cell communication in luteinized human granulosa cells? SUMMARY ANSWER: BMP2 decreases gap junction intercellular communication (GJIC) of luteinized human granulosa cells by down-regulating Cx43 expression through an activin receptor-like kinase (ALK)2/ALK3-mediated Sma- and Mad-related protein (SMAD)-dependent signaling pathway. WHAT IS KNOWN ALREADY: BMP2 and its putative receptors are highly expressed in the human corpus luteum and are involved in the process of luteolysis. Cx43-coupled gap junctions play a critical role in the development and maintenance of corpus luteum. STUDY DESIGN DURATION: This is a laboratory study conducted over a 1-year period. At least three independent experiments with three replicates were conducted and the experimental samples were compared with the appropriate vehicle controls for all of the inhibition approach, concentration-dependent or time-course studies. PARTICIPANTS/MATERIALS, SETTING, METHODS: SVOG cell line (immortalized human granulosa-lutein cells derived from in vitro fertilization patients in an academic research center) was used as the study model. The changes of Cx43 expression and levels of phosphorylated SMAD1/5/8 protein were evaluated after exposure to recombinant human BMP2. Real-time quantitative PCR and Western blot analysis were used to examine the specific mRNA and protein levels, respectively. The BMP/TGF-beta type I receptor inhibitors (Dorsomorphin, DMH-1 and SB431542) and target depletion small interfering RNAs (ALK2, ALK3, ALK6 and SMAD4) were used to investigate the underlying molecular mechanisms. A scrape loading and dye transfer assay was used to evaluate the GJIC between the SVOG cells. MAIN RESULTS AND THE ROLE OF CHANCE: Treatment with BMP2 down-regulated the expression of Cx43 and decreased the GJIC activity, whereas it increased the phosphorylated SMAD1/5/8 protein in SVOG cells (P < 0.05). These biological effects were abolished by pre-treatment with the BMP type I receptor inhibitors, Dorsomorphin and DMH-1 (P < 0.05), but not SB431542. Additionally, the individual or concomitant small interfering RNA-mediated knockdown of ALK2 and ALK3, but not ALK6 attenuated the BMP2-induced increases in phosphorylated SMAD1/5/8 and down-regulation of Cx43 expression (P < 0.05). The knockdown of SMAD4 completely abolished the BMP2-induced down-regulation of Cx43 expression (P < 0.05). LIMITATIONS REASONS FOR CAUTION: This experimental study was conducted in an in vitro cell culture system, and may not reflect a realistic intra-ovarian environment. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggested that BMP2 may be involved in the local modulation of cell-cell communication in the luteal phase. This study also represents the first comprehensive research of molecular mechanisms of BMP2 in the down-regulation Cx43 in luteinized human granulosa cells. Such data may provide valuable insights into ovarian physiology and benefit the development of potential therapeutic methods for patients suffering from luteal insufficiency. LARGE SCALE DATA: N/A. STUDY FUNDING AND COMPETING INTEREST(s): This research was supported by an operating grant from the China-Canadian Joint Health Research Initiative Grants Program to P.C.K. Leung and J.Z. Sheng. The authors declare no competing interest with the contents of this article. PMID- 27986933 TI - The Spodoptera exigua (Lepidoptera: Noctuidae) ABCC2 Mediates Cry1Ac Cytotoxicity and, in Conjunction with Cadherin, Contributes to Enhance Cry1Ca Toxicity in Sf9 Cells. AB - In insects, the mode of Cry1A toxins action has been studied in detail and many receptors that participate in the process are known. Recent evidence has revealed that an ABC transporter (ABCC2) is involved in conferring resistance to Cry1A toxins and that ABCC2 could be a receptor of Cry1A. However, it is not known whether Cry1Ca interacts with the same receptor proteins as Cry1A. In this study, we report the cloning of an ABC transporter gene, SeABCC2b, from the midgut of Spodoptera exigua (Hubner) larvae, and its expression in Sf9 cells for a functional analysis. The addition of Cry1Ca and Cry1Ac to Sf9 cell culture caused swelling in 28.5% and 93.9% of the SeABCC2-expressing cells, respectively. In contrast, only 7.4% and 1.3% of the controls cells swelled in the presence of Cry1Ca and Cry1Ac. Thus, SeABCC2b-expressing Sf9 cells had increased susceptibility to Cry1Ca and Cry1Ac. Similarly, S. exigua cadherin (SeCad1b) expressed in Sf9 cells caused 47.1% and 1.8% of the SeCad1b-expressing cells to swell to Cry1Ca and Cry1Ac exposure. Therefore, Sf9 cells expressing SeCad1b were more sensitive to Cry1Ca than Cry1Ac. Together, our data suggest that SeABCC2b from S. exigua mediates Cry1Ac cytotoxicity and, in conjunction with SeCad1b, contributes to enhance Cry1Ca toxicity in Sf9 cells. PMID- 27986934 TI - Effects of Insecticides and Fungicides Commonly Used in Tomato Production on Phytoseiulus persimilis (Acari: Phtyoseiidae). AB - The twospotted spider mite, Tetranychus urticae Koch (Acari: Tetranychidae), is an important pest of tomatoes in North Carolina. Resident populations of the predatory mite Phytoseiulus persimilis have recently been detected on field-grown tomatoes in central North Carolina, and potentially can be a useful biological control agent against T. urticae Laboratory bioassays were used to assess lethal and reproductive effects of 10 insecticides and five fungicides commonly used in commercial tomato production (chlorantraniliprole, spinetoram, permethrin, imidacloprid, dimethoate, dinotefuran, thiamethoxam, bifenthrin, fenpropathrin, lambda-cyhalothrin, azoxystrobin, chlorothalonil, boscalid, cyazofamid, and mancozeb) on P. persimilis adult females and eggs. Insecticides were tested using concentrations equivalent to 1*, 0.5*, and 0.1* of the recommended field rates. Fungicides were tested at the 1* rate only. Dimethoate strongly impacted P. persimilis with high adult mortality, reduced fecundity, and reduced hatch of eggs laid by treated adults, particularly at high concentrations. The pyrethroids lambda-cyhalothrin, bifenthrin, and fenpropathrin were associated with repellency and reproductive effects at high concentrations. Bifenthrin additionally caused increased mortality at high concentrations. Chlorantraniliprole, dinotefuran, and permethrin did not significantly affect mortality or reproduction. Imidacloprid significantly reduced fecundity and egg viability, but was not lethal to adult P. persimilis Thiamethoxam negatively impacted fecundity at the 1* rate. There were no negative effects associated with fungicide exposure with the exception of mancozeb, which impacted fecundity. Field trials were conducted to explore the in vivo impacts of screened insecticides on P. persimilis populations in the field. Field trials supported the incompatibility of dimethoate with P. persimilis populations. PMID- 27986929 TI - Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents. AB - : Toll-like receptor 4 (TLR4) is a critical component of innate immune signaling and has been implicated in alcohol responses in preclinical and clinical models. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA Neuroimmune) consortium tested the hypothesis that TLR4 mediates excessive ethanol drinking using the following models: (1) Tlr4 knock-out (KO) rats, (2) selective knockdown of Tlr4 mRNA in mouse nucleus accumbens (NAc), and (3) injection of the TLR4 antagonist (+)-naloxone in mice. Lipopolysaccharide (LPS) decreased food/water intake and body weight in ethanol-naive and ethanol-trained wild-type (WT), but not Tlr4 KO rats. There were no consistent genotypic differences in two-bottle choice chronic ethanol intake or operant self administration in rats before or after dependence. In mice, (+)-naloxone did not decrease drinking-in-the-dark and only modestly inhibited dependence-driven consumption at the highest dose. Tlr4 knockdown in mouse NAc did not decrease drinking in the two-bottle choice continuous or intermittent access tests. However, the latency to ethanol-induced loss of righting reflex increased and the duration decreased in KO versus WT rats. In rat central amygdala neurons, deletion of Tlr4 altered GABAA receptor function, but not GABA release. Although there were no genotype differences in acute ethanol effects before or after chronic intermittent ethanol exposure, genotype differences were observed after LPS exposure. Using different species and sexes, different methods to inhibit TLR4 signaling, and different ethanol consumption tests, our comprehensive studies indicate that TLR4 may play a role in ethanol-induced sedation and GABAA receptor function, but does not regulate excessive drinking directly and would not be an effective therapeutic target. SIGNIFICANCE STATEMENT: Toll-like receptor 4 (TLR4) is a key mediator of innate immune signaling and has been implicated in alcohol responses in animal models and human alcoholics. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium participated in the first comprehensive study across multiple laboratories to test the hypothesis that TLR4 regulates excessive alcohol consumption in different species and different models of chronic, dependence driven, and binge-like drinking. Although TLR4 was not a critical determinant of excessive drinking, it was important in the acute sedative effects of alcohol. Current research efforts are directed at determining which neuroimmune pathways mediate excessive alcohol drinking and these findings will help to prioritize relevant pathways and potential therapeutic targets. PMID- 27986936 TI - Quarantine Treatments of Imported Nursery Plants and Exported Cut Flowers by Phosphine Gas (PH3) as Methyl Bromide Alternative. AB - Quarantine treatments by phosphine (PH3) gas have been performed to replace methyl bromide (MeBr) for export cut flowers and imported nursery plant in Korea. In this preliminary study, two dominant insect pests of cut flowers, Tetranychus urticae Koch and Frankliniella occidentalis Pergande, and the dominant insect pest of nursery plants, Planococcus citri Risso, were used to certify optimum concentration and fumigation time, along with evaluation of phytotoxic damages. To validate the results of preliminary tests, quarantine treatments for export cut flowers was performed in a 58-m3 reefer container. When 14 species of cut flowers were fumigated with 2 g m-3 PH3 for 24 h (Ct product was 30.9 g h m-3) at 5 degrees C, all pests were effectively controlled and no phytotoxic damage were observed on roses and chrysanthemums. On quarantine trials for imported nursery trees, which was performed at 10 m3 scale covered with a PVC-tarpaulin tent, 2 g m-3 of PH3 for 24 h (Ct product was 30.0 g h m-3) at 15 degrees C was enough to kill all pests and no damage was observed on seven species of nursery plants. Phosphine gas shows the promise as MeBr alternative to perishable commodities in terms of efficacy to certain quarantine pest and maintenance of its quality as well as being a more environmentally safe fumigant. PMID- 27986935 TI - Bioassay and Scanning Electron Microscopic Observations Reveal High Virulence of Entomopathogenic Fungus, Beauveria bassiana, on the Onion Maggot (Diptera: Anthomyiidae) Adults. AB - When flies were dipped in 1 * 108 conidia/ml conidia suspensions and then kept in the incubator (22 +/- 1 degrees C, 70 +/- 5% RH), scanning electron microscope observations revealed that, at 2 h, the majority of adhering Beauveria bassiana conidia were attached to either the wing surface or the interstitial area between the macrochaetae on the thorax and abdomen of the onion maggot adults. Germ tubes were being produced and had oriented toward the cuticle by 18 h. Penetration of the insect cuticle had occurred by 36 h, and by 48 h, germ tubes had completely penetrated the cuticle. Fungal mycelia had emerged from the insect body and were proliferating after 72 h. The superficial area and structure of the wings and macrochaetae may facilitate the attachment of conidia and enable effective penetration. The susceptibility of adults to 12 isolates, at a concentration of 1 * 107 conidia/ml, was tested in laboratory experiments. Eight of the more potent strains caused in excess of 85% adult mortality 8 d post inoculation, while the median lethal time (LT50) of these strains was <6 d. The virulence of the more effective strains was further tested, and the median lethal concentrations (LC50) were calculated by exposing adults to doses ranging from 103-107 conidia/ml. The lowest LC50 value, found in the isolate XJWLMQ-32, for the adults was 3.87 * 103 conidia/ml. These results demonstrate that some B. bassiana strains are highly virulent to onion maggot adults and should be considered as potential biocontrol agents against the adult flies. PMID- 27986937 TI - A Combination Treatment Using Ethyl Formate and Phosphine to Control Planococcus citri (Hemiptera: Pseudococcidae) on Pineapples. AB - Citrus mealybug, Planococcus citri (Risso), is a known quarantine pest that is difficult to control with phosphine (PH3) or low concentrations of ethyl formate (EF), particularly at low temperatures. Methyl bromide (MB) is a fumigant used for quarantine and preshipment (QPS) that can eradicate target pests with short fumigation periods. However, MB, which is an ozone-depleting substance, is scheduled to be phased out in South Korea over the next decade. There is no ideal alternative fumigant to replace MB for QPS of perishable commodities. A laboratory study was conducted to compare the individual effects of EF and PH3 individually, and the effects of EF mixed with PH3 as an MB alternative for the control of P. citri adults, nymphs, and eggs. In comparison to treatments with EF and PH3 individually, EF mixed with PH3 resulted in high toxicity to all stages of P. citri. The eggs were more tolerant than the nymphs and adults. A mixed treatment of EF and PH3 achieved complete control of eggs infesting pineapples at concentrations of 25.1/1.0 (EF/PH3) mg/liter at 8 degrees C for 4 h of exposures. This new combined EF/PH3 fumigation technology could offer shorter exposure times and less damage to perishable commodities at low temperatures, and could potentially be extended to controlling other quarantine pests as a replacement treatment for fruit and vegetables in which methyl bromide is currently being used. PMID- 27986938 TI - Effects of Insecticides on Oviposition and Host Discrimination Behavior in Trichogramma chilonis (Hymenoptera: Trichogrammatidae). AB - Trichogramma chilonis Ishii is an important natural enemy of many lepidopterous pests on various crops. Effects of two conventional insecticides on oviposition and host discrimination behavior in T. chilonis were evaluated in the laboratory through video tracking. During the oviposition period, when the number of host eggs was limited (only one host egg), females exposed to beta-cypermethrin LC1 or LC20 exhibited significantly higher feeding and re-drilling rate and significantly longer post-oviposition duration than control females. Spinosad LC20 treatment not only decreased the wasp oviposition rate but also significantly extended the oviposition duration. When the number of host eggs was six, similarly, females exposed to spinosad LC20 exhibited a significantly lower oviposition rate (79.2%) than control ones (100%). In the host discrimination experiment, females exposed to LC20 of both tested insecticides (beta cypermethrin and spinosad) spent significantly more time on the extra-patch area. The females that survived spinosad LC20 could not discriminate between unparasitized and parasitized host eggs. Our study suggests that even the LC1 and LC20 of the tested insecticides had negative effects on the oviposition and host discrimination behavior of T. chilonis Thus, the use of these two insecticides should be carefully evaluated. PMID- 27986939 TI - Efficacy of alpha-Copaene, Cubeb, and Eucalyptol Lures for Detection of Redbay Ambrosia Beetle (Coleoptera: Curculionidae: Scolytinae). AB - Redbay ambrosia beetle, Xyleborus glabratus Eichhoff, is a wood-boring pest that has now invaded nine states in the southeastern United States. The beetle's dominant fungal symbiont (Raffaelea lauricola) is phytopathogenic, inducing laurel wilt in trees within the family Lauraceae. Members of the genus Persea are particularly susceptible to the lethal disease, including native redbay (P. borbonia) and swampbay (P. palustris), as well as commercial avocado (P. americana). Cubeb oil lures are the current standard for detection of X. glabratus, but recently eucalyptol and a 50% alpha-copaene oil have been identified as additional attractants. This study used a combination of binary choice bioassays, field cage release-and-recapture assays, and a 12-wk field trial to compare efficacy of eucalyptol and copaene lures relative to commercial cubeb lures. In addition, GC-MS was used to quantify emissions from lures field aged for 12 wk. In laboratory bioassays, copaene lures were more attractive than eucalyptol lures. In field cage assays, copaene lures recaptured a higher percentage of released beetles than cubeb lures. In the field test, cubeb lures captured fewer beetles than copaene lures, and lowest captures were obtained with eucalyptol lures. Combining eucalyptol with either copaene or cubeb lures did not increase captures over those lures deployed alone. Both copaene and cubeb lures were effective in attracting X. glabratus for 12 wk, but field life of eucalyptol lures was only 4 wk, consistent with the quantification of lure emissions. Results suggest that the 50% alpha-copaene lure provides the best pest detection currently available for X. glabratus. PMID- 27986940 TI - Effect of Contact Insecticides Against the Invasive Goldspotted Oak Borer (Coleoptera: Buprestidae) in California. AB - The goldspotted oak borer, Agrilus auroguttatus Schaeffer (Coleoptera: Buprestidae), was linked in 2008 to ongoing tree mortality in oak woodlands of southern California. Mortality of coast live oak, Quercus agrifolia Nee, and California black oak, Q. kelloggii Newb., continues as this exotic phloem borer spreads in southern California. Management options are needed to preserve high value oaks and maintain management objectives. From 2009 to 2012, we tested four contact insecticide formulations in four experiments against A auroguttatus in California. The impact of contact insecticides was evaluated ~<1, 8, and 12 mo postapplication against A auroguttatus adults in no-choice leaf-feeding or walking bioassays. At <1 mo postapplication, bifenthrin, carbaryl, lambda cyhalothrin, and permethrin all reduced adult survival and feeding in leaf feeding and walking bioassays. At 8 mo postapplication, only bifenthrin reduced adult feeding, but had no effect on survivorship. At 12 mo postapplication, adult A auroguttatus survived fewer days and fed less in leaf-feeding bioassays with bifenthrin, carbaryl, and permerthin. These results support the annual application of contact insecticides prior to A auroguttatus' flight period to reduce adult leaf maturation feeding and activity on the bark surface (e.g., oviposition), but additional studies are needed to show these contact treatments can prevent tree mortality from this invasive species. PMID- 27986941 TI - Egg Hatch Rate and Nymphal Survival of the Bed Bug (Hemiptera: Cimicidae) After Exposure to Insecticide Sprays. AB - Few studies have addressed the efficacy of insecticides used against eggs and first-instar nymphs of the bed bug, Cimex lectularius L. (Hemiptera: Cimicidae). Insect eggs are often resistant to insecticides; therefore, information on which products are effective is important. We evaluated the efficacy of four commonly used insecticide sprays applied directly to bed bug eggs. We also evaluated the efficacy of these insecticides to first-instar nymphs exposed to residuals resulting from directly spraying eggs. Temprid SC (beta-cyfluthrin, imidacloprid) was the most effective insecticide at preventing egg hatch (13% hatch rate) for pyrethroid-resistant, field-strain (Jersey City) bed bugs compared with a control (water [99% hatch rate]), Bedlam (MGK-264, sumithrin [84% hatch rate]), Demand CS (lambda-cyhalothrin [91% hatch rate]), and Phantom SC (chlorfenapyr [95% hatch rate]). Demand CS and Temprid SC were most effective at preventing egg hatch (0%) for an insecticide-susceptible (Harold Harlan) strain, followed by Bedlam (28%). Phantom SC produced a hatch rate similar to the control (97% and 96%, respectively). Harold Harlan-strain nymphs showed 100% survival for the control but 0% survival for Bedlam and Phantom SC. Jersey City-strain nymphs showed 100% survival for the control, 99% survival for Bedlam, 0% survival for Demand CS, 4% survival for Phantom SC, and 38% survival for Temprid SC. Demand CS was less effective at preventing hatch (91% hatch rate) of Jersey City-strain nymphs but was the only product to kill all nymphs (0% survival). One of the least effective products for preventing Jersey City-strain egg hatch (Phantom SC, 95% hatch rate) was the second most effective at killing nymphs, leaving only six of 141 alive. These findings indicate that survival of directly sprayed eggs and residually exposed, first-instar nymphs varies by strain, life stage, and product used. PMID- 27986942 TI - Reproductive Cost Associated With Juvenile Hormone in Bt-Resistant Strains of Helicoverpa armigera (Lepidoptera: Noctuidae). AB - Transgenic Bacillus thuringiensis (Bt) crops are increasingly significant in pest control, but resistance development of target pests is a major issue in the sustainable deployment of Bt crops. The fitness cost of resistance in target pests is regarded as one of the main factors delaying resistance when adopting the refuge strategy. In this study, we compared the life-history traits of three independent sets of Helicoverpa armigera (Hubner, 1809) adults, of each there were a susceptible population and a Cry1Ac-resistant population derived by selection from it. Confirming to the previous studies, resistant individuals exhibited fewer progeny, less fecundity, lower egg hatching rate, and longer adult longevity. And poor fecundity in resistant strains was associated with the decline of the mature follicular amount, the ovarian weight ratio, and the length of the longest ovarian tubule. Interestingly, the juvenile hormone (JH) level appeared higher in resistant strains relative to susceptible strains. Application of methoprene (JH analogue) in vivo was effective in reducing fecundity and hatchability with the up-regulation of detected JH titer. These results suggested that resistance against Bt toxin reduced the reproductive capacity of H. armigera, and JH level is affected in the tradeoff between reproductive capacity and Bt resistance. PMID- 27986943 TI - Flight of Rhyzopertha dominica (Coleoptera: Bostrichidae)-a Spatio-Temporal Analysis With Pheromone Trapping and Population Genetics. AB - The flight of the lesser grain borer, Rhyzopertha dominica (F.), near grain storages and at distances from them, was investigated to assess the potential of these beetles to infest grain and spread insecticide resistance genes. We caught R. dominica in pheromone-baited flight traps (and blank controls) set at storages, in fields away from storages, and in native vegetation across a 12-mo period. A functional set of highly polymorphic microsatellite markers was developed, enabling population genetic analyses on the trapped beetles. Pheromone baited traps caught just as many R. dominica adults at least 1 km from grain storages as were caught adjacent to grain storages. Samples of beetles caught were genetically homogeneous across the study area (over 7,000 km2) in South Queensland, Australia. However, a change in genetic structure was detected at one bulk storage site. Subsequent analysis detected a heterozygous excess, which indicated a population bottleneck. Only a few beetles were caught during the winter months of June and July. To assess the mating status and potential fecundity of dispersing R. dominica females, we captured beetles as they left grain storages and quantified offspring production and life span in the laboratory. Nearly all (95%) of these dispersing females had mated and these produced an average of 242 offspring. We demonstrated that R. dominica populations in the study area display a high degree of connectivity and this is a result of the active dispersal of mated individuals of high potential fecundity. PMID- 27986944 TI - Survival and Development of Hermetia illucens (Diptera: Stratiomyidae): A Biodegradation Agent of Organic Waste. AB - The black soldier fly, Hermetia illucens (L.) (Diptera: Stratiomyidae), was reared on artificial diet (wheat bran and chicken feed) in the laboratory at 28oC (immature stages) and under a greenhouse set at 28oC (adults). Data were collected and analyzed based on an age-stage, two-sex life table. The intrinsic rate of increase (r), finite rate of increase (lambda), net reproduction rate (R0), and mean generation time (T) were 0.0759 (d-1), 1.0759 (d-1), 68.225 offspring, and 55.635 d, respectively. The maximum reproductive value of females occurred at 54 d. Only six females out of 21 were able to successfully oviposit. The number of eggs laid per female ranged from 236 to a maximum of 1,088 eggs. We demonstrated that first-instar larvae of H. illucens are more susceptible to perishing when reared under artificial diet than are later instars. PMID- 27986951 TI - Profile of Stephen Beverley. PMID- 27986950 TI - Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells. AB - Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain. SC exhibited cancer- or hypoxia-induced CXCR4/CXCR7 expression in vivo and in vitro and migrated toward CXCL12-expressing PCC. Glia-specific depletion of CXCR4/CXCR7 in mice abrogated the chemoattraction of SC to PCC. PDAC mice with pancreas specific CXCL12 depletion exhibited diminished SC chemoattraction to pancreatic intraepithelial neoplasia and increased abdominal hypersensitivity caused by augmented spinal astroglial and microglial activity. In PDAC patients, reduced CXCR4/CXCR7 expression in nerves correlated with increased pain. Mechanistically, upon CXCL12 exposure, SC down-regulated the expression of several pain-associated targets. Therefore, PDAC-derived CXCL12 seems to induce tumor infiltration by SC during early carcinogenesis and to attenuate pain, possibly resulting in delayed diagnosis in PDAC. PMID- 27986953 TI - Antimonide-based membranes synthesis integration and strain engineering. AB - Antimonide compounds are fabricated in membrane form to enable materials combinations that cannot be obtained by direct growth and to support strain fields that are not possible in the bulk. InAs/(InAs,Ga)Sb type II superlattices (T2SLs) with different in-plane geometries are transferred from a GaSb substrate to a variety of hosts, including Si, polydimethylsiloxane, and metal-coated substrates. Electron microscopy shows structural integrity of transferred membranes with thickness of 100 nm to 2.5 [Formula: see text]m and lateral sizes from [Formula: see text]m2 to [Formula: see text] cm2 Electron microscopy reveals the excellent quality of the membrane interface with the new host. The crystalline structure of the T2SL is not altered by the fabrication process, and a minimal elastic relaxation occurs during the release step, as demonstrated by X ray diffraction and mechanical modeling. A method to locally strain-engineer antimonide-based membranes is theoretically illustrated. Continuum elasticity theory shows that up to [Formula: see text]3.5% compressive strain can be induced in an InSb quantum well through external bending. Photoluminescence spectroscopy and characterization of an IR photodetector based on InAs/GaSb bonded to Si demonstrate the functionality of transferred membranes in the IR range. PMID- 27986952 TI - Deletion of the sclerotome-enriched lncRNA PEAT augments ribosomal protein expression. AB - To define a complete catalog of the genes that are activated during mouse sclerotome formation, we sequenced RNA from embryonic mouse tissue directed to form sclerotome in culture. In addition to well-known early markers of sclerotome, such as Pax1, Pax9, and the Bapx2/Nkx3-2 homolog Nkx3-1, the long noncoding RNA PEAT (Pax1 enhancer antisense transcript) was induced in sclerotome directed samples. Strikingly, PEAT is located just upstream of the Pax1 gene. Using CRISPR/Cas9, we generated a mouse line bearing a complete deletion of the PEAT-transcribed unit. RNA-seq on PEAT mutant embryos showed that loss of PEAT modestly increases bone morphogenetic protein target gene expression and also elevates the expression of a large subset of ribosomal protein mRNAs. PMID- 27986955 TI - Editorial: NAR Awards 2016. PMID- 27986954 TI - Aspen phenylpropanoid genes' expression levels correlate with genets' tannin richness and vary both in responses to soil nitrogen and associations with phenolic profiles. AB - Condensed tannin (CT) contents of European aspen (Populus tremula L.) vary among genotypes, and increases in nitrogen (N) availability generally reduce plants' tannin production in favor of growth, through poorly understood mechanisms. We hypothesized that intrinsic tannin production rates may co-vary with gene expression responses to soil N and resource allocation within the phenylpropanoid pathway (PPP). Thus, we examined correlations between soil N levels and both expression patterns of eight PPP genes (measured by quantitative-reverse transcription PCR) and foliar phenolic compounds (measured by liquid chromatography-mass spectrometry) in young aspen genets with intrinsically extreme CT levels. Monitored phenolics included salicinoids, lignins, flavones, flavonols, CT precursors and CTs. The PPP genes were consistently expressed more strongly in high-CT trees. Low N supplements reduced expression of genes throughout the PPP in all genets, while high N doses restored expression of genes at the beginning and end of the pathway. These PPP changes were not reflected in pools of tannin precursors, but varying correlations between gene expression and foliar phenolic pools were detected in young and mature leaves, suggesting that processes linking gene expression and the resulting phenolics vary spatially and temporally. Precursor fluxes suggested that CT-related metabolic rate or sink controls are linked to intrinsic carbon allocation strategies associated with N responses. Overall, we found more negative correlations (indicative of allocation trade-offs) between PPP gene expression and phenolic products following N additions in low-CT plants than in high-CT plants. The tannin-related expression dynamics suggest that, in addition to defense, relative tannin levels may also be indicative of intraspecific variations in the way aspen genets respond to soil fertility. PMID- 27986960 TI - Radon as a potential health hazard for clients and workers of selected thermal spas in Poland. AB - The radiation exposure due to 222Rn and its progeny inhalation for clients and employees of selected thermal water spas was assessed. The radon risk was calculated using the measured 222Rn activity concentrations in the investigated thermal waters and radon transfer coefficient, defined as a fraction of radon released from the swimming pool water to the indoor air of swimming pool. The total radon in air concentration was not measured. The annual effective doses for workers and clients of the studied spa centers excluding Ladek-Zdroj ranged from 0.02 to 2.69 mSv and 0.40 to 48 MUSv, respectively. For thermal water from Ladek Zdroj (Ladek-Zdroj L-2), significantly elevated doses were observed both for workers (10.8 mSv) and clients (194 MUSv). PMID- 27986956 TI - Single-molecule analysis of phiC31 integrase-mediated site-specific recombination by tethered particle motion. AB - Serine and tyrosine site-specific recombinases (SRs and YRs, respectively) provide templates for understanding the chemical mechanisms and conformational dynamics of strand cleavage/exchange between DNA partners. Current evidence suggests a rather intriguing mechanism for serine recombination, in which one half of the cleaved synaptic complex undergoes a 180 degrees rotation relative to the other. The 'small' and 'large' SRs contain a compact amino-terminal catalytic domain, but differ conspicuously in their carboxyl-terminal domains. So far, only one serine recombinase has been analyzed using single substrate molecules. We now utilized single-molecule tethered particle motion (TPM) to follow step-by-step recombination catalyzed by a large SR, phage phiC31 integrase. The integrase promotes unidirectional DNA exchange between attB and attP sites to integrate the phage genome into the host chromosome. The recombination directionality factor (RDF; phiC31 gp3) activates the excision reaction (attL * attR). From integrase-induced changes in TPM in the presence or absence of gp3, we delineated the individual steps of recombination and their kinetic features. The gp3 protein appears to regulate recombination directionality by selectively promoting or excluding active conformations of the synapse formed by specific att site partners. Our results support a 'gated rotation' of the synaptic complex between DNA cleavage and joining. PMID- 27986961 TI - Design of an Extended Range Long Counter Using Super Monte Carlo Simulation. AB - We have designed an extended range neutron long counter on the basis of work optimized using SuperMC code. The problem of the existing traditional long counters is that their response function falls rapidly above 5 MeV. We proposed a new designed by adding two layers of converter material inside the polyethylene moderator. The relatively low density chromium and high density lead metals convert high energy neutron by (n, xn) spallation reaction. This produces more neutrons of lower energies, which have higher probability of being detected by thermal 3He-counter. The response function at lower neutron energies was improved by inserting small polyethylene cylinder in front of 3He counter. In this design we achieved to extent the flat response function of the long counter from few keV up to 150 MeV. The total fluctuation of response curve is less than +/-9% over the entire energy range. The designed long counter is suitable to be used as neutron monitor for monitoring neutron fluence at high-energy neutron source. PMID- 27986962 TI - The Mayak Worker Dosimetry System (MWDS-2013): How to Weight the Absorbed Dose to Different Lung Regions in the Calculation of Lung Dose. AB - In the Mayak Worker Dosimetry System-2013, lung dose is calculated as an average of the three absorbed doses to the bronchial, the bronchiolar and the alveolar regions. Previous epidemiological studies involving Mayak Workers have used a lung dose calculated as the total energy deposited in the lungs divided by the mass. These two definitions lead to very different estimates of lung dose, especially for radon dosimetry. This paper uses the results of recent epidemiological studies to justify the use of a regionally weighted lung dose (wi = 1/3, I = 1, 3) over the use of an 'average lung' dose. PMID- 27986963 TI - Eye Lens Radiation Exposure in Greek Interventional Cardiology Article. AB - The lens of the eye is one of the radiosensitive tissues of the human body; if exposed to ionizing radiation can develop radiation-induced cataract at early ages. This study was held in Greece and included 44 Interventional Cardiologists (ICs) and an unexposed to radiation control group of 22 persons. Of the note, 26 ICs and the unexposed individuals underwent special eye examinations. The detected lens opacities were classified according to LOCS III protocol. Additionally, the lens doses of the ICs were measured using eye lens dosemeters. The mean dose to the lenses of the ICs per month was 0.83 +/- 0.59 mSv for the left and 0.35 +/- 0.38 mSv for the right eye, while the annual doses ranged between 0.7 and 11 mSv. Regarding the lens opacities, the two groups did not differ significantly in the prevalence of either nuclear or cortical lens opacities, whereas four ICs were detected with early stage subcapsular sclerosis. Though no statistically difference was observed in the cohort, the measured doses indicate that the eye doses received from the ICs can be significant. To minimize the radiation-induced risk at the eye lenses, the use of protective equipment and appropriate training on this issue is highly recommended. PMID- 27986964 TI - Assessment of General Public Exposure to LTE signals compared to other Cellular Networks Present in Thessaloniki, Greece. AB - To assess general public exposure to electromagnetic fields from Long Term Evolution (LTE) base stations, measurements at 10 sites in Thessaloniki, Greece were performed. Results are compared with other mobile cellular networks currently in use. All exposure values satisfy the guidelines for general public exposure of the International Commission on Non-Ionizing Radiation Protection (ICNIRP), as well as the reference levels by the Greek legislation at all sites. LTE electric field measurements were recorded up to 0.645 V/m. By applying the ICNIRP guidelines, the exposure ratio for all LTE signals is between 2.9 * 10-5 and 2.8 * 10-2. From the measurements results it is concluded that the average and maximum power density contribution of LTE downlink signals to the overall cellular networks signals are 7.8% and 36.7%, respectively. PMID- 27986965 TI - TEMPERATURE CORRECTION OF HISTORIC ERYTHEMA EFFECTIVE SOLAR UV DATA RESULTING IN A CONTINUOUS 25-YEAR DATA SET AT CHILTON, UK. AB - Public Health England has a solar network which has been established for over 25 years which measures erythema effective UV, UVA and photopic radiation. At the Chilton site there are erythema effective solar UV data available for 25 years from 1991 to 2015. Until October 2004, the data were gathered using a Solar Light R-B 500 radiometer (SL-500), which is not temperature regulated. From October 2004, the data are from a temperature regulated Solar Light R-B 501 radiometer (SL-501). A temperature correction model has been developed using overlapping SL 500 and SL-501 data from 2006 and verified using overlapping SL-500 and SL-501 data from 2005. This correction has been applied to the non-temperature regulated SL-500 Chilton data from 1991 to 2004 resulting in a 25-year dataset of SL-501 equivalent data for the analysis of long-term trends. The development and verification of this model is described. PMID- 27986966 TI - The Mayak Worker Dosimetry System (Mwds-2013): Plutonium Dissolution in The Lungs An Analysis of Mayak Workers. AB - Lung doses resulting from inhalation of plutonium aerosols are highly dependent on the assumed rate of particle clearance, which occurs by two competing processes: (1) particle transport clearance to the alimentary tract and to the thoracic lymph nodes and (2) clearance to systemic tissues, which occurs by dissolution of particles in lung fluid followed by uptake to blood, which is a process collectively known as absorption. Unbiased and accurate estimates of the values of lung absorption parameters are required to obtain reliable estimates of lung dose, particularly those inferred from urine bioassay. Parameter values governing the rate of absorption are best estimated from data, such as autopsy measurements of plutonium in the lungs and systemic tissues, which directly relate to the exposed workers of interest. However, because the mathematical models that determine clearance from the lungs and systemic tissues are complex and consist of many parameters, estimates of model parameter values are subject to significant uncertainties. With this in mind, this paper uses a Bayesian approach to estimate one of the most important dissolution parameters: the slow rate of dissolution. This is estimated for both plutonium nitrate and plutonium oxide bearing aerosols in the lungs of former workers of the Mayak Production Association. A value of 2.6 * 10-4 d-1 is estimated for plutonium nitrates, and 4.7 * 10-5 d-1 for plutonium oxides. PMID- 27986967 TI - The Evaluation of The Real Alpha Value in Brazil and its Projection until The Year 2050. AB - When a cost-benefit analysis is applied to the optimization of practices involving radiation protection, the alpha value is used to determine the amount of money required to be invested in a practice to minimize radiation doses to acceptable levels. The alpha value is often linked to the gross domestic product (GDP) per capita, so the monetary reference value of person-Sievert can often be different in each country. Evaluation of the alpha value in Brazil was performed in 1993 and 2000 making use of the procedure advised by ICRP to produce projections up to 2015 and subsequently in 2004 by using the procedure recommended by the IAEA. This paper, in response to the social and economic situation in Brazil, calculates the alpha value and compares it with the projections of the 1993 and 2000 papers and includes a dollar correction to take account of the differences in the purchasing power from that time. This procedure illustrates the significant gap of value in use and that the actual value should be two to three times higher. By GDP per capita, the authors could calculate the alpha value updated to various countries including the European Union and compare them with the official value currently in use. In conclusion, it is believed that all countries that adopt an alpha value should upgrade it to the present day. PMID- 27986968 TI - What explains anorectal chlamydia infection in women? Implications of a mathematical model for test and treatment strategies. AB - OBJECTIVES: Female anorectal Chlamydia trachomatis (chlamydia) infections are common irrespective of recent anal sex. We explored the role of anorectal infections in chlamydia transmission and estimated the impact of interventions aimed at improved detection and treatment of anorectal infections. METHODS: We developed a pair compartmental model of heterosexuals aged 15-29 years attending STI clinics, in which women can be susceptible to or infected with chlamydia urogenitally and/or anorectally and men urogenitally. Transmission probabilities per vaginal and anal sex act, together with an autoinoculation probability, were estimated by fitting to anatomic site-specific prevalence data (14% urogenital; 11% anorectal prevalence). We investigated the 10-year reduction in female chlamydia prevalence of interventions (universal anorectal testing of female STI clinic attendees or doxycycline use for urogenital chlamydia) relative to continued current care (anorectal testing on indication and doxycycline for anorectal and azithromycin for urogenital chlamydia). RESULTS: The transmission probability per anal sex act was 5.8% (IQR 3.0-8.3%), per vaginal sex act 2.0% (IQR 1.7-2.2%) and the daily autoinoculation probability was 0.7% (IQR 0.5-1.0%). More anorectal chlamydia infections were caused by autoinoculation than by recent anal sex. Universal anorectal testing reduced population prevalence modestly with 8.7% (IQR 7.6-9.7%), yet the reduction was double that of doxycycline use for urogenital infections (4.3% (IQR 3.5-5.3%)) relative to continued current care. CONCLUSIONS: Autoinoculation between anatomic sites in women might play a role in sustaining high chlamydia prevalence. A shift to more anorectal testing of female STI clinic attendees may be considered for its (albeit modest) impact on reducing prevalence. PMID- 27986969 TI - Outbreaks of syphilis among men who have sex with men attending STI clinics between 2007 and 2015 in the Netherlands: a space-time clustering study. AB - OBJECTIVES: Infectious syphilis (syphilis) is diagnosed predominantly among men who have sex with men (MSM) in the Netherlands and is a strong indicator for sexual risk behaviour. Therefore, an increase in syphilis can be an early indicator of resurgence of other STIs, including HIV. National and worldwide outbreaks of syphilis, as well as potential changes in sexual networks were reason to explore syphilis trends and clusters in more depth. METHODS: National STI/HIV surveillance data were used, containing epidemiological, behavioural and clinical data from STI clinics. We examined syphilis positivity rates stratified by HIV status and year. Additionally, we performed space-time cluster analysis on municipality level between 2007 and 2015, using SaTScan to evaluate whether or not there was a higher than expected syphilis incidence in a certain area and time period, using the maximum likelihood ratio test statistic. RESULTS: Among HIV-positive MSM, the syphilis positivity rate decreased between 2007 (12.3%) and 2011 (4.5%), followed by an increasing trend (2015: 8.0%). Among HIV-negative MSM, the positivity rate decreased between 2007 (2.8%) and 2011 also (1.4%) and started to increase from 2013 onwards (2015: 1.8%). In addition, we identified three geospatial clusters. The first cluster consisted of MSM sex workers in the South of the Netherlands (July 2009-September 2010, n=10, p<0.001). The second cluster were mostly HIV-positive MSM (58.5%) (Amsterdam; July 2011-December 2015; n=1123, p<0.001), although the proportion of HIV-negative MSM increased over time. The third cluster was large in space (predominantly the city of Rotterdam; April-September 2015, n=72, p=0.014) and were mostly HIV-negative MSM (62.5%). CONCLUSIONS: Using SaTScan analysis, we observed several not yet recognised outbreaks and a rapid resurgence of syphilis among known HIV-positive MSM first, but more recently, also among HIV-negative MSM. The three identified clusters revealed locations, periods and specific characteristics of the involved MSM that could be used when developing targeted interventions. PMID- 27986970 TI - Optimising clinical performance during resuscitation using video evaluation. AB - Video evaluation of resuscitation is becoming increasingly integrated into practice in a number of clinical settings. The purpose of this review article is to examine how video may enhance clinical care during resuscitation. As healthcare and available therapeutic interventions evolve, re-evaluation of accepted paradigms requires data to describe current practice and support change. Analysis of video recordings affords creation of a framework to evaluate individual and team performance and develop unique and tailored strategies to optimise care delivery. While video has been used in a number of non-clinical settings, there has been a recent increase of video systems in the prehospital and other clinical areas. This paper reviews the key opportunities in the emergency department-based resuscitation setting to enhance ergonomics, technical and non-technical skills-at both team and individual level-through video-assisted care performance analysis and feedback. PMID- 27986971 TI - Management of bleeding in patients receiving non-vitamin K antagonists. AB - Anticoagulation with non-vitamin K antagonists (Non vitamin K oral anticoagulant (NOACs)) including dabigatran, rivaroxaban, apixaban and edoxaban is at least as effective as warfarin, has fewer drug and food interactions and does not require monthly monitoring. Although major bleeding with NOACs is infrequent, there remains concern about the ability to effectively treat episodes of major bleeding. New agents have been developed that are capable of providing rapid reversal of the anticoagulation effect of NOACs. Idarucizumab normalises the dilute thrombin time and the ecarin clotting time, both of which are elevated with dabigatran. Andexanet alfa reduces increased anti-factor Xa activity seen with the use of rivaroxaban and apixaban. A universal reversal agent is in development. These agents, unlike agents to reverse the anticoagulation effect of vitamin K antagonists, appear to reverse the specific NOAC anticoagulant. The development of reversal agents is a major advancement in managing bleeding in the era of NOACs. Future studies will be required to determine the impact on important clinical outcomes. PMID- 27986972 TI - Effects of Vitamin D on Endometriosis-Related Pain: A Double-Blind Clinical Trial. AB - BACKGROUND Endometriosis is a disabling disease of reproductive-age women. Dysmenorrhea, dyspareunia, and pelvic pain are the main symptoms of endometriosis. Its etiology is not clear. Endometriosis may have various causes, including vitamin D deficiency, but its effect is controversial. MATERIAL AND METHODS In this double-blind clinical trial, we enrolled patients with endometriosis diagnosed and treated by laparoscopy, with scores of at least 3 for of dysmenorrhea and/or pelvic pain at 8 weeks after surgical treatment. They were randomly prescribed vitamin D (50 000 IU weekly for 12 weeks) or placebo. Severity of pain in the 2 groups (placebo and treatment) was compared by VAS test at 24 weeks after surgical treatment. RESULTS There were 19 patients in the vitamin D group and 20 in the placebo group. Baseline characteristics in the 2 groups were similar. Following the treatment with vitamin D or placebo, we did not find significant differences in severity of pelvic pain (p=0.24) and dysmenorrhea (p=0.45) between the 2 groups. Mean pelvic pain at 24 weeks after laparoscopy in the vitamin D group was 0.84+/-1.74 and in placebo group it was 0.68+/-1.70 (p=0.513). Mean dysmenorrhea was 2.10+/-2.33 in the vitamin D group and 2.73+/-2.84 in the placebo group (p=0.45). CONCLUSIONS After ablative surgery for endometriosis, vitamin D treatment did not have a significant effect in reducing dysmenorrhea and/or pelvic pain. PMID- 27986974 TI - Effects of a Serotonin 2C Agonist and a 2A Antagonist on Actigraphy-Based Sleep Parameters Disrupted by Methamphetamine Self-Administration in Rhesus Monkeys. AB - Sleep disorders and substance abuse are highly comorbid and we have previously shown that methamphetamine self-administration significantly disrupts activity based sleep parameters in rhesus monkeys. To the best of our knowledge, no study has evaluated the effectiveness of any pharmacological intervention to attenuate the effects of methamphetamine on nighttime activity under well-controlled conditions in laboratory animals. Thus, we examined the effects of a 5-HT2C receptor agonist, WAY163909, and a 5-HT2A receptor antagonist, M100907, given alone and in combination, on actigraphy-based sleep parameters disrupted by methamphetamine self-administration in non-human primates. Adult male/female rhesus monkeys self-administered methamphetamine (0.03 mg/kg/injection, i.v.) under a fixed-ratio 20 schedule of reinforcement (60-min sessions once a day, 5 days per week). Nighttime activity was evaluated using Actiwatch monitors. WAY163909 (0.1, 0.3, and 1.0 mg/kg), M100907 (0.03, 0.1, and 0.3 mg/kg), and a combination (0.1 mg/kg M100+0.3 mg/kg WAY) were administered i.m. before lights out. Each dose was given for five consecutive days during which self administration took place in the morning. Both drugs improved activity-based sleep measures disrupted by methamphetamine by decreasing sleep latency and increasing sleep efficiency compared with vehicle. By combining these drugs, their individual effects were significantly enhanced. Agonists at the 5-HT2C receptor and antagonists at the 5-HT2A receptor show promise as potential treatments for the sleep-disrupting effects of stimulants when used alone and in combination. Combining subthreshold doses of WAY and M100 produced significant improvements in nighttime activity measures while avoiding the general motor decreasing effects of the high dose of WAY. PMID- 27986973 TI - Dysregulation of Specialized Delay/Interference-Dependent Working Memory Following Loss of Dysbindin-1A in Schizophrenia-Related Phenotypes. AB - Dysbindin-1, a protein that regulates aspects of early and late brain development, has been implicated in the pathobiology of schizophrenia. As the functional roles of the three major isoforms of dysbindin-1, (A, B, and C) remain unknown, we generated a novel mutant mouse, dys-1A-/-, with selective loss of dysbindin-1A and investigated schizophrenia-related phenotypes in both males and females. Loss of dysbindin-1A resulted in heightened initial exploration and disruption in subsequent habituation to a novel environment, together with heightened anxiety-related behavior in a stressful environment. Loss of dysbindin 1A was not associated with disruption of either long-term (olfactory) memory or spontaneous alternation behavior. However, dys-1A-/- showed enhancement in delay dependent working memory under high levels of interference relative to controls, ie, impairment in sensitivity to the disruptive effect of such interference. These findings in dys-1A-/- provide the first evidence for differential functional roles for dysbindin-1A vs dysbindin-1C isoforms among phenotypes relevant to the pathobiology of schizophrenia. Future studies should investigate putative sex differences in these phenotypic effects. PMID- 27986975 TI - Roles of Hippocampal Somatostatin Receptor Subtypes in Stress Response and Emotionality. AB - Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an inhibitory feedback on stress but the mechanisms involved remain unclear. We investigated herein the role of hippocampal somatostatin receptor subtypes in both stress response and behavioral emotionality using C57BL/6, wild type and sst2 or sst4 knockout mice. Inhibitory effects of hippocampal infusions of somatostatin agonists on stress-induced hypothalamo-pituitary-adrenal axis (HPA) activity were tested by monitoring peripheral blood and local hippocampus corticosterone levels, the latter by using microdialysis. Anxiolytic and antidepressant-like effects were determined in the elevated-plus maze, open field, forced swimming, and stress-sensitive beam walking tests. Hippocampal injections of somatostatin analogs and sst2 or sst4, but not sst1 or sst3 receptor agonists produced rapid and sustained inhibition of HPA axis. sst2 agonists selectively produced anxiolytic-like behaviors whereas both sst2 and sst4 agonists had antidepressant-like effects. Consistent with these findings, high corticosterone levels and anxiety were found in sst2KO mice and depressive like behaviors observed in both sst2KO and sst4KO strains. Both hippocampal sst2 and sst4 receptors selectively inhibit stress-induced HPA axis activation but mediate anxiolytic and antidepressive effects through distinct mechanisms. Such results are to be accounted for in development of pathway-specific somatostatin receptor agents in the treatment of hypercortisolism (Cushing's disease) and stress-related neuropsychiatric disorders. PMID- 27986977 TI - Risk factors for postoperative mortality in congenital diaphragmatic hernia: a single-centre observational study. AB - BACKGROUND: The management of congenital diaphragmatic hernia (CDH) is a major challenge. The mortality is dependent on associated malformations, the severity of pulmonary hypoplasia, pulmonary hypertension and iatrogenic lung injury associated with aggressive mechanical ventilation. The aims of the study were to investigate the mortality over time in a single paediatric surgical centre, to compare the results with recent reports and to define the risk factors for mortality. METHODS: The medical records of infants with CDH from two time periods: 1995-2005 and 2006-2016 were reviewed. Cox regression was used for statistical analysis. RESULTS: The study included 113 infants. The mortality rate was significantly decreased in the later time period, compared to the earlier, 4.4 and 17.9%, respectively. At the early time period five patients (7.5%) were treated with ECMO and in the later time period ECMO was used in three patients (6.5%). The mortality in ECMO-treated patients was 50% in both time periods. Prenatal diagnosis, intrathoracic liver, low Apgar score and low birth weight were defined as independent risk factors for mortality. CONCLUSION: Despite no significant differences in the incidence of independent risk factors and the use of ECMO between the two time periods, mortality decreased over time. The mortality was lower than previously reported. The results indicate that there are many important factors involved in a successful outcome after CDH repair. Large multicentre studies are necessary to define those critical factors and to determine optimal treatment strategies. PMID- 27986978 TI - [Triggers of exanthematous drug eruptions: Stop intake, treat through or desensitization?] AB - Drug hypersensitivity reactions affect over 7% of the population and are problematic both for patients and doctors. They frequently occur in the form of exanthematous drug eruptions. The clinical manifestation of delayed hypersensitivity reactions is very variable ranging from localized fixed drug eruptions to life-threatening, severe bullous mucocutaneous eruptions or systemic drug hypersensitivity syndromes. In the case of suspicion of an exanthematous drug eruption, the causality should initially be assessed according to the proposed algorithm. If both the chronology and the clinical symptoms are indicative of a delayed drug hypersensitivity reaction, the suspected drug should be avoided. Only in cases of urgent therapeutic indications and if alternative drugs are not available, the options of "treating through" and temporary tolerance induction by "desensitization" should be considered after an individual risk-benefit analysis. PMID- 27986980 TI - [Chest pain in the emergency department : Differential diagnosis and diagnostic strategy]. AB - Chest pain as the leading symptom in emergency patients can have numerous causes and requires an immediate and targeted diagnostic and therapeutic strategy. Clinical scoring systems facilitate risk assessment for individual patients. In the emergency department, critical factors for success are defined professional qualification standards for physicians and nursing staff combined with a well functioning organization of all technical procedures. PMID- 27986981 TI - [Pulmonary causes of chest pain]. AB - Chest pain represents one of the most frequent symptoms of pulmonary diseases, in addition to dyspnea and cough. The broad differential diagnostics include the intensely painful but prognostically benign acute pleurisy as well as potentially life-threatening events, such as acute pulmonary embolism or malignant chest diseases. Primary spontaneous pneumothorax is characterized by acute chest pain. Pain associated with a respiratory infection, such as pneumonia rarely poses a difficult diagnostic problem. Painful diseases of the lungs can be differentiated in an initial approach by asking the patient if the pain is related to breathing, which is characteristic of pleuritic chest diseases. Pulmonary hypertension, lung cancer and mesothelioma show more constant pain unrelated to respiratory movements. It is most important to differentiate pain associated with acute exacerbation of chronic obstructive pulmonary disease (COPD), whereby a possible cardiac comorbidity, such as acute coronary syndrome (ACS) should always be considered. PMID- 27986979 TI - Liraglutide attenuates partial warm ischemia-reperfusion injury in rat livers. AB - Ischemia-reperfusion (IR) injury constitutes the most important cause of primary dysfunction of liver grafts. In this study, we have addressed the possible hepatoprotective action of liraglutide against partial warm hepatic IR injury in male rats. Rats were randomly assigned into: sham, IR, and liraglutide-pretreated IR groups. Liraglutide was administered 50 MUg/kg s.c. twice daily for 14 days, and then, hepatic IR was induced by clamping portal vein and hepatic artery to left and median lobes for 30 min followed by reperfusion for 24 h. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) activities were determined. Malondialdehyde (MDA) level, reduced glutathione (GSH) content, tumor necrosis factor-alpha (TNF-alpha), phosphoralated Akt (p-Akt), and caspase-3 levels of the liver were determined. Hematoxylin and eosin (H&E) stained sections from liver were examined as well as immunohistochemical sections for detection of Bcl-2 expression. IR injury increased ALT, AST, and GGT while decreased GSH and p-Akt with increase in MDA, TNF-alpha, and caspase-3 levels in the liver with necrosis and inflammatory cellular infiltration with decreased Bcl-2 expression. Pretreatment with liraglutide decreased ALT, AST, and GGT activities while increased glutathione content and Akt activation with decrements in MDA, TNF-alpha, and caspase-3 levels with attenuation of necrosis and inflammation while enhanced Bcl-2 expression in the liver. Liraglutide protects against IR injury of the liver through antiinflammatory and antioxidant actions as well as inhibition of apoptosis. PMID- 27986976 TI - Selective susceptibility to nanosecond pulsed electric field (nsPEF) across different human cell types. AB - Tumor ablation by nanosecond pulsed electric fields (nsPEF) is an emerging therapeutic modality. We compared nsPEF cytotoxicity for human cell lines of cancerous (IMR-32, Hep G2, HT-1080, and HPAF-II) and non-cancerous origin (BJ and MRC-5) under strictly controlled and identical conditions. Adherent cells were uniformly treated by 300-ns PEF (0-2000 pulses, 1.8 kV/cm, 50 Hz) on indium tin oxide-covered glass coverslips, using the same media and serum. Cell survival plotted against the number of pulses displayed three distinct regions (initial resistivity, logarithmic survival decline, and residual resistivity) for all tested cell types, but with differences in LD50 spanning as much as nearly 80 fold. The non-cancerous cells were less sensitive than IMR-32 neuroblastoma cells but more vulnerable than the other cancers tested. The cytotoxic efficiency showed no apparent correlation with cell or nuclear size, cell morphology, metabolism level, or the extent of membrane disruption by nsPEF. Increasing pulse duration to 9 us (0.75 kV/cm, 5 Hz) produced a different selectivity pattern, suggesting that manipulation of PEF parameters can, at least for certain cancers, overcome their resistance to nsPEF ablation. Identifying mechanisms and cell markers of differential nsPEF susceptibility will critically contribute to the proper choice and outcome of nsPEF ablation therapies. PMID- 27986984 TI - Bone marrow sFRP5 level is negatively associated with bone formation markers. AB - : Secreted frizzled-related protein 5 (sFRP5) level in bone marrow environment is inversely correlated with bone formation markers, suggesting that it decreases bone mass by inhibiting bone formation. Besides, it functions in a local fashion when regulating bone metabolism. sFRP5 may be a target when developing anti osteoporotic agents. INTRODUCTION: The purpose of the study is to investigate the relationship between bone marrow sFRP5 level and bone turnover state. METHODS: Eighty-three total knee arthroplasty patients were enrolled in this study. Data were collected prospectively and reviewed retrospectively. Lumbar spine and femoral neck bone mineral density (BMD), marrow adipose tissue (MAT) sFRP5 messenger RNA (mRNA) expression level, sFRP5 concentrations in marrow fluid and serum, concentrations of bone formation and resorption markers were measured for each participant. RESULTS: Marrow fluid sFRP5 concentration was positively correlated with both MAT sFRP5 expression (p = 0.040) and serum sFRP5 concentration (p = 0.043). Significantly positive correlation existed between MAT sFRP5 expression level and BMD (p < 0.05). Marrow fluid sFRP5 concentration had a moderate but not significant positive association with BMD. MAT sFRP5 was negatively related to serum bone formation markers including N-terminal propeptide of type 1 procollagen (P1NP) (p = 0.011), osteocalcin (OC), and alkaline phosphatase (ALP). Marrow fluid and serum sFRP5 concentrations also had mild negative correlations with bone formation markers but reached no significance. There was no significant correlation between bone resorption marker beta-crosslaps (beta-CTX) and sFRP5. The mRNA expression level of MAT sFRP5 was positively related with those of MAT leptin, peroxisome proliferator-activated receptor-gamma (PPARgamma), and adiponectin, and its correlation with leptin was statistically significant (p = 0.026). CONCLUSIONS: Bone marrow sFRP5 level is closely correlated with BMD and bone formation markers. sFRP5 may be a potential negative regulator of bone mass by inhibiting bone formation. It may exert its effects on bone metabolism in a paracrine, rather than endocrine manner. PMID- 27986983 TI - Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care. AB - : This trial compared the effects of daily treatment with vitamin D or placebo for 1 year on blood tests of vitamin D status. The results demonstrated that daily 4000 IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention. INTRODUCTION: The aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000 IU (100 MUg), 2000 IU (50 MUg) or placebo for 1 year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes. METHODS: This is a randomized placebo-controlled trial in 305 community-dwelling people aged 65 years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function. RESULTS: Mean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12 months in those allocated 4000 IU, 2000 IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90 nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000 IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function. CONCLUSIONS: After accounting for average 70% compliance in long-term trials, doses of 4000 IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies. PMID- 27986986 TI - A pharmacokinetic study of lipegfilgrastim in children with Ewing family of tumors or rhabdomyosarcoma. AB - PURPOSE: Neutropenia is a common complication from chemotherapy, limiting optimal dosing and treatment. Lipegfilgrastim is a long-acting granulocyte colony stimulating factor developed for the management of chemotherapy-induced neutropenia. The objectives of this phase 1, multinational, open-label, single arm study were to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a single body weight-adjusted dose of lipegfilgrastim and to evaluate the efficacy, safety, and tolerability of the drug in children with Ewing family of tumors or rhabdomyosarcoma treated with myelosuppressive chemotherapy. METHODS: Enrolled patients received lipegfilgrastim (100 ug/kg) 24 h after the last chemotherapy treatment in week 1. Patients were stratified into three age groups: 2 to <6, 6 to <12, and 12 to <18 years. Blood samples for PK analyses were obtained at baseline and at 3, 8, 24, 30, 48, 72, 96, 144, and 240 h postdose for the two oldest groups and up to 144 h in the youngest group. RESULTS: Twenty-one patients were enrolled and received lipegfilgrastim, seven in each age group. Lipegfilgrastim exposure levels were comparable across age groups, with concentrations maintained over a prolonged period after a single injection. Differences in PD were mainly associated with chemotherapy type. Most investigator-reported adverse events were attributed to chemotherapy and not to lipegfilgrastim. Severe adverse events were noted in 57% of patients; febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia were more frequent among the oldest patients. CONCLUSIONS: Results support the use of a body weight adjusted dose to achieve equivalent initial peak exposure levels of lipegfilgrastim in children of various ages. PMID- 27986989 TI - Cyclops lesions detected by MRI are frequent findings after ACL surgical reconstruction but do not impact clinical outcome over 2 years. AB - OBJECTIVES: To assess the impact of cyclops lesions with MRI in patients treated for anterior cruciate ligament (ACL) tears on clinical outcome. METHODS: In 113 patients (age 29.8 +/- 10.5y; 55 females; BMI 24.8 +/- 3.7 kg/m2) with complete ACL tear, 3 T-MRI scans were obtained before, 6-months, 1-year (n = 75) and 2 years (n = 33) after ACL reconstruction. Presence and volume of cyclops lesions were assessed. Clinical outcomes were measured using the Knee injury and Osteoarthritis Outcome Score (KOOS) and differences between time points (?KOOS) were calculated. Changes of KOOS subscales were compared between patients with and without cyclops lesion. KOOS was also correlated with lesion volume. RESULTS: Cyclops lesions were found in 25% (28/113), 27% (20/75) and 33% (11/33) of patients after 6-months, 1- and 2-years, respectively. The lesion volume did not change significantly (P > 0.05) between time points, measuring 0.65 +/- 0.59, 0.81 +/- 0.70 and 0.72.9 +/- 0.96 cm3, respectively. Clinical outcomes based on KOOS subscales were not significantly different in patients with cyclops lesions compared to those without cyclops lesions (each comparison P > 0.05), and no significant associations of clinical outcomes with lesion volume were found (P > 0.05). CONCLUSIONS: Neither presence nor size of cyclops lesions within the first 2-years after ACL surgery were associated with inferior clinical outcome. KEY POINTS: * Cyclops lesions had a prevalence of 25% in patients after ACL reconstruction. * Subjects with cyclops lesions did not have an inferior clinical outcome. * Cyclops lesions developed within the first 6 months after surgery. * The size of cyclops lesions did not significantly change over a period of 2 years. PMID- 27986987 TI - Glia: silent partners in energy homeostasis and obesity pathogenesis. AB - Body weight stability requires homeostatic regulation to balance energy intake and energy expenditure. Research on this system and how it is affected by obesity has largely focused on the role of hypothalamic neurons as integrators of information about long-term fuel storage, short-term nutrient availability and metabolic demand. Recent studies have uncovered glial cells as additional contributors to energy balance regulation and obesity pathogenesis. Beginning with early work on leptin signalling in astrocytes, this area of research rapidly emerged after the discovery of hypothalamic inflammation and gliosis in obese rodents and humans. Current studies have revealed the involvement of a wide variety of glial cell types in the modulation of neuronal activity, regulation of hormone and nutrient availability, and participation in the physiological regulation of feeding behaviour. In addition, one glial type, microglia, has recently been implicated in susceptibility to diet-induced obesity. Together, these exciting new findings deepen our understanding of energy homeostasis regulation and raise the possibility of identifying novel mechanisms that contribute to the pathogenesis of obesity. PMID- 27986991 TI - Recombinant expression and characterization of a L-amino acid oxidase from the fungus Rhizoctonia solani. AB - L-Amino acid oxidases (L-AAOs) catalyze the oxidative deamination of L-amino acids to the corresponding alpha-keto acids, ammonia, and hydrogen peroxide. L AAOs are homodimeric enzymes with FAD as a non-covalently bound cofactor. They are of potential interest for biotechnological applications. However, heterologous expression has not succeeded in producing large quantities of active recombinant L-AAOs with a broad substrate spectrum so far. Here, we report the heterologous expression of an active L-AAO from the fungus Rhizoctonia solani in Escherichia coli as a fusion protein with maltose-binding protein (MBP) as a solubility tag. After purification, it was possible to remove the MBP-tag proteolytically without influencing the enzyme activity. MBP-rsLAAO1 and 9His rsLAAO1 converted basic and large hydrophobic L-amino acids as well as methyl esters of these L-amino acids. The progress of the conversion of L-phenylalanine and L-leucine into the corresponding alpha-keto acids was determined by HPLC and 1H-NMR analysis of reaction mixtures, respectively. Enzymatic activity was stimulated 50-100-fold by SDS treatment. K m values ranging from 0.9-10 mM and v max values from 3 to 10 U mg-1 were determined after SDS activation of 9His rsLAAO1 for the best substrates. The enzyme displayed a broad pH optimum between pH 7.0 and 9.5. In summary, a successful overexpression of recombinant L-AAO in E. coli was established that results in a promising enzymatic activity and a broad substrate spectrum for biotechnological application. PMID- 27986990 TI - Multiparametric computer-aided differential diagnosis of Alzheimer's disease and frontotemporal dementia using structural and advanced MRI. AB - OBJECTIVES: To investigate the added diagnostic value of arterial spin labelling (ASL) and diffusion tensor imaging (DTI) to structural MRI for computer-aided classification of Alzheimer's disease (AD), frontotemporal dementia (FTD), and controls. METHODS: This retrospective study used MRI data from 24 early-onset AD and 33 early-onset FTD patients and 34 controls (CN). Classification was based on voxel-wise feature maps derived from structural MRI, ASL, and DTI. Support vector machines (SVMs) were trained to classify AD versus CN (AD-CN), FTD-CN, AD-FTD, and AD-FTD-CN (multi-class). Classification performance was assessed by the area under the receiver-operating-characteristic curve (AUC) and accuracy. Using SVM significance maps, we analysed contributions of brain regions. RESULTS: Combining ASL and DTI with structural MRI resulted in higher classification performance for differential diagnosis of AD and FTD (AUC = 84%; p = 0.05) than using structural MRI by itself (AUC = 72%). The performance of ASL and DTI themselves did not improve over structural MRI. The classifications were driven by different brain regions for ASL and DTI than for structural MRI, suggesting complementary information. CONCLUSIONS: ASL and DTI are promising additions to structural MRI for classification of early-onset AD, early-onset FTD, and controls, and may improve the computer-aided differential diagnosis on a single-subject level. KEY POINTS: * Multiparametric MRI is promising for computer-aided diagnosis of early onset AD and FTD. * Diagnosis is driven by different brain regions when using different MRI methods. * Combining structural MRI, ASL, and DTI may improve differential diagnosis of dementia. PMID- 27986992 TI - Comprehensive characterization of a theophylline riboswitch reveals two pivotal features of Shine-Dalgarno influencing activated translation property. AB - Tuneable gene expression controlled by synthetic biological elements is of great importance to biotechnology and synthetic biology. The synthetic riboswitch is a pivotal type of elements that can easily control the heterologous gene expression in diverse bacteria. In this study, the theophylline-dependent synthetic riboswitch and the corresponding variants with varied spacings between Shine Dalgarno (SD) sequence and start codon were employed to comprehensively characterize the induction and regulation properties through combining a strong promoter aprE in Bacillus subtilis. Amongst the sets of newly constructed expression elements, the expression element with 9-bp spacing exhibited the higher expression level, a superior induction fold performance, and a considerably lower leaky expression than those with longer or shorter spacings. The riboswitch expression element with 9-bp spacing showed an approximately linear dose dependence from 0 to 8 mM of theophylline. Modification of the SD sequence through the insertion of a single A base prior to the native sequence enables the increase of the expression level post induction while decreasing the induction fold as a result of the elevated leaky level. The riboswitch elements with the engineered SD and the optimal 9-bp spacing exhibit an altered dose dependency in which the approximately linear range shifts to 0-4 mM, although it has a similar profile to the induction process. These results not only provide comprehensive data for the induced expression by a theophylline riboswitch combined with a strong native promoter from B. subtilis but also provide the two pivotal features of SD essential to the modular design of other synthetic riboswitches. PMID- 27986995 TI - The Effect of Atrazine on Louisiana Gulf Coast Estuarine Phytoplankton. AB - Pesticides may enter water bodies in areas with a high proportion of agricultural land use through surface runoff, groundwater discharge, and erosion and thus negatively impact nontarget aquatic organisms. The herbicide atrazine is used extensively throughout the Midwest and enters the Mississippi River through surface runoff and groundwater discharge. The purpose of this study was to determine the extent of atrazine contamination in Louisiana's estuaries from Mississippi River water under different flow and nutrient regimes (spring and summer) and its effect on the biomass and oxygen production of the local phytoplankton community. The results showed that atrazine was consistently present in these systems at low levels. Microcosm experiments exposed to an atrazine-dilution series under low and high nutrient conditions to determine the phytoplankton stress response showed that high atrazine levels greatly decreased phytoplankton biomass and oxygen production. Phytoplankton exposed to low and moderate atrazine levels under high nutrient conditions were able to recover after an extended acclimation period. Communities grown under high nutrient conditions grew more rapidly and produced greater levels of oxygen than the low nutrient treatment groups, thus indicating that atrazine exposure may induce a greater stress response in phytoplankton communities under low-nutrient conditions. The native community also experienced a shift from more sensitive species, such as chlorophytes, to potentially more resilient species such as diatoms. The phytoplankton response to atrazine exposure at various concentrations can be especially important to greater trophic levels because their growth and abundance can determine the potential productivity of the entire ecosystem. PMID- 27986993 TI - Characterization of a vacuolar H+-ATPase G subunit gene from Juglans regia (JrVHAG1) involved in mannitol-induced osmotic stress tolerance. AB - KEY MESSAGE: JrVHAG1 is an important candidate gene for plant osmotic tolerance regulation. Vacuolar H+-ATPase (V-ATPase) is important for plant responses to abiotic stress; the G subunit is a vital part of V-ATPase. In this study, a G subunit of V-ATPase was cloned from Juglans regia (JrVHAG1) and functionally characterized. JrVHAG1 transcription was induced by mannitol that increasing 17.88-fold in the root at 12 h and 19.16-fold in the leaf at 96 h compared to that under control conditions. JrVHAG1 was overexpressed in Arabidopsis and three lines (G2, G6, and G9) with highest expression levels were selected for analysis. The results showed that under normal conditions, the transgenic and wild-type (WT) plants displayed similar germination, biomass accumulation, reactive oxygen species (ROS) level, and physiological index. However, when treated with mannitol, the fresh weight, root length, water-holding ability, and V-ATPase, superoxide dismutase, and peroxidase activity of G2, G6, and G9 were significantly higher than those of WT. In contrast, the ROS and cell damage levels of the transgenic seedlings were lower than those of WT. Furthermore, the transcription levels of V-ATPase subunits, ABF, DREB, and NAC transcription factors (TFs), all of which are factors of ABA signaling pathway, were much higher in JrVHAG1 transgenic plants than those in WT. The positive induction of JrVHAG1 gene under abscisic acid (ABA) treatments in root and leaf tissues indicates that overexpression of JrVHAG1 improves plant tolerance to osmotic stress relating to the ABA signaling pathway, which is transcriptionally activated by ABF, DREB, and NAC TFs, and correlated to ROS scavenging and V ATPase activity. PMID- 27986994 TI - The effects of a skeletal muscle titin mutation on walking in mice. AB - Titin contributes to sarcomere assembly, muscle signaling, and mechanical properties of muscle. The mdm mouse exhibits a small deletion in the titin gene resulting in dystrophic mutants and phenotypically normal heterozygotes. We examined the effects of this mutation on locomotion to assess how, and if, changes to muscle phenotype explain observed locomotor differences. Mutant mice are much smaller in size than their siblings and gait abnormalities may be driven by differences in limb proportions and/or by changes to muscle phenotype caused by the titin mutation. We quantified differences in walking gait among mdm genotypes and also determined whether genotypes vary in limb morphometrics. Mice were filmed walking, and kinematic and morphological variables were measured. Mutant mice had a smaller range of motion at the ankle, shorter stride lengths, and shorter stance duration, but walked at the same relative speeds as the other genotypes. Although phenotypically similar to wildtype mice, heterozygous mice frequently exhibited intermediate gait mechanics. Morphological differences among genotypes in hindlimb proportions were small and do not explain the locomotor differences. We suggest that differences in locomotion among mdm genotypes are due to changes in muscle phenotype caused by the titin mutation. PMID- 27986996 TI - The Degree of Impairment of Foraging in Crayfish (Orconectes virilis) due to Insecticide Exposure is Dependent upon Turbulence Dispersion. AB - As toxicants move into aquatic systems, the concentration at any point in space or time is heavily influenced by the flow dynamics. The dispersion of these chemicals creates a toxicant concentration that fluctuates widely in time and is highly dependent on the spatial heterogeneity of turbulence. Despite this knowledge on the movement of toxicants in natural systems, most ecotoxicological studies use static exposure paradigms that ignore the spatio-temporal dynamics of toxicants in aquatic systems. Although recent studies have begun to use pulsed paradigms in an attempt to mimic natural conditions, the heterogeneity of real concentrations in natural systems rarely is considered for use in these tests. Thus, understanding how organisms are impaired by naturally distributed toxicants is relatively unknown. The purpose of this experiment was to determine how turbulent dispersion of a toxicant negatively impacts a behavioral task and if altering the nature of turbulence will change the negative impact of the toxicant. Crayfish were exposed to a turbulent plume of carbaryl, an insecticide, under two different turbulent conditions and two different spatial conditions. Turbulence was altered by placing an obstruction within the flow which mimics a natural obstruction in lentic systems. Crayfish were exposed to sublethal concentrations of carbaryl for 48 h under these different dynamic conditions. After toxicant exposure, crayfish foraging ability was measured in a flow-through Y maze. We hypothesized that crayfish exposed to the toxicant under more turbulent conditions would exhibit more detrimental responses due to the increased variation in chemical fluctuations. The fine-scale chemical distribution of the toxicant and the three-dimensional velocity profile were characterized for each of the turbulent conditions and each of the spatial locations. Analyses of these data showed that changes in turbulence or spatial location created a unique exposure condition. Particularly, significant variations in the rise time, intermittency, and slope of toxicant pulses were quantified, whereas average concentration of the peaks remained constant across locations. Deficits in the foraging ability of crayfish exposed under these dynamic conditions paralleled the differences quantified in parameters of the turbulent toxicant plume. Given these results, the concept of toxicant exposure needs revision and needs to incorporate the more temporally based measures of toxicant dispersion. In addition, static and pulsed exposure models do not duplicate natural exposure and may not reflect behavioral or physiological impairments that occur under more realistic exposure conditions. PMID- 27986998 TI - Are even geriatric patients becoming older and older? : Changes in the age structure of geriatric inpatients in the course of two decades. AB - BACKGROUND: The life expectancy of the German population has steadily risen in the course of the past decades. As especially the oldest members of the population are treated in geriatric clinics, it would be of interest to investigate whether the increase in population age can also be found among geriatric inpatients. PATIENTS AND METHODS: The demographic data of inpatients of a geriatric clinic in Hannover in the years 1994, 2004 and 2014 were analyzed according to age, gender and classification as acute care or geriatric rehabilitation. RESULTS: The mean patient age rose by 6 years in the past two decades. This was the case for both men and women but the age of men (+7.5 years) rose more than that of women (+4.9 years). Whereas the patient average age increased, especially in the first decade (+3.9 years), this increase slowed down in the following decade (+1.7 years). The 80 to 89-year-old patients remained the biggest and steadily increasing group (in 1994: 41.1%, 2004: 46.9% and 2014: 51.3%). The greatest increase, however, was found for those aged 90 years and older (1994: 4.8%, 2004: 12.2% and 2014: 17.7%). CONCLUSION: The results confirm the professional experiences of many geriatricians in that they care for an increasingly aging clientele. Particularly very old male patients in geriatric clinics are increasing. All health professional groups involved will have to face this challenge. PMID- 27987000 TI - CIRSE Guidelines on Percutaneous Ablation of Small Renal Cell Carcinoma. PMID- 27986997 TI - Risk of parkinsonism induced by flunarizine or cinnarizine: a population-based study. AB - PURPOSE: This retrospective cohort study used a population-based dataset to test the risk for parkinsonism in patients receiving flunarizine and cinnarizine, compared with matched controls. METHODS: Data were obtained from the National Health Insurance Research Dataset of Taiwan. Patients receiving flunarizine or cinnarizine for more than 1 month between 2000 and 2005 were enrolled. Exclusion criteria included receiving flunarizine, cinnarizine, or antipsychotics for more than 1 month during 1997-1999, a history of neurodegenerative diseases, and an age of less than 30 years. One matched control for each patient was selected. Each participant was followed for diagnosis of parkinsonism within a 3-year observation period. Stroke, diabetes mellitus, total prescription days, and doses of flunarizine or cinnarizine were recorded. RESULTS: The study and control groups consisted of 9830 subjects. In the study group, 280 patients (2.9 %) were diagnosed with parkinsonism with a median observation period of 1.2 years, and 49 participants (0.5 %) were diagnosed in the control group with a median observation period of 1.9 years. The adjusted hazard ratio for parkinsonism among patients receiving flunarizine and cinnarizine was 5.117 (95 % CI = 3.758-6.967). Age, stroke, and diabetes mellitus were significant risk factors, but female sex and total doses of the study drugs were not. CONCLUSIONS: This study demonstrates that flunarizine and cinnarizine significantly increase the risk for parkinsonism. The treatment benefits of these two agents should be balanced with this adverse effect. Physicians must look carefully for early signs of parkinsonism in patients treated with flunarizine and cinnarizine. PMID- 27987001 TI - Balloon-Assisted Chemoembolization Using a Micro-Balloon Catheter Alongside a Microcatheter for a Hepatocellular Carcinoma with a Prominent Arterioportal Shunt: A Case Report. AB - Although transcatheter arterial chemoembolization is one of the established treatments for hepatocellular carcinoma (HCC), it is difficult to treat HCCs with prominent arterioportal (AP) shunts because anticancer drugs and embolic materials migrate into the non-tumorous liver through the AP shunts and may cause liver infarction. We developed a novel method of balloon-assisted chemoembolization using a micro-balloon catheter alongside a microcatheter simultaneously inserted through a single 4.5-Fr guiding sheath, comprising proximal chemoembolization with distal arterial balloon occlusion. We applied this method to treat an HCC with a prominent distal AP shunt induced by previous proton beam therapy and achieved successful chemoembolization without non tumorous liver infarction under temporal balloon occlusion of a distal AP shunt. PMID- 27987002 TI - Gender-associated comorbidities in rheumatoid arthritis and their impact on outcome: data from GENIRA. AB - GENIRA [Gender in Rheumatoid Arthritis (RA)] is a comprehensive project aimed at studying gender differences in RA patients and how these differences impact on these patient outcomes. We are now reporting such data. Seventy RA patients of each gender were cross-sectionally evaluated following a preestablished protocol. Univariate and multivariate analyses focused in the different gender-associated comorbidity profiles and how they impact in the quality of life and disability of RA patients as assessed by the SF-36 and the Modified Health Assessment Questionnaire (M-HAQ), respectively. Both groups were comparable regarding their main demographic and clinical features. Different comorbidity profiles were found in both genders, with higher frequencies of diabetes mellitus, peptic ulcer, ischemic heart disease, smoking and chronic obstructive pulmonary disease among men and of depression and osteoporosis among women. The M-HAQ was lower in women than in men (0.89 +/- 2.6 vs 0.22 +/- 0.9, p = 0.04) as there were some sub scales of the SF-36 [mental health (63.7 +/- 22.0 vs 71.8 +/- 21.1; p = 0.02), general health (41.3 +/- 21.7 vs 50.0 +/- 24.3; p = 0.02), physical functioning (PF) (57.7 +/- 22.1 vs 67.3 +/- 22.7; p = 0.01) and the physical summary component (PSC) (39.3 +/- 8.9 vs 42.4 +/- 9.3, p = 0.04)]. Multivariate analysis indicated the independent association between depression and osteoporosis rather than gender with the M-HAQ, PSC and PF and of only depression with the MH and GH. Women with RA present significantly worse disability and QOL outcomes than men; these differences can be explained by female gender-associated comorbidities such as depression and osteoporosis rather than gender per se. PMID- 27987003 TI - Relationship between oxidative stress biomarkers and SYNTAX score. PMID- 27986999 TI - [Non-pharmacological treatment of dementia in geriatric psychiatry care units : Scoping review]. AB - BACKGROUND: The number of persons suffering from dementia will continuously increase in the coming years; therefore, evidence-based interventions are needed in geriatric psychiatric care. When evidence is poor scoping reviews may help to identify knowledge gaps and needs for research. AIM OF THE ARTICLE: To present an overview of clinical trials on non-pharmacological treatment for elderly with dementia in hospitals, wards and nursing homes, specializing in gerontopsychiatric care. MATERIAL AND METHODS: A systematic search was carried out by one of the authors for clinical trials (randomized controlled, controlled and single group pre-post design, English and German, 1998-2014) in PsycINFO, PubMED, PSYNDEX and the Cochrane Library as well as a manual search in two relevant German peer-reviewed journals. Two authors included studies according to a priori defined inclusion criteria. One author extracted data after consulting the second author in cases of ambiguity. The risk of bias of the studies was not assessed. RESULTS AND DISCUSSION: A total of 77 studies were identified, 29 studies on restructured treatment pathways or settings, 14 trials on environmental changes and 34 studies on therapeutic single or group interventions. Both the methodological quality of the studies and the evidence for the efficacy of non-pharmacological treatment were limited. There are clear indications for an advantage of specialized environments and treatment settings for the elderly with dementia in hospitals, wards and nursing homes. There are consistent indications for positive effects of psychosocial activation alone or in combination with cognitive or physical activation, partly with high-quality study designs. This is consistent with the German S3 guidelines for dementia. For single interventions, such as electroconvulsive therapy or horticultural activities, the level of evidence remains limited. PMID- 27987015 TI - Insulated-tip knife endoscopic polypectomy for difficult pedunculated colorectal polyps: a prospective pilot study. AB - BACKGROUND: Endoscopic polypectomy is widely used for colorectal polyps. However, for giant pedunculated colorectal polyps (>=3 cm), conventional techniques are so difficult with en bloc resection that patients had to be transferred to surgery. We had firstly reported our first experience with an insulated-tip knife to successfully remove a giant pedunculated polyp in the sigmoid colon. In this study, our aim was to explore safety and feasible of insulated-tip knife endoscopic polypectomy (IT-EP) for difficult pedunculated colorectal polyps. METHODS: A total of seven consecutive patients with giant pedunculated colorectal polyps (>=3 cm) were prospectively enrolled. IT-EP was conducted with the help of clips for all the seven patients, and data of them was recorded and analyzed. RESULTS: Of seven patients, five were men and two were women with a mean age 61 years (49-72 years). The mean diameter of polyp head and stalk was 36.4 +/- 4.9 mm (30-42 mm) and 14.6 +/- 3.6 mm (10-20 mm), respectively. All the polyps were successfully removed with IT-EP, with a mean operation time of 14.9 +/- 3.5 min (11-20 min). No serious bleeding or perforation was experienced, and no surgery was needed. There was no recurrence or residual of polyps at a mean 8.1-month follow-up. CONCLUSIONS: Insulated-tip knife endoscopic polypectomy is a safe and feasible alternative for difficult pedunculated colorectal polyps. PMID- 27987016 TI - Factors affecting the postoperative morbidity and survival of patients with liver cirrhosis following colorectal cancer surgery. AB - PURPOSE: Data are lacking on the appropriate risk stratification of patients undergoing surgery for colorectal cancer (CRC). This study aimed to evaluate the predictive factors for perioperative morbidity and oncological outcomes in CRC patients with liver cirrhosis (LC). METHODS: A retrospective analysis of prospectively collected data was conducted. A total of 161 LC patients who underwent surgery for CRC were identified between January 2001 and December 2010. RESULTS: The mean patient age was 60 +/- 10 years, and the median follow-up period was 54.0 months (range 0.5-170.0). The proportions of patients with Child Pugh classifications for LC were as follows: A (n = 118; 73.3%), B (n = 39; 24.2%), and C (n = 4; 2.5%). The median model for end-stage liver disease (MELD) score was 8 (range 6-21). The postoperative morbidity rate was 37.3% (60/161). Hyperbilirubinemia (p = 0.002), prothrombin time (PT) prolongation (p = 0.020), and intraoperative transfusion (p = 0.003) were the significant factors for postoperative morbidity in multivariate analysis. The postoperative mortality rate was 3.1% (5/161), and the 5-year cancer-specific and 5-year overall survival rates were 86.1 and 59.9%, respectively. The significant clinical risk factors by multivariate analysis that influenced overall survival were the TNM stage of CRC (p = 0.035), MELD score (>8 points) (p < 0.001), and the coexistence of hepatocellular carcinoma (HCC) (p = 0.012). CONCLUSIONS: Hyperbilirubinemia, PT prolongation, and intraoperative transfusion are significant risk factors for postoperative morbidity in LC patients who undergo surgery for CRC. Additionally, not only advanced TNM stage but also a high MELD score and the coexistence of HCC are associated with poor overall survival in CRC patients with LC. PMID- 27987018 TI - [Osteosynthesis of distal fibular fractures with IlluminOss : Video article]. AB - OBJECTIVE: The aim was minimally invasive osteosynthesis of a distal fibular fracture under the premises of poor soft tissue conditions and existing chronic comorbidities to enable rapid recovery and to reduce soft tissue stress in order to avoid postoperative infections and achieve early weight bearing. INDICATIONS: This involved a distal fibula fracture, classified as 44 B1.1, B1.2, B1.3 according to the working group for osteosynthesis (AO) or a B fracture after Danis and Weber with indications for surgery (cortical disruption and shaft offset > 5 mm), age > 65 years, poor soft tissue conditions and a Charlson score >= 1. CONTRAINDICATIONS: Acute or incompletely healed infection in the implantation area, allergy to dental adhesive or implant material, open fractures, multifragmentary and severely dislocated fractures. SURGICAL TECHNIQUE: The surgical technique is demonstrated in detail with the help of a video of the operation and which is available online. A 1-2 cm long incision at the distal pole of the fibula, insertion of an intramedullary wire, reaming of the medullary canal and insertion of the IlluminOss balloon implant, filling the balloon with monomer and curing using visible blue light (436 nm), shortening of the implant, radiological control and wound closure. FOLLOW-UP: Postoperative cooling and elevation of the affected limb, free mobility after postoperative day 1, pain-adjusted full load bearing in VacoPed boot for 6 weeks (depending on pain and swelling). RESULTS: Study currently ongoing, no complications or revisions so far. PMID- 27987019 TI - Comment on Qian et al. entitled "Outcomes of radical debridement versus no debridement for the treatment of thoracic and lumbar spinal tuberculosis". PMID- 27987020 TI - Bio-HMGB1 from breast cancer contributes to M-MDSC differentiation from bone marrow progenitor cells and facilitates conversion of monocytes into MDSC-like cells. AB - Myeloid-derived suppressor cells (MDSC) constitute the major cell population that regulates immune responses. They are known to accumulate in tumors, chronic inflammatory and autoimmune diseases. Previous data indicate that high mobility group box 1(HMGB1) facilitates MDSC differentiation from bone marrow, suppresses NK cells, CD4+ and CD8+ T cells and is involved in cancer development. However, it remains unclear what potential mechanisms of HMGB1 facilitate MDSC differentiation. In the present work, we clearly demonstrate that HMGB1 secreted by cancer cells is N-glycosylated at Asn37, which facilitates monocytic (M)-MDSC differentiation from bone marrow via the p38/NFkappaB/Erk1/2 pathway and also contributes to conversion of monocytes into MDSC-like cells; HMGB1 blockade by a monoclonal antibody against the HMGB1 B box obviously reduced the accumulation of M-MDSC in tumor-bearing mice, delaying tumor growth and development; additionally, MDSC expansion and HMGB1 up-regulation were also found in breast cancer patients. All these data indicate that HMGB1 might be a potential tumor immunotherapy target. PMID- 27987017 TI - Life in the fat lane: seasonal regulation of insulin sensitivity, food intake, and adipose biology in brown bears. AB - Grizzly bears (Ursus arctos horribilis) have evolved remarkable metabolic adaptations including enormous fat accumulation during the active season followed by fasting during hibernation. However, these fluctuations in body mass do not cause the same harmful effects associated with obesity in humans. To better understand these seasonal transitions, we performed insulin and glucose tolerance tests in captive grizzly bears, characterized the annual profiles of circulating adipokines, and tested the anorectic effects of centrally administered leptin at different times of the year. We also used bear gluteal adipocyte cultures to test insulin and beta-adrenergic sensitivity in vitro. Bears were insulin resistant during hibernation but were sensitive during the spring and fall active periods. Hibernating bears remained euglycemic, possibly due to hyperinsulinemia and hyperglucagonemia. Adipokine concentrations were relatively low throughout the active season but peaked in mid-October prior to hibernation when fat content was greatest. Serum glycerol was highest during hibernation, indicating ongoing lipolysis. Centrally administered leptin reduced food intake in October, but not in August, revealing seasonal variation in the brain's sensitivity to its anorectic effects. This was supported by strong phosphorylated signal transducer and activator of transcription 3 labeling within the hypothalamus of hibernating bears; labeling virtually disappeared in active bears. Adipocytes collected during hibernation were insulin resistant when cultured with hibernation serum but became sensitive when cultured with active season serum. Heat treatment of active serum blocked much of this action. Clarifying the cellular mechanisms responsible for the physiology of hibernating bears may inform new treatments for metabolic disorders. PMID- 27987021 TI - Impaired contraction and decreased detrusor innervation in a female rat model of pelvic neuropraxia. AB - INTRODUCTION AND HYPOTHESIS: Bilateral pelvic nerve injury (BPNI) is a model of post-radical hysterectomy neuropraxia, a common sequela. This study assessed the time course of changes to detrusor autonomic innervation, smooth muscle (SM) content and cholinergic-mediated contraction post-BPNI. METHODS: Female Sprague Dawley rats underwent BPNI or sham surgery and were evaluated 3, 7, 14, and 30 days post-BPNI (n = 8/group). Electrical field-stimulated (EFS) and carbachol induced contractions were measured. Gene expression was assessed by qPCR for muscarinic receptor types 2 (M2) and 3 (M3), collagen type 1alpha1 and 3alpha1, and SM actin. Western blots measured M2 and M3 protein expression. Bladder sections were stained with Masson's trichrome for SM content and immunofluorescence staining for nerve terminals expressing vesicular acetylcholine transporter (VAChT), tyrosine hydroxylase (TH), and neuronal nitric oxide synthase (nNOS). RESULTS: Bilateral pelvic nerve injury caused larger bladders with less SM content and increased collagen type 1alpha1 and 3alpha1 gene expression. At early time points, cholinergic-mediated contraction increased, whereas EFS-mediated contraction decreased and returned to baseline by 30 days. Protein and gene expression of M3 was decreased 3 and 7 days post-BPNI, whereas M2 was unchanged. TH nerve terminals surrounding the detrusor decreased in all BPNI groups, whereas VAChT and nNOS terminals decreased 14 and 30 days post-BPNI. CONCLUSIONS: Bilateral pelvic nerve injury increased bladder size, impaired contractility, and decreased SM and autonomic innervation. Therapeutic strategies preventing nerve injury-mediated decline in neuronal input and SM content may prevent the development of a neurogenic bladder and improve quality of life after invasive pelvic surgery. PMID- 27987022 TI - Long-term outcomes of intravesical dimethyl sulfoxide/heparin/hydrocortisone therapy for interstitial cystitis/bladder pain syndrome. AB - INTRODUCTION AND HYPOTHESIS: For decades, intravesical dimethyl sulfoxide (DMSO) cocktail therapy has been used for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS), but little is known about its long-term efficacy. We aimed to assess the long-term efficacy of intravesical DMSO/heparin/hydrocortisone/bupivacaine therapy in patients with IC/BPS. METHODS: Patients with IC/BPS from our institutions who underwent this therapy with >2 years follow-up were surveyed with O'Leary-Sant interstitial cystitis symptom and problem index questionnaires before and after therapy. Chart reviews and telephone surveys were then conducted to determine their posttherapy course. RESULTS: Of 68 eligible women, 55 (80.0%) with a median follow-up of 60 months (range 24-142) were surveyed. Their mean age at therapy onset was 44.8 years and their mean body mass index was 26.2 kg/m2. There were statistically significant improvements in O'Leary-Sant and pain scores of 23-47% at both 6 weeks and the end of the follow-up period. At the end of the follow-up period, 19 of the 55 women (34.5%) were cured (requiring no further treatment) and 12 (21.8%) were significantly improved (requiring only ongoing oral medication). Univariate and multivariate analyses showed that DMSO treatment failure was more likely in patients with pretreatment day-time urinary frequency more than 15 episodes per day (OR 1.41), nocturia more than two episodes per night (OR 2.47), maximum bladder diary voided volume <200 ml (OR 1.39) and bladder capacity under anaesthesia <500 ml (OR 1.6). CONCLUSIONS: At a median follow-up of 60 months, intravesical DMSO cocktail therapy appeared moderately effective for the treatment of IC/BPS. Treatment failure was more frequent in patients with pretreatment symptoms of reduced bladder capacity. PMID- 27987023 TI - Comparative study of episiotomy angles achieved by cutting with straight Mayo scissors and the EPISCISSORS-60 in a birth simulation model. AB - INTRODUCTION AND HYPOTHESIS: We compared the clinician's ability to cut episiotomies at the recommended 60 degrees angle with traditional straight Mayo scissors compared with patented fixed-angle episiotomy scissors EPISCISSORS-60(r) in a simulated setting using mounted incision pads. The hypothesis was that fixed angle episiotomies would achieve a more accurate cutting angle of 60 degrees . METHODS: Angles were cut on episiotomy incision pads in a mounted birth model simulating crowning: 110 midwives and doctors cut an 60 degrees episiotomy with Mayo scissors and then EPISCISSORS-60. Angles were measured with protractors. Average angles were calculated and the one-tailed paired t test was used to compare groups. RESULTS: Mean angle was 45 degrees with Mayo scissors [SD = 9, 95% confidence interval (CI) = 43.3-46.7, interquartile range (IQR) 38-50] and 60 degrees with the EPISCISSORS-60 (SD = 3, 95% CI = 59.3-60.7, IQR = 58-60). Two thirds of cuts with Mayo scissors were below 50 degrees . CONCLUSIONS: In a simulated setting the majority of operators are unable to cut an episiotomy at the recommended 60 degrees angle with Mayo scissors. The EPISCISSORS-60 cut an episiotomy a statistically significant 15 degrees wider than regular Mayo scissors and achieved the recommended 60 degrees in the vast majority of cases. If these findings translate into real life situations, then cutting episiotomies at 60 degrees is expected to make a valuable contribution in reducing third- and fourth-degree tears in both spontaneous and operative vaginal deliveries. Variability in mediolateral episiotomies should be reduced by use of fixed-angle scissors or through validated health professional training programmes to improve visual accuracy. PMID- 27987025 TI - SPRi-MALDI MS: characterization and identification of a kinase from cell lysate by specific interaction with different designed ankyrin repeat proteins. AB - We report on the direct coupling of surface plasmon resonance imaging (SPRi) with matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) for the investigation of specific, non-covalent interactions, using the example of designed ankyrin repeat proteins (DARPins) and ribosomal protein S6 kinase 2 (RPS6KA2) directly from lysate of SH-SY5Y cells, derived from human bone marrow. Due to an array format, tracing of binding kinetics of numerous DARPins simultaneously and in real time becomes possible. By optimizing both the proteolytic digest directly on the SPRi chip (amount of trypsin, incubation time, and temperature) as well as the MALDI matrix application (concentration of matrix and number of spray cycles), we are able to identify the specific interaction with RPS6KA2 directly from the cell lysate at a surface coverage of only 0.8 fmol/mm2. Graphical Abstract Workflow of the direct coupling of SPRi with MALDI mass spectrometry. PMID- 27987024 TI - Risk factors for urinary incontinence among postmenopausal Mexican women. AB - INTRODUCTION AND HYPOTHESIS: Previous studies of racial/ethnic variation in urinary incontinence (UI) suggest that population-specific studies of UI risk factors are needed to develop appropriate public health recommendations. We assessed UI risk factors among postmenopausal Mexican women enrolled in the Mexican Teachers' Cohort. METHODS: We conducted a cross-sectional study among 15,296 postmenopausal women who completed the 2008 questionnaire. UI cases were women who reported experiencing UI during menopause. Self-reported potential UI risk factors included age, reproductive variables, smoking status, adiposity, and several health conditions. We estimated multivariate-adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) for UI using multivariable logistic regression. RESULTS: Among these postmenopausal women, the prevalence of UI was 14 %. Odds of UI were higher among women with >=4 children vs nulliparous women (OR 1.43, 95 % CI 1.04-1.96) or body mass index (BMI) >=30 vs <22 kg/m2 (OR 2.00, 95 % CI: 1.55-2.57). Age at first birth <20 vs 20-24 years, past or current vs never smoking, larger waist-to-hip ratio, and history of asthma, high blood pressure, or diabetes were also associated with higher odds of UI (OR 1.2-1.3). We found a trend of lower odds of UI with older age. CONCLUSIONS: Our data suggest that information about UI and UI prevention strategies might be particularly useful for Mexican postmenopausal women with 4 or more children or higher BMI. Further studies with longitudinal UI data, in addition to data on UI severity and subtype, are needed to provide more specific information about UI risk factors to Mexican women. PMID- 27987026 TI - Phosphoproteomics of colon cancer metastasis: comparative mass spectrometric analysis of the isogenic primary and metastatic cell lines SW480 and SW620. AB - The contributions of phosphorylation-mediated signaling networks to colon cancer metastasis are poorly defined. To interrogate constitutive signaling alterations in cancer progression, the global phosphoproteomes of patient-matched SW480 (primary colon tumor origin) and SW620 (lymph node metastasis) cell lines were compared with TiO2 and immobilized metal affinity chromatography phosphopeptide enrichment followed by liquid chromatography-tandem mass spectrometry. Network analysis of the significantly altered phosphosites revealed differential regulation in cellular adhesion, mitosis, and messenger RNA translational machinery. Messenger RNA biogenesis and splicing, transport through the nuclear pores, initiation of translation, and stability and degradation were also affected. Although alterations in these processes have been associated with oncogenic transformation, control of messenger RNA stability has typically not been associated with cancer progression. Notably, the single phosphosite with the greatest relative change in SW620 cells was Ser2 on eukaryotic translation initiation factor 2 subunit 2, suggesting that SW620 cells translate faster or with greater efficiency than SW480 cells. These broad changes in the regulation of translation also occur without overexpression of eukaryotic translation initiation factor 4E. The findings suggest that metastatic cells exhibit constitutive changes to the phosphoproteome, and that messenger RNA stability and translational efficiency may be important targets of deregulation during cancer progression. PMID- 27987027 TI - Identifying known unknowns using the US EPA's CompTox Chemistry Dashboard. AB - Chemical features observed using high-resolution mass spectrometry can be tentatively identified using online chemical reference databases by searching molecular formulae and monoisotopic masses and then rank-ordering of the hits using appropriate relevance criteria. The most likely candidate "known unknowns," which are those chemicals unknown to an investigator but contained within a reference database or literature source, rise to the top of a chemical list when rank-ordered by the number of associated data sources. The U.S. EPA's CompTox Chemistry Dashboard is a curated and freely available resource for chemistry and computational toxicology research, containing more than 720,000 chemicals of relevance to environmental health science. In this research, the performance of the Dashboard for identifying known unknowns was evaluated against that of the online ChemSpider database, one of the primary resources used by mass spectrometrists, using multiple previously studied datasets reported in the peer reviewed literature totaling 162 chemicals. These chemicals were examined using both applications via molecular formula and monoisotopic mass searches followed by rank-ordering of candidate compounds by associated references or data sources. A greater percentage of chemicals ranked in the top position when using the Dashboard, indicating an advantage of this application over ChemSpider for identifying known unknowns using data source ranking. Additional approaches are being developed for inclusion into a non-targeted analysis workflow as part of the CompTox Chemistry Dashboard. This work shows the potential for use of the Dashboard in exposure assessment and risk decision-making through significant improvements in non-targeted chemical identification. Graphical abstract Identifying known unknowns in the US EPA's CompTox Chemistry Dashboard from molecular formula and monoisotopic mass inputs. PMID- 27987028 TI - Left ventricular function in response to dipyridamole stress: head-to-head comparison between 82Rubidium PET and 99mTc-sestamibi SPECT ECG-gated myocardial perfusion imaging. AB - PURPOSE: Myocardial perfusion imaging (MPI) with 99mTc-sestamibi (sestamibi) SPECT and rubidium-82 (82Rb) PET both allow for combined assessment of perfusion and left ventricular (LV) function. We sought to compare parameters of LV function obtained with both methods using a single dipyridamole stress dose. MATERIALS AND METHODS: A group of 221 consecutive patients (65.2 +/- 10.4 years, 52.9% male) underwent consecutive sestamibi and 82Rb MPI after a single dipyridamole stress dose. Sestamibi and 82Rb summed rest (SRS), stress (SSS) and difference (SDS) scores, and LV end-diastolic (EDV) and end-systolic (ESV) volumes and left ventricular ejection fraction (LVEF) were compared. RESULTS: Bland-Altman analysis showed that with increasing ESV and EDV the difference between the two perfusion tracers increased both at rest and post-stress. The mean difference in EDV and ESV between the two perfusion tracers at rest could both be independently explained by the 82Rb SDS and the sestamibi SRS. The combined models explained approximately 30% of the variation in these volumes between the two perfusion tracers (R2 = 0.261, p = 0.005; R2 = 0.296, p < 0.001, for EDV and ESV respectively). However, the mean difference in LVEF between sestamibi and 82Rb showed no significant trend post-stress (R2 = 0.001, p = 0.70) and only a modest linear increase with increasing LVEF values at rest (R2 = 0.032, p = 0.009). CONCLUSIONS: Differences in left ventricular volumes between sestamibi and 82Rb MPI increase with increasing volumes. However, these differences did only marginally affect LVEF between sestamibi and 82Rb. In clinical practice these results should be taken into account when comparing functional derived parameters between sestamibi and 82Rb MPI. PMID- 27987029 TI - Erratum to: The need of standardization and of large clinical studies in an emerging indication of [18 F]FDG PET: the autoimmune encephalitis. PMID- 27987031 TI - The new grasper-integrated single use flexible cystoscope for double J stent removal: evaluation of image quality, flow and flexibility. AB - BACKGROUND: A new single use digital flexible cystoscope (FC) Isiris alpha from Coloplast(r) with an incorporated grasper has been developed to perform double J stent removal. There is a lack of data regarding the comparison of image quality, flexibility and flow between classic cystoscopes and the new Isiris alpha. MATERIALS AND METHODS: Five different FC were used to compare the image quality, the field of view, the loss of flow and the deflection loss. Two standardized grids, three stones of different composition and a ruler's image were filmed in four standardized different scenarios. These videos were shown to thirty subjects that had to evaluate them. Water outflow was measured in ml/sec in all devices with and without the grasper inside, instruments tip deflection was measured using a software. RESULTS: In the subjective analysis of the image quality Isiris alpha was the second FC best scored. At 3 cm of distance, the field view of Isiris alpha was the narrowest. Comparing the water flow in the different FCs, we observed a water flow decrease in all cystoscopes when the grasper was loaded in the working channel. Isiris alpha deflection and flow increase when the grasper is activated. CONCLUSION: In terms of quality of vision and water flow, the FC Isiris alpha is comparable to the other digital FC tested. Field of view is narrower. The results displayed a valid alternative to the standard procedure for DJ removal. PMID- 27987030 TI - Improved decision making in intermediate-risk prostate cancer: a multicenter study on pathologic and oncologic outcomes after radical prostatectomy. AB - BACKGROUND: Prognoses for intermediate-risk prostate cancer (PCa) remain heterogeneous. Improved substratification could optimize treatment and monitoring strategies. The objective was to validate this subclassification in a radical prostatectomy (RP) series. METHODS: Between 2000 and 2011, 4038 patients who underwent RP for intermediate-risk PCa in seven French academic centers were included. Unfavorable intermediate-risk (UIR) PCa was defined as having a primary Gleason score of 4, >=50% positive biopsy cores (PPBC), or more than one D'Amico intermediate-risk factor (i.e., cT2b, PSA 10-20, or Gleason score 7). Remaining PCa cases were classified as favorable. Main endpoints were pathologic results (pT stage, final Gleason score, surgical margin status), and oncologic outcomes were assessed according to PSA recurrence-free survival (PSA-RFS). Univariate and multivariate analyses were performed using the log-rank test and the Cox proportional hazards model. RESULTS: Median follow-up was 48 months (95% CI = [45 49]). Patients with UIR had worse PSA-RFS (68.17 vs. 81.98% at 4 years, HR = 1.97, 95% CI = [1.71; 2.27], p < 0.0001) compared to those with a favorable disease. The need for adjuvant therapy was significantly greater for UIR patients (43.5 vs. 29.2%, p < 0.0001). In multivariate analysis, primary Gleason score of 4 (HR = 1.81, 95% CI = [1.55; 2.12], p < 0.0001) and PPBC >= 50% (HR = 1.26, 95% CI = [1.02; 1.56], p = 0.0286) were significant preoperative predictors for worse PSA-RFS. CONCLUSIONS: This study highlights the heterogeneity of NCCN intermediate-risk patients and validates (in a large RP cohort) the previously proposed subclassification for this group. This classification can significantly predict both pathologic and oncologic outcomes. This easy-to-use stratification could help physicians' decision making. Prospective study and new tools as genomic tests and novel molecular-based approaches can improve this stratification in the future for patient counseling. PMID- 27987032 TI - Zero hospital admissions for infection after 577 transperineal prostate biopsies using single-dose cephazolin prophylaxis. AB - PURPOSE: To determine the rate of hospital admissions for infection after transperineal biopsy of prostate (TPB) with single-dose cephazolin prophylaxis using a prospective database. METHOD: Between April 2013 and February 2016, 577 patients undergoing TPB had 2 g of cephazolin given intravenously at induction of anaesthesia. Data collected from these patients included age, PSA, prostate volume, number of cores taken and post-operative complications. RESULTS: No patients were readmitted to hospital with infection post-TPB. Seven patients developed acute urinary retention, and one patient developed clinical prostatitis that was treated with oral antibiotics in the community. CONCLUSION: It is safe to use single-dose cephazolin only as antibiotic prophylaxis prior to TPB, negating the need for quinolones. This study supports Australia's current Therapeutic Guidelines recommendation for TPB prophylaxis and the existing evidence that sepsis post-TPB is a rare complication. Whether any antibiotic prophylaxis is needed at all for TPB is the subject of a future study. PMID- 27987033 TI - Occupational noise exposure, psychosocial working conditions and the risk of tinnitus. AB - PURPOSE: The purpose of this study was to evaluate the influence of occupational noise (current and cumulative doses) and psychosocial work factors (psychological demands and decision latitude) on tinnitus occurrence among workers, using objective and non-self-reported exposure measures to prevent reporting bias. METHODS: In a cross-sectional study, we analyzed data from a Danish survey from 2009 to 2010 that included 534 workers from children day care units and 10 manufacturing trades. Associations between risk factors (current noise exposure, cumulative noise exposure and psychosocial working conditions) and tinnitus were analyzed with logistic regression. RESULTS: We found no statistically significant associations between either current [OR 0.95 (95% CI 0.89; 1.01)] or cumulative [OR 0.93 (95% CI 0.81; 1.06)] occupational noise exposure and tinnitus. Likewise, results for psychosocial working conditions showed no statistically significant association between work place decision latitude [OR 1.06 (95% CI 0.94; 1.13)] or psychological demands [OR 1.07 (95% CI 0.90; 1.26)] and tinnitus. CONCLUSIONS: Our results suggest that current Danish occupational noise levels (in combination with relevant noise protection) are not associated with tinnitus. Also, results indicated that the psychosocial working conditions we observed in this cohort of mainly industrial workers were not associated with tinnitus. Therefore, psychosocial working conditions comparable to those observed in this study are probably not relevant to take into account in the evaluation of workers presenting with tinnitus. PMID- 27987034 TI - Retrograde suction decompression of a large internal carotid aneurysm using a balloon guide catheter combined with a blood-returning circuit and STA-MCA bypass: a technical note. AB - It is difficult to treat large internal carotid aneurysms with simple surgical clipping. Here, we present a retrograde suction decompression (RSD) procedure for large internal carotid aneurysms using a balloon guide catheter combined with a blood-returning circuit and a superficial temporal artery to middle cerebral artery (STA-MCA) bypass.All patients underwent an STA-MCA bypass before the temporary occlusion of the internal carotid artery (ICA). A 6-French sheath was inserted into the common carotid artery (CCA), and a 6-French Patrive balloon catheter was placed into the ICA 5 cm past the bifurcation. Aneurysm exposure was obtained; temporary clips were placed on the proximal M1, A1, and posterior communicating (Pcom) segments; and an extension tube was then connected to the balloon catheter. A three-way stopcock was placed, and aspiration was performed through the device to collapse the aneurysm. The aspirated blood was returned to a venous line with an added heparin to prevent anemia after aspiration. During the decompression, the blood flow to the cortical area was supplied through the STA-MCA bypass. After the aneurysm collapse, the surgeon carefully dissected the perforating artery from the aneurysm dome or neck, and permanent clips were then placed on the aneurysm neck. Our procedure has several advantages, such as STA MCA bypass without external carotid artery occlusion for preventing ischemic complications of the cortical area, anemia may be avoided because of the return of the aspirated blood, and a hybrid operation room is not required to perform this method. PMID- 27987035 TI - Distant recurrences limit the survival of patients with thalamic high-grade gliomas after successful resection. AB - The indications of surgery for thalamic high-grade gliomas are not well established. The present study investigated the outcome of 21 patients treated by surgery and reports the high incidence of distant recurrences including disseminations after successful removal. Twenty-one patients with thalamic high grade gliomas not invading the pyramidal tract or midbrain underwent cytoreductive surgery at our institute from June 1997 to August 2015. Surgery was performed with the aid of a neuronavigation system, electrophysiological monitoring, and fluorescence navigation. Tumor histology included 12 cases of the World Health Organization grade III and nine cases of grade IV. Gross total resection was achieved in six cases, subtotal in 13, and partial in two. Motor weakness accompanied by sensory disturbance deteriorated immediately after surgery in 13 patients. However, five patients were determined to show deterioration at 2 months after surgery. Postoperative radiation and chemotherapy were given to every patient, and median progression-free survival of patients with grade III and IV tumors was 12.1 and 7.0 months, respectively. Median overall survival of patients with grade III and IV tumors was 25.6 and 12.6 months, respectively. High incidence of distant recurrences was found, with distant lesions at recurrence in 13 of 19 patients with recurrence, suggesting the life-restricting factor in these patients. Thalamic high-grade glioma without invasion into the pyramidal tract and brainstem can be considered as a candidate for surgical resection. Distant lesion limits the survival of patients after successful resection. PMID- 27987036 TI - Characterization of a bacterioferritin comigratory protein family 1-Cys peroxiredoxin from Candidatus Liberibacter asiaticus. AB - To defend against the lethality of the reactive oxygen species (ROS), nature has armed microorganisms with a range of antioxidant proteins. These include peroxiredoxin (Prx) super family proteins which are ubiquitous cysteine-based non heme peroxidases. The phytopathogenic bacterium Candidatus Liberibacter asiaticus (CLA), an etiological agent of citrus plants diseases, posses many genes for defense against oxidative stress. The bacterioferritin comigratory protein (BCP), a member of Prxs, is part of an oxidative stress defense system of CLA. The key residue of these enzymes is peroxidatic Cys (termed CPSH) which is contained within an absolutely conserved PXXX (T/S) XXC motif. In the present study, a 1 Cys Prx enzyme (CLa-BCP), having CPSH/sulfenic acid cysteine (C-46) but lacking the resolving cysteine (CRSH), was characterized from CLA. The peroxidase activity was demonstrated using a non-physiological electron donor DTT against varied substrates. The protein was shown to have the defensive role against peroxide-mediated cell killing and an antioxidant activity. In vitro DNA-binding studies showed that this protein can protect supercoiled DNA from oxidative damage. To the best of our knowledge, this is the first report on a 1-Cys BCPs to have an intracellular reactive oxygen species scavenging activity. PMID- 27987037 TI - Molecular cloning and functional analysis of the phosphomannomutase (PMM) gene from Dendrobium officinale and evidence for the involvement of an abiotic stress response during germination. AB - Phosphomannomutase (PMM, EC 5.4.2.8) catalyzes the interconversion of mannose-6 phosphate to mannose-1-phosphate, the precursor for the synthesis of GDP-mannose. In this study, the complementary DNA (cDNA) of the Phosphomannomutase (PMM) gene was initially cloned from Dendrobium officinale by RACE method. Transient transform result showed that the DoPMM protein was localized in the cytoplasm. The DoPMM gene was highly expressed in the stems of D. officinale both in vegetative and reproductive developmental stages. The putative promoter was cloned by TAIL-PCR and used for searched cis-elements. Stress-related cis elements like ABRE, TCA-element, and MBS were found in the promoter regions. The DoPMM gene was up-regulated after treatment with abscisic acid, salicylic acid, cold, polyethylene glycol, and NaCl. The total ascorbic acid (AsA) and polysaccharide content in all of the 35S::DoPMM Arabidopsis thaliana transgenic lines #1, #2, and #5 showed a 40, 39, and 31% increase in AsA and a 77, 22, and 39% increase in polysaccharides, respectively more than wild-type (WT) levels. All three 35S::DoPMM transgenic lines exhibited a higher germination percentage than WT plants when seeded on half-strength MS medium supplemented with 150 mM NaCl or 300 mM mannitol. These results provide genetic evidence for the involvement of PMM genes in the biosynthesis of AsA and polysaccharides and the mediation of PMM genes in abiotic stress tolerance during seed germination in A. thaliana. PMID- 27987038 TI - Efficient genome editing of differentiated renal epithelial cells. AB - Recent advances in genome editing technologies have enabled the rapid and precise manipulation of genomes, including the targeted introduction, alteration, and removal of genomic sequences. However, respective methods have been described mainly in non-differentiated or haploid cell types. Genome editing of well differentiated renal epithelial cells has been hampered by a range of technological issues, including optimal design, efficient expression of multiple genome editing constructs, attainable mutation rates, and best screening strategies. Here, we present an easily implementable workflow for the rapid generation of targeted heterozygous and homozygous genomic sequence alterations in renal cells using transcription activator-like effector nucleases (TALENs) and the clustered regularly interspaced short palindromic repeat (CRISPR) system. We demonstrate the versatility of established protocols by generating novel cellular models for studying autosomal dominant polycystic kidney disease (ADPKD). Furthermore, we show that cell culture-validated genetic modifications can be readily applied to mouse embryonic stem cells (mESCs) for the generation of corresponding mouse models. The described procedure for efficient genome editing can be applied to any cell type to study physiological and pathophysiological functions in the context of precisely engineered genotypes. PMID- 27987039 TI - Salivary oxidative stress biomarkers in chronic periodontitis and acute coronary syndrome. AB - OBJECTIVES: The study aimed at assessing oxidative stress (OS) biomarker levels in the saliva of patients with chronic periodontitis (CP) and acute coronary syndrome (ACS) and establishing their correlation to periodontal parameters and markers for cardiovascular events. MATERIALS AND METHODS: The present study enrolled 24 patients with ACS and CP (the ACSCP group), 24 patients with ACS only (the ACS group), 24 patients with CP only (the CP group), and 24 healthy controls. Plaque index (PI), gingival index, bleeding on probing, probing pocket depth (PPD), and clinical attachment loss were recorded. Markers for cardiovascular events included serum high sensitivity C-reactive protein (hsCRP) and plasma fibrinogen. 8-Hydroxydeoxyguanosine (8-OHdG), protein carbonyl (PC), malondialdehyde (MDA), and total antioxidant capacity (TAOC) were used as OS biomarkers. RESULTS: Salivary 8-OHdG, MDA, and PC levels were significantly higher in the ACSCP, ACS, and CP groups than in healthy controls (p < 0.05). There were significant correlations between salivary PC levels and PI or PPD (p < 0.05) as well as between salivary 8-OHdG levels and all periodontal parameters (p < 0.05). TAOC levels in saliva were correlated to both serum hsCRP and plasma fibrinogen (p < 0.05). Salivary MDA levels were correlated to all periodontal parameters and biomarkers for cardiovascular events (p < 0.05). CONCLUSIONS: Salivary OS biomarker levels were higher in diseased groups compared to control. They also correlated to clinical periodontal parameters and markers for cardiovascular events in ACS patients, with or without CP. CLINICAL RELEVANCE: Salivary OS biomarkers could potentially serve as diagnostic tools for cardiovascular and/or periodontal diseases. PMID- 27987040 TI - Lipid-lowering therapy stabilizes the complexity of non-culprit plaques in human coronary artery: a quantitative assessment using OCT bright spot algorithm. AB - To quantitatively evaluate the change of plaque complexity with cholesterol lowering therapy. A total of 44 non-culprit plaques from 30 patients who had serial image acquisition at baseline, 6-months, and 12-months by both optical coherence tomography (OCT) and intravascular ultrasound (IVUS) were included. Patients were treated with atorvastatin 60 mg (AT60, n = 16) or 20 mg (AT20, n = 14). We applied an OCT bright spot algorithm, which identifies a variety of plaque components including macrophages. The density of bright spot was measured within the superficial 250 um of the vessel wall. Significant reduction of bright spot density was observed from baseline to 12-months [-0.49% (-0.95, -0.20), p < 0.001], particularly during the second 6 months [first 6 months: -0.01% (-0.57, 0.60), p = 0.939; second 6 months: -0.49% (-0.98, 0.14), p < 0.001]. Although there was no significant difference at 12 months in the reduction of bright spot density between plaques with acute coronary syndrome (ACS, n = 33) and those with stable angina (n = 11) [-0.49% (-0.93, -0.19) vs. -0.39% (-1.01, -0.21), p = 0.748], a significant reduction of bright spot density during the first 6 months was observed only in plaques with ACS. There was no significant difference in the change of bright spot density between the AT60 group (n = 22) and AT20 group (n = 22) [-0.61% (-0.93, -0.34) vs. -0.41% (-0.98, -0.19), p = 0.483]. Coronary plaque complexity evaluated by a quantitative OCT algorithm significantly decreased with 12 month atorvastatin therapy irrespective of the dose and initial clinical presentation. PMID- 27987041 TI - Prevalence of deep venous thrombosis detected by ultrasonography before surgery in patients with gastric cancer: a retrospective study of 1140 consecutive patients. AB - BACKGROUND: The prevalence of deep venous thrombosis (DVT) in patients with gastric cancer before surgery is unknown. This study aimed to clarify the risk factors for DVT of the lower extremities in patients with gastric cancer before surgery and to evaluate the usefulness of ultrasonographic screening for prevention of postoperative pulmonary thromboembolism (PTE). METHODS: Patients who had undergone lower-extremity venous ultrasonography before surgery for gastric cancer were retrospectively analyzed. Univariate and multivariate logistic regression analyses were performed to identify the predictors of DVT before surgery. Perioperative management of patients with DVTs and the incidence of postoperative PTE were investigated. RESULTS: Of the total 1140 patients, 86 had DVT preoperatively. On univariate analysis, the incidence of DVT was significantly higher with: female sex; age >=80 years; PS >= 1 (vs. PS = 0); stage IV (vs. stages I-III); history of preoperative chemotherapy; and the presence of a central venous catheter (CVC). Multivariate logistic regression analysis demonstrated that sex, age >=80 years, PS >= 1, history of preoperative chemotherapy, and the presence of CVC were significantly correlated with DVT before surgery. Postoperative PTE occurred in 2 patients with proximal DVT. No patients in whom DVT was not detected developed PTE. CONCLUSIONS: Female sex, older age, worse PS, the presence of CVC, and a history of preoperative chemotherapy were the independent risk factors for DVT. Routine lower-extremity venous ultrasonographic screening is useful for prevention of PTE because it can identify patients at high or low risk for PTE. PMID- 27987043 TI - Nevus spilus: treatment with fractional CO2 laser in combination with MedLite C6 laser: a preliminary study. PMID- 27987042 TI - Using dendritic cells to evaluate how Burkholderia cenocepacia clonal isolates from a chronically infected cystic fibrosis patient subvert immune functions. AB - Infection with Burkholderia cepacia complex (Bcc) bacteria is a threat to cystic fibrosis (CF) patients, commonly leading to a fatal pneumonia, the cepacia syndrome. It causes a massive production of pro-inflammatory cytokines and leucocyte recruitment to airway epithelium without resolving infection and contributing to tissue lesion. To dissect how Bcc bacteria subvert the immune response, we developed a co-culture model with human dendritic cells (DCs) and B. cenocepacia clonal variants isolated from a chronically infected CF patient, who died with cepacia syndrome. We demonstrated that the two late variants were sevenfold and 17-fold (respectively) more internalized by DCs than the variant that initiated infection. The late variants showed improved survival within DCs (60.29 and 52.82 CFU/DC) compared to the initial variant (0.38 CFU/DC). All clonal isolates induced high expression of inflammatory cytokines IL-8, IL-6, IL 1beta, IL-12, IL-23, TNF-alpha and IL-1beta. This pro-inflammatory trait was significantly more pronounced in DCs infected with the late variants than in DCs infected with the variant that initiated patient's infection. All infected DCs failed to upregulate maturation markers, HLA-DR, CD80, CD86 and CD83. Nevertheless, these infected DCs activated approximately twice more T cells than non-infected DCs. Similar T cell activation was observable with respective conditioned media, suggesting a non-antigen-specific activation. Our data indicate that during prolonged infection, B. cenocepacia acquires ability to survive intracellularly, inducing inflammation, while refraining DC's maturation and stimulating non-antigen-specific T cell responses. The co-culture model here developed may be broadly applied to study B. cenocepacia-induced immunomodulation. PMID- 27987044 TI - Short-wavelength infrared laser activates the auditory neurons: comparing the effect of 980 vs. 810 nm wavelength. AB - Research on auditory neural triggering by optical stimulus has been developed as an emerging technique to elicit the auditory neural response, which may provide an alternative method to the cochlear implants. However, most previous studies have been focused on using longer-wavelength near-infrared (>1800 nm) laser. The effect comparison of different laser wavelengths in short-wavelength infrared (SWIR) range on the auditory neural stimulation has not been previously explored. In this study, the pulsed 980- and 810-nm SWIR lasers were applied as optical stimuli to irradiate the auditory neurons in the cochlea of five deafened guinea pigs and the neural response under the two laser wavelengths was compared by recording the evoked optical auditory brainstem responses (OABRs). In addition, the effect of radiant exposure, laser pulse width, and threshold with the two laser wavelengths was further investigated and compared. The one-way analysis of variance (ANOVA) was used to analyze those data. Results showed that the OABR amplitude with the 980-nm laser is higher than the amplitude with the 810-nm laser under the same radiant exposure from 10 to 102 mJ/cm2. And the laser stimulation of 980 nm wavelength has lower threshold radiant exposure than the 810 nm wavelength at varied pulse duration in 20-500 MUs range. Moreover, the 810 nm laser has a wider optimized pulse duration range than the 980-nm laser for the auditory neural stimulation. PMID- 27987045 TI - Continuous fetal head flexion as a marker for prenatal diagnosis of lethal multiple pterygium syndrome: a case report. AB - Lethal multiple pterygium syndrome (LMPS) is a fatal hereditary disease associated with abnormalities such as pterygium-induced congenital contractures. Fetal hydrops is present in more than half of all patients with LMPS, and all patients with LMPS are either stillborn or die in the early neonatal period. Ultrasonography findings for the prenatal diagnosis of LMPS include the detection of cutaneous webbing at multiple joints, multiple joint contractures, absent limb movement, and increased nuchal translucency. Here, we describe a patient who was diagnosed as having LMPS due to continuous fetal head flexion, despite the absence of the usual characteristics of the condition, including pterygium at the joints. Thus, continuous fetal head flexion can be a useful marker for prenatally diagnosing LMPS. PMID- 27987046 TI - Matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) for rapid identification of micro-organisms in the routine clinical microbiology laboratory. AB - The study evaluates the utility of matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) Vitek MS for identification of microorganisms in the routine clinical microbiology laboratory. From May 2013 to April 2014, microbial isolates recovered from various clinical samples were identified by Vitek MS. In case of failure to identify by Vitek MS, the isolate was identified using the Vitek 2 system (bioMerieux, France) and serotyping wherever applicable or otherwise by nucleic acid-mediated methods. All the moulds were identified by Lactophenol blue mounts, and mycobacterial isolates were identified by molecular identification systems including AccuProbe (bioMerieux, France) or GenoType Mycobacterium CM (Hain Lifescience, Germany). Out of the 12,003 isolates, the Vitek MS gave a good overall ID at the genus and or species level up to 97.7% for bacterial isolates, 92.8% for yeasts and 80% for filamentous fungi. Of the 26 mycobacteria tested, only 42.3% could be identified using the Saramis RUO (Research Use Only) database. VITEK MS could not identify 34 of the 35 yeast isolates identified as C. haemulonii by Vitek 2. Subsequently, 17 of these isolates were identified as Candida auris (not present in the Vitek MS database) by 18S rRNA sequencing. Using these strains, an in-house superspectrum of C. auris was created in the VITEK MS database. Use of MALDI-TOF MS allows a rapid identification of aerobic bacteria and yeasts in clinical practice. However, improved sample extraction protocols and database upgrades with inclusion of locally representative strains is required, especially for moulds. PMID- 27987048 TI - A case of combined laparoscopic reduction and open preperitoneal mesh repair for incarcerated small bowel in a retroperitoneal hernia between the external and internal iliac vessels. AB - We report a rare case of an incarcerated retroperitoneal hernia with or involving the small bowel through the orifice between the right external and internal iliac vessels. A 39-year-old woman was admitted to our hospital because of vomiting and abdominal pain. She had a history of right oophorocystectomy and appendectomy. Abdominal computed tomography revealed small bowel obstruction resulting from an incarcerated retroperitoneal hernia. The small bowel herniated into the retroperitoneal fossa through the orifice between the right external and internal iliac vessels. Laparoscopic reduction of the small bowel was performed, followed by ligation of the sac and placement of a mesh prosthesis through the preperitoneal approach, using a lower midline incision along the previous laparotomy scar. Her postoperative course was uneventful and no recurrence has been observed after surgery. PMID- 27987047 TI - Evaluation of the novel artus C. difficile QS-RGQ, VanR QS-RGQ and MRSA/SA QS-RGQ assays for the laboratory diagnosis of Clostridium difficile infection (CDI), and for vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) screening. AB - Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are worldwide prevalent healthcare associated pathogens. We have evaluated three Qiagen artus QS-RGQ assays for the detection of these pathogens. We examined 200 stool samples previously tested for C. difficile infection (CDI), 94 rectal swabs previously screened for VRE and 200 MRSA screening nasal swabs. With the routine diagnostic laboratory results being adopted as the gold standard, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the artus C. difficile assay were 100%, for the artus VanR QS-RGQ assay, 95, 68, 44 and 98%, and for the artus MRSA/SA assay, 80, 94, 93 and 83%, respectively. The artus VanR assay detected the vanA and/or vanB genes in 32% of culture-negative VRE screens; in 71% of these cases, only vanB was detected. An over-estimation of the rate of faecal VRE colonisation could be due to a patient population with high rates of faecal carriage of non-enterococcal species carrying vanB. Based on our findings, we conclude that all three artus QS-RGQ assays could be a useful addition to a diagnostic laboratory, and that the optimal choice of assay should be determined according to user needs. PMID- 27987049 TI - Inter- and intraannual growth patterns of urban small-leaved lime (Tilia cordata mill.) at two public squares with contrasting microclimatic conditions. AB - The effects of urban conditions on tree growth have been investigated in an increasing number of studies over the last decades, emphasizing the harsh environment of cities. Urban trees often grow in highly paved, compacted sites with consequently less soil moisture, higher soil temperatures, and greater vapor pressure deficits. However, there is still a knowledge gap regarding the impact of harsh paved environments on urban tree growth during drought years on the growth patterns of urban trees. The present study investigated the structure and growth of the common urban tree species small-leaved lime (Tilia cordata) at a highly paved public square (CPS) compared with a contrasting more open, greener square (OGS). Continuously, measured high precision dendrometer data along with meteorological data of the extreme dry and warm summer 2015 as well as dendrochronological data of the sampled trees were investigated to analyze tree growth during a drought year. The results highlight different tree dimensions and growth patterns of the trees at both sites, influenced by tree age and distinct site conditions. While the trees at OGS grew up to 2.5 mm from July until mid of August, the trees at CPS had only 0.4-mm diameter increment. After the initial expansion at CPS, tree diameter contracted again during summer to the point of shrinkage (up to 0.8 mm) at the end of our investigation. Further drought year analysis confirmed the patterns of significant stem growth reductions in the consecutive two years following the drought. A correlation analysis revealed that transpiration, air temperature, and vapor pressure deficit were negatively correlated with the daily diameter growth, whereas precipitation had a strong positive effect. Due to high transpiration rates associated with anisohydric water use behavior, T. cordata was able to provide evaporative cooling even during drought. However, this anisohydric behavior resulted in substantial growth decline afterwards especially at paved sites like CPS. Our results suggest selection of tree species, such as those with isohydric water use behavior, which may achieve a better balance between growth, transpiration, and hence evaporative cooling. PMID- 27987050 TI - Mycobacterium tuberculosis PE_PGRS18 enhances the intracellular survival of M. smegmatis via altering host macrophage cytokine profiling and attenuating the cell apoptosis. AB - Mycobacterium tuberculosis PE/PPE family proteins, named after the presence of conserved PE (Pro-Glu) and PPE (Pro-Pro-Glu) domains at N-terminal, are prevalent in M. tuberculosis genome. The function of most PE/PPE family proteins remains elusive. To characterize the function of PE_PGRS18, the encoding gene was heterologously expressed in M. smegmatis, a nonpathogenic mycobacterium. The recombinant PE_PGRS18 is cell wall associated. M. smegmatis PE_PGRS18 recombinant showed differential response to stresses and altered the production of host cytokines IL-6, IL-1beta, IL-12p40 and IL-10, as well as enhanced survival within macrophages largely via attenuating the apoptosis of macrophages. In summary, the study firstly unveiled the role of PE_PGRS18 in physiology and pathogenesis of mycobacterium. PMID- 27987051 TI - Expression patterns indicate that BMP2/4 and Chordin, not BMP5-8 and Gremlin, mediate dorsal-ventral patterning in the mollusk Crassostrea gigas. AB - Though several bilaterian animals use a conserved BMP2/4-Chordin antagonism to pattern the dorsal-ventral (DV) axis, the only lophotrochozoan species in which early DV patterning has been studied to date, the leech Helobdella robusta, appears to employ BMP5-8 and Gremlin. These findings call into question the conservation of a common DV patterning mechanism among bilaterian animals. To explore whether the unusual DV patterning mechanism in H. robusta is also used in other lophotrochozoan species, we investigated the expression of orthologous genes in the early embryo of a bivalve mollusk, Crassostrea gigas. Searching of the genome and phylogenetic analysis revealed that C. gigas possesses single orthologs of BMP2/4, Chordin, and BMP5-8 and no Gremlin homolog. Whole mount in situ hybridization revealed mRNA localization of BMP2/4 and Chordin on the opposite sides of embryos, suggesting the potential involvement of a BMP2/4 Chordin antagonism in DV patterning in this species. Furthermore, universal BMP5 8 expression and the absence of a Gremlin homolog in the C. gigas genome called into question any major contribution by BMP5-8 and Gremlin to early DV patterning in this species. Additionally, we identified seven genes showing asymmetric expression along the DV axis, providing further insight into DV patterning in C. gigas. We present the first report of a Chordin gene in a lophotrochozoan species and of the opposite expression of BMP2/4 (dorsal) and Chordin (ventral) along the D/V axis of a lophotrochozoan embryo. The findings of this study further the knowledge of axis formation in lophotrochozoan species and provide insight into the evolution of the animal DV patterning mechanism. PMID- 27987053 TI - Protection against hormone-mediated mood symptoms. AB - We present the case of a woman with bipolar I disorder with severe premenstrual mood instability, confusion, and psychosis resembling the clinical features of postpartum psychosis when estrogen levels are expected to be low, and hypomania when estrogen levels are expected to be elevated. While depressive symptoms across the menstrual cycle have been extensively documented in the literature, there is little information regarding manic and hypomanic symptoms. In addition, we describe the successful treatment of her menstrual-cycle related symptoms. Approaches to the management of menstrual psychosis have not been systematically studied, and clinical guidelines do not exist. Clinical experiences such as the one reported here, in which the clinical formulation of the patient was consistent with known neuroendocrine phenomena and in which the treatment approach was successful, are crucial to developing promising approaches that can be tested in controlled trials. PMID- 27987052 TI - Thoracic outlet syndrome: wide literature for few cases. Status of the art. AB - Despite its low prevalence and incidence, considerable debate exists in the literature on thoracic outlet syndrome (TOS). From literature analysis on nerve entrapments, we realized that TOS is the second most commonly published entrapment syndrome in the literature (after carpal tunnel syndrome) and that it is even more reported than ulnar neuropathy at elbow, which, instead, is very frequent. Despite the large amount of articles, there is still controversy regarding its classification, clinical picture, diagnostic objective findings, diagnostic modalities, therapeutical strategies and outcomes. While some experts believe that TOS is underrated, overlooked and very frequent, others even doubt its existence as a nosological entity. In the attempt to shed more light on this condition, we performed a systematic review of the literature and report evidence and opinions around this controversial subject. Only articles focused on neurogenic TOS were considered. Understanding the status of the art and the underlying reasons of doubts and weaknesses could help clinical practice and set the stage for future research. PMID- 27987054 TI - The differential relationship between trait anxiety, depression, and resting frontal alpha-asymmetry. AB - Relatively larger resting right frontal cortical brain activation has been labeled as a risk factor for emotion-related disorders. In light of this framework, the present studies' aim was twofold. First, we wanted to determine whether a relationship between symptoms of anxiety and depression and frontal asymmetry does already manifest in a sample of so far healthy individuals showing a large symptom range. This could be expected if frontal asymmetry constitutes a risk factor for depression and anxiety. Second, we aimed to investigate whether symptoms of depression and anxiety are independently related to frontal asymmetry, or whether either anxiety or depression is superior in predicting the relationship with frontal asymmetry. To address these questions, trait-like resting frontal alpha-asymmetry by means of EEG, as well as trait anxiety and depressive symptoms by questionnaire were measured from 43 healthy students (28 female). Results indicate that higher symptom severity of depression and anxiety were both significantly correlated with relatively larger right frontal cortical activation. However, in a regression analysis, frontal asymmetry was predicted by anxiety only. Controlling for depression and mood, anxiety explained 13% of variance, while controlling for mood and anxiety, depression did explain <1% of variance within frontal asymmetry. In conclusion, although both anxiety and depression add to the relationship, relatively larger right frontal cortical activity might be influenced more strongly by symptoms of anxiety. Moreover, as this effect is present already in healthy individuals, the findings might further support the notion that right frontal cortical asymmetry constitutes a risk factor for anxiety or depression. PMID- 27987055 TI - Description and phylogeny of a new microsporidium from the elm leaf beetle, Xanthogaleruca luteola Muller, 1766 (Coleoptera: Chrysomelidae). AB - This study describes a new genus and species of microsporidia which is a pathogen of the elm leaf beetle, Xanthogaleruca luteola Muller, 1776 (Coleoptera: Chrysomelidae). The beetles were collected from Istanbul in Turkey. All developmental stages are uninucleate and in direct contact with the host cell cytoplasm. Giemsa-stained mature spores are oval in shape and measured 3.40 +/- 0.37 MUm in length and 1.63 +/- 0.20 MUm in width. These uninucleate spores have an isofilar polar filament with 11 turns. The spore wall was trilaminar (75 to 115 nm) with a rugose, electron-dense exospore (34 to 45 nm) and a thickened, electron-lucent endospore (65 to 80 nm) overlaying the plasmalemma. Morphological, ultrastructural, and molecular features indicate that the described microsporidium is dissimilar to all known microsporidian taxa and confirm that it has different taxonomic characters than other microsporidia infecting X. luteola and is named here as Rugispora istanbulensis n. gen., n. sp. PMID- 27987056 TI - Diet regulates liver autophagy differentially in murine acute Trypanosoma cruzi infection. AB - Chagas disease is a tropical parasitic disease caused by the protozoan Trypanosoma cruzi, which affects about ten million people in its endemic regions of Latin America. After the initial acute stage of infection, 60-80% of infected individuals remain asymptomatic for several years to a lifetime; however, the rest develop the debilitating symptomatic stage, which affects the nervous system, digestive system, and heart. The challenges of Chagas disease have become global due to immigration. Despite well-documented dietary changes accompanying immigration, as well as a transition to a western style diet in the Chagas endemic regions, the role of host metabolism in the pathogenesis of Chagas disease remains underexplored. We have previously used a mouse model to show that host diet is a key factor regulating cardiomyopathy in Chagas disease. In this study, we investigated the effect of a high-fat diet on liver morphology and physiology, lipid metabolism, immune signaling, energy homeostasis, and stress responses in the murine model of acute T. cruzi infection. Our results indicate that in T. cruzi-infected mice, diet differentially regulates several liver processes, including autophagy, a stress response mechanism, with corresponding implications for human Chagas disease patients. PMID- 27987057 TI - Transcriptome analysis of the freshwater pearl mussel (Cristaria plicata) mantle unravels genes involved in the formation of shell and pearl. AB - Cristaria plicata, a bivalve widespread in Eastern Asia fresh water, is utilized as the freshwater pearl mussel in China. With a high economic value in pearl production, it is also an ideal object used for the studies on biomineralization in freshwater. In the research, we performed a large-scale sequencing of Cristaria plicata mantle transcriptome using Illumina HiSeqTM 2500, obtaining 98,501 unigenes with 67,817,724 bases. 22.28 and 16.64% of the unigenes were annotated in the NR and Swiss-Prot databases, respectively. Most of the annotated unigenes were homologous with proteins of Crassostrea gigas (47.4%) and some were similar to proteins of Aplysia californica (16.7%). Here, we identified 109 homologous unigenes of 15 decided shell matrix proteins, including nacrein, Pif, perlucin, tyrosinase (Tyr), PfN44, PUSP1, chitinase, shell matrix protein, MSI80, fibronectin type III, AmOxCo, perlwapin, BMSP, PfCHS1 and CaLP. Two other mantle transcriptomes of Pinctada margaritifera and Pinctada fucata were also analyzed to perform a biomineralization protein comparison of the three molluscan transcriptomes. All the three compared mollusks shared four proteins, including nacrein, Pif, Tyr and PfCHS1. It was also discovered that Cristaria plicata shared more biomineralization proteins with Pinctada fucata than that with Pinctada margaritifera. Our study explored a whole draft of mantle transcriptome of freshwater mussel and unraveled genes involved in the formation of shell and pearl, making it possible to identify massive novel biomineralization proteins in mollusks. PMID- 27987058 TI - Vitamin D Treatment Attenuates Neuroinflammation and Dopaminergic Neurodegeneration in an Animal Model of Parkinson's Disease, Shifting M1 to M2 Microglia Responses. AB - Microglia-mediated neuroinflammation has been described as a common hallmark of Parkinson's disease (PD) and is believed to further exacerbate the progressive degeneration of dopaminergic neurons. Current therapies are unable to prevent the disease progression. A significant association has been demonstrated between PD and low levels of vitamin D in patients serum, and vitamin D supplement appears to have a beneficial clinical effect. Herein, we investigated whether vitamin D administered orally in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced preclinical animal model of PD protects against glia-mediated inflammation and nigrostriatal neurodegeneration. Vitamin D significantly attenuated the MPTP-induced loss of tyrosine hydrlase (TH)-positive neuronal cells, microglial cell activation (Iba1-immunoreactive), inducible nitric oxide synthase (iNOS) and TLR-4 expression, typical hallmarks of the pro-inflammatory (M1) activation of microglia. Additionally, Vitamin D was able to decrease pro inflammatory cytokines mRNA expression in distinct brain areas of the MPTP mouse. Importantly, we also assessed the anti-inflammatory property of vitamin D in the MPTP mouse, in which it upregulated the anti-inflammatory cytokines (IL-10, IL-4 and TGF-beta) mRNA expression as well as increasing the expression of CD163, CD206 and CD204, typical hallmarks of alternative activation of microglia for anti-inflammatory signalling (M2). Collectively, these results demonstrate that vitamin D exhibits substantial neuroprotective effects in this PD animal model, by attenuating pro-inflammatory and up-regulating anti-inflammatory processes. PMID- 27987059 TI - Melatonin Increases Oligodendrocyte Differentiation in Cultured Neural Stem Cells. AB - Neural stem cell (NSC) culture is a remarkable tool to investigate the potential therapeutic benefits of drugs in neurological diseases. The purpose of this study was to determine the effect of melatonin on proliferation and differentiation of NSCs in vitro. NSCs were isolated and expanded from mouse embryonic E14 cortex, and the effect of various concentrations of melatonin (0.05, 0.1, 0.5, 1, 5 and 10 MUM) on NSC proliferation was assessed by MTT and neurosphere assay. Results showed that melatonin significantly increased NSC viability and NSC proliferation in a dose-dependent manner, in comparison to controls. Similarly, neurosphere formation frequency and cell counts increased significantly with increasing melatonin concentrations and reached its peak at 0.5 MUM, in comparison to controls. Moreover, NSCs treated with either low (0.05 uM) or high concentrations (5 uM) of melatonin showed that the mean percentage of glial fibrillary acidic protein (GFAP) positive cells were not significantly different in PDGF or melatonin at 5 MUM, in comparison to controls. However, low melatonin concentrations (0.05 uM) showed a slight significant increase in comparison to controls and PDGF. On the other hand, both concentrations of melatonin treatment significantly increased the percentage of myelin basic protein (MBP) positive cells (oligodendrocytes), in comparison to controls and to PDGF. Our results demonstrated, for the first time, that melatonin increased oligodendrocyte differentiation from NSCs. These results suggest that melatonin might have a potential therapeutic effect for some neurological diseases that involve oligodendrocyte and myelin pathologies. PMID- 27987060 TI - Omega-3 fatty acids and mood stabilizers alter behavioral and oxidative stress parameters in animals subjected to fenproporex administration. AB - Studies have shown that oxidative stress is involved in the pathophysiology of bipolar disorder (BD). It is suggested that omega-3 (omega3) fatty acids are fundamental to maintaining the functional integrity of the central nervous system. The animal model used in this study displayed fenproporex-induced hyperactivity, a symptom similar to manic BD. Our results showed that the administration of fenproporex, in the prevent treatment protocol, increased lipid peroxidation in the prefrontal cortex (143%), hippocampus (58%) and striatum (181%), and omega3 fatty acids alone prevented this change in the prefrontal cortex and hippocampus, whereas the co-administration of omega3 fatty acids with VPA prevented the lipoperoxidation in all analyzed brain areas, and the co administration of omega3 fatty acids with Li prevented this increase only in the prefrontal cortex and striatum. Moreover, superoxide dismutase (SOD) activity was decreased in the striatum (54%) in the prevention treatment, and the administration of omega3 fatty acids alone or in combination with Li and VPA partially prevented this inhibition. On the other hand, in the reversal treatment protocol, the administration of fenproporex increased carbonyl content in the prefrontal cortex (25%), hippocampus (114%) and striatum (91%), and in prefrontal coxter the administration of omega3 fatty acids alone or in combination with Li and VPA reversed this change, whereas in the hippocampus and striatum only omega3 fatty acids alone or in combination with VPA reversed this effect. Additionally, the administration of fenproporex resulted in a marked increase of TBARS in the hippocampus and striatum, and omega3 fatty acids alone or in combination with Li and VPA reversed this change. Finally, fenproporex administration decreased SOD activity in the prefrontal cortex (85%), hippocampus (52%) and striatum (76%), and the omega3 fatty acids in combination with VPA reversed this change in the prefrontal cortex and striatum, while the co-administration of omega3 fatty acids with Li reversed this inhibition in the hippocampus and striatum. In conclusion, our results support other studies showing the importance of omega3 fatty acids in the brain and the potential for these fatty acids to aid in the treatment of BD. PMID- 27987062 TI - Gaze Following in Children with Autism: Do High Interest Objects Boost Performance? AB - This study tested whether including objects perceived as highly interesting by children with autism during a gaze following task would result in increased first fixation durations on the target objects. It has previously been found that autistic children differentiate less between an object another person attends to and unattended objects in terms of this measure. Less differentiation between attended and unattended objects in ASD as compared to control children was found in a baseline condition, but not in the high interest condition. However, typically developing children differentiated less between attended and unattended objects in the high interest condition than in the baseline condition, possibly reflecting reduced influence of gaze cues on object processing when objects themselves are highly interesting. PMID- 27987061 TI - Management of aggressive growth hormone secreting pituitary adenomas. AB - Aggressive GH-secreting pituitary adenomas (GHPAs) represent an important clinical problem in patients with acromegaly. Surgical therapy, although often the mainstay of treatment for GHPAs, is less effective in aggressive GHPAs due to their invasive and destructive growth patterns, and their proclivity for infrasellar invasion. Medical therapies for GHPAs, including somatostatin analogues and GH receptor antagonists, are becoming increasingly important adjuncts to surgical intervention. Stereotactic radiosurgery serves as an important fallback therapy for tumors that cannot be cured with surgery and medications. Data suggests that patients with aggressive and refractory GHPAs are best treated at dedicated tertiary pituitary centers with multidisciplinary teams of neuroendocrinologists, neurosurgeons, radiation oncologists and other specialists who routinely provide advanced care to GHPA patients. Future research will help clarify the defining features of "aggressive" and "atypical" PAs, likely based on tumor behavior, preoperative imaging characteristics, histopathological characteristics, and molecular markers. PMID- 27987063 TI - Increased Eye Contact During Conversation Compared to Play in Children With Autism. AB - Children with autism have atypical gaze behavior but it is unknown whether gaze differs during distinct types of reciprocal interactions. Typically developing children (N = 20) and children with autism (N = 20) (4-13 years) made similar amounts of eye contact with an examiner during a conversation. Surprisingly, there was minimal eye contact during interactive play in both groups. Gaze behavior was stable across 8 weeks in children with autism (N = 15). Lastly, gaze behavior during conversation but not play was associated with autism social affect severity scores (ADOS CSS SA) and the Social Responsiveness Scale (SRS-2). Together findings suggests that eye contact in typical and atypical development is influenced by subtle changes in context, which has implications for optimizing assessments of social communication skills. PMID- 27987065 TI - Combination of clinical and ECG criteria may increase validity of triage scales. PMID- 27987064 TI - Usefulness of combining admission brain natriuretic peptide (BNP) plus hospital discharge bioelectrical impedance vector analysis (BIVA) in predicting 90 days cardiovascular mortality in patients with acute heart failure. AB - Heart failure is a disease characterized by high prevalence and mortality, and frequent rehospitalizations. The aim of this study is to investigate the prognostic power of combining brain natriuretic peptide (BNP) and congestion status detected by bioelectrical impedance vector analysis (BIVA) in acute heart failure patients. This is an observational, prospective, and a multicentre study. BNP assessment was measured upon hospital arrival, while BIVA analysis was obtained at the time of discharge. Cardiovascular deaths were evaluated at 90 days by a follow up phone call. 292 patients were enrolled. Compared to survivors, BNP was higher in the non-survivors group (mean value 838 vs 515 pg/ml, p < 0.001). At discharge, BIVA shows a statistically significant difference in hydration status between survivors and non-survivors [respectively, hydration index (HI) 85 vs 74, p < 0.001; reactance (Xc) 26.7 vs 37, p < 0.001; resistance (R) 445 vs 503, p < 0.01)]. Discharge BIVA shows a prognostic value in predicting cardiovascular death [HI: area under the curve (AUC) 0.715, 95% confidence interval (95% CI) 0.65-0.76; p < 0.004; Xc: AUC 0.712, 95% CI 0.655 0.76, p < 0.007; R: AUC 0.65, 95% CI 0.29-0.706, p < 0.0247]. The combination of BIVA with BNP gives a greater prognostic power for cardiovascular mortality [combined receiving operating characteristic (ROC): AUC 0.74; 95% CI 0.68-0.79; p < 0.001]. In acute heart failure patients, higher BNP levels upon hospital admission, and congestion detected by BIVA at discharge have a significant predictive value for 90 days cardiovascular mortality. The combined use of admission BNP and BIVA discharge seems to be a useful tool for increasing prognostic power in these patients. PMID- 27987067 TI - Prophylactic antibiotic treatment following laparoscopic robot-assisted radical prostatectomy for the prevention of catheter-associated urinary tract infections: did the AUA guidelines make a difference? AB - We sought to evaluate the effectiveness of the American Urological Association (AUA) antibiotic prophylaxis guidelines in patients undergoing robot-assisted laparoscopic radical prostatectomy (RALP). Our prospective registry database was reviewed for all RALP cases. The following variables were evaluated: age, associated comorbidities, body mass index (BMI), total operative time, length of stay (LOS), prostate weight, pathological grade and stage. Until 11/2011, RALP patients were treated with antibiotics administered in the operating room and continued until urethral catheter removal. Since 11/2011, all patients were treated with a single intravenous dose of Cephalosporin and Aminoglycoside given within 30 min of surgical incision. The rate of catheter-associated urinary tract infection (CAUTI) was evaluated in both groups. 229 RALP patients were identified. The first 60 patients (26.2%) were treated according to the old protocol (Group 1) while the remaining 169 (73.8%) were treated according to the new protocol (Group 2). Group match was identified in all categories but LOS. Moreover, LOS was found to be longer in Group 1 compared with Group 2 (5.8 vs. 4.5 days, p < 0.001). CAUTI rate was similar in both groups (8.3 vs. 8.9%, respectively, p = 0.89). Logistic regression analysis did not demonstrate any association between treatment protocol and potential risk for CAUTI. Therefore, a single preoperative dose of antibiotics does not increase the rate of CAUTI following RALP compared with prolonged antibiotic treatment. Moreover, it was found to be associated with shorter LOS. Complying with the AUA guidelines may reduce morbidity and medical costs. PMID- 27987066 TI - Pediatric Whole Exome Sequencing: an Assessment of Parents' Perceived and Actual Understanding. AB - Whole exome sequencing (WES) is an integral tool in the diagnosis of genetic conditions in pediatric patients, but concerns have been expressed about the complexity of the information and the possibility for secondary findings that need to be conveyed to those deciding about WES. Currently, there is no validated tool to assess parental understanding of WES. We developed and implemented a survey to assess perceived and actual understanding of WES in parents who consented to clinical WES for their child between July 2013 and May 2015. Fifty three eligible surveys were returned (57% response rate). Areas with both low perceived and actual understanding about WES included how genes are analyzed and lack of protection against life insurance discrimination. Parents also had low actual understanding for two questions related to secondary findings - reporting of secondary findings in a parent (if tested) and whether secondary findings can be related to traits such as height and hair color. Further work to develop a validated tool to assess understanding of WES would be beneficial as WES is integrated more frequently into clinical care. PMID- 27987068 TI - Single site robotic-assisted apical lateral suspension (SS R-ALS) for advanced pelvic organ prolapse: first case reported. AB - While single-port laparoscopy for gynecological surgery is technically challenging, the Da Vinci Single-Site(r) robotic surgery platform may help to overcome some of the difficulties of this rapidly evolving technique. The authors of this article present the first case of single-incision, robotic apical lateral suspension (R-ALS) using this device in pelvic organ prolapse (POP) surgery. A 71 year-old female with advanced symptomatic anterior and apical prolapse (POP-Q stage III/III) was operated with a single-site approach using the Da Vinci Single Site(r) robotic surgery device. After docking the robot, the complete surgery was performed by robotic approach; only abdominal sub-peritoneal passages of the lateral arms of the mesh were performed extra-corporeally as described in the canonical surgical technique of R-ALS. The procedure was successfully completed in 155 min. No surgical complications occurred during the intervention and the postoperative stay and no conversion to laparotomy or additional trocars were required. To the best of our knowledge, this is the first case of R-ALS using the Da Vinci Single-Site robotic surgery platform to be reported. The procedure is feasible and safe and its main advantages are reduced instrument clashes and less surgical scars for the patient. Restoration of triangulation and the lack of monopolar scissors are still limits which are partially overcome by the degrees of freedom of robotic instruments. PMID- 27987069 TI - Use of Banana (Musa acuminata Colla AAA) Peel Extract as an Antioxidant Source in Orange Juices. AB - Using banana peel extract as an antioxidant in freshly squeezed orange juices and juices from concentrate was evaluated. Free radical scavenging capacity increased by adding banana peel extracts to both types of orange juice. In addition, remarkable increases in antioxidant capacity using 2,2'-azino-bis-(3 ethylbenzothiazoline)-6-sulfonic acid (ABTS) radical were observed when equal or greater than 5 mg of banana peel extract per ml of freshly squeezed juice was added. No clear effects were observed in the capacity to inhibit lipid peroxidation. Adding 5 mg banana peel extract per ml of orange juice did not substantially modify the physicochemical and sensory characteristics of either type of juice. However, undesirable changes in the sensory characteristics (in mouth sensations and colour) were detected when equal or greater than 10 mg banana peel extract per ml of orange juice was added. These results confirm that banana peel is a promising natural additive that increases the capacity to scavenge free radicals of orange juice with acceptable sensory and physicochemical characteristics for the consumer. PMID- 27987070 TI - Local Radiation Treatment of HER2-Positive Breast Cancer Using Trastuzumab Modified Gold Nanoparticles Labeled with 177Lu. AB - PURPOSE: To compare the effectiveness of trastuzumab-modified gold nanoparticles (AuNP) labeled with 177Lu (trastuzumab-AuNP-177Lu) targeted to HER2 with non targeted AuNP-177Lu for killing HER2-overexpressing breast cancer (BC) cells in vitro and inhibiting tumor growth in vivo following intratumoral (i.t.) injection. METHODS: AuNP (30 nm) were modified with polyethylene glycol (PEG) polymers linked to trastuzumab or to 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid (DOTA) chelators to complex 177Lu. The binding and internalization of trastuzumab-AuNP-177Lu in HER2-positive SK-BR-3, BT-474 and MDA-MB-361 human BC cells were studied. Clonogenic survival and DNA double-strand breaks (DSBs) were measured after exposure of SK-BR-3 or MDA-MB-361 cells to trastuzumab-AuNP-177Lu or AuNP-177Lu. NOD/SCID mice with s.c. MDA-MB-361 tumor xenografts were treated by i.t. injection of 3 MBq (0.15 mg) of trastuzumab-AuNP 177Lu, AuNP-177Lu or normal saline. Tumor growth was measured over 16 days and normal tissue toxicity evaluated. RESULTS: Trastuzumab-AuNP-177Lu was bound and internalized by HER2 positive BC cells (KD = 7.6 +/- 2.0 nM). Trastuzumab-AuNP 177Lu was 42.9 and 2.6-fold more effective than AuNP-177Lu at decreasing the clonogenic survival of SK-BR-3 (1.3 * 106 HER2/cell) and MDA-MB-361 (5.1 * 105 HER2/cell) cells, respectively, exposed overnight to these agents (1.5 nM; 20 MBq/mg Au). Under the same treatment conditions, 10-fold and 2.8-fold more DNA DSBs were observed in SK-BR-3 and MDA-MB-361 cells, respectively, exposed to trastuzumab-AuNP-177Lu than AuNP-177Lu. Trastuzumab-AuNP-177Lu was 1.8-fold more effective at inhibiting tumor growth than AuNP-177Lu. No or minimal normal tissue toxicity was observed for trastuzumab-AuNP-177Lu or AuNP-177Lu treatments. CONCLUSION: Trastuzumab-AuNP-177Lu enables an efficient local radiation treatment of HER2-positive BC. PMID- 27987071 TI - Parasympathetic Nervous System Reactivity Moderates Associations Between Children's Executive Functioning and Social and Academic Competence. AB - This study examined whether children with poor executive functioning (EF) evidenced less social and academic impairments, compared to other children, if they demonstrated adaptive parasympathetic nervous system (PNS) regulation during experiences of failure. Participants with and without clinical elevations in ADHD symptoms (N = 61; 9-13 years; 48% male; 85% Caucasian) were administered a battery of EF tests and completed manipulated social and cognitive failure tasks. While participants completed failure tasks, respiratory sinus arrhythmia reactivity (RSA-R) was measured as an indicator of PNS reactivity. Children's social and academic impairment in daily life was assessed based on parent and teacher report on multiple measures. RSA-R during social failure moderated the association between poor EF and adult-rated social impairment and RSA-R during cognitive failure moderated the association between poor EF and adult-rated academic impairment. Simple effects indicated that poor EF was significantly associated with impairment when children demonstrated RSA activation (increased PNS activity) but not when children demonstrated RSA withdrawal (decreases in PNS activity). Domain-crossed models (e.g., reactivity to social failure predicting academic impairment) were not significant, suggesting that the moderating effect of RSA-R was domain-specific. Results suggest that not all children with poor EF evidence social and academic impairment; RSA withdrawal during experiences of failure may be protective specifically for children with impaired EF skills. PMID- 27987072 TI - The value of electrophysiologic study in decision-making regarding the need for pacemaker implantation after TAVI. AB - PURPOSE: The purpose of this study was to evaluate electrophysiologic study (EPS) in risk stratification of relative indications for pacemaker implantation (PMI) after transcatheter aortic valve implantation (TAVI). METHODS: We reviewed files of all patients who had a left bundle branch block (LBBB) and underwent EPS after TAVI between 3/2009 and 5/2015. The indications for EPS were new-onset LBBB and the presence of an old or a new-onset LBBB associated with either PR prolongation after TAVI (?PR >20 ms) or with "slow" atrial fibrillation (<100/min). Pacemakers were implanted when significant infranodal disease was demonstrated. The control group comprised of 55 consecutive patients who underwent TAVI and had an indication for an EPS per our definitions. These patients were discharged without further intervention. All patients were followed during 1 year for the composite endpoint of mortality or PMI after hospital discharge. RESULTS: Indications for EPS were new LBBB (n = 8, 30.8%), new LBBB + ?PR >20 ms (n = 9, 34.6%), baseline LBBB + ?PR >20 ms (n = 7, 26.9%) and new LBBB + slow AF <100 bpm (n = 2, 7.7%). Multilevel conduction disturbances involving the AV node (n = 19, 73.1%), the His (n = 3, 11.5%), and the infra-His system (n = 4, 15.4%) were found. Post discharge, there were 5 (9%) deaths and 3 (5.5%) PMI in the control group compared to none in the EPS group corresponding to event-free survival of 85 and 100%, respectively (p = 0.04). CONCLUSIONS: Patients with LBBB with or without ?PR >20 ms are at a higher risk of mortality and late PMI at 1-year follow-up. EPS can be used to safely identify patients in whom a PMI is needed. PMID- 27987074 TI - Medical students' perceptions of the patient-centredness of the learning environment. AB - BACKGROUND: Patient-centred care is an important aspect of quality health care. The learning environment may impact medical students' adoption of patient-centred behaviours. METHODS: All medical students at a single institution received an anonymous, modified version of the Communication, Curriculum, and Culture instrument that measures patient-centredness in the training environment along three domains: role modelling, students' experience, and support for patient centred behaviours. We compared domain scores and individual items by class year and gender, and qualitatively analyzed responses to two additional items that asked students to describe experiences that demonstrated varying degrees of patient-centredness. RESULTS: Year 1 and 2 students reported greater patient centredness than year 3 and 4 students in each domain: role modelling (p = 0.03), students' experience (p = <0.001), and support for patient-centred behaviours (p < 0.001). Female students reported less support for patient-centred behaviours compared with male students (p = 0.03). Qualitative analysis revealed that explicit patient-centred curricula and positive role modelling fostered patient centredness. Themes relating to low degrees of patient-centredness included negative role modelling and students being discouraged from being patient centred. CONCLUSIONS: Students' perceptions of the patient-centredness of the learning environment decreased as students progressed through medical school, despite increasing exposure to patients. Qualitative analysis found that explicit patient-centred curricula cultivated patient-centred attitudes. Role modelling impacted student perceptions of patient-centredness within the learning environment. PMID- 27987073 TI - Comparison of Four Protocols to Generate Chondrocyte-Like Cells from Human Induced Pluripotent Stem Cells (hiPSCs). AB - Stem cells (SCs) are a promising approach to regenerative medicine, with the potential to treat numerous orthopedic disorders, including osteo-degenerative diseases. The development of human-induced pluripotent stem cells (hiPSCs) has increased the potential of SCs for new treatments. However, current methods of differentiating hiPSCs into chondrocyte-like cells are suboptimal and better methods are needed. The aim of the present study was to assess four different chondrogenic differentiation protocols to identify the most efficient method of generating hiPSC-derived chondrocytes. For this study, hiPSCs were obtained from primary hu man dermal fibroblasts (PHDFs) and differentiated into chondrocyte like cells using four different protocols: 1) monolayer culture with defined growth factors (GF); 2) embryoid bodies (EBs) in a chondrogenic medium with TGF beta3 cells; 3) EBs in chondrogenic medium conditioned with human chondrocytes (HC-402-05a cell line) and 4) EBs in chondrogenic medium conditioned with human chondrocytes and supplemented with TGF-beta3. The cells obtained through these four protocols were evaluated and compared at the mRNA and protein levels. Although chondrogenic differentiation of hiPSCs was successfully achieved with all of these protocols, the two fastest and most cost-effective methods were the monolayer culture with GFs and the medium conditioned with human chondrocytes. Both of these methods are superior to other available techniques. The main advantage of the conditioned medium is that the technique is relatively simple and inexpensive while the directed method (i.e., monolayer culture with GFs) is faster than any protocol described to date because it is does not require additional steps such as EB formation. PMID- 27987075 TI - The role of assessment in supporting the movement toward patient-centred care. PMID- 27987076 TI - HOP expression is regulated by p53 and RAS and characteristic of a cancer gene signature. AB - The Hsp70/Hsp90 organising protein (HOP) is a co-chaperone essential for client protein transfer from Hsp70 to Hsp90 within the Hsp90 chaperone machine. Although HOP is upregulated in various cancers, there is limited information from in vitro studies on how HOP expression is regulated in cancer. The main objective of this study was to identify the HOP promoter and investigate its activity in cancerous cells. Bioinformatic analysis of the -2500 to +16 bp region of the HOP gene identified a large CpG island and a range of putative cis-elements. Many of the cis-elements were potentially bound by transcription factors which are activated by oncogenic pathways. Luciferase reporter assays demonstrated that the upstream region of the HOP gene contains an active promoter in vitro. Truncation of this region suggested that the core HOP promoter region was -855 to +16 bp. HOP promoter activity was highest in Hs578T, HEK293T and SV40- transformed MEF1 cell lines which expressed mutant or inactive p53. In a mutant p53 background, expression of wild-type p53 led to a reduction in promoter activity, while inhibition of wild-type p53 in HeLa cells increased HOP promoter activity. Additionally, in Hs578T and HEK293T cell lines containing inactive p53, expression of HRAS increased HOP promoter activity. However, HRAS activation of the HOP promoter was inhibited by p53 overexpression. These findings suggest for the first time that HOP expression in cancer may be regulated by both RAS activation and p53 inhibition. Taken together, these data suggest that HOP may be part of the cancer gene signature induced by a combination of mutant p53 and mutated RAS that is associated with cellular transformation. PMID- 27987080 TI - ? PMID- 27987079 TI - Benchmarking the use of blood products in cardiac surgery to stimulate awareness of transfusion behaviour : Results from a four-year longitudinal study. AB - INTRODUCTION: Cardiac operations account for a large proportion of the blood transfusions given each year, leading to high costs and an increased risk to patient safety. Therefore, it is important to explore initiatives to reduce transfusion rates. This study aims to provide a benchmark for transfusion practice by inter-hospital comparison of transfusion rates, blood product use and costs related to patients undergoing coronary artery bypass grafting (CABG), valve surgery or combined CABG and valve surgery. METHODS: Between 2010 and 2013, patients from four Dutch hospitals undergoing CABG, valve surgery or combined CABG and valve surgery (n = 11,150) were included by means of a retrospective longitudinal study design. RESULTS: In CABG surgery the transfusion rate ranged between 43 and 54%, in valve surgery between 54 and 67%, and in combined CABG and valve surgery between 80 and 88%. With the exception of one hospital, the trend in transfusion rate showed a significant decrease over time for all procedures. Hospitals differed significantly in the units of blood products given to each patient, and in the use of specific transfused combinations of blood products, such as red blood cells (RBCs) and a combination of RBCs, fresh frozen plasma (FFP) and platelets. CONCLUSION: This study indicates that benchmarking blood product usage stimulates awareness of transfusion behaviour, which may lead to better patient safety and lower costs. Further studies are warranted to improve awareness of transfusion behaviour and increase the standardisation of transfusion practice in cardiac surgery. PMID- 27987081 TI - [Do questionnaires for the assessment of change really assess change?] AB - PROBLEM: Two methods for the assessment of change are evaluated: (1) subjects' ratings of the outcome taken after termination of the treatment, and (2) comparison of test scores taken before the beginning and after termination of the treatment. METHODS: Included in the analysis are 82 subjects with chronic headache and/or back pain who participated in psychological group treatment for pain. They were given an outcome rating scale with 15 items (ORS) after therapy in addition to pain diaries and questionnaires for the assessment of physical symptoms, mood and quality of life. Diaries and questionnaires were filled in twice, before and after therapy. RESULTS: The ORS demonstrates satisfying psychometric properties. Internal consistency is 0.94 (Cronbach's alpha) and retest reliability is 0.74. Correlations of this scale with outcome criteria based on pre-post comparisons, however, are mostly nonsignificant. Significant correlations are found when the ORS scores are related to the questionnaire scores after therapy. CONCLUSION: It is concluded that, contrary to the formulation of the items, the ORS scale does not so much assess change, but rather depicts the state of the subjects at the time the assessment is made. PMID- 27987082 TI - ? PMID- 27987078 TI - Heterogeneous Diagnoses Underlying Radial Ray Anomalies. AB - OBJECTIVE: To review perinatal Radial Ray Anomaly (RRA) cases born at the National Institute of Perinatology, Mexico, and to reveal the heterogeneous diagnoses of these patients. METHODS: All patients with RRA over a 18 mo period were included; 4/15 were detected prenatally and 11/15 postnatally. Karyotype was performed for all patients with bilateral RRA; and chromosomal breakage analysis, when the karyotype was normal. RESULTS: Fifteen RRA patients were identified: one with trisomy 18, three with an isolated defect, six with monogenic disease, four with a genetic association and one with diabetic embryopathy. Five were stillborn and two died during the early neonatal period; all of whom presented with multiple defects. Three of the live born patients and one stillborn with multiple defects had Fanconi anemia. RRAs carry a high perinatal mortality rate (47%) when they occur in association with other defects. CONCLUSIONS: The assessment of these patients needs to involve the combined use of ultrasound, clinical, genetic, cytogenetic and molecular testing. The present results indicate that the chromosome breakage test should always be performed to rule out Fanconi anemia in this group. PMID- 27987077 TI - Graves' orbitopathy, idiopathic orbital inflammatory pseudotumor and Epstein-Barr virus infection: a serological and molecular study. AB - OBJECTIVE: One of the hypotheses on the pathogenesis of autoimmune diseases, including Graves' disease (GD) and Graves' orbitopathy (GO), involves bacterial or viral infections. Recently, Epstein-Barr virus (EBV) has been proposed to play a role in the pathogenesis of idiopathic orbital inflammatory pseudotumor (IOIP) in Asians. The aim of the present study was to investigate the possible association of GO with EBV infection/exposure, as compared with IOIP, using serum and tissue samples, as well as primary cultures of orbital fibroblasts. METHODS: Thirty-one patients were studied, including four with IOIP, ten with GO, nine with GD without GO and eight control patients without IOIP, GD and GO. All patients with IOIP and GO underwent orbital decompression. Control patients underwent palpebral surgery. Fibroadipose orbital tissue samples were collected. Serum anti-EBV antibodies were measured in all patients. EBV-DNA was measured in blood samples, orbital tissue samples and primary cultures of orbital fibroblasts. RESULTS: Serum assays showed that the vast majority of patients have had a previous exposure to EBV, but no one had an acute infection. EBV-DNA was detected in ~40% of blood samples from GO, GD and control patients, but in none of the IOIP samples. EBV-DNA was not detected in any of the orbital tissue samples tested or in primary cultures of orbital fibroblasts. CONCLUSIONS: EBV infection does not seem to be associated with GD, GO and IOIP in Caucasians. Whether EBV is involved in IOIP in Asians or other populations remains to be confirmed. PMID- 27987084 TI - Introduction to the Special Section: The Puzzle of Sexual Orientation: What Is It and How Does It Work? PMID- 27987087 TI - The Dual Role of Media Internalization in Adolescent Sexual Behavior. AB - Sexualizing media content is prevalent in various media types. Sexualizing media messages and portrayals emphasize unattainable body and appearance ideals as the primary components of sexual desirability. The internalization of these ideals is positively related to self-objectification and sexual body consciousness. In turn, self-objectification and sexual body consciousness affect adolescents' sexual behavior, albeit in opposing directions. While objectifying self perceptions are linked to higher levels of sexual behavior, body consciousness during physical intimacy is linked to lower levels of sexual behavior. Based on this knowledge, the present three-wave panel study of 824 Belgian, predominant heterosexual adolescents (M age = 15.33; SD = 1.45) proposes a dual-pathway model that investigates two different pathways through which the internalization of media ideals may impact adolescents' sexual behavior. An inhibitory pathway links media internalization to lower levels of sexual behavior through sexual body consciousness, and a supportive pathway links media internalization to higher levels of sexual behavior through self-objectification. Structural equation analyses supported the proposed dual-pathway, showing that the impact of media internalization on adolescents' sexual behavior proceeds through an inhibitory pathway and a supportive pathway. Regarding the supportive pathway, media internalization (W1) positively predicted sexual behavior (W3), through valuing appearance over competence (W2). Regarding the inhibitory pathway, media internalization (W1) positively predicted body surveillance, which, in turn, positively predicted sexual body consciousness (all W2). Sexual body consciousness (W2) is negatively related to sexual behavior (W3). From a sexual developmental perspective, these findings emphasize the importance of guiding adolescents in interpreting and processing sexualizing media messages. PMID- 27987085 TI - Preferences for Condomless Sex in Sexually Explicit Media Among Black/African American Men Who Have Sex with Men: Implications for HIV Prevention. AB - Accumulating evidence suggests that viewing sexually explicit media (SEM; i.e., pornography) may be related to the sexual behaviors of men who have sex with men (MSM). Furthermore, stereotypical depictions of Black/African American MSM engaging in sexual risk behaviors in SEM may serve to normalize condomless sex, reinforce low peer norms around condom use, and facilitate HIV risk taking among Black/African American MSM. Despite this evidence, very little is known about the correlates of SEM consumption among Black/African American MSM, including HIV risk behaviors and their relation to preferences for viewing condomless sex in SEM. Participants were 653 HIV-seronegative Black-identified MSM ages 18-62 (M 33.58, SD 11.01) who completed a cross-sectional survey as a part of a HIV prevention trial in Atlanta, Georgia. Over three-quarters of the men (n = 514) reported a preference for condomless sex in SEM. In multivariate models, engaging in serodiscordant condomless sex was not significantly associated with preferences for condomless sex in SEM; however, men who self-identified as bisexual, engaged in transactional sex, and reported greater agreement with sexual risk cognitions (i.e., heat-of-the-moment thoughts about condom use) had significantly greater odds of reporting a preference for condomless sex in SEM. Study findings highlight the need for future research exploring the role of SEM in the sexual health of Black/African American MSM, including the extent to which SEM exposure alters norms and expectations about sexual behaviors among Black/African American MSM and how this might be addressed in HIV prevention programs. PMID- 27987086 TI - A Latent Class Analysis of Seroadaptation Among Gay and Bisexual Men. AB - Initial research into seroadaptive strategies suggests that, individually, they are potentially effective behavioral methods to reduce risk of HIV transmission. Combining strategies, therefore, has the potential to increase risk reduction. The aim of this study was to determine how gay and bisexual men (GBM) combine strategies. To this end, a total of 774 sexually active GBM, aged >=16 years, in Metro Vancouver, Canada, were recruited. Grouped by self-reported HIV status, latent class analysis of self-reported condom use, strategic positioning, anal sex avoidance, serosorting, viral-load sorting, and withdrawal were conducted. Multinomial logistical regression identified explanatory variables of class membership (i.e., sensation seeking, treatment optimism, sexual altruism, relationship status, number of partners, anal sex preference). Four latent classes were identified: Condom Users, Multiple Prevention Users, Viral-Load Sorters, and Serosorters. The majority of HIV-negative/unknown men (72 %) and a large proportion of HIV-positive men (42 %) belonged to the Condom Users class. Class membership was associated with age, relationship status, treatment optimism, sexual altruism, sensation seeking, number of recent male anal sex partners, and recent condomless anal sex with a serodiscordant or unknown-status partner. Understanding these distinct patterns allows for tailored interventions addressing GBM's sexual health needs. PMID- 27987088 TI - Elevated Kin-Directed Altruism Emerges in Childhood and Is Linked to Feminine Gender Expression in Samoan Fa'afafine: A Retrospective Study. AB - Androphilia refers to sexual attraction toward adult males, whereas gynephilia refers to sexual attraction toward adult females. The kin selection hypothesis posits that androphilic males help kin increase their reproductive output via kin directed altruism, thus offsetting their own lowered reproduction and contributing to the fitness of genes underpinning male androphilia. Support for this hypothesis has been garnered in several Samoan studies showing that feminine androphilic males (known locally as fa'afafine) report elevated willingness to invest in nieces and nephews in adulthood. Also, recalled childhood kin attachment and concern for kin's well-being are elevated among Canadian androphilic males (i.e., gay men) and positively associated with childhood feminine gender expression. This study examined whether these childhood patterns were cross-culturally consistent and associated with adulthood kin-directed altruism in a Samoan sample. Samoan gynephilic men, androphilic women, and fa'afafine (N = 470) completed measures of recalled childhood kin attachment and concern for the well-being of kin, recalled childhood gender expression, and willingness in adulthood to invest in nieces and nephews. Fa'afafine recalled elevated anxiety due to separation from kin relative to men and elevated concern for kin's well-being relative to both men and women. Within groups, these characteristics were most robustly associated with childhood feminine gender expression and willingness in adulthood to invest in nieces and nephews among fa'afafine. These findings are consistent with the kin selection hypothesis and the adaptive feminine phenotype model, which proposes that a disposition toward elevated kin-directed altruism among androphilic males is associated with feminine gender expression. PMID- 27987089 TI - National survey of pediatric hospitalizations due to Kawasaki disease and coronary artery aneurysms in the USA. AB - Several studies revealed the epidemiology of Kawasaki disease-related hospitalizations among children in the USA and other countries. However, disparities of developing coronary artery aneurysms by race/ethnicity, patient socioeconomic status, and geographic locations remain unknown in the USA. Hospital discharge record data of patients with Kawasaki disease aged 19 years or younger were obtained from the 2003, 2006, 2009, and 2012 Kid's Inpatient Database. The data were weighted to estimate the annual hospitalization rates with respect to age, gender, and race/ethnicity in the USA. Multivariable logistic regression was conducted to ascertain the factors associated with the development of coronary artery aneurysms. Total annual hospitalization rates of Kawasaki disease showed a decreasing trend, ranging from 6.54 per 100,000 children in 2003 to 6.11 per 100,000 children in 2012 (p < 0.001). The proportions of coronary artery aneurysms among patients with Kawasaki disease ranged from 2.25 to 3.20%. Factor associated with the development of coronary artery aneurysms was hospitals in West (OR 2.15, 95% CI 1.42-3.26). Race/ethnicity, health insurance status, and household income were not associated with the development of coronary artery aneurysms. Total hospitalization rates of Kawasaki disease showed a decreasing trend. Children admitted to hospitals in West region were more likely to develop coronary artery aneurysms. PMID- 27987090 TI - Enhanced succinic acid production under acidic conditions by introduction of glutamate decarboxylase system in E. coli AFP111. AB - Biological synthesis of succinic acid at low pH values was favored since it not only decreased investment cost but also simplified downstream purification process. In this study, the feasibility of using glutamate decarboxylase system to improve succinic acid production of Escherichia coli AFP111, a succinate producing candidate with mutations in pfl, ldhA, and ptsG, under acidic conditions was investigated. By overexpressing gadBC operon in AFP111, a recombinant named as BA201 (AFP111/pMD19T-gadBC) was constructed. Fermentation at pH 5.6 showed that 30 g L-1 glucose was consumed and 26.58 g L-1 succinic acid was produced by BA201, which was 1.22- and 1.32-fold higher than that by the control BA200 (AFP111/pMD19T) containing the empty vector. Analysis of intracellular enzymes activities and ATP concentrations revealed that the activities of key enzymes involved in glucose uptake and products synthesis and intracellular ATP levels were all increased after overexpression of gadBC which were benefit for cell metabolism under weak acidic conditions. To further improve the succinic acid titer by recombinant BA201 at pH 5.6, the extracellular glutamate concentration was optimized and the final succinic acid titer increased 20.4% to 32.01 g L-1. Besides, the fermentation time was prolonged by repetitive fermentation and additional 15.78 g L-1 succinic acid was produced by recovering cells into fresh medium. The results here demonstrated a potential strategy of overexpressing gadBC for increased succinic acid production of E. coli AFP111 under weak acidic conditions. PMID- 27987091 TI - Structured model and parameter estimation in plant cell cultures of Thevetia peruviana. AB - In this work, a mechanistic model for predicting the dynamic behavior of extracellular and intracellular nutrients, biomass production, and the main metabolites involved in the central carbon metabolism in plant cell cultures of Thevetia peruviana is presented. The proposed model is the first mechanistic model implemented for plant cell cultures of this species, and includes 28 metabolites, 33 metabolic reactions, and 61 parameters. Given the over parametrization of the model, its nonlinear nature and the strong correlation among the effects of the parameters, a parameter estimation routine based on identifiability analysis was implemented. This routine reduces the parameter's search space by selecting the most sensitive and linearly independent parameters. Results have shown that only 19 parameters are identifiable. Finally, the model was used for analyzing the fluxes distribution in plant cell cultures of T. peruviana. This analysis shows high uptake of phosphates and parallel uptake of glucose and fructose. Furthermore, it has pointed out the main central carbon metabolism routes for promoting biomass production in this cell culture. PMID- 27987092 TI - Design and analysis of flow velocity distribution inside a raceway pond using computational fluid dynamics. AB - Open raceway ponds are widely adopted for cultivating microalgae on a large scale. Working depth of the raceway pond is the major component to be analysed for increasing the volume to surface area ratio. The working depth is limited up to 5-15 cm in conventional ponds but in this analysis working depth of raceway pond is considered as 25 cm. In this work, positioning of the paddle wheel is analysed and corresponding Vertical Mixing Index are calculated using CFD. Flow pattern along the length of the raceway pond, at three different paddle wheel speeds are analysed for L/W ratio of 6, 8 and 10, respectively. Effect of clearance (C) between rotor blade tip and bottom surface is also analysed by taking four clearance conditions i.e. C = 2, 5, 10 and 15. Moving reference frame method of Fluent is used for the modeling of six blade paddle wheel and realizable k-epsilon model is used for capturing turbulence characteristics. Overall objective of this work is to analyse the required geometry for maintaining a minimum flow velocity to avoid settling of algae corresponding to 25 cm working depth. Geometry given in [13] is designed using ANSYS Design modular and CFD results are generated using ANSYS FLUENT for the purpose of validation. Good agreement of results is observed between CFD and experimental Particle image velocimetry results with the deviation of 7.23%. PMID- 27987093 TI - Quality of life of older African American breast cancer survivors: a population based study. AB - INTRODUCTION: Factors associated with lower health-related quality of life (HRQOL) among older African American (AA) breast cancer survivors (BCS) have not been elucidated. METHODS: Using the Surveillance, Epidemiology, and End Results Medicare Health Outcome Survey linked dataset, all resected AA BCS over 65 were identified. Using the most recent survey after diagnosis, individuals with a VR12 physical (PCS) or mental (MCS) component score 10 points lower than the median were categorized as having poor HRQOL. Univariate and multivariate (MV) analyses identified predictors of poor HRQOL. RESULTS: Of 373 AA BCS (median age 74.6), median time from diagnosis to survey was 68.4 months with median follow-up of 138.6 months. Median PCS was 35.9 (IQR 28.5-44.5) with 76 (20.1%) reporting poor PCS. Median MCS was 50.6 (IQR 41.3-59.1) with 101 (27.1%) reporting poor MCS. Predictors of poor PCS included advanced age, larger tumor size, >=2 comorbidities, inability to perform >2 of 6 activities of daily living (ADLs), modified/radical mastectomy, infiltrating lobular carcinoma, and stage III or IV disease (all p < 0.05). Comorbidities >=2 and inability to perform >2 of 6 ADLs (p < 0.05) predicted poor MCS. Inability to perform >2 of 6 ADLs was the only independent predictor of poor PCS (OR 10.9, 95% CI 3.0-39.3; p < 0.001) and MCS (OR 7.6, 95% CI 4.3-13.3; p < 0.001). CONCLUSION: In elderly AA BCS, poor HRQOL was not associated with socioeconomic status or tumor-specific factors but rather impairment in ADLs. Physical and mental HRQOL in African American breast cancer survivors is not dependent on socioeconomic or tumor-related characteristics, but rather on inability to perform ADLs. PMID- 27987095 TI - Letter to the editor-chronic disseminated candidiasis. PMID- 27987094 TI - Role of benzydamine hydrochloride in the prevention of oral mucositis in head and neck cancer patients treated with radiotherapy (>50 Gy) with or without chemotherapy. AB - PURPOSE: Benzydamine is recommended for prophylaxis of oral mucositis (OM) in head and neck cancer (HNC) patients for radiation doses (<50 Gy). This study evaluates role of benzydamine for higher radiation doses (>50 Gy) with or without chemotherapy. METHODS: One hundred twenty patients of HNC with planned radiation doses of >=60 Gy were randomized to group A (control radiotherapy alone), group B (study radiotherapy alone), group C (control chemoradiotherapy), or to group D (study chemoradiotherapy). Groups A and C were advised saline mouth rinses, and in groups B and D, additional benzydamine rinses (0.15%) were advised. Mucositis grading was done with both WHO (WHO-M) and CTCAE (CTC-M) version 4.0 (common terminology criteria for adverse events) weekly. RESULTS: Patient characteristics are presented in the table. Patients in group B had lesser grade 3 WHO-M and CTC M as compared to group A, 62.1 vs. 36.4% (p = 0.038) and 51.7 vs. 27.3% (p = 0.043), respectively. The rates of Ryle's tube feeding (RTF), intravenous fluid supplementation (IVF), and hospitalization were also lesser in group B as compared to A, 34.5 vs. 21.2% (p = 0.18), 27.6 vs. 9.1% (p = 0.06), and 6.9 vs. 0% (p = 0.21), respectively. WHO-M and CTC-M in groups C and D were not statistically different, 64.3 vs. 43.3% (p = 0.091) and 53.6% vs. 43.3% (p = 0.30), respectively. The rates of RTF, IVF, and hospitalization were all lesser but p > 0.05. CONCLUSION: Benzydamine significantly reduces OM even at doses >50 Gy in HNC patients. Its role in patients receiving concurrent chemotherapy further needs to be evaluated. PMID- 27987096 TI - Associations between dyadic coping and supportive care needs: findings from a study with hematologic cancer patients and their partners. AB - PURPOSE: The way couples mutually cope with hematologic cancer is likely to influence their levels of supportive care needs (SCN). Therefore, this study evaluated the levels of dyadic coping (DC) and SCN and the concurrent associations between both variables. METHODS: Three hundred thirty patients with a hematologic malignancy (63% male) and their partners completed the dyadic coping inventory (DCI) and the supportive care needs survey (SCNS-SF-34-G). The levels of dyadic coping (DC) and supportive care needs (SCN) were compared with representative validation samples. Correlational analyses and actor-partner interdependence models (APIM) were calculated to estimate the association between DC and SCN. RESULTS: Partners' stress communication of cancer patients (as part of DC) was decreased in contrast to that of a non-cancer sample. The perception of partners' delegated DC was higher (both with a moderate effect size of g >= |0.50|). SCN of patients and partners were lower in the dimensions health system/information and physical problems/daily living in contrast to those of a cancer patients' validation sample (both with a small effect of g >= |0.20|). Higher perceptions of partners' negative DC were associated with higher SCN for both patients and partners. The same was true for patients' own stress communication and SCN, but only for the patients. Sociodemographic and illness related factors were only partially related with the SCN of patients and partners. CONCLUSIONS: In order to diminish SCN of patients and partners, a possible way is to strengthen the quality of the dyadic relation. Due to its associations with elevated SCN, stress communication and negative dyadic coping behaviours may be useful targets for psychosocial interventions. PMID- 27987097 TI - Radiation-induced rectovaginal fistulas in locally advanced gynaecological malignancies-new patients, old problem? AB - PURPOSE: Radiation-induced rectovaginal fistula (RI-RVF) is a chronic and serious condition with a significant influence on quality of life. The aim of this study is to evaluate the results of surgical treatment of rectovaginal fistulas of patients previously undergoing radiotherapy. METHODS: Fifty patients treated in the Gynaecological Radiotherapy Unit for gynaecologic malignancy and in the Department of General and Colorectal Surgery for RI-RVF between 2003 and 2013 were enrolled into a prospectively maintained database and underwent regular follow-up examinations in an outpatient clinic, during which surgical outcomes were assessed. RESULTS: Median age was 60 years (range 40-84 years). Cervical cancer was the most common cause of radiotherapy. Median time of fistula development after radiotherapy was 20 months (range 5-240 months). In 48 (96%) patients, only faecal diversion could be performed, while two patients underwent rectal resection. The fistula healed in six patients. Factors that correlated with fistula healing were a distance from the anal verge above 7 cm (p = 0.007 OR 18 95%CI 2.2609-14.3062) and creation of loop ileostomy (p = 0.08 OR 17 95%CI 1.2818-23.9701), whereas a prolonged course of radiotherapy of more than 6 weeks (p = 0.047) correlated negatively. In multivariate analysis, only distance from the anal verge remained significant (p = 0.031 OR 2.35 95%CI 1.0422-5.2924). CONCLUSIONS: The treatment of radiation-induced rectovaginal fistulas needs to be tailored individually to each patient. Faecal diversion remains the simplest and safest method of treating RI-RVF, especially in the group of patients who cannot undergo complicated surgical procedures, and offers acceptable quality of life. PMID- 27987098 TI - A surgical department for intensified care. AB - PURPOSE: The growing pressure to rationalize costs in the healthcare system demands the development of new healthcare models aimed at allowing patients to receive the best treatment, without ignoring the rising costs. METHODS: In the Healthcare Unit 2 located in the Abruzzo region in Italy, a new model of intensified care surgical department was designed in January 2013. The department was based on the selection of the degree of patient disease. Patients requiring a medium-low degree surgery were treated in the peripheral unit, in the Ortona hospital, while more complex surgical procedures, most cancer cases (including stomach, liver, pancreas, colon-rectum or multi-organ resections), were performed in the central unit in the Chieti hospital. RESULTS: The value of production at the peripheral unit, in Ortona, increased by 299.4% along with an increase in discharges of 112.6%, with an average DRG weight from 1.02 to 1.45. At the central unit, in Chieti, the average DRG weight produced was 3.328. In relation to quality assessment, pancreatic surgery morbidity was 27.0% and mortality was 1.7 % due to resection and 2.2% for other causes. Likewise, for colon-rectal surgery, a global morbidity of 35.0% and anastomotic leakage of 3.9% was seen. CONCLUSIONS: The 24-month preliminary results show that new models of intensified care surgical departments can be created. In addition, results clearly show that such model significantly improves both services and surgical results. This original model allows optimal use of resources favouring both service quality and patient satisfaction. PMID- 27987099 TI - The feasibility of laparoscopic pancreaticoduodenectomy-a stepwise procedure and learning curve. AB - BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD) has been proven feasible and safe. The artery-first approach emerged as a standard procedure in pancreatic surgery. In this manuscript, we describe both our stepwise, artery-first technique for LPD and methods for accumulating experience during the initial learning stage. METHOD: This is a retrospective review of 12 patients who underwent LPD between 2012 and 2015. We classified the first five patients as the early group and the remaining seven as the late group. Here, we present our stepwise procedure for LPD, along with the perioperative results and postoperative prognoses for the two groups. RESULTS: The mean operative time for the 12 patients undergoing LPD was 408.3 +/- 97.5 min. The average blood loss was 146.7 +/- 90.2 mL. The dissection time (TD) was significantly shorter in the late group compared with the early group (140 vs. 200 min, respectively; p = 0.006). However, there was no difference in the reconstruction time (TR) between the two groups (220 vs. 200 min; p = 0.807). CONCLUSION: Artery-first LPD is a feasible procedure for selected patients and has acceptable results. Using this stepwise procedure, the operative time could be reduced, mainly by reducing the time required for dissection. PMID- 27987100 TI - Non-local fluctuation phenomena in liquids. AB - Fluids in non-equilibrium steady states exhibit long-range fluctuations which extend over the entire system. They can be described by non-equilibrium thermodynamics and fluctuating hydrodynamics that assume local equilibrium for the thermophysical properties as a function of space and time. The experimental evidence for the consistency between this assumption of local equilibrium in the equations and the non-local fluctuation phenomena observed is reviewed. PMID- 27987101 TI - Systemic air embolism during pleural lavage for empyema. AB - Pleural lavage has been considered a convenient and safe method that is often performed for empyema. We report a case of systemic air embolism that developed during pleural lavage. A 53-year-old man with empyema in the organizing phase suddenly developed paralysis of the left side of the body and altered level of consciousness during pleural lavage, which was performed in a sitting position without negative pressure suction. Systemic air embolism was diagnosed based on computed tomography. In this case, use of fibrinolytic agents, positioning during pleural lavage, and pressure in an empyema cavity may have predisposed to development of systemic air embolism. Conversion from thoracoscopic therapy to open decortication or fenestration should be considered to prevent this type of complication. PMID- 27987103 TI - Changes in the Spectral Features of Zinc Phthalocyanine Induced by Nitrogen Dioxide Gas in Solution and in Solid Polymer Nanofiber Media. AB - The changes in the spectral features of zinc phthalocyanine in the visible domain as a result of its interaction with nitrogen dioxide gas were assessed in this work. This was done both in solution and when the phthalocyanine was incorporated into a solid polystyrene polymer nanofiber matrix. The spectral changes were found to be spontaneous and marked in both cases suggesting a rapid response criterion for the detection of the gas. In particular, the functionalised nano fabric material could serve as a practical fire alarm system as it rapidly detects the nitrogen dioxide gas generated during burning. PMID- 27987102 TI - Characteristics of mesenteric lymphadenitis in comparison with those of acute appendicitis in children. AB - : Mesenteric lymphadenitis (ML) is considered as one of the most common alternative diagnosis in a child with suspected acute appendicitis (AA). In this retrospective study, patients diagnosed with ML (n = 99) were compared in terms of demographic, clinical, and laboratory findings to patients diagnosed with AA (n = 102). This comparison was applied for both lymph nodes smaller and larger than 10 mm. When compared to patients with AA, patients with ML had significantly longer duration of symptoms prior to emergency department (ED) presentation (2.4 +/- 2.6 vs 1.4 +/- 1.4 days, P = 0.002) and multiple ED presentations (1.3 +/- 0.7 vs 1.05 +/- 0.3, P < 0.001) and had longer duration of stay in the ED (9.2 +/ 5.9 vs 5.2 +/- 4 h, P < 0.001), respectively. They also had significantly lower WBC (10.16 +/- 4.7 * 103/dl vs 15.8 +/- 4.4 * 103/dl, P < 0.001) with lymphocyte predominance (24.6 +/- 14 vs 13 +/- 8.7%, P < 0.001) and lower CRP levels (0.48 vs 1.6 mg/dl). Migration of pain (28 vs 7%), vomiting (62 vs 34%), and classic abdominal findings of AA (72 vs 20%) were all significantly more common for children with AA. When comparing lymph node size, no significant difference was found between those presenting with small and large nodes. CONCLUSION: This study highlights multiple clinical and laboratory findings that differentiate ML and AA. Moreover, the absence of any difference with regard to the lymph nodes size might suggest that lymph nodes enlargement is a non-specific finding. What is Known : * Mesenteric lymphadenitis is a very common diagnosis in children with suspected acute appendicitis. * Despite its prevalence, only few studies addressed the clinical characteristics of this clinical entity and their comparison with acute appendicitis. What is New: * Mesenteric lymphadenitis and acute appendicitis could be differentiated by multiple clinical and laboratory parameters. * No significant difference was found between those presenting with small and large lymph nodes. PMID- 27987105 TI - A Statewide Quality Improvement Initiative to Reduce Non-Medically Indicated Scheduled Deliveries. AB - Objectives To evaluate a large two-phase, statewide quality improvement (QI) collaborative to decrease non-medically indicated (N-MI) deliveries scheduled between 36 and 38 weeks gestation (early). Methods The New York State Department of Health (NYSDOH) convened a Perinatal Quality Collaborative to devise a two phase QI initiative using a rapid cycle incremental learning model. Phase 1 included Regional Perinatal Centers (RPCs), and Phase 2 added their affiliated perinatal hospitals. Maternal demographics, delivery characteristics, medical indications, and stillbirths were collected on scheduled inductions and cesarean section (CS) deliveries between 36 and 38 weeks. Results There were 35,091 scheduled 36-38 week deliveries reported during the collaborative's 4 years. The percentage of early N-MI scheduled deliveries decreased 41-fold in RPCs (Phase 1 and Phase 2), and 17-fold in affiliates (Phase 2). There was a significant statewide increase in deliveries at >=39 weeks (P < 0.001), with an estimated 23,732 early deliveries averted. Stillbirths did not increase over time (P = 0.42), although reporting was incomplete. Conclusions A two-phase, statewide QI collaborative in a large state with regionalized perinatal care effectively lowered the number of N-MI deliveries scheduled between 36 and 38 weeks gestation. Associated improvements in neonatal and early childhood developmental outcomes should translate to significant cost savings. This model can effectively be used for similar as well as other obstetrical QI. PMID- 27987104 TI - Phenylephrine increases near-infrared spectroscopy determined muscle oxygenation in men. AB - Phenylephrine increases mean arterial pressure (MAP) by enhanced total peripheral resistance (TPR) but near-infrared spectroscopy (NIRS) determined muscle oxygenation (SmO2) increases. We addressed that apparent paradox during supine rest and head-up tilt (HUT). Variables were determined +/- phenylephrine in males during supine rest (n = 17) and 40 degrees HUT (n = 7). MAP, stroke volume (SV), heart rate (HR), and TPR were derived by Modelflow(r) and NIRS determined biceps SmO2 and (tibial) bone oxygenation (StibialO2). For ten subjects, cardiac filling and the diameter of the inferior caval vein (ICV collapsibility index: ((ICVexpiration - ICVinspiration)/ICVexpiration) * 100) were assessed by ultrasound. Pancreatic polypeptide (PP) and atrial natriuretic peptide (proANP) in plasma were determined by immunoassay. Brachial artery blood flow was assessed by ultrasound and skin oxygenation (SskinO2) monitored by white light spectroscopy. Phenylephrine increased MAP by 34% and TPR (62%; P < 0.001) during supine rest. The ICV collapsibility index decreased (24%; P < 0.001) indicating augmented cardiac preload although volume of the left atrium and ventricle did not change. SV increased (18%; P < 0.001) as HR decreased (24%; P < 0.001). ProANP increased by 9% (P = 0.002) with unaffected PP. Brachial artery blood flow tended to decrease while SskinO2 together with StibialO2 decreased by 11% (P = 0.026) and 20% (P < 0.001), respectively. Conversely, phenylephrine increased SmO2 (9%) and restored the HUT elicited decrease in SmO2 (by 19%) along with SV (P = 0.02). Phenylephrine reduces skin and bone oxygenation and tends to reduce arm blood flow, suggesting that the increase in SmO2 reflects veno-constriction with consequent centralization of the blood volume. PMID- 27987107 TI - Simulation of NMR chemical shifts in heterocycles: a method evaluation. AB - An alternative approach to evaluating the performance of computational methods for predicting chemical shifts is presented. The influence of the theoretical level and basis set on the accuracy in calculating both proton and carbon NMR spectra of a large number of heterocyclic molecules is assessed using a linear regression method, thus omitting the need for a reference (as a potential source of error). The best theoretical levels employed herein (GIAO-PBE0/6 31G(d)//omegaB97xD/6-31G(d) or GIAO-omegaB97xD/6-31G(d)//omegaB97xD/6-31G(d)) approach the accuracy of the most elaborate benchmark-quality calculations. One interesting observation is an unexplained distortion of the derived chemical shifts when an internal reference is used: It leads to larger relative shifts and deviations when the "quality" (size) of the basis set employed is increased. This effect can be corrected by using simple linear regression, but a lack of a systematic correlation between the quality of the basis set and the accuracy of the calculated shifts can still be observed; in fact, very good results can be achieved with modest basis sets. Although the general reliability of this approach needs to be evaluated for other theoretical levels and other substance classes, the abovementioned levels of theory appear robust enough for wider applicability. Graphical Abstract Correlation between computed chemical shieldings and experimental chemical shifts for various heterocyclic compounds. PMID- 27987106 TI - Congruence between polysomnography obstructive sleep apnea and the pediatric sleep questionnaire: fatigue and health-related quality of life in juvenile idiopathic arthritis. AB - PURPOSE: To examine the congruence between polysomnography obstructive apnea hypopnea index (OAHI) and parent-reported obstructive sleep apnea (OSA) symptoms in 6- to 11-year-old children with juvenile idiopathic arthritis (JIA) and controls; and to compare fatigue and quality of life in JIA and control children based on OAHI and OSA symptoms. METHODS: Sixty-eight children with JIA and 75 controls and a parent participated. Children underwent one night of polysomnography in a sleep laboratory. Parents completed the sleep-related breathing disorders scale-pediatric sleep questionnaire (PSQ), and both children and parents completed the Pediatric Quality of Life Generic Core Scale and the Multidimensional Fatigue Scale. RESULTS: In JIA, 86% who met the OAHI clinical criteria for OSA (>=1.5) were above the PSQ OSA symptom cut-off score with a sensitivity of 0.86 and a specificity of 0.28. In the control group, 63% who met the OAHI clinical criteria for OSA were above the PSQ OSA symptom cut-off score, with a sensitivity of 0.63 and a specificity of 0.42. All children above both the clinical criteria for OAHI and OSA symptom cut-off score had the most impaired quality of life and greater fatigue compared to those below both the clinical criteria for OAHI and the OSA symptom cut-off score. CONCLUSION: Children who meet clinical criteria for OSA and also scored high on a parent-reported screening tool for OSA symptoms had the most impaired quality of life and more fatigue. The PSQ has potential to identify children at risk for OSA. PMID- 27987108 TI - Insight into electrostatic initiation of nitramine explosives. AB - The electrostatic safety of explosives is of great importance. However, the mechanism for the transfer of energy from an electrostatic spark to the reactive center of an explosive material is not well understood. Thus, in this work, we attempted to clarify the mechanism associated with the static-electricity initiated detonation of explosives using a model of the interaction that incorporated relevant parameters. Nitramine explosives were considered as examples to study the relationship between electrostatic spark energy and 32 relevant parameters. The four parameters that were most closely correlated with the electrostatic spark energy were the standard deviation of the negative electrostatic potential, the minimum surface electrostatic potential, the minimum ionization energy, and the detonation pressure. A model for the dependence of the electrostatic spark energy on these four parameters was derived using the theoretical method known as genetic function approximation. The electrostatic spark energy values predicted using this model were in good agreement with the corresponding experimental values. The results of this work should lead to a deeper understanding of the electrostatic initiation mechanism of nitramines, and help to inspire the design of new explosives. PMID- 27987109 TI - Proliferating cell nuclear antigen (PCNA) contributes to the high-order structure and stability of heterochromatin in Saccharomyces cerevisiae. AB - Heterochromatin plays important roles in the structure, maintenance, and function of the eukaryotic genome. It is associated with special histone modifications and specialized non-histone proteins and assumes a more compact structure than euchromatin. Genes embedded in heterochromatin are generally transcriptionally silent. It was found previously that several mutations of proliferating cell nuclear antigen (PCNA), a DNA replication processivity factor, reduce transcriptional silencing at heterochromatin loci in Saccharomyces cerevisiae. However, the notion that PCNA plays a role in transcriptional silencing was recently questioned because of a potential problem concerning the silencing assays used in prior studies. To determine if PCNA is a bona fide contributor to heterochromatin-mediated transcriptional silencing, we examined the effects of PCNA mutations on heterochromatin structure. We found evidence implicating PCNA in the maintenance of the high-order structure and stability of heterochromatin, which indicates a role of DNA replication in heterochromatin maintenance. PMID- 27987110 TI - Prevalence and molecular characterization of porcine Picobirnavirus in piglets of North East Region of India. AB - Picobirnaviruses (PBVs) have been recognized as one of the important causal viral agents of gastroenteritis in several animal species especially in young immunocompromised hosts. In this study, we report the prevalence and molecular epidemiology of porcine PBVs from North Eastern Hilly region of India. A total of 457 fecal samples from piglets were collected from local (n = 130) and cross (n = 327) breed piglets in different seasons for 2 years. All the samples were subjected to RNA-PAGE and RT-PCR analysis for detection of PBVs. A total of 4.59 and 11.15% samples were recorded as positive for PBVs by RNA-PAGE and RT-PCR, respectively. Rate of detection was higher from diarrhoeic animals (13.56%) compared to non-diarrhoeic (4.23%) animals. Higher prevalence rate was observed from unorganized farms (14.22%) compared to organized farms (8.0%) with slightly higher detection from cross breed (11.62%) compared to local breed (10.0%). Maximum cases of piglet diarrhea associated with PBVs were detected during summer (16.4%) and winter (14.39%) seasons compared to autumn (4.80%) and spring (6.45%). All the samples were positive for PBV genogroup I only. Based upon the sequence analysis, the isolates were unique and placed in separate clad and were not closely associated with any other Indian isolates of PBVs so far. Two isolates were closely related with one Chinese isolate recovered from sewage water. This is the first systematic study of prevalence of PBVs associated with piglet diarrhea. PMID- 27987111 TI - Efficacy of vaccination with La Sota strain vaccine to control Newcastle disease in village chickens in Nepal. AB - The efficacy of vaccination with Newcastle disease (ND) La Sota and R2B (Mukteswar) modified live strain vaccines was determined by experimental challenge and with ND La Sota vaccine under field conditions in Nepal. Booster vaccination with ND La Sota vaccine after a primary vaccination with ND La Sota vaccine, induced a geometric mean titre (GMT) of 5.0 log2 haemagglutination inhibition (HI) units, compared to a GMT of 6.0 log2 HI units following booster vaccination with R2B vaccine 1 month after primary vaccination with ND La Sota vaccine. Both vaccines provided 100% protection against challenge with a local field ND strain. Furthermore, booster vaccination with ND La Sota vaccine induced protective levels of antibody after field use in villages in Jhapa, and no outbreaks of ND occurred during the study period. The ND La Sota modified live vaccine is immunogenic and efficacious and is a suitable vaccine for use in vaccination programmes in village chickens in the rural areas of Nepal. PMID- 27987112 TI - Antimicrobial resistance and virulence profile of enterococci isolated from poultry and cattle sources in Nigeria. AB - This study investigated the occurrence, antimicrobial resistance and virulence of Enterococcus from poultry and cattle farms. Three hundred and ninety samples: cloacal/rectal swabs (n = 260) and manure (n = 130] were processed for recovery of Enterococcus species. Standard bacteriological methods were used to isolate, identify and characterize Enterococcus species for antimicrobial susceptibility and expression of virulence traits. Detection of antibiotic resistance and virulence genes was carried out by polymerase chain reaction. Enterococcus was recovered from 167 (42.8%) of the 390 samples tested with a predominance of Enterococcus faecium (27.7%). Other species detected were Enterococcus gallinarum, Enterococcus faecalis, Enterococcus hirae, Enterococcus raffinosus, Enterococcus avium, Enterococcus casseliflavus, Enterococcus mundtii and Enterococcus durans. All the isolates tested were susceptible to vancomycin, but resistance to tetracycline, erythromycin, ampicillin and gentamicin was also observed among 61.0, 61.0, 45.1 and 32.7% of the isolates, respectively. Sixty (53.1%) of the isolates were multidrug resistant presenting as 24 different resistance patterns with resistance to gentamicin-erythromycin-streptomycin tetracycline (CN-ERY-STR-TET) being the most common (n = 11) pattern. In addition to expression of virulence traits (haemolysin, gelatinase, biofilm production), antibiotic resistance (tetK, tetL, tetM, tetO and ermB) and virulence (asa1, gelE, cylA) genes were detected among the isolates. Also, in vitro transfer of resistance determinants was observed among 75% of the isolates tested. Our data revealed poultry, cattle and manure in this area are hosts to varying Enterococcus species harbouring virulence and resistance determinants that can be transferred to other organisms and also are important for causing nosocomial infection. PMID- 27987113 TI - Functional single nucleotide polymorphisms of matrix metalloproteinase 7 and 12 genes in idiopathic recurrent spontaneous abortion. AB - PURPOSE: The aim of this study was to investigate the potential association of matrix metalloproteinase 7 (MMP7) -181 A/G and MMP12 -82 A/G functional single nucleotide polymorphisms (SNP) with idiopathic recurrent spontaneous abortion (IRSA) in Slovenian reproductive couples. METHODS: A case-control study was conducted on 149 couples with 3 or more consecutive idiopathic spontaneous pregnancy loses and 149 women and men with at least 2 live births and no history of pregnancy complications. Genotyping of MMP7 -181 A/G and MMP12 -82 A/G SNPs was performed using polymerase chain reaction and restriction fragment length polymorphism methods. RESULTS: There were no statistically significant differences in the distribution of MMP7 -181 A/G and MMP12 -82 A/G genotype, allele, or haplotype frequencies between IRSA patients and controls, as well as patients' primary and secondary IRSA. We also found no association of MMP7 -181 A/G and MMP12 -82 A/G genotypes, alleles, and haplotypes with IRSA. CONCLUSIONS: We found no evidence to support the association between IRSA and MMP7 -181 A/G and MMP12 -82 A/G SNPs in Slovenian reproductive couples. PMID- 27987116 TI - Roles of PKR in differentiation and apoptosis of bone-related cells. AB - Double-stranded RNA-dependent protein kinase (PKR) is a serine/threonine protein kinase which is activated by double-stranded RNAs and related to several signal transduction pathways. To examine the effects of PKR on bone metabolism, we established PKR-K/R mutant cells in which amino acid lysine at 296 is substituted with arginine. PKR regulated apoptosis in osteoblastic cells via nuclear factor kappa-B (NF-kappaB) cascade. MC3T3-E1 cells cultured with osteoblast differentiation medium differentiated into osteoblasts, while the mutant cells did not differentiate into osteoblasts. RAW246.7 cells triggered with receptor activator of NF-kappaB ligand (RANKL) formed tartrate-resistant acid phosphatase positive multinucleated giant cells, whereas PKR-K/R mutant RAW cells did not. Differentiation of osteoblasts and osteoclasts was caused by NF-kappaB activation and signal transducer and activator of transcription 1 (STAT1) ubiquitination and degradation. We also demonstrated involvement of PKR in chondrocyte differentiation. PKR prevented tumor necrosis factor-alpha- and interleukin 1alpha-induced bone resorption in calvaria and artificially induced periodontal disease in rat. Our findings indicate that PKR regulates bone metabolism in vitro and in vivo. PMID- 27987115 TI - The concreteness effect on judgments of learning: Evaluating the contributions of fluency and beliefs. AB - Researchers have often determined how cues influence judgments of learning (JOLs; e.g., concrete words are assigned higher JOLs than are abstract words), and recently there has been an emphasis in understanding why cues influence JOLs (i.e., the mechanisms that underlie cue effects on JOLs). The analytic-processing (AP) theory posits that JOLs are constructed in accordance with participants' beliefs of how a cue will influence memory. Even so, some evidence suggests that fluency is also important to cue effects on JOLs. In the present experiments, we investigated the contributions of participants' beliefs and processing fluency to the concreteness effect on JOLs. To evaluate beliefs, participants estimated memory performance in a hypothetical experiment (Experiment 1), and studied concrete and abstract words and made a pre-study JOL for each (Experiments 2 and 3). Participants' predictions demonstrated the belief that concrete words are more likely to be remembered than are abstract words, consistent with the AP theory. To evaluate fluency, response latencies were measured during lexical decision (Experiment 4), self-paced study (Experiment 5), and mental imagery (Experiment 7). Number of trials to acquisition was also evaluated (Experiment 6). Fluency did not differ between concrete and abstract words in Experiments 5 and 6, and it did not mediate the concreteness effect on JOLs in Experiments 4 and 7. Taken together, these results demonstrate that beliefs are a primary mechanism driving the concreteness effect on JOLs. PMID- 27987114 TI - When children forget to remember: Effects of reduced working memory availability on prospective memory performance. AB - The preparatory attentional and memory processes theory (PAM) of prospective memory (PM) proposes that prospective remembering is influenced by the variation in the availability of WM resources. Consequently, PM should be impaired when WM resources are reduced either by direct WM manipulation or by individual differences associated with restricted WM performance. Our study tested this prediction in school-age children by examining the independent and interactive effects of three factors known to deplete availability of WM resources: increased processing demands of a concurrent arithmetic task, additional WM span requirements, and high trait anxiety. A sample of 10-year-old children (N = 128) performed a PM task, embedded in an ongoing arithmetic task, which progressively imposed greater WM processing demands. Half of these participants also concurrently carried out an embedded WM span task. The results supported the PAM hypothesis, showing that children's PM was compromised by the restriction of WM resources, whether this resulted from increasing the processing demands on the ongoing task, from imposing additional WM span requirements, or from high trait anxiety. However, these WM-depleting factors exerted additive effects rather than an interactive impact, suggesting that they might each deplete different aspects of WM resource availability necessary for prospective remembering. Overall findings imply that children's PM success is not only associated to their WM capacity but it mostly depends upon how many of those WM resources are available to be devoted to the PM requirement. PMID- 27987117 TI - Differential effects of type 2 diabetes on brain glycometabolism in rats: focus on glycogen and monocarboxylate transporter 2. AB - Astrocyte-neuron lactate shuttle (ANLS) is a pathway that supplies glycogen derived lactate to active neurons via monocarboxylate transporter 2 (MCT2), and is important for maintaining brain functions. Our study revealed alterations of ANLS with hippocampal hyper-glycogen levels and downregulated MCT2 protein levels underlying hippocampal dysfunctions as a complication in type 2 diabetic (T2DM) animals. Since T2DM rats exhibit brain dysfunctions involving several brain regions, we examined whether there might also be T2DM effects on ANLS's disturbances in other brain loci. OLETF rats exhibited significantly higher glycogen levels in the hippocampus, hypothalamus, and cerebral cortex than did LETO rats. MCT2 protein levels in OLETF rats decreased significantly in the hippocampus and hypothalamus compared to their controls, but a significant correlation with glycogen levels was only observed in the hippocampus. This suggests that the hippocampus may be more vulnerable to T2DM compared to other brain regions in the context of ANLS disruption. PMID- 27987118 TI - Influence of the soil sealing on the geoaccumulation index of heavy metals and various pollution factors. AB - Soil sealing belongs to the most destructive and damaging processes to the soil environment. Soil sealing interrupts or greatly restricts the exchange of matter and energy between the biosphere, hydrosphere, and atmosphere and the soil environment. The aim of this study was to compare the content of heavy metals (Cd, Cr, Cu, Hg, Fe, Ni, Pb, Zn) of Ekranic Technosols by applying indicators such as geoaccumulation index (I geo), enrichment factor (EF), and pollution load index (PLI), which allowed to determine quantitatively the impact of the soil sealing degree on the content of heavy metals and to distinguish natural from anthropogenic sources of origin of heavy metals. In general, 42 soils from different parts of the city of Torun (NW Poland) were sampled and divided into three groups according to the degree of soil sealing: completely sealed with asphalt or concrete (A), semi-permeable (partially sealed with cobblestones and concrete paving slabs (B)), and reference (non-sealed) (C). The results indicate that the artificial sealing in urban areas slightly affects the content of heavy metals in soils. However, based on PLI, I geo, and EF, it was found that the sealing has influence on soil properties and unsealed soil is the most exposed to the accumulation of pollutants. PMID- 27987119 TI - Life cycle environmental impacts of saffron production in Iran. AB - Saffron is regarded as an important crop in Iranian agricultural economics that needs to be investigated to produce the environmentally friendlier product. In the present study, saffron production as an important agricultural production system in Iran was evaluated thoroughly from an environmental point of view. Data were collected from saffron farmers in Southern Khorasan province of the country with face-to-face questionnaire method during cropping period of 2013-2014. The system boundary was considered from the production of raw input materials to the harvested saffron. In order to identify the main hotspot during cultivation, impact categories were considered using CML methodology and cumulative exergy demand (CExD) indicator. Based on the results, chemical fertilizers N and P were the main hotspots in abiotic depletion (AD), acidification (AC), global warming (GWP), and photochemical oxidation (PO) impact categories, while diesel fuel was the main hotspot in fresh water aquatic ecotoxicity (FE), marine aquatic ecotoxicity (ME), and terrestrial ecotoxicity (TE). Direct emission from diesel fuel combustion (saffron) was the main hotspot only in human toxicity (HT). The small farms had the highest amounts of AD, AC, EP, GWP, and PO indicators in comparison with the medium and large farms. Total CExD indicator for production of 1 kg saffron was 1894.23 MJ eq. Totally, large farms (bigger than 1 ha) had better environmental performance considering all the impact categories. PMID- 27987120 TI - The fate and transport of arsenic species in the aquatic ecosystem: a case study on Bestari Jaya, Peninsular Malaysia. AB - The field of arsenic pollution research has grown rapidly in recent years. Arsenic constitutes a broad range of elements from the Earth's crust and is released into the environment from both anthropogenic and natural sources due to its relative mobility under different redox conditions. The toxicity of arsenic is described in its inorganic form, as inorganic arsenic compounds can leach into different environments. Sampling was carried out in the Bestari Jaya catchment while using a land use map to locate the site, and experiments were conducted via sequential extraction and inductively coupled plasma optical emission spectroscopy to quantify proportions of arsenic in the sediment samples. The results show that metals in sediments of nonresidual fractions, which are more likely to be likely released into aquatic environments, are more plentiful than the residual sediment fractions. These findings support the mobility of heavy metals and especially arsenic through sediment layers, which can facilitate remediation in environments heavily polluted with heavy metals. PMID- 27987121 TI - Further understanding on the mechanism of alkyl ketene dimer sizing on the causticized calcium carbonate filled paper and its improvements. AB - Causticized calcium carbonate (CCC), a solid waste derived from kraft black recovery process, can be used as an alternative for the conventional precipitated calcium carbonate (PCC). However, the application of the CCC has been limited due to its low sizing efficiency in its filled paper. In this study, the characteristics of the CCC were studied aiming to improve the alkyl ketene dimer (AKD) sizing performances of the CCC filled papers, and the results were compared with those from PCC filled papers. The results showed that the CCC had higher pore structure, higher specific surface area, and more negative charge density than the PCC, thus leading to a higher cationic AKD adsorption onto the CCC filler. The lower AKD sizing efficiency in the CCC filled paper can be explained by the combination of higher AKD adsorption and migration, both of which resulted in preferred AKD adsorption onto/into the CCC fillers, rather than the cellulose fibers. Based on the above, the prior addition of polyamide-polyamine epichlorhydrin (PAE) resin to the CCC filler system was proposed to remedy the related issues, thus improving the sizing efficiency. PMID- 27987122 TI - Effective characterization of Salmonella Enteritidis by most probable number (MPN) followed by multiplex polymerase chain reaction (PCR) methods. AB - Nontyphoidal Salmonella (NTS) is a relevant pathogen involved in gastroenteritis outbreaks worldwide. In this study, we determined the capacity to combine the most probable number (MPN) and multiplex polymerase chain reaction (PCR) methods to characterize the most important Salmonella serotypes in raw sewage. A total of 499 isolates were recovered from 27 raw sewage samples and screened using two previously described multiplex PCR methods. From those, 123 isolates were selected based on PCR banding pattern-identical or similar to Salmonella Enteritidis and Salmonella Typhimurium-and submitted to conventional serotyping. Results showed that both PCR assays correctly serotyped Salmonella Enteritidis, however, they presented ambiguous results for Salmonella Typhimurium identification. These data highlight that MPN and multiplex PCR can be useful methods to describe microbial quality in raw sewage and suggest two new PCR patterns for Salmonella Enteritidis identification. PMID- 27987123 TI - Environmental investigation for the presence of Vibrio species following a case of severe gastroenteritis in a touristic island. AB - Global changes have caused a worldwide increase in reports of Vibrio-associated diseases with ecosystem-wide impacts on humans and marine animals. In Europe, higher prevalence of human infections followed regional climatic trends with outbreaks occurring during episodes of unusually warm weather. Similar patterns were also observed in Vibrio-associated diseases affecting marine organisms such as fish, bivalves, and corals. Following a possible human case of infection due to V. cholerae in the island of Kos (eastern Aegean, Greece), environmental samples were collected and tested for the presence of Vibrio species. Using chromogenic agar and MALDI-TOF MS, V. parahaemolyticus, V. vulnificus V. furnisii, V. alginolyticus, and V. fluvialis were isolated and/or identified. The presence of V. cholerae was established by PCR-sequencing analysis only. Following the susceptibility testing of the Vibrio isolates, only one, V. furnisii, showed intermediate resistance to ciprofloxacin. The rest of the isolates were susceptible to all antibiotics tested. The presence of Vibrio species in aquatic samples reveals potential dangers due to exposure to contaminated seawaters. PMID- 27987125 TI - Exploring river pollution based on sediment analysis in the Upper Tisza region (Hungary). AB - We assessed contamination in the Upper Tisza region (Hungary, Central Europe), analyzing the elemental concentrations in sediment cores of oxbows. Our hypothesis was that the metal contamination which occurred in the year 2000 and which came from the mining area in Transylvania (Romania) may be detected even 15 years after the contamination, based on the vertical profile of sediment cores. Sediment cores were collected from five oxbows, and the following elements were measured with microwave plasma-atomic emission spectrometry (MP-AES): Cu, Cr, Ba, Fe, Mn, Pb, Sr, and Zn. Among the oxbows studied, there was one protected oxbow, three were used for fishing, and one was contaminated with sewage. Our results indicated that the year of contamination is still observable in the vertical profile of the sediment cores. The pollution index (PI) was used to characterize the sediment enrichment of metal elements in the sediment cores. In the case of Cu, Pb, and Zn, the contamination which originated in the year 2000 was detected in the layers of the sediment cores. The contamination levels of Cu, Pb, and Zn were high or moderate in the studied oxbows. All oxbows were moderately contaminated by Mn, while a moderate level of contamination was found for Fe in the protected oxbow, one fishing oxbow, and the sewage-contaminated oxbow. In the fishing oxbows, a low level of contamination was found for Fe. The contamination level of Sr was low in the protected oxbow and in the two fishing oxbows, while in one of the fishing oxbows and in the sewage-contaminated oxbow, a moderate level of Sr contamination was found. The pollution index scores indicated that the contamination level for Ba and Cr was low in the sediment cores of the oxbows studied. Our results indicated that the contamination of the Tisza River from the mining area in Northern Romania has been continuous and is still ongoing. PMID- 27987124 TI - Reducing N losses through surface runoff from rice-wheat rotation by improving fertilizer management. AB - To better understand N runoff losses from rice-wheat rotation and demonstrate the effectiveness of improved fertilizer management in reducing N runoff losses, a field study was conducted for three consecutive rice-wheat rotations. Nitrogen losses through surface runoff were measured for five treatments, including CK without N application, C200, C300 simulating the conventional practices, CO200, and CO300. Optimum N rate was applied for C200 and CO200, and 30% of chemical fertilizer was substituted with organic fertilizer for CO200 and CO300 with respect to C200 and C300, respectively. Rice season had higher runoff coefficients than wheat season. Approximately 52% of total N was lost as NH4+-N in rice season, ranging from 21 to 83%, and in wheat season, the proportion of NO3--N in total N averaged 53% with a variation from 38 to 67%. The N treatments lost less total N in rice season (1.67-10.7 kg N ha-1) than in wheat season (1.72 17.1 kg N ha-1). These suggested that a key to controlling N runoff losses from rice-wheat rotation was to limit NO3--N accumulation in wheat season. In both seasons, N runoff losses for C200 and CO300 were lower than those for C300. CO200 better cut N losses than C200 and CO300, with 64 and 57% less N in rice and wheat seasons than C300, respectively. Compared with the conventional practices, optimum N inputs integrated with co-application of organic and chemical fertilizers could reduce N runoff losses with a better N balance under rice-wheat rotation. PMID- 27987126 TI - Enhancing tolerance of rice (Oryza sativa) to simulated acid rain by exogenous abscisic acid. AB - Abscisic acid (ABA) regulates much important plant physiological and biochemical processes and induces tolerance to different stresses. Here, we studied the regulation of exogenous ABA on adaptation of rice seedlings to simulated acid rain (SAR) stress by measuring biomass dry weight, stomatal conductance, net photosynthesis rate, nutrient elements, and endogenous hormones. The application of 10 MUM ABA alleviated the SAR-induced inhibition on growth, stomatal conductance, net photosynthesis rate, and decreases in contents of nutrient (K, Mg, N, and P) and hormone (auxin, gibberellins, and zeatin). Moreover, 10 MUM ABA could stimulate the Ca content as signaling molecules under SAR stress. Contrarily, the application of 100 MUM ABA aggravated the SAR-induced inhibition on growth, stomatal conductance, net photosynthesis rate, and contents of nutrient and hormone. The results got after a 5-day recovery (without SAR) show that exogenous 10 MUM ABA can promote self-restoration process in rice whereas 100 MUM ABA hindered the restoration by increasing deficiency of nutrients and disturbing the balance of hormones. These results confirmed that exogenous ABA at proper concentration could enhance the tolerance of rice to SAR stress. PMID- 27987127 TI - Formation of wood secondary cell wall may involve two type cellulose synthase complexes in Populus. AB - Cellulose biosynthesis is mediated by cellulose synthases (CesAs), which constitute into rosette-like cellulose synthase complexe (CSC) on the plasma membrane. Two types of CSCs in Arabidopsis are believed to be involved in cellulose synthesis in the primary cell wall and secondary cell walls, respectively. In this work, we found that the two type CSCs participated cellulose biosynthesis in differentiating xylem cells undergoing secondary cell wall thickening in Populus. During the cell wall thickening process, expression of one type CSC genes increased while expression of the other type CSC genes decreased. Suppression of different type CSC genes both affected the wall thickening and disrupted the multilaminar structure of the secondary cell walls. When CesA7A was suppressed, crystalline cellulose content was reduced, which, however, showed an increase when CesA3D was suppressed. The CesA suppression also affected cellulose digestibility of the wood cell walls. The results suggest that two type CSCs are involved in coordinating the cellulose biosynthesis in formation of the multilaminar structure in Populus wood secondary cell walls. PMID- 27987129 TI - The application of wrapping ureter by a pedicled gastrocolic omentum flap combined with an artificial external scaffold to prevent stoma stenosis in rabbit after ureterocutaneostomy. AB - OBJECTIVE: To evaluate the feasibility and possibility of wrapping ureter by a pedicled gastrocolic omentum flap combined with an artificial ureter external scaffold to prevent stoma stenosis in rabbit after ureterocutaneostomy. METHODS: Forty male New Zealand rabbits were involved in this study. For application of ureterocutaneostomy, the right ureter was wrapped by a pedicled gastrocolic omentum flap and combined with application of an artificial external scaffold, which served as experimental side. Traditional ureterocutaneostomy was applied in left ureter (control side). All rabbits were killed after 1 month, and the kidney, ureter and abdominal segment ureter were collected to study the morphological and pathological changes by using HE staining, Masson staining, immunohistochemistry staining and microvessel density (MVD) study. RESULTS: HE staining showed that renal medullary tubular dilatation, large number of collagen deposition, renal glomerular and renal tubular atrophy. Glomerular vascular leaves and interstitial fibrosis were detected in the kidney of control side. However, these abnormities in the kidney of experimental side were significantly alleviated compared to control side. The hydronephrosis and ureterectasia in the experimental side were dramatically attenuated compared to control side. Fibrosis in ureter around stoma and stoma stenosis were prevented by wrapping ureter by a pedicled gastrocolic omentum flap combined with an artificial external scaffold. CONCLUSION: In this study, we have demonstrated that wrapping ureter by a pedicled gastrocolic omentum flap combined with an artificial external scaffold is capable of preventing stoma stenosis in rabbit after ureterocutaneostomy, which provided a new method and theoretical basis for clinical application in the future. PMID- 27987130 TI - Ultrasound image features of intravesical prostatic protrusion indicated failure of medication therapy of finasteride and doxazosin in patients with benign prostatic hyperplasia (LUTS/BPH). AB - BACKGROUND: Intravesical prostatic protrusion (IPP) is a type of benign prostatic hyperplasia (BPH) adenoma, and it plays a critical role in the pathogenesis of bladder outlet obstruction in patients with lower urinary tract syndromes (LUTS/BPH). AIMS: The goal of this study was to investigate the effect of a combination therapy with finasteride and doxazosin on IPP in BPU/LUTS patients. METHODS: A total of 322 BPH patients with enlarged prostatic volume as well as moderate to severe symptom scores were enrolled and divided into four groups according to the degree of IPP (IPP > 10 mm, 5-10 mm, <5 mm and no IPP) in this study. Aggravated International Prostatic Symptom Score (IPSS), acute urinary retention or relevant urinary complications were considered as failure of the therapy. The degrees of IPP were recorded before and after 6 months of treatment. Student's t test and chi 2 were performed between the baseline and endpoint of the therapy. RESULTS: The results showed that the total prostate volume (TPV) and transition zone volume (TZV) of the prostate decreased significantly after 6 month combination therapy (P < 0.05), while no significant changes in IPP were observed at that point (P > 0.05). Failure rates of the medication differed significantly among the four groups. CONCLUSIONS: The study indicated that the combination therapy using finasteride and doxazosin could not reduce the degree of IPP. LUTS/BPH patients with IPP which contributes to the failure of medication tend to have a higher risk of progression. PMID- 27987128 TI - The role of glucocorticoid receptor in prostate cancer progression: from bench to bedside. AB - Glucocorticoids are a common class of adjuvant drugs for the treatment of castration-resistant prostate cancer (CRPC) combined with antitumour or antiandrogen agents. Glucocorticoids are administered clinically because they ameliorate toxic side effects and have inhibitory effects on adrenal androgen production, acting as a pituitary suppressant. However, their effects on prostate cancer cells especially the castration resistance prostate cancer cells are poorly defined. Glucocorticoids exert effects depend to a great extent on glucocorticoid receptor. In addition to a number of glucocorticoid receptor isoforms determined, it is found that the actions of glucocorticoids through GRalpha are influenced by other isoforms, such as GRbeta and GRgamma. Recently, studies found GR confers resistance to androgen deprivation therapy, and various glucocorticoids exert distinct efficacy in CRPC. In this review, we summarized the mechanisms of glucocorticoids and its clinical appliances on the basis of present evidence. PMID- 27987132 TI - Long-term variations of water quality in the Inner Murchison Bay, Lake Victoria. AB - The water quality in the Inner Murchison Bay (IMB) located in Uganda on the northern shores of Lake Victoria is affected by a complex mixture of processes and driving factors including pollution, river inflows, lake water levels, wetland management and flora and fauna populations. This study attempts to explain long-term variations of the IMB water quality and to provide a plausible water quality model. Because intermittent monitoring around the Bay hinders accurate determination of pollution, concentrations at the extreme northern shores (hotspots) are considered indicative of the pollutant loading into the bay. Delft3D-Flow was applied to study the Bay hydrodynamics and coupled with the Delwaq module to investigate water quality processes related to oxygen: organic and nutrient components i.e. dissolved oxygen (DO), biological oxygen demand (BOD) and ammonium (NH4+). It is found that the IMB water quality deteriorated exponentially in the period 2001-2014 due to increased pollution and the high residence time of water. The worst water quality was in 2010 when diffuse pollution intensified due to the lining of more drainage channels within Kampala City in addition to the declining wetland effect. The water quality towards the Outer Murchison Bay (OMB) deteriorated over time with dilution accounting for 40 60% of pollutant reduction. Although the effect of lake level variations is negligible compared to pollution into the IMB, increased lake levels after 2011 improved DO levels and mixing and hence BOD levels in the IMB. PMID- 27987131 TI - Assessment of metal contamination in the biota of four rivers experiencing varying degrees of human impact. AB - Urbanization, agriculture, and other land transformations can affect water quality, decrease species biodiversity, and increase metal and nutrient concentrations in aquatic systems. Metal pollution, in particular, is a reported consequence of elevated anthropogenic inputs, especially from urbanized areas. The objectives of this study were to quantify metal (Cu, Al, Cd, Ni, and Pb) concentrations in the waters and biota of four streams in South Georgia, USA, and relate metal concentrations to land use and abiotic and biotic stream processes. Additionally, macrophytes, invertebrates, and fish were identified to assess biodiversity at each site. Metal concentrations in the three trophic levels differed among sites and species, correlating to differences in land use surrounding the rivers. The highest metal concentrations (except Al) were found in the streams most impacted by urbanization and development. Al concentrations were highest in streams surrounded by land dominated by forested areas. Metal content in macrophytes reflected metal concentrations in the water and was at least three orders of magnitude higher than any other trophic level. Despite metal concentration differences, all four streams contained similar water quality and were healthy based on macroinvertebrate community structure. This study provides insight into the impact of urbanization and the fate and effects of metals in river ecosystems with varying degrees of anthropogenic impact. PMID- 27987134 TI - "Hole sign" of the gallbladder. PMID- 27987133 TI - TAT-PEP Enhanced Neurobehavioral Functional Recovery by Facilitating Axonal Regeneration and Corticospinal Tract Projection After Stroke. AB - Paired immunoglobulin-like receptor B (PirB) has been identified as a new receptor for myelin-associated inhibitory (MAI) proteins, which may play important role in axonal regeneration and corticospinal tract (CST) projection associated with neurobehavioral function recovery after stroke. Here, we found that the expression of PirB was increased in the cortical penumbra from 1 to 28 days after transient focal cerebral ischemic reperfusion of rats. Then, transactivator of transcription-PirB extracellular peptide (TAT-PEP) was generated that might block the interactions between MAIs and PirB. The results showed that TAT-PEP displayed high affinity for MAIs and ameliorated their inhibitory effect on neurite growth. Furthermore, TAT-PEP can widely distribute in the penumbra after intraperitoneal injection. Then, we found that TAT-PEP enhanced neurite growth and alleviated growth cone collapse after oxygen glucose deprivation (OGD) injury. In addition, TAT-PEP promoted long-term neurobehavioral functional recovery through enhancing axonal regeneration and CST projection. Finally, the observations demonstrated that POSH/RhoA/growth-associated protein 43 (GAP43) as PirB-associated downstream signaling molecules played important role in neurobehavioral functional recovery after stroke. Moreover, the underlying mechanism associated with TAT-PEP-mediated promoting axonal regeneration and CST projection was by intervening in the expression of POSH, RhoA, and GAP43. These studies suggest that TAT-PEP may represent an attractive therapeutic strategy against stroke. PMID- 27987135 TI - Predictors of severe outcomes in patients with Clostridium difficile infection from a Hispanic population. AB - BACKGROUND: Factors associated with complicated Clostridium difficile infection (CDI) may vary among populations, and predictors of severe outcomes in CDI have not been studied in Hispanic patients. The aim of this study was to identify factors associated with a higher risk of colectomy, all-cause mortality, and CDI associated mortality in a Hispanic population. METHODS: We performed a retrospective study of all hospitalized patients with a diagnosis of CDI between January 1, 2011 and September 30, 2015 in a 450-bed teaching hospital in Monterrey, northeast Mexico. Three main outcomes were defined: fulminant colitis with subsequent colectomy, all-cause mortality within 30 days of diagnosis, and CDI-attributable mortality. RESULTS: Of 261 patients with diarrhea, 176 were diagnosed with CDI. For colectomy, Charlson comorbidity index, ICU stay and mechanical ventilation prior to CDI diagnosis, days with diarrhea prior to treatment, total days of hospital stay and days after CDI diagnosis, elevated ATLAS score, days of diarrhea post CDI treatment, and treatment failure significantly predicted the necessity of surgical treatment with colectomy. CONCLUSION: Treatment failure, persistent diarrhea, and a high ATLAS score were identified as risk factors for severe outcomes of CDI. A low albumin concentration and high creatinine were associated with higher overall mortality. PMID- 27987138 TI - Predictors of Attrition Before and After Bariatric Surgery. PMID- 27987137 TI - Fasting Circulating Glicentin Increases After Bariatric Surgery. AB - INTRODUCTION: Bariatric surgery including the Roux-en-Y gastric bypass (RYGB) and the laparoscopic sleeve gastrectomy (LSG) is a well-established therapeutic option for patients with morbid or severe obesity. Metabolic modifications observed after bariatric surgery are thought to be, at least partly, linked to hormonal changes. While variation of several proglucagon-derived peptides during bariatric surgery is well documented, little is known about glicentin. The aim of this study was to investigate circulating glicentin variations after bariatric surgery. MATERIAL AND METHODS: Thirty patients eligible for bariatric surgery (18 RYGB and 12 LSG procedures) were prospectively included in the University Hospital of Nice. Clinical data and fasting biological parameters were recorded preoperatively, at 3, 6, and 12 months after bariatric surgery. RESULTS: The median age of patients was 51 years (35-56) with 33.3% men. Fasting glicentin concentration increased progressively after bariatric surgery from 6 months and was more marked at 12 months (14 +/- 3.6 pmol/L at baseline vs 19.7 +/- 2.7 pmol/L at 12 months for RYGB and 12.5 +/- 1.4 vs 16.4 +/- 1.8 pmol/L for LSG, respectively). Compared to preoperative values, the fold increase of glicentin at 12 months was 2 +/- 0.2 in the RYGB group and 1.6 +/- 0.3 in the LSG group. Glicentin variation after surgery did not correlate with anthropometric, glycemic, or lipid parameter modifications. CONCLUSION: Fasting glicentin level increases after bariatric surgery suggesting the potential interest of this peptide as a player and/or a marker of physiological changes after bariatric surgery. PMID- 27987140 TI - Introduction to RNA Vaccines. AB - RNA vaccines are attractive, because they exhibit characteristics of subunit vaccines and live-attenuated vectors, including flexible production and induction of both humoral and cellular immunity. While human proof-of-concept for RNA vaccines is still pending, the nascent field of RNA therapeutics has already attracted substantial industry and government funding as well as record investments of private venture capital. Most recently, the WHO acknowledged messenger RNA (mRNA) as a new therapeutic class. In this chapter, we briefly review key developments in RNA vaccines and outline the contents of this volume of Methods in Molecular Biology. PMID- 27987136 TI - Management of chronic constipation in patients with diabetes mellitus. AB - AIM: The aim of this review is to provide an overview of the clinical assessment and evidence-based treatment options for managing diabetes-associated chronic constipation. METHODS: A literature search of published medical reports in English language was performed using the OVID Portal, from PUBMED and the Cochrane Database of Systematic Reviews, from inception to October 2015. A total of 145 abstracts were identified; duplicate publications were removed and 95 relevant full-text articles were retrieved for potential inclusion. RESULTS: Chronic constipation is one of the most common gastrointestinal symptoms in patients with diabetes, and occurs more frequently than in healthy individuals. Treatment goals include improving symptoms and restoring bowel function by accelerating colonic transit and facilitating defecation. Based on guidelines and data from published literature, food and dietary change with exercise and lifestyle change should be the first step in management. For patients recalcitrant to these changes, laxatives should be the next step of treatment. Treatment should begin with bulking agents such as psyllium, bran or methylcellulose followed by osmotic laxatives if response is poor. Lactulose, polyethylene glycol and lactitol are the most frequently prescribed osmotic agents. Lactulose has a prebiotic effect and a carry-over effect (continued laxative effect for at least 6 to 7 days, post cessation of treatment). Stimulants such as bisacodyl, sodium picosulphate and senna are indicated if osmotic laxatives are not effective. Newer agents such as chloride-channel activators and 5-HT4 agonist can be considered for severe or resistant cases. CONCLUSION: The primary aim of intervention in diabetic patients with chronic constipation is to better manage the diabetes along with management of constipation. The physician should explain the rationale for prescribing laxatives and educate patients about the potential drawbacks of long-term use of laxatives. They should contact their physician if short-term use of prescribed laxative fails to provide relief. PMID- 27987139 TI - Signal Transducer and Activator of Transcription 1 (STAT1) Knock-down Induces Apoptosis in Malignant Pleural Mesothelioma. AB - Malignant pleural mesothelioma (MPM) is the most common primary tumor of the pleura. Its incidence is still increasing in Europe and the prognosis remains poor. We investigated the oncogenic function of signal transducer and activator of transcription 1 (STAT1) in MPM in more detail. A miRNA profiling was performed on 52 MPM tissue samples. Upregulated miRNAs (targeting SOCS1/3) were knocked down using miRNA inhibitors. mRNA expression levels of STAT1/3, SOCS1/3 were detected in MPM cell lines. STAT1 has been knocked-down using siRNA and qPCR was used to detect mRNA expression levels of all JAK/STAT family members and genes that regulate them. An immunohistochemical staining was performed to detect the expression of caspases. STAT1 was upregulated and STAT3 was downregulated, SOCS1/3 protein was not detected but it was possible to detect SOCS1/3 mRNA in MPM cell lines. The upregulated miRNAs were successfully knocked-down, however the expected effect on SOCS1 expression was not detected. STAT1 knock-down had different effects on STAT3/5 expression. Caspase 3a and 8 expression was found to be increased after STAT1 knock-down. The physiologic regulation of STAT1 via SOCS1 is completely lost in MPM and it does not seem that the miRNAs identified by now, do inhibit the expression of SOCS1. MPM cell lines compensate STAT1 knock down by increasing the expression of STAT3 or STAT5a, two genes which are generally considered to be oncogenes. And much more important, STAT1 knock-down induces apoptosis in MPM cell lines and STAT1 might therefore be a target for therapeutic intervention. PMID- 27987141 TI - Self-Replicating RNA. AB - Self-replicating RNA derived from the genomes of positive strand RNA viruses represents a powerful tool for both molecular studies on virus biology and approaches to novel safe and effective vaccines. The following chapter summarizes the principles how such RNAs can be established and used for design of vaccines. Due to the large variety of strategies needed to circumvent specific pitfalls in the design of such constructs the technical details of the experiments are not described here but can be found in the cited literature. PMID- 27987142 TI - Self-Replicating RNA Vaccine Delivery to Dendritic Cells. AB - Most current vaccines are either inactivated pathogen-derived or protein/peptide based, although attenuated and vector vaccines have also been developed. The former induce at best moderate protection, even as multimeric antigen, due to limitations in antigen loads and therefore capacity for inducing robust immune defense. While attenuated and vector vaccines offer advantages through their replicative nature, drawbacks and risks remain with potential reversion to virulence and interference from preexisting immunity. New advances averting these problems are combining self-amplifying replicon RNA (RepRNA) technology with nanotechnology. RepRNA are large self-replicating RNA molecules (12-15 kb) derived from viral genomes defective in at least one structural protein gene. They provide sustained antigen production, effectively increasing vaccine antigen payloads over time, without the risk of producing infectious progeny. The major limitation with RepRNA is RNase-sensitivity and inefficient uptake by dendritic cells (DCs)-absolute requirements for efficacious vaccine design. We employed biodegradable delivery vehicles to protect the RepRNA and promote DC delivery. Encapsulating RepRNA into chitosan nanoparticles, as well as condensing RepRNA with polyethylenimine (PEI), cationic lipids, or chitosans, has proven effective for delivery to DCs and induction of immune responses in vivo. PMID- 27987143 TI - Plant Expression of Trans-Encapsidated Viral Nanoparticle Vaccines with Animal RNA Replicons. AB - In this protocol, we outline how to produce a live viral nanoparticle vaccine in a biosafety level 1 (BSL1) environment. An animal viral vector RNA encapsidated with tobacco mosaic virus (TMV) coat protein can be fully assembled in planta. Agrobacterium cultures containing each component are inoculated together into tobacco leaves and the self-assembled hybrid nanoparticle vaccine is harvested 4 days later and purified with a simple PEG precipitation. The viral RNA delivery vector is derived from the BSL1 insect virus, Flock House virus (FHV), and replicates in human and animal cells but does not spread systemically. A polyethylene glycol purification protocol is also provided to collect and purify these vaccines for immunological tests. PMID- 27987144 TI - RNActive(r) Technology: Generation and Testing of Stable and Immunogenic mRNA Vaccines. AB - Developing effective mRNA vaccines poses certain challenges concerning mRNA stability and ability to induce sufficient immune stimulation and requires a specific panel of techniques for production and testing. Here, we describe the production of stabilized mRNA with enhanced immunogenicity, generated using conventional nucleotides only, by introducing changes to the mRNA sequence and by complexation with the nucleotide-binding peptide protamine (RNActive(r) technology). Methods described here include the synthesis, purification, and protamine complexation of mRNA vaccines as well as a comprehensive panel of in vitro and in vivo methods for evaluation of vaccine quality and immunogenicity. PMID- 27987145 TI - Nucleoside Modified mRNA Vaccines for Infectious Diseases. AB - In recent years, numerous studies have demonstrated the outstanding abilities of mRNA to elicit potent immune responses against pathogens, making it a viable new platform for vaccine development (reviewed in Weissman, Expert Rev Vaccines 14:265-281, 2015; Sahin et al., Nat Rev Drug Discov 13:759-780, 2014). The incorporation of modified nucleosides in mRNA has many advantages and is currently undergoing a renaissance in the field of therapeutic protein delivery. Its use in a vaccine against infectious diseases has only begun to be described, but offers advantages for the generation of potent and long-lived antibody responses. FPLC purification and substitution of modified nucleosides in the mRNA make it non-inflammatory and highly translatable (Kariko et al., Immunity 23:165 175, 2005; Kariko et al., Mol Ther 16:1833-1840, 2008; Kariko et al., Nucleic Acids Research 39:e142, 2011) that are crucial features for therapeutic relevance. Formulation of the mRNA in lipid nanoparticles (LNPs) protects it from degradation enabling high levels of protein production for extended periods of time (Pardi et al., J Control Release, 2015). Here, we describe a simple vaccination method using LNP-encapsulated 1-methylpseudouridine-containing FPLC purified mRNA in mice. Furthermore, we describe the evaluation of antigen specific T and B cell responses elicited by this vaccine format. PMID- 27987146 TI - Generation and Evaluation of Prophylactic mRNA Vaccines Against Allergy. AB - Due to the worldwide increase in allergies and a limited efficacy of therapeutic interventions, the need for prophylactic vaccination against allergies has been recognized. mRNA and DNA vaccines have demonstrated their high potential for preventing allergic sensitization by inducing an immunological bias that prevents TH2 sensitization. However, only mRNA vaccines fulfill the stringent safety requirements for vaccination of healthy children. In this chapter, we describe the generation of conventional as well as self-replicating mRNA vaccines and methods to test their prophylactic efficacy in animal models. PMID- 27987147 TI - Measuring the Adjuvant Activity of RNA Vaccines. AB - mRNA has recently arisen as a promising new drug class with the potential to be applied to various therapeutic modalities, including protein replacement and vaccination against cancer and infectious diseases. Numerous approaches have been pursued to develop potent mRNA vaccines, many of them have proved to be successful and have already entered human clinical trials. RNA, especially in vitro transcribed, is extremely immunogenic as it induces innate immune responses through the activation of a variety of pattern recognition receptors. This feature of RNA is potentially beneficial for vaccine development, where antigen encoding RNA might also function as an adjuvant to elicit potent antigen-specific T and B cell immune responses. Here, we describe the methods that can be used to evaluate the immunogenicity of RNA vaccines in vitro and in vivo. PMID- 27987148 TI - Generation of Immunostimulating 130 nm Protamine-RNA nanoparticles. AB - Nanoparticles of defined size can be easily obtained by simply mixing Protamine, a pharmaceutical drug that is used to neutralize heparin after surgery, and RNA in the form of oligonucleotides or messenger RNA. Depending on the concentrations of the two reagents and their salt contents, homogenous nanoparticles with a mean diameter of 50 to more than 1000 nm can spontaneously be generated. RNA is a danger signal because it is an agonist of for example TLR-3, -7, and -8; therefore, Protamine-RNA nanoparticles are immunostimulating. We and others have shown in vitro that nanoparticle size and interferon-alpha production by human peripheral blood mononuclear cells (PBMCs) are inversely correlated. Conversely, nanoparticle size and TNF-alpha production by PBMCs are positively correlated (Rettig et al., Blood 115:4533-4541, 2010). Particles of less than 450 nm are most frequently used for research and clinical applications because they are very stable, remain polydispersed and induce interferon-alpha proteins, which are a natural antiviral and anticancer protein family with 12 members in humans. Herein, we describe a method to generate 130 nm nanoparticles as well as some of their physical and biological characteristics. PMID- 27987149 TI - Electroporation of mRNA as Universal Technology Platform to Transfect a Variety of Primary Cells with Antigens and Functional Proteins. AB - Electroporation (EP) of mRNA into human cells is a broadly applicable method to transiently express proteins of choice in a variety of different cell types. We have spent more than a decade to optimize and adapt this method, first for antigen-loading of dendritic cells (DCs), and subsequently for T cells, B cells, bulk PBMCs, and several cell lines. In this regard, antigens were introduced, processed, and presented in context of MHC class I and II. Next to that, functional proteins like adhesion receptors, T-cell receptors (TCRs), chimeric antigen receptors (CARs), constitutively active signal transducers, and others were successfully expressed. We have also established this protocol under full GMP compliance as part of a manufacturing license to produce mRNA-electroporated DCs for therapeutic vaccination in clinical trials. Therefore, we here want to share our universal mRNA electroporation protocol and the experience we have gathered with this method. The advantages of the transfection method presented here are: (1) easy adaptation to different cell types, (2) scalability from 106 to approximately 108 cells per shot, (3) high transfection efficiency (80-99 %), (4) homogenous protein expression, (5) GMP compliance if the EP is performed in a class A clean room, and (6) no transgene integration into the genome. The provided protocol involves: Opti-MEM(r) as EP medium, a square-wave pulse with 500 V, and 4 mm cuvettes. To adapt the protocol to differently sized cells, simply the pulse time is altered. Next to the basic protocol, we also provide an extensive list of hints and tricks, which in our opinion are of great value for everyone who intends to use this transfection technique. PMID- 27987150 TI - Adjuvant-Enhanced mRNA Vaccines. AB - Recent advances in molecular biology have led to dramatic enhancement of the stability of in vitro transcribed (IVT) messenger RNA (mRNA) and improvement in its translational efficacy. Nowadays, mRNA-based vaccines represent a promising approach in the field of anticancer immunotherapy, gaining attention over the earlier-established bacteria-, virus-, or cell-based vaccination approaches. Here, we present the experimental procedures employed in our laboratory to induce anticancer immune responses in different murine tumor models using IVT mRNA encoding for immune activation signals and antigens of interest. PMID- 27987151 TI - Enhanced Delivery of DNA or RNA Vaccines by Electroporation. AB - Nucleic acid vaccines are a next-generation branch of vaccines which offer major benefits over their conventional protein, bacteria, or viral-based counterparts. However, to be effective in large mammals and humans, an enhancing delivery technology is required. Electroporation is a physical technique which results in improved delivery of large molecules through the cell membrane. In the case of plasmid DNA and mRNA, electroporation enhances both the uptake and expression of the delivered nucleic acids. The muscle is an attractive tissue for nucleic acid vaccination in a clinical setting due to the accessibility and abundance of the target tissue. Historical clinical studies of electroporation in the muscle have demonstrated the procedure to be generally well tolerated in patients. Previous studies have determined that optimized electroporation parameters (such as electrical field intensity, pulse length, pulse width and drug product formulation) majorly impact the efficiency of nucleic acid delivery. We provide an overview of DNA/RNA vaccination in the muscle of mice. Our results suggest that the technique is safe and effective and is highly applicable to a research setting as well as scalable to larger animals and humans. PMID- 27987152 TI - The European Regulatory Environment of RNA-Based Vaccines. AB - A variety of different mRNA-based drugs are currently in development. This became possible, since major breakthroughs in RNA research during the last decades allowed impressive improvements of translation, stability and delivery of mRNA. This article focuses on antigen-encoding RNA-based vaccines that are either directed against tumors or pathogens. mRNA-encoded vaccines are developed both for preventive or therapeutic purposes. Most mRNA-based vaccines are directly administered to patients. Alternatively, primary autologous cells from cancer patients are modified ex vivo by the use of mRNA and then are adoptively transferred to patients. In the EU no regulatory guidelines presently exist that specifically address mRNA-based vaccines. The existing regulatory framework, however, clearly defines that mRNA-based vaccines in most cases have to be centrally approved. Interestingly, depending on whether RNA-based vaccines are directed against tumors or infectious disease, they are formally considered gene therapy products or not, respectively. Besides an overview on the current clinical use of mRNA vaccines in various therapeutic areas a detailed discussion of the current regulatory situation is provided and regulatory perspectives are discussed. PMID- 27987153 TI - Discovery and Subtyping of Neo-Epitope Specific T-Cell Responses for Cancer Immunotherapy: Addressing the Mutanome. AB - Cancer accumulates 10s to 1000s of genomic mutations of which a fraction is immunogenic and may serve as an Achilles' heel of tumor cells. Mutation-specific T cells can recognize these antigens and destroy malignant cells. Strategies to immunotherapeutically address individual tumor mutations employing peptide or mRNA based vaccines are now actively investigated in mice and humans. An important step of determining the therapeutic potential of a mutanome vaccine is the detection of mutation reactive T-cell responses. In this chapter we provide protocols to identify and subtype mutation specific T cells in mice based on IFN gamma ELISpot and flow cytometry. PMID- 27987154 TI - Considerations for Producing mRNA Vaccines for Clinical Trials. AB - The approval of clinical trials by the competent authorities requires comprehensive quality documentation on the new drug to be used on the clinical trial participant. In the EU quality data is summarized as Investigational Medicinal Product Dossier (IMPD), in the USA as Investigational New Drug (IND) Application. For that, several preconditions concerning production, quality control, and assurance have to be fulfilled. Here, specific requirements related to mRNA vaccines are addressed on the basis of European standards. PMID- 27987155 TI - Nonclinical Safety Testing of RNA Vaccines. AB - In this chapter, we first consider the overall goal of nonclinical safety testing during drug development and have a brief overview of its regulatory background. We then discuss some basic requirements of safety/toxicity testing before concentrating on the safety testing of RNA vaccines and developing a sample RNA vaccine safety testing program. PMID- 27987156 TI - Immunotherapy of Uveal Melanoma: Vaccination Against Cancer. AB - Uveal melanoma is the most frequently occurring primary intraocular tumor in adults, with an incidence of about 5 out of 100,000 per year, the incidence rising with increasing age (Lipski, Klin Monbl Augenheilkd 230:1005-1019, 2013; Metz et al., Klin Monbl Augenheilkd 230:686-691, 2013; Singh and Topham, Ophthalmology 110:956-961, 2003). Often diagnosed late due to a lack of early symptoms, this kind of melanoma is associated with a poor prognosis. Approximately 50 % of the patients develop distant metastases (Lipski, Klin Monbl Augenheilkd 230:1005-1019, 2013; Metz et al., Klin Monbl Augenheilkd 230:686-691, 2013; Singh and Topham, Ophthalmology 110:956-961, 2003). In sharp contrast to cutaneous melanoma, uveal melanoma shows a strong liver tropism and spreads exclusively via the hematogenous route (except for tumors with extraocular expansion) (Heindl et al., Arch Ophthalmol 128:1001-1008, 2010). The most likely reason for this observation is the lack of lymphatic vessels in the choroid and alymphatic barrier of the sclera (Schlereth et al., Exp Eye Res 125:203-209, 2014; Schroedl et al., Invest Ophthalmol Vis Sci 49:5222-5229, 2008). Due to its location in the immune-privileged eye, the uveal melanoma is widely protected from the immune system. Therefore, the goal of the approach presented here, of a "personalized vaccination therapy" is to help the immune system recognize and fight the tumor. PMID- 27987158 TI - Telegenetics: an Update on Availability and Use of Telemedicine in Clinical Genetics Service. AB - Although telegenetics as a telehealth tool for online genetic counseling was primarily initiated to improve access to genetics care in remote areas, the increasing demand for genetic services with personalized genomic medicine, shortage of clinical geneticists, and the expertise of established genetic centers make telegenetics an attractive alternative to traditional in-person genetic counseling. We review the scope of current telegenetics practice, user experience of patients and clinicians, quality of care in comparison to traditional counseling, and the advantages and disadvantages of information and communication technology in telegenetics. We found that live videoconference consultations are generally well accepted by both clients and clinicians, and these have been successfully used in several genetic counseling settings in practice. Future use of telegenetics could increase patients' access to specialized care and help in meeting the increasing demand for genetic services. PMID- 27987157 TI - Incorporating Pharmacogenomics into Health Information Technology, Electronic Health Record and Decision Support System: An Overview. AB - As the adoption of information technology in healthcare is rising, the potentiality of moving Pharmacogenomics from benchside to bedside is aggravated. This paper reviews the current status of Pharmacogenomics (PGx) information and the attempts for incorporating them into the Electronic Health Record (EHR) system through Decision Support Systems (DSSs). Rigorous review strategies of PGx information and providing context-relevant recommendations in form of action plan dose adjustment, lab tests rather than just information- would be ideal for making clinical recommendations out of PGx information. Lastly, realistic projections of what pharmacogenomics can provide is another important aspect in incorporating Pharmacogenomics into health information technology. PMID- 27987161 TI - What is This Image? 2016: Image 4 Result. PMID- 27987160 TI - Natural History and Comparative Morphology of Immatures of Gamelia anableps (C. Felder & R. Felder) (Lepidoptera: Saturniidae, Hemileucinae). AB - Egg, larva, and pupa of Gamelia anableps (C. Felder & R. Felder, 1874) are described for the first time and the chaetotaxy of the first instar provided. Eggs and selected structures of larvae and pupae were also investigated by means of scanning electron microscopy. Eggs are laid in clusters, are ellipsoidal and laterally flat. Larvae passed through eight instars in about 78 days. Pupation occurs inside a poorly organized cocoon of yellowish silk. The dark brown pupa is cylindrical in shape with appendages firmly fused together and to the body wall. The chaeotaxy is compared with other Saturniidae species belongining to Hemileucinae, Ceratocampinae, and Saturniinae and the natural history of G. anableps compared with other Saturniidae. PMID- 27987159 TI - A Novel Nonlinear Mathematical Model of Thoracic Wall Mechanics During Cardiopulmonary Resuscitation Based on a Porcine Model of Cardiac Arrest. AB - Cardiopulmonary resuscitation (CPR) is used widely to rescue cardiac arrest patients, yet some physiological aspects of the procedure remain poorly understood. We conducted this study to characterize the dynamic mechanical properties of the thorax during CPR in a swine model. This is an important step toward determining optimal CPR chest compression mechanics with the goals of improving the fidelity of CPR simulation manikins and ideally chest compression delivery in real-life resuscitations. This paper presents a novel nonlinear model of the thorax that captures the complex behavior of the chest during CPR. The proposed model consists of nonlinear elasticity and damping properties along with frequency dependent hysteresis. An optimization technique was used to estimate the model coefficients for force-compression using data collected from experiments conducted on swine. To track clinically relevant, time-dependent changes of the chest's properties, the data was divided into two time periods, from 1 to 10 min (early) and greater than 10 min (late) after starting CPR. The results showed excellent agreement between the actual and the estimated forces, and energy dissipation due to viscous damping in the late stages of CPR was higher when compared to the earlier stages. These findings provide insight into improving chest compression mechanics during CPR, and may provide the basis for developing CPR simulation manikins that more accurately represent the complex real world changes that occur in the chest during CPR. PMID- 27987162 TI - Ensembl Plants: Integrating Tools for Visualizing, Mining, and Analyzing Plant Genomic Data. AB - Ensembl Plants ( http://plants.ensembl.org ) is an integrative resource presenting genome-scale information for 39 sequenced plant species. Available data includes genome sequence, gene models, functional annotation, and polymorphic loci; for the latter, additional information including population structure, individual genotypes, linkage, and phenotype data is available for some species. Comparative data is also available, including genomic alignments and "gene trees," which show the inferred evolutionary history of each gene family represented in the resource. Access to the data is provided through a genome browser, which incorporates many specialist interfaces for different data types, through a variety of programmatic interfaces, and via a specialist data mining tool supporting rapid filtering and retrieval of bulk data. Genomic data from many non-plant species, including those of plant pathogens, pests, and pollinators, is also available via the same interfaces through other divisions of Ensembl.Ensembl Plants is updated 4-6 times a year and is developed in collaboration with our international partners in the Gramene ( http://www.gramene.org ) and transPLANT projects ( http://www.transplantdb.eu ). PMID- 27987163 TI - PGSB/MIPS PlantsDB Database Framework for the Integration and Analysis of Plant Genome Data. AB - Plant Genome and Systems Biology (PGSB), formerly Munich Institute for Protein Sequences (MIPS) PlantsDB, is a database framework for the integration and analysis of plant genome data, developed and maintained for more than a decade now. Major components of that framework are genome databases and analysis resources focusing on individual (reference) genomes providing flexible and intuitive access to data. Another main focus is the integration of genomes from both model and crop plants to form a scaffold for comparative genomics, assisted by specialized tools such as the CrowsNest viewer to explore conserved gene order (synteny). Data exchange and integrated search functionality with/over many plant genome databases is provided within the transPLANT project. PMID- 27987164 TI - Plant Genome DataBase Japan (PGDBj). AB - A portal website that integrates a variety of information related to genomes of model and crop plants from databases (DBs) and the literature was generated. This website, named the Plant Genome DataBase Japan (PGDBj, http://pgdbj. jp/en/ ), is comprised of three component DBs and a cross-search engine which provides a seamless search over their contents. One of the three component DBs is the Ortholog DB, which provides gene cluster information based on the amino acid sequence similarity. Over 1,000,000 amino acid sequences of 40 Viridiplantae species were collected from the public DNA DBs, and plant genome DBs such as TAIR and RAP-DB were subjected to reciprocal BLAST searches for clustering. Another component DB is the Plant Resource DB for genomic- and bio-resources. This DB also integrates the SABRE DB, which provides cDNA and genome sequence resources maintained in the RIKEN BioResource Center and National BioResource Projects Japan. The third component DB of PGDBj is the DNA Marker DB, which manually or automatically collects curated information on DNA markers, quantitative trait loci (QTL), and related genetic linkage maps, from the literature and external DBs. By combining these component DBs and a cross-search engine, PGDBj serves as a useful platform to study genetic systems for both fundamental and applied researches for a wide range of plant species. PMID- 27987165 TI - FLAGdb++: A Bioinformatic Environment to Study and Compare Plant Genomes. AB - Today, the growing knowledge and data accumulation on plant genomes do not solve in a simple way the task of gene function inference. Because data of different types are coming from various sources, we need to integrate and analyze them to help biologists in this task. We created FLAGdb++ ( http://tools.ips2.u psud.fr/FLAGdb ) to take up this challenge for a selection of plant genomes. In order to enrich gene function predictions, structural and functional annotations of the genomes are explored to generate meta-data and to compare them. Since data are numerous and complex, we focused on accessibility and visualization with an original and user-friendly interface. In this chapter we present the main tools of FLAGdb++ and a use-case to explore a gene family: structural and functional properties of this family and research of orthologous genes in the other plant genomes. PMID- 27987167 TI - The Bio-Analytic Resource for Plant Biology. AB - Bioinformatic tools have become part of the way plant researchers undertake investigations. Large data sets encompassing genomes, transcriptomes, proteomes, epigenomes, and other "-omes" that have been generated in the past decade may be easily accessed with such tools, such that hypotheses may be generated at the click of a mouse. In this chapter, we'll cover the use of bioinformatic tools available at the Bio-Analytic Resource for Plant Biology at http://bar.utoronto.ca for exploring gene expression and coexpression patterns, undertaking promoter analyses, performing functional classification enrichment analyses for sets of genes, and examining protein-protein interactions. We also touch on some newer bioinformatic tools that allow integration of data from several sources for improved hypothesis generation, both for Arabidopsis and translationally. Most of the data sets come from Arabidopsis, but useful BAR tools for other species will be mentioned where appropriate. PMID- 27987166 TI - Mining Plant Genomic and Genetic Data Using the GnpIS Information System. AB - GnpIS is an information system designed to help scientists working on plants and fungi to decipher the molecular and genetic architecture of trait variations by facilitating the navigation through genetic, genomic, and phenotypic information. The purpose of the present chapter is to illustrate how users can (1) explore datasets from phenotyping experiments in order to build new datasets for studying genotype * environment interactions in traits, (2) browse into the results of other genetic analysis data such as GWAS to generate or check working hypothesis about candidate genes or to identify important alleles and germplasms for breeding programs, and (3) explore the polymorphism in specific area of the genome using InterMine, JBrowse tools embedded in the GnpIS information system. PMID- 27987168 TI - The Evolution of Soybean Knowledge Base (SoyKB). AB - Soybean Knowledge Base (SoyKB) is a comprehensive all-inclusive web resource for bridging the gap between soybean translational genomics and molecular breeding. It provides information for six entities including genes/proteins, microRNAs (miRNAs)/small interfering RNAs (sRNA), metabolites, single nucleotide polymorphisms (SNPs), and plant introduction lines and traits. It has a user friendly web interface publicly available at http://soykb.org , which integrates and presents data in an intuitive manner to the soybean researchers, breeders, and consumers. It incorporates several informatics and analytical tools for integrating and merging various multi-omics datasets. PMID- 27987169 TI - Using TropGeneDB: A Database Containing Data on Molecular Markers, QTLs, Maps, Genotypes, and Phenotypes for Tropical Crops. AB - TropGeneDB ( http://tropgenedb.cirad.fr ) is a web database that manages genomic, genetic, and phenotypic information on tropical crops. It is organized on a crop basis with currently nine public modules: banana, cocoa, coconut, coffee, cotton, oil palm, rice, rubber tree, and sugarcane. TropGeneDB contains data on molecular markers, quantitative trait loci (QTLs), genetic and physical maps, genotyping and phenotyping studies, and information on genetic resources (geographic origin, parentage, collection). Crop-specific web interfaces have been designed to allow quick consultations as well as personalized complex queries. PMID- 27987170 TI - Species-Specific Genome Sequence Databases: A Practical Review. AB - This chapter presents a use case illustrating the search for homologues of a known protein in species-specific genome sequence databases. The results from different species-specific resources are compared to each other and to results obtained from a more general genome sequence database (Phytozome). Various options and settings relevant when searching these databases are discussed. For example, it is shown how the choice of reference sequence set in a given database influences the results one obtains. The provided examples illustrate some problems and pitfalls related to interpreting results obtained from species specific genome sequence databases. PMID- 27987171 TI - A Guide to the PLAZA 3.0 Plant Comparative Genomic Database. AB - PLAZA 3.0 is an online resource for comparative genomics and offers a versatile platform to study gene functions and gene families or to analyze genome organization and evolution in the green plant lineage. Starting from genome sequence information for over 35 plant species, precomputed comparative genomic data sets cover homologous gene families, multiple sequence alignments, phylogenetic trees, and genomic colinearity information within and between species. Complementary functional data sets, a Workbench, and interactive visualization tools are available through a user-friendly web interface, making PLAZA an excellent starting point to translate sequence or omics data sets into biological knowledge. PLAZA is available at http://bioinformatics.psb.ugent.be/plaza/ . PMID- 27987172 TI - Exploring Plant Co-Expression and Gene-Gene Interactions with CORNET 3.0. AB - Selecting and filtering a reference expression and interaction dataset when studying specific pathways and regulatory interactions can be a very time consuming and error-prone task. In order to reduce the duplicated efforts required to amass such datasets, we have created the CORNET (CORrelation NETworks) platform which allows for easy access to a wide variety of data types: coexpression data, protein-protein interactions, regulatory interactions, and functional annotations. The CORNET platform outputs its results in either text format or through the Cytoscape framework, which is automatically launched by the CORNET website.CORNET 3.0 is the third iteration of the web platform designed for the user exploration of the coexpression space of plant genomes, with a focus on the model species Arabidopsis thaliana. Here we describe the platform: the tools, data, and best practices when using the platform. We indicate how the platform can be used to infer networks from a set of input genes, such as upregulated genes from an expression experiment. By exploring the network, new target and regulator genes can be discovered, allowing for follow-up experiments and more in depth study. We also indicate how to avoid common pitfalls when evaluating the networks and how to avoid over interpretation of the results.All CORNET versions are available at http://bioinformatics.psb.ugent.be/cornet/ . PMID- 27987173 TI - PlaNet: Comparative Co-Expression Network Analyses for Plants. AB - Functional relations between genes can be represented as networks. These networks have been successfully used to infer gene function and to mediate transfer of functional knowledge between species. Transcriptionally coordinated or co expressed genes tend to be functionally related, which combined with availability of transcriptomic data for multiple plant species make the co-expression networks a useful resource for the plant community. In this chapter, we describe PlaNet ( www.gene2function.de ), a database that includes comparative analyses for co expression networks of 11 plant species. We exemplify how the tools included in PlaNet can be used to predict gene function, transfer knowledge, and discover conserved and multiplied gene modules. PMID- 27987174 TI - Practical Utilization of OryzaExpress and Plant Omics Data Center Databases to Explore Gene Expression Networks in Oryza Sativa and Other Plant Species. AB - Analysis of a gene expression network (GEN), which is constructed based on similarity of gene expression profiles, is a widely used approach to gain clues for new biological insights. The recent abundant availability of transcriptome data in public databases is enabling GEN analysis under various experimental conditions, and even comparative GEN analysis across species. To provide a platform to gain biological insights from public transcriptome data, valuable databases have been created and maintained. This chapter introduces the web database OryzaExpress, providing omics information on Oryza sativa (rice). The integrated database Plant Omics Data Center, supporting a wide variety of plant species, is also described to compare omics information among multiple plant species. PMID- 27987175 TI - Pathway Analysis and Omics Data Visualization Using Pathway Genome Databases: FragariaCyc, a Case Study. AB - The species-specific plant Pathway Genome Databases (PGDBs) based on the BioCyc platform provide a conceptual model of the cellular metabolic network of an organism. Such frameworks allow analysis of the genome-scale expression data to understand changes in the overall metabolisms of an organism (or organs, tissues, and cells) in response to various extrinsic (e.g. developmental and differentiation) and/or extrinsic signals (e.g. pathogens and abiotic stresses) from the surrounding environment. Using FragariaCyc, a pathway database for the diploid strawberry Fragaria vesca, we show (1) the basic navigation across a PGDB; (2) a case study of pathway comparison across plant species; and (3) an example of RNA-Seq data analysis using Omics Viewer tool. The protocols described here generally apply to other Pathway Tools-based PGDBs. PMID- 27987176 TI - CSGRqtl: A Comparative Quantitative Trait Locus Database for Saccharinae Grasses. AB - Conventional biparental quantitative trait locus (QTL) mapping has led to some successes in the identification of causal genes in many organisms. QTL likelihood intervals not only provide "prior information" for finer-resolution approaches such as GWAS but also provide better statistical power than GWAS to detect variants with low/rare frequency in a natural population. Here, we describe a new element of an ongoing effort to provide online resources to facilitate study and improvement of the important Saccharinae clade. The primary goal of this new resource is the anchoring of published QTLs for this clade to the Sorghum genome. Genetic map alignments translate a wealth of genomic information from sorghum to Saccharum spp., Miscanthus spp., and other taxa. In addition, genome alignments facilitate comparison of the Saccharinae QTL sets to those of other taxa that enjoy comparable resources, exemplified herein by rice. PMID- 27987177 TI - Plant Genome Duplication Database. AB - Genome duplication, widespread in flowering plants, is a driving force in evolution. Genome alignments between/within genomes facilitate identification of homologous regions and individual genes to investigate evolutionary consequences of genome duplication. PGDD (the Plant Genome Duplication Database), a public web service database, provides intra- or interplant genome alignment information. At present, PGDD contains information for 47 plants whose genome sequences have been released. Here, we describe methods for identification and estimation of dates of genome duplication and speciation by functions of PGDD.The database is freely available at http://chibba.agtec.uga.edu/duplication/. PMID- 27987178 TI - Variant Effect Prediction Analysis Using Resources Available at Gramene Database. AB - The goal of Gramene database ( www.gramene.org ) is to empower the plant research community in conducting comparative genomics studies across model plants and crops by employing a phylogenetic framework and orthology-based projections. Gramene database (release #49) provides resources for comparative plant genomics including well-annotated plant genomes (39 complete reference genomes and six partial genomes), genetic or structural variation data for 14 plant species, pathways for 58 plant species, and gene expression data for 14 species including Arabidopsis, rice, maize, soybean, wheat, etc. (fetched from EBI-EMBL Gene Expression Atlas database). Gramene also facilitates visualization and analysis of user-defined data in the context of species-specific Genome Browsers or pathways. This chapter describes basic navigation for Gramene users and illustrates how they can use the genome section to analyze the gene expression and nucleotide variation data generated in their labs. This includes (1) upload and display of genomic data onto a Genome Browser track, (2) analysis of variation data using online Variant Effect Predictor (VEP) tool for smaller data sets, and (3) the use of the stand-alone Perl scripts and command line protocols for variant effect prediction on larger data sets. PMID- 27987179 TI - Plant Promoter Database (PPDB). AB - ppdb ( http://ppdb.agr.gifu-u.ac.jp ) is a web-based plant promoter database that provides promoter information of each gene in genomes of Arabidopsis, rice, poplar, and Physcomitrella patens. In this database, recognition of a promoter structure is achieved by annotating genome sequences with our sequence lists of bioinformatically identified octamers for core promoter structure (TATA boxes, Initiators, Y Patches, GA and CA Elements) and regulatory element groups (REGs), together with information of transcription start sites (TSSs) that have been experimentally identified. Our promoter elements are octamer sequences that show strongly biased localization profiles in the promoter region, extracted by the local distribution of short sequence (LDSS) analysis. In addition, REGs are linked with the information of the PLACE database and also with their physiological roles that are predicted using large-scale gene expression data. PMID- 27987180 TI - Construction of the Leaf Senescence Database and Functional Assessment of Senescence-Associated Genes. AB - Leaf senescence is the last phase of plant development and a highly coordinated process regulated by a large number of senescence-associated genes (SAGs). By broad literature survey, we constructed a leaf senescence database (LSD) in 2011 and updated it to Version 2.0 in 2014 ( http://www.eplantsenescence.org/ and http://psd.cbi.pku.edu.cn/ ) which contains a total of 5357 genes and 324 mutants from 44 species. These SAGs were retrieved based on genetic, genomic, proteomic, physiological, or other experimental evidence and were classified into different categories according to their functions in leaf senescence or morphological phenotype of mutants. To provide comprehensive information for SAGs, we made extensive annotation by both manual and computational approaches. In addition, we predicted putative orthologues of the SAGs in other species. LSD has a user friendly interface to allow users to make text queries or BLAST searches and to download SAGs sequences for local analysis. Functional analyses of putative SAGs reveal that WRKY75, AZF2, NAC16, and WRKY26 are positive regulators of leaf senescence, while MKP2 and CTR1 perform negative regulation to leaf senescence. This database has been served as a valuable resource for basic research on the function of SAGs and evolution of plant leaf senescence, as well as for the exploration of genetic traits in agronomically important plants. PMID- 27987181 TI - Association of SNPs in dopamine and serotonin pathway genes and their interacting genes with temperament traits in Charolais cows. AB - Cattle temperament is a complex trait, and molecular studies aimed at defining this trait are scarce. We used an interaction networks approach to identify new genes (interacting genes) and to estimate their effects and those of 19 dopamine- and serotonin-related genes on the temperament traits of Charolais cattle. The genes proopiomelanocortin (POMC), neuropeptide Y (NPY), solute carrier family 18, member 2 (SLC18A2) and FBJ murine osteosarcoma viral oncogene homologue (FOSFBJ) were identified as new candidates. Their potential to be associated with temperament was estimated according to their reported biological activities, which included interactions with neural activity, receptor function, targeting or synthesis of neurotransmitters and association with behaviour. Pen score (PS) and exit velocity (EV) measures were determined from 412 Charolais cows to calculate their temperament score (TS). Based on the TS, calm (n = 55; TS, 1.09 +/- 0.33) and temperamental (n = 58; TS, 2.27 +/- 0.639) cows were selected and genotyped using a 248 single-nucleotide variation (SNV) panel. Of the 248 variations in the panel, only 151 were confirmed to be polymorphic (single-nucleotide polymorphisms; SNPs) in the tested population. Single-marker association analyses between genotypes and temperament measures (EV, PS and/or TS) indicated significant associations of six SNPs from four candidate genes. The markers rs109576799 and rs43696138, located in the DRD3 and HTR2A genes, respectively, were significantly associated with both EV and TS traits. Four markers, rs110365063 and rs137756569 from the POMC gene and rs110365063 and rs135155082 located in SLC18A2 and DRD2, respectively, were associated with PS. The variant rs110365063 located in bovine SLC18A2 causes a change in the amino acid sequence from Ala to Thr. Further studies are needed to confirm the association of genetic profile with cattle temperament; however, our study represents important progress in understanding the regulation of cattle temperament by different genes with divergent functions. PMID- 27987182 TI - Modified step aerobics training and neuromuscular function in osteoporotic patients: a randomized controlled pilot study. AB - BACKGROUND: Training programs directed to improve neuromuscular and musculoskeletal function of the legs are scarce with respect to older osteoporotic patients. We hypothesized that a modified step aerobics training program might be suitable for this purpose and performed a randomized controlled pilot study to assess the feasibility of conducting a large study. Here we report on the training-related effects on neuromuscular function of the plantar flexors. PATIENTS AND METHODS: Twenty-seven patients with an age of at least 65 years were enrolled and randomized into control and intervention group. The latter received supervised modified step aerobics training (twice weekly, 1 h per session) over a period of 6 months. At baseline, and after 3 and 6 months neuromuscular function of the plantar flexors, i.e., isometric maximum voluntary torque, rate of torque development and twitch torque parameters were determined in detail in all patients of both groups. RESULTS: Twenty-seven patients (median age 75 years; range 66-84 years) were randomized (control group n = 14; intervention group n = 13). After 3 and 6 months of training, maximum voluntary contraction strength in the intervention group was significantly higher by 7.7 Nm (9.1%; 95% CI 3.3-12.2 Nm, P < 0.01) and 12.4 Nm (14.8%; 95% CI 6.4-18.5 Nm, P < 0.01) compared to controls. These changes were most probably due to neural and muscular adaptations. CONCLUSION: It is worthwhile to investigate efficacy of this training program in a large randomized trial. However, a detailed neuromuscular assessment appears feasible only in a subset of participants. PMID- 27987183 TI - A gamma-distribution convolution model of 99mTc-MIBI thyroid time-activity curves. AB - BACKGROUND: The convolution approach to thyroid time-activity curve (TAC) data fitting with a gamma distribution convolution (GDC) TAC model following bolus intravenous injection is presented and applied to 99mTc-MIBI data. The GDC model is a convolution of two gamma distribution functions that simultaneously models the distribution and washout kinetics of the radiotracer. The GDC model was fitted to thyroid region of interest (ROI) TAC data from 1 min per frame 99mTc MIBI image series for 90 min; GDC models were generated for three patients having left and right thyroid lobe and total thyroid ROIs, and were contrasted with washout-only models, i.e., less complete models. GDC model accuracy was tested using 10 Monte Carlo simulations for each clinical ROI. RESULTS: The nine clinical GDC models, obtained from least counting error of counting, exhibited corrected (for 6 parameters) fit errors ranging from 0.998% to 1.82%. The range of all thyroid mean residence times (MRTs) was 212 to 699 min, which from noise injected simulations of each case had an average coefficient of variation of 0.7% and a not statistically significant accuracy error of 0.5% (p = 0.5, 2-sample paired t test). The slowest MRT value (699 min) was from a single thyroid lobe with a tissue diagnosed parathyroid adenoma also seen on scanning as retained marker. The two total thyroid ROIs without substantial pathology had MRT values of 278 and 350 min overlapping a published 99mTc-MIBI thyroid MRT value. One combined value and four unrelated washout-only models were tested and exhibited R squared values for MRT with the GDC, i.e., a more complete concentration model, ranging from 0.0183 to 0.9395. CONCLUSIONS: The GDC models had a small enough TAC noise-image misregistration (0.8%) that they have a plausible use as simulations of thyroid activity for querying performance of other models such as washout models, for altered ROI size, noise, administered dose, and image framing rates. Indeed, of the four washout-only models tested, no single model approached the apparent accuracy of the GDC model using only 90 min of data. Ninety minutes is a long gamma-camera acquisition time for a patient, but a short a time for most kinetic models. Consequently, the results should be regarded as preliminary. PMID- 27987184 TI - Look who's talking-the crosstalk between oxidative stress and autophagy supports exosomal-dependent release of HCV particles. AB - Autophagy is a highly conserved and regulated intracellular lysosomal degradation pathway that is essential for cell survival. Dysregulation has been linked to the development of various human diseases, including neurodegeneration and tumorigenesis, infection, and aging. Besides, many viruses hijack the autophagosomal pathway to support their life cycle. The hepatitis C virus (HCV), a major cause of chronic liver diseases worldwide, has been described to induce autophagy. The autophagosomal pathway can be further activated in response to elevated levels of reactive oxygen species (ROS). HCV impairs the Nrf2/ARE dependent induction of ROS-detoxifying enzymes by a so far unprecedented mechanism. In line with this, this review aims to discuss the relevance of HCV dependent elevated ROS levels for the induction of autophagy as a result of the impaired Nrf2 signaling and the described crosstalk between p62 and the Nrf2/Keap1 signaling pathway. Moreover, autophagy is functionally connected to the endocytic pathway as components of the endosomal trafficking are involved in the maturation of autophagosomes. The release of HCV particles is still not fully understood. Recent studies suggest an involvement of exosomes that originate from the endosomal pathway in viral release. In line with this, it is tempting to speculate whether HCV-dependent elevated ROS levels induce autophagy to support exosome-mediated release of viral particles. Based on recent findings, in this review, we will further highlight the impact of HCV-induced autophagy and its interplay with the endosomal pathway as a novel mechanism for the release of HCV particles. PMID- 27987185 TI - Cloning, Characterization, and Expression Analysis of a Gene Encoding a Putative Lysophosphatidic Acid Acyltransferase from Seeds of Paeonia rockii. AB - Tree peony (Paeonia section Moutan DC.) is an excellent woody oil crop, and the cloning and functional analysis of genes related to fatty acid (FA) metabolism from this organism has not been reported. Lysophosphatidic acid acyltransferase (LPAAT), which converts lysophosphatidic acid (LPA) to phosphatidic acid (PA), catalyzes the addition of fatty acyl moieties to the sn-2 position of the LPA glycerol backbone in triacylglycerol (TAG) biosynthesis. This project reports a putative lysophosphatidic acid acyltransferase gene PrLPAAT1 isolated from Paeonia rockii. Our data indicated that PrLPAAT1 has 1047 nucleotides and encodes a putative 38.8 kDa protein with 348 amino acid residues. Bioinformatic analysis demonstrated that PrLPAAT1 contains two transmembrane domains (TMDs). Subcellular localization analysis confirmed that PrLPAAT1 is a plasma membrane protein. Phylogenetic analysis revealed that PrLPAAT1 shared 74.3 and 65.5% amino acid sequence identities with the LPAAT1 sequences from columbine and grape, respectively. PrLPAAT1 belongs to AGPAT family, and may have acyltransferase activity. PrLPAAT1 was ubiquitously expressed in diverse tissues, and PrLPAAT1 expression was higher in the flower and developing seed. PrLPAAT1 is probably an important component in the FA accumulation process, especially during the early stages of seed development. PrLPAAT1 overexpression using a seed-specific promoter increased total FA content and the main FA accumulation in Arabidopsis transgenic plants. PMID- 27987186 TI - Microbial Community Structure of Activated Sludge for Biosolubilization of Two Different Rock Phosphates. AB - A microbial consortium was directly taken from activated sludge and was used to solubilize rock phosphates (RPs) in a lab-scale bioreactor in this study. Results showed that the microbial consortium could efficiently release soluble phosphorus (P) from the RPs, and during 30-day incubation, it grew well in the bioreactor and reduced the pH of the solutions. The biosolubilization process was also illustrated by the observation of scanning electron microscopy combined with an energy dispersive X-ray spectroscopy (SEM-EDX), which showed an obvious corrosion on the ore surfaces, and most elements were removed from the ore samples. The analysis of microbial community structure by Illumina 16S ribosomal RNA (rRNA) gene and 18S rRNA gene MiSeq sequencing reflected different microbial diversity and richness in the solutions added with different ore samples. A lower richness and diversity of bacteria but a higher richness and diversity of fungi occurred in the solution added with ore sample 1 compared to that of in the solution added with ore sample 2. Alphaproteobacteria and Saccharomycetes were the dominating bacterial and fungal group, respectively, both in the solutions added with ore samples 1 and 2 at the class level. However, their abundances in the solution added with ore sample 1 were obviously lower than that in the solution added with ore sample 2. This study provides new insights into our understanding of the microbial community structure in the biosolubilization of RPs by a microbial consortium directly taken from activated sludge. PMID- 27987187 TI - Cations Optimization for Protein Enrichment in Rice Straw by Mixed Cultures of Neurospora crassa 14-8 and Candida utilis Using Response Surface Methodology. AB - This study investigated the effect of cation optimization by mixed cultures of Neurospora crassa and Candida utilis on the true protein (TP) content. Firstly, to enhance the nutritional contents of rice straw (RS), two fermentation parameters (effect of inoculation ratio and inoculation time) were optimized. It was found that when C. utilis was inoculated 60 h later than N. crassa with the inoculation ratio of 1:5 (N. crassa to C. utilis), the maximum TP yield was obtained. In order to further optimize TP content, Plackett-Burman design (PBD) and Box-Behnken design (BBD) of response surface methodology (RSM) were adopted. The results of PBD indicated that Mn2+, Zn2+, and Cu2+ were the significant variables. The optimum values for the three cations determined by the BBD were as follows: Mn2+ 0.06 g/L, Zn2+ 0.15 g/L, and Cu2+ 0.2 g/L. After the optimization of RSM, a model was proposed to predict the optimum value 10.36% confirmed by the experimental result 9.84%. The TP content increased from 3.98 to 9.84%, with 147.24% of its increase rate. This study proposed an ecofriendly and economical way to convert RS into protein-enriched livestock feed. PMID- 27987188 TI - Purification and Biochemical Characterization of a Neutral Serine Protease from Trichoderma harzianum. Use in Antibacterial Peptide Production from a Fish By Product Hydrolysate. AB - This study reports the purification and biochemical characterization of an extracellular neutral protease from the fungus Trichoderma harzianum. The protease (Th-Protease) was purified from the culture supernatant to homogeneity by a three-step procedure with 14.2% recovery and 9.06-fold increase in specific activity. The purified enzyme appeared as a single protein band after sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) with a molecular mass of about 20 kDa. The optimum pH and temperature for the proteolytic activity were pH 7.0 and 40 degrees C, respectively. The enzyme was then investigated for its potential application in the production of antibacterial peptides. Interestingly, Scorpaena notata viscera protein hydrolysate prepared using the purified serine protease (Th-Protease) showed remarkable in vitro antibacterial activities. A peptide with a high antibacterial activity was further purified by a three-step procedure, and its sequence was identified as FPIGMGHGSRPA. The result of this study offers a promising alternative to produce natural antibacterial peptides from fish protein hydrolysate. PMID- 27987189 TI - Immunomodulatory Properties of Filamentous Fungi Cultivated through Solid-State Fermentation on Rapeseed Meal. AB - Water extracts from solid-state fermentation (SSF) on rapeseed meal using filamentous fungi exhibit interesting immunomodulatory activities in vitro. Immunomodulation was determined by the capacity of the compounds to activate blood neutrophils and to influence cytokine production in human peripheral blood mononuclear cells (PBMC) and mouse bone marrow-derived macrophages (BMDM). Among the strains tested, Aspergillus sojae mycelium and SSF extracts were the most promising in terms of enhancing the immune response. The filamentous fungus was also successfully cultivated in a pre-pilot bioreactor with forced aeration. The results indicated that the extracts not only activated blood neutrophils but also significantly modulated IL-1beta cytokine levels with lipopolysaccharide (LPS) stimulated PBMC and BMDM without any cytotoxicity in immune cells. IL-1beta was down-regulated in a dose-dependent manner in the presence of A. sojae crude mycelium and SSF extract with PBMC, which indicated that there was an anti inflammatory activity, whereas IL-1beta secretion was up-regulated in the presence of stimulated BMDM with the highest concentration that was tested (100 MUg/mL). The non-fermented rapeseed had no effect at the same concentration. SSF culture, as a natural product, may be a good source for the development of functional feed with an immunostimulating effect or could potentially be used in medicinal applications. PMID- 27987191 TI - Continuous Hydrogen Production from Agricultural Wastewaters at Thermophilic and Hyperthermophilic Temperatures. AB - The objective of this study was to investigate the effects of hydraulic retention time (HRT) (8 to 0.5 h) and temperature (55 to 75 degrees C) in two anaerobic fluidized bed reactors (AFBR) using cheese whey (AFBR-CW = 10,000 mg sugars L-1) and vinasse (AFBR-V = 10,000 mg COD L-1) as substrates. Decreasing the HRT to 0.5 h increased the hydrogen production rates in both reactors, with maximum values of 5.36 +/- 0.81 L H2 h-1 L-1 in AFBR-CW and 0.71 +/- 0.16 L H2 h-1 L-1 in AFBR V. The optimal conditions for hydrogen production were the HRT of 4 h and temperature of 65 degrees C in AFBR-CW, observing maximum hydrogen yield (HY) of 5.51 +/- 0.37 mmol H2 g COD-1. Still, the maximum HY in AFBR-V was 1.64 +/- 0.22 mmol H2 g COD-1 at 4 h and 55 degrees C. However, increasing the temperature to 75 degrees C reduced the hydrogen production in both reactors. Methanol and butyric, acetic, and lactic acids were the main metabolites at temperatures of 55 and 65 degrees C, favoring the butyric and acetic metabolic pathways of hydrogen production. The increased productions of lactate, propionate, and methanol at 75 degrees C indicate that the hydrogen-producing bacteria in the thermophilic inoculum were inhibited under hyperthermophilic conditions. PMID- 27987192 TI - Effect of Furfural on Saccharomyces carlsbergensis Growth, Physiology and Ethanol Production. AB - This work described the effect of furfural, a product resulting from the lignocellulosic material pretreatment, on Saccharomyces carlsbergensis growth and ethanol production. Flow cytometry was used to evaluate the yeast membrane potential, membrane integrity, reactive oxygen species production and lipid content. Above 0.3 g/L of furfural, a progressive decrease in the maximal specific growth rate was observed, reaching 53% of the value obtained in the absence of toxic when the cells were grown in the presence of 4 g/L of furfural. In general, the yeast biomass concentration and yield were less affected by the furfural presence than the specific growth rate, and a maximum reduction of 25% was observed for the assay at 4 g/L. The ethanol production was even less affected by the furfural presence than the yeast growth. At 4 g/L of furfural, the maximum ethanol concentration was reduced by only 10% relatively to the maximum ethanol concentration observed in the absence of toxic. At 5 g/L of furfural, the yeast cells were barely able to keep metabolic functions and produced a final ethanol concentration of 0.87 g/L although growth was undetectable. S. carlsbergensis membrane potential was affected by the furfural presence, concomitantly with the ethanol production. However, at 4 g/L, most of the yeast cells (90%) displayed the cytoplasmic membrane depolarized. The proportion of cells with increasing reactive oxygen species (ROS) production levels increased for the experiments at 0-4 g/L. For the experiment at 4.5 g/L of furfural, ROS production was observed for only 11% of the yeast cells. The yeast lipid content was also severely affected by the furfural presence. Both polar and neutral lipids decreased in the presence of furfural, and this reduction was more notorious during the stationary phase. PMID- 27987190 TI - Domain-Specific Monoclonal Antibodies Against Human Rev-erbbeta. AB - The nuclear receptor Rev-erbbeta is a potent transcriptional factor whose functional study has been limited by the lack of suitable antibodies against it. To better understand Rev-erbbeta's biological roles, we generated five hybridoma cell lines secreting antibodies against human Rev-erbbeta in mice immunized with the purified, prokaryotically expressed recombinant Rev-erbbeta-6His fusion protein. Using Western blotting and immunofluorescence analyses, all the five monoclonal antibodies (MAbs) showed strong immunoreactivity to both prokaryotically and eukaryotically expressed recombinant Rev-erbbeta. An immunoprecipitation study showed that all five monoclonal antibodies against Rev erbbeta were able to pull down the recombinant Rev-erbbeta-Flag protein, but only one of the MAbs against Rev-erbbeta, 37H8, could pull down the endogenous Rev erbbeta protein. Furthermore, domain specificity of these MAbs was characterized. Due to the high similarities between Rev-erbalpha and Rev-erbbeta in the C and E domains, those C and E domain-specific anti-Rev-erbbeta antibodies can react with human Rev-erbalpha as well. The MAbs produced in the study will provide a valuable tool for investigating the function of Rev-erbbeta. PMID- 27987193 TI - Amitkumar Mehta on the Immunomodulating Effects of Targeted Therapy for Multiple Myeloma. PMID- 27987194 TI - Isolated Limb Perfusion for Stage III Melanoma: Does It Still Have a Role in the Present Era of Effective Systemic Therapy? AB - The management of advanced-stage melanoma has changed dramatically with the introduction of systemic targeted therapy and immunotherapy. Patients with stage IV melanoma currently benefit from agents that are extremely effective, especially when compared with classic chemotherapeutic agents. The field is still evolving, and these newer agents are now used in patients with stage III disease, in the setting of adjuvant trials after resection of the disease bulk. Patients with bulky and numerous in-transit metastases form a very distinct subset of melanoma patients. The disease is classically staged as stage III, but because it is usually unresectable, a regional or systemic rather than a local approach is warranted. Isolated limb perfusion (ILP) is a regional technique that has been shown to provide high response rates and tumor control. The impressive results of ILP were obtained in the era of ineffective systemic agents. Now that this situation has profoundly changed, questions arise as to what the role of ILP is in the treatment of patients with melanoma in-transit metastases, which patients are ideal candidates for ILP, and whether ILP is here to stay-or will become obsolete in the near future. PMID- 27987195 TI - New Does Not Always Mean Better: Isolated Limb Perfusion Still Has a Role in the Management of In-Transit Melanoma Metastases. PMID- 27987196 TI - Point: The Role of Stem Cell Transplantation in Mantle Cell Lymphoma: Where It Fits in the New Paradigm. PMID- 27987197 TI - Counterpoint: The Role of Stem Cell Transplantation in Mantle Cell Lymphoma: The Pendulum Swings Again: Time to Reassess the Role of ASCT in First Complete Remission. PMID- 27987198 TI - Breast Cancer Following Radiation for Hodgkin Lymphoma: Clinical Scenarios and Risk-Reducing Strategies. AB - Since most patients with Hodgkin lymphoma survive their disease, long-term issues such as development of second primary malignancies arise, especially in patients treated with multimodal therapy including radiation therapy plus chemotherapy. The risk of breast cancer is significantly elevated in women exposed to high-dose ionizing radiation to the chest before age 40. The case of a 48-year-old patient with a lump in her right breast is presented as a clinical scenario in this article. We review available strategies for screening and risk reduction through chemoprevention or risk-reducing surgery, as well as challenges for management of breast cancer in patients with prior exposure to radiation for Hodgkin lymphoma. The Children's Oncology Group clinical practice guidelines for long-term follow up care of pediatric cancer survivors provide recommendations that have been endorsed by American and European oncologists. PMID- 27987199 TI - Breast Cancer After Hodgkin Lymphoma: The Price of Success. PMID- 27987200 TI - Metastatic Papillary Adenocarcinoma in a 22-Year-Old: Is Her History of Mayer Rokitansky-Kuster-Hauser Syndrome Causative or Incidental? PMID- 27987201 TI - Treatment of Acute Lymphoblastic Leukemia in Adults: Applying Lessons Learned in Children. AB - Although pediatric acute lymphoblastic leukemia (ALL) has cure rates of over 90%, adult ALL remains a challenging disease to treat, with cure rates roughly half those seen in children. The inferior outcomes in adults can be attributed mainly to adverse genetic features, as well as the inability-particularly of older adults-to tolerate chemotherapy. Modest improvements have been seen in outcomes for adolescents and young adults; these can largely be attributed to the use of pediatric-type combination chemotherapy regimens in patients aged 50 years or younger. In patients with Philadelphia chromosome-positive ALL, once a very-high risk group, outcomes have markedly improved as a result of the use of tyrosine kinase inhibitors in combination with chemotherapy. The persistence of minimal residual disease has emerged as the single most important prognostic factor for ALL and is increasingly being used to help make decisions regarding allogeneic hematopoietic stem cell transplantation or novel salvage therapies. Relapsed/refractory ALL has had a dismal prognosis. In recent years, novel immune based therapies have been developed that have shown impressive results and that have the potential to improve the outcome of relapsed ALL. These include antibody drug conjugates, the bispecific T-cell-engaging antibody blinatumomab, and chimeric antigen receptor-modified T cells. PMID- 27987202 TI - The Heartaches of Cancer Therapy: Acute and Late Cardiotoxicity in Cancer Survivors. PMID- 27987203 TI - ACR Appropriateness Criteria(r) Recurrent Hodgkin Lymphoma. AB - This topic addresses the management of recurrent Hodgkin lymphoma. While autologous stem cell transplantation may be appropriate for select cases of recurrent disease following comprehensive combined-modality therapy, other options exist for patients treated with lower-dose therapy for early-stage disease. Additionally, innovative targeted therapies provide newer salvage options to consider. The American College of Radiology Appropriateness Criteria(r) are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the complex decision-making associated with the management of recurrent Hodgkin lymphoma. PMID- 27987204 TI - Childhood trauma and mixed episodes are associated with poor response to lithium in bipolar disorders. AB - OBJECTIVES: Reliable predictors of response to lithium are still lacking in bipolar disorders (BDs). However, childhood trauma has been hypothesized to be associated with poor response to lithium. METHODS: We included 148 patients with BD, euthymic when retrospectively and clinically assessed for response to lithium and childhood trauma using reliable scales. RESULTS: According to the 'Alda scale', the sample consisted in 20.3% of excellent responders, 49.3% of partial responders and 30.4% of non-responders to lithium. A higher level of physical abuse significantly correlated with a lower level of response to lithium (P = 0.009). As compared to patients not exposed to any abuse, patients with at least two trauma abuses (emotional, physical or sexual) were more at risk of belonging to the non-responders group (OR = 4.91 95% CI (1.01-27.02)). Among investigated clinical variables, lifetime presence of mixed episodes and alcohol misuse were associated with non-response to lithium. Multivariate analyses demonstrated that physical abuse and mixed episodes were independently associated with poor response to lithium (P = 0.005 and P = 0.013 respectively). CONCLUSIONS: Childhood physical abuse might be involved in a poor future response to lithium prophylaxis, this effect being independent of the association between clinical expression of BD and poor response to lithium. PMID- 27987205 TI - Mid-life environmental enrichment increases synaptic density in CA1 in a mouse model of Abeta-associated pathology and positively influences synaptic and cognitive health in healthy ageing. AB - Early-life cognitive enrichment may reduce the risk of experiencing cognitive deterioration and dementia in later-life. However, an intervention to prevent or delay dementia is likely to be taken up in mid to later-life. Hence, we investigated the effects of environmental enrichment in wildtype mice and in a mouse model of Abeta neuropathology (APPSWE /PS1dE9 ) from 6 months of age. After 6 months of housing in standard laboratory cages, APPSWE /PS1dE9 (n = 27) and healthy wildtype (n = 21) mice were randomly assigned to either enriched or standard housing. At 12 months of age, wildtype mice showed altered synaptic protein levels and relatively superior cognitive performance afforded by environmental enrichment. Environmental enrichment was not associated with alterations to Abeta plaque pathology in the neocortex or hippocampus of APPSWE /PS1dE9 mice. However, a significant increase in synaptophysin immunolabeled puncta in the hippocampal subregion, CA1, in APPSWE /PS1dE9 mice was detected, with no significant synaptic density changes observed in CA3, or the Fr2 region of the prefrontal cortex. Moreover, a significant increase in hippocampal BDNF was detected in APPSWE /PS1dE9 mice exposed to EE, however, no changes were detected in neocortex or between Wt animals. These results demonstrate that mid to later-life cognitive enrichment has the potential to promote synaptic and cognitive health in ageing, and to enhance compensatory capacity for synaptic connectivity in pathological ageing associated with Abeta deposition. PMID- 27987206 TI - Zika virus is not thermostable: very effective virus inactivation during heat treatment (pasteurization) of human serum albumin. AB - BACKGROUND: The ongoing Zika virus (ZIKV) outbreak in the Americas has also raised concerns around the potential for ZIKV transmission via blood products. Plasma-derived products are considered safe, because effective viral-inactivation and removal methods are implemented in their manufacturing processes. However, a recent study has indicated that ZIKV is "thermally stable" compared with the closely related Dengue virus, thus raising the question of whether heat treatments, as embedded in the manufacturing of plasma-derived products, are as effective against ZIKV as was previously shown for other Flaviviruses. Therefore, the sensitivity of ZIKV to heat inactivation was investigated using the pasteurization of human serum albumin (HSA) as an example. STUDY DESIGN AND METHODS: Heat treatment (58.0 +/- 1.0 degrees C for 590 +/- 10 minutes) of HSA was investigated for the capacity to reduce ZIKV in two different protein concentrations (5% and 25% HSA). The results were compared with data obtained in identical set-ups for the closely related West Nile virus, tick-borne encephalitis virus, and bovine viral diarrhea virus. RESULTS: Heat treatment of HSA inactivated ZIKV to below the limit of detection already during the heating phase to 57.0 degrees C, that is, even before the 10-hour incubation at 58.0 +/- 1.0 degrees C commenced. For West Nile virus, bovine viral diarrhea virus, and tick-borne encephalitis virus, incubations up to 180 minutes were required to achieve inactivation to below the limit of detection. CONCLUSION: ZIKV was more sensitive to heat treatment than other members of the Flaviviridae and thus does not pose a concern for plasma products that include a heat treatment in their manufacturing process. PMID- 27987207 TI - Disordered eating in ethnic minority adolescents with overweight. AB - High rates of disordered eating exist among adolescents with overweight and among ethnic/racial minority adolescents. Given the lack of research examining how eating disorder risk is moderated by both overweight and ethnicity/race, this study aimed to explore interactions between ethnicity/race and overweight status on disordered eating behaviors in a population-based adolescent sample. Cross sectional data from adolescents (n = 2,271; 52% females) of White (23%), Black (34%), Hispanic (20%), and Asian (23%; 82% Hmong) ethnicity/race participating in the EAT 2010 study were used to examine associations between overweight status and disordered eating behaviors across ethnic/racial groups. Disordered eating behaviors occurred more frequently among adolescents with overweight compared with those without overweight across all ethnic/racial groups. Although some differences in the prevalence of disordered eating were found by ethnicity/race, particularly in girls, no consistent patterns of interaction emerged. Overweight White and Hispanic girls reported the highest risk for dieting, while the highest risk for unhealthy weight control behaviors was among overweight Black girls, and for overeating among overweight White and Asian girls. Within a society in which thinness is highly valued and being overweight is stigmatized, across diverse cultural groups, adolescents with overweight are at risk for disordered eating. PMID- 27987208 TI - Poor stem cell harvest may not always be related to poor mobilization: lessons gained from a mobilization study in patients with beta-thalassemia major. AB - BACKGROUND: Hematopoietic stem cell mobilization and leukapheresis in adult patients with beta-thalassemia have recently been optimized in the context of clinical trials for obtaining hematopoietic stem cells for thalassemia gene therapy. In some patients, however, the yield of cluster of differentiation 34 positive (CD34+) cells was poor despite successful mobilization, and a modification of apheresis settings was mandatory for harvest rescue. STUDY DESIGN AND METHODS: Data were analyzed from 20 adult patients with beta-thalassemia who were enrolled in a clinical trial of optimizing mobilization strategies for stem cell gene therapy. The aim of this post-hoc analysis was to assess how certain hematological and/or clinical parameters may correlate with low collection efficiency in the presence of adequate numbers of circulating stem cells after pharmacological mobilization and standard leukapheresis procedures. RESULTS: Among 19 patients who achieved optimal mobilization with Plerixafor, four who underwent splenectomy demonstrated disproportionately poor CD34+ cell harvests, as determined by their circulating CD34+ cell counts after mobilization. All four patients who underwent splenectomy presented at baseline and before first apheresis with lymphocytosis resulting in lymphocyte/neutrophil ratios well above 1 and marked reticulocytosis compared with patients who achieved optimal mobilization/CD34+ cell harvest. Such unexpected expansion of specific cell populations disrupted the normal cell layer separation and necessitated modification of the apheresis settings to rescue the harvests. CONCLUSIONS: By close examination of certain hematological and/or clinical parameters before leukapheresis, patients who, despite adequate mobilization, are at risk for poor CD34+ cell harvests may be identified, and harvest failure can be prevented by adjusting the apheresis settings. PMID- 27987209 TI - The sodium transporter encoded by the HKT1;2 gene modulates sodium/potassium homeostasis in tomato shoots under salinity. AB - Excessive soil salinity diminishes crop yield and quality. In a previous study in tomato, we identified two closely linked genes encoding HKT1-like transporters, HKT1;1 and HKT1;2, as candidate genes for a major quantitative trait locus (kc7.1) related to shoot Na+ /K+ homeostasis - a major salt tolerance trait - using two populations of recombinant inbred lines (RILs). Here, we determine the effectiveness of these genes in conferring improved salt tolerance by using two near-isogenic lines (NILs) that were homozygous for either the Solanum lycopersicum allele (NIL17) or for the Solanum cheesmaniae allele (NIL14) at both HKT1 loci; transgenic lines derived from these NILs in which each HKT1;1 and HKT1;2 had been silenced by stable transformation were also used. Silencing of ScHKT1;2 and SlHKT1;2 altered the leaf Na+ /K+ ratio and caused hypersensitivity to salinity in plants cultivated under transpiring conditions, whereas silencing SlHKT1;1/ScHKT1;1 had a lesser effect. These results indicate that HKT1;2 has the more significant role in Na+ homeostasis and salinity tolerance in tomato. PMID- 27987210 TI - Anti-anhedonic effect of selective serotonin reuptake inhibitors with affinity for sigma-1 receptors in picrotoxin-treated mice. AB - BACKGROUND AND PURPOSE: Prefrontal dopamine release by the combined activation of 5-HT1A and sigma-1 (sigma1 ) receptors is enhanced by the GABAA receptor antagonist picrotoxin in mice. Here, we examined whether this neurochemical event was accompanied by behavioural changes. EXPERIMENTAL APPROACH: Male mice were treated with picrotoxin to decrease GABAA receptor function. Their anhedonic behaviour was measured using the female encounter test. The expression of c-Fos was determined immunohistochemically. KEY RESULTS: Picrotoxin caused an anxiogenic effect on three behavioural tests, but it did not affect the immobility time in the forced swim test. Picrotoxin decreased female preference in the female encounter test and attenuated the female encounter-induced increase in c-Fos expression in the nucleus accumbens. Picrotoxin-induced anhedonia was ameliorated by fluvoxamine and S-(+)-fluoxetine, selective serotonin reuptake inhibitors with high affinity for the sigma1 receptor. The effect of fluvoxamine was blocked by a 5-HT1A or a sigma1 receptor antagonist, and co-administration of the sigma1 receptor agonist (+)-SKF-10047 and the 5-HT1A receptor agonist osemozotan mimicked the effect of fluvoxamine. By contrast, desipramine, duloxetine and paroxetine, which have little affinity for the sigma1 receptor, did not affect picrotoxin-induced anhedonia. The effect of fluvoxamine was blocked by a dopamine D2/3 receptor antagonist. Methylphenidate, an activator of the prefrontal dopamine system, ameliorated picrotoxin-induced anhedonia. CONCLUSION AND IMPLICATIONS: Picrotoxin-treated mice show anhedonic behaviour that is ameliorated by simultaneous activation of 5-HT1A and sigma1 receptors. These findings suggest that the increased prefrontal dopamine release is associated with the anti-anhedonic effect observed in picrotoxin-treated mice. PMID- 27987213 TI - Increased fetal lung T2 signal is not due to increasing surfactant concentration: an in vitro T2 mapping analysis. AB - OBJECT: The aim of this study was to perform in vitro T2 mapping of serial dilutions of pharmaceutical surfactant. MATERIALS AND METHODS: Magnetic resonance imaging. Magnetic resonance scanning was performed on serial dilutions of surfactant on large bore clinical magnets at a field strength of 1.5 T Philips and 3.0 T (Achieva TX, Philips Healthcare, the Netherlands). RESULTS: The curves demonstrate a small increasing trend between surfactant concentration and R2 (shortened T2's), with a 7.3% increase in R2 for each doubling of surfactant concentration (95% confidence interval: 6.1-8.6%, p < 0.001). CONCLUSIONS: The increasing lung/liver T2 signal ratio seen in fetal lungs with increasing gestational age is not due to increasing surfactant concentration. (c) 2016 John Wiley & Sons, Ltd. PMID- 27987214 TI - Targeting and transforming major depression. AB - OBJECTIVE: To detail limitations to the construct of 'major depression', argue for repositioning it as a proxy for 'clinical depression' and then operationalize it and its principal constituent depressive subtypes, while preserving the DSM criteria-based format. METHOD: We summarize limitations to major depression being viewed as a diagnostic entity. Data from 391 clinically depressed patients were analysed to identify high-prevalence non-specific depressive symptoms to define 'clinical depression' as well as the features showing specificity to a melancholic depressive subtype. RESULTS: We identified a set of high-prevalence and generalized symptoms for defining clinical depression and with many being current criteria for major depression. We also developed a refined set of melancholic features and with their underlying distributions generating two classes that correlated strongly with clinical diagnoses of a melancholic or non melancholic depression, thus validating its capacity to so differentiate. We append criteria sets for diagnosing clinical depression and its principal diagnostic subtypes (psychotic, melancholic and non-melancholic). CONCLUSION: This heuristic study reframes and modifies major depression's criteria set to define a domain of clinical depression with additional criteria and then allowing the delineation of three diagnostic subtypes. If this paradigm shift is accepted and further refined, greater precision in diagnosis, treatment and research would be anticipated. PMID- 27987211 TI - Inhibiting thyrotropin/insulin-like growth factor 1 receptor crosstalk to treat Graves' ophthalmopathy: studies in orbital fibroblasts in vitro. AB - BACKGROUND AND PURPOSE: Crosstalk between thyrotropin (TSH) receptors and insulin like growth factor 1 (IGF-1) receptors initiated by activation of TSH receptors could be important in the development of Graves' ophthalmopathy (GO). Specifically, TSH receptor activation alone is sufficient to stimulate hyaluronic acid (HA) secretion, a major component of GO, through both IGF-1 receptor dependent and -independent pathways. Although an anti-IGF-1 receptor antibody is in clinical trials, its effectiveness depends on the relative importance of IGF-1 versus TSH receptor signalling in GO pathogenesis. EXPERIMENTAL APPROACH: TSH and IGF-1 receptor antagonists were used to probe TSH/IGF-1 receptor crosstalk in primary cultures of Graves' orbital fibroblasts (GOFs) following activation with monoclonal TSH receptor antibody, M22. Inhibition of HA secretion following TSH receptor stimulation was measured by modified HA elisa. KEY RESULTS: TSH receptor antagonist, ANTAG3 (NCGC00242364), inhibited both IGF-1 receptor -dependent and independent pathways at all doses of M22; whereas IGF-1 receptor antagonists linsitinib and 1H7 (inhibitory antibody) lost efficacy at high M22 doses. Combining TSH and IGF-1 receptor antagonists exhibited Loewe additivity within the IGF-1 receptor-dependent component of the M22 concentration-response. Similar effects were observed in GOFs activated by autoantibodies from GO patients' sera. CONCLUSIONS AND IMPLICATIONS: Our data support TSH and IGF-1 receptors as therapeutic targets for GO, but reveal putative conditions for anti-IGF-1 receptor resistance. Combination treatments antagonizing both receptors yield additive effects by inhibiting crosstalk triggered by TSH receptor stimulatory antibodies. Combination therapy may be an effective strategy for dose reduction and/or compensate for any loss of anti-IGF-1 receptor efficacy. PMID- 27987212 TI - The occurrence and control of nitric oxide generation by the plant mitochondrial electron transport chain. AB - The plant mitochondrial electron transport chain (ETC) is bifurcated such that electrons from ubiquinol are passed to oxygen via the usual cytochrome path or through alternative oxidase (AOX). We previously showed that knockdown of AOX in transgenic tobacco increased leaf concentrations of nitric oxide (NO), implying that an activity capable of generating NO had been effected. Here, we identify the potential source of this NO. Treatment of leaves with antimycin A (AA, Qi site inhibitor of Complex III) increased NO amount more than treatment with myxothiazol (Myxo, Qo -site inhibitor) despite both being equally effective at inhibiting respiration. Comparison of nitrate-grown wild-type with AOX knockdown and overexpression plants showed a negative correlation between AOX amount and NO amount following AA. Further, Myxo fully negated the ability of AA to increase NO amount. With ammonium-grown plants, neither AA nor Myxo strongly increased NO amount in any plant line. When these leaves were supplied with nitrite alongside the AA or Myxo, then the inhibitor effects across lines mirrored that of nitrate grown plants. Hence the ETC, likely the Q-cycle of Complex III generates NO from nitrite, and AOX reduces this activity by acting as a non-energy-conserving electron sink upstream of Complex III. PMID- 27987216 TI - Solar radiation increases suicide rate after adjusting for other climate factors in South Korea. AB - OBJECTIVE: Previous studies have indicated that suicide rates have significant seasonal variations. There is seasonal discordance between temperature and solar radiation due to the monsoon season in South Korea. We investigated the seasonality of suicide and assessed its association with climate variables in South Korea. METHOD: Suicide rates were obtained from the National Statistical Office of South Korea, and climatic data were obtained from the Korea Meteorological Administration for the period of 1992-2010. We conducted analyses using a generalized additive model (GAM). First, we explored the seasonality of suicide and climate variables such as mean temperature, daily temperature range, solar radiation, and relative humidity. Next, we identified confounding climate variables associated with suicide rate. To estimate the adjusted effect of solar radiation on the suicide rate, we investigated the confounding variables using a multivariable GAM. RESULTS: Suicide rate showed seasonality with a pattern similar to that of solar radiation. We found that the suicide rate increased 1.008 times when solar radiation increased by 1 MJ/m2 after adjusting for other confounding climate factors (P < 0.001). CONCLUSION: Solar radiation has a significant linear relationship with suicide after adjusting for region, other climate variables, and time trends. PMID- 27987215 TI - Cortical spreading depression preconditioning mediates neuroprotection against ischemic stroke by inducing AMP-activated protein kinase-dependent autophagy in a rat cerebral ischemic/reperfusion injury model. AB - Cortical spreading depression (CSD), based on its similarities with peri-infarct depolarization, is an ideal model for investigating transformation from the ischemic penumbra to infarct core. However, the underlying mechanisms remain unclear. To our knowledge, this is the first study to use a middle cerebral artery occlusion ischemic-reperfusion (I/R) injury model to determine whether AMP activated protein kinase (AMPK)-dependent autophagy contributes to the neuroprotection of CSD preconditioning in rat cortex. In this study, we topically applied a pledget soaked in 1 mol/L KCl solution on rat cortex for 2 h to elicite CSD or 1 mol/L NaCl solution as a control. The results demonstrated that CSD preconditioning significantly decreased the infarct volume, neurological deficits and neuronal apoptosis in the cortical penumbra of middle cerebral artery occlusion rats, which was inhibited by the autophagy inhibitor 3-methyladenine (3 MA, 200 nmol). Furthermore, CSD increased the protein levels of the autophagy markers LC3-II, Beclin-1 and the p-AMPK (Thr172 )/AMPK ratio at 12 h and decreased P62 and p-P70S6K (Thr389 ). Moreover, the AMPK inhibitor Compound C (20 mg/kg) down-regulated the LC3-II, p-AMPK (Thr172 )/AMPK and ULK1 levels, up regulated the P62 and p-P70S6K (Thr389 ) levels induced by CSD. The neuroprotection of CSD is likely a result of AMPK-mediated autophagy activity and autophagy-induced neuronal cells apoptosis inhibition. These novel findings support a central role for AMPK and autophagy in CSD-induced ischemic tolerance. AMPK-mediated autophagy may represent a new target for stroke. PMID- 27987218 TI - The effects of tracheal tube cuffs filled with air, saline or alkalinised lidocaine on haemodynamic changes and laryngotracheal morbidity in children: a randomised, controlled trial. AB - We studied the effects of tracheal tube cuffs filled with air, saline or alkalinised lidocaine on haemodynamic changes during tracheal extubation and postoperative laryngotracheal morbidity in children. We randomly allocated 164 children aged 3-13 years undergoing general anaesthesia to one of four groups; tracheal tube cuffs filled with air (n = 41); saline (n = 41); alkalinised lidocaine 0.5% (n = 41); or alkalinised lidocaine 1% (n = 41). Intracuff pressure was monitored and maintained below 20 cmH2 O. The mean (SD) increases in systolic blood pressure after tracheal extubation compared with before extubation were 10.9 (10.8) mmHg, 7.3 (17.7) mmHg, 4.1 (10.5) mmHg and 1.9 (9.5) mmHg in the air, saline, 0.5% and 1% alkalinised lidocaine groups, respectively (p = 0.021). The mean (SD) increases in diastolic blood pressure after tracheal extubation compared with before extubation were 3.9 (9.7) mmHg, 7.9 (14.6) mmHg, 0.7 (10.4) mmHg and 3.6 (6.9) mmHg in the air, saline, 0.5% and 1% alkalinised lidocaine groups, respectively (p = 0.019). The mean (SD) increases in heart rate after tracheal extubation compared with before extubation were 14.2 (7.6) beats.min-1 , 15.5 (13.1) beats.min-1 , 5.2 (9.6) beats.min-1 and 4.1 (6.6) beats.min-1 in the air, saline, 0.5% and 1% alkalinised lidocaine groups, respectively (p < 0.001). The incidence of sore throat 8 h after tracheal extubation was 22.0% in the air filled group, 9.8% in the saline group, 4.9% in the 0.5% alkalinised lidocaine group and 2.4% in the 1% alkalinised lidocaine group, p = 0.015. We conclude that filling the tracheal tube cuff with alkalinised lidocaine-filled reduces the haemodynamic response to tracheal extubation and postoperative laryngotracheal morbidity in children. PMID- 27987217 TI - 17 to 23: A novel complementary mini Y-STR panel to extend the Y-STR databases from 17 to 23 markers for forensic purposes. AB - A Y-STR multiplex system has been developed with the purpose of complementing the widely used 17 Y-STR haplotyping (AmpFlSTR Y Filer(r) PCR Amplification kit) routinely employed in forensic and population genetic studies. This new multiplex system includes six additional STR loci (DYS576, DYS481, DYS549, DYS533, DYS570, and DYS643) to reach the 23 Y-STR of the PowerPlex(r) Y23 System. In addition, this kit includes the DYS456 and DYS385 loci for traceability purposes. Male samples from 625 individuals from ten worldwide populations were genotyped, including three sample sets from populations previously published with the 17 Y STR system to expand their current data. Validation studies demonstrated good performance of the panel set in terms of concordance, sensitivity, and stability in the presence of inhibitors and artificially degraded DNA. The results obtained for haplotype diversity and discrimination capacity with this multiplex system were considerably high, providing further evidences of the suitability of this novel Y-STR system for forensic purposes. Thus, the use of this multiplex for samples previously genotyped with 17 Y-STRs will be an efficient and low-cost alternative to complete the set of 23 Y-STRs and improve allele databases for population and forensic purposes. PMID- 27987219 TI - Relative efficacy of tranexamic acid and preoperative anemia treatment for reducing transfusions in total joint arthroplasty. AB - BACKGROUND: This study aimed to evaluate the efficacy of a perioperative blood management (PBM) protocol at a large, tertiary hospital at reducing blood transfusions after total hip or knee arthroplasty (THA or TKA). STUDY DESIGN AND METHODS: A retrospective review of the PBM for patients undergoing THA or TKA was performed. Adjusted multiple logistic and Poisson regression models examined the effect of patient characteristics and preoperative, intraoperative, and postoperative factors on the likelihood of transfusion and units transfused. RESULTS: Of 883 study patients, 330 (37.4%) had surgery before PBM protocol implementation and served as the control population while 553 (62.6%) were eligible for the protocol. Having a higher preoperative hemoglobin (Hb) was independently associated with a decreased odds of transfusion (odds ratio [OR], 0.480; p < 0.001). Preoperative treatment for anemia (88 [15.9%] patients) did result in a significant, yet modest, increase in preoperative Hb (11.92 g/dL to 12.35 g/dL; p < 0.001) but treatment was not a significant predictor of transfusion. Receiving intraoperative tranexamic acid (TXA; 204 [36.9%] patients) had the greatest effect in reducing the odds of transfusion (OR, 0.289; p < 0.001) and the number of units transfused (-0.6; p = 0.008). CONCLUSION: Having a decreased Hb was shown to be an independent risk factor both for requiring a perioperative blood transfusion and for the volume of transfusion. The very modest increase in Hb achieved by the costly and time-consuming preoperative anemia optimization program, however, may not be justified when the use of intraoperative TXA led to drastic reductions in both transfusions and transfusion volumes. PMID- 27987220 TI - 'Dropped from the system': the experiences and challenges of long-term breast cancer survivors. AB - AIMS: The aim of this study was to explore breast cancer patients' experiences during survivorship. Particular attention is given to the role of specialist breast care nurses in supporting women throughout this phase. BACKGROUND: There is a relative lack of research involving long-term breast cancer survivors. Yet, many survivors experience substantial psychosocial and iatrogenic harms created by diagnosis, symptoms of disease and treatment. A more comprehensive understanding may assist in supporting the needs of breast cancer survivors. DESIGN: An exploratory qualitative approach was used to collect data on breast cancer survivors' experiences during 2013. METHODS: Semi-structured interview data were collected from seven British women aged 38-80 years exploring the support received during survivorship. Data were analysed using Interpretive Phenomenological Analysis. FINDINGS: Breast cancer survivors perceived a systemic absence in support from oncology teams and rapid deterioration of support from personal support networks. Despite this, survivors were able to find benefits from the cancer experience. This allowed for adjustment and enabled patients to assume a new identity as a breast cancer survivor. We recommend specialist breast care nurses would be suitably placed to provide extended support allowing for a salient transition from treatment to survivorship. CONCLUSION: This study yields insights into breast cancer survivorship and specifically the role of specialist breast care nurses. Given the growing cohort of breast cancer survivors and the increased importance on promoting and supporting optimal psychosocial adjustment, we advise the cost-effectiveness of providing continuing nursing support and the mode of administration requires further research. PMID- 27987221 TI - Active and placebo transcranial magnetic stimulation effects on external and internal auditory hallucinations of schizophrenia. AB - OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) over the left temporo-parietal region has been proposed as a treatment for resistant auditory verbal hallucinations (AVH), but which patients are more likely to benefit from rTMS is still unclear. This study sought to assess the effects of rTMS on AVH, with a focus on hallucination phenomenology. METHOD: Twenty-seven patients with schizophrenia and medication-resistant AVH participated to a randomized, double blind, placebo-controlled, add-on rTMS study. The stimulation targeted a language perception area individually determined using functional magnetic resonance imaging and a language recognition task. AVH were assessed using the hallucination subscale of the Scale for the Assessment of Positive Symptoms (SAPS). The spatial location of AVH was assessed using the Psychotic Symptom Rating Scales. RESULTS: A significant improvement in SAPS hallucination subscale score was observed in both actively treated and placebo-treated groups with no difference between both modalities. Patients with external AVH were significantly more improved than patients with internal AVH, with both modalities. CONCLUSIONS: A marked placebo effect of rTMS was observed in patients with resistant AVH. Patients with prominent external AVH may be more likely to benefit from both active and placebo interventions. Cortical effects related to non-magnetic stimulation of the auditory cortex are suggested. PMID- 27987222 TI - The Antinociceptive Effect of a Tapentadol-Ketorolac Combination in a Mouse Model of Trigeminal Pain is Mediated by Opioid Receptors and ATP-Sensitive K+ Channels. AB - Preclinical Research The aim of the present study was to evaluate the antinoceptive interaction between the opioid analgesic, tapentadol, and the NSAID, ketorolac, in the mouse orofacial formalin test. Tapentadol or ketorolac were administered ip 15 min before orofacial formalin injection. The effect of the individual drugs was used to calculate their ED50 values and different proportions (tapentadol-ketorolac in 1:1, 3:1, and 1:3) were assayed in the orofacial test using isobolographic analysis and interaction index to evaluate the interaction between the drugs. The combination showed antinociceptive synergistic and additive effects in the first and second phase of the orofacial formalin test. Naloxone and glibenclamide were used to evaluate the possible mechanisms of action and both partially reversed the antinociception produced by the tapentadol-ketorolac combination. These data suggest that the mixture of tapentadol and ketorolac produces additive or synergistic interactions via opioid receptors and ATP-sensitive K+ channels in the orofacial formalin-induced nociception model in mice. Drug Dev Res 78 : 63-70, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27987223 TI - Attenuation correction in 4D-PET using a single-phase attenuation map and rigidity-adaptive deformable registration. AB - PURPOSE: Four-dimensional positron emission tomography (4D-PET) imaging is a potential solution to the respiratory motion effect in the thoracic region. Computed tomography (CT)-based attenuation correction (AC) is an essential step toward quantitative imaging for PET. However, due to the temporal difference between 4D-PET and a single attenuation map from CT, typically available in routine clinical scanning, motion artifacts are observed in the attenuation corrected PET images, leading to errors in tumor shape and uptake. We introduced a practical method to align single-phase CT with all other 4D-PET phases for AC. METHODS: A penalized non-rigid Demons registration between individual 4D-PET frames without AC provides the motion vectors to be used for warping single-phase attenuation map. The non-rigid Demons registration was used to derive deformation vector fields (DVFs) between PET matched with the CT phase and other 4D-PET images. While attenuated PET images provide useful data for organ borders such as those of the lung and the liver, tumors cannot be distinguished from the background due to loss of contrast. To preserve the tumor shape in different phases, an ROI-covering tumor was excluded from nonrigid transformation. Instead the mean DVF of the central region of the tumor was assigned to all voxels in the ROI. This process mimics a rigid transformation of the tumor along with a nonrigid transformation of other organs. A 4D-XCAT phantom with spherical lung tumors, with diameters ranging from 10 to 40 mm, was used to evaluate the algorithm. The performance of the proposed hybrid method for attenuation map estimation was compared to (a) the Demons nonrigid registration only and (b) a single attenuation map based on quantitative parameters in individual PET frames. RESULTS: Motion-related artifacts were significantly reduced in the attenuation corrected 4D-PET images. When a single attenuation map was used for all individual PET frames, the normalized root-mean-square error (NRMSE) values in tumor region were 49.3% (STD: 8.3%), 50.5% (STD: 9.3%), 51.8% (STD: 10.8%) and 51.5% (STD: 12.1%) for 10-mm, 20-mm, 30-mm, and 40-mm tumors, respectively. These errors were reduced to 11.9% (STD: 2.9%), 13.6% (STD: 3.9%), 13.8% (STD: 4.8%), and 16.7% (STD: 9.3%) by our proposed method for deforming the attenuation map. The relative errors in total lesion glycolysis (TLG) values were -0.25% (STD: 2.87%) and 3.19% (STD: 2.35%) for 30-mm and 40-mm tumors, respectively, in proposed method. The corresponding values for Demons method were 25.22% (STD: 14.79%) and 18.42% (STD: 7.06%). Our proposed hybrid method outperforms the Demons method especially for larger tumors. For tumors smaller than 20 mm, nonrigid transformation could also provide quantitative results. CONCLUSION: Although non-AC 4D-PET frames include insignificant anatomical information, they are still useful to estimate the DVFs to align the attenuation map for accurate AC. The proposed hybrid method can recover the AC-related artifacts and provide quantitative AC-PET images. PMID- 27987225 TI - Arrhythmias in Adults with Congenital Heart Disease: What Are Risk Factors for Specific Arrhythmias? AB - INTRODUCTION: An increasing number of patients with congenital heart disease are now surviving into adulthood. This has also led to the emergence of complications from the underlying congenital heart disease, related surgical interventions, and associated combordities. While the prevalence of particular arrhythmias with specific congenital heart disease has been previously described, a detailed analysis of all lesions and a large number of comorbidities has not been previously published. METHODS: Admissions with congenital heart disease were identified in the National Inpatient Sample. Associated comorbidities were also identified for these patients. Univariate analysis was done to compare those risk factors associated with specific arrhythmias in the setting of congenital heart disease. Next, regression analysis was done to identify what patient characteristics and comorbidities were associated with increased risk of specific arrhythmias. RESULTS: A total of 52,725,227 admissions were included in the analysis. Of these, 109,168 (0.21%) had congenital heart disease. Of those with congenital heart disease, 27,088 (25%) had an arrhythmia at some point. The most common arrhythmia in those with congenital heart disease was atrial fibrillation, which was noted in 86% of those with arrhythmia followed by atrial flutter which was noted in 20% of those with congenital heart disease. The largest burden of arrhythmia was found to be in those with tricuspid atresia with a 51% prevalence of arrhythmia in this group followed by Ebstein anomaly which had an arrhythmia prevalence of 39%. Increasing age, male gender, double outlet right ventricle, atrioventricular septal defect, heart failure, obstructive sleep apnea, transposition of the great arteries, congenitally corrected transposition, and tetralogy of Fallot were frequently noted to be independent risk factors of specific arrhythmias. CONCLUSION: Approximately, 25% of adult admissions with congenital heart disease are associated with arrhythmia. The burden of arrhythmia varies by the specific lesion and other risk factors as well. Understanding of these can help in risk stratification and can help devise strategies to lower this risk. PMID- 27987226 TI - Modular fluidic resistors to enable widely tunable flow rate and fluidic switching period in a microfluidic oscillator. AB - Microfluidic systems with modular components are attractive alternatives to monolithically integrated microfluidic systems because of their flexibility. In this study, we apply the modular concept on a water-head-pressure-driven microfluidic oscillator and obtain a widely tunable flow rate and fluidic switching period. Modular fluidic resistors can be easily mounted onto and demounted from a main chip by means of plastic male connectors. The connectors enable a leak-free connection between the modular resistors and main chip (leakage pressure > 140 kPa). With modular resistors, we show independent control of the flow rate and flow switching period of the oscillator system in a wide range (2.5 s-6.4 h and 2 MUL/min-2 mL/min). This modular approach can be used to enhance the flexibility of instruction-embedded microfluidic circuits in which their operational range is limited. PMID- 27987224 TI - Effectiveness of a mobile cooperation intervention during the clinical practicum of nursing students: a parallel group randomized controlled trial protocol. AB - AIM: The aim of this study was to describe a study protocol for a study evaluating the effectiveness of a mobile cooperation intervention to improve students' competence level, self-efficacy in clinical performance and satisfaction with the clinical learning environment. BACKGROUND: Nursing student nurse teacher cooperation during the clinical practicum has a vital role in promoting the learning of students. Despite an increasing interest in using mobile technologies to improve the clinical practicum of students, there is limited robust evidence regarding their effectiveness. DESIGN: A multicentre, parallel group, randomized, controlled, pragmatic, superiority trial. METHODS: Second-year pre-registration nursing students who are beginning a clinical practicum will be recruited from one university of applied sciences. Eligible students will be randomly allocated to either a control group (engaging in standard cooperation) or an intervention group (engaging in mobile cooperation) for the 5-week the clinical practicum. The complex mobile cooperation intervention comprises of a mobile application-assisted, nursing student-nurse teacher cooperation and a training in the functions of the mobile application. The primary outcome is competence. The secondary outcomes include self-efficacy in clinical performance and satisfaction with the clinical learning environment. Moreover, a process evaluation will be undertaken. The ethical approval for this study was obtained in December 2014 and the study received funding in 2015. DISCUSSION: The results of this study will provide robust evidence on mobile cooperation during the clinical practicum, a research topic that has not been consistently studied to date. PMID- 27987227 TI - How education must reawaken empathy. PMID- 27987229 TI - Neuronal damage biomarkers in the identification of patients at risk of long-term postoperative cognitive dysfunction after cardiac surgery. AB - Biomarkers of neurological injury can potentially predict postoperative cognitive dysfunction. We aimed to identify whether classical neuronal damage-specific biomarkers, including brain fatty acid-binding protein, neuron-specific enolase and S100 calcium-binding protein beta, as well as plasma-free haemoglobin concentration as a measure of haemolysis, could be used to predict the risk of long-term cognitive decline after coronary artery bypass grafting with or without cardiopulmonary bypass. We assessed cognitive function using the CogState brief computerised cognitive test battery at 3 months and at 15 months after surgery. Blood samples were obtained pre-operatively, after sternal closure, and at 6 h and 24 h postoperatively. We found signs of cognitive decline at 3 months in 15 of 57 patients (26%), and in 13 of 48 patients (27%) at 15 months. Brain fatty acid-binding protein was already significantly higher before surgery in patients with postoperative cognitive dysfunction at 15 months, with pre-operative plasma levels of 22.8 (8.3-33.0 [0-44.6]) pg.ml-1 compared with 9.7 (3.9-17.3 [0-49.0]) pg.ml-1 in patients without cognitive dysfunction. This biomarker remained significantly higher in patients with cognitive decline throughout the entire postoperative period. At 3 months after surgery, high levels of plasma-free haemoglobin at sternal closure were associated with a negative influence on cognitive performance, as were high baseline scores on neuropsychological tests, whereas a higher level of education proved to beneficially influence cognitive outcome. We found that postoperative cognitive dysfunction at 3 months was associated with cognitive decline at 15 months after surgery, and served as a valuable prognostic factor for declines in individual cognitive performance one year later. Classical neuronal injury-related biomarkers were of no clear prognostic value. PMID- 27987228 TI - Pharmacokinetics and pharmacodynamics of intrathecally administered Xen2174, a synthetic conopeptide with norepinephrine reuptake inhibitor and analgesic properties. AB - AIM: Xen2174 is a synthetic 13-amino acid peptide that binds specifically to the norepinephrine transporter, which results in inhibition of norepinephrine uptake. It is being developed as a possible treatment for moderate to severe pain and is delivered intrathecally. The current study was performed to assess the pharmacodynamics (PD) and the cerebrospinal fluid (CSF) pharmacokinetics (PK) of Xen2174 in healthy subjects. METHODS: This was a randomized, blinded, placebo controlled study in healthy subjects. The study was divided into three treatment arms. Each group consisted of eight subjects on active treatment and two or three subjects on placebo. The CSF was sampled for 32 h using an intrathecal catheter. PD assessments were performed using a battery of nociceptive tasks (electrical pain, pressure pain and cold pressor tasks). RESULTS: Twenty-five subjects were administered Xen2174. CSF PK analysis showed a higher area under the CSF concentration-time curve of Xen2174 in the highest dose group than allowed by the predefined safety margin based on nonclinical data. The most common adverse event was post-lumbar puncture syndrome, with no difference in incidence between treatment groups. Although no statistically significant differences were observed in the PD assessments between the different dosages of Xen2174 and placebo, pain tolerability in the highest dose group was higher than in the placebo group [contrast least squares mean pressure pain tolerance threshold of Xen2174 2.5 mg placebo (95% confidence interval), 22.2% (-5.0%, 57.1%); P = 0.1131]. CONCLUSIONS: At the Xen2174 dose level of 2.5 mg, CSF concentrations exceeded the prespecified exposure limit based on the nonclinical safety margin. No statistically significant effects on evoked pain tests were observed. PMID- 27987230 TI - The lymphatic superficial circumflex iliac vessels deep branch perforator flap: A new preventive approach to lower limb lymphedema after groin dissection preliminary evidence. AB - OBJECTIVE: Groin dissection is the procedure with the highest risk of lower limb lymphedema.As lymph stasis causes irreversible alterations to the limb over time,therapies should be administered in early stages,or better yet, lymphatic drainage impairment should be prevented.We developed a new preventive approach to lymphedema after groin dissection, and we report our preliminary experience. PATIENTS AND METHODS: We enrolled 5 patients undergoing bilateral groin dissection for vulvar cancer. Preoperative study of lower limbs lymphatic function was obtained by lymphoscintigraphy, with lymphatic transport index, indocyanine green (ICG) lymphography, and volume measurement with lower extremity lymphedema (LEL) index calculation. At the end of lymphadenectomy, one groin was closed in the standard way. On the other side, a lymphatic flap pedicled on the distal perforator of the deep branch of the superficial circumflex iliac vessels, was transposed into the groin region. Lymphatic function examination of the limbs was repeated 6 months after surgery. RESULTS: Before surgery no patient showed lymphatic drainage impairment at lymphoscintigraphy or lymphography, LEL index was in every limb lower than 250 (mean: 217.3 +/- 13.83). After surgery the limbs treated with the flap showed no pathological swelling, LEL-index < 250 (mean: 235.4 +/- 13.069), linear pattern at lymphography, and normal lymphoscintigraphy. The untreated limbs showed from moderate to severe edema with 265 < LEL-index < 310 (mean: 283 +/- 16.3), diffuse dermal backflow at lymphography and interruption of lymph flow, with dermal backflow, at lymphoscintigraphy. Mean difference between preoperative and postoperative volumes was 64.8 +/- 25.1 in the untreated side and 19 +/- 11.7 in the side with the flap. The difference between preoperative and postoperative volumes compared between the treated and untreated side was statistically significant (P < .01). CONCLUSION: Our preliminary evidence suggests that this flap can prevent lymphedema after groin dissection. Further studies are necessary to confirm these results. PMID- 27987231 TI - Levodopa-entacapone-carbidopa intestinal gel in Parkinson's disease: A randomized crossover study. AB - BACKGROUND: The addition of oral entacapone to levodopa-carbidopa intestinal gel treatment leads to less conversion of levodopa to 3-O-methyldopa, thereby increasing levodopa plasma concentration. The objective of this study was to compare systemic levodopa exposure of the newly developed levodopa-entacapone carbidopa intestinal gel after a 20% dose reduction with levodopa exposure after the usual levodopa-carbidopa intestinal gel dose in a randomized crossover trial in advanced Parkinson's disease patients. METHODS: In this 48-hour study, 11 patients treated with levodopa-carbidopa intestinal gel were randomized to a treatment sequence. Blood samples were drawn at prespecified times, and patient motor function was assessed according to the treatment response scale. RESULTS: Systemic exposure of levodopa did not differ significantly between treatments (ratio, 1.10 [95% confidence interval, 0.951-1.17]). Treatment response scale scores did not significantly differ between treatments (P = 0.84). CONCLUSIONS: Levodopa-entacapone-carbidopa intestinal gel allowed a lower amount of levodopa administration and was well tolerated. Long-term studies are needed to confirm the results. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27987232 TI - The paradoxical changes of membrane and soluble herpes virus entry mediator in hepatocellular carcinoma patients. AB - BACKGROUND AND AIM: The herpes virus entry mediator (HVEM) network has become new directions in targeting novel checkpoint inhibitors for cancer therapy. However, the changes of membrane-bound HVEM (mHVEM) and soluble HVEM (sHVEM) in hepatocellular carcinoma (HCC) are not fully understood. This study aims to study the changes of mHVEM and sHVEM in HCC patients. METHODS: Serum samples were collected from 65 HCC patients, from which sHVEM levels were examined by enzyme linked immunosorbent assay. Expressions of mHVEM on peripheral lymphocytes from 20 HCC patients were determined using flow cytometry, and associations between mHVEM on T and B cells were analyzed. RESULTS: The levels of mHVEM were downregulated on peripheral lymphocytes in HCC patients, with a strong positive correlation between mHVEM expression on T and B cells. In contrast, the levels of soluble HVEM were upregulated in the serum of HCC patients. Furthermore, we found that the increase in sHVEM level was correlated with advanced stages HCC. CONCLUSION: Our data demonstrated paradoxical changes of membrane and soluble HVEM in the peripheral blood of HCC patients for the first time. These data supported the notion that roles of HVEM are likely to be immunosuppressive rather than activating tumor immunity. Future studies are warranted to further explore the translational values of mHVEM and sHVEM in peripheral blood as diagnostic markers and therapeutic targets. PMID- 27987234 TI - Deciphering fungal dimorphism: Farnesol's unanswered questions. AB - Candida albicans excretes E,E-farnesol as a virulence factor and quorum sensing molecule that prevents the yeast to hyphal conversion. Polke et al. (2016) identified eed1Delta/Delta as the first farnesol hypersensitive mutant of C. albicans. eed1Delta/Delta also excretes 10X more farnesol and while able to form hyphae, it cannot maintain hyphae. This mutant enables new research into unanswered questions, including the existence of potential farnesol receptors and transporters, regulation of farnesol synthesis, and relationships among farnesol, germ tube formation and hyphal maintenance. The eed1 farnesol hypersensitivity can be explained by higher internal concentrations of farnesol or lower thresholds for response. One possibility invokes misexpression of a transporter. Saccharomyces cerevisiae and C. albicans have transporters for farnesylated peptides, like the a-factor pheromone, which could potentially also transport farnesol for virulence and quorum sensing. Significantly, these transporters are repressed in MTLa/MTLalpha C. albicans. An evolutionary pressure for C. albicans to become diploid could derive from its use of farnesol. Alternatively, maintenance of hyphal growth may increase the farnesol response threshold. Finally, Dpp1p, Dpp2p and Dpp3p are non-specific pyrophosphatases responsible for farnesol synthesis. Changes in expression of these enzymes do not explain differences in farnesol levels implicating involvement of additional factors like a scaffolding molecule. PMID- 27987233 TI - Imaging Extracellular Lactate In Vitro and In Vivo Using CEST MRI and a Paramagnetic Shift Reagent. AB - Overproduction of lactate is a hallmark of cancer, yet a method to quantitatively measure lactate production by cancer cells is not straight-forward. Chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) can potentially be used to image lactate but the small difference in chemical shift of the lactate -OH proton and water proton resonances make it challenging. Like other spectroscopic methods, CEST MRI cannot discriminate intracellular lactate from extracellular lactate. Herein, we demonstrate a relatively simple way to shift the lactate -OH proton resonance far away from water by addition of the paramagnetic shift reagent, EuDO3A, while retaining the CEST properties of lactate itself. The potential of the method was demonstrated by imaging extracellular lactate excreted from lung cancer cells in tissue culture without interference from other components in the culture media and by imaging excess lactate excreted into the bladder of a mouse. PMID- 27987235 TI - ADORA1 mutations are not a common cause of Parkinson's disease and dementia with Lewy bodies. PMID- 27987237 TI - Bladder cancer cells induce immunosuppression of T cells by supporting PD-L1 expression in tumour macrophages partially through interleukin 10. AB - Immunotherapy based on BCG vaccination is an effective treatment in bladder cancer, but a positive response is restricted to a subset of patients and for a limited period of time only. This suggests that T cells antitumour responses are effective but can become compromised in bladder cancer. To investigate the underlying mechanisms, we first identified peripheral blood monocytes and tumour macrophages using the pan-monocyte/macrophage marker CD14, and found that the PD L1 expression on the monocytes/macrophages in bladder cancer patients was significantly higher than that in controls. The monocytes from bladder cancer patients were also more capable at inducing apoptosis and inhibiting proliferation in activated autologous T cells than monocytes from controls, which was directly associated with the level of PD-L1 expression. We next investigated the tumour cells' participation in upregulating PD-L1 in monocytes/macrophages. Significant elevation of PD-L1 was observed in monocytes after culturing with autologous tumour cells, which did not require direct contact but required soluble factors. The STAT phosphorylation pattern in monocytes after tumour cell co-culture was consistent with effects of the interleukin (IL)-10 signalling pathway. We then found that removal of IL-10 in monocyte-tumour cell co-culture reduced the PD-L1 upregulation in monocytes, but IL-10 by itself was unable to directly upregulate PD-L1. Primary bladder tumour cells secreted significant levels of IL-10, indicating that they could serve as the source of IL-10. Together, these results demonstrated a novel pathway that bladder cancer cells induced immunosuppression of T cells by supporting PD-L1 expression in tumour macrophages partially through IL-10. PMID- 27987236 TI - Evaluation of the counter-regulatory responses to hypoglycaemia in patients with type 1 diabetes during opiate receptor blockade with naltrexone. AB - AIMS: Hypoglycaemia is the major limiting factor in achieving optimal glycaemic control in people with type 1 diabetes (T1DM), especially intensively treated patients with impaired glucose counter-regulation during hypoglycaemia. Naloxone, an opiate receptor blocker, has been reported to enhance the acute counter regulatory response to hypoglycaemia when administered intravenously in humans. The current study was undertaken to investigate the oral formulation of the long acting opiate antagonist, naltrexone, and determine if it could have a similar effect, and thus might be useful therapeutically in treatment of T1DM patients with a high risk of hypoglycaemia. MATERIALS AND METHODS: We performed a randomized, placebo-controlled, double-blinded, cross-over study in which 9 intensively treated subjects with T1DM underwent a 2-step euglycaemic hypoglycaemic-hyperinsulinaemic clamp on 2 separate occasions. At 12 hours and at 1 hour before the clamp study, participants received 100 mg of naltrexone or placebo orally. Counter-regulatory hormonal responses were assessed at baseline and during each step of the hyperinsulinaemic-clamp. RESULTS: Glucose and insulin levels did not differ significantly between the naltrexone and placebo visits; nor did the glucose infusion rates required to keep glucose levels at target. During hypoglycaemia, naltrexone, in comparison with the placebo group, induced an increase in epinephrine levels ( P = .05). However, no statistically significant differences in glucagon, cortisol and growth hormone responses were observed. CONCLUSION: In contrast to the intravenous opiate receptor blocker naloxone, overnight administration of the oral long-acting opiate receptor blocker, naltrexone, at a clinically used dose, had a limited effect on the counter-regulatory response to hypoglycaemia in intensively treated subjects with T1DM. PMID- 27987238 TI - Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder. AB - AIM: Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. METHODS: We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. RESULTS: Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. CONCLUSION: Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease. PMID- 27987239 TI - Territorial origin of olive oil: representing georeferenced maps of olive oils by NMR profiling. AB - Proton NMR profiling is nowadays a consolidated technique for the identification of geographical origin of food samples. The common approach consists in correlating NMR spectra of food samples to their territorial origin by multivariate classification statistical algorithms. In the present work, we illustrate an alternative perspective to exploit territorial information, contained in the NMR spectra, which is based on the implementation of a geographic information system (GIS). Nuclear magnetic resonance spectra are used to build a GIS map permitting the identification of territorial regions having strong similarities in the chemical content of the produced food (terroir units). These terroir units can, in turn, be used as input for labeling samples to be analyzed by traditional classification methods. In this work, we describe the methods and the algorithms that permit to produce GIS maps from NMR profiles and apply the described method to the analysis of the geographical distribution of olive oils in an Italian region. In particular, we analyzed by 1 H NMR up to 98 georeferenced olive oil samples produced in the Abruzzo Italian region. By using the first principal component of the NMR variables selected according to the Moran test, we produced a GIS map, in which we identified two regions incidentally corresponding to the provinces of Teramo and Pescara. We then labeled the samples according to the province of provenience and built an LDA model that provides a classification ability up to 99% . A comparison between the variables selected in the geostatistics and classification steps is finally performed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27987240 TI - Efficacy and safety of dapagliflozin over 1 year as add-on to insulin therapy in Japanese patients with type 2 diabetes: the DAISY (Dapagliflozin Added to patients under InSulin therapY) trial. AB - AIMS: To evaluate the efficacy and safety of dapagliflozin as add-on to insulin in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: Insulin-treated Japanese patients were randomized to 5 mg dapagliflozin or placebo during a 16 week double-blind treatment period. Both groups then received dapagliflozin 5 or 10 mg (the dose was increased at or after week 24 if glycated haemoglobin [HbA1c] at the previous visit was >7.5%) during a 36-week open-label extension period. The exploratory efficacy endpoint was to assess the maintenance efficacy of 5/10 mg dapagliflozin + insulin over 52 weeks of treatment. Safety was assessed in terms of adverse events, laboratory variables and vital signs. RESULTS: The changes in HbA1c from baseline to weeks 16 and 52 were -0.62% and -0.74%, respectively, in the dapagliflozin group, vs -0.08% and -0.83%, respectively, in the placebo-dapagliflozin group. Body weight decreased at both time points in the dapagliflozin group and after switching to open-label dapagliflozin in the placebo-dapagliflozin group. The total insulin dose decreased slightly after starting dapagliflozin. Adverse events occurred in 82.9% and 71.7% of patients in the dapagliflozin and placebo-dapagliflozin groups, respectively. Hypoglycaemia occurred in 35.0% and 41.7% of patients in the dapagliflozin and placebo dapagliflozin groups, respectively, but the incidence was not increased by use of dapagliflozin in either trial period. Genital/urinary tract infections, renal impairment/failure, volume depletion, fracture and hepatic disorders occurred in <=5% of patients. CONCLUSION: This trial showed that administration of dapagliflozin as an add-on to insulin therapy was effective, was well tolerated and had insulin-sparing effects in Japanese patients with type 2 diabetes. PMID- 27987241 TI - Major depressive disorder and generalized anxiety disorder show different autonomic dysregulations revealed by heart-rate variability analysis in first onset drug-naive patients without comorbidity. AB - AIM: The aim of the present study was to examine whether depression and anxiety disorder manifest different autonomic dysregulations using heart-rate variability (HRV) and heart rate (HR) measurements. METHODS: HRV and HR were recorded both at rest and during task execution (random-number generation) in first-onset drug naive patients with major depressive disorder (MDD, n = 14) and generalized anxiety disorder (GAD, n = 11) as well as in healthy controls (n = 41). The patients showed no comorbidity of depression and anxiety disorder. GAD patients did not exhibit panic or phobic symptoms at the time of measurement. Following power spectrum analysis of HR trend, the high- (HF) and low-frequency (LF) components, the sum (LF + HF), and the LF/HF ratio were compared among the groups. RESULTS: In the MDD patients, as previously reported, HF was low and the LF/HF ratio was high during the initial-rest condition, and HF was less reactive to the task. In contrast, GAD patients showed significantly high HF, although autonomic reactivity was not impaired. CONCLUSION: The results indicate that baseline autonomic activity and its reactivity to behavioral changes are different between MDD and GAD in the early stage of illness. High parasympathetic tone in GAD may reflect responses of the parasympathetic system to anxiety. MDD is accompanied by an autonomic shift toward sympathetic activation and a reduced reactivity to task. PMID- 27987242 TI - Acetyl-CoA synthetases of Saccharopolyspora erythraea are regulated by the nitrogen response regulator GlnR at both transcriptional and post-translational levels. AB - Saccharopolyspora erythraea has three AMP-forming acetyl-CoA synthetases (Acs) encoded by acsA1, acsA2, and acsA3. In this work, we found that nitrogen response regulator GlnR can directly interact with the promoter regions of all three genes and can activate their transcription in response to nitrogen availability. The typical GlnR-binding boxes were identified in the promoter regions. Moreover, the activities of three Acs enzymes were modulated by the reversible lysine acetylation (RLA) with acetyltransferase AcuA and NAD+ -dependent deacetylase SrtN. Interestingly, GlnR controlled the RLA by directly activating the expression of acuA and srtN. A glnR-deleted mutant (DeltaglnR) caused a growth defect in 10 mM acetate minimal medium, a condition under which RLA function is critical to control Acs activity. Overexpression of acuA reversed the growth defect of DeltaglnR mutant. Total activity of Acs in cell-free extracts from DeltaglnR strain had a 4-fold increase relative to that of wildtype strain. Western Blotting showed that in vivo acetylation levels of Acs were influenced by nitrogen availability and lack of glnR. These results demonstrated that GlnR regulated acetyl-CoA synthetases at transcriptional and post-translational levels, and mediated the interplay between nitrogen and carbon metabolisms by integrating nitrogen signals to modulate the acetate metabolism. PMID- 27987243 TI - AHNS Series: Do you know your guidelines? Principles of surgery for head and neck cancer: A review of the National Comprehensive Cancer Network guidelines. AB - This article continues a series developed by the American Head and Neck Society's Education Committee entitled "Do you know your guidelines?" It is hoped that these features will increase awareness of and adherence to current best practices in head and neck cancer care. In this installment, the National Comprehensive Cancer Network (NCCN) guidelines for surgical therapy are reviewed. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 791-796, 2017. PMID- 27987244 TI - Aspirin treatment for chronic wounds: Potential beneficial and inhibitory effects. AB - Aspirin is a generally well-tolerated drug that is now widely used in aged patients for its antithrombotic action. Aspirin works through several pathways to reduce inflammation, fever and to alter platelet activity. The scientific literature suggests that inhibition of the cyclooxygenase enzymes by aspirin or other nonsteroidal anti-inflammatory drugs may be deleterious to normal wound repair processes and result in healing inhibition. However, novel effects of aspirin on other pathways that regulate inflammation and repair have been reported more recently. These pathways, including inhibition of inflammatory second messengers and transcription factor pathways and production of anti inflammatory, pro-resolution factors (lipoxins), provide a possible explanation for beneficial effects of aspirin in chronic wound healing. There have been limited studies to date that provide good evidence to support aspirin use in chronic venous leg ulcers but this may change as we see results from randomized trials that are currently being undertaken. In this article, we look at possible effects that aspirin administration may have on venous leg ulcer healing and the expanding knowledge of potential beneficial effects of aspirin that operate via novel pathways. Though the literature suggests that aspirin treatment and cyclooxygenase inhibition may have deleterious effects in normal healing, it is possible that in chronic wounds that may be trapped in an inflammatory state that aspirin treatment may result in beneficial outcomes. PMID- 27987247 TI - Motives for choosing and resigning from nursing by men and the definition of masculinity: a qualitative study. AB - AIM: The aim of the study is to establish the main motives for choosing nursing by men in Poland and the results for leaving the profession. BACKGROUND: Nursing is a profession less frequently chosen by men. On average, one person in ten working in nursing is a man, but in Poland this percentage is especially low, amounting to 1.8%. DESIGN: Qualitative research with a grounded theory approach. METHOD: Individual semi-structured interviews were used for data collection. The study included 17 licensed male nurses. Data were collected between January 2014 June 2015. RESULTS: The study revealed the most common motives for choosing nursing as declared by men: vocation, interest in medicine, accident and pragmatic motivation. The men for whom hegemonic masculinity constitutes the point of reference more frequently emphasize their interest in medicine and the pragmatic reasons for choosing nursing; they also more frequently try to gain managerial positions and higher income. The most common reason for men leaving the nursing profession was low income. CONCLUSIONS: Despite the common stereotype, men also choose nursing because of vocation and/or their willingness to help others, but they more frequently declare that chance was the direct reason for their choice of nursing, which helps reduce the dissonance associated with choosing a non-traditional male career path. Leaving the profession was associated with beliefs about its feminine dimension, but it seems that in Poland low income is a much more important reason for such a decision. PMID- 27987245 TI - Quantitative and longitudinal imaging of intramuscular transplanted islets of Langerhans with SPECT using [ 123 I]IBZM. AB - A non-invasive imaging method to monitor islet grafts could provide novel and improved insight into the fate of transplanted islets and, potentially, monitor the effect of therapeutic interventions. Therefore, such an imaging method could help improve long-term transplantation outcome. Here, we investigated the use of [ 123 I]IBZM for insulin positive graft volume quantification and longitudinal graft monitoring. SPECT images were acquired 6 weeks after islet transplantation in the calf muscle of rats. For longitudinal graft analysis, rats were monitored by SPECT for 10 weeks. After animals were euthanized, graft containing muscles were dissected for ex vivo analysis and insulin-positive graft volume determination. Six weeks after transplantation, a clear signal was observed in all grafts by SPECT imaging. Moreover, the intensity of the SPECT signal correlated linearly with insulin-positive graft volume, as determined histologically. Longitudinal graft follow-up showed a clear SPECT signal of the transplant from 3 until 10 weeks after transplantation. In this study, we demonstrate for the first time the successful application of a radiotracer, [ 123 I]IBZM, for non-invasive, in vivo graft volume quantification and longitudinal graft monitoring. PMID- 27987246 TI - The 2014 International Pressure Ulcer Guideline: methods and development. AB - AIM: A discussion of the methodology used to develop the Prevention and Treatment of Pressure Ulcers: Clinical Practice Guideline. (2014). BACKGROUND: International experts representing National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel and Pan Pacific Pressure Injury Alliance developed the second edition of this clinical guideline. DESIGN: Discussion paper - methodology. DATA SOURCES: A comprehensive search for papers published up to July 2013 was conducted in 11 databases and identified 4286 studies. After critical appraisal, 356 studies were included and assigned a level of evidence. IMPLICATIONS FOR NURSING: Guideline recommendations provide guidance on best practice in pressure ulcer prevention and treatment. Understanding the development process of a guideline increases the meaningfulness of recommendations to clinicians. FINDINGS: Five hundred and seventy five recommendations arose from the research and its interpretation. The body of evidence supporting each recommendation was assigned a strength of evidence. A strength of recommendation was assigned to recommendation statements using the GRADE system. Recommendations are primarily supported by a body of evidence rated as C (87% of recommendations), representing low quality and/or indirect evidence (30%) and expert opinion (57%). Two hundred and forty seven recommendations (43%) received a strong recommendation ('Do it'). CONCLUSION: Recommendations were developed with consideration to research of the highest methodological quality evidence and studies that add to clinical insight and provide guidance for areas of care where minimal research has been conducted. Recommendations in the guideline reflect best practice and should be implemented with consideration to local context and resources and the individual's preferences and needs. PMID- 27987248 TI - Understanding and overcoming metformin gastrointestinal intolerance. AB - Metformin is the most widely prescribed drug for patients with type 2 diabetes mellitus and the first-line pharmacological option as supported by multiple international guidelines, yet a rather large proportion of patients cannot tolerate metformin in adequate amounts because of its associated gastrointestinal (GI) adverse events (AEs). GI AEs typically encountered with metformin therapy include diarrhoea, nausea, flatulence, indigestion, vomiting and abdominal discomfort, with diarrhoea and nausea being the most common. Although starting at a low dose and titrating slowly may help prevent some GI AEs associated with metformin, some patients are unable to tolerate metformin at all and it may also be difficult to convince patients to start metformin again after a bout of GI AEs. Despite this clinical importance, the underlying mechanisms of the GI intolerance associated with metformin are poorly known. In the present review, we discuss: the epidemiology of metformin-associated GI intolerance and its underlying mechanisms; genotype variability and associated factors affecting metformin GI intolerance, such as comorbidities, co-medications and bariatric surgery; clinical consequences and therapeutic strategies to overcome metformin GI intolerance. These strategies include appropriate titration of immediate release metformin, use of extended-release metformin, the promise of delayed release metformin and gut microbiome modulators, as well as alternative pharmacological therapies when metformin cannot be tolerated at all. Given the available data, all efforts should be made to maintain metformin before considering a shift to another drug therapy. PMID- 27987250 TI - Lung disease severity in idiopathic pulmonary fibrosis is more strongly associated with impedance measures of bolus reflux than pH parameters of acid reflux alone. AB - BACKGROUND: Gastroesophageal reflux (GER) has been associated with idiopathic pulmonary fibrosis (IPF). Pathogenesis may be related to chronic micro aspiration. We aimed to assess objective measures of GER on multichannel intraluminal impedance and pH study (MII-pH) and their relationship with pulmonary function testing (PFT) results, and to compare the performance of pH/acid reflux parameters vs corresponding MII/bolus parameters in predicting pulmonary dysfunction in IPF. METHODS: This was a retrospective cohort study of IPF patients undergoing prelung transplant evaluation with MII-pH off acid suppression, and having received PFT within 3 months. Patients with prior fundoplication were excluded. Severe pulmonary dysfunction was defined using diffusion capacity of the lung for carbon monoxide (DLCO) <=40%. Six pH/acid reflux parameters with corresponding MII/bolus reflux measures were specified a priori. Multivariate analyses were applied using forward stepwise logistic regression. Predictive value of each parameter for severe pulmonary dysfunction was calculated by area-under-the-receiver-operating-characteristic-curve or c statistic. KEY RESULTS: Forty-five subjects (67% M, age 59, 15 mild-moderate vs 30 severe) met criteria for inclusion. Patient demographics and clinical characteristics were similar between pulmonary dysfunction groups. Abnormal total reflux episodes and prolonged bolus clearance time were significantly associated with pulmonary dysfunction severity on univariate and multivariate analyses. No pH parameters were significant. The c-statistic of each pH parameter was lower than its MII counterpart in predicting pulmonary dysfunction. CONCLUSIONS & INFERENCES: MII/bolus reflux, but not pH/acid reflux, was associated with pulmonary dysfunction in prelung transplant patients with IPF. MII-pH may be more valuable than pH testing alone in characterizing GER in IPF. PMID- 27987251 TI - Simultaneous resting-state functional MRI and electroencephalography recordings of functional connectivity in patients with schizophrenia. AB - AIM: It remains unclear how functional connectivity (FC) may be related to specific cognitive domains in neuropsychiatric disorders. Here we used simultaneous resting-state functional magnetic resonance imaging (rsfMRI) and electroencephalography (EEG) recording in patients with schizophrenia, to evaluate FC within and outside the default mode network (DMN). METHODS: Our study population included 14 patients with schizophrenia and 15 healthy control participants. From all participants, we acquired rsfMRI data, and simultaneously recorded EEG data using an MR-compatible amplifier. We analyzed the rsfMRI-EEG data, and used the CONN toolbox to calculate the FC between regions of interest. We also performed between-group comparisons of standardized low-resolution electromagnetic tomography-based intracortical lagged coherence for each EEG frequency band. RESULTS: FC within the DMN, as measured by rsfMRI and EEG, did not significantly differ between groups. Analysis of rsfMRI data showed that FC between the right posterior inferior temporal gyrus and medial prefrontal cortex was stronger among patients with schizophrenia compared to control participants. CONCLUSION: Analysis of FC within the DMN using rsfMRI and EEG data revealed no significant differences between patients with schizophrenia and control participants. However, rsfMRI data revealed over-modulated FC between the medial prefrontal cortex and right posterior inferior temporal gyrus in patients with schizophrenia compared to control participants, suggesting that the patients had altered FC, with higher correlations across nodes within and outside of the DMN. Further studies using simultaneous rsfMRI and EEG are required to determine whether altered FC within the DMN is associated with schizophrenia. PMID- 27987253 TI - Treatment and risk factors of Internet use disorders. AB - Recently, many young people have developed Internet use disorders (IUD) as a result of the proliferation of Internet-enabled devices, leading to serious health and social problems worldwide. On occasion, medical and educational institutions, governments, and other groups have sought to take preventive action or treat IUD. In many cases, the preferred treatment for IUD is to set recommendations for appropriate Internet use. Reportedly, psychosocial therapies (including cognitive behavioral therapy, family therapy, and compound therapy) for IUD and pharmacotherapies (including antidepressant drugs and psychostimulants) for comorbid psychiatric or development disorders have been effective at reducing the degree and symptoms of IUD. In some countries, treatment camps have been developed for adolescents with IUD, and preventive education (including lectures and group discussions) has been provided for general adolescents. Such efforts have been effective at reducing the average degree of IUD severity. Some future IUD risk factors (e.g. being male, suffering from attention-deficit hyperactivity disorder, and exhibiting deteriorating psychiatric symptoms) have begun to be identified. However, clinical studies, treatment, and preventive actions are insufficient for treating IUD and standard treatments and preventive systems have yet to be established. Educational and medical institutions, government, families, and others must take greater action and cooperate more effectively in order to treat or prevent IUD. PMID- 27987252 TI - Similar pharmacokinetics and pharmacodynamics of rapid-acting insulin lispro products SAR342434 and US- and EU-approved Humalog in subjects with type 1 diabetes. AB - AIM: To compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 3 rapid acting insulin lispro products: SAR342434 solution, United States (US)-approved Humalog and European Union (EU)-approved Humalog. METHODS: In a single-centre, randomized, double-blind, 3-treatment, 3-period, 6-sequence, crossover, euglycaemic clamp study (NCT02273258), adult male subjects with type 1 diabetes were randomized to receive 0.3 U/kg of SAR342434 solution, US-approved and EU approved Humalog under fasted conditions. PK and PD (glucose infusion rate [GIR]) were assessed up to 12 hours. RESULTS: Of the 30 subjects randomized, 28 completed all 3 treatment periods. Mean concentration and GIR vs time profiles were similar for all 3 products. Exposure (INS-Cmax , INS-AUClast and INS-AUC) and activity (GIRmax and GIR-AUC0-12h ) of SAR342434, US-approved and EU-approved Humalog were similar in all comparisons (point estimates of treatment ratios, 0.95-1.03 for PK parameters and 1.00-1.07 for PD parameters), with 90% confidence intervals for the ratios of geometric least squares means within the pre specified bioequivalence limit (0.80-1.25) and no significant differences in time related parameters. Within-subject variability of exposure and activity was low across the 3 clamps, indicating high day-to-day reproducibility in clamp performance, irrespective of the individual product. Adverse events were similar for all 3 products. No safety concerns were noted in vital signs or in laboratory and electrocardiogram data. CONCLUSIONS: The results of this study demonstrate similarity in insulin lispro exposure profiles and PD activity of SAR342434 solution to both US- and EU-approved Humalog, and between both US- and EU approved Humalog, supporting the use of SAR342434 solution for injection as a follow-on product. PMID- 27987254 TI - Application of free serratus anterior fascial flap for reconstruction of ear deformity due to hemifacial microsomia: A report of two cases. AB - Reconstructing congenital auricular defects due to hemifacial microsomia (HFM) is often required to deal with low hairline and defects of the temporal fascia/muscular systems. In this report, we present two cases of HFM patients (16 year-old and 20-year-old) with positional anomaly of the remnant lobule and 95% low hairline, who were treated with serratus anterior fascial flap (SFF) at the second stage of auricular construction. At the first stage, 3D costal cartilage framework was placed following the removal of hair-bearing skin, and was resurfaced with the pericranial flap. At the second stage, ear elevation was performed with cartilage block grafting, then the free SFF was used to construct cephaloauricular sulcus because of local fascial defect. The pedicles of SFF, subscapular vessels were anastomosed to the cervical vessels. No complications developed during the follow-up period of 4 years in both cases and projections of the constructed ears were satisfactorily maintained. The free SFF is naturally thin and flexible with sufficient circulation and it may be an alternative to temporo-parietal fascia flap in complicated microtia construction in HFM. (c) 2016 Wiley Periodicals, Inc. Microsurgery 37:436-441, 2017. PMID- 27987255 TI - Assessment of spermatozoa in fertile alpaca (Vicugna pacos) males: Study of sperm head morphometry using a nonautomated digital method and sperm morphology based on strict criteria. AB - Although computer-assisted systems for sperm morphometry and morphological analysis are important tools in the study of male fertility, their use in extensive systems in alpacas is limited by factors such as the expense of equipment and the high altitudes of the Andean region. The objectives of this study were to evaluate alpaca sperm head morphometry using a nonautomated digital method and determine the frequency of sperm abnormalities based on strict criteria for sperm morphology in fertile male alpacas. Ejaculates (n = 15) from seven alpacas were collected, and sperm smears stained with modified Papanicolaou were processed. For morphometric analysis, 3,000 sperm (200 cells/sample) images were captured at 400* magnification and Quick Photo MICRO 3.0 software was used for manual measurement of basic (sperm head length, width, perimeter and area) and derived variables (ellipticity, shape factor, elongation and regularity). For morphology assessment, smears were observed at 1000* magnification according to WHO and strict criteria. Average morphometric parameters were length 5.48 MUm, width 2.99 MUm, perimeter 13.62 MUm, area 12.43 MUm2 , ellipticity 1.86, shape factor 1.20, elongation 0.29 and regularity 1.05. Significant between-individual and within-individual differences were found in morphometric parameters. Based on morphometric study, sperm heads were classified as elliptical or normal (49%), long (18%), short (2%), pyriform (12%), round (9%), large (6%) and small (4%). Morphological analysis found no additional sperm head defects in 49% of normal sperm obtained by morphometry, although a 4% incidence of neck/mid-piece defects and a 16% incidence of principal-piece defects were found. We conclude that sperm head morphometry assessment in fertile alpacas using a nonautomated digital method is feasible, and that defects in sperm heads constitute the main morphological alteration (>50% of the sperm population), based on WHO and strict criteria. PMID- 27987257 TI - A new tool to improve delivery of patient-engaged care and satisfaction in facial treatments: the Aesthetic Global Ranking Scale. AB - BACKGROUND: Physicians face the challenge of individualizing aesthetic treatments in order to match the aesthetic needs of patients with their expectations. OBJECTIVE: To review issues underlying patient satisfaction with minimally invasive aesthetic treatment and to present a patient-centric assessment tool (the Global Ranking Scale [GRS]) designed to set higher standards for patient consultation and treatment experience; ensure a comprehensive patient-centric aesthetic consultation process; and raise patient satisfaction with facial rejuvenation treatment. METHODS: A review of the design and content of the GRS and its use as part of the wider Galderma Harmony Program. Results of a small survey of clinicians who have switched to the GRS, and case studies of patients who have used the tool, are also presented. RESULTS: The GRS is used in ~500 clinics around the world. In a small survey, physicians who have used the GRS report that it has changed the way that patients are assessed and treated. While no patient survey was conducted, anecdotal evidence suggests that patients are satisfied with the GRS procedure and the outcomes of treatment. CONCLUSIONS: The GRS is a new patient assessment tool that is designed as a guide for clinicians to help ensure consistency in the quality of patient assessment and consultation in their clinics offering minimally invasive facial cosmetic procedures. Qualitative research suggests that it gives patients a better chance to achieve results aligned with their needs resulting in a higher level of satisfaction with aesthetic treatments, but this needs to be confirmed in a formal patient survey. PMID- 27987249 TI - Achondroplasia: Development, pathogenesis, and therapy. AB - Autosomal dominant mutations in fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia (Ach), the most common form of dwarfism in humans, and related chondrodysplasia syndromes that include hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD). FGFR3 is expressed in chondrocytes and mature osteoblasts where it functions to regulate bone growth. Analysis of the mutations in FGFR3 revealed increased signaling through a combination of mechanisms that include stabilization of the receptor, enhanced dimerization, and enhanced tyrosine kinase activity. Paradoxically, increased FGFR3 signaling profoundly suppresses proliferation and maturation of growth plate chondrocytes resulting in decreased growth plate size, reduced trabecular bone volume, and resulting decreased bone elongation. In this review, we discuss the molecular mechanisms that regulate growth plate chondrocytes, the pathogenesis of Ach, and therapeutic approaches that are being evaluated to improve endochondral bone growth in people with Ach and related conditions. Developmental Dynamics 246:291-309, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27987260 TI - Radiation Oncology research grants awarded by the Royal Australian and New Zealand College of Radiologists: Value for money? AB - INTRODUCTION: The Royal Australian and New Zealand College of Radiologists (RANZCR) and other medical colleges have provided research grants from their budgets for many years. This survey-based project aimed to determine whether the RANZCR Faculty of Radiation Oncology (FRO) is realizing value for money from its seed funding, and to compare this with grant activities of the other colleges. METHODS: Eligible FRO grant recipients between 1999 and 2014 were surveyed regarding bibliometric data, subjective outcomes and factors considered important in completing their research projects. The other colleges were also approached via email and phone interviews. RESULTS: A records search identified 26 eligible individuals who received 42 grants for 41 projects. The survey response rate was 100%, identifying 33 secondary grants, 65 conference presentations, 10 prizes and 69 publications associated with the FRO grants and consequential research. At least seven higher degrees also resulted. The funding process was very positively perceived by grant recipients, and the two factors identified as most important in project completion were local infrastructure and RANZCR funding. In 2015, FRO allocated AUD$150K for grants compared with $10K-$2.6M from 10 of the other 15 Australasian Medical Colleges. In general, appraisal of funding outcomes relative to expenditure has been only low level until recently. CONCLUSIONS: This project has identified significant research output and subjective benefit from relatively modest FRO seed grants, implying a favourable cost-benefit ratio. Such outcomes monitoring needs to be more widely pursued within Australasian medical colleges. PMID- 27987256 TI - The regulation of antimicrobial peptide resistance in the transition to insect symbiosis. AB - Many bacteria utilize two-component systems consisting of a sensor kinase and a transcriptional response regulator to detect environmental signals and modulate gene expression for adaptation. The response regulator PhoP and its cognate sensor kinase PhoQ compose a two-component system known for its role in responding to low levels of Mg2+ , Ca2+ , pH and to the presence of antimicrobial peptides and activating the expression of genes involved in adaptation to host association. Compared with their free-living relatives, mutualistic insect symbiotic bacteria inhabit a static environment where the requirement for sensory functions is expected to be relaxed. The insect symbiont, Sodalis glossinidius, requires PhoP to resist killing by host derived antimicrobial peptides. However, the S. glossinidius PhoQ was found to be insensitive to Mg2+ , Ca2+ and pH. Here they show that Sodalis praecaptivus, a close non host-associated relative of S. glossinidius, utilizes a magnesium sensing PhoP-PhoQ and an uncharacterized MarR like transcriptional regulator (Sant_4061) to control antimicrobial peptide resistance in vitro. While the inactivation of phoP, phoQ or Sant_4061 completely retards the growth of S. praecaptivus in the presence of an antimicrobial peptide in vitro, inactivation of both phoP and Sant_4061 is necessary to abrogate growth of this bacterium in an insect host. PMID- 27987259 TI - Rapid multiplug filtration cleanup method for the determination of 124 pesticide residues in rice, wheat, and corn. AB - A simple and rapid multiplug filtration cleanup method based on multiwalled carbon nanotubes was developed to determine 124 pesticide residues in rice, wheat, and corn, which could be done in a few seconds without conditioning and elution steps. Various combinations of sorbents were optimized for each matrix with a dispersive solid-phase extraction procedure to get a satisfactory recovery and clean-up performance. Good linearity was obtained for all pesticides with calibration curve coefficients larger than 0.9958. Most recoveries for the majority pesticides were between 70 and 120% (n = 5) with relative standard deviations below 20%. The limit of detection was 0.1-1.3 MUg/kg, and the limit of quantification was 0.2-4.3 MUg/kg for the pesticides in all matrices. The work suggests that the multiplug filtration cleanup method is better than the dispersive solid-phase extraction method and it could be applied to routinely monitor pesticide residues in market samples. PMID- 27987262 TI - Electrophysiological evidence for defective fast-spiking GABAergic neurones in a schizophrenia model. PMID- 27987261 TI - Confirmation and next-generation sequencing of allele HLA-B*35:279 found in a family of a leukaemia patient with Western Asia origin. AB - The confirmation of novel allele HLA-B*35:279 in a family of a leukaemia patient with Western Asia origin is reported. Moreover, next-generation sequencing (NGS) resulted in whole-gene sequence data and revealed the inheritance of HLA-B*35:279 on the paternal haplotype. PMID- 27987264 TI - Synthesis of linear regression coefficients by recovering the within-study covariance matrix from summary statistics. AB - Recently, the number of regression models has dramatically increased in several academic fields. However, within the context of meta-analysis, synthesis methods for such models have not been developed in a commensurate trend. One of the difficulties hindering the development is the disparity in sets of covariates among literature models. If the sets of covariates differ across models, interpretation of coefficients will differ, thereby making it difficult to synthesize them. Moreover, previous synthesis methods for regression models, such as multivariate meta-analysis, often have problems because covariance matrix of coefficients (i.e. within-study correlations) or individual patient data are not necessarily available. This study, therefore, proposes a brief explanation regarding a method to synthesize linear regression models under different covariate sets by using a generalized least squares method involving bias correction terms. Especially, we also propose an approach to recover (at most) threecorrelations of covariates, which is required for the calculation of the bias term without individual patient data. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27987263 TI - eDNA metabarcoding: a promising method for anuran surveys in highly diverse tropical forests. AB - Understanding the geographical distribution and community composition of species is crucial to monitor species persistence and define effective conservation strategies. Environmental DNA (eDNA) has emerged as a powerful noninvasive tool for species detection. However, most eDNA survey methods have been developed and applied in temperate zones. We tested the feasibility of using eDNA to survey anurans in tropical streams in the Brazilian Atlantic forest and compared the results with short-term visual and audio surveys. We detected all nine species known to inhabit our focal streams with one single visit for eDNA sampling. We found a higher proportion of sequence reads and larger number of positive PCR replicates for more common species and for those with life cycles closely associated with the streams, factors that may contribute to increased release of DNA in the water. However, less common species were also detected in eDNA samples, demonstrating the detection power of this method. Filtering larger volumes of water resulted in a higher probability of detection. Our data also show it is important to sample multiple sites along streams, particularly for detection of target species with lower population densities. For the three focal species in our study, the eDNA metabarcoding method had a greater capacity of detection per sampling event than our rapid field surveys, and thus, has the potential to circumvent some of the challenges associated with traditional approaches. Our results underscore the utility of eDNA metabarcoding as an efficient method to survey anuran species in tropical streams of the highly biodiverse Brazilian Atlantic forest. PMID- 27987265 TI - Simultaneous quantification of ten Amadori compounds in tobacco using liquid chromatography with tandem mass spectrometry. AB - Amadori compounds are aroma precursors formed in the initial phase of the Maillard reaction. Based on their similar structures, simultaneous quantification of more than six Amadori compounds in tobacco has not been reported yet. In this study, a simple and rapid method was developed to simultaneously quantify ten Amadori compounds including the isomers of Fructose-isoleucine and Fructose leucine in tobacco. The separation was performed on an Atlantis T3 column (2.1 * 250 mm, 5 MUm) by gradient elution using acetonitrile and water as the mobile phases. The quantification method was systematically evaluated and proven to be sensitive and accurate. The linearity was good, with correlation coefficients of 0.9977-0.9999. The limits of detection and quantitation were 1.354-2.532 and 4.516-8.444 ng/mL, respectively. The recoveries were 84.0-119.6%, and the relative standard deviations were 1.33-5.40%. The method was used to analyze the changes in the amounts of ten Amadori compounds in tobacco before and after tobacco primary processing. The analysis shows that the Maillard reaction occurs during the short processing period. PMID- 27987266 TI - Neuroimaging of chronic alcohol misuse. AB - Alcohol is one of the most commonly abused substances worldwide. It results in a wide range of diseases and disorders affecting many organ systems. Alcohol related nutritional deficiencies and electrolyte disturbance leave chronic abusers at risk of a range of demyelinating conditions to which the radiologist and clinician should always be alert. These include Wernicke's encephalopathy, Korsakoff's syndrome, Marchiafava-Bignami disease and osmotic demyelination. Cerebral volume loss is also a commonly encountered neuroimaging phenomenon in chronic alcohol abusers. Neuroimaging with CT and MR, with a focus on FLAIR and diffusion-weighted MR sequences, play an important role in the diagnosis and often monitoring of these conditions. We present an educational review of these entities in terms of their clinical features, neuropathology and imaging features along with a case example of each condition. PMID- 27987267 TI - Carbonate Ions Induce Highly Efficient Electrocatalytic Water Oxidation by Cobalt Oxyhydroxide Nanoparticles. AB - Synthetic models of oxygen evolving complex (OEC) are used not only to gain better understanding of the mechanism and the roles of cofactors for water oxidation in photosynthesis, but also as water oxidation catalysts to realize artificial photosynthesis, which is anticipated as a promising solar fuel production system. However, although much attention has been paid to the composition and structure of active sites for development of heterogeneous OEC models, the cofactors, which are essential for water oxidation by the photosynthetic OEC, remain little studied. The high activity of CoO(OH) nanoparticles for electrocatalytic water oxidation is shown to be induced by a CO32- cofactor. The possibility of CO32- ions acting as proton acceptors for O-O bond formation based on the proton-concerted oxygen atom transfer mechanism is proposed. The O-O bond formation is supposed to be accelerated due to effective proton acceptance by adjacent CO32- ions coordinated on the CoIV center in the intermediate, which is consistent with Michaelis-Menten-type kinetics and the significant H/D isotope effect observed in electrocatalysis. PMID- 27987268 TI - Detecting invertebrate species in archived collections using next-generation sequencing. AB - Invertebrate biodiversity measured at mostly family level is widely used in biological monitoring programmes to assess anthropogenic impacts on ecosystems. However, next-generation sequencing (NGS) could allow development of new more sensitive biomonitoring tools by allowing rapid species identification. This could be accelerated if archived invertebrate collections and environmental information from past programmes are used to understand species distributions and their environmental responses. In this study, we take archived macroinvertebrate samples from two sites collected on multiple occasions and test whether NGS can successfully detect species. Samples had been stored in 70% ethanol at room temperature for up to 12 years. Three amplicons ranging from 197 to 274 bps within the DNA barcode region were amplified from samples and compared to DNA barcoding libraries to identify species. We were able to amplify partial DNA barcodes from most samples, and species were often detected with multiple amplicons. However, some singletons and taxa poorly covered by DNA barcoding were missed. This suggests additional DNA barcodes will be required to fill 'gaps' in current DNA barcode libraries for aquatic macroinvertebrates and/or that it may not be possible to detect all taxa in a sample. Furthermore, older samples often detected fewer taxa and were less reliable for amplification, suggesting NGS is best used on samples within 8 years of collection. Nevertheless, many common taxa with existing DNA barcodes were reliably identified with NGS and were often present at sites across multiple years, showing the potential of NGS for detecting common and abundant species in archived material. PMID- 27987270 TI - The role of oxidative stress in early-onset androgenetic alopecia. AB - BACKGROUND: Androgenetic alopecia (AGA) is the most common cause of alopecia in men. In the literature, although there are in vitro studies investigating the relationship between oxidative stress and AGA, any in vivo study does not exist. AIM: Our aim was to evaluate the oxidative stress status in male patients with early-onset AGA by measuring total oxidant levels (TOS), total antioxidant levels (TAS), and oxidative stress index (OSI). METHODS: Our study included 33 male patients with early-onset AGA and 30 healthy men between ages of 18 and 30 years old. TAS and TOS measurements were taken, and OSI was calculated. RESULTS: When TAS, TOS, and OSI levels were compared between patient and control groups, there was no difference for TAS level, while TOS and OSI were significantly higher in patient group. In patient group, correlation between TAS, TOS, and OSI levels and age, and disease onset age and disease duration was evaluated. Highly significant negative correlation was determined between TAS level and both age and disease duration. When TAS, TOS, and OSI levels were assessed according to AGA stage, there was no significant difference between groups, while OSI level was significantly higher in patients with family history. CONCLUSIONS: We found increased oxidative stress in younger patients with early-onset AGA. There is need for further molecular studies on the role of oxidative stress in the etiopathogenesis of AGA. We also think that topical or systemic antioxidants can be promising in treatment of AGA, especially for young patients. PMID- 27987269 TI - Survival prognostic factors for metachronous second primary head and neck squamous cell carcinoma. AB - We examined the overall survival rates of a national cohort to determine optimal treatments and prognostic factors for patients with metachronous second primary head and neck squamous cell carcinomas (mspHNSCCs) at different stages and sites. We analyzed data of mspHNSCC patients collected from the Taiwan Cancer Registry database. The patients were categorized into four groups based on the treatment modality: Group 1 (control arm; chemotherapy [CT] alone), Group 2 (reirradiation [re-RT] alone with intensity-modulated radiotherapy [IMRT]), Group 3 (concurrent chemoradiotherapy alone [irradiation with IMRT]), and Group 4 (salvage surgery with or without RT or CT). We enrolled 1741 mspHNSCC patients without distant metastasis. Multivariate Cox regression analyses revealed that Charlson comorbidity index (CCI) >=6, stage of second HNSCC, stage of first HNSCC, and duration from first primary HNSCC of <3 years were significant poor independent prognostic risk factors for overall survival. After adjustment, adjusted hazard ratios and 95% confidence intervals for the overall all-cause mortality risk at mspHNSCC clinical stages III and IV were 0.72 (0.40-1.82), 0.52 (0.35-0.75), and 0.32 (0.22-0.45) in Groups 2, 3, and 4, respectively. A Cox regression analysis indicated that a re-RT dose of >=6000 cGy was an independent protective prognostic factor for treatment modalities. CCI >= 6, stage of second HNSCC, stage of first HNSCC, and duration from first primary HNSCC of <3 years were significant poor independent prognostic risk factors for overall survival. A re RT dose of >=6000 cGy may be necessary for mspHNSCCs. PMID- 27987271 TI - Previous malignancy is an independent predictor of follow-up mortality after percutaneous treatment of mitral valve regurgitation by means of MitraClip. AB - AIMS: To investigate the prognostic burden of previously diagnosed and treated malignancies in candidates for percutaneous mitral valve repair (MVR) with MitraClip. METHODS AND RESULTS: A total of 165 patients underwent MVR and 19 (11.5%) had been previously treated for malignancy and considered healed with life expectancy over 1 year at time of percutaneous MVR. There was a significant trend for an increased overall risk profile (euroSCORE II 14.0+/-11.4 vs 10.0+/ 6.7, P=.01) in patients with a previous diagnosis of neoplasia. Moreover, neoplastic patients had lower device success rates (78.9% vs 97.3%; P=.001), longer hospitalization (12.3+/-10.6 vs 7.5+/-4.9 days, P=.001), and higher 30-day mortality (10.5% vs 2.7%, P=.09). Kaplan-Meier overall estimated 1-, 2-, 3-, and 4-year survival of the overall cohort was 72%, 61%, 48%, and 44%, respectively. Estimated 1- and 2-year survival were 44.4% and 22.2 % in patients with previous neoplasia and 75.3% and 65% in the remaining patients (P<.0001). Median survival was 312 days in the neoplastic group (CI 95%: 182.6-441.4 days) and 1209 days in the remaining patients (CI 95%: 758.8-1659.2 days) (P<.0001). At Cox regression, the strongest determinant for mortality was an anamnesis for neoplasia (HR 2.4, 95% CI 1.4-4.3, P=.001). CONCLUSIONS: Previous neoplasm is a significant independent predictor of increased mortality after MVR with MitraClip. This association is even stronger than that of other cardiac and overall comorbidities and should be kept into consideration when referring patients for treatment. PMID- 27987273 TI - Implant maintenance for the prevention of biological complications: Are you ready for the next challenge? AB - With increasing knowledge of wound biology and material sciences, the provision of dental implants as a treatment modality has become increasingly predictable and more commonly used to replace missing teeth. However, without appropriate follow up, peri-implant diseases could develop and affect the long-term success of implants. Currently, there is not enough focus on the prevention of peri implant diseases, as compared to the definition of the disease, its prevalence, and treatment. In the present study, we aim to summarize various factors influencing the successful maintenance of dental implants and highlight current gaps in knowledge. Factors influencing the successful maintenance of dental implants can be divided into three categories: implant-, dentist-, and patient related factors. Patients with dental implants are often more dentally aware, and this offers an advantage. Compared to gingiva, peri-implant mucosa responds at a different pace to the bacterial challenge. Dental practitioners should be aware of how treatment protocols affect long-term success, and be vigilant in detecting peri-implant diseases at an early stage. Compared to periodontal maintenance, less longitudinal studies on implant maintenance are available, and therefore, there is a tendency to rely heavily on information extrapolated from the periodontal literature. More studies on the significance of implant maintenance care are required. PMID- 27987274 TI - Breast interest group faculty of radiation oncology: Australian and New Zealand patterns of practice survey on breast radiotherapy. AB - INTRODUCTION: This patterns of practice study was conducted on behalf of the RANZCR Breast Interest Group in order to document current radiotherapy practices for breast cancer in Australia and New Zealand. The survey identifies variations and highlights potential contentious aspects of radiotherapy management of breast cancer. METHODS: A fifty-eight question survey was disseminated via the Survey Monkey digital platform to 388 Radiation Oncologists in Australia and New Zealand. RESULTS: In total, 156 responses were received and collated. Areas of notable consensus among respondents included hypofractionation (77.3% of respondents would 'always' or 'sometimes' consider hypofractionation in the management of ductal carcinoma in-situ and 99.3% in early invasive breast cancer); margin status in early breast cancer (73.8% believe a clear inked margin is sufficient and does not require further surgery) and use of bolus in post mastectomy radiotherapy (PMRT) (91.1% of participants use bolus in PMRT). Areas with a wider degree of variability amongst respondents included regional nodal irradiation and components of radiotherapy planning and delivery (examples include the technique used for delivery of boost and frequency of bolus application for PMRT). CONCLUSION: The results of these patterns of practice survey informs radiation oncologists in Australia and New Zealand of the current clinical practices being implemented by their peers. The survey identifies areas of consensus and contention, the latter of which may lead to a development of research trials and/or educational activities to address these areas of uncertainty. PMID- 27987272 TI - Agarolytic bacterium Persicobacter sp. CCB-QB2 exhibited a diauxic growth involving galactose utilization pathway. AB - The agarolytic bacterium Persicobacter sp. CCB-QB2 was isolated from seaweed (genus Ulva) collected from a coastal area of Malaysia. Here, we report a high quality draft genome sequence for QB2. The Rapid Annotation using Subsystem Technology (RAST) annotation server identified four beta-agarases (PdAgaA, PdAgaB, PdAgaC, and PdAgaD) as well as galK, galE, and phosphoglucomutase, which are related to the Leloir pathway. Interestingly, QB2 exhibited a diauxic growth in the presence of two kinds of nutrients, such as tryptone and agar. In cells grown with agar, the profiles of agarase activity and growth rate were very similar. galK, galE, and phosphoglucomutase genes were highly expressed in the second growth phase of diauxic growth, indicating that QB2 cells use galactose hydrolyzed from agar by its agarases and exhibit nutrient prioritization. This is the first report describing diauxic growth for agarolytic bacteria. QB2 is a potential novel model organism for studying diauxic growth in environmental bacteria. PMID- 27987275 TI - Self-assembled magnetic nanoparticle supported zeolitic imidazolate framework-8: An efficient adsorbent for the enrichment of triazine herbicides from fruit, vegetables, and water. AB - Zeolitic imidazolate frameworks have positive surface charges and high adsorption capabilities. In this work, zeolitic imidazolate frameworks-8 and negatively charged magnetic nanoparticles were self-assembled by electrostatic attraction under sonication. The extraction performance of the synthesized hybrid material was evaluated by using it as a magnetic adsorbent for the enrichment of triazine herbicides in various sample matrices prior to analysis using ultrafast liquid chromatography. The main parameters, that is, extraction time, adsorbent dosage, salt concentration, and desorption conditions, were evaluated. Under the optimum conditions, good linear responses from 2.5 to 200 ng/mL for atrazine (simazine) and 1 to 200 ng/mL for prometryn (ametryn), with correlation coefficients (R2 ) higher than 0.9992 were obtained. The detection limits of the method (S/N = 3) were 0.18-0.72 ng/mL. The proposed method was successfully used to determine triazine herbicides in six samples, namely, apple, pear, strawberry, pakchoi, lettuce, and water. The amounts of simazine in all the fruit and vegetable samples were 10.8-25.2 ng/mL. The recoveries of all the analytes were 88.0 101.9%, with relative standard deviations of less than 8.8%. PMID- 27987276 TI - In-gantry MRI guided prostate biopsy diagnosis of prostatitis and its relationship with PIRADS V.2 based score. AB - INTRODUCTION: The recent literature has focussed predominantly on prostate cancer detection which has been revolutionized by multiparametric magnetic resonance imaging (mpMRI). Due to an overlap of features, prostatitis may mimic prostate cancer on MRI, especially in patients with chronic prostatitis. We retrospectively analysed our in-gantry MRI-guided biopsy (MRGB) results to determine incidental detection rate of prostatitis in Prostate Imaging Reporting and Data System (PIRADS) 3, 4 and 5 foci reported on diagnostic MRI of the prostate. METHODS: About 137 patients underwent in-gantry MRGB for lesions with PIRADS score of 3 or above. All the biopsies were performed utilizing the dynaTRIMTM system (Invio Inc, Germany) on a three-tesla MRI scanner (Ingenia 3.0T, Philips, Netherlands) by a Radiologist and a Urologist. RESULTS: We biopsied 228 lesions in 137 patients. There were 55 lesions that returned positive for prostate cancer with a Gleason Score of 3 + 3 = 6 or above. There were 62 lesions that showed inflammation. The distribution of these lesions was 3 (5%) in the central zone, 32 (52%) in the transitional zone and 27 (43%) in the peripheral zone. Inflammation was found in 36 (58%) PIRADS 3 lesions, 24 (39%) PIRADS 4 lesions and 2 (3%) PIRADS 5 lesions on pre biopsy MRI evaluation. CONCLUSION: In our series, biopsies which showed inflammation had a radiological appearance on mpMRI more likely of a PIRADS 3 or 4 lesions with only 3% of PIRADS 5 biopsies showing inflammation. This would suggest that a higher PIRADS score can more reliably differentiate between prostate cancer and prostatitis. PMID- 27987277 TI - Eculizumab refractory thrombotic thrombocytopenic purpura secondary to post endoscopic retrograde cholangiopancreatography pancreatitis in a patient. AB - Thrombotic thrombocytopenic purpura (TTP) is a rare multisystem microvascular disorder, which is characterized by pentad of thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction due to occlusive thrombi. The proposed pathophysiology involves an imbalance between unusually large von Willebrand factor multimers and the cleaving protease ADAMTS13. Acute pancreatitis is a well described consequence of TTP, but TTP secondary to acute pancreatitis is a rare phenomenon. We present a patient who developed TTP due to post-ERCP pancreatitis with hematologic, cardiovascular, pulmonary, and renal complications and is the first case of this kind. Despite early initiation of therapy, the patient did not recover making it among the 10% of cases of TTP that prove fatal despite appropriate therapy. PMID- 27987278 TI - Clozapine-associated cardiac dysfunction during a gastroenteritis outbreak. AB - We report that two young adult patients who were initiated with clozapine for severe psychosis during a hospital-wide gastroenteritis outbreak went into severe shock. Neither patient had troponin elevation. Each required left ventricular assist device support for myocarditis. Endomyocardial biopsy revealed lymphocytic myocarditis in one patient and eosinophilic myocarditis in the other. The former patient expired. Polymerase chain reaction testing was negative for Coxsackie virus. These two patients illustrate that myocarditis can occur at usual incipient doses and that there may be an epidemiologic risk associated with gastroenteritis. Although the white blood cell (WBC) count is expected to decrease with clozapine, these patients had persistently elevated WBC counts. In conclusion, physicians should exercise caution when prescribing clozapine, especially for those with diarrhea. PMID- 27987279 TI - Falsely elevated troponin: rare occurrence or future problem. AB - INTRODUCTION: Troponins are known to be released in response to cardiac damage and therefore are the biomarkers of choice for the early diagnosis of acute myocardial infarction (AMI), improving outcome in patients presenting with chest pain. However, false results can occur due to interference from other substances in the blood. CASE: A 52-year-old male with a past medical history of alcohol abuse, hypertension, and coronary artery bypass graft at age 34 with normal stress test 2 years before presented to the emergency department (ED) complaining of 1 day of non-exertional chest pain with radiation to the neck and left arm. His troponin was elevated to 5 ng/mL in two samples drawn 12 h apart, with normal CK-MB. Renal function was normal. Electrocardiogram (ECG) showed normal sinus rhythm with no ST elevations or depressions. He underwent cardiac catheterization which showed no obstructive lesions. Five years later, he returned to the ED with abdominal pain and shortness of breath. Troponin was elevated and showed no signs of downtrend on repeat every 6 h. ECG was unchanged from 5 years before. He was discharged with a follow-up cardiac computed tomography (CT). Troponin was measured on the day of his scan and remained elevated; he was asymptomatic. Cardiac CT showed unremarkable coronaries and bypass grafts. Given persistently positive troponin in the setting of minimal to no symptoms, he was thought to have falsely elevated troponins. Centrifugation and 2:1 dilution of the sample resulted in the same general value, respectively. Rheumatoid factor and heterophile antibodies were negative. When his blood sample was sent to a different hospital utilizing a three-site immunoassay method, the value was found zero. DISCUSSION: Cardiac troponins (cTn) are structural proteins unique to the heart, not expressed outside of cardiac tissue and have high sensitivity and specificity for myocardial damage. Therefore, it is the test of choice for the diagnosis of AMI. When an increased troponin value is encountered in the absence of myocardial infarction, other etiologies should be explored, including vasculitis, drug abuse, myocarditis, pulmonary embolism, sepsis, and renal failure. If the clinical picture is not consistent with the elevated lab value, it is necessary to think of other causes, including false-positive results. The prevalence of this type of interference is likely to worsen in the future because of the emergence of immunotherapy in the treatment of a wide range of conditions and the use of radiolabeled antibodies in diagnosis using immunoscintigraphic procedures. Therefore, it is important to consider this as part of the differential. PMID- 27987280 TI - Abdominal pain - learning when not to intervene! AB - Epiploic appendagitis (EA) is an uncommon cause of abdominal pain. It is a benign condition but may mimic other serious causes of acute abdomen such as appendicitis, diverticulitis, and gynecological emergency in severe cases. Knowledge of this condition in the differential diagnosis of abdominal pain can save unnecessary hospital admission, antibiotics, and surgery. In this article, we present the case of a 43-year-old female who presented to our hospital with a 2-day history of right lower quadrant abdominal pain and diarrhea. She was diagnosed with EA with computed tomography of abdomen with contrast and was managed conservatively with good outcome. PMID- 27987281 TI - A rare case of lamotrigine-induced acute interstitial nephritis. AB - Medications, especially non-steroidal anti-inflammatory drugs and antimicrobials, have been most commonly associated with acute interstitial nephritis (AIN); antiepileptic drugs (AEDs) are rarely known to cause AIN. This is a case of a 27 year-old male who was recently started on treatment with lamotrigine for bipolar disorder and was found to have rapidly progressive renal failure. Renal biopsy features were suggestive of AIN. Lamotrigine-induced AIN was suspected to be the most likely cause. Discontinuation of the drug and treatment with steroids resulted in complete renal recovery. Lamotrigine use has been recently gaining popularity, not only as an AED but also as a mood stabilizer. With the use of this drug becoming more popular, it is important to emphasize that - although rare - AIN is one of its potential complications. PMID- 27987282 TI - Dermatomyositis and HIV. AB - HIV has been linked to several autoimmune disorders since its emergence in the 1980s. By affecting different cells and pathways in the immune system, HIV induces the development of certain autoimmune diseases while prohibiting the emergence of others. Dermatomyositis has been rarely described in patients with HIV. We present a case of dermatomyositis in a patient with HIV and explore the pathogenesis of autoimmune disorders in HIV focusing on dermatomyositis. PMID- 27987283 TI - Non-necrotizing colonic granuloma induced by schistosomiasis. AB - Schistosomiasis is an important parasitic disease with various clinical presentations caused by trematode blood flukes. It can present with asymptomatic, chronic colonic ulcerations, strictures, or inflammatory mass causing bowel obstruction. Intestinal polyps are uncommon and induced by antigens released from the schistosome eggs that trigger a cell-mediated inflammatory response with granuloma formation involving T cells, macrophages, and necrosis. This is very relevant while evaluating chronic intermittent gastrointestinal symptoms and eosinophilia in an immigrant patient from endemic areas of schistosomiasis. Here, we describe a case of chronic intestinal schistosomiasis which was found to have schistosomiasis-induced colonic polyp with non-necrotizing granuloma. With increase in immigrant population from the endemic areas of schistosomiasis in the United States, physicians should be aware of this disease and its various manifestations. Gastroenterologist should keep this as one of the differentials for colonic polyps. Diagnosis and treatment in time prevents further progression of the disease and its complications. PMID- 27987284 TI - Acute ischemia of bilateral lower extremities as a presenting feature of disseminated mucormycosis endocarditis: A case report. AB - Disseminated mucormycosis endocarditis is extremely rare, and only a few cases have actually been reported in the literature. It is almost universally fatal despite aggressive surgical and medical management. In this article, we present the case of a 48-year-old immunocompromised male with mucormycosis endocarditis, who presented with acute bilateral lower extremity ischemia and passed away due to subsequent multi-organ failure. To our knowledge, this is the first case report of disseminated mucormycosis native valve endocarditis presenting as acute bilateral lower extremity ischemia. PMID- 27987285 TI - The changing anatomic position of squamous cell carcinoma of the lung - a new conundrum. AB - BACKGROUND: Traditionally, squamous cell carcinoma (SCC) of the lung is a central rather than a peripheral form of lung cancer. Rates of SCC in the lung periphery are typically sited in the 15-30% range. Recently, we observed that a significant portion of newly diagnosed SCC was located on a periphery. A comprehensive review of the tumor data at our facility, a busy teaching hospital with a large cohort of cancer patients, was undertaken to assess whether there had been a substantive change in the traditional epidemiologic distributions of the lung cancer, specifically with respect to SCC. Given the differences in cell biology and carcinogenesis of central versus peripheral SCC, a potential epidemiologic shift might suggest a change in tumor biology. METHODS: From May 12, 2012 through May 13, 2013, all histopathologically confirmed diagnoses of SCC of the lung were retrospectively reviewed. Each patient's lesion was then classified as peripheral or central based on CT evidence. RESULTS: A total of 56 patients were diagnosed with SCC. Of these, 55% (n=31) had peripheral and 45% (n=25) had central SCC. Twenty-nine patients did not have any prior history of malignancy. Of this subset of patients, 62% (n=18) had peripheral SCC, and 38% (n=11) had central SCC. CONCLUSION: Our findings appear to correlate with our initial observation that, within our institution, there has been a substantive shift in the traditional distribution of SCC with the majority of these cancers now being diagnosed in the lung periphery as opposed to the more central locations. PMID- 27987286 TI - Acute hepatitis E presenting with clinical feature of autoimmune hepatitis. AB - A 32-year-old immigrant man presented with new onset jaundice. His past medical history was significant for type 2 diabetes mellitus, hypertension, and hyperlipidemia. His initial laboratory finding and liver biopsy were suggestive of autoimmune hepatitis (AIH). The plan was to start steroids pending negative results for viral serology, but it came back positive for hepatitis E virus. The patient's liver function test and clinical condition improved significantly on conservative management over a period of 1 month. Therefore, we suggest testing for hepatitis E especially in immigrants or recent travelers to endemic areas who presents with clinical features suggestive of AIH. PMID- 27987287 TI - Actual use of pocket-sized ultrasound devices for cardiovascular examination by trained physicians during a hospitalist rotation. AB - BACKGROUND: In actual clinical practice as opposed to published studies, the application of bedside ultrasound requires a perception of need, confidence in one's skills, and convenience. OBJECTIVE: As the frequency of ultrasound usage is evidence to its perceived value in patient care, we observed the pattern of autonomous use of a pocket-sized device (PSD) by ultrasound-trained residents during a night hospitalist rotation. METHODS: Consecutive internal medicine residents (n=24), trained in a cardiac limited ultrasound examination (CLUE) as a mandatory part of their curriculum, were sampled on their PSD use after their admitting nights, regarding perceived necessity, deterring factors, detected abnormalities, and imaging difficulties. A detailed analysis was performed with one resident who used a PSD on every admission to compare the proportion of abnormal CLUEs and utility in patients with and without a perceived need. RESULTS: Residents admitted 542 patients (mean age: 55+/-17 years, range: 17-95 years) during 101 shifts and performed CLUE on 230 patients (42%, range: 17-85%). Residents elected not to scan 312 (58%) patients due to 1) lack of perceived necessity (231, 74%), 2) time constraints (44, 14%), and 3) patient barriers (37, 12%). In the detailed analysis (n=71), the resident felt CLUE was necessary in 32 (45%) patients versus unnecessary in 39 (55%) patients, with abnormality rates of 50% versus 20.5% (p=0.01) and utility rates of 28.1% versus 15.4% (p=0.25), respectively. CONCLUSION: When unbiased residents acting as hospitalists are provided with a PSD to augment initial cardiac examination, usage is frequent and suggests clinical value in hospital medicine. PMID- 27987288 TI - Spontaneous pneumomediastinum, pneumoretroperitoneum, and cervicofacial subcutaneous emphysema after repeatedly and forcefully blowing into a bottle. AB - Spontaneous pneumomediastinum (SPM) is an uncommon, self-limiting condition associated with increased intra-thoracic pressure resulting in alveolar rupture. Search of the literature revealed no detailed case report about a 26-year-old psychiatric patient who repeatedly and forcefully blew air into a bottle for 5 days resulting in a combined condition of spontaneous pneumoretroperitoneum, pneumomediastinum, and cervicofacial subcutaneous emphysema. It is crucial to find a primary source and treat appropriately. Psychiatric patients may have psychotic behaviors mimicking Valsalva's maneuver that increases intra-thoracic pressure and causing SPM. Optimal medications should be given to control psychotic behaviors. Family members and caregivers should be explained about this unusual behavior so that they can prevent this rare condition. PMID- 27987289 TI - Cryptococcemia in an HIV-negative patient with decompensated liver cirrhosis. AB - BACKGROUND: Cryptococcal infections have been mostly associated with immunocompromised individuals, 80-90% of whom have been HIV-positive patients. Increasingly, cryptococcal infections are being reported in cirrhotic patients who are HIV-negative. The underlying immunologic defects in cirrhotic patients seem to play an important role in predisposing them to cryptococcosis and affecting their morbidity and mortality. CASE PRESENTATION: We present a case of disseminated cryptococcosis in an HIV-negative patient with underlying cirrhosis, who had rapid worsening of his hyponatremia with renal failure and was unable to recover, despite aggressive measures. CONCLUSION: Cryptococcus is a more common culprit of infections seen in cirrhotic patients than what it was previously known, and a high index of suspicion is required to diagnose these patients. Identification of poor prognostic factors, early diagnosis and intervention is crucial in the management of these patients. PMID- 27987290 TI - Effects of time and day of admission on the outcome of critically ill patients admitted to ICU. AB - BACKGROUND: Studies have shown that patients admitted to hospitals on weekends and after-hours experience worse outcome than those admitted on weekdays and daytime hours. Although admissions of patients to intensive care units (ICUs) occur 24 hours a day, not all critical care units maintain the same level of staffing during nighttime, weekends, and holidays. This raises concerns in view of evidence showing that the organizational structure of an ICU influences the outcome of critically ill patients. The objective of this study is to evaluate the effects of day and time of admission to ICU on patients' outcome. METHODS: A single-center, prospective, observational study was conducted among all consecutive admissions to ICU in a community teaching hospital during a 4-month period. RESULTS: A total of 282 patients were admitted during the study period. Their mean age was 59.5 years (median 59, range 17-96), and the majority were male (157, 55.7%). Mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 18.9 (median 33, range 1-45), and mean ICU length of stay was 3.1 days (median 2, range 1-19). Of the patients, 104 patients (36.9%) were admitted during weekends and 178 (63.1%) during weekdays. A total of 122 patients (43.3%) were admitted after-hours, constituting 68.5% of all admissions during weekdays. Fifty-six patients (19.9%) were admitted during daytime hours, representing 31.5% of all weekday admissions. Forty-five patients (15.9%) died in ICU. Compared to patients admitted on weekends, those admitted on weekdays had increased ICU mortality (operating room (OR)=0.437; 95% confidence interval=0.2054-0.9196; p=0.0293). CONCLUSION: Admissions to ICU during weekends were not independently associated with increased mortality. A linear relationship between weekdays and after-hours admissions to ICU with mortality was observed at our institution. PMID- 27987291 TI - Design of a clinical competency committee to maximize formative feedback. AB - BACKGROUND: As the next phase in the roll-out of Next Accreditation System, US residency programs are to develop Clinical Competency Committees (CCCs) to formally implement outcome-based medical education objectives in the resident assessment process. However, any changes to an assessment system must consider balancing formative and summative tensions, flexibility and standardization tensions, fairness and transparency to learners, and administrative burden for faculty. OBJECTIVES/METHODS: In this article, one program discusses the approach one internal medicine residency took to create a developmental model CCC. In this model, a learner's mentor presents the argument for competence to the CCC, while a second reviewer presents challenges to that argument to the rest of the committee members. The CCC members provide other insights and make recommendations. The mentor presents the final committee recommendations to that resident, who then works with the mentor to develop a plan for future action. RESULTS: CCC second reviewers spent an average of 30.4 min (SD: 11.4) preparing for each resident's discussion, a duty performed 5-7 times every 6 months. Faculty development was associated with an increase in the number of action oriented comments in the meeting minutes (3.2-4.1 comments per resident, p=0.001). CCC members and mentors gave higher Likert-type ratings than residents for fairness (4.8 vs. 4.0) and learning prioritization (4.7 vs. 4.2), but similar ratings for transparency (4.0 vs. 4.2). CONCLUSION: Developmental model CCCs may be feasible for residency programs, but faculty development may be necessary. PMID- 27987293 TI - Diagnostic testing in the context of high-value care: Incorporating prior probability. AB - This is the fifth article of a series on fundamental concepts in biostatistics and research. In this article, the author reviews the fundamental concepts in diagnostic testing, prior probability and predictive value, and how they relate to the concept of high-value care. The topics are discussed in common language with a minimum of jargon and mathematics. Emphasis is given to conceptual understanding. A companion article preceding this one focused on sensitivity and specificity. PMID- 27987294 TI - Azygous lobe: a normal variant of pulmonary anatomy. PMID- 27987292 TI - Tracheomalacia and recurrent exacerbations of chronic obstructive pulmonary disease: a case report and review of the literature. AB - Chronic obstructive pulmonary disease (COPD) is one of the leading causes of disability and death worldwide. COPD exacerbation is usually treated with antibiotics, systemic corticosteroids, and inhaled bronchodilators. We present a case of recurrent COPD exacerbation that was treated repeatedly with standard therapy. Dynamic expiratory computed tomography of the chest was done, which revealed concomitant tracheomalacia. COPD and tracheomalacia may coexist during recurrent exacerbations of COPD, and delayed diagnosis can be associated with severe comorbidities. Ordering the appropriate imaging may aid in the correct diagnosis and facilitate appropriate management. PMID- 27987295 TI - JCHIMP - an idea whose time has come. PMID- 27987296 TI - Intimate partner violence and challenges facing women living with HIV/AIDS in accessing antiretroviral treatment at Singida Regional Hospital, central Tanzania. AB - BACKGROUND: Human immunodeficiency virus (HIV) remains a global public health problem. Sub-Saharan Africa is the region most affected by HIV/AIDS in the world. Globally, and in Tanzania in particular, women are more affected by HIV/AIDS than men. Tanzania has been reported to be among the countries with the highest burden of intimate partner violence (IPV). This study explored the challenges facing women living with HIV/AIDS (LWHA) attending the care and treatment clinic (CTC) in Singida Regional Hospital in Tanzania. DESIGN: A qualitative study was performed in which data were collected through in-depth interviews with 35 women LWHA who also experienced IPV. Content analysis was used to analyse the data. RESULTS: The study findings showed that women LWHA experienced challenges from their male partners in the form of lack of fare to attend CTC, delayed attendance to CTC, verbal threats and intimidation, mistrust partner resulting in changed antiretroviral (ARV) dosing time. Also, systemic challenges such as malfunction of CD4 count testing apparatus contributed to mistrust from their male partners which led to IPV. CONCLUSION: In this study, women LWHA experienced IPV challenges that resulted in poor adherence to ARV medication and CTC attendance, as well as insufficient time to collect ARV medication. It is recommended that the government address systemic challenges faced by women LWHA, introduce multiple approaches to address the needs of women LWHA experiencing IPV, and develop strong policies to prevent IPV against women in Tanzania, regardless of their HIV status. PMID- 27987297 TI - Misdiagnosis of obstetrical cases and the clinical and cost consequences to patients: a cross-sectional study of urban providers in the Philippines. AB - BACKGROUND: Misdiagnosis may be a significant and under-recognized quality of care problem. In birthing facilities located in anurban Philippine setting, we investigated the diagnostic accuracy for three obstetric conditions: cephalopelvic disproportion (CPD), post-partum hemorrhage (PPH), and pre eclampsia. DESIGN: Identical simulated cases were used to measure diagnostic accuracy for every provider (n=103). We linked misdiagnosis - identified by the simulated cases - to obstetrical complications of the patients at the participating facilities. Patient-level data on health outcomes and costs were obtained from medical records and follow-home in-person interviews. RESULTS: The prevalence of misdiagnosis among obstetric providers was 29.8% overall, 25% for CPD, 33% for PPH, and 31% for pre-eclampsia. Linking provider decision-making to patients, we found those who misdiagnosed the simulated cases were more likely to have patients with a complication (OR 2.96; 95% CI 1.39-3.77) compared with those who did not misdiagnose. Complicated patients were significantly less likely to be referred to a hospital immediately, were more likely to be readmitted to a hospital after delivery, had significantly higher medical costs, and lost more income than non-complicated patients. CONCLUSION: Diagnosis is arguably the most important task a clinician performs because it determines the subsequent course of evaluation and treatment, with the direct and indirect costs of diagnostic error, placing large financial burdens on the patient. PMID- 27987298 TI - The role of civil society in strengthening intercultural maternal health care in local health facilities: Puno, Peru. AB - BACKGROUND AND OBJECTIVE: Peru's Ministry of Health has made efforts to increase the cultural inclusiveness of maternal health services. In 2005, the Ministry adopted an intercultural birthing policy (IBP) that authorizes and encourages the use of culturally acceptable birthing practices in government-run health facilities. However, studies suggest that indigenous women may receive inconsistent benefits from these kinds of policies. This article examines whether a grassroots accountability initiative based on citizen monitoring of local health facilities by indigenous women can help to promote the objectives of the IBP and improve intercultural maternal health care. DESIGN: Findings are drawn from a larger qualitative research study completed in 2015 that included fieldwork done between 2010 and 2011. Semi-structured interviews were conducted with 23 women working as citizen monitors in local health facilities in Puno and 30 key informants, including frontline health workers, health officials, and civil society actors in Puno and Lima, and human rights lawyers from the Defensoria del Pueblo Office in Puno. RESULTS: Monitors confirmed from their own personal experiences in the 1990s and early 2000s that respect for intercultural aspects of maternal health care, including traditional indigenous birthing practices, were not readily accepted in publicly funded health facilities. It was also common for indigenous women to face discrimination when seeking health service provided by the state. Although the government's adoption of the IBP in 2005 was a positive step, considerable efforts are still needed to ensure high quality, culturally appropriate maternal health care is consistently available in local health facilities. CONCLUSIONS: Despite important progress in the past two decades, policies aimed at improving intercultural maternal health care are unevenly implemented in local health facilities. Civil society, in particular indigenous women themselves, can play an important role in holding the state accountable for quality care. PMID- 27987299 TI - An Improved Tibial Force Sensor to Compute Contact Forces and Contact Locations In Vitro After Total Knee Arthroplasty. AB - Contact force imbalance and contact kinematics (i.e., motion of the contact location in each compartment during flexion) of the tibiofemoral joint are both important predictors of a patient's outcome following total knee arthroplasty (TKA). Previous tibial force sensors have limitations in that they either did not determine contact forces and contact locations independently in the medial and lateral compartments or only did so within restricted areas of the tibial insert, which prevented them from thoroughly evaluating contact force imbalance and contact kinematics in vitro. Accordingly, the primary objective of this study was to present the design and verification of an improved tibial force sensor which overcomes these limitations. The improved tibial force sensor consists of a modified tibial baseplate which houses independent medial and lateral arrays of three custom tension-compression transducers each. This sensor is interchangeable with a standard tibial component because it accommodates tibial articular surface inserts with a range of sizes and thicknesses. This sensor was verified by applying known loads at known locations over the entire surface of the tibial insert to determine the errors in the computed contact force and contact location in each compartment. The root-mean-square errors (RMSEs) in contact force are <= 6.1 N which is 1.4% of the 450 N full-scale output. The RMSEs in contact location are <= 1.6 mm. This improved tibial force sensor overcomes the limitations of the previous sensors and therefore should be useful for in vitro evaluation of new alignment goals, new surgical techniques, and new component designs in TKA. PMID- 27987301 TI - Evaluating the Effects of Ankle-Foot Orthosis Mechanical Property Assumptions on Gait Simulation Muscle Force Results. AB - Musculoskeletal modeling and simulation techniques have been used to gain insights into movement disabilities for many populations, such as ambulatory children with cerebral palsy (CP). The individuals who can benefit from these techniques are often limited to those who can walk without assistive devices, due to challenges in accurately modeling these devices. Specifically, many children with CP require the use of ankle-foot orthoses (AFOs) to improve their walking ability, and modeling these devices is important to understand their role in walking mechanics. The purpose of this study was to quantify the effects of AFO mechanical property assumptions, including rotational stiffness, damping, and equilibrium angle of the ankle and subtalar joints, on the estimation of lower limb muscle forces during stance for children with CP. We analyzed two walking gait cycles for two children with CP while they were wearing their own prescribed AFOs. We generated 1000-trial Monte Carlo simulations for each of the walking gait cycles, resulting in a total of 4000 walking simulations. We found that AFO mechanical property assumptions influenced the force estimates for all the muscles in the model, with the ankle muscles having the largest resulting variability. Muscle forces were most sensitive to assumptions of AFO ankle and subtalar stiffness, which should therefore be measured when possible. Muscle force estimates were less sensitive to estimates of damping and equilibrium angle. When stiffness measurements are not available, limitations on the accuracy of muscle force estimates for all the muscles in the model, especially the ankle muscles, should be acknowledged. PMID- 27987302 TI - Four-trophic level food webs reveal the cascading impacts of an invasive plant targeted for biocontrol. AB - Biological invasions are a major threat to biodiversity and as such understanding their impacts is a research priority. Ecological networks provide a valuable tool to explore such impacts at the community level, and can be particularly insightful for planning and monitoring biocontrol programmes, including the potential for their seldom evaluated indirect non-target effects. Acacia longifolia is among the worst invasive species in Portugal, and has been recently targeted for biocontrol by a highly specific gall-wasp. Here we use an ambitious replicated network approach to: (1) identify the mechanisms by which direct and indirect impacts of A. longifolia can cascade from plants to higher trophic levels, including gallers, their parasitoids and inquilines; (2) reveal the structure of the interaction networks between plants, gallers, parasitoids and inquilines before the biocontrol; and (3) explore the potential for indirect interactions among gallers, including those established with the biocontrol agent, via apparent competition. Over a 15-month period, we collected 31,737 galls from native plants and identified all emerging insects, quantifying the interactions between 219 plant-, 49 galler-, 65 parasitoid- and 87 inquiline species-one of the largest ecological networks to date. No galls were found on any of the 16 alien plant species. Invasion by A. longifolia caused an alarming simplification of plant communities, with cascading effects to higher trophic levels, namely: a decline of overall gall biomass, and on the richness, abundance and biomass of galler insects, their parasitoids, and inquilines. Correspondingly, we detected a significant decline in the richness of interactions between plants and galls. The invasion tended to increase overall interaction evenness by promoting the local extinction of the native plants that sustained more gall species. However, highly idiosyncratic responses hindered the detection of further consistent changes in network topology. Predictions of indirect effects of the biocontrol on native gallers via apparent competition ranged from negligible to highly significant. Such scenarios are incredibly hard to predict, but even if there are risks of indirect effects it is critical to weigh them carefully against the consequences of inaction and invasive species spread. PMID- 27987300 TI - Implantable Sensors for Regenerative Medicine. AB - The translation of many tissue engineering/regenerative medicine (TE/RM) therapies that demonstrate promise in vitro are delayed or abandoned due to reduced and inconsistent efficacy when implemented in more complex and clinically relevant preclinical in vivo models. Determining mechanistic reasons for impaired treatment efficacy is challenging after a regenerative therapy is implanted due to technical limitations in longitudinally measuring the progression of key environmental cues in vivo. The ability to acquire real-time measurements of environmental parameters of interest including strain, pressure, pH, temperature, oxygen tension, and specific biomarkers within the regenerative niche in situ would significantly enhance the information available to tissue engineers to monitor and evaluate mechanisms of functional healing or lack thereof. Continued advancements in material and fabrication technologies utilized by microelectromechanical systems (MEMSs) and the unique physical characteristics of passive magnetoelastic sensor platforms have created an opportunity to implant small, flexible, low-power sensors into preclinical in vivo models, and quantitatively measure environmental cues throughout healing. In this perspective article, we discuss the need for longitudinal measurements in TE/RM research, technical progress in MEMS and magnetoelastic approaches to implantable sensors, the potential application of implantable sensors to benefit preclinical TE/RM research, and the future directions of collaborative efforts at the intersection of these two important fields. PMID- 27987303 TI - Nonconsumptive effects of a predator weaken then rebound over time. AB - Predators can influence prey traits and behavior (nonconsumptive effects [NCEs]), often with cascading effects for basal resources and ecosystem function. But critiques of NCE experiments suggest that their duration and design produce results that describe the potential importance of NCEs rather than their actual importance. In light of these critiques, we re-evaluated a toadfish (predator), crab (prey), and oyster (resource) NCE-mediated trophic cascade. In a 4-month field experiment, we varied toadfish cue (NCE) and crab density (approximating variation in predator consumptive effects, CE). Toadfish initially benefitted oyster survival by causing crabs to reduce consumption. But this NCE weakened over time (possibly due to prey hunger), so that after 2 months, crab density (CE) dictated oyster survivorship, regardless of cue. However, the NCE ultimately re-emerged on reefs with a toadfish cue, increasing oyster survivorship. At no point did the effect of toadfish cue on mud crab foraging behavior alter oyster population growth or sediment organic matter on the reef, which is a measure of benthic-pelagic coupling. Instead, both decreased with increasing crab density. Thus, within a system shown to exhibit strong NCEs in short-term experiments (days) our study supported predictions from theoretical models: (a) within the generation of individual prey, the relative influence of NCEs appears to cycle over longer time periods (months); and (b) predator CEs, not NCEs, drive longer term resource dynamics and ecosystem function. Thus, our study implies that the impacts of removing top predators via activities such as hunting and overfishing will cascade to basal resources and ecosystem properties primarily through density-mediated interactions. PMID- 27987305 TI - A descriptive study of effect-size reporting in research reviews. AB - AIM: To describe effect-size reporting in research reviews completed in support of evidence-based practice in nursing. BACKGROUND: Many research reviews report nurses' critical appraisal of level, quality and overall strength of evidence available to address clinical questions. Several studies of research-review quality suggest effect-size information would be useful to include in these reviews, but none focused on reviewers' attention to effect sizes. DESIGN: Descriptive. METHODS: One hundred and four reviews indexed in CINAHL as systematic reviews and published from July 2012-February 2014 were examined. Papers were required to be peer-reviewed, written in English, contain an abstract and have at least one nurse author. Reviews were excluded if they did not use critical appraisal methods to address evidence of correlation, prediction or effectiveness. Data from remaining papers (N = 73) were extracted by three or more independent coders using a structured coding form and detailed codebook. Data were stored, viewed and analysed using Microsoft Office Excel(r) spreadsheet functions. RESULTS: Sixteen percent (n = 12) of the sample contained effect-size information. Of the 12, six included all the effect-size information recommended by APA guidelines. Independent of completeness of reporting, seven contained discussion of effect sizes in the paper, but none included effect-size information in abstracts. CONCLUSION: Research reviews available to practicing nurses often fail to include information needed to accurately assess how much improvement may result from implementation of evidence-based policies, programs, protocols or practices. Manuscript reviewers are urged to hold authors to APA standards for reporting/discussing effect-size information in both primary research reports and research reviews. PMID- 27987304 TI - Identification of lanthanum-specific peptides for future recycling of rare earth elements from compact fluorescent lamps. AB - As components of electronic scrap, rare earth minerals are an interesting but little used source of raw materials that are highly important for the recycling industry. Currently, there exists no cost-efficient technology to separate rare earth minerals from an electronic scrap mixture. In this study, phage surface display has been used as a key method to develop peptides with high specificity for particular inorganic targets in electronic scrap. Lanthanum phosphate doped with cerium and terbium as part of the fluorescent phosphors of spent compact fluorescent lamps (CFL) was used as a target material of economic interest to test the suitability of the phage display method to the separation of rare earth minerals. One random pVIII phage library was screened for peptide sequences that bind specifically to the fluorescent phosphor LaPO4 :Ce3+ ,Tb3+ (LAP). The library contained at least 100 binding pVIII peptides per phage particle with a diversity of 1 * 109 different phage per library. After three rounds of enrichment, a phage clone containing the surface peptide loop RCQYPLCS was found to bind specifically to LAP. Specificity and affinity of the identified phage bound peptide was confirmed by using binding and competition assays, immunofluorescence assays, and zeta potential measurements. Binding and immunofluorescence assays identified the peptide's affinity for the fluorescent phosphor components CAT (CeMgAl11 O19 :Tb3+ ) and BAM (BaMgAl10 O17 :Eu2+ ). No affinity was found for other fluorescent phosphor components such as YOX (Y2 O3 :Eu3+ ). The binding specificity of the RCQYPLCS peptide loop was improved 3-51 fold by using alanine scanning mutagenesis. The identification of peptides with high specificity and affinity for special components in the fluorescent phosphor in CFLs provides a potentially new strategic approach to rare earth recycling. Biotechnol. Bioeng. 2017;114: 1016-1024. (c) 2016 Wiley Periodicals, Inc. PMID- 27987307 TI - Prevalence and nature of fungi in root canal infections: a systematic review and meta-analysis. AB - The role of bacteria in causing apical periodontitis has been widely established, whilst the role of other microorganisms is studied less thoroughly. This systematic review and meta-analysis reviewed the literature for the prevalence and diversity of fungi in root canal infections. An extensive literature search was carried out in the Cochrane databases, EMBASE, MEDLINE, LILACS, SciELO and Web of Science. Additional studies were identified from six endodontic journals, four main endodontic textbooks and references of relevant papers. Selected clinical studies included sampling of necrotic pulps in permanent teeth and microbial analysis of these samples. Studies were critically appraised using the Joanna Briggs Institute Prevalence Critical Appraisal Checklist. Meta-analysis was performed using MetaXL. The screening of 1041 titles and abstracts and full text reading yielded 54 studies. The overall prevalence of fungi in root canal infections was 7.5% (CI 95%: 3.6-11.8%) in the inverse variance fixed effect heterogeneity model. Candida albicans was the most frequently isolated species. Significant heterogeneity was observed (P < 0.001, I2 = 85.04%). Subgroup analyses based on geographical location, period of publication, type of infection, state of general health, communication with the oral cavity, type of sample and identification method revealed no factor influencing the prevalence. Better standardized techniques and a comprehensive analysis will reveal a more detailed and accurate representation of the prevalence and nature of fungi in root canal infections. PMID- 27987306 TI - Identification of Sidt2 as a lysosomal cation-conducting protein. AB - A screen to identify lysosomal-expressed ion channels led to the discovery of the human Sidt2 protein. Sidt2 is expressed within lysosomal organelles but as a result of heterologous overexpression the protein is also detectable within the plasma membrane of human embryonic kidney cells. The overexpressed protein leads to cell depolarization upon sodium addition. Accordingly in whole-cell patch clamp experiments a spontaneous noninactivating monovalent cation current can be detected in Sidt2-overexpressing cells. Strong overexpression of Sidt2 in HEK293 cells is attended by a significant reduction/loss of detectable lysosomes, indicating that the overexpressed protein leads to lysosomal dysfunction, a hallmark of Alzheimer's disease. Sidt2 is located on chromosome 11q23, a locus repeatedly found by chromosomal mapping of Alzheimer's disease-related genes. PMID- 27987308 TI - A systematic review on the role of imiquimod in lentigo maligna and lentigo maligna melanoma: need for standardization of treatment schedule and outcome measures. AB - Lentigo maligna (LM) is an in situ variant of melanoma. Our objective was to systematically review clinical and histological clearance and recurrence rates of imiquimod treatment of LM with emphasis on progression to lentigo maligna melanoma (LMM). PubMed, EMBASE and the Cochrane library were searched from inception to May 2015. Articles were included if they described histologically proven LM treated with imiquimod 5% monotherapy or combined with another topical therapy. Analysed outcomes were clinical and histological clearance, recurrence rates and number of LMM. The quality was assessed using the GRADE-like checklist, and results were reported according to the PRISMA Statement. Twenty-six case reports, 11 retrospective studies, three prospective studies and one randomized controlled trial were included. One case report of poor quality was excluded. Complete clinical clearance was seen in 369 of 471 patients (78.3%). Histological clearance was present in 285 of 370 (77%) patients. LMM was diagnosed in nine (1.8%) patients 3.9 months (range 0-11 months) post-treatment. Univariate multinominal logistic regression showed that 6-7 applications/week had a 6.47 greater odds (P = 0.017) of resulting in complete clinical clearance compared to 1-4 applications/week. An intensity of 6-7 applications/week showed a 8.85 greater odds (P = 0.003) of resulting in histological clearance compared to 1-4 applications. Applying imiquimod >60 times during a treatment period of 12 weeks (range 4-36) showed a 7.75 greater odds (P = 0.001) of resulting in histological clearance compared to <60 total applications. In conclusion, a treatment schedule using imiquimod 6-7 applications per week, with at least 60 applications, shows the greatest odds of complete clinical and histological clearance of LM. Imiquimod is an option for patients unfit for or not willing to undergo surgery or radiotherapy. Nine cases of LM progressed to LMM shortly after treatment. Our hypothesis is that these LMM may have been present before starting imiquimod. PMID- 27987309 TI - Regucalcin is widely distributed in the male reproductive tract and exerts a suppressive effect on in vitro sperm capacitation in the water buffalo (Bubalus bubalis). AB - Regucalcin is a multi-functional, calcium-binding protein with roles in calcium homeostasis, apoptosis, cell proliferation, and free radical neutralization. Regucalcin is broadly expressed in the male reproductive organs of rat and bovine; here, we report its expression in the reproductive tract of male buffalo especially in testis, epididymis, seminal vesicle, prostate, and bulbourethral gland of buffalo-as analyzed by real-time PCR, Western blot, and immunolocalization. Regucalcin degradation in seminal plasma, despite its high abundance in vesicular fluid, was demonstrated using recombinant regucalcin co incubated with buffalo seminal plasma. This depletion of regucalcin appears to be related to its suppressive effect on in vitro sperm capacitation, observed using the chlortetracycline assay after treating buffalo spermatozoa with recombinant protein. Indeed, addition of recombinant regucalcin to capacitating media significantly reduced (P < 0.05) the percentage of capacitated spermatozoa to 6.1 +/- 0.6 from 36.4 +/- 1.8 in the untreated group. Taken together, the wide distribution of regucalcin in male buffaloes, versus its degradation in the seminal plasma and suppressive effects on in vitro capacitation of spermatozoa, indicate its possible anti-capacitation role in the reproductive tract. Mol. Reprod. Dev. 84: 212-221, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27987310 TI - Iron controls over di-nitrogen fixation in karst tropical forest. AB - Limestone tropical forests represent a meaningful fraction of the land area in Central America (25%) and Southeast Asia (40%). These ecosystems are marked by high biological diversity, CO2 uptake capacity, and high pH soils, the latter making them fundamentally different from the majority of lowland tropical forest areas in the Amazon and Congo basins. Here, we examine the role of bedrock geology in determining biological nitrogen fixation (BNF) rates in volcanic (low pH) vs. limestone (high pH) tropical forests located in the Maya Mountains of Belize. We experimentally test how BNF in the leaf-litter responds to nitrogen, phosphorus, molybdenum, and iron additions across different parent materials. We find evidence for iron limitation of BNF rates in limestone forests during the wet but not dry season (response ratio 3.2 +/- 0.2; P = 0.03). In contrast, BNF in low pH volcanic forest soil was stimulated by the trace-metal molybdenum during the dry season. The parent-material induced patterns of limitation track changes in siderophore activity and iron bioavailability among parent materials. These findings point to a new role for iron in regulating BNF in karst tropical soils, consistent with observations for other high pH systems such as the open ocean and calcareous agricultural ecosystems. PMID- 27987313 TI - Assessment of EGF receptor ligand expression in gastric carcinoma and in lesional skin of paraneoplastic acanthosis nigricans: a case report. PMID- 27987311 TI - A novel isoform of the human mitochondrial complex I subunit NDUFV3. AB - Human mitochondrial complex I is the first enzyme of the mitochondrial respiratory chain. Complex I is composed of 45 subunits, seven encoded by mitochondrial DNA, while the remainder are encoded by nuclear DNA. All nuclear encoded subunits are thought to be expressed as a single isoform. Here we reveal subunit NDUFV3 to be present in both the canonical 10 kDa and a novel 50 kDa isoform, generated through alternative splicing. Both isoforms assemble into complex I and their levels vary in different tissues. While the 50 kDa isoform appears to be dominant in HEK293T cells, we find either isoform alone is sufficient for assembly of mature complex I. NDUFV3 represents the first known complex I subunit present in two functional isoforms. PMID- 27987312 TI - Comparison of Cytotoxic Activity in Leukemic Lineages Reveals Important Features of beta-Hairpin Antimicrobial Peptides. AB - Several reports described different modes of cell death triggered by antimicrobial peptides (AMPs) due to direct effects on membrane disruption, and more recently by apoptosis and necrosis-like patterns. Cytotoxic curves of four beta-hairpin AMPs (gomesin, protegrin, tachyplesin, and polyphemusin) were obtained from several human leukemic lineages and normal monocytes and Two cell lines were then selected based on their cytotoxic sensitivity. One was sensitive to AMPs (K562) and the other resistant (KG-1) and their effect compared between these lineages. Thus, these lineages were chosen to further investigate biological features related with their cytotoxicities to AMPs. Stimulation with AMPs produced cell death, with activation of caspase-3, in K562 lineage. Increase on the fluidity of plasmatic membrane by reducing cholesterol potentiated cytotoxicity of AMPs in both lineages. Quantification of internal and external gomesin binding to the cellular membrane of both K562 and KG-1 cells showed that more peptide is accumulated inside of K562 cells. Additionally, evaluation of multi-drug resistant pumps activity showed that KG-1 has more activity than K562 lineage. A comparison of intrinsic gene patterns showed great differences between K562 and KG-1, but stimulation with gomesin promoted few changes in gene expression patterns. Differences in internalization process through the plasma membrane, multidrug resistance pumps activity, and gene expression pattern are important features to AMPs regulated cell death. J. Cell. Biochem. 118: 1764 1773, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27987314 TI - Risk, Benefit, and Cost Thresholds for Emergency Department Testing: A Cross sectional, Scenario-based Study. AB - BACKGROUND: While diagnostic testing is common in the emergency department, the value of some testing is questionable. The purpose of this study was to assess how varying levels of benefit, risk, and costs influenced an individual's desire to have diagnostic testing. METHODS: A survey through Amazon Mechanical Turk presented hypothetical clinical situations: low-risk chest pain and minor traumatic brain injury. Each scenario included three given variables (benefit, risk, and cost), that was independently randomly varied over four possible values (0.1, 1, 5, and 10% for benefit and risk and $0, $100, $500, and $1,000 for the individual's personal cost for receiving the test). Benefit was defined as the probability of finding the target disease (traumatic intracranial hemorrhage or acute coronary syndrome). RESULTS: One-thousand unique respondents completed the survey. With an increased benefit from 0.1% to 10%, the percentage of respondents who accepted a diagnostic test went from 28.4% to 53.1%. (odds ratio [OR] = 3.42; 95% confidence interval [CI] = 2.57-4.54). As risk increased from 0.1% to 10%, this number decreased from 52.5% to 28.5%. (OR = 0.33; 95% CI = 0.25-0.44). Increasing cost from $0 to $1,000 had the greatest change of those accepting the test from 61.1% to 21.4%, respectively (OR = 0.15; 95% CI = 0.11-0.2). CONCLUSIONS: The desire for testing was strongly sensitive to the benefits, risks, and costs. Many participants wanted a test when there was no added cost, regardless of benefit or risk levels, but far fewer elected to receive the test as cost increased incrementally. This suggests that out-of-pocket costs may deter patients from undergoing diagnostic testing with low potential benefit. PMID- 27987316 TI - Telangiectasia of the face: risk factors for reappearance in patients treated with dye laser. AB - BACKGROUND: Lasers can be successfully used in the treatment of facial telangiectasias. Nevertheless, reappearance of telangiectasias after successful laser treatment is a significant problem. Risk factors involved in the reappearance have not been previously investigated. OBJECTIVE: To evaluate whether personal, clinical and behavioural factors can influence the recurrence or new appearance of telangiectasias after treatment. METHODS: Four hundred and fifteen women and 69 men obtaining complete clearance after laser treatment were included in the study and the role of different risk factors in the reappearance of telangiectasias was analysed. Immunocompromised patients were excluded. A statistical analysis was then performed. RESULTS: Twenty four percent of women and 14.5% of men enrolled showed a persistent clearance after treatment. In women in whom telangiectasias reappeared, logistic regression highlighted the importance of tanning addiction, aesthetic medicine and surgery procedures as risk factors, while therapy for menopause was found to be a protective factor. Hypertension was found to be a risk factor in men. CONCLUSIONS: The efficacy of laser for treatment of telangiectasias of the face has been previously proven. Nevertheless, this is the first study presenting an analysis of risk factors involved in the new appearance of telangiectasias after the clearance induced by therapy. PMID- 27987317 TI - Do species' strategies and type of stress predict net positive effects in an arid ecosystem? AB - A proposed refinement to the stress-gradient hypothesis requires consideration of the strategies of the interacting species and the characteristics of the stress factors. While the strength and direction of these interactions can be predicted for different ecosystems, this idea remains largely untested in the field. We performed a manipulative field experiment complemented with a descriptive study to test the predictions in a natural setting that represents the extreme end of a precipitation gradient. There, wind driven desiccation and water availability are the main stressors (non-resource and resource-based stresses, respectively). We evaluated the interaction between the shrub and grasses that are dominant in the Patagonian steppe. The species had differences in morpho-functional traits and drought tolerance that fit into the C-S axis of Grime's strategies. We experimentally separated root zones to limit direct competition for soil moisture and reduce the resource-based stress on grasses. We also manipulated the distance to shrubs to evaluate non-resource stress amelioration by canopies (e.g., sun and wind) on grasses. Finally, we evaluated the distribution of naturally established C and S grasses in the neighborhood of C and S shrubs to infer process-pattern relationships. Our growth data coincide to a large degree to the predictions. We found positive effects on the growth of beneficiaries when stress was non resource based and when strategies differed (i.e., Cshrub -Sgrass and Sshrub Cgrass ). We also found strong negative effects when the abiotic stress was driven by water, particularly on C grasses. Additionally, shrubs only increased the survival of grasses when strategies differed (i.e., Cshrub -Sgrass and Sshrub -Cgrass ). Our manipulative and descriptive study supported previous results that showed that stress-tolerant species are important for the persistence of competitive species at high stress. While the applicability and generality of these predictions remains to be tested with more field experiments, some ecological factors, such as stress types and species traits, can explain much of the variation in how dominant shrubs and grasses interact in this extreme arid environment. Moreover, this framework could be extended to specifically test the importance of facilitation under different levels of stress. PMID- 27987315 TI - Partial Protection by Dietary Antioxidants Against Ethanol-Induced Osteopenia and Changes in Bone Morphology in Female Mice. AB - BACKGROUND: Chronic alcohol consumption leads to increased fracture risk and an elevated risk of osteoporosis by decreasing bone accrual through increasing osteoclast activity and decreasing osteoblast activity. We have shown that this mechanism involves the generation of reactive oxygen species (ROS) produced by NADPH oxidases. It was hypothesized that different dietary antioxidants, N-acetyl cysteine (NAC; 1.2 mg/kg/d), and alpha-tocopherol (Vit.E; 60 mg/kg/d) would be able to attenuate the NADPH oxidase-mediated ROS effects on bone due to chronic alcohol intake. METHODS: To study the effects of these antioxidants, female mice received a Lieber-DeCarli liquid diet containing ethanol (EtOH) with or without additional antioxidant for 8 weeks. RESULTS: Tibias displayed decreased cortical bone mineral density in both the EtOH and EtOH + antioxidant groups compared to pair-fed (PF) and PF + antioxidant groups (p < 0.05). However, there was significant protection from trabecular bone loss in mice fed either antioxidant (p < 0.05). Microcomputed tomography analysis demonstrated a significant decrease in bone volume (bone volume/tissue volume) and trabecular number (p < 0.05), along with a significant increase in trabecular separation in the EtOH compared to PF (p < 0.05). In contrast, the EtOH + NAC and EtOH + Vit.E did not statistically differ from their respective PF controls. Ex vivo histologic sections of tibias were stained for nitrotyrosine, an indicator of intracellular damage by ROS, and tibias from mice fed EtOH exhibited significantly more staining than PF controls. EtOH treatment significantly increased the number of marrow adipocytes per mm as well as mRNA expression of aP2, an adipocyte marker in bone. Only NAC was able to reduce the number of marrow adipocytes to PF levels. EtOH-fed mice exhibited reduced bone length (p < 0.05) and had a reduced number of proliferating chondrocytes within the growth plate. NAC and Vit.E prevented this (p < 0.05). CONCLUSIONS: These data show that alcohol's pathological effects on bone extend beyond decreasing bone mass and suggest a partial protective effect of the dietary antioxidants NAC and Vit.E at these doses with regard to alcohol effects on bone turnover and bone morphology. PMID- 27987319 TI - Unusual scrotal and penile ulcerations together with palmar-plantar erythrodysesthesia syndrome in a patient with metastatic colon carcinoma treated with capecitabine. PMID- 27987318 TI - Adaptation in families of children with Down syndrome in East Asian countries: an integrative review. AB - AIM: The purpose of this integrative literature review was to understand the experiences of East Asian families of children with Down syndrome and identify factors affecting their adaptation in the Resiliency Model of Family Stress, Adjustment and Adaptation. BACKGROUND: Socio-cultural factors influence how well families adapt following the birth of a child with Down syndrome. Existing literature in this area has focused primarily on families from Western cultures. This is problematic because nurses care for families from all over the world. Therefore, the focus of this review is on families of children with Down syndrome living in East Asia, where Confucianism is dominant. DESIGN: Integrative literature review. DATA SOURCES: Online databases (i.e. PubMed, CINAHL and PsycINFO) and a public search engine (i.e. Google Scholar) were used along with manual searches of reference lists and major journals. Studies were limited to original publications written in English and published between 1990-2014. REVIEW METHODS: Two authors independently performed integrative review processes proposed by Whittemore and Knafl and a quality assessment using the Mixed Methods Appraisal Tool. RESULTS: Like families in Western cultures, some East Asian families of children with Down syndrome adapted well and even thrived while others struggled. Various socio-cultural factors, including some associated with Confucianism, played a role in how individuals, dyads and families adapted. CONCLUSION: An understanding of socio-cultural influences can help nurses implement culturally sensitive family-centred interventions with families of children with Down syndrome. It may also facilitate policy changes concerning resources for these families. PMID- 27987320 TI - Association between AXL, Hippo Transducers, and Survival Outcomes in Male Breast Cancer. AB - Male breast cancer (MBC) is an uncommon malignancy. We have previously reported that the expression of the Hippo transducers TAZ/YAP and their target CTGF was associated with inferior survival in MBC patients. Preclinical evidence demonstrated that Axl is a transcriptional target of TAZ/YAP. Thus, we herein assessed AXL expression to further investigate the significance of active TAZ/YAP driven transcription in MBC. For this study, 255 MBC samples represented in tissue microarrays were screened for AXL expression, and 116 patients were included. The association between categorical variables was verified by the Pearson's Chi-squared test of independence (2-tailed) or the Fisher Exact test. The relationship between continuous variables was tested with the Pearson's correlation coefficient. The Kaplan-Meier method was used for estimating survival curves, which were compared by log-rank test. Factors potentially impacting 10 year and overall survival were verified in Cox proportional regression models. AXL was positively associated with the TAZ/CTGF and YAP/CTGF phenotypes (P = 0.001 and P = 0.002, respectively). Patients with TAZ/CTGF/AXL- or YAP/CTGF/AXL expressing tumors had inferior survival compared with non-triple-positive patients (log rank P = 0.042 and P = 0.048, respectively). The variables TAZ/CTGF/AXL and YAP/CTGF/AXL were adverse factors for 10-year survival in the multivariate Cox models (HR 2.31, 95%CI:1.02-5.22, P = 0.045, and HR 2.27, 95%CI:1.00-5.13, P = 0.050). Nearly comparable results were obtained from multivariate analyses of overall survival. The expression pattern of AXL corroborates the idea of the detrimental role of TAZ/YAP activation in MBC. Overall, Hippo-linked biomarkers deserve increased attention in this rare disease. J. Cell. Physiol. 232: 2246-2252, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27987322 TI - Concept analysis: lack of anonymity. AB - AIM: To re-examine and expand understanding of the concept 'lack of anonymity' as a component of rural nursing theory. BACKGROUND: Early healthcare literature reports lack of anonymity as part of social and working environments, particularly rural nursing. Rural nursing theory included the first published concept analysis on lack of anonymity but lacked empirical referents. Workforce, societal and rural healthcare changes support an updated analysis. To further understand lack of anonymity, its present day use and applicability to diverse environments, research from multiple disciplines was reviewed. DESIGN: Concept analysis. DATA SOURCES: A literature search using eight terms in eleven databases was conducted of literature published between 2008-2013. METHOD: Walker and Avant's concept analysis methodology guided the analysis. RESULTS: The previous concept analysis is supported in part by current literature. The defining attributes, 'identifiable', 'establishing boundaries for public and private self and interconnectedness' in a community were updated. Updated antecedents include: (i) environmental context; (ii) opportunities to become visible; (iii) developing relationships and (iv) unconscious or limited awareness of public or personal privacy. Consequences are: (i) familiarity; (ii) visibility; (iii) awareness of privacy and (iv) manage or balance of lack of anonymity. Cases were constructed and empirical referents identified. CONCLUSION: The concept of lack of anonymity was updated; portions of the original definition remain unchanged. Empirical referents reveal the defining attributes in daily life and may guide future research on the effect of lack of anonymity on nursing practice. This analysis advances the conceptual understanding of rural nursing theory. PMID- 27987321 TI - Human White Adipocytes Convert Into "Rainbow" Adipocytes In Vitro. AB - White adipocytes are plastic cells able to reversibly transdifferentiate into brown adipocytes and into epithelial glandular cells under physiologic stimuli in vivo. These plastic properties could be used in future for regenerative medicine, but are incompletely explored in their details. Here, we focused on plastic properties of human mature adipocytes (MA) combining gene expression profile through microarray analysis with morphologic data obtained by electron and time lapse microscopy. Primary MA showed the classic morphology and gene expression profile of functional mature adipocytes. Notably, despite their committed status, MA expressed high levels of reprogramming genes. MA from ceiling cultures underwent transdifferentiation toward fibroblast-like cells with a well differentiated morphology and maintaining stem cell gene signatures. The main morphologic aspect of the transdifferentiation process was the secretion of large lipid droplets and the development of organelles necessary for exocrine secretion further supported the liposecretion process. Of note, electron microscope findings suggesting liposecretion phenomena were found also in explants of human fat and rarely in vivo in fat biopsies from obese patients. In conclusion, both MA and post-liposecretion adipocytes show a well-differentiated phenotype with stem cell properties in line with the extraordinary plasticity of adipocytes in vivo. J. Cell. Physiol. 232: 2887-2899, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27987324 TI - TUDCA: An Agonist of the Bile Acid Receptor GPBAR1/TGR5 With Anti-Inflammatory Effects in Microglial Cells. AB - Bile acids are steroid acids found in the bile of mammals. The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is neuroprotective in different animal models of stroke and neurological diseases. We have previously shown that TUDCA has anti-inflammatory effects on glial cell cultures and in a mouse model of acute neuroinflammation. We show now that microglial cells (central nervous system resident macrophages) express the G protein-coupled bile acid receptor 1/Takeda G protein-coupled receptor 5 (GPBAR1/TGR5) in vivo and in vitro. TUDCA binding to GPBAR1/TGR5 caused an increase in intracellular cAMP levels in microglia that induced anti-inflammatory markers, while reducing pro-inflammatory ones. This anti-inflammatory effect of TUDCA was inhibited by small interference RNA for GPBAR1/TGR5 receptor, as well as by treatment with a protein kinase A (PKA) inhibitor. In the mouse model of acute neuroinflammation, treating the animals with TUDCA was clearly anti-inflammatory. TUDCA biased the microglial phenotype in vivo and in vitro toward the anti-inflammatory. The bile acid receptor GPBAR1/TGR5 could be a new therapeutic target for pathologies coursing with neuroinflammation and microglia activation, such as traumatic brain injuries, stroke, or neurodegenerative diseases. TUDCA and other GPBAR1/TGR5 agonists need to be further investigated, to determine their potential in attenuating the neuropathologies associated with microglia activation. J. Cell. Physiol. 232: 2231-2245, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27987325 TI - Short- and long-term effects of habitat fragmentation differ but are predicted by response to the matrix. AB - Habitat loss and fragmentation are major threats to biodiversity and ecosystem processes. Our current understanding of the impacts of habitat loss and fragmentation is based largely on studies that focus on either short-term or long term responses. Short-term responses are often used to predict long-term responses and make management decisions. The lack of studies comparing short- and long-term responses to fragmentation means we do not adequately understand when and how well short-term responses can be extrapolated to predict long-term responses, and when or why they cannot. To address this gap, we used data from one of the world's longest-running fragmentation experiments, The Wog Wog Habitat Fragmentation Experiment. Using data for carabid beetles, we found that responses in the long term (more than 22 yr post-fragmentation ~22 generations) often contrasted markedly with those in the short term (5 yr post-fragmentation). The total abundance of all carabids, species richness and the occurrence of six species declined in the short term in the fragments but increased over the long term. The occurrence of three species declined initially and continued to decline, whilst another species was positively affected initially but decreased in the long term. Species' responses to the matrix that surrounds the fragments strongly predicted both the direction (increase/decline in occurrence) and magnitude of their responses to fragmentation. Additionally, species' responses to the matrix were somewhat predicted by their preferences for different types of native habitat (open vs. shaded). Our study highlights the degree of the matrix's influence in fragmented landscapes, and how this influence can change over time. We urge caution in using short-term responses to forecast long-term responses in cases where the matrix (1) impacts species' responses to fragmentation (by isolating them, creating new habitat or altering fragment habitat) and (2) is likely to change through time. PMID- 27987323 TI - Translation system engineering in Escherichia coli enhances non-canonical amino acid incorporation into proteins. AB - The ability to site-specifically incorporate non-canonical amino acids (ncAAs) into proteins has made possible the study of protein structure and function in fundamentally new ways, as well as the bio synthesis of unnatural polymers. However, the task of site-specifically incorporating multiple ncAAs into proteins with high purity and yield continues to present a challenge. At the heart of this challenge lies the lower efficiency of engineered orthogonal translation system components compared to their natural counterparts (e.g., translation elements that specifically use a ncAA and do not interact with the cell's natural translation apparatus). Here, we show that evolving and tuning expression levels of multiple components of an engineered translation system together as a whole enhances ncAA incorporation efficiency. Specifically, we increase protein yield when incorporating multiple p-azido-phenylalanine(pAzF) residues into proteins by (i) evolving the Methanocaldococcus jannaschii p-azido-phenylalanyl-tRNA synthetase anti-codon binding domain, (ii) evolving the elongation factor Tu amino acid-binding pocket, and (iii) tuning the expression of evolved translation machinery components in a single vector. Use of the evolved translation machinery in a genomically recoded organism lacking release factor one enabled enhanced multi-site ncAA incorporation into proteins. We anticipate that our approach to orthogonal translation system development will accelerate and expand our ability to site-specifically incorporate multiple ncAAs into proteins and biopolymers, advancing new horizons for synthetic and chemical biotechnology. Biotechnol. Bioeng. 2017;114: 1074-1086. (c) 2016 Wiley Periodicals, Inc. PMID- 27987327 TI - Translating knowledge about abiotic stress tolerance to breeding programmes. AB - Plant breeding and improvements in agronomic practice are making a consistent contribution to increasing global crop production year upon year. However, the rate of yield improvement currently lags behind the targets set to produce enough food to meet the demands of the predicted global population in 2050. Furthermore, crops that are exposed to harmful abiotic environmental factors (abiotic stresses, e.g. water limitation, salinity, extreme temperature) are prone to reduced yields. Here, we briefly describe the processes undertaken in conventional breeding programmes, which are usually designed to improve yields in near-optimal conditions rather than specifically breeding for improved crop yield stability under stressed conditions. While there is extensive fundamental research activity that examines mechanisms of plant stress tolerance, there are few examples that apply this research to improving commercial crop yields. There are notable exceptions, and we highlight some of these to demonstrate the magnitude of yield gains that could be made by translating agronomic, phenological and genetic solutions focused on improving or mitigating the effect of abiotic stress in the field; in particular, we focus on improvements in crop water-use efficiency and salinity tolerance. We speculate upon the reasons for the disconnect between research and research translation. We conclude that to realise untapped rapid gains towards food security targets new funding structures need to be embraced. Such funding needs to serve both the core and collaborative activities of the fundamental, pre-breeding and breeding research communities in order to expedite the translation of innovative research into the fields of primary producers. PMID- 27987326 TI - Risk factors for recurrence after successful treatment of warts: the role of smoking habits. AB - BACKGROUND: Several therapies have been proposed for cutaneous warts without results concerning factors affecting recurrences. OBJECTIVE: To determine the importance of individual characteristics and different therapy modalities in the occurrence of relapses. METHODS: Observational prospective cohort study including 199 patients affected by multiple plantar warts treated as follows: 49 with keratolytics, 50 with CO2 laser, 50 with pulsed dye laser (PDL) and 50 with cryotherapy. Personal data were evaluated through a questionnaire, and treatment information was collected. A Cox regression analysis was performed to identify independent factors for relapse occurrence. RESULTS: Of patients, 57.8% showed a persistent clearance of warts after treatment with a higher recurrence-free interval when treated with PDL. Accordingly, the risk of recurrence was increased with CO2 laser [hazard ratio (HR) 2.92, 95% confidence interval (CI) 1.49-5.74] and keratolytic treatment (HR 3.23, 95% CI 1.60-6.54), as compared to PDL. Furthermore, the multivariate analysis highlighted a higher risk of recurrence in patients between 26 and 35 years (HR 1.88, 95% CI 1.03-3.45), older than 35 (HR 2.23, 95% CI 1.23-4.07) and smokers (HR 4.90, 95% CI 3.09-7.78). CONCLUSIONS: Pulsed dye laser is characterized by the lowest rate of recurrence. Furthermore, our study highlights that the risk of warts relapse is 5-fold higher in smokers compared to non-smokers, revealing the importance of the effects of smoking on inflammation and immune response. PMID- 27987328 TI - TRPM1 (melastatin) expression is an independent predictor of overall survival in clinical AJCC stage I and II melanoma patients. AB - BACKGROUND: The expression of TRPM1 (melastatin) mRNA is an independent marker, as measured by radioactive in situ hybridization (RISH), of disease-free survival in primary cutaneous melanoma (PM). The aim of the study was to determine if chromogenic in situ hybridization (CISH) can reproduce results examining diagnostic and prognostic utility of TRPM1 mRNA expression in melanocytic proliferations as measured by RISH. METHODS: The expression of TRPM1 mRNA was detected by CISH in melanocytic nevi (MN, n = 61), PM (n = 145) and metastatic melanomas (MMs, n = 15). RESULTS: A progressive loss of TRPM1 was found moving from MN to PM to MM. The histologic stepwise model of melanoma progression revealed that loss of TRPM1 occurred at the transition of RGP PM to VGP PM. As a diagnostic marker, TRPM1 gradient loss showed 93.8% sensitivity and 52.4% specificity for PM. Loss of TRPM1 mRNA correlated with melanoma aggressiveness markers and was independent predictor of disease-free and overall survival. The corresponding survival curves for degree of melanoma pigmentation matched those for degree of loss of TPRM1 mRNA. CONCLUSION: Loss of TRPM1 mRNA expression appears to be a crucial event in the progression of melanoma to a more malignant, metastatic phenotype. PMID- 27987330 TI - Protection of Dexmedetomidine Against Ischemia/Reperfusion-Induced Apoptotic Insults to Neuronal Cells Occurs Via an Intrinsic Mitochondria-Dependent Pathway. AB - Dexmedetomidine, an agonist of alpha2-adrenergic receptors, is used for critically ill patients to induce and maintain sedation and analgesia. Brain ischemia/reperfusion (I/R) usually causes severe neuronal injuries to intensive care unit patients. This study was aimed to evaluate the effects of dexmedetomidine on I/R-induced insults to neuronal cells and the possible mechanisms. Treatment of neuro-2a cells with dexmedetomidine did not affect cell viability but could protect against I/R-induced cell death. Separately, the I/R triggered cell shrinkage, DNA fragmentation, and apoptosis in neuro-2a cells were alleviated by dexmedetomidine. As to the mechanisms, exposure of neuro-2a cells to dexmedetomidine substantially attenuated I/R-induced translocation of Bax protein from the cytosol to mitochondria and reduction in the mitochondrial membrane potential (MMP). Successively, dexmedetomidine decreased cytochrome c release from mitochondria to the cytoplasm and consequent cascade activations of caspases-9, -3, and -6 in I/R-treated neuro-2a cells. Interestingly, downregulating caspase-6 activity synergistically improved dexmedetomidine induced defense against I/R-induced apoptosis of neuro-2a cells. The dexmedetomidine-involved neuroprotection was further confirmed in the other NB41A3 neuronal cells by significantly attenuating I/R-induced changes in the MMP, caspase-3 activation, DNA fragmentation, and cell apoptosis. Taken together, this study has shown the neuroprotective effects of dexmedetomidine against I/R induced apoptotic insults via an intrinsic Bax-mitochondria-cytochrome c-caspase protease pathway. J. Cell. Biochem. 118: 2635-2644, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27987329 TI - Fetal Alcohol Exposure Alters Blood Flow and Neurological Responses to Transient Cerebral Ischemia in Adult Mice. AB - BACKGROUND: Prenatal alcohol exposure (PAE) can result in physical and neurocognitive deficits that are collectively termed "fetal alcohol spectrum disorders" (FASD). Although FASD is associated with lifelong intellectual disability, the mechanisms mediating the emergence of secondary mental health and physical disabilities are poorly understood. Based on our previous data showing that maternal ethanol (EtOH) exposure in mice resulted in an immediate reduction in cranially directed fetal blood flow, we hypothesized that such exposure would also result in persistent alterations in cranially directed blood flow in the prenatally alcohol-exposed (PAE) adult. We also hypothesized that PAE adults exposed to an acute cerebrovascular insult would exhibit more brain damage and neurobehavioral impairment compared to non-PAE adult controls. METHODS: Pregnant C57BL/6 mice were exposed to EtOH, 3 g/kg, or water by intragastric gavage. Blood flow in carotid, renal, and femoral arteries was assessed by ultrasound imaging in PAE and control adults at 3, 6, and 12 months of age. To mimic ischemic stroke in young adult populations, 3-month-old PAE and control animals were subject to transient middle cerebral artery occlusion (MCAo) and subsequently assessed for behavioral recovery, stroke infarct volume, and brain cytokine profiles. RESULTS: PAE resulted in a significant age-related decrease in blood acceleration in adult mice, specifically in the carotid artery. A unilateral transient MCAo resulted in equivalent cortico-striatal damage in both PAE and control adults. However, PAE adult mice exhibited significantly decreased poststroke behavioral recovery compared to controls. CONCLUSIONS: Our data collectively show that PAE adult mice exhibit a persistent, long-term loss of cranially directed blood flow, and decreased capacity to compensate for brain trauma due to acute-onset adult diseases like ischemic stroke. PMID- 27987331 TI - IRS1/beta-Catenin Axis Is Activated and Induces MYC Expression in Acute Lymphoblastic Leukemia Cells. AB - Insulin-like growth factor 1 (IGF1) and its receptor IGF1R regulate normal cell growth and contribute to cell transformation through activation of downstream signaling pathways. In fibroblast cells, insulin receptor substrate 1 (IRS1), through IGF1 signaling, was found to be the key protein for nuclear translocation of beta-catenin and MYC transcription activation. We herein investigated the IRS1/beta-catenin axis in acute lymphoblastic leukemia (ALL) cells. Samples were obtained from 45 patients with ALL and 13 healthy donors. ALL cell lines were used. Gene expression was measured by quantitative PCR. Protein expression, associations, and cellular localization were evaluated by immunoprecipitation, subcellular fractionation, and confocal microscopy. Cells were submitted to IGF1 stimulation and/or IGF1R pharmacological inhibition (OSI-906). IRS1, beta catenin, and MYC mRNA expression were significantly elevated in ALL patients, compared to normal controls. MYC mRNA expression positively correlated with beta catenin and IRS1. Increased age and MYC expression negatively affected overall survival by univariate analysis. Total and phospho-IGF1R and IRS1, MYC and beta catenin protein expression were higher in ALL cells, compared to normal peripheral blood mononuclear cells (PBMC). IRS1 and beta-catenin were found to be colocalized in the nuclei and the cytoplasm of ALL cell lines, whereas both proteins were only slightly detected in the cytoplasm of normal PBMC. In Jurkat cells, a constitutive IRS1 and beta-catenin protein interaction were observed; OSI-906 treatment decreased IGF1R tyrosine phosphorylation, IRS1 expression and phosphorylation, nuclear translocation of beta-catenin, IRS1 and beta-catenin association, and MYC protein expression. In conclusion, the IRS1/beta-catenin axis is activated in ALL cells. J. Cell. Biochem. 118: 1774-1781, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27987333 TI - Ritodrine-induced rhabdomyolysis, infantile myotonic dystrophy, and maternal myotonic dystrophy unveiled. AB - A primiparous pregnant woman in remission of myositis suffered very acute-onset ritodrine-induced rhabdomyolysis. At 29 gestational weeks, ritodrine was administered for threatened preterm labor. Just 3 h later, she complained of severe limb muscle pain, with serum creatinine phosphokinase elevated to 32 019 U/L and myoglobinuria. The muscle pain disappeared immediately after ceasing administration of ritodrine. At 31 weeks, premature rupture of the membranes occurred, necessitating cesarean section, yielding a baby with weak tonus, and the presence of infantile muscle diseases was suspected. Genetic analysis of the infant confirmed myotonic dystrophy (dystrophia myotonica, DM), which prompted us to perform maternal genetic analysis, confirming maternal DM. Ritodrine can induce rhabdomyolysis even in the prodromal phase with a mild phenotype of DM. A literature review suggested that ritodrine-induced rhabdomyolysis may be likely to occur more acutely after ritodrine administration in DM compared with non-DM mothers. PMID- 27987334 TI - Echocardiography findings in a case with Ballantyne syndrome. AB - Marked fluid retention occurs in Ballantyne syndrome, but few reports are available on changes in cardiac morphology in this syndrome. A woman with generalized edema, dyspnea, fetal hydrops (skin edema and ascites), thickened placenta, and elevated plasma B-type natriuretic peptide level (344 pg/mL) was admitted to our hospital at gestational week (GW) 20+3 . Blood pressure remained within the normal range. However, acute increases in left atrial volume index, pulmonary artery systolic pressure, and hyperdynamic left ventricular function (as evidenced by increased left ventricular ejection fraction to 74% with cardiac index of 5.1 L/min/m2 ) occurred preceding fetal death at GW 21+4 in the presence of increased inferior vena cava diameter (23 mm) and relatively low systemic vascular resistance of 752 dyn.s/cm5 . These findings suggested life-threatening heart failure and required cesarean delivery at GW 21+5 resulting in complete recovery. The placenta suggested cytomegalovirus infection. PMID- 27987332 TI - Neddylated Cullin 3 is required for vascular endothelial-cadherin-mediated endothelial barrier function. AB - Vascular endothelial (VE)-cadherin, a major endothelial adhesion molecule, regulates vascular permeability, and increased vascular permeability has been observed in several cancers. The aim of this study was to elucidate the role of the NEDD8-Cullin E3 ligase, in maintaining barrier permeability. To this end, we investigated the effects of the inhibition of Cullin E3 ligases, by using inhibitors and knockdown techniques in HUVECs. Furthermore, we analyzed the mRNA and protein levels of the ligases by quantitative RT-PCR and Western blotting, respectively. The results revealed that NEDD8-conjugated Cullin 3 is required for VE-cadherin-mediated endothelial barrier functions. Treatment of HUVECs with MLN4924, a chemical inhibitor of the NEDD8-activating enzyme, led to high vascular permeability due to impaired cell-cell contact. Similar results were obtained when HUVECs were treated with siRNA directed against Cullin 3, one of the target substrates of NEDD8. Immunocytochemical staining showed that both treatments equally depleted VE-cadherin protein localized at the cell-cell borders. However, quantitative RT-PCR showed that there was no significant difference in the VE-cadherin mRNA levels between the treatment and control groups. In addition, cycloheximide chase assay revealed that the half-life of VE cadherin protein was dramatically reduced by Cullin 3 depletion. Together, these findings suggest that neddylated Cullin 3 plays a crucial role in endothelial cell barrier function by regulating VE-cadherin. PMID- 27987335 TI - Gestational choriocarcinoma: Rare spinal metastasis during a viable pregnancy. AB - Gestational choriocarcinoma metastasizing to the bones, especially to the spine, is extremely rare. In addition, there are few reports of choriocarcinoma during a viable pregnancy. We report a case of gestational choriocarcinoma that metastasized to the lumbar spine during a viable pregnancy in a 41-year-old woman with a history of a missed abortion. A heterogeneous cervical mass was detected at gestational week 16. Subsequently, a metastatic lesion appeared during the pregnancy, and fetal demise in utero occurred. Pathological examination revealed that the cervical tumor and metastatic spinal tumor were choriocarcinoma. The patient's condition deteriorated rapidly and we were unable to save her life, despite multidrug chemotherapy. Surgical tumor resection and pregnancy might involve a substantial risk of choriocarcinoma metastasis. It is important to obtain an early diagnosis for this life-threatening disease in order to facilitate appropriate treatment, despite pregnancy. PMID- 27987336 TI - Frequency of malformed infants in a tertiary center in Hokkaido, Japan over a period of 10 years. AB - AIM: This retrospective study was performed to determine the frequency of malformed infants born at a tertiary center in Hokkaido, Japan. The accuracy of prenatal diagnosis rates was also investigated. METHODS: An observational study was performed using data of 1509 and 1743 newborn infants at a single center during two study periods, 2005-2009 (first) and 2010-2014 (second), respectively. Cases including minor anomalies (accessory auricle, nevus and fistula auris congenita) were not included. RESULTS: In total, 274 and 569 malformations were identified in 191 and 337 newborn infants in the first and second study periods, respectively. The number of malformed infants increased significantly over time (13% [191/1509] vs 19% [337/1743], respectively; P < 0.001), mainly as a result of an increase in cases of congenital heart disease (CHD), from 59 to 141 (31% [59/191] vs 42% [141/337] of all malformed infants in the first and second periods, respectively). The overall accurate prenatal diagnosis rate improved over time from 47% (128/274) to 58% (329/569) because of significant improvements in accurate prenatal diagnosis of CHD subtypes (23% [16/70] vs 65% [151/232] in the first and second periods, respectively, P < 0.0001). CONCLUSIONS: The frequency of malformed newborns was higher in the tertiary center than in the general population. The increased number of cases with prenatal suspicion and diagnosis of CHD contributed to the increased frequency of malformed infants during the study period. PMID- 27987337 TI - Replication of GWAS loci revealed the moderate effect of TNRC6B locus on susceptibility of Saudi women to develop uterine leiomyomas. AB - AIM: Uterine leiomyomas (UL) are smooth muscular nodes, whose growth is dependant up on the complex interplay of hormones with genes and uterine physiology. Global statistics indicate the role of ethnic and racial background as contributory factors for UL development. Owing to the lack of data, this study aimed to examine the association between genetic polymorphisms and susceptibility of Arab women of developing UL. METHODS: We genotyped 105 UL patients and 112 healthy controls for five genetic polymorphisms through real time PCR method. The strength of the association between genotype and allele frequencies with risk of developing UL was tested with their chi2 and odds ratio (OR) values. The synergistic cooperation between genetic polymorphisms was estimated through multifactor dimensionality reduction assay. RESULTS: We found that Saudi women with the AG genotype for the rs12484776 polymorphism are at a 2.6-fold higher risk of developing UL compared to those with other genotypes (OR, 2.69; 95% confidence interval [CI]: 1.45-5.00; P < 0.001). This significance persisted even under co-dominant models (i.e., AA vs GG + AG [OR, 2.74; 95%CI: 1.48-5.08; P = 0.001; and AG vs GG + AG [OR, 2.41; 95% CI: 1.33-4.39; P = 0.003). Genotype distribution frequencies for rs1056836, rs7913069, rs2280543, and rs4247357 were not shown to elevate the disease risk (for all tests P > 0.05). CONCLUSION: The rs12484776 significantly contributes to UL risk among Saudi women, both in single and also in synergistic cooperation with rs2280543, rs7913069, and rs1056836 markers. Our results have yielded mixed findings in replicating European- and Japanese-specific UL genetic susceptibility loci among a geographically and culturally distinct population of the Saudi Arabian Peninsula. PMID- 27987338 TI - Effect of interleukin-1beta and lipoxin A4 in human endometriotic stromal cells: Proteomic analysis. AB - AIM: Lipoxin A4 (LXA4 ) can function as an endogenous 'breaking signal' in inflammation and plays an important role in the progression of endometriosis. The proteome responses to interleukin-1beta (IL-1beta) or LXA4 in human endometriotic stromal cells (ESC) are not well understood. METHODS: In this study, primary ESC were cultured from ovarian endometriosis tissue. Three groups were established: the control group; the IL-1beta stimulation group; and the IL-1beta and LXA4 incubation group. Proteins were assessed on 2-D polyacrylamide gel electrophoresis (2D-PAGE), and differentially expressed protein spots were further identified on matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry (MALDI-TOF-MS). Wound healing and transwell assays were performed to assess the migration and invasion of ESC after treatment. RESULTS: In total, 40 differentially expressed protein spots were identified successfully on MALDI-TOF-MS. The proteins identified were related to cell structure, metabolism, signal transduction, protein synthesis and membrane structure, processes that may be involved in the development of endometriosis. Vinculin and IL-4 were further analyzed on western blot and quantitative real time polymerase chain reaction. Moreover, LXA4 could suppress the migration and invasion of ESC induced by IL-1beta. CONCLUSION: LXA4 may inhibit the progression of endometriosis partly by lowering or raising the effect of IL-1beta, mediated via some inflammation-related proteins (e.g. vinculin) and immune response related protein (e.g. IL-4) in vitro. PMID- 27987339 TI - Evaluation of ovarian reserve using anti-mullerian hormone and antral follicle count in Sjogren's syndrome: Preliminary study. AB - AIM: The aim of this study was to determine ovarian reserve status using anti mullerian hormone (AMH) level and antral follicle count (AFC) in patients with Sjogren's syndrome (SS). METHODS: Twenty-four women with SS diagnosed according to the classification criteria proposed by the American-European Consensus Group and 25 healthy women as controls were enrolled in this study. Ovarian reserve was assessed on clinical findings, AFC, and serum AMH and reproductive hormone levels. RESULTS: Compared with the healthy controls, in the SS patients, the duration of menstrual cycle was significantly shorter (P = 0.043); serum AMH (P = 0.001) and AFC (P = 0.001) were significantly lower, and serum luteinizing hormone (LH) was significantly higher (P = 0.019). The right (P = 0.555) and left ovarian (P = 0.386) volumes were also lower but this did not reach statistical significance. Serum follicle-stimulating hormone (P = 0.327), estradiol (P = 0.241), and prolactin (P = 0.55) were similar between the two groups. CONCLUSIONS: Ovarian reserve may be reduced in SS patients. For the assessment of ovarian reserve, serum AMH and ovarian AFC with serum LH may be useful. Further studies with long-term follow-up are required to determine the course of ovarian reserve abnormalities and best possible biomarkers of reduced ovarian reserve in SS patients. PMID- 27987340 TI - Ethnic analogies and differences in fetal heart rate variability signal: A retrospective study. AB - AIM: We aimed to analyze computerized cardiotocographic (cCTG) parameters (including fetal heart rate baseline, short-term variability, Delta, long-term irregularity [LTI], interval index [II], low frequency [LF], movement frequency [MF], high frequency [HF], and approximate entropy [ApEn]) in physiological term pregnancies in order to correlate them with ethnic differences. The clinical meaning of numerical parameters may explain physiological or paraphysiological phenomena that occur in fetuses of different ethnic origins. METHODS: A total of 696 pregnant women, including 384 from Europe, 246 from sub-Saharan Africa, 45 from South-East Asia, and 21 from South America, were monitored from the 37th to the 41st week of gestation. Statistical analysis was performed with the analysis of variance test, Pearson correlation test and receiver-operator curves (P < 0.05). RESULTS: Our results showed statistically significant differences (P < 0.05) between white and black women for Delta, LTI, LF, MF, HF, and ApEn; between white and Asian women for Delta, LTI, MF, and the LF/(HF + MF) ratio; and between white and Latina women for Delta, LTI, and ApEn. In particular, Delta and LTI performed better in the white group than in the black, Asian, and Latina groups. Instead, LF, MF, HF, and ApEn performed better in the black than in the white group. CONCLUSION: Our results confirmed the integrity and normal functionality of both central and autonomic nervous system components for all fetuses investigated. Therefore, CTG monitoring should include both linear and nonlinear components of fetal heart rate variability in order to avoid misinterpretations of the CTG trace among ethnic groups. PMID- 27987341 TI - FDG-PET-positive ovarian thecoma with GLUT5 expression: Five cases. AB - Positron emission tomography (PET) with fluorodeoxyglucose F18 (18 F-FDG) is useful for detecting malignancies, but benign lesions occasionally have false positive 18 F-FDG uptake. Here, we report the cases of five postmenopausal women with solid ovarian tumors suspected to be ovarian cancer on magnetic resonance imaging and 18 F-FDG uptake. Mean age of the five patients was 57 years (range, 53-65 years). Average early standardized uptake value (SUV) of 18 F-FDG was 5.76 (range, 2.2-12.0) and delayed SUV was 6.56 (range, 2.4-13.8). In all five patients, frozen section diagnosis at surgery was thecoma, and bilateral salpingo oophorectomy was performed. On immunohistochemistry, immunoreactive glucose transporter 5 (GLUT5) expression was detected in thecoma tissues. This case shows that thecoma sometimes has positive 18 F-FDG uptake on positron emission tomography-computed tomography (PET-CT), indicating the need for caution regarding false-positive PET-CT in patients with benign solid ovarian tumor. PMID- 27987342 TI - Comparison between two management protocols for postpartum hemorrhage during cesarean section in placenta previa: Balloon protocol versus non-balloon protocol. AB - AIM: This study was conducted to compare two management protocols for post-partum hemorrhage (PPH) during cesarean section (CS) in placenta previa (PP), Bakri balloon protocol versus non-balloon protocol. Secondary analysis among balloon treated cases was also performed to identify predictors of success, failure or complications, if any. METHODS: A prospective cohort study was conducted in two hospitals in Saudi Arabia, including cases that developed PPH during CS for PP. The primary outcome measure was success in preventing hysterectomy, while secondary outcome measures were amount of blood loss, need for blood transfusion, need for return to theater and admission to intensive care unit. RESULTS: One hundred and fifty-one cases were identified as low-lying placenta and PP, of which 114 developed PPH. Two patients were unstable and required immediate hysterectomy. The remaining 112 cases were managed by balloon (72 cases) or non balloon protocols (40). The balloon alone was successful in achieving hemostasis in 87.5% of cases. When analyzed specifically, balloon success was associated with the absence of accreta (odds ratio 0.001, confidence interval 0.000-0.974) and short operation duration (odds ratio 1.143, confidence interval 1.018-1.282). CONCLUSION: Application of the Bakri balloon for the management of PPH after CS in cases of PP is an effective strategy that should be affordable worldwide. PMID- 27987343 TI - Mature cystic teratoma coexisting with clear-cell carcinoma in the ovary. AB - Mature cystic teratoma (MCT) is the most common benign ovarian tumor; clear-cell carcinoma (CCC) is a relatively common malignant ovarian tumor in Japan, but there are few reports on the coexistence of MCT and CCC. Here we report a case of simultaneous MCT and CCC in the ovary and review the relevant literature. The patient was a 49-year-old woman. A 5-cm MCT was found in the left ovary on initial gynecological examination, and she was referred to hospital for treatment because it was expanding. Magnetic resonance imaging showed a multilocular cystic tumor 16 * 10 * 9.5 cm in the left ovary, and surgery was performed. The final pathological diagnosis was MCT, endometriotic cyst, clear-cell adenofibroma, clear-cell borderline tumor, and CCC in the left ovary. PMID- 27987344 TI - Safety and efficacy of transcatheter arterial chemoembolization with embospheres in treatment of hepatocellular carcinoma. AB - OBJECTIVE: To investigate the safety and efficacy of transcatheter arterial chemoembolization (TACE) with embospheres for the treatment of unresectable hepatocellular carcinoma (HCC). METHODS: Patients with unresectable HCC who were treated with TACE followed by embosphere treatment (Embo-TACE) or conventional TACE (cTACE) between May 2010 and March 2014 were retrospectively included in this study. The Embo-TACE group received lipiodol and chemotherapeutic agent emulsion, followed by embospheres. The cTACE group received lipiodol and chemotherapeutic agent emulsion, followed by gelatin sponge pellets. Time to progression (TTP), overall survival (OS), overall response rate (ORR), and safety were compared between the two groups. Univariate and multivariate regression analyses of the factors affecting survival were conducted. RESULTS: The median TTP and OS in the Embo-TACE group were significantly longer than those in the cTACE group (TPP: 7.0 months vs 5.4 months, P = 0.035; OS: 15 months vs 12 months, P = 0.032). Seven days after the first TACE treatment, alanine aminotransferase level was higher in the cTACE group than in the Embo-TACE group (P = 0.015). The ORR did not significantly differ between the two groups (P = 0.827). Additional therapy and local responses one month after the first TACE treatment were associated with OS. CONCLUSIONS: Embo-TACE resulted in a significant improvement in TTP and OS for patients with unresectable HCC, compared with cTACE. Furthermore, Embo-TACE was better tolerated. Additional therapy and local responses one month after the first TACE were independent prognostic factors for OS. PMID- 27987345 TI - Retrospective study of tadalafil for fetal growth restriction: Impact on maternal and perinatal outcomes. AB - AIM: The aim of this retrospective study was to assess tadalafil treatment in pregnant women with fetal growth restriction (FGR) in terms of maternal and perinatal outcomes. METHODS: We retrospectively analyzed 11 Japanese singleton pregnant women with FGR who received tadalafil along with conventional management for FGR at Mie University Hospital from July 2015 to February 2016 (tadalafil group). These women were matched for maternal age, parity, gestational age, and estimated fetal weight at enrollment with 14 singleton pregnant women who received only the conventional management for FGR in 2014 (conventional management group). The conventional management for FGR was performed according to guidelines for obstetric practice in Japan. RESULTS: Both birthweight and fetal growth velocity from enrollment to birth were significantly higher in the tadalafil group than in the conventional management group. The cesarean delivery rate was approximately twofold higher in the conventional management group than in the tadalafil group. Importantly, cesarean section due to non-reassuring fetal status was performed in seven pregnant women in the conventional management group (58.3%) but in none in the tadalafil group (P < 0.05, chi-squared test). CONCLUSIONS: Tadalafil may improve perinatal outcome in FGR by modulating fetal growth through maintenance or improvement of fetal well-being. PMID- 27987346 TI - Diagnosis and potential management of gestational diabetes mellitus using the International association of diabetes and pregnancy study groups criteria. AB - AIM: Appropriate screening and plasma glucose control is important during pregnancy, but an international consensus has not been reached regarding the recommended method of screening and diagnosis of gestational diabetes mellitus (GDM). We investigated glucose intolerance in pregnant women diagnosed with GDM, applying stricter screening criteria. METHODS: The study involved 452 women with singleton pregnancies, who underwent a 2 h 75 g oral glucose tolerance test between January 2006 and December 2010. They had previously been screened for GDM using Japan Society of Obstetrics and Gynecology (JSOG) criteria. We retrospectively re-evaluated their status using International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. The major differences between JSOG and IADPSG criteria are the number of applicable threshold values, and the threshold value for fasting glucose measured by the glucose tolerance test. The insulinogenic index and insulin resistance according to the homeostasis model assessment were compared among groups in the presence or absence of obesity. RESULTS: GDM was diagnosed in 56 (1.07%) and 133 (2.54%) women based on the JSOG and IADPSG criteria, respectively. Compared to non-GDM, non-obese women, those diagnosed with GDM according to IADPSG criteria had significantly higher insulin resistance, while those diagnosed with GDM exceeding two or more threshold values had significantly lower insulinogenic indexes. CONCLUSION: Adopting stricter diagnostic criteria increased the prevalence of GDM 2.37-fold, as women previously diagnosed with milder abnormalities in glucose levels were then diagnosed as having GDM. PMID- 27987347 TI - Integrated analysis reveals candidate mRNA and their potential roles in uterine leiomyomas. AB - AIM: Uterine leiomyomas (UL) are the most common pelvic tumors, and the etiology and pathophysiology are not well understood. We aimed to elucidate the genes responsible for UL development. METHODS: Integrated analyses of four datasets of mRNA profiling for UL were performed. Functional annotation of differentially expressed genes (DEG) was used to systematically characterize the global expression profiles. The UL-specific protein-protein interaction network was constructed. RESULTS: Integrated analysis led to the discovery of 2167 DEG (1042 upregulated and 1125 downregulated). The aberrant expression of NAV2, KIF5C, DCX, CAPN6, COL4A2, ALDH1A1, and DPT may play important roles in UL tumorigenesis. In addition, the dysregulation of MEST, LGALS3, and TLR3 may be involved in the progression of UL by a common mechanism. Functional annotation showed that extracellular matrix receptor interaction may be more active and cause the extracellular matrix abnormally formed in UL. Moreover, focal adhesion and cell adhesion molecules may play roles in the development of UL. Furthermore, chemokine signaling pathway and cytokine-cytokine receptor interaction were most probably involved in the development of UL. CONCLUSION: In conclusion, our study observed that a set of aberrantly expressed genes and the related biochemical pathways may lead to transformation of normal myometrium in pathological focuses. PMID- 27987348 TI - Conservative management of post-partum hemorrhage secondary to placenta previa accreta with hypogastric artery ligation and endo-uterine hemostatic suture. AB - AIM: The aim of this study was to investigate maternal and neonatal outcomes of conservative management of post-partum hemorrhage due to placenta previa-accreta using hypogastric artery ligation and endo-uterine hemostatic suture to lower uterine segment. METHODS: The records of 38 patients who were managed conservatively with hypogastric artery ligation and endo-uterine hemostatic suture to control post-partum hemorrhage secondary to placenta previa-accreta between April 2014 and January 2016, were reviewed retrospectively. Placenta previa-accreta was diagnosed according to gray-scale, color and 3-D power Doppler ultrasonography in addition to the intraoperative findings based on fragmentary or difficult separation of the placenta. In the case of conservative treatment protocol failure, cesarean hysterectomy was performed. RESULTS: Of these patients, 55.2% were between 25 and 35 years old; 97.5% were multiparous; 71.2% had two or more previous cesarean section and 68.5% had preterm delivery. Women with placenta accreta had a median estimated blood loss of 450 mL; 57.8% of patients had blood transfusion (mean intraoperative transfusion, 2 units packed red blood cells; range, 0-9 units). Median duration of operation was 112.5 min (range, 45-305 min) and 32 patients (84.3%) with placenta accreta did not undergo cesarean hysterectomy. CONCLUSION: Conservative treatment of post-partum hemorrhage secondary to placenta previa-accreta with hypogastric artery ligation and endo-uterine hemostatic sutures to the lower segment of the uterus is associated with lower hysterectomy rate compared with the other conservative methods reported in the literature. PMID- 27987349 TI - Differentials in variables associated with past history of artificial abortion and current contraception by age: Results of a randomized national survey in Japan. AB - AIM: This study analyzes differentials in the variables associated with the experience of artificial abortion (abortion) and use of contraception by age among women in Japan. METHODS: The 2010 National Lifestyle and Attitudes Towards Sexual Behavior Survey was distributed to 2693 men and women aged 16-49 selected from the Japanese population using a two-stage random sampling procedure. From the 1540 respondents, we selected 700 women who reported having had sexual intercourse at least once. We used logistic regression to analyze how social and demographic factors were associated with the experience of abortion and contraceptive use. RESULTS: The abortion rate according to the survey was 19.3%. Of the 700 women in the sample, 6.9% had experienced two or more abortions. Logistic regression revealed that, although significant variables depended on age, a high level of education and discussions about contraceptive use with partners were negatively associated with the experience of abortion. Self-injury, approval of abortion and first sexual intercourse between the age of 10 and 19 were positively associated with the experience of abortion. Marriage, smoking and first sexual intercourse between the age of 10 and 19 were negatively associated with contraceptive use. Higher education and discussion of contraception with partners were positively associated with contraceptive use. CONCLUSIONS: To prevent unwanted pregnancy and abortion, social support and sexual education should be age-appropriate. It is vital to educate young people of the importance of discussing contraceptive use with their partners. PMID- 27987350 TI - Influence of Behcet's disease on first and second trimester serum screening markers. AB - AIM: Behcet's disease (BD) is a rare and multisystemic vasculitis disease. In this study, we investigated whether BD had any effect on the biochemical components of first and second trimester aneuploidy screening tests. METHODS: A case-control retrospective study was conducted with 32 pregnant women with BD and 60 healthy pregnant women as controls. All pregnant womens' first trimester maternal serum pregnancy-associated plasma protein-A, free beta-human chorionic gonadotropin and second trimester serum alpha-fetoprotein, unconjugated estriol and total human chorionic gonadotropin levels were examined from medical records. First and second serum screening markers were compared between pregnancies with BD and without. RESULTS: There was no difference in age, body mass index and obstetric history between the groups. No significant difference was observed between the groups in terms of first and second trimester serum screening test results in the absence of aneuploidy or neural tube defect. Gestational age at birth, birth weight and neonatal intensive care admission rate were also similar between the groups. CONCLUSION: Both first and second serum screening tests for Down syndrome may be recommended to pregnant women with BD without the need to readjust these markers. Pregnancy with BD was not associated with adverse perinatal outcome with respect to gestational age at birth or birth weight. PMID- 27987351 TI - The role of relative membrane capacitance and time delay in cerebellar Purkinje cells. AB - The membrane capacitance of a neuron can influence the synaptic efficacy and the speed of electrical signal propagation. Exploring the role of membrane capacitance will help facilitate a deeper understanding of the electrical properties of neurons. Thus, in this paper, we investigated the neuronal firing behaviors of a two-compartment model in Purkinje cells. We evaluated the influence of membrane capacitance under two different circumstances: in the absence of time delay and in the presence of time delay. Firstly, we separately studied the influence of somatic membrane capacitance Cs and dendritic membrane capacitance Cd on neuronal firing patterns. Through numerical simulation, we observed that they had two different types of period-adding scenarios, i.e. with and without chaotic bursting. Secondly, our results indicated that when the time delay was included in the model, periodic motions were more inclined to be destroyed, while at the same time, corresponding new chaotic motions were induced. These findings suggested that membrane capacitance and time delay play a pivotal functional role in modulating dynamical firing properties of neurons, especially aspects which lead to behaviors which result in changes to bursting patterns. PMID- 27987352 TI - Design of a right ventricular mock circulation loop as a test bench for right ventricular assist devices. AB - Right heart failure (RHF), e.g. due to pulmonary hypertension (PH), is a serious health issue with growing occurrence and high mortality rate. Limited efficacy of medication in advanced stages of the disease constitutes the need for mechanical circulatory support of the right ventricle (RV). An essential contribution to the process of developing right ventricular assist devices (RVADs) is the in vitro test bench, which simulates the hemodynamic behavior of the native circulatory system. To model healthy and diseased arterial-pulmonary hemodynamics in adults (mild and severe PH and RHF), a right heart mock circulation loop (MCL) was developed. Incorporating an anatomically shaped silicone RV and a silicone atrium, it not only enables investigations of hemodynamic values but also suction events or the handling of minimal invasive RVADs in an anatomical test environment. Ventricular pressure-volume loops of all simulated conditions as well as pressure and volume waveforms were recorded and compared to literature data. In an exemplary test, an RVAD was connected to the apex to further test the feasibility of studying such devices with the developed MCL. In conclusion, the hemodynamic behavior of the native system was well reproduced by the developed MCL, which is a useful basis for future RVAD tests. PMID- 27987353 TI - A seepage outlet boundary condition in hemodynamics modeling. AB - BACKGROUND: In computational fluid dynamics (CFD) models for hemodynamics applications, boundary conditions remain one of the major issues in obtaining accurate fluid flow predictions. OBJECTIVE: As an important part of the arterial circulation, microcirculation plays important roles in many aspects, such as substance exchange, interstitial fluid generation and inverse flow. It is necessary to consider microcirculation in hemodynamics modeling. This is a methodological paper to test and validate a new type of boundary condition never applied to microcirculation before. METHODS: In order to address this issue, we introduce microcirculation as a seepage outlet boundary condition in computational hemodynamics. Microcirculation is treated as a porous medium in this paper. Numerical comparisons of the seepage and traditional boundary conditions are made. RESULTS: The results show that the seepage boundary condition has significant impacts on numerical simulation. Under the seepage boundary condition, the fluctuation range of the pressures progressively rises in the artery zone. The results obtained from the traditional boundary condition show that the pressure fluctuation range gradually falls. In addition, the wall shear stresses under the traditional outlet boundary condition are much higher than those under the seepage outlet boundary condition. CONCLUSIONS: The proposed boundary condition is more suitable in hemodynamics modeling. PMID- 27987354 TI - Physiologic changes of urinary proteome by caffeine and excessive water intake. AB - BACKGROUND: Diurnal variations and physiologic changes of urinary proteome have been suggested in the urinary proteomics field. However, no clear evidence has been demonstrated. The present study thus aimed to define changes in urinary proteome by physiological stimuli, i.e. caffeine intake and excessive water drinking, both of which cause physiologic diuresis. METHODS: Urine samples were collected from 30 healthy individuals under three different conditions: (i) morning void as the control; (ii) after drinking a cup of coffee; and (iii) after drinking 1 L of water within 20 min. Thereafter, differentially excreted proteins were analyzed by 2-DE proteomics approach and validated by Western blotting and ELISA. RESULTS: Spot matching, quantitative intensity analysis, and ANOVA followed by Tukey's post-hoc multiple comparisons and the Bonferroni correction revealed significant differences in levels of five protein spots among three different conditions. These proteins were identified by quadrupole time-of-flight mass spectrometry (Q-TOF MS) and/or MS/MS analyses as kininogen 1 isoform 3, beta actin, prostaglandin D synthase (PGDS), fibrinogen alpha-chain and immunoglobulin light chain. Among these, the decreased level of immunoglobulin was successfully validated by Western blotting and ELISA. CONCLUSIONS: These data indicated that caffeine intake and excessive water drinking could affect urinary excretion of some proteins and may affect urinary proteome analysis. PMID- 27987355 TI - miRNA assays in the clinical laboratory: workflow, detection technologies and automation aspects. AB - microRNAs (miRNAs) are short non-coding RNA molecules that regulate gene expression in eukaryotes. Their differential abundance is indicative or even causative for a variety of pathological processes including cancer or cardiovascular disorders. Due to their important biological function, miRNAs represent a promising class of novel biomarkers that may be used to diagnose life threatening diseases, and to monitor disease progression. Further, they may guide treatment selection or dosage of drugs. miRNAs from blood or derived fractions are particularly interesting candidates for routine laboratory applications, as they can be measured in most clinical laboratories already today. This assures a good accessibility of respective tests. Albeit their great potential, miRNA-based diagnostic tests have not made their way yet into the clinical routine, and hence no standardized workflows have been established to measure miRNAs for patients' benefit. In this review we summarize the detection technologies and workflow options that exist to measure miRNAs, and we describe the advantages and disadvantages of each of these options. Moreover, we also provide a perspective on data analysis aspects that are vital for translation of raw data into actionable diagnostic test results. PMID- 27987356 TI - The impact of admission neutrophil-to-platelet ratio on in-hospital and long-term mortality in patients with infective endocarditis. AB - BACKGROUND: Infective endocarditis (IE) is associated with increased neutrophil and reduced platelet counts. We assessed the relationship between the neutrophil to-platelet ratio (NPR) on admission and adverse outcomes in patients with IE. METHODS: Patients diagnosed with IE between January 2009 and July 2015 (n=1293) were enrolled, and 1046 were finally entered into the study. Study subjects were categorized into four groups according to NPR quartiles: Q1<18.9 (n=260); Q2: 18.9-27.7 (n=258); Q3: 27.7-43.3 (n=266); and Q4>43.3 (n=262). Cox proportional hazards regression was performed to identify risk factors for long-term mortality; the optimal cut-off was evaluated by receiver operating characteristic curves. RESULTS: Risk of in-hospital death increased progressively with NPR group number (1.9 vs. 5.0 vs. 9.8 vs. 14.1%, p<0.001). The follow-up period was a median of 28.8 months, during which 144 subjects (14.3%) died. Long-term mortality increased from the lowest to the highest NPR quartiles (7.6, 11.8, 17.4, and 26.2%, respectively, p<0.001). Multivariate Cox proportional hazard analysis revealed that lgNPR (HR=2.22) was an independent predictor of long-term mortality. Kaplan-Meier survival curves showed that subjects in Q4 had an increased long-term mortality compared with the other groups. CONCLUSIONS: Increased NPR was associated with in-hospital and long-term mortality in patients with IE. As a simple and inexpensive index, NPR may be a useful and rapid screening tool to identify IE patients at high risk of mortality. PMID- 27987357 TI - microRNAs in lipoprotein and lipid metabolism: from biological function to clinical application. AB - microRNAs (miRNAs) are short (~22 nucleotides), non-coding, single-stranded RNA molecules that regulate the expression of target genes by partial sequence specific base-pairing to the targeted mRNA 3'UTR, blocking its translation, and promoting its degradation or its sequestration into processing bodies. miRNAs are important regulators of several physiological processes including developmental and metabolic functions, but their concentration in circulation has also been reported to be altered in many pathological conditions such as familial hypercholesterolemia, cardiovascular diseases, obesity, type 2 diabetes, and cancers. In this review, we focus on the role of miRNAs in lipoprotein and lipid metabolism, with special attention to the well-characterized miR-33a/b, and on the huge potential of miRNAs for clinical application as biomarkers and therapeutics in the context of cardiometabolic diseases. PMID- 27987358 TI - Relationship between anti-Mullerian hormone and antral follicle count across the menstrual cycle using the Beckman Coulter Access assay in comparison with Gen II manual assay. AB - BACKGROUND: The study aim was to validate Beckman Coulter's fully automated Access Immunoassay System (BC Access assay) for anti-Mullerian hormone (AMH) and compare it with Beckman Coulter's Modified Manual Generation II assay (BC Mod Gen II), with regard to cycle AMH fluctuations and antral follicle counts. METHODS: During one complete menstrual cycle, transvaginal ultrasound was performed on regularly menstruating women (n=39; 18-40years) every 2 days until the dominant ovarian follicle reached 16mm, then daily until observed ovulation; blood samples were collected throughout the cycle. Number and size of antral follicles was determined and AMH levels measured using both assays. RESULTS: AMH levels measured by the BC Access assay vary over ovulatory menstrual cycles, with a statistically significant pre-ovulatory decrease from -5 to +2 days around objective ovulation. Mean luteal AMH levels were significantly lower (-7.99%) than mean follicular levels but increased again towards the end of the luteal phase. Antral follicle count can be estimated from AMH (ng/mL, BC Access assay) concentrations on any follicular phase day. BC Access assay-obtained AMH values are considerably lower compared with the BC Mod Gen II assay (-19% on average); conversion equation: AMH BC Access (ng/mL)=0.85 [AMH BC Mod Gen II (ng/mL)]0.95. CONCLUSIONS: AMH levels vary throughout the cycle, independently of assay utilised. A formula can be used to convert BC Access assay-obtained AMH levels to BC Mod Gen II values. The number of antral follicles can be consistently estimated from pre-ovulatory AMH levels using either assay. PMID- 27987360 TI - The unfinished story of interference in thyroid hormones with Roche immunoassays: when prewashing procedures matter. PMID- 27987361 TI - Analytical evaluation of point-of-care procalcitonin (PCT) and clinical performances in an unselected population as compared with central lab PCT assay. PMID- 27987359 TI - Effects of apixaban on prothrombin time, activated partial thromboplastin time and anti-Xa assays: a European survey. PMID- 27987362 TI - Effect of multiple freeze-thaw cycles on selected biochemical serum components. AB - BACKGROUND: To maintain the best performance a frozen serum sample should be thawed once to prevent repeated freeze-thaw cycles. Archival biobanks often have one tube of a sample available, causing repeated freeze-thaw cycles when the sample is used in multiple research projects. In this study, we investigated potential effects of freeze-thaw cycles on several biochemical components in serum. METHODS: Serum from 40 fasting donors of both genders, aged 30-60 years, were frozen at -25 degrees C. Aliquots of the 40 different samples went through 1, 2, 3, 4, 5 and 10 thaws, respectively. They were analyzed after 3 month of storage for 15 serum components including electrolytes and metabolites, proteins and enzymes, lipids, hormones and vitamins. One-way analyses of variance (ANOVA) with repeated measurements and equivalence tests were used to examine differences in component levels. RESULTS: Albumin, aspartate-aminotransferase (ASAT), cholesterol, creatinine, C-reactive protein, glucose, immunoglobulin G, potassium, testosterone, triglycerides, urea and vitamin B12 levels did not show significant difference for pairwise comparisons after 10 repeated thaws. Although albumin, ASAT, bilirubin, potassium, sodium, testosterone and thyroid stimulating hormone (TSH) showed overall statistically significant changes in serum levels, only bilirubin, sodium and TSH were significant for the pairwise comparisons investigated. Clinical significance were shown for albumin, ASAT, bilirubin, sodium and testosterone. CONCLUSIONS: Twelve components (albumin, ASAT, cholesterol, creatinine, C-reactive protein, glucose, immunoglobulin G, potassium, testosterone, triglycerides, urea and vitamin B12) were robust to 10 repeated thaws compared to baseline level. Three components (bilirubin, sodium and TSH) showed statistical significant difference for pairwise comparisons, however, TSH was not clinically affected. PMID- 27987363 TI - Escitalopram in disorder of laughter and crying with predominant laughter incontinence. PMID- 27987365 TI - Evaluation of the performance of the IQ-Check kits and the USDA Microbiology Laboratory Guidebook methods for detection of Shiga toxin-producing Escherichia coli (STEC) and STEC and Salmonella simultaneously in ground beef. AB - AIMS: To evaluate the performance of the IQ-Check kits and the USDA Microbiology Laboratory Guidebook (MLG) methods for detection of the top seven Shiga toxin producing Escherichia coli (STEC) (O157:H7, O26, O45, O103, O111, O121 and O145) in ground beef and both STEC and Salmonella in co-inoculated samples. METHODS AND RESULTS: Ground beef samples inoculated with ~10 CFU of STEC or both STEC and Salmonella Typhimurium were stored at 4 degrees C for 72 h, followed by screening with the IQ-Check and BAX System kit (MLG) methods that employ different enrichment media. STEC and S. Typhimurium were detected after 12 and 18 h and their presence was confirmed by colony isolation. CONCLUSIONS: Both methods were able to detect STEC in ground beef after 12 h of enrichment in samples inoculated with low levels of the pathogen. STEC and S. Typhimurium can be detected and isolated in co-inoculated ground beef samples. SIGNIFICANCE AND IMPACT OF THE STUDY: The IQ-Check methods are comparable to the MLG methods for detection of STEC and simultaneous detection of STEC and S. Typhimurium in seeded ground beef after a short enrichment time, thus the IQ-Check method can be useful for the food industry for rapid detection of these pathogens. PMID- 27987366 TI - When alternative female Kangaroo care is provided by other immediate postpartum mothers, it reduces postprocedural pain in preterm babies more than swaddling. AB - AIM: Research on alternative female Kangaroo care (KC) has been hampered by high maternal refusal rates. We assessed the efficacy of Kangaroo mother care (KMC), alternative KC provided by other postpartum mothers and swaddling for postprocedural pain relief in preterm babies. METHODS: The study was carried out in a tertiary armed forces hospital, where mothers did not have support from other female relatives and other postpartum mothers agreed to act as alternative female KC providers. We exposed 51 stable preterm neonates, with a gestational age of 30-36 weeks, to KMC, alternative female KC and swaddling for 30 minutes before heel lancing. The outcome measures included the Preterm Infant Pain Profile (PIPP) scores at 30 seconds and the time taken for the heart rate to return to baseline. RESULTS: The mean PIPP scores were lower with KMC (10.59) and alternative female KC (11.24) than swaddling (12.96) and heart rate normalisation took 111, 117 and 149 seconds respectively. The p values were <0.001 for individual groups and outcomes. KMC fared better than alternative female KC for both pain (p = 0.045) and heart rate (p = 0.013). CONCLUSION: Providing KMC and alternative female KC before heel lancing resulted in better pain relief than swaddling. PMID- 27987364 TI - Effect of the Polymorphism of Folylpolyglutamate Synthetase on Treatment of High Dose Methotrexate in Pediatric Patients with Acute Lymphocytic Leukemia. AB - BACKGROUND The aim of this study was to investigate the association of the polymorphism of folylpolyglutamate synthetase (FPGS) with the dynamic plasma concentration of methotrexate (MTX) in pediatric patients with acute lymphocytic leukemia (ALL), as well as the prognosis. MATERIAL AND METHODS 57 ALL patients and 31 age and sex-matched children (control) were included in this study. Polymerase chain reaction-restriction fragment length polymorphism was performed for the analysis of the genotype of FPGS rs1544105 and high-performance liquid chromatography for measurement of MTX plasma concentration after 24-h and 44-h treatment. Overall survival was analyzed by Kaplan-Meier method. RESULTS No differences were observed between patients and controls regarding the distribution frequency of genotype and alleles of rs1544105. Patients carrying AA genotype had a significantly higher plasma concentration of MTX after 24 h than those carrying GG or GA (P<0.05) and no differences were found after 44 h. Kaplan Meier survival analysis showed a longer median survival time in patients with AA than other genotypes with significant difference in overall survival. CONCLUSIONS Polymorphism of FPGS rs1544105 might be used as an effective approach for prediction of the treatment outcome of MTX. PMID- 27987367 TI - Activation of MMP-9 by membrane type-1 MMP/MMP-2 axis stimulates tumor metastasis. AB - An artificial receptor for proMMP-9 was created by fusing tissue inhibitor of MMP 1 (TIMP-1) with type II transmembrane mosaic serine protease (MSP-T1). Expression of MSP-T1 in 293T cells induced binding of proMMP-9, which was processed by MMP-2 activated by membrane type 1 MMP (MT1-MMP). HT1080 cells transfected with the MSP T1 gene produced activated MMP-9 in collagen gel, and addition of proMMP-2 to the culture augmented it, which resulted in intensive collagen digestion. These cells metastasized into chick embryonic liver more than control cells. Treatment of HT1080 cells with concanavalin A in the presence of exogenous proMMP-2 induced activation of not only proMMP-2 but also proMMP-9. Knockdown of MT1-MMP or TIMP-2 expression with siRNA suppressed activation of both proMMP-2 and proMMP-9. Transfection of TIMP-1 siRNA suppressed cell binding and activation of proMMP-9, but not proMMP-2 activation. Knockdown of a disintegrin and metalloproteinase 10 (ADAM10) expression reduced cell binding and processing of proMMP-9. These results suggest that proMMP-9, which binds to a receptor complex containing TIMP 1 and ADAM10, is activated by the MT1-MMP/MMP-2 axis, and MMP-9 thus activated stimulates cellular proteolysis and metastasis. PMID- 27987369 TI - Procurement professionalization: a mandatory step to improve the availability and quality of whole pancreas grafts. PMID- 27987368 TI - Postnatal systemic inflammation and neuro-ophthalmologic dysfunctions in extremely low gestational age children. AB - AIM: Compared to infants born at term, children born very preterm are at increased risk of visual dysfunctions and neonatal systemic inflammation. Here, we explore whether these two propensities are related. METHODS: As part of the ELGAN study, the concentrations of 16 mediators of inflammation were measured in blood obtained on postnatal days 1, 7, 14, 21 and 28 from 1062 children born before the 28th week of gestation. Presence of visual field deficit, strabismus and/or impaired visual fixation was recorded at age two. The concentrations of each protein were divided into quartiles within gestational week categories. We calculated odds ratios with 99% confidence intervals for having each disorder comparing children with concentration in the top quartile of each protein to children whose concentration was in the lower quartiles on the corresponding day. Analyses were adjusted for gestational age and birth weight Z-score. RESULTS: Only one of 80 assessments (16 proteins on five different days) was significant for visual field deficit, and one for impaired fixation. No association was found between strabismus and any inflammatory mediator. CONCLUSION: None of the three neuro-ophthalmologic dysfunctions assessed at two years appears to be associated with systemic inflammation measured the first four postnatal weeks. PMID- 27987370 TI - Cued memory reconsolidation in rats requires nitric oxide. AB - It is well-known that the reactivation of consolidated fear memory under boundary conditions of novelty and protein synthesis blockade results in an impairment of memory, suggesting that the reactivated memory is destabilized and requires synthesis of new proteins for reconsolidation. We tested the hypothesis of nitric oxide (NO) involvement in memory destabilization during the reconsolidation process in rats using memory reactivation under different conditions. We report that administration of NO-synthase selective blockers 3-Br-7-NI or ARL in the conditions of reactivation of memory under a protein synthesis blockade prevented destabilization of fear memory to the conditioned stimulus. Obtained results support the role of NO signaling pathway in the destabilization of existing fear memory triggered by reactivation, and demonstrate that the disruption of this pathway during memory reconsolidation may prevent changes in long-term memory. PMID- 27987371 TI - Synergistic Combination for Chemoprevention of Hepatocellular Carcinoma: An In Silico and In Vitro Approach. AB - Combination therapy is one of the best methods to manage the fatality rate in hepatocellular carcinoma (HCC). This study aimed to formulate a synergistic combination of synthetic and herbal compounds for the treatment of HCC as well as to elucidate a possible signalling mechanism. MTT and enzymatic assay were performed to determine the synergistic effect of drug combination (sorafenib, vitamin K1 and trans-chalcone) on HepG2 cell lines after intoxication with H2 O2 . Protein-protein interaction and docking studies were performed using Pathwaylinker2.0 and Schrodinger's software application to find out the mechanism of action and major targets for drug combination. The overall in vitro result showed that combination of trans-chalcone, vitamin K1 and sorafenib (10, 5 and 5 MUM concentration, respectively) enhanced the resistance against oxidative stress generated by H2 O2 . The interaction studies helped in identification of few targets for docking of ligands (trans-chalcone, vitamin K1 and sorafenib). The study reports the synergistic effects of the formulation that can protect the cells from oxidative stress and restore normal levels of cellular enzymes in HepG2 cell line. We were able to determine the mechanism of action of herbal and synthetic formulation through in silico studies. Finally, docking studies confirmed potential targets for inhibition of hepatocarcinogenesis. PMID- 27987374 TI - Touchscreen generation: children's current media use, parental supervision methods and attitudes towards contemporary media. AB - AIM: To explore media preferences and use among young children, as well as to obtain information about parental supervision methods and beliefs about media. METHOD: Ninety parents of three- to six-year-olds, recruited from a relatively economically advantaged area in the United Kingdom, completed a media opinion survey. RESULTS: Although traditional television remains the favourite type of media platform among young children, touchscreen devices are gaining in popularity, and may promote simultaneous multi-screen use. Moreover, parents believe that the effects of media on developmental outcomes are generally positive. However, they do monitor the content of traditional and new media their children are exposed to. CONCLUSION: This study shows an emerging evidence of concurrent multi-screen use among very young children. More detailed examination of early media multitasking, and its relationship to cognitive and behavioural outcomes, is necessary. PMID- 27987372 TI - SIX1 maintains tumor basal cells via transforming growth factor-beta pathway and associates with poor prognosis in esophageal cancer. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. Although improvement in both surgical techniques and neoadjuvant chemotherapy has been achieved, the 5-year survival rate of locally advanced tumors was, at best, still 55%. Therefore, elucidation of mechanisms of the malignancy is eagerly awaited. Epithelial-mesenchymal transition (EMT) by transforming growth factor-beta (TGF-beta) has been reported to have critical biological roles for cancer cell stemness, whereas little is known about it in ESCC. In the current study, a transcriptional factor SIX1 was found to be aberrantly expressed in ESCCs. SIX1 cDNA transfection induced overexpression of transforming growth factors (TGFB1 and TGFB2) and its receptor (TGFBR2). Cell invasion was reduced by SIX1 knockdown and was increased in stable SIX1 transfectants. Furthermore, the SIX1-transfectants highly expressed tumor basal cell markers such as NGFR, SOX2, ALDH1A1, and PDPN. Although mock-transfectants had only a 20% PDPN-high population, SIX1-transfectants had 60-70%. In two sets of 42 and 85 ESCC patients receiving surgery alone or neoadjuvant chemoradiotherapy followed by surgery, the cases with high SIX1 mRNA and protein expression level significantly showed a poor prognosis compared with those with low levels. These SIX1 high cases also expressed the above basal cell markers, but suppressed the differentiation markers. Finally, TGF-beta signaling blockade suppressed ESCC cell growth in association with the reduction of PDPN-positive tumor basal cell population. The present results suggest that SIX1 accelerates self-renewal of tumor basal cells, resulting in a poor prognosis for ESCC patients. PMID- 27987373 TI - Circadian regulation of mouse suprachiasmatic nuclei neuronal states shapes responses to orexin. AB - Our knowledge of how circadian and homeostatic brain circuits interact to temporally organize physiology and behavior is limited. Progress has been made with the determination that lateral hypothalamic orexin (OXA) neurons control arousal and appetitive states, while suprachiasmatic nuclei (SCN) neurons function as the master circadian clock. During the day, SCN neurons exhibit heterogeneity in spontaneous resting membrane potential (RMP), with some neurons becoming severely depolarized (hyperexcited) and ceasing to fire action potentials (APs), while other neurons rest at moderate RMP and fire APs. Intriguingly, the day phase is when the SCN clock is most readily influenced by arousal, but it is unclear if and how heterogeneity in the excitability state of SCN neurons shapes their response to arousal signals, such as OXA. In whole-cell recordings we show that during the day OXA recruits GABA-GABAA receptor signaling to suppress the RMP of hyperexcited silent as well as moderately hyperpolarized AP-firing SCN neurons. In the AP-firing neurons, OXA hyperpolarized and silenced these SCN cells, while in the hyperexcited silent neurons OXA suppressed the RMP of these cells and evoked either AP-firing, depolarized low-amplitude membrane oscillations, or continued silence at a reduced RMP. These results demonstrate how the resting state of SCN neurons determines their response to OXA, and illustrate that the inhibitory action of this neurochemical correlate of arousal can trigger paradoxical AP firing. PMID- 27987375 TI - Stimulus-specific adaptation to visual but not auditory motion direction in the barn owl's optic tectum. AB - Whether the auditory and visual systems use a similar coding strategy to represent motion direction is an open question. We investigated this question in the barn owl's optic tectum (OT) testing stimulus-specific adaptation (SSA) to the direction of motion. SSA, the reduction of the response to a repetitive stimulus that does not generalize to other stimuli, has been well established in OT neurons. SSA suggests a separate representation of the adapted stimulus in upstream pathways. So far, only SSA to static stimuli has been studied in the OT. Here, we examined adaptation to moving auditory and visual stimuli. SSA to motion direction was examined using repeated presentations of moving stimuli, occasionally switching motion to the opposite direction. Acoustic motion was either mimicked by varying binaural spatial cues or implemented in free field using a speaker array. While OT neurons displayed SSA to motion direction in visual space, neither stimulation paradigms elicited significant SSA to auditory motion direction. These findings show a qualitative difference in how auditory and visual motion is processed in the OT and support the existence of dedicated circuitry for representing motion direction in the early stages of visual but not the auditory system. PMID- 27987377 TI - Retinal vascular caliber associated with cardiac and renal target organ damage in never-treated hypertensive patients. AB - OBJECTIVE: The aim of this study was to assess the relationship between retinal vascular caliber and target organ damage in HT patients. METHODS: Data were collected on cardiac, renal, vascular, and retinal variables in 88 consecutive never-treated HT subjects. Retinal vascular calibers were measured from fundus photographs by using a semi-automated computer-assisted program and summarized as CRAE and CRVE. RESULTS: Mean CRAE and CRVE were significantly lower in patients with left ventricular hypertrophy (left ventricular mass >=110 g/m2 for women, 125 g/m2 for men) than in those with normal left ventricular (CRAE: 129.4+/-3.7 vs 138.2+/-2.3 MUm; P=.04; CRVE: 195.6+/-4.4 vs 209.8+/-2.7 MUm; P=.008). CRAE and CRVE were negatively correlated with urinary albumin excretion (beta+/-SE= 15.4+/-3.2, P<.0001 and beta+/-SE=-11.9+/-4.4, P=.001, respectively) but were not correlated with estimated glomerular filtration rate (P=.21 and P=.75, respectively), carotid-to-femoral pulse wave velocity (P=.24 and P=.14), or carotid augmentation index (P=.43 and P=.16). CONCLUSION: In never-treated HT patients, reduced CRAE and CRVE were associated with cardiac and renal preclinical damage, ie, left ventricular hypertrophy and albuminuria, but not estimated glomerular filtration rate or vascular stiffness. PMID- 27987376 TI - Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes. AB - Pioglitazone is used globally for the treatment of type 2 diabetes mellitus (T2DM) and is one of the most effective therapies for improving glucose homeostasis and insulin resistance in T2DM patients. However, its mechanism of action in the tissues and pathways that regulate glucose metabolism are incompletely defined. Here we investigated the direct effects of pioglitazone on hepatocellular pyruvate metabolism and the dependency of these observations on the purported regulators of mitochondrial pyruvate transport, MPC1 and MPC2. In cultured H4IIE hepatocytes, pioglitazone inhibited [2-14 C]-pyruvate oxidation and pyruvate-driven oxygen consumption and, in mitochondria isolated from both hepatocytes and human skeletal muscle, pioglitazone selectively and dose dependently inhibited pyruvate-driven ATP synthesis. Pioglitazone also suppressed hepatocellular glucose production (HGP), without influencing the mRNA expression of key HGP regulatory genes. Targeted siRNA silencing of MPC1 and 2 caused a modest inhibition of pyruvate oxidation and pyruvate-driven ATP synthesis, but did not alter pyruvate-driven HGP and, importantly, it did not influence the actions of pioglitazone on either pathway. In summary, these findings outline a novel mode of action of pioglitazone relevant to the pathogenesis of T2DM and suggest that targeting pyruvate metabolism may lead to the development of effective new T2DM therapies. PMID- 27987378 TI - In vitro differentiation of neural stem cells derived from human olfactory bulb into dopaminergic-like neurons. AB - This study describes a new accessible source of neuronal stem cells that can be used in Parkinson's disease cell transplant. The human olfactory bulb contains neural stem cells (NSCs) that are responsible for neurogenesis in the brain and the replacement of damaged cellular components throughout life. NSCs are capable of differentiating into neuronal and glial cells. We isolated NSCs from the olfactory bulb of brain-death donors and differentiated them into dopaminergic neurons. The olfactory bulb tissues obtained were cultured in Dulbecco's modified Eagle's medium/nutrient mixture F12, B27 supplemented with basic fibroblast growth factor, epidermal growth factor and leukemia inhibitory factor. The NSCs and proliferation markers were assessed. The multipotentiality of olfactory bulb NSCs was demonstrated by their capacity to differentiate into neurons, oligodendrocytes and astrocytes. To generate dopaminergic neurons, olfactory bulb NSCs were differentiated in neurobasal medium, supplemented with B27, and treated with sonic hedgehog, fibroblast growth factor 8 and glial cell-derived neurotrophic factor from the 7th to the 21st day, followed by detection of dopaminergic neuronal markers including tyrosine hydroxylase and aromatic l-amino acid decarboxylase. The cells were expanded, established in continuous cell lines and differentiated into the two classical neuronal phenotypes. The percentage of co-positive cells (microtubule-associated protein 2 and tyrosine hydroxylase; aromatic l-amino acid decarboxylase and tyrosine hydroxylase) in the treated cells was significantly higher than in the untreated cells. These results illustrate the existence of multipotent NSCs in the adult human olfactory bulb that are capable of differentiating toward putative dopaminergic neurons in the presence of trophic factors. Taken together, our data encourage further investigations of the possible use of olfactory bulb NSCs as a promising cell based therapeutic strategy for Parkinson's disease. PMID- 27987379 TI - New mothers' experiences of the urban environment with their preterm infants involve complex social, emotional and psychological processes. AB - AIM: Studies have explored how mothers and premature babies make the transition from a neonatal unit (NNU) to home, but little is known about how mothers cope with urban life with a vulnerable baby. This controlled trial investigated how first-time mothers with singleton preterm babies handled that experience in the first few months after discharge from a NNU, compared to the first-time mothers of healthy, singleton term-born infants. METHODS: This parent-led, qualitative study was carried out in London, UK, from 2013 to 2015 and used diaries and walking interviews with researchers. Thematic network analysis was performed to provide insights into the experiences of these 19 mothers. RESULTS: The two groups had similar experiences and needs in the urban environment, and these common experiences of city life shaped their new identities as mothers. However, the mothers of preterm babies had difficulties developing supportive relationships and seeking affirming social environments. CONCLUSION: This study highlights what the mothers of preterm babies experienced in the first few months after their infant was discharged from hospital. It stresses the need to understand the complexity of the mothers' social, emotional and psychological processes when they make the transition from home to visit the city with a vulnerable baby. PMID- 27987380 TI - Coxiella burnetii (Q fever) prevalence in associated populations of humans and small ruminants in The Gambia. AB - OBJECTIVES: To simultaneously estimate the prevalence of antibodies against Coxiella burnetii (Q fever) among adults and small ruminants, and C. burnetii shedding prevalence among small ruminants in households in the Kiang West district of The Gambia, and to assess associated risk factors. METHODS: Sera of 599 adults and 615 small ruminants from 125 compounds within 12 villages were tested for antibodies against C. burnetii using ELISA. Vaginal swabs and milk samples of 155 small ruminants were tested using PCR to investigate shedding of C. burnetii. RESULTS: A total of 3.8-9.7% of adults, depending on ELISA test cut off, and 24.9% of small ruminants in Kiang West were seropositive. Having at least one seropositive animal in one's compound was a risk factor for human seropositivity (OR: 3.35, 95% CI: 1.09-14.44). A grazing area within a village was a risk factor for seropositivity in small ruminants (OR: 2.07, 95% CI: 1.26 3.50); others were having lambed (OR: 2.75, 95% CI: 1.37-5.76) and older age of the animals (OR: 2.75, 95% CI: 1.37-5.76 for 1-3 years and OR 5.84, 95% CI: 3.10 11.64 for >3 years); 57.4% of sampled small ruminants were shedding C. burnetii. CONCLUSION: Coxiella burnetii infection is endemic among both humans and small ruminants in this area of The Gambia. Human and animal exposure to C. burnetii were related at compound level. Further research into the clinical relevance of C. burnetii infection in West Africa is needed. PMID- 27987381 TI - Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease. AB - Alzheimer's disease (AD) is associated with deficiencies in cerebrovascular functions, e.g. reduced cerebral blood flow and capillary amyloid angiopathy, both of which are evident during the early phase of AD, thus local hypoxia/ischemia could augment the pathogenesis of AD. There is abundant literature revealing that exposures to hypoxia/ischemia increase the amyloidogenic processing of amyloid-beta precursor protein (APP) leading to the accumulation of amyloid-beta peptides in brain. This hypoxia-induced response has been attributed to a significant increase in the activities of beta- and gamma secretases, whereas alpha-secretase activity decreases in hypoxia. Recent studies have indicated that hypoxia-inducible factor-1alpha (HIF-1alpha) stimulates the transcription of the beta-secretase 1 (BACE1) gene through the hypoxia-response element in the BACE1 promoter. Moreover, HIF-1alpha protein can directly interact with the gamma-secretase complex and increase its activity in a non transcriptional manner. Hypoxia/ischemia also trigger endoplasmic reticulum stress and impair autophagy in brain, which consequently can stimulate the expression of presenilin 1 (PS1) and activate gamma-secretase. Subsequently, PS1 protein can stabilize HIF-1alpha protein and in addition, APP intracellular domain peptide is able to induce the expression of HIF-1alpha. The activation of beta- and gamma-secretases is an evolutionarily conserved hypoxia response, e.g. it is also present in zebrafish. Given that beta- and gamma-secretases have many substrates in addition to APP, one could postulate that AD pathology is a byproduct of the rescue process mediated by these two aspartyl proteinases under hypoxic/ischemic conditions. We will review the recent evidence indicating that vascular dysfunctions can provoke AD pathology by activating beta- and gamma secretases. PMID- 27987382 TI - Effect of 4-methoxy 1-methyl 2-oxopyridine 3-carbamide on Staphylococcus aureus by inhibiting UDP-MurNAc-pentapeptide, peptidyl deformylase and uridine monophosphate kinase. AB - AIMS: The present study aimed to investigate the anti-Staphylococcus aureus and anti-biofilm properties of 4-methoxy-1-methyl-2-oxopyridine-3-carbamide (MMOXC) on S. aureus UDP-MurNAc-pentapeptide (MurF), peptidyl deformylase (PDF) and uridine monophosphate kinase (UMPK). METHODS AND RESULTS: The in vitro efficacy of MMOXC was evaluated using quantitative polymerase chain reaction, in vitro assays and broth microdilution methods. Further, the minimum inhibitory concentration (MIC), IC50 and zone of inhibition were recorded in addition to the anti-biofilm property. MMOXC inhibited pure recombinant UMPK and PDF enzymes with a Ki of 0.37 and 0.49 MUmol l-1 . However Ki was altered for MurF with varying substrates. The MurF Ki for UMT, d-Ala-d-Ala and ATP as substrates was 0.3, 0.25 and 1.4 MUmol l-1 , respectively. Real-time PCR analysis showed a significant reduction in PDF and MurF expression which correlated with the MIC90 at 100 MUmol l-1 and IC50 in the range 42 +/- 1.5 to 50 +/- 1 MUmol l-1 against all strains tested. At 5 MUmol l-1 MMOXC was able completely to remove preformed biofilms of S. aureus and other drug resistant strains. CONCLUSIONS: MMOXC was able to kill S. aureus and drug resistant strains tested by inhibiting MurF, UMPK and PDF enzymes and completely obliterated preformed biofilms. SIGNIFICANCE AND IMPACT OF THE STUDY: Growth reduction and biofilm removal are prerequisites for controlling S. aureus infections. In this study MMOXC exhibited prominent anti-S. aureus and anti-biofilm properties by blocking cell wall formation, RNA biosynthesis and protein maturation. PMID- 27987383 TI - Model-based inference from microvascular measurements: Combining experimental measurements and model predictions using a Bayesian probabilistic approach. AB - OBJECTIVE: In vivo imaging of the microcirculation and network-oriented modeling have emerged as powerful means of studying microvascular function and understanding its physiological significance. Network-oriented modeling may provide the means of summarizing vast amounts of data produced by high-throughput imaging techniques in terms of key, physiological indices. To estimate such indices with sufficient certainty, however, network-oriented analysis must be robust to the inevitable presence of uncertainty due to measurement errors as well as model errors. METHODS: We propose the Bayesian probabilistic data analysis framework as a means of integrating experimental measurements and network model simulations into a combined and statistically coherent analysis. The framework naturally handles noisy measurements and provides posterior distributions of model parameters as well as physiological indices associated with uncertainty. RESULTS: We applied the analysis framework to experimental data from three rat mesentery networks and one mouse brain cortex network. We inferred distributions for more than 500 unknown pressure and hematocrit boundary conditions. Model predictions were consistent with previous analyses, and remained robust when measurements were omitted from model calibration. CONCLUSION: Our Bayesian probabilistic approach may be suitable for optimizing data acquisition and for analyzing and reporting large data sets acquired as part of microvascular imaging studies. PMID- 27987384 TI - Salmonella typhimurium PtsJ is a novel MocR-like transcriptional repressor involved in regulating the vitamin B6 salvage pathway. AB - The vitamin B6 salvage pathway, involving pyridoxine 5'-phosphate oxidase (PNPOx) and pyridoxal kinase (PLK), recycles B6 vitamers from nutrients and protein turnover to produce pyridoxal 5'-phosphate (PLP), the catalytically active form of the vitamin. Regulation of this pathway, widespread in living organisms including humans and many bacteria, is very important to vitamin B6 homeostasis but poorly understood. Although some information is available on the enzymatic regulation of PNPOx and PLK, little is known on their regulation at the transcriptional level. In the present work, we identified a new MocR-like regulator, PtsJ from Salmonella typhimurium, which controls the expression of the pdxK gene encoding one of the two PLKs expressed in this organism (PLK1). Analysis of pdxK expression in a ptsJ knockout strain demonstrated that PtsJ acts as a transcriptional repressor. This is the first case of a MocR-like regulator acting as repressor of its target gene. Expression and purification of PtsJ allowed a detailed characterisation of its effector and DNA-binding properties. PLP is the only B6 vitamer acting as effector molecule for PtsJ. A DNA-binding region composed of four repeated nucleotide sequences is responsible for binding of PtsJ to its target promoter. Analysis of binding stoichiometry revealed that protein subunits/DNA molar ratio varies from 4 : 1 to 2 : 1, depending on the presence or absence of PLP. Structural characteristics of DNA transcriptional factor-binding sites suggest that PtsJ binds DNA according to a different model with respect to other characterised members of the MocR subgroup. PMID- 27987386 TI - Corrigendum to "Ankle motion influences the external knee adduction moment and may predict who will respond to lateral wedge insoles?: An ancillary analysis from the SILK trial" [Osteoarthr Cartil 23 (2015) 1316-1322]. PMID- 27987387 TI - Possible common neurological breakdowns for alexithymia and humour appreciation deficit: A case study. AB - This brief work is an attempt to point to the possible common neurological breakdowns in giving rise to alexithymia, and impaired appreciation of humour. In particular, we present the case of a patient who lost the ability to enjoy humour after the surgical removal of a frontal groove meningioma, although he was still able to detect it, while at the same time was diagnosed with organic alexithymia. Our results indicate that problems in the affective appreciation of humour and in emotionalizing (alexithymic symptoms) may be the result of damage to the ventral rostral portions of the ACG/mPFC, which prevent the patient from assessing the salience of emotion and motivational information, and generating emotional reactions; as a result he has trouble experiencing emotions, knowing how he and others feel, and enjoy humour. PMID- 27987385 TI - MHC Class I Chain-Related Gene A (MICA) Donor-Recipient Mismatches and MICA-129 Polymorphism in Unrelated Donor Hematopoietic Cell Transplantations Has No Impact on Outcomes in Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome: A Center for International Blood and Marrow Transplant Research Study. AB - Single-center studies have previously reported associations of MHC Class I Chain Related Gene A (MICA) polymorphisms and donor-recipient MICA mismatching with graft-versus-host disease (GVHD) after unrelated donor hematopoietic cell transplantation (HCT). In this study, we investigated the association of MICA polymorphism (MICA-129, MM versus MV versus VV) and MICA mismatches after HCT with 10/10 HLA-matched (n = 552) or 9/10 (n = 161) unrelated donors. Included were adult patients with a first unrelated bone marrow or peripheral blood HCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome that were reported to the Center for International Blood and Marrow Transplant Research between 1999 and 2011. Our results showed that neither MICA mismatch nor MICA-129 polymorphism were associated with any transplantation outcome (P < .01), with the exception of a higher relapse in recipients of MICA mismatched HLA 10/10 donors (hazard ratio [HR], 1.7; P = .003). There was a suggestion of association between MICA mismatches and a higher risk of acute GVHD grades II to IV (HR, 1.4; P = .013) There were no significant interactions between MICA mismatches and HLA matching (9/10 versus 10/10). In conclusion, the findings in this cohort did not confirm prior studies reporting that MICA polymorphism and MICA mismatches were associated with HCT outcomes. PMID- 27987388 TI - The relationship between shear force, compression, collagen characteristics, desmin degradation and sarcomere length in lamb biceps femoris. AB - This study aimed to identity the relationships between known variants of tenderness (collagen content (total and soluble), desmin degradation and sarcomere length) and shear force and compression in the biceps femoris aged for 14days from 112 mixed sex lambs. Desmin degradation was related to compression (P<0.05) such that as desmin degradation increased compression decreased. Sarcomere length (SL) was related to shear force (P<0.05), such that as SL increased shear force declined. Shear force was also related to compression (P<0.05), and soluble collagen (P<0.05), with male lambs producing higher shear force values than females (4.4+/-1.72N: P<0.05) when adjusted for compression, sarcomere length and soluble collagen. The findings from this experiment indicate that the known variants (soluble collagen, sarcomere length and desmin degradation) are related to shear force and compression in ovine biceps femoris. PMID- 27987389 TI - Structural differences in hippocampal subfields among schizophrenia patients, major depressive disorder patients, and healthy subjects. AB - Many MRI studies have reported a volume reduction of the hippocampus in psychiatric diseases. However, disease-related volume differences in hippocampus subfields remain unclear. Here we compared the volumes of hippocampus subfields in patients with schizophrenia, patients with major depressive disorder (MDD), and healthy subjects as controls. T2-weighted images were acquired in 20 patients with schizophrenia, 36 with MDD, and 35 healthy volunteers by 3-Tesla MRI. Hippocampal subfields were segmented using an automatic algorithm, Automatic Segmentation of Hippocampal Subfields (ASHS). Schizophrenia patients exhibited significant volume reductions in the cornu ammonis (CA)1 compared to the controls, and in the dentate gyrus compared to the controls and MDD patients without medication, whereas there was no significant difference between the MDD patients and controls. There was a nominal negative correlation between the perirhinal cortex volume and depression severity in the MDD patients without medication, whereas there were negative correlations between CA2 volume and both negative symptoms and the duration of illness in the schizophrenia patients. We identified differing volume reductions in hippocampal subfields and varying correlations between disease severity and subfield volumes depending on diagnosis, suggesting that volume differences in hippocampus subfields may provide important information regarding the pathophysiology of schizophrenia and MDD. PMID- 27987390 TI - Simultaneous analysis of glucocorticosteroid fluticasone propionate and its metabolite fluticasone propionate 17beta-carboxylic acid in human plasma by UPLC MS/MS at sub pg/mL level. AB - A highly sensitive and rapid ultra performance liquid chromatography-tandem mass spectrometry method has been developed for the simultaneous determination of fluticasone propionate (FP) and its major metabolite, fluticasone propionate 17beta-carboxylic acid (FP 17beta-CA) in human plasma. The analytes and their deuterated internal standards, FP-d3 and FP 17beta-CA-d3 were extracted from 500MUL plasma samples by solid phase extraction on Oasis MAX cartridges. The chromatographic analysis was performed on ACQUITY UPLC BEH C18 (50mm*2.1mm, 1.7MUm) column using methanol-acetonitrile (50:50, v/v) and 2.0mM ammonium trifluroacetate (ATFA) (85:15, v/v) as the mobile phase. Following separation of the analytes, protonated precursor->product ion transitions (FP: m/z 501.1 >293.2, FP17beta-CA: m/z 453.3->293.2, FP-d3: m/z 504.2->293.2, FP 17beta-CA-d3: m/z 456.3->293.2) were monitored on FP 17beta-CA a triple quadrupole mass spectrometer, operating in multiple reaction monitoring (MRM) and positive ionization mode. The calibration curves were established in the range of 0.5 100pg/mL with a correlation coefficient (r2)>=0.9992 for both the analytes. The intra-batch and inter-batch accuracy and precision varied from 95.5-103.4% and 0.74-5.06% across quality controls for both the analytes. The mean assay recoveries for FP and FP 17beta-CA were 84.2% and 93.5% respectively. The validated method was successfully applied to support a bioequivalence study of 200MUg FP, administered using nasal spray formulation in 18 healthy Indian subjects. Reproducibility of the method was assessed by reanalysis of 98 incurred study samples. PMID- 27987391 TI - Fast Screening of Tissue Samples for Glycogen. AB - Screening of tissue samples for glycogen is very important in assessing the ageing, but also the state of health of the tissue. Therefore, two needle stochastic sensors based on maltodextrins presenting different dextrose equivalence (DE) MD-m (DE 13.0-17.0), and MD-M (DE 16.5-19.5) immobilized in diamond paste (obtained from synthetic diamond and paraffin oil) were designed and characterized. These stochastic sensors were used reliable for both qualitative and quantitative analysis for the assay of glycogen in tissue samples with limits of determination as low as 1fmol L-1. PMID- 27987392 TI - Urinary metabolic profiling of cisplatin nephrotoxicity and nephroprotective effects of Orthosiphon stamineus leaves elucidated by 1H NMR spectroscopy. AB - Orthosiphon stamineus (OS) is a popular medicinal herb used in traditional Chinese medicine as a diuretic agent and for renal system disorders. This study employed 1H NMR based metabolomics approach to investigate the possible protective activity of OS in cisplatin induced nephrotoxicity owing to its diuretic and antioxidant activities. Aqueous (OSAE) and 50% aqueous ethanolic (OSFE) extracts of OS leaves were orally administered at 400mg/kg BW doses to rats which were then intraperitoneally injected with cisplatin at 5mg/kg BW dose. The 1H NMR profile of the urine samples collected on day 5 after cisplatin administration were analyzed by multivariate pattern recognition techniques, whereby 19 marker metabolites suggestive in the involvement of TCA cycle, disturbed energy metabolism, altered gut microflora and BCAA metabolism pathways were identified. It was observed that OSFE caused significant changes (p<0.05) in the levels of 8 markers namely leucine, acetate, hippurate, lysine, valine, 2 oxoglutarate, 3-HBT and acetoacetate resulting in a moderate ameliorative effect, however, it did not completely protect from nephrotoxicity. OSAE did not demonstrate significant down regulatory effects on any markers, albeit, it potentiated the cisplatin nephrotoxicity by inducing significant increase in glucose, glycine, creatinine, citrate, TMAO, acetate and creatine levels. A Principal Component Analysis (PCA) of the 1H NMR spectra of OS extracts identified that OSFE had higher concentrations of the secondary metabolites such as caffeic acid, chlorogenic acid, protocatechuic acid and orthosiphol, among others. Whereas, OSAE was characterized by higher concentrations of acetate, lactate, succinic acid, valine and phosphatidylcholine. This research denotes the first comprehensive analysis to identify the effects of OS extracts on cisplatin nephrotoxicity. PMID- 27987393 TI - Renewal of an old European Pharmacopoeia method for Terazosin using modeling with mass spectrometric peak tracking. AB - An older method for terazosin was reworked in order to reduce the analysis time from 90min (2*45min) to below 5min. The method in European Pharmacopoeia (Ph.Eur.) investigates the specified impurities separately. The reason of the different methods is that the retention of two impurities is not adequate in reversed phase, not even with 100% water. Therefore ion-pair-chromatography has to be applied and since that two impurities absorb at low UV-wavelength they had to be analyzed by different method than the other specified impurities. In our new method we could improve the retention with pH elevation using a new type of stationary phases available for high pH applications. Also a detection wavelength could be selected that is appropriate for the detection and quantification of all impurities. The method development is the bottleneck of liquid chromatography even today, when more and more fast chromatographic systems are used. Expert knowledge with intelligent programs is available to reduce the time of method development and offer extra information about the robustness of the separation. Design of Experiments (DoE) for simultaneous optimization of gradient time (tG), temperature (T) and ternary eluent composition (tC) requires 12 experiments. A good alternative way to identify a certain peak in different chromatograms is the molecular mass of the compound, due to its high specificity. Liquid Chromatography-Mass Spectrometry (LC-MS) is now a routine technique and increasingly available in laboratories. In our experiment for the resolution- and retention modeling the DryLab4 method development software (Version 4.2) was used. In recent versions of the software the use of (m/z)-MS-data is possible along the UV-peak-area-tracking technology. The modelled and measured chromatograms showed excellent correlations. The average retention time deviations were ca. 0.5s and there was no difference between the predicted and measured Rs,crit -values. PMID- 27987394 TI - Liver X receptors agonists suppress NLRP3 inflammasome activation. AB - Inflammasomes are multiprotein complexes that control the production of IL-1beta and IL-18. NLRP3 inflammasome, the most characterized inflammasome, plays prominent roles in defense against infection, however aberrant activation is deleterious and leads to diseases. Therefore, its tight control offers therapeutic promise. Liver X receptors (LXRs) have significant anti-inflammatory properties. Whether LXRs regulate inflammasome remains unresolved. We thus tested the hypothesis that LXR's anti-inflammatory properties may result from its ability to suppress inflammasome activation. In this study, LXRs agonists inhibited the induction of IL-1beta production, caspase-1 cleavage and ASC oligomerization by NLRP3 inflammasome. The agonists also inhibited inflammasome associated mtROS production. Importantly, the agonists inhibited the priming of inflammasome activation. In vivo data also showed that LXRs agonist prevented NLRP3-dependent peritonitis. In conclusion, LXRs agonists are identified to potently suppress NLRP3 inflammasome and the regulation of LXRs signaling is a potential therapeutic for inflammasome-driven diseases. PMID- 27987395 TI - Randomised controlled trial of sustained lung inflation for resuscitation of preterm infants in the delivery room. AB - AIM: To compare the effects of sustained lung inflation (SLI) vs. standard resuscitation on physiologic responses of preterm infants during resuscitation. METHODS: Preterm infants (25-32 weeks gestational age) requiring positive pressure ventilation or continuous positive airway pressure were randomly assigned to either the SLI group (SLI at 25cmH2O for 15s) or Non-SLI group (standard resuscitation alone). The heart rate (HR), oxygen saturation (SpO2), oxygen requirement, and intubation rate in the delivery room were evaluated. RESULTS: Eighty-one infants were enrolled (SLI group, 43; Non-SLI group, 38). The use of SLI effectively reduced the oxygen requirement. The mean fraction of inspired oxygen 10min after birth was 0.28 (95% CI, 0.26-0.30) in the SLI group and 0.47 (95% CI, 0.43-0.52) in the Non-SLI group (p<0.001). During the first 5min, infants in the SLI group trended towards a higher HR and SpO2 than those in the Non-SLI group. The intubation rate in the delivery room was not different between the two groups; however, among infants <=28 weeks gestational age, the intubation rate was lower in the SLI than Non-SLI group (5 of 17 [29%] vs. 10 of 16 [63%], respectively; p=0.05). The duration of respiratory support, survival without bronchopulmonary dysplasia, and the occurrence of pneumothorax were not different between the groups. CONCLUSION: SLI in infants who require respiratory support appears to be effective in facilitating postnatal transition as determined by HR and SpO2 responses, resulting in less oxygen supplementation. Further studies are needed to confirm the benefits of SLI. PMID- 27987396 TI - Cardiopulmonary resuscitation duration and survival in out-of-hospital cardiac arrest patients. AB - AIM: Relationship between cardiopulmonary arrest and resuscitation (CPR) durations and survival after out-of-hospital cardiac arrest (OHCA) remain unclear. Our primary aim was to determine the association between survival without neurologic sequelae and cardiac arrest intervals in the setting of witnessed OHCA. METHODS: We analyzed 27,301 non-traumatic, witnessed OHCA patients in France included in the national registry from June 1, 2011 through December 1, 2015. We analyzed cardiac arrest intervals, designated as no-flow (NF; from collapse to start of CPR) and low-flow (LF; from start of CPR to cessation of resuscitation) in relation to 30-day survival without sequelae. We determined the influence of recognized prognostic factors (age, gender, initial rhythm, location of cardiac arrest) on this relation. RESULTS: For the entire cohort, the area delimited by a value of NF greater than 12min (95% confidence interval: 11-13min) and LF greater than 33min (95% confidence interval: 29 45min), yielded a probability of 30-day survival of less than 1%. These sets of values were greatly influenced by initial cardiac arrest rhythm, age, sex and location of cardiac arrest. Extended CPR duration (greater than 40min) in the setting of initial shockable cardiac rhythm is associated with greater than 1% survival with NF less than 18min. The NF interval was highly influential on the LF interval regardless of outcome, whether return of spontaneous circulation (p<0.001) or death (p<0.001). CONCLUSION: NF duration must be considered in determining CPR duration in OHCA patients. The knowledge of (NF, LF) curves as function of age, initial rhythm, location of cardiac arrest or gender may aid in decision-making vis-a-vis the termination of CPR or employment of advanced techniques. PMID- 27987397 TI - Prophylactic versus clinically-driven antibiotics in comatose survivors of out-of hospital cardiac arrest-A randomized pilot study. AB - AIM: To investigate benefits of prophylactic antibiotics in comatose survivors of out-of-hospital cardiac arrest (OHCA). METHODS: Patients without evidence of tracheobronchial aspiration on admission bronchoscopy were randomized to prophylactic Amoxicillin-Clavulanic acid 1.2g every 8h (P) or clinically-driven antibiotics (C) administered if signs of infection developed during initial 7days of intensive care unit (ICU) stay. RESULTS: Among 83 patients enrolled between September 2013 and February 2015, tracheobronchial aspiration was documented in 23 (28%). Accordingly, 60 patients were randomized. Percentage of patients on antibiotics between days 1-5 was significantly greater in P group. White blood count, C-reactive protein, procalcitonin (PCT) and CD 64 significantly increased during the postresuscitation phase. Except for lower CRP and PCT in group P on day 6 (p<0.05), there was no significant differences. Mini BAL on day 3 was less often positive in group P (7% vs. 42%; p<0.01). There was no significant difference in other microbiological samples and X-ray signs of pneumonia cumulatively documented in 50% in both groups. Use of vasopressors/inotropes (93% in both groups), duration of mechanical ventilation (5.4+/-3.7 vs. 5.2+/-3.1 days), tracheal intubation (6.5+/-4.6 vs. 5.9+/-4.3 days), ICU stay (7.7+/-5.2 vs. 6.9+/-4.5 days), survival (73% vs. 73%) and survival with good neurological outcome (50% vs. 40%) were also comparable between P and C groups. CONCLUSION: Bronchoscopy on admission documented tracheobronchial aspiration in 28% of comatose survivors of OHCA. In the absence of aspiration, prophylactic antibiotics did not significantly alter systemic inflammatory response, postresuscitation pneumonia, ICU treatment and outcome (ClinicalTrials.gov Identifier: NCT02899507). PMID- 27987399 TI - Association between cerebrospinal fluid dopamine concentrations and catechol-O methyltransferase gene polymorphisms in forensic autopsy cases of methamphetamine abusers. AB - Methamphetamine (MA) is an illicit psychostimulant that stimulates the release of catecholamines from sympathetic nerve terminals and is widely abused worldwide. Since catechol-O-methyltransferase (COMT) metabolizes catecholamines and mediates adrenergic, noradrenergic, and dopaminergic signaling responses, we investigated the effects of the COMT polymorphisms rs4633 and rs4680 on cerebrospinal fluid (CSF) catecholamine concentrations in autopsies of subjects who died of drug intoxication. 28 MA abusers and 22 fatal psychotropic drug intoxication cases were evaluated. No correlations were identified between rs4633 or rs4680 polymorphisms and CSF concentrations of adrenaline (Adr), noradrenaline (Nad), or dopamine (DA) in fatal psychotropic cases. However, among MA abusers, DA concentrations in the CSF were significantly higher in those with the T allele (CT and TT) of rs4633 than in CC genotype carriers (p=0.004). Moreover, among MA abusers, DA concentrations were significantly higher in those with the A allele (GA and AA) of rs4680 than in GG genotype carriers (p=0.017). In subsequent haplotype analyses of MA abusers, a strong correlation was identified between two COMT haplotypes and CSF DA concentrations (p=0.002). However, the CSF concentrations of Adr and Nad were not associated with COMT genotypes or haplotypes. The present results indicate that rs4633 and rs4680 polymorphisms influence CSF DA concentrations and MA toxicity in MA abusers. PMID- 27987400 TI - An insertion/deletion polymorphism within 3'UTR of RYR2 modulates sudden unexplained death risk in Chinese populations. AB - Sudden unexplained death (SUD) constitutes a part of the overall sudden death that can not be underestimated. Over the last years, genetic testing on SUD has revealed that inherited channelopathies might play important roles in the pathophysiology of this disease. Ryanodine receptor type-2 (RYR2) is a kind of ion channel extensively distributed in the sarcoplasmic reticulum (SR) of myocardium. Studies on RYR2 have suggested that either dysfunction or abnormal expression of it could lead to arrhythmia, which may cause cardiac arrest. In this study, we conducted a case-control study to evaluate the association of a 4 base pair (4-bp) Indel polymorphism (rs10692285) in the 3'UTR of RYR2 with the risk of SUD and sudden cardiac death induced by coronary heart disease (SCD-AS) in a Chinese population. Logistic regression analysis showed that the insertion allele of rs10692285 had significantly increased the risk of SUD [OR=2.03; 95% confidence interval (CI)=1.08-3.77; P=0.0161; statistical power=0.743]. No relevance was observed between rs10692285 and SCD-AS. Further genotype-phenotype association analysis suggested that the expression level of RYR2 in human myocardium tissues with the insertion allele was higher than that with the deletion allele at both mRNA and protein levels. Dual-Luciferase activity assay system was used to detect the effect of rs10692285 on the transcription activity of RYR2. As expected, the result indicated that the transcription activity of RYR2 with the ins/ins genotype was higher than that with the del/del genotype. Finally, in-silico prediction revealed that different alleles of rs10692285 could alter the local structure of RYR2 mRNA and microRNA (miRNA) binding. In summary, our findings provided evidence that rs10692285 might contribute to SUD susceptibility through affecting the expression of RYR2, which suggest that abnormal ion channel activity is very likely to be the underlying mechanism of SUD, but not for SCD-AS. Thus, rs10692285 may become a potential marker for molecular diagnosis and genetic counseling of SUD. PMID- 27987401 TI - Biodegradation of the endocrine disrupter 4-tert-octylphenol by the yeast strain Candida rugopelliculosa RRKY5 via phenolic ring hydroxylation and alkyl chain oxidation pathways. AB - 4-(1,1,3,3-tetramethylbutane)-phenol (4-tert-OP) is one of the most prevalent endocrine disrupting pollutants. Information about bioremediation of 4-tert-OP remains limited, and no study has been reported on the mechanism of 4-tert-OP degradation by yeasts. The yeast Candida rugopelliculosa RRKY5 was proved to be able to utilize 4-methylphenol, bisphenol A, 4-ethylphenol, 4-tert-butylphenol, 4 tert-OP, 4-tert-nonylphenol, isooctane, and phenol under aerobic conditions. The optimum conditions for 4-tert-OP degradation were 30 degrees C, pH 5.0, and an initial 4-tert-OP concentration of 30mgL-1; the maximum biodegradation rate constant was 0.107d-1, equivalent to a minimum half-life of 9.6d. Scanning electron microscopy revealed formation of arthroconidia when cells were grown in the presence of 4-tert-OP, whereas the cells remained in the budding form without 4-tert-OP. Identification of the 4-tert-OP degradation metabolites using liquid chromatography-hybrid mass spectrometry revealed three different mechanisms via both branched alkyl side chain and aromatic ring cleavage pathways. PMID- 27987398 TI - Relationship between timing of cooling and outcomes in adult comatose cardiac arrest patients treated with targeted temperature management. AB - AIM OF THE STUDY: Studies examining associations between time to target temperature and outcomes in cardiac arrest patients who underwent targeted temperature management (TTM) have shown inconsistent results. We examined these associations separately for time from restoration of spontaneous circulation to TTM initiation (pre-induction time) and time from TTM initiation to target temperature (induction time). Furthermore, we examined whether critical time thresholds exist if there is an association. METHODS: This was a single-centre retrospective observational study including adult cardiac arrest patients treated with TTM from 2008 to 2015. We tested the associations of pre-induction time and induction time with outcomes at hospital discharge using multivariate logistic regression analysis. We then performed additional multivariate analyses, each with the significant timing variable at different binary cutoffs. RESULTS: A total of 515 patients were analysed. At hospital discharge, 357 patients (69.3%) were alive, of whom 161 (31.3%) had a favourable neurologic outcome. In multivariate analysis, a shorter pre-induction time was independently associated with a favourable neurologic outcome (odds ratio [OR], 1.110; 95% confidence interval [CI], 1.025-1.202), whereas the induction time was not (OR, 0.954; 95% CI, 0.852-1.067). We found two pre-induction time thresholds (120 and 360min) that were associated with neurologic outcome. CONCLUSION: We found that a shorter pre-induction time was independently associated with a favorable neurologic outcome at hospital discharge, whereas induction time was not. We also found two time thresholds at 120 and 360min, after which initiation of cooling was associated with a worse neurologic outcome. PMID- 27987402 TI - Efficacy of human umbilical cord derived-mesenchymal stem cells in treatment of rat bone marrow exposed to gamma irradiation. AB - To assess the therapeutic effects of the human umbilical cord blood (hUCB) derived mesenchymal stem cells (MSCs) on rat bone marrow (BM) exposed to gamma rays, 3 groups (n=15 each) of adult male Wistar albino rats were utilized as follows: the 1st group received PBS (control group), the 2nd group was exposed to gamma rays 1.04Gy/min (R group) and the 3rd group exposed to same dose as RG and injected hUCB-MSCs. The BM of femurs was processed for histological and immunohistochemical staining with proliferating cell nuclear antigen antibody (PCNA), anti human CD105 and anti human CD34. Hb content, leukocytes and platelet counts were analyzed as well as fat cells and megakaryocytic counts. Also, the BM vascular spaces and the optical density of immunostaining for PCNA were analyzed. The leukocytes and platelet counts were significantly lower in the R (2.85+/ 235.8; P=0.000 and 95.27+/-3.01; P=0.000 respectively) when compared with the control (10.40+/-443.2; P=0.000 and 430.18+/-20.28; P=0.000 respectively). The fat cell count was significantly higher in the R (36.55+/-1.83; P=0.000) than in control (7.64+/-0.61; P=0.000) and in R injected h-MSCs tissues (18.82+/-2.03; P=0.000). The megakaryocytic count was significantly higher in the R injected h MSCs (5.36+/-0.310; P=0.000) than in control (2.82+/-0.263; P=0.000) and in the R BM (0.45+/-0.157; P=0.000). The vascular spaces were dilated and significantly increased in the R injected h-MSCs (50.10+/-2.40; P=0.000) than in control (33.36+/-1.01; P=0.000). The optical density of PCNA expression was significantly lower in R (0.18+/-0.11; P=0.005) than in control (0.41+/-0.40; P=0.005) and in R injected h-MSCs groups (0.30+/-0.17; P=0.005). The present study concluded that injection of hUCB-MSCs improves destructive effects of bone marrow induced by gamma radiation. Use of radio-protective agents during exposure is recommended. PMID- 27987403 TI - The effect of ethephon on immune system in male offspring of mice. AB - Ethephon can liberate ethylene which could interfere the plant growth process. The aim of the present study was to determine the effect of ethephon on developing immune system of male offspring. Ethephon could enhance NK cell activity in male mice. For 4-week-old male mice, lymphocytes of peripheral blood increased while the hemolytic plaque number decreased. Delayed type hypersensitivity(DTH) was inhibited in all groups. The expression of protein Bcl11b and p-p38 in thymus of treatment groups were lower than control group. Our results indicated that cellular immunity of male offspring is more sensitive to ethephon when exposed in pregnancy and lactation period. It should be emphasized that exposure to ethephon during the in utero stage and lactation stage still could damage the immune function of animal in the period before fully mature even in the dosage that could not influence the immune function of adult animal. PMID- 27987404 TI - Diagnostic accuracy of Cancer Antigen 125 (CA125) for endometriosis in symptomatic women: A multi-center study. AB - STUDY OBJECTIVE: To assess the diagnostic accuracy of serum Cancer Antigen 125 (CA 125)>=30units/milliliter (u/ml) for diagnosing endometriosis in symptomatic women. STUDY DESIGN: Prospective observational cohort study including patients with symptoms of pelvic pain or subfertility undergoing elective diagnostic laparoscopy at two tertiary referral hospitals. We excluded patients suspected to have other gynecological pathology. We evaluated the accuracy of serum CA 125 (index test) with histologically confirmed endometriosis (reference standard). MAIN RESULTS: Fifty-eight consecutive women recruited between October 2013 to March 2015. Women with endometriosis had a higher CA 125 level than those without endometriosis (mean 54.7+/-71.6 vs 16.2+/- 8.0). The specificity of CA 125>=30u/ml was 96% (95% CI 81.7-99.9%) and sensitivity was 57% (95% CI 37.4 74.5%). The positive likelihood ratio for the histological presence of endometriosis with a CA 125>=30u/ml was 15.8 (95% CI 2.3-112) providing a post test probability of 94% (95% CI 71%-99%) in women with pelvic pain or subfertility. The area under the curve, 0.85 (95% CI 0.74-0.96) indicates high test accuracy. CONCLUSIONS: CA 125>=30u/ml is highly predictive of endometriosis in women with symptoms of pain and/or subfertility. CA 125 should be considered as a rule-in test for expediting the diagnosis and management of endometriosis, CA 125 <30u/ml is, however, unable to rule out endometriosis. PMID- 27987405 TI - How effective is repetitive transcranial magnetic stimulation for bipolar depression? PMID- 27987406 TI - "I didn't think we'd be dealing with stuff like this": A qualitative study of volunteer support for very disadvantaged pregnant women and new mothers. AB - OBJECTIVE: to identify the particular issues associated with volunteer support for very disadvantaged mothers (who were young, had insecure immigration status, were recent migrants whose English was poor,misused drugs or alcohol, or were involved in crime), from the perspective of the volunteers. DESIGN: a qualitative descriptive study, informed by phenomenological social psychology. Semi structured qualitative interviews were carried out between July 2013 and March 2015. Interview transcripts were analysed using inductive thematic analysis. SETTING: nine volunteer support projects for pregnant women and new mothers, run by third sector organisations in England. PARTICIPANTS: 38 volunteer supporters. MEASUREMENTS AND FINDINGS: three key themes were identified: 'Meeting challenges', 'Needing support' and 'Identifying successes'. 'Meeting challenges' contained the subthemes 'making the relationship of trust','remaining non judgemental', 'maintaining boundaries' and 'dealing with child protection'. 'Needing support' contained the subthemes 'feeling prepared', 'feeling supported' and 'staying safe'. 'Identifying successes' contained the subthemes 'celebrating the small wins', 'validation as a mother', and 'supporting access to services'. KEY CONCLUSIONS: volunteers were able to build strong, empowering relationships with some very disadvantaged women during pregnancy and afterwards, including where the mothers did not readily engage with professionals. However, supporting women with complex needs is emotionally challenging and volunteers need to be carefully selected, realistically trained and robustly supervised and supported during their volunteering. IMPLICATIONS FOR PRACTICE: third sector organisations offering volunteer support for pregnant women and new mothers can be valuable partners in reaching very disadvantaged women who may find it difficult to engage with services. Volunteers can build up a relationship of trust with vulnerable mothers over time, but need to be well supported to do this safely and effectively. PMID- 27987407 TI - Direct, label-free, selective, and sensitive microbial detection using a bacteriorhodopsin-based photoelectric immunosensor. AB - A photoelectric immunosensor using purple membranes (PM) as the transducer, which contains photoactive bacteriorhodopsin, is here first demonstrated for direct and label-free microbial detection. Biotinylated polyclonal antibodies against Escherichia coli were immobilized on a PM-coated electrode through further surface biotinylation and bridging avidin or NeutrAvidin. The photocurrent generated by the antibody-coated sensor was reduced after incubation with E. coli K-12 cultures, with the reduction level increased with the culture populations. The immunosensor prepared via NeutrAvidin exhibited much better selectivity than the one prepared via avidin, recognizing almost none of the tested Gram-positive bacteria. Cultures with populations ranging from 1 to 107CFU/10mL were detected in a single step without any preprocessing. Both AFM and Raman analysis confirmed the layer-by-layer fabrication of the antibody-coated substrates as well as the binding of microorganisms. By investigating the effect of illumination orientation and simulating the photocurrent responses with an equivalent circuit model containing a chemical capacitance, we suggest that the photocurrent reduction was primarily caused by the light-shielding effect of the captured bacteria. Using the current fabrication technique, versatile bacteriorhodopsin based photoelectric immunosensors can be readily prepared to detect a wide variety of biological cells. PMID- 27987408 TI - Label-free electrical sensing of bacteria in eye wash samples: A step towards point-of-care detection of pathogens in patients with infectious keratitis. AB - The diagnosis of keratitis is based on visual exam, tissue cytology, and standard microbial culturing to determine the type of the infectious pathogen. To prescribe appropriate therapy, it is important to distinguish between bacterial, fungal, and viral keratitis, as the treatments are quite different. Diagnosis of the causative organism has a substantial prognostic importance. Further, timely knowledge of the nature of the pathogen is also critical to adapt therapy in patients unresponsive to empiric treatment options, which occurs in 10% of all cases. Currently, the identification of the nature of the pathogen that causes keratitis is achieved via microbial culture screening, which is laboratory-based, expensive, and time-consuming. The most frequent pathogens that cause the corneal ulcers are P. aeruginosa and S. aureus. Here, we report a microchip for rapid (<1h) detection of P. aeruginosa (6294), S. aureus(LAC), through on-chip electrical sensing of bacterial lysate. We evaluated the microchip with spiked samples of PBS with bacteria concentration between 101 to 108 CFU/mL. The least diluted bacteria concentration in bacteria-spiked samples with statistically significant impedance change was 10 CFU/mL. We further validated our assay by comparing our microchip results with the standard culture-based methods using eye washes obtained from 13 infected mice. PMID- 27987409 TI - Competitive RNA-RNA hybridization-based integrated nanostructured-disposable electrode for highly sensitive determination of miRNAs in cancer cells. AB - A new method for the detection of miRNAs making use of a competitive RNA/RNA hybridization configuration is described in this work. A biotinylated miRNA (biotin-miRNA) of identical sequence to that of the target miRNA is mixed with the samples to be analyzed allowing competition to be accomplished with the target miRNA for a thiolated RNA probe assembled onto a gold nanoparticles (AuNPs) modified screen-printed electrode. After labeling the hybridized biotin miRNA with streptavidin-HRP conjugates, amperometric detection at -0.20V was carried out using the H2O2/hydroquinone (HQ) system. The decrease in the amperometric response was proportional to the concentration of model target miRNA 21 in the 100 fM to 25.0 pM range. The integrated sensor provided a very low detection limit (25 fM, 0.25 attomol in 10MUL sample) for miRNA-21 without any amplification step, a complete discrimination against single nucleotide mismatched sequences under practical conditions and high storage stability. The usefulness of the developed method was demonstrated by determining the endogenous levels of the mature target miRNA in total RNA (RNAt) extracted from cancerous and non-cancerous cells. PMID- 27987410 TI - Detection and differentiation of influenza viruses with glycan-functionalized gold nanoparticles. AB - Accurate diagnosis of influenza viruses is difficult and generally requires a complex process because of viral diversity and rapid mutability. In this study, we report a simple and rapid strategy for the detection and differentiation of influenza viruses using glycan-functionalized gold nanoparticles (gGNPs). This method is based on the aggregation of gGNP probes on the viral surface, which is mediated by the specific binding of the virus to the glycans. Using a set of gGNPs bearing different glycan structures, fourteen influenza virus strains, including the major subtypes currently circulating in human and avian populations, were readily differentiated from each other and from a human respiratory syncytial virus in a single-step colorimetric procedure. The results presented here demonstrate the potential of this gGNP-based system in the development of convenient and portable sensors for the clinical diagnosis and surveillance of influenza viruses. PMID- 27987411 TI - Preconditions for successful advance care planning in nursing homes: A systematic review. AB - OBJECTIVES: There is growing evidence of the potential effectiveness of advance care planning. Yet important knowledge gaps remain regarding the preconditions for successful implementation of advance care planning in the nursing home setting. We aim to identify the preconditions related to successful advance care planning in the nursing home setting. By specifying those, we would be able to make well-founded choices for the future design and planning of advance care planning intervention programs. DESIGN: A systematic review. DATA SOURCES: PubMed, PsycINFO, EMBASE and CINAHL. REVIEW METHODS: Two authors independently screened publications. One author assessed methodological quality and extracted textual data, which was double-checked for a random sample. We extracted textual data and used thematic synthesis to identify "preconditions", defined as requirements, conditions and elements necessary to achieve the desired outcome of advance care planning, i.e. attaining concordance between residents' preferences and actual care or treatment received at the end of life. MAIN FINDINGS: Based on 38 publications, we identified 17 preconditions at five different levels: resident, family, health-care professional, facility and community. Most preconditions were situated on multiple levels but the majority addressed professionals and the nursing home itself. We summarized preconditions in five domains: to have sufficient knowledge and skills, to be willing and able to participate in advance care planning, to have good relationships, to have an administrative system in place, and contextual factors supporting advance care planning within the nursing home. CONCLUSION: There are multiple preconditions related to successfully implementing advance care planning in the complex nursing home setting that operate at micro, meso and macro level. Future interventions need to address these multiple domains and levels in a whole-system approach in order to be better implementable and more sustainable, while simultaneously target the important role of the health-care professional and the facility itself. PMID- 27987412 TI - A novel Bayesian hierarchical model for road safety hotspot prediction. AB - In this paper, we propose a Bayesian hierarchical model for predicting accident counts in future years at sites within a pool of potential road safety hotspots. The aim is to inform road safety practitioners of the location of likely future hotspots to enable a proactive, rather than reactive, approach to road safety scheme implementation. A feature of our model is the ability to rank sites according to their potential to exceed, in some future time period, a threshold accident count which may be used as a criterion for scheme implementation. Our model specification enables the classical empirical Bayes formulation - commonly used in before-and-after studies, wherein accident counts from a single before period are used to estimate counterfactual counts in the after period - to be extended to incorporate counts from multiple time periods. This allows site specific variations in historical accident counts (e.g. locally-observed trends) to offset estimates of safety generated by a global accident prediction model (APM), which itself is used to help account for the effects of global trend and regression-to-mean (RTM). The Bayesian posterior predictive distribution is exploited to formulate predictions and to properly quantify our uncertainty in these predictions. The main contributions of our model include (i) the ability to allow accident counts from multiple time-points to inform predictions, with counts in more recent years lending more weight to predictions than counts from time-points further in the past; (ii) where appropriate, the ability to offset global estimates of trend by variations in accident counts observed locally, at a site-specific level; and (iii) the ability to account for unknown/unobserved site specific factors which may affect accident counts. We illustrate our model with an application to accident counts at 734 potential hotspots in the German city of Halle; we also propose some simple diagnostics to validate the predictive capability of our model. We conclude that our model accurately predicts future accident counts, with point estimates from the predictive distribution matching observed counts extremely well. PMID- 27987413 TI - Intervention recommendations and subsequent access to services following clinical assessment for fetal alcohol spectrum disorders. AB - BACKGROUND: Children with fetal alcohol spectrum disorders (FASD) and prenatal alcohol exposure (PAE) experience multiple difficulties requiring various interventions. Researchers have called for investigation into service use with respect to clinically recommended interventions. AIMS: To examine intervention recommendations for children with FASD/PAE and subsequent access to these recommended interventions. METHODS AND PROCEDURES: Intervention recommendations following FASD assessment were examined for children (1-17 years). Recommendations were compared according to diagnostic status and demographic and environmental variables. Subsequent access to several interventions was examined for 45 participants. OUTCOMES AND RESULTS: A variety of recommendations were given. Children with FASD received more recommendations overall and received more education, anticipatory guidance, family support, and safety recommendations than undiagnosed children with PAE. Undiagnosed children received more mental health and reassessment recommendations. Older children received fewer family support and developmental therapy recommendations but more mental health recommendations than younger age groups. Many families accessed modified school programming, developmental therapy, psychiatry, child counseling, and parent support as recommended. CONCLUSIONS AND IMPLICATIONS: Children with FASD and PAE have extensive needs and should receive individualized recommendations. An assessment is valuable even without an FASD diagnosis. Areas of high/low service access may provide insight into accessibility and perceived importance of interventions. WHAT THIS PAPER ADDS: This study responds to important research questions regarding the intervention needs of individuals with FASD. It is novel in its exploration of intervention recommendations given to children prenatally exposed to alcohol without an FASD diagnosis (rather than only children with FASD) and in its examination of post-assessment service use patterns specifically in relation to clinical recommendations. PMID- 27987414 TI - Targeting antigens to Dec-205 on dendritic cells induces a higher immune response in chickens: Hemagglutinin of avian influenza virus example. AB - It is widely known that targeting a variety of antigens to the DEC-205 receptor on dendritic cells (DCs) significantly potentiate immunity. This communication reports the development of a new murine monoclonal antibody (mAb) against the chicken DEC-205, using as immunogen the carbohydrate recognition domain-2 (CRD-2) heterologously expressed. This mAb recognizes a protein band of 250kDa by immunoprecipitation analysis and shows strong cross-reactivity with human and pig DEC-205. Furthermore, the hemagglutinin (HA) of avian influenza H5N2 virus was cloned and expressed using insect cell-baculovirus expression system. We chemically conjugated the anti-chicken DEC-205 antibody with the highly purified HA to direct the antigen to the dendritic cells and evaluate the immune response elicited in vivo by this conjugate. A single dose of chemical conjugate was sufficient to elicit a strong immune response in chickens as early as fourteen days after priming. In addition, the conjugate induced an earlier and higher response compared to unconjugated HA. These results suggest that the strategy described here has potential to be used in the future design and development of successful vaccines against different chicken infectious diseases with direct impact in biotechnology and veterinary fields. PMID- 27987415 TI - Characteristics, circumstances and pathology of sudden or unnatural deaths of cases with evidence of pathological hoarding. AB - The study aimed to determine the characteristics and circumstances of cases sudden or unnatural death (n = 61) with evidence of pathological hoarding, their major organ pathology and toxicology. The mean age was 65.8 yrs (a mean of 16.1 years of potential life lost), 62.3% were male, and 28.2% were obese. 95.1% lived alone, and 96.7% died in their residence, with no medical intervention. In all cases severe squalor and extensive hoarding were noted. The direct cause of death was attributed to disease in 75.4%, heart disease being a significant factor in 52.5%. Accidents causing death directly related to hoarding occurred in two cases. Autopsy revealed extensive pathology: severe coronary artery narrowing (42.4%), myocardial replacement fibrosis (44.1%), emphysema (39.0%), nephrosclerosis (46.6%). Signs of hypothermia were present in 14.8%, and diabetes was diagnosed in 21.3%. The most commonly detected substance was alcohol (32.1%). Medications for heart disease (5.4%) or diabetes (7.1%) were rare. The overall clinical picture was of an isolated group, with a heavy burden of physical disease and, in all probability, a high level of psychiatric disorders, who died alone in their homes. PMID- 27987417 TI - Sketching people: Prospective investigations of the impact of life drawing on body image. AB - Three studies were conducted to establish the extent to which life drawing is effective at promoting positive body image. Study 1 (N=84 women) showed that life drawing had a positive impact on state body image, but only if artists observed a human model and not non-human objects. Study 2 (N=61 women, 61 men) showed that life drawing had a positive impact on state body image for women and men, irrespective of whether artists observed a sex-congruent or -incongruent model. Study 3 (N=23) showed that participating in weekly life drawing sessions for a 6 week period resulted in significantly elevated trait positive body image (body appreciation and body pride) and embodiment, and in reduced social physique anxiety; however, the intervention had no significant impact on negative body image (drive for thinness or muscularity). These results highlight the potential of life drawing for promoting positive body experiences. PMID- 27987416 TI - Tissue resident memory T cells and viral immunity. AB - Tissue resident memory T cells (TRM) constitute a recently identified T cell lineage that is responsible for frontline defense against viral infections. In contrast to central and effector memory T cells, which constitutively recirculate between tissues and blood, TRM reside permanently within tissues. As the main surveyors of non-lymphoid tissues, TRM are positioned to rapidly respond upon reinfection at barrier sites. During a viral reinfection, TRM trigger the local tissue environment to activate and recruit immune cells and establish an antiviral state. Consistent with this function, there is empirical evidence that TRM accelerate control in the event of reinfection or possible reactivation of latent infections in solid organs and barrier tissues. Here we review recent literature highlighting the protective functions of TRM in multiple viral challenge models and contextualize the implications of these findings for vaccine development. PMID- 27987418 TI - Effect of tributyltin on antioxidant ability and immune responses of zebrafish (Danio rerio). AB - Tributyltin (TBT) is a toxic compound released into aquatic ecosystems through antifouling paints. This study was designed to examine the effects of TBT on antioxidant ability and immune responses of zebrafish (Danio rerio). Three hundred sixty healthy zebrafish were randomly grouped into four groups and exposed to different doses of TBT (0, 1, 10 and 100ngL-1). At the end of 8 weeks, the fish were sampled, and antioxidant capability, immune parameters and immune related genes were assessed. The results showed that with an increase in TBT dose, the concentration of malonaldehyde in the liver was significantly increased (p<0.05), whereas the activities of total superoxide dismutase, catalase and glutathione peroxidase were significantly decreased (p<0.05) compared to the control. The activity and expression of lysozyme and the content of immunoglobulin M were significantly decreased compared to those of the fish exposed to 0ngL-1 TBT (p<0.05). However, the expression of the HSP70, HSP90, tumor necrosis factor-alpha(TNF-alpha), interleukins (IL-1beta, IL-6), and nuclear factor-kappa B p65 (NF-kappa B p65) genes were all enhanced with an increase in TBT dose. The results indicated that TBT induced oxidative stress and had immunotoxic effects on zebrafish. PMID- 27987419 TI - Clobetasol propionate causes immunosuppression in zebrafish (Danio rerio) at environmentally relevant concentrations. AB - Synthetic glucocorticoids (GCs) are potential endocrine disrupting compounds that have been detected in the aquatic environment around the world in the low ng/L (nanomolar) range. GCs are used as immunosuppressants in medicine. It is of high interest whether clobetasol propionate (CP), a highly potent GC, suppresses the inflammatory response in fish after exposure to environmentally relevant concentrations. Bacterial lipopolysaccharide (LPS) challenge was used to induce inflammation and thus mimic pathogen infection. Zebrafish embryos were exposed to <=1000nM CP from ~1h post fertilization (hpf) to 96 hpf, and CP uptake, survival after LPS challenge, and expression of inflammation-related genes were examined. Our initial experiments were carried out using 0.001% DMSO as a solvent vehicle, but we observed that DMSO interfered with the LPS challenge assay, and thus masked the effects of CP. Therefore, DMSO was not used in the subsequent experiments. The internal CP concentration was quantifiable after exposure to >=10nM CP for 96h. The bioconcentration factor (BCF) of CP was determined to be between 16 and 33 in zebrafish embryos. CP-exposed embryos showed a significantly higher survival rate in the LPS challenge assay after exposure to >=0.1nM in a dose dependent manner. This effect is an indication of immunosuppression. Furthermore, the regulation pattern of several genes related to LPS challenge in mammals supported our results, providing evidence that LPS-mediated inflammatory pathways are conserved from mammals to teleost fish. Anxa1b, a GC-action related anti-inflammatory gene, was significantly down-regulated after exposure to >=0.05nM CP. Our results show for the first time that synthetic GCs can suppress the innate immune system of fish at environmentally relevant concentrations. This may reduce the chances of fish to survive in the environment, as their defense against pathogens is weakened. PMID- 27987420 TI - Pyrene biodegradation with layer-by-layer assembly bio-microcapsules. AB - Biotechnology is considered as a promising technology for the removal of polycyclic aromatic hydrocarbons from the environment. Free bacteria are often sensitive to some biotic and abiotic factors in the environment to the extent that their ability to effect biodegradation of organic pollutants, such as polycyclic aromatic hydrocarbons, is hampered. Consequently, it is imperative to carry out investigations into biological systems that will obviate or aid tolerance of bacteria to harsh environmental conditions. Chitosan/alginate bio microcapsules produced using layer-by-layer (LBL) assembly method were tested for pyrene (PYR) biodegradation under harsh environmental conditions. Morphology observation indicated that the flake bio-microcapsules could be successfully prepared through LBL assembly method. Surface analysis showed that the bio microcapsules had large fractions of mesopores. The results of the biodegradation experiments revealed that the 95% of 10mgL-1 PYR could be removed by the bacteria encapsulated chitosan/alginate bio-microcapsules in 3 days, which was higher than that of the free bacteria (59%). Compared to the free cells, the bacteria encapsulated chitosan/alginate bio-microcapsules produced 1-6 times higher PYR biodegradation rates at a high initial PYR concentration (50mgL-1) and extremely low pH values (pH =3) or temperatures (10 degrees C or 40 degrees C), as well as high salt stress. The results indicated that bacteria in microcapsules treatment gained a much higher tolerance to environmental stress and LBL bio-microcapsule could be promising candidate for remediating the organic pollutants. PMID- 27987421 TI - Successful oral treatment of Ganciclovir resistant cytomegalovirus with Maribavir in the context of primary immunodeficiency: First case report and review. PMID- 27987422 TI - Diagnostic performance of serological assays for anti-HBs testing: Results from a quality assessment program. AB - BACKGROUND: Post-vaccination testing after hepatitis B vaccination is indispensable to evaluate long-term immunological protection. Using a threshold level of antibodies against hepatitis B surface antigen (anti-HBs) to define serological protection, implies reproducible and valid measurements of different diagnostic assays. OBJECTIVES: In this study we assess the performance of currently used anti-HBs assays. STUDY DESIGN: In 2013, 45 laboratories participated in an external quality assessment program using pooled anti-HBs serum samples around the cutoff values 10IU/l and 100IU/l. Laboratories used either Axsym (Abbott Laboratories), Architect (Abbott Laboratories), Access (Beckman-Coulter), ADVIA Centaur anti-HBs2 (Siemens Healthcare Diagnostics), Elecsys, Modular or Cobas (Roche Diagnostics) or Vidas Total Quick (Biomerieux) for anti-HBs titre quantification. We analysed covariance using mixed-model repeated measures. To assess sensitivity/specificity and agreement, a true positive or true negative result was defined as an anti-HBs titre respectively above or below the cutoff value by >=4 of 6 assays. RESULTS: Different anti-HBs assays were associated with statistically significant (P<0.05) differences in anti-HBs titres in all dilutions. Sensitivity and specificity ranged respectively from 64%-100% and 95%-100%. Agreement between assays around an anti-HBs titre cutoff value of 10IU/l ranged from 93%-100% and was 44% for a cutoff value of 100IU/l. CONCLUSIONS: Around a cutoff value of 10IU/l use of the Access assay may result in false-negative results. Concerning the cutoff value of 100IU/l, a sample being classified below or above this cutoff relied heavily on the specific assay used, with both the Architect and the Access resulting in false-negative results. PMID- 27987423 TI - Investigating the relationship between temperature, conformation and calcium binding in heparin model oligosaccharides. AB - Glycosaminoglycans such as heparan sulfate (HS) are major components of the cell surface and extracellular matrix (ECM) of all multicellular animals, connecting cells to each other as well as to their environment. The ECM must, therefore, both sense and accommodate changes to external conditions. Heparin, a model compound for HS, responds to increased temperatures, involving changes in the populations of conformational states with implications for the binding of HS to proteins, cations and, potentially, for its activity. A fully 13C and 15N labelled model octasasccharide; D-GlcNS6S alpha(1-4) L-IdoA2S [alpha(1-4) D GlcNS6S alpha(1-4) L-IdoA2S]2 alpha(1-4) D-GlcNS6S alpha(1-4) L-IdoA1,6an, was studied by 1H, 13C and 15N NMR, revealing complex changes in chemical shifts and conformation, over temperatures (280-305 K), comfortably within the range relevant to terrestrial biology. These complex conformational changes indicated an interaction between the carboxylate group of L-iduronate and D-glucosamine residues that was susceptible to temperature changes in this range, while the well-documented hydrogen bond between the N-sulfamido group of glucosamine and the hydroxyl group at position-3 of iduronate remained intact. Unexpectedly, despite the presence of similar thermally-induced conformational changes in a heparin octasaccharide fraction in the sodium ion form, its subsequent binding to calcium ions and their resulting conformation was stringently maintained, as judged by comparisons of 1H NMR chemical shifts. PMID- 27987424 TI - A psychometric validation study of the Impulsive-Compulsive Behaviours Checklist: A transdiagnostic tool for addictive and compulsive behaviours. AB - The occurrence of repetitive behaviours that are often harmful has been attributed to traits traditionally described as "impulsive" or "compulsive" e.g. substance dependence, excessive gambling, and hoarding. These behaviours are common and often co-occur in both the general population and psychiatric populations. The lack of measures to concurrently index a range of such behaviours led to the development of the Impulsive-Compulsive Behaviours (ICB) Checklist. This study aims to validate the ICB Checklist in a general community sample. Factor analyses revealed a two-factor structure, demonstrating good model fit in two independent samples. These were labelled Impulsive-Compulsions and Compulsive-Impulsions, comprising of classically compulsive and impulsive behaviours respectively. Reliability and construct validity were further confirmed using correlations with existing measures of impulsivity and compulsivity. Results suggest that the ICB Checklist is a valid and practical assessment that can be used to monitor behavioural clusters characterised by deficits in inhibition. PMID- 27987425 TI - Rifle bullet penetration into ballistic gelatin. AB - The penetration of a rifle bullet into a block of ballistic gelatin is experimentally and computationally studied for enhancing our understanding of the damage caused to human soft tissues. The gelatin is modeled as an isotropic and homogeneous elastic-plastic linearly strain-hardening material that obeys a polynomial equation of state. Effects of numerical uncertainties on penetration characteristics are found by repeating simulations with minute variations in the impact speed and the angle of attack. The temporary cavity formed in the gelatin and seen in pictures taken by two high speed cameras is found to compare well with the computed one. The computed time histories of the hydrostatic pressure at points situated 60 mm above the line of impact are found to have "two peaks", one due to the bullet impact and the other due to the bullet tumbling. Contours of the von Mises stress and of the effective plastic strain in the gelatin block imply that a very small region adjacent to the cavity surface is plastically deformed. The angle of attack is found to noticeably affect the penetration depth at the instant of the bullet tumbling through 90 degrees . PMID- 27987426 TI - Structure-function relationships of human meniscus. AB - Biomechanical properties of human meniscus have been shown to be site-specific. However, it is not known which meniscus constituents at different depths and locations contribute to biomechanical properties obtained from indentation testing. Therefore, we investigated the composition and structure of human meniscus in a site- and depth-dependent manner and their relationships with tissue site-specific biomechanical properties. Elastic and poroelastic properties were analyzed from experimental stress-relaxation and sinusoidal indentation measurements with fibril reinforced poroelastic finite element modeling. Proteoglycan (PG) and collagen contents, as well as the collagen orientation angle, were determined as a function of tissue depth using microscopic and spectroscopic methods, and they were compared with biomechanical properties. For all the measurement sites (anterior, middle and posterior) of lateral and medial menisci (n=26), PG content and collagen orientation angle increased as a function of tissue depth while the collagen content had an initial sharp increase followed by a decrease across tissue depth. The highest values (p<0.05) of elastic parameters (equilibrium and instantaneous moduli) and strain-dependent biomechanical parameters (strain-dependent fibril network modulus and permeability) were observed in the anterior horn of the medial meniscus. This location had also higher (p<0.05) PG content in the deep meniscus, higher (p<0.05) collagen content in the entire tissue depth, and lower (p<0.05) collagen orientation angle at the superficial tissue, as compared to many other locations. On the other hand, in certain comparisons (such as anterior vs. middle sites of the medial meniscus) significantly higher (p<0.05) collagen content and lower orientation angle, without any difference in the PG content, were consistent with increased meniscus modulus and/or nonlinear permeability. This study suggests that nonlinear biomechanical properties of meniscus, caused by the collagen network and fluid, may be strongly influenced by tissue osmotic swelling from the deep meniscus caused by the increased PG content, leading to increased collagen fibril tension. These nonlinear biomechanical properties are suggested to be further amplified by higher collagen content at all tissue depths and superficial collagen fibril orientation. However, these structure-function relationships are suggested to be highly site-specific. PMID- 27987427 TI - Importance of the variable periodontal ligament geometry for whole tooth mechanical function: A validated numerical study. AB - When mammalian teeth breakdown food, several juxtaposed dental tissues work mechanically together, while balancing requirements of food comminution and avoiding damage to the oral tissues. One important way to achieve this is by channeling mastication forces into the surrounding jaw bone through a thin and compliant soft tissue, the periodontal ligament (PDL). As a result, during a typical chewing stroke, each tooth moves quite substantially in its anchor-site. Here we report a series of experiments, where we study the reaction of three rooted teeth to a single chewing event by finite element (FE) modelling. The nonlinear behaviour of the PDL is simulated by a hyperelastic material model and the in silico results are validated by our own in vitro experiments. We examine the displacement response of the complete tooth-PDL-bone complex to increasing chewing loads. We observe that small spatially-varying geometric adjustments to the thickness of the PDL lead to strong changes in observed tooth reaction movement, as well as PDL strain and bone stress. When reproducing the regionally varying thickness of the PDL observed in vivo, FE simulations reveal subtle but significant tooth motion that leads to an even distribution of the stresses in the jaw bone, and to lower strains in the PDL. Our in silico experiments also reproduce the results of experiments performed by others on different animal models and are therefore useful for overcoming the difficulties of obtaining tooth-PDL-bone loading estimates in vivo. This data thus enhances our understanding of the role the variable PDL geometry plays in the tooth-PDL-bone complex during mastication. PMID- 27987428 TI - Fabrication of novel magnesium-matrix composites and their mechanical properties prior to and during in vitro degradation. AB - In our previous study, we developed Mg-matrix composites with bredigite as the reinforcing phase and achieved improved degradation resistance in comparison with Mg. However, the effects of materials processing method and process parameters on the mechanical behavior of the composites before and during degradation were still unknown. This research was aimed at determining the mechanical properties of Mg-bredigite composites prior to and during degradation. It was found that by optimizing the process parameters of Pressure Assisted Sintering (PAS), low porosity Mg-bredigite composites with strong interfaces between homogeneously distributed bredigite particles and the Mg matrix could be fabricated. By reinforcing Mg with 20vol% bredigite particles, the ultimate compressive strength and ductility of Mg increased by 67% and 111%, respectively. The in vitro degradation rate of the Mg-20% bredigite composite in a cell culture medium was 24 times lower than that of monolithic Mg. As a result of retarded degradation, the mechanical properties of the composite after 12 days of immersion in the cell culture medium were comparable to those of cortical bone. The encouraging results of this research warrant further investigations on the in vivo degradation behavior and mechanical properties of the composites. PMID- 27987430 TI - Effects of the cortisol stress response on the psychotherapy outcome of panic disorder patients. AB - BACKGROUND: A proportion of patients with panic disorder (PD) fail to show a remission after psychotherapy. Biological correlates of psychotherapy non response have rarely been described in the literature. The aim of the present study was to research the relationship between the cortisol stress response and the psychotherapy outcome in PD patients. METHODS: Twenty-eight PD patients (20 females, mean age+/-SD: 35.71+/-13.18) seeking psychological treatment for PD and n=32 age- and sex-matched healthy control participants (21 females, aged 34.66+/ 12.07) participated in this study. The patients underwent five weeks of cognitive behavioural therapy (CBT). Within the first two weeks of the CBT, both study groups were confronted with the Trier Social Stress Test (TSST). Blood sampling for cortisol and adrenocorticotropic hormone (ACTH) evaluation as well as fear rating (Visual Analogue Scale; Primary Appraisal and Secondary Appraisal Questionnaire, PASA) accompanied the TSST. The global severity of PD (Panic & Agoraphobia Scale; PAS), agoraphobic cognitions (Agoraphobic Cognitions Questionnaire; ACQ), fear of bodily sensations (Bodily Sensations Questionnaire; BSQ), agoraphobic avoidance (Mobility Inventory; MI), and depressiveness (Beck Depression Inventory; BDI) were assessed before and after the CBT (except the BDI). RESULTS: The statistical analysis revealed significant main effects of time for cortisol and the ACTH concentration in response to the TSST, independently of the study group. 42.9% of the PD patients and 65.6% of the healthy control participants showed a cortisol stress response to the TSST>=55.2nmol/l (descriptive finding). The data showed a significant inverse association of the TSST cortisol stress response with the MI total score when accompanied. Further, a significant association of the PASA subjective level of fear and the BSQ as well as a trend for an association of the PASA with the ACQ were observed. CONCLUSION: Consistent with prior research, we could replicate findings of decreased cortisol concentrations in the PD patients in comparison to the healthy control participants. Furthermore, our findings agree with previous data showing an association of the attenuated cortisol stress response with the psychotherapy non-response. In the present sample, those patients with the lowest cortisol concentrations showed the least improvement in agoraphobic avoidance after psychotherapy. The patients with the highest level of fear showed the most improvement in fear of bodily sensations. Study limitations as well as implications for future studies will be discussed. PMID- 27987429 TI - A reduction in long-term spatial memory persists after discontinuation of peripubertal GnRH agonist treatment in sheep. AB - Chronic gonadotropin-releasing hormone agonist (GnRHa) administration is used where suppression of hypothalamic-pituitary-gonadal axis activity is beneficial, such as steroid-dependent cancers, early onset gender dysphoria, central precocious puberty and as a reversible contraceptive in veterinary medicine. GnRH receptors, however, are expressed outside the reproductive axis, e.g. brain areas such as the hippocampus which is crucial for learning and memory processes. Previous work, using an ovine model, has demonstrated that long-term spatial memory is reduced in adult rams (45 weeks of age), following peripubertal blockade of GnRH signaling (GnRHa: goserelin acetate), and this was independent of the associated loss of gonadal steroid signaling. The current study investigated whether this effect is reversed after discontinuation of GnRHa treatment. The results demonstrate that peripubertal GnRHa-treatment suppressed reproductive function in rams, which was restored after cessation of GnRHa treatment at 44 weeks of age, as indicated by similar testes size (relative to body weight) in both GnRHa-Recovery and Control rams at 81 weeks of age. Rams in which GnRHa-treatment was discontinued (GnRHa-Recovery) had comparable spatial maze traverse times to Controls, during spatial orientation and learning assessments at 85 and 99 weeks of age. Former GnRHa-treatment altered how quickly the rams progressed beyond a specific point in the spatial maze at 83 and 99 weeks of age, and the direction of this effect depended on gonadal steroid exposure, i.e. GnRHa-Recovery rams progressed quicker during breeding season and slower during non-breeding season, compared to Controls. The long-term spatial memory performance of GnRHa-Recovery rams remained reduced (P<0.05, 1.5-fold slower) after discontinuation of GnRHa, compared to Controls. This result suggests that the time at which puberty normally occurs may represent a critical period of hippocampal plasticity. Perturbing normal hippocampal formation in this peripubertal period may also have long lasting effects on other brain areas and aspects of cognitive function. PMID- 27987431 TI - Acriflavine Inhibits Acquired Drug Resistance by Blocking the Epithelial-to Mesenchymal Transition and the Unfolded Protein Response. AB - : Epithelial-to-mesenchymal transition (EMT) is linked to tumor invasion, drug resistance and aggressive disease and this is largely dependent on the cell's microenvironment. Acriflavine (ACF) is an old antibacterial drug recently also suggested as anticancer agent and HIF inhibitor. We wanted to study the effect of acriflavine on EMT in different human cancer models. Pancreatic cancer cells (Panc-1) were exposed to TGF-beta1 or cobalt chloride (to mimick severe hypoxia) to induce EMT. For our third model we exposed HepG2 liver cancer cells to sorafenib which resulted in development of acquired drug resistance with strong features of EMT and aggressive behavior. These models were morphologically and functionally (invasion assay) characterized. Markers of EMT were determined using qRT-PCR and Western blotting. Transcriptome analysis was performed following gene expression determination and combining the iRegulon tool and Gene Set Enrichment Analysis (GSEA). We made the following observations: (1) acriflavine inhibited EMT based on changes in cell morphology, invasive capacities and markers of EMT (at protein and gene expression level). (2) Transcriptome analysis revealed potent inhibition of ATF4 target genes and of the unfolded protein response. We showed that acriflavine blocked eIF2a phosphorylation and reduced ATF4 translation thereby inhibiting the PERK/eIF2a/ATF4 UPR pathway. (3) ACF restored drug sensitivity of cells that obtained acquired resistance. CONCLUSIONS: We identified acriflavine as a potent inhibitor of EMT and the UPR, thereby re sensitizing the cancer cells to antineoplastic drugs. PMID- 27987432 TI - Differential accumulation of photosynthetic proteins regulates diurnal photochemical adjustments of PSII in common fig (Ficus carica L.) leaves. AB - Molecular processes involved in photosystem II adaptation of woody species to diurnal changes in light and temperature conditions are still not well understood. Regarding this, here we investigated differences between young and mature leaves of common fig (Ficus carica L.) in photosynthetic performance as well as accumulation of the main photosynthetic proteins: light harvesting complex II, D1 protein and Rubisco large subunit. Investigated leaf types revealed different adjustment mechanisms to keep effective photosynthesis. Rather stable diurnal accumulation of light harvesting complex II in mature leaves enabled efficient excitation energy utilization (negative L-band) what triggered faster D1 protein degradation at high light. However, after photoinhibition, greater accumulation of D1 during the night enabled them faster recovery. So, the most photosynthetic parameters, as the maximum quantum yield for primary photochemistry, electron transport and overall photosynthetic efficiency in mature leaves successfully restored to their initial values at 1a.m. Reduced connectivity of light harvesting complexes II to its reaction centers (positive L band) in young leaves increased dissipation of excess light causing less pressure to D1 and its slower degradation. Decreased electron transport in young leaves, due to reduced transfer beyond primary acceptor QA- most probably additionally induced degradation of Rubisco large subunit what consequently led to the stronger decrease of overall photosynthetic efficiency in young leaves at noon. PMID- 27987433 TI - Food cravings prospectively predict decreases in perceived self-regulatory success in dieting. AB - Food cravings are assumed to hamper dieting success, but most findings are based on cross-sectional studies. In the current study, female students were tested at the beginning of their first semester at university and six months later. They completed the Food Cravings Questionnaire-Trait-reduced (FCQ-T-r), the disinhibition subscale of the Eating Inventory, and the Perceived Self-Regulatory Success in Dieting Scale, and their height and weight were measured. Scores on the FCQ-T-r prospectively predicted higher disinhibition and lower perceived self regulatory success in dieting after six months. Although FCQ-T-r scores did not predict increases in body mass index (BMI) directly, a serial mediation model revealed an indirect effect of FCQ-T-r scores at baseline on BMI after six months via increased disinhibition scores and decreased perceived self-regulatory success in dieting. To conclude, the current results provide evidence for a prospective relationship between trait food craving and decreases in dieting success. Furthermore, they suggest a possible mediator of this association (i.e., increases in disinhibited eating) as well as an indirect effect on body weight. Measurement of trait food craving may be a useful tool for predicting or monitoring treatment changes and relapse in eating- and weight disorders. PMID- 27987434 TI - Disparities in self-rated health across generations and through the life course. AB - Extensive evidence leads us to expect that health disparities by race and socioeconomic status found in one generation might be reproduced in the next. To the extent that this occurs it is important to assess life course processes responsible for the reproduction. Prospective evidence concerning such life course processes is hard to come by as it requires long-term follow-up of individuals from childhood through adult life. We present data from the Child Health and Development Disparities study that provides evidence relevant to this issue with respect to self-rated health. Mothers and offspring recruited in California's Bay Area between 1959 and 1967 were assessed during pregnancy with follow-up exams of offspring along with in-person interviews with mothers (at offspring ages 5, 9-11, 15-17) and offspring (at ages 15-17, ~50). Available data allow us to assess the importance of three potential life course pathways in the reproduction of inequalities in self-rated health - socioeconomic pathways, cognitive pathways and pathways involving emerging health itself. As expected we found that race and SES disparities in SRH are reproduced across generations. They are evident in mothers, not strong or significant in offspring at 15-17, but present once again in offspring at age ~50. Concerning potential pathways, we found that indicators of child health were related to adult SRH and played some role in accounting for race but not SES disparities in adult SRH. Cognitive abilities were unrelated to adult SRH with childhood SES controlled. Childhood SES was associated with adult SRH independent of other childhood factors and is reduced to non-significance only when offspring college attainment is controlled. Race and SES disparities in self-reported health in one generation are re expressed in the next with strongest support for SES pathways in this transmission. PMID- 27987435 TI - Social-structural properties and HIV prevention among young men who have sex with men in the ballroom house and independent gay family communities. AB - The endogenous social support systems of young Black men who have sex with men (YBMSM), like surrogate families and social networks, are considered crucial assets for HIV prevention in this population. Yet, the extent to which these social systems foster sexual health protections or risks remains unclear. We examine the networked patterns of membership in ballroom houses and independent gay families, both Black gay subcultures in the United States, and how these memberships are related to HIV protective and risk traits of members. Drawing from a population-based sample of 618 YBMSM living in Chicago between June 2013 and July 2014, we observe a suite of protective and risk traits and perform bivariate analyses to assess each of their associations with being a member of a house or family. We then present an analysis of the homophilous and heterophilous mixing on these traits that structures the patterns of house and family affiliations among members. The bivariate analyses show that members of the house and family communities were more likely than non-members to report protective traits like being aware of PrEP, having health coverage, having a primary care doctor, and discouraging sex drug use among peers. However, members were also more likely to engage in the use of sex drugs. With respect to how these traits inform specific house/family affiliations, results show that members who had a recent HIV test, who were PrEP aware, or who engaged in exchange sex were more likely to belong to the same house or family, while HIV positive individuals were less likely to cluster within houses or families. These findings provide insights regarding the strengths and vulnerabilities of the house and gay family communities that can inform more culturally specific interventions that build on the existing human and social capital in this milieu. PMID- 27987436 TI - Effects of selenite on green microalga Haematococcus pluvialis: Bioaccumulation of selenium and enhancement of astaxanthin production. AB - Algae are at a low trophic level and play a crucial role in aquatic food webs. They can uptake and accumulate the trace element selenium (Se), which can be either essential or toxic to algal growth depending on the dosage and species. Se toxicity and algae resistance varied across different organisms. In order to investigate the effects of Se on the unicellular green alga Haematococcus pluvialis, an important industrial resource for natural astaxanthin, the algal growth rate, chlorophyll content, and fluorescence parameters were derived from experimental treatment with different concentrations of selenite. The results showed that the EC50 for the algal growth rate was 24mg/L, and that a low dosage of selenite (3mg/L) may not hinder H. pluvialis cell growth, but selenite at levels higher than 13mg/L do restrain cell growth. Bioaccumulation experiments showed that H. pluvialis accumulated up to 646MUg/g total Se and 380MUg/g organic Se, dry weight. However, treatment with high concentrations of selenite significantly increased intracellular hydrogen peroxide levels, antioxidant enzyme activity, and the production of astaxanthin, suggesting that Se bioaccumulation might be toxic to H. pluvialis. PMID- 27987437 TI - Theranostic Approach for Metastatic Pigmented Melanoma Using ICF15002, a Multimodal Radiotracer for Both PET Imaging and Targeted Radionuclide Therapy. AB - PURPOSE: This work reports, in melanoma models, the theranostic potential of ICF15002 as a single fluorinated and iodinated melanin-targeting compound. METHODS: Studies were conducted in the murine syngeneic B16BL6 model and in the A375 and SK-MEL-3 human xenografts. ICF15002 was radiolabeled with fluorine-18 for positron emission tomography (PET) imaging and biodistribution, with iodine 125 for metabolism study, and iodine-131 for targeted radionuclide therapy (TRT). TRT efficacy was assessed by tumor volume measurement, with mechanistics and dosimetry parameters being determined in the B16BL6 model. Intracellular localization of ICF15002 was characterized by secondary ion mass spectrometry (SIMS). RESULTS: PET imaging with [18F]ICF15002 evidenced tumoral uptake of 14.33+/-2.11%ID/g and 4.87+/-0.93%ID/g in pigmented B16BL6 and SK-MEL-3 models, respectively, at 1 hour post inoculation. No accumulation was observed in the unpigmented A375 melanoma. SIMS demonstrated colocalization of ICF15002 signal with melanin polymers in melanosomes of the B16BL6 tumors. TRT with two doses of 20 MBq [131I]ICF15002 delivered an absorbed dose of 102.3 Gy to B16BL6 tumors, leading to a significant tumor growth inhibition [doubling time (DT) of 2.9+/-0.5 days in treated vs 1.8+/-0.3 in controls] and a prolonged median survival (27 days vs 21 in controls). P53S15 phosphorylation and P21 induction were associated with a G2/M blockage, suggesting mitotic catastrophe. In the human SK-MEL-3 model, three doses of 25 MBq led also to a DT increase (26.5+/-7.8 days vs 11.0+/ 3.8 in controls) and improved median survival (111 days vs 74 in controls). CONCLUSION: Results demonstrate that ICF15002 fulfills suitable properties for bimodal imaging/TRT management of patients with pigmented melanoma. PMID- 27987439 TI - Barriers to management of tree diseases: Framing perspectives of pinewood managers around Dothistroma Needle Blight. AB - Forest Managers in the UK and elsewhere are facing new threats such as climate change and novel pests and diseases. Strategies seek to coordinate and steer appropriate responses through raising awareness and encouraging action but little is known about how individual managers respond to disease threats. We studied how managers have responded to the threat of Dothistroma Needle Blight (DNB), a disease which can affect growth and cause mortality of many pine species, and the key frames influencing their responses. Frames involve values and beliefs and allow people to make sense of, and interpret, events, experiences or issues. Interviews revealed broad awareness of the disease and threat it poses, but also high levels of inaction. Lack of action was associated with several framings grouped around causes and perceived severity of DNB, locating responsibility for prevention and management, mistrust/scepticism of advice and uncertainties over the future impact. These framings need to be considered as strategies are refined and new knowledge of disease behaviour is communicated to those from whom action is required. PMID- 27987438 TI - Unsupervised Analysis of Array Comparative Genomic Hybridization Data from Early Onset Colorectal Cancer Reveals Equivalence with Molecular Classification and Phenotypes. AB - AIM: To investigate whether chromosomal instability (CIN) is associated with tumor phenotypes and/or with global genomic status based on MSI (microsatellite instability) and CIMP (CpG island methylator phenotype) in early-onset colorectal cancer (EOCRC). METHODS: Taking as a starting point our previous work in which tumors from 60 EOCRC cases (<=45 years at the time of diagnosis) were analyzed by array comparative genomic hybridization (aCGH), in the present study we performed an unsupervised hierarchical clustering analysis of those aCGH data in order to unveil possible associations between the CIN profile and the clinical features of the tumors. In addition, we evaluated the MSI and the CIMP statuses of the samples with the aim of investigating a possible relationship between copy number alterations (CNAs) and the MSI/CIMP condition in EOCRC. RESULTS: Based on the similarity of the CNAs detected, the unsupervised analysis stratified samples into two main clusters (A, B) and four secondary clusters (A1, A2, B3, B4). The different subgroups showed a certain correspondence with the molecular classification of colorectal cancer (CRC), which enabled us to outline an algorithm to categorize tumors according to their CIMP status. Interestingly, each subcluster showed some distinctive clinicopathological features. But more interestingly, the CIN of each subcluster mainly affected particular chromosomes, allowing us to define chromosomal regions more specifically affected depending on the CIMP/MSI status of the samples. CONCLUSIONS: Our findings may provide a basis for a new form of classifying EOCRC according to the genomic status of the tumors. PMID- 27987440 TI - Elucidating carbon sources driving microbial metabolism during oil sands reclamation. AB - Microbial communities play key roles in remediation and reclamation of contaminated environments via biogeochemical cycling of organic and inorganic components. Understanding the trends in in situ microbial community abundance, metabolism and carbon sources is therefore a crucial component of effective site management. The focus of this study was to use radiocarbon analysis to elucidate the carbon sources driving microbial metabolism within the first pilot wetland reclamation project in the Alberta oil sands region where the observation of H2S had indicated the occurrence of microbial sulphate reduction. The reclamation project involved construction of a three compartment system consisting of a freshwater wetland on top of a sand cap overlying a composite tailings (CT) deposit. Radiocarbon analysis demonstrated that both dissolved and sediment associated organic carbon associated with the deepest compartments (the CT and sand cap) was primarily fossil (Delta14C = -769 to -9550/00) while organic carbon in the overlying peat was hundreds to thousands of years old (Delta14C = -250 to 3500/00). Radiocarbon contents of sediment associated microbial phospholipid fatty acids (PLFA) were consistent with the sediment bulk organic carbon pools (Peat: Delta14CPLFA = -2570/00; Sand cap Delta14CPLFA = -8050/00) indicating that these microbes were using sediment associated carbon. In contrast, microbial PLFA grown on biofilm units installed in wells within the deepest compartments contained much more modern carbon that the associated bulk carbon pools. This implied that the transfer of relatively more modern carbon was stimulating the microbial community at depth within the system. Correlation between cellular abundance estimates based on PLFA concentrations and the Delta14CPLFA indicated that the utilization of this more modern carbon was stimulating the microbial community at depth. These results highlight the importance of understanding the occurrence and potential outcomes of the introduction of relatively bioavailable carbon to mine wastes in order to predict and manage the performance of reclamation strategies. PMID- 27987441 TI - Justice involvement among homeless individuals with mental illnesses: Are self report and administrative measures comparable? AB - Individuals with mental illnesses who experience homelessness have frequent interactions with the criminal justice system. Correctly measuring this involvement is essential to develop and evaluate the efficacy of intervention programs. Criminal justice involvement is typically assessed through administrative records or self-reported accounts. The aims of this study are to: 1) assess agreement between self-report and administrative data related to court appearances, and 2) identify individual characteristics that affect discrepancies between sources. Participants were 468 homeless persons with mental illness from the Montreal site of the At Home/Chez Soi randomized controlled trial, in Canada. Self-reported data was collected through an interviewer-administered questionnaire. Administrative data was collected through provincial and municipal court databases. Overall, agreement was good. Discrepancies were more common among those with a diagnosis of mood disorder with psychotic features, and those with a criminal history. Increased age and interviewer's perception of sincerity and interest increased likelihood of concordance. Generally, high agreement between self-report and administrative data suggests that either source can provide reliable information. Further work to understand predictors of discrepancies could further enhance the quality of data collected through these different sources. PMID- 27987442 TI - Molecular analysis of the coagulase gene in clinical and nasal carrier isolates of methicillin-resistant Staphylococcus aureus by restriction fragment length polymorphism. AB - OBJECTIVES: The coagulase enzyme, encoded by the coa gene, is an important virulence factor of Staphylococcus aureus and can be used for typing of S. aureus isolates. In this study, coa gene typing was used to study the epidemiology of S. aureus at a university hospital in Hamadan (Iran). METHODS: A total of 200 S. aureus strains were analysed, among which 150 were isolated from clinical samples and 50 were from nasal swab specimens of carriers. Methicillin resistance was confirmed by presence of the mecA gene by PCR. For polymorphism analysis, the coa gene was amplified by PCR and the products were subjected to restriction digestion using the enzyme AluI. RESULTS: Amplification of the coa gene produced five classes of bands based on size, ranging from 300bp to 800bp. The 600-bp amplicon included coa 3 genotype predominated in S. aureus isolated from clinical and carrier specimens (150/200; 75.0%). AluI digestion of the PCR products produced eight distinct restriction fragment length polymorphism (RFLP) patterns, designated coa 1-8. The results showed that the 700-bp and 800-bp amplicons formed two (coa 4a and 4b) and three (coa 5a, 5b and 5c) patterns following AluI digestion, respectively, whereas the 300-, 500- and 600-bp fragments generated unique patterns designated coa 1, coa 2 and coa 3, respectively. CONCLUSIONS: This study performed coagulase typing, a technique used to determine the molecular epidemiology of S. aureus clinical isolates. coa gene amplification has been considered a simple and accurate method for typing of S. aureus. PMID- 27987443 TI - Detection of a new class C beta-lactamase (CMY-139) in Klebsiella pneumoniae of food origin from India. PMID- 27987444 TI - Environmental friendly technology for aluminum electrolytic capacitors recycling from waste printed circuit boards. AB - up to now, the recycling of e-waste should be developed towards more depth and refinement to promote industrial production of e-waste resource recovery. in the present study, the recycling of aluminum electrolytic capacitors (AECs) from waste printed circuit boards (WPCBs) is focused on. First of all, AECs are disassembled from WPCBs by a self-designed machine; meanwhile, the disassembled AECs are subjected to an integrated process, involving heating treatment, crushing, sieving, and magnetic separating, to recover aluminum and iron; finally, the off-gas and residue generated during the aforementioned processes are analyzed to evaluate environmental risks. The results indicate that 96.52% and 98.68% of aluminum and iron, respectively, can be recovered from AECs under the optimal condition. The off-gas generated during the process is mainly composed of elements of C, H, and O, indicating that the off-gas is non-toxic and could be re-utilized as clean energy source. The residue according with toxicity characteristics leaching standard can be landfilled safely in sanitary landfill site. The present study provides an environmentally friendly and industrial application potential strategy to recycle AECs to promote e-waste recycling industry. PMID- 27987445 TI - Assessment of phytotoxicity grade during composting based on EEM/PARAFAC combined with projection pursuit regression. AB - Improper treatment of organic waste may result in environmental pollution and harm to plant growth due to the high concentration of phytotoxin. Composting has widely been used for recycling organic waste and reducing phytotoxin to improve soil properties. Assessing the phytotoxicity grades of compost products is essential for achieving high quality compost to guarantee its marketability. In this study, a technique combined parallel factor (PARAFAC) of excitation-emission matrices (EEMs) spectroscopy with projection pursuit regression (PPR) was applied to improve the sensitivity of phytotoxicity assessment during composting. Results showed that composting reduced the concentration of phytotoxin, and increased the germination index (GI). Composts were divided into four grades based on GI values. Five components containing simple DOM (component C1 and C2) and complex DOM (component C3-C5) were successfully developed by PARAFAC. Correlation analysis between phytotoxicity, chemical indices and fluorescence components demonstrated that C1, C4, complex DOM, and the ratio of simple/complex DOM components were more suitable to assess phytotoxicity of composting products. These results revealed that PARAFAC/PPR enabled a rapid and accurate method to assess the phytotoxicity of compost materials for composting plant. PMID- 27987446 TI - Exploring the interactions and binding sites between Cd and functional groups in soil using two-dimensional correlation spectroscopy and synchrotron radiation based spectromicroscopies. AB - Understanding how heavy metals bind and interact in soils is essential for predicting their distributions, reactions and fates in the environment. Here we propose a novel strategy, i.e., combining two-dimensional correlation spectroscopy (2D COS) and synchrotron radiation based spectromicroscopies, for identifying heavy metal binding to functional groups in soils. The results showed that although long-term (23 yrs) organic fertilization treatment caused the accumulation of Cd (over 3 times) in soils when compared to no fertilization and chemical fertilization treatments, it significantly (p<0.05) reduced the Cd concentration in wheat grain. The 2D COS analyses demonstrated that soil functional groups controlling Cd binding were modified by fertilization treatments, providing implications for the reduced bioavailability of heavy metals in organic fertilized soils. Furthermore, correlative micro X-ray fluorescence spectromicroscopy, electron probe micro-analyzer mapping, and synchrotron-radiation-based FTIR spectromicroscopy analysis showed that Cd, minerals, and organic functional groups were heterogeneously distributed at the micro-scale in soil colloids. Only minerals, rather than organic groups, had a similar distribution pattern with Cd. Together, this strategy has a potential to explore the interactions and binding sites among heavy metals, minerals and organic components in soil. PMID- 27987447 TI - Experimental study of the mechanical stabilization of electric arc furnace dust using fluid cement mortars. AB - This article shows the results of an experimental study carried out in order to determine the maximum amount of electric arc furnace dust (EAFD) that can be incorporated into fluid cement-based mortars to produce mechanically stable monolithic blocks. The leaching performance of all mixes was studied in order to classify them according to the EU Council Decision 2003/33/EC. Two mortars were used as reference and three levels of EAFD incorporation were tested in each of the reference mortars. As the incorporation ratio of EAFD/cement increases, the mechanical strength decreases. This is due to the greater EAFD/cement and water/cement ratios, besides the presence of a double-hydrated hydroxide of Ca and Zn (CaZn2(OH)6.2H2O) instead of the portlandite phase (Ca(OH)2) in the mixes made with EAFD, as well as non-hydrated tricalcium silicate. A mass ratio of 2:1 (EAFD: cement-based mortar) can be added maintaining a stable mechanical strength. The mechanical stabilization process also reduced the leaching of metals, although it was not able to reduce the Pb concentration below the limit for hazardous waste. The high amount of EAFD mechanically stabilized in this experimental study can be useful to reduce the storage volume required in hazardous waste landfills. PMID- 27987448 TI - The optimization, kinetics and mechanism of m-cresol degradation via catalytic wet peroxide oxidation with sludge-derived carbon catalyst. AB - The sludge-derived carbon catalyst modified with 0 degrees C HNO3 solution was tested in catalytic wet peroxide oxidation of m-cresol (100mgL-1) with systematical mathematical models and theoretical calculation for the first time. The reaction conditions were optimized by response surface methodology (RSM) as T=60 degrees C, initial pH=3.0, C0,H2O2(30%)=1.20gL-1 (lower than the stoichiometric amount of 1.80gL-1) and Ccat=0.80gL-1, with 96% of m-cresol and 47% of TOC converted after 16min and 120min of reaction, respectively, and xi (mg TOC/g H2O2 fed)=83.6mg/g. The end time of the first kinetic period in m-cresol model was disclosed to be correlated with the fixed residue m-cresol concentration of about 33%. Furthermore, the kinetic constants in models of TOC and H2O2 exactly provide convincing proof of three-dimensional response surfaces analysis by RSM, which showed the influence of the interaction between organics and H2O2 on effective H2O2 utilization. The reaction intermediates over time were identified by gas chromatography-mass spectrometer based on kinetics analysis. Four degradation pathways for m-cresol were proposed, of which the possibility and feasibility were well proven by frontier molecule orbital theory and atomic charge distribution via density functional theory method. PMID- 27987449 TI - Enhanced desorption of cesium from collapsed interlayer regions in vermiculite by hydrothermal treatment with divalent cations. AB - Adsorption of cesium (Cs) on phyllosilicates has been intensively investigated because natural soils have strong ability of immobilizing Cs within clay minerals resulting in difficulty of decontamination. The objectives of present study are to clarify how Cs fixation on vermiculite is influenced by structure change caused by Cs sorption at different loading levels and how Cs desorption is affected by various replacing cations induced at different treating temperature. As a result, more than 80% of Cs was readily desorbed from vermiculite with loading amount of 2% saturated Cs (5.49*10-3mmolg-1) after four cycles of treatment of 0.01M Mg2+/Ca2+ at room temperature, but less than 20% of Cs was desorbed from saturated vermiculite. These distinct desorption patterns were attributed to inhibition of Cs desorption by interlayer collapse of vermiculite, especially at high Cs loadings. In contrast, elevated temperature significantly facilitated divalent cations to efficiently desorb Cs from collapsed regions. After five cycles of treatment at 250 degrees C with 0.01M Mg2+, ~100% removal of saturated Cs was achieved. X-ray diffraction analysis results suggested that Cs desorption was completed through enhanced diffusion of Mg2+ cations into collapsed interlayer space under hydrothermal condition resulting in subsequent interlayer decollapse and readily release of Cs+. PMID- 27987450 TI - Fungicides induced triazole-resistance in Aspergillus fumigatus associated with mutations of TR46/Y121F/T289A and its appearance in agricultural fields. AB - Azole resistance in Aspergillus fumigatus is a growing public health problem. The sources of this resistance have been gained much attention. The present study was conducted to assess if resistant strain of A. fumigatus and its associated mutations in cyp51A could be induced by triazole fungicides and whether the resistant strain of A. fumigatus exist in agricultural fields. The results indicated that the resistance in A. fumigatus with mutations of TR46/Y121F/T289A, A284T, G448S and P222Q could be induced by agricultural triazoles (epoxiconazole, tebuconazole, propiconazole, hexaconazole, and metconazole). TR46/Y121F/T289A was the most common mutation in the induced resistant strain of A. fumigatus. A total of 144 soil samples were collected from different greenhouses for vegetables and fruits in Zhejiang, China. Among them, 2 voriconazole-resistant strains (No. 15 and 44) harboring the mutation of TR46/Y121F/T289A and 1 itraconazole-resistant strain (No. 51) harboring the mutation of TR34/L98H/S297T/F495I were isolated and identified. This implies that resistant strain of A. fumigatus has already distributed at least in 5.8% of the greenhouses. These findings might imply that there is a direct link between the agricultural use of triazoles and the appearance of the resistance in A. fumigatus to triazole medicals and its associated mutations in cyp51A. PMID- 27987451 TI - Calix[4]pyrrole for the removal of arsenic (III) and arsenic (V) from water. AB - Although extensive research has been carried on anion complexation reactions involving calix[4]pyrrole, nothing has been reported regarding this receptor and its interaction with arsenic species. The fact that a single step reaction is required for the synthesis of this receptor, calls upon the need to explore its removal ability for these species from water as a starting point for the development of a new technological approach for water remediation purposes based on Supramolecular Chemistry. This paper reports a detailed study on the interactions involving calix[4]pyrrole with As(III) and As(V). The interaction of As species and calix[4]pyrrole was assessed by 1H NMR using a phase transfer approach aided by molecular simulation studies. The X-ray spectrum confirms the presence of arsenic species in the solid receptor. Optimal conditions for removing As(III) and As(V) from water were established. The kinetics of extraction is fast and calix[4]pyrrole is able to remove 15.28 and 14.29mg/g of arsenate and arsenite respectively. Material was tested for removing arsenic species from real samples collected from different contaminated sites in Argentina. Percentages of arsenate, arsenite and organic arsenic removed from these samples are higher than 85%. PMID- 27987452 TI - Colorimetric detection and removal of radioactive Co ions using sodium alginate based composite beads. AB - We demonstrate a simple method for the visual determination and removal of Co ions using a bead-shaped, capturing probe based on hybridized sodium alginate. For Co ions, the designed protocol consisted of three main constituents: an azopyridine-based Co ion-probe for visual detection; sodium alginate as an adsorbent for the Co ion and a bead construct for removal and structure; silica as a linker for the probe and the alginate, leading to a robust structure. When the composite beads were exposed to Co ions, the yellow color of the beads turned to intensive violet and the color intensity was associated with the Co ion concentration. The color variation was quantified using red-green-blue (RGB) color values that were obtained with a scanner and evaluated with Photoshop. The technique achieved both visual recognition with obvious color change of the beads and efficient removal of the radioactive 60Co ion. The sensing and removal of any radioactive isotope could be achieved with an appropriate sensing probe, to provide a simple and universal platform for remediation. PMID- 27987453 TI - Recovery of valuable metals from waste cathode materials of spent lithium-ion batteries using mild phosphoric acid. AB - Sustainable recycling of valuable metals from spent lithium-ion batteries (LIBs) may be necessary to alleviate the depletion of strategic metal resources and potential risk of environmental pollution. Herein a hydrometallurgical process was proposed to explore the possibility for the recovery of valuable metals from the cathode materials (LiCoO2) of spent LIBs using phosphoric acid as both leaching and precipitating agent under mild leaching conditions. According to the leaching results, over 99% Co can be separated and recovered as Co3(PO4)2 in a short-cut process involved merely with leaching and filtrating, under the optimized leaching conditions of 40 degrees C (T), 60min (t), 4 vol.% H2O2, 20mLg 1 (L/S) and 0.7mol/L H3PO4. Then leaching kinetics was investigated based on the logarithmic rate kinetics model and the obtained results indicate that the leaching of Co and Li fits well with this model and the activation energies (Ea) for Co and Li are 7.3 and 10.2kJ/mol, respectively. Finally, it can be discovered from characterization results that the obtained product is 97.1% pure cobalt phosphate (Co3(PO4)2). PMID- 27987454 TI - Patient-reported outcomes in ductal carcinoma in situ: A systematic review. AB - Ductal carcinoma in situ (DCIS) is a pre-invasive breast cancer with excellent prognosis but with potential adverse impacts of diagnosis and treatment on quality of life and other patient-reported outcomes (PROs). We undertook a systematic review to synthesise current evidence about PROs following diagnosis and treatment for DCIS. We searched five electronic databases (from database inception to November 2015), cross-referenced and contacted experts to identify studies that reported PROs after DCIS treatment. Two reviewers independently applied inclusion and quality criteria, and extracted findings. Of 2130 papers screened, 23 were eligible, reporting 17 studies. Short- and long-term PRO evidence about differences between DCIS treatment options was lacking. Evidence pooled across treatments indicated core aspects of quality of life (physical, role, social, emotional function, pain, fatigue) and psychological distress (anxiety, depression) were impacted significantly initially, with most aspects returning to population norms by 6-12 months, and all by 2 years post operatively. Fears of recurrence and dying from breast cancer were exaggerated, occurred early and persisted for many years. Sexuality and body image impacts were generally low and resolved within 1-3 months after surgery. A minority of women experienced considerable impact, including depression and sexual issues associated with body image problems. Well-powered PRO studies are required to track recovery trajectories and long-term impacts of the range of contemporary and emerging local and systemic treatments for DCIS. PRO data would enable care providers to prepare patients for short-term sequelae and enable patients who have treatment options to exercise preferences in choosing among them. PMID- 27987455 TI - Biomimetic synthesis of sericin and silica hybrid colloidosomes for stimuli responsive anti-cancer drug delivery systems. AB - Colloidosomes are becoming popular due to their significant flexibility with respect to microcapsule functionality. This study reports a facile approach for synthesizing silica colloidosomes by using sericin microcapsule as the matrix in an environment-friendly method. The silica colloid arrangement on the sericin microcapsules are orchestrated by altering the reaction parameters. Doxorubicin (DOX), used as a hydrophilic anti-cancer drug model, is encapsulated into the colloidosomes in a mild aqueous solution and becomes stimuli-responsive to different external environments, including pH values, protease, and ionic strength are also observed. Colloidosomes with sub-monolayers, close-packed monolayers, and close-packed multi-layered SiO2 colloid shells can be fabricated under the optimized reaction conditions. A flexible DOX release from colloidosomes can be obtained via modulating the SiO2 colloid layer arrangement and thickness. The close-packed and multi-layered SiO2 colloid shells can best protect the colloidosomes and delay the rapid cargo release. MG-63 cells are killed when doxorubicin is released from the microcapsules due to degradation in the microenvironment of cancer cells. The drug release period is prolonged as SiO2 shell thickness and integrity increase. This work suggests that the hybrid colloidosomes can be effective in a bioactive molecule delivery system. PMID- 27987456 TI - Asymmetric cationic liposomes designed for heat-activated association with cells. AB - Improved anticancer drugs and drug carriers are needed in combination therapies, such as hyperthermia-assisted chemotherapy. Liposomal drug carriers with advanced functions are attractive candidates for targeted accumulation and drug release in response to heat stimulus. We report on the design of liposomes with a heat activated surface function. Our design is based on asymmetric lipid membranes with a defined gel to liquid-crystalline phase-transition temperature around 41 degrees C. Asymmetry between the inner and the outer membrane leaflets was generated through selective PEGylation of cationic lipids in the outer membrane leaflet. In a physiological buffer, the PEGylated asymmetric liposomes had a neutral zeta potential and did not bind to planar anionic model membranes. In contrast, following upon heat-activation, binding of liposomes to the model membranes occurred. Release of a hydrophilic dye encapsulated in the asymmetric liposomes occurred at 40 degrees C. Enhanced uptake of the asymmetric liposomes by hypopharyngeal carcinoma cells (FaDu cells) was observed when hyperthermia was applied compared to experiments performed at 37 degrees C. These results show the potential of asymmetric liposomes for localized delivery of drugs into cells in response to (external) temperature stimulus. PMID- 27987457 TI - Synergistic performance of lecithin and glycerol monostearate in oil/water emulsions. AB - The effects of the combination of two low-molecular weight emulsifiers (lecithin and glycerol-monostearate (GMS)) on the stability, the dynamic interfacial properties and rheology of emulsions have been studied. Different lecithin/GMS ratios were tested in order to assess their impact in the formation and stabilization of oil in water emulsions. The combination of the two surfactants showed a synergistic behaviour, mainly when combined at the same ratio. The dynamic film properties and zeta-potential showed that lecithin dominated the surface of oil droplets, providing stability to the emulsions against flocculation and coalescence, while allowing the formation of small oil droplets. At long times of adsorption, all of the mixtures showed similar interfacial activity. However, higher values of interfacial pressure at the initial times were reached when lecithin and GMS were at the same ratio. Interfacial viscoelasticity and viscosity of mixed films were also similar to that of lecithin alone. On the other hand, emulsions viscosity was dominated by GMS. The synergistic performance of lecithin-GMS blends as stabilizers of oil/water emulsions is attributed to their interaction both in the bulk and at the interface. PMID- 27987458 TI - Neutron Reflectometry reveals the interaction between functionalized SPIONs and the surface of lipid bilayers. AB - The safe application of nanotechnology devices in biomedicine requires fundamental understanding on how they interact with and affect the different components of biological systems. In this respect, the cellular membrane, the cell envelope, certainly represents an important target or barrier for nanosystems. Here we report on the interaction between functionalized SuperParamagnetic Iron Oxide Nanoparticles (SPIONs), promising contrast agents for Magnetic Resonance Imaging (MRI), and lipid bilayers that mimic the plasma membrane. Neutron Reflectometry, supported by Quartz Crystal Microbalance with Dissipation monitoring (QCM-D) experiments, was used to characterize this interaction by varying both SPION coating and lipid bilayer composition. In particular, the interaction of two different SPIONs, functionalized with a cationic surfactant and a zwitterionic phospholipid, and lipid bilayers, containing different amount of cholesterol, were compared. The obtained results were further validated by Dynamic Light Scattering (DLS) measurements and Cryogenic Transmission Electron Microscopy (Cryo-TEM) images. None of the investigated functionalized SPIONs were found to disrupt the lipid membrane. However, in all case we observed the attachment of the functionalized SPIONs onto the surface of the bilayers, which was affected by the bilayer rigidity, i.e. the cholesterol concentration. PMID- 27987459 TI - Hollow cross-linked enzyme aggregates (h-CLEA) of laccase with high uniformity and activity. AB - Hollow cross-linked enzyme aggregates of laccase (h-CLEA laccase) can be prepared by employing a millifluidic reactor carrying two coaxial laminar flows. In a confluence zone where acetonitrile and an aqueous solution of laccase meet, diffusion of acetonitrile into the aqueous solution gives rise to rapid precipitation of laccase aggregates at the water/acetonitrile interface, as is evidenced by fluorescence images. By controlling the flow rates carefully in the laminar flow regions, h-CLEA laccase around 220+/-10nm can be obtained, and the size of the h-CLEA laccase increases with increasing flow rates of both solutions. The h-CLEA laccase particles are distinctly different from CLEA laccase prepared in batch processes. The former only consist a crust of cross linked enzymes (with a hollow core) whereas the latter has a highly porous structure. When the h-CLEA laccase is used as biocatalysts, their activity (0.26U/mg) is comparable to that of free enzymes at neutral pH due to the hollow structure. Moreover, the activity of h-CLEA laccase is higher than that of free laccase at high pH. For example, trypan blue (a dye molecule) can be decolorized completely in the presence of h-CLEA laccase within 270min even at pH 10.0, at which the free enzyme completely loses its activity. Because of their uniform sizes, h-CLEA laccase can be trapped in a membrane for continuous degradation of trypan blue up to 96h without losing any activity. This study shows the superiority of h-CLEA laccase compared to other types of immobilized enzymes. PMID- 27987460 TI - Temperature and pH sensitivity of a stabilized self-nanoemulsion formed using an ionizable lipid-like material via an oil-to-surfactant transition. AB - Lipids functionalized with tertiary amines (ionizable lipids) for a pH-dependent positive charge have been developed extensively as a carrier material for delivering nucleic acids. We previously developed an SS-cleavable proton activated lipid-like material (ssPalm) as a component of a functionalized lipid envelope structure of a nanoparticle that encapsulated plasmid DNA and short interfering RNA. In this study, we report on the unique characteristics of such an ionizable lipid: the formation of a nano-sized emulsion (ave. 40nm) via pH triggered self-emulsification in the absence of a cargo (nucleic acids). The particle has a neutral charge at physiological pH and is stabilized by helper lipids and polyethyleneglycol (PEG)-conjugated lipids. The generalized polarization of 6-dodecanoyl-2-dimethylaminonaphthalene (Laurdan), which indicates the surface polarity caused by the invasion of water onto the surface, changes dynamically in response to pH and temperature, while the fluidity of the intra-particle compartment, as measured by the fluorescence anisotropy of 1,6 Diphenyl-1,3,5-hexatriene (DPH), is not affected. Even when the particle contains a high density of PEG on the surface, it shows a high fusogenecity to negatively charged liposomes in response to an acidic pH to a higher degree than a conventional cationic lipid. These characteristics suggest that the ssPalm particle possesses unique properties for delivering lipophilic drugs across the biomembrane. PMID- 27987461 TI - Modelling the photochemical attenuation pathways of the fibrate drug gemfibrozil in surface waters. AB - Gemfibrozil (GFZ) is a relatively persistent pollutant in surface-water environments and it is rather recalcitrant to biological degradation. The GFZ photochemical lifetimes are relatively short in shallow waters with low levels of dissolved organic carbon (DOC), but they can reach the month-year range in deep and high-DOC waters. The main reason is that GFZ undergoes negligible reaction with singlet oxygen or degradation sensitised by the triplet states of chromophoric dissolved organic matter, which are the usually prevalent photochemical pathways in deep and high-DOC sunlit waters. Nitrate and nitrite scarcely affect the overall GFZ lifetimes, but they can shift photodegradation from direct photolysis to the OH process. These two pathways are the main GFZ phototransformation routes, with the direct photolysis prevailing in shallow environments during summer. Under these conditions the GFZ photochemical lifetimes are also shorter and the environmental significance of photodegradation correspondingly higher. The direct photolysis of GFZ under UVB irradiation yielded several transformation intermediates deriving from oxidation or cleavage of the aliphatic lateral chain. A quinone derivative (2,5-dimethyl-1,4 benzoquinone), a likely oxidation product of the transformation intermediate 2,5 dimethylphenol, is expected to be the most acutely and chronically toxic compound arising from GFZ direct photolysis. Interestingly, literature evidence suggests that the same toxic intermediate would be formed upon OH reaction. PMID- 27987462 TI - Potential effects of rainwater-borne H2O2 on competitive degradation of herbicides and in the presence of humic acid. AB - In a previous piece of work, we reported some preliminary experimental results showing that hydrogen peroxide at a concentration range frequently encountered in rainwater could lead to degradation of three common herbicides (diuron, butachlor and glyphosate). However, the work was limited to the observation on the effects of Fenton process on the individual herbicides. In field conditions, different types of herbicides along with other organic molecules may occur concurrently. It is unclear how different herbicides and various organic molecules compete for the available hydroxyl radical. In this study, further laboratory experiments were conducted to observe the changes in the herbicides in the scenarios where multiple herbicides or humic acid are present. The results show that humic acid impeded hydroxyl radical-driven degradation of the diuron and butachlor. However, humic acid had no significant effects on reducing glyphosate removal rate. Glyphosate could compete strongly with the humic acid for the available hydroxyl radical in the reaction systems. The reactivity of glyphosate with hydroxyl radical was much higher than those of diuron and butachlor due possibly to its relatively simpler chemical structure, as compared to either diuron or butachlor, which are aromatic compounds that have higher chemical stability. Butachlor degradation was much weaker in the combined diuron and butachlor system than in the combined glyphosate and butachlor system. In the glyphosate-butachlor system, the opposite was observed. The findings have moved another step forward to understanding the potential role of rainwater-borne H2O2 in degrading herbicides in open water environments. PMID- 27987463 TI - A taxonomy of chemicals of emerging concern based on observed fate at water resource recovery facilities. AB - As reuse of municipal water resource recovery facility (WRRF) effluent becomes vital to augment diminishing fresh drinking water resources, concern exists that conventional barriers may prove deficient, and the upcycling of chemicals of emerging concern (CECs) could prove harmful to human health and aquatic species if more effective and robust treatment barriers are not in place. A multiple month survey, of both primary and secondary effluents, from three (3) WRRFs, for 95 CECs was conducted in 2014 to classify CECs by their persistence through conventional water reclamation processes. By sampling the participating WRRF process trains at their peak performance (as determined by measured bulk organics and particulates removal), a short-list of recalcitrant CECs that warrant monitoring to assess treatment performance at advanced water reclamation and production facilities. The list of identified CECs for potable water reclamation (indirect or direct potable reuse) include a herbicide and its degradants, prescription pharmaceuticals and antibiotics, a female hormone, an artificial sweetener, and chlorinated flame retardants. PMID- 27987464 TI - Confirming improved detection of gadolinium in bone using in vivo XRF. AB - The safety of using Gd in MRI contrast agents has recently been questioned, due to recent evidence of the retention of Gd in individuals with healthy renal function. Bone has proven to be a storage site for Gd, as unusually high concentrations have been measured in femoral heads of patients undergoing hip replacement surgery, as well as in autopsy samples. All previous measurements of Gd in bone have been invasive and required the bone to be removed from the body. X-ray fluorescence (XRF) offers a non-invasive and non-destructive method for carrying out in vivo measurements of Gd in humans. An updated XRF system provides improved detection limits in a short measurement time of 30-min. A new four detector system and higher activity Cd-109 excitation source of 5GBq results in minimum detection limits (MDLs) of 1.64-1.72MUgGd/g plaster for an average overlaying tissue thickness of the tibia. These levels are well within the range of previous in vitro Gd measurements. Additional validation through comparison with ICP-MS measurements has confirmed the ability of the XRF system for detecting Gd further, proving it is a feasible system to carry out human measurements. PMID- 27987466 TI - Fricke gel dosimeter as a tool in quality assurance of the radiotherapy treatment plans. AB - Ferrous xylenol gel was evaluated as a dosimeter in verifications of treatment plans for treatments of female breast tumors in external-beam radiation therapy. The dosimeter was calibrated in a cubic wax phantom irradiated with 6 and 15MV beams of an Elekta clinical linear accelerator and then used for measurements of doses in an anthropomorphic phantom of a female torso, which mimicked female breasts after modified radical mastectomy and breast-conserving surgery. Doses measured with the gel in specific locations in the phantom were compared with values predicted by treatment plans created with the XiO treatment planning system (Elekta / IMPAQ) and with results of measurements with an IBA CC13 ionization chamber in the same locations. Differences between the values measured with the gel and predicted by the treatment planning system or measured with the ionization chamber were within 1.5% in most cases. In an area of as steep dose gradient, the difference reached 2.7%, which was explicable in terms of the finite size of the gel dosimeter. The dose response of the gel is dose rate and energy independent in the ranges used in most clinical linacs. The results have shown that ferrous xylenol gels can be used as dosimeters in quality assurance in radiation therapy. PMID- 27987465 TI - Determination of low-level Radium isotope activities in fresh waters by gamma spectrometry. AB - A new portable sampling system was developed to extract Radium isotopes from large volumes (up to 300L) of fresh surface- and ground-waters of low Ra activities (<5mBq/L). Ra is quantitatively adsorbed on a small amount (6.5g) of MnO2-coated acrylic fibers, which are then dried and burned at 600 degrees C in the laboratory. The resulting Mn-oxide powder (about 2cm3 when compacted) is then analyzed through gamma-ray spectrometry which allows measurement of the whole Ra quartet (226Ra, 228Ra, 224Ra and 223Ra) in a single counting of a few days. The usual relative standard combined uncertainties (1sigma) are 2-3% for 226Ra, 228Ra and 224Ra; and less than 10% for 223Ra. This method was applied to the analysis of Ra in karstic waters of the Lez aquifer, and surface- and ground-waters of the upper and middle Vidourle watershed (South of France). The analyzed waters have relatively low 226Ra activities (1-4mBq/L) in both cases, regardless of the contrasted geology (Mesozoic limestone vs crystalline Variscan basement), but clearly distinct (228Ra/226Ra) ratios in agreement with the differences in Th/U ratios of the two drained areas. Short-lived Ra isotopes (224Ra and 223Ra) appear to be mainly influenced by near-surface desorption/recoil processes for most of the sampling sites. PMID- 27987468 TI - Neurotomy of the rectus femoris nerve: Short-term effectiveness for spastic stiff knee gait: Clinical assessment and quantitative gait analysis. AB - BACKGROUND: Stiff knee gait is a troublesome gait disturbance related to spastic paresis, frequently associated with overactivity of the rectus femoris muscle in the swing phase of gait. OBJECTIVE: The aim of this study was to assess the short term effects of rectus femoris neurotomy for the treatment of spastic stiff-knee gait in patients with hemiparesis. PATIENTS AND METHODS: An Intervention study (before-after trial) with an observational design was carried out in a university hospital. Seven ambulatory patients with hemiparesis of spinal or cerebral origin and spastic stiff-knee gait, which had previously been improved by botulinum toxin injections, were proposed a selective neurotomy of the rectus femoris muscle. A functional evaluation (Functional Ambulation Classification and maximal walking distance), clinical evaluation (spasticity - Ashworth scale and Duncan Ely test, muscle strength - Medical Research Council scale), and quantitative gait analysis (spatiotemporal parameters, stiff knee gait-related kinematic and kinetic parameters, and dynamic electromyography of rectus femoris) were performed as outcome measures, before and 3 months after rectus femoris neurotomy. RESULTS: Compared with preoperative values, there was a significant increase in maximal walking distance, gait speed, and stride length at 3 months. All kinematic parameters improved, and the average early swing phase knee extension moment decreased. The duration of the rectus femoris burst decreased post-op. CONCLUSION: This study is the first to show that rectus femoris neurotomy helps to normalise muscle activity during gait, and results in improvements in kinetic, kinematic, and functional parameters in patients with spastic stiff knee gait. PMID- 27987467 TI - Fucoidan inhibits LPS-induced inflammation in vitro and during the acute response in vivo. AB - Studies have been focused on natural products with antibacterial and anti inflammatory activities, such as fucoidan. Many in vivo studies have evaluated the effect of fucoidan on tumor growth, diabetes, obesity, ischemia reperfusion, and oxidative stress. However, the effects of fucoidan on bacteria-induced gingival inflammation and periodontitis have not been reported. We previously characterized the anti-inflammatory effect of fucoidan in vitro. Here, we confirmed the anti-inflammatory activity of fucoidan in a macrophage cell line in terms of its inhibition of the expression of inflammatory mediators and pro inflammatory cytokines. Additionally, we confirmed the ability of fucoidan to inhibit gingival inflammation, expression of pro-inflammatory cytokines, and neutrophil recruitment in the gingival tissue of mice injected with LPS prepared from P. gingivalis. Interestingly, however, fucoidan did not inhibit the expression of pro-inflammatory cytokines in a P. gingivalis-infected mouse model of periodontitis. Additionally, fucoidan treatment did not lead to clearance of P. gingivalis or improvement of P. gingivalis infection-mediated bone loss in the periodontitis model. We conclude that fucoidan exerts anti-inflammatory effects in vitro and in vivo, together with a limited antibacterial effect in vivo. PMID- 27987470 TI - A new method to detect and correct sample tilt in scanning transmission electron microscopy bright-field imaging. AB - Important properties of functional materials, such as ferroelectric shifts and octahedral distortions, are associated with displacements of the positions of lighter atoms in the unit cell. Annular bright-field scanning transmission electron microscopy is a good experimental method for investigating such phenomena due to its ability to image light and heavy atoms simultaneously. To map atomic positions at the required accuracy precise angular alignment of the sample with the microscope optical axis is necessary, since misalignment (tilt) of the specimen contributes to errors in position measurements of lighter elements in annular bright-field imaging. In this paper it is shown that it is possible to detect tilt with the aid of images recorded using a central bright field detector placed within the inner radius of the annular bright-field detector. For a probe focus near the middle of the specimen the central bright field image becomes especially sensitive to tilt and we demonstrate experimentally that misalignment can be detected with a precision of less than a milliradian, as we also confirm in simulation. Coma in the probe, an aberration that can be misidentified as tilt of the specimen, is also investigated and it is shown how the effects of coma and tilt can be differentiated. The effects of tilt may be offset to a large extent by shifting the diffraction plane detector an amount equivalent to the specimen tilt and we provide an experimental proof of principle of this using a segmented detector system. PMID- 27987469 TI - Investigation of associations between recurrence of major depressive disorder and spinal posture alignment: A quantitative cross-sectional study. AB - The aim of this study was to investigate associations between poor spinal posture and the recurrence of major depressive episodes and severity of symptoms in patients with major depressive disorder (MDD). This was a cross-sectional quantitative study of MDD patients. Outpatients were recruited from consecutive admissions at a mood disorders unit of a tertiary psychiatric hospital. Of 136 MDD patients, 72 (53 women, 19 men; mean age, 42.4+/-9.1years) met all the criteria and completed the study. Forty-one patients were classified with a recurrent episode (RE) of MDD and 31 with a single episode (SE). Quantitative assessments of postural deviations were made using photogrammetry, including kyphosis, shoulder protraction, and head inclination. The severity of depressive episodes was assessed using the Hamilton Depression Rating Scale. The diagnosis and classification of patients were performed according to DSM-IV-TR and SCID criteria. Multivariate analysis of variance indicated that the RE group had greater anterior head inclination (35.39; SD: 1.57), greater scapular abduction (1.69; SD: 0.93), and worse thoracic kyphosis (139.38; SD: 1.19) than the SE group (p<0.001 for all). Multivariate analysis of covariance showed an interaction between the severity of depressive symptoms and the degree of thoracic kyphosis (p=0.002). Recurrence of depressive episodes is associated with measures of postural misalignment. PMID- 27987471 TI - Use of Nicotiana tabacum transplastomic plants engineered to express a His-tagged CP47 for the isolation of functional photosystem II core complexes. AB - This work focuses on the development of a molecular tool for purification of Photosystem II (PSII) from Nicotiana tabacum (L.). To this end, the chloroplast psbB gene encoding the CP47 PSII subunit was replaced with an engineered version of the same gene containing a C-terminal His-tag. Molecular analyses assessed the effective integration of the recombinant gene and its expression. Despite not exhibiting any obvious phenotype, the transplastomic plants remained heteroplasmic even after three rounds of regeneration under antibiotic selection. However, the recombinant His-tagged CP47 protein associated in vivo to the other PSII subunits allowing the isolation of a functional PSII core complex, although with low yield of extraction. These results will open up possible perspectives for further spectroscopic and structural studies. PMID- 27987472 TI - Seed priming improves chilling tolerance in chickpea by modulating germination metabolism, trehalose accumulation and carbon assimilation. AB - Chilling stress is one of the major abiotic stresses affecting chickpea productivity worldwide. This study evaluated the potential role of seed priming in improving resistance to chilling stress in chickpea (cv. Punjab, 2008). The priming treatments involved soaking seeds of chickpea cultivar Punjab 2008 in either water for 8 h (on-farm priming), aerated water (hydropriming) for 18 h, or CaCl2 solution (psis -1.25 MPa; osmopriming) for 18 h. Primed and untreated seeds were grown either at 18/15 degrees C (control) or 13/10 degrees C (chilling stress). Chilling stress suppressed the growth of chickpea while seed priming mitigated the adverse effects of chilling stress by improving stand establishment, growth, water relations, photosynthesis, alpha-amylase activity, sugar metabolism, antioxidant enzyme activity, membrane stability, and leaf accumulation of proline, nitrogen, potassium and soluble phenolics. Seed priming also improved the performance of chickpea under optimal (control) conditions. The overall order of improvement in resistance to chilling by using seed priming was osmopriming > hydropriming > on-farm priming. Osmopriming improved seedling dry weight, specific leaf area, leaf CO2 net assimilation rate, maximal photochemical efficiency of PSII, alpha-amylase activity, trehalose content and leaf relative water content by 10, 22, 17, 20, 73, 48 and 7%, respectively, relative to the non primed control under chilling stress. Under optimal temperature conditions, the corresponding values were 30, 32, 16, 10, 83, 75 and 5%, respectively. Sugar metabolism, especially trehalose content, was strongly linked with stand establishment, photosynthesis, antioxidant potential (under chilling stress) and plant biomass. Overall, seed priming improved chickpea performance under both optimal temperature conditions and chilling stress through better germination metabolism and the accumulation of trehalose, which protected from oxidative damage and helped to maintain carbon assimilation and seedling growth. PMID- 27987473 TI - Euphorbia milii-native bacteria interactions under airborne formaldehyde stress: Effect of epiphyte and endophyte inoculation in relation to IAA, ethylene and ROS levels. AB - Better understanding of plant-bacteria interactions under stress is of the prime importance for enhancing airborne pollutant phytoremediation. No studies have investigated plant-epiphyte interactions compared to plant-endophyte interactions under airborne formaldehyde stress in terms of plant Indole-3-acetic acid (IAA), ethylene, reactive oxygen species (ROS) levels and pollutant removal efficiency. Euphorbia milii was inoculated with native plant growth-promoting (PGP) endophytic and epiphytic isolates individually to investigate plant-endophyte compared to plant-epiphyte interactions under continuous formaldehyde fumigation. Under airborne formaldehyde stress, endophyte interacts with its host plant closely and provides higher levels of IAA which protected the plant against formaldehyde phytotoxicity by lowering intracellular ROS, ethylene levels and maintaining shoot epiphytic community; hence, higher pollutant removal. However, plant-epiphyte interactions could not provide enough IAA to confer protection against formaldehyde stress; thus, increased ROS and ethylene levels, large decrease in shoot epiphytic population and lower pollutant removal although epiphyte contacts with airborne pollutant directly (has greater access to gaseous formaldehyde). Endophyte-inoculated plant synthesized more tryptophan as a signaling molecule for its associated bacteria to produce IAA compared to the epiphyte-inoculated one. Under stress, PGP endophyte interacts with its host closely; thus, better protection against stress and higher pollutant removal compared to epiphyte which has limited interactions with the host plant; hence, lower pollutant removal. PMID- 27987474 TI - Temperature and CO2 dependency of the photosynthetic photon flux density responses of leaves of Vitis vinifera cvs. Chardonnay and Merlot grown in a hot climate. AB - Comparisons of the photosynthetic responses to light and temperature between related cultivars are important to understand how well matched they are to the climate where they are grown. Photosynthetic light responses at a range of leaf temperatures and two CO2 concentrations were measured on leaves of two grapevine cultivars (Vitis vinifera L.) Chardonnay and Merlot vines growing in field conditions. The objective was to assess the interaction between photon flux density (PFD), leaf temperature and CO2 on photosynthesis and to compare the two cultivars. Merlot leaves maintained higher light-saturated rates of photosynthesis at all leaf temperatures compared with the Chardonnay leaves. At low temperatures, a reduced photon yield offset with a high stomatal conductance accounted for the low rates of the Chardonnay leaves. At moderate to high temperatures, photon yields, PFDs at light saturation and stomatal conductances did not account for differences between Merlot and Chardonnay leaves. At elevated CO2 (800 MUmol mol-1) concentrations, the differences in photosynthetic performance between the cultivars were enhanced, with 30% higher light saturated rates for Merlot compared with Chardonnay leaves. Merlot berries accumulated more sugar, consistent with published data. These results demonstrate Chardonnay, unlike Merlot, appeared to be poorly matched to the hot climate. However, considering the current market and political trends, low alcoholic wines (and, thus, low sugar grapes) should be preferred. Especially in hot climates, it is always hard to obtain such kind of wines and, thus, the most interesting agronomical challenge, especially for Chardonnay vines could be interpreted in an opposite way. PMID- 27987475 TI - Marijuana practices and patterns of use among young adult medical marijuana patients and non-patient marijuana users. AB - BACKGROUND: Little is known about young adult medical marijuana patients (MMP) and their marijuana using patterns and practices, which includes frequency of use, sourcing of marijuana products, forms/modes of administration, and patterns of illicit/prescription drug misuse, compared to non-patient marijuana users (NPU). METHODS: Young adults (N=366) aged 18-26 years old were sampled in Los Angeles in 2014-15 and segmented into NPU (n=156), marijuana users who never had a medical marijuana (MM) recommendation, and MMP (n=210), marijuana users with a current, verified MM recommendation. Differences regarding self-reported marijuana and other drug use during the past 90days are expressed as unadjusted risk ratios or differences in means. RESULTS: MMP reported significantly greater mean days of use (76.4 vs. 59.2, p<0.001) and mean dollars spent on marijuana products (564.5 vs. 266.9, p<0.001) than NPU. Approximately one-quarter (22.6%) of both MMP and NPU report selling marijuana obtained from a dispensary to someone else in the past 90days. MMP were more likely to report vaporization modalities for concentrates (URR=1.5, 95% C.I.=1.2, 2.0) and for marijuana (URR=1.5, 95% C.I.=1.1, 2.1) than NPU. Though not significant, trends toward lower misuse of prescription drugs in the past 90days were observed among MMP compared to NPU. CONCLUSION: MMP reported greater access to marijuana via dispensaries, more frequent and intensive use of marijuana, and greater use of non-combustible forms of marijuana compared to NPU. MMP reported less recent misuse of prescription drugs compared to NPU. PMID- 27987476 TI - Mortality and virological failure among HIV-infected people who inject drugs on antiretroviral treatment in China: An observational cohort study. AB - OBJECTIVE: HIV-infected people who inject drugs (PWID) have a disproportionally low rate of access to antiretroviral therapy (ART). We aimed to assess the impact of ART on 12-month mortality and virological failure of HIV-infected PWID in China, stratified by methadone maintenance treatment (MMT) and active drug use status. METHODS: HIV-infected PWID who initiated ART at 29 clinics in 2011 were enrolled and followed in this prospective cohort study. Kaplan-Meier curves and log-rank tests were used to compare the survival probability. Risk factors for mortality and virological failure were evaluated by Cox proportional hazards models and logistic regression analyses. RESULTS: A total of 1,633 participants initiated ART. At the time of initiation, 324 were on MMT, 625 were engaged in active drug use, and 684 had discontinued drug use but were not on MMT. At the 12 month follow-up, 80.3% remained on ART, 13.5% had discontinued ART, and 6.2% had died. Among the MMT group, active drug use group, and drug abstinent group, we observed all-cause mortality of 4.9%, 12.0%, and 1.5% and virological suppression of 51.9%, 41.1%, and 68.7%, respectively. Factors associated with both mortality and virological failure were drug use status, unemployment, and treatment facility type. CONCLUSION: For HIV-infected PWID receiving ART, engagement in MMT and discontinuation of drug use were more likely to be associated with lower mortality and virological failure compared with active drug use. In order to maximize the clinical impact of ART, HIV treatment programs in China should be further integrated with MMT and social services. PMID- 27987477 TI - Individual and family factors associated with self-esteem in young people with epilepsy: A multiple mediation analysis. AB - OBJECTIVE: As young people experience added demands from living with epilepsy, which may lead to poor psychosocial adjustment, it is essential to examine mechanisms of change to provide practitioners with knowledge to develop effective interventions. The aim of this study was to examine individual and family-level factors - stress and illness perceptions, coping behaviors and family resilience that promote or maintain young people's self-esteem. METHODS: From November 2013 to August 2014, young people attending a neurology clinic in KK Women's and Children's Hospital, Singapore, participated in a cross-sectional survey (n=152; 13-16years old). Multiple mediation analyses were conducted to evaluate whether these variables mediated the relationship between illness severity (i.e., low, moderate, high) and self-esteem. RESULTS: Multiple mediation analyses demonstrated that illness severity had a direct effect on young people's self esteem. Compared to those with moderate illness severity (reference group), young people with low severity had significantly higher self-esteem (c=3.42, p<0.05); while those with high severity had a more negative view of themselves (c=-3.93, p<0.001). Illness severity also had an indirect influence on self-esteem through its effects on mediators, such as perceived stress, illness perceptions and family resilience (D1: Total ab=3.46, 95% CI 1.13, 5.71; D2: Total ab=-2.80, 95% CI -4.35, -1.30). However, young people's coping levels did not predict their self-esteem, when accounting for the effects of other variables. SIGNIFICANCE: The continued presence of seizure occurrences is likely to place greater demands on young people and their families: in turn, increased stress and negative illness perceptions negatively affected family processes that promote resilience. As the mediating effect of these modifiable factors were above and beyond the contributions of illness characteristics and young people's levels of coping, this has implications for developing individual and family interventions aimed to support young people living with epilepsy. PMID- 27987478 TI - Relevance of focal osseous uptake on FDG PET with or without CT changes in oncology patients. AB - OBJECTIVE: To assess significance of focal FDG uptake in osseous structures, with and without CT correlate, in patients undergoing FDG PET/CT for oncological indications. METHODS: 57 patients with focally increased FDG activity in bones and a definite follow up were included. RESULTS: 85.2% of lesions without changes were found to be malignant. Sensitivity and PPV of a CT correlate in metastatic lesions was expectedly high, 62.9% and 86.7% respectively, however, the NPV was only 14.8%. CONCLUSION: Osseous foci are valuable in predicting metastatic disease even in the absence of low dose CT correlate. PMID- 27987479 TI - A convenient method for determination of quizalofop-p-ethyl based on the fluorescence quenching of eosin Y in the presence of Pd(II). AB - A convenient fluorescence quenching method for determination of Quizalofop-p ethyl(Qpe) was proposed in this paper. Eosin Y(EY) is a red dye with strong green fluorescence (lambdaex/lambdaem=519/540nm). The interaction between EY, Pd(II) and Qpe was investigated by fluorescence spectroscopy, resonance Rayleigh scattering(RRS) and UV-Vis absorption. Based on changes in spectrum, Pd(II) associated with Qpe giving a positively charged chelate firstly, then reacted with EY through electrostatic and hydrophobic interaction formed ternary chelate could be demonstrated. Under optimum conditions, the fluorescence intensity of EY could be quenched by Qpe in the presence of Pd(II) and the RRS intensity had a remarkable enhancement, which was directly proportional to the Qpe concentration within a certain concentration range, respectively. Based on the fluorescence quenching of EY-Pd(II) system by Qpe, a novel, convenient and specific method for Qpe determination was developed. To our knowledge, this is the first fluorescence method for determination of Qpe was reported. The detection limit for Qpe was 20.3ng/mL and the quantitative determination range was 0.04-1.0MUg/mL. The method was highly sensitive and had larger detection range compared to other methods. The influence of coexisting substances was investigated with good anti interference ability. The new analytical method has been applied to determine of Qpe in real samples with satisfactory results. PMID- 27987480 TI - Quantification of cell-free DNA in blood plasma and DNA damage degree in lymphocytes to evaluate dysregulation of apoptosis in schizophrenia patients. AB - Oxidative DNA damage has been proposed as one of the causes of schizophrenia (SZ), and post mortem data indicate a dysregulation of apoptosis in SZ patients. To evaluate apoptosis in vivo we quantified the concentration of plasma cell-free DNA (cfDNA index, determined using fluorescence), the levels of 8-oxodG in cfDNA (immunoassay) and lymphocytes (FL1-8-oxodG index, flow cytometry) of male patients with acute psychotic disorders: paranoid SZ (total N = 58), schizophreniform (N = 11) and alcohol-induced (N = 14) psychotic disorder, and 30 healthy males. CfDNA in SZ (N = 58) does not change compared with controls. In SZ patients. Elevated levels of 8-oxodG were found in cfDNA (N = 58) and lymphocytes (n = 45). The main sources of cfDNA are dying cells with oxidized DNA. Thus, the cfDNA/FL1-8-oxodG ratio shows the level of apoptosis in damaged cells. Two subgroups were identified among the SZ patients (n = 45). For SZ-1 (31%) and SZ-2 (69%) median values of cfDNA/FL1-8-oxodG index are related as 1:6 (p < 0.0000001). For the patients with other psychotic disorders and healthy controls, cfDNA/FL1-8-oxodG values were within the range of the values in SZ-2. Thus, apoptosis is impaired in approximately one-third of SZ patients. This leads to an increase in the number of cells with damaged DNA in the patient's body tissues and may be a contributing cause of acute psychotic disorder. PMID- 27987481 TI - Dietary taurine supplementation ameliorates the lethal effect of phenanthrene but not the bioaccumulation in a marine teleost, red sea bream, Pagrus major. AB - The present study was performed to evaluate the effect of dietary taurine on the hepatic metabolic profiles of red sea bream (Pagrus major) and on phenanthrene (a polyaromatic hydrocarbon) toxicity and bioaccumulation. The fish were fed a diet supplemented with 0% (TAU0%), 0.5% (TAU0.5%), or 5% (TAU5%) taurine for 40-55d and subjected to phenanthrene acute toxicity and bioaccumulation tests. Taurine deficiency in feed severely affected the hepatic metabolic profiles of fish, which indicated a complementary physiological response to taurine deficiency. For the acute toxicity test, fish were fed the test diets for 55d and were then exposed to 0-893ug/L phenanthrene for 96h. Tolerance to phenanthrene was significantly improved by 0.5% of taurine inclusion in feed relative to TAU0%, but not by 5.0% inclusion. Reduced glutathione in the liver, which acts as an oxygen-free radical scavenger, was associated with a reduction in the toxicity of phenanthrene. For the bioaccumulation test, fish were fed the test diets for 40d and were thereafter chronically exposed to 20ug/L phenanthrene for 13d followed by depuration for 3d. The activity of hepatic biomarker, ethoxyresorufin-O deethylase, was increased by phenanthrene exposure in the taurine inclusion groups. However, phenanthrene concentrations in the liver and muscle of fish fed TAU5.0% tended to be higher than those of fish fed TAU0% and TAU0.5% during the exposure period. These results indicate that 0.5% of taurine inclusion in feed plays an important role in the alleviation of phenanthrene toxicity but not bioaccumulation. Furthermore, larger amount of taurine inclusion (TAU5%) did not show marked beneficial effects against phenanthrene exposure. This study provides insight about a major concern of environmental contaminants into aquatic environment and can be effectively used for improvement of aquaculture. PMID- 27987482 TI - Profiles of lead in urban dust and the effect of the distance to multi-industry in an old heavy industry city in China. AB - Lead (Pb) concentration in urban dust is often higher than background concentrations and can result in a wide range of health risks to local communities. To understand Pb distribution in urban dust and how multi-industrial activity affects Pb concentration, 21 sampling sites within the heavy industry city of Jilin, China, were analyzed for Pb concentration. Pb concentrations of all 21 urban dust samples from the Jilin City Center were higher than the background concentration for soil in Jilin Province. The analyses show that distance to industry is an important parameter determining health risks associated with Pb in urban dust. The Pb concentration showed an exponential decrease, with increasing distance from industry. Both maximum likelihood estimation and Bayesian analysis were used to estimate the exponential relationship between Pb concentration and distance to multi-industry areas. We found that Bayesian analysis was a better method with less uncertainty for estimating Pb dust concentrations based on their distance to multi-industry, and this approach is recommended for further study. PMID- 27987483 TI - The diagnostic utility of sonographic carotid flow time in determining volume responsiveness. AB - OBJECTIVE: We aimed to predict volume responsiveness and to assess the diagnostic accuracy of carotid flow time (FTc) with the change in hydration status before and after a passive leg raise (PLR) maneuver. METHODS: Participants who presented at a community health fair in a dehydrated state following a prolonged fast while observing the month of Ramadan were recruited. Sonographic FTc measurements were obtained in the semi-Fowler position and after a PLR maneuver while participants were in a fasting state and repeated approximately 3 hours after breaking their fast. RESULTS: In total, 123 participants with mean age of 47+/-14 years, 55% male, were enrolled. Participants had fasted for an average of 16.9 hours and consumed an average of 933 mL between the 2 ultrasound measurements. Mean FTc values were significantly lower in the fasting state compared with the nonfasting state (312+/-22 vs 345+/-25milliseconds, P value < .001). Relative increases in FTc following a PLR maneuver demonstrated strong discrimination of volume status (area under the receiver operating curve: 0.86 [95% confidence interval, 0.81 0.91]). CONCLUSIONS: The use of point-of-care ultrasound to measure FTc may provide a noninvasive alternative to determine fluid status. Percentage change in FTc of >=5% provides a reliable diagnostic accuracy for predicting fluid status. PMID- 27987484 TI - Social relationships in young adults at ultra high risk for psychosis. AB - Studies suggest that individuals with schizophrenia have smaller social networks and less satisfying relationships. However, much is still unknown about the typical quantity and quality of social relationships in young adults during the ultra high-risk (UHR) period. Investigating these relationships holds significant importance for improving understanding of etiological processes, mapping the social environment, and highlighting treatment targets in a critical period. A total of 85 participants (44 UHR and 41 healthy controls) completed measures examining the participants' social relationships, social support, and loneliness. Mean differences between the UHR and healthy control participants and associations between social relationships and symptoms and functioning were examined. Results indicated significant differences between groups on several indices. Specifically, the UHR youth reported fewer close friends, less diverse social networks, less perceived social support, poorer relationship quality with family and friends, and more loneliness. Notably, within the UHR group, being lonely and having fewer and worse quality relationships was associated with greater symptom severity and lower overall functioning. This study suggests that youth at high-risk of developing psychosis have fewer and poorer quality social relationships. Interventions that focus on increasing the quantity and quality of young adults' social networks may be beneficial for this population. PMID- 27987486 TI - Piperlongumine derived cyclic sulfonamides (sultams): Synthesis and in vitro exploration for therapeutic potential against HeLa cancer cell lines. AB - A novel modification of piperlongumine is designed, bearing a cyclic sulphonamide (sultam) and its synthesis is described. For the first time herein we report the synthesis and biological evaluation of the natural product derived cyclic sulfonamides using Grubbs second generation catalyst (Grubbs II) via ring closing metathesis approach. Synthesis of a series of piperlongumine derived sultams is done in a moderate to good yield using Wittig reaction, Ring-Closing Metathesis (RCM) and, amide synthesis by using mixed anhydride, approach. All synthesized compounds were evaluated for anticancer activity and some demonstrated dose dependent reduction in HeLa cell growth. Of these 7, 10 and 14 significantly reduced the cell growth. Consequently their calculated GI50 values were found to be 0.1 or <0.1 MUM. PMID- 27987485 TI - Design, synthesis, docking and QSAR study of substituted benzimidazole linked oxadiazole as cytotoxic agents, EGFR and erbB2 receptor inhibitors. AB - The synthesis of benzimidazole linked oxadiazole derivatives designed as potential EGFR and erbB2 receptor inhibitors with anticancer and apoptotic activity were studied. Compounds 7a specifically inhibit EGFR and erbB2 receptor at 0.081 and 0.098 MUM concentration. Some of the compounds showed strong, broad spectrum antiproliferative activitiy when tested against five human cancer cell lines. Compounds 7a and 7n were more cytotoxic than 5-fluorouracil against MCF-7 cancer cell, with IC50 values of 5.0 and 2.55 MUM whereas, only 7a led to cell cycle arrest at G2/M phase accompanied by an increase in apoptosis. Compounds 7a and 7n showed normal architecture of myofibrils in cardiomyopathy study whereas only compound 7a showed nearly equal biochemical parameters (SGOT and SGPT) when compared to control. Molecular docking & 3D-QSAR studies were used to establish interactions of 7a and 7n within the active site of enzyme for ATP binding site of kinase domain. PMID- 27987487 TI - A rapid method for sensitive profiling of folates from plant leaf by ultra performance liquid chromatography coupled to tandem quadrupole mass spectrometer. AB - Previous published methods for the analysis of folates are time consuming because of lengthy sample extraction, clean-up and total running time. This study details the development and validation of a rapid, sensitive and robust method that combines a simple extraction step with ultra-performance liquid chromatography coupled to tandem quadrupole mass spectrometry. Here, we reported application of a tandem quadrupole mass spectrometer to analyze maximum seven vitamers of folate from plant origin. The analytical performance was evaluated by linearity, sensitivity, precision, recovery test and analysis of certified reference materials. The limit of detection and limit of quantification ranged between 0.003 and 0.021MUg/100g FW and between 0.011 and 0.041MUg/100g FW, respectively; the recovery and precession ranged from 71.27 to 99. 01% and from 1.7 to 7.8% RSD, respectively, depending upon folate vitamers. This newly developed and validated method is rapid (a chromatographic run time of 5min), easy to be performed (no laborious and time consuming clean-up) and can be used to simultaneously analyze seven vitamers of folate from plant sources. PMID- 27987488 TI - Comparison of different mass spectrometric approaches coupled to gas chromatography for the analysis of organochlorine pesticides in serum samples. AB - Gas chromatography-triple quadrupole mass spectrometry (GC-QqQMS) was applied for the determination of eight organochlorine pesticides (OCPs) in human serum. OCPs were extracted from the serum sample by solid phase extraction (SPE) and analyzed by gas chromatography mass spectrometry (GC-MS) or gas chromatography tandem mass spectrometry (GC-MS/MS). Electron ionization (EI) and negative chemical ionization (NCI) under two data acquisition modes, namely selected ion monitoring (SIM) and multiple reaction monitoring (MRM), were compared. The use of MRM generally provided higher selectivity and sensitivity because less interference from the sample matrix existed. The EI mode is more suitable for less electronegative compounds such as dichlorodiphenyldichloroethanes (DDDs) with detection limits ranging from 0.0060 to 0.060ng/mL. In the NCI mode, MRM analysis provided good and lower detection limits (0.0011-0.0030ng/mL) for pesticides containing more chlorines. The methods were validated by analyzing the pesticides in spiked serum at different levels with recoveries ranged from 83% to 116% and relative standard deviations of less than 10%. The developed method was applied for the determination of the OCPs in real human serum samples. PMID- 27987489 TI - Enrichment and separation of quercetin-3-O-beta-d-glucuronide from lotus leaves (nelumbo nucifera gaertn.) and evaluation of its anti-inflammatory effect. AB - This work aimed to establish a systematic strategy to enrich and separate quercetin-3-O-beta-d-glucuronide (Q3GA) from lotus leaves with macroporous resin and semi-preparative HPLC. Six resins were tested, and LX-5 was chosen as the appropriate resin for Q3GA based on the adsorption and desorption performances. After one-step enrichment, the content of Q3GA increased from 2.15% in crude extract to 52.25% in 30% ethanol fraction with yield of 11.97%. The Q3GA was then isolated from the 30% ethanol fraction by semi-preparative HPLC, and the purity of Q3GA was above 98.00% with yield of 19.76%. These results suggested that the aforementioned strategy was a useful and economic method to enrich and separate Q3GA from lotus leaves. Additionally, the anti-inflammatory effect of Q3GA was evaluated in lipopolysaccharide-treated RAW264.7 macrophages, and the result demonstrated that Q3GA could significantly inhibit LPS-induced NO release in vitro in a dose-dependent manner compared with control group. PMID- 27987490 TI - Revisiting the relationship between wages and sleep duration: The role of insomnia. AB - This paper uses the 2005 and 2010 Canadian General Social Surveys (Time Use) to investigate the effect of wages on the sleep duration of individuals in the labour force. The endogeneity of wages is taken into account with an instrumental variables approach; we find that the wage rate affects sleeping time in general, corroborating Biddle and Hamermesh's (1990) main conclusion. A ten percent increase in the wage rate leads to an 11-12min decrease in sleep per week. But this number masks several effects. The responsiveness of sleep time to wage rate changes depends upon the sex of the individual, whether or not sleep problems are present and general economic conditions. By far the largest adjustment is found for insomniacs in 2010, a year of general economic downturn in Canada. We also investigate the non-randomness of insomnia in the population by using a Heckman procedure, and find that the sleep time of female non-insomniacs is even more responsive to wage rate changes once account is taken of this selection bias, but otherwise selection was not a problem in our samples. PMID- 27987491 TI - The intergenerational transmission of body mass index across countries. AB - There is a worldwide epidemic of obesity. We are just beginning to understand its consequences for child obesity. This paper addresses one important component of the crisis; namely the extent to which adiposity, or more specifically, BMI, is passed down from one generation to the next. We find that the intergenerational elasticity of BMI is very similar across countries and relatively constant - at 0.2 per parent. Our substantive finding is that this elasticity is very comparable across time and countries - even if these countries are at very different stages of economic development. Quantile analysis suggests that this intergenerational transmission mechanism is substantively different across the distribution of children's BMI; more than double for the most obese children what it is for the thinnest children. These findings have important consequences for the health of the world's children.1. PMID- 27987492 TI - [Significance and diagnostic value of synovial fluid anti-cyclic citrullinated peptide antibody and anti-mutated citrullinated vimentin antibodies in patients with serum negative rheumatoid arthritis]. AB - OBJECTIVE: To explore the significance of synovial fluid (SF) anti-cyclic citrullinated peptide (CCP) antibodies and anti-mutated citrullinated vimentin (MCV) antibodies in the diagnosis of serum negative rheumatoid arthritis (SNRA). METHODS: Enzyme linked immunosorbent assay (ELISA) method was apllied in the detection of two groups of patients with knee joint fluid resistance against CCP antibody and antibody of MCV, the experimental group to SNRA patients, a total of 29 cases, and the control for patients with osteoarthritis (OA), a total of 28 cases, and clinical manifestations and laboratory parameters of the two groups were collected. RESULTS: The positive rate of synovial fluid anti-CCP was 34.5% in the SNRA patients, which was significantly higher than 10.7% in the control patients(chi2=4.571, P<0.05). The positive rate of synovial fluid anti-MCV was 20.7% in the SNRA patients, which was significantly higher than 7.1% in the control patients(chi2=2.167, P>0.05). The SNRA patients of SF anti-CCP and anti MCV positive had no significant difference from the SNRA patients of SF anti-CCP and anti-MCV negative in age, course and morning stiffness. The levels of erythrocyte sedimentation rate (ESR), C-reactive protein(CRP) and DAS28 scores in the SF anti-CCP positive patients were higher than those of the SF anti-CCP negative patients. The levels of ESR, CRP and DAS28 scores in the SF anti-MCV positive patients were higher than those of the SF anti-MCV negative patients, (all P<0.01). SF anti-CCP had correlation with ESR, CRP(r=0.567, P<0.01; r=0.664, P<0.01). SF anti-MCV had correlation with ESR, CRP (r=0.344, P<0.01; r=0.749, P<0.01). CONCLUSION: SF anti-CCP and anti-MCV are helpful for the diagnosis of SNRA and judgement of SNRA activity. PMID- 27987493 TI - [Significance of antibodies to the citrullinated glucose-6-phosphate isomerase peptides in rheumatoid arthritis]. AB - OBJECTIVE: To detect the anti-citrullinated glucose-6-phosphate isomerase (GPI) 70-88 peptide antibody (anti-C-GPI(70-88) antibody), anti-citrullinated GPI 435 453 peptide antibody (anti-C-GPI(435-453) antibody), anti-GPI 70-88 peptide antibody (anti-GPI(70-88) antibody) and anti-GPI 435-453 peptide antibody(anti GPI(435-453) antibody) in the serum of rheumatoid arthritis (RA) patients, and examine the diagnostic values of the anti-C-GPI peptide antibodies in RA. METHODS: The anti-C-GPI(70-88) antibody, anti-C-GPI(435-453) antibody, anti GPI(70-88) antibody and anti-GPI(435-453) antibody were detected by enzyme-linked immunosorbent assay (ELISA) in 191 RA patients, 129 other rheumatic diseases and 74 healthy controls. The clinical and laboratory data of the patients with RA were collected, and the values of anti-C-GPI peptide antibodies in the diagnosis of RA and the relationships of anti-C-GPI peptide antibodies with the clinical and laboratory parameters analyzed. RESULTS: (1) The mean titers of the anti-C GPI(70-88) antibody and the anti-C-GPI(435-453) antibody in the RA patients (respectively, 68.71 +/- 4.20 and 51.78 +/- 3.13) were significantly higher than those with other rheumatic diseases and healthy individuals (P <0.05). However, the mean titers of the anti-GPI(70-88) antibody and anti-GPI(435-453) antibody in the RA patients were similar to those with other rheumatic diseases and healthy individuals. (2) The diagnostic sensitivity and specificity of the anti-C-GPI(70-88) antibody for RA were 41.88% and 84.50% respectively; and the diagnostic sensitivity and specificity of the anti-C-GPI(435-453) antibody for RA were 46.05% and 86.05% respectively. The sensitivity of combined detection of the two anti-C-GPI peptide antibodies was 50.79%, and the specificity was 81.40%. (3) The positive rates of the anti-C-GPI(70-88) antibody and the anti-C-GPI(435-453) antibody were 35% and 45% respectively in those patients with negative anti cyclic citrullinated peptide antibody, anti-keratin antibody, and rheumatoid factor. (4) There was no significant difference in clinical and laboratory indicators between the anti-C-GPI(70-88) antibody or anti-C-GPI(435-453) antibody positive group and negative group. CONCLUSION: The anti-C-GPI(70-88) antibody and anti-C-GPI(435-453) antibody can be detected in the serum of RA patients, and C GPI may be involved in the pathogenesis of RA. There is a certain diagnostic significance for the sera-negative RA. PMID- 27987494 TI - [Significance of glucose-6-phosphate isomerase assay in early diagnosis of rheumatoid arthritis]. AB - OBJECTIVE: To explore the titer of glucose-6-phosphate isomerase (GPI) for early diagnosis of the outpatient with rheumatoid arthritis (RA) in real life, and to analyze its relationship with disease activity. METHODS: In the study, 1 051 patients with arthritis were collected in the group who had joints tender and swelling, and 90 cases of healthy people as a control group. ELISA method was used to detect the serum level of GPI, and according to clinical features and laboratory test, all the patients including 525 RA patients, the other patients including osteoarthritis (OA), 134 cases of seronegative spine joint disease (SpA), 104 cases of systemic lupus erythematosus (SLE), 31 cases of primary Sjogren syndrome (pSS), 24 cases of gout arthritis (GA), 22 cases of other connective tissue diseases (including polymyalgia rheumatica, dermatomyositis, systemic sclerosis, adult Still disease) and 46 cases of other diseases (including 165 cases of osteoporosis, avascular necrosis of the femoral head, traumatic osteomyelitis, bone and joint disease, juvenile rheumatoid arthritis, tumor). The diagnostic values of GPI were assessed, and the differences between the GPI positive and negative groups of the RA patients in clinical characteristics, disease activity, severity and inflammatory index analyzed. RESULTS: The positive rate of serum GPI in the patients with RA was 55.4%, contrasting to other autoimmune diseases (14.3%) and healthy controls (7.78%)(P<0.001). Compared with the OA and SpA patients, the RA group was increased more significantly, and the difference was statistically significant (P<0.001). The diagnostic value of GPI alone for RA was 0.39 mg/L, the sensitivity was 54.2%, and specificity was 87.3%. The positive rate of GPI in RF negative patients was 36.1%; the positive rate of GPI in anti-CCP antibody negative patients was 34.2%; the positive rate of GPI in RF and anti-CCP antibody negative patients was 24.1%. The level of GPI had positive correlation (P<0.05) with ESR, RF, anti-CCP antibody and HRF-IgG. CONCLUSION: GPI is sensitive in the patients with RA; GPI positive is important in the diagnosis of RA with anti-CCP antibody and/or RF negative patients. The titer of GPI is related with disease activity of RA. PMID- 27987495 TI - [Significance of v-raf murine sarcoma viral oncogene homologue B1 in rheumatoid arthritis]. AB - OBJECTIVE: To detect serum v-raf murine sarcoma viral oncogene homologue B1 (BRAF) protein levels and to investigate their clinical significance in rheumatoid arthritis (RA) patients. METHODS: Serum samples were obtained from 78 RA patients, 32 osteoarthritis (OA) patients, 16 systemic lupus erythematosus (SLE) patients, 16 gout patients, 16 ankylosing spondylitis (AS) patients, 16 Sjogren syndrome (SS) patients and 30 healthy controls. BRAF protein in the sera was examined by enzyme-linked immunosorbent assay (ELISA). The associations between BRAF levels and the clinical features including age, sex, disease duration, swelling joints, tenderness joints, duration of moning stiffness, joint deformity, visual assessment scale (VAS) and extra articular manifestations and laboratory parameters including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), disease activity score in 28 joints (DAS28), anti-cyclic citrullinated peptide (CCP) antibody, antikeratin antibody, antnuclear antibody (ANA), immunoglobulin and cytokines, such as TNF-alpha, IL 1beta, IL-6 and IL-17A in RA patients were evaluated. Data analyses were performed by using SPSS 19.0 program. RESULTS: The serum BRAF protein levels in the RA patients were significantly higher than those of other rheumatic diseases groups including OA, SLE, AS, SS, gout patients and healthy controls, the P value was 0.002, <0.001, <0.001, <0.001, 0.001 and <0.001 respectively. The level of serum BRAF protein in the RA patients showed a positive correlation with the rheumatoid factor (P=0.009) and IgA levels (P=0.006), but no correlation with clinical features, such as age and duration or other laboratory parameters, including CRP, ESR, anti-CCP antibody, IgM, IgG, TNF-alpha, IL-1beta, IL-6 and IL 17A. The RA patients were further divided into normal levels of BRAF protein group and elevated levels of BRAF protein group. Compared with the clinical features and laboratory indexes of normal and elevated levels of BRAF protein groups in the RA patients, there was no significant difference between the two groups in age, duration, DAS28, CRP, ESR, RF, anti-CCP, IgA, IgG, IgM, TNF-alpha or IL-6. CONCLUSION: The elevated level of BRAF protein in the RA patients showed that BRAF might play a role in the pathogenesis of RA. Further researches on BRAF gene expression may help to clarify the role of BRAF in RA. PMID- 27987496 TI - [Detection of peripheral follicular helper T cells in rheumatoid arthritis]. AB - OBJECTIVE: To detect cell frequency and surface markers of peripheral CD4+CXCR5+ follicular helper T (Tfh) cells and analyze the correlation between CD4+CXCR5+Tfh cells and rheumatoid arthritis (RA) disease activity. METHODS: Forty RA patients meeting the American College of Rheumatology classification criteria for RA and twenty healthy controls (HC) were included. The peripheral blood mononuclear cells and sera were collected. The expressions of CD4+CXCR5+Tfh cells (CXCR5, C-X C chemokine receptor type 5) and inducible T cell costimulator (ICOS), programmed death 1 positive (PD-1), interleukin-21 receptor (IL-21R) and CD40 ligand (CD40L) positive on CD4+CXCR5+Tfh cells were analyzed by flow cytometry. The transcript levels of B-cell lymphoma 6 (Bcl-6), as well as IL-21 and IL-21R, were measured by real-time polymerase chain reaction. Besides, serum IL-21 and CXCL13 concentrations were determined by enzyme-linked immunosorbent assay. The potential association between Tfh cells and RA disease activity was detected. RESULTS: The cell surface marker of CXCR5+ on CD4+ cells was significantly increasingly higher across the following groups versus HC: total RA patients (16.75+/-3.92 vs.7.49+/-1.84, P<0.001); RA patients with low disease activity or remission (16.62+/-3.43 vs. 7.49+/-1.84, P<0.001); RA patients with moderate disease activity (16.82+/-3.07 vs. 7.49+/-1.84, P<0.001) and RA patients with high disease activity (16.87+/-5.50 vs. 7.49+/-1.84, P<0.001). Besides, the percentages of ICOS+, PD-1+, IL-21R+ on CD4+CXCR5+Tfh cells in the RA patients were significantly higher than that of HC (ICOS+CD4+CXCR5+cells, 8.37+/-4.28 vs. 3.72+/-1.81, P<0.001; PD-1+CD4+CXCR5+cells, 1.57+/-1.10 vs. 0.24+/-0.30, P=0.035; IL-21R+CD4+CXCR5+ cells, 4.60 +/-4.05 vs. 0.20+/-0.19, P=0.006). But the percentage of CD40L+ on CXCR5+CD4+Tfh cells in the RA patients was not significantly higher than that of HC (3.38+/-3.71 vs. 0.54+/-0.34, P=0.135). The IL-21R mRNA expression was elevated significantly (5.00+/-4.94 vs. 0.74+/-0.55, P<0.001) in the RA patients but not in Bcl-6 mRNA[4.54(3.33, 7.23) vs. 5.31(2.81, 7.44), P=0.329]or IL-21 mRAN[0.72(0.26, 3.45) vs. 0.56(0.27, 3.71), P=0.195]. Additionally, the serum interleukin-21 (IL-21) and CXCL13 levels in the RA patients were higher than in the healthy controls [IL-21, (200.49+/-154.56) ng/L vs. (8.21+/-5.95) ng/L, P<0.001; CXCL13, (93.72+/-49.72) ng/L vs. (43.09+/-1.28) ng/L, P<0.001] and were both positively correlated with RA disease activity indexes, including erythrocyte sedimentation rate, the disease activity score in 28 joints (ESR-based or CRP-based), clinical disease activity index, and simplified disease activity index. However, none of the Tfh cells, anti citrullinated protein antibody or rheumatoid factor had any relationship with RA disease activity. CONCLUSION: Peripheral Tfh cells and their relevant cytokines are higher in RA patients than healthy controls, indicating Tfh cells may participate in the pathogenesis of RA, therefore, blocking the pathway of Tfh cells may be reasonable cellular targets for therapeutic intervention. PMID- 27987497 TI - [Significance of different T follicular helper subsets in rheumatoid arthritis]. AB - OBJECTIVE: To detect the expressions of T follicular helper (Tfh) subsets and T follicular helper effect memory (Tfhem) cells in circulation of patients with rheumatoid arthritis (RA), as well as to examine their roles in providing biomarkers for active RA. METHODS: This study enrolled 41 patients with RA, who were navely-treated or had no application of hormone and disease-modifying anti rheumatic drugs in recent 3 months, as well as 32 healthy controls. The percentages of Tfhem (CD4+CXCR5+CCR7lowPD1high) cells, Tfh (CD3+CD4+CXCR5+CD45RA ) subsets, Tfh1 (CXCR3+CCR6-Tfh),Tfh2 (CXCR3-CCR6-Tfh),and Tfh17 (CXCR3 CCR6+Tfh), were determined by flow cytometry of peripheral blood from the patients with RA and health controls. Serum levels of cytokines were detected by enzyme-linked immunosorbent (ELISA). The correlations of Tfhem/Tfh subsets with clinical indicators were analyzed. RESULTS: The mean age of the patients was (56.1+/-14.0) years (range: 20-82 years), the mean disease duration was (8.2+/ 8.1) years. There was no significant difference between the RA patients and the health controls with age and gender. As compared with the health control, the percentage of Tfhem was significantly increased in the peripheral blood of the RA patients (12.8%+/-5.7% vs. 8.7%+/-2.0%, P=0.001). Moreover, the increased Tfhem was correlated with the higher disease activity score in 28 joints (DAS28) and erythrocyte sedimentation rate (ESR), but not with other clinical indicators, such as C-reactive protein (CRP), anti-cyclic citrullinated peptide (CCP) antibodies, and rheumatoid factors (RF). In addition, the percentage of Tfh2 subset, but not Tfh1 or Tfh17, was significantly increased in the RA patients (3.002%+/-0.408% vs. 1.730%+/-0.160%, P=0.013). As compared with Tfh2-low group, serum levels of Ig (immunoglobulin) A [(3.045+/-0.261) g/L vs.(3.963+/-0.815) g/L, P=0.172], IgG [(13.800+/-0.862) g/L vs.(16.980+/-0.224) g/L, P=0.161], IgM [(1.135+/-0.083) g/L vs.(1.731+/-0.380) g/L, P=0.140], IL (interleukin)-4 [(2.322+/-0.214) ng/L vs.(3.994+/-0.751) ng/L, P=0.056] and IL-10[(1.898+/-0.105) ng/L vs. (3.125+/-0.880) ng/L, P=0.140] in Tfh2-high group tended to increase with no significant statistical difference. CONCLUSION: Our data suggest that Tfhem is associated with disease activity and is a valuable marker for active RA. It also presents a potential pathogenesis in the development of RA and the target for future therapies. Meanwhile, the increased Tfh2 and associated cytokines might be involved in the development of RA. PMID- 27987499 TI - [Therapeutic effect of adipose tissue-derived stem cells on bleomycin-induced mice of scleroderma]. AB - OBJECTIVE: To investigate the effects and mechanisms of adipose-derived stem cells (ADSCs) on bleomycin-induced mice of scleroderma. METHODS: In the study, 24 C57BL/6J female mice were randomly divided into control group, bleomycin(BLM)group, ADSCs (hypodermic injection) group and ADSCs (intravenous injection) group . BLM [2 mg/(kg*d)] was injected into the mice to establish the model of scleroderma. There were 6 mice in each group .The control group mice were injected with normal saline 2 mL/(kg*d) by subcutaneously. The rest of the three groups were injected with BLM. ADSCs groups were injected with ADSCs (2*105) subcutaneously and intravenously, respectively. T-helper 17 (Th17) and regulatory T cell (Treg cell) of spleen cells were detected by flow cytometry. The levels of cytokines in the lung tissue and in the serum were detected by real time fluorescence quantification. Real-time polymerase chain reaction(PCR) and enzyme-linked immuno sorbent assay(ELISA). The pathology change of skin and lung tissue was observed by hematoxylin eosin (HE) staining. RESULTS: The proportion of Th17 and Treg increased in BLM group than in control group(15.30%+/-1.29% vs.4.32%+/-0.79%; 9.90%+/-1.95% vs.5.18%+/-1.35%, P<0.05), the expression of Th17 significantly decreased (5.02%+/-0.83%, 6.00%+/-0.82% vs.15.30%+/-1.29%, P<0.05) and the expression of Treg increased after the ADSCs therapy (14.32%+/-1.59%, 11.09%+/-4.31% vs. 9.90%+/-1.95%, P<0.05). The expression levels of IL-17,IL 6,tumor necrosis factor-alpha (TNF-alpha)mRNA in the lung tissue and IL-6 in the serum increased in BLM group than in control group [3.54+/-0.30, 10.65+/-0.66, 5.37+/-0.52 vs. 1.00+/-0.00; (21.2+/-1.74) ng/L vs. (16.87+/-1.09) ng/L, P<0.05]. The expression of these cytokines significant decreased after the ADSCs therapy [1.63+/-0.45,1.50+/-0.29 vs.3.54+/-0.30; 3.11+/-0.85, 2.98+/-0.76 vs.10.65+/ 0.66;1.45+/-0.47, 1.59+/-0.41 vs. 5.37+/-0.52; (17.87+/-1.45) ng/L, (17.61+/ 1.16) ng/L vs. (21.2+/-1.74) ng/L, P<0.05]. But there was no obvious difference between ADSCs (hypodermic injection) group and ADSCs (intravenous injection) group(P>0.05). The expression of TGF-beta in the serum increased in BLM group than in control group[(33.95+/-2.49) ng/L vs. (28.8+/- 2.29) ng/L, P<0.05], however, the expression of TGF-beta mRNA had no significant differences than that of control group (1.17+/-0.11 vs.1.00+/-0.00, P>0.05). The expression of TGF-beta mRNA and protein had no significant differences than that of BLM group [1.25+/ 0.11,1.26+/-0.12 vs.1.17+/-0.11; (31.84+/-2.04) ng/L, (31.25+/-2.36) ng/L vs. (33.95+/-2.49) ng/L, P>0.05]. HE staining showed that the inflammation of lung tissue was relieved and the dermal thickness and collagen deposition were decreased after the ADSCs therapy. CONCLUSION: ADSCs could effectively alleviate inflammation of the lungs and fibrosis of skin; the effects of anti-inflammatory and anti-fibrosis were associated with immune regulating function. PMID- 27987498 TI - [Role of galectin-1 in regulation of umbilical cord mesenchymal stem cells on T cells of rheumatoid arthritis]. AB - OBJECTIVE: The therapeutic potential of umbilical cord mesenchymal stem cells (UC MSCs) in rheumatoid arthritis (RA) has attracted more and more attention, because of it can suppress the various inflammatory effects of T cells. Galectin-1 is highly expressed in UC-MSCs, as the first lectin mediating the immunomodulatory effect of MSCs. Our study will investigate the effects of galectin-1 in regulation of UC-MSCs on rheumatoid arthritis T cells. METHODS: Lentivirus transfected shRNA technique was used to knock down the expression of galectin-1 in UC-MSCs to construct UC-MSCs(Gal-1-). The effects of UC-MSCs and UC-MSCs(Gal-1 ) on CD4+ T cells in RA patients were investigated by contact system, including negative control group (CD4+ T cells), positive control group [CD4+ T-phytohemagg lutinin (PHA)], UC-MSCs-CD4+ T cells co-culture group, UC-MSCs(control shRNA) CD4+ T cells co-culture group, and UC-MSCs(Gal-1-)-CD4+ T cells co-culture group. The proliferation of CD4+ T cells was detected by MTS assay. The level of tumor necrosis factors alpha (TNF-alpha) in cells supernatant was detected by enzyme linked immunosorbent assay (ELISA). The effect of UC-MSCs on helper T cell (Th) subset was detected by flow cytometry. RESULTS: In vitro, UC-MSCs were capable of inhibiting PHA induced proliferation of CD4+ T cells from RA patients, but UC MSCs(Gal-1-) did not show the significant inhibitory effect. Galectin-1 affect the TNF-alpha level of CD4+ T cells regulated by UC-MSCs. UC-MSCs and UC MSCs(control shRNA) significantly inhibited the expression of TNF-alpha in PHA induced CD4+ T cells. However, UC-MSCs(Gal-1-) had no significant inhibitory effect. Furthermore, the Th1 cells were also significantly suppressed by UC-MSCs and UC-MSCs(control shRNA) (4.83%+/-1.37% and 5.13%+/-0.87%,P=0.012 and P=0.018). These was no significant difference in the proportion of the Th1 cells between the control group and UC-MSCs(Gal-1-) group (8.51%+/-2.04% and 6.41%+/ 0.96%,P=0.101). The Th2 cells were protected after silence galectin-1 in UC-MSCs, whereas there was no significant difference. The proportion of Th17 was decreased by co-culture with UC-MSCs and UC-MSCs (control shRNA), but these was also no significant difference. CONCLUSION: UC-MSCs can inhibit the proliferation and differentiation of CD4+ T cells from RA patients, but these effect declined after knocking down the expression of galectin-1. Galectin-1 maybe take part in the regulation of UC-MSCs on rheumatoid arthritis CD4+ T cells. PMID- 27987501 TI - [Diagnostic significance of anti-collectin 11 in systemic lupus erythematosus]. AB - OBJECTIVE: To analyze the role of anti-collectin 11 in the diagnosis of systemic lupus erythematosus (SLE) and in the evaluation of disease activity. METHODS: This was a cross-sectional study. Five groups of patients were enrolled: SLE active (SLE disease activity index-2000,SLEDAI-2000>=9), SLE remission (SLEDAI 2000<=4 and there was no organ involvement), rheumatoid arthritis (RA), primary Sjogren Syndrome (SS) and healthy control (HC). Serum anti-collectin 11 was detected in all the groups by ELISA. One-way ANOVA analysis and LSD-t-test as post-hoc analysis were used to compare the levels of anti-collectin 11 among all the groups. Receiver operating characteristic (ROC) curve and the area under curve (AUC) were used to analyze the value of anti-collectin 11 in the diagnosis of SLE. RESULTS: In the study, 30 patients were enrolled in each group, including 13 males and 137 females with an average age of (34+/-14) years (18-77 years). The age and gender of the other three groups were comparable to the two SLE groups. The difference of serum anti-collectin 11 between the SLE active group and SLE remission group was not statistically significant (88.8+/-16.8 vs. 89.7+/ 24.7, P=0.896). The level of serum anti-collectin 11 was significantly higher in SLE group (as a whole) (89.1+/-19.4) than in RA group (49.1+/-22.0), SS group (56.9+/-30.1) and HC group (72.7+/-24.6) (P<0.001, P<0.001, P=0.007, respectively). The AUC was 0.806 for the diagnosis of SLE by serum anti-collectin 11. Further descriptive analysis showed that the positive rate of anti-collectin 11 was very high in the patients of SLE in whom both anti-double-stranded DNA (dsDNA) and Sm antibody were negative. The nervous system and gastrointestinal system involvement were the most common in the patients with positive anti collectin 11. CONCLUSION: The level of serum anti-collectin 11 was significantly higher in SLE than in RA, SS and HC. anti-collectin 11 antibody had a relatively high value in the diagnosis of SLE and it might have some complementary function in the diagnosis of SLE. It might be a relatively specific autoantibody for SLE. PMID- 27987500 TI - [Analgesic effects of ionotropic glutamate receptor antagonists MK-801 and NBQX on collagen-induced arthritis rats]. AB - OBJECTIVE: The ionotropic glutamate receptorantagonists include two types: MK 801, antagonist of N-methyl-D-asparticacid (NMDA) receptor, and NBQX, antagonist of non-NMDA receptor.The above-mentioned ionotropic antagonists can block the glutamate and its corresponding receptor binding to produce analgesic effect. The objective of this research was to study two antagonists in analgesic effect on rat behavior,as well as to investigate the down-regulation and up-regulation of cyclooxygenase-2 (COX-2) and Janus-activated kinase (Jak3) in collagen-induced arthritis (CIA) rat serum and tissue fluid after the application of these antagonists, that is, the effect on molecular biology. METHODS: This study used the ionotropic glutamate receptors as the target and established CIA rat model. Vivo studies were used to observe changes in behavior and molecular biology of the CIA rat.Behavioral assessment includedmechanical allodynia and joint swelling in the CIA rat,where themechanical allodynia was measured using the paw withdrawal threshold (PWT) with VonFrey filaments according to the "Up-Down" method,and the drainage volume was used to assess joint swelling. Then the blood samples taken from the heart of the rat and the tissue homogenate were collected to detect the down-regulation and up-regulation of COX-2 and Jak3 in the serum and tissue fluid after the antagonists wereused. RESULTS: Using MK-801, NBQX alone or using the combination of these two antagonists,these three methods all could alleviate pain(P<0.01).The analgesic effect lasted more than 24 h.Both antagonists reached the peak of analgesia at the end of 4 hours post-injection. NBQX had stronger analgesic effect than MK-801 (P<0.05).Whether alone or combined use of these two antagonists,could not change the CIA rats' swelling of the joint (P>0.05). MK-801 could decrease the expression of COX-2 (P<0.01).At the same time, NBQX did not have this effect (P>0.05). Using MK-801, NBQX alone or combination of these two antagonists could not affect the increased expression of Jak3 caused by the CIA (P>0.05). CONCLUSION: MK-801 and NBQX could both alleviate pain, NBQX was much better than MK-801. Neither MK-801 nor NBQX had the effect on the swelling of the joint. NMDA receptor and COX-2 inflammatory pathways had certain interactions. For Jak3, it could not be found to have cross-function with ionotropic glutamate signaling pathways by this experiment. PMID- 27987502 TI - [Effect of type 1 sphingosine-1-phosphate receptor siRNA on human salivary gland cells]. AB - OBJECTIVE: To construct sphingosine 1-phosphate receptor-1 (S1P1)-small interfering RNA (siRNA) lentiviral vectors and infect human salivary gland cells (HSG), and to investigate its possible therapy on Sjogren's syndrome. METHODS: HSG cells were divided into blank group, empty vector group, scramble-siRNA group and S1P1-siRNA group. The lentiviral vectors expressing siRNA against S1P1 and the pLL3.7 were respectively transfected into 293T cells with pMD2.G, pMDL g/p RRE, pRSV-REV to produce virus, and then infect HSG cells. The efficiency was observed by flow cytometry after the transfection for 48 h. The expression levels of S1P1 mRNA of HSG were detected by real-time RT-PCR and the expression of S1P1 protein was detected by immunohistochemistry method. The expression levels of interferon-gamma (IFN-gamma) and interleukin (IL)-17 in the supernatant of the cells were detected by ELISA method. RESULTS: (1) The scramble-siRNA, S1P1-siRNA lentiviral vector was successfully constructed, and the lentivirus titer was about 3.5*108 TU/mL. (2) The level of S1P1 mRNA was lower in S1P1-siRNA group than those in the blank group, empty vector group, and scramble-siRNA group 48 h after infection, there were significant differences between them (P<0.05). (3) The expression of S1P1 protein was lower in S1P1-siRNA group than those in blank group, empty vector group, and scramble-siRNA group 48 h after transfection, there were significant differences between them (P<0.05). (4) The levels of IL-17 were lower in S1P1-siRNA group than those in blank group, empty vector group, and scramble-siRNA group 48 h after transfection, there were significant differences between them (P<0.05). (5) The levels of IFN-gamma in S1P1-siRNA group were lower than those in blank group, empty vector group, and scramble-siRNA group 48 h after transfection, there were significant differences between them (P<0.05). CONCLUSION: The lentiviral vector targeting S1P1 was successfully constructed. S1P1 siRNA could suppress the levels of S1P1 mRNA and protein, and decrease the expression of IL-17 and IFN-gamma. S1P1 siRNA could infect HSG cells stably and inhibit the expression of S1P1 gene specifically and efficiently, and reduce the levels of inflammatory cytokines. PMID- 27987504 TI - [Diagnostic value of carotid atherosclerosis score for ischemic stroke]. AB - OBJECTIVE: To discuss the diagnostic value of carotid atherosclerosis score for ischemic stroke. METHODS: In the study, 151 patients with ischemic stroke were enrolled, who were diagnosed by cranial CT scan or cranial MRI scan, and examined with carotid duplex ultrasound, and 151 healthy check-up cases matched by age and sex were chosen as control group, who were excluded ischemic stroke by cranial CT scan or cranial MRI scan. All the control cases were examined with carotid duplex ultrasound also. Intima-media thickness (IMT), the number of carotid plaques, the size of each plaque, the location of the plaque and each plaque's echo, texture, surface regularity were estimated by carotid duplex ultrasound. RESULTS: The IMT of the case group and the control group were (0.946+/-0.185) mm and (0.863+/ 0.148) mm, and there were significant differences (P<0.001); The parameters of arterial plaque correlated with ischemic stroke were plaque's echo, texture and surface regularity, however the plaque size and location were not correlated with ischemic stroke. The median and quartile of carotid artery plaque score were 3 and 2 respectively in case group, 1 and 2 respectively in control group, and there were significant differences (P<0.001); The parameters of carotid arterial atherosclerosis associated with ischemic stroke were carotid artery plaque score,carotid stenosis degree and IMT, but not the number of carotid plaques. The median and quartile of carotid arterial atherosclerosis score were 5 and 4 respectively in case group, 2 and 4 respectively in control group, and there were significant differences (P<0.001); The area under the curve (AUC) for IMT, the number of carotid plaques, carotid artery plaque score and carotid arterial atherosclerosis score were 0.679, 0.677, 0.704 and 0.805,respectively (P<0.001). The accuracy of carotid atherosclerosis score was the highest. CONCLUSION: Carotid artery plaque score and carotid atherosclerosis score can be used for the diagnosis of ischemic stroke, and the accuracy of carotid atherosclerosis score is higher. PMID- 27987503 TI - [Association of single nucleotide polymorphism rs6983267 with ulcerative colitis and colorectal cancer]. AB - OBJECTIVE: To investigate the association of rs6983267 polymorphism with risk of sporadic colorectal cancer; to compare the distribution of rs6983267 polymorphism between ulcerative colitis and general population. METHODS: 186 patients with sporadic colorectal cancer, 129 patients with ulcerative colitis and 189 healthy donors were recruited in the case-control study. Peripheral venous blood was obtained, and genomic DNA was extracted. All samples were genotyped using matrix assisted laser desorption ionization time-of-flight mass spectrometry techniques. Allelic and genotypic frequencies were compared and adjusted for age and gender using unconditional Logistic regression. RESULTS: The allelic frequency of G and the genotypic frequencies of GG and GT were predominant in colorectal cancer group compared with control group, which were statistically significant after adjustment for age and gender (P<0.001). The allelic frequency of G and the genotypic frequencies of GG and GT were predominant in ulcerative colitis group compared with control group, which were statistically significant as well (P=0.041, P=0.006 and P<0.001). CONCLUSION: rs6983267 polymorphism was associated with risk of sporadic colorectal cancer. The distribution of rs6983267 may be different between ulcerative colitis and general population, and the frequency of risk allele G may be higher in ulcerative colitis patients compared with general population. PMID- 27987505 TI - [Patient-related independent clinical risk factors for early complications following interventional pulmonology procedures]. AB - OBJECTIVE: To investigate the early complication rate and identify patient related independent clinical risk factors for early complications in patients following interventional pulmonology procedures. METHODS: In the period from December 2014 to December 2015, sufficient data of Peking University First Hospital Respiratory and Critical Care Medicine Department for analysis were identified in 218 subjects. Interventional pulmonology procedures were performed in all the patients. Early complications after the procedures were defined as newly respiratory failure, arrhythmia requiring treatment, severe hemoptysis, pneumothorax, pneumomediastinum, pulmonary edema, tracheoesophageal fistulae, bronchopleural fistulae, acute coronary syndrome, acute cerebrovascular accident, and death. Patient-related clinical risk factors were defined as coronary atherosclerotic heart disease, cerebral infarction, diabetes mellitus, cirrhosis, chronic kidney disease, arrhythmia, asthma, chronic obstructive pulmonary disease, hypertension, and previous interventional pulmonology treatment. The patient-related independent clinical risk factors which had close relations to the occurrence of early complications were analyzed by multivariate statistical analysis with Logistic regression. RESULTS: There were 56.4% male and 43.6% female subjects in this study. There were 10.6% current smokers, 26.6% former smokers, and 62.8% non-smokers. The overall early complication rate was 8.3%. In all the subjects groups, the patient-related independent clinical risk factors for the early complication rate were coronary atherosclerotic heart disease (B=1.545, P=0.006, OR=4.686, 95% CI 1.568-14.006), chronic obstructive pulmonary disease (B=1.037, P=0.049, OR=2.820, 95% CI 1.675-11.790), and current smoking status (B=1.412, P=0.032, OR=4.139, 95% CI 1.134-15.109); for the newly respiratory failure rates were coronary atherosclerotic heart disease (B=2.207, P=0.004, OR=9.087, 95% CI 2.028-40.714), chronic obstructive pulmonary disease (B=1.646, P=0.048, OR=5.188, 95% CI 1.783-34.375), and lesions involving three central airways (B=1.899, P=0.032, OR=6.680, 95% CI 1.182-37.740). In the malignant group, the patient-related independent clinical risk factor for the early complication rate was current smoking status (B=2.953, P=0.006, OR=19.161, 95% CI 2.360-155.572). In the benign group, the patient-related independent clinical risk factor for the early complication rate was only coronary atherosclerotic heart disease (B=1.976, P=0.022, OR=7.214, 95% CI 1.324-39.298). CONCLUSION: Closer monitoring of patients with identified clinical risk factors is advisable prior and immediately after interventional pulmonology procedures. In order to avoid or minimize early complications, special attention should be directed toward patients who are current smokers, or patients with lesions involving three central airways, or with coronary atherosclerotic heart disease or chronic obstructive pulmonary disease. PMID- 27987506 TI - [Clinical application and prognostic analysis of interventional treatment for cesarean scar pregnancy]. AB - OBJECTIVE: To analyze the clinical value and prognosis of cesarean scar pregnancy (CSP) treated by uterine artery embolization (UAE). METHODS: In the study, 492 cases of patients in Nanjing Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University diagnosed as CSP between January 2011 and December 2014 were chosen, of which 283 were of high-risk group and 209 of low-risk group. According to whether to take UAE, the high-risk group was subdivided into high risk UAE group(UAE+laparoscopic group), 167 cases, and high-risk non UAE group (chemotherapy+laparoscopic group), 116 cases, while the low-risk group was subdivided into low-risk UAE group (UAE+curettage group), 113 cases, and low-risk non UAE group(chemotherapy+curettage group), 96 cases. The differences of the intraoperative bleeding, length of stay, blood beta human chorionic gonadotropin (beta-HCG) dropped to normal time, menstruation recovery time and the hospitalization expenses were compared. And multivariate regression analysis was used to predict the recurrence risk of CSP. RESULTS: The high-risk UAE group was better than the high-risk non UAE group in comparison of intraoperative bleeding [(36.5+/-14.8) mL vs.(76.5+/-39.7) mL], length of stay [(5.9+/-0.9) d vs.(9.6+/ 1.3) d], blood beta-HCG dropped to normal time [(17.9+/-8.7) d vs.(28.7+/-10.1) d] and menstruation recovery time [(18.1+/-1.6) d vs.(24.3+/-1.8) d],while the low-risk UAE group was better than the low-risk non UAE group in comparison of intraoperative bleeding [(93.2+/-43.3) mL vs.(284.8+/-110.5) mL], length of stay [(10.2+/-1.4) d vs. (30.7+/-9.6) d], blood beta-HCG dropped to normal time [(50.1+/-17.6)d vs.(67.5+/-22.9)d] and menstruation recovery time[(56.3+/-6.7)d vs.(65.9+/-9.3) d], all P<0.05. The high-risk UAE group was higher than the high risk non UAE group in comparison of hospitalization expenses [(20 140+/-1 520 )Yuan vs.(13 510+/-1 013) Yuan], and the low-risk group UAE was also higher than the low-risk non UAE group in comparison of hospitalization expenses [(10 095+/ 962 )Yuan vs.(3 890+/-457) Yuan], all P<0.01. Multivariate Logistic regression analysis showed that the treatment method was independent predictor of CSP recurrence risk (OR 2.407, 95%CI 1.176-5.092, P<0.05), and using the comprehensive treatment including UAE could reduce the risk of recurrent CSP. CONCLUSION: As the efficacy of interventional therapy for CSP was rapid and reliable, fewer complications, faster recovery and lower recurrence, hospitalization with good conditions, and particularly for those patients with CSP who want to fertility again, the comprehensive treatment including UAE treatment should be the first choice. PMID- 27987507 TI - [Polymethylmethacrylate augmentation of bone cement-injectable cannulated pedicle screws for the treatment of degenerative lumbar diseases with osteoporosis]. AB - OBJECTIVE: To describe the application of polymethylmethacrylate augmentation of bone cement-injectable cannulated pedicle screws for the treatment of degenerative lumbar diseases with osteoporosis. METHODS: Observation group included 14 cases of degenerative lumbar diseases with osteoporosis received polymethylmethacrylate augmentation of bone cement-injectable cannulated pedicle screws from November 2014 to July 2015, control group included 12 cases of degenerative lumbar diseases with osteoporosis received polymethylmethacrylate augmentation with traditional pedicle screws.The operation time, blood loss, number of pedicle screws and number of augmented pedicle screws in the two groups were compared. The bone cement leakage and pulmonary bone cement embolism in the two groups were also compared. The fusion rate and pedicle screws loosening by lumbar X ray and dynamic X ray were evaluated. The clinical results were assessed by visual analog scale (VAS) of pain on lumbar and lower limbers, lumbar Japanese Orthopaedic Association scores (JOA), Prolo functional scores and Oswestry disability (ODI) scores. RESULTS: Differences of operation time and blood loss in the two groups were not statistically significant. The average number of pedicle screws was 9.9+/-4.7 and the average number of augmented pedicle screws was 5.9+/ 2.6 in observation group while the average number of pedicle screws was 7.1+/-2.8 and the average number of augmented pedicle screws was 3.0+/-1.9 in control group. The ratio of augmented pedicle screws was higher in observation group than in control group (0.69+/-0.30 vs.0.47+/-0.30,P<0.05). The bone cement leakage rate was lower in observation group than in control group (5/83 vs. 12/42, P<0.01). All the cases in observation group were without leakage to the interspinal canal while one case in control group suffered from bone cement leakage to the interspinal canal with augmentation of 3 pedicle screws. The follow up period was (10.6+/-2.3) months in observation group and (36.5+/-7.2) months in control group. In final follow up, no case with non-fusion or pedicle screws loosening was found in both groups. Lumbar VAS, lower limbers VAS, lumbar JOA scores, Prolo functional scores and ODI scores were all better than pre operation (P<0.01). CONCLUSION: Polymethylmethacrylate augmentation of bone cement-injectable cannulated pedicle screws for the treatment of degenerative lumbar diseases with osteoporosis was effective, with simple working processes and lower risk of bone cement leakage. The short-term clinical result was good. PMID- 27987508 TI - [Analysis of anterolateral approach and lateral approach for the treatment of coronal shear fracture of the distal humeral]. AB - OBJECTIVE: To treat the coronal shear fracture of the distal humeral during open reduction and internal fixation by anterolateral approach and lateral approach, and to analyze the advantage and disadvantage of each approach. METHODS: From September 2006 to July 2014, 10 patients with coronal fracture of the distal humeral were analyzed, who were all treated with Open Reduction and Internal Fixation (ORIF), 5 with anterolateral approach (group A) and 5 with lateral approach (group B). For the anterior-lateral approach, the radial nerve and brachioradialis were retracted laterally and the brachialis was retracted medially, the capsule was incised and the fracture line was exposed, usually the capitellum and the lateral part of the trochlear could be exposed clearly but the exposure was limited. For the lateral approach, the brachioradialis was retracted anteriorly, the lateral collateral ligament (LCL) was protected or released from the starting point on the lateral condyle of the humeral, the elbow could be dislocated and the capitellum and part of the trochlear could be exposed. The fractures were classified with the system of Dubberley, the complications were analyzed and the ultimate results were evaluated according to the Mayo elbow performance index (MEPI). RESULTS: For group A, 4 re-operations were performed, 2 for the irritation of the screws,1 for stiff elbow and 1 for failure of the internal fixation. One radial nerve injury happened but recovered later. The mean MEPI was 82 points. For group B, 1 failure of the internal fixation and instability of the elbow happened. The revision operation was performed for this patient. The mean MEPI was 91 points. CONCLUSION: Lateral approach is better,it gives more exposure for the joint and the radial nerve is safe, but the trochlear is difficult to be exposed, and the LCL must be protected or repaired during the operation. Anterolateral approach can be used to expose the capitellum and the radial side of the trochlear, but the radial nerve is dangerous and more complications may happen. PMID- 27987509 TI - [Preoperative prognostic factors and preoperative risk stratification of upper tract urothelial carcinoma]. AB - OBJECTIVE: To identify the preoperative prognostic factors of upper tract urothelial carcinoma (UTUC) and construct preoperative risk stratification system. METHODS: A retrospective study including 686 patients who were diagnosed with UTUC and received radical nephroureterectomy or partial ureterectomy in Peking University First Hospital during 2003 and 2013. RESULTS: Of the 686 UTUC patients, 303 (44.2%) were male and 383 (55.8%) female. The postoperative pathological examination showed that 203 (29.6%) had high tumor stages (T3, T4), 300 (43.7%) had high tumor grades (G3) and 54 (7.9%) had lymph nodes metastasis (N1). After multivariate analysis, renal pelvic tumor, large tumor, estimated glomerular filtration rate (eGFR)>=30 mL/min, and male were associated with high tumor stage. Ureteral tumor, large tumor, and non-smoking history were associated with high tumor grade. Renal pelvis tumor, large tumor, and preoperative anemia were associated with positive N status. During the follow-up, 208 (30.3%) died for cancer and 210 (30.6%) developed intravesical recurrence. Multivariate analysis showed: large tumor (P=0.001), concomitant ipsilateral hydronephrosis (P=0.041), and preoperative anemia (P=0.001) were independently associated cancer specific mortality after surgery, while ureteral tumor (P=0.04), multiple tumor (P=0.005), and high preoperative creatinine (P=0.036) were independent risk factors for intravesical recurrence. CONCLUSION: Of the preoperative clinical parameters of UTUC patients, the large tumor, concomitant ipsilateral hydronephrosis, and preoperative anemia were independently associated with cancer specific mortality after surgery. Ureteral tumor, multiple tumor, and high preoperative creatinine were independently associated with intravesical recurrence after surgery. PMID- 27987510 TI - [Comparison of two shaping methods for double-lumen endotracheal tube intubation by Shikani optical stylet laryngoscope]. AB - OBJECTIVE: To compare the efficacy and safety of two different shaping methods for double-lumen endotracheal tube (DLT).DLT was shaped with the rod of a Shikani optical stylet (SOS) with the tracheal orifice aligned with the convex aspect of the distal curvature or the concave aspect of the distal curvature. METHODS: Patients scheduled for elective thoracic surgery and required intubation with a left-sided DLT were enrolled in this study. They were randomized into two groups. They were intubated with a DLT, which was shaped with the rod of a SOS with its tracheal orifice aligned with the convex aspect of the distal curvature (group T) or the concave aspect of the distal curvature (group U). Time for SOS manipulation, intubation attempts, intubation resistance score, malposition of bronchial intubation, time for fiberoptic bronchoscope (FOB) identification of bronchial placement, total intubation time and oral mucosal or dental injury were recorded. Hoarseness and throat sore of the patients were evaluated 1 hour and 24 hours after surgery. RESULTS: A total of 136 patients completed the study, with 68 in each group. Time for SOS manipulation was significantly shorter in group U [(35.1+/-6.1) s vs. 39.6+/-11.8) s, P=0.007]. First attempt success rate did not differ between the groups (92.6% vs.88.2%, P=0.561). Intubation resistance score was significantly lower in group U. Group T had fewer patients who suffered malposition of bronchial intubation than group U (4 vs.13, P=0.020) and cost less time for FOB identification of bronchial placement [(44.1+/-20.9) s vs.(53.6+/ 29.2) s, P=0.032]. Total intubation time and the incidence of oral mucosal or dental injury did not differ between the groups. The severity and incidence of hoarseness were lower in group U than in group T 1 hour after surgery. The severity and incidence of sore throat were lower in group U than in group T 1 hour and 24 hours postoperatively. CONCLUSION: When lacing a left-sided DLT using a SOS, shaping the DLT with the tracheal orifice aligned with the concave aspect of the distal curvature saves SOS manipulation time, decreases the severity and incidence of postoperative hoarseness and sore throat. However, this modified shaping method increases the incidence of malposition of bronchial intubation and time for FOB identification of bronchial placement. PMID- 27987511 TI - [Synthesis and in vitro characterization of chitosan microspheres/ceramic bovine bone composite scaffold]. AB - OBJECTIVE: The chitosan microspheres encapsulated with bone morphogenetic protein 2 (BMP-2) were prepared by the emulsion cross-linking method. Then the chitosan microspheres were loaded in the ceramic bovine bone (CBB) to achieve the drug delivery system. METHODS: The chemical structure and surface morphology of the drug delivery system were investigated by Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscope (SEM) observation. Characterization preserved the loading capacity and encapsulation efficiency of the BMP-2. The dynamic immersion method was used to examine the in vitro release characteristic of BMP-2. RESULTS: The chitosan microspheres were successfully encapsulated BMP-2 by cross-linking method. The microspheres were micron-sized (5.982 MUm) and spherical in shape with smooth surface morphology. From the release experiments, it was found that 5 mg chitosan/BMP-2 soaked for 21 days with a gradual release of BMP-2. The concentration of BMP-2 was (239.1+/-20.0) mg/L on Day 21. The in vitro experiment showed that this novel drug delivery system could accelerate MC3T3-E1 cells proliferation and osteogenic differentiation. CONCLUSION: The drug delivery system achieves the biological function of BMP-2 and sustaining slow release in bone repair parts. Also it can provide the basis for repair of bone tissue defect treatment and the selection of bone tissue engineering scaffolds. PMID- 27987512 TI - [Diagnosis and treatment of diffuse tenosynovial giant cell tumor arising from temporomandibular joints]. AB - OBJECTIVE: To retrospectively analyze the clinical features, treatment and prognosis to the diffuse tenosynovial giant cell tumor (D-TSGCT) arising from the temporomandibular joint (TMJ), and to give a reference for the early diagnosis and treatment of this disease. METHODS: In this study, 15 patients finally diagnosed as D-TSGCT of TMJ histopathologically at the Peking University Hospital of Stomatology from October 2003 to August 2015 were selected and reviewed. Their clinical manifestations, imaging and histological features, diagnoses and differential diagnoses, treatments and follow-ups were summarized and discussed. RESULTS: D-TSGCT of TMJ showed obvious female predominance (12/15), the main symptoms included painful preauricular swelling or mass, limited mouth-opening and mandibular deviation with movement. D-TSGCT on computed tomography (CT) scan often showed ill-defined soft tissue masses around TMJ, enhancement after contrast administration, usually with widening of the joint spaces and with bone destruction of the condyle, the fossa and even the skull base. On magnetic resonance images (MRI), the majority of lesions on T1 weighted images and T2 weighted images both showed the characteristics of low signals (6/11). The lesions could extend beyond the joints (9/11) and into the infratemporal fossa (4/11) and the middle cranial fossa (4/11). Surgical resection was performed in 14 cases and biopsy in 1 case. Postoperative radiotherapy was performed in 3 cases. In follow-ups, 3 cases showed recurrence postoperatively. CONCLUSION: D TSGCT arising from TMJ should be differentiated with TMJ disorders, other tumors and tumor-like lesions of TMJ and parotid neoplasms, etc. CT and MRI examinations have important values in the diagnosis and treatment design of D-TSGCT. Because of the local aggressive and extensive behavior, complete resection should be performed as soon as possible. Postoperative radiotherapy was helpful for the extensive lesions including destruction of skull base and may be a good supplementary therapy. Because of the possibility of recurrence and malignancy, long-term follow-up was suggested. PMID- 27987513 TI - [Preliminary clinical evaluation of the esthetic effect of deep discolored anterior teeth restored with zirconia veneers]. AB - OBJECTIVE: To observe the esthetic effect of deep discolored anterior teeth restored by zirconia veneers. METHODS: Small defected deep discolored anterior teeth with complete root canal therapy were restored by zirconia veneers (n=15). The same name teeth on the other side of the same dental arch were chosen as control teeth. The color difference values DeltaE of the neck 1/3, the middle 1/3 and the incisor 1/3 between the deep discolored tooth and the normal control tooth before and after therapy were measured to evaluate the esthetic effect of zirconia veneer restoration. At the same time, the marginal fit of zirconia veneers was checked by the standard of United States Public Health Service (USPHS). The integrity of the veneers was also examined. RESULTS: On the labial side, fibers color difference values DeltaE of the neck 1/3, the middle 1/3 and the incisor 1/3 between deep discolored teeth and normal control teeth were measured by the electronic colorimeter, which were 24.92+/-3.00,26.64+/-4.00 and 21.94+/-3.31 respectively. All the values were above 4.0, which were considered unacceptable in clinic. After restoration by zirconia veneers, the color difference values DeltaE of the middle 1/3 and the incisor 1/3 between the restored and control teeth were 1.82+/-0.17 and 1.84+/-0.21. Both values were less than 2.0, which indicated both good color matching. The color difference value DeltaE of the neck 1/3 was 3.92+/-0.48, which was less than 4.0 and could be accepted in clinic. The statistical analysis of the colors of the teeth before and after restoration compared with the control teeth was done by Paired t test. The t values in the neck 1/3, the middle 1/3 and the incisor 1/3 were 30.37, 21.56, 23.37 respectively. In the three group, all the P<0.001. There were obvious statistical differences. According to the standard of USPHS, the marginal fit of all the restored teeth was perfect (grade A). No zirconia veneers were broken or detached in the period of observation. CONCLUSION: Zirconia veneers can be a good method to restore deep discolored anterior teeth. However, it should be used cautiously when the patient's esthetic expectation was too high. PMID- 27987514 TI - [Effects of breast-feeding duration, bottle-feeding duration and oral habits on the occlusal characteristics of primary dentition]. AB - OBJECTIVE: To assess the effects of breast-feeding duration, bottle-feeding duration and oral habits on the occlusal characteristics of primary dentition in 3-6-year-old children in Beijing. METHODS: This cross sectional study was conducted via an examination of the occlusal characteristics of 734 children combined with a questionnaire completed by their parents/guardians. The examination was performed by a single, previously calibrated examiner and the following variables were evaluated: presence or absence of deep overbite, open bite, anterior cross bite, posterior cross bite, deep overjet, terminal plane relationship of the second primary molar, primary canine relationship, crowding and spacing. Univariate analysis and multiple Logistic regressions were applied to analyze the associations. RESULTS: It was found that a short duration of breast-feeding (never or <=6 months) was directly associated with posterior cross bite (OR=3.13, 95%CI=1.11-8.82, P=0.031) and no maxillary space (OR=1.63, 95%CI=1.23-2.98, P=0.038). In children breast-fed for <=6 months, the probability of developing pacifier-sucking habits was 4 times that for those breast-fed for >6 months (OR=4.21, 95%CI=1.85-9.60, P=0.000 2). The children who were bottle-fed for over 18 months had a 1.45-fold higher risk of nonmesial step occlusion and a 1.43-fold higher risk of class II canine relationship compared with those who were bottle-fed for 6-18 months. Non-nutritive sucking habits were also found to affect occlusion: a prolonged digit-sucking habit increased the probability of an anterior open bite, while a pacifier-sucking habit was associated with excessive overjet and absence of lower arch developmental space. Tongue-thrust habit was associated with anterior open bite (OR=4.21, 95%CI=1.85-9.60, P=0.000 2) and posterior cross bite (OR=7.24, 95%CI=1.30-40.13, P=0.024). Lower lip sucking habit was associated with deep overjet and had a negative association with class III canine relationship. Unilateral chewing was associated with spacing in mandibular (OR=1.57, 95%CI=1.03-2.41, P=0.037). Mouth breathing was associated with chronic rhinitis and adenoidal hypertrophy and had an association with spacing in maxillary. The chi-square test did not indicate a statistically significant association between upper lip sucking habit and any occlusal characteristics. CONCLUSION: Breast-feeding duration was shown to be associated with the prevalence of posterior crossbite, or no maxillary space in the deciduous dentition and development of a pacifier-sucking habit. Children who had a longer duration of bottle-feeding were more likely to develop class II canine relationship. Children who had an oral habit were more likely to develop abnormal occlusal characteristics. PMID- 27987515 TI - [Study on the properties of felodipine solid dispersions prepared by different technologies]. AB - OBJECTIVE: To prepare felodipine/copovidone solid dispersions, which were made based on different preparation technologies. Insoluble felodipine was selected as the model drug in this research. This drug belonged to Biopharmaceutics Classification System II (BCSII) with insoluble property and good permeability across intestinal mucosa simultaneously. A comparative study was carried out for further investigating their corresponding pharmaceutical properties. METHODS: Felodipine/copovidone solid dispersions were achieved by four methods including spray-drying method, microwave-induced fusion quench cooling method, freeze drying method and co-precipitation method. These solid dispersions were produced based on corresponding processes that corresponded to these methods. Internal properties of co-povidone solid dispersions were analyzed by various approaches including scanning electron microscope (SEM), differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The improvement on insoluble properties of felodipine by solid dispersions produced by different technologies was characterized by dissolution experiments based on dissolution instrument. Crystallization inhibition effect of polymers against drugs was studied by supersaturated experiments through determining the concentration value at different time points. RESULTS: The internal drug was dispersed in amorphous form in solid dispersions produced by spray-drying, microwave method, microwave/quench cooling method and co-precipitation method. Freeze-drying method resulted in a form of crystal in felodipine/copovidone solid dispersions. Compared with other technologies, microwave-induced quench cooling method could significantly improve the dissolution of insoluble drug felodipine (P<0.05). The dissolution concentration reached approximately 4.65 mg/L at 60 min time point. Copovidone could inhibit or retard the crystallization of felodipine in a supersaturated state. In the solution pre-dissolved with maximum copoyidone polymer, the minimum crystallization rate of supersaturated felodipine was observed at 240 min time point. The value of crystallization rate was 0.19 mg/(L*min). CONCLUSION: The study is helpful to understand and clarify the internal properties of solid dispersions obtained by different technologies. The research also provides beneficial consultation for the choice of technology in practical production of drug-polymer solid dispersions. PMID- 27987516 TI - [Non-Hodgkin's lymphoma mimicking Mikulicz disease: a case report]. AB - IgG4-related disease is a systemic disorder involving a spectrum of multiple indications, and various histopathological features are shared among different IgG4-related disease subtypes, which challenge diagnosis, although certain syndromes have organ-specific involvement. Among them, Mikulicz's disease affecting the salivary and lacrimal glands, distinguished by often elevated levels of serum IgG4, infiltration of IgG4+ plasma cells into target tissues, and diffuse swelling, mass formation, or fibrosis of affected organs. However, there are several diseases, which could manifest as salivary gland swelling, mimicking Mikulicz's disease, such as Sjogren's syndrome, mumps virus infection, obstruction of parotid duct, non-Hodgkin's lymphoma (NHL), and so on. So differential diagnosis is important and essential as to the salivary gland swelling. In this paper, we analyzed a case of a 59-year-old male with symmetric salivary gland swelling. Mikulicz's disease was misdiagnosed at the beginning without biopsy. Prednisone treatment ever seemed to be effective and antibiotics had no effect. Besides salivary involvement, the patient also manifested as testicle swelling and severe pancytopenia with the development of the disease, which rarely appeared in Mikulicz's disease. Physical examination showed skin, sclera yellow dye, swollen submandibular, sublingual and lacrimal gland and splenomegaly. As a result, biopsy of right submandibular gland was made, and mucosa-associated lymphoid tissue lymphoma was confirmed by morphology and immunohistochemistry. Bone marrow biopsy also confirmed that lymphoma cells were found in the bone marrow. Finally, the diagnosis of mucosa-associated lymphoid tissue lymphoma (Phase IVE, Group A) was made on the patient, who was transferred to the hematology department for the treatment. NHL, especially, primary extranodal lymphoma usually involves the salivary gland, and painless swelling of the salivary gland is a common manifestation, similar with Mikulicz's disease. So although salivary gland swelling is often associated with autoimmune diseases such as Sjogren's syndrome and IgG4-related disease, the awareness and suspicion of a possibility of NHL are essential for rheumatologists. Biopsy is a necessary examination to decrease or avoid misdiagnosis. PMID- 27987517 TI - [Cerebral infarction in a patient with primary Sjogren's syndrome: a case report and literature review]. AB - Sjogren's syndrome (SS) is a chronic autoimmune disorder characterized by lymphocytes infiltration in the exocrine glands. Central nervous system complications of primary SS are not rare, but ischemic stroke has been rarely reported. Here we report a 43-year-old female with a two-year history of primary SS, presenting with sudden cerebral infarction. Her primary SS was diagnosed on the basis of clinical features, high levels of serum anti-SSA and anti-SSB antibodies, salivary gland secretion evaluation and positive sublingual gland biopsy results. Magnetic resonance imaging revealed infarct lesions in the parietal and occipital lobes, as well as in the left basal ganglia. Magnetic resonance angiography showed a remarkable stenosis in the left middle cerebral artery. Other differential diagnoses were ruled out. Corticosteroid and immunosuppressor, together with anti-platelet and statin were effective, and the patient recovered quickly without sequelae. Based on these findings, vasculitis due to primary SS should be considered among the causes of stroke. The literature was reviewed and the relationship between primary SS and cerebral infarction explored. The pathogenesis of ischemic stroke in primary SS is still unknown and warrants further studies. PMID- 27987518 TI - [Clinical characteristics of 4 cases of scleritis associated with systemic lupus erythematosus]. AB - Episcleritis and scleritis are relatively rare ocular diseases, which are commonly associated with rheumatic diseases including systemic lupus erythematosus (SLE). To investigate clinical and laboratory features of SLE associated episcleritis and scleritis, we now report 4 cases of inpatients who were diagnosed with episcleritis or scleritis secondary to SLE from September 2005 to July 2016 in the Department of Rheumatology and Immunology in Peking University People's Hospital. Demographic, clinical and laboratory characteristics were summarized together with the treatment regimen and the prognosis; the literature was reviewed. There were 3 female and 1 male patients. The average age was (49.0+/-23.8) years and the mean duration of SLE at the onset of episcleritis or scleritis was (2.1+/-1.4) years. In addition to the eye involvement, the patients had mucocutaneous manifestations, serositis, lupus nephritis and interstitial pneumonia simultaneously; in the past, 1 patient experienced arthritis, 2 presented Raynaud's phenomenon, and 2 had hematologic involvement. All the patients had antinuclear antibody (ANA) of high titer. The anti double-stranded DNA (ds-DNA) antibody titers were increased in 2 patients. Three patients had positive anti-nucleosome antibody (ANuA) while the other 1 patient did not test it. The complement levels were decreased in 3 patients. The systemic lupus erythematosus disease activity index (SLEDAI) scores were more than 4 points in all the patients (ranging from 7-16), suggesting active disease. Ocular symptoms included pain, redness of the eye and tears. Ophthalmic examinations revealed 3 cases of episcleritis and 1 case of scleritis. Among the 4 patients, 2 patients experienced ocular complications including decrease in vision and uveitis. All the patients were treated with systemic corticosteroids combined with hydroxycloroquine; 3 patients were treated with immunosuppressants (cyclophosphamide in 2 patients and leflunomide in 1 patient). All of the 4 patients received topical steroid and 1 patient received periocular injection of triamcinolone acetonide; 1 patient received topical nonsteroidal anti inflammatory drug (NSAID).No recurrence of episcleritis or scleritis was observed during the follow-ups. As a conclusion, scleritis and episcleritis, although uncommon, may occur in patients with autoimmune rheumatic diseases including SLE. The occurrence of episcleritis and scleritis may suggest active disease of SLE. Ocular complications need to be aware of in the patients. Prompt diagnosis and treatment was associated with good visual outcomes in the follow-ups. PMID- 27987519 TI - [Autoimmune disorder secondary to DiGeorge syndrome: a long-term follow-up case report and literature review]. AB - DiGeorge syndrome is the most common chromosome microdeletion disease. The classical complications include congenital heart disease, hypothyroidism, immunodeficiency, facial abnormalities, and hypocalcemia. According to whether there is an absence or hypoplasia of the thymus, DiGeorge syndrome can be divided into two types, complete DiGeorge syndrome and partial DiGeorge syndrome. The patient was a female born with congenital heart disease, facial abnormalities and cleft palate. When the patient went to school, she had learning difficulty and had problems in communication and personal social behavior. Breath-holding occurred when she was 6 years old. She got infections about 2-3 times a year, which was easy to be cured each time. Chromosome microdeletion test of peripheral blood showed the classical 22q11.2 microdeletion, and no evidence showed that she has thymus absence, thus her disease was diagnosed as partial DiGeorge syndrome. When the patient was 6 years old, the blood routine test showed slight thrombocytopenia, and reexaminations after that indicated the similar result. When 9 years old, she was found with anemia and severe thrombocytopenia. At the age of 10, the patient was admitted to our hospital, complaining of petechia in the body and mucous of mouth. According to the various examinations results, doctors eventually considered the situation as an autoimmune disorder phenomenon. After being treated by pulse-dose methylprednisolone for three days, the bleeding ceased. Then the patient orally took prednisone acetate and pulse-dose cyclophosphamide, however the thrombocyte and hemoglobin levels had not been back to a normal range. But when the dose of prednisone acetate was reduced, the blood platelet count declined again while the hemoglobin kept normal. The long-term follow-up of this case lasted for more than 20 years. Until now, the patient is taking orally prednisone acetate as a maintainance treatment, and the anemia has been improved since, but thrombocytopenia still exists. The mechanism of DiGeorge syndrome in combination with immunodeficiency is still unclear. The most likely reason is that this phenomenon has some relationship with the dysfunction of the thymus and finally had an effect on the function of T cells. The clinical manifestation is always stubborn and need treatment and follow-up visit for a long time. PMID- 27987520 TI - [Dental implantation and soft tissue augmentation after ridge preservation in a molar site: a case report]. AB - For ideal implant rehabilitation, an adequate bone volume, optical implant position, and stable and healthy soft tissue are required. The reduction of alveolar bone and changes in its morphology subsequent to tooth extraction will result in insufficient amount of bone and adversely affect the ability to optimally place dental implants in edentulous sites. Preservation of alveolar bone volume through ridge preservation has been demonstrated to reduce the vertical and horizontal contraction of the alveolar bone crest after tooth extraction and reduce the need for additional bone augmentation procedures during implant placement. In this case, a patient presented with a mandible molar of severe periodontal disease, the tooth was removed as atraumatically as possible and the graft material of Bio-Oss was loosely placed in the alveolar socket without condensation and covered with Bio-Gide to reconstruct the defects of the alveolar ridge. Six months later, there were sufficient height and width of the alveolar ridge for the dental implant, avoiding the need of additional bone augmentation and reducing the complexity and unpredictability of the implant surgery. Soft tissue defects, such as gingival and connective tissue, played crucial roles in long-term implant success. Peri-implant plastic surgery facilitated development of healthy peri-implant structure able to withstand occlusal forces and mucogingival stress. Six months after the implant surgery, the keratinized gingiva was absent in the buccal of the implant and the vestibular groove was a little shallow. The free gingival graft technique was used to solve the vestibulum oris groove supersulcus and the absence of keratinized gingiva around the implant. The deepening of vestibular groove and broadening of keratinized gingiva were conducive to the long-term health and stability of the tissue surrounding the implant. Implant installation and prosthetic restoration showed favorable outcome after six months. PMID- 27987521 TI - [Role of hypoxia-inducible factor in the pathogenesis of rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is a destructive chronic autoimmune disease characterized by synovium inflammation, cartilage destruction, bone erosion and the presence of autoantibodies. Hypoxia is a prominent micro-environmental feature in a range of disorders including RA. A combination of increased oxygen consumptionby inflamed resident cells and infiltrating immune cells along with a disrupted blood supply due to vascular dysfunction contribute to tissue hypoxia in RA. Hypoxia in turn regulates a number of key signaling pathways that help adaptation. The primary signaling pathway activated by hypoxia is the hypoxia inducible factor (HIF) pathway. It has been shown that HIFs are highly expressed in the synovium of RA. HIFs mediate the pathogenesis of RA through inducing inflammation, angiogenesis, cell migration, and cartilage destruction, and inhibiting the apoptosis of synovial cells and inflammatory cells. HIF expressed in RA can be regulated in both oxygen-dependent and independent fashions, like inflammatory cytokines, leading to the aggravation of this disease. Considering the vital role of HIF in the pathogenesis of RA, we reviewed the new advances about hypoxia and RA. In this review, we firstly discussed the hypoxia-inducible factor and its regulation, and then, the pathologic role of hypoxia in RA, mainly elucidating the role of hypoxia in synovitis and cartilage destruction and immune cells. Finally, we provided evidence about the potential therapeutic target for treating RA. PMID- 27987522 TI - [Interleukin-2 signaling pathway regulating molecules in systemic lupus erythematosus]. AB - Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease, which characterized by complex immunological abnormalities and multiple tissue and organ damages. The etiology and pathogenesis of SLE have not been entirely recognized. Genetic, environmental and viral infections and other factors might be related to the pathogenetic mechanisms of SLE. Interleukin-2 (IL-2) is a critical cytokine produced by T cells upon activation and is important for the generation of T regulatory cells and activation-induced cell death. In SLE patients, T cells display decreased capacity to produce IL-2. Impaired IL-2 expression resulted in decreased generation of regulatory T lymphocytes, and defect of activation-induced cell death. Former researches indicated that IL-2 deficiency in SLE is important for the pathogenesis and treatment of SLE. Several regulating molecules can affect the transcription of IL-2 gene and had an important role in the pathogenesis of SLE. These molecules include cyclic AMP responsive element modulator (CREM), protein phosphatase 2A (PP2A), E-74 like factor 1 (Elf-1), B lymphocyte induced maturation protein-1 (Blimp-1) and interferon regulator factor 5 (IRF-5). CREM is a transcriptional inhibitor that can repress the transcription of the IL-2 gene by binding to the promoter of the IL-2 gene. PP2A is a Ser/Thr phosphatase that expressed in eukaryotic cells ubiquitously, it represents a negative regulator of the IL-2 gene promoter activity. Elf-1 belongs to the Ets family of transcription factors and can promote the expression of IL-2. Blimp-1 is a crucial transcription factors for regulating B lymphocyte terminal differentiation, an important function of Blimp 1 in T cells is to repress IL-2 gene transcription directly. Interferon regulatory factors (IRFs) are distinctive transcriptional regulators of type I interferons (IFNs) and IFN inducible genes, IRF-5 is a member of the IRFs family. IRF-5 is found to be increased in SLE and can regulate the production of IL-2 negatively. PP2A can inhibit the synthesis of IL-2 in two ways: on the one hand, activating the IL-2 transcription inhibitory factor CREMalpha, on the other hand, inhibiting IL-2 stimulating transcription factor Elf-1. While IRF-5 can activate the IL-2 transcription negative regulator Blimp-1 as to inhibit IL-2 expression. These molecules participate in the regulation of IL-2 through different pathways. This paper reviews the current knowledge of IL-2 signaling pathway regulating molecules in SLE. PMID- 27987523 TI - Culture methods impact recovery of antibiotic-resistant Enterococci including Enterococcus cecorum from pre- and postharvest chicken. AB - : Pathogenic strains of Enterococcus cecorum (EC) expressing multidrug resistance have emerged. In National Antimicrobial Resistance Monitoring System (NARMS) data, EC is rarely recovered from chickens. Two NARMS methodologies (FDA and USDA) were compared with standard culture (SC) techniques for recovery of EC. NARMS methods failed to detect EC in 58 caecal samples, 20 chicken breast or six whole broiler samples. EC was recovered from 1 of 38 (2.6%) and 2 of 38 (5.2%) preharvest spinal lesions (USDA and FDA method, respectively). In contrast, using the SC method, EC was recovered from 44 of 53 (83%) caecal samples, all 38 (100%) spinal lesions, 14 of 20 (70%) chicken breast samples, and all three spinal lesions identified in whole carcasses. Compared with other Enterococcus spp., EC isolates had a higher prevalence of resistance to macrolides. The NARMS methods significantly affected recovery of enterococcal species other than EC. When the postharvest FDA method was applied to preharvest caecal samples, isolates of Enterococcus faecium were preferentially recovered. All 11 E. faecium isolates were multidrug resistant, including resistance to penicillin, daptomycin and linezolid. These findings confirm that current methodologies may not accurately identify the amount and range of antimicrobial resistance of enterococci from chicken sources. SIGNIFICANCE AND IMPACT OF THE STUDY: Enterococci are an important reservoir for antimicrobial resistance. This study demonstrates how current culture methods underreport resistance to macrolides in enterococci by selecting against strains of Enterococcus cecorum in pre- and postharvest chicken. Further, the application of postharvest surveillance methods to preharvest samples resulted in selective recovery of Enterococcus faecium over Enterococcus faecalis. Isolates of E. faecium recovered exhibited multidrug resistance including penicillin, daptomycin and linezolid resistance. These findings suggest that culture methodology significantly impacts the range and amount of antimicrobial resistance detected in enterococci isolated from chicken. PMID- 27987525 TI - The evolution of cooperation by negotiation in a noisy world. AB - Cooperative interactions among individuals are ubiquitous despite the possibility of exploitation by selfish free riders. One mechanism that may promote cooperation is 'negotiation': individuals altering their behaviour in response to the behaviour of others. Negotiating individuals decide their actions through a recursive process of reciprocal observation, thereby reducing the possibility of free riding. Evolutionary games with response rules have shown that infinitely many forms of the rule can be evolutionarily stable simultaneously, unless there is variation in individual quality. This potentially restricts the conditions under which negotiation could maintain cooperation. Organisms interact with one another in a noisy world in which cooperative effort and the assessment of effort may be subject to error. Here, we show that such noise can make the number of evolutionarily stable rules finite, even without quality variation, and so noise could help maintain cooperative behaviour. We show that the curvature of the benefit function is the key factor determining whether individuals invest more or less as their partner's investment increases, investing less when the benefit to investment has diminishing returns. If the benefits of low investment are very small then behavioural flexibility tends to promote cooperation, because negotiation enables cooperators to reach large benefits. Under some conditions, this leads to a repeating cycle in which cooperative behaviour rises and falls over time, which may explain between-population differences in cooperative behaviour. In other conditions, negotiation leads to extremely high levels of cooperative behaviour, suggesting that behavioural flexibility could facilitate the evolution of eusociality in the absence of high relatedness. PMID- 27987524 TI - Importance and outcome relevance of central pathology review in prostatectomy specimens: data from the SAKK 09/10 randomized trial on prostate cancer. AB - OBJECTIVE: To conduct a central pathology review within a randomized clinical trial on salvage radiation therapy (RT) in the presence of biochemical recurrence after prostatectomy to assess whether this results in changes in histopathological prognostic factors, such as Gleason score. PATIENTS AND METHODS: A total of 350 patients were randomized and specimens from 279 patients (80%) were centrally reviewed by a dedicated genitourinary pathologist. Gleason score, tumour classification and resection margin status were reassessed and compared with the results of local pathology review. Agreement was assessed using contingency tables and Cohen's kappa coefficient. The association between other histopathological features (e.g. largest diameter of carcinoma) and rapid biochemical progression (up to 6 months after salvage RT) was also investigated. RESULTS: There was good concordance between central and local pathology review for seminal vesicle invasion (pT3b: 91%; kappa = 0.95 [95% confidence interval {CI} 0.89, 1.00]), extraprostatic extension (pT3a/b: 94%; kappa = 0.82 [95% CI 0.75, 0.89]) and positive surgical margin (PSM) status (87%; kappa = 0.7 [95% CI 0.62, 0.79]). The rate of agreement was lower for Gleason score (78%; kappa = 0.61 [95% CI 0.52, 0.70]). The median (range) largest diameter of carcinoma was 16 (3-38) mm. A total of 49 patients (18%) experienced rapid biochemical progression after salvage RT. Largest diameter of carcinoma (odds ratio [OR] 2.04 [95% CI 1.30, 3.20]; P = 0.002), resection margin status (OR 0.36 [95% CI 0.18, 0.72]; P = 0.004) and Gleason score (OR 1.55 [95% CI 1.00, 2.42]; P = 0.05) remained associated with rapid progression after salvage RT after backward selection. CONCLUSION: The results of the central pathology analyses showed concordance between central and local pathology review with regard to seminal vesicle invasion, extraprostatic extension and PSM status, but a lower rate of agreement for Gleason score. Largest diameter of carcinoma was found to be a potential prognostic factor for rapid biochemical progression after salvage RT. PMID- 27987526 TI - Molecular Phylogeny of Paraphelidium letcheri sp. nov. (Aphelida, Opisthosporidia). AB - Aphelids remain poorly known parasitoids of algae and have recently raised considerable interest due to their phylogenetic position at the base of Holomycota. Together with Cryptomycota (Rozellosporidia) and Microsporidia, they have been recently re-classified as the Opisthosporidia, which constitutes the sister group to the fungi within the Holomycota. Molecular environmental studies have revealed a huge diversity of aphelids, but only four genera have been described: Aphelidium, Amoeboaphelidium, Paraphelidium, and Pseudaphelidium. Here, we describe the life cycle of a new representative of Aphelida, Paraphelidium letcheri sp. nov., and provide the 18S rRNA gene sequence for this species. Molecular phylogenetic analysis indicates that P. letcheri is sister to Paraphelidium tribonemae and together they form a monophyletic cluster which is distantly related to both, Aphelidium, with flagellated zoospores, and Amoebaphelidium, with amoeboid zoospores. PMID- 27987527 TI - Development, validation and clinical application of Pelvic Lymphadenectomy Assessment and Completion Evaluation: intraoperative assessment of lymph node dissection after robot-assisted radical cystectomy for bladder cancer. AB - OBJECTIVES: To develop a scoring tool, Pelvic Lymphadenectomy Appropriateness and Completion Evaluation (PLACE), to assess the intraoperative completeness and appropriateness of pelvic lymph node dissection (PLND) following robot-assisted radical cystectomy (RARC). PATIENTS, SUBJECTS AND METHODS: A panel of 11 open and robotic surgeons developed the content and structure of PLACE. The PLND template was divided into three zones. In all, 21 de-identified videos of bilateral robot assisted PLNDs were assessed by the 11 experts using PLACE to determine inter rater reliability. Lymph node (LN) clearance was defined as the proportion of cleared LNs from all PLACE zones. We investigated the correlation between LN clearance and LN count. Then, we compared the LN count of 18 prospective PLNDs using PLACE with our retrospective series performed using the extended template (No PLACE). RESULTS: A significant reliability was achieved for all PLACE zones among the 11 raters for the 21 bilateral PLND videos. The median (interquartile range) for LN clearance was 468 (431-545). There was a significant positive correlation between LN clearance and LN count (R2 = 0.70, P < 0.01). The PLACE group yielded similar LN counts when compared to the No PLACE group. CONCLUSIONS: Pelvic Lymphadenectomy Appropriateness and Completion Evaluation is a structured intraoperative scoring system that can be used intraoperatively to measure and quantify PLND for quality control and to facilitate training during RARC. PMID- 27987529 TI - Melatonin promotes circadian rhythm-induced proliferation through Clock/histone deacetylase 3/c-Myc interaction in mouse adipose tissue. AB - Melatonin is synthesized in the pineal gland and controls circadian rhythm of peripheral adipose tissue, resulting in changes in body weight. Although core regulatory components of clock rhythmicity have been defined, insight into the mechanisms of circadian rhythm-mediated proliferation in adipose tissue is still limited. Here, we showed that melatonin (20 mg/kg/d) promoted circadian and proliferation processes in white adipose tissue. The circadian amplitudes of brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (Bmal1, P<.05) and circadian locomotor output cycles kaput (Clock, P<.05), period 2 (Per2, P<.05), cyclin E (P<.05), and c-Myc (P<.05) were directly increased by melatonin in adipose tissue. Melatonin also promoted cell cycle and increased cell numbers (P<.05), which was correlated with the Clock expression (P<.05). Further analysis demonstrated that Clock bound to the E-box elements in the promoter region of c-Myc and then directly stimulated c-Myc transcription. Moreover, Clock physically interacted with histone deacetylase 3 (HDAC3) and formed a complex with c-Myc to promote adipocyte proliferation. Melatonin also attenuated circadian disruption and promoted adipocyte proliferation in chronic jet-lagged mice and obese mice. Thus, our study found that melatonin promoted adipocyte proliferation by forming a Clock/HDAC3/c-Myc complex and subsequently driving the circadian amplitudes of proliferation genes. Our data reveal a novel mechanism that links circadian rhythm to cell proliferation in adipose tissue. These findings also identify a new potential means for melatonin to prevent and treat sleep deprivation-caused obesity. PMID- 27987530 TI - Obesity, insulin resistance, and microvascular adaptation. AB - Two of the primary risk factors for the progressive evolution of cardiovascular disease are obesity and impaired glycemic control-including both insulin resistance and overt type 2 diabetes mellitus, leading to increased research emphasis on these conditions, their mechanistic bases, and their health outcomes. This Special Topics Issue of the journal Microcirculation summarizes a symposium at the recent Joint Meeting of the American Physiological Society and the Physiological Society, held in Dublin, Ireland, on July 30, 2016. This symposium, "Adaptive outcomes of microvascular networks to obesity and type 2 diabetes mellitus/insulin resistance," presented four lectures, each of which addressed the larger issue from a different perspective. PMID- 27987531 TI - How to Survive a High-Deductible Health Plan. Is your insurance giving you a bad case of sticker shock? Here are ways to ease the pain. PMID- 27987532 TI - Colon cancer runs in my family: Should I get a genetic test? I worry that'll affect my insurance. PMID- 27987528 TI - Mouse fat storage-inducing transmembrane protein 2 (FIT2) promotes lipid droplet accumulation in plants. AB - Fat storage-inducing transmembrane protein 2 (FIT2) is an endoplasmic reticulum (ER)-localized protein that plays an important role in lipid droplet (LD) formation in animal cells. However, no obvious homologue of FIT2 is found in plants. Here, we tested the function of FIT2 in plant cells by ectopically expressing mouse (Mus musculus) FIT2 in Nicotiana tabacum suspension-cultured cells, Nicotiana benthamiana leaves and Arabidopsis thaliana plants. Confocal microscopy indicated that the expression of FIT2 dramatically increased the number and size of LDs in leaves of N. benthamiana and Arabidopsis, and lipidomics analysis and mass spectrometry imaging confirmed the accumulation of neutral lipids in leaves. FIT2 also increased seed oil content by ~13% in some stable, overexpressing lines of Arabidopsis. When expressed transiently in leaves of N. benthamiana or suspension cells of N. tabacum, FIT2 localized specifically to the ER and was often concentrated at certain regions of the ER that resembled ER-LD junction sites. FIT2 also colocalized at the ER with other proteins known to be involved in triacylglycerol biosynthesis or LD formation in plants, but not with ER resident proteins involved in electron transfer or ER-vesicle exit sites. Collectively, these results demonstrate that mouse FIT2 promotes LD accumulation in plants, a surprising functional conservation in the context of a plant cell given the apparent lack of FIT2 homologues in higher plants. These results suggest also that FIT2 expression represents an effective synthetic biology strategy for elaborating neutral lipid compartments in plant tissues for potential biofuel or bioproduct purposes. PMID- 27987533 TI - Zero Tolerance. AB - There's a type of hospital infection that's often deadly--and almost entirely preventable. Though rates have dropped, too many institutions are still needlessly exposing patients to dangerous bacteria, our investigation reveals. Here, which hospitals do a good job--and which don't. Plus how to keep yourself and your family safe. PMID- 27987534 TI - An Essential Heart-Surgery Device Has a Rare But Deadly Side Effect. AB - Hospitals and federal officials are scrambling to manage a newly discovered infection risk in open chest surgeries. What patients need to know to protect themselves. PMID- 27987535 TI - The Safest Car Seat for Your Child. AB - Our crash tests reveal the benefit of moving children to a convertible seat sooner than previously recommended. PMID- 27987537 TI - Comparison of hepatic MDCT, MRI, and DSA to explant pathology for the detection and treatment planning of hepatocellular carcinoma. AB - BACKGROUND/AIMS: The diagnosis and treatment plan for hepatocellular carcinoma (HCC) can be made from radiologic imaging. However, lesion detection may vary depending on the imaging modality. This study aims to evaluate the sensitivities of hepatic multidetector computed tomography (MDCT), magnetic resonance imaging (MRI), and digital subtraction angiography (DSA) in the detection of HCC and the consequent management impact on potential liver transplant patients. METHODS: One hundred and sixteen HCC lesions were analyzed in 41 patients who received an orthotopic liver transplant (OLT). All of the patients underwent pretransplantation hepatic DSA, MDCT, and/or MRI. The imaging results were independently reviewed retrospectively in a blinded fashion by two interventional and two abdominal radiologists. The liver explant pathology was used as the gold standard for assessing each imaging modality. RESULTS: The sensitivity for overall HCC detection was higher for cross-sectional imaging using MRI (51.5%, 95% confidence interval [CI]=36.2-58.4%) and MDCT (49.8%, 95% CI=43.7-55.9%) than for DSA (41.7%, 95% CI=36.2-47.3%) (P=0.05). The difference in false-positive rate was not statistically significant between MRI (22%), MDCT (29%), and DSA (29%) (P=0.67). The sensitivity was significantly higher for detecting right lobe lesions than left lobe lesions for all modalities (MRI: 56.1% vs. 43.1%, MDCT: 55.0% vs. 42.0%, and DSA: 46.9% vs. 33.9%; all P<0.01). The sensitivities of the three imaging modalities were also higher for lesions >=2 cm vs. <2 cm (MRI: 73.4% vs. 32.7%, MDCT: 66.9% vs. 33.8%, and DSA: 62.2% vs. 24.1%; all P<0.01). The interobserver correlation was rated as very good to excellent. CONCLUSION: The sensitivity for detecting HCC is higher for MRI and MDCT than for DSA, and so cross-sectional imaging modalities should be used to evaluate OLT candidacy. PMID- 27987538 TI - Vitamin D deficiency and its impact on asthma severity in asthmatic children. AB - BACKGROUND: Despite obtaining evidences on association between vitamin D and development of lung in fetus, little is known about vitamin D level and its impact on severity of asthma in children. The present study aimed to assess the relationship between the asthma severity and vitamin D deficiency in asthmatic children. METHODS: This case-control study was conducted on 106 individuals including asthmatic (n = 53) and healthy children (n = 53) who referred to Mofid hospital in Tehran in 2013. The level of serum vitamin D in both groups was measured by radioimmunoassay method at the reference lab and was categorized as sufficient (> 30 ng/ml), insufficient (20 to 30 ng/ml), or deficient (< 20 ng/ml). The control status of asthma in patients group was classified as controlled, partially controlled, and uncontrolled. RESULTS: In the groups with and without asthma, the prevalence of vitamin D deficiency was 73.6 and 49.1%, and the prevalence of vitamin D insufficiency was 18.9 and 18.9%, while normal vitamin D level was revealed in 7.5 and 32.1%, respectively with a significant difference (p = 0.005). Using the multivariate logistic regression analysis, the presence of asthma was associated with reduced level of vitamin D (OR = 1.068, 95% CI: 1.027-1.110, P = 0.001). In this context, the risk for asthma in the children with vitamin D deficiency was 6.3 times of those with normal vitamin D level. Although the presence of asthma was strongly associated with reduced level of vitamin D in serum, neither severity of asthma nor control status of asthma were associated with vitamin D deficiency. CONCLUSION: The presence of vitamin D deficiency effectively predict increased risk for childhood asthma; however the severity or control status of this event may not be predicted by confirming vitamin D deficiency. PMID- 27987536 TI - Acute kidney injury in liver cirrhosis: new definition and application. AB - The traditional diagnostic criteria of renal dysfunction in cirrhosis are a 50% increase in serum creatinine (SCr) with a final value above 1.5 mg/dL. This means that patients with milder degrees of renal dysfunction are not being diagnosed, and therefore not offered timely treatment. The International Ascites Club in 2015 adapted the term acute kidney injury (AKI) to represent acute renal dysfunction in cirrhosis, and defined it by an increase in SCr of 0.3 mg/dL (26.4 umoL/L) in <48 hours, or a 50% increase in SCr from a baseline within <=3 months. The severity of AKI is described by stages, with stage 1 represented by these minimal changes, while stages 2 and 3 AKI by 2-fold and 3-fold increases in SCr respectively. Hepatorenal syndrome (HRS), renamed AKI-HRS, is defined by stage 2 or 3 AKI that fulfils all other diagnostic criteria of HRS. Various studies in the past few years have indicated that these new diagnostic criteria are valid in the prediction of prognosis for patients with cirrhosis and AKI. The future in AKI diagnosis may include further refinements such as inclusion of biomarkers that can identify susceptibility for AKI, differentiating the various prototypes of AKI, or track its progression. PMID- 27987540 TI - Introduction: Toward Precision Medicines for Kidney Disease. PMID- 27987539 TI - Altered network efficiency in major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) is associated with dysfunction between cognitive control and affective processing system. However, little is known about alterations of the nodal and edge efficiency in abnormal systems of MDD patients. We used two independent datasets and two different structural templates to investigate the alterations of the nodal and edge efficiency of whole-brain functional networks of MDD. METHOD: Forty-two MDD and forty-two age, education-matched controls were selected to investigate network efficiency abnormalities of the MDD patients' cortical and subcortical regions, as well as the disrupted functional connectivity between these regions, from the perspective of network topological architectures. In addition, another dataset, which included thirty MDD patients and thirty controls, was also investigated using the same method. RESULTS: Results showed that MDD group demonstrated significant increase in the local efficiency, although not change of global efficiency. In addition, nodal efficiency was found to increase in affective processing regions (i.e., amygdale, thalamus, hippocampus), but decrease in cognitive control related regions, which included dorsolateral prefrontal cortex and anterior cingulate cortex. The edge efficiency was found to increase, involving both connectivity between thalamus and limbic system regions and connectivity between hippocampus and regions (i.e., amygdala, thalamus). More important, result was replicated within independent datasets for the first and different structural templates for another. CONCLUSIONS: Our results indicated that MDD was associated with disrupted functional connectivity networks between cognitive control and affective processing systems. The findings might shed light on the pathological mechanism of depression and provide potential biomarkers for clinic treatment of depression. PMID- 27987542 TI - An Introduction to the Glom-NExT Inaugural Symposium: Toward Precision Medicine in Nephrology. PMID- 27987543 TI - Personalized Comments on Challenges and Opportunities in Kidney Disease Therapeutics: The Glom-NExT Symposium. AB - In the face of ever-increasing incidence and prevalence of kidney disease worldwide, the unmet need for new treatments is unprecedented. Precision medicine is defined as the use of modern technologies to identify mechanisms of diseases in individual patients, and thus deploy treatment using tailored, targeted approaches, in the hopes of avoiding unnecessary toxicities and complications. Is there a place for kidney disease therapeutics in this space? If so, what is required to make significant progress toward precision nephrology? To answer these critical questions, we present a series of personalized comments corresponding to the responses offered to these very questions during the Inaugural Glom-NExT Symposium held at Harvard Medical School on October 23, 2014, a national meeting focused exclusively on kidney disease therapeutics. PMID- 27987544 TI - Clinical Trials in FSGS: Past Challenges and New Trial Designs. PMID- 27987545 TI - Podocyte-Targeted Treatment for Proteinuric Kidney Disease. PMID- 27987546 TI - Tales of Personalized Cancer Treatment. PMID- 27987541 TI - Developing Treatments for Chronic Kidney Disease in the 21st Century. AB - Chronic kidney disease (CKD) is a lethal and rapidly increasing burden on society. Despite this, there are relatively few therapies in development for the treatment of CKD. Several recent costly phase 3 trials have failed to provide improved renal outcomes, diminishing interest in pharmaceutical investment. Furthermore, poor patient, physician, and payer awareness of CKD as a diagnosis has contributed to slow trial enrollment and successful implementation of these trials. Nevertheless, several therapeutics remain in development for the treatment of CKD, including mineralocorticoid-receptor antagonists, sodium/glucose cotransporter 2 inhibitors, anti-inflammatory drugs, and drugs that mitigate oxidative injury. Success of future CKD therapeutic trials will depend not only on improved understanding of disease pathogenesis, but also on improved trial enrollment rates, through increasing awareness of this disease by the public, policy makers, and the greater medical community. PMID- 27987547 TI - Genetics of Familial FSGS. PMID- 27987548 TI - Genetics of Kidney Diseases. PMID- 27987549 TI - Genetics of Diabetic Kidney Disease. PMID- 27987550 TI - Back to the Future: Paving the Way for the Next Generation of Renal Therapeutics. PMID- 27987551 TI - Cholinergic influences on vision. PMID- 27987552 TI - Letter From the Editors. PMID- 27987553 TI - Molecular Imaging of Extrapyramidal Movement Disorders. AB - Extrapyramidal movement disorders including Parkinson disease, multiple systems atrophy, progressive supranuclear palsy, and corticobasal degeneration are neurodegenerative syndromes with distinct neuropathological changes, indicating differing underlying etiologies. Clinical features that may distinguish among these conditions are often absent, particularly early after the onset of symptoms. Therapy is presently limited, and there are no established disease modifying or neuroprotective interventions. Advances in therapeutics will depend on the early and accurate diagnostic classification of patients. Existing molecular imaging approaches demonstrate ability to separate several of these syndromes, but are clinically underutilized or are available only in research settings. The development of additional, specific imaging approaches targeting the misfolded protein deposits that characterize these neurodegenerative pathologies promises to advance not only the sensitive and specific endophenotyping of patients, but may also serve to measure directly potential therapeutic responses in the initial evaluations of new treatments. PMID- 27987554 TI - Updates in Molecular Brain Imaging. PMID- 27987555 TI - Clinical Amyloid Imaging. AB - Amyloid plaques, along with neurofibrillary tangles, are a neuropathologic hallmark of Alzheimer disease (AD). Recently, amyloid PET radiotracers have been developed and approved for clinical use in the evaluation of suspected neurodegenerative disorders. In both research and clinical settings, amyloid PET imaging has provided important diagnostic and prognostic information for the management of patients with possible AD, mild cognitive impairment (MCI), and other challenging diagnostic presentations. Although the overall impact of amyloid imaging is still being evaluated, the Society of Nuclear Medicine and Molecular Imaging and Alzheimer's Association Amyloid Imaging Task Force have created appropriate use criteria for the standard clinical use of amyloid PET imaging. By the appropriate use criteria, amyloid imaging is appropriate for patients with (1) persistent or unexplained MCI, (2) AD as a possible but still uncertain diagnosis after expert evaluation and (3) atypically early-age-onset progressive dementia. To better understand the clinical and economic effect of amyloid imaging, the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study is an ongoing large multicenter study in the United States, which is evaluating how amyloid imaging affects diagnosis, management, and outcomes for cognitively impaired patients who cannot be completely evaluated by clinical assessment alone. Multiple other large-scale studies are evaluating the prognostic role of amyloid PET imaging for predicting MCI progression to AD in general and high-risk populations. At the same time, amyloid imaging is an important tool for evaluating potential disease-modifying therapies for AD. Overall, the increased use of amyloid PET imaging has led to a better understanding of the strengths and limitations of this imaging modality and how it may best be used with other clinical, molecular, and imaging assessment techniques for the diagnosis and management of neurodegenerative disorders. PMID- 27987556 TI - Presurgical Focus Localization in Epilepsy: PET and SPECT. AB - Positron emission tomography (PET) and single photon emission computed tomography (SPECT) can be used to assist localization of seizure foci in patients with drug resistant epilepsy. Both should be interpreted in the context of clinical, electrographic, and magnetic resonance imaging data. PET has wider research applications, particularity when used with ligands for neurotransmitter receptors or inflammatory processes. PMID- 27987557 TI - Brain Tumors: An Update on Clinical PET Research in Gliomas. AB - A previous review published in 2012 demonstrated the role of clinical PET for diagnosis and management of brain tumors using mainly FDG, amino acid tracers, and 18F-fluorothymidine. This review provides an update on clinical PET studies, most of which are motivated by prediction of prognosis and planning and monitoring of therapy in gliomas. For FDG, there has been additional evidence supporting late scanning, and combination with 13N ammonia has yielded some promising results. Large neutral amino acid tracers have found widespread applications mostly based on 18F-labeled compounds fluoroethyltyrosine and fluorodopa for targeting biopsies, therapy planning and monitoring, and as outcome markers in clinical trials. 11C-alpha-methyltryptophan (AMT) has been proposed as an alternative to 11C-methionine, and there may also be a role for cyclic amino acid tracers. 18F-fluorothymidine has shown strengths for tumor grading and as an outcome marker. Studies using 18F-fluorocholine (FCH) and 68Ga labeled compounds are promising but have not yet clearly defined their role. Studies on radiotherapy planning have explored the use of large neutral amino acid tracers to improve the delineation of tumor volume for irradiation and the use of hypoxia markers, in particular 18F-fluoromisonidazole. Many studies employed the combination of PET with advanced multimodal MR imaging methods, mostly demonstrating complementarity and some potential benefits of hybrid PET/MR. PMID- 27987558 TI - Recent Developments in Molecular Brain Imaging of Neuropsychiatric Disorders. AB - Molecular imaging with PET or SPECT has been an important research tool in psychiatry for as long as these modalities have been available. Here, we discuss two areas of neuroimaging relevant to current psychiatry research. The first is the use of imaging to study neurotransmission. We discuss the use of pharmacologic probes to induce changes in levels of neurotransmitters that can be inferred through their effects on outcome measures of imaging experiments, from their historical origins focusing on dopamine transmission through recent developments involving serotonin, GABA, and glutamate. Next, we examine imaging of neuroinflammation in the context of psychiatry. Imaging markers of neuroinflammation have been studied extensively in other areas of brain research, but they have more recently attracted interest in psychiatry research, based on accumulating evidence that there may be an inflammatory component to some psychiatric conditions. Furthermore, new probes are under development that would allow unprecedented insights into cellular processes. In summary, molecular imaging would continue to offer great potential as a unique tool to further our understanding of brain function in health and disease. PMID- 27987559 TI - Blunted Dopamine Transmission in Addiction: Potential Mechanisms and Implications for Behavior. AB - Positron emission tomography (PET) imaging consistently shows blunted striatal dopamine release and decreased dopamine D2 receptor availability in addiction. Here, we review the preclinical and clinical studies indicating that this neurobiological phenotype is likely to be both a consequence of chronic drug consumption and a vulnerability factor in the development of addiction. We propose that, behaviorally, blunted striatal dopamine transmission could reflect the increased impulsivity and altered cost/benefit computations that are associated with addiction. The factors that influence blunted striatal dopamine transmission in addiction are unknown. Herein, we give an overview of various factors, genetic, environmental, and social, that are known to affect dopamine transmission and that have been associated with the vulnerability to develop addiction. Altogether, these data suggest that blunted dopamine transmission and decreased D2 receptor availability are biomarkers both for the development of addiction and resistance to treatment. These findings support the view that blunted dopamine reflects impulsive behavior and deficits in motivation, which lead to the escalation of drug use. PMID- 27987560 TI - Abeta-amyloid and Tau Imaging in Dementia. AB - The introduction of in vivo imaging of Abeta-amyloid (Alphabeta) pathology more than a decade ago, transformed the assessment of Alzheimer disease (AD) allowing the evaluation of Abeta deposition over time by providing highly accurate, reliable, and reproducible quantitative statements of regional or global Abeta burden in the brain to the extent that Abeta imaging has already been approved for clinical use and is being used for both patient recruitment and outcome measure in current anti-Alphabeta therapeutic trials. Abeta imaging studies have deepened our insight into Abeta deposition, showing that Abeta accumulation is a slow and protracted process extending for more than two decades before the onset of the clinical phenotype. Although cross-sectional evaluation of Alphabeta burden does not strongly correlate with cognitive impairment in AD, Alphabeta burden does correlate with memory impairment and a higher risk for cognitive decline in the aging population and mild cognitive impairment subjects. These associations suggest that Alphabeta deposition is not a benign process. The recent addition of selective tau imaging will allow to elucidate if these effects are directly associated with Alphabeta deposition or if they are mediated, in toto or in parte, by tau as it spreads out of the mesial temporal lobe into neocortical association areas. The combination of Abeta and tau imaging studies would likely help elucidate the relationship or interplay between the two pathologic hallmarks of the disease. Longitudinal observations to assess their potential independent or synergistic, sequential or parallel effects on cognition, disease progression, and other disease-specific biomarkers of neurodegeneration would be required to further clarify the respective role of Alphabeta and tau deposition play in the course of AD. PMID- 27987561 TI - Imaging in Central Nervous System Drug Discovery. AB - The discovery and development of central nervous system (CNS) drugs is an extremely challenging process requiring large resources, timelines, and associated costs. The high risk of failure leads to high levels of risk. Over the past couple of decades PET imaging has become a central component of the CNS drug development process, enabling decision-making in phase I studies, where early discharge of risk provides increased confidence to progress a candidate to more costly later phase testing at the right dose level or alternatively to kill a compound through failure to meet key criteria. The so called "3 pillars" of drug survival, namely; tissue exposure, target engagement, and pharmacologic activity, are particularly well suited for evaluation by PET imaging. This review introduces the process of CNS drug development before considering how PET imaging of the "3 pillars" has advanced to provide valuable tools for decision-making on the critical path of CNS drug development. Finally, we review the advances in PET science of biomarker development and analysis that enable sophisticated drug development studies in man. PMID- 27987562 TI - [The assessment of family resources and need for help: Construct validity and reliability of the Systematic Exploration and Process Inventory for health professionals in early childhood intervention services (SEVG)]. AB - BACKGROUND: Health professionals in early childhood intervention and prevention make an important contribution by helping burdened families with young children cope with everyday life and child raising issues. A prerequisite for success is the health professionals' ability to tailor their services to the specific needs of families. METHODS: The "Systematic Exploration and Process Inventory for health professionals in early childhood intervention services (SEVG)" can be used to identify each family's individual resources and needs, enabling a valid, reliable and objective assessment of the conditions and the process of counseling service. The present paper presents the statistical analyses that were used to confirm the reliability of the inventory. RESULTS: Based on the results of the reliability analysis and principal component analysis (PCA), the SEVG seems to be a reliable and objective inventory for assessing families' need for support. It also allows for calculation of average values of each scale. CONCLUSION: The development of valid and reliable assessments is essential to quality assurance and the professionalization of interventions in early childhood service. PMID- 27987563 TI - [Quality management in a clinical research facility: Evaluation of changes in quality in-house figures and the appraisal of in-house quality indicators]. AB - For long-term maintenance and improvement of quality within a clinical research institute, the implementation and certification of a quality management system is suitable. Due to the implemented quality management system according to the still valid DIN EN ISO 9001:2008 desired quality objectives are achieved effectively. The evaluation of quality scores and the appraisal of in-house quality indicators make an important contribution in this regard. In order to achieve this and draw quality assurance conclusions, quality indicators as sensible and sensitive as possible are developed. For this, own key objectives, the retrospective evaluation of quality scores, a prospective follow-up and also discussions establish the basis. In the in-house clinical research institute the measures introduced by the quality management led to higher efficiency in work processes, improved staff skills, higher customer satisfaction and overall to more successful outcomes in relation to the self-defined key objectives. PMID- 27987564 TI - How contextual issues can distort shared decision making. AB - Shared decision making in medicine has become a widely promoted approach. The goal is for patients and physicians to reach a mutual, informed decision by taking into consideration scientific evidence, clinical experience, and the patient's personal values or preferences. Shared decision making, however, is not a straightforward process. In practice, it might fall short of what it promises and might even be misused to whitewash monetary motives. In this article, which summarizes a presentation given at the 17th Annual Conference of the German Network Evidence-based Medicine on March 4th, 2016 in Cologne, Germany, we discuss three contextual factors that in our opinion can have a tremendous impact on any informed decision making: 1) opinions and convictions of physicians or other clinicians; 2) uncertainty of the evidence regarding benefits and harms; 3) uncertainty of patients about their own values and preferences. But despite barriers and shortcomings, modern medicine currently does not have an alternative to shared decision making. Shared decision making has become a central theme in good quality health care because it has a strong ethical component. Advocates of shared decision making, however, must realize that not all patients prefer to participate in decision making. For those who do, however, we must ensure that shared decisions can be made in a neutral environment as free of biases and conflicts of interest as possible. PMID- 27987565 TI - Economic burden of deep infiltrating endometriosis of the bowel and the bladder in Germany: The statutory health insurance perspective. AB - BACKGROUND: Until now, there has been little discussion of the costs of the deep infiltrating endometriosis (DIE) of the bowel or the bladder. The aim of the present secondary data analysis was to describe the population affected by this disease and to determine the economic burden in Germany from a payer's perspective. METHODS: Health claims data of women diagnosed with DIE of the bladder or bowel, who were surgically treated as inpatients between Jan 1, 2008 and Dec 31, 2012, were evaluated retrospectively. All data were extrapolated on a national statutory health insurance (SHI) level and normalized based on the year of surgery (index year). Case-individual information on age, comorbidities and prescribed drugs were presented for the index year. Direct medical cost data were analysed before and after the index year, differentiated by cost sector and age group. RESULTS: The data of 825 women with DIE were analysed. Sample size for different time points varied depending on insurance eligibility and continuous case information. The average age at surgery was 39 years. Besides DIE, 41 % of the women had at least one additional disease of the peritoneum. The mean annual total healthcare costs per DIE case were 12,868 Euros in the index year. Before surgery, mean annual costs varied between 548 and 2,475 Euros per case and after surgery between 1,739 and 2,818 Euros per case. In total, mean costs were higher in younger women as compared to older women, with a cost difference of 616 Euros over all time points. CONCLUSION: Direct costs are highest during the year of surgical treatment, but DIE of the bowel and bladder places a substantial burden on the SHI also before and after surgery. Further studies on indirect costs would be desirable to complete the knowledge on the economic burden of DIE. PMID- 27987567 TI - Quality of secondary prevention of coronary heart disease in Swiss primary care: Lessons learned from a 6-year observational study. AB - INTRODUCTION: Across Europe, great variations have been identified in the quality of preventive healthcare services delivered in primary care (PC). We aimed to assess the quality of secondary prevention in Swiss PC patients with coronary heart disease (CHD) and its evolution over six years. METHODS: In the database of the Swiss "Family Medicine ICPC Research using Electronic Medical Records" (FIRE) project, we identified electronical record data of 2,807 patients with CHD treated for at least 15 months between 2009 and 2014. Primary outcome was the proportion of patients per year meeting four quality indicators of the British Quality and Outcome Framework (QOF): 1) blood pressure (BP) <= 150mmHg, 2) total serum cholesterol <= 5mmol/L, 3) prescription of anti-platelet therapy, 4) recommended drug prescriptions for patients with previous myocardial infarction (MI). Secondary outcome was the proportion of patients who were ineligible for indicator calculation because of incomplete record data. RESULTS: From 2009 to 2014, 85.9, 83.1, 82.0, 81.9, 81.5, and 81.0 % of the patients met BP targets and 73.6, 77.0, 69.2, 73.6, 69.4, and 69.1% met cholesterol targets. Anti-platelet therapy was prescribed to 74.8, 76.1, 73.9, 70.2, 72.2, and 72.5 % of the patients. Finally, 83.3, 84.4, 87.5, 75.6, 89.8, and 89.2 % of the patients with previous MI received the recommended drug therapy. Changes over time were not significant. Missing BP records concerned 12.4-15.9 % of the patients, and missing cholesterol records 69.0-75.6 %. Females and patients with less cardiovascular comorbidities were more likely to show missing records. CONCLUSIONS: Quality of secondary prevention did not improve when measured against QOF indicators in the period under investigation. Missing data in electronic medical records inhibited full quality indicator assessment. Especially in female patients and those with less cardiovascular comorbidity, closer medical documentation should be encouraged in order to facilitate quality of care measurements. PMID- 27987566 TI - Predictors and determinants for weight reduction in overweight and obese children and adolescents. AB - INTRODUCTION: Worldwide, overweight and obesity are known as posing serious health risks. Successful methods for weight reduction have remained elusive. This multicenter non-randomised trial aimed to identify parameters and determinants of long-term weight reduction. PATIENTS AND METHODS: A total of 143/159 overweight and obese children and adolescents (90 %) completed the prospective multicenter trial (age 13.9+/-2.4 years, BMI 31.2+/-5.4kg/m2, BMI-SDS 2.51+/-0.57). During a 6-week rehabilitation period the patients participated in a structured treatment and teaching program (STTP). Following in-patient treatment the children and adolescents were monitored over a period of 24 months (physical examination, measurements of BMI, BMI-SDS, body composition, carotid intima-media thickness, laboratory parameters, blood pressure, standardized questionnaires to assess socio-demographic and socio-economic parameters, eating behavior, well-being, quality of life, intelligence, intrafamilial conflicts, self-efficacy, resilience, sense of coherence, stress management, social support, actual body shape). RESULTS: 66% of the children and adolescents had abnormal laboratory parameters as well as higher blood pressure and/or an increased carotid intima media thickness. The mean carotid intima-media thickness was 0.53+/-0.09mm (range 0.40 to 0.80); 15% of the patients showed normal range values (< 0.45mm), 40% a slightly elevated (>= 0.45 to <= 0.50mm) and 45% an elevated (> 0.50mm) thickness. After the inpatient treatment lasting 40.4+/-4.1 (range 28 to 49) days, children and adolescents reached a mean weight reduction of 5.52+/-3.94 (0.4 to 13.3) kg (p<0.01) that was accompanied by a reduction in body fat mass. Using multivariate analyses, the most important psychological factors associated with long-term weight reduction were identified (R-square=0.53): well-being (beta=-0.543), resilience (beta=0.434), and sense of coherence (beta=0.315). CONCLUSION: The different parameters (i. e., well-being, resilience, sense of coherence) have demonstrated their utility, and strategies should be developed allowing an adaption of these into the STTPs. PMID- 27987568 TI - [ICD coding quality for outpatient cancer diagnoses in SHI claims data]. AB - BACKGROUND: Despite their importance for the morbidity-oriented risk structure compensation scheme, the ICD coding quality for outpatient diagnoses is often criticized. However, the coding quality for outpatient cancer diagnoses remains unclear. In this study, we examined the ICD-10 coding quality for outpatient breast, prostate and colorectal cancer diagnoses in statutory health insurance (SHI) claims data. METHODS: The cohort study comprised 34,756 members of the BARMER GEK statutory health insurance fund diagnosed with breast, prostate or colorectal cancer in 2012 and with no respective diagnosis in the previous 4 quarters. Using internal validation approaches, we examined the proportion of diagnoses confirmed by persistence (further diagnoses or death) and/or congruence (EBM, OPS and ATC codes). RESULTS: The proportion of diagnoses confirmed by a further diagnosis or death within one quarter of follow-up was 69.8 % for breast cancer, 73.0 % for prostate cancer and 64.6 % for colorectal cancer, increasing to 71.8 %, 74.6 % and 68.0 %, respectively, when considering provision of care using EBM, OPS and ATC codes. By extending the diagnosis-free lead time to 16 quarters and the follow-up time to 4 quarters, the proportion rose to 83.9 %, 85.1 % and 75.8 %, respectively. Results varied by sex, age, the Associations of SHI Physicians and settlement pattern. CONCLUSIONS: Because there were no further indications confirming the incident outpatient cancer diagnoses a proportion of diagnoses remain unconfirmed. When conducting studies based on SHI claims data, these limitations in the ICD coding quality for outpatient cancer diagnoses should be taken into account by using internal validation approaches. PMID- 27987570 TI - ? PMID- 27987569 TI - [Centrally and non-centrally designed exams in nursing: Comparisons of the final exams in 2008 to 2013 in Berlin focusing on different concepts of professional nursing education]. AB - INTRODUCTION: In Germany, nursing education ends with a final written, oral and practical exam. In the federal state of Berlin, Germany, all nursing students take centrally standardized written exams, while the practical and oral exams are developed by each individual nursing school or university and conducted without standardized protocols (non-central). Comparability might be seriously limited by this procedure. Since there is no official statistics available, the objective of this study is to compare the results of the final written, oral and practical exams of different nursing education institutions with an additional focus on different educational concepts. METHODS: In a secondary data analysis, the final grades (written, oral, practical) of 4,342 nursing students in all 16 educational institutions in Berlin from 2008 to 2013 were analyzed. RESULTS: The mean (SD) of all written, oral and practical exams taken was 2.9 (0.7), 2.6 (1.1) and 2.2 (1.0), respectively. In each type of exam, the trend in grades was stable over the observation period. There was a statistically significant increase in the prevalence of initially failed exams from 2008 (7.9 %) to 2013 (12.0 %). In institutions following a traditional concept of education, the difference in grades between oral/practical exams on the one hand and written exams on the other ranged from 0.1 to 0.9, while in generalist (academic) institutions it ranged between -0.1 and 0.3 (-0.1 to 0). CONCLUSION: In nursing schools with a traditional approach to education, there was a big difference in grades between written and oral/practical exams. Standardization of oral and practical exams should be initiated to ensure greater comparability between different educational institutions. PMID- 27987571 TI - [Active participation in research and teaching during post-graduate GP training: perspectives of future general practitioners]. AB - BACKGROUND: Academic institutions of general practice at German medical faculties have grown during the past years. This leads to an increase in the need of qualified young researchers and teachers in general practice (GP). Little is known about the interest in research and teaching skills and their training among general practice trainees and young GPs. RESEARCH QUESTION: This cross-sectional survey among GP trainees and young GPs examined 1. if there is an interest in the training in research and teaching skills during post-graduate GP training, 2. which fostering and hindering factors have an effect on this interest and 3. which roles are attributed to academic institutions of general practice. METHODS: A web-based cross-sectional study was performed among members of "Verbundweiterbildungplus", a network of GP trainees, as well as "Junge Allgemeinmedizin Deutschland", the German network of young GPs. Descriptive analysis was conducted. RESULTS: 148 GP trainees and young GPs participated in the study, 76% (n=109) of them were GP trainees. There was interest in a position in research and teaching during post-graduate GP training among 55% (n=78). Factors associated with the interest in a position in research and teaching during post-graduate GP training were (MV 5-point Likert scale +/- SD): compatibility of clinical work and research/teaching and of family and career (4.4+/-0.8; 4.7+/-0.6 respectively). The roles of academic institutions of general practice were attributed to training of medical students (4.6+/-0.6), post-graduate GP training (4.5+/-0.7) and research (4.5+/-0.7). GP trainees assessed the importance of training in research and teaching skills during post graduate GP training and of the compatibility of family and career differently from young GPs (3.7+/-1.0 vs. 4.1+/-0.8 p=0.027; 4.8+/-0.5 vs. 4.3+/-0.9, p=0.016). Those interested in a position in research and teaching during post graduate GP training showed a stronger interest in specific training in research skills (3.7+/-1.1 vs. 2.8+/-1.1, p<0.001), a future clinical position in a research practice (3.8+/-1.2 vs. 2.5+/-1.2, p<0.001) and as a lecturer at an academic institution of general practice (4.3+/-0.9 vs. 3.9+/-1.1, p=0.04). DISCUSSION: There is an interest in professional involvement in research and teaching during post-graduate GP training among GP trainees and young GPs. For those interested, structured concepts (e.g. "clinician scientist") need to be developed in order to facilitate the combination of clinical work and a position in research and teaching during post-graduate GP training. In doing so, the existing potential could be better exploited and more future GPs could be involved in research and teaching. PMID- 27987572 TI - [Changing to a career in general practice - a qualitative study reveals motives of specialists]. AB - BACKGROUND: In 2011, the national German Medical Association (Bundesarztekammer) published guidelines for a slim-lined training program in general practice (Quereinstieg) for qualified medical specialists in other fields (e. g., surgeons, internists or anesthesiologists). This step is part of a strategy to prevent further shortages of general practitioners in Germany. In the state of Baden-Wuerttemberg, qualified medical specialists are allowed to complete their general practice training in approximately two years instead of five. The aim of this study was to understand the reasons of specialists for changing to a career in general practice. METHODS: The postgraduate training program VerbundweiterbildungplusBaden-Wurttemberg had 597 trainees at the time of the study in December 2015. Previously qualified specialists in another medical discipline were identified and invited to participate in this study. Qualitative data was gathered using semi-structured interviews with content analysis of the interviews performed by three independent members of the research team. RESULTS: In total, 36 out of 597 trainees were identified as previously qualified specialists in another medical discipline. All 36 were invited to take part and 15 agreed to participate in this study. Overall, 15 interviews were performed, with a mean time of 24.19minutes. Participants with a median age of 40 years (33 59 years) - mainly anesthesiologists (n=7), surgeons (n=3) and internists (n=3) - presented with an average of 6.5 years of professional experience in their specialty. First, the participants' motivation to switch career arose from the wish to intensify the quality of patient contacts with a holistic approach including family and social background and from the infinite variety of general practice. Another reason given for a career change was self-employment opportunities. Finally, feelings of frustration over poor working conditions in hospitals resulted in a job search elsewhere in medicine, taking account of the challenges of ageing and family life. A major finding was that without the slim lined program, the majority of participants would not have changed their career. DISCUSSION: The slim-lined training program in general practice attracts experienced medical doctors. Specialists decide to change career because of the particular ways of working in general practice and with the intention to improve their daily work as a physician, either to improve individual working conditions and/or to improve their individual curative work profile. In addition, specialists are attracted by the concept of self-employment in general practice. Therefore, appreciation of the specific ways of working in general practice as well as management skills are most important during the reduced 2-year training. Further studies should investigate if facilitating a career switch to general practice is a good way to improve the shortage of general practitioners. PMID- 27987573 TI - Editorial: Appropriateness - How Sweet the Sound. PMID- 27987574 TI - [New "choosing wisely" recommendations of inappropriate interventions: the perspective of general practioners in Switzerland]. AB - AIM: As part of the "Choosing wisely" campaign expert-driven recommendations of inappropriate interventions which lead to overdiagnosis and overtreatment are being published. The aim of our work was to describe an innovative method for developing recommendations together with general practitioners (GPs) and to compare the results with the "Choosing wisely" campaign lists as well as with the Swiss "Smarter medicine" shortlist. METHODS: We asked 109 GPs who attended a medical education conference to form groups (of 5 to 7 GPs each) and develop three interventions that are relevant to their work and should be avoided. We then compared the most frequently suggested interventions with those of the "Choosing wisely" campaign list and the "Smarter medicine" campaign shortlist. Finally, we asked the Swiss Young GPs Association (JHaS) members for additional suggestions. RESULTS: Five groups suggested avoidance of check-up examinations, especially in younger or asymptomatic individuals. Further unnecessary interventions, which were mentioned with similar frequency, included resting or exercise electrocardiography in asymptomatic individuals and cholesterol analysis in individuals older than 75 years, or statin therapy in primary prevention and/or high age. Four groups suggested avoiding arthroscopy or magnetic resonance imaging of the knee joint after an injury (in the absence of joint instability or blockade), and three groups recommended to avoid imaging diagnostic procedures in patients with unspecific headache (in the absence of red flags). There was no consistency between interventions of the GPs' list and the list of the Swiss "Smarter medicine" official campaign. The interventions that were most frequently mentioned by the GPs are also present on the lists issued by are present on lists of medical societies that have joined the "Choosing wisely" campaign. The response rate from the Swiss Young GPs association members was impressively low. CONCLUSION: The perspective of users (GPs) is crucial for the development of lists of potentially inappropriate interventions. In order to enhance the degree of identification with and adherence to the recommendations. The interventions suggested in our study could lead to further recommendations on interventions to be avoided in primary care, ideally in collaboration with the "Smarter medicine" campaign. Empathic communication with patients about harms and benefits of potentially inappropriate interventions is crucial for the implementation of this policy. PMID- 27987575 TI - ? PMID- 27987576 TI - Radiologic-pathologic correlation of response to chemoradiation in resectable locally advanced NSCLC. AB - OBJECTIVES: Accurate assessment of tumor response to chemoradiation has the potential to guide clinical decision-making regarding surgical resection and/or dose escalation for patients. Early assessment has implications for Optimal local therapy for operable locally advanced non-small cell lung cancer (LA-NSCLC) is controversial. This study evaluated quantitative CT-based tumor measurements to predict pathologic response. MATERIALS AND METHODS: Patients with operable LA NSCLC treated with chemoradiation followed by surgical resection were assessed. Tumor diameter and volume were quantified from CT imaging obtained prior to chemoradiation and post-chemoradiation prior to surgical resection. Univariate and multivariate logistic regression were used to determine association with the primary endpoint of pathologic complete response (pCR). Overall survival, locoregional recurrence, and distant metastasis were assessed as secondary endpoints. RESULTS: 101 LA-NSCLC patients were identified and treated with preoperative chemoradiation and surgical resection. The median RT dose was 54Gy (range, 46-70) and 98% of patients received concurrent chemoradiation as part of their preoperative treatment. Reduction of CT-defined tumor volume was associated with pCR (OR 1.06 [1.02-1.09], p=0.002) and LRR (HR 1.01 [1.00-1.02], p=0.048). Conventional response assessment determined by RECIST (p=0.213) was not associated with pCR or any secondary endpoints. CONCLUSION: CT-measured reductions in tumor volume after chemoradiation are associated with pCR and provide greater clinical information about tumor response than conventional response assessment (RECIST) or absolute tumor sizes or volumes. This study demonstrates that change in tumor volumes provides better radiologic-pathologic correlation and is thus an additional tool to assess tumor response following chemoradiation. PMID- 27987577 TI - Coexistence of p16/CDKN2A homozygous deletions and activating EGFR mutations in lung adenocarcinoma patients signifies a poor response to EGFR-TKIs. AB - OBJECTIVES: Activating mutations in the epidermal growth factor receptor (EGFR) are strongly predictive of EGFR-tyrosine kinase inhibitor (TKI) activity in non small cell lung cancer (NSCLC). However, primary resistance to EGFR-TKIs occurs in approximately 20-30% of NSCLC patients with EGFR mutations. The goal of this study was to determine whether p16/CDKN2A homozygous deletion (HD) is associated with primary resistance to EGFR-TKIs in lung adenocarcinoma patients with EGFR activating mutations. METHODS: We investigated 127 patients with stage IIIB or IV lung adenocarcinoma harboring activating EGFR mutations, and who had received EGFR-TKIs as first-line therapy. Dual-color fluorescence in situ hybridization for p16/CDKN2A and chromosome 9 was performed in tumor biopsy samples obtained before initiation of EGFR-TKI treatment. RESULTS: p16/CDKN2A HD was detected in 24.4% (31/127) of patients, and the overall response rate in patients with and without this mutation was 48.4% and 78.1%, respectively (P=0.0027). The median progression-free survival was 5.3 months (95% confidence interval [CI]: 4.582 6.018) for patients with p16/CDKN2A HD and 10.5 months (95% CI: 9.365-11.635 months) for patients without the mutation (P=0.001). No correlations between p16/CDKN2A HD and patient characteristics including gender, age, smoking history, EGFR mutation type, tumor-node-metastasis stage, and performance status were found. CONCLUSIONS: Our study demonstrates that the coexistence of p16/CDKN2A HDs and activating EGFR mutations in lung adenocarcinoma patients signifies a poor response to EGFR-TKI therapy. PMID- 27987579 TI - Response and acquired resistance to crizotinib in Chinese patients with lung adenocarcinomas harboring MET Exon 14 splicing alternations. AB - Approximately 10% of lung adenocarcinomas harbor aberrations that are targetable using the approved multitargeted TKI crizotinib. MET exon 14 skipping mutation predicts for response to crizotinib in human lung adenocarcinomas. However, a substantial part of patients still has no sufficient tissue to perform genomic analysis. As a promising noninvasive biomarker and potential surrogate for the entire tumor genome, circulating tumor DNA (ctDNA) has been applied to the detection of driver gene mutations. Here we described the MET exon 14 splicing mutations in cell-free circulating-tumor DNA by next-generation sequencing (NGS) technology. Patient firstly responded to crizotinib therapy within four months, however, three acquired mutation in the MET kinase domain, D1228N/H and Y1230H, were found at the time of disease progression. To our knowledge, this is the first clinical report of three mutations simultaneously arising in a patient with MET exon 14 splicing mutation. PMID- 27987578 TI - Impact of age and comorbidity on treatment of non-small cell lung cancer recurrence following complete resection: A nationally representative cohort study. AB - OBJECTIVE: Older patients with non-small cell lung cancer (NSCLC) are less likely to receive guideline-recommended treatment at diagnosis, independent of comorbidity. However, national data on treatment of postoperative recurrence are limited. We evaluated the associations between age, comorbidity, and other patient factors and treatment of postoperative NSCLC recurrence in a national cohort. MATERIALS AND METHODS: We randomly selected 9001 patients with surgically resected stage I-III NSCLC in 2006-2007 from the National Cancer Data Base. Patients were followed for 5 years or until first NSCLC recurrence, new primary cancer, or death, whichever came first. Perioperative comorbidities, first recurrence, treatment of recurrence, and survival were abstracted from medical records and merged with existing registry data. Factors associated with active treatment (chemotherapy, radiation, and/or surgery) versus supportive care only were analyzed using multivariable logistic regression. RESULTS: Median age at initial diagnosis was 67; 69.7% had >1 comorbidity. At 5-year follow-up, 12.3% developed locoregional and 21.5% developed distant recurrence. Among patients with locoregional recurrence, 79.5% received active treatment. Older patients (OR 0.49 for age >75 compared with <55; 95% CI 0.27-0.88) and those with substance abuse (OR 0.43; 95% CI 0.23-0.81) were less likely to receive active treatment. Women (OR 0.62; 95% CI 0.43-0.89) and patients with symptomatic recurrence (OR 0.69; 95% CI 0.47-0.99) were also less likely to receive active treatment. Among those with distant recurrence, 77.3% received active treatment. Older patients (OR 0.42 for age >75 compared with <55; 95% CI 0.26-0.68) and those with any documented comorbidities (OR 0.59; 95% CI 0.38-0.89) were less likely to receive active treatment. CONCLUSION: Older patients independent of comorbidity, patients with substance abuse, and women were less likely to receive active treatment for postoperative NSCLC recurrence. Studies to further characterize these disparities in treatment of NSCLC recurrence are needed to identify barriers to treatment. PMID- 27987581 TI - RETRACTED: Kaiso is expressed in lung cancer: Its expression and localization is affected by p120ctn. PMID- 27987580 TI - Lung cancer mutation profile of EGFR, ALK, and KRAS: Meta-analysis and comparison of never and ever smokers. AB - Lung cancer is the leading cause of cancer-related mortality. While the majority of lung cancers are associated with tobacco smoke, approximately 10-15% of U.S. lung cancers occur in never smokers. Evidence suggests that lung cancer in never smokers appears to be a distinct disease caused by driver mutations which are different than the genetic pathways observed with lung cancer in smokers. A meta analysis of human epidemiologic data was conducted to evaluate the profile of common or therapy-targetable mutations in lung cancers of never and ever smokers. Epidemiologic studies (N=167) representing over 63,000 lung cancer cases were identified and used to calculate summary odds ratios for lung cancer in never and ever smokers containing gene mutations: EGFR, chromosomal rearrangements and fusion of EML4 and ALK, and KRAS. This analysis also considered the effect of histopathology, smoking status, sex, and ethnicity. There were significantly increased odds of presenting the EGFR and ALK-EML4 mutations in 1) adenocarcinomas compared to non-small cell lung cancer and 2) never smokers compared to ever smokers. The prevalence of EGFR mutations was higher in Asian women as compared to women of Caucasian/Mixed ethnicity. As the smoking history increased, there was a decreased odds for exhibiting the EGFR mutation, particularly for cases >30 pack-years. Compared to ever smokers, never smokers had a decreased odds of KRAS mutations among those of Caucasian/Mixed ethnicity (OR=0.22, 95% CI: 0.17-0.29) and those of Asian ethnicity (OR=0.39, 95% CI: 0.30 0.50). Our findings show that key driver mutations and several patient features are highly prevalent in lung cancers of never smokers. These associations may be helpful as patient demographic models are developed to predict successful outcomes of targeted therapeutic interventions NSCLC. PMID- 27987582 TI - A folylpoly-gamma-glutamate synthase single nucleotide polymorphism associated with response to pemetrexed treatment combined with platinum for non-small cell lung cancer. AB - OBJECTIVES: In this study, we investigated whether single nucleotide polymorphisms (SNPs) in folylpoly-gamma-glutamate synthase (FPGS), which catalyzes the polyglutamation of pemetrexed (PEM), is related to FPGS expression and the response to PEM in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We first examined FPGS protein expressions according to FPGS SNPs genotype groups in 15 lung adenocarcinoma cell lines. Next, 101 non-squamous NSCLC patients treated with PEM and platinum drugs were classified into FPGS SNP genotype groups to investigate the relation between FPGS SNP genotypes and treatment outcome. RESULTS: When the 15 adenocarcinoma cell lines were classified into FPGS SNP 2572C>T genotype groups, we found that the FPGS protein expression was significantly higher in the CC genotype group than in the TT+CT genotype group (p=0.0022). In contrast, there was no significant difference in FPGS expression when another FPGS SNP was analyzed. We also examined the FPGS SNP 2572C>T genotype in 101 non-squamous NSCLC patients treated with PEM and platinum drugs. Among these 101 patients, response rate was significantly higher in the CC genotype group than in the TT+CT genotype group (p=0.0034). When we examined the patients treated with PEM, platinum drugs and Bev, almost all (29/33) were classified into the TT+CT genotype group. The response rate, progression-free survival, and over-all survival were all significantly better in the patients of the TT+CT genotype group who also received Bev than in those who did not receive Bev (p=0.034, 0.021, 0.018, respectively). CONCLUSION: FPGS SNP 2572C>T is a predictive marker of the efficacy of PEM and platinum drugs for NSCLC. PMID- 27987584 TI - Corneal graft rejection in a patient treated with nivolumab for primary lung cancer. AB - We report the case of a 58-year-old woman treated with nivolumab for an unresectable squamous non-small cell lung cancer, after first-line cisplatin and gemcitabine combination chemotherapy. This woman had a history of left corneal graft. After 9 cycles of nivolumab, the patient described decreased visual acuity in the left eye with watering and conjunctival erythema. Ophthalmological examination revealed chronic corneal graft rejection. The patient was then treated with an intravenous bolus of corticosteroids (500mg of methylprednisolone) for 3 days, followed by oral prednisone for 4 weeks and subconjunctival corticosteroid injections every 48h, while treatment with nivolumab was discontinued. No clinical benefit was observed 4 weeks later and the corneal graft became totally unfunctional despite of the therapy. We hypothesise that the treatment was started too late. To our knowledge, this is the first reported case of corneal graft rejection related to nivolumab. PMID- 27987583 TI - The addition of anti-angiogenic tyrosine kinase inhibitors to chemotherapy for patients with advanced non-small-cell lung cancers: A meta-analysis of randomized trials. AB - OBJECTIVES: The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy. MATERIALS AND METHODS: We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology. RESULTS: The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P<0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P<0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P=0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P=0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P=0.008). However, both grade >=3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P<0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI. CONCLUSION: The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs. PMID- 27987585 TI - Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum based chemotherapy (IUNO study). AB - OBJECTIVE: The phase III IUNO trial assessed the benefit of maintenance erlotinib versus erlotinib at progression in advanced/metastatic non-small-cell lung cancer (NSCLC) that had not progressed following four cycles of platinum-based chemotherapy. MATERIALS AND METHODS: Patients had stage IIIB/IV NSCLC, no known epidermal growth factor receptor (EGFR)-activating mutation, and objective response or disease stabilization after platinum-based induction chemotherapy. Central EGFR-mutation testing was undertaken on tumors from patients with unknown or wild-type EGFR status following local testing. Patients were randomized to receive blinded maintenance erlotinib 150mg/day ('early erlotinib') or placebo. Those who progressed on placebo received open-label erlotinib ('late erlotinib'); patients who progressed on erlotinib received approved second-line chemotherapy or best supportive care. Primary endpoint: overall survival (OS). RESULTS: 643 patients were randomized to receive maintenance erlotinib (n=322) or placebo (n=321). As of March 23, 2015, 242 (75.2%) OS events had occurred with 'early erlotinib' versus 235 (73.2%) with 'late erlotinib'. Median OS was 9.7 and 9.5 months with 'early erlotinib' and 'late erlotinib', respectively (HR, 1.02, 95% CI: 0.85-1.22; log-rank p=0.82). No progression-free survival, objective response rate, or disease control rate benefit was observed with maintenance erlotinib. 410 patients entered the second-line phase of the study: 160 patients (50%) from the maintenance erlotinib arm and 250 patients (78%) from the maintenance placebo arm. The pattern of adverse events (AEs) was consistent with previous trials; 11 patients who received blinded erlotinib and 3 who received placebo died during the blinded maintenance phase due to nontreatment-related AEs. CONCLUSIONS: OS with maintenance erlotinib was not superior to second-line treatment in patients whose tumor did not harbor an EGFR-activating mutation. Safety results were consistent with the established safety profile of erlotinib. Thus, maintenance treatment with erlotinib in patients with advanced/metastatic NSCLC without EGFR activating mutations is considered unfavorable. PMID- 27987586 TI - Histological transformation of ALK rearranged adenocarcinoma into small cell lung cancer: A new mechanism of resistance to ALK inhibitors. AB - Various mechanisms of resistance to ALK inhibitors in ALK rearranged adenocarcinomas are reported including secondary gatekeeper mutations, bypass signaling or ALK amplifications as the commonest ones. We report a new mechanism of resistance with transformation of adenocarcinoma into small cell lung cancer. A 53-year-old non-smoker woman, experienced cancer progression after two lines of ALK inhibitors. A new biopsy showed a small cell lung cancer. FISH revealed persistent ALK rearrangement with an atypical pattern and complete loss of the 5' region of the ALK gene. PMID- 27987587 TI - Clinical relevance of ROS1 rearrangements detection in advanced squamous cell carcinomas. AB - Non-small cell lung cancers (NSCLCs) have molecular characterization and most druggable genetic and molecular abnormalities, such as EGFR, ERBB2 and BRAF mutations, and ALK and ROS1 rearrangements, have been observed in a subset of adenocarcinomas or large cell carcinomas [1]. Even if these abnormalities are seldom detected in squamous cell carcinomas (SQCC), some rare cases of SQCC have been reported to harbor EGFR, ROS1 or ALK genetic alterations with in some cases a response to targeted therapies [2,3]. Here, we describe a patient with a SQCC harboring ROS1 rearrangement and a response to the target therapy, crizotinib. PMID- 27987588 TI - Report of two cases of pseudoprogression in patients with non-small cell lung cancer treated with nivolumab-including histological analysis of one case after tumor regression. AB - The recent approval of nivolumab and other immune-checkpoint inhibitors for the treatment of certain solid tumors including non-small cell lung cancer (NSCLC) has transformed cancer therapy. However, it will be important to characterize effects of such agents not seen with classical cytotoxic drugs or other targeted therapeutics. We here report two cases of NSCLC showing so-called pseudoprogression during nivolumab treatment. In both cases, imaging assessment revealed that liver metastatic lesions initially progressed but subsequently shrank during continuous nivolumab administration, with treatment also resulting in a decline in serum levels of carcinoembryonic antigen. Histological evaluation of the liver metastatic lesion of one case after regression revealed fibrotic tissue containing infiltrated lymphocytes positive for CD3, CD4, or CD8 but no viable tumor cells, suggestive of a durable immune reaction even after a pathological complete response. Given the increasing use of immune-checkpoint inhibitors in patients with NSCLC or other solid tumors, further clinical evaluation and pathological assessment are warranted to provide a better understanding of such pseudoprogression. PMID- 27987589 TI - Premorbid body mass index and mortality in patients with lung cancer: A systematic review and meta-analysis. AB - OBJECTIVES: We aimed to assess the association between premorbid obesity, measured using body mass index (BMI) and lung cancer-related mortality, through a systematic review and meta-analysis. MATERIALS AND METHODS: Observational studies reporting statistical measures of association between premorbid BMI categories and lung cancer-related mortality were included in our study. We estimated hazard ratios (aHR) with 95% confidence intervals (CI), comparing lung cancer-related mortality across BMI categories. The main outcome measure was lung cancer-related mortality in obese (BMI>=30kg/m2) and overweight participants (BMI 25.0 29.9kg/m2), compared with normal BMI participants. RESULTS: We included 14 studies (including 2 pooled cohort studies) comprising 3,008,137 cancer-free participants at inception, reporting 28,592 lung cancer-related deaths. On meta analysis, we observed a significantly lower lung cancer-related mortality in overweight (aHR, 0.76; 95% CI, 0.68-0.85) and obese (aHR, 0.68, 95% CI; 0.57 0.81) participants as compared to participants with normal BMI, with considerable heterogeneity; after excluding one study with large effect size, a more conservative and consistent association was observed between BMI and lung cancer related mortality (overweight vs. normal BMI: aHR, 0.84; 95% CI, 0.79-0.90; obese vs. normal BMI: aHR, 0.81; 95% CI, 0.75-0.87), with moderate heterogeneity. Were similar in men vs. women, non-smokers vs. smokers, and Western vs Asia-Pacific populations. CONCLUSIONS: Based on meta-analysis, we observed an independent protective association between premorbid obesity and lung cancer-related mortality. This association was observed across sex, smoking status and geographic region. Further studies are needed to prospectively study this association. PMID- 27987590 TI - Prognostic impact of pleural lavage cytology in patients with primary lung cancer. AB - OBJECTIVES: Positive pleural lavage cytology (PLC) has been reported to have a negative prognostic impact in patients with surgically resected non-small cell lung cancer (NSCLC). However, positive PLC does not upgrade the stage according to the 7th edition of TNM classification for lung cancer. The objectives of this study were to evaluate the prognostic impact of positive PLC in patients with NSCLC and to clarify its contribution to TNM classification. MATERIALS AND METHODS: Seven hundred fifty-four patients who underwent surgical resection of NSCLC from January 2007 through December 2013 were retrospectively studied. PLC was performed using 50ml of saline immediately after thoracotomy. RESULTS: Thirty eight of the 754 patients were positive for PLC (5.1%). The overall survival (OS) of patients with positive PLC was significantly shorter than that of those with negative PLC (P=0.007, log-rank test). In multivariate analyses of OS, positive PLC was a significant independent prognostic factor (hazard ratio=2.21, 95% confidence interval: 1.21-4.04, P=0.009). The OS of patients with positive PLC was significantly shorter than that of those with negative PLC and pT1 (P<0.0001) or negative PLC and pT2 (P<0.0001) and almost overlapped with that of those with negative PLC and pT3 disease (P=0.601). CONCLUSION: Positive PLC is an independent prognostic factor in patients with resected NSCLC. Based on our analyses, we propose that patients with positive PLC be staged as pT3. PMID- 27987591 TI - Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial. AB - OBJECTIVES: LUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with stage IIIB/IV or recurrent non squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500mg/m2 on Day 1 plus nintedanib 200mg orally twice daily or matching placebo on Days 2-21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint. RESULTS: Based on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n=353 nintedanib/pemetrexed; n=360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR]=0.83, 95% confidence interval [CI] 0.70-0.99, p=0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR=1.01, 95% CI 0.85-1.21, p=0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade >=3 elevated alanine aminotransferase (23.3% vs 7.3%), elevated aspartate aminotransferase (12.1% vs 1.7%) and diarrhea (3.5% vs 1.1%) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis. CONCLUSION: Although recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile. PMID- 27987592 TI - Drebrin: A new oncofetal biomarker associated with prognosis of lung adenocarcinoma. AB - OBJECTIVES: With the aim of searching for novel oncofetal tumor biomarkers of lung adenocarcinoma other than carcinoembryonic antigen (CEA) and alpha fetoprotein (AFP), we developed a strategy involving monoclonal antibodies generated from embryonic tissue of miniature swine. MATERIALS AND METHODS: Using immunohistochemistry, we selected suitable hybridoma clones that were reactive against swine fetal lung but not adult lung using tissue microarray loading of human normal lung, lung cancer, and fetal and adult swine tissues. RESULTS: The selected clones included several that were uniquely reactive against both swine fetal lung and human lung adenocarcinoma, and protein microarray revealed that the antigen they recognized was "drebrin" (DBN1). We then examined the association between the pattern of drebrin expression and the clinicopathological characteristics of lung adenocarcinoma using surgically resected samples of human lung adenocarcinoma. Two hundred formalin-fixed and paraffin-embedded tumor samples were immunostained for drebrin using clone B246, one of the clones that were reactive against drebrin. The cases were divided into those with strong (n=85) and weak (n=115) drebrin expression. In terms of disease-free survival, cases showing strong drebrin expression had a significantly poorer prognosis than those with weak drebrin expression (p=0.033). CONCLUSION: The present findings indicate that "drebrin" is a unique oncofetal protein that can be applied as a new biomarker of lung adenocarcinoma. PMID- 27987593 TI - Clinical course of stage IV invasive mucinous adenocarcinoma of the lung. AB - INTRODUCTION: An invasive mucinous adenocarcinoma (IMA) is a distinct lung adenocarcinoma variant. The characteristics of stage IV IMAs are relatively unclear since most previous studies described resected cases from stage I to III. The present study aimed to investigate the clinical course of stage IV IMAs and compare the findings to those of stage IV invasive non-mucinous adenocarcinomas (INMAs). METHODS: The study included 36 IMA patients and 210 INMA patients. The clinicopathological parameters, treatment methods and responses, overall survival (OS), and progression-free survival (PFS) were evaluated. RESULTS: IMAs were predominantly located in the lower lobes and frequently presented with multifocal consolidation and lung-to-lung or pleural metastasis. KRAS mutations were noted in 60.0% of the examined IMAs. Non-TKI chemotherapy (CTx) was used in 72.2% of the IMA patients. OS was significantly better in untreated IMA patients than in untreated INMA patients. IMA patients treated with non-TKI CTx had no improvement of OS compared to the untreated IMA patients. However, among INMA patients, OS was best with TKIs in patients harbouring targetable mutations, followed by non TKI CTx. IMA and INMA patients treated with non-TKI CTx had similar PFS. CONCLUSIONS: Stage IV IMAs have distinct clinicopathological characteristics, and they might be less aggressive than INMAs. Since non-TKI CTx might not be beneficial in IMA patients, new therapeutic approach is necessary. PMID- 27987594 TI - Characterization of microbiome in bronchoalveolar lavage fluid of patients with lung cancer comparing with benign mass like lesions. AB - OBJECTIVES: Disruption in the stability of respiratory microbiota is known to be associated with many chronic respiratory diseases. However, only few studies have examined microbiomes in lung cancer. Therefore, we characterized and compared the microbiomes of patients with lung cancer and those with benign mass-like lesions. MATERIALS AND METHODS: Bronchoalveolar fluid was collected prospectively to evaluate lung masses in patients who had undergone bronchoscopies from May to September 2015. Twenty-eight patients (20 male, 8 female) were enrolled: 20 diagnosed with lung cancer and 8 diagnosed with benign diseases. Samples were analysed by 16S rRNA-based next-generation sequencing. RESULTS: The participants' mean age was 64+/-11years. Bacterial operational taxonomic units were classified into 26 phyla, 44 classes, 81 orders, 153 families, 288 genera, and 797 species. The relative abundance of two phyla (Firmicutes and TM7) was significantly increased in patients with lung cancer (p=0.037 and 0.035, respectively). Furthermore, two genera (Veillonella and Megasphaera) were relatively more abundant in lung cancer patients (p=0.003 and 0.022, respectively). The area under the curve of a combination of these two genera used to predict lung cancer was 0.888 (sensitivity=95.0%, specificity=75.0% and sensitivity=70.0%, specificity=100.0%; p=0.002). CONCLUSION: The results indicate that differences exist in the bacterial communities of patients with lung cancer and those with benign mass-like lesions. The genera Veillonella and Megasphaera showed the potential to serve as biomarkers to predict lung cancer. Thus, the lung microbiota may change the environment in patients with lung cancer. PMID- 27987595 TI - Tumour size reduction after the first chemotherapy-course and outcomes of chemoradiotherapy in limited disease small-cell lung cancer. AB - OBJECTIVES: Concurrent chemotherapy and thoracic radiotherapy (TRT) is recommended for limited disease small-cell lung cancer (LD SCLC). TRT should start as early as possible, often meaning with the second course due to patient referral time and the fact that TRT planning takes time. Early assessment of response to the first course of chemotherapy may be a useful way to individualise treatment. The aims of this study were to assess tumour size reduction after the first chemotherapy-course, and whether this reduction was associated with outcomes in LD SCLC. MATERIAL AND METHODS: A randomised trial comparing twice daily (45Gy/30 fractions) with once-daily (42Gy/15 fractions) TRT, given concurrently with four courses of cisplatin/etoposide (n=157) was the basis for this study. Tumour size was assessed on CT scans at baseline and planning scans for TRT according to RECIST 1.0. RESULTS: CT scans were available for 135 patients (86%). Ninety-four percent had a reduction in tumour size after the first chemotherapy-course. The median reduction in sum of diameters (SOD) of measurable lesions was /16mm (/84 to +10mm), corresponding to /18% (/51 to +12%). Eighty-two percent had stable disease, 18% partial response. Reduction in SOD was significantly associated with complete response at first follow-up (OR: 1.05, 95% CI 1.01-1.09; p=0.013), PFS (HR: 0.97, 95% CI 0.96-0.99; p=0.001), and overall survival (HR: 0.98, 95% CI 0.96-1.00; p=0.010). CONCLUSION: Response from the first course of chemotherapy had a significant positive association with outcomes from chemoradiotherapy, and might be used to stratify and randomise patients in future studies. PMID- 27987597 TI - Editors' message. PMID- 27987596 TI - The challenge of molecular testing for clinical trials in advanced non-small cell lung cancer patients: Analysis of a prospective database. AB - OBJECTIVES: Molecular testing has become important in the biomarker program of clinical trials for advanced non-small lung cancer (NSCLC). These tissue samples often have to be analyzed in a central laboratory. We evaluated the turnaround time and possible delay in start of therapy in this process and how often testing resulted in inclusion in a clinical trial. METHODS: We reviewed our prospective database on all molecular testing cases for clinical trial suitability in patients with advanced NSCLC between March 1, 2011 and October 31, 2014. RESULTS: 250 patients were considered for biomarker-driven trials. Twenty-three cases did not have further analysis and 20 patients had failure of central biomarker analysis. Results were obtained for 207 (83%) patients. In 91 of 227 (40%) samples sent, a biomarker of interest was documented. This led to 34 (15%) clinical trial inclusions. The mean waiting time between informed consent and request for tissue sections from the pathology lab and receipt of biomarker result from central lab was 24.4 (SD 13.7) calendar days. CONCLUSION: While molecular biomarker testing is crucial in many NSCLC trials, our results show that waiting times for central laboratory analysis can cause an important delay in treatment initiation, and even ineligibility for the trial(s) under consideration. Start of therapy based on properly validated local testing, with a posteriori central biomarker testing to guarantee the integrity of the trial, would be more rewarding for quite some patients. PMID- 27987599 TI - A preclinical animal study of a novel, simple, and secure percutaneous vessel occluder for the treatment of varicose veins. AB - BACKGROUND: Secure, permanent occlusion of the great and small saphenous veins, their tributaries, and perforators is critical for the successful treatment of varicose veins. Current minimally invasive methods replacing surgery are all endoluminal and involve heat (radiofrequency or laser), chemicals (sclerosants and glues), or a combination of mechanical and chemical interventions. This study evaluated in a porcine model the performance of a percutaneous delivery of the Amsel Vessel Occluder (AVO; Amsel Medical Corp, Cambridge, Mass) using ultrasound guidance. The AVO has received United States Food and Drug Administration premarket 510(k) clearance for use in open surgical procedures for tubular structures with diameters of 2 to 7 mm. METHODS: The AVO, a novel mechanical occlusion clip similar to a transfixion suture, is delivered through an 18-gauge hypodermic needle. The AVO is subsequently expanded on either side of the vessel wall, collapsed, and locked together to effect secure vascular occlusion, thus transfixing the targeted vessel. The targeted vessels in five swine (weight >60 kg) under general anesthesia were identified, and the vessel size was measured. Patency of the targeted vessels was confirmed on duplex ultrasound imaging. Each animal provided multiple vessels for percutaneous AVO occlusion. Occlusion was confirmed by duplex ultrasound imaging and by direct examination of the occluded vessel after open surgical exploration. RESULTS: Thirty vessel occlusions were performed percutaneously, including the common and superficial femoral arteries and veins (n = 24), the carotid artery (n = 4), and the external jugular vein (n = 1) and external jugular vein tributary (n = 1). Measured vessel sizes ranged from 1.8 to 12.7 mm. After vessel transfixion, occlusion was achieved in <30 seconds. A second AVO, if necessary, was delivered to completely occlude the targeted vessel where the vessel was >7 mm diameter (n = 2; external jugular vein, 12.7 mm; carotid artery, 7 mm), or where the initial AVO did not occlude the vessel because of nontransfixion (n = 1). Surgical exposure after occlusion confirmed that all targeted vessels were successfully occluded and demonstrated no evidence of injury to any of the adjacent structures. CONCLUSIONS: This study confirms that the AVO can be effectively delivered percutaneously under ultrasound guidance to occlude blood vessels in the porcine model and may be a useful, time-saving, and cost-effective adjunct to current primary methods of treating reflux in the saphenous veins, their tributaries, or perforators for the treatment of symptomatic varicose veins. PMID- 27987600 TI - Ruptured external jugular varix. AB - Venous dilations of the jugular veins are uncommon and external jugular varix even rarer. We present the case of a 57-year-old woman with ruptured external jugular varix and the surgical repair of such. Surgical intervention is warranted in these rare venous malformations to prevent known complications of thromboembolism and rupture. PMID- 27987598 TI - Role of vessel-to-prosthesis size mismatch in venous valve performance. AB - BACKGROUND: Efforts to treat chronic venous insufficiency have focused on the development of prosthetic venous valves. The role of prosthetic valve-to-vessel size matching has not been determined. The purpose of this investigation was to assess the effect of size mismatching on venous valve function and to establish a mismatch limit that affects valve hemodynamic performance and venous wall stress to improve future valve designs and implants. METHODS: Flow dynamics of prosthetic venous valves were studied in vitro using a pulse duplicator flow loop. Valve performance based on flow rate and pressure measurements was determined at oversizing ratios ranging from 4.2% to 25%. Valve open area ratios at different size mismatching ratios were investigated by image analysis. Finally, a wall stress analysis was used to determine the magnitude of circumferential (hoop) stress in the venous wall at various degrees of oversizing. RESULTS: Our findings indicate that valve regurgitate volume, closing time, and pressure difference across the valve are significantly elevated at mismatch ratios greater than ~15%. This is supported by increases in regurgitate velocity and open area relative to valves tested at near-nominal diameters. At this degree of size mismatch, the wall stress is increased by a factor of two to three times relative to physiologic pressures. CONCLUSIONS: These findings establish a relationship between valve size matching and valve hemodynamic performance, including vessel wall stress, which should be considered in future valve implants. The size of the prosthetic valve should be within 15% of maximum vein size to optimize venous valve hemodynamic performance and to minimize the hoop wall stress. PMID- 27987601 TI - Congenital, meandering transdiaphragmatic aortocaval-right atrial arteriovenous fistula. PMID- 27987602 TI - Cost analysis and implications of routine deep venous thrombosis duplex ultrasound scanning after endovenous ablation. AB - BACKGROUND: Duplex ultrasound (DUS) is performed by the majority of physicians after endovenous ablation (EVA) of the great saphenous vein to screen for endovenous heat-induced thrombosis (EHIT) at the saphenofemoral junction extending into the femoral vein. Several factors should be considered in assessing the value and cost of routine DUS after EVA: the natural history of EHIT is poorly defined, the incidence appears low, and the majority are both asymptomatic and Kabnick type 2 (projecting only slightly into the femoral vein). Moreover, routine postoperative DUS screening is not recommended for procedures with higher thromboembolic complication rates, such as joint replacement or bariatric surgery. METHODS: Data on the incidence of death, EHIT, and deep venous thrombosis (DVT) were derived from a systematic review after either radiofrequency or laser ablation of the saphenous vein from two sources: (1) EVA randomized controlled trials (N = 1482) and a (2) large (>150 patients) EVA case series (N = 12,363). The number of tests required to detect one case of EHIT/DVT was calculated from the incidence in the EVA and case series data bases; the cost to detect a case was estimated using the 2013 Medicare global fee schedule for the cost of a unilateral venous DUS study. RESULTS: This analysis included 13,845 EVA-treated limbs. There were no reported deaths. The incidence of DUS-detected venous thromboembolism after EVA is 0.7%. The cost of unilateral DUS according to the Medicare global reimbursement fee for office-based studies is $106.71. The total cost of performing DUS in this study population is estimated to be at least $1,477,399, and the amount of dollars expended per venous thromboembolism detected is $14,667. CONCLUSIONS: The current Society for Vascular Surgery/American Venous Forum recommendation is to perform screening DUS after EVA within 72 hours postoperatively with a weak level of recommendation (grade 2C). The current analysis demonstrates a low incidence of EHIT/DVT with a corresponding high cost to detect each case with routine DUS screening. These data combined with the unclear clinical significance of EHIT suggest that the policy of universal post-EVA screening should be revised in the near future. PMID- 27987603 TI - Evidence summary of combined saphenous ablation and treatment of varicosities versus staged phlebectomy. AB - OBJECTIVE: The objective of this review was to create an evidence summary of the available literature comparing saphenous vein ablation and concomitant phlebectomy vs ablation with staged phlebectomy. METHODS: A review of the literature for ambulatory patients treated for venous insufficiency with saphenous ablation and phlebectomy was conducted. A literature search was performed using MEDLINE, Cochrane Library, Google Scholar, and PubMed with the keywords phlebectomy, endovenous ablation, staged procedures, vein stripping, superficial venous disease, and powered phlebectomy. All studies that described a single approach, systematic reviews, case series (N < 20), and nonclinical studies were excluded. RESULTS: Eight clinical comparative studies of combined saphenous ablation and phlebectomy vs staged procedures were found: three randomized prospective studies, two prospective comparisons, and three retrospective reviews. CONCLUSIONS: Combined treatment of saphenous incompetence and symptomatic varicosities results in better short-term and better to equivalent long-term patient outcomes. PMID- 27987604 TI - Common femoral endovenectomy in conjunction with iliac vein stenting to improve venous inflow in severe post-thrombotic obstruction. AB - Post-thrombotic syndrome secondary to iliofemoral deep venous thrombosis is a significant contributor to advanced chronic venous insufficiency. Iliac vein stenting is a standard procedure to treat iliocaval obstruction. In cases with obstruction extending across the groin, venous inflow for an iliac vein stent may be poor and compromise results of iliac vein stenting. Treatment options include extension of stents across the inguinal ligament that may have limitations in improving inflow only from only one vessel. Endovenectomy in this scenario becomes an attractive option with or without iliac vein stenting to provide outflow to the profunda vein, which otherwise is "axially transformed" in chronic iliofemoral deep venous thrombosis. We describe a technique of endovenectomy in combination with iliac vein stenting to establish a patent outflow tract for profunda and femoral veins. Accompanying also is a video demonstration of endovenectomy that will help viewers understand more technical aspects of the procedure. PMID- 27987606 TI - Surveillance, anticoagulation, or filter in calf vein thrombosis. AB - OBJECTIVE: This study compared the efficacy and complication rates of inferior vena cava (IVC) filters for calf vein thrombosis (CVT) vs conservative treatment with or without anticoagulation. METHODS: Vascular laboratory studies of patients who had an isolated CVT (anterior and posterior tibialis, peroneal, soleal, and gastrocnemius veins) from April 2009 to January 2014 were retrospectively analyzed from a single institution. Of 647 patients with isolated CVT, 285 (44%) received an IVC filter, and 362 (56%) received medical treatment alone (38.9% surveillance, 11.6% prophylactic anticoagulation, and 49.4% therapeutic anticoagulation). Univariate, multivariate, propensity matching, and Kaplan-Meier analyses were performed on abstracted data, which included, but was not limited to, risk factors, treatment modalities, venous thromboembolism (VTE) complications (defined as propagation of deep vein thrombosis [DVT] or pulmonary embolism [PE]), bleeding complications, and IVC filter-related complications (ie, filter tilting >15 degrees , perforation >3 mm, fracture, migration >10 mm). RESULTS: The overall incidence of PE in was 2.5% in the IVC filter group and 3.3% in the medical group (P = .27). The overall incidence of VTE complications (propagation of DVT, PE) was 35% for the surveillance group without anticoagulation, 30% in patients treated with prophylactic anticoagulation, and 10% in patients treated with therapeutic anticoagulation (P = .0003). Only a minority of patients underwent duplex ultrasound imaging after filter insertion. In the IVC filter group, the most common reasons that contraindicated anticoagulation were bleeding (35%) or recent surgery (27%). The number of IVC filter-related complications in the IVC filter group was 29 (10%). Because the IVC filter group was older (mean age, 65 vs 61 years, P = .004) and more likely to have a history of thromboembolic events (56% vs 16%, P < .0001), and malignancy (49% vs 28%, P < .0001), propensity analyses were performed yielding a homogenous cohort. The overall complication and thromboembolic rates did not differ for muscular (soleal, gastrocnemius) vs tibial DVTs (anterior, posterior, peroneal veins). CONCLUSIONS: The use of anticoagulation in patients with CVT significantly decreases the rates of VTE complications. The use of IVC filters in this study was associated with a 10% complication rate and did not significantly reduce the incidence of PE. Nevertheless, given the overall low rates of PE and the higher risk of VTE in patients who receive filters, the decision to insert a filter in patients with calf CVT should be individualized. PMID- 27987607 TI - Long-term complications of inferior vena cava filters. AB - OBJECTIVE: Some inferior vena cava filter (IVCF) complications only manifest after prolonged dwell time (IVCF fracture, inferior vena cava [IVC] occlusion, and IVC perforation). Incidence of these complications is often based on mathematical projections given the lack of long-term imaging follow-up. The aim of this study was to assess the incidence of long-term complications of IVCFs using ideal imaging, contrast-enhanced computed tomography (CT). METHODS: From 2007 to 2009, 3303 IVCFs were placed across a large healthcare region. Only patients with contrast enhanced CTs of the abdomen at a minimum of 4 years post IVCF implantation were selected. A retrospective observational study was performed in 96 patients. Primary outcomes were prevalence and predictive factors for IVCF fracture, IVC thrombosis, and IVC perforation. RESULTS: Of 96 patients, 39 had permanent IVCFs and 57 had retrievable IVCFs. Mean dwell time at most recent CT scan was 61 months. Overall rate of fracture was 14% with the majority (92%) in Cordis OptEase and TrapEase filters (Cordis, Fremont, Calif; P < .0001). Overall rate of partial/complete IVC occlusion was 13% (7.3% total and 5.2% partial). IVC perforation rates were higher among retrievable devices (70%) compared with permanent devices (15%; P < .0001). Perforation involving retroperitoneal structures was 68% among conical retrievable devices and 5% among permanent devices (P < .0001). CONCLUSIONS: Long-term complications related to chronic IVCFs are relatively common, and the incidence of fracture and IVC perforation varies with device type. Higher rates of fracture were seen with the Cordis OptEase and TrapEase filters, whereas higher rate and degree of IVC perforation were seen with retrievable conical type devices. PMID- 27987608 TI - A quality improvement project to improve inferior vena cava filter retrieval. AB - OBJECTIVE: Poor retrieval rates for retrievable inferior vena cava filters (R IVCFs) have been reported throughout the literature, with poor follow-up a common cause. In 2009, we reported a retrieval rate of 18% despite an initial follow-up rate of 85%. Use of a registry has been shown to improve retrieval rates. As a quality improvement project, in May 2012, the vascular surgery fellowship implemented a reiterative registry to track R-IVCFs placed at Walter Reed National Military Medical Center to improve retrieval rates. We report the results in 125 patients after 38 months. METHODS: Patients receiving an R-IVCF were entered into a registry. All patients were reviewed monthly using an electronic health record. When there was no longer an indication for the R-IVCF, the patient was scheduled for an outpatient appointment with a vascular surgeon followed by retrieval. Rates of retrieval, technical success, dwell time, indication, complications, and demographics were collected. RESULTS: There were 125 R-IVCFs placed between May 2012 and June 2015; 52 filters were placed for therapeutic and 73 for prophylactic indications. Our follow-up rate improved to 94%. A total of 79 filters were retrieved (63% absolute retrieval rate). Excluding patients who died before retrieval and patients with a permanent indication, 77% of filters were retrieved. The average dwell time was 101.5 days (7-460 days), and 63% of successful R-IVCF retrievals were within 3 months of placement. Technical success for retrieval was 92%. There were two major complications from retrievals (1.5% of retrievals). CONCLUSIONS: The creation of an R-IVCF registry promoted ongoing follow-up with patients. In our earlier experience, retrieval rates were poor despite a high follow-up rate. The use of a reiterative registry improved our retrieval rate by 45% and increased our follow up rate to 94%. These results emphasize the importance of repetitive follow-up for R-IVCFs. Despite a follow-up rate >90%, around a third of R-IVCFs were not retrieved. PMID- 27987609 TI - Endovascular management of chronic total occlusions of the inferior vena cava and iliac veins. AB - OBJECTIVE: Percutaneous recanalization and stenting is currently the standard of care for symptomatic chronic total occlusions (CTOs) of the iliofemoral veins. CTO lesions involving the inferior vena cava (IVC) present a more complex patient subset. In this series we describe our single-center experience with endovascular recanalization of symptomatic occlusions of the IVC. METHODS: Patients were evaluated with duplex ultrasound imaging, venous function tests, and venography before intervention. Occluded segments were recanalized, balloon dilated, and stented. The basic stent technique modified over time to accommodate the iliocaval junction, presence of IVC filters, and lesions extending to the renal veins and atrium. RESULTS: Between November 2000 and August 2015, 71 patients (41 men [58%]) underwent IVC endovascular recanalization procedures for symptomatic chronic IVC occlusions. Patients were an average age of 51 years (range, 23-77 years). Underlying contributing factors for venous occlusion included IVC filter occlusion in 38 (54%), caval ligation/clipping in 4 (6%), and hypercoagulable disorder in 27 (38%). The technical success rate was 85% (n = 60). The proximal extent of the stents were infrarenal in 40 (67%), suprarenal in 11 (18%), or intrathoracic in 9 (15%). There was minimal perioperative morbidity (2 hematomas, 1 renal failure) and no postoperative mortality. Average follow-up was 48.0 +/- 43.3 months (range, 6-172 months). Primary, primary assisted, and secondary patency rates at 60 months were 52%, 85%, and 93%, respectively. Significant improvement in pain and swelling was seen in 91% and 83%, respectively; and complete cumulative relief of pain and swelling was 66% and 41% respectively. Ulcers were present in 18 patients and healed completely without recurrence in 14 (78%) after recanalization. The Venous Clinical Severity Score was 8.4 +/- 5.1 (range, 4-27) before the intervention and 3.9 +/- 3.2 (range, 0-14) after the intervention (P < .001). CONCLUSIONS: Endovascular recanalization of chronic total IVC occlusions can be performed with minimal morbidity and mortality. When successful, symptoms can be substantially improved, with excellent patency. PMID- 27987610 TI - Iliac vein stenting and contralateral deep vein thrombosis. PMID- 27987611 TI - Discussion. PMID- 27987605 TI - Analysis of noncatheter-associated upper extremity deep venous thrombosis from the RIETE registry. AB - OBJECTIVE: We sought to determine the risk factors for subsequent bleeding and recurrent venous thromboembolism (VTE) events following isolated noncatheter associated upper extremity deep venous thrombosis (non-CA-UEDVT) to better inform future treatment decisions for this group of patients. METHODS: The RIETE registry (Registro Informatizado de Enfermedad TromboEmbolica [Computerized Registry of Patients with Venous Thromboembolism]) is a prospective international registry of patients with objectively confirmed symptomatic VTE. Patients with a symptomatic, isolated, proximal UEDVT from March 2001 through March 2015 were analyzed. Any patient with an indwelling catheter or pacemaker lead at the DVT site and at the time of thrombosis was considered to have a CA-UEDVT and was excluded. Patient and treatment characteristics such as age, gender, comorbidities, VTE risk factors, treatment drug, and duration were collected. Outcomes examined included recurrent DVT, subsequent pulmonary embolism (PE), and hemorrhage. Multivariate analysis was performed using stepwise logistic regression. RESULTS: Of the 1100 patients who met the study criteria, 580 (53%) were male. The mean age of the patients was 50 +/- 20 years, and overall patient survival at 1 year was 85%. Recurrent VTE occurred in 59 patients (5.4%). Of these, 46 patients (4%) had recurrent DVT, 10 (0.9%) had a PE following UEDVT diagnosis, and 3 (0.3%) had both. PE was fatal in three patients (0.3%). Bleeding occurred in 50 patients (4.5%), major bleeding in 19 patients (1.7%), and fatal bleeding in 6 patients (0.5%). On multivariate analysis, malignant disease was associated with VTE recurrence (odds ratio [OR], 2.00; 95% confidence interval [CI], 1.04-3.45; P < .04), whereas hemorrhage was associated with age (OR, 1.03; 95% CI, 1.01-1.05; P = .002) and malignant disease (OR, 2.53; 95% CI, 1.34-4.76; P < .005). Hemorrhage and recurrent VTE were also significantly associated (OR, 2.79; 95% CI, 1.16-6.76; P < .03). CONCLUSIONS: PE following non-CA-UEDVT is rare. Malignant disease was associated with VTE recurrence. Age and malignant disease were associated with hemorrhage, and VTE recurrence was associated with hemorrhage. Further prospective studies should be undertaken to best determine length of anticoagulation treatment for the varied populations of patients with UEDVT. PMID- 27987613 TI - Complications of inferior vena cava filters. PMID- 27987612 TI - Magnetic resonance venography and three-dimensional image fusion guidance provide a novel paradigm for endovascular recanalization of chronic central venous occlusion. AB - OBJECTIVE: Endovascular recanalization is considered first-line therapy for chronic central venous occlusion (CVO). Unlike arteries, in which landmarks such as wall calcifications provide indirect guidance for endovascular navigation, sclerotic veins without known vascular branching patterns impose significant challenges. Therefore, safe wire access through such chronic lesions mostly relies on intuition and experience. Studies have shown that magnetic resonance venography (MRV) can be performed safely in these patients, and the boundaries of occluded veins may be visualized on specific MRV sequences. Intraoperative image fusion techniques have become more common to guide complex arterial endovascular procedures. The aim of this study was to assess the feasibility and utility of MRV and intraoperative cone-beam computed tomography (CBCT) image fusion technique during endovascular CVO recanalization. METHODS: During the study period, patients with symptomatic CVO and failed standard endovascular recanalization underwent further recanalization attempts with use of intraoperative MRV image fusion guidance. After preoperative MRV and intraoperative CBCT image coregistration, a virtual centerline path of the occluded segment was electronically marked in MRV and overlaid on real-time two dimensional fluoroscopy images. Technical success, fluoroscopy times, radiation doses, number of venograms before recanalization, and accuracy of the virtual centerline overlay were evaluated. RESULTS: Four patients underwent endovascular CVO recanalization with use of intraoperative MRV image fusion guidance. Mean (+/ standard deviation) time for image fusion was 6:36 +/- 00:51 mm:ss. The lesion was successfully crossed in all patients without complications. Mean fluoroscopy time for lesion crossing was 12.5 +/- 3.4 minutes. Mean total fluoroscopy time was 28.8 +/- 6.5 minutes. Mean total radiation dose was 15,185 +/- 7747 MUGy/m2, and mean radiation dose from CBCT acquisition was 2788 +/- 458 MUGy/m2 (18% of mean total radiation dose). Mean number of venograms before recanalization was 1.6 +/- 0.9, whereas two lesions were crossed without any prior venography. On qualitative analysis, virtual centerlines from MRV were aligned with actual guidewire trajectory on fluoroscopy in all four cases. CONCLUSIONS: MRV image fusion is feasible and may improve success, safety, and the surgeon's confidence during CVO recanalization. Similar to arterial interventions, three-dimensional MRV imaging and image fusion techniques could foster innovative solutions for such complex venous interventions and have the potential to affect a great number of patients. PMID- 27987614 TI - The bull's eye sign and other suprainguinal venographic findings to limit the use of intravascular ultrasound in patients with severe venous stasis. AB - OBJECTIVE: When assessing the common femoral and suprainguinal veins in patients with venous stasis, it is generally agreed that use of intravascular ultrasound (IVUS) is mandatory. This widely held dogma is reinforced by the fact that extrinsic compression of the iliac veins does not reproduce images consistent with eccentric stenosis as one sees in the arterial system. In an attempt to identify a subgroup of patients where the use of IVUS could be averted, we analyzed and carefully evaluated the images of patients who had both standard contrast venograms and IVUS examinations. METHODS: Ninety-two common femoral and suprainguinal venograms performed during a recent 6-month period were randomly selected for analysis. Good quality venographic images were found in 88 of these limbs (78 patients) that also had IVUS data formed the basis of this analysis. All venograms included visualization of the common femoral, external and common iliac veins, and inferior vena cava. These veins were classified as (1) normal to mild (type I) vein narrowing or dilatation of <=20% compared with the adjacent segment, (2) moderate (type II) >=21%-40%, (3) severe (type III) >=41%, and (4) bull's eye sign (type IV). The latter was defined as a central circle with minimal or no dye within a dilated vein and forking of the dye around the circle. RESULTS: In the present series, no 1-month mortality or 1-month morbidity was observed in these patients. The Clinical, Etiologic, Anatomic, and Pathologic (CEAP) classification score was class II in 24 cases (26%), class III in 36 cases (39%), class IV in 17 cases (18%), class V in nine cases (10%), and class VI in six cases (7%). There was no venographic or IVUS evidence of inferior vena cava stenosis or dilatation in this series. Of the venograms studied, 88 had positive intravascular ultrasound (PIVUS) or positive predictive value findings. The correlation of venographic findings and PIVUS was as follows: type I cases (26) had 85% PIVUS; type II (22) had 100% PIVUS; type III (25) had 100% PIVUS, and type IV (19) had 100% PIVUS. CONCLUSIONS: The new proposed classification of venographic findings can be used to treat more than two-thirds of the patients without resorting to the use of IVUS. PMID- 27987615 TI - Practice patterns of endovenous ablation therapy for the treatment of venous reflux disease. AB - OBJECTIVE: The purpose of this study was to assess practice patterns of endovenous ablation therapy for the treatment of venous reflux disease among the vein specialist members of the American Venous Forum (AVF). METHODS: An online survey was conducted of AVF members designed to identify demographics, treatment practices, and clinical variables in the selection of vein ablation devices. RESULTS: The survey was distributed to 798 practicing physicians, of whom 129 (16%) responded. The specialty distribution of respondents was as follows: vascular surgeons, 54%; phlebologists, 14%; general surgeons, 11%; interventional radiologists, 9%; and other specialties, 6%. The majority (81%) were from the United States, and 65% were self-employed. Almost half (47%) were in practice for >20 years, with 33% of all respondents performing three to five saphenous vein ablations per week. Three-quarters (79%) of respondents preferred radiofrequency ablation (RFA), with 47% believing that it was more cost-effective and more than half (57%) reporting improved patient satisfaction with this technique. Most of them (63%) responded that previous capital investment played a significant role in their choice of vein ablation device along with the associated cost of disposable equipment. A large majority (77%) of physicians responded that they had a significant role in choosing the treatment device, whereas only 17% thought that patients' choice played a major role in device choice. The capital investment affected choice of modality more significantly in newer practices (P < .0.5). CONCLUSIONS: The majority of AVF vein specialists prefer an RFA technique to laser, believing that RFA is associated with improved patient outcomes and is more cost-effective. Advances in technology, device costs, and reimbursement levels may have an impact on such preferences in the future. PMID- 27987616 TI - Deep venous thrombosis associated with caval extension of iliac stents. AB - BACKGROUND: It is generally difficult to place an iliac vein stent precisely at the iliocaval junction with venographic control or even with intravascular ultrasound guidance. Furthermore, mechanical properties of the Wallstent (Boston Scientific, Marlborough, Mass) can predispose precisely placed stents to distal displacement or stent collapse. Our center has thus advocated extending Wallstents 3 to 5 cm into the inferior vena cava to prevent complications of missed proximal lesions or stent migration. This technique has gradually been accepted, and concerns of jailing of contralateral flow were not initially recognized. We analyzed deep venous thrombosis (DVT) incidence following iliocaval stenting with two alternative techniques: (1) Wallstents with 3- to 5 cm extension into the inferior vena cava; and (2) a modified Z-stent (Cook Medical, Bloomington, Ind) technique, in which overlapping Wallstents end at the iliac confluence and caval extension is performed with a Z-stent placed at the top of the stack. The function of the Z-stent is to provide improved radial force at the iliocaval confluence and to prevent jailing of contralateral flow with larger stent interstices. METHODS: There were 755 limbs with consecutive Wallstent caval extensions (2006-2010) and 982 limbs with Z-stent extensions (2011-2015) analyzed for DVT incidence postoperatively. RESULTS: Demographics were similar for both groups. Mean age was 56 and 58 years in the Wallstent and Z stent groups, respectively. There was a female predominance (Wallstent, 69%; Z stent, 67%) and a higher incidence of left-sided disease (Wallstent, 66%; Z stent, 56%) in both groups. There was a slightly higher incidence of post thrombotic disease in the Z-stent subgroup (Wallstent, 53%; Z-stent, 68%). Cumulative freedom from contralateral DVT was 99% and 90% in the Z-stent and Wallstent groups, respectively (P < .001) during the 5 years following stent placement. However, all three patients with DVT contralateral to a Z-stent actually had high placement of the Wallstent across the confluence. Thus, no patients with proper Z-stent technique had a contralateral DVT. Cumulative freedom from ipsilateral DVT was 97% and 82% in the Z-stent and Wallstent groups, respectively (P < .001) during the 5 years following stent placement. The decrease in incidence of ipsilateral DVT appeared to be attributable to decreased missed distal lesions with increased operator experience and not attributable to the Z-stent itself. CONCLUSIONS: Contralateral DVT incidence was significantly lower with the Z-stent modification. In addition, the Z-stent modification provides greater radial strength at the iliac-caval confluence and simplifies simultaneous or sequential bilateral stenting. Use of proper technique and intravascular ultrasound is essential to limit the incidence of ipsilateral DVT. PMID- 27987618 TI - Invited commentary. PMID- 27987617 TI - Determining the origin of superficial venous reflux in the groin with duplex ultrasound and implications for varicose vein surgery. AB - OBJECTIVE: The purpose of this paper was to describe patterns of superficial reflux in the groin with respect to the terminal valve (TV), which is located at the saphenous opening to the common femoral vein, the great saphenous vein, and its tributary veins. METHODS: This study included 2019 legs with chronic venous insufficiency that received endoluminal varicose vein treatment because of varicosities with insufficiency of the saphenofemoral junction (SFJ). In a preoperative duplex ultrasound investigation of the superficial vein system, reflux after provocation in the SFJ, great saphenous vein, cranial veins (superficial external pudendal vein, superficial epigastric vein, superficial circumflex iliac vein), and anterior and posterior accessory saphenous veins was recorded and classified on the basis of the origin of reflux. RESULTS: In 1348 legs (66.8%), the reflux had its origin exclusively in the common femoral vein. In 170 legs (8.4%), the reflux had its origin in the common femoral and cranial veins. In 430 legs (21.3%), the insufficiency was due to saphenocranial reflux only. In 71 legs (3.5%), the origin of reflux could not be determined. CONCLUSIONS: Reflux in the SFJ does not involve the TV in 24.8% of the legs, implying that routine high ligation and ablation close to the TV might be overtreatment in these patients. PMID- 27987619 TI - Invited commentary. PMID- 27987620 TI - Validation of the novel venous drainage index with stepwise increases in thigh compression pressure in the quantification of venous obstruction. AB - BACKGROUND: Venous drainage from the leg is poorly understood, and it is difficult to quantify it hemodynamically. Attempts have been made using duplex ultrasound scanning and venous occlusion air plethysmography (APG). However, they have limited value in day-to-day clinical practice. This is because venous drainage measurements have never been validated successfully against increasing obstruction pressures. The hypothesis is that the novel gravitational venous drainage index (VDI) in milliliters/second is reduced in response to increasing venous obstruction, and the aim was to quantify this, using stepwise inflations of a thigh cuff. METHODS: Venous drainage tracings were obtained with APG using a dependency to elevation maneuver on the right legs of 21 volunteers (9 female) without venous disease. The test was performed once without a thigh cuff and then with a contoured thigh cuff (18 cm wide) inflated in steps at 10, 20, 30, 40, and 50 mm Hg just before elevation. The function of the thigh cuff was to mimic venous obstruction. The drainage volumes were obtained once the tracing from the elevated cuffed leg decreased to a steady line, when arterial inflow equals venous outflow. The VDI was calculated in the same way as the opposite maneuver, the venous filling index, is obtained from the venous filling tracing (elevation to dependency maneuver), namely, VDI = 90% venous drainage volume/venous drainage time to 90%. The drainage reserve volume (DRV) was defined as the undrained volume caused by the venous obstruction from the thigh cuff. RESULTS: With stepwise inflations of the thigh cuff at 0, 20, 30, 40, and 50 mm Hg, the median VDI is reduced (26.1, 24.1, 12.1, 7.8, 5.4) and the DRV is increased (0, 5.3, 15.4, 45.5, 62.6). Furthermore, the VDI reductions and the DRV increases correlated significantly (P < .0005) with increasing obstruction pressure at r = 0.69 and r = 0.793, respectively (Spearman). CONCLUSIONS: The VDI is a novel APG parameter derived from a dependency to elevation maneuver that represents the gravitational venous drainage rate of the leg. The DRV is the undrained venous volume caused by the obstruction from an inflated thigh cuff. Both parameters have been demonstrated to respond to and to correlate with increasing venous obstruction pressures. Their potential clinical value in assessing the hemodynamic significance of an iliac or femoral stenosis and in the screening and selection of patients requiring iliac stenting and follow-up requires further investigation. PMID- 27987621 TI - Invited commentary. PMID- 27987623 TI - Editorial: Special Issue on Brazilian Proteomics. PMID- 27987622 TI - Differentiation of functional venous insufficiency and leg lymphedema complicated by functional venous insufficiency using subcutaneous tissue ultrasonography. AB - OBJECTIVE: To use subcutaneous ultrasonography to differentiate legs with edema because of obesity-related functional venous insufficiency (FVIob), immobility related FVI (FVIim), secondary lymphedema (LE), LE complicated by obesity (LEob), and LE complicated by immobility (LEim). METHODS: Ninety-nine legs with edema (16 FVIob, 32 FVIim, 22 LE, 9 LEob, and 20 LEim), and 10 normal legs were examined. Subcutaneous tissue ultrasonography was performed at eight points (medial, lateral, upper, lower, thigh, and calf) in each leg. Subcutaneous echogenicity (SEG) and subcutaneous echo-free space (SEFS) were assessed, and each graded as 0, 1, and 2 according to their severity. RESULTS: In normal legs, SEG and SEFS were graded 0 in almost all parts of the leg. SEG was diffusely increased in FVIob, whereas SEG was increased in accordance with gravity in FVIim (upper medial thigh, 0.6 +/- 0.5 vs lower medial calf, 1.2 +/- 0.4; P < .001). In LE, SEG was increased in the medial side, particularly evident in upper thigh (upper medial thigh, 1.1 +/- 0.4 vs upper lateral thigh, 0.6 +/- 0.6; P < .01). SEFS was increased in accordance with gravity in all of these legs (FVIob: upper medial thigh, 0.2 +/- 0.4 vs lower medial calf, 0.7 +/- 0.8; P = .05; FVIim: upper medial thigh, 0.1 +/- 0.2 vs lower medial calf, 1.3 +/- 0.7; P < .0001; LE: upper medial thigh, 0.4 +/- 0.7 vs lower medial calf, 0.9 +/- 0.9; P < .05). The increases of SEG and SEFS in legs with LEob or LEim were diffuse and similar. As determined via stepwise logistic regression analyses, the increases in SEG in the upper medial thigh and SEFS in the lower medial thigh in LE cases, the increases in SEG in the upper lateral thigh and SEFS in the lower lateral thigh in cases with obesity-related leg edema (ie, FVIob and LEob), and the increase in SEFS in the lower lateral calf in cases with immobility-related leg edema (ie, FVIim and LEim) were determined to be significant factors to characterize each leg edema. CONCLUSIONS: Differences in the extent and distribution of SEG and SEFS might help in differentiating LE from FVIob and FVIim, although assessment of LE complicated by obesity vs immobility remains difficult. PMID- 27987625 TI - American Gastroenterological Institute Guideline on the Management of Crohn's Disease After Surgical Resection: Clinical Decision Support Tool. PMID- 27987626 TI - EQ-5D Scores for Diabetes-Related Comorbidities. AB - BACKGROUND: A single-source catalogue of nationally representative EuroQol five dimensional questionnaire (EQ-5D) scores for chronic conditions in the United States and the United Kingdom from the Medical Expenditure Panel Survey (MEPS) has been published and has been used extensively for public health and cost effectiveness modeling. OBJECTIVES: To estimate EQ-5D scores for diabetes-related chronic conditions that are consistent with the previous catalogue. METHODS: The MEPS is a nationally representative survey of the US civilian population. EQ-5D 3L questionnaire responses were mapped from short-form 12 health survey responses in 2000 to 2011 MEPS data using multinomial logistic regression. Country-specific tariffs were applied to the mapped EQ-5D responses for the United Kingdom, the United States, France, and Spain. EQ-5D scores were regressed on diabetes-related comorbidities controlling for sociodemographic characteristics, body mass index, and comorbidity using robust (median) regression. Methods were consistent with the previously published catalogue of EQ-5D scores for the United States. RESULTS: There were 20,705 individuals with diabetes and a valid mapped EQ-5D score in the 2000 to 2011 MEPS data. Unadjusted mapped EQ-5D scores for individuals with diabetes varied by country-specific tariff from 0.70 (France) to 0.79 (United States). Regression results reflecting marginal disutility estimates for EQ-5D scores are provided for 17 diabetes-related comorbidities and body mass index categories for US, UK, French, and Spanish tariffs. CONCLUSIONS: The estimates provided in this research may be useful for analysts attempting to model the impact of diabetes and diabetes-related comorbid conditions on utility. They are derived from a single-source, nationally representative population and augment the existing "off-the-shelf" catalogue of EQ-5D scores for chronic conditions. PMID- 27987627 TI - A Cost-Effectiveness Analysis of Nivolumab Compared with Ipilimumab for the Treatment of BRAF Wild-Type Advanced Melanoma in Australia. AB - PURPOSE: The aim of this study was to evaluate the cost-effectiveness of nivolumab versus ipilimumab for the treatment of previously untreated patients with BRAF-advanced melanoma (BRAF-AM) from an Australian health system perspective. METHODS: A state-transition Markov model was constructed to simulate the progress of Australian patients with BRAF-AM. The model had a 10-year time horizon with outcomes discounted at 5% annually. For the nivolumab group, risks of progression and death were based on those observed in the nivolumab arm of a phase III trial (nivolumab vs. dacarbazine). Progression-free survival and overall survival were extrapolated using parametric survival modeling with a log logistic distribution. In the absence of head-to-head evidence, overall survival and progression-free survival for ipilimumab were estimated on the basis of an indirect comparison using published data. Costs of managing AM were estimated from a survey of Australian clinicians. The cost of ipilimumab was based on the reimbursement price in Australia. The cost of nivolumab was based on expected reimbursement prices in Australia. Quality-of-life data were obtained within the trial using the EuroQol five-dimensional questionnaire. RESULTS: Compared with ipilimumab, nivolumab therapy over 10 years was estimated to yield 1.58 life years and 1.30 quality-adjusted life-years per person, at a (discounted) net cost of US $39,039 per person. The incremental cost-effectiveness ratios for nivolumab compared with ipilimumab were US $25,101 per year of life saved and $30,475 per quality-adjusted life-year saved. CONCLUSIONS: Nivolumab is a cost-effective means of preventing downstream mortality and morbidity in patients with AM compared with ipilimumab in the Australian setting. PMID- 27987628 TI - Arbitration Board Setting Reimbursement Amounts for Pharmaceutical Innovations in Germany When Price Negations between Payers and Manufacturers Fail: An Empirical Analysis of 5 Years' Experience. AB - BACKGROUND: In Germany, an arbitration board is setting reimbursement amounts for drug innovations when price negations between payers and manufacturers fail. OBJECTIVE: To empirically analyze all arbitrations since the reform of Germany's Act to Reorganize the Pharmaceuticals' Market in the Statutory Health Insurance System came into effect. METHODS: All available relevant documents up to January 2016 were screened and the identified contentious issues between the negotiation parties extracted. Reimbursement requests of both the negotiating parties and the arbitrations were transformed into a comparable format on the basis of defined daily doses and then contrasted among each other. RESULTS: In the given period, 16 arbitrations took place. The arbitration board is implementing the same criteria used in the negotiations between manufacturers and payers. Almost all arbitrations dealt with generic appropriate comparative therapies. Reimbursement amounts set by arbitration were on average 38.4% less than the mean of negotiation parties' requests (69.2% less than the manufacturers' requests). The corresponding prescription volumes were arranged rather centrally. All but one arbitration refer to a 1-year contract period. The arbitration board rarely decided on further technical contentious points. Hence, no heuristics referring to them were derivable. CONCLUSIONS: There is some evidence for a quasi algorithmic approach of the arbitration board, even though it is legally determined that it has to decide while taking the peculiar conditions of each case into due consideration, including the characteristics of the respective therapeutic area. The balance of interests proved to be within a very narrow space albeit it concerns in principle discretionary decisions. Thus, the purpose of arbitration seems not to be achieved sufficiently. PMID- 27987629 TI - Translating Pharmacometrics to a Pharmacoeconomic Model of COPD. AB - BACKGROUND: A model-based meta-analysis (MBMA) is a type of meta-regression that uses nonlinear mixed-effects models estimated on trial-level data to relate patient and trial characteristics, dosing, biomarkers, and outcomes of treatment. OBJECTIVES: To use a pharmacometric MBMA within a pharmacoeconomic model of chronic obstructive pulmonary disease (COPD). METHODS: A Markov microsimulation model was developed to estimate monthly changes in the key disease severity metrics of COPD (forced expiratory volume in 1 second [FEV1] and exacerbations) to compare a hypothetical drug that increases FEV1 to usual care. The MBMA was used to predict a baseline exacerbation rate in a group of actual trial patients, given their known baseline FEV1. The hypothetical drug increased FEV1, thereby decreasing individuals' predicted exacerbation rates. Individual patient simulations allowed stochastic changes in monthly FEV1 decline. RESULTS: In a sample of 1097 trial patients with a mean FEV1 of 50%, the MBMA predicted 0.93 exacerbations per year on average. The exacerbation rate ranged from 0.52 to 1.3 per year across moderate and severe patient subgroups. A hypothetical anti inflammatory drug that increased FEV1 by 50 ml decreased exacerbations by 26%. Given a simplified estimation of costs and quality-adjusted life-years (QALYs) associated with COPD, a drug with a 50-ml increase priced at ?35/mo had an incremental cost-effectiveness ratio ranging from ?13,000/QALY to approximately ?207,000/QALY across patient severity subgroups. CONCLUSIONS: The synergistic aspects of MBMA and pharmacoeconomic modeling are highlighted in this hypothetical example. Markov microsimulation modeling allows the finer predictions of MBMA to inform parameters. Such an approach has utility in both early-phase cost-effectiveness estimations and trial design. PMID- 27987630 TI - Order of Presentation of Dimensions Does Not Systematically Bias Utility Weights from a Discrete Choice Experiment. AB - BACKGROUND: Discrete choice experiments (DCEs) are increasingly used to value aspects of health. An issue with their adoption is that results may be sensitive to the order in which dimensions of health are presented in the valuation task. Findings in the literature regarding order effects are discordant at present. OBJECTIVES: To quantify the magnitude of order effect of quality-of-life (QOL) dimensions within the context of a DCE designed to produce country-specific value sets for the EORTC Quality of Life Utility Measure-Core 10 dimensions (QLU-C10D), a new utility instrument derived from the widely used cancer-specific QOL questionnaire, the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. METHODS: The DCE comprised 960 choice sets, divided into 60 versions of 16 choice sets, with each respondent assigned to a version. Within each version, the order of QLU-C10D QOL dimensions was randomized, followed by life duration in the last position. The DCE was completed online by 2053 individuals in France and Germany. We analyzed the data with a series of conditional logit models, adjusted for repeated choices within respondent. We used F tests to assess order effects, correcting for multiple hypothesis testing. RESULTS: Each F test failed to reject the null hypothesis of no position effect: 1) all QOL order positions considered jointly; 2) last QOL position only; 3) first QOL position only. Furthermore, the order coefficients were small relative to those of the QLU-C10D QOL dimension levels. CONCLUSIONS: The order of presentation of QOL dimensions within a DCE designed to provide utility weights for the QLU-C10D had little effect on level coefficients of those QOL dimensions. PMID- 27987631 TI - Economic Evaluations of Multicomponent Disease Management Programs with Markov Models: A Systematic Review. AB - BACKGROUND: Disease management programs (DMPs) for chronic diseases are being increasingly implemented worldwide. OBJECTIVES: To present a systematic overview of the economic effects of DMPs with Markov models. The quality of the models is assessed, the method by which the DMP intervention is incorporated into the model is examined, and the differences in the structure and data used in the models are considered. METHODS: A literature search was conducted; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was followed to ensure systematic selection of the articles. Study characteristics e.g. results, the intensity of the DMP and usual care, model design, time horizon, discount rates, utility measures, and cost-of-illness were extracted from the reviewed studies. Model quality was assessed by two researchers with two different appraisals: one proposed by Philips et al. (Good practice guidelines for decision-analytic modelling in health technology assessment: a review and consolidation of quality asessment. Pharmacoeconomics 2006;24:355-71) and the other proposed by Caro et al. (Questionnaire to assess relevance and credibility of modeling studies for informing health care decision making: an ISPOR-AMCP-NPC Good Practice Task Force report. Value Health 2014;17:174-82). RESULTS: A total of 16 studies (9 on chronic heart disease, 2 on asthma, and 5 on diabetes) met the inclusion criteria. Five studies reported cost savings and 11 studies reported additional costs. In the quality, the overall score of the models ranged from 39% to 65%, it ranged from 34% to 52%. Eleven models integrated effectiveness derived from a clinical trial or a meta-analysis of complete DMPs and only five models combined intervention effects from different sources into a DMP. The main limitations of the models are bad reporting practice and the variation in the selection of input parameters. CONCLUSIONS: Eleven of the 14 studies reported cost-effectiveness results of less than $30,000 per quality-adjusted life-year and the remaining two studies less than $30,000 per life-year gained. Nevertheless, if the reporting and selection of data problems are addressed, then Markov models should provide more reliable information for decision makers, because understanding under what circumstances a DMP is cost-effective is an important determinant of efficient resource allocation. PMID- 27987632 TI - The Cost of Costing Treatments Incorrectly: Errors in the Application of Drug Prices in Economic Evaluation Due to Failing to Account for the Distribution of Patient Weight. AB - BACKGROUND: The cost of pharmaceuticals dosed by weight or body surface area (BSA) can be estimated in several ways for economic evaluations. A review of 20 recent National Institute for Health and Care Excellence appraisals showed that 17 of them took the mean weight or BSA of patients, 2 costed the individual patient data from trials, and 2 fitted a distribution to patient-level data. OBJECTIVES: To investigate the estimated drug costs using different methodologies to account for patient characteristics for pharmaceuticals with a weight- or BSA based posology. The secondary objective was to explore the suitability of general population data as a proxy for patient-level data. METHODS: Patient-level data were pooled from three clinical trials and used to calculate a hypothetical cost per administration of eight licensed pharmaceuticals, applying the three methods used in recent National Institute for Health and Care Excellence appraisals. The same analysis was performed using data from the Health Survey for England (in place of patient-level data) to investigate the validity of using general population data as a substitute for patient-level data. RESULTS: Compared with using patient-level data from clinical trials, the mean patient characteristics (weight or BSA) led to an underestimation of drug cost by 6.1% (range +1.5% to 25.5%). Fitting a distribution to patient-level data led to a mean difference of +0.04%. All estimates were consistent using general population data. CONCLUSIONS: Estimation of drug costs in health economic evaluation should account for the distribution in weight or BSA to produce accurate results. When patient data are not available, general population data may be used as an alternative. PMID- 27987633 TI - Update to the Report of Nationally Representative Values for the Noninstitutionalized US Adult Population for Five Health-Related Quality-of-Life Scores. AB - BACKGROUND: The most recent reports of nationally representative health-related quality-of-life (HRQOL) values for the United States used data that were collected over a decade ago. OBJECTIVES: To update these values using data from 2011, stratified by age and sex. METHODS: This study used data from two sources the 2011 Medical Expenditures Panel Survey (MEPS) and the 2011 National Health Interview Survey (NHIS). Both are nationally representative surveys of the US noninstitutionalized civilian population. The MEPS was used to calculate four HRQOL scores: categorical self-rated health, mental and physical component summaries from the short form-12 items (SF-12) health survey, and the health state short form-6 dimensions (SF-6D). We also estimated Quality of Well-Being Scale scores from the NHIS. We reported means and quartiles for all continuous scores, stratified by decade of age and sex. RESULTS: There were 23,906 eligible subjects in the 2011 MEPS and 32,242 eligible subjects in the 2011 NHIS. All age and sex categories had instrument completion rates above 84%. Females reported lower mean scores than did males across all ages and instruments. In general, those in older age groups reported lower scores than did those in younger age groups, with the exception of the mental component summary scores from the SF-12 health survey. When compared with previous reports, these new values were generally lower than those in previous reports but rarely reached minimally important difference criteria. CONCLUSIONS: This report updates US nationally representative age- and sex-stratified estimates for five HRQOL scores using data from 2011. These values are important for use in both generalized comparisons of health status and in cost-effectiveness analyses. PMID- 27987638 TI - From the Co-Editors-In-Chief. PMID- 27987634 TI - A Differential Item Functioning Analysis of the EQ-5D in Cancer. AB - OBJECTIVES: To determine whether differential item functioning (DIF) was present in the EuroQol five-dimensional questionnaire (EQ-5D) used in cancer (non-small cell lung cancer and prostate cancer). METHODS: The Partial Credit Model was applied to the three-level version of the EQ-5D with data obtained from four randomized controlled trials in prostate cancer and non-small cell lung cancer completed at baseline before treatment (N = 2213). DIF was assessed across cancer type (two levels), sex (two levels), and age group (three levels) using Mantel Haenszel chi-square statistics and evaluated against the Educational Testing Service classification rules. RESULTS: The presence of DIF was determined in 14 of 25 (56%) potential DIF contrasts in all the EQ-5D domains. Although mostly the DIF was categorized as either negligible (3 of 25 [12%]) or medium (7 of 25 [28%]), large DIF was observed in 4 of the 25 contrasts (16%). The mobility domain, in particular, showed consistently large DIF across cancer type, sex, and age. CONCLUSIONS: Given the use of the instrument in health status assessments across conditions and interventions, these results may have significant implications for the EQ-5D in health economic evaluations. Further research is warranted to determine whether these results hold for other cancers. PMID- 27987639 TI - Making Choices on the Journey to Universal Health Care Coverage: From Advocacy to Analysis. PMID- 27987640 TI - How to Get Cost-Effectiveness Analysis Right? The Case of Vaccine Economics in Latin America. AB - BACKGROUND: In middle-income countries, vaccines against pneumococcal disease, rotavirus, and human papilloma virus are in general more costly, not necessarily cost saving, and less consistently cost-effective than earlier generation vaccines against measles, diphtheria, tetanus, and pertussis. Budget impact is also substantial; public spending on vaccines in countries adopting new vaccines is, on average, double the amount of countries that have not adopted. Policymakers must weigh the costs and benefits of the adoption decision carefully, given the low coverage of other kinds of cost-effective health and nonhealth interventions in these same settings and relatively flat overall public spending on health as a share of gross domestic product (GDP) over time. OBJECTIVE: This paper considers lessons learned from recent vaccine cost effectiveness analyses and subsequent adoption decisions in Latin America a, largely under the auspices of the Pro Vac Initiative. RESULTS: The paper illustrates how small methodological choices and seemingly minor technical limitations of cost-effectiveness models can have major implications for the studies' conclusions, potentially influencing countries' subsequent vaccine adoption decisions. METHODS: We evaluate the ProVac models and technical outputs against the standards and framework set out by the International Decision Support Initiative Reference Case for economic evaluation and consider the practical effects of deviations from those standards. CONCLUSIONS: Lessons learned are discussed, including issues of appropriate comparators, GDP-based thresholds, and use of average versus incremental cost-effectiveness ratios as a convention are assessed. The article ends with recommendations for the future. PMID- 27987641 TI - The International Decision Support Initiative Reference Case for Economic Evaluation: An Aid to Thought. AB - BACKGROUND: Policymakers in high-, low-, and middle-income countries alike face challenging choices about resource allocation in health. Economic evaluation can be useful in providing decision makers with the best evidence of the anticipated benefits of new investments, as well as their expected opportunity costs-the benefits forgone of the options not chosen. To guide the decisions of health systems effectively, it is important that the methods of economic evaluation are founded on clear principles, are applied systematically, and are appropriate to the decision problems they seek to inform. METHODS: The Bill and Melinda Gates Foundation, a major funder of economic evaluations of health technologies in low- and middle-income countries (LMICs), commissioned a "reference case" through the International Decision Support Initiative (iDSI) to guide future evaluations, and improve both the consistency and usefulness to decision makers. RESULTS: The iDSI Reference Case draws on previous insights from the World Health Organization, the US Panel on Cost-Effectiveness in Health Care, and the UK National Institute for Health and Care Excellence. Comprising 11 key principles, each accompanied by methodological specifications and reporting standards, the iDSI Reference Case also serves as a means of identifying priorities for methods research, and can be used as a framework for capacity building and technical assistance in LMICs. CONCLUSIONS: The iDSI Reference Case is an aid to thought, not a substitute for it, and should not be followed slavishly without regard to context, culture, or history. This article presents the iDSI Reference Case and discusses the rationale, approach, components, and application in LMICs. PMID- 27987642 TI - Country-Level Cost-Effectiveness Thresholds: Initial Estimates and the Need for Further Research. AB - BACKGROUND: Cost-effectiveness analysis can guide policymakers in resource allocation decisions. It assesses whether the health gains offered by an intervention are large enough relative to any additional costs to warrant adoption. When there are constraints on the health care system's budget or ability to increase expenditures, additional costs imposed by interventions have an "opportunity cost" in terms of the health foregone because other interventions cannot be provided. Cost-effectiveness thresholds (CETs) are typically used to assess whether an intervention is worthwhile and should reflect health opportunity cost. Nevertheless, CETs used by some decision makers-such as the World Health Organization that suggested CETs of 1 to 3 times the gross domestic product (GDP) per capita-do not. OBJECTIVES: To estimate CETs based on opportunity cost for a wide range of countries. METHODS: We estimated CETs based on recent empirical estimates of opportunity cost (from the English National Health Service), estimates of the relationship between country GDP per capita and the value of a statistical life, and a series of explicit assumptions. RESULTS: CETs for Malawi (the country with the lowest income in the world), Cambodia (with borderline low/low-middle income), El Salvador (with borderline low-middle/upper middle income), and Kazakhstan (with borderline high-middle/high income) were estimated to be $3 to $116 (1%-51% GDP per capita), $44 to $518 (4%-51%), $422 to $1967 (11%-51%), and $4485 to $8018 (32%-59%), respectively. CONCLUSIONS: To date, opportunity-cost-based CETs for low-/middle-income countries have not been available. Although uncertainty exists in the underlying assumptions, these estimates can provide a useful input to inform resource allocation decisions and suggest that routinely used CETs have been too high. PMID- 27987643 TI - Cancer Care Coordinators to Improve Tamoxifen Persistence in Breast Cancer: How Heterogeneity in Baseline Prognosis Impacts on Cost-Effectiveness. AB - OBJECTIVES: To assess the cost-effectiveness of a cancer care coordinator (CCC) in helping women with estrogen receptor positive (ER+) early breast cancer persist with tamoxifen for 5 years. METHODS: We investigated the cost effectiveness of a CCC across eight breast cancer subtypes, defined by progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, and local/regional spread. These subtypes range from excellent to poorer prognoses. The CCC helped in improving tamoxifen persistence by providing information, checking-in by phone, and "troubleshooting" concerns. We constructed a Markov macrosimulation model to estimate health gain (in quality-adjusted life years or QALYs) and health system costs in New Zealand, compared with no CCC. Participants were modeled until death or till the age of 110 years. Some input parameters (e.g., the impact of a CCC on tamoxifen persistence) had sparse evidence. Therefore, we used estimates with generous uncertainty and conducted sensitivity analyses. RESULTS: The cost-effectiveness of a CCC for regional ER+/PR-/HER2+ breast cancer (worst prognosis) was NZ $23,400 (US $15,800) per QALY gained, compared with NZ $368,500 (US $248,800) for local ER+/PR+/HER2- breast cancer (best prognosis). Using a cost-effectiveness threshold of NZ $45,000 (US $30,400) per QALY, a CCC would be cost-effective only in the four subtypes with the worst prognoses. CONCLUSIONS: There is value in investigating cost-effectiveness by different subtypes within a disease. In this example of breast cancer, the poorer the prognosis, the greater the health gains from a CCC and the better the cost-effectiveness. Incorporating heterogeneity in a cost utility analysis is important and can inform resource allocation decisions. It is also feasible to undertake in practice. PMID- 27987644 TI - Using Patient-Reported Outcomes for Economic Evaluation: Getting the Timing Right. AB - BACKGROUND: Patient-reported outcome measures (PROMs) are becoming increasingly popular in orthopedic surgery. Preoperative and postoperative follow-up often elicit PROMs in the form of generic quality-of-life instruments (e.g., Short Form health survey SF-12 [SF-12]) that can be used in economic evaluation to estimate quality-adjusted life-years (QALYs). However, the timing of postoperative measurement is still under debate. OBJECTIVES: To explore the timing of postoperative PROMs collection and the implications for bias in QALY estimation for economic evaluation. METHODS: We compared the accuracy of QALY estimation on the basis of utilities derived from the SF-12 at one of 6 weeks, 3 months, 6 months, and 12 months after total knee arthroplasty, under different methods of interpolation between points. Five years of follow-up data were extracted from the St. Vincent's Melbourne Arthroplasty Outcomes (SMART) registry (n = 484). The SMART registry collects follow-up PROMs annually and obtained more frequent outcomes on subset of patients (n = 133). RESULTS: Postoperative PROM collection at 6 weeks, 6 months, or 12 months biased the estimation of QALY gain from total knee arthroplasty by -41% (95% confidence interval [CI] -59% to -22%), 18% (95% CI 4%-32%), and -8% (95% CI -18% to -2%), respectively. This bias was minimized by collecting PROMs at 3 months postoperatively (6% error; 95% CI -9% to 21%). CONCLUSIONS: The timing of PROM collection and the interpolation assumptions between measurements can bias economic evaluation. In the case of total knee arthroplasty, we recommend a postoperative measurement at 3 months with linear interpolation between preoperative and postoperative measures. The design of economic evaluations should consider timing and interpolation issues. PMID- 27987645 TI - Health Economics as Rhetoric: The Limited Impact of Health Economics on Funding Decisions in Four European Countries. AB - BACKGROUND: A response to the challenge of high-cost treatments in health care has been economic evaluation. Cost-effectiveness analysis presented as cost per quality-adjusted life-years gained has been controversial, raising heated support and opposition. OBJECTIVES: To assess the impact of economic evaluation in decisions on what to fund in four European countries and discuss the implications of our findings. METHODS: We used a protocol to review the key features of the application of economic evaluation in reimbursement decision making in England, Germany, the Netherlands, and Sweden, reporting country-specific highlights. RESULTS: Although the institutions and processes vary by country, health economic evaluation has had limited impact on restricting access of controversial high cost drugs. Even in those countries that have gone the furthest, ways have been found to avoid refusing to fund high-cost drugs for particular diseases including cancer, multiple sclerosis, and orphan diseases. Economic evaluation may, however, have helped some countries to negotiate price reductions for some drugs. It has also extended to the discussion of clinical effectiveness to include cost. CONCLUSIONS: The differences in approaches but similarities in outcomes suggest that health economic evaluation be viewed largely as rhetoric (in D.N. McCloskey's terms in The Rhetoric of Economics, 1985). This is not to imply that economics had no impact: rather that it usually contributed to the discourse in ways that differed by country. The reasons for this no doubt vary by perspective, from political science to ethics. Economic evaluation may have less to do with rationing or denial of medical treatments than to do with expanding the discourse used to discuss such issues. PMID- 27987646 TI - Node-Splitting Generalized Linear Mixed Models for Evaluation of Inconsistency in Network Meta-Analysis. AB - BACKGROUND: Network meta-analysis for multiple treatment comparisons has been a major development in evidence synthesis methodology. The validity of a network meta-analysis, however, can be threatened by inconsistency in evidence within the network. One particular issue of inconsistency is how to directly evaluate the inconsistency between direct and indirect evidence with regard to the effects difference between two treatments. A Bayesian node-splitting model was first proposed and a similar frequentist side-splitting model has been put forward recently. Yet, assigning the inconsistency parameter to one or the other of the two treatments or splitting the parameter symmetrically between the two treatments can yield different results when multi-arm trials are involved in the evaluation. OBJECTIVES: We aimed to show that a side-splitting model can be viewed as a special case of design-by-treatment interaction model, and different parameterizations correspond to different design-by-treatment interactions. METHODS: We demonstrated how to evaluate the side-splitting model using the arm based generalized linear mixed model, and an example data set was used to compare results from the arm-based models with those from the contrast-based models. RESULTS & CONCLUSIONS: The three parameterizations of side-splitting make slightly different assumptions: the symmetrical method assumes that both treatments in a treatment contrast contribute to inconsistency between direct and indirect evidence, whereas the other two parameterizations assume that only one of the two treatments contributes to this inconsistency. With this understanding in mind, meta-analysts can then make a choice about how to implement the side splitting method for their analysis. PMID- 27987647 TI - Cost-Effectiveness of Quadrivalent versus Trivalent Influenza Vaccine in the United States. AB - BACKGROUND: Designed to overcome influenza B mismatch, new quadrivalent influenza vaccines (QIVs) contain one additional B strain compared with trivalent influenza vaccines (TIVs). OBJECTIVE: To examine the expected public health impact, budget impact, and incremental cost-effectiveness of QIV versus TIV in the United States. METHODS: A dynamic transmission model was used to predict the annual incidence of influenza over the 20-year-period of 2014 to 2034 under either a TIV program or a QIV program. A decision tree model was interfaced with the transmission model to estimate the public health impact and the cost effectiveness of replacing TIV with QIV from a societal perspective. Our models were informed by published data from the United States on influenza complication probabilities and relevant costs. The incremental vaccine price of QIV as compared with that of TIV was set at US $5.40 per dose. RESULTS: Over the next 20 years, replacing TIV with QIV may reduce the number of influenza B cases by 27.2% (16.0 million cases), resulting in the prevention of 137,600 hospitalizations and 16,100 deaths and a gain of 212,000 quality-adjusted life-years (QALYs). The net societal budget impact would be US $5.8 billion and the incremental cost effectiveness ratio US $27,411/QALY gained. In the probabilistic sensitivity analysis, 100% and 96.5% of the simulations fell below US $100,000/QALY and US $50,000/QALY, respectively. CONCLUSIONS: Introducing QIV into the US immunization program may prevent a substantial number of hospitalizations and deaths. QIV is also expected to be a cost-effective alternative option to TIV. PMID- 27987648 TI - Life Expectancy and Lifetime Health Care Expenditures for Type 1 Diabetes: A Nationwide Longitudinal Cohort of Incident Cases Followed for 14 Years. AB - OBJECTIVES: To assess additional life expectancy (LE), expected years of life lost , and lifetime health care expenditures after type 1 diabetes diagnosis, stratified by sex and age of first diagnosis (early: 0-12 years; late: 13-40 years). METHODS: A longitudinal cohort of patients with diabetes was constructed from Taiwan's National Health Insurance Research Database of 1999 to 2012. The survival functions for diabetic patients and age- and sex-matched general population were estimated by using a semiparametric extrapolation method with annual life tables. The average monthly health care expenditures were multiplied by the corresponding monthly survival rates and summed to calculate the lifetime health care expenditures. Cox proportional hazard models were constructed to corroborate the effects of sex and age, after being adjusted for comorbidities, complications, and calendar years. RESULTS: A total of 2386 cases (45% early diagnosis, 49% males) were identified. An additional LE after diabetes diagnosis was 45.12 years, with an estimated 17.63 years of life lost. The predicted total and diabetes-related lifetime costs were $56,939 and $102,140, respectively. Early diagnosed patients had a longer LE and lower health care spending compared with those of late-diagnosed patients. Male patients had a shorter LE and a higher expected years of life lost than the female patients, which corresponded to lower lifetime costs for the former. The Cox model results for overall mortality corroborated these trends. CONCLUSIONS: Early detection of type 1 diabetes and sex-specific strategies would probably improve long-term health outcomes and save on the cost of diabetes care. PMID- 27987649 TI - Cost-Effectiveness of a National Opportunistic Screening Program for Atrial Fibrillation in Ireland. AB - OBJECTIVES: To evaluate the cost-effectiveness of a national atrial fibrillation screening program in Ireland involving annual opportunistic pulse palpation of all those older than 65 years during general practitioner consultations, with an electrocardiogram being performed if an irregular pulse is detected. METHODS: A probabilistic Markov model was used to simulate costs and clinical outcomes in a hypothetical cohort of men and women with and without screening over the course of 25 years, using a societal perspective. RESULTS: Screening was associated with an incremental cost-effectiveness ratio of ?23,004/quality-adjusted life-year compared with routine care. Nevertheless, if the relative risk of stroke and systematic embolism in screen-detected patients is more than 12% lower than that in patients with atrial fibrillation identified through routine practice, then screening would not be considered cost-effective at a willingness-to-pay threshold of ?45,000/quality-adjusted life-year. An analysis comparing alternative combinations of start age and screening interval found that less frequent screening with a later start age may be more cost-effective than an annual screening from age 65 years. CONCLUSIONS: Annual opportunistic screening of men and women aged 65 years and older in primary care in Ireland is likely to be cost-effective using conventional willingness-to-pay thresholds, assuming that those detected through screening have a comparable stroke risk profile as those detected through routine practice. Raising the start age of screening or increasing the screening interval may improve the cost-effectiveness of a prospective screening program. PMID- 27987651 TI - Multifunctional theranostic Pluronic mixed micelles improve targeted photoactivity of Verteporfin in cancer cells. AB - Nanotechnology development provides new strategies to treat cancer by integration of different treatment modalities in a single multifunctional nanoparticle. In this scenario, we applied the multifunctional Pluronic P123/F127 mixed micelles for Verteporfin-mediated photodynamic therapy in PC3 and MCF-7 cancer cells. Micelles functionalization aimed the targeted delivery by the insertion of biotin moiety on micelle surface and fluorescence image-based through rhodamine-B dye conjugation in the polymer chains. Multifunctional Pluronics formed spherical nanoparticulated micelles that efficiently encapsulated the photosensitizer Verteporfin maintaining its favorable photophysical properties. Lyophilized formulations were stable at least for 6months and readily reconstituted in aqueous media. The multifunctional micelles were stable in protein-rich media due to the dual Pluronic mixed micelles characteristic: high drug loading capacity provided by its micellar core and high kinetic stability due its biocompatible shell. Biotin surface functionalized micelles showed higher internalization rates due biotin-mediated endocytosis, as demonstrated by competitive cellular uptake studies. Rhodamine B-tagged micelles allowed monitoring cellular uptake and intracellular distribution of the formulations. Confocal microscopy studies demonstrated a larger intracellular distribution of the formulation and photosensitizer, which could drive Verteporfin to act on multiple cell sites. Formulations were not toxic in the dark condition, but showed high Verteporfin induced phototoxicity against both cancer cell lines at low drug and light doses. These results point Verteporfin-loaded multifunctional micelles as a promising tool to further developments in photodynamic therapy of cancer. PMID- 27987650 TI - Psychometric Properties of the Four-Item Morisky Green Levine Medication Adherence Scale among Atherosclerosis Risk in Communities (ARIC) Study Participants. AB - OBJECTIVES: To evaluate the reliability and factorial validity of the four-item Morisky Green Levine Medication Adherence Scale (MGLS) among Atherosclerosis Risk in Communities (ARIC) Study participants. METHODS: We used the cross-sectional visit 5 data from the ARIC Study to assess the measurement properties of the MGLS. We measured the internal consistency using Cronbach alpha (where alpha > 0.70 is considered reliable for group-level measurement), the response frequency, and the inter item correlation. Factor analysis of the MGLS and five other adherence items in the survey was conducted using a polychoric correlation matrix to examine the dimensionality that underlies the MGLS. A vanishing tetrad test was conducted to assess conformity with an effect indicator model. RESULTS: Among the ARIC visit 5 participants, 6,261 (96%) responded to the MGLS and other questions related to medication adherence in the survey (mean age 76 +/- 5 years, 59% women). The Cronbach alpha for the MGLS was 0.47. The inter-item correlations ranged from 0.11 to 0.26. In the factor analysis of the medication adherence survey questions, a three-factor solution was used. One factor captured the extent of nonadherence, whereas other factors focused on the reasons for nonadherence. The MGLS items spread out across the factors that reflect the extent of as well as the reasons for nonadherence. The results of the vanishing tetrad test indicated that the MGLS consists of items other than effect indicators (P < 0.0001). CONCLUSIONS: The low reliability together with the factor analysis findings imply that the MGLS may reflect causes as well as the extent of medication adherence. The findings suggest that the MGLS, as presently used, lacks consistency in an elderly population. PMID- 27987652 TI - Enhanced antimicrobial activities of silver-nanoparticle-decorated reduced graphene nanocomposites against oral pathogens. AB - As a means of capitalizing on the synergistic properties between reduced graphene nanosheets (R-GNs) and silver nanoparticles (AgNPs), an efficient and convenient chemical reduction method was used to prepare silver-nanoparticle-decorated reduced graphene nanocomposites (R-GNs/Ag). The products were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and Raman spectroscopy, which confirmed the loading of well dispersed silver nanoparticles on reduced graphene sheets. Their antimicrobial activities against oral pathogens such as Candida albicans, Lactobacillus acidophilus, Streptococcus mutans, and Aggregatibacter actinomycetemcomitans were investigated by MIC determination, the counting of colony-forming units (CFU), agar diffusion tests, and growth curve observation. Compared with pure R-GNs and AgNPs, R-GNs/Ag composites exhibited enhanced antimicrobial properties owing to highly dispersed AgNPs on R-GNs. PMID- 27987653 TI - Free radical scavenging injectable hydrogels for regenerative therapy. AB - Pathological free radicals generated from inflamed and infarcted cardiac tissues interferes natural tissue repair mechanisms. Hypoxic microenvironment at the injured zone of non-regenerating cardiac tissues hinders the therapeutic attempts including cell therapy. Here we report an injectable, cytocompatible, free radical scavenging synthetic hydrogel formulation for regenerative therapy. New hydrogel (PEAX-P) is prepared with D-xylitol-co-fumarate-co-poly ethylene adipate co-PEG comaromer (PEAX) and PEGDiacrylate. PEAX-P hydrogel swells 4.9 times the initial weight and retains 100.07kPa Young modulus at equilibrium swelling, which is suitable for cardiac applications. PEAX-P hydrogel retains elastic nature even at 60% compressive strain, which is favorable to fit with the dynamic and elastic natural tissue counterparts. PEAX-P hydrogel scavenges 51% DPPH radical, 40% hydroxyl radicals 41% nitrate radicals with 31% reducing power. The presence of hydrogel protects 62% cardiomyoblast cells treated with stress inducing media at LD 50 concentration. The free hydroxyl groups in sugar alcohols of the comacromer influence the free radical scavenging. Comparatively, PEAX-P hydrogel based on xylitol evinces slightly lower scavenging characteristics than with previously reported PEAM-P hydrogel containing mannitol having more hydroxyl groups. The possible free radical scavenging mechanism of the present hydrogel relies on the free pi electrons associated with uncrosslinked fumarate bonds, hydrogen atoms associated with sugar alcohols/PEG and radical dilution by free water in the matrix. Briefly, the present PEAX-P hydrogel is a potential injectable system for combined antioxidant and regenerative therapy. PMID- 27987654 TI - Photo-mediated optimized synthesis of silver nanoparticles for the selective detection of Iron(III), antibacterial and antioxidant activity. AB - The AgNPs synthesized by green method have shown great potential in several applications such as biosensing, biomedical, catalysis, electronic etc. The present study deals with the selective colorimetric detection of Fe3+ using photoinduced green synthesized AgNPs. For the synthesis purpose, an aqueous extract of Croton bonplandianum (AEC) was used as a reducing and stabilizing agent. The biosynthesis was confirmed by UV-visible spectroscopy where an SPR band at lambdamax 436nm after 40s and 428nm after 30min corresponded to the existence of AgNPs. The optimum conditions for biosynthesis of AgNPs were 30min sunlight exposure time, 5.0% (v/v) AEC inoculum dose and 4mM AgNO3 concentration. The stability of synthesized AgNPs was monitored up to 9months. The size and shape of AgNPs with average size 19.4nm were determined by Field Emission Scanning Electron Microscope (FE-SEM) and High-Resolution Transmission Electron Microscope (HR-TEM). The crystallinity was determined by High-Resolution X-ray Diffractometer (HR-XRD) and Selected Area Electron Diffraction (SAED) pattern. The chemical and elemental compositions were determined by Fourier Transformed Infrared Spectroscopy (FTIR) and Energy Dispersive X-ray Spectroscopy (EDX) respectively. The Atomic Force Microscopy (AFM) images represented the lateral and 3D topological characteristics of AgNPs. The XPS analysis confirmed the presence of two individual peaks which attributed to the Ag 3d3/2 and Ag 3d5/2 binding energies corresponding to the presence of metallic silver. The biosynthesized AgNPs showed potent antibacterial activity against both gram positive and gram-negative bacterial strains as well as antioxidant activity. On the basis of results and facts, a probable mechanism was also proposed to explore the possible route of AgNPs synthesis, colorimetric detection of Fe3+, antibacterial and antioxidant activity. PMID- 27987655 TI - Bioactivity and biocompatibility of hydroxyapatite-based bioceramic coatings on zirconium by plasma electrolytic oxidation. AB - In the present work, hydroxyapatite (HAP)-based plasma electrolytic oxide (PEO) coatings were produced on zirconium at different current densities in a solution containing calcium acetate and beta-calcium glycerophosphate by a single step. The phase structure, surface morphology, functional groups, thickness and roughness of the coatings were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), eddy current method and surface profilometer, respectively. The phases of cubic-zirconia, calcium zirconate and HAP were detected by XRD. The amount of HAP and calcium zirconate increased with increasing current density. The surface of the coatings was very porous and rough. Moreover, bioactivity and biocompatibility of the coatings were analyzed in vitro immersion simulated body fluid (SBF) and MTT (3-(4,5-dimethyl thiazol 2yl)-2,5-diphenyl tetrazolium bromide) assay, hemolysis assay and bacterial formation. The apatite-forming ability of the coatings was evaluated after immersion in SBF up to 28days. After immersion, the bioactivity of HAP-based coatings on zirconium was greater than the ones of uncoated zirconium and zirconium oxide-based surface. The bioactivity of PEO surface on zirconium was significantly improved under SBF conditions. The bacterial adhesion of the coatings decreased with increasing current density. The bacterial adhesion of the coating produced at 0.370A/cm2 was minimum compared to uncoated zirconium coated at 0.260 and 0.292A/cm2. The hemocompatibility of HAP-based surfaces was improved by PEO. The cell attachment and proliferation of the PEO coatings were better than the one of uncoated zirconium according to MTT assay results. PMID- 27987656 TI - Scutellarin-graft cationic beta-cyclodextrin-polyrotaxane: Synthesis, characterization and DNA condensation. AB - As a prerequisite of gene delivery in living cells, DNA condensation has attracted more and more attention. In order to improve the efficiencies of polyamine-beta-cyclodextrin-based cationic polyrotaxanes (PR-EDA and PR-DETA) as DNA condensation materials, we have designed and prepared two novel scutellarin grafted cationic polyrotaxanes (PR-EDA-SCU and PR-DETA-SCU), in which scutellarins (SCU), the planar molecules, were conjugated on the cyclodextrin molecules of PR-EDA and PR-DETA. These materials were characterized by 1D and 2D NMR, XRD, TG and DSC. The electrophoresis assays showed that pDNA condensation efficiencies of PR-EDA and PR-DETA were better than that of PR-EDA and PR-DETA. The complexes of PR-EDA, PR-DETA, PR-EDA-SCU and PR-DETA-SCU with pDNA were further investigated by zeta potential and atomic force microscopy analysis. The results indicated that the planar structure of SCU played an important role in improvement of pDNA condensation efficiencies of PR-EDA-SCU and PR-DETA-SCU. The satisfactory pDNA condensation abilities of PR-EDA-SCU and PR-DETA-SCU could be helpful in designing non-viral gene delivery vectors to control gene expression and delivery. PMID- 27987658 TI - A novel approach to fabrication of three-dimensional porous titanium with controllable structure. AB - A new approach to fabrication of porous titanium by using the molybdenum wire as space holder was developed, in which titanium liquid was cast into the entangled molybdenum wires in a vacuum environment, and followed by etching off the space holder material in an aqua regia solution. This infiltration casting and acid corrosion method fabricated the porous titanium with different porosities with a pore diameter of 0.4mm. The porous titanium with the porosity of 32-47% exhibited the Young's modulus in the range of 23-62GPa and the yielding strength in the range of 76-192MPa. The adhesion and spreadability of the bovine osteoblast cells on the porous titanium were also evaluated in vitro. The porous titanium with 47% porosity has great potential for implant applications. PMID- 27987657 TI - Influence of interlayer design on residual thermal stresses in trilayered and graded all-ceramic restorations. AB - Residual thermal stresses are formed in dental restorations during cooling from high temperature processing. The aim of this study was to evaluate the influence of constructive design variables (composition and interlayer thickness) on residual stresses in alumina- and zirconia-graded restorations. Restorations' real-like cooling conditions were simulated using finite elements method and temperature-dependent material properties were used. Three different designs were evaluated: a bilayered restoration (sharp transition between materials); a trilayered restoration with a homogenous interlayer between core and veneer; and a trilayered restoration with a graded interlayer. The interlayer thickness and composition were varied. Zirconia restorations presented overall higher thermal stress values than alumina ones. Thermal stresses were significantly reduced by the presence of a homogeneous interlayer. The composition of the interlayer showed great influence on the thermal stresses, with the best results for homogeneous interlayers being observed for porcelain contents in the composite ranging between 30%-50% (vol.%), for both alumina and zirconia restorations. The interlayer's thickness showed a minor contribution in the thermal stress reduction. The graded interlayer showed an optimized reduction in restorations' thermal stresses. The use of graded interlayer, favoring enhanced thermal stress distributions and lower magnitude is expected to reduce the risk of catastrophic failure. PMID- 27987659 TI - Optimization of crosslinked poly(vinyl alcohol) nanocomposite films for mechanical properties. AB - The effects of glycerol, bacterial cellulose nanocrystal (BCNC) and boric acid concentrations on the mechanical properties of PVA based films, including ultimate tensile strength (UTS), elongation at break (EAB), tensile Young's modulus (TYM), tensile toughness to break (TT), ultimate puncture strength (UPS), puncture deformation (PD), puncture Young's modulus (PYM) and puncture toughness to break (PT), were scrutinized using a response surface methodology-central composite rotatable design (RSM-CCRD). Second-order polynomial models with high R2 values ranging from 0.945 to 0.977 were developed for the studied responses using multiple linear regression analysis. The models showed the maximum UTS (72.84MPa), EAB (293.43%), UPS (4.64MPa) and PD (31.80%) could be achieved at 13.89% glycerol concentration, 5.00% BCNC concentration and a boric acid content of 1.96%. The predicted values for optimum conditions were in good agreement with experimental data. Fourier-transform infrared spectroscopy (FTIR) analysis confirmed the formation of intramolecular and intermolecular hydrogen and ether crosslinkages in PVA and/or BCNC chains when boric acid is applied. Results showed that PVA/BCNC nanocomposite films plasticized with glycerol and crosslinked with boric acid showed appropriate mechanical properties that made them suitable as a disposable packaging film. PMID- 27987660 TI - Preparation of dual-responsive hybrid fluorescent nano probe based on graphene oxide and boronic acid/BODIPY-conjugated polymer for cell imaging. AB - Here, we report a pH- and thermo-responsive fluorescent nanomaterial of functionalized reduced graphene oxide (rGO) with cross-linked polymer produced via catechol-boronate diol binding mechanism. When conjugated with the hydrophobic dye boron dipyrromethane (BODIPY), this material can act as a dual responsive nanoplatform for cells imaging. 2-Chloro-3',4'-dihydroxyacetophenone (CCDP)-quaternized-poly(dimethylaminoethyl methacrylate-co-N-isopropylacrylamide) [C-PDN] was cross-linked with BODIPY and 4-chlorophenyl boronic acid (BA) quaternized-poly(ethylene glycol)-g-poly(dimethylaminoethyl methacrylate-co-N isopropylacrylamide) [BB-PPDN]. The GO was then reduced by the catechol group in the cross-linked polymer to synthesize rGO nanoparticles, which able to stabilize the quenching mechanism. This nanoplatform exhibits intense fluorescence at acidic pH and low fluorescence at physiological pH. Confocal laser scanning microscopy (CLSM) images shows bright fluorescence at lysosomal pH and total quench at physiological pH. Therefore, we have successfully developed a promising sensitive bio-imaging probe for identifying cancer cells. PMID- 27987661 TI - A novel and economical route for synthesizing akermanite (Ca2MgSi2O7) nano bioceramic. AB - Despite the benefits of akermanite, there are limited reports on making powder and dense bulk akermanite (Ca2MgSi2O7) and most articles have focused on building akermanite scaffolds. This study centers on a new and economical route for the synthesis of akermanite bioceramic via high energy ball milling and subsequent sintering of a mixed powders of eggshell (as calcium source), MgO, and SiO2. The mechanisms occurred during akermanite synthesis were carefully investigated. XRD, DTA, FTIR, TGA, SEM, TEM, ICP and EDS were used for analyzing the obtained results. Simulated body fluid (SBF) was also used for assessing in vitro bioactivity of the akermanite samples. According to the results, the method presented in this study can be introduced as a facile method for preparing akermanite samples with a good compressive strength of 210+/-7MPa. The XRD patterns also indicated that akermanite bioceramic was synthesized after heat treating at 900 degrees C which is very low compared to previous researches. With increasing the sintering time of the akermanite samples and the reduction of the surface porosities, the amount of the formed apatite and also the rate of apatite formation decreased and the compressive strength of the samples increased. PMID- 27987662 TI - Effect of copper addition on mechanical properties, corrosion resistance and antibacterial property of 316L stainless steel. AB - The effects of addition of different Cu content (0, 2.5 and 3.5wt%) on mechanical properties, corrosion resistance and antibacterial performance of 316L austenitic stainless steel (SS) after solution and aging treatment were investigated by mechanical test, transmission electron microscope (TEM), X-ray diffraction (XRD), electrochemical corrosion, X-ray photoelectron spectroscopy (XPS) and antibacterial test. The results showed that the Cu addition and heat treatment had no obvious influence on the microstructure with complete austenite features. The yield strength (YS) after solution treatment was almost similar, whereas the aging treatment obviously increased the YS due to formation of tiny Cu-rich precipitates. The pitting and protective potential of the solution treated Cu bearing 316L SS in 0.9wt% NaCl solution increased with increasing Cu content, while gradually declined after aging, owing to the high density Cu-rich precipitation. The antibacterial test proved that higher Cu content and aging were two compulsory processes to exert good antibacterial performance. The XPS results further indicated that aging enhanced the Cu enrichment in passive film, which could effectively stimulate the Cu ions release from the surface of passive film. PMID- 27987663 TI - Phytic acid/graphene oxide nanocomposites modified electrode for electrochemical sensing of dopamine. AB - An electrochemical sensor for determining dopamine was developed by modifying phytic acid/graphene oxide (PA/GO) nanocomposites onto a glassy carbon electrode (GCE). PA functionalized GO was prepared by an ultra-sonication method. Subsequently, the PA/GO nanocomposites were drop-casted on a glassy carbon substrate. The structural feature of the PA/GO modified GCE was confirmed by attenuated total reflection infrared (ATR-IR) spectroscopy. The proposed electrochemical sensor was applied to detect various concentrations of DA by differential pulse voltammetry (DPV). The PA/GO/GCE was considered to be highly sensitive to DA in the range of 0.05-10MUM. In addition, the PA/GO/GCE demonstrated high electrochemical selectivity toward DA in the presence of ascorbic acid (AA) and uric acid (UA). The prepared electrochemical DA sensor was applied for detection of DA in dopamine hydrochloride injection and spiked samples of human urine with satisfactory results. PMID- 27987664 TI - Alumina-fluorapatite composite coating deposited by atmospheric plasma spraying: An agent of cohesion between bone and prostheses. AB - In order to remedy the poor biological and tribological properties of 316L stainless steel (SS), plasma sprayed bio-ceramic coatings have been widely investigated. In the present study, a small amount of fluorapatite (Fap) was introduced into alumina in order to enhance its bioactivity. The powder feedstock was sprayed on 316L substrate by Atmospheric Plasma Spraying (APS) technology. The roughness profiles and average roughness values were determined using 3D profilometry. The cross sectional morphologies of the coatings were examined by scanning electron microscopy (SEM). Adhesive strength, micro-hardness and tribological properties were also examined. Experimental results revealed that Al2O3/Fap coating showed a good microhardness property revealing that the calcium aluminates were quite effective in improving the Fap mechanical behavior. The tribological characteristics of both alumina and alumina-Fap coating were also compared to those of classical hydroxyapatite (Hap) coatings as reported in the literature. The main finding of this work was that Fap coating can contribute to the cohesion between bone and prostheses and thus ensure a more durable and reliable prostheses. PMID- 27987666 TI - Development of novel electrochemical sensor on the base of molecular imprinted polymer decorated on SiC nanoparticles modified glassy carbon electrode for selective determination of loratadine. AB - A novel and selective electrochemical sensor was successfully developed for the determination of loratadine by drop coating of synthesized loratadine molecularly imprinted polymers on the surface of glassy carbon electrode modified with silicon carbide nanoparticles. The performance of the constructed sensor was evaluated by cyclic voltammetry, scanning electron microscopy, and electrochemical impedance spectroscopy techniques. Under optimized conditions, the resulting calibration curve exhibited a linear response within a concentration range of 1-33MUM with a low detection limit (S/N=3) of 0.15MUM. Finally, the proposed method was successfully applied as a selective, stabile, sensitive, simple, reproducibility electrochemical sensor with good repeatability for the determination of loratadine in real samples and satisfactory results were obtained. PMID- 27987665 TI - Microstructure and mechanical properties of stainless steel/calcium silicate composites manufactured by selective laser melting. AB - Selective laser melting (SLM) is raised as one kind of additive manufacturing (AM) which is based on the discrete-stacking concept. This technique can fabricate advanced composites with desirable properties directly from 3D CAD data. In this research, 316L stainless steel (316L SS) and different fractions of calcium silicate (CaSiO3) composites (weight fractions of calcium silicate are 0%, 5%,10% and 15%, respectively) were prepared by SLM technique with a purpose to develop biomedical metallic materials. The relative density, tensile, microhardness and elastic modulus of the composites were tested, their microstructures and fracture morphologies were observed using optical microscope (OM), scanning electron microscopy (SEM) and X-ray diffraction (XRD). It was found that the addition of CaSiO3 particles influenced the microstructure and mechanical properties of specimens significantly. The CaSiO3 precipitates from the overlap of adjacent tracks and became the origin of the defects. The tensile strength of specimens range 320-722MPa. The microhardness and elastic modulus are around 250HV and 215GPa respectively. These composites were ductile materials and the fracture mode of the composites was mixed mode of ductile and brittle fracture. The 316L SS/CaSiO3 composites can be a potential biomedical metallic materials in the medical field. PMID- 27987667 TI - Effect of preconditioning cobalt and nickel based dental alloys with Bacillus sp. extract on their surface physicochemical properties and theoretical prediction of Candida albicans adhesion. AB - Biofilm formation on dental biomaterials is implicated in various oral health problems. Thus the challenge is to prevent the formation of this consortium of microorganisms using a safe approach such as antimicrobial and anti-adhesive natural products. Indeed, in the present study, the effects of an antifungal extract of Bacillus sp., isolated from plant rhizosphere, on the surface physicochemical properties of cobalt and nickel based dental alloys were studied using the contact angle measurements. Furthermore, in order to predict the adhesion of Candida albicans to the treated and untreated dental alloys, the total free energy of adhesion was calculated based on the extended Derjaguin Landau-Verwey-Overbeek approach. Results showed hydrophobic and weak electron donor and electron-acceptor characteristics of both untreated dental alloys. After treatment with the antifungal extract, the surface free energy of both dental alloys was influenced significantly, mostly for cobalt based alloy. In fact, treated cobalt based alloy became hydrophilic and predominantly electron donating. Those effects were time-dependent. Consequently, the total free energy of adhesion of C. albicans to this alloy became unfavorable after treatment with the investigated microbial extract. A linear relationship between the electron donor property and the total free energy of adhesion has been found for both dental alloys. Also, a linear relationship has been found between this latter and the hydrophobicity for the cobalt based alloy. However, the exposure of nickel based alloy to the antifungal extract failed to produce the same effect. PMID- 27987668 TI - Influence of Cu, Au and Ag on structural and surface properties of bioactive coatings based on titanium. AB - In this work influence of copper, silver and gold additives on structural and surface properties of biologically active thin films based on titanium have been described. Coatings were prepared by magnetron sputtering method. During each process metallic discs (targets) - Ti and the additive (Cu, Ag or Au) were co sputtered in argon atmosphere. Structural investigation of as-deposited coatings was performed with the aid of XRD and SEM/EDS method. It was found that all prepared thin films were homogenous. Addition of Cu, Ag and Au resulted in nanocrystalline structure. Moreover, influence of these additives on hardness and antibacterial activity of titanium coatings was also studied. Ti-Cu, Ti-Ag and Ti Au films had lower hardness as-compared to Ti. According to AAS results the difference of their activity was related to the ion migration process. It was found that Ti-Ag and Ti-Au coatings had biocidal effect related to direct contact of their surface with microorganisms. In the case of Ti-Cu antimicrobial activity had direct and indirect nature due to efficient ion migration process from the film surface to the surrounding environment. Functional features of coatings such as wettability and corrosion resistance were also examined and included in the comprehensive analysis. PMID- 27987669 TI - Investigation of cell adhesion in chitosan membranes for peripheral nerve regeneration. AB - Peripheral nerve injuries have produced major concerns in regenerative medicine for several years, as the recovery of normal nerve function continues to be a significant clinical challenge. Chitosan (CHT), because of its good biocompatibility, biodegradability and physicochemical properties, has been widely used as a biomaterial in tissue engineering scaffolding. In this study, CHT membranes were produced with three different Degrees of Acetylation (DA), envisioning its application in peripheral nerve regeneration. The three CHT membranes (DA I: 1%, DA II: 2%, DA III: 5%) were extensively characterized and were found to have a smooth and flat surface, with DA III membrane having slightly higher roughness and surface energy. All the membranes presented suitable mechanical properties and did not show any signs of calcification after SBF test. Biodegradability was similar for all samples, and adequate to physically support neurite outgrowth. The in vitro cell culture results indicate selective cell adhesion. The CHT membranes favoured Schwann cells invasion and proliferation, with a display of appropriate cytoskeletal morphology. At the same time they presented low fibroblast infiltration. This fact may be greatly beneficial for the prevention of fibrotic tissue formation, a common phenomenon impairing peripheral nerve regeneration. The great deal of results obtained during this work permitted to select the formulation with the greatest potential for further biological tests. PMID- 27987670 TI - Application of acellular intima from porcine thoracic aorta in full-thickness skin wound healing in a rat model. AB - The tunica intima of aorta is made up of one layer of smooth endothelium and basement membrane. The basement membrane is rich in extracellular matrix (ECM) molecules, including collagen, glycosaminoglycans (e.g., heparan sulfate), proteoglycans (e.g., perlecan), and glycoproteins. All or most of these components are involved in wound healing process. In this work, we determined whether the acellular intima from porcine thoracic aorta can be a new kind of xenograft to repair the skin-wound surface in a rat model. Acellular intima xenografts (AIX) were prepared from tunica intima, and then the swelling ratio, moisture content ratio, water retention ratio, degradation rate, and water vapor transmission rate of the materials were measured. Prothrombin time test was applied to assess its hemostatic property in vitro, in vitro cell experiment was used to test its cellular biocompatibility, and animal experiment was used to evaluate its effect on wound healing. Results showed that AIX, with some reasonable treatments, has good hemostatic property, cell biocompatibility, and histocompatibility. AIX can also promote angiogenesis in the healing process and thus accelerate comprehensive healing, thereby confirming supporting its functionality and excellent application potential in wound healing. PMID- 27987671 TI - Role of solvent-mediated carbodiimide cross-linking in fabrication of electrospun gelatin nanofibrous membranes as ophthalmic biomaterials. AB - Due to their ability to mimic the structure of extracellular matrix, electrospun gelatin nanofibers are promising cell scaffolding materials for tissue engineering applications. However, the hydrophilic gelatin molecules usually need stabilization before use in aqueous physiological environment. Considering that biomaterials cross-linked via film immersion technique may have a more homogeneous cross-linked structure than vapor phase cross-linking, this work aims to investigate the chemical modification of electrospun gelatin nanofibrous membranes by liquid phase carbodiimide in the presence of ethanol/water co solvents with varying ethanol concentrations ranging from 80 to 99.5vol%. The results of characterization showed that increasing water content in the binary reaction solvent system increases the extent of cross-linking of gelatin nanofibers, but simultaneously promotes the effect of biopolymer swelling and distortion in fiber mat structure. As compared to non-cross-linked counterparts, carbodiimide treated gelatin nanofibrous mats exhibited better thermal and biological stability where the shrinkage temperature and resistance to enzymatic degradation varied in response to ethanol/water solvent composition-mediated generation of cross-links. Irrespective of their cross-linking density, all studied membrane samples did not induce any responses in ocular epithelial cell cultures derived from cornea, lens, and retina. Unlike many other cross-linking agents and/or methods (e.g., excessive vapor phase cross-linking) that may pose a risk of toxicity, our study demonstrated that these nanofibrous materials are well tolerated by anterior segment tissues. These findings also indicate the safety of using ethanol/water co-solvents for chemical cross-linking of gelatin to engineer nanofibrous materials with negligible biological effects. In summary, the present results suggest the importance of solvent-mediated carbodiimide cross linking in modulating structure-property relationship without compromising in vitro and in vivo biocompatibility of electrospun gelatin nanofibers for future ophthalmic applications. PMID- 27987672 TI - Antibacterial activity of agricultural waste derived wollastonite doped with copper for bone tissue engineering. AB - Bioactive ceramic materials with metal ions generation brought great attention in the class of biomaterials development and widely employed as a filler material for bone tissue regeneration. The present study aimed to fabricate calcium silicate based ceramic material doped with copper metal particles by sol-gel method. Rice straw of agricultural waste was utilized as a source material to synthesize wollastonite, then wollastonite was doped with copper to fabricate copper doped wollastonite (Cu-Ws) particles. The synthesized materials were subjected to physio-chemical characterization by TEM, DLS, FTIR, XRD and DSC analysis. It was found that the sizes of the WS particles was around 900nm, while adding copper the size was increased upto 1184nm and the addition of copper to the material sharpening the peak. The release of Cu ions was estimated by ICP analysis. The anti-bacterial potentiality of the particles suggested that better microbial growth inhibition against E. coli (Gram negative) and S. aureus (Gram positive) strains from ATCC, in which the growth inhibition was more significant against S. aureus. The biocompatibility in mouse Mesenchymal Stem cells (mMSC) showed the non-toxic effect up to 0.05mg/ml concentration while the increase in concentration was found to be toxic to the cells. So the particles may have better potential application with the challenging prevention of post implantation infection in the field of bone tissue engineering (BTE). PMID- 27987673 TI - Polyethyleneimine brushes effectively inhibit encrustation on polyurethane ureteral stents both in dynamic bioreactor and in vivo. AB - Polyurethane (PU) ureteral stents have been widely used as biomedical devices to aid the flow of the urine. Due to the biofilm formation and encrustation complications it has been hindered their long term clinical usage. To overcome these complications, in this study, cationic polyethyleneimine (PEI) brushes grafted on PU stents and their performances were tested both in a dynamic biofilm reactor system (in vitro) and in a rat model (in vivo). Thus, we hypothesized that PEI brushes inhibit bacterial adhesion owing to the dynamic motion of brushes in liquid environment. In addition, cationic structure of PEI disrupts the membrane and so kills the bacteria on time of contact. Cationic PEI brushes decreased the biofilm formation up to 2 orders of magnitude and approximately 50% of encrustation amount in respect to unmodified PU, in vitro. In addition, according to Atomic Absorption Spectroscopy (AAS) results, approximately 90% of encrustation was inhibited on in vivo animal models. Decrease in encrustation was clearly observed on the stents obtained from rat model, by Scanning Electron Microscopy (SEM). Also, histological evaluations showed that; PEI brush grafting decreased host tissue inflammation in close relation to decrease in biofilm formation and encrustation. As a results; dual effect of anti-adhesive and contact-killing antibacterial strategy showed high efficiency on PEI brushes grafted PU stents both in vitro and in vivo. PMID- 27987674 TI - Biodegradable ceramic-polymer composites for biomedical applications: A review. AB - The present work focuses on the state-of-the-art of biodegradable ceramic-polymer composites with particular emphasis on influence of various types of ceramic fillers on properties of the composites. First, the general needs to create composite materials for medical applications are briefly introduced. Second, various types of polymeric materials used as matrices of ceramic-containing composites and their properties are reviewed. Third, silica nanocomposites and their material as well as biological characteristics are presented. Fourth, different types of glass fillers including silicate, borate and phosphate glasses and their effect on a number of properties of the composites are described. Fifth, wollastonite as a composite modifier and its effect on composite characteristics are discussed. Sixth, composites containing calcium phosphate ceramics, namely hydroxyapatite, tricalcium phosphate and biphasic calcium phosphate are presented. Finally, general possibilities for control of properties of composite materials are highlighted. PMID- 27987675 TI - Preparation, physicochemical properties and biocompatibility of PBLG/PLGA/bioglass composite scaffolds. AB - In this study, novel poly(gamma-benzyl l-glutamate)/poly(lactic-co-glycolic acid)/bioglass (PBLG/PLGA/BG) composite scaffolds with different weight ratios were fabricated using a negative NaCl-templating method. The morphology, compression modulus and degradation kinetics of the scaffolds were characterized. The results showed that the PBLG/PLGA/BG composite scaffolds with a weight ratio of 5:5:1, namely PBLG5PLGA5BG composite scaffolds, displayed a pore size range of 50-500MUm, high compressive modulus (566.6+/-8.8kPa), suitable glass transition temperature (46.8+/-0.2 degrees C) and low degradation rate (>8weeks). The in vitro biocompatibility of the scaffolds was evaluated with MC3T3-E1 cells by live dead staining, MTT and ALP activity assays. The obtained results indicated that the PBLG5PLGA5BG composite scaffolds were more conducive to the adhesion, proliferation and osteoblastic differentiation of MC3T3-E1 cells than PBLG and PBLG/PLGA composite scaffolds. The in vivo biocompatibility of the scaffolds was evaluated in both SD rat subcutaneous model and rabbit tibia defect model. The results of H&E, Masson's trichrome and CD34 staining assays demonstrated that the PBLG5PLGA5BG composite scaffolds allowed the ingrowth of tissue and microvessels more effectively than PBLG/PLGA composite scaffolds. The results of digital radiography confirmed that the PBLG5PLGA5BG composite scaffolds significantly improved in vivo osteogenesis. Collectively, the PBLG5PLGA5BG composite scaffolds could be a promising candidate for tissue engineering applications. PMID- 27987676 TI - Adhesion of mesenchymal stem cells to biomimetic polymers: A review. AB - The mesenchymal stem cells (MSCs) are promising candidates for cell therapy due to the self-renewal, multi-potency, ethically approved state and suitability for autologous transplantation. However, key issue for isolation and manipulation of MSCs is adhesion in ex-vivo culture systems. Biomaterials engineered for mimicking natural extracellular matrix (ECM) conditions which support stem cell adhesion, proliferation and differentiation represent a main area of research in tissue engineering. Some of them successfully enhanced cells adhesion and proliferation because of their biocompatibility, biomimetic texture, and chemistry. However, it is still in its infancy, therefore intensification and optimization of in vitro, in vivo, and preclinical studies is needed to clarify efficacies as well as applicability of those bioengineered constructs. The aim of this review is to discuss mechanisms related to the in-vitro adhesion of MSCs, surfaces biochemical, biophysical, and other factors (of cell's natural and artificial micro-environment) which could affect it and a review of previous research attempting for its bio-chemo-optimization. PMID- 27987677 TI - Is there scientific evidence favoring the substitution of commercially pure titanium with titanium alloys for the manufacture of dental implants? AB - The development of Ti alloys to manufacture dental implants has emerged in recent years due to the increased failure of commercially pure titanium (cpTi) implants. Thus, this study reviews existing information about the mechanical, chemical, electrochemical, and biological properties of the main Ti alloys developed over the past few years to provide scientific evidence in favor of using Ti-based alloys as alternative to cpTi. Ti alloys may be considered viable substitutes in the fabrication of dental implants. Such evidence is given by the enhanced properties of alloys, such as a low elastic modulus, high tensile strength, satisfactory biocompatibility, and good corrosion and wear resistances. In addition, Ti alloys may be modified at the structural, chemical, and thermomechanical levels, which allows the development of materials in accordance with the demands of several situations encountered in clinical practice. Although several in vitro studies have established the superiority of Ti alloys over cpTi, mainly in terms of their mechanical properties, there is no scientific evidence that supports the total replacement of this material in vivo. This review demonstrates the superiority of beta-type alloys. However, it is evident that in vivo studies are encouraged to test new alloys to consolidate their use as substitutes for cpTi. PMID- 27987678 TI - Revolution from monometallic to trimetallic nanoparticle composites, various synthesis methods and their applications: A review. AB - Trimetallic nanoparticles are mainly formed by the combination of three different metals. The trimetallic catalysts were considerably more professional than bimetallic one. The trimetallic and bimetallic nanoparticles are of enormous attention than that of monometallic in both technological and scientific view as in these nanoparticles the catalytic properties can be tailored better than that of in the single monometallic catalyst. The trimetallic nanoparticles have been synthesized by different methods such as microwave, selective catalytic reduction, micro-emulsion, co-precipitation and hydrothermal etc. The surfaces area of trimetallic nanoparticles is comparatively unstable and thus gets simply precipitated away from their solution and ultimately resulted in their reduced catalytic activity. By using stabilizers like block copolymers, organic ligands, surfactants and dendrimers the trimetallic nanoparticles can be stabilized. The nanocomposites of trimetallics have been synthesized with inorganic and organic compounds such as: carbon, graphene, gelatin, cellulose, starch, chitosan, alginate, collagen and Al2O3 etc. Trimetallic nanoparticles are used as a catalyst due to their outstanding electrochemical catalytic activity in comparison with the monometallic or bimetallic nanoparticles. PMID- 27987679 TI - Ursolic acid liposomes with chitosan modification: Promising antitumor drug delivery and efficacy. AB - There are tremendous challenges on antitumor and its therapeutic drugs, and preparation of highly efficient nano-vehicles represents one of the novel topics in antitumor pharmaceutical field. Herein, the novel chitosan-coated ursolic acid (UA) liposome (CS-UA-L) was efficiently prepared with highly tumor targeting, drug controlled release and low side-effect. The CS-UA-L was uniformly spherical particles with diameter of ~130nm, and the size was more easily trapped into the tumor tissues. Chitosan modification can make liposomes carrying positive charges, which were inclined to combine with the negative charges on the surface of tumor cells, and then the CS-UA-L could release UA rapidly at pH5.0 comparing with pH7.4. Meanwhile, the CS-UA-L exhibited obvious anti-proliferative effect (76.46%) on HeLa cells and significantly antitumor activity (61.26%) in mice bearing U14 cervical cancer. The tumor tissues of CS-UA-L treated mice had enhanced cell apoptosis, extensive necrosis and low cell proliferation activity. These results demonstrated that the multifunctional CS-UA-L allowed a precision treatment for localized tumor, and reducing the total drug dose and side-effect, which hold a great promise in new safe and effective tumor therapy. PMID- 27987680 TI - Mediating bone regeneration by means of drug eluting implants: From passive to smart strategies. AB - In addition to excellent biocompatibility and mechanical performance, the new generation of bone and craniofacial implants are expected to proactively contribute to the regeneration process and dynamically interact with the host tissue. To this end, integration and sustained delivery of therapeutic agents has become a rapidly expanding area. The incorporated active molecules can offer supplementary features including promoting oteoconduction and angiogenesis, impeding bacterial infection and modulating host body reaction. Major limitations of the current practices consist of low drug stability overtime, poor control of release profile and kinetics as well as complexity of finding clinically appropriate drug dosage. In consideration of the multifaceted cascade of bone regeneration process, this research is moving towards dual/multiple drug delivery, where precise control on simultaneous or sequential delivery, considering the possible synergetic interaction of the incorporated bioactive factors is of utmost importance. Herein, recent advancements in fabrication of synthetic load bearing implants equipped with various drug delivery systems are reviewed. Smart drug delivery solutions, newly developed to provide higher tempo spatial control on the delivery of the pharmaceutical agents for targeted and stimuli responsive delivery are highlighted. The future trend of implants with bone drug delivery mechanisms and the most common challenges hindering commercialization and the bench to bedside progress of the developed technologies are covered. PMID- 27987681 TI - The interplay of plasma treatment and gold coating and ultra-high molecular weight polyethylene: On the cytocompatibility. AB - We have investigated the application of Ar plasma for creation of nanostructured ultra high molecular weight polyethylene (PE) surface in order to enhance adhesion of mouse embryonic fibroblasts (L929). The aim of this study was to investigate the effect of the interface between plasma-treated and gold-coated PE on adhesion and spreading of cells. The surface properties of pristine samples and its modified counterparts were studied by different experimental techniques (gravimetry, goniometry and X-ray photoelectron spectroscopy (XPS), electrokinetic analysis), which were used for characterization of treated and sputtered layers, polarity and surface chemical structure, respectively. Further, atomic force microscopy (AFM) was employed to study the surface morphology and roughness. Biological responses of cells seeded on PE samples were evaluated in terms of cell adhesion, spreading, morphology and proliferation. Detailed cell morphology and intercellular connections were followed by scanning electron microscopy (SEM). As it was expected the thickness of a deposited gold film was an increasing function of the sputtering time. Despite the fact that plasma treatment proceeded in inert plasma, oxidized degradation products were formed on the PE surface which would contribute to increased hydrophilicity (wettability) of the plasma treated polymer. The XPS method showed a decrease in carbon concentration with increasing plasma treatment. Cell adhesion measured on the interface between plasma treated and gold coated PE was inversely proportional to the thickness of a gold layer on a sample. PMID- 27987682 TI - Porous magnesium-based scaffolds for tissue engineering. AB - Significant amount of research efforts have been dedicated to the development of scaffolds for tissue engineering. Although at present most of the studies are focused on non-load bearing scaffolds, many scaffolds have also been investigated for hard tissue repair. In particular, metallic scaffolds are being studied for hard tissue engineering due to their suitable mechanical properties. Several biocompatible metallic materials such as stainless steels, cobalt alloys, titanium alloys, tantalum, nitinol and magnesium alloys have been commonly employed as implants in orthopedic and dental treatments. They are often used to replace and regenerate the damaged bones or to provide structural support for healing bone defects. Among the common metallic biomaterials, magnesium (Mg) and a number of its alloys are effective because of their mechanical properties close to those of human bone, their natural ionic content that may have important functional roles in physiological systems, and their in vivo biodegradation characteristics in body fluids. Due to such collective properties, Mg based alloys can be employed as biocompatible, bioactive, and biodegradable scaffolds for load-bearing applications. Recently, porous Mg and Mg alloys have been specially suggested as metallic scaffolds for bone tissue engineering. With further optimization of the fabrication techniques, porous Mg is expected to make a promising hard substitute scaffold. The present review covers research conducted on the fabrication techniques, surface modifications, properties and biological characteristics of Mg alloys based scaffolds. Furthermore, the potential applications, challenges and future trends of such degradable metallic scaffolds are discussed in detail. PMID- 27987683 TI - Internal stimuli-responsive nanocarriers for drug delivery: Design strategies and applications. AB - The design of internal stimuli-responsive nanocarriers has been extensively used for delivery of various active compounds including drugs, peptides and genes. These nanosystems are not only designed for improved solubility, enhanced bioavailability, and prolonged blood circulation time, furthermore, they can be tailored chemically to achieve selective drug release at the desired sites of action, which can enable them to bypass physiological or pathological obstacles and achieve enhanced therapeutic efficacy. This review presents current functional moieties responsive to a variety of internal stimuli, including pH, redox, enzyme, temperature. Their design strategies and biomedical applications are also highlighted in detail. It is expected that this review can provide inspiration and impetus for exploiting more promising internal stimuli-responsive nano-systems for drug delivery. PMID- 27987684 TI - Advancement of multifunctional hybrid nanogel systems: Construction and application in drug co-delivery and imaging technique. AB - Nanogel-based multifunctional drug delivery systems, especially hybrid nanogels and multicompartment nanogels have drawn more and more extensive attention from the researchers in pharmacy because it can result in achieving a superior functionality through the synergistic property enhancement of each component. The unique hybrid and compartmentalized structures provide the great potential for co delivery of multiple agents even the multiple agents with different physicochemical properties. Otherwise the hybrid nanogel encapsulating optical and magnetic resonance imaging contrast can be utilized in imaging technique for disease diagnosis. More importantly through nanogel-based multifunctional drug delivery systems the stimuli-responsive features might be easily employed for the design of targeted release of drug. This review summarizes the construction of diverse hybrid nanogels and multicompartment nanogels. The application in co delivery of multiple agents and imaging agents for diagnosis as well as the application in the design of stimuli-responsive multifunctional nanogels as drug delivery are also reviewed and discussed. The future prospects in application of multifunctional nanogels will be also discussed in this review. PMID- 27987685 TI - Biphasic calcium phosphates bioceramics (HA/TCP): Concept, physicochemical properties and the impact of standardization of study protocols in biomaterials research. AB - Biphasic calcium phosphates (BCP) bioceramics have become the materials of choice in various orthopedic and maxillofacial bone repair procedures. One of their main advantages is their biodegradation rate that can be modified by changing the proportional ratio of the composition phases. For enhanced bone tissue regeneration, the bioactivity of BCP should be increased by optimizing their physicochemical properties. To date, the ideal physicochemical properties of BCP for bone applications have not been defined. This is mostly related to lack of standard study protocols in biomaterial science especially with regards to their characterizations and clinical applications. In this paper we provided a review on BCP and their physicochemical properties relevant to clinical applications. In addition, we summarized the available literature on their use in animal models and evaluated the influences of different composition ratios on bone healing. Controversies in literature with regards to ideal composition ratio of BCP have also been discussed in detail. We illustrated the discrepancies in study protocols among researchers in animal studies and emphasized the need to develop and follow a set of generally accepted standardized guidelines. Finally; we provided general recommendations for future pre-clinical studies that allow better standardization of study protocols. This will allow better comparison and contrast of newly developed bone substitute biomaterials that help further progress in the field of biomaterial science. PMID- 27987686 TI - What are the reasons for low use of graphene quantum dots in immunosensing of cancer biomarkers? AB - Graphene quantum dots-based immunosensors have recently gained importance for detecting antigens and biomarkers responsible for cancer diagnosis. This paper reports a literature survey of the applications of graphene quantum dots for sensing cancer biomarkers. The survey sought to explore three questions: (1) Do graphene quantum dots improve immunosensing technology? (2) If so, can graphene quantum dots have a critical, positive impact on construction of immuno-devices? And (3) What is the reason for some troubles in the application of this technology? The number of published papers in the field seems positively answer the first two questions. However additional efforts must be made to move from the bench to the real diagnosis. Some approaches to improve the analytical performance of graphene quantum dots-based immunosensors through their figures of merit have been also discussed. PMID- 27987687 TI - Synthesis and in vitro evaluation of pH-sensitive magnetic nanocomposites as methotrexate delivery system for targeted cancer therapy. AB - This study focuses on the synthesis and in vitro evaluation of magnetic nanocomposites (Fe3O4@LDH) as methotrexate (MTX) delivery system for targeted anticancer therapy. In which, the Fe3O4 nanoparticles acted as magnetically responsive carriers; the coating layer of layered double hydroxide (LDH) was used as a storehouse for MTX. The prepared Fe3O4@LDH nanocomposites exhibited a suitable size, good stability and magnetic responsibility (Ms 36.66emu/g); MTX successfully intercalated into the LDH of Fe3O4@LDH at an entrapment rate (%) of 91.78% (the drug loading was 18.36%) by host-guest exchange process. Moreover, the release studies in vitro showed that the drug delivery system (Fe3O4@LDH-MTX) had excellent pH-sensitivity, 84.94% of MTX was released within 48h at pH3.5 via the co-effect of dissolution of LDH layer and ion-exchange. WST-1 assays in cancer cells (MCF-7 and HepG2) and normal cells (HUVEC) demonstrated that Fe3O4@LDH-MTX exhibited high anticancer activity while low toxicity to normal cells, and also the Fe3O4@LDH composites were practically non-toxic. Thus, our results revealed that Fe3O4@LDH-MTX would be a competitive candidate for targeted delivery and sustained and controlled release of MTX. PMID- 27987688 TI - Liposome-based drug co-delivery systems in cancer cells. AB - Combination therapy and nanotechnology offer a promising therapeutic method in cancer treatment. By improving drug's pharmacokinetics, nanoparticulate systems increase the drug's therapeutic effects while decreasing its adverse side effects related to high dosage. Liposomes are extensively used as drug delivery systems and several liposomal nanomedicines have been approved for clinical applications. In this regard, liposome-based combination chemotherapy (LCC) opens a novel avenue in drug delivery research and has increasingly become a significant approach in clinical cancer treatment. This review paper focuses on LCC strategies including co-delivery of: two chemotherapeutic drugs, chemotherapeutic agent with anti-cancer metals, and chemotherapeutic agent with gene agents and ligand-targeted liposome for co-delivery of chemotherapeutic agents. Definitely, the multidisciplinary method may help improve the efficacy of cancer therapy. An extensive literature review was performed mainly using PubMed. PMID- 27987689 TI - Leptothrix sp. sheaths modified with iron oxide particles: Magnetically responsive, high aspect ratio functional material. AB - Smart materials of biological origin are attracting a lot of attention nowadays, especially as catalysts, carriers or adsorbents. Among them, magnetically modified biomaterials are especially important due to their response to external magnetic field. This report demonstrates that naturally occurring micrometer sized, high aspect ratio material (native and autoclaved Leptothrix sp. sheaths) efficiently bind synthetically prepared magnetite and maghemite nanoparticles and their aggregates. Magnetic modification of Leptothrix sheaths enables to prepare a promising material for advanced biotechnology and environmental technology applications. The prepared magnetically responsive sheaths were tested as inexpensive adsorbent for crystal violet removal from aqueous solutions. The observed maximum adsorption capacity was 243.1mg of dye per 1g of adsorbent. PMID- 27987690 TI - The 3D lightweight structural characteristics of the beetle forewing. AB - The present paper renewedly expounds upon the characteristics of the 3D lightweight structure of beetle forewings and notes that two biomimetic structures (models) that have appeared in recent years do not comply with these characteristics based on a comparison of the structures of the biological prototypes. The first model features transverse tubules based on observations of circular holes in cross-sectional figures of the Cybister forewing. The second is a biomimetic spherical cavity model with hollow trabeculae that reportedly exhibits superior mechanical properties because its structures are most similar to the biological prototype. Finally, a false biomimetic proposition that the mechanical properties of biomimetic structures with "fiber winding" patterns are superior to those of structures constructed of pure "epoxy" is also noted. Hopefully, the present study can serve to improve the state of research on biomimetic applications of beetle forewing structures. PMID- 27987691 TI - Effect of preparation and processing conditions on UV absorbing properties of hydroxyapatite-Fe2O3 sunscreen. AB - The development of innovative, safe and non-photocatalytic sunscreens is urgently needed, as it is essential to have sunscreen filters offering appropriate UV protection without damaging the environment and/or generating free radicals when in contact with the skin. Hydroxyapatite (Ca10(PO4)6(OH)2, HAp) when substituted with iron has UV protection properties and is not photocatalytic; HAp was used to make a sunscreen filter by treating cod fish bones in an iron-containing solution, and then calcining them at 700 degrees C. Here we present a systematic and advanced study on this material, to obtain a sunscreen with improved UV absorbing properties. Bones were treated with three different iron salts - Fe(II) chloride, Fe(II) lactate and Fe(III) nitrate - under various pH conditions. Results showed that Fe(II) chloride in basic pH led to the most effective iron inclusion. High energy ball milling or ultrasound were investigated to increase surface area and corresponding UV absorption; high energy ball milling treatment led to the best optical properties. The optimum powders were used to formulate UV protection creams, which showed Sun Protection Factor (SPF) values significantly superior to the control cream (up to 4.1). Moreover the critical wavelength (lambdacrit) was >370nm (388-389nm) and UVA/UVB ratios were very close to 1. With these properties these sunscreens can be classified as broad UV protectors. Results also showed that combining these powders with other sunscreens (i.e. titanium dioxide), a synergic effect between the different components was also observed. This investigation showed that HAp-based sunscreens of marine origin are a valid alternative to commercial products, safe for the health of the customers and, being non-photocatalytic, do not pose a threat to the environment. PMID- 27987692 TI - Bioactive materials improve some physical properties of a MTA-like cement. AB - One of the main disadvantages of MTA is its long setting time which could result in higher solubility and microleakage, producing a failed treatment. Studies have shown that the addition of bioactive glass may decrease the setting time. The aim of this study is to evaluate the compressive strength, setting time, solubility and radiopacity of a MTAlike experimental cement to which different percentage of wollastonite and bioactive glass are added. White MTA Angelus(r) was used as control; an experimental MTA-like cement (ExpC) was prepared using white Portland cement with 20wt% of Bi2O3; three wollastonite cement composites were prepared adding 10, 20 and 30wt% of wollastonite to ExpC, and three more adding the same proportions of bioactive glass. Compressive strength was tested according to ADA 30; radiopacity, setting time and solubility were tested according to ISO 6876. SEM observations of the surface were made after the solubility test. Compressive strength, setting time, solubility and radiopacity were reduced as the wollastonite increased; solubility increased with the addition of bioactive glass. The surfaces of MTA Angelus(r) and ExpC were smoother than Wollastonite and Bioactive glass groups. Addition of wollastonite and bioactive glass improved the physical properties of a MTA-like experimental cement, reducing the setting time with good solubility percentages, which would be an advantage in its clinical use. PMID- 27987693 TI - Poly(lactic acid) nanoparticles loaded with ursolic acid: Characterization and in vitro evaluation of radical scavenging activity and cytotoxicity. AB - The purpose of this study was to develop poly(lactic acid) (PLA) nanoparticles containing ursolic acid (UA) by an emulsification-solvent evaporation technique and evaluate the radical scavenging activity over hypochlorous acid (HOCl) and cytotoxicity over erythrocytes and tumor cells. Nanoparticles were successfully obtained and presented mean size of 246nm with spherical or slightly oval morphology, negative zeta potential and 96% of UA encapsulation efficiency. Analyses of FTIR, XRD and DSC-DTG suggest interaction/complexation of UA with PLA matrix and drug amorphization promoted by nanoencapsulation process. Stability study showed that room temperature was the best condition for nanoparticles storage. The in vitro release study showed UA was released from the polymeric matrix over two constants (alpha, beta), suggesting a second order kinetics. After 120h of assay, 60% of UA were released by diffusion. In the HOCl scavenging activity, after 72h of assay UA-loaded nanoparticles presented the same efficacy of free drug. In cytotoxicity test over red blood cells, UA-loaded nanoparticles showed less toxicity on cells than free drug. The cytotoxicity assay over melanoma cells line (B16-F10) showed after 72h that nanoparticles were able to reduce the cell viability in 70%. PLA nanoparticles showed be potential carriers for UA maintaining the antioxidant and antitumor activity of the UA and decreasing its cytotoxicity over normal cells. PMID- 27987694 TI - Preparation of crosslinked poly (acryloyloxyethyltrimethyl ammonium chloride) microsphere and its adsorption and mechanism towards shikimic acid. AB - Shikimic acid (SA) is a key raw material for the synthesis of the antiviral drug, but its extraction and separation from plants is still limited. Crosslinked poly (acryloyloxyethyltrimethyl ammonium chloride, DAC) microspheres were synthesized via inverse-phase suspension polymerization. In the synthesizing, N,N'-methylene bisacrylamide (MBA) was used as crosslinker, cyclohexane as dispersed medium and span-60 as dispersants, obtaining CPDAC gel microspheres. The effect of polymerization condition on balling performance and the characteristics of CPDAC were examined. The adsorption properties of CPDAC towards SA were mainly explored and the data of adsorption isotherm were analyzed by using Langmuir, Freundlich, Temkin, Sips and Toth models. Furthermore, the adsorption mechanism was analyzed in depth, and the adsorption thermodynamics was also investigated. The results show that in order to prepare CPDAC, water phase must be added dropwise to oil phase, and the volume ratio of oil-water is more than 2:1. The mean diameter of CPDAC decreases with increasing span-60 and accelerating agitating rate. The strong electrostatic interaction is formed between quaternary ammonium nitrogen of CPDAC and COO- of SA. The adsorption kinetic data is fitted well with pseudo first-order model. The adsorption ability is higher in aqueous water than ethanol, reaching 108mg/g, and Toth model is more suitable for describing the actual adsorption process. The adsorption of CPDAC towards SA is dependent on the pH value of the medium. The adsorption process is exothermic, the adsorption amount decreases with the increase of temperature, and the process is driven by enthalpy. The adsorption amount decreases with the increase of salinity. The reusability of CPDAC towards SA can keep 86.1% at the sixth cycle. PMID- 27987695 TI - Self-fluorescent drug delivery vector based on genipin-crosslinked polyethylenimine conjugated globin nanoparticle. AB - A kind of self-fluorescent, biocompatible, and low-toxic Genipin crosslinked Globin-PEI nanoparticle (Gb-G-PEI NP) with high enzymolysis-stability and photo stability was synthesized successfully. The properties of the Gb-G-PEI NP were characterized, including its particle size, surface zeta potential, morphology, paclitaxel (PTX) loading capacity and release. The Gb-G-PEI NPs as imaging probe were investigated by Confocal Laser Scanning Microscope (CLSM) in vitro and by fluorescence imaging system in vivo. Cell imaging results showed that the tumor cell line (HepG-2) had the faster cell uptake rate and metabolism rate than the normal cell line (L-O2), this difference showed its tumor selectivity. MTT assay revealed that the PTX-loaded Gb-G-PEI NPs showed almost the equal potence to tumor cell HepG-2 as the free PTX at the same PTX concentration, while a lower cytotoxicity to normal cell L-O2, suggesting its promising utilization as a drug delivery system. The imaging on mice demonstrated the possibility of the self fluorescent Gb-G-PEI NPs as probe in vivo. So Gb-G-PEI NPs can be potentially utilized as both tracking marker and tumor cell selective drug delivery system in the biomaterial field. PMID- 27987696 TI - Low friction and high strength of 316L stainless steel tubing for biomedical applications. AB - We propose herein a nondestructive surface modification technique called ultrasonic nanocrystalline surface modification (UNSM) to increase the strength and to improve the tribological performance of 316L stainless steel (SS) tubing. Nanocrystallization along nearly the complete tube thickness of 200MUm was achieved by UNSM technique that was confirmed by electron backscatter diffraction (EBSD). Nano-hardness of the untreated and UNSM-treated specimens was measured using a nanoindentation. Results revealed that a substantial increase in hardness was obtained for the UNSM-treated specimen that may be attributed to the nanocrystallization and refined grains. Stress-strain behavior of the untreated and UNSM-treated specimens was assessed by a 3-point bending test. It was found that the UNSM-treated specimen exhibited a much higher strength than that of the untreated specimen. In addition, the tribological behavior of the untreated and UNSM-treated specimens with an outer diameter (OD) of 1.6mm and an inner diameter (ID) of 1.2mm was investigated using a cylinder-on-cylinder (crossed tubes of equal radius) tribo-tester against itself under dry conditions at ambient temperature. The friction coefficient and wear resistance of the UNSM-treated specimen were remarkably improved compared to that of the untreated specimen. The significant increase in hardness after UNSM treatment is responsible for the improved friction coefficient and wear resistance of the tubing. Thus, the UNSM technique was found to be beneficial to improving the mechanical and tribological properties of 316L SS tubing for various potential biomedical applications, in particular for coronary artery stents. PMID- 27987697 TI - PEGylation of magnetic multi-walled carbon nanotubes for enhanced selectivity of dispersive solid phase extraction. AB - Carbon nanotubes (CNTs) possess large potential as extraction absorbents in solid phase extraction. They have been widely applied in biomedicine research, while very rare application in natural product chemistry has been reported. In this work, methoxypolyethylene glycol amine (mPEG-NH2) is covalently coupled to CNTs magnetic nanoparticles (CNTs-MNP) to prepare a novel magnetic nanocomposite (PEG CNTs-MNP) for use as dispersive solid-phase extraction (DSPE) absorbent. The average particle size was 86nm, and the saturation magnetization was 52.30emu/g. This nanocomposite exhibits excellent dispersibility in aqueous systems, high selectivity and fast binding kinetics when used for extraction of Z-ligustilide, the characteristic bioactive compound from two popular Asian herbal plants, R. chuanxiong and R. ligusticum. HPLC quantification of Z-ligustilide extracted from the standard sample solution showed a high recovery of 98.9%, and the extraction rate from the extracts of the above two herbs are both around 70.0%. To our knowledge, this is the first report on using PEG-CNTs-MNP as DSPE nanosorbents for selective extraction of natural products. This nano-material has promising application in isolation and enrichment of targeted components from complex matrices. PMID- 27987699 TI - Effects of simulated inflammation on the corrosion of 316L stainless steel. AB - Stainless steel alloys, including 316L, find use in orthopaedics, commonly as fracture fixation devices. Invasive procedures involved in the placement of these devices will provoke a local inflammatory response that produces hydrogen peroxide (H2O2) and an acidic environment surrounding the implant. This study assessed the influence of a simulated inflammatory response on the corrosion of 316L stainless steel. Samples were immersed in an electrolyte representing either normal or inflammatory physiological conditions. After 24h of exposure, electrochemical impedance spectroscopy (EIS) and inductively coupled plasma mass spectroscopy (ICPMS) were used to evaluate differences in corrosion behavior and ion release induced by the inflammatory conditions. Scanning electron microscopy (SEM) and energy-dispersive x-ray spectroscopy (EDX) were used to evaluate surface morphology and corrosion products formed on the sample surface. Inflammatory conditions, involving the presence of H2O2 and an acidic pH, significantly alter the corrosion processes of 316L stainless steel, promoting aggressive and localized corrosion. It is demonstrated that particular consideration should be given to 316L stainless steel implants with crevice susceptible areas (ex. screw-head/plate interface), as those areas may have an increased probability of rapid and aggressive corrosion when exposed to inflammatory conditions. PMID- 27987698 TI - A simple and selective colorimetric mercury (II) sensing system based on chitosan stabilized gold nanoparticles and 2,6-pyridinedicarboxylic acid. AB - The development of simple and cost-effective methods for the detection and treatment of Hg2+ in the environment is an important area of research due to the serious health risk that Hg2+ poses to humans. Colorimetric sensing based on the induced aggregation of nanoparticles is of great interest since it offers a low cost, simple, and relatively rapid procedure, making it perfect for on-site analysis. Herein we report the development of a simple colorimetric sensor for the selective detection and estimation of mercury ions in water, based on chitosan stabilized gold nanoparticles (AuNPs) and 2,6-pyridinedicarboxylic acid (PDA). In the presence of Hg2+, PDA induces the aggregation of AuNPs, causing the solution to change colors varying from red to blue, depending on the concentration of Hg2+. The formation of aggregated AuNPs in the presence of Hg2+ was confirmed using transmission electron microscopy (TEM) and UV-Vis spectroscopy. The method exhibits linearity in the range of 300nM to 5MUM and shows excellent selectivity towards Hg2+ among seventeen different metal ions and was successfully applied for the detection of Hg2+ in spiked river water samples. The developed technique is simple and superior to the existing techniques in that it allows detection of Hg2+ using the naked eye and simple and rapid colorimetric analysis, which eliminates the need for sophisticated instruments and sample preparation methods. PMID- 27987700 TI - Encapsulation of anticancer drug copper bis(8-hydroxyquinoline) in hydroxyapatite for pH-sensitive targeted delivery and slow release. AB - There is a conspicuous progress in increasing anticancer drug delivery through the utilization of nanoparticles (NPs) as drug delivery agents. Hydroxyapatite (HA) gives improved clinical effectiveness of drugs by reducing systemic toxicity and broadening the spectrum of drug delivery since it is biocompatible and it can be targeted towards tumor cells. Herein, investigation of the potential of enhancing controlled drug release of the template model drug, copper bis-(8 hydroxyquinoline), by encapsulating it in hollow hydroxyapatite nano-carriers, is presented. Hydroxyapatite nanoparticles are synthesized by following four different routes to optimize its efficacy of drug loading. Copper bis-(8 hydroxyquinoline) is encapsulated by Method (a) which was effected by stirring the model drug and porous HA NPs in colloidal solution and Method (b) which was done during synthesis of hydroxyapatite nanoparticles in a solution of the model drug. In synthesizing nanoporous HA NPs, calcium carbonate is used as a template to create voids in HA. In each method, Ca/P ratio was ensured to be kept at 1.67:1. Appealing results are reported for the encapsulated product which was prepared by Method (a2). Method (a) was done at three different molar ratios of PO43-:CO32- and best result was obtained for that utilized 2.003:1 molar ratio (Method (a2).). It produced 98.67% of encapsulation efficiency and 2.9522mg/g of drug loading capacity. Release kinetics was studied at a range of pH values; the lower the pH of the medium the higher is the drug release. For instance, when considering the product which exhibited high encapsulation efficiency and high drug loading capacity, at pH3.5 during the first 8h it elicited about 13% of release, at pH5.0 about 8% release while at pH6.0 it was just 2.5%. During the 24 hour span, pH3.5 exhibited about 23.8%, at pH5.0 approximately 9% with an increasing trend of release and at pH6.0 showed a value just above 2.5%. As such, acidity of the cancerous cells can be made use to increase the drug slow-release kinetics at the vicinity of the cancer cells. PMID- 27987701 TI - Magnetically modified bacterial cellulose: A promising carrier for immobilization of affinity ligands, enzymes, and cells. AB - Bacterial cellulose (BC) produced by Komagataeibacter sucrofermentans was magnetically modified using perchloric acid stabilized magnetic fluid. Magnetic bacterial cellulose (MBC) was used as a carrier for the immobilization of affinity ligands, enzymes and cells. MBC with immobilized reactive copper phthalocyanine dye was an efficient adsorbent for crystal violet removal; the maximum adsorption capacity was 388mg/g. Kinetic and thermodynamic parameters were also determined. Model biocatalysts, namely bovine pancreas trypsin and Saccharomyces cerevisiae cells were immobilized on MBC using several strategies including adsorption with subsequent cross-linking with glutaraldehyde and covalent binding on previously activated MBC using sodium periodate or 1,4 butanediol diglycidyl ether. Immobilized yeast cells retained approximately 90% of their initial activity after 6 repeated cycles of sucrose solution hydrolysis. Trypsin covalently bound after MBC periodate activation was very stable during operational stability testing; it could be repeatedly used for ten cycles of low molecular weight substrate hydrolysis without loss of its initial activity. PMID- 27987702 TI - Establishment of 3D culture and induction of osteogenic differentiation of pre osteoblasts using wet-collected aligned scaffolds. AB - Aligned fibrous scaffolds have attracted much interest in bone tissue engineering, because they are supposed to induce osteogenic differentiation. For the first time, aligned silk fibroin nanofibres were loosely packed using a novel wet-collection electrospinning method. Moreover, three-dimensional (3D) culture of MC3T3-E1 pre-osteoblasts was established on these fibrous scaffolds. Physicochemical properties of the scaffolds and the behaviour of MC3T3-E1 pre osteoblasts on the scaffolds were analysed and compared with scaffolds obtained using traditional method. Ethanol bath improved the uniformity and alignment of the fibres and increased the thickness and porosity of the scaffolds. Structures of the fibres were well maintained after immediate crosslinking in ethanol. Cells on the wet-collected scaffolds exhibited more ordered arrangement and elongated morphology as well as faster and deeper infiltration. The ordered infiltration resulted in the establishment of the 3D culture of cells, promoting proliferation and osteogenic differentiation of the pre-osteoblasts. Thus, the wet-collected aligned scaffolds with improved topographical and physicochemical properties presents significant potential application in bone regeneration. PMID- 27987703 TI - Auto-assembly of nanometer thick, water soluble layers of plasmid DNA complexed with diamines and basic amino acids on graphite: Greatest DNA protection is obtained with arginine. AB - We have investigated the ability of diamines as well as basic amino acids to condense DNA onto highly ordered pyrolytic graphite with minimum damage after re dissolution in water. Based on a bibliographic survey we briefly summarize DNA binding properties with diamines as compared to basic amino acids. Thus, solutions of DNA complexed with these linkers were drop-cast in order to deposit ultra-thin layers on the surface of HOPG in the absence or presence of Tris buffer. Atomic Force Microscopy analyses showed that, at a fixed ligand-DNA mixing ratio of 16, the mean thickness of the layers can be statistically predicted to lie in the range 0-50nm with a maximum standard deviation +/-6nm, using a simple linear law depending on the DNA concentration. The morphology of the layers appears to be ligand-dependent. While the layers containing diamines present holes, those formed in the presence of basic amino acids, except for lysine, are much more compact and dense. X-ray Photoelectron Spectroscopy measurements provide compositional information indicating that, compared to the maximum number of DNA sites to which the ligands may bind, the basic amino acids Arg and His are present in large excess. Conservation of the supercoiled topology of the DNA plasmids was studied after recovery of the complex layers in water. Remarkably, arginine has the best protection capabilities whether Tris was present or not in the initial solution. PMID- 27987704 TI - Novel electrospun nanofibers of modified gelatin-tyrosine in cartilage tissue engineering. AB - In natural cartilage tissues, chondrocytes are linked to extracellular matrix (ECM) through cell-surface binding proteins. Surface modification of gelatin can provide a new generation of biopolymers and fibrous scaffolds with chemical, mechanical, and biological properties. In this study tyrosine protein and 1,2,3 triazole ring were utilized to functionalize gelatin without Cu catalyst. Their molecular structure was characterized by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (1HNMR). Chemical cross linkers such as glutaraldehyde (GA) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysulfosuccinimide (NHS) were used to electrospin the modified gelatin. The modification of gelatin and cross-linking effects were confirmed by scanning electron microscopy (SEM), contact angle measurement, and mechanical tests. MTT assay using chondrocyte cells showed cell viability of electrospun modified gelatin scaffolds. In vitro cell culture studies showed that electrospun engineered protein scaffolds would support the attachment and growth of cells. The results also showed that cross-linked nanofibers with EDC/NHS could be considered excellent matrices in cell adhesion and proliferation before electrospinning process and their potential substrate in tissue engineering applications, especially in the field of cartilage engineering. PMID- 27987705 TI - Microstructure and degradation performance of biodegradable Mg-Si-Sr implant alloys. AB - In this work the microstructure and degradation behavior of several as-cast alloy compositions belonging to the Mg rich corner of the Mg-Si-Sr system are presented and related. The intermetallic phases are identified and analyzed describing the microstructure evolution during solidification. It is intended in this work to obtain insight in the behavior of the ternary alloys in in vitro tests and to analyze the degradation behavior of the alloys under physiologically relevant conditions. The as-cast specimens have been exposed to immersion tests, both mass loss (ML) and potentiodynamic polarization (PDP). The degradation rate (DR) have been assessed and correlated to microstructure features, impurity levels and alloy composition. The initial reactions resulted to be more severe while the degradation stabilizes with time. A higher DR is related with a high content of the Mg17Sr2 phase and with the presence of coarse particles of the intermetallics Mg2Si, MgSiSr and MgSi2Sr. Specimens with a higher DR typically have higher levels of impurities and alloy contents. PMID- 27987706 TI - Wetspun poly-L-(lactic acid)-borosilicate bioactive glass scaffolds for guided bone regeneration. AB - We developed a porous poly-L-lactic acid (PLLA) scaffold compounded with borosilicate bioactive glasses (BBGs) endowing it with bioactive properties. Porous PLLA-BBG fibre mesh scaffolds were successfully prepared by the combination of wet spinning and fibre bonding techniques. Micro-computed tomography (MUCT) confirmed that the PLLA-BBG scaffolds containing ~25% of BBGs (w/w) exhibited randomly interconnected porous (58 to 62% of interconnectivity and 53 to 67% of porosity) with mean pore diameters higher that 100MUm. Bioactivity and degradation studies were performed by immersing the scaffolds in simulated body fluid (SBF) and ultrapure water, respectively. The PLLA-BBG scaffolds presented a faster degradation rate with a constant release of inorganic species, which are capable to produce calcium phosphate structures at the surface of the material after 7days of immersion in SBF (Ca/P ratio of ~1.7). Cellular in vitro studies with human osteosarcoma cell line (Saos-2) and human adipose-derived stem cells (hASCs) showed that PLLA-BBGs are not cytotoxic to cells, while demonstrating their capacity to promote cell adhesion and proliferation. Overall, we showed that the proposed scaffolds present a tailored kinetics on the release of inorganic species and controlled biological response under conditions that mimic the bone physiological environment. PMID- 27987707 TI - Controlled delivery of icariin on small intestine submucosa for bone tissue engineering. AB - Small intestine submucosa (SIS) has been reported as an excellent biomaterial for tissue engineering because of its naturally occurring collagenous extracellular matrix property with growth factors. However, SIS from submucosal layer of intestine provides different microenvironment from bone tissue, which limits its application to bone regeneration. The object of this study was to improve osteoinductivity of SIS by controlled local delivery of icariin (Ic), a potent osteogenic compound. Sustained release of icariin from SIS scaffold was achieved for >30days and the loading of icariin on SIS scaffold was uniform as scanned by SEM. In vitro experiments revealed that expression of osteogenic differentiation markers (Alp, Bsp and Ocn) was increased after treatment of Ic-SIS scaffold, without significant cytotoxicity. In an in vivo mouse calvarial defect model, bone regeneration was enhanced by SIS implantation at 8weeks, compared to control defect. New bone formation was further improved by implantation with Ic-SIS (low and high) at both 4 and 8weeks. The results of this study suggest that SIS scaffold has the potential as an icariin delivery carrier for enhancement of bone regeneration. PMID- 27987708 TI - Extraction and encapsulation of prodigiosin in chitosan microspheres for targeted drug delivery. AB - The encapsulation of drugs in polymeric materials has brought opportunities to the targeted delivery of chemotherapeutic agents. These polymeric delivery systems are capable of maximizing the therapeutic activity, as well as reducing the side effects of anti-cancer agents. Prodigiosin, a secondary metabolite extracted from the bacteria, Serratia marcescens, exhibits anti-cancer properties. Prodigiosin-loaded chitosan microspheres were prepared via water-in oil (w/o) emulsion technique, using glutaraldehyde as a cross-linker. The morphologies of the microspheres were studied using scanning electron microscopy. The average sizes of the microspheres were between 40MUm and 60MUm, while the percentage yields ranged from 42+/-2% to 55.5+/-3%. The resulting encapsulation efficiencies were between 66.7+/-3% and 90+/-4%. The in-vitro drug release from the microspheres was characterized by zeroth order, first order and Higuchi and Korsmeyer-Peppas models. PMID- 27987709 TI - Synthesis, characterization and bioactivity of a calcium-phosphate glass-ceramics obtained by the sol-gel processing method. AB - In this work, a calcium-phosphate glass-ceramics was successfully obtained by heat treatment of a mixture of 26.52 in wt.% of fluorapatite (Fap) and 73.48 in wt.% of 77S (77 SiO214 CaO9 P2O5 in wt.%) gel. The calcium phosphate-glass ceramics was prepared by sol-gel process with tetraethyl orthosilicate (TEOS), triethyl phosphate (TEP), calcium nitrate and fluorapatite. The synthesized powders were characterized by some commonly used tools such as X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), 31P magic angle spinning nuclear magnetic resonance (MAS-NMR), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and thin-film X-ray diffraction (TF-XRD). The obtained results seemed to confirm the nucleation and growth of hydroxyapatite (Hap) nano-phase in the glass. Moreover, an in-vitro evaluation of the glass ceramic was performed. In addition, to assess its bioactive capacity, it was soaked in simulated body fluid (SBF) at different time intervals. The SEM, EDS and TF-XRD analyses showed the deposition of hydroxyapatite on the surface of the specimens after three days of immersion in SBF solution. The mechanical properties of the obtained material such as rupture strength, Vickers hardness and elastic modulus were measured. In addition, the friction coefficient of calcium phosphate-glass-ceramics was tested. The values of the composite of rupture strength (24MPa), Vickers hardness (214Hv), Young's modulus (52.3GPa), shear modulus (19GPa) and friction coefficient (0.327) were obtained. This glass ceramics can have useful applications in dental prostheses. Indeed, this material may have promising applications for implants because of its content of fluorine, the effective protector against dental caries. PMID- 27987710 TI - Rapid hemostatic and mild polyurethane-urea foam wound dressing for promoting wound healing. AB - A novel rapid hemostatic and mild polyurethane-urea foam (PUUF) wound dressing was prepared by the particle leaching method and vacuum freeze-drying method using 4, 4-Methylenebis(cyclohexyl isocyanate), 4,4-diaminodicyclohexylmethane and poly (ethylene glycol) as raw materials. And X-ray diffraction (XRD), tensile test, differential scanning calorimetry (DSC) and thermogravimetry (TG) were used to its crystallinity, stress and strain behavior, and thermal properties, respectively. Platelet adhesion, fibrinogen adhesion and blood clotting were performed to evaluate its hemostatic effect. And H&E staining and Masson Trichrome staining were used to its wound healing efficacy. The results revealed the pore size of PUUF is 50-130MUm, and its porosity is 71.01%. Porous PUUF exhibited good water uptake that was benefit to adsorb abundant wound exudates to build a regional moist environment beneficial for wound healing. The PUUF wound dressing exhibit better blood coagulation effect than commercial polyurethane dressing (CaduMedi). Though both PUUF and CaduMedi facilitated wound healing generating full re-epithelialization within 13days, PUUF was milder and lead to more slight inflammatory response than CaduMedi. In addition, PUUF wound dressing exhibited lower cytotoxicity than CaduMedi against NIH3T3 cells. Overall, porous PUUF represents a novel mild wound dressing with excellent water uptake, hemostatic effect and low toxicity, and it can promote wound healing and enhance re-epithelialization. PMID- 27987711 TI - Folic acid-modified soy protein nanoparticles for enhanced targeting and inhibitory. AB - Soy protein isolate (SPI) was hydrolyzed by compound enzymes to give water soluble low molecular soy protein (SP). SP and folic acid (FA) modified SP was polymerized with N-3- acrylamidophenylboronic acid (APBA) monomer in aqueous solution to give SP nanoparticles (SP NPs) and FA modified nanoparticles (FA-SP NPs), respectively. These NPs display excellent stability in different conditions, and have a uniform spherical shape with a diameter around of 200nm. Doxorubicin (DOX) was then successfully loaded into SP and FA-SP NPs with a desirable loading content of 13.33% and 16.01%, respectively. The cellular uptake and cytotoxicity of DOX-loaded SP NPs and FA-SP NPs were investigated using the two-dimensional (2D) monolayer cell model and three-dimensional (3D) multicellular spheroids (MCs). In vivo, tumor accumulation and growth inhibitory were then examined using H22 tumor-bearing mice. All these results demonstrated that conjugation of FA can efficiently enhance SP-based NPs' tumor accumulation and antitumor effect. PMID- 27987712 TI - Hyaluronic acid doped-poly(3,4-ethylenedioxythiophene)/chitosan/gelatin (PEDOT HA/Cs/Gel) porous conductive scaffold for nerve regeneration. AB - Conducting polymer, as a "smart" biomaterial, has been increasingly used to construct tissue engineered scaffold for nerve tissue regeneration. In this study, a novel porous conductive scaffold was prepared by incorporating conductive hyaluronic acid (HA) doped-poly(3,4-ethylenedioxythiophene) (PEDOT-HA) nanoparticles into a chitosan/gelatin (Cs/Gel) matrix. The physicochemical characteristics of Cs/Gel scaffold with 0-10wt% PEDOT-HA were analyzed and the results indicated that the incorporation of PEDOT-HA into scaffold increased the electrical and mechanical properties while decreasing the porosity and water absorption. Moreover, in vitro biodegradation of scaffold displayed a declining trend with the PEDOT-HA content increased. About the biocompatibility of conductive scaffold, neuron-like rat phaeochromocytoma (PC12) cells were cultured in scaffold to evaluate cell adhesion and growth. 8% PEDOT-HA/Cs/Gel scaffold had a higher cell adhesive efficiency and cell viability than the other conductive scaffolds. Furthermore, cells in the scaffold with 8wt% PEDOT-HA expressed higher synapse growth gene of GAP43 and SYP compared with Cs/Gel control group. These results suggest that 8%PEDOT-HA/Cs/Gel scaffold is an attractive cell culture conductive substrate which could support cell adhesion, survival, proliferation, and synapse growth for the application in nerve tissue regeneration. PMID- 27987713 TI - Gallium containing composites as a tunable material to understand neuronal behavior under variable stiffness and radiation conditions. AB - We report a composite biomaterial containing nanostructured GaOOH and MatrigelTM that can be modulated with respect to its stiffness and radiosensitization properties. A variety of concentrations of GaOOH were added to the composite to alter the mechanical properties of the material as well as to tune the radiosensitizing properties to the composite. PC-12 cells were used to study the combined effects of different stimuli on cell behavior. NGF was given to the cells to record their morphology as well as viability. An increase in the substrate stiffness caused an increase in neurite outgrowth but a decrease in cell viability. In addition, increasing the radiation dose decreased neurite outgrowth but increased cell viability when radiosensitizing particles were present. A subtractive effect between radiosensitizing and mechanical stimuli was observed when PC-12 cells were grown on the GaOOH containing composite. PMID- 27987714 TI - Microstructure, surface characterization and long-term stability of new quaternary Ti-Zr-Ta-Ag alloy for implant use. AB - The novel Ti-20Zr-5Ta-2Ag alloy was characterised concerning its microstructure, morphology, mechanical properties, its passive film composition and thickness, its long-term electrochemical stability, corrosion resistance, ion release rate in Ringer solution of acid, neutral and alkaline pH values and antibacterial activity. The new alloy has a crystalline alpha microstructure (by XRD). Long term XPS and SEM analyses show the thickening of the passive film and the deposition of hydroxyapatite in neutral and alkaline Ringer solution. The values of the electrochemical parameters confirm the over time stability of the new alloy passive film. All corrosion parameters have very favourable values in time which attest a high resistance to corrosion. Impedance spectra evinced a bi layered passive film formed by the barrier, insulating layer and the porous layer. The monitoring of the open circuit potentials indicated the stability of the protective layers and their thickening in time. The new alloy releases (by ICP-MS measurements) very low quantities of Ti, Zr, Ag ions and no Ta ions. The new alloy exhibits a low antibacterial activity. PMID- 27987715 TI - Sterilization of collagen scaffolds designed for peripheral nerve regeneration: Effect on microstructure, degradation and cellular colonization. AB - In this study we investigated the impact of three different sterilization methods, dry heat (DHS), ethylene oxide (EtO) and electron beam radiation (beta), on the properties of cylindrical collagen scaffolds with longitudinally oriented pore channels, specifically designed for peripheral nerve regeneration. Scanning electron microscopy, mechanical testing, quantification of primary amines, differential scanning calorimetry and enzymatic degradation were performed to analyze possible structural and chemical changes induced by the sterilization. Moreover, in vitro proliferation and infiltration of the rat Schwann cell line RSC96 within the scaffolds was evaluated, up to 10days of culture. No major differences in morphology and compressive stiffness were observed among scaffolds sterilized by the different methods, as all samples showed approximately the same structure and stiffness as the unsterilized control. Proliferation, infiltration, distribution and morphology of RSC96 cells within the scaffolds were also comparable throughout the duration of the cell culture study, regardless of the sterilization treatment. However, we found a slight increase of chemical crosslinking upon sterilization (EtO600MUM versus the IC50 of curcumin found between 100 and 200MUM. Surprisingly, Cur-[G-2]-OH drives cell death of C6 cells by a different mechanism of apoptosis triggered by curcumin. Together, these results suggest that curcumin dendronization could promote molecular and cellular mechanisms that are different from those induced by curcumin, presumably due to structural factors and not only for improved water solubility. PMID- 27987719 TI - Fabrication and characterization of polyvinyl alcohol/metal (Ca, Mg, Ti) doped zirconium phosphate nanocomposite films for scaffold-guided tissue engineering application. AB - Nanocomposite films of polyvinyl alcohol (PVA) and zirconium phosphate (ZrP)/doped ZrP (doped with Ca, Mg, Ti) nanoparticles have been developed by solvent casting method to assess their potential as matrix material in scaffold guided tissue engineering application. The prepared ZrP and doped ZrP nanoparticles as well as the nanocomposite films were characterized by various spectroscopic and microscopic techniques. Nanoindentation studies revealed improved nanomechanical properties in the PVA/doped ZrP nanocomposite films (highest for PVA/Ti doped ZrP: hardness=262.4MPa; elastic modulus=5800MPa) as compared to the PVA/ZrP and neat PVA films. In-vitro cell culture experiments carried out to access the cellular viability, attachment, proliferation, and migration on the substrates, using mouse fibroblast (3T3) cell lines, inferred enhanced bioactivity in the PVA/doped ZrP nanocomposite films (highest for PVA/Ca doped ZrP) in contrast to PVA/ZrP and neat PVA films. Controlled biodegradability as well as swelling behavior, superior bioactivity and improved mechanical properties of the PVA/doped ZrP nanocomposite films make them promising matrix materials for scaffold-guided tissue engineering application. PMID- 27987720 TI - Fabrication and characterization of platelet-rich plasma scaffolds for tissue engineering applications. AB - Platelet-Rich Plasma (PRP), as a rich source of growth factor, can form a fibrin gel that recapitulates the extracellular matrix of the tissues. The aim of this study was to evaluate the effects of different concentrations of CaCl2 on the PRP scaffold structure which in turn could change the cell's behavior. PRP was mixed with 2.5, 5 and 10% (w/v) CaCl2. Then, the tensile strength, biodegradability and water content of the scaffolds were evaluated. We also performed immunostaining for assessment of the actin stress fiber orientation and SEM for detecting the cell phenotype and physical properties of the fibers. Cell viability, attachment and migration were also evaluated. The highest cell attachment and short term proliferation rate was observed on the scaffolds with 2.5% CaCl2. The cells cultured on the scaffold with higher CaCl2 concentration had fusiform phenotype with few cell processes and parallel arrangement of stress fibers while those cultured on the other scaffolds were fibroblast-like with more processes and net like stress fibers. The scaffolds with 10% CaCl2 demonstrated the highest osmolarity (358.75+/-4.99mOsmole), fiber thickness (302.1+/-54.3nm), pore size (332.1+/-118.9nm2) and the longest clotting time (12.2+/-0.776min) compared with the other scaffolds. Water content, branching angle, porosity, orientation and tensile strength did not change by gelation with different CaCl2 concentrations. In conclusion, the cell shape, viability and proliferation were modified by culturing on the PRP scaffolds prepared with various concentrations of CaCl2, and as a result, the scaffolds showed different physical and biological properties. PMID- 27987721 TI - Nanostructured poly (lactic acid) electrospun fiber with high loadings of TiO2 nanoparticles: Insights into bactericidal activity and cell viability. AB - Researchers have been looking for modifying surfaces of polymeric biomaterials approved by FDA to obtain nanofeatures and bactericidal properties. If modified, it would be very interesting because the antibiotic administration could be reduced and, therefore, the bacterial resistance. Here, we report the electrospinning of poly (lactic acid) (PLA) with high loadings of titanium dioxide nanoparticles (TiO2, 1-5wt%) and their bactericidal properties. TiO2 nanoparticles have been recognized for a long time for their antibacterial, low cost and self-cleaning properties. However, their ability to reduce bacteria functions when used in polymers has not been well studied to date. In this context, we aimed here to generate nanostructured PLA electrospun fiber-TiO2 nanoparticle composites for further evaluation of their bactericidal activity and cell viability. TEM and SEM micrographs revealed the successful electrospinning of PLA/TiO2 and the generation of polymer-TiO2 nanostructures. When increasing the TiO2 concentration, we observed a proportional increase in the nanoparticle density along the fiber and surface. The nanostructured PLA/TiO2 nanofibers showed no mammalian cell toxicity and, most importantly, possessed bactericidal activity with higher TiO2 loads. Such results suggest that the present PLA electrospun fiber-TiO2 nanoparticle composites should be further studied for a wide range of biomedical applications. PMID- 27987722 TI - Nanomolar simultaneous determination of tryptophan and melatonin by a new ionic liquid carbon paste electrode modified with SnO2-Co3O4@rGO nanocomposite. AB - This work describes the development of a new sensor for simultaneous determination of tryptophan and melatonin. The proposed sensor was an ionic liquid carbon paste electrode modified with reduced graphene oxides decorated with SnO2-Co3O4 nanoparticles. The voltammetric oxidation of the analytes by the proposed sensor confirmed that the electrooxidation process undergoes a two electron/one-proton reaction for melatonin and a two-electron/two-proton reaction for tryptophan in diffusion-controlled processes. Moreover, based on the excellent electrochemical properties of the modified electrode, a sensitive voltammetric method was used for individual and simultaneous determination of melatonin and tryptophan in the aqueous solutions. Under the optimized experimental conditions, a linear response obtained in the range of 0.02 to 6.00MUmolL-1 with detection limits of 4.1 and 3.2nmolL-1 for melatonin and tryptophan, respectively. The prepared sensor possessed accurate and rapid response toward melatonin and tryptophan with a good sensitivity, selectivity, stability, and repeatability. Finally, the applicability of the proposed sensor was verified by evaluation of melatonin and tryptophan in various real samples including human serum and tablet samples. PMID- 27987723 TI - Effects of asperities and organic-inorganic interactions on the strength of nacre mimetic composites. AB - Nacre is a natural organic-inorganic hybrid composite, whose hierarchical structure has a complex influence on its high strength. Many structural features have been discovered, which influence the mechanical properties of nacre, and the authors have a particular interest in the role of the asperities and organic inorganic interactions. In this study, a composite was prepared which mimics the asperity structure using clay minerals. Organic-inorganic bonding was induced with silane treatment. Both factors increased the yield strength of the composites; however, different deformation behavior was exhibited. It was found that asperities improved the strength of the composite, and that composition influences the stiffness of the composite. The organic-inorganic interaction between the resin and the other components of the composite reduced the deformation of the composite and consequently improved strength. PMID- 27987724 TI - A novel tantalum-containing bioglass. Part II. Development of a bioadhesive for sternal fixation and repair. AB - With over a million median sternotomy surgeries performed worldwide every year, sternal wound complications have posed a serious risk to the affected patients. A rigid therapeutic sternal fixation device has therefore become a necessity. In this work, the incorporation of up to 0.5mol% of tantalum pentoxide (Ta2O5), in exchange for zinc oxide (ZnO), into the SiO2-ZnO-CaO-SrO-P2O5 glass system is presented. The effect of Ta incorporation on the physical, chemical and biological properties of the glass polyalkenoate cements (GPCs) prepared from them have been presented in this manuscript. The data obtained have confirmed that Ta2O5 incorporation into the reference glass system results in increased working times, radiopacity, ion solubility, and long-term mechanical stability. The formulated glass systems have also shown clear antibacterial and antifungal activity against both Gram-negative (Escherichia coli) and Gram-positive prokaryotes (Staphylococcus aureus and Streptococcus epidermidis), as well as eukaryotes (Fusarium solani). Cytotoxicity testing showed that Ta incorporation results in no toxicity effect and may simulate osseo-integration when tested in animal models. These new metallic-containing biomaterial adhesives have been developed for sternal fixation and repair. As a permanent implant, the formulated adhesives can be used in conjunction with sternal cable ties to offer optimal fixation for patients and reduce post-operative complications such as bacterial infection and pain from micro-motion. PMID- 27987725 TI - In vitro and in vivo assessment of nanotoxicity of CdS quantum dot/aminopolysaccharide bionanoconjugates. AB - The nanotoxicity of Cd-containing quantum dots (QDs) for biomedical applications is very controversial and not completely understood. In this study, we evaluated the cytotoxicity of surface-biofunctionalized CdS QDs with chitosan directly synthesized via aqueous route at room temperature. These core-shell CdS-chitosan nanoconjugates showed different degrees of cytotoxic responses using MTT cell proliferation assay toward three human cell cultures, human osteosarcoma cell line (SAOS), non-Hodgkin's B cell lymphoma (Toledo), and human embryonic kidney cell line (HEK293T), under three exposure times (1, 3, and 5days) and three colloidal concentrations (10nM, 50nM, and 100nM). The results clearly demonstrated that the CdS QDs, regardless to the fact that they were coated with a biocompatible aminopolysaccharide shell, induced a severe dose- and time dependent inhibition of cell viability. In addition, the HEK293T and SAOS cell lines showed much more sensitive response compared to Toledo, which indicated that the cytotoxicity was also cell-type dependent. The exceptional resistance of Toledo cells to toxic effects of CdS nanoconjugates even at severe test conditions was assigned to specific role of B-lineage cells of the immune defense system. Remarkably, no conclusive evidence of toxicity of CdS nanoconjugates was observed in vivo using intravenous injections of CdS nanoconjugates in BALB/c mouse animal models for 30days, but localized fluorescence was detected in ex vivo liver tissue samples. Therefore, these results prove that there is no guarantee of "risk-free" use of CdS nanoconjugates for in vivo applications, even when functionalized with biopolymer ligands, as they can pose an excessive threat due to unpredicted and uncorrelated responses under in vitro and in vivo biological assays with highly toxic cadmium ions. PMID- 27987726 TI - Effect of PEGylation on performance of protein microbubbles and its comparison with lipid microbubbles. AB - Aqueous suspensions of microbubbles are being used in various biomedical applications such as contrast imaging, targeted drug and gene delivery, delivery of drugs through blood brain barrier (BBB) and IV O2 delivery etc. Major microbubble formulations use either proteins or lipids as their shell material. Protein microbubble formulations mainly consist of serum albumin, lysozyme etc., while lipid microbubble formulations consist of phospholipids like 1,2-Distearoyl sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC), etc. This work focuses on comparing performance of protein and lipid microbubbles in terms of their shelf life and in vitro performance. Protein microbubbles were produced using Bovine serum albumin (BSA) as main ingredient and N-acetyl-dl-tryptophan (Tryp) as an additive. Lipid microbubbles were produced using a mixture of DSPC as main ingredient and PEG40S (90:10molar ratio) as emulsifier. A narrow sized range (3-5MUm) microbubble suspension was produced using sonication method followed by size isolation using centrifugation. These microbubbles were stored in a (PGO) solution containing 10% 1,2 propanediol (P), 10% glycerol (G) and 80% original solution used to make microbubbles (O) and were studied for their shelf stability, in vitro stability, immunogenicity and ability to produce contrast. For a 4weeks of observation period, a least reduction in concentration of around 18% was observed for PEGylated BSA microbubbles whereas highest reduction of 38% was observed for DSPC-PEG40S microbubbles. In-vitro persistence performance for PEGylated BSA microbubbles was found to be better than non-PEGylated BSA microbubbles as well as DSPC-PEG40S microbubbles. Non PEGylated BSA microbubbles were found to be immunogenic whereas PEGylated BSA and DSPC-PEG40S microbubles were found to be non-immunogenic. PMID- 27987728 TI - Fabrication and evaluation of silica-based ceramic scaffolds for hard tissue engineering applications. AB - In recent decades, bone scaffolds have received a great attention in biomedical applications due to their critical roles in bone tissue regeneration, vascularization, and healing process. One of the main challenges of using scaffolds in bone defects is the mechanical strength mismatch between the implant and surrounding host tissue which causes stress shielding or failure of the implant during the course of treatment. In this paper, space holder method was applied to synthesize diopside/forsterite composite scaffolds with different diopside content. During the sintering process, NaCl, as spacer agent, gradually evaporated from the system and produced desirable pore size in the scaffolds. The results showed that adding 10wt.% diopside to forsterite can enormously improve the bioactivity, biodegradability, and mechanical properties of the composite scaffolds. The size of crystals and pores of the obtained scaffolds were measured to be in the range 70-100nm and 100-250MUm, respectively. Composite scaffolds containing 10wt.% diopside showed similar compressive strength and Young's modulus (4.36+/-0.3 and 308.15+/-7MPa, respectively) to that of bone. PMID- 27987727 TI - Synthesis of polypyrrole nanowires with positive effect on MC3T3-E1 cell functions through electrical stimulation. AB - Conducting polymer polypyrrole (PPy) possesses good biocompatibility and conductivity and has been used as functional coatings in bone tissue regeneration. In this study, a cholic acid doped PPy nanowires (PPy NWs) coating was electrochemically polymerized on the surface of titanium (Ti). The porous intertwined PPy NWs coating exhibited excellent electrical conductivity and electrochemical activity, better hydrophilicity and higher surface energy. In vitro cell experiments demonstrated that the PPy NWs coating together with a 10MUA substrate-mediate electrical stimulation (ES) was capable to positive regulate the functions of MC3T3-E1 such as cell adhesion, proliferation and differentiation. Further long-term functions of cell tests including alkaline phosphatase (ALP) activity, bone-carboxyglutamic acid-containing protein (BGP) and calcium deposition were all thoroughly increased. These confirmed that the combination of PPy NWs and ES could accelerate MC3T3-E1 cells mature and osteogenesis. Hence, the PPy NWs coating was an electro bioactive coating and may have potential applications in the treatment of bone damage repairing and regeneration with ES. PMID- 27987729 TI - Mesoporous hydroxyapatite nanoparticles hydrothermally synthesized in aqueous solution with hexametaphosphate and tea polyphenols. AB - Mesoporous hydroxyapatite (HA) nanoparticles with high surface area have been widely investigated for drug delivery. Herein we report a facile and simple strategy for the preparation of such materials using hexametaphosphate salt as inorganic phosphorus source. In the hydrothermal processing, hexametaphosphate plays an important role in the formation of mesoporous structure. The as-prepared mesoporous HA nanoparticles can be candidates for pH-responsive anticancer drug delivery by using doxorubicin (Dox) as a model drug. Furthermore, modification of these mesoporous HA nanoparticles using tea polyphenols is attempted. The presence of tea polyphenols in the HA synthesis processing result in mesoporous HA nanoparticles with tailored morphology and properties, making them more pH sensitive for drug delivery. Both hexametaphosphate and tea polyphenols can be potential chemical sources in synthesizing mesoporous HA. PMID- 27987730 TI - Reconciling in vivo and in vitro kinetics of the polymorphic transformation in zirconia-toughened alumina for hip joints: II. Theory. AB - In this paper, an updated analytical model for the kinetics of the tetragonal to monoclinic (t->m) polymorphic transformation in ZTA composites for hip joints is proposed and discussed. The model builds upon the so-called Mehl-Avrami-Johnson (MAJ) description of transformation kinetics, which combines two overlapping processes: nucleation of monoclinic sites, and their successive growth. Dependencies on two specific factors are introduced in the model, namely the initial fraction of monoclinic polymorph as received from the manufacturer, and the presence of different types of transition-metal stains (e.g., Ti, CoCr, and Fe) on the ZTA surface. These two factors were studied because clear indications of their potential roles on the environmental stability of implantable ZTA components were found in previous phenomenological analyses of retrievals. Nucleation and growth of monoclinic domains are two key processes whose interplay decides the actual kinetics of the overall transformation process according to two main parameters: an apparent activation energy value function of time and temperature, and a nuclei growth exponent. These parameters were clearly altered by the presence of transition metal contamination, whose effect was incorporated into the model to explain exacerbations of surface degradation. In accordance with a general analytical description of transformation kinetics for isothermal or isochronal evolutions in terms of time and temperature, the modified model of the MAJ description assesses the effect of the initial monoclinic fraction. The updated model has been validated using systematic in vitro experiments, and appears to partly reconcile in vitro and in vivo data of t->m transformation discrepancies in ZTA hip components. PMID- 27987732 TI - Apoptotic and anti-apoptotic genes transcripts patterns of graphene in mice. AB - Recent studies showed that a large amount of graphene oxide accumulated in kidney and liver when it injected intravenously. Evaluation of lethal and apoptosis gene expression in these tissues, which are under stress is very important. In this paper the in vivo dose-dependent effects of graphene oxide and reduced graphene oxide nanoplatelets on kidney and liver of mice were studied. Balb/C mice were treated by 20mg/kg body weight of nanoplatelets. Molecular biology analysis showed that graphene nanoplatelets injected intravenously lead to overexpression of BAX gene in both kidney and liver tissues (P>=0.01). In addition these nanoparticles significantly increase BCL2 gene expression in both kidney and liver tissues (P>=0.05). Graphene significantly increase level of SGPT in groups 1 (220.64+/-13), 2 (164.44+/-9.3) in comparison to control group (P<=0.05). Also in comparison with control group (148.11+/-10.4), (P<=0.05), the level of SGOT in groups 1(182.01+/-12.6) and 2 (178.2+/-2.2) significantly increased. PMID- 27987731 TI - Aldehyde-functionalized dendritic mesoporous silica nanoparticles as potential nanocarriers for pH-responsive protein drug delivery. AB - We developed a potential pH-responsive protein drug delivery system based on aldehyde-functionalized dendritic mesoporous silica nanoparticles (DMSNs-CHO) as nanocarriers. The structure, protein drug loading and release behavior, in vitro cytotoxicity and cell uptake of the DMSNs-CHO nanoparticles were investigated. The results showed that the uniform DMSNs-CHO nanoparticles had an average particle size of 174+/-17nm and a mesopore size of 7.7nm. Using bovine serum albumin (BSA) as a model protein drug, BSA could be loaded into DMSNs-CHO nanoparticles owing to the formation of imine bonds between aldehyde groups and primary amines of BSA molecules. BSA loading capacity was about 136MUg/mg, and BSA release from DMSNs-CHO nanocarriers was dependent on pH environment. Furthermore, the DMSNs-CHO nanoparticles had no cytotoxicity and could be efficiently taken up by cells. Therefore, the DMSNs-CHO nanoparticles would be promising as nanocarriers for pH-responsive delivery of protein drugs. PMID- 27987733 TI - Optimizing structural and mechanical properties of cryogel scaffolds for use in prostate cancer cell culturing. AB - Prostate cancer (PCa) currently is the second most diagnosed cancer in men and the second most cause of cancer death after lung cancer in Western societies. This sets the necessity of modelling prostatic disorders to optimize a therapy against them. The conventional approach to investigating prostatic diseases is based on two-dimensional (2D) cell culturing. This method, however, does not provide a three-dimensional (3D) environment, therefore impeding a satisfying simulation of the prostate gland in which the PCa cells proliferate. Cryogel scaffolds represent a valid alternative to 2D culturing systems for studying the normal and pathological behavior of the prostate cells thanks to their 3D pore architecture that reflects more closely the physiological environment in which PCa cells develop. In this work the 3D morphology of three potential scaffolds for PCa cell culturing was investigated by means of synchrotron X-ray computed micro tomography (SXCMUT) fitting the according requirements of high spatial resolution, 3D imaging capability and low dose requirements very well. In combination with mechanical tests, the results allowed identifying an optimal cryogel architecture, meeting the needs for a well-suited scaffold to be used for 3D PCa cell culture applications. The selected cryogel was then used for culturing prostatic lymph node metastasis (LNCaP) cells and subsequently, the presence of multi-cellular tumor spheroids inside the matrix was demonstrated again by using SXCMUT. PMID- 27987735 TI - Combined effect of grain refinement and surface modification of pure titanium on the attachment of mesenchymal stem cells and osteoblast-like SaOS-2 cells. AB - Surface modification is an important step in production of medical implants. Surface roughening creates additional surface area to enhance the bonding between the implant and the bone. Recent research provided a means to alter the microstructure of titanium by severe plastic deformation (SPD) in order to increase its strength, and thereby reduce the size of the implants (specifically, their diameter). The purpose of the present study was to examine the effect of bulk microstructure of commercially pure titanium with coarse-grained (CG) and ultrafine-grained (UFG) bulk structure on the surface state of these materials after surface modification by sand blasting and acid etching (SLA). It was shown that SLA-modified surface characteristics, in particular, roughness, chemistry, and wettability, were affected by prior SPD processing. Additionally, biocompatibility of UFG titanium was examined using osteosarcoma cell line SaOS-2 and primary human adipose-derived mesenchymal stem cell (adMSC) cultures. Enhanced cell viability as well as increased matrix mineralization during osteogenic differentiation of MSCs on the surface of ultrafine-grained titanium was shown. PMID- 27987734 TI - Bioactivity and electrochemical behavior of hydroxyapatite-silicon-multi walled carbon nano-tubes composite coatings synthesized by EPD on NiTi alloys in simulated body fluid. AB - In order to improve the surface bioactivity of NiTi bone implant and corrosion resistance, hydroxyapatite coating with addition of 20wt% silicon, 1wt% multi walled carbon nano-tubes and both of them were deposited on a NiTi substrate using a cathodic electrophoretic method. The apatite formation ability was estimated using immersion test in the simulated body fluid for 10days. The SEM images of the surface of coatings after immersion in simulated body fluid show that the presence of silicon in the hydroxyapatite coatings accelerates in vitro growth of apatite layer on the coatings. The Open-circuit potential and electrochemical impedance spectroscopy were measured to evaluate the electrochemical behavior of the coatings in the simulated body fluid at 37 degrees C. The results indicate that the compact structure of hydroxyapatite 20wt% silicon and hydroxyapatite-20wt% silicon-1wt% multi walled carbon nano tubes coatings could efficiently increase the corrosion resistance of NiTi substrate. PMID- 27987736 TI - Biophysical and biological characterization of intraoral multilayer membranes as potential carriers: A new drug delivery system for dentistry. AB - The current study developed through layer-by-layer deposition a multilayer membrane for intraoral drug delivery and analyzed the biochemical, functional, and biological properties of this membrane. For that purpose, we designed a three layer chlorhexidine-incorporated membrane composed by pure chitosan and alginate. The biochemical, functional, and biological properties were analyzed by the following tests: degradation in saliva medium; controlled drug release; water absorption, mass loss; pH analysis; and biocompatibility through fibroblast cell viability by MTT assay. All tests were conducted at three different periods (24, 48 and 72hours). The results demonstrated that hybrid membranes composed by alginate and chitosan with glycerol had greater water absorption and mass loss in buffer solution and in artificial saliva. The controlled drug release test revealed that the hybrid membrane exhibited greater drug release (0.075%). All chlorhexidine-incorporated membranes reduced the cell viability, and chitosan membranes with and without glycerol did not interfere with fibroblast viability. The biochemical and biophysical characteristics of the designed membranes and the findings of cell viability tests indicate great potential for application in Dentistry. PMID- 27987737 TI - Pegylated and amphiphilic Chitosan coated manganese ferrite nanoparticles for pH sensitive delivery of methotrexate: Synthesis and characterization. AB - Magnetic nanoparticles (MNPs) are the major class of nanoparticles (NPs) with specific functional properties that make them good candidates for biomedical applications. Due to their response to the magnetic field, they can be used in targeted drug delivery systems. In current research, the MNPs were synthesized with the general formula of Fe1-xMnxFe2O4 by the co-precipitation technique. First, the effect of the Fe2+ ions in the system was investigated. Succinic anhydride was used as the first stabilizer to prepare surface for binding two types of polymer, including Polyethylene glycol (PEG) and palmitoylated Polyethylene glycol-grafted Chitosan (Cs-PEG-PA) were introduced as a polymeric shell. The composition, size, structure and magnetic properties of NPs were determined by the particle size analysis (PSA), X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR) and vibrating sample magnetometer (VSM). Determining the well-defined properties of MNPs, methotrexate (MTX), as a common anticancer drug, was encapsulated into the coated MNPs. The drug encapsulation efficiency was as high as 92.8% with the magnetization value of 19.7emu/g. The in-vitro release pattern was studied, showing only 6% of the drug release in pH=7.4 (as a model of the physiological environment) and 25% in pH=5.4 (as a model of the tumor tissue environment) after 72h. Based on these results, we may be able to introduce this specific system as a novel pH sensitive MNP system for MTX targeting to tumor tissues in cancer chemotherapy. PMID- 27987738 TI - Fabrication and evaluation of chitosan/NaYF4:Yb3+/Tm3+ upconversion nanoparticles composite beads based on the gelling of Pickering emulsion droplets. AB - The rare earth ion doped upconversion nanoparticles (UCNPs) synthesized by hydrophobic organic ligands possess poor solubility and low fluorescence quantum yield in aqueous media. To conquer this issue, NaYF4:Yb3+/Tm3+ UCNPs, synthesized by a hydrothermal method, were coated with F127 and then assembled with chitosan to fabricate the chitosan/NaYF4:Yb3+/Tm3+ composite beads (CS/NaYF4:Yb3+/Tm3+ CBs) by Pickering emulsion system. The characterization results revealed that the as-synthesized NaYF4:Yb3+/Tm3+ UCNPs with an average size of 20nm exhibited spherical morphology, high crystallinity and characteristic emission upconversion fluorescence with an overall blue color output. The NaYF4:Yb3+/Tm3+ UCNPs were successfully conjugated on the surface of chitosan beads by the gelling of emulsion droplets. The resultant CS/NaYF4:Yb3+/Tm3+ CBs showed good upconversion luminescent property, drug-loading capacity, release performance and excellent biocompatibility, exhibiting great potentials in targeted drug delivery and tissue engineering with potential tracking capability and lasting release performance. PMID- 27987739 TI - Microstructure, mechanical behavior and biocompatibility of powder metallurgy Nb Ti-Ta alloys as biomedical material. AB - Microstructures, mechanical properties, apatite-forming ability and in vitro experiments were studied for Nb-25Ti-xTa (x=10, 15, 20, 25, 35at.%) alloys fabricated by powder metallurgy. It is confirmed that the alloys could achieve a relative density over 80%. Meanwhile, the increase in Ta content enhances the tensile strength, elastic modulus and hardness of the as-sintered alloys. When increasing the sintering temperatures, the microstructure became more homogeneous for beta phase, resulting in a decrease in the modulus and strength. Moreover, the alloys showed a good biocompatibility due to the absence of cytotoxic elements, and were suitable for apatite formation and cell adhesion. In conclusion, Nb-25Ti-xTa alloys are potentially useful in biomedical applications with their mechanical and biological properties being evaluated in this work. PMID- 27987740 TI - A graded nano-TiN coating on biomedical Ti alloy: Low friction coefficient, good bonding and biocompatibility. AB - In order to solve wear resistance of Ti alloy biomaterials, the concept of a graded nano-TiN coating has been proposed. The coating was prepared on Ti-6Al-4V bio-alloy by DC reactive magnetron sputtering. The wear performance of the coated specimens was measured in Hank's solution under the load of 10N, and the biocompatibility was evaluated according to ISO-10993-4 standard. The results show that the gradient coating exhibits a gradual change in compositions and microstructures along the direction of film growth. Nano-TiN with the size of several to dozens nanometers and Ti4N3-x transitional phase with variable composition form a graded composite structure, which significantly improves adhesion strength (Lc1=80N, Lc2=120N), hardness (21GPa) and anti-wear performance (6.2*10-7mm3/Nm). The excellent bonding and wear resistance result from a good match of mechanical properties at substrate/coating interface and the strengthening and toughening effects of the nanocrystalline composite. The nano TiN coating has also been proved to have good biocompatibility through in-vitro cytotoxicity, hemocompatibility and general toxicity tests. And thus, the proposed graded nano-TiN coating is a good candidate improving wear resistance of many implant medical devices. PMID- 27987741 TI - A novel nanoparticles impregnated ocular insert for enhanced bioavailability to posterior segment of eye: In vitro, in vivo and stability studies. AB - The present investigation was carried out to demonstrate with the help of in vitro and in vivo studies that nanoparticles impregnated ocular inserts effectively delivers significant concentration of drug to the posterior segment of eye after topical administration for treatment of glaucoma. Drug loaded Nanoparticles and their ocular insert have been reported to reduce side effects of orally administered Acetazolamide. Eudragit NPs were prepared by the solvent diffusion nanoprecipitation technique. The prepared NPs were evaluated for various parameters such as particle size, zeta potential, % entrapment efficiency, % drug loading, DSC, FTIR, TEM and stability studies. Ocular inserts of NPs were prepared by solvent casting method. The prepared ocular inserts were evaluated for thickness, content uniformity, folding endurance, disintegration time, morphology and stability study. The NPs and ocular inserts were evaluated for in-vitro drug diffusion study, ex-vivo trans-corneal permeability study, in vivo ocular tolerability and intra ocular pressure (IOP) reduction study. The optimized batch was stable for a period of 3months in lyophilized form. The optimized formulations had size range of 367nm+/-8nm, zeta potential around +7mV+/-1.3mV and 51.61%+/-3.84% entrapment efficiency with 19%+/-1.40% drug loading. The ex-vivo trans-corneal study showed higher cumulative corneal permeation, flux across corneal tissue (2.460+/-0.028MUg/ml) and apparent corneal permeability (3.926*10-6cm2/s & 3.863*10-6cm2/s) from drug loaded Eudragit NPs and Ocular inserts as compared to drug solution (0.671+/-0.020MUg/ml & 3.166*10 6cm2/s). In-vivo study showed the Eudragit NPs and ocular insert produced significant (P<0.001) lowering in intra ocular pressure compared with the solution of free drug after 3h of topical ocular administration. Plain Eudragit NPs caused no inflammation and/or discomfort in rabbit eyes and neither affected the intra ocular pressure establishing their safety and non irritancy. PMID- 27987742 TI - Preparation, properties and anticancer effects of mixed As4S4/ZnS nanoparticles capped by Poloxamer 407. AB - Arsenic sulfide compounds have a long history of application in a traditional medicine. In recent years, realgar has been studied as a promising drug in cancer treatment. In this study, the arsenic sulfide (As4S4) nanoparticles combined with zinc sulfide (ZnS) ones in different molar ratio have been prepared by a simple mechanochemical route in a planetary mill. The successful synthesis and structural properties were confirmed and followed via X-ray diffraction and high resolution transmission electron microscopy measurements. The morphology of the particles was studied via scanning electron microscopy and transmission electron microscopy methods and the presence of nanocrystallites was verified. For biological tests, the prepared As4S4/ZnS nanoparticles were further milled in a circulation mill in a water solution of Poloxamer 407 (0.5wt%), in order to cover the particles with this biocompatible copolymer and to obtain stable nanosuspensions with unimodal distribution. The average size of the particles in the nanosuspensions (~120nm) was determined by photon cross-correlation spectroscopy method. Stability of the nanosuspensions was determined via particle size distribution and zeta potential measurements, confirming no physico-chemical changes for several months. Interestingly, with the increasing amount of ZnS in the sample, the stability was improved. The anti-cancer effects were tested on two melanoma cell lines, A375 and Bowes, with promising results, confirming increased efficiency of the samples containing both As4S4 and ZnS nanocrystals. PMID- 27987743 TI - Reconciling in vivo and in vitro kinetics of the polymorphic transformation in zirconia-toughened alumina for hip joints: III. Molecular scale mechanisms. AB - Understanding the intrinsic reason(s) for the enhanced tetragonal to monoclinic (t->m) polymorphic phase transformation observed on metal-stained surfaces of zirconia-toughened alumina (ZTA) requires detailed knowledge of off-stoichiometry reactions at the molecular scale. In this context, knowledge of the mechanism(s) for oxygen vacancy creation or annihilation at the material surface is a necessary prerequisite. The crucial aspect of the surface destabilization phenomenon, namely the availability of electrons and holes that allow for vacancy creation/annihilation, is elucidated in this paper. Metal-enhanced alterations of the oxygen sublattice in both Al2O3 and ZrO2 of the ZTA composite play a decisive role in accelerating the polymorphic transformation. According to spectroscopic evidences obtained through nanometer-scale analyses, enhanced annihilation of oxygen vacancies triggers polymorphic transformation in ZrO2 near the metal stain, while the overall Al2O3 lattice tends to dehydroxylate by forming oxygen vacancies. A mechanism for chemically driven "reactive metastability" is suggested, which results in accelerating the polymorphic transformation. The Al2O3 matrix is found to play a key-role in the ZrO2 transformation process, with unambiguous confirmation of oxygen and hydrogen transport at the material surface. It is postulated that this transport is mediated by migration of dissociated O and H elements at the surface of the stained transition metal as they become readily available by the thermally activated surrounding. PMID- 27987744 TI - High-definition micropatterning method for hard, stiff and brittle polymers. AB - Polystyrene (PS) is the most commonly used material in cell culture devices, such as Petri dishes, culture flasks and well plates. Micropatterning of cell culture substrates can significantly affect cell-material interactions leading to an increasing interest in the fabrication of topographically micro-structured PS surfaces. However, the high stiffness combined with brittleness of PS (elastic modulus 3-3.5GPa) makes high-quality patterning into PS difficult when standard hard molds, e.g. silicon and nickel, are used as templates. A new and robust scheme for easy processing of large-area high-density micro-patterning into PS film is established using nanoimprinting lithography and standard hot embossing techniques. Including an extra step through an intermediate PDMS mold alone does not result in faithful replication of the large area, high-density micropattern into PS. Here, we developed an approach using an additional intermediate mold out of OrmoStamp, which allows for high-quality and large-area micro-patterning into PS. OrmoStamp was originally developed for UV nanoimprint applications; this work demonstrates for the first time that OrmoStamp is a highly adequate material for micro-patterning of PS through hot embossing. Our proposed processing method achieves high-quality replication of micropatterns in PS, incorporating features with high aspect ratio (4:1, height:width), high density, and over a large pattern area. The proposed scheme can easily be adapted for other large-area and high-density micropatterns of PS, as well as other stiff and brittle polymers. PMID- 27987745 TI - Fabrication of oxide layer on zirconium by micro-arc oxidation: Structural and antimicrobial characteristics. AB - The aim of this study was to cover the surfaces of zirconium (Zr) with an antimicrobial layer for biomedical applications. For this purpose, the micro-arc oxidation (MAO) process was employed in a sodium silicate and sodium hydroxide containing base electrolyte with and without addition of silver acetate (AgC2H3O2). In general, synthesized MAO layers were composed of zirconium oxide (ZrO2) and zircon (ZrSiO4). Addition of AgC2H3O2 into the base electrolyte caused homogenous precipitation of silver-containing particles in the MAO layer, which exhibited excellent antibacterial efficiency against methicillin-resistant Staphylococcus aureus (MRSA) as compared to the untreated and MAO-treated Zr. PMID- 27987746 TI - Chitosan-based particles: The (forgotten) interplay between process, properties and performance. PMID- 27987747 TI - Highly selective solid phase extraction and preconcentration of Azathioprine with nano-sized imprinted polymer based on multivariate optimization and its trace determination in biological and pharmaceutical samples. AB - In this research, for first time selective separation and determination of Azathioprine is demonstrated using molecularly imprinted polymer as the solid phase extraction adsorbent, measured by spectrophotometry at lambdamax 286nm. The selective molecularly imprinted polymer was produced using Azathioprine and methacrylic acid as a template molecule and monomer, respectively. A molecularly imprinted solid-phase extraction procedure was performed in column for the analyte from pharmaceutical and serum samples. The synthesized polymers were characterized by infrared spectroscopy (IR), field emission scanning electron microscopy (FESEM). In order to investigate the effect of independent variables on the extraction efficiency, the response surface methodology (RSM) based on Box Behnken design (BBD) was employed. The analytical parameters such as precision, accuracy and linear working range were also determined in optimal experimental conditions and the proposed method was applied to analysis of Azathioprine. The linear dynamic range and limits of detection were 2.5-0.01 and 0.008mgL-1 respectively. The recoveries for analyte were higher than 95% and relative standard deviation values were found to be in the range of 0.83-4.15%. This method was successfully applied for the determination of Azathioprine in biological and pharmaceutical samples. PMID- 27987748 TI - Dual-modality NIRF-MRI cubosomes and hexosomes: High throughput formulation and in vivo biodistribution. AB - Engineered nanoparticles with multiple complementary imaging modalities are of great benefit to the rapid treatment and diagnosis of disease in various organs. Herein, we report the formulation of cubosomes and hexosomes that carry multiple amphiphilic imaging contrast agents in their self-assembled lipid bilayers. This is the first report of the use of both near infrared fluorescent (NIRF) imaging and gadolinium lipid based magnetic resonance (MR) imaging modalities in cubosomes and hexosomes. High-throughput screening was used to rapidly optimize formulations with desirable nano-architectures and low in vitro cytotoxicity. The dual-modal imaging nanoparticles in vivo biodistribution and organ specific contrast enhancement were then studied. The NIRF in vivo imaging results indicated accumulation of both cubosomes and hexosomes in the liver and spleen of mice up to 20h post-injection. Remarkably, the biodistribution of the nanoparticle formulations was affected by the mesophase (i.e. cubic or hexagonal), a finding of significant importance for the future use of these compounds, with hexosomes showing higher accumulation in the spleen than the liver compared to cubosomes. Furthermore, in vivo MRI data of animals injected with either type of lyotropic liquid crystal nanoparticle displayed enhanced contrast in the liver and spleen. PMID- 27987749 TI - Poly(acrylic acid) conjugated hollow mesoporous carbon as a dual-stimuli triggered drug delivery system for chemo-photothermal synergistic therapy. AB - In this work, we described the development of the redox and pH dual stimuli responsive drug delivery system and combination of the chemotherapy and photothermal therapy for cancer treatment. The poly(acrylic acid) (PAA) was conjugated on the outlets of hollow mesoporous carbon (HMC) via disulfide bonds. PAA was used as a capping to block drug within the mesopores of HMC for its lots of favorable advantages, such as good biocompatibility, appropriate molecular weight to block the mesopores of HMC, extension of the blood circulation, and the improvement of the dispersity of the nano-carriers in physiological environment. The DOX loaded DOX/HMC-SS-PAA had a high drug loading amount up to 51.9%. The in vitro drug release results illustrated that DOX/HMC-SS-PAA showed redox and pH dual-responsive drug release, and the release rate could be further improved by the near infrared (NIR) irradiation. Cell viability experiment indicated that DOX/HMC-SS-PAA had a synergistic therapeutic effect by combination of chemotherapy and photothermal therapy. This work suggested that HMC-SS-PAA exhibited dual-responsive drug release property and could be used as a NIR adsorbing drug delivery system for chemo-photothermal synergistic therapy. PMID- 27987751 TI - Study of in vitro bioactivity and mechanical properties of diopside nano bioceramic synthesized by a facile method using eggshell as raw material. AB - In this study, diopside bioceramic was synthesized using a mechanical milling process and subsequent heat treatment. The simplicity of experiments and also the high energy available in ball milling lead to rapid synthesis of the products in comparison with other synthesis methods. Magnesium oxide (MgO), silicon dioxide (SiO2) and eggshell (as the calcium source) powders were weighted in stoichiometric conditions and milled to initial activation of the surface of the powder's mixture. Then a sintering process was conducted to complete formation of diopside nanopowder and also evaluates its thermal stability. The mechanisms occurred during the synthesis of this bioceramic were carefully investigated. X Ray diffraction analysis (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), thermogravimetry (TG), differential thermal analysis (DTA), and inductive coupled plasma atomic emission spectroscopy (ICP-AES) were used for gathering and analyzing data. The ability and rate of apatite formation on the sample surface were evaluated by Simulated Body Fluid (SBF) test, a method that is well recognized to characterize the in vitro bioactivity of ceramic materials. According to the results obtained, the diopside samples had a significant potential to form apatite layer on their surface during soaking in the SBF solution. Besides, the bonding strength of this bioceramic was about 350+/-7MPa which was almost more than three times of that reported for hydroxyapatite. An excellent fracture toughness of 4+/-0.3MPam0.5 was also obtained for this ceramic which was higher than that of previously reported works. PMID- 27987750 TI - In vitro corrosion properties and cytocompatibility of Fe-Ga alloys as potential biodegradable metallic materials. AB - The in vitro biodegradable properties and cytocompatibility of Fe-Ga alloys including Fe81Ga19, (Fe81Ga19)98B2 and (Fe81Ga19)99.5(TaC)0.5, and pure Fe were investigated for biomedical applications. The microstructure of the alloys was characterized using X-ray diffraction spectroscopy and optical microscopy. The results showed that A2 and D03 phases were detected for the three types of Fe-Ga alloys, and additional Fe2B and TaC phases were found in the (Fe81Ga19)98B2 and (Fe81Ga19)99.5(TaC)0.5 alloys, respectively. The corrosion rates of the Fe-Ga alloys were higher than that of pure Fe, as demonstrated by both potentiodynamic polarization measurements and immersion tests in simulated body fluid. The alloying element Ga lowered the corrosion potential of the Fe matrix and made it more susceptible to corrosion. Severe pitting corrosion developed on the surface of the Fe81Ga19 alloy after the addition of ternary B or TaC due to the multi phase microstructures. The MC3T3-E1 cells exhibited good adhesion and proliferation behavior on the surfaces of the Fe-Ga alloys after culture for 4h and 24h. PMID- 27987752 TI - Ofloxacin loaded gellan/PVA nanofibers - Synthesis, characterization and evaluation of their gastroretentive/mucoadhesive drug delivery potential. AB - The purpose of this investigation is to formulate a gastroretentive sustained drug release system for ofloxacin to improve its retention time, pharmacological activity, bioavailability and therapeutic efficacy in the stomach. Ofloxacin loaded gellan/poly vinyl alcohol (PVA) nanofibers were fabricated using a simple and versatile electrospinning technique. The fabricated nanofibers were evaluated for percent drug encapsulation efficiency and in vitro drug release in simulated gastric medium (pH1.2). The in vitro release profile and kinetic studies for drug indicated the sustained release of ofloxacin from the nanofibers through Fickian diffusion kinetics. The antimicrobial activity of the ofloxacin loaded nanofibers was assessed in comparison to the pure ofloxacin by means of minimal inhibitory concentrations (MIC) against microbial strains of Enterococcus faecalis, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The optimized ofloxacin loaded gellan/PVA nanofibers displayed biphasic drug release profile with considerable mucoadhesion and gastric retention in the rat's gastric mucosal membrane. Data obtained, suggested that the developed gastroretentive drug delivery can potentially enhance the pharmacological activity of ofloxacin and can also serve as a viable alternative for improving drug bioavailability via oral route. PMID- 27987753 TI - Sequel of MgO nanoparticles in PLACL nanofibers for anti-cancer therapy in synergy with curcumin/beta-cyclodextrin. AB - Pharmaceutical industries spend more money in developing new and efficient methods for delivering successful drugs for anticancer therapy. Electrospun nanofibers and nanoparticles loaded with drugs have versatile biomedical applications ranging from wound healing to anticancer therapy. We aimed to attempt for fabricating elastomeric poly (l-lactic acid-co-epsilon-caprolactone) (PLACL) with Aloe Vera (AV), magnesium oxide (MgO) nanoparticles, curcumin (CUR) and beta-cyclodextrin (beta-CD) composite nanofibers to control the growth of MCF 7 cells for breast cancer therapy. The study focused on the interaction of MgO nanoparticle with CUR and beta-CD inhibiting the proliferation of Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. FESEM micrographs of fabricated electrospun PLACL, PLACL/AV, PLACL/AV/MgO, PLACL/AV/MgO/CUR and PLACL/AV/MgO/beta CD nanofibrous scaffolds achieved bead free, random and uniform nanofibers with fiber diameter in the range of 786+/-286, 507+/-171, 334+/-95, 360+/-94 and 326+/ 80nm respectively. Proliferation of MCF-7 cells was decreased by 65.92% in PLACL/AV/MgO/CUR with respect to PLACL/AV/MgO nanofibrous scaffolds on day 9. The obtained results proved that 1% CUR interacting with MgO nanoparticles showed higher inhibition of MCF-7 cells among all other nanofibrous scaffolds thus serving as a promising biocomposite material system for the breast cancer therapy. PMID- 27987754 TI - Incorporation of biguanide compounds into poly(GL)-b-poly(GL-co-TMC-co-CL)-b poly(GL) monofilament surgical sutures. AB - A new biodegradable coating was developed for bioabsorbable monofilament sutures. Specifically, a random copolymer having 35wt-% and 65wt-% of lactide and trimethylene carbonate units showed appropriate flexibility, stickiness and degradation rate, as well as capability to produce a complete and uniform coating. Monofilament sutures of polyglycolide-b-poly(glycolide-co-trimethylene carbonate-co-epsilon-caprolactone)-b-polyglycolide were loaded with chlorhexidine (CHX) and poly(hexamethylene biguanide) (PHMB) to explore the possibility to achieve antimicrobial activity without adverse cytotoxic effects. To this end, two processes based on single drug adsorption onto the suture surface and incorporation into the coating copolymer were used and subsequently evaluated. Although the second process could be considered more complex, clear benefits were observed in terms of drug loading efficiency, antimicrobial effect and even lack of cytotoxicity. In general, drugs could be loaded in an amount leading to a clear bacteriostatic effect for both Gram-negative and Gram-positive bacteria without causing significant cytotoxicity. Release profiles of PHMB and CHX were clearly different. Specifically, adsorption of the drug onto the fiber surface which prevented complete release was detected for PHMB. This polymer had advantages derived from its high molecular size, which hindered penetration into cells, thus resulting in lower cytotoxicity. Furthermore, bacterial growth kinetics measurements and bacterial adhesion assays showed greater effectiveness of this polymer. PMID- 27987755 TI - Controlled release of cefazolin sodium antibiotic drug from electrospun chitosan polyethylene oxide nanofibrous Mats. AB - Antimicrobial electrospun chitosan-polyethylene oxide (CS-PEO) nanofibrous mats containing cefazolin, fumed silica (F. silica) and cefazolin-loaded fumed silica nanoparticles (NPs) were produced for biomedical applications. The FE-SEM images revealed that the F. silica and F. silica-cefazolin NPs had average diameters of 40+/-10 and 60+/-15nm, respectively. Also, the fibers diameters were approximately 160+/-30, 90+/-20 and 70+/-15nm for the pure CS-PEO, CS-PEO-1% F. silica and CS-PEO-1% F. silica-0.5% cefazolin nanofibrous mats, respectively indicating addition of F. silica and cefazolin loaded F. silica NPs to the CS-PEO mat led to decreasing the nanofiber diameter. Both of the CS-PEO mats containing 2.5% cefazolin and 1% F. silica-0.50% cefazolin showed 100% bactericidal activities against both S. aureus and E. coli bacteria. The cefazolin release from mats was sharply increased within first 24 and 6hours for the CS-PEO mats including 2.5% cefazolin and 1% F. silica-0.50% cefazolin but after that the drug was released very slowly. The improved hydrophilicity, higher tensile strength and sustained drug release for CS-PEO-1% F. silica-0.50% cefazolin suggested that it was the best nanocomposite tissue/device for biomedical applications among the mats CS-PEO-2.5% cefazolin and CS-PEO-1% F. silica. The wound healing ability of the CS-PEO-F. silica-cefazolin mat was evaluated on the wounded skins of the female Wistar rats and it was shown that the wounded skins of the rats were almost entirely healed after ten days using this mat as a wound dressing scaffold. PMID- 27987756 TI - Synthesis and characterization of strontium-substituted hydroxyapatite nanoparticles for bone regeneration. AB - The production of stable suspensions of strontium-substituted hydroxyapatite (Sr HA) nanopowders, as Sr ions vector for bone tissue regeneration, was carried out in the present work. Sr-HA nanopowders were synthesized via aqueous precipitation methods using Sr2+ amount from 0 to 100mol% and were characterized by several complementary techniques such as solid-state Nuclear Magnetic Resonance spectroscopy, X-ray diffraction, Infrared spectroscopy, N2 physisorption and Transmission Electron Microscopy. The substitution of Ca2+ with Sr2+ in HA is always isomorphic with gradual evolution between the two limit compositions (containing 100% Ca and 100% Sr), this pointing out the homogeneity of the synthesized nanopowders and the complete solubility of strontium in HA lattice. Strontium addition is responsible for an increasing c/a ratio in the triclinic unit cell. A significant variation of the nanopowders shape and dimension is also observed, a preferential growth along the c-axis direction being evident at higher strontium loads. Modifications in the local chemical environment of phosphate and hydroxyl groups in the apatite lattice are also observed. Stable suspensions were produced by dispersing the synthesized nanopowders in bovine serum albumin. Characterization by Dynamic Light Scattering and zeta-potential determination allowed to show that Ca2+->Sr2+ substitution influences the hydrodynamic diameter, which is always twice the particles size determined by TEM, the nanoparticles being always negatively charged as a result from the albumin rearrangement upon the interaction with nanoparticles surface. The biocompatibility of the suspensions was studied in terms of cell viability, apoptosis, proliferation and morphology, using osteosarcoma cell line SAOS-2. The data pointed out an increased cell proliferation for HA nanoparticles containing larger Sr2+ load, the cells morphology remaining essentially unaffected. PMID- 27987757 TI - In situ production of silver nanoparticles for high sensitive detection of ascorbic acid via inner filter effect. AB - In the present research, a sensitive biosensing method was proposed for the detection of trace amounts of ascorbic acid (AA). Herein, colloidal silver nanoparticles (SNPs) were successfully in-situ produced by chemical reduction of silver ion in the presence of AA, as a reducing agent. The one-pot in-situ produced silver nanoparticles were characterized by UV-vis, dynamic light scattering (DLS), zeta potential and transmission electron microscopic (TEM). SNPs act as a strong fluorescence quencher for the CdTe quantum dots via an inner filter effect (IFE). Since the absorption band of SNPs entirely covered both emission and excitation bands of QDs. Therefore, the decreasing in the fluorescence signal depends on the AA concentration in the linear range of 0.2 88.0ngmL-1 and with a detection limit of 0.02ngmL-1. Relative standard deviations of 2.3% and 2.8% (n=5) were achieved for the determination of 1.8 and 8.8ngmL-1 AA, respectively. This novel QDs nanosensor based on IFE could provide noticeable advantages of simplicity, convenience, cost-effectiveness, and sensitivity. This method was successfully applied for the detection of ascorbic acid in human real samples serums. PMID- 27987759 TI - Covalent and injectable chitosan-chondroitin sulfate hydrogels embedded with chitosan microspheres for drug delivery and tissue engineering. AB - Injectable hydrogels and microspheres derived from natural polysaccharides have been extensively investigated as drug delivery systems and cell scaffolds. In this study, we report a preparation of covalent hydrogels basing polysaccharides via the Schiff' base reaction. Water soluble carboxymethyl chitosan (CMC) and oxidized chondroitin sulfate (OCS) were prepared for cross-linking of hydrogels. The mechanism of cross-linking is attributed to the Schiff' base reaction between amino and aldehyde groups of polysaccharides. Furthermore, bovine serum albumin (BSA) loaded chitosan-based microspheres (CMs) with a diameter of 3.8-61.6MUm were fabricated by an emulsion cross-linking method, followed by embedding into CMC-OCS hydrogels to produce a composite CMs/gel scaffold. In the current work, gelation rate, morphology, mechanical properties, swelling ratio, in vitro degradation and BSA release of the CMs/gel scaffolds were examined. The results show that mechanical and bioactive properties of gel scaffolds can be significantly improved by embedding CMs. The solid CMs can serve as a filler to toughen the soft CMC-OCS hydrogels. Compressive modulus of composite gel scaffolds containing 20mg/ml of microspheres was 13KPa, which was higher than the control hydrogel without CMs. Cumulative release of BSA during 2weeks from CMs embedded hydrogel was 30%, which was significantly lower than those of CMs and hydrogels. Moreover, the composite CMs/gel scaffolds exhibited lower swelling ratio and slower degradation rate than the control hydrogel without CMs. The potential of the composite hydrogel as an injectable scaffold was demonstrated by encapsulation of bovine articular chondrocytes in vitro. These results demonstrate the potential of CMs embedded CMC-OCS hydrogels as an injectable drug and cell delivery system in cartilage tissue engineering. PMID- 27987758 TI - Nanostructured lipid dispersions for topical administration of crocin, a potent antioxidant from saffron (Crocus sativus L.). AB - Crocin, a potent antioxidant obtained from saffron, shows anticancer activity in in vivo models. Unfortunately unfavorable physicochemical features compromise its use in topical therapy. The present study describes the preparation and characterization of nanostructured lipid dispersions as drug delivery systems for topical administration of crocin and the evaluation of antioxidant and antiproliferative effects of crocin once encapsulated into nanostructured lipid dispersions. Nanostructured lipid dispersions based on monoolein in mixture with sodium cholate and sodium caseinate have been characterized by cryo-TEM and PCS. Crocin permeation was evaluated in vitro by Franz cells, while the oxygen radical absorbance capacity assay was used to evaluate the antioxidant activity. Furthermore, the antiproliferative activity was tested in vitro by the MTT test using a human melanoma cell line. The emulsification of monoolein with sodium cholate and sodium caseinate led to dispersions of cubosomes, hexasomes, sponge systems and vesicles, depending on the employed emulsifiers. Permeation and shelf life studies demonstrated that nanostructured lipid dispersions enabled to control both rate of crocin diffusion through the skin and crocin degradation. The oxygen radical absorbance capacity assay pointed out an interesting and prolonged antioxidant activity of crocin while the MTT test showed an increase of crocin cytotoxic effect after incorporation in nanostructured lipid dispersions. This work has highlighted that nanostructured lipid dispersions can protect the labile molecule crocin from degradation, control its skin diffusion and prolong antioxidant activity, therefore suggesting the suitability of nanostructured lipid dispersions for crocin topical administration. PMID- 27987761 TI - Investigation of holder pressure and size effects in micro deep drawing of rectangular work pieces driven by piezoelectric actuator. AB - Micro forming is a manufacturing process to fabricate micro parts with high quality and a cost effective manner. Deep drawing could be a favorable method for production of complicated parts in macro and micro sizes. In this paper piezoelectric actuator is used as a novel approach in the field of micro manufacturing. Also, in current work, investigations are conducted with four rectangular punches and blanks with various thicknesses. Blank holder pressure effects on thickness distributions, punch force, and springback are studied. According to the results of this work, increasing of blank holder pressure in scaled deep drawing, in contrast to thickness of drawn part, leads to decrease in the punch forces and springback. Furthermore, it is shown that in micro deep drawing, the effects of holder pressure on mentioned parameters can be ignored. PMID- 27987760 TI - Cell-laden 3D bioprinting hydrogel matrix depending on different compositions for soft tissue engineering: Characterization and evaluation. AB - Cell-printing techniques that can construct three-dimensional (3D) structures with biocompatible materials and cells are of great interest for various biomedical applications, such as tissue engineering and drug-screening studies. For successful cell-printing with cells, bioinks are critical for both the processability of printing and the viability of printed cells. However, the influence of composition on 3D bio-printing with cells has not been well explored. In this study, we investigated different compositions of alginate bioinks by varying the concentrations of high molecular weight alginate (High Alg) and low molecular weight alginate (Low Alg). Bioinks of 3wt% alginate containing High Alg alone or a 1:2 (Low Alg:High Alg) composite allowed for the construction of 3D scaffolds with good processability and shapes. Cell-printing with fibroblasts and in vitro culture studies revealed good viability and growth of the printed cells after up to 7days of culture. Bioinks prepared with High and Low Alg at a 2:1 ratio exhibited better cell growth compared with those of other compositions. This study progresses the design and applications of alginate-based bioinks for cell-printing platforms in soft tissue engineering. PMID- 27987762 TI - The use of abrasive polishing and laser processing for developing polyurethane surfaces for controlling fibroblast cell behaviour. AB - Studies have shown that surfaces having micro and nano-scale features can be used to control cell behaviours including; cell proliferation, migration and adhesion. The aim of this work was to compare the use of laser processing and abrasive polishing to develop micro/nano-patterned polyurethane substrates for controlling fibroblast cell adhesion, migration and proliferation. Laser processing in a directional manner resulted in polyurethane surfaces having a ploughed field effect with micron-scale features. In contrast, abrasive polishing in a directional and random manner resulted in polyurethane surfaces having sub-micron scale features orientated in a linear or random manner. Results show that when compared with flat (non-patterned) polymer, both the laser processed and abrasive polished surface having randomly organised features, promoted significantly greater cell adhesion, while also enhancing cell proliferation after 72h. In contrast, the abrasive polished surface having linear features did not enhance cell adhesion or proliferation when compared to the flat surface. For cell migration, the cells growing on the laser processed and abrasively polished random surface showed decreased levels of migration when compared to the flat surface. This study shows that both abrasive polishing and laser processing can be used to produce surfaces having features on the nano-scale and micron-scale, respectively. Surfaces produced using both techniques can be used to promote fibroblast cell adhesion and proliferation. Thus both methods offer a viable alternative to using lithographic techniques for developing patterned surfaces. In particular, abrasive polishing is an attractive method due to it being a simple, rapid and inexpensive method that can be used to produce surfaces having features on a comparable scale to more expensive, multi-step methods. PMID- 27987763 TI - Novel therapeutic intervention for osteoporosis prepared with strontium hydroxyapatite and zoledronic acid: In vitro and pharmacodynamic evaluation. AB - Osteoporosis therapeutics has been monopolized mainly by bisphosphonates, which are potent anti-osteoporotic drugs, while they do not promote bone formation or replenish the already resorbed bone. Although strontium substituted hydroxyapatite (SrHA) has been proclaimed to improve bone properties in an osteoporotic animal model, there is no published data on direct delivery of SrHA nanoparticles by bisphosphonate-like zoledronic acid (ZOL) to the bone. Therefore, this study was designed to investigate the potential of using SrHA/ZOL nanoparticle-based drug formulation in an ovariectomized rat model of postmenopausal osteoporosis. SrHA and SrHA/ZOL nanoparticles were prepared and characterized by field-emission scanning electron microscopy (FESEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Twelve weeks after ovariectomy, rats were treated with either single intravenous dose of SrHA/ZOL (100, 50 or 25MUg/kg); ZOL (100MUg/kg); or SrHA (100MUg/kg). Saline treated OVX and SHAM-OVX groups served as controls. The energy-dispersive X-ray (EDX) microanalysis of bone specimen obtained from SrHA/ZOL groups yielded range between 64.3+/-6.7 to 66.9+/-6.8 of calcium weight (wt) % and 1.64+/-0.6 to 1.74+/-0.8 of calcium/phosphorus (Ca/P) ratio which was significantly higher when compared with 39.7+/-9.3 calcium and 1.30+/-0.2 Ca/P ratio for OVX group. Moreover, the strontium wt% in SrHA/ZOL group (between 3.1+/-0.5 and 6.8+/-0.4) was significantly higher than SrHA group (1.8+/-0.9). These results confirmed targeted delivery of SrHA nanoparticles by ZOL to the bone. Therapy with SrHA/ZOL showed significant improvements in trabecular bone microarchitecture and mechanical strength as compared to ZOL or SrHA (p<0.05). Moreover, treatment with SrHA/ZOL significantly precluded an increase in serum bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase than either ZOL or SrHA (p<0.05). These results strongly implicate that SrHA/ZOL nanoparticle-based drug formulation showed better efficacy at a much lower dose of ZOL. SrHA/ZOL drug formulation has a therapeutic advantage over ZOL or SrHA monotherapy for experimental osteoporosis. PMID- 27987764 TI - Synthesis and antioxidant activity of star-shape phenolic antioxidants catalyzed by acidic nanocatalyst based on reduced graphene oxide. AB - Phenolic antioxidants play important role in prevention of oxidation in different industrials. The research objective in the current study was synthesis and evaluate of antioxidant activity of star-shape phenolic antioxidants. The synthetic compounds were prepared in the presence of sulfonated reduced graphene oxide. The antioxidant activity of synthesized compounds was investigated by spectrophotometrically method according to the DPPH assay. Overall, these compounds are potentially important antioxidant and also to limit activity of reactive oxygen species. PMID- 27987765 TI - Antibacterial and non-cytotoxic ultra-thin polyethylenimine film. AB - In recent years, a common strategy, to obtain more uniform and controlled synthesis of polyelectrolytes multilayers (PEMs), relies on a previous polyethylenimine (PEI) coating of the substrate surface. PEI is a synthetic cationic polymer which provides a positive charge distribution on the materials to be covered with PEMs. Despite being an important step, this pre-layer deposition is frequently overlooked and no comprehensive characterizations or deep discussions are reported in literature. In that sense, this work reports on the synthesis of a typical PEI film that works as a precursor for PEMs, and its detailed physicochemical characterization. As many PEMs are produced for antibacterial and biomedical applications, the cytotoxicity of the film was also tested using fibroblasts, and its antibacterial activity was studied using Staphylococcus aureus and Pseudomonas aeruginosa. Our results present the formation of an ultra-thin film of PEI with a thickness around 3.5nm, and with a significant percent of NH3+ (35% of the total amount of N) in its chemical structure; NH3+ is a key chemical group because it is considered an important bacterial killer agent. The film was stable and did not present important cytotoxic effect for fibroblasts up to 7days, contrary to other reports. Finally, the PEI film showed high antibacterial activity against the S. aureus strain: reductions in cell density were higher than 95% up to 24h. PMID- 27987766 TI - Fabrication of biodegradable composite microneedles based on calcium sulfate and gelatin for transdermal delivery of insulin. AB - To reduce the inconvenience and pain of subcutaneous needle injection, the calcium sulfate and gelatin biodegradable composite microneedle patches with high aspect-ratio microneedles (MNs) and a flexible substrate have been developed. The microneedles with an aspect-ratio approximate 6:1 exhibit excellent mechanical property which can achieve 0.4N for each needle. The cross-section views show the inside of microneedles that have abundant pores and channels which offer potential for different drug-release profiles. The preparation procedures, degradable property for the biodegradable composite microneedle patches are described in the paper. Insulin, the drug to control blood glucose levels in diabetic patients, has been embedded into the biodegradable composite MNs. The hypoglycemic effect for transdermal delivery of insulin is studied using diabetic Sprague-Dawley (SD) rats as models in vivo. After transdermal administration to the diabetic rats, the released insulin from biodegradable composite MNs exhibit an obvious and effective hypoglycemic effect for longer time compared with that of subcutaneous injection route. This work suggests that biodegradable composite MNs containing of insulin have a potential application in diabetes treatment via transdermal ingestion. PMID- 27987767 TI - Sustained drug release and electrochemical performance of ethyl cellulose magnesium hydrogen phosphate composite. AB - In this, a sol-gel method was applied to prepare ethyl cellulose-magnesium hydrogen phosphate (EC-MgHPO4) composite that can have potential applications in the sensory, pharmaceutical, and biomedical sectors. The formed composite was thoroughly characterized by making use of the instrumental analysis such as UV Vis, FT-IR, HRTEM, EDAX, SEM and XRD. For the composite, the other parameters determined includes the water uptake, porosity, thickness, bulk and tapped densities, angle of repose, Carr's index and Hausner ratio. From the results, the material found to exhibit good flowing properties with a Carr's index of 11.11%, Hausner ratio of 1.125, and angle of response of 33 degrees . The EDAX spectrum and HRTEM analysis confirmed for the composite formation and the particles size is investigated to be around 52nm. The surface porosity due to the EC matrices was confirmed by the SEM analysis, which further used for the loading of drug, Proguanil. In addition, the material's conductivity was studied by taking uni univalent electrolyte solution (KCl and NaCl) indicated that the conductivity follows the order of KCl>NaCl, while the activation energy obtained from Arrhenius method resembled that the conductivity is strongly influenced by the electrolyte type used. We found from the analysis that, with a decrease in the size of hydrated radii of ions, the conductivity of EC-MgHPO4 material also observed to be decreased in the order K+>Na+ and the material proved to be mechanically stable and can be operated over a range of pHs, temperatures, and electrolyte solutions. Further, the drug loading and efficiency studies indicated that the material can trap up to 80% of Proguanil (antimalarial drug) applied for its loading. The Proguanil drug release profiles confirmed for the controlled and sustained release from the EC-MgHPO4 matrix, as the material can release up to 87% of its total loaded drug over a 90min period. Finally, the cell viability and proliferation studies tested against two different cell cultures of BRL-3A rat liver and H9c2 cardiomyoblasts indicated the non-toxic nature and safer applicability of the EC-MgHPO4 (25-500MUg/mL, 24h). Overall, the results of the study confirm for the safer applicability of the composite towards biosensor, drug delivery, scaffolding, and bioanalytical (quality control) applications. PMID- 27987768 TI - Significance of surface functionalization of Gold Nanorods for reduced effect on IgG stability and minimization of cytotoxicity. AB - Gold nanorods (AuNRs) used for biomedical applications could be encountered by biomolecules in the bloodstream, of which IgG is the most abundant antibody. With a view to mitigate their side effect on encountered proteins, the effect of Au concentration (5-40MUM) and functionalization (CTAB-positive;PSS-negative; PEG neutral) of AuNRs was investigated on the stability of a model protein, IgG (1MUM). Electron microscopic images and particle size analyses indicated least aggregation behavior for PEG-AuNRs, which can be correlated to their neutral charge (from zeta potential analyses) or stearic hindrance of PEG chains. Variations in tryptophan domain were probed by UV-visible absorption and fluorescence quenching studies. Synchronous fluorescence study helped to provide information regarding variations in the hydrophobic region of IgG. The denaturation studies also indicated the stability of AuNR-IgG complex formation. These studies showed that positively charged IgG (pI: 7.8+/-1.0) was mostly affected by negatively charged PSS-AuNRs and least affected by PEG-AuNRs. This was verified by secondary structural investigations performed using CD and FTIR spectroscopy. For cytotoxicity studies on human lymphocytes, CTAB-AuNRs are known to show higher toxicity compared to PSS-AuNRs and PEG-AuNRs (least). Though PSS functionalized AuNRs were shown to affect cells to a lesser degree based on the negative charge of cell membrane, they could hamper with positively charged biomolecules in the bloodstream before they reach the target, which must also be considered for choosing the right AuNR functionalization. Thus, this work indicates the effect of different AuNR functionalization on protein and cellular toxicity and stresses the necessity to use neutral particles to mitigate their side effect for theranostic applications. PMID- 27987769 TI - Synthesis of the light/pH responsive polymer for immobilization of alpha-amylase. AB - In this study, light/pH responsive methoxy poly (ethylene glycol)-(5 propargylether-2-nitrobenzyl bromoisobutyrate)-poly methylacrylic acid-b polystyrene (mPEG-ONB-PMAA-b-PS) polymers were synthesized, and successfully utilized to fabricate micelles and immobilize alpha-amylase. The critical micelle concentrations (CMC) of the polymers were measured with Pyrene Fluorescent Probe Technique. The morphology and diameter of micelles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). In addition, the effects of pH, temperature and light-responsive on the catalytic activity were investigated. The optimized fabrication conditions of alpha-amylase loaded micelles which alpha-amylase gave the higher activity were as follows: Immobilization time, 60min; Immobilization temperature, 50 degrees C; enzyme concentration, 10UmL-1; PBS buffer, pH=5.4. alpha-Amylase immobilized in these micelles was much more stable than that free alpha-amylase. PMID- 27987770 TI - Surface characterization of polymers used in fabrication of interim prostheses after treatment with photopolymerized glaze. AB - The material used for interim prostheses fabrication must present excellent physical properties for greater longevity in the face of environmental conditions, which can occur in the oral cavity. The purpose of this study was to evaluate the effect of a photopolymerized glaze on the physical and mechanical properties of polymers used for the fabrication of interim prostheses, before and after thermocycling and immersion in staining solutions. One hundred samples of composite and acrylic resins were fabricated: Dencor chemically activated acrylic resin (CAAR) (n=20) and heat-polymerized acrylic resin (HPAR) (n=20), Charisma (n=20), Structur (n=20), and Protemp (n=20). A mechanical polishing was performed on half of the samples, and a chemical polishing was performed on the remaining samples. Subsequently, all samples were submitted to thermocycling and immersion in coffee staining solution for 21days. Analysis of color and microhardness, as well as atomic force microscopy (AFM), scanning electron microscopy (SEM), and energy dispersive x-ray spectrometry (EDS) were performed. The data were submitted to repeated-measures analysis of variance (ANOVA), followed by the Tukey test (alpha=0.05) and the Student t-test (alpha=0.05). It was verified that the glaze decreased the chromatic alteration values, and increased the microhardness values of the samples, with the exception of the Charisma resin. The samples that did not receive chemical polishing had the greatest number of surface irregularities. This study concluded that the groups with glaze presented less color alteration. In addition, Charisma and Structur resins exhibited the greatest chromatic stability. As to the microhardness, the values were greater when the samples were treated with the glaze, with the exception of the Charisma group. PMID- 27987771 TI - Adhesion and metabolic activity of human corneal cells on PCL based nanofiber matrices. AB - In this work, polycaprolactone (PCL) was used as a basic polymer for electrospinning of random and aligned nanofiber matrices. Our aim was to develop a biocompatible substrate for ophthalmological application to improve wound closure in defects of the cornea as replacement for human amniotic membrane. We investigated whether blending the hydrophobic PCL with poly (glycerol sebacate) (PGS) or chitosan (CHI) improves the biocompatibility of the matrices for cell expansion. Human corneal epithelial cells (HCEp) and human corneal keratocytes (HCK) were used for in vitro biocompatibility studies. After optimization of the electrospinning parameters for all blends, scanning electron microscopy (SEM), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), and water contact angle were used to characterize the different matrices. Fluorescence staining of the F-actin cytoskeleton of the cells was performed to analyze the adherence of the cells to the different matrices. Metabolic activity of the cells was measured by cell counting kit-8 (CCK-8) for 20days to compare the biocompatibility of the materials. Our results show the feasibility of producing uniform nanofiber matrices with and without orientation for the used blends. All materials support adherence and proliferation of human corneal cell lines with oriented growth on aligned matrices. Although hydrophobicity of the materials was lowered by blending PCL, no increase in biocompatibility or proliferation, as was expected, could be measured. All tested matrices supported the expansion of human corneal cells, confirming their potential as substrates for biomedical applications. PMID- 27987772 TI - Effect of immersion time on the passive and electrochemical response of annealed and nano-grained commercial pure titanium in Ringer's physiological solution at 37 degrees C. AB - In the present study, various electrochemical tests were used to investigate the passive and electrochemical response of annealed and nano-grained commercial pure Titanium in Ringer's physiological solution at 37 degrees C. Nano-grained pure Titanium, which typically has an average grain size of 90+/-5nm, was obtained by six-cycle accumulative roll bonding process. Polarization and electrochemical impedance spectroscopy plots illustrated that as a result of grain refinement process, the passive response of the nano-grained sample was improved compared to that of its coarse-grained counterpart in Ringer's physiological solution. Mott Schottky analysis indicated that the passive films behaved as n-type semiconductors in Ringer's physiological solution and grain refinement did not change the conductivity type of the passive films. Additionally, Mott-Schottky analysis showed that the donor density decreased by grain size reduction. Finally, nano-grained sample appeared to be more suitable for implant applications, mainly due to the formation of thicker and less defective oxide film. PMID- 27987774 TI - Effect of high energy electron beam (10MeV) on specific heat capacity of low density polyethylene/hydroxyapatite nano-composite. AB - In the present work, thermal properties of low density polyethylene (LDPE) and its nano composites are investigated. For this purpose LDPE reinforced with different weight percents of hydroxyapatite (HAP) powder which was synthesized via hydrolysis method are produced. The samples were irradiated with 10MeV electron beam at doses of 75 to 250kGy. Specific heat capacity measurement have been carried out at different temperatures, i.e. 25, 50, 75 and 100 degrees C using modulated temperature differential scanning calorimetry (MTDSC) apparatus and the effect of three parameters include of temperature, irradiation dose and the amount of HAP nano particles as additives on the specific heat capacity of PE/HAP have been investigated precisely. The MTDSC results indicate that the specific heat capacity have decreased by addition of nano sized HAP as reinforcement for LDPE. On the other hand, the effect of radiation dose is reduction in the specific heat capacity in all materials including LDPE and its nano composites. The HAP nano particles along with cross-link junctions due to radiation restrain the movement of the polymer chains in the vicinity of each particle and improve the immobility of polymer chains and consequently lead to reduction in specific heat capacity. Also, the obtained results confirm that the radiation effect on the specific heat capacity is more efficient than the reinforcing effect of nano-sized hydroxyapatite. PMID- 27987773 TI - Scaffolds of hydroxyl apatite nanoparticles disseminated in 1, 6 diisocyanatohexane-extended poly(1, 4-butylene succinate)/poly(methyl methacrylate) for bone tissue engineering. AB - Poly(1, 4-butyl succinate) extended 1, 6-diisocyanatohexane (PBSu-DCH) polymers and Polymethylmethacrylate (PMMA) scaffolds decorated with nano hydroxyl apatite have been prepared and characterized for regeneration of bone in cranio maxillofacial region. Synthesized scaffolds revealed good response in bone regeneration and excellent cell viability in comparison to commercial available glass plate, which lead to better proliferation of MG-63 cell lines. Additionally, they demonstrate high porosity and excellent water retention ability. Moreover, controlled degradation (in pH=7.4) and sustained drug release in pH (4.5 and 7.4) are advantages of these scaffolds to serve as delivery vehicles for therapeutic drugs. Samples also provide the protection against Escherichia coli and Methicillin Resistant Staphylococcus aureus microorganisms which can be helpful for quick recovery of the patient. In-vitro inflammatory response has been assessed via adsorption of human plasma/serum proteins on the surface of the scaffolds. Results suggest that prepared scaffolds have good bone regeneration ability and provide friendly environment for the cell growth with the additional advantage of protection of the surrounding tissues from microbial infection. With all these features, it is speculated that these scaffolds will have wide utility in the area of tissue engineering and regenerative medicine. PMID- 27987775 TI - Zein/Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) electrospun blend fiber scaffolds: Preparation, characterization and cytocompatibility. AB - In the present work, a series of Zein/Poly(3-hydroxybutyrate-co-4 hydroxybutyrate) blend fiber scaffolds have been prepared by electrospinning method. The electrospun fibers showed a circular and uniform morphology with random distribution. The blend fiber scaffolds possessed well interconnected porous fibrous network structure with high porosity and large aspect surface areas. The FTIR and XPS spectra of Zein/P(3HB-co-4HB) blend fibers demonstrated the same characteristics to that of pure Zein and P(3HB-co-4HB) electrospun fibers. However, Zein might hinder the crystallization of P(3HB-co-4HB) owing to the formation of weak intermolecular interactions, which can affect the preferential orientation of P(3HB-co-4HB) molecules. Only one glass transition temperature (Tg) can be detected for electrospun Zein/P(3HB-co-4HB) blend fiber scaffolds implying the miscibility of Zein and P(3HB-co-4HB) in the blend fibers. The Zein/P(3HB-co-4HB) blend fiber scaffolds showed about 50% of improvement in tensile strength and 400% of increase in elongation at break by increasing P(3HB co-4HB) content from 20% to 80%. The cytocompatibility of the Zein/P(3HB-co-4HB) blend fiber scaffolds was preliminarily evaluated by cell culture in vitro. The as-prepared electrospun Zein/P(3HB-co-4HB) blend fiber scaffolds with the characteristics of good biocompatibility, excellent pore characteristic as well as sufficient mechanical properties should be more promising for applications as tissue engineering scaffold. PMID- 27987776 TI - Microstructure and mechanical properties of biodegradable poly (D/L) lactic acid/polycaprolactone blends processed from the solvent-evaporation technique. AB - In this study, polymer blends comprising poly(D/L) lactic acid (PDLLA) and 0 30wt% polycaprolactone (PCL) was prepared by a solvent-evaporation technique. The effect of PCL content on the dynamic-mechanical properties and tensile and flexural characteristics of the blends was evaluated. The creep and stress relaxation behaviors were also determined and using various known models such as power law, Burgers model and Weibull distribution equation. The results showed that by increasing the PCL content from 10 to 30wt%, the yield stress and flexural strength decreased from 47MPa to 26MPa and 72MPa to 29MPa respectively. In addition to tensile and flexural strength, the elastic modulus of neat PDLLA declined with increasing the PCL content, whereas the elongation or the strain percentage at the break point increased considerably. Biphasic regions were observed in the microstructures of the blends, indicating the immiscibility of PCL in PDLLA matrix. However, the PCL spherulites with an average particle diameter of 100nm to 5MUm were homogeneously dispersed in PDLLA phase even at high PCL concentrations. Moreover, the microstructures of the fractured surfaces of the polymers confirmed that PDLLA with a brittle fracture behavior tends toward a soft fracture behavior when it is blended with PCL. The dynamic mechanical tests indicated that the damping energy and dissipative ability of PDLLA improve by adding PCL. Moreover, Tg of neat PDLLA by adding of 10, 20 and 30wt% decreases from 67.3 to 66.2, 65.1 and 63.5 degrees C respectively. Increasing in the recovered viscoelastic strain due to the addition of PCL was also experienced which can be attributed to the presence of large volumetric backbone of PCL chains as well as easy movement of them in the matrix. The results of modeling studies showed a good correlation between the experimentally obtained data. PMID- 27987777 TI - Synthesis and characterization of polycaprolactone for anterior cruciate ligament regeneration. AB - Anterior cruciate ligament (ACL) is the most frequently torn ligament in the knee, and complete healing is unlikely due to lack of vascularization. Current approaches for the treatment of ACL injuries include surgical interventions and grafting, however recent reports show that surgeries have 94% recurrency, and that repaired tissues are biomechanically inferior to the native tissue. These necessitate the need for new strategies for scar-free repair/regeneration of ACL injuries. Polycaprolactone (PCL) is a biodegradable and biocompatible synthetic polymer, which has been widely used in the connective tissue repair/regeneration attempts. Here, we report on the synthesis of PCL via ring opening polymerization using epsilon-caprolactone as the monomer, and ammonium heptamolybdate as a catalyst. The synthesized PCL was characterized using Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance (NMR) spectroscopy. It was then processed using electrospinning to form nanofiber-based scaffolds. These scaffolds were characterized in terms of surface as well as mechanical properties, and compared to the properties of commercially available PCL, and of native ACL tissue harvested from sheep. In addition, scaffolds fabricated with synthesized PCL were evaluated regarding their cell attachment capacity using human bone marrow mesenchymal stem cells (hBMSCs). Our findings demonstrated that the synthesized PCL is similar to its commercially available counterpart in terms of surface morphology and mechanical properties. In addition, fibrous scaffolds generated with electrospinning showed weaker mechanical properties visa vis native ACL tissue in terms of ultimate stress, and elastic modulus. Also, the synthesized PCL can accommodate cell attachment when tested with hBMSCs. Putting together, these observations reveal that the PCL synthesized in this study could be a good candidate as a biomaterial for ligament repair or regeneration. PMID- 27987778 TI - The role of grain refinement and film formation potential on the electrochemical behavior of commercial pure titanium in Hank's physiological solution. AB - In this study, the electrochemical behavior and semiconducting properties of the passive film formed on the nano-grained commercial pure titanium (CP-Ti), successfully made by seven-cycle accumulative roll bonding process, were compared to those for annealed CP-Ti in Hank's physiological solution at 37 degrees C. Polarization plots and electrochemical impedance spectroscopy measurements revealed that the passive behavior of the nano-grained sample was significantly improved in comparison with that of annealed CP-Ti. Mott-Schottky analysis showed that the passive film formed on the nano-grained CP-Ti had a lower donor density and reduced flat-band potential than annealed sample. Moreover, based on the Mott Schottky analysis in conjunction with the point defect model, it was shown that with increasing formation potential, the calculated donor density for both annealed and nano-grained samples decreases exponentially and the thickness of the passive film increases linearly along with the formation potential. These observations were consistent with the point defect model predictions, noting that the point defects within the passive film are metal interstitials, oxygen vacancies, or both. From the viewpoint of passive stability, nano-grained CP-Ti appeared to be more suitable for implant applications compared to that of annealed CP-Ti, mainly due to the formation of thicker and less defective passive film. PMID- 27987779 TI - Lipid-coated hollow mesoporous silica nanospheres for co-delivery of doxorubicin and paclitaxel: Preparation, sustained release, cellular uptake and pharmacokinetics. AB - A carrier consisting of lipid-coated hollow mesoporous silica nanospheres (L HMSN) was produced for the combination of the water-insoluble drug (paclitaxel, PTX) and the water-soluble drug (doxorubicin, DOX). DOX was adsorbed into the nanoscale hollow structure of the hollow mesoporous silica nanospheres (HMSN) by adsorption and PTX was wrapped in the phospholipid layer of the HMSN surface by lipid film hydration method. The characterization results showed that DOX and PTX were present in the nanopheres in an amorphous state. The loaded L-HMSN (DOX/PTX@L-HMSN) in vitro drug release showed a sustained release in phosphate buffered solution (PBS) at pH6.8 and 0.001%SDS. The cellular uptake experiment indicated that L-HMSN was successfully taken up by A549 cells. In addition, the combination of DOX and PTX in L-HMSN exhibited a marked synergistic effect in inhibiting the proliferation of A549 cells. The pharmacokinetic study demonstrated that L-HMSN could significantly improve the relative bioavailability of DOX and PTX. These results confirm that L-HMSN is a promising carrier for successful drug combination. PMID- 27987780 TI - Collagen/glycosaminoglycan coatings enhance new bone formation in a critical size bone defect - A pilot study in rats. AB - Bone regeneration in critical size bone defects still represents an important but unsolved clinical problem. Glycosaminoglycans (GAGs) like chondroitin sulfate (CS) or hyaluronan (HA) are important multifunctional components of the extracellular matrix (ECM) in bone and may stimulate bone healing by recruitment of mesenchymal stromal cells and by supporting their differentiation. Sulfation of GAGs affects their biological activity and thus their interactions with growth factors and/or cells involved in the bone healing process. The aim of this pilot study was to evaluate the osteogenic capacity of chemically high-sulfated chondroitin sulfate (sCS3) and hyaluronan (sHA3) with an average degree of sulfation DS~3 on bone healing. Titanium-coated polyetheretherketone (Ti-PEEK) plates were coated with collagen type I (col), collagen-based artificial ECMs containing CS or HA and compared to col/sCS3 and col/sHA3 coatings bridging a critical size bone defect in rat femur. After 4weeks the gap size of 5.1mm+/ 0.1mm following surgery was significantly reduced to 1.4mm+/-0.9mm for col/sHA3 and to 0.9mm+/-0.7mm for col/CS. The highest amount of newly formed bone was detected for col/CS (79%+/-30%) and col/sHA3 (36%+/-20%) compared to uncoated plates (13%+/-3%) or col-coated plates (18%+/-16%). Enchondral ossification could be confirmed for col/CS, col/HA, and col/sHA3 by positive staining for Alcian blue and collagen type II. These results suggest that an artificial ECM has osteogenic effects and is able to enhance bone healing in critical situations. PMID- 27987781 TI - Construction of a non-enzymatic sensor based on the poly(o-phenylenediamine)/Ag NPs composites for detecting glucose in blood. AB - A non-enzymatic glucose sensor, based on the silver nanoparticles (Ag-NPs)/poly (o-phenylenediamine) (PoPD) composites, is developed by the electrochemical polymerization of o-phenylenediamine and electrodeposition of silver nanoparticles on an indium tin oxide electrode. The Ag-NPs/PoPD composites are characterized by atomic force microscopy, scanning electronic microscopy and energy dispersive spectrometer. Under the optimized experimental conditions, the proposed glucose sensor demonstrates a wide linear range from 0.15 to 13mmolL-1 with a correlation coefficient of 0.998. The proposed glucose sensor can be used to detect glucose in blood sample with a satisfactory result. In addition, the proposed sensor presents the advantages, such as facile preparation, low cost, high sensitivity and fast response time. It also exhibits good anti-interference performance and stability. PMID- 27987782 TI - Incorporation of silver and strontium in hydroxyapatite coating on titanium surface for enhanced antibacterial and biological properties. AB - Implant-related infection in primary total joint prostheses has attracted considerable research attention. As a measure to improve the antimicrobial properties of implant materials, silver (Ag) was incorporated into calcium phosphate (CaP) coatings on Titanium (Ti) via a hydrothermal method. Further, strontium (Sr) was added as a binary dopant to reduce the cytotoxicity of Ag in the coatings. Results showed that the CaP coatings were uniformly deposited on Ti with enhanced hydrophilicity and nanoscale surface roughness. Moreover, cell adhesion, proliferation, and differentiation were improved after the CaP coating deposition. The antibacterial properties of the coatings were distinctly improved by the incorporation of Ag, but the cell proliferation and differentiation were significantly decreased. Owing to the incorporation of Sr, the Ag-CaP coatings were able to effectively counteract the negative effects of Ag while maintaining good antibacterial properties. In summary, hydrothermally deposited CaP coatings doped with Ag and Sr exhibit excellent biocompatibility and antimicrobial activity. Thus, such co-doped CaP coatings have considerable potential for orthopaedic implant modification. PMID- 27987783 TI - A new approach for the immobilization of poly(acrylic) acid as a chemically reactive cross-linker on the surface of poly(lactic) acid-based biomaterials. AB - A new approach for the immobilization of poly(acrylic) acid (PAA) as a chemically reactive cross-linker on the surface of poly(lactic) acid-based (PLA) biomaterials is described. The proposed technique includes non-covalent attachment of a PAA layer to the surface of PLA-based biomaterial via biomaterial surface treatment with solvent/non-solvent mixture followed by the entrapment of PAA from its solution. Surface morphology and wettability of the obtained PLA-PAA composite materials were investigated by AFM and the sitting drop method respectively. The amount of the carboxyl groups on the composites surface was determined by using the fluorescent compounds (2-(5-aminobenzo[d]oxazol-2 yl)phenol (ABO) and its acyl derivative N-(2-(2-hydroxyphenyl)benzo[d]oxazol-5 yl)acetamide (AcABO)). It was shown that it is possible to obtain PLA-PAA composites with various surface relief and tunable wettability (57 degrees , 62 degrees and 66 degrees ). The capacity of the created PAA layer could be varied from 1.5nmol/cm2 to 0.1MUmol/cm2 depending on the modification conditions. Additionally, using bovine serum albumin (BSA) it was demonstrated that such composites could be modified with proteins with high binding density (around 0.18nmol/cm2). Obtained fluoro-labeled PLA-PAA materials, as well as PLA-PAA composites themselves, are valuable since they can be used for biodegradable polymer implants tracking in living systems and as drug delivery systems. PMID- 27987784 TI - A novel l-leucine modified Sol-Gel-Carbon electrode for simultaneous electrochemical detection of homovanillic acid, dopamine and uric acid in neuroblastoma diagnosis. AB - Neuroblastoma is a pediatric neuroblastic tumor arising in the sympathetic nervous crest cells. A high grade of Neuroblastoma is characterized by a high urinary excretion of homovanillic acid and dopamine. In this work l-leucine modified Sol-Gel-Carbon electrode was used for a sensitive voltammetric determination of homovanillic acid and dopamine in urine. The electrochemical response characteristics were investigated by cyclic and differential pulse voltammetry; the modified electrode has shown an increase in the effective area of up to 40%, a well-separated oxidation peaks and an excellent electrocatalytic activity. High sensitivity and selectivity in the linear range of 0,4-100MUML-1 of homovanillic acid and 10-120MUML-1 of dopamine were also obtained. Moreover, a sub-micromolar limit of detection of 0.1MUM for homovanillic acid and 1.0MUM for the dopamine was achieved. Indeed, high reproducibility with simple preparation and regeneration of the electrode surface made this electrode very suitable for the determination of homovanillic acid and dopamine in pharmaceutical and clinical preparations. The mechanism of homovanillic acid and the electrochemical oxidation at l-leucine modified Sol-Gel-Carbon electrode is described out the B3P86/6-31+G(d,p) level of theory as implemented in Gaussian software. PMID- 27987785 TI - Electrophoretic deposition of silica and its composite coatings on Ti-6Al-4V, and its in vitro corrosion behaviour for biomedical applications. AB - Novel bioceramics have an intriguing role in implants and prostheses as surface protecting agents. These bioceramics have promising features such as biocompatible, bioactive, and corrosion-resistant natures. Among bioceramics, silica glass and its composite unravel its better desirability against corrosion and wear with interfacial bone bonding capability in physiological systems by nucleating calcium phosphates over the surface, thereby enhancing the osteoinductive property. In the current study, SiO2 and ZnO were obtained by processing silica and zinc oxide precursors at low temperature using low thermal volatilization sol-gel method. SiO2, ZnO, and its composite powders were characterized by Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (XRD), and scanning electron microscopy (SEM) coupled with energy dispersive X-ray analysis (EDAX). Electrophoretic deposition (EPD) was used for coating on Ti-6Al-4V for improved coating characteristics. In addition, the effect of additives such as iodine and Polyvinylpyrrolidone (PVP) on coating limits was also optimized. Thin-film XRD, Optical Microscopy, SEM-EDAX, Raman spectroscopy, and the scratch resistance test characterized the coating. Tafel polarization and electrochemical impedance spectroscopy (EIS) studies were also carried out to assess corrosion resistance behaviour of the coating. The results showed that the composite coating has greater corrosion resistance than uncoated Ti-6Al-4V. Furthermore, improved mechanical property with better scratch resistance was also observed. These observations showed that composite coating could be useful in biomedical applications. PMID- 27987786 TI - Comparison of glutaraldehyde and carbodiimides to crosslink tissue engineering scaffolds fabricated by decellularized porcine menisci. AB - The objectives of this study were to fabricate porous scaffolds using decellularized meniscus, and to explore a preferable crosslinking condition to enhance mechanical properties of scaffolds. Moreover, the microstructure, porosity, biodegradation and cytotoxicity were also evaluated. EDAC or GTA in different concentration was used to crosslink scaffolds. FTIR demonstrated functional groups change in crosslinking process. SEM photography showed that crosslinked scaffolds had blurry edges, which resulted scaffolds crosslinked by 1.2mol/l EDAC had smaller porosity than other groups. The structure change enhanced antidegradation property. After immersing in enzyme solution for 96h, scaffolds crosslinked by GTA and EDAC could maintain their mass >70% and 80%. Most importantly, mechanical properties of crosslinked scaffolds were also improved. Uncrosslinked Scaffolds had only 0.49kPa in compression modulus and 12.81kPa in tensile modulus. The compression and tensile modulus of scaffolds crosslinked by 1.0% GTA were 1.42 and 567.44kPa respectively. The same value of scaffolds crosslinked by 1.2mol/l EDAC were 1.49 and 532.50kPa. Scaffolds crosslinked by 1.0% and 2.5% GTA were toxic to cells, while EDAC groups showed no cytotoxicity. Chondrocytes could proliferate and infiltrate within scaffolds after seeding. Overall, 1.2mol/l EDAC was a preferable crosslinking condition. PMID- 27987787 TI - Electrospun polycaprolactone/gelatin composites with enhanced cell-matrix interactions as blood vessel endothelial layer scaffolds. AB - During the fabrication of tissue engineering scaffolds and subsequent tissue regeneration, surface bioactivity is vital for cell adhesion, spreading, and proliferation, especially for endothelium dysfunction repair. In this paper, synthetic polymer polycaprolactone (PCL) was blended with natural polymer gelatin at four different weight ratios followed by crosslinking (i.e., 100:0, 70:30, 50:50, 30:70, labeled as PCL-C, P7G3-C, P5G5-C, and P3G7-C) to impart enhanced bioactivity and tunable mechanical properties. The PCL/gelatin blends were first dissolved in 2,2,2-trifluroethanol (TFE) and supplementary acetic acid (1% relative to TFE) solvent, electrospun, and then cross-linked to produce PBS-proof fibrous scaffolds. Scanning electron micrographs (SEM) indicated that fibers of each sample were smooth and homogeneous, with the fiber diameters increasing from 1.01+/-0.51MUm to 1.61+/-0.46MUm as the content of gelatin increased. While thermal resistance and crystallization of the blends were affected by the presence of gelatin, as reflected by differential scanning calorimetry (DSC) results, water contact angle (WCA) tests confirmed that the scaffold surfaces became more hydrophilic. Tensile tests showed that PCL-C and P7G3-C scaffolds had mechanical properties comparable to those of human coronary arteries. As for cytocompatibility, skeleton staining images showed that human mesenchymal stem cells (hMSCs) had more favorable binding sites on PCL/gelatin scaffolds than those on PCL scaffolds. Cell proliferation assays revealed that P7G3-C scaffolds could support the most number of hMSCs. The results of this study demonstrated the enhanced cell-matrix interactions and potential use of electrospun PCL/gelatin scaffolds in the tissue engineering field, especially in wound dressings and endothelium regeneration. PMID- 27987788 TI - Antibody-coupled hydroxyapatite nanoparticles as efficient tools for labeling intracellular proteins. AB - Smart biomaterials for active targeting are a novel way for biosensing, gene and drug delivery, and bioimaging. The functional additives are chosen according to the material carrier characteristics, i.e. the functional mercapto acids of different lengths. In order to identify the target tissue, cell, organ or molecule, the biomaterial must be equipped with a recognizing molecule on its surface. In most cases, semiconductor o metal materials are employed in bioimaging and biosensing applications; in gene and drug delivery area, it is useful to employ porous nanoparticles as carriers. Hydroxyapatite nanoparticles have been proved efficiently in drug delivery. In this work we established a new protocol to obtain smart hydroxyapatite nanoparticles with 3-mercaptopropionic acid and anti-Actin molecules in order to localize actin molecules in cells. PMID- 27987789 TI - Influence of quercetin and nanohydroxyapatite modifications of decellularized goat-lung scaffold for bone regeneration. AB - In the present study, goat-lung scaffold was fabricated by decellularization of lung tissue and verified for complete cell removal by DNA quantification, DAPI and H&E staining. The scaffold was then modified by crosslinking with quercetin and nanohydroxyapatite (nHAp), and characterized to evaluate the suitability of quercetin-crosslinked nHAp-modified scaffold for regeneration of bone tissue. The crosslinking chemistry between quercetin and decellularized scaffold was established theoretically by AutoDock Vina program (in silico docking study), which predicted multiple intermolecular hydrogen bonding interactions between quercetin and decellularized scaffold, and FTIR spectroscopy analysis also proved the same. From MTT assay and SEM studies, it was found that the quercetin crosslinked nHAp-modified decellularized scaffold encouraged better growth and proliferation of bone-marrow derived mesenchymal stem cells (BMMSCs) in comparison to unmodified decellularized scaffold, quercetin-crosslinked decellularized scaffold and nHAp-modified decellularized scaffold. Alkaline Phosphatase (ALP) assay results showed highest expression of ALP over quercetin crosslinked nHAp-modified scaffold among all the tested scaffolds (unmodified decellularized scaffold, quercetin-crosslinked decellularized scaffold and nHAp modified decellularized scaffold) indicating that quercetin and nHAp is very much efficient in stimulating the differentiation of BMMSCs into osteoblast cells. Alizarin red test quantified in vitro mineralization (calcium deposits), and increased expression of alizarin red over quercetin-crosslinked nHAp-modified scaffold indicating better stimulation of osteogenesis in BMMSCs. The above findings suggest that quercetin-crosslinked nHAp-modified decellularized goat lung scaffold provides biomimetic bone-like microenvironment for BMMSCs to differentiate into osteoblast and could be applied as a potential promising biomaterial for bone regeneration. PMID- 27987790 TI - Surface biomimetic modification with laminin-loaded heparin/poly-l-lysine nanoparticles for improving the biocompatibility. AB - Late thrombus and restenosis caused by delayed endothelialization and insufficient biocompatibility of polymer coating continue to be the greatest limitations of drug-eluting stents. In this study, based on the specific structure of vascular basement membrane, a novel biomimetic nano-coating was constructed by incorporating laminin into electrostatic-assembled heparin/poly-l lysine nanoparticles. Alteration of heparin and poly-l-lysine concentration ratio in a certain range has no significantly influence nanoparticle size, uniformity and stability, but may affect the chemical property and subsequently the binding efficiency to dopamine-coated titanium surface. By use of this feature, four different nanoparticles were synthesized and immobilized on titanium surface for creating gradient nanoparticle binding density. According to in vitro biocompatibility evaluation, the nanoparticle modified surfaces were found to effectively block coagulation pathway and reduce thrombosis formation. Moreover, NP10L and NP15L modified surface with relatively low heparin exposing density (4.9 to 7.1MUg/cm2) showed beneficial effect in selective promoting EPCs and ECs proliferation, as well as stimulating cell migration and NO synthesis. PMID- 27987791 TI - Antibacterial ability and angiogenic activity of Cu-Ti-O nanotube arrays. AB - Bacterial infection and loosening of orthopedic implants remain two disastrously postoperative complications. Angiogenesis is critical important to facilitate implant osseointegration in vivo. TiO2 nanotubes arrays (NTAs) with proper dimensions possess good osseointegration ability. Accordingly, the present work incorporated copper (Cu) into TiO2 NTAs (Cu-Ti-O NTAs) to enhance their antibacterial ability and angiogenesis activity, which was realized through anodizing magnetron-sputtered TiCu coatings with different Cu contents on pure titanium (Ti). Our results show ordered Cu-Ti-O NTAs can be produced under proper Cu content (<15.14%) in TiCu coatings. The NTAs possess excellent long-term antibacterial ability against Staphylococcus aureus (S. aureus), which may be ascribed to sustained release of Cu2+. The cytotoxicity of Cu-Ti-O NTAs to endothelial cells (ECs) could be negligible and can even promote cell proliferation as revealed by live/dead staining and MTT. Meanwhile, Cu-Ti-O NTAs can up-regulate nitric oxide (NO) synthesis and vascular endothelial growth factors (VEGF) secretion of ECs on the sample surfaces compared with that of pure TiO2 NTAs (control). Furthermore, the angiogenic activity is also enhanced in ionic extracts of Cu-Ti-O NTAs compared with the control. The excellent long-term antibacterial ability and favorable angiogenic activity render Cu-Ti-O NTAs to be promising implant coatings. PMID- 27987792 TI - A new pollen-derived microcarrier for pantoprazole delivery. AB - Plant-derived carriers have emerged as promising materials for drug encapsulation. Especially, sporopollenin microcapsules extracted from diverse pollen species have been proved to be effective drug carriers due to their biocompatibility, homogeneity in size, resistance to harsh chemical conditions and high thermal stability. Here in this study, sporopollenin microcapsules were isolated successfully from the pollens of a common tree (Corylus avellana, the European hazelnut) and used as a carrier for pantoprazole (PaNa) (a proton pump inhibitor). The drug entrapment efficiency was recorded as 29.81%. SEM micrographs clearly showed the drug was loaded into the microcapsules through the apertures of microcapsule and also some drugs were adsorbed on the surface of microcapsules. FT-IR spectra analysis confirmed the drug loading. Thermogravimetric analysis revealed that thermal stability of PaNa was enhanced by encapsulation. In vitro release studies showed that PaNa-loaded sporopollenin microcapsules exhibited better release performance than the control. C. avellana sporopollenin microcapsules can make an efficient carrier for delivery of PaNa. PMID- 27987794 TI - Bioflavonoid hesperetin overcome bicalutamide induced toxicity by co-delivery in novel SNEDDS formulations: Optimization, in vivo evaluation and uptake mechanism. AB - In the present study, we designed Bicalutamide (BCT) and Hesperetin (HSP) co loaded self nano-emulsifying drug delivery system (SNEDDS) to encounter the problem of BCT induced toxicity, low solubility, and bioavailability. Optimized BCT-HSP SNEDDS would produce an emulsion of globule size 30.84+/-1.24nm with a high encapsulation efficiency of BCT (91.29%) and HSP (88.19%), and showed rapid drug release. DPPH assay confirmed the retention of antioxidant potential of HSP in SNEDDS. DCFH-DA confirmed intense green fluorescence in HSP treated groups due to the generation of reactive oxygen species. Thermogravimetric analysis showed the change in the polymorphic form of BCT. After 14days of sub-acute toxicity study, no significant increase (p>0.05) in the hepatotoxicity markers was observed but BCT-HSP SNEDDS significantly decreased (p<0.001) the levels of nephrotoxicity biochemical markers. Additionally, the histopathological study showed that pulmonary fibrosis and alteration in the bowman's by BCT treatment were conquered by co-administration of HSP. BCT-HSP SNEDDS revealed high AUC0-t of BCT (1.23 fold) and HSP (3.42 fold) than aqueous suspension in male Sprague Dawley rats. The BCT-HSP SNEDDS were absorbed by clathrin-mediated endocytosis and lymphatic transport absorption pathway. Our results proposed that the co delivery approach may be useful for in vivo management of prostate cancer. PMID- 27987793 TI - Dermal-epidermal membrane systems by using human keratinocytes and mesenchymal stem cells isolated from dermis. AB - Dermal-epidermal membrane systems were developed by co-culturing human keratinocytes with Skin derived Stem Cells (SSCs), which are Mesenchymal Stem Cells (MSCs) isolated from dermis, on biodegradable membranes of chitosan (CHT), polycaprolactone (PCL) and a polymeric blend of CHT and PCL. The membranes display physico-chemical, morphological, mechanical and biodegradation properties that could satisfy and fulfil specific requirements in skin tissue engineering. CHT membrane exhibits an optimal biodegradation rate for acute wounds; CHT-PCL for the chronic ones. On the other hand, PCL membrane in spite of its very slow biodegradation rate exhibits mechanical properties similar to in vivo dermis, a lower hydrophilic character, and a surface roughness, all properties that make it able to sustain cell adhesion and proliferation for in vitro skin models. Both CHT-PCL and PCL membranes guided epidermal and dermal differentiation of SSCs as pointed out by the expression of cytokeratins and the deposition of the ECM protein fibronectin, respectively. In the dermal-epidermal membrane systems, a more suitable microenvironment for the SSCs differentiation was promoted by the interactions and the mutual interplay with keratinocytes. Being skin tissue biased stem cells committed to their specific final dermal and/or epidermal cell differentiation, SSCs are more suitable for skin tissue engineering than other adult MSCs with different origin. For this reason, they represent a useful autologous cell source for engineering skin substitutes for both in vivo and in vitro applications. PMID- 27987795 TI - Biocompatible hyperbranched polyglycerol modified beta-cyclodextrin derivatives for docetaxel delivery. AB - The development of biocompatible vector for hydrophobic drug delivery remains a longstanding issue in cancer therapy. We design and synthesis a drug delivery system based on HPG modified beta-CD (beta-CD-HPG) by conjugating HPG branches onto beta-CD core and its structure was confirmed by NMR, FTIR, GPC and solubility. In vitro biocompatibility tests showed that HPG modification significantly improved red blood cells morphology alteration and hemolysis cause by beta-CD and beta-CD-HPG displayed cell safety apparently in a wide range of 0.01-1mg/mL. An anti-cancer drug, docetaxel, was effectively encapsulated into beta-CD-HPG which was confirmed by DSC analysis. This copolymer could form nanoparticles with small size (<200nm) and exhibited better DTX loading capacity and controlled release kinetics without initial burst release behavior compared with beta-CD. Furthermore, antitumor assay in vitro show that beta-CD-HPG/DTX effectively inhibited proliferation of human breast adenocarcinoma cells. Therefore, beta-CD-HPG/DTX exhibit great potential for cancer chemotherapy. PMID- 27987796 TI - Enhancing osteogenic differentiation of MC3T3-E1 cells by immobilizing RGD onto liquid crystal substrate. AB - To understand the effects of GRGDF modification on MC3T3-E1 cell behavior, we cultured these cells onto a biomimetic liquid crystalline matrix modified with GRGDF peptide (OPC-GA-RGD). Successful immobilization of GRGDF on the liquid crystalline surface was verified by fluorescent labeling, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS). OPC-GA-RGDs retained its liquid crystalline feature after surface modification. The RGD-immobilized OPC substrate was hardly beneficial to initial cell adhesion but could support long-term cell survival. The enhancement in cell proliferation did not correlate with RGD density. The lower GRGDF density immobilized on the liquid crystalline OPC matrix (OPC-GA RGD3) promoted cell adhesion, proliferation, ALP expression level and mineralization, suggesting that both the viscoelasticity-based mechanical stimuli and receptor/ligand-based biochemical cue synergistically modulate MC3T3-E1 cell behavior. PMID- 27987797 TI - Reverse indentation size effects in gamma irradiated blood compatible blend films of chitosan-poly (vinyl alcohol) for possible medical applications. AB - In the present work binary blends of polyvinyl alcohol (PVA) and chitosan (CS) were prepared by solution cast method and characterized by analytical methods like FTIR, XRD and SEM for seeking structural and morphological information. The blends were exposed to gamma radiation and evaluated for their improved mechanical strength. It was found that the tensile strength and microhardness increased after irradiation of CS-PVA films. Plastic effect due to absorption of water molecules and scissoring effect due to gamma irradiation were found to decrease the softness or increase the microhardness of the blends. Improved mechanical properties were attributed to intermolecular and intramolecular hydrogen bonds and adhesive nature of the blends also. The blends were also investigated for water intake behavior and in vitro blood compatibility property on the basis of certain in vitro tests like protein adsorption, haemolysis and blood clot formation on the un-irradiated and irradiated blend samples. The increased % swelling with time could be assigned to the fact that increasing water content facilitates the phase separation process within the blend which results in advancement in interstitial nano-void spaces which are occupied by water molecules. The blood compatibility results showed that when the amount of CS was varied from 0.5% to 2%, the amount of blood clot and percent haemolysis decreased while the protein adsorption increased with increasing CS content of the blend films. PMID- 27987798 TI - Transmission electron microscopical study of teenage crown dentin on the nanometer scale. AB - This is the first transmission electron microscopic study of teenage crown dentin on the nanometer scale. Samples for TEM were prepared by mechanical thinning and chemical polishing that allowed obtaining the electron transparent foils. It was firstly shown that human dentin possesses the layered morphology: the layers are oriented normally to the main axis of a tooth and have the thickness of ~50nm. HA inorganic phase of teenage crown dentin is in the amorphous state. The cellular structure, which was formed from collagen fibers (diameter is ~5nm), are observed near DEJ region in teenage dentin, whereas bioorganic phase of teenage crown dentin near the pulp camera does not contain the collagen fibers. Cracks in dentin thin foils have sharp tips, but big angles of opening (~30 degrees ) with plastic zone ahead crack tip. It means that young crown human dentin exhibits ductile or viscous-elastic fracture behavior on the nanometer scale. PMID- 27987799 TI - Molecular imprinting functionalized silica xerogel for selective recognition of levorotatory ofloxacin. AB - In the present work, molecular imprinting silica xerogel (MISX) with selective recognition function aiming to regulate drug therapy was synthesized using biomimetic method with poly(ethyleneimine)s (PEIs) as the polymer template and levorotatory ofloxacin (LOFL) as recognition template. Ultraviolet spectroscopy wavelength scanning was used to test the removal process of LOFL, and characteristics of selective loading ofloxacin (OFL) into MISX were investigated using Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). Molecular recognition functionality of MISX was intensively studied, including OFL loading and release. The results suggested that MISX possessed ability to recognize and selectively adsorb LOFL into MISX in OFL aqueous solution. Amorphous phase of adsorbed molecules contributed to molecular recognition because amorphous state increased the stability of LOFL that were selectively adsorbed into MISX, which induced stronger hydrogen bonding formed between LOFL and MISX so as to improve LOFL recognition ability. In vitro release revealed that OFL-MISX tablet initially released LOFL and later gradually OFL into dissolution medium. Thus conversion of drug release with different pharmacological activity had special value in delivering systems. PMID- 27987800 TI - Laponite as a rheology modifier of alginate solutions: Physical gelation and aging evolution. AB - The rheological behavior of alginate and Laponite/alginate solutions was studied. It was observed that the Cross viscosity model successfully describes the steady state shear behavior of this polysaccharide. The scaling behavior analyzed for the entangled regime is in good agreement with polyelectrolyte solutions (Ge~cp3/2), with interactions generated between the alginate and the charged surfaces of the Laponite platelets. Therefore, the effect of Laponite as a rheology modifier is influenced by the alginate concentration. Higher alginate concentrations hindered the formation of the house of cards microstructure. Frequency sweep tests were performed to analyze the transition from solid-like to liquid-like behavior in a solid-like dominated domain. Soft physical gels were obtained at low alginate concentrations. The gel point was determined (1.65wt.% of alginate and 2wt.% of Laponite) through the Kramers-Kronig damping factor, and time sweep tests revealed the evolution of the storage (G') and loss modulus (G") as functions of the waiting time (tw). The growing elasticity revealed that Laponite/alginate solutions undergo aging. PMID- 27987801 TI - Resistant starch/pectin free-standing films reinforced with nanocellulose intended for colonic methotrexate release. AB - Although resistant starch/pectin (RS/P) films have previously displayed suitable properties for colon-specific drug delivery, nanocomposite films were developed aiming to enhance physicochemical, thermal, mechanical and barrier properties, as well as the low oral bioavailability of methotrexate (MTX). FEG-SEM micrographs of nanocomposite films showed different interaction patterns occurring among nanocellulose and RS/P. The nanofiller addition led to an increase in the thermal stability, probably due to its interaction with RS crystalline double helices. Results also displayed an improvement of the puncture strength, while barrier properties revealed a low water vapor permeability. Ex vivo bioadhesion test displayed the nanocomposites films to interact strongly with porcine gastrointestinal mucosa. In vitro drug release studies showed that the films developed enhanced the drug dissolution rates with approximately 80% of MTX release in 150min, suggesting the potential of these materials as a poor solubility drugs carrier, which constitutes an important tool for enhancing oral bioavailability. PMID- 27987802 TI - Flexible regenerated cellulose/polypyrrole composite films with enhanced dielectric properties. AB - Flexible regenerated cellulose/polypyrrole (RC-PPy) conductive composite films were prepared by insitu polymerization of pyrrole on regenerated cellulose (RC) matrix using ammonium persulphate as oxidant. FTIR, XPS and XRD analysis of RC PPy composite films revealed strong interaction between polypyrrole (PPy) and RC matrix. XRD results indicated that crystalline structure of RC matrix remains intact even after composite formation. SEM micrographs revealed the formation of a continuous conductive network of PPy particles in the RC matrix, leading to significant improvement in electrical and dielectric properties. The electrical conductivity of RC-PPy composites with 12wt% of PPy was 3.2*10-5S/cm, which is approximately seven fold higher than that of RC. Composites showed high dielectric constant and low dielectric loss values, which is essential in capacitor application. PMID- 27987803 TI - Grafting-from cellulose nanocrystals via photoinduced Cu-mediated reversible deactivation radical polymerization. AB - In this work we describe the grafting of cellulose nanocrystals (CNCs) by surface initiated photoinduced Cu-mediated reversible-deactivation radical polymerization (RDRP). Initially, CNCs obtained through sulfuric acid hydrolysis were functionalized with a tertiary bromo-ester moiety as an initiating group for the subsequent RDRP of methyl acrylate, targeting three different degrees of polymerization for the polymer grafts: 50, 300 and 600. The polymerizations proceeded in DMSO in the presence of CuBr2 and Me6TREN as the catalytic system utilizing a UV source (lambdamax~360nm). The technique proved highly versatile for the modification of CNCs with poly(methyl acrylate), where considerably high grafting was achieved in short reaction times (90min), with simple purification steps. CNC morphology was maintained and polymer grafts were evident through FT IR spectroscopy, thermal analysis, contact angle measurements, X-ray photoelectron microscopy and x-ray diffraction. PMID- 27987804 TI - Studies on cellulose nanocrystals isolated from groundnut shells. AB - Today, various renewable biomass resources are accepted as waste material and are mostly burnt or used as cattle feed. The commercial value of these wastes can be increased by utilising them in production of nanomaterials. So, the present work was conducted for isolation of cellulose nanocrystals (CNCs) from groundnut shells which are produced annually as waste in large quantity (~7 million tons). The structural, thermal, morphological & elemental analyses were assessed through corresponding techniques. Light Scattering studies were performed to analyse more likely weight average molecular weight (Mw) & radius of radius (Rg). The high Mw ~105g/mol obtained for CNCs in lithium chloride (LiCl)/N,N-dimethylacetamide (DMAc) system, was an interesting feature which gets affected by LiCl and polymer concentrations. Solution with high polymer and low LiCl concentration was found to show higher values of Mw & Rg. PMID- 27987805 TI - Spray freeze-dried nanofibrillated cellulose aerogels with thermal superinsulating properties. AB - Nanofibrillated cellulose (NFC) aerogels were prepared by spray freeze-drying (SFD). Their structural, mechanical and thermal insulation properties were compared to those of NFC aerogels prepared by conventional freeze-drying (CFD). The purpose of this investigation is to develop superinsulating bioaerogels by reducing their pore size. Severe reduction of the aerogel pore size and skeleton architecture were observed by SEM, aerogels prepared by SFD method show a fibril skeleton morphology, which defines a mesoporous structure. BET analyses confirm the appearance of a new organization structure with pores of nanometric sizes. As a consequence, the thermal insulation properties were significantly improved for SFD materials compared to CFD aerogel, reaching values of thermal conductivity as low as 0.018W/(mK). Moreover, NFC aerogels have a thermal conductivity below that of air in ambient conditions, making them one of the best cellulose based thermal superinsulating material. PMID- 27987806 TI - Effect of spray drying on the properties of amylose-hexadecylammonium chloride inclusion complexes. AB - Water soluble amylose-hexadecyl ammonium chloride complexes were prepared from high amylose corn starch and hexadecyl ammonium chloride by excess steam jet cooking. Amylose inclusion complexes were spray dried to determine the viability of spray drying as a production method. The variables tested in the spray drying process were the% solids of the amylose-hexadecyl ammonium chloride complex being fed into the spray dryer, feed rate and the spray dryer outlet temperature. The amylose-inclusion complexes remained intact in all spray drying conditions tested as determined by X-ray diffraction. The rheological properties of solutions of the spray dried amylose-complexes remained unchanged when compared with the freeze dried control. Particle density and moisture content decreased with increased outlet temperature while particle size increased. X-ray diffraction and DSC analysis confirmed the formation of type II amylose inclusion complexes. Spray drying is a high throughput, low cost continuous commercial production method, which when coupled with excess steam jet cooking allows for the industrial scale production of cationic amylose-hexadecyl ammonium chloride complexes which may have value as flocculating and filtration enhancing agents and other aspects of paper production. PMID- 27987807 TI - Opuntia dillenii (Ker-Gawl) Haw cladode mucilage: Physico-chemical, rheological and functional behavior. AB - The yield of mucilage extracted from cladodes of Opuntia dillenii (Ker-Gawl) Haw in aqueous medium was 6.2%. The neutral sugar comprised of arabinose (38.80%), galactose (33.00%), rhamnose (15.70%), xylose (5.10%), and glucose (5.10%). The mucilage showed pseudo plastic behavior with good swelling index (20%), water holding capacity (g water/g dry sample; 4+/-0.10) and micrometric properties. In addition, mucilage presented intrinsic viscosity of 3.7 dL/g with average molecular weight of 1.9*103kDa. The FTIR and NMR spectra of extracted mucilage showed characteristic polysaccharide nature. Further, the mucilage exhibited anti obesity property through lipase inhibition. These findings could highlight that isolated mucilage could be exploited as an additive in food and pharmaceutical sector. PMID- 27987808 TI - Hydrophilic polymeric nanoparticles prepared from Delonix galactomannan with low cytotoxicity for ocular drug delivery. AB - Delonix is a galactomannan polysaccharide extracted from the endosperm of Delonix regia plant. This study aims at the development of Delonix nanoparticle and assesses its potential for ocular delivery by evaluating its in-vitro stability, toxicity and cellular uptake. Fluorescent nanoparticles (BODIPY-loaded nanoparticles) were prepared by a Quality-by-Design modified nanoprecipitation technique. Optimized nanoparticles had mean sizes <240nm, PdI<0.2 and zeta potential of <-30mV. Mixture of surfactants with different hydrophilic-lipophilic balance controlled nanoparticle swelling. Nanoparticles, which were stable in the presence of simulated lachrymal fluid and lysozyme also sustained the release of BODIPY. In-vitro studies suggest no toxicity of the nanoparticles in concentration range of 100-1483.3MUg/mL on retinal and corneal epithelial cells. Flow cytometry and confocal microscopy techniques showed that retinal cells but not corneal cells, uptake 18% of the nanoparticles. Therefore, Delonix nanoparticles could be a safe and promising tool for ocular drug delivery. PMID- 27987809 TI - Studies on performance evaluation of a green plasticizer made by enzymatic esterification of furfuryl alcohol and castor oil fatty acid. AB - The esterification of furfuryl alcohol (FA) and castor oil fatty acid (COFA) at 3:1 molar ratio, by immobilized Candida antarctica Lipase B (NS 435 from Novozyme) in a solvent free system gave a maximum yield of 88.64% (%w/w) at 5h. Performance of the FA-COFA ester plasticized Ethyl Cellulose (EC) films were evaluated by surface morphologies, XRD analysis, mechanical properties,thermal properties, water vapor permeability and migration stability test. It was an effective plasticizer with better mechanical properties and thermal stability at the increasing concentration of FA-COFA ester (15-25%) containing EC film, than the traditional plasticizer, i.e; dibutyl phthalate (DBP) in producing good quality films. Chemical structure and the intermolecular interactions between FA COFA ester and ethyl cellulose chains were the causative agents of these outstanding performances. Therefore, this FA-COFA ester, with significant plasticizing property, at a certain concentration, can be a substitute of DBP. PMID- 27987810 TI - A new approach for imparting durable multifunctional properties to linen containing fabrics. AB - This study focused on upgrading the antibacterial activity, UV-protection property, self-cleaning ability and durability to wash of linen and linen/cotton (50/50) blend fabrics to develop multifunctional textile materials without adversely affecting their hydrophilicity. Herein, linen-containing fabrics were first pre-carboxymethylated to create new active sites (-CH2COOH groups) to facilitate subsequent loading of selected active ingredients namely chitosan (Cs), organosilane quaternary ammonium compound (Si-QAC), silver-nanoparticles (Ag-NPs) and titanium oxide nanoparticles (TiO2-NPs) individually and in admixtures. The developed products, especially in case of using mixed active ingredients, exhibit a noticeable improvement in the imparted functional properties regardless of the used substrate. The effectiveness of the imparted functions is determined by type of substrate, its extent of modification, type, concentration and degree of fixation of the used active ingredient onto the pre modified substrate. Functionalized samples loaded with mixed active ingredients demonstrated a high durability to wash even after 15 washing cycles. PMID- 27987811 TI - Effect of nanocellulose as a filler on biodegradable thermoplastic starch films from tuber, cereal and legume. AB - Starches from different vegetal sources (tuber, cereal and legume) were plasticized with an invariant glycerol content and reinforced with cellulose nanocrystals by solution casting method. The influence of both, starch nature and filler amount, in the crystallinity and the extension of plasticization have been analyzed by X-ray diffraction. Thermoplastic starches (TPS) morphologies were obtained by scanning electron microscopy. Mechanical properties and thermal stability were analyzed by dynamomechanical and thermogravimetric analysis. Water absorption evolution was studied as well. A major extension in plasticization (high amylopectin starches) led to matrices with large starch-rich domains, a good thermal stability and resistance to water absorption but low stiffness. The incorporation of cellulose nanoparticles favoured plasticization and increased the rigidity in TPS films, as well as the thermal stability and moisture resistance. The aim of this work was to obtain bio-based thermoplastic starch films for replacing petroleum-derived ones in packaging industry, especially for short-life applications. PMID- 27987812 TI - Effect of xyloglucan molar mass on its assembly onto the cellulose surface and its enzymatic susceptibility. AB - Xyloglucan from tamarind seed has been submitted to an ultrasound treatment that reduces its molecular size to investigate the impact of molar mass on the interaction with cellulose. A low molar mass xyloglucan fraction (XGu, 1.04*105gmol-1) was purified and its adsorption on the cellulose nanocrystal (CNC) surface has been investigated comparatively to the native fraction that presents high molar mass (XGn, 10.28*105gmol-1). XGn arranged as loops and tails on CNCs whereas XGu formed trains onto the cellulose surface. Despite the extended conformation, XGu is able to cross-link cellulose nanocrystals in the layer-by-layer CNC-XG-CNC assemblies. Hydrolysis of model films by a xyloglucan specific endoglucanase confirmed the greater accessibility of XGn loops and tails compared to the XGu trains. More importantly, in situ ellipsometry revealed that the presence of loops and tails facilitated swelling of CNC layers linked by XGn whereas the CNC-XGu-CNC structure did not experience swelling. PMID- 27987813 TI - Recent advances in endophytic exopolysaccharides: Production, structural characterization, physiological role and biological activity. AB - Endophytes are microorganisms that colonize living, internal tissues of plants without causing any immediate, overt negative effects. In recent years, both endophytic bacteria and fungi have been demonstrated to be excellent exopolysaccharides (EPS) producers. This review focuses on the recent advances in EPS produced by endophytes, including its production, isolation and purification, structural characterization, physiological role and biological activity. In general, EPS production is influenced by media components and cultivation conditions. The structures of purified EPS range from linear homopolysaccharides to highly branched heteropolysaccharides. These structurally novel EPS not only play important roles in plant-endophyte interactions; but also exhibit several biological functions, such as antioxidant, antitumor, anti-inflammatory, anti allergic and prebiotic activities. In order to utilize endophytic EPS on an industrial scale, both yield and productivity enhancement strategies are required at several levels. Besides, the exact mechanisms on the physiological roles and biological functions of EPS should be elucidated in future. PMID- 27987814 TI - Multi-objective optimization of process conditions in the manufacturing of banana (Musa paradisiaca L.) starch/natural rubber films. AB - Multi-objective optimization was used to evaluate the effect of adding banana (Musa paradisiaca L.) starch and natural rubber (cis-1,4-poliisopreno) at different ratios (1-13w/w) to the manufacturing process of biodegradable films, specifically the effect on the biodegradability, crystallinity and moisture of the films. A structural characterization of the films was performed by X-ray diffraction, Fourier transform infrared spectroscopy and SEM, moisture and biodegradability properties were studied. The models obtained showed that degradability vs. moisture tend to be inversely proportional and crystallinity vs. degradability tend to be directly proportional. With respect to crystallinity vs. moisture behavior, it is observed that crystallinity remains constant when moisture values remain between 27 and 41%. Beyond this value there is an exponential increase in crystallinity. These results allow for predictions on the mechanical behavior that can occur in starch/rubber films. PMID- 27987815 TI - Isolation, purification, structural analysis and immunostimulatory activity of water-soluble polysaccharides from Grifola Frondosa fruiting body. AB - A new polysaccharide had been successfully isolated from maitake mushroom (Grifola Frondosa)-GFP. HPLC and Monosaccharide analysis showed that the average molecular weight of GFP was 155kDa and it was mainly composed of rhamnose, xylose, mannose, glucose, molar ratio of 1.00: 1.04: 1.11: 6.21. FTIR, methylation analysis and NMR were used to analyze the structural characterization of GFP. Structural analysis results revealed that its backbone consisted of (1 >4)-linked methylation, Glcp residues were major structural polysaccharide GFP units, accounting of the polysaccharide backbone speculate GFP every->3)-Glcp-(1 >and one->3,4)-Glcp-(1->connected interval with a small amount of 1->, 1->4, 1->6 glycosidic linkage. MTT assay showed that GFP could significantly improve the proliferation activity of RAW264.7 cells in a certain range of concentrations and time. Scanningelectro microscopy (SEM) results indicated that GFP could induce RAW264.7 cells activation. GFP could obviously increase the proliferation index and enhance the immunostimulatory activity such as the cytokine and chemokine production. PMID- 27987816 TI - Temperature stability of nanocellulose dispersions. AB - Cellulose nanofibrils (CNF) have potential as rheology modifiers of water based fluids, e.g. drilling fluids for use in oil wells or as additives in injection water for enhanced oil recovery (EOR). The temperature in oil wells can be high (>100 degrees C), and the retention time long; days for drilling fluids and months for EOR fluids. Hence, it is important to assess the temperature stability over time of nanocellulose dispersions to clarify their suitability as rheology modifiers of water based fluids at such harsh conditions. Dispersions of CNF produced mechanically, by using TEMPO mediated oxidation and by using carboxymethylation as pretreatment, in addition to cellulose nanocrystals (CNC), have been subjected to heat aging. Temperature stability was best for CNC and for mechanically produced CNF that were stable after heating to 140 degrees C for three days. The effect of additives was evaluated; cesium formate and sodium formate increased the temperature stability of the dispersions, while there was no effect of using phosphate buffer. PMID- 27987817 TI - Sequence-dependent association of alginate with sodium and calcium counterions. AB - Molecular dynamics simulation is used to study in detail the binding of sodium and calcium ions to alginate chains, and its dependence on the content of guluronic (G) acid residues. Our previous studies showed that chains with different G content associate through different structural mechanisms due to differing degrees of rigidity of the ion-alginate chain complexes. Polymannuronate and polyguluronate chains form highly ordered structures due to their more rigid nature. Heteropolymer chains are more flexible and hence associate at higher ion and alginate concentrations, however, with association behavior that has a clear dependence on G content. The nature of interactions of sodium and calcium ions are shown to differ for poly-M, poly-G, and the heteropolymer compositions. Scattering curves of Ca2+-alginate solutions where found to have good agreement with the broken-rod SAXS model with nontrivial but clear dependence on G content, which is explained by chain flexibility and its relation to ion condensation. PMID- 27987818 TI - Antioxidant edible films based on chitosan and starch containing polyphenols from thyme extracts. AB - The aim of this study was to analyse the antioxidant activity of different polymeric matrices based on chitosan and starch, incorporating a thyme extract (TE) rich in polyphenols. TE provided the films with remarkable antioxidant activity. When mixed with chitosan, the polyphenols interacted with the polymer chains, acting as crosslinkers and enhancing the tensile behaviour of films. The opposite effect was observed when incorporated into the starch matrix. All the films became darker, more reddish and less transparent when TE was incorporated. These colour changes were more marked in starch matrices, which suggests that TE compounds were poorly encapsulated. The use of chitosan-based matrices carrying TE polyphenols is recommended as a means of obtaining antioxidant films, on the basis of their tensile response and greater antioxidant activity, which could be associated with the development of polyphenol-chitosan interactions, contributing to a better protection of the functionality of polyphenols during film formation and conditioning. PMID- 27987819 TI - Gelatin/potato starch edible biocomposite films: Correlation between morphology and physical properties. AB - The paper presents the results of studies of the microstructure morphology and the operational properties of the gelatin/potato starch/glycerol edible biocomposite films varying in the starch content from 0 to 50wt% prepared by casting film-forming solution and dying at 36 degrees C for 15h. The biocomposite films were shown phase separated heterogeneous morphology with the gelatin matrix as a continuous phase and microgranules of starch as a minor phase. It is found that when the starch content <= 30wt% the phase separation mechanism is nucleation and grow, whereas the starch content > 30wt% then the spinodal decomposition is the dominant mechanism. The work focuses on findings the influence of the phase separation mechanisms on the size of starch granules during the drying process, as well as the impact of these mechanisms on optical, frictional, mechanical, thermal and water-barrier properties. PMID- 27987820 TI - Electrospun ultra-fine cellulose acetate fibrous mats containing tannic acid-Fe3+ complexes. AB - Cellulose acetate (CA) fibrous mats with improved mechanical and antioxidant properties were produced by a simple, scalable and cost-effective electrospinning method. Fibers loaded with small amounts of TA-Fe3+ complexes showed an increase in tensile strength of ~117% when compared to that of neat CA and were more resistant than those loaded with TA alone. The water uptake of the fibers increased upon TA or TA-Fe3+ incorporation while their thermal behavior was only slightly affected. Fibrous mats loaded with TA-Fe3+ showed comparable antioxidant activity with that of CA/TA mats, and a much slower TA release. These results suggest that TA-Fe3+ complexes can be incorporated into electrospun CA fibers to improve their mechanical properties and antioxidant activity which may be of interest for the development of active packaging that can extend the shelf life of perishable foods. PMID- 27987821 TI - Removal of Lead(II) ions from aqueous solutions using biocompatible polymeric nano-adsorbents: A comparative study. AB - Low-cost and biocompatible chitin nanofiber and chitosan nanoparticle as natural polymers synthesized successfully by means of a mechanical and a chemical procedure respectively. The surface properties and size of chitin nanofibers (CNFs) and chitosan nanoparticles (CNPs) were characterized using a scanning electron microscope (SEM). CNF and CNP were utilized for separation of lead(II) metal ions from aqueous solution, and the influence of effective factors were investigated. It was found that both adsorbents can adsorb lead ions from the solution effectively, but sorption efficiency for CNP at all the stages was greater than CNF. Furthermore, the results of corresponding equilibrium data with adsorption isotherms revealed that CNF and CNP are more compatible with Freundlich and Langmuir adsorption isotherms respectively. It shows that, for CNF, adsorption process occurs as a heterogeneous and multi-layer process, while for CNP, adsorption process is predicted to befall as a homogenous and single layer process. At the end kinetics and thermodynamic studies were performed for both Nano-adsorbents. PMID- 27987822 TI - Enhanced adsorption of active brilliant red X-3B dye on chitosan molecularly imprinted polymer functionalized with Ti(IV) as Lewis acid. AB - A Ti(IV) functionalized chitosan molecularly imprinted polymer (Ti-CSMIP) was successfully prepared. Ti4+ as Lewis acidic was used to modify chitosan MIP by producing metal hydroxyl group and protonated surface of adsorbent in aqueous solution to recognize X-3B molecule as a Lewis base. The adsorbent was characterized by FTIR, SEM, XRD, BET, elemental and zeta potential analysis. XRD illustrated Ti-CSMIP exhibited a weak anatase phase when Ti4+ cross-linked with chitosan. Batch adsorption experiments were performed to evaluate adsorption condition, including sorption isotherm, kinetics and reusability. The maximum adsorption capacity of Ti-CSMIP for X-3B was 161.1mg/g at 293K when solution pH was in the range of 6.0-7.0. Equilibrium data was well analyzed by three parameter isotherm model, and the kinetics of adsorption followed the pseudo second kinetics equation. Regeneration experiments indicated a possible application as an effective sorbent for the selective removal of azo anionic dye in aqueous solutions. PMID- 27987823 TI - Novel moisture-preserving derivatives of hyaluronan resistant to hyaluronidase and protective to UV light. AB - Current studies have revealed the excellent moisture absorption-retention capacity of hyaluronan (HA); however, HA is easily degraded by hyaluronidase on the surface of skin. So, it is very necessary to develop an alternative derivative with low cytotoxicity and resistance to hyaluronidase. Herein, a HA decorated with photocaged groups was synthesized. The moisture absorption retention capacity and hyaluronidase resistance of photocaged HA (HA-DMNB) and products of HA-DMNB irradiated by ultraviolet for different time (IHA-DMNB), were investigated. Results show that HA-DMNB is more resistant to hyaluronidase than HA, and HA-DMNB could release free carboxyl groups of HA upon ultraviolet to bond with H2O. More importantly, HA-DMNB was protective against UV light. In addition, HA-DMNB and IHA-DMNB were observed to be nontoxic to HaCat cells. This study indicates that HA-DMNB may be effectively used as a moisture-preserving reagent. PMID- 27987824 TI - Synthesis of thiolated polysaccharides for formation of polyelectrolyte multilayers with improved cellular adhesion. AB - Intrinsic cross-linking is not only useful for increasing stability, but also for tailoring mechanical properties of polyelectrolyte multilayers (PEM) on implants and tissue engineering scaffolds. Here, a novel route for synthesizing thiolated chitosan (t-Chi) based on the application of 3,3'-dithiodipropionic acid was applied, while thiolated chondroitin sulfate (t-CS) was conjugated by 3,3' dithiobis (propanoic hydrazide). Both products were subsequently reduced to obtain the free thiols. The thiol content, structural changes and degree of substitution were studied by UV-vis, FTIR, Raman and 1H NMR spectroscopy, respectively. Chi and CS can be used for PEM formation with the layer-by-layer method, due to the cationic nature of Chi at pH values below 5.0 and the anionic character of CS. Comparative studies on the formation of native Chi/CS versus t Chi/t-CS PEM with surface plasmon resonance and ellipsometry revealed higher layer mass. We also found that the PEM composed of t-Chi/t-CS had superior cell adhesion properties for human keratinocytes in comparison to the native PEM. PMID- 27987825 TI - A composite chitosan-gelatin bi-layered, biomimetic macroporous scaffold for blood vessel tissue engineering. AB - A composite chitosan-gelatin macroporous hydrogel-based scaffold with bi-layered tubular architecture was engineered by solvent casting-co-particulate leaching. The scaffold constituted an inner macroporous layer concealed by a non-porous outer layer mimicking the 3D matrix of blood vessels with cellular adhesion and proliferation. The scaffold was evaluated for its morphological, physicochemical, physicomechanical and biodurability properties employing SEM, FTIR, DSC, XRD, porositometry, rheology and texture analysis. The fluid uptake and biodegradation in the presence of lysozymes was also investigated. Cellular attachment and proliferation was analysed using human dermal fibroblasts (HDF-a) seeded onto the scaffold and evaluated by MTT assay, SEM, and confocal microscopy. Results demonstrated that the scaffold had a desirable tensile strength=95.81+/-11kPa, elongation at break 112.5+/-13%, porosity 82% and pores between 100 and 230MUm, 50% in vitro biodegradation at day 16 and proliferated fibroblasts over 20 days. These results demonstrate that scaffold may be an excellent tubular archetype for blood vessel tissue engineering. PMID- 27987827 TI - A review of the chemical modification techniques of starch. AB - Starch is a naturally occurring storage copolymer with unique physicochemical properties. There are, however, some key structural properties of starch that can be modified in order to functionalize the copolymer to meet specific requirements. Specifically, the chemical modification of starch provides a variety of physicochemical benefits, some of which have been used previously to functionalize preformed drug delivery systems. Of the three main chemical modification methods reviewed (namely: oxidation, esterification and etherification), surface chemical oxidation introduces more pertinent physicochemical properties that increase overall drug delivery system efficacy and applicability. Surface oxidation evidently is the more preferable chemical modification method of pre-formed starch particles and has the greatest potential for further development when compared to the other reviewed chemical modification methods. The use of modified starch in clinical trials as well as the potential future implications of these systems is also included in this review. PMID- 27987826 TI - Xanthan and kappa-carrageenan based alkaline hydrogels as electrolytes for Al/air batteries. AB - Xanthan and kappa-carrageenan were used to prepare alkaline hydrogels to be used as electrolytes in aluminium air primary batteries. Two pasty gels were obtained starting from xanthan and KOH solutions (1M and 8M), while only the 8M KOH solution permitted the formation of a stable, elastic and gumminess hydrogel with kappa-carrageenan. Discharge tests, performed on three Al/air cells assembled with Al anodes, electrolyte gels and Pt based cathodes, evidenced that all hydrogels exhibited appreciable properties of Al ion conductivities, according to the following performance order: xanthan with KOH 1M3)-beta-d glucopyranosyl, two (1->6)-beta-d-glucopyranosyl, two (1->6)-alpha-d glucopyranosyl, and one (1->4)-alpha-d-glucopyranosyl residues, out of which one (1->3)-beta-d-glucopyranosyl residue was branched at O-6 position with terminal alpha-d-glucopyranosyl residue and one (1->4)-alpha-d-glucopyranosyl residue branched at O-6 position with terminal beta-d-glucopyranosyl residue. In vitro antioxidant studies showed that the MGPS exhibited hydroxide radical scavenging activity (IC50=390MUg/mL), superoxide radical scavenging activity (IC50=70MUg/mL), and ferrous ion chelating activity (IC50=290MUg/mL). PMID- 27987829 TI - Chitosan-cellulose nanocrystal microencapsulation to improve encapsulation efficiency and stability of entrapped fruit anthocyanins. AB - For improving stability of fruit anthocyanins (ACN), this study investigated the use of cellulose nanocrystal (CNC) as a macroion crosslinking agent to develop blueberry anthocyanin extract (BB)-loaded chitosan (CH)-CNC microcapsules, and compared with CH-sodium tripolyphosphate (TPP) ones. The yield of microcapsules (~6.9g) and total monomeric anthocyanin recovery (~94%) were significantly (P<0.05) higher in CH-CNC microcapsules than those (~0.3g and ~33%, respectively) in CH-TPP microcapsules. ACN distribution (%) in CH-CNC microcapsules was 61% on the surfaces, 12% bound with the matrix, and 27% in cores, but that in CH-TPP microcapsules was mostly presented on the surfaces (99%). CH-CNC microcapsules were more stable at pH 7.4 buffer by showing less ACN release (%) than that of CH TPP, but no difference at pH 1.2. CH-CNC and CH-TPP microcapsules showed different structural and morphological properties. This study demonstrated that CNC is a promising crosslinking agent forming stable BB-loaded CH microcapsules. PMID- 27987830 TI - Preparation and characterization of zein thermo-modified starch films. AB - A new method of preparing films from zein thermo-modified starch was presented. According to data of micro-visco-amylography and rheometer, dry heating with zein significantly decreased the pasting properties of waxy corn starch and distarch phosphate, the values of G' and G" of starches dry heated with zein decreased, while the loss tangent increased as a function of heating time. Scanning electron microscopy images showed that the surfaces of starch granules became rough after dry heating with zein, suggesting interactions between zein and the granule surface. In films made from mixtures, the starch/zein compatibility was improved through dry heating. Compared with films cast from mixtures of separately heat treated starch and zein, films made from the starch/zein mixtures heated together possessed higher water contact angle and tensile strength. Simple dry heating with zein could thus be used as a promising modification method for improving the functionality of edible films from starches. PMID- 27987831 TI - Development and characterization of a bioglass/chitosan composite as an injectable bone substitute. AB - SiO2-CaO-P2O5 based bioglass (BG) systems constitute a group of materials that have wide applications in bone implants. Chitosan (Cn) is a biocompatible and osteoconductive natural polymer that can promote wound healing. In this study, bioactivity of chitosan/bioglass (CnB) composites as minimally invasive bone regenerative materials was assessed both in vitro and in vivo. Injectability tests and scanning electron microscopy (SEM) results demonstrated the formation of uniform injectable paste-like composites using BG particles and Cn. Fourier transform infrared spectroscopy (FTIR) and SEM images confirmed hydroxyapatite deposition in vitro after incubation in simulated body fluid (SBF). Higher BG content in the composite correlated with increased human osteoblast proliferation. An in vivo study in a rat spinal fusion model confirmed that increasing the amount of BG improved osteoconductivity. Manual palpation, radiographic images and pathological assessments proved that the composites promote bone formation. Based on these data, the synthesized composites have a potential application in orthopedic and reconstructive surgeries as a minimally invasive bone substitute. PMID- 27987832 TI - Dual pH/redox responsive and CD44 receptor targeting hybrid nano-chrysalis based on new oligosaccharides of hyaluronan conjugates. AB - A smart hybrid microenvironment-mediated dual pH/redox-responsive polymeric nanoparticles combined with inorganic calcium phosphate (CaP) was fabricated, which we term as armored nano-chrysalis inspired by butterfly pupa. The nano chrysalis has an inner core composed of specially designed oligosaccharides of hyaluronan (oHA) targeting CD44 receptor. The inner core has two functions, i.e., the dual pH/redox responsive polymeric conjugate and the fluorescent curcumin prodrug function. The prepared nano-chrysalis possessed a smaller size (102.5+/ 4.6nm) than the unarmored nano-chrysalis (122.5+/-6.6nm). Interestingly, while the nano-chrysalis were stable under pH 7.4, when incubated under the tumor acidic conditions (pH 6.5) the outer CaP armor would dissolve in a pH-dependent, sustained manner. Moreover, nano-chrysalis was demonstrated to present the most effective antitumor efficacy than other formulations. This study provides a promising smart nano-carrier platform to enhance the stability, decrease the side effects, and improve the therapeutic efficacy of anticancer drugs. PMID- 27987833 TI - The polysaccharide and low molecular weight components of Opuntia ficus indica cladodes: Structure and skin repairing properties. AB - The Opuntia ficus-indica multiple properties are reflected in the increasing interest of chemists in the identification of its natural components having pharmaceutical and/or cosmetical applications. Here we report the structural elucidation of Opuntia ficus-indica mucilage that highlighted the presence of components differing for their chemical nature and the molecular weight distribution. The high molecular weight components were identified as a linear galactan polymer and a highly branched xyloarabinan. The low molecular weight components were identified as lactic acid, D-mannitol, piscidic, eucomic and 2 hydroxy-4-(4'-hydroxyphenyl)-butanoic acids. A wound healing assay was performed in order to test the cicatrizing properties of the various components, highlighting the ability of these latter to fasten dermal regeneration using a simplified in vitro cellular model based on a scratched keratinocytes monolayer. The results showed that the whole Opuntia mucilage and the low molecular weight components are active in the wound repair. PMID- 27987834 TI - Injectable hydrogels prepared from partially oxidized hyaluronate and glycol chitosan for chondrocyte encapsulation. AB - Hyaluronate has attracted great attention in tissue engineering as a scaffolding material. However, hyaluronate typically requires chemical cross-linking molecules to form hydrogels, which may induce undesirable side effects in the body. In this study, hyaluronate was partially oxidized with sodium periodate to generate aldehyde groups in the backbone, and simply mixed with glycol chitosan to form gels via Schiff base formation. The effects of the degree of oxidization, polymer concentration, and polymer composition on the mechanical properties of oxidized hyaluronate/glycol chitosan hydrogels were investigated in vitro. Degradation behavior and biocompatibility of oxidized hyaluronate/glycol chitosan gels were also evaluated in vitro. This system may be potentially useful as an injectable system in many tissue engineering applications, including cartilage regeneration. PMID- 27987835 TI - Monomer composition of chitooligosaccharides obtained by different degradation methods and their effects on immunomodulatory activities. AB - Three kinds of chitooligosaccharides were prepared using traditional (ZCOS), microwave irradiation (WCOS), and enzymatic hydrolysis (YCOS), and their monomer compositions and in vitro and in vivo immunomodulatory activities were determined. ZCOS was mainly comprised of disaccharides and trisaccharides; WCOS was mainly comprised of disaccharides to hexasaccharides with or without acetyl groups; and YCOS was mainly comprised of trisaccharides to pentasaccharides without acetyl groups. Differences in monomer composition and acetyl groups affected their immunomodulatory activities. Chitooligosaccharides degraded by different methods: all significantly stimulated the immune system by acting through cellular and humoral immunities. WCOS, obtained by microwave irradiation, had the best immunomodulatory activity. It significantly increased the spleen index and significantly stimulated delayed-type hypersensitivity compared the other two chitooligosaccharides. These activities might have been the result of the hexamer and acetyl groups of WCOS. PMID- 27987836 TI - Chemical structure, antiproliferative and antioxidant activities of a cell wall alpha-d-mannan from yeast Kluyveromyces marxianus. AB - Cell wall polysaccharides from filamentous fungi and yeasts have been reported as antioxidant and antiproliferative polymers. Thus, we evaluated these activities from cell wall polysaccharides from Kluyveromyces marxianus CCT7735. By using a centrifugal filter, a 203kDa alpha-d-mannan (KMM-5) was obtained. KMM-5 exhibited no effect on HeLa cells and a weak antiproliferative activity against Hep-G2 cells. In addition, at higher concentrations, it presented a cytotoxicity to the normal cell line, 3T3. However, KMM-5 showed copper- and iron-chelating abilities, the latter of which presented improved activity. By using 2D-NMR COSY, HSQC edited and HMBC experiments, a structure arrangement was proposed. The main chain was formed by 6)-alpha-d-Manp-(1->6) units substituted at the 2-O-position by non-reducing terminals alpha-d-Manp-(1->2) and by a branched tetrasaccharide. The latter was formed by an internal 2)-alpha-d-Manp-(1->2) unit with linked to it a 2,3)-alpha-d-Manp-(1->2) unit substituted at the 2-O-position by a non reducing terminal alpha-d-Manp-(1->2), and at the 3-O-position by a non-reducing terminal alpha-d-Manp-(1->3). In conclusion, we considered K. marxianus CCT7735 a source of natural and renewable polysaccharides with pharmacological properties. PMID- 27987837 TI - Pilot production of ulvans from Ulva sp. and their effects on hyaluronan and collagen production in cultured dermal fibroblasts. AB - Ulvans from Ulva sp. were tested for their potential cosmetic properties on human dermal fibroblasts. The crude ulvans (ULVAN-01, 57kDa), extracted using a patented acid- and solvent-free process, were subjected to depolymerization using ion exchange resin to obtain a low molecular weight ulvan (ULVAN-DEP, 4kDa). The biochemical characterization and UHPLC-HRMS analyses of these extracted ulvans showed that they were of high purity and predominantly composed of a repeated ulvanobiouronic acid disaccharide. Fibroblast proliferation, as well as hyaluronan and collagen release were assessed, demonstrating that ULVAN-01 reduced fibroblast proliferation rate while ULVAN-DEP had no significant effect. Both ulvans were ineffective to induce collagen production but induced a significant increase in hyaluronan production, with a strong influence of the molecular weight. Thus, crude and depolymerized ulvans had different metabolic activities on dermal fibroblasts, which makes them promising to envisage further development in the skin care field. PMID- 27987838 TI - Pectin from carrot pomace: Optimization of extraction and physicochemical properties. AB - In this study, the central composite design for four variables in five levels was applied to determine the effects of pH (0.5-2.5), temperature (50-90 degrees C), heating time (30-150min) and liquid/solid ratio (10-50v/w) on the yield and degree of esterification (DE) of carrot pomace pectin. The results showed that the pectin yield ranged from 5.0 to 15.2% and also, this pectin is classified as low methoxyl pectin (DE of 22.1-51.8%). The pH of 1.3, temperature of 90 degrees C, time of 79.8min and liquid/solid ratio of 23.3v/w were determined as optimal conditions with a maximum yield of 15.6+/-0.5%, which was close to the predicted values (16.0%). Under the optimal extraction conditions, the galacturonic acid content and emulsifying activity were 75.5 and 60.3% respectively; moreover, the emulsions had a high stability at two different storage temperatures (4 and 23 degrees C). Furthermore, carrot pectin solutions exhibited viscous and pseudoplastic behavior at 1% w/v. PMID- 27987839 TI - Polymer blend of PLA/PHBV based bionanocomposites reinforced with nanocrystalline cellulose for potential application as packaging material. AB - The current research discusses the development of poly (lactic acid) (PLA) and poly-(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) reinforced nanocrystalline cellulose bionanocomposites. The nanocrystalline cellulose was derived from waste oil palm empty fruit bunch fiber by acid hydrolysis process. The resulting nanocrystalline cellulose suspension was then surface functionalized by TEMPO mediated oxidation and solvent exchange process. Furthermore, the PLA/PHBV/nanocrystalline cellulose bionanocomposites were produced by solvent casting method. The effect of the addition of nanocrystalline cellulose on structural, morphology, mechanical and barrier properties of bionanocomposites was investigated. The results revealed that the developed bionanocomposites showed improved mechanical properties and decrease in oxygen permeability rate. Therefore, the developed bio-based composite incorporated with an optimal composition of nanocrystalline cellulose exhibits properties as compared to the polymer blend. PMID- 27987840 TI - Mechanical and moisture sensitivity of fully bio-based dialdehyde carboxymethyl cellulose cross-linked soy protein isolate films. AB - Dialdehyde carboxymethyl cellulose (DCMC) crosslinked soy protein isolate (SPI) films were prepared by solvent casting method. Effect of DCMC treatment on mechanical properties, water sensitivity, light barrier properties and thermal stability were investigated. Significant increase in tensile strength (TS) was observed (up to 218%), suggesting occurrence of highly effective crosslinking between SPI and DCMC. Significant improvement in TS compared to other dialdehyde polysaccharide crosslinking agents such as dialdehyde starch is likely due to higher compatibility of DCMC with SPI, as was further confirmed by SEM images. Crosslinking also led to reduction in water vapor permeability and moisture content along with an increase of insoluble mass percentage, indicating improvement in water resistance of these bio-based protein films. Thermal stability of protein films also showed improvement post crosslinking of DCMC. PMID- 27987841 TI - Biocompatible testing and physical properties of curdlan-grafted poly(vinyl alcohol) scaffold for bone tissue engineering. AB - Curdlan was grafted to poly(vinyl alcohol) (PVA) to form a porous scaffold. The grafted PVA-curdlan 3D scaffold was then examined by Fourier transform infrared spectroscopy (FT-IR). Grafting increased the water absorbency of the scaffold by 280%. Scanning electron microscopic (SEM) observations of the material revealed that the 3D scaffold was highly porous when it was fabricated using a homogenizer at 300rpm. Compression testing revealed that, increasing the amount of curdlan increased the strength of the 3D scaffold to 8-16*10-3MPa. Over 28days, various enzymes degraded the 3D scaffold, causing a weight loss of up to 20-40%. In vivo tests revealed favorable cell proliferation and growth in a 3D scaffold. PMID- 27987842 TI - Synthesis of tunable hydrogels based on O-acetyl-galactoglucomannans from spruce. AB - Hydrogels with tunable mechanical properties based on O-acetyl galactoglucomannans (GGMs) from spruce functionalized with tyramine, a molecule containing crosslinkable phenolic groups, were prepared. Gel formation was induced by enzymatic crosslinking at the addition of horse radish peroxidase and hydrogen peroxide to the modified GGMs. The degree of substitution determined the hydrogels final properties, and was varied by TEMPO oxidation of GGM to a degree of oxidation from 10 to 60%. GGM and its derivatives were characterized by gas chromatography and high pressure size exclusion chromatography to analyze sugar composition and molar mass, respectively. Tyramine-conjugated GGM was evaluated by nuclear magnetic resonance, fourier transform infrared spectroscopy and elemental analysis. Measurements of moduli over time showed crosslinking within 20s and maximum stress of the prepared gels were compared by compression testing. Overall this system presents a cell friendly hydrogel from a renewable, low cost resource which could be applied in cell delivery, wound dressings, and biofabrication. PMID- 27987843 TI - Simple citric acid-catalyzed surface esterification of cellulose nanocrystals. AB - A simple straightforward route for the surface esterification of cellulose nanocrystals (CNC) is herein proposed. CNC obtained from microcrystalline cellulose were acetylated using as catalyst citric acid, a alpha-hydroxy acid present in citrus fruits and industrially produced by certain molds in sucrose or glucose-containing medium. No additional solvent was added to the system; instead, the acylant (acetic anhydride) was used in sufficient excess to allow CNC dispersion and proper suspension agitation. By tuning the catalyst load, CNC with two different degree of substitution (i.e. DS=0.18 and 0.34) were obtained. Acetylated cellulose nanocrystals were characterized in terms of chemical structure, crystallinity, morphology, thermal decomposition and dispersion in a non-polar solvent. Results illustrated for the first time the suitability of the protocol proposed for the simple surface acetylation of cellulose nanocrystals. PMID- 27987844 TI - Homogeneous esterification mechanism of bagasse modified with phthalic anhydride in ionic liquid. Part 2: Reactive behavior of hemicelluloses. AB - The phthalation of bagasse was comparatively investigated with the isolated three main components in 1-allyl-3-methylidazium chloride (AmimCl) to reveal the reaction behavior of bagasse. In the present study, the reaction behavior of hemicelluloses during the homogeneous phthalation was extensively explored. The phthalation degree of hemicellulosic samples ranged from 16.37% to 52.14%. The reaction priority on the main and side chains of hemicelluloses were revealed by the changes of monosaccharide contents upon phthalation. The results indicated that side-chains of hemicelluloses were more easily phthalated than main-chains, and the phthalation of secondary hydroxyl groups on uronic acids was more difficult than that on neutral sugars. 13C NMR and HSQC analyses suggested the similar reactivity of the secondary hydroxyls at C-2 and C-3 positions in anhydroxylose units. These results provide more detailed understanding of the homogenous modification of lignocellulose. PMID- 27987845 TI - Alginate/bacterial cellulose nanocomposite beads prepared using Gluconacetobacter xylinus and their application in lipase immobilization. AB - Alginate/bacterial cellulose nanocomposite beads, with well-controlled size and regular spherical shapes, were prepared in a simple manner by entrapping Gluconacetobacter xylinus in barium alginate hydrogel beads, followed by cultivation of the entrapped cells in culture media with a low sodium ion concentration. The entire surface of the alginate hydrogel beads containing the cells was covered with cellulose fibers (~30nm) after 36h of cultivation. The cellulose crystallinity index of the alginate/bacterial cellulose beads was 0.7, which was slightly lower than that of bacterial cellulose prepared by cultivating dispersed cells. The water vapor sorption capacity of the alginate/bacterial cellulose beads increased significantly from 0.07 to 38.00 (g/g dry bead) as cultivation time increased. These results clearly indicate that alginate/bacterial cellulose beads have a much higher surface area, crystallinity, and water-holding capacity than alginate beads. The immobilization of lipase on the surface of the nanocomposite beads was also investigated as a potential application of this system. The activity and specific activity of lipase immobilized on alginate/bacterial cellulose beads were 2.6- and 3.8-fold higher, respectively, than that of lipase immobilized on cellulose beads. The alginate/bacterial cellulose nanocomposite beads prepared in this study have several potential applications in the biocatalytic, biomedical, and pharmaceutical fields because of their biocompatibility, biodegradability, high crystallinity, and large surface area. PMID- 27987846 TI - Differential growth of bowel commensal Bacteroides species on plant xylans of differing structural complexity. AB - Alterations to the composition of the bowel microbiota (dysbioses) are associated with particular diseases and conditions of humans. There is a need to discover new, indigestible polysaccharides which are selective growth substrates for commensal bowel bacteria. These substrates (prebiotics) could be added to food in intervention studies to correct bowel dysbiosis. A collection of commensal bacteria was screened for growth in culture using a highly-branched xylan produced by New Zealand flax. Two, Bacteroides ovatus ATCC 8483 and Bacteroides xylanisolvens DSM 18836 grew well on this substrate. The utilisation of the xylan was studied chromatographically and by constituent sugar analysis. The two closely related species utilised the xylan in different ways, and differently from their use of wheat arabinoxylan. The growth of Bacteroides species on other plant xylans having differing chemical structures was also investigated. Novel xylans expand the choice of potential prebiotics that could be used to correct bowel dysbioses. PMID- 27987848 TI - Pre- and post-modification of mixed cyclodextrin-calixarene co-polymers: A route towards tunability. AB - Various pre-modified and post-modified cyclodextrin-calixarene hyper-reticulated co-polymers were synthesized, fully characterized by different techniques (FT-IR, 13C{1H} CP-MAS and LGFS solid-state NMR, thermogravimetry, porosimetry), and tested to assess their absorption abilities as nanosponges. The construction of the polymer network was accomplished exploiting the well-known CuAAC reaction between two different heptakis-6-azido-beta-cyclodextrins and two different propargyloxy-calix[4]arenes. Post-modification was aimed to achieve the presence of ionizable (acidic or basic) groups on the polymer framework. Sequestration tests towards two model pollutant molecules surprisingly showed that both pristine and post-modified materials actually possess the abilities to act as pH tunable nanosponges. PMID- 27987847 TI - Preparation and characterization of chitosan physical hydrogels with enhanced mechanical and antibacterial properties. AB - The chitosan physical hydrogels formed under gaseous ammonia atmospheres usually have poor mechanical properties and low antibacterial activities, which limit its application as biomaterials. In the current study, CTS-Ag+/NH3 physical hydrogels with great comprehensive properties were prepared by the gelation of chitosan in the presence of AgNO3 under a gaseous ammonia atmosphere. Compared with the previously reported hydrogels made with chitosan and AgNO3, the CTS-Ag+/NH3 hydrogels were more homogeneous and transparent. In addition, the AgNO3 content in the hydrogels was decreased to 0.064-0.424wt.%. The formation mechanism and the influence of reaction conditions on the structures and properties of CTS Ag+/NH3 physical hydrogels were characterized by FT-IR, SEM, XPS, XRD and rheological measurement. Tensile testing suggested that CTS-Ag+/NH3 physical hydrogels had a higher tensile strength than the CTS/NH3 hydrogel. Moreover, the CTS-Ag+/NH3 physical hydrogels showed excellent antibacterial activities against both gram positive and negative bacteria. PMID- 27987849 TI - Heat-induced conformation transition of the comb-branched beta-glucan in dimethyl sulfoxide/water mixture. AB - We studied the chain conformation transition of the comb-branched beta-glucan (AF1) isolated from Auricularia auricula-judae by heating associated with dimethyl sulfoxide (DMSO). The results from 1H NMR and differential scanning calorimeter (DSC) indicated that the reversible hydrogen bonds between side chains of AF1 and water clusters formed at relatively low temperatures. With increasing vDMSO to 0.70, the transition temperature (Tm) increased from 9 to 71 degrees C, and then decreased to 57 degrees C with continuously increasing vDMSO due to the competition between DMSO and water for forming hydrogen bonds. Additionally, the combined analysis of 13C NMR, viscosity and light scattering revealed an obvious stiff-to-flexible chain conformation transition of AF1, which occurred at 95-130 degrees C, 120-145 degrees C and 130-160 degrees C with vDMSO of 0.90, 0.85 and 0.70, respectively. This work demonstrated that AF1 has complex structure under different conditions, and the results obtained herein would benefit us to understand its specific behaviors including hollow fibril and anti hepatoma activity. PMID- 27987850 TI - Influence of ultrasonic treatment on formation of amylose nanoparticles prepared by nanoprecipitation. AB - Amylose aqueous solutions (1wt%, 3wt% and 5wt%) were treated with 100W ultrasound for various periods of time and used to prepare amylose nanoparticles (ANPs) via nanoprecipitation by adding the amylose solutions drop-wise into absolute ethanol. Viscosity average molecular weight and size distribution of the ultrasonic treated amylose were determined by measuring intrinsic viscosity and using size exclusion chromatography, respectively. The ANPs were characterized using dynamic light scattering, scanning electron microscopy, and X-ray diffraction. Results showed that the ultrasonic treatments led to decrease in viscosity of amylose solutions, scission of amylose chains, and narrowing of size distribution of amylose molecules, which gave rise to smaller ANPs with more uniform size. The effect of the ultrasonic treatments on crystalline structure of the ANPs was negligible. This study indicates that ultrasonic treatment can be utilized to prepare smaller starch nanoparticles through nanoprecipitation with higher efficiency and lower cost. PMID- 27987851 TI - Grafting of polyethylenimine onto cellulose nanofibers for interfacial enhancement in their epoxy nanocomposites. AB - Cellulose nanofibers (CNFs) were surface-modified with polyethyleneimine (PEI), which brought plentiful amine groups on the surface of CNFs, leading to a reduced hydrogen bond density between CNFs and consequently less CNFs agglomerates. The amine groups could also react with the epoxy as an effective curing agent that could increase the interfacial crosslinking density and strengthen interfacial adhesion. The tensile strength and Young's modulus of CNFs-PEI/Epoxy nanocomposites were 88.1% and 237.6% higher than those of neat epoxy, respectively. The tensile storage modulus of the nanocomposites also increased significantly at the temperature either below or above the Tg. The coefficient of thermal expansion for the CNFs-PEI/Epoxy nanocomposites was 22.2ppmK-1, much lower than that of the neat epoxy (88.6ppmK-1). In addition, the thermal conductivity of the nanocomposites was observed to increase as well. The exceptional and balanced properties may provide the nanocomposites promising applications in automotive, construction and electronic devices. PMID- 27987852 TI - Surface functionalization of cellulose nanocrystals with polymeric ionic liquids during phase transfer. AB - In this study, the cellulose nanocrystals (CNCs) were prepared by method of acid hydrolysis, while the polymeric ionic liquid (PIL) [PEP-MIM]DBS was synthesized by epichlorohydrin, o-phthalic anhydride as well as N-methylimidazole then anion exchanged by sodium dodecyl benzene sulfonate. It was demonstrated that [PEP MIM]DBS could modify CNCs by non-covalent interaction to change its surface properties, such as amphiphilicity. The chemical structure of the composite CNCs/[PEP-MIM]DBS was characterized via FTIR, 13C NMR, TGA, XRD, etc. Moreover, the properties and applications were characterized through a series of dispersion experiments, contact angle tests, FE-SEM, etc. This study showed that the PIL modification improved the dispersion of CNCs in non-polar organic solvents with their chemical structure integrated. PMID- 27987853 TI - Exfoliation/dispersion of low-temperature expandable graphite in nanocellulose matrix by wet co-milling. AB - Viability and future of graphene depends, to a great extent, on a methodology that can mass-produce high-quality graphene in an affordable way. In this work, wet co-milling of low-temperature expandable graphite (LTEG) with bamboo cellulose fibers through a grinder was proved to be a scalable and environmentally friendly approach for the exfoliation/dispersion of graphene-like carbon in an aqueous suspension in which the mechanically isolated cellulose nanofibers (CNFs) acted as a "green" dispersant. The exfoliation/dispersion degree of LTEG was studied as a function of passing times through the grinder. Under the assistance of CNFs, stable aqueous dispersions of CNFs/few-layer graphene (FLG) were obtained. Based on the CNFs/FLG dispersions, a series of nanocomposite films with high mechanical strength and excellent flexibility were fabricated. The tensile strength, Young's modulus, and elongation at break of the CNFs/FLG nanocomposite film were enhanced to 59.14MPa, 4.13GPa and 4.17% respectively after 100 passing times through the grinder. However, with the passing time increased, the electrical conductivity and electromagnetic interference shielding effectiveness (EMI SE) decreased, in agreement with the good dispersion of FLG in CNFs matrix. The strategy proposed here is simple, highly efficient, and low in cost, exhibiting great potential for producing exfoliated FLG with few defects at an industrial scale. PMID- 27987854 TI - Synthesis and bio-evaluation of xylan-5-fluorouracil-1-acetic acid conjugates as prodrugs for colon cancer treatment. AB - In the present study, xylan-5-fluorouracil-1-acetic acid (Xyl-5-FUAC) conjugates as colon specific prodrugs were synthesized and evaluated by in-vitro release study. The chemical stability of the conjugates was performed in acidic (pH 1.2) and basic buffers (pH 7.4), which showed their stability in upper gastrointestinal tract. The in-vitro drug release profiles of the conjugates were studied in the presence of rat's gastrointestinal contents. The results showed that the low amounts of drug 3-4% and 5-7% were released in gastric and small intestine contents respectively, while 53-61% of the drug was released in cecum and colonic contents. The cytotoxicity studies of the conjugates were also evaluated on human colorectal cancer cell line (HTC-15 and HT-29), which showed that the conjugates are more cytotoxic than the free drug. Therefore the results reveal that Xyl-5-FUAC conjugates are potential candidates for colon specific drug delivery in the treatment of colonic cancer with minimal undesirable side effects. PMID- 27987855 TI - Enhancement of membrane stability on magnetic responsive hydrogel microcapsules for potential on-demand cell separation. AB - It is of high interest to obtain hydrogel membranes with optimum mechanical stability, which is a prerequisite to the successful fabrication of hydrogel microcapsules for cell separation. In this work, we developed magnetic responsive alginate/chitosan (MAC) hydrogel microcapsules by co-encapsulation of microbial cells and superparamagnetic iron oxide nanoparticles (SPIONs) reacting under a high voltage electrostatic field. We investigated the influence of the molecular weight of chitosan, microcapsules size, and membrane crosslinking time on the swelling behavior of microcapsules as an indicator of stability of the membranes. The results demonstrated that the suitable membrane stability conditions were obtained by a crosslinking of the microspheres with a chitosan presenting a molecular weight of 70kDa for 15-30min resulting in a membrane thickness of approximately 30mm. Considering the need of maintaining the cells inside the microcapsules, fermentation at 37 degrees C and at neutral pH was favorable. Moreover, the MAC microcapsules sizing between 300 and 380MUm were suitable for immobilizing Bacillus licheniformis in a 286h multiple fed-bath operation with no leakage of the SPIONs and cells. Overall, the results of this study provided strategies for the rational design of magnetic microcapsules exhibiting suitable mechanical stable membranes. PMID- 27987856 TI - Development of in vitro resistance to chitosan is related to changes in cell envelope structure of Staphylococcus aureus. AB - The bacterial cell envelope is believed to be a principal target for initiating the staphylocidal pathway of chitosan. The present study was therefore designed to investigate possible changes in cell surface phenotypes related to the in vitro chitosan resistance development in the laboratory strain S. aureus SG511 Berlin. Following a serial passage experiment, a stable chitosan-resistant variant (CRV) was identified, exhibiting >50-fold reduction in its sensitivity towards chitosan. Our analyses of the CRV identified phenotypic and genotypic features that readily distinguished it from its chitosan-susceptible parental strain, including: (i) a lower overall negative cell surface charge; (ii) cross resistance to a number of antimicrobial agents; (iii) major alterations in cell envelope structure, cellular bioenergetics and metabolism (based on transcriptional profiling); and (iv) a repaired sensor histidine kinase GraS. Our data therefore suggest a close nexus between changes in cell envelope properties with the in vitro chitosan-resistant phenotype in S. aureus SG511-Berlin. PMID- 27987857 TI - Effective attenuation of vascular restenosis following local delivery of chitosan decorated sirolimus liposomes. AB - Assuring the efficient local delivery via biocompatible nanosystems can be considered as a promising therapy for restenosis. The aim of the present study was preparation, in vitro characterization, and in vivo efficacy evaluation of sirolimus containing chitosan decorated liposomes for restenosis treatment. Liposomes were coated with chitosan, leading to ~38nm increase in the particle size and a positive shift in the zeta potential from -1mV to +21mV. Chitosan modification was also confirmed by TEM, increased stability against detergent solubilization, and FTIR analyses. High entrapment efficiency (>=83%) and sustained release behaviors were demonstrated in both coated and uncoated vesicles. Compared to control groups, treatment of balloon injured rats with uncoated and chitosan-coated liposomes (50MUg sirolimus) significantly reduced stenosis by 39% and 62%, respectively. The effect was also confirmed by immunohistochemical and in vivo CT angiography imaging studies. Chitosan-coated liposomes could be a novel platform for restenosis treatment. PMID- 27987858 TI - Co-delivery of antineoplastic and protein drugs by chitosan nanocapsules for a collaborative tumor treatment. AB - Although combination delivery (co-delivery) shows much superiority in the defect compensation of single-agent therapy, the construction and application of co delivery systems are still challenging, especially for protein-based joint systems. In this work, a series of chitosan (CS)-amino acid derivatives (Arg-CS, Lys-CS, and Phe-CS) with different degrees of substitution (DS) were synthesized to prepare CS nanocapsules (CNCs) using a simple emulsification method in the presence of linoleic acid (LA). The hydrophobic drug can be loaded in LA droplets, and a positively charged protein stabilized the optimized Arg-CS nanocapsules (Arg-CNCs) on their negative surfaces. The in vitro antitumor efficacy of Arg-CNCs co-delivering paclitaxel and recombinant human caspase-3 was evaluated in HeLa cells. The co-delivery system displayed much lower IC50 values and a higher percentage of apoptotic cells compared with the control groups. This system provides a promising and universal strategy for co-delivery, leading to collaborative tumor treatment. PMID- 27987859 TI - Physicochemical characterization of kappa-carrageenan (Euchema cottoni) based films incorporated with various plant oils. AB - This study investigated the effects of different types of plant oil (olive oil, corn oil, soybean oil and sunflower oil) on the physical and mechanical properties of kappa-carrageenan films from Euchema cottoni species. The incorporation of plant oils increased the film thickness significantly (P<0.05). However, the moisture content, solubility and tensile strength of films decreased significantly (P<0.05) as plant oils were added. The incorporation of plant oils also contributed to a plasticizing effect, whereby the values for elongation at break increased significantly (P<0.05), from 22.3% to 108.8%. Higher oil content also led to carrageenan films with lower opacity, which contradicted with previous studies. In conclusion, the plant oils used in this research significantly improved film properties, thus demonstrating the potential of these materials to be used as food packaging films and coatings. PMID- 27987860 TI - Cellulose oxidation by Laccase-TEMPO treatments. AB - In this work, laccase-TEMPO (Lac-T) treatments were applied to bleached commercial dissolving pulp in order to introduce carbonyl and carboxyl groups, which were found to improve dry and wet strength-related properties. Also the solubility behavior towards xanthate reactions was assessed. The effect of a refining step (R) before the oxidative treatment, the absence or presence of oxygen pressure, TEMPO dose (2 or 8% oven dried pulp) and reaction time (8 or 20h) were thoroughly examined. Treatments conducted in the presence of oxygen pressure exhibited greater amount of functional groups. Introducing a pre refining treatment resulted in similar functional groups but higher wet strength was achieved. Specifically, a high W/D strength ratio was observed, indicating that wet strength-related property was satisfactorily developed. Besides the fact that all Lac-T treatments caused severe cellulose degradation, no fiber strength loss was detected. In fact, all oxidized samples presented higher Wet Zero-Span Tensile Strength, mainly in R+ Lac-T (O2) sample, which suggested the formation of hemiacetal linkages between the new introduced aldehyde groups and available free hydroxyl groups resulting from fibrillation. PMID- 27987861 TI - Fabrication and mechanical properties of composite based on beta-chitin and polyacrylic acid. AB - Squid beta-chitin has been exfoliated in aqueous acrylic acid (AA), after which a composite film of chitin microfibrils in polyacrylic acid (PAA) has been prepared by in situ polymerization of the AA. The segregated chitin fibrils in the composite are 4-6nm in diameter, with an aspect ratio >250. After drying cast films of the composites containing 1, 2 and 3% (w/w) chitin at 140 degrees C for four hours, there was a dramatic resistance to swelling in water, in that the dried films showed only small changes in shape and properties after four hours immersed in water.The most profound impact of the reinforcement on the mechanical properties is observed at high relative humidity (RH), when the PAA is in the rubbery state. At 97.5% RH and room temperature, the elastic moduli of the composites with 1, 2 and 3% (w/w) chitin were 150, 230 and 2100MPa respectively, compared to 65MPa for pure PAA. The main contribution to the filler-reinforcing effect is the high aspect ratio of fibrils and non-covalent interactions, but the stability in water suggests the presence of chemical bonding between the PAA and chitin. PMID- 27987863 TI - Facile production of nanostructured cellulose from Elaeis guineensis empty fruit bunch via one pot oxidative-hydrolysis isolation approach. AB - Cellulose in nanostructures was successfully isolated from empty fruit bunch biomass via a novel one-pot oxidative-hydrolysis technique. The physicochemical properties of nanocellulose prepared via one-pot process have shown comparable characteristics as products isolated via conventional multistep purification approach (namely dewaxing, chlorite bleaching process, alkalization, and acid hydrolysis). The chemical composition study indicated that the one-pot oxidative hydrolysis process successfully extracted cellulose (91.0%), with the remaining minority being hemicellulose and lignin (~6%) in the final product. Crystallinity profile of one-pot treated product (80.3%) was higher than that of multistep isolated nanocellulose (75.4%), which indicated that the disorder region (amorphous) in cellulose fibers was successfully removed. In additional to that, the morphology study demonstrated that nanocellulose prepared by one-pot process rendered spider-web-like network nanostructure, with an average diameter of fibers at a range of 51.6+/-15.4nm. The nanocellulose product showed high thermal stability (320 degrees C), which was ready for nanocomposite application. One-pot oxidative-hydrolysis technique is a simple and versatile route for the preparation of nanocellulose from complex biomass within 90 degrees C and 6h period, with minimum wastewater as compared to the multistep process. PMID- 27987864 TI - 1D NMR methods for determination of degree of cross-linking and BDDE substitution positions in HA hydrogels. AB - Hyaluronic acid polymers cross-linked with BDDE are today among the most used hydrogels for biomedical applications. The physical properties of the hydrogels depend, among other parameters, on the degree of cross-linking of HA. Another parameter likely to affect the physical properties is the substitution position of the linker on the HA functional groups. A NMR-based method for the determination of these parameters in hyaluronic acid hydrogels is presented. The method is based on the degradation of HA cross linked hydrogels by chondroitinase ABC followed by one-dimensional 1H and 13C NMR analysis. The necessary structural information to obtain both the degree of cross-linking and the substitution positions can be obtained from the same NMR sample and no chromatographic separation step is required prior to NMR analysis. PMID- 27987862 TI - Structural features and anticancer activity in vitro of fucoidan derivatives from brown alga Saccharina cichorioides. AB - A fucoidan ScF from brown alga Saccharina cichorioides was extracted, purified and partially depolymerized by autohydrolysis at 37 degrees C for 24, 48 and 72h. Supernatant (SN) and pellet (PL) fractions were obtained by ethanol precipitation of each sample. Unlike spectral data of ScF, NMR of PL derivatives clearly suggested the structure: 1,3-linked alpha-l-Fucp-4-OSO3- repeating unit. Molecular weights (MWs) of PL fractions were 30, 26 and 18kDa for 24, 48 and 72h of autohydrolyis, respectively. MALDI-TOFMS, size-exclusion HPLC and carbohydrate polyacrylamide-gel electrophoresis (C-PAGE) indicated a similarity of SN mixtures. They consisted mainly of a polysaccharide part (MW 6kDa, C-PAGE data) with a structure similar to PL components (NMR data) and monosaccharides alpha-l Fucp-4-OSO3-, alpha-l-Fucp-2,4-di-OSO3-. PL fractions exhibited almost identical antiproliferative activity in vitro as native fucoidan, while an SN sample for 72h of autohydrolysis was slightly more active against colony formation of colorectal carcinoma cells HT-29. PMID- 27987865 TI - Effect of the glass transition temperature on alpha-amylase activity in a starch matrix. AB - This study optimises a protocol for the estimation of alpha-amylase activity in a condensed starch matrix in the vicinity of the glass transition region. Enzymatic activity on the vitrified starch system was compared with that of a reference substrate, maltodextrin. The activity was assayed as the rate of release of reducing sugar using a dinitrosalicylic acid procedure. The condensed carbohydrate matrices served the dual purpose of acting as a substrate as well as producing a pronounced effect on the ability to enzymatic hydrolysis. Activation energies were estimated throughout the glass transition region of condensed carbohydrate preparations based on the concept of the spectroscopic shift factor. Results were used to demonstrate a considerable moderation by the mechanical glass transition temperature, beyond the expected linear effect of the temperature dependence, on the reaction rate of starch hydrolysis by alpha amylase in comparison with the low-molecular weight chain of maltodextrin. PMID- 27987866 TI - Spongy bilayer dressing composed of chitosan-Ag nanoparticles and chitosan Bletilla striata polysaccharide for wound healing applications. AB - The purpose of this study was to develop a promising wound dressing. Though chitosan cross-linked with genipin has been widely used as biomaterials, with the addition of partially oxidized Bletilla striata polysaccharide, the newly developed material in this study (coded as CSGB) showed less gelling time, more uniform aperture distribution, higher water retention, demanded mechanical strength and more L929 cell proliferation compared to the chitosan cross-linked only with genipin. Owning to partial blocking of free amino groups of chitosan, CSGB revealed almost no antibacterial activities, thus the bilayer composite of chitosan-silver nanoparticles (CS-AgG) on CSGB was designed to inhibit microbial invasion. The in vivo studies indicated that both CSGB and bilayer wound dressing significantly accelerated the healing rate of cutaneous wounds in mice, and the bilayer exhibited better mature epidermization with less inflammatory cells on Day 7. Therefore, this novel bilayer composite has great potential in wound dressing applications. PMID- 27987867 TI - Optical devices for the detection of cyanide in water based on ethyl(hydroxyethyl)cellulose functionalized with perichromic dyes. AB - Films of three polymers, based on ethyl(hydroxyethyl)cellulose functionalized with protonated perichromic dyes, were used for anion sensing. The polymer functionalized with protonated Brooker's merocyanine acts as a chromogenic/fluorogenic system for the selective detection of cyanide in water. An increase of >28 times was verified for the fluorescence lifetime of the sensing units in the polymer in comparison with protonated Brooker's merocyanine in water. Moreover, an increase in the pKa values was verified for the sensing units in the polymers. Data suggest that the hydrocarbonic polymeric chains provide an adequate microenvironment to protect the sensing unit from bulk water. The other polymer, functionalized with an iminophenol, also showed high selectivity for cyanide (detection limit=9.36*10-6molL-1 and quantification limit=3.12*10-5molL-1). The polymer functionalized with azophenol units is unable for the detection of cyanide, due to the low pKa value verified for its chromogenic units. PMID- 27987868 TI - Cellulose nanocrystals as templates for cetyltrimethylammonium bromide mediated synthesis of Ag nanoparticles and their novel use in PLA films. AB - In the present paper, we reported how cellulose nanocrystals (CNC) from microcrystalline cellulose have the capacity to assist in the synthesis of metallic nanoparticles chains. A cationic surfactant, cetyltrimethylammonium bromide (CTAB), was used as modifier for CNC surface. Silver nanoparticles were synthesized on CNC, and nanoparticle density and size were optimized by varying concentrations of nitrate and reducing agents, and the reduction time. The experimental conditions were optimized for the synthesis and the resulting Ag grafted CNC (Ag-g-CNC) were characterized by means of TGA, SEM, FTIR and XRD, and then introduced in PLA matrix. PLA nanocomposite containing silver grafted cellulose nanocrystals (PLA/0.5Ag-g-1CNC) was characterized by optical and thermal analyses and the obtained data were compared with results from PLA nanocomposites containing 1% wt. of CNC (PLA/1CNC), 0.5% wt. of silver nanoparticles (PLA/0.5Ag) and hybrid system containing CNC and silver in the same amount (PLA/1CNC/0.5Ag). The results demonstrated that grafting of silver nanoparticles on CNC positively affected the thermal degradation process and cold crystallization processes of PLA matrix. Finally, the antibacterial activity of the different systems was studied at various incubation times and temperatures, showing the best performance for PLA/1CNC/0.5Ag based nanocomposite. PMID- 27987869 TI - Minor polysaccharidic constituents from the red seaweed Hypnea musciformis. Appearance of a novel branched uronic acid. AB - Two polysaccharide fractions isolated from Hypnea musciformis after room temperature- and hot water extraction, soluble after KCl precipitation of the more abundant carrageenans, were subfractionated by ion-exchange chromatography eluting with increasing concentrations of NaCl. The lowest NaCl concentration (0.2M) eluted agarans. The dl-hybrids (or mixtures) eluted at intermediate concentrations of NaCl. The d/l-galactose ratio and the sulfate proportion increased with the NaCl concentration. Different types of substitution were present, mainly at C-3 with sulfate, Xyl and methylated Gal stubs, as well as low amounts of 3,6-AnGal. A novel constituent, identified as 3-C-carboxy-d-erythrose1 in its beta-furanosic form, was found linked to C-6 of beta-Gal units. A search carried out in other species like Iridaea undulosa and Kappaphycus alvarezii also revealed the same constituent. Finally, the late-eluting fractions were mostly carrageenans, with a structure consistent with that of a kappa/iota/nu carrageenan hybrid. PMID- 27987870 TI - Synthesis of chitosan/polyvinyl alcohol/zeolite composite for removal of methyl orange, Congo red and chromium(VI) by flocculation/adsorption. AB - A chitosan/polyvinyl alcohol (PVA)/zeolite composite was fabricated in this study. The composite was analyzed through field emission scanning electron microscopy, Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), thermogravimetric analysis, and weight loss test. FTIR and XRD results revealed a strong interaction among chitosan, PVA, and zeolite. Weight loss test results indicated that the composite was stable in acidic and basic media. Congo red was removed through flocculation, and the removal rate was 94% at an initial concentration of 100mg/L for a dose of 1g/L. The removal rate of methyl orange was controlled by adsorption at an initial concentration of less than 100mg/L. Flocculation occurred at high concentrations. The removal rate was also 94% at an initial concentration of 500mg/L for a dose of 5g/L. The adsorption behavior of the composite for the removal of methyl orange and Cr(VI) was described by using a pseudo-second-order kinetic model. The adsorption capacity of the composite for Cr(VI) was 450mg/g. Therefore, the synthesized composite exhibited versatility during the removal of dyes and heavy metals. PMID- 27987871 TI - Nanocrystalline cellulose extracted from pine wood and corncob. AB - The extraction of nanocrystalline cellulose from agro-residues is an interesting alternative to recover these materials. In the present study, nanocrystalline cellulose was extracted from pine wood and corncob. In addition, microcrystalline cellulose was used as a reference to compare results. Initially, the lignocellulosic residues were submitted to delignification pre-treatments. At the end of the process, the bleached fibre was submitted to acid hydrolysis. Additionally, microparticles were obtained from the spray-drying of the nanocrystalline cellulose suspensions. The nanocrystalline cellulose yield for the pine wood was 9.0-% of the value attained for the microcrystalline cellulose. For the corncob, the value was 23.5-%. Therefore, complementary studies are necessary to improve the yield. The spray-dried microparticles showed a crystallinity index of 67.8-% for the pine wood, 70.9-% for the corncob and 79.3 % for the microcrystalline cellulose. These microparticles have great potential for use in the production of polymer composites processed by extrusion. PMID- 27987872 TI - The effect of chitosan on the flammability and thermal stability of polylactic acid/ammonium polyphosphate biocomposites. AB - This work reports our recent efforts on introducing chitosan (CS) in association with ammonium polyphosphate (APP) into polylactic acid (PLA) by melt blending to improve the flame retardancy of the biocomposites. The flammability of the composites was characterized by limiting oxygen index (LOI), UL-94 vertical burning test and cone calorimetry test (CONE). The results showed that the PLA sample containing 2% CS and 5% APP achieved the maximal LOI value of 33.1, passed the UL-94 V-0 rating, and decreased the peak heat release rate to 425.6kW/m2. The morphology characterization of char residue by scanning electron microscope indicated a dense, homogeneous and continuous residue char could be formed by the presence of APP and CS in PLA. Fourier transform infrared spectroscopy and thermal gravity analysis suggested that CS could act as a novel carbon agent owning to its high content of carbon atoms and multi-hydroxyl groups, and the interaction between CS and APP could provide synergistic effects in improving the flame retardancy of PLA biocomposites. X-ray diffraction and differential scanning calorimetry results demonstrated that the presence of APP and CS could promote the crystallization of PLA. PMID- 27987873 TI - Influence of Na+ and Ca2+ on flame retardancy, thermal degradation, and pyrolysis behavior of cellulose fibers. AB - Flame-retardant cellulose-Na and cellulose-Ca fibers were successfully synthesized by grafting Na+ and Ca2+ onto cellulose fibers, and confirmed by FTIR. The combustion behavior of the fibers was assessed by the limiting oxygen index (LOI) and cone calorimeter (CONE). The maximum LOI values of cellulose-Na and cellulose-Ca fibers were 31 and 30, which are higher than that (19) of cellulose fibers. The CONE results showed that the values of heat-release rate and total heat release for cellulose-Na and cellulose-Ca fibers were significantly lower than those for cellulose fibers. The thermogravimetric analysis (TG) and differential thermogravimetric analysis (DTG) curves in the continuous and trigger modes showed that the cellulose-Na and cellulose-Ca fibers generated more residues than cellulose fibers. Thermogravimetric analysis-gas chromatography-mass spectrometry was used to detect the characteristic gases produced in the pyrolysis of cellulose-Na and cellulose-Ca fibers. PMID- 27987874 TI - Synthesis and characterization of seaweed cellulose derived carboxymethyl cellulose. AB - In the present study, cellulose (SWC) extracted from green seaweed Ulva fasciata was processed to synthesize carboxymethyl cellulose (SWCMC). The seaweed cellulose (~15% DW) was first processed for alpha cellulose extraction (10.1% on DW) followed by the synthesis and characterization of SWCMC. Thin films were prepared using commercial CMC (CCMC), SWCMC and SWCMC-metal nanoparticle (2% wt/v) by solvent evaporation technique. Films were studied for molecular weight, degree of carboxylation, viscosity and characterized by FT-IR and TGA. AFM surface morphology of SWCMC-metal nanoparticle film confirms the uniform distribution of sphere shaped metal nanoparticle on the film surface with the size in the range of 50-75nm. Further, SWCMC film showed antimicrobial activity when prepared with Ag and leaf extract of Azadirachta indica. The biodegradable nature of SWCMC film was confirmed by growing marine fungus Cladosporium spherospermum on CMC agar plates. Thus, SWCMC films exhibit potential applications in cosmetic, food, textiles, medical, agricultural and pharmaceutical industries. PMID- 27987875 TI - Size effect of ZnO nanorods on physicochemical properties of plasticized starch composites. AB - This work demonstrates that the size of ZnO nanorods (ZnONR) with similar aspect ratio determines several physicochemical and microbiological properties of thermoplastic starch composites (TPS/ZnONR) at a given concentration of ZnONRs. A combination of sol-gel and hydrothermal methods was developed to synthesize ZnONR with different sizes but similar aspect ratios. Starch composites containing 1wt.% of ZnONR were prepared by casting. Composites with smaller size nanorods (ZnONR-S) showed more efficiency in shielding UVA radiation and had a higher solubility and water vapor permeability than those with larger nanorods (ZnONR L). Mechanical properties, biodegradability and antibacterial activity were also influenced by the size of the ZnONR. X-ray diffraction analysis showed that composites with ZnONR-S maintained the typical B-V type starch structure, intensifying the V-type starch structure peaks, while composite with ZnONR-L induced the formation of an amorphous structure, preventing starch retrogradation during storage. Properties affected by nanorods size are fundamental in determining composite applications. PMID- 27987876 TI - Effect of glycosylation with gum Arabic by Maillard reaction in a liquid system on the emulsifying properties of canola protein isolate. AB - In this research, the improvement of emulsifying properties of chemically modified canola protein isolate (CPI) with gum Arabic (GA) through Maillard reaction under natural pH at 90 degrees C was investigated. The stability, rheology and morphology of oil-in-water emulsions stabilized by conjugate of two biopolymers were evaluated by determination of droplet size, emulsifying activity (EAI), emulsifying stability (ESI) and creaming indices. The conjugate-stabilized emulsion showed smaller mean droplet size and lower creaming index values which were more effective to stabilize the emulsion compared to CPI and mixture of two biopolymers especially if pH was near the isoelectric point of CPI or when emulsions heated from 30 to 90 degrees C. Moreover, our results demonstrated that EAI, ESI and viscosity of emulsion for CPI-GA conjugate were significantly more than those of CPI-GA mixture and CPI. These results suggested that Maillard reaction could be one of the most promising approaches to improve emulsifying properties of CPI for food applications. PMID- 27987877 TI - Starch phosphorylation plays an important role in starch biosynthesis. AB - Starch phosphate esters are crucial in starch metabolism and render valuable functionality to starches for various industrial applications. A potato glucan, water dikinase (GWD1) was introduced in tubers of two different potato genetic backgrounds: an amylose-containing line Kardal and the amylose-free mutant amf. In both backgrounds, this resulted in two contrasting effects, a number of plants showed higher phosphate content compared to the respective control, while others lines exhibited lower phosphate content, thereby generating two series of starches with broad-scale variation in phosphate content. The results of systematic analyses on these two series of starches revealed that starch phosphate content strongly influenced starch granule morphology, amylose content, starch fine structure, gelatinization characteristics and freeze-thaw stability of starch gels. Further analyses on the expression level of genes involved in starch metabolism suggested that starch phosphorylation regulates starch synthesis by controlling the carbon flux into starch while simultaneously modulating starch-synthesizing genes. PMID- 27987878 TI - Interaction and formation mechanism of binary complex between zein and propylene glycol alginate. AB - The anti-solvent co-precipitation method was used to fabricate the zein-propylene glycol alginate (PGA) binary complex with different mass ratios of zein to PGA (20:1, 10:1, 5:1, 2:1 and 1:1) at pH 4.0. Results showed that attractive electrostatic interaction between zein and PGA occurred and negatively charged binary complex with large size and high turbidity was formed due to the charge neutralization. Hydrogen bonding and hydrophobic effects were involved in the interactions between zein and PGA, leading to the changed secondary structure and improved thermal stability of zein. Aggregates in the irregular shape with large size were obviously observed in the AFM images. PGA alone exhibited a fine filamentous network structure, while zein-PGA binary complex showed a rough branch-like pattern and the surface of "branch" was closely adsorbed by lots of spherical zein particles. Q in zein-PGA binary complex dispersions presented the improved photochemical and thermal stability. The potential mechanism of a two step process was proposed to explain the formation of zein-PGA binary complexes. PMID- 27987879 TI - Preparation of oxidized sodium alginate with different molecular weights and its application for crosslinking collagen fiber. AB - A series of periodate oxidized sodium alginate (OSA) were prepared as green polysaccharide-based crosslinkers. The molecular weight of OSA decreased, while their aldehyde group content increased with increasing dosage of sodium periodate. A typical OSA was further fractionated to four fractions by ethanol with a narrower molecular weight distribution. Then the crosslinking performances of OSAs/fractions on collagen fiber (CF) were investigated. DSC and SEM analyses showed that the thermal stability and dispersion degree of crosslinked CF was considerably enhanced with decreasing molecular weight of OSA. The effect of aldehyde group content of OSA on its crosslinking performance was less obvious than that of molecular weight, probably because the aldehyde group content in each OSA sample was higher than the amino group content of CF involved in the crosslinking reaction. In general, molecular weight of OSA plays a decisive role in improving properties of the crosslinked CF. PMID- 27987880 TI - Structural elucidation and immunostimulating property of a novel polysaccharide extracted from an edible mushroom Lentinus fusipes. AB - A water soluble heteroglycan (PS-II) with an average molecular weight~60kDa was isolated from the hot aqueous extract of an edible mushroom Lentinus fusipes. The structural characterization of PS-II was carried out using total acid hydrolysis, methylation analyses, periodate oxidation, Smith degradation and 1D/2D NMR experiments. Total acid hydrolysis indicated the presence of D-galactose and D glucose in a molar ratio of approximately 1:1. The chemical and NMR analyses revealed that the proposed repeating unit of the PS-II had a backbone chain consisting of three (1->6)-linked alpha-d-galactopyranosyl residue and two (1->6) linked beta-d-glucopyranosyl residues, one of the beta-d-glucopyranosyl residue was branched at O-3 position with a terminal beta-d-glucopyranosyl. The PS-II exhibited significant in vitro splenocyte and macrophage activations with optimum dose of 20MUg/ml and 80MUg/ml respectively. Flow cytometry study revealed the protective role of the PS-II against nicotine stimulated lymphocytes. Moreover, the ROS scavenging property of PS-II was also established using DPPH radical scavenging assay. PMID- 27987881 TI - Development of chitosan based gold nanomaterial as an efficient antifilarial agent: A mechanistic approach. AB - The gold nanoparticles (AuNPs) have been synthesized biogenically by using black pepper (Piper nigrum) extract according to the principles of green chemistry in presence and absence of a biopolymer, chitosan. A comprehensive study (up to cellular level) on the antifilarial (against Setaria cervi) activity of AuNPs has been made for the first time with a view to use it clinically. The bioactivity of biopolymer capped biogenic AuNP increases significantly compared to simple biogenic AuNP. The biopolymer plays an important role in inspiring AuNP through its inherent positive charges and hydrophobicity. The developed nanomaterial boosts the production of ROS (reactive oxygen species) and misbalances the antioxidant parameters of parasites such as GSH, GST, GPx, SOD and catalase. The produced ROS ultimately induces oxidative stress, which leads to apoptotic cell death in filarial worms. The synthesized nanomaterials exhibit negligible toxicity towards human PBMCs. The present study may serve as a fruitful platform to explore biopolymer capped gold nanoparticles as efficient antifilarial therapeutics. PMID- 27987882 TI - Preparation and characterization of a novel bionanocomposite edible film based on pectin and crystalline nanocellulose. AB - In this study, for the first time, the edible pectin film was reinforced by crystalline nanocelullose (CNC). The incorporation of three levels of CNC (2, 5 and 7% w/w) on mechanical, thermal and water vapor barrier properties of pectin based biodegradable film were investigated using solution casting evaporation method for film preparation. The optimum result was obtained through the nanocomposite film with 5% CNC in terms of mechanical and water vapor properties as the tensile strength increased up to 84% and water vapor permeability decreased by 40%. However, analysis of thermal properties indicated no significant effect of CNC on glass transition temperature. X-ray diffraction (XRD) studies illustrated a positive correlation between the degree of crystallinity and the CNC level. Moreover, AFM images presented good dispersion of CNC in the pectin matrix suggesting appropriate interaction between the filler and matrix, which is in agreement with mechanical consequences. According to the overall results, the reinforcement of pectin film with 5% CNC compared to other strengthening strategies had a higher effect and therefore it could be introduced as a good candidate for the development of strong, completely biodegradable and renewable food packaging material. PMID- 27987883 TI - Atrial natriuretic peptide-conjugated chitosan-hydrazone-mPEG copolymer nanoparticles as pH-responsive carriers for intracellular delivery of prednisone. AB - A chitosan-hydrazone-mPEG (CH-Hz-mPEG) copolymer which is stable at extracellular pH and cleaves at slightly acidic intracellular pH was synthesized and characterized. Blank polymeric nanoparticles (B-PNPs) and prednisone-loaded polymeric nanoparticles (P-PNPs) were then formulated by dialysis/precipitation method. The cell-specific ligand, atrial natriuretic peptide (ANP) was then conjugated to P-PNPs (ANP-P-PNPs) by a coupling reaction. Particle size and morphological analyses revealed uniform spherical shape of PNPs. In vitro pH dependent degradation of PNPs was investigated. Drug release profile of ANP-P PNPs indicated a slow release of prednisone at pH 7.4, but a rapid release at pH 5.0 due to the cleavage of hydrazone linkage. Cytotoxicity studies demonstrated greater compatibility of B-PNPs compared to ANP-P-PNPs. Cellular internalization of ANP-P-PNPs was higher than P-PNPs owing to receptor-mediated endocytosis. The results from this investigation support the hypothesis that chitosan based ANP-P PNPs could act as an intracellular pH-responsive and targeted drug delivery system. PMID- 27987884 TI - Enhanced production of curdlan by coupled fermentation system of Agrobacterium sp. ATCC 31749 and Trichoderma harzianum GIM 3.442. AB - A coupled fermentation system of Agrobacterium sp. ATCC 31749 and Trichoderma harzianum GIM 3.442 (AT-CFS) with wheat bran as the optimal nitrogen source was established for producing low-molecular-weight curdlan with high production, which can potentially reduce the cost of low-molecular-weight curdlan biosynthesis. The initial inoculate ratio, pH and the fermentation time were optimized. Compared with the curdlan from the single fermentation system of Agrobacterium sp. ATCC 31749 (A-SFS), the molecular weight (Mw) of the curdlan produced from AT-CFS decreased by 34.01% (from 110.85kDa to 73.15kDa), and the curdlan production (47.9g/L) and conversion rate of glucose to curdlan (0.60gg-1) increased by 119.93% and 36.36%, respectively. The results of RT-PCR showed high curdlan production in AT-CFS was highly correlated with aerobic respiration intensity and curdlan synthase activity. The structure of the curdlan from AT-CFS was the same as that from A-SFS. PMID- 27987885 TI - Synthesis and factorial design applied to a novel chitosan/sodium polyphosphate nanoparticles via ionotropic gelation as an RGD delivery system. AB - Chitosan nanoparticles have been extensively studied for both drug and protein/peptide delivery. The aim of this study was to develop an optimized chitosan nanoparticle, by ionotropic gelation method, using 32 full factorial design with a novel polyanion, sodium polyphosphate, well known under the trade name Graham salt. The effects of these parameters on the particle size, zeta potential, and morphology and association efficiency were investigated. The optimized nanoparticles showed an estimated size of 166.20+/-1.95nm, a zeta potential of 38.7+/-1.2mV and an efficacy of association of 97.0+/-2.4%. The Atomic Force Microscopy (AFM) and Scanning Electronic Microscopy (SEM) revealed spherical nanoparticles with uniform size. Molecular interactions among the components of the nanoparticles and peptide were evaluated by Fourier Transform Infrared Spectra (FTIR) and Differential Scanning Calorimetry (DSC). The obtained results indicated that, the developed nanoparticles demonstrated high biocompatible, revealing no or low toxicity in the human cancer cell line (Caco 2). In conclusion, this work provides parameters that contribute to production of chitosan nanoparticles and sodium polyphosphate with desirable size, biocompatible and enabling successful use for protein/peptides delivery. PMID- 27987886 TI - Fabrication of basil seed gum nanoparticles as a novel oral delivery system of glutathione. AB - Plant derived polymers like mucilage have evoked great attention in the field of functional food ingredient delivery. The objective of this study was to evaluate the potential of basil seed gum nanoparticles (BSG NPs) as an oral delivery system for glutathione (GSH). BSG NPs (1-0.25mgml-1) were fabricated by ion gelling technique and calcium was used as a cross-linking agent (0.7-0.3mgml-1). The results showed that BSG NPs (298-595nm) have spherical shape and the relative viscosity revealed that the possibility of agglomeration of BSG NPs is low. The interaction between BSG and GSH was confirmed by FTIR and DSC studies. Entrapment and loading efficiency of BSG-GSH nanoparticles were in the range of 6.5-43% and 7-13%, respectively. GSH release in gastrointestinal environment showed release speed in pH 1.2 was lower in compared with pH 6.8. As a result, smaller amounts of GSH will be destroyed in the stomach during digestion time. PMID- 27987887 TI - Alginate- and gelatin-based bioactive photocross-linkable hybrid materials for bone tissue engineering. AB - The paper presents the synthesis, the physico-chemical and the biological properties of novel hybrid materials prepared from photo-crosslinked gelatin/alginate-based hydrogels and silica particles exhibiting potential for the regeneration of bone tissue. Both alginate and gelatin were functionalized with methacrylate and methacrylamide moieties, respectively to render them photo crosslinkable. Submicron silica particles of two sizes were dispersed within three types of polymeric sols including alginate, gelatin, and gelatin/alginate blends, which were subsequently photo-crosslinked. The swelling ratio, the gel fraction and the mechanical properties of the hybrid materials developed were examined and compared to these determined for reference hydrogel matrices. The in vitro cell culture studies have shown that the prepared materials exhibited biocompatibility as they supported both MEFs and MG-63 mitochondrial activity. Finally, the in vitro experiments performed under simulated body fluid conditions have revealed that due to inclusion of silica particles into the biopolymeric hydrogel matrices the mineralization was successfully induced. PMID- 27987888 TI - Functional and rheological properties of cold plasma treated rice starch. AB - The present work deals with aimed to study the effect of cold plasma treatment on the functional and rheological properties of rice starch using two different power levels (40 and 60W). The changes in amylose content, turbidity, pH, water and fat absorption due to plasma treatment were evaluated. Where decrease in the turbidity and pH after the treatment was observed. Gel hydration properties and syneresis study revealed that there is an increase in leaching of amylose molecules after the treatment. Rapid Visco Analyzer examination showed an increase in pasting and final viscosities. From G' and G" moduli determination we observed that there is decrease in retrogradation tendency of starch gels. XRD did not show any change in A-type pattern but decrease in the relative crystallinity was observed due to depolymerization caused by active plasma species. FTIR shows some of the additional functional groups after treatment. SEM showed formation of fissures on the surface of starch granules due to etching caused by the plasma species. Thus, plasma treatment can be one of the methods for physical modification of starch. PMID- 27987889 TI - Efficient biosynthesis of levan from sucrose by a novel levansucrase from Brenneria goodwinii. AB - Levan, a unique homopolysaccharide consisting of fructose residues linked by beta (2, 6) bonds, possess promising physiochemical and physiological properties with numerous potential applications. In this study, a novel levan-producing levansucrase was characterized from Brenneria goodwinii. The polysaccharide produced by the recombinant enzyme from sucrose was structurally determined to be levan-type fructan connected by beta-(2, 6) linkages. The optimum pH was measured to be pH 6.0 for both sucrose hydrolysis and transfructosylation. The optimum temperature was 35, 45, and 40 degrees C for transfructosylation, sucrose hydrolysis, and total activity, respectively. Higher sucrose concentration greatly favored to levan biosynthesis. The purified recombinant enzyme produced 185g/L levan from 50% (w/v) sucrose at pH 6.0 and 35 degrees C for 12h. The molecular weight of the produced levan polysaccharide reached 1.3*108Da, which was much higher than the ones produced by many reported levansucrases. PMID- 27987890 TI - Fabrication of chitosan-polycaprolactone composite nanofibrous scaffold for simultaneous delivery of ferulic acid and resveratrol. AB - Wound healing is a complex cellular process involving various mechanisms making it intricate for designing a scaffold for therapeutic use. This study deals with the designing and development of coaxial electrospun Chitosan-Polycaprolactone nanofiber wound dressings for efficient simultaneous drug delivery. Ferulic acid and resveratrol were chosen for incorporation into core-shell nanofibers for their efficacy in anti-inflammatory and pro-angiogenic activities respectively. Structural and physico-chemical characterization of the scaffold confirmed the encapsulation of both the molecules. The in vitro release studies showed sustained release of both resveratrol and ferulic acid up to 48% and 55% respectively till 120h. Functional characterization of the nanofibrous wound dressing exhibited good in vitro and in vivo biocompatibility. The scaffold treated rats exhibited complete healing in 15days in comparison to the controls that healed in 20days. The study therefore, opens up venues for designing sequential and sustained drug delivery systems in wound therapeutics. PMID- 27987891 TI - The use of heparin chemistry to improve dental osteogenesis associated with implants. AB - In this study, we designed a hybrid Ti by heparin modifying the Ti surface followed by Growth/differentiation factor-5 (GDF-5) loading. After that, products were characterized by physicochemical analysis. Quantitative analysis of functionalized groups was also confirmed. The release behavior of GDF-5 grafted samples was confirmed for up to 21days. The surface modification process was found to be successful and to effectively immobilize GDF-5 and provide for its sustained release behavior. As an in vitro test, GDF-5 loaded Ti showed significantly enhanced osteogenic differentiation with increased calcium deposition under nontoxic conditions against periodontal ligament stem cells (PDLSc). Furthermore, an in vivo result showed that GDF-5 loaded Ti had a significant influence on new bone formation in a rabbit model. These results clearly confirmed that our strategy may suggest a useful paradigm by inducing osseo-integration as a means to remodeling and healing of bone defects for restorative procedures in dentistry. PMID- 27987892 TI - Influence of Pectin as a green polymer electrolyte on the transport properties of Chitosan-Pectin membranes. AB - Novel blend membranes have been prepared from Chitosan (CH), Pectin (PEC) and their mixtures. The obtained samples were cross-linked and sulfonated before characterization. The results show that CH/PEC membranes display structural changes on the chemical and physical properties as a function of composition. DSC analysis reveals an endothermic peak due to the scission of the ionic pairs between carboxylic groups and ammonium groups, which produces a strong change on physical properties such as methanol permeability and proton conductivity. The methanol permeability decreases with the amount of Pectin from (4.24+/-0.04)*10 6cm2/s for pure Chitosan membrane to (1.51+/-0.03)*10-6cm2/s for blend CH/PEC membranes when the amount of Pectin is 50% (v/v). The proton conductivities of the blend membranes follow a similar behavior. For a pure CH membrane the conductivity is 2.44*10-3S/cm, decreasing with pectin content until the composition 50/50 (v/v), in which the conductivity drops almost one order of magnitude. PMID- 27987893 TI - In vitro macrophage nitric oxide production by Pterospartum tridentatum (L.) Willk. inflorescence polysaccharides. AB - Pterospartum tridentatum (L.) Willk. decoctions of dried inflorescences are used in Portugal due to their claimed beneficial properties for various health disorders. To disclose the potential contribution of its polysaccharides to health benefits, in this work, hot water extracts from P. tridentatum inflorescences were prepared and fractionated by ethanol precipitation and anion exchange chromatography. The fraction rich in acetylated galactomannans evidenced an increase in nitric oxide (NO) production by macrophages. This activity decreased 60-75% after saponification, confirming that acetylation is an important structural feature for this biological property. In addition, the treatment of pectic polysaccharides with endo-polygalacturonase showed that type I and type-II arabinogalactans, as well as low molecular weight galacturonans and xyloglucans, may also contribute to macrophage NO production. Thus, the polysaccharides present in P. tridentatum dried inflorescences may contribute to the health beneficial properties frequently attributed to the decoctions of this plant. PMID- 27987894 TI - Reaction pathways during oxidation of cereal beta-glucans. AB - Oxidation of cereal beta-glucans may affect their stability in food products. Generally, polysaccharides oxidise via different pathways leading to chain cleavage or formation of oxidised groups within the polymer chain. In this study, oxidation pathways of oat and barley beta-glucans were assessed with different concentrations of hydrogen peroxide (H2O2) or ascorbic acid (Asc) with ferrous iron (Fe2+) as a catalyst. Degradation of beta-glucans was evaluated using high performance size exclusion chromatography and formation of carbonyl groups using carbazole-9-carbonyloxyamine labelling. Furthermore, oxidative degradation of glucosyl residues was studied. Based on the results, the oxidation with Asc mainly resulted in glycosidic bond cleavage. With H2O2, both glycosidic bond cleavage and formation of carbonyl groups within the beta-glucan chain was found. Moreover, H2O2 oxidation led to production of formic acid, which was proposed to result from Ruff degradation where oxidised glucose (gluconic acid) is decarboxylated to form arabinose. PMID- 27987895 TI - Thermomechanical characterization of an amylose-free starch extracted from cassava (Manihot esculenta, Crantz). AB - The aim of this study was to determine and compare the melting (Tm), glass transition (Tg) and mechanical relaxation (Talpha) temperatures of a new waxy cassava starch. Thermal transitions measurements were obtained by Differential Scanning Calorimetry (DSC) and Dynamical Mechanical Thermal Analysis (DMTA). The experimental data showed a high correlation between water volume fraction and melting temperature (Tm) indicating that the Flory-Huggins theory can be used to describe the thermal behavior of this starch. The Tm of waxy cassava starch-water mixes were lower than a waxy corn starch-water reference system, but differences were not statistically significant. The mechanical relaxation temperatures taken at tan delta peaks were found 29-38 degrees C larger than Tg. The Talpha and Tg measured for waxy cassava starch exhibited similar properties to the ones of waxy corn starch, implying that waxy cassava starch can be used in food and materials industry. PMID- 27987897 TI - Microwave assisted conversion of microcrystalline cellulose into value added chemicals using dilute acid catalyst. AB - One of the grand challenges of this century is to transition fuels and chemicals production derived from fossil feedstocks to renewable feedstocks such as cellulosic biomass. Here we describe fast microwave conversion of microcrystalline cellulose (MCC) in water, with dilute acid catalyst to produce valuable platform chemicals. Single 10min microwave assisted treatment was able to convert >60% of MCC, with >50mol% yield of desirable products such as glucose, HMF, furfural and levulinic acid. Recycling of residual MCC with make-up fresh MCC resulted in an overall conversion of >93% after 5 cycles while maintaining >60% conversion in each cycle. Addition of isopropanol (70%v/v) as a co-solvent increased the yields of HMF and levulinic acid. This work shows for the first time proof of concept for complete conversion of recalcitrant microcrystalline cellulose in mild conditions of low temperature, dilute acid and short residence time using energy efficient microwave technology. PMID- 27987898 TI - Incorporation of ZnO and their composite nanostructured material into a cotton fabric platform for wearable device applications. AB - The central idea of this paper is to innovate a new approach for the development of wearable device materials through the coating of cotton fabric with ZnO and Sb /Ag-/ZnO composites. The study was designed in order to have a clear understanding of the role of ZnO as well as the modified composite thereof under investigation. Cotton fabric with uniform ZnO/ZnO-composite layers on the surface was successfully synthesized via a solvothermal method. The growth behaviors were investigated by comparing ZnO and ZnO-composites. The structural, morphological, chemical states, optical, electrical and thermopower properties of these fabrics were studied. Nanostructured ZnO-composite fabric had enhanced UV shielding with a value of 83.96. It is found that the ZnO-composite fabrics have increased electrical conductivity. The thermopower value of the ZnO-composite fabric could reach 471.9MUVK-1. Such materials are anticipated to be worthwhile as wearable electronic devices and as protective textiles. PMID- 27987896 TI - Time and energy-efficient homogeneous transesterification of cellulose under mild reaction conditions. AB - In this research, cellulose aliphatic esters (CEs) were synthesized efficiently in an N, N-dimethylacetamide/lithium chloride system (DMAc/LiCl) with vinyl esters (VEs, number of carbon atoms ranging from 4 to 12) as acylation reagent and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) as catalyst. The structures and properties of the products have been characterized by various analytical techniques. The key concept in this cellulose modification was the achievement the degree of substitution (DS) >2.75 at much milder temperature and shorter reaction time (under 30 degrees C within 15min-30min), other than previous research. Generally, the DS of obtained CEs showed a reverse trend with the length of the aliphatic chain increasing. The priority of reactions in three positions of the CEs followed the same order of C6>C2>C3 for a homogeneous conversion. There was no decrease of molecule weight under this mild reaction. This research provides a novel homogeneous technology to synthesize various CEs efficiently. PMID- 27987899 TI - Synthesis and characterization of poly(carboxymethyl)-cellulose for enhanced La(III) sorption. AB - The grafting of amino and carboxylic acid groups on cellulose increased La(III) sorption efficiency of cellulose: maximum sorption capacity increased from 38mgLag-1 for cellulose to 101 and 170mgLag-1 for amino derivative (PAC) and amino-carboxylic derivative (PCMC). Langmuir equation successfully fits sorption isotherms while uptake kinetics are effectively modeled using the pseudo-first order rate equation (though resistance to intraparticle diffusion plays a significant role in the control of metal recovery). Uptake equilibrium occurred within 150-180min. The thermodynamic study shows that the reaction is spontaneous, endothermic and entropic. Nitric acid solutions (0.5M concentration) can be efficiently used for metal recovery and sorbent can be recycled for at least 5 cycles with limited decrease in sorption performance for the three sorbents. The materials were characterized by elemental analysis, acid-base titration, FTIR spectrometry, x-ray diffraction analysis, X-ray photoelectron spectroscopy, SEM-EDX analysis and also by TGA. PMID- 27987900 TI - Effect of surface modification of cellulose nanocrystal on nonisothermal crystallization of poly(beta-hydroxybutyrate) composites. AB - Ring-opening polymerization of l-lactide from cellulose nanocrystal (CNC) surface yielded polylactide-grafted CNC (CNC-g-PLA). The structure and chemical composition of the CNC-g-PLA were characterized by FT-IR, 1H NMR, XPS and XRD. The crystallization behavior and lamellar structure of poly(beta-hydroxybutyrate) (PHB) in the presence of pristine CNC and CNC-g-PLA were elucidated via DSC and SAXS, and Babinet's reciprocity theory was applied. Crystallization kinetics were further analyzed using Ozawa, Mo and Kissinger models. In the presence of pristine CNC, nucleation of PHB crystals led to an increase in the crystallization temperature (Tc) of PHB; while CNC-g-PLA acted as antinucleation agent, resulting in a remarkable reduction in Tc of PHB. Accordingly, the composite with pristine CNC possessed a higher crystallization rate than neat PHB, while CNC-g-PLA displayed the lowest crystallization rate. However, the lamellar structure of PHB was not affected by the presence of pristine and modified CNCs, and almost identical crystallization activation energies as the neat PHB were observed, indicating that nucleation is dominant during PHB crystallization, instead of crystal growth. This study offers a promising approach of using pristine and modified CNCs to control the crystallization of biodegradable aliphatic polyesters. PMID- 27987901 TI - A facile and efficient strategy for the fabrication of porous linseed gum/cellulose superabsorbent hydrogels for water conservation. AB - The linseed gum/cellulose composite hydrogels were successfully fabricated by mixing cellulose and linseed gum solutions dissolved in the NaOH/urea aqueous system and cross-linked with epichlorohydrin. The morphology and structure of the composite hydrogels were investigated by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, X-ray diffractometry (XRD) and thermogravimetric analysis (TGA). The swelling ratio and water retention properties were investigated. The results revealed that linseed gum mainly contributed to water adsorption, whereas the cellulose acted as a backbone to strengthen the porous structure. This work provided a simple way to prepare cellulose-based superabsorbent hydrogels, which could be potentially applied as an effective water conservation material in agriculture. PMID- 27987902 TI - Study of interactions between hyaluronan and cationic surfactants by means of calorimetry, turbidimetry, potentiometry and conductometry. AB - The thermodynamics of the micelle formation of the cationic surfactants tetradecyltrimethylammonium bromide (TTAB) and cetyltrimethylammonium bromide (CTAB) with and without the addition of hyaluronan of two molecular weights was studied in aqueous solution by titration calorimetry. Macroscopic phase separation, which was detected by calorimetry and also by conductometry, occurs when charges on the surfactant and hyaluronan are balanced. In contrast, turbidimetry and potentiometry showed hyaluronan-surfactant interactions at very low surfactant concentrations. The observed differences between systems prepared with CTAB and TTAB indicate that besides the electrostatic interactions, which probably predominate, hydrophobic effects also play a significant role in hyaluronan interactions with cationic surfactants. PMID- 27987903 TI - Degradation kinetics of peptide-coupled alginates prepared via the periodate oxidation reductive amination route. AB - Biomaterials based on peptide-coupled alginates must provide both optimal biological environments and tuneable stability/degradation profiles. The present work investigates the degradation pattern and kinetics of peptide-coupled alginates prepared via the periodate oxidation reductive amination route. Alginates degrade slowly (non-enzymatically) under physiological conditions by acid-catalysed hydrolysis and alkali-catalysed beta-elimination, both operating simultaneously but dominated by the latter. While periodate oxidation alone largely increases the rate of beta-elimination, substitution restores the susceptibility towards beta-elimination to that of the parent alginate. For acid hydrolysis the rate of depolymerization is proportional to the degree of substitution, being approximately one order of magnitude larger than the parent alginate, but still lower than for the corresponding materials with fully reduced dialdehydes. Results also suggest a composition-dependent preference for substitution at C2 or C3. These results demonstrate how the various chemistries introduced by the coupling provide useful means to tune the biodegradability profiles. PMID- 27987904 TI - Crosslinking of poly(vinylpyrrolidone)/acrylic acid with tragacanth gum for hydrogels formation for use in drug delivery applications. AB - Tragacanth gum (TG) is generally recognized as safe by the Food and Drug Administration. The present article discusses the design of ciprofloxacin loaded TG based hydrogels for use in drug delivery especially to improve the pharmacotherapy of diverticulitis. The polymers were characterized by SEMs, FTIR, 13C NMR, XRD, TGA, DSC, gel strength and swelling studies. The polymer network parameters, mucoadhesion, gel strength, drug release mechanism and kinetic model were also determined. The release of drug occurred through non-Fickian diffusion mechanism and best fitted in the Korsmeyer-Peppas model. The pH of the swelling medium has also exerted a strong effect on polymer network structure and mechanical strength. These hydrogels have been observed pH responsive and mucoadhesive in nature and could be utilized for site specific drug delivery. PMID- 27987905 TI - Physico-chemical characterization of succinyl chitosan-stabilized liposomes for the oral co-delivery of quercetin and resveratrol. AB - In the present work, quercetin and resveratrol, natural polyphenols with strong antioxidant and anti-inflammatory properties, were co-loaded in polymer associated liposomes conceived for oral delivery, by exploiting the potential of pH-sensitive succinyl-chitosan. Chitosan was succinylated, characterized by Nuclear Magnetic Resonance spectroscopy and Gel Permeation Chromatography, and used to form a protective shell on the surface of liposomes. The physico-chemical properties of the succinyl-chitosan liposomes were assessed by light scattering, zeta potential, cryogenic transmission electron microscopy, and small angle X-ray scattering. Small, spherical, uni- and bilamellar vesicles were produced. The succinyl-chitosan shell increased not only the physical stability of the vesicular system, as demonstrated by accelerated stability tests, but also the release of the polyphenols to a greater extent at pH 7.0, mimicking the intestinal environment. The proposed approach based on polyphenol vesicular formulations may be of value in the treatment of pre-cancerous/cancerous intestinal conditions associated with inflammation and oxidative stress. PMID- 27987906 TI - gamma-Polyglutamic acid/chitosan nanoparticles for the plant growth regulator gibberellic acid: Characterization and evaluation of biological activity. AB - The growth regulator gibberellic acid (GA3) has several uses in the field, improving germination, plant development, productivity, and the quality of food. This work describes the development of a nanocarrier system for GA3, based on the poly(gamma-glutamic acid) (gamma-PGA) and chitosan (CS) polymers, Nanoparticles without GA3 (nano-gammaPGA/CS-GA3) showed colloidal characteristics, with an average size of 117+/-9nm, PDI of 0.43+/-0.07, and zeta potential of -29+/-0.5mV. The encapsulated nanoparticles (nano-gammaPGA/CS-GA3) presented an average size of 134+/-9nm, PDI of 0.35+/-0.05, zeta potential of 27.9+/-0.5mV, and 61% encapsulation. The images of nanoparticles observed by Transmission and scanning electron microscopy (TEM and SEM) showed a spherical shape of the nanoparticles. The system showed sustained release, with 58% release after 48h. Evaluation of thermal properties using DSC and TGA analyses indicated that there was an interaction between the CS and gamma-PGA polymers. In tests using Phaseolus vulgaris seeds, nano-gammaPGA/CS-GA3 showed high biological activity, enhancing the rate of germination in the first day (50-70%) when compared with free GA3 (10 16%). Encapsulated GA3 was also more efficient than the free hormone in the increase of leaf area and the induction of root development (including the formation of lateral roots). These effects were not observed when seeds were treated with nano-gammaPGA/CS without GA3. The results demonstrated the considerable potential of nano-gammaPGA/CS-GA3 for use in agriculture. PMID- 27987907 TI - The release kinetics of beta-carotene nanocapsules/xanthan gum coating and quality changes in fresh-cut melon (cantaloupe). AB - The main aim of this work was to evaluate the effect of the beta-carotene release rate from nanocapsules incorporated into a xanthan gumcoating on the physical and physicochemical properties of fresh-cut melon (var. cantaloupe). Several coatings were studied: xanthan gum alone (XG), xanthan gum combined with nanocapsules (Ncs/XG), xanthan gum combined with nanospheres (Nsp/XG), nanocapsules (Ncs), and nanospheres (Nsp), all of which were compared to untreated fresh-cut melon in order to determine their preservation efficiency. The beta-carotene release profiles from the Ncs and Ncs/XG treatments corresponded better to a Higuchi-type behavior (t1/2) for matrix systems (R2>0.95). Also observed was a good correlation between the release of beta-carotene by the Ncs/XG treatment and the minor changes observed in the whiteness index (<=10%) and firmness (<=2%). These results lead to the conclusion that incorporating beta-carotene nanocapsules into a polysaccharide matrix improves the properties of the coatings, thereby increasing storage time to 21days at 4 degrees C. PMID- 27987908 TI - Oriented Cellulose Nanopaper (OCNP) based on bagasse cellulose nanofibrils. AB - The purpose of this study is to explore the suitability of bagasse fiber for production of Cellulose Nanofiber (CNF) and Oriented Cellulose Nanopaper (OCNP) for the first time. Different types of CNF were thus produced either mechanically by homogenization or with enzymatic pre-treatment followed by homogenization. The CNF was thereafter used for the production of nanopapers through two approaches; i) Dispersion Casting (DC) and ii) Dynamic Sheet Former (DSF). Then, the prepared nanopapers were characterized in terms of surface, structural, morphological and mechanical properties. It was found that compared to DC method, the OCNP had higher crystallinity as well as superior tensile and tear indices. The results also showed that the highest tensile strength index value of 189Nm/g was measured for the OCNP at the Machine Direction (MD).This would most probably be attributed to the presumptive anisotropic orientation of the nanofibrils due to the shearing forces induced from the DSF. These unique characteristics of the OCNP are promising for potential applications in food packaging. PMID- 27987909 TI - Physicochemical characterization of cellulose nanocrystal and nanoporous self assembled CNC membrane derived from Ceiba pentandra. AB - This research involves the rare utilisation of the kapok fibre (Ceiba pentandra) as a raw material for the fabrication of cellulose nanocrystal (CNC) and self assembled CNC membranes. The isolation of CNC from Ceiba pentandra began with the extraction of cellulose via the chemical alkali extraction by using 5wt% NaOH, followed by the typical acidified bleaching method and, finally, the CNC production through acid hydrolysis with 60wt% H2SO4 at the optimum time of 60min. The prepared CNC was then employed for the preparation of self-assembled membrane through the water suspension casting evaporation technique. The obtained CNC membrane was characterised in terms of its composition, crystallinity, thermal stability, as well as, structural and morphological features with the use of several techniques including FTIR, XRD, AFM, TEM, FESEM, and TGA. The FESEM and AFM analyses had illustrated the achievement of a self-assembled CNC membrane with a smooth surface and a well-distributed nano-porous structure, with the porosity of 52.82+/-7.79%. In addition, the findings proved that the self assembled CNC membrane displayed good adsorption capability indicated by the recorded efficiency of 79% and 85% for 10mg/L and 5mg/L of methylene blue in an aqueous solution, respectively. PMID- 27987910 TI - Optimization of alginate alkaline extraction technology from Sargassum latifolium and its potential antioxidant and emulsifying properties. AB - Alginate was recovered from Sargassum latifolium biomass using different conditions of alkali treatment. Box-Behnken experimental design was evaluated to study the influence of alkali:alga ratio, temperature and time on alginate yield, and its molecular weight (MW) and mannuronic/guluronic acid ratio (M/G). The second-order polynomial equations were analyzed by appropriate statistical methods. Extraction temperature and time were the most important factors during alginate alkaline extraction. MW and M/G ratio played an important role in controlling the reducing power of alginate. Increasing pH of the alginate solutions enhanced its reducing capacity, while thermal treatment showed a negative effect. Additionally, alginate exhibited good emulsion stabilizing capacities with diverse hydrophobic compounds. Emulsifying activity was less sensitive to temperature, ionic strength and more stable at acidic pH. PMID- 27987911 TI - Facile synthesis of novel soluble cellulose-grafted hyperbranched polymers as potential natural antimicrobial materials. AB - A new class of soluble cellulose-grafted hyperbranched polymers has been synthesized by a facile "hypergrafting" reaction using bis(2-chloroethyl)amine and soluble cellulose tosylates. The molecular structures of the obtained new materials were characterized by 13C NMR, FTIR spectroscopy, and elemental analysis. The degree of substitution of the hyperbranched cellulose derivatives ranges between 0.13-0.53. The new cellulose-based materials were soluble in various polar aprotic organic solvents. The thermal properties of the new cellulose materials were investigated by thermal gravimetric analysis. Antibacterial activity of the new cellulose derivatives was evaluated by diffusion disk tests against various gram negative and positive bacteria. Our results suggested that the obtained natural cellulosic materials can act as effective polymeric biocides, and may have great potential in various antimicrobial materials applications. PMID- 27987912 TI - Original method for synthesis of chitosan-based antimicrobial agent by quaternary ammonium grafting. AB - Functionalized high molar mass chitosan derivatives with increased antibacterial properties were prepared by the reaction of chitosan with different quaternary ammonium salts. Benzalkonium bromide, pyridinium bromide and triethyl ammonium bromide were synthesized by a quaternization reaction between 1,4-dibromobutane and the respective tertiary amines (N, N-dimethylbenzylamine, triethylamine and pyridine) to obtain three ammonium salts with a bromide end-group capable of reacting with a functional group from the chitosan backbone. The ammonium salts were chemically grafted along the chitosan macromolecular chains. Four different chitosan derivatives were obtained and their chemical structures analyzed and confirmed by 1H NMR and FT-IR. The corresponding thermal stability was analyzed by TGA. Antibacterial activity has been assessed by determining their minimal inhibitory concentration upon Escherichia coli and Staphylococcus aureus. Furthermore, the antibiogram method was used to complement the antibacterial analysis. The bacteria inhibitory property of the chitosan derivatives exhibited a remarkable improvement compared to unmodified chitosan. PMID- 27987913 TI - Bionanocomposite foams based on the assembly of starch and alginate with sepiolite fibrous clay. AB - Bionanocomposite foams based on alginate, potato starch and the microfibrous clay mineral sepiolite as reinforcing filler were prepared by lyophilization. Spectroscopic techniques were applied in order to assess the interaction mechanism established between the inorganic fibers and the polysaccharide chains, which is established between the hydroxyl groups in the polysaccharide chains and the silanol groups at the external surface of the sepiolite fibers. The textural properties studied by means of mercury intrusion porosimetry, FE-SEM and X-ray microtomography, revealed a decrease in porosity as the sepiolite content increased. Mechanical properties were also determined for the studied foams, showing an increase in compression moduli from 7.3MPa in the foam without sepiolite to 29MPa in foams containing 10% starch, 40% sepiolite and 50% alginate. Horizontal burning tests were carried out for a preliminary evaluation of the role of the inorganic fibers on the fire resistance properties of the bionanocomposite foams, revealing that bionanocomposite foams with sepiolite content >25% behave as auto-extinguishable materials. Post-synthesis cross linking with CaCl2 was carried out in some of these samples, leading to an increase in the compression modulus up to 40MPa for the optimal composition. PMID- 27987914 TI - Effects of dilute acid and flowthrough pretreatments and BSA supplementation on enzymatic deconstruction of poplar by cellulase and xylanase. AB - To help understand factors controlling the recalcitrance of lignocellulosic biomass to deconstruction to sugars, poplar was pretreated with liquid hot water (LHW) and extremely dilute acid (EDA) at 140 degrees C and 180 degrees C in batch and flowthrough reactors. The resulting solids were then subjected to enzymatic hydrolysis by eight combinations of cellulase, xylanase, and bovine serum albumin (BSA). Co-addition of xylanase to cellulase resulted in up to 11 percentage points higher overall sugar yield than their sequential addition. In general, supplementation of BSA to enzymes had a larger impact on flowthrough solids with reduced lignin content than batch solids with high lignin content. BSA did not affect xylan yields and while it had low impact on LHW solids, it caused large increases in sugar yields from EDA solids. Flowthrough pretreatment produced less recalcitrant solids than did batch operation, but using very dilute acid reduced recalcitrance even more. PMID- 27987915 TI - Transition-metal-free synthesis of supramolecular ionic alginate-based polyurethanes. AB - Novel high molecular weight alginate-based supramolecular ionic polyurethane (SPU) networks were prepared via the reaction of chemically modified polyanionic alginate and isocyanate-terminated cationic oligourethanes under transition-metal free conditions. Alginate, a naturally occurring polyanionic carbohydrate diol possessing carboxylate groups, was considered as both chain extender and the anionic part of SPU network. The tailor-made, ionically crosslinked linear alginate-based SPUs illustrated superior thermal stability with a decomposition temperature around 500 degrees C at 10% weight loss which specializes them as highly thermally stable, wonder materials compared to the today's high-tech products. PMID- 27987916 TI - The interaction of wood nanocellulose dressings and the wound pathogen P. aeruginosa. AB - Chronic wounds pose an increasingly significant worldwide economic burden (over L1 billion per annum in the UK alone). With the escalation in global obesity and diabetes, chronic wounds will increasingly be a significant cause of morbidity and mortality. Cellulose nanofibrils (CNF) are highly versatile and can be tailored with specific physical properties to produce an assortment of three dimensional structures (hydrogels, aerogels or films), for subsequent utilization as wound dressing materials. Growth curves using CNF (diameter <20nm) in suspension demonstrated an interesting dose-dependent inhibition of bacterial growth. In addition, analysis of biofilm formation (Pseudomonas aeruginosa PAO1) on nanocellulose aerogels (20g/m2) revealed significantly less biofilm biomass with decreasing aerogel porosity and surface roughness. Importantly, virulence factor production by P. aeruginosa in the presence of nanocellulose materials, quantified for the first time, was unaffected (p>0.05) over 24h. These data demonstrate the potential of nanocellulose materials in the development of novel dressings that may afford significant clinical potential. PMID- 27987917 TI - Hepatoprotection of enzymatic-extractable mycelia zinc polysaccharides by Pleurotus eryngii var. tuoliensis. AB - The purpose of this work was designed to investigate the hepatoprotective and antioxidant effects of enzymatic-extractable mycelia zinc polysaccharides (En MZPS) from Pleurotus eryngii var. tuoliensis on the hyperlipidemic mice induced by high-fat-high-cholesterol emulsion (HFHCM). The results showed that the supplementation of En-MZPS had potential anti-hyperlipidemia effects on reducing hepatic lipid levels by monitoring the serum enzyme activities (ALP, ALT and AST) and serum lipid levels (TC, TG, HDL-C, LDL-C and VLDL-C), enhancing the antioxidant enzymes (SOD, GSH-Px, CAT and T-AOC), and decreasing the lipid peroxidation (MDA and LPO). Furthermore, the in vitro scavenging results indicated that the inhibition effects of En-MZPS on hydroxyl radicals and 1,1 diphenyl-2-picrylhydrazyl (DPPH) radicals reached 59.98+/-6.29% and 37.01+/ 2.15%, respectively. These conclusions demonstrated that the En-MZPS might be suitable for functional foods and natural drugs in preventing the HFHCM-induced hyperlipidemia and non-alcoholic fatty liver. PMID- 27987918 TI - Construction of silver sulfadiazine loaded chitosan composite sponges as potential wound dressings. AB - Chitosan/silver sulfadiazine (CS/AgSD) composite sponges were prepared by incorporating AgSD particles into CS matrix in order to develop novel biomaterials for wound healing. The co-existence of CS and AgSD in the composite sponges was confirmed by SEM, FTIR and XRD spectra, respectively. The porosity and swelling properties of the fabricated CS/AgSD composite sponges were examined and the results indicated that they had high porosity and excellent swelling behaviors. Antibacterial property of the CS/AgSD composite sponges was also performed against E. coli, C. albicans, S. aureus and B. subtilis, respectively. The results showed that they possessed broad spectrum of antibacterial activity. The cytotoxicity of the prepared composite sponges was performed by MTT viability assay and fluorescence staining method on HEK293 cell lines. The cell viability results indicated that the designed sponges had no significant cytotoxicity. The results of this study demonstrated that the CS/AgSD composite sponges have potential application in antimicrobial wound dressing materials. PMID- 27987919 TI - Number of branch points in alpha-limit dextrins impact glucose generation rates by mammalian mucosal alpha-glucosidases. AB - alpha-Amylase first hydrolyzes starch structures to linear maltooligosaccharides and branched alpha-limit dextrins, then complete hydrolysis to glucose takes place through the mucosal alpha-glucosidases. In this study, we hydrolyzed waxy corn starch (WCS) by human pancreatic alpha-amylase to determine the digestion and structural properties of different size fractions of the branched alpha-limit dextrins. The alpha-amylolyzed WCS was separated by size exclusion chromatography, and the analyzed chromatograms showed four main hydrolyzate fractions. The first three eluted peaks (regions I-III) corresponded to branched alpha-limit dextrins, while region IV was the linear maltooligosaccharides. Based on the chromatographic and NMR analyses of the individual peaks, Region I, II, and III had multiple (>2), two, and one alpha-1,6 linkages, respectively, and region I was the most slowly hydrolyzed to glucose by mucosal alpha-glucosidases (hydrolysis rate: Region I50) led to microparticles when involved in the preparation procedure. However with lower DE (<30), no microparticles could be obtained from 2% ester solution concentrations. This difference in reactivity was explained by the formation of hydrophobic microdomains with the alkyl esters that hindered the transacylation reaction, as opposed to hydroxyalkyl esters that bore hydrophilic ester groups. PMID- 27987929 TI - Structure elucidation of an immunostimulatory arabinoxylan-type polysaccharide prepared from young barley leaves (Hordeum vulgare L.). AB - We recently isolated an immunostimulating polysaccharide (BLE-P-I), which possesses a large proportion of arabinoxylan, from young barley leaves. In the present study, to elucidate the structural details of BLE-P-I, it was fractionated into enzyme-resistant fraction (BLE-P-I-X1) and arabinoxylan-rich oligosaccharide fraction (BLE-P-I-X2) after endo-xylanase hydrolysis. Commercial wheat arabinoxylan was also fractionated into WAX-XI and WAX-X2 after the same treatment. BLE-P-I-X2 consisted of arabinose and xylose, including 11 types of neutral glycosidic linkages, whereas WAX-X2 had less, with 6 types of linkages. Mass spectrometric results indicated that WAX-X2 was composed of a xylan backbone bearing only arabinose. In contrast, BLE-P-I-X2 consisted of a xylan backbone with acetate, arabinose, galactose, glucuronic acid, and 4-O-methylglucuronic acid, resembling structural characteristics as glucuronoarabinoxylan. Macrophage stimulatory activity showed that BLE-P-I-X2 has a role in the expression of the activity. These results indicate that the structural complexity of arabinoxylan seems to be responsible for the immunomodulatory activity in barley leaf. PMID- 27987931 TI - Rheological properties of nanocrystalline cellulose suspensions. AB - Rheological behavior, including linear and nonlinear, as well as transient rheology of nanocrystalline cellulose (NCC) suspensions was studied in this work. Two kinds of polymer solutions, aqueous poly(vinyl alcohol) (PVA) with flexible chain structure and aqueous carboxymethyl cellulose (CMC) with semi-rigid chain structure, were used as the suspension media to further explore the role that the interactions among NCC and polymers played during shear flow. The results reveal that NCC has lower values of percolation threshold in the PVA solution than in the CMC one during small amplitude oscillatory shear (SAOS) flow because the flexible PVA chain has higher adsorbed level onto NCC particles than the negatively charged semi-rigid CMC chain, which is further confirmed by the Fourier transformed infrared (FT-IR) spectroscopy tests. As a result, the NCC suspension shows a weak strain overshoot in PVA solution during large amplitude oscillatory shear (LAOS) flow, which cannot be seen on the one in CMC solution. During startup shear flow, both of these two suspensions show evident stress overshoot behavior with the strain-scaling characteristics, indicating the formation of ordered long-term structure of rod-like NCC particles with self similarity during flow. However, NCC suspension have far stronger stress overshoot response in CMC solution relative to the one in PVA solution. A possible synergy mechanism between NCC and CMC chain is hence proposed. PMID- 27987930 TI - Synthesis and catalytic properties of silver nanoparticles supported on porous cellulose acetate sheets and wet-spun fibers. AB - Cellulose acetate fibers (CAfiber), and sheets (CAsheet) were prepared by wet spinning, and doctor blade methods, respectively. For CAfiber, the CA-acetone solution was pushed through narrow orifice of the medical syringe into a coagulating bath containing water. The same polymer solution was used for the fabrication of CAsheet. The prepared CAfiber and CAsheet were dipped in a 0.1M aqueous AgNO3 solution followed by treatment with 0.1M NaBH4 aqueous solution to synthesize the Ag nanoparticles over stated substrates. The virgin CAfiber and CAsheet as well as Ag nanoparticles containing samples (Ag/CAfiber and Ag/CAsheet) were characterized by FE-SEM, XRD, FTIR, and TGA. These materials were tested as catalysts in hydrogenation of the 2,6-dinitrophenol (2,6-DNP) by NaBH4. The Ag/CAfiber played better catalytic role in the hydrogenation of 2,6 DNP as compared to the Ag/CAsheet. Moreover, the catalyst amount effect on the reaction rate constant, ease of separation and reusability of the prepared materials were discussed. PMID- 27987932 TI - By-products of Scyliorhinus canicula, Prionace glauca and Raja clavata: A valuable source of predominantly 6S sulfated chondroitin sulfate. AB - Chondroitin sulfate (CS) was isolated from Scyliorhinus canicula (fin, head and skeleton), Prionace glauca (head), and Raja clavata (skeleton) by-products from fish processing industry using environmentally friendly processes. The molecular weight was determined by gel permeation chromatography and the sugar composition and sulfation position by NMR and SAX-HPLC after enzymatic digestion. The CSs showed a prevalent 6S GalNAc sulfation for the 3 species (4S/6S ratio lower than 1). A higher 6S sulfation was observed for P. glauca head and R. clavata skeleton (4S/6S ratio below 0.20) than for S. canicula (4S/6S ratio ca. 0.6). The existence of CS samples with such low 4S/6S ratio has only been observed before in a rare species of shark (Mitsukutina owatoni, globin shark). The good extraction yields achieved make S. canicula, P. glauca and R. clavata fish industry by-products a useful source of 6-sulfated chondroitin sulfate. PMID- 27987933 TI - Chitosan-based DNA delivery vector targeted to gonadotropin-releasing hormone (GnRH) receptor. AB - The main purpose of this study was to investigate the application of modified chitosan as a potential vector for gene delivery to gonadotropin-releasing hormone receptor (GnRHR)-expressing cells. Such design of gene carrier could be useful in particular for gene therapy for cancers related to the reproductive system, gene disorders of sexual development, and contraception and fertility control. In this study, a decapeptide GnRH was successfully conjugated to chitosan (CS) as confirmed by proton nuclear magnetic resonance spectroscopy (1H NMR) and Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). The synthesized GnRH-conjugated chitosan (GnRH-CS) was able to condense DNA to form positively charged nanoparticles and specifically deliver plasmid DNA to targeted cells in both two-dimensional (2D) and three-dimensional (3D) cell cultures systems. Importantly, GnRH-CS exhibited higher transfection activity compared to unmodified CS. In conclusion, GnRH-conjugated chitosan can be a promising carrier for targeted DNA delivery to GnRHR-expressing cells. PMID- 27987934 TI - Role of nanostructured aggregation of chitosan derivatives on [5 methionine]enkephalin affinity. AB - Affinities of quaternary ammonium-chitosan conjugates, their thiolated derivatives and corresponding nanostructured aggregates towards the hydrophilic drug [5-methionine]enkephalin were compared by Nuclear Magnetic Resonance (NMR) spectroscopic methods based on proton selective relaxation rate measurements. Nanoaggregates showed enhanced drug affinity in comparison with corresponding polymers, especially in the case of thiolated systems. PMID- 27987935 TI - Chitosan-based core-shell nanomaterials for pH-triggered release of anticancer drug and near-infrared bioimaging. AB - As a naturally-abundant biopolymer, chitosan (CS) exhibit pH-sensitive structural transformation within a narrow pH range. Integrating hydrophobic groups to CS molecules gives modified CS polymers with more adjustable pH responsiveness. In this paper, near-infrared (NIR) photoluminescent Ag2S QDs capped by long-chain carboxylic acid were synthesized and then conjugated with CS via esterification reaction. The anticancer drug doxorubicin (DOX) has an affinity for the hydrophobic oleoyl groups and was entrapped by them to produce Ag2S(DOX)@CS nanospheres. A variety of experiments were performed to characterize the nanospheres. In vitro and in vivo experiments showed that the nanospheres can release DOX at lowered pH in tumor cells and have high antitumor efficacy. In addition, the strong NIR signal derived from the encapsulated Ag2S QDs makes real time monitoring of the nanosphere distribution in a body possible. This study provides a new CS-based nanocomposite drug carrier for efficient cancer therapy. PMID- 27987936 TI - Removal of metal ions from aqueous solutions using carboxymethyl cellulose/sodium styrene sulfonate gels prepared by radiation grafting. AB - Sodium Carboxymethyl Cellulose (CMCNa)/Sodium Styrene Sulfonate (SSS) hydrogels with grafted and crosslinked polymeric networks were prepared by gamma-radiation at atmosphere condition. The obtained hydrogels were characterized by gel fraction, swelling ratio, TGA and FTIR spectroscopy. The results showed the ratio of CMC and SSS 1:0 gave the highest gel fraction, compared with other ratios. The swelling capacity increased by increasing SSS content due to the presence of SO3Na, OH groups in gel structure. The FTIR spectrum of CMC/SSS gel showed the new absorption peaks at 1034 and 1012cm-1 corresponds to SO3Na group. The metal ion adsorption capacity of CMC/SSS gel was investigated. The grafted gel effectively removed metal ions, especially Cr and Pb. The effects of hydrogel composition, contact time, and initial concentration on the adsorption capacity of the grafted hydrogels were studied. The adsorption kinetics and equilibrium isotherms were investigated using pseudo-second-order model and Langmuir model. PMID- 27987937 TI - Flexible polypyrrole/copper sulfide/bacterial cellulose nanofibrous composite membranes as supercapacitor electrodes. AB - Polypyrrole (PPy) and copper sulfide (CuS) have been successfully deposited on bacterial cellulose (BC) membranes to prepare nanofibrous composite electrodes of PPy/CuS/BC for flexible supercapacitor applications. The introduction of CuS remarkably improves the specific capacitance and cycling stability of BC-based electrodes. The specific capacitance of the supercapacitors based on the PPy/CuS/BC electrodes can reach to about 580Fg-1 at a current density of 0.8mAcm 2 and can retain about 73% of their initial value after 300 cycles, while the PPy/BC-based device could retain only 21.7% after 300 cycles. This work provides a promising approach to fabricate cost-effective and flexible nanofibrous composite membranes for high-performance supercapacitor electrodes. PMID- 27987938 TI - Monitoring molecular dynamics of bacterial cellulose composites reinforced with graphene oxide by carboxymethyl cellulose addition. AB - Broadband Dielectric Relaxation Spectroscopy was performed to study the molecular dynamics of dried Bacterial Cellulose/Carboxymethyl Cellulose-Graphene Oxide (BC/CMC-GO) composites as a function of the concentration of CMC in the culture media. At low temperature the dielectric spectra are dominated by a dipolar process labelled as a beta-relaxation, whereas electrode polarization and the contribution of dc-conductivity dominate the spectra at high temperatures and low frequency. The CMC concentration affects the morphological structure of cellulose and subsequently alters its physical properties. X-ray diffractometry measurements show that increasing the concentration of CMC promotes a decrease of the Ialpha/Ibeta ratio. This structural change in BC, that involves a variation in inter- and intramolecular interactions (hydrogen-bonding interactions), affects steeply their molecular dynamics. So, an increase of CMC concentration produces a significantly decrease of the beta-relaxation strength and an increase of the dc-conductivity. PMID- 27987939 TI - Chitosan nanoparticles for combined drug delivery and magnetic hyperthermia: From preparation to in vitro studies. AB - Chitosan nanoparticles (CSNPs) ionically crosslinked with tripolyphosphate salts (TPP) were employed as nanocarriers in combined drug delivery and magnetic hyperthermia (MH) therapy. To that aim, three different ferrofluid concentrations and a constant 5-fluorouracil (5-FU) concentration were efficiently encapsulated to yield magnetic CSNPs with core-shell morphology. In vitro experiments using normal cells, fibroblasts (FHB) and cancer cells, human glioblastoma A-172, showed that CSNPs presented a dose-dependent cytotoxicity and that they were successfully uptaken into both cell lines. The application of a MH treatment in A 172 cells resulted in a cell viability of 67-75% whereas no significant reduction of cell viability was observed for FHB. However, the A-172 cells showed re-growth populations 4h after the application of the MH treatment when CSNPs were loaded only with ferrofluid. Finally, a combined effect of MH and 5-FU release was observed with the application of a second MH treatment for CSNPs exhibiting a lower amount of released 5-FU. This result demonstrates the potential of CSNPs for the improvement of MH therapies. PMID- 27987940 TI - Correlation between type of alkali rinsing, cytotoxicity of bio-nanocellulose and presence of metabolites within cellulose membranes. AB - The study aimed at evaluation of various types of alkali rinsing with regard to their efficacy in terms of removal, not only of bacteria but also bacterial metabolites, from cellulose matrices formed by three Komagataeibacter xylinus strains. Moreover, we tested the type of alkali rinsing on membrane cytotoxicity in vitro in fibroblast and osteoblast cells and we compared matrices' ability to induce oxidative stress in macrophages. We identified 11 metabolites of bacterial origin that remained in cellulose after rinsing. Moreover, our results indicated that the type of alkali rinsing should be adjusted to specific K. xylinus strains that are used as cellulose producers to obtain safe biomaterials in the context of low cytotoxicity and macrophage induction. The findings have translational importance and may be of direct significance to cellulose dressing manufacturers. PMID- 27987941 TI - Investigation of bio polymer electrolyte based on cellulose acetate-ammonium nitrate for potential use in electrochemical devices. AB - Proton conducting materials create prime interest in electro chemical device development. Present work has been carried out to design environment friendly new biopolymer electrolytes (BPEs) using cellulose acetate (CA) complex with different concentrations of ammonium nitrate (NH4NO3), which have been prepared as film and characterized. The 50mol% CA and 50mol% NH4NO3 complex has highest ionic conductivity (1.02*10-3Scm-1). Differential scanning calorimetry shows the changes in glass transition temperature depends on salt concentration. Structural analysis indicates that the highest ionic conductivity complex exhibits more amorphous nature. Vibrational analysis confirms the complex formation, which has been validated theoretically by Gaussian 09 software. Conducting element in the BPEs has been predicted. Primary proton battery and proton exchange membrane fuel cell have been developed for highest ionic conductivity complex. Output voltage and power performance has been compared for single fuel cell application, which manifests the present BPE holds promise application in electrochemical devices. PMID- 27987942 TI - Physicochemical and crystalline properties of standard maize starch hydrothermally treated by direct steaming. AB - The changes in physicochemical properties of standard maize starch (SMS) by three hydrothermal treatments; DV-HMT (Direct Vapor-Heat Moisture Treatment), RP-HMT (Reduced Pressurized-Heat Moisture Treatment) and DIC (instantaneous controlled pressure drop) were investigated at different processing conditions; steam pressure (SP) varied from 1 to 3bar during 20min. Starch was steamed by direct contact, whose interest was to intensify the heat transfer phenomenon but also the water transfer. The physicochemical changes of SMS depended on process conditions and their extent followed this order: DIC>RP-HMT>DV-HMT. All treatments significantly increased gelatinization temperatures and decreased the enthalpies, confirmed by loss of granules birefringence. From 2bar, the crystalline structure changed from A-type to Vh-type, revealing formation of amylose-lipid complexes during steaming. The results clearly showed that the particle size distribution depends on the melting extent of crystalline structure during treatment. At severe processing conditions the melted fraction increased and more complex aggregates of different sizes have been formed. PMID- 27987943 TI - Evaluation of folic acid tagged aminated starch/ZnO coated iron oxide nanoparticles as targeted curcumin delivery system. AB - The role of 'superparamagnetic iron oxide nanoparticles' has gained considerable interest in various biomedical applications. However extensive researches are still going on to modify the nanoparticle size, surface properties etc. in order to get full benefit of the material. In this study, iron oxide nanoparticles have been modified with folic acid tagged aminated starch/ZnO coating to formulate a targeted drug delivery system. The nanoparticles were characterized by Fourier Transform Infra-red Spectroscopy, X-ray Diffraction, Scanning Electron Microscopy and Transmission Electron Microscopy. Both the swelling and in vitro drug release was performed in both acidic and alkaline pH. The cytotoxicity of the drug loaded nanoparticles was analysed by MTT assay in human lymphocytes, HepG2 and MCF7 cell lines. The cell uptake efficiencies and Reactive Oxygen Species generation with the drug loaded nanoparticles was estimated in HepG2 cell lines. The uptake capacity of fluorescein isothiocyanate tagged nanoparticles was assessed by fluorescence microscope. PMID- 27987944 TI - Strontium-containing, carbohydrate-based polymer networks as tooth-adherent systems for the treatment of dentine hypersensitivity. AB - This study describes the design/physicochemical properties of strontium containing, mucoadhesive carbohydrate polymeric platforms, designed as treatments for dentine hypersensitivity. Interactive networks were composed of strontium chloride (10% w/w), one of two base polymers (sodium carboxymethylcellulose, NaCMC or hydroxyethylcellulose, HEC), polycarbophil (PC) and, when required, polyvinylpyrrolidone (PVP). The physicochemical properties were characterised using oscillatory and flow rheometry, texture profile analysis, mucoadhesion analysis and, additionally, the strontium release properties were examined. All platforms exhibited pseudoplastic flow. Increasing polymer concentrations increased network viscoelasticity, consistency, hardness, compressibility, gel strength, adhesiveness, mucoadhesion and, retarded strontium release. Principally zero-order strontium release was observed from all platforms. Incorporation of strontium reduced the network elasticity, consistency, hardness, compressibility, gel strength and mucoadhesion; HEC-based platforms being affected to a greater extent than NaCMC platforms. NaCMC-based platforms containing 10% strontium chloride, PVP (3% w/w) and PC (3% w/w) potentially displayed the correct balance of physicochemical properties for the treatment of dentine sensitivity. PMID- 27987945 TI - Effect of calcium sulphate nanorods on mechanical properties of chitosan hydroxyethyl methacrylate (HEMA) copolymer nanocomposites. AB - Copolymers of chitosan and hydroxyetheyl methacrylate (HEMA) were successfully synthesized using ceric ammonium nitrate (CAN) as an initiator, via in situ polymerization method, followed by efficacious preparation of their nanocomposites by incorporating calcium sulphate nanorods via solution blending process. Hydrophilicity studies confirmed that grafting of HEMA in the backbone of the hydrophobic chitosan chains induced the improvement in hydrophilicity of chitosan, while mechanical properties of the nanocomposites were also enhanced significantly up to 20%, due to availability of enlarged surface area and higher aspect ratio of CaSO4 nanorods. This was supported by FE-SEM and XRD analysis in terms of proper distribution of nanofiller through the copolymer matrix and corresponding rise in percentage crystallanity respectively. Results obtained from biodegradation studies proved the efficiency of CaSO4 nanofillers to improve biomechanical strength of chitosan nanocomposites, without affecting their normal degradation profile that renders the products to be applicable for biomedical applications. PMID- 27987946 TI - Lactoferrin-coated polysaccharide nanoparticles based on chitosan hydrochloride/hyaluronic acid/PEG for treating brain glioma. AB - Curcuminoid (Cur) loaded polysaccharide nanoformulations with blood-brain barrier (BBB) penetration and brain targeting properties, based on hyaluronic acid (HA) and chitosan hydrochloride (CSH) (Lf-Cur-PSNPs) were developed as a novel delivery system for malignant glioma. Formulations were investigated for physicochemical characteristics, cytotoxicity, uptake, and BBB penetration. The results showed that LfM-Cur-PSNPs (concentration of Lf was 0.5mg/mL) were preferentially taken up by brain capillary endothelial cells than Cur-PSNPs at any time. After crossing the BBB, LfM-Cur-PSNPs remained largely intact and were more effective in targeting glioma cells (C6). In vivo imaging studies in mice exposed LfM-PSNPs could effectively permeate BBB and preferentially accumulate in the brain (2.39 times greater than PSNPs). Moreover, PSNPs were detected in brain up to 72h. This data indicates that Lf-Cur-PSNPs could effectively target and accumulate within the gliomas after enhanced permeation through BBB, thus should be further explored for their potential in CNS maliganancies. PMID- 27987947 TI - A hierarchically porous cellulose monolith: A template-free fabricated, morphology-tunable, and easily functionalizable platform. AB - Recently, monoliths with continuous porous structure have received much attention for high-performance separation/adsorption matrix in biomedical and environmental fields. This study proposes a novel route to prepare cellulose monoliths with hierarchically porous structure by selecting cellulose acetate (CA) as the starting material. Thermally induced phase separation of CA solution using a mixed solvent affords a CA monolith, which is converted into the cellulose monolith by alkaline hydrolysis. Scanning electron microscopy images of the CA and cellulose monoliths reveal a continuous macropore with rough surface, and nitrogen adsorption/desorption analysis indicates the formation of a mesoporous structure. The macroporous structure could be controlled by changing the fabrication parameters. A series of reactive groups are introduced by chemical modifications on the surface of the cellulose monolith. The facile and diverse modifiability combined with its hydrophilic property make the hierarchically porous cellulose monolith a potential platform for use in separation, purification and bio-related applications. PMID- 27987948 TI - Magnetic cellulose ionomer/layered double hydroxide: An efficient anion exchange platform with enhanced diclofenac adsorption property. AB - Polymeric ionomers with anion exchange capability are considered to be classes of environmentally friendly compounds as combination of them with anionic layered hydroxides constitute emerging advance materials. Biosorption by polymeric ionomer - layered double hydroxide (LDH) hybrid material exhibits an attractive green, low cost and low toxic - clean way. As a result, a novel anion exchange platform has been developed by the reaction of CaAl - LDH with Fe2+, cellulose solution, epichlorohydrin and pyridine. Magnetite cellulose - LDH (MCL) and the ionomer were used for efficient biosorption of diclofenac sodium (DF). Results showed that ionomer has more efficiency for DF adsorption relative to MCL. Magnetite ionomer showed fast equilibrium time (2min) with maximum uptake of 268mgg-1. Isotherm and Kinetic models were also studied. Regeneration of the sorbent was performed with a mixture of methanol -NaOH (2.0molL-1) solution. PMID- 27987949 TI - Applications of bacterial cellulose as precursor of carbon and composites with metal oxide, metal sulfide and metal nanoparticles: A review of recent advances. AB - This mini review is limited to very recent studies (last 5-10 years) on two major issues, concerning: the production and physical/chemical modification of bacterial cellulose (BC), and its transformation into carbon and integrated synthesis of metal oxides (TiO2, ZnO, Fe3O4, etc.), metal sulfide (ZnS, CdS, etc.) and metal nanoparticles (Au, Ag, Pt, Pd, etc.) within bacterial cellulose nanoribbons network. We believe that the crossover of these two domains could be of considerable interest in the view of improving the performance of materials prepared with bacterial cellulose. The diversity of these nanomaterials allows targeting of many very different properties/applications: electrochemical devices, catalysis and photocatalysis, sensors, etc. After an introduction to the most important chemical and physical characteristics of BC, production parameters, and its physical and chemical modifications, we review the use of BC as a precursor of inorganic materials like carbon and composites with metal or inorganic nanoparticles. PMID- 27987950 TI - Bronsted acidic ionic liquids: Innovative starch desizing agents. AB - The possibility of using a synthesized inexpensive Bronsted acidic ionic liquids for starch desizing of a textile substrate for the first time was investigated under different conditions in terms of temperature, concentration and treatment time. The samples evaluation was carried out by Fourier transform infrared spectroscopy, microscopic studies, Tegewa tests, measuring weight loss, tensile strength, wetting properties and changes in the samples shades. The results indicated that the ionic liquids have strong effect on the cotton fabric starch desizing (Tegewa 6 or higher) with no adverse effect on the samples strength and whiteness. Thus, it was revealed that proper ionic liquids could be counted as novel starch desizing agents and alternative for the enzymatic process. In addition, it was observed that the acidic ionic liquids because of their specific structure do not have negative aspects of common acidic processes with no sensitivities and drawbacks of enzymatic treatments. PMID- 27987951 TI - Hyaluronic acid-coated nanoparticles for targeted photodynamic therapy of cancer guided by near-infrared and MR imaging. AB - In this study, the multifaceted properties of hyaluronic acid (HA) were used for the targeted therapy of cancer by photodynamic therapy (PDT) guided by molecular imaging. Near-infrared (NIR) photosensitizers (Chlorin e6; Ce6) were encapsulated into poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) coated with HA that can act as CD44 targeting ligand. The abundant carboxylate groups of HA also enabled the chelation of gadolinium ions (Gd3+), T1-weighted MRI contrast agents, on the surface of PLGA NPs. Through both in vitro and in vivo fluorescence and MRI signal analysis, we confirmed that the HA-Gd-Ce6-PLGA NPs (HAGCP-NPs) could efficiently target CD44-overexpressing A549 cancer cells. When an NIR laser was illuminated to irradiate A549 tumor-bearing mice, the groups treated with HAGCP NPs showed remarkable delays in tumor growth or tumor regression. Taken together, the HAGCP-NPs are expected to be used as a theranostic platform for the dual modal (MR/NIR) imaging and PDT of cancer. PMID- 27987952 TI - Synthesis and swelling behaviors of carboxymethyl cellulose-based superabsorbent resin hybridized with graphene oxide. AB - Well-dispersed graphene oxide sheets were successfully incorporated into a superabsorbent resin through in situ graft polymerization of acrylic acid on carboxymethyl cellulose backbone in the presence of graphene oxide as filler. The structure and properties of the resultant superabsorbent resin were studied in detail by means of a variety of characterization methods. The influence of the feed ratio of starting materials (such as GO, initiator, cross-linker, the ratio of CMC to AA and the neutralized degree of AA) and pH values on water absorbency and retention ability was extensively determined and discussed. The obtained results showed that the introduction of graphene oxide had no obvious influence on the inherent structure of the superabsorbent resin but changed the surface morphology significantly. Importantly, the hybrid superabsorbent resin showed an enhanced thermal stability and remarkably improved swelling ratio as well as water-retention ability comparing with that of the pure superabsorbent resin. PMID- 27987953 TI - Structural elucidation of three antioxidative polysaccharides from Tricholoma lobayense. AB - Tricholoma lobayense is a nutritious mushroom with great health benefits. Three polysaccharides with purity higher than 99% were successfully extracted from Tricholoma lobayense. The molecular weights of TLH-1, TLH-2 and TLH-3 were determined to be 8.43*105,5.36*105 and 4.53*103Da, respectively. The backbones of TLH-1 and TLH-2 were mainly composed of 1,4-linked alpha-d-glucopyranosyl. However, polysaccharide TLH-3 was found to be a highly branched glucogalactan, which is made up of 1,3-linked alpha-d-glucopyranosyl branched at C-6 and 1,3 linked beta-d-galactopyranosyl. In vitro antioxidant activity assays revealed that TLH-3 exhibited highest antioxidant activities among the polysaccharides from Tricholoma lobayense, which were comparable to those of ascorbic acid. The results suggested that the outstanding antioxidant activities of TLH-3 might depend on its low molecular weight, high branch degree, versatile linkage types and complex conformation. These characteristics make TLH-3 an attractive natural antioxidant for food and pharmaceutical applications. PMID- 27987954 TI - Smart composite materials based on chitosan microspheres embedded in thermosensitive hydrogel for controlled delivery of drugs. AB - Smart composite hydrogels (SCHs) consisting of chitosan (CS) microspheres physically embedded within a thermoresponsive hydrogel are synthesized and tested for their capacity of loading and long-term release of a small molecule drug. CS microspheres were used since they display pH-sensitive properties and have the capacity to bind electrostatically the opposite charged salicylic acid (SA), taken as model drug. These microspheres are ulterior physically entrapped within a thermoresponsive hydrogel based on poly(N-isopropylacrylamide-co hydroxyethylacrylamide) copolymer, cross-linked with N,N'-methylenebisacrylamide. The morphology, swelling behavior, temperature and pH sensitivity, degradability and drug release behavior of the new smart drug delivery system were investigated. Swelling ratios as well as the sharpness of the phase transition, largely depended on the cross-linking degree. The thermoresponsive network slightly protected the CS microspheres from the in vitro degradation. In vitro studies showed that the SA followed a prolonged release profile from SCHs in accordance with pH and temperature. PMID- 27987955 TI - Novel nanofibrillated cellulose/polyvinylpyrrolidone/silver nanoparticles films with electrical conductivity properties. AB - Nanofibrillated cellulose (NFC) isolated from rice straw pulp was used with polyvinylpyrrolidone (PVP) and silver nanoparticles (AgNPs) to prepare nanocomposites in the form of flexible films. The later films have promising mechanical and electrical conductivity properties. The isolated cellulose nanofibers were characterized by transmission electron microscopy (TEM) and X-ray diffraction (XRD). Silver nanoparticles prepared via in-situ reduction in PVP were characterized using TEM and UV-vis spectroscopy. Tensile properties, microscopic structure, and electrical properties of nanocomposites films were studied. TEM and UV-vis spectroscopy proved the in-situ formation of AgNPs in PVP matrix. Films with good flexibility and tensile strength properties could be obtained from NFC/PVP/AgNPs as revealed from the (SEM) images and tensile properties testing. The electrical conductivity of NFC/PVP/AgNPs supports this system to be an excellent choice for sensitive electronic components packing as it can be used as antistatic and electrostatic dissipative materials. PMID- 27987957 TI - Characterization of xanthan gum produced from glycerol by a mutant strain Xanthomonas campestris CCTCC M2015714. AB - Xanthan gum was produced by a mutant strain X. campestris CCTCC M2015714 with glycerol as the sole carbon source. The monosaccharide composition and molar ratio of xanthan gum produced from glycerol are glucose: mannose: glucuronic acid=2.0:1.65:1.0. Meanwhile, chemical structure of xanthan gum produced from glycerol is similar to that of the commercial xanthan through FT-IR and NMR. Remarkably, the molecular weight of xanthan gum produced using our method (3.0+/ 0.14*106Da) is about half that of the commercial one (5.8+/-0.25*106Da), and the consistency index (K) of which is less than 1/10 that of the commercial xanthan. This work paves the way for xanthan production from glycerol and is useful for studying the structure/application of xanthan gum. PMID- 27987956 TI - Chemical treatment and characterization of soybean straw and soybean protein isolate/straw composite films. AB - This work investigated changes in the chemical composition and structure of soybean straw (SS) treated with alkali (NaOH 5% and 17.5%) and bleached with hydrogen peroxide (H2O2) or sodium hypochlorite (NaOCl). Removal of the amorphous constituents increased the degree of crystallinity and the content of cellulose fibers particularly after reaction with high concentrations of alkali. Treatment with NaOH 17.5% contributed to the allomorph transition from cellulose I to II regardless of the bleaching agent, but H2O2 as bleaching agent promoted more effective delignification. This work also evaluated the potential use of treated and non-treated SS as reinforcement filler in soy protein isolate film (SPI). Films added with treated SS presented higher mechanical resistance, lower elongation at break, and lower solubility in water. Addition of non-treated SS did not affect the properties of the SPI film significantly. The low solubility and the reasonable water vapor permeability of the composite films make them suitable packaging materials for fresh fruit and vegetables. PMID- 27987958 TI - Determination of the optimal reaction conditions for the preparation of highly substituted carboxymethyl Cassia tora gum. AB - Highly substituted carboxymethyl Cassia tora gum (CM-CTG) was prepared from CTG by treatment with monochloroacetic acid (MCA) in ethanolic aqueous solutions after alkalization under different reaction conditions. The influence of the etherification temperature, alkalization and etherification times, molar ratio of sodium hydroxide to MCA (nNaOH/nMCA), theoretical degree of substitution (DSt), and weight percentage of water (WH2O%) in the solution on the degree of substitution (DS) and reaction efficiency (RE) of the reaction were investigated. Optimum preparation conditions for a CM-CTG with DS of 1.05 are: etherification temperature, 60 degrees C; alkalization time, 60min; etherification time, 180min; nNaOH/nMCA, 2.1; DSt, 1.4; and WH2O%, 20%. Fourier-transform infrared analysis of the products indicated that carboxymethylation was successful. Rheological studies show that all the CM-CTG pastes are pseudoplastic fluids, and the shear sensitivity varies with DS. The degree of crystallinity of CM-CTG decreases with increasing DS, as shown by X-ray diffraction measurements. PMID- 27987959 TI - Comparison of porous starches obtained from different enzyme types and levels. AB - The objective was to compare the action of different hydrolases for producing porous corn starches. Amyloglucosidase (AMG), alpha-amylase (AM), cyclodextrin glycosyltransferase (CGTase) and branching enzyme (BE) were tested using a range of concentrations. Microstructure, adsorptive capacity, pasting and thermal properties were assessed on the porous starches. SEM micrographs showed porous structures with diverse pore size distribution and pore area depending on the enzyme type and its level; AMG promoted the largest holes. Adsorptive capacity was significantly affected by enzymatic modification being greater influenced by AMG activity. Unexpectedly, amylose content increased in the starch treated with AMG and BE, and the opposite trend was observed in AM and CGTase treated samples, suggesting different mode of action. A heatmap illustrated the diverse pasting properties of the different porous starches, which also showed significant different thermal properties, with lower To and Tp. Porous starch properties could be modulated by using different enzymes and concentrations. PMID- 27987960 TI - Analysis of beta-glucan molar mass from barley malt and brewer's spent grain with asymmetric flow field-flow fractionation (AF4) and their association to proteins. AB - beta-Glucan benefits are related with its molar mass and it would be of interest to better understand how this parameter can be changed by processing and variety for design of food with specific health effects. For this purpose, extracts from barley malts and brewers' spent grain, processed at different conditions, were analysed regarding beta-glucan content, molar mass, and protein content. Molar mass distribution was assessed using asymmetric flow field-flow fractionation (AF4) with multiangle light scattering (MALS), differential refractive index (dRI) and fluorescence (FL) detection. beta-Glucan was detected in a wide molar mass range, <2000 to approximately 6.7*106g/mol. Differences in molar masses were more noticeable between barley varieties and steeping malting conditions than by mashing of malt. Barley products processed to preserve beta-glucan contained more beta-glucan of high molar mass with potential to shift the fermentation site to the distal colon. Enzymatic degradation of proteins indicated presence of aggregates containing beta-glucan and protein. PMID- 27987961 TI - A novel solution blending method for using olive oil and corn oil as plasticizers in chitosan based organoclay nanocomposites. AB - In the current study a novel reflux-solution blending method is being followed with the introduction of small ethanol volumes into chitosan acetic acid aquatic solution in order to incorporate olive oil and corn oil in chitosan and its organoclay nanocomposites. Ethanol enables the direct interaction of chitosan with oils and results in effective plasticization of chitosan/oil films with remarkable increase of the strain at break from 8% of chitosan and chitosan/oil aquatic samples to app. 22% for chitosan/oil ethanol samples. Compared with olive oil, corn oil is less effective as plasticizer (max strain at break app. 14%). Addition of oils is beneficial for water sorption, water vapor permeability and oxygen permeability response of the obtained films. Barrier properties are further improved after the use of OrgMMT, however OrgMMT results in significant reduction of strain at break of all oil containing samples (app. 8%) acting as stress concentrator upon deformation. PMID- 27987962 TI - Production of starch nanoparticles by dissolution and non-solvent precipitation for use in food-grade Pickering emulsions. AB - The aim of this study was to investigate non-solvent precipitation of starch to produce nanoparticles that could be used in Pickering emulsions. The material used was waxy maize, modified with octenyl succinic anhydride. Different methods of non-solvent precipitation were investigated, and a method based on direct mixing of an 8% starch solution and ethanol (ratio 1:1) was found to produce the smallest particles. The particle size was measured using AFM and AF4, and was found to be in the range 100-200nm. However, both larger particles and aggregates of nanoparticles were observed. The emulsion produced using the precipitated starch particles had a droplet size that between 0.5 and 45MUm, compared to emulsions produced from waxy maize granules, in which had a size of 10-100MUm. The drop in size contributed to increased stability against creaming. The amount of starch used for emulsion stabilization could also be substantially reduced. PMID- 27987964 TI - Adsorption of divalent heavy metal ion by mesoporous-high surface area chitosan/poly (ethylene oxide) nanofibrous membrane. AB - In this study, chitosan/poly (ethylene oxide) nanofibres were fabricated at different chitosan:PEO weight ratio by electrospinning process. The effects of chitosan/PEO composition onto adsorption capability for Cu(II), Zn(II) and Pb(II) ions were studied. Formation of beadless fibres were achieved at 60:40 chitosan:PEO ratio. Average fiber diameter, maximum tensile strength and the specific surface area of the beadless fibres were found to be 115+/-31nm, 1.58MPa and 218m2/g, respectively. Chitosan/PEO composition that produced beadless fibres tend to possess higher hydrophilicity and maximum specific surface area. These characteristics lead the beadless fibres to the maximum adsorption capability. Adsorption equilibrium data were analysed by Langmuir and Freundlich isotherm. Freundlich isotherm showed the better fit with the experimental data and proved the existence of the monolayer adsorption conditions. The maximum adsorption capacity of the beadless fibres for Cu(II), Zn(II) and Pb(II) ions were found to be 120, 117 and 108mgg-1, respectively. PMID- 27987966 TI - Guar gum as biosourced building block to generate highly conductive and elastic ionogels with poly(ionic liquid) and ionic liquid. AB - In this study, we report on the simple and straightforward preparation of ionogels arising from the addition of guar gum (a plant-based polysaccharide) in a solution of precisely-defined poly(ionic liquid) chains (PIL) in imidazolium based ionic liquid (IL). The development of intermolecular polar interactions (mainly hydrogen bonds) and topologic chain entanglements induces the formation of physical biohybrid ionogels, whose elastic properties can be easily tuned by varying the composition (up to 30000Pa). The combined presence of guar gum and PIL confers excellent dimensional stability to the ionogels with no IL exudation combined with high thermal properties (up to 310 degrees C). The resulting materials are shown to exhibit gel scattering profiles and high conductivities (> 10-4S/cm at 30 degrees C). The benefit linked to the formation of guar/PIL associations in IL medium enables to find a good compromise between the mechanical cohesion and the mobility ensuring the ionic transport. PMID- 27987963 TI - Quaternized cashew gum: An anti-staphylococcal and biocompatible cationic polymer for biotechnological applications. AB - Chemical modifications to cashew gum (CG) structure have been previously reported to obtain new physicochemical characteristics, however until now there were no reports of modifications by introduction of new functional groups to add cationic character. This study presents a quaternization route for CG using a quaternary ammonium reagent. The chemical features of the quaternized cashew gum derivatives (QCG) were analyzed by: FTIR, elemental analysis, degree of substitution, Zeta potential, 1H NMR and 1H-13C correlation (HSQC). QCG were evaluated for their anti-staphylococcal activity by determining minimum inhibitory and bactericidal concentrations against pathogenic Staphylococcus spp. and by imaging using atomic force microscopy. Moreover, the mammalian cell biocompatibility were also assessed through hemolytic and cell toxicity assays. QCG presented promising antimicrobial activity against methicillin-resistant S. aureus and biocompatibility on tested cells. These results show that QCG could be a promising tool in the development of biomaterials with an anti-septic action. PMID- 27987967 TI - Mechanism of surface charge triggered intestinal epithelial tight junction opening upon chitosan nanoparticles for insulin oral delivery. AB - Intestinal epithelium is a major barrier limiting the absorption of oral insulin owing to the presence of intercellular tight junctions (TJs). Previous studies proved that carboxymethyl chitosan/chitosan-nanoparticles (CMCS/CS-NPs) exhibited surface charge depending promotion of intestinal absorption. This study further confirmed the better performances of insulin:CMCS/CS-NPs(-) in enhancing epithelial permeation, increasing bioavailability and extending blood duration of insulin than insulin:CMCS/CS-NPs(+). Immunohistochemistry sections found that TJs on jejunum epithelium completely disappeared in insulin:CMCS/CS-NPs(-) group, partially existed in insulin:CMCS/CS-NPs(+) group and appeared no change in control. Surface charges of CMCS/CS-NPs triggered intestinal epithelial TJs opening through different mechanisms. Although a down-regulation of TJs protein claudin-4 was detected in both nanoparticles groups, for phosphorylated claudin 4, the activating form, whose down-regulation occurred only in insulin:CMCS/CS NPs(-) group. Counting upon synergetic effects of Ca2+ deprivation from adherens junctions and claudin-4 dephosphorylation and degradation, CMCS/CS-NPs(-) triggered more extensive disintegration of TJs and stronger paracellular permeability than the positive. PMID- 27987965 TI - Effect of Cu(II) ions on the enhancement of tetracycline adsorption by Fe3O4@SiO2 Chitosan/graphene oxide nanocomposite. AB - Fe3O4@SiO2-Chitosan/GO (MSCG) nanocomposite was investigated by various techniques (SEM, TEM, XRD, VSM, FT-IR, XPS) for the removal of tetracycline (TC). Effects of pH, zeta potential and initial contaminant concentration were studied in detail. Four background cations (Na+, K+, Ca2+ and Mg2+) with a concentration of 0.01M showed little influence on the TC adsorption at the studied pH range while the divalent heavy metal cation Cu(II) could significantly enhance the adsorption. The results indicated that the highest adsorption capacity of TC were 183.47mmol/kg and 67.57mmol/kg on MSCG with and without Cu(II), respectively. According to mechanism investigation for the adsorption of TC by pH impact study and XPS analysis, besides electrostatic interaction and pi-pi interactions, the Cu(II) also acts as a bridge between TC and MSCG, which significantly improve the adsorption of TC. This study provided valuable guidance and effective method for the removal of TC from aquatic environments. PMID- 27987968 TI - Gamma sterilization of diclofenac sodium loaded- N-trimethyl chitosan nanoparticles for ophthalmic use. AB - This study was conducted to investigate the effect of gamma irradiation on physicochemical properties of N-trimethyl chitosan (TMC), diclofenac sodium (DC) and diclofenac sodium loaded N-trimethylchitosan nanoparticles (DC-TMCNs), and to determine suitable doses of gamma rays for sterilization of DC-TMCNs. Physicochemical properties of TMC, DC and DC-TMCNs before and after exposure to gamma rays at various doses were investigated. It was found that gamma irradiation at doses of 5-25kGy did not cause any significant changes in physical and chemical properties of TMC, DC and DC-TMCNs. The bioburden of DC-TMCNs was 1.5*106 CFU/vial. The initial contaminating bacteria were radiosensitive bacteria. A number of microorganisms was reduced to 10-6 after exposure to 9.9kGy of gamma rays. Therefore, DC-TMCNs could be sterilized by gamma irradiation at a dose of 10kGy, which did not alter their physicochemical properties and did not produce any substances toxic to the eye. PMID- 27987969 TI - Micro-/nanofibers prepared via co-assembly of paclitaxel and dextran. AB - In this paper, we reported the preparation of micro-/nanofibers via co-assembly with paclitaxel (PTX) and dextran (DEX). The co-assembly fibers formed in PTX and DEX mixture solution via non-covalent interactions including hydrophilic/hydrophobic interactions and pi-pi stacking. The micro-/nanofibers could be obviously observed when the mixed solution became turbid and ivory-white in color. The properties of fibers were characterized by SEM, TEM, FTIR, DSC, XRD, in vitro release and MTT assay. The length of fibers could reach several centimeters. The diameter of microfibers and nanofibers was about 800nm and 80nm, respectively. In addition, the PTX loading efficiency was over 78% in co-assembly fibers and up to 84% when PTX and DEX (Mw: 40,000) both were 2mg/mL. The sustained drug release and low cytotoxicity in vitro of PTX/DEX fibers were also demonstrated. Therefore, we believe that PTX/DEX micro-/nanofibers would have great potential for drug delivery of PTX. PMID- 27987971 TI - Antioxidant activities of the polysaccharides of Chuanminshen violaceum. AB - The water-soluble polysaccharides were extracted and purified from the root of Chuanminshen violaceum (CVPS). The antioxidant activities of the CVPS were evaluated both with in vitro and in vivo experiments. The results of the in vitro antioxidant assay suggested that the CVPS scavenged DPPH, hydroxyl, and superoxide anion radicals. The oral administration of three different doses of CVPS administered over a period of 6 weeks to D-galactose induced aging mice models, enhanced the activities of T-SOD, Mn-SOD, Cu, Zn-SOD, and CAT, and markedly decreased the content of MDA. Therefore, significant up-regulation of mRNA expression levels of Cu, Zn-SOD, Mn-SOD, CAT, glutathione peroxidase 1 (GPx), thioredoxin 1 (Trx1), and thioredoxin 2 (Trx1) occurred. Finally, the results demonstrated that the CVPS are a novel potential resource for natural antioxidants and anti-aging drugs. PMID- 27987970 TI - A facile and green emulsion casting method to prepare chitin nanocrystal reinforced citrate-based bioelastomer. AB - Chitin nanocrystal (ChiNC) is a promising reinforcing nanofiller for biomedical polymers. However, its self-aggregation characteristics caused processing difficulty in developing ChiNC-based nanocomposites. Herein, a new degradable crosslinked bioelastomer, designated as poly(1,8-octanediol-co-Pluronic F127 citrate) (POFC) was synthesized by melt polycondensation of citric acid, 1,8 octanediol, and Pluronic F127. In comparison to poly(1,8-octanediol citrate) (POC), POFC pre-polymer exhibited self-emulsifying property. Once ChiNC was introduced into the emulsion, a ChiNC stabilized Pickering emulsion was formed. Coupled with a facile green emulsion casting/evaporation method, the ChiNC ultimately reinforced ChiNC/POFC nanocomposite elastomer was fabricated. The presence of F127 segments endowed POFC with better hydrophilicity and shorter degradation time relative to POC. The incorporation of ChiNC into POFC network led to highly increased tensile modulus and strength. In vitro cytotoxicity tests indicated that the ChiNC/POFC elastomer nanocomposite had a good cytocompatibility and it appeared as a potential biomaterial for tissue engineering application. PMID- 27987972 TI - Morphologies and gelatinization behaviours of high-amylose maize starches during heat treatment. AB - The granule morphologies and gelatinization behaviours of high-amylose maize starches during heating treatment were investigated by confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Maltese crosses demonstrated that the high-amylose maize starches maintained a granular structure even at 120 degrees C. The granules of high-amylose maize starches swelled slightly at 100 degrees C and swelled remarkably at approximately 120 degrees C. The destruction of the starch structure began at the centre and expanded rapidly to the periphery. The intense fluorescence of high-amylose maize starch granules gradually became feeble, and the darker region spread outward during heating at 130 degrees C for 30min, indicating that the amylose component may have been damaged and shifted. The starch granules treated at 140 degrees C were substantially destroyed, and the CLSM, normal light microscopy (NL) and SEM images displayed no discernible granules, which indicated that the original starch granules formed a continuous integrated matrix. PMID- 27987973 TI - Cellulose nanofibers coated with silver nanoparticles as a SERS platform for detection of pesticides in apples. AB - A nanocomposite based on cellulose nanofibers (CNFs) coated with silver nanoparticles (AgNPs) was developed in this study as a flexible and effective substrate for use in surface-enhanced Raman spectroscopy (SERS) analysis. An effective Raman indicator molecule, 4-aminothiophenol (pATP), was used to characterize AgNPs impregnated on CNFs. The CNF-AgNP films were used in SERS analysis to detect thiabendazole (TBZ) pesticides in apples. The influence of pH on the SERS spectra of TBZ was investigated because TBZ is a neutral molecule that has a low affinity for AgNPs. The pH of TBZ solution was decreased to below the TBZ's pKa, thus enabling the electrostatic attraction between TBZ and AgNPs. CNFs can prevent the uncontrolled aggregation of AgNPs in low pH environment and serve as an effective AgNP/nanocellulose platform for SERS analysis. Results of this study demonstrate that CNF-AgNP nanocomposites can be used to rapidly detect TBZ pesticides in various food products. PMID- 27987974 TI - Deciphering the potential of guar gum/Ag-Cu nanocomposite films as an active food packaging material. AB - Guar gum (GG) based nanocomposite (NC) films were prepared by incorporating silver-copper alloy nanoparticles (Ag-Cu NPs) through solution casting method. Effect of NP loadings (0.5-2%) on the thermo-mechanical, optical, spectral, oxygen barrier and antimicrobial properties of the GG/Ag-Cu NC films were investigated. Tensile testing showed an improvement in the mechanical strength, and a decrease in elongation at break for all NP loadings. NP incorporation into GG films showed a marked influence on the color values. The NC films showed excellent UV, light and oxygen barrier capability. Thermal properties of the NC films were improved as evidenced from the differential scanning calorimetry and the thermal conductivity data. NC films became rough and coarse over neat GG film as visualized through the scanning electron microscopy. A strong antibacterial activity was exhibited by NC films against both Gram-positive and Gram-negative bacteria, and therefore, the film could be considered as an active food packaging. PMID- 27987975 TI - Preparation and characterization of in-situ ionic cross-linked pectin films: II. Biodegradation and drug diffusion. AB - In the present study the enzymatic biodegradation of a series of calcium pectinate (CaP) films, produced by in-situ crosslinking of pre-formed low methoxy pectin films in a calcium chloride (CaCl2) solution, has been assessed. The degradation level was determined by measuring the concentration of short chain fatty acid salts (SCFA), which are the natural metabolites of pectin. To this end an ex-vivo model, mimicking the colon's environment, was utilized. The results showed that a fully calcified film from a high concentration of CaCl2 solution did not exhibit any tendency to biodegradability throughout the test time. Contrastively, a low concentration of the crosslinking solution resulted in fully calcified films which could clearly present considerably higher biodegradability. SEM analysis was used to characterize the surface of CaP films after an exposure to human feces. The permeability of CaP films to different model drugs was also tested. PMID- 27987976 TI - Orange waste: A valuable carbohydrate source for the development of beads with enhanced adsorption properties for cationic dyes. AB - Eco-friendly pectin and pectin/cellulose microfibers beads (PB and PB-CF) were synthesized using compounds extracted from orange bagasse, a solid waste from the food industry. PB-CF beads showed remarkable differences regarding several properties as compared to the beads without CF. The adsorption capability of PB and PB-CF was tested towards the removal of methylene blue (MB) from aqueous solution. The effect of various parameters on the MB adsorption was investigated. The kinetics and mechanism of adsorption were explained by the pseudo-second order kinetics and intra-particle diffusion models. Equilibrium adsorption data are explained by the Langmuir isotherm model, which revealed a maximum adsorption capacity of 1550.3mg/g for PB and 2307.9mg/g for PB-CF5. Thermodynamic analysis suggests that the adsorption of MB on the beads is spontaneous and favorable. Recycling study demonstrated that both PB and PB-CF5 can be implemented in 6 consecutive adsorption/desorption cycles without losing their adsorption capacity. These results enable the use of PB and PB-CF as potentially low-cost adsorbents for wastewater treatments. PMID- 27987978 TI - Immobilization of pectinase onto chitosan magnetic nanoparticles by macromolecular cross-linker. AB - Pectinase was immobilized onto chitosan magnetic nanoparticles (CMNPs) by dextran polyaldehyde as a macromolecular cross-linking agent. The parameters like cross linking concentration, time and CMNPs to enzyme ratio were optimized. Further, prepared magnetic pectinase nanobiocatalyst was characterized by FT-IR and XRD. The thermal kinetic studies for immobilized pectinase showed two folds improved thermal stability in the range of 55-75 degrees C as compared to free form. The Vmax and Km values of immobilized pectinase were found to be nearly equal to native form which indicated that conformational flexibility of pectinase was retained even after immobilization. The residual activity of immobilized pectinase was 85% after seven successive cycles of reuse, while it retained upto 89% residual activity on storage of fifteen days which exhibited excellent stability and durability. The conformational changes in pectinase after immobilization were evaluated by FT-IR spectroscopy data analysis tools. Finally, magnetic pectinase nanobiocatalyst was employed for apple juice clarification which showed turbidity reduction upto 74% after 150min treatment. PMID- 27987977 TI - Innovative plasticized alginate obtained by thermo-mechanical mixing: Effect of different biobased polyols systems. AB - Plasticized alginate films with different biobased polyols (glycerol and sorbitol) and their mixtures were successfully prepared by thermo-mechanical mixing instead of the usual casting-evaporation procedure. The microstructure and properties of the different plasticized alginate formulations were investigated by SEM, FTIR, XRD, DMTA and uniaxial tensile tests. SEM and XRD results showed that native alginate particles were largely destructured with the plasticizers (polyols and water), under a thermo-mechanical input. With increasing amount of plasticizers, the samples showed enhanced homogeneity while their thermal and mechanical properties decreased. Compared to sorbitol, glycerol resulted in alginate films with a higher flexibility due to its better plasticization efficiency resulting from its smaller size and higher hydrophilic character. Glycerol and sorbitol mixtures seemed to be an optimum to obtain the best properties. This work showed that thermo-mechanical mixing is a promising method to produce, at large scale, plasticized alginate-based films with improved properties. PMID- 27987979 TI - Seasonal dynamics of polysaccharides in Norway spruce (Picea abies). AB - Annual dynamics of accumulation and changes in the monosaccharide composition of pectin-, arabinan- and galactan-containing polysaccharides and binding glycans isolated from greenery (thin branches with needles) of Norway spruce were investigated in this study. The polysaccharides were compared with polysaccharides of Siberian fir according to the yields, composition and content of typical components. It was shown that Norway spruce greenery contains lowly methyl-esterified pectin extracted with ammonium oxalate, which is a part of protopectic complex and is bound with components of cell walls via ionic bonds. In contrast, Siberian fir greenery contains mainly water-extracted highly methyl esterified pectin, weakly bound to cell wall components. It was concluded that an autumn-winter period is the optimal time for harvesting Norway spruce and Siberian fir greenery for isolation of the pectic polysaccharides. The revealed regularities indicate that there is a certain biorhythm of accumulation of the compounds, probably determined by genetic factors. PMID- 27987980 TI - Novel chitosan-sulfonated chitosan-polycaprolactone-calcium phosphate nanocomposite scaffold. AB - New bioactive nanocomposite scaffolds from chitosan, sulfonated chitosan, and poly(epsilon-caprolactone) nanofibers were prepared. In this study, sulfonated chitosan was prepared using chlorosulfonic acid and combined with chitosan in order to improve the bioactivity of chitosan-based scaffolds. Meanwhile, different amounts of chopped-hydrophilic PCL nanofibers were incorporated into the fabricated scaffold in order to mimic extracellular matrix-like structure. In the end, apatite formed on/in the composite scaffolds through alternate dipping in calcium and phosphate rich solutions. The morphology, apatite forming ability, and mechanical properties of the scaffolds were evaluated. The results indicated that larger pore sizes, higher porosity and apatite deposition are obtained as a result of adding more PCL nanofibers. Contrary to the effects of increased pore size, addition of PCL nanofibers enhanced the mechanical properties. Cell culture experiments with osteoblast-like cells on the scaffolds demonstrated that incorporation of PCL nanofibers into the fabricated scaffolds improves cell viability and attachment. PMID- 27987981 TI - Photochromic paper from wood pulp modification via layer-by-layer assembly of pulp fiber/chitosan/spiropyran. AB - Cellulosic fiber introducing with photochromic properties can be used in many fields such as security packaging, printing paper, and rewritable paper. To introduce photochromic property to individual fiber, a polyelectrolyte composite layer composed of cationic chitosan (CS) and anionic carboxyl-containing spiropyran (SPCOOH) on pulp fibers was designed using layer-by-layer assembly technique. Scanning electron microscope observation showed that the SPCOOH was successfully absorbed onto the surface of fiber. The photochromic characteristic of LbL-treated fiber could be triggered by UV-vis absorption spectrum and the LbL treated fibers had a good compatibility with pulp fibers. This study gives a highly effective method to impart the photochromic characteristic to paper. PMID- 27987982 TI - Thermoplastic starch modified with microfibrillated cellulose and natural rubber latex: A broadband dielectric spectroscopy study. AB - Thermoplastic starch (TPS) biocomposites modified with cellulose microfibers and/or natural rubber were prepared via extrusion compounding. Glycerol and water served as plasticizers for starch. The dielectric properties of the TPS composites were examined via broadband dielectric spectroscopy in the temperature and frequency ranges of 30 degrees C-65 degrees C and 0.1Hz-10MHz, respectively. Each specimen was tested twice in order to study the effect of absorbed water. The hydrophobic/hydrophilic character of the modifiers governed the dielectric performance of the corresponding TPS biocomposites. Conducted analysis revealed two relaxation processes attributed to matrix-water-reinforcement interfacial polarization and glass to rubber transition of the TPS. Evaporation of water significantly affected the first process and only slightly the second one. Energy density, prior and after water evaporation, was also determined at constant field. By employing dielectric reinforcing function the contributions of water assisted and constituents' originated interfacial phenomena could be separated. PMID- 27987984 TI - Biological and structural analyses of bovine heparin fractions of intermediate and high molecular weight. AB - Low molecular weight heparin, which is generally obtained by chemical and enzymatic depolymerization of unfractionated heparin, has high bioavailability and can be subcutaneously injected. The aim of the present investigation was to fractionate bovine heparin using a physical method (ultrafiltration through a 10kDa cut-off membrane), avoiding structural modifications that can be caused by chemical or enzymatic treatments. Two fractions with different molecular weights were obtained: the first had an intermediate molecular weight (B-IMWH; Mn=9587Da) and the other had a high molecular weight (B-HMWH; 22,396Da). B-IMWH and B-HMWH have anticoagulant activity of 103 and 154IU/mg respectively, which could be inhibited by protamine. Both fractions inhibited alpha-thrombin and factor Xa in vitro and showed antithrombotic effect in vivo. Moreover, ex vivo aPTT assay demonstrated that B-IMWH is absorbed by subcutaneous route. The results showed that ultrafiltration can be used to obtain two bovine heparin fractions, which differ on their molecular weights, structural components, anticoagulant potency, and administration routes. PMID- 27987983 TI - Extraction, characterization and biological activity of a (1,3)(1,6)-beta-d glucan from the pathogenic oomycete Pythium insidiosum. AB - Pythiosis is a life-threatening infectious disease caused by the pathogenic oomycete Pythium insidiosum. This study is the first to evaluate the P. insidiosum glucan content and its biological activities. The enzymatic quantification of the glucans in P. insidiosum mycelia showed that the beta glucan content was 18.99%+/-3.59. The cell wall polysaccharide extract consisted of ~81.7% carbohydrates (exclusively glucose) and ~18.3% residual amino acids and peptides. The results from monosaccharide composition, methylation and 1D/2D NMR spectroscopy analyses indicated the presence of a highly branched (1,3)(1,6)-beta d-glucan, with (1,6)-beta-d-glucopyranosil side-branching unit on average every 1 2 repeat units. In vitro, the beta-d-glucan extract could significantly promote spleen lymphocyte proliferation in human, equine and mouse cell cultures. BALB/c mice that were subcutaneously pre-immunized with three doses of 0.5, 2.5 and 5.0mg of beta-glucan/mouse, showed a significant increase in IL-2, IL-6, IL-10, TNF-alpha and IL-17A production compared to non-immunized mice. These results suggested that beta-d-glucan extract induces significant and specific Th17 cellular immune response and provided the theoretical basis for further experiments. PMID- 27987985 TI - NMR characterization of methylcellulose: Chemical shift assignment and mole fraction of monomers in the polymer chains. AB - Methylcellulose samples with different degrees of substitution were prepared by a heterogeneous reaction of cellulose. Two-dimensional NMR spectroscopy provided complete assignment of the 1H and 13C chemical shifts of the un-, 2-mono-, 3-mono , 6-mono-, 2,3-di-, 2,6-di-, 3,6-di-, and 2,3,6-tri-substituted anhydroglucose units (AGUs). Comparative analysis of the chemical shift data revealed the relationship between the methyl substituents at the 2-, 3-, and 6-positions and the 1H and 13C chemical shifts of the AGUs; additivity could be applied to the 1H and 13C chemical shifts of methylcellulose. Quantitative 13C NMR spectra of the samples determined the composition of the eight AGUs and the substituent distribution at the 2-, 3-, and 6-positions of cellulose. This provided estimations of the hydroxyl group reactivity toward methylation and the interactions between the substituent groups within the same AGU. PMID- 27987986 TI - Nano-MgO reinforced chitosan nanocomposites for high performance packaging applications with improved mechanical, thermal and barrier properties. AB - Chitosan nanocomposite thin films were fabricated by incorporating MgO nanoparticles to significantly improve its physical properties for potential packaging applications. A novel in-situ method was developed to synthesise spherical shaped MgO nanoparticles by heat-treating magnesium carbonate/poly(methyl methacrylate) (PMMA) composite precursor. Optimum mechanical properties of chitosan composites were yielded at 5 (w/w%) of MgO concentration, where tensile stress and elastic modulus significantly improved by 86% and 38%, respectively, compared to those of pure chitosan films. These improvements are due to the interaction of hydroxyl and amine groups of chitosan with MgO as confirmed by FTIR spectroscopy. Fracture surface morphology indicated the interplay between MgO dispersion and aggregation on the mechanical properties at different MgO concentrations. Furthermore, the chitosan/MgO nanocomposites displayed remarkable thermal stability, flame retardant properties (satisfied V0 rating according to the UL-94 standards), UV shielding and moisture barrier properties, which could certainly add value to the packaging material. PMID- 27987987 TI - Development of non-water soluble, ductile mung bean starch based edible film with oxygen barrier and heat sealability. AB - This research determined the effects of starch concentration (3.5-5.0%w/w), and plasticizer [glycerol (0-30%w/w) or sorbitol (0-60%w/w)] on properties of mung bean starch (MBS) films. The result showed that increasing plasticizer concentration tended to decrease tensile strength (TS), elastic modulus (EM) and oxygen permeability (OP); but increase elongation (%E), solubility, water vapor permeability (WVP) and seal strength. The extent of those changes also depended on starch concentration. Glycerol provided better plasticizer efficiency than sorbitol. A bimodal melting endotherm of retrograded structure was evident in non plasticized film. However, only a low temperature endotherm was observed in polyol-plasticized films, indicating a plasticizer-induced structural modification. The developed ductile MBS films, (TS of 7.14+/-0.95 to 46.30+/ 3.09MPa, %E of 2.46+/-0.21 to 56.95+/-4.34% and EM of 16.29+/-3.40 to 1428.45+/ 148.72MPa) with an OP of 0.2397+/-0.0365 to 1.1520+/-0.1782 ccmm/m2daykPa and seal strength up to 422.36+/-7.93N/m, demonstrated in this study indicate the potential for food packaging applications. PMID- 27987988 TI - Thermal sensitivity and protein anti-adsorption of hydroxypropyl cellulose-g- poly(2-(methacryloyloxy) ethyl phosphorylcholine). AB - Zwitterionic graft copolymers, hydroxypropyl cellulose graft poly(2 (methacryloyloxy) ethyl phosphorylcholine) (HPC-g-PMPC) with well-defined architecture were synthesized by atom transfer radical polymerization (ATRP). The self-assembly behaviors and thermal sensitivity of HPC-g-PMPC copolymers and their correlations with graft density and side chain length were investigated in details. HPC-g-PMPC copolymers can self-assemble into spherical aggregate structure above the critical aggregation concentration (CAC) at room temperature. Meanwhile, the size of the aggregates mainly depended on the graft density. The obtained aggregates were thermal sensitive and their low critical solution temperature (LCST) was efficiently regulated by varying the graft density. Above the LCST, the aggregates were transferred into aggregates with core-shell structure, in which the HPC rich core was stabilized by the PMPC rich shell. The interaction between the HPC-g-PMPC aggregates and BSA was investigated. The results indicated that the anti-adsorption of BSA on the aggregates surface depended on the length and graft density of the PMPC zwitterionic side chains. PMID- 27987990 TI - One-pot synthesis of injectable methylcellulose hydrogel containing calcium phosphate nanoparticles. AB - A thermo-sensitive hydrogel based on calcium phosphate nanoparticles was prepared using a novel one-pot method in which added precursor salts induced a salt-out effect in the methylcellulose (MC) solution. The calcium phosphate nanoparticles were synthesized in situ from precursor ions (Ca2+ and HPO42-) in the hydrogel, and residual ions (HPO42- and Cl-) in the formation of the nanoparticles decreased the gelation temperature of the MC solution. This one-pot synthesis was an effective way to streamline the previous multi-step process and to easily prepare a thermo-sensitive hydrogel containing bioactive nanoparticles. The thermo-sensitive properties of different concentrations of MC hydrogels were characterized by a rheometer and infrared (IR) spectroscopy. The gelation behavior of MC according to the addition of various salts was monitored by rheometer. With respect to a selected concentration and precursor, the structure of the MC hydrogel containing calcium phosphate nanoparticles was analyzed by scanning electron microscopy (SEM), X-ray diffraction (XRD) and IR. PMID- 27987989 TI - Effects of pectin structure and crosslinking method on the properties of crosslinked pectin nanofibers. AB - We reported crosslinking of electrospun nanofibers of three representative pectins (high-methoxylated, low-methoxylated, low-methoxylated and amidated pectin) and characterization of the crosslinked nanofibers. One mono-crosslinking strategy and two dual-crosslinking strategies were developed. Mono-crosslinking is achieved using calcium ions (Ca2+) to crosslink carboxylate ions in galacturonic acid residues. Dual-crosslinking is achieved using covalent crosslinking reagents glutaraldehyde (GLU) or adipic acid dihydrazide (ADH) to further crosslink hydroxyl groups or carboxylate ions after Ca2+ crosslinking. Mechanical tests and degradation experiments indicated pectin structure affected mechanical and degradation properties of Ca2+-crosslinked nanofibers remarkably. Subsequent GLU crosslinking improved their mechanical strength moderately but did not inhibit their degradation, while subsequent ADH crosslinking improved their mechanical strength and slowed down their degradation dramatically. Cell studies demonstrated that most crosslinked pectin nanofibers were of no obvious cytotoxicity, and both ADH crosslinking and high degree of methoxylation facilitated cell adhesion and proliferation on pectin nanofiber mats. PMID- 27987991 TI - Physico-chemical and microstructural properties of fish gelatin/agar bio-based blend films. AB - This study was conducted with the aim of improving the physico-chemical properties of fish gelatin (FG) based films. For this purpose, FG was blended with agar (AG) in different compositions to acquire biodegradable films (100:0, 80:20, 60:40, 50:50 & 0:100, FG:AG). The obtained results showed that the AG addition strongly increased the film rigidity and resistance to fracture, while reducing the film stretchability, mainly at 50FG: 50AG ratio. AG incorporation greatly reduced the water vapor permeability (WVP) and solubility of gelatin films, as this decline for the blend film with a 50:50 ratio of biopolymers has been about 41% and 66%, respectively (p<0.05). Additional advantages of AG inclusion to FG films are the reduction of the UV-transmittance. Both polymers showed good compatibility, as demonstrated by scanning electron microscopy (SEM) and atomic force microscopy (AFM) images. Therefore, the blend composition influenced the properties of FG/AG bio-based films. PMID- 27987992 TI - Cellulose nanocrystals: A layered host candidate for fabricating intercalated nanocomposites. AB - The stacking of cellulose chains along planes and weak intersheet interactions make cellulose nanocrystals (CNCs) promising as a layered host candidate for fabricating intercalated nanocomposites. As a proof-of-concept, we demonstrate the intercalation of alkyls into CNCs through the in situ intercalative chemical reaction between terminal groups of N-octadecyl isocyanates and hydroxyl groups on the (200) planes in CNCs. Results showed that CNCs could intercalate alkyls in a high degree of substitution to form dense brushes on their (200) planes. After intercalation, a significant enlargement of interlayer spacing was observed. Moreover, alkyls were fully extended in all-trans configuration and crystallized in a co-existing organization of alphaH, betaH and betaO crystalline forms. This meant that the molecular arrangement in CNCs/alkyl intercalated nanocomposites would involve a bilayer model in which alkyls were in the ordered packing and titled to (200) plane. Furthermore, CNCs/alkyl intercalated nanocomposites possessed increased thermal properties and decreased char residue. PMID- 27987993 TI - Structural elucidation and immunostimulatory activity of polysaccharide isolated by subcritical water extraction from Cordyceps militaris. AB - Water-soluble polysaccharides were obtained from Cordyceps militaris (C. militaris) (CMP) by subcritical water extraction (SWE). Two polysaccharides fractions, CMP-W1 and CMP-S1, were isolated from CMP using DEAE-52 cellulose and Sephadex G-150 column chromatography. The structural characteristics of CMP-W1 and CMP-S1 were investigated. The results showed that the molecular weight of CMP W1 and CMP-S1 are 3.66*105Da and 4.60*105Da, respectively, and both of them were heteropolysaccharides composed of d-mannose, d-glucose, d-galactose with the molar ratios of 2.84:1:1.29 and 2.05:1:1.09, respectively. FT-IR spectra analysis suggested that CMP-W1 and CMP-S1 belonged to pyranose form sugar and protein free. For immunostimulatory activity assay in vitro, CMP-W1 and CMP-S1 significantly promoted lymphatic spleen cell proliferation of mice. Therefore, the polysaccharides obtained from C. militaris by SWE can be used as potential natural immunostimulant in functional foods or medicine. PMID- 27987994 TI - Microwave-induced biomimetic approach for hydroxyapatite coatings of chitosan scaffolds. AB - Simulated body fluid (SBF) can form calcium phosphates on osteoinductive materials, so it is widely used for coating of bone scaffolds to mimic natural extracellular matrix (ECM). However, difficulties of bulk coating in 3D scaffolds and the necessity of long process times are the common problems for coating with SBF. In the present study, a microwave-assisted process was developed for rapid and internal coating of chitosan scaffolds. The scaffolds were fabricated as superporous hydrogel (SPH) by combining microwave irradiation and gas foaming methods. Then, they were immersed into 10x SBF-like solution and homogenous bone like hydroxyapatite (HA) coating was achieved by microwave treatment at 600W without the need of any nucleating agent. Cell culture studies with MC3T3-E1 preosteoblasts showed that microwave-assisted biomimetic HA coating process could be evaluated as an efficient and rapid method to obtain composite scaffolds for bone tissue engineering. PMID- 27987995 TI - Chitosan hydrogel formation using laccase activated phenolics as cross-linkers. AB - Chitosan hydrogels are gaining increasing interest for biomedical applications due to attractive properties such as biocompatibility. In order to replace toxic chemical cross-linkers for hydrogel formation, we investigated the cross-linking potential of laccase oxidized phenolics. HPLC-TOF-MS and ATR-FTIR demonstrated that phenolics were bond to glucosamine as chitosan model substrate. Phenolics concentrations required for hydrogel formation varied from 500MUM for catechol to 5000MUM for sinapic acid. The hydrogels showed different swelling and release properties assessed using methylene blue release as a model. Laccase oxidized caffeic acid and pyrogallol-chitosan hydrogels showed excellent behavior in up taking water with a swelling of 208.7% for caffeic acid. Biocompatibility results did not show any significant inhibition of growth of HEK293 cell line when phenolics like catechol or eugenol were used. Therefore, this study demonstrates that laccase oxidized phenolics are potential cross-linking agents of chitosan as a novel green approach to synthesizing chitosan hydrogels. PMID- 27987996 TI - Synthesis of modified gum tragacanth/graphene oxide composite hydrogel for heavy metal ions removal and preparation of silver nanocomposite for antibacterial activity. AB - New composite hydrogels were synthesized based on gum tragacanth (GT) carbohydrate and graphene oxide (GO). GT was sulfonic acid-functionalized and cross-linked by using 2-acrylamido-2-methylpropanesulfonic acid (AMPS) and N,N' methylenebisacrylamide (MBA) monomers and ceric ammonium nitrate (CAN) as an initiator. The prepared hydrogels were characterized by Fourier transform infrared spectrum (FT-IR), field emission scanning electron microscope (FE-SEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). Adsorption process for removal of heavy metal ions has followed the pseudo-first-order kinetic model and fitted well with the Langmuir model. The maximum adsorption capacity (Qm) was 142.50, 112.50 and 132.12mgg-1 for Pb(II), Cd(II), and Ag(I), respectively. The removal percentage decreased slightly after several adsorption/desorption cycles. The adsorbed Ag(I) ions in hydrogel were transformed to Ag0 nanoparticles (with a narrow distribution and mean size of 13.0nm) by using Achillea millefolium flower extract. The antibacterial performance of the Ag0 nanocomposite hydrogel was also investigated. PMID- 27987998 TI - Preparation and characterization of intelligent starch/PVA films for simultaneous colorimetric indication and antimicrobial activity for food packaging applications. AB - We have developed an intelligent starch/poly-vinyl alcohol (PVA) film that is capable of monitoring pH changes and inhibiting undesired microbial growth in foods. Starch and PVA polymers in the film were doubly cross-linked by sodium trimetaphosphate and boric acid to improve their water-resistance and mechanical strength. Anthocyanins (ANT) and limonene (LIM) were used to achieve simultaneous colorimetric indication and antimicrobial activity. Firstly, the characterization of surface morphology using SEM confirmed that the starch-PVA-ANT-LIM film possessed a smooth surface. Secondly, the results of the mechanical strength test showed that starch-PVA-ANT-LIM possesses the highest mechanical strength. Additionally, there was a distinguishable change of colors as the film was immersed in solutions of pH ranging from 1.0 to 14.0. Moreover, the film showed excellent antimicrobial activity for three typical undesired microorganisms in foods, Bacillus subtilis, Aspergillus niger, and Staphylococcus aureus. Finally, the film exhibited good color indication and antimicrobial activity on pasteurized milk. The results suggest that the intelligent film reported here shows good capability for both alerting and inhibiting food spoilage. PMID- 27987999 TI - Dispersion of chitosan in liquid crystalline lamellar phase: Production of biofriendly hydrogel of nano cubic topology. AB - Bicontinuous cubic phases were produced with introduction of chitosan in phospholipid/water hydrogel, providing composites of defined molecular organization. The ratio of lipid/water was constant and swelling of lipids bilayer is delimited by incorporation of polymer molecules into the structure. By means of synchrotron small angle X-ray scattering we identified topologies of coexisting cubic phases. The expected liquid crystalline Lalpha lamellar phase was suppressed by 0.2wt% chitosan leading to formation of diamond Pn3m and gyroid Ia3d cubic topology, with close lattice distances. An increment to 0.4wt% chitosan caused large increase in Pn3m lattice distance. However a higher 0.6wt% evolved this phase to a newly acquired primitive Im3m topology. The structuring process of the three-dimensional complex network is principally governed by demands of chitosan physical requirements over lipids bilayers interfacial curvature. The composite hydrogel of specific topologies presents reduced time release of gallic acid and may find application as new material for time sustained delivery of bioactive compounds. PMID- 27987997 TI - Enhanced anti-obesity effects of complex of resistant starch and chitosan in high fat diet fed rats. AB - This study investigated the interventional effect of resistant starch (RS), chitosan (CS) and chitosan-starch complexes (CL) on blood glucose, lipid composition and oxidative stress in high-fat diet fed rats. Compared with RS or CS alone, CL administration performed more efficiently in controlling body weight and adipose tissue mass, together with an increase in HDL-C concentration, oxidative stress suppression by increasing body antioxidant capacity. Gene expression analysis demonstrated the fatty acid and triglyceride synthesis and metabolism gene SREBP-1, adipocyte differentiation gene PPARgamma, cholesterol synthesis gene HMGCR, gluconeogenesis gene GAPDH, were significantly down regulated, whilst lipid oxidation gene Acox1 and liver functional genes Gstm2, Gclc were up-regulated following CL consumption compared with single RS or CS treatment. Hypolipidemic effects were observed by CL administration and oxidative stress suppression by CL appeared to be associated with elevated antioxidant enzyme activity, increased lipid oxidation, as well as improved fatty acid and cholesterol homeostasis. PMID- 27988000 TI - Co-loading and intestine-specific delivery of multiple antioxidants in pH responsive microspheres based on TEMPO-oxidized polysaccharides. AB - In this study, pH-responsive microspheres loaded with multiple antioxidants were developed for intestine-specific delivery and exhibited synergistic activity. They consist of chitosan (CS)-coated microspheres made of TEMPO-oxidized Konjac glucomannan (OKGM) polymers, of which the carboxyl (COO-) groups are cross-linked via ferric ions (Fe3+), allowing the hydrophobic (beta-carotene) and hydrophilic (anthocyanins) antioxidants to be simultaneously incorporated. CLSM images showed successful co-encapsulation of beta-carotene and anthocyanins. The in vitro release kinetics of co-loaded CS-OKGM microspheres in simulated GI fluids indicated that the microspheres retain the dual antioxidants in an acidic gastric environment and release them at intestinal pH. Free radical scavenging experiments demonstrated that multiple antioxidants loaded into OKGM system had synergistic activity with enhanced stability against heat. The multi-functional CS-OKGM microspheres showed great potential for multiple antioxidants and intestine-specific delivery with enhanced stability. PMID- 27988001 TI - Novel cellulose-based amorphous solid dispersions enhance quercetin solution concentrations in vitro. AB - Quercetin (Q) is a bioactive flavonol with potential to benefit human health. However, Q bioavailability is relatively low, due to its poor aqueous solubility and extensive phase-II metabolism. Strategies to increase solution concentrations in the small intestinal lumen have the potential to substantially increase Q bioavailability, and by extension, efficacy. We aimed to achieve this by incorporating Q into amorphous solid dispersions (ASDs) with cellulose derivatives. Q was dispersed in matrices of cellulose esters including 6 carboxycellulose acetate butyrate (CCAB), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and cellulose acetate suberate (CASub) to afford ASDs that provided stability against crystallization, and pH-triggered release. Blends of CASub and CCAB with the hydrophilic polyvinylpyrrolidone (PVP) further enhanced dissolution. The ASD 10% Q:20% PVP:70% CASub most significantly enhanced Q solution concentration under intestinal pH conditions, increasing area under the concentration/time curve (AUC) 18-fold compared to Q alone. This novel ASD method promises to enhance Q bioavailability in vivo. PMID- 27988002 TI - O,N-(2-sulfoethyl)chitosan: Synthesis and properties of solutions and films. AB - A series of water-soluble sulfoethylated chitosans (SEC) with degrees of substitution (DS) up to 130% were obtained using a heterogeneous reaction of chitosan with sodium 2-chloroethanesulfonate in 85% isopropanol in the presence of NaOH. NMR and FTIR spectroscopy confirmed that sulfoethylation of chitosan preferentially happens at hydroxyl groups and to some extent at amino groups, giving mixed substituted O,N-SEC. Chitosan shows positive birefringence, whereas SEC shows negative values, indicating self-organization in dilute solution. Dynamic light scattering studies revealed the presence of aggregates in dilute solutions of chitosan and SEC. The sizes of the SEC aggregates are sensitive to the DS and the nature of the solvent. X-ray diffraction of SEC films revealed that the introduction of sulfoethyl groups into chitosan leads to amorphization, which is more pronounced at higher DS. During the storage of SEC films, the samples loose solubility due to the formation of ionic crosslinks upon dehydration. PMID- 27988003 TI - N,N,N-Trimethyl chitosan: An advanced polymer with myriad of opportunities in nanomedicine. AB - N,N,N-trimethyl chitosan (TMC), a quaternized hydrophilic derivative of chitosan (CHT), outperformed the well-known solubility issues raised by CHT. The excellent properties offered by TMC provide it a significant edge for nanoparticle (NP) formation over other nanocarrier materials. Recently, TMC NPs have been applied to various fields like pharmaceutical, biomedical, biomaterials, and biotechnological field. The aim of this review is, therefore, to bring the TMC into the limelight so as to appraise it as an attractive functional polymer for nanomedicine applications which is facing oversight, at present, by regulatory agencies and manufacturers. The versatility of surface-tailoring, the capability of further chemical modifications, and the feasibility of ligand-conjugations in TMC polymer will further assist the scientists for reaching new dimensions in the nano-assembly of novel structures based on TMC. PMID- 27988004 TI - Pectin-silica gels as matrices for controlled drug release in gastrointestinal tract. AB - The synthesis of pectin-silica gels for controlled drug release in gastrointestinal tract (GIT) using low methoxyl (LM) and high methoxy (HM) pectins and tetraethoxysilane (TEOS) as precursor is described. The FTIR spectra of the pectin-silica gels show intense absorption bands at 1246cm-1 and 802cm-1 corresponding to the vibrations COSi bonds, which absent in the FTIR spectra of the native pectins that indicate the formation covalent bond between silica and pectin macromolecules in the pectin-silica gels. Pectin-TEOS, pectin-Ca-TEOS and pectin-TEOS-Ca beads with mesalazine are synthesized by different combinations of sol-gel method using TEOS and ionotropic gelation method using calcium chloride. The best resistant of pectin-TEOS and pectin-Ca-TEOS beads during incubation in simulated gastric fluid for 2h and subsequently in simulated intestinal fluids for 18h is indicated. Pectin-TEOS beads are characterized by higher encapsulation efficiency (to 28%) than pectin-Ca-TEOS beads (to 16%). The drug release of pectin-silica beads in simulated GIT occurs gradually up to 80% and is directly dependent on the hardness of the beads. The surface morphology of beads is shown. The use of pectin-silica beads is promising with regard to the development of controlled release of drug formulations. PMID- 27988005 TI - Corrigendum to "Plant-crafted starches for bioplastics production" [Carbohydr. Polym. 152 (2016) 398-408]. PMID- 27988006 TI - Corrigendum to "Polymeric micelles of amphiphilic graft copolymer of a-tocopherol succinate-g-carboxymethyl chitosan for tamoxifen delivery: Synthesis, characterization and in vivo pharmacokinetic study" [Carbohydr. Polym. 151 (2016) 1162-1174]. PMID- 27988007 TI - Erratum to "Characterization and antimicrobial properties of cotton fabric loaded with green synthesized silver nanoparticles" [Carbohydr. Polym. 151(October) (2016) 841-850]. PMID- 27988008 TI - Microwave as skin permeation enhancer for transdermal drug delivery of chitosan-5 fluorouracil nanoparticles. AB - This study investigated transdermal drug delivery mechanisms of chitosan nanoparticles with the synergistic action of microwave in skin modification. Chitosan nanoparticles, with free or conjugated 5-fluorouracil, were prepared by nanospray-drying technique. Their transdermal drug delivery profiles across untreated and microwave-treated skins (2450MHz 5min, 5+5min; 3985MHz 5min) were examined. Both constituent materials of nanoparticles and drug encapsulation were required to succeed transdermal drug delivery. The drug transport was mediated via nanoparticles carrying drug across the skin and/or diffusion of earlier released drug molecules from skin surfaces. The drug/nanoparticles transport was facilitated through constituent nanoparticles and microwave fluidizing protein/lipid domains of epidermis and dermis (OH, NH, CH, CN) and dermal trans to-gauche lipid conformational changes. The microwave induced marked changes to the skin ceramide content homogeneity. The chitosan nanoparticles largely affected the palmitic acid and keratin domains. Combined microwave and nanotechnologies synergize transdermal drug delivery. PMID- 27988009 TI - NMR study of hydroxy and amide protons in hyaluronan polymers. AB - Hyaluronan (HA) is an important and well characterized glycosaminoglycan with high viscosity and water-retaining capacity. Nonetheless, it is not fully understood whether conformational properties of the easily characterized HA oligomers can be transferred to HA polymers. To investigate possible differences in hydration, hydrogen bonding and flexibility between HA polymers and oligomers, hydroxy and amide protons of HA polymers were studied by solution-state and high resolution magic angle spinning (HR-MAS) NMR spectroscopy. Measurements of chemical shifts, temperature coefficients and NOEs in HA polymers revealed that the NMR data are very similar compared to the interior of a HA octasaccharide, supporting transient hydrogen bond interactions across the beta(1->3) and beta(1 >4) glycosidic linkages. However, differences in NOEs suggested a cis-like orientation between NH and H2 in the HA polymer. The lack of concentration dependence of the hydroxy proton chemical shifts suggests that there are no direct inter-chain interactions involving hydroxy protons at the concentrations investigated. PMID- 27988010 TI - PAMAM-pullulan conjugates as targeted gene carriers for liver cell. AB - Targeted nano-carriers are highly needed to promote nucleic acid delivery into the specific cell for therapeutic approaches. Pullulan as a linear carbohydrate has an intrinsic liver targeting property interacting with asialoglycoprotein receptor (ASGPR) found on liver cells. In the present study, we developed polyamidoamine (PAMAM)-pullulan conjugates and investigated their targeting activity in delivering gene into liver cells. The particle size, zeta potential, buffering capacity and ethidium bromide exclusion assays of the conjugates were evaluated. The cytotoxicity and transfection efficiency of new derivatives were assessed following in vitro transfection of HepG2 (receptor positive) and N2A (receptor negative) cell lines. Size of conjugated polymers ranged between 118 and 184 nanometers and their cytotoxicity were similar to PAMAM. Among six produced nanocarriers, G4PU4 and G5PU4 enhanced transfection efficiency in HepG2 cells compared to unmodified PAMAM. Therefore, the PAMAM-pullulan derivatives seem to improve delivery of nucleic acids into the liver cells expressing asialoglycoprotein receptor with minimal transfection in non-targeted cells. PMID- 27988011 TI - Improvement of N-phthaloylchitosan based gel polymer electrolyte in dye sensitized solar cells using a binary salt system. AB - A binary salt system utilizing lithium iodide (LiI) as the auxiliary component has been introduced to the N-phthaloylchitosan (PhCh) based gel polymer electrolyte consisting of ethylene carbonate (EC), dimethylformamide (DMF), tetrapropylammonium iodide (TPAI), and iodine (I2) in order to improve the performance of dye-sensitized solar cell (DSSC) with efficiency of 6.36%, photocurrent density, JSC of 17.29mAcm-2, open circuit voltage, VOC of 0.59V and fill factor, FF of 0.62. This efficiency value is an improvement from the 5.00% performance obtained by the DSSC consisting of only TPAI single salt system. The presence of the LiI in addition to the TPAI improves the charge injection rates and increases the iodide contribution to the total conductivity and both factors contribute to the increase in efficiency of the DSSC. The interaction behavior between polymer-plasticizer-salt was thoroughly investigated using EIS, FTIR spectroscopy and XRD. PMID- 27988012 TI - Inclusion complex of ITH12674 with 2-hydroxypropyl-beta-cyclodextrin: Preparation, physical characterization and pharmacological effect. AB - ITH12674 is a multitarget drug, designed to exert a dual "drug-prodrug" mechanism of action, able to induce the phase II antioxidant and anti-inflammatory response for the treatment of brain ischemia. However, its physicochemical properties limit its potential preclinical development due to its low water solubility and instability towards heat and pH variations. In order to improve its properties, we prepared the inclusion complex of ITH12674 with 2-hydroxypropyl-beta cyclodextrin (HP-beta-CD) by the freeze-drying method. The formation of the inclusion complex was confirmed by FT-IR spectroscopy, PXRD, DSC, 1H NMR and SEM techniques. Experimental results showed that the inclusion complex enhanced its water solubility and stability against heat, acidic and basic conditions. Furthermore, the inclusion complex, prepared in water solution, exerted the same potency to induce the phase II antioxidant response as the pure ITH12674. Thus the formation of the inclusion complex with HP-beta-CD is a very effective method to stabilize and solubilize the active compound for its future preclinical development. PMID- 27988013 TI - Reuse of waste cotton cloth for the extraction of cellulose nanocrystals. AB - Cellulose nanocrystals (CNCs) were prepared from waste cotton cloth and degreasing cotton was used as a comparison. The cellulose was first extracted by alkali and bleaching treatments, and then the CNCs were isolated by the mix acid solution hydrolysis of cellulose under the controlled conditions. The CNCs were analyzed by Attenuated total reflectance Fourier transform infrared spectroscopy, Transmission electron microscopy, X-ray diffraction analysis, thermogravimetric and differential scanning calorimetry analysis. The results confirmed that the resultant samples were the cellulose species, and the CNCs obtained from waste cotton cloth exhibited a high crystallinity index of 55.76+/-7.82%, which had higher thermostability than that from the degreasing cotton. The morphology analysis results showed that the ranges of length and diameter of CNC extracted from waste cotton cloth were from 28 to 470nm and 3 to 35nm. The preparation of CNCs with a high aspect ratio and good thermostability in this work paves the way for an alternative reuse of waste cotton cloth. PMID- 27988014 TI - Hydroxypropylcellulose as matrix carrier for novel cage-like microparticles prepared by spray-freeze-drying technology. AB - The objective of this study is to design novel dissolution-enhanced microparticles loaded poorly soluble drug nanocrystals used a low viscosity of hydroxypropylcellulose (HPC) as matrix carrier. An interesting approach combined homogenization and the spray-freeze-drying technique was developed. The results demonstrated that the ratio of HPC to drug played an important role in size reduction efficiency of drug during homogenization. And the formation of cage like structure of the composite particles depended on ratio of HPC to drug. The spray-freeze-dried composite particles with HPC ratio of 1:2, 1:1 and 2:1 possessed excellent redispersibility, which attributed to its porous matrix and large surface area (3000m2/g). The dissolution of spray-freeze-dried composite particles with higher ratios of HPC (1:2 and 1:1) was significantly enhanced, which attributed to the particle size reduction of drug. The HPC could immobilize drug nanocrystals in its cage-like structure and prevent it from the subsequent agglomeration during storage. In conclusion, the prepared cage-like microparticles is a promising basis for further formulation development. PMID- 27988015 TI - Isolation and characterization of cellulose nanofibers from cassava root bagasse and peelings. AB - This work aimed to obtain and characterize nanofibers from cassava bagasse and peelings, which are waste originating from cassava starch extraction. To isolate the nanofibers, a combination of pre-treatments (alkaline treatment, Q-chelating treatment, bleaching), acid hydrolysis, and a final ultrasonic disintegration step were used. Acidic hydrolysis was conducted at a constant temperature of 60 degrees C; the acid concentration (30, 40, and 50%) and the treatment time (30, 60, and 90min) were varied. The nanofibers were characterized for their morphology, surface charge, crystallinity index (XRD), and functional groups (FTIR). The diameters of the nanofibers ranged from 2.3nm to 5.4nm. The zeta potential values were lower than -47.7mV. As expected, all the products derived from acid hydrolysis displayed high crystallinity index. Finally, FTIR analysis confirmed that the isolation processes effectively removed amorphous materials such as lignin and hemicellulose from the nanofibers. PMID- 27988016 TI - Effect of replacement of corn starch by whey protein isolate in biodegradable film blends obtained by extrusion. AB - The aim of this study was to evaluate the effect of replacing corn starch by whey protein isolated (WPI) in biodegradable polymer blends developed by extrusion. X ray diffraction showed the presence of a Vh-type crystalline arrangement. The films were homogeneous, indicating strong interfacial adhesion between the protein and the thermoplastic starch matrix (TPS) as observed in scanning electron microscopy. The addition of WPI on TPS matrix promoted an increase in the thermal stability of the materials. It was observed 58.5% decrease in the water vapor permeability. The effect of corn starch substitution by WPI on mechanical properties resulted in a more resistant and less flexible film when compared the TPS film. The addition of WPI caused greenish yellow color and less transparent films. The substitution of corn starch by WPI made it possible to obtain polymer blends with improved properties and represents an innovation for application as a packaging material. PMID- 27988017 TI - Design of pectin-sodium alginate based films for potential healthcare application: Study of chemico-physical interactions between the components of films and assessment of their antimicrobial activity. AB - In this study, pectin based films including different amounts of sodium alginate were prepared by casting method. All the films, with and without polyglycerol as plasticizer, were crosslinked with zinc ions in order to extend their potential functionality. The development of junction points, occurring during the crosslinking process with zinc ions, induced the increasing of free volume with following changing in chemico-physical properties of films. The inclusion of alginate in pectin based formulations improved the strength of zinc ions crosslinking network, whereas the addition of polyglycerol significantly improved mechanical performance. Finally, zinc-crosslinked films evidenced antimicrobial activity against the most common exploited pathogens: Staphylococcus Aureus, Escherichia Coli and Candida Albicans. These results suggest that zinc crosslinked based films can be exploitable as novel bio-active biomaterials for protection and disinfection of medical devices. PMID- 27988018 TI - Utilization of chitosan-caged liposomes to push the boundaries of therapeutic delivery. AB - Liposomes are self-assembled bilayer vesicles which have attracted a great deal of interest as potential carriers for a wide range of therapeutic agents. They have significantly decreased toxicity of drugs while improving or at least maintaining their efficacy. However, their further development has been hampered by their considerable instabilities and, in some cases, providing comparable efficacy to conventional products. Decoration of liposomal nanocarriers with chitosan (CS) and its derivatives has recently gained importance to overcome this obstacle. CS, a cationic polysaccharide, has prompted the continuous impetus for the advent of efficient drug delivery systems owing to its unique characteristics. CS decoration of liposomes confers high mucoadhesion capacity, enhanced carrier permeability, and sterically stabilized properties. The number of examples having been explained within the present review through different administration routes and for various applications clearly heralds the promise of CS caged liposomes for the pharmaceutical market. PMID- 27988019 TI - Nano-carbohydrates: Synthesis and application in genetics, biotechnology, and medicine. AB - Combining nanoparticles with carbohydrate has triggered an exponential growth of research activities for the design of novel functional bionanomaterials, nano carbohydrates. Recent advances in versatile synthesis of glycosylated nanoparticles have paved the way towards diverse biomedical applications. The accessibility of a wide variety of these structured nanosystems, in terms of shape, size, and organization around stable nanoparticles, has readily contributed to their development and application in nanomedicine. Glycosylated gold nanoparticles, glycosylated quantum dots, fullerenes, single-wall nanotubes, and self-assembled glyconanoparticles using amphiphilic glycopolymers or glycodendrimers have received considerable attention for their application in powerful imaging, therapeutic, and biodiagnostic devices. Recently, nano carbohydrates were used for different types of microarrays to detect proteins and nucleic acids. PMID- 27988020 TI - United States Adolescents' Television, Computer, Videogame, Smartphone, and Tablet Use: Associations with Sugary Drinks, Sleep, Physical Activity, and Obesity. AB - OBJECTIVE: To quantify the relationships between youth use of television (TV) and other screen devices, including smartphones and tablets, and obesity risk factors. STUDY DESIGN: TV and other screen device use, including smartphones, tablets, computers, and/or videogames, was self-reported by a nationally representative, cross-sectional sample of 24 800 US high school students (2013 2015 Youth Risk Behavior Surveys). Students also reported on health behaviors including sugar-sweetened beverage (SSB) intake, physical activity, sleep, and weight and height. Sex-stratified logistic regression models, adjusting for the sampling design, estimated associations between TV and other screen device use and SSB intake, physical activity, sleep, and obesity. RESULTS: Approximately 20% of participants used other screen devices for >=5 hours daily. Watching TV >=5 hours daily was associated with daily SSB consumption (aOR = 2.72, 95% CI: 2.23, 3.32) and obesity (aOR = 1.78, 95% CI: 1.40, 2.27). Using other screen devices >=5 hours daily was associated with daily SSB consumption (aOR = 1.98, 95% CI: 1.69, 2.32), inadequate physical activity (aOR = 1.94, 95% CI: 1.69, 2.25), and inadequate sleep (aOR = 1.79, 95% CI: 1.54, 2.08). CONCLUSIONS: Using smartphones, tablets, computers, and videogames is associated with several obesity risk factors. Although further study is needed, families should be encouraged to limit both TV viewing and newer screen devices. PMID- 27988021 TI - Altered Cerebellar Development in Preterm Newborns: Chicken or Egg? PMID- 27988022 TI - Partial hypopituitarism in a female patient with a 45,X/46,XY mosaicism. PMID- 27988023 TI - Patient registries and clinical research. PMID- 27988024 TI - Spatial distribution of dinoflagellates from the tropical coastal waters of the South Andaman, India: Implications for coastal pollution monitoring. AB - Dinoflagellate community structure from two semi-enclosed areas along the South Andaman region, India, was investigated to assess the anthropogenic impact on coastal water quality. At the densely inhabited Port Blair Bay, the dominance of mixotrophs in water and Protoperidinoids in sediments was attributed to anthropogenic nutrient enrichment and prey availability. A significant decrease in dinoflagellate abundance from inner to outer bay emphasize the variation in nutrient availability. The dominance of autotrophs and Gonyaulacoid cysts at the North Bay highlight low nutrient conditions with less anthropogenic pressure. The occurrence of oceanic Ornithocercus steinii and Diplopsalis sp. could evince the oceanic water intrusion into the North Bay. Nine potentially harmful and red-tide forming species including Alexandrium tamarense complex, A. minutum were identified in this study. Although there are no harmful algal bloom (HABs) incidences in this region so far, increasing coastal pollution could support their candidature towards the future HABs initiation and development. PMID- 27988025 TI - Inventory and transport of plastic debris in the Laurentian Great Lakes. AB - Plastic pollution in the world's oceans has received much attention, but there has been increasing concern about the high concentrations of plastic debris in the Laurentian Great Lakes. Using census data and methodologies used to study ocean debris we derive a first estimate of 9887 metric tonnes per year of plastic debris entering the Great Lakes. These estimates are translated into population dependent particle inputs which are advected using currents from a hydrodynamic model to map the spatial distribution of plastic debris in the Great Lakes. Model results compare favorably with previously published sampling data. The samples are used to calibrate the model to derive surface microplastic mass estimates of 0.0211 metric tonnes in Lake Superior, 1.44 metric tonnes in Huron, and 4.41 metric tonnes in Erie. These results have many applications, including informing cleanup efforts, helping target pollution prevention, and understanding the inter state or international flows of plastic pollution. PMID- 27988027 TI - Cardiothoracic surgery education: The times they are a changin'. PMID- 27988026 TI - [Assessment of amylase and lipase levels following puncture biopsy and fine needle aspiration guided by endoscopic ultrasound in pancreatic lesions]. AB - BACKGROUND: Puncture biopsy and fine needle aspiration guided by endoscopic ultrasound has been used as an effective technique and is quickly becoming the procedure of choice for diagnosis and staging in patients suspected of having pancreatic cancer. This procedure has replaced retrograde cholangiopancreatography and brush cytology due to its higher sensitivity for diagnosis, and lower risk of complications. OBJECTIVE: To assess the levels of pancreatic enzymes amylase and lipase, after the puncture biopsy and fine needle aspiration guided by endoscopic ultrasound in pancreatic lesions and the frequency of post-puncture acute pancreatitis. MATERIAL AND METHODS: A longitudinal and descriptive study of consecutive cases was performed on outpatients submitted to puncture biopsy and fine needle aspiration guided by endoscopic ultrasound in pancreatic lesions. Levels of pancreatic enzymes such as amylase and lipase were measured before and after the pancreatic puncture. Finally we documented post-puncture pancreatitis cases. RESULTS: A total of 100 patients who had been diagnosed with solid and cystic lesions were included in the study. Significant elevation was found at twice the reference value for lipase in 5 cases (5%) and for amylase in 2 cases (2%), none had clinical symptoms of acute pancreatitis. Eight (8%) of patients presented with mild nonspecific pain with no enzyme elevation compatible with pancreatitis. CONCLUSION: Pancreatic biopsy needle aspiration guided by endoscopic ultrasound was associated with a low rate of elevated pancreatic enzymes and there were no cases of post-puncture pancreatitis. PMID- 27988029 TI - Discussion. PMID- 27988028 TI - Outcomes of early surgery for infective endocarditis with moderate cerebral complications. AB - OBJECTIVES: We sought to clarify the effect of stroke severity on clinical outcomes in patients with infective endocarditis (IE) with cerebral complications and evaluate the impact of early surgery in the active phase on long-term prognosis in patients with nonsevere neurologic deficits. METHODS: Clinical data were reviewed retrospectively in 170 consecutive patients with active left-sided IE with cerebral complications from 1990 to 2014. The mean age was 60 +/- 17 years, and 93 (55%) were men. The National Institutes of Health Stroke Scale (NIHSS) was used to evaluate the severity of stroke. Major adverse cardiac events were defined as a composite of IE-related death, repeat surgery, and recurrence of IE. RESULTS: Baseline NIHSS score was associated strongly with clinical outcome. When patients were divided into 2 groups according to NIHSS, 33 patients had severe stroke (NIHSS >=11) and 137 had nonsevere stroke (NIHSS <=10); freedom from IE-related death and major adverse cardiac events was significantly lower in patients with severe stroke than in those with nonsevere stroke. Of 137 patients with nonsevere stroke, 65 underwent early surgery within 2 weeks of onset, and conventional treatment was applied in 72. Freedom from IE-related death was significantly greater in patients undergoing early surgery than in those on conventional treatment (P = .007). Moreover, adjusted survival analysis using the inverse probability treatment weighting method showed a significant beneficial effect of early surgery in reducing IE-related death (P = .012) in patients with nonsevere stroke. CONCLUSIONS: Early surgery might be beneficial in patients with nonsevere stroke. PMID- 27988030 TI - Bridge to durable left ventricular assist device for refractory cardiogenic shock. AB - OBJECTIVE: The role of short-term mechanical circulatory support has increased in patients with refractory cardiogenic shock. However, limited data exist on the outcomes of a bridge to a durable left ventricular assist device strategy using short-term mechanical circulatory support. METHODS: We retrospectively reviewed 382 patients who underwent continuous-flow left ventricular assist device insertion between 2004 and 2014. Of these, 45 (12%) were bridged with short-term mechanical circulatory support devices for refractory cardiogenic shock. We analyzed early and midterm outcomes in this bridged cohort. Multivariate Cox proportional hazards modeling was performed to evaluate the predictor of overall death in the entire cohort. RESULTS: The mean age of the bridged cohort was 53 +/ 10 years, and 87% were male. The types of initial support included percutaneous devices in 24 patients (53%) and external continuous-flow ventricular assist device in 21 patients (47%). The median duration of short-term mechanical circulatory support was 14.0 (interquartile range, 7.5-29.5) days. The short-term mechanical circulatory support significantly improved end-organ function and hemodynamics. After conversion to durable left ventricular assist device insertion, in-hospital mortality was 18%. The incidence of right ventricular assist device use was high at 27%. The overall survival was 70% and 62% at 1 and 2 years, respectively. Cox multivariate hazard analysis in the entire cohort demonstrated that the use of a postoperative right ventricular assist device was a significant predictor of overall death (hazard ratio, 4.04; P < .001; 95% confidence interval, 1.97-7.94), but the use of a short-term mechanical circulatory support was not (P = .937). CONCLUSIONS: Short-term mechanical circulatory support can optimize patients in refractory cardiogenic shock and serve as a bridge to implantation of a durable left ventricular assist device. However, the early mortality rate after durable left ventricular assist device implantation is high because of unrecognized right ventricular failure. PMID- 27988031 TI - Response to multimodal anesthesia with the addition of methadone is superior to epidural analgesia. PMID- 27988032 TI - Neuroacanthocytosis: A case with unusual clinical features & novel response to treatment. PMID- 27988034 TI - BSNR training guidance for mechanical thrombectomy. PMID- 27988033 TI - Magnetic resonance imaging and histology correlation in Cushing's disease. AB - INTRODUCTION: We continuously look for new techniques to improve the radicality of resection and to eliminate the negative effects of surgery. One of the methods that has been implemented in the perioperative management of Cushing's disease was the combination of three magnetic resonance imaging (MRI) sequences: SE, SPGR and fSPGR. MATERIAL AND METHODS: We enrolled 41 patients (11 males, 30 females) diagnosed with Cushing's disease. A 3D tumour model with a navigation console was developed using each SPGR, fSPGR and SE sequence. The largest model was then used. In all cases, a standard four-handed, bi-nostril endoscopic endonasal technique was used. Endocrinological follow-up evaluation using morning cortisol sampling was performed for 6-34 months in our study. RESULTS: In total, 36 patients (88%) were disease-free following surgery. Our results indicate we achieved 100% sensitivity of MR. Overall, the conformity of at least one donor site, as compared with the places designated on MR, was in 78% of patients. We searched the place of compliance in individual locations. There is a consensus in individual locations in 63 of the 123 cases (or 56%). The correlation gamma function at a 5% significance level was then 0.27. DISCUSSION: The combination of MR sequences (SE, SPGR, fSPGR), neuronavigation system and iMRI led to increased sensitivity of up to 100%. Specificity reached 56% in our study. CONCLUSION: We found a high success rate in surgical procedure in terms of the correlation between MR findings and histology, which leads to remission of Cushing's disease. PMID- 27988035 TI - Selective nonoperative management of abdominal gunshot wounds with isolated solid organ injury. AB - OBJECTIVE: To review selective nonoperative management (SNOM) of gunshot wound (GSW) patients with isolated abdominal solid organ injury. METHODS: Patients who sustained isolated solid organ injury secondary to GSW from 2003 to 2014 were studied. The use of SNOM over time was analyzed, and comparisons of initial SNOM and operative management (OM) groups were performed. RESULTS: Of 127 patients, 63 (50%) underwent SNOM. There were no significant differences between the early/late or SNOM/OM groups in demographics, physiologic presentation, or Injury Severity Score. SNOM increased from the early to late cohorts (31%-67%, p < 0.001), without any change in outcomes. SNOM patients had shorter hospital stays (5.8 vs. 10.0 days, p < 0.001), received fewer PRBCs (0.8 vs. 4 units, p < 0.001), and suffered fewer complications (13% vs. 28%, p < 0.05) than the OM group. CONCLUSION: An increase in SNOM vs. OM was associated with equivalent outcomes. Patients undergoing SNOM received fewer PRBCs and had shorter LOS. PMID- 27988036 TI - A female head-neck model for rear impact simulations. AB - Several mathematical cervical models of the 50th percentile male have been developed and used for impact biomechanics research. However, for the 50th percentile female no similar modelling efforts have been made, despite females being subject to a higher risk of soft tissue neck injuries. This is a limitation for the development of automotive protective systems addressing Whiplash Associated Disorders (WADs), most commonly caused in rear impacts, as the risk for females sustaining WAD symptoms is double that of males. In this study, a finite element head and neck model of a 50th percentile female was validated in rear impacts. A previously validated ligamentous cervical spine model was complemented with a rigid body head, soft tissues and muscles. In both physiological flexion-extension motions and simulated rear impacts, the kinematic response at segment level was comparable to that of human subjects. Evaluation of ligament stress levels in simulations with varied initial cervical curvature revealed that if an individual assumes a more lordotic posture than the neutral, a higher risk of WAD might occur in rear impact. The female head and neck model, together with a kinematical whole body model which is under development, addresses a need for tools for assessment of automotive protection systems for the group which is at the highest risk to sustain WAD. PMID- 27988037 TI - Algorithm for the diagnosis and follow-up of acute pulmonary embolisms. AB - The urgent diagnosis of acute pulmonary thromboembolism benefits from the use of evidence-based clinical guidelines that improve patients' prognoses and reduce the unnecessary use of imaging tests. This article explains the diagnostic algorithms for pulmonary thromboembolism most recently published by the relevant scientific societies both for the general population and for special situations, trying to clear up common doubts and analyzing persistent controversies. It also discusses the need to follow up the thromboembolism after anticoagulation treatment, which is not currently recommended in the guidelines. PMID- 27988038 TI - [Acute psychiatric symptoms during methylphenidate intravenous injections: A case report]. AB - We report the case of a 32-year-old man who developed acute psychiatric disorders after repeated intravenous injections of methylphenidate. The behavioural disorders with extreme psychomotor restlessness and delirious syndrome have resolved within 24hours. The available data highlight the fact that the prescriptions of methylphenidate, an amphetamine-like substance, are constantly increasing in Europe and Northern America. The potential of abuse and addiction to this drug, which is growingly misused, is now clearly established. The medical professionals should be cautious and attentive to the risk of misuse of this drug. PMID- 27988040 TI - Tuning rules for robust FOPID controllers based on multi-objective optimization with FOPDT models. AB - In this paper a set of optimally balanced tuning rules for fractional-order proportional-integral-derivative controllers is proposed. The control problem of minimizing at once the integrated absolute error for both the set-point and the load disturbance responses is addressed. The control problem is stated as a multi objective optimization problem where a first-order-plus-dead-time process model subject to a robustness, maximum sensitivity based, constraint has been considered. A set of Pareto optimal solutions is obtained for different normalized dead times and then the optimal balance between the competing objectives is obtained by choosing the Nash solution among the Pareto-optimal ones. A curve fitting procedure has then been applied in order to generate suitable tuning rules. Several simulation results show the effectiveness of the proposed approach. PMID- 27988039 TI - Comparison of Patient Characteristics and Course of Hypertensive Hypokinetic Cardiomyopathy Versus Idiopathic Dilated Cardiomyopathy. AB - Hypertensive hypokinetic cardiomyopathy (HHC) is defined by left ventricular (LV) systolic dysfunction with a history of systemic hypertension as the only possible cause. Although commonly encountered in clinical practice, its characterization and differences with true idiopathic dilated cardiomyopathy (IDC) are lacking. The aim of this study was to characterize the clinical instrumental features and the natural history of HHC. We analyzed the data of 4,191 patients referred to our center for newly diagnosed LV systolic dysfunction from 2005 to 2010. Of them, 310 presented idiopathic LV systolic dysfunction (LV ejection fraction <50%): 136 (44%) had a history of systemic hypertension and were defined HHC. The remaining 174 patients were considered IDC. Compared with patients with IDC, those with HHC were older (63 +/- 11 vs 47 +/- 14 years, p <0.001), with worse comorbidity profile, higher blood pressure, and increased LV mass. During follow up, patients with HHC showed earlier and higher proportion of LV reverse remodeling (46% vs 21% at 6 months' follow-up). Moreover, they had a better long term survival free from cardiovascular death/ventricular assist device/heart transplant/malignant ventricular arrhythmias (5.1 vs 12.6 in HHC and IDC, p = 0.03). Indeed, their mortality was mainly driven by noncardiovascular causes (at 10 years 9.6% vs 1.7% in HHC and IDC, p <0.001). In conclusion, HHC has a high prevalence among patients with "idiopathic" LV dysfunction. The natural history of patients with HHC is characterized by a rapid response to optimal therapy for heart failure, a favorable cardiovascular outcome, and a relevant incidence of noncardiovascular events. PMID- 27988041 TI - Obstructive ectopic intratracheal thyroid. PMID- 27988042 TI - Endoscopic electrocauterization for congenital pyriform sinus fistula treatment in paediatrics. Case series. AB - Pyriform sinus fistulas are rare anomalies of the branchial arches. Most of them are located on the left side. They extend from the apex of the pyriform sinus of the hypopharynx to the thyroid gland or adjacent tissues. The diagnosis is suspected in the presence of acute suppurative thyroiditis or recurrent cervical abscesses, and is confirmed by endoscopic visualization of the fistula hole. The traditional treatment consists of excision of the fistulous tract, with or without thyroid lobectomy, by cervical approach. However, less invasive alternatives that obliterate the path of the fistula have been developed, such as endoscopic electrocautery. We describe our experience with 7 patients with this condition, who were treated with endoscopic cauterization using radiofrequency electrocautery, and we evaluate the effectiveness and safety of the treatment performed. PMID- 27988043 TI - Asbestos. Laryngeal cancer. PMID- 27988044 TI - Development and efficacy assessments of tea seed oil makeup remover. AB - INTRODUCTION: The efficacy of tea seed oil to clean foundation and eyeliner was evaluated. The safe and efficient tea seed oil makeup remover was developed. MATERIALS AND METHODS: In vitro cleansing efficacy of makeup remover was UV spectrophotometric validated. The stability evaluation by means of accelerated stability test was conducted. In vitro and in vivo cleansing efficacy of the removers was conducted in a comparison with benchmark majorly containing olive oil. RESULTS: Tea seed oil cleaned 90.64+/-4.56% of foundation and 87.62+/-8.35% of eyeliner. The stable with most appropriate textures base was incorporated with tea seed oil. Three tea seed oil removers (50, 55 and 60%) were stabled. The 60% tea seed oil remover significantly removed foundation better than others (94.48+/ 3.37%; P<0.001) and the benchmark (92.32+/-1.33%), but insignificant removed eyeliner (87.50+/-5.15%; P=0.059). Tea seed oil remover caused none of skin irritation as examined in 20 human volunteers. A single-blind, randomized control exhibited that the tea seed oil remover gained a better preference over the benchmark (75.42+/-8.10 and 70.00+/-7.78%; P=0.974). CONCLUSION: The safe and efficient tea seed oil makeup removers had been developed. The consumers' choices towards the makeup remover containing the bio-oils are widen. In vitro cleansing efficacy during the course of makeup remover development using UV spectrophotometric method feasible for pharmaceutic industries is encouraged. PMID- 27988045 TI - Multi-spacer typing as an effective method to distinguish the clonal lineage of Clostridium butyricum strains isolated from stool samples during a series of necrotizing enterocolitis cases. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease with high morbidity and mortality that predominantly affects preterm neonates during outbreaks. In a previous study, the present authors identified 15 Clostridium butyricum isolates from stool samples during a series of NEC cases involving four neonatal intensive care units. A clonal lineage of these strains was observed by in-silico multi-locus sequence typing. AIM: To confirm the previous findings by sequencing a larger number of C. butyricum genomes and using other genotyping approaches. METHODS: The previously isolated 15 C. butyricum strains were characterized and compared with 17 other commensal and environmental C. butyricum strains using whole-genome sequencing (WGS). In addition, the clustering was analysed using multi-spacer sequence typing (MST). FINDINGS: The core genome of C. butyricum was composed of 1251 genes, and its pan-genome consisted of 12,628 genes with high variability between strains. It was possible to distinguish the clonal lineage of strains from a series of NEC cases, forming three clades with geographical clustering. The results obtained using WGS and MST approaches were congruent. CONCLUSION: MST is a fast, cheap and effective genotyping method for investigating NEC outbreaks associated with C. butyricum. PMID- 27988046 TI - [The validity of the Spanish Minimum Basic Data Set to identify congenital anomalies in the Valencian Community (Spain)]. AB - OBJECTIVE: To assess the validity of the Spanish Minimum Basic Data Set (MBDS) for identifying major congenital anomalies in the Valencian Community. METHODS: A retrospective epidemiological study was carried out. Children under the age of one year, born in 2007 and residing in the Valencian Community with congenital anomalies code 740-759 CIE9-MC, were selected from the MBDS, in addition to a random sample of children under the age of 1 year without these discharge codes. Having reviewed the clinical documentation, the cases were classified as true positives and negatives and false positives and negatives. Positive and negative predictive value and sensitivity were calculated. The kappa test was applied to analyse diagnostic consistency between the MBDS and the clinical documentation. RESULTS: A total of 2305 discharges of 1651 patients were identified. 4 out of the 5434 patients sampled had a major congenital abnormality. The positive predictive value was 56.4% (95% confidence interval [95%CI]: 53.9-58.8) and the negative predictive value was 99.3% (95%CI: 98.6-100.0). MBDS sensitivity was 68.6% (95%CI: 66.1-71.1). The most common codes in the true positives were: 745.5 (atrial septal defect), 745.4 (ventricular septal defect) and 747.0 (patent ductus arteriosus) and in the false positives: 747.0, 745.5 and 752.51 (cryptorchidism). 25.5% of diagnoses with congenital anomaly from the MBDS were not in the clinical documentation. Considering all diagnoses coded in the MBDS, the correlation was 0.70 (95%CI: 0.68-0.72) CONCLUSIONS: The MBDS is the main source of information to detect cases in the registry of congenital anomalies of the Valencian Community. Its main limitation is the high number of false positive cases detected. PMID- 27988048 TI - Opioid Use in Gynecologic Oncology; Balancing Efficacy, Accessibility and Safety: An SGO Clinical Practice Statement. PMID- 27988047 TI - Pre-diagnosis health-related quality of life, surgery, and survival in women with advanced epithelial ovarian cancer: A SEER-MHOS study. AB - OBJECTIVE: Health-related quality of life (HRQOL) has been found to be associated with overall survival in women with ovarian cancer. However, previous studies assessed HRQOL after surgery within clinical trial populations only. The study goal was to determine the association of pre-cancer diagnosis HRQOL with the likelihood of receiving surgery and with overall survival in a national, population-based cohort of older women with advanced ovarian cancer. METHODS: The Surveillance, Epidemiology, and End Results (SEER)-Medicare Health Outcomes Survey (MHOS) database was queried to identify 374 women aged 65years and older with advanced stage epithelial ovarian cancer from 1998 to 2011. Responses to the Short Form 36 (SF-36) and Veterans-RAND-12 (VR-12), two single-item global health questions, and Activities of Daily Living (ADLs) were abstracted. Multivariable models were used to quantify associations of HRQOL and ADL assessments with surgery and overall survival, adjusted for demographic and clinical characteristics. RESULTS: Of 374 women with a HRQOL assessment prior to diagnosis, 199 (53%) underwent surgery. Increases in physical and mental HRQOL domains were significantly associated with receipt of surgery. The relationship between HRQOL domains and overall survival were not statistically significant. For ADLs, only difficulty in toilet use was significantly associated with survival. CONCLUSION: In this population-based sample of older women with advanced epithelial ovarian cancer, pre-diagnosis HRQOL was predictive of receiving surgery, but not of overall survival. PMID- 27988049 TI - Update on Feline Ionized Hypercalcemia. AB - Hypercalcemia in cats is recognized with increased frequency, especially idiopathic hypercalcemia, which is the most common cause. Idiopathic hypercalcemia seems to be unique to the cat, not occurring in the dog as a specific syndrome. There are many causes of hypercalcemia, and diagnosis relies on evaluation of clinical signs, physical examination, diagnostic imaging, serum biochemistry, urinalysis, and evaluation of calcium metabolic hormones. With an accurate diagnosis, treatment options can be tailored to the individual. PMID- 27988050 TI - A Quick Reference on Phosphorus. AB - Phosphorus, or phosphate, is the body's major intracellular anion involved in numerous biological processes. Most phosphate is intracellular, with the remaining amount contained within soft tissues and the extracellular space. Parathyroid hormone, calcitriol, calcitonin, and phosphatonins regulate normal phosphate homeostasis by adjusting renal and/or gastrointestinal absorption and/or excretion. Hypophosphatemia occurs secondary to decreased gastrointestinal absorption, transcellular shifts, increased renal excretion, or some combination of these general mechanisms. Hyperphosphatemia results from decreased renal excretion, increased intake or iatrogenic administration, transcellular shifts, or some combination of these. PMID- 27988052 TI - What PEEP level should I use in my patient? PMID- 27988051 TI - The clinical characteristics of AQP4 antibody positive NMO/SD in a large cohort of Chinese Han patients. AB - We aim to summarize the clinical features of AQP4-ab-positive NMO/SD in a large Chinese Han cohort. The clinical data of 145 AQP4-ab-seropositive patients was retrospectively reviewed. 55.9% (81/145) of the patients were defined as NMO while 39.3% (57/145) were defined as NMOSD according to the criteria established in 2006 and 2007. The mean onset age was 34.4years and the female to male ratio was 8.7:1. The median disease duration was 57months. The median of "time to second attack" and "time to develop NMO" was 7 and 13months respectively. Ratio of monophasic to relapsing was 1:7.1. Myelitis and optic neuritis (ON) were the most common manifestations at onset, followed by postrema syndrome. The median age of patients presenting with ON at disease onset was significantly younger than patients presenting with myelitis. Only 17.2% of the patients younger than 30years presented with longitudinally extensive transverse myelitis (LETM) at onset, while 55.6% of the patients over 30years presented with LETM at onset. The patients presenting with ON at disease onset all exhibited a relapsing course, had a higher probability of subsequent involvement of other CNS regions and developing into definite NMO over time compared with those with LETM as the first attack. AQP4-ab levels were higher in patients with circulating auto-antibodies such as ANA, SSA, anti-Ro-52, anti-dsDNA, anti-histone antibody, pANCA and SSB, and positively correlated with CSF protein concentrations. PMID- 27988053 TI - Perineal reconstruction: The use of a gracilis muscle flap for urethral fistula coverage, our point of view. PMID- 27988054 TI - [Suture simulator - Cleft palate surgery]. AB - INTRODUCTION: Cleft palate requires surgery in the first years of life, furthermore repairing anatomically the soft and hard palate is complex on a surgical level because of the fine tissues and the local intraoral configuration. It is valuable to train first on simulators before going to the operating room. However, there is no material dedicated to learning how to perform intraoral sutures in cleft palate surgery. We made one, in an artisanal manner, in order to practice before the real surgical gesture. BUILDING THE SIMULATOR: The simulator was designed based on precise anatomical data. A steel pipe, fixed on a rigid base represented the oral cavity. An adapted split spoon represented the palate. All pieces could be removed in order to apply a hydrocellular dressing before training for sutures. USE OF THE SIMULATOR: Our simulator was tested by 3 senior surgeons in our department in close to real-life conditions in order to evaluate its anatomical accuracy. CONCLUSION: It is valuable to have a simulator to train on cleft palate sutures within teaching university hospitals that manage this pathology. Our simulator has a very low cost, it is easy to make and is anatomically accurate. PMID- 27988055 TI - Role of First-Line Noninvasive Ventilation in Non-COPD Subjects With Pneumonia. AB - INTRODUCTION: The use of noninvasive ventilation (NIV) in non-COPD patients with pneumonia is controversial due to its high rate of failure and the potentially harmful effects when NIV fails. The purpose of the study was to evaluate outcomes of the first ventilatory treatment applied, NIV or invasive mechanical ventilation (MV), and to identify predictors of NIV failure. METHODS: Historical cohort study of 159 non-COPD patients with pneumonia admitted to the ICU with ventilatory support. Subjects were divided into 2 groups: invasive MV or NIV. Univariate and multivariate analyses with demographic and clinical data were performed. Analysis of mortality was adjusted for the propensity of receiving first-line invasive MV. RESULTS: One hundred and thirteen subjects received first line invasive MV and 46 received first-line NIV, of which 27 needed intubation. Hospital mortality was 35, 37 and 56%, respectively, with no significant differences among groups. In the propensity-adjusted analysis (expressed as OR [95% CI]), hospital mortality was associated with age (1.05 [1.02-1.08]), SAPS3 (1.03 [1.00-1.07]), immunosuppression (2.52 [1.02-6.27]) and NIV failure compared to first-line invasive MV (4.3 [1.33-13.94]). Compared with invasive MV, NIV failure delayed intubation (p=.004), and prolonged the length of invasive MV (p=.007) and ICU stay (p=.001). NIV failure was associated with need for vasoactive drugs (OR 7.8 [95% CI, 1.8-33.2], p=.006). CONCLUSIONS: In non-COPD subjects with pneumonia, first-line NIV was not associated with better outcome compared with first-line invasive MV. NIV failure was associated with longer duration of MV and hospital stay, and with increased hospital mortality. The use of vasoactive drugs predicted NIV failure. PMID- 27988056 TI - Unintentional Pediatric Ingestion of Electronic Cigarette Nicotine Refill Liquid Necessitating Intubation. AB - Liquid nicotine used in electronic cigarette devices is highly concentrated, unreliably packaged, and poorly regulated. We present a case report of a 6-year old female who developed severe toxicity and required intubation after an unintentional oral ingestion of approximately 703 mg (35 mg/kg) of liquid nicotine, with accompanying serum and urine concentrations of nicotine and its metabolites. Analysis of the ingested liquid suggests a nicotine concentration of 140.6 mg/mL in the purchased commercial product, or 234% of its labeled concentration. Clinicians should be aware of these products and the potential severity of toxicity they may incur. PMID- 27988057 TI - The RNA Epistructurome: Uncovering RNA Function by Studying Structure and Post Transcriptional Modifications. AB - A large fraction of higher metazoan genomes transcribe RNA molecules whose functions extend far beyond carrying instructions for protein synthesis. Although RNA is apparently a simple molecule, the ways in which it performs many of its functions have remained highly elusive for decades. As learned from studying ribosomal and transfer RNAs, two of the key features influencing the function of RNA are its structure and post-transcriptional modifications. A deep understanding of RNA function therefore requires rapid and straightforward approaches to study the complex and intricate landscape of RNA structures and modifications. In this review we summarize and discuss the most recent methods and findings in the field of RNA biology, with an eye toward new frontiers and open questions. PMID- 27988058 TI - The relative biological effectiveness of antiprotons. AB - BACKGROUND AND PURPOSE: Aside from the enhancement of physical dose deposited by antiprotons annihilating in tissue-like material compared to protons of the same range a further increase of biological effective dose has been demonstrated. This enhancement can be expressed in an increase of the relative biological effectiveness (RBE) of antiprotons near the end of range. We have performed the first-ever direct measurement of the RBE of antiprotons both at rest and in flight. MATERIALS AND METHODS: Experimental data were generated on the RBE of an antiproton beam entering a tissue-like target consisting of V79 cells embedded in gelatin with an energy providing a range of approximately 10cm. RESULTS: The RBE in the entrance channel (the "plateau") is only slightly above the value for a comparable proton beam, and remains low until the proximal edge of the spread-out Bragg peak (SOBP). A steep increase of RBE is seen starting from the onset of the SOBP. CONCLUSIONS: This paper reports the final results of the experiment AD 4/ACE at CERN on the first-ever direct measurement of RBE of antiprotons and constitutes the first step toward developing treatment plans. PMID- 27988059 TI - Letter to editor: "Sweet taste disorder and vascular complications in patients with abnormal glucose tolerance". PMID- 27988061 TI - Is physical activity really associated with reduced odds of elevated red cell distribution width? PMID- 27988060 TI - Syncope and risk of sudden cardiac arrest in coronary artery disease. AB - BACKGROUND: Syncope has been associated with increased risk of sudden cardiac arrest (SCA) in specific patient populations, such as hypertrophic cardiomyopathy, heart failure, and long QT syndrome, but data are lacking on the risk of SCA associated with syncope among patients with coronary artery disease (CAD), the most common cause of SCA. We investigated this association among CAD patients in the community. METHODS: All cases of SCA due to CAD were prospectively identified in Portland, Oregon (population approximately 1 million) as part of the Oregon Sudden Unexpected Death Study 2002-2015, and compared to geographical controls. Detailed clinical information including history of syncope and cardiac investigations was obtained from medical records. RESULTS: 2119 SCA cases (68.4+/-13.8years, 66.9% male) and 746 controls (66.7+/-11.7years, 67.0% male) were included in the analysis. 143 (6.8%) of cases had documented syncope prior to the SCA. SCA cases with syncope were >5years older and had more comorbidities than other SCA cases. After adjusting for clinical factors and left ventricular ejection fraction (LVEF), syncope was associated with increased risk of SCA (OR 2.8; 95%CI 1.68-4.85). When analysis was restricted to subjects with LVEF >=50%, the risk of SCA associated with syncope remained significantly elevated (adjusted OR 3.1; 95%CI 1.68-5.79). CONCLUSIONS: Syncope was associated with increased risk of SCA in CAD patients even with preserved LV function. These findings suggest a role for this clinical marker among patients with CAD and normal LVEF, a large sub-group without any current means of SCA risk stratification. PMID- 27988062 TI - Review: Eicosanoids in preterm labor and delivery: Potential roles of exosomes in eicosanoid functions. AB - Preterm delivery is a major obstetric health problem contributing to poor neonatal outcome including low birth weight, respiratory distress syndrome, gastrointestinal, immunologic, central nervous system, hearing, and vision problems. Worldwide, approximately 15 million babies are born prematurely each year. The critical question which remains is how to identify women destined to deliver preterm from those who will achieve a term delivery. Prostaglandins, in all mammals, are important in the parturient process. Increased intrauterine prostaglandin production is associated with labor and in fact prostaglandin E2 (PGE2) or analogs are widely used clinically for cervical ripening and labor induction. Measurements of circulating eicosanoids have been problematic because of the rapid and major clearance by the lungs and then kidneys resulting in very low concentrations in plasma. Moreover, since eicosanoids are produced by all mammalian tissues, the sources of the measured eicosanoids are unknown. Our understanding of how cells communicate has undergone a paradigm shift with the recognition of the role of exosomes in intercellular signaling. Recent publications have identified enzymes and products of arachidonic acid metabolism (eicosanoids) within exosomes. This review will explore the potential roles of exosomes in eicosanoid functions that are critical in preterm labor and delivery. PMID- 27988064 TI - Cutaneous EBV-related lymphoproliferative disorders. AB - This article will focus on the cutaneous lymphoproliferative disorders associated with EBV, with an emphasis on the upcoming changes in the revised 4th Edition of the WHO classification of tumors of the hematopoietic system, many of which deal with cutaneous disorders derived from NK-cells or T-cells. Extranodal NK/T-cell lymphoma usually presents in the upper aerodigestive tract, but can involve the skin secondarily. EBV-associated T- and NK-cell lymphoproliferative disorders (LPD) in the pediatric age group include the systemic diseases, chronic active EBV infection (CAEBV) and systemic EBV+ T-cell lymphoma of childhood. Hydroa vacciniforme (HV)-like LPD is a primarily cutaneous form of CAEBV and encompasses the lesions previously referred to as HV and HV-like lymphoma (HVLL). All the T/NK-cell-EBV-associated diseases occur with higher frequency in Asians, and indigenous populations from Central and South America and Mexico. Among the B cell EBV-associated LPD two major changes have been introduced in the WHO. The previously designated EBV-positive diffuse large B-cell lymphoma (EBV-DLBCL) of the elderly, has been changed to EBV-DLBCL with 'not otherwise specified' as a modifier (NOS). A new addition to the WHO system is the more recently identified EBV+ mucocutaneous ulcer, which involves skin and mucosal-associated sites. PMID- 27988065 TI - Cilioretinal obstruction during pregnancy. AB - PURPOSE: To determine the number of patients diagnosed over a 5-year period with isolated occlusion of the cilioretinal artery (CRAO) whilst pregnant, as well as to describe the outcomes and ophthalmological sequelae of this condition in pregnant woman. METHODS: A retrospective study of the medical records. RESULTS: From the 135 patients diagnosed with retinal arterial occlusion of all of our series, 20 (14.8%) had CRAO, and 2 (1.48%) of these were pregnant. Case 1: A 34 year-old pregnant woman with a centrocaecal scotoma and visual acuity of 20/20 in right eye. Fundus examination: A soft exudate in the papillomacular bundle with retinal oedema and embolism on a cilioretinal artery branch. The exudate and oedema disappeared after 5 weeks, and the scotoma was reduced. Case 2: A 30 year old pregnant woman, with normal visual acuity in right eye, and a centrocaecal scotoma. Fundoscopy: An area of retinal interpapillomacular infarction due to cilioretinal artery occlusion. The fundus returned to normal in 4 weeks, with an improvement of the scotoma. CONCLUSIONS: The aetiology of CRAO is usually associated with carotid disease or other thromboembolic events related to hypercoagulable states and autoimmunity. Pregnancy is considered a hypercoagulable state, and it is not known if it is a risk factor for arterial embolism. Further studies are required to determine the correlation between pregnancy and CRAO. PMID- 27988063 TI - [Noise level in the NICU: Impact of monitoring equipment]. AB - BACKGROUND: The sound level in the neonatal intensive care unit (NICU) may induce adverse effects for neonates, their family, and the staff. This study evaluated the sound level in a NICU before and after the implementation of an educational program. MATERIAL AND METHODS: A baseline audit determined the most exposed area of the NICU and the most exposed periods over 24 h. Then an educational program started, including sound level measurement methods, side effects for neonates, results from the baseline audit, and new visual monitoring equipment (SoundEar(r)). Sound levels were measured before, 1, 2, and 3 months after starting the educational program and the use of SoundEar(r). The NICU staff was blind to the periods of sound level measurements. RESULTS: The base noise level was high, especially near the central part of the NICU and during transmission time (mean Leq: 60.6+/-3.6dB(A); sound peaks: 94.8+/-6.8dB(A)). A decrease in the sound level (P<0.001) was found 1 and 2, but not 3 months after starting the educational program. It remained high compared to the guidelines. CONCLUSION: Human activity was responsible for most of the sound level. An educational program was effective in reducing the sound level, but did not reach the guideline's target. The continuous use of sound-monitoring equipment after starting the project reduced the sound level for 2 months, but no longer. Therefore, a continuous educational program about the sound level in the NICU including feedback monitoring every 2-3 months should be encouraged. PMID- 27988066 TI - Laryngeal Mucosal Reaction during Bronchial Histamine Challenge Test Visualized by Videolaryngostroboscopy. AB - OBJECTIVES/HYPOTHESIS: To examine the changes in the larynx, as well as self reported voice and throat symptoms, among patients undergoing a histamine challenge test. Thus, to understand the possible clinical effects of histamine on the larynx. STUDY DESIGN: Controlled, open prospective study. METHODS: Thirty adult patients with prolonged cough and suspicion of bronchial asthma underwent a histamine challenge test. Videolaryngostroboscopy was performed immediately before and after the challenge. Voice and throat symptoms immediately before and after the challenge test were assessed using a visual analog scale. RESULTS: Videolaryngostroboscopy after exposure showed significant increases in edema (P < 0.001) as well as redness (P < 0.001) of the vocal folds after the exposure. Self reported voice complaints increased significantly for 8 of 11 symptoms. A moderate positive correlation was found between the increase in edema of the vocal folds and reported heartburn/regurgitation symptoms (r = 0.42, P < 0.05). Atopy, asthma, nasal symptoms, or bronchial hyperreactivity during the histamine challenge test were not associated with laryngeal reactions. CONCLUSIONS: According to the results, the laryngeal mucosal reaction during a histamine challenge test can be objectively visualized. Videolaryngostroboscopy findings, together with an increase in self-reported voice and throat symptoms, show that histamine has potential effects on vocal folds. The mucosal reaction seems to be pronounced among patients with reflux symptoms, probably reflecting the permeability features of the vocal folds. PMID- 27988067 TI - Three-dimensional Vocal Tract Morphology Based on Multiple Magnetic Resonance Images Is Highly Reproducible During Sustained Phonation. AB - OBJECTIVES: The extraction of a three-dimensional (3D) morphology of the human vocal tract (VT) from magnetic resonance imaging (MRI) during sustained phonation can be used for various analyses like numerical simulations or creating physical models. The precision of visualizing techniques nowadays allows for very targeted acoustical simulation evaluating the influence of subsections of the VT for the transfer function. The aim of the study was to assess the accuracy of the 3D geometry based on MRI data in repetitive trials. STUDY DESIGN: This is a prospective study. METHODS: Four experienced singers underwent an MRI while repeating a specific vocal task 20 times consecutively. Audio recordings were made by means of an optical microphone. Images were restacked and subsections of the VT were segmented on multi-image-based cross sections using a semiautomatic algorithm. Different volume and area measures were evaluated. RESULTS: A high reproducibility of the morphologic data based on multiple images by means of the applied segmentation method could be shown with an overall variation of around 8%. CONCLUSIONS: 3D modeling of the VT during sustained phonation involves a complex experimental setting and elaborate image processing techniques. Functional comparative analysis or acoustical simulations based on such data should take the found variability into account. PMID- 27988068 TI - In vivo pharmacodynamics of piperacillin/tazobactam: implications for antimicrobial efficacy and resistance suppression with innovator and generic products. AB - Recent studies have shown that the pharmacodynamic (PD) index driving the efficacy of beta-lactam/beta-lactamase inhibitor combinations such as ceftazidime/avibactam and ceftolozane/tazobactam is the percentage of time the free inhibitor concentration is above a threshold (fT>threshold). However, data with piperacillin/tazobactam (TZP) are scarce. Here we aimed to assess the relationship between fT>threshold and TZP antibacterial efficacy by a population pharmacokinetic study in mice and dose-effect experiments in a neutropenic murine thigh infection model with two isogenic strains of Escherichia coli differentially expressing TEM-1 beta-lactamase. We also explored the dynamics of resistance selection with the innovator and a non-equivalent generic, extrapolated the results to the clinic by Monte Carlo simulation of standard TZP doses, and estimated the economic impact of generic-selected resistance. The fT>threshold index described well the efficacy of TZP versus E. coli, with threshold values from 0.5 mg/L to 2 mg/L and mean exposures of 42% for stasis and 56% for 1 log10 kill. The non-equivalent generic required a longer exposure (fT>threshold 33%) to suppress resistance compared with the innovator (fT>threshold 22%), leading to a higher frequency of resistance selection in the clinical simulation (16% of patients with the generic vs. 1% with the innovator). Finally, we estimated that use of TZP generics in a scenario of 25% therapeutic non-equivalence would result in extra expenses approaching US$1 billion per year in the USA owing to selection of resistant micro-organisms, greatly offsetting the savings gained from generic substitution and further emphasising the need for demonstrated and not assumed therapeutic equivalence. PMID- 27988070 TI - Marine Genomics Special issue "Genome-powered perspectives in integrative physiology and evolutionary biology". PMID- 27988069 TI - A simple hemodynamic parameter to predict clinical worsening in pulmonary arterial hypertension. AB - BACKGROUND: Predicting prognosis is a cornerstone in management of pulmonary arterial hypertension. Hemodynamic parameters are among the robust indicators of right ventricular function and prognosis. In this study we have investigated the association of a simple hemodynamic parameter with clinical worsening in pulmonary arterial hypertension. METHODS AND PATIENTS: 120 patients were enrolled in a single center prospective cohort study after confirmation of precapillary pulmonary hypertension and were followed for an average of 36months on guideline recommended treatment protocols. cSvO2 was calculated as the ratio of right atrial pressure over Mixed Venous Oxygen Saturation. Independent predictors of clinical worsening were identified using multivariable Cox regression models. RESULTS: By the end of the follow up a total of 21 patients died and 63 were hospitalized for pulmonary hypertension. Time-to-event Cox regression model showed a strong association between cSvO2 and time to clinical worsening (HR: 250.13, CI: (38.56-1622.34) &p-value: <0.0001). CONCLUSION: The index of cSvO2 includes both parameters of cardiac output and right ventricular filling pressure and might be beneficial in predicting clinical worsening in patients with pulmonary arterial hypertension. PMID- 27988071 TI - Patient perception of methadone dose adequacy in methadone maintenance treatment: The role of perceived participation in dosage decisions. AB - OBJECTIVE: In clinical practice, methadone maintenance treatment (MMT) entails tailoring the methadone dose to the patient's specific needs, thereby individualizing treatment. The aim of this study was to identify the independent factors that may significantly explain methadone dose adequacy from the patient's perspective. METHOD: Secondary analysis of data collected in a treatment satisfaction survey carried out among a representative sample of MMT patients (n=122) from the region of La Rioja (Spain). As part of the original study protocol, participants completed a comprehensive battery to assess satisfaction with MMT, psychological distress, opinion of methadone as a medication, participation in dosage decisions, and perception of dose adequacy. RESULTS: Multivariate binary logistic regression showed that the only variable independently associated with the likelihood of a patient perceiving methadone dose as inadequate was the variable perceived-participation in methadone dosage decisions (OR=0.538, 95% CI=0.349-0.828). CONCLUSION: Patient participation in methadone dosage decisions was predictive of perceived adequacy of methadone dose beyond the contribution of other socio-demographic, clinical, and MMT variables. PRACTICE IMPLICATIONS: Patient participation in methadone dosage decision-making is valuable for developing a genuinely patient-centred MMT. PMID- 27988072 TI - Epicardial adipose tissue is related to cardiac function in elderly women, but not in men. AB - BACKGROUND AND AIM: Epicardial adipose tissue (EAT) is easily quantifiable visceral adipose tissue that is closely associated with cardiometabolic disease including heart failure with preserved left ventricular (LV) ejection fraction. As body fat distribution and metabolism are different between men and women, we evaluated the sex difference in EAT thickness and its relationship to cardiac function. METHODS AND RESULTS: A total of 152 consecutive patients (76 men) with mean age of 62 +/- 9 years were enrolled. Conventional echocardiography was performed and EAT thickness was measured perpendicularly on the right ventricular free wall at end systole. Mean EAT thickness in all patients was 6.5 +/- 2.0 mm. EAT thickness was associated with patient age, body mass index, and the presence of hypertension. EAT thickness was not different by sex in patients younger than 60 years (men, 6.4 +/- 2.0 mm; women, 6.2 +/- 1.8 mm, p = 0.716); however, among patients aged 60 years or older, EAT thickness was significantly greater in women than men (men, 6.0 +/- 1.7 mm; women 7.7 +/- 2.1 mm, p < 0.001). LV function represented by E/e' and s' was significantly related to EAT thickness only in women (E/e', beta = 0.330, p = 0.002; lateral s', beta = -0.225, p = 0.042). CONCLUSION: EAT thickness was greater in women than men after 60 years old and its relationship with LV function was significant only in women. Greater increase in EAT thickness in elderly women after menopause might partially account for this difference. PMID- 27988073 TI - Longitudinal trajectories of cortical thickness as a biomarker for psychosis in individuals with 22q11.2 deletion syndrome. AB - OBJECTIVE: 22q11.2 deletion syndrome (DS) or velo-cardio-facial syndrome (VCFS) is a genetic condition that has been identified as the highest genetic risk factor for developing psychotic illnesses. This unique biological nature of 22q11DS provides a valuable opportunity to explore predictive biomarkers of psychosis. In this study, we examined the relationship of cortical thickness and surface area between various brain regions and prodromal symptoms of psychosis. METHODS: 75 probands with 22q11DS, 32 age-matched controls and 28 siblings underwent MRIs over 2 or 3 timepoints. Longitudinal mixed model regression analyses, with age as an interaction variable, were carried out to study the differences in longitudinal trajectories of change in average cortical thickness and surface area over 6-9years. Similar analyses were carried out to examine the relationship with positive prodromal symptoms of psychosis. RESULTS: Significant differences were noted in the inferior and superior parietal regions in both the average thickness and longitudinal change in cortical thickness with age between the probands and controls. Significant associations were also noted between regions in the frontal cortex and positive prodromal symptoms among probands. No associations were noted with cortical surface area. CONCLUSION: Our results indicate that individuals with 22q11DS who develop positive prodromal symptoms demonstrate differential longitudinal trajectories of cortical thickness in some regions of the frontal lobe. Our results suggest that the pruning stage associated with adolescent brain development may be disrupted. PMID- 27988074 TI - The acetylcholine administration time plays the key role for provoked spasm in the spasm provocation test. AB - BACKGROUND: Acetylcholine (ACh) was administered for 3min in the ENCORE study, while the Japanese Circulation Society guidelines recommended the 20s ACh injection as an ACh test. OBJECTIVES: We compared the ischemic findings between ACh administration for 3min and ACh injection for 20s in the same patients and in the same ACh doses without administration of nitrates in the left coronary artery. METHODS: We investigated 30 patients with ischemic heart disease (25 men, 67+/-10 years, ACh 50MUg: 3, ACh 100MUg: 9, ACh 200MUg: 18) by the above two ACh injection procedures. Temporary pacemaker was inserted and set at the rate of 40/min. Positive provoked spasm was defined as transient >=90% narrowing and typical chest symptoms or ischemic electrocardiographic (ECG) changes. RESULTS: Provoked spasm was observed in 22 patients with ACh 20s injection, while 10 patients had provoked spasm by ACh 3min administration (73.3% vs. 33.3%, p<0.05). Ischemic ECG changes (50.0% vs. 23.3%, p<0.05) and chest symptoms (73.3% vs. 43.3%, p<0.05) were significantly higher with ACh 20s injection than ACh 3min administration. Pacemaker rhythm was recognized in 19 patients with ACh 20s injection, whereas 7 patients with ACh 3min administration had a pacemaker rhythm (63.3% vs. 23.3%, p<0.01). Maximal ST elevation by ACh 20s injection was significantly higher than that by ACh 3min administration (0.47+/-0.94 vs. 0.13+/ 0.51, p<0.05), while maximal ST depression was not different between the two procedures. Coronary artery diameter after ACh 20s injection was significantly lower than that after ACh 3min administration in the left anterior descending artery. CONCLUSIONS: ACh administration procedures (3min or 20s injection) may influence the ischemic findings in spasm provocation testing. PMID- 27988075 TI - Editor's reply. PMID- 27988076 TI - Electrospun biocompatible Chitosan/MIL-101 (Fe) composite nanofibers for solid phase extraction of Delta9-tetrahydrocannabinol in whole blood samples using Box Behnken experimental design. AB - The nanofibers of biocompatible Chitosan/MIL-101 (Fe) composite were synthesized by a simple, cheap and accessible electrospining method and applied for mat-based extraction of trace amount of Delta9-tetrahydrocannabinol (THC) from human whole blood sample following its combination by high performance liquid chromatography ultraviolet detection. The composite nanofibres were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction and N2 adsorption-desorption experiments. The volume of eluting solvent, sorbent amount, pH and% NaCl (w/v) influencing on the responses were investigated using factorial experimental design. The optimum point was achieved by analysis of the results according to design expert (DX) software. The volume of eluting solvent, sorbent amount and pH were significant variables, and 150MUL, 7mg and 7.0 were respectively chosen for obtaining the best extraction response. Under the optimum conditions, the method was exhibited a linear range of 0.1-100MUgL-1 (R2=0.9943) for THC with a detection limit of 0.04MUgL-1. Acceptable values for intra-day (3.2%) and inter-day (4.8%) relative standard deviations were obtained. The high preconcentration factor (970) and satisfactory recoveries (88.2%-92.4%) in whole blood samples were achieved which proved the capability of the method for trace determination of THC in the human whole blood samples. PMID- 27988077 TI - Alternating isocratic and step gradient elution high-speed counter-current chromatography for the isolation of minor phenolics from Ormocarpum kirkii bark. AB - A total of 14 compounds were isolated from the ethanol bark extract of O. kirkii S. Moore (Fabaceae) by alternating isocratic and step gradient elution high-speed counter-current chromatography (HSCCC) methods, using several solvent systems with reference to the polarity of compounds being purified. The extract was successively fractionated with generic solvent systems including n-hexane-ethanol water (4:2:2) and ethyl acetate-water (1:1). Resulting fractions were further purified using the following preparative gradient elution consisting of ethyl acetate-n-butanol-water (X:Y:10), (X:Y=9:1 (I); 8:2 (II); 7:3 (III); 6:4 (IV); 5:5 (V); 4:6 (VI) 3:7 (VII) and n-hexane- ethyl acetate-methanol-water (1:X:1:1), X=1, 2, 2.5, 3 solvent systems. Two flavone glycosides, apigenin-6-C-beta-d glucopyranosyl-4'-O-[beta-d-glucopyranosyl-(1->5)]-beta-d-apiofuranoside (1) and apigenin-6-C-beta-d-glucopyranosyl-4'-O-beta-d-apiofuranoside (2), and one biflavanone diglycoside 7,7"-di-O-beta-d-glucosylliquiritigeninyl-(I-3,II-3) naringenin (4) were isolated as new compounds along with other 11 known ones. The structures of the isolated compounds were identified by HPLC-UV, ESI-MS, 1D and 2D NMR and comparison with literature data. Thus, over common traditional chromatographic methods, the present study shows that HSCCC is a useful and fast method for natural product research with no losses and lower solvent use. PMID- 27988078 TI - Determination of salicylic acid using a magnetic iron oxide nanoparticle-based solid-phase extraction procedure followed by an online concentration technique through micellar electrokinetic capillary chromatography. AB - In this study, a magnetic iron oxide nanoparticle-based solid-phase extraction procedure combined with the online concentration and separation of salicylic acid (SA) through micellar electrokinetic chromatography-UV detection (MEKC-UV) was developed. Under optimal experimental conditions, a good linearity in the range of 0.01-100MUmolL-1 was obtained with a coefficient of correlation of 0.9999. The detection sensitivity of the proposed method exhibited an approximately 1026-fold improvement compared with a single MEKC method without online concentration, and the detection limit (S/N=3) was 3.80nmolL-1. The repeatability of the method was evaluated using intraday and interday RSDs (11.5% and 17.0%, respectively). The method was used to determine SA concentrations in tobacco leaves (Nicotiana tabacum L. cv. Samsun) from the NN genotype, nn genotype, and Nt-NahG mutant strains, as well as in shampoo and ointment samples. Rapid extraction and separation (<50min), acceptable repeatability (RSD<17.0%), and high spiked recoveries (95.8%-102.4%) were observed for plants, detergents, and pharmaceuticals. PMID- 27988080 TI - A comparative study of the effects of Escherichia coli and Clostridium perfringens upon boar semen preserved in liquid storage. AB - The present study compares the sperm quality of boar seminal doses artificially inoculated with Escherichia coli and Clostridium perfringens, and maintained in liquid storage at 15 degrees C for a 9-day period. Seminal doses from 10 sexually mature Pietrain boars were diluted in a Beltsville Thawing Solution (BTS)-based extender and infected either with E. coli or C. perfringens, with bacterial loads ranging from 101 to 107cfumL-1. During storage, the changes in sperm quality were determined by assessing pH, sperm viability, sperm motiliy, sperm morphology, sperm agglutination degree, and sperm-bacteria interaction. The infection of seminal doses led to an alkalinization of the medium, which was of higher extend in doses infected with C. perfringens. The effect of contamination on sperm viability and motility relied on bacterial type and load. Therefore, while E. coli was more harmful than C. perfringens in bacterial loads ranging from 101 to 106cfumL-1, the detrimental impact of C. perfringens was more apparent than that of E. coli at a bacterial load of 107cfumL-1. Despite sperm morphology not being affected by either bacterial type or load, sperm agglutination and sperm-bacteria interaction were characteristic of doses infected with E. coli, and increased concomintantly with bacterial load and along storage period. In conclusion, the effects of infection by E. coli on sperm quality were dependent of both bacterial load and storage period, whereas the effects of C. perfringens were mainly dependent on the bacterial load, with a threshold at 107cfumL-1 from which the sperm quality of seminal doses was greatly impaired. PMID- 27988079 TI - Urinary metabolomics revealed arsenic exposure related to metabolic alterations in general Chinese pregnant women. AB - Arsenic exposure is considered a major environmental threat to human health. It is already known that high-level arsenic exposure has adverse effects on human health. Since the pregnant women are known to be more susceptible to some chemical exposures than ordinary people, the understanding regarding the health effects of low-level arsenic exposure on pregnant women is critical and remains unclear. The aim of this study is to investigate the urinary metabolic changes of pregnant women exposed to low-dose arsenic, and to identify biomarkers from metabolomics analysis. Urine samples of 246 pregnant women were collected in the first trimester of pregnancy and were divided into three groups based on the tertile distribution of urinary arsenic concentrations which were determined using inductively coupled plasma mass spectrometry (ICP-MS). Changes in the metabolite profile were measured using ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF MS). Arsenic- related metabolic biomarkers were investigated by comparing the samples of the first and third tertiles of arsenic exposure classifications using a partial least-squares discriminant model (PLS-DA). Nine urine potential biomarkers were putatively identified, including LysoPC (14:0), glutathione, 18 carboxy-dinor-LTE4, 20-COOH-LTE4, cystathionine ketimin, 1-(beta-d-ribofuranosyl) 1,4-dihydronicotinamide, thiocysteine, p-cresol glucuronide and vanillactic acid. The obtained results showed that environmental arsenic exposure, even at low levels, could cause metabolite alterations in pregnant women which might be associated with adverse health outcomes. This is the first report on metabolic changes in pregnant women for arsenic exposure. The findings may be valuable for the arsenic risk assessment for pregnant women. PMID- 27988081 TI - Multiple lung metastases? PMID- 27988082 TI - Optimal periprocedural antithrombotic therapy in percutaneous coronary intervention: Between a rock and a hard place? PMID- 27988083 TI - Percutaneous treatment of left main disease: Still learning about the optimal PCI strategy. PMID- 27988084 TI - Reply: A different kind of anchor: An alternative to the distal anchoring technique. PMID- 27988085 TI - Reply: Time to start implementing lean and six sigma in the catheterization laboratory. PMID- 27988087 TI - The question of double identity. PMID- 27988086 TI - Impact of chronic kidney disease in patients undergoing percutaneous or surgical carotid artery revascularization: Insights of the healthcare cost and utilization Project's National Inpatient Sample. AB - BACKGROUND/PURPOSE: Carotid artery stenting (CAS) and carotid artery endarterectomy (CEA) are complementary techniques for management of patients with carotid artery stenosis. This study investigates the impact of chronic kidney disease (CKD) and age on outcomes after carotid artery revascularization. METHODS/MATERIALS: National Inpatient Sample was surveyed for CAS and CEA among stage 3 and 4 CKD and stage 5/end stage renal disease (ESRD) patients from 2004 to 2012. Primary endpoint was in-hospital major adverse cardiovascular and cerebrovascular events (MACCE) stratified by kidney function and age. Regression analysis and propensity score matching were utilized. RESULTS: There were 3299 patients that underwent CEA and 652 underwent CAS with stage 3 and 4 CKD. Whereas, 1630 patients underwent CEA and 511 patients underwent CAS with stage 5 CKD/ESRD. Patients undergoing CAS had more in-hospital MACCE. Coronary artery disease (OR1.35, 95%CI:1.07-1.70) and CAS (OR1.35, 95%CI:1.02-1.77) were independently associated with MACCE for stage 3 and 4 CKD patients. For the stage 5 CKD/ESRD cohort, CAS (OR1.75, 95%CI:1.29-2.37) was independently associated with MACCE. Stratifying by age, showed no difference in event rates except for higher MACCE among patients <60years old with stage 5 CKD/ESRD undergoing CAS (p<0.001). Propensity score matching showed that treatment type had no significant effect on MACCE rates. CONCLUSIONS: Among CKD cohorts studied nationally, in-hospital MACCE were higher for patients that underwent CAS. Overall, age group analyses showed that there was no difference in MACCE rates between CAS and CEA. Although CAS was independently associated with MACCE, propensity score matching showed no risk difference of MACCE between CAS and CEA for either CKD cohort. PMID- 27988088 TI - Biotransformation of bromhexine by Cunninghamella elegans, C. echinulata and C. blakesleeana. AB - Fungi is a well-known model used to study drug metabolism and its production in in vitro condition. We aim to screen the most efficient strain of Cunninghamella sp. among C. elegans, C. echinulata and C. blakesleeana for bromhexine metabolites production. We characterized the metabolites produced using various analytical tools and compared them with mammalian metabolites in Rat liver microsomes (RLM). The metabolites were collected by two-stage fermentation of bromhexine with different strains of Cunninghamella sp. followed by extraction. Analysis was done by thin layer chromatography, high performance thin layer chromatography, Fourier transform infrared spectroscopy, high performance liquid chromatography and Liquid chromatography-mass spectrometry. The role of Cytochrome P3A4 (CYP3A4) enzymes in bromhexine metabolism was studied. Fungal incubates were spiked with reference standard - clarithromycin to confirm the role of CYP3A4 enzyme in bromhexine metabolism. Three metabolites appeared at 4.7, 5.5 and 6.4min retention time in HPLC. Metabolites produced by C. elegans and RLM were concluded to be similar based on their retention time, peak area and peak response of 30.05%, 21.06%, 1.34%, and 47.66% of three metabolites and bromhexine in HPLC. The role of CYP3A4 enzyme in metabolism of bromhexine and the presence of these enzymes in Cunninghamella species was confirmed due to absence of peaks at 4.7, 5.4 and 6.7min when RLM were incubated with a CYP3A4 enzyme inhibitor - clarithromycin. PMID- 27988089 TI - Predictors of Mortality Among U.S. Veterans With Streptococcus Pneumoniae Infections. AB - INTRODUCTION: Serious Streptococcus pneumoniae infections, encompassing pneumonia, bacteremia, and meningitis, are a major cause of mortality. However, literature regarding mortality is often limited to invasive pneumococcal disease, excluding pneumonia. This study sought to identify predictors of mortality among adults with serious pneumococcal disease, including pneumonia and invasive pneumococcal disease. METHODS: This was a nested case-control study of unvaccinated older Veterans with positive S. pneumoniae cultures (blood, cerebrospinal fluid, respiratory) admitted to Veterans Affairs medical centers nationally between 2002 and 2011. Patients vaccinated against pneumococcal disease were excluded. Using multivariable logistic regression, predictors of 30 day mortality were identified, including patient demographics, comorbidities during admission, and medical history within the previous year. RESULTS: Among 9,468 patients, there were 9,730 serious pneumococcal infections; 1,764 (18.6%) resulted in death within 30 days (cases), whereas 7,966 did not (controls). Pneumonia accounted for half (49.4%, n=871) of all deaths. Mortality predictors consistent with vaccine recommendations included dialysis (during hospitalization, OR=3.35, 95% CI=2.37, 4.72), moderate to severe liver disease (during hospitalization, OR=2.47, 95% CI=1.53, 3.99; within 1 year, OR=1.49, 95% CI=1.01, 2.20), and neutropenia (during hospitalization, OR=2.67, 95% CI=1.32, 5.42). Predictors not included in current recommendations included dementia (during hospitalization, OR=1.8, 95% CI=1.23, 2.61) and neurologic disorders (during hospitalization, OR=1.86, 95% CI=1.42, 2.45; within 1 year, OR=1.28, 95% CI=1.02, 1.59). CONCLUSIONS: Several mortality predictors among unvaccinated Veterans with serious pneumococcal disease were consistent with pneumococcal vaccine recommendations, including organ or immune system dysfunction-related conditions. Other predictors, including neurologic disorders or dementia, may warrant expanded vaccination recommendations. PMID- 27988090 TI - Recent Findings on the Prevalence of E-Cigarette Use Among Adults in the U.S. AB - INTRODUCTION: This study uses a recent source of nationally representative data from in-person surveys to examine national estimates of e-cigarette use among adults and their relationship with demographic, socioeconomic, and health behavior measures. METHODS: Data were provided by the National Health Interview Survey, conducted by the Centers for Disease Control and Prevention. A total of 34,356 respondents aged >=18 years were examined for 2014, the most recent and only year in which the National Health Interview Survey included questions on e cigarette use. E-cigarette information included ever and current use. Univariate and multivariable logistic regression analyses were performed, adjusting for age, sex, race/ethnicity, education level, marital status, poverty, and smoking status. Analyses were conducted in 2016. RESULTS: Compared with those who had never tried e-cigarettes, e-cigarette users were more likely to be younger, male, non-Hispanic white, non-married, poorer, and current smokers. Multivariable logistic regression suggested that respondents with high school or some college education had significantly higher adjusted odds of ever using e-cigarettes relative to those with less than high school education. However, the adjusted odds were not significantly different for college or graduate school education. CONCLUSIONS: The results suggest that, unlike tobacco use, ever using e cigarettes is positively related to income. Interestingly, e-cigarette use exhibits a non-linear relationship with education. Reasons for the relationship of e-cigarettes with education are unclear and warrant further research. PMID- 27988091 TI - Pulmonary Complications After Open Abdominal Aortic Surgery: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Postoperative pulmonary complications (PPC) are among the most common complications after noncardiac surgery. Men, smokers, and elderly patients with chronic obstructive pulmonary disease or heart failure are more likely to experience PPC. The majority of patients undergoing vascular surgery belong in these categories and are at higher risk of developing PPC. Moreover, the surgical site is one of the most important risk factors associated with PPC, and aortic surgery carries the highest risk. The aim of this systematic review was to obtain an additional understanding of the real incidence of PPC after open abdominal aortic surgery and the impact of PPC on survival. DESIGN: Systematic review and meta-analysis. SETTING: Hospitals PARTICIPANTS: Patients who underwent open abdominal aortic surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A literature search was performed on BioMedCentral, PubMed, Embase, and the Cochrane Register of clinical trials. All prospective or retrospective studies reporting data on PPC after open abdominal aortic surgery were included. Co primary endpoints were the PPC rate and the correlation between PPC and perioperative mortality. The secondary endpoint was the difference in the PPC rate and mortality between elective and urgent surgery. Data on 269,637 patients from 213 studies were analyzed. The overall median incidence of PPC was 10.3% (interquartile range 5.55%-19.1%). Pneumonia, respiratory insufficiency, prolonged mechanical ventilation, need for unplanned mechanical ventilation, atelectasis, acute respiratory distress syndrome, pulmonary edema, and pleural effusions were the most common PPC reported in the literature. Occurrence of PPC was associated with postoperative mortality (r = 0.65, p<0.01) and was significantly higher in urgent procedures (p<0.001). CONCLUSIONS: Incidence of PPC after open abdominal aortic surgery is high and is associated with increased postoperative morbidity and mortality. PMID- 27988092 TI - Safety of Tranexamic Acid in Pediatric Cardiac Surgery: A Nationwide Database Study. AB - OBJECTIVES: The present study aimed to examine the association between tranexamic acid (TXA) use and adverse effects (seizures, thromboembolism, and renal dysfunction) in a pediatric cardiac surgery population using a national inpatient database in Japan. The authors also assessed the association between TXA use and other clinical outcomes (length of hospital stay and in-hospital mortality). DESIGN: A nationwide, retrospective cohort study using propensity score analyses. SETTING: Japanese Diagnosis Procedure Combination inpatient database. PARTICIPANTS: Pediatric patients who underwent cardiac surgery using cardiopulmonary bypass between July 2010 and March 2014 (N = 11,275). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Propensity-score matching created 3,739 pairs of patients with and without TXA administration. Propensity matched analysis showed that the proportion of seizures was significantly higher in the TXA group than in the non-TXA group (1.6% v 0.2%, difference, 1.4%; 95% confidence interval, 1.0-1.9; p<0.001). However, none of the other outcomes was significantly different between the groups. CONCLUSIONS: TXA use is associated with a significantly increased risk of seizures. However, there is no difference in any other outcomes between the TXA and non-TXA groups. PMID- 27988093 TI - The "Strengthen your ankle" program to prevent recurrent injuries: A randomized controlled trial aimed at long-term effectiveness. AB - OBJECTIVES: Recurrent ankle sprains can be reduced by a neuromuscular training program (NMT). The way NMT is delivered may influence the incidence of long term recurrent injuries, residual pain and disability. DESIGN: This RCT with a follow up of twelve months, evaluated whether the implementation method of a proven effective NMT program delivered by a mobile application or a written instruction booklet, resulted in differences in injury incidence rates, functional ankle disability/pain in the long term, assuming equal compliance - as is shown in previous research - with the 8-week intervention. METHODS: 220 athletes with a history of ankle sprain were recruited for this RCT. 110 athletes were offered the freely available "Strengthen your ankle App" and the other 110 received a printed Booklet. Primary outcome measure was incidence density of ankle sprains. Secondary outcome measures were residual pain/disability and the individual cumulative number of ankle sprains during follow-up. RESULTS: The incidence densities of self-reported ankle sprain recurrences were not significantly different between both groups (HR 1.06; 95% CI 0.76-1.49). Median FADI (Functional Ankle and Disability Index) scores increased equally over time in both groups, indicating a lower rate of limitation and pain in both groups at follow-up. Neither FADI scores nor cumulative recurrent injuries were significantly different between groups. CONCLUSIONS: This study showed that the implementation method of a NMT program by using an App or a Booklet did neither lead to different injury incidence rates in the long term nor did it influence residual functional disability/pain. Assuming equal compliance during the 8-week intervention, both methods show similar effectiveness in twelve-month follow-up. PMID- 27988094 TI - Human schistosomiasis in the post mass drug administration era. AB - Profound changes are occurring in the epidemiology of schistosomiasis, a neglected tropical disease caused by a chronic infection with parasitic helminths of the genus Schistosoma. Schistosomiasis currently affects 240 million people worldwide, mostly in sub-Saharan Africa. The advent and proliferation of mass drug administration (MDA) programmes using the drug praziquantel is resulting in substantial increases in the number of people, mainly children aged 6-14 years, being effectively treated, approaching the point where most people in endemic areas will receive one or more treatments during their lifetimes. Praziquantel treatment not only cures infection but also frees the host from the powerful immunomodulatory action of the parasites. The treatment simultaneously enhances exposure to key parasite antigens, accelerating the development of protective acquired immunity, which would take many years to develop naturally. At a population level, these changes constitute a substantial alteration to schistosome ecology in that the parasites are more likely to be exposed not only to praziquantel directly but also to hosts with altered immune phenotypes. Here, we consider the consequences of this for schistosome biology, immunoepidemiology, and public health. We anticipate that there could be substantial effects on chronic pathology, natural immunity, vaccine development strategies, immune disorders, and drug efficacy. This makes for a complex picture that will only become apparent over decades. We recommend careful monitoring and assessment to accompany the roll-out of MDA programmes to ensure that the considerable health benefits to populations are achieved and sustained. PMID- 27988095 TI - Toxoplasma gondii: One Organism, Multiple Models. AB - Toxoplasma gondii is an intensely studied protozoan parasite. It is also used as a model organism to research additional clinically relevant human and veterinary parasites due to ease of in vitro culture and genetic manipulation. Recently, it has been developed as a model of inflammatory bowel disease, due to their similar pathologies. However, researchers vary widely in how they use T. gondii, which makes study comparisons and interpretation difficult. The aim of this review is to provide researchers with a tool to: (i) determine the appropriateness of the different T. gondii models to their research, (ii) interpret results from the wide range of study conditions, and (iii) consider new advances in technology which could improve or refine their experimental setup. PMID- 27988096 TI - Ribosome Assembly in Trypanosomatids: A Novel Therapeutic Target. AB - In Liu et al., the authors present a 2.5-A structure of the Trypanosoma cruzi 60S ribosomal subunit and propose a model for the stepwise assembly of the large subunit ribosomal RNA (rRNA). Based on this study, we discuss how the unique features of trypanosomatid ribosome assembly offer potential drug targets. PMID- 27988099 TI - Erratum. PMID- 27988097 TI - Parasites Dampen Dendritic Cell Activation to Ensure Their Survival. AB - Dendritic cells (DCs) are critical for induction of protective immunity against Leishmania major. However, DC activation occurs only several weeks after parasite transmission. Parasites synthesize a macrophage-inducible C-type lectin (Mincle) ligand. Engagement of Mincle by the parasite ligand dampens DC activation, thus delaying induction of interferon-gamma-producing T cells responsible for parasite eradication. PMID- 27988098 TI - Targeting MET Exon 14 Skipping Alterations: Has Lung Cancer MET Its Match? PMID- 27988100 TI - Trials and Tribulations of EGFR and MET Inhibitor Combination Therapy in NSCLC. PMID- 27988101 TI - False-Negative MRI Findings for Leptomeningeal Metastases with Use of Bevacizumab. PMID- 27988102 TI - Little Influence of Bevacizumab in Diagnosis of Leptomeningeal Metastases in Current Study. PMID- 27988103 TI - Rapid Acquisition of T790M Mutation after Treatment with Afatinib in an NSCLC Patient Harboring EGFR Exon 20 S768I Mutation. PMID- 27988104 TI - Postoperative Radiotherapy in Completely Resected Stage II and III Thymoma: How to Translate the Potential Survival Benefit in the Setting of the Future Adoption of the IASLC-ITMIG TNM-Based Staging System. PMID- 27988105 TI - Corrigendum to "The role of hepassocin in the development of non-alcoholic fatty liver disease". PMID- 27988106 TI - External factors influencing mesenchymal stem cell fate in vitro. AB - Mesenchymal stem cells (MSCs) have extensive potentials, which make them attractive candidates for the developmental biology, drug discovery and regenerative medicine. However, the use of MSCs is limited by their scarceness in tissues and in culture conditions. They also exhibit various degrees of potency which subsequently influencing their applications. Nowadays, questions remain about how self-renewal and differentiation of MSCs can be controlled in vitro and in vivo, how they will behave and migrate to the right place and how they modulate the immune system. Therefore, identification of factors and culture conditions to affect the fate and function of MSCs may be effective to enhance their applications in clinical situations. Studies have indicated that the fate of MSCs in culture is influenced by various external factors, including the specific cell source, donor age, plating density, passage number and plastic surface quality. Some other factors such as cell culture media and their supplementary factors, O2 concentration, mechano-/electro-stimuli and three dimensional scaffolds are also shown to be influential. This review addresses the current state of MSC research for describing and discussing the findings about external factors that influence the fate and function of MSCs. Additionally, the new discoveries and suggestions regarding their molecular mechanisms will be explained. PMID- 27988107 TI - Understanding psychogenic nonepileptic seizures-Phenomenology, semiology and the Integrative Cognitive Model. AB - Psychogenic Nonepileptic Seizures (PNES) are one of the commonest differential diagnoses of epilepsy. This paper provides a narrative review of what has been learnt in the last 25 years regarding the visible manifestations, physiological features, subjective experiences and interactional aspects of PNES. We then explore how current insights into PNES semiology and phenomenology map onto the Integrative Cognitive Model (ICM), a new account of these phenomena that unifies previous approaches within a single explanatory framework. We discuss to what extent recent psychological and neurophysiological research is consistent with the ICM and indicate how the more detailed analysis of physiological data, connectivity analyses of EEG and functional or structural MRI data may provide greater insights into the biopsychosocial underpinnings of a disabling and under researched disorder. PMID- 27988108 TI - Parents' Traditional Cultural Values and Mexican-Origin Young Adults' Routine Health and Dental Care. AB - PURPOSE: To investigate the prospective associations between Mexican-origin mothers' and fathers' traditional cultural values and young adults' health and dental care utilization and to test the moderating role of youth gender. METHODS: Mexican-origin parents and youth (N = 246 families) participated in home interviews and provided self-reports of parents' cultural values (time 1) and young adults' health status and routine health and dental care (time 2; 5 years later). Logistic regressions tested parents' traditional cultural values as predictors of routine health and dental care, accounting for parent nativity, parent acculturation, family socioeconomic status, youth gender, youth age, and youth physical health status. We also tested whether youth gender moderated the associations between parents' cultural values and young adults' routine care. RESULTS: Young adults whose mothers endorsed strong familism values when they were in mid-to-late adolescence were more likely to report at least one routine physician visit in the past year as young adults (odds ratio [OR] = 3.47, 95% confidence interval [CI]: 1.23-9.83, p = .019). Furthermore, for females only, mothers' more traditional gender role attitudes predicted reduced odds of receiving routine health (OR = .22; 95% CI: .08-.64, p = .005) and dental care (OR = .26; 95% CI: .09-.75, p < .012) in young adulthood. CONCLUSIONS: Our findings highlight the importance of examining intragroup variability in culturally specific mechanisms to identify targets for addressing ethnic/racial disparities in health care utilization among Mexican-origin young adults, during a period of increased risk for health-compromising behaviors and reduced access to care. PMID- 27988109 TI - Receptor Tyrosine Kinases: Translocation Partners in Hematopoietic Disorders. AB - Receptor tyrosine kinases (RTKs) activate various signaling pathways and regulate cellular proliferation, survival, migration, and angiogenesis. Malignant neoplasms often circumvent or subjugate these pathways by promoting RTK overactivation through mutation or chromosomal translocation. RTK translocations create a fusion protein containing a dimerizing partner fused to an RTK kinase domain, resulting in constitutive kinase domain activation, altered RTK cellular localization, upregulation of downstream signaling, and novel pathway activation. While RTK translocations in hematological malignancies are relatively rare, clinical evidence suggests that patients with these genetic abnormalities benefit from RTK-targeted inhibitors. Here, we present a timely review of an exciting field by examining RTK chromosomal translocations in hematological cancers, such as Anaplastic Lymphoma Kinase (ALK), Fibroblast Growth Factor Receptor (FGFR), Platelet-Derived Growth Factor Receptor (PDGFR), REarranged during Transfection (RET), Colony Stimulating Factor 1 Receptor (CSF1R), and Neurotrophic Tyrosine Kinase Receptor Type 3 (NTRK3) fusions, and discuss current therapeutic options. PMID- 27988110 TI - The effect of by-product inclusion level on milk production, nutrient digestibility and excretion, and rumen fermentation parameters in lactating dairy cows offered a pasture-based diet. AB - The objective of this study was to investigate the effects of replacing barley and soybean meal with increasing levels of by-products on production, digestive, and metabolic parameters in early-mid lactation dairy cows offered perennial ryegrass-based pasture. Forty-eight (32 multiparous and 16 primiparous) dairy cows that were 64 +/- 24 d in milk were assigned to 1 of 4 pasture-based dietary treatments (n = 12) in a randomized block design experiment that ran for 70 d. Treatments consisted of a perennial ryegrass-based pasture and 1 of 4 supplementary concentrates: BP35, BP55, BP75, and BP95 containing 35, 55, 75, and 95% by-products, respectively, in the concentrate on a dry matter basis. The by products used were soyhulls, dried distillers grains, and palm kernel extract in equal proportions. Barley and soybean meal were replaced as by-product inclusion level increased. In this study, intakes of pasture dry matter (15.7 kg) and total dry matter (21.1 kg) were not affected by treatment. Similarly, milk production parameters (milk yield, milk composition, somatic cell count, and urea) were not different between treatments. Unsaturated fatty acids were lower in the milk of cows offered BP35 and BP55 compared with those offered BP75 and BP95. Concentrations of beta-hydroxybutyrate, nonesterified fatty acids, and other blood metabolites were within normal range and did not differ between treatments, and cow body condition score and body weight were also not different. Equally, N was unaffected by diet. Blood urea N was lower in the BP75 group compared with BP35. This study demonstrated that barley and soybean meal can be replaced with soyhulls, dried distillers grains, and palm kernel extract without affecting milk production, digestive, or metabolic parameters in dairy cows offered a pasture based diet. PMID- 27988111 TI - Diagnostic accuracy of a standardized scheme for identification of Streptococcus uberis in quarter milk samples: A comparison between conventional bacteriological examination, modified Rambach agar medium culturing, and 16S rRNA gene sequencing. AB - Bacteriological examination of milk samples is a prerequisite for pathogen specific therapy and aids in limiting antimicrobial resistance. The aims of this study were to establish a standardized scheme for reliable Streptococcus uberis identification in routine diagnosis and to evaluate the accuracy of conventional tests and growing patterns of Strep. uberis on a selective medium (modified Rambach agar medium, MRAM) using 16S rRNA gene sequencing analysis as a reference method. We obtained isolates of presumptive Strep. uberis (n = 336) from quarter milk samples of dairy cows with intramammary infections and classified the isolates into 2 clusters using biochemical characterization. In cluster 1 (n = 280), cocci grew as non-hemolytic colonies, hydrolyzing esculin, carrying no Lancefield antigen (A/B/C/D/G) or Christie Atkins Munch-Petersen factor, and their growth was inhibited on an Enterococcus agar. Production of beta-d galactosidase on MRAM was shown by 257 of the cluster 1 isolates (91.79%), and 16S rRNA gene sequencing verified 271 (96.79%) of the isolates to be Strep. uberis. In 264 isolates (94.29%), MRAM agreed with the sequencing results. In cluster 2 (n = 56), isolates showed different characteristics: 37 (66.07%) were beta-d-galactosidase-positive, and based on 16S sequencing results, 36 (64.29%) were identified correctly as Strep. uberis using biochemical methods. Identification success in this group differed significantly between routine diagnosis and MRAM application: MRAM agreed with sequencing results in 47 isolates (83.93%). To identify Strep. uberis and differentiate it from other lactic acid bacteria in routine diagnosis, we suggest using catalase reaction, hemolysis, esculin hydrolysis, and growth on enterococci agar. Isolates that show a typical biochemical profile can be identified satisfactorily with these tests. For Strep. uberis isolates with divergent patterns, application of MRAM as a follow-up test increased the diagnostic accuracy to 94.64%. PMID- 27988112 TI - Addition of sodium caseinate to skim milk increases nonsedimentable casein and causes significant changes in rennet-induced gelation, heat stability, and ethanol stability. AB - The protein content of skim milk was increased from 3.3 to 4.1% (wt/wt) by the addition of a blend of skim milk powder and sodium caseinate (NaCas), in which the weight ratio of skim milk powder to NaCas was varied from 0.8:0.0 to 0.0:0.8. Addition of NaCas increased the levels of nonsedimentable casein (from ~6 to 18% of total casein) and calcium (from ~36 to 43% of total calcium) and reduced the turbidity of the fortified milk, to a degree depending on level of NaCas added. Rennet gelation was adversely affected by the addition of NaCas at 0.2% (wt/wt) and completely inhibited at NaCas >=0.4% (wt/wt). Rennet-induced hydrolysis was not affected by added NaCas. The proportion of total casein that was nonsedimentable on centrifugation (3,000 * g, 1 h, 25 degrees C) of the rennet treated milk after incubation for 1 h at 31 degrees C increased significantly on addition of NaCas at >=0.4% (wt/wt). Heat stability in the pH range 6.7 to 7.2 and ethanol stability at pH 6.4 were enhanced by the addition of NaCas. It is suggested that the negative effect of NaCas on rennet gelation is due to the increase in nonsedimentable casein, which upon hydrolysis by chymosin forms into small nonsedimentable particles that physically come between, and impede the aggregation of, rennet-altered para-casein micelles, and thereby inhibit the development of a gel network. PMID- 27988113 TI - Short communication: Analytical method and amount of preservative added to milk samples may alter milk urea nitrogen measurements. AB - Milk urea N (MUN) is used by dairy nutritionists and producers to monitor dietary protein intake and is indicative of N utilization in lactating dairy cows. Two experiments were conducted to explore discrepancies in MUN results provided by 3 milk processing laboratories using different methods. An additional experiment was conducted to evaluate the effect of 2-bromo-2-nitropropane-1, 3-diol (bronopol) on MUN analysis. In experiment 1, 10 replicates of bulk tank milk samples, collected from the Pennsylvania State University's Dairy Center over 5 consecutive days, were sent to 3 milk processing laboratories in Pennsylvania. Average MUN differed between laboratory A (14.9 +/- 0.40 mg/dL; analyzed on MilkoScan 4000; Foss, Hillerod, Denmark), laboratory B (6.5 +/- 0.17 mg/dL; MilkoScan FT + 6000), and laboratory C (7.4 +/- 0.36 mg/dL; MilkoScan 6000). In experiment 2, milk samples were spiked with urea at 0 (7.3 to 15.0 mg/dL, depending on the laboratory analyzing the samples), 17.2, 34.2, and 51.5 mg/dL of milk. Two 35-mL samples from each urea level were sent to the 3 laboratories used in experiment 1. Average analyzed MUN was greater than predicted (calculated for each laboratory based on the control; 0 mg of added urea): for laboratory A (23.2 vs. 21.0 mg/dL), laboratory B (18.0 vs. 13.3 mg/dL), and laboratory C (20.6 vs. 15.2 mg/dL). In experiment 3, replicated milk samples were preserved with 0 to 1.35 mg of bronopol/mL of milk and submitted to one milk processing laboratory that analyzed MUN using 2 different methods. Milk samples with increasing amounts of bronopol ranged in MUN concentration from 7.7 to 11.9 mg/dL and from 9.0 to 9.3 mg/dL when analyzed on MilkoScan 4000 or CL 10 (EuroChem, Moscow, Russia), respectively. In conclusion, measured MUN concentrations varied due to analytical procedure used by milk processing laboratories and were affected by the amount of bronopol used to preserve milk sample, when milk was analyzed using a mid infrared analyzer. Thus, it is important to maintain consistency in milk sample preservation and analysis to ensure precision of MUN results. PMID- 27988114 TI - Lactation and body composition responses to fat and protein supplies during the dry period in under-conditioned dairy cows. AB - An experiment was designed to study the effect of precalving supplementation with protein (Pr) and rumen-inert fat (F) on body composition and subsequent milk production and composition. Forty Holstein-Friesian dairy cows were allocated to 1 of 4 dietary treatments in the dry period (DP) based on a first-cut ryegrass silage, with 6 mature (in their third or greater pregnancy) and 4 young (in their second pregnancy) cows per treatment. These were low Pr, low F (silage alone); low Pr, high F (silage with 10% rumen-inert fat, mixed on a dry matter basis); high Pr, low F [silage with 5% high-protein corn gluten meal (CGM)]; and high Pr, high F (silage with 5% CGM and 10% rumen-inert fat). All the diets were individually offered ad libitum and dry matter intake (DMI) was recorded daily during the DP. After calving, all cows received ryegrass silage plus 8 kg/d of a commercial dairy concentrate. During the DP, DMI was higher for mature than for young cows. All animals recovered body condition score (0.13 units/wk, 1-5 scale), reaching a maximum score of 2.4 some days before calving. Precalving maximum muscle longissimus dorsi (LD) depth was greater for mature (47.5 mm) than for young cows (45.7 mm), and milk fat concentration was also higher for mature than for young cows (40.2 and 39.0 g/kg, respectively). Supplementation with CGM increased maximum LD depth (from 45.9 to 47.6 mm), calf birth weight (low Pr = 43.2, high Pr = 46.3 kg), and milk crude protein concentration (from 30.8 to 31.6 g/kg). Fat supplementation in the DP of the mature cows increased maximum back fat depth (from 3.6 to 4.5 mm), milk yield (low F = 26.3, high F = 28.7 kg/d), and Pr yields (low F = 837, high F = 899 g/d). Inclusion of F in the DP diets reduced casein concentration in milk at wk 3 of lactation from 26.3 to 24.5 g/kg. Milk CP yield was also increased by CGM supplementation when compared within cows receiving F-supplemented silages (low Pr, high F = 832 g/d; high Pr, high F= 877 g/d). It can be concluded that CGM supplementation in the DP increased subsequent milk Pr concentration, but milk Pr yield increased only in those animals also receiving F supplementation. Dry period diet supplementation with F increased maximum back fat depth and milk and CP yields in the mature cows, and led to more LD muscle mobilization during early lactation. Second-calving cows had a lower DMI and milk fat concentration than mature cows. PMID- 27988115 TI - Effects of dietary physically effective neutral detergent fiber content on the feeding behavior, digestibility, and growth of 8- to 10-month-old Holstein replacement heifers. AB - The objective of this study was to evaluate the effects of dietary physically effective neutral detergent fiber (peNDF) content on the feeding behavior, digestion, ruminal fermentation parameters, and growth of 8- to 10-mo-old dairy heifers and to predict the adequacy of dietary fiber in growing dairy heifers. Twenty-four Holstein dairy heifers (245 +/- 10.8 d of age, 305.6 +/- 8.5 kg initial live weight) were randomly divided into 4 treatments with 6 replicates as a completely randomized design. During the 60-d period with a 10-d adaptation, heifers were offered 1 of 4 diets, which were chemically identical but included different peNDF8.0 (particle size is >8 mm and <19 mm) content (% DM): 10.8, 13.5, 18.0, or 19.8%, which was achieved by chopping forage into different lengths (fine = 1 cm, short = 3 cm, medium = 5 cm, and long = 7 cm). The concentrate and silage were mixed and fed restrictedly and exclusive of forage (Chinese ryegrass hay) were offered ad libitum. The body weight and frame size of the heifers were measured every 15 d during the experimental period. Samples of the rumen content (2 h after the morning feeding) were taken for pH, ammonia, and volatile fatty acid determination. The dry matter intake and average daily gain of the heifers were not significantly affected by peNDF8.0 content. The body frame size (including withers height, body length, and heart girth) of the heifers was not increased significantly by enhanced peNDF8.0 content. Ruminal pH and ammonia concentration were both increased with increasing dietary peNDF8.0 content. The ruminal total volatile fatty acid concentration and percentage of acetate and butyrate profiles were not significantly affected by dietary peNDF8.0 content. However, the enhanced peNDF8.0 content led to a decrease in the propionate percentage. The ratio of acetate to propionate in the 13.5% treatment was highest among the treatments. Increasing the particle size and dietary peNDF8.0 content resulted in increased eating and chewing time but had no effect on rumination time. Heifer total eating and chewing time and eating and chewing time per kilogram of dry matter intake were increased with increasing dietary peNDF8.0 content. The apparent digestibility of acid detergent fiber and crude protein was improved with an increasing content of dietary peNDF8.0. The results suggest that an optimal or advisable dietary particle size and peNDF8.0 content improves chewing activity, rumen fluid pH, and ruminal fermentation. The data based on feeding behavioral and growth responses of heifers as well as rumen fermentation and digestion by improving total eating and chewing time indicate that 18.0% dietary peNDF8.0 content is the most suitable for 8- to 10-mo-old Holstein heifers. PMID- 27988116 TI - Effect of gradual or abrupt cessation of milking at dry off on milk yield and somatic cell score in the subsequent lactation. AB - The objective of this study was to assess the effect of milk cessation method (abrupt or gradual) at dry off on milk yield and somatic cell score (SCS) up to 120 d in milk during the subsequent lactation. Data from 428 cows from 8 dairy herds in Ohio were analyzed. Abrupt cessation cows kept the farm's regular milking schedule (2 or 3 times) through dry off and gradual cessation cows were milked once daily for the final week of lactation. Milk yield and SCS were collected using Dairy Herd Improvement Association test-day records. Aseptic quarter milk samples were collected approximately 1 wk before dry off, at dry off, and within 1 wk after calving for bacterial culture to determine the presence of intramammary infections. Overall, milk cessation method was not significantly associated with either milk yield or SCS in early lactation; however, interaction between the milk cessation method and herd was highly significant. Cows producing greater amounts of milk around dry off had significantly higher SCS in the following lactation. Shorter dry periods were significantly associated with decreased milk yield in the following lactation, especially among abruptly dried off cows. Additionally, as expected, several other factors, such as parity of cows and stage of lactation, were significantly associated with both outcomes. No interactions between the milk cessation method and the other explanatory variables in the final models were significant. The results of the current study suggest that higher milk yield at dry off was associated with higher SCS in the following lactation, even though milk cessation method at the end of lactation had a varying effect on test-day milk yield and SCS in different herds during the first 120 d in milk in the following lactation. The specific herd characteristics influencing this could not be identified within this study, warranting further research. PMID- 27988117 TI - Technical note: Mammary gland ultrasonography to evaluate mammary parenchymal composition in prepubertal heifers. AB - Bovine mammary gland development studies are often terminal or involve invasive biopsy procedures. Therefore, noninvasive means of assessing mammary development should be considered as alternative methods in live animals. The objective was to test if mammary ultrasonography can be used as a noninvasive way to estimate mammary parenchyma (PAR) composition in prepubertal dairy heifers with different average daily body weight gains. In the 84 d preceding, the ultrasound exam heifers were maintained in 1 of 3 treatment groups. Individual heifers were fed a high gain (1 kg/d; n = 6), low gain (0.5 kg/d, n = 6), or maintenance (n = 6) treatment diet. To achieve desired body weight gains, heifers were fed differing amounts of the same silage-based diet. Mammary glands of 18 crossbred heifers Holstein:Gyr underwent a single mammary ultrasound exam immediately before heifer slaughter, which took place when heifers weighed 142.0 +/- 8.0 kg and were 200 d old. The 4 mammary glands of each heifer were evaluated using a real-time B-mode ultrasound machine equipped with a 6.5-MHz micro-convex transducer. Digital images (8-bit) of glands were obtained and PAR was identified within gland. Average pixel values per unit of PAR area were determined for each gland and analyzed at the level of heifer. Pixel results were interpreted on the basis that lower average pixel values reflect PAR with relatively high amounts of protein as opposed to fat. To help validate that the pixel value within PAR is associated with composition of PAR, pixel findings were compared with histological [number of adipocytes in PAR (Nad) and epithelial area in PAR (Ep)] and biochemical [percent crude protein in PAR (%CP), percent ether extract in PAR (%EE), PAR weight (WPAR), and mammary fat pad weight (WFAT)] composition of PAR in these same heifers. Within PAR, %EE and WFAT were positively correlated with pixel values, whereas %CP, Ep, and Nad were negatively correlated. Parenchyma weight did not correlate with pixel values. Regression analyses (fixed effect log-pixel value; random effect treatment) were used to estimate Nad, Ep, %CP, %EE, WPAR, and WFAT. Sensitivity analysis of regression equations revealed that accuracy of tested equations ranged from 0.77 to 0.93 and precision ranged from 0.56 to 0.82. Concordance correlation coefficients of the equations ranged from 0.41 to 0.76. In conclusion, ultrasonography of PAR can accurately measure and predict PAR composition in prepubertal dairy heifers growing at various rates of gain. PMID- 27988118 TI - Effects of feeding betaine-containing liquid supplement to transition dairy cows. AB - Betaine is a natural compound found in sugar beets that serves as a methyl donor and organic osmolyte when fed to animals. The objective was to evaluate the effect of feeding betaine-containing molasses on performance of transition dairy cows during late summer in 2 trials. In early September, cows were randomly assigned to betaine (BET) or control (CON) groups either shortly after dry off (trial 1; n = 10 per treatment) or 24 d before calving (trial 2; n = 8 per treatment) based on parity and previous mature equivalent milk yield. Cows were fed common diets supplemented either with a liquid supplement made of molasses from sugar cane and condensed beet solubles containing betaine [BET, 89.1 g/kg of dry matter (DM)] or a sugar cane molasses-based liquid supplement without betaine (CON) until 8 wk postpartum. The liquid supplements had similar nutrient contents and were fed at a rate of 1.1 and 1.4 kg DM/d for pre- and postpartum cows, respectively. Starting at their entry in the studies, cows were housed in the same freestall barn without a cooling system. After calving, all cows were housed in the same barn cooled by misters and fans and milked thrice daily. Intake was recorded daily and body weight and body condition score were assessed every 2 wk. Milk yield was recorded at each milking and composition was analyzed weekly. Blood samples were collected weekly from a subset of cows to assess concentrations of metabolites and AA. No treatment effects were apparent for DM intake and body weight in the prepartum and postpartum periods. For cows enrolled at dry off, BET supported higher milk yield (45.1 vs. 41.9 kg/d) and fat content (4.78 vs. 4.34%) and elevated plasma concentrations of nonesterified fatty acids and beta-hydroxybutyrate in early lactation compared to CON. However, no differences were observed for milk yield, most milk component contents and yields, and blood metabolites between treatments for cows enrolled during the close-up period. Compared to cows in the CON group, BET cows enrolled during the far-off period tended to have lower plasma concentrations of Met, Thr, and Trp during the pre- and postpartum periods. They also had lower plasma concentrations of Lys and Phe before calving but higher plasma Gly concentration after parturition. In conclusion, feeding a betaine-containing liquid supplement from far-off through early lactation improves lactation performance but increases adipose tissue mobilization and production of ketone bodies in early lactation. PMID- 27988119 TI - Rumination time and reticuloruminal temperature as possible predictors of dystocia in dairy cows. AB - The objectives of this study were to explore changes of rumination time and reticuloruminal pH and temperature of dairy cows and heifers (means +/- standard deviation; age = 5.8 +/- 1.9; parity = 2.7 +/- 1.4; body condition score = 3.2 +/ 0.2) with eutocic (EUT, n = 10) and dystocic calving (DYS, n = 8). The recording period lasted from 3 d before calving until 7 d in milk. For the comparison of rumination time and reticuloruminal characteristics between groups, time to return to baseline (the time interval required to return to baseline from the delivery of the calf) and area under the curve (AUC; both for prepartum and postpartum periods) were calculated for each parameter. Rumination time decreased from baseline 28 h before calving both for EUT and DYS cows; after 20 h before calving, it decreased to 32.4 +/- 2.3 and 13.2 +/- 2.0 min/4 h between 8 and 4 h before delivery in EUT and DYS cows, respectively, and then it decreased below 10 and 5 min during the last 4 h before calving. Until 12 h after delivery, rumination time reached 42.6 +/- 2.7 and 51.0 +/- 3.1 min/4 h in DYS and EUT dams, respectively; however, AUC and time to return to baseline suggested lower rumination activity in DYS cows than in EUT dams for the 168-h postpartum observational period. Reticuloruminal pH decreased from baseline 56 h before calving both for EUT and DYS cows, but did not differ between groups before delivery. Reticuloruminal pH showed a decreasing tendency and clear diurnal variation after calving for both EUT and DYS cows, with slightly higher AUC values in DYS cows. In DYS cows, reticuloruminal temperature decreased from baseline 32 h before calving by 0.23 +/- 0.02 degrees C, whereas in EUT cows such a decrease was found only 20 h before delivery (0.48 +/- 0.05 degrees C). The AUC of reticuloruminal temperature calculated for the prepartum period was greater in EUT cows than in DYS cows. During the first 4 h after calving, reticuloruminal temperature decreased from 39.68 +/- 0.09 to 38.96 +/- 0.10 degrees C and from 39.80 +/- 0.06 to 38.81 +/- 0.08 degrees C in EUT and DYS cows, respectively, and reached baseline levels after 35.4 +/- 3.4 and 37.8 +/- 4.2 h after calving in EUT and DYS cows, respectively. Based on our results, continuous monitoring of changes in rumination time and reticuloruminal temperature seems to be promising in the early detection of cows with a higher risk of dystocia. Depressed rumination activity of DYS cows after calving highlights the importance of the postpartum monitoring of cows experiencing difficulties at calving. The effect of dystocia on postpartum reticuloruminal pH was not pronounced. PMID- 27988120 TI - Isolation and genetic identification of spore-forming bacteria associated with concentrated-milk processing in Nebraska. AB - Spore-forming bacteria are heat-resistant microorganisms capable of surviving and germinating in milk after pasteurization. They have been reported to affect the quality of dairy products by the production of enzymes (lipolytic and proteolytic) under low-temperature conditions in fluid milk, and have become a limiting factor for milk powder in reaching some selective markets. The objective of this research was to isolate and identify the population of spore-forming bacteria (psychrotrophic and thermophilic strains) associated with concentrated milk processing in Nebraska. During 2 seasons, in-process milk samples from a commercial plant (raw, pasteurized, and concentrated) were collected and heat treated (80 degrees C/12 min) to recover only spore-formers. Samples were spread plated using standard methods agar and incubated at 32 degrees C to enumerate mesophilic spore counts. Heat-treated samples were also stored at 7 degrees C and 55 degrees C to recover spore-formers that had the ability to grow under those temperature conditions. Isolates obtained from incubation or storage conditions were identified using molecular techniques (16S or rpoB sequencing). Based on the identification of the isolates and their relatedness, strains found in raw, pasteurized, and concentrated milk were determined to be similar. Paenibacillus spp. were associated with both raw and concentrated milk. Due to their known ability to cause spoilage under refrigeration, this shows the potential risk associated with the transferring of these problematic organisms into other dairy products. Other Bacillus species found in concentrated milk included Bacillus clausii, Bacillus subtilis, Lysinibacillus sp., Bacillus safensis, Bacillus licheniformis, Bacillus sonorensis, and Brevibacillus sp., with the last 3 organisms being capable of growing at thermophilic temperatures. These strains can also be translocated to other dairy products, such as milk powder, representing a quality problem. The results of this research highlight the importance of understanding spore-formers associated with the processing of condensed milk, which then may allow for specific interventions to be applied to control these microorganisms in this processing chain. To our knowledge, this is the first study evaluating spore-formers associated with concentrated milk in the United States. PMID- 27988121 TI - Enterococcus faecium and Enterococcus durans isolated from cheese: Survival in the presence of medications under simulated gastrointestinal conditions and adhesion properties. AB - In this study, we evaluated the survival of Enterococcus faecium and Enterococcus durans, isolated from cheese, in the presence of medications and under simulated in vitro gastrointestinal conditions. The presence of genes encoding virulence factors, the susceptibility to antimicrobial agents, and adhesion properties were also assessed. Enterococcus faecium and E. durans both exhibited resistance to most of the tested medications but showed a large sensitivity to analgesics and antihypertensives; they also showed wide susceptibility to antimicrobial agents. Enterococcus durans SJRP29 had greater resistance to the presence of medications in comparison with the probiotic Lactobacillus acidophilus La-5. The strains, except for E. durans SJRP05, did not harbor virulence genes. Enterococcus durans SJRP14, SJRP17, and SJRP26 were sensitive to all tested antimicrobial agents. Enterococcus faecium was more stable during the simulation of gastrointestinal tract and showed greater viability. At the end of the assay, except for E. durans SJRP17, all strains showed high viability (>7 log cfu/mL). Enterococcus durans SJRP29 stood out from the other strains and was selected for further evaluation; it tolerated up to 3.0% NaCl at 30 and 37 degrees C, besides having good adhesion properties (high values of auto-aggregation, co-aggregation, and hydrophobicity). Additionally, the microorganism did not show bile salt hydrolase activity or mucin degradation. These results encourage carrying out additional tests to evaluate the probiotic features by using in vitro dynamic models and in vivo tests before applying these strains to a food system. PMID- 27988122 TI - Deciphering upper respiratory tract microbiota complexity in healthy calves and calves that develop respiratory disease using shotgun metagenomics. AB - Bovine respiratory disease (BRD) is a multifactorial disorder responsible for severe economic losses in dairy and feedlot herds. Advances in next-generation sequencing mean that microbial communities in clinical samples, including non culturable bacteria, can be characterized. Our aim was to evaluate the microbiota of the upper respiratory tract of healthy calves and calves with BRD using whole genome sequencing (shotgun metagenomics). We performed deep nasopharyngeal swabs on 16 Holstein heifer calves (10 healthy and 6 diagnosed with BRD during the study) at 14 and 28 d of life in 1 dairy herd near Ithaca, New York. Total DNA was extracted, and whole-genome sequencing was performed using the MiSeq Illumina platform (Illumina Inc., San Diego, CA). Samples included 5 predominant phyla: Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, and Tenericutes. At the genus level, we observed differences between groups for Pseudomonas spp. At the species level, Mannheimia haemolytica was the most abundant bacterium detected. We detected significant differences between groups of calves in the relative abundance of Pseudomonas fluorescens. Pasteurella multocida was among the 20 most abundant species, and Moraxella catarrhalis, commonly associated with pneumonia in humans, was detected in all groups. Analysis of resistance to antibiotics and compounds profiling revealed differences in cobalt-zinc-cadmium resistance. Further research to elucidate the role of Moraxella catarrhalis in BRD is warranted. Genes that were resistant to cobalt-zinc-cadmium, observed mostly in calves with BRD, might be associated with difficulties in antibiotic treatment. PMID- 27988123 TI - Short communication: Inhibition of angiotensin 1-converting enzyme by peptides derived from variants of bovine beta-casein upon apical exposure to a Caco-2 cell monolayer. AB - This study investigated the consequence of genetically contingent amino acid substitutions in bovine beta-casein (CN) genetic variants A1, A2, B, and I on the structure and bioactive potential of peptides following in vitro digestion. The beta-CN variants were digested in vitro using pepsin and pancreatin, and a peptide profile was obtained by liquid chromatography tandem mass spectrometry, revealing among others, the beta-casomorphin precursor peptides VYPFPGPIHN and VYPFPGPIPN, derived from variant A1/B and from A2/I, respectively. These 2 peptides were synthesized and assessed for angiotensin 1-converting enzyme (ACE) inhibitory capacity before and after incubation with a monolayer of Caco-2 intestinal cells. The VYPFPGPIHN was a stronger ACE inhibitor than VYPFPGPIPN, with the concentration needed to reach half-maximal inhibition (IC50) of 123 +/- 14.2 MUM versus 656 +/- 7.6 MUM. Exposure to a Caco-2 intestinal cell monolayer did not affect ACE inhibition by VYPFPGPIHN, but resulted in an almost 2-fold increase in inhibition by VYPFPGPIPN after incubation. Subsequent tandem mass spectrometric analysis identified the truncated peptide VYPFPGPIP, suggesting hydrolysis by a cell membrane associated peptidase. Thus, genetic variation in bovine beta-CN results in the generation of peptides that differ in bioactivity, and are differently affected by intestinal brush border peptidases. PMID- 27988124 TI - Increased serum serotonin improves parturient calcium homeostasis in dairy cows. AB - Hypocalcemia in dairy cows is caused by the sudden increase in calcium demand by the mammary gland for milk production at the onset of lactation. Serotonin (5-HT) is a key factor for calcium homeostasis, modulating calcium concentration in blood. Therefore, it is hypothesized that administration of 5-hydroxy-l tryptophan (5-HTP), a 5-HT precursor, can increase 5-HT concentrations in blood and, in turn, induce an increase in blood calcium concentration. In this study, 20 Holstein dairy cows were randomly assigned to 2 experimental groups. Both groups received a daily i.v. infusion of 1 L of either 0.9% NaCl (C group; n = 10) or 0.9% NaCl containing 1 mg of 5-HTP/kg of BW (5-HTP group, n = 10). Infusions started d 10 before the estimated parturition and ceased the day of parturition, resulting in at least 4 d of infusion (8.37 +/- 0.74 d of infusion). Until parturition, blood samples were collected every morning before the infusions, after parturition samples were taken daily until d 7, and a final sample was collected on d 30. Milk yield was recorded during this period. No differences between groups were observed for blood glucose, magnesium, and beta hydroxybutyrate. Cows receiving the 5-HTP infusion showed an increase in fatty acid concentrations from d -3 to -1 before parturition. Serum 5-HT concentrations were increased at d -4 related to parturition until d 5 postpartum in the 5-HTP group compared with the C group. In addition, cows from the 5-HTP group had increased 5-HT concentrations in colostrum, but not in mature milk, on d 7 postpartum. Serum calcium concentrations decreased in both groups around parturition; however, calcium remained higher in the 5-HTP group than in controls, with a significant difference between groups on d 1 (1.62 +/- 0.08 vs. 1.93 +/- 0.09 mmol/L in control and 5-HTP groups, respectively) and d 2 (1.83 +/- 0.06 vs. 2.07 +/- 0.07 mmol/L in control and 5-HTP groups, respectively). Additionally, colostrum yield (first milking) was lower in the 5-HTP group compared with the C group, but without consequences on colostrum IgG concentrations. Milk yield did not differ between groups during the rest of the experiment. The study data were consistent with the concept that infusion of 5 HTP to dairy cows increases blood 5-HT concentrations, which in turn is a significant regulatory component in the chain of effectors that affect calcium status around parturition, hence the occurrence of clinical or subclinical hypocalcemia. PMID- 27988125 TI - Investigating rennet coagulation properties of recombined highly concentrated micellar casein concentrate and cream for use in cheese making. AB - Highly concentrated micellar casein concentrate (HC-MCC) contains ~18% casein with ~70% of whey proteins removed by microfiltration and diafiltration of skim milk, followed by vacuum evaporation for further concentration. When blended with cream, HC-MCC forms recombined concentrated milk (RCM), which could be used as a starting material in cheese making. Our objective was to investigate the rennet coagulation properties of RCM while varying parameters such as casein level, pH, rennet level, and coagulation temperature. The HC-MCC was mixed with cream using low shear at 50 degrees C for 10 min, followed by cooling to 31, 28, or 25 degrees C and adding rennet, and rheological properties were determined. Rennet coagulation time [RCT, the time at which storage modulus (G') = loss modulus (G")] decreased from 8.7 to 7.4 min as casein level increased from 3.2 to 5.7%, without a significant additional difference in RCT at casein levels >5.7%. The initial G" (G"0) increased about 10-fold when casein levels were increased from 3.2 to 10.9%, whereas no change in initial G' (G'0) was observed. When G' was measured relative to RCT (i.e., 1, 1.5, or 2 times RCT after RCT was reached, and expressed as G'1, G'1.5, and G'2), log relationship was found between relative G' and casein level (R2 > 0.94). Lowering coagulation temperature from 31 to 25 degrees C increased G"0 by 6 fold and extended RCT from 7.4 to 9.5 min. After coagulation, relative G' was initially higher at the lower temperature with G'1 of 3.6 Pa at 25 degrees C and 2.0 Pa at 31 degrees C, but delayed in further development with G'2 of 0.8 kPa at 25 degrees C and 1.1 kPa at 31 degrees C. Lowering pH of RCM from 6.6 to 6.2 resulted in reduced RCT from 11.9 to 6.5 min with increased relative G' after coagulation. When less rennet was used, RCT increased in a linear inverse relationship without changes in relative G' or G". The microstructure of RCM coagulum (~11% casein), observed using transmission electron microscopy, confirmed that RCM curd had a rigid protein matrix containing extensively cross-linked protein strands. PMID- 27988126 TI - Effect of high-oleic-acid soybeans on production performance, milk fatty acid composition, and enteric methane emission in dairy cows. AB - The objective of this study was to investigate the effect of 3 soybean sources differing in fatty acid profile and processing method on productivity, milk composition, digestibility, rumen fermentation, and enteric methane emission in lactating dairy cows. The soybean sources were conventional, high-linoleic-acid variety extruded soybean meal (ESBM; 8.7% ether extract with 15% oleic and 54% linoleic acids); extruded Plenish (DuPont Pioneer, Johnston, IA), high-oleic-acid variety soybean meal (EPSBM; 8.4% ether extract with 73% oleic and 8% linoleic acids); and whole, heated Plenish soybeans (WPSB; 20.2% ether extract). The study involved 15 Holstein cows in a replicated 3 * 3 Latin square design experiment with three 28-d periods. The inclusion rate of the soybean sources in the diet was (dry matter basis) 17.1, 17.1, and 7.4% for ESBM, EPSBM, and WPSB, respectively, which resulted in ether extract concentration of the diets of 3.99, 3.94, and 4.18%, respectively. Compared with ESBM, the Plenish diets tended to increase dry matter intake and decreased feed efficiency (but had no effect on energy-corrected milk feed efficiency). The Plenish diets increased milk fat concentration on average by 5.6% and tended to increase milk fat yield, compared with ESBM. The WPSB diet tended to increased milk true protein compared with the extruded soybean meal diets. Treatments had no effect on rumen fermentation and enteric methane or carbon dioxide emissions, except pH was higher for WPSB versus EPSBM. The Plenish diets decreased the prevalence of Ruminococcus and increased that of Eubacterium and Treponema in whole ruminal contents. Total-tract apparent digestibility of organic matter and crude protein were decreased by WPSB compared with ESBM and EPSBM. Compared with the other treatments, urinary N excretion was increased by EPSBM and fecal N excretion was greater for WPSB. Treatments had marked effects on milk fatty acid profile. Generally, the Plenish diets increased mono-unsaturated (mostly cis-9 18:1) and decreased polyunsaturated, total trans-, and conjugated linoleic fatty acids concentrations in milk fat. In this study, compared with conventional, high-linoleic-acid variety extruded soybean meal, the Plenish soybean diets increased milk fat concentration and tended to increase fat yield, decreased feed efficiency, and modified milk fatty acid profile in a manner expected from the greater concentration of oleic acid in Plenish soybean oil. PMID- 27988127 TI - The effect of storage conditions on the composition and functional properties of blended bulk tank milk. AB - The objective of this study was to investigate the effects of storage temperature and duration on the composition and functional properties of bulk tank milk when fresh milk was added to the bulk tank twice daily. The bulk tank milk temperature was set at each of 3 temperatures (2, 4, and 6 degrees C) in each of 3 tanks on 2 occasions during two 6-wk periods. Period 1 was undertaken in August and September when all cows were in mid lactation, and period 2 was undertaken in October and November when all cows were in late lactation. Bulk tank milk stored at the 3 temperatures was sampled at 24-h intervals during storage periods of 0 to 96 h. Compositional parameters were measured for all bulk tank milk samples, including gross composition and quantification of nitrogen compounds, casein fractions, free amino acids, and Ca and P contents. The somatic cell count, heat stability, titratable acidity, and rennetability of bulk tank milk samples were also assessed. Almost all parameters differed between mid and late lactation; however, the interaction between lactation, storage temperature, and storage duration was significant for only 3 parameters: protein content and concentrations of free cysteic acid and free glutamic acid. The interaction between storage temperature and storage time was not significant for any parameter measured, and temperature had no effect on any parameter except lysine: lysine content was higher at 6 degrees C than at 2 degrees C. During 96 h of storage, the concentrations of some free amino acids (glutamic acid, lysine, and arginine) increased, which may indicate proteolytic activity during storage. Between 0 and 96 h, minimal deterioration was observed in functional properties (rennet coagulation time, curd firmness, and heat stability), which was most likely due to the dissociation of beta-casein from the casein micelle, which can be reversed upon pasteurization. Thus, this study suggests that blended milk can be stored for up to 96 h at temperatures between 2 degrees C and 6 degrees C with little effect on its composition or functional properties. PMID- 27988128 TI - Pathway-based genome-wide association analysis of milk coagulation properties, curd firmness, cheese yield, and curd nutrient recovery in dairy cattle. AB - It is becoming common to complement genome-wide association studies (GWAS) with gene-set enrichment analysis to deepen the understanding of the biological pathways affecting quantitative traits. Our objective was to conduct a gene ontology and pathway-based analysis to identify possible biological mechanisms involved in the regulation of bovine milk technological traits: coagulation properties, curd firmness modeling, individual cheese yield (CY), and milk nutrient recovery into the curd (REC) or whey loss traits. Results from 2 previous GWAS studies using 1,011 cows genotyped for 50k single nucleotide polymorphisms were used. Overall, the phenotypes analyzed consisted of 3 traditional milk coagulation property measures [RCT: rennet coagulation time defined as the time (min) from addition of enzyme to the beginning of coagulation; k20: the interval (min) from RCT to the time at which a curd firmness of 20 mm is attained; a30: a measure of the extent of curd firmness (mm) 30 min after coagulant addition], 6 curd firmness modeling traits [RCTeq: RCT estimated through the CF equation (min); CFP: potential asymptotic curd firmness (mm); kCF: curd-firming rate constant (% * min-1); kSR: syneresis rate constant (% * min-1); CFmax: maximum curd firmness (mm); and tmax: time to CFmax (min)], 3 individual CY-related traits expressing the weight of fresh curd (%CYCURD), curd solids (%CYSOLIDS), and curd moisture (%CYWATER) as a percentage of weight of milk processed and 4 milk nutrient and energy recoveries in the curd (RECFAT, RECPROTEIN, RECSOLIDS, and RECENERGY calculated as the % ratio between the nutrient in curd and the corresponding nutrient in processed milk), milk pH, and protein percentage. Each trait was analyzed separately. In total, 13,269 annotated genes were used in the analysis. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases were queried for enrichment analyses. Overall, 21 Gene Ontology and 17 Kyoto Encyclopedia of Genes and Genomes categories were significantly associated (false discovery rate at 5%) with 7 traits (RCT, RCTeq, kCF, %CYSOLIDS, RECFAT, RECSOLIDS, and RECENERGY), with some being in common between traits. The significantly enriched categories included calcium signaling pathway, salivary secretion, metabolic pathways, carbohydrate digestion and absorption, the tight junction and the phosphatidylinositol pathways, as well as pathways related to the bovine mammary gland health status, and contained a total of 150 genes spanning all chromosomes but 9, 20, and 27. This study provided new insights into the regulation of bovine milk coagulation and cheese ability that were not captured by the GWAS. PMID- 27988129 TI - Source of supplemental dietary copper, zinc, and manganese affects fecal microbial relative abundance in lactating dairy cows. AB - Appropriate trace mineral supplementation can improve immune response and hoof health in cattle and at much higher rates of supplementation to swine and poultry can alter microbial colonization of the gut, resulting in improved gut health. Diet can influence fecal microbial excretion in cattle, and the fecal microbiome may serve as a means for assessing gastrointestinal microbial changes. We hypothesized that feeding diets that differed in source of supplemental Cu, Zn, or Mn would alter the relative abundance of fecal microbes in lactating dairy cattle and that organic Zn would have the greatest effect. Twenty-four cows were fed diets devoid of supplemental Cu, Zn, and Mn for a 16-d preliminary phase (basal diet provided 9, 29, and 32 mg/kg of Cu, Zn, and Mn, respectively), and then were randomly assigned to 1 of 3 treatment diets (n = 8 cows/treatment): one group of cows was fed supplemental Cu, Zn, and Mn from sulfate minerals; the second group was fed glycinate minerals; and the third group was fed Cu and Mn sulfate with glycinate Zn. Assayed total dietary concentrations were approximately 21, 73, and 72 mg/kg for Cu, Zn, and Mn, respectively. Milk production (averaged 38.8 kg/d), DMI (averaged 25.8 kg/d), and milk components were not affected by treatment. Fecal DNA was extracted, amplified using a universal primer targeting the V4-V5 hypervariable region of the 16S rRNA gene, and sequenced to compare microbial community composition between treatments. Relative abundances of Treponema species-level operational taxonomic units (OTU) were less for animals fed Cu and Mn sulfate with glycinate Zn compared with sulfates alone, but were similar to animals fed glycinate mineral sources. Relative abundances for exclusive glycinate mineral and sulfate mineral treatments were similar. Treponema OTU and cultured representatives are often associated with bovine digital dermatitis. These data may provide an additional link between organic Zn supplementation and improved hoof health. To our knowledge this is the first report of a dietary treatment decreasing the relative abundance of Treponema OTU in cattle feces; however, the potential benefits of this response on overall animal health and the mechanism for the observed responses are unknown and warrant further investigation. PMID- 27988131 TI - Effects of milking stall dimensions on behavior of dairy cows during milking in different milking parlor types. AB - Dairy cow body size has increased over time because of breeding selection for higher milk yield, but milking stall dimensions have never been adjusted and are based on the practical experience of milking-machine manufacturers and advisory institutions. Narrow, limited milking stall dimensions might lead to behavioral changes during milking due to lack of comfort. The aim of this study was to examine the current space allowance in milking stalls on dairy farms and assess the effect of space allowance on cow behavior during milking. On 15 Swiss dairy farms, we measured clear milking stall dimensions and cow body dimensions. We calculated space ratios for length (SRlength) and width (SRwidth) by dividing the milking stall length or width by cow body length or belly width, respectively. When the space ratio was >1, we assumed that the body length or width of cow was smaller than the milking stall length or width. On each farm, 10 healthy cows were chosen for behavioral observation during 1 evening milking. We recorded rumination, elimination, and latency to enter the milking stall by direct observation. Hind leg activity was recorded using acceleration loggers. Data were analyzed using general linear mixed-effects models with farm as a random effect. Due to a strong collinearity between SRwidth and SRlength, we chose SRlength for further analysis, because it is based on skeletal characteristics. The SRlength was smallest in side-by-side parlors (1.07 +/- 0.01) and largest in tandem parlors (1.18 +/- 0.01). More cows had a tendency to ruminate with increasing SRlength (odds ratio: 1.8). None of hind leg activity, maximum peaks of hind leg accelerations, or latency to enter the milking stall were significantly affected by SRlength. Latency to enter the milking stall was longer for group milking parlors (side-by-side: 44.0 +/- 3.2 s; herringbone: 34.3 +/- 2.9 s) than for tandem parlors (19.0 +/- 2.7 s). Milking parlor type had no effect on hind leg activity, maximum peaks of hind leg accelerations or rumination. The SRlength affected rumination behavior to some extent, indicating that cow comfort was positively affected by larger milking stall length. Because cow comfort is important for good milking performance, further investigations of milking stall dimensions for cow comfort and thus welfare are needed. Furthermore, the results showed that parlor type affected cow behavior, irrespective of SRlength, making future research necessary to identify the factors leading to this effect of parlor type. PMID- 27988130 TI - Rapid assessment of bovine colostrum quality: How reliable are transmission infrared spectroscopy and digital and optical refractometers? AB - The objectives of this study were to evaluate the performance of the transmission infrared (IR) spectroscopic method and digital and optical Brix refractometers for measurement of colostral IgG concentration and assessment of colostrum quality of dairy cows. Colostrum samples (n = 258) were collected from Holstein cows on 30 commercial dairy farms in Nova Scotia and Newfoundland, Canada. Colostral IgG concentrations of 255 samples were measured by the reference radial immunodiffusion (RID) assay and IR spectroscopy. The Brix scores were determined on 240 of these samples using both the digital and optical Brix refractometers. Approximately half (48%) of the colostrum samples had RID IgG concentrations <50 g/L, which was the cut-point for poor quality. The correlation between RID and IR IgG concentrations was 0.88. The correlations between RID IgG concentration and Brix scores, as determined by the digital and optical refractometers, were 0.72 and 0.71, respectively. The optimal cutoff levels for distinguishing good- and poor-quality colostrum using IR spectroscopy, and digital and optical Brix refractometers were at 35 g/L and 23% Brix, respectively. The IR spectroscopy showed higher sensitivity (90%) and specificity (86%) than the digital (74 and 80%, respectively) and optical (73 and 80%, respectively) Brix refractometers for assessment of colostrum quality, as compared with RID. In conclusion, the transmission-IR spectroscopy is a rapid and accurate method for assessing colostrum quality, but is a laboratory-based method, whereas Brix refractometers were less accurate but could be used on-farm. PMID- 27988132 TI - Survival and detection of coliforms, Enterobacteriaceae, and gram-negative bacteria in Greek yogurt. AB - Despite the widespread use of coliforms as indicator bacteria, increasing evidence suggests that the Enterobacteriaceae (EB) and total gram-negative groups more accurately reflect the hygienic status of high-temperature, short-time pasteurized milk and processing environments. If introduced into milk as postpasteurization contamination, these bacteria may grow to high levels and produce a wide range of sensory-related defects. However, limited information is available on the use and survival of bacterial hygiene indicators in dairy products outside of pasteurized fluid milk and cheese. The goal of this study was to (1) provide information on the survival of a diverse set of bacterial hygiene indicators in the low pH environment of Greek yogurt, (2) compare traditional and alternative detection methods for their ability to detect bacterial hygiene indicators in Greek yogurt, and (3) offer insight into optimal hygiene indicator groups for use in low-pH fermented dairy products. To this end, we screened 64 bacterial isolates, representing 24 dairy-relevant genera, for survival and detection in Greek yogurt using 5 testing methods. Before testing, isolates were inoculated into plain, 0% fat Greek yogurt (pH 4.35 to 4.65), followed by a 12-h hold period at 4 +/- 1 degrees C. Yogurts were subsequently tested using Coliform Petrifilm (3M, St. Paul, MN) to detect coliforms; Enterobacteriaceae Petrifilm (3M), violet red bile glucose agar and the D-Count (bioMerieux, Marcy-l'Etoile, France) to detect EB; and crystal violet tetrazolium agar (CVTA) to detect total gram-negative bacteria. Overall, the non-EB gram-negative isolates showed significantly larger log reductions 12 h after inoculation into Greek yogurt (based on bacterial numbers recovered on CVTA) compared with the coliform and noncoliform EB isolates tested. The methods evaluated varied in their ability to detect different microbial hygiene indicators in Greek yogurt. Crystal violet tetrazolium agar detected the highest portion of coliforms, whereas EB Petrifilm detected the highest portion of EB, as well as highest portion of total gram negative bacteria. Additionally, the D-Count method allowed for faster detection of EB in yogurt by generating results in approximately 13 h rather than the 24 h required when using EB Petrifilm and violet red bile glucose agar. Results from this study indicate that the coliform and EB groups encompass a broad range of dairy-relevant gram-negative bacteria with the ability to survive in Greek yogurt, supporting their use as microbial hygiene indicator groups in low-pH fermented dairy products. PMID- 27988133 TI - Lipids and Their Effects in Chronic Lymphocytic Leukemia. PMID- 27988134 TI - Ocular tuberculosis: Position paper on diagnosis and treatment management. AB - : Delay in diagnosis or treatment of ocular tuberculosis can result in loss of vision. However, due to the fact that early diagnosis is rarely achieved, there are still a broad variety of diagnostic and treatment approaches. Our aim was to reach a consensus on the management of diagnosis and treatment of ocular tuberculosis. METHODS: Critical appraisal of the literature and expert opinion on diagnosis and treatment of ocular tuberculosis. RESULTS AND CONCLUSION: The currently recommended method for ocular TB diagnosis is screening for tuberculosis in any uveitis of unknown etiology, recurrent or not responding to conventional therapy; in ocular findings highly suggestive of ocular TB and before immunosuppression (particularly biologic agents). TB screening in these cases includes tuberculosis skin testing and interferon gamma testing, along with complete medical history, ophthalmologic evaluation and chest imaging. Positively screened patients should be treated for active tuberculosis with 4 drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) for 6-9 months. Patients should be reviewed at the end of the initiation phase (two months) and at the end of the overall treatment (6-9 months). PMID- 27988135 TI - Progress of the attractiveness of Rheumatology among medical speciality training candidates (MIR) in Spain. AB - OBJECTIVE: To describe the progress of the attractiveness of rheumatology at successive MIR calls, from 1983 to 2014. METHODS: Candidates in the Spanish training system for medical doctors choose their specialties sequentially, ordered by their ranking in the qualifying exam (MIR). The highest, median and lowest rank of candidates choosing rheumatology training positions in every MIR call from 1983 to 2014 was requested from the Department of Management of Specialized Medical Training (General Department of Professional Regulation; Spanish Ministry of Health). To compare, the same data was requested for other specialties. In order to define and analyze the attractiveness of each specialty we introduce an 'index of attractiveness', based on the normalized difference of the actual median rank reported for each year and the average median obtained in 1000 simulations in which candidates choose specialties at random. RESULTS: Regarding the median of the election of rheumatology, the range went from 244th in 1983 to 3394th in 2008, showing a progressive increase over the years in absolute figures. A mathematical simulation allowed quantifying the difference between the observed median and what would have happened if specialties had been chosen by pure chance. Results show a tendency to recover the attractiveness of rheumatology in recent years. CONCLUSIONS: After a sharp decline in the attractiveness of rheumatology during the last years of the 20th century, there seems to be a recovery. PMID- 27988136 TI - Estimating population exposure to ambient polycyclic aromatic hydrocarbon in the United States - Part I: Model development and evaluation. AB - PAHs (polycyclic aromatic hydrocarbons) in the environment are of significant concern due to their negative impact on human health. PAH measurements at the air toxics monitoring network stations alone are not sufficient to provide a complete picture of ambient PAH levels or to allow accurate assessment of public exposure in the United States. In this study, speciation profiles for PAHs were prepared using data assembled from existing emission profile data bases, and the Sparse Matrix Operator Kernel Emissions (SMOKE) model was used to generate the gridded national emissions of 16 priority PAHs in the US. The estimated emissions were applied to simulate ambient concentration of PAHs for January, April, July and October 2011, using a modified Community Multiscale Air Quality (CMAQ) model (v5.0.1) that treats the gas and particle phase partitioning of PAHs and their reactions in the gas phase and on particle surface. Predicted daily PAH concentrations at 61 air toxics monitoring sites generally agreed with observations, and averaging the predictions over a month reduced the overall error. The best model performance was obtained at rural sites, with an average mean fractional bias (MFB) of -0.03 and mean fractional error (MFE) of 0.70. Concentrations at suburban and urban sites were underestimated with overall MFB= 0.57 and MFE=0.89. Predicted PAH concentrations were highest in January with better model performance (MFB=0.12, MFE=0.69; including all sites), and lowest in July with worse model performance (MFB=-0.90, MFE=1.08). Including heterogeneous reactions of several PAHs with O3 on particle surface reduced the over-prediction bias in winter, although significant uncertainties were expected due to relative simple treatment of the heterogeneous reactions in the current model. PMID- 27988137 TI - Causal inference in cumulative risk assessment: The roles of directed acyclic graphs. AB - Cumulative risk assessments (CRAs) address exposures to multiple chemical and nonchemical stressors and often focus on characterization of health risks in vulnerable populations. Evaluating complex exposure-response relationships in CRAs requires the use of formal and rigorous methods for causal inference. Directed acyclic graphs (DAGs) are graphical causal models used to organize and communicate knowledge about the underlying causal structure that generates observable data. Using existing graphical theories for causal inference with DAGs, risk analysts can identify confounders and effect measure modifiers to determine if the available data are both internally valid to obtain unbiased risk estimates and are generalizable to populations of interest. Conditional independencies implied by the structure of a DAG can be used to test assumptions used in a CRA against empirical data in a selected study and can contribute to the evidence evaluations related to specific causal pathways. This can facilitate quantitative use of these data, as well as help identify key research gaps, prioritize data collection activities, and evaluate risk management alternatives. DAGs also enable risk analysts to be explicit about sources of uncertainty and to determine whether a causal effect can be estimated from available data. Using a conceptual model and DAG for a hypothetical community located near a concentrated animal feeding operation (CAFO), we illustrate the advantages of using DAGs for evaluating causality in CRAs. DAGs also can be used in conjunction with weight of evidence (WOE) methodology to improve causal analysis for CRA, which could lead to more effective interventions to reduce population health risks. PMID- 27988138 TI - Non-specialist health workers to treat excessive alcohol consumption and depression. PMID- 27988139 TI - Brain abnormalities in fetuses: in-utero MRI versus ultrasound. PMID- 27988140 TI - Use of MRI in the diagnosis of fetal brain abnormalities in utero (MERIDIAN): a multicentre, prospective cohort study. AB - BACKGROUND: In-utero MRI (iuMRI) has shown promise as an adjunct to ultrasound but the comparative diagnostic performance has been poorly defined. We aimed to assess whether the diagnostic accuracy and confidence of the prenatal diagnosis of fetal brain abnormalities is improved with iuMRI and assess the clinical impact and patient acceptability of iuMRI. METHODS: We did a multicentre, prospective, cohort study in the UK, at 16 fetal medicine centres, of pregnant women aged 16 years or older whose fetus had a brain abnormality detected by ultrasound at a gestational age of 18 weeks or more, had no contraindications to iuMRI, and consented to enter the study. Women carrying a fetus suspected of having a brain anomaly on ultrasound had iuMRI done within 14 days of ultrasound. The findings were reviewed by two independent panels and used to estimate diagnostic accuracy and confidence by comparison with outcome diagnoses. Changes in diagnosis, prognosis, and clinical management brought about by iuMRI and patient acceptability were assessed. FINDINGS: Participants were recruited between July 29, 2011, and Aug 31, 2014. The cohort was subdivided by gestation into the 18 weeks to less than 24 weeks fetus cohort (n=369) and into the 24 weeks or older fetus cohort (n=201). Diagnostic accuracy was improved by 23% (95% CI 18-27) in the 18 weeks to less than 24 weeks group and 29% (23-36) in the 24 weeks and older group (p<0.0001 for both groups). The overall diagnostic accuracy was 68% for ultrasound and 93% for iuMRI (difference 25%, 95% CI 21-29). Dominant diagnoses were reported with high confidence on ultrasound in 465 (82%) of 570 cases compared with 544 (95%) of 570 cases on iuMRI. IuMRI provided additional diagnostic information in 387 (49%) of 783 cases, changed prognostic information in at least 157 (20%), and led to changes in clinical management in more than one in three cases. IuMRI also had high patient acceptability with at least 95% of women saying they would have an iuMRI study if a future pregnancy were complicated by a fetal brain abnormality. INTERPRETATION: iuMRI improves diagnostic accuracy and confidence for fetal brain anomalies and leads to management changes in a high proportion of cases. This finding, along with the high patient acceptability, leads us to propose that any fetus with a suspected brain abnormality on ultrasound should have iuMRI to better inform counselling and management decisions. FUNDING: National Institute for Health Research Health Technology Assessment programme. PMID- 27988141 TI - Filgotinib for Crohn's disease-expanding treatment options. PMID- 27988142 TI - Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. AB - BACKGROUND: Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered, Janus kinase 1 (JAK1)-selective inhibitor. The FITZROY study examined the efficacy and safety of filgotinib for the treatment of moderate-to-severe Crohn's disease. METHODS: We did a randomised, double-blind, placebo-controlled phase 2 study, which recruited patients from 52 centres in nine European countries. We enrolled eligible patients aged 18-75 years with a documented history of ileal, colonic, or ileocolonic Crohn's disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohn's Disease Activity Index (CDAI) score during screening between 220 and 450 inclusive. Patients were randomly assigned (3:1) to receive filgotinib 200 mg once a day or placebo for 10 weeks. Patients were stratified according to previous anti-tumour necrosis factor alpha exposure, C-reactive protein concentration at screening (<=10 mg/L or >10 mg/L), and oral corticosteroid use at baseline, using an interactive web-based response system. The primary endpoint was clinical remission, defined as CDAI less than 150 at week 10. After week 10, patients were assigned based on responder status to filgotinib 100 mg once a day, filgotinib 200 mg once a day, or placebo for an observational period lasting a further 10 weeks. The filgotinib and placebo treatment groups were compared using ANCOVA models and logistic regression models containing baseline values and randomisation stratification factors as fixed effects. Analyses were done on the intention-to-treat non-responder imputation set. The trial was registered at ClinicalTrials.gov, number NCT02048618. FINDINGS: Between Feb 3, 2014, and July 10, 2015, we enrolled 174 patients with active Crohn's disease confirmed by centrally read endoscopy (130 in the filgotinib 200 mg group and 44 in the placebo group). In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9-39], p=0.0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo. INTERPRETATION: Filgotinib induced clinical remission in significantly more patients with active Crohn's disease compared with placebo, and had an acceptable safety profile. FUNDING: Galapagos. PMID- 27988143 TI - The Healthy Activity Program (HAP), a lay counsellor-delivered brief psychological treatment for severe depression, in primary care in India: a randomised controlled trial. AB - BACKGROUND: Although structured psychological treatments are recommended as first line interventions for depression, only a small fraction of people globally receive these treatments because of poor access in routine primary care. We assessed the effectiveness and cost-effectiveness of a brief psychological treatment (Healthy Activity Program [HAP]) for delivery by lay counsellors to patients with moderately severe to severe depression in primary health-care settings. METHODS: In this randomised controlled trial, we recruited participants aged 18-65 years scoring more than 14 on the Patient Health Questionnaire 9 (PHQ 9) indicating moderately severe to severe depression from ten primary health centres in Goa, India. Pregnant women or patients who needed urgent medical attention or were unable to communicate clearly were not eligible. Participants were randomly allocated (1:1) to enhanced usual care (EUC) alone or EUC combined with HAP in randomly sized blocks (block size four to six [two to four for men]), stratified by primary health centre and sex, and allocation was concealed with use of sequential numbered opaque envelopes. Physicians providing EUC were masked. Primary outcomes were depression symptom severity on the Beck Depression Inventory version II and remission from depression (PHQ-9 score of <10) at 3 months in the intention-to-treat population, assessed by masked field researchers. Secondary outcomes were disability, days unable to work, behavioural activation, suicidal thoughts or attempts, intimate partner violence, and resource use and costs of illness. We assessed serious adverse events in the per protocol population. This trial is registered with the ISRCTN registry, number ISRCTN95149997. FINDINGS: Between Oct 28, 2013, and July 29, 2015, we enrolled and randomly allocated 495 participants (247 [50%] to the EUC plus HAP group [two of whom were subsequently excluded because of protocol violations] and 248 [50%] to the EUC alone group), of whom 466 (95%) completed the 3 month primary outcome assessment (230 [49%] in the EUC plus HAP group and 236 [51%] in the EUC alone group). Participants in the EUC plus HAP group had significantly lower symptom severity (Beck Depression Inventory version II in EUC plus HAP group 19.99 [SD 15.70] vs 27.52 [13.26] in EUC alone group; adjusted mean difference -7.57 [95% CI -10.27 to -4.86]; p<0.0001) and higher remission (147 [64%] of 230 had a PHQ-9 score of <10 in the HAP plus EUC group vs 91 [39%] of 236 in the EUC alone group; adjusted prevalence ratio 1.61 [1.34-1.93]) than did those in the EUC alone group. EUC plus HAP showed better results than did EUC alone for the secondary outcomes of disability (adjusted mean difference -2.73 [-4.39 to -1.06]; p=0.001), days out of work (-2.29 [-3.84 to -0.73]; p=0.004), intimate partner physical violence in women (0.53 [0.29-0.96]; p=0.04), behavioural activation (2.17 [1.34-3.00]; p<0.0001), and suicidal thoughts or attempts (0.61 [0.45 0.83]; p=0.001). The incremental cost per quality-adjusted life-year gained was $9333 (95% CI 3862-28 169; 2015 international dollars), with an 87% chance of being cost-effective in the study setting. Serious adverse events were infrequent and similar between groups (nine [4%] in the EUC plus HAP group vs ten [4%] in the EUC alone group; p=1.00). INTERPRETATION: HAP delivered by lay counsellors plus EUC was better than EUC alone was for patients with moderately severe to severe depression in routine primary care in Goa, India. HAP was readily accepted by this previously untreated population and was cost-effective in this setting. HAP could be a key strategy to reduce the treatment gap for depressive disorders, the leading mental health disorder worldwide. FUNDING: Wellcome Trust. PMID- 27988145 TI - Deliberate chemical dermatoglyphic burns in a political refugee. PMID- 27988144 TI - Counselling for Alcohol Problems (CAP), a lay counsellor-delivered brief psychological treatment for harmful drinking in men, in primary care in India: a randomised controlled trial. AB - BACKGROUND: Although structured psychological treatments are recommended as first line interventions for harmful drinking, only a small fraction of people globally receive these treatments because of poor access in routine primary care. We assessed the effectiveness and cost-effectiveness of Counselling for Alcohol Problems (CAP), a brief psychological treatment delivered by lay counsellors to patients with harmful drinking attending routine primary health-care settings. METHODS: In this randomised controlled trial, we recruited male harmful drinkers defined by an Alcohol Use Disorders Identification Test (AUDIT) score of 12-19 who were aged 18-65 years from ten primary health centres in Goa, India. We excluded patients who needed emergency medical treatment or inpatient admission, who were unable to communicate clearly, and who were intoxicated at the time of screening. Participants were randomly allocated (1:1) by trained health assistants based at the primary health centres to enhanced usual care (EUC) alone or EUC combined with CAP, in randomly sized blocks of four to six, stratified by primary health centre, and allocation was concealed with use of sequential numbered opaque envelopes. Physicians providing EUC and those assessing outcomes were masked. Primary outcomes were remission (AUDIT score of <8) and mean daily alcohol consumed in the past 14 days, at 3 months. Secondary outcomes were the effect of drinking, disability score, days unable to work, suicide attempts, intimate partner violence, and resource use and costs of illness. Analyses were on an intention-to-treat basis. We used logistic regression analysis for remission and zero-inflated negative binomial regression analysis for alcohol consumption. We assessed serious adverse events in the per-protocol population. This trial is registered with the ISCRTN registry, number ISRCTN76465238. FINDINGS: Between Oct 28, 2013, and July 29, 2015, we enrolled and randomly allocated 377 participants (188 [50%] to the EUC plus CAP group and 190 [50%] to the EUC alone group [one of whom was subsequently excluded because of a protocol violation]), of whom 336 (89%) completed the 3 month primary outcome assessment (164 [87%] in the EUC plus CAP group and 172 [91%] in the EUC alone group). The proportion with remission (59 [36%] of 164 in the EUC plus CAP group vs 44 [26%] of 172 in the EUC alone group; adjusted prevalence ratio 1.50 [95% CI 1.09-2.07]; p=0.01) and the proportion abstinent in the past 14 days (68 [42%] vs 31 [18%]; adjusted odds ratio 3.00 [1.76-5.13]; p<0.0001) were significantly higher in the EUC plus CAP group than in the EUC alone group, but we noted no effect on mean daily alcohol consumed in the past 14 days among those who reported drinking in this period (37.0 g [SD 44.2] vs 31.0 g [27.8]; count ratio 1.08 [0.79-1.49]; p=0.62). We noted an effect on the percentage of days abstinent in the past 14 days (adjusted mean difference [AMD] 16.0% [8.1-24.1]; p<0.0001), but no effect on the percentage of days of heavy drinking (AMD -0.4% [-5.7 to 4.9]; p=0.88), the effect of drinking (Short Inventory of Problems score AMD-0.03 [-1.93 to 1.86]; p=0.97), disability score (WHO Disability Assessment Schedule score AMD 0.62 [-0.62 to 1.87]; p=0.32), days unable to work (no days unable to work adjusted odds ratio 1.02 [0.61-1.69]; p=0.95), suicide attempts (adjusted prevalence ratio 1.8 [-2.4 to 6.0]; p=0.25), and intimate partner violence (adjusted prevalence ratio 3.0 [-10.4 to 4.4]; p=0.57). The incremental cost per additional remission was $217 (95% CI 50-1073), with an 85% chance of being cost effective in the study setting. We noted no significant difference in the number of serious adverse events between the two groups (six [4%] in the EUC plus CAP group vs 13 [8%] in the EUC alone group; p=0.11). INTERPRETATION: CAP delivered by lay counsellors plus EUC was better than EUC alone was for harmful drinkers in routine primary health-care settings, and might be cost-effective. CAP could be a key strategy to reduce the treatment gap for alcohol use disorders, one of the leading causes of the global burden among men worldwide. FUNDING: Wellcome Trust. PMID- 27988147 TI - Simplified antibiotic regimens for community management of neonatal sepsis. PMID- 27988148 TI - Current issues in child sexual abuse, gender and health outcomes: Shedding new lights to inform worldwide policy and practice. PMID- 27988146 TI - Simplified antibiotic regimens for treatment of clinical severe infection in the outpatient setting when referral is not possible for young infants in Pakistan (Simplified Antibiotic Therapy Trial [SATT]): a randomised, open-label, equivalence trial. AB - BACKGROUND: Parenteral antibiotic therapy for young infants (aged 0-59 days) with suspected sepsis is sometimes not available or feasible in countries with high neonatal mortality. Outpatient treatment could save lives in such settings. We aimed to assess the equivalence of two simplified antibiotic regimens, comprising fewer injections and oral rather than parenteral administration, compared with a reference treatment for young infants with clinical severe infection. METHODS: We undertook the Simplified Antibiotic Therapy Trial (SATT), a three-arm, randomised, open-label, equivalence trial in five communities in Karachi, Pakistan. We enrolled young infants (aged 0-59 days) who either presented at a primary health-care clinic or were identified by a community health worker with signs of clinical severe infection. We included infants who were not critically ill and whose family refused admission. We randomly assigned infants to either intramuscular procaine benzylpenicillin and gentamicin once a day for 7 days (reference); oral amoxicillin twice daily and intramuscular gentamicin once a day for 7 days; or intramuscular procaine benzylpenicillin and gentamicin once a day for 2 days followed by oral amoxicillin twice daily for 5 days. The primary outcome was treatment failure within 7 days of enrolment and the primary analysis was per protocol. We judged experimental treatments as efficacious as the reference if the upper bound of the 95% CI for the difference in treatment failure was less than 5.0. This trial is registered at ClinicalTrials.gov, number NCT01027429. FINDINGS: Between Jan 1, 2010, and Dec 26, 2013, 2780 infants were deemed eligible for the trial, of whom 2453 (88%) were enrolled. Because of inadequate clinical follow-up or treatment adherence, 2251 infants were included in the per-protocol analysis. 820 infants (747 per protocol) were assigned the reference treatment of procaine benzylpenicillin and gentamicin, 816 (751 per protocol) were allocated amoxicillin and gentamicin, and 817 (753 per protocol) were assigned procaine benzylpenicillin, gentamicin, and amoxicillin. Treatment failure within 7 days of enrolment was reported in 90 (12%) infants who received procaine benzylpenicillin and gentamicin (reference), 76 (10%) of those given amoxicillin and gentamicin (risk difference with reference -1.9, 95% CI -5.1 to 1.3), and 99 (13%) of those treated with procaine benzylpenicillin, gentamicin, and amoxicillin (risk difference with reference 1.1, -2.3 to 4.5). INTERPRETATION: Two simplified antibiotic regimens requiring fewer injections are equivalent to a reference treatment for young infants with signs of clinical severe infection but without signs of critical illness. The use of these simplified regimens has the potential to increase access to treatment for sick young infants who cannot be referred to hospital. FUNDING: The Saving Newborn Lives initiative of Save the Children, through support from the Bill & Melinda Gates, and by WHO and USAID. PMID- 27988149 TI - A technique for facial reanimation: The partial temporalis muscle-tendon transfer with a fascia lata sling. AB - BACKGROUND: This report describes the results of a surgical procedure for facial reanimation. This single-stage technique involves the orthodromic transfer of only a superficial segment of the temporalis tendon. This is extended with fascia lata to achieve elevation of the oral commissure along the desired vector in the paralysed hemi-face. METHODS: A retrospective case note review was performed. Patients' photographs were objectively evaluated with Facial Assessment by Computer Evaluation (FACE) software. RESULTS: Thirty-nine patients underwent the procedure from 2001 to 2011. Median age at the operation was 57.0 years (interquartile range (IQR) 38.2-66.3 years), and median duration of follow-up was 0.9 years (IQR 0.5-1.8 years). All patients achieved early improvements in appearance and function after surgery. Three patients underwent further, minor procedures for aesthetic and functional adjustments around the oral commissure. Complications occurred in three patients: two minor facial haematomas and one thigh wound infection. The surgery did not disturb natural temporalis muscle function. FACE analysis demonstrated that no significant movement of the oral commissure occurred during attempted smiling in the paralysed hemi-face before surgery. However, symmetry was achieved when the healthy and paralysed hemi-faces were compared post-operatively, both in repose and during controlled smiling. CONCLUSIONS: This modified, single-stage technique for facial reanimation improves commissure mobilisation and has been objectively shown to restore symmetry of the commissure to the reanimated hemi-face. PMID- 27988150 TI - Nipple-areola complex reconstruction improves psychosocial and sexual well-being in women treated for breast cancer. AB - INTRODUCTION: Women choose to undergo nipple-areola complex (NAC) reconstruction as part of breast reconstruction following breast cancer treatment. However, the effect of this procedure on psychosocial and sexual well-being is not well studied. The present study aimed to evaluate how NAC reconstruction affects patient satisfaction with regard to psychosocial and sexual well-being. METHODS: A retrospective chart review was performed for all patients who underwent NAC reconstruction at Magee-Women's Hospital from January 1, 2004 to July 31, 2011. A letter and questionnaire based on the BREAST-Q were mailed to patients to request their participation in the study. Patient satisfaction and health-related quality of life were measured before and after NAC reconstruction. RESULTS: In total, 107 of 328 patients (32.6%) completed the survey. The BREAST-Q scale score for satisfaction with outcome following NAC reconstruction was 85.1 +/- 15.8, with higher satisfaction scores for patients with a follow-up of <1.5 years than those with a follow-up of >2.5 years (82.5 +/- 21.7 vs. 69.5 +/- 19.5; p < 0.01). No significant differences were found in satisfaction with the breast mound before and after NAC reconstruction. Women scored significantly higher on the psychosocial and sexual well-being scales after NAC reconstruction (p < 0.002 and 0.00004, respectively). CONCLUSIONS: This study indicates that patients are highly satisfied after undergoing NAC reconstruction. Satisfaction with the procedure, however, may decrease over time. NAC reconstruction significantly contributes to patient psychosocial and sexual well-being, and this effect did not change over time. NAC reconstruction improves patient outcomes in those who choose to undergo the procedure. PMID- 27988151 TI - Delayed procedure in propeller perforator flap: Defining the venous perforasome. PMID- 27988152 TI - Editorial Comment. PMID- 27988153 TI - Editorial Comment. PMID- 27988154 TI - Estimation of health-related-quality of life depends on which utility measure is selected for patients with carpal tunnel syndrome. AB - STUDY DESIGN: Cross-sectional. INTRODUCTION: Carpal tunnel syndrome (CTS) refers to the compression neuropathy of the median nerve at the wrist. PURPOSE OF THE STUDY: To establish the interinstrument reliability, convergent construct validity, and the levels of agreement of health utility indexes 2 and 3 (HUI-2 and HUI-3), EuroQol 5-dimensions (EQ-5D), EuroQol-visual analog scale (EQ-VAS) and to determine the difference of these utility measures based on age and gender in patients with carpal tunnel syndrome. METHODS: Seventy-four patients with a confirmed diagnosis of carpal tunnel syndrome completed the 3 questionnaires and EQ-VAS a month before surgery. Demographic characteristics were reported. Intraclass correlation coefficients were used to assess relative interinstrument reliability. Pearson correlation coefficients (r) were used to establish convergent construct validity. Bland-Altman plots and t tests were used to describe the levels of agreement between the 4 utility measures. A 2-way analysis of variance was performed to determine the effect of age and gender on the utility measures; HUI-2, HUI-3, and EQ-5D. RESULTS: The intraclass correlation coefficients were 0.85 for HUI-3 vs HUI-2 and 0.80 for HUI-2 vs EQ-VAS. Pearson correlation coefficients ranged from 0.60 to 0.89; HUI-3 vs HUI-2: 0.89, and HUI 3 vs EQ-5D: 0.60. One-sample t test demonstrated significant differences between HUI-3 vs HUI-2, HUI-3 vs EQ-5D, and HUI-3 vs EQ-VAS measures, with mean differences of -0.12, -0.15, and -0.14, respectively. A 2-way analysis of variance test controlling for age and gender indicated neither as predictors of outcome scores. CONCLUSIONS: The HUI-3 vs HUI-2 and HUI-2 vs EQ-VAS demonstrated excellent interinstrument relative reliability measures. The HUI-3 vs HUI-2 displayed very strong convergent construct validity measures, and strong validity measures were established between the remaining utility measures. In addition, the pair-wise utility comparisons demonstrated minimal bias between HUI-2 vs EQ 5D, HUI-2 vs EQ-VAS, and EQ-VAS vs EQ-5D measures. DISCUSSION: N/A. LEVEL OF EVIDENCE: N/A. PMID- 27988155 TI - Inflammatory aortic aneurysm in a young patient with ankylosing spondylitis. AB - Inflammatory conditions are a rare cause of aortic aneurysms, accounting for 3% to 10% of cases. Patients with ankylosing spondylitis uncommonly present with ascending aortic aneurysms related to long-standing, aggressive disease. We review the case of a young man with ankylosing spondylitis exhibiting complex inflammatory aortic aneurysms atypically involving the abdominal and descending thoracic aorta, as well as ectasia of medium-sized visceral vessels. Inflammatory aneurysms require a multidisciplinary approach incorporating diagnostic modalities to confirm etiology, targeted immunosuppressive therapy to control disease activity, and aneurysm repair. Evidence suggests that endovascular approaches should be considered first-line therapy for patients requiring reconstruction when anatomy is appropriate. PMID- 27988156 TI - Benchtop quantification of gutter formation and compression of chimney stent grafts in relation to renal flow in chimney endovascular aneurysm repair and endovascular aneurysm sealing configurations. AB - BACKGROUND: The chimney technique has been successfully used to treat juxtarenal aortic aneurysms. The two main issues with this technique are gutter formation and chimney graft (CG) compression, which induce a risk for type Ia endoleaks and stent thrombosis, respectively. In this benchtop study, the geometry and renal artery flow of chimney endovascular aneurysm repair configurations were compared with chimney configurations with endovascular aneurysm sealing (ch-EVAS). METHODS: Seven flow phantoms were constructed, including one control and six chimney endovascular aneurysm repairs (Endurant [Medtronic Inc, Minneapolis, Minn] and AFX [Endologix Inc, Irvine, Calif]) or ch-EVAS (Nellix, Endologix) configurations, combined with either balloon-expandable or self-expanding CGs with an intended higher positioning of the right CG in comparison to the left CG. Geometric analysis was based on measurements at three-dimensional computed tomography angiography and included gutter volume and CG compression, quantified by the ratio between maximal and minimal diameter (D-ratio). In addition, renal artery flow was studied in a physiologic flow model and compared with the control. RESULTS: The average gutter volume was 343.5 +/- 142.0 mm3, with the lowest gutter volume in the EVAS-Viabahn (W. L. Gore & Associates, Flagstaff, Ariz) combination (102.6 mm3) and the largest in the AFX-Advanta V12 (Atrium Medical Corporation, Hudson, NH) configuration (559.6 mm3). The maximum D-ratio was larger in self-expanding CGs than in balloon-expandable CGs in all configurations (2.02 +/- 0.34 vs 1.39 +/- 0.13). The CG compression had minimal influence on renal volumetric flow (right, 390.7 +/- 29.4 mL/min vs 455.1 mL/min; left, 423.9 +/- 28.3 mL/min vs 410.0 mL/min in the control). CONCLUSIONS: This study showed that gutter volume was lowest in ch-EVAS in combination with a Viabahn CG. CG compression was lower in configurations with the Advanta V12 than with Viabahn. Renal flow is unrestricted by CG compression. PMID- 27988157 TI - Successful microscopic renal autotransplantation for left renal aneurysm associated with segmental arterial mediolysis. AB - Segmental arterial mediolysis (SAM) is an uncommon, nonarteriosclerotic vascular disease. SAM is characterized by lysis of arterial media and can lead to aneurysm formation. The renal arteries are the third most common arteries associated with SAM. We report the case of a 32-year-old man with left renal artery aneurysm associated with SAM. We successfully performed left renal autotransplantation using microscopic vascular reconstruction. SAM is characterized by vascular fragility; therefore, microscopic surgery is favorable for treating aneurysms associated with SAM. PMID- 27988158 TI - The effect of surgeon and hospital volume on mortality after open and endovascular repair of abdominal aortic aneurysms. AB - BACKGROUND: Higher hospital and surgeon volumes are independently associated with improved mortality after open repair of abdominal aortic aneurysms (AAAs) in the era before endovascular AAA repair (EVAR). The effects of both surgeon and hospital volume on mortality after EVAR and open repair in the current era are less well defined. METHODS: We studied Medicare beneficiaries who underwent elective AAA repair from 2001 to 2008. Volume was measured by procedure type during the 1-year period preceding each procedure and was further categorized into quintiles of volume for surgeon and hospital. Multilevel logistic regression models were used to evaluate the effect of surgeon volume, accounting for hospital volume, on mortality after adjusting for patient demographic and comorbid conditions as well as the analogous effect of hospital volume adjusting for surgeon volume. The multilevel models included random effects for surgeon and hospital to account for the clustering of multiple patients within the same surgeon and within the same hospital. RESULTS: We studied 122,495 patients who underwent AAA repair (open: 45,451; EVAR: 77,044). After EVAR, perioperative mortality did not differ by surgeon volume (quintile 1 [0-6 EVARs]: 1.8%; quintile 5 [28-151 EVARs]: 1.6%; P = .29), but decreased with greater hospital volume (quintile 1 [0-9 EVARs]: 1.9%; quintile 5 [49-198 EVARs]: 1.4%; P < .01). After open repair, perioperative mortality decreased with both higher surgeon volume (quintile 1 [0-3 open repairs]: 6.4%; quintile 5 [14-62 open repairs]: 3.8%; P < .01) and hospital volume (quintile 1 [0-5 open repairs]: 6.3%; quintile 5 [14-62 open repairs]: 3.8%; P < .01). After adjustment for other predictors, surgeon volume was not associated with perioperative mortality after EVAR (odds ratio [OR], 0.9; 95% confidence interval [CI], 0.7-1.1); however, hospital volume was associated with higher perioperative mortality (quintile 1: OR, 1.5; 95% CI, 1.2-1.9; quintile 2: OR, 1.3; 95% CI, 1.02-1.6; and quintile 3: OR, 1.2; 95% CI, 1.01-1.5, compared with 5). After open repair, higher surgeon volume was also associated with lower mortality (quintile 1: OR, 1.5; 95% CI, 1.3-1.8; quintile 2: OR, 1.3; 95% CI, 1.1-1.6; and quintile 3: OR, 1.2; 95% CI, 1.1-1.4, compared with 5). Risk of mortality also was higher for patients treated at lower-volume hospitals (quintile 1: OR, 1.3; 95% CI, 1.1-1.5; quintile 2: OR, 1.3; 95% CI, 1.1 1.5; and quintile 3: OR, 1.2; 95% CI, 1.1-1.4, compared with 5). CONCLUSIONS: After EVAR, hospital volume is minimally associated with perioperative mortality, with no such association for surgeon volume. After open AAA repair, surgeon and hospital volume are both strongly associated with mortality. These findings suggest that open surgery should be concentrated in hospitals and surgeons with high volume. PMID- 27988159 TI - Antimicrobial-bonded graft patency in the setting of a polymicrobial infection in swine (Sus scrofa). AB - BACKGROUND: Polytetrafluoroethylene (PTFE) and Dacron are commonly used as arterial conduits in vascular trauma or infection when vein interposition graft may not be available. This study used a previously validated large animal model of polymicrobial infection to assess the patency and infectious resistance of a novel, antibiotic-impregnated graft material compared with PTFE and Dacron. METHODS: Forty-eight animals were placed into five groups for a 21-day survival period. A 6-mm PTFE, Dacron, or antimicrobial-bonded graft was used to replace the iliac artery and then inoculated with 1 * 107 colonies/mL of genetically labeled Pseudomonas aeruginosa and Staphylococcus aureus. Native vessels with and without contamination served as control groups. The primary end points were graft patency (determined by duplex ultrasound and necropsy) and graft infection (culture with molecular analysis). Secondary end points included physiologic measurements, blood cultures, laboratory data, and histopathology. RESULTS: At 21 days, 50% of PTFE, 62.5% of Dacron, and 100% of the antimicrobial-bonded grafts remained patent (P = .04). PTFE and Dacron had an equivalent number of overall infections, 87.5% and 75%, respectively (P = 1.0). There was no significant difference of infectious organisms between standard materials. The infection rate of the antimicrobial-bonded graft (25%) was significantly less than that of both PTFE and Dacron (P < .01), and all of these infections were secondary to P. aeruginosa. Clinical data did not vary significantly between groups. There were no mortalities in the protocol secondary to graft blowout or sepsis. CONCLUSIONS: The antimicrobial-bonded graft material outperformed standard PTFE and Dacron in the setting of polymicrobial infection with regard to graft patency and infection. The novel prosthetic material appears to be resistant to infection with S. aureus and to limit the growth of P. aeruginosa. Additional studies are recommended to explore the role of this antibiotic-bonded graft for use in the setting of vascular infection or trauma. PMID- 27988160 TI - Vascular surgeon-hospitalist comanagement improves in-hospital mortality at the expense of increased in-hospital cost. AB - OBJECTIVE: We have shown that vascular surgeon- hospitalist co management resulted in improved in-hospital mortality rates. We now aim to assess the impact of the hospitalist co management service (HCS) on healthcare cost. METHODS: A total of 1558 patients were divided into three cohorts and compared: 516 in 2012, 525 in 2013, and 517 in 2014. The HCS began in January 2013. Data were standardized for six vascular surgeons that were present 2012-2014. New attendings were excluded. Ten hospitalists participated. Case mix index (CMI), contribution margin, total hospital charges (THCs), length of stay (LOS), actual direct costs (ADCs), and actual variable indirect costs (AVICs) were compared. Analysis of variance with post-hoc tests, t-tests, and linear regressions were performed. RESULTS: THC rose by a mean difference of $14,578.31 between 2012 and 2014 (P < .001) with a significant difference found between all groups during the study period (P = .0004). ADC increased more than AVIC; however, both significantly increased over time (P = .0002 and P = .014, respectively). A mean $3326.63 increase in ADC was observed from 2012 to 2014 (P < .0001). AVIC only increased by an average $392.86 during the study period (P = .01). This increased cost was observed in the context of a higher CMI and longer LOS. CMI increased from 2.25 in 2012 to 2.53 in 2014 (P = .006). LOS increased by a mean 1.02 days between 2012 and 2014 (P = .016), and significantly during the study period overall (P = .018). After adjusting for CMI, LOS increases by only 0.61 days between 2012 and 2014 (P = .07). In a final regression model, THC is independently predicted by comanagement, CMI, and LOS. After adjusting for CMI and LOS, the increase in THC because of comanagement (2012 vs 2014) accounts for only $4073.08 of the total increase (P < .001). During this time, 30-day readmission rates decreased by ~7% (P = .005), while related 30-day readmission rates decreased by ~2% (P = .32). Physician contribution margin remained unchanged over the 3-year period (P = .76). The most prevalent diagnosis-related group was consistent across all years. Variation in the principal diagnosis code was observed with the prevalence of circulatory disorders because of type II diabetes replacing atherosclerosis with gangrene as the most prevalent diagnosis in 2013 and 2014 compared with 2012. CONCLUSIONS: In-hospital cost is significantly higher since the start of the HCS. This surge may relate to increased CMI, LOS, and improved coding. This increase in cost may be justified as we have observed sustained reduction in in-hospital mortality and slightly improved readmission rates. PMID- 27988161 TI - Developmental changes in neural correlates of cognitive reappraisal: An ERP study using the late positive potential. AB - OBJECTIVE: The reduction of the amplitude of the late positive potential (LPP) following cognitive reappraisal has been used as a neural marker of emotion regulation. However, studies employing this neural marker in children are scarce and findings are not conclusive, with most studies showing a lack of LPP modulation after reappraisal in children in the age range of 5-12 years. The aim of the current study was therefore to investigate developmental changes in sensitivity of LPP modulation to cognitive reappraisal. To do so, LPP modulation due to cognitive reappraisal of negative pictures was compared between two age groups (8- to 11- versus 12- to 15-year-olds) and regression analyses were applied within the total sample to test whether sensitivity of LPP modulation shows a linear increase with age. METHOD: In 63 children the LPP was measured after negative pictures that were either combined with a negative story or with a neutral, reappraising story. RESULTS: Although groups did not differ for self reports on reappraisal, a significant reduction of LPP following cognitive reappraisal was only found in the older children, whereas such an effect was absent in the younger children. Findings were similar for boys and girls. Additional analyses showed a linear increase in sensitivity of LPP modulation with age. CONCLUSIONS: The results indicate that LPP modulation as measured in the current paradigm can be used as a valid index of emotion regulation in boys and girls but that caution is recommended using it in younger children. PMID- 27988162 TI - Synergetic Role of Hypromellose and Methacrylic Acid Copolymer in the Dissolution Improvement of Amorphous Solid Dispersions. AB - Synergetic role of polymer blending on dissolution of amorphous solid dispersion was investigated. Dissolution rates of hypromellose (HPMC) and methacrylic acid copolymer (EUD) from the HPMC/EUD spray-dried sample (SPD) were improved compared to those of each single polymer SPD. Differential scanning calorimetry measurements revealed that the structural change in HPMC following heating was inhibited by co-spray-drying with EUD, suggesting an intermolecular interaction between the polymers. 13C solid-state nuclear magnetic resonance (NMR) spectroscopy detected the change induced in the hydroxyl group of HPMC by co spray-drying with EUD. Moreover, the carbonyl peak shape of EUD in the 13C NMR spectra differed between EUD SPD and HPMC/EUD SPD, indicating that the dimer structure of the carboxylic acid of EUD was partially disrupted by the interaction with HPMC. An intermolecular interaction occurred between HPMC and EUD. The hydrogen bond reformation likely improved the dissolution rates of the polymers. The ternary griseofulvin (GRF)/HPMC/EUD SPD showed a significantly higher supersaturation level of GRF than the mixtures containing equal amounts of binary GRF/HPMC and GRF/EUD SPDs. The change of interaction mode between polymers improved the dissolution of solid dispersion. Therefore, polymer blending based on interpolymer interactions could be a practical strategy for designing excellent solid dispersion formulations. PMID- 27988164 TI - Effects of a Single-Dose Interscalene Block on Pain and Stress Biomarkers in Patients Undergoing Arthroscopic Rotator Cuff Repair: A Randomized Controlled Trial. AB - PURPOSE: To compare the effects of a single-dose interscalene block and general anesthesia (SISB/GA) with the effects of GA only in the early postoperative period after arthroscopic rotator cuff repair by evaluating subjective pain visual analog scale scores and objective pain-related stress biomarkers. METHODS: Patients refractory to conservative treatment of the affected shoulder were enrolled in this prospective, randomized endpoint study. Patients diagnosed with a rotator cuff tear (1-4 cm) based on magnetic resonance imaging were included. Exclusion criteria were small (<1 cm) and massive (>4 cm) rotator cuff tears. Thirty-one patients each were randomized into the SISB/GA and GA treatment groups. Preoperative pain scores were measured at 6:00 AM on the day of surgery, measured again at 1 and 6 hours postoperatively, and then every 6 hours until 3 days postoperatively. Blood sampling was performed to evaluate the stress biomarkers insulin, dehydroepiandrosterone sulfate, and fibrinogen preoperatively at 6:00 AM on the day of surgery and postoperatively at 18, 42, and 66 hours (6:00 AM on postoperative days 1-3). RESULTS: Pain scores were significantly decreased in the SISB/GA group (2.50 +/- 0.94) versus the GA group (3.82 +/- 1.31) on the day of surgery (P < .001), and especially at 6 hours postoperatively (SISB/GA: 2.42 +/- 1.43; GA: 4.23 +/- 2.17; P < .001). Insulin was decreased significantly in the SISB/GA group (10.55 +/- 7.92 MUU/mL) versus the GA group (20.39 +/- 25.60 MUU/mL) at 42 hours postoperatively (P = .048). There was no significant change in dehydroepiandrosterone sulfate or fibrinogen over time (P > .05). CONCLUSIONS: After arthroscopic rotator cuff repair, an SISB effectively relieved pain on the day of surgery without any complications. In addition, insulin levels were significantly reduced at 42 hours postoperatively. LEVEL OF EVIDENCE: Level I, prospective randomized controlled trial. PMID- 27988166 TI - Erratum to "Relationships between left atrial pericardial fat and permanent atrial fibrillation: Results of a case-control study" [Diagn. Interv. Imaging. 97 (2016) 307-13]. PMID- 27988165 TI - Increased Femoral Anteversion Influence Over Surgically Treated Recurrent Patellar Instability Patients. AB - PURPOSE: To verify the influence that increased femoral anteversion (FA) has on patients with recurrent patellar instability (RPI) treated by anteromedialization tibial tubercle osteotomy (TTO) combined with medial patellofemoral ligament reconstruction (MPFLR) and to present the midterm outcomes of these patients. METHODS: From January 2008 to August 2013, skeletally mature patients with RPI and tibial tubercle (TT)-trochlear groove (TG) >= 17 mm who underwent anteromedialization TTO combined with MPFLR were evaluated for J sign, patellar glide, apprehension test, increased FA, Caton index, trochlea dysplasia, TT-TG, Kujala, International Knee Documentation Committee subjective knee evaluation form, and Tegner. Increased FA was determined clinically by a difference of more than 30 degrees between hip internal and external rotation, 70 degrees or more of hip internal rotation, and 30 degrees or more of femoral neck anteversion. A subgroup analysis involving increased FA was made. RESULTS: Forty-eight patients composed the study group. Mean follow-up was 41.5 +/- 11.05 months. The J-sign was present in 86% before surgery and none postoperatively (P < .001). All patients had a positive apprehension test or a patellar luxation at the patellar glide test rated as grade 4 before surgery. After surgery, the mean glide was 1.29 +/- 0.45 with no apprehension (P < .001). Increased FA was present in 18.7%. Caton index before surgery was 1.11 +/- 0.21 and 0.99 +/- 0.11 postoperatively (P = .004). Trochlea dysplasia was present in all patients. TT-TG preoperatively was 20.77 +/- 2.12 mm and 11.33 +/- 1.24 mm postoperatively (P < .001). Functional scores improved preoperatively to postoperatively (P < .001) with Kujala and International Knee Documentation Committee means: 59.08 to 84.37; 52.6 to 85.5, respectively. Tegner preinjury score was 5.4 and postoperatively was 5.2 (P = .01). Increased FA group had worse Kujala compared with the normal FA group and worse Kujala improvement: 77.7 and 85.89 (P = .012), and 21.7 and 26.1, respectively (P < .001). CONCLUSIONS: Increased FA in patients with RPI had a negative effect on the outcome of anteromedialization TTO combined with MPFLR. Combined anteromedialization TTO and MPFLR had good functional midterm outcomes in treating patients with RPI and TT-TG >= 17 mm. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 27988163 TI - The Degradation Chemistry of Farglitazar and Elucidation of the Oxidative Degradation Mechanisms. AB - The chemical degradation of farglitazar (1) was investigated using a series of controlled stress testing experiments. Farglitazar drug substance was stressed under acidic, natural pH, basic, and oxidative conditions in solution. In the solid state, the drug substance was stressed with heat, high humidity, and light. Farglitazar was found to be most labile toward oxidative stress. A series of mechanistic experiments are described in which the use of 18O-labelled oxygen demonstrated that oxidative degradation of farglitazar is caused primarily by singlet oxygen formed under thermal conditions. Major degradation products were isolated and fully characterized. Mechanisms for the formation of degradation products are proposed. Drug product tablets were also stressed in the solid state with heat, high humidity, and light. Stressed tablets afforded many of the same degradation products observed during drug substance stress testing, with oxidation again being the predominant degradation pathway. Evidence for the activity of singlet oxygen, formed during thermal stress testing of the solid oral dosage form, is presented. The degradation pathways observed during stress testing matched those observed during long-term stability trials of the drug product. PMID- 27988167 TI - Does Parmelina tiliacea lichen photosystem II survive at liquid nitrogen temperatures? AB - Parmelina tiliacea lichens kept in the wet and dry state were stored in liquid nitrogen for 1 week and the subsequent recovery of their photosynthetic apparatus was followed. The chlorophyll a fluorescence rise and the maximum quantum yield of primary photochemistry phiPo (FV/FM) were analysed for this purpose. Storage of wet thalli for 1 week in liquid nitrogen led to an impairment of photosystem II and probably the photosynthetic apparatus as a whole, from which the thalli did not recover over time. Thalli exposed in the dry state thalli were far less affected by the treatment and recovered well. These results indicate that the thalli are extremely tolerant to liquid nitrogen temperatures only in the dry state. PMID- 27988168 TI - DNA methylation and histone deacetylation regulating insulin sensitivity due to chronic cold exposure. AB - In this study, we investigated the causal relationship between chronic cold exposure and insulin resistance and the mechanisms of how DNA methylation and histone deacetylation regulate cold-reduced insulin resistance. 46 adult male mice from postnatal day 90-180 were randomly assigned to control group and cold exposure group. Mice in cold-exposure group were placed at temperature from -1 to 4 degrees C for 30 days to mimic chronic cold environment. Then, fasting blood glucose, blood insulin level and insulin resistance index were measured with enzymatic methods. Immunofluorescent labeling was carried out to visualize the insulin receptor substrate 2 (IRS2), Obese receptor (Ob-R, a leptin receptor), voltage-dependent anion channel protein 1 (VDAC1), cytochrome C (cytC), 5 methylcytosine (5-mC) positive cells in hippocampal CA1 area. Furthermore, the expressions of some proteins mentioned above were detected with Western blot. The results showed: 1 Chronic cold exposure could reduce the insulin resistance index (P < 0.01) and increase the number of IRS2 positive cells and Ob-R positive cells in hippocampus (P < 0.01). 2 The expressions of mitochondrial energy-relative proteins, VDAC1 and cytC, were higher in cold-exposure group than in control group with both immunohistochemical staining and Western blot (P < 0.01). 3 Chronic cold exposure increased DNA methylation and histone deacetylation in the pyramidal cells of CA1 area and led to an increase in the expression of histone deacetylase 1 (HDAC1) and DNA methylation relative enzymes (P < 0.01). In conclusion, chronic cold exposure can improve insulin sensitivity, with the involvement of DNA methylation, histone deacetylation and the regulation of mitochondrial energy metabolism. These epigenetic modifications probably form the basic mechanism of cold-reduced insulin resistance. PMID- 27988169 TI - The Effects of Spacing, Naps, and Fatigue on the Acquisition and Retention of Laparoscopic Skills. AB - BACKGROUND: Earlier research has shown that laparoscopic skills are trained more efficiently on a spaced schedule compared to a massed schedule. The aim of the study was to estimate to what extent the spacing interval, naps, and fatigue influenced the effectiveness of spacing laparoscopy training. METHODS: Overall 4 groups of trainees (aged 17-41y; 72% female; Nmassed = 40; Nbreak = 35; Nbreak nap = 37; Nspaced = 37) without prior experience were trained in 3 laparoscopic tasks using a physical box trainer with different scheduling interventions. The first (massed) group received three 100-minute training sessions consecutively on a single day. The second (break) group received the sessions interrupted with two 45-minute breaks. The third (break-nap) group had the same schedule as the second group, but had two 35-minute powernap intervals during the breaks. The fourth (spaced) group had the 3 sessions on 3 consecutive days. A retention session was organized approximately 3 months after training. RESULTS: The results showed an overall pattern of superior performance at the end of training and at retention for the spaced group, followed by the break-nap, break, and massed group, respectively. The spaced and break-nap group significantly outperformed the break and massed group, with effect sizes ranging from 0.20 to 0.37. CONCLUSIONS: Spacing laparoscopic training over 3 consecutive days or weeks is superior to massed training, even if the massed training contains breaks. Breaks with sleep opportunity (i.e., lying, inactive, and muted sensory input) enhance performance over training with regular breaks and traditional massed training. PMID- 27988170 TI - Assessing Resident Surgical Volume Before and After Initiation of a Female Pelvic Medicine and Reconstructive Surgery Fellowship. AB - OBJECTIVES: The effect of fellowship programs on resident training for gynecologic surgery volume has not been clearly defined. The purpose of our study is to assess resident surgical volume for laparoscopic and vaginal hysterectomy before and after initiation of a female pelvic medicine and reconstructive surgery (FPMRS) fellowship. DESIGN: A retrospective review of Accreditation Council for Graduate Medical Education Resident Case Logs of obstetrics and gynecology residents who graduated in the 3 years before and after initiation of a FPMRS fellowship was performed. Mean values of vaginal and laparoscopic hysterectomies were compared using two-tailed t-tests with statistical significance set at p < 0.05. SETTING: Obstetrics and gynecology resident case logs at the Ronald Reagan University of California Los Angeles (UCLA) Medical Center were assessed. The UCLA Medical Center, located in Los Angeles, CA, is a tertiary referral center with a graduating class of 7 obstetrics and gynecology residents yearly. PARTICIPANTS: Obstetrics and gynecology residents who graduated from residency 3 years before and after imitation of a FPMRS fellowship were included. In the 3 years before the start of the fellowship, 20 residents graduated, whereas 21 residents graduated after the start of the fellowship. RESULTS: Residents who graduated in the 3 years after the start of the FPMRS fellowship, finished with 4.6 less vaginal hysterectomies compared with residents who graduated before the fellowship (p = 0.022). Residents who graduated in the 3 years after the start of the FPMRS fellowship finished with 3.2 more laparoscopic hysterectomies compared with residents who graduated before the fellowship although this was not significant (p = 0.25). CONCLUSIONS: Resident surgical volume was significantly decreased for vaginal hysterectomy after the initiation of a FPMRS fellowship, whereas laparoscopic hysterectomy volume was not significantly changed. Longer follow-up and a national assessment are necessary to determine the broader effect of fellowship training on resident surgical experience. PMID- 27988171 TI - Evaluation of a rapid immunochromatographic test for the detection of OXA-48 carbapenemase. AB - We evaluated the OXA-48K-Set, a rapid immunochromatographic test for the detection of Oxacillinase-48 (OXA-48) carbapenemases, among 37 strains expressing OXA-48 and OXA-48-like carbapenemases and 20 additional strains harboring other beta-lactamases. The test showed 100% sensitivity and specificity and the results were obtained in 15minutes. PMID- 27988172 TI - [Antiemetics and cardiac effects potentially linked to prolongation of the QT interval: Case/non-case analysis in the national pharmacovigilance database]. AB - OBJECTIVES: Observational retrospective studies have linked domperidone and prolonged QT interval, ventricular arrhythmias and risk of sudden death. Since then, antiemetic prescription was applied to other molecules (including metopimazine). The aim of this study was to evaluate the profile of adverse cardiac effects associated with QT prolongation for each antiemetic available in France. METHODS: We conducted disproportionality analyses (case/non-case method), based on the observations recorded consecutively in the French national pharmacovigilance database between 2004 and 2013. Cases were defined by following MedDRA terms: prolongation of the QT interval, syncope, sudden death, cardiac arrest, ventricular arrhythmias including torsades de pointes; non-cases were other adverse events reported during the same period. We analyzed the presence of each antiemetic among cases and non-cases and measured the disproportionality by reporting odds ratios (ROR). We validate the assay with a positive control (methadone) and a negative control (acetaminophen). RESULTS: We compared 2093 cases (94 with antiemetics) to 253,665 non-cases (7015 with antiemetics). Among antiemetics, adverse cardiac effects studied were more frequently found with notifications including domperidone (ROR=2.0, 95% CI=[1.3; 3.0]), ondansetron (ROR=1.8, 95% CI=[1.3; 2.6]) and granisetron (ROR=3.4, 95% CI=[1.5; 7.6]). Metopimazine was not statistically associated with that risk (ROR=2.0; 95% CI=[0.8; 4.8]). CONCLUSION: We confirmed a risk of cardiac adverse event related to prolongation of the QT interval with domperidone and setrons. These results suggest caution when prescribing antiemetics and encourage systematic reporting of adverse cardiac effects observed with these molecules. PMID- 27988173 TI - First survey on antibiotic resistance markers in Enterobacteriaceae in Cochabamba, Bolivia. AB - A molecular survey was conducted in Cochabamba, Bolivia, to characterize the mechanism involved in the resistance to clinically relevant antibiotics. Extended Spectrum beta-lactamase encoding genes and plasmid-mediated quinolone resistance (PMQR) markers were investigated in a total of 101 oxyimino-cephalosporin resistant enterobacteria recovered from different health centers during four months (2012-2013). CTX-M enzymes were detected in all isolates, being the CTX-M 1 group the most prevalent (88.1%). The presence of blaOXA-1 was detected in 76.4% of these isolates. A high quinolone resistance rate was observed among the included isolates. The aac(6')-Ib-cr gene was the most frequent PMQR identified (83.0%). Furthermore, 6 isolates harbored the qnrB gene. Interestingly, qepA1 (6) and oqxAB (1), were detected in 7 Escherichia coli, being the latter the first to be reported in Bolivia. This study constitutes the first molecular survey on resistance markers in clinical enterobacterial isolates in Cochabamba, Bolivia, contributing to the regional knowledge of the epidemiological situation. The molecular epidemiology observed herein resembles the scene reported in South America. PMID- 27988174 TI - [Medico-economic evaluation of urological cares of spinal cord injured patients: A review]. AB - INTRODUCTION: To provide an overview of the urological management of spinal cord injured patients based on an economic analysis. MATERIALS AND METHODS: A literature search from January 1994 to December 2014 was performed using Medline and Embase database using the following keywords: cost-effectiveness; cost benefit; cost-utility; spinal cord injury; neurogenic bladder; intermittent catheterization; antimuscarinics; botulinum toxin; sacral neuromodulation; tibial nerve; Brindley; sphincterotomy. The tool used for comparison was the QALY ("quality adjusted life years"); an indicator between 0 and 1 allowing the comparison between two medical treatments using cost per QALY. RESULTS: Solifenacin (5 to 10mg) is the most cost-effective treatment with an incremental cost-effectiveness ratio (ICER) of 19,893 ?/QALY compared to trospium 40mg, of 16,657 ?/QALY compared to trospium 60mg, of 12,309 L/QALY compared to oxybutinin. Botulinum toxin A is also cost-effective with an ICER of 24,720 $/QALY compared to best supportive cares for anticholinergic-refractory neurogenic detrusor overactivity. CONCLUSION: Solifenacin and botulinum toxin A appears to be the most cost-effective treatments for spinal injured urological cares. There is a pressing need to both increase and improve data collection and research on spinal cord injury. PMID- 27988175 TI - [The Allium ureteral stent in the management of ureteral stenoses, a retrospective, multicenter study]. AB - OBJECTIVE: To evaluate the performance of the Allium ureteral stent in the management of patients initially treated with double J stents for the long-term treatment of stenoses. MATERIALS AND METHODS: We performed a retrospective multicenter study involving 36 patients who received 37 Allium ureteral stents (metallic 24 Fr) between September 2011 and January 2015 in one of three French teaching hospital centers. The mean age of the patients was 63.8 years (min-max: 33-88 years) and most were women (70%). Of these patients, 5.6% had ureteral fistulae and 94.4% stenoses. Mean stenosis length was 4.15cm (min-max: 0.5-12cm). All analyses were two-tailed with an alpha risk of 0.05. Statistical significance was set at P<0.05. Results were expressed as hazard ratios (HR) with 95% confidence intervals and P-values. RESULTS: During the follow-up period, 37% of the stents were removed due to migration (complication occurring in 18.9% of the studied population), infection (10.8%) or intolerance (8.1%). The other stents were removed after 1 year. Clinical effectiveness, defined as a lack of stenosis or fistula recurrence, was 52.8% after a mean follow-up of 7.1 months. CONCLUSION: Clinically effective in more than 50% of cases, the Allium ureteral stent appears to be an alternative to indwelling double J stents. LEVEL OF EVIDENCE: 4. PMID- 27988176 TI - Anxiogenic-like effects of fluoxetine render adult male rats vulnerable to the effects of a novel stress. AB - Fluoxetine (FLX) has paradoxical anxiogenic-like effects during the acute phase of treatment. In adolescent (35d-old) male rats, the stress-like effects induced by short-term (3d-4d) FLX treatment appear to involve up-regulation of paraventricular nucleus (PVN) arginine vasopressin (AVP) mRNA. However, studies on FLX-induced anxiety-like effects in adult rodents are inconclusive. Herein, we sought to study the response of adult male rats (60-65d-old) to a similar FLX treatment, also investigating how the stressful component, inherent to our experimental conditions, contributed to the responses. We show that FLX acutely increased plasma corticosterone concentrations while it attenuated the stress induced-hyperthermia (SIH) as well as it reduced (~40%) basal POMC mRNA expression in the arcuate nucleus (ARC). However, FLX did not alter the basal expression of PVN-corticotrophin-releasing hormone (CRH), anterior pituitary-pro opiomelanocortin (POMC) and raphe nucleusserotonin transporter (SERT). Nonetheless, some regressions point towards the plausibility that FLX activated the hypothalamic-pituitary-adrenal (HPA). The behavioral study revealed that FLX acutely increased emotional reactivity in the holeboard, effect followed by a body weight loss of ~2.5% after 24h. Interestingly, i.p. injection with vehicle did not have behavioral effects, furthermore, after experiencing the stressful component of the holeboard, the rats kept eating and gaining weight as normal. By contrast, the stress-naive rats reduced food intake and gained less weight although maintaining a positive energy state. Therefore, on one hand, repetition of a mild stressor would unchain compensatory mechanisms to restore energy homeostasis after stress increasing the resiliency to novel stressors. On the other hand, FLX might render stressed adult rats vulnerable to novel stressors through the emergence of counter-regulatory changes, involving HPA axis activation and diminished sympathetic output may be due to reduced melanocortin signaling. Therefore, complex interactions between hypothalamic CRH and POMC might be determining the adaptive nature of the response of adult male rats to FLX and/or stress. PMID- 27988178 TI - A novel protein coding potential of long intergenic non-coding RNAs (lincRNAs) in the kinetoplastid protozoan parasite Leishmania major. AB - Cutaneous leishmaniasis (CL) is caused by a kinetoplastid protozoan parasite Leishmania major, as a skin ulcer at the site of the sandfly bite. CL is curable and in most cases ulcers heal spontaneously within three to six months leaving a scar and disfiguration. Complete genome of L. major was reported in 2005 at the very initial phase of kinetoplastid parasite genome sequencing project. Presently, L. major genome is most studied and comprehensively annotated genome and therefore, it is being used as a reference genome for annotating recently sequenced Leishmanial genomes. A recent study reporting global transcriptome of L. major promastigotes, identified 1884 uniquely expressed non-coding RNAs (ncRNA) in L. major. In the current study, an in-depth analysis of the 1884 novel ncRNAs was carried out using a proteogenomic approach to identify their protein coding potential. Our analysis resulted in identification of eight novel protein coding genes based on mass spectrometry data. We have analyzed each of these eight novel CDS and in the process have improved the genome annotation of L. major on the basis of mass spectrometry derived peptide data. Although sequenced a decade ago, the improvement in the L. major genome annotation thus is an ongoing process. PMID- 27988177 TI - Unbiased estimation of cell number using the automatic optical fractionator. AB - A novel stereology approach, the automatic optical fractionator, is presented for obtaining unbiased and efficient estimates of the number of cells in tissue sections. Used in combination with existing segmentation algorithms and ordinary immunostaining methods, automatic estimates of cell number are obtainable from extended depth of field images built from three-dimensional volumes of tissue (disector stacks). The automatic optical fractionator is more accurate, 100% objective and 8-10 times faster than the manual optical fractionator. An example of the automatic fractionator is provided for counts of immunostained neurons in neocortex of a genetically modified mouse model of neurodegeneration. Evidence is presented for the often overlooked prerequisite that accurate counting by the optical fractionator requires a thin focal plane generated by a high optical resolution lens. PMID- 27988179 TI - Shifting of attentional set is inadequate in severe burnout: Evidence from an event-related potential study. AB - Individuals with prolonged occupational stress often report difficulties in concentration. Work tasks often require the ability to switch back and forth between different contexts. Here, we studied the association between job burnout and task switching by recording event-related potentials (ERPs) time-locked to stimulus onset during a task with simultaneous cue-target presentation and unpredictable switches in the task. Participants were currently working people with severe, mild, or no burnout symptoms. In all groups, task performance was substantially slower immediately after task switch than during task repetition. However, the error rates were higher in the severe burnout group than in the mild burnout and control groups. Electrophysiological data revealed an increased parietal P3 response for the switch trials relative to repetition trials. Notably, the response was smaller in amplitude in the severe burnout group than in the other groups. The results suggest that severe burnout is associated with inadequate processing when rapid shifting of attention between tasks is required resulting in less accurate performance. PMID- 27988180 TI - Factors associated with reaching or not reaching target HbA1c after initiation of basal or premixed insulin in patients with type 2 diabetes. AB - AIMS: To evaluate factors associated with reaching or not reaching target glycated haemoglobin (HbA1c) levels by analysing the respective contributions of fasting hyperglycaemia (FHG), also referred to as basal hyperglycaemia, vs postprandial hyperglycaemia (PHG) before and after initiation of a basal or premixed insulin regimen in patients with type 2 diabetes. METHODS: This post-hoc analysis of insulin-naive patients in the DURABLE study randomised to receive either insulin glargine or insulin lispro mix 25 evaluated the percentages of patients achieving a target HbA1c of <7.0% (<53mmol/mol) per baseline HbA1c quartiles, and the effect of each insulin regimen on the relative contributions of PHG and FHG to overall hyperglycaemia. RESULTS: Patients had comparable demographic characteristics and similar HbA1c and FHG values at baseline in each HbA1c quartile regardless of whether they reached the target HbA1c. The higher the HbA1c quartile, the greater was the decrease in HbA1c, but also the smaller the percentage of patients achieving the target HbA1c. HbA1c and FHG decreased more in patients reaching the target, resulting in significantly lower values at endpoint in all baseline HbA1c quartiles with either insulin treatment. Patients not achieving the target HbA1c had slightly higher insulin doses, but lower total hypoglycaemia rates. CONCLUSION: Smaller decreases in FHG were associated with not reaching the target HbA1c, suggesting a need to increase basal or premixed insulin doses to achieve targeted fasting plasma glucose and improve patient response before introducing more intensive prandial insulin regimens. PMID- 27988182 TI - The importance of catchment vegetation for alkalinity, phosphorus burial and macrophytes as revealed by a recent paleolimnological study in a soft water lake. AB - The land use within a catchment may markedly affect the environmental conditions in a lake and the storage capability of its sediments. This study investigated how changes in the dominant catchment vegetation (from local stands of deciduous trees over extensive heathland with some agriculture to mainly coniferous forest) occurring during the last ca. 200years were reflected in the sediments of a soft water lake and how these changes influenced the lake ecosystem. Pollen, macrofossils, metals, different phosphorus (P) forms, organic matter, carbon and nitrogen contents were determined in short sediment cores. This novel combination of proxies revealed that 1) the reduction of deciduous trees in the watershed seemingly reduced the calcium (Ca) supply to the lake and thereby its buffering capacity. This development was accompanied by decreased abundances of Ca dependent species and subsequent increases in acidophilic species. 2) The sedimentary contents of organic matter, non-reactive P and humic-bound P were evidently higher in sediments deposited during the time when deciduous trees were abundant, which is probably linked to a stabilising effect by Ca. 3) An erosion event clearly reduced the amounts of macrofossils of isoetid species and characeans, indicating a reduction in their maximum distribution depth because of lower water transparency. Overall, the results of our paleolimnological study are of importance within lake management by convincingly showing how land use changes may (irreversibly) affect environmental conditions and species composition in soft water lakes and the storage of organic matter and P in their sediments. PMID- 27988181 TI - Incidence of Adverse Reactions to Metal Debris From 28-mm Metal-on-Metal Total Hip Arthroplasties With Minimum 10 Years of Follow-Up: Clinical, Laboratory, and Ultrasound Assessment of 44 Cases. AB - BACKGROUND: Total hip arthroplasty with metal-on-metal (MoM) bearings has been suspected to cause adverse reactions to metal debris (ARMD), with the incidence varying greatly by implant type and patient gender. The prevalence of ARMD from small-diameter MoM bearings in women is unknown, especially after 10 years of follow-up (FU). METHODS: Cementless 28-mm MoM total hip arthroplasty bearings (Metasul) were implanted consecutively in 42 active women between 1996 and 2002. They were reviewed after a minimum of 10 years' FU with clinical, laboratory, radiological, and ultrasound assessments. RESULTS: Mean FU was 15.9 years (range, 13-18). The mean Postel-Merle d'Aubigne and Oxford scores were 16.9 (range, 13 18) and 15.1 (range, 12-24), respectively, at FU. Mean cup inclination angle was 46.3 degrees (range, 35 degrees -57 degrees ). No femoral osteolysis was detected, but limited acetabular osteolysis (11%) over the screw holes occurred in 5 cases. No liquid or solid synovial reactions or ARMD were apparent on ultrasound, even in the 5 cases of pelvic osteolysis. Mean chromium levels were 1.32 MUg/L (range, 0.1-7.9) and cobalt levels were 1.85 MUg/L (range, 0.35-13.6). Cobalt was >3 MUg/L in only 3 cases. The 15.9-year survivorship was 95% (range, 94.1%-98.9%). CONCLUSION: Reliable results were obtained with 28-mm MoM bearings, notably in young, active patients. This implant configuration requires very accurate positioning. No ARMD was seen in this group at 16 years' FU. PMID- 27988183 TI - Spatio-temporal distribution and sources of Pb identified by stable isotopic ratios in sediments from the Yangtze River Estuary and adjacent areas. AB - To understand the spatio-temporal distribution and sources of Pb in the sediments of the Yangtze River Estuary and its adjacent areas, 25 surface sediments and 1 sediment core were collected from the study areas. The concentrations of Al and Pb of these sediments exhibit a decreasing trend from the nearshore towards the offshore, with higher concentrations in the coastal areas of the East China Sea (ECS) and southwest of Jeju Island. According to the stable isotopic ratios of Pb, in combination with the elemental ratios and clay mineral data, it is inferred that sedimentary Pb in the surface sediments of the coastal areas of the ECS may come primarily from the Yangtze River, while the Pb southwest of Jeju Island is probably derived from both the Yangtze and Yellow Rivers. The particulate Pb derived from the Yangtze River was possibly dispersed along two paths: the path southward along the coastline of the ECS and the path eastward associated with the Changjiang Diluted Water (CDW), which crosses the shelf of the ECS towards the area southeast of Jeju Island. Although the Yangtze River Basin witnessed rapid economic development during the period from the late 1970s to the middle 1990s, the influence of human activity on Pb concentration remained weak in the Yangtze River Estuary. Since the early 2000s, however, sedimentary Pb has been significantly increasing in the coastal mud areas of the ECS due to the increasing influence of human activity, such as the increase in atmospheric emission of anthropogenic Pb in China, construction of the Three Gorges Dam (TGD), and the construction of smaller dams in the upper reaches of the Yangtze River. Coal combustion and the smelting of non-ferrous metals are possible anthropogenic sources for the sedimentary Pb in the Yangtze River Estuary. PMID- 27988184 TI - Pyrite oxidation in the presence of hematite and alumina: I. Batch leaching experiments and kinetic modeling calculations. AB - Pyrite is one of the most common and geochemically important sulfide minerals in nature because of its role in the redox recycling of iron (Fe). It is also the primary cause of acid mine drainage (AMD) that is considered as a serious and widespread problem facing the mining and mineral processing industries. In the environment, pyrite oxidation occurs in the presence of ubiquitous metal oxides, but the roles that they play in this process remain largely unknown. This study evaluates the effects of hematite (alpha-Fe2O3) and alumina (alpha-Al2O3) on pyrite oxidation by batch-reactor type experiments, surface-sensitive characterization of the oxidation layer and thermodynamic/kinetic modeling calculations. In the presence of hematite, dissolved sulfur (S) concentration dramatically decreased independent of the pH, and the formation of intermediate sulfoxy anionic species on the surface of pyrite was retarded. These results indicate that hematite minimized the overall extent of pyrite oxidation, but the kinetic model could not explain how this suppression occurred. In contrast, pyrite oxidation was enhanced in the alumina suspension as suggested by the higher dissolved S concentration and stronger infrared (IR) absorption bands of surface-bound oxidation products. Based on the kinetic model, alumina enhanced the oxidative dissolution of pyrite because of its strong acid buffering capacity, which increased the suspension pH. The higher pH values increased the oxidation of Fe2+ to Fe3+ by dissolved O2 (DO) that enhanced the overall oxidative dissolution kinetics of pyrite. PMID- 27988185 TI - Global land-use allocation model linked to an integrated assessment model. AB - We developed a global land-use allocation model that can be linked to integrated assessment models (IAMs) with a coarser spatial resolution. Using the model, we performed a downscaling of the IAMs' regional aggregated land-use projections to obtain a spatial land-use distribution, which could subsequently be used by Earth system models for global environmental assessments of ecosystem services, food security, and climate policies. Here we describe the land-use allocation model, discuss the verification of the downscaling technique, and explain the influences of the downscaling on estimates of land-use carbon emissions. A comparison of the emissions estimated with and without downscaling suggested that the land-use downscaling would help capture the spatial distribution of carbon stock density and regional heterogeneity of carbon emissions caused by cropland and pasture land expansion. PMID- 27988186 TI - Organochlorine pesticides in tree bark and human hair in Yunnan Province, China: Concentrations, distributions and exposure pathway. AB - The concentrations and distributions of organochlorine pesticides (OCPs) in West China were investigated and internal and external exposure of humans to OCPs were assessed by analyzing samples of human hair and tree bark collected in Kaiyuan, in Yunnan Province, China. Dichlorodiphenyltrichloroethane and its metabolites (collectively called DDTs), hexachlorocyclohexanes (HCHs), and hexachlorobenzene (HCB) were the dominant OCPs in the human hair and tree bark samples. The mean total DDT, total HCH, and HCB concentrations in the tree bark samples were 298pg/g dry weight (dw), 100pg/g dw, and 183pg/g dw, respectively, and the mean total DDT, total HCH, and HCB concentrations in the hair samples were 2850pg/g dw, 348pg/g dw, and 1026pg/g dw, respectively. The results indicated that relatively new DDT and lindane inputs have occurred in the study area. DDT and lindane may have been released in products that are used locally. The HCB in the environment in the study area is mainly supplied by long-range atmospheric transport. External exposure was found to be the main factor controlling the p,p' DDT, gamma-HCH, and HCB concentrations in human hair, whereas p,p'-DDE and beta HCH were found to be mainly controlled by internal exposure. PMID- 27988187 TI - Validation of integrated water vapor from OMI satellite instrument against reference GPS data at the Iberian Peninsula. AB - This paper shows the validation of integrated water vapor (IWV) measurements retrieved from the Ozone Monitoring Instrument (OMI), using as reference nine ground-based GPS stations in the Iberian Peninsula. The study period covers from 2007 to 2009. The influence of two factors, - solar zenith angle (SZA) and IWV -, on OMI-GPS differences was studied in detail, as well as the seasonal dependence. The pseudomedian of the relative differences is -1 +/- 1% and the inter-quartile range (IQR) is 41%. Linear regressions calculated over each station show an acceptable agreement (R2 up to 0.77). The OMI-GPS differences display a clear dependence on IWV values. Hence, OMI substantially overestimates the lower IWV data recorded by GPS (~ 40%), while underestimates the higher IWV reference values (~ 20%). In connection to this IWV dependence, the relative differences also show an evident SZA dependence when the whole range of IWV values are analyzed (OMI overestimates for high SZA values while underestimates for low values). Finally, the seasonal variation of the OMI-GPS differences is also associated with the strong IWV dependence found in this validation exercise. PMID- 27988188 TI - Environmental exposure to DDT and its metabolites in cord serum: Distribution, enantiomeric patterns, and effects on infant birth outcomes. AB - Previous in vivo studies have suggested that prenatal exposure to dichlorodiphenyltrichloroethane (DDT) is endocrine disrupting, and may cause adverse health risks to newborns. In this cross-sectional study, non-invasive cord serum samples were collected from maternal-neonate pairs of an island population. Concentrations of DDT and its metabolites were analyzed to provide insights into the environmental exposure patterns and to elucidate their effects on birth outcomes. The average concentrations of p,p'-DDE, o,p'-DDD, p,p'-DDD, o,p'-DDT, p,p'-DDT and total DDTs were 0.463, 0.293, 0.089, 0.098, 0.441 and 1.384MUgg-1 lipid weight, respectively. Several maternal characteristics were identified as influencing factors on the environmental exposure distribution. The isomer ratios of individual components and the enantiomeric patterns of o,p'-DDD and o,p'-DDT indicated that historical technical DDT remains the predominant exposure source, though new sources of dicofol-type of DDT pollution must not be ignored. Using multivariable linear regression, increasing p,p'-DDD and p,p'-DDT levels were found to be significantly associated with an increase in neonatal birth weight, which deserves additional attention to obesity risks. No other birth outcome was found to be significant regarding DDT exposure. These findings raise the awareness of the prenatal risk of DDT and its metabolites among infants in contaminated areas. PMID- 27988189 TI - Frequency of extreme weather events and increased risk of motor vehicle collision in Maryland. AB - BACKGROUND: Previous studies have shown increased precipitation to be associated with higher frequency of traffic collisions. However, data regarding how extreme weather events, projected to grow in frequency, intensity, and duration in response to a changing climate, might affect the risk of motor vehicle collisions is particularly limited. We investigated the association between frequency of extreme heat and precipitation events and risk of motor vehicle collision in Maryland between 2000 and 2012. METHODS: Motor vehicle collision data was obtained from the Maryland Automated Accident Reporting System. Each observation in the data set corresponded to a unique collision event. This data was linked to extreme heat and precipitation events that were calculated using location and calendar day specific thresholds. A time-stratified case-crossover analysis was utilized to assess the association between exposure to extreme heat and precipitation events and risk of motor vehicle collision. Additional stratified analyses examined risk by road condition, season, and collisions involving only one vehicle. RESULTS: Overall, there were over 1.28 million motor vehicle collisions recorded in Maryland between 2000 and 2012, of which 461,009 involved injuries or death. There was a 23% increase in risk of collision for every 1-day increase in extreme precipitation event (Odds Ratios (OR) 1.23, 95% Confidence Interval (CI): 1.22, 1.27). This risk was considerably higher for collisions on roads with a defect or obstruction (OR: 1.46, 95% CI: 1.40, 1.52) and those involving a single vehicle (OR: 1.41, 95% CI: 1.39, 1.43). Change in risk associated with extreme heat events was marginal at best. CONCLUSION: Extreme precipitation events are associated with an increased risk of motor vehicle collisions in Maryland. PMID- 27988190 TI - Including the spatial variability of metal speciation in the effect factor in life cycle impact assessment: Limits of the equilibrium partitioning method. AB - In life cycle assessment (LCA), the potential terrestrial ecotoxicity effect of metals, calculated as the effect factor (EF), is usually extrapolated from aquatic ecotoxicological data using the equilibrium partitioning method (EqP) as it is more readily available than terrestrial data. However, when following the AMI recommendations (i.e. with at least enough species that represents three different phyla), there are not enough terrestrial data for which soil properties or metal speciation during ecotoxicological testing are specified to account for the influence of soil property variations on metal speciation when using this approach. Alternatively, the TBLM (Terrestrial Biotic Ligand Model) has been used to determine an EF that accounts for speciation, but is not available for metals; hence it cannot be consistently applied to metals in an LCA context. This paper proposes an approach to include metal speciation by regionalizing the EqP method for Cu, Ni and Zn with a geochemical speciation model (the Windermere Humic Aqueous Model 7.0), for 5213 soils selected from the Harmonized World Soil Database. Results obtained by this approach (EFEqPregionalized) are compared to the EFs calculated with the conventional EqP method, to the EFs based on available terrestrial data and to the EFs calculated with the TBLM (EFTBLMregionalized) when available. The spatial variability contribution of the EF to the overall spatial variability of the characterization factor (CF) has been analyzed. It was found that the EFsEqPregionalized show a significant spatial variability. The EFs calculated with the two non-regionalized methods (EqP and terrestrial data) fall within the range of the EFsEqPregionalized. The EFsTBLMregionalized cover a larger range of values than the EFsEqPregionalized but the two methods are not correlated. This paper highlights the importance of including speciation into the terrestrial EF and shows that using the regionalized EqP approach is not an acceptable proxy for terrestrial ecotoxicological data even if it can be applied to all metals. PMID- 27988192 TI - What is the Best We Have to Offer? PMID- 27988191 TI - Motion correction for diffusion weighted SMS imaging. PMID- 27988193 TI - A 4-Year Prospective Urological Assessment of In Utero Myelomeningocele Repair Does Gestational Age at Birth Have a Role in Later Neurogenic Bladder Pattern? AB - PURPOSE: Premature delivery is a major complication of in utero myelomeningocele repair. The prematurity rate in MOMS (Management of Myelomeningocele Study) was 79%, with a mean gestational age at birth of 34 weeks. We speculated that prematurity could also influence urological outcome in patients operated on prenatally for myelomeningocele. MATERIALS AND METHODS: Beginning in November 2011, we prospectively followed a population of patients with myelomeningocele who had undergone in utero repair. RESULTS: We compared patients based on gestational age at birth, ie younger than 34 weeks (group 1, 42 patients) and 34 weeks or older (group 2, 37 patients). Mean gestational age at birth was 28.3 weeks (range 25 to 33) in group 1 and 35.2 weeks (34 to 38) in group 2. Of the cases 47.5% in group 1 were classified as high risk, 35% as incontinent, 10% as hypocontractile and 7.5% as normal. By comparison, 54.5% of cases in group 2 were classified as high risk, 33.3% as incontinent and 12.1% as normal. Differences between the groups were not statistically significant. Mean followup was 27.9 months in group 1 and 24.3 months in group 2. CONCLUSIONS: Our results show that gestational age at birth has little impact on bladder pattern. These data reinforce the need to follow this population closely. PMID- 27988195 TI - A rare mandibular tumour. PMID- 27988194 TI - Hyper-CVAD Compared With BFM-like Chemotherapy for the Treatment of Adult Acute Lymphoblastic Leukemia. A Retrospective Single-Center Analysis. AB - BACKGROUND: Several induction regimens have been developed for treatment of adult patients with acute lymphoblastic leukemia (ALL). However, only a few prospective randomized trials have directly compared these regimens. PATIENTS AND METHODS: In this report, we retrospectively evaluated the outcome of 62 adult ALL patients treated with either hyper-CVAD (hyper fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; n = 38) or a BFM (Berlin-Frankfurt-Munster)-like regimen (n = 24) between November 2000 and January 2016 at the American university of Beirut Medical Center in Lebanon. The feasibility of allogeneic stem cell transplantation (allo-SCT) for those patients was also evaluated. RESULTS: The median follow-up time was 29 (range, 1-129) months. Fifteen (39%) and 10 (42%) patients underwent allo-SCT in the hyper-CVAD and BFM-like group, respectively. At the time of the last follow-up, 28 patients (74%) were in complete remission in the hyper-CVAD group versus 18 patients (75%) in the BFM like group. Of those, 20 patients (53%) versus 11 patients (46%) were minimal residual disease-negative at the last follow-up, respectively. The 3-year overall survival rate (71.9% vs. 76.9%; P = .808) and 3-year disease-free survival (54.7% vs. 76.4%; P = .435) were similar in hyper-CVAD group compared with the BFM-like group, respectively. Both chemotherapies were relatively well tolerated. CONCLUSION: Overall, despite the older age and a greater number of patients with high-risk category (including Philadelphia chromosome-positive) in the hyper-CVAD group, this did not translate into a difference in survival outcome between the 2 groups. The hyper-CVAD regimen appears to be feasible for adult patients with ALL in terms of tolerability and efficacy. PMID- 27988196 TI - The effect of non-diabetic chronic renal failure on olfactory function. AB - OBJECTIVES: In chronic renal failure (CRF), deterioration of glomerular filtration results in accumulation of metabolites in the body which affect all organs. This study was performed to investigate the olfactory functions, and determine if hemodialysis or peritoneal dialysis improves olfactory function in non-diabetic CRF patients. MATERIALS AND METHODS: The olfactory functions were analyzed in CRF patients not on a dialysis program and had a creatinine level>=2mg/dL, in CRF patients on hemodialysis or peritoneal dialysis, and in healthy controls. Diabetic patients were excluded since diabetes alone is a cause of olfactory dysfunction. The study group consisted of a total of 107 individuals including 38CRF patients on a hemodialysis program, 15 CRF patients on peritoneal dialysis, 30 patients with a creatinine level >= 2mg/dL without any need for dialysis, and 24 healthy controls with normal renal functions. Olfactory functions were analyzed with "Sniffin' sticks" test, and the groups were compared for the test results. RESULTS: All test parameters were impaired in patients with CRF. The median TDI scores of the patients with CRF and the healthy subjects were 24.75 (13-36) and 32.5 (27.75-37.75), respectively, with a statistically significant difference in between (P<0.001). The olfactory functions for the dialysis patients were better than those for the CRF patients not on a dialysis program (P=0.020). CONCLUSION: Non-diabetic CRF affects olfactory functions negatively. Dialysis improves olfactory functions in those patients. PMID- 27988197 TI - An unusual prenatal laryngeal image. PMID- 27988198 TI - Primary total laryngectomy and pharyngolaryngectomy in T4 pharyngolaryngeal cancers: Oncologic and functional results and prognostic factors. AB - OBJECTIVES: The aims of this study were to assess oncologic and functional outcome in primary total laryngectomy or pharyngolaryngectomy (TL/TL/TPL) for laryngeal or hypopharyngeal cancer with extra-laryngeal extension (T4) and to determine the predictive factors of these results. MATERIAL AND METHODS: A retrospective analysis was performed on the computerized medical records of all patients undergoing primary TL/TPL for T4 larynx or hypopharynx squamous cell carcinoma between 2000 and 2014 at our institution. Predictive factors of oncologic and functional outcome were investigated on univariate and multivariate analysis. RESULTS: Sixty-three patients (58 men, 5 women; mean age, 68.8+/-9.7 years) were included. Overall and disease-specific survivals were 69% and 80% at 3 years, and 56% and 69% at 5 years, respectively. On multivariate analysis, gender (female, P<0.001), ASA score (ASA>=3; P=0.006) and vascular embolism (P=0.006) had significant pejorative impact on overall survival. Six months after end of treatment, 90% of patients had recovered independent oral feeding and 83% of those with tracheoesophageal voice prostheses had recovered an intelligible voice. CONCLUSION: Primary TL/TPL remains the gold standard treatment for T4 larynx or hypopharynx cancer. It provides satisfactory oncologic and functional outcomes. PMID- 27988199 TI - Desmoid tumours of the head and neck in children: Review of management. AB - OBJECTIVE: Desmoid tumours of the head and neck in children are rare, local invasive and potentially fatal tumours. The purpose of this review is to discuss the management of these tumours in the light of a case series and a review of the literature. MATERIAL AND METHODS: This retrospective study summarised the medical data of children treated for desmoid tumours of the head and neck between 1976 and 2014. RESULTS: Five of the 6 children were treated by radical surgical resection, with positive surgical margins (R1) in 2 cases, followed by recurrence requiring further resection. One child with a very advanced lesion was treated by weekly methotrexate and vinorelbine chemotherapy for 18months, allowing 93% reduction of tumour volume without recurrence. CONCLUSIONS: Desmoid tumours of the head and neck in children are more aggressive than their adult counterparts and are associated with high morbidity and mortality and a high recurrence rate. CT and MRI imaging assessment should preferably be performed before biopsy. External beam radiotherapy must be avoided in children as it is less effective than in adults, and is responsible for long-term cosmetic and functional sequelae and even a risk of second tumours. Treatment is surgical whenever radical resection is possible. In patients presenting an excessive risk of morbidity and mortality, chemotherapy devoid of long-term adverse effects (such as methotrexate in combination with a Vinca alkaloid) can be proposed. Long-term follow-up must be ensured due to the risk of recurrence. PMID- 27988200 TI - Dissecting Costs of CT Study: Application of TDABC (Time-driven Activity-based Costing) in a Tertiary Academic Center. AB - RATIONALE AND OBJECTIVES: The lack of understanding of the real costs (not charge) of delivering healthcare services poses tremendous challenges in the containment of healthcare costs. In this study, we applied an established cost accounting method, the time-driven activity-based costing (TDABC), to assess the costs of performing an abdomen and pelvis computed tomography (AP CT) in an academic radiology department and identified opportunities for improved efficiency in the delivery of this service. MATERIALS AND METHODS: The study was exempt from an institutional review board approval. TDABC utilizes process mapping tools from industrial engineering and activity-based costing. The process map outlines every step of discrete activity and duration of use of clinical resources, personnel, and equipment. By multiplying the cost per unit of capacity by the required task time for each step, and summing each component cost, the overall costs of AP CT is determined for patients in three settings, inpatient (IP), outpatient (OP), and emergency departments (ED). RESULTS: The component costs to deliver an AP CT study were as follows: radiologist interpretation: 40.1%; other personnel (scheduler, technologist, nurse, pharmacist, and transporter): 39.6%; materials: 13.9%; and space and equipment: 6.4%. The cost of performing CT was 13% higher for ED patients and 31% higher for inpatients (IP), as compared to that for OP. The difference in cost was mostly due to non radiologist personnel costs. CONCLUSIONS: Approximately 80% of the direct costs of AP CT to the academic medical center are related to labor. Potential opportunities to reduce the costs include increasing the efficiency of utilization of CT, substituting lower cost resources when appropriate, and streamlining the ordering system to clarify medical necessity and clinical indications. PMID- 27988201 TI - Early detection of Toxoplasma gondii infection by using a interferon gamma release assay: A review. AB - Antibody-based serological tests are currently the most common diagnostic methods for detection of Toxoplasma gondii; however, these tests bear several limitations. Recently, Interferon-gamma release assay (IGRA), a T-cell-based test, was introduced as an in vitro test for detection of T. gondii infection. Few studies have investigated the potential role of cell immunity in diagnosis of toxoplasmosis. IGRA accurately distinguished infected from uninfected individuals, showing strong lymphocyte activation after in vitro stimulation with T. gondii antigens, even during the first days of life. IGRA is an easy-operation and low-cost method to measure cell mediated immunity against T. gondii. The results of this review underline the importance of evaluating cellular immunity to establish an early diagnosis particularly for congenital toxoplasmosis. Therefore, ELISA-based IGRA holds the potential to become a useful diagnostic tool for early detection of T. gondii infection. PMID- 27988202 TI - Echo-X Ray Fusion in Paravalvular Leak Closure. PMID- 27988203 TI - External Validation of the Prestroke Independence, Sex, Age, National Institutes of Health Stroke Scale Score for Predicting Pneumonia After Stroke Using Data From the China National Stroke Registry. AB - BACKGROUND AND PURPOSE: Pneumonia is an important risk factor for mortality and morbidity after stroke. The Prestroke Independence, Sex, Age, National Institutes of Health Stroke Scale (ISAN) score was shown to be a useful tool for predicting stroke-associated pneumonia based on UK multicenter cohort study. We aimed to externally validate the score using data from the China National Stroke Registry (CNSR). METHODS: Eligible patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) in the CNSR from 2007 to 2008 were included. The area under the receiver operating characteristic (AUC) curve was used to evaluate discrimination. The Hosmer-Lemeshow goodness of fit test and Pearson correlation coefficient were performed to assess calibration of the model. RESULTS: A total of 19,333 patients (AIS = 14400; ICH = 4933) were included and the overall pneumonia rate was 12.7%. The AUC was .76 (95% confidence interval [CI]: .75-.78) for the subgroup of AIS and .70 (95% CI: .68-.72) for the subgroup of ICH. The Hosmer-Lemeshow test showed the ISAN score with the good calibration for AIS and ICH (P = .177 and .405, respectively). The plot of observed versus predicted pneumonia rates suggested higher correlation for patients with AIS than with ICH (Pearson correlation coefficient = .99 and .83, respectively). CONCLUSIONS: The ISAN score was a useful tool for predicting in-hospital pneumonia after acute stroke, especially for patients with AIS. Further validations need to be done in different populations. PMID- 27988205 TI - High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy. AB - OBJECTIVES: The objective of the present study was to evaluate the prevalence of obstructive sleep apnea (OSA) in patients with late-onset epilepsy (LOE) who were considered at higher risk of cardiovascular disease. METHODS: Polysomnography was performed on 27 patients with LOE. Berlin questionnaires and Epworth sleepiness score were performed on all patients. We compared clinical, demographic and anthropometric characteristics, questionnaire scores on the patients with no or mild OSA (group 1) and the patients with moderate or severe OSA (group 2). Patients eligible for continuous positive airway pressure (CPAP) therapy were reviewed in consultation. RESULTS: Twenty-four patients (88.9%) had OSA and 55.6% had moderate or severe OSA. Patients in group 2 (n=15) were older than patients in group 1 (n=12). The two groups were similar in terms of body mass index (BMI), neck circumference, nocturnal seizure frequency, vascular cardiovascular risk factors and excessive daytime sleepiness. Leukoaraiosis in MRI was highly prevalent in our patients (40.7%), especially in group 2 patients. Eighty percent of the patients who had begun CPAP therapy experienced decreased seizure frequency. CONCLUSION: Patients with LOE should be screened for the presence of OSA and treated accordingly. PMID- 27988206 TI - What Do Pediatric Residents Gain From an Experience in Juvenile Justice? A Qualitative Analysis of Community-Based Learning. AB - BACKGROUND: Training in advocacy and community pediatrics often involves the use of community site visits. However, data on the specific knowledge, skills, and attitudes gained from these experiences are limited. In this study we used qualitative analysis of written narratives to explore the response of residents to a juvenile justice experience. METHODS: Pediatric residents participated in a week-long experience in the juvenile probation department and completed a written narrative. Narratives were analyzed using grounded theory to explore the effects of this experience on residents' views of youth in the juvenile justice system. RESULTS: Analysis of 29 narratives revealed 13 themes relating to 5 core concepts: social determinants of behavior, role of professionals and institutions, achieving future potential, resolving discrepancies, and distancing. A conceptual model was developed to explore the interactions of these concepts in the resident view of youth in the juvenile justice system. Of the themes only 3 (23%) were related to content explicitly covered in the assigned reading materials. CONCLUSIONS: Several important concepts emerged as elements of this experience, many of which were not covered in the explicit curriculum. Variability in attitudinal response to the experience raised important questions about the influence of the ideological framework of the learner and the hidden curriculum on the learning that occurs in community settings. We propose a theoretical model that delineates the factors that influence learning in community settings to guide educators in planning these types of experiences. PMID- 27988204 TI - SMAD transcription factors are altered in cell models of HD and regulate HTT expression. AB - Transcriptional dysregulation is observable in multiple animal and cell models of Huntington's disease, as well as in human blood and post-mortem caudate. This contributes to HD pathogenesis, although the exact mechanism by which this occurs is unknown. We therefore utilised a dynamic model in order to determine the differential effect of growth factor stimulation on gene expression, to highlight potential alterations in kinase signalling pathways that may be in part responsible for the transcriptional dysregulation observed in HD, and which may reveal new therapeutic targets. We demonstrate that cells expressing mutant huntingtin have a dysregulated transcriptional response to epidermal growth factor stimulation, and identify the transforming growth factor-beta pathway as a novel signalling pathway of interest that may regulate the expression of the Huntingtin (HTT) gene itself. The dysregulation of HTT expression may contribute to the altered transcriptional phenotype observed in HD. PMID- 27988207 TI - Location, Location, Location: Teaching About Neighborhoods in Pediatrics. PMID- 27988208 TI - Acid retention with reduced glomerular filtration rate increases urine biomarkers of kidney and bone injury. AB - Diets high in acid of developed societies that do not cause metabolic acidosis in patients with chronic kidney disease nevertheless appear to cause acid retention with associated morbidity, particularly in those with reduced glomerular filtration rate. Here we used a rat 2/3 nephrectomy model of chronic kidney disease to study induction and maintenance of acid retention and its consequences on indicators of kidney and bone injury. Dietary acid was increased in animals eating base-producing soy protein with acid-producing casein and in casein-eating animals with added ammonium chloride. Using microdialysis to measure the kidney cortical acid content, we found that nephrectomized animals had greater acid retention than sham-operated animals when both ate the soy diet. Each increment in dietary acid further increased acid retention more in nephrectomized than in sham rats. Nephrectomized and sham animals achieved similar steady-state daily urine net acid excretion in response to increments in dietary acid but nephrectomized animals took longer to do so, contributing to greater acid retention that was maintained until the increased dietary acid was stopped. Acid retention was associated with increased urine excretion of both N-acetyl-beta-D glucosaminidase and deoxypyridinoline, greater in nephrectomized than control rats, consistent with kidney tubulointerstitial and bone matrix injury, respectively. Greater acid retention in nephrectomized than control animals was induced by a slower increase in urinary net acid excretion rate in response to the increment in dietary acid and also maintained until the dietary acid increment was stopped. Thus, acid retention increased biomarkers of kidney and bone injury in the urine, supporting untoward consequences to these two tissues. PMID- 27988210 TI - Neuropilin1 regulates glomerular function and basement membrane composition through pericytes in the mouse kidney. AB - Neuropilin1 (Nrp1) is a co-receptor best known to regulate the development of endothelial cells and is a target of anticancer therapies. However, its role in other vascular cells including pericytes is emergent. The kidney is an organ with high pericyte density and cancer patients develop severe proteinuria following administration of NRP1B-neutralizing antibody combined with bevacizumab. Therefore, we investigated whether Nrp1 regulates glomerular capillary integrity after completion of renal development using two mouse models; tamoxifen-inducible NG2Cre to delete Nrp1 specifically in pericytes and administration of Nrp1 neutralizing antibodies. Specific Nrp1 deletion in pericytes did not affect pericyte number but mutant mice developed hematuria with glomerular basement membrane defects. Despite foot process effacement, albuminuria was absent and expression of podocyte proteins remained unchanged upon Nrp1 deletion. Additionally, these mice displayed dilation of the afferent arteriole and glomerular capillaries leading to glomerular hyperfiltration. Nidogen-1 mRNA was downregulated and collagen4alpha3 mRNA was upregulated with no significant effect on the expression of other basement membrane genes in the mutant mice. These features were phenocopied by treating wild-type mice with Nrp1-neutralizing antibodies. Thus, our results reveal a postdevelopmental role of Nrp1 in renal pericytes as an important regulator of glomerular basement membrane integrity. Furthermore, our study offers novel mechanistic insights into renal side effects of Nrp1 targeting cancer therapies. PMID- 27988209 TI - Renal tubular angiotensin converting enzyme is responsible for nitro-L-arginine methyl ester (L-NAME)-induced salt sensitivity. AB - Renal parenchymal injury predisposes to salt-sensitive hypertension, but how this occurs is not known. Here we tested whether renal tubular angiotensin converting enzyme (ACE), the main site of kidney ACE expression, is central to the development of salt sensitivity in this setting. Two mouse models were used: it ACE mice in which ACE expression is selectively eliminated from renal tubular epithelial cells; and ACE 3/9 mice, a compound heterozygous mouse model that makes ACE only in renal tubular epithelium from the ACE 9 allele, and in liver hepatocytes from the ACE 3 allele. Salt sensitivity was induced using a post L NAME salt challenge. While both wild-type and ACE 3/9 mice developed arterial hypertension following three weeks of high salt administration, it-ACE mice remained normotensive with low levels of renal angiotensin II. These mice displayed increased sodium excretion, lower sodium accumulation, and an exaggerated reduction in distal sodium transporters. Thus, in mice with renal injury induced by L-NAME pretreatment, renal tubular epithelial ACE, and not ACE expression by renal endothelium, lung, brain, or plasma, is essential for renal angiotensin II accumulation and salt-sensitive hypertension. PMID- 27988212 TI - Natural regulatory T cells from patients with end-stage renal disease can be used for large-scale generation of highly suppressive alloantigen-specific Tregs. AB - Natural occurring regulatory T cells (nTregs) have the potential to offer a targeted approach of immunosuppression and are the cell type of interest for inducing tolerance in kidney transplantation. End-stage renal disease (ESRD) profoundly affects the composition and function of circulating T cells but little is known with respect to how nTreg potential is affected. To address this, nTregs of patients with ESRD (on dialysis or not) and healthy individuals were isolated, expanded using allogeneic mature monocyte-derived dendritic cells followed by anti-CD3/anti-CD28-coated beads and the different nTregs were extensively characterized by the demethylation status of the Treg-specific demethylated region within FOXP3 and expression of typical nTreg markers. Additionally, the suppressive capacity as well as cytokine producing cells were analyzed for allogeneic mature monocyte-derived dendritic cell-expanded nTregs. Compared to age- and gender-matched healthy individuals, similar frequencies of nTregs were present within the circulation of patients with ESRD either on dialysis or not. The isolated nTregs could be equally well or even better expanded using allogeneic mature monocyte-derived dendritic cells and extensive characterization did not reveal significant differences. The demethylation status of the Treg specific demethylated region was maintained or even further promoted as was the expression of markers characteristic for nTregs. Moreover, suppressive capacity and the cytokine profile of allogeneic mature monocyte-derived dendritic cell expanded nTregs was similar to that of healthy individuals. Thus, circulating nTregs of patients with ESRD can effectively be expanded to stable allo antigen specific nTregs with potential clinical applicability. PMID- 27988211 TI - Graft dysfunction in chronic antibody-mediated rejection correlates with B-cell dependent indirect antidonor alloresponses and autocrine regulation of interferon gamma production by Th1 cells. AB - Chronic antibody-mediated rejection, a common cause of renal transplant failure, has a variable clinical phenotype. Understanding why some with chronic antibody mediated rejection progress slowly may help develop more effective therapies. B lymphocytes act as antigen-presenting cells for in vitro indirect antidonor interferon-gamma production in chronic antibody-mediated rejection, but many patients retain the ability to regulate these responses. Here we test whether particular patterns of T and B cell antidonor response associate with the variability of graft dysfunction in chronic antibody-mediated rejection. Our results confirm that dynamic changes in indirect antidonor CD4+ T-cell responses correlate with changes in estimated glomerular filtration rates, independent of other factors. Graft dysfunction progressed rapidly in patients who developed unregulated B-cell-driven interferon-gamma production. However, conversion to a regulated or nonreactive pattern, which could be achieved by optimization of immunosuppression, associated with stabilization of graft function. Functional regulation by B cells appeared to activate an interleukin-10 autocrine pathway in CD4+ T cells that, in turn, impacted on antigen-specific responses. Thus, our data significantly enhance the understanding of graft dysfunction associated with chronic antibody-mediated rejection and provide the foundation for strategies to prolong renal allograft survival, based on regulation of interferon-gamma production. PMID- 27988213 TI - Down-regulation of ABCG2, a urate exporter, by parathyroid hormone enhances urate accumulation in secondary hyperparathyroidism. AB - Hyperuricemia occurs with increasing frequency among patients with hyperparathyroidism. However, the molecular mechanism by which the serum parathyroid hormone (PTH) affects serum urate levels remains unknown. This was studied in uremic rats with secondary hyperparathyroidism where serum urate levels were found to be increased and urate excretion in the intestine and kidney decreased, presumably due to down-regulation of the expression of the urate exporter ABCG2 in intestinal and renal epithelial membranes. These effects were prevented by administration of the calcimimetic cinacalcet, a PTH suppressor, suggesting that PTH may down-regulate ABCG2 expression. This was directly tested in intestinal Caco-2 cells where the expression of ABCG2 on the plasma membrane was down-regulated by PTH (1-34) while its mRNA level remained unchanged. Interestingly, an inactive PTH derivative (13-34) had no effect, suggesting that a posttranscriptional regulatory system acts through the PTH receptor to regulate ABCG2 plasma membrane expression. As found in an animal study, additional clinical investigations showed that treatment with cinacalcet resulted in significant reductions in serum urate levels together with decreases in PTH levels in patients with secondary hyperparathyroidism undergoing dialysis. Thus, PTH down-regulates ABCG2 expression on the plasma membrane to suppress intestinal and renal urate excretion, and the effects of PTH can be prevented by cinacalcet treatment. PMID- 27988215 TI - Biotransformation of prednisone and dexamethasone by cytochrome P450 based systems - Identification of new potential drug candidates. AB - Prednisone and dexamethasone are synthetic glucocorticoids widely used as anti inflammatory and immunosuppressive drugs. Since their hydroxylated derivatives could serve as novel potential drug candidates, our aim was to investigate their biotransformation by the steroid hydroxylase CYP106A2 from Bacillus megaterium ATCC13368. In vitro we were able to demonstrate highly selective 15beta hydroxylation of the steroids with a reconstituted CYP106A2 system. The reactions were thoroughly characterized, determining the kinetic parameters and the equilibrium dissociation constant. The observed lower conversion rate in the case of dexamethasone hydroxylation was clarified by quantum chemical calculations, which suggest a rearrangement of the intermediately formed radical species. To identify the obtained conversion products with NMR, CYP106A2-based Bacillus megaterium whole-cell systems were applied resulting in an altered product pattern for prednisone, yet no significant change for dexamethasone conversion compared to in vitro. Even the MS941 control strain performed a highly selective biotransformation of prednisone producing the known metabolite 20beta dihydrocortisone. The identified novel prednisone derivatives 15beta, 17, 20beta, 21-tetrahydroxy-preg-4-en-3,11-dione and 15beta, 17, 20beta, 21-tetrahydroxy-preg 1,4-dien-3,11-dione as well as the 15beta-hydroxylated variants of both drugs are promising candidates for drug-design and development approaches. PMID- 27988214 TI - Characterization of glomerular extracellular matrix by proteomic analysis of laser-captured microdissected glomeruli. AB - Abnormal extracellular matrix (ECM) remodeling is a prominent feature of many glomerular diseases and is a final common pathway of glomerular injury. However, changes in ECM composition accompanying disease-related remodeling are unknown. The physical properties of ECM create challenges for characterization of composition using standard protein extraction techniques, as the insoluble components of ECM are frequently discarded and many ECM proteins are in low abundance compared to other cell proteins. Prior proteomic studies defining normal ECM composition used a large number of glomeruli isolated from human kidneys retrieved for transplantation or by nephrectomy for cancer. Here we examined the ability to identify ECM proteins by mass spectrometry using glomerular sections compatible with those available from standard renal biopsy specimens. Proteins were classified as ECM by comparison to the Matrisome database and previously identified glomerular ECM proteins. Optimal ECM protein identification resulted from sequential decellularization and protein extraction of 100 human glomerular sections isolated by laser capture microdissection from either frozen or formalin-fixed, paraffin-embedded tissue. In total, 147 ECM proteins were identified, including the majority of structural and GBM proteins previously identified along with a number of matrix and glomerular basement membrane proteins not previously associated with glomeruli. Thus, our study demonstrates the feasibility of proteomic analysis of glomerular ECM from retrieved glomerular sections isolated from renal biopsy tissue and expands the list of known ECM proteins in glomeruli. PMID- 27988216 TI - Kinetic models for batch ethanol production from sweet sorghum juice under normal and high gravity fermentations: Logistic and modified Gompertz models. AB - The aim of this study was to model batch ethanol production from sweet sorghum juice (SSJ), under normal gravity (NG, 160g/L of total sugar) and high gravity (HG, 240g/L of total sugar) conditions with and without nutrient supplementation (9g/L of yeast extract), by Saccharomyces cerevisiae NP 01. Growth and ethanol production increased with increasing initial sugar concentration, and the addition of yeast extract enhanced both cell growth and ethanol production. From the results, either logistic or a modified Gompertz equation could be used to describe yeast growth, depending on information required. Furthermore, the modified Gompertz model was suitable for modeling ethanol production. Both the models fitted the data very well with coefficients of determination exceeding 0.98. The results clearly showed that these models can be employed in the development of ethanol production processes using SSJ under both NG and HG conditions. The models were also shown to be applicable to other ethanol fermentation systems employing pure and mixed sugars as carbon sources. PMID- 27988218 TI - Degenerated uterine fibroid with rupture of the surface leading to haemoperitoneum. PMID- 27988217 TI - Attitudes and Performance of Cardiologists Toward Sexual Issues in Cardiovascular Patients. AB - INTRODUCTION: The aim of the present study was to evaluate the attitudes and performance of cardiologists regarding sexual issues in patients with cardiovascular diseases. METHODS: A nationwide survey was conducted in a sample of cardiologists, representative of Iranian cardiologists, in 2015. MAIN OUTCOME MEASURES: Appropriate questionnaires were developed and used to ask participants about their attitudes, performance, and barriers regarding discussing sexual issues with patients with cardiovascular disease. RESULTS: The study population consisted of 202 cardiologists (138 men and 63 women) with a mean age of 44.25 years (SD = 8.45). Overall, 93.15% of cardiologists agreed with the importance of discussing sexual issues with their patients with cardiovascular diseases. Almost 76.7% of cardiologists agreed they had a responsibility to deal with patients' sexual problems, and 79.9% of them were aware of the association of cardiovascular disease with sexual problems of cardiac patients, but only 33% of them were confident in their knowledge and skills in this regard. Only 10.6% of cardiologists reported they frequently or always assessed sexual problems with their patients, but 51.50% of them stated they were responding to patients' questions about sexual problems. There was a significant association between performance and responsibility. CONCLUSION: The results of this study indicate a gap between cardiologist's attitudes and their actual performance and that their professional responsibility to address patients' sexual issues is a significant parameter for better performance. PMID- 27988220 TI - Percentage of Youth Meeting Federal Fruit and Vegetable Intake Recommendations, Youth Risk Behavior Surveillance System, United States and 33 States, 2013. AB - BACKGROUND: National- and state-level self-reported frequency of fruit and vegetable (F/V) consumption is available for high school students from the Centers for Disease Control and Prevention's Youth Risk Behavior Surveillance System (YRBSS). YRBSS monitors priority health-risk behaviors among a nationally representative sample of US high school students and representative samples of students in states and selected large urban school districts. However, YRBSS measures intake in times per day and not the cup equivalents that national goals use, which limits interpretation. OBJECTIVE: To help states track youth progress, scoring algorithms were developed from external data and applied to 2013 YRBSS data to estimate the percentages of high school students in the nation and 33 states meeting the US Department of Agriculture's Food Patterns F/V intake recommendations. DESIGN: Twenty-four-hour dietary recalls were used from the 2007 2010 National Health and Nutrition Examination Survey to fit sex-specific models for 14- to 18-year-olds that estimate probabilities of meeting recommendations as a function of reported frequency of consumption and race/ethnicity, adjusting for day-to-day dietary variation. Model regression parameters were then applied to national cross-sectional YRBSS data (n=12,829) and to data from the 33 states (n=141,006) that had complete F/V data to estimate percentages meeting recommendations. RESULTS: Based on the prediction equations, 8.5% of high school students nationwide met fruit recommendations (95% CI 4.9% to 12.1%) and 2.1% met vegetable recommendations (95% CI 0.0% to 8.1%). State estimates ranged from 5.3% in Nebraska and Missouri to 8.9% in Florida for fruit and 1.0% in New Jersey, North Dakota, and South Carolina to 3.3% in New Mexico for vegetables. CONCLUSIONS: This method provides a new tool for states to track youth progress toward meeting dietary recommendations and indicates that a high percentage of youth in all states examined have low intakes of F/V. PMID- 27988219 TI - Dietary Changes Impact the Gut Microbe Composition in Overweight and Obese Men with Prostate Cancer Undergoing Radical Prostatectomy. AB - BACKGROUND: Diet and obesity influence prostate cancer risk and progression effects that may be mediated through the gut microbiome. OBJECTIVE: Our aim was to explore relationships among diet, gut microbes, and Gleason sum in overweight and obese prostate cancer patients enrolled in a presurgical weight-loss trial. DESIGN: Randomized controlled trial (NCT01886677) secondary analysis. PARTICIPANTS/SETTING: In 2013-2014, 40 prostate cancer patients in the southeastern United States were randomized and allocated equally to weight-loss and wait-list control arms while they awaited prostatectomy; stool samples were collected on a subset of 22 patients. INTERVENTION: Registered dietitian nutritionists and exercise physiologists provided semi-weekly in-person and telephone-based guidance on calorie-restricted diets and exercise to promote an approximate weight loss of 0.91 kg/wk. MAIN OUTCOME MEASURES: Baseline and follow up 24-hour dietary recalls were conducted and analyzed (using the Automated Self Administered 24-hour dietary recall system; National Cancer Institute, Bethesda, MD) for macronutrients, micronutrients, and food groups. Microbiome analysis targeting the V4 region of the 16S ribosomal RNA gene was performed on fecal samples. Biopsy Gleason sum data were accessed from diagnostic pathology reports. STATISTICAL ANALYSES PERFORMED: Associations between dietary factors and operational taxonomic units were determined by beta-diversity analysis. Wilcoxon signed rank, and Mann-Whitney U testing assessed within- and between-arm differences. Associations between Gleason sum and operational taxonomic units, and diet and operational taxonomic units, were analyzed using Spearman correlations. RESULTS: At baseline, Proteobacteria (median 0.06, interquartile range 0.01 to 0.16) were abundant, with four orders positively associated with Gleason sum. Gleason sum was associated with Clostridium (rho=.579; P=0.005) and Blautia (rho=-0.425, P=0.049). Increased red meat consumption from baseline was associated with Prevotella (rho=-.497; P=0.018) and Blautia (rho=.422; P=0.039). Men who increased poultry intake had decreased Clostridiales abundance (P=0.009). CONCLUSIONS: This hypothesis-generating study provides a starting point for investigating the relationships between the fecal microbiome, diet, and prostate cancer. Adequately powered studies are required to further explore and validate these findings. PMID- 27988221 TI - Differential Diagnosis of Breast Category 3 and 4 Nodules Through BI-RADS Classification in Conjunction with Shear Wave Elastography. AB - Ultrasound (US) has become one of the important imaging methods for differentiating benign from malignant breast lesions. In 2013, the American College of Radiology published the fifth edition of the Breast Imaging-Reporting and Data System (BI-RADS). BI-RADS is a guide with recommendations for the standardization of breast imaging (US, mammography and magnetic resonance imaging) reports and for the auditing of centers employing such methods. Its objective is to standardize the nomenclature used in the reports. However, current US examinations are neither adequately sensitive nor sufficiently specific enough. The average Young's modulus was measured through shear wave elastography (SWE) to evaluate the diagnostic value of the BI-RADS classification in conjunction with SWE in differentiating BI-RADS 3 and 4 nodules. A total of 100 consecutive women with 126 breast lesions, including 65 benign and 61 malignant lesions, were included. The average Young's modulus of breast nodules and peri-nodule tissue (Emean1 and Emean2) was also determined through SWE. A receiver operating characteristic curve was drawn on the basis of pathologic results. The highest cut-off values were C1 and C2. At Emean1 > C1 or Emean2 > C2, BI-RADS 3 was increased to 4a and BI-RADS 4a was increased to 4b. At Emean1 <= C1 and Emean2 <= C2, BI-RADS 4b was decreased to 4a. Other BI-RADS classifications remained unchanged. BI-RADS 3 and 4a were considered benign. BI RADS 4b and 4c were malignant. The area under the curve, sensitivity and specificity of the BI-RADS classification in conjunction with SWE were 0.952, 93.4% and 95.4%, respectively. The area under the curve, sensitivity and specificity of the original BI-RADS classification were 0.883, 82.0% and 87.7%, respectively. Differences were statistically significant (p = 0.028, Z-test). The diagnostic sensitivity and specificity were increased effectively. As a new method, BI-RADS classification in conjunction with SWE that combines the average Young's modulus yields a high value in terms of the differential diagnosis of breast nodules. PMID- 27988222 TI - [Upgrading to triple-site ventricular stimulation from conventional cardiac resynchronization therapy in a non-responder patient in atrial fibrillation. A feasible therapeutic option?] PMID- 27988223 TI - Mexican registry of pulmonary hypertension: REMEHIP. AB - OBJECTIVE: REMEHIP is a prospective, multicentre registry on pulmonary hypertension. The main objective will be to identify the clinical profile, medical care, therapeutic trends and outcomes in adult and pediatric Mexican patients with well-characterized pulmonary hypertension. METHODS: REMEHIP a multicenter registry began in 2015 with a planned recruitment time of 12 months and a 4-year follow-up. The study population will comprise a longitudinal cohort study, collecting data on patients with prevalent and incident pulmonary hypertension. Will be included patients of age >2 years and diagnosis of pulmonary hypertension by right heart catheterization within Group 1 and Group 4 of the World Health Organization classification. The structure, data collection and data analysis will be based on quality current recommendations for registries. The protocol has been approved by institutional ethics committees in all participant centers. All patients will sign an informed consent form. Currently in Mexico, there is a need of observational registries that include patients with treatment in the everyday clinical practice so the data could be validated and additional information could be obtained versus the one from the clinical trials. In this way, REMEHIP emerges as a link among randomized clinical trials developed by experts and previous Mexican experience. PMID- 27988224 TI - Photoinactivation of single and mixed biofilms of Candida albicans and non albicans Candida species using Photodythazine(r) [corrected]. AB - This study evaluated the effectiveness of antimicrobial photodynamic therapy (aPDT) mediated by Photodithazine(r) (PDZ) formulated in hydrogel, in the inactivation of mono and duo-species biofilms of Candida albicans, Candida glabrata and Candida tropicalis. Standardized suspensions of each strain were prepared and after biofilm formation, mono-species were treated with 150 and 175mg/L of PDZ for 20min (pre-irradiation time), and exposed to LED light at a dose of 37.5J/cm2 (660nm). The duo-species biofilms (C. albicans+C. glabrata and C. albicans+C. tropicalis) were treated with 150mg/L of PDZ and light. Additional samples were treated with PDZ or light only, and the control did not receive any treatment. Next, microbiological evaluation was performed by spreading the cells on Sabouraud Dextrose Agar and CHROMagar Candida for colony forming units (CFU/mL). Moreover, the total biomass of biofilm was verified using the crystal violet staining assay (CV). The data were submitted to ANOVA and Tukey post-hoc (alpha=0.05). The use of PDZ 150mg/L promoted a reduction of 1.0, 1.2, 1.5 log10 in the viability of C. glabrata, C. albicans and C. tropicalis, respectively. The same concentration reduced in 1.0 log10 the viability of each species grown as duo-species biofilms. The crystal violet assay showed that the use of 150mg/L reduced 24.4%, 39.2% and 43.7% of the total biomass of C. albicans, C. tropicalis and C. glabrata, respectively. aPDT did not reduce the total biomass to the duo species biofilms. Thus, PDZ-mediated aPDT was more effective in the inactivation of mono-species biofilms of Candida spp. compared with duo-species biofilm. PMID- 27988225 TI - The Epigenetic Paradox of Pluripotent ES Cells. AB - The propagation and maintenance of gene expression programs are at the foundation of the preservation of cell identity. A large and complex set of epigenetic mechanisms enables the long-term stability and inheritance of transcription states. A key property of authentic epigenetic regulation is being independent from the instructive signals used for its establishment. This makes epigenetic regulation, particularly epigenetic silencing, extremely robust and powerful to lock regulatory states and stabilise cell identity. In line with this, the establishment of epigenetic silencing during development restricts cell potency and maintains the cell fate choices made by transcription factors (TFs). However, how more immature cells that have not yet established their definitive fate maintain their transitory identity without compromising their responsiveness to signalling cues remains unclear. A paradigmatic example is provided by pluripotent embryonic stem (ES) cells derived from a transient population of cells of the blastocyst. Here, we argue that ES cells represent an interesting "epigenetic paradox": even though they are captured in a self-renewing state characterised by extremely efficient maintenance of their identity, which is a typical manifestation of robust epigenetic regulation, they seem not to heavily rely on classical epigenetic mechanisms. Indeed, self-renewal strictly depends on the TFs that previously instructed their undifferentiated identity and relies on a particular signalling-dependent chromatin state where repressive chromatin marks play minor roles. Although this "epigenetic paradox" may underlie their exquisite responsiveness to developmental cues, it suggests that alternative mechanisms to faithfully propagate gene regulatory states might be prevalent in ES cells. PMID- 27988226 TI - Trypanocidal activity of the compounds present in Aniba canelilla oil against Trypanosoma evansi and its effects on viability of lymphocytes. AB - Aniba canelilla (H.B.K.) Mez, popularly known as "casca-preciosa" (precious bark), is a plant of the Lauraceae family, widely distributed in the Amazon region. Its major constituent is 1-nitro-2-phenylethane, a rare molecule in plants which is responsible for this plant's cinnamon scent. The present study aimed to report the chemical characterization of the oil extracted from Aniba canelilla using gas-chromatography/mass spectrometry and to assess its in vitro trypanocidal activity against Trypanosoma evansi, a prevalent haemoflagellate parasite that affects a broad range of mammal species in Africa, Asia and South America. The oil presented 1-nitro-2-phenylethane (83.68%) and methyleugenol (14.83%) as the two major components. The essential oil as well as both major compounds were shown to exert trypanocidal effect. Methyleugenol was slightly more active than 1-nitro-2-phenylethane. In vitro studies showed that the oil extracted from the stems of A. canelilla may be regarded as a potential natural treatment for trypanosomosis, once proven their in vivo action, may be an interesting alternative in the treatment of infected animals with T. evansi. PMID- 27988228 TI - Right ventricular speckle tracking echocardiography: A new tool for decision making after surgical repair of tetralogy of Fallot? PMID- 27988229 TI - Determinants of safety of early discharge after primary percutaneous coronary intervention. PMID- 27988227 TI - Methods for the analysis of early oogenesis in Zebrafish. AB - Oocyte differentiation is a highly dynamic and intricate developmental process whose mechanistic understanding advances female reproduction, fertility, and ovarian cancer biology. Despite the many attributes of the zebrafish model, it has yet to be fully exploited for the investigation of early oocyte differentiation and ovarian development. This is partly because the properties of the adult zebrafish ovary make it technically challenging to access early stage oocytes. As a result, characterization of these stages has been lacking and tools for their analysis have been insufficient. To overcome these technical hurdles, we took advantage of the juvenile zebrafish ovary, where early stage oocytes can readily be found in high numbers and progress in a predictable manner. We characterized the earliest stages of oocyte differentiation and ovarian development and defined accurate staging criteria. We further developed protocols for quantitative microscopy, live time-lapse imaging, ovarian culture, and isolation of stage-specific oocytes for biochemical analysis. These methods have recently provided us with an unprecedented view of early oogenesis, allowing us to study formation of the Balbiani body, a universal oocyte granule that is associated with oocyte survival in mice and required for oocyte and egg polarity in fish and frogs. Despite its tremendous developmental significance, the Bb has been little investigated and how it forms was unknown in any species for over two centuries. We were able to trace Balbiani body formation and oocyte symmetry breaking to the onset of meiosis. Through this investigation we revealed novel cytoskeletal structures in oocytes and the contribution of specialized cellular organization to differentiation. Overall, the juvenile zebrafish ovary arises as an exciting model for studies of cell and developmental biology. We review these and other recent advances in vertebrate oogenesis in an accompanying manuscript in this issue of Developmental Biology. Here, we describe the protocols for ovarian investigation that we developed in the zebrafish, including all experimental steps that will easily allow others to reproduce such analysis. This juvenile ovary toolbox also contributes to establishing the zebrafish as a model for post-larval developmental stages. PMID- 27988230 TI - Spontaneous coronary artery dissection: Still a lot to learn. AB - Non-atherosclerotic spontaneous coronary artery dissection (SCAD) is an uncommon but probably underdetected pathological substrate for acute coronary syndrome. Clinical associations have been noted, like female gender and young age, but its pathophysiology is not yet fully understood. In this report we describe the case of a 50-year-old woman, without cardiovascular risk factors presenting with non ST segment elevation myocardial infarction, in whom SCAD was diagnosed. Treatment was initially conservative but due to aggravation of the dissection she eventually underwent a complex percutaneous coronary intervention, requiring implantation of multiple stents, but with a good clinical outcome. The procedure was guided by optical coherence tomography (OCT). Carefully analyzing the combined pictures of OCT and angiography, the dissection appeared to be filled with a clear fluid, but not contrast. PMID- 27988231 TI - Effects of percutaneous renal sympathetic denervation on cardiac function and exercise tolerance in patients with chronic heart failure. AB - INTRODUCTION: Sympathetic hyperactivity, a vital factor in the genesis and development of heart failure (HF), has been reported to be effectively reduced by percutaneous renal denervation (RDN), which may play an important role in HF treatment. OBJECTIVE: To determine the effects of percutaneous RDN on cardiac function in patients with chronic HF (CHF). METHODS: Fourteen patients (mean age 69.6 years; ejection fraction [EF] <45%) with CHF received bilateral RDN. Adverse cardiac events, blood pressure (BP), and biochemical parameters were assessed before and six months after percutaneous operation. Patients also underwent echocardiographic assessment of cardiac function and 6-min walk test before and at six months after percutaneous operation. RESULTS: The distance achieved by the 14 patients in the 6-min walk test increased significantly from 152.9+/-38.0 m before RDN to 334.3+/-94.4 m at six months after RDN (p<0.001), while EF increased from 36.0+/-4.1% to 43.8+/-7.9% (p=0.003) on echocardiography. No RDN related complications were observed during the follow-up period. In 6-month follow-up, systolic BP decreased from 138.6+/-22.1 mmHg to 123.2+/-10.5 mmHg (p=0.026) and diastolic BP from 81.1+/-11.3 mmHg to 72.9+/-7.5 mmHg (p=0.032). Creatinine levels did not change significantly (1.3+/-0.65 mg/dl to 1.2+/-0.5 mg/dl, p=0.8856). CONCLUSION: RDN is potentially an effective technique for the treatment of severe HF that can significantly increase EF and improve exercise tolerance. PMID- 27988232 TI - For the improvement of Heart Failure treatment in Portugal - Consensus statement. AB - Heart failure is a syndrome with high prevalence, morbidity and mortality, but awareness of the disease is poor among the general public and policy makers. This document, which was prepared by a group of experts consisting of cardiologists, internists and general practitioners, aims to set out in detail the problem of heart failure in Portugal at several levels: burden of the disease, diagnosis, treatment and monitoring. To this aim, different aspects of the management of the various stages of the disease are identified and discussed in detail, covering both outpatients and hospitalized patients. In order to optimize the medical care provided to these patients, various short-, medium- and long-term solutions and strategies are put forward that have the potential to improve the integration and use of available resources. The intention is to highlight strategies that are not based on a single model but can be adapted to different regional circumstances, in order to increase awareness and improve management of heart failure in Portugal. PMID- 27988233 TI - Identification and functional analysis of pointed homologs in Bombyx mori. AB - Using gene-knockdown techniques, we searched for endogenous Ets family proteins involved in the regulation of Escherichia coli-dependent lebocin promoter activation in the E. coli-responsive silkworm cell line NIAS-Bm-aff3. Results showed that the gene knockdown of BmPointeds (BmPNTs), Drosophila Pointed orthologs, enhanced E. coli-dependent lebocin promoter activation, suggesting that endogenous BmPNTs repress the activation of this promoter. Furthermore, we found that i) the BmPNT gene produced at least two alternative splicing isoforms, BmPNT1 and BmPNT2, both of which function as repressors; ii) BmPNTs were not associated with an already-reported repressor element, most proximal GGAA/T motif (EtsRE3), in lebocin promoter, which plays a role in the repression of E. coli- and BmRelish1-dependent lebocin promoter activation; iii) although BmPNTs did not directly affect BmRelish1-dependent lebocin promoter activation, they were able to directly repress its activation on the promoter lacking EtsRE3, probably because of competitive inhibition of binding of BmRelish1 to kappaB sites by BmPNTs; and iv) BmPNTs were mainly expressed in larval hemocytes, and the gene expression levels of BmPNT2, but not of BmPNT1, were decreased in response to E. coli and Bacillus subtilis. These findings suggest that endogenous BmPNTs are directly and indirectly involved in the repression of E. coli-mediated lebocin promoter activation in NIAS-Bm-aff3 cells. PMID- 27988234 TI - Deletion of the vacJ gene affects the biology and virulence in Haemophilus parasuis serovar 5. AB - Haemophilus parasuis is an important pathogen causing severe infections in pigs. However, the specific bacterial factors that participate in pathogenic process are poorly understood. VacJ protein is a recently discovered outer membrane lipoprotein that relates to virulence in several pathogens. To characterize the function of the vacJ gene in H. parasuis virulent strain HS49, a vacJ gene deletion mutant DeltavacJ and its complemented strain were constructed. Our findings supported that VacJ is essential for maintenance of cellular integrity and stress tolerance of H. parasuis, by the demonstrations that the DeltavacJ mutant showed morphological change, increased NPN fluorescence and, and decreased resistance to SDS-EDTA, osmotic and oxidation pressure. The increased susceptibility to several antibiotics in the DeltavacJ mutant further suggested that the stability of the outer membrane was impaired as a result of the mutation in the vacJ gene. Compared to the wild-type strain, the DeltavacJ mutant strain caused a decreased survival ratio from the serum and complement killing, and exhibited a significant decrease ability to adhere to and invade PK-15 cell. In addition, the DeltavacJ mutant showed reduced biofilm formation compared to the wild-type strain. Furthermore, the DeltavacJ was attenuated in a murine (Balb/C) model of infection and its LD50 value was approximately fifteen-fold higher than that of the wild-type or complementation strain. The data obtained in this study indicate that vacJ plays an essential role in maintaining outer membrane integrity, stress tolerance, biofilm formation, serum resistance, and adherence to and invasion of host cells related to H. parasuis and further suggest a putative role of VacJ lipoprotein in virulence regulation. PMID- 27988235 TI - Quality assurance in gastrointestinal endoscopy: An Egyptian experience. AB - Over the last four decades, gastrointestinal endoscopy has become of paramount importance to diagnose, treat and prevent diseases of the digestive tract. Practice variation, however, is likely to have an important effect on the effectiveness of endoscopy and can impair the delivery of high-quality endoscopic procedures. There have been increasing demands to assess the quality of service and track and improve patient outcomes. Quality assurance has paved its way into professional guidelines for physicians. Developing a modern endoscopy unit demands the institution of a quality assurance programme, continuous training and monitoring of service delivery. This article describes our experience in implementing a quality assurance programme in endoscopy in a secondary care government hospital in Egypt. The implementation of quality assurance and improvement programme can lead to dramatic improvements in the quality of endoscopic care and patient outcomes. Quality assurance and continual improvement can be applied in developing countries. PMID- 27988236 TI - Predicting mortality of patients with cirrhosis admitted to medical intensive care unit: An experience of a single tertiary center. AB - BACKGROUND AND STUDY AIMS: Prognosis for patients with cirrhosis admitted to a medical intensive care unit (MICU) is poor and no previous studies have been published from Qatar or other countries in the region to investigate this issue. The objective of this study was to assess the predictors for in-hospital mortality and admission of cirrhotic patients to MICU in a single tertiary hospital in Qatar. PATIENTS AND METHODS: All adult cirrhotic MICU patients hospitalized from 2007 through 2012 to Hamad General Hospital-Qatar were included. We compared them to cirrhotic patients admitted to medical wards during same period of time. All data were recorded and analyzed with respect to demographic parameters, clinical features and laboratory as well as radiology characteristics on day one of admission to MICU. Cirrhosis diagnosis was established either with a liver biopsy or the combination of physical, laboratory and radiologic findings. Predictors of mortality were defined by logistic regression analysis. RESULTS: The cohort comprised 109 cirrhotic MICU patients (86.2% males), and their mean age+/-SD was 51.6+/-11.5. MICU-cirrhotic patients had longer hospital stays than medical wards-cirrhotic patients (p=0.01). Admission with severe hepatic encephalopathy, upper gastrointestinal bleeding and SOFA (Sepsis Related Organ Failure Assessment) score were the independent predicting factors for MICU admission. Mortality was higher for the MICU cirrhotic group than medical wards group (27 (24.8%) deaths vs. 12 (5.3%) deaths, respectively, p=0.001). In multivariate logistic regression analyses, older age>60years (p=0.04), APACH-II score (p=0.001) and MELD score (p=0.02) were independent predicting factors for overall mortality. CONCLUSION: Severe hepatic encephalopathy, upper gastrointestinal bleeding and SOFA score predict MICU admission of cirrhotic patients. Among MICU cirrhotic patients, older age, APACH II score and MELD score predict mortality. PMID- 27988237 TI - Research Into Childhood Obstructive Sleep-Disordered Breathing: A Systematic Review. AB - BACKGROUND: Despite recent clinical guideline development, the best pathway of care for children with symptoms of obstructive sleep-disordered breathing (oSDB) is still debated. This systematic review aims to map the research in childhood oSDB that has been conducted so far to support further guideline development, identify evidence gaps, and guide future research. METHODS: A systematic search was performed in PubMed, EMBASE, and the Cochrane Library from inception to November 26, 2015. All publications on childhood oSDB were included, irrespective of type and language. The annual number of publications in the field of oSDB was counted over all years; for those published since January 1, 2011 (ie, the date of the latest literature search of the American Academy of Pediatrics guideline), total and annual numbers of publications across main research themes and methodologies were calculated. RESULTS: Of the 7,637 unique records retrieved, 5,871 publications were eligible for inclusion. There was an increase in annual publications since 2000, with 46% published since 2011. Most publications (61%) focused on individual treatment modalities, incidence, or prognosis. Few publications (2.7%) focused on health service delivery, outcomes, and health economics. Observational studies composed 78.5% of publications, 2.4% were randomized controlled trials, and 0.4% used a qualitative approach as their main methodology. CONCLUSIONS: A recent surge in research activity into childhood oSDB has improved the knowledge base for this condition; however, the lack of health services, health economics, and outcomes research impacts the applicability of evidence informing current guidance and leaves important questions for future research. REGISTRATION: PROSPERO: registration number CRD42015029291. PMID- 27988238 TI - Collaborative Review of Risk Benefit Trade-offs Between Partial and Radical Nephrectomy in the Management of Anatomically Complex Renal Masses. AB - BACKGROUND: While partial nephrectomy (PN) is the recommended treatment for many small renal masses, anatomically complex tumors necessitate a clear understanding of the potential risks and benefits of PN and radical nephrectomy (RN). OBJECTIVE: To critically review the comparative effectiveness evidence of PN versus RN; to describe key trade-offs involved in this treatment decision; and to highlight gaps in the current literature. EVIDENCE ACQUISITION: A collaborative critical review of the medical literature was conducted. EVIDENCE SYNTHESIS: Patients who undergo PN for an anatomically complex or large mass may be exposed to perioperative and potential oncologic risks that could be avoided if RN were performed, while patients who undergo RN may forgo long-term benefits of renal preservation. Decision-making regarding the optimal treatment with PN or RN among patients with anatomically complex or large renal mass is highly nuanced and must balance the risks and benefits of each approach. Currently, high-quality evidence on comparative effectiveness is sparse. Retrospective comparisons are plagued by selection biases, while the one existing prospective randomized trial, albeit imperfect, suggests that nephron-sparing surgery may not benefit all patients. CONCLUSIONS: For anatomically complex tumors, PN preserves renal parenchyma but may expose patients to higher perioperative risks than RN. The risks and benefits of each surgical approach must be better objectified for identification of patients most suitable for complex PN. A prospective randomized trial is warranted and would help in directing patient counseling. PATIENT SUMMARY: Treatment decisions for complex renal masses require shared decision-making regarding the risk trade-offs between partial and radical nephrectomy. PMID- 27988239 TI - Contribution of clinical gait analysis to single-event multi-level surgery in children with cerebral palsy. AB - Clinical gait analysis (CGA) has been proven useful in understanding the gait disturbances seen in children and adolescents with cerebral palsy. Another major benefit provided by CGA is a clinical and scientific evaluation of how orthopaedic surgical procedures modify gait. The information provided by instrumented CGA complements the clinical data, and the two must be interpreted jointly. Although there is some variability in the surgical details of therapeutic strategies, CGA undoubtedly influences the planning of surgery. Although CGA improves surgical outcomes, these remain challenging to predict. CGA seems cost-effective. Internal hip rotation gait is used as an example to illustrate those benefits. PMID- 27988240 TI - Intraoperative spinal cord monitoring: Lesional level diagnosis. AB - BACKGROUND: In spinal deformity surgery, iatrogenic spinal cord injury is the most feared complication. Intraoperative monitoring (IOM) of the spinal cord assesses its functional integrity and allows significant reduction of the rate of spinal cord injury. HYPOTHESIS: In case of severe IOM alert, lesional level diagnosis constitutes supplementary and useful information. MATERIAL AND METHODS: This study was retrospective and monocentric. In our institution, 1062 pediatric spinal deformity surgeries have been monitored since 2004. We review the records of the six patients who presented a severe and prolonged IOM alert with lesional level determination. Somatosensory evoked potentials (SSEP), neurogenic mixed evoked potentials (NMEP) and D-waves were performed. In cases of IOM alert, sequentially moving an epidural electrode along the spinal cord allows lesional level determination, using this electrode either for stimulation or recording. RESULTS: Six patients, aged 12 to 17 years, characterized by severe IOM alerts during spinal deformity surgery are reported. Postoperative neurological examination was normal for five out of six cases. For patient 2, lesional level diagnosis allowed to determine a bi-laminar claw between T2 and T3 as the etiology of IOM alert. This IOM alert was delayed in time, being detectable only 30minutes after the placement of this claw. Postoperative neurological examination was normal. For patient 6, a Stagnara wake-up test demonstrated paraplegia. Lesional level was established. Following corrective surgical maneuvers, postoperative neurologic deficit was limited to a pyramidal syndrome in one lower limb. Postoperative MRI demonstrated a spinal cord lesion at the determined lesional level. CONCLUSION: During an IOM alert, lesional level determination allows localization of spinal cord dysfunction. This data, obtainable whatever the IOM device, constitutes supplementary information in order to rapidly identify the etiology of IOM alert and thus to react in the most appropriate way. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 27988241 TI - Current Understandings of the Research-Practice Gap From the Viewpoint of Complementary Medicine Academics: A Mixed-Method Investigation. AB - CONTEXT: Research plays an important role in advancing health and healthcare. However, much research evidence is not reflected in contemporary complementary and alternative medicine (CAM) practice. Understanding and addressing the reasons for this research-practice gap may have positive implications for quality of care. OBJECTIVE: To shed light on the gap between research and CAM practice. DESIGN: Descriptive cross-sectional, mixed-method study. SAMPLE AND SETTING: A total of 126 senior CAM academics across Australasia, Europe, UK, and North America. OUTCOME MEASURES: Participants completed a 30-item online survey and a semi-structured interview; both of which explored the research-practice gap in CAM. RESULTS: A total of 43 (34%) academics completed the survey, with 29 (67%) respondents undergoing an interview. There was general agreement among respondents that CAM research should be informed by practice, and practice informed by research; however, most agreed that this did not reflect the current situation. Translational issues were perceived to be the primary reason for the research-practice gap in CAM. Suggested strategies for closing the gap focussed mostly around improving CAM student/practitioner education and training, and researcher-practitioner engagement and collaboration. CONCLUSIONS: Study findings point toward the presence of a research-practice gap in CAM, with several factors likely to be instrumental in sustaining this gap. Attention now needs to focus on understanding the views of CAM clinicians on this issue. Insights gained from this research will help inform the development of a multi-modal strategy that will effectively target the barriers to change in order to bring CAM research and practice closer together. PMID- 27988242 TI - Home-based Tai Chi Chuan May Reduce Fall Rate Compared to Lower Extremity Exercise Training in Older Adults with History of Falls. PMID- 27988244 TI - Trial of neurodynamic treatment was reported accurately and appropriately. PMID- 27988243 TI - Radiocarbon concentration in tree-ring samples collected in the south-west Slovakia (1974-2013). AB - Radiocarbon measurements of tree-ring samples collected in Vysoka pri Morave were compared with tree-ring data of the Zlkovce monitoring station situated 5km south east from the Jaslovske Bohunice Nuclear Power Plant (NPP). Radiocarbon concentrations in Vysoka pri Morave and in Zlkovce tree rings were decreasing exponentially with decay constants of 14.48+/-1.23 y and 17.96+/-1.97 y, respectively, in agreement with similar results obtained at other radiocarbon stations. The Suess effect, represented by a dilution in 14C levels by fossil fuel CO2 emissions, was observed in both tree-ring data sets. The Vysoka pri Morave 14C data were during 1974-1995 systematically lower by about 500/00 than the Schauinsland (Germany) clean air reference values due to a regional fossil fuel impact. However, after 1996 the Vysoka pri Morave 14C data were closer to the Schauinsland data due to lower CO2 emissions as a result of closing some of the heavy industry technologies in the region. PMID- 27988245 TI - The changing landscape of patient outcome assessment. PMID- 27988246 TI - Identification of neuronal and angiogenic growth factors in an in vitro blood brain barrier model system: Relevance in barrier integrity and tight junction formation and complexity. AB - We previously demonstrated that the co-cultivation of endothelial cells with neural cells resulted in an improved integrity of the in vitro blood-brain barrier (BBB), and that this model could be useful to evaluate the transport properties of potential central nervous system disease drugs through the microvascular brain endothelial. In this study we have used real-time PCR, fluorescent microscopy, protein arrays and enzyme-linked immunosorbent assays to determine which neural- and endothelial cell-derived factors are produced in the co-culture and improve the integrity of the BBB. In addition, a further improvement of the BBB integrity was achieved by adjusting serum concentrations and growth factors or by the addition of brain pericytes. Under specific conditions expression of angiogenic, angiostatic and neurotrophic factors such as endostatin, pigment epithelium derived factor (PEDF/serpins-F1), tissue inhibitor of metalloproteinases (TIMP-1), and vascular endothelial cell growth factor (VEGF) closely mimicked the in vivo situation. Freeze-fracture analysis of these cultures demonstrated the quality and organization of the endothelial tight junction structures and their association to the two different lipidic leaflets of the membrane. Finally, a multi-cell culture model of the BBB with a transendothelial electrical resistance up to 371 (+/-15) Omega*cm2 was developed, which may be useful for preliminary screening of drug transport across the BBB and to evaluate cellular crosstalk of cells involved in the neurovascular unit. PMID- 27988247 TI - Sensory-specific satiety: Added insights from autonomic nervous system responses and facial expressions. AB - As a food is consumed, its perceived pleasantness declines compared to that of other foods. Although this phenomenon, referred to as sensory-specific satiety, is well-established by means of measuring food intake and pleasantness ratings, this study was aimed at gaining more insight into the mechanisms that underlie such cognitive output behavior using two measures used in (food) emotion research, namely Autonomic Nervous System (ANS) responses and facial expressions. Twenty-four healthy female participants visited four times in a hungry state, in which they received 4 different semi-liquid meals (2 sweet and 2 savory) delivered via a time-controlled pump leading to sensory-specific satiety. Before and after the meals they were presented with a sip of all four different test meals where ANS responses (heart rate, skin conductance and skin temperature) and facial expressions were recorded. As expected, pleasantness ratings showed a significant decrease after eating the same meal or a meal similar in taste (sweet or savory) (p<0.001), and less decrease after eating a meal with a different taste. In general, consumption of the test meals resulted in increased heart rate, reduced skin conductance and skin temperature, as well as intensified anger and disgusted facial expressions (p<0.05). In addition, skin conductance, skin temperature, sad and angry expressions also showed effects reflecting sensory specific satiety. In conclusion, ANS responses and facial expressions indicate that sensory specific satiety of foods 1) not only reduces the food's pleasantness but also arousal and 2) are possibly mediated by changes in food emotions. PMID- 27988249 TI - Deconvoluting physical and chemical heat: Temperature and spiciness influence flavor differently. AB - Flavor is an essential, rich and rewarding part of human life. We refer to both physical and chemical heat in similar terms; elevated temperature and capsaicin are both termed hot. Both influence our perception of flavor, however little research exists into the possibly divergent effect of chemical and physical heat on flavor. A human sensory panel was recruited to determine the equivalent level of capsaicin to match the heat of several physical temperatures. In a subsequent session, the intensities of multiple concentrations of tastant solutions were scaled by the same panel. Finally, panelists evaluated tastants plus equivalent chemical or physical "heat". All basic tastes aside from umami were influenced by heat, capsaicin, or both. Interestingly, capsaicin blocked bitter taste input much more powerfully than elevated temperature. This suggests that despite converging percepts, chemical and physical heat have a fundamentally different effect on the perception of flavor. PMID- 27988248 TI - Does eating good-tasting food influence body weight? AB - Does eating good-tasting food influence body weight? To investigate, we first established some concentrations of sucralose and mineral oil in chow that mice strongly preferred. Then, in Experiment 1, we compared groups of 16 mice fed plain chow (i.e., chow with no additives) to groups fed chow with added (a) sucralose, (b) mineral oil, (c) sucralose and mineral oil, or (d) sucralose on odd days and mineral oil on even days. During a 6-week test, the body weights and body compositions of the five groups never differed. In Experiment 2, we compared groups of 18 mice fed plain chow or plain high-fat diet to groups fed these diets with added sucralose. During a 9-week test, the high-fat diet caused weight gain, but the body weights of mice fed the sucralose-sweetened diets did not differ from those fed the corresponding plain versions. Two-cup choice tests conducted at the end of each experiment showed persisting strong preferences for the diets with added sucralose and/or mineral oil. In concert with earlier work, our results challenge the hypothesis that the orosensory properties of a food influence body weight gain. A good taste can stimulate food intake acutely, and guide selection toward nutrient-dense foods that cause weight gain, but it does not determine how much is eaten chronically. PMID- 27988250 TI - Pheochromocytoma behind takotsubo(stress)-cardiomyopathy: The great pretender. PMID- 27988251 TI - Upper extremity deep vein thrombosis in a triathlete: Again intense endurance exercise as a thrombogenic risk. AB - Triathlon followers increase each year and long-distance events have seen major growth worldwide. In the cycling phase, athletes must maintain an aerodynamic posture on the bike for long periods of time. We report a case of a 38-year-old triathlete with symptoms of an axillary vein thrombosis 48h after a long triathlon competition. After 3days of hospitalization with a treatment consisted on enoxaparin anticoagulant and acenocumarol, the patient was discharged with instructions to continue treatment under home hospitalization with acetaminophen. Four weeks after the process, the patient was asymptomatic and the diameter of his arm was near normality. Due to the growing popularity of events based on endurance exercise, it is necessary more research to determine the etiopathogeny of deep venous thrombosis in athletes. PMID- 27988252 TI - Airway and circulatory collapse due to retropharyngeal hematoma after blunt vertebral artery injury. AB - Retropharyngeal hematoma following blunt cervical spine injury is a known cause of airway obstruction, but it is not known to cause hemorrhagic shock. We report the case of a massive retropharyngeal hematoma caused by a blunt vertebral artery transection leading simultaneously to airway obstruction and hemorrhagic shock. An 83-year-old woman was injured in a motorcycle accident. In the field, the patient exhibited paradoxical breathing with no breath sounds, and her blood pressure could not be measured. Therefore, emergency intubation and fluid resuscitation were initiated and the patient was transferred to the emergency department. Computed tomography angiography revealed a massive retropharyngeal hematoma with contrast extravasation from the right vertebral artery, which caused airway obstruction and hemorrhagic shock. The right vertebral artery was transected at the C5 level, which was associated with C4/C5 dislocation. Vertebral artery transection was successfully treated by endovascular embolization, which was followed by complication of asymptomatic posterior circulation stroke. Blunt vertebral artery transection can cause massive retropharyngeal hematoma, which can rapidly expand and lead to hemorrhagic shock in addition to airway obstruction. In cases of massive retropharyngeal hematoma with hemorrhagic shock following blunt cervical spine injury, blunt vertebral artery transection should be suspected. If blunt vertebral artery transection is detected and hemorrhagic shock is persistent, endovascular embolization should be performed immediately in addition to emergency intubation. PMID- 27988253 TI - Odontogenic cutaneous sinus tract presenting as a growing cheek mass in the emergency department. AB - An odontogenic cutaneous sinus tract (OCST) is a rare extraoral sinus tract related to a chronic draining dental infection, typically apical periodontitis. OCST usually presents as an erythematous and non-tender nodule and often requires endodontic treatment for resolution of the sinus tract. If there is disruption of the mandibular cortex, it may be difficult to differentiate an OCST from a non odontogenic malignant mass in patients without dental symptoms. This report describes a rare case of OCST presenting as a left cheek mass in a 21-year-old man which was initially diagnosed in the emergency department. PMID- 27988254 TI - Targeted temperature management after cardiac arrest with anaphylaxis. AB - Fatal anaphylaxis is uncommon but not rare. Extrapolated mortality rates are 0.52% of total anaphylaxis patients Bock et al. (Jan. 2001) [1]. Nevertheless, compared with the incidence of the other cardiac arrest events, the incidence of cardiac arrest due to anaphylaxis is relatively small. As a result, the effect using targeted temperature management after anaphylaxis is not clearly understood. We report the case of a 63-year-old man who developed cardiac arrest after ingestion of two pieces of peach. He was resuscitated and his circulation returned spontaneously after approximately 11min of cardiopulmonary resuscitation, but he was unresponsive and had fixed dilated pupils. We initiated therapeutic hypothermia on the basis of protocol for 24h. The patient was gradually and successfully cooled and rewarmed. The patient opened his eyes spontaneously on day 5, obeyed commands on day 6, and was discharged on day 18. At the time of discharge, he had no neurologic deficiencies or other complications. PMID- 27988255 TI - Reversible cerebral vasoconstriction syndrome presenting as subarachnoid hemorrhage: A rare cause of postpartum seizure. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is a rare cerebrovascular disorder affecting large- and medium-sized arteries, occurring most commonly in young women. Thunderclap headache is the usual primary symptom; seizure is uncommon. During the postpartum period, seizure is a significant concern. The main causes of postpartum seizures are posterior reversible encephalopathy syndrome and cortical venous thrombosis; RCVS-related postpartum seizure is rare. Despite its rarity, its course may be fulminant, resulting in permanent disability or death if the diagnosis is delayed and treatment is not started promptly. We report an unusual case of RCVS presenting as a subarachnoid hemorrhage in a 31-year-old woman admitted for postpartum seizure. PMID- 27988256 TI - Oocyte Competence in Women with Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and affects fertility and pregnancy in cases of oligoanovulation. Ovulation induction is often used to treat anovulatory patients with PCOS, but many of these women fail to conceive and resort to assisted reproductive technologies. Alterations in oocyte competence (OC) are considered potential causative factors for subfertility in women with PCOS. In this review we present and critically assess all recent clinical and experimental data regarding OC in women with PCOS. Our analysis demonstrates that the contribution of OC to reproductive potential in women with PCOS varies and largely depends on the PCOS phenotype and comorbidities associated with PCOS. PMID- 27988259 TI - EphA5 and EphA7 forward signaling enhances human hematopoietic stem and progenitor cell maintenance, migration, and adhesion via Rac1 activation. AB - The proliferation, differentiation, adhesion, and migration of hematopoietic stem and progenitor cells (HSPCs) are dependent upon bone marrow stromal cells (BMSCs). In this study, we found that human primitive HSPCs (CD34+CD38-), but not lineage-committed hematopoietic cell populations, express the tyrosine kinase receptors EphA5 and EphA7. Moreover, we found that the ephrinA5 ligand, the high affinity binding partner of EphA5 and EphA7, is highly expressed by primary human BMSCs. Previous studies have reported that interactions between EphA and ephrinA play important roles in hematopoietic cell trafficking; however, their role in BMSC support of hematopoiesis had not been described previously. Herein, we show that stimulating EphA5 and/or EphA7 forward signaling in HSPCs using soluble ephrinA5-Fc molecules promoted human HSPC-derived colony formation significantly and was associated with increased expression of granulocyte macrophage colony stimulating factor receptor on HSPCs. Studies using functional blocking peptides to EphA5/7 found that disruption of EphA5/ephrinA5 and/or EphA7/ephrinA5 interactions inhibited HSPC function in BMSC-dependent long-term culture initiating cell assays. Furthermore, the adhesion and migration of HSPCs was increased significantly in the presence of ephrinA5-Fc molecules compared with human immunoglobulin G-treated controls. Conversely, blocking EphA5 activation led to a reduction of HSPC adhesion, whereas inhibiting EphA5 and/or EphA7 activation hindered HSPC migration. Analysis of HSPC cultured in the presence of ephrinA5-Fc showed that EphA forward signaling stimulated Rac1 gene and protein expression and the Rac1 target molecule WAVE1. Moreover, a significant reduction of ephrinA5-mediated HSPC adhesion and migration was observed in the presence of Rac1 inhibitor. These findings suggest that interactions between EphA and ephrinA5 are important in maintaining the HSPC niche mediated in part by activation of Rac1 signaling. PMID- 27988257 TI - Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimulation. AB - Vagus nerve stimulation (VNS) has emerged as a therapy to treat a wide range of neurological disorders, including epilepsy, depression, stroke, and tinnitus. Activation of neurons in the locus coeruleus (LC) is believed to mediate many of the effects of VNS in the central nervous system. Despite the importance of the LC, there is a dearth of direct evidence characterizing neural activity in response to VNS. A detailed understanding of the brain activity evoked by VNS across a range of stimulation parameters may guide selection of stimulation regimens for therapeutic use. In this study, we recorded neural activity in the LC and the mesencephalic trigeminal nucleus (Me5) in response to VNS over a broad range of current amplitudes, pulse frequencies, train durations, inter-train intervals, and pulse widths. Brief 0.5s trains of VNS drive rapid, phasic firing of LC neurons at 0.1mA. Higher current intensities and longer pulse widths drive greater increases in LC firing rate. Varying the pulse frequency substantially affects the timing, but not the total amount, of phasic LC activity. VNS drives pulse-locked neural activity in the Me5 at current levels above 1.2mA. These results provide insight into VNS-evoked phasic neural activity in multiple neural structures and may be useful in guiding the selection of VNS parameters to enhance clinical efficacy. PMID- 27988260 TI - Myths in the Evaluation and Management of Ovarian Torsion. AB - BACKGROUND: Ovarian torsion is a rare but serious cause of pelvic pain in females. Making the diagnosis is important because misdiagnosis can lead to an ischemic ovary and subsequent infertility. OBJECTIVE: Although all emergency physicians are aware of ovarian torsion, there are several myths regarding its epidemiology, diagnosis, and treatment. This article attempts to review some of these myths to improve emergency diagnosis and evaluation. DISCUSSION: Ovarian torsion is not an easy diagnosis to make and it is commonly missed. Signs and symptoms often mimic other disorders such as appendicitis, pyelonephritis, and nephrolithiasis. The diagnosis becomes more challenging in that torsion can occur in female patients of all ages, including infants and the elderly. Normal arterial blood flow on ultrasound does not rule out ovarian torsion and not every patient will have a mass on imaging or a palpable mass on examination. Patients may have symptoms for several hours or days, and thus, ovarian torsion may be present even with a longer duration of symptoms. Surgery is the definitive treatment and may still be effective after several hours of symptoms. CONCLUSIONS: Although ovarian torsion is a challenging diagnosis, understanding myths surrounding the disorder may help emergency physicians consider it in unusual populations. If there is any clinical concern for ovarian torsion, a gynecologic consult may be helpful, even if imaging findings are not conclusive. Surgery remains the standard method for definitive diagnosis and treatment. PMID- 27988258 TI - Allostatic load and pain severity in older adults: Results from the English Longitudinal Study of Ageing. AB - Pain is common in older adults, is frequently experienced as stressful, and is associated with increased morbidity and mortality. Stress regulatory systems are adaptive to challenge and change, allostasis, until demands exceed the adaptive capacity contributing to dysregulation, resulting in a high allostatic load. A high allostatic load is associated with increased risk of morbidity and mortality. Pain severity, based on the average intensity of frequent pain, was hypothesized to be positively associated with AL. Four formulations of AL were investigated. Cross-sectional data from Wave 4 (2008-2009) of the English Longitudinal Study of Aging (ELSA) were analyzed. Covariates in the model included age, sex, education, smoking status, alcohol consumption, activity level, depression and common comorbid health conditions. A total of 5341 individuals were included; mean age 65.3(+/-9.2) years, 55% female, 62.4% infrequent or no pain, 12.6% mild pain, 19.1% moderate pain, and 5.9% severe pain. Severe pain was associated with greater AL defined by all four formulations. The amount of variance explained by pain severity and the covariates was highest when allostatic load was defined by the high risk quartile (12.9%) and by the clinical value (11.7%). Findings indicate a positive relationship between pain severity and AL. Further investigation is needed to determine if there is a specific AL signature for pain that differs from other health conditions. PMID- 27988261 TI - Spontaneous Nasal Septal Abscess Presenting as a Soft Tissue Mass in a Child. AB - BACKGROUND: Nasal septal abscess (NSA) is a rare condition most commonly seen as a complication of nasal trauma. The diagnosis of NSA requires emergent treatment, because delayed management can result in significant morbidity. Typically, NSA presents as a purulent collection that can be managed with drainage, either surgically or at bedside. CASE REPORT: We report an unusual presentation of a spontaneous NSA in a 7-year-old boy as a solid nasal mass eroding the nasal septum. The solid, tumor-like nature of the mass necessitated intervention beyond drainage and was ultimately excised. Imaging initiated in the emergency department revealed a partially cystic mass and erosion of the septum, which was key to the diagnosis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Given the ease with which a diagnosis of NSA may be missed and the need for urgent management upon diagnosis of a NSA, we aim to highlight the clinical, radiologic, and histopathologic aspects that aid in diagnosis of NSA. Imaging, obtaining culture results, and initiation of antibiotics are paramount in management. In addition, NSAs may also necessitate bedside drainage given their emergent nature. PMID- 27988262 TI - Impact of Scribes on Billed Relative Value Units in an Academic Emergency Department. AB - BACKGROUND: Scribe use throughout health care is becoming more common. There is limited peer-reviewed literature supporting this emerging role in health care despite rapid uptake of the role. OBJECTIVES: Our study assesses impact of scribes on relative value units (RVUs) in adult and pediatric emergency departments (EDs). METHODS: A prospective cohort study was developed in a tertiary academic ED. Charts were coded by an external billing and coding company, then returned and mapped by International Classification of Diseases, 9th revision diagnostic codes. After training by a staff member with significant experience in implementing scribe programs, scribes provided 1-to-1 support to a provider as staffing allowed. Comparisons were made between scribed and nonscribed visits. RESULTS: There were 49,389 patient visits during the study period (39,926 adult [80.84%] and 9463 pediatric [19.16%] visits), of which 7865 (15.9%) were scribed. For adults, scribed visits produced 0.20 additional RVUs per patient (p < 0.001). Scribes generated additional RVUs in Emergency Severity Index (ESI) 2 (p < 0.001) and 3 (p < 0.001) patients. There were variable effects of scribes on RVUs by diagnostic codes. For pediatric patients, scribed encounters generated 0.08 fewer RVUs per patient (p = 0.007). ESI score had no effect on RVUs. The impact of scribes on pediatric diagnostic groupings was inconsistent. CONCLUSIONS: Scribes had a positive impact on RVUs in adult but not pediatric patients. Among adults, scribes led to higher RVUs in ESI 2 and 3 but not 4 and 5 patients, perhaps suggesting a limitation to improve revenue capture on lower-acuity patients. PMID- 27988263 TI - CT-Guided Microwave Ablation of 45 Renal Tumors: Analysis of Procedure Complexity Utilizing a Percutaneous Renal Ablation Complexity Scoring System. AB - PURPOSE: To develop a scoring system that stratifies complexity of percutaneous ablation of renal tumors. MATERIALS AND METHODS: Analysis was performed of 36 consecutive patients (mean age, 64 y; range, 30-89 y) who underwent CT-guided microwave (MW) ablation of 45 renal tumors (mean tumor diameter, 2.4 cm; range, 1.2-4.0 cm). Technical success and effectiveness were determined based on intraprocedural and follow-up imaging studies. The RENAL score and the proposed percutaneous renal ablation complexity (P-RAC) score were calculated for each tumor. RESULTS: Technical success was 93.3% (n = 42). Biopsy of 38 of 45 renal tumors revealed 23 renal cell carcinomas. Median follow-up period was 9.7 months (range, 2.9-46.8 months). There were no tumor recurrences. One major complication, ureteropelvic junction stricture, occurred (2.6%). The P-RAC score was found to differ statistically from the RENAL score (t = 3.754, df = 44, P = .001). A positive correlation was found between the P-RAC score and number of antenna insertions (r = .378, n = 45, P = .011) and procedure duration (r = .328, n = 45, P = .028). No correlation was found between the RENAL score and number of MW antenna insertions (r = .110, n = 45, P = .472) or procedure duration (r = .263, n = 45, P = .081). Hydrodissection was significantly more common in the P RAC high-complexity category than in low-complexity category (chi2 = 12.073, df = 2, P = .002). CONCLUSIONS: The P-RAC score may be useful in stratifying percutaneous renal ablation complexity. Further studies with larger sample sizes are necessary to validate the P-RAC score and to determine if it can predict risk of complications. PMID- 27988265 TI - Re: Chen et al.: Efficacy of Daily Low-dose Tadalafil for Treating Overactive Bladder: Results of a Randomized, Double-blind, Placebo-controlled Trial (Urology 2017;100:59-64). PMID- 27988264 TI - Re: Hussein et al.: Development and Validation of a Quality Assurance Score for Robot-assisted Radical Cystectomy: A 10-Year Analysis (Urology 2016;97:124-129). PMID- 27988266 TI - UroLift in Place of Fiducial Markers for Patients With Benign Prostatic Hyperplasia Undergoing External Beam Radiation Therapy. AB - OBJECTIVE: To investigate if using a novel treatment for obstructive benign prostatic hyperplasia (UroLift) to relive lower urinary tract symptoms (LUTS) prior to external beam radiotherapy (EBRT) could also supplant the use of fiducial markers obviating the need for a second transrectal procedure while facilitating symptom-free voiding during and after EBRT a series of patients are reported on. METHODS: The medical records of 7 consecutive patients who underwent placement of UroLift for simultaneous treatment of obstructive LUTS due to benign prostatic hyperplasia and targeting of EBRT for treatment of prostate cancer between September and December of 2015 were reviewed. RESULTS: The UroLift clips were sufficiently radiopaque to make targeting possible for EBRT. All patients were able to complete a full course of radiotherapy without placement of fiducial markers. No patient experienced complications that could be attributed to the UroLift implants or procedure during their course of radiotherapy. None of the patients required additional alpha-blockers during radiation therapy. CONCLUSION: The UroLift system can serve as fiducial markers in patients undergoing EBRT. Although the current clip utilized in the UroLift system is generally radiopaque, it does not project well on the sagittal plane and would be significantly enhanced if a more strongly opaque substance was incorporated. It remains to be proven if the UroLift system can significantly reduce the symptoms of LUTS during and post EBRT. PMID- 27988268 TI - Unscheduled vaginal bleeding with progestin-only contraceptive use. AB - Nearly 20% of women using contraception are using progestin-only contraception, including progestin-only pills, depot-medroxyprogesterone acetate, subdermal etonogestrel implants, and levonorgestrel intrauterine devices. This number will continue to grow with the increased provision of long-acting reversible contraception. Although overall satisfaction among women using progestin-only contraception is high, dissatisfaction and discontinuation may be associated with unscheduled bleeding and spotting. The exact etiology of irregular bleeding associated with progestin-containing contraceptives is not completely understood, yet several mechanisms have been suggested. Several therapies targeting these mechanisms have been evaluated with mixed results. This paper will review the physiology and management of unscheduled bleeding with progestin-containing contraceptives. PMID- 27988267 TI - Poor Sleep Quality Predicts Hypogonadal Symptoms and Sexual Dysfunction in Male Nonstandard Shift Workers. AB - OBJECTIVE: To investigate the impact of sleep quality in hypogonadal symptoms and sexual function in men working nonstandard shifts. MATERIALS AND METHODS: Men treated at a single andrology clinic between July and October 2014 completed questionnaires assessing sleep quality, hypogonadal symptoms (Androgen Deficiency in the Aging Male [ADAM/qADAM]), and sexual function (International Index of Erectile Function [IIEF]). Serum hormone levels were assessed at the time of survey completion. RESULTS: One hundred eighty-two men were identified as working nonstandard shifts (work that starts before 7 a.m. or after 2 p.m., rotates, or regularly includes hours outside of the standard 7 a.m. to 6 p.m. workday) with a mean +/- SD age of 41.1 +/- 10.8 years. Of men working nonstandard shifts, those with better sleep quality had fewer hypogonadal symptoms and better sexual function. Multivariate regression analysis revealed significant linear associations between sleep quality and qADAM score (P = .008), positive ADAM responses (P = .003), and IIEF score (P = .0004). When comparing individual groups, men who were "very satisfied" (n = 60) with sleep quality had higher qADAM scores than men who were "somewhat dissatisfied" (P = .02), and men who were "very dissatisfied" had significantly lower IIEF scores than men who were "very satisfied" (P = .001) and "somewhat satisfied" (P = .005). No associations between sleep quality and mean serum testosterone, free testosterone, estrogen, dehydroepiandrosterone, follicle-stimulating hormone, and luteinizing hormone levels were observed. CONCLUSION: Men who work nonstandard shifts and have poor sleep quality are at increased risk for hypogonadal symptoms and sexual dysfunction. PMID- 27988271 TI - Risk perception regarding drug use in pregnancy. AB - Pregnant women, but also physicians, have unrealistically high perceptions of teratogenic drug effects. This may result in suboptimal treatment of disease and even influence decisions of whether to continue pregnancy. To attain more realistic teratogenic risk perceptions, several factors that influence this issue should be considered, and these are further discussed in this Clinical Opinion. Importantly, drug use may have several benefits, both for the pregnant woman's health and to avoid negative fetal effects of untreated maternal disease. A greater focus on this aspect may act to balance risk perceptions. Furthermore, both pregnant women and physicians need access to drug information sources that provide realistic risk estimates to increase confidence in appropriate drug use and prescribing. We suggest that access to decision support and individually tailored information provided by drug information centers may contribute to this goal. PMID- 27988269 TI - Assessment of vulvar discomfort with sexual activity among women in the United States. AB - BACKGROUND: Multidimensional self-report measures of sexual function for women do not include the assessment of vulvar discomfort, limiting our understanding of its prevalence. In an effort to improve the measurement of patient-reported health, the National Institutes of Health funded the creation of the Patient Reported Outcomes Measurement Information System (PROMIS). This included the development of the PROMIS Sexual Function and Satisfaction measure, and version 2.0 of the Sexual Function and Satisfaction measure included 2 scales to measure vulvar discomfort with sexual activity. OBJECTIVES: The objectives of the study were to describe the development of 2 self-reported measures of vulvar discomfort with sexual activity, describe the relationships between these scales and scales for lubrication and vaginal discomfort, and report the prevalence of vulvar discomfort with sexual activity in a large, nationally representative sample of US women. STUDY DESIGN: We followed PROMIS measure development standards, including qualitative development work with patients and clinicians and psychometric evaluation of candidate items based on item response theory, in a probability sample of 1686 English-speaking US adult women. We tested 16 candidate items on vulvar discomfort. We present descriptive statistics for these items, correlation coefficients among the vulvar and vaginal scales, and mean PROMIS scores with 95% confidence intervals separately by menopausal status for the 1046 women who reported sexual activity in the past 30 days. RESULTS: Based on the psychometric evaluation of the candidate items, we created 2 separate 4 item scales, one to measure labial discomfort and pain and one to measure clitoral discomfort and pain. Additional items not included in the scales assess pain quality, numbness, and bleeding. The correlations between the lubrication, vaginal discomfort, and the 2 vulvar discomfort measures ranged from 0.46 to 0.77, suggesting that these measures represent related yet distinct concepts. In our nationally representative sample, 1 in 5 US women endorsed some degree of vulvar discomfort with sexual activity in the past 30 days. Menopausal status was associated with lower lubrication and higher vaginal discomfort but not with vulvar discomfort. CONCLUSION: The PROMIS Vulvar Discomfort with Sexual Activity Labial and Vulvar Discomfort with Sexual Activity-Clitoral scales are publicly available for use in research and clinical settings. There is limited overlap between vulvar discomfort and lubrication or vaginal discomfort. The importance of measuring vulvar discomfort as part of a comprehensive assessment of sexual function is underscored by its prevalence. PMID- 27988270 TI - Validity of self-reported history of Chlamydia trachomatis infection. AB - BACKGROUND: Chlamydia trachomatis infection is common and largely asymptomatic in women. If untreated, it can lead to sequelae such as pelvic inflammatory disease and infertility. It is unknown whether a patient's self-reported history of Chlamydia trachomatis infection is a valid marker of past infection. OBJECTIVE: Our objective was to evaluate the validity of women's self-reported history of Chlamydia trachomatis infection compared with Chlamydia trachomatis serology, a marker for previous infection. STUDY DESIGN: We analyzed data from the Fertility After Contraception Termination study. We compared participants' survey responses with the question, "Have you ever been told by a health care provider that you had Chlamydia?" to serological test results indicating the presence or absence of antibodies to Chlamydia trachomatis as assessed by a microimmunofluorescence assay. Prevalence of past infection, sensitivity, specificity, predictive values, and likelihood ratios were calculated. The Cohen's kappa statistic was computed to assess agreement between self-report and serology. RESULTS: Among 409 participants, 108 (26%) reported having a history of Chlamydia trachomatis infection, whereas 146 (36%) had positive serological test results. Relative to positive microimmunofluorescence assay, the sensitivity and specificity of self reported history of Chlamydia trachomatis infection were 52.1% (95% confidence interval, 43.6-60.4%) and 87.8% (95% confidence interval, 83.3-91.5%), respectively. The positive predictive value of the self-report was 70.4% (95% confidence interval, 60.8-78.8%), and the negative predictive value was 76.7% (95% confidence interval, 71.6-81.4%). The likelihood ratio was found to be 4.28. Agreement between self-report and serology was found to be moderate (kappa = 0.42, P < .001). CONCLUSION: Self-reported history of Chlamydia trachomatis infection commonly yields false-negative and false-positive results. When definitive status of past Chlamydia trachomatis infection is needed, serology should be obtained. PMID- 27988272 TI - The impact of postnatal leuprolide acetate treatment on reproductive characteristics in a rodent model of polycystic ovary syndrome. AB - In this study, a GnRH agonist, leuprolide acetate (LA), was given as a single depot injection before 48 h of life to Wistar female rats allotted to prenatal (E16-18) and postnatal androgenization (day 5 of life) by the use of testosterone propionate, looking for reproductive endpoints. Remarkably, a single injection of LA increased the estrus cycles in the postnatal group (PostN) from 0% to 25% of the estrus cycles in the postnatal LA treated group (PostN L). LA also reduced the serum testosterone levels and cysts and atretic follicles in PostN L in contrast with rats (>100 days) from the PostN group (p = 0.04). Prenatally androgenized rats (PreN) exhibited significant modifications in the hypothalamic genes, such as Gnrh. To the best of our knowledge, this is the first study to show that blockage of the GnRH axis with leuprolide acetate depot prevented the development of typical features (anovulation, cysts, atretic follicles) in a postnatal testosterone propionate rat model of PCOS. PMID- 27988273 TI - The association of maximum Troponin values post out-of-hospital cardiac arrest with electrocardiographic findings, cardiac reperfusion procedures and survival to discharge: A sub-study of ROC PRIMED. AB - BACKGROUND: The role of Troponin (Tn) levels in the management of patients post out-of-hospital cardiac arrest (OHCA) is unclear. METHODS: All OHCA patients enrolled in the Resuscitation Outcomes Consortium Prehospital Resuscitation using an IMpedance valve and Early versus Delayed analysis trial and admitted to hospital with a Tn level and a 12-lead electrocardiogram were stratified by ST elevation (STE) or no STE in a regression model for survival to discharge adjusted for Utstein predictors and site. RESULTS: Of the 15,617 enrolled OHCA patients, 4118 (26%) survived to admission to hospital; 17% (693) were STE and 77% (3188) were no STE with 6% unknown; 83% (3460) had at least one Tn level. Reperfusion rates were higher when Tn level >2ng/ml (p>0.1ng/ml) improved with a diagnostic cardiac catheterization (p<0.001). CONCLUSIONS: Elevated Tn levels >2ng/ml were associated with improved survival to discharge in patients post OHCA with STE. Survival in patients with no STE and Tn values >0.1ng/ml was higher when associated with diagnostic cardiac catheterization or treated with reperfusion or revascularization. PMID- 27988275 TI - Erratum to "Bone marrow lesions in hip osteoarthritis are characterized by increased bone turnover and enhanced angiogenesis" [Osteoarthritis Cartilage 24 (2016) 1745-1752]. PMID- 27988274 TI - Improving efficacy of the adjustable gastric band: studies of the use of adjuvant approaches in a rodent model. AB - BACKGROUND: The laparoscopic adjustable gastric band (AGB) has been effective in reducing excess weight by approximately 50% for at least 16 years. However, as with all weight loss approaches, reduction in weight resulting from bariatric surgery is associated with a compensatory reduction in energy expenditure, which may confound and limit weight loss. Adjuvant therapies that reduce food intake and increase energy expenditure may be used to improve weight loss outcomes by ameliorating, or even reversing, this reduction in energy expenditure. METHODS: Rats were either fitted with an AGB or were sham operated and received one of 2 adjunctive pharmacologic treatments, (1) thyroxine or (2) bupropion/naltrexone (Contrave), at a range of doses and matched with vehicle controls (n = 6-8/group) over a 4-week period of combined treatments. Metabolic parameters including food intake, weight, fat mass, and energy expenditure in brown adipose tissue (BAT), whole body calorimetry, and physical activity were assessed. RESULTS: Inflation of the AGB caused a reduction in weight gain that was further enhanced by cotreatment with either thyroxine or Contrave (P<.05). Thyroxine completely ameliorated the reduction in AGB-induced BAT thermogenesis and significantly improved weight loss, particularly in fat mass. Contrave also augmented the loss of weight and fat mass associated with the AGB and increased BAT thermogenesis in banded rats even at doses below that required to change food intake. CONCLUSION: Adjuvant therapies can improve the efficacy of the AGB, at least in part by negating the compensatory reduction in energy expenditure, but also via a combined effect on food intake. PMID- 27988276 TI - High throughput, quantitative analysis of human osteoclast differentiation and activity. AB - Osteoclasts are multinuclear cells that degrade bone under both physiological and pathophysiological conditions. Osteoclasts are therefore a major target of osteoporosis therapeutics aimed at preserving bone. Consequently, analytical methods for osteoclast activity are useful for the development of novel biomarkers and/or pharmacological agents for the treatment of osteoporosis. The nucleation state of an osteoclast is indicative of its maturation and activity. To date, activity is routinely measured at the population level with only approximate consideration of the nucleation state (an 'osteoclast population' is typically defined as cells with >=3 nuclei). Using a fluorescent substrate for tartrate-resistant acid phosphatase (TRAP), a routinely used marker of osteoclast activity, we developed a multi-labelled imaging method for quantitative measurement of osteoclast TRAP activity at the single cell level. Automated image analysis enables interrogation of large osteoclast populations in a high throughput manner using open source software. Using this methodology, we investigated the effects of receptor activator of nuclear factor kappa-B ligand (RANK-L) on osteoclast maturation and activity and demonstrated that TRAP activity directly correlates with osteoclast maturity (i.e. nuclei number). This method can be applied to high throughput screening of osteoclast-targeting compounds to determine changes in maturation and activity. PMID- 27988277 TI - The New Zealand Norwood Procedure Experience: 22-Year Cumulative Review. AB - BACKGROUND: Babies born with a functional single ventricle heart and systemic outflow tract obstruction may require a Norwood (NW) procedure as the first of three staged procedures to obtain a Fontan circulation. This procedure and the following treatment pathway are associated with significant mortality. Risk factors for the Norwood procedure and the subsequent pathway are not necessarily the same. To identify these factors within New Zealand, the collective experience with the Norwood procedure was examined. METHODS: Charts from 133 New Zealand children undergoing Norwood procedure from 1992 to 2014 were examined. Deaths were assigned as "early" (30-day or in-hospital) or "late" (based on timeframe from the Norwood procedure). Cardiac anatomic, patient demographic and surgery related variables were examined. Important risk factors were identified using univariate and multivariate analysis. Kaplan-Meier survival curves were calculated. RESULTS: Survival following the Norwood procedure was 83%. Overall survival was 67% at six months, 65% at one year, and 63% at five years. Size of the ascending aorta appeared as an important risk factor with "early" death while New Zealand deprivation index and low birth weight appeared more important for "late" death. These factors each impacted overall survival. CONCLUSIONS: The Norwood procedure and subsequent medical treatment carries significant mortality in New Zealand. Cardiac anatomical factors affect survival of the immediate Norwood procedure whereas social factors weigh more significantly on longer term survival. Nevertheless, both anatomical and social factors carry real survival risk. PMID- 27988278 TI - Right Ventricular Response During Exercise in Patients with Chronic Obstructive Pulmonary Disease. AB - AIM: Right ventricular (RV) pump function is of essential clinical and prognostic importance in a variety of heart and lung diseases. While the evaluation of RV performance at rest has been implemented in the clinical setting, it is unknown whether this assessment during exercise may provide additional benefit. With this aim, we evaluated the exercise-induced pulmonary arterial systolic pressure (PASP) increase during exercise in patients with severe chronic obstructive pulmonary disease (COPD) as an expression of RV contractile reserve. METHOD: Cardiopulmonary exercise testing (CPET) with synchronic echocardiography was performed in 81 patients. Patients were classified into two groups according to an exercise-induced PASP increase above 30mmHg (High PSAP) or below 30mmHg (Low PSAP) during maximal exercise. Patients were then followed for three years. RESULTS: Sixteen patients (20%) had low PSAP and 65 (80%) showed high PSAP. These were not significant clinical and functional differences. Low PSAP was associated with a significantly lower peak VO2 (mean (SD), 35 (2) % predicted) compared to high PSAP response (peak VO2 45 (3) % predicted), p=0.045. Factors associated with mortality were age and exercise-induced PASP. Seventeen patients died during the three years of follow-up (7 (39%) in the low PSAP group and only 10 (1%) in the high PSAP group, p=0.041). CONCLUSION: Cardiopulmonary exercise testing with a synchronic echocardiography may be a useful tool for the assessment of RV contractile reserve in severe COPD patients. Exercise-induced PSAP emerges as a possible prognostic factor in these patients. PMID- 27988279 TI - Thigh Oedema. PMID- 27988280 TI - Comparison of Efficacy, Pattern of Response, Occurrence of Arrhythmias, and the Tolerability of Nitroglycerine and Isoprenaline as Provocative Drugs During Head Up Tilt Test. AB - BACKGROUND: Various protocols exist for performing head-up tilt test (HUTT). Serious ventricular arrhythmias have been reported during HUTT using Isoprenaline (ISO) provocation and their incidence with sublingual Nitroglycerine provocation is unknown. This study aims to assess the efficacy, pattern of response, tolerability, and frequency of arrhythmias during head-up tilt test with sublingual Nitroglycerine (NTG) provocation compared to ISO) provocation. METHODS: This is a retrospective observational study. RESULT: From 2007 to 2015, a total of 816 patients (68% men, median age 49 IQR 25.75-65 years) underwent head-up tilt testing using sublingual NTG provocation whereas ISO was used in 189 patients (66.1% men, median age 48 IQR 36-60 years). A positive response was more frequently observed in the NTG group than the ISO group (48.4% vs 35.9%, p=0.002), with more frequent type II b (cardio-inhibition with >3sec asystole) and type III (vasodepressor) responses ([15. 9% vs 4.1%, p=0.001] and 0% vs 29.4%, p=0.004) respectively. Bradyarrhythmias occurring always as a part of a positive HUTT response were the commonest arrhythmias (29% in NTG group vs 25.4% in ISO group, p=0.31). Tachyarrhythmias (or premature beats) were more frequent in the ISO group (12.7% vs 7.9%, p=<0.005). The use of NTG was significantly associated with a positive response (OR 1.775, 95% CI 1.269-2.483, p=0.001), whereas the use of ISO predicted the occurrence of premature beats/tachyarrhythmias (OR 3.06, 95% CI 2.195-4.267, p<0.005). Intolerance needing termination of the test was significantly more frequent in the ISO group than NTG group (1.6% vs 0.12%, p= 0.02). CONCLUSION: Head-up tilt test with NTG provocation has a higher yield of a positive response, lower incidence of unwanted arrhythmias and better tolerability compared to ISO. The occurrence of VASIS type II b and type III response was more with Nitroglycerine than Isoprenaline. PMID- 27988281 TI - Distribution of ABO Blood Groups and Coronary Artery Calcium. AB - BACKGROUND: ABO blood groups have been confirmed to be associated with cardiovascular diseases such as coronary artery disease. However, whether ABO blood group is correlated with coronary artery calcium (CAC) is still unknown. METHOD: 301 patients with coronary artery calcium score (CACS) assessed by computed tomography were consecutively enrolled and divided into two groups: with calcium group (CACS>0, n=104) and without calcium group (CACS=0, n=197). Distribution of ABO blood groups was evaluated between the two groups. RESULTS: The percentage of A blood type was significantly higher (p=0.008) and O blood type was significantly lower (p=0.037) in the calcium group. Univariate regression analysis showed that age, total cholesterol, low density lipoprotein cholesterol, high-sensitivity C-reactive protein, A blood type were positively correlated with CAC, and O blood type was inversely associated with CAC. Multivariate regression analysis showed that A blood type was independently associated with CAC (odds ratio: 2.217, 95% confidence interval: 1.260-3.900, p=0.006) even after further adjustment for variables that were clearly different between the two groups. CONCLUSIONS: Our data has suggested for the first time that A blood type was an independent risk marker for CAC. PMID- 27988282 TI - Publishing negative findings and the challenge of avoiding type II errors in studies of suspect teratogens: Example of a recent ondansetron publication. AB - It is important that negative, as well as positive, studies be published to complete the available picture in areas of scientific inquiry. At the same time, it is critical that the implications of a negative study not be overstated and generalized when major issues of study design and data accuracy may be the reason that no relationship was discovered. The challenge of avoiding type II errors in interpreting negative findings has major public health implications, especially when the relationship of an exposure to birth defects is the concern. This is particularly important when interpreting the report by Fazio et al. (June issue of Reproductive Toxicology) on the relationship of ondansetron exposure to pregnancy outcome and birth defects. This review addresses the study design and conclusions and suggests that an alternative concluding statement would be more apropos, given the limitations of the data. PMID- 27988283 TI - Identification and evolutionary analysis of tissue-specific isoforms of mitochondrial complex I subunit NDUFV3. AB - Mitochondrial complex I is the largest respiratory chain complex. Despite the enormous progress made studying its structure and function in recent years, potential regulatory roles of its accessory subunits remained largely unresolved. Complex I gene NDUFV3, which occurs in metazoa, contains an extra exon that is only present in vertebrates and thereby evolutionary even younger than the rest of the gene. Alternative splicing of this extra exon gives rise to a short NDUFV3 S and a long NDUFV3-L protein isoform. Complexome profiling revealed that the two NDUFV3 isoforms are constituents of the multi-subunit complex I. Further mass spectrometric analyses of complex I from different murine and bovine tissues showed a tissue-specific expression pattern of NDUFV3-S and NDUFV3-L. Hence, NDUFV3-S was identified as the only isoform in heart and skeletal muscle, whereas in liver, brain, and lung NDUFV3-L was expressed as the dominant isoform, together with NDUFV3-S present in all tissues analyzed. Thus, we identified NDUFV3 as the first out of 30 accessory subunits of complex I present in vertebrate- and tissue-specific isoforms. Interestingly, the tissue-specific expression pattern of NDUFV3-S and NDUFV3-L isoforms was paralleled by changes in kinetic parameters, especially the substrate affinity of complex I. This may indicate a regulatory role of the NDUFV3 isoforms in different vertebrate tissues. PMID- 27988284 TI - Anti-effects of cordycepin to hypoxia-induced membrane depolarization on hippocampal CA1 pyramidal neuron. AB - Cordycepin has important neuroprotective effects in hypoxic or ischemic insult. However, the direct electrophysiological evidence of cordycepin's neuroprotection from hypoxic or ischemic insult remains unknown. Hence, in this study, the electrophysiological mechanism by which cordycepin protects against ischemic and hypoxic damages has been studied using an energy-deprivation injury model through whole-cell patch clamp techniques. Results revealed that cordycepin (80uM) significantly delayed hypoxia-induced membrane depolarization, including cordycepin reduced slope, and extended the duration of slow depolarization, prolonged the ability to generate spontaneous action potential (AP) firing, delayed the onset of rapid depolarization, and maintained the more hyperpolarized membrane potential after rapid depolarization. Additionally, cordycepin also delayed the hypoxia-induced decrease in the evoked AP amplitude. Furthermore, cordycepin can rescue the neuronal electrophysiological function after the 5min hypoxia pretreatment insult as seen the recovery on the evoked spike amplitude, membrane potential, and evoked AP latency during reoxygenation of hippocampal slices with cordycepin. Collectively, the results in this study provide direct evidence demonstrating the important neuroprotective effects of cordycepin against the hypoxic insult via improvement of the neuronal electrophysiological function, and the mechanism underlying the anti hypoxia-induced membrane depolarization is strongly recommended. PMID- 27988285 TI - Cardamonin attenuates hyperalgesia and allodynia in a mouse model of chronic constriction injury-induced neuropathic pain: Possible involvement of the opioid system. AB - Neuropathic pain arises from the injury of nervous system. The condition is extremely difficult to be treated due to the ineffectiveness and presence of various adverse effects of the currently available drugs. In the present study, we investigated the antiallodynic and antihyperlagesic properties of cardamonin, a naturally occurring chalcone in chronic constriction injury (CCI)-induced neuropathic pain mice model. Our findings showed that single and repeated dose of intra-peritoneal administration of cardamonin (3, 10, 30mg/kg) significantly inhibited (P<0.001) the chronic constriction injury-induced neuropathic pain using the Hargreaves plantar test, Randall-Selitto analgesiometer test, dynamic plantar anesthesiometer test and the cold plate test in comparison with the positive control drug used (amitriptyline hydrochloride, 20mg/kg, i.p.). Pre treatment with naloxone hydrochloride (1mg/kg, i.p.) and naloxone methiodide (1mg/kg, s.c) significantly reversed the antiallodynic and antihyperalgesic effects of cardamonin in dynamic plantar anesthesiometer test and Hargreaves plantar test, respectively. In conclusion, the current findings demonstrated novel antiallodynic and antihyperalgesic effects of cardamonin through the activation of the opioidergic system both peripherally and centrally and may prove to be a potent lead compound for the development of neuropathic pain drugs in the future. PMID- 27988286 TI - Human native Cav1 channels in chromaffin cells: contribution to exocytosis and firing of spontaneous action potentials. AB - The present study was performed to evaluate the Cav1 channel subtypes expressed in human chromaffin cells and the role that these channels play in exocytosis and cell excitability. Here we show that human chromaffin cells obtained from organ donors express Cav1.2 and Cav1.3 subtypes using molecular and pharmacological techniques. Immunocytochemical data demonstrated the presence of Cav1.2 and Cav1.3 subtypes, but not Cav1.1 or Cav1.4. Electrophysiological experiments were conducted to investigate the contribution of Cav1 channels to the exocytotic process and cell excitability. Cav1 channels contribute to the exocytosis of secretory vesicles, evidenced by the block of 3MUM nifedipine (36.5+/-2%) of membrane capacitance increment elicited by 200ms depolarizing pulses. These channels show a minor contribution to the initiation of spontaneous action potential firing, as shown by the 2.5 pA of current at the threshold potential ( 34mV), which elicits 10.4mV of potential increment. In addition, we found that only 8% of human chromaffin cells exhibit spontaneous action potentials. These data offer novel information regarding human chromaffin cells and the role of human native Cav1 channels in exocytosis and cell excitability. PMID- 27988287 TI - Endoscopic multiple biopsy and rapid diagnosis by in situ fixation and histopathologic processing. AB - BACKGROUND AND AIMS: Endoscopic forceps biopsy and fixation are laborious and prolong the procedure and anesthesia. Multiple biopsy overcomes these shortcomings with a single endoscope pass that cuts, like a needle biopsy, up to 25 biopsy samples of uniform size and depth during endoscope withdrawal. Biopsy specimens are collected in acquisition order and stored in a perforated plastic storage chamber within the perforated metal tip. The tip is cut off, immersed in fixative, and sent to pathology. A formatted log identifies each biopsy specimen by site and position. In pathology, the plastic storage cylinder, designed for processing and microtomy with biopsy specimens in situ, supports rapid diagnosis by frozen section and microwave or routine paraffin processing. METHODS: After a 10-patient Institutional Review Board safety study and US Food and Drug Administration registration, biopsies were performed in 57 patients during colonoscopy, upper GI endoscopy, and ERCP. A blinded retrospective study compared colon surveillance biopsies in 15 patients who underwent multiple biopsy with 15 patients who underwent forceps biopsies performed by anonymous physicians on the same day. Patient information was removed from slides, and forceps biopsies were oriented manually for blinding. RESULTS: Multiple biopsy specimens fixed and processed in situ were not significantly different from batched processed forceps biopsy specimens for depth, orientation, fixation, artifacts, and diagnostic information. Multiple biopsy colonic specimens were significantly (26%) smaller with better epithelial preservation than forceps specimens. Each biopsy saves 61 seconds during withdrawal. CONCLUSIONS: Single-pass multiple biopsy reduces biopsy time with less specimen damage, work, workplace risk, and soiling. Diagnostic quality is equal to forceps biopsy with better epithelial preservation, although 26% smaller. In pathology, in situ processing and microtomy reduce work and workplace risk. Grossing and manual orientation are unnecessary. Rapid diagnosis by frozen section and microwave or paraffin processing are facilitated. Multiple biopsy speeds diagnosis and improves productivity in endoscopic biopsy and histopathologic processing. PMID- 27988288 TI - Prospective multicenter randomized controlled trial comparing adenoma detection rate in colonoscopy using water exchange, water immersion, and air insufflation. AB - BACKGROUND AND AIMS: Adenoma detection rate (ADR), defined as the proportion of patients with at least one adenoma of any size, is a quality indicator. We tested the hypothesis that water exchange (WE) improves ADR but water immersion (WI) has no adverse effect on ADR compared with air insufflation (AI). METHODS: A prospective study was conducted at the Dalin Tzu Chi Hospital in southern Taiwan and the Hualien Tzu Chi Hospital in eastern Taiwan on patients randomly assigned to WE, WI, or AI with stratification by the 3 study colonoscopists. The primary outcome was ADR. RESULTS: From July 2013 to December 2015, 651 patients were recruited and randomized into 3 groups with a 1:1:1 ratio (217 patients per group). Overall, ADR met quality standards: WE 49.8% (95% CI, 43.2%-56.4%), AI 37.8% (95% CI, 31.6%-44.4%), and WI 40.6% (95% CI, 34.2%-47.2%). Compared with AI, WE significantly increased ADR (P = .016). There was no difference between WI and WE. ADRs of WI and AI were comparable. Compared with AI, WE confirmed a longer insertion time, higher cleanliness score, but similar adenoma per positive colonoscopy (APPC) and withdrawal time with polypectomy. Subgroup analysis found WE significantly increased ADR in propofol-sedated patients. Multivariate generalized linear mixed model analysis revealed that age >=50 years, WE (vs AI), colonoscopy indication, no previous history of colonoscopy, and withdrawal time >8 minutes were significant predictors of increased ADR. CONCLUSIONS: Confirmation of prior reports showing WE, but not WI, increased ADR further strengthened the validity of our observations. WE significantly increased ADR in propofol-sedated patients. The outcome differences justify assessment of the role of WE in colorectal cancer prevention. Similar APPC and withdrawal times suggest that adequate inspection was performed on colonoscope withdrawal in each of the study arms. (Clinical trial registration number: NCT01894191.). PMID- 27988289 TI - The impact of N-glycosylation on conformation and stability of immunoglobulin Y from egg yolk. AB - Immunoglobulin Y (IgY) is a new therapeutic antibody, and its applications in industry are very broad. To provide insight into the effects of N-glycosylation on IgY, its conformation and stability were studied. In this research, IgY was extracted from egg yolk and then digested by peptide-N4-(N-acetyl-beta glucosaminyl) asparagine-amidase. SDS-PAGE and infrared absorption spectrum showed that carbohydrates were distinctly reduced after enzymolysis. The circular dichroism spectrum indicated that the IgY molecule became more flexible and disordered after removal of N-glycan. The fluorescence intensity revealed that Trp residues were buried in a more hydrophobic environment after disposal of N glycan. Storage stability decreased with the removal of oligosaccharide chains based on size-exclusion chromatography analysis. Deglycosylated IgY exhibited less resistance to guanidine hydrochloride-induced unfolding. After deglycosylation, IgY was more sensitive to pepsin. Therefore, N-glycosylation played an important role in the maintenance of the structure and stability of IgY. PMID- 27988290 TI - Chitosan and carboxymethyl cellulose based magnetic nanocomposites for application of peroxidase purification. AB - Recently, protein purification methods have a very wide area of research. Many of these methods are both expensive and multi-stage methods, that are needed in specific equipment. In this study, biopolymer coated magnetic nanoparticles, carboxymethyl cellulose (CMC) and chitosan (CH) coated Fe3O4 (magnetite) nanocomposites, are used in a new purification process. The structure of the synthesized magnetic nanocomposites were characterized by Fourier transform infrared (FTIR) spectrometry, X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscope (TEM), thermogravimetric (TGA) analysis and zeta potential for surface charge of magnetic nanocomposites. Molecular weight and purification degree of peroxidase were estimated with SDS PAGE. Peroxidase enzyme was purified a yield of 82.55% with carboxymethyl cellulose and 76.72% with chitosan using this method. PMID- 27988291 TI - Dilute solution properties of Prunus armeniaca gum exudates: Influence of temperature, salt, and sugar. AB - The aim of the current paper was to investigate the effect of different temperatures, salts and sugars on dilute solution properties of Prunus armeniaca gum exudates (PAGE) as a starting point to evaluate the potential utilization of this novel source of hydrocolloids in food and pharmaceutical systems. Berry number and the slope of master curve indicated that PAGE samples in all evaluated conditions were in dilute domain without coil overlapping and entanglement. Furthermore, the slope power law model also demonstrated that the molecular conformation of PAGE in all tested temperatures was close to rode-like. On the other hand, PAGE samples had random coil conformation in the presence of sugars and ions studied. Activation energy and chain flexibility of PAGE were found to be 0.83*107 (J/kg) and 997.3, respectively. This result revealed that temperature has a slight effect on intrinsic viscosity of PAGE solution, implying this gum can be introduced as a promising ingredient in food formulation that need to high stability against temperature. The data obtained in the present study and results thereof can be useful when considering the effect of additives generally used in food products and/or processing parameters like temperature in food systems. PMID- 27988292 TI - Electrophoretic mobility, catalytic rate, and activation energy of catalysis of single molecules of the enzyme beta-glucuronidase from Escherichia coli. AB - Single molecule assays were performed on the enzyme E. coli beta-glucuronidase using a capillary electrophoresis-based protocol. Electrophoretic mobility, catalytic rate and activation energy of catalysis were all found to be heterogeneous. The average mobility at 22 degrees C was -1.1*10-8+/-0.1m2V-1s-1 (N=49) with a total range of -0.6 to -1.3*10-8m2V-1s-1. The range in electrophoretic mobility suggests that the differences in shape or charge of the individual molecules underlying the heterogeneity are likely minimal. The average catalytic rate at 22 degrees C was 37,000+/-19,000min-1 (N=49) with a total range of 14,000 to 130,000min-1. Both of these properties were measured simultaneously for each of the molecules. There was a weak correlation (r2=0.43) between mobility and rate with the molecules with a less negative mobility having a tendency to have a higher rate. The average activation energy of catalysis, as determined by comparing rates at 22 and 35 degrees C, was found to be 48+/ 18kJmol-1 (N=7) with a total range of 18-66kJmol-1. PMID- 27988293 TI - Processing and properties of eco-friendly bio-nanocomposite films filled with cellulose nanocrystals from sugarcane bagasse. AB - Novel synthesis strategy of eco-friendly bio-nanocomposite films have been exploited using cellulose nanocrystals (CNC) and polyvinyl alcohol/carboxymethyl cellulose (PVA/CMC) blend matrix as a potential in food packaging application. The CNC were extracted from sugarcane bagasse using sulfuric acid hydrolysis, and they were successfully characterized regarding their morphology, size, crystallinity and thermal stability. Thereafter, PVA/CMC-CNC bio-nanocomposite films, at various CNC contents (0.5-10wt%), were fabricated by the solvent casting method, and their properties were investigated. It was found that the addition of 5wt% CNC within a PVA/CMC increased the tensile modulus and strength by 141% and 83% respectively, and the water vapor permeability was reduced by 87%. Additionally, the bio-nanocomposites maintained the same transparency level of the PVA/CMC blend film (transmittance of ~90% in the visible region), suggesting that the CNC were dispersed at the nanoscale. In these bio nanocomposites, the adhesion properties and the large number of functional groups that are present in the CNC's surface and the macromolecular chains of the PVA/CMC blend are exploited to improve the interfacial interactions between the CNC and the blend. Consequently, these eco-friendly structured bio-nanocomposites with superior properties are expected to be useful in food packaging applications. PMID- 27988294 TI - Role of the recognition helix of response regulator WalR from Bacillus anthracis in DNA binding and specificity. AB - WalRK two-component system of Bacillus anthracis potentially regulates multiple genes spanning diverse cellular functions. Its constituent response regulator (RR), WalR belongs to the OmpR/PhoB family which possesses a winged helix-turn helix motif for DNA binding. An in silico knowledge based model of WalR C terminal DNA binding domain in complex with its ftsE promoter region binding motif was used to identify specific residues of the recognition helix important for DNA binding. The model was validated by mutagenesis in conjunction with in vitro DNA binding analysis. The ftsE promoter region DNA binding motif was also varied. Optimal binding of WalR to DNA required the presence of both half-sites in its binding motif. Substitution of invariant bases of WalR DNA binding motif abrogated the binding whereas changes at variable motif positions governed affinity. D199 was not in direct contact with the DNA but its substitution modified the WalR-DNA specificity indicating the importance of contact avoidance by this residue for DNA specificity. This represents the first in-depth study of RR-DNA interaction from B. anthracis. PMID- 27988295 TI - Surfactant- and oxidant-stable alkaline proteases from Bacillus invictae: Characterization and potential applications in chitin extraction and as a detergent additive. AB - A newly alkaline proteases producing strain was isolated from sea water. The strain was identified as Bacillus invictae on the basis of biochemical characteristics and 16S rRNA sequence analysis. The crude protease activity showed an optimal activity at approximately 60 degrees C and in wide pH interval ranging from 9.0 to 11.0. At least six clear caseinolytic protease bands were observed in a zymogram. Phenylmethylsulfonyl fluoride (PMSF), a serine-protease inhibitor, was found to inhibit completely the protease activity. The crude alkaline proteases showed high stability toward solid and liquid detergents. Furthermore, wash performance analysis revealed that the crude enzyme could effectively remove blood stain when added to commercial detergent. In addition, the crude proteases were found to be effective in the deproteinization of shrimp shell waste. The percent of protein removal after 3h of hydrolysis at 50 degrees C with an E/S ratio of 10U/mg of protein or after fermentation by the strain were about 76% and 82%, respectively. Thus, the results of the present study showed that the crude proteases of B. invectae could be effectively used in several industrial applications, as an eco-friendly agent. PMID- 27988296 TI - Interaction between bioactive compound 11a-N-tosyl-5-deoxi-pterocarpan (LQB-223) and Calf thymus DNA: Spectroscopic approach, electrophoresis and theoretical studies. AB - The interaction of small molecules with DNA has been quite important, since this biomolecule is currently the major target for a wide range of drugs in clinical use or advanced clinical research phase. Thus, the present work aimed to assess the interaction process between the bioactive compound 11a-N-tosyl-5-carba pterocarpan, (LQB-223), that presents antitumor activity, with DNA, employing spectroscopic techniques, electrophoresis, viscosity and theoretical studies. Through UV-vis and molecular fluorescence spectroscopy, it was possible to infer that the preferential quenching mechanism was static, characterized by non fluorescent supramolecular complex formation between the LQB-223 and DNA. The binding constant was 1.94?103Lmol-1 (30 degrees C) and, according to the thermodynamic parameters, the main forces involved in the interaction process are hydrophobic. Potassium iodide assay, competition with ethidium bromide, fluorescence contact energy transfer and melting temperature profile of DNA were employed to evaluate the binding mode. Except for KI assay, all results obtained indicated minor groove as the preferential binding mode of LQB-223 to DNA. These observations were supported by ionic strength assay, viscosity and molecular dynamics and docking studies. Finally, electrophoresis analysis demonstrated that the interaction does not promote DNA fragmentation, but it leads to variation in the migration profile after increasing the ligand concentration. PMID- 27988297 TI - Increasing sputum levels of gamma-glutamyltransferase may identify cystic fibrosis patients who do not benefit from inhaled glutathione. AB - Glutathione (GSH) is decreased in cystic fibrosis (CF) airways, thus its resupply by inhalation has been employed to restore antioxidant defense. CF airways present however increased activity of gamma-glutamyltransferase (GGT), the enzyme specifically capable of degrading GSH, and thus inhaled GSH might be promptly catabolized. In addition, prooxidant reactions are known to originate during GGT mediated GSH catabolism. We determined levels of GGT in the sputum samples obtained from a previously published trial of GSH inhalation treatment, and analyzed their correlations with inflammatory markers and FEV1% values. Results indicate that differentiating patients with increasing vs. decreasing GGT activity - as measured in sputum before and after the six months duration of the study - may discriminate subjects more likely profiting from inhaled GSH, as opposed to those with increasing GGT in which these treatments might even produce aggravation of the damage. PMID- 27988299 TI - Deep brain stimulation for cerebral palsy, stability of cognitive functioning and what parents think. PMID- 27988300 TI - Zinc finger factor ZNF121 is a MYC-interacting protein functionally affecting MYC and cell proliferation in epithelial cells. AB - MYC is a potent oncoprotein that modulates multiple cellular processes including proliferation, apoptosis, differentiation, stemness, senescence, and migration. Functioning primarily as a transcriptional factor, MYC interacts with a large number of proteins, and identification and characterization of MYC-interacting proteins are important for understanding how MYC functions. In this study, we used different systems to demonstrate that a novel zinc finger transcription factor, ZNF121, physically interacted with MYC, and the interaction involved their N-terminal regions. Overexpression of ZNF121 increased, while its knockdown decreased, the expression of MYC in multiple epithelial cell lines, and MYC had similar effects on ZNF121 expression. An expression correlation was also detectable in a panel of epithelial cell lines and a cohort of human breast cancer tissues. Functionally, knockdown of ZNF121 in several breast epithelial cell lines attenuated the expressions of MYC and its target genes (e.g., EGR1, CDC2, and nucleolin) and slowed cell proliferation, accompanied by cell cycle arrest in the G1 phase and expression alteration of cell cycle regulators (cyclin D1, p14 and p21). Analysis of publically available databases showed that ZNF121 expression is up-regulated in human breast cancer, and the up-regulation significantly associates with worse patient survival in the luminal A subtype of breast cancer. These findings establish ZNF121 as a MYC-interacting protein with functional effects on MYC and cell proliferation. PMID- 27988301 TI - Leishmania and its quest for iron: An update and overview. AB - Parasites of genus Leishmania are the causative agents of complex neglected diseases called leishmaniasis and continue to be a significant health concern globally. Iron is a vital nutritional requirement for virtually all organisms, including pathogenic trypanosomatid parasites, and plays a crucial role in many facets of cellular metabolism as a cofactor of several enzymes. Iron acquisition is essential for the survival of parasites. Yet parasites are also vulnerable to the toxicity of iron and reactive oxygen species. The aim of this review is to provide an update on the current knowledge about iron acquisition and usage by Leishmania species. We have also discussed about host strategy to modulate iron availability and the strategies deployed by Leishmania parasites to overcome iron withholding defences and thus favour parasite growth within host macrophages. Since iron plays central roles in the host's response and parasite metabolism, a comprehensive understanding of the iron metabolism is beneficial to identify potential viable therapeutic opportunities against leishmaniasis. PMID- 27988302 TI - Prolonged controlled delivery of nerve growth factor using porous silicon nanostructures. AB - Although nerve growth factor (NGF) is beneficial for the treatment of numerous neurological and non-neurological diseases, its therapeutic administration represents a significant challenge, due to the difficulty to locally deliver relevant doses in a safe and non-invasive manner. In this work, we employ degradable nanostructured porous silicon (PSi) films as carriers for NGF, allowing its continuous and prolonged release, while retaining its bioactivity. The PSi carriers exhibit high loading efficacy (up to 90%) of NGF and a continuous release, with no burst, over a period of>26days. The released NGF bioactivity is compared to that of free NGF in both PC12 cells and dissociated dorsal root ganglion (DRG) neurons. We show that the NGF has retained its bioactivity and induces neurite outgrowth and profound differentiation (of >50% for PC12 cells) throughout the period of release within a single administration. Thus, this proof-of-concept study demonstrates the immense therapeutic potential of these tunable carriers as long-term implants of NGF reservoirs and paves the way for new localized treatment strategies of neurodegenerative diseases. PMID- 27988298 TI - Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer. AB - Abrogation of endoplasmic reticulum (ER) protein folding triggered by exogenous or endogenous factors, stimulates a cellular stress response, termed ER stress. ER stress re-establishes ER homeostasis through integrated signaling termed the ER-unfolded protein response (UPRER). In the presence of severe toxic or prolonged ER stress, the pro-survival function of UPRER is transformed into a lethal signal transmitted to and executed through mitochondria. Mitochondria are key for both apoptotic and autophagic cell death. Thus ER is vital in sensing and coordinating stress pathways to maintain overall physiological homeostasis. However, this function is deregulated in cancer, resulting in resistance to apoptosis induction in response to various stressors including therapeutic agents. Here we review the connections between ER stress and mitochondrial apoptosis, describing potential cancer therapeutic targets. PMID- 27988303 TI - Anticonvulsant efficacy of antihistamine cyproheptadine in rats exposed to the chemical warfare nerve agent soman. AB - Organophosphate compounds, such as soman and sarin, are highly toxic chemical warfare nerve agents that cause a build-up of acetylcholine in synapses and neuromuscular junctions. Current therapies aim to prevent seizures and protect against brain injury following exposure. The present study was designed to evaluate the effectiveness of the antihistamine cyproheptadine in improving survival and controlling seizures in rats exposed to soman. Rats were pretreated with the oxime reactivator HI-6 (125mg/kg, ip) 30min prior to soman exposure (225MUg/kg, sc) and then treated with atropine methylnitrate (AMN, 2.0mg/kg, im) 1min after soman. Cyproheptadine (10, 13, 16 or 20mg/kg, ip) was given at one of three time points: 1min after soman intoxication, at the onset of soman-induced seizures or 5min after seizure onset. Control animals were exposed to soman and given an equivalent volume of sterile water instead of cyproheptadine. The incidence of seizures, mortality, neuron counts, neuropathology and apoptosis in specific regions of the brain were evaluated. In animals given HI-6 and AMN the incidence of soman-induced seizure and mortality rate within the first 24h were 100%. When cyproheptadine was given at a dose of 13 or 20mg/kg 1min after soman exposure, the incidence of seizures was reduced from 100% to 13% and 30%, respectively. In addition, cyproheptadine given at 1min after soman exposure increased the survival rate to 100% regardless of dose. When cyproheptadine was administered at seizure onset, seizures were terminated in 100% of the animals at doses above 10mg/kg. The survival rate with cyproheptadine treatment at the onset of seizure was >=83%. Seizures terminated in >=75% of the animals that received cyproheptadine 5min after soman-induced seizure onset. When given at 5min after seizure onset the survival rate was 100% at all tested doses of cyproheptadine. The neuropathology scores and the number of TUNEL positive cells in the brain regions examined decreased at all time points and cyproheptadine doses tested. These observations indicate that cyproheptadine treatment can effectively control seizures, improve survival, reduce seizure duration and reduce the number of dying cells in the brain following soman exposure. PMID- 27988304 TI - Overview of the membrane-associated RING-CH (MARCH) E3 ligase family. AB - E3 ligases are critical checkpoints for protein ubiquitination, a signal that often results in protein sorting and degradation but has also been linked to regulation of transcription and DNA repair. In line with their key role in cellular trafficking and cell-cycle control, malfunction of E3 ligases is often linked to human disease. Thus, they have emerged as prime drug targets. However, the molecular basis of action of membrane-bound E3 ligases is still unknown. Here, we review the current knowledge on the membrane-embedded MARCH E3 ligases (MARCH-1-6,7,8,11) with a focus on how the transmembrane regions can contribute via GxxxG-motifs to the selection and recognition of other membrane proteins as substrates for ubiquitination. Further understanding of the molecular parameters that govern target protein recognition of MARCH E3 ligases will contribute to development of strategies for therapeutic regulation of MARCH-induced ubiquitination. PMID- 27988305 TI - Mutations in basal core promoter is associated with significant fibrosis in both HBeAg positive and negative treatment-naive chronic hepatitis B. AB - AIM: Assessment of liver fibrosis is important for the decision of whether to administrate antiviral treatment in chronic Hepatitis B (CHB) patients. The objective was to investigate the relationship between clinical factors and fibrosis, identify predictors of significant fibrosis in Chinese CHB patients. METHODS: Two hundred and seventy-four treatment-naive CHB patients (208 HBeAg positive and 66 HBeAg-negative) who performed transient elastography were consecutively included. We assessed ALT, HBsAg, HBeAg, HBV-DNA, HBV genotype and precore (PC)/basal core promoter (BCP) variants and liver stiffness measurement (LSM) values. RESULTS: One hundred and nine patients (39.78%) had significant fibrosis (F>=2, include those with liver cirrhosis). On univariate analysis, significant fibrosis was associated with older age (P<0.001), high ALT levels (P=0.003), lower HBsAg levels (P<0.001), lower HBV DNA levels (P<0.001), HBeAg negative (P<0.001), presence of BCP (P<0.001) and combined BCP/PC mutations (P=0.001). Multivariate logistic regression analysis showed that the strongest independently associated predictors of significant fibrosis (F>=2) were the presence of HBV BCP mutations (P<0.001) and older age (P<0.001), followed by presence of lower HBsAg (P<0.001), higher ALT levels (P=0.006), PC mutations (P=0.011). The diagnostic accuracy of the combination (age, ALT, HBsAg, BCP/PC variants) model with an area under the receiver-operating characteristic curve of 0.819 (cut-off value was 0.349, P<0.001, 95% CI 0.731-0.914) in predicting significant fibrosis. CONCLUSIONS: We identified four independent risk factors (age, ALT, HBsAg, HBV BCP/PC variants) in predicting significant fibrosis. HBV BCP variants was the strongest predictor of significant fibrosis. The combination of these four variables may facilitate the assessment and management of fibrosis in HBV infected patients. PMID- 27988306 TI - Eccentric exercise in ischemic cardiac patients and functional capacity: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Eccentric (ECC) exercise is an "economical" type of exercise with low energy requirements and does not cause early fatigue. Therefore, it is used for cardiac patients, who have low physical activity and exercise intolerance, as an easier kind of training. OBJECTIVE: This systematic review aimed to investigate the efficacy of ECC exercise for functional capacity (FC) in patients with ischemic heart disease. DESIGN: Systematic review. METHODS: MEDLINE via PubMed and EBSCO databases were searched for articles of randomized controlled trials of adults with ischemic heart disease who underwent ECC training as compared with other forms of exercise (concentric exercise) or no exercise and assessed FC. The methodologic quality of studies was assessed by the PEDro scale. A meta-analysis was performed with sufficient homogeneity between at least 2 studies in the pre defined comparisons. RESULTS: Four studies, investigating a total of 99 subjects, met the inclusion criteria. The results of the studies did not clearly indicate whether ECC exercise could improve FC better than traditional forms of exercise. However, the small number of studies and their methodologic weaknesses do not allow for drawing firm conclusions. CONCLUSIONS: We found contradictory results about the effectiveness of ECC as compared with concentric exercise in terms of FC in ischemic cardiac patients. Further investigation with well-designed randomized trials is needed to determine the effectiveness of this kind of exercise for FC in such patients. PMID- 27988307 TI - Interleukin-6 and neuregulin-1 as regulators of utrophin expression via the activation of NRG-1/ErbB signaling pathway in mdx cells. AB - Duchenne muscular dystrophy (DMD) is a neuromuscular disease originated by mutations in the dystrophin gene. A promising therapeutic approach deals with functional substitution of dystrophin by utrophin, a structural homolog that might be able to compensate dystrophin absence in DMD muscle fibers. It has been described that both interleukin-6 (IL-6) and neuregulin-1 (NRG-1; Heregulin-HRG) induce utrophin expression in skeletal muscle. We investigated a possible functional link among IL-6, NRG-1 and utrophin, in normal (C57) and dystrophic (mdx) skeletal muscle cells. Western Blot analysis allowed us to demonstrate that IL-6 (100ng/mL) induces NRG-1 receptor phosphorylation (ErbB2/ErbB3) in both cell types, in a process that depends on intracellular Ca2+ and metalloproteinase activity; it also induces a transient increase of ERK1 and GABPalpha phosphorylation only in dystrophic myotubes. Semiquantitative PCR showed that IL 6 treatment increases utrophin mRNA levels just in mdx myotubes. We observed that utrophin mRNA induction was abolished by BAPTA-AM (an intracellular Ca2+ chelator), GM6001 (a general metalloproteinase inhibitor), genistein (a general protein tyrosine kinase inhibitor), PD-158780 (an ErbB receptor tyrosine kinase inhibitor) and PD-98059 (a MEK inhibitor), whereas Ly-294002 and wortmannin (PI3K inhibitors) did not affect utrophin induction evoked by IL-6 in dystrophic myotubes. Our results suggest that IL-6 induces utrophin expression in mdx myotubes through activation of a NRG-1/ErbBs signaling cascade. Soluble NRG-1 elicited by proteolytic processing of transmembrane NRG-1 might induce ErbBs phosphorylation and ERK1/2 pathway activation, leading to utrophin up-regulation. PMID- 27988308 TI - A novel MKK gene (AjMKK3/6) in the sea cucumber Apostichopus japonicus: Identification, characterization and its response to pathogenic challenge. AB - The mitogen-activated protein kinase kinases (MKKs) are key components of MAP kinase (MAPK) cascades and function as redox-regulated signaling factors in pathological and physiological processes. In this study, we identified a novel MKK3/6 gene in the sea cucumber Apostichopus japonicus (designated as AjMKK3/6) by transcriptome database mining and rapid amplification of cDNA ends (RACE) approaches. Sequence analysis and protein structure prediction showed that AjMKK3/6 is highly conserved as compared to those from other invertebrate and vertebrate species. Molecular phylogeny result revealed that AjMKK3/6 exhibited a closest relationship with that from Strongylocentrotus purpuratus. Quantitative real-time PCR was employed to determine the expression profiles of AjMKK3/6 in healthy adult A. japonicus tissues and in coelomocytes after Vibrio splendidus infection in vivo, respectively. As results shown, AjMKK3/6 was ubiquitously expressed in all examined tissues of healthy adult A. japonicus with a relative expression level from high to low as body wall > tube feet > coelomocytes > respiratory tree > intestine > longitudinal muscle. Significant expression changes of AjMKK3/6 in coelomocytes were observed at 12 h- and 72 h-after V. splendidus infection, respectively. In general, the current study will enrich our knowledge of characterizations and immno-functions of MKK3/6 in sea cucumbers. PMID- 27988309 TI - Naringenin suppresses Edwardsiella tarda infection in GAKS cells by NanA sialidase inhibition. AB - Edwardsiella tarda (E. tarda) is a gram-negative bacterium, which causes Edwardsiellosis in aquaculture. Previous studies indicate that E. tarda NanA sialidase plays crucial roles in infection through the desialylation of glycoproteins in fish cells. On the other hand, 2-deoxy-2,3-dehydro-N acetylneuraminic acid, classic sialidase inhibitor, negatively regulates E. tarda infection of goldfish scale GAKS cells. Here, to development the suppression model of E. tarda infection for aquaculture application, the possibility of NanA inhibitory activities in citrus phytochemicals was evaluated as citrus extracts have widely been used as a supplement in fish diets for the improvement of meat quality. Some flavanones such as naringenin, hesperetin, hesperidin and naringin showed sialidase inhibitory activity toward recombinant NanA in vitro. Among them, naringenin showed the most potent inhibitory activity and its inhibitory pattern was non-competitive. Naringenin significantly suppressed E. tarda infection in GAKS cells at 200 and 400 MUM without bactericidal effect on E. tarda. On the other hand, naringin, glycosylation form of naringenin, showed slight suppression of E. tarda infection toward GAKS cells, suggesting the glycosides on flavanone could be important for NanA inhibition. Fluorescence microscopy analysis verified that number of invading E. tarda in GAKS cells was declined by naringenin treatment. The present study exhibited the possibility of naringenin as an effective ingredient in fish diet for the inhibition of E. tarda infection. PMID- 27988310 TI - Melaleuca alternifolia essential oil enhances the non-specific immune system and prevents oxidative damage in Rhamdia quelen experimentally infected by Aeromonas hydrophila: Effects on cholinergic and purinergic systems in liver tissue. AB - The aim of this study was to evaluate the effects of M. alternifolia essential oil used to treat silver catfish (Rhamdia quelen) experimentally infected by Aeromonas hydrophila on oxidative stress variables, and for the first time, on hepatic enzymes of the cholinergic and adenosinergic systems. For that, fish were divided into six groups (A-F), each containing seven animals. Groups A, B and C were composed of uninfected animals, while animals in groups D, E and F were intramuscularly inoculated with A. hydrophila. Groups B and E received a prophylactic bath with M. alternifolia essential oil (50 MUL/L, diluted in ethanol) for seven days, while groups C and F were exposed to ethanol. After the prophylactic baths, groups D, E and F were inoculated with 100 MUL of A. hydrophila solution (2.1 * 109 colony-forming unit). Two days after inoculation, the animals were euthanized and liver samples were collected. Infected animals (the group D) showed increased TBARS and protein carbonylation levels, while CAT, AChE and ADA activities decreased compared to uninfected animals (the group A). The prophylactic treatment with M. alternifolia essential oil (the group E) prevented the alterations caused by A. hydrophila, but it did not change AChE activity. Thus, the prophylactic treatment prevents damage caused by lipids and proteins, as well as alterations of the adenosinergic system, demonstrating that the anti-inflammatory effect of TTO is mediated by the adenosinergic pathway. In addition, TTO prophylactic treatment might be considered an important approach to prevent the hepatic damage caused by A. hydrophila. PMID- 27988311 TI - First detection and molecular identification of Babesia microti in Rattus losea captured from the offshore Kinmen Island of Taiwan. AB - Babesia microti was firstly detected and identified in brown country rats (Rattus losea, Swinhoe) captured from the offshore Kinmen Island of Taiwan. The prevalence of Babesia infection in 283 rodents was screened by polymerase chain reaction (PCR) assay using a piroplasma-conserved primer set (Piro A/B) and the thirty-seven PCR-positive rodents were further examined by PCR using a species specific primer set (Bab 1/4) targeting the gene encoding the nuclear small subunit ribosomal RNA (18S rRNA) of Babesia species. B. microti was detected only in Rattus losea with a total infection rate of 9.9% (28/283). Positivity examined by species-specific PCR (9.9%) is higher than examined by blood smear (4.6%). Sequence and phylogenetic analyses revealed that Babesia species detected in Taiwan were genetically affiliated to the genotypes of B. microti, and can be easily distinguished from other genotypes of Babesia parasites by neighbour joining and maximum-parsimony methods. Intra- and inter-species analysis also indicate that all these Taiwan species have a lower level of genetic divergence (genetic distance values <0.084) within the genotypes of B. microti, and were genetically more distant to other genotypes (>0.218) of Babesia parasites. This study provides the first evidence of B. microti identified in R. losea in Taiwan, and the high prevalence of Babesia infection in R. losea may imply its possible role served as reservoir host for maintaining an enzoonotic cycle of Babesia transmission in Kinmen Island. The possible vector tick responsible for the transmission of Babesia infection need to be further identified. PMID- 27988312 TI - Search strategy selection in the Morris water maze indicates allocentric map formation during learning that underpins spatial memory formation. AB - Using a Matlab classification algorithm, we demonstrate that a highly salient distal cue array is required for significantly increased likelihoods of spatial search strategy selection during Morris water maze spatial learning. We hypothesized that increased spatial search strategy selection during spatial learning would be the key measure demonstrating the formation of an allocentric map to the escape location. Spatial memory, as indicated by quadrant preference for the area of the pool formally containing the hidden platform, was assessed as the main measure that this allocentric map had formed during spatial learning. Our C57BL/6J wild-type (WT) mice exhibit quadrant preference in the highly salient cue paradigm but not the low, corresponding with a 120% increase in the odds of a spatial search strategy selection during learning. In contrast, quadrant preference remains absent in serotonin 1A receptor (5-HT1AR) knockout (KO) mice, who exhibit impaired search strategy selection during spatial learning. Additionally, we also aimed to assess the impact of the quality of the distal cue array on the spatial learning curves of both latency to platform and path length using mixed-effect regression models and found no significant associations or interactions. In contrast, we demonstrated that the spatial learning curve for search strategy selection was absent during training in the low saliency paradigm. Therefore, we propose that allocentric search strategy selection during spatial learning is the learning parameter in mice that robustly indicates the formation of a cognitive map for the escape goal location. These results also suggest that both latency to platform and path length spatial learning curves do not discriminate between allocentric and egocentric spatial learning and do not reliably predict spatial memory formation. We also show that spatial memory, as indicated by the absolute time in the quadrant formerly containing the hidden platform alone (without reference to the other areas of the pool), was not sensitive to cue saliency or impaired in 5-HT1AR KO mice. Importantly, in the absence of a search strategy analysis, this suggests that to establish that the Morris water maze has worked (i.e. control mice have formed an allocentric map to the escape goal location), a measure of quadrant preference needs to be reported to establish spatial memory formation. This has implications for studies that claim hippocampal functioning is impaired using latency to platform or path length differences within the existing Morris water maze literature. PMID- 27988313 TI - Age-dependent changes in spatial memory retention and flexibility in mice. AB - In humans, memories for events happening early in life are forgotten more rapidly than those for events later in life. This form of accelerated forgetting in infancy is also observed in non-human species, and has been most extensively characterized in rats. Here we expand the characterization of infantile forgetting to mice, a species where a broader range of genetic tools can be used to understand the neurobiological mechanisms underlying this form of forgetting. Using a hidden platform version of the water maze task, we first assessed retention in mice that ranged in age from 15 to 150days-old at the beginning of training. All groups exhibited spatial memory when tested one day after training. However, only mice that were 20days or older at the time of training could remember one month later. Second, forgetting in younger cohorts of mice was not due to weaker encoding, since when younger mice were over-trained, such that their performance exceeded that of adult mice, they still exhibited forgetting. Third, in young mice, presentation of a reminder one month following training led to memory recovery, indicating that forgetting was due to a retrieval, rather than storage, deficit. Fourth, younger mice exhibited superior reversal learning compared to older mice, raising the possibility that a by-product of infantile forgetting might be greater flexibility. PMID- 27988314 TI - The sleep phenotype of Borderline Personality Disorder: A systematic review and meta-analysis. AB - AIM: To delineate the sleep profile of Borderline Personality Disorder (BPD). METHOD: A meta-analysis to synthesise findings on the objective and subjective sleep characteristics of BPD. RESULTS: We identified 32 studies published between 1980 and December 2015. Meta-analysis indicated significant differences between BPD and healthy control groups across objective sleep continuity (sleep onset latency, total sleep time, sleep efficiency) and architecture (rapid eye movement latency/density, slow wave sleep) measures, and self-reported sleep problems (nightmares, sleep quality). Findings were independent of depression (in clinical and community populations), and concomitant psychotropic medication use. There were few significant differences between BPD and clinical (majority depressed) control groups. CONCLUSION: BPD is associated with comparable sleep disturbances to those observed in depression. These disturbances are not solely attributable to comorbid depression. Given growing evidence that sleep disturbance may exacerbate emotional dysregulation and suicide risk, treatments for BPD should explicitly address sleep problems. Future studies should utilise prospective designs to ascertain whether (and in which circumstances) sleep problems predate or follow the onset of the disorder. PMID- 27988315 TI - Child maltreatment and emotion socialization: Associations with executive function in the preschool years. AB - This study examined executive function (EF) among preschoolers exposed to maltreatment, and tested whether caregiver practices related to emotion socialization (e.g., reactions to children's emotions; discussion of emotion) moderate the relationship between maltreatment and EF in this period. Participants were (n=107) children aged 4-5 years (M=4.75; SD=0.57; 39% female), with various levels of exposure to maltreatment. Using the Maltreatment Classification System, substantiated reports of maltreatment were coded to produce an index of the multiplicity of abuse subtypes to which children had been exposed. EF was indexed using a composite of scores on three performance-based tests (Happy-Sad Stroop Task; Tapping Test; Dimensional Change Card Sort). Caregivers reported on their use of emotion related socialization behaviors (ERSBs) with the Coping with Children's Negative Emotions Scale. Exposure to maltreatment and ERSBs were both found to account for unique variance in EF, independent of developmental-ecological factors including children's receptive language and maternal depression. Significant interactions between maltreatment and ERSBs were also found to suggest that nonsupportive ERSBs (e.g., punitive reactions to negative child emotion) may amplify the risk for poor EF associated with maltreatment, whereas supportive ERPBs (e.g., expressive encouragement) protect against it. PMID- 27988316 TI - Effect of melatonin injection into the periaqueductal gray on antinociception and tonic immobility in male rats. AB - Melatonin (MLT) is a neurohormone with significant involvement in several biological functions, of which antinociception and tonic immobility (TI) may be the key neurobehavioral components to survive in adverse conditions such as a predator attack. TI-induced antinociception can be elicited, facilitated, or increased through opioid and gamma-aminobutyric acid (GABA) among other chemical mediators at several levels of the central nervous system, mainly in the periaqueductal gray (PAG). The aim of this study was to assess the effect of the microinjection of MLT into the main PAG regions that are related to different integrated defensive responses, namely dorsal (D) and ventrolateral (VL), on both antinociception through the tail-flick (TF) test and TI duration as single behavioral response and on combined behavioral responses (TF/TI). We found that the microinjection of MLT into the main PAG areas produced antinociception but did not affect the TI duration. The microinjection of MLT into the D-PAG decreased TF latency during TI in the combined trial (TF/TI), which implies that TI-induced antinociception was blocked. The microinjection of MLT into the VL-PAG maintained the antinociceptive capability of the TI without addition or increase in the antinociceptive effects, implying a permissive effect by MLT on the TI induced antinociception. MLT administration into the D-PAG decreased the TI duration on the TF/TI, whereas MLT administration into the VL-PAG had the opposite effect of significantly increasing TI duration with the TF/TI trial. PMID- 27988317 TI - Nonequilibrium response of a voltage gated sodium ion channel and biophysical characterization of dynamic hysteresis. AB - Here we have studied the dynamic as well as the non-equilibrium thermodynamic response properties of voltage-gated Na-ion channel. Using sinusoidally oscillating external voltage protocol we have both kinetically and energetically studied the non-equilibrium steady state properties of dynamic hysteresis in details. We have introduced a method of estimating the work done associated with the dynamic memory due to a cycle of oscillating voltage. We have quantitatively characterised the loop area of ionic current which gives information about the work done to sustain the dynamic memory only for ion conduction, while the loop area of total entropy production rate gives the estimate of work done for overall gating dynamics. The maximum dynamic memory of Na-channel not only depends on the frequency and amplitude but it also depends sensitively on the mean of the oscillating voltage and here we have shown how the system optimize the dynamic memory itself in the biophysical range of field parameters. The relation between the average ionic current with increasing frequency corresponds to the nature of the average dissipative work done at steady state. It is also important to understand that the utilization of the energy from the external field can not be directly obtained only from the measurement of ionic current but also requires nonequilibrium thermodynamic study. PMID- 27988318 TI - Prevalence of thyroid dysfunction and autoimmunity in the older population and implications of age-specific reference ranges. AB - OBJECTIVE: To investigate the prevalence of thyroid dysfunction and autoimmunity (TAI) and to determine age-specific reference ranges in individuals <60 and >=60 year-old. Furthermore we investigated the impact of the age-specific reference ranges on the prevalence of thyroid dysfunction. DESIGN: Retrospective analysis of laboratory data collected over six months in 2015, mainly from individuals consulting the outpatient clinic. METHOD: Data from 676 individuals were withheld, after having applied strict exclusion criteria to avoid confounders. After exclusion of individuals with TAI (TPO-abs >60kIU/L) and/or outliers, data of 547 individuals were used to determine age-specific reference ranges. The prevalence of subclinical hypothyroidism (SCH) and subclinical hyperthyroidism (sch) was determined according to the reference ranges from the commercial assay and also according to the calculated age-specific reference ranges. From our study population. RESULTS: From the 676 individuals included, 559 (83%) were <60year-old and 117 (17%) >=60year-old. The prevalence of sch and TAI was comparable between both groups (8.6% vs. 13.7% and 15.4% vs. 20.5% respectively). The prevalence of SCH was significantly higher in individuals >=60years, compared to that in individuals <60years (14.5% vs. 5.4%; p<0.001). The calculated 2.5 and 97.5 percentile for the age-specific TSH range was 0.24 and 4.4 mIU/L in individuals <60years and 0.15 and 8.2mIU/L in individuals >=60years. When these the prevalence of sch and SCH was then determined on the basis of the age specific reference ranges, the prevalence of SCH significantly decreased in individuals >=60years (14.5% to 5%; p=0.027) and it then became comparable with that in individuals <60years (5% vs. 3%). CONCLUSIONS: The prevalence of SCH was higher in individuals >=60years, compared to that in individuals <60years, but when age-specific TSH reference ranges were used, it was comparable between both study groups. In order to avoid misclassification in older individuals, it is important to use age-specific reference ranges in daily clinical practice. PMID- 27988319 TI - Unsaturated plasma phospholipids are consistently lower in the patients diagnosed with gestational diabetes mellitus throughout pregnancy: A longitudinal metabolomics study of Chinese pregnant women part 1. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is a milder degree of hyperglycaemia diagnosed during pregnancy that can lead to serious, long-term consequences for both mother and foetus. The pathophysiology of GDM is not fully understood. The number of pregnant women diagnosed with GDM has been steadily increasing, but effective screening tools for early risk stratification are still missing. The emerging field of metabolomics has the potential to provide new insights and as a result is increasingly being used in studies of GDM. However, no study to date has investigated the longitudinal changes associated with GDM as pregnancy progresses. We investigated maternal plasma of a longitudinal cohort of normal pregnancies and pregnancies complicated by GDM. METHODS: Based on ultra performance hydrophilic interaction liquid chromatography/hybrid quadrupole time of-flight mass spectrometry, an untargeted metabolomics study was performed to explore the changes in the plasma metabolome of GDM cases and healthy controls. Innovative sample preparation and multilevel statistical methods were employed to enhance our ability to analyse the longitudinal plasma samples by LC-MS. RESULTS: A number of polyunsaturated or chemically modified phospholipids were significantly lower in the plasma of pregnant women that developed GDM when compared to healthy controls, while no difference was observed for the saturated phospholipids. The reduction of these lipid species in the participants that developed GDM could be detected as early in the first trimester and the changes were independent of the stage of gestation and the steroid hormones in the plasma. CONCLUSIONS: These differences observed in our study were detected well before the onset of GDM, and might provide further insights into the etiology or pathophysiology of GDM. PMID- 27988321 TI - Sex differences in emotional perception: Meta analysis of divergent activation. AB - Behavioral and physiological sex differences in emotional reactivity are well documented, yet comparatively few neural differences have been identified. Here we apply quantitative activation likelihood estimation (ALE) meta-analysis across functional brain imaging studies that each reported clusters of activity differentiating men and women as they participated in emotion-evoking tasks in the visual modality. This approach requires the experimental paradigm to be balanced across the sexes, and thus may provide greater clarity than previous efforts. Results across 56 emotion-eliciting studies (n=1907) reveal distinct activation in the medial prefrontal cortex, anterior cingulate cortex, frontal pole, and mediodorsal nucleus of the thalamus in men relative to women. Women show distinct activation in bilateral amygdala, hippocampus, and regions of the dorsal midbrain including the periaqueductal gray/superior colliculus and locus coeruleus. While some clusters are consistent with prevailing perspectives on the foundations of sex differences in emotional reactivity, thalamic and brainstem regions have not previously been highlighted as sexually divergent. These data strongly support the need to include sex as a factor in functional brain imaging studies of emotion, and to extend our investigative focus beyond the cortex. PMID- 27988320 TI - Heterogeneous increases of regional cerebral blood flow during preterm brain development: Preliminary assessment with pseudo-continuous arterial spin labeled perfusion MRI. AB - The human brain develops rapidly during 32-45 postmenstrual weeks (PMW), a critical stage characterized by dramatic increases of metabolic demand. The increasing metabolic demand can be inferred through measurements of regional cerebral blood flow (CBF), which might be coupled to regional metabolism in preterm brains. Arterial spin labeled (ASL) perfusion MRI is one of the few viable approaches for imaging regional CBF of preterm brains, but must be optimized for the extremely slow blood velocity unique in preterm brains. In this study, we explored the spatiotemporal CBF distribution in newborns scanned at the age of 32-45PMW using a pseudo-continuous ASL (pCASL) protocol adapted to slow blood flow in neonates. A total of 89 neonates were recruited. PCASL MRI was acquired from 34 normal newborns and phase contrast (PC) images from 19 newborns. Diffusion tensor images (DTI) were acquired from all 89 neonates for measuring cortical fractional anisotropy (FA), which characterizes cortical microstructure. Reproducible CBF measurements were obtained with the adjusted pCASL sequence. Global CBF measurement based on PC MRI was found to double its value in the 3rd trimester. Regional CBF increases were heterogeneous across the brain with a significantly higher rate of CBF increase in the frontal lobe and a lower rate of CBF increase in the occipital lobe. A significant correlation was found between frontal cortical CBF and cortical FA measurements (p<0.01). Increasing CBF values observed in the frontal lobe corresponded to lower FA values, suggesting that dendritic arborization and synaptic formation might be associated with an elevated local CBF. These results offer a preliminary account of heterogeneous regional CBF increases in a vital early developmental period and may shed the light on underlying metabolic support for cortical microstructural changes during the developmental period of 32-45PMW. Preterm effects and limitations of pCASL techniques in newborns need to be carefully considered for interpretation these results. PMID- 27988322 TI - A multi-centre evaluation of eleven clinically feasible brain PET/MRI attenuation correction techniques using a large cohort of patients. AB - AIM: To accurately quantify the radioactivity concentration measured by PET, emission data need to be corrected for photon attenuation; however, the MRI signal cannot easily be converted into attenuation values, making attenuation correction (AC) in PET/MRI challenging. In order to further improve the current vendor-implemented MR-AC methods for absolute quantification, a number of prototype methods have been proposed in the literature. These can be categorized into three types: template/atlas-based, segmentation-based, and reconstruction based. These proposed methods in general demonstrated improvements compared to vendor-implemented AC, and many studies report deviations in PET uptake after AC of only a few percent from a gold standard CT-AC. Using a unified quantitative evaluation with identical metrics, subject cohort, and common CT-based reference, the aims of this study were to evaluate a selection of novel methods proposed in the literature, and identify the ones suitable for clinical use. METHODS: In total, 11 AC methods were evaluated: two vendor-implemented (MR-ACDIXON and MR ACUTE), five based on template/atlas information (MR-ACSEGBONE (Koesters et al., 2016), MR-ACONTARIO (Anazodo et al., 2014), MR-ACBOSTON (Izquierdo-Garcia et al., 2014), MR-ACUCL (Burgos et al., 2014), and MR-ACMAXPROB (Merida et al., 2015)), one based on simultaneous reconstruction of attenuation and emission (MR-ACMLAA (Benoit et al., 2015)), and three based on image-segmentation (MR-ACMUNICH (Cabello et al., 2015), MR-ACCAR-RiDR (Juttukonda et al., 2015), and MR ACRESOLUTE (Ladefoged et al., 2015)). We selected 359 subjects who were scanned using one of the following radiotracers: [18F]FDG (210), [11C]PiB (51), and [18F]florbetapir (98). The comparison to AC with a gold standard CT was performed both globally and regionally, with a special focus on robustness and outlier analysis. RESULTS: The average performance in PET tracer uptake was within +/-5% of CT for all of the proposed methods, with the average+/-SD global percentage bias in PET FDG uptake for each method being: MR-ACDIXON (-11.3+/-3.5)%, MR-ACUTE (-5.7+/-2.0)%, MR-ACONTARIO (-4.3+/-3.6)%, MR-ACMUNICH (3.7+/-2.1)%, MR-ACMLAA ( 1.9+/-2.6)%, MR-ACSEGBONE (-1.7+/-3.6)%, MR-ACUCL (0.8+/-1.2)%, MR-ACCAR-RiDR ( 0.4+/-1.9)%, MR-ACMAXPROB (-0.4+/-1.6)%, MR-ACBOSTON (-0.3+/-1.8)%, and MR ACRESOLUTE (0.3+/-1.7)%, ordered by average bias. The overall best performing methods (MR-ACBOSTON, MR-ACMAXPROB, MR-ACRESOLUTE and MR-ACUCL, ordered alphabetically) showed regional average errors within +/-3% of PET with CT-AC in all regions of the brain with FDG, and the same four methods, as well as MR-ACCAR RiDR, showed that for 95% of the patients, 95% of brain voxels had an uptake that deviated by less than 15% from the reference. Comparable performance was obtained with PiB and florbetapir. CONCLUSIONS: All of the proposed novel methods have an average global performance within likely acceptable limits (+/-5% of CT-based reference), and the main difference among the methods was found in the robustness, outlier analysis, and clinical feasibility. Overall, the best performing methods were MR-ACBOSTON, MR-ACMAXPROB, MR-ACRESOLUTE and MR-ACUCL, ordered alphabetically. These methods all minimized the number of outliers, standard deviation, and average global and local error. The methods MR-ACMUNICH and MR-ACCAR-RiDR were both within acceptable quantitative limits, so these methods should be considered if processing time is a factor. The method MR ACSEGBONE also demonstrates promising results, and performs well within the likely acceptable quantitative limits. For clinical routine scans where processing time can be a key factor, this vendor-provided solution currently outperforms most methods. With the performance of the methods presented here, it may be concluded that the challenge of improving the accuracy of MR-AC in adult brains with normal anatomy has been solved to a quantitatively acceptable degree, which is smaller than the quantification reproducibility in PET imaging. PMID- 27988324 TI - A novel multiplex poliovirus binding inhibition assay applicable for large serosurveillance and vaccine studies, without the use of live poliovirus. AB - Large-scale serosurveillance or vaccine studies for poliovirus using the "gold standard" WHO neutralisation test (NT) are very laborious and time consuming. With the polio eradication at hand and with the removal of live attenuated Sabin strains from the oral poliovirus vaccine (OPV), starting with type 2 (as of April 2016), laboratories will need to conform to much more stringent laboratory biosafety regulations when handling live poliovirus strains. In this study, a poliovirus binding inhibition multiplex immunoassay (polio MIA) using inactivated poliovirus vaccine (IPV-Salk) was developed for simultaneous quantification of serum antibodies directed to all three poliovirus types. Our assay shows a good correlation with the NT and an excellent correlation with the ELISA-based binding inhibition assay (POBI). The assay is highly type-specific and reproducible. Additionally, serum sample throughput increases about fivefold relative to NT and POBI and the amount of serum needed is reduced by more than 90%. In conclusion, the polio MIA can be used as a safe and high throughput application, especially for large-scale surveillance and vaccine studies, reducing laboratory time and serum amounts needed. PMID- 27988323 TI - A semi-automated method for rapid detection of ripple events on interictal voltage discharges in the scalp electroencephalogram. AB - BACKGROUND: High frequency oscillations are emerging as a clinically important indicator of epileptic networks. However, manual detection of these high frequency oscillations is difficult, time consuming, and subjective, especially in the scalp EEG, thus hindering further clinical exploration and application. Semi-automated detection methods augment manual detection by reducing inspection to a subset of time intervals. We propose a new method to detect high frequency oscillations that co-occur with interictal epileptiform discharges. NEW METHOD: The new method proceeds in two steps. The first step identifies candidate time intervals during which high frequency activity is increased. The second step computes a set of seven features for each candidate interval. These features require that the candidate event contain a high frequency oscillation approximately sinusoidal in shape, with at least three cycles, that co-occurs with a large amplitude discharge. Candidate events that satisfy these features are stored for validation through visual analysis. RESULTS: We evaluate the detector performance in simulation and on ten examples of scalp EEG data, and show that the proposed method successfully detects spike-ripple events, with high positive predictive value, low false positive rate, and high intra-rater reliability. COMPARISON WITH EXISTING METHOD: The proposed method is less sensitive than the existing method of visual inspection, but much faster and much more reliable. CONCLUSIONS: Accurate and rapid detection of high frequency activity increases the clinical viability of this rhythmic biomarker of epilepsy. The proposed spike-ripple detector rapidly identifies candidate spike-ripple events, thus making clinical analysis of prolonged, multielectrode scalp EEG recordings tractable. PMID- 27988326 TI - Everolimus TDM using Thermo Fisher QMS immunoassay on Indiko, Beckman DxC, AU680, and AU5800 analyzers. AB - OBJECTIVES: Everolimus (EVR), a mTOR inhibitor immunosuppressant approved for renal, liver and cardiac transplants. This study established the appropriate TDM performances of the Thermo Scientific QMS EVR Assay by using the Beckman DxC, followed by comparison to the Thermo Scientific Indiko and a previously published LC-MS/MS assay, and Beckman AU680 and AU5800 analyzers. DESIGN AND METHODS: The study initially established acceptable linearity, precision and accuracy of the QMS EVR turbidimetric assay. Sample preparation was initiated by mixing patient whole blood with methanol and a precipitation reagent. Supernatant was transferred to sample cups. Drug in the supernatant and drug coated on microparticle compete for the limited number of antibody binding sites. If EVR is absent in the sample supernatant, EVR coated microparticles are agglutinated in the presence of antibody reagent. If EVR is present, agglutination is partially inhibited, depending on EVR concentration. Calibrators range was from 1.5 to 20ng/mL. Comparison studies data were analyzed by Deming Regression and Bland Altman plots. RESULTS: Precision studies showed the following mean concentrations 4.00-4.72, 7.70-8.20 and 14.80-15.56ng/mL, and CVs of 3.1-8.7%, 3.4-8.9% and 2.6 4.4% respectively. Comparison of analyses of 107 de-identified transplant samples by three analyzers - Indiko, DxC and AU680 showed: EVR concentrations from <1.5 to 13.6ng/mL, slopes 1.000 to 1.076, intercepts -0.053 to 0.462, and R 0.945 to 0.981. Another series of comparison studies (n=104) of Indiko and AU680 with LC MS/MS showed the following: slopes 1.035 to 1.086, intercepts -0.019 to -0.265, and R 0.924 to 0.980. 2013-2016 CAP survey results were acceptable. CONCLUSIONS: Based on the experience of the past 3.5years, Thermo Scientific QMS EVR Immunoassay using four different analyzers offered adequate limit of detection and acceptable accuracy and precision, suitable for monitoring renal and liver transplant recipients. PMID- 27988325 TI - Pegylated liposomal doxorubicin (Caelyx(r)) interference with the spectrophotometric Jaffe method for quantitative determination of creatinine in human plasma. PMID- 27988327 TI - Nanocrystals embedded in chitosan-based respirable swellable microparticles as dry powder for sustained pulmonary drug delivery. AB - In this study, nanocrystals embedded in microparticles were designed to achieve sustained pulmonary drug delivery of hydrophobic drugs. Chitosan based microparticles were engineered to allow sustained drug release via swelling and mucoadhesive properties of the polymer. Taking cinaciguat as a hydrophobic model drug, drug nanocrystals were prepared by high pressure homogenization and then encapsulated in chitosan microparticles via spray drying. Through various in vitro characterizations, it was shown that drug loaded microparticles had a high drug loading with promising aerosolization characteristics (mean volume diameter (Dv50) 3-4MUm, experimental mass mean aerodynamic diameter (MMADe) 4-4.5MUm, fine particle fraction (FPF%) 40-45%, emitted dose (ED%) 94-95%). The microparticles showed high swelling capacity within 5min, with various sustained drug release rates depending on chitosan concentration and molecular weight. Furthermore, aerosolization performances under various inhalation conditions were investigated. It was found that both inspiratory flow rate and volume had an influence on the aerosolization of developed microparticles, indicating actual inhalation efficiency might be compromised under disease conditions. Taken together, in vitro data indicate that chitosan based swellable microparticles could potentially be useful as nanocrystal carrier to achieve sustained pulmonary delivery. To complete the feasibility assessment of this formulation principle, future in vivo safety and efficacy studies are needed. PMID- 27988328 TI - Emodin self-emulsifying platform ameliorates the expression of FN, ICAM-1 and TGF beta1 in AGEs-induced glomerular mesangial cells by promoting absorption. AB - Emodin, a potential anti-diabetic nephropathy agent, is limited by its oral use due to the poor water solubility. The present study aimed to enhance the absorption and the suppressive effects of emodin on renal fibrosis by developing a self-microemulsifying drug delivery system (SMEDDS). Solubility studies, compatibility tests, pseudo-ternary phase diagrams analysis and central composite design were carried out to obtain the optimized formulation. The average droplet size of emodin-loaded SMEDDS was about 18.31+/-0.12nm, and the droplet size and zeta potential remained stable at different dilution ratios of water and different values of pH varying from 1.2 to 7.2. Enhanced cellular uptake in both the Caco-2 cells and glomerular mesangial cells (GMCs) is great advantageous for the formulation. The AUC0-24h of emodin-loaded SMEDDS was 1.87-fold greater than that of emodin suspension, which may be attributed to enhanced uptake in Caco-2 cells. Moreover, emodin-loaded SMEDDS showed better suppressive effects on the protein level of fibronectin (FN), transforming growth factor-beta 1 (TGF-beta1) and intercellular adhesion molecule 1 (ICAM-1) than the crude emodin in advanced glycation-end products (AGEs)-induced GMCs and renal tubular epithelial cells (NRK-52E). Our study illustrated that developed SMEDDS improved the oral absorption of emodin, and attained better suppressive effects on the protein level of renal fibrosis compositions in AGEs-induced GMCs and NRK-52E cells. PMID- 27988329 TI - Wheelchair pushrim kinetics measurement: A method to cancel inaccuracies due to pushrim weight and wheel camber. AB - The commercially available SmartWheelTM is largely used in research and increasingly used in clinical practice to measure the forces and moments applied on the wheelchair pushrims by the user. However, in some situations (i.e. cambered wheels or increased pushrim weight), the recorded kinetics may include dynamic offsets that affect the accuracy of the measurements. In this work, an automatic method to identify and cancel these offsets is proposed and tested. First, the method was tested on an experimental bench with different cambers and pushrim weights. Then, the method was generalized to wheelchair propulsion. Nine experienced wheelchair users propelled their own wheelchairs instrumented with two SmartWheels with anti-slip pushrim covers. The dynamic offsets were correctly identified using the propulsion acquisition, without needing a separate baseline acquisition. A kinetic analysis was performed with and without dynamic offset cancellation using the proposed method. The most altered kinetic variables during propulsion were the vertical and total forces, with errors of up to 9N (p<0.001, large effect size of 5). This method is simple to implement, fully automatic and requires no further acquisitions. Therefore, we advise to use it systematically to enhance the accuracy of existing and future kinetic measurements. PMID- 27988330 TI - The gut microbiome composition associates with bipolar disorder and illness severity. AB - The gut microbiome is emerging as an important factor in regulating mental health yet it remains unclear what the target should be for psychiatric treatment. We aimed to elucidate the complement of the gut-microbiome community for individuals with bipolar disorder relative to controls; and test for relationships with burden of disease measures. We compared the stool microbiome from individuals with bipolar disorder (n = 115) and control subjects (n = 64) using 16S ribosomal RNA (rRNA) gene sequence analysis. Analysis of molecular variance (AMOVA) revealed global community case-control differences (AMOVA p = 0.047). Operational Taxonomical Unit (OTU) level analysis revealed significantly decreased fractional representation (p < 0.001) of Faecalibacterium after adjustment for age, sex, BMI and false discovery rate (FDR) correction at the p < 0.05 level. Within individuals with bipolar disorder, the fractional representation of Faecalibacterium associated with better self-reported health outcomes based on the Short Form Health Survey (SF12); the Patient Health Questionnaire (PHQ9); the Pittsburg Sleep Quality Index (PSQI); the Generalized Anxiety Disorder scale (GAD7); and the Altman Mania Rating Scale (ASRM), independent of covariates. This study provides the first detailed analysis of the gut microbiome relationships with multiple psychiatric domains from a bipolar population. The data support the hypothesis that targeting the microbiome may be an effective treatment paradigm for bipolar disorder. PMID- 27988332 TI - Suicide attempts and markers of immune response in individuals with serious mental illness. AB - Previous studies have identified elevations in antibodies to Toxoplasma gondii in individuals with a history of suicide attempts but studies have not measured the association between suicide attempts and a panel of antibody markers. We assessed 162 patients receiving treatment for schizophrenia, bipolar disorder, or major depression on the Columbia Suicide Severity Rating Scale for suicide attempt history and other clinical measures. All participants had a blood sample drawn from which were measured antibodies to Toxoplasma gondii and other neurotropic infectious agents. A total of 72 (44%) of participants had a lifetime suicide attempt; these individuals had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV). We also found an association between the levels of these antibodies and the number of suicide attempts. There was a particularly strong odds of a suicide attempt history in individuals who had elevated levels of IgM antibodies to both Toxoplasma gondii and to CMV suggesting an additive risk associated with the antibodies. These findings remained significant when adjusting for current cigarette smoking and history of drug/alcohol use which were also associated with suicide attempts. We did not find an association between a suicide attempt history and IgG class antibodies to Toxoplasma gondii, CMV, or IgM or IgG antibodies to the Epstein Barr Virus or other antigens tested. The identification of blood-based antibody markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses. PMID- 27988331 TI - Parental warmth and psychiatric disorders among Puerto Rican children in two different socio-cultural contexts. AB - BACKGROUND: Parental warmth (PW) has a strong influence on child development and may precede the onset of psychiatric disorders in children. PW is interconnected with other family processes (e.g., coercive discipline) that may also influence the development of psychiatric disorders in children. We prospectively examined the association between PW and child psychiatric disorders (anxiety, major depression disorder, ADHD, disruptive behavior disorders) over the course of three years among Puerto Rican youth, above and beyond the influence of other family factors. METHODS: Boricua Youth Study participants, Puerto Rican children 5 to 13 years of age at Wave 1 living in the South Bronx (New York) (SB) and San Juan and Canguas (PR) (n = 2,491), were followed for three consecutive years. Youth psychiatric disorders were measured by the Diagnostic Interview Schedule for Children-IV (DISC-IV). Generalized Linear Mixed models tested the association between PW (Wave 1) and psychiatric disorders in the next two years adjusting for demographic characteristics and family processes. RESULTS: Higher levels of PW were related to lower odds of child anxiety and major depressive disorder over time (OR = 0.69[0.60; 0.79]; 0.49[0.41; 0.58], respectively). The strength of the association between PW and ADHD and disruptive behavior disorder declined over time, although it was still significant in the last assessment (OR = 0.44[0.37; 0.52]; 0.46[0.39; 0.54], respectively). PW had a unique influence on psychiatric disorders beyond the influence of other parenting and family processes. Stronger associations were observed among girls for depression and ADHD. CONCLUSIONS: Incorporating PW behaviors such as acceptance, support, and comforting into interventions focused on parenting skills may help prevent child psychiatric disorders. PMID- 27988333 TI - Delamanid is not metabolized by Salmonella or human nitroreductases: A possible mechanism for the lack of mutagenicity. AB - Nitro-containing compounds such as nitrofuran and nitroimidazole are drugs used for the treatment of infectious diseases. However, many of these nitro-containing drugs are positive in the bacterial reverse mutation assay (Ames test). The recently approved anti-multidrug-resistant tuberculosis (MDR-TB) drug, delamanid (DeltybaTM; OPC-67683), a derivative of 4-nitroimidazole, was negative for mutagenicity in the Ames assay. In Salmonella typhimurium, mutagenicity of nitro compounds has been closely associated with the ability of nitroreductase to metabolize (degradation)these compounds. To explore the lack of mutagenicity for delamanid, we examined the initial metabolic rate and mutagenic-specific activity of a series of nitro compounds in S. typhimurium TA100. The order of maximum mutagenic-activity was nitrofuran > 2-nitroimidazole > 5-nitroimidazole >= 4 nitroimidazole, which is very similar to the order of initial metabolic rate, i.e., the Pearson's correlation coefficient (r = 0.85) showed a correlation between metabolic rate and mutagenic-activity. No metabolism of delamanid was detected even after 60 h of treatment. In addition, delamanid was not reduced by two human nitroreductases. These facts may explain the absence of genotoxicity of delamanid in both in vitro and in vivo tests. PMID- 27988334 TI - Activation of HIF-1alpha and its downstream targets in rat hippocampus after long term simulated microgravity exposure. AB - Microgravity has many detrimental impact on brain functions, however the underlying mechanism remain unclear. In present study, 28 days of tail-suspension (30 degrees ) was used to simulate microgravity in rats. We showed that oxidative stress in hippocampus was increased after 28 days of simulated microgravity in consideration of the decreased expression of NF-E2-related factor 2 (Nrf2) and the declined activities of total superoxide dismutase (T-SOD), CuZn-SOD, glutathione peroxidase (GSH-PX) and total antioxidant capacity (T-AOC). Using RNA seq, we further investigated the effect of simulated microgravity on the expression of genes in hippocampus, and 849 genes were found to be differentially expressed. According to pathway analysis, the differentially expressed genes involved in cytoskeleton, metabolism, immunity, transcription regulation, etc. It is interesting to note that the differentially expressed genes were involved in hypoxia-associated pathway. In agreement with this, the expression of hypoxia induced factor-1alpha (HIF-1alpha), the master regulator of oxygen homeostasis, was significantly increased. Meanwhile, HIF-2alpha, a HIF-1alpha paralog, was elevated compared with the control group. The expression of pyruvate dehydrogenase kinase 1 (PDK1), lactate dehydrogenase A (LDHA) and vascular endothelial growth factor (VEGF), three well-defined downstream targets of HIF 1alpha, were up-regulated in hippocampus after 28 days of simulated microgravity exposure. Additionally, brain oxygen saturation (SO2) and blood flow analyzed by the tissue oxygen analysis system were also significantly reduced. These findings indicate that simulated microgravity might cause an alteration in oxygen homeostasis, providing novel insight into better understanding of how simulated microgravity affects the function of hippocampus and a new direction to the development of countermeasure for brain dysfunction during spaceflight (actual microgravity). PMID- 27988335 TI - Cultured human amniocytes express hTERT, which is distributed between nucleus and cytoplasm and is secreted in extracellular vesicles. AB - BACKGROUND: An increasing number of studies on stem cells suggests that the therapeutic effect they exert is primarily mediated by a paracrine regulation through extracellular vesicles (EVs) giving solid grounds for stem cell EVs to be exploited as agents for treating diseases or for restoring damaged tissues and organs. Due to their capacity to differentiate in all embryonic germ layers, amniotic fluid stem cells (AFCs), represent a highly promising cell type for tissue regeneration, which however is still poorly studied and in turn underutilized. In view of this, we conducted a first investigation on the expression of human hTERT gene - known to be among the key triggers of organ regeneration - in AFCs and in the EVs they secrete. METHODS: Isolated AFCs were evaluated by RT-qPCR for hTERT expression. The clones expressing the highest levels of transcript, were analyzed by Immunofluorescence imaging and Nuclear/cytoplasmic fractionation in order to evaluate hTERT subcellular localization. We then separated EVs from FBS depleted culture medium by serial (ultra) centrifugations steps and characterized them using Western blotting, Atomic force Microscopy and Nanoplasmonic assay. RESULTS: We first demonstrated that primary cultures of AFCs express the gene hTERT at different levels. Then we evidenced that in AFCs with the higher transcript levels, the hTERT protein is present in the nuclear and cytoplasmic compartment. Finally, we found that cytosolic hTERT is embodied in the EVs that AFCs secrete in the extracellular milieu. CONCLUSIONS: Our study demonstrates for the first time the expression of the full protein hTERT by AFCs and its release outside the cell mediated by EVs, indicating a new extra telomeric role for this protein. This finding represents an initial but crucial evidence for considering AFCs derived EVs as new potential sources for tissue regeneration. PMID- 27988336 TI - JSI-124 inhibits IgE production in an IgE B cell line. AB - IgE is a key effector molecule in atopic diseases; however, the regulation mechanisms of IgE production in IgE B cells remain poorly understood. In the present study, we demonstrate that JSI-124 (cucurbitacin I), a selective STAT3 inhibitor, selectively inhibits production of IgE by a human IgE B cell line, CRL 8033 cells, while does not affect the IgG production by IgG B cell lines. In the aspect of molecular mechanism, we found that Iglambda, but not Ighe, gene expression was suppressed by JSI-124. The above effects of JSI-124 were not mediated by affecting cellular proliferation or apoptosis. Furthermore, multiple B cell differentiation-related genes expression was not significantly affected by JSI-124. Taken together, we demonstrate a potential strategy of therapeutically suppressing IgE production without affecting IgG production in atopic patients. PMID- 27988337 TI - micorRNA-101 silences DNA-PKcs and sensitizes pancreatic cancer cells to gemcitabine. AB - Gemcitabine sensitization is important for the treatment of pancreatic cancer. We have previously shown that DNA-dependent protein kinase catalytic subunit (DNA PKcs) over-expression causes Akt activation and gemcitabine resistance in pancreatic cancer cells. Here, we aim to downregulate DNA-PKcs via introduction of micorRNA-101 ("miR-101"). We showed that forced-expression of miR-101 downregulated DNA-PKcs and potentiated gemcitabine-induced PANC-1 pancreatic cancer cell death and apoptosis. Contrarily, miR-101 depletion through expressing antagomiR-101 in PANC-1 cells resulted in DNA-PKcs upregulation and gemcitabine resistance. DNA-PKcs downregulation is the primary reason of gemcitabine sensitization by miR-101. DNA-PKcs inhibition (by NU7026) or silence (by targeted siRNAs) disabled miR-101-mediaetd gemcitabine sensitization. Significantly, Akt Ser-473 phosphorylation in PANC-1 cells was also inhibited by miR-101, but was augmented with antagomiR-101 expression. Importantly, we showed that miR-101 level was downregulated in gemcitabine-resistant human pancreatic cancer tissues, which was correlated with DNA-PKcs upregulation. Together, these results suggest that miR-101 sensitizes PANC-1 cells to gemcitabine possibly via downregulating DNA-PKcs. PMID- 27988338 TI - DHA-derived oxylipins, neuroprostanes and protectins, differentially and dose dependently modulate the inflammatory response in human macrophages: Putative mechanisms through PPAR activation. AB - Whereas the anti-inflammatory properties and mechanisms of action of long chain omega3 PUFAs have been abundantly investigated, research gaps remain regarding the respective contribution and mechanisms of action of their oxygenated metabolites collectively known as oxylipins. We conducted a dose-dependent and comparative study in human primary macrophages aiming to compare the anti inflammatory activity of two types of DHA-derived oxylipins including the well described protectins (NPD1 and PDX), formed through lipoxygenase pathway and the neuroprostanes (14-A4t- and 4-F4t-NeuroP) formed through free-radical mediated oxygenation and expected to be new anti-inflammatory mediators. Considering the potential ability of these DHA-derived oxylipins to bind PPARs and knowing the central role of these transcription factors in the regulation of macrophage inflammatory response, we performed transactivation assays to compare the ability of protectins and neuroprostanes to activate PPARs. All molecules significantly reduced mRNA levels of cytokines such as IL-6 and TNF-alpha, however not at the same doses. NPD1 showed the most effect at 0.1uM (-14.9%, p<0.05 for IL-6 and 26.7%, p<0.05 for TNF-alpha) while the three other molecules had greater effects at 10uM, with the strongest result due to the cyclopentenone neuroprostane, 14 A4t-NeuroP (-49.8%, p<0.001 and -40.8%, p<0.001, respectively). Part of the anti inflammatory properties of the DHA-derived oxylipins investigated could be linked to their activation of PPARs. Indeed, all tested oxylipins significantly activated PPARgamma, with 14-A4t-NeuroP leading to the strongest activation, and NPD1 and PDX also activated PPARalpha. In conclusion, our results show that neuroprostanes and more especially cyclopentenone neuroprostanes have potent anti inflammatory activities similar or even more pronounced than protectins supporting that neuroprostanes should be considered as important contributors to the anti-inflammatory effects of DHA. PMID- 27988339 TI - Divergent roles of endothelial nitric oxide synthases system in maintaining cardiovascular homeostasis. AB - Accumulating evidence has demonstrated the importance of reactive oxygen species (ROS) as an essential second messenger in health and disease. Endothelial dysfunction is the hallmark of atherosclerotic cardiovascular diseases, in which pathological levels of ROS are substantially involved. The endothelium plays a crucial role in modulating tone of underlying vascular smooth muscle by synthesizing and releasing nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) factors in a distinct vessel size-dependent manner through the diverse roles of the endothelial NO synthases (NOSs) system. Endothelium-derived hydrogen peroxide (H2O2) is a physiological signaling molecule serving as one of the major EDH factors especially in microcirculations and has gained increasing attention in view of its emerging relevance for cardiovascular homeostasis. In the clinical settings, it has been reported that antioxidant supplements are unexpectedly ineffective to prevent cardiovascular events. These lines of evidence indicate the potential importance of the physiological balance between NO and H2O2/EDH through the diverse functions of endothelial NOSs system in maintaining cardiovascular homeostasis. A better understanding of cardiovascular redox signaling is certainly needed to develop novel therapeutic strategies in cardiovascular medicine. In this review, we will briefly summarize the current knowledge on the emerging regulatory roles of redox signaling pathways in cardiovascular homeostasis, with particular focus on the two endothelial NOSs-derived mediators, NO and H2O2/EDH. PMID- 27988341 TI - Can lumbosacral orthoses cause trunk muscle weakness? A systematic review of literature. AB - BACKGROUND: Wearing lumbosacral orthosis (LSO) is one of the most common treatments prescribed for conservative management of low back pain. Although the results of randomized controlled trials suggest effectiveness of LSO in reducing pain and disability in these patients, there is a concern that prolonged use of LSO may lead to trunk muscle weakness and atrophy. PURPOSE: The present review aimed to evaluate available evidence in literature to determine whether LSO results in trunk muscle weakness or atrophy. STUDY DESIGN: This is a systematic review. METHODS: A systematic search of electronic databases including PubMed, Scopus, ScienceDirect, and Medline (via Ovid) followed by hand search of journals was performed. Prospective studies published in peer-reviewed journals, with full text available in English, investigating the effect of lumbar orthosis on trunk muscle activity, muscle thickness, strength or endurance, spinal force, and intra abdominal pressure in healthy subjects or in patients with low back pain, were included. Methodological quality of selected studies was assessed by using the modified version of Downs and Black checklist. This research had no funding source, and the authors declare no conflicts of interest-associated biases. RESULTS: Thirty-five studies fulfilled the eligibility criteria. The mean and standard deviation of the quality score was 64+/-9.7%. Most studies investigating the effect of lumbar orthosis on electromyographic activity (EMG) of trunk muscles demonstrated a decrease or no change in the EMG parameters. A few studies reported increased muscle activity. Lumbosacral orthosis was found to have no effect on muscle strength in some studies, whereas other studies demonstrated increased muscle strength. Only one study, which included ultrasound assessment of trunk muscle stabilizers, suggested reduced thickness of the abdominal muscles and reduced cross-sectional area of the multifidus muscles. Out of eight studies that investigated spinal compression load, the load was reduced in four studies and unchanged in three studies. One study showed that only elastic belts reduced compression force compared to leather and fabric belts and ascribed this reduction to the elastic property of the lumbar support. CONCLUSION: The present review showed that the changes in outcome measures associated with muscle work demands were inconsistent in their relation to the use of lumbar supports. This review did not find conclusive scientific evidence to suggest that orthosis results in trunk muscle weakness. PMID- 27988340 TI - A novel maturation index based on neonatal diffusion tensor imaging reflects typical perinatal white matter development in humans. AB - Human birth presents an abrupt transition from intrauterine to extrauterine life. Here we introduce a novel Maturation Index (MI) that considers the relative importance of gestational age at birth and postnatal age at scan in a General Linear Model. The MI is then applied to Diffusion Tensor Imaging (DTI) in newborns for characterizing typical white matter development in neonates. DTI was performed cross-sectionally in 47 neonates (gestational age at birth=39.1+/-1.6 weeks [GA], postnatal age at scan=25.5+/-12.2days [SA]). Radial diffusivity (RD), axial diffusivity (AD) and fractional anisotropy (FA) along 27 white matter fiber tracts were considered. The MI was used to characterize inflection in maturation at the time of birth using GLM estimated rates of change before and after birth. It is proposed that the sign (positive versus negative) of MI reflects the period of greatest maturation rate. Two general patterns emerged from the MI analysis. First, RD and AD (but not FA) had positive MI on average across the whole brain (average MIAD=0.31+/-0.42, average MIRD=0.22+/-0.34). Second, significant regions of negative MI in RD and FA (but not AD) were observed in the inferior corticospinal regions, areas known to myelinate early. Observations using the proposed method are consistent with proposed models of the white matter maturation process in which pre-myelination is described by changes in AD and RD due to oligodendrocyte proliferation while true myelination is characterized by changes in RD and FA due to myelin formation. PMID- 27988342 TI - Prognostic factors in patients with spinal metastasis: a systematic review and meta-analysis. AB - BACKGROUND CONTEXT: Incidence of symptomatic spinal metastasis has increased owing to improvement in treatment of the disease. One of the key factors that influences decision-making is expected patient survival. To our knowledge, no systematic reviews or meta-analysis have been conducted that review independent prognostic factors in spinal metastases. PURPOSE: This study aimed to determine independent prognostic factors that affect outcome in patients with metastatic spine disease. STUDY DESIGN: This is a systematic literature review and meta analysis of publications for prognostic factors in spinal metastatic disease. PATIENT SAMPLE: Pooled patient results from cohort and observational studies. OUTCOME MEASUREMENT: Meta-analysis for poor prognostic factors as determined by hazard ratio (HR) and 95% confidential interval (95% CI). METHODS: We systematically searched relevant publications in PubMed and Embase. The following search terms were used: ("'spinal metastases'" OR "'vertebral metastases'" OR ""spinal metastasis" OR 'vertebral metastases') AND ('"prognostic factors"' OR "'survival'"). Inclusion criteria were prospective and retrospective cohort series that report HR and 95% CI of independent prognostic factors from multivariate analysis. Two reviewers independently assessed all papers. The quality of included papers was assessed by using Newcastle-Ottawa Scale for cohort studies and publication bias was assessed by using funnel plot, Begg test, and Egger test. The prognostic factors that were mentioned in at least three publications were pooled. Meta-analysis was performed using HR and 95% CI as the primary outcomes of interest. Heterogeneity was assessed using the I2 method. RESULTS: A total of 3,959 abstracts (1,382 from PubMed and 2,577 from Embase) were identified through database search and 40 publications were identified through review of cited publications. The reviewers selected a total of 51 studies for qualitative synthesis and 43 studies for meta-analysis. Seventeen poor prognostic factors were identified. These included presence of a neurologic deficit before surgery, non-ambulatory status before radiotherapy (RT), non ambulatory status before surgery, presence of bone metastases, presence of multiple bone metastases (>2 sites), presence of multiple spinal metastases (>3 sites), development of motor deficit in <7 days before initiating RT, development of motor deficit in <14 days before initiating RT, time interval from cancer diagnosis to RT <15 months, Karnofsky Performance Score (KPS) 10-40, KPS 50-70, KPS<70, Eastern Cooperative Oncology Group (ECOG) grade 3-4, male gender, presence of visceral metastases, moderate growth tumor on Tomita score (TS) classification, and rapid growth tumor on TS classification. CONCLUSIONS: Seventeen independent poor prognostic factors were identified in this study. These can be categorized into cancer-specific and nonspecific prognostic factors. A tumor-based prognostic scoring system that combines all specific and general factors may enhance the accuracy of survival prediction in patients with metastatic spine disease. PMID- 27988343 TI - Influence of the mental health status on a new measure of objective functional impairment in lumbar degenerative disc disease. AB - BACKGROUND CONTEXT: The Timed Up and Go (TUG) test has recently been proposed as a simple and standardized measure for objective functional impairment (OFI) in patients with lumbar degenerative disc disease (DDD). PURPOSE: The study aimed to explore the relationship between a patient's mental health status and both patient-reported outcome measures (PROMs) and TUG test results. STUDY DESIGN/SETTING: This is a prospective institutional review board-approved two center study. PATIENT SAMPLE: The sample was composed of 375 consecutive patients scheduled for lumbar spine surgery and a healthy cohort of 110 control subjects. OUTCOME MEASURES: Patients and control subjects were assessed with the TUG test and a comprehensive panel of subjective PROMs of pain intensity (visual analog scale [VAS]), functional impairment (Roland-Morris Disability Index [RMDI]), Oswestry Disability Index [ODI]), as well as health-related quality of life (hrQoL; Euro-Qol [EQ]-5D). METHODS: Standardized age- and sex-adjusted TUG test T scores were calculated. The dependent variable was the short-form (SF)-12 mental component summary (MCS) quartiles, and the independent variables were the TUG T scores and PROMs. Direct and adjusted analyses of covariance were performed to estimate the interaction between the SF-12 MCS quartiles and the independent variables. RESULTS: In patients, there was a significant decrease in the subjective PROMs, notably the VAS back pain (p=.001) and VAS leg pain (p=.035), as well as significant increase in the RMDI (p<.001), ODI (p<.001), and the EQ-5D index (p<.001) with every increase in the quartile of the SF-12 MCS. There were no significant group differences of OFI as measured by the TUG T-scores across the SF-12 MCS quartiles (p=.462). In the healthy control group, a significant decrease in VAS leg pain (p=.028), RMDI (p=.013), and ODI (p<.001), as well as a significant increase in the EQ-5D index (p<.001), was seen across the SF-12 MCS quartiles, whereas TUG T-scores remained stable (p=.897). CONCLUSIONS: There are significant influences of mental hrQoL on subjective measures of pain, functional impairment, and hrQoL that might lead to bias when evaluating patients with lumbar DDD who suffer from reduced mental hrQoL. The TUG test appears to be a stable instrument and especially helpful in the evaluation of patients with lumbar DDD and mental health problems. PMID- 27988345 TI - Use of lining materials under posterior resin composite restorations in the UK. AB - OBJECTIVES: To investigate opinions on, and current use of lining materials prior to the placement of posterior resin composite restorations by general dental practitioners (GDPs) in the UK. A further objective was to investigate aspects of posterior resin composite restoration placement techniques employed by UK GDPs. METHODS: A questionnaire was devised to gain the information sought. It was sent to 500 UK dentists, chosen at random from the register of the General Dental Council. RESULTS: Three hundred and fifty four replies were received, which gave a response rate of 71%. Eighty two percent of respondents reported placing lining materials in deep cavities to be restored with resin composite. Regarding moderately deep cavities, half of the respondents indicated a preference to place a lining material, whilst 44% were not sure if a lining was required. The remaining 6% did not respond to the question. Of the respondents, 39% reported that they did not place lining materials in shallow cavities. Regarding techniques for posterior resin composite placement, two-step etch and rinse systems were the most common adhesive bonding systems used (60%). The majority of respondents (80%) reported not using rubber dam when restoring posterior teeth with resin composite. CONCLUSIONS: There was considerable confusion about the need to place a lining prior to resin composite restorations placement in moderate depth and shallow cavities, whilst most favoured the placement of a lining in deep posterior cavities. The majority of GDPs may not routinely use rubber dam for the placement of posterior resin composite restorations. CLINICAL SIGNIFICANCE: Decision making and operative techniques for cavity linings under posterior composite restorations in moderately deep and deep cavities is contentious among dentists, resulting in a need to generate more convincing, practice-relevant data on the use of lining materials to inform the dental profession. PMID- 27988346 TI - Experiencing a reaching task passively with one arm while adapting to a visuomotor rotation with the other can lead to substantial transfer of motor learning across the arms. AB - The extent of transfer following visuomotor adaptation across the arms is typically limited as compared to that within the same arm. However, we have demonstrated that interlimb transfer can occur nearly completely if one arm performs reaching movements associated with a desired trajectory repeatedly and actively during an initial training session in which the other arm adapts to a novel visuomotor adaptation. Based on that finding, we argued that the absence of instances associated with specific motor effectors is the major reason for limited interlimb transfer. Here, we examined whether providing movement instances associated with one arm passively while adapting to a visuomotor rotation with the opposite arm could also lead to a greater extent of interlimb transfer. We had subjects perform reaching movements either actively or passively with the right arm while adapting to a 30 degrees visuomotor rotation with the left arm (training session), and then had them perform reaching movements under the rotation condition with the right arm (transfer session). Results showed that the extent of transfer observed in the active and the passive training groups was significantly greater than that observed in a control group who only experienced the testing session. This finding suggests that providing effector-specific instances can increase the extent of interlimb transfer substantially, regardless of whether the instances are provided actively or passively. The current finding may have implications for neurorehabilitation targeted for individuals with motor impairment, such as persons with stroke or spinal cord injury. PMID- 27988344 TI - Combined chondroitinase and KLF7 expression reduce net retraction of sensory and CST axons from sites of spinal injury. AB - Axon regeneration in the central nervous system is limited both by inhibitory extracellular cues and by an intrinsically low capacity for axon growth in some CNS populations. Chondroitin sulfate proteoglycans (CSPGs) are well-studied inhibitors of axon growth in the CNS, and degradation of CSPGs by chondroitinase has been shown to improve the extension of injured axons. Alternatively, axon growth can be improved by targeting the neuron-intrinsic growth capacity through forced expression of regeneration-associated transcription factors. For example, a transcriptionally active chimera of Kruppel-like Factor 7 (KLF7) and a VP16 domain improves axon growth when expressed in corticospinal tract neurons. Here we tested the hypothesis that combined expression of chondroitinase and VP16-KLF7 would lead to further improvements in axon growth after spinal injury. Chondroitinase was expressed by viral transduction of cells in the spinal cord, while VP16-KLF7 was virally expressed in sensory neurons of the dorsal root ganglia or corticospinal tract (CST) neurons. After transection of the dorsal columns, both chondroitinase and VP16-KLF7 increased the proximity of severed sensory axons to the injury site. Similarly, after complete crush injuries, VP16 KLF7 expression increased the approach of CST axons to the injury site. In neither paradigm however, did single or combined treatment with chondroitinase or VP16-KLF7 enable regenerative growth distal to the injury. These results substantiate a role for CSPG inhibition and low KLF7 activity in determining the net retraction of axons from sites of spinal injury, while suggesting that additional factors act to limit a full regenerative response. PMID- 27988347 TI - Tissue-engineered nerve graft with tetramethylpyrazine for repair of sciatic nerve defects in rats. AB - A tissue-engineered nerve with tetramethylpyrazine (TMP) was repaired for sciatic nerve defects in rats. A total of 55 adult Sprague Dawley (SD) rats were classified into 4 groups, with 15 rats in each of groups A, B, and C as well as 10 rats in group D. About 1.5cm of a sciatic nerve of the right hind limb located 0.5cm below the inferior margin of the piriformis was resected to form the defects. Four types of nerve grafts used for bridging nerve defects in the SD rats corresponded to the 4 groups: tissue-engineered nerves with TMP in group A, tissue-engineered nerves without TMP in group B, acellular nerve grafts (ANGs) in group C, and autologous nerves in group D. Twelve weeks post-surgery, the sciatic functional index, nerve conduction velocity, and gastrocnemius wet weight of groups A and D were higher than those of groups B and C (P<0.05). Results of fluorescence microscopy and histological staining indicated that group A performed better than groups B and C (P<0.05). Similarly, the number of horseradish peroxidase-labeled positive cells was significantly larger in group A than in groups B and C. Regenerative nerve fibers were abundant in group A and consisted mainly of myelinated nerve fibers, which were better than those in groups B and C (P<0.05). The study demonstrated that tissue-engineered nerves constructed by ANGs seeded with neural stem cells and combined with TMP can effectively repair sciatic nerve defects in rats. PMID- 27988348 TI - Balance reactions to light touch displacements when standing on foam. AB - We hypothesized that standing on an unstable surface would increase the relevance of light touch to standing balance, such that unexpected displacement of a touch reference would result in more consistent expression of balance corrections, compared to standing on a firm surface. Ten healthy participants stood on a foam block atop a force plate without vision, while lightly touching a reference. The touch plate was unexpectedly displaced forwards 10 times. Responses in tibialis anterior (TA) were observed more frequently across the 10 trials compared with standing on a firm surface. However, the responses evoked in trials 2-10 were functionally distinct from those following the first trial. We suggest the first trial responses represent balance corrective responses induced by the slip of the finger relative to the reference. In contrast, the subsequent responses in TA are likely related to an arm-tracking reaction that emerges, indicating a rapid repurposing of the tactile feedback. PMID- 27988349 TI - Sarsasapogenin reverses depressive-like behaviors and nicotinic acetylcholine receptors induced by olfactory bulbectomy. AB - Cholinergic signalling in the hippocampus may contribute to the aetiology of mood regulation. Antidepressants can reverse the increase in acetylcholinesterase (AChE) activity induced by olfactory bulbectomy. The activation of nicotinic acetylcholine receptors (nAChRs) also alleviates the symptoms of depression. This study advances the development of sarsasapogenin, which interacts with cholinergic signalling and has a favourable antidepressant profile in olfactory bulbectomised (OB) rats. We examined OB-induced changes in cholinergic signalling, as well as AChE, alpha4-nAChR, and alpha7-nAChR expression in the hippocampus. The results indicate that abnormal cholinergic signalling in the hippocampus contributes to the development of depression in the OB rat model. This depression may be alleviated following treatment with sarsasapogenin. PMID- 27988351 TI - Duplication of neuropeptide Y and peptide YY in Nile tilapia Oreochromis niloticus and their roles in food intake regulation. AB - In vertebrates, the neuropeptide Y (NPY) family peptides have been recognized as key players in food intake regulation. NPY centrally promotes feeding, while peptide YY (PYY) and pancreatic polypeptide (PP) mediate satiety. The teleost tetraploidization is well-known to generate duplicates of both NPY and PYY; however, the functional diversification between the duplicate genes, especially in the regulation of food intake, remains unknown. In this study, we identified the two duplicates of NPY and PYY in Nile tilapia (Oreochromis niloticus). Both NPYa and NPYb were primarily expressed in the central nervous system (CNS), but the mRNA levels of NPYb were markedly lower than those of NPYa. Hypothalamic mRNA expression of NPYa, but not NPYb, decreased after feeding and increased after 7 days of fasting. However, both NPYa and NPYb caused a significant increase in food intake after an intracranial injection of 50ng/g body weight dose. PYYb, one of the duplicates of PYY, had an extremely high expression in the foregut and midgut, whereas another form of duplicate PYYa showed only moderate expression in the CNS. Both hypothalamic PYYa and foregut PYYb mRNA expression increased after feeding and decreased after 7-days of fasting. Furthermore, the intracranial injection of PYYb decreased food intake, but PYYa had no significant effect. Our results suggested that although the mature peptides of NPYa and NPYb can both stimulate food intake, NPYa is the main endogenous functional NPY for feeding regulation. A functional division has been identified in the duplicates of PYY, which deems PYYb as a gut-derived anorexigenic peptide and PYYa as a CNS-specific PYY in Nile tilapia. PMID- 27988350 TI - Quantitative proteomics analysis of cartilage response to mechanical injury and cytokine treatment. AB - Mechanical damage at the time of joint injury and the ensuing inflammatory response associated with elevated levels of pro-inflammatory cytokines in the synovial fluid, are reported to contribute to the progression to osteoarthritis after injury. In this exploratory study, we used a targeted proteomics approach to follow the progression of matrix degradation in response to mechanical damage and cytokine treatment of human knee cartilage explants, and thereby to study potential molecular biomarkers. This proteomics approach allowed us to unambiguously identify and quantify multiple peptides and proteins in the cartilage medium and explants upon treatment with +/-injurious compression +/ cytokines, treatments that mimic the earliest events in post-traumatic OA. We followed degradation of different protein domains, e.g., G1/G2/G3 of aggrecan, by measuring representative peptides of matrix proteins released into the medium at 7 time points throughout the 21-day culture period. COMP neo-epitopes, which were previously identified in the synovial fluid of knee injury/OA patients, were also released by these human cartilage explants treated with cyt and cyt+inj. The absence of collagen pro-peptides and elevated levels of specific COMP and COL3A1 neo-epitopes after human knee trauma may be relevant as potential biomarkers for post-traumatic OA. This model system thereby enables study of the kinetics of cartilage degradation and the identification of biomarkers within cartilage explants and those released to culture medium. Discovery proteomics revealed that candidate proteases were identified after specific treatment conditions, including MMP1, MMP-3, MMP-10 and MMP-13. PMID- 27988352 TI - Increased plasma orexin-A levels in patients with insomnia disorder are not associated with prepro-orexin or orexin receptor gene polymorphisms. AB - Orexins, also known as hypocretins, play a regulatory role in the sleep-wake cycle by activating orexin receptors. Previous animal studies have shown that sleep deprivation can elevate orexinergic peptide levels. However, the relationship between insomnia disorder and orexin-A levels in humans has not been explored. In the current study, we examined plasma orexin-A levels in patients with insomnia disorder and in normal sleepers. We also studied the possible mechanisms underlying changes in orexin-A levels between the study groups; this included investigations of prepro-orexin and orexin receptor gene polymorphisms as well as exploration of other variables. We measured plasma orexin-A levels in 228 patients with insomnia disorder and 282 normal sleepers. The results indicated that the patients with insomnia disorder had significantly higher orexin-A levels than normal sleepers (63.42+/-37.56 vs. 54.84+/-23.95pg/ml). A positive relationship was detected between orexin-A level and age in patients with insomnia disorder. Orexin-A levels were elevated in relation to course of insomnia, as well as in relation to increased Insomnia Severity Index score. None of the evaluated prepro-orexin gene single nucleotide polymorphisms were informative between the two study populations. After sequencing all orexin receptor exons, one variation (rs2271933) in the OX1R gene and one variation (rs2653349) in the OX2R gene were found. However, no significant differences were found in either genotypic or allelic frequency distributions between the two study groups. It is suggested that the increased plasma orexin-A levels in patients with insomnia disorder are associated with the course and severity of insomnia, but not with prepro-orexin and orexin receptor gene polymorphisms. PMID- 27988353 TI - The effects of urotensin II on migration and invasion are mediated by NADPH oxidase-derived reactive oxygen species through the c-Jun N-terminal kinase pathway in human hepatoma cells. AB - AIMS: Urotensin II (UII) is a vasoactive neuropeptide involved in migration and invasion in various cell types. However, the effects of UII on human hepatoma cells still remain unclear. The aim of this study was to investigate the role and mechanism of UII on migration and invasion in human hepatoma cells. METHODS: Migration was measured by wound healing assays and a Transwell(r) methodology, and invasion was analyzed using Matrigel(r) invasion chambers. Reactive oxygen species (ROS) levels were detected using a 2', 7'-dichlorofluorescein diacetate probe, and flow cytometry, and protein expression levels were evaluated by western blotting. Cell proliferation and actin polymerization were examined using cell proliferation reagent WST-1 and F-actin immunohistochemistry staining. RESULTS: Exposure to UII promoted migration and invasion in hepatoma cells compared with that in cells without UII. UII also increased matrix metalloproteinase-2 (MMP2) expression in a time-independent manner. Furthermore, UII markedly enhanced ROS generation and NADPH oxidase subunit expression, and consequently facilitated the phosphorylation of c-Jun N-terminal kinase (JNK). The UT antagonist urantide or the antioxidant/NADPH oxidase inhibitor apocynin decreased UII-induced ROS production. JNK phosphorylation, migration, invasion, and MMP9/2 expression were also reversed by pretreatment with apocynin. Urantide and JNK inhibitor SP600125 abrogated migration, invasion, or MMP9/2 expression in response to UII. UII induced actin polymerization and fascin protein expression, and could be reversed by apocynin and SP600125. CONCLUSIONS: Exogenous UII induced migration and invasion in hepatoma cells that mainly involved NADPH oxidase-derived ROS through JNK activation. UT played an additional role in regulating hepatoma cells migration and invasion. Thus, our data suggested an important effect of UII in hepatocellular carcinoma metastasis. PMID- 27988354 TI - The anti-tumor effects of the recombinant toxin protein rLj-RGD3 from Lampetra japonica on pancreatic carcinoma Panc-1 cells in nude mice. AB - Recombinant Lampetra japonica RGD peptide (rLj-RGD3) is a soluble toxin protein with three RGD (Arg-Gly-Asp) motifs and a molecular weight of 13.5kDa. The aim of this study was to investigate the effects and mechanisms of rLj-RGD3 on tumor growth and survival in pancreatic carcinoma Panc-1 cell-bearing mice. A Panc-1 human pancreatic carcinoma-bearing nude mouse model was successfully generated, and the animals were treated with different doses of rLj-RGD3 for 3 weeks. The volume and weight of the subcutaneous tumors, the survival of the nude mice, histopathological changes, the intratumoral MVD, the number of apoptotic Panc-1 cells, and apoptosis-related proteins and gene expressions were determined. rLj RGD3 significantly decreased the tumor volumes and weights, and the maximum tumor volume and weight IR values were 53.2% (p<0.001) and 55.9% (p<0.001), respectively. The life expectancy of Panc-1-bearing nude mice treated with rLj RGD3 was increased by 56.3% (p<0.001). Meanwhile, rLj-RGD3 promoted the expression of Bax, caspase-3, and caspase-9 and inhibited Bcl-2 and VEGF expression. In addition, rLj-RGD3 did not change FAK, PI3K and Akt expression, but p-FAK, p-PI3K and p-Akt, levels were down-regulated. These results show that rLj-RGD3 induced potent anti-tumor activity in vivo and suppressed the growth of transplanted Panc-1 cells in a nude mouse model, implying that rLj-RGD3 may serve as a potent clinical therapeutic agent for human pancreatic carcinoma. PMID- 27988355 TI - Agmatine modulates melanogenesis via MITF signaling pathway. AB - Agmatine contained in soybean is also found in Manaca, an anti-aging plant, inhabited in Amazon and induces vasodilation by the promotion of NO synthesis in blood vessel. However, the research of agmatine on melanin synthesis related to hair greying is lacking. The aim of this study was to investigate the melanogenic effect of agmatine via regulation of MITF signaling pathway in B16F1 cells. It was determined whether agmatine regulates melanin synthesis at cellular level in addition to the effect of agmatine on mushroom tyrosinase in vitro in the presence of different concentrations of agmatine. Furthermore, the effect of agmatine on the protein expressions of tyrosinase, TRP-1, TRP-2, BMP-4, BMP-6, C KIT, p-p38, MITF and C-FOS were examined by western blot analysis. In addition, immunofluorescence staining was carried out to visualize the location of MITF expression in cell. Agmatine at 256MUM or more increased melanin synthesis as well as tyrosinase activity. Moreover, whereas agmatine increased the expression levels of TRP-1, BMP-6, p-p38 and MITF, it reduced the expression level of BMP-4. It was also found that agmatine enhanced the expression level of MITF in nucleus. These results suggest that agmatine could induce melanin synthesis though the regulation of MITF transcription factor via BMP-6/p38 signaling pathway. PMID- 27988356 TI - Race-ethnicity on blood pressure control after ischemic stroke: a prospective cohort study. AB - Disparities in health care access and socioeconomic status (SES) have been associated with racial-ethnic differences in blood pressure (BP) control. We examined post-ischemic stroke BP in a multiethnic cohort with good health care access. We included all hypertensive patients (n = 2972) from a randomized quality improvement trial on secondary stroke prevention, conducted in 14 Kaiser Permanente hospitals in Northern California from 2004-2006 (QUISP). Average age 73.2 +/- 12.2 years; 52% female, 66% non-Hispanic white, 14% African-American, 11% Asian, 8% Hispanic, and 1% other. Demographics, diagnoses, health care utilization, BP measurements, and medications were obtained as part of routine care. We used random effects logistic regression models to examine race as a predictor of blood pressure control (<140/90 mm Hg) at 6 months post-discharge, adjusted for SES, age, gender, dementia, antihypertensive therapy, and attendance at follow-up visits. At 6 months, BP was controlled in 52.7% of blacks compared to 61.4% of whites (OR = 0.63, 95% CI, 0.48-0.82, P = .001). Black race remained independently associated with poorer BP control in adjusted analysis, although blacks were as likely to attend post-discharge visits, and more likely to be on any antihypertensive therapy than whites. Greater difficulty in controlling BP and lifestyle differences may account for this difference. PMID- 27988357 TI - Recombinant alpha-1-microglobulin: a potential treatment for preeclampsia. AB - Preeclampsia is a serious pregnancy-specific condition, affecting 10 million women annually worldwide. No specific treatment is currently available. Recent studies have demonstrated abnormal production and accumulation of free fetal hemoglobin in the preeclamptic placenta, and identified subsequent leakage into the maternal circulation as an important factor in the development of preeclampsia. A recombinant version of alpha-1-microglobulin, an endogenous well characterized heme and radical scavenger, has been developed. Intravenous administration of recombinant alpha-1-microglobulin in animal models has been proved to eliminate or significantly reduce the manifestations of preeclampsia. Recombinant alpha-1-microglobulin has the potential to become the first specific therapy for preeclampsia. PMID- 27988358 TI - Feature selection in clinical proteomics: with great power comes great reproducibility. AB - In clinical proteomics, reproducible feature selection is unattainable given the standard statistical hypothesis-testing framework. This leads to irreproducible signatures with no diagnostic power. Instability stems from high P-value variability (p_var), which is inevitable and insolvable. The impact of p_var can be reduced via power increment, for example increasing sample size and measurement accuracy. However, these are not realistic solutions in practice. Instead, workarounds using existing data such as signal boosting transformation techniques and network-based statistical testing is more practical. Furthermore, it is useful to consider other metrics alongside P-values including confidence intervals, effect sizes and cross-validation accuracies to make informed inferences. PMID- 27988360 TI - Targeted delivery for regenerative medicines: an untapped opportunity for drug conjugates. AB - Regenerative approaches are promising avenues to effectively cure diseases rather than merely treating symptoms, but are associated with concerns around proliferation in other organs. Given that targeted delivery holds the promise of delivering a drug precisely to its desired site of action, usually with the prospect of increasing the therapeutic index, it can be considered as an essential enabler of regenerative medicines. Although significant progress has been made predominantly in oncology for the delivery of cytotoxic drugs using antibody-drug conjugates (ADCs), the physiological conditions and safety requirements for regenerative medicines are very different. Drug conjugates need to be approached differently and, we herein suggest using a broader range of homing modalities and a specific framework to develop safe linkers. PMID- 27988359 TI - Targeting amino acid metabolism for cancer therapy. AB - To support sustained biomass accumulation, tumor cells undergo metabolic reprogramming. Nutrient transporters and metabolic enzymes are regulated by the same oncogenic signals that drive cell-cycle progression. Some of the earliest cancer therapies used antimetabolites to disrupt tumor metabolism, and there is now renewed interest in developing drugs that target metabolic dependencies. Many cancers exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis. Strategies to exploit such 'metabolic addictions' include depleting amino acids in blood serum, blocking uptake by transporters and inhibiting biosynthetic or catabolic enzymes. Recent findings highlight the importance of using appropriate model systems and identifying target patient groups as potential therapies advance into the clinic. PMID- 27988361 TI - Molecular modifications by regulating cAMP signaling and oxidant-antioxidant defence mechanisms, produce antidepressant-like effect: A possible mechanism of etazolate aftermaths of impact accelerated traumatic brain injury in rat model. AB - Traumatic brain injury (TBI) is one of the leading cause of psychiatric conditions in patients, amongst which, depression and anxiety are more frequent. Despite the preclinical antidepressant-like effects, clinical development of Phospodiesterase-4 (PDE4) enzyme inhibitors has been hampered due to serious side effect profiles, such as nausea and vomiting. Etazolate (ETZ) is a new generation PDE4 inhibitor with encouraging safety and tolerance profiles. In our previous studies we have addressed that ETZ produces antidepressant-like effects in animal models of depression, however, the underlying mechanism(s) following TBI have not been completely explored. Impact accelerated TBI by weight drop method causes depression-like behavioral deficits in modified open field exploration, hyper emotionality and sucrose consumption paradigms. TBI not only causes immediate mechanical damage to the brain, but also induces biochemical changes that lead to delayed neural cell loss leading to a secondary injury. The present study examines the antidepressant effects of ETZ on the TBI-induced depression-like behavior deficits and attempts to explore the underlying mechanism. In order to understand the underlying pathology of TBI and mechanism(s) of ETZ in TBI molecular markers namely, brain cAMP, cAMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) were estimated. Additionally, the level of oxidative (lipid peroxidation) & nitrosative (nitrite) stress markers, along with antioxidant enzymes markers, such as, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were measured. Furthermore, the involvement of hypothalamic-pituitary adrenal (HPA) axis activity in underlying mechanism was also investigated by measuring serum corticosterone (CORT) level. The results revealed that TBI significantly altered cAMP, pCREB and BDNF levels. Moreover, a significant increase in oxidative nitrosative stress markers levels, while, significant decreases in antioxidant enzymes markers level were observed. However, no significant change was observed in serum CORT level. Chronic ETZ (0.5 and 1 mg/kg) treatment significantly attenuated TBI-induced behavioral deficits and restored the TBI induced derangements in molecular and biochemical markers. This study indicates that ETZ modulates cAMP signaling and oxidative/antioxidant markers in the TBI model suggesting its prospect as a potential candidate for the pharmacotherapy of depression. PMID- 27988362 TI - Appropriate use criteria for transesophageal echocardiography in Greece: A single center experience. AB - INTRODUCTION: The American College of Cardiology Foundation (ACCF) along with the American Society of Echocardiography (ASE) have enabled an accurate and clinically oriented evaluation of echocardiography indications by introducing Appropriate Use Criteria (AUC). AIM: This study was designed to evaluate the degree of implementation of AUC for transesophageal echocardiography (TEE) during daily clinical practice in a tertiary university hospital in Greece during the era of economic recession. MATERIALS AND METHODS: From November 2014 to May 2014, we prospectively enrolled 300 patients who were examined in the Echocardiography Laboratory of the First University Cardiology. We recorded the participants' demographic and clinical characteristics using questionnaires and followed a scoring process according to ACCF guidelines to classify patients into an appropriate, inappropriate or uncertain category. The primary endpoint was to assess the association between the class of appropriateness and abnormal TEE results. RESULTS: In 89.4% of patients labelled appropriate, TEE was abnormal and significantly higher compared to patients of uncertain eligibility (50%) and to patients for whom TEE was considered to be inappropriate (35%) (p < 0.001). Subgroup analysis revealed a positive association between AUC and an increased possibility for abnormal TEE in female subjects (p = 0.001) as well as in patients who were younger than 50 years old (p < 0.001). A significant association was finally established between AUC and abnormal findings in TEE in patients with no risk factors (p = 0.028) and in patients with more than 3 risk factors (p = 0.013). CONCLUSION: TEE constitutes a medical practice with an optimal cost/effectiveness ratio and should be further encouraged in our country in accordance with the austerity policy as long as the AUC are generally applied. PMID- 27988363 TI - In vitro antiglioma action of indomethacin is mediated via AMP-activated protein kinase/mTOR complex 1 signalling pathway. AB - We investigated the role of the intracellular energy-sensing AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in the in vitro antiglioma effect of the cyclooxygenase (COX) inhibitor indomethacin. Indomethacin was more potent than COX inhibitors diclofenac, naproxen, and ketoprofen in reducing the viability of U251 human glioma cells. Antiglioma effect of the drug was associated with p21 increase and G2M cell cycle arrest, as well as with oxidative stress, mitochondrial depolarization, caspase activation, and the induction of apoptosis. Indomethacin increased the phosphorylation of AMPK and its targets Raptor and acetyl-CoA carboxylase (ACC), and reduced the phosphorylation of mTOR and mTOR complex 1 (mTORC1) substrates p70S6 kinase and PRAS40 (Ser183). AMPK knockdown by RNA interference, as well as the treatment with the mTORC1 activator leucine, prevented indomethacin-mediated mTORC1 inhibition and cytotoxic action, while AMPK activators metformin and AICAR mimicked the effects of the drug. AMPK activation by indomethacin correlated with intracellular ATP depletion and increase in AMP/ATP ratio, and was apparently independent of COX inhibition or the increase in intracellular calcium. Finally, the toxicity of indomethacin towards primary human glioma cells was associated with the activation of AMPK/Raptor/ACC and subsequent suppression of mTORC1/S6K. By demonstrating the involvement of AMPK/mTORC1 pathway in the antiglioma action of indomethacin, our results support its further exploration in glioma therapy. PMID- 27988364 TI - Rice Chitin Receptor OsCEBiP Is Not a Transmembrane Protein but Targets the Plasma Membrane via a GPI Anchor. PMID- 27988365 TI - BKI1 Regulates Plant Architecture through Coordinated Inhibition of the Brassinosteroid and ERECTA Signaling Pathways in Arabidopsis. AB - Hundreds of leucine-rich repeat receptor-like kinases (LRR-RLKs) play indispensable roles in a wide range of plant developmental and physiological processes. The mechanisms controlling LRR-RLKs at a basal and inactive status are essential but rarely studied. BKI1 is the only reported inhibitor of receptor kinases in Arabidopsis, which negatively regulates BRI1 in the brassinosteroid pathway. In this study, we found that BKI1 can also interact with another important LRR-RLK, ERECTA (ER). Phenotypic analysis showed that BKI1 and ER together regulate plant architecture, including pedicel orientation, which is a newly reported phenotype in the BR- and ER-mediated developmental processes. Gene expression analysis revealed that BKI1 regulates a subset of ER-responsive genes. Kinase assays demonstrated that BKI1 inhibits ER kinase activity. In addition, the release of BKI1 inhibition on ER signaling relies largely on BRI1 activation. Our data provide significant insights into the regulation and activation of RLKs and suggest that BKI1 functions as a common suppressor of the BRI1 and ER signaling pathways. PMID- 27988366 TI - Higher sensitivity to sweet and salty taste in obese compared to lean individuals. AB - Although putatively taste has been associated with obesity as one of the factors governing food intake, previous studies have failed to find a consistent link between taste perception and Body Mass Index (BMI). A comprehensive comparison of both thresholds and hedonics for four basic taste modalities (sweet, salty, sour, and bitter) has only been carried out with a very small sample size in adults. In the present exploratory study, we compared 23 obese (OB; BMI > 30), and 31 lean (LN; BMI < 25) individuals on three dimensions of taste perception - recognition thresholds, intensity, and pleasantness - using different concentrations of sucrose (sweet), sodium chloride (NaCl; salty), citric acid (sour), and quinine hydrochloride (bitter) dissolved in water. Recognition thresholds were estimated with an adaptive Bayesian staircase procedure (QUEST). Intensity and pleasantness ratings were acquired using visual analogue scales (VAS). It was found that OB had lower thresholds than LN for sucrose and NaCl, indicating a higher sensitivity to sweet and salty tastes. This effect was also reflected in ratings of intensity, which were significantly higher in the OB group for the lower concentrations of sweet, salty, and sour. Calculation of Bayes factors further corroborated the differences observed with null-hypothesis significance testing (NHST). Overall, the results suggest that OB are more sensitive to sweet and salty, and perceive sweet, salty, and sour more intensely than LN. PMID- 27988367 TI - Is there an association between food patterns and life satisfaction among Norway's inhabitants ages 65 years and older? AB - The lack of information regarding older adults' health and lifestyles makes it difficult to design suitable interventions for people at risk of developing unhealth lifestyles. Therefore, there is a need to increase knowledge about older adults' food patterns and quality of life. Our aim was to determine associations among food patterns, anxiety, depression, and life satisfaction in Norwegian inhabitants ages 65+. The Nord-Trondelag Health Study (The HUNT Study) is a large, population-based cohort study that includes data for 125 000 Norwegian participants. The cohort used for this study is wave three of the study, consisting of 11 619 participants age 65 and over. Cluster analysis was used to categorize the participants based on similarities in food consumption; two clusters were identified based on similarities regarding food consumption among participants. Significant differences between the clusters were found, as participants in the healthy food-patterns cluster had higher life satisfaction and lower anxiety and depression than those in the unhealthy food-patterns cluster. The associations among food patterns, anxiety, depression, and life satisfaction among older adults show the need for increased focus on interactions among food patterns, food consumption, and life satisfaction among the elderly in order to explore how society can influence these patterns. PMID- 27988368 TI - Conditioned flavor preferences in animals: Merging pharmacology, brain sites and genetic variance. AB - The elucidation of the behavioral, neurochemical, neuroanatomical and genetic substrates mediating the development of conditioned flavor preferences (CFP) is one of the multi-faceted scientific contributions that Dr. Anthony Sclafani has made to the study of food intake. This review summarizes the results of thirty five publications over nearly twenty years of collaborations between the Sclafani and Bodnar laboratories. This includes the different approaches employed to study the orosensory (flavor-flavor) and post-ingestive (flavor-nutrient) processes underlying CFP including its acquisition (learning) and expression. It describes how CFP is elicited by different sugars (sucrose, glucose, fructose) and fats (corn oil) in rats, and how strain-specific CFP effects can be observed through the use of inbred mouse strains to evaluate genetic variance. The roles of pharmacological substrates (dopamine, glutamate, opioids, acetylcholine, GABA, cannabinoids) mediating sugar- and fat-CFP acquisition and expression are elucidated. Finally, neuroanatomical sites of action (nucleus accumbens, amygdala, medial prefrontal and orbital frontal cortices, lateral hypothalamus) are evaluated at which dopamine signaling mediates acquisition and expression of different forms of CFP. PMID- 27988369 TI - Factors for consumer choice of dairy products in Iran. AB - Little is known about consumers' behavior especially their choice behavior toward purchasing and consuming dairy products in developing countries. Hence, the aim of the present work is understanding the factors that affect on consumers' choice behavior toward dairy products in Iran. The study applies the theory of consumption values, which includes the functional values (taste, price, health, and body weight), social value, emotional value, conditional value and epistemic value. The sample were 1420 people (men and women). The data was collected using face to face survey in summer and fall 2015. Chi-square, confirmatory factor analysis, and structural equation modelling is used to assess data collected. The results indicate that functional values, social value, emotional value and epistemic value have a positive impact on choosing dairy products and conditional value didn't have a positive impact. It was concluded that the main influential factors for consumers' choice behavior toward dairy products included consumers experience positive emotion (e.g. enjoyment, pleasure, comfort and feeling relaxed) and functional value-health. This study emphasized the proper pricing of dairy products by producers and sellers. PMID- 27988370 TI - "Chip off the old block"-Do genetic factors contribute to postoperative heart block? PMID- 27988372 TI - A long RP supraventricular tachycardia: What is the mechanism? PMID- 27988373 TI - Cost-effectiveness of interventions for treating anxiety disorders: A systematic review. AB - BACKGROUND: Anxiety disorders are highly prevalent mental disorders that constitute a major burden on patients and society. As a consequence, economic evaluations of the interventions have become increasingly important. However, no recent overview of these economic evaluations is currently available and the quality of the published economic evaluations has not yet been assessed. Therefore, the current study has two aims: to provide an overview of the evidence regarding the cost-effectiveness of interventions for anxiety disorders, and to assess the quality of the studies identified. METHODS: A systematic review was conducted using PubMed, PsycINFO, NHS-EED, and the CEA registry. We included full economic evaluations on interventions for all anxiety disorders published before April 2016, with no restrictions on study populations and comparators. Preventive interventions were excluded. Study characteristics and cost-effectiveness data were collected. The quality of the studies was appraised using the Consensus on Health Economic Criteria. RESULTS: Forty-two out of 826 identified studies met the inclusion criteria. The studies were heterogeneous and the quality was variable. Internet-delivered cognitive behavioural therapy (iCBT) appeared to be cost-effective in comparison with the control conditions. Four out of five studies comparing psychological interventions with pharmacological interventions showed that psychological interventions were more cost-effective than pharmacotherapy. LIMITATIONS: Comparability was limited by heterogeneity in terms of interventions, study design, outcome and study quality. CONCLUSIONS: Forty-two studies reporting cost-effectiveness of interventions for anxiety disorders were identified. iCBT was cost-effective in comparison with the control conditions. Psychological interventions for anxiety disorders might be more cost-effective than pharmacological interventions. PMID- 27988374 TI - Safety of warfarin in "high-risk" populations: A meta-analysis of randomized and controlled trials. AB - INTRODUCTION: Few data are available about safety of vitamin K antagonists (VKAs) in patients with clinical/demographic characteristics predisposing to an increased risk of bleeding. We performed a meta-analysis to evaluate the safety of VKAs in patients with atrial fibrillation (AF) or venous thromboembolism (VTE) in the following subgroups of "high-risk" patients: elderly patients, patients with low body weight and patients with impaired renal function. MATERIALS AND METHODS: Major electronic databases were systematically searched to identify randomized controlled trials (RCTs) addressing this issue. Pooled Risk Ratios (RR) and 95% Confidence Intervals (CI) were calculated for each outcome using a random effects model. RESULTS: Eleven RCTs for a total of 41,015 patients treated with VKAs (25,901 with AF and 15,114 with VTE) were included. We found a significant association between age>75years and bleeding in patients receiving VKAs (RR: 1.62, 95%CI: 1.28-2.05; P<0.0001). Moreover, the prevalence of bleeding events under VKAs was significantly higher in patients with low body weight (RR: 1.20, 95%CI: 1.03-1.40; P=0.02) and in those with impaired renal function (RR: 1.59, 95%CI: 1.30-1.94; P<0.00001). Results were confirmed when separately analyzing data on AF and VTE. Regression models showed that treatment duration did not impact on the differences found in the safety profile of VKAs in different settings analyzed. CONCLUSIONS: Results of our meta-analysis suggest an increased risk of bleeding complications in "high-risk" patients. Although all results are significant, other studies focused on this issue are warranted to further validate these results. PMID- 27988375 TI - Reciprocal links between venous thromboembolism, coagulation factors and ovarian cancer progression. AB - Ovarian cancer is the most lethal gynecological malignancy, which is due to late presentation. Treating advanced stage ovarian cancer is difficult, and tumor recurrence and chemoresistance frequently occur. In addition, early detection remains a major challenge as there are no early warning signs and no appropriate biomarkers. To reduce mortality rates of ovarian cancer patients, novel drug targets and biomarkers are needed. We postulate that hemostatic keyplayers are of importance when combatting ovarian cancer. The majority of ovarian cancer patients have abnormal hemostatic blood serum marker levels, which indicate an activated coagulation system. This makes patients more prone to experiencing venous thromboembolism (VTE), and the occurrence of VTE in ovarian cancer patients adversely affects survival. Coagulation activation also promotes tumor progression as it influences tumor biology at several stages and the decreased survival rates associated with ovarian cancer-associated thrombosis are more likely due to cancer metastasis rather than to fatal thromboembolic events. In this review, we will discuss; (1) Population studies that address the bidirectional relationship between VTE and ovarian cancer, and the most important risk factors involved; (2) The mechanisms of coagulation factors and platelets that are critically involved in the development of VTE, and the progression of ovarian cancer; (3) Roles and future directions of coagulation factors in ovarian cancer therapy, and in diagnosis and prognosis of ovarian cancer as biomarkers. PMID- 27988371 TI - Fine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations. AB - BACKGROUND: The electrocardiographically measured QT interval (QT) is heritable and its prolongation is an established risk factor for several cardiovascular diseases. Yet, most QT genetic studies have been performed in European ancestral populations, possibly reducing their global relevance. OBJECTIVE: To leverage diversity and improve biological insight, we fine mapped 16 of the 35 previously identified QT loci (46%) in populations of African American (n = 12,410) and Hispanic/Latino (n = 14,837) ancestry. METHODS: Racial/ethnic-specific multiple linear regression analyses adjusted for heart rate and clinical covariates were examined separately and in combination after inverse-variance weighted trans ethnic meta-analysis. RESULTS: The 16 fine-mapped QT loci included on the Illumina Metabochip represented 21 independent signals, of which 16 (76%) were significantly (P-value<=9.1*10-5) associated with QT. Through sequential conditional analysis we also identified three trans-ethnic novel SNPs at ATP1B1, SCN5A-SCN10A, and KCNQ1 and three Hispanic/Latino-specific novel SNPs at NOS1AP and SCN5A-SCN10A (two novel SNPs) with evidence of associations with QT independent of previous identified GWAS lead SNPs. Linkage disequilibrium patterns helped to narrow the region likely to contain the functional variants at several loci, including NOS1AP, USP50-TRPM7, and PRKCA, although intervals surrounding SLC35F1-PLN and CNOT1 remained broad in size (>100 kb). Finally, bioinformatics-based functional characterization suggested a regulatory function in cardiac tissues for the majority of independent signals that generalized and the novel SNPs. CONCLUSION: Our findings suggest that a majority of identified SNPs implicate gene regulatory dysfunction in QT prolongation, that the same loci influence variation in QT across global populations, and that additional, novel, population-specific QT signals exist. PMID- 27988376 TI - In-line monitoring of compaction properties on a rotary tablet press during tablet manufacturing of hot-melt extruded amorphous solid dispersions. AB - As the number of applications for polymers in pharmaceutical development is increasing, there is need for fundamental understanding on how such compounds behave during tableting. This research is focussed on the tableting behaviour of amorphous polymers, their solid dispersions and the impact of hot-melt extrusion on the compaction properties of these materials. Soluplus, Kollidon VA 64 and Eudragit EPO were selected as amorphous polymers since these are widely studied carriers for solid dispersions, while Celecoxib was chosen as BCS class II model drug. Neat polymers and physical mixtures (up to 35% drug load) were processed by hot-melt extrusion (HME), milled and sieved to obtain powders with comparable particle sizes as the neat polymer. A novel approach was used for in-line analysis of the compaction properties on a rotary tablet press (Modul P, GEA) using complementary sensors and software (CDAAS, GEA). By combining 'in-die' and 'out-of-die' techniques, it was possible to investigate in a comprehensive way the impact of HME on the tableting behaviour of amorphous polymers and their formulations. The formation of stable glassy solutions altered the formulations towards more fragmentary behaviour under compression which was beneficial for the tabletability. Principal component analysis (PCA) was applied to summarize the behaviour during compaction of the formulations, enabling the selection of Soluplus and Kollidon VA 64 as the most favourable polymers for compaction of glassy solutions. PMID- 27988377 TI - Fabrication and characterisation of drug-loaded electrospun polymeric nanofibers for controlled release in hernia repair. AB - The chemical distribution and mechanical effects of drug compounds in loaded electrospun scaffolds, a potential material for hernia repair mesh, were characterised and the efficacy of the material was evaluated. Polycaprolactone electrospun fibres were loaded with either the antibacterial agent, irgasan, or the broad-spectrum antibiotic, levofloxacin. The samples were subsequently characterised by rheological studies, scanning electron microscopy (SEM), atomic force microscopy (AFM), contact angle goniometry (CAG), in vitro drug release studies, antibacterial studies and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Increased linear viscoelastic regions observed in the rheometry studies suggest that both irgasan and levofloxacin alter the internal structure of the native polymeric matrix. In vitro drug release studies from the loaded polymeric matrix showed significant differences in release rates for the two drug compounds under investigation. Irgasan showed sustained release, most likely driven by molecular diffusion through the scaffold. Conversely, levofloxacin exhibited a burst release profile indicative of phase separation at the edge of the fibres. Two scaffold types successfully inhibited bacterial growth when tested with strains of E. coli and S. aureus. Electrospinning drug-loaded polyester fibres is an alternative, feasible and effective method for fabricating non-woven fibrous meshes for controlled release in hernia repair. PMID- 27988378 TI - Cancer therapeutics with epigallocatechin-3-gallate encapsulated in biopolymeric nanoparticles. AB - With the recent quantum leap in chemoprevention by dietary products, their use as cancer therapeutics is garnering worldwide attention. The concept of effortlessly fighting this deadly disease by gulping cups of green tea or swallowing green tea extract capsules is appreciated universally. Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, has generated significant interest in controlling carcinogenesis due to its growth-inhibitory efficacy against a variety of cancers by targeting multiple signaling pathways. However, the success of EGCG in preclinical studies is difficult to translate into clinical trials due to issues of low solubility, bioavailability and an uncertain therapeutic window. The laborious and expensive journey of drugs from the laboratory to commercialization can be improved by utilizing nanoparticles as anti-cancer drug carriers. Exploitation of biopolymeric nanoparticles in recent years has improved EGCG's biodistribution, stability and tumor selectivity, revealing its superior chemopreventive effects. This review briefly summarizes recent developments regarding the targets and side effects of EGCG, complications associated with its low bioavailability and critically analyses the application of biopolymeric nanoparticles encapsulating EGCG as a next generation delivery systems. PMID- 27988379 TI - Raloxifene microsphere-embedded collagen/chitosan/beta-tricalcium phosphate scaffold for effective bone tissue engineering. AB - Engineering novel scaffolds that can mimic the functional extracellular matrix (ECM) would be a great achievement in bone tissue engineering. This paper reports the fabrication of novel collagen/chitosan/beta-tricalcium phosphate (CCTP) based tissue engineering scaffold. In order to improve the regeneration ability of scaffold, we have embedded raloxifene (RLX)-loaded PLGA microsphere in the CCTP scaffold. The average pore of scaffold was in the range of 150-200MUm with ideal mechanical strength and swelling/degradation characteristics. The release rate of RLX from the microsphere (MS) embedded scaffold was gradual and controlled. Also a significantly enhanced cell proliferation was observed in RLX-MS exposed cell group suggesting that microsphere/scaffold could be an ideal biomaterial for bone tissue engineering. Specifically, RLX-MS showed a significantly higher Alizarin red staining indicating the higher mineralization capacity of this group. Furthermore, a high alkaline phosphatase (ALP) activity for RLX-MS exposed group after 15days incubation indicates the bone regeneration capacity of MC3T3-E1 cells. Overall, present study showed that RLX-loaded microsphere embedded scaffold has the promising potential for bone tissue engineering applications. PMID- 27988380 TI - Salinity alters snakeskin and mesh transcript abundance and permeability in midgut and Malpighian tubules of larval mosquito, Aedes aegypti. AB - This study examined the distribution and localization of the septate junction (SJ) proteins snakeskin (Ssk) and mesh in osmoregulatory organs of larval mosquito (Aedes aegypti), as well as their response to altered environmental salt levels. Ssk and mesh transcripts and immunoreactivity were detected in tissues of endodermal origin such as the midgut and Malpighian tubules of A. aegypti larvae, but not in ectodermally derived hindgut and anal papillae. Immunolocalization of Ssk and mesh in the midgut and Malpighian tubules indicated that both proteins are concentrated at regions of cell-cell contact between epithelial cells. Transcript abundance of ssk and mesh was higher in the midgut and Malpighian tubules of brackish water (BW, 30% SW) reared A. aegypti larvae when compared with freshwater (FW) reared animals. Therefore, [3H]polyethylene glycol (MW 400Da, PEG-400) flux was examined across isolated midgut and Malpighian tubule preparations as a measure of their paracellular permeability. It was found that PEG-400 flux was greater across the midgut of BW versus FW larvae while the Malpighian tubules of BW-reared larvae had reduced PEG-400 permeability in conjunction with increased Cl- secretion compared to FW animals. Taken together, data suggest that Ssk and mesh are found in smooth SJs (sSJs) of larval A. aegypti and that their abundance alters in association with changes in epithelial permeability when larvae reside in water of differing salt content. This latter observation suggests that Ssk and mesh play a role in the homeostatic control of salt and water balance in larval A. aegypti. PMID- 27988381 TI - Achalasia Caused by a Peptic Stricture. PMID- 27988383 TI - Low Risk of High-Grade Dysplasia or Esophageal Adenocarcinoma Among Patients With Barrett's Esophagus Less Than 1 cm (Irregular Z Line) Within 5 Years of Index Endoscopy. AB - BACKGROUND & AIMS: Many patients with a < 1 cm segment of columnar metaplasia in the distal esophagus, also called an irregular Z line, are encountered. These patients, often referred to as patients with Barrett's esophagus (BE), are enrolled in surveillance programs. However, little is known about their risk of high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC). We aimed to determine the incidence of HGD and EAC in patients with irregular Z line with intestinal metaplasia. METHODS: We performed a prospective, multicenter cohort study of patients who underwent endoscopic examination for BE at tertiary care referral centers in the United States and Europe. We analyzed data from 1791 patients (mean age, 56 +/- 17 years) found to have non-dysplastic BE at the index endoscopy and after 1 year or more of follow-up. Patients were followed for a median of 5.9 years (interquartile range, 3.1-8.3 years). We calculated rates of progression to HGD or EAC between groups of patients with irregular Z line (n = 167) and those with BE of >= 1 cm (n = 1624). RESULTS: A higher proportion of patients in the irregular Z-line group were female (26.3%) than in the BE group (14.8% female BE) (P <.001). A lower proportion of patients in the irregular Z line group were smokers (33.5%) than in the BE group (52.6% smokers). None of the patients with irregular Z line developed HGD or EAC during a median follow-up period of 4.8 years (interquartile range, 3.2-8.3 years). All 71 incident cases of HGD or EAC developed in patients with BE of >=1 cm in length. On multivariate analysis, patients with irregular Z line and patients with BE of >= 1 cm did not differ significantly in age, race, or duration of follow-up. CONCLUSIONS: In a prospective, multicenter cohort study, we found that patients with irregular Z line do not develop HGD or esophageal cancer within 5 years after index endoscopy. PMID- 27988384 TI - The opposing roles of NO and oxidative stress in cardiovascular disease. AB - Nitric oxide (NO) plays a pivotal role in the maintenance of cardiovascular homeostasis. A reduction in the bioavailability of endogenous NO, manifest as a decrease in the production and/or impaired signaling, is associated with many cardiovascular diseases including hypertension, atherosclerosis, stroke and heart failure. There is substantial evidence that reactive oxygen species (ROS), generated predominantly from NADPH oxidases (Nox), are responsible for the reduced NO bioavailability in vascular and cardiac pathologies. ROS can compromise NO function via a direct inactivation of NO, together with a reduction in NO synthesis and oxidation of its receptor, soluble guanylyl cyclase. Whilst nitrovasodilators are administered to compensate for the ROS-mediated loss in NO bioactivity, their clinical utility is limited due to the development of tolerance and resistance and systemic hypotension. Moreover, efforts to directly scavenge ROS with antioxidants has had limited clinical efficacy. This review outlines the therapeutic utility of NO-based therapeutics in cardiovascular diseases and describes the source and impact of ROS in these pathologies, with particular focus on the interaction with NO. Future therapeutic approaches in the treatment of cardiovascular diseases are highlighted with a focus on nitroxyl (HNO) donors as an alternative to traditional NO donors and the development of novel Nox inhibitors. PMID- 27988385 TI - Polypharmacy in older adults: Association Rule and Frequent-Set Analysis to evaluate concomitant medication use. AB - The aim of this study was to apply Association Rule and Frequent-Set analysis, and novel means of data visualisation to ascertain patterns of medication use and medication combinations contributing to medication group clusters according to geriatric syndrome status in older adults. Participants were community-dwelling men (aged >=70 years, n=1686), Sydney, Australia. Medication exposure was categorised at medication class level and data were analysed according to geriatric syndrome status (presence of at least one syndrome including frailty, falls, cognitive impairment and urinary incontinence). Association Rule and Frequent-Set analysis were performed to identify "interesting" patterns of medication combinations that occur together. This analysis involves advanced computer algorithms that investigated all possible combinations of medications in the dataset in order to identify those which are observed more or much less frequently than expected. Frequent-Set Analysis demonstrated one unexpected medication combination, antiulcer and antidiabetic medications (3.5% of participants) in the overall population (n=1687). Frequency of medication combinations was similar in participants with (n=666) and without (n=1020) geriatric syndromes. Among participants with geriatric syndromes, the most frequent combinations included antigout with lipid-lowering agents (5.7%) followed by angiotensin II and diuretics combination (22%). This novel methodology can be used to detect common medication combinations overall by data visualisation, and against specific adverse drug reactions such as geriatric syndromes. This methodology may be a valuable pharmacovigilance approach to monitor large databases for the safety of medications. PMID- 27988386 TI - New approaches to target glycinergic neurotransmission for the treatment of chronic pain. AB - Inhibitory glycinergic neurotransmission in the spinal cord dorsal horn plays an important role in regulating nociceptive signalling by inhibiting neuronal excitation. Blocking glycinergic transmission in the dorsal horn causes normally innocuous stimuli to become painful (allodynia) and increases sensitivity to noxious stimuli (hyperalgesia). Loss of inhibitory signalling is thought to contribute to the development of pathological pain. Management of neuropathic pain with current therapeutics is challenging and there is a great need for more effective treatments. Preclinical studies using drugs that increase glycinergic signalling by potentiating glycine receptor activity or inhibiting transporter activity suggest that targeting this system is a good therapeutic strategy. The spatially restricted expression of glycine receptors and transporters is an advantage for targeting specific pathologies such as pain. However, until recently there have been few pharmacological modulators identified and most of which do not specifically target glycinergic signalling. This mini-review provides an overview of recent advances in the development of therapeutics and novel approaches that aim to increase glycinergic neurotransmission for the treatment of persistent pain. PMID- 27988387 TI - Insights into the role of maladaptive hexosamine biosynthesis and O-GlcNAcylation in development of diabetic cardiac complications. AB - Diabetes mellitus significantly increases the risk of heart failure, independent of coronary artery disease. The mechanisms implicated in the development of diabetic heart disease, commonly termed diabetic cardiomyopathy, are complex, but much of the impact of diabetes on the heart can be attributed to impaired glucose handling. It has been shown that the maladaptive nutrient-sensing hexosamine biosynthesis pathway (HBP) contributes to diabetic complications in many non cardiac tissues. Glucose metabolism by the HBP leads to enzymatically-regulated, O-linked attachment of a sugar moiety molecule, beta-N-acetylglucosamine (O GlcNAc), to proteins, affecting their biological activity (similar to phosphorylation). In normal physiology, transient activation of HBP/O-GlcNAc mechanisms is an adaptive, protective means to enhance cell survival; interventions that acutely suppress this pathway decrease tolerance to stress. Conversely, chronic dysregulation of HBP/O-GlcNAc mechanisms has been shown to be detrimental in certain pathological settings, including diabetes and cancer. Most of our understanding of the impact of sustained maladaptive HBP and O-GlcNAc protein modifications has been derived from adipose tissue, skeletal muscle and other non-cardiac tissues, as a contributing mechanism to insulin resistance and progression of diabetic complications. However, the long-term consequences of persistent activation of cardiac HBP and O-GlcNAc are not well-understood; therefore, the goal of this timely review is to highlight current understanding of the role of the HBP pathway in development of diabetic cardiomyopathy. PMID- 27988382 TI - The Vagus Nerve in Appetite Regulation, Mood, and Intestinal Inflammation. AB - Although the gastrointestinal tract contains intrinsic neural plexuses that allow a significant degree of independent control over gastrointestinal functions, the central nervous system provides extrinsic neural inputs that modulate, regulate, and integrate these functions. In particular, the vagus nerve provides the parasympathetic innervation to the gastrointestinal tract, coordinating the complex interactions between central and peripheral neural control mechanisms. This review discusses the physiological roles of the afferent (sensory) and motor (efferent) vagus in regulation of appetite, mood, and the immune system, as well as the pathophysiological outcomes of vagus nerve dysfunction resulting in obesity, mood disorders, and inflammation. The therapeutic potential of vagus nerve modulation to attenuate or reverse these pathophysiological outcomes and restore autonomic homeostasis is also discussed. PMID- 27988388 TI - Analysis of mitochondrial metabolism in situ: Combining stable isotope labeling with selective permeabilization. AB - To date, it is well-established that mitochondrial dysfunction does not only play a vital role in cancer but also in other pathological conditions such as neurodegenerative diseases and inflammation. An important tool for the analysis of cellular metabolism is the application of stable isotope labeled substrates, which allow for the tracing of atoms throughout metabolic networks. While such analyses yield very detailed information about intracellular fluxes, the determination of compartment specific fluxes is far more challenging. Most approaches for the deconvolution of compartmented metabolism use computational models whereas experimental methods are rare. Here, we developed an experimental setup based on selective permeabilization of the cytosolic membrane that allows for the administration of stable isotope labeled substrates directly to mitochondria. We demonstrate how this approach can be used to infer metabolic changes in mitochondria induced by either chemical or genetic perturbations and give an outlook on its potential applications. PMID- 27988389 TI - Probiotics and prevention of Clostridium difficile infection. AB - The role of probiotics as adjunctive measures in the prevention of Clostridium difficile infection (CDI) has been controversial. However, a growing body of evidence has suggested that they have a role in primary prevention of CDI. Elements of this controversy are reviewed and the proposed mechanisms of action, the value and cost effectiveness of probiotics are addressed with a focus on three agents, Saccharomyces boulardii, Lactobacillus rhamnosus GG and the combination of Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, Lactobacillus rhamnosus CLR2 (Bio-K+). PMID- 27988390 TI - Low antibiotic resistance among anaerobic Gram-negative bacteria in periodontitis 5 years following metronidazole therapy. AB - The objective of this study was to assess antibiotic susceptibility among predominant Gram-negative anaerobic bacteria isolated from periodontitis patients who 5 years prior had been subject to mechanical therapy with or without adjunctive metronidazole. One pooled sample was taken from the 5 deepest sites of each of 161 patients that completed the 5 year follow-up after therapy. The samples were analyzed by culture. A total number of 85 anaerobic strains were isolated from the predominant subgingival flora of 65/161 patient samples, identified, and tested for antibiotic susceptibility by MIC determination. E tests against metronidazole, penicillin, amoxicillin, amoxicillin + clavulanic acid and clindamycin were employed. The 73/85 strains were Gram-negative rods (21 Porphyromonas spp., 22 Prevotella/Bacteroides spp., 23 Fusobacterium/Filifactor spp., 3 Campylobacter spp. and 4 Tannerella forsythia). These were all isolated from the treated patients irrespective of therapy procedures (+/-metronidazole) 5 years prior. Three strains (Bifidobacterium spp., Propionibacterium propionicum, Parvimonas micra) showed MIC values for metronidazole over the European Committee on Antimicrobial Susceptibility Testing break point of >4 MUg/mL. All Porphyromonas and Tannerella strains were highly susceptible. Metronidazole resistant Gram-negative strains were not found, while a few showed resistance against beta-lactam antibiotics. In this population of 161 patients who had been subject to mechanical periodontal therapy with or without adjunct metronidazole 5 years prior, no cultivable antibiotic resistant anaerobes were found in the predominant subgingival microbiota. PMID- 27988391 TI - Genomic studies of adaptive evolution in outcrossing Arabidopsis species. AB - Large-scale population genomic approaches have very recently been fruitfully applied to the Arabidopsis relatives Arabidopsis halleri, A. lyrata and especially A. arenosa. In contrast to A. thaliana, these species are obligately outcrossing and thus the footprints of natural selection are more straightforward to detect. Furthermore, both theoretical and empirical studies indicate that outcrossers are better able to evolve in response to selection pressure. As a result, recent work in these species serves as a paradigm of population genomic studies of adaptation both to environmental as well as intracellular challenges. PMID- 27988392 TI - Operative Outcomes of Opportunistic Bilateral Salpingectomy at the Time of Benign Hysterectomy in Low-Risk Premenopausal Women: A Systematic Review. AB - Opportunistic bilateral salpingectomy (OBS) is gaining momentum as a potential strategy for preventing epithelial ovarian cancer (EOC). OBS has been associated with a 40% to 65% decrease in the incidence of EOC when performed at the time of benign hysterectomy in patients at population-level risk for EOC. Current data suggest minimal disadvantage or "cost" to the patient and system from this practice in terms of estimated blood loss (EBL), operative time, length of hospital stay, ovarian reserve depletion, and complications attributable to OBS. These costs merit additional scrutiny in comparison with potential benefits before OBS can be adopted or recommended universally as a preventative strategy. This systematic review identifies 10 comparative studies (8 cohorts and 2 randomized controlled studies) ranging from 19 to 425 180 patients that cumulatively demonstrate a small to no increase in operative time and no additional EBL, hospital stay, or complications attributable to OBS at the time of benign hysterectomy. We anticipate that more widespread adoption of OBS will necessarily incorporate more difficult salpingectomies, thus potentially increasing the time, EBL, and complications associated with this practice in large studies. This consideration should be weighed into discussions of whether salpingectomy at the time of hysterectomy would ever be considered mandatory (or failure to perform OBS be considered negligent) and may have to be considered for fair reimbursement for any additional time and risk of this surgical step. Given the available evidence of benefit, further randomized controlled trials for salpingectomy versus no salpingectomy at the time of hysterectomy are unlikely to be feasible and may be unethical. Going forward, additional large prospective cohorts with historical control subjects will be valuable in assessing the additional costs of universal OBS at the time of benign hysterectomy. PMID- 27988393 TI - Binary combinations of organophosphorus and synthetic pyrethroids are more potent acetylcholinesterase inhibitors than organophosphorus and carbamate mixtures: An in vitro assessment. AB - Anticholinesterase insecticides such as organophosphorous (OP) and carbamates pesticides (CB); and synthetic pyrethroids (SP) pesticides commonly co-occur in the environment. This raises the possibility of antagonistic, additive, or synergistic neurotoxicity in exposed organisms. Acetylcholinesterase (AChE) inhibition has been demonstrated to be useful as a biomarker for exposure to OP and CBs in many environments. This study investigated the response of housefly (Musca domestica) head AChE (HF-AChE) exposed to five OPs; chlorpyrifos (CPF), malathion (MLT), triazophos (TRZ), monocrotophos (MCP) and profenofos (PRF) and two CBs; carbaryl (CRB) and carbofuran (CBF) as individual compounds and as binary mixtures of OPs and CBs under in vitro conditions. In addition, the selected OPs and CBs were evaluated for their toxicity in binary combinations with two SPs; deltamethrin (DLT) and cypermethrin (CYP) at fixed concentrations of 0.1 and 10MUg/L. The toxicological interaction of five OPs with two CBs pesticides was evaluated under oxidised and un-oxidised conditions using a toxic unit (TU) approach and a concentration addition (CA) model. Pyrethroid combinations were assessed only under oxidised conditions. Since OPs and CBs act by a similar mechanism of inhibition of AChE, a dose additive effect was expected, but not conclusively found. TRZ with either CBF or CRB exhibited synergism under oxidised and un-oxidised conditions but the degree of synergism was stronger under un-oxidised conditions. Additivity was exhibited by CBF+MCP, CRB+MCP, CRB+MLT and CBF+MCP under un-oxidised conditions and CRB+MCP and CRB+CPF under oxidised conditions. Pyrethorids in combination with OPs (TRZ, MLT and CPF) were highly synergistic. In the present study, we used pure housefly head AChE without any interference of monooxygenase and/or esterase enzyme activities. Therefore these other enzymes were not producing the observed deviations from concentration-addition in the binary combinations between OPs, CBs and SPs. The mechanisms of OP, CB and SP interactions in pesticide mixtures requires further investigation. PMID- 27988394 TI - Insights on wood combustion generated proinflammatory ultrafine particles (UFP). AB - This study aimed to collect, characterize ultrafine particles (UFP) generated from the combustion of wood pellets and logs (softwood and hardwood) and to evaluate their pro-inflammatory effects in THP-1 and A549 cells. Both cell lines responded to UFP producing interleukin-8 (IL-8), with wood log UFP being more active compared to pellet UFP. With the exception of higher effect observed with beech wood log UFP in THP-1, the ability of soft or hard woods to induce IL-8 release was similar. In addition, on weight mass, IL-8 release was similar or lower compared to diesel exhaust particles (DEP), arguing against higher biological activity of smaller size particles. UFP-induced IL-8 could be reduced by SB203580, indicating a role of p38MAPK activation in IL-8 production. The higher activity of beech wood log UFP in THP-1 was not due to higher uptake or endotoxin contamination. Qualitatively different protein adsorption profiles were observed, with less proteins bound to beech UFP compared to conifer UFP or DEP, which may provide higher intracellular availability of bioactive components, i.e. levoglucosan and galactosan, toward which THP-1 were more responsive compared to A549 cells. These results contribute to our understanding of particles emitted by domestic appliances and their biological effects. PMID- 27988395 TI - A revisited structure for nitrosoprodenafil from NMR, mass spectrometry, X-ray and hydrolysis data. AB - The sildenafil analogue adulterant previously identified as a nitroso derivative (nitrosoprodenafil) in a dietary supplement (DS) marketed to increase sexual performance and sold in Europe in the early 2010s is the same as that found in the same type of DS available in Japan whose structure was established as a nitro derivative (mutaprodenafil or nitroprodenafil). Indeed, the compound isolated from the Man Power DS has identical UV, IR, NMR and MS spectroscopic characteristics and hydrolysis behavior than nitrosoprode-nafil. By revisiting its NMR assignments and MS and MS/MS data interpretation, it is demonstrated that the compound is actually a nitrothioimidazole-methisosildenafil hybrid, i.e. nitroprodenafil, whose structure is unequivocally confirmed by X-ray crystallography and synthesis experiments. Because the product is converted to methisosildenafil by hydrolysis, it is named nitropromethisosildenafil. PMID- 27988396 TI - Total sesquiterpene lactones prepared from Inula helenium L. has potentials in prevention and therapy of rheumatoid arthritis. AB - BACKGROUNDS: Inula helenium L. is an herb with anti-inflammatory properties. Sesquiterpene lactones (SLs), mainly alantolactone (AL) and isoalantolactone (IAL), are considered as its active ingredients. However, the anti-inflammatory effects of SL-containing extracts of I. helenium have not been explored. Here we prepared total SLs from I. helenium (TSL-IHL), analyzed its chemical constituents, and performed cellular and animal studies to evaluate its anti inflammatory activities. MATERIALS AND METHODS: The chemical profile of TSL-IHL was analyzed by HPLC-UV. Its in vitro effects on the activation of signaling pathways and expression of inflammatory genes were examined by western blotting and quantitative real-time PCR, respectively, and compared with those of AL and IAL. Its in vivo anti-inflammatory effects were evaluated in adjuvant- and collagen-induced arthritis rat models. RESULTS: Chemical analysis showed that AL and IAL represent major constituents of TSL-IHL. TSL-IHL, as well as AL and IAL, could inhibit TNF-alpha-induced activation of NF-kappaB and MAPK pathways in b. End3 cells, suppress the expressions of MMP-3, MCP-1, and IL-1 in TNF-alpha stimulated synovial fibroblasts, and IL-1, IL-6, and iNOS in LPS-activated RAW 264.7 cells in a dose-dependent manner in the range of 0.6-2.4MUg/mL. Oral administration of TSL-IHL at 12.5-50mg/kg could dose-dependently alleviate the arthritic severity and paw swelling in either developing or developed phases of arthritis of rats induced by adjuvant or collagen CONCLUSIONS: These results indicated potentials of TSL-IHL in prevention and therapy of rheumatoid arthritis. PMID- 27988397 TI - Total coumarins of Hedyotis diffusa induces apoptosis of myelodysplastic syndrome SKM-1 cells by activation of caspases and inhibition of PI3K/Akt pathway proteins. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hedyotis diffusa is an ethno-medicine used for anti-cancer treatment in the clinic of traditional Chinese medicine (TCM). The total coumarins of Hedyotis diffusa (TCHD) was a selected extract with observed antiproliferative activity, which has not been tested in treatment of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). AIM OF THE STUDY: This study aimed to evaluate the apoptosis-inducing effect of TCHD on human MDS cell line (SKM-1) and explore its action mechanism in association with caspase family and PI3K/Akt signaling pathway. MATERIALS AND METHODS: The chemical constituents and total coumarins content of TCHD were determined by High Performance Liquid Chromatography-tandem mass spectrometry (HPLC-MS/MS) and UV vis spectrophotometry, respectively. MTT assay, Hoechst 33258 staining, and Annexin V-FITC/PI double labeling were applied to evaluate TCHD's efficacy on SKM 1 cells. Western blot analysis was also used to clarify the action mechanism of TCHD on protein expression level. RESULTS: Two compounds, p-coumaric acid and E-6 O-p-coumaroyl scandoside methyl ester, were identified in TCHD, and its total coumarins content reached 87.4%. By MTT assay, apoptosis-inducing effect of TCHD on SKM-1 cells was found in a dose-dependent manner after 24-48h treatment, with IC50 values of 104.48MUg/ml and 100.66MUg/ml, respectively. Morphological and flow cytometry observation also confirmed such effect of TCHD. Western blot analysis clarified its action mechanism associating with the activation of caspases and inhibition of PI3K/Akt pathway proteins. CONCLUSIONS: This is the first report regarding the apoptosis-inducing efficacy and mechanism of TCHD on SKM-1 cells, providing a promising candidate of TCM for MDS and AML therapy with fewer side effects. PMID- 27988398 TI - Control of stress-induced depressive disorders by So-ochim-tang-gamibang, a Korean herbal medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: So-ochim-tang-gamibang (SOCG) is a Korean herbal medicine formula that has been applied to treat depressive moods and depression associated somatoform pain. This decoction consists of Cyperus rotundus L. (Cyperi Rhizoma), Lindera aggregata (Sims) Kosterm. (Linderae Radix), Aquilaria agallochum (Lour.) Roxb. ex Finl. (Aquilariae Resinatum Lignum), Glycyrrhiza uralensis Fisch. (Glycyrrhizae Radix) Platycodon grandiflorum (Jacq.) A. DC. (Platycodi Radix), and Citrus aurantium L. (Aurantii Fructus). The aim of this study is to assess antidepressant-like effects of SOCG and to investigate its possible cellular and molecular mechanisms. MATERIAL AND METHODS: Using chronic restraint stress animal model, effects of SOCG on depressive-like behaviors, corticosterone, and hippocampal expressions of a neurotrophic factor and an apoptotic marker, were investigated. Mice were exposed to restraint stress 6h per day over a period of two weeks, and orally administrated either SOCG (30, 100, or 300mg/kg/day). The depressive-like behaviors were analyzed by forced swimming test and open field test. The serum levels of corticosterone were measured by enzyme-linked immunosorbent assay. Expressions of caspase-3 and BDNF in the hippocampus were analyzed by immunofluorescence. Further, effects of SOCG were examined in corticosterone-treated PC12 cells. Cellular toxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays. Real-time PCR was applied to investigate the cellular expression levels of Bax, Bcl-2, and BDNF. The levels of caspase-3 and BDNF were examined by Western blotting. RESULTS: Administration of SOCG not only reduced immobility time of restraint-stressed mice in a dose-dependent manner, but also significantly increased the distance mice moved and the number of crossings in the open field test. Further, SOCG significantly reduced the serum level of corticosterone and expression of caspase-3, while increased expression of BDNF in vivo. SOCG increased cell viability in corticosterone treated PC12 cells, which was accompanied by decreased caspase-3 expression and the ratio of Bax/Bcl-2 mRNA expression as well as increased BDNF expression in vitro. CONCLUSIONS: Taken together, our data suggested that SOCG may have potential as an antidepressant agent controlling depressive behaviors and corticosterone-induced neuronal damage caused by chronic stress. PMID- 27988399 TI - Spasmogenic and spasmolytic activities of Agastache mexicana ssp. mexicana and A. mexicana ssp. xolocotziana methanolic extracts on the guinea pig ileum. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Agastache mexicana has been used in traditional medicine for relief of abdominal pain and treatment of other diseases. Two subspecies have been identified: A. mexicana ssp. mexicana (AMM) and A. mexicana ssp. xolocotziana (AMX) and both are used traditionally without distinction or in combination. AIM OF THE STUDY: To determine the effect of methanol extracts of A. mexicana ssp. mexicana and A. mexicana ssp. xolocotziana on gut motility and their possible mechanism of action. MATERIALS AND METHODS: The effect of AMM and AMX methanol extracts were tested on the spontaneous activity in the isolated guinea pig ileum and on tissues pre-contracted with KCl, electrical field stimulation (EFS) or ACh. In addition, the possible mechanism of action of each subspecies on gut motility was analyzed in the presence of hexametonium, indomethacin, L-NAME, verapamil, atropine or pyrylamine. A comparative chromatographic profile of these extracts was also done to indicate the most abundant flavonoids presents in methanol extracts of both subspecies. RESULTS: AMM, but not AMX, induced a contractile effect in the guinea pig ileum. This spasmogenic effect was partially inhibited by atropine, antagonist of muscarinic receptors; and pyrilamine, antagonist of H1 receptors. In contrast, AMX, but not AMM, diminished the contractions induced by KCl, EFS or ACh. The spasmolytic activity of AMX was partially inhibited by hexamethonium, ganglionic blocker; and indomethacin, inhibitor of the synthesis of prostaglandins; but not by L-NAME, inhibitor of nitric oxide synthase. In addition, AMX diminished the maximal contraction induced by CaCl2 in a calcium-free medium. Chromatographic analyses of these methanol extracts showed the presence of acacetin and tilanin in both. CONCLUSIONS: These results suggest that in folk medicine only AMX should be used as spasmolytic, and not in combination with AMM as traditionally occurs, due to the spasmogenic effects of the latter. In addition, activation of nicotinic receptors, prostaglandins and calcium channels, but not nitric oxide mechanisms, could be responsible for the spasmolytic activity of AMX. On the other hand, release of ACh and histamine could be involved in the spasmogenic effect induced by AMM. Acacetin and tilanin are present in methanol extracts of both subspecies and both flavonoids were more abundant in AMX than AMM. Our findings contribute to the validation of the traditional use of Agastache mexicana in relieving gastrointestinal disorders, but indicate that the subspecie that should be used for this effect is A. mexicana ssp. xolocotziana. PMID- 27988400 TI - Alibertia edulis (L.C. Rich.) A.C. Rich - A potent diuretic arising from Brazilian indigenous species. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Although Alibertia edulis (L.C. Rich.) A.C. Rich decoction is used in Brazilian folk medicine due to its possible antihypertensive effect, this species has never been critically investigated as a hypotensive drug. So, the aim of this study was to evaluate the possible hypotensive and antihypertensive effects of the oral administration of Alibertia edulis aqueous extract (AEAE) in normotensive and hypertensive rats, and evaluate its inter relation with a possible diuretic activity. MATERIAL AND METHODS: Different doses of AEAE (20, 65 and 200mg/kg) were tested on the mean arterial pressure (MAP) of normotensive Wistar rats and after induction of renovascular hypertension (two kidney, one-clip Goldblatt model). In addition, the diuretic effects of AEAE were compared with hydrochlorothiazide (HCTZ) in an acute and repeated-dose treatment for 7 days. Volume, sodium, potassium, chloride, calcium contents, pH and density were estimated in urine samples collected after 8 or 24h. Plasma sodium, potassium, total protein, urea, creatinine, AST and ALT concentrations were measured in samples collected at the end of the experimental period (seventh day). Finally, the antioxidant activity of the AEAE was assessed using the DPPH radical scavenging and ferric ions reducing power assay. RESULTS: The intraduodenal administration of the HCTZ and AEAE significantly reduced, in a dose-dependent manner, the MAP in both normotensive and hypertensive rats. Otherwise, the heart rate was not affected by any treatment. Acute and prolonged oral administration of AEAE (200mg/kg) and HCTZ caused a significant increase in volume and urinary concentrations of sodium, potassium and chloride. Moreover, urinary calcium concentration was significantly increased after administration of AEAE (200mg/kg). Finally, AEAE was able to present important in vitro antioxidant properties. CONCLUSION: The results obtained have shown that AEAE presents potent diuretic activity and significant hypotensive and antihypertensive effect. In addition, this study may confirm part of the pharmacological activity popularly attributed to this species and opens perspective for the future use in various renal and cardiovascular diseases. PMID- 27988401 TI - Geniposide attenuates ANIT-induced cholestasis through regulation of transporters and enzymes involved in bile acids homeostasis in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Geniposide (GE) is one of the major iridoid glycosides isolated from the fruit of Gardenia jasminoides Ellis that has been used to treat hepatic disorders including cholestasis. However, the underlying mechanisms for GE ameliorating the reduction in bile acids accumulation by alpha naphthylisothiocyanate (ANIT) remain unclear. AIM OF THE STUDY: The purpose of this study is to characterize the efficacy of GE in regulation of bile acids uptake, synthesis, metabolism, and transport in ANIT-induced rats. MATERIALS AND METHODS: Sprague-Dawley rats were orally administrated with vehicle, GE (25, 50, and 100mg/kg), and ursodeoxycholic acid (UDCA) (60mg/kg) once daily for seven days. On the fifth day, a single dose of ANIT (75mg/kg) was administrated via oral gavage. Blood biochemical determination, bile flow rate and liver histopathology were measured to evaluate the protective effect of GE. The mRNA expressions and protein levels of transporters and enzymes involved in bile acids homeostasis were determined by quantitative real-time polymerase chain reaction (PCR) and western blot to study the underlying mechanism of GE against ANIT induced rats. RESULTS: GE (25, 50, and 100mg/kg, po) dose-dependently prevented ANIT-induced changes in serum markers for liver injury. GE treatment reduced basolateral bile acids uptake via repression of OATP2 (P<0.05). Bile acids biosynthesis was decreased through down-regulation of CYP7A1, CYP8B1, and CYP27A1 (P<0.05). GE significantly increased canalicular bile acids secretion via BSEP (P<0.05), subsequently stimulating bile flow during cholestasis. GE also markedly enhanced mRNA level of basolateral transporter OSTbeta (P<0.01). Bile acids transported to the plasma were cleared into the urine, resulting in down regulation of plasma bile acids. However, GE did not alter the mRNA levels of CYP3A2, UGT1A1 and SULT2A1. Furthermore, the gene and protein expression analysis demonstrated activation of FXR, PXR, and SHP after GE administration. CONCLUSION: GE attenuates ANIT-induced hepatotoxicity and cholestasis in rats, due to regulation enzymes and transporters responsible for bile acids homeostasis. PMID- 27988402 TI - Traditional uses, phytochemistry and pharmacology of wild banana (Musa acuminata Colla): A review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Musa acuminata, the wild species of banana is a plant of the tropical and subtropical regions. Over the past few decades, the health benefits of M. acuminata have received much attention. All parts of the plant including fruits, peel, pseudostem, corm, flowers, leaves, sap and roots have found their use in the treatment of many diseases in traditional medicine. Literature review have indicated use of M. acuminata in the treatment of various diseases such as fever, cough, bronchitis, dysentery, allergic infections, sexually transmitted infections, and some of the non-communicable diseases. The reported pharmacological activities of M. acuminata include antioxidant, antidiabetic, immunomodulatory, hypolipidemic, anticancer, and antimicrobial especially anti-HIV activity. This review presents information on the phytochemicals and pharmacological studies to validate the traditional use of different parts of M. acuminata in various diseases and ailments. A comprehensive assessment of the biological activities of M. acuminata extracts is included and possible mechanisms and phytochemicals involved have also been correlated to provide effective intervention strategies for preventing or managing diseases. MATERIALS AND METHODS: A literature search was performed on M. acuminata using ethnobotanical textbooks, published articles in peer-reviewed journals, local magazines, unpublished materials, and scientific databases such as Pubmed, Scopus, Web of Science, ScienceDirect, and Google Scholar. The Plant List, Promusa, Musalit, the Integrated Taxonomic Information System (ITIS) databases were used to validate the scientific names and also provide information on the subspecies and cultivars of M. acuminata. RESULT AND DISCUSSION: The edible part of M. acuminata provides energy, vitamins and minerals. All other parts of the plant have been used in the treatment of many diseases in traditional medicine. The rich diversity of phytochemicals present in them probably contributes to their beneficial effects, and validates the role of M. acuminata plant parts used by various tribes and ethnic groups across the geographical areas of the world. CONCLUSION: This review presents information on phytochemicals and pharmacological activities of M. acuminata plant parts. Pharmacological studies support the traditional uses of the plant, and probably validate the uses of M. acuminata by the indigenous people to treat and heal many infections and diseases. Some studies on animal models have been carried out, which also provide evidence of efficacy of the M. acuminata plant as a therapeutic agent. These observations suggest that M. acuminata plant parts possesses pluripharmacological properties, and can be used in designing potent therapeutic agents. However, individual bioactive constituent(s) from different parts of this plant need further investigations to confirm various pharmacological claims, and to explore the potential of M. acuminata in the development of drugs and use in functional foods. PMID- 27988403 TI - Asian American and Pacific Islander substance use treatment admission trends. AB - BACKGROUND: A national analysis of Asian Americans and Pacific Islanders (AAPI) substance use treatment admissions has yet to be studied. We sought to explore admission trends for AAPI, demographic and treatment variable change, and individual state admission change over time. METHODS: We used retrospective time series logistic regression treating year as a predictor of yearly treatment admission trends, between-state test for heterogeneity of treatment effects among states' AAPI admissions, and percent-changes of AAPI demographic and treatment characteristics. Participants included AAPI (n=135,356) and comparison non-AAPI (n=8,938,982) treatment groups' first-time admissions (N=9,074,338) in United States treatment centers receiving public funding from 2000 to 2012. RESULTS: AAPI demonstrated a greater increase in admissions than non-AAPI from 2000 to 2012 (p<0.0001; OR=1.02, 95% CI=1.019-1.022). Large percent increases were demonstrated in multiple demographic and treatment characteristic, most notably in prescription opioids as a problem substance, age of first use for the oldest and youngest groups, and homelessness. In addition, trends are provided for individual states to help prioritize resource need. CONCLUSIONS: The present demographic and treatment characteristics revealed specific variables that may help to improve a culturally competent understanding of increasing risk factors among AAPI clients. The present findings may help to demonstrate which states may need to increase AAPI-specific resources and interventions. PMID- 27988404 TI - Bauxite residue neutralization with simultaneous mineral carbonation using atmospheric CO2. AB - Simultaneous carbon mineralization during neutralization of bauxite residue, a caustic alkaline by-product of alumina refining, was tested using laboratory batch and a field pilot study in contact with atmospheric CO2. Since CO2 sequestration is limited by the Ca concentration in the bauxite residue, extra Ca sources were added in a semi-soluble mineral and salt form (flue gas desulfurization gypsum or CaCl2) to verify whether this Ca addition accelerated and enlarged the CO2 sequestration obtained as a consequence of neutralization. The results of 55 days of batch and longer-term field tests were in good agreement, and the neutralization rate was accelerated through the addition of both Ca sources. Without the addition of the extra Ca source, atmospheric CO2 contributed to neutralization of pore water alkalinity alone, while Ca addition induced further neutralization through mineral carbonation of atmospheric CO2 to CaCO3. This simple addition of environmentally benign Ca to bauxite residue may provide a feasible bauxite residue management practice that is cost-effective and easy to apply in the field. PMID- 27988405 TI - Self-quenched semiconducting polymer nanoparticles for amplified in vivo photoacoustic imaging. AB - Development of photoacoustic (PA) imaging agents provides opportunities for advancing PA imaging in fundamental biology and medicine. Despite the promise of semiconducting polymer nanoparticles (SPNs) for PA imaging, the molecular guidelines to enhance their imaging performance are limited. In this study, semiconducting polymers (SPs) with self-quenched fluorescence are synthesized and transformed into SPNs for amplified PA imaging in living mice. The self-quenched process is induced by the incorporation of an electron-deficient structure unit into the backbone of SPs, which in turn promotes the nonradiative decay and enhances the heat generation. Such a simple chemical alteration of SP eventually leads to 1.7-fold PA amplification for the corresponding SPN. By virtue of the targeting capability of cyclic-RGD, the amplified SPN can effectively delineate tumor in living mice and increase the PA intensity of tumor by 4.7-fold after systemic administration. Our study thus provides an effective molecular guideline to amplify the PA brightness of organic imaging agents for in vivo PA imaging. PMID- 27988406 TI - Diabetes impairs arterio-venous specification in engineered vascular tissues in a perivascular cell recruitment-dependent manner. AB - Cell-based tissue engineering is a potential treatment alternative for organ replacement. However, the lack of a robust vasculature, especially in the context of diseases such as diabetes, is a major hindrance to its success. Despite extensive research on the effects of diabetes in angiogenic sprouting, its effects on vessel arterio-venous (AV) specification have not been addressed. Using an engineered tissue that yields functional vessels with characteristic AV identities, we demonstrate that type 1 diabetes negatively affects vessel AV specification and perivascular cell (PVC) coverage. Blockage of PVC recruitment in normoglycemia does not affect blood flow parameters, but recapitulates the vascular immaturity found in diabetes, suggesting a role for PVCs in AV specification. The downregulation of Jagged1 and Notch3, key modulators of endothelial-perivascular interaction, observed in diabetes support this assertion. Co-culture assays indicate that PVCs induce arterial identity specification by inducing EphrinB2 and downregulating EphB4. This is antagonized by high glucose or blockage of endothelial Jagged1. Engineered tissues composed of microvessels from diabetic mice display normal PVC coverage and Jagged1/Notch3 gene expression when implanted into non-diabetic hosts. These indicate a lack of legacy effect and support the use of a more aggressive treatment of diabetes in patients undergoing revascularization therapies. PMID- 27988407 TI - Biophysical regulation of mouse embryonic stem cell fate and genomic integrity by feeder derived matrices. AB - For maintaining pluripotency, mouse embryonic stem cells (mESCs) are typically grown on mitotically inactivated mouse embryonic fibroblasts (MEFs). While the role of MEF conditioned media (MEFCM) and leukemia inhibitory factor (LIF) in regulating mESC pluripotency has led to culturing of mESCs on LIF/MEFCM supplemented gelatin-coated substrates, the role of physical interactions between MEFs and mESCs in regulating mESC pluripotency remains to be fully understood. Here, we address this question by characterizing the physicochemical properties of MEF derived matrices (MEFDMs), and probing their role in regulating mESC fate. We show that MEFDM composition and stiffness-dictated by MEF contractility regulates mESC pluripotency by modulating mESC contractility through integrin mediated mechanoadaptation. While baseline mESC pluripotency is maintained at early time points, activation of mESC contractility by LPA leads to drop in pluripotency levels. In contrast, addition of blebbistatin and LIF independently increases pluripotency by suppressing mechanoadaptation, highlighting the role of mechanoadaptation in regulating pluripotency and illustrating the role of LIF as a mechano-inhibitor in mESCs. Long-term culture of mESCs on MEFDMs under LIF-free conditions triggers loss of pluripotency, and induces ligand-dependent expression of the osteogenic transcription factor Runx2. Maintenance of genomic integrity (euploidy) on MEFDMs but not on gelatin-coated substrates, combined with the ability of MEFDMs in supporting LIF-free expansion and differentiation of mESCs, illustrates the suitability of MEFDMs for clinical and regenerative medicine applications. PMID- 27988408 TI - Risk of human helminthiases: geospatial distribution and targeted control. AB - OBJECTIVES: We conducted a cross-sectional survey in 2012 among 22 rural barangays in Northern Samar, the Philippines in order to determine the prevalence of single and multiple species helminth infections, their geospatial distribution and underlying risk factors. METHODS: A total of 10,434 individuals who had completed both a medical questionnaire and a stool examination were included in the analysis. Barangay specific prevalence rates were displayed in ArcMap. RESULTS: The prevalence of Trichuris trichiura infection was found to be the highest at 62.4%, followed by Ascaris lumbricoides, hookworm and S. japonicum with the prevalence rates of 40.2%, 31.32%, and 27.1%, respectively. 52.7% of people were infected with at least two parasites and 4.8% with all four parasites. Males aged 10-19 years were the most vulnerable to coinfection infection. Students, fishermen, farmers and housewives were the most vulnerable occupations for co-infection of A. lumbricoides and T. trichiura. Considerable heterogeneity in the spatial distribution was observed for the different parasite species. There was a considerably higher risk of A. lumbricoides and T. trichiura co-infection in villages with no schistosomiasis infection (P<0.0001) regardless of MDA treatment. CONCLUSIONS: A better understanding of the geospatial distribution of multi-parasitism will guide future integrated strategies leading to elimination. PMID- 27988410 TI - Sofosbuvir: an antiviral drug with potential efficacy against Zika infection. PMID- 27988409 TI - Cerebral Rhizomucor Infection Treated by Posaconazole Delayed-Release Tablets in an Allogeneic Stem Cell Transplant Recipient. AB - Mucormycosis (zygomycosis) is an emerging fungal disease in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. A 30-year-old woman diagnosed with acute myelomonocytic leukemia and needing allo-HSCT presented pulmonary and cerebral infection due to Rhizomucor pusillus. This fungal infection was treated with surgical treatment and posaconazole delayed-release tablets. This strategy allowed reaching high drug levels that could not be obtained with the posaconazole solution. PMID- 27988411 TI - Treatment outcomes for inpatients with obsessive-compulsive personality disorder: An open comparison trial. AB - BACKGROUND: The current case-control study compared rates of clinically significant and reliable change in psychopathology and global functioning, prevalence of clinical deterioration, and rates of symptom remission among adult patients with obsessive compulsive personality disorder OCPD (n=52) and well matched inpatients with any other personality disorder (n=56) and no personality disorder (n=53). METHODS: Propensity score matching (PSM) was utilized to select patients matched on specific criteria present in the OCPD group. Multivariate analysis of variance models measured differences in admission functioning and RCI change across depression and anxiety severity, emotion dysregulation and suicidal ideation. RESULTS: Patients diagnosed with OCPD admit to treatment with higher rates of depression, anxiety, difficulty with emotion regulation and non acceptance of emotional experience than inpatient controls. Furthermore, OCPD patients respond to treatment at a similar rate to inpatient controls, but experience lower rates of anxiety remission upon discharge. Post-hoc analyses indicate individuals meeting stubbornness and rigidity (OCPD Criteria 8) were nine times more likely to report moderate to severe anxiety at point of discharge. LIMITATIONS: Limitations include a predominantly Caucasian, inpatient sample, use of self-report measures and a non-manualized treatment approach. CONCLUSIONS: Overall, OCPD inpatients benefit from an intensive multimodal psychiatric treatment, but experience more anxiety than non-PD patients upon discharge. PMID- 27988412 TI - Breast reconstruction after mastectomy: A ten-year analysis of trends and immediate postoperative outcomes. AB - : The landscape of breast reconstruction has changed significantly. This study assesses trends in type of reconstruction performed after mastectomy and impact on immediate postoperative complications. METHODS: Data for 67,450 patients undergoing mastectomy for breast cancer were analyzed using the National Surgical Quality Improvement Program (NSQIP) database for years 2005-2014. Primary outcomes were wound, nonwound related infections, and bleeding complications. Data were analyzed by univariate and multivariate analysis. RESULTS: The percentage of patients that underwent reconstruction after breast cancer increased from 26.94% in 2005 to 43.30% in 2014 (p < 0.01). There was increased wound (5.59%), bleeding (6.82%), and infection (1.80%) complications after flap based reconstruction (p < 0.01). There was no difference in wound, infection, and bleeding complications between immediate implant reconstruction and tissue expander (TE) at 4.38 vs. 3.89% (p = 0.18), 0.82 vs. 0.7%, p = 0.46), and 0.76 vs. 0.64% (p = 0.45), respectively. Several independent factors were associated with increased wound complications in patients undergoing all or any forms of reconstruction after mastectomy such as being overweight (OR 1.38, CI 1.23-1.55), obese (OR 2.11, CI 1.89-2.35), morbidly obese (OR 3.84, CI 3.34-4.43), ASA Class III (OR 1.35, CI 1.08-1.69), ASA Class IV (OR 1.49, 1.06-2.10), diabetic (OR 1.28 , CI 1.14-1.43), and smokers (OR 1.76, CI 1.59-1.94). TRAM flap was associated with increased risk of wound complication (OR 1.87, CI 1.28-2.75). CONCLUSION: More women are undergoing reconstruction as utilization of TE increases drastically. Immediate implant placement has only seen moderate increase likely due to surgeon preference. PMID- 27988414 TI - Racial differences in the link between alcohol expectancies and adolescent drinking. AB - INTRODUCTION: Alcohol expectancies are important determinants and predictors of adolescent alcohol use. Research with African Americans has shown that the endorsement of positive alcohol expectancies differs from that of Whites during childhood and predicts different alcohol outcomes during young adulthood. However, limited research has explored racial differences in the relationship between expectancy endorsement and alcohol use in school-aged adolescents. The current study examines the effect of White or African American race on the relationship between positive alcohol expectancies and alcohol use. METHODS: Participants were 104 adolescents ages 12-18 who identified as either non Hispanic White or non-Hispanic African American. Participants completed self report measures of alcohol consumption and positive social alcohol expectancies. RESULTS: Preliminary analyses revealed no racial differences in alcohol expectancies or consumption. However, race moderated the relationship between alcohol expectancies and alcohol use such that more positive expectancies predicted alcohol use among White youth, but not African American youth. CONCLUSIONS: These results suggest that alcohol expectancies, which were thought to be important mediators of the relationship between social and personality factors and adolescent alcohol use may not be as impactful for African Americans. Future research should focus on identifying factors posing unique risk for alcohol consumption in this population. PMID- 27988413 TI - White matter abnormalities in long-term anabolic-androgenic steroid users: A pilot study. AB - Recent studies of long-term anabolic-androgenic steroid (AAS) users reported amygdala structural and functional connectivity abnormalities. We assessed white matter microstructure in the inferior-fronto-occipital fasciculus (IFOF), a major associative bundle of the amygdala network. Diffusion weighted images acquired from 9 male long-term AAS users and 8 matched controls aged 36-51 years old were processed using a standardized pipeline (Tract-Based Spatial Statistics). Group differences were examined using linear regression with adjustment for age and current testosterone level. Compared to nonusers, AAS users exhibited significantly higher fractional anisotropy (FA) in the IFOF. Users showed markedly greater FA than nonusers on the left IFOF but only a modest, nonsignificant difference on the right IFOF. Moreover, FA was positively associated with lifetime cumulative AAS dose. Our results suggest that long-term AAS use alters IFOF white matter organization and integrity, which in turn might affect amygdala-related processes such as reward system function. Accordingly, further studies are needed to replicate findings in larger subject groups to determine the functional significance of the FA abnormality. PMID- 27988415 TI - Emergence of electronic cigarette use in US adolescents and the link to traditional cigarette use. AB - BACKGROUND: Electronic cigarettes (e-cigarettes) are increasingly used by US adolescents and may be a gateway to traditional cigarette use. We examine rates of both products by age and examine differences in age-varying rates by sex and race/ethnicity. METHODS: Data are from the 2014 National Youth Tobacco Survey, a national sample of US middle and high school students (n=22.007); students ages 11-19 were included. Past 30-day e-cigarette and traditional cigarette use were examined as a function of age; sex and race/ethnicity were included as moderators. The age-varying association between e-cigarette and traditional cigarette use was also examined. RESULTS: Rates of e-cigarette use increase faster than traditional cigarette use from ages 13-16. Compared to females, males had higher rates of e-cigarette use from ages 14-17.5 and traditional cigarette use from ages 15-18. Between ages 12-14, more Hispanic adolescents used e cigarettes compared to White or Black adolescents; after age 14 Hispanics and Whites reported similar rates, peaking at twice the rate for Blacks. Hispanic adolescents report greater traditional cigarette use versus Whites between ages 12-13, but lower rates between ages 15-18. E-cigarette use was strongly associated with traditional cigarette use, particularly during early adolescence [OR>40 before age 12]. CONCLUSIONS: Young Hispanic adolescents are at elevated risk for use of e-cigarettes and traditional cigarettes during early adolescence. During early adolescence, youth using e-cigarettes are more likely to smoke traditional cigarettes compared to youth not using e-cigarettes. The study of age varying effects holds promise for advancing understanding of disparities in health risk behaviors. PMID- 27988416 TI - Energy metabolism and metabolomics response of Pacific white shrimp Litopenaeus vannamei to sulfide toxicity. AB - The toxicity and poisoning mechanisms of sulfide were studied in Litopenaeus vannamei from the perspective of energy metabolism and metabolomics. The lethal concentrations of sulfide in L. vannamei (LC50) at 24h, 48h, 72h, and 96h were determined. Sulfide at a concentration of 0, 1/10 (425.5MUg/L), and 1/5 (851MUg/L) of the LC50 at 96h was used to test the metabolic responses of L. vannamei for 21days. The chronic exposure of shrimp to a higher sulfide concentration of 851MUg/L decreased shrimp survival but did not affect weight gain or the hepatopancreas index. The glycogen content in the hepatopancreas and muscle and the activity of hepatopancreas cytochrome C oxidase of the shrimp exposed to all sulfide concentrations were significantly lower, and the serum glucose and lactic acid levels and lactic acid dehydrogenase activity were significantly lower than those in the control. Metabolomics assays showed that shrimp exposed to sulfide had lower amounts of serum pyruvic acid, succinic acid, glycine, alanine, and proline in the 425.5MUg/L group and phosphate, succinic acid, beta-alanine, serine, and l-histidine in the 851MUg/L group than in the control. Chronic sulfide exposure could disturb protein synthesis in shrimp but enhance gluconeogenesis and substrate absorption for ATP synthesis and tricarboxylic acid cycles to provide extra energy to cope with sulfide stress. Chronic sulfide exposure could adversely affect the health status of L. vannamei, as indicated by the high amounts of serum n-ethylmaleamic acid, pyroglutamic acid, aspartic acid and phenylalanine relative to the control. This study indicates that chronic exposure of shrimp to sulfide can decrease health and lower survival through functional changes in gluconeogenesis, protein synthesis and energy metabolism. PMID- 27988417 TI - Impacts of the antidepressant fluoxetine on the anti-predator behaviours of wild guppies (Poecilia reticulata). AB - Chemical pollution from pharmaceuticals is increasingly recognised as a major threat to aquatic communities. One compound of great concern is fluoxetine, which is one of the most widely prescribed psychoactive drugs in the world and frequently detected in the environment. The aim of this study was to investigate the effects of 28-d fluoxetine exposure at two environmentally relevant levels (measured concentrations: 4ng/L and 16ng/L) on anti-predator behaviour in wild guppies (Poecilia reticulata). This was achieved by subjecting fluoxetine-exposed and unexposed guppies to a simulated bird strike and recording their subsequent behavioural responses. We found that exposure to fluoxetine affected the anti predator behaviour of guppies, with exposed fish remaining stationary for longer (i.e. 'freezing' behaviour) after the simulated strike and also spending more time under plant cover. By contrast, control fish were significantly more active and explored the tank more, as indicated by the distance covered per minute over the period fish spent swimming. Furthermore, behavioural shifts were sex dependent, with evidence of a non-monotonic dose-response among the fluoxetine exposed fish. This is one of the first studies to show that exposure to environmentally relevant concentrations of fluoxetine can alter the anti-predator behaviour of adult fish. In addition to the obvious repercussions for survival, impaired anti-predator behaviour can have direct impacts on fitness and influence the overall population dynamics of species. PMID- 27988418 TI - Supercritical water oxidation of quinazoline: Reaction kinetics and modeling. AB - This paper presents a first quantitative kinetic model for supercritical water oxidation (SCWO) of quinazoline that describes the formation and interconversion of intermediates and final products at 673-873 K. The set of 11 reaction pathways for phenol, pyrimidine, naphthalene, NH3, etc, involved in the simplified reaction network proved sufficient for fitting the experimental results satisfactorily. We validated the model prediction ability on CO2 yields at initial quinazoline loading not used in the parameter estimation. Reaction rate analysis and sensitivity analysis indicate that nearly all reactions reach their thermodynamic equilibrium within 300 s. The pyrimidine yielding from quinazoline is the dominant ring-opening pathway and provides a significant contribution to CO2 formation. Low sensitivity of NH3 decomposition rate to concentration confirms its refractory nature in SCWO. Nitrogen content in liquid products decreases whereas that in gaseous phase increases as reaction time prolonged. The nitrogen predicted by the model in gaseous phase combined with the experimental nitrogen in liquid products gives an accurate nitrogen balance of conversion process. PMID- 27988419 TI - Health anxiety in obsessive compulsive disorder and obsessive compulsive symptoms in severe health anxiety: An investigation of symptom profiles. AB - Severe health anxiety (SHA) shares features with obsessive-compulsive disorder (OCD) and in recent years there has been a debate as to whether the two disorders may represent two facets of the same condition. Few studies have however investigated the overlap and differences in symptom profiles between the disorders. The primary aim of the present study was to investigate these aspects using one sample of participants with a principal diagnosis of SHA and one sample of participants with a principal OCD diagnosis. The second aim was to examine differences in improvement trajectories on measures of health anxiety and OCD symptoms in patients with SHA receiving treatment with exposure and response prevention. We compared persons participating in clinical trials with a principal diagnosis of SHA (N=290) to persons with a principal diagnosis of OCD (n=95) on measures of health anxiety, OCD symptoms, and depressive symptoms. A subsample of SHA participants (n=99) received exposure and response prevention (ERP) for SHA over 12 weeks and was assessed at baseline and post-treatment. The results showed large and significant differences between SHA and OCD patients on measures of health anxiety (ds=2.99-3.09) and OCD symptoms (ds=1.64-2.14), while they had equivalent levels of depressive symptoms (d=0.19, 95% CI [-0.04, 0.43]). In the SHA sample 7.6% had comorbid OCD, and in the OCD sample 9.5% had SHA. For participants with a principal diagnosis of SHA, ERP led to large reductions of health anxiety, but effects on OCD symptoms were small to moderate. Among participants with comorbid OCD, effect sizes were large on measures of health anxiety and moderate to large on OCD measures. We conclude that SHA and OCD are separate psychiatric disorders with limited overlap in symptom profiles. PMID- 27988421 TI - Voltage-gated sodium channels viewed through a structural biology lens. AB - Voltage-gated sodium (Nav) channels initiate and propagate action potentials in excitable cells, and are frequently dysregulated or mutated in human disease. Despite decades of intense physiological and biophysical research, eukaryotic Nav channels have so far eluded high-resolution structure determination because of their biochemical complexity. Recently, simpler bacterial voltage-gated sodium (BacNav) channels have provided templates to understand the structural basis of voltage-dependent activation, inactivation, ion selectivity, and drug block in eukaryotic Nav and related voltage-gated calcium (Cav) channels. Further breakthroughs employing BacNav channels have also enabled visualization of bound small molecule modulators that can guide the rational design of next generation therapeutics. This review will highlight the emerging structural biology of BacNav channels and its contribution to our understanding of the gating, ion selectivity, and pharmacological regulation of eukaryotic Nav (and Cav) channels. PMID- 27988420 TI - Aptima HPV Assay versus Hybrid Capture(r) 2 HPV test for primary cervical cancer screening in the HPV FOCAL trial. AB - BACKGROUND: Cervical cancer screening programs are switching from Pap screening to high-risk HPV testing. OBJECTIVES: To compare the Aptima HPV Assay (AHPV) with the Hybrid Capture(r) 2 High-Risk HPV DNA Test(r) (HC2) for primary cervical screening. STUDY DESIGN: HPV FOCAL is a randomized trial comparing HC2 to liquid based cytology (LBC) for screening women aged 25-65. AHPV and HC2 were compared at the baseline screen (n=3473). Genotyping was by the Aptima HPV 16 18/45 Genotype Assay. We assessed HPV genotyping and reflex LBC for colposcopy triage. RESULTS: AHPV/HC2 agreement was 96.5% (kappa 0.76); positive agreement was 77.4%. The AHPV positive rate was 7.2% vs. 8.4% for HC2 (p=0.06). Based on HC2 screening, round 1 CIN2 and CIN3+ rates were 9.2/1000 and 5.2/1000 respectively. Using HC2 as the comparator test, AHPV CIN2+ and CIN3+ relative sensitivities were 0.96 and 1.00 (p=1.00) respectively. High-grade reflex LBC and HPV 16 infection were significantly associated with CIN3+. AHPV specificity was 0.94 vs. 0.93 (p=0.05) for HC2. Compared with triage of HC2+ with abnormal cytology or HPV persistence for 12 months, colposcopy referral would be significantly reduced (38.3/1000 vs. 60.8/1000; p<0.001) if AHPV+ women with abnormal LBC and HPV 16/18/45 were referred at baseline. CIN2+ and CIN3+ detection rates were not significantly different for the two strategies. CONCLUSIONS: AHPV vs. HC2 screening had equivalent CIN2+ and CIN3+ detection. Triage of AHPV+ by abnormal reflex LBC and the presence of HPV 16/18/45 would result in a significantly lower colposcopy referral rate with similar CIN2+ and CIN3+ detection rates as the overall HC2+ referral algorithm. PMID- 27988422 TI - Simulations of disordered proteins and systems with conformational heterogeneity. AB - Intrinsically disordered proteins (IDPs) and protein regions can facilitate a wide variety of complex physiological processes such as binding, signaling, and formation of membraneless organelles. They can however also play pathological roles by aggregating into cytotoxic oligomers and fibrils. Characterizing the structure and function of disordered proteins is an onerous task, primarily because these proteins adopt transient structures, which are difficult to capture in experiments. Simulations have emerged as a powerful tool for interpreting and augmenting experimental measurements of IDPs. In this review we focus on computer simulations of disordered protein structures, functions, assemblies, and emerging questions that, taken together, give an overview of the field as it exists today. PMID- 27988423 TI - MTSS1 is epigenetically regulated in glioma cells and inhibits glioma cell motility. AB - Epigenetic silencing by DNA methylation in brain tumors has been reported for many genes, however, their function on pathogenesis needs to be evaluated. We investigated the MTSS1 gene, identified as hypermethylated by differential methylation hybridization (DMH). Fifty-nine glioma tissue samples and seven glioma cell lines were examined for hypermethylation of the MTSS1 promotor, MTSS1 expression levels and gene dosage. GBM cell lines were treated with demethylating agents and interrogated for functional consequences of MTSS1 expression after transient transfection. Hypermethylation was significantly associated with IDH1/2 mutation. Comparative SNP analysis indicates higher incidence of loss of heterozygosity of MTSS1 in anaplastic astrocytomas and secondary glioblastomas as well as hypermethylation of the remaining allele. Reversal of promoter hypermethylation results in an increased MTSS1 expression. Cell motility was significantly inhibited by MTSS1 overexpression without influencing cell growth or apoptosis. Immunofluorescence analysis of MTSS1 in human astrocytes indicates co-localization with actin filaments. MTSS1 is down-regulated by DNA methylation in glioblastoma cell lines and is part of the G-CIMP phenotype in primary glioma tissues. Our data on normal astrocytes suggest a function of MTSS1 at focal contact structures with an impact on migratory capacity but no influence on apoptosis or cellular proliferation. PMID- 27988424 TI - miR-3940-5p Functions as a Tumor Suppressor in Non-Small Cell Lung Cancer Cells by Targeting Cyclin D1 and Ubiquitin Specific Peptidase-28. AB - miR-3940-5p level was lower in non-small cell lung cancer (NSCLC) tumor tissues than that in the matched tumor-adjacent tissues and correlated with clinicopathological features. Cyclin D1 (CCND1), a key driver of malignant transformation in NSCLC, was overexpressed in many cancers, including NSCLC. The ubiquitin specific peptidase-28 (USP28) was also overexpressed in NSCLC and associated with poor prognosis of NSCLC patients. We searched for miR-3940-5p targets by using TargetScan and miRanda online tools and found that CCND1 and USP28 were potential targets of miR-3940-5p. Based on these findings, we speculated that miR-3940-5p might target CCND1 and USP28 to inhibit NSCLC growth. We determined the expression of miR-3940-5p, CCND1, and USP28 by quantitative real-time polymerase chain reaction and Western blot assays, respectively, and found downregulation of miR-3940-5p and upregulation of CCND1 and USP28 in NSCLC tissues and cell lines. Cell proliferation and apoptosis assays showed that miR 3940-5p suppressed proliferation and promoted apoptosis in NSCLC cells, and silencing CCND1 and USP28 both recapitulated the effects of miR-3940-5p on NSCLC cells. Furthermore, we verified that CCND1 and USP28 were direct targets of miR 3940-5p and also found that the effects of NSCLC cell proliferation and apoptosis by miR-3940-5p were attenuated by overexpression of CCND1 or USP28. The animal experiments also showed that overexpression of miR-3940-5p inhibited the growth of NSCLC tumors in vivo. These results confirmed our speculation that miR-3940-5p inhibits proliferation and induces apoptosis in NSCLC cells by targeting CCND1 and USP28. These findings facilitate a better understanding of the molecular mechanisms underlying NSCLC initiation and progression and provide promising diagnostic markers and therapeutic targets for NSCLC. PMID- 27988425 TI - Internet Addiction Disorder: Personality characteristics and risk of pathological overuse in adolescents. AB - AIM: Few studies have investigated Internet Addiction (IA) in adolescents in relation to personality characteristics. The aim of this study was to determine whether personality differences exist between adolescents with problematic/pathological Internet use and those with normal Internet use. Our hypothesis was that certain psychopathological personality traits may predispose to the development of maladaptive Internet use. METHODS: The Internet Addiction Test (IAT) and the Minnesota Multiphasic Personality Inventory-Adolescent (MMPI A) were administered to a sample of 224 high school students. RESULTS: Analysis of IAT scores showed that 24.6% of the students had problematic Internet use and 1.6% had IA. Comparison of the MMPI-A scores between subjects with normal Internet use and those with problematic or pathological use based on the IAT score showed that some subscales, including schizophrenia and bizarre mentation, were strongly associated with problematic/pathological Internet use. Also, male sex, attending a vocational school, and unhappy childhood were found to be risk factors for IA. CONCLUSIONS: Certain psychological dimensions regarding mood and the psychotic area, as well as low self-esteem, family, school and conduct problems could represent risk factors. Taken together, our data suggest a personality profile, with problems at various levels in subjects with problematic or pathological Internet use. PMID- 27988426 TI - The association between sleep dysfunction and psychosis-like experiences among college students. AB - Sleep problems are prominent and pervasive clinical issues experienced by many people with psychotic disorders, often causing distress and functional impairment. Sleep problems are also related to psychosis-like experiences (PLE; non-diagnosable phenomenon such as transient perceptual disturbances, unusual thoughts, periodic suspiciousness) in epidemiological studies. Prior studies in this field have used brief measures that precluded the ability to test (1) whether risk for psychosis-like experiences are related to specific sub-types of sleep disturbance, and (2) whether sleep disturbance is specifically related to clinically significant (i.e., distressing) psychosis-like experiences. The current project examined the relation between specific sleep issues, and PLEs and distress associated with PLEs, in a college sample. Participants (N=420) completed the Prodromal Questionnaire-Brief (PQ-B), which assesses PLEs and associated distress, and the Iowa Sleep Disturbances Inventory - extended version (ISDI-E), which assesses thirteen separate disturbed sleep domains. Symptoms of fragmented sleep, sleep hallucinations, and night anxiety significantly correlated with PLEs, and several sleep domains were significantly associated with PLE-related distress. PMID- 27988427 TI - Generic versus disorder specific cognitive behavior therapy for social anxiety disorder in youth: A randomized controlled trial using internet delivery. AB - The study examined whether the efficacy of cognitive behavioral treatment for Social Anxiety Disorder for children and adolescents is increased if intervention addresses specific cognitive and behavioral factors linked to the development and maintenance of SAD in young people, over and above the traditional generic CBT approach. Participants were 125 youth, aged 8-17 years, with a primary diagnosis of SAD, who were randomly assigned to generic CBT (CBT-GEN), social anxiety specific CBT (CBT-SAD) or a wait list control (WLC). Intervention was delivered using a therapist-supported online program. After 12-weeks, participants who received treatment (CBT-SAD or CBT-GEN) showed significantly greater reduction in social anxiety and post-event processing, and greater improvement in global functioning than the WLC but there was no significant difference between CBT-SAD and CBT-GEN on any outcome variable at 12-weeks or 6-month follow-up. Despite significant reductions in anxiety, the majority in both treatment conditions continued to meet diagnostic criteria for SAD at 6-month follow-up. Decreases in social anxiety were associated with decreases in post-event processing. Future research should continue to investigate disorder-specific interventions for SAD in young people, drawing on evidence regarding causal or maintaining factors, in order to enhance treatment outcomes for this debilitating condition. PMID- 27988428 TI - Attitudes towards drug policies in Latin America: Results from a Latin-American Survey. AB - BACKGROUND: In recent years Latin American countries have increasingly rejected the traditional prohibitionist paradigm of drug policy, reflecting its failure to reduce either consumption or trafficking. The extent to which these policy trends currently command pubic support is unclear, however. This article goes some way to filling this gap, providing a snapshot of public attitudes towards drug policies in nine Latin American countries. METHODS: The 2014 Annual Survey of the Observatory of Drug Policies and Public Opinion, which has representative population samples, was used to measure public opinion. Country comparisons are made using descriptive and inferential statistics. RESULTS: Countries fall into three groups: Peru, Bolivia and El Salvador are the most conservative countries on drug policy and perceptions of risks of cannabis use; they also score lowest on Human Development Index. On the other hand, the public in Chile and Uruguay are more likely to support drug policy reform. The remaining four countries (Argentina, Colombia, Mexico and Peru) tend to occupy the middle ground between these extremes. In addition, cannabis legalization is explained by its recreational use, being this the main meaning attached to cannabis policy among Latin American citizens. CONCLUSION: There is a significant heterogeneity in attitudes towards drug policies in Latin American countries, which suggests that people are questioning the policies that set the norm in Latin America without achieving any consensus regarding future measures for each country. PMID- 27988429 TI - Calcineurin inhibitors versus cyclophosphamide for idiopathic membranous nephropathy: A systematic review and meta-analysis of 21 clinical trials. AB - OBJECTIVE: To compare the efficacy and safety of calcineurin inhibitors (CNIs) with cyclophosphamide (CTX) in the treatment of idiopathic membranous nephropathy (IMN). METHODS: A literature search was carried out using PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and three Chinese databases (WanFang Data, Chongqing VIP and China National Knowledge Infrastructure) from inception through June 2016. Randomized controlled trials (RCTs) comparing the efficacy and safety of CNIs with CTX in IMN patients were included. Two authors independently extracted data and assessed the quality of each study. Statistical analyses were performed using Revman 5.3 software. Odds ratio (OR) for dichotomous data and mean difference (MD) for continuous data with 95% confidence interval (CI) were calculated and data were pooled with a random effect model. RESULTS: A total of twenty-one studies involving 1187 patients were included in this study. CNIs had significant merits in increasing total remission (CSA vs CTX: OR 1.91, 95%CI 1.09 to 3.34, P=0.02; TAC vs CTX: OR 2.95, 95%CI 1.84 to 4.75, P<0.00001), elevating serum albumin (CSA vs CTX: MD 3.83, 95%CI 2.49 to 5.16, P<0.00001; TAC vs CTX: OR 8.57, 95%CI 5.08 to 12.07, P<0.00001) and reducing proteinuria (CSA vs CTX: MD -0.73, 95%CI -1.25 to -0.22, P=0.005; TAC vs CTX: MD -1.7, 95%CI -2.29 to -1.10, P<0.00001) compared with CTX after 6months of treatment. However, no similar results were found after 12months. Moreover, CSA had a higher relapse rate than CTX (OR 3.89, 95%CI 1.53 to 9.92, P=0.004), which was not found in the comparison of TAC and CTX. The incidences of leukopenia, alopecia and liver damage were higher in the CTX group (OR (95%CI): 0.23 (0.09 to 0.59), 0.10 (0.04 to 0.24), and 0.36 (0.19 to 0.69, respectively), whereas the incidences of hirsutism, gingival hyperplasia, worsening hypertension and hyperuricemia were higher in the CSA group (OR (95%CI): 8.64 (1.97 to 37.79, 4.44 (1.09 to 17.99), 4.59 (1.43 to 14.82) and 9.05 (1.53 to 53.36), respectively). CONCLUSIONS: Our systematic review demonstrates that CNIs are promising alternatives to CTX for IMN patients, primarily due to their better short-term efficacy and safety. Well-designed clinical trials are needed to further evaluate the long-term efficacy and safety of CNIs and CTX. PMID- 27988430 TI - Kinin receptors: Key regulators of autoimmunity. AB - The central function of the immune system is to protect the host from environmental agents such as microbes or chemicals, thereby preserving the integrity of the body, and preventing the onset of illness and infection. Moreover, the immune system is constantly challenged to discriminate self vs. non self and mediate the correct response, a phenomenon called self-tolerance. The failure of mechanisms responsible for self-tolerance and induction of an immune response against components of the self, induces autoimmunity and culminates however, in several autoimmune diseases. The precise etiology of autoimmune diseases is not known, although the classic sign of an autoimmune disease is inflammation. In this context, kinins are a family of peptides involved in different physiological and pathological states, comprising inflammatory, vascular and pain processes, and are highly relevant as well as to a variety of diseases including hypertension, kidney diseases, Alzheimer's disease, cancer, obesity, epilepsy and traumatic injuries. These kinin effects are mediated by two related G-protein-coupled receptors named the bradykinin receptors (BKRs), B1 and B2. The kallikrein-kinin system (KKS) and their receptors appear to be involved in both the development and progression of autoimmune diseases, suggesting that modulators of BKRs, administered in monotherapy or in combination with existing therapies, may represent a potential new venue for an effective autoimmune disease treatment. This review article highlights historical and recent progress in understanding the role of BKRs as potential therapeutics for a number of autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel diseases, and others. PMID- 27988431 TI - Clinical utility of circulating anti-N-methyl-d-aspartate receptor subunits NR2A/B antibody for the diagnosis of neuropsychiatric syndromes in systemic lupus erythematosus and Sjogren's syndrome: An updated meta-analysis. AB - BACKGROUND/PURPOSE: Neuropsychiatric (NP) events are found in patients with rheumatic diseases, commonly in systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). The standard nomenclature and case definitions for 19 NPSLE syndromes by the American College of Rheumatology (ACR) Committee on Research cover a wide range of NP events seen in both SLE and SS. Despite advances in the understanding of SLE and SS, NP syndromes continue to pose diagnostic challenges. Correct attribution of NP events is critical in determining the correct treatment and prognosis. Anti-N-methyl-d-aspartate receptor subunits NR2A/B (anti-NR2A/B) antibodies have been demonstrated in the sera of SLE and SS patients and have been associated with collective or specific NP syndromes, though not consistently. Interpretation of anti-NR2A/B antibody data in the medical literature is rendered difficult by small sample size of patient groups. By combining different studies to generate a pooled effect size, a meta-analysis can increase the power to detect differences in the presence or absence of NP syndromes. Hence, we set out to perform a meta-analysis to assess the association between anti-NR2A/B antibodies and NP syndromes in SLE and SS. METHODS: A literature search was conducted using PubMed and other databases from inception to June 2016. We abstracted data relating to anti-NR2A/B antibodies from the identified studies. The random effects model was used to calculate overall combined odds ratio (OD) with its corresponding 95% confidence interval (CI) to evaluate the relationship between anti-NR2A/B antibodies and NP syndromes in SLE and SS patients with and without NP events. We also included our own cohort of 57 SLE patients fulfilling the ACR 1997 revised classification criteria and 58 healthy controls (HCs). RESULTS: In total, 17 studies with data on anti-NR2A/B antibodies in 2212 SLE patients, 66 SS patients, 99 disease controls (DCs) (e.g. antiphospholipid syndrome, myasthenia gravis and autoimmune polyendocrine syndrome I) and 538 HCs were used in this analysis. Overall pooled prevalence of serum/plasma anti-NR2A/B antibodies was higher in SLE patients [24.6% (95% CI 18.5-32.0%)] and SS patients [19.7% (95% CI 11.8-31.0%)] compared to DCs [14.8% (95% CI 2.2-56.9)] and HCs [7.6% (95% CI 4.6-12.4%)] (p=0.001). There was a significantly greater proportion of SLE and SS patients with NP syndromes who demonstrated positivity for serum/plasma anti-NR2A/B antibody [pooled OR=1.607 (95% CI 1.041-2.479), p=0.032] as compared to SLE and SS patients without NP syndromes in 13 studies. Usable data for cerebrospinal fluid anti-NR2A/B antibodies were available in only 4 studies [pooled OR=0.831 (95% CI 0.365 1.888), p=0.658]. Among the 19 NP syndromes, serum/plasma anti-NR2A/B antibodies were not specifically associated with any NP syndrome, including cognitive dysfunction (p=0.259) and mood disorder (p=0.503). Meta-regression identified proportion of anti-double-stranded deoxyribonucleic acid antibody positivity (p=0.009) and SLE Disease Activity Index (p=0.028) as moderators for the heterogeneity of serum/plasma anti-NR2A/B antibodies. CONCLUSION: Circulating anti-NR2A/B antibody testing has a diagnostic value for NP syndromes in SLE and SS collectively. However, the evidence to date suggests that anti-NR2A/B antibody positivity cannot distinguish specific NP syndromes. PMID- 27988433 TI - IgG4-related disease: Evidence from six recent cohorts. AB - IgG4-related disease (IgG4-RD) is a rare autoimmune fibrosing disorder. In this review we aim to describe and compare the characteristics of the six largest IgG4 RD cohorts, since the new 2012 consensus diagnostic criteria were released. These observational studies were published between 2012 and 2015. Patients were included using the comprehensive diagnostic criteria or the 2012 consensus criteria. Results were reviewed and summarized. Most patients were middle aged men. Fibro-inflammatory masses developed in virtually all organs except the brain, with an unexplained preference for salivary glands, lymph nodes and pancreas. Corticosteroids were the treatment of choice but up to 40% of patients relapsed within the first year. Standardized response assessment tools, biomarkers and the validation of new treatments are still in development. In conclusion, the features of IgG4-RD are similar across the globe. At the moment, corticosteroids are the only validated treatment but rituximab seems to be promising. PMID- 27988434 TI - Anti-RO/SSA and anti-La/SSB antibodies: Association with mild lupus manifestations in 645 childhood-onset systemic lupus erythematosus. AB - BACKGROUND: To our knowledge there are no studies assessing anti-Ro/SSA and anti La/SSB autoantibodies in a large population of childhood-systemic lupus erythematosus (cSLE) patients. METHODS: This was a retrospective multicenter cohort study performed in 10 Pediatric Rheumatology services, Sao Paulo state, Brazil. Anti-Ro/SSA and anti-La/SSB antibodies were measured by enzyme linked immunosorbent assay (ELISA) in 645 cSLE patients. RESULTS: Anti-Ro/SSA and anti La/SSB antibodies were evidenced in 209/645 (32%) and 102/645 (16%) of cSLE patients, respectively. Analysis of cSLE patients with and without anti-Ro/SSA antibodies revealed higher frequencies of malar rash (79% vs. 71%, p=0.032), photosensitivity (73% vs. 65%, p=0.035), cutaneous vasculitis (43% vs. 35%, p=0.046) and musculoskeletal involvement (82% vs. 75%, p=0.046) in spite of long and comparable disease duration in both groups (4.25 vs. 4.58years, p=0.973). Secondary Sjogren syndrome was observed in only five patients with this antibody (2.5% vs. 0%, p=0.0035), two of them with concomitant anti-La/SSB. The presence of associated autoantibodies: anti-Sm (50% vs. 30%, p<0.0001), anti-RNP (39% vs. 21%, p<0.0001) and anti-ribossomal P protein (46% vs. 21%, p=0.002) was also significantly higher in patients with anti-Ro/SAA antibodies. Further evaluation of cSLE patients with the presence of anti-La/SSB antibodies compared to those without these autoantibodies showed that the frequency of alopecia (70% vs. 51%, p=0.0005), anti-Sm (59% vs. 31%, p<0.0001) and anti-RNP (42% vs. 23%, p<0.0001) were significantly higher in the former group. CONCLUSIONS: Our large multicenter cohort study provided novel evidence in cSLE that anti-Ro/SSA and/or anti-La/SSB antibodies were associated with mild manifestations, particularly cutaneous and musculoskeletal. Secondary Sjogren syndrome was rarely observed in these patients, in spite of comparable frequencies of anti-Ro/SSA and/or anti-La/SSB reported for adult SLE. PMID- 27988435 TI - In vivo distribution of single chain variable fragment (scFv) against atherothrombotic oxidized LDL/beta2-glycoprotein I complexes into atherosclerotic plaques of WHHL rabbits: Implication for clinical PET imaging. AB - BACKGROUND: Oxidized LDL (oxLDL) can exist as a complex with beta2-glycoprotein I (beta2GPI) in plasma/serum of patients with non-autoimmune atherosclerotic disease or antiphospholipid syndrome (APS). Nonetheless, direct in vivo evidence supporting the pathophysiological involvement of oxLDL/beta2GPI complexes and specific autoantibody against the complexes in developing atherothrombosis has yet been established. In the present study, we demonstrated in vivo distribution of single chain variable fragment of IgG anti-oxLDL/beta2GPI complexes (3H3-scFv) in Watanabe heritable hyperlipidemic (WHHL) rabbits by PET/CT imaging. METHODS: An antibody-based PET probe, 64Cu-3H3-scFv, was established, and WHHL rabbits were applied for a non-autoimmune atherosclerotic model to demonstrate in vivo distribution of the probe. RESULTS: 3H3-scFv has exhibits specificity towards beta2GPI complexed with oxLDL but neither a free form of beta2GPI nor oxLDL alone. Post-intravenous administration of 64Cu-3H3-scFv into WHHL rabbits has demonstrated a non-invasive approach for in vivo visualization of atherosclerotic lesion. The imaging probe achieved ideal blood clearance and distribution for optimal imaging capacity in 24h, significantly shorter than that of an intact IgG based imaging probe. 64Cu-3H3-scFv targeted on atherosclerotic plaques in aortas of WHHL rabbits where extensive accumulation of lipid deposits was observed by lipid staining and autoradiography. The accumulation of 64Cu-3H3-scFv in aortic segments of WHHL rabbits was 2.8-folds higher than that of controls (p=0.0045). CONCLUSIONS: The present in vivo evidence supports the pathophysiological involvement of oxLDL/beta2GPI complexes in atherosclerotic complications of WHHL rabbits. 64Cu-3H3-scFv represents a novel PET imaging probe for non-invasive pathophysiological assessment of oxLDL/beta2GPI complexes accumulated in atherosclerotic plaques. PMID- 27988436 TI - A scoping review of the use of non-biologic disease modifying anti-rheumatic drugs in the management of large vessel vasculitis. AB - Takayasu's arteritis (TA) and Giant cell arteritis (GCA) comprise the large vessel vasculitides (LVV). Patients with LVV are treated with disease-modifying anti-rheumatic drugs (DMARDs), both conventional (cDMARDs) and biologic (bDMARDs). We undertook a scoping review to assess the effectiveness of cDMARDs in TA and GCA. We could identify 11 studies in TA and 18 studies in GCA. There were only 3 randomized controlled trials on methotrexate, one on hydroxychloroquine and two on cyclosporine in GCA, the others being case series (including all studies on TA). Most of these studies had small patient numbers (median 15 in TA and 27 in GCA). Outcome measures reported in different studies were heterogenous. Overall, methotrexate, leflunomide, azathioprine, mycophenolate mofetil and cyclophosphamide were effective in TA (low quality of evidence). Methotrexate (high quality of evidence), hydroxychloroquine and cyclosporine (moderate quality of evidence) appeared to be ineffective in GCA. Azathioprine (moderate quality of evidence), leflunomide, mycophenolate mofetil, cyclophosphamide and dapsone (low quality of evidence) were effective in GCA. There exists a paucity of high quality evidence to guide use of cDMARDs in TA and GCA. There is an unmet need to conduct large multi-centric randomized placebo controlled trials to accurately assess the utility on cDMARDs in LVV. PMID- 27988432 TI - TLRs, future potential therapeutic targets for RA. AB - Toll like receptors (TLR)s have a central role in regulating innate immunity and in the last decade studies have begun to reveal their significance in potentiating autoimmune diseases such as rheumatoid arthritis (RA). Earlier investigations have highlighted the importance of TLR2 and TLR4 function in RA pathogenesis. In this review, we discuss the newer data that indicate roles for TLR5 and TLR7 in RA and its preclinical models. We evaluate the pathogenicity of TLRs in RA myeloid cells, synovial tissue fibroblasts, T cells, osteoclast progenitor cells and endothelial cells. These observations establish that ligation of TLRs can transform RA myeloid cells into M1 macrophages and that the inflammatory factors secreted from M1 and RA synovial tissue fibroblasts participate in TH-17 cell development. From the investigations conducted in RA preclinical models, we conclude that TLR-mediated inflammation can result in osteoclastic bone erosion by interconnecting the myeloid and TH-17 cell response to joint vascularization. In light of emerging unique aspects of TLR function, we summarize the novel approaches that are being tested to impair TLR activation in RA patients. PMID- 27988437 TI - Sjogren's syndrome-associated myositis with germinal centre-like structures. AB - OBJECTIVE: Muscular impairment is a rare systemic manifestation of SS that is rarely described in the literature and classically non-specific, both clinically and histologically. We reviewed the cases of 4 patients with primary SS presenting with myositis and a common histologic pattern on muscular biopsy with germinal centre-like structures resembling that which occurs in salivary glands. METHODS: We analysed the data files of patients with SS who had muscular manifestations and underwent a muscular biopsy. Among 23 patients with SS who had muscle biopsies, 13 had non-specific myositis and 10 (4 primary and 6 secondary SS) had a common histologic pattern consisting of germinal centre-like structures. We analysed the data files of the 4 patients with primary SS presenting with myositis with muscular germinal-centre like structures. RESULTS: The 4 patients had an unspecific clinical presentation, with myalgias, muscular weakness and normal or elevated values of CPK. In the four patients, SS associated myositis had common histologic characteristics, with endomysial and perimysial inflammatory infiltrate. The cellular infiltrate was composed predominantly of CD4+ T lymphocytes and B lymphocytes. The B and T CD4+ cells infiltrates may gather into masses, even forming lymphoid follicles. Three patients were treated with corticosteroids and/or hydroxychloroquine with improvement of myositis and 1 patient was lost to follow-up. CONCLUSIONS: We describe four patients with a common histologic appearance of myositis with lymphoid follicles associated with primary SS. The clinical presentation was non specific and non-severe, with favorable outcome with corticosteroids and/or hydroxycholoroquine. The discovery of this particular histologic appearance in a muscle biopsy independent of the final diagnosis should indicate the possibility of SS. PMID- 27988438 TI - Detection of lupus anticoagulant in the era of direct oral anticoagulants. AB - Lupus anticoagulant (LAC) is an in vitro phenomenon determining a phospholipid dependent elongation of clotting times. The presence of LAC associated with anticardiolipin (aCL) and anti-beta2 glycoprotein I (anti-beta2GPI) antibodies is strongly associated with thrombosis and pregnancy morbidity. Direct oral anticoagulants (DOACs) targeting thrombin and factor Xa are currently widely use to prevent and treat venous and arterial thromboembolism. Some concern has, however, been expressed about the possibility of false laboratory results during LAC assessment in patients taking these drugs. Several in vitro studies, spiking DOACs into normal plasma as well as ex vivo at peak levels in treated patients, led in false-positive LAC. The dilute Russell Viper Venom time is the assay that is most influenced by rivaroxaban, edoxaban, dabigatran and less by apixaban. Both screening and confirmatory tests have resulted equally prolonged for activated partial thromboplastin time and have not led to false-positive results, but this may depend on the type of reagent used for the test. Taipan/Ecarin snake venoms ratios, has been recommend by some investigators as they do not seem to be affected by rivaroxaban or edoxaban, but these tests are neither standardized nor generally available in clinical practice. In conclusion, for the time being it does not seem advisable to carry out LAC testing during anti-factor Xa and anti factor IIa treatment because of the risk of false-positive results. Whenever needed in deciding the suspension of DOACs or in case of recurrent thrombosis, LAC determination should be carried out at trough better if DOAC concentration is known. PMID- 27988439 TI - Biomechanical characterization of spider webs. AB - In light of recent focus on the behaviour of the natural structures for revolutionary technological growth, spider web seems to have seized considerable attention of product designer due to its amazing behaviour. In present work, mechanism behind the structural integrity of the spider web along with the materialistic analysis of its constituent silk threads has been extensively investigated. The nanoindentation tool both in static and dynamic mode has been utilized for complete analysis of the mechanical behaviour of the spiral and radial threads separately. Both the average elastic modulus and hardness of the radial silk thread is higher than the spiral silk thread which reveals the radial silk thread is the major structural component of the web. The sustainability of spider webs under storm, windy conditions and during the impact of pray has been investigated under dynamic conditions. The radial silk thread exhibits elastic like response and the spiral silk thread exhibits viscous like response in a wide frequency range (1-200Hz). The damping characteristic of the radial and spiral silk threads, an important parameter to investigate the energy dissipation properties of the materials has also been investigated in windy conditions. PMID- 27988440 TI - Evaluation of the mechanical properties of powder metallurgy Ti-6Al-7Nb alloy. AB - Titanium and its alloys are common biomedical materials owing to their combination of mechanical properties, corrosion resistance and biocompatibility. Powder metallurgy (PM) techniques can be used to fabricate biomaterials with tailored properties because changing the processing parameters, such as the sintering temperature, products with different level of porosity and mechanical performances can be obtained. This study addresses the production of the biomedical Ti-6Al-7Nb alloy by means of the master alloy addition variant of the PM blending elemental approach. The sintering parameters investigated guarantee that the complete diffusion of the alloying elements and the homogenization of the microstructure is achieved. The sintering of the Ti-6Al-7Nb alloy induces a total shrinkage between 7.4% and 10.7% and the level of porosity decreases from 6.2% to 4.7% with the increment of the sintering temperature. Vickers hardness (280-300 HV30) and tensile properties (different combination of strength and elongation around 900MPa and 3%) are achieved. PMID- 27988441 TI - Atherosclerotic plaque delamination: Experiments and 2D finite element model to simulate plaque peeling in two strains of transgenic mice. AB - Finite element analyses using cohesive zone models (CZM) can be used to predict the fracture of atherosclerotic plaques but this requires setting appropriate values of the model parameters. In this study, material parameters of a CZM were identified for the first time on two groups of mice (ApoE-/- and ApoE-/- Col8-/-) using the measured force-displacement curves acquired during delamination tests. To this end, a 2D finite-element model of each plaque was solved using an explicit integration scheme. Each constituent of the plaque was modeled with a neo-Hookean strain energy density function and a CZM was used for the interface. The model parameters were calibrated by minimizing the quadratic deviation between the experimental force displacement curves and the model predictions. The elastic parameter of the plaque and the CZM interfacial parameter were successfully identified for a cohort of 11 mice. The results revealed that only the elastic parameter was significantly different between the two groups, ApoE-/- Col8-/- plaques being less stiff than ApoE-/- plaques. Finally, this study demonstrated that a simple 2D finite element model with cohesive elements can reproduce fairly well the plaque peeling global response. Future work will focus on understanding the main biological determinants of regional and inter individual variations of the material parameters used in the model. PMID- 27988442 TI - Regional distribution of circumferential residual strains in the human aorta according to age and gender. AB - The biomechanical response of the human aorta varies with axial location, but little is known about the respective variation of residual strains. Such data are available for common lab animals, but in the traditional opening angle measurement the aorta is considered as an ideal cylinder and average residual strains are measured, so that the spatial variations of local residual strains are not determined. The present study provides opening angle and residual strain data throughout the course and around the circumference of the aorta harvested during autopsy. Opening angle showed notable topographical variation; the highest value was at the top of aortic arch, declining abruptly toward the ascending aorta and to a near-constant value in the descending aorta, and rising in the abdominal aorta. The variation of curvature and of external but not internal residual stretch resembled that of opening angle. Extensive residual stress and wall thickness differences were evidenced among quadrants, with the more pre stressed being also the thicker quadrants. Gender had overall minor effects, but aging led to increased parameters, occurring earlier in the distal aorta but at later stages becoming predominant proximally. Differences in caliber were pronounced in older subjects, unlike those in opening angle, residual stretches, and thickness that were striking in middle-aged subjects. By contrast, curvature decreased with aging in relation to the smaller percentwise opening angle differences. Detailed knowledge of the zero-stress/no-load geometry of the human aortic wall is critical for an in-depth understanding of aortic physiology, while providing the basis for comparison with disease. PMID- 27988443 TI - Brief report: Associations of physical activity with anxiety and depression symptoms and status among adolescents. AB - The purpose of this study is to investigate associations between physical activity (PA), depression, and anxiety among adolescents in Ireland. Adolescents (N = 481; 281 male, 200 female) aged 15.1 +/- 1.7y self-reported PA level, depression, and anxiety. Approximately 21% of adolescents were high trait anxious, and ~37% reported scores indicating probable depression. Anxiety and depressive symptoms were higher for low PA (60 min/d, 0-2 d/wk) compared to moderate (60 min/d, 3-4 d/wk) and high (60 min/d, 5-7 d/wk) PA. After adjustment for relevant covariates, reduced odds of depression were 30% and 56% for moderate and high PA, respectively; reduced odds of high trait anxiety were 46% and 47% for moderate and high PA, respectively. These findings support the need for adolescents to engage in moderate PA, with potential for increased benefits with increased PA. To conclude, moderate and high PA are inversely associated with anxiety and depressive symptoms, and risk of depression and high trait anxiety in adolescents. PMID- 27988445 TI - Angular absorption of light used for evaluation of structural damage to porcine meat caused by aging, drying and freezing. AB - Meat as a rich source of protein is sought after by people from all over the world. It is also very susceptible to decay because of many internal and external processes affecting it. In this work an easy and quick method of detection of structural damage caused by decay or mishandling the meat is attempted by the method of angular absorption of light. The difference between structural changes due to aging, drying and freezing is explored and the resulting changes in light absorption in meat samples are presented. This work demonstrates that the measurement of optical angular dependency of absorption in relation to the muscle fibers in muscle tissue has the potential of detecting structural damage to the sample for meat quality control purposes. PMID- 27988444 TI - Regional and inter-hospital differences in the utilisation of liver surgery for patients with synchronous colorectal liver metastases in the Netherlands. AB - BACKGROUND: The objective of this study was to map referral patterns in patients with synchronous colorectal liver metastases (SCLM) and to investigate if type, volume and location of the hospital of diagnosis are associated with whether or not patients underwent liver resection. METHODS: This population-based study includes all patients diagnosed with SCLM between 2008 and 2012, based on the Netherlands Cancer Registry. To study inter-hospital variation, the proportion of patients undergoing liver surgery was calculated per hospital of diagnosis. Multivariable multilevel logistic regression analysis was used to investigate the association between hospital characteristics and liver resection. RESULTS: Of 10,520 patients with SCLM, 12% (n = 1259) underwent liver surgery. Of these patients, 58% (n = 733) were referred to another hospital to undergo liver surgery. In 53% of the patients (n = 647), liver resection was performed in a university hospital, in 39% (n = 482) in a dedicated liver centre and in 8% (n = 102) in a general hospital. There was a large inter-hospital variation in the proportion of patients undergoing liver resection (2-26%). In a multilevel logistic regression model, the odds of undergoing liver surgery were higher when patients were diagnosed in hospitals where liver surgery was performed compared with the general hospitals (dedicated liver centre: odds ratio 1.36 [95% confidence intervals 1.08-1.70], university hospital: odds ratio 1.69 [95% confidence intervals 1.22-2.34]). CONCLUSION: There is a large inter-hospital and inter-regional variation in the utilisation of liver resection. Patients diagnosed with SCLM in expert centres had a higher chance of undergoing liver resection. PMID- 27988447 TI - Daily PM2.5 concentration prediction based on principal component analysis and LSSVM optimized by cuckoo search algorithm. AB - Increased attention has been paid to PM2.5 pollution in China. Due to its detrimental effects on environment and health, it is important to establish a PM2.5 concentration forecasting model with high precision for its monitoring and controlling. This paper presents a novel hybrid model based on principal component analysis (PCA) and least squares support vector machine (LSSVM) optimized by cuckoo search (CS). First PCA is adopted to extract original features and reduce dimension for input selection. Then LSSVM is applied to predict the daily PM2.5 concentration. The parameters in LSSVM are fine-tuned by CS to improve its generalization. An experiment study reveals that the proposed approach outperforms a single LSSVM model with default parameters and a general regression neural network (GRNN) model in PM2.5 concentration prediction. Therefore the established model presents the potential to be applied to air quality forecasting systems. PMID- 27988446 TI - A novel variant in RyR2 causes familiar catecholaminergic polymorphic ventricular tachycardia. AB - Catecholaminergic polymorphic ventricular tachycardia is a rare familial arrhythmogenic disease. It usually occurs in juvenile patients with a structurally normal heart and causes exercise-emotion triggered syncope and sudden cardiac death. The main gene associated with catecholaminergic polymorphic ventricular tachycardia is RyR2, encoding the cardiac ryanodine receptor protein which is involved in calcium homeostasis. After the identification of a 16 year old man presenting with exercise-induced sudden cardiac death, clinically diagnosed as catecholaminergic polymorphic ventricular tachycardia, we collected the family information and performed a comprehensive genetic analysis using Next Generation Sequencing technology. The initial electrocardiogram in the emergency department revealed ventricular fibrillation. On electrocardiogram monitoring, sinus tachycardia degenerated into bidirectional ventricular and into ventricular fibrillation. Catecholaminergic polymorphic ventricular tachycardia was clinically diagnosed in 5 of the 14 family members evaluated. There were no additional reports of seizures, pregnancy loss, neonatal death, or sudden cardiac death in family members. Genetic analysis of the index case identified only one rare novel variant p.Ile11Ser (c.32T>G) in the RyR2 gene. Subsequent familial analysis identified segregation of the genetic variant with the disease. All current evidence supports that novel p.Ile11Ser variant in the RyR2 gene is a potential disease-causing variant in catecholaminergic polymorphic ventricular tachycardia. To our knowledge, there has been no previous case report of catecholaminergic polymorphic ventricular tachycardia associated to this missense variant. PMID- 27988448 TI - Particle-size speciation of Pu isotopes in surface soils from Inner Mongolia (China) and its implications for Asian Dust monitoring. AB - To study the applications of Pu isotopes in long-distance dust migration monitoring, Pu isotopes in surface soil of Inner Mongolia have been analyzed using SF-ICP-MS after size fractionation. 240Pu/239Pu atom ratios ranged narrowly (0.169-0.200) and indicated global fallout character, while 239+240Pu activities increased with decreasing particle size. A spherical model could well simulate 239+240Pu activities as a function of particle diameter when soil particle size was less than 600um, and the soil particle surface sorption phenomenon of Pu isotopes in natural soil samples was revealed. Furthermore, 239+240Pu activity in fine particles (sized less than 53um) had good consistency with that in atmospheric depositions of Japan since the 2000s, suggesting new Asian Dust sources (i.e. central Inner Mongolia) other than the well-known Chinese deserts. PMID- 27988449 TI - Detecting lane departures from steering wheel signal. AB - Current lane departure warning systems are video-based and lose data when road- and weather conditions are bad. This study sought to develop a lane departure warning algorithm based on the signal drawn from the steering wheel. The rationale is that a car-based lane departure warning system should be robust regardless of road- and weather conditions. N=34 professional driver students drove in a high-fidelity driving simulator at 80km/h for 55min every third hour during 36h of sustained wakefulness. During each driving session we logged the steering wheel- and lane position signals at 60Hz. To derive the lane position signal, we quantified the transfer function of the simulated vehicle and used it to derive the absolute lane position signal from the steering wheel signal. The Pearson correlation between the derived- and actual lane position signals was r=0.48 (based on 12,000km). Next we designed an algorithm that alerted, up to three seconds before they occurred, about upcoming lane deviations that exceeded 0.2m. The sensitivity of the algorithm was 47% and the specificity was 71%. To our knowledge this exceeds the performance of the current video-based systems. PMID- 27988450 TI - Branch bark of holm oak (Quercus ilex L.) for reconstructing the temporal variations of atmospheric deposition of hexavalent chromium. AB - The bark from the annual segments of the branches of holm oak (Quercus ilex L.) is exposed to trace element deposition for a known period of time and thus it is a possible candidate as a bioindicator for reconstructing historical changes in pollution. A series of samples were analysed for Cr(VI) concentration by electrothermal atomic absorption spectrometry (ET-AAS) after selective extraction in a sodium carbonate solution. In this way the atmospheric deposition of Cr(VI) was reconstructed from 2001 to 2010 in an area where an industrial plant produced Cr(VI) compounds until 2003. The present study shows the potential of this type of sample as a natural archive for persistent pollutants, useful for monitoring changes that occur before a monitoring programme is established, with the advantage of being easy to collect almost everywhere. PMID- 27988451 TI - Combined effects of low-molecular-weight organic acids on mobilization of arsenic and lead from multi-contaminated soils. AB - A batch experiment was conducted to examine the combined effects of three common low-molecular-weight organic acids (LMWOAs) on the mobilization of arsenic and lead in different types of multi-contaminated soils. The capacity of individual LMWOAs (at a same molar concentration) to mobilize soil-borne As and Pb varied significantly. The combination of the organic acids did not make a marked "additive" effect on the mobilization of the investigated three elements. An "antagonistic" effect on element mobilization was clear in the treatments involving oxalic acid for some soils. The acid strength of a LMWOA did not play an important role in controlling the mobilization of elements. While the mobilization of As and Pb was closely associated with the dissolution of soil borne Fe, soil properties such as original soil pH, organic matter contents and the total amount of the element relative to the total Fe markedly complicated the mobility of that element. Aging led to continual consumption of proton introduced from addition of LMWOAs and consequently caused dramatic changes in solution borne Fe, which in turn resulted in change in As and Pb in the soil solution though different elements behaved differently. PMID- 27988452 TI - Long term effects of carbaryl exposure on antiviral immune responses in Xenopus laevis. AB - Water pollutants associated with agriculture may contribute to the increased prevalence of infectious diseases caused by ranaviruses. We have established the amphibian Xenopus laevis and the ranavirus Frog Virus 3 (FV3) as a reliable experimental platform for evaluating the effects of common waterborne pollutants, such as the insecticide carbaryl. Following 3 weeks of exposure to 10 ppb carbaryl, X. laevis tadpoles exhibited a marked increase in mortality and accelerated development. Exposure at lower concentrations (0.1 and 1.0 ppb) was not toxic, but it impaired tadpole innate antiviral immune responses, as evidenced by significantly decreased TNF-alpha, IL-1beta, IFN-I, and IFN-III gene expression. The defect in IFN-I and IL-1beta gene expression levels persisted after metamorphosis in froglets, whereas only IFN-I gene expression in response to FV3 was attenuated when carbaryl exposure was performed at the adult stage. These findings suggest that the agriculture-associated carbaryl exposure at low but ecologically-relevant concentrations has the potential to induce long term alterations in host-pathogen interactions and antiviral immunity. PMID- 27988453 TI - Occurrence of cocaine and metabolites in hospital effluent - A risk evaluation and development of a HPLC method using DLLME. AB - A fast method for the determination of cocaine and its metabolites in hospital effluent samples was worked out by using liquid chromatography with the aid of fluorescence and diode array detection. Solid phase extraction and dispersive liquid -liquid microextraction were employed during the sample preparation stage. The experiment was conducted by using Chromabond(r) C18 ec 6 ml/500 mg cartridges, with recoveries higher than 96.6%, 88.3%, 78.7%, and LOQm 0.15; 0.18 and 0.30 MUg L-1 for cocaine, benzoylecgonine and anhydroecgonine respectively. In the case of DLLME, different chemical conditions and solvent combinations were tested to find the best settings for the microextraction: pH 9; addition of 0.3 mol L-1 NaCl; 150 MUL extractor (chloroform) and 350 MUL disperser (methanol). The recoveries for cocaine were as high as 98.3% with LOQm 0.3 MUg L-1. After validation, these methods were applied to quantification of the analytes. While the concentration of the anhydroecgonine, (the main pyrolytic metabolite of cocaine), remained below the limit of detection, the range of concentrations of cocaine and benzoylecgonine determined were 0.4-4.9 MUg L-1 and 0.9-8.6 MUg L-1, respectively. The occurrence has a relatively median/high environmental impact. These concentration values suggest that a role is played by other sources of cocaine, probably related to transport, or handling and the consumption of the drug. The outcome is that cocaine can be quantified by using DLLME as well as SPE, however, DLLME offered clear benefits like simplicity, affordability, and speed, as well as only requiring a small volume of solvents and samples. PMID- 27988454 TI - Soil environmental quality in greenhouse vegetable production systems in eastern China: Current status and management strategies. AB - Greenhouse vegetable production (GVP) has become an important source of public vegetable consumption and farmers' income in China. However, various pollutants can be accumulated in GVP soils due to the high cropping index, large agricultural input, and closed environment. Ecological toxicity caused by excessive pollutants' accumulation can then lead to serious health risks. This paper was aimed to systematically review the current status of soil environmental quality, analyze their impact factors, and consequently to propose integrated management strategies for GVP systems. Results indicated a decrease in soil pH, soil salinization, and nutrients imbalance in GVP soils. Fungicides, remaining nutrients, antibiotics, heavy metals, and phthalate esters were main pollutants accumulating in GVP soils comparing to surrounding open field soils. Degradation of soil ecological function, accumulation of major pollutants in vegetables, deterioration of neighboring water bodies, and potential human health risks has occurred due to the changes of soil properties and accumulation of pollutants such as heavy metals and fungicides in soils. Four dominant factors were identified leading to the above-mentioned issues including heavy application of agricultural inputs, outmoded planting styles with poor environmental protection awareness, old-fashion regulations, unreasonable standards, and ineffective supervisory management. To guarantee a sustainable GVP development, several strategies were suggested to protect and improve soil environmental quality. Implementation of various strategies not only requires the concerted efforts among different stakeholders, but also the whole lifecycle assessment throughout the GVP processes as well as effective enforcement of policies, laws, and regulations. PMID- 27988455 TI - Delayed diagnosis of Wernicke encephalopathy with irreversible neural damage after subtotal gastrectomy for gastric cancer: A case of medical liability? AB - INTRODUCTION: Wernicke's encephalopathy (WE) is a neurological syndrome caused by thiamine deficiency, and clinically characterized by ophthalmoplegia, ataxia and acute confusion. In developed countries, most cases of WE have been seen in alcohol misusers. Other reported causes are gastrointestinal tract surgery, hyperemesis gravidarum, chronic malnutrition, prolonged total parenteral nutrition without thiamine supplementation, and increased nutrient requirements as in trauma or septic shock. WE is a well-known postoperative complication of gastric restrictive surgery for morbid obesity, after which patients often experience protracted nausea and vomiting, leading to malnutrition and massive weight loss. PRESENTATION OF CASE: This case report concerns WE occurring in a patient who underwent Roux-en-Y subtotal gastrectomy for gastric cancer, and subsequently experienced neurological symptoms that proved irreversible probably due to the lengthy time elapsing between their clinical presentation and the diagnosis of WE. DISCUSSION: There have been some reports of WE occurring after total or subtotal gastrectomy for gastric cancer in non-obese patients with no history of alcoholism, but monitoring for WE has yet to be recommended in the clinical guidelines in this setting (as it has for bariatric surgery). Because of its rarity and variable clinical presentation, WE is often under-diagnosed and under-treated, and confused with other neurological problems. CONCLUSION: There is an urgent need for the specific guidelines to take into account not only the neoplastic follow-up of such patients, but also the possible side effects of necessary surgery, since this could help to ensure the timely diagnosis and management of WE in this setting, and to avoid, when possible, claims for medical malpractice that may cause enormous costs both in economical and professional terms. PMID- 27988456 TI - Acute gastric volvulus: A vicious twist of tummy-case report. AB - INTRODUCTION: Gastric volvulus is an uncommon disorder and can present either in the acute or chronic setting with variable symptoms. A robust blood supply of the stomach from different sources does not allow ischemia to develop early. When it occurs in the acute scenario, patients present with severe epigastric pain and retching without vomiting. Together with inability to pass nasogastric tube, they constitute Borchardt's triad. PRESENTATION OF CASE: We report a case which presented in the emergency department with severe abdominal pain, abdominal distension and vomiting and a previous history of pulmonary tuberculosis. An incidental finding of uterovaginal prolapse was present. A diagnosis of acute gastric volvulus with peritonitis was made and total gastrectomy with Roux-en-Y esophagojejunostomy for gangrenous and perforated stomach was performed. DISCUSSION: Primary gastric volvulus occurs in the absence of any defect in the diaphragm or adjacent organ pathology and may be caused by weakening of gastric supports. We wish to highlight if there is a possible association of primary gastric volvulus with uterovaginal prolapse reflecting a general laxity of body ligaments or with fibrosis of the lung secondary to pulmonary tuberculosis resulting into the twisting of the stomach. CONCLUSION: Acute gastric volvulus is a surgical emergency requiring early diagnosis and aggressive management, as a delay results into complications like gangrene and perforation which substantially increase the morbidity and mortality in these patients. PMID- 27988458 TI - Tripterygium wilfordii polyglycosidium ameliorates pouchitis induced by dextran sulfate sodium in rats. AB - BACKGROUND: The aim of this study was to investigate the therapeutic effects of Tripterygium wilfordii polyglycosidium (TWP) to rats with dextran sulfate sodium (DSS)-induced pouchitis and its possible mechanism. METHODS: Sprague-Dawley rats underwent surgery of ileal pouch anal anastomosis (IPAA) and pouchitis was induced by DSS. Rats were randomly divided into no intervention (NI), normal saline (NS) and TWP groups. Rats were lavaged with normal saline (3ml/day in NS group) or TWP (12mg/kg/day in TWP group) for 7days. General conditions of animals and histopathological examinations were evaluated. Interleukin (IL)-1beta, IL-6, IL-10, and tumor necrosis factor (TNF)-alpha mRNA expression was measured. Levels of occludin and Zo-1 proteins were measured by immunohistochemistry. In addition, ALT and AST were assessed. RESULTS: TWP significantly attenuated the symptoms of pouchitis characterized by body weight loss, diarrhea, and bloody stool. Furthermore, TWP diminished histological damage compared with other groups. There was a significant reduction in levels of IL-1beta, IL-6, and TNF-alpha, as well as an increase in IL-10 in the TWP group. The expression of tight junction proteins occludin and Zo-1 were increased in the TWP group. There were no statistical differences in serum ALT and AST among the three groups. CONCLUSIONS: TWP significantly ameliorated pouchitis and inhibited the production of IL-1beta, IL-6, and TNF-alpha as well as increased the levels of IL-10, occludin, and Zo-1 protein in rats. These findings suggest TWP might be a potential therapeutic agent for patients with pouchitis. PMID- 27988457 TI - In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models. AB - The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor alpha/beta (PDGFRalpha/beta) and FGFR1-3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents. We report here the in vitro and in vivo antitumor activity of lucitanib in experimental models with or without FGFR1/2 amplification or mutations. In cell assays, lucitanib potently inhibited the growth of tumor cell lines with amplified FGFR1 or mutated/amplified FGFR2. In all xenograft models studied, lucitanib demonstrated marked tumor growth inhibition due to potent inhibition of angiogenesis. Notably, in two lung cancer models with FGFR1 amplification, the antitumor efficacy was higher, suggesting that the simultaneous inhibition of VEGF and FGF receptors in FGFR1 dependent tumors can be therapeutically advantageous. Similar antitumor activity was observed in FGFR2 wild-type and amplified or mutated xenograft models. Pharmacokinetic studies showed lucitanib plasma concentrations in the micro/sub-micromolar range demonstrated drug accumulation following repeated lucitanib administration. PMID- 27988459 TI - Suppression of LPS-induced NF-kappaB activity in macrophages by the synthetic aurone, (Z)-2-((5-(hydroxymethyl) furan-2-yl) methylene) benzofuran-3(2H)-one. AB - Suppressing cytokine responses has frequently been shown to have promising therapeutic effects for many chronic inflammatory and autoimmune diseases. However, the severe side effects associated with the long-term use of current treatments, such as allergic reactions and increased risk of stroke, have focused attention towards the targeting of intracellular signaling mechanisms, such as NF kappaB, that regulate inflammation. We synthesized a series of non-natural aurone derivatives and investigated their ability to suppress pro-inflammatory signaling in human monocyte (THP-1) and murine macrophage-like (RAW 267.4) cell lines. One of these derivatives, (Z)-2-((5-(hydroxymethyl) furan-2-yl) methylene) benzofuran 3(2H)-one (aurone 1), was found to inhibit LPS-induced secretion of the pro inflammatory cytokines, tumor-necrosis factor alpha (TNFalpha), interleukin 1beta (IL-1beta), and IL-8 by THP-1 cells. To investigate the mechanism, we probed the effect of aurone 1 on LPS-induced MAPK and NF-kappaB signaling in both THP-1 and RAW264.7. While aurone 1 pre-treatment had no effect on the phosphorylation of ERK, JNK, or p38 MAPK, it strongly suppressed activation of IKK-beta, as indicated by attenuation of Ser176/180 phosphorylation, resulting in decreased phosphorylation of p65 (ser536) as well as phosphorylation (ser32) and degradation of IkappaBalpha. Consistent with this, aurone 1 significantly reduced LPS-stimulated nuclear translocation of p65-containing NF-kappaB transcription factors and expression of an mCherry reporter of TNFalpha gene transactivation in RAW264.7 cells. Inhibition of TNFalpha expression at the transcription level was also demonstrated in THP-1 by qRT-PCR. In addition to its effects on cytokine expression, aurone 1 pre-treatment decreased expression of iNOS, a bona fide NF kappaB target gene and marker of macrophage M1 polarization, resulting in decreased NO production in RAW264.7 cells. Together, these data indicate that aurone 1 may have the potential to function as a pharmacological agent for the treatment of chronic inflammation disorders. PMID- 27988460 TI - Biological evaluation and molecular docking studies of nitro benzamide derivatives with respect to in vitro anti-inflammatory activity. AB - A series of nitro substituted benzamide derivatives were synthesized and evaluated for their potential anti-inflammatory activities in vitro. Firstly, all compounds (1-6) were screened for their inhibitory capacity on LPS induced nitric oxide (NO) production in RAW264.7 macrophages. Compounds 5 and 6 demonstrated significantly high inhibition capacities in a dose-dependent manner with IC50 values of 3.7 and 5.3MUM, respectively. These two compounds were also accompanied by no cytotoxicity at the studied concentrations (max 50MUM) in macrophages. Molecular docking analysis on iNOS revealed that compounds 5 and 6 bind to the enzyme more efficiently compared to other compounds due to having optimum number of nitro groups, orientations and polarizabilities. In addition, 5 and 6 demonstrated distinct regulatory mechanisms for the expression of the iNOS enzyme at the mRNA and protein levels. Specifically, both suppressed expressions of COX 2, IL-1beta and TNF-alpha significantly, at 10 and 20MUM. However, only compound 6 significantly and considerably decreased LPS-induced secretion of IL-1beta and TNF-alpha. These results suggest that compound 6 may be a multi-potent promising lead compound for further optimization in structure and as well as for in vivo validation studies. PMID- 27988461 TI - Divergent regulatory roles of extracellular ATP in the degranulation response of mouse bone marrow-derived mast cells. AB - Mast cells (MCs) play a critical role in allergic inflammation. Although purinergic signalling is implicated in the regulation of various immune responses, its role in MC function is not fully understood. In this study, we investigated the regulatory role of purinergic signalling in MC degranulation, using mouse bone marrow-derived mast cells (BMMCs). Notably, BMMCs expressed various functional P2 adenosine triphosphate (ATP) receptors, including ionotropic P2X4 and P2X7, involved in the regulation of BMMC degranulation. Thus, P2X7 receptor activation induced a marked degranulation from BMMCs directly. Although P2X4 receptor activation did not independently induce degranulation, it significantly potentiated the degranulation triggered by antigen-induced, high affinity IgE receptor (FcepsilonRI) stimulation. In addition, ATP synergistically augmented degranulation induced by adenosine A3 receptor activation. Moreover, BMMCs highly expressed ecto-nucleotidase CD39, but not ecto-5'-nucleotidase (CD73), and were therefore unable to directly convert ATP to adenosine. However, in the presence of CD73-expressing cells, ATP-mediated BMMC stimulation caused a marked degranulation in a CD73- and adenosine-dependent manner. These results demonstrate that purinergic signalling plays an important role in MC degranulation through at least three distinct mechanisms: (1) higher ATP concentrations directly induce degranulation via P2X7 receptor activation, (2) lower ATP concentrations augment FcepsilonRI-mediated degranulation via P2X4 receptor activation, and (3) in an ecto-nucleotidase-enrich environment, ATP and the converted product adenosine induce a synergistic degranulation by P1 and P2 receptor co-activation. PMID- 27988463 TI - Thiazolidinediones and PPAR orchestra as antidiabetic agents: From past to present. AB - Thiazolidinediones a class of drug, that provided a major breakthrough in the management of type 2 diabetes since 1990. Following the discovery of PPARs, TZDs were the first class to be reported as PPARgamma modulators. This review is an attempt to summarize the chemical modifications around TZDs in past two decades to obtain a potent antidiabetic molecule. TZDs literature were initially dominated by their hypoglycemic & hypolipidemic activities, later PPARgamma activity was also been incorporated. Moreover, in some cases, both benzyl and benzylidene derivatives were reported in the same manuscript for the sake of comparison. We thought of presenting the review on the basis of the variation in the linker region. Optimal linker at the time of discovery of the Ciglitazone was oxymethyl and it went on to evolve as oxyethyl (Pioglitazone) and oxyethylamino (Rosiglitazone). Few attempts were made to restrict the flexibility of the linker by introducing the cyclic structures and were summarized immediately after the respective linker class. PMID- 27988462 TI - Spatial distribution of airway wall displacements during breathing and bronchoconstriction measured by ultrasound elastography using finite element image registration. AB - With every breath, the airways within the lungs are strained. This periodic stretching is thought to play an important role in determining airway caliber in health and disease. Particularly, deep breaths can mitigate excessive airway narrowing in healthy subjects, but this beneficial effect is absent in asthmatics, perhaps due to an inability to stretch the airway smooth muscle (ASM) embedded within an airway wall. The heterogeneous composition throughout an airway wall likely modulates the strain felt by the ASM but the magnitude of ASM strain is difficult to measure directly. In this study, we optimized a finite element image registration method to measure the spatial distribution of displacements and strains throughout an airway wall during pressure inflation within the physiological breathing range before and after induced narrowing with acetylcholine (ACh). The method was shown to be repeatable, and displacements estimated from different image sequences of the same deformation agreed to within 5.3MUm (0.77%). We found the magnitude and spatial distribution of displacements were radially and longitudinally heterogeneous. The region in the middle layer of the airway experienced the largest radial strain due to a transmural pressure (Ptm) increase simulating tidal breathing and a deep inspiration (DI), while the region containing the ASM (i.e., closest to the lumen) strained least. During induced narrowing with ACh, we observed temporal longitudinal heterogeneity of the airway wall. After constriction, the displacements and strain are much smaller than the relaxed airway and the pattern of strains changed, suggesting the airway stiffened heterogeneously. PMID- 27988464 TI - Synthesis and biological screening of novel 2-morpholinoquinoline nucleus clubbed with 1,2,4-oxadiazole motifs. AB - Novel series of 2-morpholinoquinoline scaffolds (6a-n), containing the 1,2,4 oxadiazole and moiety, was designed and synthesized in good yield (76-86%). The synthesized compounds were screened for their preliminary in vitro antimicrobial activity against a panel of pathogenic strains of bacteria and fungi. Molecular docking and pharmacokinetic study were carried out for the prepared compounds. The cytotoxicity of the synthesized compounds was tested at different concentrations using bioassay of S. pombe cells at the cellular level. The effect of synthesized compounds on the DNA integrity of S. pombe was observed on agarose gel. Compounds 6d, 6e, 6g, 6h, 6j and 6n exhibited excellent antimicrobial potency as compared to the standard drugs (i.e Ampicillin, Norfloxacin, Chloramphenicol, Ciprofloxacin). Compounds 6d, 6e, 6g, 6k and 6n were found to have significant antifungal activity as compared to griseofulvin. Compounds 6f, 6i, 6k, 6l were found very less cytotoxic, while compounds 6d, 6e, 6g, 6h were found to exhibit maximum toxicity. The rest of the synthesized compounds were found to be moderately toxic. PMID- 27988465 TI - Occurrence and ecological distribution of Heat Resistant Moulds Spores (HRMS) in raw materials used by food industry and thermal characterization of two Talaromyces isolates. AB - In this study, screening of some raw materials used to produce pasteurized products was carried out to determine the occurrence and ecological distribution of heat-resistant fungi. The search for Heat Resistant Mould Spores (HRMS) resulted in the isolation of a limited number of fungal genera: Arthrinium, Aspergillus with either Eurotium-type or Neosartorya-type ascoma, Byssochlamys, Hyphodermella, Monascus, Penicillium, Rasamsonia, Talaromyces and Thermoascus. Sexual aspergilli constituted an overwhelming percentage of the mycobiota, totaling 93.5% of the heat-resistant fungi detected, and being the only fungi to be simultaneously detected in discrete concentrations on almost all matrices found positive for HRMS. Talaromyces spp., Penicillium spp. and Monascus sp. occurred at low percentages (up to 2.1%), though they were the most commonly occurring genera in lemon cells (Talaromyces, Monascus) and blueberries (Penicillium spp.). Among these isolates, two Talaromyces spp. (T. trachyspermus and T. bacillisporus) were tested for heat-resistance in both blueberry and grape juice or in buffered glucose solution, in order to assess their D- and z-values. Data obtained from thermal death curves and statistical elaboration of raw data showed that D-values of T. trachyspermus ranged between 50.0 and 90.9min at 75 degrees C; 13.6 and 20.8min at 78 degrees C; 5.1 and 12.4min at 80 degrees C; 1.6 and 2.6min at 82 degrees C. D values of T. bacillisporus ranged between 44.4 and 60.9min at 82 degrees C; 11.9 and 15.5min at 85 degrees C; 2.7 and 4.1min at 88 degrees C and were equal to 1.2min at 91 degrees C, depending on the medium. The heating times needed for inactivation were comparable to those applied to most heat-resistant species, but significantly lower than those applied to Talaromyces macrosporus or less common ascospore-forming fungal species such as Hamigera avellanea and Thermoascus crustaceus. Therefore, a traditional pasteurization process would be insufficient to avoid potential spoilage problems with T. trachyspermus or T. bacillisporus, even if HRMS contamination of the raw materials processed by food industries is generally low (<100CFU/kg), since the food industry generally tries to achieve five or more log-reduction in their products. PMID- 27988466 TI - A structural equation model on the attributes of a skills enhancement program affecting clinical competence of pre-graduate nursing students. AB - BACKGROUND: Clinical competence remains an issue in nursing and has received greater emphasis than academic competence. Although skill enhancement programs are recommended and beneficial, there is limited evidence on its influence on the clinical competence of pre-graduate nursing students. OBJECTIVE: This study explored the attributes of a skills enhancement program that affect the perceived clinical competence of pre-graduate nursing students. DESIGN AND SETTING: A cross sectional study was conducted in a private higher education institution in the Philippines from April to May 2016. PARTICIPANT AND METHODS: A total of 245 pre graduate nursing students participated and completed a three-part survey composed of the respondent's robotfoto, the Skills Enhancement Program Questionnaire, and the Clinical Competence Questionnaire. Factor analysis explicated the attributes of the skills enhancement program while structural equation modeling and path analysis analyzed the variables' relationship. RESULTS: Findings showed that a skills enhancement program has 4 attributes: supportive clinical instructor, comprehensive orientation, formative goals and objectives, and conducive learning environment. Although all attributes of the program positively affected clinical competence, a supportive clinical instructor had the strongest influence on all clinical competency dimensions. CONCLUSION: A skills enhancement program that has a supportive clinical instructor, comprehensive orientation, formative goals and objectives, and conducive learning environment facilitates clinical competency development among pre-graduate nursing students. This knowledge provides momentum for nursing educators to review and refine their skills and the existing design of their skills enhancement program to further develop clinical competency among pre-graduate nursing students. PMID- 27988467 TI - Vancomycin-resistant Enterococcus colonization does not accurately predict resistant Enterococcus infections. PMID- 27988468 TI - Porous carbon derived from Sunflower as a host matrix for ultra-stable lithium selenium battery. AB - A novel porous carbon material using the spongy tissue of sunflower as raw material is reported for the first time. The obtained porous carbon has an extremely high surface area of 2493.0m2g-1, which is beneficial to focus on encapsulating selenium in it and have an inhibiting effect about diffusion of polyselenides over the charge/discharge processes used as the host matrix for Li Se battery. The porous carbon/Se composite electrode with 63wt% selenium delivers a high specific capacitance of 319mAhg-1 of the initial capacity, and maintains 290mAhg-1, representing an extremely high capacity retention of 90.9% after 840 cycles with the rate of 1C. PMID- 27988469 TI - Comparative study of the role of extracellular polymeric substances in biosorption of Ni(II) onto aerobic/anaerobic granular sludge. AB - This study was carried out to comparatively evaluate the role of extracellular polymeric substances (EPS) in biosorption of Ni(II) onto aerobic/anaerobic granular sludge (AGS and AnGS). Batch sorption experiments data suggested that Ni(II) sorption onto AGS and AnGS were better fitted to Langmuir and Freundlich model, respectively. The contribution of EPS in the sorption of AnGS was higher than that of AGS. Interaction between EPS and Ni(II) was investigated by a combined three-dimensional excitation-emission matrix (3D-EEM), synchronous fluorescence spectra, two-dimensional correlation spectroscopy (2D-COS) and fourier transform infrared spectroscopy (FTIR). 3D-EEM showed that protein (PN) like substances were the main peaks in EPS from AGS and AnGS. The quenched types of AGS and AnGS in the presence of Ni(II) belonged to dynamic and static quenching, respectively. Additionally, 2D-COS demonstrated that fluorescence change took place sequentially followed to humic-like region>PN-like region in AGS and fulvic-like fraction>PN-like and humic-like fractions in AnGS. According to FTIR spectra, hydroxyl group and amino group in both EPS were the key functional groups for Ni(II) sorption. PMID- 27988470 TI - Precise glioblastoma targeting by AS1411 aptamer-functionalized poly (l-gamma glutamylglutamine)-paclitaxel nanoconjugates. AB - Chemotherapy is still the main adjuvant strategy after surgery in glioblastoma therapy. As the main obstacles of chemotherapeutic drugs for glioblastoma treatment, the blood brain barrier (BBB) and non-specific delivery to non-tumor tissues greatly limit the accumulation of drugs into tumor tissues and simultaneously cause serious toxicity to nearby normal tissues which altogether compromised the chemotherapeutic effect. In the present study, we established an aptamer AS1411-functionalized poly (l-gamma-glutamyl-glutamine)-paclitaxel (PGG PTX) nanoconjugates drug delivery system (AS1411-PGG-PTX), providing an advantageous solution of combining the precisely active targeting and the optimized solubilization of paclitaxel. The receptor nucleolin, highly expressed in glioblastoma U87 MG cells as well as neo-vascular endothelial cells, mediated the binding and endocytosis of AS1411-PGG-PTX nanoconjugates, leading to significantly enhanced uptake of AS1411-PGG-PTX nanoconjugates by tumor cells and three-dimension tumor spheroids, and intensive pro-apoptosis effect of AS1411-PGG PTX nanoconjugates. In vivo fluorescence imaging and tissue distribution further demonstrated the higher tumor distribution of AS1411-PGG-PTX as compared with PGG PTX. As a result, the AS1411-PGG-PTX nanoconjugates presented the best anti glioblastoma effect with prolonged median survival time and most tumor cell apoptosis in vivo as compared with other groups. In conclusion, the AS1411-PGG PTX nanoconjugates exhibited a promising targeting delivery strategy for glioblastoma therapy. PMID- 27988471 TI - Early histological, hormonal, and molecular changes during pineapple (Ananas comosus (L.) Merrill) artificial flowering induction. AB - Natural flowering can cause serious scheduling problems in the pineapple (Ananas comosus) industry and increase harvest costs. Pineapple flowering is thought to be triggered by increased ethylene levels and artificial forcing of pineapple flowering is a common practice to promote flowering synchronisation. However, little is known about the early hormonal and molecular changes of pineapple flowering induction and development. Here, we aimed to analyse the molecular, hormonal, and histological changes during artificial pineapple flowering by Ethrel(r)48 treatment. Histological analyses of the shoot apical meristem, leaf gibberellic acid (GA3), and ethylene quantification were carried out during the first 72h after Ethrel(r)48 treatment. Expression profiles from ethylene biosynthesis (AcACS2 and AcACO1), gibberellin metabolism (AcGA2-ox1 and AcDELLA1), and flower development (FT-like gene (AcFT), LFY-like gene (AcLFY), and a PISTILLATA-like gene (AcPI)) genes were analysed during the first 24h after Ethrel(r)48 treatment. Differentiation processes of the shoot apical meristem into flower buds were already present in the first 72h after Ethrel(r)48 treatment. Ethrel(r)48 lead to a reduction in GA3 levels, probably triggered by elevated ethylene levels and the positive regulation AcGA2-ox1. AcLFY activation upon Ethrel(r)48 may also have contributed to the reduction of GA3 levels and, along with the up-regulation of AcPI, are probably associated with the flower induction activation. AcFT and AcDELLA1 do not seem to be regulated by GA3 and ethylene. Decreased GA3 and increased ethylene levels suggest an accumulation of AcDELLA1, which may display an important role in pineapple flowering induction. Thus, this study shows that molecular, hormonal, and histological changes are present right after Ethrel(r)48 treatment, providing new insights into how pineapple flowering occurs under natural conditions. PMID- 27988472 TI - Co-delivery of docetaxel and verapamil by reduction-sensitive PEG-PLGA-SS-DTX conjugate micelles to reverse the multi-drug resistance of breast cancer. AB - The clinical usage of docetaxel (DTX) has been blocked in the clinic because of its poor solubility and tumour multi-drug resistance (MDR). The dominating mechanism of MDR is the over-expression of p-gp on tumour cells. Traditional nano medicines, such as nanoparticles and micelles, have been used to physically entrap DTX to improve their solubility, while the drug loading content was very low and the tumour resistance was neglected. In this study, the synthesized reduction-sensitive mPEG-PLGA-SS-DTX conjugate was utilized to load the p-gp inhibitor veraparmil (VRP) to prepare DTX and VRP co-delivered mPEG-PLGA-SS DTX/VRP (PP-SS-DTX/VRP) multi-functional micelles to reverse MDR and enhance the anti-tumour effect of DTX. The micelles had a high drug loading content and showed an obvious reduction-sensitive release property for both DTX and VRP. In addition, an in vitro anti-tumour assay revealed that the micelles markedly inhibited the efflux activity of p-gp and accelerated cell apoptosis, resulting in the improvement of anti-tumour activity and reversal of MDR. The PP-SS-DTX micelles markedly enhanced the in vivo circulation time and increased the drug accumulation in tumour tissues. Therefore, the PP-SS-DTX/VRP micelle is a desirable drug delivery system for multi-drug resistance therapy of DTX and is very promising for clinical usage. PMID- 27988473 TI - alpha-Tocopheryl linolenate solid lipid nanoparticles for the encapsulation, protection, and release of the omega-3 polyunsaturated fatty acid: in vitro anti melanoma activity evaluation. AB - The main target of this study was the preparation, characterization and antioxidant activity evaluation of alpha-tocopheryl linolenate based solid lipid nanoparticles (SLNs-TL), able to incorporate omega-3 alpha-linolenic acid, useful for the treatment of melanoma, a type of skin cancer. In particular, alpha linolenic acid was successfully derivatized with alpha-tocopherol and the obtained compound was characterized by Fourier transform infrared (FT-IR) and by 1H NMR to confirm the ester linkage. Both the empty SLNs-TL that SLNs-TL-LIN, containing omega-3-linolenic acid, were prepared through the technique of the microemulsion. The nanoparticles were characterized for entrapment efficiency, size and shape. Their antioxidant activity was investigated in rat liver microsomal membranes in inhibiting the lipid peroxidation induced by tert-butyl hydroperoxide (tert-BOOH), which endogenously produces alkoxyl radicals by Fenton reactions. The obtained results indicate that the alpha-tocopherol, linked by ester bond to alpha-linolenic acid, maintains an excellent antioxidant activity. The encapsulation efficiency was equal to 77% and the polydispersity index 0.198 indicating a good dimensional distribution. Furthermore, the nanoparticles were tested in vitro for their cytotoxic activity against human melanoma cancer cell line C32. Both empty SLNs-TL and loaded SLNs-TL-LIN showed a high biological activity, being more effective than alpha-linolenic acid and alpha-tocopherol. The results indicated that these nanoparticles could provide the delivery and the protection of unstable molecules, such as alpha-linolenic acid, from degradation induced by mechanisms of oxidative stress. PMID- 27988474 TI - Mapping of endoglucanases displayed on yeast cell surface using atomic force microscopy. AB - The surface of yeast cells has been an attractive interface for the effective use of cellulose. Surface enzymes, however, are difficult to visualize and evaluate. In this study, two kinds of unique anchoring regions were used to display the cellulase, endoglucanase (EG), on a yeast cell surface. Differences in the display level and the localization of EG were observed by atomic force microscopy. By surveying the yeast cell surface with a chemically modified cantilever, the interactive force between the cellulose and EG was measured. Force curve mapping revealed differences in the display levels and the localization of EG according to anchoring regions. The proposed methodology enables visualization of displayed enzymes such as EG on the yeast cell surface. PMID- 27988475 TI - Two-stage cultivation of Nannochloropsis oculata for lipid production using reversible alkaline flocculation. AB - Two-stage cultivation for microalgae biomass is a promising strategy to boost lipid accumulation and productivity. Most of the currently described processes use energy-intensive centrifugation for cell separation after the first cultivation stage. This laboratory study evaluated alkaline flocculation as low cost alternative separation method to harvest Nannochloropsis oculata prior to cultivation in the second nutrient-depleted cultivation stage. Biomass concentration over time and the maximum quantum yield of photosystem II expressed as Fv:Fm ratio showed identical patterns for both harvesting methods in both stages. The composition of total lipids, carbohydrates, and protein was similar for biomass harvested via alkaline flocculation or centrifugation. Likewise, both harvest methods yielded the same increase in total lipid content, to 40% within the first 2days of the nutrient-depleted stage, with an enrichment in C16 fatty acid methyl esters. Centrifugation can therefore be replaced with alkaline flocculation to harvest Nannochloropsis oculata after the first cultivation stage. PMID- 27988476 TI - Alkali pretreatment at ambient temperature: A promising method to enhance biomethanation of rice straw. AB - Anaerobic digestion is the most cost effective technology for sustainable biogas production from rice straw. Rice straw was subjected to ambient pretreatment with alkali and subsequently digested anaerobically. A dimensional equation was developed to predict the efficacy of alkali treatment in terms of soluble COD. Biomethanation process parameters like temperature, initial pH, particle size, substrate/inoculum ratio, trace element supplementation, C/N ratio and hydraulic retention time were optimized. The highest biogas production under optimized conditions was 514L/kg VS/day (~59% CH4) from milled rice straw (1mm) pretreated with sodium hydroxide (1% w/v) at ambient temperature for 180min. The digester was operated at 15days HRT at 37 degrees C and neutral pH. C/N ratio was optimized at 25 using urea. Higher biogas yield from rice straw treated with lower concentration of NaOH at ambient temperature may make this process more economical than the previous reports. PMID- 27988477 TI - Effectiveness and tolerability of antiepileptic drugs in 104 girls with Rett syndrome. AB - : Approximately 60-80% of girls with Rett Syndrome (RTT) have epilepsy, which represents one of the most severe problems clinicians have to deal with, especially when patients are 7-12years old. The aim of this study was to analyze the antiepileptic drugs (AEDs) prescribed in RTT, and to assess their effectiveness and tolerability in different age groups from early infancy to adulthood. We included in this study 104 girls, aged 2-42years (mean age 13.9years): 89 had a mutation in MECP2, 5 in CDKL5, 2 in FOXG1, and the mutational status was unknown in the remaining 8. Epilepsy was present in 82 patients (79%). Mean age at epilepsy onset was 4.1years. We divided the girls into 5 groups according to age: <5, 5-9, 10-14, 15-19, 20years and older. Valproic acid (VPA) was the most prescribed single therapy in young patients (<15years), whereas carbamazepine (CBZ) was preferred by clinicians in older patients. The most frequently adopted AED combination in the patients younger than 10years and older than 15 was VPA and lamotrigine (LTG). Seizures in the group aged 10-14years were the most difficult to treat, requiring a mean of three different AEDs, often used in combination and mostly including VPA. Seizures in fifteen patients (18%) were considered drug resistant. VPA was reported as the most effective AED in younger girls (in 40% of the patients aged <5years, in 19% of the girls aged 5-9years), and CBZ the most effective in the patients 15years or older. Adverse reactions did not differ from expected: agitation, drowsiness, and weight loss were the most frequently reported. In our sample, LTG was the least tolerated AED. We did not find correlations with MECP2 mutations in terms of effectiveness or adverse reactions. CONCLUSION: in this study we observed different effectiveness of AEDs based on age, and suggest that clinicians consider age-dependency when prescribing appropriate AEDs in the RTT population. PMID- 27988478 TI - Monitoring the short-term effect of intravenous immunoglobulins in multifocal motor neuropathy using motor unit number index. AB - OBJECTIVE: To determine whether motor unit number index (MUNIX) is pertinent to monitor the effect of intravenous immunoglobulins (IVIg) in multifocal motor neuropathy (MMN). METHODS: MUNIX was assessed longitudinally in 7 MMN patients and 17 healthy controls in the abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. A MUNIX sum-score and a compound muscle action potential (CMAP) sum-score were calculated by summing up the scores of APB and ADM. MMN patients were evaluated on the first day of IVIg infusion, 5 MMN patients were evaluated 22days after IVIg infusion, and 3 MMN patients were evaluated 1month after two IVIg infusions. RESULTS: Intraclass correlation coefficient of the MUNIX sum-score in healthy controls was 0.85, showing good test-retest reproducibility. MUNIX and CMAP sum-scores were lower in MMN patients than in healthy controls (p<0.01 and 0.02, respectively). MUNIX sum-score improved in three of the five patients 22days after IVIg infusion and in two of the three patients 1month after 2 IVIg infusions, whereas CMAP sum-score improved in only one patient in both evaluations. CONCLUSIONS: In this preliminary study, MUNIX seems to be a reliable and sensitive tool to monitor the short-term efficiency of IVIg in MMN. SIGNIFICANCE: MUNIX can help monitor IVIg treatment in MMN. PMID- 27988479 TI - Label-free and high-throughput biosensing of multiple tumor markers on a single light-addressable photoelectrochemical sensor. AB - The sensitive and label-free detection of multiple biomarkers on a single electrode by photoelectrochemical (PEC) sensors based on light addressing strategies is very attractive for developing portable and high-throughput biosensing systems. The essential prerequisite of this proposal is the employment of uniform photovoltaic material modified electrodes with high conversion efficiency. Herein, a novel two-step constant potential deposition method for the rapid fabrication of bismuth sulfide film modified ITO electrodes (Bi2S3/ITO) was established. The produced Bi2S3/ITO, with excellent uniformity and high conversion efficiency in visible light ranges, was further modified with gold nanoparticles (AuNPs) and then divided into separated identical sensing zones by insulative paints. The adsorption-based immobilization of antibodies of three tumor markers, i.e., a-fetoprotein (AFP), carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9), onto different sensing zones of the electrode and the further blocking with BSA established a label-free and light-addressable PEC sensor (LF-LAPECS), which can achieve the rapid and sensitive detection of these biomarkers with wide linear ranges, low detection limits and self-calibration ability. Moreover, the detection throughput can be conveniently improved by enlarging the size of the substrate electrode and increasing the number of separated sensing zones. The present work thus demonstrates the promising applications of PEC techniques for developing sensitive, time-saving, cost effective and high-throughput biosensing methods. PMID- 27988480 TI - Simultaneous quantitation of cytokeratin-19 fragment and carcinoembryonic antigen in human serum via quantum dot-doped nanoparticles. AB - A novel quantum dot-doped polystyrene nanoparticles-based lateral flow test strips (QPs-LFTS) system was developed to simultaneously detect a cytokeratin-19 fragment (CYFRA 21-1) and carcinoembryonic antigen (CEA) in human serum to aid the diagnosis and prognosis of lung cancer. Quantum dot-doped carboxylate functionalized polystyrene nanoparticles (QPs) were prepared and introduced as fluorescent reporters in QPs-LFTS. The detection was based on a sandwich immunoassay and performed on lateral flow test strips, with an assay time of 15min. The strips were read by a fluorescence strip reader to obtain the fluorescence peak heights of the test lines (HT) and the control line (HC). The ratio of HT/HC was used for quantitation. The QPs showed excellent photoproperties and good performance. Under optimal conditions, the QPs-LFTS system exhibited a wide linear range for CYFRA 21-1 (1.3-480ng/mL) and CEA (2.8 680ng/mL). The detection limits for CYFRA 21-1 and CEA were 0.16 and 0.35ng/mL, respectively. The recovery and reproducibility of the method were satisfactory. Furthermore, excellent correlations (n =120, R2 =0.9862, P<0.0001 for CYFRA 21-1; n =70, R2 =0.9509, P<0.0001 for CEA) were obtained between the QPs-LFTS and commercially available chemiluminescence immunoassay kits in clinical serum testing. The results indicate that this developed test system is highly efficient and is expected to be useful for early screening and prognosis evaluation for lung cancer patients. PMID- 27988481 TI - Major intrinsic proteins repertoire of Morus notabilis and their expression profiles in different species. AB - Leaf moisture content in Morus is a significant trait regulating the yield of silk production. Studies have shown that fresh leaves or leaves with high water content are preferably eaten by silk worm. Water and certain other molecules transport in plants is known to be regulated by aquaporins or Major Intrinsic Proteins (MIPs). Members of the MIP gene family have also been implicated in plant development and stress responsiveness. To understand how members of MIP gene family are regulated and evolved, we carried out an extensive analysis of the gene family. We identified a total of 36 non redundant MIPs in Morus notabilis genome, belonging to five subfamilies PIPs, TIPs, NIPs, XIPs and SIPs) have been identified. We performed a Gene ontology (GO) term enrichment analysis and looked at distribution of cis elements in their 2K upstream regulatory region to reveal their putative roles in various stresses and developmental aspects. Expression analysis in developmental stages revealed their tissue preferential expression pattern in diverse vegetative and reproductive tissues. Comparison of expression profiles in the leaves of three species including Morus notabilis, Morus serrata and Morus laevigata led to identification of differential expression in these species. In all, this study elaborates a basic insight into the structure, function and evolutionary analysis of MIP gene family in Morus which is hitherto unavailable. Our analysis will provide a ready reference to the mulberry research community involved in the Morus improvement program. PMID- 27988483 TI - The Role of Task Understanding on Younger and Older Adults' Performance. AB - OBJECTIVES: Age-related performance decrements have been linked to inferior strategic choices. Strategy selection models argue that accurate task representations are necessary for choosing appropriate strategies. But no studies to date have compared task representations in younger and older adults. Metacognition research suggests age-related deficits in updating and utilizing strategy knowledge, but other research suggests age-related sparing when information can be consolidated into a coherent mental model. METHOD: Study 1 validated the use of concept mapping as a tool for measuring task representation accuracy. Study 2 measured task representations before and after a complex strategic task to test for age-related decrements in task representation formation and updating. RESULTS: Task representation accuracy and task performance were equivalent across age groups. Better task representations were related to better performance. However, task representation scores remained fairly stable over the task with minimal evidence of updating. DISCUSSION: Our findings mirror those in the mental model literature suggesting age-related sparing of strategy use when information can be integrated into a coherent mental model. Future research should manipulate the presence of a unifying context to better evaluate this hypothesis. PMID- 27988482 TI - Toward a More Comprehensive Concept of Successful Aging: Disability and Care Needs. AB - Rowe and Kahn's model of Successful Aging 2.0 argues that changing environmental settings, societal policies, and individual life styles will lead to a significant extension of healthy life years. Recent epidemiological research, however, confirms the dilemma that the ongoing extension of life expectancy prolongs not only the years in good health but also those in poor health. We see it as a major limitation that Rowe and Kahn's model is not able to cover the emerging linkage between increasing life expectation and aging with disability and care needs. Therefore, we suggest a set of propositions towards a more comprehensive model of successful aging which captures desirable living situations including for those who grow old with disabilities and care needs. We describe individual, environmental, and care related strategies and resources for autonomy and quality of life when facing disabilities and care needs in late life, putting emphasis on inter-individual differences and social inequality. We argue that expanding the traditional concept of successful aging to aging with disabilities and care needs serves not to undermine, but rather to anchor the concept in aging science and in public perception. PMID- 27988486 TI - Preventing Electrostatic Contamination of Breast Implants: An Effective and Simple Intraoperative Method. PMID- 27988487 TI - Separation and Sensitive Detection of Lanthanides by Capillary Electrophoresis and Contactless Conductivity Detection. AB - A rapid and sensitive capillary zone electrophoresis method for the simultaneous separation and determination of lanthanide ions, combined with capacitively coupled contactless conductivity detection (C4D), is reported. The influence of experimental parameters on separation was investigated. The optimal separation conditions were obtained when 4.5 mM 2-hydroxyisobutyric acid and 1 mM acetic acid (HAc) at pH 4.5 were used as buffer solution. Under these conditions, complete separation of all 14 lanthanide ions was achieved in 6 min. With the use of the C4D detector, the sensitive detection of non-UV active lanthanide ions was achieved without the need of a UV active ligand or a visualization agent. The sensitivities were further enhanced with a sample stacking procedure. The limits of detection were to be found between 2.77 and 8.26 nmol/L and the limits of quantification were between 9.29 and 27.5 nmol/L for 14 lanthanide ions. PMID- 27988484 TI - Fixed-Dose Artesunate-Amodiaquine Combination vs Chloroquine for Treatment of Uncomplicated Blood Stage P. vivax Infection in the Brazilian Amazon: An Open Label Randomized, Controlled Trial. AB - BACKGROUND: Despite increasing evidence of the development of Plasmodium vivax chloroquine (CQ) resistance, there have been no trials comparing its efficacy with that of artemisinin-based combination therapies (ACTs) in Latin America. METHODS: This randomized controlled trial compared the antischizontocidal efficacy and safety of a 3-day supervised treatment of the fixed-dose combination artesunate-amodiaquine Winthrop(r) (ASAQ) versus CQ for treatment of uncomplicated P. vivax infection in Manaus, Brazil. Patients were followed for 42 days. Primary endpoints were adequate clinical and parasitological responses (ACPR) rates at day 28. Genotype-adjustment was performed. RESULTS: From 2012 to 2013, 380 patients were enrolled. In the per-protocol (PP) analysis, adjusted ACPR was achieved in 100% (165/165) and 93.6% (161/172) of patients in the ASAQ and CQ arm (difference 6.4%, 95% CI 2.7%; 10.1%) at day 28 and in 97.4% (151/155) and 77.7% (129/166), respectively (difference 19.7%, 95% CI 12.9%; 26.5%), at day 42. Apart from ITT D28 assessment, superiority of ASAQ on ACPR was demonstrated. ASAQ presented faster clearance of parasitaemia and fever. Based on CQ blood level measurements, CQ resistance prevalence was estimated at 11.5% (95% CI: 7.5 17.3) up to day 42. At least one emergent adverse event (AE) was recorded for 79/190 (41x6%) in the ASAQ group and for 85/190 (44x7%) in the CQ group. Both treatments had similar safety profiles. CONCLUSIONS: ASAQ exhibited high efficacy against CQ resistant P. vivax and is an adequate alternative in the study area. Studies with an efficacious comparator, longer follow-up and genotype-adjustment can improve CQR characterization. CLINICAL TRIALS REGISTRATION: NCT01378286. PMID- 27988488 TI - Identification and Structure Elucidation of Forced Degradation Products of the Novel Propionic acid Derivative Loxoprofen: Development of Stability-Indicating Chromatographic Methods Validated as per ICH Guidelines. AB - Loxoprofen sodium (LOX) is a recently developed novel propionic acid derivative. Owing to its instability under both hydrolytic and oxidative conditions, the development of simple, rapid and sensitive methods for its determination in the presence of its possible forced degradation products becomes essential. Two simple chromatographic methods, high-performance thin layer chromatography (HPTLC) and high-performance liquid chromatography (HPLC), were developed associated with ultraviolet (UV) detection. In HPTLC-densitometric method, the separation of LOX from its degradation products was achieved using silica gel F254 plates and toluene:acetone:acetic acid (1.8:1.0:0.1, v/v/v) as the developing system followed by densitometric scanning at 220 nm. In the HPLC-UV method, the separation was performed using isocratic elution system with acetonitrile: 0.15% triethylamine (pH 2.2) (50:50, v/v) on C18 analytical column. The flow rate was optimized at 1.0 mL.min-1 and UV detection was achieved at 220 nm. Validation was performed in accordance with the International Conference on Harmonization guidelines and the method was perfectly applied for determination of LOX in its pharmaceutical preparation. The results obtained were statistically compared to those obtained after application of the official HPLC method, where no significant difference was found incompliance with precision and accuracy. Identification and characterization of the possible hydrolytic degradation product under alkaline conditions and that produced during oxidative degradation using hydrogen peroxide were structurally elucidated using infrared and mass spectrometry analyses. PMID- 27988485 TI - Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses. AB - BACKGROUND: Candida auris, a multidrug-resistant yeast that causes invasive infections, was first described in 2009 in Japan and has since been reported from several countries. METHODS: To understand the global emergence and epidemiology of C. auris, we obtained isolates from 54 patients with C. auris infection from Pakistan, India, South Africa, and Venezuela during 2012-2015 and the type specimen from Japan. Patient information was available for 41 of the isolates. We conducted antifungal susceptibility testing and whole-genome sequencing (WGS). RESULTS: Available clinical information revealed that 41% of patients had diabetes mellitus, 51% had undergone recent surgery, 73% had a central venous catheter, and 41% were receiving systemic antifungal therapy when C. auris was isolated. The median time from admission to infection was 19 days (interquartile range, 9-36 days), 61% of patients had bloodstream infection, and 59% died. Using stringent break points, 93% of isolates were resistant to fluconazole, 35% to amphotericin B, and 7% to echinocandins; 41% were resistant to 2 antifungal classes and 4% were resistant to 3 classes. WGS demonstrated that isolates were grouped into unique clades by geographic region. Clades were separated by thousands of single-nucleotide polymorphisms, but within each clade isolates were clonal. Different mutations in ERG11 were associated with azole resistance in each geographic clade. CONCLUSIONS: C. auris is an emerging healthcare-associated pathogen associated with high mortality. Treatment options are limited, due to antifungal resistance. WGS analysis suggests nearly simultaneous, and recent, independent emergence of different clonal populations on 3 continents. Risk factors and transmission mechanisms need to be elucidated to guide control measures. PMID- 27988489 TI - Frequent Experience of LGBQ Microaggression on Campus Associated With Smoking Among Sexual Minority College Students. AB - Introduction: Lesbian, gay, bisexual, or queer/questioning (LGBQ) microaggressions refer to often-unintentional insults, assaults, and invalidations that denigrate sexual minorities. While experiencing hostile discrimination and violence has previously been associated with elevated rates of smoking cigarettes for LGBQ college students, the relationship between LGBQ microaggressions and smoking is unknown. Methods: Data from a national anonymous online survey of sexual and gender minority college students were used to examine the relationship between past month cigarette smoking and interpersonal LGBQ microaggressions. Multivariable logistic regression assessed the relationship between smoking and frequent (chronic) experiences of microaggressions, using a hierarchical procedure to control for demographics, predictors of smoking, and academic factors. Results: Past year frequent LGBQ microaggression was reported by 48% of respondents and was more common among students who smoked in past 30 days. Experiencing past year physical violence was reported by 15% and did not differ by smoking status. Past year frequent experience of microaggressions was associated with increased odds of 1.72 (95% CI 1.03-2.87) for past 30-day smoking after adjusting for age, gender, race, socioeconomic indicators, alcohol misuse, physical violence, as well as academic stress and engagement. Conclusions: The results indicate that frequently experiencing LGBQ microaggressions is a risk factor for LGBQ college students smoking cigarettes. The mechanisms underlying this relationship require additional research, as does identifying positive coping strategies and institutional strategies to address LGBQ microaggressions on campuses. Tobacco control efforts should consider the impact of microaggression on the social environment for the prevention and treatment of tobacco use among LGBQ individuals. Implications: Microaggressions related to sexual minority identity include subtle forms of discrimination experienced during daily interactions that can create hostile and stressful social environments for a socially disadvantaged group. Prior research has demonstrated that LGBQ college students have higher rates of cigarette smoking, and that experiencing identity-based violence is a risk factor. This study revealed that experiencing frequent LGBQ microaggressions on college campus is associated with increased likelihood of current smoking among LGBQ college students. PMID- 27988491 TI - Chronic disease and assessing quality of life? PMID- 27988490 TI - Hydrogen Sulfide Ameliorates Homocysteine-Induced Cognitive Dysfunction by Inhibition of Reactive Aldehydes Involving Upregulation of ALDH2. AB - Background: Homocysteine, a risk factor for Alzheimer's disease, induces cognitive dysfunction. Reactive aldehydes play an important role in cognitive dysfunction. Aldehyde-dehydrogenase 2 detoxifies reactive aldehydes. Hydrogen sulfide, a novel neuromodulator, has neuroprotective effects and regulates learning and memory. Our previous work confirmed that the disturbance of hydrogen sulfide synthesis is invovled in homocysteine-induced defects in learning and memory. Therefore, the present work was to explore whether hydrogen sulfide ameliorates homocysteine-generated cognitive dysfunction and to investigate whether its underlying mechanism is related to attenuating accumulation of reactive aldehydes by upregulation of aldehyde-dehydrogenase 2. Methods: The cognitive function of rats was assessed by the Morris water maze test and the novel object recognition test. The levels of malondialdehyde, 4-hydroxynonenal, and glutathione as well as the activity of aldehyde-dehydrogenase 2 were determined by enzyme linked immunosorbent assay; the expression of aldehyde dehydrogenase 2 was detected by western blot. Results: The behavior experiments, Morris water maze test and novel objects recognition test, showed that homocysteine induced deficiency in learning and memory in rats, and this deficiency was reversed by treatment of NaHS (a donor of hydrogen sulfide). We demonstrated that NaHS inhibited homocysteine-induced increases in generations of MDA and 4-HNE in the hippocampus of rats and that hydrogen sulfide reversed homocysteine-induced decreases in the level of glutathione as well as the activity and expression of aldehyde-dehydrogenase 2 in the hippocampus of rats. Conclusion: Hydrogen sulfide ameliorates homocysteine-induced impairment in cognitive function by decreasing accumulation of reactive aldehydes as a result of upregulations of glutathione and aldehyde-dehydrogenase 2. PMID- 27988493 TI - Focal Gain Control of Thalamic Visual Receptive Fields by Layer 6 Corticothalamic Feedback. AB - The projections between the thalamus and primary visual cortex (V1) are a key reciprocal neural circuit, relaying retinal signals to cortical layers 4 & 6 while being simultaneously regulated by massive layer 6 corticothalamic feedback. Effectively dissecting the influence of this corticothalamic feedback circuit in higher mammals remains a challenge for vision research. By pharmacologically increasing the focal gain of visually driven layer 6 responses of cat V1 in a controlled fashion, we examined the effects of such focal cortical changes on the response amplitudes and spatial structure of the receptive fields (RFs) of individual dorsal lateral geniculate nucleus (dLGN) cells. We found that enhancing visually driven cortical feedback could facilitate or suppress the overall responses of dLGN cells, and such an effect was linked to the orientation preference of the cortical neuron. Related to these selective retinotopic gain changes, enhanced feedback induced the RFs of dLGN cells to expand, contract or shift their spatial focus. Our results provide further evidence for a functional mechanism through which the cortex can selectively gate visual information flow from the thalamus back to the visual cortex. PMID- 27988494 TI - A High-Bandwidth Dual-Channel Olfactory Stimulator for Studying Temporal Sensitivity of Olfactory Processing. AB - Animals encounter fine-scale temporal patterns of odorant mixtures that contain information about the distance and number of odorant sources. To study the role of such temporal cues for odorant detection and source localization, one needs odorant delivery devices that are capable of mimicking the temporal stimulus statistics of natural odor plumes. However, current odorant delivery devices either lack temporal resolution or are limited to a single odorant channel. Here, we present an olfactory stimulator that features precise control of high bandwidth stimulus dynamics, which allows generating arbitrary fluctuating binary odorant mixtures. We provide a comprehensive characterization of the stimulator's performance and use it to demonstrate that odor background affects the temporal resolution of insect olfactory receptor neurons, and we present a hitherto unknown odor pulse-tracking capability of up to 60 Hz in Kenyon cells, which are higher order olfactory neurons of the insect brain. This stimulator might help investigating whether and how animals use temporal stimulus cues for odor detection and source localization. Because the stimulator is easy to replicate it can facilitate generating the same odor stimulus dynamics at different experimental setups and across different labs. PMID- 27988492 TI - Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen Treated Patients: Evaluating the Importance of Loss of Heterozygosity. AB - Tamoxifen therapy for estrogen receptor-positive breast cancer reduces the risk of recurrence by approximately one-half. Cytochrome P-450 2D6, encoded by the polymorphic cytochrome P-450 2D6 gene (CYP2D6), oxidizes tamoxifen to its most active metabolites. Steady-state concentrations of endoxifen (4-hydroxy-N desmethyltamoxifen), the most potent antiestrogenic metabolite, are reduced in women whose CYP2D6 genotypes confer poor enzyme function. Thirty-one studies of the association of CYP2D6 genotype with breast cancer survival have yielded heterogeneous results. Some influential studies genotyped DNA from tumor infiltrated tissues, and their results may have been susceptible to germline genotype misclassification from loss of heterozygosity at the CYP2D6 locus. We systematically reviewed 6 studies of concordance between genotypes obtained from paired nonneoplastic and breast tumor-infiltrated tissues, all of which showed excellent CYP2D6 genotype agreement. We applied these concordance data to a quantitative bias analysis of the subset of the 31 studies that were based on genotypes from tumor-infiltrated tissue to examine whether genotyping errors substantially biased estimates of association. The bias analysis showed negligible bias by discordant genotypes. Summary estimates of association, with or without bias adjustment, indicated no clinically important association between CYP2D6 genotype and breast cancer survival in tamoxifen-treated women. PMID- 27988495 TI - Aeromonas as a Cause of Purulent Folliculitis: A Case Report and Review of the Literature. AB - Aeromonas species are rarely an identified cause of folliculitis. Here, we describe the case of a patient who had purulent folliculitis of the breast caused by an Aeromonas species and review 4 other cases presented in the literature, highlighting the commonalities observed. Aeromonas infection should be considered in patients who present with purulent folliculitis, particularly those with exposure to nonchlorinated pools or baths. PMID- 27988496 TI - Resurgence of Rotavirus Genotype G12 in St. Louis During the 2014-2015 Rotavirus Season. AB - Background: Rotaviruses are a leading cause of gastroenteritis. Rotavirus vaccination has dramatically reduced rotavirus occurrence; however, we have noticed mild to moderate recurrences in the St. Louis area in alternate years. In 2013, we found rotavirus genotype G12 to be the dominant strain in the St. Louis region. In this study, we again determined the distribution of genotypes and ascertained vaccine history in patients infected with rotavirus G12 during the 2014-15 season. Methods: Samples submitted to the St. Louis Children's Hospital Microbiology Laboratory were tested for rotavirus using an antigen assay. We determined the VP7 genotype using amplicon sequence analysis. We determined genome sequences using high-throughput sequencing. We evaluated rotavirus immunization records when available. Results: Of 30 typed viruses from 2014-15, 29 were G12 (97%). Whole-genome sequencing revealed few changes from G12 viruses analyzed in 2012-13. VP4 and VP7 sequences were >99% identical to previously sequenced G12 strains from St. Louis, and immune epitopes were conserved. Vaccination histories were available from 17 patients. Of these, 4 had been vaccinated, 3 had received incomplete vaccination or had a vaccine history that could not be confirmed, and 10 had not been vaccinated. Conclusions: G12 re emerged as the predominant rotavirus genotype in 2014-15, comprising a higher percentage of cases than in 2012-13. The majority of patients with G12 and available vaccination histories were unvaccinated. There was no genomic evidence to indicate that the G12 strains in St. Louis had evolved to escape vaccine protection. Our work emphasizes the need for continued surveillance. PMID- 27988497 TI - Late Survival After Aortic Valve Replacement in Patients With Moderately Reduced Kidney Function. AB - BACKGROUND: The influence of moderately reduced kidney function on late survival after surgical aortic valve replacement (AVR) is unknown. We analyzed survival after AVR in patients with moderately reduced kidney function. METHODS AND RESULTS: All patients who underwent primary AVR in Sweden 1997-2013 were identified from the Swedish Web system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies register. Patients were categorized according to estimated glomerular filtration rate (eGFR). Of 13 102 patients, 9836 (75%) had normal kidney function (eGFR >60 mL/min per 1.73 m2) and 3266 (25%) had moderately reduced kidney function (eGFR 30-60 mL/min per 1.73 m2). Mean follow-up time was 6.2 years. Mortality was higher in patients with moderately reduced kidney function; 5-, 10-, and 15-year survival was 76%, 48%, and 25% versus 89%, 73%, and 55% (adjusted hazard ratio [HR], 1.28; 95% CI, 1.18-1.38; P<0.001). Patients with moderately reduced kidney function had a nonsignificantly higher risk of major bleeding (HR, 1.18; 95% CI, 1.00-1.39; P=0.051) and a lower risk for aortic valve reoperation (HR, 0.54; 95% CI, 0.38-0.79; P=0.001) compared to those with normal kidney function. In patients with moderately reduced kidney function, survival was similar in those who received bioprostheses compared to those who received mechanical valves (HR, 0.85; 95% CI, 0.70-1.03; P=0.094). CONCLUSIONS: Moderately reduced kidney function was strongly associated with increased mortality after AVR. These results have important implications for preoperative risk stratification, and suggest that patients with eGFR 30 to 60 mL/min per 1.73 m2 warrant careful observation after AVR. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02276950. PMID- 27988499 TI - The effect of storage temperature fluctuations on the stability of biochemical analytes in blood serum. AB - BACKGROUND: Irreproducibility of scientific results constitutes an undesirably onerous economic burden and is in many cases caused by low-quality materials. Therefore, researchers are increasingly devoting their attention to the bioresources they use. In turn, those bioresources are required to validate their preanalytical processes in order to ensure best possible quality. The present study thus aimed to evaluate the impact of repeated temperature fluctuations, as they occur in most research biobanks due to repetitive opening and closing of freezer doors, on the stability of 26 biochemical analytes. METHODS: Serum of 43 individuals was randomly assigned to a fluctuation (n=21) and a control group (n=22). Serum of the fluctuation group underwent controlled temperature fluctuations (30 fluctuations <-75 degrees C - <-65 degrees C - <-75 degrees C under real-life freezer conditions within 21 days). Control sera were stored at constant conditions. After 10, 20, and 30 fluctuations, results derived from the fluctuation group were compared to baseline and to the control group by means of general linear models. RESULTS: Sixteen biomarkers showed statistically significant changes over time, whereas only seven of those presented with diagnostically/clinically relevant changes at certain time points (aspartate aminotransferase, amylase, calcium, uric acid, creatinine, inorganic phosphate and total protein). However, there was no difference between the fluctuation and the control group. CONCLUSIONS: Some serum analytes are influenced by storage, even at temperatures as low as <-70 degrees C. In contrast, we found no evidence that complex temperature fluctuations produced by storage of and access to biospecimens in biobank freezers generate any additional variability. PMID- 27988498 TI - Measuring Water Distribution in the Heart: Preventing Edema Reduces Ischemia Reperfusion Injury. AB - BACKGROUND: Edema is present in many heart diseases, and differentiation between intracellular (ICW) and extracellular (ECW) myocardial water compartments would be clinically relevant. In this work we developed a magnetic resonance imaging based method to differentiate ICW and ECW and applied it to analyze ischemia reperfusion-induced edema. METHODS AND RESULTS: Isolated rat hearts were perfused with gadolinium chelates as a marker of extracellular space. Total water content was measured by desiccation. Gadolinium quantification provided ECW, and ICW was calculated by subtraction of ECW from total water content. In separate experiments, T1, T2, diffusion-weighted imaging and proton-density parameters were measured in isolated saline-perfused hearts. In in-situ rat hearts, ECW and ICW were 79+/-10 mL and 257+/-8 mL of water per 100 g of dry tissue, respectively. After perfusion for 40 minutes, ECW increased by 92.4+/-3% without modifying ICW (-1+/-3%). Hyposmotic buffer (248 mOsm/L) increased ICW by 16.7+/ 2%, while hyperosmotic perfusion (409 mOsm/L) reduced ICW by 26.5+/-3%. Preclinical imaging showed good correlation between T2 and diffusion-weighted imaging with ECW, and proton-density correlated with total water content. Ischemia-reperfusion resulted in marked myocardial edema at the expense of ECW, because of cellular membrane rupture. When cell death was prevented by blebbistatin, water content and distribution were similar to normoxic perfused hearts. Furthermore, attenuation of intracellular edema with hyperosmotic buffer reduced cell death. CONCLUSIONS: We devised a method to determine edema and tissue water distribution. This method allowed us to demonstrate a role of edema in reperfusion-induced cell death and could serve as a basis for the study of myocardial water distribution using magnetic resonance imaging. PMID- 27988500 TI - Non-coding RNAs: the cancer genome dark matter that matters! AB - Protein-coding genes comprise only 3% of the human genome, while the genes that are transcribed into RNAs but do not code for proteins occupy majority of the genome. Once considered as biological darker matter, non-coding RNAs are now being recognized as critical regulators in cancer genome. Among the many types of non-coding RNAs, microRNAs approximately 20 nucleotides in length are best characterized and their mechanisms of action are well generalized. microRNA exerts oncogenic or tumor suppressor function by regulation of protein-coding genes via sequence complementarity. The expression of microRNA is aberrantly regulated in all cancer types, and both academia and biotech companies have been keenly pursuing the potential of microRNA as cancer biomarker for early detection, prognosis, and therapeutic response. The key involvement of microRNAs in cancer also prompted interest on exploration of therapeutic values of microRNAs as anticancer drugs and drug targets. MRX34, a liposome-formulated miRNA-34 mimic, developed by Mirna Therapeutics, becomes the first microRNA therapeutic entering clinical trial for the treatment of hepatocellular carcinoma, renal cell carcinoma, and melanoma. In this review, we presented a general overview of microRNAs in cancer biology, the potential of microRNAs as cancer biomarkers and therapeutic targets, and associated challenges. PMID- 27988501 TI - Elevation of creatine kinase is linked to disease severity and predicts fatal outcomes in H7N9 infection. PMID- 27988502 TI - Identification and quantitation of phosphatidylethanols in oral fluid by liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: Phosphatidylethanols (PEth) are formed from phosphatidylcholines and ethanol and are used as a specific and sensitive alcohol biomarker. An analytical method for analysis of PEth in oral fluid based on high-performance liquid chromatography coupled to a quadrupole tandem mass spectrometer (LC-MS/MS) was developed and validated and applied on samples collected from patients undergoing alcohol detoxification. METHODS: A 200-MUL aliquot of oral fluid, collected using the QuantisalTM device, was extracted with chloroform/methanol containing internal standard and subjected to LC-MS/MS analysis of three selected PEth forms (16:0/16:0, 16:0/18:1, and 16:0/18:2). Chromatographic separation was achieved on a UPLC BEH phenyl column, using a mobile phase consisting of acetonitrile and water containing 10 mmol/L ammonium hydrogen carbonate with 0.1% ammonia. The MS instrument was operated in negative electrospray ionization and selected reaction monitoring mode. RESULTS: The detection limit for PEth 16:0/16:0, 16:0/18:1, and 16:0/18:2 was ~0.1 ng/mL, and the extraction recoveries at 2.0 ng/mL were in the range of 99%-114%. Method linearity over a concentration range up to 200 ng/mL was >=0.99. No significant deviation in results was observed in an analyte stability study of two different concentrations at two different temperatures over 3 months. In 35 oral fluid samples collected from patients undergoing alcohol detoxification, the highest concentration was observed for PEth 16:0/18:1 (Detected range, 0.51-55.3 ng/mL; mean, 8.5; median, 3.1). In addition, all three PEth forms were variably identified in a majority (63%) of the oral fluid samples. The PEth 16:0/18:1 values in oral fluid showed a weak positive correlation with the corresponding values in whole blood samples (r=0.50, p=0.026, n=20). CONCLUSIONS: The LC-MS/MS method could reliably detect and quantify PEth in oral fluid samples collected after alcohol exposure. The method was characterized by validation data with satisfactory recovery, sensitivity, accuracy, and imprecision, and applied for analysis of clinical samples. The results suggest that measurement of PEth in oral fluid can be used as a biomarker for alcohol consumption, and as such a non-invasive complement to analysis in blood. However, further studies are required to evaluate the test characteristics (e.g. sensitivity and half-life) in comparison with PEth in blood. PMID- 27988503 TI - Differences between quantification of genotype 3 hepatitis C virus RNA by Versions 1.0 and 2.0 of the COBAS AmpliPrep/COBAS TaqMan HCV Test. AB - BACKGROUND: Differences between the designs of hepatitis C virus (HCV) viral load assays can result in genotype-related variability in RNA quantification. We tested paired aliquots of plasma specimens from HCV-infected individuals using two versions (v1.0 and v2.0) of the Roche COBAS AmpliPrep/COBAS TaqMan HCV Test (CAP/CTM HCV) and noted variability between results for a subset of specimens; we then sought to determine whether discrepant results were more prevalent among specific HCV genotypes. METHODS: Archived and prospectively-collected plasma samples from 114 unique patients were tested using CAP/CTM HCV v1.0 and v2.0. The HCV genotype result for each patient was determined by retrospectively reviewing laboratory records. RESULTS: All (46/46) specimens with quantifiable viral loads from patients with genotype 1 or 2 infection had CAP/CTM HCV v1.0 and v2.0 results that were within 0.5 log10 IU/mL; in contrast, only 3/11 (27.3%) from patients with HCV genotype 3 (mean difference, 0.56 log10 IU/mL higher with v2.0) and 0/3 (0%) from patients with HCV genotype 4 (mean difference, 0.91 log10 IU/mL higher with v2.0) had results within 0.5 log10 IU/mL. Among specimens with detectable HCV RNA below the lower limit of quantification with v1.0, greater proportions of genotype 3 (4/7, 57.1%) and genotype 4 (3/4, 75.0%) specimens than genotype 1 or 2 specimens (6/30, 20.0%) had v2.0 results within the quantifiable range. CONCLUSIONS: In patients infected with HCV genotype 3, sequential CAP/CTM HCV viral load results should be compared with caution and interpreted in the context of the specific assay version used. PMID- 27988504 TI - Tackling serum folate test in European countries within the health technology assessment paradigm: request appropriateness, assays and health outcomes. AB - Several authors have recently claimed an excess in serum folate test ordering, suggesting phasing out it from clinical use. According to studies performed in countries undergoing folic acid fortification policies, it is indeed no more cost effective to test folate in the face of deficiency prevalence <1%. In this paper, we sought to evaluate request appropriateness, analytical issues, and cost effectiveness of serum folate determination for clinical purposes in the European context, considering if evidence retrieved in fortified countries may be generalized. Studies performed in non-fortified countries have generally reported a suboptimal folate intake and suggest a remarkable prevalence of folate deficiency. Our internal data suggest that ~20%-25% of the subjects undergoing serum folate test are at risk for deficiency. However, a reliable evaluation of the risk for deficiency implies the knowledge of all issues related to the total testing process of folate measurement as well as the identification of the appropriate population in which to perform the test. The cost-effectiveness of the test is maximized when the request is oriented to subjects suggestive/at risk for deficiency, becoming low if the test is used as a screening tool or for monitoring of vitamin intake/supplementation. Because the individual folate status has a key role in ensuring normal development, physiologic growth, and maintenance of optimal health, the evaluation of its serum levels has to be retained in the clinical use in non-fortified countries, boosting for more appropriate request, and evidence from countries following fortification policies should be cautionary interpreted. PMID- 27988505 TI - Quality Indicators in Laboratory Medicine: the status of the progress of IFCC Working Group "Laboratory Errors and Patient Safety" project. AB - The knowledge of error rates is essential in all clinical laboratories as it enables them to accurately identify their risk level, and compare it with those of other laboratories in order to evaluate their performance in relation to the State-of-the-Art (i.e. benchmarking) and define priorities for improvement actions. Although no activity is risk free, it is widely accepted that the risk of error is minimized by the use of Quality Indicators (QIs) managed as a part of laboratory improvement strategy and proven to be suitable monitoring and improvement tools. The purpose of QIs is to keep the error risk at a level that minimizes the likelihood of patients. However, identifying a suitable State-of the-Art is challenging, because it calls for the knowledge of error rates measured in a variety of laboratories throughout world that differ in their organization and management, context, and the population they serve. Moreover, it also depends on the choice of the events to keep under control and the individual procedure for measurement. Although many laboratory professionals believe that the systemic use of QIs in Laboratory Medicine may be effective in decreasing errors occurring throughout the total testing process (TTP), to improve patient safety as well as to satisfy the requirements of International Standard ISO 15189, they find it difficult to maintain standardized and systematic data collection, and to promote continued high level of interest, commitment and dedication in the entire staff. Although many laboratories worldwide express a willingness to participate to the Model of QIs (MQI) project of IFCC Working Group "Laboratory Errors and Patient Safety", few systematically enter/record their own results and/or use a number of QIs designed to cover all phases of the TTP. Many laboratories justify their inadequate participation in data collection of QIs by claiming that the number of QIs included in the MQI is excessive. However, an analysis of results suggests that QIs need to be split into further measurements. As the International Standard on Laboratory Accreditation and approved guidelines do not specify the appropriate number of QIs to be used in the laboratory, and the MQI project does not compel laboratories to use all the QIs proposed, it appears appropriate to include in the MQI all the indicators of apparent utility in monitoring critical activities. The individual laboratory should also be able to decide how many and which QIs can be adopted. In conclusion, the MQI project is proving to be an important tool that, besides providing the TTP error rate and spreading the importance of the use of QIs in enhancing patient safety, highlights critical aspects compromising the widespread and appropriate use of QIs. PMID- 27988506 TI - Plasma concentrations of osteocalcin are associated with the timing of pubertal progress in boys. AB - BACKGROUND: Animal models have shown that the skeletal hormone osteocalcin stimulates testicular testosterone synthesis. To assess whether osteocalcin might be a useful marker to detect pubertal development disorders, we examined osteocalcin plasma concentrations in children and adolescents with and without disorders of pubertal development. METHODS: Osteocalcin concentrations were investigated in a total of 244 patients with endocrine disorders (122 males, mean age: 11.87+3.77 years), including patients with precocious puberty and constitutional delay of puberty. RESULTS: Osteocalcin concentrations were highest among adolescents with precocious puberty and advanced pubertal development (120.60+/-45.22 ng/mL), while the concentrations were lowest among patients with constitutional delay of puberty (102.20+/-37.13 ng/mL). Overall, osteocalcin concentrations were strongly correlated with markers of bone metabolism. CONCLUSIONS: Although plasma osteocalcin concentrations are associated with pubertal development in boys, it does not appear to be a useful diagnostic marker for altered pubertal development. PMID- 27988507 TI - Epilepsy and vitamin D: a comprehensive review of current knowledge. AB - Vitamin D has been considered as neurosteroid, and its pivotal role in neuroprotection, brain development, and immunomodulation has been noticed in studies; however, our knowledge regarding its role in neurological disorders is still developing. The potential role of vitamin D in the pathophysiology and treatment of epilepsy, as one the most prevalent neurological disorders, has received less attention in recent years. In this article, we review the possible relationship between vitamin D and epilepsy from different aspects, including the action mechanism of vitamin D in the central nervous system and ecological and epidemiological findings. We also present the outcome of studies that evaluated the level of vitamin D and the impact of administrating vitamin D in epileptic patients or animal subjects. We also review the current evidence on interactions between vitamin D and antiepileptic drugs. PMID- 27988508 TI - Generalized partial linear varying multi-index coefficient model for gene environment interactions. AB - Epidemiological studies have suggested the joint effect of simultaneous exposures to multiple environments on disease risk. However, how environmental mixtures as a whole jointly modify genetic effect on disease risk is still largely unknown. Given the importance of gene-environment (G*E) interactions on many complex diseases, rigorously assessing the interaction effect between genes and environmental mixtures as a whole could shed novel insights into the etiology of complex diseases. For this purpose, we propose a generalized partial linear varying multi-index coefficient model (GPLVMICM) to capture the genetic effect on disease risk modulated by multiple environments as a whole. GPLVMICM is semiparametric in nature which allows different index loading parameters in different index functions. We estimate the parametric parameters by a profile procedure, and the nonparametric index functions by a B-spline backfitted kernel method. Under some regularity conditions, the proposed parametric and nonparametric estimators are shown to be consistent and asymptotically normal. We propose a generalized likelihood ratio (GLR) test to rigorously assess the linearity of the interaction effect between multiple environments and a gene, while apply a parametric likelihood test to detect linear G*E interaction effect. The finite sample performance of the proposed method is examined through simulation studies and is further illustrated through a real data analysis. PMID- 27988509 TI - Rivaroxaban-Induced Gastrointestinal Bleeding Presenting as Acute Colon Obstruction. AB - BACKGROUND: Rivaroxaban is a member of the novel target-specific oral anticoagulants (TSOACs) family of drugs recently approved for the prevention and treatment of venous thromboembolism events. A major drawback of the drug is its potential for causing severe hemorrhagic events, which may be difficult to treat in an emergency setting due to lack of effective antidote. Here, we describe a case of acute gastrointestinal (GI) hemorrhage leading to complete colon obstruction in a patient treated with rivaroxaban. Summary and Key Messages: The case presented here demonstrates a chain of events originating from an unprovoked intramural bleeding in a patient using rivaroxaban, leading to an organized giant clot formation, and to complete colon obstruction. In the available literature, the specific site of the GI bleeding has not been discussed. A further study is recommended and re-examination of bleeding events and exploration of new cases due to the use of TSOACs can help predict the course and the outcomes of such complications. PMID- 27988510 TI - In the Era of Therapeutic Hypothermia, How Well Do Studies of Perinatal Neuroprotection Control Temperature? AB - In the era of therapeutic hypothermia, reliable preclinical studies are integral to successfully identify neuroprotective strategies to further improve outcomes of encephalopathy at term. We reviewed preclinical neuroprotection studies reported between January 2014 and June 2016 to assess the use of effective temperature monitoring and control. As a secondary measure, we examined whether studies addressed other methodological issues such as stage of brain development, sex differences, the timing of the treatment relative to the insult, and the histological and functional endpoints used after hypoxia-ischemia. The extent and duration of temperature monitoring was highly inconsistent. Only a minority of papers monitored core (19/61; 31%) or brain temperature (3/61; 5%). Most (40/45) of the neuroprotectants either were likely to affect thermoregulation or their impact is unknown. In 85% of papers neonatal rodents were used (67% at P7); 51% of papers did not report the sex of the animals or tested the effect of potential neuroprotectants on just one sex. In 76% of studies, treatment was before or immediately after the insult (within the first 2 h), and few studies assessed long-term histological and behavioral outcomes. In conclusion, many recent preclinical neonatal studies cannot exclude the possibility that apparent neuroprotection might be related to drug-induced hypothermia or to other methodological choices. Close monitoring and control of brain temperature during, as well as for many days after, experimental hypoxia-ischemia are now critical to reliably develop new ways to improve neurodevelopmental outcomes after perinatal hypoxic-ischemic encephalopathy. PMID- 27988512 TI - Urine Epidermal Growth Factor, Monocyte Chemoattractant Protein-1 or Their Ratio as Biomarkers for Interstitial Fibrosis and Tubular Atrophy in Primary Glomerulonephritis. AB - BACKGROUND/AIMS: The degree of tubular atrophy and interstitial fibrosis (IFTA) is an important prognostic factor in glomerulonephritis. Imbalance between pro inflammatory cytokines such as monocyte chemoattractant protein- 1 (MCP-1) and protective cytokines such as epidermal growth factor (EGF) likely determine IFTA severity. In separate studies, elevated MCP-1 and decreased EGF have been shown to be associated with IFTA severity. In this study, we aim to evaluate the predictive value of urinary EGF/MCP-1 ratio compared to each biomarker individually for moderate to severe IFTA in primary glomerulonephritis (GN). METHODS: Urine samples were collected at biopsy from primary GN (IgA nephropathy, focal and segmental glomerulosclerosis, minimal change disease, membranous nephropathy). MCP-1 and EGF were analyzed by enzyme-linked immunosorbent assay. RESULTS: EGF, MCP-1 and EGF/MCP-1 ratio from primary GN, all correlated with IFTA (n=58). By univariate analysis, glomerular filtration rate, EGF, and EGF/MCP-1 ratio were associated with IFTA. By multivariate analysis, only EGF/MCP-1 ratio was independently associated with IFTA. EGF/MCP-1 ratio had a sensitivity of 88% and specificity of 74 % for IFTA. EGF/MCP-1 had good discrimination for IFTA (AUC=0.85), but the improvement over EGF alone was not significant. CONCLUSION: EGF/MCP-1 ratio is independently associated IFTA severity in primary glomerulonephritis, but the ability of EGF/MCP-1 ratio to discriminate moderate to severe IFTA may not be much better than EGF alone. PMID- 27988511 TI - Pigs with Severe Combined Immunodeficiency Are Impaired in Controlling Influenza A Virus Infection. AB - Influenza A viruses (IAV) infect many host species, including humans and pigs. Severe combined immunodeficiency (SCID) is a condition characterized by a deficiency of T, B, and/or natural killer (NK) cells. Animal models of SCID have great value for biomedical research. Here, we evaluated the pathogenesis and the innate immune response to the 2009 H1N1 pandemic IAV (H1N1pdm09) using a recently identified line of naturally occurring SCID pigs deficient in T and B lymphocytes that still have functional NK cells. SCID pigs challenged with H1N1pdm09 showed milder lung pathology compared to the non-SCID heterozygous carrier pigs. Viral titers in the lungs and nasal swabs of challenged SCID pigs were significantly higher than in carrier pigs 7 days postinfection, despite higher levels of IL 1beta and IFN-alpha in the lungs of SCID pigs. The lower levels of pulmonary pathology were associated with the T and B cell absence in response to infection. The higher viral titers, prolonged shedding, and delayed viral clearance indicated that innate immunity was insufficient for controlling IAV in pigs. This recently identified line of SCID pigs provides a valuable model to understand the immune mechanisms associated with influenza protection and recovery in a natural host. PMID- 27988513 TI - Relationship between Serum Inflammatory Biomarkers and Thrombus Characteristics in Patients with ST Segment Elevation Myocardial Infarction. AB - OBJECTIVES: To compare angiographic and optical coherence tomography (OCT) data pertinent to thrombi, along with the histologic characteristics of aspirated thrombi in patients presenting with ST elevation myocardial infarction (STEMI) with or without inflammation, as assessed by C-reactive protein (CRP) and myeloperoxidase (MPO). METHODS: In the OCTAVIA (Optical Coherence Tomography Assessment of Gender Diversity in Primary Angioplasty) study, 140 patients with STEMI referred for primary percutaneous intervention were enrolled. The patients underwent OCT assessment of the culprit vessel, along with blood sampling of CRP and MPO, and histologic analysis of the thrombus. RESULTS: Biomarkers were available for 129 patients, and histology and immunohistochemistry of the thrombi were available for 78 patients. Comparisons were made using the median thresholds of CRP and MPO (2.08 mg/L and 604.124 ng/mL, respectively). There was no correlation between CRP and MPO levels in the whole population (p = 0.685). Patients with high CRP levels had higher thrombus grades and more frequent TIMI flow 0/1 compared with those with low CRP levels (5 [1st quartile 3; 3rd quartile 5] vs. 3.5 mg/L [1; 5], p = 0.007, and 69.3 vs. 48.5%, p = 0.04, respectively). Patients with high MPO levels more commonly had early thrombi than had those with low MPO levels (42.5 vs. 20.0%, p = 0.04). CONCLUSIONS: CRP and MPO were not correlated in STEMI patients, possibly reflecting different pathogenic mechanisms, with CRP more related to thrombus burden and MPO to thrombus age. PMID- 27988514 TI - The "Hitch Stitch": An Effective Method of Preventing Migration in High Tracheal Stenosis. AB - BACKGROUND: The incidence of caudal stent migration in high tracheal stenting is 13-21% and is common with silicone stents. This can lead to major problems, including emergency repeat procedures. Several antimigration methods are described, but have limitations in terms of their success rate, availability, cost or ease of the procedure. OBJECTIVES: We describe an innovative method of stent migration prevention using a simple percutaneous anchoring "hitch stitch", validated in a large series. METHODS: After tracheal stent placement, an Ethilon suture was passed into the stent lumen through an 18-G needle. To take this suture back to the exterior to complete the stitch, a retrieval loop was passed through another 14-G percutaneous cannula inserted into the stent lumen. Bronchoscopically, using a forceps the first suture was pulled inside the loop, the loop was retracted, the suture was exteriorized, and the knot was completed and embedded subcutaneously. While removing the stent, an endoscopic scissor was used to cut the stitch to free the stent. RESULTS: A total of 42 "hitch stitches" were done in 29 patients over 5 years, predominantly for silicone stents. Indications for stenting included postintubation tracheal stenosis (83.3%), malignancy (11.9%) and tracheoesophageal fistula (4.8%, metal stents). The procedure was successful in 41/42 (97.6%) patients. Stitch removal was uncomplicated. CONCLUSION: This is the largest series of an external stent anchoring procedure as a migration prevention strategy in high tracheal stenting, applicable to both silicone and metal stents. Stent migration prevention using this "hitch stitch" is simple, safe and successful, without any complications during stent removal. PMID- 27988515 TI - Cognitive Impairment and Structural Neuroimaging Abnormalities Among Patients with Chronic Kidney Disease. AB - BACKGROUND/AIMS: Cognitive impairment and abnormal structural neuroimaging is common in chronic kidney disease patients. We aimed to explore its association with dialysis modality and the relationship between cognitive impairment and abnormal structural neuroimaging. METHODS: Sixty peritoneal dialysis patients and 30 hemodialysis and 30 non-dialyzed stage 3-5 chronic kidney disease patients without history of stroke were enrolled for the study. Participants were matched for age, gender, education, diabetes status, and dialysis duration (if appropriate). Cognitive functions were measured using a battery of recognized instruments. Brain features were examined with 3-dimensional magnetic resonance imaging. RESULTS: Cognitive impairment was significantly more severe in dialysis patients than in non-dialyzed patients. The global and specific cognitive function were not significantly different between patients on peritoneal dialysis and hemodialysis. Hemodialysis patients had more severe white matter hyperintensity, sulcal and ventricular atrophy, and SVIs than other patients. In all groups, higher white matter grade, ventricular grade, and hippocampal atrophy were significantly associated with global cognitive impairment, with hazard ratios of 1.80 (1.22-2.64), 1.67 (1.09-2.57), and 2.49 (1.07-5.77), respectively. White matter grade was also significantly associated with delayed memory (hazard ratio 1.63; 1.12-2.39). CONCLUSION: Dialysis modality showed no association with cognitive impairment, although hemodialysis patients had more severe neuroimaging abnormalities. For the whole group, white matter hyperintensity, and ventricular and hippocampal atrophy, were independently associated with global cognitive impairment in chronic kidney disease patients. PMID- 27988516 TI - Laparoscopic Extravesical Submucosal Tunneling Ureteroneocystostomy Combined with Psoas Hitch for Medium-Length Distal Ureteral Defects in Adults. AB - OBJECTIVE: This study aims to describe the technique and feasibility of laparoscopic submucosal tunneling ureteroneocystostomy in combination with psoas hitch to restore urinary tract continuity in patients showing medium-length distal ureteral defects. MATERIALS AND METHODS: From January 2012 to April 2016, a total of 13 patients (4 males and 9 females) with a mean age of 37 years were performed with the laparoscopic operation of ureteral submucosal tunneling reimplantation combined with psoas hitch. The mean defective length was 5.5 cm (range 4-8 cm). The etiologies included ureteral strictures secondary to endoscopic laser lithotripsy in 2 patients, previous gynecological surgeries in 4, infiltrative ureteral endometriosis in 3, as well as ureteral strictures without obvious causes in the remaining 4. RESULTS: The operations were successfully performed in all patients. The mean operating time was 179 min (range 150-230 min). The mean estimated blood loss was 32 mL (range 15-80 mL). The mean drainage time was 5.8 days (range 4-8 days). No major complications occurred during the perioperative period. The mean follow-up time was 25 months. All patients experienced symptomatic relief and showed good urine drainage. CONCLUSION: Extravesical submucosal tunneling ureteroneocystostomy combined with psoas hitch under laparoscopy is a feasible and effective option for medium length distal ureteral defects in selected patients. PMID- 27988517 TI - Malignant Transformation of Hepatocellular Adenoma. AB - The patient was a 20-year-old male in whom a hepatic hypervascular mass accompanied by intratumoral hemorrhage was detected on examination for epigastric pain. Based on the enlargement of the mass and diagnostic imaging, hepatocellular adenoma (HCA) was suspected and hepatectomy was performed. The lesion was diagnosed as malignant transformation of beta-catenin-activated HCA. There are only few reports of cases with malignant transformation of HCA in Japan; it is necessary to accumulate cases to investigate it. PMID- 27988518 TI - Conduction Abnormalities after Transcatheter Aortic Valve Implantation and Diastolic Dysfunction. AB - OBJECTIVES: Transcatheter aortic valve implantation (TAVI) is frequently associated with the development of conduction abnormalities. We assessed the effect of conduction abnormalities on diastolic function following TAVI. METHODS: In total, 101 consecutive post-TAVI patients were included, each with echocardiographic follow-up at 1 and 6 months. Diastolic properties were correlated with the occurrence of a long PR interval and wide QRS, and their change from baseline. The measured diastolic parameters included E/A ratio, E wave deceleration time, E wave to e' ratio, left atrial (LA) volume, and systolic pulmonary artery pressure (SPAP). The clinical outcome was all-cause mortality. RESULTS: Overall, TAVI was associated with a consistent decrease in SPAP at the 1 and 6-month follow-up. LA volumes were increased at 1 month post-TAVI in patients with a wide compared to normal QRS (p = 0.03) and at 6 months in patients with a normal compared to prolonged PR (p = 0.03). PR prolongation above 40 ms was associated with lower SPAP at the 1- but not 6-month follow-up. Survival was not influenced by conduction abnormalities. CONCLUSIONS: TAVI is associated with a reduction in SPAP. A postprocedural wide QRS and normal PR interval may unfavorably influence the left-sided filling performance, resulting in an increased LA volume. Other diastolic parameters, as well as survival, are not significantly affected by postprocedural conduction abnormalities. PMID- 27988519 TI - Nobiletin Relaxes Isolated Mesenteric Arteries by Activating the Endothelial Ca2+ eNOS Pathway in Rats. AB - AIMS: Nobiletin, a natural polymethoxylated flavonoid compound, has various beneficial properties, such as anticancer, anti-inflammatory, and antioxidant effects, and it also improves memory. Therefore, we investigated the effects and mechanisms of nobiletin on rat isolated mesenteric arteries (MAs). METHODS: We examined vasodilation induced by nobiletin on rat isolated MA rings with a tension study, the expression and activity of endothelial nitric oxide synthase (eNOS) with Western blotting, NO production with DAF- FMDA fluorescence, and intracellular Ca2+ concentration ([Ca2+]i) with Fluo-3AM. RESULTS AND CONCLUSION: Our study showed that nobiletin elicited a dose-dependent vasodilation in phenylephrine precontracted MA rings, but it did not elicit the same response in pulmonary artery rings. Vasodilation was related to endothelium and activated partly by eNOS. Vasodilation was inhibited by denudation of the endothelium or inhibition of eNOS activity. Nobiletin increased NO production by promoting the phosphorylation of eNOS at Ser-1177 without changing the level of eNOS expression in rat mesenteric artery endothelial cells (RMAECs). Nobiletin increased the concentration of endothelial [Ca2+]i, which enhances eNOS activity in RMAECs. In summary, vasodilation induced by nobiletin was dependent on the endothelium and partly on eNOS activation, which is mediated by high endothelial [Ca2+]i. Results suggest nobiletin may offer a therapeutic benefit and could potentially be used as a vasodilator for the treatment of hypertension. PMID- 27988520 TI - DNA-Sensing and Nuclease Gene Expressions as Markers for Colorectal Cancer Progression. AB - OBJECTIVE: Oncogene-driven stress-related DNA damage has been observed in lesions of colon cancer. Furthermore, DNA sensors and nucleases are stimulated during active DNA damage and replication. However, their changes and influences with respect to cancer remain largely unknown. METHODS: The gene expression levels of cGAS, IFI16, STING, TBK1, IFNB1, TREX1, SAMHD1, RNASEH2A, RNASEH2B, and RNASEH2C were examined in the paired colorectal cancer and adjacent normal part tissues of 53 patients. Their associations with the clinical stages of cancer were then analyzed. RESULTS: All cytosolic DNA-sensing and nuclease-related genes except cGAS, RNASEH2A, and RNASEH2B showed lower mRNA expressions in the colorectal tumor tissues. Moreover, cGAS upregulation was found to be associated with early stage colorectal cancers, while higher expressions of RNASEH2B, RNASEH2C, and SAMHD1 correlated with metastasis. RNASEH2C knockdown in a colon cancer cell line impaired cell migration, and analysis of the cancer RNA-seq data from The Cancer Genome Atlas (TCGA) database revealed a negative correlation between RNASEH2C expression and E-cadherin levels. CONCLUSIONS: In contrast to DNA-sensing events in viral infections or autoimmunity, cGAS-STING-IFNB signaling is disrupted in colorectal cancer. The expression levels of cGAS, RNASEH2B, RNASEH2C, and SAMHD1 could be prognostic markers of colorectal cancer. PMID- 27988522 TI - Australian mycophagous species of the genus Deplorothrips (Thysanoptera, Phlaeothripinae). AB - The genus Deplorothrips Mound & Walker is recorded from Australia for the first time. The genus is found widely across the continent, and descriptions and an illustrated identification key are provided to 14 new species. These have been found living on dead twigs and branches, particularly of Eucalyptus trees. Typical members of this genus have short maxillary stylets that are scarcely retracted into the head capsule, but some of the species have more deeply retracted stylets. Structural polymorphism is recorded in several species, associated both with sex and with body size. Remarkable variation is recorded for some species in the number of sense cones on the antennal segments. PMID- 27988521 TI - Inhibitors of Acetylcholinesterase Derived from 7-Methoxytacrine and Their Effects on the Choline Transporter CHT1. AB - BACKGROUND: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic. METHODS: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C4-C5 chains and 5 N-alkylated C4-C8 side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1. RESULTS: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA. All derivatives were able to inhibit CHT1, probably via quaternary ammonium, and this interaction could be involved in the enhancement of their detrimental side effects and/or in the attenuation of their promising effects. Under conditions of disrupted lipid rafts, the unfavorable effects of some derivatives were weakened. Only tacrine was probably able to stereospecifically interact with the naturally occurring amyloid-beta isoform and to simultaneously stimulate CHT1. Some derivatives, when coincubated with amyloid beta, did not influence CHT1. All derivatives also increased the fluidity of the cortical membranes. CONCLUSION: The N-alkylated derivative of 7-MEOTA bearing from C4 side chains appears to be the most promising compound and should be evaluated in future in vivo research. PMID- 27988523 TI - The Moroccan species of Chyromyidae (Diptera) with descriptions of five new species of Aphaniosoma Becker. AB - Nineteen species of Chyromyidae from Morocco are listed with data and compared to the fauna of the other North African countries bordering the Mediterranean. Five new species of Aphaniosoma, A. gatti, A. nigripes, A. nitidum, A. soror and A. zizense spp. n. are described and their relationships discussed and 11 species are recorded from Morocco for the first time. PMID- 27988524 TI - New taxa and some clarification of the tribe Steirodontini (Orthoptera: Tettigoniidae; Phaneropterinae): Tenth contribution to the suprageneric organization of Neotropical phaneropterines. AB - The tribe of the giant katydids Steirodontini is reviewed, its relationship with other groups of Phaneropterinae from the Old and New World is discussed, and an updated key to genera is presented. Nicklephyllum n. gen. is established to accommodate one species described as Stilpnochlora acanthonotum Nickle, 1985 from Colombia. Cnemidophyllum tani n. sp. from the Colombian Amazon is described. Another new combination and two synonymies are proposed: Steirodon (Frontinus) emsleyi (Piza, 1979) n. comb., Steirodon (Posidippus) parastahli Piza, 1979 n. syn. (of Steirodon (Steirodon) ponderosum Stal, 1873), and Steirodon (Posidippus) tricenarius (Piza, 1974) n. syn. (of Steirodon (Frontinus) rufolineatum Emsley, 1970). Finally, Steirodon (Posidippus) rarospinulosum (Brunner von Wattenwyl, 1891), only known from Peru, is reported from the Colombian Amazon. PMID- 27988525 TI - A review of the genus Orionis Shaw (Hymenoptera: Braconidae: Euphorinae) and first records of the genus from South America and the Oriental Region. AB - Orionis is a small Neotropical euphorine genus, currently in the tribe Perilitini. Although the biology of the genus is unknown, Orionis eximius (Muesebeck) was described from a single female specimen reared from a cocoon associated with Lantana camara. Here, we present a taxonomic revision of Orionis and the first records of the genus from South America and Thailand, with descriptions of three new species: O. brasiliensis sp. nov., O. ecuadoriensis sp. nov. and O. orientalis sp. nov. We also report the first record of O. eximius from South America (Ecuador). A revised key for the described species is presented. PMID- 27988526 TI - A new species of the genus Rhinoleucophenga (Diptera: Drosophilidae) and redescription of five species from Neotropical region. AB - The genus Rhinoleucophenga Hendel comprises 29 nominal species with New World distribution. In the present study five species are redescribed: R. angustifrons Malogolowkin; R. lopesi Malogolowkin; R. matogrossensis Malogolowkin; R. nigrescens Malogolowkin and Rhinoleucophenga personata Malogolowkin. R. capixabensis Culik & Ventura is proposed as a new junior synonymy of R. lopesi. Other species, R. jacareacanga sp. nov., is described from the specimens deposited at CEIOC/Fiocruz. The description of new species and review of some former descriptions of Rhinoleucophenga is indispensable since the distribution records of some species are doubtful. PMID- 27988527 TI - A new species of Physomerus Burmeister (Hemiptera: Heteroptera: Coreidae: Coreinae), with a key to the species of India. AB - A new species from India, Physomerus centralis sp. nov. (Hemiptera: Heteroptera: Coreidae) is described and illustrated with both male and female genitalia. Morphological measurements and their ratios were taken as additional diagnostic characters. A key to the Indian species of the genus Physomerus Burmeister is provided. PMID- 27988528 TI - Two new species of Sphaeronemoura (Plecoptera: Nemouridae) from Oriental China. AB - Two new species of the genus Sphaeronemoura of the stonefly family Nemouridae, S. asymmetria sp. n. from Guizhou Province and S. hainana sp. n. from Hainan Province, respectively, are described from China. These findings represent the first record of the genus from these two provinces. Their relationships with other species from adjacent regions are discussed. With the new species described herein, 16 species of Sphaeronemoura are now known. PMID- 27988529 TI - Hotspots of mite new species discovery: Sarcoptiformes (2013-2015). AB - A list of of type localities and depositories of new species of the mite order Sarciptiformes published in two journals (Zootaxa and Systematic & Applied Acarology) during 2013-2015 is presented in this paper, and trends and patterns of new species are summarised. The 242 new species are distributed unevenly among 50 families, with 62% of the total from the top 10 families. Geographically, these species are distributed unevenly among 39 countries. Most new species (72%) are from the top 10 countries, whereas 61% of the countries have only 1-3 new species each. Four of the top 10 countries are from Asia (Vietnam, China, India and The Philippines). PMID- 27988530 TI - Revision of Diplosynapsis Enderlein, 1914 (Diptera, Asilidae, Asilinae) with description of four new species. AB - The robber fly genus Diplosynapsis Enderlein, 1914 is reviewed and four new species are described-D. chela sp. nov. (Amazonas state, Brazil), D. fisheri sp. nov. (Guapiles, Heredia, Limon, Puntarenas province, Costa Rica), D. spina sp. nov. (Rio de Janeiro state, Brazil) and D. uncinata sp. nov. (Amazonas state, Brazil). A lectotype is designated for D. cellata (Schiner, 1868) pres. desig. and comments are made on D. remus Tomasovic, 2002. An identification key and illustrations are presented for all species. PMID- 27988531 TI - Monophyly, review, six new species and DNA barcode of micropterous Afromontane Afropictinus (Heteroptera: Aradidae). AB - The micropterous East African flat bug genus Afropictinus Heiss, 1986 (Heteroptera: Aradidae: Mezirinae) is revised. In addition to the type and only known species A. congoensis (Hoberlandt, 1956) from Rwanda, four new species from Tanzania (A. castor sp. nov., A. hylas sp. nov., A. idas sp. nov., A. nauplius sp. nov.), one new species from the Democratic Republic of the Congo (A. kahuzianus sp. nov.), and one new species from Ethiopia (A. nabu sp. nov.) are described and illustrated. An identification key is presented to all seven nominal species of Afropictinus. DNA barcodes of 28 individuals of Afropictinus species were newly generated and together with 12 sequences of other Aradidae were made publicly available at dx.doi.org/10.5883/DS-AFROPICT. These mtDNA sequences were analyzed phylogenetically using Maximum Likelihood approach with 500 bootstraps. Obtained topology reveals a monophyletic Afropictinus with high statistical support (84%), although its sister group remains elusive. Both specimens of non-Tanzanian Afropictinus species included in the study (A. kahuzianus and A. nabu) were nested among Tanzanian congeners. The internal clades within Afropictinus, except for those at species and population level, had lesser statistical support. Despite of intense sampling, no Afropictinus species was found in mountain forests of geologically young (<2 Ma) volcanic highlands of the Ngorongoro-Kilimanjaro Volcanic Belt, which suggest reduced dispersal capacities. PMID- 27988532 TI - A new species of crayfish in the genus Orconectes (Decapoda: Cambaridae) from the Tennessee River Drainage with comments on and key to members of the O. juvenilis Species Complex. AB - The crayfish subgenus Procericambarus (genus Orconectes) found in the Eastern Highlands of the United States represents a rich assemblage of stream-dwelling macroinvertebrates. While the taxonomic status and distribution of its members were clarified in a previous study, newly diagnosed characters and newly collected specimens warranted a revision to previous hypotheses of Procericambarus membership in the southeastern United States. Using morphological characters, we describe herein a new species of crayfish occurring in the Tennessee River drainage of northern Alabama and southwestern Tennessee. We also provide a revised key for the identification of members of O. juvenilis Species Complex. PMID- 27988533 TI - Determinants and taxonomic consequences of extreme egg shell variability in Ramazzottius subanomalus (Biserov, 1985) (Tardigrada). AB - Nearly a half of known eutardigrade species lay ornamented eggs. The ornamentation is thought to provide attachment of the egg to the substrate and protection for the developing embryo, but from the taxonomic point of view chorion morphology may also provide key characters for species differentiation and identification, especially between closely related taxa. Nonetheless, despite the evolutionary and taxonomic importance of the egg shell, the determinants of its morphology are very poorly, if at all, understood. Here, we combine morphological, molecular and experimental approaches in an attempt to separate the genetic and environmental factors that shape egg chorion morphology in Ramazzottius subanomalus (Biserov, 1985). Our integrative study, based on a population of R. subanomalus isolated from a single moss sample, revealed (1) remarkable variation in egg shell morphology, but (2) relatively little variation in animal morphometric traits, and (3) genetic differentiation, expressed as two ITS-2 haplotypes, but no parallel polymorphism in COI. Although animals did not differ morphometrically between the haplotypes, eggs laid by haplotype 1 and 2 females exhibited highly statistically significant differences in all measured traits. The study demonstrates, for the first time, a correlation between phenotypic and genetic variability within a tardigrade species. The revealed congruence between genetic and morphological traits might be viewed as an example of incipient speciation that illustrates early evolutionary steps leading to species complexes that differ primarily in terms of egg shell morphology. Moreover, our data confirm the value of the ITS-2 fragment in distinguishing very closely related tardigrade lineages. PMID- 27988534 TI - A new species of the genus Diogenes Dana, 1851 (Crustacea: Decapoda: Anomura: Diogenidae) from Gujarat, northwestern India. AB - A new species of diogenid hermit crab, Diogenes chhapgari n. sp., is described on the basis of material collected during the crustacean faunal survey along the coastal areas of the Gujarat State, northwestern India. The new species is referred to the D. edwardsii (De Haan, 1849) species group and appears closest to D. singaporensis Rahayu, 2015. However, D. chhapgari n. sp. is distinguished from this species by the armature on the fourth segment of the antennal peduncle and carpus of the left cheliped. PMID- 27988535 TI - A new species of the genus Meganola Dyar, 1898 (Lepidoptera, Nolidae, Nolinae) from China. AB - Meganola is a large and morphologically rather diverse genus, which is widely distributed on all continents, although it proved to be the most species rich in the mountains of Southeast Asia. In this article, the new species Meganola tibetensis was collected at Tibet and reminds externally Himalayan-Indochinese species Meganola mediofusca Laszlo, Ronkay & Witt, 2007. These two species have similar configuration of female genitalia concerning the spinulose signum, but their male genitalia are totally different. In male genitalia, harpe approximate trapezoid and aedeagus without cornuti in new species, while in M. mediofusca harpe claw-like and aedeagus armed with many spines. Adults and genitalia of both species are illustrated. PMID- 27988536 TI - Hotspots of mite new species discovery: Trombidiformes (2013-2015). AB - This paper reveals the hotspots of new mite discovery through of a survey of type localities of new Trombidiformes species described in two journals (Systematic & Applied Acarology and Zootaxa) during the last three years (2013-2015). Taxonomically, the 491 new species of the Trombidiformes are highly unevenly distributed among 55 families with top 10 families accounting for over 66% of the total. The Eriophyidae is the top-ranked family. Geographically, these 491 new species are from 55 countries around the world and their distribution among the countries is highly uneven. The majority of these new species (69%) are from the top 10 countries and six of the top ten countries are also megadiversity countries. The top three countries are all from Asia (Iran, China and Malaysia) and they together accounted for over one third of all new species of the Trombidiformes described in the two journals during 2013-2015. PMID- 27988537 TI - Taxonomic study of the genus Atkinsonia Stainton, 1859 (Lepidoptera, Stathmopodidae) in China, with descriptions of two new species. AB - The genus Atkinsonia Stainton, 1859 is reviewed in China. Eight species are recognized, including two new species: A. brevisaccula sp. nov. and A. parignipicta sp. nov.; A. clerodendronella Stainton, 1859 is newly recorded for China; two new combinations and one new synonymy are proposed: A. butalistis (Strand, 1917) comb. nov. from Oedematopoda, A. furcata (Wang, 2008) comb. nov. from Oedematopoda, and Oedematopoda jiyuanica Wang, 2008 syn. nov. of A. swetlanae Sinev, 1988. Photographs of adults and illustrations of genitalia are provided, along with a key to identifying the described Chinese species and a map to show their collecting localities. PMID- 27988538 TI - A new biogeographically disjunct giant gecko (Gehyra: Gekkonidae: Reptilia) from the East Melanesian Islands. AB - The East Melanesian Islands have been a focal area for research into island biogeography and community ecology. However, previously undescribed and biogeographically significant new species endemic to this region continue to be discovered. Here we describe a phylogenetically distinct (~20% divergence at the mitochondrial ND2 gene) and biogeographically disjunct new species of gecko in the genus Gehyra, from the Admiralty and St Matthias Islands. Gehyra rohan sp. nov. can be distinguished from all congeners by the combination of its very large size, ring of bright orange scales around the eye, moderate degree of lateral folding on the limbs and body, and aspects of head, body and tail scalation. Molecular data indicate mid to late Miocene divergence of the new species from nearest relatives occurring nearly 2000 kilometres away in Vanuatu and Fiji. Large Gehyra have not been recorded on the intervening large islands of the Bismark Archipelago (New Britain and New Ireland) and the Solomon Islands, suggesting this dispersal pre-dated the current configuration of these islands, extinction in intervening regions, or potentially elements of both. Conversely, low genetic divergence between disjunct samples on Manus and Mussau implies recent overseas dispersal via either natural or anthropogenic means. PMID- 27988539 TI - A new species of Dicrotendipes (Diptera: Chironomidae) from Florida. AB - A new species of Dicrotendipes is described in all life stages from Florida. Adults of this new species are nearly identical to D. modestus (Say); pupae are similar to D. modestus, D. neomodestus (Malloch) and D. tritomus (Kieffer); while the larvae are unique and were keyed by Epler (1992, 1995, 2001) as Dicrotendipes sp. A. The taxonomic status of D. modestus and D. pulsus (Walker) is discussed. PMID- 27988540 TI - Two new species of the genus Phaea Newman, 1840 (Coleoptera: Cerambycidae) from Mexico. AB - Two new species of the genus Phaea Newman are described from Mexico. Phaea chemsaki sp. nov. from Chiapas, and P. parallela sp. nov. from Morelos. The descriptions are supplemented with photographs. PMID- 27988541 TI - Review and key to all known species of the genus Epacromius Uvarov, 1942 (Orthoptera: Acrididae). AB - This paper provides a review and key to all species of the genus Epacromius Uvarov, 1942. The first description of the male of the species Epacromius fallax Wang, 2007 is given. PMID- 27988542 TI - A new species of Anacroneuria Klapalek 1909 (Plecoptera: Perlidae) from Espirito Santo State, southeastern Brazil and comments on additional species. AB - Specimens of Perlidae (Plecoptera) from Espirito Santo State in southeastern Brazil were studied. A new species, Anacroneuria ruschii n. sp. is described. Brief remarks on A. debilis (Pictet) and Kempnyia neotropica (Jacobson & Bianchi) are also presented. PMID- 27988543 TI - ERRATUM: Formal description of Protosticta nigra spec. nov. from Vietnam. AB - Regrettably I neglected to indicate the type series for one of the new species described in Kompier (2016). Fixation of a holotype, or syntypes, is compulsory for names published after 1999 (ICZN 1999, Article 16.4.1). I am doing so here as a necessary element to validate the species description. The published paper contains a diagnosis and illustrations for the species. The diagnosis is repeated here for formal reasons. The name Protosticta nigra is thus only available from the present publication. I thank Jan van Tol and Dennis Paulson for their assistance. PMID- 27988544 TI - Review of the Madagascan Orphninae (Coleoptera: Scarabaeidae) with a revision of the genus Triodontus Westwood. AB - The subfamily Orphninae (Coleoptera: Scarabaeidae) is reviewed from Madagascar. A total of four genera and 39 species were found, all being endemic to the island. The following five new species are described: Triodontus ankarafantsikae, Triodontus lemoulti, Triodontus viettei, Triodontus fairmairei, and Triodontus inexpectatus. The following new synonymies are proposed: Orphnus nigrita Brancsik, 1893 is synonym of Triodontus hova (Fairmaire, 1868); Triodontus occidentalis Paulian, 1977 and Orphnus obsoletus Brancsik, 1893 are synonyms of Triodontus nitidulus (Guerin-Meneville, 1844); Triodontus vadoni Paulian, 1977 and Triodontus perrotorum Paulian, 1977 are synonyms of Triodontus owas Westwood, 1852. Lectotypes are designated for the following names: Orphnus nitidulus Guerin Meneville, 1844 and Orphnidius modestus Benderitter, 1914. Keys, descriptions, illustrations of habitus and male genitalia, and distributional records maps are given for all species. PMID- 27988545 TI - Pamphagidae (Orthoptera: Acridoidea) from the Palaearctic Region: taxonomy, classification, keys to genera and a review of the tribe Nocarodeini I.Bolivar. AB - The very rich material of Palaearctic Pamphagidae preserved in the collections including the type specimens of all taxa, the historical unidentified specimens and newly collected material have been studied. 58 genera and 295 species and subspecies are listed. The higher classification of the family is reviewed mainly based on the male phallic complex as well as the traditional and some new external characters. The tribe Haplotropiidini is transferred to the subfamily Thrinchinae. Previously synonymized subfamily Tropidaucheninae is validated as an independent tribe of Pamphaginae. The tribe Nocarodeini is taxonomically reviewed except the genus Bufonocarodes Mistshenko. The male phallic complex is also used as one of the main characters in decisions of the genus group taxa. The following 10 genera are synonymized: Pseudotmethis Bey-Bienko, 1948 and Paratmethis Zheng & He, 1996 (with Filchnerella Karny, 1908), Sinotmethis Bey-Bienko, 1959 and Kanotmethis Yin, 1994 (with Beybienkia Tsyplenkov, 1956), Paktia Pfadt, 1970 (with Mistshenkoella Cejchan, 1969), Pseudosavalania Demirsoy, 1973 (with Paranocarodes I. Bolivar, 1912), Nocaropsis Ramme, 1951 (with Paranothrotes Mistshenko, 1951), Paranocaracris Mistshenko, 1951 and Oronothrotes Mistshenko, 1951 (with Nocaracris Uvarov, 1928) and Savalania Mistshenko, 1951 (with Nocarodes Fischer von Waldheim, 1846). The genera Mistshenkoella Cejchan and Cryptonothrotes La Greca are proposed as subgenera of Saxetania Mistshenko. The following genera are divided: Eremocharis Saussure into 4 species groups, Paranocarodes I. Bolivar into 2 species groups, Paranothrotes Mistshenko into 4 species groups, Nocaracris Uvarov into 7 species groups and Nocarodes Fischer von Waldheim into 4 species groups. The following 24 species and subspecies are synonymized: Tmethis cinerascus cyanipes Werner, 1939 [with Eremopeza angusta (Uvarov, 1934)], Iranotmethis cyanipennis cyanipes Bey-Bienko, 1951 [with Iranotmethis cyanipennis iranicus (Werner, 1939)], Eremocharis granulosa roseipes Uvarov, 1943 [with Eremocharis granulosa granulosa (Walker, 1871)], Eremocharis subsulcata minor Cejchan, 1969 (with Eremocharis maior Ramme, 1952), Asiotmethis limbatus motasi Ramme, 1951 [with Asiotmethis limbatus (Charpentier, 1845)], Tropidauchen marginatum Bolivar, 1912 (with Tropidauchen escalerai Bolivar, 1912), Paranocarodes straubei serratus Uvarov, 1949, Paranocarodes straubei insularis Ramme, 1951 and Paranocarodes fieberi mytilenensis Ramme, 1951 [with Paranocarodes fieberi (Brunner von Wattenwyl, 1882)], Paranocarodes atympanicus Ramme, 1951 (with Paranocarodes tolunayi tolunayi Ramme, 1949), Paranocarodes cilicicus Ramme, 1951 (with Paranocarodes lubricus Mistshenko, 1951), Paranothrotes opacus hakkariana Demirsoy, 1973 [with Paranothrotes opacus opacus (Brunner von Wattenwyl, 1882)], Paranothrotes tenuicornis sordidus Mistshenko, 1951 and Paranothrotes iranicus (Ramme, 1951) (with Paranothrotes tenuicornis Mistshenko, 1951), Paranothrotes elbursianus (Ramme, 1951) [with Paranothrotes demawendi (Ramme, 1951)], Paranocarodes aserbeidshanicus Ramme, 1951 [with Paranothrotes margaritae (Miram, 1938)], Nocaracris burri obscurata Ramme, 1951 [with Nocaracris furvus furvus (Mistshenko, 1951)], Paranocaracris rimansonae ventosus Mistshenko, 1951 [with Nocaracris rimansonae (Uvarov, 1918)], Paranocaracris rigidus Mistshenko, 1951 (with Nocaracris tauricolus Ramme, 1951), Nocaracris cyanipes tristis Ramme, 1951 [with Nocaracris cyanipes (Motschulsky, 1846)], Nocarodes armenus Ramme, 1951 (with Nocarodes serricollis Fischer von Waldheim, 1846), Nocarodes specialis Mistshenko, 1951 [with Nocarodes iranicus (Werner, 1939)], Nocarodes gibbosus Mistshenko, 1951 (with Nocarodes humerosus Mistshenko, 1951), Nocarodes urmianus carinatus Mistshenko, 1951 (with Nocarodes urmianus Ramme, 1939). One new genus in the tribe Nocarodeini, Turkanocaracris Unal gen. nov., and the following 29 new species and subspecies in four tribes are described: Eremopeza soltanii Unal, sp. nov., Eremopeza kashmirensis Unal, sp. nov., Eremocharis subsulcata beccalonii Unal, ssp. nov., Orchamus massai Unal, sp. nov., Paracinipe suezensis Unal & Massa, sp. nov., Saxetania (Mistshenkoella) gorochovi Unal, sp. nov., Paranocarodes anatoliensis anamas Unal, ssp. nov., Paranothrotes buzuldagi Unal, sp. nov., Paranothrotes dentatus Unal, sp. nov., Paranothrotes eximius bitlis Unal, ssp. nov., Paranothrotes siirt Unal, sp. nov., Nocaracris furvus kazdagi Unal, ssp. nov., Nocaracris istanbul Unal, sp. nov., Nocaracris tunceli Unal, sp. nov., Nocaracris tardus Unal, Bugrov & Jetybayev, sp. nov., Nocaracris emirdagi Unal, sp. nov., Nocaracris cejchani Unal, sp. nov., Nocaracris judithae Unal, sp. nov., Nocaracris minutus Unal, sp. nov., Nocaracris karadagi Unal, sp. nov., Nocaracris palandoken Unal, sp. nov., Nocaracris monticolus Unal, sp. nov., Nocaracris van Unal, sp. nov., Nocaracris dilekensis Unal, sp. nov., Nocaracris karshitoros Unal, sp. nov., Nocaracris goektepe Unal, sp. nov., Nocaracris crassipes Unal, sp. nov., Turkanocaracris levigatus Unal, sp. nov., Turkanocaracris davisi Unal, sp. nov. Lectotypes are designated for the following 12 species: Strumiger desertorum desertorum Zubovski, 1896, Ocnerosthenus brunnerianus (Saussure, 1887), Orchamus gracilis (Brunner von Wattenwyl, 1882), Saxetania iranicum (Werner, 1939) [syn. of Saxetania (s.str.) cultricolle (Saussure, 1887)], Paranocarodes straubei (Fieber, 1853), Paranocarodes fieberi (Brunner von Wattenwyl, 1882), Paranothrotes shelkovnikovi (Uvarov, 1918), Paranothrotes nigripes (Stshelkanovtzev, 1916), Eunothrotes derjugini Adelung, 1907, Nocaracris rimansonae (Uvarov, 1918), Nocaracris tridentatus (Stshelkanovtzev, 1916) and Araxiana woronowi (Uvarov, 1918). Many species are given in new combinations and new statuses. Some taxa are proposed as reverted combinations, reverted statuses, reverted genera, species and subspecies. Nomenclatural problems are discussed under the relevant taxa. The authorship of 4 species are discussed and changed as follow: Eremopeza festiva (I. Bolivar, 1884), Paranocarodes tolunayi tolunayi Ramme, 1949, Nocaracris rubripes (Motschulsky, 1846), Nocaracris cyanipes (Motschulsky, 1846). Identification keys for subfamilies, tribes and genera (except the N. African and European genera of Pamphagini) and for each level of the tribe Nocarodeini are prepared. This study is also a review of the Pamphagidae species of Turkey. Therefore all Turkish species are studied in detail except the two genera recently revised by the author, Glyphotmethis Bey-Bienko and Asiotmethis Uvarov. Geographically this paper includes all Pamphagidae species of the following countries and regions: Bulgaria, Turkey, Cyprus, Syria, Israel, Palestine, Jordan, Iraq, Armenia, Georgia, Nakhichevan, Azerbaijan, Pakistan, Greece (except one species), Lebanon (except two species), Arabian Peninsula (except one species), Afghanistan (except some Saxetania) and Iran (except some Saxetania and Tropidauchen). In addition, 848 original figures including 10 distributional maps are provided. PMID- 27988546 TI - Studies on Adriaphaenops Noesske with the description of five new species from the Dinarides (Coleoptera: Carabidae: Trechini). AB - The species belonging to the trechine genus Adriaphaenops Noesske, 1928 are studied. As a result, seven currently known and five newly described species are recognized. Morphological characters of the habitus (especially the shape of head and pronotum) as well as male genitalia are widely used to delimit the species. The following new species are described: A. albanicus sp. nov. (Albania, Shkoder, Boga, Thate Mts.), A. jasminkoi sp. nov. (Bosnia & Hercegovina, Nevesinje, Novakova pecina cave), A. mlejneki sp. nov. (Montenegro, Gornje Stravce, Kucke planine Mts.), A. njegosiensis sp. nov. (Montenegro, Cetinje, Cetinjska pecina cave) and A.rumijaensis sp. nov. (Montenegro, Virpazar, Rumija Mts.). Lectotype for A. stirni (Pretner, 1959) is designated. Data on the distribution and ecology of new taxa, complemented with descriptions of the type localities are provided. Key to the identification of all twelve Adriaphaenops species, as well as a key of all hitherto known aphaenopsoid Trechini genera from Dinarides are also given. PMID- 27988547 TI - Event-based biogeography of Eusarcus dandara sp. nov. (Opiliones: Gonyleptidae), an endemic species of the Northern Atlantic Rainforest of Brazil, and its closely related species. AB - Here, we describe a new species of Eusarcus and reconstruct the geographical evolution of its species group based on biogeographical event-based analysis. Eusarcus dandara sp. nov. has been recorded from Alagoas state, in northeastern Brazil, which represents an important range extension of the genus to the northern Atlantic Rainforest. We performed a cladistic morphological analysis based on new data and data from a previous systematic review of the genus to reconstruct the phylogenetic placement of the new species. This analysis resulted in six most parsimonious cladograms. We performed the biogeographical reconstruction using the Treefitter 1.3B1 algorithm for the clade of eight species that includes E. dandara sp. nov., and we tested the significance of the reconstructions. We found two alternative reconstructions depended on the differences in species relationships; both were significant (0.002 <= p <= 0.019). The phylogenetic placement of the new species is consistent with some expectations based on previous biogeographical studies of Atlantic Rainforest harvestmen. Reconstructions reveal the origin of the species group in the northeast region, in the Atlantic Rainforest plus interior and dry biomes, such as the Caatinga xeric shrubland and Cerrado savanna, with subsequent dispersal to the southeast region. Harvestmen are good models to study the historical biogeography of the Atlantic Rainforest, especially those species that are endemic, like most Eusarcus. We have demonstrated a complex history of the spatial evolution of the group and the importance of the adjacent drier biomes in the evolution of endemic organisms of the Atlantic Rainforest. PMID- 27988548 TI - A new species of the genus Paramesotriton (Caudata: Salamandridae) from Fujian, southeastern China. AB - New amphibian species have been constantly discovered throughout southern China, including from areas close to heavily populated cities that remain poorly surveyed for amphibian diversity. We describe a new species of the newt genus Paramesotriton from Fujian, a developed province on the southeastern coast of mainland China. The mitochondrial genealogy suggests that the new species is the sister taxon to Paramesotriton hongkongensis, separated by an uncorrected pairwise distances of 5.8% at the ND2 gene fragment analyzed. In addition to the genetic divergence, the new species can be readily differentiated from its congeners by having: a very rough skin; a continuous, orange, vertebral ridge; few warts on each side of the vertebral ridge; numerous small irregular orange red or yellow spots on the chin, venter, underside of axillae, flanks, lateral side of the tail, base of limbs and cloaca; a small groove at the base of the vomerine tooth series; relatively long tail, relatively flat cloaca in females; normally developed eyes, and the absence of vestigial gills and gill filaments in adults. PMID- 27988549 TI - The identity of Vespertilio oreias Temminck, 1840-solving a taxonomic puzzle. AB - Vespertilio oreias (generally known as Myotis oreias) has long been considered an endemic bat species to Singapore but its taxonomic status has been in doubt, and no specimens have been found since its description in 1840. Temminck formally described it based on a mounted skin (now in poor condition and accompanied by some skull fragments). The holotype was re-examined and we found it to be a composite, consisting of two separate individuals representing two distinct genera, the skin belonging to a Kerivoula whereas the skull fragments are of a Myotis. The mounted skin is accepted herewith as the name-bearing type, as the skull fragments were taken out after Temminck had published his description. Unfortunately, neither the skin nor the dental remains show enough anatomical details to identify the species unambiguously. Hence, the name Vespertilio oreias is considered a nomen dubium and the name oreias should be referred to the genus Kerivoula. PMID- 27988550 TI - A new large Myloplus Gill 1896 from rio Negro basin, Brazilian Amazon (Characiformes: Serrasalmidae). AB - Myloplus lucienae, new species, is described from the blackwater tributaries of the rio Negro basin. It is one of the few Myloplus species typically found in rapid areas of the Guiana Shield. It is diagnosed from congeners by the combination of an elongated body, small prepelvic spines that reach anteriorly just to the middle of the abdomen between verticals through pectoral- and pelvic fin origin, and large scales on flanks resulting in smaller scale counts. PMID- 27988551 TI - Nomenclatural changes in Mymaridae (Hymenoptera: Chalcidoidea). AB - Three New World species are transferred from Polynema Haliday to other genera of Mymaridae and redescribed based on examination of their type specimens: Polynema albicoxa Ashmead to Acmopolynema Ogloblin as Acmopolynema albicoxa (Ashmead), comb. n., Polynema porteri (Brethes) to Agalmopolynema Ogloblin as Agalmopolynema porteri (Brethes), comb. n., and Polynema giraulti Perkins, for which a lectotype is designated, to Stephanodes Enock as Stephanodes giraulti (Perkins), comb. n. Agalmopolynema shajovskoii Fidalgo, syn. n. is synonymized under Agalmopolynema porteri; Polynema (Dorypolynema) gaucho Triapitsyn & Aquino, syn. n. and P. grenadensis Ashmead, syn. n., are synonymized under Polynema (Dorypolynema) magniceps Ashmead, for which taxonomic notes are given. Caenomymar Yoshimoto, syn. n. is synonymized under Omyomymar Schauff, and its only species Caenomymar howdeni Yoshimoto is transferred to Omyomymar as Omyomymar howdeni (Yoshimoto), comb. n. Gonatocerus chula Triapitsyn & Bernal is transferred to Cosmocomoidea Howard as Cosmocomoidea chula (Triapitsyn & Bernal), comb. n. Erythmelus mirus Girault is transferred to Cleruchoides Lin & Huber as Cleruchoides mirus (Girault), comb. n. and compared with Cleruchoides noackae Lin & Huber, a species introduced from Australia into South America as a biological control agent of Thaumastocoris peregrinus Carpintero & Dellape (Hemiptera: Thaumastocoridae), an introduced pest of Eucalyptus. Four spelling corrections are made to species names in Cosmocomoidea and Lymaenon Walker. PMID- 27988552 TI - Two new species of the genus Sphingonotus Fieber, 1852 (Orthoptera: Oedipodidae) from China. AB - Two new species of the genus Sphingonotus Fieber, 1852, namely Sphingonotus taiwanensis sp. nov. and Sphingonotus zhongningensis sp. nov. are described in this paper from China. The new species Sphingonotus taiwanensis sp. nov. is similar to Sphingonotus nebulosus (Fiescher-Waldheim, 1846), but differs from the latter by interspace of mesosternum wider, width 1.8 times the length; hind femur pale red on inner side; hind tibia pale red, with 13 spines on inner side and 10 spines on outer side; hind wing pale yellow at base. The new species Sphingonotus zhongningensis sp. nov. is similar to Sphingonotus salinus (Pallas, 1773), but differs from the latter in: vertical diameter of eye 1.3 times horizontal diameter; metazona of pronotum is 2.0 times prozona in length; hind tibiae with 13 spines on inner side and 12 spines on outer side; black band of hind wing wider in the middle, apical part not narrowed; black band of hind wing in the apical part larger, not divided into two. The type specimens are deposited in the Taiwan Agricultural Research of Institute (TARI), Taichung Taiwan, China and in the College of Plant Protection, China Agricultural University, Beijing, China respectively. PMID- 27988553 TI - Revision of the genus Pselaphomorphus Motschulsky, 1855 (Staphylinidae, Pselaphinae: Jubini). Corrections. AB - In my revision of the genus Pselaphomorphus Motschulsky, 1855 (Vasquez-Velez 2016) the depository of the holotype of P. cayennensis Vasquez-Velez, 2016 was not listed. As a result, the requirements of Article 16.4.2 of the International Code of Zoological Nomenclature (International Commission on Zoological Nomenclature 1999) have not been met, making the name unavailable. This note aims at correcting the earlier mistake: the holotype of P. cayennensis is deposited at the Museum of natural history (Museum d'histoire naturelle), Geneva, Switzerland. PMID- 27988554 TI - ANDREAS SCHMIDT-RHAESA & CHRISTIAN J. SCHWARZ (2016) Nematomorpha from the Philippines, with description of two new species. Zootaxa, 4158 (2): 246 260. PMID- 27988555 TI - Catalogue of distribution of lizards (Reptilia: Squamata) from the Brazilian Amazonia. III. Anguidae, Scincidae, Teiidae. AB - We present distribution data of all Anguidae, Scincidae, and Teiidae lizards known from the Brazilian Amazonia, totaling 29 species-level taxa, belonging to 14 genera. This represents 11 more species-level taxa than previously reported for these families in this area. Data were based on literature and 46,806 specimens deposited in three North American and eight Brazilian museums, including the main collections harboring Amazonian material. Most species (~55%) are endemic to Amazonia. Except for Ameiva ameiva, that is present in several environments and domains, non-endemic species are either associated with open dry (semideciduous) forest or open vegetation (savanna) enclaves in Amazonia, occupying similar environments outside Amazonia, gallery forests within the Cerrado, or present disjunct populations in the Atlantic Forest. As a whole, six taxa are widespread in Amazonia, four are restricted to eastern Amazonia, four to western Amazonia, three to southwestern Amazonia, one to northern Amazonia, and seven to the southern peripheral portion of Amazonia. Besides, two species present apparently more restricted, unique distributions. Only three species have a distribution that is congruent with one of the areas of endemism (AE) recognized for other organisms (birds and primates), of which two occur in AE Guiana and one in AE Inambari. PMID- 27988556 TI - Description of three new species of the tropical Asian jumping spider genus Onomastus Simon, 1900 from high altitude cloud forests of Sri Lanka (Araneae: Salticidae). AB - Spiders of the tropical Asian jumping spider genus Onomastus Simon, 1900 are small to medium-sized, delicate, translucent, commonly found inhabitants of Asian evergreen forest foliage. In this paper, three new species of the genus, O. jamestaylori sp. nov. (??), O. corbetensis sp. nov. (??) and O. maskeliya sp. nov. (??) are described from Sri Lanka. The three new species are added to the matrix of a previous study to assess their phylogenetic position. The resulting cladistic analysis, based on 35 morphological characters from 18 taxa (13 Onomastus species and 5 outgroups) supports the monophyly of the genus. Additionally, a monophyletic, well-supported South Asian clade (India, Sri Lanka), which is restricted to the Sri Lanka-Western Ghats biodiversity hotspot, is recovered in most analysis. The three newly described species might be endangered due to their small population size and restricted distribution in high altitude cloud forest. PMID- 27988557 TI - ? AB - Two new species (Speonemobius bifasciatus sp. nov., Speonemobius fulvus sp. nov.) are found in southwest China. The morphology and genitalia are described in this paper. The specimens are deposited in East China Normal University, Biology of History Museum (ECNU) and Collection of Chang-Chin Chen, Tianjin, China (CCCC). PMID- 27988558 TI - Morphological and molecular characterization of Pratylenchoides persicus n. sp. (Nematoda: Merliniidae) and additional data on two other species of the genus from Iran. AB - Some nematologists recently placed the genus Pratylenchoides, ("Lesion Nematode like") in the family Merliniidae. To investigate Pratylenchoides species diversity and their relationships with other Merliniidae genera, specimens were collected from various habitats in the northern and northwestern provinces of Iran. The morphological and molecular study yielded three species of the genus Pratylenchoides, including P. persicus n. sp. This new species is characterized by having lip region rounded or slightly flattened anteriorly with four or five fine but distinct annuli, pharyngeal glands off-set or slightly overlapping the intestine dorsally, all three gland nuclei located anterior to the pharyngo intestinal valve and tail cylindrical with truncate to low rounded terminus. Morphologically, P. persicus n. sp. can be distinguished from the most closely related species, P. heathi by having shorter body and stylet length in females and males, as well as a shorter tail with different terminus in females. Pratylenchoides laticauda and P. cf. nevadensis are reported from Iran for the first time. Phylogenetic analysis based on the D2/D3 region of the large subunit of ribosomal DNA revealed Pratylenchoides as a monophyletic genus, and it supports the delineation of the new species, P. persicus n. sp. PMID- 27988559 TI - A new genus and new species of subfamily Trioxinae (Hymenoptera: Aphidiidae) from the Far East of Russia. AB - A new Trioxinae (Aphidiidae) genus Sergeyoxis gen. nov., with type species S. monoceratus sp. nov., is described and illustrated from the Russian Far East. This new genus is closely related to Parabioxys Shi et Chen, 2001, but differs from the latter by the development of a single long process (prong) which is not fused with the sixth sternite, fore wing darkened and narrow, and petiole short. Sergeyoxis gen. nov. differs from the all other trioxine taxa by the presence of mobile unpaired process between two last sternites of metasoma. PMID- 27988560 TI - The advertisement call and geographic distribution of Proceratophrys dibernardoi Brandao, Caramaschi, Vaz-Silva & Campos 2013 (Anura, Odontophrynidae). AB - Proceratophrys dibernardoi Brandao, Caramaschi, Vaz-Silva & Campos 2013 has recently been described and allocated into the P. cristiceps species group, but no information about its advertisement calls has been provided (Brandao et al. 2013). Here, we describe for the first time the advertisement calls of P. dibernardoi based on specimens from Central Brazil. We also expand P. dibernardoi's geographic distribution by reporting a new population in the State of Mato Grosso do Sul, Brazil, constituting the westernmost record for this species, and extending its known range approximately 330 km westward of the municipality of Apore, State of Goias (P. dibernardoi's former westernmost record). PMID- 27988561 TI - The advertisement call of Stumpffia be Kohler, Vences, D'Cruze & Glaw, 2010 (Anura: Microhylidae: Cophylinae). AB - We describe the calls of Stumpffia be Kohler, Vences, D'Cruze & Glaw, 2010. This is the first call description made for a species belonging to the large-bodied northern Madagascan radiation of Stumpffia Boettger, 1881. Stumpffia is a genus of small (~9-28 mm) microhylid frogs in the Madagascar-endemic subfamily Cophylinae Cope. Little is known about their reproductive strategies. Most species are assumed to lay their eggs in foam nests in the leaf litter of Madagascar's humid and semi-humid forests (Glaw & Vences 1994; Klages et al. 2013). They exhibit some degree of parental care, with the males guarding the nest after eggs are laid (Klages et al. 2013). The bioacoustic repertoire of these frogs is thought to be limited, and there are two distinct call structures known for the genus: the advertisement call of the type species, S. psologlossa Boettger, 1881, is apparently unique in being a trill of notes repeated in short succession. All other species from which calls are known emit single, whistling or chirping notes (Vences & Glaw 1991; Vences et al. 2006). PMID- 27988562 TI - A new species of Lygephila Billberg, 1820 from Java (Lepidoptera, Erebidae, Toxocampinae). AB - The revision of the Lygephila dorsigera species-group led to the recognition of a number of distinct species which may occur partly sympatrically with each other in the continental SE Asia and the island of Sri Lanka (Ceylon). The study of an old Lygephila material from the island of Java and from Flores harboured in the RMNH and recently collected material from Sulawesi preserved in NMPC revealed the presence of an unknown species of the dorsigera group which appears as new for science. This species is described below under the name Lygephila javanica sp. n., the diagnostic comparison is made with Lygephila dorsigera (Walker, 1865). This is the first record of the genus from the Greater Sunda Islands, no records of a Lygephila species is known from Sumatra and Borneo. PMID- 27988563 TI - Coendutermes tucum Fontes (Isoptera, Termitidae, Nasutitermitinae): description of the imago caste and additional notes. AB - Coendutermes Fontes, 1985 is a monotypic South American termite genus. Coendutermes tucum Fontes, 1985, was described based on morphological characters from soldiers and workers collected in Mato Grosso, Brazil, and Jodensavanne, Suriname. Herein, I describe the imago caste of C. tucum for the first time with additional notes on soldiers, workers, and new distributional records. The studied material is deposited at the Museu de Zoologia da Universidade de Sao Paulo, Sao Paulo, Brazil (MZUSP). I use the terminology of Fontes (1987) to describe worker mandibles, and that of Noirot (2001) for the different parts of the digestive tube of workers. I measured the imagoes morphometric characters following Roonwal (1970): LH, length of head capsule (9); WH, width of head capsule without eyes (18); OF, occipito-fontanelle distance (23); DE, diameter of eye (48); LO, length of ocellus (55); WO, width of ocellus (56); EOD, eye-ocellus distance (57); LP, length of pronotum (65); WP, width of pronotum (68); LT, length of hind tibia (85). I took photographs of all castes with a stereomicroscope (Leica M205C) attached to a video camera (Leica DFC295) and images of gizzard and enteric valve under a microscope (Leica DM750B) attached to a video camera (Leica ICC50HD), then I combined the stacks of images with the software Leica LAS EZ 2.0 or Helicon Focus 5.2.11 X64. For the scanning electron micrographs (SEM), one soldier was dried to critical point while directly mounted on a stub with double face adhesive tape, then coated with gold and photographed with the SEM (Zeiss LEO 440 (r)). PMID- 27988564 TI - New synonymies in the plant bug family Miridae (Hemiptera: Heteroptera) from Northern China. AB - The plant bug fauna of China is highly diverse and relatively poorly documented, with almost 900 currently known species, about a half of which had been revealed during the last two decades (Qi et al. 2003, 2007, Konstantinov & Namyatova 2008, 2009, Konstantinov et al. 2013). Future studies would almost certainly reveal many new species from the region. However, the present day distributions of Chinese plant bugs apparently reflect significant climate change since the Tertiary Period, and are largely influenced by influx of species from other regions. Particularly, the plant bug fauna of the Northwestern China is most similar to the faunas of Central Asia and Mongolia, having almost identical generic composition and sharing many common species (Kerzhner & Josifov 1999). This paper provides seven new synonymies of Miridae originally known from Central Asia and Mongolia and recently described as new from the Northern China. PMID- 27988565 TI - Revision of early taxa of Australian gall midges (Diptera: Cecidomyiidae). AB - Australian Cecidomyiidae described by Schiner (1868), Skuse (1888, 1890), Koebele (1893), Felt (1915), Edwards (1916) and Rubsaamen (1916), totalling 111 species and three subgenera, are revised. Chastomera Skuse, 1888 is confirmed to be a junior synonym of Haplusia Karsch, 1878 and Gonioclema Skuse, 1888 and Necrophlebia Skuse, 1888 are declared nomina dubia. Twenty-two species are placed to genus, an additional four species are placed to supertribe or subfamily, all of them redescribed. The remaining species are declared junior synonyms or nomina dubia. Diadiplosis koebelei (Koebele, 1893) is a new junior synonym of Diadiplosis plumbea (Skuse, 1888). Dasineura tomentosa Dorchin, 2011 is a new junior synonym of Dasineura frauenfeldi (Schiner, 1868). Sphenolasioptera Kolesik & Gagne gen. nov. (Cecidomyiinae: Lasiopterini) is erected to contain Sphenolasioptera vastatrix (Skuse, 1888) n. comb. The following genera are recorded from Australia for the first time: Ledomyia Kieffer (Cecidomyiinae: Ledomyiini), represented by L. vitulans (Skuse), n. comb.; Bremia Rondani (Cecidomyiinae: Aphidoletini), represented by B. actiosa (Skuse) n. comb. and B. oreas (Skuse) n. comb.; Divellepidosis Fedotova & Sidorenko (Porricondylinae: Porricondylini), represented by D. pallidina (Skuse) n. comb. and D. indubitata (Skuse) n. comb. Additions are made to the key to genera of Cecidomyiinae of Australia and Papua New Guinea (Kolesik 2014) to accomodate Bremia, Ledomyia and Sphenolasioptera. PMID- 27988566 TI - On the synonymy of two wolf spider species of the genus Alopecosa (Araneae, Lycosidae) from the steppe zone of Russia. AB - Alopecosa atypica Ponomarev, 2008 is known from the holotype male collected in Western Kazakhstan. Here we synonymize it with A. cronebergi (Thorell, 1875), which was described from two syntype females from the Volga River and Daghestan. This species is redescribed in detail and its distribution is shown to be restricted to Russia and Ukraine, and previous records from Hungary are probably mistaken. PMID- 27988567 TI - Plectranthias takasei, new species of anthiadine fish from southern Japan (Teleostei: Serranidae). AB - Plectranthias takasei is described from two specimens collected in Izu Oceanic Park, Sagami Bay, Honshu, Japan. It is distinguished from congeners in having the following combination of characters: dorsal rays X,15; no fleshy flaps on dorsal fin spines; pectoral rays 13, all unbranched; branched caudal-fin rays 8 + 7; lateral line scales 28 (including intermittent and terminal pitted scales); circumpeduncular scales 12; fourth dorsal-fin spine longest; and preopercle without antrorse spines or serrations ventrally, with 2-3 weak serrations or crenulations posteriorly. PMID- 27988568 TI - Description of the puparium of Hermetia pulchra (Diptera: Stratiomyidae) from Brazil. AB - The puparium of Hermetia pulchra is described, based on a single specimen reared in laboratory under controlled conditions until the emergence of an adult female. The puparium of H. pulchra was compared with puparium of H. illucens and some differential features were indicated. A checklist of the Brazilian species of the genus Hermetia is included, with new distributional records for H. pulchra in the Brazilian States of Bahia and Distrito Federal. Hermetia sphecodes is recorded for the first time for Brazil (State of Amazonas). PMID- 27988569 TI - Motuotrichius yangi, a new genus and species from southeastern Tibet, China (Coleoptera: Scarabaeidae: Cetoniinae: Trichiini). AB - Motuotrichius yangi, new genus, new species is described from Motuo, southeastern Tibet. Motuotrichius seems to have a mixture of characters observed in the genera Epitrichius Tagawa, 1941, Indotrichius Krikken, 2009, Lasiotrichius Reitter, 1899, and Trichius Fabricius, 1775, but is separable from all the known Eurasian genera of Trichiina by the presence of a tooth on the inner side of the mesotibia in both sexes. The habitus, external characters, and male genitalia of Motuotrichius yangi are illustrated. The following new combinations are given: Gnorimotrichius albomaculatus (Moser, 1902), Gnorimotrichius signatus (Chujo, 1940), Gnorimotrichius trilineatus (Ma, 1992), and Gnorimotrichius tronqueti (Antoine, 2002). PMID- 27988570 TI - Notes on the genus Yunnantettix Zheng (Tetrigidae: Cladonotinae), with descriptions of two new species from Thailand. AB - Two new species, Yunnantettix nanensis sp. nov. and Yunnantettix variabilis sp. nov. are described from Thailand, and current knowledge on their ecology and habits are presented. Generic characteristics of Yunnantettix are updated according to all known species, and a precise key to all known species of the genus is given. Yunnantettix and its allied genera are compared, which clarifies diagnostically valuable characters. Morphology of the wings covered by pronotum is analyzed. PMID- 27988571 TI - New species of Zenoria Mulsant (Coleoptera: Coccinellidae) from Brazil and Peru. AB - Four new species of Zenoria Mulsant, 1850 are described: Zenoria limitrophi sp. nov. from Brazil; and Z. westerduijni sp. nov., Z. carbo sp. nov., and Z. miroi sp. nov. from Peru. Diagnostic characters are illustrated and relationships with previously described species are discussed. PMID- 27988572 TI - Description of a new species of the Afrotropical spider genus Afroneutria (Araneae, Ctenidae). AB - A species of the Afrotropical spider genus Afroneutria is newly described. Afroneutria tanga sp. nov is endemic to Tanzania, southeast Africa, and can be distinguished from the remaining species of the genus by the retrolateral excavation of the embolus. An identification key for all Afroneutria species is presented. PMID- 27988573 TI - Taxonomy of 'Euconnus complex'. Part IX. Problematic synonymy between Pycnophus and Nudatoconnus (Coleoptera, Staphylinidae, Scydmaeninae). AB - The subgenus Nudatoconnus Franz of Euconnus Thomson was established for a group of Neotropical species, but later this name was placed as a junior synonym of Pycnophus Casey; the type species of the latter taxon is Nearctic. Examination of the type series of Scydmaenus rasus LeConte (type species of Pycnophus) and Euconnus sphaerocephalus Franz (type species of Nudatoconnus) revealed that both taxa share strikingly similar general appearance, especially the shape of the head and pronotum and largely reduced dorsal setae, and many taxonomically important structures that may justify the previously proposed synonymy. Differences are relatively minor (e.g., Sc. rasus lacks prosternal process, present as a narrow carina in E. sphaerocephalus), except for the shape of the mesoventral intercoxal process. In Sc. rasus, the process is typical as in Euconnus s. str. (and all remaining, previously studied subgenera of Euconnus), i.e., narrowly carinate and strongly elevated. In E. sphaerocephalus, however, the mesoventral process is strongly broadened and flattened ventrally. This unusual structure may justify not only removing Nudatoconnus from synonymy with Pycnophus, but even treating it as a separate genus. However, similarities in other structures between Sc. rasus and E. sphaerocephalus are so numerous that it seems unlikely that the two species are not closely related. More logical explanation is that the unusual form of the mesoventral process is derived from the typical narrow keel and has evolved as an autapomorphy of E. sphaerocephalus or a group of species related to the latter, possibly within Euconnus (Pycnophus). The synonymy is maintained, pending further study. PMID- 27988574 TI - Review of the Oriental and Palaearctic bee fly genus Euchariomyia Bigot (Diptera: Bombyliidae: Bombyliinae). AB - The bee fly genus Euchariomyia Bigot is reviewed and new records from the Oriental Region are given. Five names (for four species-level taxa) have been associated with species in the genus. Examinations of types, as well as homotypic and topotypic specimens, shows all five names to belong to a highly variable single species, Euchariomyia dives Bigot. The following species are here shown to be the same as Euchariomyia dives Bigot: Bombylius pulchellus Wulp, 1880, Bombylius scintillans Brunetti, 1909, and Bombylius brunettii Senior-White, 1922, n. syn. The genus is known primarily from the southern and eastern Oriental Region and ranges into the Palaearctic in eastern China. We extend the distribution of the genus with new records in the southeastern Oriental Region [Indonesia (Sumatra), Laos, Peninsular Malaysia, and Vietnam]. PMID- 27988575 TI - A new genus of the subfamily Cillaeinae (Coleoptera, Nitidulidae) from the Philippines and New Guinea with notes on the taxonomy and phylogeny of the subfamily. AB - Allenipeplus gen. nov. represented by A. philippinensis sp. nov., type species (Philippines, Luzon), A. alius sp. nov. (Philippines, Mindoro), A. harmonicus sp. nov. (Philippines, Mindanao) and A. vitellinus sp. nov. (Indonesian New Guinea), is described. This new genus combines characters with a mosaic spread among other cillaeine genera. We present a wide comparison of genera among the subfamily Cillaeinae, making it possible to elaborate a detailed diagnosis of the new genus and trace some order in character patterns and propose a hypothesis on the relationship of this genus to other groups known from the Indo-Malayan and Australian Regions. A detailed diagnosis of the new genus and key to the new species are given. The Adocimus-complex of the related genera including Allenipeplus gen. nov., Adocimus Murray, 1864, Ithyphenes Murray, 1864, Platynema Ritsema, 1885 and probably Brittonema Kirejtshuk, 2011 is defined. Some notes on the taxonomy of the genera Liparopeplus Murray, 1864 and Xanthopeplus Fairmaire, 1880, stat. nov. are given. Additionally, designation of a lectotype for Liparopeplus colastoides Murray, 1864 is made. PMID- 27988576 TI - Flightless Catapionus (Coleoptera: Curculionidae: Entiminae) in Southwest China survive the Holocene trapped on mountaintops: new species, unknown phylogeny and clogging taxonomy. AB - This paper reports the first discovery of the weevil genus Catapionus in Southwest China. Eighteen specimens of C. mopsus sp.n. were collected in two high altitude localities some 360 km apart: Mt. Haba in Yunnan (the type locality) at 4,158-4,195 m and Mt. Gongga in Sichuan at 3,533-4,143 m. Habitus and genitalia of a male and a female from each locality are extensively illustrated. Six specimens from each locality were DNA barcoded (dx.doi.org/10.5883/DS-CATAPCH). Taxonomic validation of the new species name was made by referring to high quality illustrations of the holotype and to its DNA barcode, and without providing a customary verbal description. This novel approach was chosen partly due to the redundancy of description in the presence of high quality images, and partly due to the lack of adequate and unambiguously identified comparative material. Analysis of mtDNA sequences dated the separation of both geographical populations at about 3.65 Ma. The disjunct distribution of Catapionus in Asia is discussed and mapped for the first time. Monophyly and internal relationships of the genus are discussed and remain untested, together with the generic assignment to the phylogenetically vague Cneorhinini and/or Dermatodini. Discovery of the southernmost members of Catapionus high in the mountains of Southwest China evokes a hypothesis on interglacial refugia. A new term "clogging taxonomy" is introduced for situations as encountered in Catapionus when an abundance of obscure historical species-group names impedes further research. PMID- 27988577 TI - Galeus corriganae sp. nov., a new species of deepwater catshark (Carcharhiniformes: Pentanchidae) from Papua New Guinea. AB - A new species of catshark, provisionally placed in the genus Galeus, is described from Papua New Guinea based on 7 specimens collected during recent deepwater surveys of the region. The new species, Galeus corriganae, is closest to G. priapus from New Caledonia and G. gracilis from northwestern Australia but differs in several morphological characters. A reclassification of the catshark groups is required to revise the familial and generic arrangement of the group. PMID- 27988578 TI - Review of Scydmaenus (Geoscydmaenus) of Madagascar (Coleoptera, Staphylinidae, Scydmaeninae). AB - Two species of Scydmaenus (Geoscydmaenus) are known to occur in Madagascar, but original descriptions do not allow for unambiguous identification. Based on the type specimens and a recently collected additional material, Sc. isaloensis Franz and Sc. madagassicus Franz are redescribed. Several differences between these species listed by Franz had been misinterpreted; consequently species diagnoses are emended. Morphological structures of Geoscydmaenus are illustrated and discussed, and it is concluded that in future this taxon may be elevated to genus rank. However, as morphological structures of most subgenera of Scydmaenus remain exceptionally poorly studied and knowledge of character variability is scarce, it is too early to reclassify this large genus. PMID- 27988579 TI - Catalogue of the Teratomyzidae (Diptera, Opomyzoidea) of the World. AB - A catalogue of Teratomyzidae of the world is presented comprising 23 described species in seven genera. Geographic records for nine undescribed species are also listed. All valid names and synonyms are presented, totaling 34 names. All references known to us from the taxonomic and biological literature, including information about name, author, year of publication, page number, type genus, type species, type locality and references are given to the categories of family, genus and species. Camur willii McAlpine has its distributional record enlarged to Parana (Brazil). PMID- 27988580 TI - A new species of Athaumasta Hampson, 1906 from eastern Kazakhstan (Lepidoptera, Noctuidae, Bryophilinae). AB - The name Athaumasta was introduced by Hampson (1906) as replacement for Thaumasta Staudinger, 1871 (nec. Gistl). Athaumasta is a small Bryophilinae genus found in southern Siberia, Mongolia, Kazakhstan, Russian Far East, Korea and China. By the male genitalia structure Athaumasta is very close to Victrix Staudinger and Bryophila Treitschke, but characteristic forewing pattern, strong pectinate of male antennae, narrow and dorso-lateral flattened uncus, and distally narrowed and apically pointed valvae are characteristic for the genus. The genus includes six described species, one of which has recently been described (Volynkin 2012), and many species are still undescribed. The species cortex Alpheraky, 1887 was incorrectly included to Athaumasta by Poole (1989), and transferred to the genus Parvispinia Babics, Kononenko & Saldaitis by Babics et al. (2012). The species miltina Pungeler, 1902 distributed in the Tien Shan mountain massif (Pungeler 1902; Lehmann & Bergmann 2005) has appearance very close to Athaumasta, but male antennae much less pectinate (Fig. 12). It was treated by Poole (1989) and Lehmann & Bergmann (2005) as a member of the genus Oederemia Hampson (= Victrix), but was not mentioned by Fibiger et al. (2009) in the checklist of Palaearctic taxa of the genus. The male genitalia of miltina (Fig. 22) differ from those of all other Athaumasta by the broad uncus, apically broadened and rounded valvae, and presence of a torn in cornutus in vesica, whereas in Athaumasta uncus is narrow, valvae are apically narrowed and pointed, cornutus is plate-like or absent. By the male genitalia structure, miltina resembles the genus Victrix, subgenus Rasihia Kocak, but have broader uncus and strongly different appearance. Thus, the genus position of miltina is unclear. Here we treated miltina as a member of Athaumasta (sensu lato), but its genus position will be revised later in a further revision of Eurasiatic Bryophilinae. PMID- 27988581 TI - Diagnostic clarification, new morphological data and phylogenetic placement of Amphisbaena arenaria Vanzolini, 1991 (Amphisbaenia, Amphisbaenidae). AB - Several decades ago, Vanzolini (1991) described Amphisbaena arenaria Vanzolini, 1991 based on a single individual (MZUSP 65817) collected at Raso da Catarina, a large flat sandy deposit at the southern bank of Sao Francisco River. In the same paper he described A. frontalis Vanzolini, 1991 based on specimens collected at another sandy area, at the northern bank of Sao Francisco River, both in Bahia state, Brazil. As conflicting values are presented throughout his paper, the diagnosis of A. arenaria still needs clarification. We here comment on these differences and re-diagnose A. arenaria including new topotypic material, providing its phylogenetic placement and a new state record. PMID- 27988582 TI - Taxonomic notes on the genera Brypoctia Schoorl, 1990 and Schreiteriana Fletcher & Nye, 1982 (Lepidoptera, Cossidae). AB - Currently, the Cossidae of South America are rather poorly studied. Data on the distribution and taxonomy of Neotropical carpenter moths are lacking. An exception is the clarification of the taxonomic position of the genus Miacora Dyar, 1905 (Yakovlev 2014), Neotropical Cossidae checklist (Donahue 1995), and a preliminary list of Cossidae of Argentina (Penco & Yakovlev 2015). The majority of Neotropical Cossidae genera have not been studied and the taxonomic position of some genera remains completely unresolved. Additionally, images of genitalia of the Neotropical genera have not been published, including the genera Brypoctia Schoorl, 1990 and Schreiteriana Fletcher & Nye, 1982 (Cossidae: Zeuzerinae). The taxonomic position of the second genus was questioned by Schoorl (1990). PMID- 27988583 TI - Checklist of host associations of European bat flies (Diptera: Nycteribiidae, Streblidae). AB - Bat flies are obligate blood-sucking ectoparasites of bats. They are divided into two families: Nycteribiidae and Streblidae. Europe has 17 species of bat flies and 45 species of bats (Mammalia: Chiroptera). This checklist is based on both published records and our own field data and provides updated information on all associations between bat flies and their hosts in Europe. The host-parasite association between Basilia italica Theodor and Plecotus auritus (Linnaeus) is reported for the first time. Moreover, our records of B. italica on Myotis alcathoe Helversen & Heller, B. nana Theodor & Moscona on Plecotus auritus, Nycteribia kolenatii Theodor & Moscona on M. bechsteinii (Kuhl) and Penicillidia dufourii (Westwood) on M. daubentonii (Kuhl) represent new host associations for Hungary. PMID- 27988584 TI - A diversity and conservation inventory of the Herpetofauna of the Cuautlapan Valley, Veracruz, Mexico. AB - We compiled an inventory of the amphibians and reptiles of the Cuautlapan Valley, Veracruz, Mexico based on field surveys and museum and literature records. We found a total of 78 species: 28 amphibians (6 Salamanders and 22 anurans); and 50 reptiles (three turtles, 18 lizards, and 29 snakes). These taxa represent 26 families (eight amphibian families, 18 reptile families) and 60 genera (19 amphibian genera, 41 reptile genera). Two of these species are not native to the area (Rhinoclemmys pulcherrima and Hemidactylus frenatus). According to the IUCN red list, five species are Critically Endangered, two are Endangered, four are Near Threatened, and four are Vulnerable. In the SEMARNAT (Secretaria del Medio Ambiente y Recursos Naturales) listing, one species is Endangered, eight species are Threatened, and 25 are Subject to Special Protection. Even though the Cuautlapan Valley is represented by a relatively small area it hosts a rich diversity of amphibian and reptile species, many of which are at risk and protected under Mexican law. This valley lies between the growing cities of Orizaba and Cordoba which have contributed to habitat degradation threatening the existence of the wildlife that occurs there. PMID- 27988585 TI - New taxonomic and faunistic data on the Himalayan Lesteva Latreille, 1797 (Coleoptera: Staphylinidae: Omaliinae). AB - New taxonomic and faunistc data for seven species of the genus Lesteva Latreille, 1797 of the Himalayas are presented. Two species are redescribed: L. (s.str.) kargilensis Cameron, 1934 and L. (s.str.) steeli Lohse, 1982. The aedeagus of L. (s.str.) steeli is illustrated. One synonym is proposed: L. (s.str.) brevipennis Cameron, 1941 = L. pakistana Coiffait, 1984 syn. n. A lectotype and paralectotypes for L. (s.str.) torrentum Cameron, 1924 are designated. A key to species known from the Himalayan Region is provided. PMID- 27988586 TI - Three new species of Claudiella Reichardt & Vanin, 1976 (Coleoptera, Torridincolidae) from Brazil. AB - The monotypic Neotropical genus Claudiella Reichardt & Vanin, 1976 is currently known only from Brazil (C. ingens Reichardt & Vanin, 1976). We describe here three new species from Brazil, C. jefersoni sp. n., C. jeaneae sp. n. and C. anamariae sp. n., from Roraima, Minas Gerais and Bahia states, respectively, bringing to four the number of species included in Claudiella. These species can be distinguished by different characteristics observed in the legs, mouth parts, metathoracic wings and male genitalia. PMID- 27988587 TI - A new species and new records of Melittiini from China and Vietnam (Lepidoptera, Sesiidae). AB - We review the Melittiini fauna of mainland China and list a total of 14 species in two genera. Melittia proxima Le Cerf, 1917, Melittia fulvipes Kallies & Arita, 2004, Melittia distincta Le Cerf, 1916, and Macroscelesia vietnamica Arita & Gorbunov, 2000 are recorded from China for the first time. Macroscelesia perlucida Kallies & Arita, sp. nov. is described as new to science based on specimens collected in China (Guangxi Province) and in northern Vietnam. Melittia formosana Matsumura, 1911 is considered a subspecies of Melittia eurytion (Westwood, 1848) (stat. nov.), and Melittia eurytion nagaii Arita & Gorbunov, 1997 is treated as a junior subjective synonym of M. eurytion formosana (syn. nov.). PMID- 27988588 TI - Simonachorutes, a new genus of Pseudachorutinae (Collembola, Neanuridae) from Europe. AB - Simonachorutes gen. nov. a new genus of subfamily Pseudachorutinae is described from Europe. It has a unique suite of morphological characters (8 + 8 ocelli, very long buccal cone, mandibles absent, tibiotarsal chaetotaxy reduced, furcula present) and is similar to Pseudachorutes Tullberg, 1871, Paranurida Skarzynski & Pomorski, 1994 and Pongeia Najt & Weiner, 2002. S. romeroi comb. nov. and S. agrensis comb. nov. are redescribed and S. weinerae sp. nov. from Poland is described. PMID- 27988589 TI - New Earwigs in Protodiplatyidae (Insecta: Dermaptera) from the Middle Jurassic Jiulongshan Formation of Northeastern China. AB - Two new genera, each with a new species, Perissoderma triangulum gen. et sp. nov. and Abrderma gracilentum gen. et sp. nov., of the family Protodiplatyidae are described from the latest Middle Jurassic Jiulongshan Formation of Daohugou, Inner Mongolia, China. They are the first records of Protodiplatyidae from the latest Middle Jurassic Daohugou locality. Both new genera are assigned to Protodiplatyidae based mainly on diagnostic characters of antennae, pronotum, tegmina, tarsi and the distinct long, slender, multi-segmented cerci. We summarize the distributions and ages of all described fossil Archidermaptera and infer that the Dermaptera might have originated in Eurasia and started their diversification and migration to a worldwide distribution. The new taxon of Abrderma gracilentum gen. et sp. nov. provides one more example of an early earwig with well-preserved pentamerous tarsi on the hind leg. PMID- 27988590 TI - Pseudotrichonotus belos new species, first record of the fish family Pseudotrichonotidae from Australia (Teleostei: Aulopiformes). AB - Pseudotrichonotus belos new species, described from three specimens trawled in 100-120 m offshore between Exmouth Gulf and Shark Bay, Western Australia, represents the first record of the sand-diving fish family Pseudotrichonotidae from Australian waters. It differs from its two congeners in having a more posteriorly positioned dorsal fin (predorsal length 39.6-41.2 % SL) and fewer dorsal- and anal-fin rays (31-33 and 12, respectively). PMID- 27988591 TI - Two new species of Batrisodes Reitter (Coleoptera: Staphylinidae: Pselaphinae) from China. AB - Two new species, Batrisodes linyejiei Jiang and Yin, new species and Batrisodes petalosus Jiang and Yin, new species, are described from China. The former species is associated with Formica ants and the latter with Myrmica ants. A key to all 11 Batrisodes species known to occur in China is provided. PMID- 27988592 TI - Redescriptions of two closely related East Asian flatfish species of the genus Pleuronichthys. AB - Because of the taxonomic confusion, including misapplication of their scientific names, resulting from the morphological similarity of two East Asian flatfish species, Pleuronichthys lighti Wu, 1929 and Pleuronichthys cornutus (Temminck & Schlegel, 1846), both species are redescribed, with particular emphasis on some new key characters. New common names are proposed for each species. PMID- 27988593 TI - Four new species of the genus Philanthaxia Deyrolle, 1864 (Coleoptera: Buprestidae: Thomassetiini). AB - Descriptions of four new species of the genus Philanthaxia Deyrolle, 1864: P. depressifrons sp. nov. (Vietnam), P.granum sp. nov., P. hanloni sp. nov. and P. purpureifrons sp. nov (all from The Philippines). All described species are illustrated and compared with the similar or sympatric congeners. PMID- 27988594 TI - A taxonomic revision of the genus Diplonevra Lioy (Diptera: Phoridae) from China. AB - The Chinese species of Diplonevra are revised, with 16 recognised species from both the Oriental and Palaearctic parts of China. The following 8 species are described as new to science: D. corniculata sp. nov., D. trapezia sp. nov., D. vecticrassa sp. nov., D. lamella sp. nov., D. furcavectis sp. nov., D. brevicula sp. nov., D. triangulata sp. nov., D. spinibotra sp. nov. All known species are re-identified, re-described and illustrated. Diagnostic characters of the base of the posterior face of the hind trochanter and femur are depicted in detail. A revised identification key to Chinese species based on males is presented. PMID- 27988595 TI - A new species of iguanid lizard, genus Stenocercus (Squamata, Iguania), from the Central Andes in Peru. AB - We describe a new species of Stenocercus from the montane forest of the right margin of the Maranon river in the northern portion of the Central Andes in northern Peru (Amazonas and La Libertad departments), at elevations ranging from 2300 to 3035 m. Stenocercus omari sp. nov. differs from other Stenocercus species, with the exception of S. amydrorhytus, S. chrysopygus, S. cupreus, S. johaberfellneri, S. latebrosus, S. melanopygus, S. modestus, S. ornatissimus, S. orientalis, and S. stigmosus, by having granular scales on the posterior surfaces of thighs, a conspicuous antehumeral fold and by lacking a vertebral crest. However, Stenocercus omari sp. nov. is easily distinguished from the aforementioned species, except S. orientalis, by the presence of prominently keeled dorsal head scales. The new species differs from S. orientalis by lacking a prominent oblique neck fold and by having a distinct deep postfemoral mite pocket. PMID- 27988596 TI - Leptobotia bellacauda, a new species of loach from the lower Yangtze basin in China (Teleostei: Cypriniformes: Botiidae). AB - A new species, Leptobotia bellacauda is described from the lower Yangtze River basin. The new species is distinguished from all other species of Leptobotia by a combination of the following characters: body plain brown, prominent black bar in caudal fin, dorsal half of head dusky black, ventral half of head cream colour, eye well developed, lobes of caudal fin rounded, origin of pelvic fins beneath or anterior to dorsal-fin origin, and pectoral fin in adult males enlarged, with numerous tubercles. PMID- 27988597 TI - Two new species of the genus Deontolaimus de Man, 1880 (Nematoda: Leptolaimidae) from mangrove ecosystems of Vietnam. AB - Two new species of the free-living marine nematode genus Deontolaimus (Leptolaimidae) are described from mangrove forests of the Can Gio Biosphere Reserve and Tien Yen, Quang Ninh, Vietnam. D. mangrovi sp. nov. is distinguished from D. papillatus de Man, 1880 and D. cangioensis sp. nov. by tail shape: conical and then elongated, without pointed tip. Deontolaimus cangioensis sp. nov. resembles D. papillatus in body shape, especially in the pointed tail terminus. D. cangioensis differs from D. papillatus in having a complicated gubernaculum with dorsally curved apophyses. PMID- 27988598 TI - Identifying Neogobius species from the southern Caspian Sea by otolith shape (Teleostei: Gobiidae). AB - Three Neogobius species are common in the southern Caspian Sea. Identification of these species, especially from remains, is not fully understood. The present study compares the morphological characteristics of sagittal otoliths of N. caspius, N. pallasi and N. melanostomus. Furthermore, it also provides a dichotomous identification key based on otoliths morphology. PMID- 27988599 TI - The advertisement calls of Quasipaa shini (Ahl, 1930) (Anura: Dicroglossidae). AB - The genus Quasipaa (Family Dicroglossidae) is currently composed of 11 species distributed in China and Southeast Asia: Quasipaa acanthophora (Dubois & Ohler 2009), Q. boulengeri (Gunther 1889), Q. courtoisi (Angel 1922), Q. delacouri (Angel 1928), Q. exilispinosa (Liu & Hu, 1975), Q. fasciculispina (Inger 1970), Q. jiulongensis (Huang & Liu, 1985), Q. shini (Ahl 1930), Q. spinosa (David 1875), Q. verrucospinosa (Bourret 1937), Q. yei (Chen, Qu & Jiang 2002) (Frost 2016). These species are morphologically similar, and their taxonomy is subject to controversy (Che et al. 2009). Analyses of nuclear and mitochondrial genes suggest the genus likely encompass additional cryptic species (Ye et al. 2013). Bioacoustics has contributed to studies on the taxonomy of the genus (Ye et al. 2013; Shen et al. 2015), however, to date, only the advertisement calls of Q. spinosa are known (Yu & Zheng 2009; Chen et al. 2012; Shen et al. 2015). Here, we describe the advertisement calls of Q. shini, which inhabits streams in the southern part of central China(Guizhou, Hunan, Guangxi and Jiangxi) and is characterized by the presence of keratinized skin spines on the lateral surfaces of the body. PMID- 27988600 TI - A description of the unknown female of Coleophora arenbergerella Baldizzone, 1985 (Lepidoptera: Coleophoridae). AB - During a trip to Cyprus, 27 September-4 October 2015, 4 specimens (3? and 1?) of a Coleophora sp. unknown to the author were collected in the Oreites Forest, above Kouklia, Paphos District (N34 7307149: E32 6366901, altitude 340m). Two males and the one female were dissected. No match in habitus, or for the genitalia of either sex, was found when compared with any of the Coleophora sp. recorded for Cyprus (Fauna Europaea), other than C. arenbergerella about which no information could be found. The author contacted Giorgio Baldizzone, the author of the species, to see whether he could provide any information on C. arenbergerella; he kindly sent a copy of photos he had of the ? holotype, informing the author that the species was only known from that male. This allowed the author to confirm that the four specimens were C. arenbergerella, a species given as close to Coleophora kuehenella (Goeze) in Baldizzone (1985). So far this species is only known from Cyprus so may be endemic to the island. PMID- 27988601 TI - A world catalogue of Aholcocerus Yakovlev, 2006 (Lepidoptera, Cossidae) with description of a new species from Indonesia. AB - Aholcocerus jakli Yakovlev & Witt sp. nov. is described from Indonesia. A catalogue of the genus Aholcocerus Yakovlev, 2006 is provided. External appearance of all species of the genus is illustrated. PMID- 27988602 TI - New records of the rare pandalid shrimp Plesionika exigua (Rathbun, 1906 (Crustacea: Decapoda: Caridea) in the western Pacific. AB - The rare species Plesionka exigua (Rathbun, 1906) is recorded for the first time from three western Pacific localities New Caledonia, Vanuatu and Ryukyu Islands of Japan. Redescription, illustrations on distinguishing characters and color photograph are provided for this poorly known species. PMID- 27988603 TI - Key for identification of Cladocera of the subfamily Aloninae (Anomopoda: Chydoridae) from South-East Asia. AB - An identification key for Cladocera of subfamily Aloninae (Anomopoda: Chydoridae) of South-East Asia is provided. The key includes 42 species known from the region to date, and encompass all recent changes in taxonomy of the subfamily Aloninae. Drawings and descriptions of diagnostic characters for each species are provided. This is the first identification key for Aloninae of the region published in the last forty years. PMID- 27988604 TI - A new genus and species of Laelapidae (Acari: Mesostigmata) from Iran. AB - A new monotypic mite genus of the family Laelapidae, Persicolaelaps gen. nov., is described to accommodate a new species, P. hallidayi sp. nov., on the basis of adult female specimens collected from decaying wood, soil and litter in northern Iran, Golestan and Mazandaran provinces, respectively. The new genus can be distinguished from other members of the family by a combination of morphological attributes, some of which are unique or rarely observed in laelapids, such as (1) a series of small subrectangular sclerites flanking dorsally coxae I and gnathosomal base and adjoining podal plates anterolaterally, which are extending from and fused with sternal shield between coxae I and II; (2) an epigynal shield, so broad as to reach or even overlap acetabula III-IV, posteriorly axe shaped; (3) metasternal setae absent; (4) a typical anal shield, though capturing pair of opisthogastric setae JV3; (5) gnathotectum triangular and acuminate; (6) the presence of six setae on trochanter IV; (7) genu IV with two ventral setae (occasional in Laelapidae); (8) internal malae with a series of thick, elongate filaments. PMID- 27988605 TI - Revision of the genus Metaterpna Yazaki, 1992 (Lepidoptera, Geometridae, Geometrinae), with description of a new species from China. AB - The genus Metaterpna is revised. The two species known, M. differens (Warren, 1909) and M. thyatiraria (Oberthur, 1913), are redescribed, with emphasis on the considerable variability of M. thyatiraria, and the status of the related type specimen was discussed. In addition, one new species, M. batangensis sp. nov., is described from Batang and Daocheng, Sichuan province, and Lijiang, Yunnan province, southwestern China. M. thyatiraria and M. batangensis show clear distance by DNA barcode sequences. Illustrations of moths and genitalia are presented. PMID- 27988606 TI - Andraca yauichui sp. n., a new species endemic to mid elevation forests of Taiwan (Bombycidae sensu lato, Lepidoptera). AB - A new endemic, montane species of the genus Andraca, A. yauichui sp. nov., in Taiwan is described. It can be separated well from a lower montane, notable tea tree pest A. theae (Matsumura, 1909), based on morphological characters of adult, e.g. larger wingspan size, head vertex white rather than brown, valval apex truncate rather than bifurcate, and final instar larva, e.g. the presence of a pair of white spot on lateral part of each abdominal segment and a distinct short anal horn rather than the absence of two characters. The subgeneric placement of this new species in Andraca is also discussed. PMID- 27988607 TI - Molecular and morphological identification of pistachio armored scale insects (Hemiptera: Diaspididae), with description of a new species. AB - Members of the family Diaspididae (Hemiptera: Coccomorpha) can be devastating pests that suck parenchyma cell contents from crops and cause severe damage to pistachio trees (Pistacia vera L.). The current research collected and characterized diaspidid species from pistachio orchards in Kerman province, Iran, according to their morphological and molecular features. Lepidosaphes pistaciae Archangelskaya, Suturaspis davatchi (Balachowsky & Kaussari) and Melanaspis inopinata (Leonardi) are redescribed and a new species, Melanaspis pistaciae Hosseininaveh & Kaydan sp. n., is described. Phylogenetic trees based on molecular analysis of COI and 28S rDNA fragments placed all the species in separated clades and confirmed M. pistaciae as a new taxon which is concluded by morphological differences. Molecular analysis suggests non-monophyly of the populations of each species. Melanaspis pistaciae sp. n. has spread to most cultivated pistachio areas in Iran and has probably been misidentified as M. inopinata in the past. Further investigation of the biology of this species may lead to development of more effective approaches for controlling this pest. PMID- 27988608 TI - Lost and found: the Plecoptera types of Blanchard and Mabille, with further contributions to the stoneflies of Chile. AB - Types of five of the six Plecoptera species described by Emile Blanchard and the holotype of the single stonefly described by Jules Francois Mabille were discovered in the National Museum Prague, Czech Republic. The identity of P. myrmidon Mabille, 1891 and P. pictetii Blanchard, 1854 are confirmed as Potamoperla myrmidon and Pictetoperla gayi (Pictet, 1841), respectively. Perla virescentipennis Blanchard, 1851 is considered as Diamphipnopsis virescentipennis comb. n., with Diamphipnosis samali Illies, 1960 syn. n. as a junior subjective synonym, and Diamphipnoa chillanae nom. n. is proposed for D. virescentipennis sensu Illies 1960. Lectotypes are designated for three species: Nemoura rufescens Blanchard, 1851 is redescribed as Austronemoura rufescens (Blanchard, 1851) comb. n., with Perla infuscata Blanchard, 1851 syn. n. and Perla blanchardi Jakobson & Bianchi, 1905 syn. n. designated as junior subjective synonyms, whereas Perla stictica Blanchard, 1851 is treated as Neonemura stictica (Blanchard, 1851) comb. n., nomen dubium. Paralectotypes of these three species belong to further four taxa. Due to the missing syntypes, Perla lineatocollis Blanchard, 1851 is treated as a nomen dubium of uncertain suborder assignment. Specimens of the Blanchard collections that cannot regarded as types are enumerated belonging to six species. Recent collections of 15 species from Chile are also reported. PMID- 27988609 TI - The Ando-Patagonian Stigmella magnispinella group (Lepidoptera, Nepticulidae) with description of new species from Ecuador, Peru and Argentina. AB - On the basis of morphological studies of collection samples from the Andes (Ecuador, Peru and Argentina), we describe five new species of Stigmella Schrank (Lepidoptera: Nepticulidae): S. varispinella Diskus & Stonis, sp. nov. (Ecuador), S. olekarsholti Remeikis Diskus & Stonis, sp. nov., S. magnispinella Remeikis & Stonis, sp. nov. (Peru), S. dolia Remeikis & Stonis, sp. nov., and S. patagonica Remeikis & Stonis, sp. nov. (Argentina). All treated taxa belong to the newly designated S. magnispinella group. Images of adults and genitalia, pictorial keys, a distribution map, and photographs of the leaf-mines of S. olekarsholti are included. PMID- 27988610 TI - Review of the genus Hannemania (Acari: Leeuwenhoekiidae) with description the two new species in amphibians from Chile. AB - The genus Hannemania includes 25 species of parasites of amphibians; Chile has one species: H. pattoni Sambon, 1928. This work reviews the genus Hannemania and describes two new species from Chile: Hannemania ortizi sp. nov., a parasite of Pleurodema thaul (Lesson) (Anura: Leptodactylidae) and Eupsophus contulmoensis Ortiz, Ibarra-Vidal, Formas (Anura: Alsodidae) and Hannemania gonzaleacunae sp. nov., a parasite of E. nahuelbutensis Ortiz and Ibarra-Vidal (Anura: Alsodidae). The new species differ from H. pattoni and other nearby species principally by character states of the palp and leg setae. A comparison of the diagnostic characters for all species of Hannemania is included. PMID- 27988611 TI - Study on Tychini of Balkan Peninsula (Coleoptera, Staphylinidae, Pselaphinae). AB - Tychus albanicus sp. n. from southern Albania is described and illustrated, and placed in the Tychus monilicornis group. The following new records of Tychus species are given for Balkan Peninsula: Tychus corsicus spissatus Rey, 1888 for Croatia; Tychus cordiger Besuchet, 1969, Tychus monilicornis Reitter, 1880, and Tychus niger Paykull, 1800 for Montenegro, and Tychus caudatus Reitter, 1884 for Albany. Tychus sbordonii Meggiolaro, 1967 is trasferred from the Tychus dalmatinus group to the Tychus monilicornis group. PMID- 27988612 TI - MAURO PIETRO NEGRI & CESARE CORSELLI (2016) Bathyal Mollusca from the cold-water coral biotope of Santa Maria di Leuca (Apulian margin, southern Italy). Zootaxa, 4186: 001-097. PMID- 27988613 TI - Early-diverging bumblebees from across the roof of the world: the high-mountain subgenus Mendacibombus revised from species' gene coalescents and morphology (Hymenoptera, Apidae). AB - The bumblebees of the subgenus Mendacibombus of the genus Bombus are the sister group to all other extant bumblebees and are unusual among bees for specialising in some of the highest elevation habitats with entomophilous plants on Earth. Most named taxa in this group (24 available names, from a total of 49 published names) were described originally from small differences in the colour pattern of the hair, many as parts (e.g. subspecies) of just one species. Subsequent taxonomic treatments recognised multiple species, but have described very few morphological characters, most of which are in the male genitalia. We examined 4413 specimens representing all of the named taxa from throughout the group's global range to describe variation in DNA, in skeletal morphology, and in the colour patterns of the hair. Using Bayesian inference of the phylogeny from an evolutionary model for the fast-evolving COI gene, and fitting either general mixed Yule/coalescent models or Poisson tree process models, we identify COI gene coalescents, which are expected to characterise species as evolutionarily independent lineages. None of the conditions most likely to compromise this interpretation (biased sampling, paralogy, introgression, heteroplasmy, incomplete lineage sorting) appears to be a substantial problem in this case. In an integrative analysis, we show that colour patterns are often variable within these groups and do not diagnose the same groups as we recognise from genes; in contrast, the groups recognised from gene coalescents can also be diagnosed from differences we identify in morphology. We infer that the 12 groups with coalescents in the COI gene that are corroborated by morphology constitute species, whereas many of these species are polymorphic in colour pattern. Lectotypes are designated for 15 taxa in order to reduce uncertainty in the identity and application of the names. We provide new morphological keys and distribution maps for the species. Then we use four genes (fast-evolving mitochondrial COI and 16S; and slower nuclear PEPCK and opsin) to obtain an absolute chronogram of phylogenetic relationships among the species. From published estimates that the most recent common ancestor of the subgenus Mendacibombus diverged from the other bumblebees at the beginning of the Oligocene, our results support the crown group of Mendacibombus as having diversified in the late Miocene, events that both appear to have been associated with periods of climate cooling. Relative conservatism in the alpine/subalpine climate niche of Mendacibombus, as compared with the much more diversified climate niches in the sister group of all other bumblebees, may have contributed to constraining the number of Mendacibombus species to just one twentieth of the total number of extant bumblebee species. PMID- 27988614 TI - Annotated zoogeography of non-marine Tardigrada. Part III: North America and Greenland. AB - This paper is the third monograph of the series that describes the global records of limno-terrestrial water bears (Tardigrada). Here, we provide a comprehensive list of non-marine tardigrades recorded from the North America, providing an updated and revised taxonomy accompanied by geographic co-ordinates, habitat, and biogeographic comments. It is hoped this work will serve as a reference point and background for further zoogeographical and taxonomical studies. PMID- 27988615 TI - Revision of the genus Odocnemis Allard, 1876 (Coleoptera: Tenebrionidae: Helopini) from Turkey, the Caucasus and Iran with observations on feeding habits. AB - A revision of the genus Odocnemis of Turkey, the Caucasus and Iran is presented. Thirty species and four subspecies are distributed in this territory. The following 20 new species and subspecies are described: O. dichroa sp. n., O. allardi sp. n., O. merkli sp. n., O. seducta sp. n., O. aegaeica sp. n., O. euritopica sp. n., O. subtuberculigera sp. n., O. subtuberculigera thracica subsp. n., O. erseni sp. n., O. molecularica sp. n., O. shokhini sp. n., O. inornata sp. n., O. altimontana sp. n., O. amanosica sp. n., O. cordiformis sp. n., O. kakunini sp. n. O. evestigata sp. n., O. torosica sp. n., O. torosica subangulata subsp. n., Odocnemis hakkariensis sp. n. The name of the genus is feminine, therefore all species names are transformed from masculine to feminine. Almost all new taxa are described from Turkey; O. amanosica sp. n. is additionally recorded from Syria, O. allardi sp. n.-from Armenia, Azerbaijan (Nakhchivan) and Iran, O. kakunini sp. n. from Iran. New synonymies are established: Odocnemis anatolica (Pic, 1899) = Stenomax korbi Reitter 1902: 219, syn.n.; Odocnemis recticollis (Allard, 1877) = Stenomax kurdistanus Reitter, 1902: 221, syn.n.; Odocnemis punctata Allard, 1876 = Cylindronotus (Odocnemis) pseudoclarus Reitter, 1922, syn.n. The following lectotypes are designated: Helops (Odocnemis) anatolicus Pic, 1899, Helops (Stenomax) seriegranatus Seidlitz, 1896, Cylindronotus (Odocnemis) opertus Reitter, 1922, Stenomax recticollis Allard, 1876, Odocnemis punctata Allard, 1876, Helops (Odocnemis) protinus Reitter in Bodemeyer, 1900. Holotypes and paratypes of all other Turkish species of Odocnemis are studied. Two new combinations are established: Odocnemis gloriosa (Faldermann, 1837), comb. n. (from Nalassus Mulsant, 1854) and Odocnemis terminasianae (Nabozhenko, 2011), comb. n. (from Armenohelops Nabozhenko, 2002). Five species O. bosphoranus (Allard, 1876), O. amasiae (Seidlitz, 1896), O. scutellatus (Reitter, 1902), O. fundator (Reitter, 1908), O. strangulatus (Reitter, 1922)) are not revised in this work and will be included in the genus Armenohelops in a future revision. Three species which were previously recorded from Turkey erroneously (O. exarata (Germar, 1817), O. crenatostriata (Allard, 1877), O. caudata Allard, 1876) should be removed from the Turkish list. Eight species-groups are characterized in the paper. The following aspects are considered and discussed: classification of the genus, morphology and main evolutionary tendencies, distribution and bionomics. A key to the Turkish, Caucasian and Iranian species of Odocnemis is given. PMID- 27988616 TI - Butterflies of Guinea-Bissau: VIII. New data, new reports, corrections and biodiversity (Lepidoptera: Papilionoidea). AB - New records are added to the Papilionoidea of Guinea-Bissau, many of which were obtained within the country's Protected Areas. Examination of the collected material yielded 9 new genera and 47 new species for the country, significantly increasing the knowledge of local butterfly diversity. 99 genera and 244 species are now known to occur in Guinea-Bissau, representing an increase of almost 20 % in the number of species and 7 % in the genera in relation to previous data. For each species, the studied material, probable abundance and proposed conservation status in the country are reported; some corrections relative to a few previous misidentifications are added. A gazetteer of the prospected localities is included, as well as species' occurrences within the Protected Areas and previous bibliographic references in Guinea-Bissau. The known geographical range, primary habitat and host-plants of each species/subspecies are also provided. PMID- 27988617 TI - Taxonomic revision and phylogeny of the ant genus Prenolepis (Hymenoptera: Formicidae). AB - The formicine ant genus Prenolepis is here revised for the first time. Thirteen extant species are recognized of which four are described as new. A key for the worker caste is provided, and the worker of each species is imaged, with males and queens imaged in species where they are known. Worker-based characters were used to construct a species-level phylogeny of Prenolepis. Both maximum parsimony and Bayesian inference methods were used for the phylogenetic analyses. A morphological diagnosis for the genus is provided, with a discussion of useful morphological characters for separating Prenolepis from other genera in the Prenolepis genus-group. Major taxonomic changes are proposed. The new species are: P. darlena, P. fustinoda, P. mediops, and P. shanialena. Prenolepis jerdoni subopaca is elevated to full species. Three species are excluded from Prenolepis and transferred to Nylanderia and Paratrechina as new combinations: N. emmae, N. flaviabdominis, and P. umbra. Two species are excluded from Paratrechina and transferred to Nylanderia and Paraparatrechina as new combinations: N. guanyin and P. kongming. One species, Z. darlingtoni, is excluded from Nylanderia and transferred to Zatania as a new combination. Several synonyms are proposed: Prenolepis sphingthoraxa = Nylanderia flaviabdominis; P. imparis arizonica, P. imparis colimana, P. imparis coloradensis, and P. imparis veracruzensis = P. imparis; P. melanogaster carinifrons and P. nigriflagella = P. melanogaster; P. longiventris and P. magnocula = P. naoroji; and P. septemdenta = Nylanderia opisopthalmia. PMID- 27988618 TI - Consolidated Checklist of Hard Corals of the Genus Acropora Oken, 1815 (Scleractinia: Acroporidae) in North Borneo, East Malaysia. AB - Acropora is the most biologically diverse group of reef-building coral, and its richness peaks at the Indo-Malay-Philippine Archipelago, the centre of global coral reef biodiversity. In this paper, we describe the species richness of Acropora fauna of North Borneo, East Malaysia, based on review of literature and as corroborated by voucher specimens. Eighty-three species of Acropora are reported here; four species are literature based and 79 are supported by voucher specimens that were subsequently photographed. New records for North Borneo were recorded for 12 species, including Acropora suharsonoi Wallace 1994 that was previously thought to be confined to a few islands along Lombok Strait, Indonesia. The diversity of Acropora in North Borneo is comparable to that of Indonesia and the Philippines, despite the area's smaller reef areas. This further reinforces its inclusion as part the global hotspot of coral biodiversity. PMID- 27988619 TI - Braconid wasps of subfamily Alysiinae (Hymenoptera: Braconidae) as endoparasitoids of Selachops flavocinctus Wahlberg, 1844 (Diptera: Agromyzidae) in the Central Urals, Russia. AB - The Agromyzidae fly Selachops flavocinctus Wahlberg, 1844 as host of the Alysiinae genera Asyntactus Marshall, 1898 (Alysiini) and Protochorebus Perepechaenko, 1997 (Dacnusini) is recorded for the first time. A new species from Central Urals, Protochorebus pervushini sp. nov., is described and illustrated. The new material for Asyntactus rhogaleus Marshall, 1898 is studied. A key to Protochorebus species is provided. Description of puparium of Selachops flavocinctus and new data on its life history are published for the first time. PMID- 27988620 TI - ADDENDUM to Roca-Cusachs, M. & Goula, M. 2016. New genus and species of ant-like true bug (Hemiptera: Miridae) from the Canary Islands. Zootaxa 4173 (1): 066-074. AB - Genus Perenotus and species Perenotus malobae were recently described as a new genus and species by Roca-Cusachs & Goula (2016). Article 16.4.2 of ICZN (1999) requires a statement of intent that the holotype is deposited in a collection and a statement indicating the name and location of that collection. Unfortunately, it is unclear if this requirement was satisfied. PMID- 27988621 TI - Description of a new species of Dascillus Latreille from Sichuan, China Coleoptera: Dascillidae). AB - Dascillidae are a small and rarely studied family that includes nine currently recognized genera (Lawrence 2005; Ivie & Barclay 2011; Jin et al. 2013) and about 80 described species divided into two poorly defined subfamilies-a free-living Dascillinae and variously morphologically modified Karumiinae, some of which are apparently associated with subterranean termites. Dascillinae inhabit mostly forested areas of the Northern Hemisphere and Australia (Lawrence 2005). PMID- 27988622 TI - A new hydryphantid genus from the Tien Shan Mountains of Kazakhstan (Acari, Hydrachnidia: Hydryphantidae). AB - Kazakhithyas pectinatus, n. gen. n. sp., is described from a rheohelocrene spring from the Tien Shan Mountains, Kazakhstan. PMID- 27988623 TI - The tale of the headless turtle. AB - Pelomedusoides is the most diverse clade of side-necked turtles and there is an extensive fossil record (de Broin, 1988; Lapparent de Broin, 2000; Gaffney et al., 2006, 2011) that dates back at least to the Barremian (Lower Cretaceous) (Romano et al., 2014). Its large fossil record evidences a greater diversity in the past, particularly at the end of the Mesozoic, and exhibits a good sampling of species that are represented by skull material (Gaffney et al., 2006, 2011). As a consequence, the most complete and recent phylogenetic hypotheses for this clade (e.g. Romano et al., 2014; Cadena, 2015) are based on matrices comprising a great amount of cranial characters derived largely from Gaffney et al. (2006, 2011). In addition, it is well established that shell characters show a lot of phenotypic plasticity, even in the fossil species (Romano, 2008; Gaffney et al., 2006, 2011). In most cases it consequently is not justified to rely on "diagnostic features" of poorly informative shell-only material for describing a new species. Because of that, most authors remark new morphotypes in the literature when such aberrant specimens are recovered, but do not make any nomenclatural act by proposing a new yet poorly supported species (e.g. Romano et al., 2013; Ferreira & Langer, 2013; Menegazzo et al., 2015). Unfortunately, such a supposedly new bothremydid turtle (Pleurodira: Bothremydidae) from the Early Paleocene of Brazil was recently described based on poorly diagnostic remains (Carvalho et al., 2016; hereafter CGB, for the authors initials) and a correction of this unfounded nomenclatural act is required. In addition I present some comments on shell only material from Brazil in order to guide splitter taxonomists to stop describing poorly preserved fossil specimens as new species. PMID- 27988624 TI - A new species of Chirothripoides (Thysanoptera: Tubulifera) from India and Malaysia. AB - Chirothripoides brahmaputrai sp.n. is described based on a holotype female from Assam State, India, and a paratype female from Peninsular Malaysia. A key to the six species of Chirothripoides is provided, and partial sequence data of mitochondrial cytochrome c oxidase (mtCOI) from the holotype of the new species is generated and submitted to Barcode of Life Database. PMID- 27988625 TI - Opisa takafuminakanoi, a new species of Opisidae from Hokkaido, Japan (Crustacea: Amphipoda). AB - Opisa is a small amphipod genus including three species: O. eschrichtii (Kroyer, 1842) from the North Atlantic Ocean (Sars 1895; Bousfield 1987), the Arctic Ocean (Bousfield 1987), and the western Pacific Ocean (Stebbing 1906; Derzhavin 1929); O. odontochela Bousfield, 1987 from the southeast Alaska (Bousfield 1987); and O. tridentata Hurley, 1963 from the Pacific coasts of North America (Bousfield 1987). During field survey of the marine benthic fauna of Hokkaido, Japan, one of the authors (KK) collected an undescribed species of Opisa from off the southeast of Akkeshi Bay using a sledge net. This paper describes and illustrates the new species in detail. PMID- 27988626 TI - Some taxonomic notes on the Caradrina (Eremodrina) filipjevi (Boursin, 1936) species group (Lepidoptera, Noctuidae). AB - Caradrina Ochsenheimer, 1816 is a large xylenine genus restricted to Holarctic and Ethiopian regions. The full revision of the genus has been published by Hacker (2004). The genus subdivided into eight subgenera: Caradrina, Platyperigea Smith, 1894, Boursinidrina Hacker, 2004, Kalchbergiana Hacker, 2004, Eremodrina Boursin 1937, Levantrina Hacker, 2004, Weigertrina Hacker, 2004 and Paradrina Boursin 1937, and contains 156 described species (Hacker 2004; Hacker & Legrain 2006; Fibiger & Hacker 2007). PMID- 27988627 TI - Barsine amaculata, a new species from Vietnam (Lepidoptera, Erebidae, Arctiinae). AB - Barsine Walker, 1854 is a large genus of lichen-moths (family Erebidae, subfamily Arctiinae, tribe Lithosiini) including about a hundred of described species and widely distributed in Oriental tropics. A number of species is also known from the Russian Far East, Japan, Korea, China and Taiwan. The genus long time was treated as a synonym or a subgenus of Miltochrista Hubner, [1819] (Hampson 1900; Strand 1917; Reich 1937; Daniel 1951; 1952; 1955; Inoue 1980; Holloway 1982; Fang 1991; 2000; Cerny 1995), and was revived by Holloway (2001). Many new species of the genus were described during last two decades (Fang 2000; Holloway 2001; Kaleka 2003; Cerny & Pinratana 2009; Bucsek 2012; 2014; Dubatolov et al. 2012; Dubatolov & Bucsek 2013; Wu et al. 2013). The genus is under revision by authors of the present paper. During studies of Lithosiini materials collected in Vietnam, an undescribed Barsine species was found. The species is described below. PMID- 27988628 TI - A new cave species of Coecobrya Yosii (Collembola, Entomobryidae, Entomobryinae) from South Africa, with an identification key to the genus. AB - Coecobrya anaguilae sp. nov., a new species of springtail from Cango Caves, South Africa is described and illustrated. The new species is similar to other species of tenebricosa-group such as C. communis (Chen & Christiansen), C. edenticulata (Handschin), and C. tropicalis Qu, Chen & Greenslade in some elements of dorsal chaetotaxy, absence of eyes, unguis with one unpaired median tooth, and manubrium without smooth chaetae, but differs from them in dorsal head, mesothoracic and collophore chaetotaxy. This is the first species of Coecobrya described from Africa as well as the first indisputable record of the genus for the whole continent. In this study an updated key to the species of the genus is provided, adding 14 species to the most recently published identification key. We also discuss some aspects of distribution and evolution of Coecobrya. PMID- 27988629 TI - Electric organ discharges of South African Marcusenius species (Teleostei: Mormyridae) and their effectiveness as indicators of local species diversity. AB - Recent morphological and genetic studies have revealed two new species of snoutfish in South Africa, Marcusenius caudisquamatus and M. krameri, which had been confused with M. pongolensis, the South African bulldog fish. All known mormyriform fish are nocturnal and emit electric organ discharges (EODs) for communication that are characteristic for their species. This paper examines whether or not the EODs of these three closely-related South African species can be differentiated from each other. An EOD pulse of a bulldog fish consists of a head-positive phase P, followed by a head-negative phase N of short duration. We measured and compared six variables of the EOD pulse waveform for South African samples for the three species from different locations using MANOVA, ANOVA and Discriminant Analysis, with M. devosi from Kenya as an outgroup. The EOD waveforms, normalized to the same P-phase amplitude, varied significantly from each other in four variables, most strongly in the amplitude of the N phase and the duration of the P phase. In two species, M. devosi and M. krameri, there was no evidence of difference between sexes, in contrast to M. pongolensis and M. caudisquamatus whose male pulses were of longer duration. M. devosi and M. krameri were statistically significantly independent of each other and of any other group studied. By contrast, the M. pongolensis specimens from different locations showed a high degree of variability amongst each other, including significant separation, and overlap with M. caudisquamatus. PMID- 27988630 TI - Two new species of Amphinemura (Plecoptera: Nemouridae) from the Gaoligong Mountains of Yunnan, China. AB - Two new species of the nemourid genus Amphinemura, A. apicilobata sp. nov. and A. bimaculata sp. nov. are described from the Gaoligong Mountains of Yunnan Province, China. The new species are compared with related congeners. PMID- 27988631 TI - The larva of Wormaldia asterusia Malicky 1972 (Trichoptera: Philopotamidae) with notes on its ecology and an update on the Wormaldia of Greece with a larval key for species of the genus. AB - The previously unknown larva of Wormaldia asterusia Malicky 1972 is described. The diagnostic features of the species are listed and illustrated and some information on its ecology is included. An update on the knowledge of the genus in Greece is given and a larval key of the known West Palearctic Wormaldia species is provided. PMID- 27988632 TI - The Re-discovery of live populations of Cnemaspis tropidogaster (Boulenger, 1885) (Sauria, Gekkonidae) from Sri Lanka after 120 years. AB - Gonatodes kandianus var. tropidogaster was described by Boulenger (1885) with only "Ceylon" (=Sri Lanka) as its locality. This taxon was later assigned to the genus Cnemaspis and then recorded from many different parts of the country. Misleading taxonomic publications and muddled nomenclatural issues has since rendered its taxonomic position unclear. Recent studies have revealed, however, that C. tropidogaster is a species complex, and the species and its types have been redescribed. Unfortunately, no live populations of this species have been recorded until now. Here we report the rediscovery of live populations of this species 120 years after its last collection date records. C. tropidogaster was rediscovered from a low elevation (50-80 m asl.) of the wet zone of Sri Lanka. The rediscovered population was attributed to C. tropidogaster on the basis of a suite of matching morphometric and meristic characters that distinguish C. tropidogaster from other Sri Lankan Cnemaspis. PMID- 27988633 TI - The subfamily Mendesellinae (Hymenoptera: Braconidae) in Brazil, with the description of six new species. AB - In this paper, we study the Mendesellinae wasps from Brazil deposited at Departamento de Ecologia e Biologia Evolutiva da Universidade Federal de Sao Carlos, Sao Carlos, SP, Brazil collection. Two new species of Epsilogaster (E. masoni sp. n. and E. whitfieldi sp. n.) and four new species of Mendesella (M. albipleura sp. n., M. itatiaia sp. n., M. japi sp. n., M. yamadai sp. n.) are described and illustrated. PMID- 27988634 TI - Two remarkable new species of Hypothenemus Westwood (Curculionidae: Scolytinae) from Southeastern USA. AB - Two new Hypothenemus species found in southern and southeastern USA are described: Hypothenemus piaparolinae sp. n. and Hypothenemus subterrestris sp. n. The distribution and habits suggest these species are native and widely distributed, but elusive, and not recently arrived exotics. Both appear to have unusual biology: H. subterrestris appears to live in material on or in the ground, and H. piaparolinae has only been collected from the xylem of extensively rotten, fungus-filled twigs. PMID- 27988635 TI - Two new species of the genus Gibbotettix Zheng, 1992 (Orthoptera: Tetrigidae, Cladonotinae) from China. AB - Taxonomy of a tetrigid genus Gibbotettix Zheng is reviewed. Two new species, Gibbotettix serrifemurus sp. nov. and Gibbotettix parvipulvillus sp. nov. are described from China.The distribution and an updated identification key to all known species of the genus are given. PMID- 27988636 TI - Papuaneon, a new genus of jumping spiders from Papua New Guinea (Araneae: Salticidae: Neonini). AB - The genus Neon Simon stands alone as a phylogenetically isolated astioid jumping spider, the only member of the Neonini. The new genus Papuaneon is established for the jumping spider Papuaneon tualapa sp. nov. from Papua New Guinea. Resembling a large, hirsute Neon, it is here shown to be the sister group to Neon, based on data from the nuclear 28S and Actin 5C, and the mitochondrial 16SND1 region. Photographs of living specimens are provided. PMID- 27988637 TI - Germalus species of the Malagasy region (Heteroptera: Lygaeoidea: Geocoridae). AB - Malagasy species of the genus Germalus Stal, 1862 were reviewed based on material of different European museums. Comments on the description of Germalus kinbergi (Stal, 1859) are given with new distribution data on Reunion. Two new species, Germalus banari sp. nov. and Germalus benyovszkyi sp. nov. are described. PMID- 27988638 TI - Revision of the South American genus Tetragonopterus Cuvier, 1816 (Teleostei: Characidae) with description of four new species. AB - The systematics of the characid genus Tetragonopterus is reviewed based on morphological and molecular data of specimens from its entire geographical range encompassing all major South American river drainages from Orinoco basin southward to the La Plata basin. Eight previously described species (T. anostomus, T. araguaiensis, T. argenteus, T. carvalhoi, T. chalceus, T. denticulatus, T. georgiae n. comb., and T. rarus) are recognized as valid, four of which are redescribed (T. argenteus, T. chalceus, T. georgiae, and T. rarus), and four new species from the Brazilian Shield in the Amazon and Sao Francisco river basins are herein described. We also provide evidence for the reallocation of Moenkhausia georgiae into Tetragonopterus and recognize T. akamai as junior synonym of T. anostomus. DNA barcodes of Tetragonopterus revealed genetic support for each recognized species and provided valuable population-level information within T. argenteus, T. chalceus, T. georgiae, and T. rarus. PMID- 27988639 TI - Remarkable diversity of the genus Endonura Cassagnau, 1979 (Collembola: Neanuridae: Neanurinae) in the Caucasus. AB - Endonura alticola (Stach, 1951) comb. nov. is redescribed based on the type material and seven new species of the genus Endonura are described from the various parts of the Caucasus. E. paracantabrica sp. nov. can be recognized by the number of chaetae (L+So) on head and a fusion of tubercles Di and De on the first thoracic segment. Specific traits of E. aibgai sp. nov. include small body size, low number of chaetae (L+So) on head, nonogival labrum, dentate claws, and long tibiotarsal chaetae B4 and B5. E. diminutichaeta sp. nov. is characterized by an unusually short chaeta Di1on abdomen IV. E. dobrolyubovae sp. nov. can be distinguished from its congeners by notably long chaeta Ocp on head and the presence of male ventral organ. The absence of chaetae E and O on head, ogival labrum, cryptopygy and dentate claws are typical of E. cryptopyga sp. nov. E. ossetica sp. nov. is most easily recognized by an unusual shape of tubercle Af on head connected with chaetae D and E. Main characteristics of E. kremenitsai sp. nov. include the presence of chaeta E and five chaetae Dl on head. A key to all known species of the genus including the above outlined taxa is given. General remarks on distribution and possible historical biogeography of the genus are also provided. PMID- 27988640 TI - Biogeography and taxonomy of racket-tail hummingbirds (Aves: Trochilidae: Ocreatus): evidence for species delimitation from morphology and display behavior. AB - We analyzed geographic variation, biogeography, and intrageneric relationships of racket-tail hummingbirds Ocreatus (Aves, Trochilidae). Presently, the genus is usually considered monospecific, with O. underwoodii including eight subspecies (polystictus, discifer, underwoodii, incommodus, melanantherus, peruanus, annae, addae), although up to three species have been recognized by some authors. In order to evaluate the current taxonomy we studied geographic variation in coloration, mensural characters, and behavioral data of all Ocreatus taxa. We briefly review the taxonomic history of the genus. Applying the Biological Species Concept, species delimitation was based on a qualitative-quantitative criteria analysis including an evaluation of character states. Our results indicate that the genus should be considered a superspecies with four species, the monotypic Ocreatus addae, O. annae, and O. peruanus, and the polytypic O. underwoodii (including the subspecies underwoodii, discifer, incommodus, melanantherus, polystictus). In this taxonomic treatment, O. annae becomes an endemic species to Peru and O. addae is endemic to Bolivia. We recommend additional sampling of distributional, ethological, and molecular data for an improved resolution of the evolutionary history of Ocreatus. PMID- 27988641 TI - Copepods (Cyclopoida) associated with top shells (Vestigastropoda: Trochoidea: Tegulidae) from coastal waters in southern Japan, with descriptions of three new species. AB - Four species of copepods are described based on specimens of both sexes from tegulid top shells (Vestigastropoda) caught from coastal waters of southern Japan. Three species, including two undescribed and one known of the genus Panaietis (Copepoda: Cyclopoida: Anthessiidae) were found in the pharynx and esophagus of gastropods. Panaietis incamerata Stebbing, 1900, P. doraconis n. sp., and P. satsuma n. sp. are distinguished from its congeners by the dorsal plates on the first pedigerous somite, the genital somite, the shape of the spines on legs, the number of setae on legs 1 and 2, and the position and shape of leg 5. Pseudanthessius imo n. sp. (Cyclopoida: Pseudanthessiidae) was found in the mantle cavity of the host. This copepod differs from its congeners in the proportions of the caudal ramus, the armature and proportion of the antenna, the armature of the exopod and general shape of the endopod of leg 4, and the presence of a post-rostral process. PMID- 27988642 TI - New species and synonymies in Xenopygus Bernhauer (Coleoptera: Staphylinidae: Staphylinini). AB - Two species are described as new in Xenopygus, X. davidi sp. n. and X. pycnos sp. n. Dysanellus (Leptodiastemus) excellens Bernhauer is transferred to Xenopygus as X. excellens comb. n. and the subgenus Leptodiastemus syn.n. is placed in synonymy with Xenopygus. Xenopygus sancticamillus Caron and Castro syn. n. is shown to be a junior synonym of X. excellens. Gastrisus punctatus Sharp is transferred to Xenopygus as X. punctatus comb. n. Gastrisus cribrum Fauvel syn. n. and X. petilicolis Caron and Castro syn. n. are shown to be junior synonyms of X. punctatus. Two informal species groups are proposed to accommodate the existing species in Xenopygus and an updated key is provided for the identification of the species. PMID- 27988643 TI - A new species of long-legged terrestrial Terrapotamon Ng, 1986 (Crustacea: Brachyura: Potamidae) from limestone formations in Satun, southern Thailand. AB - A new species of terrestrial potamid crab, Terrapotamon longitarsus, is described from limestone hills in Satun Province in southern Thailand. It is easily distinguished from other Terrapotamon species by its conspicuously long ambulatory legs (all congeners have proportionately short legs), relatively smooth dorsal surface of carapace, transversely narrow male thoracic sternites 1 4, and a characteristically structured male first gonopod. PMID- 27988644 TI - DNA barcoding and morphological studies confirm the occurrence of three Atarbolana (Crustacea: Isopoda: Cirolanidae) species along the coastal zone of the Persian Gulf and Gulf of Oman. AB - Two species of Atarbolana (Cirolanidae: Isopoda) from the intertidal zone of the Gulf of Oman and the Persian Gulf were studied and redescribed. The known distribution of this small genus is limited to the northern areas of the Indian Ocean, from the Pakistan coasts to the Persian Gulf. The analyses of DNA barcodes as well as detailed morphological studies clearly support the existence of three distinct Atarbolana species along the coastal zone of the Persian Gulf and northern Arabian Sea. Furthermore, A. dasycolus Yasmeen, 2004 is synonymized with A. setosa Javed and Yasmeen, 1989. PMID- 27988645 TI - A new leaf-galling Holopothrips (Thysanoptera: Phlaeothripidae) and the structural alterations on Myrcia retorta (Myrtaceae). AB - Holopothrips striatus sp. n. is described inducing leaf-galls on Myrcia retorta (Myrtaceae) in Southern Brazil. The thrips is one of the few species of Holopothrips known to have the metanotum with striate rather than reticulate sculpture. The galls are green with brownish spots, and are characterised by a mix of folding and rolling of the leaf lamina upwards. PMID- 27988646 TI - Barsine deliciosa, a new species from China (Lepidoptera, Erebidae, Arctiinae). AB - A new Lithosiini species, Barsine deliciosa Volynkin & Cerny, sp. n. is described from North China, Shanxi and Shaanxi provinces. A diagnostic comparison is made with Barsine flammealis Moore, 1878, Barsine linga Moore, 1859, Barsine delicia Swinhoe, 1891, Barsine conicornutata (Holloway, 1982), Barsine lucibilis Swinhoe, 1892 and Barsine striata (Bremer et Grey, 1852). Adults, male and female genitalia of the new, related and externally close species are illustrated. PMID- 27988647 TI - The status of three little known names proposed by Miranda-Ribeiro (1926) and the synonymization of Pyrrhura snethlageae Joseph & Bates, 2002 (Psittaciformes: Psittacidae: Arinae). AB - The presence of complex geographic variation among species allied to the absence of clear morphological breaks among populations has led to many poorly defined taxa in the genus Pyrrhura (Psittacidae: Arinae: Arini). This article addresses nomenclature of the Pyrrhura picta species complex, particularly the identity of three little-known names introduced by Miranda-Ribeiro (1926): Pyrrhura luciani ochrotis, P. l. pallescens and P. l. melanoides. We show that these names represent subjective synonyms of Pyrrhura snethlageae Joseph & Bates, 2002. Furthermore, we argue that Pyrrhura pallescens (Miranda-Ribeiro, 1926) n. comb. should be considered as the valid senior name because: (1) there is no doubt about the type locality (near the type locality of P. snethlageae) and, as a consequence, it "will best serve stability and universality of nomenclature" as recommended by the International Code of Zoological Nomenclatural, and; (2) it corresponds to the most common phenotype usually referred to as P. snethlageae, the species name that has been used for bird specimens from this region. Those considering P. snethlageae lucida Arndt, 2008 as a valid taxon should refer to this population as Pyrrhura pallescens lucida (Arndt, 2008) n. comb. In a near future P. pallescens melanoides (Miranda-Ribeiro, 1926) n. comb. is likely to be considered the best senior synonym of P. p. lucida given its type locality (Teles Pires River, MT). PMID- 27988648 TI - New species and new records of Cumacea (Crustacea: Peracarida: Cumacea) from mesophotic reefs of Puerto Rico and U.S. Virgin Islands, Caribbean Sea. AB - The cumacean fauna of the Caribbean mesophotic reefs is remarkably rich but understudied. Herein, we present the description of 22 new species of the family Nannastacidae, including one from shallow reefs, 20 of them belonging to Cumella (Cumella) and two new species belonging to the subgenus Cumewingia. We have also included range extensions and new locations for ten previously known species of Cumella, two species in the genus Vaunthompsonia (family Bodotriidae) and one species in the genus Cubanocuma (family Nannastacidae). Taxonomic keys are provided for the western tropical Atlantic species of Cumella (Cumella) and Cumella (Cumewingia), separately for the adult males and females. Large sampling efforts and careful systematic studies, even in relatively well-characterized regions such as the Caribbean, can yield a surprising number of new discoveries. Our current findings emphasize our previous assertion that the mesophotic reefs are treasure troves of undiscovered benthic fauna and might be qualified as biodiversity hotspots. PMID- 27988649 TI - The Australian Ciidae (Coleoptera: Tenebrionoidea): A Preliminary Revision. AB - The Australian ciid fauna is revised based on 75 described species (56 of them new) and three undescribed species, placed in 22 genera (nine of them new and nine newly recorded from Australia). The revision is considered preliminary, since about 50 other undescribed Australian species have been seen (usually as uniques or in short series), and it is likely that more will be found with increased intensive collecting. One additional New Caledonian species is also described, and one Cis species is considered to be based on a mislabelled Hawaiian specimen. The subfamily Ciinae, to which all species belong, is described based on adults and larvae, and keys are included to all known Australian genera and described species. Where material has been available, male and female genitalia have been described and many of those illustrated. The following new genera are described: Amphibolocis Lawrence gen. nov., Australocis Lawrence gen. nov., Ctenocis Lawrence gen. nov., Echinocis Lawrence gen. nov., Ditrichocis Lawrence gen. nov., Glyphidope Lawrence gen. nov., Malleecis Lawrence gen. nov., Notapterocis Lawrence gen. nov., Pseudeuxestocis Lawrence gen. nov. The following genera are recorded for the first time from Australia: Acanthocis Miyatake, Ceracis Mellie, Dichodontocis Kawanabe, Ennearthron Mellie, Hadreule Thomson, Neoennearthron Miyatake, Paratrichapus Scott, Scolytocis Blair and Xylographella Miyatake (the last three without described Australian species). The following new species are described (all native to Australia or its territories, unless otherwise indicated): Amphibolocis glabratus Lawrence, sp. nov., Australocis ruber Lawrence, sp. nov., Ceracis christmasensis Lawrence, sp. nov., Cer. communis Lawrence, sp. nov., Cer. divergens Lawrence sp. nov., Cer. fictus Lawrence sp. nov., Cis biconcavus Lawrence & Paviour-Smith, sp. nov., C. bisericeus Lawrence sp. nov., C. blackburni Lawrence & Paviour-Smith sp. nov., C. canberrae Lawrence sp. nov., C. capillatus Lawrence sp. nov., C. clypeodentes Lawrence & Paviour-Smith sp. nov., C. convexiformis Lawrence sp. nov., C. crassus Lawrence sp. nov., C. deficiens Lawrence sp. nov., C. denticulatus Lawrence sp. nov., C. deserticolus Lawrence sp. nov., C. dissidens Lawrence sp. nov., C. echidnoides Lawrence & Paviour-Smith sp. nov., C. eremicus Lawrence sp. nov., C. guangxiensis Lawrence sp. nov. (introduced from China), C. inflatus Lawrence, sp. nov., C. microcerus Lawrence sp. nov., C. minutipunctatus Lawrence sp. nov., C. nitidonotum Lawrence sp. nov., C. obscuronotum Lawrence sp. nov., C. parviniger Lawrence sp. nov., C. planomarginatus Lawrence & Paviour-Smith sp. nov., C. simillimus Lawrence sp. nov., C. sordidus Lawrence & Paviour-Smith, sp. nov., C. subglaber Lawrence & Paviour-Smith sp. nov., C. subparallelus Lawrence sp. nov., C. tasmanorae Lawrence sp. nov., C. tricolor Lawrence sp. nov., C. victoriae Lawrence sp. nov., C. yorkensis Lawrence sp. nov., Ctenocis caledonicus Lawrence sp. nov. (New Caledonia), Ctenocis pectinipes Lawrence & Paviour-Smith sp. nov., Dichodontocis queenslandicus Lawrence sp. nov., Echinocis phellinophilus Lawrence sp. nov., Ennearthron alienindicus Lawrence sp. nov. (introduced from India), Glyphidope simplex Lawrence sp. nov., G. variabilis Lawrence sp. nov., Hadreule australiense Lawrence sp. nov., Malleecis flavus Lawrence sp. nov., Neoennearthron meridionale sp. nov., Notapterocis ellipticus Lawrence sp. nov., Notapterocis globulus Lawrence sp. nov., Notapterocis grossulus Lawrence sp. nov., Notapterocis hirsutulus Lawrence sp. nov., Notapterocis sannio Lawrence sp. nov., Octotemnus ambiguus Lawrence sp. nov., Octotemnus exilis Lawrence sp. nov., Orthocis latemarginatus Lawrence sp. nov., Orthocis quadrimaculatus Lawrence sp. nov., Pseudeuxestocis burwelli Lawrence sp. nov. The following new combinations are proposed: Acanthocis armiger (Blair, 1940) (Cis), comb. nov., Ctenocis zeelandicus (Reitter, 1880) (Cis), comb. nov., Ditrichocis pulchellus (Scott, 1926) (Ennearthron), comb. nov., Ditrichocis bifasciatus (Reitter, 1877) (Cis), comb. nov. and Paratrichapus lobipes (Broun, 1895) (Cis), comb. nov. The following synonymies are proposed: Cis recurvatus Broun, 1883 (= Cis victoriensis Blackburn, 1891 syn. nov., = Cis tasmanicus Blair, 1940 syn. n.). The following 13 genera are redescribed: Acanthocis Miyatake, 1955; Ceracis Mellie, 1849; Cis Latreille, 1796; Dichodontocis Kawanabe, 1994; Ennearthron Mellie, 1847; Hadreule Thomson, 1859; Neoennearthron Miyatake, 1954; Octotemnus Mellie, 1847; Orthocis Casey, 1898; Paratrichapus Scott, 1926; Scolytocis Blair, 1928; Xylographella Miyatake, 1985; Xylographus Mellie, 1847. The following 20 species are redescribed: Acanthocis armiger (Blair, 1940); Cis australis Blackburn, 1888; Cis bilamellatus Wood, 1884; Cis cavifrons Blair, 1940; Cis cervus Blair, 1940; Cis chinensis Lawrence, 1991; Cis clarki Blair, 1940; Cis fuscipes Mellie, 1849; Cis laminicollis Blair, 1940; Cis recurvatus Broun, 1883; Cis sellatus Blair, 1940; Cis setiferus Blackburn, 1888; Cis walkeri Blair, 1940; Ditrichocis pulchellus (Scott, 1926); Octotemnus dilutipes (Blackburn, 1891); Octotemnus walkeri Blair, 1940; Orthocis aequalis (Blackburn, 1888); Orthocis auriculariae Lawrence, 1991; Orthocis leanus (Blackburn, 1907); Xylographus bynoei Blair, 1940. The introduced species Cis chinensis Lawrence, 1991, and Orthocis auriculariae Lawrence, 1991, are recorded for the first time from Australia. The species Cis adelaidae Blackburn, 1888, is considered to be based on a mislabelled Hawaiian species near Cis setarius Sharp in Blackburn & Sharp, 1885. The name Cis sharpi Lawrence nom. nov. is proposed as a replacement name for another species in this Hawaiian group: Cis bimaculatus Sharp in Blackburn & Sharp, 1885, not Germain, 1855. Lectotypes are designated for Acanthocis armiger (Blair, 1940), Cis cavifrons Blair, 1940, Cis clarki Blair, 1940, Cis laminicollis Blair, 1940, Cis recurvatus Broun, 1883, Octotemnus walkeri Blair, 1940 and Orthocis leanus (Blackburn, 1907). PMID- 27988650 TI - Catalogue of the family Ologamasidae Ryke (Acari: Mesostigmata). AB - Mites of the family Ologamasidae are very conspicuous and abundant in soil and litter, especially in the Southern Hemisphere. Little is known of their biology and behaviour, but they appear to be generalist predators. The family is placed in the Rhodacaroidea, but its status and composition have been very unstable. The existing classification and identification keys are obsolete and difficult to use. We present a historical review of the literature on the classification of the Ologamasidae, with revised diagnoses for the family and its included genera, and a new key to genera. We also present a complete catalogue of the species, with details of their nomenclature and bibliography, and a summary of the locality and habitat data for the types for each species. The family includes a total of 467 species arranged in 44 genera. The largest genera are Gamasiphis Berlese (74 species), Gamasellus Berlese (70 species) and Geogamasus Lee (33 species). These three genera together include more than 35% of the valid species in the family. Seven of the genera are monotypic. We list a further 29 species that appear to belong to the family Ologamasidae, but which cannot be confidently assigned to a genus on the basis of the available information. We also list 74 species that have been placed in the Ologamasidae at some time, but which are now placed in other families, especially the Veigaiidae, Digamasellidae, Parasitidae, and Eviphididae. New combinations are proposed for 15 species. The genus Pachymasiphis is described as new, because this name was not made available correctly when it was first proposed. PMID- 27988651 TI - Sublittoral and bathyal sea cucumbers (Echinodermata: Holothuroidea) from the Northern Mozambique Channel with description of six new species. AB - The 2009 expedition with the research vessel Miriky sampled the sublittoral and bathyal waters of the northern Mozambique Channel. This exploration campaign resulted in a small, but very diverse collection of holothuroids comprising 174 specimens representing 31 species, 18 genera, 10 families and 5 orders. Of these species, many were hitherto unknown for Madagascar or even for the Indian Ocean, and six, Bathyplotes aymeric sp. nov., Holothuria (Cystipus) yann sp. nov., Holothuria (Stauropora) bo sp. nov., Holothuria (Metriatyla) alex sp. nov., Holothuria (Theelothuria) cyrielle sp.nov., Molpadia thandari sp. nov., are new to science. Molpadia lenticulum (Cherbonnier & Feral, 1981) is a new combination. This contribution provides an illustrated and annotated overview of the poorly known, highly biodiverse, sublittoral and bathyal sea cucumber fauna of the northern Mozambique Channel. Our findings demonstrate how ignorant we are about the poorly explored habitats of our planet and therefore stress the urgent need for more explorations to such regions. PMID- 27988652 TI - Re-description of the Arctic tardigrade Tenuibiotus voronkovi (Tumanov, 2007 (Eutardigrada; Macrobiotidea), with the first molecular data for the genus. AB - Tardigrada is phylum of micrometazoans widely distributed throughout the world, because of old descriptions and insufficient morphometric data, many species currently need revision and re-description. Tenuibiotus voronkovi (Tumanov, 2007) is tardigrade previously only recorded from the Svalbard archipelago. This species' original description was based on two individuals with destroyed claws on the fourth pair of legs and a lack of complete morphometric data for buccal tube and claws. In this paper, we present a re-description of T. voronkovi, supplementing the original description using the original paratype and additional material from Svalbard: Spitsbergen, Nordaustlandet and Edgeoya. This species is characterised by two macroplacoids and a microplacoid, claws of Tenuibiotus type, dentate lunules under claw IV, and faint granulation on legs I-III and strong granulation on the legs IV. We include a new morphological description with microphotographs, morphometric, and molecular data (including: mitochondrial cytochrome c oxidase subunit I (COI), internal transcribed spacers (ITS1-5.8S rDNA-ITS2), and nuclear ribosome subunits 28S rRNA and 18S rRNA). These are the first published molecular data for the genus Tenuibiotus Pilato and Lisi, 2011, analysis of which indicated an affiliation of Tenuibiotus to the family Macrobiotidae. We found no differences in body size between individuals from different islands (Nordaustlandet and Edgeoya), but did observe variability in the eggs. After revision of the literature and the published figures, we concluded that Dastych's (1985) report of T. willardi (Pilato, 1976) from Svalbard, was actually T. voronkovi, which has the greater distribution in Svalbard, and other Arctic locations, than previously believed. PMID- 27988653 TI - Taxonomic revision of the moss salamander Nototriton barbouri (Schmidt (Caudata: Plethodontidae), with description of two new species from the Cordillera Nombre de Dios, Honduras. AB - Moss salamanders (genus Nototriton) are represented in northern Central America by nine putative species: N. barbouri, N. brodiei, N. lignicola, N. limnospectator, N. mime, N. picucha, N. saslaya, N. stuarti, and N. tomamorum. I estimate the phylogenetic relationships for these species based on data from three mitochondrial gene fragments (16S, cytochrome b, and COI), and compare morphological variation among putative taxa. As evidenced here and in previous studies, the taxon N. barbouri is paraphyletic with respect to populations from the Cordillera Nombre de Dios in northern Honduras. I restrict this taxon to populations from the Sierra de Sulaco in central Yoro, Honduras, and describe two new species from the Cordillera Nombre de Dios. PMID- 27988654 TI - A checklist of the soldier beetles (Coleoptera: Elateroidea: Cantharidae) of Iran. AB - The present paper is a collection of data and records taken from literature on the Cantharidae of Iran. New original records are also included. These data indicate that 12 genera and 84 species and subspecies of Cantharidae have been recorded from Iran. Fifteen of these species-level records require further data to confirm. Synonymies and distributional information, both general and local, are provided. Two genera: Macrocerus and Themus, and three species: Cordicantharis cordicollis (Kuster, 1854), Themus glazunovi glazunovi (Barovskij, 1909) and Macrocerus oculatus Motschulsky, 1845, are reported as new country records for Iran. PMID- 27988655 TI - Description of a new species of Characidium Reinhardt, 1867 (Characiformes: Crenuchidae) from the Chapada Diamantina, Bahia, and redescription of Characidium bimaculatum Fowler, 1941. AB - A new species of Characidium Reinhardt, 1867 endemic to tributaries of the upper rio Paraguacu in the Chapada Diamantina, Bahia, Brazil, is described. The new species can be distinguished from its congeners except C. bahiense, C. bimaculatum, C. laterale, C. nana, C. nupelia, and C. xavante, by having a conspicuous peduncular blotch in addition to the basicaudal spot on the base of the middle caudal-fin rays. Among other features, the new species differs from C. bahiense, C. laterale, C. nana, C. nupelia, and C. xavante by having a complete lateral line with 32-36 perforated scales (vs. lateral line short, with 9-11 perforated scales), and from C. bimaculatum by the body pigmentation pattern, with secondary bars present (vs. absent), total bars 11-16 (vs. 10-12), peduncular blotch rounded (vs. horizontally elongated), and mature males not having a darker dorsal fin (vs. proximal third of dorsal fin darker in mature males). Characidium bimaculatum, a poorly known species from Northeastern Brazil, is redescribed. PMID- 27988656 TI - Description of two new species from China in a new species group of the fig wasp genus Sycophaga Westwood (Hymenoptera: Chalcidoidea: Agaonidae: Sycophaginae). AB - A new species group, the brevis-group, is established for two new species of the fig wasp genus Sycophaga Westwood (Hymenoptera: Agaonidae) reared from the monoecious fig tree Ficus orthoneura (Moraceae, Ficus, subgenus Urostigma) in China. The two new species, S. brevis n. sp. and S. diutius n. sp. are described and illustrated, supplemented by COI sequence data. In contrast with two other species groups newly recognized in Sycophaga, the explorator-group for species previously classified in Apocryptophagus Ashmead and the sycomori-group for other species previously classified in Sycophaga, the brevis-group is uniquely defined by the long pronotum of females and a Ficus host within the subgenus Urostigma. PMID- 27988657 TI - Duocrassana longula, new genus and species of leafhopper (Hemiptera: Cicadellidae: Deltocephalinae) from southern Mexico and its relationship to other genera in Athysanini. AB - The new leafhopper genus, Duocrassana Pinedo-Escatel, Zahniser & Dietrich, gen. nov., and its type species, Duocrassana longula Pinedo-Escatel, Zahniser & Dietrich sp. nov., are described and illustrated based on material from Oaxaca, Mexico. The relationship with other genera in the tribe Athysanini is discussed, highlighting the importance of male genitalia for its identification. PMID- 27988658 TI - Description of the sexuales of Myzodium modestum (Hottes) (Hemiptera: Aphididae) discovered in the Swiss Alps. AB - The sexuales (apterous oviparous female and alate male) of Myzodium modestum (Hottes) are described for the first time from specimens captured in the Swiss Alps. This is also the first record of this species in Switzerland. This is the first evidence that an aphid may be able to complete its life cycle on mosses. PMID- 27988659 TI - The Indian genus Ajothrips (Thysanoptera: Thripidae) newly recorded from China, with description of the male. AB - The genus Ajothrips was erected for two new species from India (Bhatti 1967), although subsequently a third Indian species was added (Bhatti 1997). All three species have remained known only from females, although Mound (2009) recorded the presence of sternal pore plates in unspecified males of this genus. The purpose of this note is to record the type species, A. karma, from China, and to describe the unknown male. The systematic position of the genus has a confusing history. Considered by Bhatti (1967) as related to Scirtothrips, it was subsequently excluded from the Scirtothrips genus-group (Masumoto & Okajima 2007). However, more recent studies (Ng & Mound 2015; Lima & Mound 2016) have retained the systematic relationship proposed by Bhatti. PMID- 27988660 TI - Erratum: OLEG E. KOSTERIN (2016) Reconsideration of the genera Merogomphus Martin, 1904, and Anisogomphus Selys, 1857, including erection of a new genus, with a new species and discussion of additional specimens from Cambodia. Zootaxa, 4171: 51-76. PMID- 27988661 TI - Lucinid bivalves of Guadeloupe: diversity and systematics in the context of the tropical Western Atlantic (Mollusca: Bivalvia: Lucinidae). AB - Intensive sampling of molluscs from the intertidal to depths of 800 m around the islands of Guadeloupe in the Lesser Antilles (KARUBENTHOS 2012, 2015) recovered 25 species of Lucinidae. All the Guadeloupe species are described and illustrated including details of larval shells and the taxonomy revised within the context of the wider western Atlantic fauna and recent classifications. Concurrent molecular analysis has helped separate frequently confounded species. 'Myrtea' pristiphora is placed in the Leucosphaerine genus Myrtina previously known from the Indo-West Pacific. A second western Atlantic species of Callucina, C. pauperatus previously known from the Pliocene of Jamaica is recognised from the southern Caribbean and off Brazil. The deeper water species 'Myrteopis' lens is placed in Afrolucina previously known from the eastern Atlantic. Lucinids commonly identified as Ctena orbiculata are shown to belong to two distinct species, C. orbiculata in the Gulf of Mexico and Florida and C. imbricatula in the Caribbean. Epicodakia is recognised for the first time in the western Atlantic with E. pectinata widely distributed across the region and E. filiata recorded from deeper water. Three species of Lucina are recognised, Lucina pensylvanica in the Gulf of Mexico and Florida and the similar Lucina roquesana from the Caribbean and Bahamas while the smaller L. aurantia has a wide distribution from central America to the Bahamas. A new species of Parvilucina, P. latens is described; this is similar to P. pectinella but has an internal ligament. The long problematic species 'Codakia' cubana is assigned to Ferrocina. A new genus, Guyanella is introduced for Parvilucina clenchi the smallest known lucinid. A critical reassessment of the lucinid fauna of the western Atlantic Ocean identifies 46 species for the region with 33 of these living at depths less than 200 m. Deeper-water habitats have been much less investigated except at sites of hydrocarbon seeps. Some species are widespread throught the whole region but others have more restricted ranges. Notable are species pairs, for example of Ctena, Lucina, Lucinisca and Parvilucina that are either largely Caribbean or Gulf of Mexico/Floridian in distribution. Although extralimital, two problematic species from the mid-south Atlantic island of St Helena are refigured and placed in Cavilinga. PMID- 27988662 TI - New molecular phylogeny of Lucinidae: increased taxon base with focus on tropical Western Atlantic species (Mollusca: Bivalvia). AB - A new molecular phylogeny of the Lucinidae using 18S and 28S rRNA and cytochrome b genes includes many species from the tropical Western Atlantic as well as additional taxa from the Indo-West Pacific. This study provides a phylogenetic framework for a new taxonomy of tropical Western Atlantic lucinids. The analysis confirmed five major clades-Pegophyseminae, Leucosphaerinae, Myrteinae, Codakiinae and Lucininae, with Monitilorinae and Fimbriinae represented by single species. The Leucosphaerinae are expanded and include Callucina winckworthi and the W. Atlantic Myrtina pristiphora that groups with several Indo-West Pacific Myrtina species. Within the Codakiinae two abundant species of Ctena from the Western Atlantic with similar shells are discriminated as C. orbiculata and C. imbricatula, while in the Indo-West Pacific Ctena bella is a probable species complex. The Lucininae is the most species rich and disparate subfamily with several subclades apparent. Three species of Lucina are recognized in the W. Atlantic L. aurantia, L. pensylvanica and L. roquesana. Pleurolucina groups near to Cavilinga and Lucina, while Lucinisca muricata is more closely related to the E. Pacific L. fenestrata than to the Atlantic L. nassula. A new species of Parvilucina is identified from molecular analyses having been confounded with Parvilucina pectinata but differs in ligament structure. Also, the former Parvilucina clenchi is more distant and assigned to Guyanella. PMID- 27988663 TI - Two new species of Portanini (Hemiptera: Cicadellidae: Aphrodinae) from Southeastern Brazil. AB - Two new species, Portanus restingalis and Paraportanus marica, are described and illustrated from Restinga de Marica, a sandy coastal plain in Rio de Janeiro State, Southeastern Brazil. Comparative notes on the two new species are given. Portanus youngi and Paraportanus eburatus are newly recorded from Brazil and Guyana, respectively. A checklist of all known species of Portanini with their geographic distribution is provided. PMID- 27988664 TI - Description of two new species of Coeliccia from Vietnam (Odonata: Platycnemididae). AB - Coeliccia hayashii sp. nov. (holotype male, from Doi waterfall, KaNat, K'Bang district, Gia Lai Province, central Vietnam, deposited in VNMN) and Coeliccia mattii sp. nov. (holotype male and female allotype, from Doi Cao, Loc Tan, Bao Lam district, Lam Dong Province, southern Vietnam, deposited in VNMN) are described. The males of both species are characterized by extensive pruinosity on the thorax. PMID- 27988665 TI - Two new species of Haploperla (Plecoptera: Chloroperlidae) from China. AB - Two new species of the chloroperline genus Haploperla, H. tuanjiena sp. nov. from Sichuan Province, China and H. datongensis sp. nov. from Qinghai Province, China are described and illustrated. Haploperla tuanjiena is characterized by terga 10 with a medially triangular sclerotized area and the epiproct subtriangular, anterolateral margin sclerotized with apex acute. Haploperla datongensis is characterized by the epiproct tongue-shaped, anterior margin and anteroventrally strongly sclerotized. The new species are compared with similar taxa of the genus. An identification key is provided for the seven known Chinese species of Haploperla. PMID- 27988666 TI - A new species of Oreodera Audinet-Serville, 1835 from Ecuador (Coleoptera, Cerambycidae, Lamiinae) and new geographical records. AB - Oreodera antonkozlovi, new species from Ecuador is described and illustrated. A key to species of Oreodera, currently known from Ecuador, is provided. Moreover, the following new country records are reported in Oreodera: O. basicretata (Brazil); O. cretata (Peru); O. sororcula (Brazil); O. wappesi (Costa Rica and Guatemala). Additionally, new state records from Brazil are added: O. bituberculata (Goias); O. griseozonata (Amapa); O. melzeri (Amazonas). PMID- 27988667 TI - Niltavinae, a new taxon of Old World flycatchers (Aves: Muscicapidae). AB - The relationships among Old World chats and flycatchers (Muscicapidae) have recently been clarified in two independent molecular phylogenetic studies (Sangster et al. 2010, Zuccon & Ericson 2010). Both studies recovered a well supported clade of predominantly blue flycatchers of the genera Niltava, Cyornis, Eumyias and Cyanoptila, some species traditionally included in the genus Rhinomyias and one species traditionally included in Ficedula (F. monileger). The family-group name Niltavinae Sangster, Alstrom, Forsmark & Olsson, 2010, was introduced for this clade (Sangster et al. 2010). Unfortunately, our description of the new taxon Niltavinae did not include a diagnosis (sensu ICZN article 13.1.1) and thus inadvertently made this name unavailable for nomenclatural purposes (Zuccon 2011). The supplementary data associated with our original paper included evidence by which the taxon Niltavinae can be diagnosed: a 1 base pair (bp) deletion in the ornithine decarboxylase gene, as shown in Figure S1 in the online version (doi:10.1016/j.ympev.2010.07.008), but this was not mentioned in the printed version of our paper. Given that Niltavinae Sangster, Alstrom, Forsmark & Olsson, 2010 represents a nomen nudum, and the clade for which this name was intended thus remains unnamed, we here provide the following description. PMID- 27988668 TI - Study of the Oriental genus Alishania Vilbaste (Hemiptera: Cicadellidae: Deltocephalinae) from China with description of one new species. AB - The Oriental leafhopper genus Alishania Vilbaste, is reviewed and includes A. formosana, A. fodingensis, A. attenuata and a new species, A. quadrilamina sp. nov., found during a survey of leafhoppers in Xizang and described here. A key to males of Alishania species, together with descriptions, a checklist and figures are provided. Based on the structure of the aedeagus, Alishania is here transferred from subtribe Opsiina to subtribe Circuliferina of tribe Opsiini. PMID- 27988669 TI - Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences. AB - The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemesio 2007; Donegan 2008, 2009; Nemesio 2009a-b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016. PMID- 27988670 TI - A new species of Tambitnotia from Peru, with the first reported female of the genus (Lepidoptera: Tortricidae: Olethreutinae). AB - Tambitnotia peruviana n. sp. (Tortricidae: Olethreutinae), is described from Junin Department, Peru, along with the first reported female for the genus. Illustrations of adults and genitalia are provided. PMID- 27988671 TI - Revision of the West-Palaearctic species of the tribe Cerioidini (Diptera, Syrphidae). AB - The West-Palaearctic cerioidines (Syrphidae: Cerioidini) are revised, including species of the genera Ceriana Rafinesque, Primocerioides Shannon, and Sphiximorpha Rondani. Three new species are described, Ceriana glaebosa van Steenis & Ricarte sp. n. (Cyprus), Ceriana media van Steenis & Ricarte sp. n. (Afghanistan and Iran) and Ceriana skevingtoni van Steenis & Ricarte sp. n. (Armenia, Azerbaijan and Iran). The following names are proposed as junior synonyms: Cerioides caucasicus Paramonov, 1927 [= Ceriana conopsoides (Linnaeus, 1758)], Ceria binominata Verrall, 1901 [= Sphiximorpha garibaldii (Rondani, 1860)], Ceriana worelli, Bradescu, 1972b [= Sphiximorpha garibaldii (Rondani, 1860)] and Sphiximorpha hiemalis Ricarte, Nedeljkovic & Hancock, 2012 [= Primocerioides regale Violovitsh, 1985]. Identification keys, biological data and distribution maps for the studied taxa are provided. Conops vaginicornis Schrank, 1803 is discarded as a synonym of Ceriana conopsoides and should be considered as nomen dubium. PMID- 27988672 TI - Myrmeleon almohadarum sp. nov., from Spain and North Africa, with description of the larva (Neuroptera Myrmeleontidae). AB - A new antlion (Neuroptera Myrmeleontidae Myrmeleontini), Myrmeleon almohadarum sp. nov., is described from southern Spain and Tunisia. The new taxon is closely related to the mostly sympatric M. inconspicuus Rambur and M. mariaemathildae Pantaleoni, Cesaroni & Nicoli Aldini but differing in body pattern, wing venation and larval chaetotaxy. The validity of the new species is also supported by a phylogenetic analysis based on COI sequences. The larva of this new species is described and compared with congeners. M. almohadarum appears to be associated with sandy environments. PMID- 27988673 TI - Nine new species of the genus Deinopteroloma Jansson, 1946 (Coleoptera: Staphylinidae: Omaliinae: Anthophagini) from China and Vietnam. AB - Nine new species of the genus Deinopteroloma Jansson, 1946 are described and illustrated: D. bisbisinuatum sp.n. and D. draco sp.n. from China, Sichuan (Gongga Shan), D. emeicola sp.n., D. minor sp.n., D. ruzickai sp.n., D. sextuberculatum sp.n. and D. yinyang sp.n. from China, Sichuan (Emei Shan), D. rougemonti sp.n. from China, Yunnan (Dehong Dai and Jingpo Autonomous Prefecture) and D. vesiculosum sp.n. from North Vietnam. Three species groups within the genus are identified and characterized and closely relationships among them are briefly discussed. A check-list and key to the species of Deinopteroloma are provided. The distribution of all described and recorded species is mapped. Additional records of D. spectabile Smetana, 1996 from Nepal are given. PMID- 27988674 TI - Three new species and redescription of the type species of Soesilarishius Makhan, 2007 (Araneae: Salticidae: Euophryini). AB - Four syntopic species of Soesilarishius Makhan, 2007 are recorded from the Floresta Estadual do Trombetas, Oriximina, Para, Brazil. The first is the type species of the genus, S. amrishi Makhan, 2007, of which we redescribe the male and describe the female for the first time. The other three species are new and described herein based on both sexes: S. laticlavus sp. nov., S. trombetas sp. nov. and S. elongatulus sp. nov. PMID- 27988675 TI - A new species of Auriculostoma (Trematoda: Allocreadiidae) from the intestine of Brycon guatemalensis (Characiformes: Bryconidae) from the Usumacinta River Basin, Mexico, based on morphology and 28S rDNA sequences, with a key to species of the genus. AB - We describe a new species of Auriculostoma Scholz, Aguirre-Macedo & Choudhury, 2004 based on several sources of information including morphology (light and scanning electron microscopy [SEM]), sequences of two nuclear genes, host association, and geographical distribution. Morphologically, the new species most closely resembles Auriculostoma astyanace Scholz, Aguirre-Macedo & Choudhury, 2004, but differs by having deeply lobated testes and cirrus-sac extending posteriorly to seminal receptacle level. Auriculostoma lobata n. sp. can be readily distinguished from all the other congeners by the combination of the following characters: testes located in tandem, testes deeply lobated, and larger body size. A phylogenetic analysis using 28S rDNA sequences along with those available for other allocreadiid trematodes, revealed that the new species is a sister taxon of A. astyanace, a species described from the banded astyanax, Astyanax fasciatus (Cuvier) in Nicaragua. Auriculostoma totonacapanensis Razo Mendivil, Mendoza-Garfias, Perez-Ponce de Leon & Rubio-Godoy, 2014 from the Mexican tetra, Astyanax mexicanus (De Filippi) in Mexico is the sister taxon of A. astyanace plus the new species. Genetic divergence levels for the 28S rDNA and ITS2 were estimated among the Middle-American species of Auriculostoma infecting characiforms. The validity of the new species is then established by reliable morphological differences, its host association to bryconids (Brycon guatemalensis Regan), restricted geographical distribution (Usumacinta and Lacantun River basins), and genetic divergence levels, albeit relatively low. A morphometric comparison between the new species and the other seven congeneric species was undertaken and, in addition, a taxonomic key to identify the species contained in the genus Auriculostoma, widely distributed across the Americas, is provided. PMID- 27988676 TI - Opistognathus ensiferus, a new species of jawfish (Opistognathidae) from the Gulf of Mannar, India, with redescription of O. solorensis Bleeker. AB - A new species of jawfish, Opistognathus ensiferus n. sp., is described based on a single specimen from Manauli Reef in the Gulf of Mannar, India. It is a member of a species group that also includes Opistognathus solorensis Bleeker (Indonesia, Philippines, Taiwan and Palau) and O. verecundus Smith-Vaniz (northwestern Australia). From these two species O. ensiferus n. sp. differs in lacking dark oral pigmentation, except inner lining of upper jaw and adjacent membranes with a single dark stripe (vs. two stripes) and in having a lateral line ending below the 6th or 7th segmented dorsal-fin ray (vs. below the 1st to 4th ray). Opistognathus solorensis is redescribed and in the absence of extant type specimens a neotype is designated. Two strikingly different color morphs are documented for O. solorensis, including the less common one which is almost entirely yellow. PMID- 27988677 TI - Genetic evidence supports Sylvilagus mansuetus (Lagomorpha: Leporidae) as a subspecies of S. bachmani. AB - Since Sylvilagus bachmani (Lagomorpha: Leporidae) from the Baja California Peninsula and S. mansuetus from San Jose Island, Mexico, display an allopatric distribution and are closely related, their taxonomy is unclear. The phylogenetic relationships among specimens of both species were evaluated using two mitochondrial genes (Cyt b, COI) and the beta-fibrinogen nuclear gene intron 7 (beta-fib I7). The genetic analyses revealed that S. mansuetus was included within the S. bachmani clade as the sister-group of S. b. cerrosensis. The genetic distances among S. b. cerrosensis and mansuetus were relatively low (1.3% with Cyt b), similar to intraspecific distances observed within other species of Sylvilagus. We consider mansuetus to be a subspecies of S. bachmani, and the morphological traits previously used to differentiate the two taxa should be used to distinguish S. b. mansuetus from the other subspecies of S. bachmani. PMID- 27988678 TI - A new cave-dwelling species of the genus Mesoiulus Berlese, 1886 (Diplopoda, Julida, Julidae) from Turkey. AB - A new cave-dwelling species of the poorly defined genus Mesoiulus Berlese, 1886, M. taurus sp. nov., is described from the Zindan Cave, Isparta, Western Taurides, Turkey. A brief discussion of the relationship between M. taurus sp. nov. and the most similar species (M. ciliciensis Strasser, 1975) is presented, as well as a map showing the distribution of the genus Mesoiulus in Turkey. PMID- 27988679 TI - A taxonomic review of the anilline genus Zeanillus Jeannel (Coleoptera: Carabidae: Bembidiini) of New Zealand, with descriptions of seven new species, re classification of the species, and notes on their biogeography and evolution. AB - Based upon external features of adults of the genus Zeanillus ten species are recognized, seven of which are new to science. Because of significant morphological differences, all species are arranged in four subgenera: the nominotypical subgenus Zeanillus, including Z. phyllobius (Broun), Z. punctigerus (Broun), and Z. nunni, new species (New Zealand, South Island, Otago, Trotters George); the monobasic subgenus Brounanillus, new subgenus, including Z. pallidus (Broun); the monobasic subgenus Nunnanillus, new subgenus, including Z. pellucidus, new species (New Zealand, South Island, Otago, Oamaru); and the most species-rich subgenus Otagonillus, new subgenus, including Z. brouni, new species (New Zealand, South Island, Otago, Oamaru), Z. lescheni, new species (New Zealand, South Island, Southland, Waikaia Forest), Z. carltoni, new species (New Zealand, South Island, Otago, Mount Watkin), Z. montivagus, new species (New Zealand, South Island, Otago, North Rough Ridge), and Z. nanus, new species (New Zealand, South Island, Otago, Waipori River Valley). Based on new morphological data, a redescription of genus, redescriptions of previously described species, and descriptions of all new taxa are given and a taxonomic key for all known species is provided. Maps of species distributions and illustrations of main taxonomic characters used in the text are also included. Some biogeographic/evolutionary aspects of Zeanillus origin and diversification are discussed. PMID- 27988680 TI - Diversity of shrews in Ethiopia, with the description of two new species of Crocidura (Mammalia: Lipotyphla: Soricidae). AB - Two new species of white-toothed shrews, Crocidura afeworkbekelei and Crocidura yaldeni, are described from southern Ethiopia. Comparisons are made with other species of Crocidura known to occur in Ethiopia. A list of 28 species of shrews known from Ethiopia is provided, 10 of which (including both newly described species) are currently considered to be endemic to Ethiopia. The endemic shrew fauna consists of forest and montane species known to occur within the altitudinal range of 1200-4050 m a.s.l. The remarkable number of endemic species of Crocidura shows that the Ethiopian Plateau is an important centre of diversity and adaptive radiation of the genus. Current cytogenetic and molecular data support the monophyly of most species of Crocidura endemic to Ethiopia. PMID- 27988681 TI - Australian freshwater sponges with a new species of Pectispongilla (Porifera: Demospongiae: Spongillida). AB - This paper focus on the biodiversity assessment of Australian inland water. Checklists of Australian Spongillida are also provided with biogeographic notes together with the geographic range of all species of freshwater sponges in Australia. New discoveries on freshwater sponges are reported from ephemeral freshwater habitats in Kakadu National Park (Australia Northern Territory). Morphological analyses show that the sponges belong to Radiospongilla and Pectispongilla in the family Spongillidae. Radiospongilla cfr. philippinensis shows a single layer of radial gemmuloscleres and the absence of tangential gemmuloscleres in the gemmular theca. Pectispongilla gagudjuensis n. sp. diverges from the diagnostic traits of the four species currently assigned to the genus i.e. skeletal megascleres are dominant acanthostrongyles and less frequent acanthoxeas shorter than in the other species, microscleres are absent, and gemmules are larger than in the other species of the genus. PMID- 27988682 TI - Mature larva of Stenichnus godarti (Latreille) (Coleoptera: Staphylinidae, Scydmaeninae): redescription, hypothesis of displaced epicranial suture and alternative interpretation of homology between chaetotaxic structures. AB - The mature larva of Stenichnus godarti is redescribed on the basis of a shed larval skin; identification was made by rearing the adult. New data on the life history of St. godarti are provided, including feeding behavior of the larva and adult and longevity of the adult under laboratory conditions. Possible serial homology of chaetotaxic structures across body segments is discussed, and morphological structures of immature St. godarti are compared with those of previously described St. collaris. It is concluded that despite structural similarities and some chaetotaxic structures (mainly on the antennae, mouthparts, legs and thoracic sternites) shared by St. godarti and St. collaris, differences in some important body regions are so profound that it is difficult to draw homologies between setal pattern on the head, thoracic and most of the abdominal tergites, based solely on topological evidence. Differences in the chaetotaxy of the head are especially puzzling and a hypothesis of displaced frontal arms of the epicranial suture is proposed, assuming homology between the presutural setae of St. godarti with postsutural setae of St. collaris. Furthermore, alternative interpretations of dorsal thoracic setae are discussed. PMID- 27988683 TI - Tobrilus methanus sp. n. and Tripyla posolskii sp. n. (Nematoda, Triplonchida) from Lake Baikal, Russia. AB - Two new nematode species found in Lake Baikal (Russia) are described and illustrated. Tobrilus methanus sp. n. is morphologically close to T. modestus Gagarin, 1996 and T. incognitus Tsalolikhin, 1972. The new species differs from T. modestus by the thinner body (a = 20-29 vs a = 15.5-18.5), longer pharynx (b = 3.4-4.4 vs b = 5.0-6.2), comparatively longer tail (c' = 3.4-5.0 vs c' = 2.0 2.5), less number of supplementary organs (6 vs 7-8) and presence of subterminal seta. T. methanus sp. n. differs from T. incognitus by the thicker body (a = 20 29 vs a = 35-37), longer pharynx (b = 3.4-4.4 vs b = 5.1-5.8), shorter outer labial setae (3-4 um long vs 10 um long) and presence of crystalloids. Tripyla posolskii sp. n. is close to T. dybowskii Tsalolikhin, 1976, but differs by the shorter body (L = 1548-2078 um vs L = 2400-3530 um), shorter tail (c = 4.7-7.2, c' = 5.8-7.9 vs c = 2.8-4.8, c' = 7.3-11.9) and shorter spicules (47-57 um long vs 85-92 um long). A key for the identification of valid species of the genus Tobrilus from Lake Baikal is given. PMID- 27988684 TI - Scale ontogeny in the cardinalfish family Apogonidae. AB - Following the discovery of spinoid scales in species of the cardinalfish genus Siphamia, a survey of 20 apogonid genera, using scanning electron microscopy, found that scale ontogeny in the Apogonidae usually proceeds along three phases, cycloid, spinoid and transforming ctenoid, that develop in that order. The transforming ctenoid scales of the Pempheridae, considered a sister group of the Apgogonidae by some authors, follow the same ontogenetic pattern. Transforming ctenoid scales are the ancestral scale type in the Apogonidae, making their spinoid and cycloid scales a secondary loss or reversal. Though sharing the transforming ctenoid scale type with the apogonids, the ontogeny of this scale type in several scorpionfishes (Scorpaenidae) does not have a spinoid phase. Recent molecular studies indicate that gobiids are related to apogonids, but the goby species examined in this study have peripheral ctenoid scales that lacked a spinoid phase in their ontogeny. The observations made in this study suggest that the peripheral ctenoid scale, the whole ctenoid scale and the crenate scale found in percomorph fishes were derived from a transforming ctenoid scale. Scale morphology and ontogeny could provide useful characters for resolving relationships between percomorph families. PMID- 27988685 TI - Sexual dimorphism in a freshwater atyid shrimp (Decapoda: Caridea) with direct development: a geometric morphometrics approach. AB - Neocaridina davidi is a caridean shrimp that has gained popularity in recent years as an ornamental species. Using geometric morphometrics, we investigated sexual dimorphism in carapace and second abdominal segment shape of N. davidi. Adult females displayed a more elongated carapace and a longer rostrum than males. However, male carapace shape was similar to that of juvenile females. The second abdominal pleura was more elongated and wider in adult females than in males. Significant differences were found in centroid size for the carapace and the second abdominal segment between sexes, which is consistent with sexual size dimorphism. These results support the hypothesis of a "pure search" mating system in N. davidi, where small males search actively for receptive females, and after insemination they continue searching. PMID- 27988686 TI - Five new species and a new country record in American Cerambycidae Coleoptera). AB - Five new species are described from American fauna: Stizocera boliviensis and Sphaerion lingafelteri from Bolivia (Elaphidiini); Ectenessa wappesi from Panama (Ectenessini); Mecometopus martinsi from Peru and Ecuador (Clytini); Recchia volcanensis from Bolivia (Aerenicini). The new species are included in previous keys. Sphaerion rusticum Burmeister, 1865 is recorded from Bolivia for the first time. PMID- 27988687 TI - The oldest representative of the modern snipe fly genus Symphoromyia (Diptera: Rhagionidae). AB - We describe and illustrate from the earliest Eocene amber of France the oldest representative of the rhagionid modern genus Symphoromyia, under the name of S. eocenica sp. nov. Its mouthpart structure shows that it was hematophagous as is the modern representatives of the genus, demonstrating a remarkable morphological stability for 53 Myr. PMID- 27988688 TI - Revision of the types of male Sciaridae (Diptera) described from Australia by F.A.A. Skuse. AB - A total of 27 male sciarid types described by Skuse (1888 and 1890), held in the Australian National Insect Collection, Canberra, and the Australian Museum, Sydney, were remounted and examined microscopically. Of these, 25 species were described as Sciara Meigen, one as Zygoneura Meigen and one as Trichosia Winnertz. Revision of these species revealed the following: 13 species belong to the genus Bradysia Winnertz (B. amabilis, B. conjuncta, B. crassicornis, B. exsequialis, B. frequens, B. froggatti, B. luctifica, B. maesta, B. mastersi, B. ornatula, B. pernitida, B. pictipes, B. unica), 1 species to the genus Corynoptera Winnertz (C. minutela), 4 species to the genus Austrosciara Schmitz & Mjoberg (Aus. infrequens, Aus. montivaga, Aus. spectabilis, Aus. winnertzi), 2 species to the genus Pseudolycoriella Menzel & Mohrig (Psl. cavatica, Psl. ignobilis), 1 species to the genus Pseudozygomma Mohrig (Pseudoz. maculipennis), 1 species to the genus Sciara Meigen (Sc. tryoni), and 1 species to the genus Scythropochroa Enderlein (Scyth. macleayi). In total 26 species were new combinations. Eight species names were declared as new synonyms: Bradysia pictipes (Skuse, 1888) = Sciara notata Skuse, 1888 syn. n. and = Bradysia seticornis Vilkamaa, Hippa & Mohrig, 2012 (from New Caledonia) syn. n.; Bradysia conjuncta (Skuse, 1890) = Sciara serenipennis Skuse, 1890 syn. n.; Pseudolycoriella cavatica (Skuse, 1888) = Sciara familiaris Skuse, 1888 syn. n. and = Sciara festiva Skuse, 1888 syn. n.; Bradysia luctifica (Skuse, 1888) = Bradysia planistylata Vilkamaa, Hippa & Mohrig, 2012 syn. n.; Sciara tryoni Skuse, 1890 = Sciara insulana Vilkamaa, Hippa & Mohrig, 2015 syn. n. (both species are from New Caledonia); Austrosciara winnertzi (Skuse, 1888) = Sciara rufulenta Edwards, 1927 syn. n. (from New Zealand). Lectotype specimens were designated for 17 species in order to fix the names. PMID- 27988689 TI - Myocoptid mites (Acariformes: Myocoptidae) of the fauna of the former USSR. AB - Mites of the family Myocoptidae (Acariformes: Sarcoptoidea) of the former USSR are revised based on the collection of the Zoological Institute RAS (St. Petersburg, Russia). Seventeen described species are recorded. Four species are described as new for science: Trichoecius dubininae sp. nov. from Lasiopodomys gregalis (Pallas) (Rodentia: Cricetidae) from Russia (Chelyabinsk Prov., type locality), Kazakhstan and Kirghizia, T. lemmus sp. nov. from Lemmus sibiricus (Kerr) (Rodentia: Cricetidae) from Russia (Taymyr peninsula), T. meriones sp. nov. from Meriones meridianus (Pallas) (Rodentia: Muridae) from Turkmenia, and Myocoptes meriones sp. nov. from Meriones tamariscinus (type host) from Kirghizia (type locality) and Meriones libycus (Lichtenstein) from Tajikistan. In addition, the presence of 7 more species in the fauna of the former USSR is considered highly probable. Myocoptids of the former USSR represent all 6 genera currently recognized in the family. Keys to species, their hosts and localities are provided and all data are summarized in tabular format. A new name Apocalyptoides nom. nov. is proposed for the preoccupied generic name Apocalypsis Bochkov, 2010 not Butler (1876). PMID- 27988690 TI - Review of the genus Signoretia (Hemiptera: Cicadellidae: Signoretiinae) of the Oriental region with description of nine new species. AB - Species of Signoretia Stal from the Oriental region are reviewed and types of five species described by Baker, two species described by Distant and one species described by Schmidt are illustrated. A checklist of 20 species of the genus from the Oriental region including 9 new species is given. The new species described and illustrated are Signoretia dulitensis sp. nov. (Malaysia: Mt Dulit), S. lunglei sp. nov. (India: Mizoram), S. mishmiensis sp. nov. (Myanmar: Mishmi Hills), S. quoinensis sp. nov. (Malaysia: Quoin Hill), S. rubra sp. nov. (Thailand: Chiang Mai), S. sahyadrica sp. nov. (India: Kerala), S. similaris sp. nov. (Vietnam: Fyan), S. sinuata sp. nov. (India: West Bengal) and S. takiyae sp. nov. (India: Andaman Is.). Both S. aureola Distant and S. maculata Baker are redescribed and illustrated. Lectotypes are designated for S. greeni Distant and S. aureola Distant. PMID- 27988691 TI - A review of the Tillicera genus group with a revision of Plathanocera Schenkling (Coleoptera, Cleridae, Clerinae). AB - The Tillicera genus group is revised and defined to contain 40 species in the following six genera: Apopempsis Schenkling, 1903; Cardiostichus Quedenfeldt, 1885; Hemitrachys Gorham, 1876; Placocerus Klug, 1837; Plathanocera Schenkling, 1902 and Tillicera Spinola, 1941. The definition of the Tillicera genus group is mainly based on the presence of the dorsoventrally compressed and expanded antennae (from antennomere 3 onwards). The antennomeres are dilated at least from antennomeres 5 to 9 onwards, and are broader than long, always vested with dense long setae. A key to the constituent genera, color photographs, and distribution maps are provided. The genus Plathanocera is taxonomically revised, including a key to species and genital figures. PMID- 27988692 TI - A taxonomic revision of the Musician Wren, Cyphorhinus arada (Aves, Troglodytidae), reveals the existence of six valid species endemic to the Amazon basin. AB - Cyphorhinus arada, an Amazonian endemic, shows considerable geographic variation in plumage that has led to the recognition of eight subspecies. These include C. a. arada, C. a. salvini, C. a. modulator, C. a. transfluvialis, C. a. interpositus, C. a. griseolateralis, C. a. urbanoi and C. a. faroensis. However, a thorough taxonomic revision of the Cyphorhinus arada complex has never been undertaken, so we revise the taxonomy based on morphological and vocal characters. We analyzed a total of 515 museum specimens and 146 voice recordings representing and encompassing the distributions of all named taxa, including those currently considered not valid. Vocal analyses showed major variation within the complex, from which several trends could be identified between populations. We concluded that six species (C. arada, C. transfluvialis, C. modulator, C. salvini, C. interpositus and C. griseolateralis) should be recognized under the Phylogenetic Species Concept based on the diagnosis of stable plumage and vocal patterns of each. PMID- 27988693 TI - First Amazonian species of Maracaynatum, with comments on the genus (Opiliones: Laniatores: Samoidae). AB - Among Opiliones, the family Samoidae Sorensen, 1886 is a group of small Laniatores with a wide tropical distribution. Neotropical samoids are distributed mainly in the Caribbean subregion, with species recorded from insular localities and the Venezuelan coastal range. Previously, for continental South America only three genera and just a few specimens of unidentified Samoidae have been recorded from Brazil. In this paper we describe Maracaynatum isadorae sp. nov., the first record of the genus for Brazil and the first samoid described for the Amazon biome. We also provide an emended diagnosis for the genus and a map with its distribution. PMID- 27988694 TI - Review of the leafhopper genus Alnetoidia Dlabola (Hemiptera: Cicadellidae: Typhlocybinae: Erythroneurini) from China, with descriptions of two new species. AB - Generic characteristics of genus Alnetoidia Dlabola are revised based on study of nine species from China, including two new species: A. (Alnetoidia) gracilis, A. (Alnella) dentata spp. nov., and four new records to China. A key to species for identification of Chinese adult males is provided. PMID- 27988695 TI - Amendments to some scale insect names (Hemiptera: Sternorrhyncha: Coccomorpha). AB - The following scale insect specific names need gender changes to agree with their genus group names in the current printed catalogues and in ScaleNet, a database of the scale insects (Garcia Morales et al. 2016). This action is taken to agree with Article 31.2 of the International Code of Zoological Nomenclature (International Commission on Zoological Nomenclature 1999). PMID- 27988696 TI - Redescription, distribution and mating call of Pristimantis colomai (Lynch and Duellman, 1997) (Anura, Craugastoridae). AB - We redescribe Pristimantis colomai (Lynch & Duellman, 1997) on the basis of new specimens from Colombia and Ecuador. Also provide a new diagnosis, reassess its distribution, and describe the mating call for the first time. Besides the data in the original description, only is available for this species: (i) new records from Ecuador (Yanez-Munoz et al. 2011) and (ii) molecular phylogenetic inferences that place this species in the Pristimantis ridens series (Hedges et al. 2008; Padial et al. 2014). Pristimantis colomai is currently classified as endangered due to its restrict distribution and habitat quality (Castro et al. 2004). PMID- 27988697 TI - On the taxonomy of the genus Acronicta (Lepidoptera, Noctuidae). III. Acronicta lutea species group. AB - The present paper is the third in a series of articles on the genus Acronicta Ochsenheimer, 1816 (Volynkin et al. 2015; Volynkin 2015). Here we focus on the taxonomy of the Acronicta lutea species group, designating the lectotype of Acronicta lutea (Bremer & Grey, 1852), revising synonym status of Acronycta metaxantha funesta Draudt, 1950 and Pharetra leucoptera Butler, 1881, transferring Acronicta nigricans (Leech, 1900) to the subgenus Viminia Chapman, 1890 and introducing the new synonymy A. nigricans = Acronicta regifica Draudt, 1937 syn. n. PMID- 27988698 TI - Erratum: VEENAKUMARI KAMALANATHAN & PRASHANTH MOHANRAJ (2016) A new Indian species of Pardoteleia Kozlov & Le (Hymenoptera: Scelionidae: Scelioninae) and first description of the male. Zootaxa, 4158 (4): 592-600. PMID- 27988699 TI - Ten new species of Oreophryne (Anura, Microhylidae) from Papua New Guinea. AB - Oreophryne presently represents the second-most-diverse genus of microhylid frogs, with 57 named species, most occurring on New Guinea and its satellite islands. Nonetheless, a diversity of species remains to be described. Using morphological, color-pattern, and advertisement-call data, I describe ten new species of Oreophryne from the Papuan Peninsula of New Guinea and adjacent islands, which together form the East Papuan Composite Terrane. All but two of these species can be placed into two species groups based on call type. I refer to these species groups as the O. anser group and the O. equus group, both being based on species described herein. Members of the O. anser group produce calls reminiscent of a goose honk, whereas members of the O. equus group produce calls reminiscent of a horse's whinny. Description of three new species in the O. anser group requires me to first rediagnose O. loriae, which has previously been interpreted as including the frogs named herein as O. anser sp. nov. The honk call type has not previously been reported within Oreophryne, and the whinny call may be novel as well, although it is possibly derived from other New Guinean species having calls consisting of a slower series of peeps. Based on their unique call types, I hypothesize that both species groups are monophyletic. If true, each would appear endemic to the East Papuan Composite Terrane. Only five additional species of Oreophryne are known from this region that do not belong to one or the other of these two species groups; hence, these newly identified species groups represent the majority of diversity in Oreophryne from the Papuan Peninsula and its satellite islands. PMID- 27988700 TI - Census of Cnidaria (Medusozoa) and Ctenophora from South American marine waters. AB - We have compiled available records in the literature for medusozoan cnidarians and ctenophores of South America. New records of species are also included. Each entry (i.e., identified species or still as yet not determined species referred to as "sp." in the literature) includes a synonymy list for South America, taxonomical remarks, notes on habit, and information on geographical occurrence. We have listed 800 unique determined species, in 958 morphotype entries: 5 cubozoans, 905 hydrozoans, 25 scyphozoans, 3 staurozoans, and 20 ctenophores. Concerning nomenclatural and taxonomical decisions, two authors of this census (Miranda, T.P. & Marques, A.C.) propose Podocoryna quitus as a nomen novum for the junior homonym Hydractinia reticulata (Fraser, 1938a); Euphysa monotentaculata Zamponi, 1983b as a new junior synonym of Euphysa aurata Forbes, 1848; and Plumularia spiralis Milstein, 1976 as a new junior synonym of Plumularia setacea (Linnaeus, 1758). Finally, we also reassign Plumularia oligopyxis Kirchenpauer, 1876 as Kirchenpaueria oligopyxis (Kirchenpauer, 1876) and Sertularella margaritacea Allman, 1885 as Symplectoscyphus margaritaceus (Allman, 1885). PMID- 27988701 TI - Morphological and molecular data reveal the cryptic diversity among populations of Aegla paulensis (Decapoda, Anomura, Aeglidae), with descriptions of four new species and comments on dispersal routes and conservation status. AB - The taxonomy of the Brazilian aeglid species Aegla paulensis Schmitt, 1942 from two disjunct hydrographic basins is revised using morphological and molecular data. Results show that six disjunctive populations of Aegla paulensis form a species complex. Aegla paulensis sensu stricto is redescribed and Aegla rosanae Campos Jr., 1998 is revalidated. The four remaining populations previously assigned to Aegla paulensis are now recognized as different species, namely Aegla vanini n. sp., Aegla japi n. sp., Aegla jaragua n. sp. and Aegla jundiai n. sp. All new species are described and illustrated and are well supported by both morphological and molecular data. Aegla lancinhas Bond-Buckup & Buckup in Santos et al., 2015, which until recently was confounded with Aegla paulensis s. str., is supported as a valid species. A key to all members of the A. paulensis species complex is provided, and their phylogenetic and biogeographic relationships to other closely related species is discussed. PMID- 27988702 TI - Nine new Trechisibus species from Peru and Argentina (Coleoptera: Carabidae: Trechinae). AB - Nine new Trechisibus species are described, four from Central Peru (T. huascarani n. sp. and T. recuayi n. sp. from Dept. Ancash, T. curtii n. sp. and T. lemairei n. sp. from Dept. Huanuco) and five from Patagonian Argentina, Province of Rio Negro (T. brevis n. sp., T. longipenis n. sp., T. parvulus n. sp., T. sciakyi n. sp., T. striatus n. sp.). PMID- 27988703 TI - Croatian freshwater oligochaetes: species diversity, distribution and relationship to surrounding countries. AB - This paper presents a checklist of the freshwater oligochaetes of Croatia, including data related to the ecoregions, river basins and habitat types in which species were recorded. The checklist is based on literature data and new records from unpublished research conducted since 1975. A total of 71 freshwater oligochaete species were recorded at 345 sampling sites. The family Naididae was most species rich (31 species), followed by the family Tubificidae (27 species), Lumbriculidae (6 species) and Pristinidae (4 species). The families Haplotaxidae, Propappidae and Lumbricidae were least diverse, with only one species recorded for each. Approximately two-thirds of the oligochaete species occurred in both the Dinaric western Balkan and the Pannonian lowland ecoregions. Similar patterns in species richness were detected for the Black Sea and the Adriatic Sea basins. Species richness varied between habitat types, with rivers as the most speciose habitats. In comparison to adjacent countries, the Croatian oligochaete fauna was most similar to that of Bosnia and Herzegovina, Hungary and Austria. PMID- 27988704 TI - Description of a new Oriental stonefly species, Phanoperla constanspina (Plecoptera: Perlidae) from Mindanao, Philippines and association of life stages using DNA barcoding. AB - A new perlid stonefly, Phanoperla constanspina sp. nov. is described from Mt. Malindang, northern Mindanao, Philippines. The male of the new species is distinguished by lacking lobes on penial sac and large black spines at the penial apex. The female is distinguished by the egg. DNA barcoding was used to associate male, female, and nymphal specimens with 0% divergence. Morphological variation was observed in the shape of the hemitergal anterior processes and the 9th tergal setal patches of male adult and body pigmentation of the nymph. A key to the Philippine Phanoperla species and a checklist of Oriental Phanoperla are also provided. PMID- 27988705 TI - Checklist of the earthworms (Oligochaeta) of Kerala, a constituent of Western Ghats biodiversity hotspot, India. AB - A checklist of earthworm species hitherto known from Kerala, a constituent of the Western Ghats biodiversity hotspot in India, is presented. In total, 88 species and subspecies are recorded, of which 55 are Kerala endemics, 9 near endemics, 14 exotics and 10 native peregrines. These belong to 26 genera and 9 families. The checklist includes the literature citation to the original description, type locality, any significant subsequent generic placements, and the district distributional pattern for each species/ subspecies. PMID- 27988706 TI - Melanopareia bitorquata (d'Orbigny & Lafresnaye, 1837) is a distinct species: an appraisal of morphological variation in the Collared Crescentchest Melanopareia torquata (zu Wied-Neuwied, 1831) (Aves: Melanopareiidae). AB - The Collared Crescentchest Melanopareia torquata is a poorly known and inconspicuous species of open savannas and grasslands in central Brazil, Paraguay and Bolivia. Three subspecies are currently recognized, but their taxonomic limits, ranges and conservation status are far from well-established. This paper analyses individual and geographic variation in this species on the basis of body measurements and plumage coloration of 119 specimens. A clinal pattern of body size variation and considerable mensural overlap precludes a clear-cut separation between the two subspecies restricted to Brazil, and there is evidently sexual dichromatism in some Brazilian populations. However, M. t. bitorquata shows highly distinct plumage features in parapatry with other forms, strongly suggesting it should be treated as a full species. PMID- 27988707 TI - Resolving the taxonomy and nomenclature of Metochus abbreviatus (Hemiptera: Heteroptera: Rhyparochromidae). AB - The identity of Metochus abbreviatus Scott, 1874 (Hemiptera: Heteroptera: Rhyparochromidae: Rhyparochrominae: Rhyparochromini) is clarified based on reexamination of the lectotype. The subjective synonymy of Dieuches kreyenbergi Breddin, 1906 with M. abbreviatus is confirmed. The following new subjective synonymies are proposed: Rhyparochromus erosus Walker, 1872 = Metochus abbreviatus Scott, 1874, syn. nov. = Metochus holsti Distant, 1918, syn. nov. Bibliographies of the names are provided and it is demonstrated that the name M. abbreviatus is in prevailing usage. Reversion to the senior name Rh. erosus is considered to be undesirable, therefore an application has simultaneously been submitted to the International Commission on Zoological Nomenclature to give the specific name abbreviatus precedence over the specific name erosus. The diagnostic characters, bionomics and distribution of the species are briefly reviewed. PMID- 27988708 TI - On a new marine podocopid genus and species (Ostracoda: Hemicytheridae) from Brazil. AB - Bulbocythere calida gen. et sp. nov., a benthic marine ostracode, is herein described and illustrated. The geographic and bathymetric distributions of this new taxon are based on the analysis of 923 bottom samples collected along the entire Brazilian continental shelf in a depth range of about 11 to 280 m, plus sediments of 176 samples from the Sepetiba Bay and 37 samples from the Tamandare Bay. In the study material, this ostracode was rare, and restricted to the warm waters of the E and NE shelves and to the substrates around the reefs of the Tamandare Bay. PMID- 27988709 TI - Cotylegaleata iskenderunensis n. sp., the second known species of the rotifer family Cotylegaleatidae (Monogononta: Ploima). AB - Cotylegaleata iskenderunensis n. sp. is described from a freshwater wetland (Sariseki) at Iskenderun, Turkey. This is the second species within the genus. Cotylegaleata iskenderunensis n. sp. differs from the only known congener, C. perplexa De Smet, 2007, in the shape of the trunk and foot, and particularly the shape of the cotyle and the structure of the trophi. The diagnosis of the genus and family is amended. PMID- 27988710 TI - First record of order Embioptera (Insecta) for the State of Tocantins, Brazil, with description of a new species of Clothoda Enderlein. AB - This paper provides the first record of order Embioptera for the State of Tocantins, Brazil, with the description of Clothoda tocantinensis sp. nov. This genus has just three previously described species; only C. nobilis (Gerstacker) has been recorded from Brazil (Amazon basin). An identification key is provided for males of Clothoda. PMID- 27988711 TI - The taxonomic implication of frontal tubercles in Polypedilum subgenera diagnoses, with re-description of Polypedilum isigabeceum Sasa & Suzuki (Diptera, Chironomidae). AB - Polypedilum isigabeceum Sasa et Suzuki, 2000 was described as belonging to subgenus Polypedilum s. str. However, if we accept the conclusion of Saether et al. (2010), the species might be placed into Kribionympha with P. unagiquartum Sasa, 1985 because of the presence of distinct frontal tubercles in the adult males. However, other taxonomic characters do not support their treatment. P. isigabeceum is re-described and reconfirmed to be assigned to the subgenus Polypedilum s. str. The taxonomic meaning of frontal tubercles is discussed for defining the subgeneric rankings within genus Polypedilum. PMID- 27988712 TI - The type specimen and generic placement of Tridactylus galla Saussure, 1895 (Orthoptera: Caelifera: Tridactylidae). AB - Tridactylus galla was described by Henri de Saussure (1895) on the basis of a single adult female collected during Vittorio Bottego's first expedition to the Horn of Africa in 1892 and 1893. The species appears in lists compiled by Fenizia (1896), Lucas (1898) and Kirby (1906), but aside from a brief mention by Gunther (1995), is entirely overlooked by subsequent authors and is absent from Otte's (1997) catalogue. During the course of compiling an annotated catalogue of the Orthoptera described by Saussure (Hollier and Heads, 2012) we were able to relocate the type of Tridactylus galla in the collection of the Museo Civico di Storia Naturale "Giacomo Doria" in Genova, Italy. Our examination of the specimen confirmed Gunther's (1995) assertion that its placement in Tridactylus Olivier, 1789 is erroneous, and the species is herein formally transferred to the genus Xya Latreille, 1809. PMID- 27988713 TI - The first record of the genus Tanaostigma (Hymenoptera: Tanaostigmatidae) in the Old World, with the description of a new species from India. AB - Tanaostigma Howard (Hymenoptera: Tanaostigmatidae) is recorded for the first time in the fauna of the Old World, with T. indica Gupta sp. n. described and illustrated from southern India, reared from Millettia (=Pongamia) pinnata (Fabaceae). PMID- 27988714 TI - Review of the genus Encolapta Meyrick, 1913 (Lepidoptera: Gelechiidae: helariini) from China, with descriptions of six new species. AB - Seventeen species of the genus Encolapta Meyrick, 1913 from China are reviewed. Six species are described as new: E. bifasciaria sp. nov., E. cornuta sp. nov., E. aciprojecta sp. nov., E. obliquata sp. nov., E. trapezoidea sp. nov. and E. lunata sp. nov.; the previously unknown female of E. marginans (Li et Zheng, 1998) is described for the first time; and one new combination, E. valvispinata (Li, 2002) comb. nov., is proposed. All these species are placed into two species groups based on morphological characters: the tegulifera-group and the epichthonia-group. Photographs of adults and genitalia are provided, along with a key to all the described Chinese species and two maps showing their localities. PMID- 27988715 TI - Two new species of ground-dwelling Cyrtodactylus (Geckoella) from the Mysore Plateau, south India. AB - Two new species of ground-dwelling geckos of the genus Cyrtodactylus (Geckoella) are described from the Mysore Plateau, in southern India. The new species are members of the C. collegalensis species complex, with 8.7 % uncorrected ND2 sequence divergence from each other and greater than 10 % divergence from described members of the C. collegalensis complex, from which they differ in subtle aspects of colour pattern and morphometric ratios. The type localities of the new species are ~ 130 km apart, and 100 km and 225 km from the type locality of C. collegalensis in the Biligiriranga Hills. The discovery of these new species in isolated mountains within a small area suggests other high elevation areas in the region may have undescribed species, and a redefinition of biodiversity patterns in peninsular India. PMID- 27988716 TI - A new species of Scinax Wagler (Anura: Hylidae) from Parana, Southern Brazil. AB - In this article, we describe a new species of Scinax from the state of Parana, southern Brazil, based on the external morphology of adults and their advertisement calls. The new species is diagnosed by the size of its males (SVL 27.8-31.6 mm); the snout subovoid in the dorsal view and slightly acuminate in profile; the vocal sac subgular and ventrally not reaching the pectoral region; and the advertisement call composed of a single pulsed note with 7-13 pulses, and a duration of 0.16-0.25s. This new species occurs in natural highland grassland formations, in the threatened ecosystem of the Atlantic Forest in the state of Parana, southern Brazil. PMID- 27988717 TI - Hepneriana Dworakowska (Hemiptera: Cicadellidae: Typhlocybinae: Erythroneurini), first record from China, with descriptions of eleven new species. AB - A redescription of the erythroneurine leafhopper genus Hepneriana Dworakowska and a key to Chinese species of the genus are provided. Eleven new species, Hepneriana applanata, H. bicruris, H. concava, H. euryaedeaga, H. longa, H. menglunensis, H. paragamma, H. prostrata, H. robusta, H. taibaoensis and H. undulata spp. nov. are described and H. joannae (Dworakowska) is newly recorded from China. PMID- 27988718 TI - A taxonomic review of Korean Liogluta Thomson (Coleoptera, Staphylinidae, Aleocharinae) with descriptions of three new species. AB - A taxonomic review of the Liogluta Thomson in Korea is presented. The genus is represented in Korea by eight species including three new species, L. changwhani Lee & Ahn, sp. nov., L. jinilli Lee & Ahn, sp. nov. and L. rufescens Lee & Ahn, sp. nov. Two species [L. distans (Sharp) and L. ursi (Sawada)] are new to the Korean peninsula and L. pyonganica is recorded for the first time in South Korea. A key, descriptions, habitus photographs and illustrations of the diagnostic characters are provided. PMID- 27988719 TI - Diaphorodoris alba Portmann & Sandmeier, 1960 is a valid species: molecular and morphological comparison with D. luteocincta (M. Sars, 1870) (Gastropoda: Nudibranchia). AB - The nudibranch Diaphorodoris luteocincta (M. Sars, 1870) shows two colour morphotypes defined as D. luteocincta var. alba and D. luteocincta var. reticulata, which are easy to identify and which share an overlapping distribution in the Mediterranean Sea and the North-Eastern Atlantic Ocean. Their systematics has long been discussed by several authors until recently when a molecular study proposed the two varieties as intraspecific colour variability occurring within D. luteocincta species. In order to solve their ranking status, we have carried out a morphological study on anatomical characters and molecular analyses on the mitochondrial markers (COI and 16S rDNA) and the nuclear H3 gene. Results proved the usefulness of the integrative taxonomy approach in assessing species delimitation; in fact Diaphorodoris alba stat. nov. and D. luteocincta were revealed to be two different species. D. luteocincta var. reticulata is confirmed as synonym of D. luteocincta s.str. A hypothesis on phylogenetic relationship among most of the currently recognised species of the genus Diaphorodoris Iredale & O'Donoghue, 1923 is also here presented. PMID- 27988720 TI - The species of the genus Diamesa (Diptera, Chironomidae) known to occur in Italian Alps and Apennines. AB - Some rare species from Italian Alps, belonging to the genus Diamesa Meigen, 1835 (Diptera, Chironomidae) are here redescribed as adult males, because only old, incomplete descriptions are available for these taxa. Terminology of male genitalia is reviewed, diagnostic features are illustrated in detail, and notes on biology and geographical distribution of the examined species are provided. An identification key to the known adult males is presented. PMID- 27988721 TI - Cambarus (Depressicambarus) clairitae, a new species of crayfish (Decapoda: Cambaridae) from Alabama with a review of the halli Group in the subgenus Depressicambarus. AB - Cambarus (Depressicambarus) clairitae, new species, is an epigean crayfish from two drainages of the Locust Fork system in Blount and Jefferson counties, Alabama. It belongs to the halli Group in the subgenus Depressicambarus. The new species is morphologically most similar to Cambarus (Depressicambarus) englishi. They differ in a several morphological characters. Cambarus englishi has a more strongly recurved central projection, a wider areola, and a more distinct and set off rostral acumen than the new species. It also has light gray to white antennae while the antennae of the new species are brown. In addition to the description of the new species, the halli Group in Alabama is discussed. PMID- 27988722 TI - New species of Protosticta Selys from Vietnam with a key to the males of the P. curiosa group (Odonata: Platystictidae). AB - Three new species of Protosticta Selys, 1855, are described from Vietnam: P. proboscis spec. nov. and P. albifrons spec. nov., while P. satoi dark form is elevated to specific status as P. nigra spec. nov. based on structural and morphological differences. The female of P. linnaei is described for the first time and a key provided to the males of the P. curiosa group in Vietnam. PMID- 27988723 TI - The mutillid wasps of the Dasymutilla paradoxa species-group (Hymenoptera, Mutillidae). AB - The Dasymutilla paradoxa species-group is newly proposed to include taxa formerly included in the genera Dasymutilla Ashmead, 1899, Traumatomutilla Andre, 1901 and some previously incertae sedis. This species-group now includes the following eight species: D. fasciventris Mickel, D. guanacaste Manley & Pitts, D. naranjo Manley & Pitts, D. paradoxa (Gerstaecker), comb. nov., D. paraparadoxa, sp. nov., D. phya (Cameron), comb. nov., D. relata (Cameron), and D. sliepniri Manley & Pitts. Dasymutilla paraparadoxa Luz, Bartholomay & Williams, sp. nov. (Mexico, Guatemala) is described and illustrated. New synonymy is proposed (valid names are first) for: Dasymutilla fasciventris Mickel, 1938 (=Dasymutilla citromaculosa Manley & Pitts, 2007, syn. nov., =Dasymutilla chamela Manley & Pitts, 2007, syn. nov.); Mutilla paradoxa Gerstaecker, 1874 (=Sphaerophthamla [sic!] icaris Cameron, 1895, syn. nov.); Sphaerophthalma [sic!] phya Cameron, 1895 (=Sphaerophthalma [sic!] melissa Cameron, 1895, syn. nov.). The key to species is given. PMID- 27988724 TI - The inaequalis species-group (Hymenoptera, Chrysididae, Chrysis) in China, with description of a new species. AB - The Chinese Chrysis of the inaequalis species-group are revised and C. extraordinaria sp. nov. is described. Chrysis extraordinaria sp. nov. is recognisable by the following characteristics: mesopleuron tridentate, apex of T3 with six teeth, and T3 metallic blue, contrasting with T1 and T2 golden to metallic red. A modification to the species-group key by Kimsey & Bohart (1991) is proposed. PMID- 27988725 TI - The nymph, habitat, and status of Eatonigenia in China (Ephemeroptera: Ephemeridae). AB - The nymphs of a new species of Eatonigenia have more modified labrum and smaller foreclaws than congeners, and the males have a more reddish-brown colored body, cerci, genitalia and more sclerotized projections of gonopores. These characters indicate a new species which is named E. zhangi sp. nov. The nymphs live in fine sandy/muddy substrates of large rivers. PMID- 27988726 TI - New records and species of Crepidodera Chevrolat (Coleoptera: Chrysomelidae) in Eocene European amber, with a brief review of described fossil beetles from Bitterfeld amber. AB - Based on six relatively well-preserved specimens from Eocene Baltic amber, Crepidodera tertiotertiaria sp. nov. is described. The new species is illustrated and compared with morphologically similar extant and fossil relatives. It is the third described fossil species of Crepidodera Chevrolat. In addition to the new taxon, new fossil records of C. decolorata Nadein & Perkovsky from Baltic and Bitterfeld amber are presented. A key to species of Crepidodera described from fossil resins is provided, and a checklist of Coleoptera described from Bitterfeld amber is compiled. PMID- 27988727 TI - A review of the families and genera of the superfamily PLATYSCELOIDEA Bowman & Gruner, 1973 (Crustacea: Amphipoda: Hyperiidea), together with keys to the families, genera and species. AB - The systematics and phylogenetic relationships of the families and genera of the superfamily Platysceloidea are examined, following a thorough examination of the morphology of an example of the type species of each genus, or a substitute species if the true identity of the type species is in doubt. The mouthparts are described for each type species, often for the first time, providing additional characters for phylogenetic analysis. Genera are diagnosed using the taxonomic database program DELTA (Dalwitz et al. 1999). This database is also used for a phylogenetic analysis of the genera using PAUP (Swofford 2000). Proposed taxonomic changes resulting from this study are summarised as follows. The family Pronoidae is restricted to the monotypic genus Pronoe because it has some unique characters not found in any other platysceloidean. Paralycaea, previously in Pronoidae, has characters in common with Amphithyrus and Amphithyropsis gen. nov., a new genus proposed for Paralycaea platycephala Zeidler, 1998 (here re determined a junior synonym of Tetrathyrus pulchellus Barnard, 1930), and together they form the proposed new family Amphithyridae fam. nov. Eupronoe and Parapronoe, also previously in Pronoidae, are similar in the morphology of the mouthparts, antennae and gnathopoda, and together form the proposed new family Eupronoidae fam. nov. The family Brachyscelidae is restricted to the genus Brachyscelus because Thamneus, previously included in Brachyscelidae, has a number of characters that differ considerably from any other genus of Hyperiidea and it is therefore placed in a family of its own, Thamneidae fam. nov. The status of the family Anapronoidae, for Anapronoe, is confirmed, as is the status of the family Tryphanidae for Tryphana. The family Lycaeidae is limited to Lycaea and Simorhynchotus. The family Oxycephalidae maybe polyphyletic but more work is required to resolve the systematic status of the eight genera currently recognised. Metalycaea globosa Stephensen, 1925, sometimes included in the Oxycephalidae, is confirmed to be a junior synonym of Lycaea serrata Claus, 1879. The family Platyscelidae is restricted to four genera, Platyscelus, Paratyphis, Hemityphis and Tetrathyrus; Amphithyrus having been removed to the new family Amphithyridae. The family Parascelidae is also restricted to four genera, Parascelus, Thyropus, Schizoscelus and Euscelus. Hemiscelus, previously included in this family, is regarded a junior synonym of Hemityphis. Keys are provided for families, genera and all currently known species. All records of associations with gelatinous zooplankton are also documented, providing additional data to help resolve the phylogeny and evolutionary origins of the Hyperiidae. PMID- 27988728 TI - The genus Eustigmaeus Berlese (Acari: Stigmaeidae) from Greece. AB - The present study summarizes the previous limited knowledge on the genus Eustigmaeus from Greece. Based on material collected from many localities, nine species are recorded from Greece for the first time and four species, Eustigmaeus irregularis sp. nov., E. fantinoui sp. nov., E. microvacuolatus sp. nov., and E. capitatus sp. nov. are described as new to science. Additionally, males of five known species of Eustigmaeus are described for the first time. A list of the world species of the genus Eustigmaeus and a key to species of this genus recorded in Greece are provided. PMID- 27988729 TI - A preliminary assessment of the deep-sea Decapoda collected during the KARUBENTHOS 2015 Expedition to Guadeloupe Island. AB - A preliminary assessment of the deep-sea Decapoda is proposed for Guadeloupe Island based solely on high definition macro photographs taken during the KARUBENTHOS 2015 Expedition to the Island (R/V Antea, 7-29 June 2015). Overall, 190 species are recognized, several of which are depicted with their fresh color for the first time. Previous records in the Lesser Antilles are documented and the geographic distribution of the species in these Islands is given. The historical contribution of the steamer Blake (1878-1879) in the Lesser Antilles is emphasized. All species inventoried during KARUBENTHOS 2015 were already reported in the western Atlantic but 34 of them are new records for the Lesser Antilles and 116 are reported for the first time from Guadeloupe Island. This preliminary inventory is estimated to include about 38% of the deep-sea Decapoda potentially occurring around Guadeloupe Island. PMID- 27988730 TI - World review of the genus Strongylophthalmyia Heller (Diptera: Strongylophthalmyiidae). Part I: Introduction, morphology, species groups, and review of the Strongylophthalmyia punctata subgroup. AB - The Strongylophthalmyia punctata subgroup, comprising 24 species with armored fore femora, and restricted primarily to SE Asia, is reviewed. Eighteen new species, S. albisternum, n. sp. (Thailand), S. borneensis, n. sp. (Borneo), S. caestus, n. sp. (Philippines), S. darlingi, n. sp. (Sumatra), S. federeri, n. sp. (Philippines), S. hauseri, n. sp. (Thailand, Vietnam), S. indochinensis, n. sp. (Cambodia, Thailand, Vietnam), S. inundans, n. sp. (Philippines), S. laosensis, n. sp. (Laos), S. lowi, n. sp. (Peninsular Malaysia), S. malayensis, n. sp. (Peninsular Malaysia), S. nigripalpis, n. sp. (Peninsular Malaysia), S. oxybeles, n. sp. (Sumatra), S. pappi, n. sp. (Thailand), S. phillindablank, n. sp. (China), S. sichuanica, n. sp. (China), S. sumatrana, n. sp. (Sumatra), and S. thailandica, n. sp. (Thailand) are described and illustrated, S. microstyla Shatalkin and S. punctata Hennig are redescribed based on examination of the holotypes, and a key to species of the subgroup is presented. A general taxonomic overview of the genus Strongylophthalmyia is given with discussion of and keys to proposed species groups. PMID- 27988731 TI - The 'foremost ornithological mystery of Costa Rica': Amazilia alfaroana Underwood, 1896. AB - The hummingbird Amazilia alfaroana is known from a single specimen, collected on the Volcan de Miravalles, in north-west Costa Rica, in September 1895. Since the early 20th century, the taxon has been almost always been treated as a subspecies of Indigo-capped Hummingbird A. cyanifrons, which is otherwise endemic to Colombia, although it has also been tentatively suggested that the holotype might represent a hybrid between two unnamed species of trochilids. Our detailed analysis of the specimen reveals species-level differences between A. alfaroana and A. cyanifrons, and no evidence of characters that might suggest a hybrid between two species known to occur in the relevant region. Until molecular techniques have been brought to bear, we believe that A. alfaroana is best treated as a possibly now extinct species. PMID- 27988732 TI - Endemic earthworms (Oligochaeta: Lumbricidae) of the Balkan Peninsula: a review. AB - A list of the endemic earthworms of the Balkan Peninsula is presented. Comprehensive information on the ecology, distribution on the Balkan Peninsula and zoogeographical type of all endemics is given. The list comprises 90 species and subspecies, belonging to 11 genera of the family Lumbricidae. The largest number of the Balkan endemic earthworms belongs to a narrow range group (63.3%). Broad range endemic species take part with 36.7%. Our study shows that the degree of endemism on the Balkan Peninsula is extremely high (about 40%) suggesting an important process of autochthonous speciation on the Balkan Peninsula. This appearance is attributable to relative isolation of the mountains compared to the lowlands within the context of paleoenvironmental changes. PMID- 27988733 TI - New synonymies among species of Nitornus (Hemiptera: Heteroptera: Reduviidae). AB - Based on examination of types and additional specimens, the following new synonymies are proposed in the genus Nitornus Stal, 1859 (Hemiptera: Heteroptera: Reduviidae: Stenopodainae): Nitornus lobulatus Stal, 1859 = Nitornus monrosi (Wygodzinsky, 1959), syn. nov. = Nitornus barberi Froeschner, 1999, syn. nov.; and Nitornus parkoi (Costa Lima & Campos Seabra, 1945) = Nitornus seabrai (Prosen & Martinez, 1958), syn. nov. These synonymies result in Nitornus having only two valid species. Comments on morphological variations and the male genitalia of the species studied here are provided. PMID- 27988734 TI - A new subterranean Iberian Cephennium with unusually modified metatrochanters (Coleoptera, Staphylinidae, Scydmaeninae). AB - Cephennium (Geodytes) gladiator sp. n. is described from north-western Spain (Galicia). This is the first known species of Cephennium (and Cephenniini) with males showing monstrously modified metatrochanters in the form of blade-like projections as long as 3/4 of femora. Similar modifications in Scydmaeninae were known previously only among Oriental and South Pacific Glandulariini. Morphological structures of the new species and its placement in the subgenus Geodytes are discussed. PMID- 27988735 TI - A new species of Decomia Poppius from Laos and Thailand, with an annotated checklist and keys to genera and species of tribe Decomiini from Indochina (Hemiptera: Heteroptera: Miridae: Phylinae). AB - The Indochinese phyline plant bugs, belonging to the recently established tribe Decomiini Schuh & Menard, are reviewed. Fourteen species in four genera, Decomia Poppius, Decomioides Schuh, Malaysiamiris Schuh and Rubrocuneocoris Schuh, are now recognized from Indochina, including a remarkable new species, Decomia ishikawai Yasunaga, Duwal & Lee n. sp., herein diagnosed, described and discussed. The male of Decomia nigrissima Yasunaga, described only on the holotype female, is for the first time reported. An annotated checklist and a key to genera and species are provided to facilitate identification of the Indochinese taxa of the Decomiini. PMID- 27988736 TI - New species of the earthworm genus Zapatadrilus (Clitellata, Acanthodrilidae) from northern Mexico. AB - Three new species of the earthworm genus Zapatadrilus are described from Tamaulipas, Mexico: Zapatadrilus aurelius sp. nov., Zapatadrilus huastecus sp. nov., and Zapatadrilus montezumensis sp. nov. Delimitation of the new species was supported by morphological and molecular (genetic distances) evidence. Diagnostic characters of the three new species include: tubulo-racemose prostates in segments 18 and 20, penial setae absent, typhlosole present and intestine beginning in 17/18. Z. montezumensis sp. nov. is separated by its metandric condition, Z. aurelius sp. nov. by the last hearts in 13 and Z. huastecus sp. nov. by the shape of the spermathecae and patterns of genital markings. PMID- 27988737 TI - A new deepwater legskate, Sinobatis kotlyari n. sp. (Rajiformes, Anacanthobatidae) from the southeastern Indian Ocean on Broken Ridge. AB - Sinobatis kotlyari n. sp. is described, based on the nearly adult 331 mm TL holotype male from 1400 m depth in the southeastern Indian Ocean at Broken Ridge. The new species is assigned to Sinobatis due to mainly characters of its clasper and cranium fontanelle distinguishing it from congeners and other anacanthobatid skates with clasper features known. It further differs from its morphologically closest congener, S. borneensis, which is only known from the northwestern Pacific Ocean, e.g. in larger maturing size, longer snout and head, the absence of a snout filament and skin fold on tail, a longer caudal fin, and in colouration. The two congeners known from the eastern Indian Ocean, S. bulbicauda and S. cae-rulea, mature at much larger size, grow to larger maximum size and differ in numerous morphometric and meristic characters, as well as in colouration. The type locality appears to be very remote as compared with other Indian Ocean legskates, which have primarily been found on continental and insular slopes. PMID- 27988738 TI - Descriptions of three larvae of Osmylus species from Japan (Neuroptera: Osmylidae), with a proposed naming system for the larval sclerites. AB - The naming system of sclerites on osmylid larvae is proposed by observation of three Japanese osmylid species, Osmylus (Osmylus) hyalinatus McLachlan, 1875, O. (O.) pryeri McLachlan, 1875, and O. (Plesiosmylus) tessellatus McLachlan, 1875. The last instar larvae of the genus and species are described with biological notes and a key to the species. Osmylus kisoensis Iwata, 1928 is synonymized with O. (O.) pryeri McLachlan, 1875. PMID- 27988739 TI - The genus Neohydatothrips (Thysanoptera: Thripidae) in Iran with one new species and first record of a micropterous form. AB - Neohydatothrips amygdali sp. n. is described from southern Iran together with the first record of a micropterous form of Neohydatothrips abnormis (Karny). The new species is unusual among Sericothripinae in having only one pair of mid-dorsal setae on tergite IX. An illustrated identification key is provided to 5 species of Neohydatothrips namely, N. abnormis, N. amygdali, N. gracilicornis (Williams), N. gracilipes (Hood) and N. tadzhicus (Pelikan) from Iran. PMID- 27988740 TI - Redescription of four species of Cytaea Keyserling, 1882 (Araneae: Salticidae). AB - Four species of Cytaea Keyserling, 1882 are diagnosed, redescribed, and illustrated: C. laticeps (Thorell, 1878), C. nimbata (Thorell, 1881), C. rubra (Walckenaer, 1837), and C. sinuata (Doleschall, 1859). PMID- 27988741 TI - Description of a new species of Lutosa Walker, 1869 (Orthoptera: Anostostomatidae: Lutosinae) from the Brazilian Atlantic Forest, with biological and behavioral information. AB - Lutosa horribilis sp. nov., a new species of Anostostomatidae is described from a Brazilian Atlantic Forest environment. Notes on defensive behavior and diet are also provided. PMID- 27988742 TI - Review of Frigitilla Williams in Bartholomay et al., 2015, with description of a new species from Panama (Hymenoptera: Mutillidae). AB - Frigitilla panamensis Cambra, Brothers & Quintero sp. nov., from Panama, based on females, is described and illustrated. This new species represents the northernmost distribution record for the Neotropical genus Frigitilla Williams in Bartholomay et al., 2015. New synonymy and combination are proposed for Frigitilla simulatrix (F. Smith, 1879), comb. nov. =Mutilla frigidula Cresson, 1902, syn. nov. A lectotype is designated for Mutilla simulatrix F. Smith, 1879. The differentiating characters for the genus are briefly discussed. PMID- 27988743 TI - A description of two new species of the genus Erenna (Siphonophora: Physonectae: Erennidae), with notes on recently collected specimens of other Erenna species. AB - Two new Erenna species, E. insidiator sp. nov. and E. sirena sp. nov., are described from specimens collected in the vicinity of Monterey Bay, California, and also, for E. sirena at the southern end of the Gulf of California, Mexico. Further information on the three extant Erenna species is given, based on specimens collected in the same areas. These have enabled, for instance, the identification of three types of tentilla on the tentacles of E. cornuta Pugh, 2001, rather than the two noted on the single previously known specimen. The genus is remarkable for the presence of bioluminescent lures on the tentilla of all five species. In E. sirena sp. nov. the tentilla are also covered by a red fluorescent layer, which was briefly described by Haddock et al. (2005), and further details are given herein. Another extraordinary feature of the colonies E. sirena sp. nov. is that the main part of the tentacle, with its tentilla, can be extended away from the siphosomal stem on a long peduncle. This phenomenon also appears to occur in E. laciniata Pugh, 2001, and has not been observed before for other physonect species. PMID- 27988744 TI - Revision of the Australian species of Figulus MacLeay, 1819 (Coleoptera: Lucanidae). AB - The Australian species of the genus Figulus MacLeay, 1819 (Coleoptera: Lucanidae: Lucaninae: Figulini) are reviewed. Four new synonymies are established: F. howei De Lisle, 1967 and F. tambourinensis Mjoberg, 1916 are junior synonyms of F. nitens Waterhouse, 1874 (new synonymy); F. laevithorax Bomans is a junior synonym of F. regularis Westwood, 1834 (new synonymy); F. mento Albers, 1883 and F. mento foveatus Kriesche, 1922 are junior synonyms of F. sulcicollis Hope in Westwood, 1845 (new synonymy). The number of Figulus species known from Australia thus decreases to seven, four of which are endemic to Australia and one to Christmas Island. Lectotypes are designated for F. australicus Thomson, 1862, F. clivinoides Thomson, 1862, F. nitens Waterhouse, 1874, F. rossi Gahan, 1900, and F. tambourinensis Mjoberg, 1916. All the seven valid species are redescribed and a key is given for their identification. Photographs of the habitus, the mentum and illustrations of the aedeagus for all the taxa are also included. New unpublished data on the host plants and habitats for some of the Australian species are included. PMID- 27988745 TI - Eight new species of Andrena Fabricius (Hymenoptera: Apoidea: Andrenidae) from Israel-a Mediterranean hotspot for wild bees. AB - More than 150 solitary bee species of the genus Andrena Fabricius are known from Israel and the West Bank, where they are distributed along a broad climatic gradient and diverse habitats and vegetation types. Extensive collecting throughout Israel in recent years has yielded eight new species and one new subspecies, adding to the rich bee fauna of the region: A. crocusella Pisanty & Scheuchl n. sp., A. danini Pisanty & Scheuchl n. sp., A. hermonella Scheuchl & Pisanty n. sp., A. israelica Scheuchl & Pisanty n. sp., A. judaea Scheuchl & Pisanty n. sp., A. menahemella Scheuchl & Pisanty n. sp., A. palaestina Pisanty & Scheuchl n. sp., A. perahia Pisanty & Scheuchl n. sp., and A. sphecodimorpha mediterranea Pisanty & Scheuchl n. ssp. The previously unknown female of A. fimbriatoides Scheuchl 2004 and male of A. wolfi Gusenleitner & Scheuchl 2000 are also described here for the first time. The discovery of males of A. wolfi lead us to reinstate A. iohannescaroli Nobile 2000 as a valid taxon. Detailed morphological description and differential diagnosis against closest relatives are provided for all species, as well as information on the distribution, phenology and flower visitation, when available. A neotype is designated for A. sphecodimorpha Hedicke, the holotype of which is considered to be lost. Additional collecting efforts in diverse habitats and seasons, incorporating diverse collecting techniques, are required in order to deepen our knowledge of the rich bee fauna in threatened habitats in the Mediterranean Basin, which constitutes one of the world's major hotspots for wild bees. PMID- 27988746 TI - A historical review of the classification of Erebinae (Lepidoptera: Erebidae). AB - Erebidae is one of the most diverse families within the order Lepidoptera (butterflies and moths), with nearly 25,000 described species. The nominal subfamily Erebinae is among the most species rich and taxonomically complex. It reaches its highest diversity in the tropics, where much of the fauna remains undescribed. Species in this subfamily feed on a broad range of host plants, with associated radiations on grasses and legumes, and some species are pests of agriculture and forestry. The Erebinae, as defined today, comprises a large portion of the former noctuid subfamily Catocalinae. However, many lineages have tenuous or uncertain systematic placement. Here, we review the complex historical classification of Erebinae, and discuss the possible placement of some of these lineages in light of traditional morphological groupings and recent molecular phylogenetic analyses. We present an updated list of named erebine tribes and their relationships, and identify morphological traits from literature used to group genera within these tribes. PMID- 27988747 TI - Two new Cambodian semi-aquatic earthworms in the genus Glyphidrilus Horst, 1889 (Oligochaeta, Almidae), based on morphological and molecular data. AB - Combining morphological and molecular data is a powerful approach to support the discovery of new species. Here, two new species of the semi-aquatic earthworm genus Glyphidrilus, G. jamiesoni sp. n. and G. kralanhensis sp. n., are described from the Mekong Basin in Cambodia. They are morphologically distinguished by the respective locations of wings and spermathecae; furthermore, G. kralanhensis sp. n. has three pairs of ovaries, probably an autapomorphic trait. In addition, two mitochondrial gene fragments (COI and 16s rRNA) were sequenced of types of the new species and of five further Glyphidrilus species described recently from the Mekong basin in Thailand and Laos. They revealed a high level of genetic divergence of the new species compared to the other earthworm taxa. The evolutionary relationships among the Mekong Glyphidrilus members is discussed with reference to the recent paleogeography of the Mekong River drainage. PMID- 27988748 TI - A taxonomic revision of the kalshoveni species-group of the genus Nemophora Hoffmannsegg (Lepidoptera, Adelidae), with descriptions of six new species from Indonesia and Papua New Guinea. AB - A monophyletic group of seven externally similar, grey to light brown species of the genus Nemophora Hoffmannsegg from the islands of Indonesia and Papua New Guinea, recognised as the new kalshoveni species-group, is revised. All species of this group possess an oblique light stripe, which arises from the costal margin of the forewing at 0.7-0.8 of its length towards the middle of an external wing margin. The proboscis of these species is unusually thick due to a dense cover of raised dark brown and black scales. A key to the species based on external characters and on male genitalia is provided; new species are described from the Sangir (N. humerella sp. nov.) and New Guinea (N. agassizi sp. nov., N. bistrigata sp. nov., N. dohertyi sp. nov., N. toxopeusi sp. nov. and N. stenopterella sp. nov.). PMID- 27988749 TI - Review of the Ulopella leafhopper genus group (Auchenorrhyncha, Cicadellidae, Ulopinae) with description of a new genus and species collected from pitfall traps in Zambia. AB - A new ulopine leafhopper genus and species, Kafulopa bicolor gen. nov., sp. n. from Zambia, is described and illustrated and placed in the Ulopella genus group (Ulopini). A checklist and key to the genera of the group are provided together with images of representatives of each genus. Most species of the group are flightless with elytra-like forewings and some, including the new species described here, were collected from baited pitfall traps, suggesting at least a partial association with the soil surface. Aethiopulopa hovana (Lallemand) is re examined and transferred from the Ulopella group to the Ulopa group (Ulopini), genus Kivulopa comb. nov. and figures of its external features and male genitalia are provided for the first time. PMID- 27988750 TI - Two new species of Halictophagidae (Insecta: Strepsiptera) including the first record of genus Coriophagus Kinzelbach from India. AB - Coriophagus calcaneus n. sp. (Coriophaginae) and Halictophagus prominens n. sp. (Halictophaginae) are described from India. Coriophagus calcaneus is the first record of the genus Coriophagus Kinzelbach from India. The genus Coriophagus is restricted in the Gondwanaland, while Halictophagus Curtis has a cosmopolitan distribution. PMID- 27988751 TI - The larva of Lepidostoma doehleri Malicky 1976 (Trichoptera: Lepidostomatidae) with notes on ecology and a key to larvae for species of the genus in Greece. AB - The hitherto unknown larva of Lepidostoma doehleri Malicky 1976 is described. The diagnostic features of the species are listed and illustrated, and some information on its ecology is included. In addition, diagnostic characters for the larvae of the known Lepidostoma species occurring in Greece are provided. PMID- 27988752 TI - A replacement name for Flavala Behounek, Han & Kononenko, 2012 (Lepidoptera: Noctuidae: Pantheinae). AB - The genus name Flavala Behounek, Han & Kononenko, 2012 (homonym nov.) must be replaced by Mooreia nomen nov. because Flavala is preoccupied by Flavala Berio, 1966, the junior synonym of Thioptera Franclemont, 1950, the Nearctic Eustrotiinae genus (Lepidoptera, Noctuidae, Eustrortiinae). The name Mooreia is dedicated to Frederic Moore, the famous British lepidopterologist of the nineteenth century, the explorer of the Oriental fauna, described many Lepidoptera taxa including Acronycta flavala Moore, 1867. PMID- 27988753 TI - The first described male Tube-web Spider for mainland Australia: Ariadna kiwirrkurra sp. nov. (Araneae: Segestriidae). AB - Males of Ariadna kiwirrkurra sp. nov., collected on the 2015 Bush Blitz biodiscovery expedition to the Kiwirrkurra Indigenous Protected Area (IPA) are the first Segestriid males described for mainland Australia. PMID- 27988754 TI - ZHEN LIU, JUN-HUA HE & XUE-XIN CHEN (2016) The genus Pholetesor Mason, 1981 (Hymenoptera, Braconidae, Microgastrinae) from China, with descriptions of eleven new species. Zootaxa, 4150 (4): 351-387. PMID- 27988755 TI - Orthoptera (Insecta: Tettigonioidea, Pyrgomorphoidea, Acridoidea) of Kafa Biosphere Reserve, Bale Mountains National Park and other areas of conservation interest in Ethiopia. AB - An annotated checklist of 51 Orthoptera taxa (Tettigonioidea, Pyrgomorphoidea and Acridoidea) of Kafa Biosphere Reserve, Bale Mountains National Park and some additional sites in Ethiopia is presented. Ten species are newly recorded for the country. Four species are new to science: Peropyrrhicia attilioi n. sp., P. keffensis n. sp., P. semiensis n. sp. and Coryphosima danieli n. sp. The status of Peropyrrhicia cooperi Uvarov, 1934 and P. scotti Uvarov, 1934 is revised: both are considered valid species. PMID- 27988756 TI - The Goblin spider genus Xestaspis in Sri Lanka (Araneae: Oonopidae). AB - Three new species of the genus Xestaspis Simon, 1884: X. nuwaraeliya sp. nov., X. padaviya sp. nov. and X. pophami sp. nov. are described based on both sexes. Xestaspis kandy Eichenberger, 2012 is illustrated based on new material. A key and a distribution map for Sri Lankan Xestaspis is provided. Phylogenetic placement of Sri Lankan Xestaspis spp. obtained by the analysis of 43 morphological characters is presented and discussed. In all our analysis Gamasomorpha species appear paraphyletic suggesting that Xestaspis is most probably a junior synonym of Gamasomorpha. Thus, forming monophyletic group of oriental hard bodied oonopids. PMID- 27988757 TI - Two new species of the genus Xenotoca Hubbs and Turner, 1939 (Teleostei, Goodeidae) from central-western Mexico. AB - The subfamily Goodeinae (Goodeidae) is one of the most representative and well studied group of fishes from central Mexico, with around 18 genera and 40 species. Recent phylogenetic studies have documented a high degree of genetic diversity and divergences among populations, suggesting that the diversity of the group may be underestimated. The species Xenotoca eiseni has had several taxonomic changes since its description. Xenotoca eiseni is considered a widespread species along the Central Pacific Coastal drainages of Mexico, inhabiting six independent drainages. Recent molecular phylogenetic studies suggest that X. eiseni is a species complex, represented by at least three independent evolutionary lineages. We carried out a meristic and morphometric study in order to evaluate the morphological differences among these genetically divergent populations and describe two new species. The new species of goodeines, Xenotoca doadrioi and X. lyonsi, are described from the Etzatlan endorheic drainage and upper Coahuayana basin respectively. PMID- 27988758 TI - An update on the genus Longidorus, Paralongidorus and Xiphinema (Family Longidoridae) in Portugal. AB - The tribe Longidorini within the subfamily Longidorinae (Longidorus spp. and Paralongidorus spp.) and the subfamily Xiphineminae (Xiphinema spp.) are two large nematode groups with about 260 and 230 known species, respectively. They are globally two important groups of ectoparasitic nematodes considered to be major pests because of their activity as vectors of important plant nepovirus, with some species included in the list of quarantine pathogenic organisms in many European countries. Knowledge of the biodiversity and occurrence of this nematode group is a prerequisite for the establishment of sound management strategies and control measures. According to data collected from the databases (such as EPPO, FSTA, and Web of Science) and published in specialised literature, a total of 15 Longidorus, 1 Paralongidorus and 40 Xiphinema species have been recorded as present in Portugal. However, the taxonomic status of some species is controversial, and thus needs to be clarified. A comprehensive review for unravelling the biodiversity and occurrence of nematode species of the genus Longidorus, Paralongidorus and Xiphinema in Portugal is herein provided. This review includes an updated checklist of species with information on the localities, host plants and geographical distribution. Additionally, maps on the species distributions of Longidorinae and Xiphineminae nematodes present in Continental Portugal and the Portuguese Macaronesian islands are provided, as well as unpublished data on authors and comments on the current taxonomic status. Finally, new insights and directions for future research on Longidoridae in Portugal are presented. PMID- 27988759 TI - Three new and a known species of the genus Proleptonchus Lordello, 1955 (Nematoda: Leptonchidae) with a diagnostic compendium of the genus. AB - This paper deals with the description of three new and one known species of the genus Proleptonchus Lordello, 1955. Proleptonchus kazirangus n. sp. from Kaziranga National Park, India is characterized by having 1.08-1.45 mm long body; cap-like, offset, lip region; 7-8 um long odontostyle and 10-12 um long odontophore; short, pear-shaped pharyngeal bulb offset by a constriction, occupying about 18-21% of total neck length; female genital system mono prodelphic; pars dilatata uteri with distinctly sclerotized central lumen containing refringent apophyses; posterior uterine sac 78-112 um long, with sac like structure representing a rudimentary oviduct; transverse vulva, short, rounded-conoid tail and males with 31-33 um long spicules, lateral guiding pieces and seven, regularly spaced ventromedian supplements. P. prerectus n. sp. from Japan is characterized by having 1.18-1.43 mm long body; lip region cap-like, offset by a slight constriction; odontostyle 8 um, odontophore 9-10 um; short cylindroid basal bulb offset by a constriction, occupying about 16-20% of total neck length; female genital system mono-prodelphic; pars dilatata uteri with sclerotized refringent apophyses; posterior uterine sac small, 27-36 um; transverse vulva; a prerectal chamber and short, rounded-hemispheroid tail. P. japonicus n. sp. also from Japan is characterized by having 0.91-1.04 mm long body; lip region cap-like, set off by a slight constriction; odontostyle 5 um and odontophore 10-11 um long; pharynx consists of a very slender, non-muscular anterior part, separated from pyriform basal bulb by a constriction, with thickened lumen in posterior region, occupying about 18-20% of total neck length; female genital system mono-prodelphic; posterior uterine sac small, 20-24 um long; transverse vulva and short, rounded-conoid tail. P. shamimi Bajaj & Bhatti, 1980 is redescribed and its relationship with closely related species is discussed. A diagnostic compendium of all the valid species of Proleptonchus is also provided. PMID- 27988760 TI - New species, new records, and new collection data of Rhyacophila from China (Trichoptera: Rhyacophilidae). AB - Four new species of Rhyacophila, R. acanthoida n. sp., R. tongmuensis n. sp., R. shiliae n. sp., and R. bisbifida n. sp., are diagnosed, described, and illustrated. Two species, R. inaequalis Denning & Schmid and R. manicata Kimmins are found to be new records for China. Remarks on six Species Groups, to which the four new species and two newly recorded species belong, are presented. New collection data are added for R. bidens Kimmins, R. claviforma Sun & Yang, R. haplostephana Sun & Yang, R. quadrifida Sun & Yang, and R. tetracantha Sun & Yang. PMID- 27988761 TI - Four new species of Chinaia Bruner & Metcalf (Hemiptera: Cicadellidae: Neocoelidiinae) from the Neotropical Region. AB - Four new species of Chinaia Bruner & Metcalf, Chinaia bicornis sp. nov., Chinaia longicauda sp. nov., Chinaia modesta sp. nov., and Chinaia peruviana sp. nov. are described and illustrated. The new species can be distinguished from the other species of the genus by characters of the male genitalia, especially the morphology of the pygofer and aedeagus. A generic diagnosis and a complete description, together with illustrations and pictures of the new species, are provided. PMID- 27988762 TI - A new genus and a new species in the sea cucumber subfamily Colochirinae (Echinodermata: Holothuroidea: Dendrochirotida: Cucumariidae) in the Mediterranean Sea. AB - A new genus Hemiocnus is here erected to accommodate the Mediterranean dendrochirotid sea cucumber Cladodactyla syracusana Grube, currently classified, with some doubt, in the cucumariid genus Pseudocnella. At the same time a new cucumariid species, Hemiocnus rubrobrunneus, is described from some Tunisian material, misidentified as Pseudocnella syracusana (Grube), received from the United States National Museum. The new genus appears most closely related to Pseudocnella than to any other genus within the Colochirinae. Although its body wall ossicles resemble those of Pseudocnella spp. it differs in that the two ventral-most tentacles are reduced and in the presence of rosettes in the tentacles. P. syracusana also cannot be classified in Ocnus because of the presence of multi-layered, fir-cone shaped plates in the body wall, often with one end denticulate; such ossicles are lacking in the type species of the latter genus. The new species, Hemiocnus rubrobrunneus, on the other hand, shows some resemblance to H. syracusanus in its characteristic buttons and incomplete baskets, differing in its softer body wall, lack of fir-cone-shaped plates and in the presence of rosettes and complete baskets in the body wall. There are also some resemblances of the new species to the Mediterranean species of Ocnus viz. O. brunneus, O. planci and O. lacteus, but the soft nature of the body wall, shallow quadrilocular instead of deep trilocular baskets, and the presence of large knobbed plates in the anal region precludes its inclusion in this genus. PMID- 27988763 TI - A new Aceria species (Acari: Prostigmata: Eriophyoidea) from Minuartia frutescens (Caryophyllaceae) in Hungary. AB - A new species of eriophyoid mite, Aceria wassalberti n. sp. associated with Minuartia frutescens (Caryophyllaceae), is described and illustrated from Hungary. A key to the Aceria species known on Caryophyllaceae is given. Remarks are provided on the eriophyoid mites currently known from caryophyllaceous host plants. PMID- 27988764 TI - Description of a new Tiporus Watts, 1985 from northern Queensland, Australia (Coleoptera: Dytiscidae, Hydroporinae). AB - Tiporus queenslandicus sp. n. is described from NE Queensland. The new species is similar to T. undecimmaculatus (Clark, 1862) and T. giuliani (Watts, 1978) from the Northern Territory and north-western Australia but well characterized by its larger size, more elongate habitus, and form of median lobe and parameres. Tiporus queenslandicus sp. n. is a lotic species being collected from rest pools of intermittent creeks and rivers with a sandy bottom. Important species-defining characters (habitus, median lobe, paramere, protibia of male) are illustrated. Together with T. queenslandicus sp. n. the genus comprises now 13 species. PMID- 27988765 TI - The Pselaphinae (Coleoptera: Staphylinidae) of Madagascar. VI. Description of Ambohitantella banari gen. et sp. n. with notes on Nearticerodes Jeannel, 1954 and Triceratomerus Jeannel, 1960. AB - A new genus and a new species, Ambohitantella banari gen. et sp. n., from Madagascar (Ambohitantely Special Reserve) is described. The diagnosis is given for related genera Triceratomerus Jeannel, 1960 and Nearticerodes Jeannel, 1954. The lectotype is designated for Triceratomerus sparsepunctatus Jeannel, 1960. An identification key to genera of malagasy Clavigerodina with 3-segmeneted antennae is provided. PMID- 27988766 TI - First record of Isegama Krombein (Hymenoptera, Chrysididae, Amiseginae) from China, with description of a new species. AB - The genus Isegama Krombein is recorded from China for the first time and one new species, Isegama sinica Li & Xu, sp. nov. (China: Guangxi, Hainan, Yunnan) is described and illustrated. Key to species of the genus is provided. PMID- 27988767 TI - A new species of Cactopinus Schwarz from central Mexico (Coleoptera: Curculionidae: Scolytinae). AB - A new species in the genus Cactopinus Schwarz is described from central Mexico bringing the total of known species to 22. PMID- 27988768 TI - The Glyptothorax of Sundaland: a revisionary study (Teleostei: Sisoridae). AB - The species of Glyptothorax of Sundaic Southeast Asia (Malay Peninsula, Sumatra, Borneo and Java) are revised in this study. A total of 17 species are recognized, of which six (G. amnestus, G. decussatus, G. famelicus, G. keluk, G. pictus and G. stibaros) are described as new here. A lectotype is designated for G. platypogon. The Sundaic Glyptothorax species are diagnosed by combinations of color pattern, morphometry (with particular regard to the eye, head, body depth, and caudal peduncle), dorsal-spine and thoracic adhesive apparatus morphology. PMID- 27988769 TI - Hidden diversity in deep-water bandfishes: review of Owstonia with descriptions of twenty-one new species (Teleostei: Cepolidae: Owstoniinae). AB - The bandfish family Cepolidae, comprising the subfamilies Owstoniinae and Cepolinae, is characterized, and defining characters of the three groups are identified and discussed. Characters of larvae of both subfamilies are described and illustrated. Six nominal genera of owstoniines had been proposed by various authors, but we recognize only Owstonia Tanaka. Utility of selected identification characters of the genus are discussed. Differences in lateral-line patterns have been the primary character used by some recent authors for recognition of two owstoniine genera, with Sphenanthias Weber possessing the plesiomorphic lateral-line condition. Several other patterns also occur in these fishes bringing into question the phylogenetic significance of lateral line plasticity. Sexual dimorphism in pelvic fin lengths is also present in several species. Identification keys, descriptions, synonymies, distribution maps and photographs or illustrations are provided for all Owstonia species for which adults are available. Although only 15 valid species were previously known, a remarkable hidden diversity of these fishes was discovered in major museum collections with the following 21 species here described as new: O. ainonaka (eastern Australia), O. contodon (Philippines), O. crassa (New Caledonia and Solomon Islands), O. dispar (Solomon Islands), O. elongata (New Caledonia and Vanuatu), O. fallax (eastern Australia and New Caledonia), O. geminata (Vanuatu and Philippines), O. hastata (eastern Australia), O. hawaiiensis (Hawaiian Islands); O. ignota (Mariana Islands), O. lepiota (Tanzania), O. melanoptera (Philippines), O. merensis (eastern Australia, Torres Strait), O. mundyi (Kiribati, Christmas Island), O. nalani (eastern Australia and New Caledonia), O. nudibucca (eastern Indian Ocean, Mentawai Islands and off Myanmar), O. psilos (Western Australia), O. raredonae (Mozambique), O. rhamma (Vanuatu), O. scottensis (Western Australia, Scott Reefs) and O. similis (Madagascar). Several specimens based on small juveniles, which we describe as Owstonia sp., appear to be additional new species but are not formally described as such. PMID- 27988770 TI - Bathyal Mollusca from the cold-water coral biotope of Santa Maria di Leuca (Apulian margin, southern Italy). AB - This paper describes 97 molluskan species (45 Bivalvia, 3 Scaphopoda, 49 Gastropoda) recovered from bathyal bottoms off Santa Maria di Leuca (Puglia, Italy), in the northern Ionian Sea, and provides data about their taxonomy, geographical distribution, habitat, ecological requirements and fossil record. Only 6 species remain unidentified, and all are illustrated. The bivalve dominated assemblages belong to the so-called "cold-water coral ecosystem". They appear to depend mainly on substrate characteristics, with faunas related to hard substrate around coral-colonized mound tops, and mud-related ones in inter-mound areas, respectively. Nuculanoida and Pectinoidea among bivalves, and Conoidea and Pyramidelloidea among gastropods are the most diverse suprafamilial groups. The present paper is the first comprehensive taxonomic overview of Mediterranean bathyal mollusks including larval shell characters. PMID- 27988771 TI - Guide to the Parasites of Fishes of Canada Part V: Nematoda. AB - Keys are provided for the identification of the nematode species known to be parasites of Canadian fishes. The nematodes are described and illustrated, with a note of the site(s) they occupy in named fish host(s) and their geographical distribution. Parasite records are given by author and date, full details of which can be found in a bibliography of over 800 references. Diagnoses and keys for 22 Families, 47 genera and 88 species of nematodes are also given, together with a glossary of terms, a host-parasite list, and indices to both nematode parasites and hosts. PMID- 27988772 TI - New records of sabellids and serpulids (Polychaeta: Sabellidae, Serpulidae) from the Tropical Eastern Pacific. AB - Sabellids and serpulids are two well represented families in the polychaete fauna of the Tropical Eastern Pacific, with 31 and 34 species respectively; however, most records come from the Gulf of California or the western coast of Baja California Peninsula. Only a few records are from localities in the large expanse of the central and southern Mexican Pacific. Thus, sabellids and serpulids were collected from several shallow water habitats along the coast of Mexican Pacific, such as coastal lagoons, coral reefs, rocky shores and from man-made structures as marinas, piers and ships of several harbors; additionally, specimens from national collections were revised. More than 8,400 specimens of sabellids and serpulids from the states of Baja California, Baja California Sur, Sonora, Sinaloa, Michoacan, Guerrero, Oaxaca and Chiapas, and some specimens from Panama and Peru were examined. In the present work we record new localities of four sabellids and 24 serpulids. One sabellid, Branchiomma bairdi, is an exotic/invasive species in Oaxaca, Sinaloa and Baja California Sur, while four species of serpulids are exotic and/or cryptogenic species: Ficopomatus uschakovi, Hydroides dirampha, H. elegans and H. sanctaecrucis. Additionally, the geographical range has been extended for five species: the sabellids Pseudobranchiomma punctata from Oahu, Hawaii to La Paz Bay, and Parasabella pallida from California to Puerto Escondido, Baja California Sur; and for three serpulids, Hydroides inermis from the Galapagos Islands to Agua Blanca, Oaxaca, H. gairacensis from Panama to Puerto Angel, Oaxaca, and H. panamensis from Panama to Huatulco, Oaxaca and Faro de Bucerias, Michoacan. Hydroides cf. amri, previously recorded as H. brachyacantha from Oahu, Hawaii, is more similar to H. amri from Australia. The number of sabellids recorded for the Tropical Eastern Pacific increased to 33, the serpulid species to 35. PMID- 27988773 TI - A new species of eriophyoid mite (Acari: Trombidiformes: Eriophyoidea) on Chaenomeles x superba (Frahm) Rehder (Rosaceae). AB - A new species, Epitrimerus chaenomeli n. sp., is described and illustrated in this paper. The description is based on the morphology of protogynes, deutogynes and nymphs. This new species was recorded on Chaenomeles x superba (Frahm) Rehder and its cultivar Crimson and Gold (Rosaceae) which have not previously been noted as a host for eriophyoid mites. Mites of this species caused slight rusting on the under-surfaces of infested leaf blades. In addition, a list of all known species of Epitrimerus found on Rosaceae is also provided. PMID- 27988774 TI - Halosaur fishes (Notacanthiformes: Halosauridae) from Atlantic Spanish waters according to integrative taxonomy. AB - From 2009 to 2011 thirty-five specimens belonging to six halosaurid species of the family Halosauridae were captured in two different locations in the northern waters of Spain. The specimens were identified as belonging to the genera Halosauropsis Collett, 1896, Halosaurus Johnson, 1864 and Aldrovandia Goode & Bean, 1896, including the following species: Halosauropsis macrochir (Gunther, 1878), Halosaurus ovenii Johnson, 1864, Halosaurus johnsonianus Vaillant, 1888, Aldrovandia affinis (Gunther, 1877), Aldrovandia phalacra (Vaillant, 1888) and Aldrovandia oleosa Sulak, 1977. The morphometric measurements and meristic characters of these specimens are given. As a result, a new northern limit of distribution of A. oleosa from the northeastern Atlantic is reported. Using a taxonomical integrative approach, the mitochondrial DNA COI gene sequences from all individuals where determined and their comparison with morphological characters showed no incongruities. Among these specimens, the highest genetic distance within species was 0.8% while the lowest value between species was 3.3%. This ample barcoding gap has allowed the delimitation and assignment of all species reported in a way that matches the traditional taxonomical methods previously employed. PMID- 27988775 TI - A new widespread European bee species of the genus Dasypoda Latreille (Hymenoptera, Apoidea). AB - A new bee species of the genus Dasypoda Latreille (Hymenoptera, Apoidea, Melittidae), D. morawitzi Radchenko sp. nov., is described. This species is closely related to, and easily confusable with, D. hirtipes (Fabricius), and its specimens have been previously attributed to the latter species. A comparative morphological analysis of D. morawitzi with other species of the D. hirtipes group is provided. The distribution and trophic links of this new species are discussed. PMID- 27988776 TI - Alloionema californicum n. sp. (Nematoda: Alloionematidae): a new alloionematid from USA. AB - A new species of the family Alloionematidae was isolated from a rotten winged gourd at White Crane Garden, San Francisco, USA, sampled by Christopher Nelson in November 2010, and a live culture is deposited in Felix Lab Strain Database (http://www.justbio.com/worms/index.php), IBENS, Paris, France. Specimens from the culture have been examined. Both morphologically and molecularly, the nematode described herein as Alloionema californicum n. sp. differs from the other alloionematid species, A. appendiculatum and Neoalloionema tricaudatum. It is characterised by having a narrow stoma, 2.5-3.5 or 4 times longer than broad in adults or dauer juveniles respectively. Lateral fields are not present in adults but occur as one prominent ridge in dauers. Males have no bursa, six pairs of genital papillae and one single papilla. Dauers have large apparent phasmids in the middle of the tail. The ecology of the newly described species is unknown but probably it is a saprobic bacteriophagous nematode preferring rotting organic material. PMID- 27988777 TI - Morphological differences between Stenocionops furcatus (Olivier, 1791) and S. coelatus (A. Milne-Edwards, 1878) (Crustacea, Decapoda, Brachyura, Majoidea). AB - Stenocionops furcatus (Olivier, 1791) and S. coelatus (A. Milne-Edwards, 1878) have been treated either as subspecies or as species in their own right, but never as each other's synonyms. Compared to S. coelatus, S. furcatus has been regarded as having smoother dorsal surface carapace, shorter rostral spines, straighter and less divergent rostrum. and smaller interorbital width. These morphological differences between the two species, however, can be attributed to changes over ontogeny and, therefore, cannot be used as distinguishing characters. Adults of S. coelatus and S. furcatus can, however, be safely separated from each other by the presence in S. coelatus of a strong crenation on the anterior margin of the male sterno-abdominal cavity, which is absent in S. furcatus. A lectotype for S. coelatus is designated. The synonymy between S. furcatus, Cancer cornudo Herbst, 1804, and Chorinus armatus Randall, 1839, is confirmed based on the holotypes of the latter two species. PMID- 27988778 TI - Three new species and one new record of the leafhopper genus Agnesiella Dworakowska, 1970 (Hemiptera: Cicadellidae: Typhlocybinae: Typhlocybini) from China. AB - Three new species and one species newly recorded from China in the genus Agnesiella Dworakowska, 1970 are described and illustrated: A. (Draberiella) xantha sp. nov., A. (Draberiella) erosa sp. nov. and A. (Draberiella) latusa sp. nov., A. (Draberiella) azra Dworakowska, 1994 new record. A key to known Chinese species is given. The type specimens of the new species are deposited in the Institute of Entomology, Guizhou University, Guiyang, China (GUGC). PMID- 27988779 TI - Species of the Poaceae-associated genus Bamboosiella (Thysanoptera, Phlaeothripidae) from China, with three new species. AB - In the Poaceae-associated genus Bamboosiella Ananthakrishnan, eleven species are here recognized from China, including antennatus sp.n. and longisetis sp.n. from Yunnan, and magnus sp.n. from Hainan. Four species are newly recorded from China, bicoloripes Ananthakrishnan, fasciata Okajima, flavescens Okajima and semiflava Okajima. One species from Zhejiang, Bamboosiella brevibristla Sha, Guo, Feng & Duan is placed as a new synonym of B. exastis (Ananthakrishnan & Kudo). An illustrated identification key is provided to the eleven Bamboosiella species now recognised from China. PMID- 27988780 TI - A new species of Polyplocia Lestage from Malaysia with comments on the genus (Ephemeroptera, Euthyplociidae, Euthyplociinae). AB - Polyplocia nebulosa sp. nov. is described based on male and female imagos from Malaysia, Sabah State. Nymphs provisionally assigned to this species are also described. This species can be readily separated from P. vitalisi by the color pattern of the wings, with light brown longitudinal veins, narrow dark brown clouds on cross veins and margins of wings tinged with brown. The male genitalia are distinct from those of other species of Polyplocia: penes are broad, T shaped, with large lateral projecting lobes, which are apically rounded, and with a small dorsolateral spine on each lobe; the styliger plate is short and not projected posteriorly. Eggs of the genus are described for the first time using scanning electron microscopy. Eggs are 265-267 um in length, 170-186 um in width, barrel-shaped, without polar caps or other attachment structures, with one visible micropyle and with chorion forming an irregular mesh with raised ridges (mesh between 3.8-8 um). A key to male adults of Polyplocia is provided and additional records of Polyplocia from Thailand are given. PMID- 27988781 TI - Five new species of the Clubiona corticalis species group (Araneae, Clubionidae) from China. AB - Five new species of the genus Clubiona collected in Mt. Gaoligong, Yunnan Province, China are described: C. biforamina n. sp., C. dactylina n. sp., C. falciforma n. sp., C. multidentata n. sp. and C. tangi n. sp., all belonging to the corticalis species group and known from both males and females. PMID- 27988782 TI - New data on brachypterous Paederus (Coleoptera, Staphylinidae) of mainland China. AB - Material of the brachypterous Paederus of the Chinese provinces Henan, Anhui, Zhejiang, Hunan, Fujian, Guizhou, Sichuan, Shaanxi, Yunnan, Guangdong and Guangxi was examined. In total, twelve species are recognized, among which two are described here as new: P. daicongchaoi sp. n. (Anhui: Yaolouping) and P. nanlingensis sp. n. (Guangdong: Nanling). One species probably undescribed remains unnamed and one synonymy is proposed: Paederus (Gnathopaederus) bursavacua Willers, 2001 = Paederus (Gnathopaederus) daozhenensis Li & Zhou, 2009, nov. syn. A key to the brachypterous Paederus species of mainland China is provided. PMID- 27988783 TI - Cave species of the genus Anurida (Collembola: Neanuridae) from Korea, with the description of new species. AB - Three troglobiontic species of Anurida Laboulbene, i.e. A. troglodyta sp. nov., A. decipiens Yosii, 1966, and A. plurichaetotica Yosii, 1966, were found in limestone caves of Korea during recent investigation. The new species, A. troglodyta sp. nov., is characterized by morel-like PAO having more than 100 vesicles and by having 16-17 sensilla on antennal segment IV. It is most similar to A. plurichaetotica, A. okamotoi Yosii, 1970, and A. irieti Yosii, 1970 also possessing several macrochaetae on dorsal side of a head, but can easily be distinguished by characteristic PAO and the absence of macrochaetae in p1 position on abdominal tergum V. A. decipiens is redescribed based on new material from the cave of the types' origin. PMID- 27988784 TI - Erratum: MANON FOURRIERE, HECTOR REYES-BONILLA, ARTURO AYALA-BOCOS, JAMES KETCHUM & JUAN CARLOS CHAVEZ-COMPARAN (2016) Checklist and analysis of completeness of the reef fish fauna of the Revillagigedo Archipelago, Mexico. Zootaxa, 4150 (4): 436-466. PMID- 27988785 TI - Anxiety in adolescence. Can we prevent it? AB - BACKGROUND: Emotions are potent modulators and motivators of the behaviour that the individual displays in the different situations they have to live and they can act as a protection factor or vulnerability of the adapted or maladaptive behaviour. This study focuses on anxiety in adolescence. OBJECTIVES: The objective is, through a longitudinal study, to analyse the psychological processes and emotions that facilitate the symptoms of anxiety and those which protect the adolescent from these symptoms. MATERIAL AND METHODS: 417 adolescents (192 boys and 225 girls) participated in a three-wave longitudinal study in Valencia, Spain. In the first wave, adolescents were either in the third year of secondary school (81 boys and 85 girls) or the fourth year of secondary school (111 boys and 140 girls). The mean age was 14.70 (SD = 0.68; range = 13-17 years). This study monitored participating adolescents for three years. RESULTS: The results indicate a differential profile in the evaluated emotions according to sex, with the girls being the ones to experiment more anxiety and more empathy, while the boys show more emotional instability and aggression. CONCLUSIONS: It is concluded that the best predictors for anxiety are anger state, aggressive behaviour, empathic concern together with the lack of coping mechanisms focused on problem solving and the perception of stress as a threat. PMID- 27988786 TI - Association Between the Left Atrial and Left Atrial Appendages Systole Strain Rate in Patients with Atrial Fibrillation. AB - BACKGROUND The aim of this research was to explore the association between the left atrial (LA) and left atrial appendages (LAA) systole strain rate (SSR) in patients with atrial fibrillation (AF), and to provide evidence to aid in the assessment of disease progression. MATERIAL AND METHODS A total of 180 patients with AF were selected for the study (130 patients with paroxysmal AF (Par AF) and 50 patients with persistence AF (PerAF).In addition, 60 healthy individuals were selected as a control group. The total and side wall SSRs were calculated. RESULTS The total SSR in the control group was higher than in the ParAF and PerAF groups (2.87+/-0.45 vs. 2.15+/-0.56 vs. 1.92+/-0.62 and 6.24+/-1.61 vs. 4.45+/ 1.42 vs. 3.66+/-1.55). The total SSR of LAA was correlated with that of LA in the AF patient groups and the control group; the correlation coefficients were 0.720, 0.563, and 0.421. However, the ratio of total SSR of LAA to that of LA was not significant statistically different among the three groups (2.24+/-0.41 vs. 2.35+/-0.58 vs. 2.03+/-0.56). The posterior wall had the lowest SSRs in the control group and ParAF group. CONCLUSIONS The SSRs of AF patients were lower than that of healthy individuals, and the degree was associated with disease progression. The SSR was different in different side walls, and gradually shorten with disease progression. PMID- 27988787 TI - Hyponatremia, Cognitive Function, and Mobility in an Outpatient Heart Failure Population. AB - BACKGROUND The association of hyponatremia with cognitive impairment and mobility in heart failure (HF) patients is unknown. The purpose of this study was to determine if hyponatremia is associated with cognitive and mobility impairment as measured by simple, validated, and time-sensitive tests. MATERIAL AND METHODS This was a prospective study in patients with reduced and preserved ejection fraction (HFrEF, HFpEF) seen in outpatient HF clinics. Hyponatremia was defined as sodium level <=136 mEq/L. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) tool, and mobility was measured with the Timed Up and Go test (TUG-t). RESULTS A total of 121 patients were evaluated; 30% were hyponatremic (134+/-1.9 mEq/l, range 128-136 mEq/l). Overall, 92% of hyponatremic patients had cognitive impairment (MoCA <26) compared to 76% of the non hyponatremic patients [relative risk 1.2 (confidence interval: 1.02-1.4, p=0.02)]. In regard to mobility, 72% of hyponatremic patients and 62% of non hyponatremic patients (p=0.4) had TUG-t times that were considered to be worse than average. A total of 84% (N=76) of HFrEF and 71% (N=22) of HFpEF patients had cognitive impairment (p=0.86). HFrEF patients had significantly lower overall MoCA scores (21.2+/-3.7 vs. 23.3+/-3.6, p=0.006) and similar TUG-t times compared to HFpEF patients. CONCLUSIONS Most heart failure patients (HFrEF and HFpEF) seen in an ambulatory setting had impairment of cognitive function and mobility, with a higher prevalence among those with hyponatremia. Screening can be done using tests that can be administered in a clinical setting. PMID- 27988788 TI - PDV2 has a dosage effect on chloroplast division in Arabidopsis. AB - KEY MESSAGE: PDV2 has a dosage effect on chloroplast division in Arabidopsis thaliana , but this effect may vary in different plants. Chloroplasts have to be divided as plants grow to maintain an optimized number in the cell. Chloroplasts are divided by protein complexes across the double membranes from the stroma side to the cytosolic side. PDV2 is a chloroplast division protein on the chloroplast outer membrane. It recruits the dynamin-related GTPase ARC5 to the division site. The C-terminus of PDV2 and the C-terminus of ARC6 interact in the intermembrane space, which is important for the localization of PDV2. Previously, it was shown that overexpression of PDV2 can increase the division of chloroplasts in Arabidopsis and moss, so the authors concluded that PDV2 determines the rate of chloroplast division in land plants. PDV2 was also shown to inhibit the GTPase activity of ARC5 by in vitro experiment. These results look to be contradictory. Here, we identified a null allele of PDV2 in Arabidopsis and studied plants with different levels of PDV2. Our results suggested that the chloroplast division phenotype in Arabidopsis is sensitive to the level of PDV2, while this is not the case for ARC6. The level of PDV2 protein is reduced sharply in fast-growing leaves, while the level of ARC6 is not. The levels of PDV2 and ARC6 in several other plant species at different developmental stages were also investigated. The results indicated that their expression pattern varies in different species. Thus, PDV2 is an important positive factor of chloroplast division with an apparent dosage effect in Arabidopsis, but this effect for different chloroplast division proteins in different plants may vary. PMID- 27988790 TI - Pharmacokinetics of lenalidomide during high cut-off dialysis in a patient with multiple myeloma and renal failure. AB - INTRODUCTION: High cut-off dialysis, increasingly used in multiple myeloma patients, is susceptible to influence anticancer drug elimination. We report about lenalidomide disposition in a patient on high cut-off dialysis for renal failure secondary to myeloma cast nephropathy. METHODS: The patient received a higher dosage of lenalidomide (5 mg b.i.d.), owing to concerns about a potential decrease in lenalidomide exposure during dialysis sessions. A set of blood samples was taken in order to develop a pharmacokinetic model accounting for lenalidomide concentrations in this setting. RESULTS: According to our model, the area under the curve was 3273 ug h/L, i.e., 60% higher than expected under usual dosage (25 mg q.d.) with normal renal function. Despite this, the patient did not develop major hematological toxicity. CONCLUSIONS: Lenalidomide doses of 5 mg b.i.d. led to high exposure in a patient with renal failure undergoing high cut off dialysis. Yet, the dosage of 5 mg q.d. recommended in conventional dialysis would probably be adequate in such patients. PMID- 27988789 TI - Systematic review of rheumatic disease phenotypes and outcomes in the Indigenous populations of Canada, the USA, Australia and New Zealand. AB - We performed a systematic review designed to characterize clinical phenotypes and outcomes in Indigenous populations with rheumatic disease to enhance the understanding of how rheumatic disease presents in Indigenous populations and allow for better projection of the healthcare needs of the communities affected. A systematic search was performed in medical (Medline, EMBASE, CINAHL), Indigenous and conference abstract databases (to June 2015). Search terms for Indigenous populations were combined with terms for inflammatory arthritis conditions, connective tissue disorders, crystal arthritis and osteoarthritis. Studies were included if they reported on disease features, disease activity measures, or patient-reported outcomes in Canadian, American, Australian or New Zealand Indigenous populations. Data were extracted in duplicate, and a narrative summary was prepared. A total of 5269 titles and abstracts were reviewed, of which 504 underwent full-text review and 85 met inclusion criteria. Nearly all the studies described outcomes in the North American populations (n = 77), with only four studies from Australia and four studies from New Zealand. The majority of studies were in rheumatoid arthritis (n = 31) and systemic lupus erythematosus (n = 19). Indigenous patients with rheumatoid arthritis had higher disease activity and reported more significant impact on patient-reported outcomes and quality of life than non-Indigenous patients. Spondyloarthropathy features were described in North American populations, with most patients having advanced manifestations. In systemic lupus erythematosus, nephritis was more frequent in Indigenous populations. Gout and osteoarthritis were more severe in New Zealand Maori populations. The existing literature supports differences in disease phenotype and severity in Indigenous populations of Canada, America, Australia and New Zealand. We encourage investigators in this area of research to undertake contemporary studies that disentangle differences between phenotype and severity that are biologic in etiology or merely reflecting differences in access to care and that provide a longitudinal assessment of outcomes in more diverse populations. PMID- 27988791 TI - Semimembranosus muscle herniation: a rare case with emphasis on muscle biomechanics. AB - Muscle herniations are rare and most reported cases involve muscles of the lower leg. We use a case of muscle herniation involving the semimembranosus muscle, presenting as a painful mass in an adolescent male after an unspecified American football injury, to highlight a simple concept of muscle biomechanics as it pertains to muscle hernia(s): decreased traction upon muscle fibers can increase conspicuity of muscle herniation(s)-this allows a better understanding of the apt provocative maneuvers to employ, during dynamic ultrasound or magnetic resonance imaging, in order to maximize diagnostic yield and, thereby, limit patient morbidity related to any muscle herniation. Our patient subsequently underwent successful decompressive fasciotomy and has since returned to his normal daily activities. PMID- 27988793 TI - The microbiome in health and disease: a new role of microbes in molecular medicine. PMID- 27988792 TI - Microbiome and chronic inflammatory bowel diseases. AB - It is nowadays generally accepted that the microbiome is a central driver of chronic inflammatory bowel diseases based on observations from human patients as well as inflammatory rodent models. Many studies focussed on different aspects of microbiota and some scientists believe that a primary dis-balance results in a direct microbial induced inflammatory situation. It is also clear that the microbiome is influenced by environmental and genetic factors and is also tightly regulated by host defense molecules such as antimicrobial peptides (defensins et al.). Different lines of investigations showed different complex antimicrobial barrier defects in inflammatory bowel diseases which also influence the composition of the microbiome and generally impact on the microbial-mucosal interface. In this review, we aim to discuss the bigger picture of these different aspects and current views and conclude about therapeutic consequences for future concepts beyond anti-inflammatory treatment. PMID- 27988794 TI - Teriparatide treatment in a heart transplant patient with a chronic kidney disease and a low-turnover bone disease: a case report. AB - Low-turnover bone disease is a complication of chronic kidney disease and a long term steroid therapy. Currently, the only bone anabolic treatment available is teriparatide (TPTD). So far, no data exist in heart transplant patients, and only one single case with histomorphometric analysis of a dialysis patient with a low turnover bone disease has been published. The current report shows the effect of a 1-year TPTD therapy in a cardiac transplant patient with 10 vertebral and 3 peripheral fractures who had developed a chronic kidney failure while receiving triple immunosuppressive therapy. A transiliac bone biopsy following tetracycline labeling was performed prior and after 1 year of treatment, showing an increase in the bone formation and improvement of the structural indices (20-fold increase of osteoid volume/bone volume, fourfold increase of osteoid surface/bone surface and increases of wall thickness (+15%), trabecular thickness (+9%), and trabecular number (+38%)). Bone mineral density was stable, no new vertebral fractures had occurred, the therapy was well-tolerated, and the patient improved clinically. PMID- 27988795 TI - A novel anti-viral role for STAT3 in IFN-alpha signalling responses. AB - The cytokine, Interferon (IFN)-alpha, induces a wide spectrum of anti-viral mediators, via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. STAT1 and STAT2 are well characterised to upregulate IFN stimulated gene (ISG) expression; but even though STAT3 is also activated by IFN alpha, its role in anti-viral ISG induction is unclear. Several viruses, including Hepatitis C and Mumps, reduce cellular STAT3 protein levels, via the promotion of ubiquitin-mediated proteasomal degradation. This viral immune evasion mechanism suggests an undiscovered anti-viral role for STAT3 in IFN-alpha signalling. To investigate STAT3's functional involvement in this Type I IFN pathway, we first analysed its effect upon the replication of two viruses, Influenza and Vaccinia. Viral plaque assays, using Wild Type (WT) and STAT3-/- Murine Embryonic Fibroblasts (MEFs), revealed that STAT3 is required for the inhibition of Influenza and Vaccinia replication. Furthermore, STAT3 shRNA knockdown also enhanced Influenza replication and hindered induction of several, well characterised, anti-viral ISGs: PKR, OAS2, MxB and ISG15; while STAT3 expression had no effect upon induction of a separate ISG group: Viperin, IFI27, CXCL10 and CCL5. These discoveries reveal, for the first time, an anti-viral role for STAT3 in the IFN-alpha pathway and characterise a requirement for STAT3 in the expression of specific ISGs. These findings also identify STAT3 as a therapeutic target against viral infection and highlight it as an essential pathway component for endogenous and therapeutic IFN-alpha responsiveness. PMID- 27988796 TI - Cross-sectional and prospective relationship between physical activity and chronic diseases in European older adults. AB - OBJECTIVES: This study examined the relationship between physical activity (PA) and chronic diseases in European older adults, using a prospective analysis with data from 2011 and 2013. METHODS: Participants were 37,524 older adults (16,204 men) who responded to the fourth (in 2011) and fifth (in 2013) wave of SHARE project, from 13 European countries. Participants' answers to interview questions about the presence of chronic conditions and PA. The cross-sectional and prospective association between PA and the number of chronic diseases was assessed using general linear models. RESULTS: Among men and women, moderate or vigorous physical activity (MVPA) in 2011 was associated with fewer reported chronic diseases in 2011 and 2013. In prospective analysis, MVPA in 2011 was inversely associated with the number of chronic diseases in 2013 in the unadjusted model. In the adjusted model MVPA more than once a week remained as a significant predictor of fewer chronic diseases. CONCLUSIONS: PA should be prescribed to older adults in order to prevent and reduce the number of chronic diseases, and, when possible, vigorous intensity PA should be recommended. PMID- 27988797 TI - Unilateral occurrence of five different thyroid arteries-a need of terminological systematization: a case report. AB - This article highlights an unusual and unilateral variation in the blood supply to the inferior portion of the thyroid gland observed on the right lobe during anatomy dissection course. The rare variation of the occurrence of two anomalous arteries: the middle thyroid artery and the aberrant accessory inferior thyroid artery, and one uncommon variant, the thyroid ima artery, was detected in an adult female cadaver. The two generally constant arteries, the superior thyroid artery and the inferior thyroid artery, have been found in their usual anatomical location. Both the middle thyroid artery and aberrant accessory inferior thyroid artery arose from the right common carotid artery. The middle thyroid artery coursed as a very short branch ventromedially to enter the inferior lateral portion of the right lobe of the thyroid gland. It was at the same level, in which the inferior thyroid artery reached the lateral border of the thyroid gland. The aberrant accessory inferior thyroid artery originated similarly, from the ventromedial surface of the right common carotid artery and passed to supply the inferior pole of the right lobe. The thyroid ima artery was found to arise from the brachiocephalic trunk, entering the isthmus of the thyroid gland. Information about the embryological background might be helpful to clarify why such a type of variation occurs. It is necessary to understand the possible existence of this anomaly, to carry out successful radical neck dissection and to minimize the risk of postoperative complications in patients. PMID- 27988799 TI - Development of a fast method for simultaneous determination of hippuric acid, mandelic acid, and creatinine in urine by capillary zone electrophoresis using polymer multilayer-coated capillary. AB - This paper reports the development of a fast separation method employing capillary zone electrophoresis for the simultaneous determination of hippuric acid, mandelic acid, and creatinine in samples of urine using a coated capillary. The background electrolyte was composed of 10 mmol L-1 tris(hydroxymethyl)aminomethane and 30 mmol L-1 2-hydroxy-isobutyric acid at pH 3.6. The internal standard was 3,5-dihydroxybenzoic acid. Separations were performed in a fused silica capillary (32 cm total length, 8.5 cm effective length, and 50 MUm internal diameter) coated with crosslinked hydroxypropyltrimethyl ammonium chloride chitosan and kappa-carrageenan. Direct UV detection was performed at a wavelength of 200 nm. Samples and standards were injected hydrodynamically (-50 mbar, 3 s) using the short-end injection procedure. The electrophoretic system was operated under constant voltage of 30 kV with positive polarity on the injection side. The separation time for hippuric acid, mandelic acid, and creatinine was less than 70 s. The evaluation of some analytical parameters of the method for the three analytes showed good linearity (R 2 > 0.99), limit of detections of 0.21 to 0.63 mg L-1, inter-day precision better than 3.0% (peak area), and recovery in the range of 98 to 106%. The method developed was applied in the analysis of the three analytes in urine samples. Graphical Abstract New method using capillary zone electrophoresis for analysis of creatinine, hippuric acid and mandelic acid in urine. PMID- 27988800 TI - ClarityTM digital PCR system: a novel platform for absolute quantification of nucleic acids. AB - In recent years, digital polymerase chain reaction (dPCR) has gained recognition in biomedical research as it provides a platform for precise and accurate quantification of nucleic acids without the need for a standard curve. However, this technology has not yet been widely adopted as compared to real-time quantitative PCR due to its more cumbersome workflow arising from the need to sub divide a PCR sample into a large number of smaller partitions prior to thermal cycling to achieve zero or at least one copy of the target RNA/DNA per partition. A recently launched platform, the ClarityTM system from JN Medsys, simplifies dPCR workflow through the use of a novel chip-in-a-tube technology for sample partitioning. In this study, the performance of ClarityTM was evaluated through quantification of the single-copy human RNase P gene. The system demonstrated high precision and accuracy and also excellent linearity across a range of over 4 orders of magnitude for the absolute quantification of the target gene. Moreover, consistent DNA copy measurements were also attained using a panel of different probe- and dye-based master mixes, demonstrating the system's compatibility with commercial master mixes. The ClarityTM was then compared to the QX100TM droplet dPCR system from Bio-Rad using a set of DNA reference materials, and the copy number concentrations derived from both systems were found to be closely associated. Collectively, the results showed that ClarityTM is a reliable, robust and flexible platform for next-generation genetic analysis. PMID- 27988801 TI - Measuring the actual I-131 thyroid uptake curve with a collar detector system: a feasibility study. AB - Radionuclide therapy using I-131 is commonly used for the treatment of benign thyroid diseases. The therapeutic dose to be administered is calculated based on the type of disease, the volume of the thyroid, and the measured uptake percentage. This methodology assumes a similar biological half-life of iodine, whereas in reality a large variation in biological half-life is observed. More knowledge about the actual biological half-life of iodine for individual patients will improve the quantification of the delivered radiation dose during radioiodine therapy and could aid the evaluation of the success of the therapy. In this feasibility study we used a novel measurement device [Collar Therapy Indicator (CoTI)] to measure the uptake curve of patients undergoing I-131 radioiodine therapy. The CoTI device is a light-weight wearable device that contains two independent gamma radiation detectors that are placed in a collar. By comparing results of thyroid uptake measurements with results obtained with a gamma camera, the precision of the system is demonstrated. Additionally, for three patients the uptake curve is measured during 48 h of admission in the hospital. The presented results demonstrate the feasibility of the new measurement device to measure the uptake curve during radioiodine therapy. PMID- 27988798 TI - Novel insights into biosynthesis and uptake of rhamnolipids and their precursors. AB - The human pathogenic bacterium Pseudomonas aeruginosa produces rhamnolipids, glycolipids with functions for bacterial motility, biofilm formation, and uptake of hydrophobic substrates. Rhamnolipids represent a chemically heterogeneous group of secondary metabolites composed of one or two rhamnose molecules linked to one or mostly two 3-hydroxyfatty acids of various chain lengths. The biosynthetic pathway involves rhamnosyltransferase I encoded by the rhlAB operon, which synthesizes 3-(3-hydroxyalkanoyloxy)alkanoic acids (HAAs) followed by their coupling to one rhamnose moiety. The resulting mono-rhamnolipids are converted to di-rhamnolipids in a third reaction catalyzed by the rhamnosyltransferase II RhlC. However, the mechanism behind the biosynthesis of rhamnolipids containing only a single fatty acid is still unknown. To understand the role of proteins involved in rhamnolipid biosynthesis the heterologous expression of rhl-genes in non-pathogenic Pseudomonas putida KT2440 strains was used in this study to circumvent the complex quorum sensing regulation in P. aeruginosa. Our results reveal that RhlA and RhlB are independently involved in rhamnolipid biosynthesis and not in the form of a RhlAB heterodimer complex as it has been previously postulated. Furthermore, we demonstrate that mono-rhamnolipids provided extracellularly as well as HAAs as their precursors are generally taken up into the cell and are subsequently converted to di-rhamnolipids by P. putida and the native host P. aeruginosa. Finally, our results throw light on the biosynthesis of rhamnolipids containing one fatty acid, which occurs by hydrolyzation of typical rhamnolipids containing two fatty acids, valuable for the production of designer rhamnolipids with desired physicochemical properties. PMID- 27988803 TI - Trans-glycosylation capacity of a highly glycosylated multi-specific beta glucosidase from Fusarium solani. AB - An extracellular beta-glucosidase from Fusaruim solani cultivated on wheat bran was purified by only two chromatographic steps. The purified enzyme exhibited optimal temperature and pH at 60 degrees C and pH 5, respectively. The purified beta-glucosidase behaves as a very large protein due to its high degree of glycosylation. More interestingly, the endoglycosidase H (Endo H) treatment led to 97.55% loss of its initial activity after 24 h of treatment. Besides, the addition of Tunicamycin (nucleoside antibiotic blocking the N-glycosylation first step) during the culture of the fungus affected seriously the glycosylation of the enzyme. Both treatments (endo H and Tunicamycin) strengthened the idea that the hyperglycosylation is involved in the beta-glucosidase activity and thermostability. This enzyme was also shown to belong to class III of beta glucosidases (multi-specific) since it was able to act on either cellobiose, gentiobiose or sophorose which are disaccharide composed of two units of D glucose connected by beta1-4, beta1-6 and beta1-2 linkage, respectively. The beta glucosidase activity was strongly enhanced by ferrous ion (Fe2+) and high ionic strength (1 M KCl). The purified enzyme exhibited an efficient transglycosylation capacity allowing the synthesis of cellotriose and cellotetraose using cellobiose as donor. PMID- 27988802 TI - Local recurrence of prostate cancer after radical prostatectomy is at risk to be missed in 68Ga-PSMA-11-PET of PET/CT and PET/MRI: comparison with mpMRI integrated in simultaneous PET/MRI. AB - PURPOSE: The positron emission tomography (PET) tracer 68Ga-PSMA-11, targeting the prostate-specific membrane antigen (PSMA), is rapidly excreted into the urinary tract. This leads to significant radioactivity in the bladder, which may limit the PET-detection of local recurrence (LR) of prostate cancer (PC) after radical prostatectomy (RP), developing in close proximity to the bladder. Here, we analyze if there is additional value of multi-parametric magnetic resonance imaging (mpMRI) compared to the 68Ga-PSMA-11-PET-component of PET/CT or PET/MRI to detect LR. METHODS: One hundred and nineteen patients with biochemical recurrence after prior RP underwent both hybrid 68Ga-PSMA-11-PET/CTlow-dose (1 h p.i.) and -PET/MRI (2-3 h p.i.) including a mpMRI protocol of the prostatic bed. The comparison of both methods was restricted to the abdomen with focus on LR (McNemar). Bladder-LR distance and recurrence size were measured in axial T2w TSE. A logistic regression was performed to determine the influence of these variables on detectability in 68Ga-PSMA-11-PET. Standardized-uptake-value (SUVmean) quantification of LR was performed. RESULTS: There were 93/119 patients that had at least one pathologic finding. In addition, 18/119 Patients (15.1%) were diagnosed with a LR in mpMRI of PET/MRI but only nine were PET-positive in PET/CT and PET/MRI. This mismatch was statistically significant (p = 0.004). Detection of LR using the PET-component was significantly influenced by proximity to the bladder (p = 0.028). The PET-pattern of LR-uptake was classified into three types (1): separated from bladder; (2): fuses with bladder, and (3): obliterated by bladder). The size of LRs did not affect PET-detectability (p = 0.84), mean size was 1.7 +/- 0.69 cm long axis, 1.2 +/- 0.46 cm short-axis. SUVmean in nine men was 8.7 +/- 3.7 (PET/CT) and 7.0 +/- 4.2 (PET/MRI) but could not be quantified in the remaining nine cases (obliterated by bladder). CONCLUSION: The present study demonstrates additional value of hybrid 68Ga-PSMA 11-PET/MRI by gaining complementary diagnostic information compared to the 68Ga PSMA-11-PET/CTlow-dose for patients with LR of PC. PMID- 27988805 TI - Critical appraisal of some factors pertinent to the functional designs of the gas exchangers. AB - Respiration acquires O2 from the external fluid milieu and eliminates CO2 back into the same. Gas exchangers evolved under certain immutable physicochemical laws upon which their elemental functional design is hardwired. Adaptive changes have occurred within the constraints set by such laws to satisfy metabolic needs for O2, environmental conditions, respiratory medium utilized, lifestyle pursued and phylogenetic level of development: correlation between structure and function exists. After the inaugural simple cell membrane, as body size and structural complexity increased, respiratory organs formed by evagination or invagination: the gills developed by the former process and the lungs by the latter. Conservation of water on land was the main driver for invagination of the lungs. In gills, respiratory surface area increases by stratified arrangement of the structural components while in lungs it occurs by internal subdivision. The minuscule terminal respiratory units of lungs are stabilized by surfactant. In gas exchangers, respiratory fluid media are transported by convection over long distances, a process that requires energy. However, movement of respiratory gases across tissue barriers occurs by simple passive diffusion. Short distances and large surface areas are needed for diffusion to occur efficiently. Certain properties, e.g., diffusion of gases through the tissue barrier, stabilization of the respiratory units by surfactant and a thin tripartite tissue barrier, have been conserved during the evolution of the gas exchangers. In biology, such rare features are called Bauplans, blueprints or frozen cores. That several of them (Bauplans) exist in gas exchangers almost certainly indicates the importance of respiration to life. PMID- 27988804 TI - Monosymptomatic nocturnal enuresis in pediatric patients: multidisciplinary assessment and effects of therapeutic intervention. AB - BACKGROUND: Few studies manage patients with isolated monosymptomatic enuresis (MNE) with multidisciplinary evaluation and pre- and long-term post-intervention monitoring. METHODS: This was a prospective study of MNE patients, aged 6-16 years, diagnosed by multidisciplinary assessment. Of the 140 initial applicants (58.6%) with MNE, 82 were included in the study and randomized for therapeutic intervention in three treatment groups, namely: alarm, desmopressin and alarm + desmopressin. Therapeutic response was evaluated 12 months after treatment withdrawal. RESULTS: Of the 82 patients [mean age 9.5 (SD +/- 2.6) years, n = 62 males (75.6%)], 91.1% had a family history of nocturnal enuresis (NE) in first /second-degree relatives, 81.7% had constipation and 40.7% had mild-to-moderate apnea. Prior to randomization, management of constipation and urotherapy led to remission in seven of the 82 patients; 75 patients were randomized to intervention. There were 14/75 (18.7%) dropouts during the intervention, especially in the alarm group (p = 0.00). Initial complete/partial response was achieved in 56.6% of the alarm group, 70% of the desmopressin group and 64% in the combined group (p = 0.26). Continued success occurred in 70% of the alarm group, 84.2% of the desmopressin group and 100% of the combined group (p = 0.21). Recurrence occurred in 3/20 (15%) patients in the alarm group and 1/19 (5.2 %) patients of the desmopressin group. Post-intervention Child Behavior Checklist (CBCL) and PedsQL 4.0 scores showed significant improvement. CONCLUSIONS: The three therapeutic modalities were effective in managing MNE with low relapse rates; the alarm group showed the highest dropout rate. Therapeutic success was associated with improvement of behavioral problems and quality of life scores. PMID- 27988806 TI - Medications influencing central cholinergic pathways affect fixation stability, saccadic response time and associated eye movement dynamics during a temporally cued visual reaction time task. AB - RATIONALE: Anticholinergic medications largely exert their effects due to actions on the muscarinic receptor, which mediates the functions of acetylcholine in the peripheral and central nervous systems. In the central nervous system, acetylcholine plays an important role in the modulation of movement. OBJECTIVE: This study investigated the effects of over-the-counter medications with varying degrees of central anticholinergic properties on fixation stability, saccadic response time and the dynamics associated with this eye movement during a temporally-cued visual reaction time task, in order to establish the significance of central cholinergic pathways in influencing eye movements during reaction time tasks. METHODS: Twenty-two participants were recruited into the placebo controlled, human double-blind, four-way crossover investigation. Eye tracking technology recorded eye movements while participants reacted to visual stimuli following temporally informative and uninformative cues. The task was performed pre-ingestion as well as 0.5 and 2 h post-ingestion of promethazine hydrochloride (strong centrally acting anticholinergic), hyoscine hydrobromide (moderate centrally acting anticholinergic), hyoscine butylbromide (anticholinergic devoid of central properties) and a placebo. RESULTS: Promethazine decreased fixation stability during the reaction time task. In addition, promethazine was the only drug to increase saccadic response time during temporally informative and uninformative cued trials, whereby effects on response time were more pronounced following temporally informative cues. Promethazine also decreased saccadic amplitude and increased saccadic duration during the temporally-cued reaction time task. CONCLUSION: Collectively, the results of the study highlight the significant role that central cholinergic pathways play in the control of eye movements during tasks that involve stimulus identification and motor responses following temporal cues. PMID- 27988807 TI - Effects of bright light exposure during daytime on peripheral clock gene expression in humans. AB - Light is the strongest synchronizer controlling circadian rhythms. The intensity and duration of light change throughout the year, thereby influencing body weight, food preferences, and melatonin secretion in humans and animals. Although the expression of clock genes has been examined using human samples, it currently remains unknown whether bright light during the daytime affects the expression of these genes in humans. Therefore, we herein investigated the effects of bright light exposure during the daytime on clock gene expression in the hair follicular and root cells of the human scalp. Seven healthy men (20.4 +/- 2.2 years old; 172.3 +/- 5.8 cm; 64.3 +/- 8.5 kg; BMI 21.7 +/- 3.1 kg/m2, mean +/- SD) participated in this study. Subjects completed 3-day experimental sessions twice in 1 month during which they were exposed to bright and dim light conditions. The mRNA expression of Per1-3, Cry1-2, Rev-erb-alpha (Nr1d1), Rev-erb-beta (Nr1d2), and Dec1 was analyzed using branched DNA probes. No significant changes were observed in the expression of Per1, Per2, Per3, Cry1, Cry2, Rev-erb-alpha (Nr1d1), or Dec1 following exposure to bright light conditions. However, the expression of Rev-erb-beta (Nr1d2) tended to be stronger under bright light than dim light conditions. These results suggest that the bright light stimulus did not influence the expression of clock genes in humans. Long-lasting bright light exposure during the daytime may be required to change the expression of clock genes in humans. PMID- 27988810 TI - Video analysis of epileptic-like motor patterns in REM behaviour disorder: a case series. PMID- 27988808 TI - Inheritance and quantitative trail loci mapping of adventitious root numbers in cucumber seedlings under waterlogging conditions. AB - The hypocotyl-derived adventitious root (AR) is an important morphological acclimation to waterlogging stress; however, its genetic basis has not been adequately understood. In the present study, a mixed major gene plus polygene inheritance model was used to analyze AR numbers (ARN) 7 days after waterlogging treatment in six generations (P1, P2, F1, B1, B2, and F2), using cucumber waterlogging tolerant line Zaoer-N and sensitive Pepino as parents. The results showed that the genetic model D-4, mixed one negative dominance major gene and additive-dominance polygenes, is the best-fitting genetic model for waterlogging triggered ARN phenotype. A genetic linkage map spanning 550.8 cM and consisting of 149 simple sequence repeat (SSR) markers segregating into seven linkage groups was constructed. Three QTLs (ARN3.1, ARN5.1, and ARN6.1) distributed on chromosomes 3, 5, and 6 were identified by composite interval mapping. The major effect QTL, ARN6.1, located between SSR12898 and SSR04751, was the only locus detected in three seasons, with least likelihood (LOD) scores of 8.8, 10.4, and 9.5 and account for 17.6, 24, and 19.8% of the phenotypic variance, respectively. Using five additional single nucleotide polymorphism (SNP) makers, the ARN6.1 was narrowed down to a 0.79 Mb interval franked by SSR12898 and SNP25558853. Illumina RNA-sequencing data generated on hypocotyls of two parents 48 h after waterlogging treatment revealed 15 genes in the 0.79 Mb interval were differentially expressed, including Csa6G503880 encoding a salicylic acid methyl transferase-like protein, Csa6G504590 encoding a cytochrome P450 monooxygenase, and Csa6G505230 encoding a heavy metal-associated protein. Our findings shed light on the genetic architecture underlying adventitious rooting during waterlogging stress in cucumber, and provide a list of potential gene targets for further elucidating waterlogging tolerance in plants. PMID- 27988811 TI - Natural products as modulator of autophagy with potential clinical prospects. AB - Natural compounds derived from living organisms are well defined for their remarkable biological and pharmacological properties likely to be translated into clinical use. Therefore, delving into the mechanisms by which natural compounds protect against diverse diseases may be of great therapeutic benefits for medical practice. Autophagy, an intricate lysosome-dependent digestion process, with implications in a wide variety of pathophysiological settings, has attracted extensive attention over the past few decades. Hitherto, accumulating evidence has revealed that a large number of natural products are involved in autophagy modulation, either inducing or inhibiting autophagy, through multiple signaling pathways and transcriptional regulators. In this review, we summarize natural compounds regulating autophagy in multifarious diseases including cancer, neurodegenerative diseases, cardiovascular diseases, metabolic diseases, and immune diseases, hoping to inspire further investigation of the underlying mechanisms of natural compounds and to facilitate their clinical use for multiple human diseases. PMID- 27988812 TI - CD28, CTLA-4 and CCL5 gene polymorphisms in patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint destruction caused by infiltrating leukocytes including T cells. An important role in T cell co-stimulation is played by the CD28, as a stimulatory signal transducer and the inhibitory CTLA-4. CCL5 is produced by circulating T cells and plays an active role in the chemotactic activity of T cells in RA. The aim of this study was to examine the associations between polymorphisms within CD28, CTLA-4, and CCL5 genes and RA. We examined 422 patients (340 female, 82 male, mean age 57.5 +/- 12.5 years) with rheumatoid arthritis and 338 healthy subjects (261 female, 77 male). Disease activity was determined on the basis of DAS28 score. The patients with DAS28 of <=2.5 were classified as subjects in remission of disease symptoms; the patients who had DAS28 of >2.5 were classified as subjects with active form of RA. There were no statistically significant differences in the distribution of studied genotypes and alleles between RA patients and the control group. A statistically significant difference was observed in the distribution of CTLA4 exon 1 +49A>G rs231775 genotypes between patients with DAS28 <= 2.5 and DAS28 > 2.5 where the increased frequency of AA genotype among patients with DAS28 > 2.5 was revealed (OR 1.55; 95% CI 1.01 2.38). The results of our study suggest no significant association between CD28 rs1980422, CCL5 rs2107538, CTLA-4 exon 1 +49A>G rs231775 and rs3087243 gene polymorphisms and RA in the Polish population. Our results indicate a possible association between CTLA-4 exon 1 +49A>G rs231775 gene polymorphism and RA activity. PMID- 27988813 TI - Cardiovascular risk assessment in patients with rheumatoid arthritis: a correlative study of noninvasive arterial health testing. AB - This study aimed to determine the relationship between noninvasive measures of arterial health and both estimated 10-year cardiovascular risk and measures of disease activity over time in established rheumatoid arthritis. Fifty rheumatoid arthritis patients underwent noninvasive arterial health testing (brachial artery reactivity, aortic augmentation index [AIx], pulse wave velocity, carotid artery intima-media thickness, and carotid artery plaque presence) and assessment of clinical disease activity (tender or swollen joint counts, Clinical Disease Activity Index [CDAI], and Health Assessment Questionnaire II [HAQ-II]). Clinical measures during 3 years before the study visit were averaged. Arterial health testing was compared with the American Heart Association/American College of Cardiology (AHA/ACC) Pooled Cohort Equation. Spearman methods identified correlations between disease activity measures, cardiac biomarkers, and arterial health parameters. Among the patients (mean age, 57.5 years), disease activity was moderate (mean [SD] CDAI, 16.9 [15.3]). At the study visit, corrected aortic augmentation index correlated with CDAI (r = 0.37, P = .009) and HAQ-II (r = 0.33, P = .02). AIx correlated with time-averaged tender joint count (r = 0.37, P = .008), CDAI (r = 0.36, P = .01), HAQ-II (r = 0.36, P = .01), swollen joint count (r = 0.36, P = .10), patient global assessment (r = 0.33, P = .02), physician global assessment (r = 0.35, P = .01), and pain score (r = 0.38, P = .007). The AHA/ACC low-risk group (<5% 10-year risk) had highest prevalence of carotid plaques. Arterial health testing may identify increased risk of cardiovascular disease compared with risk obtained through AHA/ACC Pooled Cohort Equation. Measures of arterial stiffness correlate with the burden of disease activity over time. PMID- 27988814 TI - Remodeling of the gut microbiota and structural shifts in Preeclampsia patients in South China. AB - Preeclampsia (PE) is one of the pregnancy metabolic diseases. Since Gut microbiota play important roles in the hosts' metabolism, it is necessary to investigate the gut microbiota in PE patients, so that some intestinal dysbiosis might be detected as a biomarker for PE early diagnosis or as a target for intervention. One hundred subjects were categorized into four groups: 26 PE patients in late pregnancy, healthy individuals in early, middle, and late pregnancy (26/24/24 women). Gut microbiota were analyzed by sequencing the V4 region of the 16S rDNA gene using Illuminal MiSeq. Data were analyzed by multivariate statistics. Bacteroidetes was the dominant bacterium (47.57-52.35%) in the pregnant women in South China. Tenericutes increased while Verrucomicrobia almost disappeared in late pregnancy. In the PE patients, there was an overall increase in pathogenic bacteria, Clostridium perfringens (p = 0.03) and Bulleidia moorei (p = 0.00) but a reduction in probiotic bacteria Coprococcus catus (p = 0.03). Our research suggests that there is a significant structural shift of the gut microbiota in PE patients, which might be associated with the occurrence and development of the disease. However, further studies are required to understand the underlying mechanisms. PMID- 27988816 TI - Author's reply to comment on: is it possible to prevent recurrent vulvovaginitis? The role of Lactobacillus plantarum I1001 (CECT7504). PMID- 27988815 TI - Novel portable platform for molecular detection of toxigenic Clostridium difficile in faeces: a diagnostic accuracy study. AB - BACKGROUND: A novel portable platform for nucleic acid amplification enables rapid detection of diarrhoea causing toxigenic Clostridium difficile directly from faeces, even in resource-limited settings. We evaluated the accuracy and precision of the new commercial molecular test system. METHODS: One thousand one hundred and sixty faecal samples from patients suspected of having Clostridium difficile infection (CDI) were analysed using the Orion GenRead C. difficile test system (Orion Diagnostica Oy, Espoo, Finland) and comparative methods in three teaching hospital laboratories in Finland and France. The precision of the Orion GenRead C. difficile test system was evaluated in a reproducibility study with a set of blind-coded samples. The test system is based on a new isothermal amplification technology (Strand Invasion Based Amplification, SIBA(r)) and detection of the tcdB gene of C. difficile. We calculated the sensitivity, specificity, and the overall agreement according to Clinical and Laboratory Standards Institute recommendations. FINDINGS: The overall agreement of the Orion GenRead C. difficile test when compared to the comparative methods in routine use in the participating laboratories was between 96.7% and 98.8%. In the reproducibility study; the total percent agreement between three laboratories was 99.8%. INTERPRETATION: The identification of toxigenic C. difficile from faeces with the light-weight portable Orion GenRead test system was highly sensitive and specific, and the results were reproducible in the participating laboratories. This platform could enable fast and accurate molecular pathogen detection even in resource-limited or point-of-care settings. PMID- 27988818 TI - Plasma membrane-anchored chloroplasts are necessary for the gravisensing system of Ceratopteris richardii prothalli. AB - The prothalli of the fern Ceratopteris richardii exhibit negative gravitropism when grown in darkness. However, no sedimentable organelles or substances have been detected in the prothallial cells, suggesting that a non-sedimentable gravisensor exists. We investigated whether chloroplasts are involved in the gravisensing system of C. richardii prothalli. We used a clumped-chloroplast mutant, clumped chloroplast 1 (cp1), in which the chloroplasts are detached from the plasma membrane and clustered around the nucleus likely because of a partial deletion in the KINESIN-LIKE PROTEIN FOR ACTIN-BASED CHLOROPLAST MOVEMENT 1 gene. The cp1 mutation resulted in prothalli that had a significantly diminished gravitropic response, while the phototropic response occurred normally. These results suggest that plasma membrane-anchored chloroplasts in prothallial cells function as one of the gravisensors in C. richardii prothalli. PMID- 27988817 TI - Activity and roles of Arabidopsis thaliana XRN family exoribonucleases in noncoding RNA pathways. AB - RNA metabolism is mediated by several sophisticated exo- or endo- ribonucleases. XRN family proteins are the conserved 5'-3' exoribonucleases in eukaryotes. A. thaliana genome encodes three XRN homologs (AtXRN2, AtXRN3 and AtXRN4) and their independent or redundant roles, which are possibly plant-specific in some cases, have been reported. AtXRN2 acts in maturation of ribosomal RNAs partially with AtXRN3. AtXRN3 is also involved in elimination of 3' remnants of microRNA precursors and in termination of mRNA transcription events. AtXRN4 degrades not only a small fraction of mRNAs in stress response but also 3' cleavage products of miRNA-mediated cleavage of target mRNAs. Moreover, all AtXRNs are important factors to suppress unexpected RNA silencing occurrence. Thus, this review summarizes and discusses multiple roles of AtXRN exoribonucleases and their relationship with noncoding RNA pathways including RNA silencing pathways. PMID- 27988819 TI - Egg hatching response to a range of ultraviolet-B (UV-B) radiation doses for four predatory mites and the herbivorous spider mite Tetranychus urticae. AB - Egg hatchability of four predatory mites-Phytoseiulus persimilis Athias-Henriot, Iphiseius [Amblyseius] degenerans Berlese, Amblyseius swirskii Athias-Henriot, and Euseius finlandicus Oudemans (Acari: Phytoseiidae)-and the spider mite Tetranychus urticae Koch (Acari: Tetranychidae) was determined under various UV-B doses either in constant darkness (DD) or with simultaneous irradiation using white light. Under UV-B irradiation and DD or simultaneous irradiation with white light, the predator's eggs hatched in significantly lower percentages than in the control non-exposed eggs, which indicates deleterious effects of UV-B on embryonic development. In addition, higher hatchability percentages were observed under UV-B irradiation and DD in eggs of the predatory mites than in eggs of T. urticae. This might be caused by a higher involvement of an antioxidant system, shield effects by pigments or a mere shorter duration of embryonic development in predatory mites than in T. urticae, thus avoiding accumulative effects of UV-B. Although no eggs of T. urticae hatched under UV-B irradiation and DD, variable hatchability percentages were observed under simultaneous irradiation with white light, which suggests the involvement of a photoreactivation system that reduces UV-B damages. Under the same doses with simultaneous irradiation with white light, eggs of T. urticae displayed higher photoreactivation and were more tolerant to UV-B than eggs of the predatory mites. Among predators variation regarding the tolerance to UV-B effects was observed, with eggs of P. persimilis and I. degenerans being more tolerant to UV-B radiation than eggs of A. swirskii and E. finlandicus. PMID- 27988820 TI - Bridges to Better Health and Wellness: An Adapted Health Care Manager Intervention for Hispanics with Serious Mental Illness. AB - This study examined the feasibility, acceptability, and initial impact of bridges to better health and wellness (B2BHW), a culturally-adapted health care manager intervention for Hispanics with serious mental illness (SMI). Thirty-four Hispanics with SMI and at risk for cardiovascular disease were enrolled. Mixed linear models were used to examine changes over 12-months on patient activation, self-efficacy, patient-rated quality of care, receipt of preventive primary care services, and quality of life. The majority of participants completed the intervention (85%) with high satisfaction. Significant improvements were found for patient activation, self-efficacy, patients' ratings of quality of care, and receipt of preventive primary care. PMID- 27988822 TI - Promoting improved social support and quality of life with the CenteringPregnancy(r) group model of prenatal care. AB - This prospective cohort study compared women participating in CenteringPregnancy(r) group prenatal care (N = 120) with those in standard individual care (N = 221) to determine if participation in Centering was associated with improvements in perceived social support and quality of life, with concomitant decreases in screens of postpartum depression and improvements in breastfeeding rates. Participants completed surveys at the onset of prenatal care, in the late third trimester and in the postpartum period. Centering participants had higher scores of perceived social support from friends after participating in group care (p < 0.05) with associated improvements in quality of life in the psychological and relational domains (p < 0.05) compared to standard care participants who showed higher scores of perceived support from family (p < 0.05) but did not show concomitant improvements in quality of life. This did not translate to any significant difference in scores on postpartum depression screens but was associated with improvements in breastfeeding continuation rates among Centering participants in the postpartum period. This study indicates that Centering care is associated with improved perceptions of peer social support with associated improvements in quality of life and higher rates of continued breastfeeding. PMID- 27988821 TI - Comparative metabolomics reveals the mechanism of avermectin production enhancement by S-adenosylmethionine. AB - It was found that S-adenosylmethionine (SAM) could effectively improve avermectin titer with 30-60 MUg/mL addition to FH medium. To clearly elucidate the mechanism of SAM on intracellular metabolites of Streptomyces avermitilis, a GC-MS-based comparative metabolomics approach was carried out. First, 230 intracellular metabolites were identified and 14 of them remarkably influenced avermectin biosynthesis were discriminative biomarkers between non-SAM groups and SAM treated groups by principal components analysis (PCA) and partial least squares (PLS). Based on further key metabolic pathway analyses, these biomarkers, such as glucose, oxaloacetic acid, fatty acids (in soybean oil), threonine, valine, and leucine, were identified as potentially beneficial precursors and added in medium. Compared with single-precursor feeding, the combined feeding of the precursors and SAM markedly increased the avermectin titer. The co-feeding approach not only directly verified our hypothesis on the mechanism of SAM by comparative metabolomics, but also provided a novel strategy to increase avermectin production. PMID- 27988823 TI - Social spatial cognition in rat tetrads: how they select their partners and their gathering places. AB - Spatial organization is an extensively studied field, in which most of the research has been on how the physical environment is perceived and conceived. There is a consensus that physical attributes such as environment geometry and landmarks are key factors in shaping spatial cognition. Nevertheless, the numerous studies of spatial behavior have usually been carried out on individuals, thereby overlooking the possible impact of the social environment. In the present study, rats were exposed to an unfamiliar open-field, first alone and then in tetrads of unfamiliar individuals, in order to monitor and analyze when and how their individual spatial behavior converged to a group spatial behavior. We found that the unfamiliar rats spent most of their time in companionship, first with preferred partners and ultimately as a quartet. Specifically, group formation was dynamic and gradual, with the rats first forming duos, then trios, and ultimately a quartet. Trios and quartets mostly huddled in the same specific corner that became a shared home base, from which they took solo or duo roundtrips to the arena. The present study unveils how, by means of gradual interactions among self, place, and conspecifics, four unfamiliar rats organized together their social spatial behavior. PMID- 27988824 TI - Rats' acquisition of the ephemeral reward task. AB - The ephemeral reward task provides a subject with a choice between two alternatives A and B. If it chooses alternative A, reinforcement follows and the trial is over. If it chooses alternative B, reinforcement follows but the subject can also respond to alternative A which is followed by a second reinforcement. Thus, it would be optimal to choose alternative B. Surprisingly, Salwiczek et al. (PLoS One 7:e49068, 2012. doi: 10.1371/journal.pone.00490682012 ) reported that adult fish (cleaner wrasse) mastered this task within 100 trials, whereas monkeys and apes had great difficulty with it. The authors attributed the species differences to ecological differences in the species foraging experiences. However, Pepperberg and Hartsfield (J Comp Psychol 128:298-306, 2014) found that parrots too learned this task easily. We have found that with a similar task pigeons are not able to learn to choose optimally within 400 trials (Zentall et al. in J Comp Psychol 130:138-144, 2016). In Experiment 1 of the present study, we found that rats did not learn to choose optimally in 840 trials; however, in Experiment 2 we added a prior commitment to the initial choice by increasing delay to reinforcement for the choice response from a single lever press to the first lever press after 20 s (FI20 s). In a comparable amount of training to Experiment 1, the rats learned to choose optimally. Although the use of a prior commitment increases the delay to reinforcement, it appears to reduce impulsive responding which in turn leads to optimal choice. PMID- 27988825 TI - Milk and Dairy Products Intake Is Associated with Low Levels of Lead (Pb) in Workers highly Exposed to the Metal. AB - Lead (Pb) is a toxic metal, frequently associated with occupational exposure, due to its widespread use in industry and several studies have shown high Pb levels in workers occupationally exposed to the metal. The aim of this study was to evaluate the influence of milk and dairy products (MDP) on Pb levels in blood (B Pb), plasma (P-Pb), and urine (U-Pb), in workers from automotive battery industries in Brazil. The study included 237 male workers; information concerning diet and lifestyle were gathered through a questionnaire, and B-Pb, P-Pb, and U Pb were determined by ICP-MS. Mean B-Pb, P-Pb, and U-Pb were 21 +/- 12, 0.62 +/- 0.73 MUg/dL, and 39 +/- 47 MUg/g creatinine, respectively. Forty three percent of participants declared consuming <=3 portions/week of MDP (classified as low-MDP intake), while 57% of individuals had >3portions/week of MDP (high-MDP intake). B Pb and P-Pb were correlated with working time (r s = 0.21; r s = 0.20; p < 0.010). Multivariable linear regressions showed a significant influence of MDP intake on B-Pb (beta = -0.10; p = 0.012) and P-Pb (beta = -0.16; p < 0.010), while no significance was seen on U-Pb. Our results suggest that MDP consumption may modulate Pb levels in individuals highly exposed to the metal; these findings may be due to the Pb-Ca interactions, since the adverse effects of Pb are partially based on its interference with Ca metabolism and proper Ca supplementation may help to reduce the adverse health effects induced by Pb exposure. PMID- 27988826 TI - Rutin-Nickel Complex: Synthesis, Characterization, Antioxidant, DNA Binding, and DNA Cleavage Activities. AB - The rutin-nickel (II) complex (RN) was synthesized and characterized by elemental analysis, UV-visible spectroscopy, IR, mass spectrometry, 1H NMR, TG-DSC, SEM, and molar conductivity. The low molar conductivity value investigates the non electrolyte nature of the complex. The elemental analysis and other physical and spectroscopic methods reveal the 1:2 stoichiometric ratio (metal/ligand) of the complex. An antioxidant study of rutin and its metal complex against DPPH radical showed that the complex has more radical scavenging activity than free rutin. The interaction of complex RN with DNA was determined using fluorescence spectra and agarose gel electrophoresis. The results showed that RN can intercalate moderately with DNA, quench a strong intercalator ethidium bromide (EB), and compete for the intercalative binding sites. The complex showed significant cleavage of pBR 322 DNA from supercoiled form (SC) to nicked circular form (NC), and these cleavage effects were dose-dependent. Moreover, the mechanism of DNA cleavage indicated that it was a hydrolytic cleavage pathway. These results revealed the potential nuclease activity of the complex to cleave DNA. PMID- 27988827 TI - Atherogenic Dyslipidemia Remission 1 Year After Bariatric Surgery. AB - PURPOSE: Given the lack of evidence of the effect of bariatric surgery (BS) on atherogenic dyslipidemia (AD), which is a characteristic of obese subjects, this study aimed to describe the remission rate of AD 1 year after BS in severely obese patients. MATERIALS AND METHODS: A non-randomised, prospective cohort study was conducted in patients undergoing laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy with a 1-year follow-up. AD was defined as triglycerides >=1.71 mmol/l or treatment with fibrates and low high-density lipoprotein (HDL) cholesterol (<1.03 mmol/l in men or <1.3 mmol/l in women). RESULTS: AD was present in 81 (22.8%) of the 356 patients; these were more frequently men and presented higher total cholesterol and non-HDL cholesterol concentrations. AD remission rate was 74.1% at 3 months, 90.1% at 6 months and 96.3% at 12 months, respectively, after BS. In this group of patients, HDL cholesterol levels rose progressively (1.0 +/- 0.2 to 1.5 +/- 0.3 mmol/l, p < 0.001) and triglycerides decreased (2.5 +/- 0.9 to 1.2 +/- 0.5 mmol/l, p < 0.001) during follow-up. Regarding previous lipid-lowering therapy, fibrates and ezetimibe were withdrawn in all patients and statins in 69.4% 1 year after surgery. CONCLUSION: BS has beneficial effects on lipid profile, achieving complete remission of AD at 1 year of follow-up in almost all patients. PMID- 27988828 TI - Mushroom poisoning: a retrospective study concerning 11-years of admissions in a Swiss Emergency Department. AB - Wild mushroom intoxication is an unusual cause of toxic ingestion in Europe. A great diversity of clinical symptoms may arise depending on the variety of wild mushrooms ingested. These initial symptoms are often non-specific, with frequent gastrointestinal symptoms, and have no direct correlation with the outcome. Therefore, management of mushroom poisoning and risk evaluation are a challenge for emergency clinicians. We retrospectively reviewed all cases of mushroom poisoning identified in the ED database spanning 11 years. Demographic and clinical data, time from consumption to symptoms, type of mushrooms, the number of patients presenting at the same time, treatment(s) provided, length of stay, discharge diagnosis, in-hospital mortality, and serious complications were evaluated. We identify 87 cases of mushroom poisoning. The most common symptoms are nausea and vomiting (71 cases, 82%), followed by diarrhea (68%), syncope (10%), abdominal pain (8%), and hallucinations (7%). Sixty-four patients (74%) exhibited early symptoms (appearance <6 h after ingestion) and 23 (26%) late symptoms (appearance >6 h after ingestion). Eleven patients (13%) required hospitalization over 24 h. Patients with late symptoms tended to have longer in hospital lengths of stay. Only one patient had Amanita phalloides intoxication, with a favorable outcome. Thirty-eight patients (44%) were involved in cluster presentations. Mushroom poisoning is an unusual but potentially severe form of intoxication. Patients presenting with late-appearing symptoms (>6 h) are associated with a higher risk of A. phalloides intoxication, and therefore require specific investigation and management. PMID- 27988829 TI - Cost effectiveness of pneumococcal urinary antigen in Emergency Department: a pragmatic real-life study. AB - Community-acquired pneumonia (CAP) is frequent and can be life-threatening. Streptococcus pneumoniae is the main bacteria involved, and is susceptible to penicillin A. Rapid microbiological diagnosis could then help reduce the antimicrobial spectrum. The pneumococcal urinary antigen (PUA) test is fast and easy to perform, but its impact on antimicrobial prescription and cost effectiveness in emergency departments (ED) is not well known. We performed a pragmatic real life retrospective study in an adult ED to assess its usefulness: proportion of positive results, impact on antimicrobial prescriptions and cost effectiveness. Over 3 years (from January 1st 2012 to December 31st 2014), 979 PUA tests were reutilized in our ED among 1224 patients who consulted for CAP; 51 (5.2%) were positive. Among them, 10 led to a modification of the antimicrobial treatment, but only 7 (14.3%) were in accordance with the results. The total cost of a PUA test is 27?. As only 7 PUA tests led to appropriate antimicrobial modification, we deemed that 972 had no impact, and the potential cost savings, if the test had not been used, would have been 26,244 ? (972 * 27) during 3 years, that is 8748 ? per year. Thus, it seems that the PUA test should not be generally used in the ED considering its low rate of positivity and the difficulties for physicians to adapt antibiotic treatment accordingly. This attitude change in utilization would lead to substantial cost savings. PMID- 27988830 TI - Wolbachia Infections Responsible for Thelytoky in Dryinid Wasps. The Case of Gonatopus bonaerensis Virla (Hymenoptera: Dryinidae). AB - We studied the occurrence of Wolbachia in the parasitoid Gonatopus bonaerensis Virla (Hymenoptera: Dryinidae). In order to verify the existence of natural infections in the parasitoid, a field survey was conducted. Identification of Wolbachia was performed on the basis of 16S rDNA, wsp_F1, and wsp_R1-sequences. After the detection of the bacteria, infected specimens of G. bonaerensis were treated with a solution of tetracycline. In Tucuman, parasitoids hold Wolbachia endosymbiont, which seems to control the wasp's reproduction in the nature turning it into thelytokous. The symbiont was identified as the Wolbachia sp. wRi strain. The cure of infected unfertilized females determined the normal arrhenotokous parthenogenesis and the production of male offspring. As a consequence of this procedure, the male of G. bonaerensis is described for the first time. PMID- 27988831 TI - Could pregabalin cause oculomotor symptoms in lower dose? A case with down beat nystagmus as a side effect. PMID- 27988832 TI - Autoimmune cerebellar ataxia with glutamic acid decarboxylase 65 antibodies associated with central vestibular symptoms. PMID- 27988833 TI - Right coronary artery stenosis associated with tricuspid valve ring annuloplasty. AB - A 70-year-old man with severe symptomatic functional mitral valve regurgitation underwent successful mitral valve repair combined with tricuspid valve ring annuloplasty. Pre-operative coronary angiography (CAG) showed no significant stenosis. One-and-a-half years later, the patient presented with an acute exacerbation of heart failure. Repeat CAG demonstrated tight stenosis in the right coronary artery (RCA) with arterial kinking that corresponded to the same point as the stenosis where the RCA is the closest to the tricuspid valve ring. The new lesion probably occurred as a consequence of the tricuspid valve ring annuloplasty. PMID- 27988834 TI - Selexipag: A Review in Pulmonary Arterial Hypertension. AB - Selexipag (Uptravi(r)) is an orally active, first-in-class, selective prostacyclin IP receptor agonist. Selexipag was approved recently in the EU for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients with WHO functional class (FC) II or III as combination therapy in patients insufficiently controlled with an endothelin receptor antagonist and/or a phosphodiesterase type 5 inhibitor or as monotherapy in patients who are not candidates for these therapies, and in the USA for the treatment of PAH (WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. Selexipag (200-1600 MUg twice daily, as tolerated) significantly reduced the risk of the primary composite endpoint of all-cause death or a complication related to PAH (whichever happened first) versus placebo in patients with PAH (mainly WHO FC II or III) in the large, randomized, placebo-controlled GRIPHON study. The treatment effect was largely driven by significant reductions in disease progression and hospitalization for PAH. However, selexipag did not significantly reduce all-cause mortality. Additionally, the observed treatment effect was consistent in a broad range of prespecified subgroups, including treatment-naive patients and those patients who were already receiving PAH specific treatment at baseline. Exercise capacity was also improved with selexipag versus placebo. Selexipag was generally well tolerated, with an adverse event profile consistent with other therapies targeting the prostacyclin pathway. Thus, selexipag extends the treatment options available in patients with PAH. PMID- 27988835 TI - Cost-Effectiveness Analysis of Apixaban, Dabigatran, Rivaroxaban, and Warfarin for Stroke Prevention in Atrial Fibrillation in Taiwan. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the cost effectiveness of novel oral anticoagulants (NOACs) for stroke prevention among atrial fibrillation (AF) patients by incorporating Taiwanese demographic information derived from a population-based database, the National Health Insurance Research Database (NHIRD), into cost-effectiveness analysis. METHODS: From 1 January to 31 December 2012, 98,213 AF patients were selected from the NHIRD database. A Markov model was constructed that combined published secondary data with the Taiwan NHIRD to compare the cost and incremental cost effectiveness of apixaban 5 mg twice daily, dabigatran 110 or 150 mg twice daily, rivaroxaban 20 mg once daily, and warfarin. RESULTS: The lifetime costs of warfarin, dabigatran 110 mg, dabigatran 150 mg, rivaroxaban 20 mg, and apixaban 5 mg were US$10,660, US$13,693, US$13,426, US$13,455, US$15,965, respectively. Apixaban resulted in an incremental cost effectiveness of US$39,351, US$27,039, US$41,298, and US$48,896 per quality-adjusted life-year (QALY) compared with warfarin, dabigatran 110 mg, dabigatran 150 mg, and rivaroxaban 20 mg, respectively. In Monte-Carlo analyses, apixaban 5 mg, rivaroxaban 20 mg, warfarin, and dabigatran 110 mg were cost effective in 83, 10.4, 7, and 0.8%, respectively, of the simulations using a willingness-to-pay (WTP) threshold of US$50,000 per QALY. CONCLUSIONS: Apixaban was more cost effective than warfarin, dabigatran, and rivaroxaban for stroke prevention in patients with AF. Among the anticoagulant therapies, the WTP threshold of apixaban was about US$50,000 per QALY gained. These cost-effectiveness estimations provide useful information to aid clinical decision making in stroke prevention for AF patients. PMID- 27988836 TI - An intra-laboratory cultural and real-time PCR method comparison and evaluation for the detection of subclinical paratuberculosis in dairy herds. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is a vigorous microorganism which causes incurable chronic enteritis, Johne's disease (JD) in cattle. A target of control programmes for JD is to accurately detect MAP-infected cattle early to reduce disease transmission. The present study evaluated the efficacy of two different cultural procedures and a TaqMan real-time PCR assay for detection of subclinical paratuberculosis in dairy herds. Therefore, sixty-one faecal samples were collected from two Dutch dairy herds (n = 40 and n = 21, respectively) which were known to be MAP-ELISA positive. All individual samples were assessed using two different cultural protocols in two different laboratories. The first cultural protocol (first laboratory) included a decontamination step with 0.75% hexadecylpyridinium chloride (HPC) followed by inoculation on Herrold's egg yolk media (HEYM). The second protocol (second laboratory) comprised of a decontamination step using 4% NaOH and malachite green oxalic acid followed by inoculation on two media, HEYM and in parallel on modified Lowenstein-Jensen media (mLJ). For the TaqMan real-time PCR assay, all faecal samples were tested in two different laboratories using TaqMan(r) MAP (Johne's) reagents (Life Technologies). The cultural procedures revealed positive reactions in 1.64% of the samples for cultivation protocol 1 and 6.56 and 8.20% of the samples for cultivation protocol 2, respectively. The results of the TaqMan real-time PCR performed in two different laboratories yielded 13.11 and 19.76% positive reaction. The kappa test showed proportional agreement 0.54 between the mLJ media (second laboratory) and TaqMan(r) real-time PCR method (second laboratory). In conclusion, the TaqMan real-time PCR could be a strongly useful and efficient assay for the detection of subclinical paratuberculosis in dairy cattle leading to an improvement in the efficiency of MAP control strategies. PMID- 27988837 TI - Talimogene Laherparepvec (T-VEC) and Other Oncolytic Viruses for the Treatment of Melanoma. AB - Many mammalian viruses have properties that can be commandeered for the treatment of cancer. These characteristics include preferential infection and replication in tumor cells, the initiation of tumor cell lysis, and the induction of innate and adaptive anti-tumor immunity. Furthermore, viruses can be genetically engineered to reduce pathogenicity and increase immunogenicity resulting in minimally toxic therapeutic agents. Talimogene laherparepvec (T-VEC; ImlygicTM), is a genetically modified herpes simplex virus, type 1, and is the first oncolytic virus therapy to be approved for the treatment of advanced melanoma by the US FDA. T-VEC is attenuated by the deletion of the herpes neurovirulence viral genes and enhanced for immunogenicity by the deletion of the viral ICP47 gene. Immunogenicity is further supported by expression of the human granulocyte macrophage colony-stimulating factor (GM-CSF) gene, which helps promote the priming of T cell responses. T-VEC demonstrated significant improvement in durable response rate, objective response rate, and progression-free survival in a randomized phase III clinical trial for patients with advanced melanoma. This review will discuss the optimal selection of patients for such treatment and describe how therapy is optimally delivered. We will also discuss future directions for oncolytic virus immunotherapy, which will likely include combination T-VEC clinical trials, expansion of T-VEC to other types of non melanoma skin cancers, and renewed efforts at oncolytic virus drug development with other viruses. PMID- 27988838 TI - Polymorphisms of Genes Encoding Multidrug Resistance Proteins as a Predictive Factor for Second-Line Docetaxel Therapy in Advanced Non-small Cell Lung Cancer. AB - Multidrug resistance (MDR) remains a substantial problem in chemotherapy. The purpose of the study was to investigate potential factors, including MDR genes polymorphisms, that could be used in qualification for second-line docetaxel therapy in non-small cell lung cancer (NSCLC) patients after failure of platinum based chemotherapy. Study group comprised of 58 Caucasian subjects. Evaluation of Single Nucleotide Polymorphisms (SNPs) of ABCC2/MRP2 and ABCB1/MDR1 genes was performed using the High Resolution Melting (HRM) technique. TUBB3 gene expression was evaluated on RNA isolated from tumor tissue. Results with p value of <0.05 were considered significant. Factors associated with reduced risk of disease progression included good performance status (PS), long period between diagnosis and docetaxel treatment, and smoking for <10 pack-years. Disease control occurred more often in patients with G/G genotype of the ABCC2/MRP2 gene. Median overall survival was 4.25 months. Factors such as: good PS, disease control after docetaxel, long period from diagnosis to docetaxel, lack of significant weight loss, and third-line treatment were associated with prolongation of patients survival. Overall survival probability was significantly lower in patients with significant weight loss, poor PS, lack of disease control after docetaxel, and without third-line treatment. Factors that characterized the highest risk of survival shortening were: inability to apply third-line treatment, lack of best response to first-line therapy, poor PS, and C/G or G/G genotypes of ABCC2/MRP2 gene. We concluded that assessed factors had mainly prognostic and not predictive value. Finding reliable molecular predictors for second line docetaxel therapy requires further clinical trials. PMID- 27988839 TI - DRalpha1-MOG-35-55 Reduces Permanent Ischemic Brain Injury. AB - Stroke induces a catastrophic immune response that involves the global activation of peripheral leukocytes, especially T cells. The human leukocyte antigen DRalpha1 domain linked to MOG-35-55 peptide (DRalpha1-MOG-35-55) is a partial major histocompatibility complex (MHC) class II construct which can inhibit neuroantigen-specific T cells and block binding of the cytokine/chemokine macrophage migration inhibitory factor (MIF) to its CD74 receptor on monocytes and macrophages. Here, we evaluated the therapeutic effect of DRalpha1-MOG-35-55 in a mouse model of permanent distal middle cerebral artery occlusion (dMCAO). DRalpha1-MOG-35-55 was administered to WT C57BL/6 mice by subcutaneous injection starting 4 h after the onset of ischemia followed by three daily injections. We demonstrated that DRalpha1-MOG-35-55 post treatment significantly reduced brain infarct volume, improved functional outcomes, and inhibited the accumulation of CD4+ and CD8+ T cells and expression of pro-inflammatory cytokines in the ischemic brain 96 h after dMCAO. In addition, DRalpha1-MOG-35-55 treatment shifted microglia/macrophages in the ischemic brain to a beneficial M2 phenotype without changing their total numbers in the brain or blood. This study demonstrates for the first time the therapeutic efficacy of the DRalpha1-MOG-35 55 construct in dMCAO across MHC class II barriers in C57BL/6 mice. This MHC independent effect obviates the need for tissue typing and will thus greatly expedite treatment with DRalpha1-MOG-35-55 in human stroke subjects. Taken together, our findings suggest that DRalpha1-MOG-35-55 treatment may reduce ischemic brain injury by regulating post-stroke immune responses in the brain and the periphery. PMID- 27988840 TI - Claudin proteins, outside-in signaling, and carcinogenesis. AB - Environment affects an individual's development and disease risk which then suggest that the environmental cues must have ways of reaching to the cellular nuclei to orchestrate desired genetic changes. Polarized and differentiated epithelial cells join together by cell-cell adhesions to create a protective sheet which separates body's internal milieu from its environment, albeit in highly regulated manner. Among these cell-cell adhesions, a key role of tight junction, the apical cell-cell adhesion, in maintaining epithelial cell polarity and differentiation is well recognized. Moreover, significant changes in expression and cellular distribution of claudin proteins, integral component of the tight junction, characterize pathophysiological changes including neoplastic growth and progression. Studies have further confirmed existence of complex claudin-based interactomes and demonstrated that changes in such protein partnering can influence barrier integrity and communication between a cell and its environment to produce undesired outcome. Cell signaling is the process by which cells respond to their environment to make dynamic decisions to live, grow and proliferate, or die. Thus, pivotal role of the deregulated tight junction structure/function in influencing cellular signaling cascades to alter cellular phenotype can be envisaged, however, is not well understood. Needless to mention that advanced knowledge in this area can help improve therapeutic considerations and preventive measures. Here, we discuss potential role of the tight junction in the regulation of "outside-in" signaling to regulate cancer growth, with specific focus upon the claudin family of proteins. PMID- 27988842 TI - Current developments in cancer care: including the patients' perspective-3rd European Roundtable Meeting (ERTM) June 17, 2016, Berlin, Germany. AB - PURPOSE: National Cancer Control Plans (NCCP) are necessary to improve cancer care and reduce mortality. We have reported previously on European institutional health structures and transformation of theoretical health care standards into a practical approach. For the latter consideration of the patients' perspective was considered as highly important and chosen as subject for this meeting. RESULTS: Several European organizations have realized deficits in this area. They promote equal and timely access to cancer care since current inequities lead to disparities in cancer survival across Europe. Patients' support working groups are focussing on employment issues, financial services, psychosocial screening and support, palliative care and rehabilitation. They also identified cancer research including patients' views as highly important. Workshops during the 3rd European Roundtable Meeting (ERTM) covered the issues transparency in patient care, implementation of new knowledge and decision making in partnership with the patient. CONCLUSIONS: It was concluded that patient views and perspectives have to be considered during the whole continuum of cancer care. Access to treatment, transparency and including patients into the development process are relevant aspects. PMID- 27988843 TI - Fingerprint changes among cancer patients treated with paclitaxel. AB - BACKGROUND: Fingerprints have long been used for personal identification; however, some case reports suggested that some chemotherapy agents such as paclitaxel lead to fingerprints loss due to hand-and-foot syndrome (HFS). METHODS: This case-control study was performed on 65 patients who received chemotherapy regimens with/without paclitaxel. Patients with the history of receiving any drugs with significant HFS adverse effect or patients with any conditions that affect fingerprints were excluded. Baseline and post-chemotherapy images of fingerprint examples were referred to the Iranian Society of Legal Medicine to compare changes in the fingerprints. RESULTS: Thirty-one patients entered in the paclitaxel and 34 subjects in the control groups. Seventeen patients (54.8%) in the paclitaxel group experienced fingerprint changes, whereas no patient had fingerprint changes in the control group. By physical examination, no patients in the two groups experienced HFS. After adjusting for age, sex, occupation, and cancer type, there was a significant difference between the two groups regarding fingerprint changes (P = 0.002, OR 13.69, 95% CI 2.05 to infinite). CONCLUSIONS: Considering that fingerprint recognition has been utilized in both government and civilian investigation, patients taking paclitaxel and centers necessitating fingerprint identification should be informed about possible fingerprint changes by paclitaxel. PMID- 27988841 TI - SO4= uptake and catalase role in preconditioning after H2O2-induced oxidative stress in human erythrocytes. AB - Preconditioning (PC) is an adaptive response to a mild and transient oxidative stress, shown for the first time in myocardial cells and not described in erythrocytes so far. The possible adaptation of human erythrocytes to hydrogen peroxide (H2O2)-induced oxidative stress has been here verified by monitoring one of band 3 protein functions, i.e., Cl-/HCO3- exchange, through rate constant for SO4= uptake measurement. With this aim, erythrocytes were exposed to a mild and transient oxidative stress (30 min to either 10 or 100 MUM H2O2), followed by a stronger oxidant condition (300- or, alternatively, 600-MUM H2O2 treatment). SO4= uptake was measured by a turbidimetric method, and the possible role of catalase (CAT, significantly contributing to the anti-oxidant system in erythrocytes) in PC response has been verified by measuring the rate of H2O2 degradation. The preventive exposure of erythrocytes to 10 MUM H2O2, and then to 300 MUM H2O2, significantly ameliorated the rate constant for SO4= uptake with respect to 300 MUM H2O2 alone, showing thus an adaptive response to oxidative stress. Our results show that (i) SO4= uptake measurement is a suitable model to monitor the effects of a mild and transient oxidative stress in human erythrocytes, (ii) band 3 protein anion exchange capability is retained after 10 MUM H2O2 treatment, (iii) PC response induced by the 10 MUM H2O2 pretreatment is clearly detected, and (iv) PC response, elicited by low-concentrated H2O2, is mediated by CAT enzyme and does not involve band 3 protein tyrosine phosphorylation pathways. Erythrocyte adaptation to a short-term oxidative stress may serve as a basis for future studies about the impact of more prolonged oxidative events, often associated to aging, drug consumption, chronic alcoholism, hyperglycemia, or neurodegenerative diseases. PMID- 27988844 TI - Comparison of 8-frame and 16-frame thallium-201 gated myocardial perfusion SPECT for determining left ventricular systolic and diastolic parameters. AB - The myocardial perfusion single photon emission computed tomography synchronized with the electrocardiogram (gated SPECT) has been widely used for the assessment of left ventricular (LV) systolic and diastolic functions using Quantitative gated SPECT. The aim of this study was to compare the effects of 8-frame and 16 frame thallium-201 (Tl-201) gated SPECT for determining LV systolic and diastolic parameters. The study population included 42 patients with suspected coronary artery disease who underwent gated SPECT by clinical indication. LV systolic and diastolic parameters were assessed on 8-frame and 16-frame gated SPECT. There were good correlations in end-diastolic volume (r = 0.99, p < 0.001), end systolic volume (ESV) (r = 0.97, p < 0.001) and ejection fraction (EF) (r = 0.95, p < 0.001) between 8-frame and 16-frame gated SPECT. Bland-Altman plot showed a significant negative slope of -0.08 in EDV indicating a larger difference for larger EDV. Eight-frame gated SPECT overestimated ESV by 2.3 ml, and underestimated EF by -4.2% than 16-frame gated SPECT. There were good correlations in peak filling rate (PFR) (r = 0.87, p < 0.001), one third mean filling rate (r = 0.87, p < 0.001) and time to PFR (r = 0.61, p < 0.001) between 8-frame and 16-frame gated SPECT. Eight-frame gated SPECT underestimated PFR by 0.22 than 16-frame gated SPECT. Eight-frame gated SPECT estimated as much MFR/3 and TPFR as 16-frame gated SPECT. According to the data, the study suggested that 8-frame Tl-201 gated SPECT could underestimate systolic and/or diastolic parameter when compared with 16-frame gated SPECT. PMID- 27988845 TI - An updated histological classification system for multiple sclerosis lesions. AB - Multiple sclerosis is a complex and heterogeneous, most likely autoimmune, demyelinating disease of the central nervous system (CNS). Although a number of histological classification systems for CNS lesions have been used by different groups in recent years, no uniform classification exists. In this paper, we propose a simple and unifying classification of MS lesions incorporating many elements of earlier histological systems that aims to provide guidelines for neuropathologists and researchers studying MS lesions to allow for better comparison of different studies performed with MS tissue, and to aid in understanding the pathogenesis of the disease. Based on the presence/absence and distribution of macrophages/microglia (inflammatory activity) and the presence/absence of ongoing demyelination (demyelinating activity), we suggest differentiating between active, mixed active/inactive, and inactive lesions with or without ongoing demyelination. Active lesions are characterized by macrophages/microglia throughout the lesion area, whereas mixed active/inactive lesions have a hypocellular lesion center with macrophages/microglia limited to the lesion border. Inactive lesions are almost completely lacking macrophages/microglia. Active and mixed active/inactive lesions can be further subdivided into lesions with ongoing myelin destruction (demyelinating lesions) and lesions in which the destruction of myelin has ceased, but macrophages are still present (post-demyelinating lesions). This distinction is based on the presence or absence of myelin degradation products within the cytoplasm of macrophages/microglia. For this classification of MS lesions, identification of myelin with histological stains [such as luxol fast blue-PAS] or by immunohistochemistry using antibodies against myelin basic-protein (MBP) or proteolipid-protein (PLP), as well as, detection of macrophages/microglia by, e.g., anti-CD68 is sufficient. Active and demyelinating lesions may be further subdivided into the early and late demyelinating lesions. The former is defined by the presence in macrophages of major and small molecular weight myelin proteins, such as cyclic nucleotide diphosphoesterase (CNP), myelin oligodendrocyte glycoprotein (MOG), or myelin-associated protein (MAG), whereas macrophages in the latter demonstrate merely the presence of the major myelin proteins MBP or PLP. We discuss the histological features and staining techniques required to classify MS lesions, and, in addition, describe the histological hallmarks of cortical pathology and diffuse white matter changes, as well as of remyelination. PMID- 27988846 TI - Copy number variations as potential diagnostic and prognostic markers for CNS melanocytic neoplasms in neurocutaneous melanosis. PMID- 27988848 TI - First clinical evaluation of a new single-use flexible cystoscope dedicated to double-J stent removal (IsirisTM): a European prospective multicenter study. AB - PURPOSE: We evaluated a new single-use digital flexible cystoscope with an integrated grasper designed for double-J stent removal, IsirisTM, addressing success rate, image quality, deflection, maneuverability and grasper functionality. METHODS: In September 2015, a prospective cohort study was conducted in six tertiary European reference centers. All consecutive patients included underwent double-J stent removal and were 18 years or older. Success rate was defined by complete stent removal. Image quality, deflection, maneuverability and grasper functionality were rated with a Likert scale. RESULTS: A total of 83 procedures were performed. 82% of procedures were performed in the endoscopy room, while the others were in the operating room since a consecutive endourological intervention was planned. The median duration of stent implantation was 28 days [14; 60]. In five patients, stent removal was not possible. Four patients had an incrusted double-J stent, and in one patient, the stent migrated into the ureter. After unsuccessful attempts of stent removal with conventional flexible cystoscope and grasper, the five patients had to be scheduled for an ureterorenoscopy procedure to remove the stent. In the other 78 patients, all double-J stents were removed successfully. Image quality, deflection, maneuverability and grasper functionality were rated as "very good" in 72.3, 78.3, 72.3 and 73.5%, respectively. CONCLUSION: This multicenter clinical evaluation of IsirisTM displayed good image quality, active deflection, maneuverability and grasper functionality. Further evaluation of stent removal outcomes, cost analysis and microbiology will help to delineate the possible place of IsirisTM in the current practice. PMID- 27988849 TI - Bacterial reduction and shift with NPWT after surgical debridements: a retrospective cohort study. AB - BACKGROUND: Surgical debridement, negative-pressure wound therapy (NPWT) and antibiotics are used for the treatment of open wounds. However, it remains unclear whether this treatment regimen is successful in the reduction and shift of the bacterial load. METHODS: After debridement in the operating room, NPWT, and antibiotic treatment, primary and secondary consecutive microbiological samples of 115 patients with 120 open wounds with bacterial or yeast growth in >=1 swab or tissue microbiological sample(s) were compared for bacterial growth, Gram staining and oxygen use at a level one trauma center in 2011. RESULTS: Secondary samples had significantly less bacterial growth (32 vs. 89%, p < .001, OR 17), Gram-positive bacteria (56 vs. 78%, p = .013), facultative anaerobic bacteria (64 vs. 85%, p = .011) and Staphylococcus aureus (10 vs. 46%, p = .002). They also tended to include relatively more Coagulase-negative Staphylococci (CoNS) (44 vs. 18%) and Pseudomonas species (spp.) (31 vs. 7%). Most (98%) wounds were successfully closed within 11 days, while wound revision was needed in 4%. CONCLUSIONS: The treatment regimen of combined use of repetitive debridement, irrigation and NPWT in an operating room with antibiotics significantly reduced the bacterial load and led to a shift away from Gram-positive bacteria, facultative anaerobic bacteria, and S. aureus, as well as questionably toward CoNS and Pseudomonas spp. in this patient cohort. High rates of wound closure were achieved in a relatively short time with low revision rates. Whether each modality played a role for these findings remains unknown. PMID- 27988847 TI - Calcium and vitamin D3 combinations improve fatty liver disease through AMPK independent mechanisms. AB - PURPOSE: Some research findings suggest that calcium plus vitamin D (VitD) might have a preventive effect on nonalcoholic fatty liver disease development. Moreover, contradictory evidence also exists regarding calcium and VitD deficient diets. This study aimed to evaluate the effect of four different dietary calcium and VitD3 (cholecalciferol) levels on the development of high-fat, high-fructose (HFHFr) diet-induced nonalcoholic fatty liver disease and AMP-activated protein kinase (AMPK) phosphorylation. METHODS: Thirty male Wistar rats were fed with normal or HFHFr diet containing low calcium (0.2%) and VitD3 (250 IU/kg) (LCD), normal calcium (0.5%) and VtD3 (1000 IU/kg) (CN), high calcium (1.2%) and VitD3 (4000 IU/kg) (HCD) or very high amount of calcium (2.4%) and VitD3 (10,000 IU/kg) (VHCD). After 60 days, anthropometric, metabolic and hepatic parameters were evaluated. The effect of the experimental diets on liver AMPK phosphorylation was also investigated. RESULTS: Rats fed on high calcium plus VitD3 diets, especially VHCD, demonstrated lower adiposity, serum liver enzymes, hepatic lipid accumulation and steatosis. The LCD diet also decreased hepatic lipid content and fatty changes. No evidence indicating the involvement of AMPK in the observed associations was found (P value = 0.51). CONCLUSIONS: The results showed high calcium plus VitD3 intakes considerably prevent biochemical and hepatic changes induced by HFHFr diet, probably via an insulin and AMPK-independent pathway. A low intake of these two nutrients was also linked with a significant decrease in HFHFr diet-induced hepatic steatosis. PMID- 27988851 TI - Outcomes following sclerotherapy for mucosal rectal prolapse with oily phenol injection: single-centre review. AB - AIM OF THE STUDY: To review the outcomes of injection sclerotherapy with oily phenol for mucosal rectal prolapse. METHODS: Retrospective case note review of all children who underwent sclerotherapy with oily phenol injection as primary surgical intervention for mucosal rectal prolapse, from January 2007 to December 2015. MAIN RESULTS: A total of 31 patients were identified. Mean age at presentation was 4.8 years (range 5 months-12 years). 23 patients with mucosal rectal prolapse underwent injection sclerotherapy with oily phenol as primary procedure. Patients with full-thickness rectal prolapse (n = 6) and 2 with mucosal prolapse who had Thiersch stitch were excluded from the study. The cause for mucosal rectal prolapse was considered to be due to constipation (n = 15), idiopathic (n = 7), spina bifida (n = 1). Follow-up was for minimum 6 months (median = 4 years; range 6 months-17 years). Recurrence following injection sclerotherapy with oily phenol requiring further procedures was 30.4% (7/23). CONCLUSIONS: Injection sclerotherapy with oily phenol is a safe, effective and minimally invasive primary treatment option for mucosal rectal prolapse not responding to conservative management. In case of recurrence, a cautious re examination under anaesthesia should be undertaken to exclude a missed full thickness rectal prolapse before reinjecting. PMID- 27988850 TI - Advances in understanding functional variations in the Hirschsprung disease spectrum (variant Hirschsprung disease). AB - Hirschsprung disease (HSCR) is a fairly well understood congenital, genetically based functional obstruction due to the congenital absence of ganglion cells in the distal bowel. However, although over 90% of Hirschsprung cases conform to the normally accepted histological diagnostic criteria, it has become increasingly clear that in addition to HSCR, there is a group of functional disturbances relating to a number of other congenital neurodysplastic conditions causing some degree of gastrointestinal tract malfunction. Although these represent a variety of possibly separate conditions of the enteric nervous system, this spectrum it would appear to be also influenced by similar developmental processes. The term "variant Hirschsprung" is commonly used to describe these conditions, but ganglion cells are mostly present if abnormal in number and distribution. These conditions are a problem group being amongst the most difficult to diagnose and treat with possible practical and legal consequences. The problem appears to be possibly one of definition which has proven difficult in the relative paucity of normal values, especially when correlated to age and gestation. It is the purpose of this paper to review the current position on these conditions and to explore possible shared common pathogenetic and genetic mechanisms. This article explores those conditions where a similar pathogenetic mechanisms to HSCR can be demonstrated (e.g. hypoganglionosis) as well as other neural features, which appear to represent separate conditions possibly linked to certain syndromes. PMID- 27988853 TI - Status of bovine tuberculosis and its zoonotic implications in Borana zone, Southern Ethiopia. AB - A cross-sectional study was carried out from April 2015 to June 2016 to estimate the status of bovine tuberculosis (BTB), assessment of community's current knowledge, and zoonotic importance on this disease in Borana zone, southern Ethiopia. In this study, comparative intradermal tuberculin (CIDT) test, structured questionnaires, and retrospective data were used, while the result indicated 3.8% prevalence at individual animal level with 5.6% (31/554) of doubtful reactors. Among related risk factors included, old animals were significantly infected by BTB than young one (chi 2 = 32.005, P = 0.001). Parity number again showed significant difference (chi 2 = 29.163, P = 0.001) where animals with many parity were more reactive to conducted test than few parity numbers. Animals born in the breeding center managed under semi-intensive production system were more infected (chi 2 = 10.795, P = 0.029) than those brought from outside of the center. Questionnaire survey in this study indicated that out of 130 interviewed respondents, only 30% pastoralists knew what BTB mean; whereas the level of individual knowledge from interviewed showed about 72.3% of respondents had poor understanding of BTB and only about 11.5% of them knew its zoonotic importance. Meat eating habit of communities in the area were culturally inhabited to eat cooked meat and only 12.3% (16/130) of respondents gave response on habit of eating both raw and cooked meat. Milk drinking habit of pastoralist in the area showed about 79.2% drunk raw milk and the rest 20.8% used both raw and boiled milk. A retrospective data from Yabello Hospital indicated that current prevalence of human TB as 38.79% and showing the disease was highly increasing from year to year in the study area. This implies a great importance of human tuberculosis and its future concern in Borana zone. From this, there should be detail awareness of communities on BTB, its zoonotic importance, and the need of further investigation to develop control and prevention strategies according to the pastoral settings. PMID- 27988854 TI - Use of Crude Glycerol as Sole Carbon Source for Microbial Lipid Production by Oleaginous Yeasts. AB - Crude glycerol, discharged from biodiesel production process, is a potential carbon source for microbial lipid production. The capability of using crude glycerol as sole carbon source for microbial lipid production by oleaginous yeasts Trichosporon fermentans and Trichosporon cutaneum was investigated for the first time. T. fermentans and T. cutaneum could use crude glycerol for efficient lipid production, and the optimal glycerol concentration for which were 50 and 70 g/L, respectively. The optimum nitrogen source, C/N, inoculum concentration, and pH were yeast extract + peptone, 60, 10.0%, and 6.0, respectively. The most suitable culture temperature for T. fermentans and T. cutaneum were 28 and 30 degrees C, respectively. Under the optimal conditions, the maximum biomass, lipid content, lipid yield, and lipid coefficient of T. fermentans and T. cutaneum were 16.0 g/L, 32.4%, 5.2 g/L, and 16.5%, and 17.4 g/L, 32.2%, 5.6 g/L, and 17.0%, respectively. Moreover, it was found that methanol present in the crude glycerol had minor influence on the lipid production. Addition of surfactant potassium oleate into the medium could slightly stimulate the cell growth and lipid accumulation of both yeasts. This study shows that T. fermentans and T. cutaneum are promising strains for lipid production on crude glycerol. PMID- 27988852 TI - Obsessive-compulsive symptoms and overall psychopathology in psychotic disorders: longitudinal assessment of patients and siblings. AB - The course of obsessive-compulsive symptoms (OCS) and its association with alterations in other clinical variables in patients with psychotic disorders is insufficiently known. Patients (n = 602) and unaffected siblings (n = 652) from the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study were investigated at baseline and after 3 years. Participants were assigned to four groups based on the course of OCS over time: no-OCS, persistent OCS, initial OCS and de novo OCS. In addition to cross-sectional comparisons, longitudinal associations between changes in OCS and symptoms of schizophrenia and general functioning were investigated. Patients with co-occurring OCS reported significantly higher severity of psychotic and affective symptoms as well as lower overall functioning compared to patients without OCS. These differences were stable over time for patients reporting persistent OCS. Subsequent repeated measure analysis revealed significant interaction effects for groups reporting changes in their OCS. Whereas the group with remission of initial OCS showed significant improvement in positive symptoms, emotional distress and functioning, the de novo group showed no significant change in these variables, but rather reported stable higher psychopathology. Similar results were found on a subclinical level in siblings. Patients with co-occurring OCS present a more severe clinical picture, especially if symptoms persist over time. The remission of OCS was associated with overall improvement, whereas individuals with de novo OCS already reported higher clinical impairment before OCS onset. More research is needed to elucidate causal pathways and to develop effective interventions for persistent comorbid OCS. PMID- 27988855 TI - Assessment of the Fusion Tags on Increasing Soluble Production of the Active TEV Protease Variant and Other Target Proteins in E. coli. AB - In this study, five fusion tags affecting soluble production and cleavage activity of the tobacco etch virus (TEV) protease (TEVp) variant in Escherichia coli strains BL21 (DE3) and RosettaTM (DE3) are investigated. Combination of the augmenting rare transfer RNAs (tRNAs) and the fused expressivity tag (N-terminal seven amino acid residues of E. coli translation initiation factor II) promotes the soluble TEVp partner expressed at relatively high level. Attachment of the maltose-binding protein (MBP) tag increases soluble expression of the protease released from the fusion protein in E. coli cells, but the incorporated TEVp recognition sequence slightly decreases expressivity of the fusion construct. Except for the green fluorescent protein, the attached expressivity tag shows less efficiency than the MBP tag in enhancing expression levels of the selected five target proteins in the RosettaTM (DE3) cells under different induction conditions. Our results identified that high-level production of the functional target protein as the fusion partner in E. coli is combined with the intrinsic property of fusion tag, fusion protein stability, inherent folding of target protein, rare tRNA abundance, and the incorporated linker. Purified TEVp fusion constructs with the N-terminal expressivity tag, as well as the MBP partner, are the ideal alternatives for removing fusion tag. PMID- 27988856 TI - Bioproduction of L-Aspartic Acid and Cinnamic Acid by L-Aspartate Ammonia Lyase from Pseudomonas aeruginosa PAO1. AB - Aspartase (L-aspartate ammonia lyase, EC 4.3.1.1) catalyses the reversible amination and deamination of L-aspartic acid to fumaric acid which can be used to produce important biochemical. In this study, we have explored the characteristics of aspartase from Pseudomonas aeruginosa PAO1 (PA-AspA). To overproduce PA-AspA, the 1425-bp gene was introduced in Escherichia coli BL21 and purified. A 51.0-kDa protein was observed as a homogenous purified protein on SDS PAGE. The enzyme was optimally active at pH 8.0 and 35 degrees C. PA-AspA has retained 56% activity after 7 days of incubation at 35 degrees C, which displays the hyperthermostablility characteristics of the enzyme. PA-AspA is activated in the presence of metal ions and Mg2+ is found to be most effective. Among the substrates tested for specificity of PA-AspA, L-phenylalanine (38.35 +/- 2.68) showed the highest specific activity followed by L-aspartic acid (31.21 +/- 3.31) and fumarate (5.42 +/- 2.94). K m values for L-phenylalanine, L-aspartic acid and fumarate were 1.71 mM, 0.346 MUM and 2 M, respectively. The catalytic efficiency (k cat/K m) for L-aspartic acid (14.18 s-1 mM-1) was higher than that for L phenylalanine (4.65 s-1 mM-1). For bioconversion, from an initial concentration of 1000 mM of fumarate and 30 mM of L-phenylalanine, PA-AspA was found to convert 395.31 MUM L-aspartic acid and 3.47 mM cinnamic acid, respectively. PMID- 27988857 TI - Association of LIM Domain 7 Gene Polymorphisms and Plasma Levels of LIM Domain 7 with Dilated Cardiomyopathy in a Chinese Population. AB - The aim of our study was to investigate the potential association of mRNA expression and plasma levels of the LIM domain 7 (LMO7) gene with the pathogenesis of dilated cardiomyopathy (DCM). Two SNPs of the LMO7 gene were genotyped in 310 patients with DCM and 415 controls. Our results showed that SNP rs7986131 (p = 0.002, OR = 1.38, 95% CI = 1.12-1.71), but not SNP rs4884021, was associated with DCM in the Han Chinese population. Haplotype analysis showed that the haplotype GT was associated with increased DCM susceptibility while AC was a protective haplotype. The Cox multivariate survival analysis indicated that the rs7986131 TT genotype (HR 1.659, 95% CI = 1.122-2.454, p = 0.011) was an independent multivariate predictor for shorter overall survival in patients with DCM. LMO7 mRNA expression and plasma LMO7 levels were significantly decreased in DCM (p < 0.0001). Spearman correlation test revealed that the plasma LMO7 level was negatively associated with left ventricular end-diastolic diameter (r = 0.384, p = 0.01), left ventricular end-diastolic volume (r = -0.375, p = 0.012), and brain natriuretic peptide (r = -0.482, p = 0.001). Our study suggested that the LMO7 gene may play an important role in the pathogenesis of DCM in the Han Chinese population. PMID- 27988859 TI - ATM mutations for surgeons. AB - The ataxia-telangiectasia mutated (ATM) gene encodes a protein kinase involved in DNA repair. Heterozygotic carriers are at an increased risk of developing breast cancer. As the use of genetic testing increases, identification of at-risk patients will also increase. The aim of this study is to review two cases of heterozygous ATM mutation carriers and review the literature to clarify the cancer risks and suggested management for breast surgeons who will be intimately involved in the care of these patients. PMID- 27988858 TI - Sequence-specific assignment of methyl groups from the neuronal SNARE complex using lanthanide-induced pseudocontact shifts. AB - Neurotransmitter release depends critically on the neuronal SNARE complex formed by syntaxin-1, SNAP-25 and synaptobrevin, as well as on other proteins such as Munc18-1, Munc13-1 and synaptotagmin-1. Although three-dimensional structures are available for these components, it is still unclear how they are assembled between the synaptic vesicle and plasma membranes to trigger fast, Ca2+-dependent membrane fusion. Methyl TROSY NMR experiments provide a powerful tool to study complexes between these proteins, but assignment of the methyl groups of the SNARE complex is hindered by its limited solubility. Here we report the assignment of the isoleucine, leucine, methionine and valine methyl groups of the four SNARE motifs of syntaxin-1, SNAP-25 and synaptobrevin within the SNARE complex based solely on measurements of lanthanide-induced pseudocontact shifts. Our results illustrate the power of this approach to assign protein resonances without the need of triple resonance experiments and provide an invaluable tool for future structural studies of how the SNARE complex binds to other components of the release machinery. PMID- 27988861 TI - Day Traders in South Australia: Similarities and Differences with Traditional Gamblers. AB - The present study investigated the relationship between engaging in day trading and engaging in traditional forms of gambling in South Australia. Consistent with a previous study on this issue, it would appear that most individuals who engage in day trading are heavily involved traditional gamblers who include day trading in their repertoire of activities. They differ somewhat from most gamblers in their strong preference for skill-based types of gambling, their higher overall involvement in gambling, and their higher rates of problem gambling. They also have some demographic differences, in particular, being older and having higher incomes. The present findings provide further evidence that not only do certain types of financial speculation bear some conceptual similarity to gambling, they also appear to be empirically related. PMID- 27988860 TI - The mitochondrial apoptotic pathway is induced by Cu(II) antineoplastic compounds (Casiopeinas(r)) in SK-N-SH neuroblastoma cells after short exposure times. AB - The family of Copper(II) coordination compounds Casiopeinas(r) (Cas) has shown antiproliferative activity in several tumour lines by oxidative cellular damage and mitochondrial dysfunction that lead to cell death through apoptotic pathways. The goal of this work is looking for the functional mechanism of CasIIgly, CasIIIia and CasIIIEa in neuroblastoma metastatic cell line SK-N-SH, a paediatric extra-cranial tumour which is refractory to several anti-carcinogenic agents. All Cas have shown higher antiproliferative activity than cisplatin (IC50 = 123 MUM) with IC50 values of 18, 22 and 63 uM for CasIIgly, CasIIIEa and CasIIIia, respectively. At low concentrations and early times (4 h), these compounds cause a disruption of the mitochondrial transmembrane potential (Deltapsim). Concomitantly, an important depletion of intracellular glutathione and an increase of reactive oxygen species (ROS) hydrogen peroxide and radical superoxide were observed. On the other side, the lower cytotoxic effect of Casiopeinas on cultures of human peripheral blood lymphocytes (IC50CasIIgly = 1720 uM, IC50 CasIIIEa = 3860 uM and IC50 CasIIIia = 4700 uM) show the selectivity of these compounds over the tumour cells compared with the non transformed cells. Chemically, glutathione (GSH) interacts with Casiopeinas(r) through the coordination of sulphur atom to the metal centre, process which facilitates the electron transfer to get Cu(I), GSSG and the posterior production of ROS. Additionally, the molecular structure of CasIIIia as nitrate is reported. These results have shown that the anticarcinogenic activity of Casiopeinas(r) on neuroblastoma SK-N-SH is through mitochondrial apoptosis due to the enhanced pro oxidant environment promoted by the presence of the coordination copper compounds. PMID- 27988862 TI - Social Costs of Gambling in the Czech Republic 2012. AB - Evidence about social costs of gambling is scarce and the methodology for their calculation has been a subject to strong criticism. We aimed to estimate social costs of gambling in the Czech Republic 2012. This retrospective, prevalence based cost of illness study builds on the revised methodology of Australian Productivity Commission. Social costs of gambling were estimated by combining epidemiological and economic data. Prevalence data on negative consequences of gambling were taken from existing national epidemiological studies. Economic data were taken from various national and international sources. Consequences of problem and pathological gambling only were taken into account. In 2012, the social costs of gambling in the Czech Republic were estimated to range between 541,619 and 619,608 thousands EUR. While personal and family costs accounted for 63% of all social costs, direct medical costs were estimated to range from 0.25 to 0.28% of all social costs only. This is the first study which estimates social costs of gambling in any of the Central and East European countries. It builds upon the solid evidence about prevalence of gambling related problems in the Czech Republic and satisfactorily reliable economic data. However, there is a number of limitations stemming from assumptions that were made, which suggest that the methodology for the calculation of the social costs of gambling needs further development. PMID- 27988863 TI - Change Strategies and Associated Implementation Challenges: An Analysis of Online Counselling Sessions. AB - Self-change is the most frequent way people limit or reduce gambling involvement and often the first choice of people experiencing gambling-related problems. Less well known is the range of change strategies gamblers use and how these are selected, initiated or maintained. This study examined change strategies discussed in counselling transcripts from 149 clients who accessed a national online gambling help service in Australia. Using thematic analysis, we identified the presence of six change strategies; cash control and financial management, social support, avoiding or limiting gambling, alternative activities, changing thoughts and beliefs, and self-assessment and monitoring. Four implementation issues were also identified; a mismatch between need and strategy selection or maintenance; importance and readiness versus the cost of implementation; poor or unplanned transitions between strategies; and failure to review the helpfulness of strategies resulting in premature abandonment or unhelpful prolonged application. This study is the first to identify change strategies discussed in online counselling sessions. This study suggests change strategies are frequently discussed in online counselling sessions and we identified multiple new actions associated with change strategies that had not previously been identified. However, multiple implementation issues were identified and further work is required to determine the helpfulness of change strategies in terms of their selection, initiation and maintenance. PMID- 27988865 TI - Photobiomodulation therapy: management of mucosal necrosis of the oropharynx in previously treated head and neck cancer patients. AB - Necrosis of the oral mucosa following head and neck cancer radiation therapy presents considerable clinical management challenges. We report three cases of symptomatic persisting oral ulcerations where the addition of photobiomodulation therapy resulted in a rapid resolution of the oral lesions and in patient symptoms. These cases suggest that photobiomodulation may represent an adjunct to care of these difficult to manage complications in oncology. PMID- 27988864 TI - The potential relevance of docosahexaenoic acid and eicosapentaenoic acid to the etiopathogenesis of childhood neuropsychiatric disorders. AB - Over the last 15 years, considerable interest has been given to the potential role of omega-3 polyunsaturated fatty acids (PUFAs) for understanding pathogenesis and treatment of neurodevelopmental and psychiatric disorders. This review aims to systematically investigate the scientific evidence supporting the hypothesis on the omega-3 PUFAs deficit as a risk factor shared by different pediatric neuropsychiatric disorders. Medline PubMed database was searched for studies examining blood docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) status in children with neuropsychiatric disorders. Forty-one published manuscripts were compatible with the search criteria. The majority of studies on attention-deficit/hyperactivity disorder (ADHD) and autism found a significant decrease in DHA levels in patients versus healthy controls. For the other conditions examined-depression, juvenile bipolar disorder, intellectual disabilities, learning difficulties, and eating disorders (EDs)-the literature was too limited to draw any stable conclusions. However, except EDs, findings in these conditions were in line with results from ADHD and autism studies. Results about EPA levels were too inconsistent to conclude that EPA could be associated with any of the conditions examined. Finally, correlational data provided, on one hand, evidence for a negative association between DHA and symptomatology, whereas on the other hand, evidence for a positive association between EPA and emotional well-being. Although the present review underlines the potential involvement of omega-3 PUFAs in the predisposition to childhood neuropsychiatric disorders, more observational and intervention studies across different diagnoses are needed, which should integrate the collection of baseline PUFA levels with their potential genetic and environmental influencing factors. PMID- 27988866 TI - Body image assessment in oncology: an update review. AB - PURPOSE: Body image is a psychological dimension of the experience of cancer, which varies along the clinical features of the disease itself and in its phases, as well as its effects in terms of functioning and quality of life. In 2012, Supportive Care in Cancer published a review addressing the relevance, application, and instruments of body image assessment for oncological settings. Since then, many research papers have been published on this topic and new questionnaires for assessing body image in oncology are now available. This contribution aims to offer both researchers and clinicians an updated review of body image assessment tools. METHODS: We searched PubMed, Psychology and Behavioral Sciences Collection, and Scopus databases, which allowed us to identify pertinent papers, classified according to the body image tool to which they refer. We then extracted the characteristics and the psychometric properties from each study. RESULTS: From the 657 initial records, 23 papers met the selection criteria referring to 8 body image measurements. Although increasing in number and being the subject of a growing number of studies, these papers are still not exhaustive with respect to the verified psychometric properties. In particular, it is worth noting that their applicability to all types of cancer is limited and that a focus on women with breast cancer prevails. CONCLUSION: A complete validation (including a study of all types of validity and reliability) and an indication of the case results are not currently available for any of the eight instruments described. However, studies designed to apply body image assessment tools to patients other than those experiencing breast cancer as well to cultural contexts other than English-speaking countries, are increasing. PMID- 27988867 TI - Exercise preferences and associations between fitness parameters, physical activity, and quality of life in high-grade glioma patients. AB - PURPOSE: Exercise has numerous benefits for cancer survivors, but very limited research to date has exclusively examined brain cancer patients, specifically those diagnosed with high-grade glioma (HGG). This study examined (1) the feasibility of recruiting HGG patients to an exercise-based study and performing fitness assessments; (2) exercise counseling and programming preferences; and (3) associations between fitness, physical activity (PA), and quality of life (QOL). METHODS: Participants completed assessments prior to starting Temozolamide chemotherapy with radiation (T1), at 2 months and 8 months. Fitness was measured with an incremental cycling exercise test to volitional exhaustion (VO2peak) and hand grip dynamometry. The Godin leisure time questionnaire measured PA and the functional assessment for cancer therapy, brain cancer module (FACT-Br) measured QOL. RESULTS: Of the 35 approached, N = 16 participated. Due to safety concerns, the aerobic fitness test protocol was altered. Participants preferred to exercise during treatment, alone and unsupervised, at home, and at a moderate intensity. Few participants (<25%) met guidelines for PA at any time point. At T1, aerobic capacity was associated with the FACT Trial Outcome Index (TOI) (r = 0.619, p < 0.05). At 2 months, PA minutes were associated with FACT-TOI (r = 0.653, p = 0.057), FACT-G (r = 0.711, p < 0.05), and FACT-Br scores (r = 0.722, p < 0.05). CONCLUSIONS: Recruitment rate was similar to a previous study in HGG populations, but study completion rate was lower. Most exercise counseling and programming preferences were similar to previous brain cancer patients. Assessing aerobic fitness to VO2peak was not feasible. Aerobic fitness and PA were positively associated with QOL. PMID- 27988868 TI - Breast cancer survivors' experience of making weight, dietary and physical activity changes during participation in a weight loss intervention. AB - PURPOSE: The aim of this study is to explore breast cancer survivors' experience of a weight loss intervention and identify potential facilitators and barriers of initiating and maintaining weight, dietary or physical activity changes. METHOD: Fourteen women randomised to and completing the 12-month weight loss intervention completed semi-structured interviews 7.5 +/- 0.5 months after intervention completion. An inductive thematic analysis was conducted whereby interviews were independently coded and themes identified. RESULTS: Women were (mean +/- SD) 55.6 +/- 8.5 years, 30.2 +/- 4.6 kg/m2 and 17.1 +/- 3.4 months post-diagnosis at study baseline. Four themes emerged: (1) perceived motivation to participate in the intervention, (2) facilitators, (3) challenges and (4) maintenance of weight loss and behaviour changes. All women noted the impact of social/family environments, either to facilitate (e.g., support from family members) or impede (e.g., major family event) changes. The structure and support of the intervention, particularly accountability to their coach, was also seen as facilitating. Formation of habitual physical activity facilitated dietary changes. Dietary change strategies most perceived to facilitate weight loss were reducing energy intake by dietary self-monitoring, increasing vegetable intake and portion control. Challenges included breast cancer-specific issues such as post-diagnosis weight gain, treatment-related side effects and psychological issues around readiness to change and self-regulation. Diminished accountability following intervention completion impacted the maintenance of weight loss and behaviour changes, notably dietary self-monitoring. CONCLUSIONS: Results suggest that formal involvement of a support person (e.g. family member/friend) and referring women to ongoing, community-based services to maintain patient-perceived accountability may be particularly useful strategies for future weight loss intervention trials targeting women with breast cancer. PMID- 27988870 TI - Single-Dose Dalbavancin: A Review in Acute Bacterial Skin and Skin Structure Infections. AB - Intravenous dalbavancin (Dalvance(r), Xydalba(r)), first approved as a two-dose regimen for the treatment of acute bacterial skin and skin structure infections (ABSSSI), has now been additionally approved as a single-dose regimen. This narrative review discusses the pharmacological properties of intravenous dalbavancin and its clinical efficacy and tolerability as a single-dose regimen in the treatment of adult patients with ABSSSI. Single-dose dalbavancin is an effective and generally well tolerated treatment option for adults with ABSSSI, with noninferior efficacy to the two-dose dalbavancin regimen with regard to early clinical response (at 48-72 h) and low rates of adverse events. Clinical success rates at days 14 and 28 also did not significantly differ between the single- and two-dose dalbavancin regimens; neither did clinical success rates at day 14 when analysed by baseline pathogen. It has a broad spectrum of activity against common ABSSSI-related pathogens, and a favourable pharmacokinetic profile allowing for the convenience of single-dose administration. Thus, dalbavancin presents a promising alternative to conventional antibacterials for the treatment of ABSSSI in adult patients. PMID- 27988869 TI - Comparative Pharmacology and Guide to the Use of the Serotonin 5-HT3 Receptor Antagonists for Postoperative Nausea and Vomiting. AB - Since the introduction of the serotonin 5-hydroxy tryptamine 3 (5-HT3) receptor antagonists in the early 1990s, the incidence of postoperative nausea and vomiting (PONV) and post-discharge nausea and vomiting (PDNV) has decreased, yet continues to be a problem for the surgical patient. The clinical application of the 5-HT3 receptor antagonists has helped define the approach and role of these antiemetics in the prevention and treatment of PONV and PDNV. Pharmacological and clinical differences exist among these medications resulting in corresponding differences in effectiveness, safety, optimal dosage, time of administration, and use as combination and rescue antiemetic therapy. The clinical application of the 5-HT3 receptor antagonist antiemetics has improved the prevention and treatment of PONV and PDNV. The most recent consensus guidelines for PONV published in 2014 outline the use of these antiemetics. The 5-HT3 receptor antagonists play an important role to help prevent PONV and PDNV in perioperative care pathways such as Enhanced Recovery After Surgery (ERAS). Comparisons and guidelines for use of the 5-HT3 receptor antagonists in relation to the risk for PONV and PDNV are reviewed. PMID- 27988871 TI - Current Pharmacological Approaches to Reduce Chorea in Huntington's Disease. AB - There are currently no effective pharmacological agents available to stop or prevent the progression of Huntington's disease (HD), a rare hereditary neurodegenerative disorder. In addition to psychiatric symptoms and cognitive impairments, HD causes progressive motor disturbances, in particular choreiform movements, which are characterized by unwanted contractions of the facial muscles, trunk and extremities. Management of choreiform movements is usually advised if chorea interferes with daily functioning, causes social isolation, gait instability, falls, or physical injury. Although drugs to reduce chorea are available, only few randomized controlled studies have assessed the efficacy of these drugs, resulting in a high variety of prescribed drugs in clinical practice. The current pharmacological treatment options to reduce chorea in HD are outlined in this review, including the latest results on deutetrabenazine, a newly developed pharmacological agent similar to tetrabenazine, but with suggested less peak dose side effects. A review of the existing literature was conducted using the PubMed, Cochrane and Medline databases. In conclusion, mainly tetrabenazine, tiapride (in European countries), olanzapine, and risperidone are the preferred first choice drugs to reduce chorea among HD experts. In the existing literature, these drugs also show a beneficial effect on motor symptom severity and improvement of psychiatric symptoms. Generally, it is recommended to start with a low dose and increase the dose with close monitoring of any adverse effects. New interesting agents, such as deutetrabenazine and pridopidine, are currently under development and more randomized controlled trials are warranted to assess the efficacy on chorea severity in HD. PMID- 27988873 TI - Coagulation Factor IX (Recombinant), Albumin Fusion Protein (Albutrepenonacog Alfa; Idelvion(r)): A Review of Its Use in Haemophilia B. AB - Albutrepenonacog alfa (Idelvion(r)), a fusion protein that genetically fuses recombinant factor IX (rFIX) with recombinant human albumin (rAlbumin), is indicated in the treatment of haemophilia B. This narrative review discusses the pharmacological properties and clinical data related to the use of this novel fusion protein, hereafter referred to as rIX-FP. The fusion of rFIX to rAlbumin prolongs the elimination half-life of rIX-FP in the circulation, allowing routine prophylaxis to be administered once every 7-14 days. In the pivotal phase 3 clinical trials in previously treated patients with moderately severe to severe haemophilia B, routine rIX-FP prophylaxis (administered once every 7 days in children, and once every 7-14 days in adolescents and adults) was associated with low annualized spontaneous, total and joint bleeding rates, and was associated with significantly fewer bleeding episodes than on-demand treatment. rIX-FP was also effective in controlling bleeding episodes when used as on-demand treatment and in maintaining haemostasis in the perioperative setting. rIX-FP was well tolerated in the clinical trials, with no reports of inhibitor development. In conclusion, rIX-FP provides an effective, well-tolerated option for the treatment and management of haemophilia B that, by virtue of its extended half-life, is less burdensome than conventional FIX products. PMID- 27988874 TI - Cognitive Functioning and Heat Strain: Performance Responses and Protective Strategies. AB - Despite the predominance of research on physical performance in the heat, many activities require high cognitive functioning for optimal performance (i.e. decision making) and/or health purposes (i.e. injury risk). Prolonged periods of demanding cognitive activity or exercise-induced fatigue will incur altered cognitive functioning. The addition of hot environmental conditions will exacerbate poor cognitive functioning and negatively affect performance outcomes. The present paper attempts to extract consistent themes from the heat-cognition literature to explore cognitive performance as a function of the level of heat stress encountered. More specifically, experimental studies investigating cognitive performance in conditions of hyperthermia, often via the completion of computerised tasks (i.e. cognitive tests), are used to better understand the relationship between endogenous thermal load and cognitive performance. The existence of an inverted U-shaped relationship between hyperthermia development and cognitive performance is suggested, and highlights core temperatures of ~38.5 degrees C as the potential 'threshold' for hyperthermia-induced negative cognitive performance. From this perspective, interventions to slow or blunt thermal loads and protect both task- and hyperthermia-related changes in task performances (e.g. cooling strategies) could be used to great benefit and potentially preserve cognitive performance during heat strain. PMID- 27988877 TI - Persistent shunt dependency and very late shunt failure in a 3-year-old boy with idiopathic intracranial hypertension (IIH). PMID- 27988878 TI - Endovascular treatment of giant-dissecting posterior cerebral artery aneurysm in an infant. PMID- 27988875 TI - Determinants of Change in Physical Activity in Children 0-6 years of Age: A Systematic Review of Quantitative Literature. AB - BACKGROUND: Understanding the determinants of children's health behaviours is important to develop successful behaviour-change interventions. OBJECTIVE: We aimed to synthesise the evidence around determinants ('preceding predictors') of change in physical activity (PA) in young children (0-6 years of age). METHODS: As part of a suite of reviews, prospective quantitative studies investigating change in physical activity in children aged 0-6 years were identified from eight databases (to October 2015): MEDLINE, Embase, CINAHL, PsycINFO, Web of Knowledge, British Nursing Index, Applied Social Sciences Index and Abstracts, and Sociological Abstracts. Determinants and direction of association were extracted, described and synthesised according to the socio-ecological model (individual, interpersonal, organisational, community, policy). RESULTS: Forty-four determinants, predominantly in the interpersonal and organisational domains, were reported across 44 papers (six prospective cohort, 38 interventional); 14 determinants were assessed in four or more papers. Parental monitoring showed a consistent positive association with change in PA; provider training was positively associated with change in children's moderate-to-vigorous PA only. Five (sex, parental goal setting, social support, motor skill training and increased time for PA) showed no clear association. A further seven (child knowledge, parental knowledge, parental motivation, parenting skills, parental self-efficacy, curriculum materials and portable equipment) were consistently not associated with change in children's PA. Maternal role-modelling was positively associated with change in PA in all three studies in which it was examined. CONCLUSIONS: A range of studied determinants of change in young children's PA were identified, but only parental monitoring was found to be consistently positively associated. More evidence dealing with community and policy domains from low-/middle-income countries and about lesser-explored modifiable family- and childcare-related determinants is required. INTERNATIONAL PROSPECTIVE REGISTER FOR SYSTEMATIC REVIEWS (PROSPERO) REGISTRATION NUMBER: CRD42012002881. PMID- 27988876 TI - Edaravone reduces astrogliosis and apoptosis in young rats with kaolin-induced hydrocephalus. AB - PURPOSE: We investigated the possible neuroprotective effects of the free radical scavenger edaravone in experimental hydrocephalus. METHODS: Seven-day-old Wistar rats were divided into three groups: control group (C), untreated hydrocephalic (H), and hydrocephalic treated with edaravone (EH). The H and EH groups were subjected to hydrocephalus induction by 20% kaolin intracisternal injection. The edaravone (20 mg/kg) was administered daily for 14 days from the induction of hydrocephalus. All animals were daily weighed and submitted to behavioral test and assessment by magnetic resonance imaging. After 14 days, the animals were sacrificed and the brain was removed for histological, immunohistochemical, and biochemical studies. RESULTS: The gain weight was similar between groups from the ninth post-induction day. The open field test performance of EH group was better (p < 0.05) as compared to untreated hydrocephalic animals. Hydrocephalic animals (H and EH) showed ventricular ratio values were higher (p < 0.05), whereas magnetization transfer values were lower (p < 0.05), as compared to control animals. Astrocyte activity (glial fibrillary acidic protein) and apoptotic cells (caspase-3) of EH group were decreased on the corpus callosum (p > 0.01), germinal matrix (p > 0.05), and cerebral cortex (p > 0.05), as compared to H group. CONCLUSIONS: We have demonstrated that administration of edaravone for 14 consecutive days after induction of hydrocephalus reduced astrocyte activity and that it has some beneficial effects over apoptotic cell death. PMID- 27988872 TI - Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer's Disease. AB - Alzheimer's disease (AD) should be regarded as a degenerative metabolic disease caused by brain insulin resistance and deficiency, and overlapping with the molecular, biochemical, pathophysiological, and metabolic dysfunctions in diabetes mellitus, non-alcoholic fatty liver disease, and metabolic syndrome. Although most of the diagnostic and therapeutic approaches over the past several decades have focused on amyloid-beta (Abeta42) and aberrantly phosphorylated tau, which could be caused by consequences of brain insulin resistance, the broader array of pathologies including white matter atrophy with loss of myelinated fibrils and leukoaraiosis, non-Abeta42 microvascular disease, dysregulated lipid metabolism, mitochondrial dysfunction, astrocytic gliosis, neuro-inflammation, and loss of synapses vis-a-vis growth of dystrophic neurites, is not readily accounted for by Abeta42 accumulations, but could be explained by dysregulated insulin/IGF-1 signaling with attendant impairments in signal transduction and gene expression. This review covers the diverse range of brain abnormalities in AD and discusses how insulins, incretins, and insulin sensitizers could be utilized to treat at different stages of neurodegeneration. PMID- 27988879 TI - Therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy is associated with short-term reduction of seizures after discharge from the neonatal intensive care unit. AB - INTRODUCTION: Therapeutic hypothermia for the treatment of moderate to severe neonatal hypoxic ischemic encephalopathy has been shown to reduce death and disability, but the effects on seizures after discharge from the Neonatal ICU are not known. METHODS: A retrospective cohort study was conducted involving 56 neonates admitted to the Neonatal ICU at Children's Hospital of Orange County, CA from January 1, 2007 to September 1, 2013 with hypoxic ischemic encephalopathy who met criteria for selective brain cooling. Fifteen patients received supportive care. Forty-one patients received cooling, of whom 25 were included for analysis. Sixteen patients from the hypothermia group and 12 from the no hypothermia group developed clinical seizures while inpatient. Up to 6 months, four patients (16%) had continued seizures in the therapeutic hypothermia group compared to eight (53%) patients who did not receive hypothermia. DISCUSSION: Our study shows an association between therapeutic hypothermia and reduced seizures after discharge from the neonatal intensive care unit. The short duration of follow-up, 6 months, is a limitation of this study. Another limitation is its observational nature, where reasons for treatment selection and exclusions are unmeasurable confounding factors. Further studies are needed to determine long term effects. PMID- 27988880 TI - Posterior hemivertebrectomy and short segment fixation-long term results. AB - OBJECTIVES: The objectives of this study were to study the long-term results of one-stage single and multiple level posterior hemivertebrectomies and to find out the safety and efficacy of the procedure. METHOD: Twenty patients (9 male and 11 female) with mean age of 9.2 years (2 years 4 months-14 years 10 months) with congenital scoliosis (hemivertebrae) were treated with posterior hemivertebrectomy with intraoperative neuromonitoring. Posterior exposure and transpedicular fixation of the adjoining vertebrae was done. The hemivertebra was approached from the convex side, and transpedicular decancellation followed by complete excision was done. Controlled compression at the convexity was done after a cantilever manoeuvre was done for rod capturing on the convexity to achieve the reduction. RESULTS: Average number of hemivertebra removed was 1.46 (1-3). Mean pre-op and post-op coronal Cobb angle was 48.8 degrees (range 22 to 80) and 24.2 degrees (range 7 to 41), respectively (p < 0.001). Mean pre-op and post-op sagittal Cobb angle was 32.1 degrees (range 7 to 76) and 13.6 degrees (range 0 to 23) respectively, (p < 0.005). Mean coronal and sagittal Cobb correction percentage achieved was 50.2 and 51.8%, respectively. Mean follow-up was 62.4 months (range 24-73 months). Mean loss of coronal and sagittal correction at final follow-up was 2.26 degrees (0-8) and 1.55 degrees (0-5), respectively. Maximum correction in both coronal (p = 0.167) and sagittal (p = 0.095) planes was achieved in thoracolumbar vertebrae. Maximum correction was achieved in 3 level hemivertebrae in sagittal (p = 0.9) and 2 level hemivertebrae in coronal plane (p = 0.740). CONCLUSIONS: Posterior hemivertebrectomy is a safe and effective procedure for congenital scoliosis. Not only single but up to 3 level hemivertebrae can be safely removed with good correction of deformity. Long term follow-up reveals good maintenance of correction. PMID- 27988881 TI - Rapid analysis of drugs of abuse and their metabolites in human urine using dilute and shoot liquid chromatography-tandem mass spectrometry. AB - Liquid chromatography-tandem mass spectrometric method for analysis of 113 abuse drugs and their metabolites in human urine was developed and validated. A simple sample clean-up procedure using the "dilute and shoot" approach, followed by reversed phase separation, provided a fast and reliable method for routine analysis. Drugs were separated in a Capcell Pak MG-III C18 column using a gradient elution of 1 mM ammonium formate with 0.1% formic acid in water and acetonitrile. The total time for analysis was 32 min. The multiple reaction monitoring mode using two transitions (e.g., quantifier and qualifier) was optimized for both identification and determination. The calibration curves for each analyte were linear over the concentration ranges of 1-100, 5-100, or 10-100 ng/mL using 400 MUL of human urine sample with the coefficient of determination above 0.9921. The coefficient of variation and accuracy for the intra- and inter assays of the tested drugs at three QC levels were 1.1-14.6 and 86.7-106.8%, respectively. The present method was successfully applied to the analysis of forensic urine samples obtained from 17 drug abusers. This method is useful for the rapid and accurate determination of multiple drug abuse with a small amount of urine in forensic and clinical toxicology. PMID- 27988882 TI - Beneficial effects of the Src inhibitor, dasatinib, on breakdown of the blood retinal barrier. AB - Src kinase signaling is important in the regulation of microvascular barrier function and endothelial hyperpermeability. This study was designed to evaluate the protective effect of dasatinib, a potent Src inhibitor used clinically for the treatment of cancer, against the breakdown of the blood-retinal barrier (BRB) and the retinal vascular leakage caused by vascular endothelial growth factor (VEGF) and diabetes. We examined the effects of dasatinib on VEGF-induced endothelial hyperpermeability and the loss of vascular endothelial (VE)-cadherin, an endothelial junctional protein. Dasatinib inhibited VEGF-induced phosphorylation of Src in human retinal microvascular endothelial cells (HRMECs). In vitro and in vivo vascular permeability assays showed that dasatinib blocked the VEGF-enhanced hyperpermeability of HRMECs and decreased VEGF-mediated retinal vascular leakage in mice. Immunofluorescent staining of VE-cadherin showed that dasatinib abolished the junctional disappearance of VE-cadherin in VEGF-treated HRMECs and murine retinal vasculature. In addition, we examined the protective effect of dasatinib against diabetes-induced retinal vascular leakage in streptozotocin-induced diabetic rats. An intravitreal injection of dasatinib substantially inhibited the development of hyperpermeable retinal vasculature. Our results indicate that dasatinib is a promising agent for the prevention and treatment of diabetes-induced retinal vascular leakage. PMID- 27988883 TI - Surveillance of Adverse Events After Seasonal Influenza Vaccination in Pregnant Women and Their Infants in the Vaccine Adverse Event Reporting System, July 2010 May 2016. AB - INTRODUCTION: Routine immunization of pregnant women with seasonal inactivated influenza vaccines (IIVs) is recommended in all trimesters of pregnancy. A review of the Vaccine Adverse Event Reporting System (VAERS) during 1990-2009 did not find any unexpected patterns of pregnancy complications or fetal outcomes after administration of IIV or live attenuated influenza vaccines (LAIVs). During the 2009-2010 pandemic influenza A (H1N1) vaccination campaign, a study noted that the number of VAERS reports from pregnant women who received the H1N1 2009 inactivated monovalent vaccine (n = 288) increased compared with 1990-2009 seasonal IIV pregnancy reports (n = 148). OBJECTIVES: The objective of this study was to assess the safety of seasonal influenza vaccines in pregnant women and their infants whose reports were submitted to VAERS during 2010-2016. METHODS: We searched VAERS for US reports of adverse events (AEs) in pregnant women who received IIV or LAIV from 1 July 2010 through 6 May 2016. Clinicians reviewed reports and available medical records and assigned a primary clinical category for each report. Reports were coded as serious based on the Code of Federal Regulations. RESULTS: We identified 671 reports after seasonal influenza vaccines administered to pregnant women: 544 after IIV and 127 after LAIV. Serious events occurred among 61 (11.2%) reports following IIV and one (0.8%) report following LAIV. No deaths were reported. Among reports with trimester information (n = 296), IIV was administered during the first trimester in 116 (39.2%). Among IIV reports, the most frequent pregnancy-specific AE was spontaneous abortion in 62 (11.4%) reports, followed by stillbirth in ten (1.8%) and preterm delivery in six (1.1%). The most common non-pregnancy-specific AEs were injection-site reactions (55 [10.1%]). Neonatal or infant outcomes were reported in 22 (4.0%) reports, seven of which had major birth defects of different types and no neonatal deaths. CONCLUSION: As in 2009-2010, no new or unexpected patterns in maternal or fetal outcomes were observed during 2010-2016. PMID- 27988884 TI - Proactive Regional Pharmacovigilance System Versus National Spontaneous Reporting for Collecting Safety Data on Concerning Off-Label Prescribing Practices: An Example with Baclofen and Alcohol Dependence in France. AB - INTRODUCTION: Off-label prescribing (OLP) may raise serious safety concerns that traditional spontaneous reporting of adverse drug reactions (ADRs) may not identify in a timely manner. In France, the 'Multidisciplinary Consultation Service for Off-Label Prescribing in Addiction Medicine' (CAMTEA) is a proactive regional system established to identify ADRs associated with the OLP of baclofen for alcohol dependence. OBJECTIVE: The aim was to demonstrate, using the French pharmacovigilance database (FPVD), that CAMTEA allowed for the reporting of a substantial amount of ADRs, comparable in nature to those provided via spontaneous reporting. METHOD: The 2012-2013 FPVD notifications associated with baclofen OLP were extracted. The ten most frequent types of ADRs among 'serious' and 'non-serious' reports were listed. The frequency of each type of ADR was compared between CAMTEA and spontaneous reporting, and the magnitudes of the differences were assessed using standardized differences. RESULTS: A total of 428 baclofen reports (1043 ADRs) were identified, among which 221 (51.64%) originated from CAMTEA. The ten most frequent ADRs in 'serious' reports were (1) confusion (17.3%), (2) seizures (11.5%), (3) drowsiness/sedation (11.5%), (4) agitation (10.9%), (5) coma (9.6%), (6) hallucinations (7.7%), (7) falls (7.1%), (8) behavioral disorders (5.8%), (9) withdrawal syndrome (5.1%), and (10) space-time disorientation (5.1%). A standardized difference of <0.2 was identified for six out of the ten most frequent 'serious' ADRs, and eight of the ten 'non-serious' ADRs. CONCLUSION: A proactive regional pharmacovigilance system could collect a substantial amount of safety data on a specific OLP practice. The profile of the ADRs collected was similar to that seen in the nationwide spontaneous reporting system. PMID- 27988885 TI - Lipid metabolites in seeds of diverse Gossypium accessions: molecular identification of a high oleic mutant allele. AB - MAIN CONCLUSION: Genetically diverse cottonseeds show altered compositions and spatial distributions of phosphatidylcholines and triacylglycerols. Lipidomics profiling led to the discovery of a novel FAD2 - 1 allele, fad2 - 1D - 1 , resulting in a high oleic phenotype. The domestication and breeding of cotton for elite, high-fiber cultivars have led to reduced variation of seed constituents within currently cultivated upland cotton genotypes. However, a recent screen of the genetically diverse U.S. National Cotton Germplasm Collection identified Gossypium accessions with marked differences in seed oil and protein content. Here, several of these accessions representing substantial variation in seed oil content were analyzed for quantitative and spatial differences in lipid compositions by mass spectrometric approaches. Results indicate considerable variation in amount and spatial distribution of pathway metabolites for triacylglycerol biosynthesis in embryos across Gossypium accessions, suggesting that this variation might be exploited by breeders for seed composition traits. By way of example, these lipid metabolite differences led to the identification of a mutant allele of the D-subgenome homolog of the delta-12 desaturase (fad2-1D 1) in a wild accession of G. barbadense that has a high oil and high oleic seed phenotype. This mutation is a 90-bp insertion in the 3' end of the FAD2-1D coding sequence and a modification of the 3' end of the gene beyond the coding sequence leading to the introduction of a premature stop codon. Given the large amounts of cottonseed produced around the world that is currently not processed into higher value products, these efforts might be one avenue to raise the overall value of the cotton crop for producers. PMID- 27988886 TI - Naturally occurring high oleic acid cottonseed oil: identification and functional analysis of a mutant allele of Gossypium barbadense fatty acid desaturase-2. AB - MAIN CONCLUSION: Some naturally occurring cotton accessions contain commercially attractive seed oil fatty acid profiles. The likely causal factor for a high oleate trait in pima cotton ( Gossypium barbadense ) accession GB-713 is described here. Vegetable oils are broadly used in the manufacture of many human and animal nutritional products, and in various industrial applications. Along with other well-known edible plant oils from soybean, corn, and canola, cottonseed oil is a valuable commodity. Cottonseed oil is a co-product derived from the processing of cottonseed fiber. In the past, it was used extensively in a variety of food applications. However, cottonseed oil has lost market share in recent years due to less than optimal ratios of the constituent fatty acids found in either traditional or partially hydrogenated oil. Increased awareness of the negative health consequences of dietary trans-fats, along with the public wariness associated with genetically modified organisms has created high demand for naturally occurring oil with high monounsaturate/polyunsaturate ratios. Here, we report the discovery of multiple exotic accessions of pima cotton that contain elevated seed oil oleate content. The genome of one such accession was sequenced, and a mutant candidate fatty acid desaturase-2 (FAD2-1D) gene was identified. The mutant protein produced significantly less linoleic acid in infiltrated Arabidopsis leaf assays, compared to a repaired version of the same enzyme. Identification of this gene provides a valuable resource. Development of markers associated with this mutant locus will be very useful in efforts to breed the high-oleate trait into agronomic fiber accessions of upland cotton. PMID- 27988887 TI - AhDGR2, an amaranth abiotic stress-induced DUF642 protein gene, modifies cell wall structure and composition and causes salt and ABA hyper-sensibility in transgenic Arabidopsis. AB - MAIN CONCLUSION: An amaranth DGR gene, induced under abiotic stress, modifies cell wall structure and causes hypersensitivity to ABA and salt when overexpressed in Arabidopsis. DUF642 is a highly conserved plant-specific family of unknown cell wall-associated proteins. The AhDGR2 gene, coding for a DUF642 protein, was significantly induced in grain amaranth (Amaranthus hypochondriacus) plants subjected to water-deficit and salinity stress, thereby suggesting its participation in abiotic stress tolerance in this plant. A role in development was also inferred from the higher AhDGR2 expression rates detected in young tissues. Subsequent overexpression of AhDGR2 in transgenic Arabidopsis plants (OE AhDGR2) supported its possible role in development processes. Thus, OE-AhDGR2 plants generated significantly longer roots when grown in normal MS medium. However, they showed a hypersensitivity to increasing concentrations of abscisic acid or NaCl in the medium, as manifested by shorter root length, smaller and slightly chlorotic rosettes, as well as highly reduced germination rates. Contrary to expectations, OE-AhDGR2 plants were intolerant to abiotic stress. Moreover, cell walls in transgenic plants were thinner, in leaves, and more disorganized, in roots, and had significantly modified pectin levels. Lower pectin methylesterase activity detected in leaves of OE-AhDGR2 plants, but not in roots, was contrary to previous reports associating DUF642 proteins and decreased pectin esterification levels in cell walls. Nonetheless, microarray data identified candidate genes whose expression levels explained the phenotypes observed in leaves of OE-AhDGR2 plants, including several involved in cell wall integrity and extension, growth and development, and resistance to abiotic stress. These results support the role of DUF642 proteins in cell wall-related processes and offer novel insights into their possible role(s) in plants. PMID- 27988889 TI - Clinical and genetic analysis of a family with Kartagener syndrome caused by novel DNAH5 mutations. AB - PURPOSE: Kartagener syndrome (KS), also known as visceral inversion-nasosinusitis bronchiectasis syndrome, or familial bronchiectasis, is an autosomal recessive inherited disease. In this study, through two cases of KS, we aimed to assess the clinical and genetic characteristics of KS caused by DNAH5 mutations. METHODS: The two cases of KS from the same family underwent extensive clinical assessments, with next-generation DNA sequencing and bioinformatics analysis to identify pathogenic genes. In addition, Sanger sequencing was used to verify the pedigrees. RESULTS: The present study employed a directional capture strategy for hereditary disease screening, which correctly identified the virulence sites in the pedigree, and facilitated the differential diagnosis among multiple genes. Two novel mutations were detected in DNAH5: c.7778C>T (missense mutation) and c.13729G>A (nonsense mutation). They were not found in dbSNP, 1000 Genomes, and ExAC. CONCLUSIONS: These findings demonstrated that new DNAH5 mutations could be used for molecular diagnosis of KS, providing families with genetic counseling and prenatal diagnosis. PMID- 27988888 TI - The cellular stress response of the scleractinian coral Goniopora columna during the progression of the black band disease. AB - Black band disease (BBD) is a widespread coral pathology caused by a microbial consortium dominated by cyanobacteria, which is significantly contributing to the loss of coral cover and diversity worldwide. Since the effects of the BBD pathogens on the physiology and cellular stress response of coral polyps appear almost unknown, the expression of some molecular biomarkers, such as Hsp70, Hsp60, HO-1, and MnSOD, was analyzed in the apparently healthy tissues of Goniopora columna located at different distances from the infection and during two disease development stages. All the biomarkers displayed different levels of expression between healthy and diseased colonies. In the healthy corals, low basal levels were found stable over time in different parts of the same colony. On the contrary, in the diseased colonies, a strong up-regulation of all the biomarkers was observed in all the tissues surrounding the infection, which suffered an oxidative stress probably generated by the alternation, at the progression front of the disease, of conditions of oxygen supersaturation and hypoxia/anoxia, and by the production of the cyanotoxin microcystin by the BBD cyanobacteria. Furthermore, in the infected colonies, the expression of all the biomarkers appeared significantly affected by the development stage of the disease. In conclusion, our approach may constitute a useful diagnostic tool, since the cellular stress response of corals is activated before the pathogens colonize the tissues, and expands the current knowledge of the mechanisms controlling the host responses to infection in corals. PMID- 27988891 TI - Investigation of 36 non-HLA (human leucocyte antigen) psoriasis susceptibility loci in a psoriatic arthritis cohort. AB - Psoriasis has been intensively studied recently and numerous risk-associated variants within 44 susceptibility loci have been discovered. Estimates suggest that the genetic contribution to PsA (psoriatic arthritis) may be higher than PsV (psoriasis vulgaris) yet most work has been done on the latter due to its greater population prevalence. To test whether variants in the PsV-associated loci are also related to PsA, we performed a candidate loci association study in Chinese population. Genotyping was performed by MassARRAY platform (Sequenom, San Diego, CA, USA). 50 single nucleotide polymorphisms (SNPs) with reported evidences for association with psoriasis were genotyped in 465 PsA cases and 421 healthy controls collected from Chinese population. Data handling, quality control and association analysis were performed using PLINK software (v. 1.07). SNPs in 5q33.3, 1p36 and 1q21.3 showed convincing evidence of association (rs7709212, P = 4.82 * 10-5, rs7536201, P = 3.89 * 10-4, rs1886734 P = 6.81 * 10-4, respectively). IL12B, RUNX3 and LCE were candidate genes in these regions. The combination of SNPs rs1886734 and rs7709212 was the best predictive model for PsA as compared to the control in test for gene-gene interaction. In conclusion, we assessed 36 non-HLA psoriasis susceptibility loci in PsA cohort, confirmed the association of three loci with PsA, these findings may help in developing possible genetic markers to predict PsA. PMID- 27988890 TI - Diagnostic accuracy of contemporary multidetector computed tomography (MDCT) for the detection of lumbar disc herniation. AB - OBJECTIVES: To evaluate the diagnostic accuracy of multidetector CT (MDCT) for detection of lumbar disc herniation with MRI as standard of reference. METHODS: Patients with low back pain underwent indicated MDCT (128-row MDCT, helical pitch), 60 patients with iterative reconstruction (IR) and 67 patients with filtered back projection (FBP). Lumbar spine MRI (1.5 T) was performed within 1 month. Signal-to-noise ratios (SNR) of cerebrospinal fluid (CSF), annulus fibrosus (AF) and the spinal cord (SC) were determined for all modalities. Two readers independently rated image quality (IQ), diagnostic confidence and accuracy in the diagnosis of lumbar disc herniation using MRI as standard of reference. Inter-reader correlation was assessed with weighted kappa. RESULTS: Sensitivity, specificity, precision and accuracy of MDCT for disc protrusion were 98.8%, 96.5%, 97.1%, 97.8% (disc level), 97.7%, 92.9%, 98.6%, 96.9% (patient level). SNR of IR was significantly higher than FBP. IQ was significantly better in IR owing to visually reduced noise and improved delineation of the discs. kappa (>0.90) was excellent for both algorithms. CONCLUSION: MDCT of the lumbar spine yields high diagnostic accuracy for detection of lumbar disc herniation. IR improves image quality so that the provided diagnostic accuracy is principally equivalent to MRI. KEY POINTS: * MDCT is an accurate alternative to MRI in disc herniation diagnosis. * By IR enhanced image quality improves MDCT diagnostic confidence similar to MRI. * Advances in CT technology contribute to improved diagnostic performance in lumbar spine imaging. PMID- 27988892 TI - Immunolocalization of substance P and NK-1 receptor in vascular anomalies. AB - The peptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems, but it is also ubiquitous in the human body. After binding to the neurokinin-1 (NK-1) receptor, SP regulates tumoral angiogenesis and proliferation. Thus, knowledge of this system is the key for a better understanding and, hence, a better management of many human diseases, including vascular anomalies (VA). This study aims to examine the expression and localization of both SP and the NK-1 receptor in different vascular anomalies using an immunohistochemical technique. Our results demonstrated predominantly nuclear localization of SP in venous malformations and in one haemangioma sample, in contrast with cytoplasmic expression in capillary malformations and rapidly involuting congenital hemangioma (RICH). NK-1 receptor showed a cytoplasmic localization in all VA. In summary, all these findings demonstrate that SP and NK 1 receptor are expressed in VA, with different expression patterns depending on the nature of the anomaly, suggesting that they could play an important role in the pathogenesis of VA. PMID- 27988896 TI - Jim Crow and estrogen-receptor-negative breast cancer: US-born black and white non-Hispanic women, 1992-2012. AB - PURPOSE: It is unknown whether Jim Crow-i.e., legal racial discrimination practiced by 21 US states and the District of Columbia and outlawed by the US Civil Rights Act in 1964-affects US cancer outcomes. We hypothesized that Jim Crow birthplace would be associated with higher risk of estrogen-receptor negative (ER-) breast tumors among US black, but not white, women and also a higher black versus white risk for ER- tumors. METHODS: We analyzed data from the SEER 13 registry group (excluding Alaska) for 47,157 US-born black non-Hispanic and 348,514 US-born white non-Hispanic women, aged 25-84 inclusive, diagnosed with primary invasive breast cancer between 1 January 1992 and 31 December 2012. RESULTS: Jim Crow birthplace was associated with increased odds of ER- breast cancer only among the black, not white women, with the effect strongest for women born before 1965. Among black women, the odds ratio (OR) for an ER- tumor, comparing women born in a Jim Crow versus not Jim Crow state, equaled 1.09 (95% confidence interval [CI] 1.06, 1.13), on par with the OR comparing women in the worst versus best census tract socioeconomic quintiles (1.15; 95% CI 1.07, 1.23). The black versus white OR for ER- was higher among women born in Jim Crow versus non-Jim Crow states (1.41 [95% CI 1.13, 1.46] vs. 1.27 [95% CI 1.24, 1.31]). CONCLUSIONS: The unique Jim Crow effect for US black women for breast cancer ER status underscores why analysis of racial/ethnic inequities must be historically contextualized. PMID- 27988894 TI - Increase in circulating sphingosine-1-phosphate and decrease in ceramide levels in psoriatic patients. AB - Psoriasis is characterized by hyperproliferation, deregulated differentiation and impaired apoptosis of keratinocytes. Mechanisms of lipid profile disturbances and metabolic syndrome in the psoriatic patients are still not fully understood. Sphingolipids, namely ceramides (CER) and sphingosine-1-phosphate (S1P) are signal molecules which can regulate cell growth, apoptosis and immune reactions. The aim of the study was to evaluate circulating CER and S1P levels in plaque type psoriasis and their associations with the disease activity, inflammatory or metabolic markers and the presence of psoriatic comorbidities. Eighty-five patients with exacerbated plaque-type psoriasis and thirty-two healthy controls were enrolled. Serum CER and S1P concentrations before the treatment were examined. General patient characteristics included: PASI (Psoriasis Area and Severity Index), BMI (Body Mass Index), inflammatory and biochemical markers, lipid profile and presence of psoriatic comorbidities. Total serum concentration of CER was significantly decreased (p = 0.02) and concomitantly S1P levels significantly increased (p = 0.002) in psoriatic patients compared to the healthy control group. Among patients with psoriasis no significant correlations with the disease activity and inflammation markers were observed and only patients with psoriatic arthritis had significantly higher CER total concentration. Serum sphingolipid disturbances in psoriatic patients were observed. Decreased total CER and increased S1P serum levels may reflect their epidermal altered composition and metabolism. Patients with psoriatic arthritis have higher CER levels than psoriasis with skin involvement only. It might provide additional predictive value for psoriatic arthritis and may convey higher risk of metabolic and cardiovascular disease development in this group of patients. PMID- 27988893 TI - N-Acetylglutaminoyl-S-farnesyl-L-cysteine (SIG-1191): an anti-inflammatory molecule that increases the expression of the aquaglyceroporin, aquaporin-3, in human keratinocytes. AB - Isoprenylcysteine (IPC) small molecules were discovered as signal transduction modulating compounds ~25 years ago. More recently, IPC molecules have demonstrated antioxidant and anti-inflammatory properties in a variety of dermal cells as well as antimicrobial activity, representing a novel class of compounds to ameliorate skin conditions and disease. Here, we demonstrate a new IPC compound, N-acetylglutaminoyl-S-farnesyl-L-cysteine (SIG-1191), which inhibits UVB-induced inflammation blocking pro-inflammatory cytokine interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) production. To investigate further the previously reported hydrating potential of IPC compounds, SIG-1191 was tested for its ability to modulate aquaporin expression. Specifically, aquaporin 3 (AQP3) the most abundant aquaporin found in skin has been reported to play a key role in skin hydration, elasticity and barrier repair. Results show here for the first time that SIG-1191 increases AQP3 expression in both cultured normal human epidermal keratinocytes as well as when applied topically in a three-dimensional (3D) reconstructed human skin equivalent. Additionally, SIG-1191 dose dependently increased AQP3 protein levels, as determined by specific antibody staining, in the epidermis of the 3D skin equivalents. To begin to elucidate which signaling pathways SIG-1191 may be modulating to increase AQP3 levels, we used several pharmacological pathway inhibitors and determined that AQP3 expression is mediated by the Mitogen-activated protein kinase/Extracellular signal-regulated kinase kinase (MEK) pathway. Altogether, these data suggest SIG-1191 represents a new IPC derivative with anti-inflammatory activity that may also promote increased skin hydration based on its ability to increase AQP3 levels. PMID- 27988895 TI - Radiopharmaceuticals for metastatic bone pain palliation: available options in the clinical domain and their comparisons. AB - Bone pain arising due to skeletal metastases is one of the common complications experienced by the majority of patients suffering from prostate, breast and lung cancer at the advanced stage of the disease. These patients are subjected to palliative care in order to improve the quality of their remaining life. With the gradually increasing number of cancer cases, palliation of metastatic bone pain is gaining importance. Bone-seeking radiopharmaceuticals play a pivotal role in the management of cancer pain, particularly in patients with multiple metastases, as these agents are proven to be effective in controlling the bone pain with minimum side effects. Although a plethora of such radiopharmaceuticals have been developed and evaluated in animal models, only a few are regularly used in clinics while some of these agents are at different stages of clinical evaluations. The present article describes only those bone-seeking radiopharmaceuticals, which have been reported to be clinically administered till date, along with their relative merits and drawbacks. PMID- 27988897 TI - Green mitigation strategy for cultural heritage: bacterial potential for biocide production. AB - Several biosurfactants with antagonistic activity are produced by a variety of microorganisms. Lipopeptides (LPPs) produced by some Bacillus strains, including surfactin, fengycin and iturin are synthesized nonribosomally by mega-peptide synthetase (NRPS) units and they are particularly relevant as antifungal agents. Characterisation, identification and evaluation of the potentials of several bacterial isolates were undertaken in order to establish the production of active lipopeptides against biodeteriogenic fungi from heritage assets. Analysis of the iturin operon revealed four open reading frames (ORFs) with the structural organisation of the peptide synthetases. Therefore, this work adopted a molecular procedure to access antifungal potential of LPP production by Bacillus strains in order to exploit the bioactive compounds synthesis as a green natural approach to be applied in biodegraded cultural heritage context. The results reveal that the bacterial strains with higher antifungal potential exhibit the same morphological and biochemical characteristics, belonging to the genera Bacillus. On the other hand, the higher iturinic genetic expression, for Bacillus sp. 3 and Bacillus sp. 4, is in accordance with the culture antifungal spectra. Accordingly, the adopted methodology combining antifungal screening and molecular data is represent a valuable tool for quick identification of iturin-producing strains, constituting an effective approach for confirming the selection of lipopeptides producer strains. PMID- 27988898 TI - The characteristics of steel slag and the effect of its application as a soil additive on the removal of nitrate from aqueous solution. AB - This study examined the characteristics of nitrate removal from aqueous solution by steel slag and the feasibility of using steel slag as a soil additive to remove nitrate. Steel slag adsorbents were characterized by X-ray fluorescence (XRF), X-ray diffraction (XRD), scanning electron microscopy (SEM) and infrared spectrum (IR spectrum). Adsorption isotherms and kinetics were also analysed. Various parameters were measured in a series of batch experiments, including the sorbent dose, grain size of steel slag, reaction time, initial concentration of nitrate nitrogen, relationship between Al, Fe and Si ions leached from the steel slag and residual nitrate in the aqueous solution. The nitrate adsorbing capacity increased with increasing amounts of steel slag. In addition, decreasing the grain diameter of steel slag also enhanced the adsorption efficiency. Nitrate removal from the aqueous solution was primarily related to Al, Fe, Si and Mn leached from the steel slag. The experimental data conformed to second-order kinetics and the Freundlich isothermal adsorption equation, indicating that the adsorption of nitrate by steel slag is chemisorption under the action of monolayer adsorption. Finally, it was determined that using steel slag as a soil additive to remove nitrate is a feasible strategy. PMID- 27988899 TI - Microwave-assisted enhancement of milkweed (Calotropis procera L.) leaves as an eco-friendly source of natural colorants for textile. AB - Application of natural colorants to textile fabrics has gained worldwide public acceptance due to the hazardous nature of synthetic dyes. Present study investigated the microwave's mediated extraction of natural colorants from leaves of milkweed (Calotropis procera L.) as well as their application to cotton fabrics assisted with biochemical mordants. Dye extraction from C. procera leaves was carried out in various mediums (alkali and aqueous), and the extracted dye as well as cotton fabrics was irradiated with microwaves for 2, 4, 6, 8, or 10 min. Effect of various temperature regimes and sodium chloride (NaCl) concentrations was also evaluated on the color strength of dyed cotton fabrics. The results revealed that extraction of natural colorants was enhanced when microwave radiations were applied for 4 min by using alkali as an extraction medium as compared to aqueous one. Optimum dyeing of cotton fabrics was achieved by using NaCl at a temperature of 55 degrees C. Among the chemical mordants, iron was effective for better color strength when used as pre- and post-mordant. Among the studied bio-mordants, extract of Acacia nilotica bark significantly improved the color strength and fastness properties as pre-mordant and Curcuma longa tuber as post-mordant. It was concluded that extract of C. procera leaves was a potential source of natural colorants and a high level of dye was obtained upon irradiation of alkali-solubilized extract for 4 min. Application of NaCl at concentration of 3 g/100 mL and temperature treatment of 55 degrees C significantly improved the color strength of dyed cotton fabrics. PMID- 27988900 TI - Catalytic oxidation of 1,2-DCBz over V2O5/TiO2-CNTs: effect of CNT diameter and surface functional groups. AB - A series of V2O5/TiO2-carbon nanotube (CNT) catalysts were prepared and tested to decompose gaseous 1,2-dichlorobenzene (1,2-DCBz). Several physicochemical methods, including nitrogen adsorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and H2 temperature-programmed reduction (TPR) were employed to characterise their physicochemical properties. To better understand the effect of CNT properties on the reactivity of V2O5/TiO2-CNT catalysts, the 1,2-DCBz residue remaining in the off-gas and on the catalyst surface were both collected and analysed. The results indicate that the outer diameter and the surface functional groups (hydroxide radical and carboxyl) of CNTs significantly influence upon the catalytic activity of CNT-containing V2O5/TiO2 catalysts: the CNT outer diameter mainly affects the aggregation of CNTs and the pi-pi interaction between the benzene ring and CNTs, while the introduction of -OH and -COOH groups by acid treatment can further enlarge specific surface area (SSA) and contribute to a higher average oxidation state of vanadium (V aos) and supplemental surface chemisorbed oxygen (Oads). In addition, the enhanced mobility of lattice oxygen (Olatt) also improves the oxidation ability of the catalysts. PMID- 27988901 TI - Characteristics of the overflow pollution of storm drains with inappropriate sewage entry. AB - To probe the overflow pollution of separate storm drains with inappropriate sewage entries, in terms of the relationship between sewage entries and the corresponding dry-weather and wet-weather overflow, the monitoring activities were conducted in a storm drainage system in the Shanghai downtown area (374 ha). In this study site, samples from inappropriately entered dry-weather sewage and the overflow due to storm pumps operation on dry-weather and wet-weather days were collected and then monitored for six water quality constituents. It was found that overflow concentrations of dry-weather period could be higher than those of wet-weather period; under wet-weather period, the overflow concentrations of storm drains were close to or even higher than that of combined sewers. Relatively strong first flush mostly occurred under heavy rain that satisfied critical rainfall amount, maximum rainfall intensity, and maximum pumping discharge, while almost no first flush effect or only weak first flush effect was found for the other rainfall events. Such phenomenon was attributed to lower in-line pipe storage as compared to that of the combined sewers, and serious sediment accumulation within the storm pipes due to sewage entry. For this kind of system, treating a continuous overflow rate is a better strategy than treating the maximum amount of early part of the overflow. Correcting the key inappropriate sewage entries into storm drains should also be focused. PMID- 27988902 TI - The impact of two fluoropolymer manufacturing facilities on downstream contamination of a river and drinking water resources with per- and polyfluoroalkyl substances. AB - Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are emerging contaminants that have been detected in the environment, biota, and humans. Drinking water is a route of exposure for populations consuming water contaminated by PFAS discharges. This research study reports environmental measurement concentrations, mass flows, and the fate of dozens of PFASs in a river receiving effluents from two fluoropolymer manufacturing facilities. In addition to quantified levels of PFASs using LC- and GC-MS analytical methods, the total amount of unidentified PFASs and precursors was assessed using two complementary analytical methods, absorbable organic fluorine (AOF) determination and oxidative conversion of perfluoroalkyl carboxylic acid (PFCA) precursors. Several dozen samples were collected in the river (water and sediment) during four sampling campaigns. In addition, samples were collected in two well fields and from the outlet of the drinking water treatment plants after chlorination. We estimated that 4295 kg PFHxA, 1487 kg 6:2FTSA, 965 kg PFNA, 307 kg PFUnDA, and 14 kg PFOA were discharged in the river by the two facilities in 2013. High concentrations (up to 176 ng/g dw) of odd long-chain PFASs (PFUnDA and PFTrDA) were found in sediment samples. PFASs were detected in all 15 wells, with concentrations varying based on the location of the well in the field. Additionally, the presence of previously discharged PFASs was still measurable. Significant discrepancies between PFAS concentration profiles in the wells and in the river suggest an accumulation and transformation of PFCA precursors in the aquifer. Chlorination had no removal efficiency and no unidentified PFASs were detected in the treated water with either complementary analytical method. Although the total PFAS concentrations were high in the treated water, ranging from 86 to 169 ng/L, they did not exceed the currently available guideline values. PMID- 27988903 TI - Thermal effects on development and adult longevity of endoparasitoid Chelonus murakatae Munakata (Hymenoptera: Braconidae). AB - The effects of temperature on the development duration and longevity of adult of Chelonus murakatae were studied under five constant temperatures including 22.5, 25, 27.5, 30 and 32.5 +/- 0.5 degrees C under laboratory conditions. It was observed that the development time was inversely proportional to the temperature within the range of 22.5 to 32.5 degrees C. The results indicated that the optimum temperature for development ranged from 25 to 30 degrees C. Thermal threshold was estimated by a linear model which was recorded as 15.5 and 18.5 degrees C for males and females, respectively. Number of degree days required to complete the development from egg to adult were 439.6 degree days in males and 336.8 degree days in females. Adult longevity also decreased with increase in temperature. This information can be used for optimizing mass culturing and field release for an efficient biological control of Chilo suppressalis in this specie. PMID- 27988904 TI - Activated carbon adsorptive removal of azo dye and peroxydisulfate regeneration: from a batch study to continuous column operation. AB - The performance of activated carbon (AC) for the adsorption of Acid Orange 7 (AO7) was investigated in both batch and column studies. The optimal conditions for adsorption process in batch study were found to be a stirring speed of 500 rpm, AC dosage of 5 g/L, and initial AO7 concentration of 100 mg/L. The spent AC was then treated with peroxydisulfate (PDS), and the regenerated AC was used again to adsorb AO7. Both pseudo-first-order and pseudo-second-order rate models for adsorption kinetics were investigated, and the results showed that the latter model was more appropriate. The effects of regeneration time, PDS concentration, and stirring speed on AO7-spent AC regeneration were investigated in batch studies, and the optimal conditions were time 2 h, stirring speed 700 rpm, and PDS concentration 10 g/L. Under the same adsorption conditions, 89% AO7 could be decolorized by adsorption using regenerated AC. In the column studies, the effect of flow rate was investigated and the adsorption capacity was nearly the same when the flow rate rose from 7.9 to 11.4 mL/min, but it decreased significantly when the flow rate was increased to 15.2 mL/min. The performance of regenerated AC in the column was also investigated, and a slight increase in the adsorption capacity was observed in the second adsorption cycle. However, the adsorption capacity decreased to some extent in the third cycle due to the consumption of C OH group on the AC surface during PDS regeneration. PMID- 27988905 TI - Intestinal Lesion in a Dog Due to Cryptococcus gattii Type VGII and Review of Published Cases of Canine Gastrointestinal Cryptococcosis. AB - Cryptococcosis is a mycosis caused by yeasts of genus Cryptococcus, mainly the species C. neoformans and C. gattii that can affect humans and animals. These yeasts are widely distributed in the environment and are typically associated with avian droppings and decaying wood. Most infections are related to the respiratory tract, but the central nervous system and cutaneous lesions are also reported in the literature. The present report is a case of cryptococcosis in an 18-month-old unspayed female English Bulldog with the main complaint of weight loss and diarrhea. The presence of two large masses observed in an ultrasound examination leads us to perform an exploratory laparotomy. Considering the size of the lesion and the impossibility of owner to provide intensive care, the consent for euthanasia was requested. The postmortem diagnosis of cryptococcosis was revealed by cytological evaluation, and the involvement of C. gattii VGII was confirmed by isolation and identification tests as well as by the detection of the URA5 gene restriction fragment length polymorphism PCR analysis. Reports in the literature of the involvement of Cryptococcus in gastrointestinal lesions are rare in both human and veterinary medicine. Data about different forms of cryptococcosis are important to provide more knowledge of uncommon clinical presentations of this yeast and therefore improve the diagnoses and decisions for the best therapy. PMID- 27988906 TI - Functional identification and regulatory analysis of Delta6-fatty acid desaturase from the oleaginous fungus Mucor sp. EIM-10. AB - OBJECTIVES: To enlarge the diversity of the desaturases associated with PUFA biosynthesis and to better understand the transcriptional regulation of desaturases, a Delta6-desaturase gene (Md6) from Mucor sp. and its 5'-upstream sequence was functionally identified in Saccharomyces cerevisiae. RESULTS: Expression of the Delta6-fatty acid desaturase (Md6) in S. cerevisiae showed that Md6 could convert linolenic acid to gamma-linolenic acid. Computational analysis of the promoter of Md6 suggested it contains several eukaryotic fundamental transcription regulatory elements. In vivo functional analysis of the promoter showed the 5'-upstream sequence of Md6 could initiate expression of GFP and Md6 itself in S. cerevisiae. A series deletion analysis of the promoter suggested that sequence between -919 to -784 bp (relative to start site) named as eMd6 is the key factor for high activity of Delta6-desaturase. The activity of Delta6 desaturase was increased by 2.8-fold and 2.5-fold when the eMd6 sequence was placed upstream of -434 with forward or reverse orientations respectively. CONCLUSION: To our best knowledge, the native promoter of Md6 from Mucor is the strongest promoter for Delta6-desaturase reported so far and the sequence between -919 to -784 bp is an enhancer for Delta6-desaturase activity. PMID- 27988907 TI - Appraisal assessment in patient-reported outcome research: methods for uncovering the personal context and meaning of quality of life. AB - BACKGROUND: Recent work on patient-reported outcomes (PROs) focuses on precise, brief measures, which generally convey little about what an individual's rating actually means. Individual differences in appraisal are important and relevant to PRO research. This paper highlights the advantages of integrating appraisal assessment into clinical research. METHODS: The most comprehensive method for assessing appraisal, the quality of life (QOL) Appraisal Profile, includes open ended and multiple choice questions to assess four appraisal parameters: frame of reference, sampling of experience, standards of comparison, and combinatory algorithm. We illustrate with empirical findings four classes of investigation that would benefit from appraisal assessment: methodological, interpretation of change, the backstory of resilience, and clinical applications. RESULTS: A methodological investigation of HIV/AIDS patients revealed a range of cognitive schemas induced by the then-test response shift detection method, only 15% of which reflected the presumed process invoked. In this same study and in a study of people with multiple sclerosis (MS), interpretation of change in positive versus negative mental-health response shifts was characterized by different appraisal processes. In studying resilience in MS patients, patients with more reserve-building activities were more likely to use appraisals that emphasized the positive and more controllable aspects of their illness experience, as compared to lower-reserve patients. In underserved cancer patients, the QOL Appraisal Profile was used as a clinical interview to articulate current concerns and for personalized treatment decision-making to reduce burden and promote adherence. CONCLUSIONS: Integrating appraisal assessment can provide a more textured, person-centered understanding of person-factors not captured by standard PROs. PMID- 27988908 TI - In support of an individualized approach to assessing quality of life: comparison between Patient Generated Index and standardized measures across four health conditions. AB - BACKGROUND: Individualized measures of health-related quality life (HRQL) have been used for decades and shown to provide unique information, but little work has been done to explain this uniqueness particularly across health conditions. AIMS: To estimate, across four health conditions, the magnitude of the association between scores derived from the Patient Generated Index (PGI) and those from fully standardized generic and disease-specific measures of the HRQL; to identify the extent to which the areas generated from the PGI are covered by the content of the fully standardized measures. METHODS: The PGI and other generic and disease-specific measures had been used in four different samples of people: stroke (n = 222), multiple sclerosis (MS; n = 185); advanced cancer (n = 173), and HIV+ (n = 690). Areas nominated on the PGI were harmonized to a standard nomenclature. Pearson correlations were estimated between PGI and other measures. RESULTS: Data from 1263 people indicated that PGI provided the lowest rating for HRQL across all health conditions. The areas nominated differed across conditions with walking/mobility: the most common for stroke (42%), work/school for MS (62%), health for HIV+ (97%), and fatigue for cancer (39%). Many of the aspects of health included in generic measures were not nominated using the PGI and vice versa. The highest correlations between the PGI and other measures were observed for people with MS, with correlations between 0.53 and 0.59; lowest correlations were observed for people with HIV and cancer, <=0.33. DISCUSSION: The PGI scores reflect those aspects of quality of life that are important to patients in which they would most value an improvement. Heterogeneity in HRQL across health conditions is poorly discriminated using standardized measures. A "one-size-fits-all" approach to HRQL assessment may not provide the most useful representation of this important construct. PMID- 27988910 TI - Importance of contraction history on muscle force of porcine urinary bladder smooth muscle. AB - INTRODUCTION: The purpose of this study was to provide a comprehensive dataset of porcine urinary bladder smooth muscle properties. Particularly, the history dependence of force production, namely force depression (FD) following shortening and force enhancement (FE) following stretch, was analysed. During active micturition, the circumference of the urinary bladder changes enormously. Thus, FD might be an important phenomenon during smooth muscle contraction. MATERIALS AND METHODS: Electrically stimulated, intact urinary bladder strips from pigs (n = 10) were suspended in an aerated-filled organ bath, and different isometric, isotonic, and isokinetic contraction protocols were performed to determine the force-length and the force-velocity relation. FD and FE were assessed in concentric and eccentric contractions with different ramp lengths and ramp velocities. RESULTS: Bladder smooth muscles exhibit considerable amounts of FD and FE. The amount of FD increased significantly with ramp length, while FE did not change. However, FE and FD were independent of ramp velocity. CONCLUSION: The results imply that smooth muscle bladder strips exhibit similar muscle properties and history-dependent behaviour compared to striated muscles. The provided dataset of muscle properties is important for bladder modelling as well as for the analyses and interpretation of dynamic bladder filling and voiding. PMID- 27988911 TI - Chronic kidney disease in Polish elderly population aged 75+: results of the WOBASZ Senior Survey. AB - PURPOSE: Kidney filtration decreases with age, which results in an increased frequency of chronic kidney disease (CKD) in the elderly population. The purpose of the study was to assess the prevalence and epidemiology of CKD in the Polish elderly population. METHODS: A representative sample of the Polish elderly population, composed of 918 people (F 452, M 466) in the age of >=75 years, was chosen. All participants had their history, anthropometric measures and biochemical parameters (creatinine, fasting glucose, complete cholesterol) evaluated. CKD was diagnosed when eGFR was <60 ml/min/1.73 m2. The comorbidities, anthropometric and social factors connected with the onset of CKD were also analyzed. RESULTS: The prevalence of CKD in the analyzed population was 26.9% (F 32.0%, M 15.8%), which gives an estimated number of 495,590 (95% CI 396,363 594,817) patients in the study subpopulation. The majority of these people were in the G3A category-70.1%, while the remaining fell under the G3B-25.7%, G4-3.1% and G5-1.1% categories. Disease awareness among the participants was found to be at 17%. Arterial hypertension (AH) was more frequent in people with CKD (91.0 vs. 80.3%, P < 0.001), whereas diabetes mellitus (DM) prevalence was comparable in both CKD and non-CKD groups (11.7 vs. 11.4%, ns). In the examined group, DM had no influence on the frequency of CKD. In contrast, the presence of cardiovascular diseases substantially increased the chances of developing CKD (OR 1.87, P < 0.05). CONCLUSION: 1. The prevalence of CKD in the Polish elderly population was 26.9%. 2. Awareness of CKD is low. 3. DM, increasing age and AH did not increase the risk of CKD. 4. Coexistence of cardiovascular diseases increased the risk of having CKD. PMID- 27988909 TI - Estimation of the relationship between the polymorphisms of selected genes: ACE, AGTR1, TGFbeta1 and GNB3 with the occurrence of primary vesicoureteral reflux. AB - PURPOSE: Etiopathogenesis of VUR is composite and not fully understood. Many data indicate the importance of genetic predisposition. The aim of this study was to establish the relationship of selected polymorphisms: 14094 polymorphism of the ACE, polymorphism rs1800469 of TGFbeta-1, rs5443 gene polymorphism of the GNB3 and receptor gene polymorphism rs5186 type 1 AGTR1 with the occurrence of the primary vesicoureteral reflux. MATERIAL: The study included 190 children: 90 with the primary VUR confirmed with the voiding cystourethrogram and excluded secondary VUR and a control group of 100 children without a history of the diseases of the genitourinary tract. METHODS: The study was planned in the scheme: "tested case versus control." Genomic DNA was isolated from the leukocytes of peripheral blood samples. The results were statistically analyzed in the Statistica 10 using chi 2 test and analysis of the variance Anova. RESULTS: Any of the four studied polymorphisms showed no difference in the distribution of genotypes between patients with primary vesicoureteral reflux and the control group. In patients with VUR and TT genotype polymorphism rs5443 GNB3 gene, the glomerular filtration rate was significantly higher than in patients with genotype CC or CT. CONCLUSIONS: (1) No relationship was found between the studied polymorphisms (14094 ACE gene, rs1800469 gene TGFbeta1, GNB3 gene rs5443, rs5186 AGTR1 gene) and the occurrence of primary vesicoureteral reflux. (2) TT genotype polymorphism rs5443 GNB3 gene may be a protective factor for the improved renal function in patients with primary vesicoureteral reflux in patients with genotype CC or CT. PMID- 27988912 TI - Clinical characteristics of adrenal tumors in children: a retrospective review of a 15-year single-center experience. AB - OBJECTIVE: Adrenal tumors are rare in children. The aim of this study is to review and analyze clinical data on the diagnosis and management of adrenal tumors in children. METHODS: Between 2001 and 2015, 48 pediatric patients (<14 years old) admitted to our institute with adrenal tumors were reviewed. Clinical features, imaging studies, surgical approaches, as well as pathological diagnoses were recorded. RESULTS: The series comprised 28 males and 20 females. Adrenomedullary tumors were 37, including 24 cases of neuroblastoma, 10 cases of ganglioneuroma, 2 cases of ganglioneuroblastoma, and 1 case of pheochromocytoma. Adrenocortical tumors were 10: 9 cases of cortical adenoma and 1 case of cortical cancer. The other one was hematoma. Fever, pain, and abdominal distention were the main clinical manifestations of adrenomedullary tumors, while Cushing syndrome was the most frequent presenting symptom of adrenocortical tumors. Both computed tomography and magnetic resonance imaging showed a high diagnostic yield. Some patients had an elevated hormone level. Open adrenalectomy was performed in 40 patients (83.3%), while a laparoscopic approach was employed in eight patients (16.7%). RESULTS: Adrenal tumors in children have various types,as well as clinical manifestations. Imaging and laboratory data could be useful for differentiation of malignant from benign tumor. Final diagnosis depends on pathology. Surgical excision of the adrenal tumors is the standard of care. PMID- 27988913 TI - Baseline Characteristics and Changes in Bone Mineral Density T-Scores of Bulgarian Women with Postmenopausal Osteoporosis Receiving Denosumab in Routine Clinical Practice. AB - BACKGROUND: Postmenopausal osteoporosis (PMO) is common among women over 50 years of age and is associated with an increased risk of fracture. Bone-targeted agents, such as denosumab, can reduce fracture risk in patients with PMO. OBJECTIVE: The aim was to describe baseline characteristics and changes in bone mineral density (BMD) T-scores among women with PMO receiving denosumab in Bulgaria. METHODS: This multicenter chart review included women with PMO receiving denosumab for >=1 year in Bulgaria (October 2011-August 2013). Participants were required to have a baseline BMD T-score of <=-2.5 standard deviations (SDs) at one or more skeletal sites. RESULTS: Overall, 222 women were included. The mean (SD) age at denosumab initiation was 64.2 (8.5) years; 26.6% reported a previous osteoporotic fracture and 6.8% a previous hip fracture. Only half of those reporting a previous fracture (49.2%) had received prior osteoporosis therapy. At baseline, mean (SD) BMD T-scores were lumbar spine -3.2 SD (0.6 SD), total hip -2.3 SD (0.8 SD), and femoral neck -2.7 SD (0.7 SD). After 1 year of denosumab treatment, scores increased significantly at all three sites, reaching -2.7 SD (0.6 SD), -2.1 SD (0.9 SD), and -2.4 SD (0.7 SD), respectively (all p < 0.0001 vs. baseline). No serious adverse drug reactions were identified. CONCLUSION: Denosumab is usually prescribed in women with PMO at high fracture risk. In the patients who were persistent with treatment at 1 year, denosumab was well tolerated and effective at increasing BMD T-scores at several skeletal sites. PMID- 27988914 TI - Late Potential as a Predictor of re-Hospitalization after Percutaneous Coronary Intervention for Acute Coronary Syndrome. AB - OBJECTIVE: The aim of this study was to investigate the significance of late potential (LP) after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS). METHOD: We enrolled 135 consecutive patients with ACS admitted to Tokai University Hospital from February to December 2012. Twenty-four hour high resolution ambulatory electrocardiogram was performed between post-PCI procedure and hospital discharge. The patients were divided into the LP-positive (33 patients) and LP-negative (102 patients) groups, and the relationship between LP and re-hospitalization was prospectively investigated. RESULTS: The body mass index, serum creatinine, and creatine phosphokinase-MB were higher in the LP positive group than in the LP-negative group (p < 0.05). The re-hospitalization rate was higher in the LP-positive group. (9 patients, 27.3% vs. 10 patients, 9.8%; p = 0.03). There were no significant differences in the occurrence of ventricular tachycardia or cardiac death between the groups. According to Kaplan Maier analysis, proportion of re-hospitalization was significantly lower in the LP-positive group than in the LP-negative group (p = 0.01; average follow-up, 451.4 +/- 25.9 days). The odds ratio of LP presence was 3.45 (highest among all variables; 95% confidence interval, 1.3-9.4; p < 0.01). CONCLUSION: Positive LP in patients with ACS after PCI may predict re-hospitalization. PMID- 27988915 TI - Airway Obstruction Caused by Substernal Thyrotoxic Multinodular Goiter. AB - BACKGROUND: Substernal thyrotoxic multinodular goiter (MNG) shows signs and symptoms as a result of compression of adjacent organs and thyrotoxicosis. However, acute airway obstruction is rarely caused by substernal thyrotoxic MNG. CASE REPORT: We have described a 56-year-old Japanese woman who demonstrated acute airway obstruction because of compression of the airway by substernal thyrotoxic MNG. She had been diagnosed with substernal thyrotoxic MNG 6 years back. However, because she was unwilling to undergo surgery to remove substernal thyrotoxic MNG, she was treated with methimazole. The patient maintained normal thyroid function with this therapy for 6 years. However, after 6 years the patient was admitted to our hospital because of severe dyspnea. Physical examination revealed inspiratory stridor, which indicated an airway obstruction caused by substernal thyrotoxic MNG. Airway intubation and subtotal thyroidectomy were performed. After the surgery, the dyspnea ameliorated. The general condition of the patient remained good 6 months after the surgery. CONCLUSION: This case clearly demonstrates the need for careful monitoring of substernal thyrotoxic MNG, because it may lead to an airway obstruction. PMID- 27988916 TI - Experimental Study of Intraparenchymal Fibrinogen and Topical Thrombin to Seal Pleural Defects. AB - OBJECTIVE: Fibrin sealants are used to close surgical pleural defects, but may detach, causing a postoperative air-leak. We investigated a new means of applying fibrin glue for closing pleural defects. METHODS: Pleural defects (10-mm and 4-mm diameters, respectively) were created in swine and rats via thoracotomy. They were sealed by a) injection of a fibrinogen solution into the lung parenchyma after instillation of a thrombin solution onto the pleural defect (group A), b) fibrinogen and thrombin spray (group B), c) fibrinogen instillation and a thrombin-dipped polyglycolic acid sheet (group C), or d) fibrin glue-coated collagen fleece (group D). Resistance to airway pressure was compared and the sealed areas were histologically examined. RESULTS: In group A, the minimum seal breaking airway pressure was consistently > 40 cmH2O, versus 37.2 +/- 3.6 cmH2O in group B, 37.2 +/- 4.0 cmH2O in group C, and 39.0 +/- 1.7 cmH2O in group D, which was statistically significant. Histologically, the fibrin layer infiltrated the lung parenchyma and covered the defect in group A, but not in the other groups. CONCLUSIONS: The intraparenchymal injection of fibrinogen combined with instillation of thrombin created an effective fibrin layer associated with early pleural regeneration that reliably prevented pleural air leaks. PMID- 27988918 TI - Scholastic Achievements: Graduate-entry vs. School-leaver-entry Medical Students. AB - OBJECTIVE: The objective of the present study is to conduct a retrospective analysis comparing graduate-entry program (GEP) and school-leaver-entry program (SEP) students from the perspective of scholastic achievements from admission through the national examination for medical practitioners. METHODS: The number of students who repeated one or more years, because of their poor results on examinations, the scores of graduation examinations, and the pass rates for the national examination for medical practitioners were compared, retrospectively, over the last 8 academic years between GEP and SEP students at Tokai University School of Medicine. RESULTS: The ratio of students who graduated in the prescribed course length was significantly higher (p = 0.002) in GEP students than that in SEP students. There were no differences between the average scores on the graduation examinations for GEP and SEP students, except in two academic years. The pass rate of GEP students (97%) of the national examination for medical practitioners was significantly higher (p < 0.001) than that of SEP students (89%). CONCLUSIONS: These results suggest that GEP students are more favorable candidates in terms of becoming physicians in the usualprescribed number of years than SEP students. PMID- 27988917 TI - Is the Perfusion Index Useful in Early Detection of High Spinal Subarachnoid Block during Cesarean Section? AB - OBJECTIVE: To investigate the usefulness of the perfusion index (PI) in the early detection of high spinal subarachnoid block (SAB) for cesarean section (CS). METHOD: SAB was applied in patients of CS. The patients was subdivided into two groups, according to the highest level of block: the Ce group (cervical spine level) and the Th group (thoracic spine level). The PI values in the finger and toe, and vital signs were measured at pre- and post-SAB in both groups together with SAB level. RESULTS: The PI valuses in the finger and toe were elevated post SAB in both groups; it showed no significant difference between them. However, in the Ce group, anesthesia immediately reached the upper thoracic nerves, and blood pressure showed a significant decrease post-SAB. CONCLUSIONS: Post-SAB finger PI value measuerments may not be useful for early detection of high SAB. Alternatively, the anesthesiologist should pay attention to immediate post-SAB changes in clinical signs such as a decrease in blood pressure as well as a rapid elevation of block level. PMID- 27988919 TI - Diabetes Affects Length of Stay and Hospital Costs for Elderly Patients with Pneumonia: An Analysis of a Hospital Administrative Database. AB - OBJECTIVE: The present study investigated the association of having diabetes with length of stay and hospital costs for elderly patients with pneumonia who were admitted to an acute-care hospital in Japan. METHODS: Based on the inpatient administrative claims database of an acute-care hospital in central Tokyo between 2010 and 2013, 753 patients aged >= 65 years who were admitted to the hospital presenting with pneumonia and discharged alive were analyzed. The association was analyzed using a negative binomial model, having adjusted for age, sex, body mass index, dyspnea grade, functional evaluation of feeding, use of mechanical ventilation, and use of renal replacement therapy. A log-linear regression model adjusted for the same variables was used in the analysis of hospital costs. RESULTS: Of the 753 patients (mean age, 82.5 years; men, 58.2%), 225 patients had diabetes. The negative binomial regression revealed that those with diabetes had a 1.19 times longer length of stay (95% CI = 1.06-1.33) compared to those without. The log-linear regression revealed that hospital costs were 1.14 times higher (95% CI = 1.04-1.25) in patients with diabetes. CONCLUSION: The presence of diabetes significantly correlated with longer length of stay and higher hospital costs for elderly patients with pneumonia. PMID- 27988920 TI - IP-10 Is Elevated in Virus-Induced Acute Exacerbations in Childhood Asthma. AB - OBJECTIVE: Viral infections and sensitization to aeroallergens are major factors in the exacerbation of asthma and its development during early childhood. However, the cytokine profiles and eosinophil activation status linked to the association between viral infections and sensitization to aeroallergens are incompletely understood. Here we investigated respiratory viruses, serum eosinophil cationic protein (ECP), and various cytokines/chemokines in acute exacerbation of childhood asthma. METHODS: We analyzed peripheral eosinophil counts, serum ECP, and 27 cytokines/chemokines in 76 virus-induced acute asthma cases with or without aeroallergen sensitization. Asthma due to sensitization was defined by a positive reaction to at least one aeroallergen in serum specific IgE antibody tests. Virus detection was performed using antigen detection kits and/or RT-PCR, followed by direct DNA sequencing analysis. Serum cytokines/chemokines were measured using a multi-cytokine detection system. RESULTS: Peripheral eosinophil counts and serum ECP and IL-5 levels were significantly elevated in sensitized cases compared with nonsensitized cases. Conversely, IP-10 values were significantly higher in nonsensitized cases. An inverse correlation between IP-10 and IL-5 production was identified in virus-induced acute exacerbations of asthma but not in controls. CONCLUSIONS: Cytokine profiles and eosinophil activation status might be different between sensitized and nonsensitized cases of virus induced acute exacerbations of asthma. PMID- 27988921 TI - Serial Epithelial Lining Fluid Collection Using Bronchoscopic Microsampling in a Canine Lung Transplantation Model. AB - OBJECTIVES: As a less invasive alternative to bronchoalveolar lavage (BAL), bronchoscopic microsampling (BMS) was developed to identify molecules present in the epithelial lining fluid (ELF) of the distal airways. Here, we evaluated the utility of BMS for serial collection of ELF in a canine lung transplant model. METHODS: ELF was collected hourly by BMS up to 5 hours after reperfusion in a canine left lung transplant model. Tumor necrosis factor (TNF)-alpha levels in ELF were measured using an enzyme-linked immunosorbent assay and were compared with those in BAL fluid. RESULTS: Serial collection of ELF by BMS in graft lungs was possible without adverse effects. However, the partial pressure of oxygen was markedly decreased because of ischemia-reperfusion lung injury. Probe ELF absorption ranged from 1-18 uL. TNF-alpha expression was significantly elevated and detected for 5 hours after reperfusion, whereas it was very low in the sham operated group (p < 0.05). TNF-alpha concentration in BAL fluid was less than one hundredth of that in ELF. CONCLUSIONS: BMS was safe and effective for serial ELF collection in grafted lungs. Temporal changes in TNF-alpha corresponded with ischemia-reperfusion lung injury. This is the first study to adopt BMS to elucidate pulmonary function after lung transplantation. PMID- 27988922 TI - Amoebiasis Presenting as Acute Appendicitis. AB - We report a case of amoebic appendicitis without colitis symptoms. Acute appendicitis is commonly encountered by gastroenterologists in their daily practice. The number of cases of amoebiasis increases annually in Japan, and is thought to be associated with an increase in sexually transmitted disease or travel to endemic areas. However, acute amoebic appendicitis is rare and the prognosis is very poor compared to nonamoebic appendicitis. In our case, appendectomy was performed immediately after onset, and the patient was discharged without complications. It is difficult to differentiate between amoebic and nonamoebic appendicitis preoperatively, and the possibility of amoebic appendicitis should be kept in mind. PMID- 27988923 TI - Progressive Multifocal Micronodular Pneumocyte Hyperplasia in the Lungs of a Patient with Tuberous Sclerosis Complex: A Case Report. AB - We report a case of multifocal micronodular pneumocyte hyperplasia (MMPH) in a patient with tuberous sclerosis complex, in whom the lung nodules increased in the number and size over the course of 8 years. We diagnosed MMPH following a lung biopsy performed during video-assisted thoracic surgery. In most of the previously reported cases, the number and size of lung nodules is unchanged during the clinical course. Our case is the first report of progressive disease in pathologically proven MMPH. PMID- 27988924 TI - Successful Eradication Therapy for Helicobacter pylori-positive Atrophic Gastritis at the Sixth Attempt: A Case Report. AB - A 74-year-old woman undergoing outpatient follow-up for reflux esophagitis and atrophic gastritis tested positive for Helicobacter pylori and underwent primary eradication therapy with lansoprazole (LPZ) 30 mg, amoxicillin (AMPC) 750 mg, and clarithromycin (CAM) 200 mg twice daily for 1 week in August 2012. A urea breath test (UBT) after this treatment revealed that eradication had failed. Secondary eradication therapy was carried out with esomeprazole (EPZ) 20 mg, AMPC 750 mg, and metronidazole (MNZ) 250 mg twice daily for 1 week, but this also failed. The third attempt at eradication consisted of EPZ 20 mg, AMPC 750 mg, and sitafloxacin (STFX) 100 mg twice daily for 1 week, but this also ended in failure. A fourth attempt using rabeprazole (RPZ) 20 mg (4 times daily) with MNZ 250 mg and STFX 100 mg twice daily for 2 weeks also failed, as did a fifth attempt in April 2015 using vonoprazan (VPZ) 20 mg, AMPC 750 mg, and MNZ 250 mg twice daily for 1 week. Eradication was finally successful after the sixth attempt, in which the patient was treated with vonoprazan 20 mg, MNZ 250 mg, and STFX 100 mg twice daily for 2 weeks. PMID- 27988925 TI - Contributions of Observed Parent Socialization of Coping and Skin Conductance Level Reactivity to Childhood Adjustment. AB - This research examined the longitudinal association between parent socialization of coping and child adjustment, as well as the moderating role of children's skin conductance level reactivity (SCLR). Participants were a community sample of children (n = 64, M age = 9.02, 54.5% females, 93.2% Caucasian) and their parent(s). Parent coping suggestions were observed while their child engaged in a stressful challenge task, during which the child's SCLR, a measure of children's physiological reactivity to stress, was also measured. Parent(s) completed the Child Behavior Checklist (Achenbach & Rescorla, 2001) at baseline and a 6-month follow-up to assess internalizing and externalizing problems. Results revealed that secondary control engagement suggestions predicted fewer internalizing problems over time. In addition, disengagement suggestions predicted fewer externalizing problems over time among children with high SCLR. This study provides evidence that parent coping suggestions serve as a resource that protects youth from developing adjustment problems. PMID- 27988928 TI - Long-term efficacy and safety of the dual 5-alpha reductase blocker dutasteride on male androgenetic alopecia patients. PMID- 27988929 TI - Lymphomatoid granulomatosis initially presenting as ulcerated subcutaneous and muscle lesions without pulmonary involvement. PMID- 27988926 TI - Towards a multigene phylogeny of the Cymatosiraceae (Bacillariophyta, Mediophyceae) I: novel taxa within the subfamily cymatosiroideae based on molecular and morphological data. AB - The family Cymatosiraceae, composed of two subfamilies (Cymatosiroideae and Extubocelluloideae), are elongate, non-pennate diatoms and are commonly reported in marine planktonic and benthic assemblages all over the world. The combination of the gross bilateral symmetry of the frustule and radial symmetry of the valve poration, distinct pore fields at the valve apices and DNA sequence data place this family in the controversial diatom class Mediophyceae, sister to the pennate diatoms. The relationships of the Cymatosiraceae within the Mediophyceae, and the monophyly of the two cymatosiroid subfamilies, have become less stable with the addition of new DNA sequence data. In this paper, we examined 24 cymatosiraceaen strains, including the new taxa Lambertocellus africana (Dabek & Witkowski) Dabek, Witkowski & Ashworth comb. nov., Leyanella probus Ashworth, Dabek & Witkowski sp. nov., and Leyanella pauciporis Ashworth, Dabek & Park sp. nov. to create the most complete molecular phylogeny of the Cymatosiraceae to date, using a three-gene (SSU, rbcL and psbC) data set. The results of the phylogenetic analysis supported the monophyly of the Cymatosiraceae, but not the monophyly of the subfamilies Cymatosiroideae and Extubocelluloideae. The phylogenetic analysis also suggested a close relationship of the Cymatosiraceae to the family Eupodiscaceae. The phylogenetic results have lead us to re-evaluate the taxonomy of L. africana, which is sister to Cymatosira lorenziana rather than Minutocellus as suggested in the original description. PMID- 27988931 TI - Pigmented epidermotropic metastasis from breast carcinoma. PMID- 27988930 TI - Further evidence for periodontal disease as a risk indicator for adverse pregnancy outcomes. AB - BACKGROUND: Although there is increasing evidence to suggest an association between periodontal disease and adverse pregnancy outcomes, the issue remains controversial. STUDY OBJECTIVE: This study tested the hypothesis that periodontal disease is a risk indicator for preterm delivery of low-birthweight infants. MATERIALS AND METHODS: The study sample comprised 443 pregnant women with a mean (+/- standard deviation) age of 24.13 (+/-5.30) years. At first visit, maternal oral health status was assessed by the measurement of probing pocket depth and clinical attachment loss, and periodontal status was graded as absent, mild, moderate or severe. An association was sought between pregnancy outcomes and maternal periodontal status. RESULTS: While controlling for other factors, significant associations were found between pregnancy outcomes and maternal periodontal index scores. CONCLUSION: This study provides further evidence that periodontal disease is a risk indicator for adverse pregnancy outcomes. PMID- 27988927 TI - Cardiac remodelling in a baboon model of intrauterine growth restriction mimics accelerated ageing. AB - KEY POINTS: Rodent models of intrauterine growth restriction (IUGR) successfully identify mechanisms that can lead to short-term and long-term detrimental cardiomyopathies but differences between rodent and human cardiac physiology and placental-fetal development indicate a need for models in precocial species for translation to human development. We developed a baboon model for IUGR studies using a moderate 30% global calorie restriction of pregnant mothers and used cardiac magnetic resonance imaging to evaluate offspring heart function in early adulthood. Impaired diastolic and systolic cardiac function was observed in IUGR offspring with differences between male and female subjects, compared to their respective controls. Aspects of cardiac impairment found in the IUGR offspring were similar to those found in normal controls in a geriatric cohort. Understanding early cardiac biomarkers of IUGR using non-invasive imaging in this susceptible population, especially taking into account sexual dimorphisms, will aid recognition of the clinical presentation, development of biomarkers suitable for use in humans and management of treatment strategies. ABSTRACT: Extensive rodent studies have shown that reduced perinatal nutrition programmes chronic cardiovascular disease. To enable translation to humans, we developed baboon offspring cohorts from mothers fed ad libitum (control) or 70% of the control ad libitum diet in pregnancy and lactation, which were growth restricted at birth. We hypothesized that intrauterine growth restriction (IUGR) offspring hearts would show impaired function and a premature ageing phenotype. We studied IUGR baboons (8 male, 8 female, 5.7 years), control offspring (8 male, 8 female, 5.6 years - human equivalent approximately 25 years), and normal elderly (OLD) baboons (6 male, 6 female, mean 15.9 years). Left ventricular (LV) morphology and systolic and diastolic function were evaluated with cardiac MRI and normalized to body surface area. Two-way ANOVA by group and sex (with P < 0.05) indicated ejection fraction, 3D sphericity indices, cardiac index, normalized systolic volume, normalized LV wall thickness, and average filling rate differed by group. Group and sex differences were found for normalized LV wall thickening and normalized myocardial mass, without interactions. Normalized peak LV filling rate and diastolic sphericity index were not correlated in control but strongly correlated in OLD and IUGR baboons. IUGR programming in baboons produces myocardial remodelling, reduces systolic and diastolic function, and results in the emergence of a premature ageing phenotype in the heart. To our knowledge, this is the first demonstration of the specific characteristics of cardiac programming and early life functional decline with ageing in an IUGR non-human primate model. Further studies across the life span will determine progression of cardiac dysfunction. PMID- 27988932 TI - Young Children's Reliance on Information From Inaccurate Informants. AB - Prior work shows that children selectively learn from credible speakers. Yet little is known how they treat information from non-credible speakers. This research examined to what extent and under what conditions children may or may not learn from problematic sources. In three studies, we found that children displayed trust toward previously inaccurate speakers. Children were equally likely to extend labels from previously accurate and inaccurate speakers to novel objects. Moreover, they expected third parties to share labels provided by previously inaccurate speakers. Only when there was clear evidence that the speakers' information was wrong (as in the case when speakers' perceptual access to the information was blocked), did young children reject the label. Together, the findings provide evidence that young children do not completely ignore the labels supplied by non-credible speakers unless there is strong reason to do so. PMID- 27988933 TI - Rare case of Netherton syndrome with generalized lentigines. PMID- 27988934 TI - Planning Beyond the Next Trial in Adaptive Experiments: A Dynamic Programming Approach. AB - Experimentation is at the heart of scientific inquiry. In the behavioral and neural sciences, where only a limited number of observations can often be made, it is ideal to design an experiment that leads to the rapid accumulation of information about the phenomenon under study. Adaptive experimentation has the potential to accelerate scientific progress by maximizing inferential gain in such research settings. To date, most adaptive experiments have relied on myopic, one-step-ahead strategies in which the stimulus on each trial is selected to maximize inference on the next trial only. A lingering question in the field has been how much additional benefit would be gained by optimizing beyond the next trial. A range of technical challenges has prevented this important question from being addressed adequately. This study applies dynamic programming (DP), a technique applicable for such full-horizon, "global" optimization, to model-based perceptual threshold estimation, a domain that has been a major beneficiary of adaptive methods. The results provide insight into conditions that will benefit from optimizing beyond the next trial. Implications for the use of adaptive methods in cognitive science are discussed. PMID- 27988935 TI - Perampanel effects in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and comorbid depressive-like behavior. AB - OBJECTIVE: Perampanel (PER), a selective non-competitive alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA)-receptor antagonist, exhibits broad spectrum anticonvulsant activity in several seizure models, but its potential disease-modifying effects have not been investigated. Because of the relevance of AMPA receptors in epileptogenesis and psychiatric comorbidities, we studied the effects of PER in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and depressive-like comorbidity. METHODS: We investigated the effects of acute, subchronic, and chronic treatment with PER (0.25-3 mg/kg) on absence seizures, their development, and related psychiatric/neurologic comorbidity in WAG/Rij rats. Depression-related behavior was studied by using the forced swimming and the sucrose preference test; anxiety-related behavior by using the open field and elevated plus maze test; and memory by using the passive avoidance test. RESULTS: PER (3 mg/kg/day orally for 17 weeks starting from P30) significantly reduced the development of absence seizures at 6 months of age (1 month after treatment withdrawal), but this effect was not maintained when reassessed 4 months later. Attenuated absence seizure development was accompanied by reduced depressive-like behavior in the forced swimming test (FST), whereas no effects were observed on anxiety-related behavior and memory. Subchronic (1 and 3 mg/kg/day orally for 1 week) and acute PER (0.25-1 mg/kg, i.p.) dosing did not affect established absence seizures and behavior. SIGNIFICANCE: These results suggest that AMPA receptors are involved in mechanisms of epileptogenesis in an established model of absence epilepsy, and that these mechanisms differ from those responsible for seizure generation and spread when epilepsy has become established. PMID- 27988936 TI - A metabarcoding comparison of windward and leeward airborne algal diversity across the Ko'olau mountain range on the island of O'ahu, Hawai'i1. AB - Airborne algae from sites on the windward (n = 3) and leeward (n = 3) sides of the Ko'olau Mountain range of O'ahu, Hawai'i, were sampled for a 16 d period during January and February 2015 using passive collection devices and were characterized using Illumina MiSeq sequencing of the universal plastid amplicon marker. Amplicons were assigned to 3,023 operational taxonomic units (OTUs), which included 1,189 cyanobacteria, 1,009 heterotrophic bacteria, and 304 Eukaryota (of which 284 were algae and land plants). Analyses demonstrated substantially more OTUs at windward than leeward O'ahu sites during the sampling period. Removal of nonalgal OTUs revealed a greater number of algal reads recovered from windward (839,853) than leeward sites (355,387), with the majority of these being cyanobacteria. The 1,234 total algal OTUs included cyanobacteria, diatoms, cryptophytes, brown algae, chlorophyte green algae, and charophyte green algae. A total of 208 algal OTUs were identified from leeward side samplers (including OTUs in common among samplers) and 1,995 algal OTUs were identified from windward samplers. Barcoding analyses of the most abundant algal OTUs indicated that very few were shared between the windward and leeward sides of the Ko'olau Mountains, highlighting the localized scale at which these airborne algae communities differ. Back trajectories of air masses arriving on O'ahu during the sampling period were calculated using the NOAA HY-SPLIT model and suggested that the sampling period was composed of three large-scale meteorological events, indicating a diversity of potential sources of airborne algae outside of the Hawaiian Islands. PMID- 27988937 TI - Negative symptoms mediate the relationship between neurocognition and function in individuals at ultrahigh risk for psychosis. AB - OBJECTIVE: Neurocognition is known to impact functioning in individuals at ultrahigh risk (UHR) for psychosis, but studies investigating potential mediators of this relationship are scarce. Building on evidence from schizophrenia spectrum disorders, the study tested whether negative symptoms and social skills act as mediators between neurocognition and functional outcome in UHR individuals. METHODS: Ultrahigh risk participants (N = 84) underwent neurocognitive testing using the Brief Assessment of Cognition in Schizophrenia. Social skills and negative symptoms were assessed using the High-Risk Social Challenge task and the Scale for the Assessment of Negative Symptoms respectively. Four instruments were used to assess overall functioning, and one instrument assessed quality of life encompassing social functioning. RESULTS: The cross-sectional analyses revealed that neurocognition was related to the measures of functioning. Negative symptoms mediated the relationship between neurocognition and four of the five measures of functioning. We did not find social skills to mediate between neurocognition and functioning. CONCLUSION: Negative symptoms appear to mediate the relationship between neurocognition and functional outcome in UHR individuals, but the finding needs to be confirmed and extended to longitudinal studies. This underscores the importance of focusing on both neurocognition and negative symptoms when aiming at improving the functional outcome of UHR individuals. PMID- 27988938 TI - Environmental impact on young children's participation in home-based activities. AB - AIM: To test the effect of child, family, and environmental factors on young children's participation in home-based activities. METHOD: Caregivers of young children were recruited using convenience and snowball sampling. Participants were 395 caregivers of children (222 males, 173 females) aged from 1 month to 5 years and 11 months. Demographic items and the home section of the Young Children's Participation and Environment Measure were administered online, followed by completion of the daily activities, mobility, and social/cognitive domains of the Pediatric Evaluation of Disability Inventory Computer Adaptive Test by telephone interview. RESULTS: A structural equation model fitted the data well (comparative fit index=0.91) and explained 31.2% of the variance in perceived environmental support and 42.5% of the variance in home involvement. Functional limitations and performance had an indirect effect on young children's participation through their effect on perceived environmental support. Specifically, fewer functional limitations and higher task performance were associated with greater environmental support, which in turn predicted higher levels of home involvement. INTERPRETATION: Results suggest the importance of a young child's functional abilities and task performance on caregiver perceptions of environmental support at home, and the impact of environmental support on a child's participation in home-based activities during the early childhood period. Results warrant replication with more diverse samples to evaluate model generalizability. PMID- 27988940 TI - Erythema multiforme associated with Trueperella pyogenes bacteremia. PMID- 27988941 TI - Biphasic synovial sarcoma with prominent cavernous hemangioma-like stroma. PMID- 27988939 TI - Second Language Experience Facilitates Statistical Learning of Novel Linguistic Materials. AB - Recent research has begun to explore individual differences in statistical learning, and how those differences may be related to other cognitive abilities, particularly their effects on language learning. In this research, we explored a different type of relationship between language learning and statistical learning: the possibility that learning a new language may also influence statistical learning by changing the regularities to which learners are sensitive. We tested two groups of participants, Mandarin Learners and Naive Controls, at two time points, 6 months apart. At each time point, participants performed two different statistical learning tasks: an artificial tonal language statistical learning task and a visual statistical learning task. Only the Mandarin-learning group showed significant improvement on the linguistic task, whereas both groups improved equally on the visual task. These results support the view that there are multiple influences on statistical learning. Domain relevant experiences may affect the regularities that learners can discover when presented with novel stimuli. PMID- 27988943 TI - Pazopanib induced a partial response in a patient with metastatic fibrosarcomatous dermatofibrosarcoma protuberans without genetic translocations resistant to mesna, doxorubicin, ifosfamide and dacarbazine chemotherapy and gemcitabine-docetaxel chemotherapy. PMID- 27988942 TI - Young, healthy South Asians have enhanced lipogenic sensitivity to dietary sugar. AB - OBJECTIVE: South Asians have higher rates of type 2 diabetes and cardiovascular disease compared to most other racial/ethnic groups. Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar may accelerate the development of these chronic diseases in this population. STUDY DESIGN: Hepatic DNL in response to a calorically sweetened beverage was measured in an outpatient setting in 15 South Asians and 15 Caucasians with similar and normal body mass indexes, waist circumferences, glucose tolerance and lipid profiles. Blood was sampled before and hourly for 4 h after the ingestion of a single beverage made with glucose (1.5 g/kg) and fructose (1.5 g/kg). The main outcome, DNL, was measured as the increase in %palmitate (16:0) in very low-density lipoprotein (VLDL) triglyceride (TG) over 4 h. RESULTS: After the sugar dose, the increase in %16:0 in VLDL TG was significantly greater in South Asians vs Caucasians (P = 0.01). VLDL and total TG also increased to a significantly greater extent in South Asians (P = 0.04 and <0.001, respectively). Although the fasting and postsugar levels of insulin and glucose did not differ between groups, the DNL response significantly correlated with the insulin response to sugar in South Asians (r = 0.56, P = 0.03). CONCLUSIONS: Hepatic DNL in response to a sugar challenge was greater in healthy, young South Asians compared to Caucasians despite normal indices of insulin sensitivity, and it correlated with the insulin response. These findings suggest an early, insulin-related, gene-nutrient interaction contributing to the high prevalence of diabetes and coronary disease in this population. PMID- 27988945 TI - Correction. PMID- 27988944 TI - Immunosenescence: the importance of considering age in health and disease. PMID- 27988946 TI - Design counsel: the role of clinicians in the prototyping and standard setting of anaesthetic equipment. PMID- 27988947 TI - 'Go-between' study: walk times and talk times. PMID- 27988949 TI - Vascular access after axillary lymph node surgery. PMID- 27988948 TI - Retention of laryngoscopy skills in medical students - a reply. PMID- 27988950 TI - What Anaesthesia is doing to combat scientific misconduct and investigate data fabrication and falsification. PMID- 27988951 TI - Abandoning first generation supraglottic airway devices in paediatric anaesthesia. PMID- 27988952 TI - Evidence for non-random sampling in randomised, controlled trials by Yuhji Saitoh. AB - A large number of randomised trials authored by Yoshitaka Fujii have been retracted, in part as a consequence of a previous analysis finding a very low probability of random sampling. Dr Yuhji Saitoh co-authored 34 of those trials and he was corresponding author for eight of them. We found a number of additional randomised, controlled trials that included baseline data, with Saitoh as corresponding author, that Fujii did not co-author. We used Monte Carlo simulations to analyse the baseline data from 32 relevant trials in total as well as an outcome (muscle twitch recovery ratios) reported in several. We also compared a series of muscle twitch recovery graphs appearing in a number of Saitoh's publications. The baseline data in 14/32 randomised, controlled trials had p < 0.01, of which seven p values were < 0.001. Eight trials reported four ratios of the time for the return of muscle activity after neuromuscular blockade, the distributions of which were homogeneous: the p values for the observed Q statistics were 0.0055, 0.031, 0.016 and 0.0071. Comparison of graphs revealed multiple coincident or near-coincident curves across a large number of publications, a finding also inconsistent with random sampling. Combining the continuous and categorical probabilities of the 32 included trials, we found a very low likelihood of random sampling: p = 1.27 * 10-8 (1 in 100,000,000). The high probability of non-random sampling and the repetition of lines in multiple graphs suggest that further scrutiny of Saitoh's work is warranted. PMID- 27988953 TI - Visualising odds ratios. PMID- 27988954 TI - Engineering jargon. PMID- 27988955 TI - Does mannitol contribute to hypotension after parenteral paracetamol administration in critical care? PMID- 27988956 TI - Ultra-low dose spinal anaesthesia for hip fracture surgery. PMID- 27988957 TI - Retention of laryngoscopy skills in novices. PMID- 27988958 TI - 'Go-between' study: walk times and talk times - a reply. PMID- 27988959 TI - Vascular access after axillary lymph node surgery - a reply. PMID- 27988960 TI - GE Healthcare response: performance of adjustable pressure limiting (APL) valves in two different modern anaesthesia machines. PMID- 27988961 TI - AAGBI: Consent for anaesthesia 2017: Association of Anaesthetists of Great Britain and Ireland. AB - Previous guidelines on consent for anaesthesia were issued by the Association of Anaesthetists of Great Britain and Ireland in 1999 and revised in 2006. The following guidelines have been produced in response to the changing ethical and legal background against which anaesthetists, and also intensivists and pain specialists, currently work, while retaining the key principles of respect for patients' autonomy and the need to provide adequate information. The main points of difference between the relevant legal frameworks in England and Wales and Scotland, Northern Ireland and the Republic of Ireland are also highlighted. PMID- 27988963 TI - Vascular access, cerebral air embolism and hyperbaric oxygen therapy. PMID- 27988962 TI - Duration of low-dose spinal anaesthesia for hip fracture surgery. PMID- 27988964 TI - Performance of adjustable pressure-limiting (APL) valves in two different modern anaesthesia machines. AB - The ability to gently ventilate a patient's lungs using a self-inflating bag requires a properly working adjustable pressure-limiting (APL) valve. We compared the performance of the APL valves of the GE Aisys CS2 and the Draeger Fabius anaesthetic machines during closure and opening from 1-20 and from 20-1 cmH2 O, using standardised experimental baby and adolescent patient lung models. Airway pressures and inspiratory tidal volumes were measured using an ASL-5000 test lung and a GE Aisys CS2 near-patient spirometry sensors. In both lung models, the GE Aisys CS2 APL valves demonstrated non-linear behaviours for airway pressures and for inspiratory tidal volumes, with a sharp increase at set APL pressure levels of 8-10 cmH2 O. With further closure of the GE Aisys CS2 APL valves up to 20 cmH2 O, inspiratory tidal volumes decreased to ~50% of the highest values measured. Airway pressures in the Draeger Fabius APL valves demonstrated a near linear increase and decrease. Airway pressure values measured in the Draeger Fabius were never higher than those set by the APL valves, whereas in the GE Aisys CS2 , they considerably exceeded set pressures (by up to 27 cmH2 O). We conclude that the performance of the GE Aisys CS2 APL valve does not allow safe bag-assisted ventilation of a patient's lungs. PMID- 27988965 TI - Ictal asystole: A systematic review. AB - OBJECTIVE: To comprehensively analyze ictal asystole (IA) on a large number of subjects. METHODS: We performed a systematic review of case report studies of patients diagnosed with IA (1983-2016). Each included case was characterized with respect to patient history, IA seizure characteristics, diagnostic workup, and therapy. In addition, comparative analyses were also carried out: two alignments were developed based on the delay between epilepsy onset and IA onset ("new onset" if <1 year, "late-onset" if >=1 year) and asystole duration (asystole was "very prolonged" if lasted >30 s). RESULTS: One hundred fifty-seven cases were included. All patients had focal epilepsy. In 7% of cases IA developed during a secondary generalized tonic-clonic seizure. Both the seizure-onset zone and the focal seizure activity at asystole beginning were usually temporal (p < 0.001 and p = 0.001, respectively) and were lateralized to the left hemisphere in 62% (p = 0.005 and p = 0.05, respectively). Asystole duration was 18 +/- 14 s (mean+/-SD) (range 3-96 s); 73% of patients had late-onset, 27% had new-onset IA. Compared to late-onset IA, new-onset IA was associated with female gender (p = 0.023), preexisting heart condition (p = 0.014), focal seizure activity at asystole beginning (p = 0.012), normal neuroimaging (p = 0.013), normal interictal EEG (p < 0.001), auditory aura (p = 0.012), and drug-responsive epilepsy (p < 0.001). "Very prolonged" asystole was associated with secondary generalized tonic-clonic seizures (p = 0.003) and tended to occur in extratemporal lobe seizures (p = 0.074). No IA-related death was reported. SIGNIFICANCE: Characteristics considered to be typical of IA (focal, left temporal seizures appearing on grounds of a long-lasting, intractable epilepsy) seem only partially legitimate. We suggest that in new-onset IA, female gender and a preexisting heart condition could serve as predispositions in an otherwise benign epilepsy. We speculate that in late-onset IA, male-predominant changes in neuronal networks in chronic, intractable epilepsy and an accompanying autonomic dysregulation serve as facilitating factors. PMID- 27988966 TI - Behaviour in Cornelia de Lange syndrome: a systematic review. AB - AIM: Careful study and accurate description of behaviour are important to understand developmental challenges for individuals with Cornelia de Lange syndrome (CdLS). Here we present a systematic review of current understanding of behaviour in CdLS. METHOD: A systematic search was performed for articles published between January 1946 and December 2015 evaluating autism, self-injury, and/or cognition in CdLS. After study-selection, 43 papers were included. The Cochrane quality criteria were adjusted to assign quality scores to the included studies. RESULTS: Participants were mostly categorized in the severe/profound developmental level. Methodology and quality were very heterogeneous, as well as reporting occurrence of autism. Self-injurious behaviour was reported in 15 papers. Physical conditions were reported in 21 studies, mostly related to hearing and vision. Only nine studies mentioned details about medication. INTERPRETATION: Comparison of presented results was hindered by heterogeneous assessment methods. Improving our understanding of behavioural characteristics in CdLS requires more uniform methodology. We propose a criterion standard of instruments that can ideally be used in assessment of behaviour and development. This will improve understanding of behaviour in the context of developmental level and daily functioning. PMID- 27988967 TI - Time to onset of sustained >=50% responder status in patients with focal (partial onset) seizures in three phase III studies of adjunctive brivaracetam treatment. AB - Time to onset of sustained >=50% responder status (SRS) was assessed for the pooled patient population receiving brivaracetam (BRV) 50, 100, or 200 mg/day or placebo in three randomized phase III studies (NCT00464269, NCT00490035, and NCT01261325). Patients were aged >=16 years with well-characterized focal (partial-onset) seizures (FS) uncontrolled by 1-2 concomitant antiepileptic drugs. After an 8-week baseline period, patients received study drug without up titration for a 12-week (84-day) treatment period. A patient was a sustained >=50% responder on a particular day if they completed the entire treatment period through day 84 and was a >=50% responder (based on percent reduction in FS frequency from baseline) both on that day and every successive day until day 84 (end of treatment period). In the pooled efficacy population (N = 1,160), 15.5%, 18.1%, and 19.4% of patients taking BRV 50, 100, or 200 mg/day, respectively, achieved SRS on day 1 versus 6.7% for placebo (p < 0.001). Statistically significant SRS was also achieved for most of the BRV-treated groups in the three separate studies. This suggests that BRV has an early, sustained onset of action in a subset of responders. The incidence of adverse events during the first week was similar to that in the overall treatment period. PMID- 27988969 TI - Efficacy of topical tacrolimus for treating Kyrle's disease. PMID- 27988968 TI - Premature mortality of epilepsy in low- and middle-income countries: A systematic review from the Mortality Task Force of the International League Against Epilepsy. AB - To determine the magnitude of risk factors and causes of premature mortality associated with epilepsy in low- and middle-income countries (LMICs). We conducted a systematic search of the literature reporting mortality and epilepsy in the World Bank-defined LMICs. We assessed the quality of the studies based on representativeness; ascertainment of cases, diagnosis, and mortality; and extracted data on standardized mortality ratios (SMRs) and mortality rates in people with epilepsy. We examined risk factors and causes of death. The annual mortality rate was estimated at 19.8 (range 9.7-45.1) deaths per 1,000 people with epilepsy with a weighted median SMR of 2.6 (range 1.3-7.2) among higher quality population-based studies. Clinical cohort studies yielded 7.1 (range 1.6 25.1) deaths per 1,000 people. The weighted median SMRs were 5.0 in male and 4.5 in female patients; relatively higher SMRs within studies were measured in children and adolescents, those with symptomatic epilepsies, and those reporting less adherence to treatment. The main causes of death in people with epilepsy living in LMICs include those directly attributable to epilepsy, which yield a mean proportional mortality ratio (PMR) of 27.3% (range 5-75.5%) derived from population-based studies. These direct causes comprise status epilepticus, with reported PMRs ranging from 5 to 56.6%, and sudden unexpected death in epilepsy (SUDEP), with reported PMRs ranging from 1 to 18.9%. Important causes of mortality indirectly related to epilepsy include drowning, head injury, and burns. Epilepsy in LMICs has a significantly greater premature mortality, as in high-income countries, but in LMICs the excess mortality is more likely to be associated with causes attributable to lack of access to medical facilities such as status epilepticus, and preventable causes such as drowning, head injuries, and burns. This excess premature mortality could be substantially reduced with education about the risk of death and improved access to treatments, including AEDs. PMID- 27988970 TI - Calcification score evaluation in patients listed for renal transplantation. AB - Based on native CT scans of the pelvic region using a standardized calcification score, evaluation of iliac vascular calcification was performed between 2008 and 2012 prior to listing for renal transplantation in 205 patients with chronic kidney disease. Vascular calcification showed a decrease from proximal to distal. The difference between the degree of calcification in the common iliac artery and in the external iliac artery was significant (P<.001). Risk factors for total iliac vascular calcification were age, smoking, sex, underlying renal disease, and diabetes. Multivariate analysis revealed age to be the most relevant risk factor (P<.001). The duration of hemodialysis correlated significantly with total iliac vascular calcification. As the introduction of the standardized surgical evaluation protocol, no transplantation has had to be broken off and no early graft loss due to calcification has occurred. Thus, careful scoring of vascular calcification prior to transplantation may be a valuable tool to support surgical decisions and to improve patient safety and outcome in increasingly older transplant recipients. PMID- 27988971 TI - Antibody depletion strategy for the treatment of suspected antibody-mediated rejection in lung transplant recipients: Does it work? AB - BACKGROUND: Donor-specific antibodies (DSAs) after lung transplantation correlate with poor outcomes. The ideal treatment strategy for antibody-mediated rejection AMR is not defined. Our institution implemented an aggressive multimodality protocol for the treatment of suspected AMR. METHODS: Lung transplant recipients with suspected AMR were treated with a standardized protocol of plasma exchange, steroids, bortezomib, rituximab, and intravenous immune globulin. Primary outcome was DSA clearance at 6 months in those alive. Secondary endpoints included preserved allograft function at 6 months, survival at 6 and 12 months and complications due to the protocol. RESULTS: Sixteen lung transplant recipients with documented DSA and allograft dysfunction were included in the analysis. Of the 16 patients, 11 survived to 6 months. Three of those 11 patients (27%) cleared all DSAs within 6 months of the protocol. Four of the 11 patients (36%) had preserved allograft function at 6 months. Overall 12-month patient survival was 56%. Complications included thrombocytopenia (50%) and abdominal pain or gastrointestinal discomfort (18.7%). CONCLUSIONS: This multimodality protocol resulted in clearance of DSAs and preserved lung function in a minority of lung transplant recipients with suspected AMR surviving to 6 months after therapy. There were significant side effects of the protocol. PMID- 27988972 TI - Mitochondrial DNA D-loop haplogroup contributions to the genetic diversity of East European domestic chickens from Russia. AB - To elucidate geographical and historical aspects of chicken dispersal across Eastern Europe, we analysed the complete mitochondrial DNA D-loop sequence of 86 representatives from chicken breeds traditionally raised in the territory of the East European Plain (Orloff, Pavlov, Russian White, Yurlov Crower, Uzbek Game and Naked Neck). From the 1231-1232 bp D-loop sequence, 35 variable sites that defined 22 haplotypes were identified in modern chicken. All populations, except Uzbek Game, exhibited high values of haplotype and nucleotide diversity suggesting a wide variation in maternal diversity. Inclusion of mtDNA sequences from other European and Asian countries revealed representatives from this study belonging to haplogroups A, E1 and C1. We also assessed fossil chicken material dated to the 9th-18th century from archaeological sites in Northern and Eastern Europe. Three haplotypes found in the fossil specimens belonged to haplogroup E1, while one sample dated to the 18th century was assigned to the C1 haplogroup. This is the first report of the occurrence of the C1 haplogroup in European chicken populations prior to the 20th century based on the fossil material. These results provide evidence for a relatively recent introduction of all haplotypes other than E1 into the East European chicken gene pool with the significant impact of the C1 haplogroup mainly distributed in Southern China. PMID- 27988973 TI - Characterizing human cytomegalovirus reinfection in congenitally infected infants: an evolutionary perspective. AB - Given the strong selective pressures often faced by populations when colonizing a novel habitat, the level of variation present on which selection may act is an important indicator of adaptive potential. While often discussed in an ecological context, this notion is also highly relevant in our clinical understanding of viral infection, in which the novel habitat is a new host. Thus, quantifying the factors determining levels of variation is of considerable importance for the design of improved treatment strategies. Here, we focus on such a quantification of human cytomegalovirus (HCMV) - a virus which can be transmitted across the placenta, resulting in foetal infection that can potentially cause severe disease in multiple organs. Recent studies using genomewide sequencing data have demonstrated that viral populations in some congenitally infected infants diverge rapidly over time and between tissue compartments within individuals, while in other infants, the populations remain highly stable. Here, we investigate the underlying causes of these extreme differences in observed intrahost levels of variation by estimating the underlying demographic histories of infection. Importantly, reinfection (i.e. population admixture) appears to be an important, and previously unappreciated, player. We highlight illustrative examples likely to represent a single-population transmission from a mother during pregnancy and multiple-population transmissions during pregnancy and after birth. PMID- 27988974 TI - The quick and the dead: microbial demography at the yeast thermal limit. AB - The niche of microorganisms is determined by where their populations can expand. Populations can fail to grow because of high death or low birth rates, but these are challenging to measure in microorganisms. We developed a novel technique that enables single-cell measurement of age-structured birth and death rates in the budding yeast, Saccharomyces cerevisiae, and used this method to study responses to heat stress in a genetically diverse panel of strains. We find that individual cells show significant heterogeneity in their rates of birth and death during heat stress. Genotype-by-environment effects on processes that regulate asymmetric cell division contribute to this heterogeneity. These lead to either premature senescence or early life mortality during heat stress, and we find that a mitochondrial inheritance defect explains the early life mortality phenotype of one of the strains we studied. This study demonstrates how the interplay of physiology, genetic variation and environmental variables influence where microbial populations survive and flourish. PMID- 27988975 TI - Response of vegetation phenology to urbanization in the conterminous United States. AB - The influence of urbanization on vegetation phenology is gaining considerable attention due to its implications for human health, cycling of carbon and other nutrients in Earth system. In this study, we examined the relationship between change in vegetation phenology and urban size, an indicator of urbanization, for the conterminous United States. We studied more than 4500 urban clusters of varying size to determine the impact of urbanization on plant phenology, with the aids of remotely sensed observations since 2003-2012. We found that phenology cycle (changes in vegetation greenness) in urban areas starts earlier (start of season, SOS) and ends later (end of season, EOS), resulting in a longer growing season length (GSL), when compared to the respective surrounding urban areas. The average difference of GSL between urban and rural areas over all vegetation types, considered in this study, is about 9 days. Also, the extended GSL in urban area is consistent among different climate zones in the United States, whereas their magnitudes are varying across regions. We found that a tenfold increase in urban size could result in an earlier SOS of about 1.3 days and a later EOS of around 2.4 days. As a result, the GSL could be extended by approximately 3.6 days with a range of 1.6-6.5 days for 25th ~ 75th quantiles, with a median value of about 2.1 days. For different vegetation types, the phenology response to urbanization, as defined by GSL, ranges from 1 to 4 days. The quantitative relationship between phenology and urbanization is of great use for developing improved models of vegetation phenology dynamics under future urbanization, and for developing change indicators to assess the impacts of urbanization on vegetation phenology. PMID- 27988976 TI - Adaptive downregulation of pheomelanin-related Slc7a11 gene expression by environmentally induced oxidative stress. AB - Pheomelanin is a sulphur-containing yellow-to-reddish pigment whose synthesis consumes the main intracellular antioxidant (glutathione; GSH) and its precursor cysteine. Cysteine used for pheomelanogenesis cannot be used for antioxidant protection. We tested whether the expression of Slc7a11, the gene regulating the transport of cysteine to melanocytes for pheomelanogenesis, is environmentally influenced when cysteine/GSH are most required for antioxidant protection. We found that zebra finches Taeniopygia guttata developing pheomelanin-pigmented feathers during a 12-day exposure to the pro-oxidant diquat dibromide downregulated the expression of Slc7a11 in feather melanocytes, but not the expression of other genes that affect pheomelanogenesis by mechanisms different from cysteine transport such as MC1R and Slc45a2. Accordingly, diquat-treated birds did not suffer increased oxidative stress. This indicates that some animals have evolved an adaptive epigenetic lability that avoids damage derived from pheomelanogenesis. This mechanism should be explored in human Slc7a11 to help combat some cancer types related to cysteine consumption. PMID- 27988977 TI - Prognostic Factors for Metachronous Contralateral Breast Cancer: Implications for Management of the Contralateral Breast. AB - The absolute number of breast cancer survivors who are at risk for metachronous contralateral breast cancer (mCBC) has dramatically increased. The objectives of this study were to identify factors predictive of survival for patients with mCBC and to determine clinicopathological factors predictive of advanced mCBC. Using the Surveillance, Epidemiology, and End Results data base, we identified women, ages 18-80, diagnosed with invasive breast cancer from 1992 to 2010. We excluded patients with bilateral and stage IV primary breast cancer. Patients who developed mCBC >=12 months from initial diagnosis were identified. Kaplan-Meier methods and Cox proportional hazards modeling were used to determine survival of patients with mCBC. Multivariate logistic regression was utilized to determine factors associated with advanced mCBC. We identified 6,673 patients who developed mCBC during our study period. The median interval between initial breast cancer and mCBC was 5 years. The strongest predictor of overall survival was the nodal status of the mCBC. Other significant prognostic factors included patient age; race; size, nodal status, estrogen receptor status, grade, and type of surgery of the initial breast cancer; grade of the mCBC; and use of radiation therapy for the mCBC. Overall, 25% of mCBCs were node positive. Younger age, black race, and characteristics of the initial breast cancer (increased size, invasive lobular histology, mastectomy treatment, and node-positivity) were significantly associated with node-positive mCBC (all p < 0.0.05). The most powerful predictor of survival for patients with mCBC is the nodal status of mCBC. Patients with advanced initial breast cancers are more likely to develop node-positive mCBC. Adherence to current surveillance and adjuvant therapy guidelines may minimize the risk and mortality of mCBCs. PMID- 27988978 TI - Early surgical outcomes and oncological results of robot-assisted partial nephrectomy: a multicentre study. AB - OBJECTIVE: To describe a multicentre experience of robot-assisted partial nephrectomy (RAPN) in northern England, with focus on early surgical outcomes and oncological results. PATIENTS AND METHODS: All consecutive patients undergoing RAPN at four tertiary referral centres in northern England in the period 2012 2015 were included for analysis. RAPN was performed via a transperitoneal approach using a standardized technique. Prospective data collection was performed to capture preoperative characteristics (including R.E.N.A.L. nephrometry score), and peri-operative and postoperative data, including renal function. Correlations between warm ischaemia time (WIT), positive surgical margin (PSM) rate, complication rates, R.E.N.A.L. nephrometry scores and learning curve were assessed using univariate and multivariate analyses. RESULTS: A total of 250 patients (mean age 58.1 +/- 13 years, mean +/- sd body mass index 27.3 +/- 7 kg/m2 ) were included, with a median (range) follow-up of 12 (3-36) months. The mean +/- sd tumour size was 30.6 +/- 10 mm, mean R.E.N.A.L. nephrometry score was 6.1 +/- 2 and 55% of tumours were left-sided. Mean +/- sd operating console time was 141 +/- 38 min, WIT 16.7 +/- 8 min and estimated blood loss 205 +/- 145 mL. There were five conversions (2%) to open/radical nephrectomy. The overall complication rate was 16.4% (Clavien I, 1.6%; Clavien II, 8.8%; Clavien III, 6%; Clavien IV/V; 0%). Pathologically, 82.4% of tumours were malignant and the overall PSM rate was 7.3%. The mean +/- sd preoperative and immediate postoperative estimated glomerular filtration rates were 92.8 +/- 27 and 80.8 +/- 27 mL/min/1.73 m2 , respectively (P = 0.001). In all, 66% of patients remained in the same chronic kidney disease category postoperatively, and none of the patients required dialysis during the study period. 'Trifecta' (defined as WIT < 25 min, negative surgical margin status and no peri-operative complications) was achieved in 68.4% of patients overall, but improved with surgeon experience. PSM status and long WIT were significantly associated with early learning curve. CONCLUSION: This is the largest multicentre RAPN study in the UK. Initial results show that RAPN is safe and can be performed with minimal morbidity. Early oncological outcomes and renal function preservation data are encouraging. PMID- 27988979 TI - Anaesthetic management of sleep-disordered breathing in adults. AB - Anaesthesia and sleep are different states of unconsciousness with considerable physiological common ground. Because of their shared depressant effects on muscle activation and ventilatory drive, patients with anatomically compromised airways will tend to obstruct in either state and those with impaired ventilatory capacity will tend to hypoventilate. Breathing behaviour in one state is predictive of that in the other. An essential difference is that while arousal responses are preserved during sleep, they are depressed during sedation and abolished by anaesthesia. This renders patients with sleep-related breathing disorders vulnerable to hypoventilation and asphyxia when deeply sedated. Addressing this vulnerability requires a systematic approach to identification of patients and circumstances that magnify this risk, and methods of managing it that seek to reconcile the need for safety with cost-effective use of resources. PMID- 27988980 TI - Population genomics reveals structure at the individual, host-tree scale and persistence of genotypic variants of the undomesticated yeast Saccharomyces paradoxus in a natural woodland. AB - Genetic diversity in experimental, domesticated and wild populations of the related yeasts, Saccharomyces cerevisiae and Saccharomyces paradoxus, has been well described at the global scale. We investigated the population genomics of a local population on a small spatial scale to address two main questions. First, is there genomic variation in a S. paradoxus population at a spatial scale spanning centimetres (microsites) to tens of metres? Second, does the distribution of genomic variants persist over time? Our sample consisted of 42 S. paradoxus strains from 2014 and 43 strains from 2015 collected from the same 72 microsites around four host trees (Quercus rubra and Quercus alba) within 1 km2 in a mixed hardwood forest in southern Ontario. Six additional S. paradoxus strains recovered from adjacent maple and beech trees in 2015 are also included in the sample. Whole-genome sequencing and genomic SNP analysis revealed five differentiated groups (clades) within the sampled area. The signal of persistence of genotypes in their microsites from 2014 to 2015 was highly significant. Isolates from the same tree tended to be more related than strains from different trees, with limited evidence of dispersal between trees. In growth assays, one genotype had a significantly longer lag phase than the other strains. Our results indicate that different clades coexist at fine spatial scale and that population structure persists over at least a one-year interval in these wild yeasts, suggesting the efficacy of yearly sampling to follow longer term genetic dynamics in future studies. PMID- 27988981 TI - Gender differences in long-term survival post-transplant: A single-institution analysis in the lung allocation score era. AB - The purpose of this study was to clarify the significance of recipient gender status on lung transplant outcomes in a large single-institution experience spanning three decades, we analyzed data from all lung transplants performed in our institution since 1986. Kaplan-Meier curves and Cox proportional hazard models were used to evaluate the effect of recipient characteristics on survival and BOS score >=1-free survival. Logistic regression analysis was used to explore the association of gender with short-term graft function. About 876 lung transplants were performed between 1986 and 2016. Kaplan-Meier survival estimates at 5 years post-transplant for females vs males in the LAS era were 71% vs 58%. In the LAS era, females showed greater unadjusted BOS>=1-free survival than males (35% vs 25%, P=.02) over 5 years. Female gender was the only factor in the LAS era significantly associated with improved adjusted 5-year survival [HR 0.56 (95% CI 0.33, 0.95) P=.03]. Conversely, in the pre-LAS era female gender was not associated with improved survival. Female recipients showed significantly improved survival over 5 years compared to males in the LAS era. A prospective analysis of biologic and immunologic differences is warranted. PMID- 27988982 TI - Pruritus and quality of life in renal transplant patients. AB - BACKGROUND: Pruritus has a negative impact on quality of life (QoL) in dialysis patients. The reversibility of this symptom after renal transplantation and its impact upon QoL has scarcely been studied in these patients. METHODS: Pruritus was evaluated by the Visual Analogue Scale (VAS), the Visual Rating Scale (VRS), and the Numerical Rating Scale (NRS) in 133 unselected renal transplant patients, 62 healthy subjects, and 29 hemodialysis patients. QoL was assessed by KDQOL-SFTM 1.3. The reversibility of pruritus was studied by applying retrospectively the VRS. RESULTS: The prevalence of pruritus by the VRS was 62% in hemodialysis patients, 32% in renal transplant patients, and 11% in healthy subjects (P<.001). The prevalence of pruritus among transplant patients was 32% by VRS and 38% by VAS and NRS. The prevalence of pretransplantation pruritus (68%) by the VRS recall questionnaire was higher than the prevalence of pruritus in the same patients after renal transplantation (32%, P<.01). Pruritus in transplant patients was associated with important dimensions of QoL, including social, emotional, and working limitations (P<.05 for the three comparisons). CONCLUSIONS: The prevalence of pruritus markedly reduces after renal transplantation but remains substantially higher than in the general population and impacts upon quality of life in these patients. PMID- 27988983 TI - Multiple Schwannomas in a Patient with Gynecomastia. PMID- 27988984 TI - Safety and early effectiveness of robot-assisted partial nephrectomy for large angiomyolipomas. AB - OBJECTIVE: To evaluate a multicentre series of robot-assisted partial nephrectomy (RAPN) performed for the treatment of large angiomyolipomas (AMLs). PATIENTS AND METHODS: Between 2005 and 2016, 40 patients with large or symptomatic AMLs underwent RAPN at five academic centres in the USA. Patient demographics, AML characteristics, operative and postoperative clinical outcomes were recorded and analysed. Surgical outcomes were compared between patients who underwent selective arterial embolisation (SAE) before RAPN and patients who did not undergo pre-RAPN SAE. RESULTS: The median (interquartile range [IQR]) tumour diameter was 7.2 (5-8.5) cm, and the median (IQR) nephrometry score was 9 (7-10). Six patients (15%) had a history of tuberous sclerosis and 11 (28%) had previously undergone SAE. The median (IQR) operative time and warm ischaemia time was 207 (180-231) and 22.5 (16-28) min, respectively. A non-clamping technique was used in eight (20%) patients. The median (IQR) estimated blood loss was 200 (100-245) mL, and four patients (10%) received blood transfusion postoperatively. One intraoperative complication occurred (2.5%), and seven postoperative complications occurred in six patients (15%). During a median (IQR) follow-up of 8 (1-15) months, none of the patients developed AML-related symptoms. The median estimated glomerular filtration rate preservation rate was 95%. There were no differences in operative or perioperative outcomes between patients who underwent SAE before RAPN and those who did not. CONCLUSIONS: Robot-assisted partial nephrectomy appears to be a safe primary or secondary (post-SAE) treatment for large AMLs, with a favourable perioperative morbidity profile and excellent functional preservation. Longer follow-up is required to fully evaluate therapeutic efficacy. PMID- 27988986 TI - Efficacy and safety of tadalafil 5 mg once daily in the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia in men aged >=75 years: integrated analyses of pooled data from multinational, randomized, placebo-controlled clinical studies. AB - OBJECTIVE: To assess efficacy and safety of tadalafil in men aged >=75 years with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) and additional safety in men aged >=75 years with erectile dysfunction (ED). PATIENTS AND METHODS: We conducted an integrated analysis of 12 phase II III randomized, double-blind and/or open-label extension studies to evaluate short-term (12-26 weeks) efficacy and short- and longer-term (42-52 weeks) safety in men aged <75 years vs men aged >=75 years. All men received once-daily tadalafil 5 mg or placebo. The efficacy outcome was International Prostate Symptom Score (IPSS). Safety measurements included treatment-emergent adverse events (TEAEs), adverse events (AEs) leading to discontinuation, serious AEs (SAEs), and cardiovascular AEs. All analyses were intention-to-treat. Changes from baseline to efficacy endpoint and differences in changes between treatment groups were estimated as least-squares means using analysis of covariance models. RESULTS: Change in the mean IPSS was significantly different in men aged <75 years vs those aged >=75 years across tadalafil and placebo groups (treatment-by age interaction P = 0.034). Tadalafil was not statistically significantly better than placebo in men aged >=75 years, but effect size varied between studies. Maintenance of efficacy with tadalafil was observed across age groups. Short-term tadalafil safety findings for men aged <75 vs >=75 years included: TEAEs (52 [33.8%] vs 503 [30.1%]), AEs leading to discontinuation (3 [1.9%] vs 50 [3.0%]), SAEs (4 [2.6%] vs 15 [0.9%]) and cardiovascular AEs (4 [2.6%] vs 30 [1.8%]). Long term tadalafil safety data did not reveal clinically relevant differences between age groups. Limitations include exclusion of men with serious co-existing conditions and limited sample sizes of men aged >=75 years. CONCLUSIONS: Efficacy with once-daily tadalafil 5 mg in the treatment of LUTS/BPH differed between men aged <75 vs >=75 years, with significant efficacy in the <75-year age group. The older age group had more concomitant diseases and used more drugs, which may have reduced efficacy. The small sample size precluded uni-/multivariate analyses to assess plausible interference from confounding factors. Tadalafil had a reassuring safety profile and no evidence of increased cardiovascular AEs in aging men. PMID- 27988985 TI - Altered postural control and stability in cirrhotic patients with minimal hepatic encephalopathy correlate with cognitive deficits. AB - BACKGROUND & AIMS: Cognitive dysfunction in cirrhotic patients with minimal hepatic encephalopathy (MHE) is associated with falls. Alterations in postural control and stability could contribute to increase falls risk in these patients. We aimed to assess whether postural control and direction-specific limits of stability are altered in cirrhotic patients with MHE compared to patients without MHE and controls. We also assessed if alterations in postural control correlate with neurological impairment and/or blood biomarkers. METHODS: Posturography analysis, attention Stroop test and bimanual and visuo-motor coordination tests were performed in 18 controls, 19 patients with cirrhosis without MHE and 17 with MHE, diagnosed by PHES. Posturography was assessed by NedSVE(r) /IBV system under four sensory conditions. Limits of stability and rhythmic weight-shifting tests were also performed. Blood ammonia and serum interleukins were also measured. Falls were assessed after 12-24 months follow-up. RESULTS: MHE patients show impaired balance, mainly on unstable surface with eyes open, with longer reaction and confinement times and lower success in Limits of Stability test compared to patients without MHE. Performance in attention and motor coordination tests correlated with most posturography parameters alterations. Logistic regression analysis shows that posturography parameters and bimanual coordination test are good predictors of falls. CONCLUSION: Balance patterns and limits of stability in MHE patients are impaired compared to patients without MHE and controls. This seems to contribute to a higher falls risk. Attention and motor coordination deficits could contribute to balance impairment in patients with MHE. PMID- 27988987 TI - Survival after Breast-Conserving Surgery with Whole Breast or Partial Breast Irradiation in Women with Early Stage Breast Cancer: A SEER Data-base Analysis. AB - Randomized clinical trials have demonstrated equivalency in survival outcomes for early stage breast cancer patients treated with either mastectomy or breast conserving surgery (BCS) with radiation. Recent, state-level data confirm comparable survival outcomes. Using Surveillance Epidemiology and End Research (SEER) data, we sought to evaluate survival outcomes among patients with early stage breast cancer treated with mastectomy, BCS with whole breast irradiation (BCS + WBI), or BCS with accelerated partial breast irradiation (BCS + APBI). Data on women 50 years or older diagnosed with a node negative invasive breast cancer (<=3 cm in size) between 1995 and 2009 were extracted from the SEER data base. Women treated with mastectomy alone or BCS with radiation were eligible for analysis. Kaplan-Meier estimates and Cox proportional hazard models were used to compare overall survival (OS) and cancer-specific survival (CSS) among the treatment groups. 150,171 women fulfilled inclusion criteria. OS was significantly improved among women treated with BCS and WBI or BCS and APBI compared to mastectomy alone. Adjusted hazard ratios for death in BCS with WBI or APBI (versus mastectomy alone) were 0.73 (95% CI: 0.71, 0.76) and 0.68 (95% CI: 0.58, 0.79), respectively. Adjusted CSS was also significantly improved in patients treated with BCS and WBI (HR 0.80, 95% CI: 0.76, 0.85) as compared to mastectomy. BCS with radiation (WBI or APBI) was associated with significantly improved OS and CSS, versus mastectomy alone. These results support the use of BCS with WBI or APBI (in well selected patients) for the treatment of breast cancer. PMID- 27988988 TI - Prediction of nonalcoholic fatty liver in prospective liver donors. AB - BACKGROUND: Metabolic risk factors should be important in addition to imaging for prediction of steatosis in prospective liver donors. MATERIALS AND METHODS: The study group included all prospective liver donors who had a liver biopsy during workup. Risk factors of metabolic syndrome were analyzed, and body mass index (BMI) >=25 kg/m2 was used in place of waist circumference. Three BMI cutoffs (25, 28, and 30 kg/m2 ) and two CT-measured liver attenuation index (LAI) cutoffs (<5 and <=10) were used for steatosis assessment of >=5%, >=10%, and >=20%. RESULTS: Of the 573 prospective donors (307 females), 282 (49.2%) donors had nonalcoholic fatty liver (NAFL). When donors with NAFL were compared with donors having normal histology, multivariate analysis showed BMI, ALT, triglycerides, and LAI as significant predictors of NAFL. BMI >=25 kg/m2 and LAI <10 were better cutoffs. The presence of >=2 metabolic risk factors had better sensitivity than CT-LAI for the presence of NAFL and >=20% steatosis (58% and 54% vs 47% and 22%, respectively, for CT-LAI <=10). The presence of LAI >10 and <2 metabolic risk factors predicted <10% steatosis with 96% specificity and 92% positive predictive value. CONCLUSION: The presence of >=2 metabolic risk factors improves sensitivity of CT-LAI for prediction of donor steatosis. PMID- 27988989 TI - Single-center outcomes of combined heart and liver transplantation in the failing Fontan. AB - Long-term outcomes of the Fontan operation include Fontan failure and liver disease. Combined heart-liver transplantation (CHLT) is an option for select patients although limited data exist on this strategy. A retrospective review of Fontan patients 18 years or older referred for cardiac transplant evaluation between 2000 and 2013 at the Hospital of the University of Pennsylvania was performed. All patients were considered for potential CHLT. Clinical variables such as demographics, perioperative factors, and short-term outcomes were reviewed. Of 17 referrals for cardiac transplantation, seven Fontan patients underwent CHLT. All patients who underwent CHLT had either advanced fibrosis or cirrhosis on liver biopsy. There were no perioperative deaths. The most common postoperative morbidity was acute kidney injury. Short-term complications include one episode of acute liver rejection but no cardiac rejection greater than 1R. CHLT is an acceptable therapeutic option for patients with failing Fontan physiology who exhibit concomitant advanced liver fibrosis. However, optimal patient selection is currently undefined, and long-term outcomes are not known. PMID- 27988991 TI - EGFRI-induced papulopustular rosacea-like rash successfully treated with topical ivermectin. PMID- 27988990 TI - Cervical human papillomavirus infection in the early postoperative period after liver transplantation: Prevalence, risk factors, and concordance with anal infections. AB - Solid organ transplant recipients are at increased risk of developing several human papillomavirus (HPV)-related malignancies, including cervical and anal cancers. The purpose of this prospective study was to assess the initial prevalence and risk factors for high-risk HPV (HR-HPV) cervical infections in liver transplant recipients, as well as their concordance with anal infections. A total of 50 female patients were enrolled in the Department of General, Transplant and Liver Surgery at the Medical University of Warsaw (center with >1600 liver transplantations). The initial prevalence of cervical HR-HPV infection was 10.0% (5/50). The only significant risk factor for cervical HR-HPV infection was >=4 lifetime sexual partners (P=.037). Statistical tendencies toward higher prevalence of cervical HR-HPV infections were found for patients with hepatitis B virus (HBV, P=.082) and with model for end-stage liver disease (MELD) score <=8 (P=.064). Cervical cytology was abnormal in 10 patients, including three with HR-HPV. Out of 12 patients with available data on anal HR HPV, one had concordant HPV 16 infection. In conclusion, the initial prevalence of high-risk HPV infection is relatively low, except for patients with >=4 previous sexual partners and potentially in those with HBV and/or low MELD score. PMID- 27988993 TI - Neonatal surgery and developmental outcome. PMID- 27988992 TI - Outcomes in the highest panel reactive antibody recipients of deceased donor kidneys under the new kidney allocation system. AB - Since the institution of the new kidney allocation system in December 2014, kidney transplant candidates with the highest calculated panel reactive antibodies (cPRA) of 99-100 have been transplanted at much higher rates. However, concerns have been raised that outcomes in these patients might be impaired due to higher immunological risk and longer cold ischemia times resulting from long distance sharing of kidneys. Here, we compare outcomes at the University of Wisconsin between study patients with cPRA 99-100 and all other recipients of deceased donor kidneys transplanted between 12/04/2014 and 12/31/2015. All patients had at least 6 months post-transplant follow-up. The mean follow-up was 13.9+/-3 months in cPRA >=99% and 12.3+/-3.5 months in cPRA <=98%. There was a total of 152 transplants, 25 study patients, and 127 controls. No statistically significant differences were found between the two groups in delayed graft function, rejection, kidney function, graft and patient survival, or infections. We conclude that transplanting the most highly sensitized patients with kidneys shared outside their local donation service areas is associated with excellent short-term outcomes that are comparable to controls. PMID- 27988994 TI - Progressive left leg swelling. PMID- 27988996 TI - Use of caffeine for preterm infants in Australia and New Zealand: A survey. PMID- 27988995 TI - Socio-economic status and quality of life in children with chronic disease: A systematic review. AB - Reduced quality of life (QoL) is a known consequence of chronic disease in children, and this association may be more evident in those who are socio economically disadvantaged. The aims of this systematic review were to assess the association between socio-economic disadvantage and QoL among children with chronic disease, and to identify the specific socio-economic factors that are most influential. MEDLINE, Embase and PsycINFO were searched to March 2015. Observational studies that reported the association between at least one measure of social disadvantage in caregivers and at least one QoL measure in children and young people (age 2-21 years) with a debilitating non-communicable childhood disease (asthma, chronic kidney disease, type 1 diabetes mellitus and epilepsy) were eligible. A total of 30 studies involving 6957 patients were included (asthma (six studies, n = 576), chronic kidney disease (four studies, n = 796), epilepsy (14 studies, n = 2121), type 1 diabetes mellitus (six studies, n = 3464)). A total of 22 (73%) studies reported a statistically significant association between at least one socio-economic determinant and QoL. Parental education, occupation, marital status, income and health insurance coverage were associated with reduced QoL in children with chronic disease. The quality of the included studies varied widely and there was a high risk of reporting bias. Children with chronic disease from lower socio-economic backgrounds experience reduced QoL compared with their wealthier counterparts. Initiatives to improve access to and usage of medical and psychological services by children and their families who are socio-economically disadvantaged may help to mitigate the disparities and improve outcomes in children with chronic illnesses. PMID- 27988997 TI - Progressive left leg swelling. PMID- 27988998 TI - An adolescent with limited mouth opening. PMID- 27988999 TI - No evidence that heliox inhalation therapy improves important outcomes for infants with bronchiolitis. PMID- 27989000 TI - A simple screen performed at school entry can predict academic under-achievement at age 7 in children born very preterm. PMID- 27989001 TI - Prolonged neonatal jaundice and urinary tract infection. PMID- 27989002 TI - An adolescent with limited mouth opening. PMID- 27989003 TI - Behind the fence: An account of a Nauru whistle-blower. PMID- 27989004 TI - The recovery position helps unconscious children recover. PMID- 27989005 TI - Lyme disease or a lemon? PMID- 27989006 TI - Poverty and child health. PMID- 27989007 TI - Detection of pneumothorax in the preterm infant with ultrasound. PMID- 27989008 TI - A Prospective Study Comparing Platelet-Rich Plasma and Local Anesthetic (LA)/Corticosteroid in Intra-Articular Injection for the Treatment of Lumbar Facet Joint Syndrome. AB - OBJECTIVES: To compare the effectiveness and safety between autologous platelet rich plasma (PRP) and Local Anesthetic (LA)/corticosteroid in intra-articular injection for the treatment of lumbar facet joint syndrome. METHODS: Forty-six eligible patients with lumbar facet joint syndrome were randomized into group A (intra-articular injection with PRP) and group B (intra-articular injection with LA/corticosteroid). The following contents were evaluated: pain visual analog scale (VAS) at rest and during flexion, and the Roland-Morris Disability Questionnaire (RMQ), Oswestry Disability Index (ODI), and modified MacNab criteria for pain relief and applications of post-treatment drugs. All outcome assessments were performed immediately after and at 1 week, 1, 2, 3, and 6 months after treatment. RESULTS: No significant difference between groups was observed at baseline. Compared with pretreatment, both group A and group B demonstrated statistical improvements in the pain VAS score at rest or during flexion, the RMQ, and the ODI (P < 0.01). And there were significant differences between the 2 groups on the above-mentioned items (P < 0.05). For group B, subjective satisfaction based on the modified MacNab criteria and objective success rate were highest (80% and 85%) after 1 month, but only 50% and 20% after 6 months. However, for group A, they increased over time. In addition, there were no treatment-related complications in either group during follow-up. CONCLUSIONS: Both autologous PRP and LA/corticosteroid for intra-articular injection are effective, easy, and safe enough in the treatment of lumbar facet joint syndrome. However, autologous PRP is a superior treatment option for longer duration efficacy. PMID- 27989010 TI - Effect of curcumin on the expression of p53, transforming growth factor-beta, and inducible nitric oxide synthase in oral submucous fibrosis: A pilot study. AB - AIM: The purpose of the present study was to find out the expression of p53, transforming growth factor-beta TGF-beta), and inducible nitric oxide synthase (iNOS) in oral submucous fibrosis (OSMF), proteins implicated in its pathophysiology, as well as malignant transformation. We also sought to determine the effect of curcumin on the expression of these markers through immunohistochemistry. METHODS: The expression of p53, TGF-beta, and iNOS was evaluated through immunohistochemistry in 28 patients with OSMF before and after treatment with curcumin. Expression was evaluated semiquantitatively using a four point scale based on the percentage of cells showing positive staining. RESULTS: The expression of p53, TGF-beta, and iNOS in OSMF was found to be statistically significant (P<.05). After therapy with curcumin, a decrease in the expression of p53, TGF-beta, and iNOS was seen in 25%, 32.1%, and 32.1% of the samples, respectively; however, the difference in pretreatment and post-treatment expressions was not found to be statistically significant. CONCLUSION: The present finding suggest that curcumin could have an effect on the expression of p53, iNOS, and TGF-beta in OSMF, and thus, could prove to be an effective chemopreventive agent for its management. The increased expression of p53, TGF beta, and iNOS in OSMF is suggestive of the role of these markers in its pathophysiology. PMID- 27989009 TI - microRNA from brush biopsy to characterize oral squamous cell carcinoma epithelium. AB - Few cancers are diagnosed based on RNA expression signatures. Oral squamous cell carcinoma (OSCC) is no exception; it is currently diagnosed by scalpel biopsy followed by histopathology. This study sought to identify oral tumor epithelial microRNA (miRNA) expression changes to determine if these changes could be used to diagnose the disease noninvasively. Analysis of miRNA profiles from surgically obtained OSCC tissue, collected under highly standardized conditions for The Cancer Genome Atlas, was done to determine the potential accuracy in differentiating tumor from normal mucosal tissue. Even when using small 20 subject datasets, classification based on miRNA was 90 to 100% accurate. To develop a noninvasive classifier for OSSC, analysis of brush biopsy miRNA was done and showed 87% accuracy in differentiating tumor from normal epithelium when using RT-qPCR or miRNAseq to measure miRNAs. An extensive overlap was seen in differentially expressed miRNAs in oral squamous cell carcinoma epithelium obtained using brush biopsy and those reported in saliva and serum of oral squamous cell carcinoma patients in several studies. This suggested that nonselective release of these miRNAs into body fluids from tumor epithelium was largely responsible for the changes in levels in these fluids seen with this disease. Using a variation in mirRPath we identified the KEGG pathway of neurotrophin signaling as a target of these miRNAs disregulated in tumor epithelium. This highlights the utility of brush biopsy of oral mucosa to allow simple acquisition of cancer relevant miRNA information from tumor epithelium. PMID- 27989011 TI - Temporomandibular joint findings in patients with rheumatoid arthritis, ankylosing spondylitis, and primary Sjogren's syndrome. AB - AIM: The aim of the present study was to investigate the prevalence of temporomandibular joint (TMJ) symptoms in rheumatoid arthritis (RA), primary Sjogren's syndrome (pSS), and ankylosing spondylitis (AS) patients. METHODS: The present study consisted of 79 individuals with various rheumatic disease (study group: 39 with RA, 17 with AS, 23 with pSS) and 79 age- and sex-matched healthy controls (control group). Subjective symptoms of the TMJ were recorded by means of a questionnaire. And stomatognathic examination was then performed. RESULTS: The prevalence of subjective symptoms in patients with rheumatic disease (73.4%) were significantly higher than that of the controls (22.8%; P<.05). The most common objective symptoms were pain during lateral TMJ palpation (29.1% of patients overall, 8.9% of controls) and mandibular movements (19% of patients overall, 2.5% of controls), and muscle pain during palpation (38% of patients overall, 3.8% of controls). They were significantly higher in all of the rheumatic patients than the controls (P<.05). There was not a statistically significant difference in the values for mandibular movements between the study and control groups (P>.05, Mann-Whitney U test). CONCLUSIONS: TMJ symptoms were observed to be higher in the patients with RA, AS and pSS than the control group. Dentists and rheumatologists should be aware of TMJ symptoms in patients with rheumatic diseases. PMID- 27989014 TI - Out of the box. PMID- 27989012 TI - Photobiomodulation reduces drusen volume and improves visual acuity and contrast sensitivity in dry age-related macular degeneration. AB - PURPOSE: To evaluate the efficacy of photobiomodulation (PBM) treatment for patients with dry age-related macular degeneration (AMD). METHODS: Assessments on 42 eyes with dry AMD (age related eye disease study (AREDS) 2-4) were conducted. Multiwavelength light emitting diode (LED) light comprising of yellow (590 nm), red (670 nm) and near-infrared (790 nm) bandwidths was applied to subjects' eyes for a treatment course of 3 weeks. Outcome measures were changes in best corrected visual acuity (BCVA), contrast sensitivity (CS), drusen volume and central drusen thickness. RESULTS: Significant improvement in mean BCVA of 5.90 letters (p < 0.001) was seen on completion of the 3-week treatment and 5.14 letters (p < 0.001) after 3 months. Contrast sensitivity improved significantly (log unit improvement of 0.11 (p = 0.02) at 3 weeks and 3 months (log unit improvement of 0.16 (p = 0.02) at three cycles per degree. Drusen volume decreased by 0.024 mm3 (p < 0.001) and central drusen thickness was significantly reduced by a mean of 3.78 MUm (p < 0.001), while overall central retinal thickness and retinal volume remained stable. CONCLUSION: This is the first study demonstrating improvements in functional and anatomical outcomes in dry AMD subjects with PBM therapy. These findings corroborate an earlier pilot study that looked at functional outcome measures. The addition of anatomical evidence contributes to the basis for further development of a non-invasive PBM treatment for dry AMD. PMID- 27989015 TI - Organ Donation After Euthanasia: A Pure Act of Altruism Fulfilling the Patient's Last Wish. PMID- 27989013 TI - Relationship Among Viremia/Viral Infection, Alloimmunity, and Nutritional Parameters in the First Year After Pediatric Kidney Transplantation. AB - The Immune Development in Pediatric Transplantation (IMPACT) study was conducted to evaluate relationships among alloimmunity, protective immunity, immune development, physical parameters, and clinical outcome in children undergoing kidney transplantation. We prospectively evaluated biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA) formation, viremia, viral infection, T cell immunophenotyping, and body mass index (BMI)/weight Z scores in the first year posttransplantation in 106 pediatric kidney transplant recipients. Outcomes were excellent with no deaths and 98% graft survival. Rejection and dnDSAs occurred in 24% and 22%, respectively. Pretransplant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) serologies and subsequent viremia were unrelated to BPAR or dnDSA. Viremia occurred in 73% of children (EBV, 34%; CMV, 23%; BMK viremia, 23%; and JC virus, 21%). Memory lymphocyte phenotype at baseline was not predictive of alloimmune complications. Patients who developed viral infection had lower weight (-2.1) (p = 0.028) and BMI (-1.2) (p = 0.048) Z scores at transplantation. The weight difference persisted to 12 months compared with patients without infection (p = 0.038). These data indicate that there is a high prevalence of viral disease after pediatric kidney transplantation, and underweight status at transplantation appears to be a risk factor for subsequent viral infection. The occurrence of viremia/viral infection is not associated with alloimmune events. PMID- 27989016 TI - Macular thickness in healthy eyes of adults (N = 4508) and relation to sex, age and refraction: the Tromso Eye Study (2007-2008). AB - PURPOSE: To provide sex-stratified normative data on retinal thickness and study the relationship with sex, age and refractive status. METHODS: Population-based study including 2617 women and 1891 men, aged 38-87 (mean 61 +/- 8) years, without diabetes, glaucoma and retinal diseases, and spherical equivalent refraction (SER) within +/-6 dioptres. Retinal thickness was measured with optical coherence tomography (spectral domain Cirrus HD-OCT). RESULTS: Women had thinner retina than men. Retinal thickness was significantly associated with refraction, where mean change in retinal thickness per 1 D increase in SER was 1.3 (0.2) MUm in the fovea, 0.7 (0.1) MUm in the pericentral ring and 1.4 (0.1) MUm in the peripheral ring. In the fovea, there was a non-monotonic curved relationship between retinal thickness and age in both sexes with a maximum at about 60 years (p < 0.001). In the pericentral ring, the mean reduction in retinal thickness per 10-year increase was 2.7 (0.3) MUm in women and 4.0 (0.4) MUm in men and corresponding results in the peripheral ring were 2.3 (0.3) MUm in women and 2.6 (0.4) MUm in men. In both regions, there was evidence for a nonlinear pattern with an increased rate of change with higher age. There was a significant interaction between sex and age for retinal thickness of the pericentral ring (p = 0.041). CONCLUSION: Women had thinner retina than men, and thickness varied with refractive status. Retinal thickness was associated with age in all macular regions, and the rate of change in retinal thickness varied at different ages. PMID- 27989017 TI - Evaluation of the caries-preventive effect of toothpaste containing surface prereacted glass-ionomer filler. AB - AIM: Although fluoride interventions have the most consistent benefit in preventing caries, caries still develop in high-risk individuals. Authors have evaluated the effectiveness of toothpastes containing surface prereacted glass ionomer (S-PRG) filler in preventing tooth demineralization. METHODS: Human tooth enamel blocks were randomly assigned to six groups (30 blocks/group): no treatment (a), and toothpaste containing either 1500 ppm fluoride as sodium monofluorophosphate (NaMFP) (b), 0 wt% S-PRG (b), 1 wt% S-PRG (d), 5 wt% S-PRG (e), or 20 wt% S-PRG (f). Early caries developed on each block by 7-days demineralization using a microbial caries model. Mineral loss (Deltaz) and lesion depth (LD) were determined using transverse microradiography. RESULTS: Relative to the control, all toothpastes, except 0% S-PRG, significantly (analysis of variance, Tukey's, P<.0001) reduced Deltaz and LD at varying percentages. With regard to Deltaz, all comparisons were significant (P<.0001), except 0% S-PRG vs the control. Otherwise, S-PRG 1%, 5%, and 20% had 0.50, 0.37, and 0.27 times Deltaz compared to the control, respectively, while NaMFP had 0.61 times Deltaz compared to the control. LD followed an almost similar trend as Deltaz. CONCLUSIONS: The findings of the present study demonstrate the effectiveness of toothpaste containing S-PRG filler in inhibiting tooth demineralization in the presence of bacterial plaque, thus highlighting its potential as an effective caries-control tool for individuals at high risk of developing caries. PMID- 27989019 TI - Canalization of Language Structure From Environmental Constraints: A Computational Model of Word Learning From Multiple Cues. AB - There is substantial variation in language experience, yet there is surprising similarity in the language structure acquired. Constraints on language structure may be external modulators that result in this canalization of language structure, or else they may derive from the broader, communicative environment in which language is acquired. In this paper, the latter perspective is tested for its adequacy in explaining robustness of language learning to environmental variation. A computational model of word learning from cross-situational, multimodal information was constructed and tested. Key to the model's robustness was the presence of multiple, individually unreliable information sources to support learning. This "degeneracy" in the language system has a detrimental effect on learning, compared to a noise-free environment, but has a critically important effect on acquisition of a canalized system that is resistant to environmental noise in communication. PMID- 27989020 TI - Constancy amid change: the evolution of Andrology. PMID- 27989018 TI - Effect of different lubricant eye gels on tear film thickness as measured with ultrahigh-resolution optical coherence tomography. AB - PURPOSE: To compare the effect of a single drop of different lubricant eye gels on tear film thickness (TFT) as measured with ultrahigh-resolution optical coherence tomography (UHR-OCT) in patients with mild-to-moderate dry eye disease (DED). METHODS: The study followed a randomized, single-masked, observer-blinded parallel group design. Patients received a single dose of either unpreserved trehalose 3% + hyaluronic acid 0.15% (TH), hyaluronic acid 0.2% (HA) or polyethylene glycol 0.4% + propylene glycol 0.3% (PP) eye drops. In total, 60 patients were included and TFT was measured using a custom-built UHR-OCT system. RESULTS: The mean TFT at baseline was 3.5 +/- 0.7 MUm. There was a significant difference in the time-course of TFT between the three groups (p = 0.001 between groups). Ten minutes after instillation, TFT increased by 155.8 +/- 86.6%, 65.7 +/- 71.5% and 33.4 +/- 19.6% in the PP, TH and HA group, respectively (p < 0.001 between groups). Thirty minutes after instillation, the effect of all three different agents on TFT was comparable. Sixty and 120 min after administration, a significant increase in TFT was only seen for the TH group, but not for the other products (60 min: p < 0.021 between groups; 120 min: p < 0.037 between groups). CONCLUSION: In conclusion, we observed differences in TFT after administration of the lubricant gels. Ten minutes after instillation, a pronounced increase in TFT was observed in all groups. As compared to the other products, the combination of trehalose 3% + hyaluronic acid 0.15% offers a significantly longer increase in TFT indicating for a longer residence time. PMID- 27989021 TI - Can mesenchymal stem cells improve spermatogonial stem cell transplantation efficiency? AB - Improved treatments have led to an increased survival rate in cancer patients. However, in pre-pubertal boys, these gonadotoxic treatments can result in the depletion of the spermatogonial stem cell (SSC) pool causing lifelong infertility. SSC transplantation has been proposed as a promising technique to preserve the fertility of these patients. In mice, this technique has resulted in live-born offspring, but the efficiency of colonization remained low. This could be because of a deficient microenvironment, leading to apoptosis of the transplanted SSCs. Interestingly, mesenchymal stem cells (MSCs), being multipotent and easy to isolate and multiply in vitro, are nowadays successfully and widely used in regenerative medicine. Here, we shortly review the current understanding of MSC and SSC biology, and we hypothesize that a combined MSC-SSC transplantation might improve the efficiency of SSC colonization and differentiation as paracrine factors from MSCs may contribute to the SSC niche. PMID- 27989024 TI - [The Future challenges of the Portuguese sociaty for Cardiothoracic and vascular Surgery]. PMID- 27989023 TI - Sexual functioning mirrors overall men's health status, even irrespective of cardiovascular risk factors. AB - Erectile dysfunction has been described as a sentinel marker of co-existing and undetected cardiovascular disease. Beside cardiovascular diseases, a correlation between erectile dysfunction and other major comorbidities has been also reported. The study was aimed to analyze the association between sexual functioning and overall men's health in sexually active, Caucasian-European men with new-onset sexual dysfunction. Data from the last 881 consecutive patients seeking first medical help for sexual dysfunction were cross-sectionally analyzed. The International Classification of Diseases, 9th revision, Clinical Modification was used to classify health-significant comorbidities, which were scored with the Charlson Comorbidity Index (CCI). A modified CCI score from which all potential cardiovascular risk factors (CCI-CV) were subtracted was then calculated for every patient. Patients were requested to complete the International Index of Erectile Function (IIEF). The main outcome of the study was the association between the IIEF domain scores and CCI, which scored health significant comorbidities even irrespective of cardiovascular risk factors (CCI CV). The final sample included 757 patients (85.9%) (Median age: 48 years; IQ range: 37-59). Overall, erectile dysfunction was found in 540 (71.4%) patients. Of these, 164 (21.6%) had a CCI >= 1 and 138 (18.2%) had a CCI-CV >= 1, respectively. At the analysis of variance, IIEF-Erectile Function (EF) scores significantly decreased as a function of incremental CCI and CCI-CV scores (all p < 0.01). At multivariable logistic regression analysis, both IIEF-EF and IIEF total score achieved independent predictor status for either CCI >= 1 or CCI-CV >= 1, after accounting for potential confounders (p < 0.01). We report novel findings of a significant association between erectile dysfunction severity and overall men's health, even irrespective of cardiovascular risk factors. Thereof, erectile dysfunction severity could serve as a proxy for general men's health, thus encouraging physicians to comprehensively assess patients complaining of sexual dysfunction in the real-life everyday clinical practice. PMID- 27989025 TI - [Practices and Concepts]. PMID- 27989026 TI - [Cyanotic congenital heart diseases duct dependent: Stent versus surgical shunt. Meta-analysis of observational studies]. AB - BACKGROUND: The modified Blalock-Taussig shunt (mBTS) is the method of choice in the congenital heart disease duct dependent. More recently, the percutaneous implantation of a stent in the duct (PIS) has emerged as an alternative to the surgery. OBJECTIVE: To determine the most safe and effective procedure by reading the available literature. METHODS: A systematic review of observational studies was perfomed by searching Pubmed and SciVerse/Scopus, in which neonates were submitted to mBTS or PIS. Two independent reviewers selected the articles according to the inclusion criteria. The mortality rate was defined as the primary outcome. Complications and re-interventions were defined as secondary outcomes. RESULTS: Twenty-three of 176 articles were included (n = 2243 patients, 1920 submitted to mBTS and 323 to PIS). The weighted average mortality rate of the neonates who underwent mBTS was 7,6% (95% CI: 6,5%-8,9 %) and submitted to IPS was 8.3% (95% CI: 4,6%-14,7%; p=0,7006). The weighted average rate of complications and re- interventions, weight and size of the stent and shunt did not show statistically significant differences. It was not possible to establish a relationship between these and mortality rate. Significant heterogeneity was detected for the mortality rate in the group undergoing PIS due to the different sample sizes, non-uniform patient selection and results with large confidence intervals. CONCLUSIONS: We could not find systematic evidence to suggest that PIS is safer and more advantageous than the realization of a BTSm in these pathologies. PMID- 27989027 TI - [How to manage the anesthesia of a patient bearing a left heart assisting device?] AB - Left ventricular assist devices have revolutionized the treatment of end-stage cardiac failure. Only indicated as a bridge to transplant in the early beginning, technological evolution opened new horizons and nowadays these devices are also used as bridge for recovery or even as definitive therapy. With the increasing number of devices, a growing number of patients with left ventricular assistance is being presented for non-cardiac surgery. Although ideally managed in device experienced centres, the unpredictable nature of emergent surgical pathology makes it possible for any anesthesiologist to have to deal with the managing these patients perioperative care. Due to the topic complexity and lack of literature, the purpose of this paper is to make a comprehensive and concise review of these devices basic operating principles, fundamental perioperative care for patients with ventricular assistance and the most common critical events to be aware of. PMID- 27989028 TI - Paraplegia due to spinal cord infarction following cardiac surgery. AB - Paraplegia is an extremely rare complication following any surgery, especially cardiac surgery. The underlying mechanisms remain poorly understood and even though spinal infarction has been reported previously, it is almost always associated with the use of intra-aortic balloon pump. We report the clinical case of a 75 year-old male, who developed paraplegia secondary to spinal infarction, following cardiac surgery (coronary artery bypass grafting and aortic valve replacement) in whom the intra-aortic balloon pump was not used and few other predisposing factors were present that could anticipate that complication. PMID- 27989029 TI - [Carcinoid syndrome. A clinical report]. AB - The carcinoid syndrome is a rare clinical entity, coursing with a slow evolution. Patients typically present flush, diarrhea and acute asthma attacks, which often delays the diagnostic until there is cardiac involvement, with more pronounced symptoms. We report the clinical case of a 62 years-old male, with a known significant tricuspid valve disorder. While waiting for cardiac surgery, he presented with an acute abdominal condition, which allowed the detection of a carcinoid syndrome. He underwent surgical excision of the primary tumor (right hemicolectomy), removal of hepatic metastases, and tricuspid valve replacement. PMID- 27989030 TI - Popliteal artery aneurysm surgical repair: Retrospective unicenter analysis. AB - BACKGROUND: Popliteal artery aneurysm (PAA) thromboembolic complications may result in limb loss. We review our experience reporting outcomes in terms of complications and early and long-term patency rates. METHODS: From 2004 to 2013, 116 PAA required surgical repair at Coimbra Hospital and Universitary Centre, Portugal. Outcomes were analyzed using Kaplan-Meier method with log-rank tests, X2, and Cox proportional hazards models. RESULTS: A total of 116 PAAs with a mean diameter of 3.3 cm (1.5 to 10 cm) were followed. 40% limbs were asymptomatic and 27% presented with acute ischemia. 97% underwent medial bypass procedure (venous in 66%). Early mortality was 0.9% (1/116). 30-day and five-year cumulative limb salvage was 94.0% and 87%, respectively. There was no limb loss in asymptomatic patients and 1-3 Rutherford chronic ischemia. 62% early amputations were performed in acute ischemia, half of them with functioning bypass. 30-day primary and secondary patency rates were 91% and 97% respectively, higher with GSVs (96% and 99%) than PTFE (58% and 95%, P < .05; Fig 1). The 5-year primary and secondary patency rates were 68.1% and 73,5%, respectively, higher with GSVs (83% and 87%) than PTFE (37% and 43%, P < .05). Two recurrent PAAs (1,7%) required reintervention. Predictors for both amputation and loss of primary patency were PTFE bypass (p =0,002), and emergent surgery (p = 0,005). Acute ischemia was also predictor for amputation (p = 0,026), but not for loss of primary patency. CONCLUSIONS: Results of surgery on asymptomatic PAAs are good - significantly better than those from symptomatic PAAs. The results are similarly good in claudicants. The risks of early and late amputation were higher with prosthetic grafts and in an emergent settings. PMID- 27989031 TI - [Survival analysis after open vascular surgery and angioplasty in lower limbs vascularization in Rio de Janeiro, Brazil 2006-2013]. AB - : Objective -The aim of this study is survival analysis after lower limb revascularization according to sex, age and procedures. METHOD: Were analysed in hospital administrative database coming from the Public Health System of Rio de Janeiro (SUS-RJ) from 2006 through 2010 and the Public Registers of death of Rio de Janeiro (SIM-RJ) from 2006 through 2013. Both groups of information had linkaged using the Stata program of statistics. Three groups of age were studied: 50 years old or less, 50 to 79 and over 70 years old. RESULTS: More than half of patients received angioplasty as procedures during the study. In both procedures, men were more frequent, except in angioplasty after 70 years of age. In the period of 30 days after discharge in both procedures the survival had an abrupt reduction and it continue reducing until 180 days after open surgery. After these the survival curves run in parallel until the fourth year and then they had the same performance. CONCLUSION: The greatest reduction in survival was registered in the first thirty days after discharge, mainly in women after open surgery. It is necessary to improve in-hospital care in order to improve the survival index on the first thirty days after discharge.. PMID- 27989032 TI - [An uncommon cause of lower limb oedema - Case report]. AB - The authors report the clinical case of a 50-year-old man who was observed in the emergency department because of a one week long, painless left lower limb swelling. At presentation, a gross edema was evident and peripheral pulses were present and symmetrical. The ultrasound scan findings suggested short occlusion in the transition of the common femoral (CFV) to the external iliac veins. A venography confirmed a filling defect in the above mentioned location, with normal findings throughout proximal and distal veins. On CT scans a cyst measuring 20mm of maximal diameter was disclosed, medial to the common femoral artery, compressing the CFV and seemingly continuous to the hip joint. He underwent surgical correction through open inguinal approach that allowed to confirm a complete compression of the CFV by the cyst against the inguinal ligament. The CFV recovered its normal aspect after cyst, removal and the patient was discarded home at day 2 after surgery, with complete regression of the oedema wich is maintained one year after the event, as well as absence of local ultrasound abnormalities. The hip joint is a rare location for synovial cysts. Synovial or adventitial cysts in that area may compress de CFV. The histological tests are useless for distinguishing between the two diagnosis. The clinical presentation consists of an inguinal mass or lower limb oedema due to CFV compression. Given its location underneath the vein, these masses are often difficult to detect. Vein decompression is suggested to avoid deep vein thrombosis. When a synovial cyst is present it is possible to find a dissecting plane between the two anatomical structures. Though feasible, percutaneous cyst aspiration is linked to high recurrence rates. PMID- 27989033 TI - [Aneurysmal degeneration of a saphenous vein graft - Case report]. AB - Non-anastomotic degeneration of venous conduits is a rare condition, and its etiology is not fully understood. We report the clinical a case of an aneurysmal degeneration of a femoropopliteal bypass vein graft, undertook 19 years earlier for traumatic injury of the popliteal artery of the left lower limb. Following the resection of the aneurysm, a new femoro-tibioperoneal trunk vein graft was implanted. The choice of a new autologous graft was made based on the young age of the patient and the best outcomes in the long term, related to this conduits. PMID- 27989034 TI - [Inferior vena cava transposition - A clinical report]. PMID- 27989035 TI - Aortopathy in Bicuspid Aortic Valve Stenosis with Fusion of Right-Left versus Right-Non-Coronary Cusps: Are These Different Diseases? AB - BACKGROUND: The study aim was to prospectively analyze the impact of cusp fusion pattern on aortopathy severity in patients undergoing surgery for bicuspid aortic valve (BAV) stenosis. METHODS: A total of 137 consecutive patients with BAV stenosis (93 males, 44 females; mean age 61 +/- 9 years) underwent aortic valve replacement with or without concomitant aortic surgery between January 2012 and March 2015. All patients underwent preoperative cardiac magnetic resonance imaging (cMRI) in order to evaluate morphological/functional parameters of the aortic root. Fusion of the right-left coronary cusps was identified in 99 patients (72%) (R/L group), while the remaining 38 patients (28%) had right noncoronary cusp fusion (R/N group). cMRI data were used to guide sampling of the proximal aorta during surgery. The expression/severity of aortopathy was quantified by means of proximal aortic phenotype, indexed aortic diameter, and a histological sum-score. RESULTS: There were no significant differences in proximal aortic diameter between the R/L and R/N groups. Moreover, there was no significant difference in the prevalence of distinct aortic phenotypes between the study subgroups. The histological sumscore was comparable between the R/L and R/N groups (2.9 +/- 1.5 versus 2.5 +/- 1.1, p = 0.2). The angle LV/aorta was significantly larger in the R/L group than in the R/N group (52.1 +/- 10.6 degrees versus 45.1 +/- 8.5 degrees , p = 0.001). Logistic regression analysis demonstrated the angle LV/aorta and the angle jet/aorta to be predictive of a mid ascending phenotype. The cusp fusion pattern had no significant impact on the occurrence of aortic phenotype. CONCLUSIONS: The study results demonstrated that cusp fusion morphotype has no significant impact on the expression and severity of bicuspid aortopathy in patients undergoing surgery for BAV stenosis. PMID- 27989036 TI - Ascending Aortic Stiffness with Bicuspid Aortic Valve is Variable and Not Predicted by Conventional Parameters in Young Patients. AB - BACKGROUND: Bicuspid aortic valve (BAV)-related aortopathy is characterized by histological abnormalities that result in aortic wall stiffening and aortic dilation. The study aim was to determine the range of ascending aortic stiffness seen in a clinical cohort of patients with BAV, and to identify the association of aortic stiffness with standard clinical and imaging parameters. METHODS: Patients with BAV (n = 65) and normal subjects (n = 10) were studied using conventional phase-contrast magnetic resonance imaging through the ascending aorta. Local aortic stiffness was estimated by measuring pulse wave velocity (PWV) using the flow-area (QA) method. Correlations between PWV and other imaging and clinical variables were assessed, and multiple linear regression models were used to examine independent predictors of PWV. RESULTS: BAV patients demonstrated a significantly higher mean PWV compared to normal subjects (6.53 +/- 5.88 versus 3.51 +/- 0.92 m/s; p <0.01) with a considerably wider range of values noted in the BAV group. Significant associations were found between PWV and age (r = 0.4, p <0.001) and history of hypertension (r = 0.36, p = 0.005) in the overall BAV cohort. The correlation between age and PWV was significantly strengthened above 40 years of age. In a subgroup of BAV patients aged <40 years (n = 37) there were no significant predictors of PWV identified by multiple linear regression models. CONCLUSIONS: BAV patients demonstrated an increased average ascending aortic stiffness and a dramatically higher range of stiffness values compared to normal subjects. Increased stiffness is not predicted by standard clinical or imaging parameters in patients aged <40 years. Ascending aortic stiffness may be a unique marker of early aortic dysfunction in young BAV patients. PMID- 27989037 TI - Predictors of High Post-Procedural Gradients after Catheter-Based Aortic Valve Implantation Using Direct Flow Medical Bioprostheses. AB - BACKGROUND: The Direct Flow Medical (DFM) valve is a new non-metallic and repositionable bioprosthesis used for transcatheter aortic valve implantation (TAVI). The study aim was to investigate procedural and post-implant valve data in patients receiving differently sized DFM bioprostheses. METHODS: Procedural, echocardiographic and computed tomography findings of 28 patients receiving either a 25, 27 or 29 mm DFM bioprosthesis were analyzed. RESULTS: Implantation of a 29 mm bioprosthesis was associated with longer procedure (p <0.05) and radiation (p <0.05) times, and a higher dose-area product (p <0.01) compared to the 25 mm valve. A high mean post-interventional aortic gradient indicating a suboptimal result was found in 44% patients receiving a 29 mm bioprosthesis, whereas none of the patients with a 25 or 27 mm valve had a high gradient (p <0.05). Aortic valve calcification was greatest in the 29 mm group and correlated with a higher dose-area product (p <0.01). CONCLUSIONS: DFM bioprosthesis size significantly influences the TAVI procedure and post-implant valve function. Valve calcification and use of the 29 mm DFM bioprosthesis per se possibly predict a more complicated procedure. Therefore, annulus size and valve calcification severity should be taken into consideration when deciding which bioprosthesis type might be best suited for individual patients. PMID- 27989038 TI - Quantitative Doppler for Estimation of Paravalvular Leakage after Transcatheter Aortic Valve Implantation. AB - BACKGROUND: The echocardiographic grading of paravalvular aortic leakage (PVL) after transcatheter aortic valve implantation (TAVI) severity is challenging. The study aim was to assess the value of quantitative Doppler echocardiography to monitor PVL severity. METHODS: A total of 100 subjects was enrolled in the study, including 65 consecutive patients who had undergone TAVI with a CoreValve prosthesis and without valvular aortic regurgitation, and 35 normal controls. The PVL volume was calculated using the quantitative Doppler method as the difference of left and right ventricular stroke volume (SV). PVL severity was assessed both visually and quantitatively as the circumferential extent on a short-axis view (SAX). RESULTS: The inter-observer variabilities for SVs in TAVI patients were disappointing: 14 +/- 11% for the left ventricular SV and 18 +/- 14% for right ventricular SV. The correlation (r2) between the averaged regurgitant PVL volume and circumferential SAX extent of PVL was 0.02 (p = NS). The relationship between PVL volumes and categories, defined quantitatively by the circumferential SAX extent of PVL and qualitatively by visual assessment of severity of PVL were poor. The results improved when only patients with optimal quality images were included but were still statistically non-significant. CONCLUSIONS: The relationship between calculated PVL volume in TAVI patients and other estimates of PVL severity was poor, most likely due to intrinsic errors made in the quantitative Doppler method. Therefore, one should be prudent to include the quantitative Doppler method in TAVI patients in clinical trials and clinical decision-making, in particular in patients with reduced image quality. PMID- 27989039 TI - Patho-Histological Findings of Annular Rupture Related to Left Ventricular Outflow Tract (LVOT) Calcification Following Transcatheter Aortic Valve Replacement (TAVR). AB - Peri-aortic hematoma has been recently described as a potentially life threatening complication following transcatheter aortic valve replacement (TAVR). Patient- and procedure-related factors exist that predispose to peri-aortic hematoma formation, which can progress to myocardial rupture at the aortic root myocardial junction. While conservative therapy with blood pressure control is the expectant management following peri-aortic hematoma formation, myocardial rupture can occur at the site of the aortic annulus. Hence, interventionists and echocardiologists must be prepared for emergent intervention to salvage the patient once the complication is recognized. The present report highlights the patho-histological findings related to left ventricular outflow tract calcification following TAVR. PMID- 27989040 TI - Impact of Paravalvular Aortic Insufficiency on Left Ventricular Remodeling and Mortality after Transcatheter Aortic Valve Replacement. AB - BACKGROUND: Paravalvular aortic regurgitation (PAR) remains a common complication following transcatheter aortic valve replacement (TAVR), and has been associated with increased mortality. Adverse left ventricular (LV) remodelling has been reported in patients with post-TAVR PAR, but the association between adverse LV remodeling and increased mortality remains unclear. The aim of the present study was to examine the association between PAR, LV remodeling and mortality following TAVR in a non-PARTNER (Placement of Aortic Transcatheter Valves) trial population. METHODS: A total of 195 patients that underwent TAVR was included in the study. The LV ejection fraction (LVEF), LV mass index (LVMI), LV internal dimension at systole (LVIDs) and diastole (LVIDd) were compared between patients with different degrees of PAR at baseline, and at one month and one year after TAVR. Survival analysis was performed for different degrees of PAR and LV remodeling. RESULTS: PAR >=moderate was associated with increased mortality (HR 4.58 [1.80-11.63], p = 0.001), but PAR >mild was not. The LVIDd and LVIDs were persistently increased at one year after TAVR in patients with PAR >mild compared to those with PAR <=mild (5.9 +/- 0.8 cm versus 5.4 +/- 0.7 cm, p = 0.02 and 4.4 +/- 0.8 cm versus 3.9 +/- 0.8, p = 0.03, respectively). The LVEF was improved similarly between the two groups at one year after TAVR (p = 0.1). Patients with PAR >=moderate had significantly more adverse LV remodeling at one month after TAVR in terms of LVIDd, LVIDs, and LVMI. The degree of remodeling as expressed in terms of LVIDd, LVIDs, LVMI and LVEF changes from baseline did not have a direct impact on mortality. CONCLUSIONS: A worse PAR was associated with more adverse LV remodeling and a higher mortality after TAVR in a non-PARTNER patient population. PMID- 27989042 TI - MitraClip(r): Two Weeks after Implantation. AB - A 73-year-old male received a percutaneous mitral valve repair with a MitraClip to treat severe (grade IV) symptomatic mitral regurgitation (MR). The MitraClip(r) procedure reduced the MR to grade I, but the patient died 14 days post-procedurally due to a pneumosepsis. Histological analysis of the MitraClip mesh covering showed a chronic inflammatory reaction with an abundance of multinucleated giant cells. Remarkably, signs of early onset clip-coverage were found, indicated by the presence of a few scattered myofibroblasts. PMID- 27989041 TI - Left Atrial and Left Ventricular Function and Remodeling Following Percutaneous Mitral Valve Repair. AB - BACKGROUND: Mitral regurgitation causes left atrial (LA) and left ventricular (LV) dysfunction, dilatation, and remodeling. Following percutaneous mitral valve repair (PMVR) using the MitraClip(r) approach, reverse cardiac remodeling is desirable. To date, the influence of PMVR on LA and segmental LV function and remodeling has not been investigated in detail. METHODS: Twenty-six patients who received the MitraClip device were enrolled in an open-label, single-center observational study. Patients underwent clinical assessment, conventional echocardiography and global and segmental longitudinal strain analysis of the left atrium and left ventricle by speckle tracking echocardiography at baseline and at a three-month follow up. RESULTS: PMVR improved both LV systolic function (from 40.5 +/- 2.5% to 45.0 +/- 2.5%, p = 0.04) and LV global longitudinal strain (from -8.9 +/- 0.7% to -10.7 +/- 0.9%, p = 0.004). Segmental analysis revealed improved myocardial deformation mainly in the basal (basalseptal -8.9 +/- 0.8% to -12.9 +/- 0.8%, p = 0.0002; basallateral -7.9 +/- 1.1% to -13.9 +/- 1.4%, p = 0.0005) and midventricular segments (mid-septal -12.7 +/- 0.9% to -14.5 +/- 1.1%, p = 0.02; mid-lateral -7.5 +/- 0.8% to -10.8 +/- 1.2%, p = 0.006). In patients with pre-procedural preserved LA function with sinus rhythm the impact of PMVR revealed an improvement in LA global conduit function (from 10.6 +/- 1.2% to 13.9 +/- 1.6%, p = 0.003) and global contractile function (from -2.1 +/- 0.47% to -3.5 +/- 0.5%, p = 0.03). The reversed remodeling was not associated with altered levels of the cardiac biomarkers matrix metalloproteinase 2 (MMP-2) and MMP-9, tissue-inhibitors of MMPs (TIMP-2 and ST-2). CONCLUSIONS: PMVR improves global segmental LV and LA function and leads to a reverse remodeling. PMID- 27989043 TI - Distant Position of Chordae from Coaptation Causes Mitral Regurgitation in Patients with Atrial Fibrillation. AB - BACKGROUND: The study aim was to investigate the mechanism of mitral regurgitation (MR) in lone atrial fibrillation (AF) patients using three dimensional (3D) transesophageal echocardiography (TEE). METHODS: A retrospective analysis was conducted of 64 patients with AF and a normal left ventricle, and without prolapse of the mitral valve. Among these patients, significant MR was not identified in 33 cases (AF+MR- group) but was present in 31 cases (AF+MR+ group). The distance from the coaptation to the bending point of the anterior mitral leaflet (AML), where the chorda was attached, was termed the 'bending length'. The ratio of the bending length to the distance from coaptation to anterior mitral annulus was termed the 'bending ratio' (= bending length/coaptation-annulus length). The mitral annular area (MAA) fractional change was defined as follows: (MAA at late systole - MAA at early systole)/MAA at late systole * 100%). Other parameters relating to mitral valve morphology obtained using 3D TEE were measured with commercial software (QLAB, Phillips). RESULTS: The coaptation length (CL) was smaller in the AF+MR+ group than in the AF+MR- group (p<0.001), and correlated significantly with the anteriorposterior diameter of the mitral annulus (R = 0.286, p = -0.022), MAA at mid-systole (R = 0.269, p = 0.032), MAA fractional change (R = 0.434, p <0.001), and the bending ratio (R = -0.603, p <0.001). With a multivariable analysis, the correlating factors of significant MR in lone AF patients were a decrease in MAA fractional change (p = 0.022) and an increase of the bending ratio (p = 0.009). CONCLUSIONS: Small MAA fractional changes and the distant position of the chordae tendineae on the AML from the coaptation correlated with significant MR in AF patients with normal left ventricular systolic function. PMID- 27989044 TI - Treatment of Mitral Valve Regurgitation with an Open Rigid Annuloplasty Ring. AB - BACKGROUND AND AIM OF THE STUDY: Annuloplasty constitutes a major operative step in the surgical treatment of degenerative mitral valve regurgitation (MR). The choice of ring structure to obtain an adequate remodeling of the mitral orifice and to respect the motion of the mitral apparatus remains the subject of debate. The study aim was to determine the clinical and echocardiographic outcome when using an open rigid ring to treat MR. METHODS: A total of 129 patients (94 men, 35 women; mean age 64.5 +/- 11.7 years) was referred to the authors' institution between 1997 and 2011 for the surgical management of severe MR. Patients were implanted with a modified open rigid annuloplasty ring, and also underwent anterior and/or posterior leaflet repair. The occurrence of any major adverse cardiac and cerebrovascular event (MACCE) was considered as the primary end-point and was retrospectively collected along with echocardiographic data. RESULTS: The perioperative mortality was 1.6%. The cardiopulmonary bypass and cross-clamp times were 73.3 +/- 17.1 min and 51.6 +/- 13.0 min, respectively. There was one case (0.7%) of postoperative mitral systolic anterior motion. During a mean follow up period of 6.0 +/- 3.1 years, 25 patients (19%) presented a MACCE. MACCE free survival at one, five and 10 years was respectively 96.8%, 91.3%, and 61.4%. Preoperative determinants of MACCE were paroxysmal/persistent atrial fibrillation (HR 2.53; 95% CI: 1.06-6.01; p = 0.035) and age (HR 1.05; 95% CI: 1-1.09; p = 0.035). CONCLUSIONS: Mitral valve repair with an open-rigid ring offers satisfactory long-term results with a low rate of subsequent MR recurrence and reintervention. Preoperative AF is the main determinant of long-term adverse outcome. PMID- 27989045 TI - Re-Repair of Tricuspid Valve after Tricuspid Suture Annuloplasty: An Analysis of the Causes for Reoperation and its Durability. AB - BACKGROUND: The outcomes of re-repair of the tricuspid valve to treat recurrent tricuspid regurgitation (TR) after tricuspid valve suture surgery were analyzed. METHODS: Thirty-six patients (mean age 65.3 +/- 9.3 years) who underwent re repair of the tricuspid valve to treat recurrent TR between January 1990 and November 2014 were reviewed retrospectively. All patients underwent suture annuloplasty for TR. Of these 36 patients, 15 (41.7%) underwent ring annuloplasty and 21 (58.3%) underwent re-suture annuloplasty. The mean follow up period was 5.8 +/- 6.1 years. RESULTS: The overall hospital mortality rate was 13.9% (5/36). Pre-discharge TR grades were 1.2 +/- 0.7 in the ring group and 1.4 +/- 0.8 in the re-suture group (p = 0.7353). There were no significant differences in survival, freedom from late TR and freedom from valve-related events between the two groups. At the final follow up, TR >mild was present in four patients (36.4%) in the ring group, and in 12 patients (75%) in the re-suture group (p = 0.0447). Severe TR was present in five patients (31.3%) in the re-suture group, but none was present in the ring group (p = 0.2445). CONCLUSIONS: In the present study cohort, the durability of re-repair of the tricuspid valve using a flexible prosthesis appeared to be superior to the durability following re-suture annuloplasty. PMID- 27989046 TI - Valve Replacement in Patients with Carcinoid Heart Disease: Choosing the Right Valve at the Right Time. AB - BACKGROUND AND AIM OF THE STUDY: The prosthetic valve of choice in patients with carcinoid valve disease (CVD) remains controversial due to the limited life expectancy of patients with advanced-stage neuroendocrine tumors (NETs) on the one hand, and concerns regarding structural valve deterioration (SVD) on the other hand. METHODS: The records of 17 patients (11 females, seven males; mean age 65 +/- 11 years; undergoing 18 operations) with primarily right heart failure due to CVD were reviewed. All patients received somatostatin analogs perioperatively. Hospital and follow up data (acquired via direct patient contact and echocardiography) collected included baseline characteristics, procedural details, and clinical outcomes. RESULTS: The primary NET site was the ileum (n = 11), lungs (n = 2) and stomach, colon and appendix (n = 1 each). In one patient the primary tumor location could not be identified. Preoperative urinary levels of 5-hydroxyindole acetic acid (5-HIAA; 61 +/- 36 mg/24 h) and serum levels of chromogranin A (2926 +/- 4057 ng/ml) were 10- and 50-fold greater than normal, respectively. A total of 23 valves was implanted: five tricuspid valve replacements (TVR; four tissue and one mechanical), TVR and pulmonary valve replacements (PVR; three tissue and one mechanical), and TVR and mitral valve replacements (MVR; one tissue and two mechanical). The 30-day mortality was 11% (n = 2). No patient experienced a carcinoid crisis. The mean follow up was 24 +/- 21 months (range: 4-85 months). Four patients (receiving seven valves) developed SVD at 12, 14, 15, and 20 months after surgery, and all of these patients died. The actuarial four-year survival and freedom from SVD were 23 +/- 14% and 43 +/- 15%, respectively. CONCLUSIONS: The data acquired suggested that the main advantage of tissue valve prostheses, namely to avoid lifelong, intense anticoagulation, might be offset by accelerated SVD. The use of mechanical valves should be considered in CVD patients with a large primary tumor mass and persistent high urinary levels of 5-HIAA, and who are unresponsive to therapy. PMID- 27989047 TI - Results of Contemporary Valve Surgery in Patients with Carcinoid Heart Disease. AB - BACKGROUND: Carcinoid tumor is a slow-growing type of neuroendocrine tumor, originating from enterochromaffin cells and secreting mainly serotonin. The diagnosis is based on clinical symptoms, hormone blood levels, radiological and nuclear imaging, and histological confirmation. However, most patients have metastases at the time of diagnosis because the clinical signs often remain unnoticed or are attributed to other abdominal conditions. In up to 50% of patients the endocardium is affected due to a hormonally active tumor profile. The study aim was to report the outcome of surgical treatment in patients with carcinoid heart disease, including the data of radiological and nuclear imaging, histological diagnosis, and follow up information. METHODS: Between 2008 and 2014, a total of 39 consecutive patients (28 males, 11 females; mean age 66 years; range: 28-84 years) with carcinoid heart syndrome were operated on at the authors' institution. Valvular heart disease was diagnosed with two-dimensional echocardiography. The study population included 26 patients (67%) with severe metastatic disease, who underwent radiotherapy preoperatively, and 13 patients (33%) who were metastasis-free and did not receive preoperative systemic therapy. Follow up was available for all hospital survivors, all of whom underwent serial echocardiographic follow up postoperatively. Adverse cardiac events were defined as cardiac-related death, a need for valvular reintervention, the occurrence of valve prosthesis-related complications, or echocardiographic evidence of new, high-degree valvular dysfunction during follow up. RESULTS: The majority of patients (n = 34; 87%) underwent isolated tricuspid valve replacement, while simultaneous pulmonary valve replacement was performed in five patients (13%). Postoperative complications included reoperation for bleeding in five patients (13%) and new heart block requiring pacemaker implantation in 10 (25%). The in hospital mortality was 5% (n = 2). The overall survival was 43% at six years postoperatively. At the latest follow up, 12 of the 17 survivors were in NYHA class I, and five in NYHA class II. The adverse cardiac event rate was 71%. Echocardiographically, 46% of patients (6/13) showed at least stationary or mild improvement in the right ventricular ejection fraction at follow up, with no evidence of paravalvular leak, infective endocarditis, or progressive other native valvular carcinoid affection. Postoperatively, the right atrial dimensions were preserved as normal in 23 patients (59%), mildly dilated in six (15%), moderately dilated in three (8%), and severely dilated in seven (18%). Valve-in valve transcatheter aortic valve implantation was performed in two patients (12%) due to structural degeneration of the valve bioprosthesis and native valve disease progression. CONCLUSIONS: Despite advanced systemic disease, the surgical treatment of patients with carcinoid heart syndrome is associated with an acceptable perioperative risk and satisfactory mid-term survival. Those patients who survived valve surgery benefited from a significant improvement in their functional capacity. Percutaneous procedures may represent a useful tool to reduce the risk of late valvular reinterventions. PMID- 27989048 TI - Complicated Infective Endocarditis of a Mechanical Aortic Valve due to Propionibacterium acnes. AB - Propionibacterium acnes is known to be a causative microorganism in low-grade and late prosthetic valve endocarditis. Here, the case is reported of a late, apparently culture-negative endocarditis of an aortic mechanical prosthesis, diagnosed to be caused by P. acnes after pan-bacterial polymerase chain reaction (PCR) on the explanted mechanical prosthetic valve. This endocarditis was complicated by an aortic root abscess; after surgical resection a ventricular septal defect (VSD) with overt right ventricular and multiple organ failure occurred. Low suspicion, the failure of routine blood culture to grow P. acnes and erroneous interpretation of P. acnes as contamination, frequently delay the correct diagnosis and treatment of this condition. Hence, although infection with P. acnes is usually indolent, abscess formation and a need for surgery are common. PMID- 27989049 TI - Infective Endocarditis in Hemodialysis Patients. AB - BACKGROUND AND AIM OF THE STUDY: Infective endocarditis (IE) is a major cause of morbidity and mortality in patients with end-stage renal disease (ESRD). The study aim was to evaluate the demographic, clinical, microbiological and inpatient mortality data of IE in hemodialysis patients. METHODS: Data were analyzed for all IE patients admitted to the authors' 800-bed tertiary care hospital between January 2001 and December 2014. These data included demographics, comorbidities, clinical and microbiological characteristics, echocardiographic findings, complications, outcomes, and in-patient mortality. RESULTS: A total of 296 patients, including 52 on hemodialysis, was admitted with a diagnosis of IE. The median age of patients with ESRD (28 females, 24 males) was 55.9 +/- 15.47 years. The prevalences of comorbidities such as hypertension (80%) and diabetes mellitus (46%) were significantly higher in ESRD patients, whereas other comorbidities were similarly distributed in both groups. The mitral valve was the most commonly involved (55.8%), followed by aortic (21.7%), tricuspid (21.2%) and pulmonary (1.9%) valves. Staphylococcus aureus was the most common organism (40%), followed by Enterococcus sp. (13.7%), Gram-negative staphylococci (13.7%), coagulase-negative staphylococci (11.5%), and Streptococcus sp. (5.7%). Polymicrobes were found in 11.5% of patients and cultures were negative in 19%. The mean ejection fraction in these patients was 42 +/- 4.19% and the mean area of vegetation was 63.5 +/- 40 mm2. The in-hospital course of 11 patients was complicated by embolic events, while three patients had acute heart failure and one patient had heart block secondary to IE. A total of four patients (7.7%) died during the index hospitalization. CONCLUSIONS: IE in patients receiving chronic hemodialysis is a very frequent occurrence. Its diagnosis is complex and its presence should be considered in all hemodialysis patients with bacteremia. In the present study the etiology was shown to be multifactorial, with the mitral valve being the most commonly involved and S. aureus the most common organism. PMID- 27989050 TI - Seroprevalence of Q Fever in Patients Undergoing Heart Valve Replacement Surgery. AB - BACKGROUND AND AIM OF THE STUDY: Q fever, caused by the rickettsia Coxiella burnetii, is a worldwide zoonotic disease with both acute and chronic manifestations. Endocarditis is the principal chronic manifestation. Q fever can easily be mistaken for degenerative valve disease due to its indolent presentation, the fastidious nature of the organism (routine cultures are negative), and the absence of a typical echocardiographic and macroscopic appearance for endocarditis. Prosthetic valve failure, with associated morbidity and mortality, have been described following unrecognized infections. METHODS: Previous studies have documented the value of screening strategies in areas of high prevalence. Hence, a pilot study was conducted in a low-prevalence setting, in which 139 patients at two tertiary cardiac centers attending for elective valve replacement for degenerative valvular disease underwent testing for chronic Q fever infection by serological and molecular methods on blood and valve tissue. RESULTS: Five patients (3.7%) had serological evidence of past exposure to Q fever (consistent with rates in the literature). None had evidence of chronic Q fever endocarditis. The cost of adopting a universal screening strategy is around L40,000 per case (if serology is used to screen patients prior to surgery). CONCLUSIONS: Alternative and more cost-effective methods for identifying clinically quiet cases of chronic Q fever endocarditis are required. PMID- 27989051 TI - PGA (polyglycolic acid)-P4HB (poly-4-hydroxybutyrate)-Based Bioengineered Valves in the Rat Aortic Circulation. AB - BACKGROUND AND AIM OF THE STUDY: Bioengineered living autologous valves with remodeling and growth capacity represent a promising concept for future cardiac and venous valve repair. A meticulous understanding of the mechanisms involved in recellularization and remodeling is essential for the safe and efficient clinical translation of this technology. In this context, the first investigations of bioengineered vascular grafts in immune-incompetent or transgenic rodents represented an important step. However, the in-vivo assessment of bioengineered synthetic scaffold-based (biodegradable) valve replacements in rodent models has not been achieved to date. METHODS: Miniaturized monocuspid PGA (polyglycolic acid)-P4HB (poly-4-hydroxybutyrate)-based valves were created, incorporated into metallic stents (length 2.0 mm, diameter 1.1 mm) and introduced into catheter based implantation devices. Wistar outbred rats (n = 8) underwent a laparotomy, abdominal aorta arteriotomy and valve delivery into the abdominal aorta. Valve placement and function were evaluated following deployment using ultrasound (Doppler- and M-mode). Explanted tissues were analyzed both macroscopically and histopathologically. RESULTS: No significant physiological or hemodynamic changes were observed, including heart rate, pressure gradients, velocity values and cardiac output before and after valve implantation. The cross-sectional area at the level of the stented valve was reduced by 22%. Valvular leaflet oscillation was observed in two animals, and thrombus formation in the stent was observed in one animal. Histological evaluation revealed cellular infiltration within 3 h in vivo, and no signs of thrombus deposition on the valvular surface. CONCLUSIONS: This study demonstrated the technical feasibility of the transcatheter implantation of bioengineered stented miniaturized valves into the infrarenal rat aorta, without affecting the animal's physiological and hemodynamic variables and with valvular oscillation in part of the implants. These results could serve as a basis for the implementation of a chronic rat in-vivo model for mechanistic studies in bioengineered valvular tissues under systemic hemodynamic conditions. Video 1: 2D ultrasonographic projection revealing graft's leaflet oscillation. PMID- 27989052 TI - Prognostic Value of Neutrophil-to-Lymphocyte Ratio for Patients Undergoing Heart Valve Replacement. AB - BACKGROUND AND AIM OF THE STUDY: The neutrophil-tolymphocyte ratio (NLR) was found to be a predictor of adverse outcome in patients with coronary artery disease (CAD). The ratio may also be a useful marker to predict mortality following valve replacement surgery. METHODS: A total of 932 patients was enrolled retrospectively. Patients were allocated to three tertiles based on their NLR (group 1, NLR <=1.90; group 2, 1.90 < NLR <=2.93; group 3, NLR >2.93). RESULTS: Patients in the highest tertile were older (p = 0.049, 95% CI 0.09 5.98), tended to have chronic renal failure (p = 0.028, OR: 2.6, 95% CI 1.08 6.35), and had more frequent critical CAD on preoperative angiography (p <0.001, OR 2.1, 95% CI 1.38-3.21). Postoperatively, patients in the highest NLR tertile had a higher in-hospital mortality rate than those in the first tertile (p <0.001, OR 4.67, 95% CI 2.37-9.20) and second tertile (p = 0.002, OR 2.26, 95% CI 1.32-3.86). Patients in the third tertile had the highest mortality at day 300 (log-rank p <0.001). The hazard ratio (HR) for the second tertile was 1.8 (p = 0.11, 95% CI 0.88-3.79), and for the third tertile was 2.8 (p = 0.003, 95% CI 1.40-5.59). CONCLUSIONS: The NLR is a useful parameter to assess postoperative in hospital mortality risk after valvular surgery. PMID- 27989053 TI - Conventional and Novel Predictors of Permanent Pacemaker after TAVI in Atrial Fibrillation Patients. AB - BACKGROUND AND AIM OF THE STUDY: Atrial fibrillation (AF) is common in patients submitted for transcatheter aortic valve implantation (TAVI), and these patients are at higher risk of developing conduction system disturbances requiring pacemaker (PM) implantation. Conventional predictors for PM use in this population have limited applicability. It was hypothesized that a post-procedural heart rate reduction could gauge the degree of atrioventricular (AV) node injury, and that this would be a clinically useful predictor of a need for PM. METHODS: All consecutive patients submitted for TAVI between December 2009 and August 2015 were included prospectively in a local registry. Clinical and electrocardiographic data and procedural details were recorded, and patients in sinus rhythm or with pre-existing PM were excluded. Heart rate (HR) at the start and end of the procedure were used to assess post-procedural HR reduction by calculating the HR ratio (HRratio = HRend/HRstart). The relationship between previously described predictors of PM, HRratio and implantation of a permanent PM during the 30 days after TAVI were analyzed using the Wilcoxon ranksum test and receiver operating characteristic (ROC) curve. RESULTS: A total of 102 patients was submitted for TAVI, 24 of whom had AF and no previous PM. Of the latter 24 patients, 10 (41.6%) received a PM during the 30 days after TAVI. Conventional predictors of permanent PM such as male gender, left anterior hemiblock and right bundle branch block were not significantly associated with PM implantation. The HRratio was significantly lower in patients submitted for PM implantation (median 0.76, IQR 0.68-0.86 versus 1.18, IQR 1.10-1.26; p <0.001; Wilcoxon ranksum test). ROC curve analysis of the HRratio showed a good discrimination for the need of PPM with a c-statistic of 0.93. An optimal cut-off value of 0.9 predicted the need for PM implantation with a sensitivity of 90% and specificity of 92.8% CONCLUSIONS: Conventional predictors of PM after TAVI were not associated with PM implantation in patients with AF. The fall in post-procedural HR was significantly associated with PM implantation, with an HRratio cut-off value of 0.9 accurately predicting a need for PM within 30 days. PMID- 27989054 TI - Contribution of Dobutamine Stress Echocardiography to the Diagnosis and Prognosis of Low-Flow/Low-Gradient Aortic Stenosis. AB - BACKGROUND: Aortic valve replacement (AVR) is the treatment of choice in patients with severe symptomatic aortic stenosis (AS). Patients with a low left ventricular ejection fraction (LVEF) represent a challenge for evaluation and therapeutic decision. Dobutamine stress echocardiography (DSE) allows the distinction to be made between fixed low-flow/low-gradient (LF/LG) AS and pseudosevere AS. METHODS: Between 2001 and 2014 a retrospective analysis was conducted of patients who underwent DSE to investigate severe AS. DSE was performed in 3- to 5-min steps up to a maximum dose of 20 MUg/kg/min. Parameters evaluated at baseline and at each step of DSE included: left ventricular enddiastolic volume (LVEDV) and left ventricular endsystolic volume (LVESV), maximum gradient (MaxG), mean gradient (MG) and aortic valve area (AVA). AS was considered to be severe if the AVA at peak dose was <=1 cm2. Patients were allocated to two groups according to their therapy: group 1 received only medical treatment, while group 2 underwent AVR. The average follow up was 51.5 +/- 4.4 months. RESULTS: A total of 41 patients (28 males, 13 females; mean age 71.7 +/- 8.3 years) was analyzed. Severe AS was diagnosed in 34 patients (83%). Baseline echocardiographic characteristics were: AVA 0.7 +/- 0.2 cm2, MaxG 42.0 +/- 9.1 mmHg, MG 25.6 +/- 6.4 mmHg, LVEF 33.1 +/- 8.4%, LVEDV 149.6 +/- 44.5 ml, and LVESV 104.0 +/- 42.6 ml. At peak DSE, AVA was 0.8 +/- 0.2 cm2, MaxG 62.7 +/- 18.2 mmHg, MG 38.1 +/- 11.6 mmHg, LVEF 42.2 +/- 9.9%, LVEDV 142.6 +/- 43.85 ml, and LVESV 89.7 +/- 37.4 ml. Nineteen patients were allocated to group 1, and 22 to group 2. In group 2, two patients underwent transcatheter aortic valve implantation (TAVI) and 20 had surgery. Mortality in group 1 was significantly higher than in group 2 (78.9% versus 27.3%). A Cox proportional hazard model analysis showed that no-intervention was the only predictor of mortality (unadjusted to age; hazard ratio (HR) 5.13, 95% confidence interval (CI) 1.96 13.44, p = 0.001; adjusted to age - HR 4.01, 95% CI 1.46-11.01, p = 0.007). CONCLUSIONS: LF/LG AS has a poor prognosis without intervention. DSE allows the lesion severity to be established. In the present study intervention was a predictor of survival during follow up. PMID- 27989055 TI - Anticoagulation After Biological Aortic Valve Replacement: Is There An Optimal Regimen? AB - BACKGROUND: The anticoagulation of biological heart valves remains a 'hot spot' of discussion in various domains due to the risk of developing valve thrombosis and arterial thromboembolism. The situation has always been controversial, especially during the early postoperative phase. The American College of Cardiology/ American Heart Association and European Society of Cardiology guidelines recommend the use of warfarin for the first three months after biological aortic valve replacement (BAVR), although the American College of Chest Physicians guidelines suggest that these recommendations are experience based and that the risk/benefit is unclear. The aim of the present study was to compare the efficacy of aspirin and warfarin in patients after BAVR. METHODS: A total of 863 patients who underwent BAVR between 2008 and 2015 was allocated to two groups. Each group was managed with a specific anticoagulation regimen, with 430 patients receiving warfarin during the first three postoperative months, and 433 receiving aspirin. The major study end points were bleeding, cerebral ischemic events, and survival. RESULTS: In total, 10 and 15 postoperative cerebral ischemic events occurred between 24 h and three months after surgery in patients treated with aspirin and warfarin, respectively. After three months the incidence of cerebral ischemic events did not differ greatly between the two groups. The rate of major bleeding events and rates of stroke-free survival and overall survival were not statistically significant between the warfarin and aspirin groups. CONCLUSIONS: Plasma anticoagulation with warfarin during the early postoperative phase was shown statistically to be inferior to platelet aggregation inhibition by aspirin with regards to postoperative bleeding risk, cerebral ischemic events, and survival. PMID- 27989056 TI - Sutureless Aortic Valve Replacement: An Easy and Safe Approach for Patients with Anomalous Left Circumflex Coronary Artery. AB - An anomalous origin of the left circumflex coronary artery (LCx) from the right sinus of Valsalva is a frequent coronary problem. This particular condition, though usually silent, is associated with an increased incidence of serious complications during surgical aortic valve replacement (AVR) and transcatheter aortic valve implantation. Here, the cases are described of four patients with an anomalous origin of the LCx from the right sinus of Valsalva who underwent sutureless AVR with the Sorin Perceval S prosthesis. The possible advantages of this approach are also discussed. PMID- 27989057 TI - Ventricular Septal Defect from Aortic Regurgitation Jet Lesion in Aortic Valve Infective Endocarditis. AB - Aortic valve infective endocarditis (IE) can be complicated with severe aortic regurgitation (AR) jet-related lesions such as vegetations, pseudoaneurysms, aneurysms or perforations on the anterior mitral leaflet. Herein is reported the case of a 69-year-old male with culture-negative aortic valve endocarditis complicated with aortic valve perforations resulting in severe and eccentric AR and an AR jet-related ventricular septal defect (VSD). Neither transthoracic echocardiography (TTE) nor two-dimensional transesophageal echocardiography (2D TEE) were unable to clearly discriminate an aorto-right ventricular fistula from a VSD. By contrast, three-dimensional TEE (3D-TEE) demonstrated multiple aortic valve vegetations, aortic valve perforations, severe AR, and an AR jet-related VSD. The 3D-TEE findings were confirmed at surgery, the aortic valve was replaced with a bioprosthetic valve, and the VSD was repaired with a pericardial patch. To the authors' knowledge, this is the first case of a VSD resulting from an AR jet lesion to be detected and characterized using 3D-TEE. The accurate preoperative diagnosis and characterization of the VSD with 3D-TEE contributed to successful surgery and the patient's short- and long-term survival. Video 1A: This four chamber transthoracic echocardiography (TTE) view with color Doppler shows a color-Doppler jet traversing the basal interventricular septum (IVS) into the right ventricle, predominantly during systole. However, the origin of the jet resulting from an aortic-right ventricular fistula cannot be determined. A mild to moderate degree of tricuspid regurgitation is also noted. Video 1B: Close-up view of the basal IVS demonstrates a color Doppler jet traversing the IVS, predominantly during systole and apparently originating in the left ventricular outflow tract side, as illustrated by a color Doppler acceleration zone. However, and as in Fig. 1A, the origin of the jet resulting from an aortic-right ventricular fistula cannot be determined. Video 1C: Color Doppler two-dimensional TEE view longitudinal to the aortic valve and aortic root, showing a predominantly systolic color Doppler jet originating in the left ventricular outflow tract and/or aorta and crossing the anterior and basal IVS defect into the right ventricle. Videos 1D: These three-dimensional TEE en-face left ventricular outflow tract views of the aortic valve and basal anterior IVS (Video 1D) and medial anterior close up (Video 1E) and lateral en-face (Video 1F) views of the LV outflow tract and IVS clearly define the anterior and basal location of the VSD with irregular borders and a residual mobile tissue fragment. Multiple aortic valve vegetations and a perforation are visible in Video 1D. Videos 1E: These three-dimensional TEE en-face left ventricular outflow tract views of the aortic valve and basal anterior IVS (Video 1D) and medial anterior close up (Video 1E) and lateral en-face (Video 1F) views of the LV outflow tract and IVS clearly define the anterior and basal location of the VSD with irregular borders and a residual mobile tissue fragment. Multiple aortic valve vegetations and a perforation are visible in Video 1D. Videos 1F: These three-dimensional TEE en face left ventricular outflow tract views of the aortic valve and basal anterior IVS (Video 1D) and medial anterior close up (Video 1E) and lateral en-face (Video 1F) views of the LV outflow tract and IVS clearly define the anterior and basal location of the VSD with irregular borders and a residual mobile tissue fragment. Multiple aortic valve vegetations and a perforation are visible in Video 1D. PMID- 27989058 TI - Transcatheter Aortic Valve Replacement in Type B Aortic Dissection. AB - Transcatheter aortic valve replacement (TAVR) has become an acceptable alternative to surgical aortic valve replacement in high-risk and inoperable patients. Several technical and anatomical considerations can increase the complexity and risk of the procedure, and therefore are considered as contraindications to TAVR. Patients with significant aortic disease such as aortic dissection are not usually considered for TAVR due to risk of aortic rupture or retrograde extension of the dissection. Herein is presented a report of the first successful TAVR in a patient with extensive type B dissection. PMID- 27989059 TI - Prevalence of Late Functional Tricuspid Regurgitation in Degenerative Mitral Regurgitation Surgery. AB - BACKGROUND: Although significant late tricuspid regurgitation (TR) may develop after surgery for degenerative mitral regurgitation (MR), the use of routine tricuspid annuloplasty is debatable. The study aim was to determine the prevalence and predictors of significant late TR after surgery for degenerative MR. METHODS: A total of 112 patients who had undergone surgery for degenerative MR without concomitant tricuspid valve repair (average follow up 7.7 +/- 4.0 years) was studied retrospectively. The prevalence of post-surgical TR and predictors of progression were determined. RESULTS: The majority of patients (97%) had non-significant TR (less than moderate) prior to surgery, although an overall trend of progression towards significant TR (grades 2 or 3) was noted in 17 patients (p = 0.0006). Of the 18 patients (16%) with late postoperative significant TR, only nine (8%) had severe TR with only a single referral to surgery. New-onset post-surgical atrial fibrillation was more common in patients who developed late significant TR (p = 0.002). Multivariate analysis of the pre surgery variables, age >65 years and left ventricular dysfunction were shown to be independent predictors of late functional TR. CONCLUSIONS: Significant progression in TR after surgery for degenerative MR was rare in this patient cohort. The impact of older age and left ventricular dysfunction at the time of surgery showed a strong association with post-surgical atrial fibrillation. PMID- 27989060 TI - Acute Invasive Hemodynamic Effects of Transcatheter Aortic Valve Replacement. AB - BACKGROUND: Aortic stenosis imposes a chronic pressure overload on the left ventricle, with attendant adaptations in hemodynamics, muscle mass and performance. The hemodynamic changes that occur during the initial 24 h following abrupt removal of the impediment to left ventricular outflow have not been previously examined. METHODS: A total of 52 patients with right heart catheterization was evaluated before, within 6 h and at 24 h after successful transcatheter aortic valve replacement (TAVR). Echocardiographic data were examined before and within 30 days of the procedure. RESULTS: TAVR was successful in all 52 patients, and at 24 h after the procedure resulted in: (i) an increase in cardiac index (CI) (from 2.0 +/- 0.6 to 3.1 +/- 0.7 l/min/ m2, p <0.001) and stroke volume (SV) (from 62.3 +/- 18.7 to 76.6 +/- 21.3 ml, p <0.001); (ii) reductions in systemic vascular resistance (from 1555 +/- 458 to 1021 +/- 280 dyne.s/cm5, p <0.001) and pulmonary vascular resistance (from 174 +/- 150 to 112 +/- 76 dyne.s/cm5, p = 0.001); (iii) reductions in pulmonary capillary wedge pressure (from 24.2 +/- 6.7 to 19.7 +/- 7.3 mmHg, p <0.001), mean pulmonary artery pressure (from 32.2 +/- 9.9 to 27.5 +/- 8.8 mmHg, p = 0.002) and in central venous pressure (from 13.5 +/- 4.8 to 9.4 +/- 3.9 mmHg, p <0.001); and (iv) an increase in systolic arterial pressure (from 127 +/- 25 to 135 +/- 14 mmHg, p = 0.04), along with a decrease in diastolic arterial pressure (from 58 +/ 11 to 53 +/- 9 mmHg, p = 0.009). CONCLUSIONS: Successful TAVR results in immediate and sizeable improvements in SV and CI, reductions in left and right ventricular filling pressures, and marked reductions in systemic and pulmonary vascular resistances. PMID- 27989061 TI - Predictability and Outcome of Vascular Complications after Transfemoral Transcatheter Aortic Valve Implantation. AB - BACKGROUND: Although the efficacy and safety of transfemoral transcatheter aortic valve implantation (TAVI) have been improved with new devices, careful patient selection is essential and awkward complications associated with the procedure persist. Despite a gradual reduction in the delivery system size and the development of access site arterial closure devices, vascular complications remain one of the main challenges of TAVI. The aim of this single-center study was to prospectively evaluate the incidence and predictors of vascular complications in transfemoral TAVI. METHODS: A total of 211 patients (mean age 77.98 +/- 8.20 years) who underwent transfemoral TAVI between 2011 and 2014 at the authors' institution, using two different commercially available devices, was included in the study. Technical success, vascular complications, predictors of vascular complications and mortality were each assessed. Vascular complications were defined by the current Valve Academic Research Consortium-2 (VARC-2) criteria. RESULTS: The mean logistic EuroSCORE of the patients was 21.04 +/- 7.51. An Edwards SAPIEN XT valve was used in 69.7% of cases, and a Medtronic CoreValve in 30.3%. Completely percutaneous transfemoral TAVI was successful in 81.6% of patients. Procedural and 30-day mortalities were 1.4% and 8.5%, respectively. Vascular complications occurred in 16.1% of patients (minor 10.4%, major 5.7%), and necessitated surgical repair in 25 cases (11.8%). Major vascular complications were predictive of 30-day mortality (58.3% versus 5.6% (p = 0.000). Predicted major vascular complications (by multivariate analysis) were female gender (hazard ratio (HR) 5.45; 95% confidence interval (CI) 0.91-32.5, p = 0.063), arterial calcification (HR 2,88; 95% CI 1.14-7.30, p = 0.025) and sheath to iliofemoral artery ratio (SIFAR) (HR 1.91, 95% CI 1.27-2.87, p = 0.001). CONCLUSIONS: Although vascular preclosure devices have revolutionized transfemoral TAVI, and offer a simple but effective percutaneous procedure, vascular complications are still observed in a considerable number of patients. The major vascular complications were predictive of 30-day mortality, and included female gender, iliofemoral calcification and SIFAR. Further technological and procedural developments are required to reduce vascular complication rates and related mortality. PMID- 27989062 TI - Aortic Regurgitation after TAVR: From Bad to Worse. AB - Transcatheter aortic valve replacement (TAVR) is a valuable alternative in surgical high-risk patients with symptomatic aortic valve stenosis. Here, the case is presented of very early transcatheter heart valve degeneration, probably caused by a 'Venturi effect' of a severe paravalvular regurgitant jet. This ultimately led to a leaflet being in the open position, creating severe valvular regurgitation that necessitated classical surgical revision. The occurrence of paravalvular regurgitation, and its known relationship with an adverse prognosis after TAVR, demonstrates the clear need for innovative alterations in valve design to prevent this complication. Video 1: Angiography immediately after implantation of an Edwards SAPIEN 23 mm transcatheter heart valve, showing severe paravalvular aortic valve regurgitation. The implantation position is rather low. Video 2: Transesophageal echocardiography with 2-D color imaging showing aortic valve long-axis view at 131 degrees , three days after implantation of an Edwards SAPIEN 23 mm transcatheter heart valve. Severe eccentric paravalvular aortic valve regurgitation is shown without a significant valvular component. The implantation position is rather low. Video 3: Transesophageal echocardiography with 2-D color imaging showing aortic valve long-axis view at 120 degrees , one month after implantation of an Edwards SAPIEN 23 mm transcatheter heart valve. Severe combined valvular and paravalvular aortic valve regurgitation (grade 4/4) is shown. PMID- 27989064 TI - Transcatheter Mitral Valve-in-Ring for Progressive Mitral Stenosis after Prior Repair with Annuloplasty: A Novel Balloon Sizing Technique. AB - An 83-year-old man with a previous mitral valve repair using a semi-rigid annuloplasty ring was found to have severe mitral stenosis. A transcatheter approach for mitral valve-in-ring replacement was selected due to the patient's high surgical risk. Pre-procedural computed tomography scans for transcatheter valve size selection were inconsistent with previously published recommendations. To determine the appropriate valve size, a 25 mm compliant balloon was inflated intraoperatively within the stenotic mitral ring, but yielded no resistance to movement and no 'waist'. Thus, a 29 mm balloon-expandable prosthetic valve was selected and deployed with no paravalvular leak. This novel balloon sizing technique helped lead to a successful outcome in this case. Video 1: Angiographic video displaying mitral valve-in-ring balloon sizing technique. The 25 mm compliant balloon was inflated within a stenotic mitral ring to determine which prosthetic transcatheter valve size was appropriate. As shown, this technique yielded no 'waist' and no resistance to movement, suggesting that a 29 mm valve was necessary. PMID- 27989065 TI - Repair of Anterior Mitral Leaflet Prolapse: Comparison of Mid-Term Outcomes with Chordal Transposition and Chordal Replacement Techniques. AB - BACKGROUND: The repair of anterior mitral leaflet prolapse is known to be challenging. Hence, the study aim was to compare the mid-term results of anterior leaflet prolapse (ALP) using chordal transposition with results obtained using chordal replacement with expanded polytetrafluoroethylene (ePTFE) sutures. METHODS: Between 1999 and 2012, a total of 96 consecutive patients (mean age 62 years) with ALP underwent mitral valve repair at the authors' institution. Surgery involved either chordal transposition from the posterior to the anterior leaflet (n = 67), or chordal replacement using ePTFE sutures (n = 29). Clinical, operative and follow up data were recorded prospectively for each patient. The follow up was 100% complete (mean 3.4 years; range 0 to 12.9 years). RESULTS: Mitral valve repair was accomplished in all patients, with no operative mortality. The durations of cardiopulmonary bypass and aortic cross-clamp were significantly longer in the chordal replacement group. Actuarial overall survival at one, five and 10 years was 95 +/- 3%, 87 +/- 5% and 82 +/- 7% versus 89 +/- 6%, 89 +/- 6% and 89 +/- 6% in the chordal transposition and chordal replacement groups, respectively (p = 0.84). Freedom from reoperation in the two groups at five years was 95 +/- 3% and 91 +/- 7%, respectively (p = 0.24). The recurrence of moderate or severe mitral regurgitation (MR) (grade <=2+) and of severe (grade <=3+) MR was significantly higher in patients who underwent chordal replacement compared to chordal transposition (p = 0.04 and p = 0.01, respectively). CONCLUSIONS: Provided that chordal quality is preserved, chordal transposition is easier and quicker to achieve for ALP repair, and is also durable in the mid term. Chordal replacement offers a satisfying durability even if the recurrence of severe MR appears to be higher. Preferably, both surgical techniques should be mastered to allow valve repair when anatomic conditions prevent chordal transposition. PMID- 27989066 TI - An Unusual Case of Persistent Severe Pulmonary Artery Hypertension Following Balloon Mitral Valvuloplasty. AB - Persistent pulmonary artery hypertension (PAH) after balloon mitral valvuloplasty (BMV) is not uncommon, and is generally associated with established pulmonary vascular disease, an inadequate result, or the development of mitral regurgitation. An unfavorable mitral valve morphology with a smaller post procedural mitral valve area is among the most common causes of the condition. While routine cardiac catheterization is no longer recommended prior to intervention in valvular heart disease, patients with persistent PAH after BMV should undergo a thorough evaluation before they are considered for repeat BMV. Here, a rare case is reported of symptomatic persistent PAH in a patient referred for a third BMV, less than one year after the previous intervention, where a hypertensive patent ductus arteriosus was identified, the closure of which led to a regression of the PAH. PMID- 27989067 TI - The Presence of Left Atrial Thrombus is Associated with the Neutrophil-to Lymphocyte Ratio in Patients with Rheumatic Mitral Valve Stenosis. AB - BACKGROUND: Rheumatic mitral valve stenosis (RMVS)-induced left atrial thrombus (LAT) and embolic complications may have clinically devastating consequences. Stasis in the left atrium induced by valvular obstruction is a major factor in the development of thrombus. However, the development of thrombus may not be solely associated with stasis, as it is known that the inflammatory process increases the tendency for thrombosis. The study aim was to examine the relationship between the neutrophil-to-lymphocyte ratio (NLR), an indicator of inflammation, and the existence of LAT. METHODS: A total of 313 consecutive patients with RMVS and mitral valve area (MVA) <2 cm2 was included in this cross sectional study. Patients were allocated to two groups with or without LAT using transthoracic and transesophageal echocardiography. Routine biochemical analyses and electrocardiographic examinations were also carried out. The NLR was calculated utilizing blood count analysis. RESULTS: The presence of LAT was identified in 78 RMVS patients (24.9%). No significant differences in terms of age, gender, body mass index were found between the groups with and without LAT. On echocardiographic examination, a higher mean gradient and left atrial diameter, as well as a smaller MVA, were determined in patients with LAT (p<0.001). In those patients with LAT, higher C-reactive protein levels and higher leukocyte and neutrophil counts (p <0.001) and lower lymphocyte counts were noted (p = 0.001). The NLR was shown to be higher in patients with LAT (p <0.001). Multivariate regression analysis showed that the relationship between LAT and a high NLR continued independently (OR 5.3; 95% CI 2.9-9.4; p <0.001). CONCLUSIONS: The NLR is an easily obtained, low-cost and easily repeated parameter that seems effective for identifying RMVS patients who are at high risk of developing LAT. PMID- 27989068 TI - Underlying Rheumatic Disease: An Important Determinant of Outcome in Tricuspid Valve Repair. AB - BACKGROUND: Tricuspid regurgitation (TR) accompanying severe left-sided valve disease occurs on a functional basis, secondary to pulmonary hypertension and tricuspid annular dilatation. In the context of endemic left-sided rheumatic heart disease, non-recognition of organic disease of the tricuspid valve may adversely influence surgical decision-making, resulting in suboptimal outcomes. METHODS: A retrospective analysis of the perioperative and follow up data of 30 patients who underwent tricuspid valve surgery with concomitant left-sided valve replacement was undertaken. Preoperative evaluation by two-dimensional transthoracic echocardiography was routinely employed. Outcomes were analyzed by evaluation of the perioperative and two-year follow up clinical and echocardiographic data. RESULTS: All subjects had severe TR. Mixed tricuspid valve disease occurred in 11 subjects (36.7%). Tricuspid valve repair was performed in 28 patients. A significant improvement (p <0.05) in the following parameters occurred at six weeks postoperatively: NYHA functional class, tricuspid annular diameter, systolic pulmonary artery pressure, severity of TR and tricuspid transvalvular gradient. Severe residual postoperative TR occurred in 26.7% of patients, but there were no identifiable predictors for this phenomenon. Severe residual postoperative TR was not associated with major adverse cardiovascular events. Preoperative (p = 0.013) and postoperative (p<0.002) pulmonary hypertension were associated with the development of major adverse cardiovascular events. The technique of tricuspid valve repair was not associated with the occurrence of major adverse cardiovascular events, nor with the development of severe residual postoperative TR. A satisfactory outcome was observed in only 40% of the study population. CONCLUSIONS: The coexistence of mixed tricuspid valve disease in rheumatic heart disease patients undergoing left sided valve surgery is an important determinant of outcome in tricuspid valve repair. The persistence of severe TR contributes to poor long-term outcomes, and its incidence may be lowered by the adoption of appropriate perioperative imaging techniques to delineate valve morphology. PMID- 27989069 TI - Successful Treatment of Very Early Thrombosis of SAPIEN 3 Valve with Direct Oral Anticoagulant Therapy. AB - Thrombosis of transcatheter aortic valve implantation (TAVI) is an uncommon complication that commonly occurs weeks to months following the procedure. Herein are described the details of a patient who presented with a recurrence of symptoms days after intervention with a bioprosthesis thrombosis that was successfully treated with direct oral anticoagulant (DOAC) therapy and resulted in hemodynamic improvement and resolution of symptoms. Whilst a previous trial of DOAC therapy with mechanical valves was stopped due to elevated events in comparison to warfarin, a TAVI valve may be different, and the rapid onset of action and reduced bleeding risk may be beneficial in this patient group. PMID- 27989070 TI - Thrombolysis for Left-Sided Prosthetic Valve Thrombosis: Short- and Long-Term Outcomes. AB - BACKGROUND AND AIM OF THE STUDY: Emergency valve replacement has long been the treatment of choice in left-sided prosthetic valve thrombosis (PVT) for critically ill patients in NYHA classes III-IV. Thrombolytic therapy is recommended for NYHA class I/II patients with a small thrombotic burden.METHODS: The results of thrombolytic therapy to treat left-sided PVT (eight mitral, three aortic) with streptokinase (STK) in critically ill NYHA class III/IV patients were analyzed, where surgery was either refused due to financial constraints or by the surgical team. Results were assessed clinically, using fluoroscopy and transthoracic and transesophageal echocardiography.RESULTS: Mechanical bileaflet prosthetic valves (eight mitral, four aortic) were implanted between two and 10 years previously in 11 patients (four females, seven males; age range: 32-54 years). One patient had diabetes and had undergone prior percutaneous coronary intervention with drug-eluting stent implantation to the ostial left main artery. All had cardiomegaly with ejection fraction 24-63% and an increased mean gradient across the immobile prosthetic valve. Patients presented in a hemodynamically unstable state with pulmonary edema and/or hypotensive shock. The International Normalized Ratio was <2.5 in nine patients. Eight patients with mitral valve thrombosis responded to thrombolytic therapy and survived, with complete resolution of thrombus and return of full mobility of leaflets and resolution of valve gradients. To date, all responders have survived (up to five years) without any recurrence of re-thrombosis (PVT).CONCLUSION: Intravenous STK may be life saving in critically ill NYHA class III/IV patients with left-sided PVT. Thrombolytic therapy is much cheaper and easier to administer than surgical replacement of the thrombosed prosthetic valve. PMID- 27989071 TI - Broad-Range 16S rDNA PCR on Heart Valves in Infective Endocarditis. AB - BACKGROUND AND AIM OF THE STUDY: Infective endocarditis (IE) is diagnosed by blood and/or resected valve cultivation and echocardiographic findings, as defined by the Duke criteria. Unfortunately, cultures may be negative due to prior antibiotic therapy or fastidious or slow-growing microorganisms. The study aim was to investigate the value of the broad-range polymerase chain reaction (PCR) in addition to blood and valve culture for the detection of causative microorganisms. METHODS: Between February 2012 and March 2015, valve samples from 36 patients undergoing cardiac surgery were analyzed; of these patients, 26 had a preoperative diagnosis of IE and 10 served as controls. Multiple blood cultures were obtained from 34 patients before antibiotic therapy was commenced. Valve samples were inoculated on bacteriological media and underwent analysis using broad-range PCR (16S rDNA). RESULTS: IE was confirmed microbiologically in 21 of the 26 patients (80.7%); in 20 cases (76.9%) this was by positive blood cultures and in 16 (61.5%) by positive valves. Valves were positive in 15 blood culturepositive patients, and in one blood-culture negative patient. Broad-range PCR detected a microorganism in valves significantly more frequently (n = 14; 53.8%) compared to valve culture (n = 8; 30.7%) (chisquare 11.5, p <0.001). The predominant microorganisms were Staphylococcus aureus, Streptococcus of the viridans group, coagulasenegative staphylococci and Enterococcus faecalis. Blood, valve cultures and broad-range PCR were negative in five patients (19.3%) with IE, and in all 10 subjects of the control group. CONCLUSIONS: Broad-range PCR on valves was more sensitive than valve culture. However, blood culture, if taken before the start of antibiotic therapy, was the best method for detecting IE. PMID- 27989072 TI - How to Do It - Implantation Technique for Newer-Generation Sutureless/Rapid Deployment Aortic Valve Replacement. AB - 'Sutureless' or rapid-deployment (RD) aortic valve replacement (AVR) is an emerging alternative to standard AVR in elderly high-risk surgical patients. Here, the authors describe their implantation technique for the newer-generation Edwards INTUITY-Elite(r) valve (Edwards Lifesciences, Irvine, CA, USA), a balloon expandable stented trileaflet bovine pericardial bioprosthesis that received CE Mark European approval in April 2014. PMID- 27989073 TI - Surgical Management and Postoperative Outcomes of Mechanical Valve Dysfunction: A Six-Year, Single-Center Study. AB - BACKGROUND: Although many mechanical heart valves are replaced worldwide each year, mechanical valve dysfunction (MVD) remains one of the most common complications following this surgery. In an attempt to improve the postoperative and surgical management of MVD, the study plan was to investigate a group of patients who had undergone redo mechanical valve replacement to treat MVD at the authors' institution. METHODS: A total of 52 consecutive patients diagnosed with MVD underwent redo mechanical valve replacement between January 2007 and December 2013. A retrospective analysis was made of the clinical data from patients with MVD, and to compare these data with that from patients who had undergone redo heart valve surgery for other reasons. RESULTS: Seven patients died in the early stage, with an overall mortality of 13.46%. All other patients were clinically cured and discharged. In total, nine patients died during this six-year review. CONCLUSIONS: The surgical management of MVD has a high mortality and involves complex surgical procedures, but remains an effective means of treating MVD. Adequate surgery time, preoperative improvements in cardiac function, effective myocardial preservation during surgery and reasonable perioperative management may all help to improve the postoperative and mid-term outcomes of the surgical management of MVD. PMID- 27989074 TI - Excellence and Durability: A Normally Functioning Bjork-Shiley Flat-Disc Prosthesis 42 Years Post Implantation. AB - Mechanical heart valves have been used worldwide for more than 60 years. While the composition and design of the valves, and the surgical techniques employed to implant them, have changed and advanced over that time, some of the earlier mechanical heart valves showed such great durability that they are still functioning in patients today. One of the most often-used and long-lasting mechanical prostheses was the Bjork-Shiley heart valve. While many versions of this valve were used during its 25 years of production, the most durable was the Bjork-Shiley flat-disc valve. This valve was first implanted in 1971 and was the first successful tilting-disc valve. Here, the complex medical history is reported of an elderly patient with a well-functioning Bjork-Shiley flat-disc valve in the aortic position that was placed over 42 years ago. The history of mechanical heart valves - in particular the Bjork-Shiley heart valve, including the flat-disc mechanical valve - is also briefly reviewed. PMID- 27989075 TI - MALDI Imaging Mass Spectrometry as a Lipidomic Approach to Heart Valve Research. AB - BACKGROUND: Valvular disease is characterized in part by lipid deposition, but systematic analysis of the patterns of global lipid expression in healthy and diseased valve tissues are unknown. This is due in part to tissue limitations for lipidomic preparations and technologies for evaluating lipid distribution in tissues. The study aim was to examine the application of matrixassisted laser desorption ionization imaging mass spectrometry (MALDI IMS) to the aortic valve during development and disease, as an approach to detect and map lipids and ultimately better understand valve structure and function. METHODS: Established MALDI IMS strategies were applied to thin tissue sections of heart valves to map lipids to corresponding morphological features. Healthy prenatal and adult ovine aortic valve tissues were evaluated using the developed techniques. Lipid expression levels were compared between prenatal and adult valves using Wilcoxon rank sum testing and area under the receiver operating curves. A classification algorithm was used to determine distinct lipid signatures in adult extracellular matrix (ECM) substructures, including fibrosa and spongiosa layers. Lipid patterns were examined in heart valve tissue from pediatric patients with congenital aortic valve stenosis (CAVS). RESULTS: Lipid levels were decreased in adult ovine aortic valves when compared with prenatal valves. Classification algorithms applied to lipid signatures reported distinct lipid signatures mapping to ECM substructures in the adult aortic valve, but could not distinguish amorphous structures at pre-natal day 5. In CAVS, the in-situ lipid aggregation of distinct lipid species showed unique patterning both concurrent and divergent with ECM disarray. Fatty acid content varied between normal and diseased human aortic valves. CONCLUSIONS: MALDI IMS provides a new and useful approach to evaluate lipid biology in heart valve tissue. These findings define a role for lipid regulation in aortic valve development and demonstrate patterns of lipid deregulation in congenital disease. PMID- 27989076 TI - The Immune Responses and Calcification of Bioprostheses in the alpha1,3 Galactosyltransferase Knockout Mouse. AB - BACKGROUND: The study aim was to evaluate the immune reaction, difference of degenerative calcification, and anti-calcification effect of decellularization with or without alpha-galactosidase in bovine pericardium and porcine heart valves, using an alpha1,3-galactosyltransferase (alpha-Gal) knockout (KO) mouse model. METHODS: In order to elucidate the anti-calcification effect of decellularization with or without alpha-galactosidase, bovine pericardium and porcine heart valve tissues were assigned to four groups according to the tissue preparation method: (i) glutaraldehyde (GA) fixation only; (ii) decellularization + GA fixation (Decell); (iii) alpha-galactosidase + GA fixation (alpha galactosidase); and (iv) decellularization +alpha-galactosidase + GA fixation (Decell + alpha-galactosidase). Each prepared tissue was implanted subcutaneously into alpha-Gal KO mice. Anti-alpha-Gal immunoglobulin (Ig) G and IgM antibody titers were monitored prior to implantation and at four, eight and 12 weeks after implantation using an enzyme-linked immunosorbent assay. Calcium contents of explanted tissues were measured at 12 weeks after implantation. RESULTS: There were no significant differences in the anti-alpha-Gal IgG antibody titers according to the type of bioprosthetic material or tissue preparation method (p >0.05). The calcium content was significantly lower in porcine heart valves than in bovine pericardium when implanted in alpha-Gal-KO mice (p <0.001). Calcium contents in bovine pericardium and porcine heart valves were significantly lower in the Decell, alpha-galactosidase and Decell + alpha-galactosidase groups than in the GA group (all p <0.05). CONCLUSIONS: The porcine heart valve induced lower levels of calcium deposition than did the bovine pericardium, but the anti-alpha Gal IgG antibody titers did not differ significantly between the bioprosthetic tissues. Decellularization had significant anticalcification effects in both the bovine pericardium and porcine heart valves, though there was no significant difference in the anti-alpha-Gal IgG antibody titers among tissue preparation methods. PMID- 27989077 TI - Favorable Survival after Aortic Valve Replacement Compared to the General Population. AB - BACKGROUND: A comparison was made between the long-term survival of patients undergoing aortic valve replacement (AVR) for aortic stenosis and of the general Icelandic population, using centralized registries. METHODS: A total of 366 AVR patients (231 males, 135 females; mean age 70.1 years) operated on for aortic stenosis in Iceland between 2002 and 2011 was included in the study. Concomitant coronary artery bypass grafting was performed in 54% of cases. Short-term complications and 30-day mortality were analyzed. The patients' overall survival was compared with the survival of Icelanders of the same age and gender. The median follow up was 4.7 years. RESULTS: A bioprosthesis was used in 81% of the patients; the median prosthesis size was 25 mm. Atrial fibrillation (68%) and acute kidney injury (23%) were the most common complications, and the 30-day operative mortality was 6%. Overall survival at one year and five years was 92% and 82%, respectively. There was no difference in survival between the surgical cohorts and expected survival of Icelanders of the same age and gender (p = 0.08), except for the first 30 postoperative days. CONCLUSIONS: Despite the significant rate of short-term complications, the long-term survival of patients undergoing AVR for aortic stenosis was good compared to the general population of the same age and gender. These results confirmed the value of AVR as an excellent treatment option for aortic stenosis, as it offers a normalization of the patients' life expectancy. PMID- 27989078 TI - Intravenous Recombinant Tissue Plasminogen Activator Therapy for Acute Basilar Artery Ischemic Stroke Following Transfemoral Transcatheter Aortic Valve Implantation. AB - Transcatheter aortic valve implantation (TAVI) can now be considered a standard of care for inoperable and high-risk surgical patients with severe aortic stenosis, and its uptake worldwide is rapidly increasing. Indeed, many centers performing the procedure have now moved towards treating intermediate-risk patients with TAVI rather than referring them for surgical aortic valve replacement. Although the incidence of peri-procedural acute and subacute stroke following TAVI has fallen to 2-5%, its occurrence can be life-threatening and life-changing, and every effort must be made to improve patient outcome should stroke occur. Many cardiologists would not instinctively consider the use of thrombolytic therapy for post-transfemoral TAVI ischemic stroke because of concern about the risk of major bleeding from the access site, despite it being a standard of care for ischemic stroke in other circumstances. The present case highlights the benefit of using intravenous thrombolytic therapy for an acute basilar artery thrombotic stroke after transfemoral TAVI (TF-TAVI) that would otherwise have almost certainly resulted in the patient's death. The case may also prompt interventional cardiologists to consider performing TF-TAVI under conscious sedation rather than general anesthesia, as this can result in an earlier detection of acute stroke and allow an earlier intervention with thrombolytic agents, with an improved outcome. PMID- 27989079 TI - Syphilitic Aortitis Presenting with Coronary Ostial Stenosis and Aortic Regurgitation. AB - Bilateral coronary ostial stenosis without additional coronary artery involvement is a rare presentation of syphilitic aortitis, with most cases being identified post-mortem. Herein is presented a case of bilateral coronary ostial stenosis and aortic valve insufficiency caused by syphilitic aortitis without aneurysmal dilatation of the aorta. The patient underwent aortic root replacement and coronary artery bypass grafting. The intraoperative macroscopic findings raised the suspicion of an aortitis that was later confirmed to syphilitic aortitis on histological examination. It is of note that syphilis can be a cause of bilateral ostial stenosis in young adults with no predisposition to atherosclerosis, especially if combined with aortic insufficiency resulting from an isolated leaflet dysfunction. PMID- 27989080 TI - Immediate Outcomes of Aortic Valve Replacement with Sutureless versus Stentless Bioprosthesis. AB - BACKGROUND: Aortic valve replacement (AVR) with a sutureless valve is an innovative therapy in high-risk elderly patients. The study aim was to compare the early results of AVR using sutureless aortic valves or stentless aortic bioprostheses. METHODS: A retrospective analysis was conducted of 55 patients who underwent AVR with either a sutureless valve (Perceval S; n = 24 or Edwards Intuity; n = 9) or a stentless valve (Sorin Freedom SOLOTM; n = 22). RESULTS: Baseline patient characteristics were similar in both groups, except for NYHA class. Concomitant procedures were performed in 17 patients (51.5%) of the sutureless group and in nine patients (40.9%) of the stentless group (p = 0.44). The aortic cross-clamp time was 55 +/- 23 min in the sutureless group and 102 +/- 36 min in the stentless group (p <0.0001), while the postoperative peak aortic gradient was 19.5 +/- 5.0 mmHg and 29.3 +/- 15.4 mmHg for the sutureless group and stentless group, respectively (p = 0.037). The postoperative mean gradient was 9.3 +/- 3.4 mmHg for the sutureless group and 15.1 +/- 10.5 mmHg for the stentless group (p = 0.06). Blood product transfusion was required less frequently by the sutureless group, but drainage and bleeding was similar in both groups. The intensive care unit and hospital stays were significantly shorter in favor of the sutureless group. One sutureless patient (3.0%) and two stentless patients (9.1%) died in hospital (p = 0.557). CONCLUSIONS: Early results of the present study suggested that surgical AVR with a sutureless valve is associated with a good hemodynamic performance and an improved early outcome. PMID- 27989081 TI - Value of Combined Circumferential and Longitudinal Left Ventricular Systolic Dysfunction to Predict Adverse Outcome in Patients with Asymptomatic Aortic Stenosis. AB - BACKGROUND AND AIM OF THE STUDY: Patients with asymptomatic aortic stenosis (AS) may have left ventricular systolic dysfunction (LVSD) defined as an impairment of the circumferential and/or longitudinal (C&L) myocardial fibers, despite a preserved left ventricular ejection fraction (LVEF). An assessment was made as to whether the combined LVSD of C&L fibers has a prognostic impact in asymptomatic AS.METHODS: A total of 200 asymptomatic AS patients was analyzed. Midwall shortening and mitral annular peak systolic velocity were considered as indices of C&L function and classified as low if <16.5% and <8.5 cm/s, respectively. The primary outcome was a composite of major cardiovascular events (MACE), including aortic valve-related and ischemic cardiovascular-related events.RESULTS: During a 25-month follow up period, MACE occurred in 69 patients (35%),while 46 of 72 patients (64%) had C&L LVSD and 23 of 128 patients (18%) had not (p <0.001). Cox analysis identified C&L LVSD as an independent MACE predictor, together with aortic transvalvular peak gradient, E/E' ratio and excessive left ventricular mass. C&L-LVSD also predicted the occurrence of aortic valve-related events and ischemic cardiovascular-related events analyzed separately. A receiver operating characteristic curve analysis showed that the area under the curve (AUC) for C&L LVSD in predicting MACE was 0.77, significantly higher (p = 0.002, z-statistic) than the AUCs of C&L fibers considered individually (0.64 and 0.63, respectively).CONCLUSION: C&L-LVSD provides additional prognostic information into traditional risk factors for patients with asymptomatic AS. PMID- 27989082 TI - Impact of Prosthesis-Patient Mismatch after Mitral Valve Replacement. AB - BACKGROUND: The study aim was to determine the impact of prosthesis-patient mismatch (PPM) on early and late clinical outcomes, left atrial and ventricular remodeling, late tricuspid valve regurgitation and pulmonary hypertension (PH) in patients after mitral valve replacement (MVR). METHODS: A total of 46 patients (mean age 66 +/- 9.3 years) with mitral valve diseases and undergoing isolated MVR was enrolled in the study. The mitral valve effective orifice area (EOA) was determined using the continuity equation and indexed for the patient's body surface area (EOAi). PPM was defined as EOAi <=1.2 cm2/m2. PH was defined as a systolic pulmonary artery pressure (sPAP) >40 mmHg. Both, clinical and echocardiographic follow up were performed. RESULTS: PPM was identified in 25% of patients, but no significant differences were observed in baseline and operative characteristics when comparing patients with and without PPM. The NYHA class was improved in most cases after surgery. Indeed, significant decreases in mean transvalvular gradient (from 8.6 +/- 2.8 mmHg to 5 +/- 1.3 mmHg, p = 0.001), left atrial dimension (LAD) (from 31.9 +/-9.8 mm to 29.5 +/- 7 mm, p = 0.011), left ventricular end-systolic diameter (from 42.6 +/- 18.1 mm to 35.5 +/- 6.6 mm, p = 0.044) and left ventricular end-diastolic diameter (from 55.8 +/- 19.2 mm to 48.7 +/- 6.1 mm, p = 0.024) were observed over time when comparing preoperative and postoperative echocardiographic data. In addition, at follow up (mean 6.9 +/- 1.8 years) there were significant decreases in LAD (from 31.9 +/- 9.8 mm to 28 +/- 11.1 mm, p = 0.001), left ventricular enddiastolic volume (from 106.9 +/- 32.9 ml to 92.3 +/- 21.9 ml, p = 0.024), tricuspid regurgitation (TR) (from 87% to 27%, p = 0.002) and PH (from 78.3% to 58.7%, p = 0.043) in all patients. No significant differences were observed in hemodynamic, clinical outcome and atrial natriuretic peptide levels of patients with and without PPM. CONCLUSIONS: Mitral PPM does not appear to have any negative effect on ventricular and atrial remodeling, TR and PH during the early and late postoperative periods. PMID- 27989083 TI - Untreated Mitral Regurgitation Does Not Affect Survival of Elderly Patients Undergoing TAVI. AB - BACKGROUND: The study aim was to examine the impact of concomitant significant mitral regurgitation (MR) in patients undergoing transcatheter aortic valve implantation (TAVI). TAVI has become an acceptable mode of treatment for high surgical risk patients with aortic stenosis (AS) requiring valve replacement. A significant number of patients have concomitant MR which cannot be addressed by TAVI alone, and therefore may not be considered candidates for this procedure. A comparison was conducted of results obtained from patients undergoing TAVI with or without MR. METHODS: Between 2008 and 2013, a total of 164 patients (mean age 81 +/- 8 years) underwent TAVI at the authors' institution. Of these patients, 87 (53%) had MR of moderate or greater degree. The groups were similar with respect to age, gender, presence of congestive heart failure, left ventricular function and co-morbid conditions. The logistic EuroSCORE was higher in the MR group (p = 0.02). RESULTS: Procedural (30-day) mortality was 12% (n = 19) and similar between groups. Kaplan-Meier estimates showed the overall survival at three years to be 68% and 76% for the MR and non-MR groups, respectively (p = 0.6). By Cox regression, age (p = 0.007) and peripheral vascular disease (p = 0.03) were the only predictors of late survival. Regression of MR was seen in patients with functional MR. Neither the presence of MR nor residual MR emerged as predictors of late mortality. CONCLUSIONS: In elderly patients undergoing TAVI the presence of MR does not impact survival. TAVI should not be withheld from this group of patients because of concomitant MR. PMID- 27989084 TI - Impact of Chronic Rheumatic Valve Diseases on Large Vessels. AB - BACKGROUND AND AIM OF STUDY: Rheumatic valvular heart disease, which remains a common health problem in developing countries, has numerous consequences on the heart chambers and circulation. The study aim was to investigate the effects of chronic rheumatic valve disease on the diameters of the descending aorta (DA) and inferior vena cava (IVC).METHODS: A total of 88 patients with echocardiographically documented rheumatic valvular heart disease and 112 healthy controls were enrolled into the study. All patients underwent detailed echocardiographic examinations, while their height and body weight were recorded and adjusted to their body surface area.RESULTS: The most common involvement was mitral valve disease, followed by aortic valve disease and tricuspid valve disease. The mean diameter of the DA (indexed to BSA) was 1.79 +/- 0.49 cm for patients and 1.53 +/- 0.41 for controls (p <0.001). The mean diameter of the IVC (indexed to BSA) was 1.69 +/- 0.73 for patients and 1.38 +/- 0.35 cm for controls (p <0.001). There was a significant positive correlation between mitral valve mean gradient and IVC diameter (p = 0.01, r = 0.18). There were also strong associations between the mitral valve area and the diameters of the DA (p = 0.001, r = -0.239) and IVC (p <0.001, r = -0.246).CONCLUSION: Rheumatic valve disease, especially mitral stenosis, was closely related to remodeling of the great vessels. PMID- 27989085 TI - Impaired Left Ventricular Function Does Not Predict Worse Late Outcome after Isolated Mitral Valve Surgery. AB - BACKGROUND AND AIM OF THE STUDY: The best timing for mitral valve surgery remains controversial. Decreased left ventricular function (LVF) is considered to be a predictor for increased mortality and is therefore an indication for surgery. The study aim was to investigate the independent effect of preoperative LVF on early and late mortality after mitral valve surgery.METHODS: Patients undergoing isolated mitral valve surgery between January 1998 and December 2010 at a single center were included for the analysis. Patients without recorded LVF, with active endocarditis, or patients lost to follow up were excluded. Patients were allocated to three groups based on their left ventricular ejection fraction (LVEF) measured using echocardiography as good (>50%), moderate (35-50%) or poor (<35%). A Cox regression analysis was performed to identify independent risk factors for late survival.RESULTS: A total of 549 patients underwent isolated mitral valve surgery. The 30-day mortality was not statistically different between groups (p = 0.579), and late survival was similar in all groups (log rank, p = 0.130). A moderate or poor LVF was not identified as a risk factor for late mortality (HR 1.4 [0.9-2.2], p = 0.179; HR 1.8 [0.7-4.4], respectively, p = 0.213). The difference remained insignificant after correction for other risk factors (HR 1.4 [0.8-2.3], p = 0.192; HR 2.4 [0.9-6.7], respectively, p = 0.09).CONCLUSION: A reduced LVF is not an independent risk factor for short- and long-term all-cause mortality in patients undergoing isolated mitral valve surgery for non-ischemic mitral valve disease. PMID- 27989086 TI - Triple Percutaneous Mitral Balloon Valvuloplasty for Patients with Recurrent Mitral Valve Stenosis: Long-Term Observations. AB - BACKGROUND: A third percutaneous mitral balloon valvuloplasty (PMBV) may provide a means of treating symptomatic patients with re-restenosis after successful initial and second valvuloplasties, though data related to the long-term safety and efficacy of a third PMBV are lacking. The study aim was to determine the immediate and long-term clinical outcome in patients who underwent a third PMBV to treat recurrent mitral stenosis. METHODS: Among a total of 1,849 patients who underwent PMBV at the authors' institution, seven females (mean age 38.5 +/- 12.2 years at the first procedure) required repeat second and third PMBVs. The mean interval between the first and second valvuloplasties was 6.4 +/- 2.5 years, and between the first and third valvuloplasties was 12.5 +/- 6.5 years. All procedures were performed using the Inoue balloon system. RESULTS: Second and third PMBVs resulted in a significant increase in mitral valve area (MVA), from 1.1 +/- 0.1 cm2 to 1.6 +/- 0.2 cm2, and from 1.0 +/- 0.2 cm2 to 1.6 +/- 0.4 cm2, respectively. However, as mitral degeneration progressed, four patients required mitral valve replacement (MVR) at 9.2 +/- 5.8 years (range: 6-18 years) after the third PMBV. The preoperative MVA of these patients was 0.97 +/- 0.1 cm2. One patient died due to surgical complications, while the fifth and sixth patients remain under clinical observation. If patients have a fourth recurrence of mitral stenosis they are no longer considered to be suitable candidates for re-PMBV. The seventh patient died at the age of 84 years. CONCLUSIONS: A repeat, third PMBV is a safe and feasible procedure in selected patients with recurrent stenosis after successful first and second valvuloplasties. Although the third procedure provides good immediate results, the long-term outcome is not satisfactory. Nonetheless, a third PMBV would allow MVR surgery to be postponed for a few years. PMID- 27989087 TI - The Double-Orifice Valve Technique to Treat Tricuspid Valve Incompetence. AB - BACKGROUND: A straightforward tricuspid valve (TV) repair technique was used to treat either moderate or severe functional (normal valve with dilated annulus) or for primary/organic (Ebstein's anomaly, leaflet retraction/tethering and chordal malposition/tethering, with annular dilatation) TV incompetence, and its long term outcome assessed. METHODS: A double-orifice valve technique was employed in 91 patients (mean age 52.6 +/- 23.2 years; median age 56 years; range: 0.6-82 years) with severe tricuspid regurgitation. Among the patients, three had post transplant iatrogenic chordal rupture, five had infective endocarditis, 11 had mitral valve insufficiency, 23 had Ebstein's anomaly, and 47 had isolated severe TV incompetence. The basic principle was to reduce the distance between the coapting leaflets, wherein the most mobile leaflet could coapt to the opposite leaflet, by creating two orifices, ensuring valve competence. The TV repair was performed through a median sternotomy or right anterior thoracotomy in the fifth intercostal space under cardiopulmonary bypass. The degree and extent of creating a double-valve orifice was determined by considering the minimal body surface area (BSA)-related acceptable TV diameter. Repair was accomplished by passing pledgeted mattress sutures from the middle of the true anterior annulus to a spot on the opposite septal annulus, located approximately two-thirds of the length of the septal annulus to avoid injury to the bundle of His. The annular apposition divides the TV into a larger anterior and a smaller posterior orifices, enabling valve closure, on both sides. In adults, the diameter of the anterior valve orifice should be 23-25 mm, and the posterior orifice 15-18 mm; thus, the total valve orifice area is 5-6 cm2. In children, the total valve orifice should be a standard deviation of 1.7 mm for a BSA of <1. 0m2, and 1.5 mm for a BSA of >1.0m2. RESULTS: During a mean follow up of 8.7 +/- 1.34 years (median 10 years; range: 1.5-25.9 years) there have been no reoperations for TV insufficiency or stenosis. Reoperations on three patients (mean age 42.5 +/- 8.7 years) were indicated for aortic valve replacement at 14 months postoperatively (n = 1) and for assist device implantation (n = 2) who eventually underwent heart transplant at 18 and 20 months after TV repair, respectively. The cumulative 12-year survival rate was 86.9%. CONCLUSIONS: This double-orifice technique is technically a straightforward repair to abolish TV incompetence with highly satisfactory results, particularly in patients with severe annular dilatation or with leaflet and chordal tethering. In the present series, the technique provided no pitfalls (if the location of the conduction system was borne in mind), requiring only a gentle placement of sutures. It also led to no residual regurgitation or reoperation during the follow up period. PMID- 27989088 TI - Not So EASE-Y: How Often do Hospitalized Infective Endocarditis Patients Meet Criteria for Early Surgery? AB - Infective endocarditis (IE) has historically caused significant morbidity and mortality. Valve surgery reduces systemic embolization and mortality, but the optimal timing is controversial. The EASE (Early Surgery Versus Conventional Treatment for Infective Endocarditis) trial, which employed strict inclusion and exclusion criteria, showed that early surgery could reduce the risk of embolic events for a subset of patients. The aim of the present study was to determine the proportion of adult IE patients seen in usual clinical practice at a single tertiary medical center that would meet EASE enrollment criteria. Over a four year period, only 10 of 88 patients (11.3%) were found to meet EASE enrollment criteria. These results have important research implications, and highlight the differences between populations of patients used in clinical trials and patients seen in practice. PMID- 27989089 TI - Thrombocytopenia after Aortic Valve Replacement with Perceval S Sutureless Bioprosthesis. AB - BACKGROUND AND AIM OF THE STUDY: Sutureless aortic bioprosthetic valves have become an alternative to conventional bioprostheses in high surgical risk cases. A significant decline in platelet count during the immediate postoperative period was observed in cases of Perceval S sutureless aortic valve implantation. The study aim was to determine how the reduction in platelet count after Perceval S prosthesis implantation compared to that after other bioprosthesis implants.METHODS: Between July 2011 and July 2014, a total of 77 isolated biological aortic valve replacements (AVRs) was performed at the authors' institution. These included 27 Perceval S prostheses (35.1%) and 50 Mitroflow prostheses (64.9%). Platelet counts and mean platelet volumes (MPVs) were determined on the day before surgery (T0) and at 24 h (T1), 48 h (T2) and 72 h (T3) after surgery.RESULTS: There were no significant differences in inhospital mortality (three Perceval S (11.1%) versus four Mitroflow 8%); p = 0.65), nor in morbidity between groups. A total of 16 patients (20.8%) had severe postoperative thrombocytopenia (<50*103/mm3). The incidence of severe thrombocytopenia was significantly higher (p = 0.046) in Perceval S patients (n = 9; 33.3%) than in Mitroflow patients (n = 7; 14%). The platelet count recovered in all patients with severe thrombocytopenia. In an adjusted-propensity multivariate logistic regression analysis, the Perceval S prosthesis was the major independent predictor of severe thrombocytopenia after AVR (OR 0.06, 95% CI: 0008-0.5, p = 0.009).CONCLUSION: Aortic bioprosthesis implantation with the Perceval S sutureless bioprosthesis appears to be associated with the occurrence of postoperative thrombocytopenia, though without any clinical implication for the patients. Prospective randomized trials are required to confirm these data. PMID- 27989090 TI - Biomechanical Properties of Fiber Bundle and Membrane Mesostructures of the Porcine Aortic Valve. AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve leaflets have a complex, anisotropic structure that likely plays an important role in their biomechanical function. The larger scale (bulk) biomechanical properties of the valve have been well documented. However, limited data are available regarding the biomechanical properties of individual fiber bundles and membranes that connect the bundles. The study aim was to characterize these intermediate-scale 'mesostructures' and explore biomechanical variability across the three leaflets of the aortic valve.Methods: A custom uniaxial micro-testing system was developed to test mesostructures of the aortic valve leaflet. This system uses elliptically polarized light to enhance collagen features, providing 'texture' for image correlation-based strain measurements. Porcine aortic valve membrane and fiber bundle specimens were subjected to controlled stretch-and-hold tests. Synchronized video and load data were used to measure strain, elastic modulus, relaxation time, and degree of relaxation (among other parameters). These metrics were then compared between specimen types and across the three leaflets.METHODS: A custom uniaxial micro-testing system was developed to test mesostructures of the aortic valve leaflet. This system uses elliptically polarized light to enhance collagen features, providing 'texture' for image correlation-based strain measurements. Porcine aortic valve membrane and fiber bundle specimens were subjected to controlled stretch-and-hold tests. Synchronized video and load data were used to measure strain, elastic modulus, relaxation time, and degree of relaxation (among other parameters). These metrics were then compared between specimen types and across the three leaflets.RESULTS: Fiber bundles were found to have a significantly higher elastic modulus (13.87 +/- 2.81 MPa) than the membranes (2.27+/- 0.36 MPa). Both specimen types had similar relaxation time constants (6.75 +/- 0.73 s) and degrees of relaxation (0.223 +/- 0.016). The elastic modulus of the fiber bundles from the left coronary and non-coronary leaflets was significantly higher than that of the right coronary leaflet. The fiber bundle elastic modulus also negatively correlated with the fiber bundle width.CONCLUSION: The resulting differences in biomechanical properties of mesostructures are likely related to their biomechanical and hemodynamic requirements. The study findings highlight the importance of considering aortic valve leaflets as inhomogeneous. Further studies are required to characterize the morphologies, nonaffine deformations, and biomechanical properties of the valve's complex fiber-membrane mesostructures, potentially enabling the development of improved models and designs for durable replacement/repair strategies. PMID- 27989091 TI - Transcatheter Valve-in-Valve Implantation in a Degenerated Mitral Bioprosthesis Using a Trans-Septal Anterograde Approach and 3-D Transesophageal Echocardiography Guidance. AB - Degenerated and dysfunctional prosthetic valves are usually replaced surgically. However, repeated cardiac surgery can cause prohibitive risk, especially in patients with many associated co-morbidities. Transcatheter valve-in-valve implantation (TVIV) is a novel, technically very challenging, but less invasive alternative treatment for patients with unacceptably high surgical risk of degenerated prosthetic valves. The method is attractive because it takes advantage of the presence of the degenerated prosthesis, which serves as an anchoring zone. Here, the case is presented of TVIV in an 82-year-old female with significant stenosis of a biological mitral prosthesis. In 2011, Himbert et al. were the first to successfully insert a transcatheter heart valve in the mitral ring using a transfemoral approach. To date, only a small case series has been reported on the effectiveness of TVIV using a transfemoral venous access and a trans-septal anterograde approach. The present patient was the first in which TVIV was performed in Poland and Eastern Europe. PMID- 27989092 TI - Ventricular Embolization of Two Edwards SAPIEN XT Prosthetic Valves During Trans Subclavian Aortic Valve Implantation. AB - Transcatheter aortic valve implantation (TAVI) is an alternative treatment method in high-risk patients with severe aortic stenosis (AS). Although TAVI is a minimally invasive procedure it is not free from complications. Here, the case is presented of a 61-year-old woman who underwent trans-subclavian aortic valve implantation to treat severe symptomatic rheumatic AS. The procedure was complicated by the ventricular embolization of two Edwards SAPIEN XT valves during the procedure, but was successfully managed with emergency open-heart surgery. PMID- 27989093 TI - Experimental Study on the In-Vivo Heterotopic Transplantation of Aortic Valved Homografts after De-Endothelialization. AB - BACKGROUND AND AIM OF THE STUDY: The study aims were to monitor the changes in tissue morphology, calcium content and CD40 expression in the in-vivo heterotopic transplantation of aortic valved homografts after de-endothelialization, and to seek better methods for preventing calcification and degeneration of the homograft valves.METHODS: Adult, healthy, inbred male Chinese rabbits were used as donors, and inbred adult female New Zealand White rabbits as recipients for the heterotopic transplantation of aortic valved homografts with abdominal aorta. Controls received aortic valved homografts without treatment, while the de endothelialization group received aortic valved homografts after de endothelialization. For the cryopreservation group, aortic valved homografts were treated with 10% dimethyl sulfoxide and cryopreserved in liquid nitrogen for 60 days. Recipients were randomly allocated to three groups (n = 20 per group). Grafts were removed after two, four, eight and 12 weeks of surgery and observed with light microscopy. Calcium concentrations were monitored using flame atomic absorption, and CD40 expressions with immunohistochemistry.RESULTS: At two weeks after transplantation, the calcium contents of the fresh, de-endothelialization and cryopreservation groups were similar (p >0.05). The calcium content at four, eight and 12 weeks in the fresh and cryopreservation groups was significantly higher than that in the de-endothelialization group (p <0.01), while at two, four and eight weeks after transplantation, CD40 expression in the fresh and cryopreservation groups was significantly different from that in the de endothelialization group (p <0.01).CONCLUSION:The calcium content in valve homografts was found to correlate with immune rejection. De-endothelialization could reduce immune rejection reactions and prevent calcification of aortic homograft valve. PMID- 27989095 TI - Quadruple Valve Reoperation after the Ross Procedure. AB - Reoperations after the Ross procedure are rare, with autograft as well as homograft failure being the dominant causes for redo cardiac procedures. Due to increasing experience with valve-sparing aortic valve procedures, more valves can be preserved during redo surgery. Herein are reported the details of a patient who underwent quadruple valve reoperation comprising redo with a reconstructive approach after the short-term failure of pulmonary autograft and homograft with concomitant mitral and tricuspid regurgitation. PMID- 27989094 TI - Histopathological and Immunohistochemical Evaluation of Pannus Tissue in Patients with Prosthetic Valve Dysfunction. AB - BACKGROUND: Prosthetic valve dysfunction due to pannus formation is a rare but serious complication. Currently, limited data are available concerning the pathogenesis and immunohistochemical properties of pannus. The study aim was to investigate the morphological, histopathological and immunohistochemical characteristics of pannus formation in patients with prosthetic valve dysfunction. METHODS: A total of 35 patients (10 males, 25 females; mean age 44 +/- 16 years) who had undergone re-do valve surgery due to prosthetic valve obstruction was enrolled in the study. Immunohistochemical studies were aimed at evaluating the expression of alphasmooth muscle actin (alpha-SMA) and desmin in myofibroblasts and smooth muscle cells; epithelial membrane antigen (EMA) in epithelial cells; and CD34, Factor VIII and vascular endothelial growth factor (VEGF) in endothelial cells. Matrix metalloproteinases (MMPs) -2 and -9, and transforming growth factor-beta (TGF-beta) were used to demonstrate cytokine release from macrophages, leukocytes, fibroblasts and myofibroblasts. RESULTS: Pannus appeared as a tough and thick tissue hyperplasia which began from outside the suture ring in the periannular region and extended to the inflow and outflow surfaces of the prosthetic valves. Histopathological analysis showed the pannus tissue to consist of chronic inflammatory cells (lymphocytes, plasma cells, macrophages and foreign body giant cells), spindle cells such as myofibroblasts, capillary blood vessels and endothelial cells laying down the lumens. Calcification was present in the pannus tissue of 19 explanted prostheses. Immunohistochemical studies revealed positive alpha-SMA expression in all patients, whereas 60.5% of patients were positive for desmin, 50% for EMA, 42.1% for VEGF, 39.5% for TBF-beta, 42.1% for MMP-2, 86.8% for CD34, and 97.4% for Factor VIII. MMP-9 was negative in all patients. CONCLUSIONS: Pannus tissue appears to be formed as the result of a neointimal response in periannular regions of prosthetic valves that consist of periannular tissue migration, myofibroblast and extracellular matrix proliferation with vascular components. It is a chronic active process in which mediators such as TGF-beta, VEGF and MMP-2 play roles in both matrix formation and degradation. PMID- 27989096 TI - Abiotrophia defectiva Endocarditis Complicated by Ventricular Tachycardia. AB - A 78-year-old man was admitted to the authors' hospital with a short history of shortness of breath and pyrexia. He had long-standing moderate mitral regurgitation and stable coronary artery disease. Blood cultures grew Abiotrophia defectiva coccobaccili. Transesophageal echocardiography confirmed the diagnosis of mitral valve endocarditis that necessitated treatment with intravenous benzylpenicillin and gentamicin for six weeks. At nine days after admission the patient developed several episodes of self-limiting monomorphic ventricular tachycardia, without ischemic cardiac pain, associated with hemodynamic compromise requiring treatment with intravenous amiodarone and inotropic support in the Intensive Care Unit. The patient made an uneventful recovery. This case report demonstrates that patients with A. defective endocarditis may be associated with life-threatening ventricular tachycardia, and more so if they have underlying coronary artery disease. Hence, these patients are better managed in the Coronary Care Unit with continuous electrocardiogram monitoring, especially in the early stages of the antibiotic treatment. PMID- 27989097 TI - Left Atrial Reservoir Function in Symptomatic Versus Asymptomatic Patients with Moderate Mitral Stenosis. AB - BACKGROUND AND AIM OF THE STUDY: Deformation of the left atrium during the reservoir phase may provide information regarding potential preclinical heart disease, but at present insufficient data are available concerning left atrial (LA) reservoir function in valvular heart disease. The study aim was to assess LA reservoir function in patients with moderate mitral stenosis (MS), and its relation to the patient's clinical status.METHODS: A total of 40 patients (31 females, nine males; mean age 29.47 +/- 19.1 years) with isolated moderate MS and in sinus rhythm were allocated to either symptomatic or asymptomatic groups (n = 20 in each group). All patients provided their complete medical history, were examined clinically and underwent transthoracic echocardiography to assess MS severity, systolic pulmonary artery pressure (SPAP), mean pulmonary artery pressure (MPAP), left atrial maximal volume (LAV(max)), left atrial minimal volume (LAV(min)), and indices of left atrial reservoir function, including total left atrial emptying volume Tot(empVol), indexed Tot(empVol), and total left atrial emptying fraction (LAEF). RESULTS: Symptomatic patients showed a significantly higher mean LAV(max) (79.25 +/- 19.12 versus 70.65 +/- 13.34 ml, p = 0.022), LAV(min) (54.63 +/- 6.68 versus 47.1 +/- 12.87 ml, p = 0.029), Tot(empVol) (23.83 +/- 5.33 versus 18.4 +/- 7.13 ml, p = 0.01), indexed Tot(empVol) (14.73 +/- 2.49 versus 12.53 +/- 3.18 ml/m2, p = 0.02), SPAP (44.35 +/- 7.79 versus 32.65 +/- 10.6 mmHg, p = 0.002), and MPAP (37.60 +/- 10.78 versus 30.46 +/- 7.55 mmHg, p = 0.02) and a significantly lower mean LAEF (30.40 +/- 7.26 versus 36.13 +/- 6.37%, p = 0.011). Significant negative correlations were noted between LAEF with SPAP, LAV(max) and LAV(min). Further significant associations were detected for the symptomatic group between LAEF (r = -0.43) and mitral valve area (r = -0.37). Similarly, multivariate linear regression analysis revealed a significant negative association between presence in the symptomatic group and LAEF (beta = -4.78, SE = 2.22, p <0.05). Finally, Tot(empVol) was the strongest predictor of LAEF (beta = 1.23).CONCLUSION: LA reservoir function is impaired in symptomatic patients with moderate MS. PMID- 27989098 TI - Analysis of the Early Results of 693 Patients Undergoing Valvular Reoperation Between 1993 and 2011. AB - BACKGROUND: The study aim was to identify factors affecting early mortality in valvular reoperations. METHODS: Between January 1993 and December 2011, a total of 693 patients who had undergone valvular reoperations due to problems with previously implanted mechanical and biological valves, new valve degeneration or valve failure after a reconstructive procedure was included in the study. Factors affecting early mortality were identified by the examination of preoperative and perioperative data, using multivariate analysis. RESULTS: The average age of the patients was 44.9 years. For all patients, overall hospital mortality was 15.9%, while hospital mortality rates were 12.9% and 35.3% for elective operation and urgent/emergency treatment, respectively. Factors affecting early mortality in the multivariate analysis were longer total perfusion time (>120 min, p = 0.001), emergency or urgent treatment (p = 0.001), and the presence of preoperative renal failure (p = 0.001). CONCLUSIONS: Mortality for elective patients in valvular reoperations was within an acceptable range. Total mortality was dependent on a high mortality level of emergency/urgency of the cases. The use of a well-defined protocol in valvular reoperations may decrease hospital mortality. PMID- 27989099 TI - Clinicopathologic Significance of Survivin Expression in Relation to CD133 Expression in Surgically Resected Stage II or III Colorectal Cancer. AB - BACKGROUND: Cancer stem cells have been investigated as new targets for colorectal cancer (CRC) treatment. We recently reported that CD133+ colon cancer cells showed chemoresistance to 5-fluorouracil through increased survivin expression and proposed the survivin inhibitor YM155 as an effective therapy for colon cancer in an in vitro study. Here, we investigate the relationship between survivin and CD133 expression in surgically resected CRC to identify whether the results obtained in our in vitro study are applicable to clinical samples. METHODS: We performed immunohistochemical staining for survivin and CD133 in surgically resected tissue from 187 stage II or III CRC patients. We also comparatively analyzed apoptosis according to survivin and CD133 expression using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling. RESULTS: The results of the Mantel-Haenszel test established a linear association between nuclear survivin and CD133 expression (p = .018), although neither had prognostic significance, according to immunohistochemical expression level. No correlation was found between survivin expression and the following pathological parameters: invasion depth, lymph node metastasis, or histologic differentiation (p > .05). The mean apoptotic index in survivin+ and CD133+ tumors was higher than that in negative tumors: 5.116 +/- 4.894 in survivin+ versus 4.103 +/- 3.691 in survivin- (p = .044); 5.165 +/- 4.961 in CD133+ versus 4.231 +/- 3.812 in CD133- (p = .034). CONCLUSIONS: As observed in our in vitro study, survivin expression is significantly related to CD133 expression. Survivin may be considered as a new therapeutic target for chemoresistant CRC. PMID- 27989100 TI - PD-L1 Expression and Combined Status of PD-L1/PD-1-Positive Tumor Infiltrating Mononuclear Cell Density Predict Prognosis in Glioblastoma Patients. AB - BACKGROUND: Programmed death ligand 1 (PD-L1) in tumor cells is known to promote immune escape of cancer by interacting with programmed cell death 1 (PD-1) in tumor infiltrating immune cells. Immunotherapy targeting these molecules is emerging as a new strategy for the treatment of glioblastoma (GBM). Understanding the relationship between the PD-L1/PD-1 axis and prognosis in GBM patients may be helpful to predict the effects of immunotherapy. METHODS: PD-L1 expression and PD 1-positive tumor infiltrating mononuclear cell (PD-1+tumor infiltrating mononuclear cell [TIMC]) density were evaluated using tissue microarray containing 54 GBM cases by immunohistochemical analysis; the associations with patient clinical outcomes were evaluated. RESULTS: PD-L1 expression and high PD 1+TIMC density were observed in 31.5% and 50% of GBM cases, respectively. High expression of PD-L1 in tumor cells was an independent and significant predictive factor for worse overall survival (OS; hazard ratio, 4.958; p = .007) but was not a significant factor in disease-free survival (DFS). PD-1+TIMC density was not correlated with OS or DFS. When patients were classified based on PD-1 expression and PD-1+TIMC density, patients with PD-L1+/PD-1+TIMC low status had the shortest OS (13 months, p = .009) and DFS (7 months, p = .053). CONCLUSIONS: PD-L1 expression in GBM was an independent prognostic factor for poor OS. In addition, combined status of PD-L1 expression and PD-1+TIMC density also predicted patient outcomes, suggesting that the therapeutic role of the PD-1/PD-L1 axis should be considered in the context of GBM immunity. PMID- 27989101 TI - Cantharidin Overcomes Imatinib Resistance by Depleting BCR-ABL in Chronic Myeloid Leukemia. AB - Cantharidin (CTD) is an active compound isolated from the traditional Chinese medicine blister beetle and displayed anticancer properties against various types of cancer cells. However, little is known about its effect on human chronic myeloid leukemia (CML) cells, including imatinib-resistant CML cells. The objective of this study was to investigate whether CTD could overcome imatinib resistance in imatinib-resistant CML cells and to explore the possible underlying mechanisms associated with the effect. Our results showed that CTD strongly inhibited the growth of both imatinib-sensitive and imatinib-resistant CML cells. CTD induced cell cycle arrest at mitotic phase and triggered DNA damage in CML cells. The ATM/ATR inhibitor CGK733 abrogated CTD-induced mitotic arrest but promoted the cytotoxic effects of CTD. In addition, we demonstrated that CTD downregulated the expression of the BCR-ABL protein and suppressed its downstream signal transduction. Real-time quantitative PCR revealed that CTD inhibited BCR ABL at transcriptional level. Knockdown of BCR-ABL increased the cell-killing effects of CTD in K562 cells. These findings indicated that CTD overcomes imatinib resistance through depletion of BCR-ABL. Taken together, CTD is an important new candidate agent for CML therapy. PMID- 27989102 TI - Tazarotene-Induced Gene 1 Enhanced Cervical Cell Autophagy through Transmembrane Protein 192. AB - Tazarotene-induced gene 1 (TIG1) is a retinoic acid-inducible protein that is considered a putative tumor suppressor. The expression of TIG1 is decreased in malignant prostate carcinoma or poorly differentiated colorectal adenocarcinoma, but TIG1 is present in benign or well-differentiated tumors. Ectopic TIG1 expression led to suppression of growth in cancer cells. However, the function of TIG1 in cell differentiation is still unknown. Using a yeast two-hybrid system, we found that transmembrane protein 192 (TMEM192) interacted with TIG1. We also found that both TIG1A and TIG1B isoforms interacted and co-localized with TMEM192 in HtTA cervical cancer cells. The expression of TIG1 induced the expression of autophagy-related proteins, including Beclin-1 and LC-3B. The silencing of TMEM192 reduced the TIG1-mediated upregulation of autophagic activity. Furthermore, silencing of either TIG1 or TMEM192 led to alleviation of the upregulation of autophagy induced by all-trans retinoic acid. Our results demonstrate that the expression of TIG1 leads to cell autophagy through TMEM192. Our study also suggests that TIG1 and TMEM192 play an important role in the all trans retinoic acid-mediated upregulation of autophagic activity. PMID- 27989103 TI - Detecting Positive Selection of Korean Native Goat Populations Using Next Generation Sequencing. AB - Goats (Capra hircus) are one of the oldest species of domesticated animals. Native Korean goats are a particularly interesting group, as they are indigenous to the area and were raised in the Korean peninsula almost 2,000 years ago. Although they have a small body size and produce low volumes of milk and meat, they are quite resistant to lumbar paralysis. Our study aimed to reveal the distinct genetic features and patterns of selection in native Korean goats by comparing the genomes of native Korean goat and crossbred goat populations. We sequenced the whole genome of 15 native Korean goats and 11 crossbred goats using next-generation sequencing (Illumina platform) to compare the genomes of the two populations. We found decreased nucleotide diversity in the native Korean goats compared to the crossbred goats. Genetic structural analysis demonstrated that the native Korean goat and crossbred goat populations shared a common ancestry, but were clearly distinct. Finally, to reveal the native Korean goat's selective sweep region, selective sweep signals were identified in the native Korean goat genome using cross-population extended haplotype homozygosity (XP-EHH) and a cross-population composite likelihood ratio test (XP-CLR). As a result, we were able to identify candidate genes for recent selection, such as the CCR3 gene, which is related to lumbar paralysis resistance. Combined with future studies and recent goat genome information, this study will contribute to a thorough understanding of the native Korean goat genome. PMID- 27989105 TI - Temperature-Dependent Detectivity of Near-Infrared Organic Bulk Heterojunction Photodiodes. AB - Bulk heterojunction photodiodes are fabricated using a new donor-acceptor polymer with a near-infrared absorption edge at 1.2 MUm, achieving a detectivity up to 1012 Jones at a wavelength of 1 MUm and an excellent linear dynamic range of 86 dB. The photodiode detectivity is maximized by operating at zero bias to suppress dark current, while a thin 175 nm active layer is used to facilitate charge collection without reverse bias. Analysis of the temperature dependence of the dark current and spectral response demonstrates a 2.8-fold increase in detectivity as the temperature was lowered from 44 to -12 degrees C, a relatively small change when compared to that of inorganic-based devices. The near-infrared photodiode shows a switching speed reaching up to 120 MUs without an external bias. An application using our NIR photodiode to detect arterial pulses of a fingertip is demonstrated. PMID- 27989104 TI - DNA Demethylation of the Foxp3 Enhancer Is Maintained through Modulation of Ten Eleven-Translocation and DNA Methyltransferases. AB - Stable expression of Foxp3 is ensured by demethylation of CpG motifs in the Foxp3 intronic element, the conserved non-coding sequence 2 (CNS2), which persists throughout the lifespan of regulatory T cells (Tregs). However, little is known about the mechanisms on how CNS2 demethylation is sustained. In this study, we found that Ten-Eleven-Translocation (Tet) DNA dioxygenase protects the CpG motifs of CNS2 from re-methylation by DNA methyltransferases (Dnmts) and prevents Tregs from losing Foxp3 expression under inflammatory conditions. Upon stimulation of Tregs by interleukin-6 (IL6), Dnmt1 was recruited to CNS2 and induced methylation, which was inhibited by Tet2 recruited by IL2. Tet2 prevented CNS2 re methylation by not only the occupancy of the CNS2 locus but also by its enzymatic activity. These results show that the CNS2 methylation status is dynamically regulated by a balance between Tets and Dnmts which influences the expression of Foxp3 in Tregs. PMID- 27989106 TI - Virus-Enabled Biosensor for Human Serum Albumin. AB - The label-free detection of human serum albumin (HSA) in aqueous buffer is demonstrated using a simple, monolithic, two-electrode electrochemical biosensor. In this device, both millimeter-scale electrodes are coated with a thin layer of a composite containing M13 virus particles and the electronically conductive polymer poly(3,4-ethylenedioxy thiophene) or PEDOT. These virus particles, engineered to selectively bind HSA, serve as receptors in this biosensor. The resistance component of the electrical impedance, Zre, measured between these two electrodes provides electrical transduction of HSA binding to the virus-PEDOT film. The analysis of sample volumes as small as 50 MUL is made possible using a microfluidic cell. Upon exposure to HSA, virus-PEDOT films show a prompt increase in Zre within 5 s and a stable Zre signal within 15 min. HSA concentrations in the range from 100 nM to 5 MUM are detectable. Sensor-to-sensor reproducibility of the HSA measurement is characterized by a coefficient-of-variance (COV) ranging from 2% to 8% across this entire concentration range. In addition, virus PEDOT sensors successfully detected HSA in synthetic urine solutions. PMID- 27989108 TI - Quantification of Total N-Nitrosamine Concentrations in Aqueous Samples via UV Photolysis and Chemiluminescence Detection of Nitric Oxide. AB - N-Nitrosamines are potent mutagens and carcinogens that can be formed during oxidative water treatment. This study describes a novel method for the determination of total N-nitrosamines by UV-photolysis and subsequent chemiluminescence detection of nitric oxide. Denitrosation of N-nitrosamines was accomplished with a microphotochemical reactor consisting of a knitted reaction coil and a low-pressure mercury lamp. The detection limits for differing N nitrosamines ranged between 0.07 MUM (14 pmol injected) and 0.13 MUM (26 pmol injected). The nitric oxide formation from selected N-nitrosamines was linear (R2 = 0.98-0.99) from 0.1 to 10 MUM. The small cross-section and volume of the microphotochemical reactor used in this study was optimal to reach a sensitivity level comparable to chemical denitrosation-based methods. In addition, this method had several advantages over other similar methods: (i) compared to chemical denitrosation with copper monochloride or triiodide, the UV-photolysis does not require chemicals and is not affected by interferences of byproducts (e.g., formation of NOI), (ii) the reproducibility of replicates was enhanced compared to the triiodide-based method, and (iii) a commercially available photoreactor and NO analyzer were used. The application of this method for the determination of the N-nitrosamine formation potential of personal care products demonstrates its utility for assessing whether N-nitrosodimethylamine (NDMA) or other specific nitrosamines of current interest are dominant or minor components, respectively, of the total N-nitrosamine pool in technical aquatic systems or biological samples. PMID- 27989107 TI - Atomic H-Induced Mo2C Hybrid as an Active and Stable Bifunctional Electrocatalyst. AB - Mo2C nanocrystals (NCs) anchored on vertically aligned graphene nanoribbons (VA GNR) as hybrid nanoelectrocatalysts (Mo2C-GNR) are synthesized through the direct carbonization of metallic Mo with atomic H treatment. The growth mechanism of Mo2C NCs with atomic H treatment is discussed. The Mo2C-GNR hybrid exhibits highly active and durable electrocatalytic performance for the hydrogen-evolution reaction (HER) and oxygen-reduction reaction (ORR). For HER, in an acidic solution the Mo2C-GNR has an onset potential of 39 mV and a Tafel slope of 65 mV dec-1, and in a basic solution Mo2C-GNR has an onset potential of 53 mV, and Tafel slope of 54 mV dec-1. It is stable in both acidic and basic media. Mo2C-GNR is a high-activity ORR catalyst with a high peak current density of 2.01 mA cm-2, an onset potential of 0.93 V that is more positive vs reversible hydrogen electrode (RHE), a high electron transfer number n (~3.90), and long-term stability. PMID- 27989109 TI - Worm-Like Superparamagnetic Nanoparticle Clusters for Enhanced Adhesion and Magnetic Resonance Relaxivity. AB - Nanosized bioprobes that can highlight diseased tissue can be powerful diagnostic tools. However, a major unmet need is a tool with adequate adhesive properties and contrast-to-dose ratio. To this end, this study demonstrates that targeted superparamagnetic nanoprobes engineered to present a worm-like shape and hydrophilic packaging enhance both adhesion efficiency to target substrates and magnetic resonance (MR) sensitivity. These nanoprobes were prepared by the controlled self-assembly of superparamagnetic iron oxide nanoparticles (SPIONs) into worm-like superstructures using glycogen-like amphiphilic hyperbranched polyglycerols functionalized with peptides capable of binding to defective vasculature. The resulting worm-like SPION clusters presented binding affinity to the target substrate 10-fold higher than that of spherical ones and T2 molar MR relaxivity 3.5-fold higher than that of conventional, single SPIONs. The design principles discovered for these nanoprobes should be applicable to a range of other diseases where improved diagnostics are needed. PMID- 27989110 TI - Photochemistry of Thin Solid Films of the Neonicotinoid Imidacloprid on Surfaces. AB - Imidacloprid (IMD) is the most widely used neonicotinoid insecticide found on environmental surfaces and in water. Analysis of surface-bound IMD photolysis products was performed using attenuated total reflectance Fourier transfer infrared (ATR-FTIR) analysis, electrospray ionization (ESI-MS), direct analysis in real time mass spectrometry (DART-MS), and transmission FTIR for gas-phase products. Photolysis quantum yields (phi) for loss of IMD were determined to be (1.6 +/- 0.6) * 10-3 (1s) at 305 nm and (8.5 +/- 2.1) * 10-3 (1s) at 254 nm. The major product is the imidacloprid urea derivative (IMD-UR, 84% yield), with smaller amounts of the desnitro-imidacloprid (DN-IMD, 16% yield) product, and gaseous nitrous oxide (N2O). Theoretical calculations show that the first step of the main mechanism is the photodissociation of NO2, which then recombines with the ground electronic state of IMD radical to form IMD-UR and N2O in a thermally driven process. The photolytic lifetime of IMD at a solar zenith angle of 35 degrees is calculated to be 16 h, indicating the significant reaction of IMD over the course of a day. Desnitro-imidacloprid has been identified by others as having increased binding to target receptors compared to IMD, suggesting that photolysis on environmental surfaces increases toxicity. PMID- 27989111 TI - High-Resolution Analysis of Photoanodes for Water Splitting by Means of Scanning Photoelectrochemical Microscopy. AB - In pursuance of efficient tools for the local analysis and characterization of novel photoelectrocatalytic materials, several SECM-based techniques have been developed, aiming on the combined benefit of a local irradiation of the analyzed sample and a microelectrode probe for the localized electrochemical analysis of the surface. We present the development and application of scanning photoelectrochemical microscopy (SPECM) for the laterally resolved characterization of photoelectrocatalytic materials. Particularly, the system was developed for the photoelectrochemical characterization of n-type semiconductor based photoanodes for water splitting. By using the tip microelectrode simultaneously for local irradiation and as an electrochemical probe, SPECM was capable to simultaneously provide information about the local photocurrent generated at the sample under irradiation and to detect the photoelectrocatalytically evolved oxygen at the microelectrode. In combination with a novel means of irradiation of the interrogated sample, local analysis of semiconductor materials for light-induced water splitting with improved lateral resolution is achieved. PMID- 27989112 TI - Gold Nanoparticle Modified Transparent Carbon Ultramicroelectrode Arrays for the Selective and Sensitive Electroanalytical Detection of Nitric Oxide. AB - Transparent carbon ultramicroelectrode arrays (T-CUAs) were made using a previously reported facile fabrication method (Duay et al. Anal. Chem. 2015, 87, 10109). Two modifications introduced to the T-CUAs were examined for their analytical response to nitric oxide (NO*). The first modification was the application of a cellulose acetate (CA) gas permeable membrane. Its selectivity to NO* was extensively characterized via chronoamperometry, electrochemical impedance spectroscopy (EIS), and atomic force microscopy (AFM). The thickness of the CA membrane was determined to be 100 nm and 88 +/- 15 nm using AFM and EIS, respectively. Furthermore, the partition and diffusion coefficients of NO* within the CA membrane were determined to be 0.0500 and 2.44 * 10-13 m2/s using EIS measurements. The second modification to the 1.54T-CUA was the introduction of chitosan and gold nanoparticles (CS/GNPs) to enhance its catalytic activity, sensitivity, and limit of detection (LOD) to NO*. Square wave voltammetry was used to quantify the NO* concentration at the CA membrane covered 1.54T-CUA with and without CS/GNPs; the LODs were determined to be 0.2 +/- 0.1 and 0.44 +/- 0.02 MUM (S/N = 3), with sensitivities of 9 +/- 9 and 1.2 +/- 0.4 nA/MUM, respectively. Our results indicate that this modification to the arrays results in a significant catalytic enhancement to the electrochemical oxidation of NO*. Hence, these electrodes allow for the in situ mechanistic and kinetic characterization of electrochemical reactions with high electroanalytical sensitivity. PMID- 27989113 TI - Optimization and Synthesis of Pyridazinone Derivatives as Novel Inhibitors of Hepatitis B Virus by Inducing Genome-free Capsid Formation. AB - The capsid of hepatitis B virus (HBV) plays a vital role in virus DNA replication. Targeting nucleocapsid function has been demonstrated as an effective approach for anti-HBV drug development. A high-throughput screening and mechanism study revealed the hit compound 4a as an HBV assembly effector (AEf), which could inhibit HBV replication by inducing the formation of HBV DNA-free capsids. The subsequent SAR study and drug-like optimization resulted in the discovery of the lead candidate 4r, with potent antiviral activity (IC50 = 0.087 +/- 0.002 MUM), low cytotoxicity (CC50 = 90.6 +/- 2.06 MUM), sensitivity to nucleoside analogue-resistant HBV mutants, and synergistic effect with nucleoside analogues in HepG2.2.15 cells. PMID- 27989114 TI - Characterization of Morphology, Volatile Profiles, and Molecular Markers in Edible Desert Truffles from the Negev Desert. AB - Desert truffles are mycorrhizal, hypogeous fungi considered a delicacy. On the basis of morphological characters, we identified three desert truffle species that grow in the same habitat in the Negev desert. These include Picoa lefebvrei (Pat.), Tirmania nivea (Desf.) Trappe, and Terfezia boudieri (Chatain), all associated with Helianthemum sessiliflorum. Their taxonomy was confirmed by PCR RFLP. The main volatiles of fruit bodies of T. boudieri and T. nivea were 1-octen 3-ol and hexanal; however, volatiles of the latter species further included branched-chain amino acid derivatives such as 2-methylbutanal and 3 methylbutanal, phenylalanine derivatives such as benzaldehyde and benzenacetaldehyde, and methionine derivatives such as methional and dimethyl disulfide. The least aromatic truffle, P. lefebvrei, contained low levels of 1 octen-3-ol as the main volatile. Axenic mycelia cultures of T. boudieri displayed a simpler volatile profile compared to its fruit bodies. This work highlights differences in the volatile profiles of desert truffles and could hence be of interest for selecting and cultivating genotypes with the most likable aroma. PMID- 27989115 TI - BiVO4/WO3/SnO2 Double-Heterojunction Photoanode with Enhanced Charge Separation and Visible-Transparency for Bias-Free Solar Water-Splitting with a Perovskite Solar Cell. AB - Coupling dissimilar oxides in heterostructures allows the engineering of interfacial, optical, charge separation/transport and transfer properties of photoanodes for photoelectrochemical (PEC) water splitting. Here, we demonstrate a double-heterojunction concept based on a BiVO4/WO3/SnO2 triple-layer planar heterojunction (TPH) photoanode, which shows simultaneous improvements in the charge transport (~93% at 1.23 V vs RHE) and transmittance at longer wavelengths (>500 nm). The TPH photoanode was prepared by a facile solution method: a porous SnO2 film was first deposited on a fluorine-doped tin oxide (FTO)/glass substrate followed by WO3 deposition, leading to the formation of a double layer of dense WO3 and a WO3/SnO2 mixture at the bottom. Subsequently, a BiVO4 nanoparticle film was deposited by spin coating. Importantly, the WO3/(WO3+SnO2) composite bottom layer forms a disordered heterojunction, enabling intimate contact, lower interfacial resistance, and efficient charge transport/transfer. In addition, the top BiVO4/WO3 heterojunction layer improves light absorption and charge separation. The resultant TPH photoanode shows greatly improved internal quantum efficiency (~80%) and PEC water oxidation performance (~3.1 mA/cm2 at 1.23 V vs RHE) compared to the previously reported BiVO4/WO3 photoanodes. The PEC performance was further improved by a reactive-ion etching treatment and CoOx electrocatalyst deposition. Finally, we demonstrated a bias-free and stable solar water-splitting by constructing a tandem PEC device with a perovskite solar cell (STH ~3.5%).